PMID- 15171862
TI  - [Public and private supply of health services by autonomous communities in
      Spain].
AB  - This chapter summarizes the main territorial inequalities in health care supply,
      and the related effects on access and use of health care facilities. Firstly, in
      the field of primary health care, the most notable inequalities refer to the
      process of introduction of the reform and to complementary services supply,
      together with the coverage of and access to some health care programs. Secondly,
      the distribution of hospital beds across regions is far from being uniform,
      specially with respect to geriatric and psychiatric beds. In addition, profit
      oriented private care is unequally distributed across territories. Thirdly, the
      availability of high-tech health care services is remarkably different across
      regions, although inequalities have been reduced during the last decade.
      Inequality in long-term care (not only in terms of supply, but also in access and
      use) is even higher than regional inequalities in health care supply. In addition
      to these territorial inequalities there are some significant gender inequalities.

PMID- 15171863
TI  - [The impact of healthcare financing on health inequalities].
AB  - This article summarizes the impact of health care financing instruments on
      inequalities of supply, access and use of health care services. Firstly, the new
      scheme of regional and health care financing, apart from the initial gains in
      terms of equity and sufficiency, introduces uncertainty about the volume of
      resources that will be devoted to health care facilities by the regions. This
      fact may cause some inter-territorial inequalities in the health care supply and
      the access to public services. The Health Care Cohesion Fund, which was designed
      to guarantee equality of access to the National Health Service, is not the
      optimal instrument to achieve such an ambitious goal. Secondly, the change in
      composition of health care financing sources, by increasing the burden of
      indirect taxes, may imply some losses of vertical equity or progressiveness.
      Finally, this paper analyses the possible impact that the present allocation of
      public health funds, excessively biased to specialised health care, may have on
      inequalities in the use of health care facilities.

PMID- 15171864
TI  - [New forms of management and their impact on health inequalities].
AB  - In recent years in Spain the system of health foundations has been favoured among
      the so-called new ways of management, as a mechanism to increase the efficiency
      of public health centers. The purpose of our research is to compare the running
      of health foundations with hospitals managed in the traditional way who attend a
      population with similar characteristics. From the comparison between the two
      types of centers it has been deduced that foundations have less staff in all the
      categories (doctors, nurses, etc.), and offer fewer beds and operating
      theatres/1000 inhabitants. The numbers of admissions, surgical operations,
      emergencies services, and medical consultations/1000 inhabitants are all lower in
      the foundations, although only the latter case has statistical significance.
      Also, waiting lists for surgery are longer, and expenditure/1000 inhabitants per
      year is lower, in both cases statistically significant. From all this it has been
      deduced that the foundations spend less per inhabitant because they offer fewer
      health services to the reference population, something which creates access
      problems and is a source of inequality. The foundations exhibit a notable lack of
      transparency, which has limited the variables available for study and has made it
      difficult to carry out an investigation of quality between the two models.

PMID- 15171865
TI  - [The influence of the type of insurance access on health and of education on
      health services utilization patterns].
AB  - This study analyses the utilisation of health services by gender, type of
      insurance access and the level of education. Descriptive and logistic regression
      analysis of the National Health Interview Survey, 1997, confirms that women go
      more often to the doctor than men. Differences are greater in the case of general
      practitioners (versus specialists) and public doctors (versus private). However,
      there are hardly any differences in hospitalisations and emergency visits. Having
      private access has no impact on hospitalisations, emergency visits or the
      probability of a visit (except for women), but it increases the probability of
      visits to specialists (mainly among women) and to private doctors (especially
      among men), confirming the existence of gender differences in the impact of this
      variable. In fact, the utilisation patterns by men and women with only public
      access resemble each other more than those of men and women with only private or
      dual coverage. Education is to a certain extent inversely related to the
      probability of a medical visit, visits to a GP and hospitalisations, but directly
      related to the utilisation of specialists and private doctors. Here, there are
      also gender disparities: differences in utilisation by educational level are more
      prominent among men.

PMID- 15171866
TI  - [Professional practice and gender in primary care].
AB  - In this paper we analyse the relations between sex of patients and professionals,
      social class and health insurance scheme, with the type of medical practice and
      level of satisfaction with care received by the patients. Following recent
      literature it can be said that medical practices based on the psychosocial
      paradigm obtain better results in terms of health and satisfaction. In the
      primary health care sector, there is evidence that women doctors follow a
      communication pattern grounded on the psychosocial model. In parallel, women
      patients frequently show their preferences for women doctors when their
      complaints are related to psychosocial issues. Sex and social class of patients
      and professionals are not consistently related to the level of satisfaction
      reached, although to date there is still a lack of research to support this
      point. It is necessary to incorporate in our research these analytical
      categories. Not only in data collection but also in the analysis. It would not be
      possible to fully understand the complexity of clinical activities without
      considering that gender and class shape our individual and social identity and
      therefore condition the diverse forms of interaction in patient-doctor relations.

PMID- 15171867
TI  - [Gender bias in treatment].
AB  - Both gender bias studies and evidence-based medicine share the hypothesis of the
      existence of empirical uncertainty in medical practice. Nevertheless there is a
      lack of information regarding variations and sex, possibly due to androcentric
      reasons. Many biomedical studies--including randomised controlled trials--, have
      used men as the population's prototype and applied its conclusions to women. This
      approach is based in an erroneous assumption of equality between men and women.
      Gender bias research on therapeutic efforts are focused on hospital accessibility
      for the two sexes for equivalent health needs, comparison in delays and waiting
      times from the early symptoms to care, differential therapeutic strategies and
      differential consumption of, and expenditure on, medication. Also, research on
      over prescription of therapies are included in the health problems affecting only
      or mainly women. Gender bias in therapeutic efforts depends on the gender bias in
      the diagnostic efforts. Insofar as the probability of being treated once
      suffering a problem vanishes if for any cause the individual in question is
      excluded from the diagnostic process, or diminishes if the appropriate tests are
      not performed in the diagnostic process. The aim of this paper is to present an
      approach to the evidence of gender bias in therapeutic strategies in Spain.

PMID- 15171868
TI  - [Inequalities in protection services for elderly dependent individuals].
AB  - This article analyses social welfare attention for dependence in Spain,
      especially with respect to old people and social services, with emphasis on
      social inequality. Disability affects 32.2% of older people (women 35.9%), which
      rises to 50% for people over 80. Faced with this growing problem, the welfare
      system continues to provide a timid response, which is expressed in public
      spending on this field that is much lower than that of the countries around us,
      which leads to insufficient development of long-term social and health care
      services (particularly non-residential services) and gives rise to situations of
      vulnerability and inequality for the majority of dependent persons and for those
      in charge of caring for them. The separation of health care and social systems
      and the diversity arising from our model of autonomous communities makes for
      profound differences with respect to rights of access, entrances, services
      offered, costs and sources of financing and the preparation of the professionals
      working in these fields. Consolidating welfare attention for dependence as a
      subjective, universal and guaranteed right is fundamental if we are to advance in
      the direction of a reduction of the kinds of inequality cited above and to avoid
      perpetuating a model of family health care which is based on gender
      discrimination.

PMID- 15171869
TI  - [The system of informal caregiving as inequality].
AB  - In our setting, it is families, not the health and social services, who play the
      greatest role in providing continuous care to persons in need of such services.
      Informal health care poses two key questions with regard to the issue of equity:
      differences in the burdens borne by men and women, which contribute to gender
      inequality and, depending on their educational and socio-economic level,
      inequities in their ability to choose and gain access to needed resources and
      support services, thus contributing to social class inequalities. Distributing
      the burden of caregiving between men and women, and between the family and the
      state, constitutes a crucial debate in public health. This study analyzes the
      concept and characteristics of informal care, provides data on its dimensions in
      our setting, and analyzes the profile of caregivers, as well as the work they do
      and the impact it has on their lives. Finally, it presents currently existing
      models and support strategies for informal caregivers. It is largely women who
      assume the principal role of providing informal care, undertaking the most
      difficult and demanding tasks and dedicating the largest share of their time to
      them. As a result, women bear an elevated cost in their lives in terms of health,
      quality of life, access to employment and professional development, social
      relations, availability of time for themselves, and economic repercussions.
      Unemployed, under-educated women from the least privileged social classes
      constitute the largest group of informal caregivers in our country. Any policies
      aimed at supporting those who provide such care should keep in mind the unequal
      point from which they start and be evaluated in terms of their impact on gender
      and social class inequality.

PMID- 15171870
TI  - [The phenomenon of healthcare pluralism: a reality to be researched].
AB  - Medical pluralism and the uses of Complementary and Alternative Medicine (CAM)
      are phenomena of increasing interest in the international arena. The aim of this
      chapter is to comment on Spanish studies dealing with medical pluralism and CAM.
      We have only a few scattered anthropological studies, and some data from surveys
      in Catalonia. There is an urgent need to carry out studies to ascertain the level
      of medical pluralism in Spain in order to develop care policies which provide
      assurance to the population in this area.

PMID- 15171872
TI  - [Welfare State policies for equity].
AB  - This article analyzes the evolution of public social expenditure in Spain from
      1991 to 2000. It includes the analysis of the total public social expenditure as
      well as four of its components: sickness/health care, invalidity/old age,
      survivors, family/children. Expenditure is analyzed as a percentage of the GNP,
      and expenditure per capita in purchasing power units. This article shows that
      there has been an increase since 1993 in the deficit of the public expenditure on
      social protection in Spain representing a divergence from the average expenditure
      in the UE. The article also analyzes the development of care services (child care
      and services for dependent elderly), due their impact on gender inequalities.

PMID- 15171873
TI  - [Interventions to reduce health inequalities].
AB  - The objective of this study is to compile, describe and assess interventions to
      reduce health inequalities developed in Spain by administrations, NGO or other
      entities. The search was organized in three settings: governmental strategies,
      interventions, and among the latter, those particularly addressing excluded
      social groups. Administration actions and policies were investigated through
      formal surveys addressed to regional governments (17 regions and 2 cities).
      Production of information by gender and socio-economic level (SEL), plans and
      programs, as well as interventions was explored. Key informants were consulted
      and scientific literature was reviewed in order to identify interventions.
      Medicos del Mundo and Caritas, two of the main national NGO were consulted.
      Fourteen administrations responded. In general, health information includes sex
      analysis, few administrations analyse by gender or SEL and six study inequalities
      in the general population. Most administrations produce specific information by
      pathologies (HIV/AIDS.) or social groups (women.). They mention intervention
      experiences applied to territories or vulnerable groups, evaluated through
      process indicators. In the period 1995-2002, 722 papers on inequalities in Spain
      have been published. Among them, 28 are interventions and 9 have been evaluated,
      mainly with quasi-experimental designs. Large NGO, sometimes with public funding,
      work with excluded populations through outreach programs. Most Spanish health
      information does not include yet inequalities analysis, although it is growing
      steadily. Publication of inequalities studies has increased sharply, but
      intervention publications are rare and evaluated interventions are extremely
      scarce. Administrations and NGO work in interventions mainly addressed to
      excluded populations.

PMID- 15171875
TI  - [Reproductive health: some data and reflections].
AB  - Respect for human rights goes beyond the concept of reproductive health. The
      right to a responsible, satisfactory and safe sex life and the right to choose
      the number of children means that we must also concern ourselves with such
      concepts as fertility, unwanted pregnancy and assisted reproduction. Spain has
      one of the lowest birth rates in the world, with 1.24 children per woman. Data
      from a recent national survey showed that 7.2% of Spanish women are at risk for
      an unwanted pregnancy, either due to failure to use contraceptive measures or to
      use of poorly efficient measures. The abortion ratio, which has been increasing
      since 1992, was about 7 per 1000 women in 2001. On the other hand, although more
      and more couples are consulting with problems of sterility, the public health
      services do not appear to be covering their requirements.

PMID- 15171876
TI  - [Gender and mental health in a changing world].
AB  - It is well established that human psychological development, violence and sexual
      abuse, the experience of reproduction and parenting, as well as psychopathology
      and psychiatric morbidity are different for men and women, both in quality and
      quantity. In this chapter some of these differences, including disability and the
      use of services in the Spanish population are described and analysed. Whether
      there is a need for a new discipline to study psychiatric illness and psychiatric
      treatment from the point of view of gender is discussed. There has been a deep
      process of transformation of gender roles in our society. In our opinion this
      calls for new research efforts aimed at estimating the rates of prevalence and
      associated risk factors in men and women at present. The results of such research
      will probably lead to the formulation of new and more relevant hypotheses, and to
      the development of new research strategies and more valid and reliable measuring
      instruments.

PMID- 15171877
TI  - [Partner violence and women's health].
AB  - The World Health Organization declared violence against women to be a Public
      Health priority due to its magnitude. This problem affects in Spain one out of
      seven women, as shown by the 1999 survey conducted by the Instituto de la Mujer,
      and causes more than fifty annual deaths. The purpose of this essay is to review
      causes of violence against women and its consequences in health as well as the
      impact in medical services. The authors analyse the difficulties in systematic
      recognition of abused women and their neglect, despite the high prevalence, by
      health care professionals from open care and emergency services. In addition,
      measures undertaken by Health Authorities in recent years are reviewed. A set of
      recommendations aimed to eradicate violence against women is given, including
      those for social, health and research policies and health-professionals education
      and training.

PMID- 15171878
TI  - [Gender, health professions and public health].
AB  - In this article we review the main results of historical-social research on
      gender and medical practice, propose a model for applying a gender perspective to
      the study of healthcare professions, and analyze some current forms of gender
      bias in Spanish public health societies and publications. The main conclusions
      indicate: the historic construction of gendered professional identities; the
      existence of vertical segregation by sex in scientific societies and in journal
      editorial boards; the existence of androcentric practices in the scientific
      journals, exemplified by the style of using the initial letter of the authors'
      first name; the fact that scientific societies do not collect data by sex; the
      difficulties that all of this implies for quantitative investigations that study
      the sex variable and adopt a gender perspective; and the need to promote
      qualitative research on the issue.

PMID- 15171879
TI  - [Demand for healthcare from families].
AB  - Households are the social units that mediate the relationship between individuals
      and the health system. Households provide the basic conditions for health, as
      well as the services related directly or indirectly with medical therapies. The
      range of demands on the health system is widening constantly, and it is
      forseeable that in the near future the activities of prevention, rehabilitation,
      reproduction, aesthetics and identity production, as well as with social
      organization, will become more important than the strictly curative tasks. The
      role played by new types of families has to be underlined, as well as the role of
      immigrant families, a manifestation, at the health level, of the consequences of
      globalization. The study offers much information published for the first time and
      ends with a forecast of the changes in the health care demands in Europe, due to
      demographic transformations.

PMID- 15171880
TI  - [Gender and health in the daily press].
AB  - To have a better understanding on the role of the press in the communication of
      gender and health issues, the content of the five most spread newspapers in Spain
      was studied (El Pais, ABC, El Mundo, La Vanguardia and El Periodico de Catalunya)
      for five years (1997-2001) and the electronic version of The New York Times of
      the period 1990-1999. An unequal distribution was observed in the responsibility
      as for the information related to three aspects: positions of responsibility in
      the newspapers (out of 71 main posts, 67 were men and 4 women); the authors of
      the articles on health issues (61.2% men and 38,8% women, among the articles that
      include the author) and the mentioned information sources (81.43% men and 17.77%
      women). Among the 120 health issues that were covered during the period of the
      study, only 20 explicitly mentioned a woman (16.67%). Those subjects that
      included more frequently explicit references were: ablation, iatrogenics,
      sterilization, sexual and reproductive health, incontinence, beauty and domestic
      violence. The analysis of the approach to these subjects helped to identify the
      stereotypes of gender inequality, in the language as well as in the approach.

PMID- 15171881
TI  - [Health and immigration: new situations and challenges].
AB  - The new social and demographic framework in Spain that has appeared since the
      arrival of new migrant populations, raises the need to improve the knowledge of
      their health status and to identify preventive measures and priorities in heath
      services.A bibliographic review of the available information on migration and
      health in Spain is performed, together with an analysis of their contents from a
      Public Health point of view. The high proportion of new borns from foreign
      mothers, the mental needs, deficits in oral and dental health, and the increase
      of tuberculosis in migrants, together with limited vaccine coverage in children,
      define the main health needs of these populations. The analysis of health
      services, reveals a high use of pediatric, obstetric and gynecologic resources by
      migrant populations. Conclusions; although no particular health needs have been
      identified for migrants, special attention for tuberculosis, mother and child
      health and health promotion and prevention, have to be funded for specific
      migrant populations. Health resources and services have to be reinforced with
      health agents, human resources, and specialized education for health
      professionals.

PMID- 15171882
TI  - [Spanish international cooperation in health].
AB  - In this chapter, there is a view of the relationships between the Spanish policy
      for international cooperation aid and the main health problems of the developing
      world, with a gender perspective. The population health is a result of the
      development inequity between rich and poor countries. The international
      institutions have established the frame and priorities of the cooperation aid,
      being poverty eradication the main priority. The compromise of the Millennium
      Conference was to reduce in 2/3 child mortality and 3/4 maternal mortality before
      year 2015, to stop and reduce HIV-AIDS, malaria and others serious diseases as
      tuberculosis and to facilitate developing countries the access to drugs. Although
      the resources allocated, the total amount for cooperation has been reduced 30%
      during the last years. The Spanish AOD in health is difficult to account because
      it is considered among social basic services and it is not addressed to solve the
      main health problems in the poorest countries.

PMID- 15171884
TI  - [The environment and its impact on health: old risks, new risks].
AB  - The objective of this article is to investigate three representative elements of
      environmental health from a geographical perspective taking the Autonomous
      Community as the unit of analysis: legionnaire's disease, chemical safety and
      food safety. Legionnaire's disease is a pathology with a specific epidemiological
      profile; males, adults, and with previous chronic pathologies and habits. The
      official response, with regard to recent outbreaks and the increase in the
      incidence of legionnaire's disease, has differed between autonomous communities
      due to peculiarities and different organizational cultures. Both the sinking of
      the ship Prestige and the accident at the oil refinery at Puertollano (Ciudad
      Real) have increased concern in the population about chemical substances, so
      familiar in our environment. However it is not only the big accidents which are
      relevant: it is surprising to learn that most of the registered poisonings are
      due to domestic cleaning goods. The pending challenge from the Public Health
      point of view is to elaborate the Report on Human Exposure to Environmental
      Chemical Agents which, undoubtedly, will help to establish differences between
      type and class. Finally, the number of outbreaks of food poisoning continues to
      be of concern; this should lead us to think about the effectiveness of food
      safety programmes and to focus on the home, being place where most of the
      outbreaks occur. The General Sanitary Inspection of Food ought to be a good tool
      to help improve food safety.

PMID- 15171885
TI  - [Food safety warnings in public health].
AB  - One of the mechanisms for food alerts management is the rapid interchange of
      information so that the response takes place the sooner and the impact of the
      risk can be diminished. The structure of information transmitted, the priority
      and categorization of the risk, the differentiated treatment of the information,
      the decision on who must be informed, the confidentiality of information
      transmitted, and evaluations of it, the reduction of the abuse or the use of
      precautionary principle are questions that can serve as guidelines for an
      analysis of the different systems and provide a comparison perspective that can
      help to improve the exchange of information on risks in the present day global
      market of foods. The main goal of this article is to provide a proposal for
      improvement in the food alerts management system in our country through an
      analysis and comparison of the essential elements of different systems in our
      context.

PMID- 15171886
TI  - [Health protection against electromagnetic fields].
AB  - In recent years there has been an increasing social concern in Spain about
      electromagnetic fields (EMF) and their effects on human health. Some groups have
      expressed their opposition to antennas of base stations and high voltage power
      transmission lines. The present article discusses the current status of health
      protection against EMF in Spain. The assessment is based on the background and
      justification of the European Union Council Recommendation of 12 July 1999 on the
      limitation of exposure of the general population to electromagnetic fields (0 Hz
      to 300 GHz), the Spanish Royal Decree 1006/2001 on health protection against
      radioelectric emissions and the most relevant epidemiological studies. The need
      for implementation of a comprehensive approach based on risk assessment and the
      precaution principle is emphasized. In order to be coherent with the Council
      Recommendation and Spanish EMF legislation some strategies for health protection
      are proposed.

PMID- 15171887
TI  - [The impact of the Prestige disaster on human health].
AB  - The worst environmental disaster of the history of Spain favoured a renewed
      social awareness of the intimate relationships that exist between the state of
      the environment and the health of human beings. However, the health of the
      populations most involved in the Prestige oil spill was initially not the chief
      concern of political authorities. The main aims of the present paper are: first,
      to comment succinctly on some of the most significant activities conducted by a
      variety of social actors during the Prestige crisis; and second, to suggest the
      main potential objectives and characteristics of the epidemiological studies
      necessary to assess with a sound rational basis the possible impact of the
      accident on the health of workers, volunteers and residents in the spill areas.
      The authors hope that in the near future it will be possible to scientifically
      assess the results and implications of several studies (epidemiological and of
      other sorts) well designed and conducted.

PMID- 15171888
TI  - [Evaluation of the impact of the heat wave in the summer of 2003 on mortality].
AB  - The effect of the elevated temperatures experimented in Europe during the summer
      2003 on mortality was observed in several countries. This study, carried out in
      Spain, describes the mortality between the 1st June and the 31st August and
      evaluates the effect of the heat wave on mortality. Observed deaths were obtained
      from official vital Registers of the capital city of the 50 provinces. Deaths
      from 107 randomly selected rural villages were also obtained from the same
      source. Observed deaths were compared with expected estimated applying a Poisson
      regression model to historical mortality series adjusting for the upwards trend
      and seasonality observed. Meteorological information was provided by the National
      Institute of Meteorology. Spain experienced three heat waves. Total excess deaths
      associated was 8% (43,212 observed compared with 40,046 expected). Excess deaths
      were only observed among 65 years old and over (15%). The increased mortality was
      also observed in rural villages. This phenomenon is becoming an emerging public
      health problem because of its increasing attributable risk because of the aging
      of Spanish population. Alert and response systems based on monitoring of climate
      related risks, emergency rooms activity and mortality and the strengthening of
      social and health services response capacity should be considered.

PMID- 15171889
TI  - [Geriatric assessment in Internal Medicine Departments].

PMID- 15171890
TI  - [Use of pyrazinamide as an indicator of tuberculosis epidemiology in Castilla-La
      Mancha].
AB  - OBJECTIVE: To describe the use of tuberculostatic drugs in Castilla-La Mancha
      Spanish region along the 1999-2000 period; to estimate the number of persons who
      received tuberculosis treatment in 1999 and 2000; and to compare the results with
      the case reporting data. METHOD: The pyrazinamide use data in Castilla-La Mancha
      along the 1999-2000 period were obtained from the Spanish Health Ministry. The
      defined daily dose and the daily dose per inhabitant were used as measures for
      comparison. The number of persons who had received treatment was calculated and
      this figure was compared with the case reporting of tuberculosis respiratory,
      tuberculosis, other types and tuberculous meningitis. RESULTS: The incidence of
      registered tuberculosis cases was 192 and 182 cases in 1999 and 2000,
      respectively, with rates of 11.07 and 10.49 cases per 100,000 population. In 1999
      and 2000, 388 and 389 people (22.41 and 22.43 cases per 100,000 population)
      received treatment with pyrazinamide in Castilla-La Mancha, respectively, which
      suggests that the rate of registered tuberculosis can show an underreporting of
      50%. CONCLUSIONS: An important tuberculosis underreporting is detected, with
      large differences between the different provinces. Pyrazinamide use is probably
      the better indicator to estimate the minimum incidence of tuberculosis.

PMID- 15171892
TI  - [Geriatric information in the hospital discharge reports of patients over 65
      years of age admitted to an Internal Medicine Department].
AB  - CONTEXT: The hospital discharge report (HDR) is a document that serves as a link
      between the hospital clinician and the primary care team. Our objective has been
      to evaluate the level of geriatric information in the HDR developed in the
      Internal Medicine Department of an tertiary care university hospital. Besides,
      the possible changes along the last 5 years were also evaluated. METHODS: HDRs of
      1,000 patients over 65 years (500 in 1996 and 500 in 2001) and cared in the
      Bellvitge University Hospital were evaluated. Data relative to social, functional
      (qualitative and quantitative), and cognitive (qualitative and quantitative)
      assessment were collected. RESULTS: In 269 patients (27%) there was some kind of
      geriatric information in the HDRs. In the 2001 HDRs a significant increase in the
      percentage of social, qualitative functional and qualitative cognitive
      information was observed compared to 1996 HDRs. There were no significant
      differences upon comparing the subgroup of 269 patients with geriatric data in
      their HDRs with the subgroup of 731 remaining patients. CONCLUSIONS: The level of
      geriatric information in the HDRs is low. Care of elderly patients admitted to
      the Internal Medicine Department requires an additional evaluation on the part of
      all the professionals involved in their assistance, carrying out a global
      assessment that let a better knowledge of the patient. These evaluations should
      be part of the HDR.

PMID- 15171891
TI  - [Non-Hodgkin lymphomas with systemic presentation in patients with HIV infection.
      Clinical and prognostic factors in a series evaluated before the introduction of
      the highly active antiretroviral therapy (HAART)].
AB  - PATIENTS AND METHOD: We studied patients with acquired human immunodeficiency
      virus (HIV) infection that developed non-Hodgkin's lymphoma (NHL) from January
      1985 to October 2001. RESULTS: 44 patients (36 men, 8 women; median age 34 years)
      were included. Burkitt's lymphoma was diagnosed in 34%, and diffuse large cell B
      lymphoma in 29.5%. A history of AIDS diagnosis was detected in 20 cases (45%).
      International prognostic index (IPI) was 0-1 in 19 patients (43%), 2 in 12 (27%)
      and higher than 3 in 13 (30%). Chemotherapy was used in 64% of the patients,
      radiation therapy in 2% and both in 11%. Criteria for partial response were
      reached in 13 patients (29%), for complete remission in 2 (4%) and for
      stabilization in 1 (2%). Nine (20%) patients are alive (5 without disease), 22
      (50%) died because of NHL, 5 (11%) died because of treatment associated toxicity
      and 8 died because of other causes. Median survival were 3 months, with a 1-year
      survival estimate of 24% and a 2-year survival estimate of 14%. In the univariate
      analysis of prognostic factors, IPI = 0-1 in comparison with IPI = 2-5 (p =
      0.000), physical status (PS) < or = 2 (p = 0.021) and absence of B symptoms (p =
      0.012) were significant. In the multivariate analysis, IPI = 0-1 was also
      significant (p = 0.000). CONCLUSIONS: Patients with HIV and NHL has multiple
      factors of poor prognosis. The survival is limited and chemotherapy toxicity is
      high. Patients with low IPI are a subgroup with better prognosis.

PMID- 15171893
TI  - [Changing epidemiology of smoking: Barcelona, 2000-2001].
AB  - CONTEXT: In recent years various initiatives of prevention and social changes
      have been carried out that should have an effect on epidemiology of smoking in
      our area. Their real effect is little known, however, because of methodological
      changes in the existing population surveys. In this work the data on smoking in
      the last city of Barcelona health survey (ESBA 2000-01) are analyzed, with
      reference to the cumulative information obtained along 18 years from the first
      survey in 1983. METHOD: ESBA 2000-01 is an interview health survey carried out on
      a weighted sample with 10,030 people. Data relative to tobacco use are showed for
      people 15-year-old or older included in the survey, stratified by age, sex, and
      class. Consumption context variables are also showed, and the tobacco consumption
      quitting among people who have smoked is analyzed. RESULTS: The proportion of
      daily smokers in the population over 14 years of age is 29 %, while that of
      former smokers is 21 % and 2.2 % in this population are occasional smokers. The
      prevalence is maximum in the 35-44 year-old group, and the prevalence is reduced
      drastically after this age. Stratified analysis by age, sex, and occupational
      category shows interesting differences among daily smokers. A strong gradient is
      observed according to occupational category in males. The situation is more
      complex in women. The typical smoker began when 17-year-old, and now consumes 16
      cigarettes a day. Consumption is somewhat higher in males and is maximum in the
      35-44 year-old group. Two-third of the smokers (65.7 %) want to quit smoking and
      more than one third (36 %) has attempted it along the last year. Almost half of
      smokers (48.1 %) have received advice to quit smoking from their physician. One
      of every four (24.9 %) smokers has been warned for smoking in some places. Almost
      half smokers are the only smoker in their home, and barely a third are the only
      smokers at work. The proportion of quitting increases with age in both sexes, and
      nowadays the differences in the probability of quitting smoking are few when the
      data are stratified by age groups. CONCLUSIONS: These results show the changing
      pattern of tobacco epidemiology in Barcelona: smoking is no longer the main
      behavior in no age and sex group, and the only social group in which more than
      half of its members smoke are 25-44 year-old not qualified worker males. This
      situation has occurred because of two processes: an important proportion of early
      quitting (demonstrated even in young adults) and a decrease in the beginning of
      the habit. Real differences are not observed between males and females with
      regard to the probability of quitting smoking. These data correct recent
      estimates that could be influenced by methodological changes in the instruments
      used.

PMID- 15171894
TI  - [Malaria. Analysis of 31 cases (1993-2002)].
AB  - The objective of this work is the study of malaria in the population of our
      hospital area. The characteristics of 31 cases of imported malaria diagnosed in
      the University Hospital La Fe of Valencia are described. The study included the
      period between 1993 and 2002. The predominance of males (81%), of the age group
      of 20-40 years (average: 37.68), and of the patients native from African
      countries (all except for a patient from Ecuador) of which 40% came from
      Equatorial Guinea, were outstanding results. The most prevalent species was
      Plasmodium falciparum (72%). Only 12.9% of the patients received antimalarial
      prophylaxis with mefloquine, without appropriate compliance. Malaria continues to
      be the most important protozoan infection in the world, and currently a possible
      reintroduction of this infection is observed in Spain. That is why is necessary
      to improve the information offered to the tourists who visit tropical countries.
      The clinical suspicion is also essential in patients who come from endemic areas.

PMID- 15171895
TI  - [A review of cholesterol crystals embolism].

PMID- 15171896
TI  - [The severe acute respiratory syndrome].

PMID- 15171897
TI  - [Cervical whiplash injury syndrome].

PMID- 15171898
TI  - [An erythematous purplish and ulcerated tumor in the right leg].

PMID- 15171899
TI  - [A mediastinal mass in a cirrhotic patient].

PMID- 15171900
TI  - [Degenerative arthropathy in a patient under hemodialysis].

PMID- 15171901
TI  - [Alcoholism, hypophosphatemia and rhabdomyolysis: an ominous triad].

PMID- 15171902
TI  - [Factors associated with rehospitalization in a chronic hospital].

PMID- 15171903
TI  - [Diagnostic value of double phase 99mTc-sestamibi parathyroid gammagraphy for the
      localization of a parathyroid adenoma].

PMID- 15171904
TI  - [Is chest X-ray necessary after withdrawal of thoracic drainage tube in patients
      with spontaneous pneumothorax?].

PMID- 15171906
TI  - [Cognitive assessment in the elderly. Normative data of a Spanish population
      sample older than 70 years].
AB  - BACKGROUND AND OBJECTIVE: To define the parameters of normal cognitive
      performance in an easy to administer neuropsychological battery of a Spanish
      population sample of elderly over 70 years. SUBJECTS AND METHOD: We examined 527
      home dwelling elderly from the longitudinal study Envejecer en Leganes, 71 to 99
      years old (mean age [SD] 79 [6.2] years, 51.8% women, 38.7% without formal
      education), with an extensive clinical survey, a neurological exam and the
      following neuropsychological battery: Short Portable Mental Status Questionnaire,
      Mini Mental State Examination, Benton Orientation Test, Bell Test, Verbal
      Fluency, Clock Drawing Test, Trail Making Test, Free and Cued Figures Recall,
      Logic Memory, Naming, incidental Recall, Delayed Recall, Similarities, IQCODE
      Questionnaire Of Jorm and Depression Questionnaire CES-D. 111 cases who rejected
      the assessment or had sensomotor limitations were excluded. 368 non demented
      subjects (according to DSM-IV criteria; 88.5% of the de 416 remaining cases) were
      selected to establish the normative data of every test. RESULTS: The analyzed
      subsample was representative of the total sample. The normative data for every
      neuropsychological test were obtained in the total group of non demented subjects
      and in the subgroups stratified by four age levels and two cultural levels. The
      mean values, standard deviations, range and percentiles for every test and
      subgroup are presented. CONCLUSIONS: The normative data obtained in this
      population sample for a neuropsychological battery easy to administer to poorly
      educated elderly can be useful to rigourously apply the criteria of dementia and
      mild cognitive impairment in future clinical and population studies.

PMID- 15171905
TI  - [Abnormal body fat distribution and type of antiretroviral therapy as predictors
      of cardiovascular disease risk in HIV-infected patients].
AB  - BACKGROUND AND OBJECTIVE: Dyslipidemia, insulin resistance and body fat
      redistribution are respectively short and long-term complications of protease
      inhibitor-containing antiretroviral regimens. To establish whether differences in
      the type of antiretroviral therapy (protease-containing or protease-sparing) or
      the presence and severity of body fat redistribution, explained differences in
      cardiovascular risk, we undertook a cross-sectional study. PATIENTS AND METHOD:
      The study was carried out in 219 consecutive HIV-infected patients attending an
      outpatient HIV clinic between February and April, 2002. Age, sex, smoking status,
      weight, height, waist circumference, blood pressure, antihypertensive treatment,
      total cholesterol, HDL cholesterol, triglycerides, and glucose concentrations, in
      addition to changes in body fat distribution were measured in 31 HIV-infected
      patients with no antiretroviral therapy, 35 HIV-infected patients treated with
      protease inhibitor-sparing regimens, and 153 HIV-infected patients treated with
      protease inhibitor-containing regimens. A ten-year cardiovascular disease risk
      was estimated according to the Framingham score. RESULTS: Patients treated with
      protease inhibitor-containing regimens as well as patients treated with protease
      inhibitor-sparing agents showed higher concentrations of cholesterol (p < 0.001),
      triglycerides (p = 0.004), glucose (p = 0.028), and greater changes in body fat
      distribution (p = 0.001) than patients with no antiretroviral therapy. An
      abnormal body fat distribution score was more strongly associated (p < 0.001)
      with the estimated 10-year cardiovascular disease risk than the type of HAART (p
      = 0.036). Ten-year cardiovascular disease risk increased linearly from 7.48% to
      11.16% and to 19.50% in patients with no or mild, moderate and severe
      lipodystrophy scores, respectively. CONCLUSIONS: The results of this study
      encourage the use of cardiovascular preventive strategies in HIV-infected
      patients with severe lipodystrophy.

PMID- 15171907
TI  - [Tuberculosis in health care personnel in a general hospital].
AB  - BACKGROUND AND OBJECTIVE: Tuberculosis is an occupational disease in health care
      workers. The objective of our study was to review tuberculosis cases in health
      care professionals from a general hospital and to determine their incidence in
      relation to the general population. PATIENTS AND METHOD: This was a retrospective
      study of tuberculosis cases among health care workers in a university hospital
      from 1988 to 2002, evaluating the annual cumulative incidence. RESULTS: 21
      tuberculosis cases were found in health care workers. Pulmonary disease was the
      most frequent type (62%) followed by pleural effusion (28%). The most affected
      professional category were medical residents (38%) with the emergency service
      (48%) being the work place with the highest risk. The cumulative incidence in our
      hospital was higher in relation to the general population although there was a
      variability between both populations. CONCLUSIONS: There is risk of tuberculosis
      transmission among health care workers, principally in the emergency service and
      the pathology and microbiological departments. A concerted effort is needed to
      maintain prevention measures in the work place where there is a high risk of
      infection.

PMID- 15171908
TI  - [Dementia, mild cognitive impairment and population reference values].

PMID- 15171909
TI  - [Increase of antiretroviral therapy-associated cardiovascular risk].

PMID- 15171910
TI  - [Uveitis as initial manifestation of sarcoidosis: study of 31 patients].
AB  - BACKGROUND AND OBJECTIVE: Our goal was to analyze the epidemiological and
      clinical findings, as well as the diagnostic approach in a group of patients in
      whom uveitis was the first manifestation of sarcoidosis. PATIENTS AND METHOD:
      Retrospective study (between March 1998 and July 2002) including 31 patients
      diagnosed with sarcoidosis after an episode of uveitis. The group consisted of 19
      females (61%) and 12 males (39%). Mean follow-up was 34.5 months. Age, sex,
      ocular and systemic clinical findings were recorded. Angiotensin converting
      enzyme (ACE) levels were measured and radiological studies of the thorax were
      conducted including simple radiography (Rx), computerized axial tomography (CT)
      and gallium scan (67Ga). Biopsy was carried out in 14 patients. RESULTS: Mean age
      was 59.6 years. Six different clinical presentations of uveitic sarcoidosis were
      observed, the most common being bilateral panuveitis in 13 patients (42%) and
      chronic anterior bilateral uveitis in 11 (35%). Gallium scan, thoracic CT and
      chest radiography were positive in 88%, 77% and 33% cases, respectively. ACE
      levels were raised in 7 of the 27 patients analyzed (26%). Histological
      confirmation of disease was obtained in all 14 patients biopsied with a
      specificity and sensitivity of 100%. CONCLUSIONS: Uveitis may be the presenting
      manifestation of sarcoidosis, especially in women over 60 years of age. Bilateral
      panuveitis and chronic bilateral anterior uveitis are the most common clinical
      presentations. The sensitivity of gallium scan and thoracic CT is greater than
      simple chest radiography in diagnosing pulmonary and mediastinal lesions of
      sarcoidosis. The need for biopsy should be individualized in each case depending
      on complementary exams, age and potential morbidity of the procedure.

PMID- 15171911
TI  - [Commercial effectiveness of the pharmaceutical industry. Industry cost
      effectiveness and customers value].

PMID- 15171912
TI  - [Specific immunotherapy in asthmatic patients].

PMID- 15171914
TI  - [Pulmonary embolism and prolonged fever in the presence of a thrombus attached to
      a pacemaker electrode].

PMID- 15171915
TI  - Development of a liquid chromatography-tandem mass spectrometric method for the
      determination of methamphetamine and amphetamine using small volumes of rat
      serum.
AB  - The aim of this paper was to develop LC/MS/MS methodology for the determination
      of methamphetamine (METH) and amphetamine (AMP) using low microliter volumes (20
      150 microl) of rat serum and demonstrate the use of this method for the study of
      serum pharmacokinetics in the rat. The analytes were extracted from rat serum
      using solid-phase extraction followed by an isocratic separation on a narrow-bore
      Hypersil C(18) column. Lower limits of quantitation for METH and AMP were 0.3
      ng/ml using positive ion electrospray tandem mass spectrometry. The accuracy of
      the method was within 20% of the actual values over a wide range of serum
      concentrations. The within-day and between-day precision was better than 20%
      (R.S.D.). Ion-suppression matrix effects on electrospray ionization were
      evaluated for extracted rat serum. The LC/MS/MS method was further validated by
      comparing serum concentrations of METH and AMP to serum concentrations previously
      determined using an LC/[ (3)H]-METH assay with radiochemical detection. Finally,
      the LC/MS/MS method was used to study the pharmacokinetics of METH and AMP after
      a 1mg/kg intravenous bolus dose of METH to female Sprague-Dawley rats.

PMID- 15171916
TI  - Determination of the immunosuppressant mycophenolic acid in human serum by solid
      phase microextraction coupled to liquid chromatography.
AB  - A solid phase microextraction (SPME)-HPLC-UV method for the determination of the
      immunosuppressant mycophenolic acid (MPA) in human serum samples was developed
      for the first time. The procedure, that employed a carbowax/templated resin
      (Carbowax/TPR-100) as fiber coating, required a very simple sample pretreatment,
      an isocratic elution, and provides an highly selective extraction. The linear
      range was 0.2-100 microg x ml(-1). Recovery was practically unchanged (63+/- 4%)
      passing from 0.2 to 100 microg x ml(-1) level. Within-day and between-days
      coefficient of variation ranged from 5.9 to 6.5% and from 8.8 to 9.2%,
      respectively. A detection limit of 0.05 microg x ml(-1) was estimated in spiked
      serum. The method was successfully applied to the determination of MPA in serum
      of a patient under mycophenolate mophetil ester (MMF) therapy, as demonstrated by
      the relevant concentration-time profiles.

PMID- 15171917
TI  - Heterogeneity of mitochondrial creatine kinase.
AB  - The heterogeneity of cardiac sarcomeric mitochondrial creatine kinase (creatine N
      phosphotransferase, EC 2.7.3.2, sMi-CK), namely, brain ubiquitous Mi-CK (uMi-CK)
      and an atypical Mi-CK detected in the serum of a patient with ovarian cancer, was
      studied by isoelectric focusing. These Mi-CKs were found to be slightly different
      from each other with respect to their pIs under the examined conditions. The
      atypical Mi-CK was found to be an atypically oxidized form of uMi-CK. Results
      suggest that these heterogeneities of Mi-CK are caused by the genotypes,
      structures, biological functions and metabolism/dissimilation of Mi-CKs in the
      mitochondria and intravascular circulation.

PMID- 15171918
TI  - Determination of isoflavones in soybean food and human urine using liquid
      chromatography with electrochemical detection.
AB  - A highly sensitive high-performance liquid chromatographic method with
      electrochemical detection (HPLC-ED) was developed for the determination of
      isoflavones. Electrochemical behaviour of daidzein and genistein was studied on
      carbon paste electrode (CPE) by adsorptive transfer stripping square wave
      voltammetry. The obtained electrochemical results were used for the development
      of HPLC-ED method. Furthermore, isoflavones were separated on an Atlantis dC18
      column using a mobile phase consisting of acetonitrile (solvent A) and 0.15M
      acetate buffer of pH 5.5 (solvent B) at a flow rate 0.4 mL/min. A linear gradient
      profile (solvent B) was at 0-2 min 87%; 22 min 60%; 27 min 50%; 31 min 45%; 47
      min 87%. Full scan of multi-channel coulometric detection was tested and optimal
      potential at 450 mV was chosen for our purposes. Calibration curves were linear
      (daidzein R(2) = 0.9993 and genistein R(2) = 0.9987). The detection limit for
      daidzein/genistein was 480/394 pg/mL (1.8/1.5 nM) and per column 2.4/1.9 pg.
      Isoflavones extracted from soybean products (farina, meat, milk) by the
      accelerated solvent extraction (ASE) procedure and isoflavones present in human
      urine were determined by the HPLC-ED method.

PMID- 15171919
TI  - Improved determination of bovine glutaminyl cyclase activity using precolumn
      derivatization and reversed-phase high-performance liquid chromatography with
      ultraviolet detection.
AB  - A sensitive, rapid and reproducible assay for the determination of glutaminyl
      cyclase activity is reported. This method is based on the monitoring of the
      absorption of l-pyroglutamic acid beta-naphthylamide at 235 nm, enzymatically
      formed from the substrate l-glutaminyl-beta-naphthylamide, after separation by
      high-performance liquid chromatography using a C-18 reversed-phase column by
      isocratic elution. The detection limit of this method is at a level as low as
      0.08 nmol/ml and, the time consumed for analysis is <6.5 min per sample for
      separation and quantification. The optimum pH for glutaminyl cyclase activity was
      8.0-8.5. The K(m) and V(max) values were 100.2+/-2.9 microM and 332 +/-21.7
      pmol/(h microg protein), respectively, with the use of enzyme extract obtained
      from bovine pituitary. Glutaminyl cyclase activity was strongly inhibited by
      zinc(II) ion and 1,10-phenanthroline. By using this assay, the stimulatory effect
      of bacterial lipopolysaccharide on this enzyme activity was observed in
      macrophage cell line RAW 264.7. Our newly developed assay would be useful for
      clarification of the physiological role of this enzyme.

PMID- 15171920
TI  - Analysis of microsomal metabolic stability using high-flow-rate extraction
      coupled to capillary liquid chromatography-mass spectrometry.
AB  - A method is described for on-line high-speed extraction of microsomal samples and
      analysis by capillary liquid chromatography-mass spectrometry (LC-MS) for the
      determination of metabolic stability in connection with the development of
      positron emission tomography (PET) tracers. The method allowed direct injections
      of large sample volumes at a fast extraction rate, providing a gain in both
      sensitivity and sample preparation time. The calibration curve of the test
      compound flumazenil (Ro 15-1788) was linear in the concentration range of 1-150
      nM, with a correlation coefficient exceeding 0.999. The accuracy of the method
      ranged from 98 to 101%. A high precision was obtained, with mean intra-assay and
      inter-assay relative standard deviations of at most 1.4 and 1.5%, respectively,
      for quality control (QC) samples. The extraction efficiency was determined to be
      99.4%, the total recovery 96% and the carryover to <or=0.23%. Extractions were
      performed in a concentration interval of 30-3000 nM without any sign of column
      overload. The method was successfully used for determining the microsomal
      metabolic stability of flumazenil. As a result, the described analysis system is
      currently used for metabolic screening of PET tracer candidates in our
      laboratory.

PMID- 15171922
TI  - Liquid chromatographic-fluorimetric method for the estimation of nitric oxide
      biosynthesis in the central nervous system.
AB  - Some amino acids are involved in the biosynthesis of nitric oxide (NO), which has
      a physiological and pathophysiological role. To study NO biosynthesis, we
      compared arginine and citrulline levels in the cerebrospinal fluid (CSF) from
      patients with infectious and/or inflammatory processes within the central nervous
      system (CNS), with those from patients without those disorders. Arginine
      concentration was not significantly different between the groups (P = 0.115),
      whereas citrulline was significantly elevated in the first group (P = 0.020). We
      propose a simple chromatographic method to estimate NO biosynthesis ex vivo
      within the CNS, that may be applicable for the study of neurodegenerative and
      psychiatric diseases such as Parkinson's disease and schizophrenia.

PMID- 15171921
TI  - Solid-phase extraction-liquid chromatographic method for the determination and
      pharmacokinetic studies of albiflorin and paeoniflorin in rat serum after oral
      administration of Si-Wu decoction.
AB  - A sensitive and rapid high-performance liquid chromatography (HPLC) method with
      solid-phase extraction (SPE) to simultaneously determine albiflorin and
      paeoniflorin in rat serum was described. Serum samples were pretreated with solid
      phase extraction using Extract-Clean cartridges, and the extracts were analyzed
      by HPLC on a reversed-phase C(18) column and a mobile phase of acetonitrile-0.03%
      formic acid (17:83 (v/v)) with ultraviolet detection at 230 nm. Pentoxifylline
      was used as the internal standard (IS). The linear ranges of the calibration
      curves were 29-1450 ng/ml for albiflorin and 10-2000 ng/ml for paeoniflorin. The
      intra- and inter-day precisions (R.S.D.) were <or=10.49% for albiflorin and
      <or=11.29% for paeoniflorin, respectively. Mean recovery was determined to be
      89.75% for albiflorin and 85.82% for paeoniflorin. The limit of quantification
      was 29 ng/ml for albiflorin and 10 ng/ml for paeoniflorin, respectively. The
      validated method was applicable to pharmacokinetic studies of albiflorin and
      paeoniflorin from rat serum after oral administration of Si-Wu decoction. The
      pharmacokinetic study indicated that albiflorin and paeoniflorin had poor
      absorption and rapid elimination. This assay result was necessary for the
      pharmacokinetic evaluation of Si-Wu decoction.

PMID- 15171923
TI  - Determination of cocaine, its metabolites, pyrolysis products, and ethanol
      adducts in postmortem fluids and tissues using Zymark automated solid-phase
      extraction and gas chromatography-mass spectrometry.
AB  - Demonstrating the presence or absence of cocaine (COC) and COC-related molecules
      in postmortem fluids and/or tissues can have serious legal consequences and may
      help determine the cause of impairment and/or death. We have developed a simple
      method for the simultaneous determination of COC and the COC metabolites
      benzoylecgonine (BE), norbenzoylecgonine (NBE), ecgonine methyl ester (EME),
      ecgonine (E), and norcocaine (NCOC), as well as anhydroecgonine methyl ester
      (AEME) (a unique byproduct of COC smoking), cocaethylene (a molecule formed by
      the concurrent use of COC and ethanol) and their related metabolites,
      anhydroecgonine (AE), norcocaethylene (NCE), and ecgonine ethyl ester (EEE). This
      method incorporates a Zymark RapidTrace automated solid-phase extraction (SPE)
      system, gas chromatography/mass spectrometry (GC/MS) and 2,2,3,3,3-pentafluoro-1
      propanol (PFP)/pentafluoropropionic anhydride (PFPA) derivatives. The lower
      limits of detection ranged from 0.78 to 12.5 ng/mL and the linear dynamic range
      for most analytes was 0.78-3200 ng/mL. The extraction efficiencies were from 26
      to 84% with the exception of anhydroecgonine and ecgonine, which were from 1 to
      4%. We applied this method to five aviation fatalities. This method has proven to
      be simple, robust and accurate for the simultaneous determination of COC and 11
      COC metabolites in postmortem fluids and tissues.

PMID- 15171924
TI  - Capillary electrophoresis monitors changes in the electrophoretic behavior of
      mitochondrial preparations.
AB  - The presence of electrical charges on the surface of an organelle is the source
      of the organelle's electrophoretic mobility. Recently, we reported that capillary
      electrophoresis with laser-induced fluorescence detection (CE-LIF) can be used to
      determine the electrophoretic mobility of individual mitochondria. Here, we
      describe the use of CE-LIF to monitor changes in the electrophoretic mobility
      distributions of: (i). mitochondria isolated from cultured NS-1 mouse hybridoma
      cells disrupted by nitrogen cavitation or mechanical homogenization; (ii).
      mitochondria isolated from rat liver and purified by gradient centrifugation
      before and after being frozen in liquid nitrogen; and (iii). mitochondria
      chemically transformed into mitoplasts. These results indicate that the organelle
      electrophoretic mobility observed by researchers is affected by preparation
      procedures and that CE-LIF is a complementary technique for monitoring the
      quality of mitochondrial preparations.

PMID- 15171925
TI  - Determination of extracellular hesperidin in blood and bile of anaesthetized rats
      by microdialysis with high-performance liquid chromatography: a pharmacokinetic
      application.
AB  - A method coupled with microdialysis technique and liquid chromatography was
      applied in the continuous and concurrent in vivo monitoring of extracellular
      hesperidin in the blood and bile of anaesthetized rats. Hesperidin was
      intravenously administered via the femoral vein. Sampling was achieved using two
      microdialysis probes, which were implanted into the jugular vein and into the
      bile duct. Dialysates of blood and bile were both directly injected onto the
      liquid chromatographic system, so no further clean-up procedures were required.
      Separation was performed using a reversed phase ODS-2 microbore column 150 mm x 1
      mm i.d., particle size 5 microm with mobile phase of acetonitrile-0.1M ammonium
      acetate (30:70, v/v) at flow-rate of 0.05 ml/min. The UV detection for hesperidin
      was set at a wavelength of 283 nm. This method was used to determine the
      pharmacokinetics of hesperidin and its interaction in the presence of cyclosporin
      A, which is a P-glycoprotein modulator. The results indicate that the curve of
      area under the concentration versus time (AUC) for hesperidin in bile was
      significantly greater than that for hesperidin in blood at the dose of 30 mg/kg.
      The blood-to-bile distribution ratio (k = AUC(bile)/AUC(blood)) was 8.9 +/- 2.5
      for hesperidin at 30 mg/kg. Following cyclosporin A treatment, the distribution
      ratio was reduced to 3.2 +/- 0.6. In conclusion, hesperidin goes through
      hepatobiliary elimination against the concentration gradient from blood to bile,
      and this hepatobiliary excretion of hesperidin may be regulated by the P
      glycoprotein.

PMID- 15171926
TI  - High-throughput sample preparation procedures for the quantitation of a new bone
      integrin alpha(nu)beta(3) antagonist in human plasma and urine using liquid
      chromatography-tandem mass spectrometry.
AB  - High throughput LC-MS/MS assays to quantitate a new alpha(nu)beta(3) bone
      integrin antagonist (I) in human plasma and urine have been developed using
      instruments programmed to automate sample preparation procedures. Packard liquid
      handling system-MultiPROBE II EX was programmed for preparing calibration
      standards in control plasma and urine, acidifying all standards, quality control
      (QC), and clinical samples with necessary dilutions, and adding the internal
      standard to the acidified samples. TOMTEC Quadra 96 was programmed to perform the
      solid phase extraction (SPE) process on a 3M 96-well mixed phase cation standard
      density (MPC-SD) plate to isolate the analytes from the sample matrix. The
      extract collected from both types of matrices was directly injected into reversed
      phase LC-MS/MS system with a Turbo Ion Spray (TIS) interface in the positive
      ionization mode. The plasma and urine assays have the calibration range of 0.5
      1500 and 2-6000 ng/mL, respectively. Validation of the automated and the manual
      plasma assays showed that application of MultiPROBE II to sample preparation gave
      comparable accuracy and precision. Overall, the automated approaches with minimum
      manual intervention enhanced the throughput of sample preparation.

PMID- 15171927
TI  - High-throughput liquid chromatography for drug analysis in biological fluids:
      investigation of extraction column life.
AB  - A novel method was developed and assessed to extend the lifetime of extraction
      columns of high-throughput liquid chromatography (HTLC) for bioanalysis of human
      plasma samples. In this method, a 15% acetic acid solution and 90% THF were
      respectively used as mobile phases to clean up the proteins in human plasma
      samples and residual lipids from the extraction and analytical columns. The 15%
      acetic acid solution weakens the interactions between proteins and the stationary
      phase of the extraction column and increases the protein solubility in the mobile
      phase. The 90% THF mobile phase prevents the accumulation of lipids and thus
      reduces the potential damage on the columns. Using this novel method, the
      extraction column lifetime has been extended to about 2000 direct plasma
      injections, and this is the first time that high concentration acetic acid and
      THF are used in HTLC for on-line cleanup and extraction column lifetime
      extension.

PMID- 15171928
TI  - Purification of recombinant bovine normal prion protein PrP(104-242) by HPHIC.
AB  - Purification of the prion protein (PrP) is a major concern for biological or
      biophysical analysis as are the structural specificities of this protein in
      relation to infectivity. A simple and efficient method for purification of
      recombinant bovine normal prion protein containing residues 104-242, PrP(104-242)
      expressed in Escherichia coli by high performance hydrophobic interaction
      chromatography (HPHIC) was presented in this work. The solution containing
      denatured and reduced protein in 8.0 mol/L urea extracted from the inclusion body
      was directly injected into the HPHIC column, aggregates were prevented by the
      interaction between the denatured PrP(104-242) molecules and the stationary phase
      during the chromatographic process, the soluble form of PrP(104-242) in aqueous
      solution was obtained after desorbed from the column. Several factors, including
      pH value, types of stationary phase and salt, and gradient mode, influencing the
      purification results were investigated. Optimal conditions were obtained for the
      purification of PrP(104-242) by HPHIC. This procedure yield PrP(104-242) of a
      purity of 96% with a recovery of 87%, respectively, for a single step
      purification of 40 min.

PMID- 15171929
TI  - Method development and validation for quantitative determination of methadone
      enantiomers in human plasma by liquid chromatography/tandem mass spectrometry.
AB  - A high-throughput method for quantitative determination of methadone enantiomers
      in human plasma was developed and validated by liquid chromatography/tandem mass
      spectrometry. The effects of pH and of types and concentrations of mobile-phase
      modifiers on the enantioselectivity of (R)- and (S)-methadone were investigated
      on a Chiral-AGP column. A baseline separation of the enantiomers was achieved
      with a retention time of less than 5 min. Ionization suppression and other matrix
      effects were evaluated. Morphine, cocaine, 6-monoacetylmorphine, benzoylecgonine
      and ecgonine methyl ester did not interfere with the performance of the assay.
      The specificity, linearity, intra- and inter-assay precision and accuracy, and
      extraction recovery were fully evaluated. The method showed excellent
      reproducibility (overall coefficient of variance < 8%) and accuracy (overall bias
      < 2.7%) with a broad linear range. The enantiomers were stable in human plasma
      after five freeze-thaw cycles, under bench-top storage at room temperature (RT)
      for 6h, in the extract reconstitution solution at RT for 17 h, and in processed
      extracts stored at RT for 142 h. This validated LC/MS/MS assay offers high
      throughput and improved specificity, sensitivity, linear range and ruggedness
      over previously published methods and has been successfully applied to the
      analysis of clinical samples.

PMID- 15171930
TI  - Sensitive and selective liquid chromatography-electrospray ionization tandem mass
      spectrometry analysis of hydrochlorothiazide in rat plasma.
AB  - A sensitive and selective method for the determination of hydrochlorothiazide
      (HCTZ) concentrations in rat plasma was developed using high performance liquid
      chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS). An
      aliquot of plasma (50 microl) was mixed with the solution of internal standard,
      hydrofluorothiazide (HFTZ), and extracted with tert-butyl methyl ether. The
      reconstituted extract was applied to the LC-MS/MS system with a reversed phase C8
      column and eluted with distilled water/acetonitrile (85/15, v/v). To enhance
      negative ionization of HCTZ and HFTZ in the multiple reaction monitor (MRM), the
      solution consisting of acetonitlile/1% (v/v) ammonia solution (95/5, v/v) was
      delivered after column separation. This additional technique, so-called the post
      column addition, increased sensitivity of HCTZ and HFTZ about 500- and 200-fold,
      respectively. The calibration curve showed good linearity (r = 0.999) over the
      range of 4-1000 ng/ml. Acceptable accuracy (100.8-113.1%) and precision (0.28
      16.4%) were confirmed in the intra- and the inter-day analyses. It is indicated
      that this LC-MS/MS method is useful for pharmacokinetic studies of HCTZ in small
      animals, because it enabled the serial determination of plasma level of HCTZ in
      rats.

PMID- 15171931
TI  - Validated semiquantitative/quantitative screening of 51 drugs in whole blood as
      silylated derivatives by gas chromatography-selected ion monitoring mass
      spectrometry and gas chromatography electron capture detection.
AB  - A comprehensively validated procedure is presented for simultaneous
      semiquantitative/quantitative screening of 51 drugs of abuse or drugs potentially
      hazardous for traffic safety in serum, plasma or whole blood. Benzodiazepines
      (12), cannabinoids (3), opioids (8), cocaine, antidepressants (13),
      antipsychotics (5) and antiepileptics (2) as well as zolpidem, zaleplon,
      zopiclone, meprobamate, carisoprodol, tizanidine and orphenadrine and internal
      standard flurazepam, were isolated by high-yield liquid-liquid extraction (LLE).
      The dried extracts were derivatized by two-step silylation and analyzed by the
      combination of two different gas chromatographic (GC) separations with both
      electron capture detection (ECD) and mass spectrometry (MS) operating in a
      selected ion-monitoring (SIM) mode. Quantitative or semiquantitative results were
      obtained for each substance based on four-point calibration. In the validation
      tests, accuracy, reproducibility, linearity, limit of detection (LOD) and limit
      of quantitation (LOQ), selectivity, as well as extraction efficiency and
      stability of standard stock solutions were tested, and derivatization was
      optimized in detail. Intra- and inter-day precisions were within 2.5-21.8 and 6.0
      22.5%, and square of correlation coefficients of linearity ranged from 0.9896 to
      0.9999. The limit of quantitation (LOQ) varied from 2 to 2000 ng/ml due to a
      variety of the relevant concentrations of the analyzed substances in blood. The
      method is feasible for highly sensitive, reliable and possibly routinely
      performed clinical and forensic toxicological analyses.

PMID- 15171932
TI  - Determination of milnacipran, a serotonin and noradrenaline reuptake inhibitor,
      in human plasma using liquid chromatography with spectrofluorimetric detection.
AB  - Milnacipran is an antidepressant drug belonging to the class of serotonin and
      noradrenaline reuptake inhibitors. A sensitive high performance liquid
      chromatographic during the development method coupled with a fluorimetric
      detection was set up, validated and then used routinely of the drug. After liquid
      liquid extraction, milnacipran and its internal standard were analyzed by
      reversed-phase liquid chromatography (LC). The drug was derivatized with
      fluorescamine for fluorescence detection. The identity of the liquid
      chromatography peaks was controlled using mass spectrometry. The assay linearity
      was validated up to 1000 ng/ml. The limit of quantification was set at 5 ng/ml.
      Precision values (relative standard deviations) were lower than 5.4%, whereas the
      mean accuracy was higher than 95%. The extraction recoveries were higher than 70%
      for both milnacipran and the internal standard. In clinics, the LC-fluorescence
      method was routinely used to investigate the pharmacokinetics of milnacipran in
      patients and proved to be robust and capable of quantifying milnacipran in plasma
      for at least 36 h (four- to five-fold the elimination half-life).

PMID- 15171933
TI  - Interval immobilization technique for recognition toward a highly hydrophilic
      cyanobacterium toxin.
AB  - A novel adsorption medium containing selective molecular recognition site for one
      of the powerful cyanobacterium toxins, Cylindrospermopsin (CYN) was developed
      using a special technique, namely interval immobilization technique. The
      adsorption medium was prepared using molecular assembly derived from an
      alternative-template molecule coupled with functional monomers for fixing the
      interval between the ionic functional groups in CYN. As results of liquid
      chromatographic evaluations, selective molecular recognition ability for CYN was
      observed as expected. Further studies proved that the association constant for
      CYN on this medium was slightly higher than that on blank polymer.

PMID- 15171934
TI  - Simultaneous determination of vigabatrin and amino acid neurotransmitters in
      brain microdialysates by capillary electrophoresis with laser-induced
      fluorescence detection.
AB  - Capillary electrophoresis with laser-induced fluorescence detection (CE-LIFD)
      coupled to in vivo microdialysis sampling was used in order to monitor
      simultaneously a drug and several neurotransmitters in the brain extracellular
      fluid. Determination of the antiepileptic drug vigabatrin and the amino acid
      neurotransmitters glutamate (Glu), l-aspartate (l-Asp) and gamma-aminobutyric
      acid (GABA) was performed on low-concentration samples which were derivatized
      with naphthalene-2,3-dicarboxaldehyde (NDA) and separated using a pH 9.2 75 mM
      sodium borate running buffer containing 60 mM sodium dodecyl sulfate (SDS) and
      5mM hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Glu, l-Asp and vigabatrin
      derivatized at a concentration of 1.0 x 10(-9) M, and GABA derivatized at a
      concentration of 5.0 x 10(-9) M, produced peaks with signal-to-noise ratios of
      8:1, 8:1, 4:1 and 5:1, respectively. The nature of the neurotransmitter peaks
      found in rat brain microdialysates was confirmed by both electrophoretic and
      pharmacological validations. This method was used for monitoring vigabatrin and
      amino acid neurotransmitters in microdialysates from the rat striatum during
      intracerebral infusion of the drug and revealed rapid vigabatrin-induced changes
      in GABA and Glu levels. This original application of CE-LIFD coupled to
      microdialysis represents a powerful tool for pharmacokinetic/pharmacodynamic
      investigations.

PMID- 15171935
TI  - Liquid chromatography-mass spectrometry analysis of hydroxylated polycyclic
      aromatic hydrocarbons, formed in a simulator of the human gastrointestinal tract.
AB  - Described is a liquid chromatography-mass spectrometry (LC-MS) procedure for the
      determination of hydroxylated biotransformation products of polycyclic aromatic
      hydrocarbons (PAH) in the human gastrointestinal tract. The formation of
      hydroxylated PAHs was monitored upon incubation of PAHs with colon microbiota
      from the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The
      analytical method consisted of a biomass removal step followed by a solid phase
      extraction (SPE) step using C18 packed columns to remove non-digested food
      compounds and microbial metabolites that interfere with the detection of the
      target compounds. For quantification, 9-hydroxyphenanthrene (13)C(6)was used as
      the internal standard. The detection limits of the hydroxylated PAHs were
      generally in the range 0.36-14.09 microg x l(-1), based on a signal/noise ratio
      of 3:1. The recovery of hydroxylated PAHs in intestinal suspension was variable
      ranging from 45 to 107%, with relative standard deviation (R.S.D.) between 5 and
      17%. The analytical procedure was used to show the microbial production of 1
      hydroxypyrene and 7-hydroxybenzo(a)pyrene, metabolites that may give colon
      incubated PAHs bioactive properties.

PMID- 15171936
TI  - Determination of fosmidomycin in human serum and urine by capillary
      electrophoresis.
AB  - A capillary electrophoresis method with direct UV detection was developed for the
      determination of fosmidomycin, a promising new anti-malarial drug, in human serum
      and urine. Optimization of the separation parameters resulted in a buffer system
      adjusted to pH 10.8 containing a cationic reagent and an organic modifier. Under
      these conditions, the migration time of fosmidomycin was 5.2 min with serum and
      7.4 min with urine samples. Validation of the method revealed good recoveries,
      precision and accuracy. The limit of quantification was 0.5 microg/ml in serum
      and 10 microg/ml in urine. The determination of fosmidomycin in serum was linear
      over a range of 0.1-150 microg/ml. Short and long-term stability tests resulted
      in no significant loss of fosmidomycin. The described technique will provide a
      fast and accurate analytical method for future pharmacokinetic studies.

PMID- 15171937
TI  - Liquid chromatographic determination including simultaneous "on-cartridge"
      separation of ranitidine cisapride drug combinations from paediatric plasma
      samples using an automated solid-phase extraction procedure.
AB  - HPLC methodology was investigated for the simultaneous determination of cisapride
      and ranitidine in small volume paediatric plasma samples. Such a simultaneous
      determination proved difficult due to the small sample volumes, the low
      concentrations of the drugs and the different log P values of the two compounds.
      The two drugs and their respective internal standards were separated "on
      cartridge" using HLB Solid Phase Extraction cartridges and the samples quantified
      by individual HPLC methodologies. The technique has been applied successfully to
      60 paediatric plasma samples containing both cisapride and ranitidine.

PMID- 15171938
TI  - Headspace solid-phase microextraction and capillary gas chromatographic-mass
      spectrometric determination of rivastigmine in canine plasma samples.
AB  - A simple, rapid and sensitive method for determination of rivastigmine in plasma
      samples was developed using headspace solid-phase microextraction (HS-SPME) and
      gas chromatography with mass spectrometry (GC-MS). The optimum conditions for the
      SPME procedure were: headspace extraction on a 65-microm
      polydimethylsiloxane/divinylbenzene (PDMS/DVB) fiber; 0.5 ml of plasma modified
      with 1.0 ml of sodium hydroxide-sodium carbonate solution (0.7 M:0.5M);
      extraction temperature of 100 degrees C, with stirring at 2000 rpm for 30 min.
      The calibration curve showed linearity in the range from 0.2 to 80 ng/ml with
      regression coefficient corresponding to 0.9965 and coefficient of the variation
      of the points of the calibration curve lower than 10%. The quantification limit
      for rivastigmine in plasma was 0.2 ng/ml. The method was applied to determination
      of rivastigmine in canine plasma samples from animals after a single oral
      administration.

PMID- 15171939
TI  - Reversed-phase liquid chromatography with ultraviolet detection for simultaneous
      quantitation of indinavir and propranolol from ex-vivo rat intestinal
      permeability studies.
AB  - A simple, rapid, sensitive and specific reversed-phase high performance liquid
      chromatographic (RP-HPLC) method involving ultraviolet detection (lambda = 210
      nm) was developed for analysis of indinavir along with propranolol in samples
      obtained from ex vivo intestinal permeability studies. Chromatography was carried
      out on C-18 column with mobile phase comprising of phosphate buffer-acetonitrile
      (68:32, v/v) pumped at flow rate of 1 ml/min. The proposed method has a short run
      time of 12 min and involves a simple sample preparation for the purpose of
      reducing permeability model artifacts and to concentrate the samples. Fluorescein
      was used as internal standard. The proposed method has been validated with regard
      to specificity, detection limit, recovery, accuracy and precision. For both the
      drugs, method was found to be selective, linear (R(2) approximately 0.999),
      accurate (recovery = 100-105%) and precise (<3% R.S.D.) in the range of 2-20
      microg/ml. The limit-of-detection and limit-of-quantification of the method were
      40 ng/ml and 100 ng/ml for indinavir, and 30 and 80 ng/ml for propranolol,
      respectively. Indinavir, a widely prescribed HIV protease inhibitor, suffer from
      bioavailability problems where involvement of P-glycoprotein mediated drug efflux
      may play a significant role. The proposed method was successfully applied for
      intestinal permeability of indinavir to estimate the contribution of P
      glycoprotein in limiting its oral bioavailability. The advantage of the developed
      method lies in the simultaneous determination of propranolol, a passive integrity
      marker, routinely employed in permeability studies and its selectivity in
      presence of various P-gp modulators and permeability markers.

PMID- 15171940
TI  - Solid phase extraction procedure for urinary organic acid analysis by gas
      chromatography mass spectrometry.
AB  - We have developed a solid phase extraction procedure for the detection of organic
      acids by GC-MS using a strong anion exchange column (Sep-Pak Vac RC, Accell Plus
      QMA cartridge). Extraction efficiencies of 25 organic acids were established by
      analyzing standards in water based solutions. High extraction efficiencies (90 to
      100%) were found for many of the compounds studied. We estimated the limit of
      detection for 48 organic acids and glycine conjugates. They were below 5 nmole
      with the exception of malonic and oxalic acids and mevalonic acid lactone. This
      method provides the advantage of higher recoveries for a wide range of compounds
      of interest and therefore can be a potential alternative to liquid-liquid
      extraction for organic acid screening. It is especially sensitive for the
      detection of some polar compounds, such as 3-OH-glutaric and N-acetylaspartic
      acids.

PMID- 15171941
TI  - Determination of the antiangiogenesis agent 2-methoxyestradiol in human plasma by
      liquid chromatography with ultraviolet detection.
AB  - A high-performance liquid chromatography (HPLC) assay was developed for the
      quantitative determination of 2-methoxyestradiol (2ME2) in human plasma. Sample
      pretreatment involved a solid-phase extraction of 1 ml aliquots of plasma with
      C(18) micro-columns. Separation was achieved on a Novapak C(18) column (300 mm x
      3.9 mm i.d.; 4 microm PS) at room temperature at an isocratic flow rate of 1
      ml/min with 50% acetonitrile in water. Detection was performed at a UV wavelength
      of 205 nm. Calibration curves were linear in the concentration range of 1-50
      ng/ml. The accuracy and precision values obtained from three different sets of
      quality controls analyzed in replicates of four on four separate occasions ranged
      from 90.7 to 105.2 and 3.17 to 8.27%, respectively.

PMID- 15171942
TI  - Methyl malondialdehyde is not suitable as an internal standard for
      malondialdehyde detection in urine after derivatisation with 2,4
      dinitrophenylhydrazine.
AB  - A previously described method of measurement of malondialdehyde (MDA) in human
      urine after derivatisation with 2,4-dinitrophenylhydrazine (DNPH) was tested for
      a possibility of using methyl malondialdehyde (MeMDA) as an internal standard.
      Despite structural similarity, those compounds were found to produce different
      yields of derivatisation under the same conditions depending on urine matrix. We
      conclude, that MeMDA is not suitable as an internal standard for the measurement
      of MDA in urine under previously reported conditions when DNPH is used as a
      deriviatising agent.

PMID- 15171943
TI  - High performance liquid chromatographic method for the determination of
      sumatriptan with fluorescence detection in human plasma.
AB  - A rapid and sensitive high performance liquid chromatography (HPLC) method with
      fluorescence detection has been developed for the determination of sumatriptan in
      human plasma. The procedure involved a liquid-liquid extraction of sumatriptan
      and terazosin (internal standard) from human plasma with ethyl acetate.
      Chromatography was performed by isocratic reverse phase separation on a C18
      column. Fluorescence detection was achieved with an excitation wavelength of 225
      nm and an emission wavelength of 350 nm. The standard curve was linear over a
      working range of 1-100 ng/ml and gave an average correlation coefficient of
      0.9997 during validation. The limit of quantitation (LOQ) of this method was 1
      ng/ml. The absolute recovery was 92.6% for sumatriptan and 95.6% for the internal
      standard. The inter-day and intra-day precision and accuracy were between 0.8-3.3
      and 1.1-6.3%, respectively. This method is simple, sensitive and suitable for
      pharmacokinetics or bioequivalence studies.

PMID- 15171944
TI  - Determination of midazolam in human plasma by liquid chromatography with mass
      spectrometric detection.
AB  - A liquid chromatographic assay with mass-spectrometric detection was developed
      for the quantitative determination of the cytochrome p450 3A phenotyping probe
      midazolam in human plasma. Sample pretreatment involved a one-step extraction of
      600 microl aliquots with ethyl acetate. Midazolam and the internal standard,
      lorazepam, were separated on a column (150 mm x 4.6mm, i.d.) packed with 5 microm
      Zorbax Eclipse XDB-C8 material, using a mobile phase composed of methanol and
      10mM aqueous ammonium acetate (60:40, v/v). Column effluents were analyzed using
      mass-spectrometry with an atmospheric pressure chemical ionization source.
      Calibration curves were linear in the concentration range of 1.00-200 ng/ml. The
      accuracy and precision ranged from 92.8 to 112% and 0.056 to 13.4%, respectively,
      for four different concentrations of quality control samples analyzed in
      triplicate on eight separate occasions. The developed method was subsequently
      applied to study the pharmacokinetics of midazolam in a group of 35 human
      subjects at a single dose of 25 microg/kg.

PMID- 15171945
TI  - Fumonisin-ortho-phthalaldehyde derivative is stabilized at low temperature.
AB  - Fumonisins are water soluble mycotoxins produced by the fungus Fusarium
      verticillioides (formerly F. moniliforme). Fumonisin B(1) (FB(1)) is a diester of
      propane-1,2,3-tricarboxylic acid and 2-amino-12, 16-dimethyl-3,5,10,14,15
      pentahydroxyeicosane, and is the most abundant of the naturally occurring
      fumonisins. Upon removal of the two tricarballylic acid side chains, the
      structure is referred to as hydrolyzed FB(1) (HFB(1)). FB(1) and HFB(1) are
      structurally similar to sphinganine, a sphingoid base. The fumonisins do not
      absorb UV light or fluoresce; therefore, derivatizing reagents are used for
      detection when separation is by high performance liquid chromatography (HPLC).
      The standard derivatizing reagent used for HPLC is ortho-phthalaldehyde (OPA)
      plus 2-mercaptoethanol (ME) reaction partner, however, the OPA-FB(1) derivative
      is not stable at room temperature. The objectives of this study were to: (1).
      determine the effect of temperature on the stability of the OPA-FB(1) derivative
      and (2). determine which structural characteristics of FB(1) contribute to the
      instability of the OPA-FB(1) derivative. The results indicate that OPA-FB(1), OPA
      FB(3) and OPA-HFB(1) derivatives are unstable at 24 degrees C but that their
      stability improves significantly at 4 degrees C. The OPA-sphinganine derivative
      is stable for at least 24h at 24 degrees C. Thus, the instability of the OPA
      FB(1) derivative may be attributed to its lack of a hydroxyl group at the carbon
      1 position.

PMID- 15171946
TI  - Alkalization of larval mosquito midgut and the role of carbonic anhydrase in
      different species of mosquitoes.
AB  - We have previously demonstrated the involvement of carbonic anhydrase (CA) in the
      alkalization mechanism of the Aedes aegypti larval midgut. In this study, we used
      Hansson's histochemistry to examine the distribution of the enzyme in the midgut
      of six different species of mosquito larvae (Aedes aegypti, Aedes albopictus,
      Culex quinquefasciatus, Culex nigripalpus, Ochlerotatus taeniorhynchus, Anopheles
      quadrimaculatus). Additionally, we quantitated CA content in the gastric caeca,
      anterior and posterior midgut of fourth instar larvae from these species using
      the 18O isotope exchange method coupled to mass spectrometry. We also tested the
      effect of CA inhibitors such as methazolamide and acetazolamide in the
      alkalization of the midgut for these species. Our results indicate that CA is
      present in the larval midgut of the species studied and that it appears to be
      associated with the posterior midgut and gastric caeca in some species and with
      the anterior midgut in others. CA inhibitors appear to have a profound effect on
      the alkalization mechanism of the midgut with lethal consequences for most of the
      species tested.

PMID- 15171947
TI  - Plasma appearance and tissue accumulation of non-esterified, free astaxanthin in
      C57BL/6 mice after oral dosing of a disodium disuccinate diester of astaxanthin
      (Heptax).
AB  - Oral bioavailability of natural and synthetic carotenoids is generally poor in
      rodents, and this has limited the ability to test these antioxidant compounds in
      well-defined rodent models of human disease. Various strategies have been
      employed, with variable success, to increase the percentage of the total oral
      dose absorbed by the rodent GI tract. In the current study, a novel carotenoid
      derivative (the disodium disuccinate diester of astaxanthin; Heptax) was
      administered by oral gavage in a lipophilic emulsion to C57BL/6 mice. Plasma
      appearance and tissue accumulation of non-esterified, free astaxanthin was
      studied by HPLC over 72 h after single- and multiple-dose regimens. One-time
      dosing of Heptax in emulsion at 500 mg/kg resulted in significant appearance of
      free astaxanthin in plasma (Cmax=0.2 mg/l; 381 nM) and accumulation in solid
      organs (e.g. liver Cmax=0.9 mg/l; 1735 nM), levels not previously reported after
      single carotenoid doses in rodents. At each point in the concentration/time curve
      (AUC), free astaxanthin levels in liver were greater than the corresponding
      concentration in plasma, suggesting concentrative uptake by the liver. As the
      ED50 as an antioxidant for non-esterified, free astaxanthin in model systems is
      approximately 200 nM, the current results suggest that hepatoprotection against
      oxidative insults may be achieved after a single dose of Heptax in these animals.
      In humans, where the bioavailability of oral carotenoids ranges from 40 to 60% of
      the total dose when given in lipophilic vehicle, much smaller oral doses may be
      utilized for therapeutic benefit in a particular clinical application.

PMID- 15171948
TI  - Effects of 17-beta estradiol and 4-nonylphenol on phase II electrophilic
      detoxification pathways in largemouth bass (Micropterus salmoides) liver.
AB  - The effects of in vivo exposure to a natural and synthetic estrogen upon three
      hepatic phase II enzyme pathways involved in cellular protection against reactive
      intermediates were investigated in the largemouth bass (Micropterus salmoides).
      The pathways analyzed included glutathione S-transferases (GST), glutathione
      (GSH) biosynthesis and NAD(P)H-dependent quinone reductase (QR). Following
      exposure to 17-beta estradiol (E2, a model natural estrogen; 2 mg/kg, i.p.) or 4
      nonylphenol (NP, a model synthetic estrogen; 5 mg/kg and 50 mg/kg, i.p.), serum
      vitellogenin concentrations in male fish were markedly increased. Exposure to E2
      did not affect steady-state GST-A mRNA expression, although GST catalytic
      activity toward 1-chloro 2,4-dinitrobenzene (CDNB) was elevated at 48 h post
      injection. In addition, the rates of bass liver GST-4-hydroxy-2-nonenal (GST
      4HNE) conjugation were elevated by E2 exposure at all timepoints. In contrast,
      exposure to NP decreased steady-state GST-A mRNA levels, but did not alter GST
      catalytic activities. Hepatic GSH levels were not significantly affected by
      exposure to either compound, although a trend towards increased GSH biosynthesis
      was observed with both compounds. Although bass liver quinone reductase catalyzed
      2,6-dichloroindophenol (DCP) reduction, unlike in rodents, these catalytic
      activities were not inhibited by dicoumarol. Exposure to 5 mg/kg NP significantly
      increased hepatic QR activities. Collectively, our data suggest that exposure to
      E2 or NP alters the ability of largemouth bass to biotransform environmental
      chemicals through glutathione S-transferase and quinone reductase catalytic
      pathways.

PMID- 15171949
TI  - Bluegill (Lepomis macrochirus) vitellogenin: purification and enzyme-linked
      immunosorbent assay for detection of endocrine disruption by papermill effluent.
AB  - Vitellogenin (VTG) is a highly specific marker of exposure to environmental
      estrogens and has been used extensively in field and laboratory studies of
      estrogenic endocrine disruption in fishes. The purpose of this study was to
      develop and validate a sensitive, competitive, enzyme-linked immunosorbent assay
      (ELISA) specific for bluegill (Lepomis macrochirus) vitellogenin. Bluegill VTG
      was purified by anion exchange chromatography on DEAE-agarose. The polypeptide
      had an apparent mass of 170 kDa and was specifically recognized by the rabbit
      antiserum raised against bluegill female-specific plasma protein. Plasma samples
      from vitellogenic females diluted in parallel with the purified VTG standard
      curve in the ELISA. The detection limit of the assay was 29 ng/ml and the working
      range extended to 2700 ng/ml. Recovery of purified VTG was 85.8+/-9.5%, intra
      assay variation was 6.4% and interassay variation was 12.3%. We used this ELISA
      to analyze the seasonal cycle of vitellogenesis in female bluegill and to
      evaluate potential disruption of this process by exposure to bleached kraft mill
      effluent (BKME). Captive female bluegill stocked in outdoor experimental streams
      in New Bern, NC had the lowest levels of VTG, estradiol-17beta (E2), and
      testosterone (T) and the smallest oocyte diameters in January, but these
      variables increased in March and remained elevated through August, suggesting an
      extended spawning season. Plasma VTG, E2, T and oocyte diameter were unaffected
      by exposure to BKME concentrations as high as 30%. Development of the VTG ELISA
      allowed rapid and convenient analysis of plasma samples to evaluate exposure to
      potential endocrine disrupting compounds.

PMID- 15171950
TI  - Identification of factors responsible for insecticide resistance in Helicoverpa
      armigera.
AB  - Moth larvae (Helicoverpa armigera Hubner) collected from field crops were tested
      for resistance to cypermethrin, fenvalerate, endosulfan, monocrotophos and
      quinolphos. Larvae were treated with a dose of the pesticide that would kill 99%
      of the susceptible insects. The percent survival of the resistant strains was
      determined. Highest seasonal average percentage survival was recorded by
      fenvalerate (65.0%) followed by cypermethrin (62.4%). Acetylcholinesterase of
      resistant larvae was less sensitive to monocrotophos and methyl paraoxon.
      Resistant larvae showed higher activities of esterases, phosphatases and methyl
      paraoxon hydrolase compared with susceptible larvae. The presence of high
      activity of esterases was attributed to appearance of extra bands of esterases in
      native PAGE. The presence of P-glycoprotein expression was detected in resistant
      larvae using P-gp antibodies; this was not detected in the susceptible larvae.
      Our results indicate that the high level of resistance detected in the field
      pests could be because of a combined effect of decreased sensitivity to AChE,
      higher levels of esterases, phosphatases and the expression of P-gp.

PMID- 15171951
TI  - Cytochemical localisation of vanadium (III) in the blood cells of the ascidian
      Phallusia fumigata.
AB  - Most recent studies of vanadium in ascidian blood indicate the signet ring cell
      as the cell type that stores vanadium. However, in Phallusia fumigata the
      situation is less clear, with contradictory reports. Therefore, the blood cells
      of the ascidian P. fumigata were stained with the vanadium(III) specific ligand
      2,2'-bipyridine. The presence of vanadium was revealed in the vacuolated
      amoebocyte, the second compartment cell type or pluri-vacuolated cell, as well as
      the bivacuolated cell and the signet ring cell. Staining was not observed in
      either the morula cells or the compartment cells, the predominant cell types in
      the mature animal.

PMID- 15171952
TI  - Pharmacological properties of angiotensin II receptors in cultured rabbit
      gingival fibroblasts.
AB  - We demonstrated that angiotensin II (Ang II, 10-1000 nM) induced proliferation of
      cultured rabbit gingival fibroblasts in a concentration-dependent manner. The Ang
      II-induced proliferation was inhibited by CV-11974 (AT1 antagonist; 1 microM) and
      saralasin (AT1/AT2 antagonist; 1 microM), but not by PD123,319 (AT2 antagonist; 1
      microM), suggesting that Ang II-induced proliferation was mediated via AT1
      receptors present in and/or on gingival fibroblasts. The results of Western blot
      analysis indicated the presence of AT1 and AT2 receptors in/on the fibroblasts.
      In a subsequent radioligand binding assay, the binding of [3H]Ang II to the
      fibroblasts was specific and saturable with both high- and low-affinity sites.
      Competition binding experiments indicated that Ang II completely displaced
      [3H]Ang II binding, and CV-11974 and PD123,319 maximally displaced up to
      approximately 63% and 37% of the total binding, respectively. Ang II and CV-11974
      completely displaced the [3H]DuP753 binding but PD123,319 did not, indicating a
      single population of binding site. These findings demonstrate that gingival
      fibroblasts contain both AT1 and AT2 receptor subtypes for Ang II, and support
      that Ang II stimulation of AT1 receptors results in proliferation of the
      fibroblasts.

PMID- 15171955
TI  - Foundation and sites of action of antithrombotic agents.
AB  - Thromboembolic disorders are a major cause of morbidity and mortality. As
      knowledge of the complex interactions between the vessel wall, platelets and
      coagulation and fibrinolytic enzyme systems increases, new avenues for more
      effective and safer therapies become evident. In this review, we discuss
      mechanisms of hemostasis in relation to antithrombotic agents and results of
      clinical trials using these drugs.

PMID- 15171953
TI  - Vitellogenin in rare minnow (Gobiocypris rarus): identification and induction by
      waterborne diethylstilbestrol.
AB  - Rare minnow (Gobiocypris rarus) is a tiny Chinese carp that has a short life
      cycle and is easily cultured in the laboratory. In this study, juvenile rare
      minnows were exposed to waterborne diethylstilbestrol (DES) at 0.05, 0.5 and 5
      microg/l in laboratory aquaria. After exposure for 4, 8, 13 and 21 days, juvenile
      fish were collected and vitellogenin (Vtg) was measured in whole body
      homogenates. Native and SDS electrophoresis followed by Western blotting were
      performed for Vtg identification, and a non-competitive ELISA was developed. In
      the DES exposure groups (0.5 and 5 microg/l DES), Vtg appeared after 4 days,
      increased significantly after 8 days and reached a maximum on day 13. Further, a
      significant increase in the hepatosomatic index (HSI) was found in the 5 microg/l
      DES exposure group after 21 days. These results indicate that rare minnow
      provides a good model for assessing endocrine disruption by environmental
      estrogens.

PMID- 15171956
TI  - First-generation agents: aspirin, heparin and coumarins.
AB  - Aspirin, heparin and the coumarins are the classical anti-thrombotic agents. They
      represent the platform upon which newer drugs holding the promise of greater
      efficacy and less toxicity are being developed. Even as such newer drugs arrive
      into clinical practice, the older agents remain remarkable for their decades-long
      pre-eminence. All derive from natural sources, and none from a search for
      therapeutic anti-thrombotic agents; they have saved countless lives but also
      served as essential probes into basic mechanisms of thrombosis. Testament to
      their clinical importance is that these agents are the only drugs profiled on a
      regular basis in special scientific statements by the American Heart
      Association/American College of Cardiology and by the American College of Chest
      Physicians. This chapter reviews their biology, uses and limitations.

PMID- 15171957
TI  - Platelet ADP receptor antagonists: ticlopidine and clopidogrel.
AB  - The central role of platelets in the pathophysiology of arterial vascular disease
      has focused attention on the development of effective platelet inhibitor
      modalities to mitigate the clinical consequences of atherothrombotic disease.
      Aspirin has been the gold standard of therapy and is effective in cerebral,
      coronary and peripheral arterial disease with a 25% reduction in myocardial
      infarction, stroke and vascular death. The platelet ADP receptor antagonists were
      developed to further improve the clinical results of therapy. Ticlopidine
      provides an additional 10% relative risk reduction over aspirin alone in stroke
      prevention and coronary stent placement. However, ticlopidine is accompanied by
      occasional life-threatening adverse hematological events. The action of
      clopidogrel is similar to that of ticlopidine, and it is comparably effective.
      However, the side-effect profile of clopidogrel is much more favorable.

PMID- 15171959
TI  - Low- and ultra-low-molecular-weight heparins.
AB  - Heparins and low-molecular-weight heparins (LMWHs) have been the mainstay for the
      prevention and management of venous and arterial thromboembolic disease. In
      particular, the LMWHs have become well established in the past 15 years for the
      prevention of thrombosis in medium- and high-risk surgical and medical patients
      and in the initial management of venous thromboembolism (VTE). They have also
      been widely evaluated and adopted in clinical practice in the management of
      patients with acute coronary syndromes. More recently, a variety of heparin-like
      drugs have been evaluated as potential antithrombotic agents, and the synthetic
      pentasaccharide (fondaparinux) has been developed and evaluated for the
      prevention and treatment of VTE.

PMID- 15171958
TI  - Platelet glycoprotein IIb/IIIa inhibitors.
AB  - Glycoprotein (GP) IIb/IIIa inhibitors including abciximab, eptifibatide and
      tirofiban have been studied extensively as short-term adjuncts to short-term
      heparin and indefinite aspirin in patients with acute coronary syndrome or
      undergoing percutaneous coronary interventions on native vessels. The drugs
      provide a small advantage in the composite endpoint of death, myocardial
      infarction, and need for revascularization at 30 days (1-2% of treated patients)
      at the expense of an increase in major and potentially fatal bleeding
      complications (1% of treated patients over heparin plus aspirin alone). Highest
      risk patients appear to benefit the most; clopidogrel should also be considered
      in these patients. Patients undergoing percutaneous interventions on bypass
      grafts do not benefit. Whether one GP IIb/IIIa inhibitor is superior to another
      is incompletely clarified. Abciximab causes severe immune-mediated
      thrombocytopenia (<20,000/microl) in 0.7% of cases; this is more often than
      eptifibatide or tirofiban (0.2%). Pseudothrombocytopenia should be
      differentiated. Effective use of GP IIb/IIIa inhibitors for acute coronary
      syndrome and percutaneous coronary interventions requires discerning clinical
      judgment. The value of GP IIb/IIIa inhibitors is not established in other forms
      of vascular disease.

PMID- 15171960
TI  - Fondaparinux: a new synthetic and selective inhibitor of Factor Xa.
AB  - Fondaparinux (Arixtra) is the first synthetic selective Factor Xa inhibitor. Its
      efficacy and safety in the prevention of venous thromboembolism (VTE) was first
      studied in patients undergoing major orthopedic surgery, a setting in the highest
      risk category for postoperative thrombotic complications. Low-molecular-weight
      heparins are frequently used in this setting, but the rates of VTE still range
      between 15% and 33%. In large clinical trials, fondaparinux started 6 hours
      postoperatively was significantly more effective than enoxaparin in preventing
      VTE in patients undergoing total hip replacement, total knee replacement or hip
      fracture surgery. The benefit of extended fondaparinux prophylaxis after hip
      fracture surgery was also investigated. Other trials have demonstrated that
      fondaparinux is efficacious in the prevention of VTE in other patient populations
      at risk of thrombosis and in the treatment of symptomatic VTE.

PMID- 15171961
TI  - Bivalent direct thrombin inhibitors: hirudin and bivalirudin.
AB  - Hirudin derivatives (e.g. lepirudin, desirudin) and hirudin analogues (e.g.
      bivalirudin) are bivalent direct thrombin inhibitors; that is, they bind to two
      distinct sites on thrombin-its active (catalytic) site and its fibrinogen-binding
      site (exosite 1). These bivalent binding properties contribute to their high
      affinity and high specificity for thrombin. This review compares the
      pharmacological properties of these agents, and describes studies of their
      efficacy and safety in diverse clinical settings such as immune heparin-induced
      thrombocytopenia, postoperative antithrombotic prophylaxis, and treatment of
      acute coronary syndrome. Certain disadvantages of hirudin, such as its
      predominant renal excretion and immunogenicity, have been overcome through
      development of the hirudin analogue, bivalirudin. Compared with hirudin
      derivatives, bivalirudin exhibits a shorter half-life (25 vs 80 minutes),
      predominant non-renal (enzymic) metabolism, and low immunogenicity. Further work
      is required to define the scope of clinical thrombosis problems that could
      benefit from these novel agents.

PMID- 15171962
TI  - Small-molecule direct antithrombins: argatroban.
AB  - Argatroban represents the first antithrombin agent that was approved for clinical
      use. It belongs to the peptidomimetic (arginomimetic) group of drugs with
      multiple pharmacological properties. Unlike the other antithrombin drugs, such as
      hirudins and hirulogs, argatroban is a reversible antithrombin agent and
      therefore exhibits a considerably different pharmacological profile. Although
      argatroban is considered to be a member of the antithrombin family, its
      mechanisms of action include several other processes that have not been explored
      fully to date. These include the inhibition of non-thrombin serine proteases, a
      direct effect on endothelial cells and the vasculature (generation of nitric
      oxide), and downregulation of various inflammatory and thrombotic cytokines. Due
      to its lower molecular weight, argatroban is capable of passing through
      endovascular and cellular barriers and may, therefore, be more effective than
      heparins and hirudins in the antithrombotic management of microvascular
      disorders. Argatroban is an effective anticoagulant agent that produces a
      stronger anticoagulant effect than heparins and hirudins at equivalent
      anticoagulant levels, as measured by the activated clotting time (ACT) and
      activated partial thromboplastin time (APTT). At comparable ACT (300 seconds) and
      APTT (75-90 seconds), argatroban produces stronger inhibition of thrombin
      generation, as measured by in-vitro assays. Argatroban does not generate any
      neutralizing or non-neutralizing antibodies, and has predictable antithrombotic
      effects in different patients. In addition to the inhibition of thrombogenesis,
      argatroban also facilitates blood flow, inhibition of platelet activation and
      endothelial cell stimulation, mechanisms that are not necessarily related to
      thrombin inhibition. Despite these pharmacological advantages, additional
      clinical investigations are needed to validate the use of argatroban in clinical
      indications other than those for which it is currently approved, namely, heparin
      induced thrombocytopenia and support of percutaneous coronary angioplasty.

PMID- 15171963
TI  - Ximelagatran: a new oral anticoagulant.
AB  - Vitamin K antagonists are effective oral anticoagulants, but they have
      limitations related to a narrow therapeutic range, food and drug interactions,
      slow onset of action and the need for routine coagulation monitoring.
      Ximelagatran is a promising new oral anticoagulant under investigation in
      advanced clinical trials. It is a prodrug that is converted after oral
      administration to melagatran, a direct thrombin inhibitor, with a peak effect
      after 2 hours and a half-life of approximately 3 hours with primarily renal
      excretion. Administration results in prolongation of coagulation tests, but
      routine monitoring is not required because of reliable absorption and predictable
      effects. A large clinical trials program has demonstrated effectiveness in
      prophylaxis of deep vein thrombosis (DVT) following major orthopedic surgery,
      treatment of symptomatic DVT, prevention of embolism in patients with atrial
      fibrillation, and prophylaxis of recurrent events after acute myocardial
      infarction. Bleeding complications have been similar to those with standard
      therapy, with no unexpected adverse effects except for elevation of serum
      transaminase levels in over 6% of patients beginning after 1 month of therapy.
      Ximelagatran may be an alternative oral anticoagulant for patients currently
      taking vitamin K antagonists.

PMID- 15171964
TI  - Oral delivery of heparin: SNAC and related formulations.
AB  - Unfractionated heparin is one of the most commonly used pharmacological agents in
      hospital practice. The use of this agent is inconvenient in that it must be given
      parenterally. Current research is directed at development of oral antithrombotic
      agents that will not require laboratory monitoring of the antithrombotic effect.
      This has stimulated interest in the development of orally active heparin and low
      molecular-weight heparin. It has recently been shown that the addition of SNAC
      [sodium N-(8-(2-hydroxybenzoyl)amino)caprylate] to heparin enables absorption of
      therapeutic levels of heparin. Studies to date have shown that oral heparin-SNAC
      is an effective agent for the prevention of venous thromboembolism following
      total hip replacement, and this should stimulate further studies with this agent.

PMID- 15171965
TI  - Natural anticoagulant inhibitors: activated Protein C.
AB  - Protein C is a vitamin-K-dependent zymogen, whose congenital deficiency state
      leads to increased risk for venous thrombosis. Activated Protein C (aPC) exerts
      its anticoagulant function by inhibiting the cofactors in the clotting cascade,
      Factors Va and VIIIa. In addition, aPC displays anti-inflammatory, anti-apoptotic
      and profibrinolytic activities. A recombinant form of human aPC (rhAPC) is the
      first drug reported to improve survival in patients with severe sepsis. The major
      toxicity associated with treatment is bleeding. Appropriate use of rhAPC depends
      on an understanding of its mechanisms of action and risk:benefit profile. The
      goals of this review are: to describe the Protein C pathway; to discuss the
      definitions, epidemiology and pathophysiology of severe sepsis; to provide a
      conceptual framework for understanding the role of rhAPC in this syndrome; and to
      address frequently asked questions about the day-to-day use of this agent.

PMID- 15171966
TI  - Antidotes to haemorrhage: recombinant factor VIIa.
AB  - Recombinant Factor VIIa (rFVIIa) concentrates were originally developed to treat
      the refractory bleeding complications associated with allo-antibody inhibitors in
      hemophilias A and B. As experience was gained in the hemophilias, the physiology
      of rFVIIa and its successes in controlling bleeds stimulated rFVIIa use in other
      challenging medical conditions complicated by bleeding. Thus, rFVIIa has assumed
      the role of a 'universal pancoagulant' without sufficient evidence-based data
      from well-designed, adequately powered clinical trials. This chapter discusses
      the anecdotal experience with rFVIIa based upon the few controlled trials that do
      exist, and emphasizes that these empirical dosing strategies have not yielded the
      best approach to achieve effective control of bleeding. Evidence-based data are
      necessary to establish the cost-benefit and risk-benefit profiles of rFVIIa, and
      to establish it as a standard treatment for bleeding.

PMID- 15171967
TI  - Surveillance and follow-up in cancer care: meaning and purpose.

PMID- 15171968
TI  - Nurse-led follow-up on demand or by a physician after breast cancer surgery: a
      randomised study.
AB  - The value of routine follow-up with frequent visits to a breast cancer specialist
      both in terms of detection of recurrence and patient satisfaction-has been
      questioned. The aim of this study was to compare nurse-led follow-up on demand
      versus physician follow-up after breast cancer treatment with regards to
      patients' well-being, satisfaction, access to medical care and medical safety.
      Two hundred and sixty-four consecutively selected women with newly diagnosed
      breast cancer, classified as UICC stage I or stage II, were randomised to follow
      up at two hospitals in Sweden, either by routine medical follow-up, the physician
      group (PG, n=131), or on demand by a specialist nurse, the nurse group (NG,
      n=133). Measures were done at baseline and twice a year over a period of 5 years
      by means of a questionnaire containing the Hospital Anxiety and Depression Scale
      (HAD), and the Satisfaction and Accessibility (SaaC) scale. Number of contacts
      with the health care services, number of diagnostic procedures, and time to
      recurrence or death were monitored. The ratings of HAD and SaaC did not show any
      statistically significant differences between the groups. The levels of anxiety
      and depression were generally low and levels of patient satisfaction high. There
      were no differences between the groups concerning time to recurrence or death.
      This study indicates that women with breast cancer in stages I to II can be
      followed up by a specialist nurse with high patient satisfaction and good medical
      safety.

PMID- 15171971
TI  - A multicentre study to determine the efficacy and patient acceptability of the
      Paxman Scalp Cooler to prevent hair loss in patients receiving chemotherapy.
AB  - Alopecia is a distressing and common side-effect of chemotherapy, especially
      anthracycline- and taxane-containing regimen. A series of studies and reviews
      have considered scalp cooling as a means of reducing this side-effect without a
      definitive result. The aim of the study was to determine the efficacy and patient
      acceptability of scalp cooling using the Paxman Scalp Cooler. This was an open,
      non-randomised, observational study conducted at eight sites involving 94
      patients. Alopecia was assessed using the World Health Organisation (WHO) grading
      system. Patient acceptability was assessed by questionnaire. Results were
      compiled by Scalp Cooling Assessment Groups using data from eight centres in the
      UK collected between 1997 and 2000. Use of the Paxman Scalp Cooler was adjudged a
      success for 89% of all patients using the WHO grading system for alopecia and for
      87% of patients being specifically administered the commonly used 5-fluorouracil,
      epirubicin and cyclophosphamide (FEC) regimen. When asked about degrees of
      comfort during the scalp-cooling process, 85% of patients described it as very
      comfortable, reasonably comfortable or comfortable, with only 15% of patients
      reporting a description of uncomfortable or very uncomfortable. Scalp cooling
      using the Paxman Scalp Cooler was found to be an effective technique with minimal
      side-effects for patients treated with commonly prescribed alopecia-inducing
      chemotherapy drugs.

PMID- 15171972
TI  - Social support as experienced by Chinese and Israeli husbands of women with
      breast cancer: a comparative study.
AB  - The purpose of this research was to compare the experience of social support of
      Israeli and Chinese husbands of women with breast cancer. Social support was
      examined from three different sources: wives, friends and family, and the
      healthcare team. This study is part of a larger descriptive comparative study
      investigating the husbands' adjustment to their wives' diagnosis of cancer. A
      convenience sample of 50 husbands from each cultural framework was selected.
      Support from family and friends and the healthcare team was measured by items
      from the Social Support Questionnaire (SSQ), the Psychosocial Adjustment to
      Illness Scales (PAIS) and questions developed by the authors. Israeli husbands
      reported significantly higher levels of support in all three areas. Chinese
      husbands were significantly more interested in joining a support group. The
      results of this study show that culture has an impact on spousal responses to
      their wives' illness. In developing appropriate breast cancer nursing, nurses
      need to practice sensitivity and awareness of the cultural differences in order
      to provide culturally sensitive family oriented nursing care. This study is an
      ongoing effort of collaboration between nursing professionals from the far east
      and the middle east.

PMID- 15171973
TI  - Evaluation of educational programmes for paediatric cancer nursing in England.
AB  - The results of part of a larger study to evaluate educational provision for
      paediatric oncology and palliative care nursing in England are presented here.
      Mapping of cancer care provision, based upon the English National Board 240
      programme, was undertaken by analysis of relevant curriculum documents.
      Prescribed programme outcomes were reviewed against expected course outcomes
      proposed by the European Oncology Nursing Society. Particular attention was also
      paid to expected processes of assessment of clinical practice, consideration of
      adolescent patients, and opportunities for shared learning. Widespread compliance
      with the European Oncology Nursing Society standard was found, with only two of
      the 19 areas substantially neglected. These related to the prevention and early
      detection of cancer (less relevant in paediatric cancer than for adults), and
      understanding the principles of cancer clinical trials (probably due to lack of
      explicit statement in curriculum documents rather than actual failure to address
      the topic). A range of prescribed assessment practices were noted, but the degree
      to which direct observation was involved was variable, and indirect measures
      appeared to predominate. There was little specific recognition of adolescence as
      a discrete topic to be addressed in the programmes. Shared learning tended to be
      introduced for logistical reasons of small class numbers rather than for any
      perceived intrinsic value.

PMID- 15171974
TI  - Cancer care in Denmark.

PMID- 15171976
TI  - Fifteen years medical information sciences: the Amsterdam curriculum.
AB  - OBJECTIVES: To inform the medical informatics community on the rational, goals,
      evolution and present contents of the Medical Information Sciences program of the
      University of Amsterdam and our achievements. METHODS: We elaborate on the
      history of our program, the philosophy, contents and organizational structure of
      the present-day curriculum. Besides, we describe the various didactic approaches
      in the program and the rational for these. Finally, we analyze the contents of
      our program in respect to the IMIA recommendations for dedicated programs in
      health and medical informatics. RESULTS AND CONCLUSIONS: Since its foundation in
      1987, the program has undergone several major modifications. From a degree
      program following medical school it developed into a full-fledged, dedicated 4
      year program on medical information sciences training high-school graduates for a
      master degree. The curriculum has been based from its outset within the
      University of Amsterdam-Faculty of Medicine. This organizational structure leaves
      ample opportunity for integration of the informatics-oriented components with the
      medical and health care-oriented components in the program. Student-centered
      approaches are heavily employed in the program, emphasizing students' critical
      appraisal and a style of life-long learning. Overall, our program follows the
      IMIA recommendations with slightly more focus on medicine and health care
      organization.

PMID- 15171977
TI  - Visions and strategies to improve evaluation of health information systems.
      Reflections and lessons based on the HIS-EVAL workshop in Innsbruck.
AB  - BACKGROUND: Health care is entering the Information Society. It is evident that
      the use of modern information and communication technology offers tremendous
      opportunities to improve health care. However, there are also hazards associated
      with information technology in health care. Evaluation is a means to assess the
      quality, value, effects and impacts of information technology and applications in
      the health care environment, to improve health information applications and to
      enable the emergence of an evidence-based health informatics profession and
      practice. OBJECTIVE: In order to identify and address the frequent problems of
      getting evaluation understood and recognised, to promote transdisciplinary
      exchange within evaluation research, and to promote European cooperation, the
      Exploratory Workshop on "New Approaches to the Systematic Evaluation of Health
      Information Systems" (HIS-EVAL) was organized by the University for Health
      Sciences, Medical Informatics and Technology (UMIT), Innsbruck, Austria, in April
      2003 with sponsorship from the European Science Foundation (ESF). METHODS: The
      overall program was structured in three main parts: (a). discussion of problems
      and barriers to evaluation; (b). defining our visions and strategies with regard
      to evaluation of health information systems; and (c). organizing short-term and
      long-term activities to reach those visions and strategies. RESULTS: The workshop
      participants agreed on the Declaration of Innsbruck (see ), comprising four
      observations and 12 recommendations with regard to evaluation of health
      information systems. Future activities comprise European networking as well as
      the development of guidelines and standards for evaluation studies. CONCLUSION:
      The HIS-EVAL workshop was intended to be the starting point for setting up a
      network of European scientists working on evaluation of health information
      systems, to obtain synergy effects by combining the research traditions from
      different evaluation fields, leading to a new dimension and collaboration on
      further research on information systems' evaluation.

PMID- 15171978
TI  - Enterprise resource planning for hospitals.
AB  - Integrated hospitals need a central planning and control system to plan patients'
      processes and the required capacity. Given the changes in healthcare one can ask
      the question what type of information systems can best support these healthcare
      delivery organizations. We focus in this review on the potential of enterprise
      resource planning (ERP) systems for healthcare delivery organizations. First ERP
      systems are explained. An overview is then presented of the characteristics of
      the planning process in hospital environments. Problems with ERP that are due to
      the special characteristics of healthcare are presented. The situations in which
      ERP can or cannot be used are discussed. It is suggested to divide hospitals in a
      part that is concerned only with deterministic processes and a part that is
      concerned with non-deterministic processes. ERP can be very useful for planning
      and controlling the deterministic processes.

PMID- 15171979
TI  - Information literacy-what it is about? Literature review of the concept and the
      context.
AB  - OBJECTIVES: The use of IT in health care has merged advanced knowledge and skills
      for health care professionals. Former studies indicate that basic skills in
      computer use are no more than comprehensive competencies to manage electronically
      stored information in health care. The purpose of this paper is to review the
      literature focusing on the concept information literacy in the field of health,
      nursing and medical informatics. The target is to find out how information
      literacy is defined, in what kind of context it is presented and who are the
      focus of interest. METHODS: An automated literature search was performed on-line
      to Medline and by using the EndNote Bibliographic Software. All together the
      number of papers analyzed was 97 or 78% of the total literature search result.
      RESULTS: The survey indicates that the concept information literacy does not
      exist as such in the literature, but it can be found as a synonym to 'computer
      literacy' or even more obscure concepts such as 'informatics awareness' or
      'computer experience'. The definitions of these concepts varied considerably. A
      variety of descriptions of educational programs were also found, none were based
      on the IMIA recommendations. CONCLUSIONS: In international cooperation such as
      that of IMIA WG1, a wide range of efforts still needs to be carried out to
      compile educational programmes in health informatics to enhance knowledge and
      skills in computer use among health care professionals.

PMID- 15171980
TI  - Information content in Medline record fields.
AB  - BACKGROUND: The authors have been conducting text mining analyses (extraction of
      useful information from text) of Medline records, using Abstracts as the main
      data source. For literature-based discovery, and other text mining applications
      as well, all records in a discipline need to be evaluated for determining prior
      art. Many Medline records do not contain Abstracts, but typically contain Titles
      and Mesh terms. Substitution of these fields for Abstracts in the non-Abstract
      records would restore the missing literature to some degree. OBJECTIVES:
      Determine how well the information content of Title and Mesh fields approximates
      that of Abstracts in Medline records. APPROACH: Select historical Medline records
      related to Raynaud's Phenomenon that contain Abstracts. Determine the information
      content in the Abstract fields through text mining. Then, determine the
      information content in the Title fields, the Mesh fields, and the combined Title
      Mesh fields, and compare with the information content in the Abstracts. RESULTS:
      Four metrics were used to compare the information content related to Raynaud's
      Phenomenon in the different fields: total number of phrases; number of unique
      phrases; content of factors from factor analyses; content of clusters from multi
      link clustering. The Abstract field contains almost an order of magnitude more
      phrases than the other fields, and slightly more than an order of magnitude more
      unique phrases than the other fields. Each field used a factor matrix with 14
      factors, and the combination of all 56 factors for the four fields represented 27
      separate, but not unique, themes. These themes could be placed in two major
      categories, with two sub-categories per major category: Auto-immunity
      (antibodies, inflammation) and circulation (peripheral vessel circulation,
      coronary vessel circulation). All four sub-categories included representation
      from each field. Thus, while the focus of the representation of each field in
      each sub-category was moderately different, the four sub-category structure could
      be identified by analyzing the total factors in each field. In the cluster
      comparison phase of the study, the phrases used to create the clusters were the
      most important phrases identified for each factor. Thus, the factor matrix served
      as a filter for words used for clustering. While clusters were generated for all
      four fields, the Title hierarchy tended to be fragmented due to sparsity of the
      co-occurrence matrix that underlies the clusters. Therefore, the Title clusters
      were examined at only the lower levels of aggregation. The Abstract, Mesh, and
      Mesh + Title fields had the same first level taxonomy categories, auto-immunity
      and circulation. At the second level, the Abstract, Mesh, and Mesh + Title fields
      had the autoimmune diseases and antibodies sub-category in common. The Abstract
      and Mesh fields shared fascia inflammation as the other auto-immunity sub
      category, while the other Mesh + Title sub-category focuses on vinyl chloride
      poisoning from industrial contact, and consequences of antineoplastic agents.
      However, in both cases, even though the words may be different, inflammation may
      be the common theme. CONCLUSIONS: For taxonomy generation, especially at the
      higher levels, each of the four fields has a similar thematic structure. At very
      detailed levels, the Mesh and Title fields run out of phrases relative to the
      Abstract field. Therefore, selection of field (s) to be employed for taxonomy
      generation depends on the objectives of the study, particularly the level of
      categorization required for the taxonomy. For information retrieval, or
      literature-based discovery, selection of the appropriate field again depends on
      the study objectives. If large queries, or large numbers of concepts or themes
      are desired, then the field with the largest number of technical phrases would be
      desirable. If queries or concepts represented by the more accepted popular
      terminology is adequate, then the smaller fields may be sufficient. Because of
      its established and controlled vocabulary, the Mesh field lags the Title or Abss
      the Title or Abstract fields in currency. Thus, the Title or Abstract fields
      would retrieve records with the most explicitly stated current concepts, but the
      Mesh field would capture a larger swath of fields that contained a concept of
      interest but perhaps had a wider range of specific terminology in the Abstract or
      Title text. In addition, this study provides the first validated estimate of the
      disparity in information retrieved through text mining limited to Titles and Mesh
      terms relative to entire Abstracts. As much of the older biomedical literature
      was entered into electronic databases without associated Abstracts, literature
      based discovery exercises that search the older medical literature may miss a
      substantial proportion of relevant information. On the basis of this study, it
      may be estimated that up to a log order more information may be retrieved when
      complete Abstracts are searched.

PMID- 15171981
TI  - Technology assisted speech and language therapy.
AB  - Speech and language therapists (SLTs) are faced daily with a diversity of speech
      and language disabilities, which are associated with a variety of conditions
      ranging from client groups with overall cognitive deficits to those with more
      specific difficulties. It is desirable that those working with such a range of
      problems and with such a demanding workload, plan care efficiently. Therefore,
      the introduction of methodologies, reference models of work and tools, which
      significantly improve the effectiveness of therapy, are particularly welcome.
      This paper describes the first web-based tool for diagnosis, treatment and e
      Learning in the field of language and speech therapy. The system allows SLTs to
      find the optimum treatment for each patient, it also allows any non-specialist
      user-SLT, patient or helper (relative etc.)-to explore their creativity, by
      designing their own communication aid in an interactive manner, with the use of
      editors such as: configuration and vocabulary. The system has been tested and
      piloted by potential users in Greece and the UK.

PMID- 15171982
TI  - Physicians' perceptions towards the impact of and willingness to pay for clinical
      computerization in Hong Kong.
AB  - BACKGROUND AND OBJECTIVES: We evaluated factors associated with physicians'
      perceptions towards the effects of computers on health care and on current levels
      of computerization in their practice. We also performed a contingent valuation to
      quantify physicians' perceived benefits from computerization in a hypothetical
      ambulatory, solo clinic. METHODS: We surveyed 949 representative physicians in
      Hong Kong by post. Factor analysis was performed to summarize similar items into
      categories. Multivariable log-linear regression models were employed to assess
      the relationships between different factor scores and the number of functions
      computerized. We elicited their willingness-to-pay (WTP) for three defined
      computer systems using contingent valuation techniques. WTP values were estimated
      using econometric modeling by both, parametric and geometric methods.
      Sociodemographic, attitudinal, and practice-related predictors of WTP were
      estimated through regression analyses. RESULTS: Factor analysis revealed a three
      factor solution which explained 53% of total variance. The overall mean score
      (mean = 3.51 +/- 0.45) showed a generally positive attitude towards the effects
      of computers on health care. Respondents with a higher level of computer
      knowledge had significantly higher mean overall (P = 0.002) and factor scores for
      all three factors (P < 0.01). Higher factor scores on the effects of computers on
      patient care and clinicians (P = 0.006) and on the health system (P = 0.032) were
      associated with a higher number of functions computerized. The parametric median
      WTP values for computerizing administrative, clinical, and both sets of functions
      were HK dollars 21205 (US dollars 2719), HK dollars 34231 (US dollars 4389), and
      HK dollars 45720 (US dollars 5862), respectively, which were lower than the
      estimates obtained from demand curves using the geometric method [HK dollars
      43286 (US dollars 5549), HK dollars 59570 (US dollars 7637), and HK dollars 84623
      (US dollars 10849), respectively]. Doctors with higher incomes were willing to
      pay more to computerize the clinic, with strong dose-response gradients
      demonstrated. Those who worked in corporate settings were also more likely to
      accept higher WTP values. CONCLUSIONS: Our findings confirm that better knowledge
      about computers is contributory to a more positive attitude towards the effects
      of computers on health care, which is in turn significantly associated with
      higher levels of actual computerization in clinical practice. WTP values
      represent the likelihood, in monetary terms, of translating doctors' perceived
      benefits from computerization into investment action.

PMID- 15171983
TI  - Do doctors act on their self-reported intention to computerize? A follow-up
      population-based survey in Hong Kong.
AB  - BACKGROUND AND OBJECTIVES: We performed a follow-up survey to document changes in
      the level of computerization among physicians in Hong Kong between 2000 and 2001,
      specifically examining whether their self-reported intention to computerize
      various clinical or administrative tasks actually translated into computerization
      of these tasks 1 year later. Determining such a relationship will indicate the
      reliability, and thus the utility of questions regarding self-reported intention
      to computerize clinical practice. METHODS: A self-completed follow-up postal
      questionnaire was sent to all 949 physicians who responded to the original
      questionnaire. Pairwise repeated dichotomous responses from 2000 and 2001 on the
      computerization of specific functions were compared using McNemar test. Wilcoxon
      sign-ranked test was employed to compare the total number of tasks computerized
      in the 2 years. Multivariate logistic regression modeling was carried out to
      determine predictors for the translation of intention to computerize into actual
      computerization. RESULTS: The response rate was 77.0%. There was a significant
      increase in the number of tasks computerized for both "corporate" and
      "individual" practices between 2000 and 2001. The proportion of physicians who
      intended to computerize and actually computerized ranged from 7.7 to 51.0% for
      different tasks. For five clinical tasks, more than 50% respondents in corporate
      practices translated the intention to implementation, compared to fewer than 20%
      in individual practices. Predictors found to be associated with the translation
      of intention to computerize into actual computerization included higher number of
      tasks intended to computerize, higher number of tasks already computerized, and
      more positive physicians' attitudes on the impact of computerization to clinical
      practice. CONCLUSIONS: We conclude that physicians' self-reported intention to
      computerize the clinical practice 12 months previously was moderately associated
      with actual implementation, with varying degrees of concordance for different
      clinical and administrative tasks. The identified predictors for the translation
      of intention to actual computerization may be useful in targeting specific
      strategies to promote computerization of clinical practice.

PMID- 15171984
TI  - Clinicians' perceptions of clinical decision support integrated into computerized
      provider order entry.
AB  - Computerized provider order entry systems can improve patient care by integrating
      clinical decision support. Decision support is most effective when its content
      and delivery are acceptable. The authors report the results of a multifaceted
      survey of the attitudes of housestaff and medical student users of a provider
      order entry system with integrated decision support at an academic medical
      center. The survey contained 16 items covering four themes: efficiency, quality
      of care, results reporting and embedded guidelines. Responses were captured using
      a five point Likert scale, and were compared using ANOVA and Bartlett's testing.
      Out of 491 housestaff and 128 medical students, response rates were 47 and 29%,
      respectively. Among respondents, 72% agreed or strongly agreed that the provider
      order entry system improves the quality of care that they provide, 54% that the
      decision support usually help them to provide quality patient care, and 62% that
      it improves the efficiency of order entry. Respondents were least likely to agree
      that the display of prior laboratory results influenced their decision to order a
      subsequent test. There were no significant differences between subspecialties and
      by advancing years of training among housestaff. Respondents agreed that the
      integrated clinical decision support enhanced their medical training.

PMID- 15171985
TI  - Developing a large electronic primary care database (Doctors' Independent
      Network) for research.
AB  - BACKGROUND AND OBJECTIVES: Primary care databases form a unique source of
      population-based clinical information on the prevalence and management of
      diagnosed disorders. Historically such databases have lacked individual level
      socio-economic markers. We describe the development of the Doctors' Independent
      Network (DIN) database for epidemiological and health services research. DIN
      includes a socio-economic marker (ACORN) based on postcode linkage at individual
      patient level. The validity of DIN is assessed against the General Practice
      Research Database (GPRD). METHODS: External validity is assessed by comparing the
      demographic structure and prevalence rates for treated ischemic heart disease
      (IHD) and treated hay fever with those from the GPRD. We assess the utility of a
      socio-economic measure (ACORN) based on postcode-linkage at individual patient
      level by examining the trend in prevalence rates of IHD and hay fever by ACORN
      index. RESULTS: 142 practices providing high quality data were selected, with
      1827361 fully registered patients contributing data between 1992 and 2001,
      representing an identical age-sex structure to that for England & Wales and GPRD.
      Regionally adjusted prevalence of treated IHD (7.29 and 5.37%, respectively for
      men and women aged 35+ in 1998) in DIN was highly comparable to GPRD (7.27 and
      5.42%). In DIN, the odds ratio of IHD was 1.37 (95% CI 1.30-1.44) in subjects
      living in "striving" compared to "thriving" areas. The prevalence of treated hay
      fever prevalence was similar across databases, with inverse associations seen
      with ACORN in DIN (higher rates in "thriving" areas). CONCLUSIONS: DIN provides
      comparable period prevalence rates to GPRD for two common conditions, with social
      trends as expected. Primary care databases such as these have the potential to
      replace the decennial national morbidity surveys carried out in UK general
      practices, with DIN having the important advantage of including a socio-economic
      index.

PMID- 15171986
TI  - Computerized antimicrobial decision support: an offline evaluation of a database
      driven empiric antimicrobial guidance program in hospitalized patients with a
      bloodstream infection.
AB  - INTRODUCTION: We developed a computerized antimicrobial guidance program based on
      the last 5 years of our laboratory culture data augmented by expert infectious
      disease logic. The program is designed to assist physicians with the targeting of
      empiric antimicrobials for hospitalized patients by tracking pathogenic bacteria
      and their evolving antimicrobial resistance profiles. Costs, toxicities, and
      environmental impact of antimicrobial use also influence the final
      recommendations. We undertook the following analysis to verify its potential
      safety and efficacy in hospitalized patients with a bloodstream infection.
      METHODS: We retrospectively enrolled all inpatients with a positive blood culture
      for a previously undetermined pathogen during the first 6 months of 2002 and
      determined the empiric therapy initiated within the 12h before and after the time
      of culture. Antimicrobial recommendations from the microbiologic decision support
      tool were then determined by matching specimen (blood), hospital unit, community-
      versus hospital-acquired category, age category, and gender. Generated
      antimicrobial recommendations were tailored to patient allergies, age category,
      and presence of pregnancy, lactation, or hepatic impairment. RESULTS: The
      microbiology laboratory recorded 226 unique patient/pathogen blood cultures
      during the study period. Physicians initiated effective empiric therapy in 150 of
      the 226 cases, for an effectiveness rate of 66%. The computer-guided therapy was
      effective in 195 of the 226 cases for a rate of 86%. A contingency table analysis
      showed 55 cases where the computer recommendation was effective but the
      physicians' selection was not, and eight cases where the physicians'
      antimicrobials were effective but the computer's were not (P < 0.0001).
      DISCUSSION: For patients with a bloodstream infection, we found that our computer
      guided statistically-derived antimicrobial therapy would potentially improve the
      rate of effectiveness of empirically chosen antimicrobials.

PMID- 15171987
TI  - Mobile decision support for transplantation patient data.
AB  - In high-critical medical fields instant information delivery is essential. Task
      flow analyses within the transplantation unit of the Technische Universitat
      Munchen revealed that valuable time could be saved in pre-transplantation
      management being able to retrieve data of organ receivers ubiquitously. Inspired
      by this clinical scenario, a mobile application was designed and implemented
      providing surgeons with decision-relevant information on potential organ
      receivers. It assists them in considering the prospects of forthcoming organ
      transplantations and facilitates decision making and documentation with regard to
      high security demands. The described system services three organ receiver lists
      and is used by the surgeons in every transplantation procedure. After a 6-month
      period of clinical usage, the system has been evaluated in terms of handling,
      clinical benefit and total time savings. Intuitive, ubiquitous access to decision
      relevant patient data and authenticated documentation were the major improvements
      with average total time savings of 50 min in comparison to the old system.

PMID- 15171988
TI  - The use of proliferating cell nuclear antigen immunohistochemistry with a unique
      functional marker to detect postnatal neurogenesis in paraffin-embedded sections
      of the mature pig brain.
AB  - Until recently, evidence supporting postnatal neurogenesis was controversial.
      Much of the debate has centered on the identification of the dividing cells as
      neurons versus glia. Because neurogenesis has become a well-documented
      phenomenon, there is a need for reliable protocols to identify recently divided
      neurons in a wide range of situations. To facilitate the investigation of
      postnatal neurogenesis of magnocellular neurons in the pig hypothalamus, a
      sequential immunohistochemical staining technique was developed for use on serial
      sections of paraffin-embedded tissue. Proliferating neurons were labeled using
      mouse-derived monoclonal antibodies to detect proliferating cell nuclear antigen
      (PCNA) and vasopressin (VP). PCNA, a nuclear protein essential for cell division,
      identifies recently divided cells in the brains of healthy animals. VP is a
      unique functional marker for a mature neuron. The presence of a cell with VP
      positive cytoplasm and a PCNA positive nucleus demonstrates the presence of a VP
      producing neuron that has recently divided. This protocol allowed us to safely
      and accurately label recently proliferated neurons in the mature pig hypothalamus
      and can be used on archived tissue. This data can be used for further
      morphometric analysis, as serial sectioning allows for three-dimensional
      reconstruction of hypothalamic nuclei.

PMID- 15171989
TI  - A reproducible experimental model of focal cerebral ischemia in the neonatal rat.
AB  - Recent data suggest that the incidence of focal cerebral ischemia (FCI) and
      stroke is higher than previously recognized and could account for a large
      proportion of brain lesions in the preterm and full term neonate. Therefore, it
      is critically important to develop an appropriate model of FCI in neonatal
      animals. We describe here a modified model of permanent FCI in rat pups at
      postnatal day-7 (P7). To produce permanent FCI, a suture embolus with different
      diameters (180-220 microm) was inserted into the left common carotid artery (CCA)
      of the pups with different weight (14-19 g). Then the suture embolus was advanced
      to the middle cerebral artery (MCA) to produce its occlusion. The success of
      vascular occlusion was evaluated by imaging the ischemic territory on serial
      brain sections with carbon black staining immediately after permanent FCI. The
      consistent cerebral infarction was confirmed by 2,3,5-triphenyltetrazolium
      chloride (TTC) staining 24 h after permanent FCI. Terminal
      deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphospate-biotin nick
      end labeling (TUNEL) staining showed cell death with TUNEL labeling in the
      ischemic areas, which is one of the features of apoptosis. The present model
      opens the way for advanced pathophysiological studies of FCI in neonates.

PMID- 15171990
TI  - Measuring membrane potential and electric field of brainstem neurons in vitro by
      confocal microscopy.
AB  - A method of measuring transmembrane potential and electric field of neural cells
      cultured in vitro is described in this paper. The high resolution and scanning
      speed of the method make it considerable to be used to observe the viability of
      the neurons cultured on opaque substrate. Rhodamine 123 was used to stain the
      cells in order to display different intensity corresponding to transmembrane
      potential. The fluorescence data were collected by confocal laser scanning
      microscopy (CLSM). Then the data were processed to create the graphs of
      transmembrane potential and electric field. This is the first paper describes a
      reliable method for three-dimensional visualization of potential voltage of
      neurons at the best of our knowledge.

PMID- 15171991
TI  - A procedure to label inner ear afferent nerve endings for calcium imaging.
AB  - Characterization of synaptic transmission between the inner ear sensory cells and
      primary neuron dendrites has been hampered by the limited access to the
      postsynaptic terminals. Because direct physiological recording of postsynaptic
      currents are difficult to achieve, no information regarding the synaptic and
      dendritic events are available. This is due to the small size of the postsynaptic
      afferent nerve endings that do not allow a clear identification, and thus
      compromise direct electrophysiological recordings of the buttons. To study the
      physiology of afferent nerve endings, we have developed a two-photon imaging
      technique in cochlear and vestibular slice preparations from neonatal rats and
      turtles. This technique is based on a retrograde labeling of afferent nerve
      endings with high-affinity calcium-sensitive dyes. Dye filling was achieved by 6
      h application of the dextran-amine conjugate of calcium green-1. Calcium changes
      were measured in afferent nerve endings in line scan and time lap mode. To
      address recording in a near-physiological situation, iontophoretic application of
      K+ was performed in the area of the stereocilia whereas glutamate was applied at
      the basal pole of sensory hair cells. Both types of application cause a
      reversible and sustained increase of Ca2+ in the button of afferent nerve fibers.
      Typical recordings are presented and potential interests for pharmacological
      studies of inner ear sensory cell synapses are discussed.

PMID- 15171992
TI  - A combined in situ hybridization and RT-PCR method to detect spatial and temporal
      patterns of Noggin gene expression in embryonic and postnatal rat hippocampus.
AB  - Recent studies indicate that Noggin not only plays an important role in the early
      development of the nervous system, but may also plays a role in postnatal central
      nervous system (CNS) development. In this study, we examined the relative levels
      and localization of Noggin mRNA in the hippocampus of rats of different
      developmental stages with reverse transcriptase-polymerase chain reaction (RT
      PCR) and in situ hybridization. RT-PCR showed that the peak level of expression
      of Noggin mRNA was observed at embryonic day 13 (E13), subsequently gradually
      declined at 1-3 months (P1-3M) postnatal, and was detected only at a low level at
      P18M. In situ hybridization revealed that at embryonic stages, Noggin mRNA was
      localized throughout all hippocampal regions, whereas at early postnatal ages,
      Noggin mRNA was primarily localized in the anterior subiculum. At later postnatal
      ages, Noggin mRNA expression was obviously observed in the dentate gyrus and in
      the CA1-CA3 pyramidal cell layers. Taken together, our results demonstrate that
      Noggin is expressed in embryonic and postnatal hippocampus, and that the temporal
      and spatial patterns of its expression is developmentally regulated.

PMID- 15171993
TI  - The anterograde and retrograde axonal transport of biotinylated dextran amine and
      biocytin in the nervous system of teleosts.
AB  - Biotinylated dextran amine (BDA) and biocytin are well transported both
      retrogradely and anterogradely. Both tracers have stable molecular structure for
      long-term storage and examination, and their visualizations can be realized by
      simple histochemical reactions. Therefore, the BDA and biocytin are widely used
      in neuroanatomical studies as the tract-tracing markers. The results obtained by
      BDA and biocytin applications to various areas of the nervous system in teleosts
      were qualitatively identical, and the retrogradely and anterogradely labeled
      structures could be clearly identified with reference to the counter-staining.
      Iontophoretic injections or crystal insertions resulted in filling of cell
      bodies, dendrites and terminals in the core of injection side, revealing
      morphological details of the local and distant somata, dendritic arborizations
      and axonal terminals. However, biocytin exhibited superior to BDA in anterograde
      transport, and could label very thin axons, axonal collaterals and terminal
      ramifications. In contrast, retrograde transport of BDA was superior to that of
      biocytin, and resulted in more complete dendritic filling of retrograde labeled
      neurons including dendritic arborizations and spines.

PMID- 15171994
TI  - Long double-stranded RNA-mediated RNA interference as a tool to achieve site
      specific silencing of hypothalamic neuropeptides.
AB  - RNA interference (RNAi) has become a popular tool to silence gene expression in a
      variety of in vitro and in vivo systems. However, it has met with limited success
      in inhibiting gene expression in adult mammals. Here we demonstrate that long
      double-stranded RNA (dsRNA) can be used to create a "site-specific", transient
      knockdown of genes in a fashion that is phenotypically akin to genetically
      manipulated organisms. Corticotropin-releasing factor (CRF) and arginine
      vasopressin (AVP) that regulate a variety of physiological processes including
      the hypothalamic-pituitary-adrenal axis (HPA axis), energy and water homeostasis
      were used as model systems. Stereotaxic injections of dsRNA against CRF and AVP
      in the PVN specifically abolished the expression of these genes in the PVN
      leaving expression in other loci intact. Control dsRNA did not affect CRF or AVP
      expression in any brain region, suggesting that dsRNA did not shut down global
      protein synthesis. ANOVA showed significant main effects of silencing of CRF on
      dampening of the stress-activated release of adrenocorticotrophin hormone (ACTH)
      (F(2,7)=4.87; p<0.047). Silencing of AVP resulted in increased water consumption,
      increased urine output and decreased urine osmolality as compared to control
      dsRNA-treated rats. Furthermore, dsRNA had no obvious deleterious effects on body
      weight or food consumption, variables considered essential in ruling out adverse
      physiologic effects in animal models. Thus, using long dsRNA, we were able to
      ascertain site-specific roles of CRF and AVP in adult rats without any
      developmental compensation and in a wild-type background.

PMID- 15171995
TI  - An in vivo method for recording single unit activity in lumbar spinal cord in
      mice anesthetized with a volatile anesthetic.
AB  - We describe a method to record single unit neuronal activity from mouse spinal
      cord using volatile anesthesia. The small size of the mouse can complicate usual
      methods that are used for single-unit recording in rats, but simple modifications
      can significantly increase the number of successful recordings. Stabilization of
      the vertebral column is particularly important, as are adequate ventilation of
      the animal, control of body temperature and accurate determination of anesthetic
      concentrations in respiratory gas samples.

PMID- 15171996
TI  - Salla disease and ISSD--what does the future hold?

PMID- 15171997
TI  - The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine
      hydroxylase deficiency.
AB  - About two-thirds of all mild phenylketonuria (PKU) patients are
      tetrahydrobiopterin (BH4)-responsive and thus can be potentially treated with BH4
      instead of a low-phenylalanine diet. Although there has been an increase in the
      amount of information relating to the diagnosis and treatment of this new variant
      of PKU, very little is know about the mechanisms of BH4-responsiveness. This
      review will focus on laboratory investigations and possible molecular and
      structural mechanisms involved in this process.

PMID- 15171998
TI  - Rapid, comprehensive screening of the human medium chain acyl-CoA dehydrogenase
      gene.
AB  - Newborn screening by tandem mass spectrometry (MS/MS) identifies patients with
      medium chain acyl-CoA dehydrogenase (MCAD) deficiency the most frequently
      observed disorder of fatty acid oxidation. Molecular genetic analysis is becoming
      a common tool to confirm those identified as affected by prospective screening
      and for carrier detection in family studies. The A985G (K304E) mutation accounts
      for approximately 80% of mutant alleles in MCAD deficient patients, presenting
      symptomatically, while greater variability of mutant alleles is observed among
      cases identified through prospective screening. Aside from A985G, the mutation
      spectrum in MCAD deficient patients is heterogeneous such that comprehensive gene
      analysis is required. Traditionally the MCAD gene is assayed by sequencing the
      entire coding region. Although effective and definitive, this approach is
      expensive, turn around time is slow, and is poorly amenable to a clinical service
      molecular genetics laboratory. Dye-binding/high-resolution thermal denaturation
      is a rapid and homogeneous method by which to scan a PCR product for evidence of
      sequence aberration. PCR is performed in capillaries in the presence of the dsDNA
      binding dye LCGreen I and subsequently the DNA/dye complexes are analyzed by high
      resolution thermal denaturation. DNA sequencing was limited to fragments
      displaying abnormal melting profiles. Of 18 specimens analyzed, 11 have a
      genotype consistent with MCAD deficiency and seven have a genotype consistent
      with carrier status. Clinical and biochemical data corroborate that the genotype
      results identified the affected patients and differentiates them from carriers.
      The entire process is homogeneous requiring no post-PCR manipulation and is
      completed in under 3 h.

PMID- 15171999
TI  - Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD)
      mutation IVS3-1G > C that leads to introduction of a premature termination codon
      by complete missplicing of the MCAD mRNA and is associated with phenotypic
      diversity ranging from sudden neonatal death to asymptomatic status.
AB  - Virtually all patients with medium-chain acyl-CoA dehydrogenase deficiency
      (MCADD) are homozygous or compound heterozygous for the 985A > G mutation, which
      limits the study of a possible genotype/phenotype correlation. A newborn
      Palestinian infant died suddenly on the second day of life. A previous sibling
      had also died in similar circumstances aged 3 weeks. Urine organic acid and
      bloodspot acylcarnitine analysis were consistent with MCADD. He was homozygous
      for a novel MCAD splice mutation, IVS3-1G > C. This mutation leads to deletion of
      7 bp and introduction of a premature termination codon as a result of complete
      missplicing of MCAD mRNA. This misspliced MCAD mRNA encodes a non-functional
      protein and is furthermore reduced in amounts due to nonsense-mediated decay,
      resulting in total lack of functional MCAD enzyme. This is the first molecular
      identification of MCADD in an Arab patient and the first reported splice mutation
      in the MCAD gene that has been functionally characterized. The association of
      homozygosity for a null mutation with lethal neonatal presentation in the index
      patient and presumably the previous infant suggested a genotype/phenotype
      correlation. However, a 6-year-old completely asymptomatic sibling also had the
      characteristic MCADD biochemical phenotype and was homozygous for the same IVS3
      1G > C mutation. As a first candidate to modify the disease presentation, by
      modulating the overlapping enzyme activity, we tested the entire family for the
      prevalent SCAD gene 625G > A susceptibility variant. Interestingly, all family
      members were 625G > A homozygous. Additional genetic and/or environmental factors
      must play a major role in determining the phenotypic diversity of MCADD.

PMID- 15172000
TI  - Extended [13C]galactose oxidation studies in patients with galactosemia.
AB  - Since patients with galactose-1-phosphate uridyltransferase (GALT) deficiency
      have considerable endogenous galactose formation and only limited urinary
      excretion of galactose metabolites, there must be mechanisms for disposal of the
      sugar. Otherwise, a steady-state could not be maintained and there would be
      continuous body accumulation of galactose and alternate pathway products.
      Previous studies quantitating the amount of galactose handled by oxidation to CO2
      focused on short collection periods of expired air after administering
      isotopically labeled galactose mainly designed for discerning differences in the
      capacity to oxidize the sugar in relation to genotype. Assuming that there may be
      more extensive oxidation than that observed in short-term studies in order to
      dispose the daily galactose burden, we have examined the amount of [1
      13C]galactose oxidized to 13CO2 over a 24-h period after either a single bolus or
      continuous IV administration by 11 patients with classic galactosemia including
      patients homozygous for the Q188R gene mutation. As much as 58% of the
      administered galactose was oxidized to 13CO2 in 24 h. The pathways involved
      remain to be determined but a significant amount may be metabolized by non-GALT
      pathways since a patient homozygous for gene deletion had an oxidative
      capability. We conclude that classic patients have the ability to slowly oxidize
      galactose to CO2 in 24 h in amounts comparable to that which a normal handles in
      approximately one-fifth the time. This capacity enables the galactosemic to
      maintain a balance of galactose disposal with the galactose burden imposed by
      endogenous formation and dietary intake.

PMID- 15172001
TI  - Clinical, biochemical, and molecular diagnosis of a free sialic acid storage
      disease patient of moderate severity.
AB  - The allelic autosomal recessive lysosomal storage disorders Salla disease and
      infantile free sialic acid storage disease (ISSD) result from mutations in
      SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports
      the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. ISSD
      has a severe phenotype with infantile onset, while the Finnish variant, Salla
      disease, has a milder phenotype with later onset. Both disorders cause
      developmental delay, and ISSD is generally fatal in early childhood. We describe
      a 30-month old non-Finnish, Caucasian child with global developmental delay of
      postnatal onset, language, and motor skills stagnant at a 3-4 month level,
      hypotonia, and mild but progressive coarsening of facial features. Urinary
      excretion of free sialic acid was elevated 4.5 times above control. EM of a skin
      biopsy revealed enlarged secondary lysosomes consistent with oligosaccharide
      storage. Free sialic acid in fibroblasts was 3.8+/-0.9 nmol/mg protein
      (concurrent normal controls, 0.5+/-0.1); differential centrifugation indicated a
      lysosomal location. Genomic analysis revealed compound heterozygosity for two new
      SLC17A5 mutations. This child's clinical manifestations of a lysosomal free
      sialic acid storage disease are consistent with her sialin mutations and
      biochemical findings. The differential diagnosis of postnatal developmental delay
      should include free sialic acid storage disorders such as ISSD and Salla disease.

PMID- 15172002
TI  - Potential modifier role of the R618Q variant of proalpha2(I)collagen in type I
      collagen fibrillogenesis: in vitro assembly analysis.
AB  - An arginine to glutamine substitution in the triple helix of proalpha2(I)collagen
      (R618Q) was first reported in a patient with a variant of Marfan syndrome and
      later identified in conjunction with a second mutation in a patient with
      osteogenesis imperfecta (OI). The presence of the R618Q proalpha2(I)collagen
      allele in unaffected or mildly affected family members suggests that the R618Q
      allele is either a non-affecting polymorphism or a potential genetic modifier.
      Conservation of arginine618 across species and fibrillar collagen types suggests
      it is functionally significant. To investigate the functional significance of the
      R618Q proalpha2(I)collagen allele, we isolated type I collagen from cultured
      dermal fibroblasts of control and two unrelated individuals heterozygous for the
      R618Q proalpha2(I)collagen allele and evaluated helical stability and fibrillar
      assembly. Type I collagen thermal stability analyzed by protease susceptibility
      and CD spectroscopy demonstrated no statistical difference between control and
      R618Q containing collagen molecules. In vitro fibril assembly analyses
      demonstrated that R618Q containing collagen exhibits rapid fibrillar growth with
      minimal fibril nucleation phase. Further, electron microscopy demonstrated that
      the diameter of assembled R618Q containing collagen fibrils was approximately 20%
      of control collagen fibrils. These findings suggest the R618Q variant does not
      impact triple helical stability but has a role in collagen fibril assembly,
      supporting the hypothesis that the R618Q proalpha2(I)collagen variant is a
      modifier of connective tissue structure/function and is potentially involved in
      disease pathogenesis.

PMID- 15172003
TI  - Spina bifida and genetic factors related to myo-inositol, glucose, and zinc.
AB  - BACKGROUND: Myo-inositol, glucose and zinc and related genetic factors are
      suggested to be implicated in the etiology of spina bifida. We investigated the
      biochemical concentrations of these nutrients and polymorphisms in the myo
      inositol transporter SLC5A11, myo-inositol synthase ISYNA1, and zinc transporter
      SLC39A4 in association with spina bifida risk. METHODS: Seventy-six spina bifida
      triads only were ascertained. In mothers, fathers, and spina bifida children
      polymorphisms determined were SLC5A11 (544C > T), ISYNA1 (1029A > G), and SLC39A4
      (1069C > T). Serum myo-inositol and glucose, and red blood cell zinc
      concentrations were determined in mothers and spina bifida children. Transmission
      disequilibrium tests (TDT) were applied to determine associations between the
      polymorphisms and spina bifida. Associations between biochemical values and
      genotypes were studied by one-way analysis of variance (ANOVA). Interactions
      between alleles, biochemical values, and environmental factors were analyzed by
      conditional logistic regression. RESULTS: No association between SLC5A11, ISYNA1,
      and SLC39A4 and spina bifida was shown, chi2SLC5A11=0.016, P=0.90;
      chi2SYNA1=1.52, P=0.22; chi2SLC39A4=0.016, P=0.90; and degrees of freedom (df)=1.
      Maternal glucose concentrations were comparable for the SLC5A11 genotypes.
      Significantly lower myo-inositol concentrations were observed in mothers with
      SLC5A11 CC-genotype, mean (SD) 14.2 (2.6)micromol/L compared to SLC5A11 TT
      genotype, 17.0 (3.4)micromol/L, P <0.05 . No significant associations were
      observed between ISYNA1 and myo-inositol and glucose, and between SLC39A4 and
      zinc. A significant interaction was demonstrated between a maternal glucose < 4.5
      mmol/L and ISYNA1 1029A > G polymorphism on spina bifida risk. CONCLUSION: The
      combination of maternal glucose < 4.5 mmol/L and ISYNA1 1029A > G polymorphism
      protects against spina bifida offspring. Moreover, maternal SLC5A11 544C > T
      polymorphism contributes to the serum myo-inositol concentration. Larger studies
      should confirm these findings.

PMID- 15172004
TI  - Isolated left ventricular noncompaction is rarely caused by mutations in G4.5,
      alpha-dystrobrevin and FK Binding Protein-12.
AB  - Isolated left ventricular noncompaction (LVNC) is a form of cardiomyopathy that
      most commonly presents in infancy with a hypertrophic and dilated left ventricle
      characterized by deep trabeculations and intertrabecular recesses. Our goal was
      to determine the frequency of mutations in G4.5, alpha-dystrobrevin, and FK
      Binding protein-12 in isolated LVNC patients. No mutations were identified in 47
      of the 48 patients studied, while a splice site acceptor site mutation of intron
      10 of G4.5 was identified in one patient, resulting in the deletion of exon 10
      from the mRNA.

PMID- 15172005
TI  - A novel mutation in the SLC17A5 gene causing both severe and mild phenotypes of
      free sialic acid storage disease in one inbred Bedouin kindred.
AB  - Four members of an extended consanguineous Bedouin family presented with
      different phenotypic variants of an autosomal recessive lysosomal free sialic
      acid storage disease. One affected individual had congenital ascites followed by
      rapid clinical deterioration and death, a presentation concordant with the
      clinical course of infantile free sialic acid storage disorder. His three first
      cousins had a more slowly progressive neurodegenerative disease, in line with the
      clinical phenotype of the milder form (Salla type) of this lysosomal disorder.
      Diagnosis of free sialic acid storage disease was based on clinical findings,
      histology, and biochemical assays of sialic acid. Molecular studies showed that
      all four affected individuals were homozygous for the same novel 983G > A
      mutation in exon 8 of the SLC17A5 gene, replacing glycine with glutamic acid at
      position 328 of the sialin protein. This family demonstrates the significant
      phenotypic variability of the disease in affected members of a single inbred
      kindred with precisely the same mutation, suggesting a role for modifier genes or
      environmental factors. It also highlights the need to consider this rare disorder
      in the differential diagnosis of congenital ascites and of unexplained
      psychomotor retardation, ataxia, and hypomyelination in infancy.

PMID- 15172006
TI  - Genitourinary phenotype in XX patients with distal 9p monosomy.
AB  - Although testicular development has been shown to be variably impaired in XY
      patients with distal 9p monosomy, ovarian and other genitourinary phenotype has
      poorly been studied in XX patients monosomic for the distal 9p region. Thus, we
      studied a 13-month-old infant with 46,XX,der(9)t(9;10)(p23;p13) (case 1) and an
      11-year-old girl with 46,XX,der(9)t(9;16)(p23;q22) (case 2). Case 1 had primary
      hypogonadism (basal serum follicle stimulating hormone [FSH], 40.0 mIU/mL;
      leteinizing hormone [LH], 1.2 mIU/mL; estradiol [E2], <10 pg/mL), whereas case 2
      had age-appropriate pubertal development (breast, Tanner stage 4; pubic hair,
      Tanner stage 3; menarche 11.7 years of age) and hormone values (FSH, 7.3 mIU/mL;
      LH, 6.7 mIU/mL; E2, 47 pg/mL). In addition, case 1 had hypoplastic labia majora,
      short distance between the vaginal orifice and the anus, and five renal cysts,
      and case 2 had anal atresia, short distance between the vaginal orifice and the
      anus, bilateral hydronephrosis of grade 3 with probable ureteropelvic junction
      stenosis, and renal dysfunction (serum creatinine, 1.52 mg/dL; urea nitrogen,
      34.5mg/dL). Fluorescence in situ hybridization analysis for five regions and
      microsatellite analysis for 10 loci on 9p confirmed hemizygosity for the distal
      9p region with the breakpoints between IFNA and D9S285 in case 1 and between
      D9S168 and D9S286 in case 2. The results, in conjunction with the previous data
      in XX patients with molecularly defined distal 9p monosomy, are consistent with
      the presence of a gene(s) involved in the development of indifferent gonad or
      subsequent ovarian differentiation in a approximately 11 Mb region distal to
      D9S168. In addition, it is possible that a gene(s) for anoperineal and renal
      development also maps distal to D9S168 and that for external genital development
      maps distal to D9S285 at the position approximately 16 Mb from the 9p telomere.

PMID- 15172008
TI  - Safety pharmacology matures into a unique pharmacological discipline.

PMID- 15172007
TI  - A common functional variant in the interleukin-6 gene is associated with
      increased body mass index in subjects with type 2 diabetes mellitus.
AB  - Circulating levels of interleukin-6 (IL-6) are raised in insulin resistant states
      such as obesity, impaired glucose tolerance (IGT), and type 2 diabetes mellitus
      (T2DM). Growing evidence suggests that IL-6 is not only produced by fat cells but
      is also capable of inducing insulin resistance in these cells. The expected
      result of this in vivo, would be to increase adipose mass and subsequently body
      mass index (BMI). The IL-6 -174G > C common functional gene variant has
      consistently been associated with increased plasma IL-6, insulin resistance, and
      increased cardiovascular risk. We looked at the association between genotype and
      BMI in 571 Caucasian subjects with T2DM. There was a significant linear
      association between genotype and BMI: Median (interquartile range) GG 28.8 kg/m2
      (26.0-31.6) vs GC; 29.4 kg/m2 (26.3-32.5) vs CC; 30.4 kg/m2 (26.1-33.0), p=0.05.
      When the group was divided by the median BMI (29.1 kg/m2), 62% of -174CC subjects
      were in the higher group compared to 38% in the lower group (p=0.008). By
      contrast, in 2,652 non-diabetic Caucasian men with a median BMI of 26.1 kg/m2,
      there was no difference in genotype distribution (p=0.288). The frequency of the 
      174C allele was lower in type 2 diabetes compared to the non-diabetic men (-174C
      allele frequency: 0.35[0.33-0.38] vs 0.43[0.42-0.45], p <0.00001; -174CC
      homozygotes: 12.3 vs 18.3%, respectively). The -174C allele is associated with
      higher BMI in type 2 diabetes, but not amongst healthy subjects. The increased
      cardiovascular risk associated with the -174C allele may account for the lower
      frequency of this allele in those with type 2 diabetes.

PMID- 15172009
TI  - Introduction to nonclinical safety pharmacology and the safety pharmacology
      society.

PMID- 15172010
TI  - Origins, practices and future of safety pharmacology.
AB  - The origins of safety pharmacology are grounded upon observations that organ
      functions (like organ structures) can be toxicological targets in humans exposed
      to novel therapeutic agents, and that drug effects on organ functions (unlike
      organ structures) are not readily detected by standard toxicological testing.
      Safety pharmacology is " em leader those studies that investigate the potential
      undesirable pharmacodynamic effects of a substance on physiological functions in
      relationship to exposure in the therapeutic range and above em leader "
      [International Conference on Harmonization (ICH) S7A guidelines; Safety
      Pharmacology Studies for Human Pharmaceuticals]. This publication provides a
      comprehensive review of the history of safety pharmacology, international
      regulatory guidelines that govern the practices of this important field, and the
      scientific challenges that are being faced by its rapid emergence in
      pharmaceutical development. The criticality of identifying undesired adverse
      effects of new drugs in nonclinical models, which reflect the overall human
      condition, is reflected in the importance of generating an integrated and
      accurate assessment of possible human risk. The conundrum posed by the challenge
      of formulating a reliable risk assessment is the importance of improving and
      enhancing the safe progression of new drugs to the marketplace, while preventing
      unnecessary delays (or discontinuances), based on nonclinical findings that are
      not relevant or interpretable in terms of clinical response or human risk.

PMID- 15172011
TI  - New preclinical guidelines on drug effects on ventricular repolarization: safety
      pharmacology comes of age.

PMID- 15172012
TI  - Developing a strategy for the nonclinical assessment of proarrhythmic risk of
      pharmaceuticals due to prolonged ventricular repolarization.
AB  - The aspects for developing a strategy for the preclinical testing of drug
      candidates for proarrhythmic potential are presented. The rationale for such a
      strategy reflects primarily the needs for efficient and scientifically based drug
      development and also attempts to anticipate the possible outcomes of the
      currently ongoing regulatory activity (ICH S7b and E14). Whereas a wealth of new
      data have emerged over the past few years, demonstrating the utility of test
      systems for detecting drug effects on myocardial repolarization, the current
      regulatory trend appears to not use such data for the clinical trial design or
      risk assessment. Nevertheless, certain types of preclinical tests are highly
      recommended for optimizing drug development, despite their still questionable
      regulatory acceptance. This includes (1) testing for blockade of I(Kr) or hERG
      mediated potassium current in heterologous cell systems, (2) measurement of
      effects on the myocardial action potential in vitro; and (3) assessment of
      effects on the ECG in a well-conducted in vivo study. Due to their requirement
      for little compound, the first two in vitro tests lend themselves for early
      safety testing of drug candidates still in the lead optimization phase of drug
      discovery; together, they form a useful and predictive in vitro assessment. This
      strategy is not new but reflects what was initially suggested by the Committee
      for Proprietary Medicinal Products (CPMP) some years ago. However, the validation
      of such a strategy and its utility in drug development is now well established
      and recommended, independent from future regulatory requirements.

PMID- 15172013
TI  - Review of the predictive value of the Langendorff heart model (Screenit system)
      in assessing the proarrhythmic potential of drugs.
AB  - Prolongation of the QTc interval of the electrocardiogram (ECG) is used as a
      surrogate marker for a rare, but life threatening, ventricular arrhythmia known
      as torsades de pointes (TdP). However, the clear link between QTc prolongation
      and the arrhythmogenic risk has not been demonstrated unequivocally. In the
      present review article, we examine (a) the current understanding of
      electrophysiological and pharmacological mechanisms linking changes in action
      potential (AP) properties with proarrhythmia and (b) the value of the isolated,
      paced Langendorff-perfused female rabbit heart model (Screenit system) in
      predicting the torsadogenic potential of drugs in man. The Screenit system
      records monophasic action potentials (MAPs) from which the following parameters
      are evaluated: action potential duration (APD), conduction, instability
      (indicative of beat to beat APD variability), triangulation (indicative of
      changes of Phase 3 repolarization), and reverse-use dependency (indicating that
      the APD is more prolonged at slow heart rates). So far, over 16,000 experiments
      have been conducted, including approximately 300 dedicated tests to evaluate, in
      a blinded manner, approximately 70 clinically used drugs. The drugs tested
      covered a wide range of compounds from various pharmacological and chemical
      classes with clinical torsadogenic propensity, as well as drugs without the
      latter effect in clinical settings. Overall, the Screenit system and its
      associated analysis classified the drugs based on their effects on AP morphology
      and conduction and additionally identified, in a qualitative manner, drugs
      clinically associated with TdP. Such an identification is based on the
      triangulation, reverse-use dependency, and instability of the AP, as well as on
      the direct indexes of proarrhythmia such as early afterdepolarization (EADs),
      ventricular tachycardia (VT), and ventricular fibrillation (VF). Overall, drugs
      that readily induce arrhythmia and/or EADs and/or causes triangulation, reverse
      use dependency, and/or instability and/or a chaotic Poincare plot in a range of
      concentrations likely to be achieved in man is likely to cause TdP in man,
      eventually. Only if none of these elements is present, at concentrations well
      exceeding the free therapeutic plasma concentration, can one expect that the drug
      will probably be devoid of torsadonenicity. Therefore, this in vitro model
      provides detailed information on the overall profile of drug-induced
      electrophysiological effects. In combination with other in vitro and in vivo
      repolarization assays and with pharmacokinetic data in man, it is a valuable tool
      to establish an integrated cardiovascular risk assessment of pharmaceutical
      compounds.

PMID- 15172014
TI  - Identification and measurement of genomic biomarkers of nephrotoxicity.
AB  - An accelerated pace for drug discovery and development requires the application
      of measurements of novel parameters for drug-induced toxicity. Genomic biomarkers
      can contribute to this process as indicators or predictors of toxicity.
      Transcript levels for genes such as the kidney injury molecule have been
      identified and evaluated as genomic biomarkers of nephrotoxicity.

PMID- 15172015
TI  - Gastrointestinal-tract models and techniques for use in safety pharmacology.
AB  - The gastrointestinal tract (GI tract), which extracts nutrients, electrolytes,
      minerals, and water, is prone to injury as a result of oral drug administration.
      Clinical assessment of the GI tract is often limited to measurements of transit
      time and observations of vomiting or diarrhoea, despite the existence of methods
      and techniques capable of assessing specific changes in GI function at the
      membrane, cell, and whole animal levels. Membrane studies, record the uptake of
      solutes, and electrolyte transport, assessing the affects of compounds on
      transepithelial GI transport and flux. Such methods lend themselves to
      permeability, immunohistochemistry, morphology, and molecular biology techniques.
      Isolated cells from the GI tract or cultured cell lines provide knowledge of
      regulation and function at a cellular level, whilst motility patterns, taken in
      vivo or from biopsies, provide information at a more integrated level. In
      anesthetised animals, ligated segments of the intestine can be infused with test
      compounds, providing information about absorptive and secretory processes
      important for the treatment of diarrhoea. Computer simulations and modelling are
      used to predict the disposition of a chemical and its metabolite and can, to some
      extent, replace animal testing, thereby reducing development costs. Indeed,
      software programs can be used to simulate the dissolution, absorption,
      distribution, metabolism, and excretion (ADME) properties of potential drugs in
      the human GI tract. Finally, advances in the field of imaging, combined with
      endoscopy, have resulted in a wireless capsule, allowing the inspection of the GI
      tract anatomy and pathology without surgical intervention. It is concluded that
      the field of safety pharmacology could rapidly, cheaply, and routinely
      incorporate membrane, isolated tissue, and endoscopy techniques for GI tract
      testing of drugs.

PMID- 15172016
TI  - Experimental models to study the physiology, pathophysiology, and pharmacology of
      the lower urinary tract.
AB  - The lower urinary tract is subject to a number of functional disorders, the most
      common of which, in humans, is bladder overactivity. To understand its
      pathophysiological basis, several in vitro and in vivo methodologies have been
      developed. In vitro tension recording from multicellular strips is in widespread
      use, and alternative experimental arrangements to a conventional organ bath are
      described, the relative merits are discussed, and the different experimentally
      derived variables are evaluated. Other methodologies, such as skinned fibres and
      whole bladder preparations, are also described. Electromyography in the isolated
      bladder is now feasible, and its potential uses discussed. The use of isolated
      smooth muscle cells is presented, especially with respect to the measurement of
      intracellular ion concentrations and electrophysiological parameters. The
      development of methods to prepare other cell types from the lower urinary tract
      is also introduced. A large-scale culture of urothelial and smooth muscle cells
      is possible, and their use as experimental tools, as well as a substrate for the
      development of surgical implants, is presented. Finally, different in vivo models
      of the lower urinary tract are presented, with reference to their investigation
      of clinical problems. These include models of bladder outflow obstruction,
      bladder ischaemia, bladder denervation, and congenital abnormalities and their
      influence on foetal development of the lower urinary tract.

PMID- 15172017
TI  - Experiences in method development for the analysis of in vitro study solutions
      for content.
AB  - Effects of drugs on the cardiovascular system are required to be assessed as part
      of safety pharmacology, in particular using the in vitro Human Ether-a-go-go
      Related Gene Product (HERG) and Purkinje fibre studies and can be used to predict
      safety margins prior to administration to man. Recent International Conferences
      on Harmonization (ICH) regulations, draft ICHS7B guidelines, indicate that levels
      of drug in bath solutions used should be measured if quantitative data are to be
      obtained for the estimation of safety margins. To accurately measure drug
      concentrations in bath solutions, a validated analytical method is required. This
      method is required to be accurate, precise, specific, and robust, and due to the
      increased potency of new drugs, liquid chromatography with mass spectrometric
      detection (LC-MS) has become the method of choice. Recent experiences validating
      methods for the analysis of a wide range of drugs in bath solutions has presented
      a major issue regarding the solubility of some drugs in bath solutions. This has
      resulted in the requirement of a different approach to the analysis of, in
      particular, lipophilic drugs that has in turn highlighted the potential for the
      significant overestimation of the drug concentration in these bath solutions and
      therefore inaccurate calculation of safety margins.

PMID- 15172018
TI  - From the Editor's desk.

PMID- 15172019
TI  - Letter from Ireland.

PMID- 15172020
TI  - Internal medicine in 2003 or the specialty of "invisible diseases"

PMID- 15172021
TI  - The common cold: a review of the literature.
AB  - Respiratory viral infections, also known as the common cold, are the most common
      infections in humans. Despite their benign nature, they are a major cause of
      morbidity and mortality on a worldwide basis. Several viruses have been
      associated with such illness, of which rhinovirus is the most common. Symptom
      production is a combination of viral cytopathic effect and the activation of
      inflammatory pathways. Therefore, antiviral treatment alone may not be able to
      prevent these events. The optimal use of such agents also requires earlier
      initiation; therefore, it is important to develop accurate and rapid diagnostic
      techniques for respiratory viruses. Before any reliable and effective treatment
      is available, symptomatic therapies may remain the only possible choice of
      management.

PMID- 15172022
TI  - Accuracy of chest sonography and polymorphonuclear elastase in the assessment of
      bacterial pleural effusion.
AB  - Background: The relationship between chest sonography findings and inflammatory
      markers for assessing bacterial pleural effusion is not well established. We
      decided to study the accuracy of chest sonography in determining the nature of
      bacterial pleural effusion and its relationship with polymorphonuclear elastase
      (PMN-E) results. Methods: Pleural sonography and PMN-E were evaluated in a
      prospective study of 144 consecutive patients with pleural effusion of various
      etiologies: 25 complicated parapneumonic, 18 uncomplicated parapneumonic, 33
      tuberculous, 17 malignant, 12 transudates, and 39 of unknown etiology. The
      sonographer distinguished between anechoic and septated pattern. The relationship
      between sonographic appearance and inflammatory markers was evaluated. Results:
      All of the complicated parapneumonic, 11 uncomplicated parapneumonic, and 28
      tuberculous effusions were septated. Septated pattern and PMN-E value were
      independent predictors of infectious pleural disease (p <0.05). The simultaneous
      presence of a septated pattern and a PMN-E higher than 100 microg/l had a
      sensitivity of 79.1% and a specificity of 91.1% for the diagnosis of bacterial
      effusions. Conclusions: PMN-E level and the sonographic pattern of pleural fluid
      may be useful in the diagnosis of bacterial pleural effusions.

PMID- 15172023
TI  - The effect of balneotherapy on osteoarthritis. Is an intermittent regimen
      effective?
AB  - Background: Balneotherapy is used as a treatment modality for various
      musculoskeletal disorders. The aim of this study was to evaluate the
      effectiveness of intermittent balneotherapy in patients with knee osteoarthritis
      (OA). Methods: Seventy-two patients with knee OA were included in the study.
      Patients were divided into two groups: group A (48 patients) was given
      intermittent once weekly treatment for 6 weeks; group B (24 patients) served as a
      control group. Evaluation was done prior to study entry, at weeks 4 and 6, and 4
      weeks following completion of treatment (week 10). Assessment included global
      pain score (VAS), WOMAC index, Lequesne's functional index, patients' and
      physician's disease severity score, and NSAID/analgesic consumption. Results:
      Following balneotherapy, a statistically significant improvement, determined by
      the reduction in the mean changes of most outcome parameters (VAS, WOMAC, and
      Lequesne's index), was noted in group A at weeks 4 and 6 and was sustained 4
      weeks after cessation of treatment (week 10). Significant improvement in both
      physician's and patients' disease severity scores, as well as a reduction in
      analgesic and NSAID consumption, were also noted in group A. No improvement was
      found in the control group in any of the tested parameters. Conclusions:
      Intermittent balneotherapy appears to be effective in the treatment of knee OA.

PMID- 15172024
TI  - Experimentally induced prolonged magnesium deficiency causes osteoporosis in the
      rat.
AB  - Background: It has been shown that prolonged daily peroral magnesium (Mg)
      administration, as tabs of Mg(OH)(2), used as the only treatment in
      postmenopausal osteoporosis, causes a significant increase in BMD. Objective: In
      order to obtain definitive evidence of causality of magnesium deficiency in the
      etiology of osteoporosis, we spent 1 year examining rats given a daily Mg
      deficient diet (200 ppm) and compared them with rats given a Mg-adequate diet
      (2000 ppm). Methods: Sixteen female Sprague-Dawley rats, mean weight 110 (S.D.
      23) g, were divided into two groups and randomly assigned to a semisynthetic diet
      that differed only in Mg content. Urine samples were collected every 3 months and
      blood was collected at the end of the trial. After the animals were sacrificed,
      the L3-L5 vertebrae and the femoral regions were examined for bone density (BMD)
      using dual energy X-ray absorptiometry. The femoral bones were examined for bone
      fragility and the tibiae by histomorphometry, and the mineral content of the
      bones was estimated. Results: The mean BMD of L3-L5 vertebral bone was
      significantly higher in group A (adequately nourished) than in the Mg-deficient
      group B (p=0.035, one-tail); in addition, the BMD of the femural region was
      significantly higher in group A (p=0.045, one-tail). The bending stiffness of the
      femur was slightly higher in group A than in group B; however, after correction
      to diminish the influence of the difference in bone dimensions between the two
      groups, femur rigidity (i.e., the loss of elasticity) in group B became
      significantly higher than that in group A (p=0.024). The force needed to break
      the bone was significantly higher in group A than in group B (p=0.024) and it
      remained higher after correction, although no longer significantly. In group B,
      the diminution of the trabecular bone volume, in relation to tissue volume
      (BV/TV), and the increase in the degree of trabecular interconnection (TBPf)
      clearly showed the presence of osteoporosis. On microscopy, focal osteoporosis of
      the metaphyseal spongious bone was observed in the bone rendered Mg-deficient.
      Conclusions: Because osteoporosis is characterized by lowering of BMD, increased
      bone fragility, and altered bone architecture, our study showed that maintaining
      rats for 1 year on a Mg-deficient diet gives rise to the appearance of
      osteoporosis.

PMID- 15172025
TI  - Nocardiosis in a tertiary care hospital on the island of Gran Canaria.
AB  - Background: Nocardiosis is an uncommon but serious infection increasingly found
      in immunosuppressed persons. We describe 14 cases of nocardial infection seen at
      a tertiary hospital. Methods: All positive Nocardia cultures isolated from 1991
      to 2002 were included. We analyzed predisposing factors, epidemiological and
      clinical features, laboratory and radiological findings, site(s) of infection,
      antimicrobial susceptibility pattern, treatment, and outcome. Factors related to
      mortality were analyzed. Results: Nineteen patients with a Nocardia isolate were
      identified and 14 were finally included. The most common predisposing factors
      included pulmonary diseases (71.4%), diabetes mellitus (35.7%), systemic diseases
      (28.6%) and immunosuppressive therapy (28.6%). The site of infection was
      pulmonary in 12 cases (85.71%), cutaneous or subcutaneous in one case (7.1%), and
      disseminated in another case (7.1%). The predominant clinical symptom was
      purulent expectoration (71.4%) while the predominant radiological pattern was a
      reticulonodular infiltrate (6/12, 50%). Relapse was observed in one case (7.7%)
      and death in three cases (23.1%). Diabetes mellitus was associated with the
      mortality rate (p=0.035). Treatment was highly individualized, but trimethoprim
      (TMP)-sulfamethoxazole (SMX) was the combination most often used. Conclusions:
      Nocardiosis should be part of the differential diagnosis for patients presenting
      with pulmonary symptoms, soft tissue infection, or brain abscess.

PMID- 15172026
TI  - "Best practice" in inflammatory bowel disease: an international survey and audit.
AB  - Background: An observational study was conducted at eight university and four
      district hospitals in eight countries collaborating in clinical and
      epidemiological research in inflammatory bowel disease (IBD) to compare European
      health care facilities and to define current "best practice" with regard to IBD.
      Methods: The approach used in this multi-national survey was unique. Existing
      quality norms, developed for total hospital care by a specialized organization,
      were restricted to IBD-specific care and adapted to the frame of reference of the
      study group. In each center, these norms were surveyed by means of questionnaires
      and professional audits in all participating centers. The collected data were
      reported to the center, compared to data from other hospitals, and used to
      benchmark. Group consensus was reached with regard to defining current "best
      practice". Results: The observations in each center involved patient-oriented
      processes, technical and patient safety, and quality of the medical standard.
      Several findings could be directly implemented to improve IBD care in another
      hospital (benchmarks). These included a confidential relationship between health
      care worker(s) and patients, and availability of patient data. Conclusions: The
      observed benchmarks, in combination with other subjectively chosen "positive"
      procedures, have been defined as current "best practice in IBD", representing
      practical guidelines towards better quality of care in IBD.

PMID- 15172027
TI  - Lymphocytic hypophysitis with lachrymal, salivary and thyroid gland involvement.
AB  - We report on hypophysitis associated with a prominent lymphoid infiltration of
      salivary and lachrymal glands in a 35-year-old woman with a dramatic response to
      steroids. Four years later, overt Graves' disease developed. To our knowledge,
      pseudotumoral lymphocytic infiltration of both lachrymal and salivary glands has
      never been described in association with hypophysitis. Benign lymphocytic
      hypophysitis may belong to a spectrum that extends from low-grade lymphoid
      proliferation to autoimmune disease. Such a process may follow a regional tissue
      distribution including pituitary, thyroid, lachrymal and salivary glands.

PMID- 15172028
TI  - Pleural effusion revealing giant cell arteritis.
AB  - Pulmonary involvement is considered to be rare in giant cell arteritis (GCA),
      usually occurring in the course of the disease. We describe the case of a patient
      who developed left pleural effusion revealing GCA. Thoracic CT scan demonstrated
      an abundant left pleural effusion and a thickening of the aortic wall. The
      patient's condition improved rapidly, with regression of pulmonary clinical
      features and complete clearance of pleural effusion, after institution of steroid
      therapy. Our case report reinforces the possibility of unusual presentation of
      GCA; such a diagnosis should, therefore, be considered in elderly patients
      presenting with pulmonary manifestations, even in the absence of typical clinical
      features of temporal arteritis (e.g. headache, jaw claudication, blurred vision,
      scalp tenderness) or polymyalgia rheumatica.

PMID- 15172029
TI  - Acute pseudobulbar palsy as the initial presentation of intravascular
      lymphomatosis.
AB  - We describe the case of a 76-year-old male patient who developed acute
      manifestations of pseudobulbar palsy without a history of stroke or vascular risk
      factors as the first manifestation of intravascular lymphomatosis. Neurological
      symptoms of acute pseudobulbar palsy appeared on the second postoperative day
      after transurethral prostatectomy for the treatment of prostatic hypertrophy.
      Intravascular lymphomatosis was diagnosed from microscopic findings and
      immunohistochemical staining of the surgical specimen. Chemotherapy was started,
      but the patient died due to sepsis secondary to bone marrow aplasia.
      Intravascular lymphomatosis should be considered a rare potential cause of acute
      pseudobulbar palsy.

PMID- 15172030
TI  - Doctors' working times reform: lessons from New Zealand.

PMID- 15172031
TI  - Vipera palaestinae envenomation-induced bradycardia.

PMID- 15172033
TI  - How tadpoles lose their tails: path to discovery of the first matrix
      metalloproteinase.

PMID- 15172034
TI  - The cartilaginous skeleton of an elasmobranch fish does not heal.
AB  - The inability of articular cartilage to heal satisfactorily is becoming, with
      ageing populations, an important medical problem. One question that has not been
      raised is whether a mechanism for the repair of cartilage evolved in animals with
      cartilaginous skeletons. Fin rays of dogfish were cut and the fish maintained for
      up to 6 months. The initial inflammatory reaction around the cut rays lasts for 2
      weeks. By 4 weeks the cut ends are covered by fibrous tissue. At 12 weeks some
      areas of cartilage-like tissue are developing. Development of these areas
      continues and at 26 weeks large chondrocyte-like cells are surrounded by matrix.
      This tissue is in regions of poor vascularity. It does not have the typical
      appearance of hyaline cartilage, nor is it integrated with the cartilage of the
      fin rays. No changes in the cut surfaces of the fin rays are observed at any
      time. It is concluded that no mechanism has evolved in the elasmobranch fishes
      for the repair of their cartilaginous skeleton. This is discussed in relation to
      previous investigations of the reactions of cartilage to injury in embryonic,
      neonatal and adult tissues of higher vertebrates.

PMID- 15172035
TI  - Deposition of tropoelastin into the extracellular matrix requires a competent
      elastic fiber scaffold but not live cells.
AB  - The initial steps of elastic fiber assembly were investigated using an in vitro
      assembly model in which purified recombinant tropoelastin (rbTE) was added to
      cultures of live or dead cells. The ability of tropoelastin to associate with
      preexisting elastic fibers or microfibrils in the extracellular matrix was then
      assessed by immunofluorescence microscopy using species-specific tropoelastin
      antibodies. Results show that rbTE can associate with elastic fiber components in
      the absence of live cells through a process that does not depend on crosslink
      formation. Time course studies show a transformation of the deposited protein
      from an initial globular appearance early in culture to a more fibrous structure
      as the matrix matures. Deposition required the C-terminal region of tropoelastin
      and correlated with the presence of preexisting elastic fibers or microfibrils.
      Association of exogenously added tropoelastin to the cellular extracellular
      matrix was inhibited by the addition of heparan sulfate but not chondroitin
      sulfate sugars. Together, these results suggest that the matrix elaborated by the
      cell is sufficient for the initial deposition of tropoelastin in the
      extracellular space and that elastin assembly may be influenced by the
      composition of sulfated proteoglycans in the matrix.

PMID- 15172037
TI  - Establishment and characterization of a parietal endoderm-like cell line derived
      from Engelbreth-Holm-Swarm tumor (EHSPEL), a possible resource for an engineered
      basement membrane matrix.
AB  - Engelbreth-Holm-Swarm (EHS) tumor produces large amounts of basement membrane
      (BM) components, which are widely used as cell culture substrates mimicking BM
      functions. EHS tumor arose spontaneously in an ST/Eh strain mouse and has been
      propagated by transplantation. In the present study, we established a cell line,
      EHSPEL (EHS Parietal Endoderm-Like), which can be cultured ex vivo and preserves
      the capacity to form tumors in vivo. EHSPEL cells secreted large amounts of
      laminin-1 into the medium and deposited BM components onto dishes. To further
      characterize EHSPEL cells, their gene expression profile was compared to those of
      parietal endoderm cells from Reichert's membrane at embryonic day 13.5,
      differentiated F9 embryonal carcinoma cells, and PYS-2 parietal endoderm cells.
      These analyses outlined not only common features of parietal endoderm-like cells
      that underlie the efficient production of BM components, but also germline cell
      like features of EHSPEL cells, at least some of which may play crucial roles in
      their capacity to form tumors that accumulate abundant BM components in vivo.
      Karyotyping of EHSPEL cells using chromosome painting probes showed a large
      number of interchromosomal rearrangements and partial chromosome hyperploidy.
      Exogenous introduction of a human laminin-alpha(4)-EGFP fusion protein into
      EHSPEL cells resulted in the production and deposition of human-mouse-hybrid
      laminin-8. This strategy should be applicable for creating efficient systems to
      produce chimeric laminins as well as BM-like gels with modified biological
      activity.

PMID- 15172036
TI  - Expression of serum amyloid A in chondrocytes and myoblasts differentiation and
      inflammation: possible role in cholesterol homeostasis.
AB  - Serum amyloid A (SAA) is synthesized by the liver during the acute phase. Local
      expression of SAA mRNA has been reported also in non-liver cells, a potential
      local source of SAA protein not related to the systemic acute phase response. SAA
      function has not been established yet. In the present study, we identified SAA as
      a protein expressed by chondrocytes and myoblasts in response to inflammatory
      stimula. In both cell systems, SAA mRNA and protein expression is strongly
      stimulated by bacterial lipopolysaccharide treatment. SAA mRNA expression is also
      enhanced during terminal differentiation of cells of the chondrogenic and
      myogenic lineage; mRNA is barely detectable in prechondrogenic cells and is
      highly expressed in differentiated hyperthrophic chondrocytes. An increased level
      of SAA mRNA was also observed in vivo when we compared mRNA extracted from tibiae
      of 10 day embryos, still fully cartilaginous, with tibiae from 18 day embryos, a
      stage when the endochondral ossification process has already started. p38
      activation, a well-known event of the chondrogenesis signaling cascade, controls
      expression of SAA in cartilage following inflammatory stimuli. SAA secreted by
      stimulated chondrocytes is associated with cholesterol. Cholesterol is
      synthesized by the same chondrocytes and is also increased in inflammatory
      conditions. A role of SAA in cholesterol homeostasis in chondrocytes is proposed.

PMID- 15172038
TI  - Safety overview of new disease-modifying antirheumatic drugs.
AB  - Beginning in 1998, a surge of new agents has expanded treatment options for
      rheumatoid arthritis (RA) patients. Although the disease modifying potential of
      these agents is encouraging, their use must be weighed against an evolving array
      of new safety concerns. Because of the popularity of these agents with patients
      and rheumatologists alike, clinicians must be prepared to discuss the potential
      risks associated with novel disease-modifying antirheumatic drugs and biologic
      therapies as they begin to appear with greater frequency in practice. This
      article discusses the safety issues arising from clinical trial and postmarketing
      experience with several new and commonly used agents, with specific emphasis on
      adalimumab, etanercept, infliximab, anakinra, and leflunomide.

PMID- 15172039
TI  - Consideration of the risk and treatment of tuberculosis in patients who have
      rheumatoid arthritis and receive biologic treatments.
AB  - Evidence supports the association of tuberculosis (TB) with tumor necrosis factor
      inhibitor therapy in patients who have rheumatoid arthritis. There seem to be
      differential risks of TB with the currently available inhibitors. Screening for
      latent TB infection with purified protein derivative is indicated for patients
      who are being considered for treatment; it seems to be effective in reducing the
      occurrence of TB in treated patients.

PMID- 15172040
TI  - Associations between rheumatoid arthritis and malignancy.
AB  - There are many complex associations between rheumatoid arthritis(RA) and
      malignancy. Patients with rheumatic diseases on the whole appear to be at
      increased risk for the development of certain malignancies. The data from several
      studies are persuasive that the presence of RA conveys an increased risk for the
      development of lymphoproliferative disorders and may convey a decreased risk for
      the development of malignancies of the digestive tract. Understanding the complex
      interrelationships between RA and malignancy will lead to more accurate diagnosis
      of underlying pathology, more effective treatment of symptoms and underlying
      disease, and appropriate surveillance for the development of later complications.

PMID- 15172041
TI  - Overview of radiologic efficacy of new treatments.
AB  - Randomized, double-blind trials on new treatments, including anakinra,
      etanercept, infliximab, and leflunomide, show convincing reduction in
      radiographic progression. The relative efficacy of these new treatments is
      unknown. Head-to-head comparisons have not been performed and comparing treatment
      arms across trials has several pitfalls. These possible pitfalls are discussed.

PMID- 15172042
TI  - Leflunomide.
AB  - Leflunomide is a low-molecular weight, synthetic, oral agent specifically
      developed for immunosuppression. Because of activity in animal models,
      leflunomide was tested in rheumatoid arthritis(RA). These investigations have
      demonstrated that leflunomide reduces the clinical symptoms and signs of RA,
      improves health related quality of life, and retards structural damage.
      Leflunomide has been evaluated in RA patients as monotherapy and in combination
      with methotrexate. Close monitoring for adverse events with particular attention
      for monitoring liver enzymes for hepatic toxicity is important during treatment
      with leflunomide.

PMID- 15172043
TI  - Treatment of rheumatoid arthritis with etanercept.
AB  - Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as
      monotherapy and in combination with methotrexate(MTX). Radiographic progression
      of disease was slowed significantly when the drug was used for a 24-month period
      and was statistically significantly better than MTX. In addition to its use in
      RA,etanercept is approved by the U.S. Food and Drug Administration for other
      rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis,
      and juvenile chronic arthritis.

PMID- 15172044
TI  - Infliximab treatment of rheumatoid arthritis.
AB  - Infliximab was the first anti-TNF agent used to treat rheumatoid arthritis to
      provide proof of concept of the role of TNF-alpha in this condition. It has
      become widely used since, principally as an effective treatment in combination
      with methotrexate, but also as monotherapy for the treatment of Crohn's disease,
      ankylosing spondylitis,and psoriatic arthritis. The benefits of infliximab in
      controlling signs and symptoms, improving quality of life, preventing structural
      joint damage, and possible healing of bone provide an important option for the
      treatment of rheumatoid arthritis.

PMID- 15172045
TI  - Adalimumab therapy in rheumatoid arthritis.
AB  - Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody that is
      specific for human tumor necrosis factor. Based on the data presented in this
      article, adalimumab administered alone or in patients partially responsive to
      methotrexate exhibits a rapid onset of action, provides a substantial reduction
      in signs and symptoms, and results in an improvement in physical function and
      health-related quality of life. Adalimumab has been demonstrated to inhibit
      progression of structural joint damage in patients who have long-standing
      rheumatoid arthritis. Taken together, the data support adalimumab as a new
      therapeutic option for patients with moderate to severe rheumatoid arthritis.

PMID- 15172046
TI  - The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of
      rheumatoid arthritis.
AB  - Interleukin-1 (IL-1) is a primary cytokine that is involved in the pathogenesis
      of rheumatoid arthritis; it contributes to inflammation and joint destruction.
      Anakinra (Kineret) is an IL-1 receptor antagonist that blocks the biologic
      activity of IL-1. It was approved by the U.S. Food and Drug Administration (FDA)
      for the treatment of rheumatoid arthritis in 2001. Anakinra is safe and effective
      in the treatment of rheumatoid arthritis, both as monotherapy and in combination
      with other disease-modifying antirheumatic drugs. This article reviews the
      preclinical, clinical, and postmarketing data on the safety and efficacy of
      anakinra in the treatment of rheumatoid arthritis and focuses on the pivotal
      clinical trials that led to FDA approval.

PMID- 15172047
TI  - Cytotoxic T-lymphocyte antigen 4-immunoglobulin in rheumatoid arthritis.
AB  - It is apparent that the potential to significantly affect the immune response
      exists through artificial modulation of a system of molecules on the surface of T
      cells that has been designed to specifically provide on-off switches to support
      or abrogate the activation of T cells. This approach holds considerable promise
      because it avoids toxicities associated with cell lysis, while theoretically
      specifically affecting only those T cells, which are being continuously
      stimulated to become activated. Although there is presently a paucity of studies
      in humans on the clinical effects of cytotoxic T-lymphocyte antigen 4
      immunoglobulin in patients who have rheumatoid arthritis, the existing studies
      indicate a clear therapeutic value with this approach.

PMID- 15172048
TI  - B lymphocyte depletion therapy with rituximab in rheumatoid arthritis.
AB  - B lymphocyte depletion therapy in rheumatoid arthritis can provide major clinical
      benefits. Widespread use in the future will depend on continued evidence of
      safety, particularly in the context of long term use. Rituximab is a highly
      effective agent, but it may be best used in combination with other agents.
      Substantial improvement following a single course of therapy has been found to
      last up to 42 months, and it is reasonable to hope that further development of
      strategies targeting B cells will extend this toward the original aim of truly
      long-term remission.

PMID- 15172049
TI  - Clinical experience with inhibition of interleukin-6.
AB  - Rheumatoid arthritis (RA) is a systemic disease that is associated with increased
      mortality and morbidity. Prognosis depends on disease severity and response to
      treatment. Those patients whose diseases are refractory to treatment with disease
      modifying antirheumatic drugs (DMARDs) and have persistent inflammation have
      reduced survival similar to patients with triple-vessel coronary artery disease
      and Hodgkin's lymphoma. Although DMARDs reduce inflammation and improve symptoms,
      they do not improve long-term prognosis. Chronic synovial inflammation results in
      damage to the articular cartilage and adjacent bone. Consequently,after 10 years
      of disease most patients develop significant disability due to joint damage.
      Interleukin-6 (IL-6) is a key mediator of inflammation in RA. Inhibition of IL-6
      reduces synovitis and improves symptoms. Therapies targeting IL-6 are promising
      new treatments for RA.

PMID- 15172050
TI  - Interleukin-18 and the treatment of rheumatoid arthritis.
AB  - Interleukin (IL)-18 is a new member of the IL-1 family of proinflammatory
      cytokines. Based on preclinical studies in animals, IL-18 likely plays a role in
      rheumatoid arthritis, and strategies to block IL-18 activity are underway in
      clinical trials. In one of these trials,a naturally occurring IL-18 binding
      protein (IL-18 BP) binds IL-18 with a high affinity and reduces disease severity
      in models of inflammatory diseases. IL-18 BP is not the soluble receptor for IL
      18 but rather a distinct molecule, which appears to be distantly related to the
      IL-1 receptor type II, both structurally and functionally, and hence represents
      part of the IL-1 family of receptors.

PMID- 15172051
TI  - New and emerging therapies for rheumatoid arthritis.

PMID- 15172052
TI  - Conventional MR imaging with simultaneous measurements of cerebral blood volume
      and vascular permeability in ganglioglioma.
AB  - The conventional MR imaging appearance of gangliogliomas is often variable and
      nonspecific. Conventional MR images, relative cerebral blood volume (rCBV) and
      vascular permeability (K(trans)) measurements were reviewed in 20 patients with
      pathologically proven grade 1 and 2 gangliogliomas (n = 20) and compared to a
      group of grade 2 low-grade gliomas (n = 30). The conventional MRI findings
      demonstrated an average lesion size of 4.1 cm, contrast enhancement (n = 19),
      variable degree of edema, variable mass effect, necrosis/cystic areas (n = 8),
      well defined (n = 12), signal heterogeneity (n = 9), calcification (n = 4). The
      mean rCBV was 3.66 +/- 2.20 (mean +/- std) for grade 1 and 2 gangliogliomas. The
      mean rCBV in a comparative group of low-grade gliomas (n = 30), was 2.14 +/-
      1.67. p Value < 0.05 compared with grade 1 and 2 ganglioglioma. The mean K(trans)
      was 0.0018 +/- 0.0035. The mean K(trans) in a comparative group of low-grade
      gliomas (n = 30), was 0.0005 +/- 0.001. p Value = 0.14 compared with grade 1 and
      2 ganglioglioma. The rCBV measurements of grade 1 and 2 gangliogliomas are
      elevated compared with other low-grade gliomas. The K(trans), however, did not
      demonstrate a significant difference. Gangliogliomas demonstrate higher cerebral
      blood volume compared with other low-grade gliomas, but the degree of vascular
      permeability in gangliogliomas is similar to other low-grade gliomas. Higher
      cerebral blood volume measurements can help differentiate gangliogliomas from
      other low-grade gliomas.

PMID- 15172053
TI  - Automated human frontal lobe identification in MR images based on fuzzy-logic
      encoded expert anatomic knowledge.
AB  - Identification of human brain structures in MR images comprises an area of
      increasing interest, which also presents numerous methodological challenges. Here
      we describe a new knowledge-based automated method designed to identify several
      major brain sulci and then to define the frontal lobes by using the identified
      sulci as landmarks. To identify brain sulci, sulcal images were generated by
      morphologic operations and then separated into different components based on
      connectivity analysis. Subsequently, the individual anatomic features were
      evaluated by using fuzzy membership functions. The crisp decisions, i.e., the
      identification of sulci, were made by taking the maximum of the summation of all
      the membership functions. The identification was designed in a hierarchical
      order. The longitudinal fissure was extracted first. The left and right central
      sulci were then identified based on the left and right hemispheres. Next, the
      lateral sulci were identified based on the central sulci and hemispheres.
      Finally, the left and right frontal lobes were defined from the two hemispheres.
      The method was evaluated by visual inspection, comparison with manual
      segmentation, and comparison with manually volumetric results in references. The
      average Jaccard similarities of left and right frontal lobes between the
      automated and manual segmentation were 0.89 and 0.91, respectively. The average
      Kappa indices of left and right frontal lobes between the automated and manual
      segmentation were 0.94 and 0.95, respectively. These results show relatively high
      accuracy of using this novel method for human frontal lobe identification and
      segmentation.

PMID- 15172054
TI  - A comparative evaluation of CH3-DTPA-Gd (NMS60) for contrast-enhanced magnetic
      resonance angiography.
AB  - In a canine model the signal dynamics of a new oligomer-based MR contrast agent
      (NMS60, 2158 Da) were compared to Gd-DTPA to investigate the agents' potential
      for magnetic resonance angiography (MRA). Twelve male mongrel dogs were imaged
      sequentially under anesthesia with two different MRA sequences (Tlw 3DSPGR).
      Initial enhancement was measured every 9 s for eight points in time. Thereafter,
      spatial highly resolved MRAs were obtained at 5, 10, 15, 20, 30, 45, and 60 min
      post-injection of two different dosages. Over the first 20 s following bolus
      administration the average arterial enhancement of 0.1 mmol(Gd)kg NMS60 was 44%
      greater than Gd-DTPA. Twenty minutes post-injection the relative signal intensity
      of NMS60 was as high as the peak signal intensity with Gd-DTPA at the same dosage
      level (0.1 mmol(Gd)/kg). In the animals that received NMS60 injections the
      vascular conspicuity was overly superior to those who received Gd-DTPA. No
      significant toxicity effects were noted for either dosage level. The intermediate
      weight contrast agent NMS60 offers greater vascular enhancement and retention
      time than Gd-DTPA. For a given set of optimized imaging parameters this offers
      improved spatial details, less arterial/venous overlap, and better vascular
      contrast.

PMID- 15172055
TI  - Combined diffusion-weighted and spectroscopic MR imaging in Creutzfeldt-Jakob
      disease.
AB  - A 49-year-old woman presented with progressive dementia. Diffusion-weighted MR
      images showed abnormalities in the cerebral cortex as well as the putamen and
      caudate head bilaterally. MR spectroscopic imaging revealed marked asymmetric
      decrease of normal metabolites in the right basal ganglia, with concordant
      hypoperfusion on single photon emission computed tomography. Diffusion-weighted
      MR imaging is more sensitive to cortical involvement in sporadic Creutzfeldt
      Jakob Disease, and MR spectroscopy may yield evidence of asymmetric involvement.
      Combined functional and metabolic MR imaging may be useful in studying CJD.

PMID- 15172056
TI  - Controlling the false positive rate in fuzzy clustering using randomization:
      application to fMRI activation detection.
AB  - Despite its potential advantages for fMRI analysis, fuzzy C-means (FCM)
      clustering suffers from limitations such as the need for a priori knowledge of
      the number of clusters, and unknown statistical significance and instability of
      the results. We propose a randomization-based method to control the false
      positive rate and estimate statistical significance of the FCM results. Using
      this novel approach, we develop an fMRI activation detection method. The ability
      of the method in controlling the false-positive rate is shown by analysis of
      false positives in activation maps of resting-state fMRI data. Controlling the
      false-positive rate in FCM allows comparison of different fuzzy clustering
      methods, using different feature spaces, to other fMRI detection methods. In this
      article, using simulation and real fMRI data, we compare a novel feature space
      that takes the variability of the hemodynamic response function into account (HRF
      based feature space) to the conventional cross-correlation analysis and FCM using
      the cross-correlation feature space. In both cases, the HRF-based feature space
      provides a greater sensitivity compared to the cross-correlation feature space
      and conventional cross-correlation analysis. Application of the proposed method
      to finger-tapping fMRI data, using HRF-based feature space, detected activation
      in sub-cortical regions, whereas both of the FCM with cross-correlation feature
      space and the conventional cross-correlation method failed to detect them.

PMID- 15172057
TI  - Cortical activations upon stimulation of the sensorimotor-implicated acupoints.
AB  - Sixty-seven healthy right-handed subjects were studied using a 1.5-T MRI.
      Activations, which were absent during stimulation of the adjacent nonacupoints
      over the right arm or leg, were consistently seen over the right premotor area
      during stimulation of the sensorimotor-implicated acupoints over the left arm or
      leg. The left premotor area was also activated during stimulation of the arm or
      leg acupoints. The right precentral and postcentral gyri showed activations
      during stimulation of the arm acupoints. The volume and location of activations
      vary when different combinations of the arm acupoints were stimulated. Our
      results indicate the existence of sensorimotor-implicated acupoints as sensitive
      sites to obtain somatotopic activations over the sensory cortices with co
      activation of the motor cortices.

PMID- 15172058
TI  - MRI detection of tumor in mouse lung using partial liquid ventilation with a
      perfluorocarbon-in-water emulsion.
AB  - Transverse relaxation time (T(2*))-weighted (1)H-MRI of mouse lungs has been
      performed using partial liquid ventilation (PLV) with a perfluorocarbon (PFC)-in
      water emulsion as a contrast modality for lung MRI. Significant sensitivity
      enhancement in MRI of mouse lungs has been demonstrated with the protocol. The
      results show that the T(2*) value in lung is approximately proportional to the
      infusion dose up to a dose of 5 ml/kg body weight (BW) (4.5 g PFC/kg BW) and
      becomes essentially constant beyond this dosage. T(2*) maps of lungs have been
      calculated and T(2*) in lungs is in the range of 10-35 ms with this technique,
      which is an order of magnitude greater than the T(2*) value of mouse lungs
      without using a PFC-in-water emulsion. T(2*)-weighted (1)H-MR images of mouse
      lungs have been obtained with good quality under our experimental conditions. We
      have applied this technique to detect tumors in mouse lungs. Our technique can
      detect small lung tumors of B16 melanoma, about 1 mm in diameter, in mice. With
      its significant MR sensitivity enhancement and technical simplicity, T(2*)
      weighted (1)H-MRI using PLV with PFC-in-water emulsion offers a promising
      approach to investigate lung cancers using rodent models.

PMID- 15172059
TI  - Investigation of techniques to quantify in vivo lesion volume based on comparison
      of water apparent diffusion coefficient (ADC) maps with histology in focal
      cerebral ischemia of rats.
AB  - Stroke lesion-volume estimates derived from calculated water apparent diffusion
      coefficient (ADC) maps provide a quantitative surrogate end-point for
      investigating the efficacy of drug treatment or studying the temporal evolution
      of cerebral ischemia. Methodology is described for estimating ischemic lesion
      volumes in a rat model of permanent middle cerebral artery occlusion (MCAO) based
      on absolute and percent-reduction threshold values of the water ADC at 3 h post
      MCAO. Volume estimates derived from average ADC (ADC(av)) maps were compared with
      those derived from post-mortem histological sections. Optimum ADC thresholds were
      established as those that provided the best correlation and one-to-one
      correspondence between ADC- and histologically derived lesion-volume estimates.
      At 3 h post-MCAO, an absolute-ADC(av) threshold of 47 x 10(-5) mm(2)/s
      (corresponding to a 33% reduction in ADC(av) based on a contralateral hemisphere
      comparison) provided the most accurate estimate of percent hemispheric lesion
      volume (%HLV). Experimental and data analysis issues for improving and validating
      the usefulness of DWI as a surrogate endpoint for the quantification of ischemic
      lesion volume are discussed.

PMID- 15172060
TI  - Structural changes in glutamate cell swelling followed by multiparametric q-space
      diffusion MR of excised rat spinal cord.
AB  - Diffusion in the extracellular and intracellular spaces (ECS and ICS,
      respectively) was evaluated in excised spinal cords, before and after cell
      swelling induced by glutamate, by high b-value q-space diffusion MR of specific
      markers and water. The signal decays of deuterated tetramethylammonium (TMA
      d(12)) chloride, an exogenous marker of the ECS, and N-acetyl aspartate (NAA), an
      endogenous marker of the ICS, were found to be non-mono-exponential at all
      diffusion times. The signal decays of these markers were found to depend on the
      diffusion time and the cell swelling induced by the glutamate. It was found, for
      example, that the mean displacements of the apparent fast and slow diffusion
      components of TMA-d(12) are 7.21 +/- 0.11 and 1.16 +/- 0.05 microm, respectively
      at a diffusion time of 496 ms. After exposure of the spinal cords to 10 mM of
      glutamate, these values decreased to 6.62 +/- 0.13 and 1.01 +/- 0.05 microm,
      respectively. The mean displacement of NAA, however, showed a less pronounced
      opposite trend and increased after cell swelling induced by exposure to
      glutamate. q-Space diffusion MR of water was found to be sensitive to exposure to
      glutamate, and q-space diffusion MRI showed that a more pronounced decrease in
      the apparent diffusion coefficient and the mean displacement of water is observed
      in the gray matter (GM) of the spinal cord. All these changes demonstrate that
      diffusion MR is indeed sensitive to structural changes caused by cell swelling
      induced by glutamate. Multiparametric high b-value q-space diffusion MR is useful
      for obtaining microstructural information in neuronal tissues.

PMID- 15172061
TI  - T2 relaxation time measurements in osteoarthritis.
AB  - Quantification of changes in T(2) relaxation time, in human cartilage, with
      progression of osteoarthritis (OA), and evaluation of qualitative correlations
      with clinical evaluation, histology and polarized light microscopy (PLM).
      Cartilage-bone plugs were harvested from fresh cadaveric knees (n = 10) and
      specimens after surgical knee replacement (n = 2) at 12 locations, including
      lateral and medial sides of tibia, femora and patella. Magnetic resonance imaging
      was performed at 1.5 Tesla using a.2D spin echo sequence. Histological slices
      were assessed for OA severity through a grading scale based on combined
      histological and PLM results. T(2) values in clinically moderate OA were
      generally higher than in severe OA and normal cartilage. Significant association
      was established between normal and early OA subjects and T(2) variation, in the
      medial compartment of the knee (p < 0.05) but especially in the medial tibial
      cartilage (p < 0.00005). As expected, medial and lateral tibio-femoral
      compartments underwent more severe degeneration. Additionally, there were
      intracompartmental variation of the relaxation times and histological patterns,
      which demonstrate the underlying focal involvement of OA in the knee.
      Furthermore, T(2) values reflected OA pathogenesis with a positive correlation
      with histology grading scale. Finally, increased T(2) is correlated to
      histological degeneration of cartilage and may be a good marker for early OA in
      tibial articular cartilage.

PMID- 15172062
TI  - Proton T1 and T2 relaxivities of serum proteins.
AB  - In the present study, T(1) and T(2) of phantoms containing serum sets with
      varying amounts of proteins, serum samples with certain amounts of proteins,
      serum diluted by distilled water, and serum treated with iron were measured. In
      addition, T(1) and T(2) of phantoms containing normal serum, diluted serum, and
      albumin-doped serum were also measured. Relaxation rates were plotted versus
      protein concentrations. The slope of relation was taken as relaxivity. The T(1)
      relaxivities of proteins were ranged from 0.035 to 0.080 s(-1)(g/dl)(-1), whereas
      T(2) relaxivities were ranged from 0.24 to 0.68 s(-1)(g/dl)(-1). The T(1) and
      T(2) relaxivities of transferrin iron were 2.40 and 2.60 mM(-1)s(-1),
      respectively. The contributions of diamagnetic proteins and transferrin iron to
      the relaxation rate of serum were also calculated for each of diluted serum,
      normal and albumin-doped serum. The contributions and the average TP
      relaxivities(calculated by using individual relaxivities and the ratios of
      protein fractions in TP) were used for TP calculations. The agreement between the
      calculated TP and TP by autoanalyzer and also the agreement between average TP
      relaxivities and the TP relaxivities determined from dilution experiments show
      that the data of relaxivities are reliable. The results suggest that individual
      protein relaxivities explain the influence of serum TP composition on T(1) and
      T(2) relaxation times.

PMID- 15172063
TI  - Analysis of 1H-NMR relaxation time distributions in L1 to L6 rat lumbar
      vertebrae.
AB  - A better knowledge of the NMR relaxation behavior of bone tissue can improve the
      definition of imaging protocols to detect bone diseases like osteoporosis. The
      six rat lumbar vertebrae, from L1 to L6, were analyzed by means of both
      transverse (T(2)) and longitudinal (T(1)) relaxation of (1)H nuclei at 20 MHz and
      30 degrees C. Distributions of relaxation times, computed using the
      multiexponential inversion software uniform penalty inversion, extend over
      decades for both T(2) and T(1) relaxation. In all samples, the free induction
      decay (FID) from an inversion-recovery (IR) T(1) measurement shows an
      approximately Gaussian (solid-like) component, exp[-1/2(t/T(GC))2], with T(GC)
      approximately 12 micros (GC for Gaussian component) and a liquid-like component
      (LLC) with initially simple-exponential decay. Averaging and smoothing procedures
      are adopted to obtain the ratio alpha between GC and LLC signals and to get
      separate T(1) distributions for GC and LLC. Distributions of T(1) for LLC show
      peaks centered at 300-500 ms and shoulders going down to 10 ms, whereas
      distributions of T(1) for GC are single broad peaks centered at roughly 100 ms.
      The T(2) distributions by Carr-Purcell-Meiboom-Gill at 600 micros echo spacing
      are very broad and extend from 1 ms to hundreds of ms. This long echo spacing
      does not allow one to see a peak in the region of hundreds of micros, which is
      better seen by single spin-echo T(2) measurements. Results of the relaxation
      analysis were then compared with densitometric data. From the study, a clear
      picture of the intratrabecular and intertrabecular (1)H signals emerges. In
      particular, the GC is presumed to be due to (1)H in collagen, LLC due to all the
      fluids in the bone including water and fat, and the very short T(2) peak due to
      the intratrabecular water. Overall, indications of some trends in composition and
      in pore-space distributions going from L1 to L6 appeared. Published results on
      rat vertebrae obtained by fitting the curves by discrete two-component models for
      both T(2) and T(1) are consistent with our results and can be better interpreted
      in light of the shown distributions of relaxation times.

PMID- 15172064
TI  - Biochemical characterization of metastatic lymph nodes of breast cancer patients
      by in vitro 1H magnetic resonance spectroscopy: a pilot study.
AB  - Using one-dimensional (1D) and two-dimensional (2D) proton nuclear magnetic
      resonance (NMR) methods, the perchloric acid extract of involved (n = 11) and
      noninvolved (n = 12) axillary lymph nodes (ALN) of breast cancer patients was
      investigated. Resonances from 40 metabolites such as lactate (Lac), glucose,
      several amino acids (alanine, lysine, glutamic acid, glutamine, etc.),
      nucleotides (adenosine triphosphate, guanosine triphosphate, uridine
      triphosphate, uridine monophosphate, etc.), membrane metabolites
      [glycerophosphocholine (GPC), phosphocoline (PC), phosphoethanolamine (PE),
      choline] were unambiguously assigned in both the involved and noninvolved ALN.
      The concentration of PC/GPC (p = 0.002) was significantly higher in the involved
      compared to noninvolved nodes. In addition, the concentration of glycolytic
      product Lac (p = 0.0001) was also found to be significantly higher in involved
      nodes. Increased concentration of membrane metabolites PC/GPC may be attributed
      to increased membrane synthesis in malignant cells and, therefore, suggests the
      presence of metastatic cells in lymph nodes. The higher concentration of Lac is
      indicative of the presence of malignant cells that derive energy via anaerobic
      glycolytic pathway. Present results demonstrate the potentials of in vitro proton
      NMR in detecting malignant cells in ALN and such studies may have an important
      bearing in determining the prognosis of breast cancer patients.

PMID- 15172066
TI  - In vivo 31P-MRS assessment of muscle-pH, cytolsolic-[Mg2+] and phosphorylation
      potential after supplementing hypokaliuric renal stone patients with potassium
      and magnesium salts.
AB  - Renal stone patients in rural northeast Thailand have a low potassium and
      magnesium status and low urinary excretion of citrate. We measured the changes of
      urinary citrate excretion and assessed in vivo skeletal muscle metabolism for
      intracellular-pH, cytosolic-[Mg(2+)] and phosphorylation potential (using the
      phosphorus magnetic resonance spectroscopy (31)P-MRS) after oral supplementation
      to hypokaliuric renal stone patients with oral potassium and magnesium salts. The
      patients comprised four groups: Group 1 (n = 10) control, Group 2 (n = 3), Group
      3 (n = 5) and Group 4 (n = 6) supplemented for a month with potassium citrate,
      potassium citrate plus amino acid chelated magnesium, and potassium-magnesium
      citrate, respectively. Though urinary citrate excretion was increased in all
      three supplemented groups, the increases in intracellular-pH, cytosolic-[Mg(2+)]
      and phosphocreatine (PCr)/beta-ATP were prominent only in Group 3. The increase
      in PCr/beta-ATP was also observed in Group 4.

PMID- 15172065
TI  - Occupational prolonged organic solvent exposure in shoemakers: brain MR
      spectroscopy findings.
AB  - Our purpose was to investigate, by magnetic resonance (MR) spectroscopy, the
      metabolite changes in the brains of subjects in the shoemaking industry who had
      been chronically exposed to organic solvents. A total of 49 male subjects and 30
      age-matched healthy volunteers underwent detailed neurological and psychiatric
      examinations. All subjects had long-echo [repetition time (TR) 2000 ms, echo time
      (TE) 136 ms] single-voxel MR spectroscopy. Voxels (15 x 15 x 15 mm(3)) were
      placed in the parietal white matter, thalamus, and basal ganglia. N
      acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios were calculated.
      There was no significant difference between the study subjects and the control
      group in NAA/Cr ratios obtained from thalamus, basal ganglia, and parietal white
      matter. Cho/Cr ratios in thalamus, basal ganglia, and parietal white matter were
      found to be significantly increased compared to controls. There was a positive
      correlation between basal ganglia Cho/Cr ratio and duration of exposure (r =
      0.63). MR spectroscopy should be performed to reveal metabolite changes and
      determine the degree of brain involvement in solvent-related industry workers.

PMID- 15172067
TI  - Brain metabolite concentration ratios in vivo: multisite reproducibility by
      single-voxel 1H MR spectroscopy.
AB  - Ten normal subjects were scanned identically at three separate sites (Little
      Rock, Houston, and New Orleans) to evaluate the reproducibility of brain
      metabolite ratios in single-voxel (1)H point-resolved spectroscopy sequence
      (PRESS) magnetic resonance (MR) spectroscopy in vivo. All scans were processed by
      a single individual at a single site. Coefficients of variation of the measured
      metabolite ratios generally were in the range found for previous single-voxel,
      single-site reproducibility studies. No differences were found among the sites
      for ratios of N-acetylaspartate to creatine (NAA/Cr) or choline to Cr (Cho/Cr) in
      left thalamus by multivariate ANOVA. Metabolite ratios of Cr or Cho relative to
      local brain H(2)O did not vary among the sites. However, by multivariate ANOVA,
      NAA/H(2)O differed between Little Rock and New Orleans, but not between those
      sites and Houston. Intraclass correlation coefficients suggested reasonable
      reproducibility between Little Rock and New Orleans, but not between those sites
      and Houston.

PMID- 15172068
TI  - Lithium spectroscopic imaging of rat brain at therapeutic doses.
AB  - Since the discovery that lithium (Li) is efficacious for the treatment of manic
      depressive illness, the brain Li distribution of mammals treated with lithium has
      been of interest. However, the spatial relationship of lithium in the brain
      regions to its function remains largely unknown. Knowledge of Li distribution in
      the brain is necessary to localize its action in the brain. Both the therapeutic
      and neurotoxic side effects of Li are centered mainly in the central nervous
      system and hence there is considerable interest in understanding the extent of
      lithium penetration into the central nervous system. The mechanism by which
      neurotoxic side effects are generated is not known and may, in part, be related
      to the particular distribution of lithium in the brain. The regional specificity
      in lithium's brain distribution could underlie important steps on its action. Li
      levels in various brain regions for autopsied rats and humans have been reported.
      However, many results are conflicting due to ion redistribution at death or
      during sample preparation. A direct nondestructive measurement of Li levels in
      the brain where the drug exerts its effects is certainly desirable. Because
      magnetic resonance technique can be used to observe Li, it can be an appropriate
      method to monitor and map the distribution in the brain. The application of MR
      technology to rat brain regions has provided information on lithium distribution
      in a non-invasive manner. The earlier development work at lower field strengths
      provided brain lithium information at high dose of Li administration. Here we
      demonstrate the feasibility of quantitative spectroscopic imaging on rat brain
      under therapeutic doses.

PMID- 15172070
TI  - Peripheral nerve diffusion tensor imaging.
AB  - We examined if MR diffusion tensor imaging with fiber tracking could be performed
      on the sciatic nerve. In 3 healthy volunteers the proximal thigh was examined on
      a 1.5-Tesla MR-scanner with a 2-channel phased-array coil. Though inherently
      susceptible to motion, field inhomogeneities, and fast T(2)-relaxation of the
      diffusion imaging technique, the sciatic nerve could be detected and correlated
      to T(2)-weighted images in all 3 subjects. Further investigations need to be done
      to improve the signal-to-noise ratio and to see if smaller peripheral nerves than
      the sciatic nerve can be detected.

PMID- 15172069
TI  - In vivo quantification of the metabolites in normal brain and brain tumors by
      proton MR spectroscopy using water as an internal standard.
AB  - Metabolite concentrations in normal adult brains and in gliomas were
      quantitatively analyzed by in vivo proton magnetic resonance spectroscopy (MRS)
      using the fully relaxed water signal as an internal standard. Between January
      1998 and October 2001, 28 healthy volunteers and 18 patients with gliomas were
      examined by in vivo proton MRS. Single-voxel spectra were acquired using the
      point-resolved spectroscopic (PRESS) pulse sequence with a 1.5 T scanner
      (TR/TE/Ave = 3000 ms/30 ms/64). The calculated concentrations of N-acetyl
      aspartate (NAA), creatine (Cre), choline (Cho), and water(H(2)O) in the normal
      hemispheric white matter were 23.59 +/- 2.62 mM (mean +/- SD), 13.06 +/- 1.8 mM,
      4.28 +/- 0.8 mM, and 47280.96 +/- 5414.85 mM, respectively. The metabolite
      concentrations were not necessarily uniform in different parts of the brain. The
      concentrations of NAA and Cre decreased in all gliomas (p < 0.001). The NAA/Cho
      and NAA/H(2)O ratios can distinguish the normal brain from gliomas and low-grade
      from high-grade astrocytoma (p < 0.001). The concentration of taurine (Tau) in
      medulloblastomas was 29.64 +/- 5.76 mM. This is the first quantitative analysis
      of Tau in medulloblastoma in vivo and confirms earlier in vitro findings.

PMID- 15172071
TI  - Multiple spinal epidural abscesses extending to the whole spinal canal.
AB  - Spinal epidural abscess (SEA) is a rare life-threatening disease mostly affecting
      patients with an altered immune system. It presents as a sequela of adjacent
      infection or hematogenous spread. MRI is the method of choice in evaluating
      patients with suspected SEAs and should always include the whole spinal canal,
      excluding the exceedingly rare possibility of multiple epidural collections. We
      present a rare case of a patient with no predisposing factors suffering from
      multiple SEAs, extending to the whole spinal canal.

PMID- 15172072
TI  - Postmortem toxicology.

PMID- 15172073
TI  - Preanalytic aspects in postmortem toxicology.
AB  - The preanalytic phase has been recognized to have a substantial role for the
      quality and reliability of analytical results, which very much depend on the type
      and quality of specimens provided. There are several unique challenges to select
      and collect specimens for postmortem toxicology investigation. Postmortem
      specimens may be numerous, and sample quality may be quite variable. An overview
      is given on specimens routinely collected as well as on alternative specimens
      that may provide additional information on the route of administration, a long
      term or a recent use/exposure to a drug or poison. Autolytic and putrefactive
      changes limit the selection and utility of specimens. Some data from case reports
      as well as experimental investigations on drug degradation and/or formation
      during putrefaction are discussed. Diffusion processes as well as postmortem
      degradation or formation may influence ethanol concentration in autopsy
      specimens. Formalin fixation of specimens or embalmment of the corpse may cause
      considerable changes of initial drug levels. These changes are due to alterations
      of the biological matrix as well as to dilution of a sample, release or
      degradation of the drug or poison. Most important seems a conversion of desmethyl
      metabolites to the parent drug. Some general requirements for postmortem sampling
      are given based on references about specimen collection issues, for a harmonized
      protocol for sampling in suspected poisonings or drug-related deaths does not
      exist. The advantages and disadvantages of specimen preservation are shortly
      discussed. Storage stability is another important issue to be considered.
      Instability can either derive from physical, chemical or metabolic processes. The
      knowledge on degradation mechanisms may enable the forensic toxicologist to
      target the right substance, which may be a major break down product in the
      investigation of highly labile compounds. Although it is impossible to eliminate
      all interfering factors or influences occurring during the preanalytic phase,
      their consideration should facilitate the assessment of sample quality and the
      analytical result obtained from that sample.

PMID- 15172075
TI  - Automatic screening in postmortem toxicology.
AB  - The systematic analysis of postmortem samples is one of the most challenging
      tasks in forensic toxicology. For determining cause of death, analysis of
      different tissues can be indispensable. Automation of these analyses would
      increase reproducibility and therefore lead to more reliable and comparable
      results. Recent developments in analytical toxicology and the availability of
      automation devices for various analytical stages, such as sampling, preliminary
      testing, sample extraction, chromatographic separation, identification, and data
      processing are examined and discussed. At present only parts of the analytical
      procedure have been automated-however, the goal should be the integration of
      these parts into a single, continuous process. Currently, only one "fully
      automated" procedure for the comprehensive screening of blood and urine
      (excluding sample pretreatment, which remains separate) has been published. But
      it can be expected that automation of analytical procedures in forensic
      toxicology will indeed progress, even with regard to the very complex screening
      of postmortem samples.

PMID- 15172074
TI  - Postmortem toxicology of drugs of abuse.
AB  - Conducting toxicology on post-mortem specimens provides a number of very
      significant challenges to the scientist. The range of additional specimens
      include tissues such as decomposing blood and other tissues, hair, muscle, fat,
      lung, and even larvae feeding on the host require special techniques to isolate a
      foreign substance and allow detection without interference from the matrix. A
      number of drugs of abuse are unstable in the post-mortem environment that
      requires careful consideration when trying to interpret their significance.
      Heroin, morphine glucuronides, cocaine and the benzodiazepines are particularly
      prone to degradation. Moreover, redistributive process can significantly alter
      the concentration of drugs, particularly those with a higher tissue concentration
      than the surrounding blood. The designer amphetamines, methadone and other potent
      opioids will increase their concentration in blood post-mortem. These processes
      together with the development of tolerance means that no concentration of a drug
      of abuse can be interpreted in isolation without a thorough examination of the
      relevant circumstances and after the conduct of a post-mortem to eliminate or
      corroborate relevant factors that could impact on the drug concentration and the
      possible effect of a substance on the body. This article reviews particular
      toxicological issues associated with the more common drugs of abuse such as the
      amphetamines, cannabinoids, cocaine, opioids and the benzodiazepines.

PMID- 15172076
TI  - Value of hair analysis in postmortem toxicology.
AB  - It is generally accepted that chemical testing of biological fluids is the most
      objective means of diagnosis of drug use. The presence of a drug analyte in a
      biological specimen can be used to document exposure. The standard in postmortem
      drug testing is a general unknown screening, followed by the gas
      chromatographic/mass spectrometric confirmation conducted on a whole blood
      sample. In recent years, remarkable advances in sensitive analytical techniques
      have enabled the analysis of drugs in unconventional biological specimens such as
      hair. The advantages of this sample over traditional media, like urine and blood,
      are obvious: collection is almost non-invasive, relatively easy to perform, and
      in forensic situations it may be achieved under close supervision of law
      enforcement officers to prevent adulteration or substitution. Moreover, the
      window of drug detection is dramatically extended to weeks, months or even years.
      The aim of this review is to document the current status of hair analysis in
      postmortem toxicology.

PMID- 15172077
TI  - Volatile substance abuse--post-mortem diagnosis.
AB  - A substantial number of children and adolescents world-wide abuse volatile
      substances with the intention to experience an euphoric state of consciousness.
      Although the ratio of deaths to nonfatal inhalation escapades is low, it is an
      important and preventable cause of death in young people. In the analytical
      investigation of volatile substances proper sample collection, storage and
      handling are important in view of the volatile nature of the compounds. Volatile
      organic compounds in post-mortem matrices such as blood, urine and tissues are
      generally determined by gas chromatography after extracting the compounds with
      methods such as static and dynamic headspace or even with pulse-heating and
      solvent extraction. In post-mortem cases, metabolites in urine seem less
      relevant, however, trichloroethanol and trichloroacetic acid were determined in
      several cases. When interpreting qualitative and quantitative results,
      researchers should be aware of false conclusions. The main reason why scepticism
      is necessary is the occurrence of losses of analytes during sampling, sample
      handling and storage, which results in false quantitation.

PMID- 15172078
TI  - A forensic toxicological dilemma: the interpretation of post-mortem
      concentrations of central acting analgesics.
AB  - Dora V., a 88-year-old pensioner suffering from a hiatus hernia, died at the home
      of an orthopaedist and his wife, an anaesthetist, immediately after she had
      received a dose of 300 mg pethidine via intravenous infusion in a timeframe of
      about 90 min. One day before her death a befriended notary of the couple visited
      Dora V. and obtained a blank signature. After her death, a will was forged using
      this signature, rendering the couple sole heirs of Dora V.'s estate with a value
      of several million euros. Post-mortem toxicology was performed in three different
      institutes of legal medicine. The concentrations of pethidine in peripheral
      venous blood were between 6.1 and 6.5mg/l and 9.5 and 17.2mg/kg in brain.
      Pharmacokinetic calculation confirms the given dose. There was no doubt that the
      cause of death was acute pethidine intoxication. The accused couple claimed that
      this dose of pethidine was indicated to relief pain, and as the pathologists said
      in their expert opinions that the hiatus hernia could explain her death, the
      court had to acquit the accused. This very special case demonstrates that
      preconceived murder of a sick person with suitable analgesics cannot be proven-
      at least not with the methods available to forensic toxicology and pathology.
      This has to be taken into consideration if euthanasia will be legalised under
      special circumstances.

PMID- 15172079
TI  - Fatal blood and tissue concentrations of more than 200 drugs.
AB  - Fatal drug concentrations in body fluids and tissue samples are presented for
      more than 200 drugs and chemicals of toxicologic interest. Additionally, a
      reference list is added with more than 600 original papers concerning
      intoxications with a lethal outcome. The data can be helpful for the
      interpretation and plausibility control in own cases of intoxication. However,
      they should be used with caution, because use of drug data without sufficient
      knowledge about the patient or victim, the circumstances of the case, and about
      toxicokinetics and toxicodynamics might give a wrong interpretation in a special
      case.

PMID- 15172080
TI  - Postmortem serotonin (5-HT) concentrations in the cerebrospinal fluid of
      medicolegal cases.
AB  - In a medicolegal study the postmortem serotonin (5-HT) cerebrospinal fluid (CSF)
      concentrations were determined in routine autopsies using a high performance
      liquid chromatographic procedure with electrochemical detection. There was no
      correlation between 5-HT concentrations and age, sex or blood alcohol
      concentration using a postmortem delay < or = 3 days. In suicides the
      suboccipital CSF concentrations were significantly decreased compared to the
      levels measured in the control group (8.55+/-5.99 ng/ml versus 20.15+/-13.56
      ng/ml). Additionally, a decrease of 5-HT was found in the suboccipital CSF of
      opiate fatalities (15.56+/-13.52 ng/ml). The results support the hypothesis that
      decreased 5-HT concentrations in the CSF are characteristic in suicides. However,
      due to a rather broad overlapping of values between suicides and controls the
      results failed to define a possible cut-off level in the 5-HT CSF concentration
      to distinguish between a suicidal and a non-suicidal incident.

PMID- 15172081
TI  - Brain amino acid abnormalities in kidney disease and diabetes mellitus.
AB  - The present postmortem study examines whether specific amino acid abnormalities
      associated with renal diseases or diabetes mellitus in animal experiments and on
      clinical examination may also be found in human brain samples obtained at
      clinical autopsies. The material includes 12 deceased with renal insufficiency,
      23 deceased with diabetes mellitus and 26 control cases with lethal
      cardiovascular diseases (without a history of hepatic, renal or metabolic
      disturbances). The autopsy and clinical records were retrospectively analyzed for
      age, sex, postmortem delay, cause of death, substantial preexisting diseases and
      histological findings. The analysis of free amino acid concentrations in human
      brain specimens was performed applying a Beckman amino acid analyzer. The results
      were evaluated using the U-test according to Mann, Willcox and Whitney. A P-value
      less than 0.05 was considered to be significantly different. Differences of amino
      acid concentrations attributable to sex, age and postmortem delay were not
      significant. The comparison of postmortem amino acid concentrations in the brains
      of patients with diabetes mellitus and controls did not reveal relevant changes.
      However, the patients with renal diseases, as compared to controls, showed a
      significant cerebral increase of urea, phenylethanolamine and gamma-aminobutyric
      acid. Thus, the postmortem amino acid analysis may contribute to the
      understanding of pathophysiological mechanisms of uremic encephalopathy and may
      supplement the conventional postmortem morphological diagnosis in kidney diseases
      by indication of functional impairment.

PMID- 15172082
TI  - Prevention of postmenopausal bone loss by pulsed estrogen therapy: comparison
      with transdermal route.
AB  - OBJECTIVE: To compare the efficacy of pulsed estrogen therapy following
      intranasal 17beta-estradiol (E2) (S21400) with patch E2 in preventing
      postmenopausal bone loss and on bone turnover. METHODS: In this multinational
      open study, 361 postmenopausal women aged 51.5 (S.D. 4.6) years were treated with
      S21400 300 microg per day or patch E2 (delivering 50 microg per day), two patches
      per week, for 56 weeks. Bone mineral density (BMD) was assessed at the spine and
      hip using dual X-ray absorptiometry at baseline and week 56 (W56). Bone turnover
      markers (osteocalcin, bone alkaline phosphatase, urinary type I collagen C
      telopeptides) were measured at baseline and weeks 12, 28 and 56. RESULTS: Spine
      and hip bone mineral density significantly increased in both groups (P < 0.001
      versus baseline). Mean (S.D.) percent increases were 2.1 (3.0) at the spine (both
      groups), and 1.2 (2.4) and 1.1 (2.2) at the hip in the S21400 and patch E2
      groups, respectively. Bone mineral density also significantly increased (P <
      0.001 versus baseline) in osteopenic patients following S21400 and patch E2: 3.1
      (3.5) and 2.4 (3.5) at the spine, and 2.0 (2.6) and 1.2 (2.7) at the hip,
      respectively. Bone metabolism was normalized at week 56 with a significant
      decrease (P < 0.001) from baseline in all markers: 56% and 53% for type I
      collagen C-telopeptides, and 24% and 25% for osteocalcin in the S21400 and patch
      E2 groups, respectively. CONCLUSION: Pulsed estrogen therapy was as effective in
      normalizing bone turnover and preventing postmenopausal bone loss as a reservoir
      patch.

PMID- 15172083
TI  - Vasomotor symptoms and quality of life in previously sedentary postmenopausal
      women randomised to physical activity or estrogen therapy.
AB  - OBJECTIVE: To assess if regular physical exercise or oral oestradiol therapy
      decreased vasomotor symptoms and increased quality of life in previously
      sedentary postmenopausal women. SETTING: A prospective, randomised trial at a
      University Hospital. METHODS: 75 postmenopausal, sedentary women with vasomotor
      symptoms were randomised to: exercise three-times weekly over 12 weeks (15
      women), oral oestradiol therapy for 12 weeks (15 women) and 45 women to three
      other treatment arms. Results from the exercise and oestradiol groups are
      presented here. The effects on vasomotor symptoms and wellbeing were assessed
      with logbooks and validated questionnaires. RESULTS: Ten women fulfilled 12 weeks
      of exercise. The number of flushes was rather unchanged in five women and
      decreased to 28% (range 18-42%) of baseline in the other five women. Five of the
      ten women continued to exercise another 24 weeks, thus in all 36 weeks. The mean
      number of flushes decreased by about 50% in these five women (from 6.2/24 to 3.2
      flushes/24 h at 36 weeks). In the same group a score made as the product of
      reduction in number and severity of flushes decreased by 92% at 12 weeks, 75% at
      24 weeks and 72% at 36 weeks compared with baseline. In the estrogen group
      flushes decreased from 8.4 to 0.8 (P<0.001) after 12 weeks of therapy and
      remained at this level after 36 weeks. Well-being according to different
      measurements improved significantly in both groups, albeit more markedly in the
      estrogen group. CONCLUSIONS: Apart from many other health benefits regular
      physical exercise may decrease vasomotor symptoms and increase quality of life in
      postmenopausal women, but this has to be further evaluated scientifically.
      Exercise should be introduced gradually to ensure compliance.

PMID- 15172084
TI  - Effect of hormone replacement therapy and tibolone on serum leptin levels in
      postmenopausal women.
AB  - OBJECTIVE: To evaluate the effect of estrogen replacement therapy (ERT),
      continuous combined hormone replacement therapy (HRT) and tibolone on serum
      leptin levels in healthy postmenopausal women. METHODS: Eighty-four healthy
      postmenopausal women aged 43-63 years were studied prospectively. Hysterectomized
      women (n = 16) received conjugated equine estrogens (CEE) 0.625 mg. Women with an
      intact uterus were randomly allocated either to CEE+medroxyprogesterone acetate
      (CEE/MPA) 5 mg or tibolone 2.5 mg. Serum leptin levels were assessed at baseline
      and after 6 months of treatment. RESULTS: The three groups did not differ with
      respect to age, body mass index (BMI) or baseline serum leptin levels. Overweight
      women (BMI > 25 kg/m2) had higher baseline leptin levels (27.0 +/- 11.4 ng/ml)
      compared to their lean counterparts (BMI < or = 25 kg/m2; leptin: 16.5 +/- 8.1
      ng/ml, P = 0.0001). Neither CEE nor CEE/MPA had any effect on serum leptin levels
      at the end of 6 months either in overweight or in lean women (overweight: CEE
      baseline 34.4 +/- 13.3 ng/ml, 6 months 36.9 +/- 15.8, P = 0.89, CEE/MPA baseline
      22.4 +/- 9.8 ng/ml, 6 months 26.8 +/- 8.7 ng/ml, P = 0.1; lean: CEE baseline 12.6
      +/- 4.4 ng/ml, 6 months 13.2 +/- 5.8 ng/ml, P = 0.36, CEE/MPA baseline 17.2 +/-
      10.6 ng/ml, 6 months 18.8 +/- 8.8 ng/ml, P = 0.31). Similarly serum leptin
      remained unchanged at the end of the study in both lean and overweight women on
      tibolone (overweight: baseline 22.9 +/- 8.1 ng/ml, 6 months 18.5 +/- 12 ng/ml, P
      = 0.37; lean: baseline 13.2 +/- 5.6 ng/ml, 6 months 17.3 +/- 8.4 ng/ml).
      CONCLUSION: BMI is a strong determinant of serum leptin levels in healthy
      postmenopausal women. Neither ERT/HRT nor tibolone exert any effect on serum
      leptin after 6 months in lean or overweight postmenopausal women. Further studies
      are required to verify the exact role of estrogen and tibolone on leptin
      production and function in postmenopausal women.

PMID- 15172085
TI  - Psychological status at the menopausal transition: an Italian epidemiological
      study.
AB  - OBJECTIVES: To provide epidemiological data about psychological symptoms derived
      from a large Italian non-clinical sample, and to investigate the correlation with
      psychosocial factors. METHODS: The study design was a cross-sectional postal
      survey of a sample of menopausal women recruited from the General Registry Office
      in Ferrara's province. Four thousands and seventy-three women were sent a
      questionnaire designed on the basis of the Women Health Questionnaire (WHQ).
      Together with the WHQ, women were asked to fill out a personal file to define
      social status, cultural level, family's characteristics, recent menstrual cycles,
      gynaecological history and operations, drug's assumption, life events in the last
      year and lifetime depression. RESULTS: Factor analysis resulted in eight clusters
      of symptoms. Among psychiatric symptoms, three different clusters were
      identified: depressive symptoms, depressed mood with anxiety symptoms, and
      anxiety. The cluster "depressive symptoms" was more evident in the postmenopausal
      period with respect to the premenopausal one. CONCLUSION: The cluster "depressive
      symptoms" is significantly different in the premenopausal group with respect to
      the postmenopausal group, with greater levels of symptomatology in the
      postmenopausal group. On the contrary, the factor "depressed mood with anxiety
      symptoms" is present to the same extent in the pre-, peri- and postmenopausal
      groups. Prior depression is the most predictive variable of subsequent depression
      in postmenopausal women. Factors related to more pronounced depressive symptoms
      are number of life events, postmenopausal status, place of residence in rural
      areas and lower cultural level.

PMID- 15172086
TI  - Prolonged use of gonadotropin-releasing hormone agonist and tibolone as add-back
      therapy for the treatment of endometrial hyperplasia.
AB  - OBJECTIVES: To investigate the response of the various hyperplastic disorders of
      the endometrium to a prolonged treatment with leuprolide acetate, a gonadotropin
      releasing hormone agonist (GnRH-a), plus tibolone, as add-back therapy, and
      further to study if the tibolone addition reduces the hypoestrogenic actions of
      the GnRH-analogue. METHODS: We treated 26 women with histologically confirmed
      simple (n = 9), complex (n = 15) or atypical (n = 2) endometrial hyperplasia (EH)
      for 12 months with monthly injections of 1Ampulle/3.75 mg of leuprolide acetate,
      followed by tibolone, 2.5mg per day per os. Every woman underwent a hysteroscopic
      evaluation and biopsy of the endometrium after 3 (in cases with atypical EH), 6
      and 12 months of treatment, as well as after 12 and 24 months of follow-up. The
      clinical, paraclinical and laboratory course of the disease was followed-up by
      using of a climacteric scoring system and by testing of various parameters.
      RESULTS: The histopathologic evaluation of the endometria revealed regression of
      EH in all women after 12 months of treatment, however, during the first 2 years
      of follow-up EH reappeared in four women (4/21, 19%). Bone mineral density and
      serum parameters did not show significant changes during treatment, whereas only
      a mild suffering from hypoestrogenic side-effects was noted. CONCLUSIONS: It
      seems that the combined GnRH-a/tibolone treatment in women with EH is a potent
      alternative, so far as the endometrial status and the clinical course of the
      disease are concerned, whereas tibolone appears to act sufficiently as add-back
      therapy to prolonged GnRH-a treatment. The probability of relapse of the disease
      during the follow-up period makes the close monitoring of the endometrium after
      cessation of the treatment absolutely necessary.

PMID- 15172087
TI  - Mammographic breast density changes after 1 year of tibolone use.
AB  - Hormone replacement therapy (HRT) is widely used with a large variety of regimens
      and medications. For each of these regimens the goal is the same but there is
      always a fear about side effects, especially on breast. Mammographic screening is
      a standard tool for all women receiving hormone replacement therapy. Breast
      density is very important, because it interferes with the sensitivity of the
      evaluation and it is also a predictor of malignity. OBJECTIVE: We planned a study
      to investigate the effects of tibolone on mammographic breast density. DESIGN AND
      METHODS: We studied 70 postmenopausal women who started tibolone therapy (2.5 mg
      per day) after initial mammography and blood samples taken for biochemical
      examinations. None of the women used any hormone replacement therapy before.
      Eleven of them either discontinued the therapy or lost contact. After 1 year, we
      evaluated 59 women by mammographic status, using Wolfe classification.
      Mammographies were analyzed by two independent radiologists. RESULTS:
      Mammographies of 59 women were compared with the initial ones. While in the low
      density patterns, there was a slight increase (15%; P < 0.05); in the higher
      density groups, there was a decrease of 25% as observed by one radiologist, and
      16% according to the other (P < 0.05). None of the women had a diffuse, high
      density pattern. There was no statistically significant inter-observer variation
      between two radiologists (P < 0.05). CONCLUSIONS: Wolfe classification allows
      easy interpretation of mammographic evaluation and the results are reproducible.
      Tibolone, as a tissue-specific steroid, does not have an estrogenic effect on
      breast cells. We found that it might limit, even reverse breast density increase,
      especially in postmenopausal women with high breast density.

PMID- 15172088
TI  - Effects of continuous combined conjugated estrogen/medroxyprogesterone acetate
      and 17beta-estadiol/norethisterone acetate on lipids and lipoproteins.
AB  - OBJECTIVES: Various estrogen/progestogen combinations used in hormonal
      replacement therapy (HRT) have been reported to influence lipid and lipoprotein
      fractions differently. This motivated a comparative study where the two
      continuous combined regimens most commonly used in Sweden during the 1990s have
      been studied regarding effects on lipid profile. METHODS: In a 1-year
      prospective, double-blind study, 62 post-menopausal women were randomized to
      conjugated estrogen (CE), 0.625 mg, and medroxyprogesterone acetate (MPA), 5 mg,
      or 17beta-estradiol (E2), 2 mg, and norethisterone acetate (NETA), 1 mg. Serum
      concentrations of lipids and lipoproteins were measured at baseline and after 1
      year of treatment. RESULTS: Both treatment groups significantly lowered the
      lipoprotein(a) (Lp(a)) levels. The CE/MPA group showed no significant changes in
      total cholesterol (TC), high-density (HDL) and low-density lipoprotein (LDL), but
      a significant increase of triglyceride (TG) levels. The E2/NETA group developed a
      significant lowering of total cholesterol, HDL, and LDL, but no significant
      changes of TG levels. The magnitude of change in serum concentrations of total
      cholesterol, HDL and TG differed significantly between the two treatment groups.
      CONCLUSIONS: Continuous combined treatment with CE/MPA and E2/NETA equally
      lowered Lp(a), an important risk factor for cardiovascular disease in women.
      Apart from this, the two treatments produced different effects on lipids and
      lipoproteins, findings that are more delicate to interpret.

PMID- 15172089
TI  - Panic disorder in menopause: a case control study.
AB  - OBJECTIVE: The course of panic disorder (PD) is often influenced by the different
      phases of the female reproductive cycle. The aim of this study is to assess PD in
      the climacteric stage and single out possible correlations between symptoms of PD
      and clinical and demographic variables in order to identify possible risk
      factors. METHOD: Forty-five women between 40 and 60 years of age was assessed
      through the SCL-90, the SCID, a "Climacteric Symptoms Questionnaire" (CSQ)
      devised to evaluate psychological symptoms typically associated with menopause,
      the Kupperman Index for the analysis of climacteric symptoms, and plasma level of
      allopregnanolone (ALLO). RESULTS: PD results in eight patients (18%). This group
      does not differ from the controls as far as socio-demographic data is concerned,
      but exhibits significantly higher values in the Kupperman Index, the SCL-90
      total, and the CSQ. The plasma levels of ALLO correlate significantly inversely
      with the total of CSQ and, in any case, negatively with the other variables
      analysed. CONCLUSIONS: PD may arise and worsen with menopause, in correlation
      with greater severity of the climacteric syndrome in its physical and
      psychological symptoms.

PMID- 15172090
TI  - Administration of tibolone decreases 24 h heart rate but not blood pressure of
      post-menopausal women.
AB  - OBJECTIVE: Elevation of blood pressure and heart rate increase the risk of
      cardiovascular disease. Administration of estrogens does not affect heart rate
      but may decrease 24 h blood pressure. In this study, we tested the effect of the
      estro-progestogenic compound tibolone. METHODS: Thirty healthy, post-menopausal
      women were randomized to receive placebo (n = 15) or tibolone, at the commonly
      prescribed dose of 2.5 mg per day (n = 15). Before and after 6 months of
      treatment, in each woman blood pressure and heart rate were monitored every 30
      min for 41 h by an ambulatory device. Valuable readings were those collected from
      8:00 a.m. of the second day to 8:00 a.m. of third day. Analyses were performed of
      24 h, day-time (7:00 a.m.-11:00 p.m.) and night-time (11:00 p.m.-7:00 a.m.)
      values. Day to night difference was also calculated. RESULTS: Placebo did not
      modify 24h, day-time, and night-time blood pressure or heart rate values. Day
      night differences were also not affected by placebo. Similarly to placebo,
      tibolone administration did not modify any of the blood pressure parameters taken
      into consideration. By contrast, a significant decline of 24 h heart rate (73.2
      +/- 2.3 beats/min versus 69.3 +/- 1.7 beats/min; P < 0.0008) was observed. The
      effect was significant both at day (76.6 +/- 2.4 beats/min versus 72.1 +/- 1.9
      beats/min; P < 0.0001) and night (65.8 +/ 2.6 beats/min versus 62.4 +/- 1.9
      beats/min; P < 0.05). Day-night blood pressure and heart rate differences were
      not affected by tibolone. CONCLUSIONS: In post-menopausal women, administration
      of tibolone does not influence 24 h blood pressure but reduces heart rate.

PMID- 15172091
TI  - Serum lipids and lipoproteins in relation to endogenous and exogenous female sex
      steroids and age. The Women's Health in the Lund Area (WHILA) study.
AB  - BACKGROUND: Different studies have presented conflicting results concerning the
      effect of menopause on lipid levels. AIMS: To describe the serum lipid profile
      and the prevalence of hyperlipidemia in women aged 50-60 and the perceived
      relation to endogenous and exogenous hormones and age. METHODS: Out of a total
      population of 10,766 women aged 50-59 years, 6908 (64%) participated in a health
      assessment program, including a lipid profile evaluation. The women were grouped
      according to hormonal status into pre-menopausal (PM), post-menopausal without
      hormone replacement therapy (PM0) (HRT) and post-menopausal with hormone
      replacement therapy (PMT). Age groups used were 50-54, 55-59 and >60 years.
      RESULTS: Serum cholesterol and triglycerides increased significantly by age in
      PM0 (P < 0.0001) and triglycerides also in PMT (P < 0.0001). Serum high-density
      lipoprotein cholesterol (HDL) levels decreased significantly by age in PMT (P =
      0.002) and low-density lipoprotein cholesterol (LDL) increased in PM0 (P <
      0.0001) and PMT (P = 0.007). The co-prevalence of levels of cholesterol >7 and
      triglycerides >2 mmol/l decreased by age in PM, but increased by age in PM0 and
      PMT. The prevalence of high-risk lipid levels and the prevalence of coexisting
      additional two metabolic risk factors were higher in the PM0 compared to the PMT
      group. The prevalence of serum triglycerides >1.5 and serum cholesterol >5 mmol/l
      were increasing by age in each of the hormonal groups. CONCLUSIONS: These data
      suggest that loss of endogenous sex steroids contribute substantially to an
      increased atherogenic lipid profile. Hormone replacement therapy may partly
      reverse these differences.

PMID- 15172092
TI  - Endometrial carcinoma on continuous combined HRT: case report and literature
      review.
AB  - BACKGROUND: Continuous combined hormone replacement therapy (HRT) has been
      introduced in an attempt to increase patient compliance by eliminating withdrawal
      bleeding which is one of the most significant and troublesome side effects of
      sequential HRT. Moreover, when given on a daily basis, progestin is thought to be
      more protective against the development of endometrial carcinoma. CASE REPORT: We
      describe the case of a 59-year-old woman, diagnosed with endometrial carcinoma
      while on continuous combined HRT. Her last menstrual period was 7 years ago and
      she had been on HRT ever since. Initially, she tricycled her preparation using
      transdermal gel 17beta-estradiol 1.5 mg daily along with vaginal micronised
      progesterone 200 mg daily from day 1 to 12 every 3 months for the first 5 years
      and she had regular withdrawal bleeding. She was then moved on to continuous
      combined HRT (transdermal gel 17beta-estradiol 2.25 mg daily plus dydrogesterone
      10 mg per os daily) and started to be amenorrhoeic. A routine transvaginal
      ultrasound showed an increased endometrial echo (10 mm). She was completely
      asymptomatic. Further investigations resulted in a report of a well
      differentiated grade II endometrial carcinoma with squamous differentiation. A
      review of literature confirms endometrial cancer to be rare while on continuous
      progesterone and difficulties posed in diagnosing it.

PMID- 15172093
TI  - No evidence for tau duplications in frontal temporal dementia families showing
      genetic linkage to the tau locus in which tau mutations have not been found.
AB  - Given the remarkable similarities between the genetics of tau diseases and the
      genetics of alpha-synuclein diseases, and given the fact that we have recently
      found a triplication of the alpha-synuclein locus in a family in which we had
      shown linkage to the alpha-synuclein locus, we determined to test whether some of
      the several families with autosomal dominant frontal temporal dementia which show
      genetic linkage to the tau locus but in which tau mutations have not been found
      could be caused by similar structural mutations. We did not find any such
      mutations.

PMID- 15172094
TI  - Perceptual and motor contributions to bimanual coordination.
AB  - Following earlier work by Mechsner et al. (Nature 414 (2001) 69), the purpose of
      this experiment was to determine the perceptual and motoric contributions to
      bimanual coordination. Twenty right-handed, healthy, young adults performed
      continuous, horizontal, linear movements of both upper limbs at frequencies of
      1.5 and 2.0 Hz. The goal was to control the spatial-temporal displacement of two
      flags by coordinating upper limb movements in two perceptual conditions. In a
      congruent condition, the movement of the flags matched the movement of the upper
      limbs. In an incongruent condition, the movement of the flags was opposite to the
      movement of the upper limbs. Measures of error in coordination provided support
      primarily for a motor view of bimanual coordination, and failed to replicate the
      earlier findings of Mechsner et al.

PMID- 15172096
TI  - Time course of multisensory interactions during audiovisual speech perception in
      humans: a magnetoencephalographic study.
AB  - During social interaction speech is perceived simultaneously by audition and
      vision. We studied interactions in the processing of auditory (A) and visual (V)
      speech signals in the human brain by comparing neuromagnetic responses to
      phonetically congruent audiovisual (AV) syllables with the arithmetic sum of
      responses to A and V syllables. Differences between AV and A+V responses were
      found bilaterally in the auditory cortices 150-200 ms and in the right superior
      temporal sulcus (STS) 250-600 ms after stimulus onset, showing that both sensory
      specific and multisensory regions of the human temporal cortices are involved in
      AV speech processing. Importantly, our results suggest that AV interaction in the
      auditory cortex precedes that in the multisensory STS region.

PMID- 15172095
TI  - Serotonin receptor subtypes involved in vagus nerve stimulation-induced phrenic
      long-term facilitation in rats.
AB  - Episodic vagus nerve stimulation (VNS) induces phrenic long-term facilitation
      (LTF, a persistent augmentation of phrenic nerve activity after the stimulation
      ends), sensitive to the serotonin 5-HT(1,2,5,6,7) receptor antagonist
      methysergide and similar to that elicited by episodic hypoxia or carotid sinus
      nerve stimulation. This study examined the effect of ketanserin (5-HT(2)
      antagonist) or clozapine (5-HT(2,6,7) antagonist) on VNS-induced LTF in
      anesthetized, vagotomized, paralyzed and ventilated rats to determine which
      receptor subtype(s) is involved. Three episodes of 5 min VNS (50 Hz, 0.1 ms,
      approximately 500 microA) with 5 min intervals elicited phrenic LTF in control
      (amplitude: 38% above baseline at 60 min post-VNS) and ketanserin (2 mg x kg(-1),
      i.p.) pre-treated rats (45%), but not clozapine (3 mg x kg(-1)) rats (8%). These
      data suggest that unlike hypoxia-induced LTF (5-HT(2) receptor-dependent), VNS
      induced LTF requires non-5-HT(2) serotonin receptors, perhaps 5-HT(6) and/or 5
      HT(7) subtype(s).

PMID- 15172097
TI  - Activation of mu opioid receptors in the ventrolateral periaqueductal gray
      inhibits reflex micturition in anesthetized rats.
AB  - This study tested the hypothesis that morphine and other opiates cause urinary
      retention by activating mu opioid receptors in the midbrain periaqueductal gray
      (PAG) region. Selective mu, delta and kappa receptor agonists were microinjected
      into the PAG of urethane-anesthetized rats and the amplitude and incidence of
      bladder contractions were recorded during continuous saline infusion. Arterial
      pressure was monitored through a femoral artery catheter. Microinjection of the
      mu receptor agonist DAMGO into the ventrolateral PAG (vlPAG) suppressed volume
      evoked bladder contractions completely. Bladder contractions ceased within 5 min
      of DAMGO injection and remained essentially undetectable for the rest of the 20
      min recording period. Microinjection of the delta receptor agonist DPDPE into the
      vlPAG did not significantly affect either the amplitude of bladder contractions
      or the time interval separating contractions. The kappa receptor agonist U-69593
      caused no discernible change in amplitude but increased the interval between
      bladder contractions significantly. Microinjection of DAMGO, DPDPE or U-69593
      into the lateral or dorsolateral PAG columns was ineffective. DAMGO injection
      into the vlPAG increased arterial pressure whereas DPDPE and U-69593 produced a
      small but significant depressor response. These data support the hypothesis that
      mu and kappa receptors in the vlPAG participate in the micturition reflex.

PMID- 15172098
TI  - Pharmacological discrimination of protein kinase associated exocytosis mechanisms
      between dopamine and 3,4-dihydroxyphenylalanine in rat striatum using in vivo
      microdialysis.
AB  - To explore the exocytosis mechanism of dopamine and its precursor, 3,4
      dihydroxyphenylalanine (DOPA), we determined the effects of protein-kinase,
      cyclic-AMP-dependent protein-kinase (PKA), Ca(2+)-phospholipid-dependent protein
      kinase (PKC) and Ca(2+)-calmodulin-dependent protein-kinase II (CaMK-II) on
      dopamine and DOPA releases in rat striatum using microdialysis. Basal DOPA and
      dopamine releases were reduced by PKC and CaMK-II inhibitors predominantly, and
      PKA inhibitor weakly. Ca(2+)-evoked releases were reduced by PKC and CaMK-II
      inhibitors, but not by PKA inhibitor. K(+)-evoked (20 min) releases were reduced
      by PKA and CaMK-II inhibitors predominantly, and PKC inhibitor weakly. Sustained
      K(+)-evoked (120 min) releases of DOPA and dopamine were reduced by CaMK-II
      inhibitor, but not by PKC or PKA. DOPA accumulation was reduced by PKA and CaMK
      II inhibitors strongly, and PKC inhibitor weakly. Therefore, the present study
      demonstrates that striatal DOPA exocytosis is regulated by a similar protein
      kinase-associated exocytosis mechanism as that of dopamine.

PMID- 15172099
TI  - Social stress-induced cortisol elevation acutely impairs social memory in humans.
AB  - Although stress is known to affect the memory process, little has been elucidated
      regarding its effect on social memory. In this study, 30 subjects' social memory
      (face-name association memory) performance was tested. Twenty subjects were
      exposed to social stress with a subsequent test of social memory, while the
      remaining ten subjects served as controls. Free cortisol was determined via
      saliva samples taken before and after the social stress exposure. Because stress
      hormones might have biphasic actions on neurons, we separated the subjects with
      cortisol elevations between high and low responders. The high responders had
      significantly impaired social memory. Furthermore, we observed a negative
      relation between social stress-induced cortisol elevation and social memory.
      These results indicate that social stress acutely impairs social memory.

PMID- 15172100
TI  - Lack of association of interleukin-1beta polymorphism with Alzheimer's disease in
      the Jewish population.
AB  - A growing body of evidence suggests that Alzheimer's disease (AD) is associated
      with local inflammation processes, including the activation of inflammatory
      cytokines. We performed a case-control association study between sporadic AD
      patients and the exon 5 position +3953 polymorphism in the potent pro
      inflammatory cytokine, interleukin-1beta (IL-1B). Recent association studies of
      this locus with AD revealed conflicting results, suggesting that the association 
      if it exists - is not universal but rather population specific. In our study no
      association was detected with AD: neither as a risk factor nor as a modifier gene
      affecting the age at onset and disease progression. These findings show no
      evidence for an association between the IL-1B +3953 polymorphism and AD in the
      Jewish population.

PMID- 15172101
TI  - Differential regulation of FAK and PYK2 tyrosine phosphorylation after
      electroconvulsive shock in the rat brain.
AB  - It has been suggested that FAK and PYK2 have differential regulatory pathways and
      differential functions in the central nervous system. The authors have previously
      reported that electroconvulsive shock (ECS) activates PYK2 mediated signaling in
      the rat hippocampus. In the present article, the authors examined the effect of
      ECS on PYK2 and FAK mediated signaling in the rat cerebral cortex and
      hippocampus. Our results showed that ECS activated PYK2 more preferentially than
      FAK in both the cortex and the hippocampus. The association of Src-family kinases
      with FAK and PYK2 was also distinctively affected by ECS; Src was mainly
      associated with PYK2 while Yes was associated with FAK. The phosphorylation of
      FAK and PYK2 at the key tyrosine residue was not well correlated with the
      association with Src-family kinases.

PMID- 15172102
TI  - Exclusion of CYP46 and APOM as candidate genes for Alzheimer's disease in a
      French population.
AB  - Alzheimer's disease (AD) is a complex, multifactorial disorder, probably
      resulting from an interaction between environmental and genetic factors.
      Increasing evidence points to a link between cholesterol turnover and AD,
      suggesting that genes implicated in brain cholesterol homeostasis may be
      potential candidate genes for AD. With this background, we tested the potential
      association of the CYP46, APOM and APOF genes with the risk of developing AD.
      CYP46 encodes the enzyme cholesterol 24-hydrolase, which plays a key role in
      brain cholesterol turnover, and APOF and APOM encode apolipoproteins belonging to
      the large lipocalin family, which also includes ApoE. In contrast to two previous
      reports but in accordance with one other, we were unable to detect an association
      between an intron 2 polymorphism of CYP46 and AD. We also searched for
      polymorphisms within the APOM and APOF by dHPLC. We were unable to detect any
      polymorphisms in the coding and exon/intron sequences of the APOF. Finally, we
      excluded APOM as a genetic determinant of AD in our large French case control
      population.

PMID- 15172103
TI  - Gestural recovery and the role of forward and reversed syllabic repetitions as
      stuttering inhibitors in adults.
AB  - Instead of being the core stuttering 'problem', syllabic repetitions may be a
      biological mechanism, or 'solution', to the central involuntary stuttering block.
      Simply put, stuttering is an endogenous transitory state of 'shadowed speech', a
      choral speech derivative that allows for a neural release of the central block.
      To investigate this possibility, 14 adults who stutter read while listening to
      forward fluent speech, reversed fluent speech, forward stuttered speech, and
      reversed stuttered speech. All conditions induced significant degrees of
      stuttering inhibition when compared to a control condition. However, the reversed
      fluent condition was less powerful than the other three conditions (
      approximately 42% vs. approximately 65%) for inhibiting stuttering. Stuttering
      inhibition appears to proceed by 'gestural recovery', made possible by the
      presence of an exogenous or 'second' set of speech gestures and engagement of
      mirror neurons. When reversed fluent speech was used, violations in normal
      gesture-time relationships (i.e., normal speech entropy) resulted in gestural
      configurations that apparently were inadequately recovered, and therefore, were
      not as conducive to high levels of stuttering inhibition. In contrast, high
      levels of encoding found in the simple syllabic structures of stuttered speech
      allowed its forward and reversed forms to be equally effective for gestural
      recovery and stuttering inhibition. The reversal of repeated syllables did not
      appear to significantly degrade the natural gesture-time relationships (i.e.,
      they were perceptually recognizable). Thus, exogenous speech gestures that
      displayed near normal gestural relationships allowed for easy recovery and fluent
      productions via mirror systems, suggesting a more choral-like nature. The
      importance of syllabic repetitions is highlighted: both their perceived
      (exogenous) and produced (endogenous) forms appear to be fundamental, surface
      acoustic manifestations for central stuttering inhibition via the engagement of
      mirror neurons.

PMID- 15172104
TI  - Prolongation of T(2) relaxation times of hippocampus and amygdala in Alzheimer's
      disease.
AB  - There exists controversy on the MR T(2) relaxometry of hippocampus in Alzheimer's
      disease (AD). The aim of our study was to examine whether there was a prolonged
      T(2) relaxation time (T(2)) in hippocampus and amygdala in AD, and whether in AD,
      the relaxometry data correlated to cognitive performance. In a 1.5 T MR scanner,
      T(2) of hippocampus and amygdala was measured from 51 patients with AD, 23
      subjects with vascular dementia (VaD) and 31 healthy elderly controls. The
      cognitive performance was assessed with the Alzheimer's Disease Assessment Scale 
      Cognitive Subscale (ADAS-Cog). The AD patients had longer T(2) in hippocampus
      and amygdala than VaD subjects and healthy elderly controls. In AD, the right
      hippocampal T(2) was correlated with ADAS-Cog scores, whereas amygdaloid T(2) was
      not.

PMID- 15172106
TI  - Human exposure to a specific pulsed magnetic field: effects on thermal sensory
      and pain thresholds.
AB  - Exposure to pulsed magnetic fields (MF) has been shown to have a therapeutic
      benefit in both animals (e.g. mice, snails) and humans. The current study
      investigated the potential analgesic benefit of MF exposure on sensory and pain
      thresholds following experimentally induced warm and hot sensations. Thirty-nine
      subjects (Study 1) and 31 subjects (Study 2) were randomly and double-blindly
      assigned to 30 min of MF or sham exposure between two sets of tests of sensory
      and pain thresholds and latencies at, 1 degrees C above, and 2 degrees C above
      pain thresholds. Results indicated that MF exposure does not affect sensory
      thresholds [e.g. [F(1,31) = 0.073, NS]. Pain thresholds were significantly
      increased following MF exposure [F(1,6) = 9.45, P < 0.01] but not following sham
      exposure [F (1,4) = 4.22, NS]. A significant condition by gender interaction
      existed for post-exposure pain thresholds [F(1,27) = 5.188, P < 0.05]. Taken
      together, these results indicate that MF exposure does not affect basic human
      perception, but can increase pain thresholds in a manner indicative of an
      analgesic response. The potential involvement of the placebo effect is discussed.

PMID- 15172105
TI  - Lack of evidence for association between serotonin transporter gene (5-HTTLPR)
      and obsessive-compulsive disorder by case control and family association study in
      humans.
AB  - Association studies of the serotonin transporter (SLC6A4) gene in obsessive
      compulsive disorder (OCD) have generated discrepant results. Here, we genotyped
      the 5-HTTLPR polymorphism in 106 French OCD patients and 171 healthy controls
      (case control study). We also performed a family association study on 116 trios
      including an OCD patient (73 French and 43 German). No association was detected
      between the 5-HTTLPR polymorphism and OCD in either the case control study or the
      family study.

PMID- 15172107
TI  - Okadaic acid augments utrophin in myogenic cells.
AB  - Duchenne muscular dystrophy is a fatal childhood disease caused by mutations that
      abolish the expression of dystrophin in muscle. Utrophin is a paralogue of
      dystrophin and can functionally replace it in skeletal muscle. A potential
      therapeutic approach is to increase utrophin levels in muscle. One way to achieve
      this aim is to increase the expression of the utrophin gene at a transcriptional
      level via promoter activation. In this study, we have shown that utrophin A mRNA
      levels can be induced by okadaic acid in murine myogenic C2C12 cells. We have
      found that a utrophin A promoter reporter can be induced by Sp1 in C2C12
      myoblasts, but not in myotubes. This activation can be enhanced by okadaic acid
      treatment. Our data suggest that this induction is due to Sp1 phosphorylation
      during myogenesis and thus, utrophin expression in muscle could be regulated by
      treatment with phosphatase inhibitors. Control of utrophin promoter activation
      could then be used to increase the expression of utrophin, and thus ameliorate
      the symptoms of Duchenne muscular dystrophy.

PMID- 15172108
TI  - Identification of V-ATPase as a major component in the raft fraction prepared
      from the synaptic plasma membrane and the synaptic vesicle of rat brain.
AB  - Cholesterol is important in the maintenance and remodeling of the synapse. Since
      membrane cholesterol participates in the formation of the membrane microdomain
      (raft), the characterization of raft components within membrane structures in the
      synaptic region could be a good approach to understand the role of cholesterol in
      the synaptic function. In this study, protein complexes in the raft prepared from
      synaptic plasma membrane and the synaptic vesicle were analyzed with blue-native
      polyacrylamide gel electrophoresis and vacuolar H(+)-pump (V-ATPase) was
      identified as a major raft component using mass spectrometry. The ATPase activity
      was reduced through cholesterol deprivation with methyl-beta-cyclodextrin. Since
      the H(+) -gradient is used to transport synaptic transmitters or their precursors
      into the vesicle, this result suggests the essential role of cholesterol and raft
      in the synaptic function.

PMID- 15172109
TI  - Transglutaminase activity and transglutaminase mRNA transcripts in gerbil brain
      ischemia.
AB  - Brain injury of the ischemia/reperfusion type induces neuronal damage, mainly by
      excitatory amino acid release, intracellular Ca(2+) overload and reactive oxygen
      species production. We have previously demonstrated that glutamate exposure
      increased transglutaminase activity and transglutaminase 2 expression in cultured
      cerebellar granule cells and astrocytes. The aim of this study is to evaluate
      changes in transglutaminase activity and expression using a gerbil model of
      global cerebral ischemia. Moreover, the distribution and amounts of different
      transglutaminase isoforms were examined. Transglutaminase activity was measured
      by incorporation of [(3)H]putrescine into dimethylcasein throughout 48 h of
      reperfusion following a 3 min occlusion. Compared to sham-operated brains,
      significant increases were found in the ischemic hippocampus at 24 h of
      reperfusion, while minor changes were observed in the cortex. RT-PCR demonstrated
      the presence of significant mRNA amounts of transglutaminase 2 and
      transglutaminase 1, both in the hippocampus and the cerebral cortex, while low
      levels were found for transglutaminase 3 transcripts. Interestingly,
      transglutaminase 2 and transglutaminase 1 mRNAs were 4-fold and 2-fold increased,
      respectively, in the ischemic hippocampus after 24 h of reperfusion. Western blot
      analysis of transglutaminase 2 expression confirmed a strong up-regulation in the
      ischemic hippocampus. However, it is possible to hypothesize that different
      expression rates of transglutaminase isoforms may be dependent on different
      responsiveness of their transcription regulatory elements to intracellular
      calcium overload following excitotoxic cell injury. Our results suggest that
      increases in transglutaminases may be part of the tissue stress response in
      global brain ischemia.

PMID- 15172111
TI  - Interleukin-1beta up-regulates iron efflux in rat C6 glioma cells through
      modulation of ceruloplasmin and ferroportin-1 synthesis.
AB  - A number of pathologies, including neurodegeneration and inflammation, have been
      associated with iron dysmetabolism in the brain. Hence, systems involved in iron
      homeostasis at the cellular level have aroused considerable interest in recent
      years. The iron exporter ferroportin-1 (FP) and the multicopper oxidase
      ceruloplasmin (CP) are essential for iron efflux from cells. By using RT-PCR, we
      demonstrate that FP and CP gene expression is up-regulated by treatment with the
      pro-inflammatory cytokine IL-1beta in rat C6 cells, taken as a glial cellular
      model. Following stimulation with IL-1beta, a higher expression level of CP and
      FP was also confirmed by Western blotting. Moreover, IL-1beta has been found to
      increase iron efflux from C6 cells, suggesting that both proteins may play a
      crucial role in iron homeostasis in pathological brain conditions, such as
      inflammatory and/or neurodegenerative diseases.

PMID- 15172110
TI  - Qualitative sex differences in kappa-opioid analgesia in mice are dependent on
      age.
AB  - The effects of aging on sex differences in analgesia from the kappa-opioid
      agonist, U50,488H (U50), were examined in C57BL/6J mice. U50 analgesia can be
      blocked by the N-methyl-d-aspartate receptor antagonist, MK-801 (MK), in male
      rodents and gonadectomized females, but not hormonally intact or estrogen
      replaced females, suggesting the existence of alternate neurochemical mediation
      in females. We now report that MK antagonism of U50 analgesia is age-dependent in
      females. That is, reproductively senescent females display MK-sensitive U50
      analgesia qualitatively similar to that displayed by males or hormonally deprived
      young females. Age-related reductions in U50 analgesic magnitude were also
      observed in females. Thus, age and gender are likely to alter the clinical
      efficacy of analgesic drugs active at kappa-opioid receptors.

PMID- 15172112
TI  - Decreased CD14+CCR2+ monocytes in active multiple sclerosis.
AB  - The expression of CCR2, a receptor to MCP-1, on blood monocytes was measured in
      15 patients with active multiple sclerosis (MS). We determined the ratio of
      CD4+CXCR3+cells (Th1), CD4+CCR4+cells (Th2), and CD14+CCR2+ cells using 3-color
      flow cytometry. The CD4+CXCR3+/CD4+CCR4+ ratio, which represents the Th1/Th2
      balance, was significantly elevated in the active MS patients compared to the
      healthy controls. The expression of CCR2 and CD14 on the monocytes in the MS
      patients was markedly decreased. There was a significant negative correlation
      between the Th1/Th2 ratio and the CCR2 and CD14 expression on monocytes. In the
      pathogenesis of MS, the CD14+CCR2+ blood monocytes may play an important role in
      the shift from active MS to a state in which the disease is in remission.

PMID- 15172113
TI  - Morphological and functional changes induced by the amino acid analogue 3
      nitrotyrosine in mouse neuroblastoma and rat glioma cell lines.
AB  - The amino acid analogue 3-nitrotyrosine (3-NT) is formed in neural cells as a
      result of the intense stimulation of NMDA glutamate receptors. 3-NT is involved
      in the pathology of diverse neurodegenerative disorders. The aim of our work is
      to investigate the sensitivity of cultured neural and glial cells to 3-NT. We
      report the morphological changes detected on mouse neuroblastoma (C1300) and rat
      glioma (C6) cell lines cultured in a medium supplemented with different 3-NT
      concentrations. Western blot displayed a selective incorporation of 3-NT into a
      single protein that co-migrated with tubulin. Both cell lines showed
      morphological changes, nuclear suffering, decreased viability and growth
      inhibition (starting from 90 and 360 microM for C1300 and C6, respectively). Such
      effects were dose-dependent, though glioma cells showed severe alterations at
      higher 3-NT concentrations. Our results point out a higher 3-NT sensitivity in
      the neural cells studied in comparison with those of glial origin. The dramatic
      toxicity of 3-NT in neural cells suggests further investigations focused on the
      biochemical mechanisms at the roots of neurodegenerative diseases.

PMID- 15172114
TI  - Antiproliferative crude soy saponin extract modulates the expression of
      IkappaBalpha, protein kinase C, and cyclooxygenase-2 in human colon cancer cells.
AB  - Frequent consumption of soy and soy-based products is associated with reduced
      cancer incidence particularly for breast, colon, and prostate cancer. In this
      study, we examined the effect of crude soy saponin extract on PMA (phorbol 12
      myristate 13-acetate)-induced inflammatory responses. Human adenocarcinoma cells
      (HT-29) were treated with various concentrations of saponin extract for 72 h.
      Cell growth was measured at 24, 48 and 72 h of incubation, and the PMA-induced
      expressions of cyclooxygenase-2 (COX-2), protein kinase C (PKC), and IkappaBalpha
      were determined. The results indicate that crude saponin extract decreased cell
      growth in a dose- and time-dependent manner. Crude soy saponin extract suppressed
      the degradation of IkappaBalpha in PMA-stimulated cells, while COX-2 and PKC
      expressions were significantly down-regulated. These findings support the
      hypothesis that the soy saponins reduce the risk of colon tumorigenesis possibly
      by suppressing inflammatory responses.

PMID- 15172115
TI  - Limited tumor growth (HT29) in vivo under RO205-2349 is due to increased
      apoptosis and reduced cell volume but not to decreased proliferation rate.
AB  - The peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor
      that plays a regulatory role in cell differentiation and proliferation. PPARgamma
      was first detected in adipocytes, however, it has been shown that this receptor
      is also expressed in normal as well as tumor cells including malignant colonic
      epithelial cells. In this study, the effect of the PPARgamma agonist RO205-2349,
      a recently developed thiazolidinedione, on tumor growth was evaluated. For this
      purpose, human colon cancer cells (HT29) were grown in severe combined
      immunodeficient mice. Under daily RO205-2349 treatment (50 mg/kg/day) a
      significantly reduced tumor weight became evident after 3 weeks. In the control
      (n = 10) and treatment (n = 10) groups the mean tumor weights were 0.45 and 0.16
      g, respectively. The mean percentages of apoptotic cells were 0.8 and 2.7% in the
      control and treatment groups, respectively, and the cell diameter measured on
      average 11.4 and 9.4 microm. In contrast, cell proliferation and differentiation,
      which are considered to be influenced by the PPARgamma, remained unaffected as
      could be seen by Ki-67 and carcinoembryonic antigen immunoreactivity indicating
      that increased rate of apoptosis and cell shrinkage are responsible for the
      differences in tumor growth. Hence, in this human/mouse xenograft model,
      mechanisms other than the classical activation of PPARgamma are likely reasons
      causing limited tumor growth.

PMID- 15172116
TI  - Amelioration of ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress
      and tumor promotion response by coumarin (1,2-benzopyrone) in Wistar rats.
AB  - In this study, we report the modulatory effect of coumarin (1,2-benzopyrone) on
      Ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and tumor
      promotion response in rats. Fe-NTA (9 mg Fe/kg body weight, intraperitoneally)
      enhances renal lipid peroxidation, xanthine oxidase, gamma-glutamyl
      transpeptidase and hydrogen peroxide (H2O2) generation with reduction in
      antioxidant enzymes and renal glutathione content. It also enhances blood urea
      nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and thymidine
      [3H] incorporation into renal DNA. Prophylactic treatment of rats with coumarin
      (10 and 20 mg/kg body weight) resulted in significant recovery of antioxidant
      enzymes (P < 0.001) and renal glutathione content (P < 0.01). There was also
      significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation,
      xanthine oxidase, H2O2 generation, blood urea nitrogen, serum creatinine, renal
      ODC activity and DNA synthesis (P < 0.001) Thus, our results show that coumarin
      is a potent chemopreventive agent and suppresses Fe-NTA induced nephrotoxicity in
      Wistar rats.

PMID- 15172117
TI  - Hypericum perforatum methanolic extract inhibits growth of human prostatic
      carcinoma cell line orthotopically implanted in nude mice.
AB  - The antiproliferative effect of serotonin-reuptake inhibitors (SSRI) and
      serotonin antagonists has been demonstrated in prostate tumors. Since Hypericum
      perforatum components act as serotonin-reuptake inhibitors and exert cytotoxic
      effects on several human cancer cell lines, in this work we analyzed the effect
      of a treatment with Hypericum perforatum extract (HPE) on the growth of human
      prostate cancer cells in vitro and in vivo. This study highlighted a significant
      reduction of tumor growth and number of metastasis suggesting that this natural
      compound may be useful in the treatment of prostate cancer.

PMID- 15172118
TI  - Hyperbaric oxygen alone or combined with 5-FU attenuates growth of DMBA-induced
      rat mammary tumors.
AB  - We tested the hypothesis that hyperbaric oxygen (HBO) alone and with chemotherapy
      (5-FU) attenuates tumor growth of DMBA-induced tumors in rats. Six series were
      performed: (1) Controls (air and vehicle 0.9% NaCl i.p.), (2) 5-FU (0.2 mg/kg
      i.p.), (3) HBO (2 bar for 90 min and vehicle), (4) HBO and 5-FU, (5) HBO (11
      days) and air (next 12 days), (6) HBO (23 days). All treatments were applied on
      days 1, 4, 7, 10 (Series 1-4), as well as on days 14, 17 and 23 (Series 5-6).
      Tumor diameter increased by 76.7 and 41.2% in untreated controls and in the 5-FU
      group, respectively, after 10 days. Tumor size fell by 17-24.2% in the HBO groups
      and by 35.5% when combined with 5-FU (P < 0.05 compared to HBO). HBO treatment
      reduced the total number of blood vessels in the tumors. After completion of HBO
      treatment tumor size increased, but statistically insignificant, during the next
      12 days.

PMID- 15172119
TI  - Effect of LY293111 in combination with gemcitabine in colonic cancer.
AB  - New adjuvant therapies are needed for the treatment of stage III colon cancer.
      The essential fatty acids, linoleic and arachidonic acid enhance tumorigenesis
      through the cyclooxygenase and lipoxygenase pathways. Leukotriene B4 (LTB4) is a
      product of 5-lipoxygenase (5-LOX) which has tumor-promoting effects. The LTB4
      receptor antagonist, LY293111 inhibited tumor growth and induced apoptosis in
      vitro. The effectiveness of LY293111, alone and in combination with gemcitabine
      was investigated in a heterotopic xenograft model in athymic mice using HT29 and
      LoVo human colonic cancer cells. The combined therapy markedly inhibited tumor
      growth and could warrant consideration as a new therapeutic option.

PMID- 15172120
TI  - (-)-Epigallocatechin gallate inhibits membrane-type 1 matrix metalloproteinase,
      MT1-MMP, and tumor angiogenesis.
AB  - Membrane-type 1 matrix metalloproteinase (MT1-MMP), which hydrolyzes type I
      collagen and activates MMP-2, are deeply involved in angiogenesis as well as in
      tumor cell invasion and metastasis. We previously screened a number of natural
      and synthetic compounds to obtain a specific inhibitor of MT1-MMP and observed
      that (-)-epigallocatechin gallate (EGCG) has a potent and distinct inhibitory
      activity against MT1-MMP. In the present study, we investigated the effect of
      EGCG on tumor angiogenesis. EGCG significantly inhibited the invasion of human
      umbilical vein endothelial cells (HUVECs) at the concentration of 10 microM. This
      effect was not due to the toxicity of EGCG since this concentration of EGCG did
      not affect the HUVEC growth. Furthermore, morphological change of HUVEC at this
      concentration of EGCG was not observed under confocal laser scanning microscopy.
      EGCG suppressed tube formation by HUVECs in vitro and angiogenesis in vivo by
      using dorsal air sac model. Finally, we observed that both colon 26 NL17
      carcinoma and Meth A sarcoma growth was suppressed in these tumor-bearing mice by
      EGCG administration, at least partly though the inhibition of angiogenesis.

PMID- 15172121
TI  - Association of PTEN mutation with HPV-negative adenocarcinoma of the uterine
      cervix.
AB  - Serous, mucinous, endometrioid, and clear cell adenocarcinomas arise from
      reproductive organs of mullerian origin. Although the mutation of PTEN, a tumor
      suppressor, is known to be involved in tumorigenesis of endometrioid
      adenocarcinomas of the endometrium and ovary, the role of PTEN alteration in
      endometrioid adenocarcinoma of the cervix remains to be investigated. To
      elucidate the molecular pathogenesis of cervical adenocarcinoma and adenosquamous
      carcinoma, and in particular to examine the potential role of PTEN mutation in
      endometrioid-type cancer of the cervix, we analyzed 32 cervical adeno- or
      adenosquamous carcinomas (8 endometrioid adenocarcinomas, 14 mucinous
      adenocarcinomas and 10 adenosquamous carcinomas) for PTEN mutations and HPV
      infections. PTEN mutation was detected in 2 of 8 (25.0%) endometrioid cases, 2 of
      14 (14.3%) mucinous cases, and none of 10 (0%) adenosquamous cases. HPV DNA was
      detected in 11 out of 18 (61.1%) PTEN wild-type adenocarcinomas and 8 out of 10
      (80.0%) adenosquamous carcinomas. Among 11 HPV-negative adenocarcinomas, 40.0%
      (2/5) endometrioid cases and 33.3% (2/6) mucinous cases were shown to be PTEN
      mutated, while no cases (0/21) were PTEN-mutant in the remainder (i.e.
      adenosquamous carcinomas and HPV-positive adenocarcinomas). The current
      observations suggest that PTEN mutation is frequently detected in HPV-negative
      adenocarcinomas of the cervix and the most prevalent occurrence of PTEN mutation
      in endometrioid subtype is keeping with endometrial and ovarian carcinomas.

PMID- 15172123
TI  - A new polyclonal antibody that recognizes a human receptor for hyaluronan
      mediated motility.
AB  - The receptor for hyaluronan mediated motility (RHAMM), a hyaluronan (HA) binding
      protein, has been shown to play an important role in the motility and
      invasiveness of malignant cells. We have developed a polyclonal antibody against
      human RHAMM. A new polyclonal antibody was raised against a mixture of C-terminal
      RHAMM, which is capable of binding to HA, and the central domain. The antibody
      showed immunoreactivity to these two peptides, and detected a 95 kDa protein.
      Immunohistochemically, RHAMM detected by the antibody was present in the
      cytoplasm and nucleus of malignant B cells. Binding of HA to RHAMM was almost
      completely blocked by this antibody. These findings suggest that our antibody
      recognizes RHAMM protein and is useful for blocking HA binding to RHAMM.

PMID- 15172124
TI  - Expression of prostaglandin D2 receptors DP1 and DP2 by human colorectal cancer
      cells.
AB  - The expression and function of prostaglandin (PG) D2 DP receptors during
      colorectal carcinogenesis has not been elucidated. Therefore, we studied
      expression of DP1 and DP2 receptors by reverse transcription-polymerase chain
      reaction analysis of receptor mRNA levels in five human colorectal cancer cell
      lines (HT-29, HCA-7, HCT116, SW480 and SW48) and VACO-235 human colorectal
      adenoma cells. DP1 receptor transcripts were present only in HT-29 cells. In
      addition, none of the human colorectal epithelial cell lines tested expressed DP2
      receptor mRNA. Therefore, PGD2 is unlikely to have direct activity on neoplastic
      colorectal epithelial cells via cell surface DP receptors.

PMID- 15172122
TI  - eNOS protects prostate cancer cells from TRAIL-induced apoptosis.
AB  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anti
      cancer agent because it induces apoptosis of most tumor cells with little or no
      effect on normal cells. In this study, we investigated the effect of TRAIL on
      human prostate normal and cancer cell lines, and found that the prostate cancer
      cell lines PC-3, ALVA-31, DU 145 and TSU-Pr1 were sensitive to TRAIL-induced
      apoptosis, while normal PrEC cells and cancer cell line LNCaP were resistant. No
      correlation was found between the sensitivity of cells to TRAIL and the
      expression of TRAIL receptors DR4 and DR5, and pro-apoptotic proteins Bax and
      Bak. However, LNCaP cells displayed a high Akt activity. Furthermore, we found
      that endothelial nitric oxide synthase (eNOS), one of the Akt substrates, was
      highly expressed in LNCaP but not in other cells. Inhibition of eNOS activity by
      NOS inhibitor sensitized LNCaP cells to TRAIL. Moreover, PC-3 cell clones stably
      expressing eNOS were resistant to TRAIL-induced apoptosis. Taken together, these
      results indicate that eNOS can regulate the sensitivity of prostate cancer cells
      to TRAIL, and down-regulation of eNOS activity may sensitize prostate cancer
      cells to TRAIL-based therapy.

PMID- 15172125
TI  - Increased rates of spontaneous sister chromatid exchange in lymphocytes of
      BRCA2+/- carriers of familial breast cancer clusters.
AB  - Heterozygous carriers of germ-line mutations of the BRCA2 breast cancer
      susceptibility gene are predisposed to breast, ovarian, pancreatic and other
      cancers. The BRCA2 protein is implicated in the maintenance of chromosome
      stability through its essential function in double-strand DNA repair and
      recombination. Our previous studies had revealed multiple intrachromosomal
      rearrangements, duplications, inversions and deletions on 9p23-24 in lymphocytes
      and fibroblasts of BRCA2+/- members from independently ascertained familial
      breast cancer clusters. In pursuit of evaluating if there is a subtle genomic
      instability in BRCA2+/- individuals, we have determined frequencies of
      spontaneous sister chromatid exchanges (SCEs) in BRCA2 wild-types and BRCA2
      mutation carriers of two familial breast cancer clusters. Here, we demonstrate an
      average increase of 65% of spontaneous SCEs in BRCA2+/- versus BRCA2+/+ family
      members. In one cluster, the number of metaphases with multiple SCEs was 5-times
      higher in BRCA2+/- compared to wild-type members, while in the second cluster
      BRCA2+/- members had 8.9% of metaphases with multiple SCEs compared to a level
      below detection in BRCA2 wild types. To investigate the correlation between SCE
      and genomic instability in 9p, we performed fluorescence detection of SCEs and
      FISH analysis with 9p probes. The frequency of SCE in 9p of BRCA2 mutation
      carriers was 3-4 fold (P = 0.005) higher compared to BRCA2 wild-types.
      Collectively, the increased rates of SCE in BRCA2 heterozygous mutation carriers
      indicate a BRCA2 haploinsufficiency, which might be an important factor for the
      accumulation of structural chromosomal alterations with the consequence of damage
      in as yet unidentified genes.

PMID- 15172126
TI  - Expression of 11beta-hydroxysteroid dehydrogenase types 1 and 2 in colorectal
      cancer.
AB  - Glucocorticoid hormones have been reported to operate as regulators of cell
      proliferation and differentiation and to inhibit growth of several colon tumors
      and adenocarcinoma cell lines. The glucocorticoid action is regulated, in part,
      at the pre-receptor level through the expression of isoforms of 11beta
      hydroxysteroid dehydrogenase (11betaHSD1, 11betaHSD2) which are responsible for
      the interconversion of hormonally active cortisol to cortisone. Since both of
      these isoforms are expressed in the mammalian colon, we examined whether
      11betaHSD1 and 11betaHSD2 are expressed in human colorectal cancer and whether
      their expression differs between neoplastic and autologous non-neoplastic tissue.
      We provide evidence that both isoforms of 11betaHSD are expressed in the colon
      adenocarcinoma, but their expression is not identical in neoplastic and non
      neoplastic tissue. There is a significant decrease of 11betaHSD2 mRNA abundance
      and enzyme activity in neoplastic tissue. In contrast, 11betaHSD1 activity and
      mRNA abundance are increased in some but not all tumor samples. The results
      demonstrate that (1) neoplastic transformation is associated with decreasing
      steady-state levels of 11betaHSD2 mRNA and enzyme activity and in some cases also
      with increasing expression of 11betaHSD1, and (2) colorectal tumor cells have a
      decreased capability of autocrine inactivation of glucocorticoids.

PMID- 15172127
TI  - p53 is an independent pre-treatment markers for long-term survival in stage II
      and III colorectal cancers: an analysis of interaction between genetic markers
      and fluorouracil-based adjuvant therapy.
AB  - One hundred and thirty-eight stage II and III colorectal cancer patients were
      included to evaluate the prognostic significance of genetic markers (including
      mutations of the p53, K-ras genes, and microsatellite instability) on the
      response to 5-fluorouracil (FU)-based post-operative adjuvant therapies (PAT).
      When stratified by PAT and adjusting for other prognostic variables, presence of
      p53 mutation was associated with a poor outcome (hazard ratio (HR)=3.1, 95%
      confidence interval (CI), 0.9-11.0) among patients without PAT. Our data
      confirmed that p53 mutation is an independent pre-treatment factor in stage II
      and III colorectal cancer after curative resection.

PMID- 15172128
TI  - Expression of cell cycle-related gene products in different forms of primary
      versus recurrent PVNS.
AB  - Expression patterns of cell cycle regulating gene products and Ki-67 in
      proliferating synovial cells of primary and recurrent pigmented villonodular
      synovitis (PVNS) in localized and diffuse lesions were examined by
      immunohistochemistry. Alterations of cell cycle-related proteins were seen in
      98.7% of analyzed lesions. Both RB- and p53 pathways play a role in cell cycle
      dysregulation in PVNS. The RB pathway was more frequently altered in primary
      disease, while alterations of the p53 pathway seemed to be more important in
      recurrent lesions, regardless of the histomorphological type of disease. Ki-67
      proliferation rate was elevated in recurrent tumors.

PMID- 15172129
TI  - A new screening system for proliferation-independent anti-cancer agents.
AB  - An in vitro screen for identification of novel anti-cancer agents, which can
      induce proliferation-independent apoptosis of prostate cancer (PCA) cells, is
      required, since the proliferative growth fraction of human prostate cancers in
      patients is usually <10%. This is possible using the PCA cell line LNCaP, which
      can be permanently transdifferentiated into a quiescent neuroendocrine (NE)
      phenotype without undergoing apoptosis by the cytokine interleukine-6 (IL-6).
      Transdifferentiation of LNCaP cells into a NE phenotype was documented using
      western blot analysis and immunohistochemistry for the NE markers, neuron
      specific enolase (NSE) and beta III tubulin. Accumulation of NE cells in the G0
      phase of the cell cycle was demonstrated by Ki-67 immunohistochemistry. The
      effects of paclitaxel, vinblastine and thapsigargin (TG) on viability and
      apoptosis of NE and LNCaP cells were assessed by trypan blue exclusion and 4', 6
      diamidino-2-phenylindole nuclear staining assays. In proliferating LNCaP cells,
      there was a significant decrease in viable cells after 48 h exposure to
      paclitaxel and vinblastine and a dramatic increase of apoptosis as compared with
      the controls. On the other hand, treatment with paclitaxel or vinblastine
      decreased the viability of NE cells only slightly without markedly increasing
      their rate of apoptosis compared to controls. In contrast, both LNCaP and NE
      cells showed a significant and comparable decrease in cell viability and similar
      high levels of apoptosis when treated with TG. These results demonstrate that
      terminally transdifferentiated NE cells represent a useful in vitro screening
      system for identification of novel anti-cancer agents, like TG, that can induce
      apoptosis without requiring proliferation.

PMID- 15172130
TI  - Spontaneous alpha peak frequency predicts working memory performance across the
      age span.
AB  - Working memory capacity has been consistently shown to decline with increasing
      age. Mechanisms underlying this decline are poorly understood. One index that has
      been found to predict performance on memory tests is alpha peak frequency, the
      peak of spectral alpha power of the EEG. Activity in the alpha band has been also
      associated with higher cognitive functions including attention and anticipation
      and has been shown to slow with age. Few studies, however, have examined whether
      there might be a relationship between WM decline and alpha peak frequency. The
      present study specifically investigated this relationship. Digit span was used as
      the index of WM function. The study made use of 550 normal subjects aged between
      11 and 70 years in the Brain Resource International Database. The data were
      acquired from six laboratories located in the USA (2), Europe (2) and Australia
      (2). Forward and reverse digit span were found to be lower in older relative to
      younger age groups. Spontaneous alpha peak frequency slowed with age and more so
      at anterior than posterior sites. Frontal alpha peak frequency was found to be a
      significant predictor of reverse digit span, with each 1 Hz increase in frequency
      associated with a 0.21 increase in reverse digit span score and this was
      independent of age, indicating a positive relationship between alpha peak
      frequency and working memory performance.

PMID- 15172131
TI  - PET study of brain maintenance of verbal creative activity.
AB  - This paper deals with the investigation of the brain organization of verbal
      creativity. Psychological tasks were designed in accordance with two main
      strategies used by volunteers in solving creative tasks. Regional cerebral blood
      flow (rCBF) was measured with positron emission tomography (PET) when performing
      two types of creative tasks in two groups of subjects, each type of the task
      organizing the creativity process in its own way. Valuable brain correlates of
      creativity were revealed in the left parieto-temporal regions (Brodmann areas 39
      and 40).

PMID- 15172132
TI  - Multifactorial interactions involved in linear self-transport distance estimate:
      a place for time.
AB  - As the vestibular system is the only sensory organ whose primary function is self
      motion detection, we examined the conditions under which the otoliths, which
      detect the linear acceleration of the head, could be used to estimate traveled
      distance. In order to isolate the contribution of the otoliths (with the
      somatosensory system) from contributions of the visual and motor systems subjects
      were transported in darkness. We initially hypothesized that self-transport with
      continuously varying linear velocity should facilitate distance computation by
      continuously stimulating the otoliths, and that active control of self-motion
      should also help subjects estimate the distance traveled. However, it was found
      that the distance covered during self-motion is actually better estimated when
      transport velocity is quasi-constant. Nevertheless, such estimates strongly
      depend upon velocity magnitude; subjects show an idiosyncratic preferred self
      motion velocity for which distance measurements are most accurate. Furthermore,
      the active control of self-transport improves estimates of self-motion mainly
      because the subjects can then adopt a constant velocity, and more precisely their
      preferred one. It was finally found that subjects mentally count in order to
      assess their displacement length, and that time perception is indeed disturbed by
      varying self-motion velocity.

PMID- 15172133
TI  - Functionally dissociated aspects in anterior and posterior electrocortical
      processing of facial threat.
AB  - The angry facial expression is an important socially threatening stimulus argued
      to have evolved to regulate social hierarchies. In the present study, event
      related potentials (ERP) were used to investigate the involvement and temporal
      dynamics of the frontal and parietal regions in the processing of angry facial
      expressions. Angry, happy and neutral faces were shown to eighteen healthy right
      handed volunteers in a passive viewing task. Stimulus-locked ERPs were recorded
      from the frontal and parietal scalp sites. The P200, N300 and early contingent
      negativity variation (eCNV) components of the electric brain potentials were
      investigated. Analyses revealed statistical significant reductions in P200
      amplitudes for the angry facial expression on both frontal and parietal electrode
      sites. Furthermore, apart from being strongly associated with the anterior P200,
      the N300 showed to be more negative for the angry facial expression in the
      anterior regions also. Finally, the eCNV was more pronounced over the parietal
      sites for the angry facial expressions. The present study demonstrated specific
      electrocortical correlates underlying the processing of angry facial expressions
      in the anterior and posterior brain sectors. The P200 is argued to indicate
      valence tagging by a fast and early detection mechanism. The lowered N300 with an
      anterior distribution for the angry facial expressions indicates more elaborate
      evaluation of stimulus relevance. The fact that the P200 and the N300 are highly
      correlated suggests that they reflect different stages of the same anterior
      evaluation mechanism. The more pronounced posterior eCNV suggests sustained
      attention to socially threatening information.

PMID- 15172134
TI  - Electrodermal activity in low back pain patients with and without co-morbid
      depression.
AB  - Electrodermal activity was examined at rest and during a series of pure innocuous
      tones in two groups of chronic low back pain patients, one of which consisted of
      patients suffering also from depression. A group of healthy participants and a
      group of patients suffering from depression unrelated to pain served as control
      groups. The non-depressed patients presented an increased electrodermal activity,
      especially a higher frequency of non-specific fluctuations, as compared to the
      three other groups. Skin conductance level also appeared lower in the two groups
      of depressed participants than in the healthy control group. These data show that
      the EDA recorded in chronic pain patients with and without co-morbid depression
      must advantageously be analysed separately.

PMID- 15172135
TI  - Auditory event-related potential abnormalities in bipolar disorder and
      schizophrenia.
AB  - Auditory P300 latency prolongation or amplitude reduction has been reported in
      patients affected by bipolar disorder and in schizophrenia. The purpose of this
      study was to test whether the auditory P300 and earlier event-related potential
      (ERP) components elicited during an auditory discrimination task could
      differentiate between these two disorders. Thirteen patients with manic or mixed
      bipolar disorder, 12 patients with schizophrenia, and 24 control subjects were
      evaluated. None of the subjects had a history of alcohol or substance abuse or
      dependence. ERPs were elicited during an auditory discrimination task in which a
      subject pressed a key to infrequent 1500 Hz tones interspersed amid a series of
      1000 Hz tones. The amplitude and latency of N100 and P200 were measured from ERPs
      to non-target tones, and N200 and P300 were measured from ERPs to target tones.
      N100, P200 and N200 amplitudes were reduced in schizophrenia patients, but not in
      bipolar patients. Both bipolar disorder and schizophrenia patients showed reduced
      P300 amplitude and prolonged P300 latency. Amplitude reduction in the early ERP
      components implicates auditory processing deficits in schizophrenia. Both groups
      showed reductions in P300 amplitude, suggesting a disturbance of the temporal
      parietal generators of this component. Prolonged P300 latency is consistent with
      impaired attentional processing in schizophrenia and symptomatic bipolar disorder
      patients.

PMID- 15172136
TI  - Effects of borderline personality disorder features and a family history of
      alcohol or drug dependence on P300 in adolescents.
AB  - Decrements in P300 amplitude have been associated with familial risk for
      alcoholism as well as several other psychiatric disorders characterized by
      disinhibited behavior. The present study examined the P300 in relation to
      Borderline Personality Disorder (BPD) features in adolescents with a paternal
      history of alcohol or drug dependence. One hundred and seventy-five males and
      females, aged 14-20, were assigned to groups based on BPD features (BPD+ vs. BPD
      ), family history of substance dependence (negative FH-, alcohol FHA, drug FHD)
      and gender. BPD features were assessed using the Structured Clinical Interview
      for the DSM-III-R questionnaire. P300 ERPs were recorded while each subject
      performed the Stroop color-word compatibility test. Repeated measures analyses,
      which included Conduct Disorder and Depression symptoms as covariates, indicated
      a significant reduction in P300 amplitude in the BPD+ group. There were no
      significant effects of FH or gender on P300 amplitude. These results document the
      presence of neurophysiological abnormalities associated with BPD features in an
      adolescent sample. This effect appeared to be independent of a family history of
      alcohol or substance dependence. These findings suggest that BPD symptoms during
      adolescence are relevant to the examination of the physiological antecedents of
      those forms of adult psychopathology characterized by behavioral disinhibition,
      including alcohol and drug dependence.

PMID- 15172137
TI  - Decoupling of midfrontal delta-beta oscillations after testosterone
      administration.

PMID- 15172138
TI  - New radiotherapy technologies for meningiomas: 3D conformal radiotherapy?
      Radiosurgery? Stereotactic radiotherapy? Intensity-modulated radiotherapy? Proton
      beam radiotherapy? Spot scanning proton radiation therapy. . . or nothing at all?

PMID- 15172139
TI  - Spot-scanning proton radiation therapy for recurrent, residual or untreated
      intracranial meningiomas.
AB  - BACKGROUND AND PURPOSE: To assess the safety and efficacy of spot scanning proton
      beam radiation therapy (PRT) in the treatment of intracranial meningiomas.
      PATIENTS AND METHODS: Sixteen patients with intracranial meningioma
      (histopathologically proven in 13/16 cases) were treated with PRT between July
      1997 and July 2002. Eight patients had skull base lesions. Thirteen patients
      received PRT after surgery either as adjuvant therapy for incomplete resection
      (eight patients) or for recurrence (five patients). Three patients received
      radical PRT after presumptive diagnosis based on imaging. The median prescribed
      dose was 56 CGE (range, 52.2-64, CGE=proton Gy X 1.1) at 1.8-2.0 CGE (median,
      2.0) per fraction. Gross tumor volume and planning target volume ranged from 0.8
      to 87.6 cc (median, 17.5) and 4.6-208.1 cc (median 107.7), respectively. Late
      ophthalmologic and non-ophthalmologic toxicity was assessed using the Subjective,
      Objective, Management and Analytic scale (SOMA) of the Late Effects of Normal
      Tissue scoring system and National Cancer Institute Common Terminology Criteria
      for Adverse Events (CTCAE, v3.0) grading system, respectively. The median follow
      up time was 34.1 months (range, 6.5-67.8). RESULTS: Cumulative 3-year local
      control, progression-free survival and overall survival were 91.7, 91.7 and
      92.7%, respectively. No patient died from recurrent meningioma. One patient
      progressed locally after PRT. Radiographic follow-up (median, 34 months) revealed
      an objective response in three patients and stable disease in 12 patients.
      Cumulative 3-year toxicity free survival was 76.2%. One patient presented with
      radiation induced optic neuropathy (SOMA Grade 3) and retinopathy (SOMA Grade 2)
      8.8 and 30.4 months after treatment, respectively. These patients with
      ophthalmologic toxicity received doses higher than those allowed for the
      optic/ocular structures. Another patient developed a symptomatic brain necrosis
      (CTCAE Grade 4) 7.2 months after treatment. No radiation-induced
      hypothalamic/pituitary dysfunction was observed. CONCLUSIONS: Spot-scanning PRT
      is an effective treatment for patient with untreated, recurrent or incompletely
      resected intracranial meningiomas. It offers highly conformal irradiation for
      complex-shaped intracranial meningiomas, while delivering minimal non-target
      dose. Observed ophthalmologic toxicity is dose-related.

PMID- 15172140
TI  - Survival following whole brain radiation treatment for cerebral metastases: an
      audit of 474 patients.
AB  - BACKGROUND AND PURPOSE: To report the outcome of patients with brain metastases
      from solid tumors treated with whole brain radiotherapy (WBRT) in a single
      institution. Given the high proportion of melanoma patients, a secondary aim was
      to compare our outcomes for patients with melanoma to those with other cancers.
      PATIENTS AND METHODS: A retrospective audit identified 474 patients treated
      between January 1983 and December 1999. Survival was calculated using the Kaplan
      Meier method. Cox regression modeling was used for multivariate analysis.
      RESULTS: Four hundred and fifty nine patients have died from their disease. The
      median survival was 4.1 months for the whole group and 3.6 months for the 42% of
      patients with melanoma. The 1 and 2 year survival was 15 and 5%. Six patients
      lived beyond 5 years. 105 of 186 patients with a single brain metastasis
      underwent surgery plus WBRT, and 81 received WBRT alone. Median survival was 8
      and 4 months, respectively, (P<0.0001). 30 Gy in 10 fractions was used more
      commonly in the early part of the study compared to 20 Gy in 5 fractions more
      recently. There was no difference in survival by time period. CONCLUSIONS: The
      survival in this series was comparable to other studies. Performance status,
      resection, dose, and the presence of extracranial disease appeared to be
      significant prognostic factors. The survival for the large number of patients
      with melanoma did not differ from the rest of the cohort.

PMID- 15172141
TI  - Role of 11-C-methionine positron emission tomography for the delineation of the
      tumor volume in pharyngo-laryngeal squamous cell carcinoma: comparison with FDG
      PET and CT.
AB  - BACKGROUND AND PURPOSE: Although computed tomography (CT) remains the imaging
      modality of reference in head and neck squamous cell carcinoma (HNSCC) for the
      three-dimensional (3D) conformal radiotherapy, its poor soft tissue contrast can
      hamper precisely delineate the tumor volume. Besides anatomical imaging, 2-[18F]
      fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) has been shown to
      enhance the accuracy of the tumor delineation but l-methyl [11C]-methionine
      positron emission tomography (MET-PET) has never been tested for this purpose.
      This study was undertaken to determine the potential added value of MET-PET for
      the delineation of gross target volume (GTV) in HNSCC, as compared to CT and FDG
      PET. PATIENTS AND METHODS: Twenty-three patients (10 oropharynx, 8 larynx and 5
      hypopharynx) presenting with stage II-IV HNSCC were prospectively enrolled. They
      were treated by primary radiotherapy or by total laryngectomy. Images (CT, FDG
      PET and MET-PET) were acquired with a thermoplastic mask and after
      coregistration, tumor volumes were delineated on CT and using an adaptative
      threshold-based automatic method on FDG- and MET-PET. Absolute volumes as well as
      the mismatch between modalities were compared. RESULTS: For oropharyngeal
      lesions, FDG volumes were significantly smaller (19.43 ml+/-21.36) than CT (29.04
      ml+/-30.97) (P=0.013). On the other hand, MET volumes (24.36 ml+/-20.59) were not
      different from CT volumes. Similar results were found for laryngeal and
      hypopharyngeal tumors, with volume of 24.93 ml+/-19.02 for CT, 21.84 ml+/-15.32
      for MET-PET and 14.49 ml+/-11.3 for FDG-PET (P=0.003). Large mismatches were
      observed between modalities, in particular between CT and PET. CONCLUSIONS: Our
      study confirms that the use of FDG-PET may result in a significant reduction of
      GTV's as compared to CT. On the contrary, MET-PET does not have any additional
      value since MET volumes are not different from CT volumes, probably because of
      the high uptake of MET by the normal mucosa and salivary glands surrounding the
      tumor.

PMID- 15172142
TI  - Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and
      incurable head and neck cancer: AIIMS study.
AB  - BACKGROUND AND PURPOSE: A proportion of advanced stage head and neck cancer
      patients are incurable and have a limited life expectancy of 100 days or less.
      The study aimed to offer a short course of palliative radiotherapy (PRT) and
      evaluate the symptom relief, disease response and duration of survival. PATIENTS
      AND METHODS: Between 1995 and 2001, 505 patients of stage IV squamous cell
      carcinoma received uniform dose of 20 Gy in 5 fractions over 1 week along with
      symptom relief drugs. Incurable status and decision for palliation was made
      conjointly. Distressing symptoms were assessed before PRT. Patients showing more
      than 50% objective regression (PR) at tumor and nodal sites received further RT
      (FRT) up to 70 Gy. RESULTS: The overall PR rate was 37% (189 patients), but 153
      (30%) completed FRT, and rest 352 were followed up after PRT only. None of the
      patients died due to radiation toxicity, and the radiation morbidities were
      confined to dry desquamation and patchy mucositis, which healed over 1 month.
      Symptom relief for pain, dysphagia, hoarseness, cough and otalgia was obtained in
      47%-59% of the patients following PRT. The overall survival ranged from 34 days
      to 2065 days and median survival to PRT and FRT were 200 days and 400 days,
      respectively. Only 10% were disease-free after FRT. CONCLUSIONS: Unfavourable
      advanced stage head and neck cancer can be identified for a suitable short course
      of palliative radiotherapy which will achieve growth restraint and symptom relief
      in sizeable proportions for an approximate period of 7 months.

PMID- 15172143
TI  - Caesium(137) implant as sole radiation therapy for operable breast cancer: a
      phase II trial.
AB  - BACKGROUND AND PURPOSE: Clinical trials have indicated the need for irradiation
      of the tumour-bearing quadrant in patients with operable breast cancer treated by
      conservation therapy even under circumstances where there has been complete
      pathologic clearance. The aim of this phase II trial was to replace whole breast
      irradiation with brachytherapy to the tumour bed. PATIENTS AND METHODS: A series
      of 50 patients with operable breast cancers measuring <==4 cm diameter were
      treated by combination therapy comprising tumour excision axillary clearance and
      synoperative insertion of a rigid implant to the tumour bed. The implant was
      after-loaded with medium dose rate Cs(137) sources giving a dose of 45 Gy in
      daily four fractions of about 6 h duration. No external beam radiotherapy was
      given. RESULTS: After a median follow-up of 6.3 years, of the 49 evaluable
      patients, 80% were alive without relapse. Of the 9 patients (18%) who developed a
      breast relapse, the site of recurrence was in the index quadrant in 7 cases
      (78%). Of the series, 26 (81%) gave a subjective rating of cosmetic outcome which
      was excellent or good. Objectively the treated breast was deemed to be normal in
      11 (42%) and abnormal in 15 (58%). CONCLUSIONS: This phase II study suggests that
      in a selected group of patients with early breast cancer, external whole breast
      radiotherapy can be replaced by interstitial irradiation to the tumour bed
      without compromising local disease control and giving an excellent or good
      cosmetic outcome in the majority of cases.

PMID- 15172144
TI  - Loco-regional conformal radiotherapy of the breast: delineation of the regional
      lymph node clinical target volumes in treatment position.
AB  - BACKGROUND AND PURPOSE: As the location of the regional lymph nodes (LNs) of the
      breast varies largely between patients and may be dependant on the position of
      the arm, adequate localization of these nodes is mandatory in order to fully take
      advantage of optimized conformal radiotherapy. For this purpose, the anatomical
      boundaries of the regional lymph node (LN) clinical target volumes (CTVs) for
      delineation on transverse CT-slices, made in treatment position, were
      established. PATIENTS AND METHODS: Anatomical and surgical descriptions of the
      regional LNs of the breast, as well as a shoulder dissection, were studied. Axial
      slices of a human cadaver with one arm in abduction and the other in adduction
      were investigated, to assess the displacement of LNs by abduction of the arm into
      treatment position. Based on these findings, we defined the anatomical boundaries
      of the regional LN CTVs visible on transverse CT-slices. RESULTS: Standard
      anatomical and surgical descriptions appeared to be inadequate for determination
      of the boundaries of the regional LN CTVs in treatment position. With abduction
      of the arm, a change in position of all regional LNs, except for the medial
      supraclavicular LNs and internal mammary LNs, was observed in the anatomical
      cross-sections. This was also taken into account in our delineation protocol
      proposal. CONCLUSIONS: Anatomically based guidelines for delineation of the
      regional LN CTVs for loco-regional irradiation of the breast on transverse CT
      slices, made in treatment position, have been developed in this study. These
      could be used as a basis for conformal radiotherapy.

PMID- 15172145
TI  - Is there a life-long risk of brachial plexopathy after radiotherapy of
      supraclavicular lymph nodes in breast cancer patients?
AB  - BACKGROUND AND PURPOSE: To contribute to the question whether the risk of
      radiation-related brachial plexopathy increases, remains constant or decreases
      with time after treatment. PATIENTS AND METHODS: Between 12/80 and 9/93, 140
      breast cancer patients received supraclavicular lymph node irradiation using a
      telecobalt unit. Total dose was 60 with 3Gy per fraction at a depth of 0.5 cm and
      52 with 2.6Gy per fraction to the brachial plexus at a depth of 3 cm. Twenty
      eight women received chemotherapy, 34 tamoxifen. Brachial plexopathy was graded
      using a modified LENT-SOMA score. Actuarial complication-free survival and
      overall survival were obtained from Kaplan-Meier analysis. The impact of
      chemotherapy or tamoxifen was tested using the chi2 test. The annual incidence of
      radiation-related brachial plexopathy was assessed by exponential regression as
      described by Jung et al. [Radiother Oncol 61 (2001) 233]. RESULTS: Actuarial
      overall survival was 67.1% after 5 years, 54.0% after 10 years, 49.9% after 15
      years, and 44.0% after 20 years. In 19/140 patients, brachial plexopathy
      grade>/=1 occurred after a median interval of 88 (30-217) months. The percentage
      of patients being free from plexopathy was 96.1% after 5 years, 75.5% after 10
      years, 72.1% after 15 years, and 46.0% after 19 years, respectively. A
      significant impact of type of surgery, chemotherapy or tamoxifen was not
      observed. The annual incidence of brachial plexopathy was 2.9% for grade>/=1
      lesions and 0.8% for grade>/=3 lesions. The rates did not change significantly
      with time. CONCLUSIONS: The risk of brachial plexopathy after supraclavicular
      lymph node irradiation in breast cancer patients remains constant for a
      considerable portion of the patient's life.

PMID- 15172146
TI  - The use of in vivo thermoluminescent dosimeters in the quality assurance
      programme for the START breast fractionation trial.
AB  - BACKGROUND AND PURPOSE: The use of in vivo dosimetry for patient measurement is
      recommended in many publications. It provides an additional check to verify that
      the dose delivered to the patient corresponds to the prescribed dose. In the
      context of a clinical trial investigating the effects of different fractionation
      regimens, it is imperative that the dose given is that prescribed to ensure that
      noise in the data between centres does not mask the results of the trial. The
      methodology for in vivo measurement in a clinical trial of breast radiotherapy
      was developed and verified. MATERIALS AND METHODS: A cohort of patients in the
      STAndardisation of breast RadioTherapy (START) trial was monitored using postal
      thermoluminescent dosimeters chips (TLD). All TLD were processed and analysed at
      Mount Vernon Hospital. Patients for in vivo measurements were identified at
      randomisation as a random 1 in 9 samples for the first 2500 patients randomised
      (282 TLD) increasing to 1 in 3 thereafter. The TLD were left in place for the
      duration of the tangential field treatment and thus a composite entrance and exit
      dose was recorded. RESULTS: TLD measurements were performed on 429 patients from
      33 hospitals. The average ratio of dose measured using TLD to that prescribed was
      0.99+/-0.04. Eight patients had initial measurements more than 10% different to
      the prescribed dose. The mean TLD results for a given centre correlated well with
      dose measurements performed using an ionisation chamber in a breast shaped
      phantom at that centre as part of the START trial audit. CONCLUSION:
      Thermoluminescence dosimetry has provided useful quality assurance information on
      the doses received by patients in centres participating in the START trial.

PMID- 15172147
TI  - Quality assurance in intracoronary brachytherapy. Recommendations for determining
      the planning target length to avoid geographic miss.
AB  - BACKGROUND AND PURPOSE: A new method of assessing geographic miss (GM) in
      endovascular brachytherapy (EVBT) is applied to evaluate the quality of
      intracoronary brachytherapy treatments, retrospectively. Based on the Vienna
      experience, recommendations for adequate safety margins are derived to avoid GM.
      PATIENTS AND METHODS: Evaluation is done on 136 vessels of 128 consecutive
      patients treated between October 1999 and July 2001. The quality of EVBT is
      assessed using the concept and terminology of the EVA GEC ESTRO task group.
      Evaluation of GM and/or safety margin is performed by comparing the outermost
      interventions with the reference isodose length (RIL) of the applied delivering
      devices on recorded compact disk (CD) angiograms. The RIL is defined as the
      length of the vessel segment, which receives at least 90% of the reference dose
      at the reference depth (=1 mm within the vessel). GM is defined as injured vessel
      segments, which receive a dose lower than 90% of reference dose. Measurements of
      intervention length (IL) and active source length (ASL) are performed with
      respect to anatomical landmarks within the vessel in the region of interest (e.g.
      stent edges), and by using the nominal length of the devices (balloons, sources)
      as a reference scale. The edges of RIL are determined by subtracting the length
      of the dose-fall-off zone (specific to the applied delivery devices: (192)Ir 4.5
      mm, (90)Sr 2.5 mm, (32)P 2.0 mm) from the edges of ASL. RESULTS: The described
      method to assess GM is applicable to 128 vessels (94%). GM is found in 23% of
      proximal edges and 20% of distal edges. 95% of all GM are observed if the total
      margin (proximal+distal margin) between RIL and IL is shorter than 10.5 mm.
      CONCLUSIONS: GM in intracoronary brachytherapy can be widely avoided by adding an
      appropriate safety margin to the IL (5-6 mm each edge in this study) in order to
      determine the necessary RIL for a treatment.

PMID- 15172148
TI  - Clinical and physical quality assurance for intensity modulated radiotherapy of
      prostate cancer.
AB  - The implementation of intensity modulated radiotherapy (IMRT) for patients with
      prostate cancer in daily routine has been elaborated at our department. Our
      quality assurance (QA) concept is one method to pave the way for initiating IMRT
      treatments for starting institutions. A clinical quality assurance (CQA)
      procedure has been set-up for all patients before and throughout the course of
      radiotherapy. Simultaneously medical physicists established a physical quality
      assurance (PQA) concept that has been followed for all patients as well.
      Alternative CQA and PQA procedures are discussed. The literature is reviewed and
      discussed with special respect to quality assurance in IMRT of prostate cancer
      patients.

PMID- 15172149
TI  - MRI-guided prostate brachytherapy with single needle method--a planning study.
AB  - BACKGROUND AND PURPOSE: Magnetic resonance image (MRI)-guided prostate
      brachytherapy with a conventional closed MR scanner is hampered by the limited
      access to the prostate. To handle this problem, we have designed a new
      implantation method, based on a patient lying in a closed MR scanner, a robotic
      device to be placed between patient's legs, and one needle with one insertion
      point. MATERIALS AND METHODS: The MRI-guided robotic system inserts the needle
      into the prostate to deliver the seeds. Each time, the needle will be retracted
      to the rotation point (in the body), and the insertion angle can be changed. The
      possible angles of the needle are limited by the geometry of the closed MR
      scanner and the presence of the symphysis, rectum and urethra. We have done a
      planning study to investigate the feasibility of this single needle method.
      RESULTS: The treatment plans made with the single needle method showed the
      possibility to cover the prostate with the prescribed dose without piercing the
      urethra or rectum and without pubic bone interference. The plans were comparable
      to the plans made for the multi parallel needle method, and the 144Gy isodose
      enclosed the prostate with a margin of about 2 mm. The planned angles of the
      needle were within the range of possible angles. CONCLUSIONS: This planning study
      has shown the feasibility of adequate prostate coverage with the divergent single
      needle method within the limited space inside the closed MR scanner.

PMID- 15172150
TI  - Computer tomography-assisted three-dimensional technique to assess rectal and
      bladder wall dose in intracavitary brachytherapy for uterine cervical cancer.
AB  - We used a computer tomography (CT)-assisted three-dimensional (3D) technique to
      assess dose to the rectum and bladder in intracavitary brachytherapy (ICBT) for
      patients with cervical cancer, and compared this technique with the conventional
      method. The results revealed that the difference in dose to the rectal and
      bladder wall between these two methods were significant. The CT-assisted
      technique is a feasible method, and it gives different results than the
      conventional method.

PMID- 15172151
TI  - Repositioning accuracy of a commercially available thermoplastic mask system.
AB  - BACKGROUND AND PURPOSE: To evaluate the repositioning accuracy of a commercially
      available thermoplastic mask system for single dose radiosurgery treatments and
      fractionated treatment courses. PATIENTS AND METHODS: The repositioning accuracy
      of the Raycast-HP mask system (Orfit Industries, Wijnegem, Belgium) was analyzed.
      Twenty-two patients that were treated by intensity-modulated radiation therapy
      (IMRT) or intensity modulated radiosurgery (IMRS) for 43 intracranial lesions,
      underwent repeated CT imaging during their course of treatment, or as a
      positional control immediately before radiosurgery. We evaluated multiple
      anatomical landmark coordinates and their respective shifts in consecutive
      repeated CT-controls. An iterative optimization algorithm allowed for the
      calculation of the x, y and z-components of translation of the target
      isocenter(s) for each repeated CT, as well as rotation in the respective CT data
      sets. In addition to absolute target isocenter translation, the total magnitude
      vector (i.e. sum-vector) of isocenter motion was calculated along with patient
      rotations about the three principle axes. RESULTS: Fifty-five control CT datasets
      were analyzed for the target isocenter's respective position relative to the
      original treatment planning CT simulation. Mean target isocenter translation was
      0.74+/-0.53, 0.75+/-0.60 and 0.93+/-0.78 mm in x, y and z-directions,
      respectively. Mean rotation about the x, y and z-axes was 0.67+/-0.66, 0.61+/
      0.63 and 0.67+/-0.61 degrees, respectively. The respective median and mean
      magnitude vectors of isocenter translation were 1.28 and 1.59+/-0.84 mm. Analysis
      of the accuracy of the first setup control, representative of setup accuracy for
      radiosurgery treatments, compared with setup accuracy throughout a fractionated
      radiation treatment course were statistically equivalent (P= 0.15) thus
      indicating no measurable deterioration of setup accuracy throughout the treatment
      course. CONCLUSIONS: The analyzed Orfit thermoplastic mask system performed
      favorably compared with other mask immobilization systems for which peer-reviewed
      repositioning data exist. While the performance of the system for fractionated
      treatment courses was considered to be excellent, use of this mask system for
      radiosurgery immobilization in our clinic is subject to additional quality
      assurance measures to prohibit the delivery of treatments with target
      dislocations larger than 2 mm. The measured data in the present study should
      enable the users of this system to assign appropriate margins for the generation
      of planning target volumes.

PMID- 15172153
TI  - Molecular aspects of medicine: from experimental to clinical hepatology.

PMID- 15172152
TI  - Multinational assessment of some operational costs of teletherapy.
AB  - BACKGROUND AND PURPOSE: Decisions in planning radiotherapy facilities in
      countries with limited financial resources require information on economic
      factors to make provision for sustainability. This study aims at acquiring data
      on some of these factors involved in delivery of teletherapy in 11 countries of
      different economic status. PATIENTS AND METHODS: Representatives of three
      European, one African, three Latin American and four Asian countries, were
      identified from radiation oncology institutions that operated both cobalt and
      linac teletherapy machines. Productivity data were prospectively collected for
      the year 2002. A detailed log was recorded for each machine over an arbitrary two
      week period. Data on quality assurance (QA), maintenance, the capital costs of
      each machine, and the source replacement costs for the cobalt units were also
      recorded. RESULTS: Both linear accelerators and cobalt machines treat more than
      10,000 fractions per year per machine with 2.5 and 2.3 fields per fraction,
      respectively. The capital costs of the machines vary considerably, with a factor
      of more than 10 for linear accelerators. Cobalt sources show a huge variation in
      price. The median costs of QA and maintenance of a linac was US$ 41,000 compared
      to US$ 6000 for cobalt machines. This results for the economic factors considered
      in median costs per fraction of US$ 11.02 for linear accelerators and US$ 4.87
      for cobalt machines. These figures do not include the costs for physicians.
      CONCLUSIONS: The variation of the costs per fraction is more due to the result of
      differences in machine usage and costs of equipment than of national economic
      status. A treatment fraction on a linac with functionality comparable to cobalt,
      costs 50% more than cobalt therapy. This project shows that it is possible to
      collect data on economic factors prospectively as well as retrospectively.

PMID- 15172154
TI  - High-yield coupling of antibody Fab' fragments to liposomes containing maleimide
      functionalized lipids.

PMID- 15172155
TI  - Interactions of hyaluronan-targeted liposomes with cultured cells: modeling of
      binding and endocytosis.

PMID- 15172156
TI  - Folate receptor-mediated targeting of liposomal drugs to cancer cells.

PMID- 15172157
TI  - Preparation of poly(ethylene glycol)-grafted liposomes with ligands at the
      extremities of polymer chains.

PMID- 15172158
TI  - Temperature-sensitive liposomes.

PMID- 15172159
TI  - The materials engineering of temperature-sensitive liposomes.

PMID- 15172160
TI  - Tunable pH-sensitive liposomes.

PMID- 15172161
TI  - Sterically stabilized ph-sensitive liposomes.

PMID- 15172162
TI  - Improved preparation of PEG-diortho ester-diacyl glycerol conjugates.

PMID- 15172163
TI  - Preparation of plasmenylcholine lipids and plasmenyl-type liposome dispersions.

PMID- 15172164
TI  - High efficiency entrapment of antisense oligonucleotides in liposomes.

PMID- 15172165
TI  - Cationic liposomes/lipids for oligonucleotide delivery: application to the
      inhibition of tumorigenicity of Kaposi's sarcoma by vascular endothelial growth
      factor antisense oligodeoxynucleotides.

PMID- 15172166
TI  - Requirements for delivery of active antisense oligonucleotides into cells with
      lipid carriers.

PMID- 15172167
TI  - Mass spectrometry and enzyme-linked immunosorbent assay methods for the
      quantitation of liposomal antisense oligonucleotide (LE-rafAON) in human plasma.

PMID- 15172168
TI  - Liposomal antisense oligonucleotides for cancer therapy.

PMID- 15172169
TI  - Biodistribution and uptake of liposomes in vivo.

PMID- 15172170
TI  - Transport of liposome-entrapped substances into skin as measured by electron
      paramagnetic resonance oximetry in vivo.

PMID- 15172171
TI  - Liposomal gels for vaginal drug delivery.

PMID- 15172172
TI  - Use of nitroxides to protect liposomes against oxidative damage.

PMID- 15172174
TI  - iNOS-mediated nitric oxide production and its regulation.
AB  - This review focuses on the production of nitric oxide (NO) by inducible nitric
      oxide synthase (iNOS) and its regulation under physiological and
      pathophysiological conditions. NO is an important biological mediator in the
      living organism that is synthesized from L-arginine using NADPH and molecular
      oxygen. However, the overproduction of NO which is catalyzed by iNOS, a soluble
      enzyme and active in its dimeric form, is cytotoxic. Immunostimulating cytokines
      or bacterial pathogens activate iNOS and generate high concentrations of NO
      through the activation of inducible nuclear factors, including NFkB. iNOS
      activation is regulated mainly at the transcriptional level, but also at
      posttranscriptional, translational and postranslational levels through effects on
      protein stability, dimerization, phosphorylation, cofactor binding and
      availability of oxygen and L-arginine as substrates. The prevention of the
      overproduction of NO in the living organism through control of regulatory
      pathways may assist in the treatment of high NO-mediated disorders without
      changing physiological levels of NO.

PMID- 15172175
TI  - Modulation of iNOS activity in age-related cardiac dysfunction.
AB  - Based on the role of inducible nitric oxide synthase (iNOS) in heart failure, we
      hypothesized that the elevated expression of iNOS compared to young mice in the
      myocardium contributes to the age-related decline of left ventricular (LV)
      function. Cardiac iNOS mRNA and protein expression was singularly identified in
      old, wild type (WT) male mice (I6-month) and not in young WT male mice (6-month).
      Characterized with in vivo pressure-volume loops analysis, an age-related LV
      dysfunction was found in the old WT mice. The LV dysfunction of the aged mice was
      modified to that of the younger mice by the specific iNOS inhibitors,
      aminoguanidine (AMG, 10 mg/Kg, i.v. or infusion, n = 15) and S-methyl-isothiourea
      (MITU, 3 mg/Kg, i.v. n = 7), and declined with L-arginine (10 mg/Kg, i.v. n = 7).
      All three drugs had no effects on the LV function of young WT mice or old iNOS
      knockout (KO) mice. The NOx and cGMP levels were significantly higher only in the
      old WT mice (n = 6) and cGMP levels decreased to normal with AMG administration.
      In conclusion, these results suggested that the iNOS/NO/cGMP pathway may
      contribute to ventricular dysfunction during the aging process and that
      inhibition of iNOS activity significantly improved heart function in aged mice.

PMID- 15172176
TI  - A study of serum malondialdehyde and interleukin-6 levels in young women with
      dysmenorrhea in Taiwan.
AB  - The purpose of this study was to examine whether the symptoms of dysmenorrhea in
      young women were related to serum malondialdehyde (MDA) and interleukin-6 (IL-6)
      levels. Ninety-four non-smoking and non-drinking female subjects without serious
      disease from a nursing college in Taiwan were divided into two groups. Group 1
      consisted of 51 subjects without dysmenorrheal, and Group 2 of 43 subjects with
      dysmenorrheal symptom. All subjects were provided informed consent. Results
      showed that the serum levels of MDA and of IL-6 were significantly different
      between the two groups (P < 0.05) and (P < 0.005), respectively. We conclude that
      the pathological mechanism of dysmenorrhea is mediated by oxidative stress caused
      by the action of cytokine.

PMID- 15172177
TI  - Acetylbritannilatone suppresses NO and PGE2 synthesis in RAW 264.7 macrophages
      through the inhibition of iNOS and COX-2 gene expression.
AB  - In order to elucidate the mechanism of anti-inflammatory effect of 1-o
      acetylbritannilatone (ABL) isolated from Inula Britannica-F, we investigated ABL
      for its ability to inhibit the inflammatory factor production in RAW 264.7
      macrophages. The studies showed that ABL not only inhibited LPS/IFN-gamma
      mediated nitric oxide (NO) production and inducible nitric synthase (iNOS)
      expression, but also decreased LPS/IFN-gamma-induced prostaglandin E2 (PGE2)
      production and cyclo-oxygenase-2 (COX-2) expression in a concentration-dependent
      manner. EMSA demonstrated that ABL inhibited effectively the association of NF
      kappaB, which is necessary for the expression of iNOS and COX-2, with its binding
      motif in the promoter of target genes. These data suggest that ABL suppress NO
      and PGE2 synthesis in RAW 264.7 macrophages through the inhibition of iNOS and
      COX-2 gene expression, respectively. The anti-inflammatory effect of ABL involves
      blocking the binding of NF-kappaB to the promoter in the target genes and
      inhibiting the expression of iNOS and COX-2.

PMID- 15172178
TI  - Lateral hypothalamus lesions influences water and salt intake, and sodium and
      urine excretion, and arterial blood pressure induced by L-NAME and FK 409
      injections into median preoptic nucleus in conscious rats.
AB  - Male Holtzman rats weighting 200-250 g were anesthetized with zoletil 50 mg/Kg
      (tiletamine chloridrate 125,0 mg and zolazepan chloridrate 125,0 mg) into
      quadriceps muscle and submitted an electrolytic lesion of the lateral
      hypothalamus (LH) and a stainless steel cannula was implanted into their median
      preoptic nucleus (MnPO). We investigated the effects of the injection into the
      (MnPO) of FK 409 (20 microg/0.5 microl), a nitric oxide (NO) donor, and N(W)
      nitro-L-arginine methyl ester (L-NAME) 40 microg/0.5 microl, a nitric oxide
      synthase inhibitor (NOSI), on the water and sodium appetite and the natriuretic,
      diuretic and cardiovascular effects induced by injection of L-NAME and FK 409
      injected into MnPO in rats with LH lesions. Controls were injected with a similar
      volume of 0.15 M NaCl. L-NAME injected into MnPO produced an increase in water
      and sodium intake and in sodium and urine excretion and increase de mean arterial
      pressure (MAP). FK 409 injected into MnPO did not produce any change in the hydro
      electrolytic and cardiovascular parameters in LH-sham and lesioned rats. FK 409
      injected before L-NAME attenuated its effects. These data show that electrolytic
      lesion of the LH reduces fluid and sodium intake as well as sodium and urine
      excretion, and the pressor effect induced by L-NAME. LH involvement with NO of
      the MnPO excitatory and inhibitory mechanisms related to water and sodium intake,
      sodium excretion and cardiovascular control is suggested.

PMID- 15172179
TI  - The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine
      genes expression, and cell proliferation in human peripheral blood mononuclear
      cells.
AB  - In the hope of identifying agents of therapeutic value in tissue inflammation, we
      tested ethanolic extracts of six Chinese herbs for their effects on human
      peripheral blood mononuclear cells (PBMC) proliferation in vitro. The results
      indicated that the extracts from Nelumbo nucifera Gaertn, used in treatment of
      tissue inflammation in traditional Chinese medicine, inhibited PBMC proliferation
      activated with phytohemagglutinin (PHA). By a bioassay-guided fractionation
      procedure, NN-B-4 identified from N. nucifera ethanolic extracts significantly
      suppressed activated PBMC proliferation. The inhibitory action of NN-B-4 did not
      involve direct cytotoxicity. In an attempt to further localize the point in the
      PBMC proliferation where arrest occurred, a set of key regulatory events leading
      to the cell proliferation, including cell cycle progression, production and gene
      expression of interleukin-2 (IL-2), IL-4, IL-10, and interferon-gamma (IFN-gamma)
      was examined. Cell cycle analysis indicated that NN-B-4 arrested the cell cycle
      progression of activated PBMC from the G1 transition to the S phase. The cyclin
      dependent kinase (cdk) 4 mRNA expression in PBMC stimulated with PHA was reduced
      by NN-B-4. NN-B-4 suppressed, in activated PBMC, the production and mRNA
      expression of IL-2, IL-4, IL-10, and IFN-gamma in a dose-dependent fashion. The
      suppressant effects of NN-B-4 on proliferation of PBMC activated by PHA therefore
      appear to be mediated, at least in part, through inhibition of early transcripts
      of PBMC, especially those of important IL-2, IFN-gamma, and cdk4 and arrest of
      cell cycle progression in the cells.

PMID- 15172180
TI  - Sequential changes in redox status and nitric oxide synthases expression in the
      liver after bile duct ligation.
AB  - Bile duct ligation (BDL) in rats induces portal fibrosis. This process has been
      linked to changes in the oxidative state of the hepatic cells and in the
      production of nitric oxide. Our objective was to find possible temporal
      connections between hepatic redox state, NO synthesis and liver injury. In this
      work we have characterized hepatic lesions 17 and 31 days after BDL and
      determined changes in hepatic function, oxidative state, and NO production. We
      have also analyzed the expression and localization of inducible NO synthase
      (NOS2) and constitutive NO synthase (NOS3). After 17 and 31 days from ligature,
      lipid peroxidation is increased and both plasma concentration and biliary
      excretion of nitrite+nitrate are rised. 17 days after BDL both NOS2 and NOS3 are
      expressed intensely and in the same regions. 31 days after BDL, the expression of
      NOS2 remains elevated and is localized mostly in preserved hepatocytes in portal
      areas and in neighborhoods of centrolobulillar vein. NOS3 is localized in
      vascular regions of portal spaces and centrolobulillar veins and in preserved
      sinusoids and although its expression is greater than in control animals (34%),
      it is clearly lower (50%) than 17 days after BDL. The time after BDL is crucial
      in the study of NO production, intrahepatic localization of NOS isoforms
      expression, and cell type involved, since all these parameters change with time.
      BDL-induced, peroxidation and fibrosis are not ligated by a cause-effect
      relationship, but rather they both seem to be the consequence of common
      inductors.

PMID- 15172181
TI  - The effect of the active component of Dendrostellera lessertii on the adhesive
      property of human platelets and HL-60 cells.
AB  - To evaluate the mediation of cell adhesion by Dendrostellera lessertii, an anti
      cancer medicinal plant in Iranian folk medicine, the adhesion of thrombin
      activated human platelets to the cultured monocytes or HL-60 cells was
      investigated under the effect of the plant extract (0.4 mg/ml) and one of its
      purified components, 3-hydrgenkwadaphnin (0.2 nM). Treatment of the platelets
      with the plant extract or/3-hydrgenkwadaphnin, for various time intervals,
      followed by their activation by thrombin resulted in 80-90% reduction in the
      number of monocytes with more than 10 attached platelets. Similarly, under almost
      all identical conditions, the adhesion of the activated platelets to HL-60 cells
      was decreased by 90%. The adhesion of thrombin activated platelets to the plant
      extract treated HL-60 cells was also reduced significantly (95%). These data
      clearly indicates that Dendrostellera lessertii is capable of mediating tumor
      metastasis through affecting the adhesion properties of the cells.

PMID- 15172182
TI  - The action mechanism of zinc(II) complexes with insulinomimetic activity in rat
      adipocytes.
AB  - Zinc (Zn), an essential trace element, and its complexes have recently been known
      to exhibit insulinomimetic activities. However, the action mechanism of Zn(II)
      has yet been obscure. The purpose of the present study was to estimate the action
      mechanism of the Zn(II) complexes. We found first that Zn given in the chemical
      forms such as Zn(maltolate)2 and Zn(threoninate)2 complexes is highly uptaken in
      the isolated rat adipocytes compared with that of Zn(picolinate)2. Then, the
      action mechanism for the insulinomimetic activities was examined in terms of free
      fatty acid release from the adipocytes. Four Zn(II) compounds, ZnSO4,
      Zn(picolinate)2, Zn(maltolate)2, and Zn(threoninate)2, inhibited the free fatty
      acid release from the adipocytes treated with epinephrine (adrenaline). By using
      several inhibitors for fatty acids and glucose metabolisms in the adipocytes, the
      following results were obtained. (1) Zn(picolinic acid)2 complex acts on the
      insulin receptor and PI3-k, which relate to the glucose uptake, as indicated by
      the experiments using hydroxy-2-naphthalenylmethyl phosphonic acid tris acetoxy
      methyl ester (HNMPA-(AM)3) and wortmannin, respectively. (2) ZnSO4, and
      Zn(maltolate)2 and Zn(threoninate)2 complexes affect a glucose transporter 4
      (GLUT 4), which is involved in the glucose uptake as indicated by the results
      using cytochalasin B. (3) Four Zn(II) compounds affect the activation of the
      phosphodiesterase as indicated by the experiments using cilostamide. These
      results indicate that the Zn(II) compounds promote the glucose uptake into the
      adipocytes by affecting at least three sites in the adipocytes, which in turn
      normalize the blood glucose levels in the experimental diabetic animals.

PMID- 15172183
TI  - Lipid peroxidation inhibitory compounds from daylily (Hemerocallis fulva) leaves.
AB  - Daylilies (Hemerocallis spp.) have been used as food and in traditional medicine
      for thousands of years in eastern Asia. The leaves of the plant are used in the
      treatment of inflammation and jaundice. In studies of the aqueous methanol
      extracts of fresh Hemerocallis fulva leaves, 1',2',3',4'-tetrahydro-5'-deoxy
      pinnatanine (1), pinnatanine (2), roseoside (3), phlomuroside (4), lariciresinol
      (5), adenosine (6), quercetin 3-O-beta-D-glucoside (7), quercetin 3,7-O-beta-D
      diglucopyranoside (8), quercetin 3-O-alpha-L-rhamnopyransol-(1-->6)-beta-D
      glucopyranosol-7-O-beta-D-glucopyranoside (9), isorhamnetin-3-O-beta-D-6'
      acetylglucopyranoside (10) and isorhamnetin-3-O-beta-D-6'-acetylgalactopyranoside
      (11) were isolated. All of these compounds were tested for their in vitro lipid
      peroxidation inhibitory activities. Compounds 3-5 and 7-11 were found to possess
      strong antioxidant properties, inhibiting lipid oxidation by 86.4, 72.7, 90.1,
      79.7, 82.4, 89.3, 82.2, and 93.2%, respectively at 50 microg/mL. Compound 1 is
      novel and compounds 3-6 and 8-11 described here in are isolated for the first
      time from daylily leaves.

PMID- 15172184
TI  - Microvascular in vivo assessment of reperfusion injury: significance of
      prostaglandin E(1) and I(2) in postischemic "no-reflow" and "reflow-paradox".
AB  - BACKGROUND: Microvascular ischemia-reperfusion (I/R) injury is characterized by
      failure of capillary perfusion ("no-reflow") and reoxygenation-associated
      phenomena ("reflow-paradox"), including activation of leukocyte-endothelium
      interaction with cytotoxic mediator-induced loss of endothelial integrity. The
      objectives of this study were to elucidate the impact of both prostaglandins E(1)
      (PGE(1)) and I(2) (PGI(2)) in microvascular reperfusion injury, with special
      focus on the distinct pathophysiology of no-reflow- and reflow-paradox phenomena.
      MATERIALS AND METHODS: By use of the hamster dorsal skinfold preparation and in
      vivo fluorescence microscopy, the microcirculation of a striated skin muscle was
      assessed before 4 h of pressure-induced ischemia and 0.5, 2, and 24 h after onset
      of reperfusion. RESULTS: I/R was characterized by enhanced leukocyte-endothelium
      interaction in postcapillary venules, increase of macromolecular leakage, and
      reduction of functional capillary perfusion (P < 0.05). Intravenous 2-h infusion
      of PGE(1), starting with onset of reperfusion, reduced leukocyte adhesion and
      macromolecular leakage in postcapillary venules during early reperfusion (P <
      0.05), while 6-h infusion, given during ischemia and early reperfusion, showed no
      significant effects. PGI(2) infusion also attenuated postischemic leukocyte
      adhesion, which was significant by a 6-h prolonged administration (P < 0.05), but
      did not influence the increase of microvascular permeability. Both prostaglandins
      were unable to prevent the postischemic failure of capillary perfusion (no
      reflow). CONCLUSIONS: Both prostaglandins did not significantly influence
      postischemic no-reflow phenomena, but appeared as potent inhibitors of reflow
      paradox under the experimental circumstances of this study.

PMID- 15172185
TI  - Real-time monitoring of keratin 5 expression during burn re-epithelialization.
AB  - BACKGROUND: Keratin is a major protein produced during epithelialization
      following burn injury and is a useful marker for assessing wound healing.
      Transgenic mice expressing enhanced green fluorescent protein (EGFP) driven by
      the keratin 5 (K5) promoter (K5GFP mice) were used to monitor keratin expression,
      and thus, re-epithelialization of burn wounds. MATERIALS AND METHODS: K5GFP
      transgenic mice were created using conventional techniques, with PCR and Southern
      blot confirmation of transgene incorporation, followed by selection of the line
      with the most intense and consistent basal epithelial EGFP expression. Epi
      fluorescent microscopy of 24 K5GFP mouse flanks and 10 negative littermate
      controls was used to characterize EGFP intensity, before wounding and serially
      for 30 days after administration of a standardized burn wound and excision.
      Biopsy sections of K5GFP and negative control mice were stained with K5 antibody
      and imaged with confocal microscopy to characterize the distribution of EGFP and
      K5 at baseline and after injury and to examine the correlation between K5
      expression and EGFP expression during healing. RESULTS: Green fluorescence
      intensity increased at the advancing wound margin of burned K5GFP mice, reaching
      a maximum between days 12 and 15 post-burn and then decreasing as healing
      completed. K5 and EGFP expression increased in parallel in burned K5GFP mice as
      demonstrated by confocal microscopy. CONCLUSION: EGFP expression correlated with
      K5 expression during wound healing and therefore serves as a good marker of re
      epithelialization. This transgenic model allows noninvasive, real-time assessment
      of in vivo K5 expression and will be useful in the study of wound healing.

PMID- 15172186
TI  - Thrombospondin-1 up-regulates tumor cell invasion through the urokinase
      plasminogen activator receptor in head and neck cancer cells.
AB  - BACKGROUND: We have previously demonstrated that thrombospondin-1 (TSP-1) is
      expressed in squamous cell carcinomas of the head and neck. We have also shown
      that TSP-1 promotes tumor cell invasion through up-regulation of the urokinase
      plasminogen activator receptor (uPAR), in adenocarcinoma models. We now
      determined the role of TSP-1 in the regulation of uPAR expression and tumor cell
      invasion in squamous cell carcinoma of the head and neck cells. MATERIALS AND
      METHODS: KB squamous cell carcinoma of the head and neck cells were used. The
      effect of TSP-1 on uPAR and its ligand, urokinase plasminogen activator (uPA),
      expression were determined by ELISA. The effect of TSP-1 on KB tumor cell
      invasion was determined in a modified Boyden chamber collagen invasion assay. To
      determine the role of uPAR on TSP-1-mediated KB tumor cell invasion, we used the
      three following different strategies: (a). blocking uPAR or its ligand, uPA, with
      neutralizing antibodies; (b). enzymatic cleavage of uPAR with
      glycosylphosphatidylinositol (GPI)-specific phospholipase C; and (c). inhibition
      of plasminogen binding by using epsilon-aminocaproic acid. RESULTS: TSP-I up
      regulated uPAR and uPA expression 3- and 4-fold, respectively. TSP-1 up-regulated
      KB tumor cell invasion 5-fold. Inhibition of uPAR blocked the TSP-1-mediated up
      regulation of KB tumor cell invasion. CONCLUSIONS: Our data support a central
      role for TSP-1 in the regulation of uPAR and tumor cell invasion in squamous cell
      carcinomas of the head and neck cells. Furthermore, uPAR seems to play a crucial
      role in TSP-1-mediated squamous cell carcinoma of the head and neck tumor cell
      invasion.

PMID- 15172187
TI  - Temporal gene expression following prosthetic arterial grafting.
AB  - BACKGROUND: Following prosthetic arterial grafting, cytokines and growth factors
      released within the perianastomotic tissues stimulate smooth muscle cell
      proliferation and matrix production. While much in vitro work has characterized
      this response, little understanding exists regarding the sequential up- and down
      regulation of genes following prosthetic arterial grafting. This study evaluates
      temporal gene expression at the distal anastomosis of prosthetic arterial grafts
      using microarray analysis. METHODS: Expanded polytetrafluoroethylene (ePTFE)
      carotid interposition grafts (n = 12) were surgically implanted into mongrel
      dogs. Distal anastomotic segments were harvested at 7, 14, 30, or 60 days.
      Contralateral carotid artery served as control. Total RNA was isolated from the
      anastomotic tissue and paired controls. Samples were probed with oligonucleotide
      microarrays consisting of approximately 10000 human genes to analyze differential
      gene expression at each time point. RESULTS: Forty-nine genes were found to be up
      regulated and 37 genes were found to be down-regulated at various time points.
      Six genes were found to be consistently up-regulated at all time intervals,
      including collagen type 1 alpha-1 and alpha-2, 80K-L protein (MARCKS), and
      osteopontin. Six genes were found to be consistently down-regulated, including
      smoothelin and tropomyosin 2. RT-PCR and immunohistochemistry confirmed the
      microarray data. CONCLUSIONS: This study uses microarray analysis to identify
      genes that were temporally up- and down-regulated after prosthetic arterial
      grafting. Genes with similar patterns of expression have been identified,
      providing insights into related cellular pathways that may result in the
      formation of anastomotic intimal hyperplasia.

PMID- 15172188
TI  - In vivo electroporation enhances plasmid-based gene transfer of basic fibroblast
      growth factor for the treatment of ischemic limb.
AB  - BACKGROUND: Angiogenic therapy for ischemic tissues using angiogenic growth
      factors has been reported on an experimental and a clinical level.
      Electroporation enhances the efficiency of plasmid-based gene transfer in a
      variety of tissues. The purpose of this study was to evaluate the angiogenic
      effects of plasmid-based gene transfer using basic fibroblast growth factor
      (bFGF) in combination with electroporation. MATERIALS AND METHODS: The
      transfection efficiency of in vivo electroporation in rabbit skeletal muscles was
      evaluated using pCAccluc+ encoding luciferase. To evaluate the angiogenic effects
      of bFGF gene in ischemic limb, we constructed a plasmid, pCAcchbFGFcs23,
      containing human bFGF cDNA fused with the secretory signal sequence of
      interleukin (IL)-2. Then, 500 microg of pCAcchbFGFcs23 or pCAZ3 (control plasmid)
      was injected into the ischemic thigh muscles in a rabbit model of hind limb
      ischemia with in vivo electroporation (bFGF-E(+) group and LacZ-E(+) group).
      Other sets of animals were injected with pCAcchbFGFcs23 (bFGF-E(-) group) or
      pCAZ3 (LacZ-E(-) group) without electroporation. Then 28 days later, calf blood
      pressure ratio, angiographic score, in vivo blood flow, and capillary density in
      the ischemic limb were measured. RESULTS: Gene transfer efficiency increased
      markedly with the increase in voltage up to 100 V. Regarding angiogenic
      responses, calf blood pressure ratio, in vivo blood flow, and capillary density
      only in the bFGF-E(+) group were significantly higher than those in LacZ-E(-)
      group. Angiographic scores in the bFGF-E(+) and bFGF-E(-) groups were
      significantly higher than that in the LacZ-E(-) group. CONCLUSION: These data
      suggest that in vivo electroporation enhances bFGF gene transfer for the
      treatment of ischemic limb muscles.

PMID- 15172189
TI  - Local administration of hepatocyte growth factor gene enhances the regeneration
      of dermis in acute incisional wounds.
AB  - Hepatocyte growth factor (HGF) has a number of biological activities, e.g.,
      mitogenic, motogenic, antiapoptotic, antifibrous, and morphogenic. It also has
      angiogenic and angioprotective activities for endothelial cells. The aim of this
      study was to characterize the role of HGF in wound healing by administering the
      HGF gene locally to acute incisional skin wounds created on the backs of rats. To
      create wounds, the backs of Wistar rats were clipped and three 2-cm-long
      incisional wounds were made deep to the fascia. The wounds contained pannicrus
      carnosum and were created at intervals of 2 cm. After suturing, the HGF gene was
      then administered intradermally. Apoptotic cells in wound lesions were identified
      by TUNEL method as well as by immunological detection of active caspase-3. In the
      HGF-treated animals, we found almost complete suppression of apoptosis and well
      organized wound healing. Histopathological examination revealed that the
      proliferation of fibroblasts was suppressed and that scar formation was less
      apparent in the HGF-treated animals compared to the controls. It is thought that
      administration of the HGF gene immediately after surgery may enhance the healing
      process through suppressing apoptosis, which occurred in the controls 1 week
      after suturing the incisional wound. In addition, locally increased HGF
      expression due to the introduction of the HGF gene to cells around wounds
      enhances dermal regeneration, possibly by promoting regeneration of dermal
      tissue, which results in less scarring due to its antifibrotic effect. Thus, HGF
      supplementation through gene therapy may be an effective strategy for treating
      wounds, as it increases the regeneration of the dermis to allow for "scarless
      wound healing."

PMID- 15172190
TI  - St Thomas Hospital Cardioplegia #2 fails to suppress slow reaction pacemaker cell
      electrical activity.
AB  - BACKGROUND: Inadequate right atrial myocardial preservation during cardioplegic
      arrest may promote postoperative supraventricular arrhythmias (SVA). We
      determined (1). if oxygenated St. Thomas Hospital Cardioplegia #2 (STH2) alone
      causes slow reaction pacemaker cell (SR) quiescence; and (2). if hypothermia,
      higher [K(+)], lower [Ca(2+)], and verapamil in STH2 suppresses SR electrical
      activity. MATERIALS AND METHODS: A glass microelectrode recorded SA node SR
      membrane action potentials (AP) in rabbits (n = 23, 1.93 +/- 0.45 kg) randomized
      to normothermic STH2 (33 degrees C, n = 6), hypothermia (20 degrees C, n = 4),
      hypothermic STH2 (22 degrees C, n = 3), lower calcium STH2 (n = 3), higher
      potassium STH2 (n = 4), and STH2 plus Verapamil (n = 3). RESULTS: Normothermic
      STH2 depressed SR action potential amplitude and action potential duration (APD),
      but did not completely suppress action potential generation. Hypothermia alone
      prolonged APD and sinus cycle length and suppressed SR AP. STH2 with hypothermia
      (to 20 degrees C) completely suppressed propagating AP and STH2 plus 0.04 Ca(2+)
      mEq/L inhibited SR AP generation. STH2 plus 30 mEq K(+) and STH2 plus 2.5 mmol/L
      verapamil failed to generate SR AP. CONCLUSION: STH2 cannot prevent SA node SR
      myocardial cells from low-amplitude AP autogeneration above 21 degrees C. STH2
      with 30 mEq/L K(+), STH2 with 0.02 mEq/L Ca(2+), and STH2 plus 2.5 mmol/L
      verapamil can arrest AP generation in SR and potentially prevent postoperative
      SVA.

PMID- 15172191
TI  - In vivo therapy of local tumor progression by targeting vascular endothelium with
      EMAP-II.
AB  - BACKGROUND: Continued growth of solid tumors beyond a critical diameter is
      thought to require active angiogenic mechanisms, the inhibition of which carries
      therapeutic potential. We tested this strategy in an in vivo model of local tumor
      progression utilizing an agent with previously identified direct antiendothelial
      properties. MATERIALS AND METHODS: Nonmetastatic C(6) glioma cells (10(6) per
      animal) were injected subcutaneously into the flank of nude mice with 6 to 8
      animals per treatment group. Nodules at the injection site were measured at day 3
      and every fourth day thereafter until day 15. Endothelial-monocyte-activating
      polypeptide II (EMAP-II), a substance known to induce endothelial cell apoptosis,
      was injected intraperitoneally daily from day 3 to day 15 at doses of 8 microg/kg
      (low dose) and 80 microg/kg (high dose). Tumor growth kinetics, histologic
      parameters, and tissue expression of VEGF were studied. RESULTS: Tumor growth was
      significantly decreased in the EMAP-II-treated animals. Median tumor volume (in
      mm(3)) at day 15 was 2311 (Control), 727 (low dose), and 454 (high dose, P =
      0.003). Median tumor weight (g) measured 1.8 (Control, 0.95 low dose), and 0.9
      (high dose, P = 0.06). Median 12-day specific tumor growth rate (in mm(3)/day)
      per group was 191, 60, and 36 (P = 0.003). Decreased tumor growth after EMAP-II
      treatment correlated with significantly reduced microvessel counts, higher
      vascular thrombosis rate, and reduced tumor cell proliferation indices within the
      neoplastic tissue. Tumor levels, but not serum levels, of VEGF were significantly
      reduced after EMAP-II treatment. At the doses administered, there was no obvious
      systemic toxicity. EMAP-II had no direct cytotoxic or antiproliferative effects
      on tumor cells in vitro. CONCLUSIONS: Daily administration of the antiendothelial
      agent EMAP-II led to a significant retardation of tumor growth, but no complete
      cancer abrogation. The findings support the hypothesis of an in vivo therapeutic
      benefit to antiangiogenic therapy with an agent that displays specific toxicity
      in vitro against endothelial cells. The mechanism of action remains unclear, but
      likely involves vascular thrombosis and leads to decreased VEGF expression.

PMID- 15172192
TI  - Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in
      rats.
AB  - BACKGROUND: Fatty split-liver and living-related liver transplantation is
      associated with massive hepatocellular necrosis during acute rejection.
      Uncoupling protein (UCP)-2 is a potential regulator of energy expenditure and ATP
      production. We investigated the role of UCP-2 and the effects of a
      metalloprotease inhibitor, Y-39083, on hepatocellular injury in fatty liver
      allografts in rats. MATERIALS AND METHODS: Rats were treated for 6 weeks with
      high-ethanol or isocalic dextrose-containing liquid diets that caused
      characteristic pericentral lipid accumulation. Alcoholic or nonalcoholic fatty
      livers from ACI (RT1a) rats were transplanted into LEW (RT1l) rats
      orthotopically. Hepatic necrosis was determined histologically following liver
      transplantation. UCP-2 mRNA levels in the hepatic allograft and in primary
      cultured hepatocytes from fatty liver stimulated by tumor necrosis factor (TNF)
      alpha were determined. Y-39083 was administered to recipient rats continuously at
      5 mg/kg/day using an osmotic infusion mini-pump. RESULTS: The acute rejection
      index on day 5 posttransplant in alcoholic and nonalcoholic fatty donor livers
      was higher than in lean grafts. Massive hepatocyte necrosis was more prominent in
      alcoholic than nonalcoholic fatty liver allografts and was not seen in lean
      allografts. UCP-2 transcripts in both alcoholic and nonalcoholic fatty liver
      allografts were higher than in lean allografts. Serum TNF-alpha concentrations in
      recipient rats with either fatty liver allograft were greater than in animals
      with lean allografts. In vitro UCP-2 mRNA levels in primary cultured hepatocytes
      from both alcoholic and nonalcoholic fatty livers increased more after
      stimulation with TNF-alpha than those from lean livers. In vitro TNF-alpha
      production by Kupffer cells isolated from alcohol-induced fatty liver allografts
      on day 3 posttransplant was greater than those from lean allografts. Y-39083
      significantly reduced serum concentrations of TNF-alpha and prevented massive
      hepatocellular necrosis in rats with both alcoholic and nonalcoholic fatty liver
      allografts. CONCLUSION: Liver grafts with steatosis up-regulated UCP-2. TNF-alpha
      further enhanced UCP-2 transcripts, inducing massive hepatocellular necrosis
      during acute rejection. Posttransplantation necrosis may be prevented by
      metalloprotease inhibitors.

PMID- 15172193
TI  - Angiotensin II type 2 receptor effect on microvascular hydraulic permeability.
AB  - BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor that modulates
      microvascular permeability. Angiotensin II type 1 (AT1) and type 2 (AT2)
      receptors have been described with subsequent development of their respective
      antagonists. We hypothesized that the AT2 receptor modulates microvascular
      permeability. MATERIALS AND METHODS: Hydraulic permeability (L(p)) was measured
      in rat mesenteric venules using the Landis micro-occlusion technique. Following
      baseline L(p) measurements, paired measures of microvessel L(p) were obtained
      after perfusion with a test solution. The test solutions consisted of the AT2
      receptor agonist CGP42112A at 10 microm (n = 6), 100 microm (n = 6), and 200
      microm (n = 6), as well as the AT2 receptor antagonist PD-123319 at 3 microm (n =
      6), 30 microm (n = 6), 300 microm (n = 6), and 600 microm (n = 6). RESULTS: From
      mean baseline L(p) of 0.99 +/- 0.03, 100 microm CGP42112A decreased L(p) to 0.76
      +/- 0.02 (P = 0.005), and 200 microm CGP42112A decreased L(p) to 0.61 +/- 0.02 (P
      < 0.001). From mean baseline L(p) of 0.90 +/- 0.05, PD-123319 increased L(p) at
      30 microm to 1.60 +/- 0.2 (P = 0.003), at 300 microm to 2.28 +/- 0.3 (P = 0.008),
      and at 600 microm to 4.30 +/- 0.9 (P = 0.03). Units for L(p) are mean +/- SEM x
      10(-7) cm s(-1) cmH(2)O(-1). CONCLUSION: AT2 activation decreased L(p), while AT2
      blockade increased L(p). These changes in L(p) may be explained by (1). a
      permeability-decreasing effect of the AT2 receptor that is induced by AT2
      activation and inhibited by AT2 blockade; and/or (2). a permeability-increasing
      effect of the AT1 receptor observed during AT2 blockade and selective AT1
      activation by endogenous locally released Ang II. These mechanisms would support
      the theories that the AT1 receptor increases microvascular permeability, while
      the AT2 receptor decreases microvascular permeability.

PMID- 15172194
TI  - Cyclin expression in the atrophying and proliferating lobes of the liver after
      portal vein branch ligation and hepatectomy in rats.
AB  - BACKGROUND: Portal vein branch ligation causes atrophy of the portal vein ligated
      lobes (PVL) and proliferation of the nonligated lobes (PVNL) of the liver.
      However, the mechanisms underlying atrophy of the PVL and proliferation of PVNL
      after portal vein branch ligation have not been clarified except that interleukin
      6 (IL-6), nuclear factor kappa B (NF-kappaB), signal transducer and activator of
      transcription 3 (STAT3), and immediate-early gene expression are similarly
      induced in both the PVL and the PVNL. Thus, it is still unclear what factors
      cause the subsequent atrophy and proliferation. MATERIALS AND METHODS: Male
      Wistar rats were randomly separated into a portal vein branch ligation group and
      partial hepatectomy group. In the portal vein branch ligation group, the branch
      of portal vein supplying the median and left lateral lobes of the liver was
      ligated. In the partial hepatectomy group, the correspondent lobes of the liver
      were excised. We examined cyclin expression in the PVL and PVNL after portal vein
      branch ligation in comparison to cyclin expression in the remaining liver (HEP)
      after partial hepatectomy. Cyclin D1, E, and A mRNA and protein expressions were
      analyzed by RT-PCR and Western blotting, respectively. RESULTS: The mRNA and
      protein expressions of cyclin D1 and A were not up-regulated in the PVL, whereas
      those in the PVNL and HEP were up-regulated. Cyclin D1 mRNA and protein
      expressions were significantly lower in the PVL than in the PVNL and HEP at 18 h.
      The levels of mRNA and protein expression of cyclin A were significantly lower in
      the PVL than in the PVNL and HEP at 36 h. Liver regeneration, assessed by the
      relative liver weight, thymidine incorporation into DNA, and proliferating cell
      nuclear antigen (PCNA) labeling index was delayed significantly in the PVNL
      compared to that in the HEP. Cyclin D1 mRNA and protein expressions were
      significantly lower in the PVNL than in the HEP at 12 and 18 h, respectively.
      CONCLUSIONS: Cell-cycle progression might be inhibited at G(1)-phase accompanied
      by impaired cyclin D1 expression in the PVL, which results in atrophy. The fact
      that liver proliferation of the PVNL is delayed in comparison to that of the HEP
      is likely due to delayed expression of cyclin D1.

PMID- 15172195
TI  - Steatotic liver transplantation in the mouse: a model of primary nonfunction.
AB  - BACKGROUND: The number of potential donor organs deemed suboptimal for
      transplantation because of hepatic steatosis is rising as the obesity rate
      increases. However, no mouse transplant model has been described within the
      framework of hepatic steatosis. We describe the development of and our initial
      experience with a steatotic mouse orthotopic liver transplant model using the
      ob/ob mouse. This model is technically achievable and functionally mimics primary
      nonfunction. MATERIALS AND METHODS: Adapting techniques of a nonarterialized
      murine transplant model, C57BL6 ob/ob mice aged 5-7 weeks (26-35 g) and lean
      controls served as liver donors and recipients. Orthotopic liver transplantation
      (OLT) was performed using a two-cuff technique at the infrahepatic cava and
      portal vein. The suprahepatic cava was anastomosed end to end, and the bile duct
      was stented. The hepatic artery was not reconstructed. RESULTS: Lean-to-lean OLT
      was performed with 70% (n = 10) long-term survival. ob/ob-to-age-matched lean
      recipients had 0% (n = 10) survival because of size discrepancy. ob/ob livers
      were transplanted to size-matched lean recipients (>3 months old) with short-term
      survival of 30% (n = 10). These mice survived the operation, awakened, but
      expired within 24 h. Serum transaminases revealed a significantly higher injury
      profile in the recipients of the steatotic livers, and histology showed massive
      centrilobular coagulative necrosis with hemorrhage, the overall picture being
      that of primary nonfunction. CONCLUSIONS: This novel use of the ob/ob mouse for
      OLT provides us with a model for steatotic transplantation with primary
      nonfunction as the end point and may help to better understand the response of
      the steatotic liver to the insult of transplantation.

PMID- 15172196
TI  - Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
AB  - BACKGROUND: Establishment of hematopoietic chimerism is the most stable strategy
      for donor-specific tolerance. Safer pretreatment regimens are needed for clinical
      application. We evaluated the efficacy of a simple protocol using
      cyclophosphamide (CYP) on induction of chimerism and organ transplant tolerance
      across major histocompatibility complex (MHC) barriers in the rat. MATERIALS AND
      METHODS: Bone marrow cells from BN (RT1(n)) donors were infused to LEW (RT1(l))
      recipients on day 0 after a single injection of CYP at various doses on day -1.
      Donor-derived hematopoietic chimerism was evaluated by flowcytometry. The
      recipients received BN or third party (BUF) heart allografts on day 100. RESULTS:
      While pretreatment with 200 mg/kg of CYP induced high levels of hematopoietic
      chimerism, six of eight recipients died of severe graft-versus-host-disease
      (GVHD). CYP at dose of 150 mg/kg induced 36.5 +/- 24.1% of donor-derived
      chimerism on day 10, and sustained macrochimerism was seen until day 100 without
      GVHD. Pretreatment with 100 mg/kg of CYP resulted in only transient chimerism
      (4.8 +/- 5.2%) which disappeared by day 20. In the recipients with 50 mg/kg of
      CYP, donor bone marrow cells were rapidly rejected and no chimerism was observed.
      The recipients with 150 mg/kg of CYP accepted BN heart allografts (>100 days x
      5), while rejecting BUF allografts by day 12 (n = 4). BN heart allografts were
      rejected in the recipients with 100 (MST: 57 days, n = 5) and 50 mg/kg (MST: 7
      days, n = 5) of CYP. CONCLUSIONS: A single dose of CYP can induce hematopoietic
      chimerism across MHC-barriers. The dose of 150 mg/kg seems to be optimal to
      induce organ transplant tolerance without developing GVHD.

PMID- 15172197
TI  - Ischemic preconditioning improves oxygenation of exercising muscle in vivo.
AB  - BACKGROUND: Ischemic preconditioning (IP) improves tissue tolerance to prolonged
      ischemia. In this study, we investigated the functional effect of IP on skeletal
      muscle of rat hind limb by means of near-infrared spectroscopy (NIRS) and by
      measuring myeloperoxidase (MPO) activity. MATERIALS AND METHODS: Adult male
      Sprague Dawley rats were divided into four separate protocol groups according to
      different preparations prior to 2 h of global ischemia: a group of ischemic
      reperfusion without any preparation (I/R), ischemic reperfusion with ischemic
      preconditioning (IP+IR), ischemic reperfusion with adenosine infusion (ADO+I/R),
      and sham operation. Ischemia and ischemic preconditioning were induced by
      clamping infrarenal abdominal aorta and left common iliac artery. For each rat,
      an exercise test of gastrocnemius muscles was performed by stimulating sciatic
      nerve before and after global ischemia while performing NIRS. MPO activity of
      ischemic muscles was also measured. RESULTS: Half-resaturation time after
      exercise and MPO activity were significantly improved in IP+IR and ADO+I/R
      groups. Difference of oxyhemoglobin during exercise was also improved in the
      IP+IR group. CONCLUSION: This study has demonstrated that IP provides the
      protective effect on in vivo skeletal muscle oxygenation during exercise.

PMID- 15172198
TI  - Effects of ventricular unloading on apoptosis and atrophy of cardiac myocytes.
AB  - BACKGROUND: Ventricular unloading decreases cardiac ventricular mass. This loss
      of ventricular mass can be due to either atrophy (a reversible process) or
      apoptosis (an irreversible process) of the cardiac myocytes. We investigated the
      effect of ventricular unloading on atrophy and apoptosis of cardiac myocytes,
      using working and nonworking transplant heart models in rats. MATERIALS AND
      METHODS: ACI rats underwent heterotopic heart transplantation with two different
      techniques to create working and nonworking cardiac grafts. Cardiac grafts were
      harvested at different time points after transplantation. TUNEL, caspase-3 assay,
      and electron microscopy were used to assess the degree of apoptosis while
      cellular atrophy was estimated by calculation of the cytoplasmic index (CI = mean
      sectional cytoplasmic area/nucleus). RESULTS: Ventricular mass reduction was more
      pronounced in nonworking than in working hearts (P < 0.05). Apoptotic index and
      caspase-3 activities increased in both groups, peaking at 3 days after
      transplantation, but were not significantly different between the two models. The
      cytoplasmic index was significantly lower in nonworking than in working grafts (P
      < 0.05). CONCLUSIONS: These data suggest that cellular atrophy is the primary
      mechanism that accounts for myocardial weight reduction following ventricular
      unloading. The inference is that ventricular unloading by ventricular assist
      devices may not cause permanent loss of cardiac myocytes, thus allowing for
      functional recovery.

PMID- 15172199
TI  - Role of curcumin, a naturally occurring phenolic compound of turmeric in
      accelerating the repair of excision wound, in mice whole-body exposed to various
      doses of gamma-radiation.
AB  - The healing of irradiated wounds has always been a central consideration in
      medical practice because radiation disrupts normal response to injury, leading to
      a protracted recovery period. The quest for clinically effective wound healing
      agents is important in the medical management of irradiated wounds. Therefore,
      the present study was conceptualized to investigate the effect of curcumin
      (natural yellow, diferuloylmethane), a major yellow pigment and an active
      component of turmeric on wound healing in mice exposed to whole-body gamma
      radiation. A full-thickness wound was created on the dorsum of mice whole-body
      irradiated to 2, 4, 6, or 8 Gy. The progression of wound contraction was
      monitored periodically by capturing video images of the wound. The collagen,
      hexosamine, DNA, nitric oxide, and histological profiles were evaluated at
      various postirradiation days in mice treated and not treated with curcumin before
      exposure to 0 or 6 Gy. The whole-body exposure resulted in a dose-dependent delay
      in wound contraction and prolongation of wound healing time. Irradiation caused a
      significant reduction in collagen, hexosamine, DNA, and nitric oxide synthesis.
      Pretreatment with curcumin significantly enhanced the rate of wound contraction,
      decreased mean wound healing time, increased synthesis of collagen, hexosamine,
      DNA, and nitric oxide and improved fibroblast and vascular densities. This study
      demonstrates that curcumin pretreatment has a conducive effect on the irradiated
      wound and could be a substantial therapeutic strategy in initiating and
      supporting the cascade of tissue repair processes in irradiated wounds.

PMID- 15172200
TI  - Pancreatic endocrine tumors.

PMID- 15172201
TI  - Sleep and the elderly.

PMID- 15172202
TI  - Sleep health, lifestyle and mental health in the Japanese elderly: ensuring sleep
      to promote a healthy brain and mind.
AB  - The Ministry of Health, Labor and Welfare in Japan proposed a plan called "Health
      Japan 21," which adopted sleep as one of the specific living habits needing
      improvement. This has led to increased interest in mental health needs at
      community public health sites. In addition, it was reported from a recent 2000
      survey that one in five Japanese, and one in three elderly Japanese, suffer from
      insomnia. Insomnia is becoming a serious social problem; so much so that alarm
      bells are ringing with insomnia listed as one of the refractory diseases of the
      21st century. Against this background, in January 2001, Japan began a national
      project called "Establishing a Science of Sleep." This article is an overview of
      sleep and health in the elderly, sleep mechanisms and the characteristics of
      insomnia among the elderly. At the same time, it introduces the scientific basis
      for lifestyle guidance that is effective for ensuring comfortable sleep, an
      essential condition for a healthy, energetic old age, with actual examples from
      community public health sites. The present authors reported that a short nap (30
      min between 1300 and 1500 h) and moderate exercise such as walking in the evening
      are important in the maintenance and improvement of sleep quality. The study was
      to examine the effects of short nap and exercise on the sleep quality and mental
      health of elderly people. "Interventions" by short nap after lunch and exercise
      with moderate intensity in the evening were carried out for 4 weeks. After the
      "intervention," wake time after sleep onset significantly decreased and sleep
      efficiency significantly increased, showing that sleep quality was improved. The
      frequency of nodding in the evening significantly decreased. As a result, the
      frequency of nodding before going to sleep decreased, and the quality of
      nocturnal sleep was improved. Present results demonstrated that the proper
      awakening maintenance during evening was effective in improving sleep quality.
      After the "intervention," mental health also improved with improving sleep
      quality. Furthermore, physical health also improved with improving sleep quality.
      These results suggest that this "intervention" technique is effective for the
      quality of life (QOL) and the activity of daily living (ADL) of elderly people.

PMID- 15172203
TI  - Interactions between sleep normative data and sociocultural characteristics in
      the elderly.
AB  - OBJECTIVE: To present sleep patterns in elderly individuals and factors
      associated with short sleep and long daytime and nighttime sleep. METHODS: A
      total of 8091 subjects aged between 55 and 101 years representative of the
      noninstitutionalized general population of seven European countries (France,
      Finland, Italy, Germany, Portugal, Spain, and UK) were interviewed by telephone
      about their sleep habits and sleep disorders. RESULTS: The average sleep duration
      was 6 h and 57 min. Sleep duration was longer in men than in women. Five percent
      of the sample slept 5 h or less and 5% slept 9 h or more per night. Factors
      associated with short sleep (lower fifth percentile) were age, living in UK, no
      physical exercise, drinking six cups of coffee or more per day, taking a
      medication for sleep, difficulty initiating sleep, disrupted sleep, early morning
      awakening, and presence of an anxiety disorder. Factors associated with long
      sleep (> or =95th percentile) were age, living in France, Portugal, or Spain,
      being underweight, no physical exercise, disrupted sleep, taking a medication for
      sleep, and presence of an anxiety disorder. Long daytime sleep (54 min or more)
      were age, being a man, being overweight or obese, physical disease, being
      dissatisfied with one's social life, smoking, drinking alcohol, and having a
      major depressive disorder. CONCLUSION: Sleep patterns considerably varied among
      the countries in the elderly population. Extreme values of sleep duration (short
      and long sleep) were associated with several sleep and mental health problems.

PMID- 15172204
TI  - Sleep and quantitative EEG in neurodegenerative disorders.
AB  - This paper reviews current knowledge on sleep problems, sleep architecture
      changes and quantitative EEG alteration brought on by various neurodegenerative
      diseases, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP),
      REM sleep behavior disorder (RBD), Parkinson's disease (PD), dementia with Lewy
      bodies (DLB), multiple system atrophy MSA, Huntington's disease and Creutzfeldt
      Jakob disease, in comparison to normal aging. The study of sleep variables and
      that of the spectral composition of the EEG can provide valuable information for
      understanding the pathophysiology and for assisting the diagnosis of
      neurodegenerative diseases.

PMID- 15172205
TI  - Sleep disturbances and chronic disease in older adults: results of the 2003
      National Sleep Foundation Sleep in America Survey.
AB  - OBJECTIVE: To assess the association between sleep problems and chronic disease
      in older adults. METHODS: Self-reported standardized questionnaire data from 1506
      community-dwelling men and women aged 55-84 years in the continental United
      States who completed a 20-min telephone interview when contacted from lists of
      randomly selected telephone numbers. RESULTS: A majority of the participants
      (83%) reported one or more of 11 medical conditions and nearly one in four
      elderly respondents (age 65-84 years) had major comorbidity (i.e. four or more
      conditions). Depression, heart disease, bodily pain and memory problems were
      associated with more prevalent symptoms of insomnia. Other conditions such as
      obesity, arthritis, diabetes, lung diseases, stroke and osteoporosis were
      associated with other sleep-related problems such as breathing pauses, snoring,
      daytime sleepiness, restless legs or insufficient sleep (<6 h nightly).
      CONCLUSIONS: Poll findings are consistent with epidemiological studies of sleep,
      aging and chronic disease. These results suggest that the sleep complaints common
      in older adults are often secondary to their comorbidities and not to aging per
      se. These types of studies may be useful in promoting sleep awareness among
      health professionals and among older adults, especially those with heart disease,
      depression, chronic bodily pain or major comorbidity.

PMID- 15172206
TI  - Age-related sleep change: Gender and estrogen effects on the subjective-objective
      sleep quality relationships of healthy, noncomplaining older men and women.
AB  - OBJECTIVE: The sleep of a large group of healthy older men and women was studied
      in an effort to better understand the relationship between self-reported
      subjective and objectively measured sleep quality. METHODS: We examined the
      baseline subjective and objective sleep quality of 150 healthy older (67.5+/-0.5)
      men (n=55) and women (n=95). Subjects were carefully screened to exclude sleep
      disorders and did not complain of significant sleep disturbance. RESULTS: Despite
      their noncomplaining status, significant proportions of both women (33%) and men
      (16%) endorsed Pittsburgh Sleep Quality Index (PSQI) scores of >5, a criterion
      indicative of significant sleep disturbance. When examined as a function of this
      criterion, objective sleep was significantly impaired with longer sleep latency,
      less total sleep time, and lower sleep efficiency, for the high-PSQI (H-PSQI) men
      compared to low-PSQI (L-PSQI) men. These L-PSQI versus H-PSQI differences were
      much weaker for women and disappeared completely in women on estrogen replacement
      therapy. CONCLUSIONS: This large group of healthy, noncomplaining older adults
      manifested significantly disturbed sleep relative to healthy younger subjects,
      indicating that while aging results in significant changes in sleep, it does not
      of necessity result in complaints of insomnia and that many healthy older
      individuals apparently adapt their perception of what is "acceptable" sleep. A
      considerable correspondence between subjective and objective sleep quality was
      observed for men but not for women, despite women more frequently endorsing the
      presence of significant sleep disturbance. This finding is provocative and
      suggests that what we consider objective measures of good-quality sleep may be
      appropriate for older men but that older women may be evaluating their sleep
      quality using other criteria.

PMID- 15172207
TI  - A prospective study of nocturia and the quality of life of elderly patients with
      obstructive sleep apnea or sleep onset insomnia.
AB  - OBJECTIVE: To prospectively evaluate the relationship between obstructive sleep
      apnea syndrome (OSAS), nocturia and quality of life in elderly patients free of
      the urologic and medical conditions that lead to increased nocturia. METHODS:
      Prospective study of nocturia in men 65 years and older with isolated OSAS or
      sleep onset insomnia. After a 7-day nocturia evaluation and nocturnal
      polysomnography, Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI),
      Quality of Life (SF-36) were administered. RESULTS: OSAS patients with frequent
      nocturia had significantly greater body mass index (BMI), greater apnea-hypopnea
      index (AHI), lower lowest oxygen saturation and lower SF-36 subscale scores.
      Treatment with nasal continuous positive airway pressure (CPAP) for OSAS and
      behavioral techniques for insomnia improved ESS and BDI scores for all three
      groups. SF-36 subscale scores improved more in subjects with multiple nocturia.
      AHI and BMI explain 38% of the variance for nocturia. CONCLUSION: Nasal CPAP
      reduces OSA and nocturia and improves quality of life of elderly patients.

PMID- 15172208
TI  - Nocturia, nocturnal polyuria, and sleep quality in the elderly.
AB  - Nocturia is a common symptom in the elderly, which profoundly influences general
      health and quality of life. One consequence of nocturia is sleep deterioration,
      with increased daytime sleepiness and loss of energy and activity. Accidents,
      e.g., fall injuries, are increased both at night and in the daytime in elderly
      persons with nocturia. Nocturia is caused by nocturnal polyuria, a reduced
      bladder capacity, or a combination of the two. Nocturnal polyuria can be caused
      by numerous diseases, such as diabetes insipidus, diabetes mellitus, congestive
      heart failure, and sleep apnoea. In the nocturnal polyuria syndrome (NPS), the 24
      h diuresis is normal or only slightly increased, while there is a shift in
      diuresis from daytime to night. NPS is caused by a disturbance of the vasopressin
      system, with a lack of nocturnal increase in plasma vasopressin or, in some
      cases, no detectable levels of the hormone at any time of the 24-h period. The
      calculated prevalence of NPS is about 3% in an elderly population, with no gender
      difference. In NPS, there are serious sleep disturbances, partly due to the need
      to get up for micturition, but there is also increased difficulty in falling
      asleep after nocturnal awakenings and increased sleepiness in the morning. The
      treatment of NPS may include avoidance of excessive fluid intake, use of
      diuretics medication in the afternoon rather than the morning, and desmopressin
      orally at bedtime.

PMID- 15172209
TI  - Increased utilization of health services by insomniacs--an epidemiological
      perspective.
AB  - OBJECTIVES: Epidemiological data describing the prevalence of sleep complaints in
      Hungary and its region are lacking; furthermore, limited information is available
      on health care use by individuals with sleep complaints. We assessed the
      prevalence of sleep complaints, insomnia in particular, in a nationally
      representative sample of the Hungarian population and assessed health care
      utilization by insomniacs. METHODS: Cross-sectional study, enrolling a nationally
      representative sample (N=12,643) of the adult Hungarian population. A battery of
      questionnaires was administered during a home interview. The Athens Insomnia
      Scale (AIS), additional questions on sleep behavior, as well as questions on
      current medical therapy for somatic and mental disorders were included in the
      battery of questionnaires administered. Psychosocial and demographic
      characteristics were also tabulated. RESULTS: Forty-seven percent of the sample
      reported at least one complaint related to sleep. Based on the AIS we report a 9%
      prevalence of insomnia in the total sample. Sleep deprivation was highly
      prevalent in the younger and middle-aged groups. The frequency of sleep problems
      increased with age. Individuals diagnosed with insomnia reported more frequent
      utilization of health services, including sick leave, emergency visits and
      hospitalization, than those without insomnia. CONCLUSION: Sleep complaints and
      sleep deprivation are frequent problems in the Hungarian population and are
      associated with increased health care utilization. The prevalence of insomnia in
      our sample was similar to what has been previously reported from other countries.
      The high prevalence of sleep-deprived individuals warrants further attention.
      Interventions that effectively improve insomnia may also reduce health care
      utilization by the affected individuals.

PMID- 15172210
TI  - Twenty minutes versus forty-five minutes morning bright light treatment on sleep
      onset insomnia in elderly subjects.
AB  - OBJECTIVE: To compare the efficacy of 20 min versus 45 min light exposure for
      relieving psychophysiological insomnia in the elderly. METHODS: Prospective
      recruitment of subjects 60 years and older with psychophysiological insomnia.
      Random distribution to 20 or 45 min of daily exposure to 10,000 lux for 60 days.
      Sleep latency, total sleep time, fatigue and activity were measured at baseline
      and 3 and 6 months posttreatment. Blind analysis of data and comparison were
      performed using repeated-measure analysis of variance, independent samples t test
      and Wilcoxon rank signed test. RESULTS: At 3 months, improvement was
      significantly higher in the 45-min versus 20-min condition. At 6 months,
      variables returned toward baseline in the 20-min but not in the 45-min condition.
      CONCLUSIONS: Twenty minutes of bright light treatment leads to a lesser treatment
      response than 45 min at 3-month follow-up and to a return toward baseline at 6
      month follow-up that was not seen with a 45-min exposure.

PMID- 15172211
TI  - Restless legs syndrome and periodic limb movement disorder in the elderly.
AB  - Restless legs syndrome (RLS) is a sensorimotor neurological disorder
      characterized by an urge to move the extremities, mostly the legs, caused or
      accompanied by unpleasant sensations in the affected limbs. Symptoms appear or
      increase in the evening or during the night and at rest. Sleep disturbances are
      the most frequent reason why patients seek medical aid. The diagnosis of periodic
      limb movement disorder (PLMD) requires polysomnographic confirmation and relies
      on the exclusion of other causes of sleep disturbances. The diagnosis of RLS is a
      clinical one and usually based on the patient's history. Diagnosis criteria
      should be applied in a modified form in the cognitively impaired elderly. The
      newly revised criteria emphasize behavioral indicators and supportive features in
      diagnosing RLS in this special population. Prevalence of both disorders increases
      strongly with age. Epidemiological studies revealed a 9% to 20% prevalence of RLS
      and an estimated 4% to 11% prevalence of PLMD in the elderly. Recent studies
      indicate RLS occurring approximately twice as often in older women than in older
      men. Treatment with dopaminergic drugs, opioids, anticonvulsants or hypnotics are
      usually well tolerated in the elderly. However, interaction with other
      medications and the possibility of severe sedation due to slower metabolism in
      the elderly should be considered.

PMID- 15172212
TI  - Cognitive changes and sleep disordered breathing in elderly: differences in race.
AB  - OBJECTIVES: Sleep disordered breathing (SDB) is a highly prevalent sleep disorder
      in older persons. It is known to be associated with reductions in cognitive
      function. As part of a larger study examining SDB in African-Americans and
      Caucasians, it became possible to examine whether racial background may
      differentially affect the relationship between SDB and cognitive performance.
      METHODS: Community-dwelling African-American and Caucasian elderly (ages 65+) at
      high risk for SDB were tested at two time points. During each visit, subjects
      were interviewed in their homes about their sleep and medical condition. The Mini
      Mental Status Examination (MMSE) was used to assess cognitive function. Objective
      sleep studies were recorded in the subjects' homes and scored for sleep, apneic
      events, and oxygen saturation levels. RESULTS: Increases in respiratory
      disturbance index (RDI) were associated with decreases in cognitive performance
      over time, after controlling for gender and education level. There were no
      differential effects of race on this relationship. There was no relationship
      between declining cognitive function and hypoxemia. CONCLUSIONS: Analyses of the
      data confirm that declining cognitive function in older persons with mild to
      moderate SDB is related to the amount of respiratory disturbances occurring at
      night, and suggest that the effect of SDB on cognitive decline is unrelated to
      race and measured hypoxemia. The large number of community-dwelling elderly with
      mild to moderate SDB may accrue considerable benefits (both cognitively and
      medically) from the treatment of SDB, even if they are not markedly hypoxemic.

PMID- 15172213
TI  - In vitro activity of the beta-carboline alkaloids harmane, harmine, and harmaline
      toward parasites of the species Leishmania infantum.
AB  - Harmane, harmine, and harmaline were investigated for their in vitro
      antileishmanial activity toward parasites of the species Leishmania infantum.
      Harmane and Harmine displayed a moderate antiproliferative activity toward human
      monocytes and exerted a weak antileishmanial activity toward both the
      promastigote and the amastigote forms of the parasite. Their mechanism of action
      on the promastigote form of the parasite involved interactions with DNA
      metabolism leading to an accumulation of parasites in the S-G(2)M phases of the
      cell-cycle. Harmaline, at the contrary, was deprived from toxicity toward human
      cells and Leishmania promastigotes, however it exerted a strong antileishmanial
      activity toward the intracellular amastigote form of the parasite. This property
      was shown to partly result from the capacity of the molecule to prevent parasite
      internalization within macrophages by inhibiting Leishmania PKC activity.

PMID- 15172214
TI  - Induced immunity in Antheraea assama Ww larvae against flacherie causing
      Pseudomonas aeruginosa AC-3.
AB  - This study reports for the first time the induction of immunity in Antheraea
      assama Ww larvae against bacterial flacherie. In silkworms group of disease
      caused by bacteria are collectively called "flacherie." This refers to the
      flaccid condition of the larvae due to the infections of bacterial strains
      pathogenic to muga silkworm. Antibacterial activity against pathogenic
      Pseudomonas aeruginosa AC-3 causing flacherie, was induced by injection of heat
      killed cells of the same strain. Experiments on larval survivability and viable
      cell count revealed peak immune response on third day. Comparison of the amount
      of food ingested, excreta produced and larval weight of the saline-injected
      control, live bacteria-challenged larvae and heat-killed bacteria-injected larvae
      "(vaccinated)" confirmed the development of immunity against bacterial infection
      in the "vaccinated" set. The haemolymph of A. assama larvae was analyzed for
      proteins associated with bacterial infection. Out of the total 32 detected
      proteins, eleven (A1-2, A15-20, A22-23, and A29) were constitutively synthesized
      in both the control and live bacteria-injected larvae. Four inducible proteins
      A4, A9-10, and A21 were detected in the haemolymph of the live bacteria-injected
      larvae. Synthesis of rest of the proteins varied between the control and their
      live bacteria-injected counterparts. General protein profile of "vaccinated"
      larvae injected with live bacteria were found to be similar to that of the saline
      injected control.

PMID- 15172215
TI  - Trypanosoma cruzi: the expansion of NK, T, and NKT cells in the experimental
      infection.
AB  - T and NK cells play a key role in resistance to Trypanosoma cruzi infections,
      mainly through IFN-gamma production. The expression of T and NK cells surface
      markers was studied in NWNA spleen cells of resistant C3H and susceptible BALB/c
      mice that release IFN-gamma in the early and late acute infection, respectively.
      In the progressively enlarged spleens, we found: (a) an increased percentage and
      number of NK blast cells as early as at 2 days post-infection (pi), (b) an
      enrichment of T and NK cells, in both the total and blast populations, during the
      late acute phase. At 17 days pi, there was also an accumulation of TCR-
      alphabeta+DX5+, NKT cells, mainly in resistant mice. At 21 days pi, the
      enrichment of NK cells ceased, while spleen cells and the T cell compartment
      continued their expansion. In the chronic stage, TCR-alphabeta+ blasts were
      expanded in both mouse strains, but NK blasts increased only in BALB/c that,
      unlike C3H mice, release IFN-gamma. As T and NK cell proliferation is not always
      associated to IFN-gamma release the experimental downregulation of their
      expansion to avoid tissue damage could be explored.

PMID- 15172216
TI  - Molecular cloning and characterization of a cDNA encoding a laminin-binding
      protein (AhLBP) from Acanthamoeba healyi.
AB  - Adherence of Acanthamoeba to host tissue is believed to be crucial in the
      establishment of amoebic keratitis or GAE. We have isolated a cDNA from a GAE
      causing gymnoamoeba, Acanthamoeba healyi, encoding a protein that binds laminin
      by screening with a peptide G-specific DNA probe. The cDNA clone (AhLBP) was
      identified on the basis of sequence homology to the nonintegrin mammalian
      metastasis-associated 67-kDa laminin receptor (67-LR). The predicted amino acid
      sequence is 256 residues long with a calculated molecular mass of 28.2kDa and a
      theoretical pI of 5.48. Southern and Northern blot analyses suggested the gene as
      a single copy in A. healyi genome and expressed as a single transcript of
      approximately 1.0kb. Virulent strains of Acanthamoeba revealed higher level of
      the AhLBP mRNA expression than soil isolates. Specific binding of the purified
      recombinant protein to laminin was confirmed by sandwich Western blot. The
      polypeptide encoded by AhLBP shared substantial identity with the acidic class
      ribosomal proteins involved in protein synthesis. Therefore, the AhLBP may be
      multifunctional in A. healyi, acting as a laminin-binding molecule but also
      playing a role in cell division and growth. AhLBP-EGFP fusion protein expressed
      in A. healyi was localized mainly at the cell membrane and nucleus and at
      cytoplasm with lesser degree. N-terminal 64 amino acids were important for the
      localization at the cell membrane. This is the first description of a cDNA
      encoding a laminin-binding protein from protozoan parasites.

PMID- 15172217
TI  - Purification, characterization, and cloning of a serine proteinase inhibitor from
      the ectoparasite Haematobia irritans irritans (Diptera: Muscidae).
AB  - The fly Haematobia irritans irritans is one of the most important ectoparasites
      in cattle production, due to its ability to suck large amounts of blood. This
      report describes the purification and characterization of a serine proteinase
      inhibitor (HiTI) present in H. i. irritans head and thorax extracts. The HiTI
      purified by affinity chromatography on trypsin-Sepharose has a molecular mass of
      7029Da by MALDI-TOF mass spectrometry. HiTI inhibited bovine trypsin, human
      neutrophil elastase, and a trypsin-like enzyme purified from H. i. irritans
      abdomen with dissociation constants of 0.57, 1.30, and 0.20nM, respectively. The
      HiTI partial amino acid sequence allowed its classification into the BPTI-Kunitz
      type family. An HiTI cDNA fragment was cloned in the pGEMT vector using RT-PCR.
      The translated amino acid sequence of HiTI cDNA confirmed a unique Kunitz-type
      domain protein. Our results suggest that HiTI could control some endogenous
      enzyme, e.g., the H. i. irritans trypsin-like protein.

PMID- 15172218
TI  - Arbitrary-primed PCR for genomic fingerprinting and identification of
      differentially regulated genes in Indian isolates of Leishmania donovani.
AB  - The arbitrary-primed PCR (AP-PCR) technique was employed with the twin goals of
      identifying genetic polymorphisms within the Indian isolates and to identify
      differentially expressed gene sequences. The parasite isolates from Indian Kala
      azar patients could be differentiated from Leishmania donovani isolates from
      distinct geographic regions. Moreover, differences within the Indian isolates
      could also be identified. A majority (17/19) of the Indian isolates gave
      identical AP-PCR pattern, while two isolates gave consistently divergent pattern.
      The distinctive AP-PCR fragments obtained with Indian isolates were used as
      probes in Northern blot analysis. Three such fragments were found to represent
      transcribed sequences that were differentially expressed in the two stages of the
      parasite. These sequences led to cloning and characterization of Leishmania
      Centrin gene and a novel gene termed A-1 that is over-expressed in amastigote
      stage of the parasite. The study demonstrates the utility of random genome
      sampling methods in genomic fingerprinting and in identifying differentially
      transcribed sequences that could potentially contribute to parasite virulence.

PMID- 15172219
TI  - Entamoeba histolytica: induction of cyclooxygenase-2 expression during amoebic
      liver abscess formation in hamsters (Mesocricetus auratus).
AB  - Experimental amoebic liver abscess in hamsters curses with an increase in both,
      systemic levels of prostaglandin E2 (PGE(2)) and local cyclooxygenase activity in
      liver microsomes. The cellular source of PGE(2) and the isoform of cyclooxygenase
      responsible are not completely evidenced. Cyclooxygenase-2 (COX-2) protein and
      gene expression were demonstrated on macrophages and polymorphonuclear cells as a
      result of Entamoeba histolytica infection in hamsters at 2, 4, and 7 days
      postinfection by immunohistochemistry and RT-PCR. E. histolytica trophozoites
      located in the lesion showed a strong positive signal for COX-2, however the
      enzyme was not detected in cultured trophozoites by Western blot. Our results
      indicate that the increment in PGE(2) is the result of COX-2 activity from cells
      of the reticuloendothelial system and reinforce the possibility that PGE(2)
      production by enzyme induction in macrophages may be a mechanism by which E.
      histolytica modulates the host immune response in this parasitic infection.

PMID- 15172220
TI  - Cryptosporidium parvum: effect of multi-drug reversing agents on the expression
      and function of ATP-binding cassette transporters.
AB  - In the present study, the gene expression of three multidrug resistance (MDR) and
      resistance-associated protein (MRP) transport proteins or efflux pumps was
      characterized and the phenotypic evidence for such pumps was demonstrated in
      cultured Madin-Darby canine kidney (MDCK) cells. A gradient for the fluorescent
      probe calcein was established between parasite and host cell suggestive of a
      parasite extrusion pump at the parasite-host interface. This gradient was
      decreased in a glucose-free medium containing 2-deoxyglucose or 3-O
      methylglucose, by probenecid, and by the isoflavonoid, narigenin, suggesting that
      the calcein extrusion was energy-dependent and involved an MRP-like pump. While
      neither MDR or MRP inhibiters significantly affected transcript levels of any of
      the ABC transporters, transcript levels of the Cryptosporidium parvum ABC protein
      (CpABC1), an MRP transporter, were consistently expressed 4 logs higher than
      either CpABC3 or CpABC2, suggesting a prominent role in the intracellular stages
      of the parasite.

PMID- 15172221
TI  - The glycosome membrane of Trypanosoma cruzi epimastigotes: protein and lipid
      composition.
AB  - Highly purified glycosomes from Trypanosoma cruzi epimastigotes were obtained by
      differential centrifugation and isopycnic ultracentrifugation. Glycosomal
      membranes, produced by carbonate treatment of purified glycosomes, exhibited
      about eight main protein bands and eight minor ones. Essentially the same protein
      pattern was observed in the detergent-rich fraction of a Triton X-114
      fractionation of whole glycosomes, indicating that most of the membrane-bound
      polypeptides were highly hydrophobic. The orientation of these proteins was
      studied by in situ labelling followed by limited pronase hydrolysis of intact
      glycosomes. Three glycosome membrane proteins were characterized as peripheral by
      comparing the protein bands patterns of membrane fractions obtained by different
      treatments. Noteworthy membrane polypeptides were: (1) a peripheral 75k Da
      membrane protein, oriented towards the cytosol, which was the most abundant
      glycosomal membrane protein in exponentially growing epimastigotes but was
      essentially absent in stationary phase cells; (2) a pair of integral membrane
      proteins with molecular masses in the range of 85-100 kDa, which were only
      present in stationary phase cells; (3) a heme-containing 36k Da protein, strongly
      associated to the membrane, present in both growth phases; (4) a very immunogenic
      41k Da integral membrane polypeptide, oriented towards the cytosol. The lipid
      composition of the glycosomal membranes was also investigated. The distribution
      of phospholipid species in glycosomes and glycosomal membranes was very similar
      to that of whole cells, with phosphatidyl-ethanolamine, phosphatidyl-choline, and
      phosphatidyl-serine as main components and smaller proportions of sphingomyelin
      and with phosphatidyl-inositol. On the other hand, glycosomes were enriched in
      endogenous sterols (ergosterol, 24-ethyl-5,7,22-cholesta-trien-3beta-ol), and
      precursors, when compared with whole cells, a finding consistent with the
      proposal that these organelles are involved in the de novo biosynthesis of
      sterols in trypanosomatids.

PMID- 15172222
TI  - Dose-dependent activity of albendazole against benzimidazole-resistant nematodes
      in sheep: relationship between pharmacokinetics and efficacy.
AB  - The relationship between the pharmacokinetic behaviour and the anthelmintic
      efficacy of albendazole (ABZ) against benzimidazole (BZD)-resistant nematodes was
      studied in sheep. A micronized ABZ suspension was orally administered at two
      different dose levels to sheep naturally infected with BZD-resistant
      gastrointestinal (GI) nematodes. The experimental animals were allocated into the
      following groups (n = 8): (a) untreated control; (b) orally treated with ABZ at
      3.8 mg/kg b.w.; and (c) orally treated with ABZ at 7.5 mg/kg b.w. Plasma samples
      were obtained serially over 72 h post-treatment from both treated groups and
      analysed by HPLC to measure the concentrations of ABZ and its sulphoxide (ABZSO)
      and sulphone (ABZSO(2)) metabolites. Faecal egg counts were performed prior to
      treatment and at the necropsy day. All experimental animals were sacrificed 10
      days after treatment to perform GI worm counts. While ABZ parent drug was not
      recovered in the bloodstream, ABZSO and ABZSO(2) were the molecules found in
      plasma. ABZSO was the metabolite measured at the highest concentrations in the
      bloodstream for up to 36 (treatment at 3.8 mg/kg) or 60 h (treatment at 7.5
      mg/kg) post-administration. There was a proportional relationship between the
      administered ABZ dose and the measured plasma concentrations of both ABZ
      metabolites. Over a 100% increment on the plasma AUC values for the
      anthelmintically active ABZSO metabolite was observed at the 7.5 mg/kg compared
      to the 3.8 mg/kg treatment. The low efficacy patterns (< 24%) observed against
      the GI nematodes investigated indicate a high level of resistance to ABZ given at
      3.8 mg/kg an efficacious therapeutic dose rate recommended in some countries.
      However, the higher and prolonged plasma drug concentration measured after the
      7.5 mg/kg treatment resulted in an improved efficacy pattern (estimated by both
      faecal egg and adult worm counts) against most of the GI nematodes studied
      compared to that obtained at the lower dose rate. A direct relationship between
      drug pharmacokinetic behaviour and anthelmintic efficacy against BZD-resistant
      nematodes in sheep was shown in the current work, although individual variation
      precluded the observation of statistically significant differences in worm
      counts.

PMID- 15172223
TI  - Leishmania tropica: cysteine proteases are essential for growth and
      pathogenicity.
AB  - Leishmania parasites are responsible for a diverse collection of diseases of
      humans and other animals. Cysteine proteases are putative virulence factors of
      leishmania parasites. There are differences in the susceptibility of specific
      stages in different Leishmania species to cysteine protease inhibitors. Here, we
      establish a key role of cysteine proteases in growth, viability, and
      pathogenicity of Leishmania tropica by using a specific cysteine protease
      inhibitor (N-Pip-F-hF-VS Phenyl). Reduction or arrest of promastigote growth
      occurred at inhibitor concentration of 5 and 100 microM, respectively. This shows
      an essential role for cysteine proteases in viability and growth of L. tropica
      promastigotes. It confirms that the promastigote stage of L. tropica more closely
      resembles that of Leishmania major than that of Leishmania mexicana, which is
      refractory to this inhibitor. Pathogenicity of L. tropica amastigotes in mice, as
      assessed by footpad swelling, was also reduced by treatment with the cysteine
      protease inhibitor. This suggests that cysteine proteases are essential for
      pathogenicity of L. tropica amastigote in mammalian host, similar to both L.
      major and L. mexicana.

PMID- 15172224
TI  - Haemonchus contortus: in vitro drug screening assays with the adult life stage.
AB  - Motility and feeding assays were assessed as in vitro systems for screening of
      novel compounds for anthelmintic activity against adult Haemonchus contortus. The
      study aimed to develop an assay with the parasitic adult stage of this species
      that could be used in conjunction with, or as an alternative to, the free-living
      larval stage screens commonly used for drug discovery with many parasitic
      nematode species. The feeding assay showed limitations due to the apparent
      continuation of a significant degree of feeding in worms showing greatly reduced
      motility in the presence of some drugs. Hence, it appeared most likely that the
      feeding assay would underestimate the toxicity of these drugs. The motility assay
      was able to detect toxicity of known anthelmintics, including the 'slow-acting'
      benzimidazoles. A small-scale screening exercise used the motility assay to
      detect toxicity towards adult parasites in 10 compounds out of a group of 200
      chemicals (selected due to known toxic effects in larval development assays). The
      motility assay appeared suitable for drug screening against adult H. contortus.
      The use of the adult stage for drug screening in this way ensures that the drug
      is toxic towards the parasite life stage to be targeted in vivo. A lack of
      activity in subsequent in vivo trials could, therefore, be most likely
      attributable to host pharmacokinetic factors rather than an intrinsic lack of
      activity of the drug towards the adult parasite.

PMID- 15172225
TI  - Flagellar attachment of Leishmania promastigotes to plastic film in vitro.
AB  - Trypanosomatid parasites are able to use their flagella for attachment to
      cuticular surfaces within their arthropod hosts. In this study the attachment
      mechanism of Leishmania promastigotes was investigated using a new and
      quantifiable in vitro assay system. The results showed that hemidesmosomal
      flagellar attachment to three different plastic substrates occurred (Melinex,
      Polyvinyl, Thermanox). Attachment density was increased by scratching the surface
      of the substrate or by coating with the hydrocarbons n-octacosane and paraffin.
      Variation in attachment density was observed, depending on the culture medium and
      the parasite isolate used. All four species examined, L. braziliensis, L.
      donovani, L. major and L. mexicana, were capable of flagellar attachment in
      vitro. Collectively, these data indicate that flagellar attachment is mediated by
      a non-specific hydrophobic interaction in Leishmania species.

PMID- 15172227
TI  - Echinococcus granulosus: oncosphere-specific transcription of genes encoding a
      host-protective antigen.
AB  - A recombinant antigen vaccine has been developed which is effective in preventing
      the hydatid parasite, Echinococcus granulosus from infecting its animal
      intermediate hosts. The vaccine antigen, designated EG95, is expressed by a cDNA
      cloned from E. granulosus oncosphere mRNA. The gene encoding EG95 belongs to a
      small gene family where six of the members are transcribed in the oncosphere.
      Conditions were established which allowed specific RT-PCR amplification of mRNA
      for each gene family member and these conditions were applied to determine
      transcription patterns for each gene family member in gravid adult worms,
      oncospheres, and protoscoleces. The four eg95 gene family members which encode an
      identical EG95 protein, were transcribed only in the oncosphere. In contrast, two
      gene family members that encode variant EG95 proteins did not have transcription
      patterns confined to the oncosphere. These findings suggest a common biological
      role for four genes in the gene family and a separate role for the other, more
      variant gene family members.

PMID- 15172226
TI  - Toxoplasma gondii: generation of novel truncation mutations in the linker domain
      of dihydrofolate reductase-thymidylate synthase.

PMID- 15172228
TI  - The conduction tissues in congenitally corrected transposition.

PMID- 15172229
TI  - Neuroendocrine and biologic features of primary tumors and tissue in pulmonary
      large cell carcinomas.
AB  - BACKGROUND: Because biological behavior in lung tumors with neuroendocrine
      differentiation is highly dependent on cell death (apoptosis) and angiogenesis,
      p21(waf1/cip1) and microvessel density have been targeted as potentially useful
      tumor markers. We sought to validate the importance of p21(waf1/cip1) and
      microvessel density and study their interrelationship, analyzing clinical
      factors, subclassifications, and tumor and stromal markers. METHODS: We examined
      p21(waf1/cip1) and other markers in tissue from 61 patients with surgically
      excised large cell carcinomas. The amount of tumor staining for p21(waf1/cip1)
      and microvessel density was evaluated by immunohistochemistry and morphometry.
      The study outcome was survival time until death from recurrent lung cancer.
      RESULTS: Multivariate Cox model analysis demonstrated that after surgical
      excision, histologic subtypes were significantly related to survival time (p =
      0.02), but quantitative staining of the tumor for p21(waf1/cip1) and microvessel
      density added prognostic information and these variables were more strongly
      prognostic than histologic subtype (p = 0.00). Cut points at the median staining
      of 3.5% and 3.0% for p21(waf1/cip1) and microvessel density, respectively,
      divided patients into two groups with distinctive survival times. Patients with
      p21(waf1/cip1) staining of more than 3.5% and microvessel density staining of
      more than 3.0% had a median survival time of 14 months. CONCLUSIONS: Tumor
      staining for p21(waf1/cip1) and microvessel density in resected large cell
      carcinomas and certain other types of lung tumors was strongly related to
      survival. Patients with more than 3.0% staining in their tumors were at high risk
      of death from lung cancer and may be an appropriate target for prospective
      studies of adjuvant chemotherapy after surgical resection.

PMID- 15172230
TI  - Pulmonary large cell neuroendocrine carcinoma demonstrates high proliferative
      activity.
AB  - BACKGROUND: In 1999, the World Health Organization classified large cell
      neuroendocrine carcinoma as a variant of large cell carcinoma and this has been
      categorized as lying between atypical carcinoid and small cell lung carcinoma in
      terms of clinical aggressiveness. METHODS: We analyzed the proliferative activity
      of stage 1 large cell neuroendocrine carcinoma derived from patients with primary
      lung cancer who underwent surgical resection and compared the results with stage
      1 classic large cell carcinoma cases. The mitotic rate was counted in ten high
      power fields of light microscope. Immunohistochemical staining using anti-Ki-67
      antibody was performed. The Ki-67 labeling index, expressed as a percentage of
      positive cells, was determined by light microscopy with random counting of at
      least 1000 tumor nuclei. The expression of P53 and Bcl-2 was examined and
      compared. RESULTS: The mitotic rate of large cell neuroendocrine carcinoma cases
      was significantly higher than that of classic large cell carcinoma cases. The Ki
      67 labeling index of stage 1 large cell neuroendocrine carcinoma cases was
      significantly higher than that of stage 1 classic large cell carcinoma cases.
      Immunohistochemical expression of P53 in large cell neuroendocrine carcinoma and
      classic large cell carcinoma was comparable. However, large cell neuroendocrine
      carcinoma exhibited a significantly higher expression of Bcl-2 than classic large
      cell carcinoma. The disease specific disease-free survival for patients with
      stage 1 large cell neuroendocrine carcinoma was significantly lower than that for
      patients with stage 1 classic large cell carcinoma. CONCLUSIONS: Large cell
      neuroendocrine carcinoma appears to be more clinically aggressive than classic
      large cell carcinoma with these findings indicating that large cell
      neuroendocrine carcinoma has a higher level of proliferative activity than
      classic large cell carcinoma.

PMID- 15172234
TI  - Minithoracotomy combined with mechanically stapled bronchial and vascular
      ligation for anatomical lung resection.
AB  - BACKGROUND: The most appropriate approach to anatomic pulmonary resection has
      been debated with the advance of minimally invasive techniques and especially the
      common use of mechanical staplers. Video assisted surgery and muscle-sparing
      thoracotomy are established options of surgical approach for lung resection. We
      utilize a combined technique of vertical muscle sparing minithoracotomy and
      mechanical closure of the hilum structures to accomplish lung resection. METHODS:
      From December 1995 through January 2002, 713 patients (mean age, 65 +/- 11, 44.6%
      male) underwent anatomic pulmonary resection including 64 pneumonectomies, 514
      lobectomies, and 135 formal segmental resections. Pulmonary resection was
      approached though a direct access, vertical, minithoracotomy (< 10 cm), and
      vascular ligation was performed with port-access endostapling instrumentation.
      Full mediastinal lymph node sampling was performed for primary lung cancer.
      RESULTS: The average operative time was 55 minutes for lobectomy-formal
      segmentectomy and 62 minutes for pneumonectomy. An average of 3.6 staple
      applications were utilized to ligate the pulmonary vasculature (n = 2548 for 713
      patients). Operative vascular complications included 5 minor intimal fractures, 1
      posterior segmental arterial avulsion, and 1 staple misfiring for an adverse
      event rate during stapler application of 0.27%. Only one conversion to standard
      thoracotomy was necessary to control bleeding from the pulmonary vein. There were
      no intraoperative deaths. CONCLUSIONS: Vertical minithoracotomy is a safe and
      expedited approach for anatomic lung resection. Direct visualization for
      dissection and effective pulmonary hilum mechanical closure with staplers were
      demonstrated. This approach is a reasonable option when a complete video-assisted
      surgery seems to be hazardous and a full open thoracotomy could represent an
      additional morbidity.

PMID- 15172232
TI  - Preoperative pulmonary function as a prognostic factor for stage I non-small cell
      lung carcinoma.
AB  - BACKGROUND: The aim of this study was to clarify preoperative lung function as a
      prognostic factor for the long-term survival of, and to discuss the
      appropriateness of lobectomy for, patients with stage I non-small cell lung
      carcinoma who have poor preoperative pulmonary function. METHODS: The study group
      consisted of 402 lobectomized patients with stage I non-small cell lung carcinoma
      treated by complete resection from 1985 to 1997. Preoperative percent forced
      vital capacity [(forced vital capacity/predicted forced vital capacity) x 100],
      FEV(1)% [(forced expiratory volume in 1 second/forced vital capacity) x 100],
      arterial carbon dioxide tension, and smoking were statistically analyzed as
      prognostic factors together with other host and tumor biologic factors. RESULTS:
      Multivariate analysis demonstrated that tumor size (p < 0.0001) was the most
      significant prognostic factor for survival from primary lung cancer. Age (p <
      0.0001), sex (p = 0.0036), and FEV(1)% (p = 0.0046) were found to be independent
      prognostic factors for survival from death by nonprimary lung cancer-related
      causes. Smoking was highly correlated with FEV(1)% (correlation coefficient = 
      0.511; p < 0.0001). The 100 patients with a preoperative FEV(1)% less than 70%
      included 34 patients with nonprimary lung cancer-related deaths, whereas the 302
      patients with an FEV(1)% of 70% or greater included only 23 patients (p <
      0.0001). CONCLUSIONS: Along with tumor size, FEV(1)% is the most significant
      prognostic factor for patients with stage I non-small cell lung carcinoma with
      regard to survival from death by other causes. Lobectomy may not be preferred as
      an appropriate surgical modality for patients with stage I non-small cell lung
      carcinoma with small peripheral nodules who exhibit poor pulmonary function,
      especially lowered FEV(1)%.

PMID- 15172235
TI  - Video-assisted thoracic surgery for pure ground-glass opacities 2 cm or less in
      diameter.
AB  - BACKGROUND: Small, well-circumscribed pure ground-glass opacities on high
      resolution computed tomography can represent either localized bronchioloalveolar
      carcinoma without foci of active fibroblastic proliferation, or atypical
      adenomatous hyperplasia. Since neither lesion displays lymph node metastasis,
      excellent prognosis can be expected even with limited surgical resection. In this
      study, video-assisted thoracic surgery was performed for patients with pure
      ground-glass-opacity to evaluate efficacy for both diagnostic and therapeutic
      purposes. METHODS: Thirty-nine patients with pure ground-glass opacity less than
      or equal to 2 cm in diameter (62 lesions) underwent video-assisted thoracic
      surgery with wedge resection as primary therapy. Histologic diagnoses were made
      according to Noguchi classifications. RESULTS: Single lesions were observed in 30
      patients, with multiple lesions (mean, 4 lesions) in 9 patients. Twenty-eight
      patients underwent wedge resection. Seven patients underwent lobectomy or
      segmentectomy for technical reasons. Four patients underwent conversion of wedge
      resection to lobectomy (due to active fibroblastic proliferation in 2 patients,
      and other reasons in 2 patients). All procedures were performed under videoscopic
      observation. Histologic diagnoses comprised localized bronchioloalveolar
      carcinoma without active fibroblastic proliferation either alone or in
      combination with atypical adenomatous hyperplasia in 29 patients, atypical
      adenomatous hyperplasia in 8 patients, and localized bronchioloalveolar carcinoma
      with active fibroblastic proliferation in 2 patients. All patients with localized
      bronchioloalveolar carcinoma underwent follow-up for a median period of 29.3
      months, and have survived without sign of recurrence. CONCLUSIONS: Video-assisted
      thoracic surgery may be appropriate for management of small pure ground-glass
      opacities.

PMID- 15172236
TI  - Percutaneous venovenous perfusion-induced systemic hyperthermia for lung cancer:
      a phase I safety study.
AB  - BACKGROUND: Veno-venous perfusion-induced systemic hyperthermia (VV-PISH)
      homogeneously raises core body temperature potentially improving outcomes from
      metastatic lung cancer. METHODS: Patients (n = 10) with stage IV lung cancer,
      received VV-PISH (>or= 42 degrees C to <or= 42.5 degrees C) for 120 minutes.
      General anesthesia, spontaneous ventilation, and heparinization allowed for
      percutaneous central venous access. The ThermoChem HT system provided
      extracorporeal blood flow (1000 to 1340 mL/min), used a calculated average core
      temperature for feedback control of blood heating, and included a charcoal-based
      sorbent for electrolyte homeostasis. RESULTS: The first three patients helped in
      refining the technique and reflect an evolutionary process, therefore their data
      are not included as part of the VV-PISH cohort. Venovenous perfusion-induced
      systemic hyperthermia (n = 7) had a preoperative weight loss of 4.4 +/- 2.8 Kg,
      and a Karnofsky score of >or= 70. Time to target temperature was 47 +/- 2
      minutes, as electrolytes remained normal, without patient or circuit
      complications. Extubation occurred between 6 and 18 hours. Hospital stay was 4.6
      +/- 1.1 days; median length-of-survival after hyperthermia was 271 days. For
      concurrent controls (n = 16, stage IV lung cancer), median length-of-survival
      from time of diagnosis to death was 96 days, but for the VV-PISH patients it was
      significantly longer at 450 days (p < 0.05). All patients returned to
      pretreatment status following treatment and died from progression of lung cancer.
      CONCLUSIONS: Venovenous perfusion-induced systemic hyperthermia is safe,
      technically feasible, and achieves target temperature. Survival may be enhanced
      in stage IV lung cancer.

PMID- 15172237
TI  - Evolution of surgical outcomes for nonsmall cell lung cancer: time trends in 1465
      consecutive patients undergoing complete resection.
AB  - BACKGROUND: Lung cancer is still the most common cause of death due to cancer.
      Although the 5-year survival rate of patients with lung cancer is reported to be
      increasing, whether the surgical results have actually been improving or not is
      controversial. We reviewed our experience to evaluate time trends of surgical
      outcomes in patients with nonsmall cell lung cancer. METHODS: We reviewed the
      clinical records of 1465 consecutive patients with proven primary nonsmall cell
      carcinoma who underwent complete removal of the primary tumor together with hilar
      and mediastinal lymph nodes from 1985 to 1995 (early era) and from 1996 to 2002
      (late era). The clinical characteristics, surgical outcome, and overall survival
      of the patients were analyzed, and data from the two eras were compared. RESULTS:
      There were 694 patients in the early era and 771 in the late era. As for their
      characteristics, elder age, female sex, adenocarcinoma, earlier stage of disease
      and smaller size of tumor were more frequently encountered in the late era.
      Lobectomy was the most common procedure performed during both periods, and in the
      late era, the rate of segmentectomy was doubled (11% to 25%) whereas that of
      pneumonectomy was much less (6% to 1%). Although the frequency of operative
      deaths in the two eras did not differ (0.3%), that of in-hospital deaths and of
      postoperative complications decreased significantly in the late era (2% to 0.5%
      and 28% to 12%, respectively). A significant improvement in survival probability
      was observed in patients with pathologic stage IA (p < 0.0001), IB (p = 0.0477),
      and III disease (p = 0.00120) but not in those with pathologic stage II disease
      (p = 0.5353). Also, the multivariate analysis of patients with pathologic stage I
      or III demonstrated that age, sex, and size of the tumor were significant
      prognostic determinants, and confirmed that the recent prolonged survivals
      remained significant even after simultaneous adjustment for other factors.
      CONCLUSIONS: These data indicate a significant recent improvement in surgical
      outcomes after stratification of various prognostic variables although careful
      consideration should be given to the retrospective nature of this study.

PMID- 15172239
TI  - Comparison of water seal and suction after pulmonary lobectomy: a prospective,
      randomized trial.
AB  - BACKGROUND: The objective of the present study was to assess whether placing
      chest tubes on water seal after pulmonary lobectomy reduced the duration of air
      leak compared with suction. METHODS: One hundred forty-five patients who
      underwent pulmonary lobectomy for lung cancer and with an air leak on the first
      postoperative day were prospectively randomly assigned to two groups: in group 1
      (72 patients), chest tubes were placed on water seal on the morning of the first
      postoperative day; in group 2 (73 patients), chest tubes were on continuous
      suction (-20 cm H(2)O). Eighty percent of the patients who underwent upper
      lobectomy had also a pleural tent procedure. Preoperative, operative, and
      postoperative variables were compared between the groups. RESULTS: The two groups
      were evenly matched for preoperative and operative characteristics. No
      statistically significant differences were found between group 1 and group 2 in
      terms of air leak duration (6.5 versus 6.3, respectively; p = 0.9) and the
      incidence of prolonged air leak cases (27.8% versus 30.1%, respectively; p =
      0.8). Similar results were obtained when the analysis was corrected for the
      length of the stapled parenchyma and the site of resection (upper and lower
      resections) or restricted to patients with a forced expiratory volume in 1 second
      less than 80% of predicted. Water seal patients had increased postoperative
      complications compared with suction patients (31.9% versus 17.8%, respectively; p
      = 0.056). CONCLUSIONS: Chest tubes placed on water seal after pulmonary lobectomy
      were generally well tolerated and safe; however, they did not reduce the duration
      of air leak or the incidence of prolonged air leak compared with suction.

PMID- 15172241
TI  - Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia
      reperfusion injury.
AB  - BACKGROUND: We previously demonstrated that intravenous poly (ADP) ribose
      synthetase (PARS) inhibition protects against experimental lung ischemia
      reperfusion injury (LIRI) in an in situ, hilar occlusion model. This study
      determined its efficacy when administered intratracheally (IT). METHODS: Left
      lungs of rats were rendered ischemic for 90 minutes, and reperfused for up to 4
      hours. Treated animals received INO-1001, a PARS inhibitor, intratracheally 30
      minutes before ischemia, while controls were given IT vehicle at equivalent
      volumes. All groups contained at least 4 animals. Lung injury was quantitated
      utilizing vascular permeability to radiolabeled albumin, tissue myeloperoxidase
      (MPO) content, alveolar leukocyte cell counts, and arterial pO(2) at 4 hours of
      reperfusion. Electrophoretic mobility shift assays (EMSA) assessed the nuclear
      translocation of NFkappaB and AP-1 in injured left lungs, while ELISAs
      quantitated secreted cytokine induced neutrophil chemoattractant (CINC) and MCP-1
      protein in bronchoalveolar lavage fluid. RESULTS: Intratracheal PARS inhibition
      was 73% (p < 0.0001) and 87% (p < 0.0001) protective against increases in
      vascular permeability and alveolar leukocyte accumulation, respectively, and
      improved arterial pO(2) (p < 0.0004) at 4 hours of reperfusion. Myeloperoxidase
      (MPO) activity in treated lungs was reduced by 70% (p < 0.02). The nuclear
      translocation of NFkappaB and AP-1 was attenuated at 15 minutes of reperfusion,
      and the secretion of CINC and MCP-1 (p < 0.05) protein into the alveolus was
      diminished at 4 hours of reperfusion. CONCLUSIONS: Intratracheal INO-1001
      protects against experimental LIRI. The reduction in secreted chemokine protein
      at 4 hours of reperfusion appears to be mediated at the pretranscriptional level
      through attenuated NFkappaB and AP-1 activation. This route may optimize future
      donor organ management and improve lung recipient outcomes.

PMID- 15172242
TI  - Alteration of cellular electrophysiologic properties in porcine pulmonary
      microcirculation after preservation with University of Wisconsin and Euro-Collins
      solutions.
AB  - BACKGROUND: The effect of cold storage of porcine pulmonary microvessels in
      University of Wisconsin (UW) and Euro-Collins (EC) solutions on the cellular
      electrophysiologic properties remains unknown. METHODS: The pulmonary
      microarteries (PA, 381.6 +/- 62.8 microm; n = 60) and microveins (PV, 360.8 +/-
      54.5 microm; n = 60) were incubated with Krebs (control), UW, or EC solution at 4
      degrees C for 4 hours in a myograph. The resting membrane potential and the
      endothelium-derived hyperpolarizing factor-mediated hyperpolarization to
      bradykinin (0.1 micromol/L) in the presence of inhibitors of nitric oxide and
      prostacyclin, N(omega)-nitro-l-arginine, hemoglobin, and indomethacin, in a
      single smooth muscle cell were directly measured. RESULTS: The resting membrane
      potential (-60.8 +/- 1.3 mV in PA and -48.1 +/- 0.7 mV in PV, n = 6) was
      depolarized after exposure to UW solution (to -18.4 +/- 0.7 mV in PA and -13.6 +/
      0.8 mV in PV; n = 8; p < 0.001). The amplitude of endothelium-derived
      hyperpolarizing factor-mediated hyperpolarization to bradykinin was also
      decreased (from 7.4 +/- 0.7 mV to 2.6 +/- 0.7 mV in PA and from 4.6 +/- 0.5 mV to
      0.9 +/- 0.4 mV in PV; p < 0.001). In comparison, EC depolarized the membrane
      potential to a lesser extent (to -28.3 +/- 0.9 mV in PA and to -21.3 +/- 0.8 mV
      in PV; n = 8; p < 0.001) and almost abolished the hyperpolarization to
      bradykinin. After washout, hyperpolarization was partially restored (UW, 4.9 +/-
      0.7 mV in PA and 2.0 +/- 0.3 mV in PV. p < 0.01; EC, 2.3 +/- 0.5 mV in PA and 1.0
      +/- 0.3 mV in PV. p < 0.01). CONCLUSIONS: Cold storage of porcine PA and PV with
      UW or EC solution impairs the electrophysiologic properties (hyperpolarization)
      related to endothelium-smooth muscle interaction. The alteration is more profound
      with EC than UW solution and in veins than in arteries. The findings urge further
      studies on lung preservation solutions.

PMID- 15172243
TI  - Acute postoperative pain in lung transplant recipients.
AB  - BACKGROUND: This retrospective study was designed to assess the quality of
      postoperative pain control and the facility of transition from epidural to oral
      analgesia in lung transplant recipients. METHODS: After institutional review
      board approval, data were collected from the charts of all patients who underwent
      lung transplantation at our institution between 1998 and 2002. The study group
      consisted of the patients for whom an epidural was the first postoperative pain
      management modality. To serve as a control group we reviewed the charts of 30
      patients, randomly selected over the same period, who underwent a thoracotomy for
      indications other than transplantation and who received postoperative epidural
      analgesia. RESULTS: Eighty-three patients were available for analysis. Unilateral
      and bilateral lung transplant recipients had equivalent quality of pain control.
      However, lung transplant recipients had a lower incidence of adequate pain relief
      than patients undergoing thoracotomy for other indications (73% vs 87%, p <
      0.05). Lung transplant recipients also had a higher incidence of epidural to oral
      analgesia transition failure (47% vs 20%, p < 0.01). CONCLUSIONS: This is the
      first study to assess the quality of postoperative pain control and success of
      transition from epidural to oral analgesia in lung transplant recipients.
      Prospective studies are needed to assess the impact of our findings on patients'
      outcome.

PMID- 15172245
TI  - Foramen of Morgagni hernia: changes in diagnosis and treatment.
AB  - BACKGROUND: Foramen of Morgagni hernias are uncommon diaphragmatic hernias for
      which there are limited reported data. The purpose of this study is to report a
      recent case series of foramen of Morgagni hernias in the context of new
      diagnostic and treatment modalities. METHODS: A retrospective chart review was
      performed over a 15-year period, from 1987 to 2001. Twelve patients who had a
      foramen of Morgagni hernia repaired at our hospital were identified, and data
      from these patients were collected. RESULTS: The average age at treatment was 45
      years, with 50% of patients being asymptomatic. Radiographic evaluation included
      computed tomography scans in two thirds of the patients with a 100% sensitivity
      for diagnosis. All hernias were right-sided, and the most common contents of the
      hernias were omentum and colon. The transabdominal route was the preferred
      surgical approach. Thoracoscopy was used in 2 patients to further characterize a
      mediastinal mass. Two patients underwent laparoscopic repair. Postoperative
      complications were infrequent, and there were no recurrences during a 6-month to
      10-year follow-up. CONCLUSIONS: The emergence of highly accurate diagnostic
      computed tomography scans combined with less invasive surgical techniques
      utilizing laparoscopy and thoracoscopy has aided in the treatment of foramen of
      Morgagni hernias over the last 15 years.

PMID- 15172246
TI  - Are unaudited records from an outcomes registry database accurate?
AB  - BACKGROUND: Data from outcomes registry databases are being increasingly used for
      peer review and public reporting. However, administrative and clinical databases
      are mostly unaudited; thus, their accuracy has not been verified. METHODS:
      Outcomes data from all coronary artery bypass operations from a single cardiac
      surgery practice were entered into The Society of Thoracic Surgeons (STS)
      National Cardiac Database. From our practice of 18 surgeons, we audited 247 (10%)
      of the clinical records of patients undergoing surgery in 2001 and correlated
      them with all 315 elements of the STS National Cardiac Database for verification
      of accuracy. Inaccuracies were defined as a disagreement with a nominal or
      categorical variable or, for continuous variables, as the value not being within
      a predetermined window. When discrepancies existed, the hospital clinical record
      was assumed to be accurate. Outcomes discrepancies were then analyzed by four
      major categories: components of the preoperative risk algorithm, operative
      mortality, major complications, and other outcomes. RESULTS: Discrepancies were
      noted in 5% (16) or fewer of the audited fields for 98.8% of the records. Of the
      32 variables in the mortality risk algorithms, discrepancies were present in
      fewer than 10% of the audits on 30 of the 32 variables. More than 95% of the
      audited charts had zero or one discrepancy in the seven most important variables
      in the mortality risk models. Operative mortality was determined to be completely
      accurate with no discrepancies between the database and the audited clinical
      record. Among major complications, the error rate was less than 1% for all
      complications except prolonged ventilation (4.0%). A higher rate of discrepancies
      did exist in some of the other variables, including discharge medications (14.1%)
      and ventilator time (36.4%). CONCLUSIONS: A detailed audit of a clinical outcomes
      registry database demonstrated that the major fields within this specific
      database including operative mortality, major complications, and the significant
      factors in the risk algorithm were highly accurate. Process improvement factors
      were identified to further increase the accuracy of data collection.

PMID- 15172248
TI  - Multivariable prediction of in-hospital mortality associated with aortic and
      mitral valve surgery in Northern New England.
AB  - BACKGROUND: Predicting risk for aortic and mitral valve surgery is important both
      for informed consent of patients and objective review of surgical outcomes.
      Development of reliable prediction rules requires large data sets with
      appropriate risk factors that are available before surgery. METHODS: Data from
      eight Northern New England Medical Centers in the period January 1991 through
      December 2001 were analyzed on 8943 heart valve surgery patients aged 30 years
      and older. There were 5793 cases of aortic valve replacement and 3150 cases of
      mitral valve surgery (repair or replacement). Logistic regression was used to
      examine the relationship between risk factors and in-hospital mortality. RESULTS:
      In the multivariable analysis, 11 variables in the aortic model (older age, lower
      body surface area, prior cardiac operation, elevated creatinine, prior stroke,
      New York Heart Association [NYHA] class IV, congestive heart failure [CHF],
      atrial fibrillation, acuity, year of surgery, and concomitant coronary artery
      bypass grafting) and 10 variables in the mitral model (female sex, older age,
      diabetes, coronary artery disease, prior cerebrovascular accident, elevated
      creatinine, NYHA class IV, CHF, acuity, and valve replacement) remained
      independent predictors of the outcome. The mathematical models were highly
      significant predictors of the outcome, in-hospital mortality, and the results are
      in general agreement with those of others. The area under the receiver operating
      characteristic curve for the aortic model was 0.75 (95% confidence interval [CI],
      0.72 to 0.77), and for the mitral model, 0.79 (95% CI, 0.76 to 0.81). The
      goodness-of-fit statistic for the aortic model was chi(2) [8 df] = 11.88, p =
      0.157, and for the mitral model it was chi(2) [8 df] = 5.45, p = 0.708.
      CONCLUSIONS: We present results and methods for use in day-to-day practice to
      calculate patient-specific in-hospital mortality after aortic and mitral valve
      surgery, by the logistic equation for each model or a simple scoring system with
      a look-up table for mortality rate.

PMID- 15172249
TI  - Minimally invasive mitral valve repair using the da Vinci robotic system.
AB  - BACKGROUND: Minimally invasive mitral valve repair with a shortened hospital stay
      and quick return to an active lifestyle is the ultimate goal for robotically
      assisted surgery. We evaluated our da Vinci robotically assisted mitral valve
      repair experience toward achieving this goal. METHODS: All procedures were
      performed with peripheral cardiopulmonary bypass, transthoracic aortic cross
      clamp, and antegrade cardioplegia. Two ports and a 4-cm intercostal incision in
      the right chest were used for access. All patients had a ring annuloplasty, and
      all but 1 had a posterior leaflet resection. The entire repair and all knot tying
      were performed robotically. RESULTS: Between October 2001 and October 2002, 25
      patients (18 men) underwent robotic mitral valve repair. The mean age was 56
      years (range, 37 to 81 years). There were no incisional conversions, deaths,
      strokes, or reoperations for bleeding. Twenty-one (84%) of 25 patients were
      extubated in the operating room. Overall mean study times were as follows:
      procedure, 199.7 minutes (range, 140 to 287 minutes); cardiopulmonary bypass,
      126.6 minutes (range, 89 to 186 minutes); and cross-clamp, 87.7 minutes (range,
      58 to 143 minutes). Eight (32%) patients were discharged home in less than 24
      hours, with an average length of stay of 2.7 days. Comparing the first 10
      patients to the last 15 there was a significant reduction of times: total
      operating room time, 318.5 versus 275.1 minutes; cross-clamp, 97.6 versus 81.1
      minutes; leaflet resection or repair, 26.2 versus 15.6 minutes; annuloplasty
      ring, 31.9 versus 24.8 minutes; and length of stay, from 4.2 days to 1.67 days.
      Five patients had postoperative atrial fibrillation. Two (8%) patients ultimately
      required mitral valve replacement for recurrent mitral insufficiency.
      CONCLUSIONS: Mitral valve repair can be successfully performed with the da Vinci
      robotic system. Long-term follow-up is needed to determine the durability of the
      repair compared with a standard sternotomy approach.

PMID- 15172250
TI  - Mitral valve repair with the Colvin-Galloway Future Band.
AB  - BACKGROUND: A new annuloplasty device, the Colvin-Galloway Future Band, has been
      developed to allow simple and safe mitral valve repair surgery. Here we report
      its clinical use and the clinical results after a short-term, 2-year follow-up.
      METHODS: We assessed the performance of this new device in 40 consecutive
      patients (55% male; mean age, 68.3 +/- 8.1 years) who were operated on for mitral
      valve incompetence between 2001 and 2002. Ninety percent of these patients had
      associated surgical procedures. Clinical and echocardiographic assessment was
      performed perioperatively and at a mean follow-up of 16.5 +/- 5.7 months (range,
      6 to 25 months) in all patients (100%), permitting analysis of 55 patient-years.
      RESULTS: Thirty-eight patients survived surgery, resulting in an overall early
      mortality of 5.0%. There were four noncardiac-related late deaths, resulting in
      an overall late mortality of 10.0%. Perioperative echocardiography showed no
      incidences of systolic anterior movement at the time of discharge from the
      hospital and satisfactory mitral repair results in 36 (95%) patients. At the time
      of the 2-year follow-up, echocardiography showed satisfactory mitral valve
      function in all but 2 patients (94%) and a significant postoperative ventricular
      remodeling: the left ventricular end-diastolic diameter decreased from 64.5 +/-
      6.2 mm preoperatively to 50.4 +/- 9.5 mm postoperatively (p < 0.1). At the time
      of follow-up, 29 (90.6%) patients were in New York Heart Association functional
      class I or II, all of them describing their quality of life as "significantly
      improved" if compared with their preoperative status. There were no late
      reoperations and no thromboembolic, bleeding, or other complications.
      CONCLUSIONS: The clinical results of the Colvin-Galloway Future Band in this
      short-term follow-up of patients undergoing complex mitral valve repair seem to
      be promising.

PMID- 15172252
TI  - Mitral valve surgery for chronic ischemic mitral regurgitation.
AB  - BACKGROUND: Early and midterm clinical and echocardiographic results after mitral
      valve (MV) surgery for chronic ischemic mitral regurgitation were investigated to
      evaluate the validity of the criteria for repair or replacement applied by us.
      METHODS: From 1988 to 2002, 102 patients with ischemic mitral regurgitation
      underwent MV surgery (82 repairs and 20 replacements). End-systolic distance
      between the coaptation point of mitral leaflets and the plane of mitral annulus
      was the key factor that allowed either repair (<or=10 mm) or replacement (>10
      mm). Patients who had MV replacement showed higher New York Heart Association
      class (3.2 +/- 0.5 versus 3.4 +/- 0.5; p = 0.016), lower preoperative ejection
      fraction (0.33 +/- 0.9 versus 0.38 +/- 0.12; p = 0.034), and higher end-diastolic
      volume (161 +/- 69 mL versus 109 +/- 35 mL; p < 0.001) compared with repair.
      Mitral regurgitation was 3.2 +/- 0.7 in both groups. RESULTS: Thirty-day
      mortality was 3.9% (2.4% MV repair versus 10.0% MV replacement; not significant).
      During the follow-up 26 patients died. Of the 72 survivors, 55 (76.3%) were in
      New York Heart Association classes I and II. Five-year survival was 75.6% +/-
      4.7% in MV repair and 66.0% +/- 10.5% in MV replacement (not significant).
      Survival in New York Heart Association classes I and II was 58.9% +/- 5.4% in MV
      repair and 40.0% +/- 11.0% in MV replacement (not significant). Cox analysis
      identified preoperative New York Heart Association class, ejection fraction, end
      diastolic volume, end-systolic volume, and congestive heart failure as risk
      factors common to both events. In 46 patients, late echocardiograms showed no
      volume or ejection fraction modifications. In patients who underwent MV repair,
      50% had no or mild mitral regurgitation. CONCLUSIONS: Correction of chronic
      ischemic mitral regurgitation through either repair or replacement provides a
      good 5-year survival rate, with more than 75% of the survivors in New York Heart
      Association classes I and II.

PMID- 15172253
TI  - Is a bicuspid aortic valve a risk factor for adverse outcome after an autograft
      procedure?
AB  - BACKGROUND: Recently, bicuspid aortic valve disease is posed to be a possible
      risk factor for dilatation of the pulmonary autograft. METHODS: Analysis of all
      123 patients in our prospective cohort with their native aortic valve in situ at
      the autograft procedure. RESULTS: The bicuspid aortic valve group (n = 81) had
      more males (p = 0.05), prior cardiac surgery (p = 0.02), prior aortic valve
      balloon dilatation (p = 0.01), aortic stenosis (p = 0.03), and less deterioration
      of left ventricular function (p = 0.02) than the tricuspid group (n = 42).
      Hospital mortality occurred in 3 patients (bicuspid 2, tricuspid 1). The follow
      up was 99% complete (median, 5.3 years; SD, 3.5; range, 0.1 to 13.4) with a total
      of 674 patient years. During follow-up 4 patients died (bicuspid 2, tricuspid 2).
      Overall survival was 95% (95% confidence interval [CI], 89% to 98%) at 5 and 10
      years. Seven patients required reoperation for autograft failure, all structural.
      Freedom from autograft reintervention was 97% (95% CI, 92% to 100%) at 5 years
      and 89% (95% CI, 79% to 98%) at 10 years. There were no differences in outcome
      between the groups. Four patients required reoperation for allograft failure, all
      structural. Freedom from allograft reoperation was 99% (95% CI, 97% to 100%) at 5
      years and 91% (95% CI, 82% to 100%) at 10 years. There was no difference between
      the groups. CONCLUSIONS: An autograft procedure in patients with a bicuspid
      aortic valve is justified. Bicuspid aortic valve disease is not a
      contraindication for an autograft procedure. Patients with a bicuspid aortic
      valve will meet the limitations of the autograft procedure in the same frequency
      as the overall autograft population.

PMID- 15172254
TI  - Promoting angiogenesis protects severely hypertrophied hearts from ischemic
      injury.
AB  - BACKGROUND: Myocardial hypertrophy is associated with progressive contractile
      dysfunction, increased vulnerability to ischemia-reperfusion injury, and is,
      therefore, a risk factor in cardiac surgery. During the progression of
      hypertrophy, a mismatch develops between the number of capillaries and
      cardiomyocytes per unit area, suggesting an increase in diffusion distance and
      the potential for limited supply of oxygen and nutrients. We hypothesized that
      promoting angiogenesis in hypertrophied hearts increases microvascular density,
      thereby improves tissue perfusion and substrate availability, maintains
      myocardial function, and improves postischemic recovery. METHODS: Left
      ventricular hypertrophy was created in 10-day-old rabbits by aortic banding and
      progression was monitored by echocardiography. At 4 weeks (compensated
      hypertrophy), 2 microg of vascular endothelial growth factor (VEGF) or placebo
      was administered intrapericardially. After 2 weeks, microvascular density,
      coronary flow (CF), and glucose uptake (GU) were measured. Tolerance to ischemia
      was determined by cardiac function measurements before and after ischemia
      reperfusion using an isolated heart preparation. RESULTS: Microvascular density
      increased significantly following VEGF treatment (1.43 +/- 0.08/nuclei/field vs
      1.04 +/- 0.06/nuclei/field untreated hypertrophy). Concomitantly, there was an
      increase in CF (7 +/- 0.5 vs 5 +/- 0.4 mL/min/g) and GU (1.24 +/- 0.2 vs 0.69 +/-
      0.2 micromoles/g/30 minutes; p <or= 0.05). In vivo contractile function (-0.08 +/
      0.48 vs -1.39 +/- 0.35 untreated hypertrophy; p <or= 0.05) and postischemic
      myocardial recovery (% recovery: 93 +/- 2.0 vs 73 +/- 6.8 untreated hypertrophy;
      p <or= 0.05) were significantly improved in VEGF-treated hearts compared to
      untreated hypertrophied hearts. CONCLUSIONS: Treatment of hypertrophied hearts
      with VEGF resulted in an increase of microvascular density, improved tissue
      perfusion, and glucose delivery. Promoting angiogenesis proved useful in
      preserving myocardial function in late hypertrophy and improving postischemic
      recovery of contractile function.

PMID- 15172256
TI  - Acute dissection of the descending aorta: noncommunicating versus communicating
      forms.
AB  - BACKGROUND: Noncommunicating dissecting intramural hematoma is an aortic
      dissection variant, characterized by absent flow within the false lumen.
      Noncommunicating dissecting intramural hematoma is thought to be more stable than
      communicating dissection when beginning in the descending aorta. This study
      assessed clinical characteristics, anatomic characteristics, and 1-year outcomes
      in acute descending noncommunicating dissecting intramural hematoma versus
      communicating dissection. METHODS: Retrospective database review identified
      patients who underwent magnetic resonance or computed tomography imaging
      revealing acute descending noncommunicating dissecting intramural hematoma or
      communicating dissection. Comparisons of clinical and anatomic characteristics
      and 1-year outcomes were performed. RESULTS: Twenty-four noncommunicating
      dissecting intramural hematoma and 36 communicating dissection cases were
      identified. Patients with noncommunicating dissecting intramural hematoma were
      older (68.5 +/- 8.8 versus 61.8 +/- 11.6 years; p < 0.05). Although
      noncommunicating dissecting intramural hematoma often showed abdominal aorta
      extension (50%), the infrarenal level was spared. Communicating dissection
      characteristically extended beyond the diaphragm (89%), including into the
      infrarenal aorta (28%). There was no significant difference in rates of adverse
      clinical events for noncommunicating dissecting intramural hematoma versus
      communicating dissection (13% versus 30%; 0.10 > p > 0.05). By follow-up imaging
      (87% of population), aortic deterioration was more frequent in noncommunicating
      dissecting intramural hematoma versus communicating dissection cases (60% versus
      15%; p < 0.005). CONCLUSIONS: Acute descending noncommunicating dissecting
      intramural hematoma and communicating dissection represent two variants, with
      differing clinical and anatomic characteristics, but comparable levels of 1-year
      morbidity.

PMID- 15172259
TI  - Circulatory arrest for repair of postcoarctation site aneurysm.
AB  - BACKGROUND: Aneurysm at previous coarctation repair may be seen more frequently
      as children operated for this condition survive into adulthood. We use deep
      hypothermic circulatory arrest to repair these aneurysms. METHODS: A case series
      was conducted using 12-year, single-institution, retrospective chart review.
      RESULTS: Twenty-one patients underwent left thoracotomy and repair of aneurysm at
      the site of previous coarctation repair. Three cases presented emergently as
      aortobronchial fistulas. The age range was 16 to 73 years (median, 26 years). The
      median circulatory arrest time was 33 minutes (range, 22 to 55 minutes). Repair
      involved interposition graft replacement. Six patients required additional tube
      graft replacement of the left subclavian artery. There was 1 operative mortality
      in a patient having a hypoxic brain injury secondary to an anaphylactic reaction
      to a plasma expander. There were no embolic strokes or paraplegia. One patient
      had a recurrent laryngeal nerve paresis. There was 1 case of Horner's syndrome
      after subclavian artery replacement. CONCLUSIONS: Circulatory arrest allows for
      the accurate repair of this difficult pathologic process and avoids the risk of
      clamp-related injuries. Follow-up out to 16 years demonstrates this technique of
      repair to be durable, with no late deaths or reoperations for recurrent aneurysm.

PMID- 15172258
TI  - Separate grafts or en bloc anastomosis for arch vessels reimplantation to the
      aortic arch.
AB  - BACKGROUND: This study compares the results of the separated graft technique and
      the en bloc technique as a method of arch vessels reimplantation during surgery
      of the aortic arch and determines the predictive risk factors associated with
      hospital mortality and adverse neurologic outcome during aortic arch repair.
      METHODS: Between October 1995 and March 2002, 352 patients (mean age 64.9 +/-
      11.3 years; urgent status: 49/352 [13.9%]) underwent surgery of the aortic arch
      using the separated graft technique (group A: n = 230 [65.3%]) and the en bloc
      technique (group B: n = 122 [34.7%]) to reimplant the arch vessels. An aortic
      arch replacement was performed in 32 patients (9.1%), an ascending aorta and arch
      replacement in 222 patients (53.1%), an aortic arch and descending aorta
      replacement in 16 patients (4.5%), and a complete replacement of the thoracic
      aorta in 82 patients (23.3%). Brain protection was achieved by means of antegrade
      selective cerebral perfusion in all patients. The mean cardiopulmonary bypass
      time was 204.8 +/- 61.9 minutes (group A: 199.7 +/- 57.0 minutes; group B: 214.5
      +/- 69.4 minutes; p = 0.033), the mean myocardial ischemic time was 121.5 +/-
      43.2 minutes (group A: 116.7 +/- 38.9 minutes; group B: 130.80 +/- 49.4 minutes;
      p = 0.003), and the mean antegrade selective cerebral perfusion time was 84.5 +/-
      36.4 (group A: separated graft technique 91.3 +/- 36.3 minutes; group B: 70.6 +/-
      32.7 minutes; p = 0.000). RESULTS: Overall hospital mortality was 6.8% (group A:
      6.5%; group B: 7.4%; p = not significant [NS]). The permanent neurologic
      dysfunction rate was 3.5% (group A: 4.0%; group B: 2.5%; p = NS). The transient
      neurologic dysfunction rate was 5.4% (group A: 5.5%; group B: 5.2%, p = NS).
      Postoperative systemic morbidity was similar in the two groups. A logistic
      regression analysis revealed preoperative cardiac tamponade (p = 0.011; odds
      ratio [OR] = 5.9) and cardiopulmonary bypass time (p = 0.010; OR = 1.01/min) to
      be independent predictors of hospital mortality. None of the analyzed
      preoperative variables were associated with an increased risk of permanent
      neurologic dysfunction. Age more than 70 years old (p = 0.029, OR = 5.7),
      myocardial revascularization (p = 0.001, OR = 2.9), and pump time (p = 0.013, OR
      = 1.01/min) were indicated as independent predictors of transient neurologic
      dysfunction by logistic regression. CONCLUSIONS: Antegrade selective cerebral
      perfusion was confirmed to be a safe method of cerebral protection allowing
      complex aortic arch operations to be performed with acceptable results in terms
      of hospital mortality and neurologic outcome. The separated graft technique had
      no adverse impact on hospital mortality and morbidity.

PMID- 15172260
TI  - Tau protein in the cerebrospinal fluid is a marker of brain injury after aortic
      surgery.
AB  - BACKGROUND: Tau is a protein localized primarily in neurons, especially in the
      axonal compartment. Cerebrospinal fluid tau levels are elevated in acute stroke
      and head traumas. The purpose of this study is to elucidate the alterations of
      cerebrospinal fluid tau levels in patients with or without neurologic
      complication after aortic surgery. METHODS: Twenty-eight patients undergoing
      descending thoracic (n = 8) or thoracoabdominal (n = 20) aortic surgery were
      enrolled. Cerebrospinal fluid tau levels were measured before operation and at
      seven time points up to the 72nd postoperative hour, and were compared with
      cerebrospinal fluid S100B levels. RESULTS: Two patients developed brain
      infarction, including the one with paraplegia. In these patients, 20-fold to 100
      fold tau elevation was observed, but S100B elevation was less evident in the
      patient without paraplegia. Three other patients developed spinal cord injury.
      Additional three patients suffered from temporary neurologic dysfunction of the
      brain. Tau levels in the latter three patients showed tenfold elevation and were
      higher than those in the three patients with spinal cord injury or those in the
      patients without neurologic complication up to 24 postoperative hours. The S100B
      levels were also higher in the three patients with temporary neurologic
      dysfunction of the brain than in the patients without neurologic complication at
      the conclusion of surgery. From 6 to 24 postoperative hours, they were higher in
      the three patients with spinal cord injury than in the patients without
      neurologic complication. CONCLUSIONS: These preliminary results suggest that
      cerebrospinal fluid tau levels reflect brain injury. Because tau levels may
      separate the patients with temporary neurologic dysfunction, they may serve as a
      useful marker of brain injury.

PMID- 15172261
TI  - Bilateral versus single internal thoracic artery grafting in oral-treated
      diabetic subsets: comparative seven-year outcome analysis.
AB  - BACKGROUND: Recent interest has focused on the use of arterial conduits in
      diabetic subsets. To date, the long-term benefits of bilateral internal thoracic
      artery (BITA) grafting in this subgroup remain in question. METHODS: Two hundred
      eighty-five consecutive oral-treated diabetics operated on nonemergent basis
      (1996 to 1998) were compared according to the surgical technique, left-sided
      skeletonized BITA (n = 228) or single internal thoracic artery- saphenous veins
      (SITA) (n = 57). Patients with chronic lung disease, usually preselected to SITA
      grafting, were not included. RESULTS: The respective grafts to patient ratio was
      3.1 +/- 1 and 3.2 +/- 0.8 for the SITA and BITA groups (p = NS). Complementary
      conduits used in the BITA group were gastroepiploic arteries (25%) and saphenous
      veins (13%). Early outcome was comparable, including the incidence of deep
      sternal infections (1.8% in both groups). During follow-up (range, 4 to 7.5
      years; median, 5), there were less repeat revascularizations (4.4% vs 12.3%, p =
      0.025) and major adverse cardiac events (MACE) (11.2% vs 36.8%, p < 0.0001) in
      the BITA group. At 7 years, survival (Kaplan-Meier) (75% vs 59%, p = 0.006, log
      rank), freedom from cardiac mortality (92% vs 68%, p < 0.0001), and freedom from
      MACE (70% vs 59%, p = 0.004) were superior in the BITA group. Multivariate
      analysis identified the use of BITA as a protective factor against the occurrence
      of late cardiac mortality (odds ratio [OR] 0.2) and MACE (OR 0.3); conversely,
      SITA-saphenous vein arrangements increased the risk by fivefold (OR 5, confidence
      interval limits [CL] 1.6 to 16.6, p = 0.005) and threefold (OR 3.3, CL 1.5 to 9,
      p = 0.005), respectively. CONCLUSIONS: Left-sided BITA grafting confers improved
      long-term survival and event-free survival in oral-treated diabetics. We,
      therefore, recommended this approach in this diabetic subset.

PMID- 15172262
TI  - Skeletonization of gastroepiploic artery graft in off-pump coronary artery bypass
      grafting: early clinical and angiographic assessment.
AB  - BACKGROUND: Recently skeletonization has been recognized as an alternative to
      pedicle harvesting of the internal thoracic artery as a technique that increases
      the length and caliber size of the graft compared with pedicled internal thoracic
      artery grafts; however, this is not yet popular for harvesting the gastroepiploic
      artery (GEA). We report here our experience of skeletonized GEA grafting in off
      pump coronary artery bypass grafting with early clinical and angiographic
      results. The purpose of this study was to evaluate skeletonization of GEA
      grafting in off-pump coronary artery bypass grafting with a large patient volume.
      METHODS: One hundred sixty-eight patients including 131 men and 37 women (mean
      age, 65 years; range, 45 to 87 years) underwent the skeletonized GEA grafting in
      off-pump coronary artery bypass grafting. These patients represent 41% (168 of
      407 patients) of those who underwent off-pump coronary artery bypass grafting
      operations during the same period. We used the GEA graft of choice in patients
      with right coronary artery lesion. Skeletonization was performed in a unique
      manner we developed. RESULTS: There were no in-hospital deaths among the study
      patients. One patient had a perioperative myocardial infarction, which was
      considered a result of vasospasm of the GEA graft. None of the other patients had
      severe morbidity. The patency rate of the skeletonized GEA graft was 98.1% (151
      of 154 distal anastomoses). CONCLUSIONS: This study suggests that skeletonization
      of the GEA graft can enlarge its caliber size and improve its flow capacity. In
      addition, the acceptable early clinical and angiographic outcome suggests that
      use of the skeletonized GEA graft in off-pump coronary artery bypass grafting
      surgery is safe and effective.

PMID- 15172263
TI  - Beating versus arrested heart coronary revascularization: evaluation by cardiac
      troponin I release.
AB  - BACKGROUND: This prospective randomized study aimed to compare beating and
      arrested heart revascularization in patients undergoing first elective coronary
      artery bypass graft, with cardiac troponin I release used to evaluate myocardial
      injury. METHODS: Seventy patients were randomly assigned to a beating or arrested
      heart revascularization group. Cardiac troponin I concentrations were measured in
      serial venous blood samples drawn preoperatively in both groups: after aortic
      unclamping at 6, 9, 12, and 24 hours in the arrested heart group and after the
      last anastomosis at 6, 9, 12, and 24 hours in the beating heart group. Analysis
      of covariance with repeated measures was performed to test the effect of group
      and time on cardiac troponin I concentration. RESULTS: The total amount of
      cardiac troponin I released was higher in the arrested heart revascularization
      group than in the beating heart revascularization group (8.25 +/- 6.16 vs 3.18 +/
      4.75 microg, p < 0.0001). Cardiac troponin I concentrations were significantly
      higher in the arrested heart group at hours 6, 9, 12, and 24 than in the beating
      heart group (p < 0.0001). CONCLUSIONS: The lower release of cardiac troponin I in
      the beating heart revascularization group indicates that conventional coronary
      artery bypass graft with cardioplegic arrest causes more damage to the heart than
      off-pump myocardial revascularization.

PMID- 15172264
TI  - Usefulness of preoperative intraaortic balloon pump therapy during off-pump
      coronary artery bypass grafting in high-risk patients.
AB  - BACKGROUND: In off-pump coronary artery bypass grafting (OPCABG) surgery, the
      most critical complication is hemodynamic deterioration, which can occur during
      displacement of the heart to expose the target vessels. Preoperative intraaortic
      balloon pump (IABP) therapy improves cardiac performance and facilitates access
      to the target coronary artery while maintaining hemodynamic stability, especially
      in high-risk patients. METHODS: One hundred thirty-three consecutive patients who
      underwent OPCABG through sternotomy between April 2000 and July 2003 were
      studied. We compared the clinical results of 32 patients who underwent
      preoperative IABP placement (group 1) with those of 101 patients who did not have
      IABP placement (group 2). Of the 32 patients satisfying the insertion criteria,
      15 had critical left main artery disease, 20 had unstable angina, 5 had acute
      myocardial infarction, and 5 had left ventricular dysfunction. RESULTS: There
      were no significant differences in the average number of distal anastomoses
      performed between group 1 and group 2 (3.1 +/- 0.8 versus 3.3 +/- 0.9, p = not
      significant). The complete revascularization rate was 95% in both group. There
      was no conversion to on-pump surgery in either group. There was no operative
      death in group 1 and only 1 death in group 2. In group 1, the number of patients
      who required prolonged ventilatory support (longer than 48 hours) was higher (3
      versus 1, p = 0.036), and there was a higher incidence of low cardiac output
      syndrome (1 versus 0, p = 0.074). There were no IABP-related complications in
      group 1. CONCLUSIONS: Preoperative IABP therapy for high-risk coronary patients
      is very effective in preventing hemodynamic instability and providing surgical
      results comparable with those in moderate- to lower-risk patients.

PMID- 15172266
TI  - Internal thoracic artery malperfusion: fast decision for an additional vein graft
      has impact on patient outcome.
AB  - BACKGROUND: Internal thoracic artery (ITA) malperfusion has been described as a
      potentially devastating and lethal complication of coronary artery bypass
      grafting (CABG). It is our practice to perform an additional vein graft to the
      distal left anterior descending (LAD) artery in such cases. METHODS: From August
      1999 to July 2002, 2877 CABG procedures were performed at our institution. In 65
      patients (2.3%) ITA malperfusion was observed. All of them were treated with an
      additional vein graft to the distal LAD. All patient data were screened for the
      time interval between the occurrence of ITA malperfusion and the decision to
      perform an additional vein graft. RESULTS: Of 65 patients with ITA malperfusion,
      54 patients (83%) survived (group 1), 11 patients (17%) died (group 2). There was
      no difference in preoperative risk status between the groups. Cross clamp time
      was 88 +/- 4 minutes in group 1 and 104 +/- 11 minutes in group 2 (p = 0.04).
      Intraoperative ITA flow to LAD was 6 +/- 1 mL/min in group 1 and 10 +/- 5 mL/min
      in group 2 (p = 0.2). Time between release of cross clamp and second period of
      cross clamping was 50 +/- 5 minutes in group 1 and 75 +/- 11 minute group 2 (p =
      0.02). Time between termination of cardiopulmonary bypass (CPB) and second period
      of cross clamping was 23 +/- 3 minutes in group 1 and 46 +/- 7 minutes in group 2
      (p = 0.003). Vein graft flow to distal LAD was 54 +/- 4 mL/min in group 1 and 52
      +/- 12 mL/min in group 2 (p = 0.5). Maximum postoperative troponin I was 35 +/-
      11 ng/mL in group 1 and 136 +/- 32 in group 2 (p = 0.003). CONCLUSIONS: Survivors
      of ITA malperfusion had shorter cross clamp times and less myocardial damage as
      evidenced by lower postoperative troponin I levels. Time intervals between first
      and second cross clamp and between termination of CPB and second cross clamp were
      lower in survivors, thus indicating that a fast decision for an additional vein
      graft may influence postoperative patient outcome.

PMID- 15172268
TI  - Oxygen pressure measurement during grip exercise reveals exercise intolerance
      after radial harvest.
AB  - BACKGROUND: Exercise intolerance of the hand after harvest of the radial artery
      is not well understood, although mild reductions of blood flow to the hand are
      reported. To ascertain its prevalence, patient symptoms implying potential
      exercise intolerance were evaluated by measuring transcutaneous oxygen pressure
      of the hand during grip exercise. For ascertaining predictive values, we verified
      ulnar flow reserve measured by Doppler ultrasonography before the harvest of
      radial artery. METHODS: Forty patients whose radial artery was harvested for
      coronary bypass graft, were interviewed and tested 1 year after operation, and
      their preoperative ultrasonographic data compared. RESULTS: Five patients (12.5%)
      had mild symptoms implying exercise intolerance. Exercise tests revealed severe
      decreases in tissue oxygenation in 7 patients (17.5%), but in accordance with
      symptoms (p = 0.0018). Tissue oxygenation in the operated hand was lower than in
      the nonoperated even in asymptomatic patients (p = 0.0011). Preoperative Doppler
      echography revealed that ulnar arteries of symptomatic patients were smaller (p =
      0.0019) and carried lower blood flows during manual compression of the radial
      artery (p = 0.0004) compared with those of asymptomatic patients. Smaller ulnar
      arteries (less than 1.4 mm/m(2)) with poor flow reserves (less than 60 mL x min(
      1) x m(-2) during radial compression) appear to indicate risks for exercise
      intolerance (p = 0.0004). CONCLUSIONS: More than 10% of patients after harvest of
      radial arteries had mild symptoms implying exercise-intolerance, which accorded
      with abnormal tissue oxygenation during grip exercise. Work habits of patients
      should be considered in radial harvest decisions, especially if preoperative
      Doppler echography indicates lower flow reserves for the ulnar artery.

PMID- 15172269
TI  - Digital blood flow after radial artery harvest for coronary artery bypass
      grafting.
AB  - BACKGROUND: Despite widespread use of radial artery as a bypass conduit in
      coronary artery bypass surgery, flow readjustment that takes place in the hands
      and fingers after the removal of the radial artery is poorly understood. METHODS:
      Using pulse volume recording plethysmography, a semiquantitative measurement of
      digital blood flow was carried out in 24 patients 7 days after harvesting of
      radial artery for coronary artery bypass grafting. Measurements taken from the
      fingers of the operated arms were evaluated and compared with those taken from
      the opposite or the control arms. RESULTS: Postoperatively, there was an overall
      decrease in blood flow to all the fingers of the operated arms. At the same time,
      there was evidence of redistribution of digital blood flow favoring the first two
      fingers over the last two, the same distribution pattern as seen in the fingers
      of the control arms. The pulse amplitude studies, likewise, showed a significant
      drop in all fingers of the operated arms, with the decrease most pronounced in
      the fourth and fifth fingers. None of the patients showed signs of digital
      ischemia postoperatively. CONCLUSIONS: The study showed that there was an overall
      decrease in digital blood flow after radial artery harvesting. The resulting
      blood supply by way of the remaining ulnar artery still provided more flow to the
      first two fingers over the last two fingers, indicating the existence of an
      autoregulatory mechanism operating to satisfy the physiologic needs of the
      fingers.

PMID- 15172271
TI  - Endoscopic vein harvest: advantages and limitations.
AB  - BACKGROUND: Although long saphenous vein remains the most commonly used conduit
      in coronary revascularization, traditional open vein harvest (OVH) may lead to
      significantly impaired wound healing and postoperative pain. Endoscopic vein
      harvest (EVH) attempts to reduce this morbidity and improve patient satisfaction
      with no compromise in outcome. METHODS: From September 2000 to November 2001, 108
      saphenous vein harvests were prospectively randomly assigned to EVH (n = 52) or
      OVH (n = 56); EVH was performed with the Clearglide endoscopic vein harvest
      system (Cardiovations) by a single surgeon. Endpoints included impaired wound
      healing (ASEPSIS score), operative and harvest time, vein quality (including
      histology), outcome and postoperative pain (Visual Analog Scale). Follow-up was
      as long as 3 years. RESULTS: The groups were well matched demographically.
      Endoscopic vein harvest was quicker to perform if sufficient vein for two grafts
      was needed (p < 0.01). Wound healing was significantly impaired (ASEPSIS score)
      in the OVH group compared with the EVH group (p < 0.01). The new procedure did
      not prolong the overall operative time (p = 0.77). Postoperative pain was less (p
      < 0.01) in the EVH group. Stepwise multiple regression showed age, diabetes,
      peripheral vascular disease, total operative time, type of procedure, length of
      incision, and number of vein grafts to be predictive of impaired wound healing.
      More late interventions were needed in the OVH group for wound-related morbidity.
      CONCLUSIONS: These data demonstrate that endoscopic vein harvest results in fewer
      cases of impaired wound healing and reduced postoperative pain, and it does not
      prolong the operative time significantly nor compromise the vein quality.
      Furthermore, it is quicker to perform if two grafts are needed, and it reduces
      late interventions.

PMID- 15172272
TI  - New-onset sustained ventricular tachycardia and fibrillation early after cardiac
      operations.
AB  - BACKGROUND: Malignant ventricular tachyarrhythmia early after cardiac surgery is
      an uncommon arrhythmic complication but has a negative impact on mortality. The
      purpose of this study was to evaluate the incidence of new-onset sustained
      postoperative ventricular tachycardia-ventricular fibrillation and to identify
      risk factors for the dysrhythmia. METHODS: Demographic, clinical, operative, and
      postoperative data, including a variable of postoperative ventricular
      tachycardia, were prospectively obtained from 4748 patients undergoing
      nonemergency coronary artery bypass graft and(or) valve replacement with no
      history of sustained ventricular tachycardia or sudden death. A detailed analysis
      was performed to define the risk factors for the ventricular tachycardia and the
      prognostic impact of the arrhythmia on 30-day mortality was evaluated. RESULTS:
      Forty-five patients (0.95%) had sustained ventricular tachycardia or ventricular
      fibrillation and the initial episode occurred 3.9 +/- 5.2 days (mean +/- standard
      deviation) after surgery. By multivariate analysis, female sex (odds ratio,
      1.982), left ventricular ejection fraction (< 35%: > 50%, 4.771), the presence of
      pulmonary hypertension (3.066), the presence of systemic hypertension (2.391),
      and pump time (per 10 minutes, 1.085) were independently associated with the
      dysrhythmias. Early mortality of patients with the arrhythmia was 28.9%,
      strikingly higher than that of patients without ventricular
      tachycardia/ventricular fibrillation (1.9%). CONCLUSIONS: Left ventricular
      ejection fraction is the strongest risk factor for new-onset postoperative
      sustained ventricular tachycardia-ventricular fibrillation; female sex, pump
      time, pulmonary and systemic hypertension are independent predictors of the
      dysrhythmias; the arrhythmia is associated with increased 30-day mortality after
      cardiac surgery.

PMID- 15172273
TI  - Randomized study of surgery for patients with permanent atrial fibrillation as a
      result of mitral valve disease.
AB  - BACKGROUND: The Cox Maze procedure has been used to treat atrial fibrillation in
      patients with mitral valve disease. Recently, ectopic foci, originating in the
      pulmonary veins, were demonstrated in patients with atrial fibrillation, and the
      indication was that their arrhythmia could have a focal origin. In the light of
      this new evidence, a simplified surgical technique to isolate the pulmonary veins
      was developed to eliminate permanent atrial fibrillation in patients undergoing
      mitral valve surgery. This study compares three surgical procedures proposed to
      maintain sinus rhythm after mitral valve surgery. METHODS: A prospective clinical
      trial of 30 patients with mitral valve disease and permanent atrial fibrillation
      who had undergone mitral valve surgery were randomized in accordance with the
      type of surgery used on each: (1). associated en bloc isolation of pulmonary
      veins, (2). the Maze procedure, or (3). mitral valve correction alone. The
      preoperative clinical characteristics were similar in the three groups. RESULTS:
      The overall postoperative complications were similar in all three groups. The
      cardiopulmonary bypass time and the aortic cross-clamping time were shorter in
      the control group, but this factor bore no relation to increased morbidity in the
      intervention groups. The relative risk of atrial fibrillation after surgery was
      0.08 in the group undergoing isolation of pulmonary veins (p = 0.010; 95%
      confidence interval, 0.01 to 0.71) and 0.20 in the Maze group (p = 0.044; 95%
      confidence interval, 0.04 to 1.02) compared with the control group. CONCLUSIONS:
      En bloc isolation of pulmonary veins associated with mitral valve surgery appears
      to be safe and just as effective as the Maze procedure in maintaining sinus
      rhythm in patients with permanent atrial fibrillation.

PMID- 15172275
TI  - Changing donor and recipient demographics in a heart transplantation program:
      influence on early outcome.
AB  - BACKGROUND: The purpose of this study was to investigate whether broadening
      acceptance criteria for donor hearts and changing recipient demographics resulted
      in an increased perioperative morbidity and mortality in a heart transplant
      program. METHODS: Donor and recipient data of 137 consecutive heart transplants
      performed from 1987 to 2001 were retrospectively analyzed and divided into three
      equal eras, each of 5 years: 1987 to 1991, 1992 to 1996, and 1997 to 2001.
      Multivariate analyses of recipient and donor demographics and operative factors
      were performed to identify the predictors of low cardiac output, intraaortic
      balloon pump utilization, 30-day mortality, and duration of intensive care and
      hospital stay. RESULTS: Significant increases in number of female recipients (p =
      0.025), cardiopulmonary bypass (p < 0.001), recipient cross-clamp (p < 0.001),
      donor age (p = 0.009), donor ischemic times (p < 0.001), use of cardioplegia (p <
      0.001) and the bicaval technique (p < 0.001), brain death to retrieval time (p =
      0.006), and need for postoperative dialysis were observed for the three study
      periods, whereas length of intensive care and hospital stay decreased. Female
      donor (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.0 to 5.7) was
      identified as a risk factor for low cardiac output. Female donor (OR, 3.7; 95%
      CI, 1.3 to 10.7), donor cardiac arrest (OR, 6.4; 95% CI, 1.6 to 25.9), and
      cardiopulmonary bypass time more than 2 hours (OR, 7.6; 95% CI, 2.1 to 28.1) were
      associated with increased intraaortic balloon pump utilization. Intensive care
      stay was prolonged by the biatrial technique (OR, 3.9; 95% CI, 1.3 to 11.9) and
      reduced by the use of cardioplegia (OR, 0.3; 95% CI, 0.1 to 0.9), longer
      cardiopulmonary bypass (OR, 0.2; 95% CI, 0.1 to 0.6) and aortic cross-clamp times
      (OR, 0.1; 95% CI, 0.03 to 0.6). CONCLUSIONS: Although a number of significant
      changes were observed during the study period, no donor, recipient, or operative
      factors influenced 30-day mortality. This study justifies our current donor and
      recipient selection policies.

PMID- 15172276
TI  - Preclinical readiness testing of the Arrow International CorAide left ventricular
      assist system.
AB  - BACKGROUND: Left ventricular assist system technologies are currently being
      developed as effective alternatives to cardiac transplantation. In this study, in
      vivo testing of the Arrow International CorAide left ventricular assist system
      was conducted to determine its preclinical readiness based on demonstrated system
      performance and biocompatibility. METHODS: Arrow International CorAide blood pump
      assemblies were implanted in 7 calves for 1-month (n = 4) and 3-month (n = 3)
      durations without the use of chronic anticoagulation therapy. Hemodynamic
      performance, physiologic pump control, end-organ function, and device-related
      adverse events were evaluated during the studies and at autopsy. RESULTS:
      Hemodynamics were stable in all cases with a mean pump flow of 4.1 +/- 0.8 L/min
      and a mean arterial pressure of 101 +/- 4 mm Hg. In all calves, renal and hepatic
      function remained normal with no incidence of hemolysis, infection, bleeding, or
      embolism. The CorAide physiologic control algorithm demonstrated appropriate pump
      speed and flow adjustments in response to physiologically induced inputs, and the
      system's external electronic components demonstrated no hardware or software
      malfunction. All 7 cases were sacrificed electively. Autopsy revealed no sign of
      end-organ disease on gross and histologic examinations, and no device failure,
      malfunction, or mechanical wear of the pump blood-bearing surfaces was found.
      CONCLUSIONS: The Arrow CorAide left ventricular assist system demonstrated
      effective pump performance and good biocompatibility with no incidence of device
      related adverse events. This system has completed its preclinical readiness
      testing and is approved for clinical trials in Europe in 2003.

PMID- 15172277
TI  - Diaphragmatic hernias associated with ventricular assist devices and heart
      transplantation.
AB  - BACKGROUND: Diaphragmatic hernias in heart transplant recipients with prior left
      ventricular assist device (LVAD) placement are a potentially life-threatening
      complication. This review examined the incidence, diagnostic strategies, surgical
      management, and prevention of diaphragmatic hernias in these patients. METHODS: A
      retrospective review of patients receiving a Thoratec HeartMate (Thoratec
      Laboratories Corp, Pleasanton, CA) LVAD who developed a diaphragmatic hernia
      after VAD explantation and orthotopic heart transplantation (OHT). Two groups
      were identified and their results compared. In the early group, the diaphragmatic
      defect was not closed at the time of OHT and VAD explantation, while in the late
      group the defect was closed. RESULTS: In the early group, between September 1995
      and November 1999, a total of 61 HeartMate LVADs were placed intraperitoneally as
      a bridge to transplantation, and 44 of those patients went on to OHT. Of these
      patients, 7 of 44 (15.9%) developed a diaphragmatic hernia after transplantation.
      Five of the patients underwent successful surgery by laparotomy without
      recurrence. Two patients with asymptomatic diaphragmatic hernia await repair.
      After a modification in diaphragmatic closure after VAD explantation at the time
      of OHT, in the late group between November 1999 and July 2002, 29 HeartMate LVADs
      were placed and 23 patients went on to OHT. There has been one diaphragmatic
      hernia (1 of 23, 4.3%) in this group. CONCLUSIONS: Diaphragmatic hernia following
      VAD placement and heart transplantation requires an aggressive diagnostic and
      therapeutic approach in this immunosuppressed patient population. We recommend
      primary closure of all diaphragmatic defects at the time of OHT and VAD
      explantation to reduce the incidence of this complication.

PMID- 15172278
TI  - Septal reshaping for exclusion of anteroseptal dyskinetic or akinetic areas.
AB  - BACKGROUND: Our purpose is to describe a technique for exclusion of anteroseptal
      dyskinetic or akinetic areas. METHODS: From January to December 2002, 22
      consecutive patients with myocardial infarction following left anterior
      descending artery occlusion underwent septal reshaping. All of them were admitted
      for dyspnea. Eight patients were referred for angina. After a 5 to 8 cm apical
      incision, 2 U stitches were passed from inside to join the anterior wall to the
      septum, as high as possible, following the border of the scars. An oval Dacron
      patch was then sutured from the septum (end of the direct suture through the
      border with the inferior septum) to the anterior wall (between the healthy and
      the scarred wall) up to the new apex. Purpose of the procedure is to maintain a
      longitudinal size as similar as possible to the normal. The incision was closed
      in a double layer. RESULTS: No patient died and only one had acute renal failure.
      No patients had restrictive syndrome. After a mean follow-up of 6.7 +/- 3.6
      months (3 to 15), mean New York Heart Association Class improved from 2.7 +/- 1.1
      to 1.2 +/- 0.3 (p < 0.001). Echocardiographic results showed reduction of left
      ventricle volumes and normalization of the stroke volume. In patients with low
      ejection fraction (<or=35%), left ventricular volumes decreased with a
      concomitant ejection fraction increase and a normal stroke volume. In patients
      with smaller cavities, significant reduction of left ventricular cavities was
      also obtained, with similar changes in ejection fraction and normal stroke
      volume. CONCLUSIONS: This technique treats all the dyskinetic or akinetic areas
      following left anterior descending artery occlusion, when the septal involvement
      is higher than the anterior free wall. Clinical and morphologic results are good.

PMID- 15172279
TI  - Local myocardial overexpression of growth hormone attenuates postinfarction
      remodeling and preserves cardiac function.
AB  - BACKGROUND: Ventricular remodeling with chamber dilation and wall thinning is
      seen in postinfarction heart failure. Growth hormone induces myocardial
      hypertrophy when oversecreted. We hypothesized that localized myocardial
      hypertrophy induced by gene transfer of growth hormone could inhibit remodeling
      and preserve cardiac function after myocardial infarction. METHODS: Rats
      underwent direct intramyocardial injection of adenovirus encoding either human
      growth hormone (n = 9) or empty null vector as control (n = 9) 3 weeks after
      ligation of the left anterior descending coronary artery. Analysis of the
      following was performed 3 weeks after delivery: hemodynamics, ventricular
      geometry, cardiomyocyte fiber size, and serum growth hormone levels. RESULTS: The
      growth hormone group had significantly better systolic cardiac function as
      measured by maximum left ventricular pressure (73.6 +/- 6.9 mm Hg versus control
      63.7 +/- 7.8 mm Hg, p < 0.05) and maximum dP/dt (2845 +/- 453 mm Hg/s versus 1949
      +/- 605 mm Hg/s, p < 0.005), and diastolic function as measured by minimum dP/dt
      (-2520 +/- 402 mm Hg/s versus -1500 +/- 774 mm Hg/s, p < 0.01). Ventricular
      geometry was preserved in the growth hormone group (ventricular diameter 12.2 +/-
      0.7 mm versus control 13.1 +/- 0.4 mm, p < 0.05; borderzone wall thickness 2.0 +/
      0.2 mm versus 1.5 +/- 0.1 mm, p < 0.001), and was associated with cardiomyocyte
      hypertrophy (6.09 +/- 0.63 microm versus 4.66 +/- 0.55 microm, p < 0.005). Local
      myocardial expression of growth hormone was confirmed, whereas serum levels were
      undetectable after 3 weeks. CONCLUSIONS: Local myocardial overexpression of
      growth hormone after myocardial infarction resulted in cardiomyocyte hypertrophy,
      attenuated ventricular remodeling, and improved systolic and diastolic cardiac
      function. The induction of localized myocardial hypertrophy presents a novel
      therapeutic approach for the treatment of ischemic heart failure.

PMID- 15172283
TI  - Comparison of low-flow cardiopulmonary bypass and circulatory arrest on brain
      oxygen and metabolism.
AB  - BACKGROUND: In the neonatal brain we measured oxygen (Bo(2)), extracellular
      striatal dopamine (DA), and striatal tissue levels of ortho-tyrosine (o-tyr)
      during low-flow cardiopulmonary bypass (LFCPB) or deep hypothermic circulatory
      arrest (DHCA) and the post-bypass recovery period. METHODS: Newborn piglets were
      assigned to sham (n = 6), LFCPB (n = 8), or DHCA (n = 6) groups. Animals were
      cooled to 18 degrees C and underwent DHCA or LFCPB (20 mL x kg(-1) x min(-1)) for
      90 minutes. The Bo(2) was measured by quenching the phosphorescence, DA by
      microdialysis, and hydroxyl radicals by o-tyr levels. The results are presented
      as the mean +/- SD (p < 0.05 was significant). RESULTS: Baseline Bo(2) was
      between 45 to 60 mm Hg. At the end of LFCPB, Bo(2) was 10.5 +/- 1.2 mm Hg. By 5
      and 30 minutes of arrest during DHCA, Bo(2) fell to 4.2 +/- 2.5 mm Hg and 1.4 +/-
      0.7 mm Hg, respectively. Compared with control, extracellular DA did not change
      during LFCPB. During DHCA extracellular levels of DA increased, by 750-fold from
      baseline at 45 minutes and to a maximum of 53000-fold at 75 minutes. After 2
      hours of recovery from DHCA, the o-tyr within the striatum increased about
      sixfold as compared with control. There was no change in o-tyr measured after
      LFCPB. CONCLUSIONS: In DHCA, but not LFCPB, levels of DA and o-tyr increased
      considerably in the striatum of piglets, a finding that may indicate the
      exhaustion of cellular energy levels and contribute substantially to cellular
      injury.

PMID- 15172281
TI  - Changes in mesenteric vascular reactivity and inflammatory response after
      cardiopulmonary bypass in a rat model.
AB  - BACKGROUND: Mesenteric ischemia and acidosis leading to intestinal ischemia has
      been observed during cardiopulmonary bypass (CPB) despite normal flow in the
      mesenteric vessels. The aim of this study was to assess mesenteric endothelium
      dependent reactivity and vasoconstrictor responses of small mesenteric arteries
      in a rat model of CPB without aortic cross-clamping. METHODS: After femoral
      cannulation a partial 90 minutes CPB was performed with hemodynamics and blood
      gas parameters monitoring. Blood samples and segments of small mesenteric
      arteries were obtained in rats sacrificed 2.5 hours (CPBH2.5) or 6 hours (CPBH6)
      after femoral cannulation. Sham surgery (sham H2.5, sham H6) was performed with
      femoral cannulation only. Segments of small mesenteric arteries were placed in a
      myograph in order to assess the contractile response to phenylephrine (with or
      without NO synthase inhibitor) or the endothelium-dependent relaxation to
      acetylcholine. Systemic inflammation was evaluated by measuring plasma
      concentrations of TNFalpha. Pulmonary and intestinal infiltration of activated
      leukocytes was assessed by immunohistochemistry. RESULTS: CPB induced increased
      contractile response to phenylephrine which persisted after blockade of NO
      synthesis as well as transient impairment of endothelium-dependent relaxations.
      CPB also led to early and marked release of TNFalpha. CONCLUSIONS: CPB was
      responsible for mesenteric endothelial dysfunction and direct increase in the
      contractile response to alpha1-adrenergic agonist with increased systemic
      inflammatory response. This phenomenon might contribute to an increase in the
      risk of mesenteric ischemic events during cardiac surgery especially when
      vasopressor agents are used.

PMID- 15172284
TI  - Surgical patch closure of atrial septal defects.
AB  - BACKGROUND: Development of nonsurgical techniques for closure of atrial septal
      defects (ASD) has prompted reevaluation of current surgical outcomes with an
      emphasis on less invasive methods. METHODS: This retrospective review is based on
      a single surgeon's experience between July 1, 1988 and December 21, 2002 with 176
      consecutive adult (n = 47) and pediatric (n = 129) surgeries, in which ASD was
      the primary anatomical diagnosis to ascertain current optimal methods and
      outcomes expected for surgical closure. Patch closure with pericardium was used
      in all cases. Surgical methods encompassed three phases. The first phase was
      defined by traditional sternotomy; the second phase involved a series of
      technical modifications to shorten incisions and reduce surgical trauma; the
      third phase consisted of standardized less invasive techniques based upon age and
      gender with "bikini line" incisions for adult females, limited median sternotomy
      for adult males, and mini-median sternotomy for children. All patients underwent
      echocardiography to assess ASD closure. RESULTS: There were no deaths. The most
      frequent perioperative complications were atrial fibrillation (adult 10%,
      pediatric 1.2%) and post pericardiotomy syndrome (adult 2%, pediatric 4.7%). All
      patients had secure and complete closure of ASDs with no residual shunts (trivial
      or otherwise) documented by echocardiography. No less invasive procedures
      required conversion. CONCLUSIONS: Surgical technique evolved from standard
      sternotomy to limited access incisions using modified cannulation techniques and
      incision locations determined by age and gender of the patient without
      deterioration in outcome quality. Both standard and less invasive surgical
      methods can achieve secure closure of the septum with biological patches, which
      are incorporated into the tissue structure of the heart and which are free from
      materials-related failure modes. Patient satisfaction is enhanced by utilizing
      the least invasive, least traumatic, and most cosmetically appealing techniques
      for access and cardiopulmonary bypass.

PMID- 15172286
TI  - Right ventricular outflow tract reconstruction with the Contegra bovine jugular
      vein conduit: a word of caution.
AB  - BACKGROUND: Since introduction in 1999, pulmonary valve replacement in pediatric
      patients with the Contegra conduit (Medtronic Inc, Minneapolis, MN) has gained
      widespread application with increasing enthusiasm. However, unexpected graft
      related adverse effects may occur. METHODS: Between April 2001 and December 2002,
      29 patients (20 male; mean age, 3.39 +/- 3.66 years; range, 0.01 to 13.0 years;
      mean weight, 11.62 +/- 8.73 kg) underwent right ventricular outflow tract
      reconstruction with the Contegra conduit. Seventeen patients underwent primary
      repair, 8 had prior homografts, and 4 had other previous operations. RESULTS:
      There were no deaths. Three early graft related complications were observed. In
      two infants (age, 1.8 and 3.5 months; weight, 3.6 and 3.8 kg, respectively)
      thrombus formation at the conduit valve was detected 2 weeks postoperatively.
      Under anticoagulation with low-molecular-weight heparin, thrombi resolved
      completely in both patients. One patient (4.5 months, 4.43 kg) developed severe
      regurgitation due to a fibrous layer covering the inner conduit wall and required
      conduit exchange 3 weeks postoperatively. After a mean follow-up time of 10.2 +/-
      6.4 months all patients are in good clinical condition. However, one patient with
      systemic right ventricular pressure developed pseudoaneurysm at both graft
      insertion sites and is scheduled for reoperation. Two other patients underwent
      balloon dilation. Freedom from reoperation and intervention at 1 year is 89.4%.
      With regard to regurgitation and conduit stenosis all other conduits perform
      well. CONCLUSIONS: Contegra conduits are an alternative to homografts for right
      ventricular outflow tract reconstruction. However, there is a risk of thrombus
      formation in small infants so that prophylactic anticoagulation may be necessary.
      Patients with systemic right ventricular pressure require close observation as
      pseudoaneurysm formation has been observed.

PMID- 15172287
TI  - Left atrioventricular valve regurgitation after repair of incomplete
      atrioventricular septal defect.
AB  - BACKGROUND: Excellent surgical results have been reported for repair of
      incomplete atrioventricular septal defect; however, left atrioventricular valve
      regurgitation (ltAVVR) is a major cause of late morbidity. We reviewed our entire
      experience with incomplete atrioventricular septal defect in order to investigate
      long-term results of ltAVVR after repair and determine the factors influencing
      the progression of ltAVVR in late follow-up. METHODS: Between 1983 and 2002, 61
      patients underwent surgical repair of incomplete atrioventricular septal defect,
      including 7 patients with intermediate forms. The age of operation ranged from 1
      month to 62 years old (median 5.3 years old). Thirteen patients were less than 2
      years old, including 7 infants, while there were 15 adult patients. All patients
      underwent patch closure of the ostium primum defect. Before 1995, the cleft was
      left open in 7 patients and partial closure of the cleft was done in 41 patients,
      whereas complete closure of the cleft was performed in 9 patients since 1996.
      Preoperative and postoperative ltAVVR at hospital discharge and late follow-up
      were graded 0-IV by echographic evaluation. RESULTS: There was 1 early death and
      4 late deaths with a 91% 10-year actuarial survival rate. Preoperative ltAVVR
      grade was I in 25 patients, II in 31 patients, III in 4 patients, and IV in 1
      patient. Postoperatively, ltAVVR deteriorated in 3 patients. Left AVVR decreased
      in 21 patients, whereas in 37 patients it remained the same at hospital
      discharge. Consequently, ltAVVR remained grade II in 18 patients, grade III in 2,
      and there was no patient with grade IV. During the long-term follow-up, 24
      patients were noted to have increased ltAVVR, including grade III in 8 patients
      and grade IV in 4. Reoperations for ltAVVR were required in 5 patients (8.3% of
      hospital survivors); valve replacement in 3 patients and valve repair in 2.
      Actuarial freedom from reoperation for ltAVVR was 91% at 10 years, whereas
      actuarial freedom from postoperative ltAVVR grade III or more was 89% at 5 years
      and 78% at 10 years. Multivariate analysis indicated that postoperative ltAVVR
      grade II or more at hospital discharge (p = 0.0032, odds ratio = 7.41, 95%CI:
      1.95-28.10) was the only independent variable related to late ltAVVR, whereas age
      at operation, preoperative grade of ltAVVR, and the method of cleft repair were
      not significant risk factors. CONCLUSIONS: Left AVVR is still a significant risk
      in long-term follow-up. Because the postoperative grade of ltAVVR is the only
      independent risk factor for late ltAVVR, more efforts should be focused on left
      atrioventricular valve repair so as to minimize residual regurgitation, even mild
      regurgitation.

PMID- 15172288
TI  - Congenitally corrected transposition: size of the pulmonary trunk and septal
      malalignment.
AB  - BACKGROUND: In hearts with congenitally corrected transposition of the great
      arteries, the atrial and ventricular septums are usually malaligned. This is
      associated with an abnormal location of the atrioventricular conduction system.
      However, well-aligned septums and normally positioned atrioventricular conduction
      tissues have been found in a few cases, some of which also happened to have a
      small or atretic pulmonary trunk. Our aim was to determine whether septal
      alignment could be predicted on the basis of the size of the pulmonary trunk.
      Potentially this could provide a guide to the disposition of the atrioventricular
      conduction tissues. METHODS: We examined 14 hearts. In all cases there was usual
      atrial arrangement. We carried out histologic examination of the sites of the
      atrioventricular conduction tissues in 1 heart. RESULTS: We found a statistically
      significant correlation between the size of the pulmonary trunk and the degree of
      septal malalignment. In the presence of a small or atretic pulmonary trunk, the
      septums were well aligned. Our histologic study of one such specimen revealed
      dual atrioventricular nodes connecting to a sling of conduction tissue. This
      suggests that presence of a postero-inferiorly situated atrioventricular
      conduction bundle in addition to an anteriorly located bundle may be anticipated
      when the septums are well aligned. CONCLUSIONS: The presence of a small or
      atretic pulmonary trunk in congenitally corrected transposition of the great
      arteries is associated with good septal alignment. This should alert the surgeon
      to the possibility of a slinglike arrangement of the atrioventricular conduction
      system.

PMID- 15172289
TI  - Posterior annular plication: tricuspid valve repair in Ebstein's anomaly.
AB  - BACKGROUND: Nonneonatal Ebstein's anomaly is a rare congenital anomaly for which
      numerous operative techniques have been described to repair the aberrant
      tricuspid valve, exclude the atrialized right ventricle, and address right heart
      dysfunction. We reviewed short-term outcomes in surgical patients treated by a
      simplified operative technique. METHODS: Our operative approach to Ebstein's
      anomaly is approximation of the anteroposterior commissure to the remnant septal
      leaflet with closure of the cul-de-sac longitudinally. Plication of the
      atrialized right ventricle (1 patient) and a bidirectional cavopulmonary
      connection (2 patients) were performed only if necessary. All patients were
      followed postoperatively by their cardiac surgeon and cardiologist. RESULTS:
      Seven patients with a mean age of 39 years (range, 3.6 to 63.8 years) underwent
      repair. Preoperatively all patients had 4+ tricuspid valve regurgitation and were
      New York Heart Association class III. Mean postoperative hospital stay was 7 +/-
      2 days (range, 4 to 11 days). Mean follow-up is 42 +/- 18 months (range, 7 to 58
      months). At last follow-up 5 patients are New York Heart Association class I and
      average tricuspid valve regurgitation is mild. CONCLUSIONS: Plication of the
      posterior annulus without plication of the atrialized right ventricle, resiting
      the tricuspid valve, or performing prophylactic cavopulmonary connection appears
      to be a reasonable operative approach to nonneonatal Ebstein's anomaly. Long-term
      follow-up of this cohort is necessary to determine the durability of such a
      surgical approach.

PMID- 15172290
TI  - Clinical experience with the mini-extracorporeal circulation system: an evolution
      or a revolution?
AB  - PURPOSE: We studied a cohort of 150 patients operated on with a new
      cardiopulmonary bypass (CPB) system. This is the mini-extracorporeal circulation
      (MECC) system. DESCRIPTION: The MECC is a fully heparin coated closed-loop CPB
      system that includes a centrifugal pump and has a priming volume of 450 mL.
      Between March 2001 and September 2002, 150 consecutive patients were operated on
      using the mini-CPB (MECC) method. This includes 105 coronary artery bypass graft
      and 45 aortic valve replacement patients. The median age was 66.7 +/- 10.7 years
      with a gender ratio of 3.27 males to 1 female. EVALUATION: The 30-day operative
      mortality was 1.3%. The hemoglobin concentration was stable and perioperative
      transfusion was needed in only 6% of all patients. The renal and neuropsychiatric
      complications were less than 1%. CONCLUSIONS: In our experience, the MECC system
      is a reliable new concept for CPB with good clinical results.

PMID- 15172294
TI  - Single-stage repair of tetralogy of Fallot with pseudoaneurysm: a unique
      approach.
AB  - Pseudoaneurysm is a potentially lethal complication after modified Blalock
      Taussig shunt. This report describes a frequently misdiagnosed clinical
      presentation along with noninvasive diagnosis of pseudoaneurysm after a modified
      Blalock-Taussig shunt. We report a novel single-stage surgical management of the
      pseudoaneurysm with concomitant complete repair of tetralogy of Fallot.

PMID- 15172292
TI  - Bovine glue (BioGlue) is catabolized by enzymatic reaction in the vascular dog
      model.
AB  - PURPOSE: The aim of the study is to explore the feasibility, patency, and
      histologic changes of a sutureless vascular anastomotic technique using
      biological glue as sole fixation method. DESCRIPTION: Eight mongrel dogs (+/-15
      kg) underwent direct reanastomosis of their transsected iliac arteries. Both ends
      were placed on a 5-mm balloon and the anastomosis was secured with biological
      glue (BioGlue, Cryolife, Kennesaw, GA). No intravascular suture material was
      used. All survivors were angiographically controlled for patency after 6 weeks
      and 3 months. Then the animals were euthanized and tissues were obtained for
      histologic and pathologic examination by light and electron microscopy.
      EVALUATION: All procedures were successful except for 1 animal that died of
      uncontrollable bleeding at the anastomotic site. All first-time angiographically
      controlled grafts except three were patent. One animal showed manifest signs of
      fungal infection. Histology detected early granulocyte infiltration with an
      important enzymatic reaction adjacent to the surface of glue. Later on, the glue
      gradually regressed to disappear completely. Fibroblastic neointimal lining was
      noticed in most of the anastomoses, with some marked differences in the
      endothelium compared with normal. CONCLUSIONS: Good permeability (57%) was
      observed in this new sutureless anastomotic technique in the canine model. In
      contrast to previous reported studies we noticed a clear enzymatic breakdown of
      the glue before total disappearance. It is not yet known to what extend use of
      the bovine glue was responsible for this phenomenon.

PMID- 15172296
TI  - Off-pump coronary artery bypass in patients with Takayasu's disease.
AB  - We report 2 patients with ostial stenoses of coronary arteries and heavy aortic
      calcification caused by Takayasu's disease in which severe angina was
      successfully relieved by off-pump coronary artery bypass grafting. In one case,
      visceral arteries such as the right gastroepiploic artery, the superior
      mesenteric artery, and the splenic artery were used as proximal blood sources of
      saphenous vein grafts. In another case, an aortic connector system was employed
      for proximal anastomoses of saphenous vein grafts. The use of off-pump coronary
      artery bypass grafting techniques should be considered in surgical coronary
      revascularization in patients with Takayasu's disease, thus leading to wide
      spreading indication for the surgery.

PMID- 15172295
TI  - A cluster of cases of Aspergillus endocarditis after cardiac surgery.
AB  - Aspergillus endocarditis is an ominous condition whose prevalence is increasing
      in the hospital population. Despite the life-threatening nature of the disease,
      detection of the source, establishment of the diagnosis, and treatment remain
      highly challenging. A cluster of three cases of Aspergillus endocarditis recently
      encountered at the Montreal Heart Institute are presented.

PMID- 15172297
TI  - Urgent off-pump coronary artery bypass grafting in a patient with HIV.
AB  - We report a case of successful urgent off-pump coronary artery bypass grafting
      (CABG) for unstable angina pectoris in a 54-year-old human with human
      immunodeficiency virus (HIV) infection. We studied the changes in CD4+ cells and
      HIV-RNA copy during the perioperative period. The results showed that off-pump
      CABG did not reduce the CD4+ cell count and did not affect the condition of HIV
      infection in this patient.

PMID- 15172298
TI  - Two cases of rounded atelectasis presenting after coronary artery surgery.
AB  - Rounded atelectasis developed in two patients after coronary artery bypass
      grafting. Although both lesions led to the suspicion of a primary pulmonary tumor
      on initial assessment, malignancy was excluded by biopsy and radiologic
      observation in the first patient and excision biopsy in the second.

PMID- 15172299
TI  - Marfan syndrome as a predisposing factor for traumatic aortic insufficiency.
AB  - Despite the increase in car accidents, aortic valve injury from blunt trauma
      remains rare. In one case, a 30-year-old Marfan male, who was under observation
      at our outpatient clinic, suffered from aortic regurgitation due to a tear in the
      left coronary cusp of a previously echocardiographically normal valve. Acute
      ventricular failure demanded surgical management within 3 days after an
      automobile accident. The case was successfully treated by replacement of the
      aortic valve with a no. 23 Sorin Bicarbon prosthesis. The patient fully recovered
      and experienced an uneventful 6 months of follow-up.

PMID- 15172301
TI  - Successful repair of aberrant right subclavian artery aneurysm combined with
      bicuspid aortic valve through a median sternotomy.
AB  - We report a case of a successfully repaired aberrant right subclavian artery
      aneurysm combined with bicuspid aortic valve using a multibranched vascular
      prosthesis. Approaching solely through a median sternotomy under cardiopulmonary
      bypass, hypothermic circulatory arrest, and selective cerebral perfusion, we
      performed a successful single-stage correction by aortic valve replacement,
      resection of aneurysm, and reconstruction of the right subclavian artery.

PMID- 15172300
TI  - Successful treatment of ascending aortic graft infection after operation for
      acute aortic dissection with peripheral malperfusion.
AB  - Mediastinitis with infection of an ascending aortic graft is hard to heal and is
      a highly fatal complication. We had a patient in whom mediastinitis with
      infection of such a graft as well as an ascending aorta-femoral artery bypass
      graft developed after the initial operation for type A aortic dissection
      accompanied by peripheral malperfusion. We treated it successfully by inserting a
      stent into the true lumen of the thoracoabdominal aorta and using a cryopreserved
      homograft to replace the infected ascending aortic fabric graft.

PMID- 15172302
TI  - Giant anastomotic pseudoaneurysm complicating aortic xenograft replacement.
AB  - A 74-year-old woman was referred for investigation of a 2-week history of
      progressive dyspnea. Her medical history included an aortic valve replacement
      with a stentless bioprosthesis followed 13 months later by the replacement of the
      aortic root with a porcine xenograft. Transesophageal echocardiography revealed a
      giant circular pseudoaneurysm of the aortic xenograft with compression of the
      prosthetic aortic valve and concomitant severe aortic regurgitation. Dehiscence
      of the proximal graft anastomosis was also diagnosed, and a possible distal
      anastomotic dehiscence was suspected. The latter turned out intraoperatively to
      be an almost complete dehiscence of the right coronary artery. The patient died
      intraoperatively.

PMID- 15172303
TI  - Simplified thoracic aortic aneurysm repair.
AB  - Descending thoracic and thoracoabdominal aortic operations still represent a
      challenge for the cardiovascular surgeon. In recent years, endovascular stent
      grafting has become a popular alternative to a conventional operation in selected
      patients, but is not always readily available or is technically contraindicated;
      also, long-term results are unknown. We describe a simplified surgical technique
      to secure a standard vascular prosthesis by performing a modified "elephant
      trunk" operation and discuss potential indications for its application.

PMID- 15172304
TI  - Human papillomavirus and squamous cell carcinoma in a solitary tracheal
      papilloma.
AB  - We report the case of a 52-year-old woman suffering from breathlessness on
      exertion. A chest radiograph identified a lesion in the intrathoracic trachea. A
      tumor 0.4 x 0.5 x 0.7 cm in size causing an approximately 80% reduction in the
      cross-sectional area of the trachea 3 cm above the carina was removed, and
      histology showed moderately differentiated squamous cell carcinoma. Intrathoracic
      resection of the tumor and anastomosis was performed through a right lateral
      thoracotomy. The final histology examination showed atypical papilloma.
      Polymerase chain reaction-restriction fragment length polymorphism confirmed
      human papillomavirus-6b in the tumor. The patient remained well 18 months after
      surgical intervention without recurrence.

PMID- 15172305
TI  - Extralobar pulmonary sequestration simulates posterior neurogenic tumor.
AB  - We report a case of 19-year-old asymptomatic man with posterior mediastinal mass
      thought to be of neurogenic origin on computed tomography scan. During video
      assisted thoracic surgery the mass appeared to be an extralobar pulmonary
      sequestration. Surgery was straightforward by division of vascular pedicle.
      Histopathology confirmed diagnosis.

PMID- 15172306
TI  - Pulsating thoracic tumor caused by extragenital endometriosis in a patient with
      Noonan syndrome.
AB  - We present the case of a 36-year-old woman with Noonan syndrome and congenital
      heart disease in whom extragenital endometriosis caused an extraordinarily large
      jelly-like paracardiac and abdominal mass. Protrusion through an intercostal
      space caused a pulsating subcutaneous tumor on the left lateral thoracic wall.
      The patient never complained of menstruation-related pain. Histology obtained
      during several prior surgical interventions had been inconclusive. Thus
      definitive diagnosis was delayed for years. A literature review revealed no known
      association between Noonan syndrome and endometriosis.

PMID- 15172307
TI  - Primary mediastinal hyalinizing spindle cell tumor with giant rosettes.
AB  - We describe herein a unique case of primary mediastinal hyalinizing spindle cell
      tumor with giant rosettes that occurred in a 41-year-old man. The clinical and
      pathologic features together with a brief review of the literature are reported.

PMID- 15172308
TI  - Noninvasive thymoma in the middle mediastinum.
AB  - We present a rare case of thymoma that developed entirely in the middle
      mediastinum. A 60-year-old woman was referred to our hospital with a mediastinal
      mass. The mass was located in the visceral compartment of Shields' mediastinal
      classification. Intraoperative pathologic evaluation revealed a thymoma,
      whereupon total thymectomy was performed. The postoperative course was
      uncomplicated and the patient received no postoperative adjuvant radiotherapy.

PMID- 15172309
TI  - Resection of primary pleural pedunculate hemangiopericytoma.
AB  - We are reporting an uncommon clinical case of primary pleural hemangiopericytoma,
      of which only a few reports have been published in the literature to date. A 40
      year-old woman was treated by complete surgical resection of the tumor. No
      recurrence or metastasis was detected during follow-up at 12 months after the
      resection. The postoperative pathologic examination confirmed the diagnosis of
      primary pleural hemangiopericytoma. Details of the clinical and radiographic
      feature are presented.

PMID- 15172310
TI  - Management of newborn lymphangiectasia and chylothorax after cardiac surgery with
      octreotide infusion.
AB  - Postoperative chylothorax compromises nutrition, immune function, coagulation,
      and fluid status. We report rapid short-term suppression of chylothorax by
      octreotide in an infant after surgery for complex congenital heart disease
      complicated by lymphangiectasia.

PMID- 15172311
TI  - Octreotide and low-fat breast milk in postoperative chylothorax.
AB  - Chylothorax is a rare complication following cavo-pulmonary connection and can
      lead to significant morbidity in infants and young children. We report here the
      case of a 3-month-old infant who underwent bilateral cavo-pulmonary connections,
      and developed severe chylothorax refractory to the usual conservative and
      surgical treatments. His chylothorax resolved after using a combination of
      parenteral octreotide (Sandostatin, Novartis Pharmaceuticals, East Hanover, NJ)
      and low-fat breast milk.

PMID- 15172312
TI  - Diagnosis and management of aortoesophageal fistula caused by a foreign body.
AB  - Aortoesophageal fistula is a rare cause of gastrointestinal hemorrhage often
      resulting in mortality. A case of aortoesophageal fistula caused by a swallowed
      fish bone leading to respiratory arrest is reported. The clinical presentation
      was unusual. The successful treatment required the use of hypothermic circulatory
      arrest.

PMID- 15172313
TI  - Chronic retained foreign bodies in the esophagus.
AB  - Two cases of esophageal perforations consequent upon chronic retained foreign
      bodies are presented. In both patients a mediastinal mass associated with the
      foreign body was noted on chest radiography. Retrieval of the foreign bodies,
      although feasible by esophagoscopy in 1 patient, was unsuccessful in the second
      patient, thus necessitating thoracotomy.

PMID- 15172314
TI  - Stenosed mammary artery graft depicted by multidetector computed tomography.

PMID- 15172315
TI  - Is echocardiography alone diagnostic of a cardiac mass before surgical
      intervention?

PMID- 15172316
TI  - Ross-Konno procedure in neonates: report of three patients.
AB  - The Ross-Konno procedure, applied to neonates with severe left ventricular
      outflow tract (LVOT) obstruction, offers a satisfactory solution in fully
      releasing the LVOT gradient, and in replacing the aortic valve with a pulmonary
      autograft with an excellent growth potential. We reported on three recent
      neonatal cases.

PMID- 15172317
TI  - Modified cavoatriotomy for combined PAPVC repair and maze procedure.
AB  - In patients with partial anomalous pulmonary venous connection (PAPVC) to the
      superior cavoatrial junction, the standard right-sided left atriotomy does not
      allow sufficient access to the mitral valve and the left atrium. And the injury
      and traction of the sinus node and sinus node artery should be avoided for
      prevention of the cardiac rhythm disturbance after operation. We herein report a
      useful approach to repair the sinus venosus atrial septal defect with PAPVC of
      the right pulmonary veins to the superior cavoatrial junction in patients also
      requiring mitral valve replacement and the maze procedure.

PMID- 15172318
TI  - Ventricular septal defect closure in tetralogy of Fallot: the aortic rule.
AB  - Ventricular septal defect (VSD) closure is an important part of the surgical
      repair of tetralogy of Fallot and related anomalies. Visual appreciation of the
      VSD size (either transinfundibular or transatrial) can be misleading. My
      colleagues and I describe a simple and precise way to predict the size and shape
      of the VSD patch before extracorporeal circulation: the patch should be circular
      with a diameter identical to that of the mid ascending aorta.

PMID- 15172319
TI  - Complete port-accessed lobectomy by the muscle-sparing method.
AB  - We report the case of a 53-year-old woman who underwent complete port-accessed
      middle lobectomy by a new technique that preserves all muscles, including the
      extracostal and intercostal muscles. The operation was performed by using only
      thoracovideoscopy, and the resected lobe was withdrawn in a pouch through a
      subxiphoid incision through the substernal route. This complete port-accessed
      lobectomy is a new technique and is thought to be less invasive than video
      assisted lobectomy with minithoracotomy.

PMID- 15172320
TI  - Cardiac surgery risk modeling for mortality: a review of current practice and
      suggestions for improvement.
AB  - Risk models play a vital role in monitoring health care performances. Despite
      extensive research and widespread use of risk models in cardiac surgery, there
      are methodologic problems. We reviewed the methodology used for risk models for
      short-term mortality. The findings suggest that many risk models are developed in
      an ad hoc manner. Important aspects such as selection of risk factors, handling
      of missing values, and size of the data used for model development are not dealt
      with adequately. Methodologic details presented in publications are often sparse
      and unclear. Model development and validation processes are not always linked to
      the clinical aim of the model, which may affect their clinical validity. We make
      some suggestions in this review for improvement in methodology and reporting.

PMID- 15172321
TI  - Should the internal thoracic artery be skeletonized?
AB  - Traditionally, the internal thoracic artery is harvested as a pedicle. In
      contemporary cardiac surgical practice, however, certain surgeons practice the
      internal thoracic artery-skeletonization technique. A systematic review of
      clinical studies reporting on the use of skeletonized internal thoracic arteries
      (SKT-ITA) has not yet been performed. The primary aim of this review article is
      to examine comprehensively the entire body of evidence regarding the use of SKT
      ITA. In particular, we aimed to analyze the effects of skeletonization on sternal
      blood supply, wall damage and blood flow in the harvested vessel, postoperative
      graft patency, and clinical outcome. Advantages and disadvantages of the
      skeletonization technique are highlighted and discussed.

PMID- 15172322
TI  - Atrial switch operation: past, present, and future.
AB  - The atrial switch operation was developed by the efforts of many surgeons, with
      the most notable contributions made by Blalock, Hanlon, Albert, Baffes, Senning,
      and Mustard. The atrial switch operation was the first definitive repair for
      patients with transposition of great arteries and produced good results. Although
      it is rarely performed today, the atrial switch is not merely of historical
      interest as there remain a few important indications for this operation. A
      thorough understanding of the atrial switch is still required for surgeons
      dealing with complex congenital cardiac malformations. Herein we summarize the
      history, review long-term results, and discuss the future of the atrial switch
      operation.

PMID- 15172323
TI  - Early and late arrhythmias in patients in preoperative sinus rhythm after
      superior septal approach.

PMID- 15172325
TI  - Shallow stitch close to the rim of the ventricular septal defect after pulmonary
      artery banding.

PMID- 15172327
TI  - Early Blalock-Taussig shunt thrombosis in a neonate with protein C deficiency.

PMID- 15172328
TI  - Lower sternal reinforcement to improve median sternotomy closure.

PMID- 15172330
TI  - Use of autologous arterial patches for tracheal reconstruction in young infants.

PMID- 15172332
TI  - Ultrasonic dissectors for neurogenic tumors of the superior sulcus.

PMID- 15172334
TI  - Esophageal perforations.

PMID- 15172335
TI  - Making our hospitals healthier places.

PMID- 15172336
TI  - Global warming and malaria: a call for accuracy.

PMID- 15172339
TI  - Giving identity to the faceless threat of antibiotic resistance.

PMID- 15172337
TI  - Aluminium-containing DTP vaccines.

PMID- 15172342
TI  - PCR-based diagnostics for infectious diseases: uses, limitations, and future
      applications in acute-care settings.
AB  - Molecular diagnostics are revolutionising the clinical practice of infectious
      disease. Their effects will be significant in acute-care settings where timely
      and accurate diagnostic tools are critical for patient treatment decisions and
      outcomes. PCR is the most well-developed molecular technique up to now, and has a
      wide range of already fulfilled, and potential, clinical applications, including
      specific or broad-spectrum pathogen detection, evaluation of emerging novel
      infections, surveillance, early detection of biothreat agents, and antimicrobial
      resistance profiling. PCR-based methods may also be cost effective relative to
      traditional testing procedures. Further advancement of technology is needed to
      improve automation, optimise detection sensitivity and specificity, and expand
      the capacity to detect multiple targets simultaneously (multiplexing). This
      review provides an up-to-date look at the general principles, diagnostic value,
      and limitations of the most current PCR-based platforms as they evolve from bench
      to bedside.

PMID- 15172343
TI  - Detection of circulating galactomannan for the diagnosis and management of
      invasive aspergillosis.
AB  - The availability of the Platelia Aspergillus, a sandwich ELISA kit that detects
      circulating galactomannan, has been a major advance for managing patients at risk
      for invasive aspergillosis because of the early detection of the antigen. The
      assay is now widely used throughout the world, including the USA. Although
      initial studies that assessed the performance characteristics of this assay
      reported high sensitivity and specificity, more recent studies show significant
      variation in performance. The causes of this variability are multifactorial and,
      in large part, cannot be explained because there is insufficient understanding of
      the kinetics of galactomannan in vivo. We explored some of the factors that
      affect the release of the aspergillus antigen that bears the epitope that reacts
      with the monoclonal antibody used in the ELISA, its leakage from the site of
      infection into the blood, and its binding to substances present in the blood.
      Factors that affect the detection of antigen in blood are also discussed, most
      notably the pretreatment procedure aimed at liberating the antigen from immune
      complexes. Understanding the biology of galactomannan release by aspergillus will
      greatly enhance our understanding of the kinetics of this and other surrogate
      markers and allow their optimum use in the management of invasive aspergillosis.

PMID- 15172341
TI  - The global distribution and population at risk of malaria: past, present, and
      future.
AB  - The aim of this review was to use geographic information systems in combination
      with historical maps to quantify the anthropogenic impact on the distribution of
      malaria in the 20th century. The nature of the cartographic record enabled global
      and regional patterns in the spatial limits of malaria to be investigated at six
      intervals between 1900 and 2002. Contemporaneous population surfaces also allowed
      changes in the numbers of people living in areas of malaria risk to be
      quantified. These data showed that during the past century, despite human
      activities reducing by half the land area supporting malaria, demographic changes
      resulted in a 2 billion increase in the total population exposed to malaria risk.
      Furthermore, stratifying the present day malaria extent by endemicity class and
      examining regional differences highlighted that nearly 1 billion people are
      exposed to hypoendemic and mesoendemic malaria in southeast Asia. We further
      concluded that some distortion in estimates of the regional distribution of
      malaria burden could have resulted from different methods used to calculate
      burden in Africa. Crude estimates of the national prevalence of Plasmodium
      falciparum infection based on endemicity maps corroborate these assertions.
      Finally, population projections for 2010 were used to investigate the potential
      effect of future demographic changes. These indicated that although population
      growth will not substantially change the regional distribution of people at
      malaria risk, around 400 million births will occur within the boundary of current
      distribution of malaria by 2010: the date by which the Roll Back Malaria
      initiative is challenged to halve the world's malaria burden.

PMID- 15172344
TI  - Kingella kingae: from medical rarity to an emerging paediatric pathogen.
AB  - In recent years, Kingella kingae has emerged as an important cause of invasive
      infections in young children, especially septic arthritis, osteomyelitis,
      spondylodiscitis, bacteraemia, and endocarditis, and less frequently lower
      respiratory tract infections and meningitis. The organism is part of the
      pharyngeal flora of young children and is transmitted from child-to-child. The
      clinical presentation of invasive K kingae disease is often subtle and laboratory
      tests are frequently normal. A substantial fraction of children with invasive K
      kingae infections have a recent history of stomatitis or symptoms of upper
      respiratory-tract infection. The organism is susceptible to a wide array of
      antibiotics that are usually given empirically to young children including beta
      lactams, and with the exception of cases of endocarditis, the disease runs a
      benign clinical course. Although isolation and recognition of the organism is not
      difficult, clinicians and microbiologists should be aware of its fastidious
      nature. To optimise the recovery of K kingae, inoculation of synovial fluid
      specimens into blood culture vials is strongly recommended.

PMID- 15172345
TI  - Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part
      II: Determinants operating at environmental and institutional level.
AB  - This review summarises a wide range of evidence about environmental and
      institutional factors that influence vulnerability to malaria, tuberculosis, and
      HIV infection. By combining this information with that obtained on factors
      operating at individual, household, and community level, we have identified
      potential common strategies for improving resilience to all three diseases
      simultaneously. These strategies depend on collaborations with non-health sectors
      and include progress in rapid access to funds, provision of education about
      disease transmission and management, reduction of the burden on carers
      (predominantly women), and improvement in the quality of health services.

PMID- 15172346
TI  - John C Reeder--Director of the Papua New Guinea Institute of Medical Research.
      Interview by Pam Das.

PMID- 15172350
TI  - Life after death.

PMID- 15172351
TI  - Diagnostic imaging still threatened by shortages.

PMID- 15172352
TI  - Intraoperative radiotherapy: the debate continues.

PMID- 15172353
TI  - Intraoperative radiotherapy: the debate continues.

PMID- 15172354
TI  - Non-Hodgkin lymphoma: an update.
AB  - Non-Hodgkin lymphoma (NHL) causes many deaths worldwide, and its incidence is
      increasing. Although some cases are associated with immunodeficiency,
      autoimmunity, or viral infections, in most cases the causes of NHL are not
      understood. However, there have been some important advances in our understanding
      of the development of healthy lymphocytes and the pathogenesis of NHL over the
      past 10 years. These advances have been accompanied by an improvement in
      treatment for NHL. Before the late 1990s, the only treatment option available was
      cytotoxic chemotherapy. In the past 10 years, however, high-dose chemotherapy and
      autologous stem-cell reconstitution have become established parts of treatment
      for aggressive lymphoma. Furthermore, monoclonal antibodies have become another
      therapeutic option. Rituximab (an anti-CD20 monoclonal antibody) is the most
      advanced monoclonal antibody in clinical trials and has become part of standard
      treatment for some lymphomas. Rituximab, and many other monoclonal antibodies,
      continue to be assessed in clinical studies. Monoclonal antibodies can be used
      alone or in combination with standard-dose or high-dose chemotherapy, and they
      can also be conjugated to radionuclides to enhance cytotoxicity. Here, we review
      advances in the treatment of NHL that have occurred over the past 10 years.

PMID- 15172355
TI  - Expression of epidermal growth-factor receptor in lymphangiomatosis: a new
      therapeutic target?

PMID- 15172356
TI  - Defective core-apoptosis signalling in diffuse malignant pleural mesothelioma:
      opportunities for effective drug development.
AB  - Because of a lack of effective treatments, survival from diffuse pleural
      mesothelioma remains poor. Many people do not think that treatments for this
      disease are effective. The understanding of the biology of mesothelioma relevant
      to the apoptosis-resistant phenotype has been slow to advance. However, this is
      now changing, and strategies for rational therapeutic drug development are
      emerging that have the potential to change the natural history and improve
      survival in the increasing number of patients that will be diagnosed in the next
      two decades. This review discusses recent developments in apoptosis biology that
      are specific to mesothelioma and the therapeutic implications for this aggressive
      cancer.

PMID- 15172357
TI  - Genetic predisposition to testicular germ-cell tumours.
AB  - Testicular germ-cell tumours (TGCT) are the most common neoplasm in young men.
      Various studies have suggested the existence of an inherited predisposition to
      development of these tumours. Genome-wide screens subsequently provided evidence
      of a TGCT susceptibility gene on chromosome Xq27 (TGCT1) that might also
      predispose to cryptorchism. However, this putative gene has yet to be identified,
      and other TGCT susceptibility genes probably exist. Completion of the human gene
      map and advances in genetic research will facilitate further investigation of
      genetic predisposition to TGCT. Insight into inheritance of TGCT might lead to
      the identification of individuals at increased risk of developing the disorder,
      increase our understanding of the mutation pathways that lead to sporadic cases,
      and contribute to improvement in diagnosis and treatment. Clinicians should
      record the family history of cancer and urogenital differentiation defects in
      patients with TGCT.

PMID- 15172358
TI  - Systematic review of taxane-containing versus non-taxane-containing regimens for
      adjuvant and neoadjuvant treatment of early breast cancer.
AB  - The use of taxanes in early breast cancer is increasing. However, there are few
      mature studies of taxanes in this setting, and their role is uncertain. Our
      systematic review of randomised trials of adjuvant or neoadjuvant systemic
      therapy identified ten reported trials comparing a taxane-containing group with a
      non-taxane-containing control group in women with early breast cancer. Four of
      five neoadjuvant trials showed higher rates of complete response with taxanes,
      although differences were not significant. All five adjuvant trials showed
      improvements in disease-free survival with taxanes, and these improvements were
      significant in three trials and independent of oestrogen-receptor status. Two
      trials showed a significant improvement in overall survival. These results
      support the use of adjuvant taxanes in women with early breast cancer and
      involved lymph nodes. Longer follow-up of these trials and results from
      continuing trials are needed to clarify the best use of taxanes in early breast
      cancer.

PMID- 15172359
TI  - Nodal marginal-zone lymphoma associated with monoclonal light-chain and heavy
      chain deposition disease.

PMID- 15172360
TI  - From informed consent to shared consent: a developing process in paediatric
      oncology.
AB  - Little research has been done on consent in clinical management of cancer in
      children. Many parents think that the informed-consent process is helpful but
      often confusing; discussions regularly prove more helpful. It can be difficult
      for parents to understand the notion of randomisation, not to mention the request
      for consent to this procedure. In this essay, we discuss the clinical problems
      that arise in the informed-consent process for treatment and research in
      paediatric oncology and that need an understanding of bioethical issues and
      psychological principles. We suggest that the process of informed consent is
      managed as a negotiated shared-consent process, using the problem-based learning
      method as a guide. Our model provides appropriate and honest information to
      children and adolescents through easy-to-understand dialogues with the doctor and
      we propose that medical students and doctors receive specific skills instruction
      in communications, relational behaviour, and ethics.

PMID- 15172361
TI  - Ephemeral interactions.

PMID- 15172362
TI  - Integrating PACS into the virtual electronic medical record: the time is now.

PMID- 15172363
TI  - Performance of a single lookup table (LUT) for displaying chest CT images.
AB  - RATIONALE AND OBJECTIVES: To evaluate the ability to view mediastinal and lung
      information on one window setting by processing images with a bilinear lookup
      table (LUT). MATERIALS AND METHODS: Chest computed tomography (CT) studies were
      obtained from 32 consecutive adult patient studies, which included 7 iodine
      contrast studies. From each CT examination, four sections were selected
      containing the suprasternal notch, carina, right inferior pulmonary vein, and the
      dome of the lower hemidiaphragm. Each image was processed with a bilinear LUT in
      addition to the lung setting (window width 1500 and window level -500) and
      mediastinal setting (window width 450 and window level 50) normally used. Seven
      radiologists compared the quality of the bilinear LUT with the corresponding lung
      and mediastinum display settings. A five-point scale was used to assess image
      quality, with a score of 5 being equivalent to the corresponding lung (or
      mediastinum) display, 3 being acceptable, and 1 being unacceptable. RESULTS: The
      average score of the bilinear LUT for all images and readers was 3.90 +/- 0.93
      for lung information and 3.17 +/- 1.00 for mediastinum information. Use of the
      bilinear LUT resulted in unacceptable images in 0.3% cases for lung information
      and 5.9% for mediastinum information. Chest CT images that contained iodinated
      contrast resulted in a higher score than those obtained without contrast, but
      these differences did not achieve statistical significance. CONCLUSION: Use of a
      bilinear LUT has the potential to significantly improve operational efficiency
      with acceptable image quality for most chest CT images.

PMID- 15172364
TI  - Computerized scheme for automated detection of lung nodules in low-dose computed
      tomography images for lung cancer screening.
AB  - RATIONALE AND OBJECTIVES: A computerized scheme for automated detection of lung
      nodules in low-dose computed tomography images for lung cancer screening was
      developed. MATERIALS AND METHODS: Our scheme is based on a difference-image
      technique for enhancing the lung nodules and suppressing the majority of
      background normal structures. The difference image for each computed tomography
      image was obtained by subtracting the nodule-suppressed image processed with a
      ring average filter from the nodule-enhanced image with a matched filter. The
      initial nodule candidates were identified by applying a multiple-gray level
      thresholding technique to the difference image, where most nodules were well
      enhanced. A number of false-positives were removed first in entire lung regions
      and second in divided lung regions by use of the two rule-based schemes on the
      localized image features related to morphology and gray levels. Some of the
      remaining false-positives were eliminated by use of a multiple massive training
      artificial neural network trained for reduction of various types of false
      positives. This computerized scheme was applied to a confirmed cancer database of
      106 low-dose computed tomography scans with 109 cancer lesions for 73 patients
      obtained from a lung cancer screening program in Nagano, Japan. RESULTS: This
      computed-aided diagnosis scheme provided a sensitivity of 83% (91/109) for all
      cancers with 5.8 false-positives per scan, which included 84% (32/38) for missed
      cancers with 5.9 false-positives per scan. CONCLUSION: This computerized scheme
      may be useful for assisting radiologists in detecting lung cancers on low-dose
      computed tomography images for lung cancer screening.

PMID- 15172365
TI  - Oral manganese for liver imaging at three different field strengths.
AB  - RATIONALE AND OBJECTIVES: To study the magnetic resonance imaging signal
      intensity of the liver and gall bladder before and after ingestion of a new oral
      manganese containing contrast medium at three different field strengths.
      MATERIALS AND METHODS: Twelve healthy male volunteers (mean age, 24.9 years;
      range, 20-39 years) underwent abdominal magnetic resonance imaging (T(2)W COR,
      T(1)W COR, T(1)W TRA) at 0.23 T, 0.6 T, and 1.5 T before and after the contrast
      administration. The duration of fasting was identical before the two studies.
      Volunteers were randomized into two equal groups (n = 6) to ingest either half or
      full strength CMC-001 providing either 0.8 or 1.6.g MnCl(2) plus absorption
      promoters. The CMC-001 dose was dissolved in 400 mL water and ingested 2.5 hours
      before imaging. The resulting images were evaluated with regard to visualization
      of the liver and the gall bladder by three radiologists. The signal intensity of
      the liver was also measured. Blood and urine samples were collected before and
      after ingestion of CMC-001. RESULTS: The intake of CMC-001 caused a significant
      increase in the signal intensity of the liver at all three field strengths and at
      both dosages (up to 90%) on the T(1)W images. The internal structure of the liver
      was significantly better delineated. The bile in gall bladder was bright after
      ingestion of the low dose, but dark after the full dose. On the T(2)W images, CMC
      001 lowered the signal intensity of liver with up to 30%. CMC-001 had a slight
      metallic taste, but of no importance according to the volunteers. No systematic
      adverse reactions caused by the contrast medium were registered. No changes in
      the blood levels of various routine parameters were measured. CONCLUSION: It is
      possible to increase the signal intensity of the liver significantly by oral
      intake of essential nutritional elements including manganese. The imaging window
      is more than 2 hours.

PMID- 15172366
TI  - Volumetric model and human observer comparisons of tumor detection for whole-body
      positron emission tomography.
AB  - RATIONALE AND OBJECTIVES: The performances of model and human observers were
      compared for detecting and localizing tumors in whole-body positron emission
      tomography imaging. Volumetric implementations of model observers were used
      instead of standard planar implementations to reproduce the common practice of
      using volumetric image displays to assess whole-body positron emission tomography
      images. MATERIALS AND METHODS: Observer studies with simulated data were used to
      compare three different acquisition protocols for an average patient size.
      Multiple realizations of simulated whole-body data with multiple added 1-cm
      diameter spherical lesions (targets) per image volume for efficiency were used.
      The location and contrast ratio of the targets were chosen randomly within ranges
      determined by initial calibration studies. Human observer studies were performed
      using a volumetric image display routinely used in clinical practice, and human
      observer detection performance was quantified using an alternate free-response
      operating characteristic analysis. The human detection performances were compared
      with the performances of volumetric implementations of the non-prewhitening
      matched filter and the channelized hotelling observer and also to the target
      contrast measured in the reconstructed image. RESULTS: Human observer
      detectability was generally well described as a linear function of these three
      figures of merit for the detection task considered. The best correlations (r =
      0.96, rho = 0.98) were achieved with the channelized hotelling observer and non
      prewhitening matched filter model observers. CONCLUSION: The use of volumetric
      model observers provides a means for quantitative comparisons of different
      protocols and also provides a useful tool for the optimization of key parameters
      in whole-body positron emission tomography imaging.

PMID- 15172367
TI  - Multi-detector computed tomography and 3-dimensional imaging in a multi-vendor
      picture archiving and communications systems (PACS) environment.
AB  - RATIONALE AND OBJECTIVES: To show the impact of the introduction of multi
      detector computed tomography (CT) on radiologic workflow and to demonstrate how
      this reflects on picture archiving and communications systems (PACS)
      requirements. MATERIALS AND METHODS: Production measurements were obtained from
      different CT scanners (first two single-slice CT scanners; from December 2001
      single and 4-slice CT; from April 2002 single and 16-slice CT) in number of
      patients from the radiologic information system. Implications on our PACS were
      recorded in terms of images and studies stored. Furthermore, our PACS design was
      made so that optimal use of 3-dimensional imaging within the radiologic workflow
      was possible. Finally, the number of non-diagnosed studies were recorded every
      day since the start of the transition to a filmless radiology department.
      RESULTS: This PACS design achieved a high level of integration between simple
      viewing and advanced 3-dimensional imaging and is optimized for handling large
      amounts of data. Overall increase of patients scanned with CT from January 2002
      December 2003 was 54%. The number of series increased by 286% from December 2001
      April 2003 and by 130% from April 2002-December 2003. From January 2002-February
      2003, the number of images per patient increased from 175 to 450 (157%). Non
      diagnosed studies decreased from about 100-120 before to practically zero after
      PACS implementation. CONCLUSION: PACS significantly increases productivity
      because of availability of the images and elimination of certain manual tasks.
      These results show that although the amount of examinations increases
      significantly with the introduction of MDCT, simultaneous introduction of PACS
      and filmless operation allows radiologists to handle the growth in workload.

PMID- 15172368
TI  - The integration of medical images with the electronic patient record and their
      web-based distribution.
AB  - Medical images are currently created digitally and stored in the radiology
      department's picture archiving and communication system. Reports are usually
      stored in the electronic patient record of other information systems, such as the
      radiology information system (RIS) and the hospital information system (HIS). But
      high-quality services can only be provided if electronic patient record data is
      integrated with digital images in picture archiving and communication systems.
      Clinicians should be able to access both systems' data in an integrated and
      consistent way as part of their regular working environment, whether HIS or RIS.
      Also, this system should allow for teleconferencing with other users, eg, for
      consultation with a specialist in the radiology department. This article
      describes a web-based solution that integrates the digital images of picture
      archiving and communication systems with electronic patient record/HIS/RIS data
      and has built-in teleconferencing functionality. This integration has been
      successfully tested using three different commercial RIS and HIS products.

PMID- 15172369
TI  - Carbocyanine labeled LDL for optical imaging of tumors.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to define and
      characterize carbocyanine labeled low-density lipoprotein (LDL) to be used in the
      optical imaging of LDL receptor (LDLr)-overexpressing tumor models. MATERIALS AND
      METHODS: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)
      was used to label LDL (DiI-LDL). Scatchard plots were generated to determine the
      maximum binding capacity B(max) and dissociation constants K(D) of DiI-LDL in B16
      melanoma (B16) and hepatoblastoma G(2) (HepG(2)) cell lines. Selective uptake of
      DiI-LDL into both tumor cells and corresponding subcutaneous tumors in mice were
      demonstrated by confocal microscopy and three-dimensional Cryo-imaging,
      respectively. RESULTS: The labeling efficiency of DiI-LDL was 61 ng DiI/microg
      LDL protein (34 mol DiI/mol LDL protein). B(max) and K(D) for B16 cells were
      6.311 ng LDL/mg cell protein and 60.38 microg protein/mL (117 nM), respectively.
      B(max) and K(D) were 7.573 ng LDL/mg cell protein and 26.79 microg protein/mL (52
      nM) for HepG(2) cells, respectively. Confocal microscopic images showed specific
      uptake of DiI-LDL throughout the cytoplasm in the B16/HepG(2) cells. Cryo-imaging
      demonstrated preferential accumulations of DiI-LDL in the viable tumor regions of
      both B16 and HepG(2) tumors compared with their adjacent normal tissues and
      corresponding necrotic tumor regions. In addition, uptake of DiI-LDL by the
      HepG(2) tumor was much higher than that of the B16 tumor, consistent with the
      fact that the probe binding affinity for LDLrs of HepG(2) cells is 2.3 times that
      of B16 cells. CONCLUSION: This study suggested that carbocyanine labeled LDL
      could be used for optical imaging of tumors overexpressing LDLr.

PMID- 15172370
TI  - Computer-assisted detection of subcutaneous melanomas: feasibility assessment.
AB  - RATIONALE AND OBJECTIVES: Subcutaneous melanomas may be missed on computed
      tomography because of their peripheral location or perceived unimportance, yet
      they can have clinical significance. The use of a novel computer-assisted
      detection scheme to locate subcutaneous melanoma lesions in body CT images was
      investigated. MATERIALS AND METHODS: The detection software segments subcutaneous
      fat from the rest of the body and searches for soft tissue density lesions that
      match a size and shape constraint. Sensitivity and specificity of the proposed
      method was analyzed by comparing automated lesion detection results in eight
      patients with 118 subcutaneous melanomas with ground truth data derived from
      manual tracings of a trained observer. RESULTS: The sensitivity of subcutaneous
      melanoma detection was 86%. The false-positive rate was 3.1 per slice. Analysis
      of the false-positives showed that the most common cause was incorrect
      classification of muscle as a nodule. CONCLUSION: This study showed the
      feasibility of a fully automatic subcutaneous melanoma lesion detection system
      having good sensitivity. The false-positive rate was high, but avenues for
      further reduction were identified.

PMID- 15172371
TI  - A primer on molecular biology for imagers: IV. concepts and basic methods in
      molecular biology.

PMID- 15172372
TI  - Challenges in quantitative electron-beam computed tomography measurement of
      coronary artery calcium:; Image artifacts, scan protocols, and coronary artery
      calcium scores(1).

PMID- 15172373
TI  - The effect of routine use of a computer-aided detection system on the practice of
      breast imagers: a subjective assessment.

PMID- 15172374
TI  - Trends in on-call workload in an academic medical center radiology department
      1998-2002.

PMID- 15172376
TI  - Reporting instruction for radiology residents.

PMID- 15172381
TI  - Normal MR imaging anatomy of the elbow.
AB  - The functional complexity achieved at the elbow is a reflection of the
      sophisticated architecture that embodies this articulation. In addition to
      challenging anatomic relationships to conceptualize, there are many anatomic
      variations that exist in the osseous, capsular, and muscular structures. This
      article offers a detailed description of the structural and imaging anatomy of
      the elbow, information that establishes the foundation of imaging interpretation
      of internal derangements.

PMID- 15172382
TI  - Normal MR imaging anatomy of the wrist and hand.
AB  - MR imaging is widely used in the evaluation of internal derangement of joints. In
      the past, the use of hand and wrist MR imaging lagged behind imaging of larger
      joints, largely because of technical limitations of spatial resolution and signal
      to-noise ratio when imaging the small anatomic structures. However, with recent
      technical advances in extremity coil design, MR imaging has provided us with new
      insights into the difficult anatomy of the wrist by allowing improved
      visualization of the relationship of the muscles, ligaments, tendons, and bone.
      Although the limits of spatial resolution afforded by specialized surface coils
      and signal processing methods may not have yet been completely realized at 1.5
      Tesla, the potential for significant improvements in hand and wrist imaging is
      likely to rest with the advent of higher strength magnets.

PMID- 15172383
TI  - MR imaging of ligament injuries to the elbow.
AB  - MR imaging is a highly valuable tool in the evaluation of ligamentous injuries of
      the elbow. Proper coil selection, patient positioning, and pulse sequence
      parameters are essential for optimization of image quality. Clinical evaluation
      of ligamentous injuries is often difficult and visualization at surgery may be
      limited. MR imaging can demonstrate not only ligamentous pathology but
      abnormalities in the adjacent osseous and soft tissue structures, making it an
      important aid to clinical management. In skeletally immature patients, MR imaging
      can demonstrate injury not only to the ligaments but to the physes and apophyses,
      making it useful in the evaluation of the pediatric elbow.

PMID- 15172384
TI  - MR imaging of tendon abnormalities of the elbow.
AB  - Tendon injuries about the elbow are among the most commonly encountered pathology
      in this articulation. These injuries are often the result of chronic repetitive
      microtrauma but can be seen in the setting of acute trauma. This article focuses
      on the imaging diagnosis of tendon pathology in the elbow and the associated
      findings that can be seen with tendon injury. A detailed understanding of common
      pathology and patterns of injury can facilitate the ease and accuracy of imaging
      diagnosis.

PMID- 15172385
TI  - MR imaging of entrapment neuropathies at the elbow.
AB  - MR imaging has a valuable role in the evaluation of compressive neuropathies at
      the elbow. Specific MR signs in association with clinical findings can supply an
      accurate diagnosis. A review of normal anatomy, clinical features, and MR
      assessment of nerve entrapment syndromes at the elbow is presented.

PMID- 15172386
TI  - MR imaging of common entrapment neuropathies at the wrist.
AB  - MR imaging is a useful technique in the work-up of compressive neuropathies at
      the wrist, providing fine anatomical detail and excellent diagnostic accuracy. MR
      imaging, however, should be reserved for those cases in which the clinical and
      electrodiagnostic findings are inconclusive, the symptoms are unusually severe,
      or when a tumor is suspected. This article reviews the normal anatomy and the MR
      imaging features of the most common compressive neuropathies at the wrist: carpal
      and ulnar tunnel syndromes.

PMID- 15172387
TI  - MR imaging findings in ulnar-sided wrist impaction syndromes.
AB  - Ulnar-sided wrist impaction syndromes are a common source of ulnar pain and
      limitation of motion. These conditions refer to a group of pathologic entities
      that result from repetitive or acute forced impaction between the distal ulna and
      ulnar carpus or distal radius and surrounding soft tissues. MR imaging allows
      earlier detection of the bone and soft-tissue lesions that are present in the
      different ulnar-sided wrist impaction syndromes and is helpful in formulating the
      extensive differential diagnosis in patients with ulnar wrist pain and limitation
      of motion.

PMID- 15172388
TI  - MR imaging of ligaments and triangular fibrocartilage complex of the wrist.
AB  - Imaging of the wrist with MR imaging can be difficult because of the small size
      of this joint, its complex anatomy, and its sometimes poorly understood
      pathologic lesions. A recent study by Hobby and coworkers of 98 patients revealed
      that MR imaging of the wrist influences clinicians' diagnoses and management
      plans in most patients. This article summarizes the current diagnostic criteria
      that can be useful in interpreting abnormalities of the wrist ligaments and
      triangular fibrocartilage complex (TFCC) of the wrist in this difficult topic in
      joint MR imaging.

PMID- 15172389
TI  - MR imaging of tendon lesions of the hand and wrist.
AB  - MR imaging of the hand and wrist tendons has greatly benefited from the use of
      dedicated surface coils, which allow fine depiction of the intricate anatomy of
      these structures, owing to high spatial resolution images as well as superb soft
      tissue contrast. MR imaging of the wrist and hand is obtained in the axial,
      sagittal, and coronal planes. The axial and sagittal planes provide most of the
      information necessary, however, to assess the tendons at the wrist and hand. The
      axial images are optimal for evaluating tendon morphology, longitudinal splits,
      tendon sheath fluid, and adjacent soft tissues such as overlying retinacula. The
      sagittal images are most useful for depicting abnormalities of the finger flexor
      and extensor tendons.

PMID- 15172390
TI  - MR imaging of tumors and tumor-like lesions of the upper extremity.
AB  - Many tumor and tumor-like lesions of the bone and soft tissues may involve the
      upper extremity. Certain lesions, however, are unique to this location. As is
      usually the case, MR is most sensitive to detection and most accurate in
      depicting the extent of involvement of these lesions. MR signal characteristics
      may aid in differential diagnosis. Conventional radiographs are often more
      specific in regard to the underlying histopathology.

PMID- 15172391
TI  - MR imaging: arthropathies and infectious conditions of the elbow, wrist, and
      hand.
AB  - The superior soft tissue contrast and multiplanar capability of MR imaging has
      contributed to earlier diagnosis and implementation of effective treatment for a
      variety of arthropathies and infectious conditions of the elbow, wrist, and hand.
      Because of overlapping clinical signs and symptoms, MR imaging plays an important
      role in delineating the features and staging of each of these conditions. This
      article discusses the seropositive and seronegative inflammatory arthropathies,
      with emphasis on early detection and surveillance, as well as gout, synovial
      osteochondromatosis, pigmented villonodular synovitis, tenosynovitis, and de
      Quervain's tenosynovitis. Certain noninflammatory arthritides and infectious
      conditions are also reviewed.

PMID- 15172393
TI  - Prior convictions: Bayesian approaches to the analysis and interpretation of
      clinical megatrials.
AB  - Large, randomized clinical trials ("megatrials") are key drivers of modern
      cardiovascular practice, since they are cited frequently as the authoritative
      foundation for evidence-based management policies. Nevertheless, fundamental
      limitations in the conventional approach to statistical hypothesis testing
      undermine the scientific basis of the conclusions drawn from these trials. This
      review describes the conventional approach to statistical inference, highlights
      its limitations, and proposes an alternative approach based on Bayes' theorem.
      Despite its inherent subjectivity, the Bayesian approach possesses a number of
      practical advantages over the conventional approach: 1). it allows the explicit
      integration of previous knowledge with new empirical data; 2). it avoids the
      inevitable misinterpretations of p values derived from megatrial populations; and
      3). it replaces the misleading p value with a summary statistic having a natural,
      clinically relevant interpretation-the probability that the study hypothesis is
      true given the observations. This posterior probability thereby quantifies the
      likelihood of various magnitudes of therapeutic benefit rather than the single
      null magnitude to which the p value refers, and it lends itself to graphical
      sensitivity analyses with respect to its underlying assumptions. Accordingly, the
      Bayesian approach should be employed more widely in the design, analysis, and
      interpretation of clinical megatrials.

PMID- 15172394
TI  - Ablation for atrial fibrillation: are cures really achieved?
AB  - During the past 10 years numerous studies on the treatment of paroxysmal atrial
      fibrillation (AF) by right and left atrial ablation procedures have been
      published. The results of studies based on follow-up periods of a few months have
      been repeatedly interpreted as providing evidence for curative therapy. However,
      insufficient focus on the variability of the natural history of paroxysmal AF,
      the inadequate detection of silent arrhythmic events, the eclectic post
      interventional use of antiarrhythmic drugs, and the lack of appropriate control
      groups make the reports unconvincing. Randomized controlled trials are needed to
      confirm postulated long-term cure rates for AF.

PMID- 15172395
TI  - Primary angioplasty in acute myocardial infarction at hospitals with no surgery
      on-site (the PAMI-No SOS study) versus transfer to surgical centers for primary
      angioplasty.
AB  - OBJECTIVES: To investigate primary angioplasty (PA) for high-risk acute
      myocardial infarction (AMI) at hospitals with no cardiac surgery on-site (No
      SOS), we hypothesized that a nonrandomized registry of such patients treated with
      PA would show clinical outcomes similar to those of a group randomized to
      transfer for PA, and that reperfusion would occur faster. BACKGROUND: Primary
      angioplasty provides outcomes superior to fibrinolytic therapy in AMI, but its
      use in community hospitals with No SOS has been limited. METHODS: Fibrinolytic
      eligible patients with high-risk AMI prospectively consented if they had one or
      more high-risk characteristic. Nineteen hospitals with No SOS prospectively
      enrolled 500 patients for PA on-site. Seventy-one similar Air Primary Angioplasty
      in Myocardial Infarction trial patients were randomized to transfer for PA.
      RESULTS: Primary angioplasty was performed in 88% of patients. Patients
      transferred for PA had a longer mean time to treatment (187 vs. 120 min; p <
      0.0001). Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 was achieved
      in 96% for on-site PA, 86% in the transfer group (p = 0.004). The combined
      primary end point of 30-day mortality, re-infarction, and disabling stroke
      occurred in 27 (5%) on-site PA patients and 6 (8.5%) transfer patients (p =
      0.27). Unadjusted one-year mortality was improved in on-site PA patients compared
      with those transferred (6% vs. 13%, p = 0.043), but after adjustment for
      differences in baseline variables, this difference was not significant.
      CONCLUSIONS: On-site PA and transfer groups had similar 30-day outcomes and more
      rapid reperfusion for on-site PA. Primary angioplasty in high-risk AMI patients
      at hospitals with No SOS is safe, effective, and faster than PA after transfer to
      a surgical facility.

PMID- 15172396
TI  - Primary percutaneous coronary intervention at hospitals without on-site cardiac
      surgery: expanding the use of mechanical reperfusion for acute myocardial
      infarction.

PMID- 15172397
TI  - Significant reduction in restenosis after the use of sirolimus-eluting stents in
      the treatment of chronic total occlusions.
AB  - OBJECTIVES: The aim of this study was to assess sirolimus-eluting stent (SES)
      implantation for the treatment of chronic total coronary occlusions (CTO).
      BACKGROUND: Long-term results after percutaneous coronary intervention (PCI) in
      the treatment of CTOs is hindered by a significant rate of restenosis and
      reocclusion. In the treatment of relatively simple nonocclusive lesions, SESs
      have shown dramatically reduced restenosis rates compared with bare metal stents
      (BMS), but whether these results are more widely applicable is unknown. METHODS:
      From April 2002, all patients at our institution were treated with SES as the
      device of choice during PCI. During the first six months, 563 patients were
      treated solely with SES, with treatment of a de novo CTO in 56 (9.9%). This CTO
      cohort was compared with a similar group of patients (n = 28) treated in the
      preceding six-month period with BMS. RESULTS: At one year, the cumulative
      survival-free of major adverse cardiac events was 96.4% in the SES group versus
      82.8% in the BMS group, p < 0.05. At six-month follow-up, 33 (59%) patients in
      the SES group underwent angiography with a binary restenosis rate (>50% diameter
      stenosis) of 9.1% and in-stent late loss of 0.13 +/- 0.46 mm. One patient (3.0%)
      at follow-up was found to have reoccluded the target vessel. CONCLUSIONS: The use
      of SESs in the treatment of chronic total coronary occlusions is associated with
      a reduction in the rate of major adverse cardiac events and restenosis compared
      with BMS.

PMID- 15172398
TI  - Impact of final stent dimensions on long-term results following sirolimus-eluting
      stent implantation: serial intravascular ultrasound analysis from the sirius
      trial.
AB  - OBJECTIVES: We assessed the predictive value of minimum stent area (MSA) for long
      term patency of sirolimus-eluting stents (SES) implantation compared to bare
      metal stents (BMS). BACKGROUND: Although MSA is a consistent predictor of in
      stent restenosis, its predictive value in BMS is still limited because of
      biologic variability in the restenosis process. METHODS: From the SIRolImUS
      (SIRIUS) trial, 122 cases (SES: 72; BMS: 50) with complete serial intravascular
      ultrasound (IVUS) (baseline and 8-month follow-up) were analyzed. Postprocedure
      MSA and follow-up minimum lumen area (MLA) were obtained. Based on previous
      physiologic studies, adequate stent patency at follow-up was defined as MLA >4
      mm(2). RESULTS: In both groups, a significant positive correlation was observed
      between baseline MSA and follow-up MLA (SES: p < 0.0001, BMS: p < 0.0001).
      However, SES showed higher correlation than BMS (0.8 vs. 0.65) with a higher
      regression coefficient (0.92 vs. 0.59). The sensitivity and specificity curves
      identified different optimal thresholds of MSA to predict adequate follow-up MLA:
      5 mm(2) for SES and 6.5 mm(2) for BMS. The positive predictive values with these
      cutoff points were 90% and 56%, respectively. CONCLUSIONS: In this SIRIUS IVUS
      substudy, SES reduced both biologic variability and restenosis, resulting in
      increased predictability of long-term stent patency with postprocedure MSA. In
      addition, SES had a considerably lower optimal MSA threshold compared to BMS.

PMID- 15172399
TI  - Coronary stenting versus balloon angioplasty in small vessels: a meta-analysis
      from 11 randomized studies.
AB  - OBJECTIVES: A meta-analysis of 11 randomized trials was done to compare stenting
      versus balloon angioplasty (BA) in small coronary vessels. BACKGROUND: Randomized
      studies on coronary stenting (CS) in small vessels have yielded controversial
      results. METHODS: Eleven randomized trials on CS versus BA in small vessels,
      including angiographic re-evaluation at six months, were analyzed. RESULTS: The
      BeStent (Medtronic Instent, Minneapolis, Minnesota) was used in four studies, the
      Multi-Link (Guidant, Advanced Cardiovascular Systems Inc., Santa Clara,
      California) in three trials, and the NIR (Boston Scientific Corp., Boston,
      Massachusetts), JoStent (Jomed International AB, Helsingborg, Sweden), Tenax
      (Biotronik, Berlin, Germany), and BioDivysio (Abbott Vascular Devices, Redwood
      City, California) in the remaining four trials. Overall, 3,541 patients were
      included (1,672 allocated to BA and 1,869 to stent). The rate of cross-over from
      balloon to stent in the pooled population was 19%, and unsuccessful stent
      deployment occurred in 2% of the patients allocated to stent. The pooled rates of
      restenosis were 25.8% and 34.2% in patients allocated to stent and balloon,
      respectively (p = 0.003) (risk ratio [RR] 0.77; 95% confidence interval [CI] 0.65
      to 0.92). A smaller reference vessel diameter at baseline was associated with a
      higher risk reduction in the restenosis rate (y = -3.551 + 1.826 [x]; p = 0.012).
      Patients allocated to stent had lower rates of major adverse cardiac events
      (15.0% vs. 21.8%, p = 0.002; RR 0.70; 95% CI 0.57 to 0.87) and new target vessel
      revascularizations (12.5% vs. 17.0%, p = 0.004; RR 0.75, 95% CI 0.61 to 0.91).
      CONCLUSIONS: Elective stenting is superior to provisional stenting in small
      coronary arteries. This benefit is more evident in smaller coronary arteries.

PMID- 15172400
TI  - Palliation of allograft vasculopathy with transluminal angioplasty: a decade of
      experience.
AB  - OBJECTIVES: The goal of this study was to examine the outcomes of percutaneous
      coronary interventions (PCI) and the predictors for restenosis after cardiac
      transplantation. BACKGROUND: The role of PCI as definitive therapy for allograft
      coronary disease (ACD) remains contentious. METHODS: Between January 1, 1990 and
      December 31, 2000, 62 patients (1.5 to 15.5 years after transplant) underwent 151
      procedures resulting in PCIs of 219 lesions. Follow-up after PCI angiography was
      usually obtained at three and six months, then yearly. Repeat PCI was routinely
      done to lesions with >60% restenosis. RESULTS: The primary procedural success was
      97%. Repeat PCI occurred in 74 of 219 lesions (34%); PCI-related mortality was
      2.6% (4 of 151). The freedom from re-PCI (of same vessel site) was 75% at six
      months, 65% at one year, and 57% at four years. The freedom from restenosis was
      95% at one month, 81% at three months, and 57% at six months. Multivariate
      predictors of freedom from restenosis were the use of stents, higher anti
      proliferative immunosuppressant dose, and an era effect. In the setting of one
      vessel disease at first PCI, the two-year freedom for ACD death or graft loss was
      74%, compared with 75% for two-vessel and 27% for three-vessel disease (p =
      0.009). CONCLUSIONS: Despite the increasing effectiveness of PCI for localized
      ACD, the survival after development of advanced ACD remains poor. Stents appear
      to increase effectiveness of PCI for ACD, but other factors in the current era
      contribute to improved outcomes.

PMID- 15172401
TI  - Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor
      agonist peptide-induced platelet activation in patients with an acute coronary
      syndrome.
AB  - OBJECTIVES: We sought to characterize the effects of clopidogrel on the
      activation of circulating platelets, the activation and aggregation of ex vivo
      platelets, and the interactions with leukocytes in patients with a non-ST-segment
      elevation in acute coronary syndromes (ACS). BACKGROUND: The significant benefits
      of clopidogrel in cardiovascular trials suggest that blockage of the P2Y(12)
      receptor may be associated with important biologic consequences. METHODS: Blood
      samples obtained from 23 ACS patients before and 24 h after a loading dose of
      clopidogrel (300 mg) were analyzed by whole-blood flow cytometry, light
      transmission aggregometry in platelet-rich plasma, and plasma enzyme-linked
      immunoassays. A thrombin receptor agonist peptide (TRAP) and adenosine
      diphosphate (ADP) were used as agonists. Normal individuals pretreated with
      aspirin served as controls. RESULTS: Clopidogrel attenuated platelet aggregation
      to both ADP (10 micromol/l) and TRAP (10 micromol/l) by 22% and P-selectin
      expression by 16% and 25%, respectively. The drug decreased the excess platelet
      monocyte and platelet-neutrophil conjugates found in the blood of ACS patients (p
      < 0.01) and prevented their formation ex vivo with agonist stimulation. Plasma
      levels of soluble CD40L were reduced by 27% (p < 0.001) and of soluble P-selectin
      by 15% (p < 0.001). CONCLUSIONS: Clopidogrel attenuates the agonist effects of
      ADP and TRAP on platelet secretion, aggregation, and formation of platelet
      monocyte and platelet-neutrophil conjugates in patients with ACS. These effects
      may all contribute to the clinical benefits of the drug in these syndromes.

PMID- 15172402
TI  - Platelets, the cardiologist, and coronary artery disease: moving beyond
      aggregation.

PMID- 15172403
TI  - Transient and reversible deoxyribonucleic acid damage in human left ventricle
      under controlled ischemia and reperfusion.
AB  - OBJECTIVES: We sought to describe the sequence of molecular events during
      ischemia and reperfusion of the human heart and to determine the activation of
      stress kinases and deoxyribonucleic acid (DNA) damage response elements on
      apoptosis in ischemia or reperfusion of the human heart. BACKGROUND: Brief
      ischemia is tolerated by cardiac myocytes, but it determines immediate metabolic
      changes and block of contraction. Prompt restoration of coronary blood flow is
      inexorably associated with a slow recovery of myocardial contractile function.
      The prolonged, postischemic contractile dysfunction in the viable tissue is
      called myocardial stunning. The molecular mechanisms underlying myocardial
      stunning and ischemia-reperfusion injury are still poorly understood. Their
      elucidation would be valuable in order to identify novel therapeutic strategies.
      METHODS: We examined human left ventricular samples taken from 20 patients
      undergoing elective valve surgery before aortic cross-clamping, 20 +/- 2 min
      (brief ischemia), 58 +/- 5 min after the cross-clamping period (prolonged
      ischemia), and 21 +/- 4 min after reconstitution of coronary blood flow
      (reperfusion). Stress kinases and DNA damage sensor proteins (ATM, H2AX, p53)
      were determined by immunoblotting with specific antibodies. Electron microscopy
      analysis was carried out on ischemic and reperfused samples. ATP content,
      reactive oxygen species (ROS) levels, and cytochrome oxidase activity were
      determined by biochemical assays. RESULTS: Ischemia caused accumulation of ROS,
      reduction of cytochrome C oxidase and ATP, and activation of stress kinases p38
      and Jun terminal kinase. Electron microscopy showed significant mitochondrial
      swelling in the majority of cells, but no appreciable apoptosis of
      cardiomyocytes. During ischemia, myocytes were intensely stained by TUNEL, and
      many cells showed proliferative cell nuclear antigen-positive nuclei. Finally, we
      found in ischemic tissues increased p53/p21(WAF) levels and phosphorylation of
      histone H2AX, a substrate of ATM kinase, which marks double-strand DNA breaks.
      Reperfusion caused a robust extracellular signal-regulated kinase-1/2 activation,
      a marked reduction of TUNEL staining, and persistent activation of ATM
      checkpoint. CONCLUSIONS: These data indicate that ischemia induces extensive DNA
      damage and activation of ATM checkpoint. Reperfusion allows the repair of the DNA
      lesions and salvage of ischemic cells.

PMID- 15172404
TI  - Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and
      progression to heart failure after acute myocardial infarction.
AB  - OBJECTIVES: We used acetylsalicylic acid (ASA) as a probing agent to quantify
      hydroxyl radical ((*)OH) in Controls and patients with coronary artery disease
      and to prospectively investigate (*)OH production in patients with myocardial
      infarction (MI) complicated by heart failure (HF). BACKGROUND: Oxidative stress
      status (OSS) is a mechanism for transition to HF in experimental heart injury
      models, but evidence for its causal role in humans is still limited. METHODS:
      Thirty healthy subjects (Controls), 12 patients with stable angina (Group 1), and
      74 patients with ST-segment elevation MI (Group 2) were enrolled. A dose of 250
      mg Flectadol was given intravenously before each blood collection to determine
      the 2,3-dihydroxybenzoic acid/salicylic acid (DHBA/SA) ratio. We also quantified
      vitamin E and coenzyme Q(10) to monitor antioxidant reserve, as well as tumor
      necrosis factor (TNF)-alpha, TNF-soluble receptors, interleukin (IL)-6, and IL
      1ra to assess inflammatory status. All measurements were repeated at month 6 in
      Group 2. RESULTS: There were no differences between Controls and Group 1. Group 2
      showed increased (*)OH production, peaking at 24 h, whereas vitamin E and
      coenzyme Q(10) progressively declined. Group 2 patients developing HF during
      hospitalization (Group 2Bi) presented with an increase of both (*)OH production
      at discharge and inflammatory status, as compared with patients without HF (Group
      2Ai), persisting at month 6 in post-MI patients with HF (Group 2Bii).
      CONCLUSIONS: We found a distinct pattern of (*)OH generation in post-MI patients
      who show progression to HF. The interplay between OSS and inflammatory status
      should be targeted as a possible mechanism of progression to post-MI left
      ventricular dysfunction.

PMID- 15172405
TI  - Hemoglobin level is an independent predictor for adverse cardiovascular outcomes
      in women undergoing evaluation for chest pain: results from the National Heart,
      Lung, and Blood Institute Women's Ischemia Syndrome Evaluation Study.
AB  - OBJECTIVES: This study was designed to investigate the relationship between
      hemoglobin level (Hgb) and adverse cardiovascular outcomes in women with
      suspected ischemia. BACKGROUND: Low Hgb levels correlate with increased
      cardiovascular morbidity and mortality in patients presenting with acute
      myocardial infarction (MI) or congestive heart failure (CHF). However, the
      prognostic significance of Hgb in women with suspected ischemia is unclear.
      METHODS: As part of the National Heart, Lung, and Blood Institute (NHLBI)
      sponsored Women's Ischemia Syndrome Evaluation (WISE), we prospectively studied
      936 women referred for coronary angiography to evaluate suspected ischemia. We
      compared Hgb levels with cardiovascular risk factors, core lab interpreted
      angiograms, inflammatory markers, and adverse cardiovascular outcomes. RESULTS:
      Of women enrolled, 864 (mean age 58.4 +/-11.6 years) had complete Hgb, angiogram,
      and follow-up (mean 3.3 +/- 1.7 years) data. The mean Hgb was 12.9 g/dl (range
      7.7 to 16.4 g/dl) and 184 women (21%) were anemic (Hgb <12 g/dl). Anemic women
      had higher creatinine and were more likely to be nonwhite and have a history of
      diabetes, hypertension, and CHF (p < 0.05). However, we found no difference in EF
      or severity of coronary artery disease. Anemic women had a higher risk of death
      from any cause (10.3% vs. 5.4%; p = 0.02) and total adverse outcomes (26% vs.
      16%, p < 0.01). In a multivariable model, decreasing Hgb was associated with
      significantly higher risk of adverse outcomes (hazard ratio = 1.20, p = 0.002).
      Also, anemic women had shorter survival time free of adverse outcome (p < 0.001).
      CONCLUSIONS: Our findings extend previous reports, linking lower hemoglobin
      levels with higher risk for adverse cardiovascular outcomes, to women evaluated
      for suspected ischemia in the absence of acute MI or CHF.

PMID- 15172406
TI  - Alcohol consumption and prognosis in patients with left ventricular systolic
      dysfunction after a myocardial infarction.
AB  - OBJECTIVES: We assessed the influence of alcohol intake on the development of
      symptomatic heart failure (HF) in patients with left ventricular (LV) dysfunction
      after a myocardial infarction (MI). BACKGROUND: In contrast to protection from
      coronary heart disease, alcohol consumption has been linked to cardiodepressant
      effects and has been considered contraindicated in patients with HF. METHODS: The
      Survival And Ventricular Enlargement (SAVE) trial randomized 2231 patients with a
      LV ejection fraction (EF) <40% following MI to an angiotensin-converting enzyme
      inhibitor or placebo. Patients were classified as nondrinkers, light-to-moderate
      drinkers (1 to 10 drinks/week), or heavy drinkers (>10 drinks/week) based on
      alcohol consumption reported at baseline. The primary outcome was hospitalization
      for HF or need for an open-label angiotensin-converting enzyme inhibitor.
      Analyses were repeated using alcohol consumption reported three months after MI.
      RESULTS: Nondrinkers were older and had more comorbidities than light-to-moderate
      and heavy drinkers. In univariate analyses, baseline light-to-moderate alcohol
      intake was associated with a lower incidence of HF compared with nondrinkers
      (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.57 to 0.87), whereas
      heavy drinking was not (HR 0.91; 95% CI 0.67 to 1.23). After adjustment for
      baseline differences, light-to-moderate baseline alcohol consumption no longer
      significantly influenced the development of HF (light-to-moderate drinkers HR
      0.93; 95% CI 0.75 to 1.17; heavy drinkers HR 1.25; 95% CI 0.91 to 1.72). Alcohol
      consumption reported three months after the MI similarly did not modify the risk
      of adverse outcome. CONCLUSIONS: In patients with LV dysfunction after an MI,
      light-to-moderate alcohol intake either at baseline or following MI did not alter
      the risk for the development of HF requiring hospitalization or an open-label
      angiotensin-converting enzyme inhibitor.

PMID- 15172407
TI  - Severity of left ventricular remodeling defines outcomes and response to therapy
      in heart failure: Valsartan heart failure trial (Val-HeFT) echocardiographic
      data.
AB  - OBJECTIVES: The objective of this study was to test the hypothesis that the
      severity of left ventricular remodeling predicts the response to treatment and
      outcomes in chronic heart failure. BACKGROUND: Reversal of remodeling should
      produce the most favorable outcome in patients with the most severe remodeling.
      METHODS: In 5010 heart failure patients on background therapy and randomized to
      valsartan and placebo, serial recordings of left ventricular internal diastolic
      diameter (LVIDd) and ejection fraction (EF) were read at sites that had to meet
      qualifying standards before participating. Baseline LVIDd and EF were pooled
      across treatments and retrospectively grouped by quartiles Q1 to Q4, representing
      best to worst. Kaplan-Meier survival curves were obtained by the log-rank test.
      Q1 was compared with Q4 for mortality and combined mortality and morbidity (M +
      M) from Cox regression risk ratios (RRs). Valsartan versus placebo changes from
      baseline in LVIDd and EF were analyzed by quartiles from analysis of covariance.
      Valsartan and placebo were compared by RRs for M + M. RESULTS: Survival rates
      were greater in the better quartiles for LVIDd and EF (p < 0.00001). The RR for
      Q1 versus Q4 in events approached 0.5 for both LVIDd and EF (p < 0.0001). An
      LVIDd decrease and EF increase were quartile-dependent and greater with valsartan
      than placebo at virtually all time points. The RR for M + M outcomes favored
      valsartan in the worse quartiles. CONCLUSIONS: Stratification by baseline
      severity of remodeling showed that patients with worse LVIDd and EF are at
      highest risk for an event, yet appear to gain the most anti-remodeling effect and
      clinical benefit with valsartan treatment.

PMID- 15172408
TI  - Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in
      chronic heart failure.
AB  - OBJECTIVES: This individually randomized, open-label, parallel-group pilot study
      was designed to test the hypothesis that the ability of loop diuretics to
      interfere with cardiac fibrosis in chronic heart failure (CHF) may be different
      between compounds. BACKGROUND: The apparent mortality and cardiac benefits seen
      in studies comparing torasemide with furosemide in CHF suggest that torasemide
      may have beneficial effects beyond diuresis (e.g., on the process of cardiac
      fibrosis). METHODS: Patients with New York Heart Association functional class II
      to IV CHF received diuretic therapy with either 10 to 20 mg/day oral torasemide
      (n = 19) or 20 to 40 mg/day oral furosemide (n = 17), in addition to their
      existing standard CHF therapy for eight months. At baseline and after eight
      months, right septal endomyocardial biopsies were obtained to quantify collagen
      volume fraction (CVF) with an automated image analysis system. Serum carboxy
      terminal peptide of procollagen type I (PIP) and serum carboxy-terminal
      telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and
      degradation, respectively, were measured by specific radioimmunoassays. RESULTS:
      In torasemide-treated patients, CVF decreased from 7.96 +/- 0.54% to 4.48 +/-
      0.26% (p < 0.01), and PIP decreased from 143 +/- 7 to 111 +/- 3 microg/l (p <
      0.01). Neither CVF nor PIP changed significantly in furosemide-treated patients.
      In all patients, CVF was directly correlated with PIP (r = 0.88, p < 0.001)
      before and after treatment. No changes in CITP were observed with treatment in
      either group. CONCLUSIONS: These findings suggest that loop diuretics possess
      different abilities to reverse myocardial fibrosis and reduce collagen type I
      synthesis in patients with CHF.

PMID- 15172410
TI  - A new approach for catheter ablation of atrial fibrillation: mapping of the
      electrophysiologic substrate.
AB  - OBJECTIVES: We sought to test the hypothesis that complex fractionated
      electrograms (CFAEs) recorded during atrial fibrillation (AF) could be used as
      target sites for catheter ablation of AF. BACKGROUND: Mapping of AF in humans has
      shown that areas of CFAEs correlate with areas of slowed conduction and pivot
      points of reentrant wavelets. We hypothesized that such areas of CFAEs could be
      identified in patients with AF and might serve as target sites for catheter
      ablation to maintain sinus rhythm. METHODS: The study population included 121
      patients (29 females; mean age, 63 years) with refractory AF (57 paroxysmal, 64
      chronic). All patients underwent nonfluoroscopic electroanatomic mapping (CARTO)
      during AF. Using CARTO, the biatrial replica, displayed in a three-dimensional
      color-coded voltage map, was created during AF, and areas associated with CFAEs
      were identified. Radiofrequency ablation of the area with CFAEs was performed,
      aiming to eliminate CFAE and/or convert to sinus rhythm. RESULTS: Complex
      fractionated atrial electrograms were found in seven of nine regions of both
      atria, but were mainly confined to the interatrial septum, pulmonary veins, roof
      of left atrium, and left posteroseptal mitral annulus and coronary sinus ostium.
      Ablations of the areas associated with CFAEs resulted in termination of AF
      without external cardioversion in 115 of the 121 patients (95%); 32 (28%)
      required concomitant ibutilide treatment. At the one-year follow-up, 110 (91%)
      patients were free of arrhythmia and symptoms, 92 after one ablation and 18 after
      two. CONCLUSIONS: Areas with CFAEs represent a defined electrophysiologic
      substrate and are ideal target sites for ablations to eliminate AF and maintain
      normal sinus rhythm.

PMID- 15172409
TI  - Outpatient utilization of angiotensin-converting enzyme inhibitors among heart
      failure patients after hospital discharge.
AB  - OBJECTIVES: This study was designed to assess outpatient angiotensin-converting
      enzyme inhibitor (ACEI) use after heart failure (HF) hospitalization. BACKGROUND:
      Assuring therapy with ACEIs at discharge after HF hospitalization is a key
      Medicare quality measure. The benefits of such quality improvement attempts will
      be limited if therapy is not continued long-term. METHODS: To assess the factors
      associated with filling an ACEI prescription in the 30 days postdischarge and the
      proportion of patients who filled such prescriptions subsequently up to 365 days
      postdischarge, we studied 219 patients with depressed ejection fraction (EF)
      specifically and 960 HF patients in general. RESULTS: Sixty-seven percent of
      patients with depressed EF and 55% of the total cohort were discharged with
      ACEIs. Overall 81.2%/77.1% (depressed EF/total cohort) of survivors discharged
      with ACEIs had filled a prescription by 30 days postdischarge; only 66.3%/63.3%
      were current users at 365 days. In contrast, for patients with no discharge order
      for ACEIs, only 12.7%/12.0% (depressed EF/total cohort) had filled such a
      prescription by 30 days and 12.5%/18.8% were current users at 365 days
      postdischarge. Patients with a discharge order for ACEIs were more likely to fill
      a prescription within 30 days postdischarge (hazard ratio 10.93, 95% confidence
      interval 5.28, 22.61, for patients with depressed EF). CONCLUSIONS: For patients
      with HF who are discharged while taking ACEIs, there is a significant decline in
      use after discharge. Patients not discharged with ACEIs are unlikely to be
      started as outpatients. Quality improvement efforts therefore need to be focused
      on both discharge planning and outpatient care.

PMID- 15172411
TI  - Catheter ablation of atrial fibrillation: what is the best technique for
      achieving a high cure rate with acceptable risk?

PMID- 15172413
TI  - Combining ablation of atrial fibrillation with ablation of atrial flutter: are we
      there yet?

PMID- 15172412
TI  - Clinical significance of inducible atrial flutter during pulmonary vein isolation
      in patients with atrial fibrillation.
AB  - OBJECTIVES: This study was designed to determine the prevalence and clinical
      significance of atrial flutter (AFL) that occurs during catheter ablation for
      atrial fibrillation (AF). BACKGROUND: Atrial flutter frequently occurs in
      patients with AF. METHODS: Pulmonary vein isolation was performed in 133
      consecutive patients (age 52 +/- 11 years) for paroxysmal (n = 112) or persistent
      (n = 21) AF. A clinical episode of AFL was documented in 40 of the 133 patients
      (30%). During the ablation procedure, AFL occurred in 86 patients (65%), either
      spontaneously (n = 36) or by rapid atrial pacing (n = 50), with AFL being typical
      in the majority (80%). Cavo-tricuspid isthmus ablation was performed in 28 of the
      133 patients. RESULTS: Among the 105 patients who did not undergo isthmus
      ablation, 25 patients (24%) were documented to have symptomatic AFL during a mean
      follow-up of 609 +/- 252 days. Among the clinical variables of age, gender,
      history of clinical AFL, ejection fraction, left atrial diameter, duration of AF,
      and occurrence of AFL during ablation, only a history of clinical AFL (p = 0.05)
      and occurrence of typical AFL during the ablation (p = 0.01) were independent
      predictors of symptomatic AFL during follow-up. The incidence of symptomatic AFL
      during follow-up was similar among patients who did and did not have long-term
      freedom from recurrent AF. CONCLUSIONS: In patients with AF who have either a
      history of AFL or an episode of typical AFL during an electrophysiologic study,
      symptomatic AFL is common after pulmonary vein isolation. Therefore, cavo
      tricuspid isthmus ablation is appropriate during pulmonary vein isolation if AFL
      has been observed clinically or in the electrophysiology laboratory.

PMID- 15172414
TI  - High incidence of pacemaker syndrome in patients with sinus node dysfunction
      treated with ventricular-based pacing in the Mode Selection Trial (MOST).
AB  - OBJECTIVES: We evaluated the incidence, predictors, and treatment of pacemaker
      syndrome in patients with sinus node dysfunction treated with ventricular-based
      (VVIR) pacing in the Mode Selection Trial (MOST). BACKGROUND: Pacemaker syndrome,
      or intolerance to VVIR pacing, consists of cardiovascular signs and symptoms
      induced by VVIR pacing. METHODS: The definition of pacemaker syndrome required
      that a patient with single-chamber VVIR pacing develop either congestive signs
      and symptoms associated with retrograde conduction during VVIR pacing or a >or=20
      mm Hg reduction of systolic blood pressure during VVIR pacing, associated with
      reproducible symptoms of weakness, lightheadedness, or syncope. RESULTS: Of 996
      patients randomized to VVIR pacing, 182 (18.3%) met criteria for pacemaker
      syndrome in follow-up. Pacemaker syndrome occurred early in most patients (13.8%
      at 6 months, 16.0% at 1 year, increasing to 19.7% at 4 years). Baseline
      univariate predictors of pacemaker syndrome included a lower sinus rate and
      higher programmed pacemaker rate. Previous heart failure, ejection fraction, and
      drop in systolic blood pressure with VVIR pacing at implantation did not predict
      the development of pacemaker syndrome. Post-implantation predictors of pacemaker
      syndrome were a higher percentage of paced beats, higher programmed low rate, and
      slower underlying spontaneous sinus rate. Quality of life decreased at the time
      of diagnosis of pacemaker syndrome and improved with reprogramming to atrial
      based pacing. CONCLUSIONS: Severe pacemaker syndrome developed in nearly 20% of
      VVIR-paced patients and improved with reprogramming to the dual-chamber pacing
      mode. Because prediction of pacemaker syndrome is difficult, the only way to
      prevent pacemaker syndrome is to implant atrial-based pacemakers in all patients.

PMID- 15172415
TI  - Single-lead ventricular pacing is no longer an option for sick sinus syndrome.

PMID- 15172416
TI  - Relationship of interleukin-6 and C-reactive protein to the prothrombotic state
      in chronic atrial fibrillation.
AB  - OBJECTIVES: We sought to test the hypothesis that there is a relationship between
      inflammation and the prothrombotic state in atrial fibrillation (AF). BACKGROUND:
      Atrial fibrillation is associated with a prothrombotic or hypercoagulable state,
      which may contribute to an increased risk of stroke and thromboembolism.
      Inflammation may be involved in the pathogenesis of AF, but the role of
      inflammation in the pathophysiology of the prothrombotic state of AF has not been
      studied in detail, despite evidence of a link between inflammation and arterial
      atherothrombotic disorders. METHODS: We measured plasma indexes of inflammation
      (C-reactive protein [CRP] and interleukin-6 [IL-6]) and the prothrombotic state,
      including markers of platelet activation (soluble P-selectin), endothelial
      damage/dysfunction (von Willebrand factor), the coagulation cascade (tissue
      factor [TF], fibrinogen), and indexes of blood rheology (plasma viscosity, plasma
      fibrinogen, and hematocrit) in 106 patients with chronic AF and 41 healthy
      control subjects included in a cross-sectional analysis. RESULTS: Compared with
      controls, AF patients had higher levels of IL-6 (p = 0.034), CRP (p = 0.003), TF
      (p = 0.019), and plasma viscosity (p = 0.045). Plasma IL-6 levels were higher
      among AF patients at "high" risk of stroke (p = 0.003). After adjusting for
      potential confounding clinical variables (e.g., vascular disease), AF remained
      significantly associated with a raised logarithmic transformation (log) of TF (p
      = 0.04), but the relationships between AF and log IL-6, log CRP, and plasma
      viscosity became nonsignificant. Among AF patients, log TF (p < 0.001) and high
      stroke risk (p = 0.003) were independent associates of log IL-6 (adjusted r(2) =
      0.443), whereas log fibrinogen (p < 0.001) and plasma viscosity (p = 0.04) were
      independent associates of log CRP (adjusted r(2) = 0.259). CONCLUSIONS: Increased
      plasma IL-6, CRP, and plasma viscosity support the case for the existence of an
      inflammatory state among "typical" populations with chronic AF. These indexes of
      inflammation are related to indexes of the prothrombotic state and may be related
      to the clinical variables of the patients (underlying vascular disease and co
      morbidities), rather than simply to the presence of AF itself.

PMID- 15172417
TI  - High-resolution transthoracic real-time three-dimensional echocardiography:
      quantitation of cardiac volumes and function using semi-automatic border
      detection and comparison with cardiac magnetic resonance imaging.
AB  - OBJECTIVES: We sought to validate high-resolution transthoracic real-time (RT)
      three-dimensional echocardiography (3DE), in combination with a novel semi
      automatic contour detection algorithm, for the assessment of left ventricular
      (LV) volumes and function in patients. BACKGROUND: Quantitative RT-3DE has been
      limited by impaired image quality and time-consuming manual data analysis.
      METHODS: Twenty-four subjects with abnormal (n = 14) or normal (n = 10) LVs were
      investigated. The results for end-diastolic volume (EDV), end-systolic volume
      (ESV), and ejection fraction (EF) obtained by manual tracing were compared with
      the results determined by the semi-automatic border detection algorithm.
      Moreover, the results of the semi-automatic method were compared with volumes and
      EF obtained by cardiac magnetic resonance imaging (CMRI). RESULTS: Excellent
      correlation coefficients (r = 0.98 to 0.99) and low variability (EDV -1.3 +/- 8.6
      ml; ESV -0.2 +/- 5.4 ml; EF -0.1 +/- 2.7%; p = NS) were observed between the semi
      automatically and manually assessed data. The RT-3DE data correlated highly with
      CMRI (r = 0.98). However, LV volumes were underestimated by RT-3DE compared with
      CMRI (EDV -13.6 +/- 18.9 ml, p = 0.002; ESV -12.8 +/- 20.5 ml, p = 0.005). The
      difference for EF was not significant between the two methods (EF 0.9 +/- 4.4%, p
      = NS). Observer variability was acceptable, and repeatability of the method was
      excellent. CONCLUSIONS: The RT-3DE, in combination with a semi-automatic contour
      tracing algorithm, allows accurate determination of cardiac volumes and function
      compared with both manual tracing and CMRI. High repeatability suggests
      applicability of the method for the serial follow-up of patients with cardiac
      disease.

PMID- 15172418
TI  - Real-time three-dimensional echocardiography for rheumatic mitral valve stenosis
      evaluation: an accurate and novel approach.
AB  - OBJECTIVES: Our aim was to assess which echo-Doppler method has the best
      agreement with the mitral valve area (MVA) invasively evaluated by the Gorlin's
      formula. We also evaluated the feasibility and reproducibility of real-time three
      dimensional echocardiography (RT3D) for the estimation of MVA and the Wilkins
      score in patients with rheumatic mitral stenosis (RMVS). BACKGROUND: Real-time
      three-dimensional echocardiography is a novel technique that allows us to
      visualize the mitral valvular anatomy in any desired plane orientation. The
      usefulness and accuracy of this technique for evaluating RMVS has not been
      established. METHODS: We studied a series of consecutive patients with RMVS from
      two tertiary care hospitals. Mitral valvular area was determined by conventional
      echo-Doppler methods and by RT3D, and their results were compared with those
      obtained invasively. Real-time three-dimensional echocardiography planimetry and
      mitral score were measured by two independent observers and then repeated by one
      of them. RESULTS: Eighty patients with RMVS comprised our study group (76 women;
      50.6 +/- 13.9 years). Compared with all other echo-Doppler methods, RT3D had the
      best agreement with the invasively determined MVA (average difference between
      both methods and limits of agreement: 0.08 cm(2) [-0.48 to 0.6]). Interobserver
      variability was as good for RT3D (intraclass correlation coefficient [ICC] =
      0.90) as for pressure half-time (PHT) (ICC = 0.95). For PHT and RT3D, the
      intraobserver variability was similar (ICC 0.92 and 0.96, respectively). Real
      time three-dimensional echocardiography valvular score evaluation showed a better
      interobserver agreement with RT3D than with 2D echocardiography. CONCLUSIONS:
      Real-time three-dimensional echocardiography is a feasible, accurate, and highly
      reproducible technique for assessing MVA in patients with RMVS. Real-time three
      dimensional echocardiography has the best agreement with invasive methods.

PMID- 15172419
TI  - Clinical validity of measuring time difference between onset of mitral inflow and
      onset of early diastolic mitral annulus velocity in the evaluation of left
      ventricular diastolic function.
AB  - OBJECTIVES: This study was performed to validate the clinical usefulness of
      measuring the time difference between onset of mitral inflow and onset of early
      diastolic mitral annulus velocity (T(E'-E)) for the evaluation of left
      ventricular (LV) diastolic function. BACKGROUND: In recent studies, T(E'-E)
      correlated well with the time constant of LV pressure decay (tau), and the ratio
      of IVRT/T(E'-E), where IVRT is isovolumic relaxation time, was useful in the
      prediction of elevated LV filling pressure. METHODS: Simultaneous left heart
      catheterization and Doppler echocardiography were performed in 40 patients.
      RESULTS: The T(E'-E) was evaluated in the same cardiac cycle and in the same
      hemodynamic status in 31 patients. Despite the wide range of tau (31 to 70 ms),
      there was no delay in the onset of mitral annulus velocity compared with the
      onset of mitral inflow (T(E'-E) = 0) in 27 patients and, therefore, T(E'-E) did
      not correlate with tau. Only three patients showed prolongation in T(E'-E), and
      all three showed tau >or=50 ms and pre-A-wave pressure >or=18 mm Hg. In one
      patient, mitral annulus velocity began earlier than the onset of mitral inflow.
      Because T(E'-E) was 0 in the majority of patients, the LV filling pressure could
      not be predicted by the previously suggested index of IVRT/T(E'-E.) CONCLUSIONS:
      In contrast to previous studies, T(E'-E) did not correlate with tau, and IVRT/
      T(E'-E) could not be applied in the prediction of filling pressure, because of
      the limitation of a zero denominator. However, prolongation of T(E'-E) might
      suggest an elevated filling pressure in the setting of prolonged tau.

PMID- 15172420
TI  - A clinical and echocardiographic score for assigning risk of major events after
      dobutamine echocardiograms.
AB  - OBJECTIVES: We sought to develop and validate a risk score combining both
      clinical and dobutamine echocardiographic (DbE) features in 4890 patients who
      underwent DbE at three expert laboratories and were followed for death or
      myocardial infarction for up to five years. BACKGROUND: In contrast to exercise
      scores, no score exists to combine clinical, stress, and echocardiographic
      findings with DbE. METHODS: Dobutamine echocardiography was performed for
      evaluation of known or suspected coronary artery disease in 3156 patients at two
      sites in the U.S. After exclusion of patients with incomplete follow-up, 1456
      DbEs were randomly selected to develop a multivariate model for prediction of
      events. After simplification of each model for clinical use, the models were
      internally validated in the remaining DbE patients in the same series and
      externally validated in 1733 patients in an independent series. RESULTS: The
      following score was derived from regression models in the modeling group (160
      events): DbE risk = (age.0.02) + (heart failure + rate-pressure product
      <15000).0.4 + (ischemia + scar).0.6. The presence of each variable was scored as
      1 and its absence scored as 0, except for age (continuous variable). Using cutoff
      values of 1.2 and 2.6, patients were classified into groups with five-year event
      free survivals >95%, 75% to 95%, and <75%. Application of the score in the
      internal validation group (265 events) gave equivalent results, as did its
      application in the external validation group (494 events, C index = 0.72).
      CONCLUSIONS: A risk score based on clinical and echocardiographic data may be
      used to quantify the risk of events in patients undergoing DbE.

PMID- 15172421
TI  - Training cardiovascular fellows in cardiovascular magnetic resonance and vascular
      imaging; Current status following the core cardiovascular training symposium
      (COCATS-2) guidelines.
AB  - OBJECTIVES: This survey study sought to characterize the current training
      environment in cardiovascular magnetic resonance (CMR) and vascular imaging and
      to quantify the magnitude of any gaps between current training practice and the
      recommendations of the Core Cardiovascular Training Symposium (COCATS-2)
      guidelines. BACKGROUND: The COCATS-2 guidelines published in 2002 newly included
      specific educational components of CMR and vascular imaging. An understanding of
      the current capabilities of training programs to meet these guidelines could
      produce efforts to improve training opportunities. METHODS: We surveyed all
      accredited adult cardiovascular training programs by using a 21-question,
      multiple-response survey. Data were collected on center and program
      characteristics, clinical activities, control of clinical activities, and needs
      and attitudes. Parallel data were collected for nuclear cardiology capabilities
      as a "base case." RESULTS: Only 13% of training programs reported "ownership" of
      CMR equipment, compared with 48% for nuclear equipment (p = 0.001). Dedicated
      fellow rotations in nuclear imaging are nearly universally present, whereas
      vascular (64%) and CMR imaging (29%) lag behind. A majority of programs do not
      use formal educational curricula for CMR and vascular imaging. Among centers with
      CMR training capabilities, the breadth of training opportunities is typically
      very limited, with most having only aortic imaging as their sole capability,
      except in predominately large training centers. The greatest need expressed by
      programs was educational assistance in the form of written and lecture curriculum
      materials. CONCLUSIONS: A substantial gap exists between the current training
      environment in CMR and vascular imaging and the recommendations of COCATS-2.
      Sharing training opportunities between centers is encouraged, particularly for
      smaller training programs, in order to capitalize on limited equipment,
      personnel, and curriculum resources.

PMID- 15172422
TI  - Cardiac magnetic resonance imaging and core cardiology training II (COCATS-2):
      can we get there from here?

PMID- 15172424
TI  - Infarct resorption, compensatory hypertrophy, and differing patterns of
      ventricular remodeling following myocardial infarctions of varying size.
AB  - OBJECTIVES: We sought to identify advantages of contrast-enhanced magnetic
      resonance imaging (MRI) in studying postinfarction ventricular remodeling.
      BACKGROUND: Although sequential measurements of ventricular volumes, internal
      dimensions, and total ventricular mass have provided important insights into
      postinfarction left ventricular remodeling, it has not been possible to define
      serial, directionally opposite changes in resorption of infarcted tissue and
      hypertrophy of viable myocardium and effects of these changes on commonly used
      indices of remodeling. METHODS: Using gadolinium-enhanced MRI, the time course
      and geometry of changes in infarcted and noninfarcted regions were assessed
      serially in dogs subjected to coronary occlusion for 45 min, 90 min, or
      permanently. RESULTS: Infarct mass decreased progressively between three days and
      four to eight weeks following coronary occlusion; terminal values averaged 24 +/-
      3% of those at three days. Radial infarct thickness also decreased progressively,
      whereas changes in circumferential and longitudinal extent of infarction were
      variable. The ability to define the circumferential endocardial and epicardial
      extents of infarction allowed radial thinning without epicardial expansion to be
      distinguished from true infarct expansion. The mass of noninfarcted myocardium
      increased by 15 +/- 2% following 90-min or permanent occlusion. However, the time
      course of growth of noninfarcted myocardium differed systematically from that of
      infarct resorption. Measurements of total ventricular mass frequently failed to
      reflect concurrent changes in infarcted and noninfarcted regions. Reperfusion
      accelerated infarct resorption. Histologic reductions in nucleus-to-cytoplasm
      ratios corresponded with increases in noninfarcted ventricular mass. CONCLUSIONS:
      Concurrent directionally opposite changes in infarcted and noninfarcted
      myocardium can be defined serially, noninvasively, and with high spatial
      resolution and full ventricular coverage following myocardial infarction.

PMID- 15172423
TI  - Comparative effects of valsartan versus amlodipine on left ventricular mass and
      reactive oxygen species formation by monocytes in hypertensive patients with left
      ventricular hypertrophy.
AB  - OBJECTIVES: To compare the effects of the angiotensin receptor blocker (ARB)
      valsartan versus the calcium channel blocker amlodipine, reactive oxygen species
      (ROS) formation by monocytes, C-reactive protein (CRP), and left ventricular (LV)
      mass were studied in 104 hypertensive patients with left ventricular hypertrophy
      (LVH). BACKGROUND: There is evidence that ARBs have blood pressure (BP)
      independent effects on LV mass. Whether regression of LV mass by ARBs is
      correlated to ROS formation by monocytes and CRP is not fully understood yet.
      METHODS: A cross-sectional and prospective study was performed. Participants were
      randomly assigned to either the 80-mg valsartan (n = 52) or 5-mg amlodipine (n =
      52) group and were treated for eight months. The left ventricular mass index
      (LVMI) was calculated from two-dimensional M-mode echocardiography. Formation of
      ROS by monocytes was measured by gated flow cytometry. In addition, CRP, plasma
      renin activity, plasma aldosterone, and traditional risk factors were assessed.
      RESULTS: Multiple regression analysis showed a significant correlation between
      LVMI and ROS formation by monocytes and between LVMI and CRP. Treatment reduced
      BP to a similar extent in both groups. Valsartan significantly reduced LVMI after
      eight months, but amlodipine had less effect (16% vs. 1.2%, n = 50, p < 0.01).
      Formation of ROS by monocytes was reduced to a greater extent with valsartan than
      with amlodipine (28% vs. 2%, n = 50, p < 0.01). Valsartan but not amlodipine
      reduced CRP levels. A significant correlation between changes in ROS formation by
      monocytes and LVMI or between CRP and LVMI was observed. CONCLUSIONS: The ARB
      valsartan has BP-independent effects on LVH, ROS formation by monocytes, and CRP
      in hypertensive patients with LVH.

PMID- 15172425
TI  - The year in congenital heart disease.

PMID- 15172426
TI  - Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and
      physiologically normal.
AB  - The normal low-density lipoprotein (LDL) cholesterol range is 50 to 70 mg/dl for
      native hunter-gatherers, healthy human neonates, free-living primates, and other
      wild mammals (all of whom do not develop atherosclerosis). Randomized trial data
      suggest atherosclerosis progression and coronary heart disease events are
      minimized when LDL is lowered to <70 mg/dl. No major safety concerns have
      surfaced in studies that lowered LDL to this range of 50 to 70 mg/dl. The current
      guidelines setting the target LDL at 100 to 115 mg/dl may lead to substantial
      undertreatment in high-risk individuals.

PMID- 15172427
TI  - Reactive hyperemia as a test of endothelial or microvascular function?

PMID- 15172429
TI  - Magnetic resonance to assess the aortic valve area in aortic stenosis.

PMID- 15172431
TI  - Therapy of recurrent pericarditis.

PMID- 15172433
TI  - Time course of the interaction between tadalafil and nitrates.

PMID- 15172435
TI  - Pathogenesis of human cytomegalovirus infection and cellular targets.
AB  - In acquired immunodeficiency syndrome patients with human cytomegalovirus (HCMV),
      disseminated infection, and end-organ disease, autopsy findings show a
      generalized HCMV infection of endothelial cells. On the other hand,
      immunocompromised transplanted patients show presence of virus and virus products
      in peripheral blood leukocytes (PBL), when affected by a disseminated HCMV
      infection. All diagnostic assays are based on the detection of virus and viral
      components in PBL or whole blood, including polymorphonuclear leukocytes and
      monocytes. The interplay between endothelial cells and leukocytes represents the
      pathogenetic basis for all clinical syndromes originating during disseminated
      HCMV infections and is the trigger for the transmission of HCMV from mother to
      fetus during primary infections of pregnant women. The two biologic properties of
      endothelial cell tropism and leukocyte (polymorphonuclear- and monocyte-) tropism
      are shared by all recent clinical HCMV isolates, whereas they are missing in
      laboratory-adapted strains. The potential role of HCMV in the pathogenesis of
      atherosclerosis both in the immunocompetent (after angioplasty) and the heart
      transplant patient is receiving support from seroepidemiologic findings, in vivo
      animal models, in vitro data, and also some clinical observations. The
      interaction of endothelial cells and leukocytes with subsequent spreading of
      infection to smooth muscle cells may be a major pathogenetic mechanism at the
      basis of this important vascular disease.

PMID- 15172436
TI  - Genomic variants among human cytomegalovirus (HCMV) clinical isolates: the
      glycoprotein n (gN) paradigm.
AB  - Human cytomegalovirus (HCMV) clinical isolates display genetic polymorphisms,
      which are supposed to be implicated in strain-specific tissue tropism and HCMV
      induced immunopathogenesis. One highly variable gene is ORF UL73, encoding for
      the envelope glycoprotein gN, which displays both a structural and an immunologic
      role as a component of the high-molecular weight complex gC-II. UL73 showed
      clustered polymorphisms, which originate four distinct genomic variants, denoted
      gN-1, gN-2, gN-3, and gN-4. This review reports the main features of gN genotypes
      and their potential implications on HCMV biologic properties. The clinical impact
      of gN variants is also discussed. This overview on gN clustered polymorphisms
      should be useful as a prototype model for a better understanding of the biologic
      and clinical relevance of HCMV clinical isolates genetic variability.

PMID- 15172437
TI  - Human cytomegalovirus virion proteins.
AB  - Human cytomegalovirus (HCMV) is the largest member of the family of human
      herpesviruses. The number of virus encoded proteins and the complexity of their
      functions in the life cycle of this virus are reflected in the size of its
      genome. There continues to be some controversy surrounding the exact protein
      coding capacity of the virus with estimates ranging from 160 open reading frames
      to more than 200 open reading frames. Very recent studies using mass spectrometry
      to determine the viral proteome suggests that the number of viral proteins may be
      even greater than previous estimates. The proteins of the virion capsid have
      readily identifiable homologous proteins in the capsid of the more extensively
      studied herpes simplex virus, likely because of similar capsid structure and
      assembly pathways. In contrast, the tegument and the envelope of HCMV contain a
      significant number of proteins that lack structural homology to proteins found in
      either alpha or gamma-herpesviruses. This brief overview discusses some of the
      general features and possible functions of the HCMV virion structural proteins in
      the replicative cycle of this virus.

PMID- 15172438
TI  - Clinical and biologic aspects of human cytomegalovirus resistance to antiviral
      drugs.
AB  - The emergence of human cytomegalovirus (HCMV) drug resistant strains is a life
      threatening condition in immunocompromised individuals with active HCMV
      infection. HCMV drug resistance represented a major problem in patients with
      acquired immunodeficiency syndrome until the recent introduction of highly active
      antiretroviral combination therapy, which dramatically decreased the incidence in
      this clinical setting. However, HCMV resistance to antiviral drugs is now an
      emerging problem in the transplantation setting. The molecular mechanisms of HCMV
      drug resistance have been elucidated and rely on the selection during treatment
      of HCMV strains harboring mutations in two key viral genes: UL97 coding for a
      viral phosphotransferase and UL54 coding for the viral DNA polymerase.

PMID- 15172439
TI  - Congenital cytomegalovirus infection: recent advances in the diagnosis of
      maternal infection.
AB  - In most European countries, pregnant women are tested for cytomegalovirus (CMV)
      during the first trimester of pregnancy. Within the last 5 years, European
      laboratories have made significant progress in solving diagnostic problems linked
      to infection in pregnancy. With advances in CMV serology, the presence of anti
      CMV immunoglobulin (Ig)M detected by a screening test such as enzyme immunoassay,
      can be confirmed by blot, identifying pregnant women undergoing an active or
      recent infection. Furthermore, primary infections that were proven if a
      seroconversion was observed or suspected in the presence of IgM, can now be
      readily diagnosed by disclosing the presence of anti-CMV low avidity in IgM
      positive mothers, greatly reducing the number of women who should be considered
      at risk of transmitting the virus. Virologic maternal tests are not enough to
      diagnose a recent primary maternal CMV infection and the detection or
      quantification of CMV in maternal blood does not seem to be associated with a
      higher risk for fetal infection. A cohort of 1520 pregnant women considered at
      risk of transmitting the virus were followed in a longitudinal study at the
      University of Bologna. Women were identified as part of routine CMV screening in
      several Italian regions and were IgM-positive for CMV. We documented IgG
      seroconversion in 83 women and 1437 were IgM-positive by commercial kit.

PMID- 15172440
TI  - Cytomegalovirus infection after bone marrow transplantation in children.
AB  - Cytomegalovirus (CMV) is a well-known cause of disease occurring after bone
      marrow transplantation (BMT). The manifestations of CMV range from asymptomatic
      infection, defined as active CMV replication in the blood in the absence of
      clinical manifestations or organ failure abnormalities, to CMV disease,
      characterized by CMV infection with clinical symptoms or organ function
      abnormalities. Diagnostic procedures to assess the viral load have improved
      greatly with the increased use of antigenemia, CMV DNA, and immediate early
      messenger RNA. Many conditions concur in determining the risk of developing CMV
      reactivation or disease after bone marrow transplant with serologic status of
      donor and recipient, type of bone marrow transplant, presence of graft-versus
      host disease being the most studied. However, time and quality of immune
      reconstitution seems to be the pivotal factors. Pneumonia and gastrointestinal
      involvement are the most frequently documented clinical pictures with late-onset
      CMV reactivation or disease representing a new challenge. CMV prophylaxis or pre
      emptive therapy adopted during the last few years in allogeneic BMT recipients
      has changed the natural history of the disease, reducing the risk of CMV disease,
      CMV-associated death, transplant-related mortality, and has prolonged the period
      at risk. Specific studies on children are lacking, however, the clinical pictures
      and features seems to be similar both in children and adults.

PMID- 15172441
TI  - Antiviral activity against CMV-infected fibroblasts in pediatric patients
      transplanted with CD34(+)-selected allografts from alternative donors.
AB  - Human cytomegalovirus (HCMV) remains a cause of serious infectious complications
      after allogeneic transplantation of hematopoietic stem cells, especially in
      recipients of T-cell-depleted grafts. Here we investigated the antiviral activity
      of natural killer (NK) cells from healthy donors (n = 8) as well as of
      mononuclear cells (MNC) from transplanted pediatric patients (n = 11) who had
      received CD34(+) selected (and thus T-cell-depleted) stem cells from unrelated
      and mismatched related donors. Allogeneic human fibroblasts infected with HCMV
      laboratory strain AD169 for 5 days were used as targets in a 2-h cytotoxicity
      assay. Downregulation of human leukocyte antigen class I and upregulation of the
      adhesion molecules CD54 (ICAM-1) and CD58 (LFA-3) were observed after infection.
      In this experimental setting, NK cells from healthy donors exerted no specific
      lysis. However, antibody-dependent cellular cytotoxicity (ADCC) mediated by human
      anti-CMV IgG (cytoglobin) as well as stimulation with low-dose interleukin-(IL)-2
      or IL-15 enhanced lysis markedly. MNC from two thirds of the patients (7/11) were
      capable of lysing infected targets without stimulation. Here also, lytic activity
      was significantly increased by IL-2 or IL-15, used in combination with ADCC. In
      contrast, 4/11 patients exerted no lysis. The observed antiviral activity may
      contribute to the low incidence of CMV DNAemia (29% at day 100, detected by
      polymerase chain reaction) in the whole group of our patients who have been
      transplanted with CD34(+)-selected allografts since 1995. Furthermore, our data
      suggest a potential benefit of using low-dose IL-2 or IL-15, also combined with
      anti-CMV immunoglobulinG, for immune modulation in CMV disease.

PMID- 15172442
TI  - Clinical aspects of CMV infection after stem cell transplantation.
AB  - Cytomegalovirus (CMV) infection is one of the most important infectious
      complications after stem cell transplantation (SCT). Major improvements in the
      management of CMV infection have been achieved during the last decade, including
      the introduction of safe blood product support for CMV-seronegative patients, the
      development of early pre-emptive antiviral therapy based on sensitive diagnostic
      tests, and antiviral prophylaxis. With the better control of CMV infection during
      the first 100 days after allogeneic SCT an increase in the incidence of CMV
      infection and disease after day 100 after transplantation was observed. New
      methods that allow for the reconstitution of CMV-specific immune responses such
      as adoptive T-cell therapy are promising tools that might help to improve the
      management of late CMV infection and disease.

PMID- 15172443
TI  - HLA-E-restricted recognition of human cytomegalovirus by a subset of cytolytic T
      lymphocytes.
AB  - Natural killer (NK)-cytotoxic T lymphocytes (CTL) are a subset of CD8(+)
      cytolytic T lymphocytes that express human leukocyte antigen (HLA) class I
      specific inhibitory receptors. They are detectable as monoclonal expansions in
      the blood of cytomegalovirus (CMV)-seropositive individuals displaying particular
      HLA-Cw allotypes. Similar to NK cells, they are capable of killing various
      allogeneic tumor cell lines, a function referred to as "NK-like activity." The
      mechanism underlying this unusual functional property has recently been
      clarified. Via their T-cell receptor, NK-CTL recognize the nonclassical HLA class
      I molecule HLA-E, which is characterized by a limited polymorphism and by the
      ability to bind peptides derived from the leader sequence of various HLA class I
      alleles as well as from few viral proteins. The analysis of the T-cell receptor
      avidity revealed that NK-CTL recognize with high avidity a CMV UL40-derived
      peptide. The HLA-E-restricted recognition of CMV by NK-CTL may represent an
      important immunologic strategy in defenses against this virus. Indeed, unlike
      conventional CTL, NK-CTL mediated lysis is apparently not affected by the
      downregulation of major histocompatibility complex class I that occurs during CMV
      infection. Because the CMV UL40-derived peptide is identical to the one generated
      from the leader sequence of various HLA-Cw alleles, NK-CTL are also able to
      display an "HLA-E-dependent alloreactivity" against allogeneic target cells
      expressing appropriate HLA-Cw alleles. This broad ability to recognize and kill
      allogeneic cells may pose serious problems in transplantation.

PMID- 15172444
TI  - Stalemating a clever opportunist: lessons from murine cytomegalovirus.
AB  - Cytomegaloviruses and their specific hosts have come to an arrangement that
      avoids disease but allows the viruses to persist in the individual host and to
      spread in the host species. Recent work has uncovered some of the molecular
      details of this evolutionary "contract for mutual survival." Cytomegaloviruses
      encode proteins, referred to as "immunoevasins," which are specifically committed
      to subvert the immune defense of the host for evading virus elimination. In
      reply, the hosts have evolved countermeasures to overcome the viral immunoevasins
      and present antigenic peptides to an extent that is sufficient for confining
      virus replication to below a harmful level. Accordingly, cytomegalic inclusion
      disease is a disease only of the immunocompromised. Although the details of the
      contract differ between the various cytomegalovirus host pairs, the general
      principles are strikingly analogous. Paradigmatic findings were made in the
      murine model, which adds the advantage of providing proof of principle by in vivo
      studies. With the focus on CD8 T cells and the major histocompatibility complex
      class I pathway of antigen presentation, we will discuss our view on the immune
      surveillance of cytomegalovirus in the murine model.

PMID- 15172445
TI  - CD8(+) T-cell immunity to cytomegalovirus.
AB  - Cytomegalovirus is arguable the most immunodominant antigen that is encountered
      by the human immune system. CMV latency results from chronic immune suppression
      of viral application and the CD8(+) T cell appears to be the most important
      effector cell in this regard. The magnitude of the CMV-specific CD8(+) T cell
      response has been shown in recent years to be exceptionally strong and shows the
      unusual feature of increasing with age. The specificity of this response is
      focused on two proteins, namely pp65 and IE-1, although recent work points
      towards a broader recognition of viral proteins. The phenotype of CMV-specific T
      cells is heterogeneous but is generally typical of a late differentiation pattern
      of effector T cell. During immune suppression the CD8(+) T cell response usually
      increases in magnitude but an impaired CMV-specific immune response is indicative
      of poor clinical outcome. Advances in immunological techniques have allowed great
      advances in our understanding of CMV-specific immunity in both health and disease
      which should assist translation into improved vaccination or immunotherapeutic
      approaches.

PMID- 15172446
TI  - Consequences of human cytomegalovirus mimicry.
AB  - The HCMV genome has evolved with its host by incorporating a series of genes that
      are homologous to, or functionally mimic, cellular genes. Some are designed to
      counteract the stress of infection on the host cell, notably the viral
      antiapoptotic proteins (vICA, vMIA). Others potentially help the infected cell
      maintain a low immunologic profile. These include virus-encoded chemokine
      receptors (UL33, UL78, US27, US28), FcRs (gp TRL11/IRL11, gp UL119-118), and
      proteins that directly or indirectly thwart natural killer cell activity (UL16,
      gpUL40). In addition, some viral proteins may play a role in immunopathology
      because of fortuitous cross-reactivity with host cell proteins. This overview
      discusses how these proteins affect the life of the host cell and its immediate
      neighbors.

PMID- 15172447
TI  - Predominant type 1 CMV-specific memory T-helper response in humans: evidence for
      gender differences in cytokine secretion.
AB  - Cell-mediated memory immune responses to viral antigens are important for
      protection against viruses causing persistent or acute infections. This study
      compared the cytokine profile of memory T-helper cells specific for
      cytomegalovirus (CMV) in healthy CMV-seropositive men and women. The cytokine
      response reflected T(H)1 bias, with dominant secretion of interferon (IFN)-gamma
      along with moderate levels of tumor necrosis factor-alpha, interleukin (IL)-10,
      and IL-2. Analyzed by gender, women had higher and significant spontaneous
      release of IFN-gamma and CMV-specific IL-2 secretion. Similar analysis with
      herpes simplex virus-1 showed a trend toward higher cytokine responsiveness in
      women, but the differences were not statistically significant. In contrast, men
      had statistically significant higher influenza virus-specific tumor necrosis
      factor-alpha secretion. IL-4 and IL-5, both T(H)2 cytokines, were low for all
      three viruses. The results show a predominant T(H)1 antiviral cytokine T-help
      memory response with significant differences linked to gender. Such differences
      may have an impact in the design of immunization strategies against CMV.

PMID- 15172448
TI  - Properties of CD4(+) T cells in human cytomegalovirus infection.
AB  - The correlates of protective immunity to disease-inducing viruses in man remain
      to be elucidated. We determined the kinetics and properties of cytomegalovirus
      (CMV)-specific CD4(+) T cells in healthy individuals and renal transplant
      recipients during different stages of CMV infection. Our data reveal that
      circulating CMV-specific CD4(+) T cells displayed an effector-memory phenotype,
      and produced the T helper 1 cytokines interferon-gamma and tumor necrosis factor
      alpha. In addition, they lacked molecules for secondary lymphoid organ homing and
      expressed the cytotoxic molecule granzyme B, inferring a direct role of these
      cells at target sites of infection. In asymptomatic individuals the CMV-specific
      CD4(+) T-cell response preceded CMV-specific CD8(+) T-cell responses, whereas in
      symptomatic individuals the CMV-specific effector memory CD4(+) T-cell response
      was delayed and only detectable after antiviral therapy. The appearance of
      disease symptoms in these patients suggests that functional CD8(+) T cell and
      antibody responses are insufficient to control viral replication and that
      formation of effector memory CD4(+) T cells is necessary for recovery of
      infection.

PMID- 15172450
TI  - Cytomegalovirus (CMV)-specific cellular immune responses.
AB  - A large percentage of healthy individuals (50-90%) is chronically infected with
      Cytomegalovirus (CMV). Over the past few years, several techniques were developed
      in order to monitor CMV-specific T-cell responses. In addition to the
      identification of antigen-specific T cells with peptide-loaded MHC complexes,
      most of the current strategies to identify CMV-specific T cells are centered on
      the assessment of the functions of memory T cells including their ability to
      mediate effector function, to proliferate or to secrete cytokines following
      antigen-specific stimulation. The investigation of these functions has allowed
      the characterization of the CMV-specific T-cell responses that are present during
      different phases of the infection. Furthermore, it has also been shown that the
      combination of virus-specific CD4 and CD8 T-cell responses are critical
      components of the immune response in the control of virus replication.

PMID- 15172449
TI  - Analyzing T-cell responses to cytomegalovirus by cytokine flow cytometry.
AB  - T-cell responses to human cytomegalovirus (CMV) are readily detected in
      chronically infected adults, and are thought to be important for protection from
      CMV-related pathology. Antigen-specific cytokine flow cytometry (CFC) has been
      used to establish the range of CMV-specific CD4 and CD8 T-cell frequencies in
      healthy CMV-seropositive (and seronegative) adults, as well as the dynamics of
      these cells over time. There are also emerging data regarding the primary CD4 and
      CD8 T-cell response to CMV in children and adults. Finally, CFC has been used to
      analyze CMV responses in chronic human immunodeficiency virus infection, as well
      as during immune reconstitution after bone marrow or stem cell transplantation.
      These data will be reviewed in terms of what they suggest about the threshold of
      protective T-cell immunity to CMV, and other factors in addition to T-cell
      frequencies that could be important in protecting from CMV-associated disease.

PMID- 15172451
TI  - MHC class II tetramers containing influenza hemagglutinin and EBV EBNA1 epitopes
      detect reliably specific CD4(+) T cells in healthy volunteers.
AB  - Tracking antigen specific T cells with major histocompatibility complex (MHC)
      tetramers has provided us with insights into the dynamics of the adaptive immune
      system and holds great promise to aid in patient management and drug and vaccine
      development. Progress has been made primarily using MHC class I tetramers to
      monitor CD8(+) T cells, whereas corresponding efforts to stain CD4(+) T cells
      with class II tetramers have not been as successful. Two major reasons have been
      proposed for this lack of progress: (1). The frequency of antigen-specific CD4(+)
      T cells is lower than the frequency of CD8(+) T cells and (2). some, but not all,
      antigen- specific CD4(+) T cells can bind tetramer because of low functional
      avidity. In this study, we asked if CD4(+) T cells specific for common human
      viruses (e.g., influenza and Epstein-Barr) can be detected in healthy individuals
      previously exposed to them. We were able to clearly detect specific CD4(+) T
      cells in all donors after in vitro expansion of peripheral blood mononuclear
      cells. Furthermore, we observe a clear separation of tetramer negative and
      tetramer positive CD4(+) T cells in most samples similar to patterns commonly
      seen with class I tetramers. The data indicate that MHC class II tetramers can be
      used reliably for the identification of CD4(+) T cells specific for ubiquitous
      infectious agents in normal donors.

PMID- 15172452
TI  - Use of a lentiviral vector encoding a HCMV-chimeric IE1-pp65 protein for epitope
      identification in HLA-Transgenic mice and for ex vivo stimulation and expansion
      of CD8(+) cytotoxic T cells from human peripheral blood cells.
AB  - H2-deleted, HLA-A2, or HLA-B7 transgenic mice were used to identify new human
      cytomegalovirus (HCMV)-derived major histocompatibility complex class I
      restricted epitopes. Three different approaches for mice immunization were
      compared for their ability to induce a cytotoxic CD8(+) T cell (CTL) response:
      (1). inoculation of infectious HCMV, (2). injection of immunogenic synthetic
      peptides, and (3). infection with a newly designed HIV-derived central DNA flap
      positive lentiviral vector encoding the chimeric IE1-pp65 protein (Trip-IE1
      pp65). Targets pulsed with either known immunogenic peptides or computer
      predicted ones were used to characterize CTL. Most of the mice immunized with the
      pp65 (495-NLVPMVATV-503) immunodominant peptide responded after one injection
      whereas only two of six mice responded to two successive inoculations with HCMV.
      Infection of mice with Trip-IE1-pp65 induced activation and expansion of CTL
      directed against peptides from both pp65 and IE1 and allowed identification of
      new epitopes. We further demonstrated the high capacity of monocyte-macrophage
      cells transduced with Trip-IE1-pp65 to activate and expand CTL directed against
      pp65 from peripheral blood mononuclear cells of HCMV-seropositive donors.
      Altogether these results suggest that Trip-IE1-pp65 is a powerful construct both
      to characterize new epitopes in combination with human leukocyte antigen
      transgenic mice immunization and to provide an alternative to the use of known
      infectious and noninfectious approaches to expand effector T cells for adoptive
      immunotherapy.

PMID- 15172453
TI  - Analysis of antigen-specific T-cell responses with synthetic peptides--what kind
      of peptide for which purpose?
AB  - The analysis of T-cell responses to peptides has recently become a busy area of
      immunologic research. Peptides may be used as single stimulants, pools or
      libraries, or as part of peptide/major histocompatibility complexes (MHC) for
      direct T-cell receptor staining. For stimulating T cells, peptides must be bound
      to MHC molecules. In this study we have used 9- or 10-amino acid peptides, 15
      amino acid peptides containing stimulating shorter sequences, and peptides with
      modified C-terminal function. On average 67% of the T cells from healthy
      cytomegalovirus-positive donors that bound a frequently used cytomegalovirus
      pp65/HLA-A*0201 tetramer were able to produce interferon-gamma on stimulation
      with the respective 9-amino acid peptide. Peptides of 15 amino acids length used
      at the same concentration (in microg/ml) stimulated CD8 T cells somewhat less
      efficiently (on average 77% of the frequencies induced with the respective
      shorter peptides). Modifications of 9-amino acid peptides such as addition of
      amino acids or functional groups often resulted in a decreased ability to
      stimulate. However, based on our own results, published data, and theoretic
      considerations, we conclude that sets of peptides of 15 amino acids length with
      11 amino acids overlap represent a good compromise for stimulating both CD8 and
      CD4 T cells in a number of applications. These parameters may be modified subject
      to the purpose of a study.

PMID- 15172454
TI  - Recognition of CMV pp65 protein antigen by human CD4 T-cell lines induced with an
      immunodominant peptide pool.
AB  - Cellular immunity against cytomegalovirus (CMV) is essential for recovery from
      infection and control of viral latency. In immunocompromised hosts, this balance
      between CMV and cellular immunity is lost. Accordingly, restoration of the CD8
      compartment specific for CMV is beneficial for immunocompromised patients. It is
      clear that CMV-specific CD4 cells provide helper functions facilitating long-term
      persistence of CD8 cells. Considering the dearth of data on CMV-specific T-helper
      cells, we investigated the CD4 responses to the immunodominant protein pp65 to
      define antigenic peptides. Such peptides were pooled and used to generate long
      term T-cell lines. The lines were responsive to CMV and pp65. T cells were
      selected with individual peptides to produce monospecific lines for accurate
      definition of fine epitope specificity and to confirm human leukocyte antigen HLA
      DR restriction. Furthermore, these lines lost alloreactivity, suggesting that
      they can be generated from the allodonor for adoptive immunoreconstitution of
      stem cell graft recipients.

PMID- 15172455
TI  - Progress made towards the development of a CMV peptide vaccine.
AB  - Cytomegalovirus disease still remains a major cause of morbidity and mortality in
      hematopoietic stem cell transplantation recipients. The cell-mediated immune
      response is essential in the maintenance of latency and the resolution of primary
      infections. The identification of immunodominant cytomegalovirus antigens has
      enabled researchers to determine the best candidate antigens to be included in a
      cytomegalovirus vaccine. Such a vaccine would have to stimulate both a cell
      mediated and humoral immune response. Recent advances have enabled the rapid
      identification of minimal cytotoxic epitopes required to trigger such responses.
      Epitope mapping to date has mainly focused on the pp65 antigen but other antigens
      such as IE1 are starting to be mapped. A human leukocyte antigen allele hierarchy
      is starting to emerge that is dependent on the alleles present in an individual;
      this is relevant when considering what peptides should be included in a vaccine.
      This review looks at the current methods available for epitope mapping and the
      progress that has been made to date.

PMID- 15172456
TI  - Augmentation of virus-specific immunity after hematopoietic stem cell
      transplantation by adoptive T-cell therapy.
AB  - Adoptive transfer of virus-specific T cells offers the potential for accelerating
      reconstitution of antigen-specific immunity after allogeneic hematopoietic stem
      cell transplantation. However, the logistics of producing virus-specific T cells
      and the risk of inducing graft-versus-host disease has limited their application.
      We developed a relatively simple system employing cytomegalovirus lysate-pulsed,
      monocyte-derived dendritic cells as stimulator cells, requiring only a single
      blood draw from the donor. We treated 16 patients with these T-cell lines,
      administered after the detection of human cytomegalovirus (HCMV) DNA by
      polymerase chain reaction. Massive in vivo expansions of HCMV-specific cytotoxic
      T lymphocytes (3-5 log) were observed within days of adoptive transfer. In eight
      cases viral titers were decreasing within 5 days and antiviral drug therapy was
      not required. The T-cell receptor CDR3 lengths of HCMV-specific cytotoxic T
      lymphocytes expanding in vivo were identical to those of the transferred cells. A
      low incidence of late CMV reactivation was seen (2/14 assessable patients
      compared with 45/72 historical controls, p = 0.001) and no significant toxicities
      were observed. Our findings indicate that application of cell lines generated in
      relatively short-term in vitro cultures is both feasible and effective in a
      clinical environment. This simple in vitro methodology should allow widespread
      application of adoptive transfer of virus-specific T cells.

PMID- 15172457
TI  - CMV-specific immunotherapy.
AB  - Considerable progress has been made in our understanding of the immunobiology of
      infections in immunocompromised hosts. Insights derived from animal model and
      human studies have provided the rationale to investigate immunotherapy with
      alphabeta+ T cells to restore responses considered essential for protective
      immunity to cytomegalovirus infection. Future studies will address the role of
      adoptive immunotherapy using different immunoeffector cell populations to improve
      control of virus infection. The use of genetically modified T cells has already
      been evaluated clinically and offers the potential for improving safety and
      efficacy and removing obstacles to successful immunotherapy. Although these
      studies are in the early stages and present considerable technical challenges,
      the results suggest that cellular immunotherapy will be a fruitful area for
      investigation in future years.

PMID- 15172459
TI  - Drug-eluting stents: the new gold standard for percutaneous coronary
      revascularisation.

PMID- 15172458
TI  - Gene transfer for activation of CMV specific T cells.
AB  - Cytomegalovirus (CMV) is responsible for significant morbidity and mortality in
      immunocompromised patients undergoing allogeneic hematopoietic stem cell
      transplantation. The limitations of antiviral drugs and a better understanding of
      the cellular immune response to CMV has lead to the development of alternative
      therapies that restore host cellular immunity to CMV. Infusion of donor T
      lymphocytes results in variable protection against CMV but a high incidence of
      graft-versus-host disease in the allogeneic setting. To prevent this complication
      and further improve anti-CMV immune response, several groups have developed new
      approaches, such as the introduction of a suicide gene to control alloreactivity
      against the host or the selective activation of CMV-specific T cells by antigen
      presenting cells expressing CMV antigens introduced by gene transfer. Depending
      on the target cells and the strategy chosen, adenovirus, retrovirus or poxviruses
      derived vectors are used for gene transfer. The protocols as well as the
      preclinical and clinical results obtained in the field of anti-CMV immunotherapy
      using gene transfer are reported and discussed.

PMID- 15172460
TI  - Remise in the treatment of in-stent restenosis.

PMID- 15172461
TI  - Coronary artery disease genetics: bigger is better.

PMID- 15172462
TI  - Drug-eluting stents: an early systematic review to inform policy.
AB  - AIMS: To provide systematic assessment of the clinical effectiveness of drug
      eluting stents (DES) versus non-DES to inform national guidance. METHODS AND
      RESULTS: The review was conducted according to internationally recognised
      methods. The search strategy identified published (7) and unpublished (7)
      randomised controlled trials comparing the use of DES to non-DES. Outcomes
      included death, acute myocardial infarction (AMI), revascularisation, event rate
      (composite of adverse events), and binary restenosis. Data synthesis included
      descriptive statistics and meta-analysis. Fourteen randomised clinical trials
      comparing DES to non-DES and involving 5747 patients were identified. There were
      reductions in event rates between DES and non-DES; odds ratio (OR) 0.63 (95%
      confidence interval [95% CI] 0.47, 0.84, n = 1978) for paclitaxel-eluting stents
      at 12 months, OR 0.30 (95% CI 0.22, 0.42, n = 1296) for sirolimus-eluting stents
      at 12 months. Combined event rates were inconsistently defined across trials and
      were primarily composed of revascularisations, possibly driven by protocol
      required angiograms. DES reduced binary restenosis rates at angiogram compared to
      non-DES. No significant differences in rates of death or AMI were identified.
      CONCLUSION: The early data available indicate that DES reduce adverse cardiac
      events, mainly revascularisations. However, these data are limited in terms of
      patient numbers, length of follow-up, and method of outcome assessment. The
      evaluation of rapidly evolving technologies requires the inclusion of data not
      routinely considered for inclusion in systematic reviews of effectiveness.

PMID- 15172463
TI  - Treatment of in-stent restenosis using a paclitaxel-eluting stent: acute results
      and long-term follow-up of a matched-pair comparison with intracoronary beta
      radiation therapy.
AB  - AIMS: Intracoronary radiation therapy (ICR) has significantly improved the long
      term outcome after treatment of diffuse in-stent restenosis (ISR). The efficacy
      of drug eluting stents in this setting remains less well defined. This matched
      pair analysis compared the procedural and long-term clinical and angiographic
      outcome after treatment of diffuse ISR using a paclitaxel-eluting stent (PES)
      with intracoronary beta-radiation therapy. METHODS AND RESULTS: Twenty-two
      patients receiving 25 PES (ACHIEVE, Cook, 3.1 microg paclitaxel per square
      millimeter, non-polymer based coating) for ISR underwent 6-month angiographic and
      12-month clinical follow-up. From a database including 141 patients (174 lesions)
      undergoing intracoronary beta-radiation for ISR, 25 lesions (25 patients) were
      pair-matched with the former group for lesion length and vessel size. PES
      implantation and ICR were successful in all patients with a significantly lower
      postprocedural in-stent diameter stenosis in the PES group (8+/-12% vs. 18+/-8%,
      p < 0.01). Angiographic binary in-lesion restenosis at 6 month was 20% (5/25
      lesions) in the PES group and 16% (4/25) in the ICR group (p = 1.0). PES
      implantation resulted in significantly higher in-stent MLD at FU (2.10+/-0.71 vs.
      1.75+/-0.36, p = 0.03) and a higher in-stent net gain (PES: 1.19+/-0.69, ICR:
      0.84+/-0.49, p = 0.04). Two patients in the PES group and 6 patients in the ICR
      group experienced a target lesion revascularisation at 12-month follow-up (p =
      0.25). CONCLUSION: Implantation of a non-polymer based paclitaxel-elution stent
      and conventional ICR therapy for complex ISR lead to comparable acute and long
      term clinical and angiographic follow-up results.

PMID- 15172464
TI  - Long-term, cause-specific mortality after myocardial infarction in diabetes.
AB  - AIMS: To compare long-term, cause-specific mortality after reperfusion therapy
      for ST segment elevation myocardial infarction (STEMI) in patients with and
      without diabetes. METHODS AND RESULTS: Patients with STEMI (n = 395) were
      randomised to intravenous streptokinase (SK) or primary percutaneous coronary
      intervention (PCI). Median follow-up was 7.5 years (interquartile range 5.6-8.5).
      A total of 74 patients (19%) had diabetes. Reduced left ventricular ejection
      fraction (<40%) after STEMI was more often observed in patients with diabetes
      (27% vs. 15%, P = 0.02). Patients with diabetes had a higher total mortality
      compared to patients without diabetes (HR 2.4; P < 0.001). Multivariate analysis
      confirmed that diabetes was an independent risk factor for long-term mortality
      (HR 2.3; P < 0.001). The incidence of sudden death was comparable in both patient
      groups (HR 1.6; P = 0.23). The increased mortality in patients with diabetes was
      mainly caused by heart failure (HR 3.1; P = 0.004). In patients with diabetes,
      primary PCI was associated with an improved prognosis. CONCLUSIONS: Despite
      reperfusion therapy, STEMI patients with diabetes have an increased long-term
      mortality. This is due to death by heart failure and not by an increase in sudden
      death. Primary PCI is associated with an improved prognosis, particularly in
      patients with diabetes.

PMID- 15172465
TI  - Is post-systolic motion the optimal ultrasound parameter to detect induced
      ischaemia during dobutamine stress echocardiography?
AB  - AIMS: Doppler myocardial imaging (DMI) has been suggested as a method of
      quantifying induced ischaemia during dobutamine stress echocardiography (DSE).
      The aim of the present study was to investigate both standard systolic and
      diastolic parameters, but more specifically to address the phenomenon of post
      systolic motion (PSM) as a marker of acquired ischaemia during DSE using pulsed
      wave DMI. METHODS AND RESULTS: We examined 60 patients without previous
      myocardial infarction who underwent DSE. Peak systolic, post-systolic, early and
      late diastolic velocities were measured at rest and during stress. Myocardial
      segments (n = 908) were divided into ISCHAEMIC and NON-ISCHAEMIC groups according
      to the presence of significant angiographic coronary stenosis. ISCHAEMIC segments
      (n = 357) compared with NON-ISCHAEMIC segments (n = 551) demonstrated a reduced
      increase of systolic velocity (8.0-12.7 vs 9.3-16.4 cm/s, P < 0.05), prominent
      PSM (5.8-8.3 vs 0.63-2.1 cm/s, P < 0.000001) and reduced early diastolic velocity
      (6.5-10.2 vs 7.9-13.2 cm/s, P < 0.04) during stress. The peak velocity of PSM was
      the most accurate index of induced ischaemia (sensitivity 73-100%, specificity 82
      97%) compared to systolic and early diastolic velocities (sensitivity 52-77% and
      63-68%, specificity 63-77% and 59-81%, respectively). CONCLUSION: PSM derived by
      pulsed-wave DMI during DSE was the most sensitive index of acquired ischaemia
      compared to other functional DMI indices.

PMID- 15172466
TI  - Single nucleotide polymorphism in the low-density lipoprotein receptor is
      associated with a threefold risk of stroke. A case-control and prospective study.
AB  - BACKGROUND: More than 600 different, but rare, mutations in the low-density
      lipoprotein (LDL) receptor have been identified as the cause of familial
      hypercholesterolaemia. In contrast, only a single common amino acid-changing
      polymorphism (A370T) has been reported in this gene. The association of this
      polymorphism with variations in lipid levels is at present unclear. METHODS: We
      obtained genotypes for 9238 individuals from The Copenhagen City Heart Study, of
      which 465 had stroke and 1019 had ischaemic heart disease. RESULTS: In this
      cohort from the Danish general population, 90.2% (n = 8,332), 9.5% (n = 875), and
      0.3% (n = 31) were 370A homozygotes, A370T heterozygotes, and 370T homozygotes,
      respectively. The incidences of stroke in 370A homozygotes, A370T heterozygotes,
      and 370T homozygotes were 28, 26, and 100 per 10,000 person-years, respectively
      (370T homozygotes vs. 370A homozygotes: log-rank, P = 0.002). The relative risk
      and odds ratio for stroke in 370T homozygotes vs. 370A homozygotes were 3.6 (95%
      confidence interval, 1.5-8.8) and 3.6 (95% confidence interval, 1.3-9.8) in
      prospective and cross-sectional studies, respectively. Furthermore, average age
      at onset of stroke in 370T homozygotes tended to be lower than in heterozygotes
      and 370A homozygotes combined (59 vs. 66 years, P = 0.08). In contrast, neither
      levels of cholesterol, LDL cholesterol, apolipoprotein B, or triglycerides, nor
      risk of ischaemic heart disease was associated with genotype. CONCLUSION: This is
      the first prospective study to suggest an association between a polymorphism in
      the LDL receptor and stroke. Because this association is independent of lipid
      levels, our results point toward a hitherto unknown function of this receptor in
      the brain.

PMID- 15172467
TI  - Is central nervous system processing altered in patients with heart failure?
AB  - AIMS: Breathlessness is a cardinal symptom of heart failure and the altered
      regulation of breathing is common. The contribution of abnormal central nervous
      system activity has not previously been investigated directly, although abnormal
      autonomic responses have been described. Our aim was to assess whether heart
      failure patients exhibit different patterns of regional brain activation after
      exercise stress. METHODS: We used positron emission tomography with H2(15)O, to
      measure changes in regional cerebral blood flow (rCBF) and absolute global
      cerebral blood flow (gCBF) in 6 male class II/III heart failure patients and 6
      normal controls. Breathlessness (0-5 visual analogue scale) and respiratory
      parameters were measured at rest, after horizontal bicycle exercise and during
      isocapnic hyperventilation. CBF was measured in each condition in all subjects.
      RESULTS: Both groups were similarly breathless after exercise and the respiratory
      parameters were comparable. rCBF differences for the main comparison (exercise vs
      hyperventilation) were: activation of the right frontal medial gyrus (P < 0.001,
      Z = 4.90) and left precentral gyrus (P < 0.03, Z = 4.66) in controls but not in
      patients. Both groups had rCBF increases in the left anterior cingulate (P <
      0.05, Z = 4.67) and right dorsal cingulate cortex (P < 0.05, Z = 4.66). The gCBF
      did not differ between exercise, isocapnic hyperventilation and rest in patients
      but, in controls, gCBF was greater after exercise compared to either isocapnic
      hyperventilation or rest. CONCLUSION: Heart failure patients had a distinct
      pattern of regional cortical activity with exercise-induced breathlessness but
      unvarying CBF values between conditions. These central neural differences in
      activity may contribute to some features of heart failure, such as variability in
      symptoms and autonomic dysregulation.

PMID- 15172468
TI  - Prospective randomised comparison of irrigated-tip and large-tip catheter
      ablation of cavotricuspid isthmus-dependent atrial flutter.
AB  - BACKGROUND: Radiofrequency (RF) ablation of cavotricuspid isthmus (CTI) dependent
      flutter can be performed using different types of ablation catheters. It has been
      proposed that irrigated and large-tip catheters are capable of creating larger
      lesions, resulting in greater efficacy. This prospective, randomised clinical
      study compared the efficacy of irrigated and large-tip catheters of different
      designs. METHODS: Eighty patients (69 men, 66+/-11 years) undergoing de novo RF
      ablation of CTI-dependent flutter were randomised to ablation using one of the
      following catheters: (i) externally-irrigated 20), (ii) internally-cooled (n=20),
      (iii) single sensor, 8-mm tip (n=20), or (iv) double sensor, 8-mm tip (n=20). The
      study endpoint was the demonstration of bidirectional CTI conduction block within
      12 min of cumulative RF delivery. Crossover to the externally-irrigated catheter
      was permitted if this was not achieved. The ablation and procedural parameters,
      safety and efficacy were compared. RESULTS: The primary endpoint was achieved in
      64 patients (80%), including all 20 patients randomised to the externally
      irrigated catheter. Crossover was required in 16 patients: 9 initially using the
      internally-cooled catheter (45%), 3 using single-sensor, 8-mm-tip (15%), and 4
      using double-sensor, 8-mm-tip (20%) catheters. The higher initial failure rate
      with the internally-cooled-tip catheter was significant compared to the
      externally-irrigated (p = 0.001) and single-sensor, 8-mm-tip (p = 0.04)
      catheters. The externally-irrigated catheter achieved the study endpoint more
      frequently with fewer RF applications of shorter duration compared to the
      internally-cooled-tip catheter and 8-mm-tip catheters, the difference being
      significant compared with internally cooled ablation. No major complications were
      observed. CONCLUSION: Among commonly used ablation catheters, the externally
      irrigated catheter has a higher efficacy for rapid achievement of CTI block.

PMID- 15172469
TI  - Genetic risk and gene-environment interaction in coronary artery spasm in
      Japanese men and women.
AB  - AIMS: The aim of the study was to identify genes that confer susceptibility to
      coronary artery spasm and clarify the interaction between genetic and
      environmental factors in this condition. METHODS AND RESULTS: The study
      population comprised 2188 Japanese individuals, including 593 subjects with
      coronary artery spasm (453 men, 140 women) and 1595 controls (762 men, 833
      women). The genotypes for 35 polymorphisms of 29 candidate genes were determined
      with an allele-specific DNA primer-probe assay. Multivariable logistic regression
      analysis adjusted for age, body mass index, and the prevalence of smoking,
      hypertension, diabetes mellitus, hypercholesterolaemia, and hyperuricaemia
      revealed a significant association with coronary artery spasm of one polymorphism
      (242C-->T in the NADH/NADPH oxidase p22 phox gene) in men and two polymorphisms (
      1171/5A-->6A in the stromelysin-1 gene and -634C-->G in the interleukin-6 gene)
      in women. A stepwise forward selection procedure revealed that smoking was the
      most important risk factor for coronary artery spasm and that the effects of
      these polymorphisms on this condition were statistically independent of smoking.
      CONCLUSION: The NADH/NADPH oxidase p22 phox gene is a susceptibility locus for
      coronary artery spasm in men, and the stromelysin-1 and interleukin-6 genes are
      susceptibility loci in women.

PMID- 15172470
TI  - Exercise testing of healthy men in a new perspective: from diagnosis to
      prognosis.
AB  - AIM: It has recently been suggested that exercise testing may be more valuable
      prognostically than it is diagnostically in apparently healthy subjects. We
      wanted to compare the accuracy of CHD risk assessment based on classical risk
      factors with an assessment also based on multiple exercise test parameters.
      METHODS AND RESULTS: In 1972-75, 2014 apparently healthy men aged 40-60 had a
      symptom limited exercise test during a cardiovascular survey. Three hundred died
      from CHD during 26 years of follow-up. Compared to Cox regression models solely
      including classical risk factors (CRF), models also including multiple exercise
      test parameters (CRF+X) were clearly superior (P < 0.0001). Risk scores were
      computed based on the models. CRF and CRF+X risk scores often differed markedly;
      CRF+X scores were generally most reliable in both the high and low risk range. In
      smokers with cholesterol >6.5 mmol/l (n = 470), the CRF and CRF+X models
      identified 67 vs. 110 men at the highest CHD risk level according to European
      guidelines (34.2% vs. 38.2% CHD mortality). Three in five CRF+X-identified
      smokers with cholesterol >6.5 mmol/l had CHD mortality similar to the mean of all
      2014 men. CONCLUSION: Integration of multiple exercise test parameters and
      conventional risk factors improved CHD risk assessment substantially--especially
      in smokers with high cholesterol.

PMID- 15172471
TI  - Increased left ventricular mass in obese adolescents.
AB  - AIMS: An increase of left ventricular mass (LVM) has been reported in obese
      adolescents in previous studies using echocardiography. The aim of our study was
      to determine the extent of the increase in LVM and correlation to other risk
      factors using cardiac magnetic resonance imaging in obese and lean adolescents.
      METHODS AND RESULTS: Nineteen obese and 20 lean adolescents were recruited.
      Following resting blood pressure measurements and blood sampling for insulin,
      triglycerides, and cholesterol levels, all subjects underwent cardiac magnetic
      resonance examination to assess LVM. LVM adjusted for body height was 16% greater
      in obese compared to lean adolescents (median 66 g/m, p = 0.0042). Obese subjects
      had higher resting systolic blood pressures than controls (median 115 vs. 110
      mmHg, p = 0.0077) and higher fasting triglyceride and insulin levels. HDL
      cholesterol levels were lower in the obese group compared with the lean group.
      CONCLUSIONS: Obese adolescents had a higher LVM than age-matched lean subjects,
      which correlated mainly with body mass index and systolic blood pressure. These
      findings add to the established cardiovascular risk profile of obese adolescents.

PMID- 15172472
TI  - The adhesion molecule P-selectin and cardiovascular disease--cardiac surgical
      implications.

PMID- 15172473
TI  - Coronary artery plaque temperature: what do we measure?

PMID- 15172474
TI  - Probable need for psychiatric treatment is not the same as depression.

PMID- 15172476
TI  - Screening for cardiovascular disease.

PMID- 15172478
TI  - Cardioversion threshold, IRAF and beyond.

PMID- 15172479
TI  - Survival and growth characteristics of Escherichia coli O157:H7 in pasteurized
      and unpasteurized Cheddar cheese whey.
AB  - The objective of this study was to determine the survival and growth
      characteristics of Escherichia coli O157:H7 in whey. A five-strain mixture of E.
      coli O157:H7 was inoculated into 100 ml of fresh, pasteurized or unpasteurized
      Cheddar cheese whey (pH 5.5) at 10(5) or 10(2) CFU/ml, and stored at 4, 10 or 15
      degrees C. The population of E. coli O157:H7 (on Sorbitol MacConkey agar
      supplemented with 0.1% 4-methylumbelliferyl-beta-D-glucuronide) and lactic acid
      bacteria (on All Purpose Tween agar) were determined on days 0, 1, 4, 7, 14, 21
      and 28. At all storage temperatures, survival of E. coli O157:H7 was
      significantly higher (P<0.01) in the pasteurized whey compared to that in the
      unpasteurized samples. At 10 and 15 degrees C, E. coli O157:H7 in pasteurized
      whey significantly (P<0.05) increased during the first week of storage, followed
      by a decrease thereafter. However at the same temperatures, E. coli O157:H7
      exhibited a steady decline in the unpasteurized samples from day 0. At 4 degrees
      C, E. coli O157:H7 did not grow in pasteurized and unpasteurized whey; however,
      the pathogen persisted longer in pasteurized samples. At all the three storage
      temperatures, E. coli O157:H7 survived up to day 21 in the pasteurized and
      unpasteurized whey. The initial load of lactic acid bacteria in the unpasteurized
      whey samples was approximately 7.0 log10 CFU/ml and, by day 28, greater than 3.0
      log10 CFU/ml of lactic acid bacteria survived in unpasteurized whey at all
      temperatures, with the highest counts recovered at 4 degrees C. Results indicate
      the potential risk of persistence of E. coli O157:H7 in whey in the event of
      contamination with this pathogen.

PMID- 15172481
TI  - Comparison of selective and nonselective primary enrichments for the detection of
      Listeria monocytogenes in cheese.
AB  - A completely selective enrichment procedure was compared with two partially
      nonselective ones for the detection of Listeria monocytogenes in cheeses. After
      enrichment for approximately 48 h, the enrichment media were streaked on
      selective agars and presumptive Listeria colonies were confirmed using PCR. In
      some cases, PCR was also performed directly on the enrichment broth. The
      conventional, completely selective enrichment procedure was not always the best
      choice for the detection of stressed L. monocytogenes in cheeses. Especially in
      the case of semi-hard cheeses from pasteurized milk and soft cheeses of the blue
      veined and the red smear types, the methods that incorporated a nonselective
      enrichment step gave better results than the completely selective method. For
      mold ripened, soft cheeses, the results were highly dependent on the brand of
      cheese and time of sampling, but the best results were obtained using the
      completely selective enrichment procedure.

PMID- 15172480
TI  - An inter-laboratory evaluation of selective media for the detection and
      enumeration of yeasts from blue-veined cheese.
AB  - Five countries representative of laboratories 1-5 evaluated 11 different
      selective media, designed to suppress mould and bacterial growth and support
      yeasts growth, for the recovery of yeast populations from blue veined cheeses. In
      addition, qualitative results were also incorporated. The yeast enumeration
      values were subjected to statistical analysis using analysis of variance (ANOVA)
      and the Tukey-Kramer multiple comparison test. With the exception of Laboratory
      3, none of the other laboratories was successful in recovering yeasts on all the
      media. Six of the media proved inadequate for the enumeration of yeasts in the
      mould invested environment and were therefore omitted from statistical analysis.
      No significant differences in quantitative data obtained on Rose-Bengal
      Chloramphenicol Agar (RBCA), Dichloran Rose-Bengal Chloramphenicol Agar (DRBC),
      Dichloran 18% Glycerol Agar (DG18), and Malt extract agar supplemented with NaCl
      and oxytetracycline (MES) were detected by four of the collaborating laboratories
      whereas one laboratory found RBCA to be superior for yeast enumeration. DG18 and
      Malt Extract Agar with Biphenyl (MEB), however, were ranked superior based on
      qualitative results compared to the other media, attributed to distinctive
      individual yeast colonies and mould inhibition. RBCA, DRBC, DG18, and MES on the
      other hand, all proved to be adequate in supporting yeast colony development for
      quantitative analysis in samples obtained from blue veined cheeses.

PMID- 15172482
TI  - The presence of Enterococcus, coliforms and E. coli in a commercial yeast
      manufacturing process.
AB  - This study evaluated a typical commercial yeast manufacturing process for
      bacterial contamination. Product line samples of a commercial yeast manufacturing
      process and the corresponding seed yeast manufacturing process were obtained
      upstream from the final compressed and dry yeast products. All samples were
      analysed before (non-PI) and after preliminary incubation (PI) at 37 degrees C
      for 24 h. The PI procedure was incorporated for amplification of bacterial counts
      below the lower detection limit. Enterococcus, coliform and Escherichia coli
      counts were quantified by standard pour-plate techniques using selective media.
      Presence at all stages and progressive increases in counts of Enterococcus,
      coliforms and E. coli during processing in the commercial manufacturing operation
      suggested that the primary source of contamination of both compressed and dry
      yeast with these bacteria was the seed yeast manufacturing process and that
      contamination was amplified throughout the commercial yeast manufacturing
      process. This was confirmed by surveys of the seed yeast manufacturing process
      which indicated that contamination of the seed yeast with Enterococcus, coliforms
      and E. coli occurred during scale up of seed yeast biomass destined as inoculum
      for the commercial fermentation.

PMID- 15172483
TI  - PCR-RFLP using a SNP on the mitochondrial Lsu-rDNA as an easy method to
      differentiate Tuber melanosporum (Perigord truffle) and other truffle species in
      cans.
AB  - Canned truffle products labeled Tuber melanosporum, the famous Perigord truffle,
      may contain other less tasty and cheaper truffle species. To protect consumers
      from fraud, a PCR DNA-based method was used to unequivocally identify the nature
      of the product. Several rapid and simple cell lysis procedures, used in
      conjunction with a commercially available DNA purification kit, were evaluated
      for their effectiveness in recovering DNA from canned truffle. In parallel, a
      marker for T. melanosporum was tested on the mitochondrial rDNA. These two
      techniques were then combined to differentiate T. melanosporum from other truffle
      species like T. aestivum, T. brumale or T. indicum up to the legal threshold in
      canned products. These findings not only allow a comparison of the effectiveness
      of the different DNA extraction methods but also provide a preliminary indication
      of the specificity and sensitivity of the detection with the mitochondrial marker
      that might be attainable for truffle species in a quantitative PCR-based analysis
      method.

PMID- 15172484
TI  - Influence of environmental factors on the biosynthesis of type B trichothecenes
      by isolates of Fusarium spp. from Spanish crops.
AB  - Various species of Fusarium can produce trichothecene mycotoxins that contaminate
      food commodities and can represent a risk for human and animal health. In this
      paper, a full factorial design was applied to study the influence of incubation
      temperature, water activity (a(w)) and type of isolate on the production of
      deoxynivalenol (DON), nivalenol (NIV) and 3-acetyldeoxynivalenol (3-AcDON) in
      corn kernel cultures by three isolates of Fusarium graminearum and three isolates
      of Fusarium culmorum from crops grown in Spain. The tested temperatures were 15,
      20, 28 and 32 degrees C. The a(w)-values were 0.960, 0.970 and 0.980. Moisture of
      cultures (within the studied range) did not affect significantly production of
      trichothecenes; however, the temperature affected significantly mycotoxin
      production and the optimal values were 28, 20 and 15 degrees C for DON, NIV and 3
      AcDON, respectively. Four additional isolates of F. graminearum and two
      additional isolates of F. culmorum were examined for production of these
      mycotoxins at the optimal temperatures. Of the seven isolates of F. graminearum,
      four produced DON (0.88-3.97 microg/g), seven produced NIV (1.53-124 microg/g),
      and three produced 3-AcDON (0.65-10.6 microg/g). Of the five isolates of F.
      culmorum, four produced DON (1.20-4.93 microg/g), four produced NIV (6.94-701
      microg/g), and four produced 3-AcDON (0.83-7.70 microg/g). Practically all
      isolates seem to belong to the NIV-chemotype. This is the first study done with
      regard to interaction between strain and ecological variables on type B
      trichothecene production by isolates of these two species from crops grown in
      Spain.

PMID- 15172485
TI  - Contribution of a selected fungal population to proteolysis on dry-cured ham.
AB  - The proteolytic changes taking place in dry-cured hams lead to increases in free
      amino acids. Such free amino acids not only contribute to flavour, but also serve
      as precursors of volatile compounds. Several months of ripening time are required
      to allow the particular flavour to develop. The fungal population allowed to grow
      on the surface of some types of dry-cured could play a key role on proteolysis,
      as it has been shown for dry-cured sausages. The purpose of this work was to
      study the possible contribution of fungi to proteolysis in dry-cured ham. For
      this, a strain each of non-toxigenic Penicillium chrysogenum (Pg222) and
      Debaryomyces hansenii (Dh345), selected for their proteolytic activity on
      myofibrillar proteins, were inoculated as starter cultures. Changes in the high
      ionic strength-soluble proteins of an external muscle (adductor) revealed in only
      6 months higher proteolysis in the inoculated hams when compared to non
      inoculated control hams. Proteolytic strains among the wild fungal population on
      non-inoculated control hams prevented from obtaining similar differences at the
      end of processing. However, inoculation with Pg222 and Dh345 led to higher levels
      for most free amino acids at the external muscle in fully dry-cured hams. In
      addition, the concentration for some of the more polar free amino acids (i.e.
      Asp, Glu, Ser and Gln) in inoculated hams was higher at external than at internal
      (biceps femoris) muscles. These promising results deserve further studies to know
      the impact of a selected fungal population on the volatile compounds and sensory
      properties of dry-cured ham.

PMID- 15172486
TI  - Effect of a(w), controlled by the addition of solutes or by water content, on the
      growth of Listeria innocua in broth and in a gelatine model.
AB  - The effect of a(w) on the growth of Listeria innocua was investigated in broth
      and on the surface of a gelatine food model. In broth, a(w) was controlled from
      0.91 to 0.99 by the addition of solutes such as NaCl, KCl, glucose, sucrose and
      glycerol. In the gelatine food model, a(w) was controlled by removal of water. In
      the a(w) range, 0.92-0.99, the generation times observed in broth in the presence
      of NaCl, KCl, sucrose and glucose were similar but were longer than those in
      glycerol. For lag times, the inhibition of L. innocua growth followed the order:
      NaCl = KCl = sucrose>glucose>glycerol. When comparing growth at a(w) 0.95 for the
      three media--broth + NaCl, gelatine gel (a(w) controlled by removal of water) and
      gelatine gel with NaCl (gel + NaCl, a(w) controlled by NaCl)--the shortest
      generation time was observed in broth + NaCl, followed by gel + NaCl and,
      finally, on gel with a larger gap between the last two. The generation time on
      gel was five times greater than the generation time in broth + NaCl and 2.5 times
      greater on gel + NaCl. It was concluded that not only the structure of the media
      (solid or liquid) had an effect on Listeria inhibition but also and mainly the
      way the a(w) was adjusted. Removal of water was more stressful to Listeria than
      the addition of NaCl.

PMID- 15172487
TI  - Effect of the adaptation to high bile salts concentrations on glycosidic
      activity, survival at low PH and cross-resistance to bile salts in
      Bifidobacterium.
AB  - Six derivatives with increased resistance to ox gall (MIC: > or = 1% w/v) and one
      derivative resistant to sodium cholate (MIC: 0.8% w/v) were obtained from more
      sensitive original Bifidobacterium strains. These microorganisms, and two
      additional cholate resistant derivatives obtained in a previous study (Int. J.
      Food Microbiol. 82 (2003) 191), were partially characterised in this study.
      Acquisition of resistance against a given bile salt, also conferred cross
      resistance to other bile salts, and promoted an increase in the survival of these
      microorganisms at low pH. Bile resistance levels of derivatives were dependent on
      the external pH so that the resistance was lower at neutral pH values than in
      acidic environments. In addition, the acquisition of bile resistance induced
      changes on glycoside-hydrolysing activities of derivatives obtained from five out
      of eight original strains, with certain activities such as beta-glucosidase
      showing more than tenfold increases in some of these microorganisms. These data
      suggest that the exposure to high bile salts concentrations may have induced a
      synergic response on Bifidobacterium for the adaptation to the conditions of the
      gastrointestinal tract. This could have improved the survival at low pH in these
      microorganisms, the resistance to high bile salts concentrations, and the
      assimilation of non-digestible carbohydrates by the enhancement of some glycoside
      hydrolysing activities.

PMID- 15172488
TI  - Comparison of four methods for isolation of Yersinia enterocolitica from raw and
      pasteurized milk from northern Iran.
AB  - Four methods for isolation of Yersinia enterocolitica from raw and pasteurized
      milk from northern Iran were compared. Three hundred and ten raw milk samples
      were collected from tanks on their arrival at various central dairies, and 40
      pasteurized milk samples were collected from tanks on their arrival at a
      manufacturing plant. Each sample was examined for the presence of Y.
      enterocolitica by (1) direct culture; (2) enrichment in double-strength buffered
      peptone water at 4 degrees C for 1 month; (3) enrichment in modified Rappaport
      medium at room temperature for 72 h after a preenrichment in double-strength
      peptone water at 4 degrees C for 1 month; and (4) enrichment in a medium
      containing sucrose, tris (hydroxymethyl) aminomethane, sodium azide, and
      ampicillin at 28 degrees C for 48 h after a preenrichment in double-strength
      peptone water at 4 degrees C for 1 month. All samples and enrichments were spread
      on MacConkey agar plus calcium chloride and Tween 80, Yersinia selective agar,
      and Hektoen medium plus ampicillin. Five samples (1.6%) of raw milk but no
      pasteurized milk samples were positive for Y. enterocolitica. No Y.
      enterocolitica were recovered by methods 1 or 2. Y. enterocolitica were recovered
      from 2 samples by method 3 followed by culture on Yersinia selective agar, and
      from 5 samples by method 4 followed by culture on Hektoen medium plus ampicillin.
      The isolates were biotype 1A or 1B, serotype O:7-13 or O:9 and phage type Xo or
      Xz. All isolates were resistant to ampicillin and amoxicillin, and sensitive to
      tetracycline, streptomycin, chloramphenicol, and trimethoprim-sulfamethoxazole.

PMID- 15172489
TI  - Pentadiene production from potassium sorbate by osmotolerant yeasts.
AB  - Some yeast strains belonging to the species Zygosaccharomyces rouxii and
      Debaryomyces hansenii are capable of spoiling sorbate containing high-sugar foods
      by producing pentadiene, a volatile compound reported to have 'petroleum-like'
      odour. Quantification of the diminution of sorbate and the subsequent increase of
      pentadiene was performed by growing the yeasts in experimental media containing
      600 g/l sucrose and different sorbate concentrations. Final sorbate
      concentrations were notably lower than their corresponding initial ones, and it
      was found that the higher the initial concentration of sorbate in the media, the
      higher the amount of pentadiene produced. In all cases, Z. rouxii was able to
      produce more pentadiene than D. hansenii when expressing pentadiene concentration
      as a function of cell biomass. These results suggest that pentadiene is a
      metabolite of sorbate.

PMID- 15172490
TI  - Lactic acid tolerance determined by measurement of intracellular pH of single
      cells of Candida krusei and Saccharomyces cerevisiae isolated from fermented
      maize dough.
AB  - Strains of Candida krusei and Saccharomyces cerevisiae were grown together at 30
      degrees C in MYGP broth, pH 2.5, in the presence of 106.4 mM undissociated lactic
      acid. The two C. krusei strains investigated grew within 48 h from initial counts
      of 2 x 10(4) to approximately 10(7) cells/ml whereas the two S. cerevisiae
      strains investigated survived but did not grow in the presence of 106.4 mM
      undissociated lactic acid at pH 2.5. To explain the differences in lactic acid
      tolerance of the two yeast species, we used fluorescence-ratio-imaging microscopy
      and a perfusion system to determine the short-term intracellular pH (pH(i))
      changes in single cells of C. krusei and S. cerevisiae. The changes were
      investigated both in the presence of low (20.7 mM) and high (106.4 mM)
      concentrations of undissociated lactic acid. For both the investigated species
      20.7 mM undissociated lactic acid did not seem to influence the initial pH(i)
      which for C. krusei was found to be approximately 8.0 and for S. cerevisiae 6.9
      7.5. For both C. krusei strains, perfusion with 106.4 mM undissociated lactic
      acid induced only weak short-term pH(i) responses with a decrease in pH(i) of
      less than one pH unit. Contrary, for both strains of S. cerevisiae perfusion with
      106.4 mM undissociated lactic acid resulted in a significant decrease in pH(i)
      from initially 6.9-7.5 to 6.2-6.4 after 1 min and further to a pH(i) of < or =
      5.5 after 3 min after which it remained constant. The results obtained show that
      C. krusei is more resistant to short-term pH(i) changes caused by lactic acid
      than S. cerevisiae, and this, in turn, may be part of the explanation why C.
      krusei is more tolerant to lactic acid than S. cerevisiae.

PMID- 15172491
TI  - Ring opening polymerization of L-lactide initiated by creatinine.
AB  - L-lactide was first successfully ring-opening polymerized in bulk using
      creatinine initiator. Poly(L-lactide)(PLLA) synthesized possesses a moderate
      molecular weight (MW) (Mn = 1.56 x 10(4)) and pretty narrow MW distribution (PDI
      = 1.28). Influence of temperature, time and creatinine dosage on the
      polymerization and formed PLLA's properties were examined. The polymerization
      mechanism is postulated according to (1)HNMR characterization of the propagation
      species and the synthesized PLLA product.

PMID- 15172492
TI  - The influence of wear particles in the expression of osteoclastogenesis factors
      by osteoblasts.
AB  - Orthopedic implant failures are often associated with peri-implant osteolysis.
      Particles generated from the wear process have been suspected to play an
      important role in this situation. Indeed, the peri-implant osteolysis could be
      due to the presence of particles stimulating the osteoclastogenesis process. We
      hypothesize then that the presence of a low particle concentration positively
      influences osteoblasts to produce osteoclastogenesis factors. If true, this
      hypothesis would then support the idea that the particles could be at the origin
      of the process leading to implant loosening. To check the validity of this
      hypothesis, we quantified in vitro the production of different genes involved in
      the osteoclastogenesis process using primary isolated human osteoblasts treated
      or not with particles. Results showed that low concentrations of particles might
      have a stimulating effect on osteoblasts to produce osteoclastogenesis factors as
      demonstrated by the increase of RANKL and CSF-1 gene expression in the particle
      group.

PMID- 15172493
TI  - Development and characterization of enhanced green fluorescent protein and
      luciferase expressing cell line for non-destructive evaluation of tissue
      engineering constructs.
AB  - This study investigates the utility of genetically modified cells developed for
      the qualitative and quantitative non-destructive evaluation of cells on
      biomaterials. The Fisher rat fibroblastic cell line has been genetically modified
      to stably express the reporter genes enhanced green fluorescence protein (EGFP)
      and luciferase. These reporter genes provide two unique opportunities to evaluate
      cell growth on materials without destruction of the sample. Utilizing the
      fluorescence of EGFP expressed in the cells, we were able to demonstrate
      distribution of cells in a oligo(poly(ethylene glycol) fumarate) hydrogel
      material and on a titanium fiber mesh scaffold using an inverted fluorescent
      light microscope. In addition, we were able to utilize a molecular light imaging
      system to macroscopically image the cells on these materials both with
      fluorescence and luminescence, as well as quantify the signal from the samples.
      Quantification of cell growth on the titanium mesh material for a period of 28
      days was accomplished using the molecular light imaging system. Imaging was
      extended in vivo to cells on the titanium mesh scaffolds subcutaneously implanted
      in Fisher rats for a period of 28 days. This study outlines a non-destructive
      method to evaluate cells growing on biomaterials in vitro and in vivo.

PMID- 15172494
TI  - In vitro degradation of three-dimensional porous poly(D,L-lactide-co-glycolide)
      scaffolds for tissue engineering.
AB  - In vitro degradation behaviors of three-dimensional tissue engineering porous
      scaffolds made from amorphous poly(D,L-lactide-co-glycolide) with three different
      formulations have been systematically investigated up to 26 weeks in phosphate
      buffer saline solution at 37 degrees C. The following properties of the scaffolds
      were measured as a function of degradation time: dimensions, weight, compressive
      strength and modulus, polymer molecular weight and its distribution, and pore
      morphology. Of special interest was the determination of mechanical properties in
      wet environment. The pH of the PBS media was also detected. According to the
      characteristic changes of the various properties of porous scaffolds, the
      degradation process is suggested to be roughly divided into three stages
      tentatively named as quasi-stable stage, decrease-of-strength stage, loss-of
      weight and disruption-of-scaffold stage.

PMID- 15172495
TI  - Ectopic bone formation in rats: the importance of vascularity of the acceptor
      site.
AB  - Bone graft substitutes (BGS) can be fabricated by the combination of three key
      ingredients: (1) competent bone-forming cells, (2) a suitable framework or
      scaffold, and (3) the presence of biological stimulants. Although much research
      has been done to develop the ideal BGS, still the results are not very
      consistent. In view of this, the cellularity and vascularity of the recipient
      site are supposed to be important for the osteoinductive capacity of BGS.
      Therefore, we hypothesized that a muscle recipient site could favor bone
      formation in a cell-based BGS compared to a subcutaneous recipient site due to
      the higher vascularity of muscle tissue. To prove this hypothesis, 48 titanium
      fiber mesh implants were seeded with rat bone marrow stromal cells (RBM) and
      implanted subcutaneously and intramuscularly in the adductor thigh muscle of
      rats. The amount of bone formation after 1, 3 and 6 weeks was evaluated by
      histology and histomorphometry as well as by calcium content. Analysis revealed
      that the bone formation increased during implantation. However, bone formation
      did not exceed 12% of the implant surface, both for the intramuscular and
      subcutaneous recipient site. Also, no significant differences in bone amount
      between these two sites existed. Consequently, our hypothesis could not be
      confirmed.

PMID- 15172496
TI  - The fabrication and characterization of linearly oriented nerve guidance
      scaffolds for spinal cord injury.
AB  - Strategies to promote axonal extension through a site of injury, including the
      provision of nervous system growth factors and supportive substrates, produce
      growth of axons, that is highly random and does not extend past the lesion site
      and into the host tissue (Brain Res. Bull 57(6) (2002) 833). Physically guiding
      the linear growth of axons across a site of injury, in addition to providing
      neurotrophic and/or cellular support, would help to retain the native
      organization of regenerating axons across the lesion site and into distal host
      tissue, and would potentially increase the probability of achieving functional
      recovery. In the present study, a novel procedure was developed for using freeze
      dry processing to create nerve guidance scaffolds made from agarose, with
      uniaxial linear pores. The hydrated scaffolds were soft and flexible, contained
      linear guidance pores extending through their full length, were stable under
      physiological conditions without chemical crosslinking, and could be readily
      loaded with diffusible growth stimulating proteins.

PMID- 15172497
TI  - Modification of fibrous poly(L-lactic acid) scaffolds with self-assembling
      triblock molecules.
AB  - Molecular self-assembly offers an effective method to modify the surface
      properties of common biomaterials by presenting biologically relevant chemistry
      in a controlled, ordered fashion. This work reports on self-assembling triblock
      molecules containing rigid cholesteryl segments followed by flexible oligomers of
      L-(lactic acid) and second generation L-lysine dendrons. Second harmonic
      generation and small angle X-ray scattering indicate these molecules self
      assemble into multilayer polar structures when cast from ethyl acetate solutions
      and segregate into polar polydomains when annealed. These self-assembled layers
      significantly improve water wettability when coated onto poly(L-lactic acid)
      fibers. Scaffolds formed from fibers modified by self-assembly enhance adhesion
      of 3T3 mouse calvaria cells and produce greater population growth rates. These
      results demonstrate the use of self-assembly to present biologically relevant
      chemistry on surfaces of biomaterials. Applications of this technology include
      the modification of substrates for cell culture, tissue engineering, and cell
      transplantation.

PMID- 15172498
TI  - Assessment of polyglycolic acid mesh and bioactive glass for soft-tissue
      engineering scaffolds.
AB  - Sufficient neovascularization of neotissue is currently a limiting factor for the
      engineering of large tissue constructs. 45S5 Bioglass has been investigated
      extensively in bone tissue engineering but there has been relatively little
      previous research on its application to soft-tissue engineering. The objectives
      of this study were to investigate the use of 45S5 Bioglass in soft-tissue
      engineering scaffolds using in vitro and in vivo models. A fibroblast cell line
      (208F) was used for in vitro evaluation of surfaces coated with 45S5 Bioglass.
      Increased proliferation of fibroblasts was observed after growth on polystyrene
      surfaces coated with low concentrations (0.01-0.2%wt/vol) of 45S5 Bioglass for 24
      h in vitro, determined as a change in total cell number by measuring lactate
      dehydrogenase. At higher concentrations of 45S5 Bioglass and longer periods of
      incubation (48 and 72 h) on coated surfaces, cell proliferation was reduced.
      Light microscopy revealed that the morphology of fibroblasts grown on 45S5
      Bioglass-coated surfaces was not altered at low concentrations, but at higher
      concentrations fibroblasts became vacuolated. Enzyme-linked immunosorbent assay
      of conditioned culture medium collected from fibroblasts grown for 24 h on
      surfaces coated with low concentrations of 45S5 Bioglass (0.01%wt/vol) was found
      to contain significantly higher concentrations of vascular endothelial growth
      factor. Histological examination of polyglycolic acid (PGA)/45S5 Bioglass
      composite scaffolds that had been implanted subcutaneously into rats revealed
      that 45S5 Bioglass-coated meshes were well tolerated. Light microscopy revealed
      that neovascularization into 45S5 Bioglass-coated meshes was significantly
      increased at 28 and 42 days. Electron microscopy revealed fibroblasts adhering
      closely to the PGA mesh but not to 45S5 Bioglass particles. The apparent ability
      of 45S5 Bioglass incorporated into scaffolds to increase neovascularization would
      be extremely beneficial during the engineering of larger soft-tissue constructs.

PMID- 15172499
TI  - In situ-formed, tissue-adhesive co-gel composed of styrenated gelatin and
      styrenated antibody: potential use for local anti-cytokine antibody therapy on
      surgically resected tissues.
AB  - Styrenated antibody (ST-Ab) and styrenated gelatin (ST-gelatin) were prepared by
      condensation reaction of antibody or gelatin with 4-vinylbenzoic acid,
      respectively. The affinity loss of ST-Ab to its antigen was minimal. ST-Ab and ST
      gelatin were copolymerized with by visible-light irradiation in the presence of a
      water-soluble camphorquinone as a photoinitiator to produce a tissue-adhesive, in
      situ-formed co-gel of ST-gelatin and ST-Ab. The amount of non-reacted ST-Ab
      released from the co-gel of ST-gelatin and ST-Ab into the medium was minimal. The
      confocal laser scanning microscopy observation showed that local accumulation of
      rhodamine-labeled bovine serum albumin (BSA) as a model antigen was noticed in
      the surface-to-subsurface region of the co-gel of ST-gelatin and anti-BSA ST-Ab,
      indicating that the gel prevented the permeation of BSA into the gel. In invasion
      double chamber assay using anti-hepatocyte growth factor (HGF) antibody, the co
      gel prevented HGF-dependent invasion of pancreatic cancer cells. The discussion
      was made for potential application of an in situ-formed tissue-adhesive co-gel of
      ST-gelatin and ST-Ab, developed in this study, as a cytokine-barrier on a
      surgically resected tissue where cancer cells might still remain after resection
      of cancerous tissue.

PMID- 15172500
TI  - Tailoring lactide/caprolactone co-oligomers as tissue adhesives.
AB  - This article introduces novel biocompatible tissue adhesives that do not involve
      any chemical or biochemical reactions, during their application in vivo. The use
      of these new adhesives is based exclusively on their temperature-dependent
      rheological properties. Since biocompatibility and biodegradability are
      additional crucial attributes of tissue adhesives, the polymers were tailored so
      that they as well as their degradation products are non-toxic. Branched oligomers
      consisting of a core molecule and biodegradable chains bound to it were
      synthesized and the relationship between their composition and their adhesive
      properties under in vitro conditions, was investigated. The oligomers comprised
      trimethylolpropane as the trifunctional central molecule, while lactoyl and
      caprolactone units formed the biodegradable segments. Oligomers with glass
      transition temperatures in the 20-25 degrees C range, were found to perform
      better. A strong connection was found between the length of the PLA blocks, the
      glass transition temperature (T(g)) of the different materials and their Adhesive
      Failure Strength (AFS) at 37 degrees C. The remarkable flexibilizing effect of
      the caprolactone units incorporated along the PLA blocks, allowed to generate
      longer biodegradable chains and to improve, therefore, the adhesive strength of
      the oligomers, while keeping their T(g) within the appropriate temperature
      interval. The TMP(LA(16)-CL(2)-LA(16)-CL(2)-LA(16))(3) oligomer attained
      especially high AFS values under in vitro conditions.

PMID- 15172501
TI  - PVA hydrogel sheet macroencapsulation for the bioartificial pancreas.
AB  - We newly developed a sheet-type macroencapsulation device entrapping rat islets
      from 3% polyvinyl alcohol (PVA) dissolved in Euro-Collins solution containing 10%
      fetal bovine serum and 5% dimethyl sulfoxide (PVA + EC) using a freezing/thawing
      technique. The same encapsulation technique but with 3% PVA dissolved only in
      double-distilled water (PVA) and a culture of free islets were served as
      controls. After 14-day culture in the CMRL-1066 medium, the islet recovery rate,
      morphological changes, insulin content, and insulin secretion were evaluated in
      vitro to prove the feasibility of this method of encapsulation. We also
      xenotransplanted the device into the peritoneal cavity of diabetic C57BL/6 mice
      to check its function in vivo. After 1-day culture, the islet recovery rate and
      insulin content in the PVA group were significantly lower than that in the PVA +
      EC and free islet groups. After 14-day culture, only the islets in the PVA+EC
      group maintained a normal morphology and effective insulin secretory response to
      high glucose while the response was not observed in the PVA group after 1-day
      culture and no longer observed in the free islets after 7-day culture. After
      transplantation of rat islets encapsulated in the PVA + EC device to diabetic
      C57BL/6 mice, nonfasting blood glucose levels showed a rapid decrease from high
      glucose levels of pre-transplantation, maintaining significantly lower glucose
      levels during the whole course of study in comparison with the sham-operated
      group. Our results indicated that this freezing/thawing macroencapsulation
      technique using 3% PVA + EC was effective for xenotransplantation of islet cells.

PMID- 15172502
TI  - Low toxicity of cationic lipid-based emulsion for gene transfer.
AB  - Cationic liposome has been studied as one of the most promising non-viral gene
      delivery systems. However, it has major drawbacks such as the formation of large
      aggregates at higher concentrations and the instability in the serum due to
      cationic lipid. As an alternative gene delivery system, cationic emulsion was
      formulated and transfection efficiency was evaluated in vitro and in vivo, in
      comparison with cationic liposome. Cationic emulsion was prepared with varying
      compositions of 3 beta [N-(N',N'-dimethylaminoethane) carbamoyl] cholesterol (DC
      Chol), dioleoylphosphatidyl ethanolamine (DOPE), caster oil and Tween 80.
      Cationic liposome was prepared with DC-Chol and DOPE. The particle size of all
      the DNA/lipid complexes varied from 150 to 230 nm. The in vitro transfection
      efficiency of plasmid DNA was assessed by the expression of green fluorescent
      protein as a reporter. Of various formulations, cationic emulsion E2 (DC
      Chol/DOPE/Castor Oil/Tween 80 = 0.3:0.3:0.3:0.15) and cationic liposome L3 (DC
      Chol/DOPE = 0.6:0.3) showed improved transfection. DNA/E2 complexes exhibited
      higher transfection efficiencies (17.39+/-0.58%) in comparison with DNA/L3
      complexes (11.47+/-0.59%). DNA/E2 complexes also showed a better physical
      stability and a stronger serum resistance than DNA/L3 complexes. Moreover, the
      cytotoxicity of DNA/E2 complexes was comparable to that of DNA/L3 complexes. When
      DNA/lipid complexes were intravenously administered, DNA/E2 complexes showed a
      prolonged circulation in blood and mRNA expression in various tissues compared
      with DNA/L3 complexes. These results suggest that cationic emulsion E2 could be a
      potential gene delivery system in clinical approaches because of enhanced in vivo
      gene transfer with low toxicity.

PMID- 15172503
TI  - Adsorptive separation of hemoglobin by molecularly imprinted chitosan beads.
AB  - A simply hemoglobin (Hb) molecularly imprinted polymer (MIP) was prepared using
      Hb as the imprinted molecule, acrylamide as the functional monomer and cross
      linked chitosan beads as the supporting matrix. The MIP was achieved by
      entrapment of the selective soft polyacrylamide gel in the pores of the cross
      linked chitosan beads by letting acrylamide monomer and the protein diffuse into
      the pores of chitosan beads before starting the polymerization. The chitosan
      beads were freed from the surrounding polyacrylamide gel by washing. The Langmuir
      and Freundlich adsorption models were applied to describe the equilibrium
      isotherms. Langmuir analysis showed that an equal class of adsorption was formed
      in the MIP and the adsorption equilibrium constant and the maximum adsorption
      capacity were evaluated. The MIP has much higher adsorption capacity for Hb than
      the non-imprinted polymer with the same chemical composition, and the MIP also
      has a higher selectivity for the imprinted molecule. The MIP can be reused in an
      easy way and the reproduction coefficient was approximately 100% at low
      concentration.

PMID- 15172504
TI  - Epidemiology and impact of headache: an overview.
AB  - Headache is one of the most common presenting complaints of patients in the
      practice of medicine. Frequently a symptom of numerous diseases, and
      frustratingly, the principle symptom of the primary headache syndromes, headache
      is experienced by 90% of the general population at some point in life.

PMID- 15172505
TI  - Diagnosis and classification of headache.
AB  - Headache is the most common neurologic complaint. Migraine is by far the most
      frequent headache type seen by office-based physicians.Migraine remains under
      recognized, under-diagnosed, and therefore under-treated in everyday medical
      practice. With time severely restricted in primary care day-to-day practice, a
      user friendly approach to assessment of headaches and differentiation into the
      broad types of "worrisome headache," migraine, tension-type, and others is
      necessary. A consensus-based, practical, rapid, six essential-question screening
      technique is outlined.

PMID- 15172506
TI  - The pathophysiology of primary headache.
AB  - Headache research has been a productive area, and understanding of primary
      headache pathophysiology has increased greatly. There are many more questions
      that need to be answered to gain a better understanding of the primary headache
      process. For the clinician,there is value in understanding the pathophysiology of
      primary headache, because this understanding can help improve diagnostic acumen
      and shape treatment plans to provide patients with more effective treatment.

PMID- 15172507
TI  - Migraine diagnosis and treatment.
AB  - Migraine is a prevalent condition that causes significant disability in otherwise
      healthy persons. Diagnosis is clinical, based on recognition of a constellation
      of signs and symptoms. Treatment includes nonpharmacologic management, including
      lifestyle alterations,abortive treatment of individual attacks, and preventive
      medications for patients with frequent or troublesome attacks. Guidelines are
      available that summarize the quality of evidence for individual interventions,
      but treatment must be individualized.

PMID- 15172508
TI  - Tension-type headaches: what they are and how to treat them.
AB  - Most clinicians and patients traditionally think of the tension-type headache
      (TTH) as the "unmigraine" or "nonmigraine." This view may be changing as
      distinctions between migraines and nonmigrainesdissolve. For many years, clinical
      diagnosis of TTH was based on nonthrobbing, bilateral pain. The mechanisms
      underlying the cause of TTH are still poorly understood. Some clinicians keep TTH
      and migraine in two separate clinical environments, while others see the two as a
      spectrum disorder with a common pathophysiology;however, there is not enough
      evidence to make anyone theory the clear-cut victor. Treatment strategies for TTH
      have evolved in favor of the patient. Newer categories of pharmacologic agents,
      often stabilizing to neuronal networks, are the modern mainstay of therapy for
      migraines and mixed headache disorders such as TTH.

PMID- 15172509
TI  - Cluster headache.
AB  - Cluster headache is a relatively rare episodic headache disorder.Although
      traditionally it is believed to be a male-related disorder,the sex ratios are
      changing toward a more even balance. The disorder is characterized by bouts of
      daily headaches with pain-free remissions for extended times. Though attacks are
      brief, they are severe and typically are associated with autonomic symptoms.
      Medical therapies are the mainstay of treatment, with the goal being prevention
      of headaches in a cycle. Acute therapies, although effective, may be limited in
      usefulness because of attack frequency. Intractable cases may benefit from
      histamine desensitization and surgical treatments.

PMID- 15172510
TI  - Miscellaneous primary headache.
AB  - There are many types of miscellaneous primary headache, but two groups have been
      selected for discussion: trigeminal autonomic cephalalgias (TAC) and cephalalgias
      without autonomic dysfunction(CWAD). TAC are strictly unilateral and CWAD are
      usually bilateral. Sudden onset and relatively short duration characterize
      most,but some are frightening to patient and doctor alike. One, thunderclap
      headache, is symptomatic until proven otherwise. Although the others are rarely
      symptomatic, therapy can be difficult until it is recognized that diagnosis often
      predicts treatment.

PMID- 15172511
TI  - Chronic daily headache.
AB  - Chronic daily headache (CDH) represents one of the most challenging medical
      conditions that a health care provider is called on to treat. This article
      outlines the scope of this misunderstood condition,updates the reader on the
      revised diagnostic criteria for chronic daily headache, and gives practical
      insight into diagnosis and treatment. Four specific subtypes of CDH are covered:
      chronic tension-type headache, chronic migraine, new daily persistent headache,
      and hemicrania continua. Through better recognition and treatment of this all too
      common condition, this segment of our population can be better helped to lead
      quality lives.

PMID- 15172512
TI  - Medication overuse headache.
AB  - Medication overuse headache may complicate any type of headache and occurs in
      young people, adults, and even elderly patients. Overuse of acute medications may
      change intermittent or self-limited headaches into chronic daily headache.
      Migraineurs seem particularly prone to analgesic rebound headache/ transformed
      migraine/chronic migraine. Prophylactic therapies are often ineffective in the
      setting of medication overuse. Recognition of this condition allows appropriate
      clinical intervention that includes cessation of the offending medications.

PMID- 15172513
TI  - Secondary headache and head pain emergencies.
AB  - The vast majority of patients presenting to primary care physicians complaining
      of headache have primary headaches, such as migraine,tension, or cluster.
      Secondary or organic headaches, however,always need to be considered, because
      when present they require prompt diagnosis and intervention. Approximately 10%of
      patients presenting to the emergency department complaining of headache have a
      secondary headache, and as many as one in three sudden severe headaches in
      patients presenting to a general practitioner's office can be attributed to an
      urgent neurologic condition that requires rapid evaluation and management.

PMID- 15172514
TI  - Common headache misdiagnoses.
AB  - The authors have a personal philosophy that it is worthwhile for a physician on
      occasion to be the patient. When this particular physician consults another
      physician for a medical problem, he is seeking treatment to eradicate that
      particular problem. It is difficult to afford the appropriate therapy for that
      problem if the correct diagnosis is not made. It is exactly the same situation
      with patients that come to us with complaints of headache. If we cannot make the
      proper diagnosis, it is unlikely we will be able to render the appropriate
      therapy. We need to keep this in mind when we evaluate patients with these
      headache problems, many of whom have suffered with an incorrect diagnosis for
      many years.

PMID- 15172515
TI  - Managing migraine in children and adolescents.
AB  - Although migraine is a well recognized phenomenon in adults, it is often
      overlooked or minimized in children and adolescents. Headache is a common
      complaint in children, and migraine often has its onset in the first two decades
      of life. Recognition and appropriate treatment can have a significant impact on
      quality of life for young sufferers and their caregivers and ultimately may
      affect the course of the illness.

PMID- 15172516
TI  - Headache in women.
AB  - Women have more migraine than men. Some secondary headaches are more common in
      women. Menses, pregnancy, and menopause have an impact on the frequency and
      treatment of headache. Oral contraceptives can be used in women with migraine
      with some precautions.

PMID- 15172517
TI  - Challenging or difficult headache patients.
AB  - This article addresses interesting and enigmatic presentations of headache from a
      diagnostic and treatment perspective. The emphasis is on migraineurs and other
      headache patients who represent a significant burden for the primary care
      provider. In particular, the author focuses on undiagnosed migraine, menstrual
      migraine, migraine in pregnancy, intractable migraine and status
      migrainosus,transformed migraine, hemiplegic migraine, basilar migraine, "triptan
      syndrome," sudden onset of severe headache, post-traumatic headache, and headache
      in elderly patients.

PMID- 15172519
TI  - Conceptions and questions concerning morphological processing.
AB  - The understanding of the nature and extent of morphological processing is
      critical to the overall investigation of how words are organized in the mind. In
      this overview article, we discuss the nature of morphological processing and the
      domain of morphological processing research. We claim that investigations
      crucially involve the understanding of relations among morphologically simple and
      morphologically complex words, and sketch how specific questions of morphological
      processing within the 2004 special issue on the mental lexicon fall under these
      categories. Finally, we discuss issues of construct, content and ecological
      validity within the field and what morphological processing can reveal about the
      association of form and meaning in the mind.

PMID- 15172520
TI  - The processing of morpheme-like units in monomorphemic words.
AB  - The word virus is not normally considered polymorphemic, yet it is clearly both
      semantically and orthographically related to the word viral. Thus, the subunit
      vir takes on the role of a bound morpheme. In contrast, the words future and
      futile also share a subunit (fut), but are semantically unrelated. The reported
      experiment demonstrates facilitation in a masked priming experiment for the
      semantically related pairs that share an initial orthographic subunit (e.g.,
      virus-viral), but not for the semantically unrelated pairs (e.g., future-futile).
      Whether the subunit was pronounced the same way in the prime and target was shown
      to be irrelevant. Furthermore, semantic relatedness was insufficient to produce
      priming when orthography was not shared. It was concluded that, while the units
      of processing within the orthographic system may be the same for the two types of
      item, their representation at a higher level may depend on the correlation
      between form with meaning. For example, virus and viral might share a higher
      level representation and thus facilitate each other, whereas future and futile
      might be represented separately at that higher level and even compete with each
      other.

PMID- 15172521
TI  - What do graded effects of semantic transparency reveal about morphological
      processing?
AB  - We examined the influence of semantic transparency on morphological facilitation
      in English in three lexical decision experiments. Decision latencies to visual
      targets (e.g., CASUALNESS) were faster after semantically transparent (e.g.,
      CASUALLY) than semantically opaque (e.g., CASUALTY) primes whether primes were
      auditory and presented immediately before onset of the target (Experiment 1a) or
      visual with an stimulus onset asynchrony (SOA) of 250 ms (Experiment 1b).
      Latencies did not differ at an SOA of 48 ms (Experiment 2) or with a forward mask
      at an SOA of 83 ms (Experiment 3). Generally, effects of semantic transparency
      among morphological relatives were evident at long but not at short SOAs with
      visual targets, regardless of prime modality. Moreover, the difference in
      facilitation after opaque and transparent primes was graded and increased with
      family size of the base morpheme.

PMID- 15172522
TI  - Morphological processing: a comparison between free and bound stem facilitation.
AB  - Linguists distinguish between words formed from free stems (e.g., actor: act) and
      those formed from bound stems (e.g., spectator: spect). In a forward masked
      priming task, we observed significant morphological facilitation for prime-target
      pairs that shared either a free (e.g., deform-CONFORM) or a bound (e.g., revive
      SURVIVE) stem. Relative to an unrelated baseline, magnitudes of facilitation for
      free (e.g., form) and bound (e.g., vive) stems were significant and comparable,
      but relative to an orthographic baseline free stem facilitation was greater than
      bound stem facilitation. In addition, the magnitude of bound (but not free) stem
      morphological facilitation correlated with the number of morphological relatives.

PMID- 15172524
TI  - What does rapid automatized naming measure? A new RAN task compared to naming and
      lexical decision.
AB  - The present research investigated the relationship between Rapid Automatized
      Naming (RAN) performance, letter-string reading measures of sight vocabulary (SV)
      and phonetic decoding (PD), and lexical decision. Criterion-based naming rates
      were obtained from three types of RAN tasks: digits, letters, and letter sounds.
      Latency measures were obtained from the naming of regular words, exception words,
      nonwords and pseudohomophones; as well as button press and verbal lexical
      decision tasks. Regression analyses supported the hypotheses that RAN-Letters
      latency reflects SV processing in that its variance is uniquely accounted for by
      exception word naming latency and button press lexical decision latency, and that
      RAN-Letter Sounds latency best reflects PD processing in that its variance is
      uniquely accounted for by pseudohomophone and nonword naming latency. Findings
      are discussed in light of what the RAN tasks are measuring, implications
      involving visual word recognition models of reading, and the utility of the new
      RAN-Letter Sounds task with respect to diagnostic and remediation applications.

PMID- 15172523
TI  - FMRI of two measures of phonological processing in visual word recognition:
      ecological validity matters.
AB  - Previous functional magnetic resonance imaging (fMRI) studies have investigated
      the role of phonological processing by utilizing nonword rhyming decision tasks
      (e.g., Pugh et al., 1996). Although such tasks clearly engage phonological
      components of visual word recognition, it is clear that decision tasks are more
      cognitively involved than the simple overt naming tasks, which more closely map
      onto normal reading behavior. Our research aim for this study was to examine the
      advantages of overt naming tasks for fMRI studies of word recognition processes.
      Process models are presented to highlight the similarities and differences
      between two cognitive tasks that are used in the word recognition literature,
      pseudohomophone naming (e.g., pronounce BRANE) and rhyming decision (e.g., do
      LEAT and JEAT rhyme?). An fMRI study identified several differences in cortical
      activation associated with the differences observed in the process models.
      Specifically, the results show that the overt naming task involved the insular
      cortex and inferior frontal gyrus, whereas the rhyming decision task engaged the
      temporal-parietal regions. It is argued that future fMRI research examining the
      neuroanatomical components of basic visual word recognition utilize overt naming
      tasks.

PMID- 15172525
TI  - On the representation of Portuguese gender-inflected words in the mental lexicon.
AB  - This study aims at verifying whether Portuguese gender-inflected nouns and
      adjectives are represented as full forms as suggested by Spanish data (Dominguez,
      Cuetos, & Segui, 1999). A series of lexical decision experiments is reported.
      Grammatical gender, frequency dominance, and grammatical category are manipulated
      and cumulative frequency is controlled. The results do not provide support for a
      full form representation of gender-inflected words. They suggest that grammatical
      category, or the nature of the inflectional process involved (lexical or
      syntactic), affects the way words are represented and accessed. Shorter
      recognition latencies were obtained for nouns drawn from Feminine dominant gender
      inflected pairs than from Masculine dominant pairs whereas a tendency in the
      opposite direction was observed in adjectives. The effect of frequency dominance
      appears, nevertheless, to be restricted to feminine nouns. The data are
      compatible with the view that masculine nouns and adjectives are represented as
      gender-unmarked forms. These results are discussed in relation to current dual
      access models of word recognition and to the notion of "interpretability" of
      lexico-syntactic features, as put forward in the Minimalist Program of Generative
      Linguistics.

PMID- 15172526
TI  - Lexicality, morphological structure, and semantic transparency in the processing
      of German ver-verbs: The complementarity of on-line and off-line evidence.
AB  - Two types of experiments investigate the visual on-line and off-line processing
      of German ver-verbs (e.g., verbittern 'to embitter'). In Experiments 1 and 2
      (morphological priming), latency patterns revealed the existence of facilitation
      effects for the morphological conditions (BITTER-VERBITTERN and BITTERN
      VERBITTERN) as compared to the neutral conditions (SAUBER-VERBITTERN and SAUBERN
      VERBITTERN). In Experiments 3 and 4 (rating tasks) participants had to judge
      whether the target (VERBITTERN) "comes from," "contains a form of," or "contains
      the meaning of" the root (BITTER) or the root+en substring (BITTERN). Taken
      together, these studies revealed the combined influence of the three factors of
      lexicality (real word status), morphological structure, and semantic
      transparency.

PMID- 15172527
TI  - The precise time course of lexical activation: MEG measurements of the effects of
      frequency, probability, and density in lexical decision.
AB  - Visually presented letter strings consistently yield three MEG response
      components: the M170, associated with letter-string processing (Tarkiainen,
      Helenius, Hansen, Cornelissen, & Salmelin, 1999); the M250, affected by
      phonotactic probability, (Pylkkanen, Stringfellow, & Marantz, 2002); and the
      M350, responsive to lexical frequency (Embick, Hackl, Schaeffer, Kelepir, &
      Marantz, 2001). Pylkkanen et al. found evidence that the M350 reflects lexical
      activation prior to competition among phonologically similar words. We
      investigate the effects of lexical and sublexical frequency and neighborhood
      density on the M250 and M350 through orthogonal manipulation of phonotactic
      probability, density, and frequency. The results confirm that probability but not
      density affects the latency of the M250 and M350; however, an interaction between
      probability and density on M350 latencies suggests an earlier influence of
      neighborhoods than previously reported.

PMID- 15172528
TI  - Representation of grammatical properties of Italian verbs in the mental lexicon.
AB  - The present study focuses on the representation of verbs in the Italian mental
      lexicon and investigates some grammatical properties: inflectional class, mood,
      tense, and person. Two experiments based on free recall of single inflected forms
      are reported. The patterns of recall and error are taken as evidence for the
      grammatical and morphological information exploited in the access to the verb
      forms. The pattern of results provides support for the hypothesis that in the
      mental lexicon the information about conjugation and mood is an organizational
      criterion for the representation of verbal forms. An interaction between mood and
      conjugation, likely to arise from the difference in productivity between
      conjugations, is also observed.

PMID- 15172529
TI  - Allomorphic variation in Arabic: implications for lexical processing and
      representation.
AB  - This study probes the effects of allomorphy on access to Arabic roots and word
      patterns in two cross-modal priming experiments. Experiment 1 used strong roots
      which undergo no allomorphy, and weak roots which undergo allomorphy and surface
      with only two of their three consonants in some derivations. Word pairs sharing a
      root morpheme prime each other reliably not only when the root was strong (e.g.,
      [see text] participant/participate), but also when it was weak (e.g., [see text]
      agreement-agree, where the weak root [wfq] surfaces fully in the target but not
      the prime). This facilitation occurred even when the weak root surfaced with
      different semantic meanings across prime and target (e.g., [see text]
      destination/confront). Experiment 2 assessed the effects of allomorphy on word
      pattern processing, comparing word pairs where the word pattern is transparently
      realised in both prime and target (e.g., [see text] spread/bear], with pairs
      which share the same underlying word pattern but where a weak root triggers an
      assimilation process in the prime (e.g., [see text] unite/smile). This
      assimilation process does not disrupt the CV-structure of the word pattern, in
      contrast to a third condition where this is disrupted in both prime and target
      (e.g., [see text] turn around/say). Strong priming effects were observed in the
      first two conditions but not in the third. The bearing of these findings on
      models of lexical processing and representation is discussed.

PMID- 15172530
TI  - Processing reduced word forms: the suffix restoration effect.
AB  - Listeners cannot recognize highly reduced word forms in isolation, but they can
      do so when these forms are presented in context (Ernestus, Baayen, & Schreuder,
      2002). This suggests that not all possible surface forms of words have equal
      status in the mental lexicon. The present study shows that the reduced forms are
      linked to the canonical representations in the mental lexicon, and that these
      latter representations induce reconstruction processes. Listeners restore
      suffixes that are partly or completely missing in reduced word forms. A series of
      phoneme-monitoring experiments reveals the nature of this restoration: the basis
      for suffix restoration is mainly phonological in nature, but orthography has an
      influence as well.

PMID- 15172531
TI  - Regularity and/or consistency in the production of the past participle?
AB  - In the present study we have investigated the acquisition of the past participle
      of Italian verbs of the second (including mostly irregular verbs) and third
      (including mostly regular verbs) conjugations in school age children, and with
      simulations with an artificial neural network. We aimed to verify the extent to
      which children are sensitive to regularity, as opposed to the consistency in the
      mapping from the infinitive to the past participle. In particular, we predicted
      that children would learn at some point that verbs of the second conjugation tend
      to be irregular, and therefore they would be more likely to produce
      irregularizations for verbs of this class, compared to the verbs of the third
      conjugation. However, they should also show sensitivity to the phonological
      mapping consistency within each subclass, learning to produce correct forms on
      the basis of phonological similarity. In contrast, children should be more likely
      to produce regular forms for verbs of the third conjugation. Thus, a larger
      regularity effect would be expected for verbs of the third than of the second
      conjugation, leading to the prediction of a regularity by conjugation
      interaction.

PMID- 15172532
TI  - The role of configurational asymmetry in the lexical access of prefixed verbs:
      evidence from French.
AB  - In this paper we investigated the effects of configurational asymmetry in
      prefixed verbs in French. We used a simple lexical decision paradigm to compare
      prefixed verbs with external and internal prefixes as specified in linguistic
      theory (Di Sciullo, 1997) where external prefixes do not change the aktionsart
      and the verb argument structure of the verb, but internal prefixes do change the
      aktionsart and may change the verb argument structure of the verb. In Experiment
      1 we tested the bi-valent prefix de- where the configurational difference between
      external and internal properties of a prefix did not elicit differential response
      latencies. However, in Experiment 2, where unambiguous prefixes (internal en- and
      external re-) were tested, the external prefix elicited longer latencies. These
      results are discussed with respect to the linguistic constraints the
      configurational properties of prefixes place upon psycholinguistic models of
      lexical access, as well as with respect to the effects of prefix bi-valence in
      the recognition of prefixed verbs.

PMID- 15172533
TI  - Speculation about behavior, brain damage, and self-organization: the other way to
      herd a cat.
AB  - This article contrasts aphasic patients' performance of word naming and lexical
      decision with that of intact college-aged readers. We discuss this contrast
      within a framework of self-organization; word recognition by aphasic patients is
      destabilized relative to intact performance. Less stable performance shows itself
      as an increase in the dispersion of patients' response times compared to college
      students'. Dispersion is also more pronounced for low-frequency words than for
      high frequency words. We speculate, that increased dispersion originates in a
      reduction of constraints that support naming and lexical decision performances. A
      sufficient reduction of constraints yields qualitative changes in performance
      such as the production of semantic errors in deep dyslexia. These hypotheses are
      offered as alternatives to postulating distinct modules.

PMID- 15172534
TI  - The word frequency effect in picture naming: contrasting two hypotheses using
      homonym pictures.
AB  - Models of speech production disagree on whether or not homonyms have a shared
      word-form representation. To investigate this issue, a picture-naming experiment
      was carried out using Dutch homonyms of which both meanings could be presented as
      a picture. Naming latencies for the low-frequency meanings of homonyms were
      slower than for those of the high-frequency meanings. However, no frequency
      effect was found for control words, which matched the frequency of the homonyms'
      meanings. Subsequent control experiments indicated that the difference in naming
      latencies for the homonyms could be attributed to processes earlier than word
      form retrieval. Specifically, it appears that low name agreement slowed down the
      naming of the low-frequency homonym pictures.

PMID- 15172535
TI  - Does a theory of language need a grammar? Evidence from Hebrew root structure.
AB  - Hebrew constrains the occurrence of identical consonants in its roots: Identical
      consonants are acceptable root finally (e.g., skk), but not root initially (e.g.,
      kks). Speakers' ability to freely generalize this constraint to novel phonemes
      (Berent, Marcus, Shimron, & Gafos, 2002) suggests that they represent segment
      identity-a relation among mental variables. An alternative account attributes the
      restriction on identical phonemes to their feature similarity, captured by either
      the number of shared features or their statistical frequency. The similarity
      account predicts that roots with partially similar consonants (e.g., sgk) should
      be at least as acceptable as roots with fully identical consonants (e.g., skk),
      and each of these roots should be less acceptable than dissimilar controls (e.g.,
      gdn). Contrary to these predictions, three lexical decision experiments
      demonstrate that full identity is more acceptable than partial similarity and (in
      some cases) controls. Speakers' sensitivity to consonant identity suggests that
      linguistic competence, in general, and phonology, in particular, encompass a
      computational mechanism that operates over variables. This conclusion is
      consistent with linguistic accounts that postulate a symbolic grammatical
      component that is irreducible to the statistical properties of the lexicon.

PMID- 15172536
TI  - Morphological units in the Arabic mental lexicon: evidence from an individual
      with deep dyslexia.
AB  - An ongoing debate in Arabic morphology concerns the nature of the smallest unit
      governing lexical organization and representation in this language. A standard
      model maintains that Arabic words are typically analyzable into a three
      consonantal root morpheme carrying the core meaning of words and a prosodic
      template responsible mostly for grammatical information. This view has been
      largely supported by research in both theoretical linguistics and
      psycholinguistics. An alternative theory holds that the meaning of words in
      Arabic is, rather, encoded in the 'etymon' comprising two unordered consonants of
      the root only. Results from a recent priming experiment have shown that the
      etymon induces strong morphological priming effects, supporting its
      morphological/lexical status. In this paper we present data from a patient with
      deep dyslexia questioning the role of the etymon as a psychologically real
      representational unit in Arabic and arguing, instead, for the central role of the
      root in both morphological and lexical representation in this language.

PMID- 15172537
TI  - Broca's aphasia, verbs and the mental lexicon.
AB  - Verb production is notoriously difficult for individuals with Broca's aphasia,
      both at the word and at the sentence level. An intriguing question is at which
      level in the speech production these problems arise. The aim of the present study
      is to identify the functional locus of the impairment that results in verb
      production deficits in Broca's aphasia. Levelt's (1989) model is used as a
      theoretical framework for this study. Two experiments have been conducted, one on
      verb movement and one on verbs with alternating transitivity. The results suggest
      that the functional impairment in Broca's aphasia should be located in Levelt's
      "grammatical encoder."

PMID- 15172538
TI  - The impact of semantic transparency of morphologically complex words on picture
      naming.
AB  - We examined the contribution of semantic similarity to morphological priming
      effects, using the immediate (Exp. 1 and 3) and the delayed variant (Exp. 2) of
      picture-word interference. Distractor words were either compounds morphologically
      related to the picture name, but differing with respect to their semantic
      transparency (hummingbird, jailbird (Exp. 1); butterfly, butter dish (Exp. 3)),
      or form-related non-compound words (e.g., trombone). All three experiments
      revealed strong facilitation of picture naming due to morphologically related
      distractors. Form-related distractors facilitated picture naming in the immediate
      variant only, and to a lesser degree than compounds. Interestingly, the size of
      the morphemic effect was almost identical for semantically transparent and opaque
      complex words, which suggests that they share morphemic representations. These
      results suggest that morphological complexity in speech production is coded at
      the level of form representations, independent of semantic transparency.

PMID- 15172539
TI  - Investigating the interplay between semantic and phonological distractor effects
      in picture naming.
AB  - In this paper, we investigate the interplay between phonological facilitation and
      semantic interference effects in picture naming. We use a double distractor
      variant of the classic picture-word interference paradigm to investigate whether
      the reported interaction between these effects is dependent on the two types of
      related information being presented by the same distractor word or not. While
      prior studies using single mixed distractors such as pigeon for the target PIG
      have reported an interaction between phonological facilitation and semantic
      interference, we find additivity when the two types of related information come
      from two different distractor words. Possible implications of this result for how
      activation is transmitted within the speech production system are discussed.

PMID- 15172540
TI  - The role of specificity in the lexical encoding of participants.
AB  - In addition to information about phonology, morphology and syntax, lexical
      entries contain semantic information about participants (e.g., Agent). However,
      the traditional criteria for determining how much participant information is
      lexically encoded have proved unreliable. We have proposed two semantic criteria
      (obligatoriness and selectivity) that jointly identify the participants that are
      lexically encoded in verbs. We tested whether one of these criteria, semantic
      selectivity, makes psychologically real distinctions between participant
      information that is lexically encoded and participant information that is not. We
      examined how readers integrated syntactically optional WH-constituents in filler
      gap sentences when the participant information conveyed by the WH-filler was
      specific to a restricted class of verbs (i.e., source locations) and when it was
      not (i.e., event locations). Our results provide support for the role of
      specificity in the lexical encoding of participant information of syntactically
      optional constituents.

PMID- 15172541
TI  - Stress priming in picture naming: an SOA study.
AB  - This study investigates whether or not the representation of lexical stress
      information can be primed during speech production. In four experiments, we
      attempted to prime the stress position of bisyllabic target nouns (picture names)
      having initial and final stress with auditory prime words having either the same
      or different stress as the target (e.g., WORtel-MOtor vs. koSTUUM-MOtor; capital
      letters indicate stressed syllables in prime-target pairs). Furthermore, half of
      the prime words were semantically related, the other half unrelated. Overall,
      picture names were not produced faster when the prime word had the same stress as
      the target than when the prime had different stress, i.e., there was no stress
      priming effect in any experiment. This result would not be expected if stress
      were stored in the lexicon. However, targets with initial stress were responded
      to faster than final-stress targets. The reason for this effect was neither the
      quality of the pictures nor frequency of occurrence or voice-key characteristics.
      We hypothesize here that this stress effect is a genuine encoding effect, i.e.,
      words with stress on the second syllable take longer to be encoded because their
      stress pattern is irregular with respect to the lexical distribution of
      bisyllabic stress patterns, even though it can be regular with respect to
      metrical stress rules in Dutch. The results of the experiments are discussed in
      the framework of models of phonological encoding.

PMID- 15172542
TI  - Semantic category effect and emotional valence in female university students.
AB  - The semantic category effect represents a category dissociation between
      biological and nonbiological objects in picture naming. The aim of this
      preliminary study was to further examine this phenomenon, and to explore the
      possible association between the effect and subjective emotional valence for the
      named objects. Using a speeded picture naming task, vocal reaction times for 45
      items were divided into four categories based on emotional valence rating and
      semantic category, and examined in 36 female university students. Analyses of the
      data indicated an "animate/inanimate" category dissociation favouring animate
      objects, in tandem with a potential relationship between subjective emotional
      valence and semantic processing underlying picture naming.

PMID- 15172543
TI  - The effect of context on the processing of type-shifting verbs.
AB  - Recent research in lexical semantics has suggested that verbs such as begin and
      enjoy semantically select for a complement that denotes an activity or an event.
      When no such activity or event is specified in the form of a progressive or
      infinitival complement, as in John began (to read/reading) the book, the verb is
      said to "coerce" the NP direct object to shift its role to encompass the activity
      that begin requires as complement (e.g., writing, reading). Empirical support for
      this view has been provided by McElree, Traxler, Pickering, Seely, & Jackendoff
      (2001). In the present study, however, in two self-paced reading experiments,
      type-shifting effects (taken to be longer reading times engendered by the
      computation of the coercion process) were not obtained with sentences in
      isolation (Experiment 1) or with sentences embedded in contexts that specified
      the nature of the activity performed over the complement NP (Experiment 2). It is
      argued that type-shifting verbs are similar to non-preferred verbs for given
      contexts and that type-shifting operations are pragmatic inferences computed over
      underspecified semantic representations.

PMID- 15172544
TI  - Processing of mass/count information in Alzheimer's disease and mild cognitive
      impairment.
AB  - This study examines the processing of a specific linguistic distinction, the
      mass/count distinction, in patients suffering from Alzheimer's disease (AD) and
      mild cognitive impairment (MCI). Fourteen AD and 10 MCI subjects were tested
      using a sentence grammaticality judgement task where grammaticality violations
      were caused by determiner-noun mismatches, as well as a sentence-picture matching
      task to assess their ability to access mass and count readings of dual nouns.
      Considerable heterogeneity was observed within each subject group, and
      performance across groups was almost identical. It is concluded that a
      combination of linguistic and attentional and/or learning factors are responsible
      for the range of impairments; specifically, a subset of subjects exhibit no
      linguistic nor attentional/learning impairment, another subset exhibit only an
      attentional and/or learning impairment but no linguistic impairment, and a third
      subset (comprising more than half of the subjects included in this study) exhibit
      a linguistic impairment. It is postulated that the latter group have difficulty
      processing sense extensions in metonymous nouns. It is further claimed that, at
      least within the limits of the study, language impairments can be of the same
      severity and nature across AD and MCI subjects.

PMID- 15172545
TI  - Category size effects revisited: frequency and masked priming effects in semantic
      categorization.
AB  - Previous work indicates that semantic categorization decisions for nonexemplars
      (e.g., deciding that TURBAN is not an animal name) are faster for high-frequency
      words than low-frequency words. However, there is evidence that this result might
      depend on category size. When narrow categories are used (e.g., Months, Numbers),
      there is no frequency effect for nonexemplars. This result is confirmed, and is
      explained in terms of a category search model, which allows a "No" decision to be
      generated without access to the lexical entry for the target word. This explains
      the absence of a frequency effect, but not the presence of a strong masked
      repetition priming effect, which is assumed to have a lexical source. It is shown
      that this effect may not be lexical, since nonwords also show similar priming.
      Both of these priming effects disappear when a larger category is used. This
      pattern of results is explained on the assumption that category search is only
      possible with small categories, and that tentative category decisions are
      generated for the unconsciously perceived prime, which leads to a marked response
      congruence effect.

PMID- 15172546
TI  - Do type and token effects reflect different mechanisms? Connectionist modeling of
      Dutch past-tense formation and final devoicing.
AB  - In this paper, we show that both token and type-based effects in lexical
      processing can result from a single, token-based, system, and therefore, do not
      necessarily reflect different levels of processing. We report three Simple
      Recurrent Networks modeling Dutch past-tense formation. These networks show token
      based frequency effects and type-based analogical effects closely matching the
      behavior of human participants when producing past-tense forms for both existing
      verbs and pseudo-verbs. The third network covers the full vocabulary of Dutch,
      without imposing predefined linguistic structure on the input or output words.

PMID- 15172547
TI  - Phonological codes are assembled before word fixation: evidence from boundary
      paradigm in sentence reading.
AB  - This experiment employed the boundary paradigm during sentence reading to explore
      the nature of early phonological coding in reading. Fixation durations were
      shorter when the parafoveal preview was the correct word than when it was a
      spelling control pseudoword. In contrast, there was no significant difference
      between correct word and pseudohomophone previews. These results suggest that the
      phonological codes are assembled before word fixation and are used for lexical
      access. Moreover, there was evidence that orthographic codes influence the
      activation of word meaning. We found that fixation durations were shorter for
      orthographically similar parafoveal previews, and this orthographic priming
      effect is limited to pseudohomophones. Thus, it seems that both the orthographic
      and the phonological similarities of the parafoveal preview to the target play a
      part in the facilitative effects of the preview.

PMID- 15172548
TI  - Monitoring syllable boundaries during speech production.
AB  - This study investigated the encoding of syllable boundary information during
      speech production in Dutch. Based on Levelt's model of phonological encoding, we
      hypothesized segments and syllable boundaries to be encoded in an incremental
      way. In a self-monitoring experiment, decisions about the syllable affiliation
      (first or second syllable) of a pre-specified consonant, which was the third
      phoneme in a word, were required (e.g., ka. No 'canoe' vs. kaN.sel 'pulpit';
      capital letters indicate pivotal consonants, dots mark syllable boundaries).
      First syllable responses were faster than second syllable responses, indicating
      the incremental nature of segmental encoding and syllabification during speech
      production planning. The results of the experiment are discussed in the context
      of Levelt's model of phonological encoding.

PMID- 15172549
TI  - Stress regularity or consistency? Reading aloud Italian polysyllables with
      different stress patterns.
AB  - Stress assignment to three- and four-syllable Italian words is not predictable by
      rule, but needs lexical look-up. The present study investigated whether stress
      assignment to low-frequency Italian words is determined by stress regularity, or
      by the number of words sharing the final phonological segment and the stress
      pattern (stress neighborhood or consistency). Experiment 1 showed an effect of
      stress neighborhood: words were read aloud faster and more accurately when they
      had a prevalence of stress "friends," irrespective of stress regularity.
      Moreover, when irregularly stressed words have a higher number of stress friends
      compared to regularly stressed words, they are read even faster (Experiment 2).
      In Experiment 3, using visual lexical decision, no difference related to the
      numerosity of stress friends was found. It is concluded that reading aloud
      Italian low-frequency words with different stress patterns is mainly affected by
      the numerosity of lexical types that share a given final sequence and the stress
      pattern. The phonological nature of the numerosity of lexical representations
      affecting reading aloud finds support in the absence of such effect in visual
      lexical decision. These results have implications for models of reading aloud
      that go beyond monosyllables.

PMID- 15172550
TI  - Semantic gender assignment regularities in German.
AB  - Gender assignment relates to a native speaker's knowledge of the structure of the
      gender system of his/her language, allowing the speaker to select the appropriate
      gender for each noun. Whereas categorical assignment rules and exceptional gender
      assignment are well investigated, assignment regularities, i.e., tendencies in
      the gender distribution identified within the vocabulary of a language, are still
      controversial. The present study is an empirical contribution trying to shed
      light on the gender assignment system native German speakers have at their
      disposal. Participants presented with a category (e.g., predator) and a pair of
      gender-marked pseudo-words (e.g., der Trelle vs. die Stisse) preferentially
      selected the pseudo-word preceded by the gender-marked determiner "associated"
      with the category (e.g., masculine). This finding suggests that semantic
      regularities might be part of the gender assignment system of native speakers.

PMID- 15172551
TI  - Segmenting two-phoneme syllables: developmental differences in relation with
      early reading skills.
AB  - This study explored developmental differences in children's segmentation skills
      of VC and CV syllables (e.g., /af/ and /fa/) in relation to their early reading
      abilities. To this end, we followed a subgroup of Dutch speaking prereaders who
      participated in, and replicated the segmentation task in first grade, at the
      outset of phonics reading instruction. Reading abilities were assessed after 6
      and 9 months. First, we confirmed that VCs offer an easier context to isolate
      phonemes than CVs. Second, matching analyses showed that this development from VC
      to CV segmentation posed comparatively increasing difficulties for poor
      segmenters. Third, this qualitatively different development was reflected in
      early reading performance. Our data emphasize the importance of phonetic factors
      and instruction-based experiences in phonological development.

PMID- 15172553
TI  - Sublexical and morphological information in speech processing.
AB  - Three experiments investigated the impact of syllabic boundary information and of
      morphological structure on performance in a sequence-monitoring task. In sequence
      monitoring, participants detect pre-specified sequences of phonemes in spoken
      carrier words. Sequences corresponded to the first syllable of the carrier word,
      to its first morpheme, or simultaneously to both. The data from Experiments 1 and
      2, using different variants of the monitoring task, showed a strong impact of
      syllable boundary cues on monitoring latencies. An effect of morphological match
      between targets and carrier words was also evident. Experiment 3, in which parts
      of the spoken carrier words were cross-spliced, revealed that syllabic boundary
      information takes precedence over morphological information. The results are in
      line with an early process of speech processing, in which syllabic cues are used
      to aid lexical access. The morphological effect is better understood as a later,
      probably lexical, contribution of morphological decomposition to monitoring
      performance.

PMID- 15172552
TI  - The elusive nature of early phonological priming effects: are there individual
      differences?
AB  - Lukatela and Turvey (2000) demonstrated a phonological priming effect in the
      lexical decision task (LDT) with a 14-ms prime and concluded that phonology plays
      a central role in word meaning activation. In contrast, several other researchers
      reported that phonological priming is significant only at much longer prime
      durations (e.g., Ferrand & Grainger, 1994). In two replication attempts
      (Experiments 1a and 1b), involving a 15-ms prime duration, we found a clear
      phonological priming effect in one LDT and no evidence of phonological priming in
      another virtually identical LDT. In Experiment 2, in an attempt to determine
      whether individual differences may account for the presence or lack of a
      phonological priming effect, we also tested phonological and perceptual skill.
      Only participants higher in perceptual and phonological skill showed a
      phonological priming effect. We conclude that these (and potentially other)
      variables may have been responsible for previous inconsistent findings of early
      phonological priming effects.

PMID- 15172554
TI  - Distinctive phonological features differ in relevance for both spoken and written
      word recognition.
AB  - This paper discusses four experiments on Dutch which show that distinctive
      phonological features differ in their relevance for word recognition. The
      relevance of a feature for word recognition depends on its phonological
      stability, that is, the extent to which that feature is generally realized in
      accordance with its lexical specification in the relevant word position. If one
      feature value is uninformative, all values of that feature are less relevant for
      word recognition, with the least informative feature being the least relevant.
      Features differ in their relevance both in spoken and written word recognition,
      though the differences are more pronounced in auditory lexical decision than in
      self-paced reading.

PMID- 15172555
TI  - Naming pseudowords in Spanish: effects of syllable frequency.
AB  - Three naming experiments were conducted to examine the role of the first and the
      second syllable during speech production in Spanish. Facilitative effects of
      syllable frequency with disyllabic words have been reported in Dutch and Spanish
      (Levelt & Wheeldon, 1994; Perea & Carreiras, 1998). In both cases, the syllable
      frequency effect was independent of-and additive to-the effect of word frequency.
      However, Levelt and Wheeldon (1994) found that words ending in a high-frequency
      syllable were named faster than words ending in a low-frequency syllable, whereas
      Perea and Carreiras (1998) found a facilitative effect of syllable frequency for
      the initial syllable. In Experiments 1-2, we manipulated the frequency of the
      first and the second syllable of disyllabic CV.CV pseudowords. In Experiment 3,
      participants named CVC disyllabic pseudowords for which only the frequency of the
      first syllable was manipulated. The experiments showed a facilitative effect of
      frequency of the first syllable. The findings are discussed in terms of the
      current models of speech production.

PMID- 15172556
TI  - Phonological underspecification and mapping mechanisms in the speech recognition
      lexicon.
AB  - The problem of recognizing phonological variations in the speech input has
      triggered numerous treatments in speech processing models. Two areas of current
      controversy are the possibility of phonological underspecification in the mental
      lexicon and the nature of the mapping mechanism from the speech signal to the
      abstract lexical entry. We present data from cross-modal repetition priming
      experiments in English designed to test the differing predictions of speech
      recognition models regarding tolerance of phonological mismatch in speech. The
      results show effects of underspecification, supporting models using
      underspecified lexical entries (e.g. Lahiri & Marslen-Wilson, 1991; Reetz &
      Lahiri, 2001) over those using fully specified lexical entries (e.g., McClelland
      & Elman, 1986). The results also show no effects of context, thus favoring
      context-independent mapping, such as that in the three-way matching mechanism of
      the Lahiri and Reetz FUL model ( Lahiri, 1999; Reetz, 1998 and Reetz, 1999; Reetz
      & Lahiri, 2001) over context-dependent mapping used in phonological inference
      rules ( Gaskell and Marslen-Wilson, 1996 and Gaskell and Marslen-Wilson, 1998).

PMID- 15172557
TI  - Neighbourhood effects on error rates in speech production.
AB  - Models of speech production differ on whether phonological neighbourhoods should
      affect processing, and on whether effects should be facilitatory or inhibitory.
      Inhibitory effects of large neighbourhoods have been argued to underlie apparent
      anti-frequency effects, whereby high-frequency default features are more prone to
      mispronunciation errors than low-frequency nondefault features. Data from the
      original SLIPs experiments that found apparent anti-frequency effects are
      analysed for neighbourhood effects. Effects are facilitatory: errors are
      significantly less likely for words with large numbers of neighbours that share
      the characteristic that is being primed for error ("friends"). Words in the
      neighbourhood that do not share the target characteristic ("enemies") have little
      effect on error rates. Neighbourhood effects do not underlie the apparent anti
      frequency effects. Implications for models of speech production are discussed.

PMID- 15172558
TI  - Psycholinguistic evidence for the underspecification of morphosyntactic features.
AB  - This paper investigates the paradigmatic relations between inflected word forms
      (or their affixes) and the feature specifications of these elements. In two
      sentence-matching experiments German speakers had to decide whether sentence
      pairs involving inflected adjectives or determiners were identical or not. In
      both experiments, there was a delay when an inflected form contained positive
      feature specifications for grammatical features that did not match the feature
      specifications of the grammatical context in which it appeared. No delay,
      however, occurred when an incorrectly inflected form had mismatching negative
      specifications, whereas its positively specified features matched the respective
      positive features of the context. This result provides evidence for a different
      status of positively and negatively specified morphosyntactic features. It
      supports the idea of radical underspecification according to which only positive
      feature specifications are part of the representations of morphologically complex
      forms or affixes, whereas negative feature specifications are assigned on the
      basis of paradigmatic contrasts.

PMID- 15172559
TI  - Naming analog clocks conceptually facilitates naming digital clocks.
AB  - This study investigates how speakers of Dutch compute and produce relative time
      expressions. Naming digital clocks (e.g., 2:45, say "quarter to three") requires
      conceptual operations on the minute and hour information for the correct relative
      time expression. The interplay of these conceptual operations was investigated
      using a repetition priming paradigm. Participants named analog clocks (the
      primes) directly before naming digital clocks (the targets). The targets referred
      to the hour (e.g., 2:00), half past the hour (e.g., 2:30), or the coming hour
      (e.g., 2:45). The primes differed from the target in one or two hour and in five
      or ten minutes. Digital clock naming latencies were shorter with a five- than
      with a ten-min difference between prime and target, but the difference in hour
      had no effect. Moreover, the distance in minutes had only an effect for half past
      the hour and the coming hour, but not for the hour. These findings suggest that
      conceptual facilitation occurs when conceptual transformations are shared between
      prime and target in telling time.

PMID- 15172560
TI  - When orthographic neighbors fail to facilitate.
AB  - Forward masked word primes that differed from the target in the initial, the
      final or both the initial and final positions tended to slow target decision
      latencies and there were no significant differences among prime types. After
      forward masked nonword primes we observed non significant facilitation when
      primes differed from the target by one letter in either the initial or final
      position and significant inhibition when primes differed in both initial and
      final positions. The patterns did not differ significantly for targets with large
      and with small neighborhoods. Only in post hoc analyses was there any indication
      of facilitation after nonword neighbor primes and it appeared only when body
      neighborhood was small. For slower participants, neighbors tended to facilitate
      target decision latencies while for relatively fast readers showed neighbors made
      inhibition that tended to vary with amount of mismatch.

PMID- 15172561
TI  - What "mice trap" tells us about the mental lexicon.
AB  - Level ordering has proven inadequate as a morphological theory, leaving
      unexplained the experimental results taken to support it as a component of innate
      grammar-young children's acceptance of irregular plurals in English compounds.
      The present study demonstrates that these results can be explained by slower
      access to the grammatically preferred singulars of irregular nouns when compounds
      are created on-line from plural stimuli. Experiments on English noun-noun
      compound production and on production of either singular or plural forms from the
      same or opposite form confirmed that more irregular than regular plurals were
      used in compounds, and showed that producing irregular singulars from plurals was
      slower than producing regular singulars. Plural responses were also slower when
      cue and required response number differed.

PMID- 15172562
TI  - Form-priming effects in nonword naming.
AB  - Form-priming effects from sublexical (syllabic or segmental) primes in masked
      priming can be accounted for in two ways. One is the sublexical pre-activation
      view according to which segments are pre-activated by the prime, and at the time
      the form-related target is to be produced, retrieval/assembly of those pre
      activated segments is faster compared to an unrelated situation. However, it has
      also been argued that form-priming effects from sublexical primes might be due to
      lexical pre-activation. When the sublexical prime is presented, it activates all
      form-related words (i.e., cohorts) in the lexicon, necessarily including the form
      related target, which-as a consequence-is produced faster than in the unrelated
      case. Note, however, that this lexical pre-activation account makes previous pre
      lexical activation of segments necessary. This study reports a nonword naming
      experiment to investigate whether or not sublexical pre-activation is involved in
      masked form priming with sublexical primes. The results demonstrated a priming
      effect suggesting a nonlexical effect. However, this does not exclude an
      additional lexical component in form priming.

PMID- 15172563
TI  - The mental representation of verb-noun compounds in Italian: evidence from a
      multiple single-case study in aphasia.
AB  - This study seeks information on the mental representation of Verb-Noun (VN)
      nominal compounds through neuropsychological methods. The lexical retrieval of
      compound nouns is tested in 30 aphasic patients using a visual confrontation
      naming task. The target names are VN compounds, Noun-Noun (NN) compounds, and
      long morphologically simple nouns (LSN). In order to check the ability to produce
      simple nouns and verbs in the same participants, a further visual confrontation
      naming task of objects and actions is used. Results of the study confirm that
      several patients with disproportionate verb deficit are also impaired in naming
      VN compounds. Data are in favor of a (de)compositional processing of compound
      words. A further group of patients is selectively more impaired with compound
      nouns than with comparably long simple nouns, irrespective of their VN or NN
      morphological structure. It is suggested that this impairment is to be ascribed
      to a specific disorder in retrieving two different lexemes with a single lexical
      entry.

PMID- 15172564
TI  - Effect of relation availability on the interpretation and access of familiar noun
      noun compounds.
AB  - Two experiments investigate whether relations that link the constituents of
      compounds during compound formation (e.g., teapot is formed by combining tea and
      pot using the relation head noun FOR modifier) also influence the processing of
      familiar compounds. Although there is evidence for the use of such relations in
      forming compounds, whether such relations affect the processing of familiar
      compounds is unknown. The data show clear effects of repetition and relational
      priming for written words on both a sense-nonsense task and a lexical decision
      task. These results indicate that the relation linking the constituents of
      familiar compounds is important to their access and use.

PMID- 15172565
TI  - Level-ordering does not constrain children's ungrammatical compounds.
AB  - English-speaking children typically avoid using regular plurals in novel
      grammatical deverbal compounds as in rat eater but allow irregular plurals as in
      mice eater (Gordon, 19985). To explain these data, it has been argued that level
      ordering model constrains the production of morphologically complex words,
      including those with which children have had little to no experience. If level
      ordering can be supported, children should avoid regular plurals in their
      ungrammatical deverbal compounds like a breaker-bottle. Seventy-two English
      speaking children were included in the present study, 36 from Britain and 36 from
      Canada. The results showed that 50% of the children who produced ungrammatical
      compounds included regular plurals in the compounds they produced. Conversely,
      none of the children who produced grammatical compounds included regular plurals.
      These results indicate that level-ordering does not constrain children's
      production of ungrammatical compounds. These results raise the possibility that
      level-ordering may not be a valid constraint of children's compounding in
      general.

PMID- 15172566
TI  - Processing polarity items: contrastive licensing costs.
AB  - We describe an experiment that investigated the failure to license polarity items
      in German using event-related brain potentials (ERPs). The results reveal
      distinct processing reflexes associated with failure to license positive polarity
      items in comparison to failure to license negative polarity items. Failure to
      license both negative and positive polarity items elicited an N400 component
      reflecting semantic integration cost. Failure to license positive polarity items,
      however, also elicited a P600 component. The additional P600 in the positive
      polarity violations may reflect higher processing complexity associated with a
      negative operator. This difference between the two types of violation suggests
      that the processing of negative and positive polarity items does not involve
      identical mechanisms.

PMID- 15172567
TI  - A model approach for evaluating effects of remedial actions on mercury speciation
      and transport in a lake system.
AB  - This paper provides a model approach for understanding mercury cycling in aquatic
      systems. The information gained is then used for evaluating three remedial
      actions, namely, natural attenuation, dredging and capping. Onondaga Lake, NY was
      used as a model aquatic system. Mercury transport and speciation in both the
      water column and the benthic sediment were simulated by using a Water Quality
      Analysis Simulation Program. Model predictions for the water column generally
      agreed with the measured values reported in literature for Onondaga Lake.
      Sensitivity analyses of the model were conducted for determining the impact of
      transport mechanisms and speciation mechanisms. Advection, sorption and settling
      were important mechanisms of Hg transport in the water column. In the benthic
      sediment, settling of Hg from the water column was the most important input
      source of Hg. Reduction, methylation and demethylation were important mechanisms
      of Hg speciation in both the water column and the benthic sediment. Assuming that
      Hg loading is steady, natural attenuation showed no positive impact for
      remediation of Hg-contaminated aquatic systems as compared with dredging and
      capping.

PMID- 15172568
TI  - Groundwater pollution on the Zambian Copperbelt: deciphering the source and the
      risk.
AB  - The protection of groundwater resources is of great importance in many semi-arid
      and sub-tropical environments. The Copperbelt of Zambia is one such environment
      and due to the high proportion of tailings impoundments, residue heaps, high
      density informal settlements and extensive sulfidic ore deposits in the region,
      its groundwater resources are under threat of anthropogenic or geogenic
      pollution. One such pollutant plume is investigated in this study, to determine
      its origin, rate of progression and the environmental and health risk it poses.
      Geological and geochemical investigation strongly suggests an upslope tailings
      impoundment as the source of contaminants, with the edge of the pollution plume
      lying 500-700 m downstream of the impoundment. Although cobalt, nickel and zinc
      concentrations were elevated within the polluted groundwater, the concentrations
      are low as a result of sulfide precipitation and adsorption within the aquifer,
      and meets guidelines for drinking water quality. Attenuation of heavy metals is
      linked to tailings dam and aquifer pH, with the high buffering capacity of each
      implying that these processes of attenuation are likely to continue removing
      harmful metals from the aquifer. Thus, it appears unlikely that the contaminated
      groundwater will present a major environmental risk at this site. However,
      tailings impoundments are widespread throughout the Copperbelt: sites with low
      tailings dam buffer capacity and in catchments on crystalline bedrock geology,
      groundwater pollution through tailings dam leachate may liberate high
      concentrations of heavy metals into the shallow groundwater, potentially posing a
      serious human health risk to the communities using the water resources and an
      environmental risk to the downstream ecosystems.

PMID- 15172569
TI  - Removal of azinphos methyl by alfalfa plants (Medicago sativa L.) in a soil-free
      system.
AB  - The objective of this study was to investigate the removal of azinphos methyl
      assisted by alfalfa plants, with special emphasis on the effects of this compound
      on some plant's physiological parameters. Hydroponic cultures of alfalfa
      (Medicago sativa L., var Romagnola) were employed as a model system. These
      cultures were exposed to a nutrient medium containing 10 mg/l of azinphos methyl.
      A first-order kinetic approach was used to describe the removal of azinphos
      methyl from the solution. After 20 days of culture, the initial amount of
      azinphos methyl was reduced to non-detectable levels in the presence of plants.
      In the absence of plants, 20% of azinphos methyl remained in the solution after
      30 days of treatment. The half-life of the pesticide was reduced from 10.8 to 3.4
      days in the presence of plants. The growth index of alfalfa plants exposed to
      azinphos methyl was negatively affected. Chlorophyll contents were reduced after
      24 h of treatment and thereafter the levels were comparable to that of control
      plants. The peroxidase activity of alfalfa roots was not affected by the presence
      of azinphos methyl. In conclusion, alfalfa plants were able to survive when
      exposed to an effective concentration of 10 mg/l of azinphos methyl in the root
      zone, with some alterations on their physiological parameters.

PMID- 15172570
TI  - Heavy metals in drinking waters from Mount Amiata (Tuscany, Italy). Possible
      risks from arsenic for public health in the Province of Siena.
AB  - Concentrations of As, Al and some heavy metals (V, Cr, Mn, Fe, Co, Ni, Cu, Zn,
      Cd, Pb) were measured in drinking waters from Siena and Grosseto districts, South
      Tuscany, Italy. The analysis, performed mostly by electrothermal activated atomic
      absorption spectroscopy equipped with graphite furnace, and in some cases high
      resolution inductively coupled plasma mass spectrometry, indicated that
      concentrations of the elements were generally far below the maximum allowed
      concentration (MAC). However, the concentration of As in some of the waters at
      sources or at the terminals of the water webs was relatively high (largest value,
      14.4(2) microg/l) when compared to the MAC(As) value (10 microg/l, December 25,
      2003; Italian Law). Relatively high concentrations of some metals had been
      detected in a few samples from the ends of the distribution webs, when compared
      to values at sources. These effects are probably due to leaching from metal
      pipes. A general 'metal index' (MI) for drinking water, which takes into account
      possible additive effects of N heavy metals on the human health that helps to
      quickly evaluate the overall quality of drinking waters, is introduced in this
      paper as MI=?(i=1,N)[C(i)/(MAC)(i)]. Samples from Ermicciolo spring and Siena
      water web had MI values of 1.1 and 1.3, respectively, showing that the quality of
      drinking water in town is somewhat worse than that at one of the main sources, at
      least regarding the 12 elements taken into account.

PMID- 15172572
TI  - Assessment of daily intake of trace elements due to consumption of foodstuffs by
      adult inhabitants of Rio de Janeiro city.
AB  - Concentrations of Al, Cd, Cr, Cu, Mn, Ni, Pb, U and Zn were determined in
      vegetables (leafy vegetables, fruit, root, grain and cereal), derived products
      (sugar, coffee, manioc flour, wheat flour, corn flour, and pasta) and animal
      products (meat, fish, milk) most frequently consumed by adult inhabitants of Rio
      de Janeiro city. A total of 90 samples were analyzed using inductively coupled
      plasma mass spectrometry (ICPMS) as the principal method following sample
      dissolution by dry and wet ashing. Generally, highest contributions for the
      intake of micronutrients (Cu, Mn, Ni and Zn) arise from bean, rice and wheat
      flour consumption. Meat, cow milk and the flours, wheat and manioc, are major
      sources of Al, Cd, Pb and U intake. The daily intake of nine elements via
      foodstuffs was estimated as: 3.4x10(-4) mg of U, 1.8x10(-3) mg of Cd, 2.8x10(-2)
      mg of Pb, 2.3x10(-2) mg of Cr, 8.9x10(-2) mg of Ni, 1.12 mg of Cu, 2.5 mg of Mn,
      3.5 mg of Al and 4.8 mg of Zn. The intake of toxic elements ranged between 2.7%
      (Cd) and 30% (U) of the provisional tolerable daily intake and reference dose
      values indicating that food consumption is, at present, no critical factor for
      the uptake of these toxic metals, in the population studied here. Concerning
      micronutrients, the recommended values of daily intake of Cu and Mn are
      conveniently supplied by the diet; however, for Cr and Zn they are lower than the
      recommend daily allowance. Due to high metal concentrations and consumption
      rates, black bean is the foodstuff that provided the highest ingestion rates of
      Cu, Mn, Ni and Zn (36-60% of the reference dose), being therefore a very
      important source of micronutrient supply.

PMID- 15172571
TI  - Long-term consequences for Northern Norway of a hypothetical release from the
      Kola nuclear power plant.
AB  - The spatial and temporal variation in radiocaesium and (90)Sr doses to two
      population groups of the two Northernmost counties of Norway, Troms and Finnmark,
      following a hypothetical accident at the Kola nuclear power plant (KNPP) have
      been estimated using a model implemented within a geographical information
      system. The hypothetical accident assumes a severe loss of coolant accident at
      the KNPP coincident with meteorological conditions causing significant
      radionuclide deposition in the two counties. External doses are estimated from
      ground deposition and the behaviour of the different population groups, and
      internal doses from predicted food product activity concentrations and dietary
      consumption data. Doses are predicted for reindeer keepers and other Norwegian
      inhabitants, taking account of existing (137)Cs and (90)Sr deposition but not
      including the remedial effect of any countermeasures that might be used. The
      predicted doses, arising mainly from radiocaesium, confirm the Arctic Monitoring
      and Assessment Programme assessment that residents of the Arctic are particularly
      vulnerable to radiocaesium contamination, which could persist for many years.
      External doses are predicted to be negligible compared to ingestion doses.
      Ingestion doses for reindeer keepers are predicted to exceed 1 mSv y(-1) for
      several decades primarily due to their high consumption of reindeer meat. Other
      Norwegians would also be potentially exposed to doses exceeding 1 mSv y(-1) for
      several years, especially if they consume many local products. Whilst reindeer
      production is the most important exposure pathway, freshwater fish, lamb meat,
      dairy products, mushrooms and berries are also significant contributors to
      predicted ingestion doses. Radionuclide fluxes, defined as the total output of
      radioactivity in food from an area for a unit time, are dominated by reindeer
      meat. The results show the need for an effective emergency response, with
      appropriate countermeasures, should an accident of the scale considered in this
      paper occur at the KNPP.

PMID- 15172573
TI  - Scalp hair analysis as a tool in assessing human exposure to heavy metals (S.
      Domingos mine, Portugal).
AB  - Hair samples from the scalp were used in a preliminary assessment of heavy metals
      exposure (As, Cd, Cr, Cu, Mn and Zn) of the human population living near an
      abandoned cupric pyrite mine (Mina de S. Domingos, Southeast Alentejo, Portugal).
      In parallel with the collection of hair samples, individuals from two different
      communities at the South and North of the mine area answered a questionnaire
      designed to obtain information about potential exposure pathways to these
      elements. The questionnaire allowed data collection about the most frequently
      consumed foodstuffs, drinking water sources, smoking habits, alcohol consumption
      and health condition. Higher concentrations, and subsequently higher ranges, of
      Cd, Cu and As were recorded in individuals living near the mine (MSD group), in
      opposition to individuals living several kilometers apart. Additionally, the
      concentrations recorded in the hair of some individuals from the MSD group were
      above the reference values for non-exposed individuals, suggesting their enhanced
      exposure. However, no significant differences were found for the average
      concentration of these elements between villages. Individuals from the CP and SC
      groups presented significantly higher concentrations of Zn and Mn in scalp hair.
      These results were in agreement with the concentrations of these elements
      recorded in soil samples. The water supplies of the area do not seem to be
      potential sources of trace elements for human beings. In opposition, individuals
      that frequently consume milk and cheese obtained from cattle that usually breeds
      in the area presented significantly higher concentrations of As and Mn in their
      scalp hair. Our results suggest that the population of S. Domingos mine area and
      neighbour localities may be exposed to some of the elements analysed namely Mn
      and Zn. The most likely exposure pathways seemed to be animal foodstuffs,
      however, a more detailed analysis of these products, as well as garden vegetables
      and fruits, should be performed.

PMID- 15172574
TI  - Use of near-infrared spectroscopy for determining the total arsenic content in
      prostrate amaranth.
AB  - The potential of near infrared spectroscopy (NIRS) for determining the total
      arsenic (As) content in the prostrate amaranth (Amaranthus blitoides S. Watson)
      was assessed. Seventy-four samples belonging to this species, were harvested at
      different maturity stages along the polluted area, and then were scanned by NIRS.
      Their As reference values were obtained by atomic absorption spectrometry and
      they were regressed against different spectral transformations using modified
      partial least square (MPLS) regression. First derivative transformation equation
      of the raw optical data, previously standardized by standard normal variate (SNV)
      and De-trending (DT) transformations, resulted in a coefficient of determination
      (r(2)) in the external validation of 0.63, indicative of equations that can be
      used for a correct separation of the samples into low, medium and high groups.
      The standard deviation to standard error of prediction ratio (RPD) and range to
      standard error of prediction ratio (RER) for the first derivative equation were
      similar to those obtained for other trace metal calibrations reported in NIRS
      reflectance. Major cell components such as chlorophyll, lipids, starch and
      proteins were used by MPLS for modeling the equations. The use of NIRS for the
      determination of the As content in A. blitoides plants offers an important saving
      of time and cost of analysis.

PMID- 15172575
TI  - Hierarchical community classification and assessment of aquatic ecosystems using
      artificial neural networks.
AB  - Benthic macroinvertebrate communities in stream ecosystems were assessed
      hierarchically through two-level classification methods of unsupervised learning.
      Two artificial neural networks were implemented in combination. Firstly, the self
      organizing map (SOM) was used to reduce the dimension of community data, and
      secondly, the adaptive resonance theory (ART) was subsequently applied to the SOM
      to further classify the groups in different scales. Hierarchical grouping in
      community data efficiently reflected the impact of the environmental factors such
      as topographic conditions, levels of pollution, and sampling location and time
      across different scales. New community data not included in the training process
      were used to test the trained network model. The input data were appropriately
      grouped at different hierarchical levels by the trained networks, and
      correspondingly revealed the impact of environmental disturbances and temporal
      dynamics of communities. The hierarchical clusters based on a two-level
      classification method could be useful for assessing ecosystem quality and
      community variations caused by environmental disturbances.

PMID- 15172576
TI  - Integrated environmental assessment of Volturno River in South Italy.
AB  - The application of a battery of toxicity and genotoxicity tests on pore water in
      parallel and in combination with physico-chemical analyses and benthic
      macroinvertebrate community investigations is discussed as a tool to assess the
      environmental quality of the Volturno River in South Italy. Toxicity testing was
      performed on the rotifer Brachionus calyciflorus and the crustacean Daphnia
      magna. Genotoxicity was determined by the SOS chromotest and Mutatox system. The
      biotic index used for macroinvertebrates was the extended biotic index that was
      developed to verify if the observed benthic community accords with the expected
      one for an identical environment without anthropic contaminations. The physico
      chemical characterization of the surface waters showed a declining trend from up
      river to down-river for dissolved oxygen and conductivity. Also, chemical
      variables showed a worsening along the river axis showing an increase in
      ammonium, phosphates, sulfates, and heavy metals. The assessment of macro
      invertebrates reflected the general ecological deterioration occurring to
      chemical as well as toxic and genotoxic pollution. Furthermore, benthic community
      composition and the sediment contamination of toxic and genotoxic substances were
      shown to be correlated. We concluded that investigations on pore water,
      integrated with benthic macroinvertebrate communities, could provide the basis
      for a robust monitoring of rivers.

PMID- 15172577
TI  - Characterization, identification of ambient air and road dust polycyclic aromatic
      hydrocarbons in central Taiwan, Taichung.
AB  - The concentrations of ambient air polycyclic aromatic hydrocarbons (PAHs) were
      measured simultaneously in an industrial area (Taichung Industrial Park, TIP) and
      suburban area (Tunghai University, THU) in central Taiwan, Taichung. A total of
      samples were collected simultaneously at the two sites between August 2002 and
      March 2003. Particle-bound PAHs (p-PAHs) were collected on quartz filters and gas
      phase PAHs (g-PAHs) on glass cartridges using polyurethane foam sampler,
      respectively. Both types of samples were extracted with dichloromethane/n-hexane
      mixture (50/50, v/v) for 24 h, then the extracts were subjected to gas
      chromatography/mass spectrometric analysis. Moreover, the roadside dust particle
      PAHs composition were also collected and analyzed at TIP, THU and traffic road
      sampling sites. The five main road lines in Taichung City were selected as
      traffic road sampling sites. Correlation studies between PAHs concentrations and
      meteorological parameters were revealed that temperature has greater effects
      (P>0.6) than other meteorological parameters such as wind speed, relative
      humidity and atmospheric pressure on g-PAHs and p-PAHs. PAHs sources were
      resolved by using principal component analysis and diagnostic ratios. The major
      sources of PAHs were combustion, traffic vehicle exhaust (diesel and gasoline
      engine), incinerator and industrial stationary sources at both sampling sites in
      central Taiwan.

PMID- 15172579
TI  - Characterization of atmospheric concentrations and partitioning of PAHs in the
      Chicago atmosphere.
AB  - An intensive sampling program has been undertaken in the absence of precipitation
      at an urban site, Chicago, to characterize the atmospheric concentration and
      partitioning of PAHs. Two different sampling programs have been carried out with
      a large number of samples. Measured ambient concentrations of PAHs were
      classified as Land and Lake samples based on wind direction and back trajectory
      calculations. Differences in ambient concentrations of PAHs were observed between
      Land and Lake samples. The concentrations of PAHs when air originated over the
      Land were approximately two-four times higher than the concentrations measured
      when air originated over the Lake. It has been demonstrated that partitioning of
      PAHs shows a consistent difference between samples taken when wind came from off
      the land rather than off the water. This was most evident by more shallow slopes
      for Lake samples compared to the slopes for Land samples, when partition
      coefficient (K(p)) is plotted on a log-log scale vs. the subcooled liquid vapor
      pressure (P(L)(0)). Experimentally, determined K(p) values were compared with the
      results obtained using two different models, one based on absorption into aerosol
      organic matter and the other adsorption onto soot carbon. Experimental K(p)
      values generally agreed well with the soot+octanol based model predictions.

PMID- 15172578
TI  - Emission comparison of urban bus engine fueled with diesel oil and 'biodiesel'
      blend.
AB  - The chemical and toxicological characteristics of emissions from an urban bus
      engine fueled with diesel and biodiesel blend were studied. Exhaust gases were
      produced by a turbocharged EURO 2 heavy-duty diesel engine, operating in steady
      state conditions on the European test 13 mode cycle (ECE R49). Regulated and
      unregulated pollutants, such as carcinogenic polycyclic aromatic hydrocarbons
      (PAHs) and nitrated derivatives (nitro-PAHs), carbonyl compounds and light
      aromatic hydrocarbons were quantified. Mutagenicity of the emissions was
      evaluated by the Salmonella typhimurium/mammalian microsome assay. The effect of
      the fuels under study on the size distribution of particulate matter (PM) was
      also evaluated. The use of biodiesel blend seems to result in small reductions of
      emissions of most of the aromatic and polyaromatic compounds; these differences,
      however, have no statistical significance at 95% confidence level. Formaldehyde,
      on the other hand, has a statistically significant increase of 18% with biodiesel
      blend. In vitro toxicological assays show an overall similar mutagenic potency
      and genotoxic profile for diesel and biodiesel blend emissions. The electron
      microscopy analysis indicates that PM for both fuels has the same chemical
      composition, morphology, shape and granulometric spectrum, with most of the
      particles in the range 0.06-0.3 microm.

PMID- 15172580
TI  - Pollution loads in urban runoff and sanitary wastewater.
AB  - While more attention has been paid in recent years to urban point source
      pollution control through the establishment of wastewater treatment plants in
      many developing countries, no considerable planning nor any serious measures have
      been taken to control urban non-point source pollution (urban stormwater runoff).
      The present study is a screening analysis to investigate the pollution loads in
      urban runoff compared to point source loads as a first prerequisite for planning
      and management of receiving water quality. To compare pollutant loads from point
      and non-point urban sources, the pollutant load is expressed as the weight of
      pollutant per hectare area per year (kg/ha.year). Unit loads were estimated in
      stormwater runoff, raw sanitary wastewater and secondary treatment effluents in
      Isfahan, Iran. Results indicate that the annual pollution load in urban runoff is
      lower than the annual pollution load in sanitary wastewater in areas with low
      precipitation but it is higher in areas with high precipitation. Two options,
      namely, advanced treatment (in lieu of secondary treatment) of sanitary
      wastewater and urban runoff quality control systems (such as detention ponds)
      were investigated as controlling systems for pollution discharges into receiving
      waters. The results revealed that for Isfahan, as a low precipitation urban area,
      advanced treatment is a more suitable option, but for high precipitation urban
      areas, urban surface runoff quality control installations were more effective for
      suspended solids and oxygen-demanding matter controls, and that advanced
      treatment is the more effective option for nutrient control.

PMID- 15172581
TI  - Occurrence and origin of phosphine in landfill gas.
AB  - A landfill (Hooge Maey, Flanders, Belgium) was subjected to an in-depth study in
      order to explain the origin of phosphine detected in high amounts in landfill
      gas, in comparison with biogas from other sources, during a previous study. The
      spatial and temporal variability of the phosphine concentration in landfill gas
      was assessed. Twenty-four wells were monitored and differences in phosphine
      concentration up to one log unit were observed (3.2-32.4 microg/m(3)). The
      phosphine concentration in each well was constant in time over a period of 4
      months. No correlation was found between the phosphine concentration and methane,
      carbon dioxide, hydrogen sulfide, ethene or ethane concentration. In a series of
      laboratory tests, it was shown that phosphine was emitted during batch
      fermentation tests inoculated with landfill leachate when Fe(0) or Al(0)
      specimens were added. Conditions favouring corrosion of iron gave rise to higher
      emissions of phosphine. The phosphine concentration in the headspace of a batch
      test rose to 1.43 mg/m(3) after 27 days of incubation. Weight loss of corroding
      steel coupons correlated with phosphine emission. Calculations showed that all
      phosphine emitted from the 0.005 km(3) landfill (160 g/year) could be attributed
      to corrosion of metals. No evidence of de novo synthesis could be established.

PMID- 15172582
TI  - Environmental impact of early Basque mining and smelting recorded in a high ash
      minerogenic peat deposit.
AB  - More than four metres of core, covering almost 5000 years of deposition, were
      collected in a high ash minerogenic peat deposit located in the High Aldudes
      valley (Basque country), an area well known for its mineral abundance, exploited
      from Roman Times at least. Although minerogenic peatlands are not generally
      considered as the best archives to reconstruct past atmospheric metal deposition
      history, lead isotopic geochemistry demonstrates the integrity of the Pb record
      at least within the three upper meters; that is to say over the last four
      millennia. Zn, Cd and Cu may have been widely redistributed either by biological
      cycling, advective groundwater movements, or diffusional processes. Anthropogenic
      lead input phases are clearly pinpointed by positive shifts in Pb/Sc ratios with
      concomitant sharp drops in (206)Pb/(207)Pb ratios. They are often accompanied by
      significant declines in tree taxa, interpreted as increasing demand for wood to
      supply energy for local mining and/or metallurgical operations. Periods of mining
      and/or smelting activity are identified during Antiquity and Modern Times, and
      are also confirmed by textual and field evidence. Inputs from the Rio Tinto
      (Southern Spain), often invoked as a major lead contributor to the European
      atmosphere during Roman Times, were not detected here. This remote source was
      probably masked by local inputs. Other mining and/or smelting phases, only
      suspected by archaeologists, are here identified as early as the Bronze Age.
      Although the durations of these phases are possibly overestimated because of
      detrital inputs consequent to the release of lead from polluted soils over a long
      period of time after major pollutant inputs, the periods at which pollution peaks
      occur are in good agreement with archaeological knowledge and palaeo-botanical
      data. The combination of geochemical and palaeo-botanical techniques with field
      archaeology, therefore provides a powerful tool in studying the interaction of
      early human societies with their environment, as regards early mining and
      smelting.

PMID- 15172583
TI  - Mercury and methylmercury concentrations and loads in the Cache Creek watershed,
      California.
AB  - Concentrations and loads of total mercury and methylmercury were measured in
      streams draining abandoned mercury mines and in the proximity of geothermal
      discharge in the Cache Creek watershed of California during a 17-month period
      from January 2000 through May 2001. Rainfall and runoff were lower than long-term
      averages during the study period. The greatest loading of mercury and
      methylmercury from upstream sources to downstream receiving waters, such as San
      Francisco Bay, generally occurred during or after winter rainfall events. During
      the study period, loads of mercury and methylmercury from geothermal sources
      tended to be greater than those from abandoned mining areas, a pattern
      attributable to the lack of large precipitation events capable of mobilizing
      significant amounts of either mercury-laden sediment or dissolved mercury and
      methylmercury from mine waste. Streambed sediments of Cache Creek are a
      significant source of mercury and methylmercury to downstream receiving bodies of
      water. Much of the mercury in these sediments is the result of deposition over
      the last 100-150 years by either storm-water runoff, from abandoned mines, or
      continuous discharges from geothermal areas. Several geochemical constituents
      were useful as natural tracers for mining and geothermal areas, including the
      aqueous concentrations of boron, chloride, lithium and sulfate, and the stable
      isotopes of hydrogen and oxygen in water. Stable isotopes of water in areas
      draining geothermal discharges showed a distinct trend toward enrichment of (18)O
      compared with meteoric waters, whereas much of the runoff from abandoned mines
      indicated a stable isotopic pattern more consistent with local meteoric water.

PMID- 15172584
TI  - Cadmium sorption in biosolids amended soils: results from a field trial.
AB  - The effect of biosolids amendment on cadmium sorption coefficient (K(d)) was
      determined for soils in a biosolids field trial. The sorptive properties of
      biosolids are thought to have a significant controlling effect upon the
      availability/uptake and mobility of potentially toxic metals. K(d) values for the
      three biosolids were 10-30 times greater than those for unamended soil. Elevated
      K(d) values were still apparent 1 and 2 years after biosolids amendment (100 t
      ha(-1)) for two of the three biosolids. Chemical extractants (sodium hypochlorite
      and hydrofluoric acid, respectively) were used in an attempt to determine K(d)
      values of isolated inorganic and organic fractions. For both biosolids amended
      soils and unamended controls, Cd sorption appeared to be dominated by the
      inorganic fraction, potentially indicating the overriding importance of this
      fraction in controlling metal mobility. However, for the biosolids themselves,
      the sum of inorganic and organic fraction contributions to K(d) accounted for
      less than half the K(d) of the whole biosolids. This discrepancy was attributed
      to the loss of highly sorptive water soluble species in both chemical
      extractions.

PMID- 15172585
TI  - Gas/particle partitioning of seven volatile polycyclic aromatic hydrocarbons in a
      heavy traffic urban area.
AB  - Air samples (vapor- and particle-phase) were taken for 19 sampling events during
      the period from December 1997 to July 1998 in an urban site in the center of
      Athens. The urban site is densely populated and characterized by heavy traffic
      circulation and elevated concentrations of VOCs, NO(x), CO and smoke. Seven
      volatile polycyclic aromatic hydrocarbons (PAHs) were determined in samples. The
      temperature dependence of gas-phase atmospheric concentration of PAHs, C(g), was
      investigated using diagrams of natural logarithm of partial pressures (lnP) vs.
      reciprocal mid-point temperatures. For the six of seven volatile PAHs, the
      temperature dependence of lnP was statistically significant (at least at the 90%
      confidence level) and the temperature accounted for 21-67% of the variability in
      gas-phase concentrations. The gas-phase concentration C(g) of the very volatile
      PAHs was affected more significantly by changes in temperature, but the variation
      of the less-volatile PAHs fluoranthene and pyrene C(g), was better explained by
      changes in temperature. The temperature dependence of gas/particle partitioning
      constant K(P) was also examined. Regressions of log(K(P))(-1) vs. T(-1) for
      fluorene, fluoranthene and pyrene were classified into two different temperature
      ranges. The gas/particle partitioning of PAHs was studied by correlating the
      partition constant to the sub-cooled liquid saturation vapor pressure (P(L)(o)).
      The Junge adsorption model underestimated the particle fraction of volatile PAHs
      probably due to the presence of non-exchangeable fraction. Slopes (m(r)) of the
      regressions logK(P) vs. logP(L)(o) were different from the value -1 as Pankow's
      theory predicts. The short distance between the sampling point and the emission
      sources is also estimated to be a factor that causes deviations from the
      theoretical value. Evidence that atmospheric conditions favorable for secondary
      aerosol formation coincide with higher value of m(r), was provided by limited
      sampling events. An interrelation was found to exist between the m(r) values,
      allowing the prediction of the gas/particle partitioning of a series of seven
      PAHs by the measurement of a single PAH partitioning.

PMID- 15172586
TI  - Nutrient fluxes and sulfur cycling in the organic-rich sediment of Makirina Bay
      (Central Dalmatia, Croatia).
AB  - Fluxes of dissolved nutrients in the organic-rich sediment of Makirina Bay
      (Croatia) were estimated in in-situ incubation experiments and compared to those
      calculated from a diagenetic model based on the concentration vs. depth profiles
      in the pore water extracted from a sediment core at the same sampling site.
      Benthic fluxes observed in the in-situ experiment were strongly influenced by the
      decomposition of sedimentary organic matter by bacterial sulfate reduction and
      precipitation of authigenic pyrite and calcite. Assimilation of dissolved nitrate
      and ammonia within the sediment resulted in peculiar nitrate and ammonia
      concentration profiles. Differences between the benthic and diffusive fluxes
      indicated that the effects of bioturbation and irrigation, which were not taken
      into account in the model calculation of diffusive fluxes, should not be
      considered as negligible. They are, however, extremely difficult to estimate
      because of the heterogeneity of the sediment. Sulfate reduction in the pore water
      could not be detected, although it was obvious from pyrite precipitation and the
      isotopic compositions of different sedimentary sulfur species. It is suggested
      that reoxidation of sulfide and upward diffusion of sulfate from the sediment
      layer accumulated during past salt production can account for the scattered
      sulfate vs. depth profile. The distribution and stable isotope compositions of
      sedimentary sulfur species were studied in more detail. The influx of sulfate was
      explained by rapid sulfate reduction in the sediment. The sulfate reduction rate
      was highest in the upper part of the sediment column, as concluded from
      delta(34)S values. In lower horizons, the concentration of organic sulfur
      increased, while concentrations of sulfide decreased. The mirror-imaged
      concentration vs. depth profiles of sulfide and organic sulfur, as well as their
      stable isotopic compositions, show that they were formed simultaneously, most
      probably in competitive processes.

PMID- 15172587
TI  - Neutral rains at Athens, Greece: a natural safeguard against acidification of
      rains.
AB  - Samples of all rains in a period from October, 1998 to January, 1999 at Athens,
      Greece, were collected. The pH values of almost all of these rains clustered in a
      high range of 7.0-7.5, with no relation between pH and their SO(4)(2-), NO(3)(-)
      and Cl(-) contents. In addition, a few rains with low contents of chemical
      components similar to pure water also were observed, giving a pH (approx. 5.5) of
      rain caused by dissolution of only atmospheric CO(2) in it. These results
      indicate that the level of air pollution of Athens by human activity has become
      lower during the last decade, restoring the neutral condition of rain in this
      area. Furthermore, the Ca contents and Ca/Mg ratios in these rains, as well as
      their chemical and isotopic behavior, suggest that particles of calcium carbonate
      taken in as dust act as a neutralizer of rains. The dust must be derived not only
      from the urban area of Athens but also from its environs or areas distant from
      it. Such a mechanism causing universally neutral rains throughout the rainy
      season at Athens must have worked as a natural safeguard against rains acidified
      naturally and artificially from ancient times up to recent years, keeping the
      remains of ancient Greece in a good state of preservation during such a long
      period.

PMID- 15172588
TI  - Distribution and behavior of trace metals in the sediment and porewater of a
      tropical coastal wetland.
AB  - Vertical profiles (0-30 cm below surface) of four trace metals-Cadmium (Cd),
      Chromium (Cr), Lead (Pb) and Zinc (Zn)-in the sediment and sediment porewater of
      an ecologically important intertidal mudflat in the Mai Po and Inner Deep Bay
      Ramsar Site were thoroughly studied over a period of 10 months (from March 1999
      to January 2000). Two surveys, one in summer and another in winter, involving a
      total of eight sampling stations were conducted to study the seasonal variation
      of the remobilization characteristics of these trace metals in the mudflat
      sediment. The range of depth averaged concentration of these trace metals in the
      mudflat sediment was: 0.3-0.8 microg/g (Cd); 9.8-91.0 microg/g (Cr); 7.3-69.1
      microg/g (Pb); and 39.5-192.0 microg/g (Zn), while that in the sediment porewater
      was: 0.3-121.1 microg/l (Cd); 3.0-2704.1 microg/l (Cr); 2.6-105.6 microg/l (Pb);
      and 32.6-4238.3 microg/l (Zn). In general, levels of dissolved trace metals in
      the sediment porewater were much higher in the summer than in the winter while
      their concentrations in the sediment were more or less the same throughout the
      year. Enrichment of Cd, Pb and Zn in the sediment porewater of the upper oxic
      layer and that of Cr in the oxic-sub-oxic boundary was generally observed.
      Regions in the vicinity of the Mai Po mangroves and the river mouths of Shenzhen
      River and Shan Pui River were found to be hotspots of trace metal pollution.
      Benthic diffusive fluxes of trace metals from the mudflat sediment were also
      estimated. Of the four trace metals, cadmium showed the greatest tendency toward
      remobilization from the sediment phase to the more bio-available porewater phase.

PMID- 15172589
TI  - Long-term trends in the uptake of radiocesium in Rozites caperatus.
AB  - Measurements of (134)Cs and (137)Cs in Rozites caperatus from 1991 to 2001 showed
      differences in the uptake pattern of Chernobyl and fallout derived radiocesium
      over time. The effective half-life of Chernobyl derived (137)Cs was determined to
      12.4 years, whereas fallout derived (137)Cs had an effective half-life of 9.8
      years. However, the trend for Chernobyl derived (137)Cs was clearly not linear.
      An effective average half-life of 3.1 years was determined for Chernobyl derived
      (137)Cs in the period from 1991 to 1994. The corresponding ecological half-life
      was 3.4 years. In the period from 1994 to 2001 it is possible that the effective
      half-life was longer than the physical, which indicates that more Chernobyl
      cesium becomes available than disappears through radioactive decay. The
      difference may be due to depth distribution of radiocesium, i.e. fallout derived
      cesium have penetrated deeper than Chernobyl. The changes in the half-lives of
      Chernobyl derived radiocesium over time together with the half-life of the older
      fallout derived radiocesium may be valuable in predictions of future radiocesium
      concentrations in mushrooms and thereby of food chain transfer to man.

PMID- 15172590
TI  - Volcanic emissions of mercury to the atmosphere: global and regional inventories.
      Comment.

PMID- 15172592
TI  - Characterisation of depleted uranium (DU) from an unfired CHARM-3 penetrator.

PMID- 15172593
TI  - Modelling the atmospheric fate and seasonality of polycyclic aromatic
      hydrocarbons in the UK.
AB  - This paper presents the results from an exercise in atmospheric contaminant fate
      modelling, which had three main objectives: (1) to investigate the balance
      between estimated national atmospheric emissions of six selected PAHs and
      observed ambient measurements for the UK, as a means of testing the current
      emission estimates; (2) to investigate the potential influence of seasonally
      dependent environmental fate processes on the observed seasonality of air
      concentrations; and (3) after undertaking the first two objectives, to make
      inferences about the likely magnitude of seasonal differences in sources. When
      addressing objective 1 with annually averaged emissions data, it appeared that
      the UK PAH atmospheric emissions inventory was reasonably reliable for fluorene,
      fluoranthene, pyrene, benzo[a]pyrene and benzo[ghi]perylene--but not so for
      phenanthrene. However, more detailed analysis of the seasonality in environmental
      processes which may influence ambient levels, showed that the directions and/or
      magnitudes of the predicted seasonality did not coincide with field observations.
      This indicates either that our understanding of the environmental fate and
      behaviour of PAHs is still limited, and/or that there are uncertainties in the
      emissions inventories. It is suggested that better quantification of PAH sources
      is needed. For 3- and 4-ringed compounds, this should focus on those sources
      which increase with temperature, such as volatilisation from soil, water,
      vegetation and urban surfaces, and possible microbially-mediated formation
      mechanisms. The study also suggests that the contributions of inefficient,
      diffusive combustion processes (e.g. domestic coal/wood burning) may be
      underestimated as a source of the toxicologically significant higher molecular
      weight species in the winter. It is concluded that many signatory countries to
      the UNECE POPs protocol (which requires them to reduce national PAH emissions to
      1990 levels) will experience difficulties in demonstrating compliance, because
      source inventories for 1990 and contemporary situations are clearly subject to
      major uncertainties.

PMID- 15172594
TI  - Modelling soot and SOF emissions from a diesel engine.
AB  - Modelling of soot and SOF emissions from a typical European turbocharged diesel
      engine has been made. The model consists of a detailed kinetic mechanism with 472
      reactions (120 chemical species) and data from the thermodynamic diagnostic
      procedure of the combustion process of the engine. The forward kinetic constants
      were obtained from literature and the background constants from a self-developed
      non-linear fitting routine based on the Marquardt algorithm. The dilution and
      mixing processes inside the engine are represented by a simple Wiebe function.
      The system of ordinary differential equations is solved with the Rosenbrock
      method for rigid systems and using the interpolating Lagrange polynomials to
      calculate the heat capacity of each species at the corresponding temperature. The
      kinetic model has been implemented in Digital Visual Fortran 6.0. The model has
      been executed for five different fuels and three mixtures of biodiesel and
      reference diesel operating under three diverse conditions from the European
      transient urban/extraurban Certification Cycle and the results of soot and SOF
      predicted are compared with experimental data.

PMID- 15172595
TI  - Use and validation of novel snow samplers for hydrophobic, semi-volatile organic
      compounds (SVOCs).
AB  - Two novel gas-tight snow samplers (snow-can and snow-tube) are presented and the
      performance of the snow-can in a field trial was assessed. The methodology for
      the sampling, extraction and analysis of persistent organic pollutants (POPs) are
      detailed. These samplers allow the various components of a snow sample to be
      analysed separately; these included the meltwater (MW), particulate matter (GFF)
      and vapour in the headspace (HS). Snow samples collected on the Punta Indren
      glacier in the Italian Alps revealed the occurrence of polychlorinated biphenyls
      (PCBs), polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides
      (OC). Replicate samples of the same snow type were undertaken as a test of
      sampling precision. Relative standard deviations (RSDs) for SigmaPCBs and
      SigmaPAHs were approximately 30% and approximately 35% respectively. The lowest
      precision was found for the particle-laden snow, notably for the heavier PCB
      homologues. For the chlorinated compounds, the pesticides lindane and endosulfan
      I had the highest levels in snow, with mean concentrations of 402 and 103 pgl(-1)
      (snow meltwater) respectively. The vapour present in the headspace (HS) comprised
      a minor component of a collected sample for all compounds, but HS concentrations
      for three lighter PAHs gave good agreement with those calculated based on their
      dimensionless Henry's law constants. This suggests that volatilisation during
      melting of aged snow-can be reasonably predicted with knowledge of the
      temperature-dependent Henry's law constant.

PMID- 15172596
TI  - Monitoring PAHs in the Brisbane River and Moreton Bay, Australia, using
      semipermeable membrane devices and EROD activity in yellowfin bream,
      Acanthopagrus australis.
AB  - Two water quality monitoring strategies designed to sample hydrophobic organic
      contaminants have been applied and evaluated across an expected concentration
      gradient in PAHs in the Moreton region. Semipermeable membrane devices (SPMDs)
      that sequester contaminants via passive diffusion across a membrane were used to
      evaluate the concentration of PAHs at four and five sites in spring and summer
      2001/2002, respectively. In addition, induction of hepatic cytochrome P4501, EROD
      activity, in yellowfin bream, Acanthopagrus australis, captured in the vicinity
      of SPMD sampling sites following deployment in summer was used as a biomarker of
      exposure to PAHs and related chemicals. SPMDs identified a clear and reproducible
      gradient in PAH contamination with levels increasing from east to west in Moreton
      Bay and upstream in the Brisbane River. The highest PAH concentrations expressed
      as B(a)P-toxicity equivalents (TEQs) were found in urban areas, which were also
      furthest upstream and experienced the least flushing. Cytochrome P4501 induction
      in A. australis was similar at all sites. The absence of clear trends in EROD
      activity may be attributable to factors not measured in this study or variable
      residency time of A. australis in contaminated areas. It is also possible that
      fish in the Moreton region are displaying enzymatic adaptation, which has been
      reported previously for fish subjected to chronic exposure to organic
      contaminants. These potential interferences complicate interpretation of EROD
      activity from feral biota. It is, therefore, suggested that future monitoring
      combine the two methods by applying passive sampler extracts to in vitro EROD
      assays.

PMID- 15172597
TI  - Nonylphenolic compounds in drinking and surface waters downstream of treated
      textile and pulp and paper effluents: a survey and preliminary assessment of
      their potential effects on public health and aquatic life.
AB  - Eleven drinking water treatment plants, located downstream of textile plants or
      pulp and paper mills, have been sampled monthly during a year for the analysis of
      17 nonylphenol ethoxylates (NP1-17EO) and two nonylphenoxycarboxylic acids (NP1
      2EC). At all but one plant, results in the drinking water, for the sum of these
      19 substances, range between below detection levels and 6.7 microg/l. Annual
      means are between 0.02 and 2.8 microg/l. At the other plant, the yearly average
      concentration is 10.4 microg/l and the monthly maximum is 43.3 microg/l. In the
      surface (pre-treatment) water, the annual mean concentrations of the 11 plants
      range between 0.14 and 17.8 microg/l and the recorded instantaneous maximum is
      55.3 microg/l. According to Canadian health authorities, drinking water is a
      negligible route of human exposure to nonylphenolic compounds, even at the
      highest concentrations found in this study. After transformation of the data into
      nonylphenol equivalents, about 20% of the surface water samples exceed the
      Canadian 1 microg/l nonylphenol water quality guideline for the protection of
      aquatic life. Some results also exceed Quebec's 6 microg/l nonylphenol guideline.
      The efficiency of the plants in removing nonylphenolic compounds from drinking
      water is highly variable, ranging from 11% to 99%.

PMID- 15172598
TI  - Atrazine and simazine degradation in Pennisetum rhizosphere.
AB  - The ability of rhizosphere of four plant species to promote the degradation of
      charcoal-fixed atrazine and simazine in cement blocks of a long-term contaminated
      soil when mixed with a normal soil at 1:1 ratio was tested. Of the four selected
      plants viz., rye grass (Lolium perenne), tall fescue (Festuca arundinacae),
      Pennisetum (Pennisetum clandestinum) and a spring onion (Allium sp.) used in this
      study, only P. clandestinum was able to survive in herbicide contaminated soil
      while other plants died within few days after germination/transplanting. Both
      atrazine and simazine were degraded at a faster rate in contaminated soil planted
      to P. clandestinum than in unplanted soil. Within 80 days, nearly 45% and 52% of
      atrazine and simazine, respectively, were degraded in soil planted to P.
      clandestinum while only 22% and 20% of the respective herbicide were degraded in
      the unplanted soil. During 80-day experimental period, both microbial biomass and
      soil dehydrogenase activity were significantly increased (7-fold) in soil planted
      to P. clandestinum over that in unplanted soil. The suspension of contaminated
      rhizosphere soil, planted to P. clandestinum exhibited an exceptional capability
      to degrade both atrazine (300 microg) and simazine (50 microg) in a mineral salts
      medium over that of non-rhizosphere soil suspension. Results indicate that P.
      clandestinum, a C4 plant, may be useful for remediation of soils contaminated
      with atrazine and simazine.

PMID- 15172599
TI  - Electrokinetic remediation of a Cu contaminated red soil by conditioning
      catholyte pH with different enhancing chemical reagents.
AB  - The effect of enhancement reagents on the efficiency of electrokinetic
      remediation of Cu contaminated red soil is evaluated. The enhancement agents were
      a mix of organic acids, including lactic acid+NaOH, HAc-NaAc and HAc-NaAc+EDTA.
      The soil was prepared to an initial Cu concentration of 438 mgkg(-1) by
      incubating the soil with CuSO4 solution in a flooded condition for 1 month.
      Sequential extraction showed that Cu was partitioned in the soil as follows: 195
      mgkg(-1) as water soluble and exchangeable, 71 mgkg(-1) as carbonate bound and
      105 mgkg(-1) as Fe and Mn oxides. The results indicate that neutralizing the
      catholyte pH maintains a lower soil pH compared to that without electrokinetic
      treatment. The electric currents varied depending upon the conditioning solutions
      and increased with an increasing applied voltage potential. The electroosmotic
      flow rate changed significantly when different conditioning enhancing reagents
      were used. It was observed that lactic acid+NaOH treatments resulted in higher
      soil electric conductivities than HAc-NaAc and HAc-NaAc+EDTA treatments.
      Ultimately, enhancement by lactic acid+NaOH resulted in highest removal
      efficiency (81% Cu removal) from the red soil. The presence of EDTA did not
      enhance Cu removal efficiencies from the red soil, because EDTA complexed with Cu
      to form negatively charge complexes, which slowly migrated toward the anode
      chamber retarding Cu2+ transport towards the cathode.

PMID- 15172600
TI  - Metabolic fate of [14C]-2,4-dichlorophenol in macrophytes.
AB  - The metabolic fate of 2,4-dichlorophenol (DCP) was investigated in six
      macrophytes representing different life forms. Salvinia natans and Lemna minor
      were chosen as surface-floating plants, Glyceria maxima and Mentha aquatica as
      emergent species and Myriophyllum spicatum and Hippuris vulgaris as submerged
      aquatic plants. After uptake of a [U-phenyl-14C]-DCP solution followed by a 48 h
      water chase, whole plants (L. minor, S. natans) or excised shoots were harvested
      and aqueous extracts were analysed by high performance liquid chromatography
      (HPLC). Metabolites were then isolated, submitted to enzymatic or chemical
      hydrolyses and characterised by electrospray ionisation-mass spectrometric
      analyses. Whereas DCP monoglucosides or more complex monoglucoside esters, either
      malonyl or acetyl, were found in most species, an unusual glucosyl-pentose
      conjugate was identified as the DCP major metabolite in L. minor and G. maxima.
      Our results showed for the first time the ability of five macrophytes to uptake
      and metabolise DCP and the characterisation of their metabolic pathways of DCP
      biotransformation.

PMID- 15172601
TI  - Environmental assessment of 5-ethylidene-2-norbornene using modeled and measured
      fate and effects results.
AB  - Several predictive models were used to assess aquatic exposure, persistence (P)
      and potential for long-range transport (LRT) of 5-ethylidene-2-norbornene (ENB).
      Such estimations are components of the assessment process for persistent,
      bioaccumulative and toxic (PBT) substances, which are also referred to as
      persistent organic pollutants (POPs). An ecological exposure assessment for ENB
      from manufacturing activities was conducted based on physical/chemical
      properties, monitoring data, and degradation, transport and distribution
      estimates. Based on the results of several model predictions, chronic exposure of
      aquatic organisms is not expected, due to the anticipated residence time of ENB
      in aquatic ecosystems. These modeled results consistently predict ENB does not
      present the potential to persist in the environment. Volatilization from water to
      the air is calculated to occur at a relatively rapid rate for ENB based on its
      Henry's Law constant. Once in the air, ENB is expected to degrade rapidly due to
      oxidation by hydroxyl radicals and ozone based on calculated atmospheric half
      lives of 57 and 27 min, respectively. Additionally, ENB is not predicted to
      undergo long-range transport based on the short atmospheric half-life due to
      oxidation by hydroxyl radicals and ozone. Additionally, based on predicted
      exposure from site-specific emission using the EPA model EFAST, ENB is not
      expected to reach concentrations of concern for chronic aquatic toxicity
      endpoints.

PMID- 15172602
TI  - Long-term effects of fertilization on the forms and availability of soil
      phosphorus in rice paddy.
AB  - The changes in total P accumulation and P compounds with time in the plough layer
      in a paddy soil in southern Korea were investigated in relation to the continuous
      application of chemical fertilizers (NPK), straw based compost (Compost),
      combination these two (NPK+Compost) for 31 years. Continuous fertilization
      increased the total and inorganic P contents in plough layers. In NPK, inorganic
      P fraction did not change with time, but organic P content increased
      significantly. Long-term application of chemical fertilizer together with compost
      accelerated the decrease in the organic P fraction, presumably due to promoting
      microbial activity in the plow layer, and then increased significantly inorganic
      P fraction. Compost application decreased the residual P and Fe-P fractions and
      then increased inorganic P fraction, in spite of continuous compost application.
      Increase in total, inorganic and extractable P with time may be closely related
      to the increase in the availability of accumulated P for rice growth.

PMID- 15172603
TI  - Uptake and accumulation behaviour of angiosperms irrigated with solutions of
      different arsenic species.
AB  - Uptake and metabolisation of arsenic as a function of both the plant type and the
      chemical form of arsenic were examined. For this purpose two different plant
      species (Silene vulgaris and Plantago major) were selected that differed in their
      vitality and accumulation behaviour on arsenic-loaded substrates. The plants were
      cultivated on soil and irrigated with aqueous solutions of an inorganic arsenic
      compound (arsenious acid) and an organic compound (dimethylarsinate). The arsenic
      species accumulated in the parts of the plants above ground were extracted by PLE
      and determined using IC-ICP-MS. The concentrations and metabolisation products of
      arsenic found in the extracts indicate different mechanisms of arsenic uptake and
      transformation in both angiosperms. The arsenic species pattern showed that S.
      vulgaris was more arsenic--tolerable than P. major which is attributed to a low
      arsenate to arsenite concentration ratio in the plant compartments. S. vulgaris
      was also able to demethylate and reduce dimethylarsinate to form arsenite in a
      high extent. P. major accumulated only eight times lower concentration of
      arsenic, and the arsenate to arsenite concentration ratio shifted to higher
      values. Metabolisation products of dimethylarsinate did not occur under the
      present experimental conditions. The vitality of the angiosperms seems to be very
      dependent on the ability of the plant to reduce arsenate to arsenite.

PMID- 15172604
TI  - Advances in color matching.
AB  - Recent advances in color matching have been driven by the market demand for high
      quality esthetic restorations. Improved shade guides, availability of shade
      taking devices, and research in the area of human color vision have improved the
      potential of clinicians to achieve excellent color-matched restorations. A
      thorough understanding of appearance attributes of natural teeth is required
      along with these new tools to maximize shade-matching results.

PMID- 15172605
TI  - Designing tooth preparations for optimal success.
AB  - The form of prepared teeth and the amount of tooth structure remove dare
      important contributors to the mechanical, biologic,and esthetic success of the
      overlying crown or fixed partial denture.Therefore, it is important to develop
      clinical guidelines that can be used to optimize success in fixed prosthodontics.

PMID- 15172606
TI  - Resistance form in tooth preparation.
AB  - Theoretical and clinical studies of resistance form are reviewed, supporting the
      basic prosthodontic principle that resistance form is an essential element in
      preparation design. Concepts of the"on-off" nature of resistance form, its
      application in guidelines for minimally acceptable preparation taper, and the
      controversy over whether there is a relationship with clinical success or failure
      are discussed. It is more challenging to obtain resistive molar preparations than
      resistive anterior preparations, and uneven preparation margins can make parallel
      0 degree taper preparations lack resistance form. The usefulness of grooves,
      especially in molar preparations with uneven margins, is illustrated. The Lewis
      and Zuckerman techniques for evaluating resistive areas of a preparation are
      shown to be consistent with each other but not with the Weed method.

PMID- 15172607
TI  - Restoration of endodontically treated teeth.
AB  - Endodontically treated teeth have lost substantial tooth structure as a result of
      previous restorations, dental caries, and the access preparation for the
      endodontic therapy. The topic of restoring these teeth is complex and
      controversial, and their long-term prognosis is directly connected to the quality
      of the final restoration. This article describes contemporary knowledge of the
      biomechanical principles related to the restoration of pulpless teeth and
      provides a critical review of currently available materials and methods.

PMID- 15172608
TI  - Cervical margin design with contemporary esthetic restorations.
AB  - The contemporary dentist has a wide variety of options to use in the restoration
      of extensively damaged or previously restored teeth. Metal-ceramic and all
      ceramic crowns are frequently used to restore esthetics and function. One of the
      essentials for success with either option is proper tooth preparation, which
      includes proper selection and preparation of the cervical margin of the
      preparation.

PMID- 15172609
TI  - Current concepts in gingival displacement.
AB  - Gingival displacement is an important procedure with fabricating indirect
      restorations. Gingival displacement is relatively simple and effective when
      dealing with healthy gingival tissues and when margins are properly placed a
      short distance into the sulcus. Several techniques have proven to be relatively
      predictable, safe,and efficacious. No scientific evidence has established the
      superiority of one technique over the others, so the choice of technique depends
      on the presenting clinical situation and operator preference.

PMID- 15172610
TI  - A review of contemporary impression materials and techniques.
AB  - The contemporary restorative dentist has a host of impression materials available
      for making impressions in fixed prosthodontics,implant dentistry, and operative
      dentistry. With proper material selection and manipulation, accurate impressions
      can be obtained for fabrication of tooth- and implant-supported restorations.
      This article outlines the ideal properties of impression materials and explains
      the importance of critical manipulative variables. Available impression materials
      are analyzed relative to these variables, and several "specialized" impression
      techniques are described. Special attention is paid to polyvinyl siloxane
      impression materials because they have become the most widely used impression
      material in restorative dentistry.

PMID- 15172611
TI  - Jaw relation records for fixed prosthodontics.
AB  - This article discusses and reviews general principles of jaw relation records,
      including the purpose of a jaw relation record and the concept of a tripod of
      vertical support with adequate horizontal stability to allow opposing dental
      casts to be mounted accurately on an articulator. The use of the maximum
      intercuspal position for the vast majority of patients is favored when the goal
      of restorative treatment is to maintain a patient's pretreatment intercuspation
      and vertical dimension of occlusion. In addition, articulator choice, purpose of
      a face bow, and materials for jaw relation records are discussed. Common errors
      in making impressions, pouring impressions,mounting casts, and making
      interocclusal records are elucidated, providing the practitioner important
      information with which to avoid inaccuracies that may lead to additional time
      spent making intraoral occlusal adjustments at the insertion of fixed
      restorations.

PMID- 15172612
TI  - Interim restorations.
AB  - Interim restorations are a critical component of fixed prosthodontic treatment,
      biologically and biomechanically. Interim restoration serves an important
      diagnostic role as a functional and esthetic try-in and as a blueprint for the
      design of the definitive prosthesis. When selecting materials for any interim
      restoration, clinicians must consider physical properties, handling properties,
      patient acceptance, and material cost. Although no single material meets all the
      requirements and material classification alone of a given product is not a
      predictor of clinical performance, bis-acryl materials are typically best suited
      to single-unit restorations, and poly(methylmethacrylate) interim materials are
      generally ideal for multi-unit, complex, long-term, interim fixed prostheses. As
      with most dental procedures, the technique used for fabrication has a greater
      effect on the final result than the specific material chosen.

PMID- 15172613
TI  - Casting alloys.
AB  - Although the role of dental casting alloys has changed in recent years with the
      development of improved all-ceramic materials and resin-based composites, alloys
      will likely continue to be critical assets in the treatment of missing and
      severely damaged teeth. Alloy shave physical, chemical, and biologic properties
      that exceed other classes of materials. The selection of the appropriate dental
      casting alloy is paramount to the long-term success of dental prostheses,and the
      selection process has become complex with the development of many new alloys.
      However, this selection process is manageable if the practitioner focuses on the
      appropriate physical and biologic properties, such as tensile strength, modulus
      of elasticity,corrosion, and biocompatibility, and avoids dwelling on the less
      important properties of alloy color and short-term cost. The appropriate
      selection of an alloy helps to ensure a longer-lasting restoration and better
      oral health for the patient.

PMID- 15172614
TI  - Dental ceramics: current thinking and trends.
AB  - Dental ceramics are presented within a simplifying framework allowing for
      understanding of their composition and development. The meaning of strength and
      details of the fracture process are explored, and recommendations are given
      regarding making structural comparisons among ceramics. Assessment of clinical
      survival data is dealt with, and literature is reviewed on the clinical behavior
      of metal-ceramic and all-ceramic systems. Practical aspects are presented
      regarding the choice and use of dental ceramics.

PMID- 15172615
TI  - Contemporary all-ceramic fixed partial dentures: a review.
AB  - High-strength all-ceramic systems for fixed partial dentures (FPDs)have become
      available for replacing missing teeth. New core materials have been developed and
      have evolved in the last decade,with yttrium tetragonal zirconia polycrystals (Y
      TZP)-based materials being the most contemporary. With the emphasis on the use of
      computer-assisted design/computer assisted-manufacturing technology, various
      production techniques have been developed for enhancing the fabrication of
      consistent and predictable restorations in terms of strength, marginal fit, and
      esthetics. Although initial results are limited, results reported in scientific
      abstracts of ongoing clinical studies assessing the long-term success of three
      unit all-ceramic FPDs and anecdotal evidence published in peer reviewed articles
      on the use of Y-TZP-based restorative systems are encouraging. This article
      reviews the evolution and development of materials and technologies for all
      ceramic FPDs.

PMID- 15172616
TI  - Fiber-reinforced composite prostheses.
AB  - Metal-free prosthetic dentistry continues to gain interest. Although the metal
      alloys contribute great strength and stiffness to restorations and prostheses,
      they do so at a considerable esthetic liability. Two somewhat divergent metal
      free approaches to fixed tooth replacement continue to be developed for a variety
      of clinical applications. These are all-ceramic and all-polymeric systems. The
      polymeric prostheses are the subject of this article.

PMID- 15172620
TI  - Therapeutic plasma exchange in a single center: Ibni Sina experience.
AB  - BACKGROUND: The number of therapeutic procedures is increasing steadily year by
      year with growing collaboration of departments other than Hematology. In the aim
      to demonstrate our single center activity we analyzed our data since four years.
      METHODS: Between years 1998 and 2001, 658 therapeutic plasma exchange (TPE)
      procedures were performed on 158 patients. Median age and male/female ratio were
      37 (range, 15-87) and 80/78, respectively. Main indications were myastenia gravis
      (n=55, 34%), TTP (n=13, 8.5%), post ABO mismatched allogeneic hematopoietic cell
      transplantation aregeneratoric anemia (n=6, 7.5%), progressive systemic sclerosis
      (n=10, 6.5%), multiple myeloma (n=10, 6.5%), Gullian Barre Syndrome (n=9, 5.9%),
      multiple sclerosis (n=7, 4.6%), Waldenstrom Macroglobulinemia (n=5, 3.4%),
      polymyositis (n=4, 2.7%), sepsis and disseminated intravascular coagulation (n=4,
      2.7%). Departments who referred the majority of the patients for TPE were
      neurology (n=199), hematology (n=153), immunology (n=78), intensive care unit
      (n=78) and thorax surgery (n=51). RESULTS: The median TPE procedure per patient
      was 4 (range, 1-50). All the procedures were performed on continuous flow cell
      separators and median plasma volume processed per cycle was 2471 ml (range 436
      5000). The replacement fluids used were 3% hydroxyethylstarch (HES) (24%), 5%
      albumin (35%), fresh frozen plasma (25%), and HES and albumin (16%). HES was
      tolerated well even as a sole replacement fluid with acceptable minor side
      effects. In three patients with progressing hypoalbuminemia HES was replaced or
      combined with 5% albumin. Close monitoring of serum albumin and fibrinogen levels
      after repeated procedures is mandatory. CONCLUSION: In our four years of TPE
      experience we have increased our collaboration with other departments. 3% HES+/
      5% Albumin is a feasible, well tolerated and cost effective replacement fluid
      combination especially for short-term plasma exchange therapy.

PMID- 15172621
TI  - Extracorporeal photoimmunotherapy for the treatment of steroid refractory
      progressive chronic graft-versus-host disease.
AB  - BACKGROUND: Chronic graft-versus-host disease (cGVHD) can arise frequently as a
      late complication after allogeneic hematopoietic cell transplantation. Patients
      with extensive disease to date require intensive and long-term immuno
      suppression. We aimed to share our single center experience using extracorporeal
      photoimmunotherapy (ECP) in our steroid refractory extensive cGVHD patients.
      PATIENTS AND METHODS: Eight patients with a median age 42 (range, 17-43) and M/F:
      2/6 were treated with ECP (UVAR XTS) on 2 consecutive days every 2-4 weeks until
      resolution of GVHD over a period of 6-15 months concomitantly with
      immunosuppressive agents. Beyond extensive steroid refractory cutaneous cGVHD,
      three patients had also bronchiolitis obliterans (BO). Skin scores were assessed
      by an experienced dermatologist. Clinical, laboratory and radiological findings
      after 4 months of ECP were accepted as response criteria. The patients received
      in this almost fully automated system mean 261.4 ml buffy-coat was processed
      within 193 min using UVADEX sterile solution. RESULTS: After a median of 12
      cycles of treatment, 6 patients showed a favorable response. ECP was tolerated
      well only one patient developed Gr4 thrombocytopenia and another patient had a
      massive GIS bleeding due to an esophageal tear. Reduction in cholestatic
      parameters was observed in patients with liver cGVHD, improvement in respiratory
      functions and CT evaluations in two, and reduction in immunosuppressive
      requirement in all patients. The most impressive result was the reduced need for
      hospitalization of these patients and improvement of skin lesions. All but one of
      the skin biopsy scores was also better after ECP. CONCLUSION: As extensive cGVHD
      is a life devastating disorder, every attempt to improve the quality of life
      should be evaluated carefully. Our findings suggest that ECP is a safe and
      effective adjunctive therapy for steroid refractory extensive cGVHD of the skin.
      ECP will find a place both for the treatment and may be for the prevention of
      GVHD as well.

PMID- 15172622
TI  - Peripheral blood stem cell apheresis for allogeneic transplants: Ibni Sina
      experience.
AB  - BACKGROUND: The rate of utilizing peripheral blood stem cells (PBSC) as a source
      for allogeneic stem cells is growing rapidly. We aimed to demonstrate our 4 years
      experience as the largest apheresis center in Turkey and analyzed the content of
      the apheresis material. PATIENTS AND METHODS: From 1998 to the end of April 2002,
      151 leukopheresis procedures were performed on 116 healthy donors (M/F:66/50)
      with a median age of 30 years (14-53). The HLA identical sibling donors received
      rhG-CSF 10 microg/kg/day sc. for 4 days and at the 5th day leukopheresis was
      started until collecting >4 x 10e6/kg CD34+ cells. Two times the donors' total
      blood volume was processed in 195 min (178-245) on continuous flow cell
      separators using peripheral venous access. RESULTS: Preapheresis WBC was 51.5 x
      10e9/L (range, 13.11-91.3). Mono nuclear cell, CD34 and CD3 quantity of the
      harvest material were 5.35 x 10e8/kg (range, 0.45-23.46), 6.4 x 10e6/kg (range,
      2.49-33.27) and 2.79 x 10e8/kg (range, 0.46-30.95), respectively. We were able to
      reach the target CD34 count after 1st cycle in 39% and 2nd cycle 61% of the
      procedures. In all donors with a peripheral blood CD34 count >80/mcl we succeeded
      to collect enough stem cells with only one leukopheresis. CONCLUSION: Collection
      of peripheral blood stem cells with continuous flow cell separators is well
      tolerated, with no mobilization failures or poor mobilizers. We collected high
      values of CD34+ cells (med. 6.4 x 10e6/kg) at the expense of high CD3+lymphocytes
      (med. 2.79 x 10e8/kg), which may increase the risk of acute and chronic GVHD
      after allogeneic hemapoietic cell transplantation.

PMID- 15172623
TI  - Hemosoft: a new software for blood bank and apheresis management.
AB  - BACKGROUND: Blood banks (BB) generate large volumes of information relating to
      patients and blood products sometimes stored indefinitely. Today computers are
      the main keys used to manage this task. BB information systems are developed
      mainly to assist BB specialists. MATERIALS AND METHODS: We developed a new
      software, Hemosoft, in our blood bank. We have carried out a great deal of
      research into BB programs around the world in terms of program features. Using
      the latest technology, Hemosoft has been designed to run on a multi-user platform
      on the basis of a modular structure, and high security levels. RESULTS:
      Hemosoft's structural advantages are: (1) its modular structure and client/server
      architecture reduce initial hardware costs. (2) Relational database structure
      provides consistent and secure data access, (3) user-friendly graphical
      interface, (4) according to operational needs, Hemosoft can be expanded and
      transferred on to different platforms. As a MS Windows based program with
      graphical user interfacing, Hemosoft has all the functions and advantages of
      windows based applications. Barcode printing is available to ISBT 128 standard.
      Hemosoft's integrated modules are: blood donation, transfusion, product
      management, administrative follow-up, apheresis, stock management, staff
      management, inter-center communication, statistics, archive, internet and video
      conferencing systems, accounts, integration and security. CONCLUSION: It fulfills
      international transfusion medicine requirements, legislative measures and
      guidelines. We believe that Hemosoft is a high quality, competitive program
      developed to meet international standards. It is our hope that it will enforce
      transfusion medicine and blood banking nationwide.

PMID- 15172625
TI  - Effects of high platelet concentration in collecting and freezing dry platelets
      concentrates.
AB  - OBJECTIVE: To evaluate, in vitro, the effects of collecting and cryopreserving
      fresh dry platelet concentrates (PCs). MATERIAL AND METHODS: Standard and dry PCs
      were collected in the same apheresis procedure. PCs were evaluated by mean
      platelet volume (MPV), pH, glucose and LDH levels. Activation was examined by
      flow cytometry using anti-CD41, anti-CD42 and anti-CD62p monoclonal antibodies
      and annexin binding assay. Platelet function was assessed by aggregation using
      ADP, collagen and arachidonic acid as agonists. Dry PCs were compared to standard
      PCs and to cryopreserved dry PCs. We also compared the use of ThromboSol to 5%
      DMSO as cryoprotectives. RESULTS: Dry PCs presented a significantly reduced pH
      and glucose (p<0.001), increased LDH levels and CD62p expression (p<0.001) and
      diminished aggregation response to ADP (p<0.001). Platelet cryopreservation was
      associated with platelet lysis, activation and loss of function. Dry PCs
      cryopreserved with TS were associated with statistically higher LDH levels
      (p<0.001) and a higher percentage of annexin binding (p=0.005), in addition to a
      lower number of CD42 positive platelets (p=0.01). CONCLUSION: Dry PCs should be
      rapidly frozen after collection to avoid a fall in pH and platelet activation. 5%
      DMSO performed better than TS to cryopreserve dry PCs.

PMID- 15172624
TI  - Biological qualification of blood units: considerations about the effects of
      sample's handling and storage on stability of nucleic acids.
AB  - BACKGROUND: In transfusional setting introduction of nucleic amplification
      technique (NAT) for HBV-DNA, HCV-RNA and HIV-RNA in biological qualification of
      blood units suggest some problems. At first the opportunity to operate on mini
      pool, at second the need to store the samples at +4 degrees C. The authors
      therefore have tried to estimate the impact of these conditions on the
      operativity of NAT testing in the transfusional setting. METHODS: The following
      parameters has been estimated: distribution of viral-load in untreated subjects,
      stability of nucleic acids during storage at +4 degrees C, stability of nucleic
      acids after repeated cycles of freezing and defrosting, robustness of the test to
      the cross-contamination, definition of the detection-limit (95%). Quantitative
      tests has been performed by using the following kits: Cobas Amplicor HBV Monitor,
      Cobas Amplicor HCV Monitor, Cobas Amplicor HIV Monitor; the qualitative tests has
      been performed by using the following kits: Ampliscreen HBV, Ampliscreen HCV 2,0,
      Ampliscreen HIV 1,5 all supplied by Roche Molecular System (Brancburg, NJ).
      RESULTS: Viral load in untreated subjects showed wide variation for HBV, HCV and
      HIV. HBV has been demonstrated much stable to the conservation +4 degrees C also
      until 168 h while for HCV and HIV a greater decrease of the viral-load was
      observed. For all and three virus the conservation to +4 degrees C until 72 h
      does not seem to involve meaningful fall in the viral-load. A remarkable
      reduction of the viral-load has been observed after five cycles of freezing and
      defrosting. All the tests showed a good robustness to cross-contamination. The
      detection-limit (95%) was 8 U/ml for HBV, 21 U/ml for HCV and 27 copy/ml for HIV.
      CONCLUSIONS: Samples for NAT testing, can be stored until 72 h to +4 degrees C
      without appreciable lowering of the viral-load. Repeated cycles of changes of
      state should be avoided. The tests showed a good robustness to cross
      contamination. NAT tests for biological qualification of blood units had a
      minimal sensibility around 50 (copy/unit/ml). In our experience the detection
      limit (95%) was 21 U/ml for HCV, 27 copies/ml for HIV, 8 U/ml for HBV. The
      availability of NAT test for HBV-DNA, HCV-RNA e HIV-RNA, sensitive and reliable,
      together with epidemiological data, suggest the opportunity to place side by
      side, in the biological qualification of the blood units, to add the tests for
      HBV-DNA and HIV-RNA to the test for HCV-RNA mandatory by low, in Italy in the
      biological qualification of blood units.

PMID- 15172626
TI  - In face of the increasing efficacy of lipid-lowering therapy, is there still a
      place for LDL-apheresis?
AB  - Based on a large body of evidence, high LDL-cholesterol concentrations in blood
      is a key factor of coronary heart disease (CHD). Overall, the observational
      studies show a curvilinear relationship between blood cholesterol level and
      coronary heart disease risk. Even more relevant are the randomised trials, firmly
      establishing that within just a few years a cholesterol-lowering therapy confers
      a dramatic effect on cardiovascular morbidity and mortality. More recent studies
      indicate that there is a greater risk reduction in those subjects achieving lower
      low-density lipoprotein cholesterol (LDL-C) levels--i.e. lower is better. While
      this favours aggressive therapy, it is nevertheless imperative to precise
      patients selection for every therapy that entails a major commitment for the
      patient and medical community. Therefore, well-defined criteria for use of LDL
      apheresis have yet to be established in the light of the expanding therapeutic
      armamentarium. Based on the current knowledge of the impact of statin therapy and
      anticipating that new options will further optimize the management of
      dyslipidemia in high-risk patients, we propose a reliable assessment of the
      effects of LDL-apheresis.

PMID- 15172628
TI  - New trends in specific immunoadsorption.
AB  - Plasma exchange is widely accepted to remove pathogenic substances from patients'
      blood that cannot be eliminated otherwise like cholesterol in severe forms of
      familial hypercholesterolaemia or immunoglobulins and circulating immune
      complexes (CIC) in many autoimmune disorders. But dilution of other plasma
      proteins, as well as side effects and costs of substitution fluids, limit its
      efficiency. In immunoadsorption, the pathogen is bound specifically, generally no
      substitution fluids are needed and plasma can be conducted over the
      immunoadsorption columns as often as needed to achieve any reduction that one
      aims at, in some instances below the detection limit (e.g. HLA-antibodies in
      transplantations). The frequency of aphaereses is determined by the speed of the
      patients' improvement and the rebound of the eliminated substance, which can in
      some disorders be slowed down or stopped by concomitant immunosuppression.
      Generally, immunoadsorption is used in patients, where less expensive and
      demanding treatment options have failed, like severe hypercholesterolaemia,
      autoimmune disorders or hyperviscosity syndromes.

PMID- 15172629
TI  - Clinical applications of long-term LDL-apheresis on and beyond refractory
      hypercholesterolemia.
AB  - Premature coronary heart disease (CHD) can result from high LDL cholesterol
      levels even in the absence of any other risk factors. A striking example is found
      in children who have the homozygous form of familial hypercholesterolemia (FH)
      with extremely high levels of LDL-cholesterol, and severe atherosclerosis and CHD
      often develop during the first decades of life. LDL-apheresis was developed for
      the treatment of severe type of FH patients who are resistant to lipid-lowering
      drug therapy. Clinical efficacy and safety of the therapeutic tool which directly
      removes LDL from circulation have already been established in the treatment for
      refractory hypercholesterolemia in FH patients. The most recently developed
      method enables lipoproteins to be adsorbed directly from whole blood, using
      polyacrylate column. In addition to benefits derived from the stabilization or
      regression of arterial lesions, we highlight other possible clinical applications
      of LDL-apheresis. However, most of these clinical benefits came from case reports
      or retrospective studies. Mechanisms related these clinical improvement remain
      unclear, and prospective randomized controlled trials should be performed for the
      new clinical indications of LDL-apheresis.

PMID- 15172630
TI  - Lipidfiltration--safe and effective methodology to perform lipid-apheresis.
AB  - Familial hypercholesterolemia (FH) not adequately responding to diet and drug
      therapy represents an indication for extracorporeal lipid-apheresis, which has
      become an highly effective and approved therapy for those patients in several
      countries. Based on different methodology, five treatment options of lipid
      apheresis exist and are in widespread practical use covered by regular
      reimbursement in Germany. All methods are safe and demonstrate equivalent
      efficacy of reducing LDL cholesterol with respect to the single apheresis session
      as well as during long-term treatment. Therefore German reimbursement guidelines
      leave the choice of the method to the discretion of the apheresis center. Related
      to properties of the used technology all methods exhibit characteristic patterns
      of additional plasma protein elimination, which do not impair, but in part may
      increase the therapeutic benefit of lipid-apheresis. Fibrinogen reduction has to
      be mentioned as an example. The Lipidfiltration system is based on
      plasmafiltration previously referred to as membrane differential filtration
      (MDF), synonymous with double filtration plasmapheresis (DFPP). The new term
      Lipidfiltration was the result of technological progress in the manufacturing
      process of the plasmafilter resulting in enhanced sieving characteristics and
      capacity. The Lipidfiltration system is completed by a specifically designed
      therapy machine with optimised performance characteristics.

PMID- 15172631
TI  - Heparin-mediated extracorporeal low-density lipoprotein precipitation: rationale
      for a specific adjuvant therapy in cardiovascular disease.
AB  - Various radical measures for the treatment of severe hypercholesterolemia such as
      partial ileal bypass, portocaval shunt, liver transplantation and plasma exchange
      have been tested in patients in whom drug and diet failed or were insufficient.
      Although effective, most of these treatments have severe side effects and are not
      routinely used. For hypercholesterolemic patients LDL-apheresis has proved to be
      the most promising and safe way as an adjuvant therapy. Several LDL-apheresis
      procedures with a varying degree of selectivity and efficiency have subsequently
      been developed. One of them is the H.E.L.P. system which was introduced in 1984
      and has now been widely used. Besides the marked reduction of LDL particles by
      all techniques it has become apparent that only the H.E.L.P. system results in an
      equally significant change in hemostaseology, hemorheology and vasomotion because
      of its simultaneously removal of LDL, Lp(a), fibrinogen and CRP. This
      contribution reviews the application of the H.E.L.P. system as a valuable
      therapeutic tool for the treatment of various atherothrombotic and
      microcirculatory disorders such as prevention of early graft occlusion after
      coronary artery bypass grafting, treatment of peripheral vascular disease, stroke
      and preeclampsia.

PMID- 15172632
TI  - Plasmapheresis in the treatment of peripheral polyneuropathy in the course of
      human immunodeficiency virus infection--preliminary report.

PMID- 15172634
TI  - Staging of the neck in patients with head and neck squamous cell cancer: imaging
      techniques and biomarkers.
AB  - Regional metastasis is an important factor in the treatment and prognosis of head
      and neck cancer patients. Current treatment strategies rely on staging based on
      the still limited accuracy of imaging techniques to detect regional metastases.
      If more certainty about the nodal status could be attained, treatment strategies
      concerning the neck could be better adjusted to the individual patient. The
      continuing improvement of established imaging techniques and the introduction of
      new imaging modalities will add to better staging. Moreover, the additional use
      of biomarkers studied on a protein, RNA or DNA level may provide even better
      information about the chance of occult nodal metastasis in head and neck cancer
      patients.

PMID- 15172635
TI  - Endocrinocarcinomas (carcinoids and their variants) of the larynx: a comparative
      consideration with those of other sites.

PMID- 15172636
TI  - Detection of cervical intranodal metastasis in oral cancer using elastic
      scattering spectroscopy.
AB  - While histopathology remains the gold standard for tissue diagnosis, several new
      diagnostic techniques are being developed that rely on physical and biochemical
      changes that mirror or precede malignant change within tissue. The aim of this
      study was to compare findings of elastic scattering spectroscopy (ESS) with
      histopathology on formalin fixed neck dissection specimens to see if this
      technique could be used as an adjunct or alternative to histopathology in
      defining nodal involvement. The technique involves the use of Mie scattering and
      is a simple non-invasive method of tissue interrogation. One hundred and thirty
      lymph nodes were examined from 13 patients who underwent neck dissection. The
      nodes were formalin fixed, bivalved and examined by ESS using a pulsed xenon
      lamp. The intensity of the spectrum at 4 points was considered for comparison; at
      360, 450, 630 and 690 nm. The nodes were then routinely processed and
      haematoxylin and eosin-stained sections examined histopathologically, and the
      results compared. Using this technique, a sensitivity of 98% and a specificity of
      68% were obtained.

PMID- 15172637
TI  - Characteristics of antitumor activity of mutant type p27Kip1 gene in an oral
      cancer cell line.
AB  - It is well known that loss of the cyclin-dependent kinase inhibitor p27Kip1
      protein correlates with the poor prognosis of various cancers including oral
      squamous cell carcinoma (SCC). Posttranslational degradation of p27Kip1 protein
      is mediated by phosphorylation of Thr-187 of p27Kip1 protein, which follows
      ubiquitination. In this study, we constructed an expression vector expressing
      mutant type p27Kip1 gene (pcDNA3.1-p27Kip1 mt), with mutation of Thr-187/Pro-188
      (ACGCCC) to Met-187/Ile-188 (ATGATC), which is not influenced by ubiquitin
      mediated degradation. We transfected mutant and wild type p27Kip1 genes into an
      oral SCC cell line, B88 to up-regulate the expression of mutant or wild p27Kip1
      gene in each transfectant. B88-p27Kip1 mt showed significant growth inhibition
      than B88-p27Kip1 wt or B88-neo in vitro (p < 0.01). Also, both types of B88
      p27Kip1 showed G1 arrest and apoptosis, however, B88-p27Kip1 mt showed remarkable
      G1 arrest. In addition, B88-p27Kip1 mt and B88-p27Kip1 wt showed markedly
      inhibition of the migration and out-growth of cancer cells than B88-p27Kip1 wt or
      B88-neo. Moreover, B88-p27Kip1 mt also showed remarkable suppression of tumor
      growth and cervical lymph metastasis than B88-p27Kip1 wt or B88-neo in vivo (p <
      0.01). In short, the mutant type p27Kip1 gene could show more potent antitumor
      effects than wild type p27Kip1 gene in B88 cells. These findings suggest that
      mutant type p27Kip1 gene has the potential to become a novel and powerful gene
      therapy tool for patients with oral cancers.

PMID- 15172638
TI  - Expression of fatty acid synthase, ErbB2 and Ki-67 in head and neck squamous cell
      carcinoma. A clinicopathological study.
AB  - Fatty acid synthase (FAS) is a multifunctional enzyme responsible for the
      synthesis of saturated fatty acids using acetyl-CoA and malonyl-CoA as
      substrates. Overexpression of FAS has been reported in several human malignancies
      and suggested as a potential prognostic factor. ErbB2 (Her-2/neu), a
      transmembrane tyrosine kinase member of the ErbB receptor family, is known to be
      overexpressed in a variety of tumors and was recently shown to regulate FAS
      production in breast epithelial cell lines. Herein we analyzed by
      immunohistochemistry the expression of FAS, ErbB2, and the proliferation marker
      Ki-67 in 62 head and neck squamous cell carcinoma (HNSCC) samples. Approximately
      78% of the cases were positive for FAS or ErbB2 at the cell membrane and 70% of
      the tumors that showed a high expression of FAS were also strongly positive for
      ErbB2 (Fisher's exact test, p = 0.01). The immunolabeling for both FAS and ErbB2
      was stronger in histologically well-differentiated lesions. Additionally, Ki-67
      expression was significantly associated with a poor prognosis (log-rank test, p =
      0.03). Taken together, the results presented here suggest that ErbB2 regulates
      FAS expression in HNSCC and point out Ki-67 as a useful prognostic marker for
      these tumors.

PMID- 15172639
TI  - Betel quid without tobacco as a risk factor for oral precancers.
AB  - The IARC monographs recently classified chewing betel quid without tobacco as a
      human carcinogen. Several studies in Taiwan have reported that betel quid without
      tobacco may increase the risk of oral precancers such as oral leukoplakia and
      oral submucous fibrosis. However in India, since most betel quid chewers prefer
      to add tobacco to the quid, the independent effect of betel quid on the risk of
      oral precancers is difficult to assess and has not yet been fully explored. We
      conducted a large case-control study in Kerala, India, including 927 oral
      leukoplakia cases, 170 oral submucous fibrosis cases, 100 erythroplakia cases,
      115 multiple oral precancer cases and 47,773 controls. The focus of this
      reanalysis is on the minority of individuals who chewed betel quid without
      tobacco. Among nonsmokers and nondrinkers, chewing betel quid without tobacco
      conferred ORs of 22.2 (95%CI = 11.3, 43.7) for oral leukoplakia, 56.2 (95%CI =
      21.8, 144.8) for oral submucous fibrosis, 29.0 (95%CI = 5.63, 149.5) for
      erythroplakia and 28.3 (95%CI = 6.88, 116.7) for multiple oral precancers, after
      adjustment for age, sex, education and BMI. Dose-response relationships were
      observed for both the frequency and duration of betel quid chewing without
      tobacco on the risk of oral precancers. In conclusion, our study supports the
      hypothesis that chewing betel quid without tobacco elevates the risks of various
      oral precancers.

PMID- 15172640
TI  - Molecular cloning, isolation and characterisation of ERK3 gene from chewing
      tobacco induced oral squamous cell carcinoma.
AB  - The mitogen activated serine/threonine kinases (MAPKs) constitute extracellular
      signal-regulated protein kinases (ERKs), c-Jun N-terminal kinases (JNKs) and p38
      MAPK, with an important role in cell proliferation and transformation. Earlier
      studies from our laboratory had indicated a role for MAPK pathway in oral cancer.
      Our current study was aimed at examining the role of a MAPK-ERK3, in chewing
      tobacco associated oral squamous cell carcinoma. We constructed a cDNA library
      from primary oral cancer tissue, cloned and isolated the ERK3 gene. The gene was
      sequenced and the sequence submitted to GenBank (Accession number AF420474). The
      oral cancer ERK3 clone demonstrated 100% homology to human ERK3 isolated from
      fetal skeletal muscle, with four specific nucleotide alterations in the non
      coding region of the gene, comprising deletion of 'TTT' between 2701 and 2705 nt;
      'G' to 'T' substitution at 188 nt; insertion of 'A' between 121 and 122 nt, and
      insertion of 'CTTTA' between 3391 and 3392 nt. Southern analysis of EcoRI genomic
      digests indicated ERK3 specific fragments of 11, 8.6, 6.5 and 3.2 kb sizes. The
      mRNA transcript analysis defined a single transcript of 4.5 kb. RT-PCR analysis
      revealed a three- to eight-fold increase in ERK3 expression in a majority (90%)
      of oral cancer tissues and peripheral blood cells (61.5%) of the patients,
      whereas absence or low levels of expression was observed in peripheral blood
      cells of 74% clinically normal healthy individuals with no tobacco habits, and
      overexpression in PBC from 26% normal individuals. The alterations in the non
      coding region of ERK3 gene cloned from oral cancer tissue, may affect stability
      or regulation of mRNA, resulting in overexpression in the patient samples. The
      overexpression of the gene in the normal healthy individuals may be indicative of
      increased risk of developing oral cancers in this group.

PMID- 15172641
TI  - Combined effects of the oral fluoropyrimidine anticancer agent, S-1 and radiation
      on human oral cancer cells.
AB  - We evaluated the orally administered S-1, in combination with ionizing radiation
      both in vivo and in vitro against human oral cancer cell lines. Human oral cancer
      cell lines were used as subcutaneous xenografts in nude mice. S-1 (10 mg/kg) was
      administered orally 1 h before radiation treatments (1.5 Gy), or 1 h after
      radiation for five consecutive days. Apoptotic cells were detected by TUNEL
      method. For in vitro analysis, attached cells were treated with S-1 (50
      microg/ml) for 1 h and then irradiated (3, 6, 9, 12, 15 Gy), or they were treated
      with S-1 for 1 h after radiation. Cell survival was determined by clonogenic
      assay. The combination of S-1 and radiation was more effective than either agent
      alone. In addition, S-1 administration before radiation was more effective than S
      1 administration after radiation. Moreover, the combination of S-1 and radiation
      could induce apoptosis significantly than either agent alone (P < 0.01). In vitro
      clonogenic survival experiments demonstrated the dose enhancement ratio of 1.22
      (radiation + S-1), 1.45 (S-1 + radiation) in B88 cells, and 1.16 (radiation + S
      1), 1.28 (S-1 + radiation) in HSG cells. These data demonstrate that the
      combination of S-1 and fractionated radiotherapy is more effective against human
      oral cancer xenografts than either agent alone, and that S-1 administration
      before radiation is more effective than after radiation, suggesting a potential
      clinical applicability of combination treatment of S-1 and radiation in oral
      cancer therapies.

PMID- 15172642
TI  - Hamsters chewing betel quid or areca nut directly show a decrease in body weight
      and survival rates with concomitant epithelial hyperplasia of cheek pouch.
AB  - Betel quid (BQ) chewing is strongly associated with the occurrence of oral
      leukoplakia, oral submucous fibrosis, and oral cancer. There are about 200-600
      million BQ chewers in the world. Previous animal studies support the potential
      carcinogenicity of BQ in different test systems. However, little animal
      experiment has let hamsters or rats to chew BQ directly, similar to that in
      humans. In the present study, we established a hamster model of chewing BQ or
      areca nut (AN). A total of 81 2-week-old hamsters were randomly divided into
      three groups: 25 for control group, 28 for BQ-chewing group, and 28 for AN
      chewing group. These animals were fed with powdered diet with/without BQ or AN
      for 18 months. Although the consumption of BQ or AN showed some variations,
      hamsters fed with powdered diet could chew and grind AN or BQ into small pieces
      of coarse fibers during the entire experimental period. The survival rate of AN
      chewing hamsters decreased significantly after 6 months of exposure. The mean
      survival time was 15.6 +/- 0.9 months for control animals, 13.6 +/- 0.98 months
      for AN-chewing animals, and 15.7 +/- 0.55 months for BQ-chewing animals. The body
      weight of BQ- or AN-chewing animals also decreased after 4-13 months. Hamsters
      fed with AN for 18 months showed hyperkeratosis in 80% and acanthosis in 50% of
      cheek pouches. Animals fed with BQ for 18 months also showed hyperkeratosis in
      93% and acanthosis in 14% of cheek pouches. These results indicate that AN and BQ
      components may induce alterations in proliferation and differentiation of oral
      epithelial cells. Animal model of chewing BQ or AN can be useful for future tumor
      initiation, promotion and chemoprevention experiments simulating the condition of
      BQ chewing in humans.

PMID- 15172643
TI  - Fatty acid synthase is required for the proliferation of human oral squamous
      carcinoma cells.
AB  - Fatty acid synthase (FAS) is the enzyme responsible for the endogenous synthesis
      of saturated long-chain fatty acids from the precursors acetyl-CoA and malonyl
      CoA. A growing body of evidence indicates that FAS is over expressed in several
      human cancers, such as prostate, breast, bladder, liver, lung, melanoma and oral
      squamous cell carcinoma (SCC). In the present study we used human oral SCC cell
      lines (SCC-4, -9, -15 and -25) as a model to investigate the role of FAS in the
      pathogenesis of oral cancer. RT-PCR and western blot experiments demonstrated
      that FAS is differentially expressed by the four oral SCC cell lines, with the
      highest production in SCC-9 followed by SCC-25. FAS expression in SCC-4 and -15
      was similarly lower than the other cell lines. Proliferation curves and
      immunocytochemistry for PCNA and Ki-67 demonstrated that SCC-25 has the highest
      proliferative potential. In addition, the specific inhibitor of FAS activity
      cerulenin was able to significantly reduce the proliferation of oral SCC cells.
      Expression of androgen receptor was low in SCC-4, -9 and -15 and undetectable in
      SCC-25, whereas EGFR and c-erb-B2 were expressed in high amounts by the four cell
      lines. Immunocytochemical reactions showed that SCC-25 expresses higher levels of
      EGF compared to the other three cell lines. Finally, oral SCC cells exposed to
      nanomolar concentrations of exogenous EGF presented a reduction in the FAS
      protein levels concomitant with a decrease in their proliferation rates. Taken
      together, our results indicate that FAS is expressed in an apparently androgen
      independent fashion in oral SCC cells and it is necessary for their
      proliferation.

PMID- 15172644
TI  - HPV DNA and survivin expression in epithelial oral carcinogenesis: a
      relationship?
AB  - HPV has been thought to be involved in the development of several oral diseases,
      such as premalignant mucosal lesions and oral carcinoma. Survivin is a recently
      characterized IAP protein, which is abundantly expressed in most solid and
      haematological malignancies, but undetectable in normal adult tissues. Aim of
      this study was to investigate survivin expression and HPV presence in oral
      premalignant lesions and oral carcinoma. 47 samples of oral tissue including 11
      squamous cell carcinomas (OSCC), 16 oral leukoplakias (OL) and 20 normal oral
      mucosa specimens, after investigation of HPV presence by nested PCR (consensus
      MY/GP primers) and viral genotype identification by direct sequencing were
      investigated by immunohistochemistry to detect survivin expression. Survivin
      expression was evident in 4/7 (57.1%) HPV+ and 4/4 (100%) HPV- OSCC, 6/7 (85.7%)
      HPV+ and 5/9 (55.5%) HPV- OL and in 0/20 (0%) control samples. Data showed high
      levels of survivin expression in HPV-positive SCCs, even if mean values were
      lower than HPV-negative ones, which in particular showed survivin expression in
      100% of cases. Conversely, survivin expression was greater in HPV+ precancerous
      lesions than in HPV- ones. Our findings suggest that survivin may be involved in
      HPV- mediated deregulation during maturation of squamous epithelium through
      modulation of the apoptotic processes and, conversely, HPV may have a direct or
      indirect effect on the regulation of the survivin expression level. In
      particular, the results of this study suggest distinguishing between cancerous
      and precancerous oral lesions with respect to survivin expression when HPV
      infection is present. The most unfavourable behaviour is likely to be for the HPV
      OSCC.

PMID- 15172645
TI  - Characterization of the human mandibular osteoblastic osteosarcoma cell line HOSM
      2 after long-term culture.
AB  - We have been subculturing a human mandible-derived osteosarcoma cell line (HOSM
      2) for approximately 15 years, and have compared the characters of early
      generations, which did not exhibit tumorigenicity, to those in the later
      generations. The shape and doubling time of the cells did not change during long
      term culture. The number of chromosomes, however, changed from 59-81 in the 6th
      generation (modal number: 70) to 54-59 (modal number: 56 and 57), and the
      chromosomal structure also changed. In addition, the cell line in the later
      generations showed tumorigenicity in nude mice, and Codon 306 of the p53 gene was
      mutated to a stop codon due to a point mutation. HOSM-2 cells expressed
      osteoblast markers, thus confirming them to be osteoblastic osteosarcoma cells.
      These results showed that changes in certain genes in the HOSM-2 cells led to
      tumorigenicity in nude mice following long-term culture. In addition, as a
      mandible-derived cell line with characteristics different from those of limb
      derived osteosarcoma cell lines, HOSM-2 cells may be a valuable model for
      mandibular osteosarcoma and osteoblasts.

PMID- 15172646
TI  - Prospective evaluation of quality of life in patients with oral and oropharyngeal
      cancer: from diagnosis to three months post-treatment.
AB  - The purpose of this study was to examine the impact of surgical, radiotherapeutic
      and combination treatment on quality of life, in patients diagnosed with cancer
      of the oral cavity and oropharynx. During the acute stage of treatment, quality
      of life was longitudinally evaluated. Quality of life was assessed at frequent
      time intervals (diagnosis, two weeks, 1 month and 3 months after treatment
      completion). Eligible patients were consecutively requested to participate and 38
      patients were recruited. Participants completed the EORTC QLQ-C30, EORTC H&N35,
      and HADS questionnaires. Functioning was found to reduce immediately post
      treatment, with most functions improving to near baseline levels by 3 months post
      treatment. Many symptoms significantly increased post-treatment, with many still
      scoring greater than at baseline levels at the end of the study. Anxiety scores
      were highest at diagnosis, depression scores were low throughout. This study
      indicates quality of life alters significantly over a short period of time from
      diagnosis and the start of treatment.

PMID- 15172647
TI  - Unusual hypersensitivity to radiation therapy in a patient with dyskeratosis
      congenita syndrome.

PMID- 15172648
TI  - The Midlands Trial of Empirical Amiodarone versus Electrophysiology-guided
      Interventions and Implantable Cardioverter-defibrillators (MAVERIC): a multi
      centre prospective randomised clinical trial on the secondary prevention of
      sudden cardiac death.
AB  - AIMS: MAVERIC was a randomised clinical trial designed to test the possibility of
      prospectively identifying patients who would benefit most from the implantable
      cardioverter-defibrillator (ICD) by electrophysiology (EP) study in the context
      of secondary prevention of sudden cardiac death (SCD) through comparing EP-guided
      interventions (anti-arrhythmic drugs, coronary revascularization, and ICD)
      against empirical amiodarone therapy. METHODS: Two hundred and fourteen survivors
      of sustained ventricular tachycardia (VT), ventricular fibrillation (VF) or SCD
      were randomized to either treatment strategy, pre-stratified for haemodynamic
      status at index event, and followed up for a median of 5 years. RESULTS: Of the
      106 amiodarone arm patients, 89 (84%) received the drug and 5 (5%) received an
      ICD after crossing over. Of the 108 EP arm patients, 31 (29%) received an ICD, 46
      (43%) received anti-arrhythmic drugs only (mainly amiodarone or sotalol) and 18
      (17%) received coronary revascularization but no ICD. No significant differences
      in survival or arrhythmia recurrence existed between the two treatment arms after
      6 years. However, ICD recipients had a lower mortality than non-ICD recipients,
      regardless of allocated treatment (hazard ratio=0.54, p=0.0391). CONCLUSIONS:
      Prospective selection of patients to receive the ICD by EP study did not improve
      survival compared with empirical amiodarone therapy among survivors of VT, VF or
      SCD, whereas ICD implantation improved survival regardless of allocated
      treatment. On this basis, routine EP study has no role in the management of such
      patients, who should be offered empirical ICD therapy according to the results of
      other secondary prevention ICD trials.

PMID- 15172649
TI  - Reproducibility of internal atrial defibrillation threshold in paroxysmal and
      persistent atrial fibrillation.
AB  - BACKGROUND: Several pharmacological or technical factors may affect atrial
      defibrillation threshold (ADFT) for internal cardioversion (ICV) in the treatment
      of atrial fibrillation (AF). METHODS: We evaluated the reproducibility of ADFT in
      lone paroxysmal (electrically induced AF, 10 pts, 51+/-4 years) or persistent AF
      (15 pts, 64+/-7 years). The AF pattern (F-F interval) was characterised before
      each ICV attempt. A first step-up synchronised ICV test (ICV1, biphasic shock
      waveform 6 ms/6 ms) with increasing energy levels from 0.2 to 20 J was performed
      by a dual-lead defibrillation system (right atrium-coronary sinus configuration)
      connected to an external cardioverter defibrillator. After 30 min of stable sinus
      rhythm, a new sustained AF was induced (>20 min duration) and ICV protocol was
      repeated (ICV2). The AF cycle length was recorded for 30 s from the lateral wall
      of right atrium in basal condition and before each cardioversion attempt.
      RESULTS: The mean values of AF cycle length before a successful shock were
      similar in both AF populations (paroxysmal AF: pre-ICV1 175+/-21 ms vs pre-ICV2
      181+/-20 ms (p=NS); persistent AF pre-ICV1 194+/-25 ms vs pre-ICV2 202+/-15 ms
      (p=NS)). No significant differences were observed between the two successful ICV
      tests concerning intensity, energy and impedance levels. The value of ADFT energy
      was reproducible in paroxysmal AF population (SD differences 1.2, coefficient of
      variability 9.6%). In persistent AF group only the impedance was reproducible (SD
      differences 2.6 Omega, coefficient of variability 4.5%), but not the energy
      requirements (SD differences 9.6, coefficient of variability 44.3%). CONCLUSIONS:
      ADFT is reproducible in paroxysmal AF patients, while a high coefficient of
      variability is present in persistent AF, possibly related to different patterns
      of re-entrant circuits in the reinduced AF. This observation is important in
      order to evaluate factors influencing ICV-ADFT correctly in AF patients.

PMID- 15172650
TI  - Arrhythmia detection by dual-chamber implantable cardioverter defibrillators. A
      review of current algorithms.
AB  - This article reviews the arrhythmia detection criteria currently available in
      dual-chamber implantable cardioverter defibrillators (ICDs), and describes the
      implementation and performance of various detection algorithms. Nearly all
      criteria implemented in single-chamber devices appear to have been included in
      dual-chamber ICDs. However, two different strategies can be distinguished: the
      first adds dual-chamber inhibition criteria to a single-chamber detection
      configuration; the second is a new approach entirely based on a dual-chamber
      detection scheme. Despite widely available clinical data, an analysis of the
      implemented detection indexes, arrhythmia characteristics (induced vs
      spontaneous, minimum duration), device programming (detection rate, programme
      maintenance and tuning during follow-up), and different storage capabilities
      among various ICD models, leaves the results of these studies ultimately
      ambiguous. New algorithms are under study, but only protocols using a single set
      of arrhythmias and the same programming for all devices may allow relevant
      comparisons of the performances of detection algorithms. Furthermore, a criterion
      is required to distinguish reliably between haemodynamically stable and unstable
      tachycardias, not simply based on rate, but including the underlying cardiac
      function.

PMID- 15172651
TI  - Efficacy and feasibility of isometric arm counter-pressure manoeuvres to abort
      impending vasovagal syncope during real life.
AB  - AIMS: Isometric arm exercises are able to increase blood pressure during the
      phase of impending vasovagal syncope. We evaluated their efficacy and feasibility
      during daily life in a group of 29 consecutive patients affected by vasovagal
      syncopes. METHODS: The patients were trained to use arm tensing and/or handgrip
      in case of occurrence of symptoms of impending syncope. RESULTS: During 14+/-6
      months of follow-up, 260 episodes of impending syncope were reported by 19
      patients; the manoeuvres were self-administered by these patients in 98% of cases
      and were able to abort syncope in 99.6% of cases. Overall, 5 episodes of syncope
      occurred in 5 patients (17%), in 4 cases without and in 1 with activation of the
      manoeuvres. Syncope recurred in 4 (40%) of 10 patients aged >65 years versus only
      1 (5%) of 19 patients aged < or =65 years, p=0.03. The non-responders had more
      episodes of impending syncope than responders (37+/-32 vs 3+/-4, p=0.001). Among
      19 clinical variables, age in years was the only significant predictor of
      syncopal recurrence. No patients had injury or other adverse morbidity related to
      the relapses. CONCLUSIONS: Isometric arm counter-pressure manoeuvres are able to
      abort impending vasovagal syncope in most patients aged < or =65 years. Arm
      counter-pressure manoeuvres are feasible, safe and well accepted by the patients
      in the daily life.

PMID- 15172652
TI  - Carotid sinus massage during evaluation for transient loss of consciousness: just
      a positive test?
AB  - An electrocardiographic recording obtained during diagnostic evaluation of
      recurrent transient loss of consciousness in a 53-year-old man is presented.
      Carotid sinus massage (CSM), having elicited a ventricular asystole of >5s
      duration was deemed to have provided a possible diagnostic basis for syncope.
      However, apart from the pause and somewhat unexpectedly, CSM also suppressed
      preexisting frequent ventricular ectopy. Explanations for this unexpected finding
      can only be considered speculative, but include direct CSM-induced
      parasympathetic suppression of ectopic activity at intra-ventricular pacemaker
      sites, concomitant diminution of sympathetic neural activity at ectopic sites, or
      interruption of 'linking' of normal ventricular activation to initiation of
      premature ventricular contractions.

PMID- 15172653
TI  - A patient with recurrent syncope and ST-elevation on the electrocardiogram.
AB  - A 56-year old woman had over 100 episodes of syncope since the age of 8. Because
      the patient's description of the episodes suggested vasovagal syncope she was
      studied by a head up tilt test (HUT). Seconds after the uncomplicated HUT the
      patient experienced a typical syncope with bradycardia, marked ST-elevation and
      chest pain. After treatment with nifedipine she has had one syncopal spell in a
      follow up period of 31 months. We conclude that the syncopal events in this
      patient were caused by a combination of vasovagal syncope and coronary spasm.

PMID- 15172655
TI  - Anatomical diversity and age-related histological changes in the human right
      atrial posterolateral wall.
AB  - AIMS: Recent clinical observations suggest that the right atrial posterolateral
      wall structures originate ectopic beats and function as anatomical obstacles.
      Because atrial arrhythmias increase in incidence after middle age, we
      investigated histological diversity and age-related changes in right atrial
      posterolateral wall. METHODS AND RESULTS: Twenty-six autopsied hearts (mean 65.2
      years, 16 men and 10 women) were studied. The entire posterolateral right atrium
      was cut serially. We determined the distribution of the sinoatrial node and
      localized it in relation to the crista terminalis and sinus venosus. We also
      compared histopathological changes in these tissues between three groups
      consisting of 31- to 50-year-old, 51- to 70-year-old and 71- to 90-year-old
      hearts. Total mean length of the crista terminalis, the sinoatrial node, and the
      sinus venosus was 46 mm, 21 mm and 29 mm, respectively, and showed no age-related
      changes, but the distribution of the sinoatrial node was varied. Mean muscular
      volume of the sinus venosus was significantly reduced in the two older groups,
      though that of the crista terminalis showed no age related-changes. CONCLUSION:
      Histological diversity of the sinoatrial node and age-related changes in the
      sinus venosus beneath the sinoatrial node may enhance histological heterogeneity
      and hence arrhythmogenicity.

PMID- 15172654
TI  - Efficacy and safety of ibutilide vs. transoesophageal atrial pacing for the
      termination of type I atrial flutter.
AB  - AIMS: Comparing efficacy and safety of ibutilide vs. transoesophageal atrial
      pacing (ATP) for the termination of type I atrial flutter (AFL). METHODS AND
      RESULTS: Eighty-seven patients affected by AFL lasting between 2 h and 30 days
      were randomized in two groups: Group 1-i.v. ibutilide treatment, up to 2 mg, and
      Group 2-ATP, with "burst" and "ramp" pacing protocols. Sinus rhythm was restored
      in 36/45 (80%) patients in Group 1 vs. 18/42 (43%) in Group 2 (P<0.0005). In
      Group 1, mean AFL duration was 11.4 +/- 7.7 days in responders vs. 12.1 +/- 7.6
      in non-responders (P=ns), while in Group 2 it was 2.7 +/- 1.4 vs. 14.2 +/- 5.4
      days (responders vs. non-responders, respectively, P<0.0001); 30/36 (83%)
      responders in Group 1 had AFL >48 h vs. 10/18 (56%) responders in Group 2
      (P<0.05). Non-sustained polymorphic ventricular tachycardia occurred in 2
      patients in Group 1 vs. none in Group 2 (P=ns). It did not require any specific
      treatment except the interruption of ibutilide infusion. CONCLUSION: Both
      ibutilide and ATP proved to be safe and effective for recent onset type I AFL
      termination, but ibutilide was more effective when the arrhythmia had lasted
      longer than 48 h.

PMID- 15172656
TI  - Characterization of subforms of AV nodal reentrant tachycardia.
AB  - BACKGROUND: Different subforms of AV nodal reentrant tachycardia (AVNRT) have
      been described ("Slow/Fast", "Slow/Slow" and "Fast/Slow"). Our aim is to improve
      definition of these subforms, based on systematic evaluation, in a large cohort
      of patients, of the site of earliest atrial activation, timing intervals, and
      evidence for the presence or absence of a lower common pathway (LCP). METHODS AND
      RESULTS: In 344 patients, AVNRT using a slow pathway (SP) for antegrade
      conduction and earliest atrial activation at the superior septum (i.e. retrograde
      fast pathway) was present in 81.4% (Slow/Fast). AVNRT using an SP for antegrade
      conduction and earliest atrial activation at the inferior septum or proximal
      coronary sinus (i.e. retrograde slow pathway; Slow/Slow) was present in 13.7%.
      AVNRT with a short A-H interval and retrograde SP conduction (Fast/Slow) was
      present in 4.9%. All timing intervals during tachycardia are dependent on
      autonomic tone. H-A intervals during tachycardia (H-A(t)) overlap in Slow/Slow
      and Slow/Fast AVNRT: Slow/Slow therefore may mimic Slow/Fast AVNRT. The H-A
      interval during pacing at the tachycardia cycle length (H-A(p)) better
      discriminates both subforms. The difference between H-A(p) and H-A(t) (Delta H-A)
      was significantly longer in Slow/Slow compared with Slow/Fast AVNRT (isoprenaline
      0.5 microg/min: 27+/-18 ms vs. 1+/-9 ms; p<0.001). Delta H-A>15 ms had a
      specificity and sensitivity for Slow/Slow of 94% and 64%, respectively. A Delta H
      A>15 ms, combined with other data, pointed to the presence of a long LCP in 36 of
      43 evaluable Slow/Slow (84%) and all Fast/Slow, but in only 10% of Slow/Fast
      (p<0.001). Retrograde conduction during ventricular pacing at the tachycardia
      cycle length was present in only 6% of Fast/Slow. CONCLUSIONS: AVNRT subforms can
      be distinguished based on a systematic evaluation of atrial activation sequence,
      timing intervals and evidence for the presence of an LCP.

PMID- 15172657
TI  - A comparison of open irrigated and non-irrigated tip catheter ablation for
      pulmonary vein isolation.
AB  - AIMS: The relative efficacy and safety of open irrigated tip catheters compared
      with conventional non-irrigated catheters for pulmonary vein isolation (PVI) is
      unknown. METHODS: Forty-eight patients undergoing PVI using an open irrigated tip
      ablation catheter (Group 1) were compared with a group of 31 historical controls
      (Group 2). The control group underwent similar procedures using a standard, 4 mm
      tip, temperature controlled ablation catheter. Electrical mapping with a circular
      catheter was used to guide segmental radiofrequency ablation at the vein ostia.
      RESULTS: At follow-up (3.5+/-3.5 months) after a single procedure 35/48 (73%)
      patients in Group 1 and 14/31 (45%) in Group 2 were in sinus rhythm (p=0.03).
      Antiarrhythmic drug use was lower among those in Group 1 maintained in sinus
      rhythm (9/35 (26%) vs 8/14 (57%), p=0.002). Recurrent atrial fibrillation was
      more common in Group 2 (28/31 (90%) vs 28/48 (58%) p=0.004). Serious
      complications were uncommon in both groups. CONCLUSIONS: Compared with an
      historical control group, pulmonary vein isolation using open irrigated tip
      catheters was superior to ablation with conventional 4 mm tip catheters. Patients
      undergoing ablation with an irrigated tip catheter were less likely to experience
      symptomatic recurrences of atrial fibrillation or require further therapy for
      post-procedural arrhythmias.

PMID- 15172658
TI  - Electroanatomic mapping and ablation of ventricular tachycardia associated with
      systemic sclerosis.
AB  - Two cases of systemic sclerosis with sustained ventricular tachycardia (VT) are
      presented. The first patient received hydroxychloroquine for skeletal muscle
      disease coexisting with cardiac involvement. In both cases, 3D-electroanatomic
      mapping showed low-voltage areas in the right ventricle. In the first patient the
      tachycardia was mapped and a protected isthmus suggesting reentry was delineated
      and ablated. Other substrate locations were indirectly identified by pacemapping
      on the right and left ventricular endocardium in the second patient. VT did not
      reoccur during follow-up. Radiofrequency catheter ablation is safe and effective
      and electroanatomic mapping may be helpful in patients with systemic sclerosis.

PMID- 15172659
TI  - Beta-blockers prevent subacute recurrences of persistent atrial fibrillation only
      in patients with hypertension.
AB  - AIM: Differential drug treatment guided by the underlying heart disease may
      improve outcome of rhythm control therapy. In the present study we investigated
      in a well-defined group with either lone atrial fibrillation (AF) or hypertension
      whether there were differences in rhythm control outcome between both groups in
      relation to the use of cardiovascular drugs. METHODS AND RESULTS: One hundred
      sixty-two patients were included after successful cardioversion of persistent AF.
      None of the patients was given a class I or III antiarrhythmic drug. Patients'
      heart rhythm was checked 3 times a day, using transtelephonic monitoring for 1
      month after cardioversion. One month after cardioversion up to 68% of patients
      had a recurrence of persistent AF. During the first 3 days almost no recurrences
      were seen on beta-blocker therapy whereas recurrences peaked on day 2-3 in the
      absence of beta-blockers. Univariate analysis showed that the use of beta
      adrenergic receptor blockers and the presence of hypertension were associated
      with a lower recurrence rate at 1 month. Multivariate logistic regression
      analysis demonstrated that beta-blockade was the only statistically significant
      parameter predicting sinus rhythm at 1 month (OR 0.40, 95% CI 0.19-0.86, P=0.02).
      CONCLUSIONS: Compared with lone AF patients, patients in the setting of
      hypertension maintain sinus rhythm much better after cardioversion when treated
      with a beta-blocker. Beta-blockade protects, in particular, against the early
      subacute recurrences. These findings underscore the importance of a differential
      approach towards drug prevention of post-cardioversion recurrences depending on
      the underlying heart disease.

PMID- 15172660
TI  - How do atrial pacing algorithms prevent atrial arrhythmias?
AB  - With an ageing population, atrial fibrillation has become an increasing cause of
      hospital admission and morbidity. Pacemaker implantation may prevent atrial
      tachyarrhythmias by preventing bradycardia and pauses. Implantable devices are
      now available with specific atrial pacing algorithms designed to prevent atrial
      arrhythmias. These algorithms work by increasing the atrial pacing rate to
      achieve continuous overdrive pacing or by responding to triggers such as
      premature atrial complexes. This article examines how the algorithms work by
      describing the functions of one of the new generation of pacemakers in detail.
      Early studies have indicated that the use of preventative pacing can reduce
      atrial arrhythmia burden and symptomatic atrial fibrillation in selected
      patients. There are clearly some patients who benefit from implantation of these
      devices but what remains unclear is how to identify this patient group.

PMID- 15172661
TI  - Interference by cellular phones with permanent implanted pacemakers: an update.
AB  - AIMS: The aim of this study was to test pacemakers with feedthru filters for
      interference with a digital cellular telephone. METHODS: The study comprised 100
      patients having their first pacemaker implantation between January 2001 and May
      2003. A GSM-standard cellular phone was tested in the standby, dialing and
      operating mode against 23 single-chamber and 77 dual-chamber pacemakers.
      Continuous surface electrocardiograms, intracardiac electrograms, and marker
      channels were recorded when calls were made by a land phone to the cellular
      phone. RESULTS: In 2 patients we observed pacing inhibition with the cellular
      phone positioned directly above the pacemaker pocket. The unipolar and bipolar
      ventricular sensitivity setting was 0.25 mV in one dual-chamber pacemaker, and
      when we changed the sensitivity to 0.50 mV and higher no interference could be
      detected. The second inhibition occurred in a single-chamber pacemaker with
      unipolar and bipolar ventricular sensitivity setting of 0.5 mV, where a
      sensitivity change to 1.0 mV eliminated the interference. CONCLUSION:
      Anticipating a correct setting of ventricular sensitivity, currently available
      pacemakers equipped with feedthru filters do not show any interference with
      cellular phones. Since interference was only observed with sensitivity settings
      below 0.50 mV, we recommend that permanent programming of ventricular sensitivity
      should be set at 2.0 mV and higher.

PMID- 15172663
TI  - Genetic dissection of diseases: design and methods.
AB  - The etiology of heritable diseases may be elucidated by localizing genes
      conferring susceptibility and by subsequent biological characterization of these
      genes. To localize genetic components for multifactorial traits, both hypothesis
      driven candidate gene and hypothesis-free genome scan approaches have been
      applied. To date, only a handful of results have been reproduced in either a
      different cohort or model organisms. The integration of genetic approaches with
      high-throughput genomic techniques is very promising. Unfortunately, most genetic
      studies completely ignore strong nongenetic effects such as low education and
      poverty even though these factors are well-known to predict, for example,
      obesity. Thus, what are most needed in future research are statistical methods
      for discovering sets of susceptibility genes and environmental factors, as well
      as systematic verifications of the gene-environment-disease network.

PMID- 15172664
TI  - Localization and identification of human quantitative trait loci: king harvest
      has surely come.
AB  - The scientific process of localization and subsequent identification of genes
      influencing risk of common diseases is still in its infancy. Initial localization
      of disease-related loci has traditionally been performed using family-based
      linkage methods to scan the genome. Early pronouncements of the failure of this
      approach for common diseases were premature and based on comparing suboptimal
      linkage designs with overly optimistic and empirically unproven association-based
      designs. On the contrary, substantial recent progress in the positional cloning
      of genes influencing such complex phenotypes suggests that modern approaches
      based around a family-based linkage paradigm will be successful. In particular,
      the rapidly growing emphasis on the analysis of the genetic basis of quantitative
      correlates of disease risk represents a novel and promising approach in which
      initial localization is performed using linkage and subsequent identification
      utilizes association approaches in positional candidate genes.

PMID- 15172665
TI  - Genetic dissection methods: designs used for tests of gene-environment
      interaction.
AB  - Given recent advances in the field of molecular genetics, many have recognized
      the need to exploit either study designs or analytical methods to test hypotheses
      with gene-by-environment (G x E) interactions. The partial-collection designs,
      including case-only, partial case-control, and case-parent trio designs, have
      been suggested as attractive alternatives to the complete case-control design
      both for increased statistical efficiency and reduced data needs. However, common
      problems in genetic epidemiology studies, such as, presence of G x E correlation
      in the population, population mixture, and genotyping error may reduce the
      validity of these designs. On the basis of previous simulation studies and
      empirical data and given the potential limitations and uncertainty of assumptions
      of partial-collection designs, the case-control design is the optimal choice
      versus partial-collection designs.

PMID- 15172666
TI  - Investigating gene function using mouse models.
AB  - Mouse models have become central to investigating and understanding mammalian
      gene function. Since the development of the first transgenic and knockout models,
      new methods have been envisioned that both simplify and increase the specificity
      of mouse models. Combinations of genetic tools have also been applied to dissect
      gene activities and to provide systems that are both spatially and temporally
      regulated. Furthermore, novel technologies have been developed that can regulate
      biological information at each level from creating specific modifications in DNA,
      to inhibiting gene transcription, to regulating protein activity.

PMID- 15172667
TI  - The genetic architecture of quantitative traits: lessons from Drosophila.
AB  - Understanding the genetic architecture of quantitative traits begins with
      identifying the genes regulating these traits, mapping the subset of genetically
      varying quantitative trait loci (QTLs) in natural populations, and pinpointing
      the molecular polymorphisms defining QTL alleles. Studies in Drosophila have
      revealed large numbers of pleiotropic genes that interact epistatically to
      regulate quantitative traits, and large numbers of QTLs with sex-, environment-
      and genotype-specific effects. Multiple molecular polymorphisms in regulatory
      regions of candidate genes are often associated with variation for complex
      traits. These observations offer valuable lessons for understanding the genetic
      basis of variation for complex traits in other organisms, including humans.

PMID- 15172668
TI  - Good copy, bad copy: choosing animal models for HLA-linked diseases.
AB  - Recent large-scale sequencing and comparative analyses of the major
      histocompatibility complex (Mhc) provide a novel view of this long-studied
      region. The main insight is that even though Mhcs are defined by the presence of
      the Mhc class I and II genes, the regions encoding class I/II histocompatibility
      antigens are the least conserved among the species; hence the difficulty of
      modeling the human class I/II-linked diseases. Fortunately, the majority of the
      genes in the Mhc, the non-class I/II genes, are conserved among the investigated
      mammals. The full set of Mhc genes in their evolutionary context presents new
      possibilities to study Mhc-linked diseases by allowing systematic evaluation of
      the various experimental animals and approaches.

PMID- 15172669
TI  - Molecular genetics of Crohn's disease.
AB  - Progress in the genetics of complex diseases has been slow over the past two
      decades compared to many simple Mendelian traits. However, rapid advances are now
      being made in inflammatory bowel disease genetics, leading already to
      identification of the first gene linked to Crohn's disease susceptibility:
      NOD2/CARD15. Since its discovery three years ago, there has been replication of
      the association of NOD2/CARD15 mutations with Crohn's disease in many
      populations, together with identification of phenotypic correlations. Functional
      studies promise to increase understanding of the primary pathophysiology involved
      in Crohn's disease and these discoveries may yet change clinical practice.

PMID- 15172670
TI  - Pathophysiology and biochemistry of cardiovascular disease.
AB  - Atherosclerosis is the major cause of cardiovascular disease.
      Hypercholesterolaemia, hypertension and cigarette smoking are the common risk
      factors for atherosclerosis. These risk factors unite behind a convergence of
      mechanism, involving oxidation and inflammation in the artery wall that, with
      time, gives rise to characteristic fatty-fibrous lesions. Physical trauma and
      inflammation produce lesion rupture, which can lead to clinical events such as
      heart attack and stroke, or resolve with plaque growth. Disease progression is
      marked by the inflammatory indicator CRP (C-reactive protein). Early indicators
      of heart attack are the inflammatory marker CD40, and the cardiac myofilament
      protein troponin. Coronary atherosclerosis is the common cause of heart failure
      (HF). Disordered calcium signalling to the myofilaments occurs in HF and in
      cardiomyopathy. Enhanced calcium signalling suppresses HF. Neuro-humoral and
      biomechanical processes, as seen in hypertension, produce cardiac hypertrophy,
      which predisposes to HF through apoptosis. Although in humans cardiac damage
      produces permanent loss of cells, because the heart cannot regenerate,
      developments in stem cell technology suggest that help is at hand.

PMID- 15172671
TI  - Why genetic investigation of psychiatric disorders is so difficult.
AB  - Genetic investigations of psychiatric disease have historically relied on
      subjectively assessed disease diagnoses to define phenotypes. Recent developments
      in several areas have provided various new approaches to behavioral disorder
      phenotyping that promise to advance our understanding of the genetic and
      environmental etiologies of these traits. Such developments include re-evaluation
      of the boundaries between different psychiatric categories, implementation of
      quantitative neurobiological assessments that may serve as endophenotypes,
      generation of increasingly sophisticated animal behavioral models, and
      investigation of explicit environmental covariates. At the same time, movement
      toward large-scale, collaborative efforts is increasing the effectiveness of
      traditional genetic mapping approaches.

PMID- 15172672
TI  - Society and ethics - the genetics of disease.
AB  - Established guidance for the protection of human subjects in research has
      provided the framework for research and clinical practice in genetics. Three key
      principles to emerge are the requirements for consent, privacy and
      confidentiality. However, recent research on genetic susceptibility to common
      diseases indicates that it may be more difficult to decide if and when genetic
      testing will be appropriate. Risks of disease may be low and interventions may
      not be available. Today, debate is primarily focussed on ethical issues raised by
      the use and storage of genetic information. One of the earliest experiences of
      genetic testing for some people is likely to be in the area of pharmacogenetics.
      Debate about ethical issues has been focused on the implications of patient
      stratification, particularly with regard to the availability of medicines for
      small groups and the significance of racial variation in response to medicines.
      The possible use of personal genetic information by insurance companies and
      employers has also been an issue that legislators have taken seriously.

PMID- 15172673
TI  - Redundancy, insult-specific sensors and thresholds: unlocking the S-phase
      checkpoint response.
AB  - DNA damage that is not properly repaired during genomic replication is a major
      source of gross chromosomal rearrangements and sequence loss during cell
      proliferation. In higher eukaryotes such mutations increase the risk of cancer.
      Eukaryotic cells have multiple checkpoint responses activated by DNA damage and
      stalled replication forks. We focus here on fork-associated events that activate
      and respond to S-phase checkpoint kinases.

PMID- 15172674
TI  - When enough is enough: genetic diseases associated with transcriptional
      derepression.
AB  - For many human genetic diseases, the underlying genetic defect has been
      determined. Thus, although traditionally a field only for researchers in medicine
      or human genetics, human diseases are now opening up to molecular biologists,
      cell biologists and biochemists. Here we discuss four human genetic disorders,
      Familial Alzheimer's disease, Rett syndrome, Klippel-Trenaunay syndrome and
      Facioscapulohumeral muscular dystrophy, and how investigations into these
      diseases are providing important lessons about human biology.

PMID- 15172675
TI  - Advances in chromatin remodeling and human disease.
AB  - Epigenetic factors alter phenotype without changing genotype. A primary molecular
      mechanism underlying epigenetics is the alteration of chromatin structure by
      covalent DNA modifications, covalent histone modifications, and nucleosome
      reorganization. Remodeling of chromatin structure regulates DNA methylation,
      replication, recombination, and repair as well as gene expression. As these
      functions would predict, dysfunction of the proteins that remodel chromatin
      causes an array of multi-system disorders and neoplasias. Insights from these
      diseases suggest that during embryonic and fetal life, environmental distortions
      of chromatin remodeling encode a 'molecular memory' that predispose the
      individual to diseases in adulthood.

PMID- 15172676
TI  - Isolates and their potential use in complex gene mapping efforts.
AB  - Linkage disequilibrium (LD), detectable with microsatellites in disease alleles
      over wide genetic intervals in population isolates, has facilitated mapping and
      positional cloning of numerous disease genes. We, among others, have shown that
      the LD intervals reach up to 1 Mb in general alleles of young subisolates, and
      that this feature most probably offers an avenue for the initial locus
      positioning for complex traits. Development of efficient SNP genotyping and
      characterization of haploblock structure of the human genome have introduced new
      prospects to LD-based fine mapping and haplotype-association studies. Encouraging
      associations have been reported for several complex diseases. Final breakthroughs
      in mapping of complex disease loci have emerged on large pedigrees in population
      isolates. Conversely, ignoring genealogical makeup of the study population seems
      to disclose false negative and false positive associations, directing resources
      down the drain.

PMID- 15172677
TI  - The role of cyclooxygenase inhibition in the effect of alpha-melanocyte
      stimulating hormone on reactive oxygen species production by rat peritoneal
      neutrophils.
AB  - The effect of alpha-MSH on reactive oxygen species (ROS) production by rat
      peritoneal neutrophils and the effect of cyclooxygenase (COX) inhibition were
      investigated using the chemiluminescence (CL) technique. Cells were obtained by
      peritoneal lavage 4h after administration of oyster glycogen to rats and were
      stimulated with lipopolysaccharide (LPS) from Salmonella enderitidis and phorbol
      12-myristate 13-acetate (PMA). The increasing concentrations of alpha-MSH (10(
      12)-10(-6) M) were added to stimulated cells alone or along with the COX
      inhibitors indomethacin, ketorolac or nimesulide (10(-8)-10(-5) M). Luminol and
      lucigenin CL levels were significantly increased in cells stimulated with LPS and
      PMA compared to unstimulated ones. alpha-MSH significantly reduced lucigenin CL
      values and this effect was completely reversed in the presence of indomethacin
      (10(-8) and 10(-7) M). In conclusion, alpha-MSH inhibits the production of
      superoxide radicals by activated rat peritoneal neutrophils and COX contributes
      to this effect.

PMID- 15172678
TI  - Effect of Iloprost on endothelin-1-induced free radical activation in rabbit
      brain stem.
AB  - Iloprost, a stable analogue of prostacyclin, was used to reverse the early period
      of vasoconstriction provoked by Endothelin-1 by administering into the rabbit
      basilar artery. We observed if this produced an effect on the central nervous
      system parenchyma mediated by free radical system. The red neurons were counted
      in brain stem sections stained with haematoxylin and eosin, while superoxide
      dismutase and malondialdehyde levels were measured in brain stem tissue samples
      as a marker of reactive oxygen metabolites; both 30 and 90 min after
      administration of either Endothelin-1 (0.25 ng) alone or Endothelin-1 followed by
      Iloprost (0.5 microg/kg) into the basilar artery. Endothelin-1 significantly
      increased the number of red neurons, while Iloprost significantly reduced them
      after 30 and 90 min. However, regarding the reactive oxygen metabolites; a
      similar reversing effect of Iloprost was not observed although superoxide
      dismutase levels were significantly decreased after Endothelin-1 infusion.

PMID- 15172679
TI  - In humans, the seasonal variation in poly-unsaturated fatty acids is related to
      the seasonal variation in violent suicide and serotonergic markers of violent
      suicide.
AB  - BACKGROUND: Depression is accompanied by a depletion of n-3 poly-unsaturated
      fatty acids (PUFAs). There is also a negative correlation between suicide and
      fish-oil intake (rich in n-3 PUFAs) across different countries. Both depression
      and suicide show a seasonal variation and are related to disorders in the
      serotonergic system. AIMS: The present study was carried out to determine if
      there is a seasonal variation in the PUFA fractions in serum phospholipids and
      whether there are significant relationships between lowered n-3 PUFA status and
      the seasonal variation in the number of suicide deaths and serotonergic markers
      of suicide. METHODS: We took monthly blood samples during 1 calendar year from 23
      healthy volunteers and analyzed the PUFA composition in serum phospholipids and
      related those data to the annual variation in the mean weekly number of suicides
      for Belgium and the Bmax [3H]-paroxetine binding to platelets in the same 23
      subjects. RESULTS: Significant annual rhythms were detected in the long-chain
      PUFAs only, i.e. arachidonic acid (C20: 4n-6; AA), eicosapentaenoic acid (C20: 5n
      3; EPA), and docosahexaenoic acid (C22: 6n-3; DHA). There was a significant
      correlation between the changes over the last 2 weeks in AA and EPA and the mean
      weekly number of violent, but not nonviolent, suicide deaths in Belgium. There
      was a significant correlation between the PUFAs, AA and DHA, and the Bmax [3H]
      paroxetine binding to platelets. CONCLUSIONS: Our results show that there is a
      true seasonality in long-chain PUFAs, such as AA, EPA and DHA. The results
      suggest that the seasonality in PUFAs may be related to the incidence of violent
      suicide and the expression of the serotonin transporter complex.

PMID- 15172680
TI  - Natural 1-O-alkylglycerols reduce platelet-activating factor-induced release of
      [3H]-serotonin in rabbit platelets.
AB  - Natural 1-O-alkylglycerols have multiple biological activities with distinct
      mechanisms. In THP-1 monocytes, they amplify platelet-activating factor
      production. In endothelial cells, they participate in the production of 1-O-alkyl
      2-acyl-sn-glycerol, a PKC inhibitor. Since PAF as well as PKC may interfere with
      platelet functions, we studied the effect of natural alkylglycerols purified from
      shark liver oil on [3H]-serotonin release from rabbit platelets in vitro. [3H]
      alkylglycerols (1 microM) were consistently incorporated into platelet lipids and
      after a 2-h incubation, they were metabolised into phosphatidylcholine,
      phosphatidylethanolamine and phosphatidylinositol, which represented 53.5+/-1.7%,
      36.3+/-1.8%, 5.3+/-0.5% of metabolised [3H]-alkylglycerols, respectively.
      Alkylglycerols (10 microM) had no effect on spontaneous [3H]-serotonin release.
      However, alkylglycerols partially inhibited PAF-induced [3H]-serotonin release
      while they did not modify thrombin-induced release. These data show that
      alkylglycerols inhibit partially and specifically PAF-induced platelet
      stimulation and suggest that this effect could result from interfering with PAF
      receptors.

PMID- 15172681
TI  - Antiplatelet effect of green tea catechins: a possible mechanism through
      arachidonic acid pathway.
AB  - We have previously reported that green tea catechins (GTC) showed an
      antithrombotic activity, which might be due to antiplatelet effect rather than
      anticoagulation. The present study was performed to investigate the effect of GTC
      on the arachidonic acid (AA) metabolism in order to elucidate a possible
      antiplatelet mechanism. GTC inhibited the collagen-, AA- and U46619-induced
      rabbit platelet aggregation in vitro in a concentration-dependent manner, with
      IC50 values of 61.0+/-2.5, 105.0+/-4.9 and 67.0+/-3.2 microg/ml, respectively.
      Moreover, GTC administered orally into rats inhibited the AA-induced platelet
      aggregation ex vivo by 46.9+/-6.1% and 95.4+/-2.2% at the doses of 25 and 50
      mg/kg, respectively. [3H]AA liberation induced by collagen in [3H]AA incorporated
      rabbit platelets was significantly suppressed by GTC compared to the control. GTC
      also significantly inhibited the thromboxane A2 (TXA2) and prostaglandin D2
      (PGD2) generations induced by addition of AA in intact rabbit platelets. GTC
      significantly inhibited TXA2 synthase activity in a concentration-dependent
      manner. Moreover, adenosine triphosphate (ATP) release from dense granule was
      inhibited by GTC in washed platelets. These results suggest that the antiplatelet
      activity of GTC may be due to the inhibition of TXA2 formation through the
      inhibition of AA liberation and TXA2 synthase.

PMID- 15172682
TI  - Functional domains and sub-cellular distribution of the Hedgehog transducing
      protein Smoothened in Drosophila.
AB  - The Hedgehog signalling pathway is deployed repeatedly during normal animal
      development and its inappropriate activity is associated with various tumours in
      human. The serpentine protein Smoothened (Smo) is essential for cells to respond
      to the Hedeghog (Hh) signal; oncogenic forms of Smo have been isolated from human
      basal cell carcinomas. Despite similarities with ligand binding G-protein coupled
      receptors, the molecular basis of Smo activity and its regulation remains
      unclear. In non-responding cells, Smo is suppressed by the activity of another
      multipass membrane spanning protein Ptc, which acts as the Hh receptor. In
      Drosophila, binding of Hh to Ptc has been shown to cause an accumulation of
      phosphorylated Smo protein and a concomitant stabilisation of the activated form
      of the Ci transcription factor. Here, we identify domains essential for Smo
      activity and investigate the sub-cellular distribution of the wild type protein
      in vivo. We find that deletion of the amino terminus and the juxtamembrane region
      of the carboxy terminus of the protein result in the loss of normal Smo activity.
      Using Green Fluorescent Protein (GFP) and horseradish peroxidase fusion proteins
      we show that Smo accumulates in the plasma membrane of cells in which Ptc
      activity is abrogated by Hh but is targeted to the degradative pathway in cells
      where Ptc is active. We further demonstrate that Smo accumulation is likely to be
      a cause, rather than a consequence, of Hh signal transduction.

PMID- 15172683
TI  - FGF2 triggers iris-derived lens regeneration in newt eye.
AB  - Lens regeneration in newts occurs exclusively from the dorsal aspect of the iris
      pigment epithelium. Although the phenomenon has been a paradigm of experimental
      tissue regeneration, little is understood about how it is initiated and
      restricted to the dorsal iris. Here we show among various growth factors injected
      in an intact eye, a single injection of FGF2 specifically caused morphological
      changes of the iris characteristic of lens regeneration, induced expression of
      transcription factor genes Pax6, Sox2 and MafB, as well as endogenous Fgf2 in
      both dorsal and ventral halves, and provoked second lens development only from
      the dorsal iris. FGF2 protein accumulated in the iris tissue after the lens was
      removed, and injection of a soluble form of FGF receptor titrating FGF2 inhibited
      all reactions observed after the lens removal or after administration of FGF2.
      These results indicate that FGF2 and/or related molecules trigger lens
      regeneration from the dorsal iris in the newt. The observations also indicate
      that the absence of lens regeneration from the ventral iris is due to a block in
      a later phase of lens developmental pathway.

PMID- 15172684
TI  - Hox gene cross-regulatory interactions in the embryonic brain of Drosophila.
AB  - During embryonic development of the Drosophila brain, the Hox gene labial is
      required for the regionalized specification of the tritocerebral neuromere. In
      order to gain further insight into the mechanisms of Hox gene action in the CNS,
      we have studied the molecular and genetic basis of cross-regulatory interactions
      between labial and other more posterior Hox genes using the GAL4/UAS system for
      targeted misexpression. Misexpression of posterior Hox genes in the embryonic
      neuroectoderm results in a labial loss-of function phenotype and a corresponding
      lack of Labial protein expression in the tritocerebrum. This is due to repression
      of labial gene transcription in the embryonic brain. Enhancer analysis suggests
      that this transcriptional repression operates on a 3.65 kb brain-specific labial
      enhancer element. A functional analysis of Antennapedia and Ultrabithorax protein
      domains shows that the transcriptional repression of labial requires homeodomain
      DNA interactions but is not dependent on a functional hexapeptide. The repressive
      activity of a Hox protein on labial expression in the tritocerebrum can, however,
      be abolished by concomitant misexpression of a Hox protein and the cofactors
      Homothorax and nuclear-targeted Extradenticle. Taken together, these results
      provide novel and detailed insight into the cross-regulatory interactions of Hox
      genes in embryonic brain development and suggest that specification of
      tritocerebral neuronal identity requires equilibrated levels of a Hox protein and
      Hth and n-Exd cofactors.

PMID- 15172685
TI  - klumpfuss regulates cell death in the Drosophila retina.
AB  - Programmed cell death (PCD) plays a central role in the sculpting and maturation
      of developing epithelia. In adult tissue, PCD plays a further role in the
      prevention of malignancy though removal of damaged cells. Here, we report that
      mutations in klumpfuss result in an excess of support cells during maturation of
      the developing Drosophila pupal retina. These ectopic cells are the result of a
      partial and specific failure of apoptotic death during normal cell fate
      selection. klumpfuss is required and differentially expressed in the cells that
      choose the life or death cell fate. We also provide genetic and biochemical
      evidence that klumpfuss regulates this process through down-regulation of the
      Epidermal Growth Factor Receptor/dRas1 signaling pathway. Based on its sequence
      Klumpfuss is an EGR-class nuclear factor, and our results suggest a mechanism by
      which mutations in EGR-class factors such as Wilms' Tumor Suppressor-1 may result
      in oncogenic events such as pediatric kidney tumors.

PMID- 15172686
TI  - Identification of kidney mesenchymal genes by a combination of microarray
      analysis and Sall1-GFP knockin mice.
AB  - SALL1, a causative gene for Townes-Brocks syndrome, encodes a zinc finger
      protein, and its mouse homolog (Sall1) is essential for metanephros development,
      as noted during gene targeting. In the embryonic kidney, Sall1 is expressed
      abundantly in mesenchyme-derived structures from condensed mesenchyme, S-, comma
      shaped bodies, to renal tubules and podocytes. We generated mice in which a green
      fluorescent protein (GFP) gene was inserted into the Sall1 locus and we isolated
      the GFP-positive population from embryonic kidneys of these mice by fluorescein
      activated cell sorting. The GFP-positive population indeed expressed mesenchymal
      genes, while the negative population expressed genes in the ureteric bud. To
      systematically search for genes expressed in the mesenchyme-derived cells, we
      compared gene expression profiles in the GFP-positive and -negative populations
      using microarray analysis, followed by in situ hybridization. We detected many
      genes known to be important for metanephros development including Sall1, GDNF,
      Raldh2, Pax8 and FoxD1, and genes expressed abundantly in the metanephric
      mesenchyme such as Unc4.1, Six2, Osr-2 and PDGFc. We also found groups of genes
      including SSB-4, Smarcd3, micro-Crystallin, TRB-2, which are not known to be
      expressed in the metanephric mesenchyme. Therefore a combination of microarray
      technology and Sall1-GFP mice is useful for systematic identification of genes
      expressed in the developing kidney.

PMID- 15172687
TI  - Ablation of the CLP-1 gene leads to down-regulation of the HAND1 gene and
      abnormality of the left ventricle of the heart and fetal death.
AB  - We have recently reported that cardiac lineage protein-1 (CLP-1), a nuclear
      protein with an acidic region that constitutes a potential protein-protein
      interaction domain, regulates transcription of the cardiac myosin light chain-2v
      (MLC-2v) gene promoter in a manner consistent with its being a transcriptional co
      activator or regulator. To test the postulate that CLP-1 is a regulator of
      cardiac genes we ablated the CLP-1 gene in mice. Past embryonic day (E)16.5, CLP
      1 null alleles did not show Mendelian inheritance suggesting that absence of CLP
      1 was lethal in late fetal stages. CLP-1 (-/-) fetal hearts exhibited a reduced
      left ventricular chamber with thickened myocardial walls, features suggestive of
      cardiac hypertrophy. Electron microscopic analysis of E16.5 CLP-1 (-/-)
      ventricular myocardium showed a marked decline in cell density and altered
      nuclear and myofibril morphologies similar to that seen in animal models of
      hypertrophic heart. Analysis of contractile and non-contractile protein genes
      known to be re-expressed during cardiac hypertrophy showed them to have higher
      expression levels in CLP-1 (-/-) hearts thereby confirming the hypertrophic
      phenotype at the molecular level. Analysis of cardiac development genes showed
      that expression of the HAND1 transcription factor, a gene involved in patterning
      of the heart tube and down-regulated in hypertrophic hearts, was also
      significantly reduced in CLP-1 (-/-) fetal hearts. CLP-1 and HAND1 have similar
      expression patterns in the developing heart ventricles. These data suggest that
      CLP-1 and the HAND transcription factors may be part of a genetic program
      critical to proper heart development, perturbation of which can lead to
      cardiomyopathy.

PMID- 15172688
TI  - The intracellular domain of X-Serrate-1 is cleaved and suppresses primary
      neurogenesis in Xenopus laevis.
AB  - The Notch ligands, Delta/Serrate/Lag-2 (DSL) proteins, mediate the Notch
      signaling pathway in a numerous developmental processes in multicellular
      organisms. Although the ligands induce the activation of the Notch receptor, the
      intracellular domain-deleted forms of the ligands cause dominant-negative
      phenotypes, implying that the intracellular domain is necessary for the Notch
      signal transduction. Here we examined the role of the intracellular domain of
      Xenopus Serrate (XSICD) in Xenopus embryos. X-Serrate-1 has the putative nuclear
      localization sequence (NLS) in downstream of the transmembrane domain.
      Biochemical analysis revealed that XSICD fragments are cleaved from the C
      terminus side of X-Serrate-1. Fluorescence microscopic analysis showed that the
      nuclear localization of XSICD occurs in the neuroectoderm of the embryo injected
      with the full-length X-Serrate-1/GFP. Overexpression of XSICD showed the
      inhibitory effect on primary neurogenesis. However, a point mutation in the NLSs
      of XSICD inhibited the nuclear localization of XSICD, which caused the induction
      of a neurogenic phenotype. The animal cap assay revealed that X-Serrate-1
      suppresses primary neurogenesis in neuralized animal cap, but X-Delta-1 does not.
      Moreover, XSICD could not activate the expression of the canonical Notch target
      gene, XESR-1 in contrast to the case of full-length X-Serrate-1. These results
      suggest that the combination of XSICD-mediated intracellular signaling and the
      extracellular domain of Notch ligands-mediated activation of Notch receptor is
      involved in the primary neurogenesis. Moreover, we propose a bi-directional
      signaling pathway mediated by X-Serrate-1 in Notch signaling.

PMID- 15172689
TI  - Correlation between invasion of Caco-2 eukaryotic cells and colonization ability
      in the chick gut in Campylobacter jejuni.
AB  - In an in vitro cell culture model using Caco-2 cells the adhesion and invasion
      properties of 11 Campylobacter (C.) jejuni isolates of different origin were
      studied. Additionally, we investigated the colonization ability of the strains in
      a chick model. Virtually, all C. jejuni showed cell adherence in the in vitro
      assay, but there were large differences in the invasion frequencies among the
      Campylobacter isolates. The colonization ability in the chick gut also differed
      markedly and enabled the formation of three groups: non-colonizing, weak or
      delayed colonization and strong colonization ability. On this occasion, we found
      a putative correlation between invasion of Caco-2 cells and colonization in the
      chick gut. Non-colonizers are not invasive or only have small invasion indexes.
      Strains which colonize weakly or exhibit delayed colonization have a medium
      invasion index and strong colonizers show markedly higher values of this
      parameter. The characterization of the flagellin gene of the used C. jejuni
      strains resulted in eight flaA types. There was no association between flaA type
      and invasion or colonization ability in the chick gut.

PMID- 15172690
TI  - PCR detection of a putative N-acetylmuramidase gene from Listeria ivanovii
      facilitates its rapid identification.
AB  - Listeria ivanovii is a Gram-positive bacterial pathogen that is capable of
      causing abortions and stillbirths in farm animals, particularly sheep and cattle.
      In terms of morphological, biochemical and molecular characteristics, L. ivanovii
      resembles other Listeria species such as L. monocytogenes, a pathogen of both man
      and animals. In this study, through comparative analysis of genomic DNA from the
      six Listeria species, a L. ivanovii specific clone (liv22-228) containing a 946
      bp insert was isolated. This clone contained the 5' ends of two divergently
      transcribed L. ivanovii genes and an intergenic spacer region, similar in
      organization to homologous regions from the L. innocua and L. monocytogenes
      genomes. Regions of low homology in the clone were identified by comparing to the
      L. innocua and L. monocytogenes genomes, and oligonucleotide primers (liv22-228F
      and liv22-228R) were designed. These primers amplified a 463 bp band from genomic
      DNA of L. ivanovii strains only, but not from other Listeria species or common
      bacteria. Thus, PCR employing L. ivanovii specific primers (liv22-228F and liv22
      228R) provides a useful and straightforward method for rapid and precise
      determination of L. ivanovii.

PMID- 15172691
TI  - Prevalence and antimicrobial resistance of Campylobacter coli isolated from
      fattening pigs in France.
AB  - Campylobacter are a leading cause of human diarrhea. The usual source of
      infection is contaminated food, particularly poultry but pork has also been
      described. The veterinary use of antimicrobial drugs has been suggested to be
      largely responsible for resistance in human isolates of this zoonotic pathogen. A
      study was carried out to investigate the occurrence and antimicrobial resistance
      of Campylobacter isolated from French fattening pigs. From March 1998 to June
      1999, stomach samples were collected at slaughter from 240 fattening pigs
      originating from 24 different farms. Half of the pigs were found to be positive
      for Campylobacter but considerable variation was observed between farms. Isolates
      all belong to the Campylobacter coli species. Susceptibilities of the strains
      were determined for five antimicrobial drugs using agar dilution. Resistance to
      tetracycline and erythromycin was high (79 and 55%, respectively). For nalidixic
      acid, enrofloxacin and ampicillin, resistance was observed in 34, 15 and 20% of
      the isolates, respectively. More than one-third of the strains was resistant to
      at least three antimicrobial drugs. A Thr86Ile modification in GyrA was observed
      in the enrofloxacin-resistant strains studied. The multiresistant strains
      analyzed expressed the multidrug transporter CmeB at a high level. Results
      indicated a high prevalence of C. coli in the stomach of the French pigs
      examined. In addition, a high proportion of the strains was resistant to
      antimicrobial drugs, particularly to tetracycline and erythromycin, or were
      multiresistant.

PMID- 15172692
TI  - Phenotypic and genotypic characteristics of Staphylococcus aureus isolates from
      raw bulk-tank milk samples of goats and sheep.
AB  - Two hundred and ninety-three isolates of Staphylococcus aureus obtained from 127
      bulk-tank milk samples of goats and sheep from Switzerland were characterised by
      pheno- and genotypic traits. Of the 293 S. aureus isolates, 193 (65.9%) were egg
      yolk-negative and 15 (5.1%) were negative for clumping factor and/or protein A
      determined by a latex agglutinating test system. For 285 isolates, PCR
      amplification of the 3' end of the coagulase gene showed a single amplicon. Five
      differently sized PCR products of 500, 580, 660, 740 and 820 bp were
      distinguished. In 191 isolates (n = 293) staphylococcal enterotoxin (SE) genes
      were detected: 123 isolates tested positive for SEC gene, 31 for SEG gene, 28 for
      SEA gene, 26 for SEJ gene, 24 for SEI gene, 4 for SEB gene and 4 for SED gene.
      Furthermore, 126 isolates were positive for the gene encoding the toxic shock
      syndrome toxin 1. Coagulase gene restriction profile analysis of the 145 isolates
      harbouring SEA or SEC genes revealed six different patterns using AluI and five
      different patterns using HaeIII. In summary, within these two groups, high
      genotypic uniformity within the different sized coagulase gene amplicons was
      demonstrated. This is the first study providing comprehensive characterisation
      data of S. aureus strains originating from bulk-tank milk samples of goats and
      sheep. Remarkable differences in phenotypic traits between S. aureus originating
      from goats and sheep and bovine milk were found. Moreover, the high prevalence of
      toxin-producing S. aureus may be important as it is relevant to food hygiene.

PMID- 15172693
TI  - Development of a PCR assay for Streptococcus iniae based on the lactate oxidase
      (lctO) gene with potential diagnostic value.
AB  - Streptococcus iniae is a well-known pathogen of both fish and humans that is
      difficult to identify by conventional biochemical tests. A PCR assay based on the
      lactate oxidase (lctO) gene of S. iniae was developed for the rapid and specific
      detection and identification of this pathogen from different sources. The PCR
      assay had a detection limit of 62-31 cells, and 25 pg of DNA per PCR reaction
      mixture. The PCR was also effective in detecting the bacterium from inoculated
      tissue homogenates, suggesting its potential use for a rapid and accurate
      diagnosis of S. iniae infections.

PMID- 15172694
TI  - Determination of species-specific sequences of superoxide dismutase A encoding
      gene sodA and chaperonin 60 encoding gene cpn60 for identification and
      phylogenetic analysis of Streptococcus phocae.
AB  - Species-specific PCR tests, based on the manganese-dependent superoxide dismutase
      A encoding gene (sodA) and the chaperonin 60 encoding gene (cpn60), were
      developed for the identification of Streptococcus phocae, a bacterial pathogen of
      seals. The selection of both oligonucleotide primer pairs was performed after
      amplification and sequencing of internal parts of both genes using universal
      oligonucleotide primers. The sequence studies of both genes additionally
      confirmed that S. phocae could taxonomically be classified to the pyogenic group
      of the genus Streptococcus.

PMID- 15172695
TI  - Enzyme immunoassay for the diagnosis of brucellosis: chimeric Protein A-Protein G
      as a common enzyme labeled detection reagent for sera for different animal
      species.
AB  - A recombinant protein combining the immunoglobulin binding sites of Proteins A
      and G, conjugated with horseradish peroxidase was used as a universal detection
      reagent for the assessment of antibodies against Brucella spp. The reagent was
      applied in an indirect enzyme immunoassay for detection of antibodies to smooth
      lipopolysaccharide antigen in sera from Brucella spp. exposed and non-exposed
      cattle, sheep, goats and pigs and to antibodies to rough lipopolysaccharide in
      sheep, dogs and cattle. The results were similar to those obtained when murine
      monoclonal antibody-enzyme conjugates were used. An added advantage was that a
      universal cut-off for all tests using the proteins A and G detection reagent
      could be established, simplifying diagnostic interpretation of the data.

PMID- 15172696
TI  - The correlation between Salmonella serology and isolation of Salmonella in Danish
      pigs at slaughter.
AB  - In Denmark, a serological Salmonella surveillance programme in finishing pig
      herds has been in place since 1995. The programme was founded on data from
      experimental studies, which demonstrated a strong association between Salmonella
      serology and the prevalence of these bacteria. The current study was carried out
      in three Danish abattoirs to evaluate the correlation under field conditions. A
      total of 160 Danish finishing pig herds were included. Seven out of these were
      examined twice, yielding a total of 167 observations. The herds were selected
      according to their herd serology based on data from the national surveillance.
      From each herd, samples were taken from 10 finishers at slaughter. The prevalence
      of Salmonella bacteria was measured at four sites: (1) caecal-content; (2)
      carcass surface; (3) pharynx; and (4) caecal lymph nodes. A logistic regression
      model was constructed for each sampling site. Abattoir, sanitary slaughter and
      herd seroprevalence were used as explanatory variables. The results demonstrated
      that there was a strong association between herd serology and the prevalence of
      Salmonella bacteria measured at three of the sampling sites: caecal-content,
      pharynx, and carcass surface. For these sites, the odds for being culture
      positive for Salmonella varied from 1.3 to 1.5 for each increase of 10% in herd
      serology (P < 0.0001). For caecal lymph nodes, however, no linear association was
      found.

PMID- 15172697
TI  - Antimicrobial susceptibility of Haemophilus parasuis and Histophilus somni from
      pigs and cattle in Denmark.
AB  - A total of 52 Haemophilus parasuis and 80 Histophilus somni isolates were tested
      for antimicrobial susceptibility by MIC-determinations. None of the isolates were
      resistant to ampicillin, ceftiofur, ciprofloxacin, erythromycin, florphenicol,
      penicillin, spectinomycin, tetracycline, tiamulin, or tilmicosin. Two H. parasuis
      isolates were resistant to trimethoprim + sulfamethoxazole. Six H. parasuis
      isolates had reduced susceptibility (0.06-0.5 microg/ml) to ciprofloxacin and 10
      reduced susceptibility to TMP + sulfamethoxazole (1-2 microg/ml). This study
      showed that Danish isolates of H. parasuis and H. somni in general are fully
      susceptible to antimicrobial agents currently used for treatment of infections
      with these pathogens.

PMID- 15172698
TI  - Conservation of deduced amino acid sequence of FimH among Escherichia coli of
      bovine, porcine and avian disease origin.
AB  - The FimH subunit of type 1 pili mediates adhesion of Escherichia coli to
      epithelium in different animal hosts. In this study, we sequenced and analyzed
      the fimH genes of 24 E. coli strains from bovine and porcine clinical cases. The
      obtained sequences were compared among each other and also with 24 known fimH
      sequences from avian E. coli strains. This comparison revealed a substantial
      homology (>99%) among strains from the different animal species origins.
      Moreover, specific mutations were found, some of which were present more
      frequently in avian strains or in bovine and porcine strains.

PMID- 15172699
TI  - Haploinsufficiency for tumour suppressor genes: when you don't need to go all the
      way.
AB  - Classical tumour suppressor genes are thought to require mutation or loss of both
      alleles to facilitate tumour progression. However, it has become clear over the
      last few years that for some genes, haploinsufficiency, which is loss of only one
      allele, may contribute to carcinogenesis. These effects can either be directly
      attributable to the reduction in gene dosage or may act in concert with other
      oncogenic or haploinsufficient events. Here we describe the genes that undergo
      this phenomenon and discuss possible mechanisms that allow haploinsufficiency to
      display a phenotype and facilitate the pathogenesis of cancer.

PMID- 15172700
TI  - The selective estrogen enzyme modulators in breast cancer: a review.
AB  - It is well established that increased exposure to estradiol (E(2)) is an
      important risk factor for the genesis and evolution of breast tumors, most of
      which (approximately 95-97%) in their early stage are estrogen-sensitive.
      However, two thirds of breast cancers occur during the postmenopausal period when
      the ovaries have ceased to be functional. Despite the low levels of circulating
      estrogens, the tissular concentrations of these hormones are significantly higher
      than those found in the plasma or in the area of the breast considered as normal
      tissue, suggesting a specific tumoral biosynthesis and accumulation of these
      hormones. Several factors could be implicated in this process, including higher
      uptake of steroids from plasma and local formation of the potent E(2) by the
      breast cancer tissue itself. This information extends the concept of
      'intracrinology' where a hormone can have its biological response in the same
      organ where it is produced. There is substantial information that mammary cancer
      tissue contains all the enzymes responsible for the local biosynthesis of E(2)
      from circulating precursors. Two principal pathways are implicated in the last
      steps of E(2) formation in breast cancer tissues: the 'aromatase pathway' which
      transforms androgens into estrogens, and the 'sulfatase pathway' which converts
      estrone sulfate (E(1)S) into E(1) by the estrone-sulfatase. The final step of
      steroidogenesis is the conversion of the weak E(1) to the potent biologically
      active E(2) by the action of a reductive 17beta-hydroxysteroid dehydrogenase type
      1 activity (17beta-HSD-1). Quantitative evaluation indicates that in human breast
      tumor E(1)S 'via sulfatase' is a much more likely precursor for E(2) than is
      androgens 'via aromatase'. Human breast cancer tissue contains all the enzymes
      (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in
      the last steps of E(2) biosynthesis. This tissue also contains sulfotransferase
      for the formation of the biologically inactive estrogen sulfates. In recent
      years, it was demonstrated that various progestins (promegestone, nomegestrol
      acetate, medrogestone, dydrogesterone, norelgestromin), tibolone and its
      metabolites, as well as other steroidal (e.g. sulfamates) and non-steroidal
      compounds, are potent sulfatase inhibitors. Various progestins can also block
      17beta-hydroxysteroid dehydrogenase activities. In other studies, it was shown
      that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate
      the sulfotransferase activity for the local production of estrogen sulfates. All
      these data, in addition to numerous agents which can block the aromatase action,
      lead to the new concept of 'Selective Estrogen Enzyme Modulators' (SEEM) which
      can largely apply to breast cancer tissue. The exploration of various progestins
      and other active agents in trials with breast cancer patients, showing an
      inhibitory effect on sulfatase and 17beta-hydroxysteroid dehydrogenase, or a
      stimulatory effect on sulfotransferase and consequently on the levels of tissular
      levels of E(2), will provide a new possibility in the treatment of this disease.

PMID- 15172702
TI  - Resuscitation Great. The contributions of Lavoisier, Scheele and Priestley to the
      early understanding of respiratory physiology in the Eighteenth Century.

PMID- 15172703
TI  - Evaluation of a medical emergency team one year after implementation.
AB  - AIM: To evaluate the activity and impact of a Medical Emergency Team (MET) one
      year after implementation. SETTING AND POPULATION: A 700-bed District General
      Hospital (DGH) in Southeast England with approximately 53,500 adult admissions
      per annum. The population studied included all adult admissions receiving
      intervention by the MET during a 12-month period between 1 October 2000 and 30
      September 2001. METHODS: Analysis of the activation of the MET using both
      prospective and retrospectively acquired data. Routinely collected hospital data
      for admissions, discharges and deaths was used to compare outcomes for the 12
      months before and after the introduction of the MET. RESULTS: There were 136
      activations of MET over 1-year. Six cases were excluded. Mean age of patients was
      73 years (range 20-97 years). 40% (52/130) survived to discharge following MET
      intervention. Of those who died 22% (28/130) were designated 'not for
      resuscitation'. Patients that died were more likely to have three or more
      physiological abnormalities present (odds ratio, OR 6.2, Chi-square (chi(2)) P =
      0.004) and had higher MET scores (P = 0.004). Commonest interventions by the MET
      were initiation or increase of oxygen therapy or ventilatory support (80%), with
      or without the administration of intravenous fluids or medications. In 10% of
      cases, oxygen therapy was the sole intervention. One year after implementation of
      the MET a reduction in cardiac arrest rate and overall mortality was noted but
      this was not statistically significant. CONCLUSION: Often only simple
      interventions are only required to reverse deterioration. Initiating 'do not
      attempt resuscitation' (DNAR) decisions is a key part of MET activity. Multiple
      physiological abnormalities are associated with increased mortality and therefore
      wider and earlier application of the MET to the hospital population may save
      lives or expedite DNAR decisions. New systems need time to develop ("bed in") and
      further research is needed to observe significant reductions in cardiac arrests
      and overall mortality.

PMID- 15172704
TI  - Evaluation of an impedance threshold device in patients receiving active
      compression-decompression cardiopulmonary resuscitation for out of hospital
      cardiac arrest.
AB  - AIMS: The purpose of this multicentre clinical randomized controlled blinded
      prospective trial was to determine whether an inspiratory impedance threshold
      device (ITD), when used in combination with active compression-decompression
      (ACD) cardiopulmonary resuscitation (CPR), would improve survival rates in
      patients with out-of-hospital cardiac arrest. METHODS AND RESULTS: Patients were
      randomized to receive either a sham (n = 200) or an active impedance threshold
      device (n = 200) during advanced cardiac life support performed with active
      compression-decompression cardiopulmonary resuscitation. The primary endpoint of
      this study was 24 h survival. The 24 h survival rates were 44/200 (22%) with the
      sham valve and 64/200 (32%) with the active valve (P = 0.02). The number of
      patients who had a return of spontaneous circulation (ROSC), intensive care unit
      (ICU) admission, and hospital discharge rates was 77 (39%), 57 (29%), and 8 (4%)
      in the sham valve group versus 96 (48%) (P = 0.05), 79 (40%) (P = 0.02), and 10
      (5%) (P = 0.6) in the active valve group. Six out of ten survivors in the active
      valve group and 1/8 survivors in the sham group had normal neurological function
      at hospital discharge (P = 0.1). CONCLUSION: The use of an impedance valve in
      patients receiving active compression-decompression cardiopulmonary resuscitation
      for out-of-hospital cardiac arrest significantly improved 24 h survival rates.

PMID- 15172705
TI  - Improved hemodynamic performance with a novel chest compression device during
      treatment of in-hospital cardiac arrest.
AB  - INTRODUCTION: The purpose of this pilot clinical study was to determine if a
      novel chest compression device would improve hemodynamics when compared to manual
      chest compression during cardiopulmonary resuscitation (CPR) in humans. The
      device is an automated self-adjusting electromechanical chest compressor based on
      AutoPulse technology (Revivant Corporation) that uses a load distributing
      compression band (A-CPR) to compress the anterior chest. METHODS: A total of 31
      sequential subjects with in-hospital sudden cardiac arrest were screened with
      institutional review board approval. All subjects had received prior treatment
      for cardiac disease and most had co-morbidities. Subjects were included following
      10 min of failed standard advanced life support (ALS) protocol. Fluid-filled
      catheters were advanced into the thoracic aorta and the right atrium and
      placement was confirmed by pressure waveforms and chest radiograph. The coronary
      perfusion pressure (CPP) was measured as the difference between the aortic and
      right atrial pressure during the chest compression's decompressed state.
      Following 10 min of failed ALS and catheter placement, subjects received
      alternating manual and A-CPR chest compressions for 90 s each. Chest compressions
      were administered without ventilation pauses at 100 compressions/min for manual
      CPR and 60 compressions/min for A-CPR. All subjects were intubated and ventilated
      by bag-valve at 12 breaths/min between compressions. Epinephrine (adrenaline)
      (1mg i.v. bolus) was given at the request of the attending physician at 3-5 min
      intervals. Usable pressure signals were present in 16 patients (68 +/- 6 years, 5
      female), and data are reported from those patients only. A-CPR chest compressions
      increased peak aortic pressure when compared to manual chest compression (153 +/-
      28 mmHg versus 115 +/- 42 mmHg, P < 0.0001, mean +/- S.D.). Similarly, A-CPR
      increased peak right atrial pressure when compared to manual chest compression
      (129 +/- 32 mmHg versus 83 +/- 40 mmHg, P < 0.0001). Furthermore, A-CPR increased
      CPP over manual chest compression (20 +/- 12 mmHg versus 15 +/- 11 mmHg, P <
      0.015). Manual chest compressions were of consistent high quality (51 +/- 20 kg)
      and in all cases met or exceeded American Heart Association guidelines for depth
      of compression. CONCLUSION: Previous research has shown that increased CPP is
      correlated to increased coronary blood flow and increased rates of restored
      native circulation from sudden cardiac arrest. The A-CPR system using AutoPulse
      technology demonstrated increased coronary perfusion pressure over manual chest
      compression during CPR in this terminally ill patient population.

PMID- 15172706
TI  - The incidence and severity of cutaneous burns following external DC
      cardioversion.
AB  - INTRODUCTION: Cutaneous burns are a common cause of morbidity following direct
      current (DC) cardioversion, but the incidence and severity have never been
      quantified. MATERIALS AND METHODS: Two hours after elective DC cardioversion in
      83 sequential patients, we measured skin temperature, erythema index, and minimum
      sensory and pain detection thresholds at paddle sites and control sites on the
      contralateral side. Visual analogue pain score (VAS) was recorded at 2 and 24h
      post-cardioversion. RESULTS: Values for areas over paddle sites were higher (P <
      0.05) than control site for all variables measured at 2h. Eighty-four percent
      patients experienced some pain and 23% patients experienced moderate to severe
      pain as assessed by VAS. Burns were greater at the edge than the centre of
      sternal sites and greater at sternal than apical sites. There were positive
      correlations between transthoracic impedance (TTI) and total energy delivered
      (r(2) = 0.048; P = 0.04); total energy and pain at 2 h (r(2) = 0.38; P < 0.0001)
      and 24 h (r(2) = 0.23; P < 0.0001); and number of shocks and pain at 2 h (r(2) =
      0.36; P < 0.0001) and 24 h (r(2) = 0.19; P < 0.0001). CONCLUSION: Elective DC
      cardioversion causes burns as measured by skin temperature, erythema index and
      sensory threshold to sharp touch. Pain experienced is related to the total energy
      and number of shocks delivered. To reduce burns, operators should apply optimal
      paddle force equally to both paddles, with the paddles applied so as to provide
      even contact along their edges. Burns may also be minimised by starting with
      lower energy shocks.

PMID- 15172707
TI  - Bystander trauma care--effect of the level of training.
AB  - BACKGROUND: The bystander is often the first person present at the scene of an
      accident. Our aim was to determine how often and how well bystanders perform
      trauma care and whether trauma care is affected by the bystander's level of
      training, relationship to the patient and numbers of bystanders present. PATIENTS
      AND METHODS: In a prospective 1-year study, the emergency medical service in two
      European cities collected data on trauma calls. Questionnaires were used to
      document the bystanders' level of training (none, basic, advanced, professional),
      the bystander's relationship to the patient, and the number of bystanders
      present, and to assess whether five separate measures of trauma care (ensuring
      scene safety, extrication of the patient, positioning, control of haemorrhage,
      prevention of hypothermia) were performed correctly, incorrectly, or not at all.
      RESULTS: Two thousand nine hundred and thirty-two trauma calls were documented
      and bystanders were present in 1720 (58.7%). All measures except ensuring scene
      safety and prevention of hypothermia were affected by the bystander's level of
      training. Correct extrication, positioning, and control of haemorrhage increased
      with the level of bystander training while the number of patients who were not
      attended decreased (P < 0.05, P < 0.005, P < 0.005), respectively. The
      relationship to the patient did not affect whether, or how well, any measure was
      performed. The number of bystanders present only affected prevention of
      hypothermia, which was performed most often when only one bystander was present.
      CONCLUSION: Improved, more widespread training could increase the frequency and
      quality of bystander trauma care further.

PMID- 15172708
TI  - Prehospital mortality in an EMS system using medical priority dispatching: a
      community based cohort study.
AB  - OBJECTIVES: This study was planned to record prehospital death rates in four
      medical priority categories (A, B, C and D) and to evaluate if deaths in lower
      urgency categories C and D (target response times 20 and 90 min) could have been
      avoided by a faster ambulance response. METHODS: The design was a community based
      cohort study including an expert panel evaluation of the deaths. The study was
      conducted in the Emergency Medical Services in Helsinki, Finland. All consecutive
      ambulance calls excluding interhospital patient transfers between 1 January 1999
      and 31 December 2002 were included. Prehospital mortality and avoidability of
      prehospital deaths by a faster ambulance response (maximum 8 min) were used as
      main outcome measures. RESULTS: A total of 151928 calls were prioritized in the
      dispatching centre (category A 8677 calls, B 41005, C 71991 and D 30255).
      Prehospital death occurred 451 times in category A, 468 times in category B, 73
      times in category C and 8 times in category D calls. Respectively, the
      prehospital death rates per 1000 calls were 52.0 (A), 11.4 (B), 1.0 (C) and 0.3
      (D) (P < 0.0001). The expert panel judged that 1 (1.3%) of category C deaths
      would have been avoidable, 24 (32.9%) potentially avoidable and 48 (65.8%) not
      avoidable by a more rapid ambulance response. The corresponding figures for
      category D deaths were 0 (0%), 5 (62.5%) and 3 (37.5%), respectively.
      CONCLUSIONS: The use of medical priority dispatching was associated with very low
      prehospital mortality in lower urgency categories C and D. Approximately, one
      third of those deaths could probably be prevented by a faster ambulance response
      but the price would be a three-fold increase in calls with blue lights and siren.
      Further studies are needed to find out if our results are applicable to other
      types of EMS systems.

PMID- 15172709
TI  - The potential use of prehospital thrombolysis in a rural community.
AB  - BACKGROUND: It is recommended that eligible patients receive thrombolytic
      treatment within 90 min of alerting medical or ambulance services. The Donegal
      Area Rapid Treatment Study (DARTS) showed that pre-hospital thrombolysis reduces
      "call to needle" times for patients living remote from the hospital base [Donegal
      Area Rapid Treatment Study (DARTS): Final Report. North Western Health Board].
      AIM: To review DARTS data to describe the potential impact of pre-hospital
      thrombolysis on a defined population. METHOD: Data from the DARTS project was
      reviewed to describe cases where thrombolysis was not administered, cases where
      thrombolysis was administered in hospital but not in the community, and to
      extrapolate these findings to other rural regions in the area to identify the
      potential for additional pre-hospital thrombolysis. RESULTS: Eighty-four patients
      from DARTS practices presented to the district hospital with AMI during the study
      period with 35% (29/84) receiving thrombolysis. Of the 29 who received
      thrombolysis, 87% (25) were referred from the general practitioner. Of these, 32%
      (8/25) were administered thrombolysis by the general practitioner. Of the general
      practitioner referrals that did not receive pre-hospital thrombolysis (n = 17),
      65% (11/17) were not thrombolysed in the community for appropriate clinical
      reasons and 35% (6/17) could have been potentially eligible for pre-hospital
      thrombolysis. Inclusion of these patients suggests a potential pre-hospital
      thrombolysis rate in the region of 56%. For the rural Donegal areas this would
      result in a potential 17 cases per year being eligible for pre-hospital
      thrombolysis. CONCLUSIONS: Currently, 35% of the 240 AMIs that occur annually in
      the region receive thrombolysis. Broad implementation of DARTS in the region
      would provide pre-hospital thrombolysis to approximately an additional 25
      patients each year, with a potential for further gains. For this to become a
      reality, support and encouragement must be provided to all rural general
      practitioners, the ambulance services, receiving hospitals and policy makers to
      implement a pre-hospital thrombolysis policy.

PMID- 15172710
TI  - A pilot randomised trial of thrombolysis in cardiac arrest (The TICA trial).
AB  - INTRODUCTION: The outcome after out of hospital cardiac arrest is dismal.
      Thrombolysis during CPR has been advocated. Our hypothesis was that early
      administration of bolus thrombolysis could lead to improved survival from out of
      hospital cardiac arrest. METHODS: A prospective, randomised, double blind placebo
      controlled trial. All victims of out of hospital cardiac arrest brought to the
      Emergency Department (ED) by the emergency medical system were eligible for
      inclusion. All patients received standard advanced cardiac life support, except
      that the first drug the patient received was either tenecteplase 50 mg or
      placebo. The primary end point was return of spontaneous circulation (ROSC).
      RESULTS: Of 35 patients enrolled, 19 received tenecteplase and 16 placebo. The
      tenecteplase group was younger (63 vs 72 years P = 0.04) and had significantly
      more ventricular fibrillation as the initial rhythm (63% versus 19%, 44%
      difference, 95% CI 15-73%). There was no difference in rhythm on arrival at the
      ED. ROSC occurred in 8 (42%) patients receiving tenecteplase and one (6%) placebo
      (36% difference, 95% CI 11-61%). Two tenecteplase and one placebo patient
      survived to leave ED, and one in each group survived to hospital discharge.
      Autopsy results were available on eight patients, five of whom had a thrombotic
      cause of death. CONCLUSION: In this pilot study, we found the use of early bolus
      tenecteplase for OHCA to be feasible, and that it appears to increase the rate of
      ROSC. Larger studies are required to determine if this translates into a survival
      benefit. Appropriate patient selection for OHCA studies remains problematic.

PMID- 15172711
TI  - Survival after out-of-hospital cardiac arrests in Katowice (Poland): outcome
      report according to the "Utstein style".
AB  - The purpose of this study was to evaluate the outcome of out-of-hospital cardiac
      arrest (CA) and cardiopulmonary resuscitation (CPR) in the city of Katowice,
      Poland, during a period of 1 year prior to the planned reorganization of the
      national emergency system. Data were collected prospectively according to a
      modified Utstein style. To ensure accurate data collection, a special method of
      reporting resuscitation events with the use of a tape-recorder was introduced.
      Patients were followed for a 1-year period. Between 1 July 2001 and 30 June 2002,
      out-of-hospital cardiac arrest was confirmed in 1153 patients. Cardiopulmonary
      resuscitation was attempted in 188 patients. Cardiac arrest of presumed cardiac
      aetiology (147) was bystander witnessed in 105 (71%) cases and lay-bystander
      basic life support was performed in 35 (24%). In the group of bystander witnessed
      arrest ventricular fibrillation (VF) or tachycardia was documented in 59,
      asystole in 40 and other non-perfusing rhythms in six patients. Of 147 patients
      with cardiac aetiology, return of spontaneous circulation (ROSC) was achieved in
      64 (44%) patients, 15 (10%) were discharged alive and 9 (6%) were alive 1 year
      later. Most of these patients had a good neurological outcome. Time to first
      defibrillatory shock was significantly shorter for survivors (median 7 min)
      compared to non-survivors (median 10 min). The most important resuscitation and
      patient characteristics associated with survival were VF as initial rhythm,
      arrest witnessed, and lay-bystander CPR.

PMID- 15172712
TI  - beta(2)-Agonist delivery via a resuscitator bag (Ambu MediBag): a comparison with
      a metered-dose inhaler using the Volumatic-Spacer.
AB  - Although the administration of beta(2)-agonists by inhalation is recommended in
      the current guidelines for treatment of patients with acute bronchospasm, the
      large volume spacer that is necessary often is not available on board an
      ambulance due to space storage problems. Accordingly, an adapter enabling the
      application of therapeutic aerosols from a metered-dose inhaler (MDI) via a
      resuscitator bag (Ambu MediBag) was developed. The aim of this double-blinded,
      randomised study was to test the clinical efficiency of the Ambu MediBag (volume:
      approximately 1500 ml) in comparison with the commonly used Volumatic-Spacer
      (volume: 750 ml). One hundred patients receiving a bronchodilator response test
      were treated with MDIs of either 200 microg salbutamol via the Volumatic-Spacer
      or 400 microg salbutamol via the Ambu MediBag. The change of lung function
      variables was measured by bodyplethysmography before and after drug application.
      In both groups of 50 patients each, a highly significant reduction of airway
      resistance was shown after treatment. However, there was no statistically
      significant difference in lung function variables between the Ambu MediBag and
      the Volumatic-Spacer. From these results, we conclude that the Ambu MediBag is as
      effective as Volumatic-Spacer and might improve preclinical and clinical
      treatment of acute bronchospasm by inhalation with bronchodilators.

PMID- 15172713
TI  - Advance orders to limit therapy in 67 long-term care facilities in Finland.
AB  - OBJECTIVE: To assess the documentation of a do-not-attempt-resuscitation (DNAR)
      or do-not-hospitalize (DNH) orders in the medical record and to determine factors
      related to these orders. MATERIALS AND METHODS: Five thousand six hundred and
      fifty four subjects from three different levels of institutional long-term care
      (LTC), chronic care hospitals (n = 1989), nursing homes (n = 3310), and assisted
      living (n = 335) in 67 LTC facilities in 19 municipalities were assessed.
      RESULTS: Out of these patients, 751 (13%) had a DNAR order and only 36 (0.6%) had
      a DNH order. The variation in DNAR orders between individual LTC institutions was
      enormous, ranging from 0 to 92%. In logistic regression analysis, individual
      institutions and their local caring cultures had the strongest explanatory value
      (R(2) = 0.49) for advance orders to limit therapy. Impaired activity in daily
      living (ADL) function (R(2) = 0.11), impaired cognition (R(2) = 0.07), level of
      LTC (R(2) = 0.05), and diagnoses (R(2) = 0.04) did not provide adequate
      explanations. Terminal prognosis was not significantly associated with advance
      orders. CONCLUSIONS: We found marked differences in the use of DNAR and DNH
      orders between caring units. Diseases and ADL status were only weakly significant
      as background factors. Open discussions, general guidelines, and research about
      the adequacy of DNAR decisions are needed to improve equality and self
      empowerment among the elderly residing in institutions.

PMID- 15172714
TI  - Perceptions, needs and mourning reactions of bereaved relatives confronted with a
      sudden unexpected death.
AB  - Many individuals die suddenly and unexpectedly outside the hospital or in the
      emergency department (ED). The aim of this study was to determine the
      perceptions, needs and mourning reactions of their bereaved relatives and to
      assess the relationship with the cause of death. Data were collected
      prospectively in the emergency department of a university hospital by means of an
      interview and a standardised questionnaire. We registered 339 deaths over a
      period of 10 months, of which 110 met the inclusion criteria for sudden and
      unexpected death. The study group included 74 relatives of 53 deceased
      individuals. The majority of relatives were confronted with a traumatic death
      outside the hospital. Most frequently reported complaints concerned a lack of
      information and being left with unanswered questions. Psychological problems
      related to mourning were mainly associated with a traumatic cause of death. The
      results of this study highlight the specific needs of relatives in case of a
      sudden death either outside the hospital or in the ED and may serve as a basis
      for recommendations for improvement of psychological care of individuals who are
      suddenly bereaved.

PMID- 15172715
TI  - Emergency airway management--experience of a tertiary hospital in South-East
      Asia.
AB  - OBJECTIVE: To study the indications and diagnoses of patients requiring emergency
      airway management and to evaluate the adequacy of airway management skills of
      emergency physicians. METHODS: Prospective observational study of all patients
      requiring advanced airway management from 1 November 1998 to 31 October 2002.
      RESULTS: There were 1068 cases, 710 (66.5%) were men. The median age was 63
      years. The most common diagnoses requiring tracheal intubation were
      cardiopulmonary arrest (37.7%), congestive heart failure (20.8%) and head injury
      (8.3%). The main indications were apnoea (42.5%), hypoxia (21.3%) and
      prophylactic airway protection (17.6%). Orotracheal intubation with no medication
      was most common (51.5%) followed by rapid sequence induction (RSI) (28.4%) and
      orotracheal intubation with sedation only (19.6%). The overall success rate for
      orotracheal intubation was 99.6%. The cricothyrotomy rate was 0.2%. Hypotension
      (4.2%), multiple intubation attempts (1.9%) and oesophageal intubation (1.5%)
      were the three most common peri-intubation complications. There was no
      statistical difference in the occurrence of hypotension between the use of
      midazolam and etomidate for sedation or induction prior to intubation. Six
      hundred and forty-six (60.5%) patients survived the immediate post-resuscitation
      period. No patient died from failure to secure the airway. CONCLUSION: Airway
      management and rapid sequence induction for intubation can be safely performed by
      emergency physicians.

PMID- 15172716
TI  - S100B protein in carbon monoxide poisoning: a pilot study.
AB  - Carbon monoxide (CO) poisoning is the most common form of lethal poisoning. The
      aim of this prospective clinical study was to assess the possible role of S100B,
      the structural protein in the astroglia, as a biochemical marker of brain injury
      in carbon monoxide poisoning. Serum S100B determination was performed in 38
      consecutive patients poisoned by carbon monoxide who were admitted to the
      Emergency Department (ED) in Ljubljana. All three unconscious patients had
      elevated S100B levels. The patient with the highest S100B died. S100B was
      elevated in two of the six patients with initial transitory unconsciousness at
      the scene. All 29 patients without loss of consciousness had normal S100B levels.
      Carbon monoxide poisoning appears to be associated with elevated S100B levels.

PMID- 15172717
TI  - Detection of evolving right ventricular infarct during right coronary artery
      stent insertion using PRIME ECG body surface mapping with colour map
      reconstruction.
AB  - We present the evolutionary changes of isolated right ventricular infarction
      (RVI) in a patient undergoing right coronary artery stenting using a novel
      imaging system. Twelve ECG and body surface maps were recorded at 30-s intervals
      during right coronary angioplasty, during which a right ventricular branch of the
      right coronary artery (RCA) occluded, resulting in a short-lived episode of chest
      pain and minor changes on a 12 lead ECG. Using computer-derived colour
      reconstruction of the ECG data, the changes of isolated right ventricular
      infarction is obvious, in contrast to the transient and equivocal changes seen on
      the 12 lead ECG. CONCLUSION: Isolated RVI may be missed on 12 lead ECG criteria.
      Body surface mapping (BSM) allows unequivocal diagnosis of isolated RVI by colour
      map reconstruction that is able to localise the ischaemic change.

PMID- 15172718
TI  - For whom the bell tolls?

PMID- 15172719
TI  - Remarks on guidelines ERC 2000: cardiac arrest associated with pregnancy.

PMID- 15172720
TI  - ILCOR-Advisory Statement: Education in Resuscitation.

PMID- 15172721
TI  - Methanol is a highly toxic alcohol.

PMID- 15172722
TI  - Evaluation of 14C abundance in soil respiration using acclerator mass
      spectrometry.
AB  - To clarify the behavior of 14C in terrestrial ecosystems, 14C abundance in soil
      respiration was evaluated in an urban forest with a new method involving a closed
      chamber technique and 14C measurement by accelerator mass spectrometry (AMS).
      Soil respiration had a higher Delta14C than the contemporary atmosphere. This
      indicates that a significant portion of soil respiration is derived from the
      decomposition of soil organic matter enriched in 14C by atmospheric nuclear
      weapons tests, with a notable time lag between atmospheric 14C addition and re
      emission from soil. On the other hand, delta14C in soil respiration demonstrated
      that 14C abundance ratio itself in soil-respired CO2 is not always high compared
      with that in atmospheric CO2 because of the isotope fractionation during plant
      photosynthesis and microbial decomposition of soil organic matter. The Delta14C
      in soil respiration was slightly lower in August than in March, suggesting a
      relatively high contribution of plant root respiration and decomposition of newly
      accumulated and/or 14C-depleted soil organic matter to the total soil respiration
      in August.

PMID- 15172723
TI  - Reconstruction of 137Cs signal in Cuba using 7Be as tracer of vertical transport
      processes in the atmosphere.
AB  - Levels of 137Cs and 7Be in aerosols have been measured in the region of
      Cienfuegos (Cuba) during the period 1994-1998. 137Cs showed the same seasonal
      trend as 7Be and the monthly regimes of precipitation seemed to be responsible
      for the observed pattern. The 137Cs/7Be ratio obtained in Cienfuegos and Miami
      (FL) in this period was used to calibrate the long-term database of 137Cs
      concentrations recorded in Miami (250 km from Cienfuegos). The database was then
      employed to reconstruct the 137Cs monthly concentrations in Cienfuegos since
      1957.

PMID- 15172724
TI  - A comparative study of (239,240)Pu in soil near the former Rocky Flats Nuclear
      Weapons Facility, Golden, CO.
AB  - The Rocky Flats Nuclear Weapons Plant near Golden, CO released plutonium into the
      environment during almost 40 years of operation. Continuing concern over possible
      health impacts of these releases has been heightened by lack of public disclosure
      of the US Department of Energy (DOE) activities. A dose reconstruction study for
      the Rocky Flats facilities, begun in 1990, provided a unique opportunity for
      concerned citizens to design and implement field studies without participation of
      the DOE, its contractors, or other government agencies. The Citizens
      Environmental Sampling Committee was formed in late 1992 and conducted a field
      sampling program in 1994. Over 60 soil samples, including both surface and core
      samples, were collected from 28 locations where past human activities would have
      minimal influence on contaminant distributions in soil. Cesium-137 activity was
      used as a means to assess whether samples were collected in undisturbed
      locations. The distribution of plutonium (as (239,240)Pu) in soil was consistent
      with past sampling conducted by DOE, the Colorado Department of Public Health and
      Environment, and others. Elevated levels of (239,240)Pu were found immediately
      east of the Rocky Flats Plant, with concentrations falling rapidly with distance
      from the plant to levels consistent with background from fallout. Samples
      collected in areas south, west, and north of the plant were generally consistent
      with background from fallout. No biases in past sampling due to choice of
      sampling locations or sampling methodology were evident. The study shows that
      local citizens, when provided sufficient resources, can design and implement
      technical studies that directly address community concerns where trust in the
      regulated community and/or regulators is low.

PMID- 15172725
TI  - Radon variations during treatment in thermal spas of Lesvos Island (Greece).
AB  - The aim of this paper was to study the variations of radon and daughter nuclei
      during treatment in the thermal spas of Lesvos Island (Greece). For this purpose,
      in the thermal spas of Lesvos we have measured the radon concentrations of
      thermal waters, as well as indoor radon, daughter and coarse particle (>500 nm)
      concentration. Various instruments and procedures were employed for measurements.
      Radon concentrations of thermal waters were found to lie in the range 10 and 304
      Bq l(-1). Concentration peaks both for radon, radon daughter and coarse particle,
      were found to appear during filling of baths in the treatment process. The doses
      delivered to the bathers during treatment were in the range of 0.00670 mSv per
      year to 0.1279 mSv per year, while the doses delivered to personnel were below 20
      mSv per year.

PMID- 15172726
TI  - Concentration of 226Ra in rocks of the southern part of Lower Silesia (SW
      Poland).
AB  - The aim of the article is to present a preliminary description of rocks in the
      southern part of Lower Silesia and the Sudety Mountains in particular, with
      regard to 226Ra content. The research demonstrates that the average content of
      this isotope was 40.4 Bq/kg in the rocks of the southern part of Lower Silesia,
      and 41.7 Bq/kg in the rocks of the Sudetes. These values are slightly higher than
      the mean 226Ra content in the upper part of the Earth's crust, while the measured
      maximum content of this isotope (244 Bq/kg) is more than twice as high as the
      upper range of the values most frequently recorded in the upper part of the
      Earth's crust. The minimum values were lower than the detection limit, which was
      about 1 Bq/kg. These results reflect the mosaic-like geological structure of
      Lower Silesia, and particularly the Sudety Mountains, the occurrence of SiO2-rich
      igneous rocks and the products of their metamorphism, as well as numerous
      manifestations of uranium mineralisation or even deposital concentrations of this
      element. The rocks with the highest 226Ra contents include (in decreasing order):
      aplites, granites, gneisses and leucogranites, granite-gneisses, granodiorites
      and rhyolites, and, finally, mudstones. The lowest values of 226Ra content, on
      the other hand, were measured in sandstones, marls and conglomerates, and
      extremely low-in marbles and quartzites. The results show that background values
      of 226Ra content in the rocks of the southern part of Lower Silesia fall within a
      range from several to about 100 Bq/kg, which is the same as the range most
      frequently recorded in the upper part of the Earth's crust. Distribution of these
      values has log-normal character. The research demonstrates that the southern part
      of Lower Silesia, and the Sudetes in particular, may be marked by an increased
      radon potential. Particularly liable areas are: the Karkonosze granite massif,
      especially in its border zones, the Ladek-Snieznik and the Izera massifs,
      especially in their gneiss parts, as well as the Orlica massif. There is an
      urgent necessity to undertake more extensive and detailed research into this
      subject in connection with radiological hazard of radon. These statements are
      compliant with observed high radon concentrations in some groundwaters and
      tourist underground objects on these areas.

PMID- 15172727
TI  - Radon concentrations in groundwaters of the Polish part of the Sudety Mountains
      (SW Poland).
AB  - In the course of researches into radon occurrence in the groundwaters of the
      Polish part of the Sudety Mountains, conducted in various research centres in
      Poland, almost 1000 radon concentration determinations have been collected. These
      results have given the basis for an attempt to characterise the groundwaters of
      this region with respect to radon content. Radon concentrations oscillated within
      the range of 0.2-1645 Bq/dm3, with the arithmetic mean at 240.0 Bq/dm3 and the
      geometric mean at 106.7 Bq/dm3. The largest number of radon concentrations found
      in the Sudetic groundwaters ranged between ca. 3-6 and 1000 Bq/dm3. The values
      over 1000 Bq/dm3 can be considered anomalously high. They constitute 3.9% of all
      the results and occur around six localities within different geological units of
      the Sudety Mountains. These are shallow circulation, low mineralised
      groundwaters, which outflow from gneisses and granites. In the face of the fact
      that from 12.8% to 72.7% (depending on the adopted norm of maximum radon
      concentration for drinking waters) of the examined waters cannot be drunk
      directly without removing at least part of the radon, and in the face of the
      possibility of recognizing as many as 63.5% of the waters as potentially
      medicinal, extensive research of radon geochemistry in the Sudety Mountains area
      should be urgently undertaken.

PMID- 15172728
TI  - Gamma dose rates and distribution of natural radionuclides in sand beaches--Ilha
      Grande, Southeastern Brazil.
AB  - In order to study the process of dispersion and the activity concentration of
      232Th and 238U series and 40K radionuclides in two island beaches in southeastern
      Brazil, analyses was made of sand samples of 0-10 cm profile, during a 12-month
      period. Moreover, the monthly variations of gamma dose rates were studied to
      determine the local environment absorbed dose rate. The average activity
      concentration of primordial radionuclides 232Th, 238U and 40K at Preta beach,
      they were 239, 121 and 110 Bq kg(-1), while at Dois Rios beach they were 48, 39
      and 412 Bq kg(-1), respectively. The absorbed dose rate in air, observed at 1 m
      above the ground, ranged from 54 to 228 nGy h(-1) at Preta beach and from 39 to
      110 nGy h(-1) at Dois Rios beach. The annual effective dose equivalent
      corresponding to Preta beach is 0.15 mSv a(-1) and to Dois Rios 0.08 mSv a(-1).

PMID- 15172729
TI  - Radon concentration in hospital buildings erected during the last 40 years in
      Bialystok, Poland.
AB  - The aim of the study was to compare radon concentrations in neighbouring hospital
      buildings which were constructed in different years during the period 1963-2000
      and are located in areas with similar radon potential. The value of arithmetic
      mean (AM) radon concentration in soil gas amounted to 14,464 Bq m(-3). In a
      hospital built 40 years ago, the AM radon concentration in the cellar was 38.4+/
      36.7 Bq m(-3) and on higher levels it was 17.1+/-10.3 Bq m(-3). In a hospital
      built 16 years ago, these values equaled 45.5+/-47.2 Bq m(-3) and 20.4+/-12.5 Bq
      m(-3), respectively. In the newest hospital, built three years ago, radon
      concentration (AM) in a cellar was 32.3+/-27.4 Bq m(-3) and the respective value
      on higher levels amounted to 20.4+/-12.6 Bq m(-3). When comparing radon
      concentrations in the cellars, no statistically significant differences were
      found. Similarly, no statistically significant differences were observed between
      radon concentrations measured on higher levels in investigated hospital
      buildings.

PMID- 15172731
TI  - Alzheimer's amyloid beta-peptide (1-42): involvement of methionine residue 35 in
      the oxidative stress and neurotoxicity properties of this peptide.
AB  - In the interesting debate entitled "Challenging Views of Alzheimer's Disease II,"
      we defended the position that factors such as oxygen, the single methionine
      residue of amyloid beta-peptide(1-42) [Abeta(1-42)], and redox metal ions were
      important for the oxidative stress and neurotoxic properties of this peptide that
      is critically involved in the pathogenesis of Alzheimer's disease. This brief
      review summarizes some of our findings relevant to the role of the single
      methionine residue of Abeta(1-42) in the oxidative stress and neurotoxic
      properties of this peptide.

PMID- 15172733
TI  - Lethal weapon: amyloid beta-peptide, role in the oxidative stress and
      neurodegeneration of Alzheimer's disease.

PMID- 15172732
TI  - Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin
      in Alzheimer's disease.
AB  - Pioneering work in the 1950s by Christian Anfinsen on the folding of ribonuclease
      has shown that the primary structure of a protein "encodes" all of the
      information necessary for a nascent polypeptide to fold into its native,
      physiologically active, three-dimensional conformation (for his classic review,
      see [Science 181 (1973) 223]). In Alzheimer's disease (AD), the amyloid beta
      protein (Abeta) appears to play a seminal role in neuronal injury and death.
      Recent data have suggested that the proximate effectors of neurotoxicity are
      oligomeric Abeta assemblies. A fundamental question, of relevance both to the
      development of therapeutic strategies for AD and to understanding basic laws of
      protein folding, is how Abeta assembly state correlates with biological activity.
      Evidence suggests, as argued by Anfinsen, that the formation of toxic Abeta
      structures is an intrinsic feature of the peptide's amino acid sequence-one
      requiring no post-translational modification or invocation of peptide-associated
      enzymatic activity.

PMID- 15172734
TI  - Cerebral amyloid angiopathy plays a direct role in the pathogenesis of
      Alzheimer's disease. Pro-CAA position statement.
AB  - For the purposes of this debate here we argue the case that cerebral amyloid
      angiopathy (CAA) has a direct role in the pathogenesis of Alzheimer's disease
      (AD). Firstly, there is a very close relationship between CAA and AD and they
      share genetic risk factors. Secondly, we propose a specific mechanism which puts
      age-related cerebrovascular degeneration at a crucial point in the pathogenesis
      of AD as follows. Amyloid beta-protein (Abeta) is normally eliminated from the
      brain along with extracellular fluid by bulk flow along the perivascular pathway.
      Age-related fibrosis of cerebral cortical and meningeal arteries leads to
      impaired drainage of Abeta along the perivascular pathway and, together with the
      production of Abeta by smooth muscle cells and perivascular cells, is responsible
      for accumulation of Abeta as CAA. Reduced elimination leads to increased
      concentration of soluble Abeta in the extracellular fluid of the brain
      parenchyma. Increased concentration of soluble Abeta leads to the formation of
      insoluble Abeta plaques, other features of AD pathology, and dementia.

PMID- 15172735
TI  - Cerebral amyloid angiopathy: major contributor or decorative response to
      Alzheimer's disease pathogenesis.
AB  - Amyloid deposition within cerebral vessels, or cerebral amyloid angiopathy (CAA),
      is common in advanced age and even more common in Alzheimer's disease. CAA may be
      complicated by lobar intracerebral hemorrhage, while rare kindreds of autosomal
      dominant CAA also show propensity for intracerebral hemorrhage, due to germline
      mutations in specific amyloidogenic precursor proteins and apparent compromise of
      structural integrity of the blood vessel wall due to marked amyloid deposition.
      The relationship between cerebral amyloid angiopathy and cognitive dysfunction,
      however, is less clear. While cognitive dysfunction in familial CAA is likely
      related to prodigious amyloid deposits and vascular luminal compromise (e.g.,
      hereditary cerebral hemorrhage with angiopathy-Dutch type (HCHWA-D)), cerebral
      amyloid angiopathy with intracerebral hemorrhage often presents sporadically in
      cognitively intact elderly patients. Moreover, while about 80% of subjects with
      Alzheimer's disease have demonstrable amyloid beta within blood vessel walls at
      autopsy, the vast majority of these fail to suffer clinically relevant
      intracerebral hemorrhage during life. The remaining 20% manage to progress and
      die of their disease with virtual no amyloid within blood vessels. Thus, the role
      of amyloid beta deposits in cerebral vessels as regards cognitive function on the
      one hand, and tendency for hemorrhage on the other, remain to be resolved for
      sporadic late onset Alzheimer's disease and CAA. Recent studies on transgenic
      APP23 mice suggest a relationship between passive immunization and amyloid
      angiopathy-associated cerebral hemorrhage, although the mechanism of hemorrhage
      was unclear from the data presented. We suggest that amyloid accumulation
      represents a response to chronic stress, and that the neurodegenerative process
      occurs at the neuronal level, encompassing oxidative stress and aberrant cell
      cycle activation. As such, CAA represents tissue homeostasis, such that an abrupt
      perturbation of this balance (e.g., amyloid beta immunization) is deleterious.

PMID- 15172737
TI  - Evidence supporting a role for anti-Abeta antibodies in the treatment of
      Alzheimer's disease.
AB  - Antibodies against Abeta have been suggested as potential therapeutic strategies
      for the treatment of Alzheimer disease (AD) for nearly 8 years. Animal studies
      have been very encouraging in that both active and passive immunization of
      transgenic mice can reduce amyloid load and reverse memory deficits found in
      these mice. Three mechanisms have been proposed to explain these results: (a).
      catalytic conversion of fibrillar Abeta to less toxic forms, (b). opsonization of
      Abeta deposits leading to microglial phagocytosis, or (c). promote the efflux of
      Abeta from the brain to the circulation. Evidence exists supporting all three
      mechanisms, which, it should be noted, are not mutually exclusive. Phase 2
      clinical trials of active immunization with vaccines against human Abeta1-42 were
      halted due to an unacceptable incidence of meningoencephalitic reactions (6% of
      patients treated). However, a recent report from a fraction of the patients in
      this trial found that those patients developing antibodies which reacted with
      brain amyloid deposits had a significantly slower progression of cognitive loss
      over a period of 12 months. This supports the continued cautious testing of
      passive immunization and, possibly even active immunization against the Abeta
      peptide using preparations less likely to cause autoimmune reactions in the
      central nervous system.

PMID- 15172738
TI  - Lessons from the AN 1792 Alzheimer vaccine: lest we forget.
AB  - Recent clinical and neuropathological data show that the AN 1792 vaccine enhanced
      the production of Abeta antibodies in the sera of Alzheimer's disease (AD)
      patients, but it appears to have been ineffective at stimulating the removal of
      Abeta deposits from the brain or at slowing the rate of cognitive decline. The 19
      cases of meningoencephalitis were not linked in an obvious way to serum antibody
      titre, but they may have been linked to infiltration of the brain by antibodies
      and/or T-cells. Brain imaging indicated that oedema associated with the
      neuroinflammation did not reflect the typical distribution of neuritic plaques in
      AD. These outcomes were not anticipated by experiments on transgenic mice because
      compared to humans, these mice have less genetic variability, and their plaques
      have a different chemical composition, making them far more soluble and easier to
      remove. Furthermore, the consequences of vaccination are different. Vaccination
      of transgenic mice removes superfluous human Abeta while leaving endogenous mouse
      Abeta intact, whereas in humans the immune response is directed against an
      endogenous target that occurs naturally and is present in healthy brain tissue.
      The most important lesson to be learned from the AN 1792 trials is that new
      strategies for treating AD should not be tested on humans until they have been
      extensively tested on non-murine species.

PMID- 15172739
TI  - Is the Abeta vaccine the answer?

PMID- 15172740
TI  - Infiltration of the brain by pathogens causes Alzheimer's disease.
AB  - Despite very numerous studies on Alzheimer's disease (AD), especially on amyloid
      plaques and neurofibrillary tangles, little information has been obtained thus on
      the causes of the disease. Evidence is described here that implicates firstly
      herpes simplex virus type 1 (HSV1) as a strong risk factor when it is present in
      brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-4).
      Indirect support comes from studies indicating the role of APOE in several
      diverse diseases of known pathogen cause. A second putative risk factor is the
      bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized
      in AD brain. Current studies aimed at "proof of principle" address the entry of
      the organism into the CNS, the neuroinflammatory response to the organism, and
      the role that the organism plays in triggering AD pathology. An infection-based
      animal model demonstrates that following intranasal inoculation of BALB/c mice
      with C. pneumoniae, amyloid plaques/deposits consistent with those observed in
      the AD brain develop, thus implicating this infection in the etiology of AD.

PMID- 15172741
TI  - Challenges and directions for the pathogen hypothesis of Alzheimer's disease.
AB  - This paper critically reviews the possibility that infiltration of the brain by
      pathogens (e.g. Herpes simplex virus type 1 (HSV1) or Chlamydophila pneumoniae
      (Cp)) acts as a trigger or co-factor for Alzheimer's disease (AD). The evidence
      currently available is limited and in some cases inconsistent, but it does
      justify the need for more vigorous investigation of this hypothesis. An issue of
      particular concern is the paucity of experimental evidence showing that pathogens
      can elicit the neuropathological changes and cognitive deficits that characterise
      AD. Other weaknesses include a failure to obtain independent confirmation of Cp
      in AD brains, and a lack of evidence for HSV1 proteins or intact virions in AD
      brain tissue. Future avenues of investigation that might prove fruitful include
      epidemiological investigations of the incidence of AD in individuals who are
      either immunosuppressed or have received chronic antiviral or antibiotic therapy.
      There is also a need to consider systemic infections as potential contributors to
      the pathogenesis of AD.

PMID- 15172742
TI  - Pathogens as a cause of Alzheimer's disease.

PMID- 15172743
TI  - ApoE genotype accounts for the vast majority of AD risk and AD pathology.
AB  - In this review, evidence is provided that apolipoprotein E (apoE) genotype
      accounts for the majority of Alzheimer's disease (AD) risk and pathology. The
      three major human isoforms, apoE2, apoE3, and apoE4, are encoded by different
      alleles (2, 3, 4) and regulate lipid metabolism and redistribution. ApoE isoforms
      differ in their effects on AD risk and pathology. Clinical and epidemiological
      data have indicated that the 4 allele may account for 50% of AD in the United
      States. Further, the rarity of AD among carriers of the 2 allele suggests that
      allelic variations in the gene encoding this protein may account for over 95% of
      AD cases. ApoE4 disrupts memory function in rodents. Further studies have
      indicated that fragments of apoE may contribute to both plaque and tangle
      formation. Thus, the epidemiologic and basic science evidence suggest that apoE
      genotype accounts for the vast majority of AD risk and pathology.

PMID- 15172744
TI  - Apolipoprotein gene and its interaction with the environmentally driven risk
      factors: molecular, genetic and epidemiological studies of Alzheimer's disease.
AB  - Herein we review the role of apolipoprotein E (ApoE) in Alzheimer's disease (AD)
      and how ApoE interacts with various risk factors. ApoE is localized with the
      major pathological hallmarks of AD, extracellular amyloid deposits and
      intracellular neurofibrillary tangles. The ApoE4 allele is associated with the
      development of late-onset familial and sporadic AD. ApoE4 has a gene dose effect
      on the risk and age of onset of AD. ApoE mRNA and protein are found predominantly
      in astrocytes within the CNS. There is also a high expression of ApoE mRNA in the
      brains of people with sporadic AD. ApoE acts as a cholesterol transporter in the
      brain. Cholesterol controls amyloid production and deposition by regulating beta
      secretase. In transgenic animal studies, ApoE4 expression causes neuropathology
      and behavioral deficits. We also discuss data from three different cohorts for AD
      in the general population, in different racial and ethnic groups and the role of
      the 4 allele in the clinical onset of the disease. Although the 4 allele is an
      important genetic risk factor for AD, it accounts for a fairly small fraction of
      disease in the population. The effect of the 4 allele on annual decline in
      episodic memory is significantly stronger than its effect on decline in other
      cognitive systems. Notably, the 2 allele has an equal and opposite effect. Thus,
      ApoE allele status influences risk of AD by a relatively selective effect on
      episodic memory. Mechanistically, the role of APoE in AD needs to be established
      in terms of its gene expression, which ultimately controls levels of various ApoE
      isoforms. Transcriptional regulation suggests complex regulation of this gene and
      the resultant ApoE protein in injured neurons. We discuss the characteristics of
      ApoE regulatory elements, including their interactions with different
      transcription factors, to understand ApoE gene expression. Thus, ApoE4
      contributes to the pathogenesis of AD, but additional environmental risk factors
      will also be identified independent of ApoE and other genetic polymorphisms.

PMID- 15172746
TI  - Contribution of glial cells to the development of amyloid plaques in Alzheimer's
      disease.
AB  - Amyloid plaques appear early during Alzheimer's disease (AD), and their
      development is intimately linked to activated astrocytes and microglia.
      Astrocytes are capable of accumulating substantial amounts of neuron-derived,
      amyloid beta(1-42) (Abeta42)-positive material and other neuron-specific proteins
      as a consequence of their debris-clearing role in response to local
      neurodegeneration. Immunohistochemical analyses have suggested that astrocytes
      overburdened with these internalized materials can eventually undergo lysis, and
      radial dispersal of their cytoplasmic contents, including Abeta42, can lead to
      the deposition of a persistent residue in the form of small, GFAP-rich,
      astrocytic amyloid plaques, first appearing in the molecular layer of the
      cerebral cortex. Microglia, most of which appear to be derived from blood
      monocytes and recruited from local blood vessels, rapidly migrate into and
      congregate within neuritic and dense-core plaques, but not diffuse plaques.
      Instead of internalizing and removing Abeta from plaques, microglia appear to
      contribute to their morphological and chemical evolution by facilitating the
      conversion of existing soluble and oligomeric Abeta within plaques to the
      fibrillar form. Abeta fibrillogenesis may occur largely within tiny, tube-like
      invaginations in the surface plasma membrane of microglia. These results
      highlight the therapeutic potential of blocking the initial intracellular
      accumulation of Abeta42 in neurons and astrocytes and inhibiting microglia
      mediated assembly of fibrillar Abeta, which is particularly resistant to
      degradation in Alzheimer brain.

PMID- 15172747
TI  - The microglial phagocytic role with specific plaque types in the Alzheimer
      disease brain.
AB  - Alzheimer disease (AD) involves glial inflammation associated with amyloid
      plaques. The role of the microglial cells in the AD brain is controversial, as it
      remains unclear if the microglia form the amyloid fibrils of plaques or react to
      them in a macrophage-phagocytic role. Also, it is not known why microglia are
      preferentially associated with some amyloid plaque types. This review will
      provide substantial evidence to support the phagocytic role of microglia in the
      brain as well as explain why microglia are generally associated with specific
      plaque types that may be explained through their unique mechanisms of formation.
      In summary, the data presented suggests that plaque associated microglial
      activation is typically subsequent to specific amyloid plaque formations in the
      AD brain.

PMID- 15172749
TI  - Challenging views of Alzheimer's disease - round II.

PMID- 15172748
TI  - Imaging is superior to cognitive testing for early diagnosis of Alzheimer's
      disease.
AB  - Alzheimer's disease (AD) starts at a molecular level possibly decades earlier
      than could be detected by neuropsychological tests (NPTs). Neuropathological and
      neuroimaging data suggest that amyloid accumulation precedes the clinical onset
      of AD. Disease-modifying agents would have to be used early to alter the course
      of AD. Therefore, preclinical diagnosis is necessary. Structural and functional
      neuroimaging are superior for detection of the earliest stages of AD. Magnetic
      resonance imaging (MRI) and positron emission tomography (PET) techniques,
      including amyloid visualization, will have therapeutic importance for prevention
      as well as intervention as further refinements of current imaging techniques and
      biochemical markers occur. Neuropsychological tests measure the effect of
      pathology for an individual based upon norms obtained from an artificial
      population-often white and relatively highly educated. Unless serial NPTs are
      performed, the individual is compared to a population to which they may not
      conform. Neuroimaging can provide objective measures of preclinical disease state
      and, when measured serially, rate of change. Such information can be used in
      prevention trials.

PMID- 15172750
TI  - Chromosomes, genes, and development of testicular germ cell tumors.
AB  - A literature review found 265 articles on testicular germ cell tumors (TGCTs)
      detailing the copy number of chromosomal regions and expression of 245 genes. An
      initial precursor stage, intratubular germ cell neoplasia (IGCN), is
      characterized by triploidization and an upregulation of KIT, ALPP, CCDN2, and
      ZNF354A, and a downregulation of CDKN2D. TGCT regularly have a series of
      chromosomal aberrations: a decrease in copy number at 4q21 approximately qter and
      5q14 approximately qter; an increase at 7p21 approximately pter, 7q21
      approximately q33, and 8q12 approximately q23 (especially high increase in
      seminoma); a decrease at 11p11 approximately p15 and 11q14 approximately q24; an
      increase at 12p11 approximately pter; a decrease at 13q14 approximately q31; an
      increase of 17q11 approximately q21 (only for nonseminoma); a decrease of 18q12
      approximately qter; and an increase at 21q21 approximately qter, 22q11
      approximately qter (only for seminoma), and Xq. Macroscopically overt TGCT is
      associated with a characteristic series of abnormalities in the retinoblastoma
      pathway including upregulation of cyclin D2 and p27 and downregulation of RB1 and
      the cyclin-dependent kinase inhibitors p16, p18, p19, and p21. TGCT thus has a
      synergistic pattern in gene expressions of the retinoblastoma pathway that is
      rare in other malignancies.

PMID- 15172751
TI  - Is fluorescence in situ hybridization a useful method in diagnosis of
      polycythemia vera patients?
AB  - Polycythemia vera (PV) is a clonal stem cell disease with trilineage myeloid
      involvement, characterized by a growth factor-independent erythroid
      proliferation. At the time of diagnosis, the percentage of cytogenetic
      abnormalities using conventional cytogenetic techniques is less than 20% of all
      PV patients. In the present study, we compare the results between conventional
      cytogenetic methods and fluorescence in situ hybridization (FISH) probes in 31
      untreated PV patients. The karyotypes of all 31 cases were obtained from 24-hour
      bone marrow cell cultures. The fixed material, proceeding from conventional
      cytogenetics cultures, was analyzed with FISH, using centromeric probes for
      chromosomes 8 and 9 and locus-specific probes for 13q14 and 20q12 regions. Five
      cases (17.8%) showed an abnormal karyotype with conventional cytogenetics. When
      FISH probes were used, three alterations not detected with conventional
      cytogenetics, were found: two cases with D20S108 deletions and one with a D13S319
      deletion, increasing the percentage of abnormal karyotypes to 19.3%. We conclude
      that, probably, the application of FISH with the mentioned probes, is not very
      useful to detect cytogenetic aberrations in untreated PV patients.

PMID- 15172752
TI  - Deletion of chromosome arm 15q and hitherto unreported duplication of del(15q) in
      myeloid disorders.
AB  - Deletion of the long arm of chromosome 15 has been described as a recurrent
      chromosomal abnormality in myeloid malignancies. We present here some additional
      case reports of deletion 15 including two cases with an extra copy of the deleted
      chromosome, a finding that has not previously been described. We compare our
      cases to those previously reported. Our findings show that, contrary to previous
      reports, this abnormality may not always be associated with an unfavorable
      prognosis. They also indicate that deletion 15q most frequently appears to be
      associated with myelomonocytic disease. Potential candidate genes on 15q that may
      be involved in the tumorigenesis of these cases are discussed.

PMID- 15172753
TI  - Hereditary breast and ovarian cancer in Cyprus: identification of a founder BRCA2
      mutation.
AB  - The entire coding regions of the two breast cancer susceptibility genes BRCA1 and
      BRCA2 from breast cancer patients from 40 Cypriot families with multiple cases of
      breast and ovarian cancer were sequenced. A total of four protein-truncating
      mutations were found in six families. In BRCA1, a novel truncating mutation
      5429delG was found in exon 21. In BRCA2, three truncating mutations were
      detected: a frameshift 8984delG in exon 22 and two nonsense mutations C1913X in
      exon 11 and K3326X in exon 27. It is noted that mutation 8984delG was found in
      three separate families, and haplotype analysis showed that this may be a founder
      mutation in the Cypriot population. In addition, a pair of rare variants, Q356R
      and S1512I, was detected in BRCA1 in patients belonging to two Cypriot families.
      The simultaneous presence of this pair of missense mutations may be associated
      with the breast cancer phenotype in the Cypriot population. We conclude that the
      BRCA2 gene appears to play a more important role in familial breast cancer in the
      Cypriot population than BRCA1.

PMID- 15172754
TI  - Aberrations involving 13q12 approximately q14 are frequent secondary events in
      childhood acute lymphoblastic leukemia.
AB  - Chromosome 13 aberrations, particularly in the region 13q12 approximately q14,
      are common events in hematological neoplasms that have a clinical significance in
      many cases. However, although chromosome 13 aberrations are a nonrandom event in
      childhood acute lymphoblastic leukemia (ALL), their biological and clinical
      associations are limited. We have studied a consecutive series of 277 cases of
      childhood ALL, including 33 initially at relapse, by conventional cytogenetic
      analysis. In 20 cases, a chromosome 13 aberration that involved the region 13q12
      approximately q14 was detected at some point during the disease. An aberration
      was identified in 15 of 244 (6.1%) presentation cases and 7 of 54 (13%) relapsed
      cases, of which in 11 cases it was shown that the abnormality arose as a
      secondary karyotypic event. To further characterize the cases, fluorescence in
      situ hybridization (FISH) using the commercially available probes LSI 13 (RB1)
      and D13S25 (both 13q14) was undertaken. These analyses provided additional
      evidence for the secondary nature of many events and suggested that 13q14
      deletions may confer a growth advantage in culture because the percentage of
      cells containing 13q14 deletions detected by FISH was often lower than that
      detected by G-banding. Since 13q12 approximately q14 aberrations in childhood ALL
      frequently occur as secondary events, these results imply that the abnormality
      has implications for disease progression.

PMID- 15172755
TI  - A complex rearrangement of chromosome 7 in human astrocytoma.
AB  - Chromosome 7 is a frequent site of cytogenetic aberrations in human astrocytomas.
      One region that is often targeted in human astrocytomas is on 7p. The U251 human
      glioblastoma cell line has a region of gain of genetic material on 7p similar to
      that seen in human astrocytomas. We used several cytogenetic techniques to study
      chromosome 7 in U251 cells and identified a complex rearrangement that accounts
      for gain of chromosome 7 genetic material in the cell line. The characteristic
      rearrangement suggests a mechanism leading to 7p gain in primary grade IV
      astrocytomas.

PMID- 15172756
TI  - Comprehensive conventional and molecular cytogenetic characterization of B-CPAP,
      a human papillary thyroid carcinoma-derived cell line.
AB  - Cell lines derived from different thyroid tumor histotypes are useful for the in
      vitro study of both the phenotypic and genetic features of these cancers.
      Although karyotypic changes are known to be associated with thyroid lesions, the
      chromosome patterns of only a few cell lines have been published. Herein, we
      report an extensive conventional and molecular cytogenetic investigation of the
      human papillary thyroid carcinoma derived cell line B-CPAP. Morphological studies
      and expression of tumor markers in this cell line have been reported previously,
      but no detailed characterization on the origin of the chromosome markers is
      available. B-CPAP cells have a rather stable hypertriploid karyotype, with
      chromosome polysomies and structural chromosome abnormalities featuring whole
      chromosome arm imbalances. Chromosome banding revealed a main clone with nine
      chromosome markers, and fluorescence in situ hybridization (FISH) with whole
      chromosome paint (wcp), partial chromosome paint (pcp), and centromeric probes
      clarified their origin. The use of centromeric probes provided accurate
      refinement of the rearrangements classified as whole-arm translocations by
      banding and FISH with wcp probes. Both chromosomal and array-based comparative
      genomic hybridization experiments confirmed the cytogenetic characterization of
      this cell line. Moreover, the use of fluorescence immunophenotyping and
      interphase cytogenetics as a tool for the investigation of neoplasms (FICTION)
      technique, which simultaneously shows nuclear ploidy and cytoplasmic
      immunofluorescence, detailed the oncocytic feature of the cells. Intriguingly,
      despite their origin, they lack most of the features expressed in papillary
      thyroid tumor cells and have a chromosomal pattern reminiscent of that of a
      subgroup of oncocytic malignant thyroid tumors.

PMID- 15172757
TI  - Combined binary ratio labeling fluorescence in situ hybridization analysis of
      chordoma.
AB  - Chordoma is a rare, low- to intermediate-grade malignant tumor involving the
      axial spine. Cytogenetic data on these tumors have been limited to 25 cases. The
      findings of clonal chromosome aberrations in five new cases are presented. One of
      these and two previously reported cases have been studied with multicolor
      combined binary ratio labeling fluorescence in situ hybridization (COBRA-FISH).
      The karyotypes were near-diploid, mostly with several numerical and structural
      aberrations. There were multiple imbalances, with loss of segments from 1p, 3p,
      3q, 9p, and chromosome 10 seen in two to four of the seven cases. No clustering
      of breakpoints was seen and no recurrent recombination between chromosomes was
      detected. The findings are consistent with previous data and indicate that
      chordoma tumor development is associated with multiple, nonrandom losses
      including chromosome segments that are frequently involved in many other solid
      tumors.

PMID- 15172758
TI  - Parental 19q loss and PEG3 expression in oligodendrogliomas.

PMID- 15172759
TI  - Developmental sculpting of social phenotype and plasticity.
AB  - Early developmental variables engender behavioral and neural variation,
      especially in species in which embryonic environment determines gonadal sex. In
      the leopard gecko, Eublepharis macularius, the incubation temperature of the egg
      (IncT) determines gonadal sex. Moreover, IncT affects the sexual differentiation
      of the individual and, consequently, within-sex variation. Individuals hatched
      from eggs incubated at an IncT that produces predominantly males are more
      masculinized than same-sex counterparts from IncTs that produce predominantly
      females. Here we review how gonadal sex and IncT interact to affect behavioral,
      endocrinological, and neural phenotype in the leopard gecko and influence
      phenotypic plasticity following hormone administration or social experience. We
      discuss the hormonal dependence of sex- and IncT-dependent behavioral and neural
      morphological and metabolic differences and highlight the parallels between IncT
      effects in geckos and intrauterine position effects in rodents. We argue that the
      leopard gecko is an important model of how the process of sex determination can
      affect sexual differentiation and of selection forces underlying the evolution of
      sex ratios.

PMID- 15172760
TI  - The neural mechanisms of object working memory: what is where in the infant
      brain?
AB  - The question of how representational capacities develop in humans has been
      engaging cognitive psychologists for decades. Looking time studies have explored
      when infants start to show signs of perceiving and remembering the properties of
      specific objects at specific locations. Here we integrate these findings into the
      neuroscientific framework of human visual working memory. We suggest that the
      development of a system involving the temporal cortex, thalamic and hippocampal
      structures and possibly the dorsolateral prefrontal cortex (later in development)
      can account for these behavioral results. Our explanation differs from most of
      the current approaches in developmental science as we put less emphasis on the
      contribution of lateral prefrontal areas. We discuss shortcomings of the theories
      that propose a functional subdivision of these areas and their difficulty in
      accounting for results from monkey lesion and infant studies. We believe that
      this shift in focus is desirable both in light of what recent results on medial
      temporal lobe processing reveal about object working memory, and given how well
      these results fit the behavioral developmental data.

PMID- 15172761
TI  - Pathological gambling: a comprehensive review of biobehavioral findings.
AB  - In this review, findings of biobehavioral research into pathological gambling
      (PG) are discussed, focusing on neuropsychological, psychophysiological,
      neuroimaging, neurochemical and genetic studies. Neuropsychological studies
      indicate deficiencies in certain executive functions. Psychophysiological studies
      indicate that arousal in PG is of importance when reward is present. Neuroimaging
      studies point to abnormalities in brain functioning. Recent research into the
      neurochemistry of PG indicates that abnormalities exist in different
      neurotransmitter systems. Finally, genetic studies indicate the existence of
      abnormal dopamine receptor genes in PG. Methodological and theoretical factors
      that may explain discrepancies between studies include differences in screening
      and assessment, heterogeneity of gambling problems and different underlying
      cognitive or motivational mechanisms. Results from the PG studies fit in with
      recent theoretical models of addiction and PG, which stress the involvement of
      brain reward pathways, neurotransmitter abnormalities, the frontal cortex and the
      psychophysiological stress system. A framework for future studies is suggested,
      indicating the need for studies that integrate knowledge from different research
      areas, and that employ stricter diagnostic screening methods and inclusion of
      clinical control groups.

PMID- 15172762
TI  - The selfish brain: competition for energy resources.
AB  - The brain occupies a special hierarchical position in the organism. It is
      separated from the general circulation by the blood-brain barrier, has high
      energy consumption and a low energy storage capacity, uses only specific
      substrates, and it can record information from the peripheral organs and control
      them. Here we present a new paradigm for the regulation of energy supply within
      the organism. The brain gives priority to regulating its own adenosine
      triphosphate (ATP) concentration. In that postulate, the peripheral energy supply
      is only of secondary importance. The brain has two possibilities to ensure its
      energy supply: allocation or intake of nutrients. The term 'allocation' refers to
      the allocation of energy resources between the brain and the periphery. Neocortex
      and the limbic-hypothalamus-pituitary-adrenal (LHPA) system control the
      allocation and intake. In order to keep the energy concentrations constant, the
      following mechanisms are available to the brain: (1) high and low-affinity ATP
      sensitive potassium channels measure the ATP concentration in neurons of the
      neocortex and generate a 'glutamate command' signal. This signal affects the
      brain ATP concentration by locally (via astrocytes) stimulating glucose uptake
      across the blood-brain barrier and by systemically (via the LHPA system)
      inhibiting glucose uptake into the muscular and adipose tissue. (2) High-affinity
      mineralocorticoid and low-affinity glucocorticoid receptors determine the state
      of balance, i.e. the setpoint, of the LHPA system. This setpoint can permanently
      and pathologically be displaced by extreme stress situations (chronic metabolic
      and psychological stress, traumatization, etc.), by starvation, exercise,
      infectious diseases, hormones, drugs, substances of abuse, or chemicals
      disrupting the endocrine system. Disorders in the 'energy on demand' process or
      the LHPA-system can influence the allocation of energy and in so doing alter the
      body mass of the organism. In summary, the presented model includes a newly
      discovered 'principle of balance' of how pairs of high and low-affinity receptors
      can originate setpoints in biological systems. In this 'Selfish Brain Theory',
      the neocortex and limbic system play a central role in the pathogenesis of
      diseases such as anorexia nervosa and obesity.

PMID- 15172763
TI  - The contribution of spatial remapping impairments to unilateral visual neglect.
AB  - Left visual neglect following right hemisphere damage is a heterogeneous
      phenomenon, in which several underlying impairments have been identified. Despite
      recent advances in understanding the neural and cognitive bases of these
      impairments, current theories of neglect, particularly those that emphasise
      attentional deficits, do not explain a number of phenomena, including:
      'Ipsilesional' neglect after left orienting. Positive or 'productive'
      manifestations. Spatial transposition errors. Mislocalisations. Revisiting
      behaviour during visual search. Lack of awareness for objects toward the
      contralesional side of space. We propose that these manifestations of neglect can
      be accounted for by an additional underlying disorder of spatial remapping due to
      parietal dysfunction. In primary visual areas, retinotopic maps are renewed and
      thus overwritten at each new ocular fixation. Remapping processes operating in
      higher-level oculocentric visual maps of the parietal cortex ensure visual
      integration of these successive retinal images over time and space, by creating a
      constantly updated representation of stimulus locations in terms of distance and
      direction from the fovea. They consist in the storage, refreshment and re
      localization of the different components of the visual scene that are
      successively attended during its exploration, and provide spatial constancy of
      visual perception and a spatial buffer for working memory [Cereb Cortex 5 (1995)
      470; Visual Cogn 7 (2000) 17]. We begin this article by reviewing theoretical and
      experimental arguments that have highlighted the importance of parietal remapping
      processes in maintaining an accurate representation of space across saccadic
      shifts. We then focus on findings from the double-step saccade task, [Ann Neurol
      38 (1995) 739] as a basis for our model of the role of remapping impairments in
      many of the symptoms of neglect. From these results, remapping impairments would
      be demonstrated when a saccade has to be guided across the midline after having
      fixated an object in either the left or right visual field for patients with
      either left- or right-side parietal lesions. In addition, patients with right
      side lesions will have remapping impairments within the left visual field
      following a saccade to a left-side target (see Fig. 5). In a large part of the
      article, we seek to build our hypothesis based on this basic model and more
      speculative assumptions supported with extensive evidence from the literature.

PMID- 15172764
TI  - A proposed architecture for the neural representation of spatial context.
AB  - The role of context in guiding animal behavior has attracted increasing attention
      in recent years, but little is known about what constitutes a context, nor how
      and where in the brain it is represented. Contextual stimuli can take many forms,
      but of particular importance are those that collectively define a particular
      place or situation. The representation of place has been linked to the
      hippocampus, because its principal neurons ('place cells') are spatially
      responsive; behavioral experiments also implicate this structure in the
      processing of contextual stimuli. Together, these findings suggest a hippocampal
      role in representing 'spatial context'. The present article outlines a proposed
      architecture for the encoding of spatial context in which spatial inputs to place
      cells are modulated (or 'gated') by non-spatial stimuli. We discuss recent
      experimental evidence that spatial context is population-coded, a property which
      could allow both discrimination between overlapping contexts and generalization
      across them, and thus provide a foundation for animals' capacity for flexible
      context-linked place learning.

PMID- 15172765
TI  - The orofacial formalin test.
AB  - The subcutaneous injection of formalin into the rat upper lip generates
      behavioral responses that last several minutes. The time course of the response
      is similar to what is observed following formalin injection into the paw, i.e.
      biphasic, with an early and short-lasting first phase followed, after a quiescent
      period by a second, prolonged (tonic) phase. The applied chemical stimulus
      (formalin) can be qualified as noxious since it produces tissue injury, activates
      Adelta and C nociceptors as well as trigeminal and spinal nociceptive neurons and
      is felt as painful in man. In addition, increasing the concentration of formalin
      causes a parallel aggravation of histological signs of tissue inflammation and
      injury. The measured behavioral response (face rubbing) is a relevant end-point:
      prolonged face rubbing is evoked by formalin but not saline injection and a
      positive relationship between the amplitude of the response and the formalin
      concentration is observed, at least up to 2.5%. At higher formalin
      concentrations, the use of other or additional end-points should be considered.
      Finally, the behavioral response in the orofacial formalin test is sensitive to
      various opioid and non-opioid analgesics. The orofacial formalin test can then be
      considered as a reliable way of producing and quantifying nociception in the
      trigeminal region of the rat.

PMID- 15172766
TI  - Kickstarting the revolution in health systems research.

PMID- 15172767
TI  - Unlocking the corporate documents of British American Tobacco: an invaluable
      global resource needs radically improved access.

PMID- 15172768
TI  - Neuromonitoring for awareness during surgery.

PMID- 15172769
TI  - Maternal effect in multiple sclerosis.

PMID- 15172770
TI  - UK immigration law disregards the best interests of children.

PMID- 15172771
TI  - Five sides of trauma.

PMID- 15172772
TI  - Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory
      drugs and congestive heart failure outcomes in elderly patients: a population
      based cohort study.
AB  - BACKGROUND: Non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) are
      associated with an increased risk of congestive heart failure, but little is
      known about the cardiovascular effects of a newer group of NSAIDS called
      selective cyclo-oxygenase (COX)-2 inhibitors. We aimed to compare rates of
      admission for congestive heart failure in elderly patients who were newly
      dispensed COX-2 inhibitors or non-selective NSAIDs. METHODS: In this population
      based retrospective cohort study we identified NSAID-naive individuals aged 66
      years or older, who were started on rofecoxib (n=14,583), celecoxib (n=18,908),
      and non-selective NSAIDs (n=5,391), and randomly selected non-NSAID users as
      controls (n=100,000). FINDINGS: Relative to non-NSAID users, patients on
      rofecoxib and non-selective NSAIDS had an increased risk of admission for
      congestive heart failure (adjusted rate ratio 1.8, 95% CI 1.5-2.2, and 1.4, 1.0
      1.9, respectively), but not celecoxib (1.0, 0.8-1.3). Compared with celecoxib
      users, admission was significantly more likely in users of non-selective NSAIDs
      (1.4, 1.0-1.9) and rofecoxib (1.8, 1.4-2.4). Risk of admission for rofecoxib
      users was higher than that for non-selective NSAID users (1.5, 1.1-2.1). Of
      patients with no admission in the past 3 years, only rofecoxib users were at
      increased risk of subsequent admission relative to controls (1.8, 1.4-2.3).
      INTERPRETATION: These findings suggest a higher risk of admission for congestive
      heart failure in users of rofecoxib and non-selective NSAIDs, but not celecoxib,
      relative to non-NSAID controls.

PMID- 15172773
TI  - Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware
      randomised controlled trial.
AB  - BACKGROUND: Awareness is an uncommon complication of anaesthesia, affecting 0.1
      0.2% of all surgical patients. Bispectral index (BIS) monitoring measures the
      depth of anaesthesia and facilitates anaesthetic titration. In this trial we
      determined whether BIS-guided anaesthesia reduced the incidence of awareness
      during surgery in adults. METHODS: We did a prospective, randomised, double
      blind, multicentre trial. Adult patients at high risk of awareness were randomly
      allocated to BIS-guided anaesthesia or routine care. Patients were assessed by a
      blinded observer for awareness at 2-6 h, 24-36 h, and 30 days after surgery. An
      independent committee, blinded to group identity, assessed every report of
      awareness. The primary outcome measure was confirmed awareness under anaesthesia
      at any time. FINDINGS: Of 2463 eligible and consenting patients, 1225 were
      assigned to the BIS group and 1238 to the routine care group. There were two
      reports of awareness in the BIS-guided group and 11 reports in the routine care
      group (p=0.022). BIS-guided anaesthesia reduced the risk of awareness by 82% (95%
      CI 17-98%). INTERPRETATION: BIS-guided anaesthesia reduces the risk of awareness
      in at-risk adult surgical patients undergoing relaxant general anaesthesia. With
      a cost of routine BIS monitoring at US16 dollars per use in Australia and a
      number needed to treat of 138, the cost of preventing one case of awareness in
      high-risk patients is about 2200 dollars.

PMID- 15172774
TI  - Combination antifungal therapies for HIV-associated cryptococcal meningitis: a
      randomised trial.
AB  - BACKGROUND: It frequently takes more than 2 weeks for drug treatments for
      cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and
      animal studies lend support to the use of combinations of amphotericin B,
      flucytosine, and fluconazole for treatment of cryptococcosis. We compared the
      fungicidal activity of combinations of these drugs for initial treatment of
      patients with cryptococcal meningitis. METHODS: 64 patients with a first episode
      of HIV-associated cryptococcal meningitis were randomised to initial treatment
      with: amphotericin B (0.7 mg/kg daily); amphotericin B plus flucytosine (100
      mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy
      with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was
      fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony
      forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of
      treatment. FINDINGS: Baseline CSF CFU counts were an important prognostic factor.
      Clearance of cryptococci from the CSF was exponential and was significantly
      faster with amphotericin B plus flucytosine than with amphotericin B alone
      (p=0.0006), amphotericin B plus fluconazole ( p=0.02), or triple therapy
      (p=0.02). INTERPRETATION: At these doses, amphotericin B plus flucytosine is the
      most rapidly fungicidal regimen. Quantification of CSF cultures provides a
      powerful new means to accurately assess the fungicidal activity of new treatment
      regimens for cryptococcal meningitis.

PMID- 15172775
TI  - Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study.
AB  - BACKGROUND: Recombinant human erythropoietin is the standard treatment for
      anaemia related to chronic kidney disease, and its widespread use has been
      favoured by a very high therapeutic index. However, since 1998, more than 200
      patients worldwide with chronic kidney disease treated in this way have developed
      neutralising antibodies to erythropoietin, causing pure red cell aplasia. We
      aimed to collate clinical and pathological features in patients unequivocally
      shown to have erythropoietin-induced pure red cell aplasia. METHODS: We
      retrospectively obtained data from the files of 47 patients with pure red cell
      aplasia. We assessed treatment and outcome of patients and defined recovery from
      pure red cell aplasia as an increase in reticulocyte counts to more than 20 000
      per microL in patients who were no longer transfusion-dependent. FINDINGS: When
      patients developed pure red cell aplasia, all were receiving erythropoietin
      subcutaneously, and the product most typically prescribed was epoetin alfa
      (Eprex, Ortho Biotech). The median delay between start of erythropoietin
      treatment and occurrence of pure red cell aplasia was 11 months (IQR 7.5-14).
      Nine patients received no immunosuppressive treatment, and none of these
      recovered. Of 37 patients who received immunosuppressive therapy, 29 (78%)
      recovered. All six patients who received a kidney transplant recovered within 1
      month, and recovery rates were between 56% and 88% in patients treated with
      corticosteroids, corticosteroids plus cyclophosphamide, or ciclosporin. No
      relapse of pure red cell aplasia happened after stopping immunosuppressive
      treatment, but no patient was rechallenged with erythropoietin. INTERPRETATION:
      Immunosuppressive treatment accelerates recovery from erythropoietin-induced pure
      red cell aplasia.

PMID- 15172776
TI  - Recurrent meningitis of unknown aetiology.

PMID- 15172777
TI  - Parent-of-origin effect in multiple sclerosis: observations in half-siblings.
AB  - Multiple sclerosis is a complex trait in which occurrence rates in offspring are
      20-50-fold greater than in the general population. Parent-of-origin effects have
      been difficult to screen for, since most cases are sporadic. We have compared
      recurrence risks in half-siblings with respect to their parent in common. Of the
      1567 index cases with half-siblings in multiple sclerosis clinics across Canada,
      we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling
      risk was 3.11%. By contrast, half-sibling risk in the same families was
      significantly lower at 1.89% (chi2 test, p=0.006), but higher than expected if
      familial risk was simply polygenic. For maternal half-siblings, the risk was
      2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of
      1577), (p=0.048). The difference in risk suggests a maternal parent-of-origin
      effect in multiple sclerosis susceptibility.

PMID- 15172778
TI  - Parkinson's disease.
AB  - Parkinson's disease is the most common serious movement disorder in the world,
      affecting about 1% of adults older than 60 years. The disease is attributed to
      selective loss of neurons in the substantia nigra, and its cause is enigmatic in
      most individuals. Symptoms of Parkinson's disease respond in varying degrees to
      drugs, and surgery offers hope for patients no longer adequately controlled in
      this manner. The high prevalence of the disease, and important advances in its
      management, mean that generalists need to have a working knowledge of this
      disorder. This Seminar covers the basics, from terminology to aspects of
      diagnosis, treatment, and pathogenesis.

PMID- 15172779
TI  - The arrogance of youth.

PMID- 15172780
TI  - Development of trauma systems and effect on outcomes after injury.
AB  - The ideal system for management of trauma remains controversial, especially in
      respect of prehospital care and regionalisation of trauma-care delivery. To
      explore these issues, we compare two differing trauma systems--in the USA the
      focus is on the trauma centre, with a lesser emphasis on prehospital care,
      whereas in France there is more emphasis on prehospital care coordinated by the
      Service d'Aide Medicale Urgente. We describe the historical developments, current
      structure, and major controversies with regard to trauma-care delivery in the two
      countries. Comparative evidence on the effectiveness of the two systems was
      obtained through a structured review of databases, but very little evidence
      permits direct comparison of outcomes across the two systems. Crude injury
      mortality rates and fatality rates from motor-vehicle accidents (crashes in US
      usage) are higher in France than in the USA, although adjustment for potential
      confounders is difficult. Adjusted mortality rates suggest equivalent outcomes
      among patients who survive to hospital, although these data are confounded by the
      lack of a contemporaneous comparator population. There are differences in the
      American and French trauma systems that might translate into measurable
      differences in trauma-related mortality. However, the lack of data to allow
      comparison of outcomes between countries significantly impedes the identification
      and implementation of components of a trauma system that are effective and the
      discarding of those that offer little benefit.

PMID- 15172781
TI  - Thalidomide.
AB  - Despite its history as a human teratogen, thalidomide is emerging as a treatment
      for cancer and inflammatory diseases. Although the evolution of its clinical
      application could not have been predicted from the tragedy associated with its
      misuse in the past, its history serves as a lesson in drug development that
      underscores the need to understand the molecular pharmacology of a compound's
      activity, including associated toxicities. Here, we summarise the applications
      for thalidomide with an emphasis on clinical trials published over the past 10
      years, and consider our knowledge of the molecular pharmacology of the drug in
      the context of clinical trial data, attempting to provide a mechanism-guided
      understanding of its activity.

PMID- 15172782
TI  - Big tobacco is watching: British American Tobacco's surveillance and information
      concealment at the Guildford depository.
AB  - The 1998 State of Minnesota legal settlement with the tobacco industry required
      British American Tobacco (BAT) to provide public access to the 8 million pages
      housed in its document depository located near Guildford, UK, and to any company
      documents sent to the Minnesota depository. While the Minnesota depository is
      managed by an independent third party, BAT's Guildford depository is run by the
      company itself. Starkly different from the Minnesota depository, at the Guildford
      depository it is extraordinarily more difficult to access, search, and obtain
      requested documents. BAT's approach to running the Guildford depository, in our
      view, amounts to concealing what is supposed to be public information. Newly
      produced BAT documents from subsequent litigation, dating from 1996 to 2001
      disclose the company's efforts to gather intelligence on visitors and their work.
      We believe that BAT has acted to make access to information more difficult by
      delaying document production requested by public visitors and refusing to supply
      requested documents in an electronic format despite, in the company's own words,
      the establishment of "big time imaging" capabilities at the Guildford depository.
      During testimony in 2000, then BAT Chairman, Martin Broughton stated to the UK
      House of Commons Health Select Committee that the scanning and subsequent
      placement of the Guildford collection online "would be an extreme effort for
      absolutely no purpose whatsoever", stating that "there is no indication to me
      that serious researchers are showing any interest in the papers em leader ". New
      documents show that not only did the company recognise the importance of research
      undertaken by visitors, but also invested substantial resources and undertook
      numerous scanning projects during that time. The vulnerability of this important
      resource is demonstrated by the decreased number of files listed on the
      electronic database and the inadvertent deletion of an audio tape housed at the
      depository. With regard to intelligence gathering, BAT's law firm reported to BAT
      on the daily activities of depository visitors. Despite assurances to the
      contrary, these depository visitor reports show that BAT apparently tracked the
      database searches of a visitor. The company also tracked the physical movement of
      visitors and, in at least one instance, observed and noted the personal mobile
      phone use of a visitor. These activities raise ethical issues about BAT and/or
      its solicitors observing the work of lawyers and researchers representing health
      and government bodies. Given this new evidence, we assert that BAT is incapable
      of operating its depository in the spirit of the Minnesota settlement and should,
      therefore, be divorced from its operation. Accordingly, we recommend that the
      company provide its entire document collection electronically to interested
      parties thus allowing greater access to the public-health community as has been
      done in the USA.

PMID- 15172783
TI  - Learning from Philip Morris: Japan Tobacco's strategies regarding evidence of
      tobacco health harms as revealed in internal documents from the American tobacco
      industry.
AB  - Japan is in the midst of a rapid increase in tobacco-related disease mortality,
      following the rapid growth of smoking after WWII. Stomach cancer was the
      country's leading cause of cancer death for most of the 20th century, until lung
      cancer took over this position in 1993. Cigarettes are the major cause of lung
      cancer in Japan, but the country's leading manufacturer, Japan Tobacco, two
      thirds of which is owned by the Japanese government, continues to question
      whether tobacco is a major cause of disease and death. Japanese courts do not
      have the power to subpoena a company's internal records, which has made it
      difficult to document Japan Tobacco's strategies concerning tobacco and health.
      Our interpretation of online archives of internal documents from American tobacco
      companies, however, is that Japan Tobacco has long known about the potential
      health risks involved in smoking and has sought to obstruct effective tobacco
      control. Beginning in the mid-1980s, these efforts were often co-ordinated with
      American tobacco manufacturers. The documentary evidence shows that cigarette
      manufacturer Philip Morris in particular assisted with and sometimes also
      supervised Japan Tobacco's actions and statements on smoking and health. In one
      instance, data gathered for an article published by the Japan Public Monopoly
      Corporation (Japan Tobacco's predecessor) were deliberately altered to lower the
      reported value of a hazard indicator (nicotine concentration in the air).
      International collaboration has made it easier for companies such as Japan
      Tobacco to develop effective anti-antismoking strategies. Evidence of such global
      industry collaborations might grow as lawsuits begin to be filed in other
      nations.

PMID- 15172784
TI  - Prevalence of non-pneumonic infections with SARS-correlated virus.

PMID- 15172785
TI  - Prevalence of non-pneumonic infections with SARS-correlated virus.

PMID- 15172786
TI  - Prevalence of non-pneumonic infections with SARS-correlated virus.

PMID- 15172787
TI  - Prevalence of non-pneumonic infections with SARS-correlated virus.

PMID- 15172789
TI  - New analyses of Heart Protection Study.

PMID- 15172791
TI  - Rosiglitazone for HIV-1 lipoatrophy.

PMID- 15172792
TI  - Fertility preservation in women undergoing cancer treatment.

PMID- 15172794
TI  - Bridging schools of public health between Iran and the USA.

PMID- 15172795
TI  - Fertility preservation in women undergoing cancer treatment.

PMID- 15172796
TI  - Global health equity.

PMID- 15172798
TI  - Smoking in the dissecting room.

PMID- 15172800
TI  - Using the EM algorithm to weight data sets of unknown precision when modelling
      fish stocks.
AB  - Stocks of commercial fish are often modelled using sampling data of various
      types, of unknown precision, and from various sources assumed independent. We
      want each set to contribute to estimates of the parameters in relation to its
      precision and goodness of fit with the model. Iterative re-weighting of the sets
      is proposed for linear models until the weight of each set is found to be
      proportional to (relative weighting) or equal to (absolute weighting) the set
      specific residual invariances resulting from a generalised least squares fit.
      Formulae for the residual variances are put forward involving fractional
      allocation of degrees of freedom depending on the numbers of independent
      observations in each set, the numbers of sets contributing to the estimate of
      each parameter, and the number of weights estimated. To illustrate the procedure,
      numbers of the 1984 year-class of North Sea cod (a) landed commercially each
      year, and (b) caught per unit of trawling time by an annual groundfish survey are
      modelled as a function of age to estimate total mortality, Z, relative catching
      power of the two fishing methods, and relative precision of the two sets of
      observations as indices of stock abundance. It was found that the survey
      abundance indices displayed residual variance about 29 times higher than that of
      the annual landings.

PMID- 15172801
TI  - Recovering the passive properties of tapered dendrites from single and dual
      potential recordings.
AB  - We demonstrate that measurement of the membrane potential at one or more sites on
      a branched and tapered neuron following a known transient injection of
      subthreshold somatic current uniquely determines the cell's passive electrical
      properties. That is, knowledge of the potentials allows recovery of the cell's
      axial resistance, membrane capacitance, membrane conductance and soma
      conductance. The argument underlying uniqueness leads immediately to a
      constructive, robust algorithm that we successfully test on synthetic data. The
      robustness stems from the fact that the algorithm requires only a few weighted
      integrals, or moments, of the measured potentials.

PMID- 15172802
TI  - A mathematical model for Chagas disease with infection-age-dependent infectivity.
AB  - In this paper we develop a mathematical model for Chagas disease with infection
      age-dependent infectivity. The effects of vector and blood transfusion
      transmission are considered, and the infected population is structured by the
      infection age (the time elapsed from infection). The authors identify the basic
      reproduction ratio R0 and show that the disease can invade into the susceptible
      population and unique endemic steady state exists if R0 > 1, whereas the disease
      dies out if R0 is small enough. We show that depending on parameters, backward
      bifurcation of endemic steady state can occur, so even if R0 < 1, there could
      exist endemic steady states. We also discuss local and global stability of steady
      states.

PMID- 15172803
TI  - SIS epidemics with household structure: the self-consistent field method.
AB  - We consider a stochastic SIS infection model for a population partitioned into m
      households assuming random mixing. We solve the model in the limit m --> infinity
      by using the self-consistent field method of statistical physics. We derive a
      number of explicit results, and give numerical illustrations. We then do
      numerical simulations of the model for finite m and without random mixing. We
      find in many of these cases that the self-consistent field method is a very good
      approximation.

PMID- 15172804
TI  - Synchronous cultures from the baby machine. A model for animal cells.
AB  - A baby-machine system that produces newborn Escherichia coli cells from cultures
      immobilised on a membrane was developed many years ago in an attempt to attain
      optimal synchrony with minimal disturbance of steady-state growth, and a model
      designed to characterise the nature and quality of the synchrony of such cells in
      a quantitative manner has been published. The baby machine has now been adapted
      for animal cells, and the present article is an attempt to modify the model to
      include these cells as well. The model consists of five elements, giving rise to
      five adjustable parameters (and a proportionality constant): a major, essentially
      synchronous group of cells with ages distributed normally about zero; a minor,
      random component from a steady-state population on the membrane that had
      undergone only very little age selection during the elution process; a fixed
      background count, to allow for the signals recorded by the electronic particle
      counter produced by debris and electronic noise; a time-shift, to account for
      differences between time of cell division and end of sample collection; and the
      coefficient of variation of the interdivision-time distribution, taken to be
      reciprocal-normal. It is this last feature, a reciprocal-normal rather than a
      Pearson type III interdivision-time distribution, that distinguishes this version
      of the model from its predecessor. The model is fitted by unconstrained non
      linear least-squares to data from three different leukemia cell lines. The
      standard errors of the parameters are quite small in all cases, making their
      estimates highly significant; the quality of the fit is striking. The five
      parameters of the model can be divided into two nuisance parameters, two that are
      associated with the methodology and one that describes an inherent property of
      the cell itself; it turns out that both methodology parameters are zero in all
      three data sets studied. We also discuss the partition of the transition-time
      dispersion between the age distribution of the newborn cells and the age
      distribution of dividing cells and show that a reliable estimate of the
      corresponding parameters requires an experiment that extends over at least two
      and a half doubling times.

PMID- 15172805
TI  - An epidemic model in a patchy environment.
AB  - An epidemic model is proposed to describe the dynamics of disease spread among
      patches due to population dispersal. We establish a threshold above which the
      disease is uniformly persistent and below which disease-free equilibrium is
      locally attractive, and globally attractive when both susceptible and infective
      individuals in each patch have the same dispersal rate. Two examples are given to
      illustrate that the population dispersal plays an important role for the disease
      spread. The first one shows that the population dispersal can intensify the
      disease spread if the reproduction number for one patch is large, and can reduce
      the disease spread if the reproduction numbers for all patches are suitable and
      the population dispersal rate is strong. The second example indicates that a
      population dispersal results in the spread of the disease in all patches, even
      though the disease can not spread in each isolated patch.

PMID- 15172806
TI  - Port surveys for introduced marine species--and the fate of the material
      collected.

PMID- 15172807
TI  - A review of pollutants in the sea-surface microlayer (SML): a unique habitat for
      marine organisms.
AB  - Boundary layers between different environmental compartments represent critical
      interfaces for biological, chemical and physical processes. The sea-surface
      microlayer (uppermost 1-1000 microm layer) forms the boundary layer interface
      between the atmosphere and ocean. Environmental processes are controlled by the
      SML, and it is known to play a key role in the global distribution of
      anthropogenic pollutants. Due to its unique chemical composition, the upper
      organic film of the SML represents both a sink and a source for a range of
      pollutants including chlorinated hydrocarbons, organotin compounds, petroleum
      hydrocarbons, polycyclic aromatic hydrocarbons (PAH) and heavy metals. These
      pollutants can be enriched in the SML by up to 500 times relative to
      concentrations occurring in the underlying bulk water column. The SML is also a
      unique ecosystem, serving as an important habitat for fish eggs and larvae.
      Concentration ranges and enrichment factors of pollutants in the SML in different
      areas of the world's oceans have been critically reviewed, together with
      available toxicity data for marine biota found within the SML. Overall, the SML
      is highly contaminated in many urban and industrialized areas of the world,
      resulting in severe ecotoxicological impacts. Such impacts may lead to drastic
      effects on the marine food web and to fishery recruitment in coastal waters.
      Studies of the toxicity of fish eggs and larvae exposed to the SML contaminants
      have shown that the SML in polluted areas leads to significantly higher rates of
      mortality and abnormality of fish embryos and larvae.

PMID- 15172808
TI  - Persistent organochlorine residues in sediments along the coast of mid-Black Sea
      region of Turkey.
AB  - The aim of this study is to determine aspects of water and surface sediment
      quality in the coastal zone of the mid-Black Sea, and of rivers discharging into
      it, by analyzing their organochlorine pesticides (OC) levels. Surface sediment
      samples and water samples were collected from 14 sites from the rivers
      Yesilirmak, Abdal, Mert, Kurtun, Engiz and Kizilirmak. In sediments, Aldrin
      ranged from 19.3 to 87.3 ng/g and p,p'-DDT ranged from 18.6 to 31.0 ng/g.

PMID- 15172809
TI  - Minor improvement for intertidal seaweeds and invertebrates after acid mine
      drainage diversion at Britannia Beach, Pacific Canada.
AB  - In December 2001, acid mine drainage (AMD) from an abandoned copper mine at
      Britannia Beach (British Columbia, Canada) was diverted to flow from Britannia
      Creek into an outfall at 30 m depth in Howe Sound. Britannia Beach was studied in
      early 2003 to determine whether AMD diversion resulted in improved conditions for
      intertidal organisms. Species number and abundance have increased at the
      intertidal zone since AMD diversion, although they were still lower than at an
      unpolluted control site nearby (Furry Creek). Survivorship and growth rates of
      transplanted Mytilus trossulus (mussel) have increased since AMD diversion,
      although they were still significantly lower than at the control site.
      Transplanted Fucus gardneri (seaweed) performed better than before the AMD
      diversion; at Britannia Beach the chlorophyll a concentration in tissues was not
      significantly different from that at the control site, although the concentration
      of chlorophyll c in tissues and the chlorophyll c to a ratio was lower than at
      the control site six weeks after transplantation. Britannia Beach is still
      subject to leaching of metals from surrounding soils, low levels of AMD coming
      down the creek, and AMD discharge from the deep outfall. Although there has been
      an improvement, the intertidal environment at Britannia Beach still seems unable
      to support normal growth and survival of organisms.

PMID- 15172810
TI  - Responses of mud snails from low and high imposex sites to sex pheromones.
AB  - Imposex, male secondary sexual characteristics in female snails, is a
      morphological indicator of sub-lethal exposure to organotin compounds. The
      relation between imposex and behavioral responses to sex pheromones was studied.
      Responses of snails to sex specific pheromones were determined in laboratory
      assays. Females and males from a low imposex site and females, imposex females
      and males from a high imposex site were tested. The snails from the low imposex
      site showed the expected strong behavioral dimorphism with females responding to
      male pheromone and males responding to female pheromone. In assays using snails
      from the high imposex site, female and imposex females showed no dimorphism in
      response to pheromones and males showed a relatively weak dimorphism. As there
      was no breeding or egg capsule deposition at the high imposex site, we conclude
      that even the morphologically normal snails were behaviorally and reproductively
      compromised.

PMID- 15172811
TI  - Distribution, enrichment and accumulation of heavy metals in coastal sediments of
      Alang-Sosiya ship scrapping yard, India.
AB  - Since its inception in 1982, the Alang-Sosiya yard has become the largest ship
      scrapping works in the world. Several hundreds of ships arrive every year. The
      degree of heavy metal contamination has been studied in bulk and fine sediments
      from the intertidal zone of this ship scrapping yard, two stations, one on either
      side at 5 km distance and one reference station 60 km distance near Mahuva,
      towards the south. The samples have been subjected to a total digestion technique
      and analysed for elements: Cd, Co, Cu, Cr, Fe, Mn, Ni, Pb, Zn and Al, and %TOC.
      The absolute metal concentrations reflected variations in BF and FF sediment
      samples with organic matter content. Enrichment factors (EF) and geoaccumulation
      indices (Igeo) have been calculated and the relative contamination levels are
      assessed at these sites. At Alang-Sosiya, the enrichment of heavy metals has been
      observed to be relatively high.

PMID- 15172812
TI  - Long-term marine litter monitoring in the remote Great Australian Bight, South
      Australia.
AB  - The Anxious Bay beach litter clearance is the longest running annual survey of
      ocean-based litter in Australia. It's remoteness from centres of human population
      and location (with respect to prevailing winds and currents) make it an ideal
      place for monitoring ocean or ship-based litter in Australia's southern oceans
      and particularly, the Great Australian Bight. Over the 1991-1999 period, a large
      but gradual decline in the amount of beach washed litter was recorded (with minor
      peaks recorded during the 1992 and 1994 surveys). Beach washed litter decreased
      by approximately 86%, from 344 kg recorded in 1991 (13.2 kg/km) to 49 kg in 1999
      (i.e. 1.9 kg/km), reaching a maximum of 390 kg in 1992 (or 15 kg/km of beach).
      However, a sharp increase in litter was recorded in 2000 (i.e. 252 kg or 9.7
      kg/km). This increase in litter yield in 2000 is probably due to stronger than
      average onshore surface flow (or Ekman Transport) in the western Eyre Peninsula
      and Bight region. Prior to the survey in 2000, the results appeared to indicate
      that ocean litter on Anxious Bay beach was beginning to level out at around 50-70
      kg/year (i.e. 2-3 kg/km). As the beach surveys involve the assumption that the
      beach is completely cleared of litter, this may represent a baseline level for
      ocean-based litter in the region. The yields and type of litter collected from
      the annual survey indicates that the majority of litter washed ashore originates
      from commercial fishing activities within the Great Australian Bight. Most of the
      fishing-related litter was directly sourced to the Southern Rock Lobster Fishery
      (i.e. bait buckets, baskets, pots), the Great Australian Bight Trawl Fishery
      (i.e. codends, trawl nets) and the Southern Shark Fishery (i.e. monofilament
      gillnets and longlines). Between 1994 and 1999, large reductions were observed in
      the amount of bait straps (77% reduction), lobster bait baskets/buckets (86%
      reduction), nets/ropes (62% reduction) and floats/buoys (83% reduction).
      Significantly, fishing-related litter in the Bight has reduced at a slower rate
      than domestic litter. While the level of glass and soft plastics on the beach
      have both reduced by almost 93% (i.e. 103-7 kg and 119-8 kg, respectively), the
      level of hard plastics, has diminished at a slower rate, with reductions of only
      75% (i.e. 122-30 kg). Some fisheries (i.e. rock lobster, Southern Shark Fishery)
      have shown marked reductions in fishing-related litter. This is probably due, to
      some extent, to significant reductions in fishing effort in the region, although
      this requires further investigation. The information from the Anxious Bay beach
      litter survey is crucial in monitoring trends in ocean litter in Australia's
      southern oceans and compliance with international litter regulations. While
      fishing-related litter remains the major source of ship-based or ocean litter in
      Australia's southern oceans, the continued reduction in ship-based litter since
      1991 supports increasing compliance to MARPOL (Annex V) by commercial fisheries
      and shipping in the Great Australian Bight. While Australia participates in
      marine debris monitoring programs in the Antarctic (under CCAMLR), there is
      currently no national program or management framework to assess, manage and
      monitor ocean-based litter along Australia's coasts, and monitor compliance with
      MARPOL. Apart from the commitments under CCAMLR for Antarctic (and sub-Antarctic)
      marine environments, there are no other regional programs, guidelines or
      monitoring protocols or to assess and manage ocean litter in the Southern Ocean.

PMID- 15172813
TI  - A survey to determine levels of chlorinated pesticides and PCBs in mussels and
      seawater from the Mid-Black Sea Coast of Turkey.
AB  - A mussel and seawater monitoring survey was conducted at six sampling points
      between Yalikoy (Ordu) and Sinop in 1999-2000 along the Mid-Black Sea Coast of
      Turkey in order to assess concentrations of organochlorine pesticides (OCs) and
      polychlorinated biphenyls (PCBs). Chlorinated pesticides and PCBs were measured
      in the mussel Mytilus Galloprovincialis and in seawater. In the mussel samples,
      the most common pollutants in terms of average concentration per g of wet weight
      (ww), were DDT (max. 1800 pg/gww, min. 240 pg/gww) and its metabolites DDD (max.
      5400 pg/gww, min. 240 pg/gww) and DDE (max. 2800 pg/gww, min. 70 pg/gww). Also,
      dieldrin, heptachlor and HCB were notable contaminants in the mussel samples.
      PCBs were determined in none of the biota or seawater samples. The concentrations
      of the OCs and PCBs in mussels were higher in coastal areas receiving river
      discharges and close to the largest city of the region, Samsun (especially in
      sampling points in the harbour area). The well-known long persistence of DDTs and
      other chlorinated compounds was confirmed by residues of these pollutants
      measured in mussels. On the other hand, even though the usage of such kind of
      persistent compounds in Turkey was banned, there may still be illegal usage and
      it is not certain whether the application of these compounds did end in the
      region.

PMID- 15172814
TI  - Spatial and temporal variability of hard-bottom macrofauna in a disturbed coastal
      lagoon (Sacca di Goro, Po River Delta, Northwestern Adriatic Sea).
AB  - The sessile and mobile macrobenthos on artificial hard bottoms was studied in 12
      stations of the Sacca di Goro lagoon, a brackish, highly stressed water basin in
      the delta of the river Po, open to the Northwestern Adriatic Sea. Three sampling
      surveys were carried out in June and September 2000 and June 2001 in order to
      make three types of temporal comparisons: (i) on a seasonal scale, before and
      after a summer dystrophic event; (ii) on an annual basis, before and after the
      works of excavation of a canal through the outer sand bank; (iii) on a
      multiannual scale, comparing the data with those of a survey carried out in 1988.
      The biocoenoses did not show large fluctuations after a moderately severe summer
      dystrophic crisis, while the digging of the canal caused clear changes in the
      macrobenthos community structure after one year. The long-term comparison showed
      a shift in the community patterns after a decade.

PMID- 15172815
TI  - Multiplex PCR allows simultaneous detection of pathogens in ships' ballast water.
AB  - There is enormous potential for global transfer of microorganisms, including
      pathogens, in ships' ballast water. We contend that a major advancement in the
      study of ballast-water microorganisms in particular, and of aquatic pathogens in
      general, will be expedited sample analysis, such as provided by the elegant
      technology of DNA microarrays. In order to use DNA microarrays, however, one must
      establish the appropriate conditions to bind target sequences in samples to
      multiple probes on the microarrays. We conducted proof-of-concept experiments to
      optimize simultaneous detection of multiple microorganisms using polymerase chain
      reaction (PCR) and Southern hybridization. We chose three target organisms, all
      potentially found in ballast water: a calicivirus, the bacterium Vibrio cholerae,
      and the photosynthetic protist Aureococcus anophagefferens. Here, we show
      simultaneous detection of multiple pathogens is possible, a result supporting the
      promising future use of microarrays for simultaneous detection of pathogens in
      ballast water.

PMID- 15172817
TI  - PSP-toxicification of the carnivorous gastropod Rapana venosa inhabiting the
      estuary of Nikoh River, Hiroshima Bay, Hiroshima Prefecture, Japan.
AB  - During surveillance on the toxicity of invertebrates such as bivalves inhabiting
      the coasts of Hiroshima Bay in 2001 and 2002, the carnivorous gastropod rapa
      whelk Rapana venosa collected in the estuary of Nikoh River, was found to contain
      toxins which showed paralytic actions in mice; the maximum toxicities (as
      paralytic shellfish poison, PSP) were 4.2 MU/g (May 2001) and 11.4 MU/g (April
      2002). Their total toxicities were 224 and 206 MU/viscera of one specimen
      throughout the monitoring period. Attempts were made to identify the toxic
      principle in the gastropod. The viscera were extracted with 80% ethanol acidified
      with acetic acid, followed by defatting with dichloromethane. The aqueous layer
      obtained was treated with activated charcoal and then applied to a Sep-Pak C18
      cartridge. The unbound toxic fraction was analyzed by high-performance liquid
      chromatography techniques. The gastropod toxin was rather unexpectedly identified
      as PSP. It was comprised of high toxic component (gonyautoxin-3; GTX3, GTX2,
      saxitoxin; STX) as the major components, which accounted for approximately 91
      mol% of all components along with C1 and C2, which are N-sulfocarbamoyl
      derivatives. Judging from their toxin patterns, it is suggested that the PSP
      toxification mechanism of the gastropod that PSP toxins produced by phytoplankton
      such as Alexandrium tamarense, are transferred to and accumulated in plankton
      feeders such as the short-necked clam, and then transferred to this carnivorous
      rapa whelk R. venosa through predation.

PMID- 15172816
TI  - Polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides in water
      columns from the Pearl River and the Macao harbor in the Pearl River Delta in
      South China.
AB  - Polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OCPs) were
      measured in suspended particles and dissolved phase from the Baiertang water
      column and the Macao water column samples as collected from the Guangzhou channel
      of the Pearl River and the Macao harbor, where the sediments were heavily
      contaminated with organic pollutants. Total OCPs concentration varies from 23.4
      to 61.7 ng/l in Baiertang water column and from 25.2 to 67.8 ng/l in Macao
      column, while total PAHs concentration varies from 987.1 to 2878.5 ng/l in the
      Baiertang water column and from 944.0 to 6654.6 ng/l in the Macao column. The
      vertical distribution profiles of pollutants and the partition of pollutants
      between particles and dissolved phases indicate that the sediments in Baiertang
      act as an important source of selected pollutants, and the pollutants in water of
      this region were mainly originated from the release and re-suspension of
      contaminants residing in the sediments. The sediments in Macao harbor act as a
      reservoir for organochlorine pesticides, such as DDTs mainly introduced by river
      inflow from Xijiang and PAHs input by brackish water from the Lingdingyang
      estuary. Combustion of fossil fuels and petroleum input are the main sources of
      PAHs in the Macao water column, while combustion of fossil fuels and coal is
      responsible for the PAHs in the Baiertang water column. The ratios of
      DDT/(DDD+DDE) for the Macao water column samples demonstrate that such chemicals
      were input into this region in recent times.

PMID- 15172818
TI  - Total and subcellular distribution of trace elements in the liver of a mother
      fetus pair of Dall's porpoises (Phocoenoides dalli).
AB  - Total and subcellular hepatic Zn, Cu, Se, Mn, V, Hg, Cd, and Ag were determined
      in a mother-fetus pair of Dall's porpoises (Phocoenoides dalli). Except for
      higher fetal Cu concentration, all maternal elements were higher. Elements
      existed mostly in the cytosol of both animals except in the case of maternal Ag
      in the microsome and fetal Cu and Ag in the nuclei and mitochondria. In the
      maternal cytosol, Zn, Mn, Hg, and Ag were present in the high-molecular-weight
      substances (HMW); Se and V were present in the low-molecular-weight substances
      (LMW); Cu and Cd were mostly sequestered by metallothionein (MT). In the fetal
      cytosol, Zn, Se, Mn, Hg, Cd, and Ag were present in the HMW and V in the LMW,
      while Cu and Ag were mostly associated with MT. MT isoforms were characterized
      using the HPLC/ICP-MS. Two and four obvious peaks appeared in the maternal and
      fetal MT fractions, respectively. The highest elemental ion intensities were at a
      retention time of 7.8 min for the mother, and for the fetus the peak elemental
      ion intensities occurred at a retention time of 4.3 min, suggesting that
      different MT isoforms may be involved in elemental accumulation in maternal and
      fetal hepatocytosols.

PMID- 15172819
TI  - Water quality and presence of pesticides in a tropical coastal wetland in
      southern Mexico.
AB  - The water quality of the Pozuelos-Murillo lagoon system in southern Mexico was
      evaluated during three periods between March and October 2002, with particular
      emphasis on the detection of organochlorine and organophosphorous pesticide
      residues in water and sediments. Physicochemical and microbiological parameters
      of water were also measured and integrated in a water quality index (WQI).
      Multivariate analysis was used to regionalise the lagoon system as a function of
      the behaviour of all measured parameters. Solid phase micro-extraction followed
      by gas chromatography (SPME-GC) was used for pesticide analysis. The
      concentration of phosphorous was found to be higher than that of nitrogenous
      compounds. This, besides a deficiency in dissolved oxygen and a high organic
      matter concentration (as COD), reflects eutrophication processes in some areas of
      the system. Measured levels of faecal coliforms and oils and greases were above
      the limits established by Mexican law and comparable to the concentrations
      reported for other highly polluted systems in Mexico. Residues of DDD (2.0 microg
      L(-1)) in water and DDE (247 ng g(-1)) and endosulfan I (814 ng g(-1)) sediments
      were detected by SPME-GC. The spatial distribution of these contaminants implies
      major potential risks because the most polluted sites were found to be those with
      the highest fishing activity. Although in general the WQI is on acceptable levels
      (65-80%), some contamination problems are evident.

PMID- 15172820
TI  - TBT contamination identified in Antarctic marine sediments.
AB  - We report for the first time butyltin contamination of near-shore sediments at
      six sites in the Ross Sea, Antarctica. A very high concentration of 2290 microg
      Sn kg(-1) sediment was recorded in one sample. The most likely source is abrasion
      of antifouling paint from the hulls of ice-breakers, but this pattern of
      contamination is also possible following ship groundings. Antifoulant biocides,
      such as TBT, have not been considered or detected in Antarctica previously and
      represent a new challenge to environmental managers and custodians.

PMID- 15172821
TI  - Interspecific variation in total arsenic body concentrations in elasmobranch fish
      from the Mediterranean Sea.

PMID- 15172822
TI  - Organotin contamination in the mussel Mytilus galloprovincialis from Portuguese
      coastal waters.

PMID- 15172823
TI  - Arsenic accumulation and distribution in tissues of black-footed albatrosses.

PMID- 15172824
TI  - Endocrine disrupting alkylphenols and bisphenol-A in coastal waters and
      supermarket seafood from Singapore.

PMID- 15172825
TI  - The 2004 Biophysical Society-Avanti Award in Lipids address: roles of bilayer
      structure and elastic properties in peptide localization in membranes.
AB  - This review details how bilayer structural/elastic properties impact three
      distinct areas of biological significance. First, the partitioning of melittin
      into bilayers and melittin-induced bilayer leakage depended strongly on bilayer
      composition. The incorporation of cholesterol into phosphatidylcholine bilayers
      decreased melittin-induced leakage from 73 to 3%, and bilayers composed of
      lipopolysaccharide (LPS), the main lipid on the surface of Gram-negative
      bacteria, also had low (3%) melittin-induced leakage. Second, transbilayer
      peptides of different hydrophobic lengths were largely excluded from bilayer
      microdomains ("rafts") enriched in sphingomyelin (SM) and cholesterol, even when
      the length of the transbilayer peptide domain matched the hydrocarbon thickness
      of the raft bilayer. This is likely due to the large area compressibility modulus
      of SM:cholesterol bilayers. Third, the major water barrier of skin, the
      extracellular lamellae of the stratum corneum, was found to contain tightly
      packed asymmetric lipid bilayers with cholesterol located preferentially on one
      side of the bilayer and a unique skin ceramide containing an unsaturated acyl
      chain on the opposite side. We argue that, in each of these three areas, key
      factors are differences in lipid hydrocarbon chain packing for different lipids,
      particularly the tight hydrocarbon chain packing caused by cholesterol's strong
      interaction with saturated chains.

PMID- 15172826
TI  - Phase separation of cholesterol from phosphatidylserine-cholesterol mixtures in
      the presence of the local anesthetic tetracaine.
AB  - Addition of the local anesthetic tetracaine (TTC) to multilamellar dispersions of
      natural phosphatidylserine (PS) causes changes in the thermotropic properties of
      the membrane, which can be detected by differential scanning calorimetry, and in
      the structure of the membrane as detected by X-ray diffraction. At molar ratio
      [PS]/ [TTC] approximately 8.5, the melting temperature of the phospholipid shifts
      downwards by approximately 2.5 degrees C. The melting endotherm is broadened;
      however, there is little change in the enthalpy of melting. In ternary mixtures
      (PS-TTC-cholesterol), the thermotropic changes are enhanced. At [PS]/ [TTC]
      approximately 13, the onset of phase separation of cholesterol crystals from PS
      in the liquid crystalline state occurs at molar fraction cholesterol (Xchol)
      approximately 0.28, marginally smaller than that found in the absence of the
      anesthetic.

PMID- 15172827
TI  - Polyisoprenoid alcohols from the mushroom Lentinus edodes.
AB  - Lipids extracted from the shiitake mushroom Lentinus edodes contain dolichols
      composed of 15 up to 19 isoprene units with Dol-17 as the dominating prenologue.
      Identification of dolichols was achieved by the application of 2D-TLC, HPLC and
      electrospray ionization mass spectrometry. Additionally a family of polyprenols
      (alpha-unsaturated counterparts) with the same chain-length was also detected.
      Dolichols comprised approximately 0.002% of the fresh weight of the mushroom.
      Dolichols accompanied by traces of polyprenols are for the first time found in
      the mushroom tissue.

PMID- 15172828
TI  - Synthesis of (5Z,8Z,11Z,14Z)-18- and 19-azidoeicosa-5,8,11,14-tetraenoic acids
      and their [5,6,8,9,11,12,14,15-3H8]-analogues through a common synthetic route.
AB  - Total synthesis of (5Z,8Z,11Z,14Z)-18- and 19-azidoeicosa-5,8,11,14-tetraenoic
      acids and their [5,6,8,9,11,12,14,15-3H8]-analogues via the corresponding p
      toluenesulphonates is reported. This synthetic approach allows the preparation of
      radioactively labelled arachidonic acid derivatives following a common synthetic
      route. Activity assays indicated that 15-lipoxygenases may tolerate the azido
      group in the substrate binding pocket and thus, radioactively labelled azido
      compounds may be used as photo-affinity probes to investigate mechanistic
      features of eicosanoid biosynthesis.

PMID- 15172829
TI  - Cholesterol modulation of sphingomyelinase activity at physiological
      temperatures.
AB  - Bacillus cereus sphingomyelinase activity was assayed on large unilamellar
      vesicles composed of sphingomyelin (SM)/cholesterol (Ch) mixtures at varying
      proportions. Natural (egg) SM was used with a gel-fluid transition temperature at
      ca. 40 degrees C. When the enzyme was assayed at 37 degrees C, the activity on
      pure SM was exceedingly low, but a small increase was observed as soon as some Ch
      was added, and a large enhancement of activity occurred with Ch proportions above
      25 mol%. The data were interpreted in terms of sphingomyelinase activity being
      higher in the cholesterol-induced liquid-ordered phase than in the gel phase. The
      abrupt increase in activity above 25 mol% Ch would occur as a result of a change
      in domain connectivity, when the Ch-rich liquid-ordered domains coalesced. In
      equimolar SM/Ch mixtures, that were in the liquid-ordered state in a wide range
      of temperatures, sphingomyelinase activity was virtually constant in the 30-70
      degrees C range. The results demonstrate that at the mammalian and bird
      physiological temperatures Ch modulates sphingomyelinase activity, and that this
      can occur precisely because most SM have a gel-fluid transition temperature above
      the physiological temperature range. In addition, Ch activation of
      sphingomyelinase and the strong affinity of Ch for SM allow the rapid, localised
      and self-contained production of the metabolic signal ceramide in specific
      microdomains (rafts).

PMID- 15172830
TI  - Short-lived fluorescence component of DPH reports on lipid--water interface of
      biological membranes.
AB  - Fluorescence measurements of 1,6-diphenyl-1,3,5-hexatriene (DPH) in large
      unilamellar phospholipid vesicles were performed to characterize the influence of
      the membrane physical properties on the short-lived lifetime component of the
      fluorescence decay. We have found that the short-lived component of DPH
      significantly shortens when the membrane undergoes a temperature-induced phase
      transition as it is known for the long-lived component of DPH. We induced
      membrane phase transitions also by alcohols, which are reported to be distributed
      different way in the membrane--ethanol close to the membrane-water interface and
      benzyl alcohol in the membrane core. A different effect of the respective alcohol
      on the short and long decay component was observed. Both the time-resolved
      fluorescence spectra of DPH taken during lipid vesicle staining and the lifetime
      dependences caused by changes of temperature and/or induced by the alcohols show
      that the short-lived fluorescence originates from the population of dye molecules
      distributed at the membrane-water interface.

PMID- 15172831
TI  - Synthesis of long chain n-3 and n-6 fatty acids having a photoactive conjugated
      tetraene group.
AB  - Fatty acids of the n-3 and n-6 families containing a photoactive conjugated
      tetraene group near the carboxylate were prepared from several naturally
      occurring fatty acids by sequential iodolactonization and treatment with excess
      1,8-diazabicyclo[5.4.0]undec-7-ene. The new conjugated fatty acids include
      5E,7E,9E,11Z,14Z- and 5E,7E,9E,11E,14Z-eicosapentaenoic acids derived from
      arachidonic acid; 5E,7E,9E,11Z,14Z,17Z- and 5E,7E,9E,11E,14Z,17Z-eicosahexaenoic
      acids from eicosapentaenoic acid; and 4E,6E,8E,10Z,13Z,16Z,19Z- and
      4E,6E,8E,10E,13Z,16Z,19Z-docosaheptaenoic acids from docosahexaenoic acid. All of
      the newly synthesized fatty acids were characterized by UV, 1H NMR and mass
      spectroscopy. These new products represent the first examples of directed
      conjugation of methylene interrupted double bond systems. The products can be
      synthesized in gram quantities and in high yields (>50%). Interestingly, it did
      not prove possible to synthesize fatty acids having a triene group near the
      carboxyl group even using mild conditions and different synthetic approaches.
      Once initiated, the isomerization always continued until a tetraene group was
      formed. Because of the sensitivity of the tetraene group to light, these fatty
      acids have the potential for being used in tracking fatty acid movements in cells
      employing fluorescence techniques and in UV light-induced cross linking to
      membrane proteins.

PMID- 15172832
TI  - X-ray diffraction analysis of internal wool lipids.
AB  - Polarised optical microscopy (POM) and X-ray diffraction techniques were applied
      to intercellular lipids extracted from wool to study their structural arrangement
      in order to determine their role in the diffusion properties of wool fibre.
      Intercellular wool lipids (IWL) arranged as concentrated liposomes were shown to
      be a good intercellular lipid model, allowing their study by X-ray diffraction
      techniques. The results confirm that intercellular lipids of wool fibre are
      organised in a lamellar structure of 5.0-8.0 nm width, termed beta-layer, which
      had been assumed to be lipids arranged as a bilayer. Structurally, internal wool
      lipids are distributed at least in two domains at low temperatures: an ordered
      phase made up of ceramides and free fatty acids (FFA) alone, arranged in crystal
      orthorhombic states separately, and a liquid crystal state when mixed together.
      At 40 degrees C there is a reversible phase transition produced by the melt of
      the crystal orthorhombic states, whereas the liquid crystal state remains until
      65 degrees C.

PMID- 15172833
TI  - Reorganizational dynamics of multilamellar lipid bilayer assemblies using
      continuously scanning Fourier transform infrared spectroscopic imaging.
AB  - We employ an implementation of rapid-scan Fourier transform infrared (FT-IR)
      microspectroscopic imaging to acquire time-resolved images for assessing the non
      repetitive reorganizational dynamics of aqueous dispersions of multilamellar
      lipid vesicles (MLVs) derived from distearoylphosphatidylcholine (DSPC). The
      spatially and temporally resolved images allow direct and simultaneous
      determinations of various physical and chemical properties of the MLVs, including
      the main thermal gel to liquid crystalline phase transition, comparisons of
      vesicle diffusion rates in both phases and the variation in lipid bilayer packing
      properties between the inner and outer lamellae defining the vesicle.
      Specifically, in the lipid liquid crystalline phase, the inner bilayers of the
      MLVs are more intermolecularly ordered than the outer regions, while the
      intramolecular acyl chain order/disorder parameters, reflecting the overall
      characteristics of the fluid phase, remain uniform across the vesicle diameter.
      In contrast, the lipid vesicle gel phase displays no intermolecular or
      intramolecular dependence as a function of distance from the MLV center.

PMID- 15172834
TI  - Effect of the glycosphingolipid, GM1 on localization of dibucaine in phospholipid
      vesicles: a fluorescence study.
AB  - Interaction of the local anesthetic dibucaine with small unilamellar vesicles of
      dimyristoylphosphatidylcholine (DMPC) and dioleoylphosphatidylcholine (DOPC)
      containing different mole percents of monosialoganglioside (GM1) has been studied
      by fluorescence spectroscopy. Fluorescence measurements on dibucaine in the
      presence of phospholipid vesicles containing various amounts of GM1 yielded a
      pattern of variation of wavelength at emission maximum and steady-state
      anisotropy which indicated that the microenvironment of dibucaine is more
      hydrophobic and rigid in membranes that contain GM1 than in membranes without it.
      Experiments on quenching of fluorescence from membrane-associated dibucaine by
      potassium iodide showed reduced quenching efficiency with the increase in GM1
      content of the vesicles, demonstrating lesser accessibility of the iodide
      quenchers to dibucaine in the presence of GM1, when compared to that in its
      absence. Total emission intensity decay profiles of dibucaine yielded two
      lifetime components of approximately 1 and approximately 2.8-3.1 ns with mean
      relative contributions of approximately 25 and approximately 75%, respectively.
      The mean lifetime in vesicles was 20-30% lower than in the aqueous medium and
      showed a definite increase in presence of GM1 from that in the absence of it. All
      the spectral properties point that dibucaine encountered regions of membrane
      containing significant amount of GM1 and penetrated deeper in hydrophobic core of
      the bilayer.

PMID- 15172835
TI  - Radical-scavenging activity of butylated hydroxytoluene (BHT) and its
      metabolites.
AB  - To clarify the radical-scavenging activity of butylated hydroxytoluene (BHT), a
      food additive, stoichiometric factors (n) and inhibition rate constants (kinh)
      were determined for 2,6-di-tert-butyl-4-methylphenol (BHT) and its metabolites
      2,6-di-tert-butyl-p-benzoquinone (BHT-Q), 3,5-di-tert-butyl-4-hydroxybenzaldehyde
      (BHA-CHO) and 3,5-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadiene-1-one
      (BHT-OOH). Values of n and kinh were determined from differential scanning
      calorimetry (DSC) monitoring of the polymerization of methyl methacrylate (MMA)
      initiated by 2,2'-azobis(isobutyronitrile) (AIBN) or benzoyl peroxide (BPO) at 70
      degrees C in the presence or absence of antioxidants (BHT-related compounds). The
      n values declined in the order BHT (1-2) > BHT-CHO, BHT-OOH (0.1-0.3) > BHT-Q (
      approximately 0). The n value for BHT with AIBN was approximately 1.0, suggesting
      dimerization of BHT. The kinh values declined in the order BHT-Q ((3.5-4.6) x
      10(4) M(-1)s(-1)) > BHT-OOH (0.7-1.9 x 10(4) M(-1)s(-1)) > BHT-CHO ((0.4-1.7 x
      10(4) M(-1)s(-1)) > BHT ((0.1-0.2 x 10(4) M(-1)s(-1)). The kinh for metabolites
      was greater than that for the parent BHT. Growing MMA radicals initiated by BPO
      were suppressed much more efficiently by BHT or BHT-Q compared with those
      initiated by AIBN. BHT was effective as a chain-breaking antioxidant.

PMID- 15172837
TI  - Stomatal control and hydraulic conductance, with special reference to tall trees.
AB  - A better understanding of the mechanistic basis of stomatal control is necessary
      to understand why modes of stomatal response differ among individual trees, and
      to improve the theoretical foundation for predictive models and manipulative
      experiments. Current understanding of the mechanistic basis of stomatal control
      is reviewed here and discussed in relation to the plant hydraulic system.
      Analysis focused on: (1) the relative role of hydraulic conductance in the
      vicinity of the stomatal apparatus versus whole-plant hydraulic conductance; (2)
      the influence of guard cell inflation characteristics and the mechanical
      interaction between guard cells and epidermal cells; and (3) the system
      requirements for moderate versus dramatic reductions in stomatal conductance with
      increasing evaporation potential. Special consideration was given to the
      potential effect of changes in hydraulic properties as trees grow taller.
      Stomatal control of leaf gas exchange is coupled to the entire plant hydraulic
      system and the basis of this coupling is the interdependence of guard cell water
      potential and transpiration rate. This hydraulic feedback loop is always present,
      but its dynamic properties may be altered by growth or cavitation-induced changes
      in hydraulic conductance, and may vary with genetically related differences in
      hydraulic conductances. Mechanistic models should include this feedback loop.
      Plants vary in their ability to control transpiration rate sufficiently to
      maintain constant leaf water potential. Limited control may be achieved through
      the hydraulic feedback loop alone, but for tighter control, an additional element
      linking transpiration rate to guard cell osmotic pressure may be needed.

PMID- 15172836
TI  - The critical micelle concentrations of lysophosphatidic acid and
      sphingosylphosphorylcholine.
AB  - The critical micelle concentrations (CMC) of lysophosphatidic acid (LPA) and
      sphingosylphosphorylcholine (SPC) were measured by isothermal titration
      calorimetry. The CMC of LPA decreases with salt concentration and acyl chain
      length. In water at 25 degrees C, the CMC values of 1-acyl-2-lyso-sn-glycero-3
      phosphatidic acid are 1.850, 0.540, 0.082, and 0.346 mM, respectively, when the
      acyl group is myristoyl, palmitoyl, stearoyl, and oleoyl. The CMC of SPC in 10 mM
      sodium phosphate buffer, pH 7.4, at 25 degrees C was 0.158 mM, and did not change
      with an increase in salt concentration.

PMID- 15172838
TI  - Time series diagnosis of tree hydraulic characteristics.
AB  - An in vivo method for diagnosing hydraulic characteristics of branches and whole
      trees is described. The method imposes short-lived perturbations of transpiration
      and traces the propagation of the hydraulic response through trees. The water
      uptake response contains the integrated signature of hydraulic resistance and
      capacitance within trees. The method produces large signal to noise ratios for
      analysis, but does not cause damage or destruction to tree stems or branches.
      Based on results with two conifer tree species, we show that the method allows
      for the simple parameterization of bulk hydraulic resistance and capacitance of
      trees. Bulk tree parameterization of resistance and capacitance predicted the
      overall diel shape of water uptake, but did not predict the overshoot water
      uptake response in trees to shorter-term variations in transpiration, created by
      step changes in transpiration rate. Stomatal dynamics likely complicated the use
      of simple resistance-capacitance models of tree water transport on these short
      time scales. The results provide insight into dominant hydraulic and
      physiological factors controlling tree water flux on varying time scales, and
      allow for the practical assessment of necessary tree hydraulic model complexity
      in relation to the time step of soil- vegetation-atmosphere transport models.

PMID- 15172839
TI  - Functional convergence in hydraulic architecture and water relations of tropical
      savanna trees: from leaf to whole plant.
AB  - Functional convergence in hydraulic architecture and water relations, and
      potential trade-offs in resource allocation were investigated in six dominant
      neotropical savanna tree species from central Brazil during the peak of the dry
      season. Common relationships between wood density and several aspects of plant
      water relations and hydraulic architecture were observed. All species and
      individuals shared the same negative exponential relationship between sapwood
      saturated water content and wood density. Wood density was a good predictor of
      minimum (midday) leaf water potential and total daily transpiration, both of
      which decreased linearly with increasing wood density for all individuals and
      species. With respect to hydraulic architecture, specific and leaf-specific
      hydraulic conductivity decreased and the leaf:sapwood area ratio increased more
      than 5-fold as wood density increased from 0.37 to 0.71 g cm(-3) for all
      individuals and species. Wood density was also a good predictor of the temporal
      dynamics of water flow in stems, with the time of onset of sap flow in the
      morning and the maximum sap flow tending to occur progressively earlier in the
      day as wood density increased. Leaf properties associated with wood density
      included stomatal conductance, specific leaf area, and osmotic potential at the
      turgor loss point, which decreased linearly with increasing wood density. Wood
      density increased linearly with decreasing bulk soil water potential experienced
      by individual plants during the dry season, suggesting that wood density was
      greatest in individuals with mostly shallow roots, and therefore limited access
      to more abundant soil water at greater depths. Despite their taxonomic diversity
      and large intrapopulation differences in architectural traits, the six co
      occurring species and their individuals shared similar functional relationships
      between all pairs of variables studied. Thus, rather than differing intrinsically
      in physiological responsiveness, the species and the individuals appeared to have
      distinct operating ranges along common physiological response curves dictated by
      plant architectural and structural features. The patterns of water uptake and
      access to soil water during the dry season appeared to be the main determinant of
      wood density, which constrained evolutionary options related to plant water
      economy and hydraulic architecture, leading to functional convergence in the
      neotropical savanna trees studied.

PMID- 15172840
TI  - Dynamics of transpiration, sap flow and use of stored water in tropical forest
      canopy trees.
AB  - In large trees, the daily onset of transpiration causes water to be withdrawn
      from internal storage compartments, resulting in lags between changes in
      transpiration and sap flow at the base of the tree. We measured time courses of
      sap flow, hydraulic resistance, plant water potential and stomatal resistance in
      co-occurring tropical forest canopy trees with trunk diameters ranging from 0.34
      0.98 m, to determine how total daily water use and daily reliance on stored water
      scaled with size. We also examined the effects of scale and tree hydraulic
      properties on apparent time constants for changes in transpiration and water flow
      in response to fluctuating environmental variables. Time constants for water
      movement were estimated from whole-tree hydraulic resistance (R) and capacitance
      (C) using an electric circuit analogy, and from rates of change in water movement
      through intact trees. Total daily water use and reliance on stored water were
      strongly correlated with trunk diameter, independent of species. Although total
      daily withdrawal of water from internal storage increased with tree size, its
      relative contribution to the daily water budget (approximately 10%) remained
      constant. Net withdrawal of water from storage ceased when upper branch water
      potential corresponded to the sapwood water potential (Psi(sw)) at which further
      withdrawal of water from sapwood would have caused Psi(sw) to decline
      precipitously. Stomatal coordination of vapor and liquid phase resistances played
      a key role in limiting stored water use to a nearly constant fraction of total
      daily water use. Time constants for changes in transpiration, estimated as the
      product of whole- tree R and C, were similar among individuals (~0.53 h),
      indicating that R and C co-varied with tree size in an inverse manner. Similarly,
      time constants estimated from rates of change in crown and basal sap flux were
      nearly identical among individuals and therefore independent of tree size and
      species.

PMID- 15172841
TI  - A potential role for xylem-phloem interactions in the hydraulic architecture of
      trees: effects of phloem girdling on xylem hydraulic conductance.
AB  - We investigated phloem-xylem interactions in Acer rubrum L. and Acer saccharum
      Marsh. Our experimental method allowed us to determine xylem conductance of an
      intact branch by measuring the flow rate of water supplied at two delivery
      pressures to the cut end of a small side branch. We found that removal of bark
      tissue (phloem girdling) upstream of the point at which deionized water was
      delivered to the branch resulted in a decrease (24% for A. rubrum and 15% for A.
      saccharum) in branch xylem hydraulic conductance. Declines in hydraulic
      conductance with girdling were accompanied by a decrease in the osmotic
      concentration of xylem sap. The decrease in xylem sap concentration following
      phloem girdling suggests that ion redistribution from the phloem was responsible
      for the observed decline in hydraulic conductance. When the same measurements
      were made on branches perfused with KCl solution (approximately 140 mOsm kg(-1)),
      phloem girdling had no effect on xylem hydraulic conductance. These results
      suggest a functional link between phloem and xylem hydraulic systems that is
      mediated by changes in the ionic content of the cell sap.

PMID- 15172842
TI  - Converging patterns of uptake and hydraulic redistribution of soil water in
      contrasting woody vegetation types.
AB  - We used concurrent measurements of soil water content and soil water potential
      (Psi(soil)) to assess the effects of Psi(soil) on uptake and hydraulic
      redistribution (HR) of soil water by roots during seasonal drought cycles at six
      sites characterized by differences in the types and amounts of woody vegetation
      and in climate. The six sites included a semi-arid old-growth ponderosa pine
      (Pinus ponderosa Dougl. ex P. Laws & C. Laws) forest, a moist old-growth Douglas
      fir (Pseudotsuga menziesii (Mirb.) Franco) forest, a 24-year-old Douglas-fir
      forest and three Brazilian savanna sites differing in tree density. At all of the
      sites, HR was confined largely to the upper 60 cm of soil. There was a common
      threshold relationship between the relative magnitude of HR and Psi(soil) among
      the six study sites. Below a threshold Psi(soil) of about -0.4 MPa, overnight
      recharge of soil water storage increased sharply, and reached a maximum value of
      80-90% over a range of Psi(soil) from ~ -1.2 to -1.5 MPa. Although amounts of
      water hydraulically redistributed to the upper 60 cm of soil were relatively
      small (0 to 0.4 mm day(-1)), they greatly reduced the rates of seasonal decline
      in Psi(soil). The effectiveness of HR in delaying soil drying diminished with
      increasing sapwood area per ground area. The relationship between soil water
      utilization and Psi(soil) in the 20-60-cm layer was nearly identical for all six
      sites. Soil water utilization varied with a surrogate measure of rhizosphere
      conductance in a similar manner at all six sites. The similarities in
      relationships between Psi(soil) and HR, soil water utilization and relative
      rhizosphere conductance among the six sites, suggests that, despite probable
      differences in maximum rooting depth and density, there was a convergence in
      biophysical controls on soil water utilization and redistribution in the upper
      soil layers where the density of finer roots is greatest.

PMID- 15172843
TI  - Elective cesarean delivery.

PMID- 15172844
TI  - Intrapartum elective cesarean delivery: a previously unrecognized clinical
      entity.
AB  - OBJECTIVE: The purpose of the study was to investigate the incidence of
      intrapartum patient choice cesarean delivery-patients' requesting cesarean
      delivery and physicians' offering it during labor-and factors possibly
      influencing these requests and offers. METHODS: For a 6-month period from May 1,
      2002, to October 31, 2002, obstetricians were asked to complete a questionnaire
      after all intrapartum cesarean deliveries regarding whether cesarean delivery was
      offered by the obstetrician or requested by the patient before being medically
      indicated. Patient medical records and physician demographic information were
      reviewed. RESULTS: There were 422 cases that met inclusion criteria.
      Questionnaires were completed in 100% of cases. Cesarean delivery was offered in
      13% before a clear medical indication and requested in 8.8%. Older obstetricians,
      maternal-fetal medicine specialists, and full-time faculty were significantly
      more likely to offer cesarean delivery (P =.009, P <.001, and P =.015,
      respectively). Patients who were unmarried or undergoing labor induction were
      less likely to request cesarean delivery (P =.029 and P =.035, respectively).
      Maternal age, parity, stage or length of labor, epidural use, gestational age,
      insurance status, day of week, and time of delivery did not affect whether
      patients requested or were offered cesarean delivery. CONCLUSION: This study
      documents a heretofore unrecognized clinical entity: intrapartum elective
      cesarean delivery. Physician characteristics, as opposed to patient
      characteristics or intrapartum factors, are a major determinant of whether
      laboring patients are being offered cesarean delivery. LEVEL OF EVIDENCE: III

PMID- 15172845
TI  - Outcomes with assisted reproductive technology: shooting first, asking questions
      later.

PMID- 15172847
TI  - Are children born after assisted reproductive technology at increased risk for
      adverse health outcomes?
AB  - As assisted reproductive technologies (ARTs) are increasingly used to overcome
      infertility, there is concern about the health of the children conceived. The
      empirical evidence for associations with outcomes related to child health is
      variable and should be evaluated with consideration of methodological
      shortcomings. Currently, there is convincing evidence that ART treatment may
      increase the risk of a few outcomes. Experimental laboratory studies document
      that various constituents in culture media affect various embryo characteristics
      both positively and negatively. Multiple-gestation pregnancy and birth are
      increased with ART, both because of multiple embryo transfer and embryo
      splitting. There is evidence of an increase in chromosomal abnormalities among
      pregnancies conceived using intracytoplasmic sperm injection and low birth weight
      and preterm delivery among singletons conceived with all types of ART; however,
      there remains uncertainty about whether these risks stem from the treatment or
      the parental infertility. For some outcomes, data of an increased risk with ART
      are suggestive at best largely because of lack of purposeful study of sufficient
      size and scope. These include specific perinatal morbidities, birth defects,
      developmental disabilities, and retinoblastoma. The evidence for an association
      between ART and spontaneous abortion is inconsistent and weak. There is
      inconclusive evidence that ART may be associated with genetic imprinting
      disorders. For childhood cancer, chronic conditions, learning and behavioral
      disorders, and reproductive effects there is insufficient empirical research to
      date, but given the data for more proximal outcomes, these outcomes merit further
      study. Future research needs to address the unique methodological challenges
      underlying study in this area.

PMID- 15172846
TI  - Perinatal outcome among singleton infants conceived through assisted reproductive
      technology in the United States.
AB  - OBJECTIVE: To examine perinatal outcome among singleton infants conceived with
      assisted reproductive technology (ART) in the United States. METHODS: Subjects
      were 62,551 infants born after ART treatments performed in 1996-2000. Secular
      trends in low birth weight (LBW), very low birth weight (VLBW), preterm delivery,
      preterm LBW, and term LBW were examined. Detailed analyses were performed for
      6,377 infants conceived in 2000. Observed numbers were compared with expected
      using a reference population from the 2000 U.S. natality file. Adjusted risk
      ratios were calculated. RESULTS: The proportion of ART singletons born LBW, VLBW,
      and term LBW decreased from 1996 to 2000. The proportion delivered preterm and
      preterm LBW remained stable. After adjustment for maternal age, parity, and
      race/ethnicity, singleton infants born after ART in 2000 had elevated risks for
      all outcomes in comparison with the general population of U.S. singletons: LBW
      standardized risk ratio 1.62 (95% confidence interval 1.49, 1.75), VLBW 1.79
      (1.45, 2.12), preterm delivery 1.41 (1.32, 1.51), preterm LBW 1.74 (1.57, 1.90),
      and term LBW 1.39 (1.19, 1.59). Risk ratios for each outcome remained elevated
      after restriction to pregnancies with only 1 fetal heart or any of 7 other
      categories: parental infertility diagnosis of male factor, infertility diagnosis
      of tubal factor, conception using in vitro fertilization without intracytoplasmic
      sperm injection or assisted hatching, conception with intracytoplasmic sperm
      injection, conception in a treatment with extra embryos available, embryo culture
      for 3 days, and embryo culture for 5 days. CONCLUSION: Singletons born after ART
      remain at increased risk for adverse perinatal outcomes; however, risk for term
      LBW declined from 1996 to 2000, whereas preterm LBW was stable. LEVEL OF
      EVIDENCE: III

PMID- 15172848
TI  - Late first-trimester invasive prenatal diagnosis: results of an international
      randomized trial.
AB  - OBJECTIVE: To assess, in a randomized trial, the safety and accuracy of
      amniocentesis and transabdominal chorionic villus sampling (CVS) performed at 11
      14 weeks of gestation, given that this time frame is increasingly relevant to
      early trisomy screening. METHODS: We compared amniocentesis with CVS from 77 to
      104 days of gestation in a randomized trial in a predominantly advanced maternal
      age population. Before randomization, the feasibility of both procedures was
      confirmed by ultrasonography, and experienced operators performed sampling under
      ultrasound guidance; conventional cytogenetic analysis was employed. The primary
      outcome measure was a composite of fetal loss plus preterm delivery before 28
      weeks of gestation in cytogenetically normal pregnancies. RESULTS: We randomized
      3,775 women into 2 groups (1,914 to CVS; 1,861 to amniocentesis), which were
      comparable at baseline. More than 99.6% had the assigned procedure, and 99.9%
      were followed through delivery. In contrast to previous thinking, in the
      cytogenetically normal cohort (n = 3,698), no difference in primary study outcome
      was observed: 2.1% (95% confidence interval 1.5, 2.8) for CVS and 2.3% (95%
      confidence interval, 1.7, 3.1) for amniocentesis. However, spontaneous losses
      before 20 weeks and procedure-related, indicated terminations combined were
      increased in the amniocentesis group (P =.07, relative risk 1.74). We found a 4
      fold increase in the rate of talipes equinovarus after amniocentesis (P =.02)
      overall and in week 13 (P =.03, relative risk = 4.65), but data were insufficient
      to determine this risk in week 14. CONCLUSION: Amniocentesis at 13 weeks carries
      a significantly increased risk of talipes equinovarus compared with CVS and also
      suggests an increase in early, unintended pregnancy loss. LEVEL OF EVIDENCE: I

PMID- 15172849
TI  - Doppler for artery-artery anastomosis and stage-independent survival in twin-twin
      transfusion.
AB  - OBJECTIVE: Treatment selection in twin-twin transfusion syndrome is increasingly
      determined by disease severity. We investigated whether detection of arterio
      arterial anastomoses predicts perinatal survival. METHODS: An artery-artery
      anastomosis was sought by Doppler and disease stage was determined in 105 cases
      of twin-twin transfusion syndrome at presentation, first treatment, and worst
      stage. Outcome measures were perinatal, double, and any (1 or more babies)
      survival rates. RESULTS: After exclusion of 10 noninformative pregnancies,
      perinatal, double, and any survival rates were 61%, 44%, and 77%, respectively.
      When an anastomosis was detected at each of the 3 time points, perinatal and
      double survival rates were higher than when one was not (at first treatment,
      perinatal survival 83% versus 53%, respectively, P =.003; double survival 78%
      versus 33%, P <.001). Perinatal and double survival (P < or =.01) were poorer
      with more advanced stage, but any survival rates were not influenced by stage or
      anastomosis detection. Multiple logistic regression demonstrated that anastomosis
      detection at treatment increased the chance of perinatal (odds ratio [OR] 5.1,
      95% confidence interval [CI] 1.6, 15.9) and double survival (OR 19.3, 95% CI 2.7,
      138), independently of stage. For stages I-III at treatment, anastomosis
      detection predicted better perinatal (100% versus 63%, 100% versus 59%, and 83%
      versus 44%, respectively) and double survival rates (100% versus 52%, 100% versus
      46%, and 78% versus 26%). Stage III, with anastomoses detected, had better
      perinatal (83% versus 63%) and double survival (78% versus 52%) than did stage I
      without detection. CONCLUSION: Antenatal detection of artery-to-artery
      anastomosis predicts higher perinatal and double survival in twin-twin
      transfusion syndrome, independently of disease stage. LEVEL OF EVIDENCE: II-3

PMID- 15172850
TI  - Risk of birth defects associated with nelfinavir exposure during pregnancy.
AB  - OBJECTIVE: The objective of this study was to examine the human teratogenic risk
      of the protease inhibitor, nelfinavir mesylate, used to treat human
      immunodeficiency virus. METHODS: This study used a subset of data from the
      Antiretroviral Pregnancy Registry, which was designed to monitor prenatal
      exposures to antiretroviral therapy and detect a potential increase in the risk
      of birth defects. The registry uses a prospective exposure-registration cohort
      design. All records of pregnant women exposed to nelfinavir, used alone or in
      combination, were extracted and analyzed. The prevalence of birth defects was
      compared with the Centers for Disease Control and Prevention's (CDC) population
      based surveillance system. RESULTS: Through July 2002, the registry had monitored
      915 live births exposed to nelfinavir. Among 301 first-trimester exposures, there
      were 9 birth defects, for a prevalence of 3% (95% confidence interval 1.4, 5.6).
      This rate is not significantly different from the CDC's system, which had a
      prevalence of 3.1 per 100 live births (95% confidence interval 3.1, 3.2; P =.99).
      There was no consistent pattern among reported birth defects. CONCLUSION:
      Adequate numbers of first-trimester exposures to nelfinavir have been monitored
      to detect a 2-fold increase in the prevalence of overall birth defects. No such
      increases have been detected when compared with the CDC rate. However, the
      numbers are not sufficient to detect any increased rate of specific defects.
      Although nelfinavir should only be used in pregnancy if the benefits outweigh the
      potential risks, the findings from this study should provide some assurance.
      LEVEL OF EVIDENCE: III

PMID- 15172851
TI  - Association of rheumatologic disease with preeclampsia.
AB  - OBJECTIVE: To determine whether maternal rheumatologic disease is associated with
      an increased risk of adverse obstetric or neonatal outcomes. METHODS: Using an
      institutional database, we identified all women with diagnosed rheumatologic
      disease (n = 114) who delivered a baby at our institution during a 33-month
      period. We compared the incidence of adverse obstetric and neonatal outcomes
      among these women with the incidence among women without rheumatologic diseases
      (n = 18,534). RESULTS: Women with rheumatologic diseases were more likely to have
      preeclampsia than women without rheumatologic disease (8.8% versus 2.3%, P <.001)
      Women with rheumatologic diseases were also at increased risk of preterm delivery
      (15.2% versus 7.8%, P =.002) and small-for-gestational-age infants (8.0% versus
      3.1%, P =.001) compared with women without rheumatologic disease. CONCLUSION: The
      finding that women with rheumatologic diseases are at increased risk of adverse
      obstetric outcomes suggests a need for heightened clinical vigilance and further
      research into the common pathophysiologic correlates. LEVEL OF EVIDENCE: II-2

PMID- 15172852
TI  - Ovarian cancer risk after the use of ovulation-stimulating drugs.
AB  - OBJECTIVE: To assess the long-term effects of ovulation-stimulating drugs on the
      risk of ovarian cancer. METHODS: A retrospective cohort study of 12,193 eligible
      study subjects (median age 30 years) who were evaluated for infertility during
      the period of 1965-1988 at 5 clinical sites identified 45 subsequent ovarian
      cancers in follow-up through 1999. Standardized incidence ratios compared the
      risk of cancer among the infertile patients to the general population, whereas
      analyses within the cohort allowed the derivation of rate ratios for drug usage
      compared with no usage after adjustment for other ovarian cancer predictors.
      RESULTS: The infertility patients had a significantly elevated ovarian cancer
      risk compared with the general population (standardized incidence ratio 1.98, 95%
      confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into
      account and risks assessed within the infertile women, the rate ratios associated
      with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4,
      2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with
      follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI
      0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI
      0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects
      did not vary by causes of infertility, there was a slightly higher risk
      associated with clomiphene use among women who remained nulligravid, based on 6
      exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7). CONCLUSION: The results of
      this study generally were reassuring in not confirming a strong link between
      ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant
      elevations in risk associated with drug usage among certain subgroups of users,
      however, support the need for continued monitoring of long-term risks. LEVEL OF
      EVIDENCE: II-2

PMID- 15172853
TI  - Identification of micrometastases in histologically negative lymph nodes of early
      stage cervical cancer patients.
AB  - OBJECTIVE: Despite histologically negative lymph nodes, approximately 15% of
      patients with early-stage cervical cancer will develop recurrence.
      Micrometastases have been shown to be important in staging and treatment of
      breast cancers and melanoma and have been identified by polymerase chain reaction
      analysis in cervical cancers. This study sought to estimate the frequency of
      micrometastases identified by immunohistochemistry in histologically negative
      lymph nodes and compare this to other known risk factors for recurrence of
      cervical cancer. METHODS: Early-stage (stages IA2, IB1, and IB2) cervical cancer
      patients of all histologic subtypes were identified from the surgical logs of the
      Los Angeles County-University of Southern California Medical Center for the
      period 1994-2000. One hundred thirty-two patients had histologically negative
      lymph nodes. Immunohistochemical assay was performed on 3,106 lymph nodes by
      using antibodies against cytokeratins AE-1 and CAM 5.2 in combination according
      to standard protocols. The stained nodes were then evaluated for the presence of
      micrometastases and compared against the respective clinicopathologic information
      in each case. RESULTS: Micrometastases were detected in 19 of 132 (15%, 95%
      confidence interval [CI] 9%, 22%) patients, found in 29 of the 3,106 (0.9%) lymph
      nodes evaluated. Vascular space invasion was seen in 50 of 132 cases (38%, 95% CI
      30%, 47%) and in 8 of 19 (42%, 95% CI 21%, 66%) cases with micrometastases.
      Surgical margins of the resected specimen were negative in 120 of 132 cases (91%,
      95% CI 84%, 95%) and in 16 of 19 (84%, 95%CI 60%, 96%) of those cases with
      micrometastases. Micrometastases were seen most frequently in pelvic lymph nodes
      (25 of 29, 86%). Patients with more than 20 lymph nodes removed were more likely
      to demonstrate metastasis (P <.001). There was no statistically significant
      association between micrometastasis and vascular space invasion or tumor volume.
      CONCLUSION: Micrometastases are identifiable in histologically negative lymph
      nodes in 15% (95% CI 9%, 22%) of early-stage cancer patients, a frequency which
      approximates the recurrence rate for patients with negative nodes. In this
      series, patients with greater numbers of lymph nodes analyzed were more likely to
      have lymph node micrometastasis identified. There appears to be no relationship
      between tumor volume and the identification of micrometastases. Although
      micrometastases can be identified in histologically negative lymph nodes, their
      presence is not strongly associated with other known factors of cervical cancer
      recurrence. Further research is needed to determine whether the presence of lymph
      node micrometastases is associated with an unfavorable prognosis. LEVEL OF
      EVIDENCE: II-3

PMID- 15172854
TI  - The gynecologic oncology consult: symptom presentation and concurrent symptoms of
      depression and anxiety.
AB  - OBJECTIVE: To detail the relationship of gynecologic symptoms and
      sociodemographic variables to depression and anxiety reports among women who were
      referred to gynecologic oncologists for evaluation. METHODS: Consecutive patients
      (N = 151) from an National Cancer Institute-designated comprehensive cancer
      center were accrued and participated on the day of consultation. Patients
      completed measures assessing depression (Center for Epidemiological Studies
      Depression Scale) and anxiety (Beck Anxiety Inventory) symptoms, common
      gynecologic signs/symptoms, and sociodemographic characteristics. Patients were
      followed up and subsequent diagnoses yielded 73 (48%) cancer and 78 (52%) benign
      cases. RESULTS: Descriptive analyses revealed that the cancer group was
      significantly older (52 versus 45 years) than the benign group, and variables
      correlated with age also differed significantly, with the cancer sample more
      likely to be postmenopausal, unemployed, and if employed, working fewer hours per
      week. Importantly, the groups did not differ on reports of depressive, anxiety,
      or gynecologic symptoms. Hierarchical multiple regression analyses, collapsing
      across groups, yielded significant correlates of emotional distress. Women who
      were older, without a spouse/partner, and who had more gynecologic symptoms had
      higher levels of both depressive and anxiety symptoms. Among the women who did
      have a partner, those with relationships of longer duration reported lower levels
      of depression/anxiety CONCLUSION: Reports of clinically significant depressive
      (42%) and anxiety symptoms (30%) were high. The number of gynecologic symptoms
      was reliably correlated with emotional distress. Age and absence of partner may
      have conferred added vulnerability. For those women with partners, lengthier
      relationships appeared to offer protection from both depressive and anxiety
      symptoms. LEVEL OF EVIDENCE: III

PMID- 15172855
TI  - Sudden death: ectopic pregnancy mortality.
AB  - OBJECTIVE: To describe the trends in ectopic pregnancy mortality in Michigan from
      1985 through 1999 and compare to those of previous time periods. METHODS: We
      reviewed all cases of maternal mortality from ectopic pregnancy in Michigan from
      1985 through 1999. We extracted data from death certificates, hospital inpatient
      and emergency department records, medical examiner autopsy reports, and reviews
      by the Michigan Maternal Mortality Study. The Health Data Development Section of
      the Michigan Department of Community Health provided data on live births and
      maternal deaths RESULTS: Of the 268 pregnancy-related deaths, 16 (6%) were caused
      by complications of ectopic pregnancy. Mean age at death was 27 (+/- 6) years.
      Thirteen deaths were to African-American women and 3 were to white women (P <
      .01). African-American women had an ectopic mortality ratio 18 times higher than
      white women (3.25/100,000 live births, compared with 0.18/100,000) Three cases of
      pregnancy-related death due to complications of ectopic pregnancy were considered
      preventable, and 2 others were of unknown preventability. CONCLUSION: Ectopic
      pregnancy treatment has changed in the last 20 years coincident with a decrease
      in maternal mortality from ectopic pregnancy. Sudden death was the presenting
      scenario in 75% of nonpreventable ectopic deaths, an increase from previous
      analyses. A large racial disparity is apparent. Ideally, pregnancy care should
      start as soon as possible after the first missed menses; however, systemwide
      changes are needed to create a new norm promoting early access to pregnancy care
      and promoting education and testing to rule out pregnancy abnormalities. LEVEL OF
      EVIDENCE: II-2

PMID- 15172856
TI  - Improving resident competency in the management of shoulder dystocia with
      simulation training.
AB  - OBJECTIVE: To determine whether a simulation training scenario improves resident
      competency in the management of shoulder dystocia. METHODS: Residents from 2
      training programs participated in this study. The residents were block-randomized
      by year-group to a training session on shoulder dystocia management that used an
      obstetric birthing simulator or to a control group with no specific training.
      Trained residents and control subjects were subsequently tested on a standardized
      shoulder dystocia scenario, and the encounters were digitally recorded. A
      physician grader from an external institution then graded and rated the
      resident's performance with a standardized evaluation sheet. Statistical analysis
      included the Student t test, chi(2), and regression analysis, as appropriate.
      RESULTS: Trained residents had significantly higher scores in all evaluation
      categories, including timelines of their interventions, performance of maneuvers,
      and overall performance. They also performed the delivery in a shorter time than
      control subjects (61 versus 146 seconds, P =.003). CONCLUSION: Training with a
      simulation-training scenario improved resident performance in the management of
      shoulder dystocia. LEVEL OF EVIDENCE: I

PMID- 15172857
TI  - Management of diabetes mellitus by obstetrician-gynecologists.
AB  - OBJECTIVE: To compare practice patterns of the American College of Obstetrician
      and Gynecologists (ACOG) Fellows for the diagnosis and treatment of gestational
      diabetes mellitus (GDM) and type 1 diabetes mellitus with current ACOG
      recommendations and prior published series. METHODS: We sent a questionnaire to
      1,398 practicing ACOG Fellows and Junior Fellows, 398 of whom comprise the
      Collaborative Ambulatory Research Network. Responses were evaluated by age and
      sex to assess differences in practice. RESULTS: Younger physicians were more
      likely to treat pregnant patients. Ninety-six percent of obstetricians routinely
      screen for GDM, nearly all by using a 50-g glucose 1-hour oral test. Nearly 60%
      of respondents establish the diagnosis of GDM using the National Diabetes Data
      Group criteria. In addition to medical nutrition therapy, almost 75% of
      respondents recommend exercise for patients with GDM. Approximately 60% of
      respondents reported that all of their patients with GDM self-monitor their blood
      glucose. When medical nutrition therapy is ineffective for their patients with
      GDM, 82% of respondents initially prescribe insulin, whereas 13% begin with
      glyburide. Nearly 75% of respondents routinely perform a postpartum evaluation of
      glucose tolerance in the patient with GDM. Most obstetricians manage the glucose
      control of their patients with type 1 diabetes mellitus themselves. CONCLUSION:
      Practicing obstetrician-gynecologists have incorporated recent recommendations
      into their practice patterns for both GDM and type 1 diabetes mellitus, including
      patients' self-monitoring of blood glucose, exercise, and postpartum testing in
      GDM. LEVEL OF EVIDENCE: III

PMID- 15172858
TI  - Calpain-10 haplotype combination and association with gestational diabetes
      mellitus.
AB  - OBJECTIVE: Gestational diabetes mellitus (GDM) is a frequent complication of
      pregnancy. Epidemiologic and pathophysiologic data suggest a close link of this
      disease to non-insulin-dependent diabetes mellitus. Within the calpain-10 gene
      various single-nucleotide polymorphisms have been identified that increased the
      risk for non-insulin-dependent diabetes mellitus. Therefore, we examined single
      nucleotide exchanges of this gene in women with GDM. METHODS: A total of 875
      unselected women were prospectively screened for GDM. Eighty women of this
      population, 40 patients with an abnormal oral glucose tolerance test and 40
      normal controls, were randomly selected. DNA samples isolated from sera of the
      control and study groups were analyzed with respect to single-nucleotide
      polymorphisms of the calpain-10 gene at positions 43, 19, and 63 using polymerase
      chain reaction amplification and restriction analysis. RESULTS: Women with GDM
      were more likely to be homozygous for the allele 1 of single-nucleotide
      polymorphism 63 (P =.02 by chi(2) test). With respect to single-nucleotide
      polymorphisms 19 and 43, no significant differences in allele distribution were
      detected between controls and women with GDM. When comparing the different
      haplotypes for calpain-10 (single-nucleotide polymorphisms 43, 19, and 63), all
      women with the haplotype combination 121/221 (n = 8) had gestational diabetes (P
      =.005 by Fisher exact test). CONCLUSION: Our results indicate that the haplotype
      121/221 of the calpain-10 gene may be associated with disturbances of glucose
      metabolism during pregnancy. LEVEL OF EVIDENCE: II-1

PMID- 15172859
TI  - Glucose screening in Mexican-American women.
AB  - OBJECTIVE: We sought to describe the predictive value for gestational diabetes
      mellitus (GDM) using different glucose challenge test thresholds in Mexican
      American women. METHODS: A prospective population-based study of 6,857 gravid
      women, who were tested with a 50-g glucose challenge test at 24-28 weeks of
      gestation, was performed. A screening value of 130 mg/dL or greater was followed
      by a 3-hour, 100-g oral glucose tolerance test. Gestational diabetes mellitus was
      diagnosed by 2 or more abnormal values using the Carpenter and Coustan criteria.
      For purpose of analysis, GDM diagnosis was categorized with glucose challenge
      test values in 10-mg/dL increments. A comparison between Carpenter-Coustan and
      the National Diabetic Data Group criteria for GDM diagnosis was performed for
      each glucose challenge test threshold category. Sensitivity and specificity for
      GDM diagnosis were further calculated for different glucose challenge test
      thresholds (130, 135, and 140 mg/dL). RESULTS: Overall, GDM was diagnosed in 469
      of 6,857 (6.8%) women, and one abnormal oral glucose tolerance test value was
      tested in 351 of 6,857 women (5.1%). Normal glucose challenge test results
      (threshold less than 130 mg/dL) were obtained in 4,316 of 6,857 women. An
      elevated glucose challenge test value increases the risk of GDM, but even in high
      glucose challenge test thresholds (more than 180 mg/dL), the predictive value for
      GDM was only 50%. The sensitivity and specificity for GDM diagnosis using 3
      different glucose challenge test thresholds were as follows: threshold 130 mg/dL
      or more: 97% and 63%; threshold 135 mg/dL or more: 91% and 73%; and threshold 140
      mg/dL or more: 85% and 78%, respectively. CONCLUSION: Data suggests that an
      elevated glucose challenge test level cannot be used as a single diagnostic tool
      for GDM even in high test thresholds. A threshold of 130 mg/dL may be recommended
      as a screening threshold for GDM in Mexican-American women. LEVEL OF EVIDENCE: II
      3

PMID- 15172860
TI  - Low maternal age and neonatal survival of extremely preterm twins (20-28 weeks of
      gestation).
AB  - OBJECTIVE: We investigated the relationship between low maternal age and neonatal
      survival among extremely preterm twins. METHODS: This was a retrospective cohort
      study on live births of extremely preterm twins delivered to teenaged mothers
      (aged 15-19 years) in the United States within the period 1995 through 1998.
      Overall neonatal and early and late neonatal mortality in this category was
      compared with that of a similar group of twins born to young adult mothers (aged
      20-29 years). We used the generalized estimating equation framework in computing
      relative risks after adjusting for intracluster correlations. RESULTS: Analysis
      involved 2,290 extremely preterm liveborn twins of teenaged mothers and 8,709
      born to young adult mothers. Overall, neonatal mortality was 29% higher among the
      extremely preterm twins born to teenaged mothers (adjusted odds ratio [OR] 1.29;
      95% confidence interval [CI] 1.04%, 1.59%). The disparity in neonatal survival
      was chiefly in the early neonatal period (adjusted OR 1.34; 95% CI 1.07%, 1.67%),
      while late neonatal mortality was comparable (adjusted OR 0.91; 95% CI 0.58%,
      1.42%). In addition, twins of teenaged mothers had significantly higher level of
      mortality, except for the birth weight category of 1,000-1,499 g. CONCLUSION: Low
      maternal age was found to be associated with elevated risk of neonatal death
      among extremely preterm twins. The preponderance of deaths among extremely
      preterm twins of teenaged mothers in the early neonatal period appeared to be
      responsible for the disparity in survival. This information may be useful for
      targeted interventions aimed at enhancing survival of extremely preterm twins
      born to teenagers, as well as for instituting optimal management options in the
      clinical setting. LEVEL OF EVIDENCE: II-2

PMID- 15172861
TI  - Changes in the utilization of prenatal diagnosis.
AB  - OBJECTIVE: The impact of prenatal screening for Down syndrome has largely been
      assessed under the assumption that screening protocols and policies are fully
      used. To measure the overall effectiveness in actual clinical practice, we
      analyzed the tests performed by a single cytogenetics laboratory. METHODS: We
      reviewed all amniotic fluid and chorionic villus samples (CVS) processed by the
      University of Connecticut Health Center's cytogenetics laboratory for the years
      1991 to 2002. We evaluated trends in the use of prenatal testing, referral
      indications, and the numbers of cytogenetic abnormalities identified. RESULTS:
      The number of women receiving amniocentesis or CVS declined more than 50% from
      1,988 in 1991 to 933 in 2002 (P <.001), despite an increase in the number of
      women of advanced maternal age in the population served. There was a 68% decline
      in the number of women who underwent invasive prenatal testing solely on the
      basis of their age (1,314 in 1991 to 423 in 2002, P <.001). The number of Down
      syndrome fetuses detected prenatally increased from 20 to 31 (P =.08),
      representing approximately one half of the affected pregnancies present in the
      population served. Between 1991 and 2002, the proportion of antenatal cytogenetic
      tests with a significant chromosomal abnormality increased from 1 in 43 (2.3%) to
      1 in 14 (7.0%; P <.001). CONCLUSION: Advances in maternal serum screening and
      second-trimester ultrasonography have resulted in more judicious use of
      amniocentesis and chorionic villus sampling. LEVEL OF EVIDENCE: II-2

PMID- 15172862
TI  - The use of intrauterine lidocaine to minimize pain during hysterosalpingography:
      a randomized trial.
AB  - OBJECTIVE: A hysterosalpingogram is an integral part of the evaluation of
      infertility but is often painful. Intrauterine anesthesia may help to alleviate
      the discomfort associated with this procedure. METHODS: We conducted a
      randomized, double-blinded, placebo-controlled trial of intrauterine lidocaine in
      women undergoing hysterosalpingography (HSG). All women were instructed to take a
      nonsteroidal analgesic before the hysterosalpingogram. Patients received 3 mL of
      buffered 2% lidocaine solution or 0.9% normal saline instilled into the uterus
      before HSG. The primary outcome was the degree of pain experienced documented via
      10-cm visual analogue pain scales. Systematic assessments of discomfort were also
      collected by the attending physician, radiology technician, and radiology
      physician. RESULTS: Sixty-four patients were randomly assigned to placebo and 63
      women were randomly assigned to the lidocaine group. There were no differences in
      mean age, race, parity, or history of dysmenorrhea or chronic pelvic pain. There
      were no differences in the pain scores at baseline, during, or after the study
      procedure between the 2 groups. Peak pain scale scores associated with the
      procedure were 5.3 +/- 0.4 in both the placebo and study groups. In addition,
      assessments of patient discomfort revealed no significant differences between the
      2 groups. CONCLUSION: We found no difference in pain between the intrauterine
      lidocaine and placebo groups. Intrauterine lidocaine does not appear to be
      effective in decreasing pain in women undergoing HSG. LEVEL OF EVIDENCE: I

PMID- 15172863
TI  - Intrauterine lidocaine infusion for pain management in first-trimester abortions.
AB  - OBJECTIVE: To study the effects of an intrauterine lidocaine infusion on
      perceived patient pain in first-trimester abortions and to measure serum
      lidocaine levels. METHODS: A randomized, double-blind, placebo control trial of
      80 women receiving either a 10-mL 1% lidocaine (n = 40) or saline (n = 40)
      intrauterine infusion and a standard paracervical block before first-trimester
      abortion was undertaken. Women completed a series of 100-mm visual analogue
      scales to measure their perceived pain (anticipated pain, after speculum
      insertion, after intrauterine infusion, after cervical dilation, after suction
      aspiration, and 30 minutes after procedure). Twenty women (10 in each group)
      volunteered for serum lidocaine levels at 10, 20, 30, 45, and 60 minutes after
      the lidocaine infusion. RESULTS: Groups were similar in respect to age, parity,
      prior abortion, ethnicity, gestational age, level of dysmenorrhea, and
      complications. Pain scores by visual analogue scale demonstrated no significant
      difference between groups at any time point during the procedure; in particular,
      pain during aspiration (saline infusion 51 +/- 26 mm, lidocaine infusion 47 +/-
      28 mm; P =.51). Peak serum levels occurred at approximately 10 minutes after
      lidocaine infusion. The highest level recorded (lidocaine group) was 2.5
      microg/mL (toxicity more than 5 microg/mL). CONCLUSION: Compared with
      paracervical block alone, the addition of a 1% intrauterine lidocaine infusion
      resulted in no improvement in patient perception of pain during first-trimester
      abortion. No subjects demonstrated symptoms or serum levels of lidocaine
      toxicity. LEVEL OF EVIDENCE: I

PMID- 15172864
TI  - Beta-thalassemia minor during pregnancy.
AB  - OBJECTIVE: To investigate pregnancy outcome of patients with beta-thalassemia
      minor. METHODS: A population-based study comparing all pregnancies of women with
      and without beta-thalassemia minor was conducted. Deliveries occurred during the
      years 1988-2002 at Soroka University Medical Center. A multivariate logistic
      regression model, with backward elimination, was constructed to find independent
      risk factors associated with maternal beta-thalassemia minor. RESULTS: During the
      study period there were 159,195 deliveries, of which 261 (0.2%) occurred in
      patients with beta-thalassemia minor. The following conditions were significantly
      associated with beta-thalassemia minor: oligohydramnios (odds ratio [OR] 2.1; 95%
      confidence interval [CI] 1.2%, 3.7%), intrauterine growth restriction (IUGR; OR
      2.4; 95% CI 1.4%, 4.2%), Jewish ethnicity (OR 1.5; 95% CI 1.2%, 1.9%), and
      previous cesarean delivery (OR 1.4; 95% CI 1.1%, 2.0%). No significant
      differences were noted between the groups regarding perinatal outcomes such as
      birth weight, low Apgar scores, congenital malformations, or perinatal mortality.
      Patients with beta-thalassemia minor were more likely to have cesarean deliveries
      than were the nonthalassemic parturients (16.9% and 12.2%, respectively; P
      =.021). However, while controlling for possible confounders such as IUGR,
      oligohydramnios, and previous cesarean delivery, with another multivariate
      analysis with cesarean delivery as the outcome variable, beta-thalassemia minor
      was not found as an independent risk factor for cesarean delivery (OR 1.3; 95% CI
      0.9%, 1.9%). CONCLUSION: The course of pregnancy of patients with thalassemia
      minor, including perinatal outcomes, is favorable. Because higher rates of IUGR
      were found, we recommend ultrasound surveillance of fetal weight for early
      detection of IUGR. LEVEL OF EVIDENCE: II-2

PMID- 15172865
TI  - Outcome of pregnancy in homozygous sickle cell disease.
AB  - OBJECTIVE: Previous reports on pregnancy in homozygous sickle cell (SS) disease
      are biased by hospital-based, more severely affected subjects and may have
      underestimated recurrent early pregnancy losses. We report pregnancy outcome in a
      representative sample of SS subjects subsequently referred to as "subjects" or
      "sickle cell subjects," and matched normal controls followed from birth. METHODS:
      The outcomes of 94 pregnancies in 52 subjects and 157 pregnancies in 68 controls
      followed in a cohort study from birth are presented. Outcome measures included
      the age at menarche, interval to first pregnancy, outcome of pregnancy, and
      maternal complications. Possible predictors of low birth weight are assessed.
      Outcomes were compared by the Kaplan-Meier analysis for interval to first
      pregnancy and by Student t test, chi(2) test, or Fisher exact test, as
      appropriate. Correction was made for multiple testing, and multiple linear
      regression was used for analysis of birth weight. RESULTS: Compared with
      controls, SS subjects had later menarche (median age 15.4 versus 13.0 years) and
      first pregnancy (median age 23.7 versus 20.1 years), and more spontaneous
      abortions (36% versus 10%). Babies of SS subjects had a lower gestational age (P
      <.001) and lower birth weight (P <.001), the latter being significantly affected
      by sickle-related events in pregnancy. There was no difference in pregnancy
      induced hypertension, preeclampsia, or antepartum or postpartum hemorrhage, but a
      retained placenta was marginally more common in SS subjects (Fisher exact test, P
      =.007 after adjustment for multiple testing). Two SS subjects died, a mortality
      rate of 2.1%. CONCLUSION: The increased fetal loss and maternal morbidity in
      mothers with homozygous sickle cell disease is confirmed. LEVEL OF EVIDENCE: II-2

PMID- 15172866
TI  - Fetal growth and infant neurodevelopmental outcome after preterm premature
      rupture of membranes.
AB  - OBJECTIVE: To evaluate the prognostic values of fetal size before birth and fetal
      growth during the latency period in patients with preterm premature rupture of
      the membranes (PROM). METHODS: A prospective cohort study of 69 singleton
      pregnancies complicated by prolonged (14 days or more) PROM (24 to 31 weeks of
      gestation). Measures of fetal size and growth were compared with corresponding
      expected values from our reference curves. The correlations between deviations
      from expected measures of fetal size and growth, short-term neonatal
      complications, and infant neurodevelopmental outcome at 2 years were studied by
      univariate methods and logistic regression. RESULTS: The mean gestational ages
      and standard deviations at membrane rupture and at birth were 27.9 +/- 2.4 and
      31.5 +/- 2.1 weeks. At a corrected age of 2 years, of the 65 (94.2%) survivors, 3
      infants (4.6%) had cerebral palsy, 13 (20%) had minor neurodevelopmental
      impairment, and 49 (75.4%) were judged to have had normal development. Compared
      with surviving infants without a major handicap, the group of infants who died
      and those with cerebral palsy had lower proportions of expected birth weight
      (0.766 +/- 0.1 as compared with 0.859 +/- 0.13, P =.029), head (0.869 +/- 0.07 as
      compared with 0.950 +/- 0.07, P =.05), and abdominal (0.793 +/- 0.04 as compared
      with 0.888 +/- 0.1, P =.001) circumference growth during latency period. In
      logistic regression analysis, lower-than-expected ultrasound measures of fetal
      abdominal circumference before birth (odds ratio 1.09; 95% confidence interval
      1.01, 1.18) or of abdominal circumference growth during the latency period (odds
      ratio 1.1; 95% confidence interval 1.01, 1.2) were significantly associated with
      an increased likelihood of an infant neurodevelopmental abnormality at 2-year
      follow-up. CONCLUSION: In pregnancies complicated by preterm PROM, lower-than
      expected measures of fetal size and fetal growth were associated with an
      increased rate of infant neurodevelopmental outcome at 2-year follow-up. LEVEL OF
      EVIDENCE: II-2

PMID- 15172867
TI  - Obstetric and neonatal outcomes in grand multiparity.
AB  - OBJECTIVE: To compare the incidence of antenatal and intrapartum complications
      and neonatal outcomes among grand multiparas with age-matched multiparas.
      METHODS: Six hundred twenty-one grand multiparas (para more than 4) women were
      prospectively compared with 621 age-matched multiparous (para 2-4) controls.
      RESULTS: Grand multiparity was associated with low socioeconomic status and
      education (odds ratio [OR]6.4; 95% confidence interval [CI] 4.5, 9.0), poorer
      prenatal care (OR 3.1; 95% CI 1.5, 6.1), smoking (OR 2.2; 95% CI 1.5, 3.2), and
      alcohol consumption (OR 9.0; 95% CI 2.1, 39.3). Grand multiparas had a higher
      body mass index (OR 1.5; 95% CI 1.2, 1.9) and rate of insulin-dependent
      gestational diabetes (OR 1.7; 95% CI 1.02, 3.1). They had more previous
      intrauterine (OR 4.2; 95% CI 1.5, 11.3) and perinatal deaths (OR 3.2; 95% CI 2.0,
      5.0). They had fewer intrapartum complications (arrests of cervical dilatation
      [OR 0.19; 95% CI 0.06, 0.66], instrumental deliveries [OR 0.31; 95% CI 0.16,
      0.59], and fever during labor [OR 0.47; 95% CI 0.26, 0.86]). Conditional logistic
      regression models found that grand multiparity was the most closely correlated
      factor to a previous history of fetal death (OR 4.3; 95% CI 1.6, 11.6), but it
      was not an independent predictor of insulin-dependent gestational diabetes
      mellitus (OR 1.3; 95% CI 0.75, 2.2). CONCLUSION: Grand multiparas, when compared
      with same-age multiparous controls, appear to have fewer intrapartum
      complications. However, they present several prenatal risk factors that require
      special antenatal care. LEVEL OF EVIDENCE: II-3

PMID- 15172868
TI  - Disparities in pregnancy outcomes according to marital and cohabitation status.
AB  - OBJECTIVE: To assess the risks and trends of adverse pregnancy outcomes among
      mothers in common-law unions versus traditional marriage relationships. METHODS:
      We conducted a birth cohort-based study of all 720,586 births registered in
      Quebec for the years 1990 to 1997. RESULTS: The proportion of births to common
      law mothers more than doubled from 20% in 1990 to 44% in 1997. Preterm birth, low
      birth weight, small for gestational age, and neonatal and postneonatal mortality
      rates increased progressively from mothers legally married, to common-law unions,
      to lone mothers with father information, to lone mothers without father
      information on birth registrations. Adjusted odd ratios with 95% confidence
      intervals (CIs) for common-law versus legally married mothers were 1.14 (95% CI
      1.11, 1.17) for preterm birth, 1.21 (95% CI 1.18, 1.25) for low birth weight,
      1.18 (95% CI 1.16, 1.20) for small for gestational age, 1.07 (95% 0.97, 1.19) for
      neonatal death, and 1.23 (95% CI 1.04, 1.44) for postneonatal death after
      controlled for observed individual- and community-level characteristics. The
      crude and adjusted odds ratios were virtually unchanged over time. CONCLUSION:
      Pregnancy outcomes are worse among mothers in common-law unions versus
      traditional marriage relationships but better than among mothers living alone.
      Modest disparities in pregnancy outcomes in common-law versus traditional
      marriage relationships have persisted despite the striking rise in common-law
      unions. LEVEL OF EVIDENCE: II-2

PMID- 15172870
TI  - The miracle of life and privilege of death.

PMID- 15172869
TI  - Randomized comparison of chromic versus fast-absorbing polyglactin 910 for
      postpartum perineal repair.
AB  - OBJECTIVE: We conducted a randomized trial to evaluate the healing
      characteristics of chromic versus fast-absorbing polyglactin 910. METHODS:
      Laboring women were randomly assigned to chromic or fast-absorbing polyglactin
      for perineal repairs. Subjects were evaluated at 24-48 hours, 10-14 days, and 6-8
      weeks to assess perineal and uterine pain, analgesic use, presence of residual
      suture, and wound dehiscence. RESULTS: Between April 2002 and January 2003, 1,361
      subjects were randomly assigned. Two thirds of women in each group (459 fast
      absorbing polyglactin and 449 chromic) required sutures for perineal repairs.
      Women were evaluated according to randomization assignment. Overall, 794 (87%) of
      subjects received the appropriate allocated suture to repair a perineal
      laceration (399 of 459, 86.9% fast-absorbing polyglactin 910; 395 of 449, 88%
      chromic catgut). At 24-48 hours, there was a statistically significant reduction
      in uterine cramping pain (25% versus 34%; P =.006) in subjects randomly assigned
      to fast-absorbing polyglactin. At 10-14 days, there were no statistically
      significant differences between the groups. At 6-8 weeks there was, again, a
      statistically significant reduction in uterine cramping pain (1% versus 4%; P
      =.017) and a statistically significant decrease in analgesic use (5% versus 10%;
      P =.048) in subjects randomly assigned to fast-absorbing polyglactin. Finally, at
      6-8 weeks postpartum there was no difference in residual suture (2 of 175 versus
      2 of 134; P =.802) or wound breakdowns (4 of 175 versus 3 of 134; P =.959) for
      fast-absorbing polyglactin 910 and chromic catgut, respectively. CONCLUSION: Our
      data suggest that fast-absorbing polyglactin 910 and chromic elicit similar
      postpartum perineal discomfort. In contrast to previous studies evaluating
      standard polyglactin, our trial demonstrated that fast-absorbing polyglactin
      rarely requires late removal and has a similar wound breakdown profile as
      compared with chromic. LEVEL OF EVIDENCE: I

PMID- 15172871
TI  - Geographic distribution of obstetrics and gynecology resident training positions.
AB  - Medical students applying to residency positions in obstetrics and gynecology
      often have strong geographical preferences. For training programs in obstetrics
      and gynecology, the distribution of categorical PGY-1 resident positions per
      million people was analyzed for each American College of Obstetricians and
      Gynecologists (ACOG) district. Data were obtained from the 2000 U.S. census and
      the 2003 resident match. The data indicate that the number of PGY-1 residency
      training positions per million people in the United States varies by geographical
      region. The fewest PGY-1 residency training positions per capita are in the West.
      In the 2003 match, Districts VIII and IX, respectively, offered 2.1 and 2.8 PGY-1
      residency positions per one million people. The greatest number of PGY-1
      positions per capita are in the East. Districts I, II, and III, respectively,
      offered 5.7, 8.0, and 5.3 PGY-1 residency positions per one million people. Many
      factors are likely to contribute to the observed geographical differences. A
      correlation coefficient of 0.81 (P <.01) was observed between population per
      square mile in each ACOG district and the number of PGY-1 positions per million
      people. Low population density likely limits the development of residency
      programs in some geographical areas. To allow medical students as much
      geographical choice as possible, additional residency positions could be
      developed in the West if educational opportunities and clinical needs support
      such a change.

PMID- 15172872
TI  - Transvaginal hysterectomy: rationale and surgical approach.
AB  - Abdominal hysterectomy is performed in the United States at a 3:1 ratio over
      vaginal hysterectomy, despite evidence that vaginal hysterectomy offers
      advantages over abdominal hysterectomy with regard to operative time,
      complication rates, recovery, return to daily activities, and overall costs of
      treatment. In fact, the predominance of the abdominal approach may be based on
      factors other than clinical considerations, including resident training, use of
      limited or obsolete guidelines, greater third-party compensation for abdominal
      procedures, a presumption rather than a confirmation that pathology exists that
      contraindicates a vaginal approach, and misconceptions about the safety and cost
      of vaginal hysterectomy. A number of studies spanning several years demonstrate
      that the use of more systematic guidelines for selecting the route of
      hysterectomy results in a major shift toward the vaginal approach. Evidence also
      shows that transvaginal hysterectomy is both feasible and optimum for types of
      patients who have long been considered inappropriate candidates for the vaginal
      route. New instrumentation facilitates the vaginal approach and contributes to
      improved hemostasis and decreased operative time. Included here is a step-by-step
      approach to determining appropriate candidates for the vaginal approach via
      assessment of access, uterus size, and extent of pathology.

PMID- 15172873
TI  - In-flight radiation exposure during pregnancy.
AB  - During high-altitude flight, the cosmic radiation dose rate in an airliner is
      greater than it is at ground level. For a casual traveler, the impact on
      pregnancy from cosmic radiation exposure during flight is trivial. Pregnant
      frequent flyers, pilots, and flight attendants can, however, receive exposures
      that exceed current recommended values if they do not appropriately modify their
      work schedules. In addition to the galactic cosmic-ray background that is the
      source of this radiation, severe disturbances on the sun may cause eruptions that
      significantly raise radiation levels at airliner altitudes for brief periods,
      possibly having an impact even on casual travelers. This article will help
      obstetrician-gynecologists provide advice to their pregnant patients about in
      flight radiation risks. That advice should be influenced by an understanding of
      recommended radiation exposure limits and a perspective on how those limits
      relate to the potential for real harm. Resources provided by the U.S. Federal
      Aviation Administration and others to help pregnant women and their physicians
      make informed decisions about the acceptability of this type of exposure are
      described.

PMID- 15172874
TI  - Systematic review of mifepristone for the treatment of uterine leiomyomata.
AB  - OBJECTIVE: To systematically review the effect of mifepristone on uterine
      leiomyoma size and symptoms and to summarize its adverse effects. DATA SOURCES: A
      computerized search in MEDLINE, EMBASE, LILACS, and Cochrane databases from 1985
      to 2002 and hand searches of conference proceedings from 1995 to 2002 were
      performed with the search terms "mifepristone" and "leiomyomata" and publication
      type "clinical trial." METHODS OF STUDY SELECTION: Titles and abstracts were
      reviewed by 2 authors; there were no areas of disagreement. Inclusion criteria
      were clinical trials of daily mifepristone for uterine leiomyomata that measured
      uterine or leiomyoma volume before and after treatment. TABULATION, INTEGRATION,
      AND RESULTS: Data from each article were abstracted by 2 reviewers. The search
      identified 6 before-and-after clinical trials involving a total of 166 women with
      symptomatic uterine leiomyomata. The subjects received 5 to 50 mg/d of
      mifepristone for 3 to 6 months. No study was placebo-controlled or blinded. Meta
      analytic techniques were not performed due to variation in outcome and
      mifepristone dose. Daily treatment with all doses of mifepristone resulted in
      reductions in uterine and leiomyoma volumes ranging from 27% to 49% and 26% to
      74%, respectively. Mifepristone treatment reduced the prevalence and severity of
      dysmenorrhea, menorrhagia, and pelvic pressure. Rates of amenorrhea ranged from
      63% to 100%. Transient elevations in transaminases occurred in 4%. Endometrial
      hyperplasia was detected in 10 (28%) of 36 women screened by endometrial biopsy.
      CONCLUSION: Published trials of mifepristone showed reduction in leiomyoma size
      and improvement in symptoms. A notable adverse effect of mifepristone was
      development of endometrial hyperplasia.

PMID- 15172875
TI  - Teaching infrequently used skills: vaginal breech delivery.

PMID- 15172877
TI  - Conversion from vertex to breech after extra-amniotic saline installation.

PMID- 15172878
TI  - Pregnancy-related mortality due to cardiomyopathy: United States, 1991-1997.

PMID- 15172880
TI  - ACOG Practice Bulletin #53. Diagnosis and treatment of gestational trophoblastic
      disease.

PMID- 15172882
TI  - Inhibition of bicarbonate reabsorption in the rat proximal tubule by activation
      of luminal P2Y1 receptors.
AB  - The present study used a stationary microperfusion technique to investigate in
      vivo the effect of P2Y1 receptor activation on bicarbonate reabsorption in the
      rat proximal tubule. Proximal tubules were perfused with a bicarbonate Ringer
      solution before flow was stopped by means of an oil block. The recovery of lumen
      pH from the initial value (pH 8.0) to stationary values (pH approximately 6.7)
      was recorded by a H+-sensitive microelectrode inserted downstream of the
      perfusion pipette and oil block. The stationary pH value and the t(1/2) of pH
      recovery were used to calculate bicarbonate reabsorption (JHCO3). Both EIPA and
      bafilomycin A1 caused significant reductions in proximal tubule JHCO3, consistent
      with the established contributions of Na/H exchange and H+-ATPase to proximal
      tubule HCO3 reabsorption. The nucleotides ADP and, to a lesser extent, ATP
      reduced JHCO3 but AMP and UTP were without effect. 2MeSADP, a highly selective
      agonist of the P2Y1 receptor, reduced JHCO3 in a dose-dependent manner. MRS-2179,
      a P2Y1 receptor-specific antagonist, abolished the effect of 2MeSADP, whereas
      theophylline, an antagonist of adenosine (P1) receptors, did not. The inhibitory
      action of 2MeSADP was blocked by inhibition of protein kinase C and reduced by
      inhibition of protein kinase A. The effects of EIPA and 2MeSADP were not
      additive. The data provide functional evidence for P2Y1 receptors in the apical
      membrane of the rat proximal tubule: receptor activation impairs acidification in
      this nephron segment.

PMID- 15172883
TI  - Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal
      injury.
AB  - Tetracyclines exhibit significant anti-inflammatory properties in a variety of
      rheumatologic and dermatologic conditions. They have also been shown to inhibit
      apoptosis in certain neurodegenerative disorders. Because ischemic renal injury
      is characterized by both apoptosis and inflammation, we investigated the
      therapeutic potential of tetracyclines in a rat model of renal ischemia
      reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for
      30 min followed by reperfusion and received either minocycline or saline for 36 h
      before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia
      as determined by terminal transferase-mediated dUTP nick end-labeling staining
      and nuclear morphology. It also decreased cytochrome c release into the cytoplasm
      and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated
      group showed a significant reduction in tubular injury and cast formation. In
      addition, minocycline reduced the number of infiltrating leukocytes, decreased
      leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression
      of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the
      minocycline-treated group. We conclude that minocycline has potent antiapoptotic
      and anti-inflammatory properties and protects renal function in this model of
      ischemia-reperfusion. Tetracyclines are among the safest and best-studied
      antibiotics. They are thus attractive candidates for the therapy of human
      ischemic acute renal failure.

PMID- 15172884
TI  - Uncoupling of vasopressin signaling in collecting ducts from rats with CBL
      induced liver cirrhosis.
AB  - Vasopressin (AVP) stimulates collecting duct water reabsorption through cAMP
      mediated membrane targeting and increased expression of the aquaporin-2 (AQP2)
      water channel. Rats with liver cirrhosis induced by common bile duct ligation
      (CBL) show decreased protein expression of AQP2 despite increased plasma
      concentrations of AVP. The present study was conducted to investigate possible
      mechanisms behind this uncoupling of AVP signaling. The rats were examined 4 wk
      after CBL or sham operation. The CBL rats had increased plasma AVP concentrations
      (CBL: 3.2 +/- 0.2 vs. sham: 1.4 +/- 0.4 pg/ml, P < 0.05) and reduced AQP2 (0.62
      +/- 0.11) and phosphorylated AQP2 (0.50 +/- 0.06) protein expression compared
      with sham-operated rats. However, examination of subcellular AQP2 localization by
      immunohistochemistry showed unchanged plasma membrane targeting in CBL rats,
      indicating a sustained ability of AQP2 short-term regulation. In a separate
      series of animals, thirsting was found to normalize AQP2 expression, indicating
      that AVP uncoupling in CBL rats is a physiological compensatory mechanism aimed
      at avoiding dilutional hyponatremia. Studies on microdissected collecting ducts
      from CBL rats showed decreased cAMP accumulation in response to AVP stimulation.
      The presence of the nonspecific phosphodiesterase inhibitor IBMX normalized the
      cAMP accumulation, indicating that cAMP-phosphodiesterase activity is increased
      in CBL rats. However, in contrast to this, Western blotting showed a decreased
      expression of several phosphodiesterase splice variants. We conclude that CBL
      rats develop an escape from AVP to prevent the formation of dilutional
      hyponatremia in response to increased plasma AVP concentrations. The mechanism
      behind AVP escape seems to involve decreased collecting duct sensitivity to AVP
      as a result of increased cAMP-phosphodiesterase activity.

PMID- 15172886
TI  - Estrogens sensitize anterior pituitary gland to apoptosis.
AB  - Tissue homeostasis results from a balance between cell proliferation and cell
      death by apoptosis. Estradiol affects proliferation as well as apoptosis in
      hormone-dependent tissues. In the present study, we investigated the apoptotic
      response of the anterior pituitary gland to lipopolysaccharide (LPS) in cycling
      female rats, and the influence of estradiol in this response in ovariectomized
      (OVX) rats. The OVX rats were chronically estrogenized with implanted Silastic
      capsules containing 1 mg of 17beta-estradiol (E2). Cycling or OVX and E2-treated
      rats were injected with LPS (250 microg/rat ip). Apoptosis was determined by the
      terminal deoxynucleotidyl-mediated dUTP nick-end labeling (TUNEL) method in
      sections of the anterior pituitary gland and spleen. Chronic estrogenization
      induced apoptosis in the anterior pituitary gland. Acute endotoxemia triggered
      apoptosis of cells in the anterior pituitary gland of E2-treated rats but not of
      OVX rats. No differences were observed in the apoptotic response to LPS in spleen
      between OVX and E2-treated rats. The apoptotic response of the anterior pituitary
      to LPS was variable along the estrous cycle, being higher at proestrus than at
      estrus or diestrus I. Approximately 75% of the apoptotic cells were identified as
      lactotropes by immunofluorescence. In conclusion, our results indicate that
      estradiol induces apoptosis and enables the proapoptotic action of LPS in the
      anterior pituitary gland. Also, our study suggests that estrogens may be involved
      in anterior pituitary cell renewal during the estrous cycle, sensitizing
      lactotropes to proapoptotic stimuli.

PMID- 15172885
TI  - Coagulation in the mesangial area promotes ECM accumulation through factor V
      expression in MsPGN in rats.
AB  - It is well known that tissue factor starts the extrinsic coagulation pathway,
      which activates factor X to Xa, and factor V is a membrane-bound potent cofactor
      for the terminating stage of prothrombin activation by factor Xa. In a previous
      in vitro study, factor V was induced in cultured mesangial cells by inflammatory
      stimulation and increased expression of factor V promoted fibrin generation on
      the cultured mesangial cell surface. We report that extracellular matrix (ECM)
      accumulation is increased in association with coagulation in the mesangial area
      through factor V expression in mesangioproliferative glomerulonephritis (MsPGN).
      Wistar rats were intravenously injected with rabbit anti-rat thymocyte serum
      accompanied with or without simultaneous injection of rabbit anti-factor V
      antibody. Time course study in immunohistochemistry revealed that factor V
      expression was prominent on day 3 and fibrin-related antigen (FRA) deposition,
      then ECM accumulation, followed from day 3 to day 8. Massive fibronectin
      depositions and transforming growth factor (TGF)-beta expression were also noted
      in glomeruli from the disease control group, markedly higher than those in the
      normal group, and these depositions and expressions were significantly decreased
      in the anti-factor V neutralizing antibody-injected group. Northern blot analysis
      revealed that factor V mRNA expression was prominent on day 3 and was weak on day
      8. Double-labeling experiments revealed the frequent colocalization of alpha
      smooth muscle actin with factor V, FRA, and fibronectin in the same mesangial
      areas of glomeruli. TGF-beta, connective tissue growth factor (CTGF), collagen
      type IV, and fibronectin mRNA were upregulated in the disease control group, and
      anti-factor V-neutralizing antibody injection suppressed these mRNA expressions
      in glomeruli. The present results suggest that ECM components accumulation may
      progress in accordance with coagulation in the mesangial area through mesangial
      factor V expression and upregulated expression of TGF-beta and CTGF in MsPGN.

PMID- 15172887
TI  - Pulsatile LH release is diminished, whereas FSH secretion is normal, in
      hypocretin-deficient narcoleptic men.
AB  - Hypocretin (orexin) peptides are involved in the regulation of energy balance and
      pituitary hormone release. Narcolepsy is a sleep disorder characterized by
      disruption of hypocretin neurotransmission. Pituitary LH secretion is diminished
      in hypocretin-deficient animal models, and intracerebroventricular administration
      of hypocretin-1 activates the hypothalamo-pituitary-gonadal axis in rats. We
      evaluated whether hypocretin deficiency affects gonadotropin release in humans.
      To this end, we deconvolved 24-h serum concentrations of LH and FSH in seven
      hypocretin-deficient narcoleptic males (N) and seven controls (C) matched for
      age, body mass index, and sex. Basal plasma concentrations of testosterone,
      estradiol, and sex hormone-binding globulin were similar in both groups. Mean 24
      h LH concentration was significantly lower in narcolepsy patients [3.0 +/- 0.4
      (N) vs. 4.2 +/- 0.3 (C) U/l, P = 0.01], which was primarily due to a reduction of
      pulsatile LH secretion [23.5 +/- 1.6 (N) vs. 34.3 +/- 4.9 (C) U.l(-1).24 h(-1), P
      = 0.02]. The orderliness of LH and FSH secretion, quantitated by the approximate
      entropy statistic, was greater in patients than in controls. In contrast, all
      other features of FSH release were similar in narcoleptic and control groups.
      Also, LH and FSH secretions in response to intravenous administration of 100
      microg of GnRH were similar in patients and controls. These data indicate that
      endogenous hypocretins are involved in the regulation of the hypothalamo
      pituitary-gonadal axis activity in humans. In particular, reduced LH release in
      the face of normal pituitary responsivity to GnRH stimulation in narcoleptic men
      suggests that hypocretins promote endogenous GnRH secretion.

PMID- 15172888
TI  - MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes.
AB  - In 3T3-L1 adipocytes, insulin activates three major signaling cascades, the
      phosphoinositide 3-kinase (PI3K) pathway, the Cbl pathway, and the mitogen
      activated protein kinase (MAPK) pathway. Although PI3K and Cbl mediate insulin
      stimulated glucose uptake by promoting the translocation of the insulin
      responsive glucose transporter (GLUT4) to the plasma membrane, the MAPK pathway
      does not have an established role in insulin-stimulated glucose uptake. We
      demonstrate in this report that PI3K inhibitors also inhibit the MAPK pathway. To
      investigate the role of the MAPK pathway separately from that of the PI3K pathway
      in insulin-stimulated glucose uptake, we used two specific inhibitors of MAPK
      kinase (MEK) activity, PD-98059 and U-0126, which reduced insulin-stimulated
      glucose uptake by approximately 33 and 50%, respectively. Neither MEK inhibitor
      affected the activation of Akt or PKCzeta/lambda, downstream signaling molecules
      in the PI3K pathway. Inhibition of MEK with U-0126 did not prevent GLUT4 from
      translocating to the plasma membrane, nor did it inhibit the subsequent docking
      and fusion of GLUT4-myc with the plasma membrane. MEK inhibitors affected glucose
      transport mediated by GLUT4 but not GLUT1. Importantly, the presence of MEK
      inhibitors only at the time of the transport assay markedly impaired both insulin
      stimulated glucose uptake and MAPK signaling. Conversely, removal of MEK
      inhibitors before the transport assay restored glucose uptake and MAPK signaling.
      Collectively, our studies suggest a possible role for MEK in the activation of
      GLUT4.

PMID- 15172889
TI  - Dissociation of lung function and airway inflammation in chronic obstructive
      pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) is defined by progressive,
      irreversible airflow limitation and an inflammatory response of the lungs,
      usually to cigarette smoke. However, COPD is a heterogeneous disease in terms of
      clinical, physiologic, and pathologic presentation. We aimed to evaluate whether
      airflow limitation, airway responsiveness, and airway inflammation are separate
      entities underlying the pathophysiology of COPD by using factor analysis. A total
      of 114 patients (99 males/15 females, age 62 +/- 8 years, 42 pack-years smoking,
      no inhaled or oral steroids > 6 months) with irreversible airflow limitation
      (postbronchodilator FEV(1) 63 +/- 9% predicted, FEV(1)/inspiratory vital capacity
      [IVC] 48 +/- 9%) and symptoms of chronic bronchitis or dyspnea were studied in a
      cross-sectional design. Postbronchodilator FEV(1) and FEV(1)/IVC, reversibility
      to inhaled beta(2)-agonists, diffusing capacity, provocative concentration of
      methacholine required to produce a 20% drop in FEV(1), total serum IgE, exhaled
      nitric oxide, and induced sputum cell counts (% eosinophils, % neutrophils) were
      collected. Factor analysis yielded 4 separate factors that accounted for 63.6% of
      the total variance. Factor 1 was comprised of FEV(1), FEV(1)/IVC, and residual
      volume/total lung capacity. Factor 2 included reversibility, IgE, provocative
      concentration of methacholine required to produce a 20% drop in FEV(1,) and
      diffusing capacity. Factor 3 contained exhaled nitric oxide and factor 4 included
      sputum % neutrophils and % eosinophils. We conclude that airflow limitation,
      airway inflammation, and features commonly associated with asthma are separate
      and largely independent factors in the pathophysiology of COPD.

PMID- 15172890
TI  - Elastic properties of the respiratory system in infants with cystic fibrosis.
AB  - Respiratory system compliance (Crs) in infants with cystic fibrosis (CF) has been
      reported as decreased or not different compared with healthy control subjects;
      however, the reported measurements of Crs were "quasi-static" or by the single
      breath occlusion technique, with all measurements limited to tidal lung volume,
      as well as using inspiratory rather than expiratory pressures. We compared the
      passive elastic properties of the respiratory system of sleeping infants with CF
      (n = 10) and healthy control subjects (n = 34) by measuring static deflation
      pressure--volume (PV) curves from a lung volume at 30 cm H(2)O (V(30)) to FRC.
      There was no significant difference between the groups for Crs, which was
      measured as the slope between airway relaxation pressures of 5 and 15 cm H(2)O,
      the linear portion of the deflation PV curve. In addition, when PV curves were
      normalized to V(30), there were no differences between the infants with CF and
      healthy control subjects in the fractional volumes at any airway pressure. The
      infants with CF had significantly lower forced expiratory flows; however, lower
      flows did not correlate with fractional volumes measured from the PV curve. Our
      findings indicate that infants with CF have normal elastic properties of the
      respiratory system.

PMID- 15172891
TI  - Genioglossus activity during sleep in normal control subjects and children with
      obstructive sleep apnea.
AB  - Children with obstructive sleep apnea syndrome (OSAS) have more collapsible
      airways compared with normal subjects, yet sustain stable breathing during
      wakefulness and part of sleep. This indicates successful neuromuscular
      compensation. Using a custom intraoral surface electrode to record pharyngeal
      dilator muscle activity (the genioglossus [EMGgg] normalized to the wakeful
      baseline), we performed overnight polysomnograms in three groups of children: (1)
      patients with OSAS without continuous positive airway pressure (CPAP) (n = 13);
      (2) patients with OSAS with CPAP (n = 5); and (3) control subjects without CPAP
      (n = 13). Our objective was to evaluate the EMGgg as a function of sleep state
      and during disordered breathing, compared with stable sleep and wakefulness. In
      control subjects, the EMGgg decreased from wakefulness to Stage 2 (mean +/- SD,
      65 +/- 6%), and further during REM (51 +/- 9%) (p < 0.05). In patients with OSAS,
      the EMGgg for apneic breaths during REM (37 +/- 9%) was lower than during stable
      breathing (83 +/- 17%) (p < 0.05) and wakefulness (p < 0.05). CPAP lowered the
      EMGgg in patients with OSAS during all sleep states. These data indicate that (1)
      EMGgg compensatory mechanisms remain active during sleep in patients with severe
      OSAS; (2) EMGgg reductions are temporally associated with sleep apnea events; and
      (3) REM sleep is associated with the lowest and most variable EMGgg.

PMID- 15172892
TI  - Treatment completion and costs of a randomized trial of rifampin for 4 months
      versus isoniazid for 9 months.
AB  - There is little published information regarding treatment completion, safety, and
      efficacy of rifampin administered daily for 4 months-a recommended alternative to
      9 months of isoniazid for therapy of latent tuberculosis infection. In an open
      label randomized trial at a university-affiliated respiratory hospital,
      consenting patients whose treating physician had recommended therapy for latent
      tuberculosis infection were randomized to daily self-administered rifampin for 4
      months or daily self-administered isoniazid for 9 months. Of 58 patients
      randomized to rifampin, 53 (91%) took 80% of doses, and 50 (86%) took more than
      90% of doses within 20 weeks compared with 44 (76%) and 36 (62%) who took 80 and
      90%, respectively, of doses of isoniazid within 43 weeks (relative risks: 80% of
      doses, 1.2 [95% confidence interval: 1.02, 1.4]; 90% of doses, 1.4 [1.1, 1.7]).
      Adverse events resulted in permanent discontinuation of therapy for two (3%)
      patients taking rifampin, and for eight (14%) patients taking isoniazid. Three
      patients developed drug-induced hepatitis--all were taking isoniazid. Total costs
      of therapy were significantly higher for isoniazid. In conclusion, completion of
      therapy was significantly better with 4 months of rifampin and major side effects
      were somewhat lower. Further studies are needed to assess the safety and efficacy
      of the 4-month rifampin regimen.

PMID- 15172893
TI  - Classifying asthma severity in children: mismatch between symptoms, medication
      use, and lung function.
AB  - Current guidelines for asthma care categorize asthma severity based on the
      frequency of asthma symptoms, medication use, and lung function measures. The
      objective of this study was to determine whether lung function measures are
      consistent with levels of asthma severity as defined by the National Asthma
      Education and Prevention Program/Expert Panel Report 2 Guidelines. Parents of
      children aged 5-18 years with asthma seen in two outpatient subspecialty clinics
      completed questionnaires regarding asthma medication use and symptom frequency
      over the preceding 1 and 4 weeks, respectively. All children performed
      spirometry. When asthma severity was based on the higher severity of asthma
      symptom frequency or medication use, asthma was mild intermittent in 6.9% of
      participants, mild persistent in 27.9%, moderate persistent in 22.4%, and severe
      persistent in 42.9%. FEV(1) % predicted did not differ by level of asthma
      severity. FEV(1)/FVC decreased as asthma severity increased (p < 0.0001) and was
      abnormal in 33% of the participants, and a greater percentage of participants had
      an abnormal FEV(1)/FVC as asthma severity increased (p = 0.0001). In children,
      asthma severity classified by symptom frequency and medication usage does not
      correlate with FEV(1) categories defined by National Asthma Education and
      Prevention Program Guidelines. FEV(1) is generally normal, even in severe
      persistent childhood asthma, whereas FEV(1)/FVC declines as asthma severity
      increases.

PMID- 15172894
TI  - Treatment of nasal inflammation decreases the ability of subjects with asthma to
      condition inspired air.
AB  - We previously showed that individuals with seasonal allergy have a reduced
      ability to condition air, which was improved by nasal inflammation. We also
      showed that subjects with asthma have a reduced ability to condition air. Because
      individuals with asthma usually have inflammation in the nose, we hypothesized
      that treatment with an intranasal steroid would reduce nasal inflammation and
      further decrease nasal conditioning capacity. We performed a randomized, double
      blind, placebo-controlled, 2-way crossover study on 20 subjects with asthma
      comparing the effect of treatment with intranasal budesonide for 2 weeks on nasal
      conditioning. Treatment with budesonide caused no significant effect on nasal
      conditioning as compared with placebo. When we evaluated the subgroup of
      nonsmoking subjects, budesonide caused a significant reduction in nasal
      conditioning. We speculate that nasal inflammation in nonsmoking individuals with
      asthma increases the conditioning capacity and reducing it with an intranasal
      steroid worsens the ability of the nose to condition air. In addition, smoking
      causes an increase in nasal conditioning capacity by non-steroid-dependent
      factors. These observations help us understand the pathophysiology of nasal
      conditioning, but do not negate the positive clinical benefits of budesonide on
      treating nasal inflammation.

PMID- 15172895
TI  - Differences in patient and bed partner-assessed quality of life in sleep
      disordered breathing.
AB  - Sleep-disordered breathing (SDB) is associated with daytime sleepiness and
      impaired quality of life. Clinical experience suggests that there is a
      discrepancy between the information provided by the patient and the bed partner.
      Although this discrepancy is widely recognized, it is not known whether there are
      differences in quality of life ratings as reported by the patient and by the bed
      partner on the patient's behalf. Using the Short-Form 36 to assess quality of
      life in 122 patients with SDB (apnea-hypopnea index > or = 5 events/hour), this
      study found that patients with SDB generally rate their quality of life higher
      than their respective bed partners. Systematic differences existed between the
      two raters in the following Short-Form 36 domains: physical functioning, general
      health, and vitality. Moreover, male patients reported a higher functional status
      compared with female patients relative to their respective bed partners. In
      contrast, no differences were noted between self and bed partner quality of life
      in normal subjects (n = 15) without SDB (apnea-hypopnea index < 5 events/hour)
      recruited from the general community. This study suggests that systematic
      differences exist between patient- and bed partner-assessed quality of life in
      SDB. Bed partner ratings provide supplemental information on quality of life
      impairment in SDB.

PMID- 15172896
TI  - Development of lung function in early life: influence of birth weight in infants
      of nonsmokers.
AB  - This study aimed to compare lung growth and development during the first year of
      life in healthy term infants of low or appropriate birth weight for gestation.
      Paired measurements of forced expiratory volume in 0.4 second, FVC, and forced
      expiratory flow when 75% of FVC has been exhaled were obtained, using the raised
      volume technique, at about 7 weeks and 9 months of age in 80 infants (32 low and
      48 appropriate birth weight for gestation) of white, nonsmoking mothers. Forced
      flows and volumes increased with growth. Longitudinal trends in results were
      compared between the two groups, using random effects modeling and adjusted for
      potential confounding factors. After adjustment for sex, age, and length, forced
      expiratory volume was significantly reduced by an average (95% confidence
      interval) of 9% (2 to 16%) in low birth weight compared with appropriate birth
      weight for gestation infants throughout the first year of life, with a similar
      trend in forced expiratory flow (8% [-2 to 17%]) and FVC (4% [-3 to 11%]). These
      findings suggest that lung function is reduced in low birth weight for gestation
      infants born to nonsmoking white mothers and that this is independent of somatic
      growth during infancy.

PMID- 15172897
TI  - Small size at birth and greater postnatal weight gain: relationships to
      diminished infant lung function.
AB  - Recent evidence suggests that impaired lung development is linked with diminished
      lung function and an increased risk of chronic obstructive airway disease in
      adulthood. To examine environmental influences on early lung development, we
      measured lung function in 131 normal-term infants aged 5-14 weeks. Adjusting for
      age at measurement, FEV at 0.4 seconds fell by 4.4% for each standard deviation
      decrease in birth weight (p = 0.047); when adjusted for FVC, FEV at 0.4 seconds
      was not related to birth weight but fell by 3.2% per standard deviation increase
      in infant weight gain (p = 0.001). Age- and sex-adjusted total respiratory system
      compliance fell by 7.0% per standard deviation decrease in birth weight (p <
      0.001) but was not related to infant weight gain. In univariate analyses, age
      adjusted forced expiratory flow at functional residual capacity was not related
      to birth weight, but decreased by 11.0% per standard deviation increase in infant
      weight gain (p = 0.007). The respiratory rate rose by 5.1% per standard deviation
      increase in infant weight gain (p = 0.001). Lung function measurements were not
      related to infant feeding. The observations suggest that lower rates of fetal
      growth and higher rates of early infancy weight gain are associated with impaired
      lung development.

PMID- 15172898
TI  - Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway
      inflammation in allergic asthma.
AB  - IgE plays an important role in allergic asthma. We hypothesized that reducing IgE
      in the airway mucosa would reduce airway inflammation. Forty-five patients with
      mild to moderate persistent asthma with sputum eosinophilia of 2% or more were
      treated with humanized monoclonal antibody against IgE (omalizumab) (n = 22) or
      placebo (n = 23) for 16 weeks. Outcomes included inflammatory cells in induced
      sputum and bronchial biopsies, and methacholine responsiveness. Treatment with
      omalizumab resulted in marked reduction of serum IgE and a reduction of IgE+
      cells in the airway mucosa. The mean percentage sputum eosinophil count decreased
      significantly (p < 0.001) from 6.6 to 1.7% in the omalizumab group, a reduction
      significantly (p = 0.05) greater than with placebo (8.5 to 7.0%). This was
      associated with a significant reduction in tissue eosinophils; cells positive for
      the high-affinity Fc receptor for IgE; CD3+, CD4+, and CD8+ T lymphocytes; B
      lymphocytes; and cells staining for interleukin-4, but not with improvement in
      airway hyperresponsiveness to methacholine. This study shows antiinflammatory
      effects of omalizumab treatment and provides clues for mechanisms whereby
      omalizumab reduces asthma exacerbations and other asthma outcomes in more severe
      asthma. The lack of effect of omalizumab on methacholine responsiveness suggests
      that IgE or eosinophils may not be causally linked to airway hyperresponsiveness
      to methacholine in mild to moderate asthma.

PMID- 15172899
TI  - Association of statin therapy with outcomes of acute coronary syndromes: the
      GRACE study.
AB  - BACKGROUND: Statins administered early in patients with acute coronary syndromes
      may lead to modest reductions in recurrent ischemic events. OBJECTIVE: To examine
      the association between previous and early in-hospital statin therapy and the
      presentation and outcomes of an acute coronary syndrome. DESIGN: Cohort study.
      SETTING: 94 hospitals in 14 countries participating in the Global Registry of
      Acute Coronary Events (GRACE). PATIENTS: 19,537 patients with an acute coronary
      syndrome who were enrolled from April 1999 to September 2002. MEASUREMENTS:
      Statin use before and after presentation with an acute coronary syndrome and
      associated rates of myocardial infarction, hospital complications, and hospital
      mortality. The composite end point included death, in-hospital myocardial
      infarction, and stroke. RESULTS: Patients who were already taking statins when
      they presented to the hospital were less likely to have ST-segment elevation
      (odds ratio [OR], 0.79 [95% CI, 0.71 to 0.88]) or myocardial infarction (OR, 0.78
      [CI, 0.70 to 0.86]). Patients who continued to take statins in the hospital were
      less likely to experience complications or die than patients who never received
      statins (OR, 0.66 [CI, 0.56 to 0.77]). Patients not previously taking statins who
      began statin therapy in the hospital were less likely to die than patients who
      never received statin therapy (OR, 0.38 [CI, 0.30 to 0.48]). However, adjustment
      for the hospital of admission attenuated the association between initiation of
      statin therapy and the composite end point (OR, 0.84 [CI, 0.65 to 1.10]).
      LIMITATIONS: This observational study cannot exclude confounding by clinical and
      hospital factors. CONCLUSIONS: These data support the hypothesis that statin
      therapy can modulate early pathophysiologic processes in patients with acute
      coronary syndromes. A randomized trial of statin therapy in acute myocardial
      infarction is warranted.

PMID- 15172900
TI  - Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous
      thrombosis: a randomized trial.
AB  - BACKGROUND: The current standard initial therapies for deep venous thrombosis are
      low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study
      of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy
      and a safety profile similar to those of low-molecular-weight heparin
      (dalteparin). OBJECTIVE: To evaluate whether fondaparinux has efficacy and safety
      similar to those of enoxaparin in patients with deep venous thrombosis. DESIGN:
      Randomized, double-blind study. SETTING: 154 centers worldwide. PATIENTS: 2205
      patients with acute symptomatic deep venous thrombosis. INTERVENTION:
      Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients
      weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body
      weight, subcutaneously twice daily for at least 5 days and until vitamin K
      antagonists induced an international normalized ratio greater than 2.0.
      MEASUREMENTS: The primary efficacy outcome was the 3-month incidence of
      symptomatic recurrent venous thromboembolic complications. The main safety
      outcomes were major bleeding during initial treatment and death. An independent,
      blinded committee adjudicated all outcomes. RESULTS: 43 (3.9%) of 1098 patients
      randomly assigned to fondaparinux had recurrent thromboembolic events compared
      with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute
      difference, -0.15 percentage point [95% CI, -1.8 to 1.5 percentage points]).
      Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of
      patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.
      LIMITATIONS: Follow-up was incomplete in 0.4% of fondaparinux-treated patients
      and 1.0% of enoxaparin-treated patients. CONCLUSIONS: Once-daily subcutaneous
      fondaparinux was at least as effective (not inferior) and safe as twice-daily,
      body weight-adjusted enoxaparin in the initial treatment of patients with
      symptomatic deep venous thrombosis.

PMID- 15172901
TI  - Effects of training in direct observation of medical residents' clinical
      competence: a randomized trial.
AB  - BACKGROUND: Faculty observation of residents and students performing clinical
      skills is essential for reliable and valid evaluation of trainees. OBJECTIVE: To
      evaluate the efficacy of a new multifaceted method of faculty development called
      direct observation of competence training. DESIGN: Controlled trial of faculty
      from 16 internal medicine residency programs using a cluster randomization
      design. SETTING: Academic medical centers. PARTICIPANTS: 40 internal medicine
      teaching faculty members: 17 in the intervention group and 23 in the control
      group. MEASUREMENTS: Changes in faculty comfort performing direct observation,
      faculty satisfaction with workshop, and changes in faculty rating behaviors 8
      months after completing the training. INTERVENTION: The direct observation of
      competence workshop combines didactic mini-lectures, interactive small group and
      videotape evaluation exercises, and evaluation skill practice with standardized
      residents and patients. RESULTS: 37 faculty members (16 in the intervention group
      and 21 in the control group) completed the study. Most of the faculty in the
      intervention group (14 [88%]) reported that they felt significantly more
      comfortable performing direct observation compared with control group faculty (4
      [19%]) (P = 0.04), and all intervention faculty rated the training as
      outstanding. For 9 videotaped clinical encounters, intervention group faculty
      were more stringent than controls in their evaluations of medical interviewing,
      physical examination, and counseling; differences in ratings for medical
      interviewing and physical examination remained statistically significant even
      after adjustment for baseline rating behavior. LIMITATIONS: The study involved a
      limited number of residency programs, and faculty did not rate the performance of
      actual residents. CONCLUSION: Direct observation of competence training, a new
      multifaceted approach to faculty development, leads to meaningful changes in
      rating behaviors and in faculty comfort with evaluation of clinical skills.

PMID- 15172902
TI  - Brief communication: early appearance of islet autoantibodies predicts childhood
      type 1 diabetes in offspring of diabetic parents.
AB  - BACKGROUND: The development of type 1 diabetes mellitus is preceded by
      autoimmunity against islet beta cells. OBJECTIVE: To determine the risk for islet
      autoimmunity and childhood diabetes in offspring of affected parents. DESIGN:
      Prospective cohort study. SETTING: German BABYDIAB study. PARTICIPANTS: 1610
      offspring of parents with type 1 diabetes. MEASUREMENTS: Autoantibodies to islet
      autoantigens were measured at 9 months, 2 years, 5 years, and 8 years of age.
      RESULTS: By 5 years of age, the frequency of islet autoantibodies was 5.9% (95%
      CI, 4.6% to 7.2%), the frequency of multiple islet autoantibodies was 3.5% (CI,
      2.5% to 4.5%), and the frequency of diabetes was 1.5% (CI, 0.9% to 2.1%). The
      risk for diabetes was highest in offspring with multiple autoantibodies (40%
      within 5 years vs. 3% in offspring with single autoantibodies; P = 0.005).
      Progression to multiple islet autoantibodies was fastest in children who were
      autoantibody positive by age 2 years (P < 0.001), and progression to diabetes was
      inversely related to the age of positivity for multiple autoantibodies (P =
      0.02). LIMITATIONS: The findings are limited to childhood diabetes in affected
      families. CONCLUSIONS: Childhood autoimmune diabetes is associated with
      autoimmunity that starts before 2 years of age.

PMID- 15172903
TI  - Effects of a quality improvement collaborative on the outcome of care of patients
      with HIV infection: the EQHIV study.
AB  - BACKGROUND: Multi-institution collaborative quality improvement programs are a
      well-established and broadly applicable quality improvement strategy, but there
      is little systematic assessment their effectiveness. OBJECTIVE: To evaluate the
      effectiveness of a quality improvement collaborative in improving the quality of
      care for HIV-infected patients. DESIGN: Controlled pre- and postintervention
      study. SETTING: Clinics receiving funding from the Ryan White Comprehensive AIDS
      Resources Emergency Act. PARTICIPANTS: 44 intervention clinics and 25 control
      clinics matched by location (urban or rural), region, size, and clinic type.
      MEASUREMENTS: Changes in quality-of-care measures abstracted from medical records
      of pre- and postintervention samples of patients at each study clinic. Measures
      examined included use and effectiveness of antiretroviral therapy, screening and
      prophylaxis, and access to care. INTERVENTION: A multi-institutional quality
      improvement collaborative (the "Breakthrough Series"). RESULTS: 9986 patients
      were studied. Clinical and sociodemographic characteristics of the intervention
      and control patients were similar (P > 0.05). Differences in changes in the
      quality of care were not statistically significant. The proportion of patients
      with a suppressed viral load increased by 11 percentage points (from 40.1% to
      51.1%) in the intervention group compared with 5.3 percentage points (from 43.6%
      to 48.8%) in the control group, but this difference was not statistically
      significant (P = 0.18). In addition, rates of appropriate screening tests and
      prophylaxis did not differ between intervention and control sites. LIMITATIONS:
      It was not possible to perform a pure randomized trial of the intervention or to
      assess other measures of quality, such as adherence and satisfaction.
      CONCLUSIONS: This prospective, matched study of almost 10 000 patients found that
      a quality improvement collaborative did not significantly affect the quality of
      care. Additional research is needed to improve methods of teaching and
      implementing quality improvement programs to achieve better results.

PMID- 15172904
TI  - Creating the evidence base for quality improvement collaboratives.
AB  - Intensive efforts are under way to improve health care quality and safety
      throughout the United States and abroad. Many of these efforts use the quality
      improvement collaborative method, an approach emphasizing collaborative learning
      and exchange of insights and support among a set of health care organizations.
      Unfortunately, the widespread acceptance and reliance on this approach are based
      not on solid evidence but on shared beliefs and anecdotal affirmations that may
      overstate the actual effectiveness of the method. More effective use of the
      collaborative method will require a commitment by users, researchers, and other
      stakeholders to rigorous, objective evaluation and the creation of a valid,
      useful knowledge and evidence base. Development of this evidence base will
      require improved conceptions of the nature of quality problems, quality
      improvement processes, and the types of research needed to elucidate these
      processes. Researchers, journal editors, and funding agencies must also cooperate
      to ensure that published evaluations are relevant, comprehensive, and cumulative.

PMID- 15172905
TI  - A new model for accreditation of residency programs in internal medicine.
AB  - A renewed emphasis on clinical competence and its assessment has grown out of
      public concerns about the safety, efficacy, and accountability of health care in
      the United States. Medical schools and residency training programs are paying
      increased attention to teaching and evaluating basic clinical skills, stimulated
      in part by these concerns and the responding initiatives of accrediting,
      certifying, and licensing bodies. This paper, from the Residency Review Committee
      for Internal Medicine of the Accreditation Council for Graduate Medical
      Education, proposes a new outcomes-based accreditation strategy for residency
      training programs in internal medicine. It shifts residency program accreditation
      from external audit of educational process to continuous assessment and
      improvement of trainee clinical competence.

PMID- 15172906
TI  - Systematic review: surveillance systems for early detection of bioterrorism
      related diseases.
AB  - BACKGROUND: Given the threat of bioterrorism and the increasing availability of
      electronic data for surveillance, surveillance systems for the early detection of
      illnesses and syndromes potentially related to bioterrorism have proliferated.
      PURPOSE: To critically evaluate the potential utility of existing surveillance
      systems for illnesses and syndromes related to bioterrorism. DATA SOURCES:
      Databases of peer-reviewed articles (for example, MEDLINE for articles published
      from January 1985 to April 2002) and Web sites of relevant government and
      nongovernment agencies. STUDY SELECTION: Reports that described or evaluated
      systems for collecting, analyzing, or presenting surveillance data for
      bioterrorism-related illnesses or syndromes. DATA EXTRACTION: From each included
      article, the authors abstracted information about the type of surveillance data
      collected; method of collection, analysis, and presentation of surveillance data;
      and outcomes of evaluations of the system. DATA SYNTHESIS: 17,510 article
      citations and 8088 government and nongovernmental Web sites were reviewed. From
      these, the authors included 115 systems that collect various surveillance
      reports, including 9 syndromic surveillance systems, 20 systems collecting
      bioterrorism detector data, 13 systems collecting influenza-related data, and 23
      systems collecting laboratory and antimicrobial resistance data. Only the systems
      collecting syndromic surveillance data and detection system data were designed,
      at least in part, for bioterrorism preparedness applications. Syndromic
      surveillance systems have been deployed for both event-based and continuous
      bioterrorism surveillance. Few surveillance systems have been comprehensively
      evaluated. Only 3 systems have had both sensitivity and specificity evaluated.
      LIMITATIONS: Data from some existing surveillance systems (particularly those
      developed by the military) may not be publicly available. CONCLUSIONS: Few
      surveillance systems have been specifically designed for collecting and analyzing
      data for the early detection of a bioterrorist event. Because current evaluations
      of surveillance systems for detecting bioterrorism and emerging infections are
      insufficient to characterize the timeliness or sensitivity and specificity,
      clinical and public health decision making based on these systems may be
      compromised.

PMID- 15172907
TI  - Observational studies of treatment effectiveness: some cautions.

PMID- 15172908
TI  - Toward the simplification of antithrombotic treatment of venous thromboembolism.

PMID- 15172909
TI  - Quality of care and quality of training: a shared vision for internal medicine?

PMID- 15172910
TI  - A tale of two patients.

PMID- 15172911
TI  - Risk factors for Helicobacter pylori resistance.

PMID- 15172912
TI  - Use of angiotensin-converting enzyme inhibitors in heart failure and renal
      insufficiency.

PMID- 15172913
TI  - Patient safety and medical malpractice.

PMID- 15172914
TI  - Practice guidelines for chronic kidney disease.

PMID- 15172915
TI  - Practice guidelines for chronic kidney disease.

PMID- 15172916
TI  - To butterfly or to needle: the pilot phase.

PMID- 15172917
TI  - A novel diagnostic method for acute pulmonary embolism: technetium-99m apcitide
      scintigraphy.

PMID- 15172918
TI  - 25 years and counting: Centers for Disease Control and Prevention identifies
      opportunities and challenges for diabetes prevention and control.

PMID- 15172919
TI  - The evolving diabetes burden in the United States.
AB  - A diabetes epidemic emerged during the 20th century and continues unchecked into
      the 21st century. It has already taken an extraordinary toll on the U.S.
      population through its acute and chronic complications, disability, and premature
      death. Trend data suggest that the burden will continue to increase. Efforts to
      pre- vent or delay the complications of diabetes or, better yet, to prevent or
      delay the development of diabetes itself are urgently needed.

PMID- 15172920
TI  - Primary prevention of type 2 diabetes mellitus by lifestyle intervention:
      implications for health policy.
AB  - More than 18 million Americans currently have diabetes mellitus. The economic and
      human cost of the disease is devastating. In the United States, diabetes is the
      most common cause of blindness among working-age adults, the most common cause of
      nontraumatic amputations and end-stage renal disease, and the sixth most common
      cause of death. For the cohort of Americans born in 2000, the estimated lifetime
      risk for diabetes is more than 1 in 3. In the next 50 years, the number of
      diagnosed cases of diabetes is predicted to increase by 165% in the United
      States, with the largest relative increases seen among African Americans,
      American Indians, Alaska Natives, Asian and Pacific Islanders, and
      Hispanic/Latino persons. Compelling scientific evidence indicates that lifestyle
      change prevents or delays the occurrence of type 2 diabetes in high-risk groups.
      This body of evidence from randomized, controlled trials conducted in 3 countries
      has definitively established that maintenance of modest weight loss through diet
      and physical activity reduces the incidence of type 2 diabetes in high-risk
      persons by about 40% to 60% over 3 to 4 years. The number of persons at high risk
      for type 2 diabetes is similar to the number of persons who have diabetes. This
      paper summarizes scientific evidence supporting lifestyle intervention to prevent
      type 2 diabetes and discusses major policy challenges to broad implementation of
      lifestyle intervention in the health system.

PMID- 15172921
TI  - Diabetes translation research: where are we and where do we want to be?
AB  - Translation research transforms currently available knowledge into useful
      measures for everyday clinical and public health practice. We review the progress
      in diabetes translation research and identify future challenges and opportunities
      in this field. Several promising interventions to optimize implementation of
      efficacious diabetes treatments are available. Many of these interventions,
      singly or in combination, need to be more formally tested in larger randomized or
      quasi-experimental practical trials using outcomes of special interest to
      patients (for example, patient satisfaction and quality of life) and policymakers
      (for example, cost and cost-effectiveness). The long-term outcomes (such as
      morbidity, mortality, quality of life, and costs) of strategies aimed at
      improving diabetes care must be assessed. Translation research also needs to
      incorporate ways of studying complex systems of care. The challenges and
      opportunities offered by translation research are tremendous.

PMID- 15172922
TI  - Understanding the environmental issues in diabetes self-management education
      research: a reexamination of 8 studies in community-based settings.
AB  - Eight studies included in a recent systematic review of the efficacy of diabetes
      self-management education were qualitatively reexamined to determine the presence
      of theoretical frameworks, methods used to ensure cultural appropriateness, and
      the quality of the instrument. Theoretical frameworks that help to explain
      complex pathways that produce health outcomes were lacking; culture indices were
      not incorporated into diabetes self-management education; and the instruments
      used to measure outcomes were inadequate. We provide recommendations to improve
      research on diabetes self-management education in community settings through use
      of a contextual framework that encourages targeting multiple levels of influence-
      individual, family, organizational, community, and policy.

PMID- 15172923
TI  - Application of economic analysis to diabetes and diabetes care.
AB  - Facing limited resources and increases in demand from competing programs,
      policymakers and health care providers seek guidance from economic studies on how
      to use health care resources wisely. Previous economic studies mainly focused on
      estimating the cost of diabetes and cost-effectiveness of different
      interventions. These studies found that diabetes is costly and that its cost will
      continue to increase; thus, more resources should be devoted to research aimed at
      finding effective means to prevent the disease and its complications. In
      addition, the cost-effectiveness of interventions varies greatly in terms of
      quality-adjusted life-years gained; therefore, efficient uses of resources should
      be an important consideration when interventions are prioritized. The need for
      economic studies will continue to grow because of increasing demand for limited
      resources from the growing number of interventions available. Future studies
      should be of better quality and broadened in areas of research.

PMID- 15172924
TI  - Moving diabetes care from science to practice: the evolution of the National
      Diabetes Prevention and Control Program.
AB  - The National Diabetes Prevention and Control Program has a dynamic and evolving
      scientific foundation. This article describes this program and how seminal
      research studies provide an impetus for its public health policy and programs.
      The charge and challenges of integrating science into past, current, and future
      program designs are detailed, as are the program's accomplishments. Areas
      requiring new science are explored, including better research to translate new
      findings into clinical and public health practice and models to evaluate the
      effect of public health on improved outcomes. The epidemic of diabetes and its
      increasing burden on public health demands a better understanding of existing
      science and its limitations and informed public dialogue and policy responses.

PMID- 15172925
TI  - Summaries for patients. Statin therapy and the outcomes during hospitalization
      for acute coronary syndromes.

PMID- 15172926
TI  - Summaries for patients. Fondaparinux or enoxaparin for deep venous thrombosis?

PMID- 15172927
TI  - Summaries for patients. Direct observation of medical trainees' clinical skills.

PMID- 15172928
TI  - Summaries for patients. Development of islet cell autoantibodies and type 1
      diabetes.

PMID- 15172929
TI  - Do quality improvement programs improve care for HIV-infected patients?

PMID- 15172930
TI  - Successful treatment of sarcoidosis.

PMID- 15172931
TI  - Clinical implications of genetic polymorphism of CYP2D6 in Mexican Americans.

PMID- 15172932
TI  - Lymphedema secondary to postmastectomy radiation: incidence and risk factors.
AB  - BACKGROUND: Postmastectomy radiotherapy (PMRT) has proven benefits for certain
      patients with breast cancer; however, one of its complications is lymphedema.
      This study examines the incidence of and risk factors associated with lymphedema
      secondary to PMRT. METHODS: The charts of patients treated with mastectomy at
      Roswell Park Cancer Institute between January 1, 1995, and April 20, 2001, who
      received PMRT were reviewed. Univariate analysis of patient, disease, and
      treatment variables was conducted. Multivariate analysis was performed on
      variables found to be significant in univariate analysis. RESULTS: One hundred
      five patients received PMRT. The incidence of lymphedema was 27%. Patient age,
      body mass index, disease stage, positive lymph nodes, nodes resected,
      postoperative infection, duration of drainage, chemotherapy, and hormonal therapy
      were not associated with lymphedema. Total dose (P =.032), posterior axillary
      boost (P =.047), overlap technique (P =.037), radiotherapy before 1999 (P =.028),
      and radiotherapy at Roswell Park Cancer Institute (P =.028) were significantly
      associated with lymphedema. Increased lymphedema was noted with supraclavicular,
      internal mammary, mastectomy scar boost, and chest wall tangential photon beam
      radiation, but the associations were not statistically significant. CONCLUSIONS:
      The high incidence and debilitating effects of lymphedema must be weighed against
      the benefits of PMRT. Efforts to prevent lymphedema should be emphasized.

PMID- 15172933
TI  - Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients
      with irresectable liver metastases using percutaneous balloon catheter
      techniques: a phase I and II study.
AB  - BACKGROUND: Isolated hepatic perfusion for irresectable metastases confined to
      the liver has reported response rates of 50% to 75%. Magnitude, costs, and
      nonrepeatability of the procedure are its major drawbacks. We developed a less
      invasive, less costly, and potentially repeatable balloon catheter-mediated
      isolated hypoxic hepatic perfusion (IHHP) technique. METHODS: In this phase I and
      II study, 18 consecutive patients with irresectable colorectal or ocular melanoma
      hepatic metastases were included. Two different perfusion methods were used, both
      with inflow via the hepatic artery, using melphalan 1 mg/kg. In the first eight
      patients, the portal vein was occluded, and outflow was via the hepatic veins
      into an intracaval double-balloon catheter. This orthograde IHHP had on average
      56% leakage. In next 10 patients, we performed a retrograde outflow IHHP with a
      triple balloon blocking outflow into the caval vein and allowing outflow via the
      portal vein. The retrograde IHHP still had 35% leakage on average. RESULTS:
      Although local drug concentrations were high with retrograde IHHP, systemic
      toxicity was still moderate to severe. Partial responses were seen in 12% and
      stable disease in 81% of patients. The median time to local progression was 4.8
      months. CONCLUSIONS: We have abandoned occlusion balloon methodology for IHHP
      because it failed to obtain leakage control. We are presently conducting a study
      using a simplified surgical retrograde IHHP method, in which leakage is fully
      controlled, which translates into high response rates.

PMID- 15172934
TI  - Hepatic resection of the intraductal papillary type of peripheral
      cholangiocarcinoma.
AB  - BACKGROUND: Peripheral cholangiocarcinoma (PCC) can be grossly classified into
      mass-forming, periductal-infiltrating, and intraductal papillary (IP) types.
      Information on IP-PCC patients undergoing hepatectomy is sparse because of the
      small number of cases. METHODS: The clinical features of 40 IP-PCC patients
      undergoing hepatectomy between 1977 and 2000 were reviewed. The clinical features
      of 94 PCC patients without IP growth undergoing hepatectomy were used for
      comparison. RESULTS: IP-PCC and non-IP-PCC groups had similar age distributions
      (P =.674), sex ratios (P =.079), and positive rates for serum carcinoembryonic
      antigen and CA 19-9 (P =.121 and.795, respectively). The two groups also
      exhibited similar rates of association between hepatolithiasis and PCC (P =.230).
      However, more IP-PCC patients exhibited signs during admission, and more had ALT
      values >36 IU/L; they also had smaller tumors, more mucobilia association, and
      tumors in earlier stages and had undergone more postoperative chemotherapy.
      Multivariate logistic regression analysis showed that only ALT >36 IU/L
      differentiated IP-PCC from non-IP-PCC patients. The two groups exhibited similar
      operative mortality (P = 1.0). Follow-up ranged from 1.6 to 125.2 months (mean
      and median, 44.6 and 5.7 months, respectively). The 1-, 3-, and 5-year overall
      survival rates were 72.9%, 41.2%, and 24.7%, respectively, in the IP-PCC group
      and 43.3, 6.03%, and 2.01% in the non-IP-PCC group. The prognosis was favorable
      for the IP-PCC patients (P <.00001), particularly for IP-PCC patients who
      received curative hepatectomy (P =.013). CONCLUSIONS: IP-PCC patients had
      significantly better survival than non-IP-PCC patients, and aggressive curative
      hepatic resection is associated with a longer survival.

PMID- 15172935
TI  - Head and neck soft tissue sarcomas: a multivariate analysis of outcomes.
AB  - BACKGROUND: Soft tissue sarcomas of the head and neck region represent a rare
      group of tumors of which a limited number of published individual- and
      institution-based experiences exist. METHODS: We performed an analysis of head
      and neck sarcoma patients identified from our institution between 1973 and 1999.
      Exclusion criteria included pediatric rhabdomyosarcomas, sarcomas of the
      neuromeningeal axis or non-head and neck primary disease sites, and bone
      sarcomas. All cases underwent pathologic re-review before statistical analysis.
      RESULTS: After pathologic review, 111 head and neck sarcoma patients remained
      (mean age, 47 +/- 20 years). The median duration of follow-up was 51 months; the
      actuarial 5-year relapse-free, disease-specific, and overall survivals were 55%,
      52%, and 44%, respectively. Forty-six percent remained free of recurrence at the
      most recent follow-up, and the most common site of recurrence was local followed
      by distant sites. By multivariate analysis, size and grade significantly
      influenced relapse-free, disease-specific, and overall survivals, whereas margin
      status additionally influenced relapse-free survival. Subset analysis of the
      fibrosarcoma/malignant fibrous histiocytoma and desmoid/dermatofibrosarcoma
      protuberans histologies was undertaken. CONCLUSIONS: Size >5 cm and high-grade
      histology are considered poor prognostic indicators. Patients with either of
      these characteristics should be considered for adjuvant trials.

PMID- 15172937
TI  - Somatoform disorders: a help or hindrance to good patient care?

PMID- 15172938
TI  - Attention-deficit hyperactivity disorder and life-span development.

PMID- 15172939
TI  - Somatoform disorders in general practice: prevalence, functional impairment and
      comorbidity with anxiety and depressive disorders.
AB  - BACKGROUND: General practitioners play a pivotal part in the recognition and
      treatment of psychiatric disorders. Identifying somatoform disorders is important
      for the choice of treatment. AIMS: To quantify the prevalence of, and functional
      impairment associated with, somatoform disorders, and their comorbidity with
      anxiety/depressive disorders. METHOD: Two-stage prevalence study: a set of
      questionnaires was completed by 1046 consecutive patients of general
      practitioners (aged 25-80 years), followed by a standardised diagnostic interview
      (SCAN 2.1). RESULTS: The prevalence of somatoform disorders was 16.1% (95% CI
      12.8-19.4). When disorders with only mild impairment were included, the
      prevalence increased to 21.9%. Comorbidity of somatoform disorders and
      anxiety/depressive disorders was 3.3 times more likely than expected by chance.
      In patients with comorbid disorders, physical symptoms, depressive symptoms and
      functional limitations were additive. CONCLUSIONS: Our findings underline the
      importance of a comprehensive diagnostic approach to psychiatric disorders in
      general practice.

PMID- 15172940
TI  - Prevalence of chronic disabling fatigue in children and adolescents.
AB  - BACKGROUND: The epidemiology of chronic fatiguing illnesses in young people is
      poorly understood. AIMS: To estimate the lifetime prevalence of different
      definitions of chronic fatigue in 8- to 17-year-olds. METHOD: Participants came
      from two population-based twin series. Parents completed self-report
      questionnaires that inquired whether either child had ever experienced more than
      a few days of disabling fatigue. Telephone interviews were undertaken for
      individuals who had experienced such an episode. RESULTS: Questionnaires were
      returned by 1468 families (65% response rate) and telephone interviews were
      undertaken regarding 99 of the 129 subjects (77%) who had experienced fatigue.
      The lifetime prevalence estimates ranged from 2.34% (95% CI 1.75-2.94) for
      disabling fatigue lasting 3 months to 1.29% (95% CI 0.87-1.71) for a disorder
      resembling adult operationally defined chronic fatigue syndrome. CONCLUSIONS:
      From the age of 11 years, young people have similar rates and types of chronic
      fatiguing illnesses to adults.

PMID- 15172941
TI  - Age of traumatisation as a predictor of post-traumatic stress disorder or major
      depression in young women.
AB  - BACKGROUND: Findings in developmental psychopathology suggest that traumatisation
      in childhood may increase the risk of both post-traumatic stress disorder (PTSD)
      and major depressive disorder, whereas traumatisation in adolescence is more
      likely to lead to elevated PTSD risk. AIMS: To estimate the impact of
      traumatisation in childhood or adolescence in a community sample. METHOD: A
      representative sample of 1966 young women from Dresden aged 18-45 years were
      interviewed for occurrence of traumatic events and the onset of PTSD and major
      depression. The sample was subdivided into a childhood trauma group (trauma up to
      age 12 years) and an adolescent trauma group (trauma from age 13 years). RESULTS:
      A quarter of all participants reported traumatic events meeting the DSM AI
      criterion. In the childhood group conditional risks for PTSD and major depressive
      disorder were 17.0% and 23.3%, respectively, compared with risks of 13.3% and
      6.5%, respectively, in the adolescent group. In 29% of those with PTSD, major
      depression was also present. CONCLUSIONS: The risk of developing major depressive
      disorder after traumatisation in childhood is approximately equal to the risk of
      developing PTSD. After age 13 years, the risk of PTSD is greater than the risk of
      major depression after traumatisation.

PMID- 15172942
TI  - Hippocampal volume change in depression: late- and early-onset illness compared.
AB  - BACKGROUND: Evidence for structural hippocampal change in depression is limited
      despite reports of neuronal damage due to hypercortisolaemia and vascular
      pathology. AIMS: To compare hippocampal and white matter structural change in
      demographically matched controls and participants with early-onset and late-onset
      depression. METHOD: High-resolution volumetric magnetic resonance imaging (MRI)
      and rating of MRI hyperintensities. RESULTS: A total of 51 people with depression
      and 39 control participants were included. Participants with late-onset
      depression had bilateral hippocampal atrophy compared with those with early-onset
      depression and controls. Hippocampal volumes did not differ between control
      participants and those with early-onset depression. Age of depression onset
      correlated (negatively) with hippocampal volume but lifetime duration of
      depression did not. Hyperintensity ratings did not differ between groups.
      CONCLUSIONS: Results suggest that acquired biological factors are of greater
      importance in late-than in early-onset illness and that pathological processes
      other than exposure to hypercortisolaemia of depression underlie hippocampal
      atrophy in depression of late life.

PMID- 15172943
TI  - Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder.
AB  - BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis function, as variously
      measured by the responses to the combined dexamethasone/corticotrophin-releasing
      hormone (dex/CRH) test, the dexamethasone suppression test (DST) and basal
      cortisol levels, has been reported to be abnormal in bipolar disorder. AIMS: To
      test the hypothesis that HPA axis dysfunction persists in patients in remission
      from bipolar disorder. METHOD: Salivary cortisol levels and the plasma cortisol
      response to the DST and dex/CRH test were examined in 53 patients with bipolar
      disorder, 27 of whom fulfilled stringent criteria for remission, and in 28
      healthy controls. Serum dexamethasone levels were measured. RESULTS: Patients
      with bipolar disorder demonstrated an enhanced cortisol response to the dex/CRH
      test compared with controls (P=0.001). This response did not differ significantly
      between remitted and non-remitted patients. These findings were present after the
      potentially confounding effects of dexamethasone levels were accounted for.
      CONCLUSIONS: The dex/CRH test is abnormal in both remitted and non-remitted
      patients with bipolar disorder. This measure of HPA axis dysfunction is a
      potential trait marker in bipolar disorder and thus possibly indicative of the
      core pathophysiological process in this illness.

PMID- 15172944
TI  - Effects of long-term prolactin-raising antipsychotic medication on bone mineral
      density in patients with schizophrenia.
AB  - BACKGROUND: High rates of osteoporosis in schizophrenia may result from the
      prolactin-raising effects of some antipsychotic medication. Aims To examine bone
      mineral density in relation to relevant endocrine variables in patients with
      schizophrenia taking prolactin-raising antipsychotics. METHOD: Fifty-five
      patients who had been receiving prolactin-raising antipsychotic medication for
      >10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip
      bones. Among the endocrine variables assessed were plasma prolactin and sex
      hormones. RESULTS: Age-related reduced bone mineral density measures were found
      in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of the
      female patients. Higher doses of medication were associated with increased rates
      of both hyperprolactinaemia and bone mineral density loss. Bone loss for the
      whole group was correlated with medication dose, and for men was inversely
      correlated with testosterone values. CONCLUSIONS: These results suggest that
      patients with schizophrenia on long-term prolactin-raising antipsychotic
      medication are at high risk of developing reduced bone mineral density as a
      consequence of hyperprolactinaemia-induced hypogonadism.

PMID- 15172945
TI  - Non-adherence to antipsychotic medication regimens: associations with resource
      use and costs.
AB  - BACKGROUND: Several factors are thought to influence resource use and costs in
      treating schizophrenia. AIMS: To assess the relative impact of non-adherence and
      other factors associated with resource use and costs incurred by people with
      schizophrenia. METHOD: Secondary analyses were made of data from a 1994 national
      survey of psychiatric morbidity among adults living in institutions in the UK.
      Factors potentially relating to resource use and costs were examined using two
      part models. RESULTS: Patients who failed to adhere to their medication regimen
      were over one-and-a-half times as likely as patients who did adhere to it to
      report use of in-patient services. Non-adherence is one of the most significant
      factors in increasing external service costs, by a factor of almost 3. Non
      adherence predicted an excess annual cost per patient of approximately 2500
      British pounds for in-patient services and over 5000 British pounds for total
      service use. CONCLUSIONS: Resource use and costs are influenced by various
      factors. Medication non-adherence consistently exhibits an association with
      higher costs. Further important factors are patient needs and the ability of the
      system to address them.

PMID- 15172946
TI  - Premorbid, psychosocial and clinical predictors of the costs of schizophrenia and
      other psychoses.
AB  - BACKGROUND: Predictors of the costs of psychosis have received insufficient
      research attention, particularly factors associated with indirect costs. AIMS: To
      identify the predictors of direct mental health care costs and indirect or time
      loss costs in psychotic disorders and to discuss their implications for future
      interventions. METHOD: Structured interview data from the Low Prevalence
      Disorders Study (n=980) were used to examine predictors of the costs of psychosis
      in Australia. Estimates of annual costs per patient were derived from the
      perspectives of government and society. Hierarchical regressions were used to
      assess the contributions to costs of premorbid, psychosocial and clinical
      factors. RESULTS: Schizophrenia involved greater costs than other psychotic
      disorders. Non-completion of high-school education and chronicity of illness
      course were predictive of higher costs across all categories, and some factors
      were linked primarily with mental health care costs (e.g. age at onset, current
      symptomatology) or indirect costs (e.g. male gender, overall disability).
      CONCLUSIONS: Several concurrent strategies were recommended, including early
      intervention programmes and assertive evidence-based rehabilitation and supported
      employment programmes aimed at reducing disability. The cost-effectiveness of
      these approaches needs to be evaluated from the perspectives of both government
      and society.

PMID- 15172947
TI  - Utilising survey data to inform public policy: comparison of the cost
      effectiveness of treatment of ten mental disorders.
AB  - BACKGROUND: Mental health survey data are now being used proactively to decide
      how the burden of disease might best be reduced. AIMS: To study the cost
      effectiveness of current and optimal treatments for mental disorders and the
      proportion of burden avertable by each. METHOD: Data for three affective, four
      anxiety and two alcohol use disorders and for schizophrenia were compared interms
      of cost, burden averted and efficiency of current and optimal treatment. We then
      calculated the burden unavertable given current knowledge. The unit of health
      gain was a reduction in the years lived with disability (YLDs). RESULTS: Summing
      across all disorders, current treatment averted 13% of the burden, at an average
      cost of 30,000 Australian dollars per YLD gained. Optimal treatment at current
      coverage could avert 20% of the burden, at an average cost of 18,000 Australian
      dollars per YLD gained. Optimal treatment at optimal coverage could avert 28% of
      the burden, at 16,000 Australian dollars per YLD gained. Sixty per cent of the
      burden of mental disorders was deemed to be unavertable. CONCLUSIONS: The
      efficiency of treatment varied more than tenfold across disorders. Although
      coverage of some of the more efficient treatments should be extended, other
      factors justify continued use of less-efficient treatments for some disorders.

PMID- 15172948
TI  - Melancholia and the probability and lethality of suicide attempts.
AB  - We compared suicide attempts associated with melancholic v. non-melancholic major
      depression in 377 patients. Controlling for depression severity and other
      covariates, melancholia at baseline assessment was associated with more serious
      past suicide attempts and with the probability of suicide attempt during follow
      up.

PMID- 15172949
TI  - Psychiatric research in Nigeria: bridging tradition and modernisation.

PMID- 15172950
TI  - Analysing the efficacy of clozapine.

PMID- 15172951
TI  - Parental age difference and schizophrenia.

PMID- 15172952
TI  - Antidepressant effects of repetitive transcranial magnetic stimulation.

PMID- 15172953
TI  - Physical illness and schizophrenia.

PMID- 15172954
TI  - Evidence in cannabis research.

PMID- 15172955
TI  - MRCPsych exams.

PMID- 15172956
TI  - 'Neurasthenia'.

PMID- 15172957
TI  - Depolarization-induced calcium influx in rat mesenteric small arterioles is
      mediated exclusively via mibefradil-sensitive calcium channels.
AB  - 1. In this study, intracellular Ca(2+) was measured as the Fura-2 ratio (R) of
      fluorescence excited at 340 and 380 nm (F(340)/F(380)) in nonpressurized rat
      mesenteric small arterioles ( (lumen diameter) 10-25 microm). 2. The response to
      depolarization using 75 mm KCl was an increase in R from a baseline of 0.96+/
      0.01 ([Ca(2+)](i) approximately 74 nm) to 1.04+/-0.01 ( approximately 128 nm)
      (n=80). The response to 75 mm K(+) was reversibly abolished in Ca(2+)-free
      physiological saline solution, whereas phentolamine (10 microm) or tetrodotoxin
      (1 microm) had no effects. LaCl(3) (200 microm) inhibited 61+/-9% of the
      response. 3. A [K(+)]-response curve indicated that the Ca(2+) response was
      activated between 15 and 25 mm K(+). The data suggest that the Ca(2+) response
      was caused by the activation of voltage-dependent Ca(2+) channels. 4. Mibefradil
      use dependently inhibited the Ca(2+) response to 75 mm K(+) by 29+/-2% (100 nm),
      73+/-7% (1 microm) or 89+/-7% (10 microm). Pimozide (500 nm) use dependently
      inhibited the Ca(2+) response by 85+/-1%. 5. Nifedipine (1 microm) inhibited the
      Ca(2+) response to 75 mm K(+) by 41+/-12%. The response was not inhibited by
      calciseptine (500 nm), omega-agatoxin IVA (100 nm), omega-conotoxin MVIIA (500
      nm), or SNX-482 (100 nm). 6. Using reverse transcriptase-polymerase chain
      reaction, it was shown that neither Ca(V)2.1a (P-type) nor Ca(V)2.1b (Q-type)
      voltage-dependent Ca(2+) channels were expressed in mesenteric arterioles,
      whereas the Ca(V)3.1 (T-type) channel was expressed. Furthermore, no
      amplification products were detected when using specific primers for the
      beta(1b), beta(2), or beta(3) auxiliary subunits of high-voltage-activated Ca(2+)
      channels. 7. The results suggest that the voltage-dependent Ca(2+) channel
      activated by sustained depolarization in mesenteric arterioles does not classify
      as any of the high-voltage-activated channels (L-, P/Q-, N-, or R-type), but is
      likely to be a T-type channel. The possibility that the sustained Ca(2+) influx
      observed was the result of a T-type window current is discussed.

PMID- 15172958
TI  - The contribution of adrenoceptor subtype(s) in the renal vasculature of diabetic
      spontaneously hypertensive rats.
AB  - 1. Diabetes and hypertension are both associated with an increased risk of renal
      disease and are associated with neuropathies, which can cause defective autonomic
      control of major organs including the kidney. This study aimed to examine the
      alpha(1)-adrenoceptor subtype(s) involved in mediating adrenergically induced
      renal vasoconstriction in a rat model of diabetes and hypertension. 2. Male
      spontaneously hypertensive rats (SHR), 220-280 g, were anaesthetized with sodium
      pentobarbitone 7-day poststreptozotocin (55 mg x kg(-1) i.p.) treatment. The
      reductions in renal blood flow (RBF) induced by increasing frequencies of
      electrical renal nerve stimulation (RNS), close intrarenal bolus doses of
      noradrenaline (NA), phenylephrine (PE) or methoxamine were determined before and
      after administration of nitrendipine (Nit), 5-methylurapidil (5-MeU),
      chloroethylclonidine (CEC) and BMY 7378. 3. In the nondiabetic SHR group, mean
      arterial pressure (MAP) was 146+/-6 mmHg, RBF was 28.0+/-1.4 ml x min(-1) x kg(
      1) and blood glucose was 112.3+/-4.7 mg x dl(-1), and in the diabetic SHR Group,
      MAP was 144+/-3 mmHg, RBF 26.9+/-1.3 ml(-1) min x kg(-1) and blood glucose
      316.2+/-10.5 mg x dl(-1). Nit, 5-MeU and BMY 7378 blunted all the adrenergically
      induced renal vasoconstrictor responses in SHR and diabetic SHR by 25-35% (all
      P<0.05), but in diabetic rats the responses induced by RNS and NA treated with 5
      MeU were not changed. By contrast, during the administration of CEC,
      vasoconstrictor responses to all agonists were enhanced by 20-25% (all P<0.05) in
      both the SHR and diabetic SHR. 4. These findings suggest that alpha(1A) and
      alpha(1D)-adrenoceptor subtypes contribute in mediating the adrenergically
      induced constriction of the renal vasculature in both the SHR and diabetic SHR.
      There was also an indication of a greater contribution of presynaptic
      adrenoceptors, that is, alpha(1B)-, and/or alpha(2)-subtypes.

PMID- 15172959
TI  - Prostacyclin release and receptor activation: differential control of human
      pulmonary venous and arterial tone.
AB  - 1. In human pulmonary vascular preparations, precontracted arteries were more
      sensitive to the relaxant effect of acetylcholine (ACh) than veins (pD(2) values:
      7.25+/-0.08 (n=23) and 5.92+/-0.09 (n=25), respectively). Therefore, the role of
      prostacyclin (PGI(2)) was explored to examine whether this mediator may be
      responsible for the difference in relaxation. 2. In the presence of the
      cyclooxygenase (COX) inhibitor, indomethacin (INDO), the ACh relaxations were
      reduced in arteries but not in veins. On the contrary, an inhibitor (l-NOARG) of
      the nitric oxide synthase blocked preferentially the relaxation in veins. 3. A
      greater release of 6-keto-PGF(1alpha), the stable metabolite of PGI(2), was
      observed in arterial preparations than in venous preparations when stimulated
      with either ACh or arachidonic acid (AA). 4. Exogenous PGI(2) produced a reduced
      relaxant effect in the precontracted vein when compared with the artery. In the
      presence of the EP(1)-receptor antagonist AH6809, the PGI(2) relaxation of veins
      was similar to arteries. 5. In veins, AA (0.1 mm) produced a biphasic response,
      namely, a contraction peak (0.4-0.5 g) followed by a relaxation. These
      contractions in venous preparations were abolished either in the absence of
      endothelium or in the presence of INDO or an EP(1)-receptor antagonist (AH6809,
      SC19220). In the arterial preparations AA induced only relaxations. 6. In both
      vascular preparations, COX-1 but not the COX-2 protein was detected in microsomal
      preparations derived from homogenized tissues or freshly isolated endothelial
      cells. 7. The differential vasorelaxations induced by ACh may be explained, in
      part, by a more pronounced production and release of PGI(2) in human pulmonary
      arteries than in the veins. In addition, while PGI(2) induced relaxation by
      activation of IP-receptors in both types of vessels, a PGI(2) constrictor effect
      was responsible for masking the relaxation in the veins by activation of the
      EP(1)-receptor.

PMID- 15172960
TI  - Redox modulation of basal and beta-adrenergically stimulated cardiac L-type
      Ca(2+) channel activity by phenylarsine oxide.
AB  - 1. Phenylarsine oxide (PAO) is commonly used to inhibit tyrosine phosphatase
      activity. However, PAO can affect a variety of different processes because of its
      ability to promote sulfhydryl oxidation. In the present study, we investigated
      the effects that PAO has on basal and beta-adrenergically stimulated L-type
      Ca(2+) channel activity in isolated cardiac myocytes. 2. Extracellular
      application of PAO transiently stimulated the basal L-type Ca(2+) channel
      activity, whereas it irreversibly inhibited protein kinase A (PKA)-dependent
      regulation of channel activity by isoproterenol, forskolin and 8-CPT-cAMP (8-p
      chlorophenylthioadenosine 3',5'-cyclic monophosphate). PAO also inhibited channel
      activity irreversibly stimulated in the presence of adenosine 5'-(3
      thiotriphosphate) tetralithium salt. 3. Neither the stimulatory nor the
      inhibitory effects of PAO were affected by the tyrosine kinase inhibitor
      lavendustin A, suggesting that tyrosine phosphorylation is not involved. 4.
      Extracellular application of the sulfhydryl-reducing agent dithiothreitol (DTT)
      antagonized both the stimulatory and inhibitory effects of PAO. Yet, following
      intracellular dialysis with DTT, only the inhibitory effect of PAO was
      antagonized. 5. The inhibitory effect of PAO was mimicked by intracellular, but
      not extracellular application of the membrane impermeant thiol oxidant 5,5'
      dithio-bis(2-nitrobenzoic acid). 6. These results suggest that the stimulatory
      effect of PAO results from oxidation of sulfhydryl residues at an extracellular
      site and the inhibitory effect is due to redox regulation of an intracellular
      site that affects the response of the channel to PKA-dependent phosphorylation.
      It is concluded that the redox state of the cell may play a critical role in
      modulating beta-adrenergic responsiveness of the L-type Ca(2+) channel in cardiac
      myocytes.

PMID- 15172961
TI  - Antiapoptotic mechanisms of benidipine in the ischemic/reperfused heart.
AB  - 1. Considerable evidence indicates that calcium plays a critical role in
      apoptosis. We have previously shown that benidipine, a vasodilatory calcium
      channel blocker, attenuates postischemia myocardial apoptosis. The present study
      was designed to determine the mechanisms by which benidipine exerts its
      antiapoptotic effect. 2. Adult male rats were subjected to 30 min of ischemia
      followed by 3 h of reperfusion. Rats were randomized to receive either vehicle or
      benidipine (10 microg x kg(-1), i.v.) 10 min before reperfusion. 3. Compared with
      rats receiving vehicle, those rats treated with benidipine had reduced
      postischemic myocardial apoptosis as evidenced by decreased TUNEL-positive
      staining (8.4+/-1.2 vs 15.3+/-1.3%, P<0.01) and caspase-3 activity (1.94+/-0.25
      vs 3.43+/-0.29, P<0.01). 4. Benidipine treatment significantly reduced
      mitochondrial cytochrome c release and caspase-9 activation, but had no effect on
      caspase-8 activation, suggesting that benidipine exerts its antiapoptotic effect
      by inhibiting the mitochondrial-mediated, but not death receptor-mediated,
      apoptotic pathway. 4. 5. Benidipine treatment not only increased the maximal
      activity of ERK1/2 at 10 min after reperfusion, but also prolonged the duration
      of ERK1/2 activation. Benidipine treatment had no significant effect on other
      apoptotic regulating molecules, such as p38 MAPK. 6. Taken together, our present
      study demonstrated for the first time the differential regulation of a calcium
      channel blocker. Benidipine tilted the balance between ERK1/2 and p38 MAPK toward
      an antiapoptotic state, decreased mitochondrial cytochrome c release, reduced
      caspase-9 activation, and attenuated subsequent caspase-3 activation and
      postischemic myocardial apoptosis.

PMID- 15172962
TI  - Endothelin-induced constriction of the ductus venosus in fetal sheep:
      developmental aspects and possible interaction with vasodilatory prostaglandin.
AB  - 1. The ductus venosus is actively regulated in the fetus, but questions remain on
      the presence of a functional sphincter at its inlet. Using fetal sheep (0.6-0.7
      gestation onwards), we have examined the morphology of the vessel and have also
      determined whether endothelin-1 (ET-1) qualifies as a natural constrictor being
      modulated by prostaglandins (PGs). 2. Masson's staining and alpha-actin
      immunohistochemistry showed a muscular, sphincter-like formation at the ductus
      inlet and a muscle layer within the wall of the vessel proper. This muscle cell
      component increased with age. 3. ET-1 contracted dose-dependently isolated
      sphincter and extrasphincter preparations of the ductus from term fetus. This ET
      1 effect also occurred in the premature, but its threshold was higher. 4. BQ123
      (1 microm) caused a rightward shift in the ET-1 dose-response curve, while
      indomethacin at a threshold concentration (28 nm) tended to have an opposite
      effect. 5. Big ET-1 also contracted the ductus sphincter but differed from ET-1
      for its lesser potency and inhibition by phosphoramidon (50 microm). 6. The
      ductus sphincter (term and preterm) and extrasphincter (term) released 6-keto
      PGF(1alpha) (hence PGI(2)) and, to a lesser degree, PGE(2) at rest and their
      release increased dose-dependently upon ET-1 treatment. Both basal and stimulated
      release was curtailed by endothelium removal. 7. BQ123 and phosphoramidon reduced
      slightly the contraction of ductus sphincter to indomethacin (2.8 microm). 8. We
      conclude that the ductus contains a contractile mechanism in the sphincter and
      extrasphincter regions. ET-1 lends itself to a role in the generation of
      contractile tone and its action may be modulated by prostaglandins.

PMID- 15172963
TI  - Epidermal growth factor differentially augments G(i)-mediated stimulation of c
      Jun N-terminal kinase activity.
AB  - 1. Signaling networks involving different receptor systems allow extracellular
      signals to be integrated and transformed into various biological activities. In
      this report, we studied the activity of the c-Jun N-terminal kinase (JNK)
      subgroup of mitogen-activated protein kinases (MAPKs), in response to stimulation
      by G protein-coupled receptors (GPCRs) and co-activation with epithermal growth
      factor receptor (EGFR). 2. Stimulation of exogenous GPCRs in Cos-7 cells induced
      JNK activation of different magnitudes depending on their G-protein coupling
      specificities (G(q)>G(i)>G(s)), and a moderate JNK activation was linked to
      stimulation of endogenous EGFR by EGF. 3. Co-stimulation with GPCR agonists and
      EGF resulted in differential augmentation of JNK activities, with G(i)-coupled
      receptors associated with a synergistic JNK activation upon co-stimulation with
      EGF, while G(q)- and G(s)-coupled receptors were incapable of triggering this
      effect. 4. This G(i)/EGF-induced synergistic JNK activation was inhibited by
      pertussis toxin and AG1478, and may involve Src family tyrosine kinases, PI3 K,
      Ca(2+)/calmodulin and small GTPases as important intermediates, while Ca(2+)
      mobilization was triggered by the stimulation of G(q)-coupled receptor or EGF
      treatment, but not by the G(i)- or G(s)-coupled receptors. 5. Transient
      expression of Gbetagamma subunits with EGF treatment, or co-activation of
      exogenous G(i)-coupled receptor with thapsigargin also resulted in a synergistic
      JNK activation. Activation of G(i)-coupled receptor accompanied with EGF
      treatment enhanced the expression level and activity of MAPK phosphatase type I,
      which occurred after the maximal synergistic JNK activation. 6. Our results
      support a mechanistic model where EGF signaling may differentially regulate the
      JNK activities triggered by GPCRs of different coupling specificities.

PMID- 15172964
TI  - Central blockade of nitric oxide synthesis reduces moxonidine-induced
      hypotension.
AB  - 1. Nitric oxide (NO) and alpha(2)-adrenoceptor and imidazoline agonists such as
      moxonidine may act centrally to inhibit sympathetic activity and decrease
      arterial pressure. 2. In the present study, we investigated the effects of
      pretreatment with l-NAME (NO synthesis inhibitor), injected into the 4th
      ventricle (4th V) or intravenously (i.v.), on the hypotension, bradycardia and
      vasodilatation induced by moxonidine injected into the 4th V in normotensive
      rats. 3. Male Wistar rats with a stainless steel cannula implanted into the 4th V
      and anaesthetized with urethane were used. Blood flows were recorded by use of
      miniature pulsed Doppler flow probes implanted around the renal, superior
      mesenteric and low abdominal aorta. 4. Moxonidine (20 nmol), injected into the
      4th V, reduced the mean arterial pressure (-42+/-3 mmHg), heart rate (-22+/-7
      bpm) and renal (-62+/-15%), mesenteric (-41+/-8%) and hindquarter (-50+/-8%)
      vascular resistances. 5. Pretreatment with l-NAME (10 nmol into the 4th V) almost
      abolished central moxonidine-induced hypotension (-10+/-3 mmHg) and renal (-10+/
      4%), mesenteric (-11+/-4%) and hindquarter (-13+/-6%) vascular resistance
      reduction, but did not affect the bradycardia (-18+/-8 bpm). 6. The results
      indicate that central NO mechanisms are involved in the vasodilatation and
      hypotension, but not in the bradycardia, induced by central moxonidine in
      normotensive rats.

PMID- 15172965
TI  - Thrombopoietin responsiveness reflects the number of doublings undergone by
      megakaryocyte progenitors.
AB  - To assess the variation of thrombopoietin (TPO) responsiveness associated with
      megakaryocyte (MK) progenitor amplification, TPO dose-response curves were
      obtained for normal human, single-cell plated CD34(+)CD41(+) cells. The number of
      MKs per well was determined in situ and expressed as number of doublings (NbD).
      Dose-response curves of the mean frequency of clones of each size versus log TPO
      concentration showed highly significant differences in the TPO concentration
      needed for half-maximum generation of clones of different sizes (TPO(50)): 1.89
      +/- 0.51 pg/mL for 1 MK clones; 7.75 +/- 0.81 pg/mL for 2 to 3 MK clones; 38.5 +/
      5.04 pg/mL for 4 to 7 MK clones, and 91.8 +/- 16.0 pg/mL for 8 to 15 MK clones.
      These results were consistent with a prediction of the generation-age model,
      because the number of previous doublings in vivo was inversely correlated with
      the number of residual doublings in vitro. TPO responsiveness decreased in vitro
      by a factor of 3.5 per doubling, reflecting the recruitment of progressively more
      ancestral progenitors. In support of this hypothesis, the more mature
      CD34(+)CD41(+)CD42(+) cell fraction had a lower TPO(50) (P < .001), underwent
      fewer NbD (P < .001), and expressed a 2.8-fold greater median Mpl receptor
      density (P < .001) than the CD34(+)CD41(+)CD42(-) fraction. Progenitors that have
      completed their proliferative program have maximum factor responsiveness and are
      preferentially induced to terminal differentiation.

PMID- 15172966
TI  - Role of protein kinase Czeta in thrombin-induced endothelial permeability
      changes: inhibition by angiopoietin-1.
AB  - Endothelial cell leakiness is regulated by mediators such as thrombin, which
      promotes endothelial permeability, and anti-inflammatory agents, such as
      angiopoietin-1. Here we define a new pathway involved in thrombin-induced
      permeability that involves the atypical protein kinase C isoform, PKCzeta.
      Chemical inhibitor studies implicated the involvement of an atypical PKC isoform
      in thrombin-induced permeability changes in human umbilical vein endothelial
      cells. Thrombin stimulation resulted in PKCzeta, but not the other atypical PKC
      isoform, PKClambda, translocating to the membrane, an event known to be critical
      to enzyme activation. The involvement of PKCzeta was confirmed by overexpression
      of constitutively active PKCzeta, resulting in enhanced basal permeability.
      Dominant-negative PKCzeta prevented the thrombin-mediated effects on endothelial
      cell permeability and inhibited thrombin-induced activation of PKCzeta. Rho
      activation does not appear to play a role, either upstream or downstream of
      PKCzeta, as C3 transferase does not block thrombin-induced PKCzeta activation and
      dominant-negative PKCzeta does not block thrombin-induced Rho activation.
      Finally, we show that angiopoietin-1 inhibits thrombin-induced PKCzeta
      activation, Rho activation, and Ca(++) flux, thus demonstrating that the powerful
      antipermeability action of angiopoietin-1 is mediated by its action on a number
      of signaling pathways induced by thrombin and implicated in permeability changes.

PMID- 15172967
TI  - Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene.
AB  - Hemophilia is a genetic disease caused by a deficiency of blood coagulation
      factor VIII or IX. Bleeding into joints is the most frequent manifestation of
      hemophilia. Hemarthrosis results in an inflammatory and proliferative disorder
      termed hemophilic synovitis (HS). In time, a debilitating, crippling arthritis,
      hemophilic arthropathy, develops. Although the clinical sequence of events from
      joint bleeding to synovitis to arthropathy is well documented, the component or
      components in blood and the molecular changes responsible for hemophilic
      synovitis are not known. Iron has long been suspected to be the culprit but
      direct evidence has been lacking. Previously, we showed that iron increased human
      synovial cell proliferation and induced c-myc expression. Here we show that
      bleeding into a joint in vivo and iron in vitro result in increased expression of
      the p53-binding protein, mdm2. Iron induced the expression of mdm2 by normal
      human synovial cells approximately 8-fold. In a murine model of human hemophilia
      A, hemarthrosis resulted in pathologic changes observed in human hemophilic
      synovitis and a marked increase in synovial cell proliferation. Iron, in vitro,
      induced the expression of mdm2. The molecular changes induced by iron in the
      blood may be the basis of the increase in cell proliferation and the development
      of hemophilic synovitis.

PMID- 15172968
TI  - Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by
      secreting the serine protease HGF-activator.
AB  - Multiple myeloma (MM) is a common hematologic neoplasm consisting of malignant
      plasma cells, which expand in the bone marrow. A potential key signal in the
      evolution of MM is hepatocyte growth factor (HGF), which acts as a potent
      paracrine and/or autocrine growth factor and survival factor for MM cells.
      Proteolytic conversion of HGF into its active form is a critical limiting step in
      HGF/MET signaling. Here, we show that malignant MM plasma cells convert HGF into
      its active form and secrete HGF-activator (HGFA), a serine protease specific for
      HGF activation. By using serine protease inhibitors and neutralizing antibodies,
      we demonstrate that HGFA produced by the MM cells is responsible for their
      ability to catalyze HGF activation. We, therefore, suggest that autocatalyzation
      of HGF conversion by MM cells is an important step in HGF/MET-induced myeloma
      growth and survival, which may have implications for the management of this
      incurable form of cancer.

PMID- 15172969
TI  - Characterization of new human CD20 monoclonal antibodies with potent cytolytic
      activity against non-Hodgkin lymphomas.
AB  - Despite the rapid and widespread integration of chimeric CD20 monoclonal antibody
      (mAb), rituximab, into the management of non-Hodgkin lymphoma, its efficacy
      remains variable and often modest when used as a single agent. To develop more
      potent reagents, human immunoglobulin transgenic mice were used to generate a
      panel of immunoglobulin G1kappa (IgG1kappa) CD20 mAbs. All reagents bound
      strongly to CD20(+) cells and recruited mononuclear cells for the lysis of
      malignant B cells. However, 2 mAbs, 2F2 and 7D8, were exceptionally active in
      complement-dependent cytotoxicity (CDC), being able to lyse a range of rituximab
      resistant targets, such as CD20-low chronic lymphocytic leukemia (CLL), in the
      presence of human plasma or unfractionated blood. Further analysis showed that
      2F2 and 7D8, like rituximab, redistributed CD20 into Triton X-100-insoluble
      regions of the plasma membrane, but that they had markedly slower off-rates. To
      determine whether off-rate influenced CDC, a non-complement activating F(ab')(2)
      antihuman kappa reagent was used. This reagent markedly slowed the off-rate of
      rituximab and increased its CDC activity to that of 2F2 and 7D8. Thus, with
      increasing evidence that mAb therapeutic activity in vivo depends on complement
      activation, these new CD20 reagents with their slow off-rates and increased
      potency in CDC hold considerable promise for improved clinical activity.

PMID- 15172970
TI  - Roles of MITF for development of mast cells in mice: effects on both precursors
      and tissue environments.
AB  - The mutant tg/tg mice, which do not express mi transcription factor (MITF), lack
      mast cells in most tissues. Since MITF is expressed in both mast cells and
      tissues where mast cells develop, there is a possibility that the tg/tg mice may
      show abnormalities in both mast cell precursors and tissue environments. We
      examined this possibility by bone marrow and skin transplantation. When bone
      marrow cells of tg/tg mice were transplanted to W/W(v) mice that possess normal
      tissue environment, mast cells did not develop in all tissues examined. The
      number of developing mast cells in the skin of W/W(v) mice was much lower when
      grafted to tg/tg recipients than when grafted to normal (+/+) recipients. These
      results indicated that mast cell precursors of tg/tg mice were defective. When
      bone marrow cells of +/+ mice were transplanted, the number of developing mast
      cells was significantly lower in examined tissues of tg/tg recipients than in
      those of W/W(v) recipients, suggesting that the tissue environment for mast cell
      development was defective in tg/tg mice. MITF appeared essential for the function
      of both mast cell precursors and tissue environments for their development.

PMID- 15172971
TI  - An endothelial laminin isoform, laminin 8 (alpha4beta1gamma1), is secreted by
      blood neutrophils, promotes neutrophil migration and extravasation, and protects
      neutrophils from apoptosis.
AB  - During extravasation, neutrophils migrate through the perivascular basement
      membrane (BM), a specialized extracellular matrix rich in laminins. Laminins 8
      (LN-8) (alpha4beta1gamma1) and 10 (LN-10) (alpha5beta1gamma1) are major
      components of the endothelial BM, but expression, recognition, and use of these
      laminin isoforms by neutrophils are poorly understood. In the present study, we
      provide evidence, using a panel of novel monoclonal antibodies against human
      laminin alpha4 (LNalpha4) chain, that neutrophils contain and secrete LN-8, and
      that this endogenous laminin contributes to chemoattractant-induced, alphaMbeta2
      integrin-dependent neutrophil migration through albumin-coated filters. Phorbol
      ester-stimulated neutrophils adhered to recombinant human (rh) LN-8, rhLN-10, and
      mouse LN-1 (mLN-1) (alpha1beta1gamma1) via alphaMbeta2-integrin, and these
      laminin isoforms strongly promoted chemoattractant-induced neutrophil migration
      via the same integrin. However, only rhLN-8 enhanced the spontaneous migration.
      In addition, recruitment of neutrophils into the peritoneum following an
      inflammatory stimulus was impaired in LNalpha4-deficient mice. rhLN-8 also
      protected isolated neutrophils from spontaneous apoptosis. This study is the
      first to identify a specific laminin isoform in neutrophils and provides evidence
      for the role of LN-8 in the adhesion, migration, extravasation, and survival of
      these cells.

PMID- 15172972
TI  - Late effects in survivors of chronic myeloid leukemia treated with hematopoietic
      cell transplantation: results from the Bone Marrow Transplant Survivor Study.
AB  - The purpose of this study was to analyze medical late effects among patients with
      chronic myeloid leukemia (CML) treated with hematopoietic cell transplantation
      (HCT). Subjects included 248 CML survivors who received an HC transplant (related
      donors [RDs], n = 150; unrelated donors [URDs], n = 70; or autologous, n = 28)
      and had survived at least 2 years, and a comparison group of 317 siblings.
      Subjects completed a 238-item survey on medical late effects. Compared with
      siblings, survivors were at a higher risk of developing ocular, oral health,
      endocrine, gastrointestinal, musculoskeletal, neurosensory, and neuromotor
      impairments. Multivariate analysis limited to RD and URD recipients found that
      chronic graft-versus-host disease (cGVHD) was associated with a higher risk of
      hypothyroidism, osteoporosis, cardiopulmonary, neurosensory, and neuromotor
      impairments. Overall health was reported as excellent, very good, or good in 78%
      of subjects, although those with cGVHD were more likely to report poor overall
      health. URD survivors were more likely to report a need for assistance with
      routine activities and that their current health prevented work or school
      attendance. This study demonstrates that HCT survivors, regardless of donor type,
      have a high prevalence of long-term health-related complications. However,
      adverse medical late effects with significant morbidity were uncommon. Chronic
      GVHD is the most important predictor of adverse medical late effects and poor
      overall health.

PMID- 15172973
TI  - Association of Foxp3 regulatory gene expression with graft-versus-host disease.
AB  - Graft-versus-host disease (GVHD) is characterized by an impairment of mechanisms
      that underlie the development of immunologic tolerance. Although the cytokine
      storm associated with GVHD leads to expression of cell surface markers on both
      effector and regulatory T cells, regulatory CD4+ T cells that play an
      instrumental role in the maintenance of tolerance appear to uniquely express the
      Foxp3 transcriptional repressor. Foxp3 mRNA expression was significantly
      decreased in peripheral blood mononuclear cells from patients with either
      allogeneic GVHD or autologous GVHD compared with patients without GVHD.
      Expression of Foxp3 negatively correlated with the severity of GVHD but
      positively correlated with recent thymic emigrants. The results suggest that
      defective thymic function contributes to the impaired reconstitution of immune
      regulatory mechanisms following transplantation. The decrease in regulatory
      mechanisms after transplantation appears to provide an environment permissive to
      the development of GVHD.

PMID- 15172974
TI  - Activation of the platelet-derived growth factor-receptor enhances survival of
      murine bone endothelial cells.
AB  - The activation of the microvascular endothelial cell platelet-derived growth
      factor (PDGF) receptor (PDGF-R) by PDGF has been implicated in neoplastic
      angiogenesis. Here, we established cultures of murine bone microvascular
      endothelial cells and examined their response to stimulation with PDGF BB ligand
      and to blockade of PDGF-R signaling with the tyrosine kinase inhibitor STI571
      (Gleevec). The addition of STI571 to cultures of bone endothelial cells blocked
      PDGF BB-induced phosphorylation in a dose-dependent manner and completely
      abrogated the activation of downstream targets Akt and ERK1/2. Coadministration
      of STI571 and Taxol also induced the activation of procaspase-3 and significant
      apoptosis. These data suggest that phosphorylation of PDGF-R stimulates survival
      pathways in bone endothelial cells and that by selectively inhibiting PDGF-R
      signaling with STI571, the cells are rendered sensitive to Taxol treatment. The
      therapeutic combination of STI571 and Taxol may be a powerful tool for targeting
      tumor-associated endothelial cells in the skeletal compartment.

PMID- 15172975
TI  - Vascular normalization by vascular endothelial growth factor receptor 2 blockade
      induces a pressure gradient across the vasculature and improves drug penetration
      in tumors.
AB  - Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise
      the delivery of therapeutics to tumors. Here we show that blocking vascular
      endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody)
      decreases interstitial fluid pressure, not by restoring lymphatic function, but
      by producing a morphologically and functionally "normalized" vascular network. We
      demonstrate that the normalization process prunes immature vessels and improves
      the integrity and function of the remaining vasculature by enhancing the
      perivascular cell and basement membrane coverage. We also show that DC101 induces
      a hydrostatic pressure gradient across the vascular wall, which leads to a deeper
      penetration of molecules into tumors. Thus, vascular normalization may contribute
      to the improved survival rates in tumor-bearing animals and in colorectal
      carcinoma patients treated with an anti-VEGF antibody in combination with
      cytotoxic therapies.

PMID- 15172976
TI  - Preexisting lymphatic endothelium but not endothelial progenitor cells are
      essential for tumor lymphangiogenesis and lymphatic metastasis.
AB  - Endothelial progenitor cells have been shown to contribute to angiogenesis in
      various tumor models. Here, we have studied the relative contributions of bone
      marrow (BM)-derived endothelial progenitors and pre-existing lymphatic vessels to
      tumor lymphangiogenesis. We did not find significant incorporation of genetically
      marked BM-derived cells in lymphatic vessels during tumor- or vascular
      endothelial growth factor C-induced lymphangiogenesis. The degree of tumor
      lymphangiogenesis correlated with lymphatic vessel density in the peritumoral
      area, and despite tumor lymphangiogenesis, lymphatic metastasis failed to occur
      in gene-targeted vascular endothelial growth factor C(+/-) mice that have
      hypoplasia of the lymphatic network. Our data demonstrate that during tumor
      lymphangiogenesis and cancer cell dissemination via the lymphatics, the newly
      formed lymphatic vessels sprout from the pre-existing local lymphatic network
      with little if any incorporation of BM-derived endothelial progenitor cells.

PMID- 15172977
TI  - Frequent silencing of low density lipoprotein receptor-related protein 1B (LRP1B)
      expression by genetic and epigenetic mechanisms in esophageal squamous cell
      carcinoma.
AB  - Low-density lipoprotein receptor-related protein 1B (LRP1B) is frequently deleted
      in tumors of various types, but its status and expression in esophageal squamous
      cell carcinomas (ESCs) have never been reported. In the course of a program to
      screen ESC cell lines for copy-number aberrations using array-based comparative
      genomic hybridization, we identified a homozygous deletion of LRP1B. Genomic PCR
      experiments revealed homozygous deletions of LRP1B in additional ESC cell lines
      (total, 6 of 43; 14.0%) and in primary esophageal tumors (30 of 70; 42.9%).
      Moreover, expression of LRP1B mRNA was frequently silenced in ESC lines without
      homozygous deletions (14 of 37; 37.8%). Using bisulfite-PCR analysis and
      sequencing, we found that LRP1B-nonexpressing cells without homozygous deletions
      were highly methylated at a CpG island of LRP1B, a sequence possessing promoter
      activity. Treatment with 5-aza-2'-deoxycytidine restored expression of LRP1B in
      those ESC lines. Histone acetylation status correlated directly with expression
      of LRP1B and inversely with the methylation status of the CpG island. Methylation
      of LRP1B was also detected in primary esophageal tumors. Restoration of LRP1B
      expression in ESC cells reduced colony formation. These results suggest that loss
      of LRP1B function in esophageal carcinogenesis most often occurs either by
      homozygous deletion or by transcriptional silencing through hypermethylation of
      its CpG island.

PMID- 15172978
TI  - Disappearance of the telomere dysfunction-induced stress response in fully
      senescent cells.
AB  - Replicative senescence is a natural barrier to cellular proliferation that is
      triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM
      activation and H2AX-gamma nuclear focus formation are sensitive markers of
      telomere dysfunction in primary human fibroblasts. Whereas the activated form of
      ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were
      readily detected in late-passage cells. The ectopic expression of telomerase in
      late-passage cells abrogated ATM activation and H2AX-gamma focus formation,
      suggesting that these stress responses were the consequence of telomere
      dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of
      TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to
      initiate the telomere signaling response; breakage of chromosomes with telomeric
      associations is not required for this activation. Although ATM activation and
      H2AX-gamma foci were readily observed in late-passage cells, they disappeared
      once cells became fully senescent, indicating that constitutive signaling from
      dysfunctional telomeres is not required for the maintenance of senescence.

PMID- 15172979
TI  - Reduced expression of the let-7 microRNAs in human lung cancers in association
      with shortened postoperative survival.
AB  - In this study, we report for the first time reduced expression of the let-7
      microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had
      undergone potentially curative resection could be classified into two major
      groups according to let-7 expression in unsupervised hierarchical analysis,
      showing significantly shorter survival after potentially curative resection in
      cases with reduced let-7 expression (P = 0.0003). Multivariate COX regression
      analysis showed this prognostic impact to be independent of disease stage (hazard
      ratio = 2.17; P = 0.009). In addition, overexpression of let-7 in A549 lung
      adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study
      represents the first report of reduced expression of let-7 and the potential
      clinical and biological effects of such a microRNA alteration.

PMID- 15172980
TI  - Presence of simian virus 40 DNA sequences in human lymphoid and hematopoietic
      malignancies and their relationship to aberrant promoter methylation of multiple
      genes.
AB  - The simian polyoma virus SV40 has been detected in specific human tumors
      including non-Hodgkin's lymphomas, although a causative role for the virus has
      not been convincingly demonstrated. Aberrant methylation of CpG islands in
      promoter regions is a frequent method of silencing tumor suppressor genes (TSGs)
      in cancers and may be induced by oncogenic viruses. We investigated the
      relationship between the presence of SV40 or EBV DNA sequences and the
      methylation profiles for 10 TSGs in 90 cases of non-Hodgkin's lymphomas/leukemias
      and 56 control tissues. SV40 sequences were present in 33/90 (37%) non-Hodgkin's
      lymphomas/leukemias, and EBV was present in 11/42 (26%) of non-Hodgkin's
      lymphomas. We found a highly significant correlation between the presence of SV40
      and methylation of seven genes (P values, 0.006 to <0.0001). In lymphomas, there
      was no relationship between EBV and methylation. Oncogenic viruses and
      methylation were rarely present in control tissues. We investigated methylation
      of the same 10 TSGs in peripheral blood mononuclear cells (PBMC) from a healthy
      volunteer infected with EBV or EBV and SV40. Promoter methylation of CDH1 and
      CDH13 were noted in dual SV40- and EBV-infected PBMC, and these two genes were
      also highly significantly correlated to the presence of SV40 sequences in tumors.
      SV40 infection also resulted in appearance of the lymphoma/leukemia-specific
      marker, methylated SHP1. Methylation was completely absent in uninfected and EBV
      infected PBMC. Our results demonstrate that the presence of SV40 in hematological
      malignancies is associated with promoter methylation of TSGs and that in all
      probability, the virus plays a role in tumor pathogenesis.

PMID- 15172982
TI  - Nitric oxide confers therapeutic activity to dendritic cells in a mouse model of
      melanoma.
AB  - Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their
      efficacy in cancer therapy. Here we show that delivery within exponentially
      growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by
      the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2
      diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of
      animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because
      DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl
      xL; activation of caspase-9; and a reduction in the mitochondrial membrane
      potential. DETA-NO also increased DC cytotoxic activity against tumor cells and
      DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO
      were mediated through cGMP generation. NO and NO-generating drugs may therefore
      be used to increase the anticancer efficacy of DCs.

PMID- 15172981
TI  - An increase in the expression of ribonucleotide reductase large subunit 1 is
      associated with gemcitabine resistance in non-small cell lung cancer cell lines.
AB  - The mechanisms of resistance to the antimetabolite gemcitabine in non-small cell
      lung cancer have not been extensively evaluated. In this study, we report the
      generation of two gemcitabine-selected non-small cell lung cancer cell lines,
      H358-G200 and H460-G400. Expression profiling results indicated that there was
      evidence for changes in the expression of 134 genes in H358-G200 cells compared
      with its parental line, whereas H460-G400 cells exhibited 233 genes that appeared
      to be under- or overexpressed compared with H460 cells. However, only the
      increased expression of ribonucleotide reductase subunit 1 (RRM1), which appeared
      in both resistant cell lines, met predefined analysis criteria for genes to
      investigate further. Quantitative PCR analysis demonstrated H358-G200 cells had a
      greater than 125-fold increase in RRM1 RNA expression. Western blot analysis
      confirmed high levels of RRM1 protein in this line compared with the gemcitabine
      sensitive parent. No significant change in the expression of RRM2 was observed in
      either cell line, although both gemcitabine-resistant cell lines had an
      approximate 3-fold increase in p53R2 protein. A partial revertant of H358-G200
      cells had reduced levels of RRM1 protein (compared with G200 cells), without
      observed changes in RRM2 or p53R2. In vitro analyses of ribonucleotide reductase
      activity demonstrated that despite high levels of RRM1 protein, ribonucleotide
      reductase activity was not increased in H358-G200 cells when compared with
      parental cells. The cDNA encoding RRM1 from H358-G200 cells was cloned and
      sequenced but did not reveal the presence of any mutations. The results from this
      study indicate that the level of RRM1 may affect gemcitabine response.
      Furthermore, RRM1 may serve as a biomarker for gemcitabine response.

PMID- 15172983
TI  - Reversible regulation of the transformed phenotype of ornithine decarboxylase-
      and ras-overexpressing cells by dominant-negative mutants of c-Jun.
AB  - c-Jun is an oncogenic transcription factor involved in the regulation of cell
      proliferation, apoptosis and transformation. We have previously reported that
      cell transformations induced by ornithine decarboxylase (ODC) and c-Ha-ras
      oncogene, commonly activated in various cancer cells, are associated with
      constitutively increased phosphorylation of c-Jun on Ser residues 63 and 73. In
      the present study, we examined the significance of c-Jun phosphorylation and
      activation on the phenotype of the ODC- and ras-transformants, by using specific
      inhibitors and dominant-negative (DN) mutants to c-Jun NH(2)-terminal kinase
      (JNK) and its upstream kinase, SEK1/MKK4 (mitogen-activated protein kinase kinase
      4), and to c-Jun. The transformed morphology of both the ODC- and ras-expressing
      cells was reversed partially by JNK inhibitors and DN JNK1, more effectively by
      DN SEK1/MKK4 and phosphorylation-deficient c-Jun mutants (c-Jun(S63,73A), c
      Jun(S63,73A,T91,93A)) and most potently by a transactivation domain deletion
      mutant of c-Jun (TAM67). Moreover, tetracycline-inducible TAM67 expression in ODC
      and ras-transformed cells showed that the transformed phenotype of the cells is
      reversibly regulatable. TAM67 also inhibited the tumorigenicity of the cells in
      nude mice. These inducible cell lines, together with their parental cell lines,
      provide good models to identify the genes and proteins relevant to cellular
      transformation.

PMID- 15172984
TI  - Genome-wide profiling of papillary thyroid cancer identifies MUC1 as an
      independent prognostic marker.
AB  - Clinicopathological variables used at present for prognostication and treatment
      selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor
      behavior, necessitating identification of novel prognostic markers. Complicating
      the assessment is the long natural history of PTC and our rudimentary knowledge
      of its genetic composition. In this study we took advantage of differences in
      clinical behavior of two distinct variants of PTC, the aggressive tall-cell
      variant (TCV) and indolent conventional PTC (cPTC), to identify molecular
      prognosticators of outcome using complementary genome wide analyses. Comparative
      genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used
      to detect changes in DNA copy number and gene expression in pathological cPTC and
      TCV. The findings from CGH and cDNA microarray analyses were correlated and
      validated by real-time PCR and immunohistochemical analyses on a series of 100
      cases of cPTC and TCV. Genes identified by this approach were evaluated as
      prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH
      identified significant differences in the presence (76 versus 27%; P = 0.001) and
      type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of
      1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4,
      5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21-31 were unique to TCV.
      Hierarchical clustering of gene expression profiles revealed significant overlap
      between TCV and cPTC, but further analysis identified 82 dysregulated genes
      differentially expressed among the PTC variants. Of these, MUC1 was of particular
      interest because amplification of 1q by CGH correlated with MUC1 amplification by
      real-time PCR analysis and protein overexpression by immunohistochemistry in TCV
      (P = 0.005). Multivariate analysis revealed a significant association between
      MUC1 overexpression and treatment outcome, independent of histopathological
      categorization (P = 0.03). Analysis of a validation series containing a matched
      group of aggressive and indolent cPTCs confirmed the association between MUC1
      overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1
      5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with
      aggressive behavior of PTC and may serve as a prognostic marker and potential
      therapeutic target in this disease.

PMID- 15172985
TI  - Structure-based assessment of missense mutations in human BRCA1: implications for
      breast and ovarian cancer predisposition.
AB  - The BRCA1 gene from individuals at risk of breast and ovarian cancers can be
      screened for the presence of mutations. However, the cancer association of most
      alleles carrying missense mutations is unknown, thus creating significant
      problems for genetic counseling. To increase our ability to identify cancer
      associated mutations in BRCA1, we set out to use the principles of protein three
      dimensional structure as well as the correlation between the cancer-associated
      mutations and those that abolish transcriptional activation. Thirty-one of 37
      missense mutations of known impact on the transcriptional activation function of
      BRCA1 are readily rationalized in structural terms. Loss-of-function mutations
      involve nonconservative changes in the core of the BRCA1 C-terminus (BRCT) fold
      or are localized in a groove that presumably forms a binding site involved in the
      transcriptional activation by BRCA1; mutations that do not abolish
      transcriptional activation are either conservative changes in the core or are on
      the surface outside of the putative binding site. Next, structure-based rules for
      predicting functional consequences of a given missense mutation were applied to
      57 germ-line BRCA1 variants of unknown cancer association. Such a structure-based
      approach may be helpful in an integrated effort to identify mutations that
      predispose individuals to cancer.

PMID- 15172986
TI  - Modulation of patched-associated susceptibility to radiation induced
      tumorigenesis by genetic background.
AB  - We described previously a basal cell carcinoma (BCC) and medulloblastoma (MB)
      phenotype for CD1Ptch1(neo67/+) mice exposed to ionizing radiation. Ptch1
      heterozygous mice mimic the predisposition to BCC and MB development of patients
      affected by nevoid BCC syndrome that inherit a mutant Patched (Ptch1) allele. To
      examine the impact of genetic background on development of BCCs and other tumors
      we used two outbred mouse lines characterized by extremely high, carcinogenesis
      susceptible (Car-S), and low, carcinogenesis-resistant (Car-R), susceptibility to
      skin carcinogenesis. Crosses between Ptch1(neo67/+) mice and Car-S (F1S) or Car-R
      mice (F1R) were exposed to ionizing radiation. F1SPtch1(neo67/+) mice were highly
      susceptible to radiation-induced BCCs, whereas F1RPtch1(neo67/+) mice were
      completely resistant, indicating that tumor penetrance can be modulated by
      genetic background. Development of microscopic and macroscopic BCC lesions was
      influenced by Car-S and Car-R genotypes, suggesting a genetic-background effect
      on both initiation and progression of BCC. Susceptibility was additionally
      increased in N2 backcross mice (Car-S x F1SPtch1(neo67/+)), showing a
      contribution from recessive-acting Car-S modifiers. The modifying effects of Car
      S-derived susceptibility alleles were tissue specific. In fact, despite higher
      susceptibility to BCC induction, Car-S-derived lines had lower MB incidence
      compared with CD1Ptch1(neo67/+) mice. BCC-associated somatic events were not
      influenced by genetic background, as shown by similar rate of wild-type Ptch1
      loss in BCCs from F1SPtch1(neo67/+) (93%) and CD1Ptch1(neo67/+) mice (100%).
      Finally, microsatellite analysis of BCCs showed Ptch1 loss through interstitial
      deletion. These results are relevant to humans, in which BCC is the commonest
      malignancy, because this model system may be used to study genes modifying BCC
      development.

PMID- 15172987
TI  - Association of breast cancer DNA methylation profiles with hormone receptor
      status and response to tamoxifen.
AB  - We have generated DNA methylation profiles of 148 human breast tumors and found
      significant differences in hormone receptor (HR) status between clusters of DNA
      methylation profiles. Of 35 DNA methylation markers analyzed, the ESR1 gene,
      encoding estrogen receptor alpha, proved to be the best predictor of progesterone
      receptor status, whereas methylation of the PGR gene, encoding progesterone
      receptor, was the best predictor of estrogen receptor status. ESR1 methylation
      outperformed HR status as a predictor of clinical response in patients treated
      with the antiestrogen tamoxifen, whereas promoter methylation of the CYP1B1 gene,
      encoding a tamoxifen- and estradiol-metabolizing cytochrome p450, predicted
      response differentially in tamoxifen-treated and nontamoxifen-treated patients.
      High levels of promoter methylation of the ARHI gene, encoding a RAS-related
      small G-protein, were strongly predictive of good survival in patients who had
      not received tamoxifen therapy. Our results reveal an as yet unrecognized degree
      of interaction between DNA methylation and HR biology in breast cancer cells and
      suggest potentially clinically useful novel DNA methylation predictors of
      response to hormonal and non-hormonal breast cancer therapy.

PMID- 15172988
TI  - Overexpression, amplification, and androgen regulation of TPD52 in prostate
      cancer.
AB  - Gains in the long arm of chromosome 8 (8q) are believed to be associated with
      poor outcome and the development of hormone-refractory prostate cancer. Based on
      a meta-analysis of gene expression microarray data from multiple prostate cancer
      studies (D. R. Rhodes et al., Cancer Res 2002;62:4427-33), a candidate oncogene,
      Tumor Protein D52 (TPD52), was identified in the 8q21 amplicon. TPD52 is a coiled
      coil motif-bearing protein, potentially involved in vesicle trafficking. Both
      mRNA and protein levels of TPD52 were highly elevated in prostate cancer tissues.
      Array comparative genomic hybridization and amplification analysis using single
      nucleotide polymorphism arrays demonstrated increased DNA copy number in the
      region encompassing TPD52. Fluorescence in situ hybridization on tissue
      microarrays confirmed TPD52 amplification in prostate cancer epithelia.
      Furthermore, our studies suggest that TPD52 protein levels may be regulated by
      androgens, consistent with the presence of androgen response elements in the
      upstream promoter of TPD52. In summary, these findings suggest that dysregulation
      of TPD52 by genomic amplification and androgen induction may play a role in
      prostate cancer progression.

PMID- 15172990
TI  - DNA polymerase beta interacts with TRF2 and induces telomere dysfunction in a
      murine mammary cell line.
AB  - DNA polymerase beta (Polbeta) is a DNA repair protein that functions in base
      excision repair and meiosis. The enzyme has deoxyribose phosphate lyase and
      polymerase activity, but it is error prone because it bears no proofreading
      activity. Errors in DNA repair can lead to the accumulation of mutations and
      consequently to tumorigenesis. Polbeta expression has been found to be higher in
      tumors, and deregulation of its expression has been found to induce chromosomal
      instability, a hallmark of tumorigenesis, but the underlying mechanisms are
      unclear. In the present study, we have investigated whether ectopic expression of
      Polbeta influences the stability of chromosomes in a murine mammary cell line.
      The results demonstrate a telomere dysfunction phenotype: an increased rate of
      telomere loss and chromosome fusion, suggesting that ectopic expression of
      Polbeta leads to telomere dysfunction. In addition, Polbeta interacts with TRF2,
      a telomeric DNA binding protein. Colocalization of the two proteins occurs at
      nontelomeric sites and appears to be influenced by the change in the status of
      the telomeric complex.

PMID- 15172989
TI  - Regulation of p27Kip1 protein levels contributes to mitogenic effects of the
      RET/PTC kinase in thyroid carcinoma cells.
AB  - We show that treatment of a panel of thyroid carcinoma cell lines naturally
      harboring the RET/PTC1 oncogene, with the RET kinase inhibitors PP1 and ZD6474,
      results in reversible G(1) arrest. This is accompanied by interruption of Shc and
      mitogen-activated protein kinase (MAPK) phosphorylation, reduced levels of G(1)
      cyclins, and increased levels of the cyclin-dependent kinase inhibitor p27Kip1
      because of a reduced protein turnover. MAP/extracellular signal-regulated kinase
      1/2 inhibition by U0126 caused G(1) cyclins down-regulation and p27Kip1 up
      regulation as well. Forced expression of RET/PTC in normal thyroid follicular
      cells caused a MAPK- and proteasome-dependent down-regulation of p27Kip1.
      Reduction of p27Kip1 protein levels by antisense oligonucleotides abrogated the
      G(1) arrest induced by RET/PTC blockade. Therefore, in thyroid cancer, RET/PTC
      mediated MAPK activation contributes to p27Kip1 deregulation. This pathway is
      implicated in cell cycle progression and in response to small molecule kinase
      inhibitors.

PMID- 15172991
TI  - Kruppel-like factor 6 is frequently down-regulated and induces apoptosis in non
      small cell lung cancer cells.
AB  - Kruppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger
      transcriptional factor, which has been suggested to be a candidate tumor
      suppressor gene in prostate cancer and astrocytic glioma. Because KLF6 is located
      at chromosome 10p15, where non-small cell lung cancers (NSCLCs) also exhibit
      frequent allelic loss, we hypothesized that the inactivation of KLF6 is also
      involved in the development of NSCLC. To determine this, we performed mutational
      analysis for 105 NSCLCs, including 9 cell lines and 96 primary tumors, and
      Northern blot analysis for 74 NSCLCs, including the 9 cell lines and 65 primary
      tumors. Although somatic mutations were not detected in the coding sequence of
      KLF6, expression of KLF6 mRNA was down-regulated in the 9 cell lines and in 55
      (85%) of the 65 primary tumors compared with normal lung tissue. Treatment of two
      cell lines expressing KLF6 at low levels with 5-azacytidine did not induce KLF6
      expression, suggesting that KLF6 down-regulation is not due to promoter
      hypermethylation. We also performed loss of heterozygosity (LOH) analysis using
      the laser capture microdissection technique, and found that 21 of 62 (34%)
      informative samples had LOH in the KLF6 gene locus. Comparing the LOH status with
      mRNA expression of KLF6, we found that 14 of the 14 (100%) samples with LOH
      showed KLF6 down-regulation, and that even 23 of 31 (74%) samples without LOH
      also showed this down-regulation. We also studied the expression of the WAF1
      gene, a possible downstream gene of KLF6, and detected simultaneous down
      regulation of WAF1 and KLF6 mRNA in 6 of 9 (67%) cell lines and 48 of the 55
      (87%) primary tumors, although there was not a significant association between
      loss of KLF6 and WAF1 expression. Furthermore, colony formation assay of two
      NSCLC cell lines (NCI-H1299 and NCI-H2009) induced a markedly reduced colony
      formation by KLF6 transfection, and Annexin V staining and terminal
      deoxynucleotidyl transferase-mediated nick end labeling assays revealed that KLF6
      induced apoptosis. Our present studies demonstrated that KLF6 is frequently down
      regulated in NSCLC and suppresses tumor growth via induction of apoptosis in
      NSCLC, which may suggest that KLF6 is a tumor suppressor for NSCLC.

PMID- 15172992
TI  - Aberrant promoter hypermethylation of the death-associated protein kinase gene is
      early and frequent in murine lung tumors induced by cigarette smoke and tobacco
      carcinogens.
AB  - Loss of expression of the death-associated protein (DAP)-kinase gene by aberrant
      promoter methylation may play an important role in cancer development and
      progression. The purpose of this investigation was to determine the commonality
      for inactivation of the DAP-kinase gene in adenocarcinomas induced in mice by
      chronic exposure to mainstream cigarette smoke, the tobacco carcinogens 4
      (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate, and the
      occupational carcinogen methylene chloride. The timing for inactivation was also
      determined in alveolar hyperplasias that arise in lung cancer induced in the A/J
      mouse by NNK. The DAP-kinase gene was not expressed in three of five NNK-induced
      lung tumor-derived cell lines or in a spontaneously arising lung tumor-derived
      cell line. Treatment with 5-aza-2'-deoxycytidine restored expression; dense
      methylation throughout the DAP-kinase CpG island detected by bisulfite sequencing
      supported methylation as the inactivating event in these cell lines. Methylation
      specific PCR detected inactivation of the DAP-kinase gene in 43% of tumors
      associated with cigarette smoke, a frequency similar to those reported in human
      non-small cell lung cancer. In addition, DAP-kinase methylation was detected in
      52%, 60%, and 50% of tumors associated with NNK, vinyl carbamate, and methylene
      chloride, respectively. Methylation was observed at similar prevalence in both
      NNK-induced hyperplasias and adenocarcinomas (46% versus 52%), suggesting that
      inactivation of this gene is one pathway for tumor development in the mouse lung.
      Bisulfite sequencing of both premalignant and malignant lesions revealed dense
      methylation, substantiating that this gene is functionally inactivated at the
      earliest histological stages of adenocarcinoma development. This study is the
      first to use a murine model of cigarette smoke-induced lung cancer and
      demonstrate commonality for inactivation by promoter hypermethylation of a gene
      implicated in the development of this disease in humans.

PMID- 15172993
TI  - Diminished hepatocellular proliferation in mice humanized for the nuclear
      receptor peroxisome proliferator-activated receptor alpha.
AB  - Lipid-lowering fibrate drugs function as agonists for the nuclear receptor
      peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained
      activation of PPARalpha leads to the development of liver tumors in rats and
      mice. However, humans appear to be resistant to the induction of peroxisome
      proliferation and the development of liver cancer by fibrate drugs. The molecular
      basis of this species difference is not known. To examine the mechanism
      determining species differences in peroxisome proliferator response between mice
      and humans, a PPARalpha-humanized mouse line was generated in which the human
      PPARalpha was expressed in liver under control of the tetracycline responsive
      regulatory system. The PPARalpha-humanized and wild-type mice responded to
      treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of
      genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and
      resultant decrease of serum triglycerides. However, surprisingly, only the wild
      type mice and not the PPARalpha-humanized mice exhibited hepatocellular
      proliferation as revealed by elevation of cell cycle control genes, increased
      incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and
      hepatomegaly. These studies establish that following ligand activation, the
      PPARalpha-mediated pathways controlling lipid metabolism are independent from
      those controlling the cell proliferation pathways. These findings also suggest
      that structural differences between human and mouse PPARalpha are responsible for
      the differential susceptibility to the development of hepatocarcinomas observed
      after treatment with fibrates. The PPARalpha-humanized mice should serve as
      models for use in drug development and human risk assessment and to determine the
      mechanism of hepatocarcinogenesis of peroxisome proliferators.

PMID- 15172995
TI  - Detection of an involvement of the human mismatch repair genes hMLH1 and hMSH2 in
      nucleotide excision repair is dependent on UVC fluence to cells.
AB  - There is conflicting evidence for the role of the mismatch repair (MMR) genes
      hMLH1 and hMSH2 in the transcription-coupled repair (TCR) pathway of nucleotide
      excision repair. In the present work, we have examined the role of these MMR
      genes in nucleotide excision repair using two reporter gene assays. AdHCMVlacZ is
      a replication-deficient recombinant adenovirus that expresses the beta
      galactosidase reporter gene under the control of the human cytomegalovirus
      immediate early promoter. We have reported previously a reduced host cell
      reactivation (HCR) for beta-galactosidase expression of UVC-irradiated AdHCMVlacZ
      in TCR-deficient Cockayne syndrome (CS) fibroblasts compared with normal
      fibroblasts, indicating that HCR depends, at least in part, on TCR. In addition,
      we have reported that UVC-enhanced expression of the undamaged reporter gene is
      induced at lower UVC fluences to cells and at higher levels after low UVC
      fluences in TCR-deficient compared with normal human fibroblasts, suggesting that
      persistent damage in active genes triggers increased activity from the human
      cytomegalovirus-driven reporter construct. We have examined HCR and UV-enhanced
      expression of the reporter gene in hMLH1-deficient HCT116 human colon
      adenocarcinoma cells and HCT116-chr3 cells (the MMR-proficient counterpart of
      HCT116) as well as hMSH2-deficient LoVo human colon adenocarcinoma cells and
      their hMSH2-proficient counterpart SW480 cells. We show a greater UV-enhanced
      expression of the undamaged reporter gene after low UVC exposure in HCT116
      compared with HCT116-chr3 cells and in LoVo compared with SW480 cells. We show
      also a reduced HCR in HCT116 compared with HCT116-chr3 cells and in LoVo compared
      with SW480 cells. However, the reduction in HCR was less or absent when cells
      were pretreated with UVC. These results suggest that detection of an involvement
      of hMLH1 and hMSH2 in TCR is dependent on UVC (254 nm) fluence to cells.

PMID- 15172994
TI  - A novel role for mixed-lineage kinase-like mitogen-activated protein triple
      kinase alpha in neoplastic cell transformation and tumor development.
AB  - Previously, no member of the mixed-lineage kinase (MLK) protein family was known
      to function as an oncogene. Here, we demonstrate that MLK-like mitogen-activated
      protein triple kinase (MLTK)-alpha, a member of the MLK family, induced
      neoplastic cell transformation and tumorigenesis in athymic nude mice.
      Introduction of small interference RNA (siRNA)-MLTK-alpha into MLTK-alpha
      overexpressing cells dramatically suppressed cell transformation. Nuclear
      accumulation of the pHisG-MLTK-alpha fusion protein was observed after epidermal
      growth factor or 12-O-tetradecanoylphorbol-13-acetate treatment. Phosphorylation
      of downstream mitogen-activated protein kinase-targeted transcription factors
      including c-Myc, Elk-1, c-Jun, and activating transcription factor (ATF) 2 was
      also differentially enhanced in MLTK-alpha-overexpressing cells exposed to
      epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate stimulation
      compared with cells expressing mock vector or siRNA-MLTK-alpha. Very importantly,
      MLTK-alpha-overexpressing cells formed fibrosarcomas when injected s.c. into
      athymic nude mice, whereas almost no tumor formation was observed in mice that
      received injections of mock or siRNA-MLTK-alpha stably transfected cells. These
      results are the first to indicate that MLTK-alpha plays a key role in neoplastic
      cell transformation and cancer development.

PMID- 15172996
TI  - Transcriptional gene silencing promotes DNA hypermethylation through a sequential
      change in chromatin modifications in cancer cells.
AB  - It is well established that DNA hypermethylation of tumor suppressor and tumor
      related genes can occur in cancer cells and that each cancer subtype has specific
      gene sets that are commonly susceptible to methylation and silencing. Glutathione
      S-transferase (GSTP1) is one example of a gene that is hypermethylated and
      inactivated in the majority of prostate cancers. We previously reported that
      hypermethylation of the GSTP1 CpG island promoter in prostate cancer cells is
      initiated by a combination of transcriptional gene silencing (by removal of the
      Sp1 sites) and seeds of methylation that, instead of being constantly removed
      because of demethylation associated with transcription, acts as a catalyst for
      the spread of methylation across the CpG island. In this study, we now
      demonstrate that the seeds of DNA methylation also play an important role in
      initiating chromatin modification. Our results address a number of central
      questions about the temporal relationship between gene expression, DNA
      hypermethylation, and chromatin modification in cancer cells. We find that for
      the GSTP1 gene, (a). histone acetylation is independent of gene expression, (b).
      histone deacetylation is triggered by seeds of DNA methylation, (c). the spread
      of DNA hypermethylation across the island is linked to MBD2 and not MeCP2
      binding, and (d). histone methylation occurs after histone deacetylation and is
      associated with extensive DNA methylation of the CpG island. These findings have
      important implications for understanding the biochemical events underlying the
      mechanisms responsible for abnormal hypermethylation of CpG island-associated
      genes in cancer cells.

PMID- 15172997
TI  - Systematic review of genomic integration sites of human papillomavirus genomes in
      epithelial dysplasia and invasive cancer of the female lower genital tract.
AB  - Cancers of the anogenital tract as well as some head and neck cancers are caused
      by persistent infections with high-risk type human papillomaviruses (HPVs). Two
      viral oncogenes, E6 and E7, induce severe chromosomal instability associated with
      centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. This
      occurs early in preneoplastic lesions, when the viral genome still persists in an
      episomal state. In most invasive cancers and also in a few high-grade dysplastic
      lesions, however, integration of high-risk HPV genomes into the host genome is
      observed. Integration seems to be a direct consequence of chromosomal instability
      and an important molecular event in the progression of preneoplastic lesions.
      Disruption or deregulation of defined critical cellular gene functions by
      insertional mutagenesis by integrated HPV genome fragments has been hypothesized
      as one major promoting factor in the pathogenesis of HPV-associated cancers. This
      hypothesis was based on the detection of HPV integration events in the area of
      tumor-relevant genes in few cases. Here, we reviewed >190 reported integration
      loci with respect to changes in the viral structure and the targeted genomic
      locus. This analysis confirms that HPV integration sites are randomly distributed
      over the whole genome with a clear predilection for genomic fragile sites. No
      evidence for targeted disruption or functional alteration of critical cellular
      genes by the integrated viral sequences could be found.

PMID- 15172998
TI  - Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through
      interaction with cyclin D1.
AB  - Kruppel-like factor 6 (KLF6) is a tumor suppressor gene inactivated in prostate
      and colon cancers, as well as in astrocytic gliomas. Here, we establish that KLF6
      mediates growth inhibition through an interaction with cyclin D1, leading to
      reduced phosphorylation of the retinoblastoma protein (Rb) at Ser(795).
      Furthermore, introduction of KLF6 disrupts cyclin D1-cyclin-dependent kinase
      (cdk) 4 complexes and forces the redistribution of p21(Cip/Kip) onto cdk2, which
      promotes G(1) cell cycle arrest. Our data suggest that KLF6 converges with the Rb
      pathway to inhibit cyclin D1/cdk4 activity, resulting in growth suppression.

PMID- 15173000
TI  - Lipoptosis: tumor-specific cell death by antibody-induced intracellular lipid
      accumulation.
AB  - A balanced lipid metabolism is crucial for all cells. Disturbance of this
      homeostasis by nonphysiological intracellular accumulation of fatty acids can
      result in apoptosis. This was proven in animal studies and was correlated to some
      human diseases, like lipotoxic cardiomyopathy. Some metabolic mechanisms of lipo
      apoptosis were described, and some causes were discussed, but reagents, which
      directly induce lipo-apoptosis, have thus far not been identified. The human
      monoclonal IgM antibody SAM-6 was isolated from a stomach cancer patient by using
      the conventional human hybridoma technology (trioma technique). The addition of
      SAM-6 to tumor cells leads to an increase in the intracellular accumulation of
      neutral lipids, followed by tumor cell apoptosis. The antibody SAM-6 does not
      react with noncancerous human epithelial and fibroblastic cells, because the M(r)
      140000 membrane molecule, recognized by the antibody, is specifically expressed
      on human malignant cells. The antibody is coded by the germ-line genes IgHV3
      30.3*01 and IgLV3-1*01 and is a component of the innate immunity to cancer. In
      this article, we describe an antibody-induced tumor-specific cell death, named
      lipoptosis. This is, to our knowledge, the first description of this specific
      form of lipo-apoptosis as an antibody-mediated mechanism of tumor cell killing.

PMID- 15172999
TI  - Akt stimulates aerobic glycolysis in cancer cells.
AB  - Cancer cells frequently display high rates of aerobic glycolysis in comparison to
      their nontransformed counterparts, although the molecular basis of this
      phenomenon remains poorly understood. Constitutive activity of the
      serine/threonine kinase Akt is a common perturbation observed in malignant cells.
      Surprisingly, although Akt activity is sufficient to promote leukemogenesis in
      nontransformed hematopoietic precursors and maintenance of Akt activity was
      required for rapid disease progression, the expression of activated Akt did not
      increase the proliferation of the premalignant or malignant cells in culture.
      However, Akt stimulated glucose consumption in transformed cells without
      affecting the rate of oxidative phosphorylation. High rates of aerobic glycolysis
      were also identified in human glioblastoma cells possessing but not those lacking
      constitutive Akt activity. Akt-expressing cells were more susceptible than
      control cells to death after glucose withdrawal. These data suggest that
      activation of the Akt oncogene is sufficient to stimulate the switch to aerobic
      glycolysis characteristic of cancer cells and that Akt activity renders cancer
      cells dependent on aerobic glycolysis for continued growth and survival.

PMID- 15173001
TI  - Expression profiles provide insights into early malignant potential and skeletal
      abnormalities in multiple endocrine neoplasia type 2B syndrome tumors.
AB  - Identifying the molecular basis for genotype-phenotype correlations in human
      diseases has direct implications for understanding the disease process and hence
      for the identification of potential therapeutic targets. To this end, we
      performed microarray expression analysis on benign (pheochromocytomas) and
      malignant (medullary thyroid carcinomas, MTCs) tumors from patients with multiple
      endocrine neoplasia (MEN) type 2A or 2B, related syndromes that result from
      distinctive mutations in the RET receptor tyrosine kinase. Comparisons of MEN 2B
      and MEN 2A MTCs revealed that genes involved in the process of epithelial to
      mesenchymal transition, many associated with the tumor growth factor beta
      pathway, were up-regulated in MEN 2B MTCs. This MEN 2B MTC profile may explain
      the early onset of malignancy in MEN 2B compared with MEN 2A patients.
      Furthermore, chondromodulin-1, a known regulator of cartilage and bone growth,
      was expressed at high levels specifically in MEN 2B MTCs. Chondromodulin-1 mRNA
      and protein expression was localized to the malignant C cells, and its high
      expression was directly associated with the presence of skeletal abnormalities in
      MEN 2B patients. These findings provide molecular evidence that associate the
      previously unexplained skeletal abnormalities and early malignancy in MEN 2B
      compared with MEN 2A syndrome.

PMID- 15173002
TI  - A novel system for simultaneous in vivo tracking and biological assessment of
      leukemia cells and ex vivo generated leukemia-reactive cytotoxic T cells.
AB  - To determine the mechanisms by which adoptive immunotherapy could reduce
      lethality to acute myelogenous leukemia (AML), a novel technique was developed to
      track both leukemic blasts and adoptively transferred cytotoxic T cells (CTLs)
      independently and simultaneously in mice. To follow the fate of ex vivo generated
      anti-AML-reactive CTLs, splenocytes obtained from enhanced green fluorescent
      protein transgenic mice were cocultured with AML lysate-pulsed dendritic cells,
      which subsequently were expanded by exposure to anti-CD3/CD28 monoclonal antibody
      coated magnetic microspheres. To track AML cells, stable transfectants of C1498
      expressing DsRed2, a red fluorescent protein, were generated. Three factors
      related to CTLs correlated with disease-free survival: (a). CTL L-selectin
      expression. L-Selectin high fractions resulted in 70% disease-free survival,
      whereas L-selectin low-expressing CTLs resulted in only 30% disease-free
      survival. (b). Duration of ex vivo expansion (9 versus 16 days). Short-term
      expanded CTLs could be found at high frequency in lymphoid organs for longer than
      4 weeks after transfer, whereas long-term expanded CTLs were cleared from the
      system after 2 weeks. Duration of expansion correlated inversely with L-selectin
      expression. (c). CTL dose. A higher dose (40 versus 5 x 10(6)) resulted in
      superior disease-free survival. This survival advantage was achieved with short
      term expanded CTLs only. The site of treatment failure was mainly the central
      nervous system where no CTLs could be identified at AML sites.

PMID- 15173003
TI  - Oncogenic Ras sensitizes normal human cells to tumor necrosis factor-alpha
      related apoptosis-inducing ligand-induced apoptosis.
AB  - Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a
      cytotoxic cytokine that induces apoptosis in tumor cells but rarely kills normal
      ones. To determine how normal human cells acquire TRAIL-sensitive phenotype
      during the process of malignant transformation, we used an experimental system
      that allows for controlled conversion of human cells from normal to cancerous by
      introduction of several genes. Human embryonic kidney cells and foreskin
      fibroblasts were first immortalized by combination of the early region of simian
      virus 40 and telomerase and then were transformed with oncogenic Ras. Both normal
      and immortalized cells were resistant to TRAIL-induced apoptosis, whereas Ras
      transformed cells were susceptible. Ras transformation enhanced TRAIL-induced
      activation of caspase 8 by increasing its recruitment to TRAIL receptors. The
      proapoptotic effects of Ras could be reversed by mutations in its effector loop
      or by inhibitors of either farnesyl transferase or mitogen-activated protein
      kinase kinase. The expression of constitutively activated mitogen-activated
      protein kinase kinase 1 enhanced caspase 8 recruitment and sensitized
      immortalized human embryonic kidney cells to TRAIL-induced death. These results
      indicate that in normal human cells the TRAIL-induced apoptotic signal is blocked
      at the level of caspase 8 recruitment and that this block can be eliminated by
      Ras transformation, involving activation of the mitogen-activated protein kinase
      pathway.

PMID- 15173004
TI  - Hypoxia increases heparanase-dependent tumor cell invasion, which can be
      inhibited by antiheparanase antibodies.
AB  - The beta-endoglucuronidase heparanase plays an important role in tumor invasion,
      a process that is significantly enhanced by hypoxia. We have used a strategy of
      stable transfection with antisense to derive ovarian carcinoma cell lines that
      express different levels of heparanase and used these to demonstrate that
      invasion correlates with heparanase activity. Secreted heparanase activity was
      increased by reduction, hypoxia, and growth of cells under reduced oxygen (1%)
      augmented heparanase activity and invasion, both of which are inhibited by
      treatment with antiheparanase antibodies. This is the first demonstration that
      heparanase activity may be regulated by microenvironmental redox conditions,
      which influence invasion, and that invasion can be blocked with specific
      heparanase-neutralizing antibodies.

PMID- 15173005
TI  - Complex regulation of signal transducers and activators of transcription 3
      activation in normal and malignant keratinocytes.
AB  - Previous work implicated activation of the signal transducer and activator of
      transcription (STAT)3 downstream of the epidermal growth factor receptor (EGFR)
      in the malignant phenotype of squamous carcinoma cells (SCC). Here, we show that
      EGFR-dependent STAT3 activation is restricted to malignant keratinocytes.
      Specifically, constitutive and epidermal growth factor-induced phosphorylation of
      STAT3 on Y705 was observed only in SCC but not in either immortalized (HaCaT) or
      normal keratinocyte strains. Furthermore, STAT3 activation as determined by DNA
      binding assays was restricted to SCC and dependent on EGFR activation. Forced
      expression of EGFR in immortalized keratinocytes (HaCaT cells) was associated
      with enhanced EGFR activation but not STAT3-Y705 phosphorylation. EGFR-dependent
      activation of mitogen-activated protein kinase (MAPK) kinase 1 negatively
      regulated STAT3-Y705 phosphorylation in normal and malignant keratinocytes.
      Together, these results underscore that EGFR activation is required but not
      sufficient for STAT3 activation to occur in malignant keratinocytes. They also
      highlight complex regulation of STAT3 phosphorylation through EGFR activation
      including negative regulation via the MAPK kinase/MAPK signaling pathway.

PMID- 15173006
TI  - Genome-wide identification of genes conferring resistance to the anticancer
      agents cisplatin, oxaliplatin, and mitomycin C.
AB  - Cisplatin is a crucial agent in the treatment of many solid tumors, yet many
      tumors have either acquired or intrinsic resistance to the drug. We have used the
      homozygous diploid deletion pool of Saccharomyces cerevisiae, containing 4728
      strains with individual deletion of all nonessential genes, to systematically
      identify genes that when deleted confer sensitivity to the anticancer agents
      cisplatin, oxaliplatin, and mitomycin C. We found that deletions of genes
      involved in nucleotide excision repair, recombinational repair, postreplication
      repair including translesional synthesis, and DNA interstrand cross-link repair
      resulted in sensitivity to all three of the agents, although with some
      differences between the platinum drugs and mitomycin C in the spectrum of
      required translesional polymerases. Putative defective repair of oxidative damage
      (imp2'Delta strain) also resulted in sensitivity to platinum and oxaliplatin, but
      not to mitomycin C. Surprisingly in light of their different profiles of clinical
      activity, cisplatin and oxaliplatin have very similar sensitivity profiles.
      Finally, we identified three novel genes (PSY1-3, "platinum sensitivity") that,
      when deleted, demonstrate sensitivity to cisplatin and oxaliplatin, but not to
      mitomycin C. Our results emphasize the importance of multiple DNA repair pathways
      responsible for normal cellular resistance to all three of the agents. Also, the
      similarity of the sensitivity profiles of the platinum agents with that of the
      known DNA interstrand cross-linking agent mitomycin C, and the importance of the
      gene PSO2 known to be involved in DNA interstrand cross-link repair strongly
      suggests that interstrand cross-links are important toxic lesions for cisplatin
      and oxaliplatin, at least in yeast.

PMID- 15173007
TI  - Proteasome-mediated destruction of the cyclin a/cyclin-dependent kinase 2 complex
      suppresses tumor cell growth in vitro and in vivo.
AB  - Cyclin-dependent kinases (cdks) represent potentially promising molecular targets
      for cancer therapeutic strategies. To evaluate the antitumor activity of
      selective cyclin/cdk inhibition, we constructed a chimeric protein composed of a
      F-box protein (TrCP) fused to a peptide comprising the cyclin/cdk2 binding motif
      in p21-like cdk inhibitors (TrCP-LFG). We now demonstrate that endogenous cyclin
      A and its binding substrate, cdk2, can be tethered to beta-TrCP, ubiquitinated,
      and effectively degraded. Degradation of cdk2 and cyclin A together, but not cdk2
      alone, results in massive tumor cell apoptosis in vitro and in vivo in a
      proteasome-dependent manner with no toxicity to normal tissue. These data
      demonstrate that cyclin A and/or the cyclin A/cdk2 complex is a promising
      anticancer target with a high therapeutic index.

PMID- 15173008
TI  - Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the
      HER-2 tyrosine kinase.
AB  - HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been
      implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of
      breast cancer patients and predicts a poor outcome in patients with primary
      disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically
      approved for HER-2-positive breast cancer but is active only in a subset of these
      tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore,
      represents an attractive alternate strategy to inhibit the growth of HER-2
      positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active
      against HER-2-overexpressing human breast cancer cell lines in vitro. It also
      inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation
      of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in
      cells at doses consistent with inhibition of cell proliferation and functions as
      an irreversible binding inhibitor, most likely by targeting a cysteine residue in
      the ATP-binding pocket of the receptor. In agreement with the predicted effects
      of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of
      downstream signal transduction events and cell cycle regulatory pathways. This
      leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell
      division cycle, ultimately resulting in decreased cell proliferation. In vivo,
      HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed
      orally on a once daily schedule. On the basis of its favorable preclinical
      pharmacological profile, HKI-272 has been selected as a candidate for additional
      development as an antitumor agent in breast and other HER-2-dependent cancers.

PMID- 15173009
TI  - Activation of protein kinase G is sufficient to induce apoptosis and inhibit cell
      migration in colon cancer cells.
AB  - The activation of protein kinase G (PKG) by cGMP has become of considerable
      interest as a novel molecular mechanism for the induction of apoptosis in cancer
      cells, because sulindac sulfone (exisulind, Aptosyn) and certain derivatives that
      inhibit cGMP-phosphodiesterases and thereby increase cellular levels of cGMP
      appear to induce apoptosis via this mechanism. However, other effects of these
      compounds have not been excluded, and the precise mechanism by which PKG
      activation induces apoptosis has not been elucidated in detail. To directly
      examine the effects of PKG on cell growth and apoptosis, we generated a series of
      mutants of PKG Ialpha: PKG IalphaS65D, a constitutively activated point mutant;
      PKG IalphaDelta, a constitutively activated N-terminal truncated mutant; and PKG
      IalphaK390R, a dominant-negative point mutant. A similar series of mutants of PKG
      Ibeta were also constructed (Deguchi et al., Mol. Cancer Ther., 1: 803-809,
      2002). The present study demonstrates that when transiently expressed in SW480
      colon cancer, the constitutively activated mutants of PKG Ibeta, and to a lesser
      extent PKG Ialpha, inhibit colony formation and induce apoptosis. We were not
      able to obtain derivatives of SW480 cells that stably expressed these
      constitutively activated mutants, presumably because of toxicity. However,
      derivatives that stably overexpressed wild-type PKG Ibeta displayed growth
      inhibition, whereas derivatives that stably expressed the dominant-negative
      mutant (KR) of PKG Ibeta grew more rapidly and were more resistant to Aptosyn
      induced growth inhibition than vector control cells. Stable overexpression of PKG
      Ibeta was associated with decreased cellular levels of beta-catenin and cyclin D1
      and increased levels of p21(CIP1). Reporter assays indicated that activation of
      PKG Ibeta inhibits the transcriptional activity of the cyclin D1 promoter. We
      also found that transient expression of the constitutively activated mutants of
      PKG Ibeta inhibited cell migration. Taken together, these results indicate that
      activation of PKG Ibeta is sufficient to inhibit growth and cell migration and
      induce apoptosis in human colon cancer cells and that these effects are
      associated with inhibition of the transcription of cyclin D1 and an increase in
      the expression of p21(CIP1).

PMID- 15173010
TI  - Apoptotic and cytostatic farnesyltransferase inhibitors have distinct
      pharmacology and efficacy profiles in tumor models.
AB  - BMS-214662 and BMS-225975 are tetrahydrobenzodiazepine-based farnesyltransferase
      inhibitors (FTIs) that have nearly identical structures and very similar
      pharmacological profiles associated with farnesyltransferase (FT) inhibition.
      Despite their similar activity against FT in vitro and in cells, these compounds
      differ dramatically in their apoptotic potency and tumor-regressing activity in
      vivo. BMS-214662 is the most potent apoptotic FTI known and exhibits curative
      responses in mice bearing a variety of staged human tumor xenografts such as HCT
      116 human colon tumor. By contrast, BMS-225975 does not cause tumor regression
      and at best causes partial tumor growth inhibition in staged HCT-116 human colon
      tumor xenografts. Lack of tumor regression activity in BMS-225975 was
      attributable to its relatively weak apoptotic potency, not to poor cell
      permeability or pharmacokinetics. Both compounds were equally effective in
      inhibiting Ras processing and causing accumulation of a variety of
      nonfarnesylated substrates of FT in HCT-116 cells. Because BMS-225975 has poor
      apoptotic activity compared with BMS-214662 but inhibits FT to the same extent as
      BMS-214662, it is very unlikely that FT inhibition alone can account for the
      apoptotic potency of BMS-214662. Clearly distinct patterns of sensitivities in a
      cell line panel were obtained for the apoptotic FTI BMS-214662 and the cytostatic
      FTI BMS-225975. Activation of the c-Jun-NH(2)-terminal kinase pathway was readily
      observed with BMS-214662 but not with BMS-225975. We developed a highly sensitive
      San-1 murine xenograft tumor model that is particularly useful for evaluating the
      in vivo activity of cytostatic FTIs such as BMS-225975.

PMID- 15173011
TI  - P27(kip1) down-regulation is associated with trastuzumab resistance in breast
      cancer cells.
AB  - Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed
      against HER-2. The objective response rate to trastuzumab monotherapy is 12-34%
      for a median duration of 9 months, by which point most patients become resistant
      to treatment. We created two trastuzumab-resistant (TR) pools from the SKBR3 HER
      2-overexpressing breast cancer cell line to study the mechanisms by which breast
      cancer cells escape trastuzumab-mediated growth inhibition. Both pools maintained
      her-2 gene amplification and protein overexpression. Resistant cells demonstrated
      a higher S-phase fraction by flow cytometry and a faster doubling time of 24-36 h
      compared with 72 h for parental cells. The cyclin-dependent kinase inhibitor
      p27(kip1) was decreased in TR cells, and cyclin-dependent kinase 2 activity was
      increased. Importantly, exogenous addition of p27(kip1) increased trastuzumab
      sensitivity. Additionally, resistant cells displayed heightened sensitivity to
      the proteasome inhibitor MG132, which induced p27(kip1) expression. Thus, we
      propose that trastuzumab resistance may be associated with decreased p27(kip1)
      levels and may be susceptible to treatments that induce p27(kip1) expression.

PMID- 15173012
TI  - A novel role for carcinoembryonic antigen-related cell adhesion molecule 6 as a
      determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells.
AB  - Most patients with pancreatic adenocarcinoma present with surgically incurable
      disease. Gemcitabine, the principal agent used to treat such patients, has little
      impact on outcome. Overexpression of carcinoembryonic antigen-related cell
      adhesion molecule (CEACAM) 6, a feature of this malignancy, is associated with
      resistance to anoikis and increased metastasis. The purpose of this study was to
      determine the role of CEACAM6 in cellular chemoresistance to gemcitabine. CEACAM6
      was stably overexpressed in Capan2 cells, which inherently express very low
      levels of the protein. Suppression of CEACAM6 expression was achieved in BxPC3
      cells, which inherently overexpress CEACAM6, by stable transfection of a CEACAM6
      small interfering RNA-generating vector. The effects of modulating CEACAM6
      expression on gemcitabine-induced cytotoxicity were determined by 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay, flow
      cytometric apoptosis quantification, caspase profiling, and Western analysis of
      cytoplasmic cytochrome c release. The roles of Akt and c-Src kinases as
      downstream targets of CEACAM6 signaling were examined. Stable overexpression of
      CEACAM6 in Capan2 increased gemcitabine chemoresistance, whereas CEACAM6 gene
      silencing in BxPC3 markedly increased the sensitivity of these cells to
      gemcitabine. Differential expression of CEACAM6 modulates Akt activity in a c-Src
      dependent manner, and CEACAM6 overexpression appears to protect cells from
      cytochrome c-induced caspase 3 activation and apoptosis.

PMID- 15173013
TI  - A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or
      low-grade toxicity on tissues highly sensitive to the toxic effects of maximum
      tolerated dose regimens.
AB  - The survival benefits of traditional maximum tolerated dose (MTD) cytotoxic
      therapy have been modest for the treatment of most types of metastatic malignancy
      and, moreover, often come with increased acute and chronic toxicity. Recent
      studies have demonstrated that the frequent administration of comparatively low
      doses of cytotoxic agents, with no extended breaks [low-dose metronomic (LDM)
      chemotherapy], may not only be at least as efficient as MTD therapy but also less
      toxic. This coincides with an apparent selectivity for "activated" endothelial
      cells of the tumor vasculature. However, the impact of LDM chemotherapy on the
      most sensitive target cell populations normally affected by MTD therapy (i.e.,
      bone marrow progenitors, gut mucosa, and hair follicle cells) has not been
      analyzed in experimental detail. Therefore, we compared effects of LDM and MTD
      cyclophosphamide (CTX) on bone marrow and gut mucosa. Furthermore, we studied the
      potential impact of LDM CTX on angiogenesis in the context of wound healing and
      evidence of organ toxicity. We show absent or moderate hematologic and intestinal
      toxicity of LDM as opposed to MTD CTX. Of note was the finding of sustained
      lymphopenia, which is not unexpected given the use of CTX as immunosuppressive
      drug. There was no negative impact on wound healing or evidence of organ
      toxicity. LDM offers clear safety advantages over conventional MTD chemotherapy
      and therefore would appear to be ideal for long-term combination therapy with
      targeted antiangiogenic drugs.

PMID- 15173014
TI  - Immunoprevention of HER-2/neu transgenic mammary carcinoma through an interleukin
      12-engineered allogeneic cell vaccine.
AB  - This study evaluated the ability of cytokine-engineered allogeneic (H-2(q)) HER
      2/neu-positive cells to prevent tumor development in mammary cancer-prone virgin
      female BALB/c (H-2(d)) mice transgenic for the transforming rat HER-2/neu
      oncogene (BALB-neuT mice). Repeated vaccinations with cells engineered to release
      interleukin (IL)-2, IL-12, IL-15, or IFN-gamma showed that IL-12-engineered cell
      vaccines had the most powerful immunopreventive activity, with >80% of 1-year-old
      BALB-neuT mice free of tumors. On the contrary all of the untreated mice and all
      of the mice vaccinated with IL-12-engineered cells lacking either HER-2/neu or
      allogeneic antigens developed mammary carcinomas within 22 or 33 weeks,
      respectively. Whole mount, histology, immunohistochemistry, and gene expression
      profile analysis showed that vaccination with IL-12-engineered cells maintained
      26-week mammary glands free of neoplastic growth, with a gene expression profile
      that clustered with that of untreated preneoplastic glands. The IL-12-engineered
      cell vaccine elicited a high production of IFN-gamma and IL-4 and a strong anti
      HER-2/neu antibody response. Immune protection was lost or markedly impaired in
      BALB-neuT mice lacking IFN-gamma or antibody production, respectively. The
      protection afforded by the IL-12-engineered cell vaccine was equal to that
      provided by the systemic administration of recombinant IL-12 in combination with
      HER-2/neu H-2(q) cell vaccine. However, IL-12-engineered cell vaccine induced
      much lower circulating IL-12 and IFN-gamma, and therefore lower potential side
      effects and systemic toxicity.

PMID- 15173015
TI  - Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.
AB  - Chemokines and their receptors play key roles in leukocyte trafficking and are
      also implicated in cancer metastasis to specific organs. Here we show that mouse
      B16F10 melanoma cells constitutively express chemokine receptor CXCR3, and that
      its ligands CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC induce cellular responses
      in vitro, such as actin polymerization, migration, invasion, and cell survival.
      To determine whether CXCR3 could play a role in metastasis to lymph nodes (LNs),
      we constructed B16F10 cells with reduced CXCR3 expression by antisense RNA and
      investigated their metastatic activities after s.c. inoculations to syngeneic
      hosts, C57BL/6 mice. The metastatic frequency of these cells to LNs was markedly
      reduced to approximately 15% (P < 0.05) compared with the parental or empty
      vector-transduced cells. On the other hand, pretreatment of mice with complete
      Freund's adjuvant increased the levels of CXCL9 and CXCL10 in the draining LNs,
      which caused 2.5-3.0-fold increase (P < 0.05) in the metastatic frequency of
      B16F10 cells to the nodes with much larger foci. Importantly, such a stimulation
      of metastasis was largely suppressed when CXCR3 expression in B16F10 cells was
      reduced by antisense RNA or when mice were treated with specific antibodies
      against CXCL9 and CXCL10. We also demonstrate that CXCR3 is expressed on several
      human melanoma cell lines as well as primary human melanoma tissues (5 of 9
      samples tested). These results suggest that CXCR3 inhibitors may be promising
      therapeutic agents for treatment of LN metastasis, including that of melanoma.

PMID- 15173016
TI  - Cripto: a novel target for antibody-based cancer immunotherapy.
AB  - Cripto, a member of the epidermal growth factor-Cripto-FRL-Criptic (EGF-CFC)
      family, has been described recently as a potential target for immunotherapy
      (Adkins et al., J Clin Invest 2003;112:575-87). We have produced rat monoclonal
      antibodies (mAbs) to a Cripto 17-mer peptide, corresponding to the "EGF-like"
      motif of Cripto. The mAbs react with most cancers of the breast, colon, lung,
      stomach, and pancreas but do not react or react weakly with normal tissues. The
      mAbs inhibit cancer cell growth in vitro, and this effect was greater with
      cytotoxic drugs such as 5-fluorouracil, epirubicin, and cisplatin. The anti
      Cripto mAbs prevent tumor development in vivo and inhibit the growth of
      established tumors of LS174T colon xenografts in Scid mice. The growth inhibitory
      effects with these mAbs may be greater than those described elsewhere, possibly
      because of IgM giving more effective cross-linking or binding to a different
      epitope (EGF-like region versus CFC region). The mechanism of inhibitory effects
      of the Cripto mAbs includes both cancer cell apoptosis, activation of c-Jun-NH(2)
      terminal kinase and p38 kinase signaling pathways and blocking of Akt
      phosphorylation. Thus, Cripto is a unique target, and mAbs to Cripto could be of
      therapeutic value for human cancers.

PMID- 15173017
TI  - In situ tumor ablation creates an antigen source for the generation of antitumor
      immunity.
AB  - Tumor-destructing techniques, like radiofrequency ablation (RFA), allow
      eradication of large tumors. Potentially, in situ tumor destruction also can
      provide the immune system with an antigen source for the induction of antitumor
      immunity. Antigen-presenting cells could take up antigens in the periphery after
      which they induce specific immune responses. Recent data show that especially
      antigen-presenting dendritic cells are crucial for the induction of potent immune
      responses. However, virtually nothing is known regarding the induction of immune
      responses after in situ tumor destruction in mice or humans. We used the well
      defined murine B16-OVA melanoma cell line to develop a novel tumor model to
      explore: (a). the immunologic consequences of in situ tumor destruction; and (b).
      the efficacy of a combination approach of tumor destruction and
      immunostimulation. Applying this model system we demonstrate that following RFA,
      a weak but detectable immune response develops, directed against OVA, but also
      against a broader range of B16 antigens. Adoptive transfer experiments further
      indicate that antitumor reactivity can be transferred to naive mice by
      splenocytes. To augment the response observed, we administered a blocking
      monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 at the
      time of tumor destruction. Interestingly, this strongly enhanced antitumor
      immunity, resulting in long-lasting tumor protection. These results illustrate
      that in situ tumor destruction can provide a useful antigen source for the
      induction of antitumor immunity, provided that additional immunostimulatory
      signals are coadministered.

PMID- 15173018
TI  - interferon regulatory factor-1 mediates the proapoptotic but not cell cycle
      arrest effects of the steroidal antiestrogen ICI 182,780 (faslodex, fulvestrant).
AB  - Antiestrogens induce both cytostasis (cell cycle arrest) and apoptosis, but the
      relationship between these end points and the signaling that regulates their
      induction are unclear. We have previously implicated the transcription factor and
      putative tumor suppressor IFN regulatory factor-1 (IRF-1) in acquired
      antiestrogen resistance (Gu et al., Cancer Res, 62: 3428-3437, 2002). We now show
      the functional significance of IRF-1 in affecting antiestrogen responsiveness in
      estrogen receptor-positive antiestrogen-sensitive models (MCF-7, T47D, and ZR-75
      1), a model of acquired antiestrogen resistance (MCF7/LCC9; estrogen receptor
      positive), and a model of de novo antiestrogen resistance (MDA-MB-231; estrogen
      receptor negative). Basal IRF-1 mRNA expression is lower in MCF7/LCC9 cells when
      compared with MCF-7, T47D, and ZR-75-1 cells. IRF-1 transcriptional activity in
      MCF-7/LCC9 cells is 18-fold lower than that seen in the parental cells (MCF
      7/LCC1) and is comparable with that in MDA-MB-231 cells. Although IRF-1 mRNA
      expression is induced by ICI 182,780 in sensitive cells, this regulation is lost
      in MCF-7/LCC9 and is absent in MDA-MB-231 cells. Loss of IRF-1 regulation appears
      specific to antiestrogen resistance-resistant cells induce IRF-1 mRNA in response
      to the cytotoxic drug doxorubicin. A dominant-negative IRF-1 eliminates the ICI
      182,780-induced apoptotic response (reduced >4-fold) and reduces MCF-7 and T47D
      cell sensitivity to the antiproliferative effects of ICI 182,780. This effect is
      not mediated by changes in cell cycle distribution; rather, dominant-negative IRF
      1 reduces ICI 182,780-induced apoptosis. These data identify a novel mechanism of
      antiestrogen resistance and implicate IRF-1 as a key component in signaling some
      ER-mediated effects on apoptosis/cell survival.

PMID- 15173019
TI  - Gene expression in the urinary bladder: a common carcinoma in situ gene
      expression signature exists disregarding histopathological classification.
AB  - The presence of carcinoma in situ (CIS) lesions in the urinary bladder is
      associated with a high risk of disease progression to a muscle invasive stage. In
      this study, we used microarray expression profiling to examine the gene
      expression patterns in superficial transitional cell carcinoma (sTCC) with
      surrounding CIS (13 patients), without surrounding CIS lesions (15 patients), and
      in muscle invasive carcinomas (mTCC; 13 patients). Hierarchical cluster analysis
      separated the sTCC samples according to the presence or absence of CIS in the
      surrounding urothelium. We identified a few gene clusters that contained genes
      with similar expression levels in transitional cell carcinoma (TCC) with
      surrounding CIS and invasive TCC. However, no close relationship between TCC with
      adjacent CIS and invasive TCC was observed using hierarchical cluster analysis.
      Expression profiling of a series of biopsies from normal urothelium and
      urothelium with CIS lesions from the same urinary bladder revealed that the gene
      expression found in sTCC with surrounding CIS is found also in CIS biopsies as
      well as in histologically normal samples adjacent to the CIS lesions.
      Furthermore, we also identified similar gene expression changes in mTCC samples.
      We used a supervised learning approach to build a 16-gene molecular CIS
      classifier. The classifier was able to classify sTCC samples according to the
      presence or absence of surrounding CIS with a high accuracy. This study
      demonstrates that a CIS gene expression signature is present not only in CIS
      biopsies but also in sTCC, mTCC, and, remarkably, in histologically normal
      urothelium from bladders with CIS. Identification of this expression signature
      could provide guidance for the selection of therapy and follow-up regimen in
      patients with early stage bladder cancer.

PMID- 15173020
TI  - Marijuana use and risk of oral squamous cell carcinoma.
AB  - Previous laboratory investigations, case reports, and a hospital-based case
      control study have suggested that marijuana use may be a risk factor for squamous
      cell head and neck cancer. We conducted a population-based case-control study to
      determine whether marijuana use is associated with the development of oral
      squamous cell carcinoma (OSCC). Case subjects (n = 407) were 18-65-year-old
      residents of three counties in western Washington State who were newly diagnosed
      with OSCC from 1985 through 1995. Control subjects (n = 615), who were similar to
      the cases with respect to age and sex, were selected from the general population
      using random-digit telephone dialing. Lifetime histories of marijuana use and
      exposure to known OSCC risk factors were ascertained using a structured
      questionnaire. Information on genetic polymorphisms in glutathione S-transferase
      enzymes was obtained from assays on participant DNA. Odds ratios for associations
      with features of marijuana use were adjusted for sex, education, birth year,
      alcohol consumption, and cigarette smoking. A similar proportion of case subjects
      (25.6%) and control subjects (24.4%) reported ever use of marijuana (adjusted
      odds ratio, 0.9; 95% confidence interval, 0.6-1.3). There were no trends in risk
      observed with increasing duration or average frequency of use or time since first
      or last use. No subgroup defined by known or suspected OSCC risk factors (age,
      cigarette smoking, alcohol consumption, and genetic polymorphisms) showed an
      increased risk. Marijuana use was not associated with OSCC risk in this large,
      population-based study.

PMID- 15173021
TI  - Correspondence re R. Lapointe et al., CD40-stimulated B lymphocytes pulsed with
      tumor antigens are effective antigen-presenting cells that can generate specific
      T cells. Cancer Res 2003;63:2836-43.

PMID- 15173022
TI  - Clinical and angiographic predictors of restenosis after percutaneous coronary
      intervention: insights from the Prevention of Restenosis With Tranilast and Its
      Outcomes (PRESTO) trial.
AB  - BACKGROUND: Restenosis prediction from published studies is hampered by
      inadequate sample size and incomplete angiographic follow-up. The prediction of
      restenosis with the existing variables is poor. The aim of the present study was
      to include the clinical and angiographic variables commonly associated with
      angiographic restenosis and develop a prediction model for restenosis from the
      PRESTO database. METHODS AND RESULTS: This study included 1312 patients with a
      single lesion enrolled in the angiographic substudy of the PRESTO trial. We
      constructed 2 risk scores. The first used preprocedural variables (female gender,
      vessel size [< or =2.5 mm, 2.5 to 3 mm, 3 to 3.5 mm, 3.5 to 4 mm, >4 mm], lesion
      length >20 mm, diabetes, smoking status, type C lesion, any previous percutaneous
      coronary intervention [PCI], and unstable angina) derived from previous studies.
      Estimated restenosis rates and corresponding variability for each possible level
      of the resultant risk score were obtained via bootstrapping techniques. The area
      under the receiver-operator characteristic (ROC) curve was 0.63, indicating
      modest discriminatory ability to predict restenosis. The second approach
      constructed a multiple logistic regression model considering significant
      univariate clinical and angiographic predictors of restenosis identified from the
      PRESTO database (treated diabetes mellitus, nonsmoker, vessel size, lesion
      length, American College of Cardiology/American Heart Association type C lesion,
      ostial location, and previous PCI). The area under the ROC curve for this risk
      score was also 0.63. CONCLUSIONS: The preprocedural clinical and angiographic
      variables from available studies and from the PRESTO trial have only modest
      predictive ability for restenosis after PCI.

PMID- 15173023
TI  - Novel gene locus for autosomal dominant left ventricular noncompaction maps to
      chromosome 11p15.
AB  - BACKGROUND: Left ventricular noncompaction (LVNC) is a congenital unclassified
      cardiomyopathy with numerous prominent trabeculations and deep intertrabecular
      recesses in a hypertrophied and hypokinetic myocardium. It has been reported to
      occur in isolation or in association with congenital heart disease. Mutations in
      the X-linked G4.5 gene are responsible for cases of isolated LVNC in male
      infants, but G4.5 mutations were not found in patients with clinical onset of
      disease in adulthood. In addition, several families with LVNC and an autosomal
      dominant pattern of inheritance suggest genetic heterogeneity. METHODS AND
      RESULTS: We performed a genome-wide linkage analysis in a family with autosomal
      dominant LVNC and show that a locus containing the LVNC disease gene maps to
      chromosome 11p15. A peak 2-point logarithm of odds score of 5.06 was obtained
      with marker D11S902 at theta=0. Haplotype analysis defined a critical interval of
      6.4 centimorgan between D11S1794 and D11S928 corresponding to a physical distance
      of 6.8 megabases. No disease-causing mutation was identified in 2 prime
      positional candidate genes, muscle LIM protein (MLP) and SOX6. CONCLUSIONS: We
      have mapped a locus for autosomal dominant LVNC to a 6.8-megabase region on human
      chromosome 11p15. Identification of the disease gene will allow genetic screening
      and provide fundamental insight into the understanding of myocardial
      morphogenesis.

PMID- 15173024
TI  - Gene transfer of parvalbumin improves diastolic dysfunction in senescent
      myocytes.
AB  - BACKGROUND: Impaired relaxation is a cardinal feature of senescent myocardial
      dysfunction. Recently, adenoviral gene transfer of parvalbumin, a small calcium
      buffering protein found exclusively in skeletal muscle and neurons, has been
      shown to improve cardiomyocyte relaxation in disease models of diastolic
      dysfunction. The goal of this study was to investigate whether parvalbumin gene
      transfer could reverse diastolic dysfunction in senescent cardiomyocytes. METHODS
      AND RESULTS: Myocytes were isolated from senescent (26 months) and adult (6
      months) F344/BN hybrid rats and were infected with Ad.Parv.GFP (where GFP is
      green fluorescent protein) or Ad.betagal.GFP at a multiplicity of infection of
      250 for 48 hours. Uninfected senescent and adult myocytes served as controls.
      After stimulation at a frequency of 0.5 Hz, intracellular calcium transients and
      myocyte contractility were measured using dual excitation spectrofluorometry and
      video-edge detection system (Ionoptix). Parvalbumin significantly improved
      relaxation parameters in senescent myocytes: Both the rate of calcium transient
      decay and the rate of myocyte relengthening were dramatically increased in
      senescent cardiac myocytes transduced with parvalbumin compared with
      nontransduced and GFP-expressing controls, with no effect on myocyte shortening.
      CONCLUSIONS: Parvalbumin expression corrects impaired relaxation in aging
      myocytes. Given that abnormalities of myocyte relaxation underlie diastolic
      dysfunction in a large proportion of elderly patients with heart failure, gene
      transfer of parvalbumin may thus be a novel approach to target diastolic
      dysfunction in senescent myocardium.

PMID- 15173025
TI  - Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk
      factors and echocardiographic left ventricular measures: the Framingham Heart
      Study.
AB  - BACKGROUND: Plasma levels of matrix metalloproteinase-9 (MMP-9), a key
      determinant of extracellular matrix degradation, are increased in heart failure
      and in acute coronary syndromes. We investigated cross-sectional relations of
      plasma MMP-9 to vascular risk factors and echocardiographic left ventricular (LV)
      measurements. METHODS AND RESULTS: We studied 699 Framingham Study participants
      (mean age, 57 years; 58% women), free of heart failure and previous myocardial
      infarction, who underwent routine echocardiography. We examined sex-specific
      distributions of LV internal dimensions (LVEDD) and wall thickness (LVWT) and
      sampled persons with both LVEDD and LVWT below the sex-specific median (referent,
      n=299), with increased LVEDD (LVEDD > or =90th percentile, n=204) and increased
      LVWT (LVWT > or =90th percentile, n=221) in a 3:2:2 ratio. Plasma MMP-9 was
      detectable in 138 persons (20%). In multivariable models, increasing heart rate
      (OR per SD, 1.41; 95% CI, 1.17 to 1.71) and antihypertensive treatment (OR, 1.63;
      95% CI, 1.06 to 2.50) were key clinical correlates of detectable plasma MMP-9. In
      multivariable-adjusted models, detectable plasma MMP-9 was associated with
      increased LVEDD (OR, 2.84; 95% CI, 1.13 to 7.11), increased LVWT (OR, 2.54; 95%
      CI, 1.00 to 6.46), and higher LV mass (P=0.06) in men but not in women (OR for
      increased LVEDD, 1.37; 95% CI, 0.54 to 3.46; for increased LVWT, 0.99; 95% CI,
      0.39 to 2.52; P=0.59 for LV mass). CONCLUSIONS: In our community-based sample,
      detectable plasma MMP-9 levels were associated with increased LV diastolic
      dimensions and increased wall thickness in men. These observations indicate that
      plasma MMP-9 level may be a marker for cardiac extracellular matrix degradation,
      a process involved in LV remodeling.

PMID- 15173026
TI  - Impaired baroreceptor control of renal sympathetic activity in human chronic
      heart failure.
AB  - BACKGROUND: The regulation of renal sympathetic activity in the setting of heart
      failure is largely unexplored. We used the norepinephrine spillover method to
      address the hypothesis that baroreflex control of renal sympathetic activity is
      blunted in heart failure. METHODS AND RESULTS: Twenty-two patients were studied,
      11 in a group with heart failure and 11 in a group with normal ventricular
      function. In both groups, renal norepinephrine spillover was assessed in response
      to sodium nitroprusside infused to steady-state conditions. Sodium nitroprusside
      resulted in significant reductions in mean systemic arterial pressure (normal
      group, -13+/-1% [mean+/-SEM]; heart failure group, -12+/-1%). In response to
      nitroprusside, there was an 85+/-34% increase in renal norepinephrine spillover
      in the normal group (from 537+/-84 to 840+/-140 pmol/min, P<0.05). Despite
      similar hemodynamic responses to nitroprusside in the heart failure group, renal
      norepinephrine spillover was unchanged (from 1420+/-153 to 1387+/-161 pmol/min,
      P=NS), a response that was significantly different from that seen in the normal
      group. CONCLUSIONS: In patients with heart failure, compared with those with
      normal ventricular function, renal sympathetic activity did not change in
      response to a steady-state infusion of sodium nitroprusside. This result provides
      evidence for reduced baroreflex control of renal sympathetic activity in heart
      failure.

PMID- 15173027
TI  - Tissue factor binding of activated factor VII triggers smooth muscle cell
      proliferation via extracellular signal-regulated kinase activation.
AB  - BACKGROUND: Tissue factor (TF) is the main initiator of coagulation in vivo.
      Recently, however, a role for TF as a cell receptor involved in signal
      transduction has been suggested. The aim of the present study was to assess
      whether activated factor VII (FVIIa) binding to TF could induce smooth muscle
      cell (SMC) proliferation and to clarify the possible intracellular mechanism(s)
      responsible for this proliferation. METHODS AND RESULTS: Cell proliferation was
      induced by FVIIa in a dose-dependent manner, as assessed by [3H]thymidine
      incorporation and direct cell counting, whereas no response was observed with
      active site-inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid
      of enzymatic activity. Similarly, no proliferation was observed when binding of
      FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of
      the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal-regulated
      kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by
      transient ERK phosphorylation in Western blots and by suppression of
      proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK
      phosphorylation was not observed with FVIIai or when cells were pretreated with
      AP-1. CONCLUSIONS: These data indicate a specific effect by which binding of
      FVIIa to TF on the surface of SMCs induces proliferation via a coagulation
      independent mechanism and possibly indicate a new link between coagulation,
      inflammation, and atherosclerosis.

PMID- 15173028
TI  - Aerobic fitness is associated with cardiomyocyte contractile capacity and
      endothelial function in exercise training and detraining.
AB  - BACKGROUND: Physical fitness and level of regular exercise are closely related to
      cardiovascular health. A regimen of regular intensity-controlled treadmill
      exercise was implemented and withdrawn to identify cellular mechanisms associated
      with exercise capacity and maximal oxygen uptake (VO2max). METHODS AND RESULTS:
      Time-dependent associations between cardiomyocyte dimensions, contractile
      capacity, and VO2max were assessed in adult rats after high-level intensity
      controlled treadmill running for 2, 4, 8, and 13 weeks and detraining for 2 and 4
      weeks. With training, cardiomyocyte length, relaxation, shortening, Ca2+ decay,
      and estimated cell volume correlated with increased VO2max (r=0.92, -0.92, 0.88, 
      0.84, 0.73; P<0.01). Multiple regression analysis identified cell length,
      relaxation, and Ca2+ decay as the main explanatory variables for VO2max (R2=0.87,
      P<0.02). When training stopped, exercise-gained VO2max decreased 50% within 2
      weeks and stabilized at 5% above sedentary controls after 4 weeks. Cardiomyocyte
      size regressed in parallel with VO2max and remained (9%) above sedentary after 4
      weeks, whereas cardiomyocyte shortening, contraction/relaxation- and Ca2+
      transient time courses, and endothelium-dependent vasorelaxation regressed
      completely within 2 to 4 weeks of detraining. Cardiomyocyte length, estimated
      cell volume, width, shortening, and Ca2+ decay and endothelium-dependent arterial
      relaxation all correlated with VO2max (r=0.85, 0.84, 0.75, 0.63, -0.54, -0.37;
      P<0.01). Multiple regression identified cardiomyocyte length and vasorelaxation
      as the main determinants for regressed VO2max during detraining (R2=0.76,
      P=0.02). CONCLUSIONS: Cardiovascular adaptation to regular exercise is highly
      dynamic. On detraining, most of the exercise-gained aerobic fitness acquired over
      2 to 3 months is lost within 2 to 4 weeks. The close association between
      cardiomyocyte dimensions, contractile capacity, arterial relaxation, and aerobic
      fitness suggests cellular mechanisms underlying these changes.

PMID- 15173029
TI  - G(-30)A polymorphism in the pancreatic promoter of the glucokinase gene
      associated with angiographic coronary artery disease and type 2 diabetes
      mellitus.
AB  - BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of coronary artery
      disease (CAD). A G(-30)A polymorphism in the beta-cell-specific promoter of
      glucokinase (GK-30PM) has been implicated in reduced pancreatic beta-cell
      function. Its impact on CAD has not been examined. METHODS AND RESULTS: The
      glucokinase G(-30)A variant was determined in 2567 patients with angiographic CAD
      and in 731 individuals in whom CAD had been ruled out by angiography. In carriers
      of the A allele, the adjusted OR of CAD was 1.39 (95% CI, 1.15 to 1.70).
      Corresponding ORs were 1.27 (95% CI, 1.02 to 1.59) and 1.92 (95% CI, 1.26 to
      2.93) in individuals without and with T2DM, respectively. The prevalence of the A
      allele increased in parallel with the Friesinger coronary score. Patients with
      T2DM were more frequent among carriers of > or =1 A allele (OR, 1.17; 95% CI,
      1.00 to 1.28). This association was stronger if CAD patients only were
      considered. The A allele was associated with higher glucose (fasting, P=0.002; 2
      hours after oral glucose, P=0.017) and glycohemoglobin (HbA1c; P=0.002).
      Furthermore, presence of 1 A allele was negatively related to beta-cell function,
      estimated by beta percent (P=0.012) and by the ratios of proinsulin to insulin
      (P=0.025) and proinsulin to C peptide (P=0.019). CONCLUSIONS: The A allele of the
      pancreatic promoter of glucokinase increases the risk of CAD in individuals with
      and without T2DM. Furthermore, at least in CAD, it is associated with an
      augmented prevalence of T2DM.

PMID- 15173030
TI  - Increased atrial and brain natriuretic peptides in adults with cyanotic
      congenital heart disease: enhanced understanding of the relationship between
      hypoxia and natriuretic peptide secretion.
AB  - BACKGROUND: Brain natriuretic peptide (BNP) levels are used in the evaluation of
      patients with heart disease, yet there is little understanding of the effect of
      hypoxia on natriuretic peptide secretion. Furthermore, recent data suggest that
      oxytocin may mediate stretch-induced atrial natriuretic peptide (ANP) secretion.
      METHODS AND RESULTS: Ten patients with cyanotic congenital heart defects and 10
      control subjects were studied. N-terminal proatrial natriuretic peptide and N
      terminal probrain natriuretic peptide levels were 4-fold (P=0.02) and 12-fold
      (P=0.03) greater in cyanotic patients than in control subjects. Cyanotic patients
      had reduced body water compared with control subjects, although the difference
      did not reach statistical significance (P=0.22). In a separate group of patients,
      cardiac myocytes were isolated from the right atrial appendage during CABG. The
      amount of oxygen in the buffered saline was varied to simulate hypoxia. Isolated
      hypoxic atrial myocytes had 43% fewer dense surface secretory granules compared
      with normoxic myocytes (P<0.0001). Immunohistochemical staining demonstrated
      decreased ANP and BNP in hypoxic compared with normoxic right atrial tissue.
      Isolated myocytes also degranulated when incubated with oxytocin (P<0.0001), but
      there was no difference in oxytocin levels in cyanotic patients compared with
      control subjects (P=0.49). CONCLUSIONS: ANP and BNP are markedly elevated in
      adults with cyanotic congenital heart disease despite reduced body water. Our
      results show that hypoxia is a direct stimulus for ANP and BNP secretion in human
      cardiac myocytes. These findings may have implications for the interpretation of
      BNP levels in the assessment of patients with heart and lung disease.

PMID- 15173031
TI  - Impact of amoxicillin prophylaxis on the incidence, nature, and duration of
      bacteremia in children after intubation and dental procedures.
AB  - BACKGROUND: Controversy exists about the impact of prophylactic antibiotics on
      bacteremia after invasive dental procedures. The purpose of this double-blind,
      randomized, placebo-controlled study was to determine the impact of amoxicillin
      prophylaxis on the incidence, nature, and duration of bacteremia from
      nasotracheal intubation and dental procedures in children. METHODS AND RESULTS:
      Children were randomly assigned before surgery to the American Heart Association
      (AHA)-recommended dose of amoxicillin or to a placebo. Aerobic and anaerobic
      blood cultures were drawn at 8 specific time points after intubation, dental
      restorative and cleaning procedures, and before, during, and after dental
      extraction(s), to include blood drawings up to 45 minutes after the last
      extraction. Aerobic and anaerobic blood culture results were used to determine
      the incidence, nature, and duration of bacteremia from these procedures. For the
      100 children enrolled (mean age, 3.5 years), the overall incidence of positive
      blood cultures, defined as at least 1 positive culture of the 8, was
      significantly higher in the placebo (84%) than the amoxicillin group (33%)
      (P<0.0001). Bacteremia occurrence rates after intubation and after dental
      restorations and cleaning were 18% and 20% in the placebo group and 4% and 6% in
      the amoxicillin group (P=0.05 and P=0.07, respectively). At 1.5 minutes after the
      initiation of dental extractions, bacteremia occurred in 76% of the placebo group
      versus 15% of the amoxicillin group (P<0.001). The majority of the 152 positive
      cultures and of the 29 different bacteria identified were Gram-positive cocci.
      Bacteremia persisted longer in the placebo group. CONCLUSIONS: Bacteremia from
      these procedures occurs more often, from a wider variety of bacterial species,
      and for a longer duration after dental extractions than previously reported in
      any age group. Amoxicillin has a significant impact on the incidence, nature, and
      duration of bacteremia after nasal intubation, dental restorative and cleaning
      procedures, and dental extractions.

PMID- 15173032
TI  - Ultrasound strain imaging of altered myocardial stiffness: stunned versus
      infarcted reperfused myocardium.
AB  - BACKGROUND: In this study we evaluate the diastolic deformation of
      ischemic/reperfused myocardium and relate this deformation to tissue elastic
      properties. METHODS AND RESULTS: Farm pigs were subjected to left anterior
      descending coronary artery occlusion followed by reperfusion to create either
      stunning (n=12) or transmural myocardial infarction (n=12). Ultrasound-derived
      radial strain rates (SR) and strain were measured in the ischemic and remote
      walls. Myocardial stiffness was estimated from diastolic pressure-wall thickness
      relationship obtained from preload alterations. At reperfusion, end-systolic
      strain (epsilon(sys)) was significantly reduced in both stunned and infarcted
      walls compared with their remote walls (3+/-3% versus 26+/-2% and 1+/-0% versus
      33+/-5%, respectively; P<0.0001) or baseline values. Diastolic passive
      deformation (epsilon(A)) and rates of deformation during early (E(SR)) and late
      (A(SR)) diastole were comparable between stunned and remote walls (epsilon(A):
      7.3+/-1.6% versus 7.9+/-1.9%; E(SR): -2.7+/-0.4 s(-1) versus -2.6+/-0.5 s(-1);
      A(SR): -1.8+/-0.2 s(-1) versus -1.9+/-0.3 s(-1); P=NS for all) but were of
      significantly lower magnitude in infarcted walls versus remote walls (epsilon(A):
      1.1+/-0.2% versus 11.4+/-1.9%; E(SR): -0.3+/-0.1 s(-1) versus -2.4+/-0.4 s(-1);
      A(SR): -0.3+/-0.1 s(-1) versus -2.5+/-0.4 s(-1); P<0.0001 for all). Stiffness
      coefficient of exponential diastolic pressure-wall thickness relation was higher
      for infarcted (P<0.05) but not for stunned walls (P=NS) compared with their
      remote walls. CONCLUSIONS: Early after postischemic reperfusion and in the
      presence of severely reduced systolic deformation, diastolic passive deformation
      (and rates of deformation) can distinguish stiff, noncompliant, transmurally
      infarcted myocardial walls from those more compliant walls containing viable but
      stunned myocardium.

PMID- 15173033
TI  - In vivo evidence of angiogenesis induced by transcription factor Ets-1: Ets-1 is
      located upstream of angiogenesis cascade.
AB  - BACKGROUND: A transcription factor, ets-1, regulates the transcription of
      metalloproteinase genes, the activity of which is necessary for matrix
      degradation and the migration of endothelial cells. However, no study has
      demonstrated that ets-1 itself has an angiogenic action in vivo. Thus, we
      examined (1) the effects of overexpression of the ets-1 gene on angiogenesis in a
      rat hindlimb ischemia model, and (2) how ets-1 induced angiogenesis. METHODS AND
      RESULTS: In this study, we used the HVJ-liposome method, which is highly
      effective for transfection, to transfect the human ets-1 gene. At 4 weeks after
      transfection, the capillary density and blood flow were significantly increased
      in a hindlimb transfected with the human ets-1 gene compared with control. These
      data clearly demonstrated that ets-1 has the ability to stimulate angiogenesis in
      vivo. To elucidate the molecular mechanisms by which ets-1 induced angiogenesis,
      we focused especially on the expression of hepatocyte growth factor (HGF) and
      vascular endothelial growth factor (VEGF), potent angiogenic growth factors,
      because the promoter regions of both genes contain ets binding sites.
      Interestingly, overexpression of ets-1 upregulated both tissue HGF and VEGF
      concentrations in rat hindlimb. More importantly, administration of neutralizing
      antibody against HGF and VEGF attenuated the increase in blood flow and BrdU
      positive cells induced by ets-1. Upregulation of HGF and VEGF by ets-1 was also
      confirmed by in vitro experiments using human vascular smooth muscle cells.
      CONCLUSIONS: The present study demonstrated that ets-1 regulated angiogenesis
      through the induction of angiogenic growth factors (VEGF and HGF). Overexpression
      of ets may provide a new therapeutic strategy to treat peripheral arterial
      disease.

PMID- 15173034
TI  - p66ShcA modulates tissue response to hindlimb ischemia.
AB  - BACKGROUND: Oxidative stress plays a pivotal role in ischemia and
      ischemia/reperfusion injury. Because p66(ShcA)-null (p66(ShcA)-/-) mice exhibit
      both lower levels of intracellular reactive oxygen species and increased
      resistance to cell death induced by oxidative stress, we investigated whether
      tissue damage that follows acute ischemia or ischemia/reperfusion was altered in
      p66(ShcA)-/- mice. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced
      by femoral artery dissection, and ischemia/reperfusion was induced with an
      elastic tourniquet. Both procedures caused similar changes in blood perfusion in
      p66(ShcA) wild-type (p66(ShcA)wt) and p66(ShcA)-/- mice. However, significant
      differences in tissue damage were found: p66(ShcA)wt mice displayed marked
      capillary density decrease and muscle fiber necrosis. In contrast, in p66(ShcA)-/
      mice, minimal capillary density decrease and myofiber death were present. When
      apoptosis after ischemia was assayed, significantly lower levels of apoptotic
      endothelial cells and myofibers were found in p66(ShcA)-/- mice. In agreement
      with these data, both satellite muscle cells and endothelial cells isolated from
      p66(ShcA)-/- mice were resistant to apoptosis induced by simulated ischemia in
      vitro. Lower apoptosis levels after ischemia in p66(ShcA)-/- cells correlated
      with decreased levels of oxidative stress both in vivo and in vitro. CONCLUSIONS:
      p66(ShcA) plays a crucial role in the cell death pathways activated by acute
      ischemia and ischemia/reperfusion, indicating p66(ShcA) as a potential
      therapeutic target for prevention and treatment of ischemic tissue damage.

PMID- 15173036
TI  - Viability assessment by delayed enhancement cardiovascular magnetic resonance:
      will low-dose dobutamine dull the shine?

PMID- 15173035
TI  - Impaired endothelium-dependent flow-mediated vasodilation in hypertensive
      subjects with hyperaldosteronism.
AB  - BACKGROUND: Recent studies suggest that aldosterone may impair endothelium
      dependent vascular function through suppression of nitric oxide formation.
      Assessments of forearm blood flow or arterial compliance suggest a similar effect
      in humans. The present study was designed to determine whether chronic
      aldosterone excess in subjects with resistant hypertension impairs endothelium
      dependent vascular reactivity as indexed by direct assessment of brachial artery
      flow-mediated dilation (FMD). METHODS AND RESULTS: Consecutive subjects (n=80)
      with resistant hypertension were prospectively evaluated with an early-morning
      ratio of plasma aldosterone to plasma renin activity and 24-hour urinary
      aldosterone and sodium. Changes in brachial artery diameter during reactive
      hyperemia were measured by high-resolution ultrasound. Hyperaldosteronism was
      diagnosed on the basis of a renin activity <1.0 ng x mL(-1) x h(-1), urinary
      aldosterone >12 microg/24 h, and urinary sodium >200 mEq/24 h. FMD was
      significantly lower in 36 subjects with hyperaldosteronism (1.8+/-1.3% versus
      3.9+/-1.9% from baseline; P<0.0001) compared with the 44 subjects without
      hyperaldosteronism. FMD was negatively and significantly correlated with plasma
      aldosterone (r=-0.38, P=0.0006), 24-hour urinary aldosterone (r=-0.49, P<0.0001),
      and ratio of plasma aldosterone to plasma renin activity (r=-0.43, P<0.0001) but
      was independent of blood pressure, age, and body mass index. In 30 subjects, 3
      months of treatment with spironolactone significantly increased FMD (2.5+/-1.7
      versus 6.0+/-2.0%; P<0.0001) independently of blood pressure change. CONCLUSIONS:
      These data demonstrate a strong association between aldosterone excess and
      impaired endothelial function in human subjects as indexed by flow-mediated
      arterial vasodilation. These results suggest that chronic aldosteronism may have
      a blood pressure-independent effect on cardiovascular disease progression in
      subjects with resistant hypertension.

PMID- 15173037
TI  - Pharmacoinvasive therapy: the future of treatment for ST-elevation myocardial
      infarction.

PMID- 15173038
TI  - Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I:
      angiogenic cytokines.

PMID- 15173040
TI  - Images in cardiovascular medicine. Household clustering of hypertrophic
      cardiomyopathy.

PMID- 15173039
TI  - Combined blockade of the renin-angiotensin system with angiotensin-converting
      enzyme inhibitors and angiotensin II type 1 receptor antagonists.

PMID- 15173041
TI  - Atherosclerotic Vascular Disease Conference: Executive summary: Atherosclerotic
      Vascular Disease Conference proceeding for healthcare professionals from a
      special writing group of the American Heart Association.

PMID- 15173042
TI  - Atherosclerotic Vascular Disease Conference: Writing Group I: epidemiology.

PMID- 15173043
TI  - Atherosclerotic Vascular Disease Conference: Writing Group II: risk factors.

PMID- 15173044
TI  - Atherosclerotic Vascular Disease Conference: Writing Group III: pathophysiology.

PMID- 15173045
TI  - Atherosclerotic Vascular Disease Conference: Writing Group IV: imaging.

PMID- 15173046
TI  - Atherosclerotic Vascular Disease Conference: Writing Group V: medical decision
      making and therapy.

PMID- 15173047
TI  - Atherosclerotic Vascular Disease Conference: Writing Group VI: revascularization.

PMID- 15173048
TI  - Improving quality of care through disease management: principles and
      recommendations from the American Heart Association's Expert Panel on Disease
      Management.

PMID- 15173049
TI  - Air pollution and cardiovascular disease: a statement for healthcare
      professionals from the Expert Panel on Population and Prevention Science of the
      American Heart Association.
AB  - Air pollution is a heterogeneous, complex mixture of gases, liquids, and
      particulate matter. Epidemiological studies have demonstrated a consistent
      increased risk for cardiovascular events in relation to both short- and long-term
      exposure to present-day concentrations of ambient particulate matter. Several
      plausible mechanistic pathways have been described, including enhanced
      coagulation/thrombosis, a propensity for arrhythmias, acute arterial
      vasoconstriction, systemic inflammatory responses, and the chronic promotion of
      atherosclerosis. The purpose of this statement is to provide healthcare
      professionals and regulatory agencies with a comprehensive review of the
      literature on air pollution and cardiovascular disease. In addition, the
      implications of these findings in relation to public health and regulatory
      policies are addressed. Practical recommendations for healthcare providers and
      their patients are outlined. In the final section, suggestions for future
      research are made to address a number of remaining scientific questions.

PMID- 15173050
TI  - The clinician as investigator: participating in clinical trials in the practice
      setting.
AB  - The rapid development of new drugs, therapies, and devices has created a dramatic
      increase in the number of trials needed to properly evaluate them. The majority
      of patients treated today, many of whom could be eligible for participation in
      these studies, are seen in community hospitals and medical practices that are not
      affiliated with an academic medical center. Thus, there is a demonstrable need
      for physicians in private practice to enlist as investigators in these trials.
      This article is intended to encourage those physicians by describing the need and
      providing the rationale for their participation. It covers basic requirements for
      participating in clinical trials and outlines ethical, regulatory, financial, and
      other logistical issues of importance for the potential investigator and provides
      an algorithm for selecting a study for participation. Finally, the appendices
      review basic elements of study design and statistical principles, which may be of
      interest to a potential investigator.

PMID- 15173051
TI  - Images in cardiovascular medicine. Left ventricular mass after treatment with
      chemotherapic drugs.

PMID- 15173052
TI  - The clinician as investigator: participating in clinical trials in the practice
      setting: Appendix 1: fundamentals of study design.

PMID- 15173053
TI  - The clinician as investigator: participating in clinical trials in the practice
      setting: Appendix 2: statistical concepts in study design and analysis.

PMID- 15173054
TI  - Why the morning?

PMID- 15173056
TI  - Inflammation as a cardiovascular risk factor.
AB  - Inflammation occurs in the vasculature as a response to injury, lipid
      peroxidation, and perhaps infection. Various risk factors, including
      hypertension, diabetes, and smoking, are amplified by the harmful effects of
      oxidized low-density-lipoprotein cholesterol, initiating a chronic inflammatory
      reaction, the result of which is a vulnerable plaque, prone to rupture and
      thrombosis. Epidemiological and clinical studies have shown strong and consistent
      relationships between markers of inflammation and risk of future cardiovascular
      events. Inflammation can potentially be detected locally by imaging techniques as
      well as emerging techniques, such as identification of temperature or pH
      heterogeneity. It can be detected systemically by measurement of inflammatory
      markers. Of these, the most reliable and accessible for clinical use is currently
      high-sensitivity C-reactive protein. A combination of methods may provide the
      best identification of persons at risk for cardiovascular events who would
      benefit from treatment. In randomized, controlled trials, 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the form of statins,
      have been shown to provide effective therapy for lowering CRP, in conjunction
      with their lipid-lowering effects. Although the magnitude of risk reduction
      associated with statin use appears to be largest for those with the highest serum
      levels of CRP, whether CRP reduction per se lowers cardiovascular risk is
      unknown.

PMID- 15173057
TI  - CRP as a mediator of disease.
AB  - Of the various hypotheses offered to explain atherosclerosis, inflammation now
      appears to provide a key to this pathological process. Inflammation has been
      shown to play a major role in precipitating a cascade of events from formation of
      the atheromatous lesion in response to vascular injury through lipid ingestion by
      macrophages, to subsequent rupture of the lesion, and myocardial infarction.
      Atherosclerosis shares many inflammatory features with rheumatoid arthritis (RA),
      an autoimmune disease, and drugs that block the inflammatory cytokine pathway now
      provide effective treatment for RA. In animal models, blockers of the
      inflammatory cytokine pathway appear to block mononuclear cell binding to
      arterial plaque. C-reactive protein (CRP), an inflammatory marker, may also play
      a proinflammatory role in activating monocyte chemotactic protein.
      Antiatherosclerotic drugs may be exerting some of their beneficial effects by
      inhibiting the harmful effects of CRP.

PMID- 15173058
TI  - Statins as immunomodulatory agents.
AB  - Statins have long been thought to exert their benefits by reducing cholesterol
      synthesis. However, the fact that mevalonate is the precursor of isoprenoids that
      regulate diverse cellular functions has led investigators to examine pleiotropic
      effects for these agents. Major histocompatibility complex class II (MHC-II)
      molecules, which affect the immune response and organ rejection after
      transplantation, may be induced by the proinflammatory cytokine interferon gamma
      (IFN-gamma). An experiment was conducted to determine whether statins affect the
      regulation of MHC-II expression by IFN-gamma in cultured human endothelial cells
      and monocyte/macrophages. Statins were found to repress the induction of MHC-II
      by IFN-gamma. This may explain the immunosuppressive effects of statins seen in
      two clinical trials of organ transplantation and suggest a potential role for
      statins as immunosuppressive agents.

PMID- 15173059
TI  - Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as
      antiinflammatory agents?
AB  - According to traditional thinking, atherosclerosis results from passive lipid
      deposition in the vascular wall. Thus, therapies predominantly targeted lipid
      metabolism. The contemporary view of atherosclerosis, however, has broadened to
      include an active and complex role for inflammation, orchestrated in part by
      mediators of the immune system. This recognition prompted the question of whether
      antiinflammatory interventions might provide a novel avenue for the treatment of
      atherosclerosis. Uncertainties about the type of antiinflammatory regimen and
      appropriate patient selection currently hamper clinical investigation. Yet
      cardiovascular scientists have begun to address these questions at the bench, in
      experimental models, and indirectly in humans. Inhibitors of 3-hydroxy-3
      methylglutaryl coenzyme A HMG-CoA reductase (statins) have emerged as promising
      tools with dual functions. Originally designed to target elevated lipids, the
      "traditional" cause of atherosclerosis, statins might also confer cardiovascular
      benefit by directly or indirectly modulating the inflammatory component of this
      prevalent disease. Yet controversy persists regarding the (clinical) relevance of
      these potential non-LDL-lowering "pleiotropic" functions of statins. This
      overview addresses the controversy by reviewing in vitro and in vivo evidence
      regarding statins as antiinflammatory agents.

PMID- 15173060
TI  - Endothelial function: a critical determinant in atherosclerosis?
AB  - Common conditions predisposing to atherosclerosis, such as hypercholesterolemia,
      hypertension, diabetes, and smoking, are associated with endothelial dysfunction.
      Endothelial function has largely been assessed as endothelium-dependent
      vasomotion, at least in part based on the assumption that impaired endothelium
      dependent vasodilation also reflects the alteration of other important functions
      of the endothelium. An important rationale for this approach has been the
      observation that endothelium-derived nitric oxide (NO), a major mediator of
      endothelium-dependent vasodilation, has important anti-inflammatory and
      antithrombotic properties, ie, inhibiting leukocyte adhesion, limiting platelet
      adhesion and aggregation, and the expression of plasminogen activator inhibitor-1
      (PAI-1), a prothrombotic protein. Accumulating data suggest that the degree of
      impairment of endothelium-dependent vasomotion has profound and independent
      prognostic implications. A common mechanism underlying endothelial dysfunction
      relates to increased vascular production of reactive oxygen species. Recent
      studies also suggest that inflammation per se and C-reactive protein in
      particular may directly contribute to endothelial dysfunction. These findings
      raise the question of whether assessment of endothelial function can be used in
      the clinical setting to identify patients at high risk. New insights into
      mechanisms of endothelial dysfunction, such as a better understanding of the
      regulation of important vascular sources of oxygen radicals, may lead to novel
      therapeutic strategies with the potential to improve prognosis.

PMID- 15173061
TI  - Effects of HMG-CoA reductase inhibitors on endothelial function: role of
      microdomains and oxidative stress.
AB  - Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A
      (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular
      cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these
      metabolic changes contribute to favorable effects on nitric oxide (NO)
      bioavailability. Given the essential role of NO in preserving vascular structure
      and function, this effect of statins is of considerable therapeutic importance.
      Statins have been demonstrated to restore endothelial NO production by several
      mechanisms, including upregulating endothelial NO synthase (eNOS) protein
      expression and blocking formation of reactive oxygen species. In this article, we
      will discuss additional ways in which statins restore endothelial NO production
      and improve endothelial function. (1) Statins modulate membrane microdomain
      formation, resulting in reduced expression of proteins that specifically inhibit
      eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with
      the formation of pathologic microdomains, including cholesterol crystalline
      structures. This observation has important implications for plaque stabilization,
      as these microdomains contribute to cholesterol crystal formation and endothelial
      apoptosis. Finally, (3) statins improve endothelial function by interfering with
      oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The
      relationships between membrane microdomains, cholesterol biosynthesis, and
      endothelial function will be discussed.

PMID- 15173062
TI  - Beyond the laboratory: clinical implications for statin pleiotropy.
AB  - Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3
      methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a
      revolution in the management of atherosclerosis. In addition to their potent
      effect on serum lipid levels, statins influence several other cellular pathways,
      including those involving inflammatory, oxidative, and thrombotic processes.
      These effects clearly have the potential to beneficially modify the atherogenic
      process, and it has been suggested that they contribute to the impressive results
      seen in the clinical trials. We review the clinical evidence for benefits of
      statin therapy that are distinct from their effect on lipid biology. In
      particular, we address three key issues: the role of statins in diseases not
      traditionally associated with elevated cholesterol levels; whether clinical
      benefits are seen with statin therapy before an effect on lipid levels; and
      whether the magnitude of clinical benefit observed with statin therapy is
      unrelated to the degree of cholesterol reduction. At present, low-density
      lipoprotein lowering seems to be the primary mechanism underlying the clinical
      benefits of statin therapy and should remain the focus of risk-reduction
      strategies in clinical practice.

PMID- 15173063
TI  - Targeting vascular endothelial growth factor for relapsed and refractory adult
      acute myelogenous leukemias: therapy with sequential 1-beta-d
      arabinofuranosylcytosine, mitoxantrone, and bevacizumab.
AB  - PURPOSE: Vascular endothelial growth factor (VEGF) promotes acute myelogenous
      leukemia (AML) cell growth and survival and may contribute to drug resistance.
      bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against
      diverse malignancies when administered with cytotoxic chemotherapy. We conducted
      a Phase II clinical trial of bevacizumab administered after chemotherapy to
      adults with refractory or relapsed AML, using a timed sequential therapy (TST)
      approach. EXPERIMENTAL DESIGN: bevacizumab 10 mg/kg was administered on day 8
      after 1-beta-d-arabinofuranosylcytosine 2 g/m(2)/72 h beginning day 1 and
      mitoxantrone 40 mg/m(2) beginning day 4. In vivo laboratory correlates included
      AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free
      serum VEGF before and during TST with bevacizumab. RESULTS: Forty-eight adults
      received induction therapy. Myelosuppression occurred in all of the patients
      similar to other TST regimens. Toxicities were decreased ejection fraction (6%),
      cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48
      (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial
      response) underwent one consolidation cycle and 5 (3 CR and 2 partial response)
      underwent allogeneic transplant. Median overall and disease-free survivals for CR
      patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts
      demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel
      density after bevacizumab. VEGF was detected in pretreatment serum in 67% of
      patients tested, increased by day 8 in 52%, and decreased in 93% (67%
      undetectable) 2 h after bevacizumab. CONCLUSIONS: In this single arm study,
      cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and
      duration in adults with AML that is resistant to traditional treatment
      approaches. The clearance of marrow blasts in some patients after bevacizumab
      suggests that VEGF neutralization might result directly in leukemic cell death.
      The potential biological and clinical activity of bevacizumab in AML warrants
      additional clinical and laboratory study.

PMID- 15173064
TI  - Successful engraftment after reduced-intensity umbilical cord blood
      transplantation for adult patients with advanced hematological diseases.
AB  - PURPOSE: The purpose of this research was to evaluate the feasibility of reduced
      intensity unrelated cord-blood transplantation (RI-UCBT) in adult patients with
      advanced hematological diseases. EXPERIMENTAL DESIGN: Thirty patients (median
      age, 58.5 years; range, 20-70 years) with advanced hematological diseases
      underwent RI-UCBT at Toranomon Hospital between September 2002 and August 2003.
      Preparative regimen composed of fludarabine 25 mg/m(2) on days -7 to -3,
      melphalan 80 mg/m(2) on day -2, and 4 Gy total body irradiation on day -1. Graft
      versus-host disease prophylaxis was composed of cyclosporin alone. RESULTS:
      Twenty-six patients achieved primary neutrophil engraftment after a median of
      17.5 days. Median infused total cell dose was 3.1 x 10(7)/kg (range, 2.0-4.3 x
      10(7)/kg). Two transplant-related mortalities occurred within 28 days of
      transplant, and another 2 patients displayed primary graft failure. Cumulative
      incidence of complete donor chimerism at day 60 was 93%. Grade II-IV acute graft
      versus-host disease occurred in 27% of patients, with median onset 36 days.
      Primary disease recurred in 3 patients, and transplant-related mortality within
      100 days was 27%. Estimated 1-year overall survival was 32.7%. Excluding 7
      patients with documented infection, 19 patients displayed noninfectious fever
      before engraftment (median onset, day 9). Manifestations included high-grade
      fever, eruption, and diarrhea. The symptoms responded well to corticosteroid
      treatments in 7 of 13 treated patients. CONCLUSION: This study demonstrated the
      feasibility of RI-UCBT in adults.

PMID- 15173065
TI  - First (18)F-labeled tracer suitable for routine clinical imaging of sst receptor
      expressing tumors using positron emission tomography.
AB  - PURPOSE: Despite excellent radionuclide characteristics, no (18)F-labeled
      peptides are available for quantitative peptide receptor mapping using positron
      emission tomography (PET) so far, mainly due to time-consuming multistep
      radiosyntheses with limited overall yields. A newly developed two-step
      chemoselective conjugation method allows rapid and high-yield [(18)F]fluorination
      of peptides via oxime formation and was applied for the synthesis of new (18)F
      labeled carbohydrated Tyr(3)-octreotate (TOCA) analogs with optimized
      pharmacokinetics suitable for clinical routine somatostatin-receptor (sst)
      imaging. EXPERIMENTAL DESIGN: (18)F-labeled glucose (Gluc-S-) and cellobiose (Cel
      S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime
      formation with 4-[(18)F]fluorobenzaldehyde ([(18)F]FBOA-peptides). Both the in
      vitro internalization profile of Gluc-S-Dpr([(18)F]FBOA)TOCA and Cel-S
      Dpr([(18)F]FBOA)TOCA in hsst(2)-expressing Chinese hamster ovary cells (dual
      tracer protocol) and their biodistribution in AR42J tumor-bearing mice were
      investigated and compared with two [(18)F]fluoropropionylated ([(18)F]FP)
      analogs, Gluc-Lys([(18)F]FP)TOCA and Gluc-S-Dpr([(18)F]FP)TOCA. RESULTS: In
      contrast to [(18)F]FP-labeling (3 h), chemo-selective [(18)F]FBOA-formation (50
      min) afforded the respective radiopeptides in high yields (65-85%). In vitro,
      Gluc-S-Dpr([(18)F]FBOA)TOCA and Cel-S-Dpr([(18)F]FBOA)-TOCA showed high
      internalization (139 +/- 2 and 163 +/- 8 of the reference [(125)I]Tyr(3)
      octreotide, respectively), which was reflected by high tumor accumulation in vivo
      [21.8 +/- 1.4 and 24.0 +/- 2.5% of injected dose/g (1 h), respectively]. How
      ever, only Cel-S-Dpr([(18)F]FBOA)TOCA and Gluc-S-Dpr([(18)F]FP)TOCA (tumor: 15.1
      +/- 1.5% of injected dose/g) with its very low accumulation in all of the
      nontarget organs showed improved tumor:organ ratios compared with Gluc
      Lys([(18)F]FP)TOCA. For Cel-S-Dpr([(18)F]FBOA)TOCA,tumor:organ ratios (1 h) were
      42:1, 27:1, 15:1, 3:1, and 208:1 for blood, liver, intestine, kidney, and muscle,
      respectively. CONCLUSION: Due to the fast and high-yield chemoselective
      radiofluorination strategy and to its excellent pharmacokinetics, Cel-S
      Dpr([(18)F]FBOA)TOCA represents the first tracer suitable for routine clinical
      application in PET somatostatin receptor imaging.

PMID- 15173066
TI  - Genetically altered fields as origin of locally recurrent head and neck cancer: a
      retrospective study.
AB  - PURPOSE: Surgeons treating patients with head and neck squamous cell carcinoma
      (HNSCC) rely heavily on histology to decide whether the resection margins are
      tumor free and subsequent adjuvant treatments can be omitted. However, despite
      the presence of tumor-free margins, 10-30% of HNSCC patients still develop a
      locally recurrent tumor. Evidence is available that recurrent cancer develops
      from either (a). outgrowth of a relatively small number of tumor cells that have
      not been detected by the pathologist or (b). a precursor lesion in which
      additional genetic alterations have led again to invasive cancer. EXPERIMENTAL
      DESIGN: In a retrospective study on 13 HNSCC cases, we analyzed the primary
      tumor, its surrounding histologically tumor-free resection margins, and local
      recurrences for loss of heterozygosity (22 microsatellite markers on 6
      chromosomes) and TP53 mutations to determine the origin of the recurrent cancer.
      RESULTS: A precursor lesion was absent in 5 of 13 (39%) cases, and the genetic
      similarity of the primary and recurrent cancer was high, providing evidence that
      residual cancer cells were the origin of recurrence. For the remaining eight
      cases (61%) a genetically related precursor lesion (field) was detected, and for
      five of these cases, evidence was found that both the primary and recurrent
      carcinoma originated from this field. The remaining three cases were less
      conclusive. CONCLUSIONS: This study explains the pathobiology of locally
      recurrent HNSCC in patients with histologically tumor-free resection margins and
      indicates that the development of novel therapies to decrease the local
      recurrence rates in HNSCC should not only be focused on eradicating residual
      cancer cells but also on the precursor lesions that are left behind.

PMID- 15173067
TI  - Molecular diagnosis of surgical margins and local recurrence in head and neck
      cancer patients: a prospective study.
AB  - PURPOSE: Approximately 10-30% of surgically treated head and neck cancer patients
      develop local recurrences while the resection margins are histologically tumor
      free. These recurrences may arise from cancer cells left behind but not detected
      by the pathologist, or they may develop from precursor lesions adjacent to the
      tumor that were not completely resected. We have investigated whether TP53
      mutated DNA in the surgical margins is suitable to identify patients with head
      and neck squamous cell carcinoma at risk for local and locoregional recurrence.
      EXPERIMENTAL DESIGN: In a prospective cohort study of 76 patients with
      histologically tumor-free margins, the presence of TP53-mutated DNA was
      determined in the surgical margins using the phage plaque assay and correlated to
      clinical outcome. Immunostaining of the molecular-positive margins for mutated
      p53 protein was used to identify whether unresected precursor lesions or residual
      tumor cells were left behind. RESULTS: The absence of TP53-mutated DNA in
      surgical margins was significantly associated with remaining free of local and
      locoregional recurrence (P = 0.027 and P = 0.028, respectively). Moreover, the
      presence of TP53-mutated DNA in the surgical margins was an independent
      prognosticator for locoregional recurrence (relative risk = 7.1; P = 0.021; 95%
      confidence interval, 0.9-56). In 20% of the cases, the presence of TP53-mutated
      DNA in the surgical margins was found to be related to the presence of tumor
      related precursor lesions. CONCLUSIONS: This study shows the value of TP53
      mutated DNA as a molecular marker to predict locally recurrent head and neck
      squamous cell carcinoma. The observation that all patients who were negative for
      TP53-mutated DNA in the surgical margins remained free of local recurrence raises
      hope that molecular analysis of histologically tumor-free surgical margins can be
      exploited to decide on postoperative radiotherapy. Furthermore, our data provide
      evidence that local recurrences originate mainly from tumor cells left behind but
      also originate, in part, from unresected precursor lesions.

PMID- 15173068
TI  - Human epidermal growth factor receptor 2 status modulates subcellular
      localization of and interaction with estrogen receptor alpha in breast cancer
      cells.
AB  - PURPOSE: Approximately two-thirds of breast cancer patients respond to endocrine
      therapy, and this population of patients is estrogen receptor (ER) positive.
      However, a significant proportion of patients do not respond to hormone therapy.
      ER hormone responsiveness is widely believed to be influenced by enhanced cross
      talk of ER with overexpressed human epidermal growth factor receptor 2 (HER2),
      and a subgroup of ER-positive tumors coexpress high HER2. EXPERIMENTAL DESIGN:
      Breast cancer cells with or without HER2 overexpression were analyzed for ER
      status, subcellular localization, and interactions with HER2 signaling components
      by biochemical and immunological methods. Experiments explored the regulatory
      interactions between the HER2 and ER pathways and the sensitivity of breast
      cancer cells to tamoxifen. RESULTS: Stable or transient or natural HER2
      overexpression in ER-positive breast cancer cells promoted the nucleus-to
      cytoplasm relocalization of ER, enhanced interactions of ER with HER2, inhibited
      ER transactivation function, and induced resistance to tamoxifen-mediated growth
      inhibition of breast cancer cells. In addition, HER2 up-regulation resulted in ER
      interaction with Sos, a component of Ras signaling, and hyperstimulation of the
      mitogen-activated protein kinase extracellular signal-regulated kinase 1/2
      (ERK1/2). Conversely, down-regulation of HER2 by the anti-HER2 monoclonal
      antibody Herceptin led to suppression of ERK1/2 stimulation, restoration of ER to
      the nucleus, and potentiation of the growth-inhibitory action of tamoxifen.
      CONCLUSION: The results presented here show for the first time that ER
      redistribution to the cytoplasm and its interaction with HER2 are important
      downstream effects of HER2 overexpression, that ERK1/2 is important for ER
      cytoplasmic localization, and that subcellular localization of ER may play a
      mechanistic role in determining the responsiveness of breast cancer cells to
      tamoxifen.

PMID- 15173069
TI  - Gene-expression profile changes correlated with tumor progression and lymph node
      metastasis in esophageal cancer.
AB  - PURPOSE: The purpose of this research was to identify molecular clues to tumor
      progression and lymph node metastasis in esophageal cancer and to test their
      value as predictive markers. EXPERIMENTAL DESIGN: We explored the gene expression
      profiles in cDNA array data of a 36-tissue training set of esophageal squamous
      cell carcinoma (ESCC) by using generalized linear model-based regression analysis
      and a feature subset selection algorithm. By applying the identified optimal
      feature sets (predictive gene sets), we trained and developed ensemble
      classifiers consisting of multiple probabilistic neural networks combined with
      AdaBoosting to predict tumor stages and lymph node metastasis. We validated the
      classifier abilities with 18 independent cases of ESCC. RESULTS: We identified 71
      genes of 1289 cancer-related genes of which the expression correlated with tumor
      stages. Of the 71 genes, 47 significantly differed between the Tumor-Node
      Metastasis pT1/2 and pT3/4 stages. Cell cycle regulators and transcriptional
      factors possibly promoting the growth of tumor cells were highly expressed in the
      early stages of ESCC, whereas adhesion molecules and extracellular matrix-related
      molecules possibly promoting invasiveness increased in the later stages. For
      lymph node metastasis, we identified 44 genes with predictive values, which
      included cell adhesion molecules and cell membrane receptors showing higher
      expression in node-positive cases and cell cycle regulators and intracellular
      signaling molecules showing higher expression in node-negative cases. The
      ensemble classifiers trained with the selected features predicted tumor stage and
      lymph node metastasis in the 18 validation cases with respective accuracies of
      94.4% and 88.9%. This demonstrated the reproducibility and predictive value of
      the identified features. CONCLUSION: We suggest that these characteristic genes
      will provide useful information for understanding the malignant nature of ESCC as
      well as information useful for personalizing the treatments.

PMID- 15173070
TI  - Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell
      lung cancer and is an independent predictor of outcome in patients.
AB  - PURPOSE: An increase in the activity of the mitogen-activated protein kinases
      (MAPKs) has been correlated with a more malignant phenotype in several tumor
      models in vitro and in vivo. A key regulatory mechanism of the MAPKs
      [extracellular signal-regulated kinase (ERK); c-jun NH(2)-terminal kinase (JNK);
      and p38] is the dual specificity phosphatase CL100, also called MAPK phosphatase
      1 (MKP-1). This study was designed to examine the involvement of CL100/MKP-1 and
      stress-related MAPKs in lung cancer. EXPERIMENTAL DESIGN: We assessed the
      expression of CL100/MKP-1 and the activation of the MAPKs in a panel of 18 human
      cell lines [1 primary normal bronchial epithelium, 8 non-small cell lung cancer
      (NSCLC), 7 small cell lung cancer (SCLC), and 2 carcinoids] and in 108 NSCLC
      surgical specimens. RESULTS: In the cell lines, CL100/MKP-1 expression was
      substantially higher in NSCLC than in SCLC. P-ERK, P-JNK, and P-p38 were
      activated in SCLC and NSCLC, but the degree of their activation was variable.
      Immunohistochemistry in NSCLC resection specimens showed high levels of CL100/MKP
      1 and activation of the three MAPK compared with normal lung. In univariate
      analysis, no relationship was found among CL100/MKP-1 expression and P-ERK, P
      JNK, or P-p38. Interestingly, high CL100/MKP-1 expression levels independently
      predicted improved survival in multivariate analysis. JNK activation associated
      with T(1-2) and early stage, whereas ERK activation correlated with late stages
      and higher T and N. Neither JNK nor ERK activation were independent prognostic
      factors when studied for patient survival. CONCLUSIONS: Our data indicate the
      relevance of MAPKs and CL100/MKP-1 in lung cancer and point at CL100/MKP-1 as a
      potential positive prognostic factor in NSCLC. Finally, our study supports the
      search of new molecular targets for lung cancer therapy within the MAPK signaling
      pathway.

PMID- 15173071
TI  - Magnetic resonance imaging measurements of the response of murine and human
      tumors to the vascular-targeting agent ZD6126.
AB  - PURPOSE: ZD6126 is a novel vascular targeting agent currently undergoing clinical
      evaluation. It acts by destabilizing the microtubulin of fragile and
      proliferating neoendothelial cells in tumors. The drug leads to blood vessel
      congestion, the selective destruction of the vasculature, and extensive necrosis
      in experimental tumors. The aim of the study reported here was to assess the
      ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure
      the antivascular effects of ZD6126 in tumors. EXPERIMENTAL DESIGN: The work was
      carried out in mice bearing C38 colon adenocarcinoma and in patients with
      advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38
      tumors) after i.v. drug administration. Contrast agent (gadolinium
      diethylenetriaminepentaacetate) enhancement was characterized by the initial area
      under the gadolinium diethylenetriaminepentaacetate uptake versus time curve
      (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of
      interstitial space. RESULTS: The median IAUC was reduced in all C38 tumors after
      ZD6126 administration [by 6-48% at 50 mg/kg (n = 3)], 58-91% at 100 mg/kg (n =
      4), and 11-93% at 200 mg/kg (n = 6). In contrast, the administration of vehicle
      only led to no consistent change in median IAUC (n = 4). The ZD6126-induced
      changes in median IAUC appeared to be dose dependent (P = 0.045). No ZD6126
      induced changes were apparent in murine muscle. Similar effects were seen in
      preliminary data from human tumors (11 tumors studied, 9 patients). At doses of
      80 mg/m(2) and higher, the median IAUC post-ZD6126 treatment was reduced in all
      of the tumors studied (8 tumors, 6 patients) to 36-72% from the baseline value.
      There was a significant trend of increasing reductions with increasing exposure
      (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent.
      The reproducibility of the median IAUC parameter was investigated in patients. In
      19 human tumors (measured in 19 patients) inter- and intratumor coefficients of
      variation were 64 and 18%. CONCLUSIONS: The contrast enhanced-MRI measured median
      IAUC is a useful end point for quantifying ZD6126 antivascular effects in human
      tumors.

PMID- 15173072
TI  - Identification of C-met oncogene as a broadly expressed tumor-associated antigen
      recognized by cytotoxic T-lymphocytes.
AB  - PURPOSE: C-Met proto-oncogene is a receptor tyrosine kinase that mediates the
      oncogenic activities of the hepatocyte growth factor. Using a DNA chip analysis
      of tumor samples from patients with renal cell carcinoma and sequencing of
      peptides bound to the HLA-A*0201 molecules on tumor cells a peptide derived from
      the c-Met protein was identified recently. EXPERIMENTAL DESIGN: We used this
      novel HLA-A*0201 peptide for the induction of specific CTLs to analyze the
      presentation of this epitope by malignant cells. RESULTS: The induced CTL
      efficiently lysed target cells pulsed with the cognate peptide, as well as HLA
      A*0201-matched tumor cell lines in an antigen-specific and HLA-restricted manner.
      Furthermore, the induced c-Met-specific CTLs recognized autologous dendritic
      cells (DCs) pulsed with the peptide or transfected with whole-tumor mRNA purified
      from c-Met-expressing cell lines. We next induced c-Met-specific CTLs using
      peripheral blood mononuclear cells and DC from an HLA-A*0201-positive patient
      with plasma cell leukemia to determine the recognition of primary autologous
      malignant cells. These CTLs lysed malignant plasma cells while sparing
      nonmalignant B- and T-lymphocytes, monocytes, and DCs. CONCLUSION: Our results
      demonstrate that c-Met oncogene is a novel tumor rejection antigen recognized by
      CTL and expressed on a broad variety of epithelial and hematopoietic malignant
      cells.

PMID- 15173073
TI  - Intravenous RNA interference gene therapy targeting the human epidermal growth
      factor receptor prolongs survival in intracranial brain cancer.
AB  - PURPOSE: The human epidermal growth factor receptor (EGFR) plays an oncogenic
      role in solid cancer, including brain cancer. The present study was designed to
      prolong survival in mice with intracranial human brain cancer with the weekly
      i.v. injection of nonviral gene therapy causing RNA interference (RNAi) of EGFR
      gene expression. EXPERIMENTAL DESIGN: Human U87 gliomas were implanted in the
      brain of adult scid mice, and weekly i.v. gene therapy was started at day 5 after
      implantation of 500000 cells. An expression plasmid encoding a short hairpin RNA
      directed at nucleotides 2529-2557 within the human EGFR mRNA was encapsulated in
      pegylated immunoliposomes. The pegylated immunoliposome was targeted to brain
      cancer with 2 receptor-specific monoclonal antibodies (MAb), the murine 83-14 MAb
      to the human insulin receptor and the rat 8D3 MAb to the mouse transferrin
      receptor. RESULTS: In cultured glioma cells, the delivery of the RNAi expression
      plasmid resulted in a 95% suppression of EGFR function, based on measurement of
      thymidine incorporation or intracellular calcium signaling. Weekly i.v. RNAi gene
      therapy caused reduced tumor expression of immunoreactive EGFR and an 88%
      increase in survival time of mice with advanced intracranial brain cancer.
      CONCLUSIONS: Weekly i.v. nonviral RNAi gene therapy directed against the human
      EGFR is a new therapeutic approach to silencing oncogenic genes in solid cancers.
      This is enabled with a nonviral gene transfer technology that delivers liposome
      encapsulated plasmid DNA across cellular barriers with receptor-specific
      targeting ligands.

PMID- 15173074
TI  - Changes in gene expression induced by phosphorothioate oligodeoxynucleotides
      (including G3139) in PC3 prostate carcinoma cells are recapitulated at least in
      part by treatment with interferon-beta and -gamma.
AB  - PURPOSE: G3139 is an antisense bcl-2 phosphorothioate oligodeoxyribonucleotide
      that is currently being evaluated in Phase III clinical trials in several human
      cancers. The aim of the present work was to further identify the apparent non-bcl
      2-dependent mechanism of this action of this compound in PC3 prostate cancer
      cells. EXPERIMENTAL DESIGN: We performed Affymetrix U95A oligonucleotide
      microarray studies on mRNA isolated from cells treated with G3139 and related
      oligonucleotides. RESULTS: Hierarchical clustering revealed the presence of a set
      of genes of which the expression was elevated on both 1 and 3 days after
      oligonucleotide treatment. Significantly, the persistence of expression of the up
      regulation of these genes, many of which are members of the IFN cascade, was
      greater for G3139 than for any other oligomer evaluated. Furthermore, many of the
      genes with the greatest up-regulation of expression are also those of which the
      expression is up-regulated after treatment of cells with IFNs. Treatment of PC3
      cells with either IFN-beta or -gamma recapitulated some of the aspects of the
      molecular and phenotypic changes observed after treatment with a G3139/Lipofectin
      complex. These include down-regulation of bcl-2 protein expression itself, down
      regulation of protein kinase C alpha protein expression (but not that of other
      protein kinase C isoforms), alteration in p21/Waf1/Cip1 protein expression, up
      regulation of MHC-I cell surface expression, and profound suppression of cell
      growth in the absence of a notable increase in cellular apoptosis. However, G3139
      (when complexed with Lipofectin) did not induce the up-regulation of expression
      of either type I or type II IFNs, nor could IFNs be found in conditioned media
      from treated cells. CONCLUSIONS: Oligonucleotide microarray experiments
      demonstrated that G3139 could induce elements of the IFN cascade in PC3 cells in
      vitro. In addition, the cellular phenotype obtained after treatment with
      exogenous IFN could, at least in part, recapitulate that obtained after G3139
      treatment. Nevertheless, the oligonucleotide microarray experiments we performed
      also demonstrated that there are extremely large qualitative and quantitative
      differences between the two treatments.

PMID- 15173075
TI  - Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies.
AB  - PURPOSE: To determine the dose-limiting toxicities, maximum tolerated dose, and
      pharmacokinetics of TLK286, a novel cancer prodrug, administered weekly. PATIENTS
      AND METHODS: Patients with advanced malignancies were treated with TLK286
      administered weekly by i.v. infusion over 30 min in escalating doses 60-960
      mg/m(2). A treatment cycle was defined as 3 weekly treatments. Patients underwent
      tumor assessments on day 43, and those patients receiving clinical benefit
      continued on treatment until disease progression or unacceptable toxicity. Safety
      was assessed by the WHO criteria. RESULTS: Thirty-seven patients received 111
      cycles of TLK286 at eight dose levels (median, 3 cycles; range, 1-16 cycles). In
      this study, TLK286 given weekly at 960 mg/m(2) was well tolerated without dose
      limiting toxicities. TLK286-related toxicities included grade 1-2 nausea and
      vomiting, fatigue and anemia. Nine of 31 evaluable patients continued therapy
      beyond day 43 and received a median of 5 cycles (range of 3-16 cycles) and
      experienced durable stable disease or minor tumor regression. Pharmacokinetic
      characteristics of TLK286 are described by an optimized two-compartment model.
      Mild to moderate renal or hepatic organ dysfunction did not impact the
      elimination of TLK286. CONCLUSIONS: TLK286 administered weekly at doses up to 960
      mg/m(2) were well tolerated. The safety and antitumor activity observed in a
      broad range of cancer types supports Phase 2 disease-specific investigations of
      TLK286 given weekly at 960 mg/m(2).

PMID- 15173076
TI  - Treatment of colon and lung cancer patients with ex vivo heat shock protein 70
      peptide-activated, autologous natural killer cells: a clinical phase i trial.
AB  - PURPOSE: The 14 amino acid sequence (aa(450-463)) TKDNNLLGRFELSG (TKD) of heat
      shock protein 70 (Hsp70) was identified as a tumor-selective recognition
      structure for natural killer (NK) cells. Incubation of peripheral blood
      lymphocyte cells with TKD plus low-dose interleukin 2 (IL-2) enhances the
      cytolytic activity of NK cells against Hsp70 membrane-positive tumors, in vitro
      and in vivo. These data encouraged us to test tolerability, feasibility, and
      safety of TKD-activated NK cells in a clinical Phase I trial. EXPERIMENTAL
      DESIGN: Patients with metastatic colorectal cancer (n = 11) and non-small cell
      lung cancer (n = 1) who had failed standard therapies were enrolled. After ex
      vivo stimulation of autologous peripheral blood lymphocytes with Hsp70-peptide
      TKD (2 microg/ml) plus low-dose IL-2 (100 units/ml), TKD was removed by extensive
      washing, and activated cells were reinfused i.v. The procedure was repeated for
      up to six cycles, applying a dose escalation schedule in 4 patients. RESULTS: The
      percentage of activated NK cells in the reinfused leukapheresis products ranged
      between 8 and 20% of total lymphocytes, corresponding to total NK cell counts of
      0.1 up to 1.5 x 10(9). Apart from restless feeling in 1 patient and itching in 2
      patients, no negative side effects were observed. Concomitant with an enhanced
      CD94 cell surface density, the cytolytic activity of NK cells against Hsp70
      membrane-positive colon carcinoma cells was enhanced after TKD/IL-2 stimulation
      in 10 of 12 patients. Concerning tumor response, 1 patient was in stable disease
      during therapy by formal staging criteria and another patient showed stable
      disease in one metastases and progression in another. CONCLUSIONS: Reinfusion of
      Hsp70-activated autologous NK cells is safe. Immunological results warrant
      additional studies in patients with lower tumor burden.

PMID- 15173077
TI  - Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric
      micelle-formulated paclitaxel, in patients with advanced malignancies.
AB  - PURPOSE: The rationale for developing an alternative paclitaxel formulation
      concerns Cremophor EL-related side effects, and a novel paclitaxel delivery
      system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle
      formulated paclitaxel free of Cremophor EL. A phase I study was performed to
      determine the maximum tolerated dosage, dose-limiting toxicities, and the
      pharmacokinetic profile of Genexol-PM in patients with advanced, refractory
      malignancies. EXPERIMENTAL DESIGN: Twenty-one patients were entered into the
      study. Genexol-PM was i.v. administered over 3 h every 3 weeks without
      premedication. The Genexol-PM dose was escalated from 135 mg/m(2) to 390 mg/m(2).
      RESULTS: All of the patients were evaluable for toxicity and response. Acute
      hypersensitivity reactions were not observed. Neuropathy and myalgia were the
      most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at
      230 and 300 mg/m(2), respectively. At 390 mg/m(2), 2 of 3 patients developed
      grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated
      dosage was determined to be 390 mg/m(2). There were 3 partial responses (14%)
      among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane
      therapy. The paclitaxel area under the curve from time 0 to infinity and peak or
      maximum paclitaxel concentration seemed to increase with escalating dose, except
      at 230 mg/m(2), which suggests that Genexol-PM has linear pharmacokinetics.
      CONCLUSION: The main dose-limiting toxicities were neuropathy, myalgia, and
      neutropenia, and the recommended dosage for a phase II study is 300 mg/m(2).
      Genexol-PM is believed to be superior to conventional paclitaxel in terms of the
      obviation of premedication and the delivery of higher paclitaxel doses without
      additional toxicity.

PMID- 15173078
TI  - A Phase I and pharmacological study with imidazolium-trans-DMSO-imidazole
      tetrachlororuthenate, a novel ruthenium anticancer agent.
AB  - PURPOSE: NAMI-A [H(2)Im[trans-RuCl(4)(DMSO)HIm] or imidazolium-trans-DMSO
      imidazole-tetrachlororuthenate] is a novel ruthenium-containing compound that has
      demonstrated antimetastatic activity in preclinical studies. This Phase I study
      was designed to determine the maximum-tolerated dose (MTD), profile of adverse
      events, and dose-limiting toxicity of NAMI-A in patients with solid tumors.
      Furthermore, the ruthenium pharmacokinetics (PK) after NAMI-A administration and
      preliminary antitumor activity were evaluated. PATIENTS AND METHODS: Adult
      patients with solid tumors received NAMI-A as an i.v. infusion over 3 h daily for
      5 days every 3 weeks. PK of total and unbound ruthenium was determined during the
      first and second treatment using noncompartmental pharmacokinetic analysis. The
      total accumulation of ruthenium in WBCs was also quantified. RESULTS: Twenty-four
      patients were treated at 12 dose levels (2.4-500 mg/m(2)/day). At 400
      mg/m(2)/day, blisters developed on the hands, fingers, and toes. At 500
      mg/m(2)/day, blisters persisted from weeks to months and slowly regressed.
      Although no formal common toxicity criteria (CTC) grade 3 developed, painful
      blister formation was considered dose limiting. Because the first signs developed
      at 400 mg/m(2)/day, the advised dose for further testing of NAMI-A was determined
      to be 300 mg/m(2)/day on this schedule. PK analysis revealed a linear
      relationship between dose and area under the concentration-time curve (AUC) of
      total and unbound ruthenium (R(2) = 0.75 and 0.96, respectively) over the whole
      dose range. Plasma clearance of total ruthenium was 0.17 +/- 0.09 liter/h, and
      terminal half-life was 50 +/- 19 h. The volume of distribution at steady state of
      total ruthenium was 10.1 +/- 2.8 liters. The accumulation of ruthenium in WBC was
      not directly proportional to the increasing total exposure to ruthenium. One
      patient with pretreated and progressive nonsmall cell lung cancer had stable
      disease for 21 weeks. CONCLUSION: NAMI-A can be administered safely as a 3-h i.v.
      infusion at a dose of 300 mg/m(2)/day for 5 days, every 3 weeks.

PMID- 15173079
TI  - Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in
      malignant glioma patients.
AB  - PURPOSE: Scarce information is available on the brain penetration of temozolomide
      (TMZ), although this novel methylating agent is mainly used for the treatment of
      malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma
      and cerebrospinal fluid (CSF) along with its inter-individual variability, to
      characterize covariates and to explore relationships between systemic or cerebral
      drug exposure and clinical outcomes. EXPERIMENTAL DESIGN: TMZ levels were
      measured by high-performance liquid chromatography in plasma and CSF samples from
      35 patients with newly diagnosed or recurrent malignant gliomas. The population
      pharmacokinetic analysis was performed with nonlinear mixed-effect modeling
      software. Drug exposure, defined by the area under the concentration-time curve
      (AUC) in plasma and CSF, was estimated for each patient and correlated with
      toxicity, survival, and progression-free survival. RESULTS: A three-compartment
      model with first-order absorption and transfer rates between plasma and CSF
      described the data appropriately. Oral clearance was 10 liter/h; volume of
      distribution (V(D)), 30.3 liters; absorption constant rate, 5.8 h(-1);
      elimination half-time, 2.1 h; transfer rate from plasma to CSF (K(plasma-->CSF)),
      7.2 x 10(-4)h(-1) and the backwards rate, 0.76 h(-1). Body surface area
      significantly influenced both clearance and V(D), and clearance was sex
      dependent. The AUC(CSF) corresponded to 20% of the AUC(plasma). A trend toward an
      increased K(plasma-->CSF) of 15% was observed in case of concomitant
      radiochemotherapy. No significant correlations between AUC in plasma or CSF and
      toxicity, survival, or progression-free survival were apparent after deduction of
      dose-effect. CONCLUSIONS: This is the first human pharmacokinetic study on TMZ to
      quantify CSF penetration. The AUC(CSF)/AUC(plasma) ratio was 20%. Systemic or
      cerebral exposures are not better predictors than the cumulative dose alone for
      both efficacy and safety.

PMID- 15173080
TI  - High expression levels of x-linked inhibitor of apoptosis protein and survivin
      correlate with poor overall survival in childhood de novo acute myeloid leukemia.
AB  - PURPOSE: Apoptosis-related proteins are important molecules for predicting
      chemotherapy response and prognosis in adult acute myeloid leukemia (AML).
      However, data on the expression and prognostic impact of these molecules in
      childhood AML are rare. EXPERIMENTAL DESIGN: Using flow cytometry and Western
      blot analysis, we, therefore, investigated 45 leukemic cell samples from children
      with de novo AML enrolled and treated within the German AML-BFM93 study for the
      expression of apoptosis-regulating proteins [CD95, Bcl-2, Bax, Bcl-xL, procaspase
      3, X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of
      apoptosis protein-1 (cIAP-1), survivin]. RESULTS: XIAP (P < 0.002) but no other
      apoptosis regulators showed maturation-dependent expression differences as
      determined by French-American-British (FAB) morphology with the highest
      expression levels observed within the immature M0/1 subtypes. XIAP (P < 0.01) and
      Bcl-xL (P < 0.01) expression was lower in patients with favorable rather than
      intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter
      overall survival was associated with high expression levels of XIAP [30 (n = 10)
      versus 41 months (n = 34); P < 0.05] and survivin [27 (n = 10) versus 41 months
      (n = 34); P < 0.05]. CONCLUSIONS: We conclude that apoptosis-related molecules
      are associated with maturation stage, cytogenetic risk groups, and therapy
      outcome in childhood de novo AML. The observed association of XIAP with immature
      FAB types, intermediate/poor cytogenetics, and poor overall survival should be
      confirmed within prospective pediatric AML trials.

PMID- 15173081
TI  - Molecular marker profiles predict locoregional control of head and neck squamous
      cell carcinoma in a randomized trial of continuous hyperfractionated accelerated
      radiotherapy.
AB  - PURPOSE: Identification of factors that assist prediction of tumor response to
      radiotherapy may aid in refining treatment strategies and improving outcome.
      Possible association of molecular marker expression profiles with locoregional
      control of head and neck squamous cell carcinoma was investigated in a randomized
      trial of conventional versus continuous hyperfractionated accelerated
      radiotherapy (CHART). EXPERIMENTAL DESIGN: Tumor material was obtained from 402
      patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and
      cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian
      information criterion was used to group tumors with similar marker expression;
      resulting expression profiles were then compared in terms of their difference in
      outcome after CHART and conventionally fractionated radiotherapy. RESULTS:
      Molecular marker profile was an independent prognostic factor for locoregional
      control. This was confirmed in multivariate analysis, including clinical
      variables such as tumor and nodal status, primary site, histological grade, age,
      and gender (P < 0.001 and P = 0.006 for local and nodal relapse, respectively).
      In particular, Bcl-2-positive tumors responded significantly better than average
      in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and
      randomly patterned Ki-67 expression, responded worse than average with no benefit
      from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining,
      with an organized pattern, benefit significantly from CHART schedule.
      CONCLUSIONS: This study demonstrates the potential of molecular profiles to
      predict radiotherapy response of head and neck squamous cell carcinoma and for
      treatment stratification. Distinct expression profiles correlate with three
      distinct clinical phenotypes, including good locoregional control, poor
      locoregional control, and an outcome strongly dependent upon fractionation
      schedule.

PMID- 15173082
TI  - Decreased absolute counts of T lymphocyte subsets and their relation to disease
      in squamous cell carcinoma of the head and neck.
AB  - PURPOSE: Apoptosis of circulating CD8+ T cells seen in patients with squamous
      cell carcinoma of the head and neck [SCCHN (Hoffmann T, et al. Clin Cancer Res
      2002;8:2553-62)] suggested a possibility of lymphocyte imbalance. Therefore,
      absolute numbers and percentages of lymphocyte subsets were examined in the
      peripheral blood of SCCHN patients and controls. EXPERIMENTAL DESIGN: Venous
      blood was obtained from 146 patients with SCCHN and 54 normal volunteers.
      Absolute numbers of CD3+, CD4+, and CD8+ T lymphocytes were determined using
      fluorobeads in a flow cytometry-based technique. Percentages of T lymphocyte
      subsets were also evaluated by flow cytometry. The patients were grouped at the
      time of blood draw [active versus no evidence of disease (NED), type of therapy
      administered, and the length of follow-up]. RESULTS: Patients with SCCHN had
      significantly lower absolute numbers of CD3+ CD4+, and CD8+ T cells than normal
      controls. However, no differences in the percentages of T-cell subsets between
      patients and normal controls were observed. Patients with active disease had
      significantly lower CD3+ and CD4+ T-cell counts than those with NED. Patients who
      had NED after surgery and radiotherapy had the lowest T-cell counts among the NED
      cohort. Patients who had NED for >2 years did not recover their T-cell counts,
      and the T-cell imbalance was evident many years after curative surgery. The tumor
      node-metastasis (TNM) stage or site of the disease was not related to the
      absolute T-cell count. Patients with recurrent disease at the time of blood draw
      tended to have the lowest CD4+ T-cell counts. CONCLUSIONS: Patients with SCCHN
      have altered lymphocyte homeostasis, which persists for months or years after
      curative therapies.

PMID- 15173083
TI  - Molecular profiles of neurofibromatosis type 1-associated plexiform
      neurofibromas: identification of a gene expression signature of poor prognosis.
AB  - PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a
      complex variety of clinical symptoms. The hallmark of NF1 is the development of
      heterogeneous benign neurofibromas, which may appear as dermal neurofibromas or
      plexiform neurofibromas. NF1 patients with plexiform neurofibromas are at risk of
      developing malignant peripheral nerve sheath tumors. EXPERIMENTAL DESIGN: To
      obtain additional insight into the molecular pathogenesis of plexiform
      neurofibromas, we used real-time quantitative reverse transcription-PCR assays to
      quantify the mRNA expression of 349 selected genes in plexiform neurofibromas in
      comparison with dermal neurofibromas and patient-matched malignant peripheral
      nerve sheath tumors. RESULTS: Thirty genes were significantly up-regulated in
      plexiform neurofibromas compared with dermal neurofibromas. None were down
      regulated. The up-regulated genes mainly encoded transcription factors and growth
      factors and secreted proteins, cytokines, and their receptors, pointing to a role
      of paracrine and autocrine signaling defects in the genesis of plexiform
      neurofibromas. We also identified a gene expression profile, based on MMP9,
      FLT4/VEGFR3, TNFRSF10B/TRAILR2, SHH, and GLI1, which discriminated those
      plexiform neurofibromas most likely to undergo malignant transformation.
      CONCLUSION: Our study has identified a limited number of signaling pathways that
      could be involved, when altered, in plexiform neurofibroma development. Some of
      the up-regulated genes could be useful diagnostic or prognostic markers or form
      the basis of novel therapeutic strategies.

PMID- 15173084
TI  - Biologically different subgroups of invasive ductal carcinoma of the pancreas:
      Dpc4 status according to the ratio of intraductal carcinoma components.
AB  - PURPOSE: Among invasive ductal carcinomas of the pancreas (IDCP), there is a
      morphologically characteristic subgroup accompanied by abundant intraductal
      carcinoma components (ICCs). With the aim of determining whether ICC-rich IDCP
      are biologically different from ICC-poor IDCP, the expression status of Dpc4
      protein was analyzed. EXPERIMENTAL DESIGN: A total of 43 IDCP was subdivided into
      two groups: (a). ICC-rich IDCP (ICCs area occupies >or=10% of the entire tumorous
      area); and (b). ICC-poor IDCP (with <10% of ICCs area). A total of 10 invasive
      carcinomas derived from intraductal papillary-mucinous neoplasms (ICs from IPMNs)
      were also analyzed. Each invasive and intraductal carcinoma area was then
      evaluated for Dpc4 protein status by immunohistochemistry. RESULTS: In a total of
      43 IDCP, there were 23 ICC-rich IDCP and 20 ICC-poor IDCP. Dpc4-positive
      immunostaining was observed in the invasive carcinoma component of ICC-rich IDCP,
      ICC-poor IDCP, and ICs from IPMN in 18 of 23 (78%), 4 of 20 (20%), and 7 of 10
      (70%) cases, respectively. In the intraductal component, positive staining for
      Dpc4 was found in 20 of 23 (87%), 3 of 7 (41%), and 8 of 10 (80%) cases,
      respectively. Dpc4 expression was found in both the invasive and ICC components
      of ICC-rich IDCP, similar to that found in IC derived from IPMN, whereas the
      expression of Dpc4 was largely diminished in ICC-poor IDCP. CONCLUSIONS:
      Morphologically distinct subgroups of invasive ductal carcinomas of the pancreas,
      namely ICC-rich IDCP and ICC-poor IDCP, are also biologically distinguishable as
      revealed by the differential expression of Dpc4.

PMID- 15173085
TI  - Down-regulation of BRCA1 in chronic pancreatitis and sporadic pancreatic
      adenocarcinoma.
AB  - PURPOSE: BRCA1 and BRCA2 are considered to be breast cancer susceptibility genes
      that may also contribute to pancreatic cancer development because family studies
      revealed mutation carriers to have an increased risk of developing pancreatic
      cancer. However, as demonstrated for breast and ovarian cancer, inactivation of
      BRCA in sporadic diseases is based on alteration in gene expression or functional
      alteration. EXPERIMENTAL DESIGN: To study a potential correlation of BRCA1 and
      BRCA2 to chronic pancreatitis and development of sporadic pancreatic
      adenocarcinoma, we have analyzed the expression of these genes by quantitative
      PCR and performed immunohistochemical analyses in normal pancreatic tissues,
      chronic pancreatitis, and pancreatic cancer specimens. RESULTS: BRCA1 expression
      was down-regulated in chronic alcoholic pancreatitis, in particular on the RNA
      level. Furthermore, our data indicate suppressed BRCA1 expression in pancreatic
      cancer on both the RNA and protein levels. Quantitative analysis of BRCA1 protein
      expression demonstrated regular staining in 50% of tumor specimens tested and
      reduced staining in 50% of tumor specimens tested. Correlation with the clinical
      outcome revealed a significantly better 1-year overall survival for patients with
      BRCA1-regular as compared with BRCA1-reduced or BRCA1-absent tumors. In contrast,
      no substantial differences in BRCA2 expression were found in chronic pancreatitis
      and pancreatic cancer samples. CONCLUSIONS: Our data demonstrate alteration of
      BRCA1 expression in chronic pancreatitis and sporadic pancreatic adenocarcinoma.
      We, for the first time, provide evidence for a role of BRCA1 in pancreatic
      carcinogenesis of noninherited tumors and for clinical outcome.

PMID- 15173086
TI  - Usefulness of 99mTc-sestamibi scintigraphy in suggesting the therapeutic effect
      of chemotherapy against gastric cancer.
AB  - PURPOSE: Imaging with (99m)Tc-sestamibi ((99m)Tc-MIBI) has been used to assess
      170-kDa P-glycoprotein (P-gp) expression and predict chemotherapy responses in
      several types of malignancy, such as breast and lung cancers. The purpose of this
      study was to evaluate the relationship between (99m)Tc-MIBI accumulation in
      tumors and sensitivity to chemotherapy in gastric cancer patients. EXPERIMENTAL
      DESIGN: Thirty-six patients with advanced gastric cancer underwent (99m)Tc-MIBI
      scintigraphy before chemotherapy. Patients also underwent endoscopic biopsy, and
      the expression of P-gp or multidrug resistance-associated protein was analyzed by
      immunohistochemical staining. The relationship between the accumulation of
      (99m)Tc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis
      diamminedichloroplatinum(II) or epirubicin was examined. RESULTS: Higher
      accumulation of (9m)Tc-MIBI in tumors was observed in 25 and 23 of 36 gastric
      cancer patients at the early (30 min) and delayed (120 min) images, respectively.
      Accelerated accumulation of (99m)Tc-MIBI negatively correlates with increased
      expression of P-gp, but not of multidrug resistance-associated protein, as
      determined by immunohistochemistry in gastric cancer tissues. The response rate
      to 5-fluorouracil/cis-diamminedichloroplatinum(II) chemotherapy in patients with
      high (99m)Tc-MIBI accumulation (15.4%) was much lower than that in patients with
      low (99m)Tc-MIBI accumulation (54.5%). In contrast, patients with high (99m)Tc
      MIBI accumulation show a higher response rate (41.7%) to chemotherapy with
      epirubicin, which is known to be a substrate of P-gp transporter. CONCLUSIONS:
      (99m)Tc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of
      patients with advanced gastric cancer.

PMID- 15173087
TI  - High specificity of quantitative excision repair cross-complementing 1 messenger
      RNA expression for prediction of minor histopathological response to neoadjuvant
      radiochemotherapy in esophageal cancer.
AB  - PURPOSE: The excision repair cross-complementing 1 (ERCC1) gene is coding for a
      nucleotide excision repair protein involved in the repair of radiation- and
      chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1
      mRNA expression to predict minor or major histopathological response to
      neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation)
      followed by transthoracic en bloc esophagectomy in patients with locally advanced
      esophageal cancer (cT(2-4), N(x), M(0)). EXPERIMENTAL DESIGN: Tissue samples were
      collected by endoscopic biopsy before treatment. RNA was isolated from biopsies,
      and quantitative real-time reverse transcriptase PCR assays were performed to
      determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were
      calculated as (ERCC1/beta-actin in tumor)/(ERCC1/beta-actin in paired normal
      tissue). ERCC1 expression levels were correlated with the objective
      histopathological response in resected specimens. Histomorphological regression
      was defined as major response when resected specimens contained <10% of residual
      vital tumor cells or in case a pathologically complete response was achieved.
      RESULTS: Twelve of 36 tumors showed a major histopathological response, and 24 of
      36 showed a minor histopathological response. Relative expression levels of ERCC1
      of >1.09 were not associated with a major histopathological response
      (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor
      histopathological response to the delivered neoadjuvant radiochemotherapy could
      be unequivocally identified. This association of dichotomized relative ERCC1 mRNA
      expression and histopathological response was statistically significant (P <
      0.001). CONCLUSIONS: Relative expression levels of ERCC1 mRNA determined by
      quantitative real-time reverse transcriptase-PCR appear highly specific to
      predict minor response to our neoadjuvant radiochemotherapy protocol in patients
      with locally advanced esophageal cancer and could be applied to prevent
      expensive, noneffective, and potentially harmful therapies in a substantial
      number (42%) of patients.

PMID- 15173088
TI  - Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased
      survival for patients with bladder cancer.
AB  - PURPOSE: RhoGDI2 was recently shown to be a metastasis suppressor gene in models
      of bladder cancer. We sought to further understand its importance in human cancer
      by determining the level of its expression and the distribution of its encoded
      protein in normal human tissues and cell lines and to evaluate whether its
      protein expression is a determinant of human bladder cancer progression.
      EXPERIMENTAL DESIGN: RhoGDI2 mRNA and protein expression was evaluated in cell
      lines and human tissues using Affymetrix and tissue microarrays, respectively.
      Tissue microarrays represented most human normal adult tissues and material from
      51 patients that had undergone radical cystectomy for bladder cancer. In these 51
      patients, the chi(2) test was used to test for associations between RhoGDI2 and
      stage, grade of urothelial carcinoma, histological type, and disease-specific
      survival status. Cox proportional hazards regression analyses were used to
      estimate the effect of RhoGDI2 expression level on time to development of
      metastatic disease and disease-specific survival time, adjusting for grade,
      stage, and histological type. RESULTS: In normal tissues, there was strong
      RhoGDI2 protein expression in WBCs, endothelial cells, and transitional
      epithelium. RhoGDI2 mRNA expression was inversely related to the invasive and
      metastatic phenotype in human bladder cancer cell lines. In patients with bladder
      cancer, univariate analysis indicated that reduced tumor RhoGDI2 protein
      expression was associated with a lower actuarial 5-year disease-free and disease
      specific survival (P = 0.01). In addition, patients with tumors that had low or
      absent RhoGDI2 had a shorter time to disease-specific death (P <or= 0.01). When
      tumor grade, stage, histological type, and RhoGDI2 staining level were examined
      using multivariate analysis, RhoGDI2 expression was found to be an independent
      predictive factor for disease-specific death (P = 0.03). CONCLUSIONS: These
      results suggest that RhoGDI2 is an independent predictor of prognosis for
      patients with bladder cancer and provide clinical evidence in support of its
      involvement in cancer metastasis.

PMID- 15173089
TI  - Carcinoembryonic antigen messenger RNA expression using nested reverse
      transcription-PCR in the peripheral blood during follow-up period of patients who
      underwent curative surgery for biliary-pancreatic cancer: longitudinal analyses.
AB  - PURPOSE: Outcome for patients with biliary-pancreatic cancer is still poor,
      despite curative operation. We investigated the clinical significance of
      molecular detection of circulating cancer cells in the blood as an early
      indicator of relapse during follow-up of patients who underwent a curative
      operation for biliary-pancreatic cancer. PATIENTS AND METHODS: We followed 53
      patients who underwent a curative operation for biliary-pancreatic cancer between
      1996 and 2001. We used reverse transcription-PCR in the peripheral blood to
      evaluate carcinoembryonic antigen (CEA) mRNA expression for molecular detection
      of circulating cancer cells. Follow-up examinations every 3 months after surgery
      included CEA mRNA expression in the blood, serum CEA, serum carbohydrate antigen
      19-9 (CA19-9), and computed tomography or magnetic resonance imaging. RESULTS:
      Sixteen of 53 patients (30.2%) were diagnosed with a recurrence by imaging
      studies. The CEA mRNA detection rate in the peripheral blood of these 16 patients
      was 75% compared with 5.4% in the 37 patients without relapse (P < 0.001).
      Sensitivity of CEA mRNA, CEA, and CA19-9 serum levels was 75.0%, 50.0%, and
      68.8%, respectively. Similarly, specificity was 94.6%, 64.9%, and 81.1%,
      respectively. CEA mRNA was expressed in the blood, even though tumor markers CEA
      and CA19-9 were within the normal range in patients with relapse. CEA mRNA
      expression in the blood, as well as the serum level of CA19-9, tended to be
      detected a few months earlier than detection by imaging modalities. CONCLUSIONS:
      During the follow-up of patients who undergo a curative operation for biliary
      pancreatic cancer, CEA mRNA expression in the peripheral blood might be a useful
      and early indicator of relapse.

PMID- 15173090
TI  - Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with
      HER2/neu overexpression and provides a novel combination predictor for poor
      prognosis in breast cancer patients.
AB  - PURPOSE: The diversity of biological functions makes p21(Cip1/WAF1) (p21) a
      controversial marker in predicting the prognosis of breast cancer patients.
      Recent laboratory studies revealed that the regulation of p21 function could be
      related to different subcellular localizations of p21 by Akt-induced
      phosphorylation at threonine 145 in HER2/neu-overexpressing breast cancer cells.
      The purpose of this study was to verify these findings in clinical settings.
      EXPERIMENTAL DESIGN: The expression status of the key biological markers in the
      HER2/neu-Akt-p21 pathway in 130 breast cancer specimens was evaluated by
      immunohistochemical staining and correlated with patients' clinical parameters
      and survival. In addition, an antibody against phospho-p21 at threonine 145
      [phospho-p21 (T145)] was also used for better validation of these findings.
      RESULTS: Cytoplasmic localization of p21 is highly correlated with overexpression
      of phospho-p21 (T145). Both cytoplasmic p21 and overexpression of phospho-p21
      (T145) are associated with high expression of HER2/neu and phospho-Akt.
      Cytoplasmic localization of p21 and overexpression of phospho-p21 (T145),
      HER2/neu, and phospho-Akt are all associated with worse overall survival.
      Multivariate analysis of the Cox proportional hazard regression model revealed
      that cytoplasmic p21 and overexpression of HER2/neu are independently associated
      with increased risk of death. Combining these two factors stratified patients'
      survival into four distinct groups, with a 5-year survival rate of 79% in low
      HER2/neu and negative/nuclear p21 patients, 60% in high HER2/neu and
      negative/nuclear p21 patients, 29% in low HER2/neu and cytoplasmic p21 patients,
      and 16% in high HER2/neu and cytoplasmic p21 patients. CONCLUSIONS: The present
      study, in addition to supporting the mechanisms of p21 regulation derived from
      laboratory investigation, demonstrates the prognostic importance of phospho-p21
      (T145) for the first time and also provides a novel combination of p21 and
      HER2/neu for better stratification of patients' survival than any single
      clinicopathological or biological marker that may play important diagnostic and
      therapeutic roles for breast cancer patients.

PMID- 15173091
TI  - Differential methylation status of tumor-associated genes in head and neck
      squamous carcinoma: incidence and potential implications.
AB  - PURPOSE: Promoter hypermethylation is one of the major mechanisms in the
      transcriptional inactivation of certain carcinoma-associated genes. Concurrent
      methylation analysis of multiple, functionally distinct genes may provide
      important information on their differential alterations and potential association
      in head and neck squamous carcinogenesis. EXPERIMENTAL DESIGN: Methylation
      specific PCR analysis of the CpG islands of 8 cancer-related genes was performed
      on 19 cell lines and 32 primary head and neck squamous cell carcinoma (HNSC)
      specimens with matched histologically normal mucosa and 6 dysplastic lesions. The
      methylation status and histological features of the specimens were investigated.
      RESULTS: In histologically normal squamous mucosa, no to low-level methylation (0
      22%) was noted in some specimens at all genes except RARbeta2 (50%). Considerable
      variation in the incidence of methylation of these genes within and between cell
      lines and tumor specimens was noted. The highest incidences of methylation in the
      cell lines and primary tumors were noted in RARbeta2 (53%), MGMT (37%), p16
      (33%), and DAP-K (25%); low incidence of methylations were noted in E-cadherin
      (2%), p73 (2%) RASSF1A (10%), and p14 (20%) genes. The incidences of methylation
      of each gene were almost similar between the HNSC cell lines and primary cancer
      specimens, although methylation of RASSF1A was observed in cell line (26%), but
      not in dysplasia and primary tumor. RARbeta, p16, and MGMT genes showed the
      highest incidences of methylation in premalignant and invasive carcinomas.
      CONCLUSIONS: Methylation of p16, RARbeta, and MGMT may constitute early events in
      HNSC tumorigenesis. The infrequent methylation at certain genes suggests a
      minimal role for this feature in their functional assessment in HNSC. The
      variability within and between cell lines and tumor specimens supports a
      heterogeneous and dynamic state of methylation in genes associated with HNSC
      tumorigenesis.

PMID- 15173092
TI  - High-level expression of the coxsackievirus and adenovirus receptor messenger RNA
      in osteosarcoma, Ewing's sarcoma, and benign neurogenic tumors among
      musculoskeletal tumors.
AB  - PURPOSE: The sensitivity of human tumor tissues to infection with recombinant
      adenoviruses correlates with the expression of the coxsackievirus and adenovirus
      receptor (CAR). CAR has been shown to function as the primary receptor for
      adenoviruses and to play a critical role in adenovirus entry into host cells. It
      is important for clinical gene therapy to determine the expression level of CAR
      in tumor tissues. EXPERIMENTAL DESIGN: We analyzed the expression of CAR mRNA in
      154 musculoskeletal tumor tissues from 154 patients and 10 normal mesenchymal
      tissues from 3 patients using reverse transcription-PCR and real-time
      quantitative PCR. An adenovirus infection assay was performed in two cell lines
      that were established from CAR-positive osteosarcoma tissue and CAR-negative
      malignant fibrous histiocytoma tissue. RESULTS: Ninety-nine of 154 tumors were
      detected as CAR positive by reverse transcription-PCR. We found that the
      expression levels of CAR mRNA varied markedly between different tumors as
      determined by real-time quantitative PCR. CAR mRNA was expressed at high levels
      in osteosarcoma, Ewing's sarcoma, neurofibroma, and schwannoma; at intermediate
      levels in exostosis, giant cell tumor, liposarcoma, synovial sarcoma, malignant
      peripheral nerve sheath tumor, and hemangioma; and at low levels in alveolar soft
      part sarcoma and desmoid. Whereas the osteosarcoma cell line that expressed a
      high level of CAR mRNA, like its parent tumor, had a high efficiency of
      adenovirus infection, the malignant fibrous histiocytoma cell line with almost
      undetectable expression of CAR mRNA, like its parent tumor, had a low efficiency
      of infection. CONCLUSIONS: Our data showed the great variations in CAR mRNA
      expression among human musculoskeletal tumors and mesenchymal tissues and
      implicated the potential usefulness of adenoviral vectors in gene therapy for
      osteosarcoma, Ewing's sarcoma, neurofibroma, and schwannoma. Efficient
      transduction with adenovirus for gene therapy could be realized in appropriate,
      sensitive tumor types.

PMID- 15173094
TI  - Synergistic effect of histone deacetylase inhibitors FK228 and m-carboxycinnamic
      acid bis-hydroxamide with proteasome inhibitors PSI and PS-341 against
      gastrointestinal adenocarcinoma cells.
AB  - PURPOSE: We investigated whether the histone deacetylase inhibitors m
      carboxycinnamic acid bis-hydroxamide (CBHA) and a bicyclic depsipeptide, FK228,
      can enhance the anticancer effect of the proteasome inhibitors PSI and PS-341 in
      gastrointestinal carcinoma cells. EXPERIMENTAL DESIGN: The anticancer effect of
      CBHA or FK228 and PSI or PS-341 was evaluated by cell death, caspase-3 activity,
      externalization of phosphatidylserine and DNA fragmentation, and colony formation
      assay. Expression of apoptosis-related molecules and cell cycle regulatory
      molecules, as well as phosphorylation of p38 were investigated by immunoblots.
      Generation of reactive oxygen species (ROS) was detected by intracellular
      oxidation of 5- (and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate.
      RESULTS: CBHA or FK228 plus PSI or PS-341 synergistically induced apoptosis in
      human colonic DLD-1 and gastric MKN45 carcinoma cell lines. CBHA or FK228, but
      not 5-fluorouracil, plus PS-341 strongly decreased plating efficiency of DLD-1
      cells. FK228 elicited ROS generation, and the free radical scavenger l-N
      acetylcysteine inhibited the synergistic anticancer effect of combined therapy.
      In addition, l-N-acetylcysteine inhibited the combined therapy-mediated elevation
      of a proapoptotic BH3-only protein Bim expression, phosphorylation of H2AX, and
      accumulation of 8-hydroxydeoxyguanosine. CONCLUSIONS: FK228 or CBHA and PSI or PS
      341 synergistically induce apoptosis in DLD-1 and MKN45 cells depending on ROS
      mediated signals. Our data suggest that a combination of FK228 or CBHA with PSI
      or PS-341 may be a valuable therapy against gastrointestinal adenocarcinoma
      cells.

PMID- 15173093
TI  - Synergistic induction of oxidative injury and apoptosis in human multiple myeloma
      cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors.
AB  - PURPOSE: The purpose of this study was to examine interactions between the
      proteasome inhibitor bortezomib (Velcade) and the histone deacetylase (HDAC)
      inhibitors sodium butyrate and suberoylanilide hydroxamic acid in human multiple
      myeloma (MM) cells that are sensitive and resistant to conventional agents.
      EXPERIMENTAL DESIGN: MM cells were exposed to bortezomib for 6 h before the
      addition of HDAC inhibitors (total, 26 h), after which reactive oxygen species
      (ROS), mitochondrial dysfunction, signaling and cell cycle pathways, and
      apoptosis were monitored. The functional role of ROS generation was assessed
      using the free radical scavenger N-acetyl-l-cysteine. RESULTS: Preincubation with
      a subtoxic concentration of bortezomib markedly sensitized U266 and MM.1S cells
      to sodium butyrate- and suberoylanilide hydroxamic acid-induced mitochondrial
      dysfunction; caspase 9, 8, and 3 activation; and poly(ADP-ribose) polymerase
      degradation; resulting in synergistic apoptosis induction. These events were
      associated with nuclear factor kappaB inactivation, c-Jun NH(2)-terminal kinase
      activation, p53 induction, and caspase-dependent cleavage of p21(CIP1),
      p27(KIP1), and Bcl-2, as well as Mcl-1, X-linked inhibitor of apoptosis, and
      cyclin D1 down-regulation. The bortezomib/HDAC inhibitor regimen markedly induced
      ROS generation; moreover, apoptosis and c-Jun NH(2)-terminal kinase activation
      were attenuated by N-acetyl-l-cysteine. Dexamethasone- or doxorubicin-resistant
      MM cells failed to exhibit cross-resistance to the bortezomib/HDAC inhibitor
      regimen, nor did exogenous interleukin 6 or insulin-like growth factor I block
      apoptosis induced by this drug combination. Finally, bortezomib/HDAC inhibitors
      induced pronounced lethality in primary CD138(+) bone marrow cells from MM
      patients, but not in the CD138(-) cell population. CONCLUSIONS: Sequential
      exposure to bortezomib in conjunction with clinically relevant HDAC inhibitors
      potently induces mitochondrial dysfunction and apoptosis in human MM cells
      through a ROS-dependent mechanism, suggesting that a strategy combining these
      agents warrants further investigation in MM.

PMID- 15173095
TI  - Noninvasive measurements of capecitabine metabolism in bladder tumors
      overexpressing thymidine phosphorylase by fluorine-19 magnetic resonance
      spectroscopy.
AB  - PURPOSE: Previous studies have shown that tumor response to capecitabine strongly
      correlates with tumor thymidine phosphorylase (TP). The aims of our study were to
      (a). investigate the pharmacological role of TP by measuring the pharmacokinetics
      (PK) of capecitabine in a human bladder tumor model that was characterized by the
      overexpression of TP and (b). develop the use of PK measurements for capecitabine
      by fluorine-19 magnetic resonance spectroscopy as a noninvasive surrogate marker
      for determining TP levels in tumors and for predicting tumor response to
      capecitabine in patients. EXPERIMENTAL DESIGN: TP overexpressing (2T10) and
      control tumors were grown s.c. in nude mice. Mice were given a dose of
      capecitabine or 5'-deoxy-5-fluorouridine (5'DFUR). (19)F tumor spectra were
      acquired for determination of rate constants of capecitabine breakdown and
      buildup and subsequent breakdown of intermediates, 5'-deoxy-5-fluorocytidine
      (5'DFCR) and 5'DFUR. The rate constant of 5'DFUR breakdown was also evaluated.
      RESULTS: The rate constant of breakdown of intermediates was significantly faster
      in 2T10 tumors than controls (P < 0.003). No significant differences in the rate
      of capecitabine breakdown or intermediate buildup were observed. The rate
      constant of 5'DFUR breakdown in the 2T10 tumors was doubled compared with
      controls (P < 0.001). CONCLUSIONS: This study confirmed the expected pathway of
      capecitabine metabolism and showed that the level of TP was related to the rate
      of 5'DFUR conversion. Using in vivo fluorine-19 magnetic resonance spectroscopy
      to mea-sure the PK of capecitabine and its intermediate metabolites in tumors may
      provide a noninvasive surrogate method for determining TP levels in tumors and
      for predicting tumor response to capecitabine in patients.

PMID- 15173096
TI  - Antitumor effect of intratumoral administration of bone marrow-derived dendritic
      cells transduced with wild-type p53 gene.
AB  - PURPOSE: Dendritic cells (DCs) are attractive effectors for cancer immunotherapy
      because of their potential to function as professional antigen-presenting cells
      for initiating cellular immune responses. The tumor suppressor gene p53 is
      pivotal in the regulation of apoptosis, and approximately 50% of human
      malignancies exhibit mutation and aberrant expression of p53. We investigated the
      antitumor effect of intratumoral administration of bone marrow-derived dendritic
      cells transduced with wild-type p53 gene. EXPERIMENTAL DESIGN: We examined
      whether intratumoral administration of DCs infected with recombinant adenovirus
      expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor
      responses against mutant p53-expressing tumors, highly immunogenic MethA, or
      weakly immunogenic MCA-207 implanted in syngeneic mice. RESULTS: Accumulation of
      wild-type p53 protein in bone marrow-derived murine DCs could be successfully
      achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53
      transduced DCs caused a marked reduction in the in vivo growth of established
      MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53
      expressing DCs suppressed the growth of both injected MCA-207 tumors and
      untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors,
      suggesting the augmentation of systemic immunogenicity against MCA-207 tumor
      cells. Moreover, intratumoral injection of p53-expressing DCs had a greater
      antitumor effect than did s.c. immunization. CONCLUSIONS: Our results indicate
      that intratumoral administration of DCs expressing murine wild-type p53 leads to
      significant systemic immune responses and potent antitumor effects in mutant p53
      expressing murine cancer models. These findings raise the possibility of using
      this strategy of intratumoral injection of p53-expressing DCs for human cancer
      treatment.

PMID- 15173097
TI  - Biomarkers, surrogate end points, and the acceleration of drug development for
      cancer prevention and treatment: an update prologue.

PMID- 15173098
TI  - Rationale for biomarkers and surrogate end points in mechanism-driven oncology
      drug development.

PMID- 15173099
TI  - Reanalysis of cancer drugs: old drugs, new tricks.

PMID- 15173100
TI  - Colorectal adenomas: a prototype for the use of surrogate end points in the
      development of cancer prevention drugs.

PMID- 15173101
TI  - Use of CA-125 in clinical trial evaluation of new therapeutic drugs for ovarian
      cancer.

PMID- 15173102
TI  - Prostate-specific antigen doubling time as a surrogate marker for evaluation of
      oncologic drugs to treat prostate cancer.

PMID- 15173103
TI  - The discovery of captopril: a reply.

PMID- 15173104
TI  - Global estimates of high-level brain drain and deficit.
AB  - Brain drain, the international migration of scientists in search of better
      opportunities, has been a long-standing concern, but quantitative measurements
      are uncommon and limited to specific countries or disciplines. We need to
      understand brain drain at a global level and estimate the extent to which
      scientists born in countries with low opportunities never realize their
      potential. Data on 1523 of the most highly cited scientists for 1981-1999 are
      analyzed. Overall, 31.9% of these scientists did not reside in the country where
      they were born (range 18.1-54.6% across 21 different scientific fields). There
      was great variability across developed countries in the proportions of foreign
      born resident scientists and emigrating scientists. Countries without a critical
      mass of native scientists lost most scientists to migration. This loss occurred
      in both developed and developing countries. Adjusting for population and using
      the U.S. as reference, the number of highly cited native-born scientists was at
      least 75% of the expected number in only 8 countries other than the U.S. It is
      estimated that approximately 94% of the expected top scientists worldwide have
      not been able to materialize themselves due to various adverse conditions.
      Scientific deficit is only likely to help perpetuate these adverse conditions.

PMID- 15173105
TI  - Evolutionary epitopes of Hsp90 and p23: implications for their interaction.
AB  - The amino-terminal domain (N-domain) of Hsp90 represents the ATP binding site and
      is important for interaction with its cochaperone, p23. Whereas some evidence
      suggests that p23 may bind to this domain in an ATP-dependent manner and that
      this process requires the dimerization of two N-domains, the interaction sites
      between them and the molecular mechanism of coupling these two events to p23
      binding remain unsolved. As a first step toward establishing the interaction
      mechanism, we used the evolutionary tracing (ET) method [Lichtarge, O., Bourne,
      H. R., and Cohen, F. E. (1996) J. Mol. Biol. 257, 342-358] to identify the
      putative functional surfaces of Hsp90 and p23, and combined with protein-protein
      docking techniques, to predict their binding interface. Both evolutionarily
      privileged surfaces of Hsp90 and p23 identified by ET appear on this putative
      interface. An analysis of the complex model produced using the ET results
      combined with available experimental data highlights a putative conformational
      pathway in the ATP binding domain of Hsp90, where a series of conformational
      changes transfer the ATP-induced N-domain dimerization signal for the binding of
      p23. In this pathway, the closure of "lid" may result in reorientation of the
      helix alpha1 and the following loop (residues 10-27 in yeast Hsp90), which will
      expose more hydrophobic surface, and thus triggers the dimerization of N-domain.

PMID- 15173106
TI  - The small leucine-rich proteoglycan biglycan modulates BMP-4-induced osteoblast
      differentiation.
AB  - Biglycan (bgn) is a small leucine-rich proteoglycan enriched in extracellular
      matrices of skeletal tissues. Bgn-deficient mice develop age-related osteopenia
      with a phenotype that resembles osteoporosis and premature arthritis. In the
      present study, we have examined the differentiation of bgn-deficient osteoblasts
      from neonatal murine calvariae and found that the absence of bgn caused less BMP
      4 binding, which reduced the sensitivity of osteoblasts to BMP-4 stimulation. The
      loss of sensitivity resulted in a reduction of Cbfa1 expression, which ultimately
      led to a defect in the differentiation of osteoblasts. However, the response of
      bgn-deficient osteoblasts to BMP-4 was completely rescued by reintroduction of
      biglycan by viral transfection. We propose that biglycan modulates BMP-4-induced
      signaling to control osteoblast differentiation.

PMID- 15173107
TI  - Genomics, prior probability, and statistical tests of multiple hypotheses.

PMID- 15173108
TI  - Genomic regionality in rates of evolution is not explained by clustering of genes
      of comparable expression profile.
AB  - In mammalian genomes, linked genes show similar rates of evolution, both at
      fourfold degenerate synonymous sites (K4) and at nonsynonymous sites (KA).
      Although it has been suggested that the local similarity in the synonymous
      substitution rate is an artifact caused by the inclusion of disparately evolving
      gene pairs, we demonstrate here that this is not the case: after removal of
      disparately evolving genes, both (1) linked genes and (2) introns from the same
      gene have more similar silent substitution rates than expected by chance. What
      causes the local similarity in both synonymous and nonsynonymous substitution
      rates? One class of hypotheses argues that both may be related to the observed
      clustering of genes of comparable expression profile. We investigate these
      hypotheses using substitution rates from both human-mouse and mouse-rat
      comparisons, and employing three different methods to assay expression
      parameters. Although we confirm a negative correlation of expression breadth with
      both K4 and KA, we find no evidence that clustering of similarly expressed genes
      explains the clustering of genes of comparable substitution rates. If gene
      expression is not responsible, what about other causes? At least in the human
      mouse comparison, the local similarity in KA can be explained by the covariation
      of KA and K4. As regards K4, our results appear consistent with the notion that
      local similarity is due to processes associated with meiotic recombination.

PMID- 15173109
TI  - The small chromosomes of Trypanosoma brucei involved in antigenic variation are
      constructed around repetitive palindromes.
AB  - Most eukaryotic genomes contain large regions of satellite DNA. These arrays are
      often associated with essential chromosomal functions, but remain largely absent
      from genome projects because of difficulties in cloning and sequence assembly.
      The numerous small chromosomes of the parasite Trypanosoma brucei fall into this
      category, yet are critical to understanding the genome because of their role in
      antigenic variation. Their relatively small size, however, makes them
      particularly amenable to physical mapping. We have produced fine-resolution maps
      of 17 complete minichromosomes and partial maps of two larger intermediate-sized
      chromosomes. This revealed a canonical structure shared by both chromosomal
      classes based around a large central core of 177-bp repeats. Around the core are
      variable-length genic regions, the lengths of which define chromosomal class. We
      show the core region to be a repetitive palindrome with a single inversion point
      common to all the chromosomes of both classes, suggesting a mechanism of genesis
      for these chromosomes. Moreover, palindromy appears to be a feature of
      (peri)centromeres in other species that can be easily overlooked. We propose that
      sequence inversion is one of the higher-order sequence motifs that confer
      chromosomal stability.

PMID- 15173110
TI  - Bacterial genomes as new gene homes: the genealogy of ORFans in E. coli.
AB  - Differences in gene repertoire among bacterial genomes are usually ascribed to
      gene loss or to lateral gene transfer from unrelated cellular organisms. However,
      most bacteria contain large numbers of ORFans, that is, annotated genes that are
      restricted to a particular genome and that possess no known homologs. The
      uniqueness of ORFans within a genome has precluded the use of a comparative
      approach to examine their function and evolution. However, by identifying
      sequences unique to monophyletic groups at increasing phylogenetic depths, we can
      make direct comparisons of the characteristics of ORFans of different ages in the
      Escherichia coli genome, and establish their functional status and evolutionary
      rates. Relative to the genes ancestral to gamma-Proteobacteria and to those genes
      distributed sporadically in other prokaryotic species, ORFans in the E. coli
      lineage are short, A+T rich, and evolve quickly. Moreover, most encode functional
      proteins. Based on these features, ORFans are not attributable to errors in gene
      annotation, limitations of current databases, or to failure of methods for
      detecting homology. Rather, ORFans in the genomes of free-living microorganisms
      apparently derive from bacteriophage and occasionally become established by
      assuming roles in key cellular functions.

PMID- 15173112
TI  - Coexpression of neighboring genes in the genome of Arabidopsis thaliana.
AB  - Large-scale analyses of expression data of eukaryotic organisms are now becoming
      increasingly routine. The data sets are revealing interesting and novel patterns
      of genomic organization, which provide insight both into molecular evolution and
      how structure and function of a genome interrelate. Our study investigates, for
      the first time, how genome organization affects expression of a gene in the
      Arabidopsis genome. The analyses show that neighboring genes are coexpressed.
      This pattern has been found for all eukaryotic genomes studied so far, but as
      yet, it remains unclear whether it is due to selective or nonselective
      influences. We have investigated reasons for coexpression of neighboring genes in
      Arabidopsis, and our evidence suggests that orientation of gene pairs plays a
      significant role, with potential sharing of regulatory elements in divergently
      transcribed genes. Using the data available in the KEGG database, we find
      evidence that genes in the same pathway are coexpressed, although this is not a
      major cause for the coexpression of neighboring genes.

PMID- 15173111
TI  - Comparative genomic hybridization provides new insights into the molecular
      taxonomy of the Saccharomyces sensu stricto complex.
AB  - The science of taxonomy is constantly improving as new techniques are developed.
      Current practice is to construct phylogenetic trees based on the analysis of the
      DNA sequence of single genes, or parts of single genes. However, this approach
      has recently been brought into question as several tree topologies may be
      produced for the same clade when the sequences for various different genes are
      used. The availability of complete genome sequences for several organisms has
      seen the adoption of microarray technology to construct molecular phylogenies of
      bacteria, based on all of the genes. Similar techniques have been used to reveal
      the relationships between different strains of the yeast Saccharomyces
      cerevisiae. We have exploited microarray technology to construct a molecular
      phylogeny for the Saccharomyces sensu stricto complex of yeast species, which is
      based on all of the protein-encoding genes revealed by the complete genome
      sequence of the paradigmatic species, S. cerevisiae. We also analyze different
      strains of S. cerevisiae itself, as well as the putative species S. boulardii. We
      show that in addition to the phylogeny produced, we can identify and analyze
      individual ORF traits and interpret the results to give a detailed explanation of
      evolutionary events underlying the phylogeny.

PMID- 15173113
TI  - Differential alu mobilization and polymorphism among the human and chimpanzee
      lineages.
AB  - Alu elements are primate-specific members of the SINE (short interspersed
      element) retroposon family, which comprise approximately 10% of the human genome.
      Here we report the first chromosomal-level comparison examining the Alu
      retroposition dynamics following the divergence of humans and chimpanzees. We
      find a twofold increase in Alu insertions in humans in comparison to the common
      chimpanzee (Pan troglodytes). The genomic diversity (polymorphism for presence or
      absence of the Alu insertion) associated with these inserts indicates that,
      analogous to recent nucleotide diversity studies, the level of chimpanzee Alu
      diversity is approximately 1.7 times higher than that of humans. Evolutionarily
      recent Alu subfamily structure differs markedly between the human and chimpanzee
      lineages, with the major human subfamilies remaining largely inactive in the
      chimpanzee lineage. We propose a population-based model to account for the
      observed fluctuation in Alu retroposition rates across primate taxa.

PMID- 15173115
TI  - Building genomic profiles for uncovering segmental homology in the twilight zone.
AB  - The identification of homologous regions within and between genomes is an
      essential prerequisite for studying genome structure and evolution. Different
      methods already exist that allow detecting homologous regions in an automated
      manner. These methods are based either on finding sequence similarities at the
      DNA level or on identifying chromosomal regions showing conservation of gene
      order and content. Especially the latter approach has proven useful for detecting
      homology between highly divergent chromosomal regions. However, until now, such
      map-based approaches required that candidate homologous regions show significant
      collinearity with other segments to be considered as being homologous. Here, we
      present a novel method that creates profiles combining the gene order and content
      information of multiple mutually homologous genomic segments. These profiles can
      be used to scan one or more genomes to detect segments that show significant
      collinearity with the entire profile but not necessarily with individual
      segments. When applying this new method to the combined genomes of Arabidopsis
      and rice, we find additional evidence for ancient duplication events in the rice
      genome.

PMID- 15173114
TI  - Coexpression analysis of human genes across many microarray data sets.
AB  - We present a large-scale analysis of mRNA coexpression based on 60 large human
      data sets containing a total of 3924 microarrays. We sought pairs of genes that
      were reliably coexpressed (based on the correlation of their expression profiles)
      in multiple data sets, establishing a high-confidence network of 8805 genes
      connected by 220,649 "coexpression links" that are observed in at least three
      data sets. Confirmed positive correlations between genes were much more common
      than confirmed negative correlations. We show that confirmation of coexpression
      in multiple data sets is correlated with functional relatedness, and show how
      cluster analysis of the network can reveal functionally coherent groups of genes.
      Our findings demonstrate how the large body of accumulated microarray data can be
      exploited to increase the reliability of inferences about gene function.

PMID- 15173116
TI  - Annotation transfer between genomes: protein-protein interologs and protein-DNA
      regulogs.
AB  - Proteins function mainly through interactions, especially with DNA and other
      proteins. While some large-scale interaction networks are now available for a
      number of model organisms, their experimental generation remains difficult.
      Consequently, interolog mapping--the transfer of interaction annotation from one
      organism to another using comparative genomics--is of significant value. Here we
      quantitatively assess the degree to which interologs can be reliably transferred
      between species as a function of the sequence similarity of the corresponding
      interacting proteins. Using interaction information from Saccharomyces
      cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Helicobacter
      pylori, we find that protein-protein interactions can be transferred when a pair
      of proteins has a joint sequence identity >80% or a joint E-value <10(-70).
      (These "joint" quantities are the geometric means of the identities or E-values
      for the two pairs of interacting proteins.) We generalize our interolog analysis
      to protein-DNA binding, finding such interactions are conserved at specific
      thresholds between 30% and 60% sequence identity depending on the protein family.
      Furthermore, we introduce the concept of a "regulog"--a conserved regulatory
      relationship between proteins across different species. We map interologs and
      regulogs from yeast to a number of genomes with limited experimental annotation
      (e.g., Arabidopsis thaliana) and make these available through an online database
      at http://interolog.gersteinlab.org. Specifically, we are able to transfer
      approximately 90,000 potential protein-protein interactions to the worm. We test
      a number of these in two-hybrid experiments and are able to verify 45 overlaps,
      which we show to be statistically significant.

PMID- 15173117
TI  - Recombinatorial cloning using heterologous lox sites.
AB  - Recombination systems based on lambda and Cre/loxP have been described to
      facilitate gene transfer from one vector to another in a high-throughput fashion,
      avoiding the bottlenecks associated with traditional cloning. However, no system
      described to date is suitable for the cloning of affinity reagents selected from
      display libraries, which requires that the recombination signals flanking the
      affinity reagent are translated with a minimum impact on functionality. As
      affinity reagents will be essential tools in the functional characterization of
      proteomes, and display technologies represent the most effective means to
      generate such affinity reagents on a genomic scale, we developed a Cre/loxP-based
      system, using mutually exclusive heterologous loxP sites placed 5' (Lox 2372) and
      3' (Lox WT) of an affinity reagent (scFv). The translated lox sites have minimal
      impact on scFv expression or functionality, and, in association with a
      conditionally lethal gene (SacB) permit efficient, high-fidelity transfer to
      destination vectors. This approach will considerably facilitate the high
      throughput downstream use of affinity reagents selected by display technologies,
      as well as being widely applicable to general recombinatorial cloning for genomic
      purposes.

PMID- 15173118
TI  - Automatic identification of subcellular phenotypes on human cell arrays.
AB  - Light microscopic analysis of cell morphology provides a high-content readout of
      cell function and protein localization. Cell arrays and microwell transfection
      assays on cultured cells have made cell phenotype analysis accessible to high
      throughput experiments. Both the localization of each protein in the proteome and
      the effect of RNAi knock-down of individual genes on cell morphology can be
      assayed by manual inspection of microscopic images. However, the use of
      morphological readouts for functional genomics requires fast and automatic
      identification of complex cellular phenotypes. Here, we present a fully automated
      platform for high-throughput cell phenotype screening combining human live cell
      arrays, screening microscopy, and machine-learning-based classification methods.
      Efficiency of this platform is demonstrated by classification of eleven
      subcellular patterns marked by GFP-tagged proteins. Our classification method can
      be adapted to virtually any microscopic assay based on cell morphology, opening a
      wide range of applications including large-scale RNAi screening in human cells.

PMID- 15173119
TI  - DNA mapping using microfluidic stretching and single-molecule detection of
      fluorescent site-specific tags.
AB  - We have developed a rapid molecular mapping technology--Direct Linear Analysis
      (DLA)--on the basis of the analysis of individual DNA molecules bound with
      sequence-specific fluorescent tags. The apparatus includes a microfluidic device
      for stretching DNA molecules in elongational flow that is coupled to a multicolor
      detection system capable of single-fluorophore sensitivity. Double-stranded DNA
      molecules were tagged at sequence-specific motif sites with fluorescent bisPNA
      (Peptide Nucleic Acid) tags. The DNA molecules were then stretched in the
      microfluidic device and driven in a flow stream past confocal fluorescence
      detectors. DLA provided the spatial locations of multiple specific sequence
      motifs along individual DNA molecules, and thousands of individual molecules
      could be analyzed per minute. We validated this technology using the 48.5 kb
      lambda phage genome with different 8-base and 7-base sequence motif tags. The
      distance between the sequence motifs was determined with an accuracy of +/-0.8
      kb, and these tags could be localized on the DNA with an accuracy of +/-2 kb.
      Thus, DLA is a rapid mapping technology, suitable for analysis of long DNA
      molecules.

PMID- 15173120
TI  - WebLogo: a sequence logo generator.
AB  - WebLogo generates sequence logos, graphical representations of the patterns
      within a multiple sequence alignment. Sequence logos provide a richer and more
      precise description of sequence similarity than consensus sequences and can
      rapidly reveal significant features of the alignment otherwise difficult to
      perceive. Each logo consists of stacks of letters, one stack for each position in
      the sequence. The overall height of each stack indicates the sequence
      conservation at that position (measured in bits), whereas the height of symbols
      within the stack reflects the relative frequency of the corresponding amino or
      nucleic acid at that position. WebLogo has been enhanced recently with additional
      features and options, to provide a convenient and highly configurable sequence
      logo generator. A command line interface and the complete, open WebLogo source
      code are available for local installation and customization.

PMID- 15173122
TI  - CRTH2 is a prominent effector in contact hypersensitivity-induced neutrophil
      inflammation.
AB  - Chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes, CRTH2,
      is a cognate receptor for prostaglandin (PG) D(2) and, in humans, is suggested to
      play a functional role in Th2-dependent allergic inflammation. While peripheral
      blood leukocytes expressing high levels of surface CRTH2 have been detected in
      disease, little is known of the functional significance of CRTH2 in disease
      etiology. We have utilized a Th2-dependent murine model of FITC-induced contact
      hypersensitivity to assess the role, if any, CRTH2-PGD(2) may play in the
      elicitation or maintenance of such pathobiology. Expression of both PGD(2) and
      CRTH2 in lesional skin was paralleled by the release of the chemoattractants
      LTB(4) and the chemokine KC, as well as a profuse dermal neutrophilic and
      eosinophilic infiltrate, closely paralleling the acute inflammatory pathology
      observed in human atopic dermatitis. A small molecule CRTH2 antagonist, but not a
      selective PGD(2)R (DP) receptor antagonist, was able to completely abrogate these
      responses. Inflammatory cascades mediated by CRTH2 ligation may therefore
      represent an important early step in the elicitation and maintenance of Th2
      dependent skin inflammation.

PMID- 15173121
TI  - eShadow: a tool for comparing closely related sequences.
AB  - Primate sequence comparisons are difficult to interpret due to the high degree of
      sequence similarity shared between such closely related species. Recently, a
      novel method, phylogenetic shadowing, has been pioneered for predicting
      functional elements in the human genome through the analysis of multiple primate
      sequence alignments. We have expanded this theoretical approach to create a
      computational tool, eShadow, for the identification of elements under selective
      pressure in multiple sequence alignments of closely related genomes, such as in
      comparisons of human-to-primate or mouse-to-rat DNA. This tool integrates two
      different statistical methods and allows for the dynamic visualization of the
      resulting conservation profile. eShadow also includes a versatile optimization
      module capable of training the underlying Hidden Markov Model to differentially
      predict functional sequences. This module grants the tool high flexibility in the
      analysis of multiple sequence alignments and in comparing sequences with
      different divergence rates. Here, we describe the eShadow comparative tool and
      its potential uses for analyzing both multiple nucleotide and protein alignments
      to predict putative functional elements.

PMID- 15173123
TI  - SOCS-1 suppresses TNF-alpha-induced apoptosis through the regulation of Jak
      activation.
AB  - Suppressor of cytokine signaling-1 (SOCS-1) was identified as one of the negative
      feedback regulators of Janus kinase (Jak)-signal-transducer-and-activator-of
      transcription (STAT) signaling. So far, it has been reported that SOCS-1 inhibits
      the action of multiple cytokines at least in vitro. We previously showed that
      SOCS-1 suppresses tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in
      murine embryonic fibroblast, but the mechanism of suppression was not fully
      clarified. In this study, we show that Jaks bind to TNF receptor-1 (TNFR-1) and
      are activated by TNF-alpha. We also show that the activations of Jaks and
      caspases by TNF-alpha are suppressed by SOCS-1. Furthermore, in Jak-deficient
      cell lines, DNA fragmentation and caspase-8 activation by TNF-alpha are
      suppressed, indicating that Jaks participate in TNF-alpha-induced apoptosis
      signaling. Taken together, these results suggest that SOCS-1 inhibits TNF-alpha
      induced apoptosis through regulation of Jaks.

PMID- 15173124
TI  - Preventing dementia by treating hypertension and preventing stroke.

PMID- 15173125
TI  - Electrocardiographic strain pattern and prediction of cardiovascular morbidity
      and mortality in hypertensive patients.
AB  - The ECG strain pattern of lateral ST depression and T-wave inversion is a marker
      for left ventricular hypertrophy (LVH) and adverse prognosis in population
      studies. However, whether ECG strain is an independent predictor of
      cardiovascular (CV) morbidity and mortality in the setting of aggressive
      antihypertensive therapy is unclear. ECGs were examined at study baseline in 8854
      hypertensive patients with ECG LVH who were treated in a blinded manner with
      atenolol- or losartan-based regimens. Strain was defined by the presence of a
      downsloping convex ST segment with an inverted asymmetrical T wave opposite to
      the QRS axis in leads V5 and/or V6 and was present in 971 patients (11.0%). The
      Losartan Intervention For Endpoint reduction in hypertension (LIFE) study
      composite end point of CV death or nonfatal myocardial infarction or stroke
      occurred in 1035 patients (11.7%). In Cox analyses adjusting only for treatment
      effect, ECG strain was a significant predictor of CV death (hazard ratio [HR]
      2.26, 95% confidence interval [CI] 1.78 to 2.86), fatal/nonfatal myocardial
      infarction (HR 2.16, 95% CI 1.67 to 2.80), fatal/nonfatal stroke (HR 1.76, 95% CI
      1.39 to 2.21), and the composite CV end point (HR 1.99, 95% CI 1.70 to 2.33).
      After further adjusting for standard CV risk factors, baseline blood pressure,
      and severity of ECG LVH, ECG strain remained a significant predictor of CV
      mortality (HR 1.53, 95% CI 1.18 to 2.00), myocardial infarction (HR 1.55, 95% CI
      1.16 to 2.06), and the composite CV end point (HR 1.33, 95% CI 1.11 to 1.59).
      Thus, ECG strain is a marker of increased CV risk in hypertensive patients in the
      setting of aggressive blood pressure lowering, independent of baseline severity
      of ECG LVH.

PMID- 15173126
TI  - Altered subcellular distribution of Na+,K+-ATPase in proximal tubules in young
      spontaneously hypertensive rats.
AB  - During early development of hypertension, the spontaneously hypertensive rat
      (SHR) demonstrates increased proximal tubule sodium reabsorption. Our previous
      observations of reduced Na+,K+-ATPase catalytic alpha1 and gamma subunit
      transcript abundance in SHR proximal tubule led us to test the hypothesis that
      increased proximal tubule sodium reabsorption may be attributable to altered
      subunit protein abundance, post-translational modification, or a shift in
      subcellular alpha1 and gamma distribution toward the basolateral membrane. We now
      extend previous gene expression studies by analyzing total cellular alpha1 and
      gamma protein abundance in proximal tubule from SHR compared with matched Wistar
      Kyoto (WKY) controls. We also used sucrose density-gradient centrifugation to
      isolate basolateral, early, and late endosomal membrane-enriched fractions as
      well as cell surface biotinylation to test the hypothesis of altered subunit
      subcellular distribution in the SHR proximal tubule. At 4 weeks of age,
      significantly greater amounts of alpha1 were present in basolateral membrane
      enriched fractions of SHR than WKY (21.1+/-1.8% versus 12.3+/-1.8%; P<0.005), and
      there was a concomitant reduction of alpha1 in late endosomal membrane-enriched
      fractions of SHR (63.3+/-2.7% versus 74.8+/-4.3%; P<0.05). This finding was
      confirmed in cell surface biotinylation studies that showed higher alpha1 (1.45+/
      0.1-fold greater; P<0.05) and gamma-subunit (3.48+/-0.7-fold greater; P<0.01)
      abundance in 4-week-old SHR proximal tubule plasma membrane compared with matched
      WKY samples. These studies support the hypothesis that development of
      hypertension in SHR may involve an altered subcellular distribution of proximal
      tubule Na+,K+-ATPase subunits.

PMID- 15173127
TI  - Is there a rationale for angiotensin blockade in the management of obesity
      hypertension?
AB  - Obesity, currently affecting >20% of the adult population in most Western
      countries, is a major risk factor for the development of hypertension.
      Hypertension in obese patients is, in the majority of instances, further
      complicated by the concomitant presence of dyslipidemia and insulin resistance.
      The latter is reflected by derangement of glucose homeostasis, ranging from
      hyperinsulinemia to frank type 2 diabetes. Hypertension in obese patients is also
      associated with an increased risk for left ventricular hypertrophy, endothelial
      dysfunction, renal hyperfiltration, microalbuminuria, and elevated markers of
      inflammation. Sodium retention, volume expansion, and increased cardiac output
      are common findings in obese individuals. These changes are largely attributable
      to increased activity of the sympathetic nervous system and insufficient
      suppression of the renin-angiotensin system. Recent data show increased
      expression of angiotensin II-forming enzymes in adipose tissue, and increased
      activity of the renin-angiotensin system has recently been implicated in the
      development of insulin resistance and type 2 diabetes. Accordingly,
      antihypertensive agents that block the renin-angiotensin system might be a
      beneficial strategy for treatment of obesity-related hypertension. Both
      angiotensin-converting enzyme inhibitors and angiotensin type-1 receptor blockers
      have been associated with favorable metabolic properties and end-organ protection
      in addition to their antihypertensive effects. Data from ongoing large trials
      will provide an indication of the protective and preventive effects of these
      treatment strategies while offering insights into the mechanisms linking obesity,
      hypertension, and other facets of the metabolic syndrome.

PMID- 15173129
TI  - The dietary sodium-blood pressure plot "stiffens".

PMID- 15173128
TI  - Dietary sodium restriction rapidly improves large elastic artery compliance in
      older adults with systolic hypertension.
AB  - We determined the temporal effects of dietary sodium restriction on large elastic
      artery compliance and systolic blood pressure (SBP) in 12 untreated, older (64+/
      2 years) men and women (6 each) with stage 1 systolic hypertension. After
      baseline measurements subjects were assigned to 4 weeks of low or normal sodium
      intake (randomized, crossover design). Urinary sodium excretion was reduced by
      60% by the end of week 1 of sodium restriction (54+/-11 mmol/d, P<0.01) versus
      baseline (135+/-14). Compared with baseline (0.11+/-0.01 mm/mm Hg), carotid
      artery compliance was increased by 27% (to 0.14+/-0.02, P<0.05) at the end of
      week 1 of sodium restriction, attaining peak levels by week 2 (+46%, to 0.16+/
      0.02, P<0.01). Similarly, supine resting brachial artery SBP was reduced by >5 mm
      Hg by week 1 of sodium restriction, attaining peak reductions by week 2 (-12 mm
      Hg, P<0.01 versus baseline). The 24-hour ambulatory SBP was approximately 3 mm Hg
      lower at week 1 of sodium restriction and approximately 6 mm Hg lower by week 2
      (P<0.01 versus baseline). The reductions in resting SBP from baseline to week 2
      of sodium restriction were strongly related to the corresponding increases in
      carotid compliance (r=0.80, P<0.01). Urinary sodium excretion, carotid artery
      compliance, and SBP were not different during normal sodium intake versus
      baseline. Other subject characteristics were not different across conditions.
      Sodium restriction rapidly improves large elastic artery compliance in older
      adults with stage 1 systolic hypertension. These improvements in central arterial
      compliance appear to be a key mechanism in the rapid normalization of SBP by
      sodium restriction in these patients.

PMID- 15173130
TI  - Funding, advances invigorate TB fight.

PMID- 15173131
TI  - Global road safety crisis remedy sought: 1.2 million killed, 50 million injured
      annually.

PMID- 15173132
TI  - Heart disease a global health threat.

PMID- 15173140
TI  - Racial and ethnic factors in outcomes of children with acute lymphoblastic
      leukemia.

PMID- 15173141
TI  - Traffic fatalities in Nepal.

PMID- 15173142
TI  - Circulating endothelial microparticles in malawian children with severe
      falciparum malaria complicated with coma.

PMID- 15173143
TI  - High prevalence of obesity among the poor in Mexico.

PMID- 15173144
TI  - Changing patterns of risk factors and mortality for coronary heart disease among
      Alaska Natives, 1979-2002.

PMID- 15173145
TI  - Effect of intensive handwashing promotion on childhood diarrhea in high-risk
      communities in Pakistan: a randomized controlled trial.
AB  - CONTEXT: Washing hands with soap prevents diarrhea, but children at the highest
      risk of death from diarrhea are younger than 1 year, too young to wash their own
      hands. Previous studies lacked sufficient power to assess the impact of household
      handwashing on diarrhea in infants. OBJECTIVE: To evaluate the effect of
      promoting household handwashing with soap among children at the highest risk of
      death from diarrhea. DESIGN, SETTING, AND PARTICIPANTS: A cluster randomized
      controlled trial of 36 low-income neighborhoods in urban squatter settlements in
      Karachi, Pakistan. Field workers visited participating households at least weekly
      from April 15, 2002, to April 5, 2003. Eligible households located in the study
      area had at least 2 children younger than 15 years, at least 1 of whom was
      younger than 5 years. INTERVENTIONS: Weekly visits in 25 neighborhoods to promote
      handwashing with soap after defecation and before preparing food, eating, and
      feeding a child. Within intervention neighborhoods, 300 households (1523
      children) received a regular supply of antibacterial soap and 300 households
      (1640 children) received plain soap. Eleven neighborhoods (306 households and
      1528 children) comprised the control group. MAIN OUTCOME MEASURE: Incidence
      density of diarrhea among children, defined as the number of diarrheal episodes
      per 100 person-weeks of observation. RESULTS: Children younger than 15 years
      living in households that received handwashing promotion and plain soap had a 53%
      lower incidence of diarrhea (95% confidence interval [CI], -65% to -41%) compared
      with children living in control neighborhoods. Infants living in households that
      received handwashing promotion and plain soap had 39% fewer days with diarrhea
      (95% CI, -61% to -16%) vs infants living in control neighborhoods. Severely
      malnourished children (weight for age z score, <-3.0) younger than 5 years living
      in households that received handwashing promotion and plain soap had 42% fewer
      days with diarrhea (95% CI, -69% to -16%) vs severely malnourished children in
      the control group. Similar reductions in diarrhea were observed among children
      living in households receiving antibacterial soap. CONCLUSION: In a setting in
      which diarrhea is a leading cause of child death, improvement in handwashing in
      the household reduced the incidence of diarrhea among children at high risk of
      death from diarrhea.

PMID- 15173146
TI  - Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted
      infections and HIV-1 infection in Kenyan sex workers: a randomized controlled
      trial.
AB  - CONTEXT: Sexually transmitted infections (STIs) are common in female sex workers
      (FSWs) and may enhance susceptibility to infection with human immunodeficiency
      virus type 1 (HIV-1). OBJECTIVE: To examine regular antibiotic prophylaxis in
      FSWs as a strategy for reducing the incidence of bacterial STIs and HIV-1.
      DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled
      trial conducted between 1998-2002 among FSWs in an urban slum area of Nairobi,
      Kenya. Of 890 FSWs screened, 466 who were seronegative for HIV-1 infection were
      enrolled and randomly assigned to receive azithromycin (n = 230) or placebo (n =
      236). Groups were well matched at baseline for sexual risk taking and STI rates.
      INTERVENTION: Monthly oral administration of 1 g of azithromycin or identical
      placebo, as directly observed therapy. All participants were provided with free
      condoms, risk-reduction counseling, and STI case management. MAIN OUTCOME
      MEASURES: The primary study end point was incidence of HIV-1 infection. Secondary
      end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia
      trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi,
      as well as bacterial vaginosis. Analysis of herpes simplex virus type 2 (HSV-2)
      infection was performed post hoc. RESULTS: Seventy-three percent of participants
      (n = 341) were followed up for 2 or more years or until they reached an
      administrative trial end point. Incidence of HIV-1 did not differ between
      treatment and placebo groups (4% [19 cases per 473 person-years of follow-up] vs
      3.2% [16 cases per 495 person-years of follow-up] rate ratio [RR], 1.2; 95% CI,
      0.6-2.5). Incident HIV-1 infection was associated with preceding infection with N
      gonorrhoeae (rate ratio [RR], 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0;
      95% CI, 1.1-8.9). There was a reduced incidence in the treatment group of
      infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR,
      0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78). The
      seroprevalence of HSV-2 infection at enrollment was 72.7%, and HSV-2 infection at
      baseline was independently associated with HIV-1 acquisition (RR, 6.3; 95% CI,
      1.5-27.1). CONCLUSIONS: Despite an association between bacterial STIs and
      acquisition of HIV-1 infection, the addition of monthly azithromycin prophylaxis
      to established HIV-1 risk reduction strategies substantially reduced the
      incidence of STIs but did not reduce the incidence of HIV-1. Prevalent HSV-2
      infection may have been an important cofactor in acquisition of HIV-1.

PMID- 15173147
TI  - Impact of the Mexican program for education, health, and nutrition (Progresa) on
      rates of growth and anemia in infants and young children: a randomized
      effectiveness study.
AB  - CONTEXT: Malnutrition causes death and impaired health in millions of children.
      Existing interventions are effective under controlled conditions; however, little
      information is available on their effectiveness in large-scale programs.
      OBJECTIVE: To document the short-term nutritional impact of a large-scale,
      incentive-based development program in Mexico (Progresa), which included a
      nutritional component. DESIGN, SETTING, AND PARTICIPANTS: A randomized
      effectiveness study of 347 communities randomly assigned to immediate
      incorporation to the program in 1998 (intervention group; n = 205) or to
      incorporation in 1999 (crossover intervention group; n = 142). A random sample of
      children in those communities was surveyed at baseline and at 1 and 2 years
      afterward. Participants were from low-income households in poor rural communities
      in 6 central Mexican states. Children (N = 650) 12 months of age or younger (n =
      373 intervention group; n = 277 crossover intervention group) were included in
      the analyses. INTERVENTION: Children and pregnant and lactating women in
      participating households received fortified nutrition supplements, and the
      families received nutrition education, health care, and cash transfers. MAIN
      OUTCOME MEASURES: Two-year height increments and anemia rates as measured by
      blood hemoglobin levels in participating children. RESULTS: Progresa was
      associated with better growth in height among the poorest and younger infants.
      Age- and length-adjusted height was greater by 1.1 cm (26.4 cm in the
      intervention group vs 25.3 cm in the crossover intervention group) among infants
      younger than 6 months at baseline and who lived in the poorest households. After
      1 year, mean hemoglobin values were higher in the intervention group (11.12 g/dL;
      95% confidence interval [CI], 10.9-11.3 g/dL) than in the crossover intervention
      group (10.75 g/dL; 95% CI, 10.5-11.0 g/dL) who had not yet received the benefits
      of the intervention (P =.01). There were no differences in hemoglobin levels
      between the 2 groups at year 2 after both groups were receiving the intervention.
      The age-adjusted rate of anemia (hemoglobin level <11 g/dL) in 1999 was higher in
      the crossover intervention group than in the intervention group (54.9% vs 44.3%;
      P =.03), whereas in 2000 the difference was not significant (23.0% vs 25.8%,
      respectively; P =.40). CONCLUSION: Progresa, a large-scale, incentive-based
      development program with a nutritional intervention, is associated with better
      growth and lower rates of anemia in low-income, rural infants and children in
      Mexico.

PMID- 15173148
TI  - Sustainability of reductions in malaria transmission and infant mortality in
      western Kenya with use of insecticide-treated bednets: 4 to 6 years of follow-up.
AB  - CONTEXT: Insecticide-treated bednets reduce malaria transmission and child
      morbidity and mortality in short-term trials, but this impact may not be
      sustainable. Previous investigators have suggested that bednet use might
      paradoxically increase mortality in older children through delayed acquisition of
      immunity to malaria. OBJECTIVES: To determine whether adherence to and public
      health benefits of insecticide-treated bednets can be sustained over time and
      whether bednet use during infancy increases all-cause mortality rates in older
      children in an area of intense perennial malaria transmission. DESIGN AND
      SETTING: A community randomized controlled trial in western Kenya (phase 1:
      January 1997 to February 2000) followed by continued surveillance of adherence,
      entomologic parameters, morbidity indicators, and all-cause mortality (phase 2:
      April 1999 to February 2002), and extended demographic monitoring (January to
      December 2002). PARTICIPANTS: A total of 130,000 residents of 221 villages in
      Asembo and Gem were randomized to receive insecticide-treated bednets at the
      start of phase 1 (111 villages) or phase 2 (110 villages). MAIN OUTCOME MEASURES:
      Proportion of children younger than 5 years using insecticide-treated bednets,
      mean number of Anopheles mosquitoes per house, and all-cause mortality rates.
      RESULTS: Adherence to bednet use in children younger than 5 years increased from
      65.9% in phase 1 to 82.5% in phase 2 (P<.001). After 3 to 4 years of bednet use,
      the mean number of Anopheles mosquitoes per house in the study area was 77% lower
      than in a neighboring area without bednets (risk ratio, 0.23; 95% confidence
      interval [CI], 0.15-0.35). All-cause mortality rates in infants aged 1 to 11
      months were significantly reduced in intervention villages during phase 1 (hazard
      ratio [HR], 0.78; 95% CI, 0.67-0.90); low rates were maintained during phase 2.
      Mortality rates did not differ during 2002 (after up to 6 years of bednet use)
      between children from former intervention and former control households born
      during phase 1 (HR, 1.01; 95% CI, 0.86-1.19). CONCLUSIONS: The public health
      benefits of insecticide-treated bednets were sustained for up to 6 years. There
      is no evidence that bednet use from birth increases all-cause mortality in older
      children in an area of intense perennial transmission of malaria.

PMID- 15173149
TI  - Prevalence, severity, and unmet need for treatment of mental disorders in the
      World Health Organization World Mental Health Surveys.
AB  - CONTEXT: Little is known about the extent or severity of untreated mental
      disorders, especially in less-developed countries. OBJECTIVE: To estimate
      prevalence, severity, and treatment of Diagnostic and Statistical Manual of
      Mental Disorders, Fourth Edition (DSM-IV) mental disorders in 14 countries (6
      less developed, 8 developed) in the World Health Organization (WHO) World Mental
      Health (WMH) Survey Initiative. DESIGN, SETTING, AND PARTICIPANTS: Face-to-face
      household surveys of 60 463 community adults conducted from 2001-2003 in 14
      countries in the Americas, Europe, the Middle East, Africa, and Asia. MAIN
      OUTCOME MEASURES: The DSM-IV disorders, severity, and treatment were assessed
      with the WMH version of the WHO Composite International Diagnostic Interview (WMH
      CIDI), a fully structured, lay-administered psychiatric diagnostic interview.
      RESULTS: The prevalence of having any WMH-CIDI/DSM-IV disorder in the prior year
      varied widely, from 4.3% in Shanghai to 26.4% in the United States, with an
      interquartile range (IQR) of 9.1%-16.9%. Between 33.1% (Colombia) and 80.9%
      (Nigeria) of 12-month cases were mild (IQR, 40.2%-53.3%). Serious disorders were
      associated with substantial role disability. Although disorder severity was
      correlated with probability of treatment in almost all countries, 35.5% to 50.3%
      of serious cases in developed countries and 76.3% to 85.4% in less-developed
      countries received no treatment in the 12 months before the interview. Due to the
      high prevalence of mild and subthreshold cases, the number of those who received
      treatment far exceeds the number of untreated serious cases in every country.
      CONCLUSIONS: Reallocation of treatment resources could substantially decrease the
      problem of unmet need for treatment of mental disorders among serious cases.
      Structural barriers exist to this reallocation. Careful consideration needs to be
      given to the value of treating some mild cases, especially those at risk for
      progressing to more serious disorders.

PMID- 15173150
TI  - Predictive value for the Chinese population of the Framingham CHD risk assessment
      tool compared with the Chinese Multi-Provincial Cohort Study.
AB  - CONTEXT: The Framingham Heart Study helped to establish tools to assess coronary
      heart disease (CHD) risk, but the homogeneous nature of the Framingham population
      prevents simple extrapolation to other populations. Recalibration of Framingham
      functions could permit various regions of the world to adapt Framingham tools to
      local populations. OBJECTIVE: To evaluate the performance of the Framingham CHD
      risk functions, directly and after recalibration, in a large Chinese population,
      compared with the performance of the functions derived from the Chinese Multi
      provincial Cohort Study (CMCS). DESIGN, SETTING, AND PARTICIPANTS: The CMCS
      cohort included 30 121 Chinese adults aged 35 to 64 years at baseline.
      Participants were recruited from 11 provinces and were followed up for new CHD
      events from 1992 to 2002. Participants in the Framingham Heart Study were 5251
      white US residents of Framingham, Mass, who were 30 to 74 years old at baseline
      in 1971 to 1974 and followed up for 12 years. MAIN OUTCOME MEASURES: "Hard" CHD
      (coronary death and myocardial infarction) was used as the end point in
      comparisons of risk factors (age, blood pressure, smoking, diabetes, total
      cholesterol, and high-density lipoprotein cholesterol [HDL-C]) as evaluated by
      the CMCS functions, original Framingham functions, and recalibrated Framingham
      functions. RESULTS: The CMCS cohort had 191 hard CHD events and 625 total deaths
      vs 273 CHD events and 293 deaths, respectively, for Framingham. For most risk
      factor categories, the relative risks for CHD were similar for Chinese and
      Framingham participants, with a few exceptions (ie, age, total cholesterol of 200
      239 mg/dL [5.18-6.19 mmol/L], and HDL-C less than 35 mg/dL [0.91 mmol/L] in men;
      smoking in women). The discrimination using the Framingham functions in the CMCS
      cohort was similar to the CMCS functions: the area under the receiver operating
      characteristic curve was 0.705 for men and 0.742 for women using the Framingham
      functions vs 0.736 for men and 0.759 for women using the CMCS functions. However,
      the original Framingham functions systematically overestimated the absolute CHD
      risk in the CMCS cohort. For example, in the 10th risk decile in men, the
      predicted rate of CHD death was 20% vs an actual rate of 3%. Recalibration of the
      Framingham functions using the mean values of risk factors and mean CHD incidence
      rates of the CMCS cohort substantially improved the performance of the Framingham
      functions in the CMCS cohort. CONCLUSIONS: The original Framingham functions
      overestimated the risk of CHD for CMCS participants. Recalibration of the
      Framingham functions improved the estimates and demonstrated that the Framingham
      model is useful in the Chinese population. For regions that have no established
      cohort, recalibration using CHD rates and risk factors may be an effective method
      to develop CHD risk prediction algorithms suited for local practice.

PMID- 15173151
TI  - Estimates of global prevalence of childhood underweight in 1990 and 2015.
AB  - CONTEXT: One key target of the United Nations Millennium Development goals is to
      reduce the prevalence of underweight among children younger than 5 years by half
      between 1990 and 2015. OBJECTIVE: To estimate trends in childhood underweight by
      geographic regions of the world. DESIGN, SETTING, AND PARTICIPANTS: Time series
      study of prevalence of underweight, defined as weight 2 SDs below the mean weight
      for age of the National Center for Health Statistics and World Health
      Organization (WHO) reference population. National prevalence rates derived from
      the WHO Global Database on Child Growth and Malnutrition, which includes data on
      approximately 31 million children younger than 5 years who participated in 419
      national nutritional surveys in 139 countries from 1965 through 2002. MAIN
      OUTCOME MEASURES: Linear mixed-effects modeling was used to estimate prevalence
      rates and numbers of underweight children by region in 1990 and 2015 and to
      calculate the changes (ie, increase or decrease) to these values between 1990 and
      2015. RESULTS: Worldwide, underweight prevalence was projected to decline from
      26.5% in 1990 to 17.6% in 2015, a change of -34% (95% confidence interval [CI], 
      43% to -23%). In developed countries, the prevalence was estimated to decrease
      from 1.6% to 0.9%, a change of -41% (95% CI, -92% to 343%). In developing
      regions, the prevalence was forecasted to decline from 30.2% to 19.3%, a change
      of -36% (95% CI, -45% to -26%). In Africa, the prevalence of underweight was
      forecasted to increase from 24.0% to 26.8%, a change of 12% (95% CI, 8%-16%). In
      Asia, the prevalence was estimated to decrease from 35.1% to 18.5%, a change of 
      47% (95% CI, -58% to -34%). Worldwide, the number of underweight children was
      projected to decline from 163.8 million in 1990 to 113.4 million in 2015, a
      change of -31% (95% CI, -40% to -20%). Numbers are projected to decrease in all
      subregions except the subregions of sub-Saharan, Eastern, Middle, and Western
      Africa, which are expected to experience substantial increases in the number of
      underweight children. CONCLUSIONS: An overall improvement in the global situation
      is anticipated; however, neither the world as a whole, nor the developing
      regions, are expected to achieve the Millennium Development goals. This is
      largely due to the deteriorating situation in Africa where all subregions, except
      Northern Africa, are expected to fail to meet the goal.

PMID- 15173152
TI  - Risk factors for typhoid and paratyphoid fever in Jakarta, Indonesia.
AB  - CONTEXT: The proportion of paratyphoid fever cases to typhoid fever cases may
      change due to urbanization and increased dependency on food purchased from street
      vendors. For containment of paratyphoid a different strategy may be needed than
      for typhoid, because risk factors for disease may not coincide and current
      typhoid vaccines do not protect against paratyphoid fever. OBJECTIVE: To
      determine risk factors for typhoid and paratyphoid fever in an endemic area.
      DESIGN, SETTING, AND PARTICIPANTS: Community-based case-control study conducted
      from June 2001 to February 2003 in hospitals and outpatient health centers in
      Jatinegara district, Jakarta, Indonesia. Enrolled participants were 1019
      consecutive patients with fever lasting 3 or more days, from which 69 blood
      culture-confirmed typhoid cases, 24 confirmed paratyphoid cases, and 289 control
      patients with fever but without Salmonella bacteremia were interviewed, plus 378
      randomly selected community controls. MAIN OUTCOME MEASURES: Blood culture
      confirmed typhoid or paratyphoid fever; risk factors for both diseases. RESULTS:
      In 1019 fever patients we identified 88 (9%) Salmonella typhi and 26 (3%)
      Salmonella paratyphi A infections. Paratyphoid fever among cases was
      independently associated with consumption of food from street vendors (comparison
      with community controls: odds ratio [OR], 3.34; 95% confidence interval [CI],
      1.41-7.91; with fever controls: OR, 5.17; 95% CI, 2.12-12.60) and flooding
      (comparison with community controls: OR, 4.52; 95% CI, 1.90-10.73; with fever
      controls: OR, 3.25; 95% CI, 1.31-8.02). By contrast, independent risk factors for
      typhoid fever using the community control group were mostly related to the
      household, ie, to recent typhoid fever in the household (OR, 2.38; 95% CI, 1.03
      5.48); no use of soap for handwashing (OR, 1.91; 95% CI, 1.06-3.46); sharing food
      from the same plate (OR, 1.93; 95% CI, 1.10-3.37), and no toilet in the household
      (OR, 2.20; 95% CI, 1.06-4.55). Also, typhoid fever was associated with young age
      in years (OR, 0.96; 95% CI, 0.94-0.98). In comparison with fever controls, risk
      factors for typhoid fever were use of ice cubes (OR, 2.27; 95% CI, 1.31-3.93) and
      female sex (OR, 1.79; 95% CI, 1.04-3.06). Fecal contamination of drinking water
      was not associated with typhoid or paratyphoid fever. We did not detect fecal
      carriers among food handlers in the households. CONCLUSIONS: In Jakarta, typhoid
      and paratyphoid fever are associated with distinct routes of transmission, with
      the risk factors for disease either mainly within the household (typhoid) or
      outside the household (paratyphoid).

PMID- 15173153
TI  - The global burden of chronic diseases: overcoming impediments to prevention and
      control.
AB  - Chronic diseases are the largest cause of death in the world. In 2002, the
      leading chronic diseases--cardiovascular disease, cancer, chronic respiratory
      disease, and diabetes--caused 29 million deaths worldwide. Despite growing
      evidence of epidemiological and economic impact, the global response to the
      problem remains inadequate. Stakeholders include governments, the World Health
      Organization and other United Nations bodies, academic and research groups,
      nongovernmental organizations, and the private sector. Lack of financial support
      retards capacity development for prevention, treatment, and research in most
      developing countries. Reasons for this include that up-to-date evidence related
      to the nature of the burden of chronic diseases is not in the hands of decision
      makers and strong beliefs persist that chronic diseases afflict only the affluent
      and the elderly, that they arise solely from freely acquired risks, and that
      their control is ineffective and too expensive and should wait until infectious
      diseases are addressed. The influence of global economic factors on chronic
      disease risks impedes progress, as does the orientation of health systems toward
      acute care. We identify 3 policy levers to address these impediments elevating
      chronic diseases on the health agenda of key policymakers, providing them with
      better evidence about risk factor control, and persuading them of the need for
      health systems change. A more concerted, strategic, and multisectoral policy
      approach, underpinned by solid research, is essential to help reverse the
      negative trends in the global incidence of chronic disease.

PMID- 15173154
TI  - International infectious disease law: revision of the World Health Organization's
      International Health Regulations.
AB  - The International Health Regulations (IHR), the only global regulations for
      infectious disease control, have not been significantly changed since they were
      first issued in 1951. The World Health Organization (WHO) is currently engaged in
      a process to modernize the IHR. This article reviews WHO's draft revised IHR and
      recommends new reforms to improve global health, which include (1) a robust
      mission, emphasizing the WHO's core public health purposes, functions, and
      essential services; (2) broad scope, flexibly covering diverse health threats;
      (3) global surveillance, developing informational networks of official and
      unofficial data sources; (4) national public health systems, setting performance
      criteria, measuring outcomes, and holding states accountable; (5) human rights
      protection, setting science-based standards and fair procedures; and (6) good
      governance, adopting the principles of fairness, objectivity, and transparency.
      The WHO should ensure state compliance with health norms and generous economic
      and technical assistance to poorer countries. An important issue for the
      international community is how sovereign countries can join together to make
      global health work for everyone, the poor and the wealthy alike.

PMID- 15173155
TI  - Scientific rationale for a change in the composition of oral rehydration
      solution.

PMID- 15173156
TI  - Clinical concerns about reduced-osmolarity oral rehydration solution.

PMID- 15173157
TI  - The challenge to improve global health: financing the Millennium Development
      Goals.

PMID- 15173158
TI  - Evidence-based global health.

PMID- 15173159
TI  - JAMA patient page. Malaria.

PMID- 15173160
TI  - Novel lipoglycopeptides as inhibitors of bacterial signal peptidase I.
AB  - Signal peptidase (SPase) I is responsible for the cleavage of signal peptides of
      many secreted proteins in bacteria. Because of its unique physiological and
      biochemical properties, it serves as a potential target for development of novel
      antibacterial agents. In this study, we report the production, isolation, and
      structure determination of a family of structurally related novel
      lipoglycopeptides from a Streptomyces sp. as inhibitors of SPase I. Detailed
      spectroscopic analyses, including MS and NMR, revealed that these
      lipoglycopeptides share a common 14-membered cyclic peptide core, an acyclic
      tripeptide chain, and a deoxy-alpha-mannose sugar, but differ in the degree of
      oxidation of the N-methylphenylglycine residue and the length and branching of
      the fatty acyl chain. Biochemical analysis demonstrated that these peptides are
      potent and competitive inhibitors of SPase I with K(i) 50 to 158 nm. In addition,
      they showed modest antibacterial activity against a panel of pathogenic Gram
      positive and Gram-negative bacteria with minimal inhibitory concentration of 8-64
      microm against Streptococcus pneumonniae and 4-8 microm against Escherichia coli.
      Notably, they mechanistically blocked the protein secretion in whole cells as
      demonstrated by inhibiting beta-lactamase release from Staphylococcus aureus.
      Taken together, the present discovery of a family of novel lipoglycopeptides as
      potent inhibitors of bacterial SPase I may lead to the development of a novel
      class of broad-spectrum antibiotics.

PMID- 15173161
TI  - beta-Catenin shows an overlapping sequence requirement but distinct molecular
      interactions for its bidirectional passage through nuclear pores.
AB  - beta-Catenin is an example of a typical molecule that can be translocated
      bidirectionally through nuclear pore complexes (NPCs) on its own in a facilitated
      manner. In this work the nuclear import and export of beta-catenin were examined
      to compare the sequence requirement of this molecule and to determine whether
      molecular interactions required for its bidirectional NPC passage are distinct or
      not. Deletion analysis of beta-catenin revealed that armadillo repeats 10-12 and
      the C terminus comprise the minimum region necessary for nuclear migration
      activity. Further dissection of this fragment showed that the C terminus tail
      plays an essential role in nuclear migration. The region of beta-catenin required
      for export substantially overlapped the region required for import. Therefore,
      the NPC translocation of beta-catenin is apparently reversible, which is
      consistent with findings reported previously. However, different translocating
      molecules blocked nuclear import and export of beta-catenin differentially. The
      data herein indicate that beta-catenin shows an overlapping sequence requirement
      for its import and export but that bidirectional movement through the NPC
      proceeds through distinct molecular interactions.

PMID- 15173162
TI  - Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol
      transporter and a key modulator of whole-body cholesterol homeostasis.
AB  - Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes
      that is critical for intestinal cholesterol absorption. The uptake of intestinal
      phytosterols and cholesterol into absorptive enterocytes in the intestine is not
      fully defined on a molecular level, and the role of NPC1L1 in maintaining whole
      body cholesterol homeostasis is not known. NPC1L1 null mice had substantially
      reduced intestinal uptake of cholesterol and sitosterol, with dramatically
      reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant
      to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic
      cholesterol profiles similar to those of wild type mice treated with the
      cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted
      in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1
      deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA
      synthase mRNA and an increase in intestinal cholesterol synthesis, down
      regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression.
      NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and
      plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug
      target for the treatment of hypercholesterolemia and sitosterolemia.

PMID- 15173163
TI  - Assignment of the four disulfides in the N-terminal somatomedin B domain of
      native vitronectin isolated from human plasma.
AB  - The primary sequence of the N-terminal somatomedin B (SMB) domain of native
      vitronectin contains 44 amino acids, including a framework of four disulfide
      bonds formed by 8 closely spaced cysteines in sequence patterns similar to those
      found in the cystine knot family of proteins. The SMB domain of vitronectin was
      isolated by digesting the protein with endoproteinase Glu-C and purifying the N
      terminal 1-55 peptide by reverse-phase high performance liquid chromatography.
      Through a combination of techniques, including stepwise reduction and alkylation
      at acidic pH, peptide mapping with matrix-assisted laser desorption ionization
      mass spectrometry and NMR, the disulfide bonds contained in the SMB domain have
      been determined to be Cys(5):Cys(9), Cys(19):Cys(31), Cys(21):Cys(32), and
      Cys(25):Cys(39). This pattern of disulfides differs from two other connectivities
      that have been reported previously for recombinant forms of the SMB domain
      expressed in Escherichia coli. This arrangement of disulfide bonds in the SMB
      domain from native vitronectin forms a rigid core around the Cys(19): Cys(31) and
      Cys(21):Cys(32) disulfides. A small positively charged loop is created at the N
      terminus by the Cys(5): Cys(9) cystine. The most prominent feature of this
      disulfide-bonding pattern is a loop between Cys(25) and Cys(39) similar to
      cystine-stabilized alpha-helical structures commonly observed in cystine knots.
      This alpha-helix has been confirmed in the solution structure determined for this
      domain using NMR (Mayasundari, A., Whittemore, N. A., Serpersu, E. H., and
      Peterson, C. B. (2004) J. Biol. Chem. 279, 29359-29366). It confers function on
      the SMB domain, comprising the site for binding to plasminogen activator
      inhibitor type-1 and the urokinase receptor.

PMID- 15173164
TI  - Cooperation between mast cell carboxypeptidase A and the chymase mouse mast cell
      protease 4 in the formation and degradation of angiotensin II.
AB  - The octapeptide angiotensin II (Ang II) exerts a wide range of effects on the
      cardiovascular system but has also been implicated in the regulation of cell
      proliferation, fibrosis, and apoptosis. Ang II is formed by cleavage of Ang I by
      angiotensin-converting enzyme, but there is also evidence for non-angiotensin
      converting enzyme-dependent conversion of Ang I to Ang II. Here we address the
      role of mast cell proteases in Ang II production by using two different mouse
      strains lacking mast cell heparin or mouse mast cell protease 4 (mMCP-4), the
      chymase that may be the functional homologue to human chymase. Ang I was added to
      ex vivo cultures of peritoneal cells, and the generation of Ang II and other
      metabolites was analyzed. Activation of mast cells resulted in marked increases
      in both the formation and subsequent degradation of Ang II, and both of these
      processes were strongly reduced in heparin-deficient peritoneal cells. In the
      mMCP-4(-/-) cell cultures no reduction in the rate of Ang II generation was seen,
      but the formation of Ang-(5-10) was completely abrogated. Addition of a
      carboxypeptidase A (CPA) inhibitor to wild type cells caused complete inhibition
      of the formation of Ang-(1-9) and Ang-(1-7) but did not inhibit Ang II formation.
      However, when the CPA inhibitor was added to the mMCP-4(-/-) cultures,
      essentially complete inhibition of Ang II formation was obtained. Taken together,
      the results of this study indicate that mast cell chymase and CPA have key roles
      in both the generation and degradation of Ang II.

PMID- 15173165
TI  - FGF-2 induced by interleukin-1 beta through the action of phosphatidylinositol 3
      kinase mediates endothelial mesenchymal transformation in corneal endothelial
      cells.
AB  - Our previous work demonstrated that both polymorphonuclear leukocytes (PMNs) and
      protein fractions released from PMNs induced de novo synthesis of fibroblast
      growth factor 2 (FGF-2), which in turn becomes the direct mediator of endothelial
      mesenchymal transformation observed in corneal endothelial cells (CECs). To
      identify the protein factor, we used ProteinChip Array technology. Protein
      fractions obtained from the conditioned medium released by PMNs were resolved by
      two-dimensional electrophoresis with immobilized pH gradient strips. Most of the
      protein spots, with molecular masses of 17 kDa, were sequentially subjected to in
      gel trypsin digestion and mass spectrometry. The 17-kDa peptide band was
      identified as interleukin-1 beta (IL-1 beta). Biological activities of IL-1 beta
      were further determined; IL-1 beta altered the shape of CECs from polygonal to
      fibroblastic morphologies in a time- and dose-dependent manner, whereas
      neutralizing IL-1 beta antibody, neutralizing antibody to FGF-2, and LY294002
      blocked the action of IL-1 beta. IL-1 beta greatly increased the levels of FGF-2
      mRNA in a time- and dose-dependent manner; IL-1 beta stimulated expression of all
      isoforms of FGF-2. IL-1 beta initially induced nuclear accumulation of FGF-2 and
      facilitated translocation of FGF-2 to plasma membrane and extracellular matrix.
      IL-1 beta activated phosphatidylinositol (PI) 3-kinase, the enzyme activity of
      which was greatly stimulated after a 5-min exposure to IL-1 beta. This early and
      rapid activation of PI 3-kinase greatly enhanced FGF-2 production in CECs;
      pretreatment with LY294002 hampered the induction activity of IL-1 beta. These
      observations suggest that IL-1 beta takes part in endothelial to mesenchymal
      transformation of CECs through its inductive potential on FGF-2 via the action of
      PI 3-kinase.

PMID- 15173166
TI  - The structure and dynamics of tandem WW domains in a negative regulator of notch
      signaling, Suppressor of deltex.
AB  - WW domains mediate protein recognition, usually though binding to proline-rich
      sequences. In many proteins, WW domains occur in tandem arrays. Whether or how
      individual domains within such arrays cooperate to recognize biological partners
      is, as yet, poorly characterized. An important question is whether functional
      diversity of different WW domain proteins is reflected in the structural
      organization and ligand interaction mechanisms of their multiple domains. We have
      determined the solution structure and dynamics of a pair of WW domains (WW3-4)
      from a Drosophila Nedd4 family protein called Suppressor of deltex (Su(dx)), a
      regulator of Notch receptor signaling. We find that the binding of a type 1 PPPY
      ligand to WW3 stabilizes the structure with effects propagating to the WW4
      domain, a domain that is not active for ligand binding. Both WW domains adopt the
      characteristic triple-stranded beta-sheet structure, and significantly, this is
      the first example of a WW domain structure to include a domain (WW4) lacking the
      second conserved Trp (replaced by Phe). The domains are connected by a flexible
      linker, which allows a hinge-like motion of domains that may be important for the
      recognition of functionally relevant targets. Our results contrast markedly with
      those of the only previously determined three-dimensional structure of tandem WW
      domains, that of the rigidly oriented WW domain pair from the RNA-splicing factor
      Prp40. Our data illustrate that arrays of WW domains can exhibit a variety of
      higher order structures and ligand interaction mechanisms.

PMID- 15173168
TI  - Cds1 phosphorylation by Rad3-Rad26 kinase is mediated by forkhead-associated
      domain interaction with Mrc1.
AB  - The protein kinase Cds1 is an effector of the replication checkpoint in the
      fission yeast Schizosaccharomyces pombe. Cds1 is required to stabilize stalled
      replication forks, and it helps to prevent the onset of mitosis until the genome
      is fully replicated. Mrc1 (mediator of the replication checkpoint-1) and Rad3
      Rad26 kinase are required for Cds1 activation, but exactly how Mrc1 mediates Cds1
      activation is unknown. Here we show that Mrc1 is required for the initial
      threonine 11 phosphorylation of Cds1 by Rad3-Rad26. Mrc1 specifically interacts
      with the forkhead-associated (FHA) domain of Cds1 in yeast two-hybrid assays.
      Mutations in the FHA domain that abolish this interaction also eliminate Thr-11
      phosphorylation of Cds1. Weak Thr-11 phosphorylation of a "kinase-dead" mutant of
      Cds1 is rescued by co-expression of wild type Cds1. The requirement for Mrc1 in
      the replication checkpoint can be partially eliminated by expression of a Rad26
      Cds1 fusion protein. These findings suggest that recognition of Mrc1 by the FHA
      domain of Cds1 serves to recruit Cds1 to Rad3-Rad26. This interaction mediates
      the initial Thr-11 phosphorylation of Cds1 by Rad3-Rad26 with subsequent
      intermolecular phosphorylation events leading to full activation of Cds1.

PMID- 15173167
TI  - Molecular cloning and functional characterization of a Lepidopteran insect beta4
      N-acetylgalactosaminyltransferase with broad substrate specificity, a functional
      role in glycoprotein biosynthesis, and a potential functional role in glycolipid
      biosynthesis.
AB  - A degenerate PCR approach was used to isolate a lepidopteran insect cDNA encoding
      a beta4-galactosyl-transferase family member. The isolation and initial
      identification of this cDNA was based on bioinformatics, but its identification
      as a beta4-galactosyltransferase family member was experimentally confirmed. The
      newly identified beta4-galactosyltransferase family member had unusually broad
      donor and acceptor substrate specificities in vitro, as transferred galactose, N
      acetylglucosamine, and N-acetylgalactosamine to carbohydrate, glycoprotein, and
      glycolipid acceptors. However, the enzyme preferentially utilized N
      acetylgalactosamine as the donor for all three acceptors, and its derived amino
      acid sequence was closely related to a known N-acetylgalactosaminyltransferase.
      These data suggested that the newly isolated cDNA encodes a beta4-N
      acetylgalactosaminyltransferase that functions in insect cell glycoprotein
      biosynthesis, glycolipid biosynthesis, or both. The remainder of this study
      focused on the role of this enzyme in N-glycoprotein biosynthesis. The results
      showed that the purified enzyme transferred N-acetylgalactosamine, but no
      detectable galactose or N-acetylglucosamine, to a synthetic N-glycan in vitro.
      The structure of the reaction product was confirmed by chromatographic, mass
      spectroscopic, and nuclear magnetic resonance analyses. Co-expression of the new
      cDNA product in insect cells with an N-glycoprotein reporter showed that it
      transferred N-acetylgalactosamine, but no detectable galactose or N
      acetylglucosamine, to this N-glycoprotein in vivo. Confocal microscopy showed
      that a GFP-tagged version of the enzyme was localized in the insect cell Golgi
      apparatus. In summary, this study demonstrated that lepidopteran insect cells
      encode and express a beta4-N-acetylgalactosaminyltransferase that functions in N
      glycoprotein biosynthesis and perhaps in glycolipid biosynthesis, as well. The
      isolation and characterization of this gene and its product contribute to our
      basic understanding of insect protein N-glycosylation pathways and to the growing
      body of evidence that insects can produce glycoproteins with complex N-glycans.

PMID- 15173169
TI  - Molecular characterization of Rab11 interactions with members of the family of
      Rab11-interacting proteins.
AB  - The Rab11 subfamily of GTPases plays an important role in vesicle trafficking
      from endosomes to the plasma membrane. At least six Rab11 effectors (family of
      Rab11-interacting proteins (FIPs)) have been shown to interact with Rab11 and are
      hypothesized to regulate various membrane trafficking pathways such as
      transferrin recycling, cytokinesis, and epidermal growth factor trafficking. In
      this study, we characterized interactions of FIPs with the Rab11 GTPase using
      isothermal titration calorimetric studies and mutational analysis. Our data
      suggest that FIPs cannot differentiate between GTP-bound Rab11a and Rab11b in
      vitro (50-100 nm affinity) and in vivo. We also show that, although FIPs interact
      with the GDP-bound form of Rab11 in vitro, the binding affinity (>1000 nm) is not
      sufficient for FIP and GDP-bound Rab11 interactions to occur in vivo. Mutational
      analysis revealed that both the conserved hydrophobic patch and Tyr628 are
      important for the GTP-dependent binding of Rab11 to FIPs. The entropy and
      enthalpy analyses suggest that binding to Rab11a/b may induce conformational
      changes in FIPs.

PMID- 15173170
TI  - Binding and kinetic mechanisms of the Zeta class glutathione transferase.
AB  - The Zeta class of glutathione transferases (GSTs) has only recently been
      discovered and hence has been poorly characterized. Here we investigate the
      substrate binding and kinetic mechanisms of the human Zeta class GSTZ1c-1c by
      means of pre-steady state and steady-state experiments and site-directed
      mutagenesis. Binding of GSH occurs at a very low rate compared with that observed
      for the more recently evolved GSTs (Alpha, Mu, and Pi classes). Moreover, the
      single step binding mechanism observed in this enzyme is reminiscent of that
      found for the Theta class enzyme, whereas the Alpha, Mu, and Pi classes have
      adopted a multistep binding mechanism. Replacement of Cys16 with Ala increases
      the rate of GSH release from the active site causing a 10-fold decrease of
      affinity toward GSH. Cys16 also plays a crucial role in co-substrate binding; the
      mutant enzyme is unable to bind the carcinogenic substrate dichloroacetic acid in
      the absence of GSH. However, both substrate binding and GSH activation are not
      rate-limiting in catalysis. A peculiarity of the hGSTZ1c-1c is the half-site
      activation of bound GSH. This suggests a primitive monomer-monomer interaction
      that, in the recently diverged GSTP1-1, gives rise to a sophisticated cooperative
      mechanism that preserves the catalytic efficiency of this GST under stress
      conditions.

PMID- 15173171
TI  - Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a
      novel self-regulatory mechanism of activity.
AB  - Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of
      isocitrate to alpha-ketoglutarate, and regulation of the enzymatic activity of
      IDHs is crucial for their biological functions. Bacterial IDHs are reversibly
      regulated by phosphorylation of a strictly conserved serine residue at the active
      site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse
      important biological functions; however, their regulatory mechanism remains
      unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with
      NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically
      relevant conformational states of the enzyme that differ substantially in the
      structure of the active site and in the overall structure. A structural segment
      at the active site that forms a conserved alpha-helix in all known NADP-IDH
      structures assumes a loop conformation in the open, inactive form of HcIDH; a
      partially unraveled alpha-helix in the semi-open, intermediate form; and an alpha
      helix in the closed, active form. The side chain of Asp279 of this segment
      occupies the isocitrate-binding site and forms hydrogen bonds with Ser94 (the
      equivalent of the phosphorylation site in bacterial IDHs) in the inactive form
      and chelates the metal ion in the active form. The structural data led us to
      propose a novel self-regulatory mechanism for HcIDH that mimics the
      phosphorylation mechanism used by the bacterial homologs, consistent with
      biochemical and biological data. This mechanism might be applicable to other
      eukaryotic NADP-IDHs. The results also provide insights into the recognition and
      specificity of substrate and cofactor by eukaryotic NADP-IDHs.

PMID- 15173172
TI  - Nuclear factor of activated T cells regulates transcription of the surfactant
      protein D gene (Sftpd) via direct interaction with thyroid transcription factor-1
      in lung epithelial cells.
AB  - Surfactant protein D (SP-D) plays critical roles in host defense, surfactant
      homeostasis, and pulmonary immunomodulation. Here, we identify a role of nuclear
      factor of activated T cells (NFATs) in regulation of murine SP-D gene (Sftpd)
      transcription. An NFAT-dependent enhancer modulated by NFATs or calcineurin and
      sensitive to cyclosporin was identified in the Sftpd promoter. Ionomycin and
      phorbol 12-myristate 13-acetate further increased the activity of this enhancer,
      whereas VIVIT, a potent NFAT inhibitor peptide, selectively interfered with the
      calcineurin-NFAT interaction and abolished enhancer function. Gel supershift and
      DNase I protection assays identified DNA elements that bind NFAT in the Sftpd
      promoter. Calcineurin and NFATc3 proteins were detected in the embryonic and
      adult mouse lung epithelium, and the mRNA expression profiles of the NFATs were
      similar in immortalized mouse lung epithelial cells and alveolar epithelial type
      II cells. NFATc3 and TTF-1 activated the Sftpd promoter, synergized
      transcription, co-immunoprecipitated from mouse lung epithelial cells, and
      physically interacted in vitro. Components of the calcineurin/NFAT pathway were
      identified in respiratory epithelial cells of the lung that potentially augment
      rapid assembly of a multiprotein transcription complex on Sftpd promoter inducing
      SP-D expression.

PMID- 15173173
TI  - Hydration and packing effects on prion folding and beta-sheet conversion. High
      pressure spectroscopy and pressure perturbation calorimetry studies.
AB  - The main hypothesis for prion diseases proposes that the cellular protein
      (PrP(C)) can be altered into a misfolded, beta-sheet-rich isoform (PrP(Sc)),
      which undergoes aggregation and triggers the onset of transmissible spongiform
      encephalopathies. Here, we compare the stability against pressure and the
      thermomechanical properties of the alpha-helical and beta-sheet conformations of
      recombinant murine prion protein, designated as alpha-rPrP and beta-rPrP,
      respectively. High temperature induces aggregates and a large gain in
      intermolecular antiparallel beta-sheet (beta-rPrP), a conformation that shares
      structural similarity with PrP(Sc). alpha-rPrP is highly stable, and only
      pressures above 5 kilobars (1 kilobar = 100 MegaPascals) cause reversible
      denaturation, a process that leads to a random and turnrich conformation with
      concomitant loss of alpha-helix, as measured by Fourier transform infrared
      spectroscopy. In contrast, aggregates of beta-rPrP are very sensitive to
      pressure, undergoing transition into a dissociated species that differs from the
      denatured form derived from alpha-rPrP. The higher susceptibility to pressure of
      beta-rPrP can be explained by its less hydrated structure. Pressure perturbation
      calorimetry supports the view that the accessible surface area of alpha-rPrP is
      much higher than that of beta-rPrP, which explains the lower degree of hydration
      of beta-rPrP. Our findings shed new light on the mechanism of prion conversion
      and show how water plays a prominent role. Our results allow us to propose a
      volume and free energy diagram of the different species involved in the
      conversion and aggregation. The existence of different folded conformations as
      well as different denatured states of PrP may explain the elusive character of
      its conversion into a pathogenic form.

PMID- 15173174
TI  - Subcellular localization determines the protective effects of activated ERK2
      against distinct apoptogenic stimuli in myeloid leukemia cells.
AB  - ERKs, mitogen-activated protein kinases, are well characterized as key mediators
      in the conveyance of signals that promote cell survival in cells of hemopoietic
      origin, a key factor in the upbringing of leukemogenesis. It is also well known
      that ERKs phosphorylate a wide array of substrates distributed throughout
      distinct cellular locations such as the nucleus, cytoplasm, and cell periphery,
      but the relative contribution of these compartmentalized signal components to the
      overall survival signal generated by activation of ERKs has yet to be
      established. To this end, we have utilized constitutively activated forms of
      ERK2, whose expression is restricted to the nucleus or to the cytoplasm, to
      investigate the consequences of compartmentalized activation of ERK in the
      survival of chronic myelogenous leukemia cells subjected to distinct apoptogenic
      stimuli. We show that cytoplasmic ERK2 activity protected against apoptosis
      caused by prolonged serum starvation, whereas ERK2 activation restricted to the
      nucleus antagonized apoptosis induced by the Bcr-Abl inhibitor STI571. On the
      other hand, neither cytoplasmic nor nuclear ERK2 activities were effective in
      counteracting apoptosis induced by UV light. These results demonstrate that the
      protective effects of ERK2 against defined apoptogenic stimuli are strictly
      dependent on the cellular localization where ERK activation takes place.
      Furthermore, we present evidence suggesting that the complex I kappa B-NF kappa B
      participates on ERK2-mediated survival mechanisms, in a fashion dependent on the
      cellular location where ERK2 is active and on the causative apoptogenic stimulus.

PMID- 15173175
TI  - Phosphorylation and recruitment of Syk by immunoreceptor tyrosine-based
      activation motif-based phosphorylation of tamalin.
AB  - Tamalin is a scaffold protein that forms a multiple protein assembly including
      metabotropic glutamate receptors (mGluRs) and several postsynaptic and protein
      trafficking scaffold proteins in distinct mode of protein-protein association. In
      the present investigation, we report that tamalin possesses a typical
      immunoreceptor tyrosine-based activation motif (ITAM), which enables Syk kinase
      to be recruited and phosphorylated by the Src family kinases.
      Coimmunoprecipitation analysis of rat brain membrane fractions showed that
      tamalin is present in a multimolecular protein assembly comprising not only
      mGluR1 but also c-Src, Fyn, and a protein phosphatase, SHP-2. The protein
      association of both tamalin and c-Src, as determined by truncation analysis of
      mGluR1 in COS-7 cells, occurred at the carboxyl-terminal tail of mGluR1. Mutation
      analysis of tyrosine with phenylalanine in COS-7 cells revealed that paired
      tyrosines at the ITAM sequence of tamalin are phosphorylated preferentially by c
      Src and Fyn, and this phosphorylation can recruit Syk kinase and enables it to be
      phosphorylated by the Src family kinases. The phosphorylated tyrosines at the
      ITAM sequence of tamalin were highly susceptible to dephosphorylation by protein
      tyrosine phosphatases in COS-7 cells. Importantly, tamalin was endogenously
      phosphorylated and associated with Syk in retinoic acid-treated P19 embryonal
      carcinoma cells that undergo neuron-like differentiation. The present
      investigation demonstrates that tamalin is a novel signaling molecule that
      possesses a PDZ domain and a PDZ binding motif and mediates Syk signaling in an
      ITAM-based fashion.

PMID- 15173176
TI  - Caspase-2 can function upstream of bid cleavage in the TRAIL apoptosis pathway.
AB  - In many mammalian cell types, engagement of the TRAIL/Apo2L death receptors DR4
      and DR5 alters mitochondrial physiology, thereby promoting the release of pro
      apoptotic proteins normally contained within this organelle. A contemporary view
      of this process is that in so-called type II cells death receptor-activated
      caspase-8 cleaves the Bcl-2 family member Bid, which generates a truncated Bid
      fragment that collaborates with Bax, another Bcl-2 relative, to promote the
      release of mitochondrial factors necessary for activation of executioner caspases
      and apoptosis. Here we show that in some type II cells caspase-2 is necessary for
      optimal TRAIL-mediated cleavage of Bid. Down-regulation of caspase-2 using RNA
      interference significantly inhibited TRAIL-induced apoptosis. Analysis of the
      TRAIL proteolytic cascade following gene silencing of specific pathway components
      revealed that caspase-2 is necessary for efficient cleavage of Bid; however,
      caspase-2 proteolytic processing, which occurs downstream of Bax, is not
      necessary for its role in Bid cleavage.

PMID- 15173177
TI  - Hepatitis B virus X protein induces expression of Fas ligand gene through
      enhancing transcriptional activity of early growth response factor.
AB  - FasL expressed in tumor cells plays an important role in the escape from immune
      surveillance by inducing apoptosis in T-cells bearing Fas. Since the Fas/FasL
      signaling pathway requires transcriptional induction of the FasL gene,
      elucidation of the precise mechanisms underlying regulation of FasL gene
      expression may provide useful molecular insights on tumor progression. We and
      others (Shin, E. C., Shin, J. S., Park, J. H., Kim, H., and Kim, S. J. (1999)
      Int. J. Cancer 82, 587-591; Lee, M. O., Kang, H. J., Cho, H., Shin, E. C., Park,
      J. H., and Kim, S. J. (2001) Biochem. Biophys. Res. Commun. 288, 1162-1168) have
      previously reported that hepatitis B virus X protein (HBx) plays a role in the
      induction of FasL expression in hepatitis B virus-associated hepatoma. In the
      present study, we analyzed the potential cis- and trans-acting factors that
      regulate FasL promoter. We found that HBx induced activity of the reporter
      containing FasL promoter through binding site for Egr but not through NFAT or SP
      1, which are known as strong activators of the FasL promoter in T-cells.
      Transient expression of antisense Egr-2 and antisense Egr-3 abolished expression
      of FasL, which further confirmed the role of Egr in the HBx-mediated FasL
      expression. Also we observed that HBx increased the transcriptional activity of
      Egr-2 and Egr-3 by enhancing expression as well as the transactivation function
      of these proteins. HBx interacted with Egr-2 and Egr-3 in vivo and enhanced
      binding of Egr to the co-activator, cAMP-response element-binding protein-binding
      protein, which may explain the molecular mechanism by which HBx induced the
      transactivation function of Egr. Finally, we found that the carboxyl terminus of
      HBx was necessary and sufficient for FasL induction as well as activation of Egr.
      Taken together, our results show a novel mechanism by which HBx induces FasL gene
      expression that is mediated by enhancing transcriptional activity of Egr-2 and
      Egr-3.

PMID- 15173178
TI  - The MisR/MisS two-component regulatory system influences inner core structure and
      immunotype of lipooligosaccharide in Neisseria meningitidis.
AB  - Lipooligosaccharide (LOS) of Neisseria meningitidis is the major inflammatory
      mediator that contributes to meningococcal pathogenesis. Variable attachments to
      the HepII residue of the LOS inner core together with the alpha-chain
      heterogeneity result in immunologically distinct LOS structures, which may be
      selected for during human infection. Lpt-3, a phosphoethanolamine (PEA)
      transferase, and LgtG, a glucosyltransferase, mediate the substitution of PEA or
      glucose at the O-3 position of HepII in L3 or L2 LOS immunotypes, respectively.
      Inactivation of a two-component response regulator, encoded by NMB0595, in N.
      meningitidis strain NMB resulted in the loss of all PEA decorations on the LOS
      inner core expressed by the NMB0595 mutant. When compared with the parental
      strain NMB that predominantly expresses L2 immunotype LOS and other minor LOS
      structures, the NMB0595 mutant expresses a pure population of a novel LOS
      structure completely substituted at the HepII O-3 position with glucose, but
      lacking other PEA decorations on the inner core. Quantitative real time PCR
      experiments showed increased transcription of lgtG in the NMB0595 mutant, and no
      significant change in lpt-3 transcription. Inactivation of lgtG resulted in LOS
      inner cores without glucose, but these structures, even though the lpt-3
      transcription was unaffected, also lacked the O-3-linked PEA. Consistently, a
      double mutation of lgtG and misR in strain NMB yielded a LOS structure without
      PEA or Glc substitution of HepII. These data indicated a new pathway for the
      regulation of LOS inner core structure in N. meningitidis through an
      environmental sensing two-component regulatory system, named
      misR(NMB0595)/misS(NMB0594) for regulator and sensor of the meningococcal inner
      core structure.

PMID- 15173179
TI  - Intimin types alpha, beta, and gamma bind to nucleolin with equivalent affinity
      but lower avidity than to the translocated intimin receptor.
AB  - The outer membrane adhesins of enteropathogenic Escherichia coli, Citrobacter
      rodentium, and enterohemorrhagic E. coli (EHEC) O157:H7 that mediate attach and
      efface intestinal lesions are classified as intimin alpha, beta, and gamma,
      respectively. Each of these intimin types binds to its cognate, bacterially
      encoded receptor (called Tir for translocated intimin receptor) to promote tight
      adherence of the organism to the host-cell plasma membrane. We previously
      reported that gamma intimin of EHEC O157:H7 also bound to a eucaryotic receptor
      that we determined was nucleolin. The objective of this study was to investigate
      in vitro and in vivo the interactions of intimins alpha, beta, and gamma with
      nucleolin in the presence of Tir from EHEC O157:H7. Protein binding experiments
      demonstrated that intimin of types alpha, beta, and gamma bound nucleolin with
      similar affinity. Moreover, all three intimin types co-localized with regions of
      nucleolin expressed on the surface of HEp-2 cells. When intimin alpha, beta, or
      gamma bound to Tir in vitro, the intimin interaction with nucleolin was blocked.
      Both Tir and nucleolin accumulated beneath intimin-presenting bacteria that had
      attached to the surface of HEp-2 cells. Taken together, these findings suggest
      that nucleolin is involved in bacterial adherence promoted by all intimin types
      and that Tir and nucleolin compete for intimin during adherence.

PMID- 15173180
TI  - Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor
      related apoptosis-inducing ligand receptor DR5 is regulated by the death effector
      domain of FADD.
AB  - Members of the tumor necrosis factor superfamily of receptors induce apoptosis by
      recruiting adaptor molecules through death domain interactions. The central
      adaptor molecule for these receptors is the death domain-containing protein Fas
      associated death domain (FADD). FADD binds a death domain on a receptor or
      additional adaptor and recruits caspases to the activated receptor. Tumor
      necrosis factor-related apoptosis-inducing ligand (TRAIL) signals apoptosis
      through two receptors, DR4 and DR5. Although there is much interest in TRAIL, the
      mechanism by which FADD is recruited to the TRAIL receptors is not clear. Using a
      reverse two-hybrid system we previously identified mutations in the death
      effector domain of FADD that prevented binding to Fas/CD95. Here we show that
      these mutations also prevent binding to DR5. FADD-deficient Jurkat cells stably
      expressing these FADD mutations did not transduce TRAIL or Fas/CD95 signaling.
      Second site compensating mutations that restore binding to and signaling through
      Fas/CD95 and DR5 were also in the death effector domain. We conclude that in
      contrast to current models where the death domain of FADD functions independently
      of the death effector domain, the death effector domain of FADD comes into direct
      contact with both TRAIL and Fas/CD95 receptors.

PMID- 15173181
TI  - Manganese induces the mitochondrial permeability transition in cultured
      astrocytes.
AB  - Manganese is known to cause central nervous system injury leading to parkinsonism
      and to contribute to the pathogenesis of hepatic encephalopathy. Although
      mechanisms of manganese neurotoxicity are not completely understood, chronic
      exposure of various cell types to manganese has shown oxidative stress and
      mitochondrial energy failure, factors that are often implicated in the induction
      of the mitochondrial permeability transition (MPT). In this study, we examined
      whether exposure of cultured neurons and astrocytes to manganese induces the MPT.
      Cells were treated with manganese acetate (10-100 microM), and the MPT was
      assessed by changes in the mitochondrial membrane potential and in mitochondrial
      calcein fluorescence. In astrocytes, manganese caused a dissipation of the
      mitochondrial membrane potential and decreased the mitochondrial calcein
      fluorescence in a concentration- and time-dependent manner. These changes were
      completely blocked by pretreatment with cyclosporin A, consistent with induction
      of the MPT. On the other hand, similarly treated cultured cortical neurons had a
      delayed or reduced MPT as compared with astrocytes. The manganese-induced MPT in
      astrocytes was blocked by pretreatment with antioxidants, suggesting the
      potential involvement of oxidative stress in this process. Induction of the MPT
      by manganese and associated mitochondrial dysfunction in astrocytes may represent
      key mechanisms in manganese neurotoxicity.

PMID- 15173182
TI  - TRPV1 acts as proton channel to induce acidification in nociceptive neurons.
AB  - The low extracellular pH of inflamed or ischemic tissues enhances painful
      sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We
      report here that activation of TRPV1 results in a marked intracellular
      acidification in nociceptive dorsal root ganglion neurons and in a heterologous
      expression system. A characterization of the underlying mechanisms revealed a
      Ca(2+)-dependent intracellular acidification operating at neutral pH and an
      additional as yet unrecognized direct proton conductance through the poorly
      selective TRPV1 pore operating in acidic extracellular media. Large organic
      cations permeate through the activated TRPV1 pore even in the presence of
      physiological concentrations of Na(+), Mg(2+), and Ca(2+). The wide pore and the
      unexpectedly high proton permeability of TRPV1 point to a proton hopping
      permeation mechanism along the water-filled channel pore. In acidic media, the
      high relative proton permeability through TRPV1 defines a novel proton entry
      mechanism in nociceptive neurons.

PMID- 15173183
TI  - Insertion of foreign T cell epitopes in human tumor necrosis factor alpha with
      minimal effect on protein structure and biological activity.
AB  - To create a human therapeutic vaccine able to circumvent self-tolerance against
      tumor necrosis factor (TNF) alpha, foreign T helper epitopes were inserted into
      human TNFalpha, with minimal effect on the native three-dimensional structure.
      TNFalpha variants were screened for solubility, structural stability, biological
      activity, and after immunization, for eliciting inhibitory antibodies. The
      longest and most flexible loop in TNFalpha, also designated loop 3, is the only
      region that is not involved in intra- or intermolecular interactions and
      therefore constitute an attractive insertion site. However, the extension of the
      flexible loop by epitope insertions destabilized the TNFalpha molecule.
      Therefore, two cysteines were introduced to form a stabilizing disulfide bond
      between loops 2 and 3. In a second design approach, three TNFalpha monomers were
      linked by two T cell epitopes and expressed as a single chain TNFalpha trimer.
      TNFalpha variants that were expressed as soluble proteins also had a conserved
      tertiary structure, as determined by circular dichroism. The biological activity
      of the TNFalpha variants was of the same magnitude as human TNFalpha in cellular
      assays. Introduction of three separate single-point mutations (D143N, A145R, or
      Y87S) diminished the cytotoxicity of the mutated variants 50-800-fold compared
      with native TNFalpha. Antisera from mice immunized with the different TNFalpha
      variants were able to cross-react with native human TNFalpha and to inhibit
      TNFalpha signaling via the TNF receptors in vitro, suggesting that the structural
      binding epitopes of native human TNFalpha and thus the native conformation were
      conserved in the constructed vaccine candidates.

PMID- 15173184
TI  - How a G protein binds a membrane.
AB  - Heterotrimeric G proteins interact with receptors and effectors at the membrane
      cytoplasm interface. Structures of soluble forms have not revealed how they
      interact with membranes. We have used electron crystallography to determine the
      structure in ice of a helical array of the photoreceptor G protein, transducin,
      bound to the surface of a tubular lipid bilayer. The protein binds to the
      membrane with a very small area of contact, restricted to two points, between the
      surface of the protein and the surface of the lipids. Fitting the x-ray structure
      into the membrane-bound structure reveals one membrane contact near the lipidated
      Ggamma C terminus and Galpha N terminus, and another near the Galpha C terminus.
      The narrowness of the tethers to the lipid bilayer provides flexibility for the
      protein to adopt multiple orientations on the membrane, and leaves most of the G
      protein surface area available for protein-protein interactions.

PMID- 15173185
TI  - Five genes involved in biosynthesis of the pyruvylated Galbeta1,3-epitope in
      Schizosaccharomyces pombe N-linked glycans.
AB  - The N-linked galactomannans of Schizosaccharomyces pombe have pyruvylated
      Galbeta1,3-(PvGal) caps on a portion of the Galalpha1,2-residues in their outer
      chains (Gemmill, T. R., and Trimble, R. B. (1998) Glycobiology 8, 1087-1095).
      PvGal biosynthesis was investigated by ethyl methanesulfonate mutagenesis of S.
      pombe, followed by the isolation of cells devoid of negatively charged N-glycans
      by Q-Sepharose exclusion and failure to bind human serum amyloid P component,
      which acts as a lectin for terminal PvGal residues. Mutant glycans were
      characterized by lectin binding, saccharide composition, exoglycosidase
      sensitivity, and NMR spectroscopy. Restoration of the cell surface negative
      charge by complementation with an S. pombe genomic library led to the
      identification of five genes involved in PvGal biosynthesis, which we designated
      pvg1-pvg5. Pvg1p may be a pyruvyltransferase, since NMR of pvg1(-) mutant N
      glycans revealed the absence of only the pyruvyl moiety. Pvg2p-Pvg5p are crucial
      for attachment of the Galbeta1,3-residue that becomes pyruvylated. Pvg3p is
      predicted to be a member of the beta1,3-galactosyltransferase family, and Pvg3p
      green fluorescent protein labeling was consistent with Golgi localization.
      Predicted Pvg1p and Pvg3p functions imply that Galbeta1,3-is added to the
      galactomannans and is then pyruvylated in situ, rather than by an en bloc
      addition of PvGalbeta1,3-caps to the outer chain. Pvg4p-green fluorescent protein
      targeted to the nucleus, and its sequence contains a MADS-box DNA-binding and
      dimerization domain; however, it does not appear to solely control transcription
      of the other identified genes. Pvg2p and/or Pvg5p may contribute to an enzyme
      complex. Whereas a functional role for the PvGal epitope in S. pombe remains
      unclear, it is nonessential for either cell growth or mating under laboratory
      conditions.

PMID- 15173186
TI  - Four N-linked glycosylation sites in human toll-like receptor 2 cooperate to
      direct efficient biosynthesis and secretion.
AB  - Most higher organisms have a system of innate immune defense that is mediated by
      a group of evolutionarily related, germ line-encoded receptors, so-called Toll
      like receptors. In mammals Toll-like receptors signal in response to pathogen
      associated microbial structures. For example, Toll-like receptor 2 appears to
      mediate responses to bacterial peptidoglycan and acylated lipoproteins and Toll
      like receptor 4 to bacterial lipopolysaccharide. However, the structural
      principles that underlie recognition of these structures are poorly understood.
      Toll-like receptors have leucine-rich repeats in their extracellular domains and
      are thus believed to adopt solenoid structures, similar to that found in platelet
      glycoprotein Ib. Additionally, all Toll-like receptors contain N-linked
      glycosylation consensus sites, and Toll-like receptor 4 requires glycosylation
      for function. Toll-like receptor glycosylation is also likely to influence
      receptor surface representation, trafficking, and pattern recognition. Using
      circular dichroism spectroscopy, we show here that purified human Toll-like
      receptor 2 and 4 proteins have secondary structure contents similar to
      glycoprotein Ib. We have also analyzed where consensus glycosylation sites are
      located in the extracellular domains of other human Toll-like receptors. We found
      that there are significant differences in the location and degree of conservation
      between sites in different Toll-like receptors. Using site-directed mutagenesis,
      we have found that in Toll-like receptor 2 extracellular domain all four
      predicted glycosylation sites are substituted, although one site is inefficiently
      core-glycosylated and its removal drastically affects secretion. The remaining
      Toll-like receptor 2 glycosylation sites also contribute to efficient protein
      secretion, albeit to a lesser degree.

PMID- 15173187
TI  - Tyrosine-phosphorylated SOCS3 interacts with the Nck and Crk-L adapter proteins
      and regulates Nck activation.
AB  - Suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of
      cytokine and growth factor signal transduction. Although the affect of SOCS
      proteins on the Jak-STAT pathway has been well characterized, their role in the
      regulation of other signaling modules is not well understood. In the present
      study, we demonstrate that SOCS3 physically interacts with the SH2/SH3-containing
      adapter proteins Nck and Crk-L, which are known to couple activated receptors to
      multiple downstream signaling pathways and the actin cytoskeleton. Our data show
      that the SOCS3/Nck and SOCS3/Crk-L interactions depend on tyrosine
      phosphorylation of SOCS3 Tyr(221) within the conserved SOCS box motif and intact
      SH2 domains of Nck and Crk-L. Furthermore, SOCS3 Tyr(221) forms a YXXP motif,
      which is a consensus binding site for the Nck and Crk-L SH2 domains. Expression
      of SOCS3 in NIH3T3 cells induces constitutive recruitment of a Nck-GFP fusion
      protein to the plasma membrane and constitutive tyrosine phosphorylation of
      endogenous Nck. Our findings suggest that SOCS3 regulates multiple cytokine and
      growth factor-activated signaling pathways by acting as a recruitment factor for
      adapter proteins.

PMID- 15173188
TI  - Trafficking of Lyn through the Golgi caveolin involves the charged residues on
      alphaE and alphaI helices in the kinase domain.
AB  - Src-family kinases, known to participate in signaling pathways of a variety of
      surface receptors, are localized to the cytoplasmic side of the plasma membrane
      through lipid modification. We show here that Lyn, a member of the Src-family
      kinases, is biosynthetically transported to the plasma membrane via the Golgi
      pool of caveolin along the secretory pathway. The trafficking of Lyn from the
      Golgi apparatus to the plasma membrane is inhibited by deletion of the kinase
      domain or Csk-induced "closed conformation" but not by kinase inactivation. Four
      residues (Asp346 and Glu353 on alphaE helix, and Asp498 and Asp499 on alphaI
      helix) present in the C-lobe of the kinase domain, which can be exposed to the
      molecular surface through an "open conformation," are identified as being
      involved in export of Lyn from the Golgi apparatus toward the plasma membrane but
      not targeting to the Golgi apparatus. Thus, the kinase domain of Lyn plays a role
      in Lyn trafficking besides catalysis of substrate phosphorylation.

PMID- 15173189
TI  - Bld10p, a novel protein essential for basal body assembly in Chlamydomonas:
      localization to the cartwheel, the first ninefold symmetrical structure appearing
      during assembly.
AB  - How centrioles and basal bodies assemble is a long-standing puzzle in cell
      biology. To address this problem, we analyzed a novel basal body-defective
      Chlamydomonas reinhardtii mutant isolated from a collection of flagella-less
      mutants. This mutant, bld10, displayed disorganized mitotic spindles and
      cytoplasmic microtubules, resulting in abnormal cell division and slow growth.
      Electron microscopic observation suggested that bld10 cells totally lack basal
      bodies. The product of the BLD10 gene (Bld10p) was found to be a novel coiled
      coil protein of 170 kD. Immunoelectron microscopy localizes Bld10p to the
      cartwheel, a structure with ninefold rotational symmetry positioned near the
      proximal end of the basal bodies. Because the cartwheel forms the base from which
      the triplet microtubules elongate, we suggest that Bld10p plays an essential role
      in an early stage of basal body assembly. A viable mutant having such a severe
      basal body defect emphasizes the usefulness of Chlamydomonas in studying the
      mechanism of basal body/centriole assembly by using a variety of mutants.

PMID- 15173190
TI  - Dynamics of putative raft-associated proteins at the cell surface.
AB  - Lipid rafts are conceptualized as membrane microdomains enriched in cholesterol
      and glycosphingolipid that serve as platforms for protein segregation and
      signaling. The properties of these domains in vivo are unclear. Here, we use
      fluorescence recovery after photobleaching to test if raft association affects a
      protein's ability to laterally diffuse large distances across the cell surface.
      The diffusion coefficients (D) of several types of putative raft and nonraft
      proteins were systematically measured under steady-state conditions and in
      response to raft perturbations. Raft proteins diffused freely over large
      distances (> 4 microm), exhibiting Ds that varied 10-fold. This finding indicates
      that raft proteins do not undergo long-range diffusion as part of discrete,
      stable raft domains. Perturbations reported to affect lipid rafts in model
      membrane systems or by biochemical fractionation (cholesterol depletion,
      decreased temperature, and cholesterol loading) had similar effects on the
      diffusional mobility of raft and nonraft proteins. Thus, raft association is not
      the dominant factor in determining long-range protein mobility at the cell
      surface.

PMID- 15173191
TI  - Ecdysone receptor directly binds the promoter of the Drosophila caspase dronc,
      regulating its expression in specific tissues.
AB  - The steroid hormone ecdysone regulates moulting, cell death, and differentiation
      during insect development. Ecdysone mediates its biological effects by either
      direct activation of gene transcription after binding to its receptor EcR-Usp or
      via hierarchical transcriptional regulation of several primary transcription
      factors. In turn, these transcription factors regulate the expression of several
      downstream genes responsible for specific biological outcomes. DRONC, the
      Drosophila initiator caspase, is transcriptionally regulated by ecdysone during
      development. We demonstrate here that the dronc promoter directly binds EcR-Usp.
      We further show that mutation of the EcR-Usp binding element (EcRBE) reduces
      transcription of a reporter and abolishes transactivation by an EcR isoform. We
      demonstrate that EcRBE is required for temporal regulation of dronc expression in
      response to ecdysone in specific tissues. We also uncover the participation of a
      putative repressor whose function appears to be coupled with EcR-Usp. These
      results indicate that direct binding of EcR-Usp is crucial for controlling the
      timing of dronc expression in specific tissues.

PMID- 15173192
TI  - Ionophore-resistant mutant of Toxoplasma gondii reveals involvement of a
      sodium/hydrogen exchanger in calcium regulation.
AB  - Calcium is a critical mediator of many intracellular processes in eukaryotic
      cells. In the obligate intracellular parasite Toxoplasma gondii, for example, a
      rise in [Ca2+] is associated with significant morphological changes and rapid
      egress from host cells. To understand the mechanisms behind such dramatic
      effects, we isolated a mutant that is altered in its responses to the Ca2+
      ionophore A23187 and found the affected gene encodes a homologue of Na+/H+
      exchangers (NHEs) located on the parasite's plasma membrane. We show that in the
      absence of TgNHE1, Toxoplasma is resistant to ionophore-induced egress and
      extracellular death and amiloride-induced proton efflux inhibition. In addition,
      the mutant has increased levels of intracellular Ca2+, which explains its
      decreased sensitivity to A23187. These results provide direct genetic evidence of
      a role for NHE1 in Ca2+ homeostasis and important insight into how this
      ubiquitous pathogen senses and responds to changes in its environment.

PMID- 15173194
TI  - Induction of CD44 and MMP expression by hyaluronidase treatment of articular
      chondrocytes.
AB  - In this study, the effects of fragmentation of the glycosoaminoglycans of the
      cell-associated matrix by hyaluronidase (HAase) on the expression of CD44
      receptor and matrix metalloproteinase (MMP) mRNAs in cultured articular
      chondrocytes were examined. Chondrocytes, isolated from rabbit and bovine
      articular cartilage, were treated with bovine testicular HAase (0-200 units/ml)
      in the presence or absence of an antibody for CD44. The mRNA levels of CD44, CD44
      variant (CD44v), MMPs (MMP-1, -3 and -9), and tissue inhibitors of
      metalloproteinases (TIMP-1 and TIMP-2) were determined by RT-PCR. The treatment
      of cultured chondrocytes with HAase resulted in the production of low molecular
      weight fragments of hyaluronan (HA). The expression of CD44, CD44v and MMP (MMP
      1, -3 and -9) mRNAs, but not TIMP-1 or TIMP-2 mRNA, was up-regulated in the
      cultures treated with HAase, whereas this expression was not affected by
      treatment with purified HA of 1.0 x 10(5) Da. Furthermore, the induction of CD44
      and MMPs on treatment with HAase was suppressed by an anti-CD44 antibody. The
      results suggest that the fragmentation of HA may lead to cartilage destruction in
      terms of the enhanced expression of MMPs as well as the upregulation of CD44.

PMID- 15173195
TI  - Preparation of recombinant alpha-thrombin: high-level expression of recombinant
      human prethrombin-2 and its activation by recombinant ecarin.
AB  - We have established a large-scale manufacturing system to produce recombinant
      human alpha-thrombin. In this system, a high yield of alpha-thrombin is prepared
      from prethrombin-2 activated by recombinant ecarin. We produced human prethrombin
      2 using mouse myeloma cells and an expression plasmid carrying the chicken beta
      actin promoter and mutant dihydrofolate reductase gene for gene amplification. To
      increase prethrombin-2 expression further, we performed fed-batch cultivation
      with the addition of vegetable peptone in 50 liters of suspension culture. After
      five feedings of vegetable peptone, the expression level of the recombinant
      prethrombin-2 reached 200 micro g/ml. Subsequently, the recombinant prethrombin-2
      could be activated to alpha-thrombin by recombinant ecarin expressed in a similar
      manner. Finally, recombinant alpha-thrombin was purified to homogeneity by
      affinity chromatography using a benzamidine-Sepharose gel. The yield from
      prethrombin-2 in culture medium was approximately 70%. The activity of the
      purified recombinant alpha-thrombin, including hydrolysis of a chromogenic
      substrate, release of fibrinopeptide A, and activation of protein C, was
      indistinguishable from that of plasma-derived alpha-thrombin. Our system is
      suitable for the large-scale production of recombinant alpha-thrombin, which can
      be used in place of clinically available alpha-thrombin derived from human or
      bovine plasma.

PMID- 15173193
TI  - Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to
      the centrosome in neuronal migration.
AB  - Humans with mutations in either DCX or LIS1 display nearly identical neuronal
      migration defects, known as lissencephaly. To define subcellular mechanisms, we
      have combined in vitro neuronal migration assays with retroviral transduction.
      Overexpression of wild-type Dcx or Lis1, but not patient-related mutant versions,
      increased migration rates. Dcx overexpression rescued the migration defect in
      Lis1+/- neurons. Lis1 localized predominantly to the centrosome, and after
      disruption of microtubules, redistributed to the perinuclear region. Dcx outlined
      microtubules extending from the perinuclear "cage" to the centrosome. Lis1+/-
      neurons displayed increased and more variable separation between the nucleus and
      the preceding centrosome during migration. Dynein inhibition resulted in similar
      defects in both nucleus-centrosome (N-C) coupling and neuronal migration. These N
      C coupling defects were rescued by Dcx overexpression, and Dcx was found to
      complex with dynein. These data indicate Lis1 and Dcx function with dynein to
      mediate N-C coupling during migration, and suggest defects in this coupling may
      contribute to migration defects in lissencephaly.

PMID- 15173196
TI  - Human annexin V binds to sulfatide: contribution to regulation of blood
      coagulation.
AB  - Annexin V is a calcium-dependent phospholipid-binding protein that exhibits
      anticoagulant activity on binding to phosphatidylserine exposed on the activated
      surfaces of endothelial cells and platelets, inhibiting activation of factor X
      and prothrombin in the blood coagulation cascade. Sulfatide (galactosylceramide
      I(3)-sulfate), one of the glycosphingolipids of the platelet cell membrane, is
      thought to be involved in blood coagulation systems via activation of factor XII.
      In this study, we examined whether or not annexin V binds to sulfatide and
      affects the coagulant activity of sulfatide. Solid phase assaying of annexin V
      revealed that it binds specifically to sulfatide, i.e. not to galactosylceramide
      or gangliosides, in the presence of calcium ions. Affinity analysis by means of
      surface plasmon resonance showed that the K(D) of the interaction between annexin
      V and sulfatide is 1.2 micro M. Kinetic turbidometric assaying of plasma
      coagulation initiated by CaCl(2) revealed that the coagulation rate in the
      presence of sulfatide or phosphatidylserine was decreased by annexin V. These
      results suggest that annexin V regulates coagulability in the blood stream by
      binding not only to phosphatidylserine but also to sulfatide.

PMID- 15173197
TI  - Effects of partial agonists and Mg2+ ions on the interaction of M2 muscarinic
      acetylcholine receptor and G protein Galpha i1 subunit in the M2-Galpha i1 fusion
      protein.
AB  - We have expressed a M(2)-Galpha(i1) fusion protein in insect cells, in which the
      G protein alpha(i1) subunit was fused with a mutant of the muscarinic receptor
      M(2) subtype without glycosylation sites and the central part of the third
      intracellular loop. The M(2)-Galpha(i1) fusion protein showed GTP-sensitive, high
      affinity agonist binding. Displacement curves by GDP of [(35)S]GTPgammaS binding
      shifted to the right in the presence of muscarinic agonists. The extent of the
      shift was greater for full agonists (120-150 fold) than for partial agonists (25
      35 fold), and virtually no shift was observed for antagonists. The affinity for
      GDP decreased with increasing MgCl(2) concentration in the presence of an agonist
      but was not affected by MgCl(2) in the presence of an antagonist. These results
      indicate that the apparent affinity for GDP of the M(2)-Galpha(i1) fusion protein
      bound to a ligand represents the efficacy of the given ligand, and that Mg(2+) is
      required for the agonist-bound M(2) to interact with Galpha(i1), reducing its
      affinity for GDP. We propose that the agonist-M(2)-Galpha(i1) complex represents
      the transition state for the GDP-GTP exchange reaction catalyzed by agonist-bound
      receptors, and that the complex has different affinities for GDP depending on the
      species of the ligand bound to M(2) receptors.

PMID- 15173198
TI  - The receptor-Galpha fusion protein as a tool for ligand screening: a model study
      using a nociceptin receptor-Galphai2 fusion protein.
AB  - As a model system to screen endogenous ligands for G(i)-coupled receptors, we
      have prepared and characterized a fusion protein of nociceptin receptor and alpha
      subunit of G(i2). We detected nociceptin binding to the fusion protein by
      measuring stimulation of [(35)S]GTPgammaS binding with an EC(50) of 2.0 nM and a
      gain of approximately five times. The stimulation by nociceptin of
      [(35)S]GTPgammaS binding to the fusion protein was clearly observed in the
      presence of an appropriate concentration of GDP, because the affinity for GDP was
      decreased in the presence of agonist. Full and partial agonists differed in their
      effects on apparent the affinity of the fusion protein for GDP: the IC(50) values
      for GDP to displace 100 pM [(35)S]GTPgammaS were estimated to be 2 micro M, 0.4
      micro M, and 0.05 micro M in the presence of full agonist (nociceptin), partial
      agonist (F/G-NC), and antagonist (NBZH), respectively. We also detected the
      activity to stimulate [(35)S]GTPgammaS binding to the fusion protein in the brain
      extract derived from 2-3 g wet weight tissue without false-positive results. The
      active component was identified as endogenous nociceptin itself. These results
      indicate that the fusion protein of GPCR and Galpha(i) is useful for screening of
      endogenous ligands.

PMID- 15173199
TI  - Stimulation of increases in intracellular calcium and prostaglandin E2 generation
      in Chinese hamster ovary cells expressing receptor-Galpha16 fusion proteins.
AB  - We examined whether fusion proteins of G protein-coupled receptors with the alpha
      subunit of G(16) (Galpha(16)) could activate downstream signals. We expressed
      fusion proteins of G(i)-coupled receptors, i.e. CX(3)C chemokine receptor 1
      (CX(3)CR1) and M(2) receptor, in Chinese hamster ovary cells. An agonist for
      CX(3)CR1 induced greater increases in intracellular Ca(2+) and prostaglandin E(2)
      generation in cells expressing CX(3)CR1-Galpha(16) fusion protein than in cells
      expressing CX(3)CR1 alone or both CX(3)CR1 and Galpha(16) separately. Similarly,
      agonist-induced prostaglandin E(2) generation was greater in cells expressing
      M(2)-Galpha(16) fusion protein than ones expressing M(2) alone or both M(2) and
      Galpha(16) separately. In cells expressing fusion proteins with Galpha(16) of
      G(q)-coupled receptors, i.e. urotensin II receptor and M(1) receptor, the
      relevant agonists induced similar increases in intracellular Ca(2+) and
      prostaglandin E(2) generation as in ones expressing the receptor alone. In cells
      expressing urotensin II receptor-Galpha(16) fusion protein, prostaglandin E(2)
      generation exhibited a lower EC(50) value than the intracellular Ca(2+) increase.
      These results indicate that agonist-stimulated receptor-Galpha(16) fusion
      proteins are coupled to downstream signaling pathways, and suggest that receptor
      Galpha(16) fusion proteins may be useful for screening for ligands of orphan G
      protein-coupled receptors and G(i)-coupled receptors.

PMID- 15173200
TI  - Expression and characterization of Saccharomyces cerevisiae Cne1p, a calnexin
      homologue.
AB  - The calnexin homologue (Cne1p) of Saccharomyces cerevisiae was expressed in
      Escherichia coli to evaluate its chaperone function. The chaperone function was
      examined as to the effects on the suppression of thermal denaturation and the
      enhancement of refolding, using citrate synthase (CS) as a nonspecific chaperone
      substrate. Cne1p effectively suppressed the thermal denaturation of CS and
      enhanced the refolding of thermally or chemically denatured CS in a concentration
      dependent manner. In addition, the chaperone function of Cne1p was greatly
      affected in the presence of monoglucosylated oligosaccharides (G1M9) that
      specifically bind to the lectin site. These results indicated that Cne1p
      functions as a molecular chaperone in Saccharomyces cerevisiae.

PMID- 15173201
TI  - Cloning and characterization of a novel Ca2+/calmodulin-dependent protein kinase
      I homologue in Xenopus laevis.
AB  - In order to investigate protein kinases expressed in the different developmental
      stages of Xenopus laevis, recently developed expression cloning was carried out.
      When two different expression libraries, Xenopus oocyte and Xenopus head
      (embryonic stage 28/30) cDNA libraries, were screened by kinase-specific
      monoclonal antibodies, cDNA clones for various known and novel protein
      serine/threonine kinases (Ser/Thr kinases) were isolated. In addition to well
      characterized Ser/Thr kinases, one cDNA clone for a putative kinase was isolated
      from the Xenopus head library. The sequence of the open reading frame of the cDNA
      encoded a protein of 337 amino acid residues with a predicted molecular weight of
      38,404. Since the deduced animo acid sequence of this protein was 75% identical
      to that of rat Ca(2+)/calmodulin-dependent protein kinase I (CaMKI), it was
      designated as CaMKIx. Although recombinant CaMKIx expressed in Escherichia coli
      showed no protein kinase activity against syntide-2, a synthetic peptide
      substrate, it was activated when phosphorylated by mouse Ca(2+)/calmodulin
      dependent protein kinase kinase alpha (CaMKKalpha). Activated CaMKIx
      significantly phosphorylated various proteins including synapsin I, histones, and
      myelin basic protein. CaMKIx could not be detected in the early stages of
      embryogenesis, but was detected in late embryos of stages 37/38 and thereafter
      when examined by Western blotting using a specific antibody. This kinase was
      found to be highly expressed in adult brain and heart, and an upstream kinase
      that could activate CaMKIx was detected in these tissues. These results suggest
      that CaMKIx plays some critical role in the late stages of embryogenesis of
      Xenopus laevis.

PMID- 15173202
TI  - Functional role of RhoA in growth regulation of primary hepatocytes.
AB  - The expression, activation and involvement in growth regulation of a small
      GTPase, RhoA, were examined in rat primary hepatocyte cultures. Hepatocytes
      freshly isolated from liver expressed RhoA protein at high levels. The total
      level of RhoA protein in the cells decreased markedly within a day in monolayer
      cultures. Thereafter, RhoA expression recovered as cell-cell attachment occurred
      during the culture. On the other hand, the level of the active form of RhoA
      decreased as the culture proceeded. Ca(2+) depletion in the medium to disrupt
      cadherin engagement triggered RhoA activation without de novo protein synthesis,
      indicating cadherin engagement regulates RhoA activation in hepatocytes.
      Hepatocyte growth stimulation by HGF was enhanced by Ca(2+) depletion or
      introduction of a constitutively active form of RhoA. The Clostridium botulinum
      C3 enzyme inhibited hepatocyte growth with stimulation by HGF. These results
      suggest that RhoA has a crucial role in hepatocyte growth control.

PMID- 15173203
TI  - A unique role of an amino terminal 16-residue region of long-type GATA-6.
AB  - Human GATA-6 mRNA utilizes two Met-codons in frame as translational initiation
      codons in cultured mammalian cells. An internal ribosome entry site (IRES) is not
      present in front of the coding region for short-type GATA-6. The 5'-upstream
      sequence with a short upstream open reading frame (uORF) did not affect the
      production of either long- or short-type GATA-6. Introduction of a canonical
      Kozak sequence around the upstream Met-codon resulted in predominant synthesis of
      long-type GATA-6, suggesting that the translation of short-type GATA-6 could be
      due to leaky scanning of the Met-codon by ribosomes. We found that at least the
      sequence comprising the 90th to 139th nucleotide bases from the first letter of
      the upstream Met-codon plays a positive role in the expression of long-type GATA
      6. This was confirmed by insertion of the corresponding sequence in frame at the
      site of deletion (the 38th to 304th nucleotide residues). However, insertion of
      the sequence comprising the 92nd to 141st bases did not suppress the negative
      effect of the deletion. These results suggest that the translation of this region
      (Glu-31-Cys-46) could be critical for the apparent production of long-type GATA
      6. We also demonstrated that long-type GATA-6 is potentially more active than the
      short-type.

PMID- 15173204
TI  - Targeting plasma cells in autoimmune diseases.
AB  - Antibodies specific for self-antigens mediate life-threatening pathology in
      several autoimmune diseases. Clearly the ability to target the plasma cells (PCs)
      producing the autoantibodies would be of great clinical benefit. Current
      immunosuppressive therapies are based on the premise that autoreactive PCs are
      short-lived and replenished from ongoing immune responses. However, recent
      results question this assumption and suggest that optimizing the treatment of
      severe autoimmune conditions will require a significant investment in elucidating
      the details of PC biology.

PMID- 15173205
TI  - Negative regulation of immunoglobulin E-dependent allergic responses by Lyn
      kinase.
AB  - A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent
      allergy has long been accepted. Contrary to this belief, Lyn kinase was found to
      have an important role as a negative regulator of the allergic response. This
      became apparent from the hyperresponsive degranulation of lyn-/- bone marrow
      derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs,
      in part, through the loss of negative regulation by COOH-terminal Src kinase
      (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in
      vivo as young lyn-/- mice showed an enhanced anaphylactic response. In vivo
      studies also demonstrated that as lyn-/- mice aged, their serum IgE increased as
      well as occupancy of the high affinity IgE receptor (FcepsilonRI). This was
      mirrored by increased circulating histamine, increased mast cell numbers,
      increased cell surface expression of the high affinity IgE receptor
      (FcepsilonRI), and eosinophilia. The increased IgE production was not a
      consequence of increased Fyn kinase activity in lyn-/- mice because both lyn-/-
      and lyn-/- fyn-/- mice showed high IgE levels. Thus, lyn-/- mice and mast cells
      thereof show multiple allergy-associated traits, causing reconsideration of the
      possible efficacy in therapeutic targeting of Lyn in allergic disease.

PMID- 15173206
TI  - Short-lived plasmablasts and long-lived plasma cells contribute to chronic
      humoral autoimmunity in NZB/W mice.
AB  - The current view holds that chronic autoimmune diseases are driven by the
      continuous activation of autoreactive B and T lymphocytes. However, despite the
      use of potent immunosuppressive drugs designed to interfere with this activation
      the production of autoantibodies often persists and contributes to progression of
      the immunopathology. In the present study, we analyzed the life span of
      (auto)antibody-secreting cells in the spleens of NZB x NZW F1 (NZB/W) mice, a
      murine model of systemic lupus erythematosus. The number of splenic ASCs
      increased in mice aged 1-5 mo and became stable thereafter. Less than 60% of the
      splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40%
      were nondividing, long-lived plasma cells with a half-life of >6 mo. In NZB/W
      mice and D42 Ig heavy chain knock-in mice, a fraction of DNA-specific plasma
      cells were also long-lived. Although antiproliferative immunosuppressive therapy
      depleted short-lived plasmablasts, long-lived plasma cells survived and continued
      to produce (auto)antibodies. Thus, long-lived, autoreactive plasma cells are a
      relevant target for researchers aiming to develop curative therapies for
      autoimmune diseases.

PMID- 15173207
TI  - Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with
      metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells.
AB  - Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to
      reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T
      cells able to control tumor relapse. We have shown earlier, in 18 human
      histocompatibility leukocyte antigen (HLA)-A*0201 patients with metastatic
      melanoma, that vaccination with peptide-loaded CD34-dendritic cells (DCs) leads
      to expansion of melanoma-specific interferon gamma-producing CD8+ T cells in the
      blood. Here, we show in 9 out of 12 analyzed patients the expansion of cytolytic
      CD8+ T cell precursors specific for melanoma differentiation antigens. These
      precursors yield, upon single restimulation with melanoma peptide-pulsed DCs,
      cytotoxic T lymphocytes (CTLs) able to kill melanoma cells. Melanoma-specific
      CTLs can be grown in vitro and can be detected in three assays: (a) melanoma
      tetramer binding, (b) killing of melanoma peptide-pulsed T2 cells, and (c)
      killing of HLA-A*0201 melanoma cells. The cytolytic activity of expanded CTLs
      correlates with the frequency of melanoma tetramer binding CD8+ T cells. Thus,
      CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill
      melanoma antigen-expressing targets. These results justify the design of larger
      follow-up studies to assess the immunological and clinical response to peptide
      pulsed CD34-DC vaccines.

PMID- 15173208
TI  - Immune responses in healthy and allergic individuals are characterized by a fine
      balance between allergen-specific T regulatory 1 and T helper 2 cells.
AB  - The mechanisms by which immune responses to nonpathogenic environmental antigens
      lead to either allergy or nonharmful immunity are unknown. Single allergen
      specific T cells constitute a very small fraction of the whole CD4+ T cell
      repertoire and can be isolated from the peripheral blood of humans according to
      their cytokine profile. Freshly purified interferon-gamma-, interleukin (IL)-4-,
      and IL-10-producing allergen-specific CD4+ T cells display characteristics of T
      helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. Tr1
      cells consistently represent the dominant subset specific for common
      environmental allergens in healthy individuals; in contrast, there is a high
      frequency of allergen-specific IL-4-secreting T cells in allergic individuals.
      Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-beta as secreted
      cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface
      molecules. Healthy and allergic individuals exhibit all three allergen-specific
      subsets in different proportions, indicating that a change in the dominant subset
      may lead to allergy development or recovery. Accordingly, blocking the suppressor
      activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific
      Th2 cell activation ex vivo. These results indicate that the balance between
      allergen-specific Tr1 cells and Th2 cells may be decisive in the development of
      allergy.

PMID- 15173209
TI  - Surface mu heavy chain signals down-regulation of the V(D)J-recombinase machinery
      in the absence of surrogate light chain components.
AB  - Early B cell development is characterized by stepwise, ordered rearrangement of
      the immunoglobulin (Ig) heavy (HC) and light (LC) chain genes. Only one of the
      two alleles of these genes is used to produce a receptor, a phenomenon referred
      to as allelic exclusion. It has been suggested that pre-B cell receptor (pre-BCR)
      signals are responsible for down-regulation of the VDJH-recombinase machinery
      (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing
      further rearrangement on the second HC allele. Using a mouse model, we show that
      expression of an inducible muHC transgene in Rag2-/- pro-B cells induces down
      regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent
      protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary
      transcripts. Similar effects were also observed in the absence of surrogate LC
      (SLC) components, but not in the absence of the signaling subunit Ig-alpha.
      Furthermore, in wild-type mice and in mice lacking either lambda5, VpreB1/2, or
      the entire SLC, the TdT protein is down-regulated in muHC+LC- pre-B cells.
      Surprisingly, muHC without LC is expressed on the surface of pro-/pre-B cells
      from lambda5-/-, VpreB1-/-VpreB2-/-, and SLC-/- mice. Thus, SLC or LC is not
      required for muHC cell surface expression and signaling in these cells.
      Therefore, these findings offer an explanation for the occurrence of HC allelic
      exclusion in mice lacking SLC components.

PMID- 15173210
TI  - The use and development of germline polymorphisms in clinical oncology.

PMID- 15173211
TI  - Monoclonal antibody therapy for prostate cancer: finally a reality?

PMID- 15173212
TI  - An ounce of prevention or a pound of cure? Investing to improve breast cancer
      outcomes for African American women.

PMID- 15173213
TI  - Benefits and costs of interventions to improve breast cancer outcomes in African
      American women.
AB  - PURPOSE: Historically, African American women have experienced higher breast
      cancer mortality than white women, despite lower incidence. Our objective was to
      evaluate whether costs of increasing rates of screening or application of
      intensive treatment will be off-set by survival benefits for African American
      women. METHODS: We use a stochastic simulation model of the natural history of
      breast cancer to evaluate the incremental societal costs and benefits of status
      quo versus targeted biennial screening or treatment improvements among African
      Americans 40 years of age and older. Main outcome measures were number of
      mammograms, stage, all-cause mortality, and discounted costs per life year saved
      (LYS). RESULTS: At the current screening rate of 76%, there is little incremental
      benefit associated with further increasing screening, and the costs are high:
      124,053 US dollars and 124,217 US dollars per LYS for lay health worker and
      patient reminder interventions, respectively, compared with the status quo. Using
      reminders would cost 51,537 US dollars per LYS if targeted to virtually
      unscreened women or 78,130 US dollars per LYS if targeted to women with a two
      fold increase in baseline risk. If all patients received the most intensive
      treatment recommended, costs increase but deaths decrease, for a cost of 52,678
      US dollars per LYS. Investments of up to 6,000 US dollars per breast cancer
      patient could be used to enhance treatment and still yield cost-effectiveness
      ratios of less than 75,000 US dollars per LYS. CONCLUSION: Except in pockets of
      unscreened or high-risk women, further investments in interventions to increase
      screening are unlikely to be an efficient use of resources. Ensuring that African
      American women receive intensive treatment seems to be the most cost-effective
      approach to decreasing the disproportionate mortality experienced by this
      population.

PMID- 15173214
TI  - XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small
      cell lung cancer patients treated with platinum chemotherapy.
AB  - PURPOSE: Platinum agents cause DNA cross-linking and oxidative damage. Genetic
      polymorphisms of DNA repair genes are associated with differential DNA repair
      activity and may explain interindividual differences in overall survival after
      therapy with platinum agents for non-small-cell lung cancer (NSCLC). METHODS: We
      used polymerase chain reaction-restriction fragment length polymorphism to
      evaluate genetic polymorphisms of the XPD (Asp312Asn) and XRCC1 (Arg399Gln) DNA
      repair genes in 103 patients with stage III (54%) and IV (46%) NSCLC treated with
      platinum-based chemotherapy. RESULTS: Median age was 58 years (range, 32 to 77
      years), 49% were females, and there were 86 deaths. Median follow-up period was
      61.9 months. Median survival time (MST) was 14.9 months; by stage, MST was 28.6
      months (IIIA), 16.0 months (IIIB), and 9.3 months (IV). Genotypes were not
      associated with stage. Increasing numbers of either XPD or XRCC1 variant alleles
      were associated with shorter overall survival (P =.003 and P =.07, respectively,
      by log-rank test). Similarly, when we compared combinations of variant alleles
      across both polymorphisms, we found that a greater number of variant alleles was
      associated with decreasing overall survival (P =.009, log-rank test). These
      polymorphisms independently predicted overall survival even after taking into
      account stage, performance status, and chemotherapy regimen. CONCLUSION: Genetic
      polymorphisms in XPD and XRCC1 may be important prognostic factors in platinum
      treated patients with advanced NSCLC.

PMID- 15173215
TI  - Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen
      monoclonal antibody J591 for androgen-independent prostate cancer.
AB  - PURPOSE: To determine the maximum-tolerated dose (MTD), toxicity, human antihuman
      antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and
      preliminary efficacy of yttrium-90-labeled anti-prostate-specific membrane
      antigen monoclonal antibody J591 ((90)Y-J591) in patients with androgen
      independent prostate cancer (PC). PATIENTS AND METHODS: Patients with androgen
      independent PC and evidence of disease progression received indium-111-J591 for
      pharmacokinetic and biodistribution determinations followed 1 week later by (90)Y
      J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m(2). Patients were
      eligible for up to three re-treatments if platelet and neutrophil recovery was
      satisfactory. RESULTS: Twenty-nine patients with androgen-independent PC received
      (90)Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen
      at 20 mCi/m(2), with two patients experiencing thrombocytopenia with non-life
      threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m(2)
      dose level was determined to be the MTD. No re-treated patients experienced DLT.
      Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone
      and soft tissue metastases was seen in the majority of patients. No HAHA response
      was seen. Antitumor activity was seen, with two patients experiencing 85% and 70%
      declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months,
      respectively, before returning to baseline. Both patients had objective
      measurable disease responses. An additional six patients (21%) experienced PSA
      stabilization. CONCLUSION: The recommended dose for (90)Y-J591 is 17.5 mCi/m(2).
      Acceptable toxicity, excellent targeting of known sites of PC metastases, and
      biologic activity in patients with androgen-independent PC warrant further
      investigation of (90)Y-J591 in the treatment of patients with PC.

PMID- 15173217
TI  - The early history of the biochemistry of muscle contraction.

PMID- 15173218
TI  - The sliding filament model: 1972-2004.

PMID- 15173219
TI  - Why biophysicists make models: quantifying modulation of the M current.

PMID- 15173221
TI  - Recoverin regulates light-dependent phosphodiesterase activity in retinal rods.
AB  - The Ca2+-binding protein recoverin may regulate visual transduction in retinal
      rods and cones, but its functional role and mechanism of action remain
      controversial. We compared the photoresponses of rods from control mice and from
      mice in which the recoverin gene was knocked out. Our analysis indicates that
      Ca2+-recoverin prolongs the dark-adapted flash response and increases the rod's
      sensitivity to dim steady light. Knockout rods had faster Ca2+ dynamics,
      indicating that recoverin is a significant Ca2+ buffer in the outer segment, but
      incorporation of exogenous buffer did not restore wild-type behavior. We infer
      that Ca2+-recoverin potentiates light-triggered phosphodiesterase activity,
      probably by effectively prolonging the catalytic activity of photoexcited
      rhodopsin.

PMID- 15173220
TI  - Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor
      mediated signaling by Gq.
AB  - Receptor-mediated modulation of KCNQ channels regulates neuronal excitability.
      This study concerns the kinetics and mechanism of M1 muscarinic receptor-mediated
      regulation of the cloned neuronal M channel, KCNQ2/KCNQ3 (Kv7.2/Kv7.3).
      Receptors, channels, various mutated G-protein subunits, and an optical probe for
      phosphatidylinositol 4,5-bisphosphate (PIP2) were coexpressed by transfection in
      tsA-201 cells, and the cells were studied by whole-cell patch clamp and by
      confocal microscopy. Constitutively active forms of Galphaq and Galpha11, but not
      Galpha13, caused a loss of the plasma membrane PIP2 and a total tonic inhibition
      of the KCNQ current. There were no further changes upon addition of the
      muscarinic agonist oxotremorine-M (oxo-M). Expression of the regulator of G
      protein signaling, RGS2, blocked PIP2 hydrolysis and current suppression by
      muscarinic stimulation, confirming that the Gq family of G-proteins is necessary.
      Dialysis with the competitive inhibitor GDPbetaS (1 mM) lengthened the time
      constant of inhibition sixfold, decreased the suppression of current, and
      decreased agonist sensitivity. Removal of intracellular Mg2+ slowed both the
      development and the recovery from muscarinic suppression. When combined with
      GDPbetaS, low intracellular Mg2+ nearly eliminated muscarinic inhibition. With
      nonhydrolyzable GTP analogs, current suppression developed spontaneously and
      muscarinic inhibition was enhanced. Such spontaneous suppression was antagonized
      by GDPbetaS or GTP or by expression of RGS2. These observations were successfully
      described by a kinetic model representing biochemical steps of the signaling
      cascade using published rate constants where available. The model supports the
      following sequence of events for this Gq-coupled signaling: A classical G-protein
      cycle, including competition for nucleotide-free G-protein by all nucleotide
      forms and an activation step requiring Mg2+, followed by G-protein-stimulated
      phospholipase C and hydrolysis of PIP2, and finally PIP2 dissociation from
      binding sites for inositol lipid on the channels so that KCNQ current was
      suppressed. Further experiments will be needed to refine some untested
      assumptions.

PMID- 15173222
TI  - Antagonistic regulation of native Ca2+- and ATP-sensitive cation channels in
      brain capillaries by nucleotides and decavanadate.
AB  - Regulation by cytosolic nucleotides of Ca2+- and ATP-sensitive nonselective
      cation channels (CA-NSCs) in rat brain capillary endothelial cells was studied in
      excised inside-out patches. Open probability (Po) was suppressed by cytosolic
      nucleotides with apparent KI values of 17, 9, and 2 microM for ATP, ADP, and AMP,
      as a consequence of high-affinity inhibition of channel opening rate and low
      affinity stimulation of closing rate. Cytosolic [Ca2+] and voltage affected
      inhibition of Po, but not of opening rate, by ATP, suggesting that the
      conformation of the nucleotide binding site is influenced only by the state of
      the channel gate, not by that of the Ca2+ and voltage sensors. ATP inhibition was
      unaltered by channel rundown. Nucleotide structure affected inhibitory potency
      that was little sensitive to base substitutions, but was greatly diminished by 3'
      5' cyclization, removal of all phosphates, or complete omission of the base. In
      contrast, decavanadate potently (K1/2 = 90 nM) and robustly stimulated Po, and
      functionally competed with inhibitory nucleotides. From kinetic analyses we
      conclude that (a) ATP, ADP, and AMP bind to a common site; (b) inhibition by
      nucleotides occurs through simple reversible binding, as a consequence of tighter
      binding to the closed-channel relative to the open-channel conformation; (c) the
      conformation of the nucleotide binding site is not directly modulated by Ca2+ and
      voltage; (d) the differences in inhibitory potency of ATP, ADP, and AMP reflect
      their different affinities for the closed channel; and (e) though decavanadate is
      the only example found to date of a compound that stimulates Po with high
      affinity even in the presence of millimolar nucleotides, apparently by competing
      for the nucleotide binding site, a comparable mechanism might allow CA-NSC
      channels to open in living cells despite physiological levels of nucleotides.
      Decavanadate now provides a valuable tool for studying native CA-NSC channels and
      for screening cloned channels.

PMID- 15173223
TI  - DFNA5: hearing impairment exon instead of hearing impairment gene?
AB  - BACKGROUND: Three mutations in the DFNA5 gene have been described in three
      families with autosomal dominant non-syndromic hearing impairment. Although these
      mutations are different at the genomic DNA level, they all lead to skipping of
      exon 8 at the mRNA level. We hypothesise that hearing impairment associated with
      DFNA5 is caused by a highly unusual mechanism, in which skipping of one specific
      exon leads to disease that is not caused by other mutations in this gene. We
      hypothesise that this represents a very specific "gain of function" mutation,
      with the truncated protein exerting a deleterious new function. METHODS: We
      performed transfection experiments in mammalian cell lines (HEK293T and COS-1)
      with green fluorescent protein (GFP) tagged wildtype and mutant DFNA5 and
      analysed cell death with flow cytometry and fluorescence microscopy. RESULTS:
      Post-transfection death of HEK293T cells approximately doubled when cells were
      transfected with mutant DFNA5-GFP compared with wildtype DFNA5-GFP. Cell death
      was attributed to necrotic events and not to apoptotic events. CONCLUSION: The
      transfection experiments in mammalian cell lines support our hypothesis that the
      hearing impairment associated with DFNA5 is caused by a "gain of function"
      mutation and that mutant DFNA5 has a deleterious new function.

PMID- 15173224
TI  - Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary
      thyroid cancer.
AB  - BACKGROUND: Familial non-medullary thyroid cancer (fNMTC) is a complex genetic
      disorder that is more aggressive than its sporadic counterpart. Thus far, three
      genetic loci have been implicated in susceptibility to fNMTC by linkage analysis.
      METHODS: We used linkage analysis to test the significance of two of the known
      susceptibility loci for fNMTC, TCO on 19p13 and NMTC1 on 2q21 in 10 fNMTC
      families, nine of which present with cell oxyphilia, a rare histological
      phenotype associated with TCO. Furthermore, we used two-locus linkage analysis to
      examine the possibility that the TCO and NMTC1 loci interact to increase the risk
      of NMTC. RESULTS: The 10 families provided evidence for linkage at both TCO and
      NMTC, with LOD scores of 1.56 and 2.85, respectively. Two-locus linkage analysis,
      using a multiplicative risk model for the development of NMTC, achieved a maximum
      LOD of 3.92, with an LOD of 4.51 when assuming 70% of families were linked,
      indicating that the segregation in these families is consistent with an
      interaction model. Most of this evidence came from a large Tyrolean family that
      singularly achieved a two-locus LOD of 3.21. CONCLUSIONS: These results provide
      further evidence that susceptibility genes for fNMTC exist at 19p13 and 2q21, and
      furthermore, raise the possibility that in a subset of fNMTC pedigrees, these
      loci interact resulting in significantly increased risk of NMTC for patients that
      carry both susceptibility loci.

PMID- 15173225
TI  - Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers
      leading to the human 22q11.2 deletion.
AB  - BACKGROUND: Analyses of the replication timing at 22q11.2 were prompted by our
      finding of a statistically significant bias in the origin of the regions flanking
      the deletion site in patients with 22q11.2 deletions, the proximal region being
      in the majority of cases of grandmaternal origin. We hypothesised that
      asynchronous replication may be involved in the formation of the 22q11.2
      deletion, the most frequently occurring interstitial deletion in humans, by
      favouring the mispairing of low-copy repeats. METHODS: Replication timing during
      S phase at 22q11.2 was investigated by fluorescent in situ hybridisation on
      interphase nuclei. We report on the detection of non-random asynchronous
      replication at the human chromosome region 22q11.2, an autosomal locus believed
      not to contain imprinted genes. RESULTS: Asynchronous replication at 22q11.2 was
      observed without exception in all 20 tested individuals; these comprised
      individuals with structurally normal chromosomes 22 (10 cases), individuals with
      translocations involving the locus 22q11.2 (eight cases), and patients with a
      22q11.2 deletion (two cases). The non-random nature of the asynchronous
      replication was observed in all individuals for whom the chromosomes 22 were
      distinguishable. The earlier replicating allele was found to be of paternal
      origin in all cases where the parental origin of the translocation or deletion
      was known.

PMID- 15173226
TI  - Prospective risk of cancer in CDKN2A germline mutation carriers.
AB  - BACKGROUND: The CDKN2A gene is the major known high-risk melanoma susceptibility
      gene. Susceptibility to other cancers has also been suggested. However, most
      studies examining the risks of other cancers classified individuals according to
      the family's CDKN2A mutation rather than determining individual mutation status.
      For non-population-based studies, risks could also be biased because of cancer
      occurrence prior to family ascertainment. METHODS: We examined the risk of non
      melanoma cancer in 117 mutation-positive and 136 mutation-negative members from
      15 families that had at least two first degree relatives with melanoma and CDKN2A
      mutations restricting the analysis to the period after the families were
      ascertained (that is, the prospective period) and using individual mutation data.
      The families have been followed prospectively for 4-26 years starting in the
      1970s. RESULTS: Overall, there was no significant association for mutation
      negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2)
      although this group had only two observed cancers. In contrast, mutation-positive
      subjects had a significantly increased risk for all cancers combined (Obs/Exp =
      12/5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours,
      particularly pancreatic cancer. No other organ systems or individual tumour sites
      showed significantly increased risks. CONCLUSIONS: Differences in CDKN2A-non
      melanoma cancer associations across studies may result from variation in genetic
      backgrounds, insufficient follow up, misclassification of mutation carriers, or
      the presence of other genetic and/or environmental risk factors in both CDKN2A
      mutation carriers and non-carriers. Larger sample sizes, prospective follow up,
      and individual mutation data will be required to understand these differences.

PMID- 15173227
TI  - High resolution profiling of X chromosomal aberrations by array comparative
      genomic hybridisation.

PMID- 15173228
TI  - Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum
      deletion intervals for key phenotypes.

PMID- 15173229
TI  - Familial X/Y translocations associated with variable sexual phenotype.

PMID- 15173230
TI  - Estimating the age of rare disease mutations: the example of Triple-A syndrome.

PMID- 15173231
TI  - A fifth locus for otosclerosis, OTSC5, maps to chromosome 3q22-24.

PMID- 15173232
TI  - 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C mutations
      are associated with DNA hypomethylation.

PMID- 15173233
TI  - Genetic analysis of PSORS2 markers in a UK dataset supports the association
      between RAPTOR SNPs and familial psoriasis.

PMID- 15173234
TI  - Systematic micro-array based identification of placental mRNA in maternal plasma:
      towards non-invasive prenatal gene expression profiling.

PMID- 15173235
TI  - An autosomal recessive cone-rod dystrophy associated with amelogenesis
      imperfecta.

PMID- 15173236
TI  - A new scoring system for the chances of identifying a BRCA1/2 mutation
      outperforms existing models including BRCAPRO.
AB  - PURPOSE: To develop a simple scoring system for the likelihood of identifying a
      BRCA1 or BRCA2 mutation. METHODS: DNA samples from affected subjects from 422 non
      Jewish families with a history of breast and/or ovarian cancer were screened for
      BRCA1 mutations and a subset of 318 was screened for BRCA2 by whole gene
      screening techniques. Using a combination of results from screening and the
      family history of mutation negative and positive kindreds, a simple scoring
      system (Manchester scoring system) was devised to predict pathogenic mutations
      and particularly to discriminate at the 10% likelihood level. A second separate
      dataset of 192 samples was subsequently used to test the model's predictive
      value. This was further validated on a third set of 258 samples and compared
      against existing models. RESULTS: The scoring system includes a cut-off at 10
      points for each gene. This equates to >10% probability of a pathogenic mutation
      in BRCA1 and BRCA2 individually. The Manchester scoring system had the best trade
      off between sensitivity and specificity at 10% prediction for the presence of
      mutations as shown by its highest C-statistic and was far superior to BRCAPRO.
      CONCLUSION: The scoring system is useful in identifying mutations particularly in
      BRCA2. The algorithm may need modifying to include pathological data when
      calculating whether to screen for BRCA1 mutations. It is considerably less time
      consuming for clinicians than using computer models and if implemented routinely
      in clinical practice will aid in selecting families most suitable for DNA
      sampling for diagnostic testing.

PMID- 15173237
TI  - Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a
      6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia.

PMID- 15173238
TI  - Site directed mutagenesis of hMLH1 exonic splicing enhancers does not correlate
      with splicing disruption.

PMID- 15173239
TI  - A mitochondrial DNA duplication as a marker of skeletal muscle specific mutations
      in the mitochondrial genome.

PMID- 15173240
TI  - Haplotype analysis of human AMPD1 gene: origin of common mutant allele.

PMID- 15173241
TI  - Spontaneous recovery of a childhood onset mitochondrial myopathy caused by a stop
      mutation in the mitochondrial cytochrome c oxidase III gene.

PMID- 15173242
TI  - Genetic influences on the circulating cytokines involved in osteoclastogenesis.

PMID- 15173243
TI  - A novel form of syndromic cutis laxa with facial dysmorphism, cleft palate, and
      mental retardation.

PMID- 15173244
TI  - Angel shaped phalangeal dysplasia, hip dysplasia, and positional teeth
      abnormalities are part of the brachydactyly C spectrum associated with CDMP-1
      mutations.

PMID- 15173245
TI  - Evidence of differing genotypic effects of PPARalpha in women and men.

PMID- 15173246
TI  - Y-linked inheritance of non-syndromic hearing impairment in a large Chinese
      family.

PMID- 15173247
TI  - Case report: a subject with a mutation in the ATG start codon of L-ferritin has
      no haematological or neurological symptoms.

PMID- 15173248
TI  - Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Ca(v)2.1
      causing episodic ataxia 2.

PMID- 15173249
TI  - A novel point mutation A170P in the SHOX gene defines impaired nuclear
      translocation as a molecular cause for Leri-Weill dyschondrosteosis and Langer
      dysplasia.

PMID- 15173250
TI  - Complement factor I: a susceptibility gene for atypical haemolytic uraemic
      syndrome.

PMID- 15173251
TI  - Screening of MECP2 coding sequence in patients with phenotypes of decreasing
      likelihood for Rett syndrome: a cohort of 171 cases.

PMID- 15173252
TI  - P gene mutations in patients with oculocutaneous albinism and findings suggestive
      of Hermansky-Pudlak syndrome.

PMID- 15173253
TI  - Broader geographical spectrum of Cohen syndrome due to COH1 mutations.

PMID- 15173254
TI  - A germline mutation in KIT in familial diffuse cutaneous mastocytosis.

PMID- 15173255
TI  - Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3
      and HPP1, contribute to genetic predisposition in German gastric cancer patients.

PMID- 15173256
TI  - Are women more susceptible to lung cancer?

PMID- 15173257
TI  - Improved biomarkers for prostate cancer: a definite need.

PMID- 15173258
TI  - Debate rages over proteomic patterns.

PMID- 15173259
TI  - Proteomics: from signature to protein identification.

PMID- 15173260
TI  - Stat bite: Lifetime probability among females of dying of cancer.

PMID- 15173261
TI  - Panel's recommendations urge 'sufficient public transparency' in outside
      activities.

PMID- 15173263
TI  - Dietary prevention of cancer: a smorgasbord of options for moving ahead.

PMID- 15173262
TI  - New gene discoveries may boost DNA stool testing for colorectal cancer.

PMID- 15173264
TI  - A full plate for future investigation in the diet-cancer connection.

PMID- 15173266
TI  - Lung cancer rates in men and women with comparable histories of smoking.
AB  - BACKGROUND: Recent case-control studies suggest that, given equal smoking
      exposure, women may have a higher relative risk of developing lung cancer than
      men. Despite prospective data that conflict with this hypothesis, mechanistic
      studies to find a biologic basis for a sex difference continue. METHODS: We
      addressed the hypothesis directly by analyzing prospective data from former and
      current smokers in two large cohorts--the Nurses' Health Study of women and the
      Health Professionals Follow-up Study of men. We calculated incidence rates and
      hazard ratios of lung cancer in women compared with men, adjusting for age,
      number of cigarettes smoked per day, age at start of smoking, and time since
      quitting, using Cox proportional hazards models. We also reviewed published
      results from prospective analyses. RESULTS: From 1986 through 2000, 955 and 311
      primary lung cancers were identified among 60 296 women and 25 397 men,
      respectively, who ranged in age from 40 to 79 years. Incidence rates per 100 000
      person-years for women and men were 253 and 232, respectively, among current
      smokers and 81 and 73, respectively, among former smokers. The hazard ratio in
      women ever smokers compared with men was 1.11 (95% confidence interval = 0.95 to
      1.31). Six published prospective cohort studies allowed assessment of comparative
      susceptibility to lung cancer by sex. None supported an excess risk of lung
      cancer for women. CONCLUSIONS: Women do not appear to have a greater
      susceptibility to lung cancer than men, given equal smoking exposure. Research
      should be focused on enhancing preventive interventions for all.

PMID- 15173267
TI  - Humoral immune response to alpha-methylacyl-CoA racemase and prostate cancer.
AB  - BACKGROUND: Although prostate-specific antigen (PSA) is a prototypic biomarker
      for prostate cancer, it has poor specificity. Expression of alpha-methylacyl-CoA
      racemase (AMACR), which is involved in the conversion of R-stereoisomers of
      branched-chain fatty acids to S-stereoisomers, has been shown to be specifically
      increased in prostate cancer epithelia. However, attempts to detect AMACR in
      circulation have not been successful. Hence, we determined whether an immune
      response to AMACR could be used as a serum biomarker for prostate cancer.
      METHODS: Sera from patients with biopsy-proven prostate cancer and from control
      subjects were screened for a humoral immune response to selected tumor antigens,
      including AMACR, by using protein microarrays (46 patients, 28 control subjects).
      Humoral immune response to AMACR was then validated using high-throughput
      immunoblot analysis (151 patients, 259 control subjects) and enzyme-linked
      immunosorbent assay (ELISA) (54 patients, 55 control subjects). Receiver
      operating characteristic curves were used to determine the sensitivity and
      specificity of the immune response to AMACR to detect prostate cancer. RESULTS:
      Immunoreactivity against AMACR was statistically significantly higher in sera
      from patients with prostate cancer than in control subjects by all three
      techniques (P(protein microarray) =.009, P(immunoblot)<.001, P(ELISA) =.011).
      High-throughput immunoblot analysis revealed that, in subjects with intermediate
      PSA levels (4-10 ng/mL), the immune response against AMACR was more sensitive and
      specific than was PSA in distinguishing sera from prostate cancer patients
      relative to control subjects (sensitivity and specificity of 77.8% and 80.6%
      versus 45.6% and 50%, respectively; area under the curve of 0.789 versus 0.492;
      P<.001). CONCLUSION: Assays to detect a humoral immune response against AMACR may
      have the potential to supplement PSA screening in identifying patients with
      clinically significant prostate cancer, especially those with intermediate PSA
      levels.

PMID- 15173268
TI  - Evaluation of carcinogen exposure in people who used "reduced exposure" tobacco
      products.
AB  - BACKGROUND: Although tobacco products with reportedly reduced carcinogen content
      are being marketed, carcinogen uptake in people who use these products has not
      been assessed systematically. METHODS: Between June 2001 and November 2002, 54
      users of smokeless tobacco and 51 cigarette smokers were randomly assigned to one
      of two groups. One used test products (Swedish snus for users of smokeless
      tobacco or OMNI cigarettes for smokers), while the other quit and used medicinal
      nicotine (the nicotine patch). All participants were assessed for urinary levels
      of total NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its
      glucuronide], metabolites of the tobacco-specific carcinogen 4
      (methylnitrosamino)-1-(3-pyridyl)-1-butanone. Smokers were also assessed for
      levels of 1-hydroxypyrene (1-HOP), a biomarker of polycyclic aromatic hydrocarbon
      uptake. Assessments were made weekly during 2 weeks of baseline normal tobacco
      use and 4 weeks of treatment. Statistical tests were two-sided. RESULTS: Primary
      data analyses were conducted on 41 users of smokeless tobacco and 38 cigarette
      smokers who met the inclusion criteria. Total NNAL levels were statistically
      significantly lower in users of smokeless tobacco after they switched to snus or
      to nicotine patch (P<.001 for both groups) than they were before the switch,
      although the overall mean total NNAL level among subjects who used the nicotine
      patch was statistically significantly lower than that among those who used snus
      (mean = 1.2 and 2.0 pmol of NNAL/mg of creatinine, respectively; mean difference
      = 0.9 pmol of NNAL/mg of creatinine, 95% confidence interval [CI] = 0.2 to 1.5; P
      =.008). Compared with baseline levels, total NNAL levels (P =.003), but not 1-HOP
      levels, were statistically significantly reduced in cigarette smokers who
      switched to the OMNI cigarette, although both total NNAL levels and 1-HOP levels
      were statistically significantly reduced in smokers who switched to the nicotine
      patch (P<.001 for both). The overall mean total NNAL levels among smokers who
      used the nicotine patch was statistically significantly lower than that among
      smokers who used the OMNI cigarette (mean = 1.2 and 1.9 pmol of NNAL/mg of
      creatinine, respectively; mean difference = 0.6 pmol of NNAL/mg of creatinine,
      95% CI = 0.1 to 1.1; P =.022). CONCLUSION: Switching to reduced-exposure tobacco
      products or medicinal nicotine can decrease levels of tobacco-associated
      carcinogens, with greater reductions being observed with medicinal nicotine.
      Medicinal nicotine is a safer alternative than modified tobacco products.

PMID- 15173269
TI  - Association between exclusive pipe smoking and mortality from cancer and other
      diseases.
AB  - BACKGROUND: Although many studies have examined the adverse health effects of
      pipe smoking combined with other forms of tobacco use, few have included large
      numbers of exclusive pipe smokers. The prevalence of pipe smoking has declined
      since the 1960s, yet usage is still common regionally, especially among older
      populations. METHODS: Using Cox proportional hazards models, we examined the
      association between pipe smoking and mortality from tobacco-related cancers and
      other diseases in a cohort of U.S. men enrolled in the Cancer Prevention Study
      II, an American Cancer Society prospective study. The cohort of 138 307 men
      included those who reported, in their 1982 enrollment questionnaire, exclusive
      current or former use of pipes (n = 15,263 men) or never use of any tobacco
      product (n = 123,044 men). Analyses were based on 23 589 men who died during 18
      years of follow-up. RESULTS: Current pipe smoking, compared with never use of
      tobacco, was associated with an increased risk of death from cancers of the lung
      (relative risk [RR] = 5.00, 95% confidence interval [CI] = 4.16 to 6.01),
      oropharynx (RR = 3.90, 95% CI = 2.15 to 7.08), esophagus (RR = 2.44, 95% CI =
      1.51 to 3.95), colorectum (RR = 1.41, 95% CI = 1.15 to 1.73), pancreas (RR =
      1.61, 95% CI = 1.24 to 2.09), and larynx (RR = 13.1, 95% CI = 5.2 to 33.1), and
      from coronary heart disease (RR = 1.30, 95% CI = 1.18 to 1.43), cerebrovascular
      disease (RR = 1.27, 95% CI = 1.09 to 1.48), and chronic obstructive pulmonary
      disease (RR = 2.98, 95% CI = 2.17 to 4.11). These risks were generally smaller
      than those associated with cigarette smoking and similar to or larger than those
      associated with cigar smoking. Relative risks of lung cancer showed statistically
      significant increases with number of pipes smoked per day, years of smoking, and
      depth of inhalation and decreases with years since quitting. CONCLUSION: Results
      from this large prospective study suggest that pipe smoking confers a risk of
      tobacco-associated disease similar to cigar smoking.

PMID- 15173270
TI  - Cancer inhibition in nude mice after systemic application of U6 promoter-driven
      short hairpin RNAs against PLK1.
AB  - BACKGROUND: RNA interference initiated by small interfering RNAs effectively
      suppresses gene expression, but the suppression is transient, which limits the
      therapeutic use of this technique. Polo-like kinase 1 (PLK1) is a key cell cycle
      regulator that is overexpressed in various human tumors. We used a xenograft
      mouse model to determine whether an RNA interference-based strategy that used
      short hairpin RNAs (shRNAs) to suppress PLK1 expression could inhibit tumor
      growth in vivo. METHODS: HeLa S3 cervical and A549 lung cancer cell lines were
      transfected with plasmids containing U6 promoter-driven shRNAs against human PLK1
      or control (parental or scrambled) plasmids. Plasmids were treated with the
      nuclease inhibitor aurintricarboxylic acid (ATA) as protection against nucleases
      in murine blood. Nude mice carrying xenograft tumors were injected with shRNA
      plasmids, and their xenograft tumor growth was assessed. Northern and western
      blot analyses were used to measure PLK1 mRNA and protein expression,
      respectively, in transfected cultured cells and in xenograft tumors. All
      statistical tests were two-sided. RESULTS: Levels of PLK1 mRNA and protein were
      lower in HeLa S3 and A549 cancer cells transfected with PLK1 shRNA plasmids than
      in corresponding cells transfected with control parental or scrambled PLK1S shRNA
      plasmids. Proliferation of cells transfected with PLK1 shRNA was lower than that
      of cells transfected with either control plasmid, and proliferation of cells
      transfected with ATA-treated PLK1 shRNA plasmids was even lower. In mice with
      human xenograft tumors, PLK1 shRNA expression from ATA-treated plasmids reduced
      tumor growth to 18% (95% confidence interval [CI] = 12% to 26%; P =.03) and from
      untreated plasmids reduced tumor growth to 45% (95% CI = 26% to 64%; P =.1) of
      that of tumors in mice treated with scrambled control PLK1S shRNA plasmids.
      CONCLUSIONS: The combination of shRNA-mediated gene silencing with effective in
      vivo gene delivery strategies appears to generate a long-lasting silencing
      signal.

PMID- 15173271
TI  - Influence of the new AJCC breast cancer staging system on sentinel lymph node
      positivity and false-negative rates.
AB  - The sixth and newest edition of the American Joint Committee on Cancer (AJCC)
      staging system for breast cancer now defines axillary sentinel lymph nodes with
      micrometastatic deposits 0.2 mm in diameter or smaller as node-negative. The aim
      of this study was to determine how this new classification scheme would affect
      axillary sentinel lymph node positivity, false-negative rate, and overall
      accuracy of an inception cohort of 205 breast cancer patients undergoing
      definitive surgery that included sentinel lymph node biopsy plus level I/II
      axillary lymphadenectomy. Based on the previous AJCC system for staging breast
      cancer, in which all sentinel lymph node metastases were considered positive, the
      rate of nodal positivity in this cohort was 47%, the overall accuracy was 99%,
      and the false-negative rate was 2.1%. According to the new classification system,
      the rate of nodal positivity in this cohort was 39.5% and the overall accuracy
      was 98%. The false-negative rate rose to 4.9% because two patients with
      micrometastatic deposits 0.2 mm or smaller, which are considered node-negative in
      the new system, had macroscopically positive disease in non-sentinel lymph nodes
      found in the completion lymphadenectomy.

PMID- 15173272
TI  - An angiogenic switch in breast cancer involves estrogen and soluble vascular
      endothelial growth factor receptor 1.
AB  - Estrogen is involved in breast tumorigenesis, but the precise mechanisms for its
      oncogenic and angiogenic actions are poorly understood. Angiogenesis is
      regulated, in part, by these critical components: vascular endothelial growth
      factor (VEGF) and its two receptors (VEGFR-1 and VEGFR-2). VEGFR-2 is a positive
      angiogenic signal transducer, whereas VEGFR-1, especially its soluble form
      (soluble VEGFR-1), is a negative regulator of VEGF availability. We found that
      breast epithelial cells express soluble VEGFR-1 and hypothesized that because
      estrogen can regulate expression of members of the VEGF family, it might
      stimulate angiogenesis in breast cancer by decreasing expression of soluble VEGFR
      1. Soluble VEGFR-1 expression decreased in estrogen receptor (ER)-positive but
      not in ER-negative breast cancer cell lines treated with estrogen. Pretreatment
      of the cells with the ER antagonist ICI 182,780 blocked the effect. The estrogen
      mediated decrease in soluble VEGFR-1 expression was accompanied by a
      statistically significant increase in angiogenesis in vivo. Our data suggest that
      inhibition of soluble VEGFR-1 expression represents a novel mechanism--an
      estrogen-driven angiogenic switch--possibly responsible for breast carcinoma
      progression.

PMID- 15173273
TI  - Long-term efficacy of zoledronic acid for the prevention of skeletal
      complications in patients with metastatic hormone-refractory prostate cancer.
AB  - In a placebo-controlled randomized clinical trial, zoledronic acid (4 mg via a 15
      minute infusion every 3 weeks for 15 months) reduced the incidence of skeletal
      related events (SREs) in men with hormone-refractory metastatic prostate cancer.
      Among 122 patients who completed a total of 24 months on study, fewer patients in
      the 4-mg zoledronic acid group than in the placebo group had at least one SRE
      (38% versus 49%, difference = -11.0%, 95% confidence interval [CI] = -20.2% to 
      1.3%; P =.028), and the annual incidence of SREs was 0.77 for the 4-mg zoledronic
      acid group versus 1.47 for the placebo group (P=.005). The median time to the
      first SRE was 488 days for the 4-mg zoledronic acid group versus 321 days for the
      placebo group (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced
      the ongoing risk of SREs by 36% (risk ratio = 0.64, 95% CI = 0.485 to 0.845; P
      =.002). Patients in the 4-mg zoledronic acid group had a lower incidence of SREs
      than did patients in the placebo group, regardless of whether they had an SRE
      prior to entry in the study. Long-term treatment with 4 mg of zoledronic acid is
      safe and provides sustained clinical benefits for men with metastatic hormone
      refractory prostate cancer.

PMID- 15173274
TI  - Re: Active tamoxifen metabolite plasma concentrations after coadministration of
      tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

PMID- 15173275
TI  - Re: Active tamoxifen metabolite plasma concentrations after coadministration of
      tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

PMID- 15173277
TI  - Re: Active tamoxifen metabolite plasma concentrations after coadministration of
      tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

PMID- 15173278
TI  - Re: Cost-effectiveness of aspirin chemoprevention for Barrett's esophagus.

PMID- 15173279
TI  - Re: Trends in the treatment of ductal carcinoma in situ of the breast.

PMID- 15173281
TI  - Re: Melatonin and breast cancer: a prospective study.

PMID- 15173282
TI  - Symptoms of posttraumatic stress disorder after orthopaedic trauma.
AB  - BACKGROUND: The purpose of this study was to determine the prevalence of
      posttraumatic stress disorder among patients seen following an orthopaedic
      traumatic injury and to identify whether injury-related or demographic variables
      are associated with the disorder. METHODS: Five hundred and eighty patients who
      had sustained orthopaedic trauma completed a Revised Civilian Mississippi Scale
      for Posttraumatic Stress Disorder questionnaire. Demographic and injury data were
      collected to analyze potential variables associated with posttraumatic stress
      disorder. RESULTS: Two hundred and ninety-five respondents (51%) met the criteria
      for the diagnosis of posttraumatic stress disorder. Patients with posttraumatic
      stress disorder had significantly higher Injury Severity Scores (p = 0.04), a
      higher sum of Extremity Abbreviated Injury Scores (p = 0.05), and a longer
      duration since the injury than those without posttraumatic stress disorder (p <
      0.01). However, none of these three variables demonstrated a good or excellent
      ability to discriminate between patients who had posttraumatic stress disorder
      and those who did not. The response to the item, "The emotional problems caused
      by the injury have been more difficult than the physical problems," was
      significantly associated with the presence of posttraumatic stress disorder (p <
      0.0001) and showed a fair ability to identify patients with the disorder.
      CONCLUSIONS: Posttraumatic stress disorder is common after orthopaedic trauma.
      Patients who respond positively to the item, "The emotional problems caused by
      the injury have been more difficult than the physical problems," may meet
      diagnostic criteria for this disorder and should be evaluated further.

PMID- 15173283
TI  - Standard surgical protocol to treat elbow dislocations with radial head and
      coronoid fractures.
AB  - BACKGROUND: The results of elbow dislocations with associated radial head and
      coronoid fractures are often poor because of recurrent instability and stiffness
      from prolonged immobilization. We managed these injuries with a standard surgical
      protocol, postulating that early intervention, stable fixation, and repair would
      provide sufficient stability to allow motion at seven to ten days postoperatively
      and enhance functional outcome. METHODS: We retrospectively reviewed the results
      of this treatment performed, at two university-affiliated teaching hospitals, in
      thirty-six consecutive patients (thirty-six elbows) with an elbow dislocation and
      an associated fracture of both the radial head and the coronoid process. Our
      surgical protocol included fixation or replacement of the radial head, fixation
      of the coronoid fracture if possible, repair of associated capsular and lateral
      ligamentous injuries, and in selected cases repair of the medial collateral
      ligament and/or adjuvant hinged external fixation. Patients were evaluated both
      radiographically and with a clinical examination at the time of the latest follow
      up. RESULTS: At a mean of thirty-four months postoperatively, the flexion
      extension arc of the elbow averaged 112 degrees +/- 11 degrees and forearm
      rotation averaged 136 degrees +/- 16 degrees. The mean Mayo Elbow Performance
      Score was 88 points (range, 45 to 100 points), which corresponded to fifteen
      excellent results, thirteen good results, seven fair results, and one poor
      result. Concentric stability was restored to thirty-four elbows. Eight patients
      had complications requiring a reoperation: two had a synostosis; one, recurrent
      instability; four, hardware removal and elbow release; and one, a wound
      infection. CONCLUSIONS: Use of our surgical protocol for elbow dislocations with
      associated radial head and coronoid fractures restored sufficient elbow stability
      to allow early motion postoperatively, enhancing the functional outcome. We
      recommend early operative repair with a standard protocol for these injuries.

PMID- 15173284
TI  - Salvage of a failed Keller resection arthroplasty.
AB  - BACKGROUND: A number of typical complications have been associated with Keller
      resection arthroplasty. Recurrent valgus deformity, cock-up deformity, and a
      flail toe may be difficult problems for the treating surgeon because options for
      salvage are limited. In this study, we evaluated arthrodesis of the first
      metatarsophalangeal joint as a salvage technique following a failed Keller
      procedure. In addition, the outcomes of motion-preserving procedures were
      reviewed in a separate series. METHODS: Arthrodesis of the first
      metatarsophalangeal joint was performed in twenty-eight patients (twenty-nine
      feet, group A), and either a repeat Keller procedure or an isolated soft-tissue
      release was performed in eighteen patients (twenty-one feet, group B). The
      patients were evaluated at least twenty-four months postoperatively, with a
      personal interview and a clinical examination with use of a modification of the
      hallux metatarsal-interphalangeal scale. Radiographs were also made for the group
      treated with the arthrodesis. RESULTS: In group A, the average duration of follow
      up was thirty-six months and fusion was achieved in twenty-six of the twenty-nine
      feet. Satisfaction was excellent or good in twenty-three cases, and the
      postoperative score according to the modified hallux metatarsal-interphalangeal
      scale averaged 76 points (maximum, 90 points). A repeat arthrodesis was necessary
      in five feet because of malposition or pseudarthrosis. In group B, the average
      duration of follow-up was seventy-four months. Satisfaction was excellent or good
      in only six cases, and the patient was dissatisfied in eleven cases. The score
      according to the modified hallux metatarsal-interphalangeal scale averaged 48
      points. Valgus deviation and cock-up deformity had recurred in the majority of
      the feet at the time of follow-up. CONCLUSIONS: Although it is more technically
      demanding, we recommend arthrodesis for salvage following a failed Keller
      procedure since it may be associated with a higher rate of patient satisfaction
      and better clinical results.

PMID- 15173285
TI  - Reliability, validity, and responsiveness of the Lysholm knee scale for various
      chondral disorders of the knee.
AB  - BACKGROUND: The Lysholm knee scale is a condition-specific outcome measure that
      was originally designed to assess ligament injuries of the knee. The purpose of
      this study was to determine the psychometric properties of the Lysholm knee scale
      for various chondral disorders of the knee. METHODS: Test-retest reliability,
      internal consistency, content validity, criterion validity, construct validity,
      and responsiveness to change were determined for the Lysholm knee scale within
      subsets of an overall study population of 1657 patients with chondral disorders
      of the knee. The study population was a heterogeneous group of patients with
      various types of traumatic and degenerative chondral lesions, including isolated
      lesions and those associated with meniscal and ligament injuries. RESULTS: The
      overall Lysholm knee scale and six of the eight domains had acceptable test
      retest reliability (intraclass correlation coefficient = 0.91) and internal
      consistency (Cronbach alpha = 0.65). The overall Lysholm knee scale demonstrated
      acceptable floor (0%) and ceiling (0.7%) effects; however, the floor effects for
      the domain of squatting and the ceiling effects for the domains of limp,
      instability, support, and locking were unacceptable (>30%). There was acceptable
      criterion validity with significant (p < 0.05) correlations between the overall
      Lysholm knee scale and the physical functioning, role-physical, and bodily pain
      domains of the Short Form-12 scale; the pain, stiffness, and function domains of
      the Western Ontario and McMaster Universities Osteoarthritis Index; and the
      Tegner activity scale. The overall Lysholm knee scale had acceptable construct
      validity, with all nine hypotheses demonstrating significance (p < 0.05), and it
      had acceptable responsiveness to change (effect size, 1.16; standardized response
      mean, 1.10), with large effects (> or = 0.80) for the domains of pain, limping,
      swelling, and squatting and a small effect (> or = 0.20) for the domain of
      instability. CONCLUSIONS: The Lysholm knee scale demonstrated overall acceptable
      psychometric performance for outcomes assessment of various chondral disorders of
      the knee, although some domains demonstrated suboptimal performance. Psychometric
      testing of other condition-specific knee instruments in patients with chondral
      disorders of the knee would be helpful to allow for comparison of psychometric
      properties.

PMID- 15173286
TI  - Closed suction drainage for hip and knee arthroplasty. A meta-analysis.
AB  - BACKGROUND: The use of closed-suction drainage systems after total joint
      replacement is a common practice. The theoretical advantages for the use of
      drains is a reduction in the occurrence of wound hematomas and infection. The aim
      of this meta-analysis was to determine, on the basis of the evidence from
      randomized controlled trials, the advantages and adverse effects of surgical
      drains. METHODS: All randomized trials, as far as we know, that compared patients
      managed with closed-suction drainage systems and those managed without a drain
      following elective hip and knee arthroplasty were considered. The trials were
      identified with use of searches of the Cochrane Collaboration with no restriction
      on languages or source. Two authors independently extracted the data, and the
      methods of all identified trials were assessed. RESULTS: Eighteen studies
      involving 3495 patients with 3689 wounds were included in the analysis. The
      pooled results indicated that there was no significant difference between the
      wounds treated with a drain and those treated without a drain with respect to the
      occurrence of wound infection (relative risk, 0.73; 95% confidence interval, 0.47
      to 1.14), wound hematoma (relative risk, 1.73; 95% confidence interval, 0.74 to
      4.07), or reoperations for wound complications (relative risk, 0.52; 95%
      confidence interval, 0.13 to 1.99). A drained wound was associated with a
      significantly greater need for transfusion (relative risk, 1.43; 95% confidence
      interval, 1.19 to 1.72). Reinforcement of wound dressings was required more
      frequently in the group managed without drains. No difference between the groups
      was seen with respect to limb-swelling, venous thrombosis, or hospital stay.
      CONCLUSIONS: Studies to date have indicated that closed suction drainage
      increases the transfusion requirements after elective hip and knee arthroplasty
      and has no major benefits. Further randomized trials with use of larger numbers
      of patients with full reporting of outcomes are indicated before the absence of
      any benefit, particularly for the outcome of wound infection, can be proved.

PMID- 15173287
TI  - Treatment of osteonecrosis of the femoral head with implantation of autologous
      bone-marrow cells. A pilot study.
AB  - BACKGROUND: Aseptic nontraumatic osteonecrosis of the femoral head is a disorder
      that can lead to femoral head collapse and the need for total hip replacement.
      Since osteonecrosis may be a disease of mesenchymal cells or bone cells, the
      possibility has been raised that bone marrow containing osteogenic precursors
      implanted into a necrotic lesion of the femoral head may be of benefit in the
      treatment of this condition. For this reason, we studied the implantation of
      autologous bone-marrow mononuclear cells in a necrotic lesion of the femoral head
      to determine the effect on the clinical symptoms and the stage and volume of
      osteonecrosis. METHODS: We studied thirteen patients (eighteen hips) with stage-I
      or II osteonecrosis of the femoral head, according to the system of the
      Association Research Circulation Osseous. The hips were allocated to a program of
      either core decompression (the control group) or core decompression and
      implantation of autologous bone-marrow mononuclear cells (the bone-marrow-graft
      group). Both patients and assessors were blind with respect to treatment-group
      assignment. The primary outcomes studied were safety, clinical symptoms, and
      disease progression. RESULTS: After twenty-four months, there was a significant
      reduction in pain (p = 0.021) and in joint symptoms measured with the Lequesne
      index (p = 0.001) and the WOMAC index (p = 0.013) within the bone-marrow-graft
      group. At twenty-four months, five of the eight hips in the control group had
      deteriorated to stage III, whereas only one of the ten hips in the bone-marrow
      graft group had progressed to this stage. Survival analysis showed a significant
      difference in the time to collapse between the two groups (p = 0.016).
      Implantation of bone-marrow mononuclear cells was associated with only minor side
      effects. CONCLUSIONS: Implantation of autologous bone-marrow mononuclear cells
      appears to be a safe and effective treatment for early stages of osteonecrosis of
      the femoral head. Although the findings of this study are promising, their
      interpretation is limited because of the small number of patients and the short
      duration of follow-up. Further study is needed to confirm the results.

PMID- 15173288
TI  - The Agility total ankle arthroplasty. Seven to sixteen-year follow-up.
AB  - BACKGROUND: We previously reported the intermediate-term results with the early
      version of the Agility total ankle replacement, a unique design that takes
      advantage of arthrodesis of the tibiofibular syndesmosis for tibial component
      support. The purpose of this study was to report longer-term results of this
      procedure in the treatment of disabling ankle arthritis. METHODS: We conducted an
      independent review of all Agility total ankle replacements performed by a single
      surgeon between 1984 and 1994. Follow-up evaluation consisted of completion of a
      validated ankle osteoarthritis scale and a short questionnaire and a review of
      the radiographs. All radiographs were evaluated for evidence of the development
      of progressive hindfoot arthritis, nonunion of the tibiofibular syndesmosis,
      progressive radiolucent lines, osteolysis, and component subsidence. RESULTS: One
      hundred and thirty-two arthroplasties were performed in 126 patients. After a
      mean follow-up period of nine years, thirty-three patients (thirty-six implants)
      had died, fourteen patients (11%) had a revision of the implant or an ankle
      arthrodesis, and one had the leg amputated because of an unrelated cause. Of the
      remaining seventy-eight patients (eighty-one ankles), sixty-seven (sixty-nine
      ankles) were followed clinically. More than 90% of them reported that they had
      decreased pain and were satisfied with the outcome of the surgery. We found
      modest differences in a comparison of the pain and disability scores with those
      of age-matched controls. Of the 117 ankles that had been followed
      radiographically for a minimum of two years, twenty-two (19%) had progressive
      subtalar arthritis, seventeen (15%) had progressive talonavicular arthritis, and
      nine (8%) had a syndesmosis nonunion. Eighty-nine (76%) of the 117 ankles had
      some evidence of peri-implant radiolucency. CONCLUSIONS: Arthrodesis of the
      tibiofibular syndesmosis impacts the radiographic and clinical outcomes with the
      Agility total ankle replacement. The relatively low rates of radiographic
      hindfoot arthritis and revision procedures at an average of nine years after the
      arthroplasty are encouraging. Agility total ankle replacement is a viable and
      durable option for the treatment of ankle arthritis in selected patients.

PMID- 15173289
TI  - Complications and failure after total ankle arthroplasty.
AB  - BACKGROUND: Second-generation total ankle arthroplasty has been reported to have
      good intermediate-term results. The purpose of the present study was to report on
      the cause and frequency of reoperation and failure after total ankle arthroplasty
      and to determine demographic and clinical predictors of reoperation and failure.
      METHODS: Three hundred and six consecutive primary total ankle arthroplasties
      were performed with use of the DePuy Agility Total Ankle System between 1995 and
      2001. At a mean of thirty-three months after the arthroplasty, we retrospectively
      reviewed the records with regard to patient age, gender, the indications for the
      index procedure, adjuvant procedures, the timing and frequency of reoperation,
      and the indications for and the type of reoperations performed. Kaplan-Meier
      analysis was performed to determine the rate of prosthetic survival, and Cox
      regression analysis was performed to determine predictors of reoperation and
      failure. RESULTS: Eighty-five patients (28%) underwent 127 reoperations
      (involving 168 procedures) after primary total ankle arthroplasty. The most
      common procedures at the time of reoperation were debridement of heterotopic bone
      (fifty-eight), correction of axial malalignment (forty), and component
      replacement (thirty-one). Eight patients underwent below-the-knee amputation. Age
      was found to be the only significant predictor of reoperation and failure after
      total ankle arthroplasty. The five-year survival rate with reoperation as the end
      point was 54%. The five-year survival rate with failure as the end point was 80%
      for all patients and 89% for patients who were more than fifty-four years of age.
      The prosthesis could not be salvaged in nine ankles (2.9%); the inability to
      salvage the prosthesis was most often due to loosening or infection. CONCLUSIONS:
      We noted a relatively high rate of reoperation after total ankle arthroplasty
      with this second-generation device. Younger age was found to have a negative
      effect on the rates of reoperation and failure. Most prostheses could be
      salvaged; however, the functional outcome of this procedure is uncertain.

PMID- 15173290
TI  - Revision total hip arthroplasty with use of a cemented femoral component. Results
      at a mean of ten years.
AB  - BACKGROUND: Revision of the femoral component of a total hip replacement with use
      of cement has been associated with early mechanical failure due to aseptic
      loosening. The purpose of the present study was to determine the long-term
      survival after revision of the femoral component with cement and to identify
      factors that were predictive of failure. METHODS: The results of 129 revision
      total hip arthroplasties that had been performed with use of a cemented femoral
      stem were reviewed to determine component survival. Ninety-seven hips that had
      been followed for a minimum of five years were included in survival analysis and
      tests of significance. Harris hip scores were used to quantify clinical outcomes.
      Clinical and surgical factors were analyzed to determine whether they were
      predictive of failure. RESULTS: The mean Harris hip score improved from 52 points
      preoperatively to 71 points at the time of the most recent follow-up (p < 0.001).
      The ten-year survival rate was 91% with rerevision of the femoral component
      because of aseptic loosening as the end point and 71% with mechanical failure as
      the end point. Patients who were more than sixty years old had greater long-term
      component survival and less pain than younger patients did (p < 0.05). A good
      quality postoperative cement mantle was associated with better long-term
      radiographic signs of fixation (p < 0.001). Poor femoral bone quality was
      associated with an increased rate of rerevision for aseptic loosening (p =
      0.021). CONCLUSIONS: Revision with use of a cemented femoral component remains an
      option for selected patients, with an acceptable ten-year survival rate and fair
      radiographic evidence of fixation. Our patients had acceptable clinical outcomes
      at ten years, and few had notable pain. The best results may be achieved in older
      patients (those who are sixty years old or more) with adequate bone stock who are
      managed with modern cementing techniques.

PMID- 15173291
TI  - Use of an intramedullary rod for treatment of congenital pseudarthrosis of the
      tibia. A long-term follow-up study.
AB  - BACKGROUND: The treatment of congenital pseudarthrosis of the tibia remains
      difficult and controversial. The purpose of this study was to evaluate the long
      term results of a technique consisting of excision of the pseudarthrosis,
      autologous bone-grafting, and insertion of a Williams intramedullary rod into the
      tibia. METHODS: Twenty-one consecutive patients with congenital pseudarthrosis of
      the tibia were managed with this technique between 1978 and 1999, and the results
      were retrospectively reviewed. The mean age of the patients at the time of the
      latest follow-up was 17.2 years (range, seven to twenty-five years), and the mean
      duration of postoperative follow-up was 14.2 years (range, three to twenty
      years). RESULTS: Initial consolidation occurred in eighteen of the twenty-one
      patients. Refracture occurred in twelve patients; five fractures healed with
      closed treatment, five healed after an additional surgical procedure, and two
      ultimately required amputation. Ten patients had an ankle valgus deformity after
      tibial union. Eleven patients had a residual limb-length discrepancy of >2 cm;
      six required a contralateral distal femoral and/or proximal tibial
      epiphyseodesis, two had a tibial lengthening, and one used a shoe-lift. Five
      patients had an amputation: two, because of a recalcitrant fracture; two, because
      of a limb-length discrepancy (6 and 9 cm); and one, because of a chronic lower
      extremity deformity. CONCLUSIONS: This technique produced a satisfactory long
      term functional outcome in sixteen of twenty-one patients and should be
      considered for the management of congenital pseudarthrosis of the tibia.

PMID- 15173292
TI  - Combined conservative and orthotic management of acute ruptures of the Achilles
      tendon.
AB  - BACKGROUND: There has been considerable debate about the best treatment for acute
      rupture of the Achilles tendon. At our institution, a well-documented and
      structured program of nonoperative management of Achilles tendon rupture with use
      of casts and a removable orthosis was developed. METHODS: We assessed the results
      in 140 consecutive patients with a complete rupture of the Achilles tendon who
      had been treated with our nonoperative regimen at our center between 1992 and
      1998. Patients were evaluated on the basis of the subjective results and
      clinically with physiological testing. RESULTS: Overall, 56% of our patients had
      an excellent result; 30%, good; 12%, fair; and 2%, poor. The overall complication
      rate was 8%, with three complete and five partial tendon reruptures, two deep
      vein thromboses, and one temporary dropfoot. CONCLUSIONS: The results of our
      nonoperative orthotic treatment were better overall than published results of
      operative repair of acute Achilles tendon rupture. Our patients were quite
      satisfied with their treatment.

PMID- 15173293
TI  - Dynamic foot-pressure measurement in the assessment of operatively treated
      clubfeet.
AB  - BACKGROUND: Decreased motion of the subtalar joint is common after operative
      treatment of idiopathic clubfeet. The purposes of this study were to validate
      parameters of dynamic foot-pressure measurement that enable detection of
      physiological pronation of the subtalar joint and to analyze the consequences of
      absent or decreased pronation following clubfoot surgery on long-term functional
      results. METHODS: To validate parameters of dynamic foot-pressure measurement, we
      initially analyzed two control groups: one of forty asymptomatic normal feet and
      the other of five feet with a previous subtalar joint arthrodesis. The resulting
      parameters were then applied to a group of nineteen patients with twenty-four
      idiopathic clubfeet for whom initial conservative treatment had failed and in
      whom a posterior surgical release (lengthening of the Achilles tendon and release
      of the posterior ankle capsule) had been performed at a mean age of twenty
      months. The mean duration of follow-up was forty-one years. All feet were
      evaluated radiographically, and the clinical results were assessed with the
      American Orthopaedic Foot and Ankle Society score. RESULTS: An interruption in
      the rise of the pressure-time curve and a short medial deviation of the center of
      pressure path immediately after heel strike are reliable and objective
      characteristics of pronation movement of the subtalar joint. Nineteen clubfeet
      had a demonstrable pronation movement, and five clubfeet did not. The nineteen
      feet with pronation movement were either asymptomatic (twelve feet) or mildly
      painful on occasion (seven feet). The mean American Orthopaedic Foot and Ankle
      Society score for the nineteen feet was 87 points. The five feet without
      pronation movement were moderately painful during strenuous activities only (four
      feet) or were nearly always painful (one foot). The mean score for those feet was
      57 points. There was a significant difference between these two groups with
      regard to the pain scores and the total scores (p < 0.001), but there was no
      appreciable difference regarding function and hindfoot motion. It was not
      possible to distinguish between these two groups on the basis of the findings of
      the physical or radiographic examinations. CONCLUSIONS: Idiopathic clubfeet with
      preserved hindfoot pronation have a better long-term prognosis. Preservation of
      functional mobility of the subtalar joint is a key factor in the treatment of
      clubfoot deformity.

PMID- 15173294
TI  - Biomechanical evaluation of arthroscopic rotator cuff stitches.
AB  - BACKGROUND: The suture configurations in arthroscopic rotator cuff repairs have
      been limited to simple and horizontal stitches. Recent objective evaluations have
      demonstrated high failure rates of arthroscopic repairs of rotator cuff tears. A
      novel stitch for arthroscopic repair of the rotator cuff, the massive cuff
      stitch, was developed to increase the strength of the suture-tendon interface.
      The goal of this study was to determine the biomechanical properties of the
      massive cuff stitch and to compare it with other stitches commonly used for
      rotator cuff repair. METHODS: Eight pairs of sheep infraspinatus tendons were
      harvested and split in half to yield a set of four tendon specimens from each
      animal. Four stitch configurations (simple, horizontal, massive cuff, and
      modified Mason-Allen) were randomized and biomechanically tested in each set of
      tendon specimens. Each specimen was first cyclically loaded on an MTS uniaxial
      load frame under force control from 5 to 30 N at 0.25 Hz for twenty cycles. Each
      specimen was then loaded to failure under displacement control at a rate of 1
      mm/sec. Cyclic elongation, peak-to-peak displacement, ultimate tensile load, and
      stiffness were measured with use of an optical motion analysis system and load
      cell output. The type of failure (suture breakage or pull-out) was also recorded.
      A repeated-measures analysis of variance was performed on the results, with the
      alpha level of significance set at p < 0.05. RESULTS: There was no difference in
      cyclic elongation or peak-to-peak displacement among the four stitches. Ultimate
      tensile load was significantly higher (p < 0.05) for the massive cuff stitch (233
      +/- 40 N) and the modified Mason-Allen stitch (246 +/- 40 N) than it was for
      either the simple stitch (72 +/- 18 N) or the horizontal stitch (77 +/- 15 N).
      There was no significant difference in the ultimate load between the massive cuff
      and modified Mason-Allen stitches. There was also no difference in stiffness
      among the four stitches. The simple and horizontal stitches failed by tissue pull
      out, whereas the massive cuff and Mason-Allen stitches failed by a mixture of
      suture breakage and pull-out. CONCLUSIONS: The massive cuff stitch provides
      strength comparable with that of the modified Mason-Allen stitch commonly used in
      open rotator cuff repair. The ultimate tensile load before failure of the massive
      cuff stitch was significantly higher (p < 0.05) than that of the simple and
      horizontal stitches.

PMID- 15173295
TI  - Primary total hip arthroplasty with a porous-coated acetabular component. A
      concise follow-up of a previous report.
AB  - We previously reported the seven-to-ten-year results of the use of a porous
      coated acetabular metal shell in a consecutive series of 204 primary total hip
      arthroplasties. In the present study, we evaluated the longer-term outcomes of
      these arthroplasties, at fifteen to eighteen years. One hundred and thirty-six
      (96%) of the 142 hips available for study retained the original acetabular metal
      shell. Three of the 142 metal shells failed secondary to aseptic loosening. Ten
      hips (7%) required a change of the modular acetabular liner because of excessive
      wear or for the treatment of osteolysis. The fifteen-year rate of survival of the
      metal shell, with failure defined as revision because of loosening or
      radiographic evidence of loosening, was 99%. The rate of survival of cementless
      acetabular reconstructions was excellent at fifteen years, although osteolysis
      and reoperations were noted to occur much more frequently as the duration of
      follow-up increased. The majority of the complications were related to wear of
      the polyethylene liner.

PMID- 15173296
TI  - Proximal ulnar reconstruction with strut allograft in revision total elbow
      arthroplasty.
AB  - BACKGROUND: The growing frequency of joint arthroplasty has led to increasing
      numbers of patients requiring revision surgery. In the treatment of a failed
      total elbow arthroplasty not associated with infection, one of the main issues is
      poor or absent proximal ulnar bone stock due to osteolysis. We report our
      experience with the use of strut allograft reconstruction of the proximal part of
      the ulna as an adjunct to revision total elbow arthroplasty with a noncustom
      implant. Our aim was to better define the indications, outcomes, and
      complications of this technique in a population of patients with a failed total
      elbow arthroplasty. METHODS: We reviewed the cases of patients with aseptic
      failure of a total elbow replacement and proximal ulnar bone deficiency who were
      treated with allograft bone struts. The patients had had an average of 2.5
      (range, one to four) prior open osseous operations addressing the elbow joint. In
      addition to revision of the prosthetic components, the deficient bone stock was
      treated with allograft strut grafts in one of four ways: (1) discrete cortical
      defects were contained, (2) periprosthetic fractures were splinted, (3) deficient
      triceps attachments were reconstructed, and (4) expanded segments were augmented
      with struts and filled with impaction graft. Twenty-one patients (twenty-two
      elbows) were followed for an average of four years (range, two to eleven years).
      RESULTS: The mean Mayo Elbow Performance Score improved from 34 points
      preoperatively to 79 points at the time of the latest follow-up. The scores for
      pain, stability, and activities of daily living improved most; there was little
      change in motion. Complications, consisting of four soft-tissue and four osseous
      problems, occurred in eight patients. Three patients had incorporation of 26% to
      50% of the graft; five, 51% to 75%; and fourteen, 76% to 100%. CONCLUSIONS: Most
      deficiencies of proximal ulnar bone stock and fractures complicating revision
      total elbow surgery can be treated with allograft strut grafting. Although the
      complication rate is high, this technique is suitable for discrete cortical
      lesions, periprosthetic fractures, and an expanded proximal part of the ulna,
      which also requires augmentation with impaction grafting. The technique has been
      unreliable, however, in restoring deficient olecranon bone stock.

PMID- 15173297
TI  - Histologic changes after vertebroplasty.
AB  - BACKGROUND: Vertebroplasty with use of polymethylmethacrylate cement is gaining
      popularity in the treatment of some specific painful lesions of the spine. It
      remains unclear, however, what possible side effects this type of cement might
      have upon the vertebral body. We performed a histologic and radiographic analysis
      of the end plate and disc to determine whether there was a difference between
      vertebroplasty with polymethylmethacrylate cement and vertebroplasty with calcium
      phosphate cement in the surrounding tissue of the goat spine. Furthermore, we
      assessed whether a defect in the end plate, simulating end-plate fracture and
      allowing for direct contact of cement with disc tissue, had any effect on end
      plate or disc degeneration. METHODS: Twenty-four mature goats were divided
      between two follow-up periods (six weeks and six months). All animals underwent a
      bilateral transpedicular vertebroplasty at two lumbar levels, where one of the
      following treatments was applied: vertebroplasty with calcium phosphate cement
      with or without an end-plate defect, and vertebroplasty with
      polymethylmethacrylate cement with or without an end-plate defect. The effect of
      the various treatments on the integrity of the intervertebral disc, end plate,
      and surrounding tissue was examined with semiquantitative histologic analysis and
      radiography. RESULTS: No sign of disc or end-plate degeneration was seen in any
      of the analyzed sections. The mean disc height did not decrease from the
      postoperative period to the time that the animals were killed in any group,
      thereby supporting the histologic findings. A mild inflammatory reaction was
      found in four vertebral bodies in the polymethylmethacrylate groups only.
      CONCLUSIONS: Calcium phosphate cement and polymethylmethacrylate cement both seem
      to be adequate bone-void fillers in terms of biological behavior in the vertebral
      body.

PMID- 15173298
TI  - Comparison of anterior-posterior-glide and rotating-platform low contact stress
      mobile-bearing total knee arthroplasties.
AB  - BACKGROUND: The anterior-posterior-glide Low Contact Stress mobile-bearing knee
      prosthesis was developed to approximate the natural kinematics of the knee more
      closely than the rotating-platform Low Contact Stress mobile-bearing knee
      prosthesis does. The purpose of the present study was to compare the results
      associated with these two prostheses in patients managed with simultaneous
      bilateral total knee replacement. METHODS: One hundred and ninety patients
      received an anterior-posterior-glide Low Contact Stress mobile-bearing prosthesis
      in one knee and a rotating-platform Low Contact Stress mobile-bearing prosthesis
      in the contralateral knee. The mean age of the patients at the time of the index
      procedure was sixty-four years. Eleven patients were men, and 179 patients were
      women. The mean duration of follow-up was 6.4 years (range, five to seven years).
      The patients were followed clinically and radiographically with use of the knee
      rating systems of the Knee Society and the Hospital for Special Surgery. RESULTS:
      The mean postoperative Hospital for Special Surgery knee score was 89.4 points
      for the knees treated with the anterior-posterior-glide mobile-bearing prosthesis
      and 88.6 points for those treated with the rotating-platform mobile-bearing
      prosthesis. Three knees in each group had a poor result. Two knees in each group
      had persistent moderate pain. One knee with an anterior-posterior-glide
      prosthesis had permanent tibial and deep peroneal nerve palsies, and one knee
      with a rotating-platform prosthesis had a permanent deep peroneal nerve palsy. No
      knee had aseptic loosening, revision, measurable wear of the tibial or patellar
      polyethylene bearing, or osteolysis. CONCLUSIONS: After a minimum duration of
      follow-up of five years, the results associated with the anterior-posterior-glide
      and rotating-platform Low Contact Stress mobile-bearing total knee replacements
      were favorable and comparable.

PMID- 15173299
TI  - Comparison of transcranial electric motor and somatosensory evoked potential
      monitoring during cervical spine surgery.
AB  - BACKGROUND: There has been little enthusiasm for somatosensory evoked potential
      monitoring in cervical spine surgery as a result, in part, of the increased risk
      of motor tract injury at this level, to which somatosensory monitoring may be
      insensitive. Transcranial electric motor evoked potential monitoring allows
      assessment of the motor tracts; therefore, we compared transcranial electric
      motor evoked potential and somatosensory evoked potential monitoring during
      cervical spine surgery to determine the temporal relationship between the changes
      in the potentials demonstrated by each type of monitoring and neurological
      sequelae and to identify patient-related and surgical factors associated with
      intraoperative neurophysiological changes. METHODS: Somatosensory evoked
      potential and transcranial electric motor evoked potential data recorded for 427
      patients undergoing anterior or posterior cervical spine surgery between January
      1999 and March 2001 were analyzed. All patients who showed substantial (at least
      60%) or complete unilateral or bilateral amplitude loss, for at least ten
      minutes, during the transcranial electric motor evoked potential and/or
      somatosensory evoked potential monitoring were identified. RESULTS: Twelve of the
      427 patients demonstrated substantial or complete loss of amplitude of the
      transcranial electric motor evoked potentials. Ten of those patients had complete
      reversal of the loss following prompt intraoperative intervention, whereas two
      awoke with a new motor deficit. Somatosensory evoked potential monitoring failed
      to identify any change in one of the two patients, and the change in the
      somatosensory evoked potentials lagged behind the change in the transcranial
      electric motor evoked potentials by thirty-three minutes in the other. No patient
      showed loss of amplitude of the somatosensory evoked potentials in the absence of
      changes in the transcranial electric motor evoked potentials. Transcranial
      electric motor evoked potential monitoring was 100% sensitive and 100% specific,
      whereas somatosensory evoked potential monitoring was only 25% sensitive; it was,
      however, 100% specific. CONCLUSIONS: Transcranial electric motor evoked potential
      monitoring appears to be superior to conventional somatosensory evoked potential
      monitoring for identifying evolving motor tract injury during cervical spine
      surgery. Surgeons should strongly consider using this modality when operating on
      patients with cervical spondylotic myelopathy in general and on those with
      ossification of the posterior longitudinal ligament in particular.

PMID- 15173300
TI  - Primary total hip arthroplasty with a proximally porous-coated femoral stem.
AB  - BACKGROUND: The use of cementless, proximally porous-coated femoral stems for
      total hip arthroplasty has increased in popularity. The purpose of the present
      report was to examine the five to ten-year results associated with the use of a
      so-called second-generation circumferentially proximally porous-coated titanium
      alloy stem. METHODS: Between 1991 and 1994, 123 Harris-Galante Multilock femoral
      stems were implanted in 101 patients. The average age of the patients at the time
      of surgery was 53.8 years. The patients were followed prospectively and were
      reevaluated at a minimum of five years postoperatively. No patient was lost to
      follow-up. Twenty-five patients (thirty hips) were interviewed by telephone, and
      four patients (five hips) died during the study period because of problems that
      were unrelated to the operation. The remaining seventy-two patients (eighty-eight
      hips) had a minimum of five years of clinical and radiographic follow-up.
      RESULTS: The average duration of follow-up was seventy-eight months. At the time
      of the most recent follow-up, the average Harris Hip Score was 95 points. Eighty
      seven (99%) of eighty-eight stems were biologically stable, with eighty-four hips
      (95%) having osseous ingrowth and three hips (3%) having stable fibrous fixation.
      One stem was revised because of loosening. Thirty-three hips (38%) had minimal
      proximal osteolysis, and no hip had diaphyseal osteolysis. Seventy-two hips (82%)
      had some degree of stress-shielding in the proximal metaphysis, but only two hips
      had cortical resorption. None of these patients required additional surgery, and
      all reported a satisfactory outcome. CONCLUSIONS: Given the young age and high
      activity level of these patients, this stem fared well: the levels of patient
      function and satisfaction were high, the rates of loosening and revision were
      very low, and distal osteolysis did not occur. Osseous fixation occurred
      reliably. Proximal stress-shielding was seen but did not seem to be clinically
      important.

PMID- 15173301
TI  - Two-bundle posterior cruciate ligament reconstruction: how bundle tension depends
      on femoral placement.
AB  - BACKGROUND: Clinically, one-bundle posterior cruciate ligament reconstructions
      frequently result in the return of abnormal posterior translation. We
      hypothesized that the return of posterior translation is caused by a nonuniform
      distribution of load among the graft fibers. The purpose of the present study was
      to determine how the femoral attachment location of the second bundle of a two
      bundle posterior cruciate ligament reconstruction affects the anterior bundle
      tension and the load distribution between the graft bundles. METHODS: One and two
      bundle posterior cruciate ligament reconstructions (one one-bundle type and three
      two-bundle types) were performed in nineteen cadaveric knees. The grafts were
      tensioned to restore posterior translation to within +/-1 mm of that of the
      intact knee at 90 degrees of flexion while a 100-N posterior force was applied to
      the proximal part of the tibia. For each reconstruction, the total graft tension
      was a minimum of 2.3 times larger than the applied posterior force. Bundle
      tension and knee motions were measured as the knee was cycled from 5 degrees to
      120 degrees of flexion while a 100-N posterior force was applied. Analysis of
      variance was used to compare the four reconstructions, and post hoc testing was
      performed with use of Fischer's protected least significant difference method.
      RESULTS: Two-bundle reconstructions involving a middle-distal or middle-middle
      second bundle significantly reduced the tension in the anterior bundle in
      comparison with the tension in the one-bundle (anterior-distal) reconstruction.
      The peak anterior-bundle tensions with the middle-distal and middle-middle second
      bundles were 43% and 37% less than the peak bundle tension for the one-bundle
      reconstruction (p < 0.001 and p = 0.002, respectively). With the exception of the
      average bundle tension, the tension parameters calculated for the middle bundle
      decreased as the distance from the articular cartilage increased. The peak
      tensions for the middle-middle and middle-proximal bundles were 32% and 61% less
      than that for the middle-distal bundle (p = 0.028 and p = 0.001, respectively).
      CONCLUSIONS: The femoral position of the second bundle significantly affected the
      tension in the anterior bundle and the load distribution. A second bundle placed
      in a middle or distal position resulted in a significant reduction in anterior
      bundle tension and in cooperative load-sharing (with the bundles functioning
      together). A proximal second bundle resulted in reciprocal loading (with one
      bundle functioning in flexion and one in extension), but the tension in the
      anterior bundle was not different from the tension in the one-bundle
      reconstruction.

PMID- 15173302
TI  - Wear and surface cracking in early retrieved highly cross-linked polyethylene
      acetabular liners.
AB  - BACKGROUND: A higher degree of cross-linking has been shown to improve the
      tribological properties of ultra-high molecular weight polyethylene in laboratory
      studies; however, its effect on in vivo behavior has not been well established.
      We investigated in vivo wear mechanisms in retrieved highly cross-linked
      polyethylene acetabular liners in order to determine if early in vivo wear
      behavior is accurately predicted by hip-simulator studies. METHODS: A total of
      twenty-four liners (twenty-one explanted and one unimplanted highly cross-linked
      liners and two explanted ethylene-oxide-sterilized non-cross-linked liners) were
      examined for this study. The average age of the patients was 59.9 years, and the
      average time in vivo was 10.1 months. Articular surface damage on the front and
      back sides of the liners was assessed with an optical scoring system. Surface
      quadrants were assigned a grade from 0 to 3 according to the observed wear
      mechanisms and the percentage of surface affected. The micromechanisms of liner
      damage were evaluated with use of scanning electron microscopy. RESULTS: The
      average front and back-side explant damage scores were 11 (range, 2 to 26.5) and
      6.7 (range, 3.7 to 13.3), respectively. There was consistent evidence of early
      surface deformation and cracking. All explants exhibited some form of surface
      change, including surface cracking, abrasion, pitting, or scratching. The
      original machining marks on the liner surface were observed to be either
      unaltered, drastically distorted, or absent. CONCLUSIONS: Highly cross-linked
      ultra-high molecular weight polyethylene acetabular liners that were retrieved at
      an average of ten months after implantation exhibited signs of surface damage
      that had not been predicted by in vitro hip-simulator studies. These devices had
      not failed clinically as a result of wear. The discrepancy between in vitro and
      in vivo wear surfaces may be due to variability in terms of in vivo lubrication
      and cyclic loading or may represent early surface damage mechanisms that are not
      well demonstrated by long-term simulator studies.

PMID- 15173303
TI  - Multiple myeloma with a pathologic fracture during pregnancy. A case report.

PMID- 15173304
TI  - Phantom-limb pain due to cervical spinal tuberculosis. A case report.

PMID- 15173305
TI  - Tension-sided femoral neck stress fracture in a skeletally immature patient. A
      case report.

PMID- 15173306
TI  - Chronic osteomyelitis due to Mycobacterium chelonae diagnosed by polymerase chain
      reaction homology matching. A case report.

PMID- 15173307
TI  - Spontaneous septic subscapular abscess. A case report.

PMID- 15173308
TI  - Health care technology assessment. Basic principles and clinical applications.
AB  - Health care technology (defined as all drugs, devices, and medical and surgical
      procedures used in medical care as well as the organizational and supportive
      systems within which such care is provided) is widely regarded as an important
      driver of escalating health care spending in the United States. Many new health
      care technologies are adopted and used in clinical practice with little or no
      evidence that their use is associated with improved patient outcomes. Orthopaedic
      surgeons are facing increasing scrutiny from hospitals and payers regarding the
      adoption and use of new technology for the treatment of patients with
      musculoskeletal disease. Health care technology assessment is a growing field
      that is concerned with the multidisciplinary evaluation of clinical data on the
      basis of safety and efficacy as well as economic aspects of technology
      acquisition. Through an understanding of the relevant literature and the concepts
      of health care technology assessment, orthopaedic surgeons have an opportunity to
      participate in the assessment process and thus influence clinical and health
      policy decisions regarding the adoption and use of new and existing technologies
      in the field of orthopaedic surgery.

PMID- 15173310
TI  - NIH Consensus Statement on total knee replacement December 8-10, 2003.

PMID- 15173311
TI  - Transchondral fractures (osteochondritis dissecans) of the talus.

PMID- 15173312
TI  - What's new in pediatric orthopaedics.

PMID- 15173313
TI  - p53-dependent apoptotic mechanism of a new designer bimetallic compound tri
      phenyl tin benzimidazolethiol copper chloride (TPT-CuCl2): in vivo studies in
      Wistar rats as well as in vitro studies in human cervical cancer cells.
AB  - We have studied the effect of tri-phenyl tin benzimadazolethiolcopper chloride
      (TPT-CuCl(2)), a novel bimetallic compound, on the regulation of apoptosis in
      HeLa cells, MCF-7 cells, and in vivo Wistar rat model. TPT-CuCl(2) induces
      significant apoptosis in HeLa cell line characterized by DNA fragmentation and
      chromosome condensation. Comet assay revealed that TPT-CuCl(2) targets and causes
      severe damage to the DNA. Treatment of HeLa cells with TPT-CuCl(2) rescues the
      accumulation of p53 from the suppression of human papilloma virus E6, resulting
      in a dramatic up-regulation of Bax and Bak and down-regulation of the
      antiapoptotic factor Survivin. Apoptotic induction by TPT-CuCl(2) was shown to
      mediate in a p53-depedent manner; loss of p53 impairs the release of cytochrome c
      and Smac/DIABLO from mitochondria to cytosol. Moreover, we have shown that TPT
      CuCl(2) induced-apoptosis was through an intrinsic mitochondrial pathway, which
      was inhibited by viral oncoprotein E1B19K. Caspase-3 was found to be
      indispensable in TPT-CuCl(2)-triggered apoptosis signaling pathway, because
      caspase-3 deficient cell line MCF-7 was resistant to TPT-CuCl(2). Furthermore, in
      vivo studies using C6 glioblastoma xenograft rat model revealed that TPT-CuCl(2)
      exhibits significant antiproliferative activity against tumor development with
      minimal cytotoxicity toward normal physiological function of the experimental
      rats. These findings imply the attractiveness of TPT-CuCl(2) as a drug candidate
      for further development.

PMID- 15173314
TI  - GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain
      barrier.
AB  - gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for
      cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant,
      and date rape drug. Recreational abuse or overdose of GHB (or its precursors
      gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous
      system (CNS) effects (respiratory depression, unconsciousness, coma, and death)
      as well as tolerance and withdrawal. An understanding of the CNS transport
      mechanisms of GHB may provide insight into overdose treatment approaches. The
      hypothesis that GHB undergoes carrier-mediated transport across the BBB was
      tested using a rat in situ brain perfusion technique. Various pharmacological
      agents were used to probe the pharmacological characteristics of the transporter.
      GHB exhibited carrier-mediated transport across the BBB consistent with a high
      capacity, low-affinity transporter; averaged brain region parameters were V(max)
      = 709 +/- 214 nmol/min/g, K(m) = 11.0 +/- 3.56 mM, and CL(ns) = 0.019 +/- 0.003
      cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta
      hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic
      anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid)
      significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and
      glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual
      inhibition was observed between GHB and benzoic acid, a well known substrate of
      the monocarboxylate transporter MCT1. These results are suggestive of GHB
      crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport
      suggest potential therapeutic approaches in the treatment of GHB overdoses. We
      are currently conducting "proof-of-concept" studies involving the use of GHB
      brain transport inhibitors during GHB toxicity.

PMID- 15173315
TI  - Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization
      of CDC25B: binding site preferences of 14-3-3 subtypes and the subcellular
      localization of CDC25B.
AB  - The dual specificity phosphatase CDC25B positively controls the G2-M transition
      by activating CDK1/cyclin B. The binding of 14-3-3 to CDC25B has been shown to
      regulate the subcellular redistribution of CDC25B from the nucleus to the
      cytoplasm and may be correlated with the G2 checkpoint. We used a FLAG-tagged
      version of CDC25B to study the differences among the binding sites for the 14-3-3
      subtypes, 14-3-3beta, 14-3-3epsilon and 14-3-3sigma, and the relationship between
      subtype binding and the subcellular localization of CDC25B. All three subtypes
      were found to bind to CDC25B. Site-directed mutagenesis studies revealed that 14
      3-3beta bound exclusively near serine-309 of CDC25B1, which is within a potential
      consensus motif for 14-3-3 binding. By contrast, 14-3-3sigma bound preferentially
      to a site around serine-216, and the presence of serine-137 and -309 enhanced the
      binding. In addition to these binding-site differences, we found that the binding
      of 14-3-3beta drove CDC25B to the cytoplasm and that mutation of serine-309 to
      alanine completely abolished the cytoplasmic localization of CDC25B. However, co
      expression of 14-3-3sigma and CDC25B did not affect the subcellular localization
      of CDC25B. Furthermore, serine-309 of CDC25B was sufficient to produce its
      cytoplasmic distribution with co-expression of 14-3-3beta, even when other
      putative 14-3-3 binding sites were mutated. 14-3-3epsilon resembled 14-3-3beta
      with regard to its binding to CDC25B and the control of CDC25B subcellular
      localization. The results of the present study indicate that two 14-3-3 subtypes
      can control the subcellular localization of CDC25B by binding to a specific site
      and that 14-3-3sigma has effects on CDC25B other than the control of its
      subcellular localization.

PMID- 15173316
TI  - Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population
      of postnatal young and old human cells with extensive expansion and
      differentiation potential.
AB  - We report here the isolation of a population of non-transformed pluripotent human
      cells from bone marrow after a unique expansion/selection procedure. This
      procedure was designed to provide conditions resembling the in vivo
      microenvironment that is home for the most-primitive stem cells. Marrow-adherent
      and -nonadherent cells were co-cultured on fibronectin, at low oxygen tension,
      for 14 days. Colonies of small adherent cells were isolated and further expanded
      on fibronectin at low density, low oxygen tension with 2% fetal bovine serum.
      They expressed high levels of CD29, CD63, CD81, CD122, CD164, hepatocyte growth
      factor receptor (cMet), bone morphogenetic protein receptor 1B (BMPR1B), and
      neurotrophic tyrosine kinase receptor 3 (NTRK3) and were negative for CD34, CD36,
      CD45, CD117 (cKit) and HLADR. The embryonic stem cell markers Oct-4 and Rex-1,
      and telomerase were expressed in all cultures examined. Cell-doubling time was 36
      to 72 hours, and cells have been expanded in culture for more than 50 population
      doublings. This population of cells was consistently isolated from men and women
      of ages ranging from 3- to 72-years old. Colonies of cells expressed numerous
      markers found among embryonic stem cells as well as mesodermal-, endodermal- and
      ectodermal-derived lineages. They have been differentiated to bone-forming
      osteoblasts, cartilage-forming chondrocytes, fat-forming adipocytes and neural
      cells and to attachment-independent spherical clusters expressing genes
      associated with pancreatic islets. Based on their unique characteristics and
      properties, we refer to them as human marrow-isolated adult multilineage
      inducible cells, or MIAMI cells. MIAMI cells proliferate extensively without
      evidence of senescence or loss of differentiation potential and thus may
      represent an ideal candidate for cellular therapies of inherited or degenerative
      diseases.

PMID- 15173317
TI  - Baculovirus P35 inhibits NO-induced apoptosis in activated macrophages by
      inhibiting cytochrome c release.
AB  - The baculovirus protein P35 inhibits apoptosis in a diverse range of animals such
      as insects, nematodes and mammals. Evidence suggests that P35 can inhibit members
      of caspase family proteases that are key mediators of mammalian apoptosis. We
      demonstrate that p35 inhibits activation-induced nitric oxide (NO)-mediated
      apoptosis in the RAW 264.7 mouse macrophages. Parent or vector-transfected RAW
      264.7 cells underwent apoptosis when treated with a combination of cisplatin and
      interferon-gamma (IFN-gamma) or LPS and IFN-gamma in a NO-dependent manner. By
      contrast, RAW 264.7 cells stably expressing P35 did not undergo apoptosis when
      treated with a combination of cisplatin and IFN-gamma or LPS and IFN-gamma.
      Activation of parent, vector- or p35-transfected cells with cisplatin and IFN
      gamma or LPS and IFN-gamma caused equivalent levels of inducible nitric oxide
      synthase (iNOS) expression and produced equal amounts of nitrite, which ruled out
      attenuated iNOS activity during P35-mediated protection. Rather, expression of
      P35 inhibited translocation of mitochondrial cytochrome c into cytosol,
      mitochondrial depolarization, activation of caspase-9 and caspase-3, and cleavage
      of poly (ADP-ribose) polymerase (PARP). These findings indicate that P35 inhibits
      NO-induced apoptotic cell death of activated macrophages by inhibiting
      mitochondrial cytochrome c release, which suggests that P35 has targets upstream
      of the caspase cascade in apoptosis.

PMID- 15173318
TI  - Akt binds prohibitin 2 and relieves its repression of MyoD and muscle
      differentiation.
AB  - In a yeast two-hybrid screen using the full-length Akt as bait, we found that
      prohibitin 2 (PHB2) specifically interacts with Akt. The C terminus of Akt (amino
      acids 413-480) and a central region of PHB2 (amino acids 120-232) are responsible
      for their mutual interaction. PHB2 acts as a transcriptional repressor in cells.
      PHB2 interacts with both MyoD and MEF2, and represses both MyoD- and MEF2
      dependent gene transcription. Furthermore, binding of PHB2 to both MyoD and MEF2
      significantly decreases upon myogenic differentiation. When stably expressed in
      C2C12 myogenic cells, PHB2 inhibits myogenin induction and phenotypic muscle
      differentiation. PHB2 was found to specifically recruit histone deacetylase 1,
      which is probably responsible for its repressive activity. Co-expression of Akt
      can partially reduce PHB2 binding to MyoD and relieve the repressive effect of
      PHB2 on myogenic reporters, which could be one of the mechanisms underlying Akt
      mediated MyoD activation and accelerated muscle differentiation.

PMID- 15173319
TI  - Human topoisomerase IIalpha nuclear export is mediated by two CRM-1-dependent
      nuclear export signals.
AB  - Resistance to chemotherapeutic drugs is a major obstacle in the treatment of
      leukemia and multiple myeloma. We have previously found that myeloma and leukemic
      cells in transition from low-density log phase conditions to high-density plateau
      phase conditions export substantial amounts of endogenous topoisomerase II alpha
      from the nucleus to the cytoplasm. In order for topoisomerase-targeted
      chemotherapy to function, the topoisomerase target must have access to the
      nuclear DNA. Therefore, the nuclear export of topoisomerase II alpha may
      contribute to drug resistance, and defining this mechanism may lead to methods to
      preclude this avenue of resistance. We have identified nuclear export signals for
      topoisomerase II alpha at amino acids 1017-1028 and 1054-1066, using FITC-labeled
      BSA-export signal peptide conjugates microinjected into the nuclei of HeLa cells.
      Functional confirmation of both signals (1017-1028 and 1054-1066) was provided by
      transfection of human myeloma cells with plasmids containing the gene for a full
      length human FLAG-topoisomerase fusion protein, mutated at hydrophobic amino acid
      residues in the export signals. Of the six putative export signals tested, the
      two sites above were found to induce export into the cytoplasm. Export by both
      signals was blocked by treatment of the cells with leptomycin B, indicating that
      a CRM-1-dependent pathway mediates export. Site-directed mutagenesis of two
      central hydrophobic residues in either export signal in full-length human
      topoisomerase blocked export of recombinant FLAG-topoisomerase II alpha,
      indicating that both signals may be required for export. Interestingly, this pair
      of nuclear export signals (1017-1028 and 1054-1066) also defines a dimerization
      domain of the topoisomerase II alpha molecule.

PMID- 15173320
TI  - The soluble D2D3(88-274) fragment of the urokinase receptor inhibits monocyte
      chemotaxis and integrin-dependent cell adhesion.
AB  - We have previously shown that chymotrypsin-cleaved soluble uPAR (D2D3(88-274))
      elicits migration of monocytic cells through interaction with FPRL-1, a G protein
      coupled receptor that is homologous to the fMLP receptor. Here, we report that
      D2D3(88-274) also modulates the ability of monocytes to migrate in response to
      other chemokines. Pretreatment of monocytes with increasing amounts of D2D3(88
      274) prevents cell migration in response to MCP-1, RANTES and fMLP. We
      demonstrate that D2D3(88-274) does not inhibit MCP-1 receptor binding, elicit
      CCR2 internalization and prevent MCP-1-induced intracellular Ca(2+) increase.
      Thus, CCR2 receptor desensitization cannot account for D2D3(88-274)-mediated
      inhibition of MCP-1-induced cell migration. Rather, we show that pretreatment of
      monocytes with D2D3(88-274) dramatically decreases chemokine-induced integrin
      dependent rapid cell adhesion by interacting with FPRL-1. Together, our results
      indicate that chemokine-dependent cell migration can be regulated not only by
      homologous and heterologous receptor desensitization, but also by inhibition of
      integrin-dependent cell adhesion, an important step in cell transmigration.

PMID- 15173321
TI  - Impairment of SHOX nuclear localization as a cause for Leri-Weill syndrome.
AB  - We report the characterization of the nuclear localization signal (NLS) of the
      short stature homeobox gene SHOX. Mutations within the SHOX gene cause Leri-Weill
      dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LD) as well as idiopathic
      short stature (ISS). Furthermore, haploinsufficiency of SHOX has also been
      implicated in Turner syndrome. SHOX has been shown to be a cell-type-specific
      transcriptional activator that localizes to the nucleus. The SHOX protein
      contains a central homeodomain that together with its transactivation domain
      regulates the transcription of its target sequences within the nucleus. The
      sequences for its nuclear localization have not been identified yet. Experimental
      characterization of SHOX-NLS by deletion mapping identified a non-classic type
      basic signal, AKCRK, in the recognition helix of the homeodomain. Fusion of this
      stretch of five amino acids to a cytoplasmic reporter protein resulted in its
      nuclear translocation. Functional analysis of a missense mutation R173C (C517T)
      affecting the identified SHOX-NLS in two families with LWS and LD showed that the
      mutated SHOX protein is unable to enter the nucleus. Conversely, we can
      demonstrate that insertion of the identified signal adjacent to the mutant site
      can restore its nuclear translocation. These results establish impairment of
      nuclear localization as a mechanistic basis for SHOX-related diseases.

PMID- 15173322
TI  - A role for yeast oxysterol-binding protein homologs in endocytosis and in the
      maintenance of intracellular sterol-lipid distribution.
AB  - The seven yeast OSH genes (OSH1-OSH7) encode a family of orthologs of the
      mammalian oxysterol-binding protein (OSBP). The OSH genes share at least one
      essential overlapping function, potentially linked to the regulation of secretory
      trafficking and membrane lipid composition. To investigate the essential roles of
      the OSH genes, we constructed conditional OSH mutants and analyzed their cellular
      defects. Elimination of all OSH function altered intracellular sterol-lipid
      distribution, caused vacuolar fragmentation, and resulted in an accumulation of
      lipid droplets in the cytoplasm and within vacuolar fragments. Gradual depletion
      of Osh proteins also caused cell budding defects and abnormal cell wall
      deposition. In OSH mutant cells endocytosis was severely impaired, but protein
      transport to the vacuole and the plasma membrane was largely unaffected. Other
      mutants affecting sterol-lipid function and distribution, namely erg2Delta and
      arv1Delta, shared similar defects. These findings suggested that OSH genes,
      through effects on intracellular sterol distribution, establish a plasma membrane
      lipid composition that promotes endocytosis.

PMID- 15173323
TI  - Mammalian class E Vps proteins, SBP1 and mVps2/CHMP2A, interact with and regulate
      the function of an AAA-ATPase SKD1/Vps4B.
AB  - SKD1 belongs to the AAA-ATPase family and is one of the mammalian class E Vps
      (vacuolar protein sorting) proteins. Previously we have reported that the
      overexpression of an ATPase activity-deficient form of SKD1 (suppressor of
      potassium transport growth defect), SKD1(E235Q), leads the perturbation of
      membrane transport through endosomes and lysosomes, however, the molecular
      mechanism behind the action of SKD1 is poorly understood. We have identified two
      SKD1-binding proteins, SBP1 and mVps2, by yeast two-hybrid screening and we
      assign them as mammalian class E Vps proteins. The primary sequence of SBP1
      indicates 22.5% identity with that of Vta1p from Saccharomyces cerevisiae, which
      was recently identified as a novel class E Vps protein binding to Vps4p. In fact,
      SBP1 binds directly to SKD1 through its C-terminal region (198-309). Endogenous
      SBP1 is exclusively localized to cytosol, however it is redirected to an aberrant
      endosomal structure, the E235Q compartment, in the cells expressing SKD1(E235Q).
      The ATPase activity of SKD1 regulates both the membrane association of, and
      assembly of, a large hetero-oligomer protein complex, containing SBP1, which is
      potentially involved in membrane transport through endosomes and lysosomes. The N
      terminal half (1-157) of human SBP1 is identical to lyst-interacting protein 5
      and intriguingly, SKD1 ATPase activity significantly influences the membrane
      association of lyst protein. The SKD1-SBP1 complex, together with lyst protein,
      may function in endosomal membrane transport. A primary sequence of mVps2, a
      mouse homologue of human CHMP2A/BC-2, indicates 44.4% identity with
      Vps2p/Did4p/Chm2p from Saccharomyces cerevisiae. mVps2 also interacts with SKD1
      and is localized to the E235Q compartment. Intriguingly, the N-terminal coiled
      coil region of mVps2 is required for the formation of the E235Q compartment but
      not for binding to SKD1. We propose that both SBP1 and mVps2 regulate SKD1
      function in mammalian cells.

PMID- 15173324
TI  - The policing of science.

PMID- 15173325
TI  - Making cycle helmets compulsory: ethical arguments for legislation.

PMID- 15173326
TI  - Predictors for falls among hospital inpatients with impaired mobility.
AB  - Gait and balance disturbances have been shown to predispose to falls in hospital.
      We aimed to investigate the patient characteristics associated with an unsafe
      gait and to determine what features predispose to falling in this group of
      hospital inpatients. In a prospective open observational study we studied 825
      patients admitted for rehabilitation following acute medical illness or a
      surgical procedure. The patient's gait was assessed with the 'get up and go' test
      and classified into one of four categories-normal; abnormal but safe with or
      without mobility aids; unsafe; or unable. 72.6% of patients were assessed as
      having an unsafe gait. The factors independently associated with an unsafe gait
      were confusion, abnormal lower limbs, hearing defects and the use of
      tranquillizers. Patients with an unsafe gait who fell were more likely than the
      non-fallers within the group to have had falls in the past (85.3% versus 73.8%)
      and to be confused (66.2% versus 34.1%). Patients with both these characteristics
      had a 37.5% chance of falling compared with 15.4% in patients with one and 11.2%
      in patients with none of these characteristics. The presence of confusion and a
      history of falls identifies those patients who are at greatest risk of falls.
      Such patients might be the focus of special efforts at falls prevention.

PMID- 15173327
TI  - GLP-1: target for a new class of antidiabetic agents?

PMID- 15173329
TI  - The two-week-wait cancer initiative in urology: useful modernization?
AB  - The two-week-wait cancer initiative in the UK was designed to speed referral of
      patients suspected of having cancer and, by so doing, improve their outcome. We
      reviewed the case notes of all patients referred under this scheme to a single
      urology department over twelve months. In the department, nearly one-third of new
      outpatient appointments came under this scheme. 124 patients were referred and
      all but 7 were seen within the 14-day deadline. In 62 the reason for referral was
      haematuria, which was macroscopic in 42. Of those with macroscopic haematuria 6
      proved to have cancer, newly diagnosed in 4 (2 bladder, 2 renal); no patient with
      microscopic haematuria had cancer. Of 35 referred with a raised prostate-specific
      antigen 11 had prostate cancer, in most cases beyond cure. Cancer was found in 1
      of 19 patients referred with a testicular mass. In patients referred under the
      two-week-wait scheme with macroscopic haematuria, cancer is common. Microscopic
      haematuria is seldom significant. Carcinoma of the prostate is usually advanced
      and beyond cure at presentation. Among patients referred with scrotal lumps,
      cancer of the testis is not common. The scheme as a whole is unlikely to improve
      cancer outcomes. Patients with macroscopic haematuria might be better served by
      one-stop clinics. For those with testicular lumps, most of which will be benign,
      the best answer might be direct general practitioner access to scrotal
      ultrasonography.

PMID- 15173328
TI  - Will off-pump coronary artery surgery replace conventional coronary artery
      surgery?

PMID- 15173330
TI  - An infectious cause of metastatic bone disease.

PMID- 15173331
TI  - Left arm pain 22 years after repair of aortic coarctation.

PMID- 15173332
TI  - Laparoscopic cholecystectomy in a patient with myotonic dystrophy.

PMID- 15173334
TI  - Encephalopathy with hypothyroidism.

PMID- 15173333
TI  - Thyrotoxicosis, sumatriptan and coronary artery spasm.

PMID- 15173335
TI  - Acute abdomen from a Meckel lipoma.

PMID- 15173336
TI  - Respiratory distress after heavy lifting.

PMID- 15173337
TI  - Medicinal uses of tobacco in history.

PMID- 15173338
TI  - Thomas Addison (1793-1860).

PMID- 15173339
TI  - Gerard de Lairesse: genius among the treponemes.

PMID- 15173340
TI  - Dilemmas in managing intracerebral haemorrhage and thromboembolism.

PMID- 15173341
TI  - Evidence-based and complementary medicine.

PMID- 15173342
TI  - Surgical waiting lists are not inevitable.

PMID- 15173344
TI  - Dilemmas in managing intracerebral haemorrhage and thromboembolism.

PMID- 15173345
TI  - Diagnostic devices in the undergraduate curriculum.

PMID- 15173346
TI  - The language of medicine.

PMID- 15173347
TI  - Ophthalmic surgical training.

PMID- 15173348
TI  - Waiting times for cancer treatment.

PMID- 15173349
TI  - Thyroid swellings in Renaissance art.

PMID- 15173352
TI  - High-throughput polyribosome fractionation.
AB  - Polyribosome sedimentation velocity centrifugation can be used to identify
      differential regulation of the translation of mRNAs. However, ultracentrifugation
      presents practical limitations on the number of sedimentation velocity gradients
      that can be run simultaneously. A method for sedimentation velocity analysis of
      polyribosomes is presented that is based on low-speed centrifugation of sucrose
      gradients prepared in deep 96-well plates, the advantage of which is that
      hundreds of polyribosome fractionations can be performed simultaneously in a
      tabletop centrifuge.

PMID- 15173353
TI  - Irreversible bodily interventions in children.

PMID- 15173354
TI  - Circumcision: a surgeon's perspective.

PMID- 15173355
TI  - Value judgment, harm, and religious liberty.

PMID- 15173356
TI  - Male circumcision: a scientific perspective.

PMID- 15173357
TI  - Rationalising circumcision: from tradition to fashion, from public health to
      individual freedom--critical notes on cultural persistence of the practice of
      genital mutilation.
AB  - Despite global and local attempts to end genital mutilation, in their various
      forms, whether of males or females, the practice has persisted throughout human
      history in most parts of the world. Various medical, scientific, hygienic,
      aesthetic, religious, and cultural reasons have been used to justify it. In this
      symposium on circumcision, against the background of the other articles by
      Hutson, Short, and Viens, the practice is set by the author within a wider,
      global context by discussing a range of rationalisations used to support
      different types of genital mutilation throughout time and across the globe. It is
      argued that in most cases the rationalisations invented to provide support for
      continuing the practice of genital mutilation--whether male or female--within
      various cultural and religious settings have very little to do with finding a
      critical and reflective moral justification for these practices. In order to
      question the ethical acceptability of the practice in its non-therapeutic forms,
      we need to focus on child rights protection.

PMID- 15173358
TI  - The development of professional guidelines on the law and ethics of male
      circumcision.
AB  - This paper does not attempt to lay out the arguments relating to male
      circumcision for non-medical reasons. Rather, the aim is to focus more on the
      process and the problems of a professional body (in this case the British Medical
      Association (BMA)) attempting to produce any consensus guidelines for its members
      on an issue which clearly polarises doctors as much as it divides society as a
      whole. The legal and ethical considerations of male circumcision are inevitably
      touched upon here but are not the central issue. In 2003, the BMA published
      professional guidance on this subject. Some thought this a pointless exercise;
      others saw it as an initiative which simply failed to go far enough. Reservations
      centred on the fact that the BMA's guidance--like that of the statutory body, the
      General Medical Council--explored the issues without either firmly rejecting or
      accepting non-therapeutic male circumcision. Was it then a fruitless project or a
      brave start to grasping the nettle?

PMID- 15173359
TI  - The law and ethics of male circumcision: guidance for doctors.

PMID- 15173362
TI  - Medical futility and physician discretion.
AB  - Some patients have no chance of surviving if not treated, but very little chance
      if treated. A number of medical ethicists and physicians have argued that
      treatment in such cases is medically futile and a matter of physician discretion.
      This paper critically examines that position. According to Howard Brody and
      others, a judgment of medical futility is a purely technical matter, which
      physicians are uniquely qualified to make. Although Brody later retracted these
      claims, he held to the view that physicians need not consult the patient or his
      family to determine their values before deciding not to treat. This is because
      professional integrity dictates that treatment should not be undertaken. The
      argument for this claim is that medicine is a profession and a social practice,
      and thus capable of breaches of professional integrity. Underlying professional
      integrity are two moral principles, one concerning harm, the other fraud.
      According to Brody both point to the fact that when the odds of survival are very
      low treatment is a violation of professional integrity. The details of this
      skeletal argument are exposed and explained, and the full argument is criticised.
      On a number of counts, it is found wanting. If anything, professional integrity
      points to the opposite conclusion.

PMID- 15173361
TI  - Ideals of patient autonomy in clinical decision making: a study on the
      development of a scale to assess patients' and physicians' views.
AB  - OBJECTIVES: Evidence based patient choice seems based on a strong liberal
      individualist interpretation of patient autonomy; however, not all patients are
      in favour of such an interpretation. The authors wished to assess whether ideals
      of autonomy in clinical practice are more in accordance with alternative concepts
      of autonomy from the ethics literature. This paper describes the development of a
      questionnaire to assess such concepts of autonomy. METHODS: A questionnaire,
      based on six moral concepts from the ethics literature, was sent to aneurysm
      patients and their surgeons. The structure of the questionnaire was assessed by
      factor analysis, and item reduction was based on reliability. RESULTS: Ninety six
      patients and 58 surgeons participated. The questionnaire consisted of four
      scales. Two of the scales reflected the paternalistic and consumerist poles of
      the liberal individualist model, one scale reflected concepts of Socratic
      autonomy and of procedural independence, and the fourth scale reflected ideals of
      risk disclosure. DISCUSSION: The Ideal Patient Autonomy Scale is a 14 item
      normative instrument. It is clearly distinct from the generally used
      psychological preference questionnaires that assess preferences for physician
      patient roles.

PMID- 15173360
TI  - Evaluation of end of life care in cancer patients at a teaching hospital in
      Japan.
AB  - OBJECTIVES: To analyse the decision making for end of life care for patients with
      cancer at a teaching hospital in Japan at two periods 10 years apart. DESIGN AND
      SETTING: Retrospective study conducted in a 550 bed community teaching hospital
      in Okinawa, Japan. PATIENTS: There were 124 terminally ill cancer patients (45
      women; 79 men; median age, 69 years) admitted either in 1989 and 1999 for end of
      life care with sufficient data to permit analysis. MAIN MEASUREMENTS: Basic
      demographic data, notification to the patient that he or she had cancer, patient
      involvement in do not resuscitate (DNR) orders, and various medical interventions
      which were performed in the month prior to the patient's death were evaluated.
      RESULTS: In 1989 none of the patients were notified of their diagnosis; in 1999
      five patients were informed (p = 0.026). Of the 113 (91%) patients with a written
      DNR order, none were involved in consenting to the DNR order. In the month before
      death, patients in both groups received non-palliative treatments such as feeding
      tube placements (five in 1989; five in 1999), total parenteral nutrition (six in
      1989; eight in 1999), and intravenous albumin infusion (four in 1989; five in
      1999). Morphine use increased (30%) significantly in 1999 compared with the 1989
      group. CONCLUSIONS: The majority of patients dying of cancer were still not
      informed of their diagnosis and were seldom involved in DNR decision making at a
      teaching hospital in Japan. There was no change in the number of potentially
      futile interventions that were performed (6-13%) but morphine use increased.
      Modern ethical education is urgently needed in Japanese medical practice to
      improve decision making process in the end of life care.

PMID- 15173363
TI  - One into two will not go: conceptualising conjoined twins.
AB  - This paper is written in response to controversial judicial decisions following
      separation surgery on conjoined twins "Jodie" and "Mary". The courts, it is
      argued, seem to have conceptualised the twins as "entangled singletons" requiring
      medical intervention to render them physically separate and thus "as they were
      meant to be", notwithstanding the death of the weaker twin, "Mary". In contrast,
      we argue that certain notions, philosophical and biological, of what human beings
      are intended to be, are problematic. We consider three compelling
      conceptualisations of conjoined twins and advocate a model that conceives them as
      two psychologically separate individuals who happen to share a body, the sharing
      of a body being integral to the individuality of each twin. While we reject an
      "essentialist" view of the conjoined state, a view which might render separation
      surgery unthinkable in all cases, we nevertheless argue against an "adversarial"
      interpretation of conjoined twins' respective best interests. We maintain that
      the physical entanglement should be regarded as a shared problem rather than one
      posed by one twin to the other. And if, after deliberation, separation surgery is
      deemed the "least detrimental alternative" or the "lesser of two evils", then
      there should be recognition of what conjoined twins will lose, as well as gain,
      through separation. The current drive to separate twins at all costs may evince a
      deeper unease with bodily configurations that appear to threaten the premium that
      the Western ethical and legal tradition places on personal sovereignty, and the
      physical circumscription that such sovereignty assumes.

PMID- 15173364
TI  - Consent for anaesthesia.
AB  - "Informed consent" is a legal instrument that allows individuals to define their
      own interests and to protect their bodily privacy. In current medical practice,
      patients who have consented to surgery are considered to have implied consent to
      anaesthesia, even though anaesthesia is associated with its own particular set of
      risks and consequences that are quite separate from those associated with
      surgery. In addition, anaesthetists often perform interventions that are the only
      medical treatment received by a patient. Anaesthetists, therefore, should always
      obtain separate consent for anaesthesia, and should regard the process of consent
      as a stimulus for active, fluid reciprocal discussion with patients about
      treatment options.

PMID- 15173365
TI  - Blinkered bioethics.

PMID- 15173366
TI  - The influence of risk and monetary payment on the research participation decision
      making process.
AB  - OBJECTIVES: To determine the effects of risk and payment on subjects' willingness
      to participate, and to examine how payment influences subjects' potential
      behaviours and risk evaluations. METHODS: A 3 (level of risk) x 3 (level of
      monetary payment), between subjects, completely randomised factorial design was
      used. Students enrolled at one of five US pharmacy schools read a recruitment
      notice and informed consent form for a hypothetical study, and completed a
      questionnaire. Risk level was manipulated using recruitment notices and informed
      consent documents from hypothetical biomedical research projects. Payment levels
      were determined using the payment models evaluated by Dickert and Grady as a
      guide. Five dependent variables were assessed in the questionnaire: willingness
      to participate, willingness to participate with no payment, propensity to neglect
      to tell about restricted activities, propensity to neglect to tell about negative
      effects, and risk rating. RESULTS: Monetary payment had positive effects on
      respondents' willingness to participate in research, regardless of the level of
      risk. However, higher monetary payments did not appear to blind respondents to
      the risks of a study. Payment had some influence on respondents' potential
      behaviours regarding concealing information about restricted activities. However,
      payment did not appear to have a significant effect on respondents' propensity to
      neglect to tell researchers about negative effects. CONCLUSIONS: Monetary
      payments appear to do what they are intended to do: make subjects more willing to
      participate in research. Concerns about payments blinding subjects to risks could
      not be substantiated in the present study. However, the findings do raise other
      concerns--notably the potential for payments to diminish the integrity of a
      study's findings. Future research is critical to make sound decisions about the
      payment of research subjects.

PMID- 15173367
TI  - Finding European bioethical literature: an evaluation of the leading abstracting
      and indexing services.
AB  - OBJECTIVES: In this study the author aimed to provide information for researchers
      to help them with the selection of suitable databases for finding medical ethics
      literature. The quantity of medical ethical literature that is indexed in
      different existing electronic bibliographies was ascertained. METHOD: Using the
      international journal index Ulrich's Periodicals Directory, journals on medical
      ethics were identified. The electronic bibliographies indexing these journals
      were analysed. In an additional analysis documentalists indexing bioethical
      literature were asked to name European journals on medical ethics. The
      bibliographies indexing these journals were examined. RESULTS: Of 290 journals on
      medical ethics 173 were indexed in at least one bibliography. Current Contents
      showed the highest coverage with 66 (22.8%) journals indexed followed by MEDLINE
      (22.1%). By a combined search in the top ten bibliographies with the highest
      coverage, a maximum coverage of 45.2% of all journals could be reached. All the
      bibliographies showed a tendency to index more North American than European
      literature. This result was verified by the supplementary analysis of a sample of
      continental European journals. Here EMBASE covered the highest number of journals
      (20.6%) followed by the Russian Academy of Sciences Bibliographies (19.2%).
      CONCLUSION: A medical ethics literature search has to be carried out in several
      databases in order to reach an adequate collection of literature. The databases
      one wishes to combine should be carefully chosen. There seems to be a regional
      bias in the most popular databases, favouring North American periodicals compared
      with European literature on medical ethics.

PMID- 15173368
TI  - Certainty and mortality prediction in critically ill children.
AB  - OBJECTIVES: The objective of this study is to investigate the relationship
      between a physician's subjective mortality prediction and the level of confidence
      with which that mortality prediction is made. DESIGN AND PARTICIPANTS: The study
      is a prospective cohort of patients less than 18 years of age admitted to a
      tertiary Paediatric Intensive Care Unit (ICU) at a University Children's Hospital
      with a minimum length of ICU stay of 10 h. Paediatric ICU attending physicians
      and fellows provided mortality risk predictions and the level of confidence
      associated with these predictions on consecutive patients at the time of
      multidisciplinary rounds within 24 hours of admission to the paediatric ICU.
      Median confidence levels were compared across different ranges of mortality risk
      predictions. RESULTS: Data were collected on 642 of 713 eligible patients (36
      deaths, 5.6%). Mortality predictions greater than 5% and less than 95% were made
      with significantly less confidence than those predictions <5% and >95%.
      Experience was associated with greater confidence in prognostication.
      CONCLUSIONS: We conclude that a physician's subjective mortality prediction may
      be dependent on the level of confidence in the prognosis; that is, a physician
      less confident in his or her prognosis is more likely to state an intermediate
      survival prediction. Measuring the level of confidence associated with mortality
      risk predictions (or any prognostic assessment) may therefore be important
      because different levels of confidence may translate into differences in a
      physician's therapeutic plans and their assessment of the patient's future.

PMID- 15173369
TI  - The stipulations of one institutional review board: a five year review.
AB  - OBJECTIVES: This study was designed to explore the prevalence and types of
      stipulations (such as clarifications or changes) required of investigators by the
      institutional review board (IRB) of one institution over a five year period.
      DESIGN: Stipulations to research proposals (n = 124) were documented from the
      minutes of the IRB meetings. SETTING: Community hospital. PARTICIPANTS: IRB
      submissions. MAIN MEASUREMENTS: Number and type of IRB stipulations. RESULTS:
      Nineteen research submissions (15.3%) were approved without any stipulations. For
      the remainder, the majority of stipulations related to consent forms (74.2%).
      CONCLUSIONS: Consent forms appear to be at highest risk for IRB stipulations.
      Being aware of high risk areas before submission of research proposals may reduce
      the frequency of stipulations required of investigators.

PMID- 15173370
TI  - Communicating information on cardiopulmonary resuscitation to hospitalised
      patients.
AB  - AIM: The primary aim of the study was to evaluate two different methods of
      communicating information on cardiopulmonary resuscitation (CPR) to patients
      admitted to general medical and elderly care wards. The information was either in
      the form of a detailed information leaflet (appendix I) or a summary document
      (appendix II). The study examined the willingness of patients in seeking detailed
      information on cardiopulmonary issues. SETTING: The study was conducted over
      three months on a general medical ward and an acute elderly care ward in two
      district general hospitals. METHODS: A detailed information leaflet on CPR was
      provided to the nursing staff on the wards. An A4 summary document summarising
      the CPR decision making process and basic information on cardiopulmonary issues
      was placed in a folder at the foot of each bed on the elderly care ward. On the
      general medical ward it was displayed prominently over the head of all beds.
      RESULTS: Out of the 274 patients admitted to the general medical ward only two
      requests were received for the detailed information leaflet. On the elderly care
      ward there were 182 admissions but no patients or their relatives requested the
      leaflet. CONCLUSIONS: Availability of basic information on cardiopulmonary
      resuscitation to all patients is practical and does not lead to unnecessary
      distress or offence to patients or their carers. It makes the decision making
      process more transparent. Detailed information leaflets are of value for a
      minority of hospitalised patients.

PMID- 15173371
TI  - What are local issues? The problem of the local review of research.
AB  - Local review of research by ethics committees in the UK has long been held to be
      an important right of the local research ethics committee and, even with the
      introduction of the European Clinical Trials Directive, the governance
      arrangements for research ethics committees continue to allow for local review of
      multicentre studies. There is no requirement for local review in either the
      European Union directive or in the guidelines on good clinical practice, and
      there is little evidence of it anywhere else in Europe. The idea that there can
      be "local", as opposed to "central" ethical issues in research is an interesting
      one, which raises important issues about the nature of research ethics and
      ethical review. The aim of this paper is to argue that there are no such things
      as local issues in research ethics, and suggest that those questions currently
      addressed as local issues properly belong within the research governance
      framework.

PMID- 15173372
TI  - Community based trials and informed consent in rural north India.
AB  - Disease control has increasingly shifted towards large scale, disease specific,
      public health interventions. The emerging problems of HIV, hepatitis, malaria,
      typhoid, tuberculosis, childhood pneumonia, and meningitis have made community
      based trials of interventions a cost effective long term investment for the
      health of a population. The authors conducted this study to explore the
      complexities involved in obtaining informed consent to participation in rural
      north India, and how people there make decisions related to participation in
      clinical research.

PMID- 15173373
TI  - Religion, the law, and medical ethics. Response to a response.

PMID- 15173374
TI  - What is genethics?

PMID- 15173376
TI  - Endometrial morphology and pituitary-gonadal axis dysfunction in women of
      reproductive age undergoing chronic haemodialysis--a multicentre study.
AB  - BACKGROUND: Although disorders of the reproductive system are very common in
      women undergoing chronic haemodialysis, this issue remains a neglected area. The
      aim of the study was to evaluate the endometrial morphology and its relationship
      with pituitary-gonadal axis dysfunction in uraemic women of reproductive age
      undergoing haemodialysis. METHODS: The baseline survey with determination of the
      sex hormones concentrations was performed in 75 haemodialysed women aged 18-45
      years. The control group consisted of 33 healthy premenopausal women, aged 18-45
      years, with normal menstruation. Then, 40 haemodialysis women, who met the
      inclusion criteria and gave their informed consent, underwent endometrium suction
      biopsy. RESULTS: The pathological endometrial morphology was observed in 80% of
      biopsied subjects. Atrophia or subatrophia was recognized in almost half of the
      cases, and proliferative changes in one-third of them. Full atrophia with no
      mitotic figures was found in all but one non-menstruating woman. In one case,
      adenocarcinoma in situ was diagnosed and successfully treated. The analysis of
      the relationship between hormonal status and endometrial morphology revealed the
      substantial influence of oestradiol on endometrium as a target organ. In women
      with atrophic changes, oestradiol concentrations were significantly decreased,
      whereas in the remaining subjects, the increase of serum oestradiol seemed to be
      accompanied by a shift in endometrium morphology from secretional pattern,
      through proliferative changes to glandular hyperplasia. Mean serum 17-beta
      oestradiol was decreased in women with amenorrhoea, and increased in those with
      eumenorrhoea (P<0.001). Except women with regular menses, mean serum progesterone
      concentrations were in the lower normal range. Seventy-five percent of the
      studied population had menstrual disorders, and amenorrhoea constituted almost a
      half of them. CONCLUSIONS: Pathological endometrium morphology is very common in
      uraemic women of reproductive age undergoing haemodialysis, with proliferative
      changes in one-third and atrophia in almost a quarter of them. The results of the
      study suggest a preserved normal reactivity of endometrium on circulating
      oestrogens.

PMID- 15173377
TI  - Demography of paediatric renal care in Europe: organization and delivery.
AB  - BACKGROUND: Members of the European Society of Paediatric Nephrology (ESPN)
      initiated a study of the demography and policy of paediatric renal care among
      European countries at the end of the 20th century. METHODS: A questionnaire was
      mailed to the presidents of each of 43 national renal paediatric societies or
      working groups in Europe. Data on each country's population, income as reflected
      by its gross national product and infant mortality rate, were obtained from the
      United Nations. The paediatric health care systems were previously divided into
      three types: general practitioner care system, paediatric care system and
      combined care system (CCS). RESULTS: In 1998, 842 specialized paediatric
      nephrologists worked in hospitals in 42 European countries. The median number of
      paediatric nephrologists per million child population (pmcp) was 4.9 (range 0
      15). The median number of children served per paediatric nephrologist was
      significantly higher in countries with the general practitioner care system than
      in those with the paediatric or combined care system (CCS), namely 370 747 vs 169
      456 and 191 788, respectively. In addition to specially trained paediatric
      nephrologists, there were 1087 paediatricians with a part-time interest/activity
      in paediatric nephrology in hospitals in 34 European countries. Eastern European
      countries had significantly more general paediatricians with part-time
      nephrological activities than countries belonging to the European Union (EU),
      16.7 vs 6.6 pmcp. In 1998, 92% of 42 European countries offered paediatric
      dialysis facilities for acute renal failure and 90% for chronic renal failure and
      55% offered paediatric renal transplantation (RTx). Only 30% of Eastern European
      countries (central omitted) offered paediatric RTx vs 87% of EU countries. The
      availability of paediatric RTx was associated significantly with the countries'
      gross national product (r = 0.53, P<0.001). The median number of paediatric
      hospitals offering dialysis for childhood chronic renal failure was 1.5 pmcp
      (range 0-5.0) and the median number of paediatric hospitals offering paediatric
      RTx was 0.4 pmcp (range 0-3.5). Fewer children were on dialysis or were
      transplanted in Eastern European countries than in the EU. CONCLUSIONS: At the
      end of the 20th century, there was a marked variation in delivery of paediatric
      renal care within Europe. This was related to factors such as size of the
      population, geographical and political situation, the type of primary paediatric
      care system and economic situation. European countries were far from equal with
      regard to access of renal replacement therapy for children. Improvement of the
      economic situation is beyond the capabilities of paediatric nephrologists.
      However, in these days of world-wide globalization paediatricians in greater
      Europe should be able to achieve better cooperation and exchange of ideas and
      information which would be the first step towards equality of renal care for
      children.

PMID- 15173378
TI  - Effect of ammonium chloride and dietary phosphorus in the azotaemic rat. I. Renal
      function and biochemical changes.
AB  - BACKGROUND: Both dietary phosphorus restriction and the ingestion of ammonium
      chloride (NH(4)Cl) given to rats on a high-phosphorus diet have been shown to
      preserve renal function in the azotaemic rat. Parathyroidectomy also has been
      reported to preserve renal function and, in addition, to prevent kidney
      hypertrophy in the remnant kidney model. Our goals were (i) to evaluate in
      azotaemic rats the effect of dietary phosphorus on renal function in a shorter
      time frame than previously studied and (ii) to determine whether NH(4)Cl
      administration (a) enhances the renoprotective effect of dietary phosphorus
      restriction and (b) improves renal function in the absence of parathyroid hormone
      (PTH). METHODS: High (H; 1.2%), normal (N; 0.6%) and low (L; <0.05%) phosphorus
      diets (PD) were given for 30 days to 5/6 nephrectomized rats. In each dietary
      group, one-half of the rats were given NH(4)Cl in the drinking water. The six
      groups were HPD + NH(4)Cl, HPD, NPD + NH(4)Cl, NPD, LPD + NH(4)Cl and LPD. The
      effect of NH(4)Cl administration was also evaluated in 5/6 nephrectomized,
      parathyroidectomized (PTX) rats on NPD. RESULTS: In each of the three dietary
      phosphorus groups, creatinine and urea clearances were greater (P<0.01) in rats
      receiving NH(4)Cl. Neither creatinine nor urea clearance was reduced by high
      dietary phosphorus. Urine calcium excretion was greatest in the LPD group and was
      increased (P < or = 0.001) in all three groups by NH(4)Cl ingestion. An inverse
      correlation was present between plasma calcium and phosphorus in the parathyroid
      intact (r = -0.79, P<0.001) and PTX groups (r = -0.46, P = 0.02). In PTX rats,
      NH(4)Cl ingestion increased (P < or = 0.01) creatinine and urea clearances and
      both an increasing plasma calcium concentration (r = 0.67, P<0.001) and urine
      calcium excretion (r = 0.73, P<0.001) increased urine phosphorus excretion.
      CONCLUSIONS: At 30 days of renal failure (i) NH(4)Cl ingestion increased
      creatinine and urea clearances, irrespective of dietary phosphorus; (ii) high
      urine calcium excretion, induced by dietary phosphorus restriction and NH(4)Cl
      ingestion, did not adversely affect renal function; (iii) high dietary phosphorus
      did not decrease renal function; (iv) the absence of PTH did not preserve renal
      function or prevent NH(4)Cl from improving renal function; and (v) both an
      increasing plasma calcium concentration and urine calcium excretion resulted in
      an increase in urine phosphorus excretion in PTX rats.

PMID- 15173379
TI  - Trends in incidence of end-stage renal disease in Japan, 1983-2000: age-adjusted
      and age-specific rates by gender and cause.
AB  - BACKGROUND: Trends in age-adjusted or age-specific incidence rates of end-stage
      renal disease (ESRD) have never been examined in Japan, a major ESRD epidemic
      area. METHODS: A nationwide registry has provided the number of ESRD patients
      commencing maintenance renal replacement therapy for time period from 1983 to
      2000. We computed gender- and age-specific incidence rates of ESRD over 2-year
      periods, in total or by cause. Age-adjusted incidence rates were calculated using
      the 1985 Model Population of Japan as the standard. RESULTS: Causes of ESRD in
      1999-2000 were, in order of decreasing frequency, diabetic nephropathy, chronic
      glomerulonephritis, unknown causes, nephrosclerosis and polycystic kidney disease
      in men, and chronic glomerulonephritis, diabetic nephropathy, unknown causes,
      nephrosclerosis and polycystic kidney disease in women. The age-adjusted all
      cause incidence of ESRD increased until 1995-1996, but has since levelled off in
      both genders. The age-adjusted rate for diabetic nephropathy has been rapidly
      increasing, while that for chronic glomerulonephritis has decreased since 1995
      1996. The former rate exceeded the latter in 1997-1998 in men. All-cause ESRD has
      rapidly increased in the eighties age group, whereas the increase slowed down in
      younger age groups in the late 1990s. The rate for diabetic nephropathy has
      linearly risen in almost every age group in men, whereas it began to level off in
      women aged 40-59 years at about 1995. For chronic glomerulonephritis, the rate
      had already started to decline in the mid-1980s in those aged <45 years. The rate
      of nephrosclerosis has been increasing independently of age. CONCLUSIONS: The
      present study shows changes in the epidemiological features of the incidence of
      ESRD in Japan from 1983 to 2000.

PMID- 15173380
TI  - DnaG interacts with a linker region that joins the N- and C-domains of DnaB and
      induces the formation of 3-fold symmetric rings.
AB  - Loading of the replicative ring helicase onto the origin of replication (oriC) is
      the final outcome of a well coordinated series of events that collectively
      constitute a primosomal cascade. Once the ring helicase is loaded, it recruits
      the primase and signals the switch to the polymerization mode. The transient
      nature of the helicase-primase (DnaB-DnaG) interaction in the Escherichia coli
      system has hindered our efforts to elucidate its structure and function. Taking
      advantage of the stable DnaB-DnaG complex in Bacillus stearothermophilus, we have
      reviewed conflicting mutagenic data from other bacterial systems and shown that
      DnaG interacts with the flexible linker that connects the N- and C-terminal
      domains of DnaB. Furthermore, atomic force microscopy (AFM) imaging experiments
      show that binding of the primase to the helicase induces predominantly a 3-fold
      symmetric morphology to the hexameric ring. Overall, three DnaG molecules appear
      to interact with the hexameric ring helicase but a small number of complexes with
      two and even one DnaG molecule bound to DnaB were also detected. The
      structural/functional significance of these data is discussed and a speculative
      structural model for this complex is suggested.

PMID- 15173381
TI  - 3'-box-dependent processing of human pre-U1 snRNA requires a combination of RNA
      and protein co-factors.
AB  - Using an in vitro system we have recently shown that the 3' ends of human pre
      snRNAs synthesized by RNA polymerase II are produced by RNA processing directed
      by the snRNA gene-specific 3' box. Towards a complete characterization of this
      processing reaction we have further investigated the in vitro requirements for
      proper 3' end formation of pre-U1 snRNA. Here we show that the 5' cap plays a
      stimulatory role and processing requires creatine phosphate. Our results also
      indicate that the pre-U1 processing activity is heat sensitive and that an RNA
      component is required. In addition, the exact sequence adjacent to the 3' box
      influences the position of the pre-U1 3' end produced in vitro. Interestingly,
      the processing extract active for 3'-box-dependent processing also contains an
      activity that converts the 3' end of RNA containing the U1 Sm protein binding
      site and the 3' terminal stem-loop into the mature form.

PMID- 15173382
TI  - The highly conserved region of the co-repressor Sin3A functionally interacts with
      the co-repressor Alien.
AB  - The Sin3 proteins are evolutionarily conserved co-repressors (CoR) that function
      as mediators of gene repression for a variety of transcriptional silencers. The
      paired amphipathic helices of Sin3A were identified and studied as protein
      protein interacting domains. Previously we have shown the interaction of Sin3A
      with the CoR Alien in vivo and in vitro. Here, we show that Alien and Sin3A
      reside together in vivo with the vitamin D3 receptor on the human 24-hydroxylase
      (CYP24) promoter containing vitamin D3 response elements by chromatin
      immunoprecipitation. We delineated and characterized the interaction domains of
      Sin3A with Alien. Interestingly, the highly conserved region (HCR) of Sin3A,
      which has not yet been functionally characterized, interacts with Alien. The HCR
      encompasses only 134 amino acids, shares more than 80% identity with Sin3B and
      binds to the N-terminus of Alien, which harbours a transferable silencing
      function. Functionally, co-expression of Sin3A enhances Alien-mediated gene
      repression and overexpression of the HCR alone leads to the inhibition of Alien
      mediated repression and to the induction of the endogenous CYP24 promoter. Our
      results therefore indicate a novel functional role of the Sin3 HCR and give novel
      insights into Alien-mediated gene repression.

PMID- 15173383
TI  - The C-terminal zinc finger of the catalytic subunit of DNA polymerase delta is
      responsible for direct interaction with the B-subunit.
AB  - DNA polymerase delta (Pol delta) plays a central role in eukaryotic chromosomal
      DNA replication, repair and recombination. In fission yeast, Pol delta is a
      tetrameric enzyme, comprising the catalytic subunit Pol3 and three smaller
      subunits, Cdc1, Cdc27 and Cdm1. Previous studies have demonstrated a direct
      interaction between Pol3 and Cdc1, the B-subunit of the complex. Here it is shown
      that removal of the tandem zinc finger modules located at the C-terminus of Pol3
      by targeted proteolysis renders the Pol3 protein non-functional in vivo, and that
      the C-terminal zinc finger module ZnF2 is both necessary and sufficient for
      binding to the B-subunit in vivo and in vitro. Extensive mutagenesis of the ZnF2
      module identifies important residues for B-subunit binding. In particular,
      disruption of the ZnF2 module by substitution of the putative metal-coordinating
      cysteines with alanine abolishes B-subunit binding and in vivo function. Finally,
      evidence is presented suggesting that the ZnF region is post-translationally
      modified in fission yeast cells.

PMID- 15173384
TI  - Definitions and analysis of DNA Holliday junction geometry.
AB  - A number of single-crystal structures have now been solved of the four-stranded
      antiparallel stacked-X form of the Holliday junction. These structures
      demonstrate how base sequence, substituents, and drug and ion interactions affect
      the general conformation of this recombination intermediate. The geometry of
      junctions had previously been described in terms of a specific set of parameters
      that include: (i) the angle relating the ends of DNA duplexes arms of the
      junction (interduplex angle); (ii) the relative rotation of the duplexes about
      the helix axes of the stacked duplex arms (J(roll)); and (iii) the translation of
      the duplexes along these helix axes (J(slide)). Here, we present a consistent set
      of definitions and methods to accurately calculate each of these parameters based
      on the helical features of the stacked duplex arms in the single-crystal
      structures of the stacked-X junction, and demonstrate how each of these
      parameters contributes to an overall conformational feature of the structure. We
      show that the values for these parameters derived from global rather than local
      helical axes through the stacked bases of the duplex arms are the most
      representative of the stacked-X junction conformation. In addition, a very
      specific parameter (J(twist)) is introduced which relates the relative
      orientation of the stacked duplex arms across the junction which, unlike the
      interduplex angle, is length independent. The results from this study provide a
      general means to relate the geometric features seen in the crystal structures to
      those determined in solution.

PMID- 15173385
TI  - Interaction of Escherichia coli DbpA with 23S rRNA in different functional states
      of the enzyme.
AB  - DEx(D)/(H) proteins catalyze structural rearrangements in RNA by coupling ATP
      hydrolysis to the destabilization of RNA helices or RNP complexes. The
      Escherichia coli DEx(D)/(H) protein DbpA specifically recognizes a region within
      the catalytic core of 23S rRNA. To better characterize the interaction of DbpA
      with this region and to identify changes in the complex between different
      nucleotide-bound states of the enzyme, RNase T1, RNase T2, kethoxal and DMS
      footprinting of DbpA on a 172 nt fragment of 23S rRNA were performed. A number of
      protections identified in helices 90 and 92 were consistent with biochemical
      experiments measuring the RNA binding and ATPase activity of DbpA with truncated
      RNAs. When DbpA was bound with AMPPNP, but not ADP, several additional footprints
      were detected in helix 93 and the single-stranded region 5' of helix 90,
      suggesting binding of the helicase domains of DbpA at these sites. These results
      propose that DbpA can act at multiple sites and hint at the targets of its
      biological activity on rRNA.

PMID- 15173386
TI  - New evidence of iron and zinc interplay at the enterocyte and neural tissues.
AB  - Because combined iron-zinc supplementation regimens are employed with increasing
      frequency in field trials to combat co-occurring iron and zinc deficiencies,
      there is a growing concern for potential antagonisms between these 2 metals.
      Several supplementation trials hinted at such a competition, and the intestinal
      divalent metal transporter-1 (DMT1) has often been cited as a possible site for
      its occurrence. We summarize new evidence showing that although iron does seem to
      reduce the absorption of zinc, the DMT1 is an unlikely site for this absorptive
      antagonism by virtue of the fact that zinc is not transported by the DMT1. We
      also propose a shift in thinking about iron-zinc interactions from the level of
      enterocyte to other sites/systems in the body that may be equally relevant for
      the outcome and interpretation of supplementation trials. We present an overview
      of iron and zinc absorption and function in neural tissue as one example of
      possible interactions.

PMID- 15173387
TI  - The discovery of vitamin D: the contribution of Adolf Windaus.

PMID- 15173388
TI  - Genistein at a concentration present in soy infant formula inhibits Caco-2BBe
      cell proliferation by causing G2/M cell cycle arrest.
AB  - Fifteen percent of all U.S. infants are fed soy formulas containing up to 47 mg/L
      of isoflavones (>65% as genistin + genistein); thus, these infants' intestines
      are exposed to a high dose of genistein, a phytoestrogen and tyrosine kinase
      inhibitor. Little attention has been focused on genistein's impact on the
      developing intestine. We hypothesized that a high dose of genistein would inhibit
      intestinal cell growth. Caco-2BBe human intestinal cells were exposed to 0, 3.7,
      and 111 micro mol/L (0, 1, and 30 mg/L) genistein in DMEM + 0.5% fetal bovine
      serum for 24-48 h. Cell number, thymidine incorporation, apoptosis, and cell
      cycle analyses were performed. The low genistein concentration increased
      intestinal cell proliferation by 28% (P = 0.001), but did not affect cell number
      or caspase-3 activity compared to the control. Furthermore, the addition of ICI,
      an estrogen receptor antagonist, negated the proliferative effect of the low
      genistein. In contrast, the high genistein concentration reduced cell number by
      40%, proliferation by 94%, and caspase-3 activity by 50% compared to the control
      (P < 0.05). Cell cycle analysis after 48 h exposure to high genistein revealed
      37% of cells in G0/G1 and 35% in G2/M vs. 71% in G0/G1 and 17% in G2/M for the
      control and low genistein groups. Thus, a biphasic effect of genistein was seen
      with a low dose stimulating intestinal cell proliferation through the estrogen
      receptor, whereas a high dose of genistein inhibited intestinal cell
      proliferation and altered cell cycle dynamics. A high dose of genistein may
      potentially compromise intestinal growth.

PMID- 15173389
TI  - Exogenous nucleosides stimulate proliferation of fetal rat hepatocytes.
AB  - Exogenous nucleotides (NT) have been reported to exert a reparative role in
      animal models of intestinal and hepatic damage. Thus, the administration of NT in
      the diet of rats with thioacetamide-induced liver cirrhosis normalized many of
      the histological and biochemical alterations produced by this hepatotoxin. We are
      currently studying the mechanism by which NT exert this effect using cell culture
      models. The aim of this work was to investigate whether exogenous nucleosides
      (NS) modulate the proliferation of hepatocytes. We used fetal rat hepatocytes,
      which, unlike adult hepatocytes, are proliferative cells. Fetal rat primary
      hepatocytes were incubated with mixtures of NS, and cell proliferation was
      studied. NS added to the medium of fetal hepatocytes were taken up in a selective
      fashion by the cells. Cell proliferation was enhanced, as demonstrated by the
      induction of c-myc and h-ras gene expression as well as by the higher percentage
      of cells in S phase, and exogenous NS increased the expression of alpha
      fetoprotein. These results suggest that exogenous NS may in fact stimulate
      proliferation of hepatic cells and help preserve the undifferentiated state of
      fetal rat hepatocytes.

PMID- 15173390
TI  - Maternal zinc deficiency raises plasma prolactin levels in lactating rats.
AB  - There is an inverse relation between zinc (Zn) intake and plasma prolactin in men
      and nonpregnant women. Whether a relation exists in lactating women is unknown,
      despite the potential consequences of perturbations in prolactin regulation on
      lactation performance. We examined the effects of low Zn intake on prolactin
      concentration, the prolactin regulatory pathway in the pituitary gland, and
      lactation performance in lactating rats. Female rats were fed diets containing 7
      (zinc deficient; ZD), 10 (marginally zinc deficient; MZD) or 25 mg Zn/kg
      (control) from 70 d preconception to lactation d 11. Rats were killed, pituitary
      glands dissected, and tissues and plasma collected and analyzed for prolactin
      concentration. Pituitary gland pituitary factor 1 (Pit-1), dopamine 2 receptor
      (D2R), and prolactin receptor mRNA expression were measured in the pituitary
      gland. Liver, mammary gland, plasma, and milk Zn were measured. Milk intake of
      the pups was also recorded. Plasma prolactin concentration was higher in rats fed
      the ZD (125.9 microg/L) diet compared with control rats (21.7 microg/L).
      Pituitary gland prolactin concentration was higher in rats fed the ZD diet (69.8
      mg/g total protein) compared with controls (29.0 mg/g). Plasma Zn concentration
      was lower in rats fed the MZD and ZD diets, and mammary gland and milk Zn
      concentrations were lower in rats fed the ZD diet compared with control rats.
      Rats fed the ZD diet had lower D2R, prolactin receptor, and Pit-1 mRNA levels,
      whereas rats fed the MZD diet had lower prolactin receptor and Pit-1 mRNA levels
      compared with control rats. Milk intake was lower in pups of rats fed the MZD and
      ZD diets. Our results suggest that marginal Zn nutriture may compromise milk
      production despite increased prolactin levels. In addition, increased circulating
      prolactin concentration is not due to altered nursing behavior, but may be due to
      alterations in the prolactin regulatory pathway in the pituitary gland.

PMID- 15173391
TI  - Fish protein hydrolysate reduces plasma total cholesterol, increases the
      proportion of HDL cholesterol, and lowers acyl-CoA:cholesterol acyltransferase
      activity in liver of Zucker rats.
AB  - There is growing evidence that soy protein improves the blood lipid profiles of
      animals and humans. We compared the effects of fish protein hydrolysate (FPH),
      soy protein, and casein (control) on lipid metabolism in Wistar rats and
      genetically obese Zucker (fa/fa) rats. In Zucker rats, FPH treatment affected the
      fatty acid composition in liver, plasma, and triacylglycerol-rich lipoproteins.
      The mRNA levels of Delta 5 and Delta 6 desaturases were reduced by FPH and soy
      protein feeding compared with casein feeding. In Zucker rats both FPH and soy
      protein treatment reduced the plasma cholesterol level. Furthermore, the HDL
      cholesterol:total cholesterol ratio was greater in these rats and in the Wistar
      rats fed FPH and soy protein compared with those fed casein. Although fecal total
      bile acids were greater in soy protein-fed Zucker rats than in casein-fed
      controls, those fed FPH did not differ from the controls. However, the acyl
      CoA:cholesterol acyltransferase activity was reduced in Zucker rats fed FPH and
      tended to be lower (P = 0.13) in those fed soy protein compared with those fed
      casein. Low ratios of methionine to glycine and lysine to arginine in the FPH and
      soy protein diets, compared with the casein diet, may be involved in lowering the
      plasma cholesterol concentration. Our results indicate that the effects of FPH
      and soy protein on fatty acid metabolism are similar in many respects, but the
      hypocholesterolemic effects of FPH and soy protein appear to be due to different
      mechanisms. FPH may have a role as a cardioprotective nutrient.

PMID- 15173392
TI  - Increased heme oxygenase-1 expression during copper deficiency in rats results
      from increased mitochondrial generation of hydrogen peroxide.
AB  - The activity of hepatic heme oxygenase (HO) in rats is elevated in response to
      copper deficiency. However, the mechanism responsible for the increase in HO
      activity is poorly understood. Oxidative stress is a common denominator for many
      of the signals that induce HO-1, the inducible isoform of HO. The present study
      evaluated the role of H(2)O(2) and the mitochondrial electron transport chain as
      a potential mechanism for the induction of HO-1 during copper deficiency.
      Mitochondria isolated from the livers of young male rats fed a copper-deficient
      diet for 5 wk had significantly (P < 0.05) reduced levels of NADH:cytochrome c
      reductase (31% reduction), succinate:cytrochrome c reductase (42% reduction), and
      cytochrome c oxidase (70% reduction) activities and significantly increased
      production of H(2)O(2) (48% increase) when glutamate was used as a substrate.
      Hepatic levels of HO-1 protein and mRNA were also significantly elevated (48 and
      20%, respectively) in copper-deficient rats, indicating that copper deficiency
      stimulated the expression of the HO-1 gene. Furthermore, hepatic HO-1 protein
      content was best described by a regression model that included mitochondrial
      NADH:cytochrome c reductase and succinate:cytochrome c reductase activities, but
      not cytochrome c oxidase activity (R(2) = 0.54, P < 0.02). Hydrogen peroxide is a
      known inducer of HO-1, and our results suggest that increased mitochondrial
      H(2)O(2) production resulting from inhibition of respiratory complex activities
      contributes to the induction of HO-1 during copper deficiency. The levels of HO-1
      protein and mRNA were also elevated (85 and 95%, respectively) in hearts from
      copper-deficient rats, indicating that the effects of copper deficiency on HO-1
      gene expression are not limited to hepatic tissue.

PMID- 15173393
TI  - The alpha' subunit from soybean 7S globulin lowers plasma lipids and upregulates
      liver beta-VLDL receptors in rats fed a hypercholesterolemic diet.
AB  - Recent data concerning the effect of soybean 7S globulin subunits on the
      upregulation of LDL receptors in Hep G2 cells identified the alpha' subunit as
      the candidate responsible for this biological effect. In vivo evaluation of this
      subunit on cholesterol homeostasis was hampered by the lack of suitable amounts
      of alpha' chain. A novel separation procedure allowed us to investigate the
      effects of alpha' subunit administration on plasma cholesterol and triglyceride
      levels, as well as on the activity of liver beta-VLDL receptors of rats fed a
      hypercholesterolemic (HC) diet. Rats were divided into 9 groups fed the following
      diets for 28 d: standard diet; HC diet; HC diets + 5, 10, and 20 mg/(kg body
      weight. d) of alpha' subunit; HC diets + 50, 100, and 200 mg/(kg body weight. d)
      of soybean 7S globulin; HC diet + 200 mg/(kg body weight. d) clofibrate. The
      highest dose of the alpha' subunit decreased plasma cholesterol and triglycerides
      36 and 34%, respectively, in rats fed the HC diet; 10-fold amounts clofibrate
      reduced plasma cholesterol and triglycerides 38 and 41%. The activity of liver
      beta-VLDL receptors of rats fed the HC diet with the highest dose of the alpha'
      subunit had a 96% increase in binding compared with the HC diet group, thus
      restoring the receptor activity to that of rats fed the standard diet. These
      results represent the first in vivo evidence of both the plasma lipid-lowering
      properties and the upregulation of liver beta-VLDL receptors induced by the
      soybean alpha' subunit.

PMID- 15173394
TI  - The chalcone xanthohumol inhibits triglyceride and apolipoprotein B secretion in
      HepG2 cells.
AB  - The present study examined the role of xanthohumol (XN), a plant chalcone, on
      apolipoprotein B (apoB) and triglyceride (TG) synthesis and secretion, using
      HepG2 cells as the model system. The data indicated that XN decreased apoB
      secretion in a dose-dependent manner under both basal and lipid-rich conditions
      (as much as 43% at 15 micromol/L). This decrease was associated with increased
      cellular apoB degradation. To determine the mechanism underlying this effect, we
      examined triglyceride availability, a major factor in the regulation of apoB
      secretion. XN inhibited the synthesis of TG in the microsomal membrane and the
      transfer of this newly synthesized TG to the microsomal lumen (decreases of 26
      and 64%, respectively, under lipid-rich conditions), indicating that TG
      availability is a determining factor in the regulation of apoB secretion under
      the experimental conditions. The inhibition of TG synthesis was caused by a
      reduction in diacylglycerol acyltransferase (DGAT) activity, which corresponded
      to a decrease in DGAT-1 mRNA expression, but not DGAT-2 expression. Microsomal
      triglyceride transfer protein (MTP) may also control the rate of TG transfer from
      the microsomal membrane to the active lumenal pool. XN decreased MTP activity in
      a dose-dependent manner (as much as 30%). Whether the reduction in TG
      accumulation in the microsomal lumen is predominantly due to DGAT and/or MTP
      activity remains unknown. In summary, the data suggest that xanthohumol is a
      potent inhibitor of apoB secretion.

PMID- 15173395
TI  - Dietary canola and soybean oil fed to SHRSP rat dams differently affect the
      growth and survival of their male pups.
AB  - Canola oil (Can), as well as some other oils, shortens the survival of SHRSP rats
      compared with soybean oil (Soy). Although detrimental factors other than
      phytosterols have not been identified, they are likely to be hydrophobic and
      transmissible to pups. To test this possibility, female SHRSP rats (F0) were fed
      a diet supplemented with Can or Soy and mated at 11 wk of age. The growth of
      suckling pups (F1) from the Can-fed dams was significantly retarded compared with
      that of pups from the Soy-fed dams. Half of the male pups (F1) were weaned to the
      same diet as their dams (Can-->Can and Soy-->Soy groups) and the rest were weaned
      to the other diet (Can-->Soy and Soy-->Can groups). The survival rate of the male
      pups (F1) was significantly lower in the Can-->Can group than in the Soy-->Can
      group, and in the Can-->Soy group than in the Soy-->Soy group, indicating that
      the oils fed to dams differently affected the growth and survival of pups. There
      were fewer pups per dam in the Can-fed dams (F0) than in the Soy-fed dams, and in
      the dams (F1) of the Can-->Can and Soy-->Can groups than in those of the Can-
      >Soy and Soy-->Soy groups. Although Can is nutritionally detrimental to SHRSP
      rats compared with Soy, no direct evidence has been obtained thus far relating
      these observations to human nutrition.

PMID- 15173396
TI  - Docosahexaenoic acid and eicosapentaenoic acid, but not alpha-linolenic acid,
      suppress deoxynivalenol-induced experimental IgA nephropathy in mice.
AB  - Diets enriched in the (n-3) PUFAs, docosahexaenoic acid (DHA), eicosapentaenoic
      acid (EPA), and their precursor alpha-linolenic acid (ALA), were evaluated for
      efficacy in ameliorating the development of IgA nephropathy (IgAN) induced in
      mice by the mycotoxin deoxynivalenol (DON). The effects of DON were compared in
      mice that were fed for 18 wk with AIN-93G diets containing 1) 10 g/kg corn oil
      plus 60 g/kg oleic acid (control); 2) 10 g/kg corn oil plus 35 g/kg oleic acid
      and 25 g/kg DHA-enriched fish oil (DHA); 3) 10 g/kg corn oil plus 33 g/kg oleic
      acid and 27 g/kg EPA-enriched fish oil (EPA); and 4) 10 g/kg corn oil plus 37
      g/kg oleic acid and 23 g/kg DHA + EPA (1:1) enriched fish oil (DHA + EPA). The
      DHA, EPA and DHA + EPA diets attenuated induction by dietary DON (10 mg/kg) of
      serum IgA and IgA immune complexes, kidney mesangial IgA deposition, and ex vivo
      IgA secretion by spleen cells. Consumption of the DHA + EPA diet for 8 wk
      significantly abrogated the DON-induced gene expression of interleukin (IL)-6, a
      requisite cytokine for DON-induced IgA nephropathy, in spleen and Peyer's
      patches. Finally, incorporation of ALA-containing flaxseed oil up to 60 g/kg in
      the AIN-93G diet did not affect DON-induced IgA dysregulation in mice. Taken
      together, both DHA and EPA, but not ALA, ameliorated the early stages of IgAN,
      and these effects might be related to a reduced capacity for IL-6 production.

PMID- 15173397
TI  - Trans10,cis12-18:2 is a more potent inhibitor of de novo fatty acid synthesis and
      desaturation than cis9,trans11-18:2 in the mammary gland of lactating mice.
AB  - To investigate the effects of 2 conjugated linoleic acid (CLA) isomers and
      trans11-18:1 (TVA) on de novo lipogenesis and desaturation in liver and mammary
      gland, lactating mice were fed diets containing 3% canola oil (control) or 2%
      canola oil plus 1% stearic acid (SA), TVA, cis9,trans11 CLA (c9t11), or
      trans10,cis12 CLA (t10c12). In mammary tissue, TVA and CLA isomers reduced mRNA
      for acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) compared with
      control, but only c9t11 and t10c12 reduced mammary ACC activity. Of the 2 CLA
      isomers, t10c12 caused a greater reduction in mammary ACC activity. Hepatic ACC
      or FAS activity and mRNA abundance were not affected by dietary treatments.
      Feeding TVA, c9t11, or t10c12 reduced mammary stearoyl-CoA desaturase 1 (SCD)
      mRNA and activity. Reduction was greater due to feeding t10c12 compared with
      c9t11. Hepatic SCD mRNA was not affected by dietary treatments, but both CLA
      isomers depressed hepatic SCD activity. Results indicated that t10c12 is a more
      potent inhibitor of mammary lipogenesis and desaturation than is c9t11. A net
      gain of 77 and 1690 micro g of c9t11 in liver and mammary tissue, respectively,
      was found in the TVA-fed group over the control and SA-fed group. However,
      reduced mammary SCD mRNA or activity due to feeding TVA may indicate a limited
      capacity for desaturation of dietary TVA to c9t11 in vivo.

PMID- 15173398
TI  - Hypothalamic gene expression is altered in underweight but obese juvenile male
      Sprague-Dawley rats fed a high-energy diet.
AB  - The incidence of obesity, with its associated health risks, is on the increase
      throughout the western world affecting all age groups, including children. The
      typical western diet is high in fat and sugar and low in complex carbohydrates.
      This study looks at the effects of feeding an equivalent high-energy (HE) diet to
      growing rats. Juvenile male Sprague-Dawley rats that were fed an HE (18.9 kJ/g)
      diet starting approximately 10 d after weaning gained less weight than
      littermates fed a nonpurified (14 kJ/g) diet. Despite an initial hyperphagia
      following the change in diet, HE rats also consumed less energy. Although they
      exhibited reduced weight gain, HE rats were relatively obese; fat pad weights
      were elevated for all 4 dissected depots. HE-fed rats exhibited symptoms of
      developing metabolic syndrome with elevated plasma concentrations of glucose,
      triglycerides, nonesterified fatty acids, insulin, and leptin. In addition,
      leptin receptor gene expression in the hypothalamic arcuate nucleus (ARC) and
      ventromedial nucleus of HE rats was reduced. Consistent with the elevated serum
      leptin and other peripheral signals in HE rats, hypothalamic gene expression for
      the orexigenic neuropeptides, neuropeptide Y (ARC and dorsomedial nucleus), and
      agouti-related peptide (AgRP), was reduced. This reduction in orexigenic
      signaling and decline in energy intake is consistent with an apparent attempt to
      counter the further development of an obese state in rats consuming an energy
      dense diet. The juvenile Sprague-Dawley rat has potential in the development of a
      model of childhood diet-induced obesity.

PMID- 15173399
TI  - Thermally oxidized dietary fat upregulates the expression of target genes of PPAR
      alpha in rat liver.
AB  - Oxidized fats affect animal metabolism in several ways. To gain a comprehensive
      understanding of the molecular mechanisms underlying the effects of dietary
      oxidized fats in rats at varying dietary vitamin E concentrations, the gene
      expression profile of the liver was monitored with an array containing 1176
      binding sites for cDNAs. Rats were fed diets with a fresh fat and vitamin E
      concentrations of 25 or 250 mg alpha-tocopherol/kg (FF25, FF250 rats) or a fat
      heated at 50 degrees C for 38 d, with vitamin E concentrations of 25 or 250 mg
      alpha-tocopherol/kg (OF25, OF250 rats) for 63 d. Differences in gene expression
      were considered to be significant at a ratio of at least 1.4. In the OF25 rats,
      the expression of 47 genes was altered; in the OF250 rats, the expression of 37
      genes was altered, and in the FF250 rats, the expression of 21 genes was altered
      compared with FF25 rats. In both OF25 and OF250 rats, a series of target genes of
      the peroxisome proliferator-activated receptor alpha (PPAR alpha) was
      upregulated. Determination of gene expression of acyl CoA oxidase and activity of
      catalase confirmed that oxidized fats caused peroxisome proliferation in the
      liver. In OF25 and OF250 rats, there was also upregulation of 12 and 5 genes
      involved in xenobiotic metabolism and stress response, of 7 and 7 genes involved
      in protein metabolism, of 5 and 2 genes encoding intracellular effectors or
      modulators and of 5 and 6 genes, respectively, encoding activators or repressors
      of transcription or translation. In conclusion, this study provides indirect
      evidence that dietary oxidized fats cause an activation of the PPAR alpha,
      irrespective of the dietary vitamin E concentration. Identification of several
      other differentially regulated genes may be helpful to understand the effects of
      oxidized fats on animal metabolism.

PMID- 15173400
TI  - Yeast-leavened oat breads with high or low molecular weight beta-glucan do not
      differ in their effects on blood concentrations of lipids, insulin, or glucose in
      humans.
AB  - Increased intestinal viscosity appears to be the major mode of action by which
      dietary oat beta-glucan increases the fecal excretion of bile acids and thereby
      lowers blood cholesterol concentrations. The objective of this experiment was to
      investigate whether there is a difference in effects on blood lipids between two
      yeast-leavened oat bran breads containing beta-glucan (6 g/d) of low or high
      average molecular weight (HMW) (217 or 797 kDa, respectively). The breads were
      fed to 22 volunteers (women, n = 11; men, n = 11) in a randomized, double-blind,
      crossover design. The participants ate one bread for 3 wk as part of their normal
      diet and switched breads after a 2-wk washout period. Blood samples were drawn
      from fasting subjects and analyzed for lipids, insulin, glucose, and alpha- and
      gamma-tocopherol. The two experimental oat breads did not differ in their effects
      on any of the variables measured. Compared to baseline, however, consumption of
      HMW bread increased serum insulin by 22.6% (P < 0.03) and decreased blood glucose
      concentrations by 3.4% (P < 0.05). These results suggest that the molecular
      weight, when beta-glucan is consumed in oat bran breads as part of the habitual
      diet, does not play an important physiological role in moderately
      hypercholesterolemic humans.

PMID- 15173401
TI  - A large pool of available folate exists in the large intestine of human infants
      and piglets.
AB  - Many microorganisms in the large intestine are capable of synthesizing folate.
      Preliminary evidence suggests that this folate may be absorbed. The purpose of
      the 2 experiments reported herein was to estimate the pool of folate in the feces
      of human infants and piglets and to ascertain, if absorbed, whether the quantity
      and form of folate are sufficient to potentially affect the folate status of the
      host organism. The folate content of milk fed to and of fecal solids collected
      from exclusively human milk-fed (n = 12) and formula-fed (n = 10) term infants (1
      6 mo old) was determined microbiologically before (short-chain folates) and after
      folate conjugase (total folate) treatment. The folate content of formula fed and
      of feces collected from 10-d-old piglets (n = 10) was also determined
      microbiologically. The proportion of 5-methyltetrahydrofolate (5-methylTHF) in
      feces of human infants and piglets that was monoglutamylated was determined by
      HPLC analysis. The folate content of fecal solids collected from infants was 93.2
      +/- 92.8 nmol/d (mean +/- SD), representing on average 50% (8.0-170.1%) of their
      mean estimated dietary folate intake. Fecal folate was largely present as short
      chain folate (66 +/- 21.3%) with the predominant form being 5-methylTHF, 52.5 +/-
      30.1% of which was monoglutamylated. In piglets, the folate content of feces was
      301.3 +/- 145.7 nmol/d, representing 36% of their dietary folate intake. Piglet
      fecal folate was largely present as short-chain folate (68.1 +/- 12.6%) with the
      predominant species being 5-methylTHF, 29.3 +/- 33.2% of which was
      monoglutamylated. Collectively, these data suggest that the quantity and form of
      folate (monoglutamylated) in the large intestine of human infants and piglets are
      sufficiently large to potentially affect folate status.

PMID- 15173402
TI  - Nonesterified phytosterols dissolved and recrystallized in oil reduce plasma
      cholesterol in gerbils and humans.
AB  - When free phytosterols are adequately heated and then cooled in fat, they
      recrystallize and are rendered bioavailable for blocking cholesterol absorption.
      To extend the application of phytosterols to fried foods, the activity of these
      modified crystals was assessed in 2 experiments with 26 male gerbils fed purified
      diets containing 0.15 g/100 g cholesterol with or without 0.75 g/100 g free
      phytosterols. The heat-modified soybean sterols were added directly to the diet
      (Expt. 1) or as phytosterol-enriched potato chips (Expt. 2). In the gerbil
      experiments, only the diet containing phytosterols significantly reduced plasma
      cholesterol (35-48%) and the total cholesterol/HDL cholesterol (HDL-C) ratio
      (40%), as well as hepatic cholesterol esters (80%). In a subsequent human study,
      subjects (n = 7) consumed two 28-g servings of tortilla chips fried in oil with
      or without phytosterols that provided 0 or 1.5 g/d for 4-wk periods in a
      crossover design (Expt. 3). During consumption of the phytosterol-enriched chips,
      significant reductions in plasma cholesterol (10%) and LDL cholesterol (15%) were
      achieved without affecting HDL-C. This novel means of delivering free
      phytosterols proved to be both functionally efficient and effective.

PMID- 15173403
TI  - Individual serum triglyceride responses to high-fat and low-fat diets differ in
      men with modest and severe hypertriglyceridemia.
AB  - It is not yet clear whether a low-fat or a high-fat diet is more suitable for the
      treatment of hypertriglyceridemia. Therefore, we conducted a dietary study with
      nonobese hypertriglyceridemic men using a randomized crossover design. After a 2
      wk acclimation period, the subjects were randomly assigned to 2 groups. One group
      consumed a low-fat (29% of energy) diet for 3 wk, followed first by a 2-wk
      washout period, then a 3-wk high-fat (40% of energy) diet period. The second
      group consumed the low- and high-fat diets in reverse order. Both diets were
      isocaloric, rich in monounsaturated fatty acids (MUFAs) and long-chain (n-3)
      PUFAs, and contained no alcohol. Absolute amounts of long-chain (n-3)-PUFAs and
      fiber were similar, as were the fatty acid and carbohydrate compositions. Serum
      triglyceride concentrations in fasting subjects decreased during the high-fat
      diet period by 34% (95% CI = -19 to -46%, P = 0.001), and during the low-fat diet
      period by 31% (95% CI = -0.5 to -51.8%, P = 0.048). Triglyceride concentrations
      did not differ between the low- and high-fat diet periods. However, the high-fat
      diet lowered triglyceride concentrations more effectively in all subjects with a
      baseline triglyceride concentration < 4.5 mmol/L, whereas the low-fat diet
      lowered triglyceride levels more effectively in half of the subjects with a
      baseline value > 4.5 mmol/L. Based on these findings, we recommend a high-fat
      triglyceride-lowering diet for patients with only slightly elevated serum
      triglyceride concentrations (<4.5 mmol/L). However, a lower-fat diet is more
      suitable for some subjects with more distinctly elevated triglyceride
      concentrations.

PMID- 15173404
TI  - Dietary echium oil increases plasma and neutrophil long-chain (n-3) fatty acids
      and lowers serum triacylglycerols in hypertriglyceridemic humans.
AB  - A wealth of evidence indicates that consumption of fish or dietary fish oils
      containing long-chain (n-3) PUFA such as eicosapentaenoic acid (EPA) and
      docosahexaenoic acid (DHA) is associated with cardiovascular benefit, including a
      reduction in circulating triacylglycerol concentrations and reduced mortality
      from coronary heart disease. Shorter-chain dietary (n-3) PUFA such as alpha
      linolenic acid from vegetable oils are inefficiently converted to EPA and DHA and
      do not possess the hypotriglyceridemic properties attributed to fish oils. The
      objective of this study was to investigate the effect of dietary Echium oil, a
      plant oil containing the 18-carbon (n-3) PUFA stearidonic acid, on tissue fatty
      acid content and serum triacylglycerol concentrations in hypertriglyceridemic
      humans. Asymptomatic subjects with mild-to-moderate hypertriglyceridemia were
      enrolled in an open-labeled study. Subjects underwent a 4-wk lead-in period and
      were then instructed to follow the National Cholesterol Education Program Step 1
      diet. Subjects (n = 11) whose serum triacylglycerol concentrations remained
      between 3.4 and 5.1 mmol/L (300 and 450 mg/dL) were instructed to consume 15 g of
      Echium oil daily for 4 wk. During the treatment period, serum triacylglycerol
      concentrations decreased by 21%, or 0.87 +/- 0.26 mmol/L (mean +/- SD) compared
      with baseline (P < 0.05); 8 of 11 subjects had a decrease in serum
      triacylglycerols ranging from 13 to 52% with a decrease from baseline of 30%, or
      1.26 +/- 0.41 mmol/L (mean +/- SD). There were no significant changes in any
      other clinical laboratory variables. Concentrations of long-chain (n-3) PUFA,
      including EPA, increased (P < 0.05) in plasma and neutrophils when subjects
      consumed Echium oil. In conclusion, dietary plant oils rich in stearidonic acid
      are metabolized to longer-chain, more unsaturated (n-3) PUFA. These oils appear
      to possess hypotriglyceridemic properties typically associated with fish oils.

PMID- 15173405
TI  - Energy expenditure is very high in extremely obese women.
AB  - To test the hypothesis that total energy expenditure (TEE) and resting energy
      expenditure (REE) are low in extremely obese individuals, factors that could
      contribute to maintenance of excess weight, a cross-sectional study was conducted
      in 30 weight stable, extremely obese women [BMI (mean +/- SEM) 48.9 +/- 1.7
      kg/m(2)]. TEE was measured over 14 d using the doubly labeled water method, REE
      and the thermic effect of feeding (TEF) were measured using indirect calorimetry,
      and activity energy expenditure (AEE) was calculated as TEE - (REE + TEF). Body
      composition was determined using a 3-compartment model. Subjects were divided
      into tertiles of BMI (37.5-45.0; 45.1-52.0; and 52.1-77.0 kg/m(2)) for data
      analysis. TEE and REE increased with increasing BMI tertile: TEE, 12.80 +/- 0.5,
      14.67 +/- 0.5, and 16.10 +/- 0.9 MJ/d (P < 0.01); REE, 7.87 +/- 0.2, 8.78 +/-
      0.3, and 9.94 +/- 0.6 MJ/d (P < 0.001), and these values were 29-38% higher than
      published means of measured TEE in nonobese individuals. No significant
      differences were observed among BMI tertiles for AEE, TEF, or physical activity
      level (PAL = TEE/REE, overall mean 1.64 +/- 0.16). The Harris-Benedict and WHO
      equations provided the closest estimates of REE (within 3%), whereas the obese
      specific equations of Ireton-Jones overpredicted (40%) and Bernstein
      underpredicted (21%) REE. Extremely obese individuals have high absolute values
      for TEE and REE, indicating that excess energy intake contributes to the
      maintenance of excess weight. Standard equations developed for nonobese
      populations provided the most accurate estimates of REE for the obese individuals
      studied here. REE was not accurately predicted by equations developed in obese
      populations.

PMID- 15173406
TI  - Psychosocial intervention improves the development of term low-birth-weight
      infants.
AB  - It is estimated that 11% of births in developing counties are term low-birth
      weight (LBW); however, there is limited information on the development of these
      infants. Our objectives were to determine the effect of psychosocial intervention
      on the development of LBW infants and to compare term LBW and normal-birth-weight
      (NBW) infants. Term LBW (n = 140) and NBW infants (n = 94) were enrolled from the
      main maternity hospital in Kingston, Jamaica. The LBW infants were randomly
      assigned to control or intervention comprising weekly home visits from birth to 8
      wk and from 7 to 24 mo of age. Development was assessed at 15 and 24 mo with the
      Griffiths Scales. The intervention benefited the infants' developmental quotient
      (DQ, P < 0.05) and performance subscale at 15 mo (P < 0.02), the hand and eye (P
      < 0.05) and performance subscales (P < 0.02) at 24 mo, and home environment at 12
      mo. The effect of the intervention on development was mediated in part by the
      improvement in the home environment. The control LBW infants had significantly
      lower scores than the NBW in DQ and several subscales, whereas there were no
      significant differences between the NBW and the LBW infants after intervention.
      In conclusion, term LBW was associated with developmental delays, which were
      reduced with psychosocial intervention.

PMID- 15173407
TI  - Weight loss during pregnancy is associated with adverse pregnancy outcomes among
      HIV-1 infected women.
AB  - In a prospective study of 1002 pregnant, HIV-1 infected Tanzanian women, we
      examined the incidence of fetal death, preterm delivery, low birth weight (LBW),
      and small for gestational age (SGA) births in relation to maternal anthropometry
      at the first prenatal visit, weight loss, and low weight gain during pregnancy.
      Anthropometric measurements were obtained monthly during the 2nd and 3rd
      trimesters. Low maternal height and weight at the first visit were significantly
      related to lower mean birth weight and increased risk of SGA, but not to preterm
      delivery. Maternal stature < 150 cm was significantly related to fetal death.
      Weight loss during pregnancy, defined as a negative slope of the regression of
      weight measurements on the week of gestation, occurred in 10% of the women. It
      was related to increased relative risk (RR) of fetal death (RR = 1.83, 95% CI =
      0.93, 3.57), preterm delivery (RR = 1.85, 95% CI = 1.40, 2.44), and LBW (RR =
      2.85, 95% CI = 1.69, 4.79) after adjusting for multivitamin supplementation,
      height, primiparity, baseline weight, malaria, CD4 cell count, HIV disease stage,
      and intestinal parasitoses. The significant association with fetal death was
      stronger for weight loss during the 2nd trimester, whereas increased risks of
      preterm delivery and LBW were higher for weight loss during the 3rd. Similar but
      weaker associations were found with low weight gain during pregnancy (slope <
      25th percentile). We conclude that poor anthropometric status at the first
      prenatal visit and weight loss during pregnancy among HIV-1 infected women are
      strong risk factors for adverse pregnancy outcomes.

PMID- 15173408
TI  - Food insecurity is associated with adverse health outcomes among human infants
      and toddlers.
AB  - The U.S. Household Food Security Scale, developed with federal support for use in
      national surveys, is an effective research tool. This study uses these new
      measures to examine associations between food insecurity and health outcomes in
      young children. The purpose of this study was to determine whether household food
      insecurity is associated with adverse health outcomes in a sentinel population
      ages < or = 36 mo. We conducted a multisite retrospective cohort study with cross
      sectional surveys at urban medical centers in 5 states and Washington DC, August
      1998-December 2001. Caregivers of 11,539 children ages < or = 36 mo were
      interviewed at hospital clinics and emergency departments (ED) in central cities.
      Outcome measures included child's health status, hospitalization history, whether
      child was admitted to hospital on day of ED visit (for subsample interviewed in
      EDs), and a composite growth-risk variable. In this sample, 21.4% of households
      were food insecure (6.8% with hunger). In a logistic regression, after adjusting
      for confounders, food-insecure children had odds of "fair or poor" health nearly
      twice as great [adjusted odds ratio (AOR) = 1.90, 95% CI = 1.66-2.18], and odds
      of being hospitalized since birth almost a third larger (AOR = 1.31, 95% CI =
      1.16-1.48) than food-secure children. A dose-response relation appeared between
      fair/poor health status and severity of food insecurity. Effect modification
      occurred between Food Stamps and food insecurity; Food Stamps attenuated (but did
      not eliminate) associations between food insecurity and fair/poor health. Food
      insecurity is associated with health problems for young, low-income children.
      Ensuring food security may reduce health problems, including the need for
      hospitalizations.

PMID- 15173409
TI  - Growth in young Filipino children predicts schooling trajectories through high
      school.
AB  - Several studies link childhood malnutrition to adverse schooling outcomes,
      including delayed or diminished enrollment and increased grade repetition.
      However, the effects of nutrition on schooling trajectories are obscured by the
      cross-sectional nature of most previous research and the complex array of other
      phenomena that affect schooling outcomes. We explored the association between
      height-for-age Z-score (HAZ) at 2 y and schooling trajectory among 2198 children
      from the Cebu Longitudinal Health and Nutrition Survey. Parity, parental
      education, maternal height, household assets, environmental cleanliness, presence
      of electricity, and household income were identified as potential confounders.
      Crude and adjusted logistic and multinomial regressions of schooling outcomes
      (entrance age, grade repetition, and grades completed) were conducted. Entrance
      age and IQ were evaluated as potential mediators between HAZ and schooling
      outcomes. After adjustment for confounders, greater height for age protected
      against late enrollment among both boys and girls and predicted early enrollment
      among boys. Taller children were less likely to repeat grades [girls OR = 0.78
      (0.67, 0.89); boys OR = 0.86 (0.74, 0.99)] and less likely to drop out during
      grade school rather than graduate from high school [girls OR = 0.74 (0.56, 0.98;
      boys OR = 0.66 (0.51, 0.84)]. Models predicting the changes in school outcomes
      associated with a change in overall height from -2 to 0 SD of HAZ were simulated.
      Absolute probability of late enrollment dropped substantially, from 6% for both
      boys and girls to 2% for boys and 1% for girls. Absolute grade repetition dropped
      approximately 7% for boys and 9% for girls. Improving early childhood nutrition
      may have long-lasting educational benefits, increasing the likelihood of high
      school completion in developing countries.

PMID- 15173410
TI  - Arctic indigenous peoples experience the nutrition transition with changing
      dietary patterns and obesity.
AB  - Indigenous Peoples globally are part of the nutrition transition. They may be
      among the most extreme for the extent of dietary change experienced in the last
      few decades. In this paper, we report survey data from 44 representative
      communities from 3 large cultural areas of the Canadian Arctic: the Yukon First
      Nations, Dene/Metis, and Inuit communities. Dietary change was represented in 2
      ways: 1) considering the current proportion of traditional food (TF) in contrast
      to the precontact period (100% TF); and 2) the amount of TF consumed by older vs.
      younger generations. Total diet, TF, and BMI data from adults were investigated.
      On days when TF was consumed, there was significantly less (P < 0.01) fat,
      carbohydrate, and sugar in the diet, and more protein, vitamin A, vitamin D,
      vitamin E, riboflavin, vitamin B-6, iron, zinc, copper, magnesium, manganese,
      phosphorus, potassium, and selenium. Vitamin C and folate, provided mainly by
      fortified food, and fiber were higher (P < 0.01) on days without TF for Inuit.
      Only 10-36% of energy was derived from TF; adults > 40 y old consistently
      consumed more (P < 0.05) TF than those younger. Overall obesity (BMI > or = 30
      kg/m(2)) of Arctic adults exceeded all-Canadian rates. Measures to improve
      nutrient-dense market food (MF) availability and use are called for, as are ways
      to maintain or increase TF use.

PMID- 15173411
TI  - A high-whey-protein diet reduces body weight gain and alters insulin sensitivity
      relative to red meat in wistar rats.
AB  - A high-protein diet can reduce body weight and increase insulin sensitivity, but
      whether the type of dietary protein affects these outcomes is unknown. We
      hypothesized that feeding insulin-resistant rats a high-protein diet (32%)
      containing whey protein concentrate (WPC) would reduce body weight and tissue
      lipid levels and increase insulin sensitivity more than a diet containing red
      meat (RM). Rats were fed a high-fat diet (300 g fat/kg diet) for 9 wk, then
      switched to a diet containing either 80 or 320 g protein/kg diet, provided by
      either WPC or RM, for 6 wk (n = 8). The rats were then killed after overnight
      food deprivation. High dietary protein reduced energy intake (P < 0.001) and
      visceral (P < 0.001), subcutaneous (P < 0.001), and carcass fat (P < 0.05).
      Increasing the dietary density of WPC, but not of RM, reduced body weight gain by
      4% (P < 0.001). Dietary WPC also reduced plasma insulin concentration by 40% (P <
      0.05) and increased insulin sensitivity, compared to RM (P < 0.05). These
      findings support the conclusions that a high-protein diet reduces energy intake
      and adiposity and that whey protein is more effective than red meat in reducing
      body weight gain and increasing insulin sensitivity.

PMID- 15173412
TI  - Avenanthramides and phenolic acids from oats are bioavailable and act
      synergistically with vitamin C to enhance hamster and human LDL resistance to
      oxidation.
AB  - The intake of phenolic acids and related polyphenolic compounds has been
      inversely associated with the risk of heart disease, but limited information is
      available about their bioavailability or mechanisms of action. Polyphenolics,
      principally avenanthramides, and simple phenolic acids in oat bran phenol-rich
      powder were dissolved in HCl:H(2)O:methanol (1:19:80) and characterized by HPLC
      with electrochemical detection. The bioavailability of these oat phenolics was
      examined in BioF1B hamsters. Hamsters were gavaged with saline containing 0.25 g
      oat bran phenol-rich powder (40 micromol phenolics), and blood was collected
      between 20 and 120 min. Peak plasma concentrations of avenanthramides A and B, p
      coumaric, p-hydroxybenzoic, vanillic, ferulic, sinapic, and syringic acids
      appeared at 40 min. Although absorbed oat phenolics did not enhance ex vivo
      resistance of LDL to Cu(2+)-induced oxidation, in vitro addition of ascorbic acid
      synergistically extended the lag time of the 60-min sample from 137 to 216 min (P
      < or = 0.05), unmasking the bioactivity of the oat phenolics from the oral dose.
      The antioxidant capability of oat phenolics to protect human LDL against
      oxidation induced by 10 micromol/L Cu(2+) was also determined in vitro. Oat
      phenolics from 0.52 to 1.95 micromol/L increased the lag time to LDL oxidation in
      a dose-dependent manner (P < or = 0.0001). Combining the oat phenolics with 5
      micromol/L ascorbic acid extended the lag time in a synergistic fashion (P < or =
      0.005). Thus, oat phenolics, including avenanthramides, are bioavailable in
      hamsters and interact synergistically with vitamin C to protect LDL during
      oxidation.

PMID- 15173413
TI  - Onset of small intestinal atrophy is associated with reduced intestinal blood
      flow in TPN-fed neonatal piglets.
AB  - Our aim was to determine the speed of onset of total parenteral nutrition (TPN)
      induced mucosal atrophy, and whether this is associated with changes in
      intestinal blood flow and tissue metabolism in neonatal piglets. Piglets were
      implanted with jugular venous and duodenal catheters and either a portal venous
      or superior mesenteric artery (SMA) blood flow probe. At 3 wk of age, piglets
      were randomly assigned to receive continuous enteral formula feeding (n = 8) or
      TPN (n = 17) for 24 or 48 h. Blood flow was recorded continuously and piglets
      were given an i.v. bolus of bromodeoxyuridine and (13)C-phenylalanine to measure
      crypt cell proliferation and protein synthesis, respectively. After 8 h of TPN,
      portal and SMA blood flow decreased 30% compared with enteral feeding (P < 0.01),
      and remained near levels of food-deprived piglets for the remaining 48 h of TPN.
      After 24 h, TPN reduced jejunal inducible nitric oxide synthase (iNOS) activity
      and protein abundance (P < 0.05), small intestinal weight, and villous height (P
      < 0.01) compared with enterally fed piglets. Cell proliferation and DNA mass were
      decreased (P < 0.05) and apoptosis increased (P < 0.05) after 48 h of TPN.
      Protein synthesis was lower (P < 0.05) after 24 h of TPN, and protein mass was
      lower (P < 0.05) after 48 h of TPN, compared with enteral feeding. These data
      indicate that the transition from enteral to parenteral nutrition induced a rapid
      (<8 h) decrease in intestinal blood flow, and this likely precedes villous
      atrophy and the suppression of protein synthesis at 24 h, and of cell
      proliferation and survival at 48 h.

PMID- 15173414
TI  - Increased lipogenesis and fatty acid reesterification contribute to hepatic
      triacylglycerol stores in hyperlipidemic Txnip-/- mice.
AB  - The effect of decreased fatty acid oxidation on liver lipid metabolism in HcB-19
      mice, a mouse model of hyperlipidemia (Txnip(-/-)), was investigated using
      metabolic labeling. De novo cholesterol synthesis and de novo lipogenesis were
      quantified using 1-(13)C(1) acetic acid, and liver triacylglycerol (TAG) derived
      from dietary fatty acids was quantified using dietary glyceryl tri(hexandecanoate
      d(31)). Tissue samples were analyzed for TAG, free cholesterol (FC), and
      cholesterol ester (CE) content. Txnip(-/-) mice had significantly elevated (P <
      0.05) serum nonesterified fatty acids compared with wild-type (WT) littermates;
      their livers weighed more and contained more TAG and total cholesterol. Txnip(-/
      ) liver also contained measurable CE; CE was not detectable in WT mice. Liver CE
      content was elevated despite lower cholesterol fractional synthesis rates (16 vs.
      31%/d in Txnip(-/-) and WT mice, respectively). FC absolute synthesis rate (ASR)
      in WT mice (0.28 +/- 0.0 micromol/d) was similar to the combined synthesis rates
      of FC (0.13 +/- 0.10 micromol/d) and CE (0.10 +/- 0.00 micromol/d) in Txnip(-/-)
      mice. Lipogenesis, as assessed by TAG-palmitate ASR, was significantly greater in
      Txnip(-/-) mice (1.47 +/- 0.08 vs. 0.49 +/- 0.06 micro mol/d) and liver fatty
      acid synthase activity was also higher (7.96 +/- 2.53 vs. 4.83 +/- 1.44 U/mg
      protein). Both elevated lipogenesis and increased fatty acid reesterification to
      glycerol and cholesterol contributed to fat in the livers of Txnip(-/-) mice.
      These data support elevated fatty acid synthesis as the primary contributor to
      liver TAG in Txnip(-/-) mice, although increased esterification of fatty acids
      also contributed to excess liver TAG. The absolute total cholesterol synthesis
      rate was not altered, but esterification of fatty acids to cholesterol provided
      an additional means to buffer physiologically the negative results of excess
      fatty acid availability.

PMID- 15173415
TI  - Dietary fiber stabilizes blood glucose and insulin levels and reduces physical
      activity in sows (Sus scrofa).
AB  - The aim of this study was to test whether a diet with a high level of fermentable
      dietary fiber can stabilize interprandial blood glucose and insulin levels,
      prevent declines below basal levels, and reduce physical activity in limited-fed
      breeding sows. Stable levels of glucose and insulin may prevent interprandial
      feelings of hunger and, consequently, increased activity. Catheterized sows (n =
      10) were fed twice daily (0700 and 1900 h) 900 g of a diet with either a low (L
      sows) or a high level of fermentable dietary fiber (H-sows; sugarbeet pulp).
      Blood samples, taken between feeding times, were analyzed for glucose and insulin
      levels (basal and area under the curve) and stability of levels (variance and sum
      of absolute differences between levels in consecutive samples). The main focus
      was on samples taken after the postprandial peak. Behavior was videotaped for
      analysis of postures and posture changes. Basal glucose and insulin levels did
      not differ between treatments. H-sows had more stable levels than L-sows.
      Interprandial levels of H-sows were higher than or equal to basal levels. L-sows
      showed a decline in glucose below basal levels at 1400 h (P < 0.05). Before 1400
      h, no difference in the frequency of posture changes was observed between
      treatments. After 1400 h, the frequency of posture changes increased more in L
      sows than in H-sows. We concluded that sugarbeet pulp as a source of fermentable
      dietary fiber stabilizes glucose and insulin levels and reduces physical activity
      in limited-fed sows several hours after feeding. This may indicate a prolonged
      feeling of satiety.

PMID- 15173416
TI  - Dietary antibiotic growth promoters enhance the bioavailability of alpha
      tocopheryl acetate in broilers by altering lipid absorption.
AB  - The influence of intestinal microbial bile salt deconjugation on absorption of
      fatty acids and alpha- and gamma-tocopherol was investigated in a trial with Ross
      208 broilers. Birds (n = 1600) were assigned to 4 dietary treatments: no
      supplementation or supplementation of antibiotics (salinomycin, 40 mg/kg feed and
      avilamycin, 10 mg/kg feed), and inclusion of either animal fat (10 g/100 g feed)
      or soybean oil (10 g/100 g feed) in the diet. At d 7, 14, 21, and 35 of age, the
      intestinal number of the bile salt hydrolase-active bacteria Clostridium
      perfringens, the concentration of conjugated and unconjugated bile salts, the
      ileal absorption of fatty acids and tocopherols, and the blood plasma
      concentrations of tocopherols were measured. All variables were significantly
      influenced by bird age. C. perfringens counts were lower and bile salt
      concentrations were greater in birds fed soybean oil. The supplementation of
      antibiotics reduced the numbers of C. perfringens in the small intestine and
      reduced the concentration of unconjugated bile salts. The ileal absorption of
      fatty acids and alpha-tocopherol, as well as the plasma concentration of alpha
      tocopherol, was greater in birds fed antibiotics. The absorption and plasma
      concentration of gamma-tocopherol were not influenced by antibiotics. Unlike
      gamma-tocopherol, which is present solely as the free alcohol, the major
      proportion of dietary alpha-tocopherol is present as alpha-tocopheryl acetate,
      which requires a bile salt-dependent enzymatic hydrolysis before absorption. In
      conclusion, proper digestion of lipid-soluble compounds is highly dependent on an
      adequate concentration of bile salts in the small intestine to provide proper
      lipid emulsification and activation of lipolytic enzymes.

PMID- 15173417
TI  - Prenatal protein restriction does not affect the proliferation and
      differentiation of rat preadipocytes.
AB  - Poor development in utero may favor the development of obesity in adulthood.
      Animal studies showed that embryo manipulation in vitro or nutritional insults
      during the embryonic and fetal stages of development may lead to obesity in adult
      life. We studied the in vitro proliferation and differentiation of adipocytes to
      investigate whether early protein restriction may program cell growth and
      development. In a series of experiments, 2 different low-protein diet protocols
      were compared. In both cases, pregnant rats were fed a diet with a high (18-20%)
      or low (8-9%) protein content during gestation and/or lactation. Preadipocytes
      were isolated from the fetuses, neonates, and weanling offspring. Moderate
      protein restriction, imposed during either gestation and/or lactation, did not
      affect the capacity of preadipose cells to divide or store fat. Because previous
      studies showed that early protein restriction alters the metabolism of sulfur
      amino acids, we also investigated the effects of methionine, taurine, and
      homocysteine on proliferation and differentiation of preadipocytes. The
      supplementation of the diet with methionine or the addition of homocysteine and
      taurine to the culture media did not influence the development of preadipocytes.
      We obtained no evidence for the direct reprogramming of the precursor or stem
      cells and suggest that the subsequent alteration in fat accretion may therefore
      reflect a change in the neuroendocrine environment.

PMID- 15173418
TI  - Well-characterized garlic-derived materials are not hypolipidemic in APOE*3
      Leiden transgenic mice.
AB  - Garlic is reported to have beneficial effects on risk factors associated with
      cardiovascular disease, including normalization of plasma lipid levels. However,
      numerous studies do not support this beneficial effect of garlic on plasma
      lipids. This contradiction may result from the use of different garlic-derived
      materials, experimental designs, and/or animal models. The present study
      investigated the hypolipidemic effect of garlic-derived materials in APOE*3
      Leiden mice, a model well suited for drug and dietary intervention studies of
      hyperlipidemia. APOE*3-Leiden mice were fed a garlic-derived sulfur-rich
      compound, either allicin (0.29 g.L drinking water(-1)) or diallyldisulfide (0.27
      g.kg diet(-1)), or powdered garlic, of either the kwai (42 g.kg diet(-1)) or
      morado (42 g.kg diet(-1)) variety. The amounts of garlic-derived materials
      supplied allowed free intake of allicin or allicin equivalents (diallyldisulfide,
      kwai, or morado) at 44 mg.kg body wt(-1).d(-1). Mice were fed a nonpurified diet
      for 4 wk, followed by a Western diet for 8 wk, both supplemented with the garlic
      derived materials. These diets had no consistent effect on plasma lipids and did
      not affect lipoprotein profiles, which are markers for whole-body cholesterol
      synthesis and intestinal sterol absorption. The current data indicate that the
      postulated effects of garlic on cardiovascular disease are not caused via
      modulation of plasma lipid levels.

PMID- 15173419
TI  - Dietary soy protein attenuates renal disease progression after 1 and 3 weeks in
      Han:SPRD-cy weanling rats.
AB  - Compared with casein, dietary soy protein slows disease progression in animal
      models of chronic renal injury. To determine whether dietary soy protein feeding
      can alter early disease progression, male Han:SPRD-cy rats (n = 87) in a very
      early stage of chronic kidney disease were fed soy protein compared with casein
      based diets for 1 or 3 wk. Kidneys were assessed for fibrosis, cyst growth, fatty
      acid composition and prostaglandin E(2) (PGE(2)) production. Soy protein feeding
      significantly reduced renal fibrosis by 22% (P = 0.0347) and 38% (P = 0.0102)
      after 1 and 3 wk of diet, and cyst growth was 34% lower after 3 wk (P < 0.0001).
      Kidney 18:2(n-6) levels were reduced in normal and diseased rats after as little
      as 1 wk of consuming the soy protein diet. Dietary soy protein also partially
      ameliorated the suppression of PGE(2) production observed in diseased kidneys.
      Compared with diseased kidneys from casein-fed rats, ex vivo PGE(2) release was
      31-32% higher after 1 (P = 0.0281) and 3 (P = 0.0189) wk of dietary soy protein
      consumption. Hence, the first signs of a beneficial soy protein effect were
      observed after 1 wk of feeding, with further improvements evident after 3 wk.
      These data demonstrate that dietary soy protein compared with casein delays
      disease progression in an early stage of chronic kidney disease.

PMID- 15173420
TI  - Bioavailability of quercetin in pigs is influenced by the dietary fat content.
AB  - The flavonol quercetin is one of the most prevalent flavonoids found in edible
      plants. In this study, the influence of dietary fat on oral bioavailability of
      quercetin was investigated. Quercetin (30 micromol/kg body weight) was
      administered either as the lipophilic aglycone or as the more hydrophilic
      quercetin-3-O-glucoside in test meals differing in fat content (3, 17, or 32 g
      fat/100 g diet) to growing pigs. Blood samples were drawn repeatedly over a 24-h
      period and analyzed by HPLC. The main metabolite found in plasma was always
      conjugated quercetin. Quercetin bioavailability from each diet was always higher
      from the glucoside than from the aglycone. Irrespective of the chemical form
      applied, the bioavailability of quercetin was higher in the 17% fat diet compared
      with the 3% fat diet (P < 0.05). No further effect on bioavailability was
      observed when the flavonols were administered with diets containing 32% fat. The
      elimination of quercetin was significantly delayed after its application with fat
      enriched diets (P < 0.05). Thus, in addition to the chemical form of the
      flavonol, the fat content of the diet influences oral bioavailability of
      quercetin.

PMID- 15173421
TI  - A very high 70%-protein diet does not induce conditioned taste aversion in rats.
AB  - This study was designed to assess the effects of transition and adaptation to a
      very high protein diet on behavioral food responses, energy intake, body weight
      gain, and body composition in rats. For this purpose, adult male Wistar rats were
      fed either a diet with 70% of energy as protein (P70 group) or a diet with 14% of
      energy as protein (P14 group) for 16 d. These two groups were compared with a P14
      pair-fed (P14-pf) group. A behavioral satiety sequence was also examined. The P70
      group ate 21% less than the P14 rats (P < 0.001) and gained less body weight (P <
      0.01). The P70 group gained more carcass weight than either P14 or P14-pf rats (P
      < 0.05). Behavior and food intake data were affected in P70 rats on d 1 of eating
      the very high protein diet and then returned to baseline values as early as d 2
      of consuming the P70 diet. Rats that adapted to the very high protein diet did
      not acquire a conditioned taste aversion but rather exhibited satiety and a
      normal behavioral satiety sequence.

PMID- 15173422
TI  - Low maternal dietary intakes of iron, magnesium, and niacin are associated with
      spina bifida in the offspring.
AB  - Evidence about the preventive effects of nutrients other than folate on the
      occurrence of spina bifida is scarce. Therefore, the aim of this work was to
      investigate the role of maternal nutritional intake and the risk of spina bifida
      in the offspring. In 106 cases and 181 controls, the mothers' nutrient intakes
      were obtained by an FFQ approximately 24 mo after conception of the index
      pregnancy. Energy-adjusted mean nutrient intakes were compared, and odds ratios
      (OR) and 95% CI were calculated. Although mean nutrient intakes were comparable
      to the Dutch food consumption survey data, fat, cholesterol, iron, and folate
      intakes were below the 1998 Dutch Recommended Daily Allowances. Case mothers had
      significantly lower intakes of plant proteins (7%), polysaccharides (4%), fiber
      (7%), iron (6%), magnesium (6%), and niacin (4%) than control mothers. Mono- and
      disaccharide intakes were significantly higher (6%) in the case mothers than in
      control mothers. The adjusted OR (95% CI) in the lowest quartiles for plant
      proteins was 5.4 (2.3-12.4), for fiber 3.1 (1.5-6.8), for iron 3.5 (1.4-8.3), for
      magnesium 1.9 (0.9-4.1), and for niacin 2.5 (1.2-5.2). Mono- and disaccharide and
      polysaccharide intakes in the highest quartile had ORs (95% CI) of 2.9 (1.4-6.3)
      and 0.5 (0.3-1.0), respectively. The nutritional intake of Dutch women from food
      groups containing iron and folate seems to be compromised. Low preconceptional
      intakes of plant proteins, iron, magnesium, and niacin are associated with a 2-
      to 5-fold increased risk of spina bifida.

PMID- 15173423
TI  - Xylooligosaccharides and fructooligosaccharides affect the intestinal microbiota
      and precancerous colonic lesion development in rats.
AB  - Certain nondigestible oligosaccharides can be selectively utilized by probiotics
      and reduce the risk of colon cancer. However, the inhibitory effects of
      xylooligosaccharides (XOS) on colon cancer are not well documented. This study
      evaluated the effects of xylooligosaccharides and fructooligosaccharides (FOS) on
      the alteration of cecal microbiota, cecal pH, cecal weight, and serum lipid
      levels, and also their inhibitory effect on precancerous colon lesions in male
      Sprague-Dawley rats. The rats were randomly assigned to 4 groups: control,
      treatment with 1,2-dimethylhydrazine (DMH) [15 mg/(kg body wt.wk) for 2 wk],
      treatment with DMH + 60 g XOS/kg diet, and treatment with DMH + 60 g FOS/kg diet.
      Rats were fed the experimental diets for 35 d, beginning 1 wk after the second
      dose of DMH. Both XOS and FOS markedly decreased the cecal pH and serum
      triglyceride concentration, and increased the total cecal weight and
      bifidobacteria population. XOS had a greater effect on the bacterial population
      than did FOS. Moreover, both XOS and FOS markedly reduced the number of aberrant
      crypt foci in the colon of DMH-treated rats. These results suggest that XOS and
      FOS dietary supplementation may be beneficial to gastrointestinal health, and
      indicate that XOS is more effective than FOS.

PMID- 15173424
TI  - A flavonoid fraction from cranberry extract inhibits proliferation of human tumor
      cell lines.
AB  - In light of the continuing need for effective anticancer agents, and the
      association of fruit and vegetable consumption with reduced cancer risk, edible
      plants are increasingly being considered as sources of anticancer drugs.
      Cranberry presscake (the material remaining after squeezing juice from the
      berries), when fed to mice bearing human breast tumor MDA-MB-435 cells, was shown
      previously to decrease the growth and metastasis of tumors. Therefore, further
      studies were undertaken to isolate the components of cranberry that contributed
      to this anticancer activity, and determine the mechanisms by which they inhibited
      proliferation. Using standard chromatographic techniques, a warm-water extract of
      cranberry presscake was fractionated, and an acidified methanol eluate (Fraction
      6, or Fr6) containing flavonoids demonstrated antiproliferative activity. The
      extract inhibited proliferation of 8 human tumor cell lines of multiple origins.
      The androgen-dependent prostate cell line LNCaP was the most sensitive of those
      tested (10 mg/L Fr6 inhibited its growth by 50%), and the estrogen-independent
      breast line MDA-MB-435 and the androgen-independent prostate line DU145 were the
      least sensitive (250 mg/L Fr6 inhibited their growth by 50%). Other human tumor
      lines originating from breast (MCF-7), skin (SK-MEL-5), colon (HT-29), lung
      (DMS114), and brain (U87) had intermediate sensitivity to Fr6. Using flow
      cytometric analyses of DNA distribution (cell cycle) and annexin V-positivity
      (apoptosis), Fr6 was shown in MDA-MB-435 cells to block cell cycle progression (P
      < 0.05) and induce cells to undergo apoptosis (P < 0.05) in a dose-dependent
      manner. Fr6 is potentially a source of a novel anticancer agent.

PMID- 15173425
TI  - Dietary supplementation with high-selenium soy protein reduces pulmonary
      metastasis of melanoma cells in mice.
AB  - The effect of high-selenium (Se) soy protein on pulmonary metastasis of murine
      B16BL6 melanoma cells was investigated in male C57BL6 mice. Isolated soy proteins
      (ISP) from soybeans grown with and without Se foliar application during seed
      development were compared. Five diets were studied, a basal AIN-93G diet or a
      basal diet containing 10% low-Se ISP, 5% low-Se + 5% high-Se ISP, 10% high-Se
      ISP, or 10% low-Se ISP supplemented with Se equivalent to that of the 10% high-Se
      ISP diet. The Se concentrations of the 5 diets were 0.13, 0.13, 1.9, 3.6, and 3.0
      microg/g, respectively. Mice were fed the diet for 2 wk before and 2 wk after an
      i.v. injection of 5 x 10(4) viable cells. At necropsy, the number and size of
      tumors that had developed in the lungs were determined. In the control group,
      13/18 mice exhibited > or = 50 tumors. The numbers of mice with > or = 50 tumors
      were 8/18, 7/18, 3/18, and 6/17 in the ISP-fed groups, respectively. The
      differences between the 10% high-Se ISP group, the Se-supplemented 10% low-Se
      group, and the control were significant (P < 0.05). Dietary supplementation with
      10% low-Se ISP significantly decreased the mean number of tumors per group and
      the tumor size compared with the control. A greater reduction in these variables
      occurred in mice fed the 10% high-Se ISP diet. The inhibition by the Se
      supplemented 10% low-Se ISP diet was similar to that by the 10% high-Se ISP diet.
      The whole-blood Se concentration was inversely related to the tumor number (R = 
      0.87, P = 0.052), tumor cross-sectional area (R = -0.91, P < 0.05), and tumor
      volume (R = -0.93, P < 0.05). These findings suggest that Se is responsible for
      the greater antimetastatic effect of the high-Se ISP. We conclude that the high
      Se soy protein has a greater inhibitory effect than the low-Se soy protein on
      pulmonary metastasis of melanoma cells in mice.

PMID- 15173426
TI  - Reproducibility and validity of major dietary patterns among Swedish women
      assessed with a food-frequency questionnaire.
AB  - Defining dietary patterns by factor analysis is an alternative approach to
      dietary assessment that has been used recently to examine diet-disease relations.
      However, only 1 study evaluated the reproducibility and validity of this method.
      Our aim was to assess both the validity and reproducibility of major dietary
      patterns based on data from a 60-item FFQ. We chose 2 independent random samples
      among over 60,000 women aged 40-74 y participating in the Swedish Mammography
      Cohort (SMC). In the validation study, the FFQ was compared with 4 7-d dietary
      records (DRs) among 129 women. For the reproducibility study, the FFQ was
      administered twice, 1 y apart in 212 women. By conducting factor analysis, 3
      major dietary patterns were identified: healthy (high in vegetables, fruits,
      fish, poultry, tomato, cereal, and low-fat dairy products), Western (processed
      meat, meat, refined grains, sweets, and fried potatoes), and drinker (beer, wine
      and liquor, snacks) pattern. These 3 patterns explained 29-34% of the total
      variance in these 2 studies. The Spearman correlation coefficients between FFQ1
      and FFQ2 (reproducibility) for healthy, Western, and drinker pattern were 0.63,
      0.68, and 0.73, respectively (all P < 0.0001). Correlation coefficients between
      the FFQ and DRs (validity) for these patterns were 0.59, 0.50, and 0.85,
      respectively (all P < 0.0001). Our results indicate that identification of
      dietary patterns through factor analysis is a reproducible and valid method. The
      dietary patterns approach might be used in nutritional epidemiology as an
      alternative method of dietary assessment.

PMID- 15173427
TI  - The intracellular free amino acid pool represents tracer precursor enrichment for
      calculation of protein synthesis in cultured fibroblasts and myocytes.
AB  - We assessed the approach of using intracellular free amino acid enrichment as
      precursor enrichment for calculating the fractional synthetic rate of using the
      stable isotope tracer incorporation technique. We assumed that the true rate of
      protein synthesis was reflected by the rate of tracer incorporation over time
      divided by the plateau enrichment in protein. Isolated human fibroblasts and
      myocytes were cultured in medium supplemented with [(15)N]glycine,
      [(15)N]proline, and [d(5)]phenylalanine. Culture medium and cells were collected
      daily from d 1 to 5. A portion of cells harvested on d 5 was subcultured for an
      additional 3 passages to d 20. Protein enrichments in both cell types reached a
      plateau after 20 d of cell culture. In fibroblasts, the true protein synthesis
      rates were 0.74, 0.85, and 0.86%/h, using protein plateau enrichments of
      [(15)N]glycine, [(15)N]proline, and [d(5)]phenylalanine as precursor enrichments,
      respectively. When the corresponding intracellular free amino acid enrichments
      were used, protein synthesis rates were 0.76, 0.79, and 0.76%/h, respectively.
      Similarly, in myocytes, the true protein synthesis rates were 0.98 and 1.14%/h by
      protein plateau enrichments of [(15)N]glycine and [d(5)]phenylalanine,
      respectively. The synthesis rates were 0.94 and 1.01%/h by the corresponding
      intracellular enrichments, respectively. Extracellular amino acid enrichments
      resulted in underestimation of protein synthesis by a variable amount. We
      conclude that the intracellular free amino acid enrichment is an optimal
      surrogate for precursor enrichment to quantify protein synthesis.

PMID- 15173428
TI  - Proceedings of the 3rd Amino Acid Assessment Workshop, dedicated to Vernon. R.
      Young. Nice, France, October 23-24, 2003.

PMID- 15173429
TI  - Introduction to the 3rd Amino Acid Assessment Workshop.
AB  - A series of Amino Acid Assessment Workshops (AAAWs) are being organized and
      conducted to bring together experts in amino acid nutrition, metabolism, cell and
      molecular biology, toxicology, and regulation/policy with the eventual goal to
      establish a paradigm for the characterization of risks associated with ingestion
      of specific intakes of amino acids by humans. In this brief introductory article,
      I present the rationale behind these AAAWs, which basically emerges from the fact
      that there is little systematic information about the adverse effects and the
      pathophysiological mechanisms of excessive intakes of single amino acids or of
      mixtures of amino acids in human subjects. This 3rd AAAW extends, as well as
      builds upon, the information collected at the 1st and 2nd AAAWs. The previous two
      workshops focused attention largely on the metabolism, mechanism of action, and
      functions of amino acids. This 3rd AAAW will focus particular attention on
      intakes needed to meet physiological requirements and above, host and diet
      factors that affect these needs and responses, as well as variation in responses
      to and levels of intake of amino acids among individuals. In this context, the
      overall objective is to establish the science and knowledge base required for use
      in determining and/or predicting the upper level of the safe range of intake of
      specific amino acids under various host, agent (diet), and environmental
      conditions.

PMID- 15173430
TI  - What are the essential elements needed for the determination of amino acid
      requirements in humans?
AB  - The aims of this introductory article are to survey and critically evaluate the
      concepts and approaches that have been used to assess amino acid adequacy and to
      hypothesize about possible future directions of research. The issue in question
      is extensive, consequently this article will be limited to: 1) definitions of
      amino acid requirements; 2) available techniques to assess amino acid
      requirements; 3) actual recommendations for healthy adults; 4) factors
      influencing requirements; and 5) requirements in acute and chronic wasting
      diseases. Recommendations for amino acid intakes for healthy adults were proposed
      by the FAO/WHO expert committee in 2001. They have not yet been published. The
      major factors affecting amino acid requirements are the stage of development,
      reproductive state, environmental factors, digestibility of dietary proteins,
      genotype of the individual, and pathological conditions. Remarkably, there are no
      conclusive data relative to changes in requirements induced by infection, injury,
      trauma, and renal or liver failure. Future research using modern methods to
      evaluate requirements must thus receive a high priority. Wasting diseases are
      associated with deficiencies and imbalances of particular amino acids causing
      specific changes in requirements. Consequently, a new approach has been used to
      categorize amino acids as conditionally indispensable according to their
      functional and physiological properties. Kinetic measurements of plasma amino
      acids might help to estimate qualitative requirements. Measurement of tissue
      intracellular free amino acid deficiencies or excesses is another method to
      estimate qualitative requirements. Based on these measurements tentative values
      for conditionally indispensable amino acids during disease are given in the
      article.

PMID- 15173431
TI  - Amino acid needs for early growth and development.
AB  - Few data exist on amino acid needs in infants and children, mainly because until
      recently, amino acid requirements were determined using nitrogen balance. The
      advent of the indicator amino acid oxidation (IAAO) method permits studies to be
      conducted with minimal adaptation to the test amino acid. In light of the very
      limited data available for human infants, toddlers, and children, it was proposed
      that a factorial approach should be used to estimate their essential amino acid
      requirements. Using amino acid oxidation techniques, dietary essential amino acid
      requirements in adults have been nearly completed. Data on changes in total body
      potassium are now available for infants and children. From these data it is
      possible to calculate protein deposition during growth, and hence, it is now
      possible to estimate the amino acid requirements in children using a factorial
      model. However, there has been no independent verification of the model. Recently
      we determined total branched chain-amino acid requirements for young adults and
      children, and we can provide data to support the validity of the factorial model.
      IAAO has been used on children with liver disease as young as 3 y. The minimally
      invasive IAAO model opens the door for determination of dietary essential amino
      acid requirements in infants and children during health and disease. For study of
      preterm neonates, we used a piglet model to show that the amino acid needs for
      parenteral feeding are markedly reduced for several essential amino acids; this
      suggests that current commercial total parenteral nutrition amino acid solutions
      are less than ideal.

PMID- 15173432
TI  - Advancing age and other factors influencing the balance between amino acid
      requirements and toxicity.
AB  - As the average human lifespan increases, so does the recognition that advancing
      age is associated with changes in nutrient intake and requirements as a
      consequence of biological, social, and pathological factors. Studies show that
      whereas protein requirements may not differ significantly between younger and
      older adults, the adaptive mechanisms and responses to nutritional or
      pathological stressors may differ and alter the balance between requirement and
      toxicity of specific amino acids (AAs). As an individual gets older,
      cardiovascular disease and cancer become the leading causes of morbidity and
      mortality. Advancing age is also associated with changes in appetite, food
      intake, and physical activity, all of which can influence protein and AA
      metabolism. The sulfur amino acids (SAAs) methionine and cysteine recently
      attracted attention because of their pivotal roles in methyl group metabolism and
      maintenance of the cellular redox state. Methionine, an indispensable AA, is
      important for methylation reactions and as a precursor for cysteine, which is the
      rate-limiting AA for glutathione (GSH) synthesis. On one hand, high intake levels
      or blood concentrations of methionine are associated with adverse consequences
      such as hyperhomocysteinemia and endothelial dysfunction, which are risk factors
      for cardiovascular disease. On the other hand, methionine deficiency is reported
      to lower the threshold of chemical-induced toxicity and play a role in
      carcinogenesis. Therefore, it is evident that understanding the biological
      significance of the interrelationship between SAAs, GSH, and methyl group
      metabolism is key to determining optimal dietary intakes of SAAs in older
      individuals.

PMID- 15173433
TI  - Amino acid adequacy in pathophysiological states.
AB  - Amino acid utilization and, therefore, demand differ between the healthy state
      and various disease states. In the healthy state most circulating amino acids are
      derived from dietary proteins that are stored and broken down in the gut and
      released gradually into the portal circulation, and from continuous turnover of
      body protein. In disease states, the amino acid composition of amino acids
      derived from periferal protein breakdown and released in the circulation, is
      different, for example because a substantial part of the branched-chain amino
      acids is broken down to yield glutamine and alanine, which are released in the
      circulation. It appears to be advantageous to mimic this continuous autoinfusion
      in patients, dependent of parenteral of enteral tube feeding. In disease,
      different endpoints should be used to assess the adequacy of the administered
      amino acid mix. Maintenance of a positive nitrogen balance and growth is less
      important than support of wound healing and immune function. Several amino acids
      such as glutamine, cysteine, and taurine are shown or suggested to be
      conditionally essential in disease, and to form substrate in the stressed patient
      for anabolic processes in liver, immune system, and injured sites. Amino acid
      toxicity is rare, and protein restriction for patients with renal or liver
      failure is obsolete because this only aggravated malnutrition. A true example of
      protein toxicity consists of gastrointestinal hemorrhage that precipitates
      hepatic encephalopathy in liver insufficiency, most likely because hemoglobin is
      an unbalanced protein because it lacks the essential amino acid isoleucine.

PMID- 15173434
TI  - Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal
      muscle during exercise.
AB  - Branched-chain amino acids (BCAAs) are essential amino acids that can be oxidized
      in skeletal muscle. It is known that BCAA oxidation is promoted by exercise. The
      mechanism responsible for this phenomenon is attributed to activation of the
      branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which catalyzes the
      second-step reaction of the BCAA catabolic pathway and is the rate-limiting
      enzyme in the pathway. This enzyme complex is regulated by a phosphorylation
      dephosphorylation cycle. The BCKDH kinase is responsible for inactivation of the
      complex by phosphorylation, and the activity of the kinase is inversely
      correlated with the activity state of the BCKDH complex, which suggests that the
      kinase is the primary regulator of the complex. We found recently that
      administration of ligands for peroxisome proliferator-activated receptor-alpha
      (PPARalpha) in rats caused activation of the hepatic BCKDH complex in association
      with a decrease in the kinase activity, which suggests that promotion of fatty
      acid oxidation upregulates the BCAA catabolism. Long-chain fatty acids are
      ligands for PPARalpha, and the fatty acid oxidation is promoted by several
      physiological conditions including exercise. These findings suggest that fatty
      acids may be one of the regulators of BCAA catabolism and that the BCAA
      requirement is increased by exercise. Furthermore, BCAA supplementation before
      and after exercise has beneficial effects for decreasing exercise-induced muscle
      damage and promoting muscle-protein synthesis; this suggests the possibility that
      BCAAs are a useful supplement in relation to exercise and sports.

PMID- 15173435
TI  - Macronutrient intakes as determinants of dietary protein and amino acid adequacy.
AB  - It has long been known that dietary amino acid adequacy is markedly influenced by
      energy balance but in recent years the importance of this has been generally
      underestimated. Important practical issues include unintentional variation in
      energy intake and consequence energy balance that may be responsible for much of
      the apparent variability in protein requirements. Because variation in energy
      expenditure and intakes in subjects in energy balance may influence nitrogen
      balance (NB), a framework for evaluating studies of protein or amino acid
      adequacy in relation to the level of energy intake needs definition. The common
      assumption that the type of energy influences protein utilization is probably
      incorrect with fat as effective as carbohydrate in maintaining NB at energy
      maintenance. A more difficult conceptual issue relates to the use of
      protein:energy (P:E) ratios in evaluating adequacy of intakes in relation to
      requirements. This is necessary given that protein intakes are determined by
      overall food energy intake that varies markedly throughout the life cycle and
      with lifestyle. For any diet that might be considered limiting in protein,
      population groups most likely to be at risk are those with the lowest energy
      requirements, the sedentary elderly. Thus, increased amino acid density of diets
      becomes more important for this population, and increased physical activity and
      higher food intakes at energy balance are likely to reduce the extent of any
      deficiency. Modeling of the implications of proposed protein and amino acid
      requirement values for likely risk of deficiency by comparing P:E ratios of
      intakes and requirements implies high levels of deficiency risk in both
      developing and developed population groups. This raises the question of whether
      proposed values for the lysine requirement need to be reevaluated and
      consideration given to the extent to which adaptive mechanisms might enable the
      metabolic requirement for protein to be met from current intakes.

PMID- 15173437
TI  - Pharmacogenetics and individual variation in the range of amino acid adequacy:
      the biological aspects.
AB  - There have been major developments in our understanding of the ways in which
      genetic variation among individuals in a population can affect responses to
      drugs, and use of such information can improve the safety and efficacy of
      medicines. The brief review summarizes the emergence of modern pharmacogenetics,
      illustrating the importance of the field using the CYP 2D6 polymorphism as a
      paradigm. These pharmacogenetic polymorphisms are compared and contrasted with
      the long-established inborn errors of amino acid biochemistry, exemplified by
      phenylketonuria, suggesting ways in which the approaches of pharmacogenetics
      might inform the safe and effective use of amino acids as food additives and
      supplements.

PMID- 15173438
TI  - Clinical manifestations of inborn errors of the urea cycle and related metabolic
      disorders during childhood.
AB  - Various disorders cause hyperammonemia during childhood. Among them are those
      caused by inherited defects in urea synthesis and related metabolic pathways.
      These disorders can be grouped into two types: disorders of the enzymes that
      comprise the urea cycle, and disorders of the transporters or metabolites of the
      amino acids related to the urea cycle. Principal clinical features of these
      disorders are caused by elevated levels of blood ammonium. Additional disease
      specific symptoms are related to the particular metabolic defect. These specific
      clinical manifestations are often due to an excess or lack of specific amino
      acids. Treatment of urea cycle disorders and related metabolic diseases consists
      of nutritional restriction of proteins, administration of specific amino acids,
      and use of alternative pathways for discarding excess nitrogen. Although
      combinations of these treatments are extensively employed, the prognosis of
      severe cases remains unsatisfactory. Liver transplantation is one alternative for
      which a better prognosis is reported.

PMID- 15173439
TI  - Variability in planning and assessment: statistical considerations and models.
AB  - Nutrition researchers are called upon to inform policymakers of the consequences
      of consuming different amounts of various nutrients: how much is enough, how much
      is too much, and why. Traditionally, requirements were described by population
      average levels and some measure of between-individual variation, whereas
      toxicities were described by single levels above which a toxic response was
      likely to occur. These statistics were used to estimate the prevalence of various
      adverse health effects in individual populations. Recently, accumulated data and
      improved understanding have led to more complete descriptions of the utilization
      of a few important nutrients and to the formulation of a model that includes both
      requirement and toxicity as extremes of the healthy-intake spectrum. This
      approach is based on estimating the full statistical distributions of individual
      nutritional deficits and surfeits within a population and using this to derive
      prevalence curves for specific adverse health effects. This information promises
      to provide policy planners with better tools to judge the health of populations,
      design feeding programs, and predict the sequelae of modifications in food supply
      and dietary habits.

PMID- 15173440
TI  - Establishing the upper end of the range of adequate and safe intakes for amino
      acids: a toxicologist's viewpoint.
AB  - The safety assessment of high intake levels of individual amino acids cannot be
      based on data from nutritional studies with proteins. Routine toxicity tests
      designed to investigate a wide range of possible effects should be undertaken for
      hazard identification and characterization using studies selected to mirror the
      predicted pattern and duration of human exposure. The approach used to establish
      an acceptable daily intake level for additives and pesticides, based on defining
      a "no observed adverse effect" level in the experimental study and dividing by
      uncertainty factors that allow for species differences and human variability, has
      a long history of use for foreign compounds and would provide a suitable basis
      for determining health-based guidance values for single amino acids. The usual
      default uncertainty factors for toxicokinetics and toxicodynamics should be
      replaced by compound-specific values if suitable data are available. In addition,
      the usual uncertainty factors should be modified to more relevant default values
      based on species differences and human variability in the biodisposition of amino
      acids in general or of groups of metabolically interrelated amino acids. There
      would be no significant health concerns if the human intake levels were below a
      health-based guidance value developed using this approach. A population
      distribution approach could be used to define the magnitude of any risk at intake
      levels above the guidance value.

PMID- 15173441
TI  - The basis for setting the upper range of adequate intake for regulation of
      macronutrient intakes, especially amino acids.
AB  - The comparison of actual intakes of essential amino acids to the dietary
      reference intakes indicates that amino acid supply is likely not a public health
      concern in industrialized countries. This fact does not preclude the interest in
      specific amino acid intake in some physiological or pathological situations in
      targeted subgroups of the population. Thus, the addition of amino acids to some
      food vehicles to create functional foods will be regulated by public authorities
      in different ways according to the regulatory contexts specific to each country.
      The main issues to be considered are, however, the same: safety of the product
      and justification of the health claim accompanying the product's promotion. In
      addition to classical scientific data, the use of Monte Carlo simulations can be
      a useful tool to support the choice of the food vehicle and the amounts added to
      this food, and to demonstrate both safety and possible efficacy of the functional
      food in the targeted population.

PMID- 15173443
TI  - The nature of human hazards associated with excessive intake of amino acids.
AB  - In recent years there has been a large increase in the consumption of individual
      amino acids as dietary supplements. This has resulted not only from the use of
      certain amino acids as flavoring agents, but other amino acids are taken for
      perceived health benefit, for enhancement of physical performance, as well as for
      psychological effects. Two reviews of the scientific literature exist that mainly
      deal with effects in animals, and three major reports consider the safety of
      amino acids for human consumption. This article is a brief summary of the
      available evidence regarding the safety of individual amino acids when taken in
      excess relative to the amounts absorbed from dietary protein.

PMID- 15173444
TI  - Biomarkers for cancer diagnosis: implications for nutritional research.
AB  - The biology of disease progression is a complex process that involves multiple
      sequential steps leading to cellular changes and metabolic events. These
      molecular events, which may serve as potential biomarkers, can be analyzed by
      laboratory methods and used to detect a disease such as cancer or indicate the
      biological exposure to environmental substances including dietary intake.
      Identification of the genetic, molecular, and clinical events involved in the
      disease process enables the development of effective therapeutic and preventive
      measures and the prediction of prognostic outcomes. This article describes
      various factors that influence nutritional and cancer biomarker research, draws
      similarities between them, and discusses the measures that have been adapted to
      validate cancer biomarkers that can potentially be applied to nutritional
      biomarker research. Nutritional research suffers from a lack of means to quantify
      relationships between diet and cancer. Biomarkers of dietary intake or
      metabolism, therefore, could have potential application in study designs for
      establishing a causal relationship between diet and disease.

PMID- 15173445
TI  - Animal models of human amino acid responses.
AB  - The principal differences between experimental animals and humans with regard to
      amino acid responses are 1) growing animals partition most of their amino acid
      intake to protein accretion, whereas growing children partition most of their
      intake to maintenance; 2) invasive assessment procedures are common in animals
      but very limited in humans; and 3) humans can describe how they feel in response
      to amino acid levels or balances, whereas animals cannot. New (pharmacologic)
      uses of amino acids have been and are being discovered (e.g., cysteine, arginine,
      leucine, glutamine), and this makes it imperative that tolerance limits be
      established. Work with pigs suggests that excessive intake of methionine and
      tryptophan present the biggest problems, whereas excessive intake of threonine,
      glutamate, and the branched-chain amino acids seems to be well tolerated.

PMID- 15173446
TI  - Potential approaches to the assessment of amino acid adequacy in rats: a progress
      report.
AB  - We report on research progress on two approaches that may be useful in
      determining the upper adequacy range for macronutrients such as amino acids. One
      approach was to attempt to identify "toxic metabolites" that were responsible for
      toxicity or biomarkers for the toxicity of excessive intake of an amino acid in
      rats. We found that there was hepatic toxicity that was specifically associated
      with L-cystine excess, but not with L-cysteine excess. We analyzed urine samples
      from rats fed basal diets or L-cystine or L-cysteine excess diets and identified
      25 peaks from gas chromatography mass spectrometry analysis that were specific
      for L-cystine excess and also correlated with toxicity markers. Another approach
      was to try to identify "metabolic limits" by measuring CO(2) arising from amino
      acid excess. Uniformly (13)C labeled L-leucine was used as tracer, in diets with
      added L-leucine fed to rats, and (13)CO(2) arising from its metabolism was
      collected over 24 h and the fraction of the ingested L-leucine that was exhaled
      as CO(2) was calculated. The fractional exhalation of (13)CO(2) increased with
      increasing L-leucine dose, but showed an inflexion point at approximately 8.9
      g/kg body weight, after which it reached a plateau. This suggested that >8.9 g/kg
      BW, the catabolism of L-leucine changed and this approximately coincided with the
      dose above which a statistically significant decrease in body weight was seen.

PMID- 15173447
TI  - Animal models of amino acid metabolism: a focus on the intestine.
AB  - One important advantage of animal models is that they permit invasive approaches
      and can be especially valuable when evaluating tissue and specific features of
      metabolism in situ. The focus of this presentation is current models, which are
      providing insights into the pivotal importance of the gastrointestinal tract in
      amino acid metabolism. Intestinal amino acid metabolism is conceptually and
      technically difficult to approach and multiple processes must be accounted for:
      protein synthesis and degradation; transit of amino acids in both directions
      across the basolateral surface of enterocytes, in addition to uptake on the
      apical side; arterio-portal differences as well as net portal appearance during
      uptake of defined amino acid mixtures appearing on the luminal side; first pass
      amino acid metabolism. These key features are largely impossible to study without
      access to invasive approaches in vivo and cannot be reproduced in vitro. Douglas
      Burrin, Ron Ball, and Vickie Baracos and their co-workers have used the domestic
      piglet to study intestinal protein metabolism in situ in three distinctly
      different and complementary approaches. Collectively, their approaches allow a
      means to describe the key elements of intestinal amino acid capture (and release)
      and the means to probe their physiological and pathological variation. It seems
      evident that the portal-drained viscera represent sites of quantitatively
      important amino acid catabolism, and that this capacity combined with hepatic
      metabolism would largely limit the possibility of toxic sequelae of amino acids
      taken orally.

PMID- 15173448
TI  - Approaches to assessment of exposure to food- and supplement-derived amino acids.
AB  - Although the amino acid composition of almost all food proteins is known,
      estimating the amino acid intake from the diet is extremely difficult because of
      the lack of available data. A conservative approach would be to determine the
      population distribution of protein intake, select the 97.5(th) or higher
      percentile of intake, assume all comes from the target protein, and estimate
      exposure to some specific amino acid. Any number of dietary survey methodologies
      could be used to conduct such a conservative approach. However, given the great
      variety of brands of food supplements, estimates of amino acid intakes from
      supplements are problematic. Firstly, few studies include supplements in their
      target nutrient sources because brand-level data would need to be retained and
      nutritional composition data would need to be recorded. Probabilistic modeling
      offers some solution provided some basic data are gathered. The percentage of the
      population regularly taking supplements and the frequency of consumption must be
      known. Therefore, data on the dietary supplement market would need to be known
      including the percent of brands containing amino acids and if possible specific
      amino acids together with concentrations. A probabilistic model as follows would
      ensue: probability of being a consumer of amino acid supplements; probability
      distribution function of frequency of use of supplements; probability
      distribution function of dose per eating occasion; market characteristics;
      probability distribution function for dietary amino acid intake. Using multiple
      iterations and perhaps bootstrapping on some elements of the model, fully worst
      case model scenarios of exposure could be computed.

PMID- 15173450
TI  - General Discussion at the 3rd Amino Acid Assessment Workshop (3rd AAAW).

PMID- 15173451
TI  - Acute otitis media in children: a continuing story.

PMID- 15173452
TI  - Physiologic growth and development during adolescence.

PMID- 15173453
TI  - Respiratory disorders in the newborn: identification and diagnosis.

PMID- 15173454
TI  - Index of suspicion.

PMID- 15173455
TI  - Munchausen syndrome by proxy.

PMID- 15173456
TI  - Rifampin.

PMID- 15173457
TI  - Fractures.

PMID- 15173459
TI  - Introduction: results from a new national survey of children's health.

PMID- 15173460
TI  - The National Survey of Early Childhood Health .
AB  - OBJECTIVES: The National Survey of Early Childhood Health (NSECH) is a new survey
      that was designed to provide nationally representative data on the health and
      development of children and to fill an information gap in the pediatric
      literature on parents' views of the delivery of health care to their young
      children. DESIGN: The selection of topics was guided by previous studies
      conducted to examine parents' expectations and needs in child health supervision
      visits. The NSECH is a random-digit-dial telephone survey of a nationally
      representative sample of 2068 children aged 4 to 35 months. This sample includes
      an oversample of black and/or Hispanic children so that results for these
      minority groups could be estimated with greater precision. The sampling frame for
      NSECH is from the State and Local Area Integrated Telephone Survey (SLAITS),
      which is a program of surveys conducted by the National Center for Health
      Statistics that makes economical use of the large sampling frame of the National
      Immunization Survey (NIS). SLAITS takes advantage of the NIS screening effort by
      fielding interviews on other health topics with households screened for the NIS.
      The respondent was the parent or guardian identified as the person most
      responsible for the sampled child's medical care. Spanish-language interviews
      composed 19% of all completed interviews. The Council of American Survey Research
      Organizations response rate was 65.6%. CONCLUSION: The NSECH provides a unique
      data set that allows a well-rounded picture of the health, health care
      utilization, health care content, and interpersonal quality of health services
      received by young children in the United States. It also contains important
      information about family characteristics, patterns of health-promoting behaviors,
      and family routines that are associated with promoting the developmental health
      of young children. NSECH results can also help national policy makers understand
      the health needs of families with young children and how well the health system
      is meeting those needs.

PMID- 15173461
TI  - Overview of the content of health supervision for young children: reports from
      parents and pediatricians.
AB  - OBJECTIVE: To describe the content of anticipatory guidance provided to parents
      of infants and toddlers and to identify primary areas of unmet need as reported
      by both parents and pediatricians. METHODS: Parent data were obtained from the
      National Survey of Early Childhood Health, a nationally representative sample of
      parents of 2068 US children aged 4 to 35 months. Pediatrician data were obtained
      from the Periodic Survey of Fellows, a national survey of members of the American
      Academy of Pediatrics. RESULTS: Parents and pediatricians tend to agree on the
      relative ranking of which topics are most frequently addressed. Parents and
      pediatricians both report that the traditional topics of preventive care-
      immunizations, feeding issues, and sleep patterns--are most frequently discussed,
      whereas topics that were more recently introduced into pediatric care related to
      developmental needs and family context are less commonly addressed. Parent
      reported discussion of these topics include reading (discussed for 61% of
      children 19-35 months) and child care (discussed for 26% of children 19-35
      months). Parent reports of some unmet need--defined as topics not discussed that
      the parent believes would have been helpful to them--affect 36% of children aged
      4 to 9 months and 56% of children aged 10 to 35 months and are highest for the
      topics of discipline strategies and toilet training. Other specific areas of
      unmet need reported by at least 15% of parents are burn prevention, child care,
      reading, vocabulary development, and social development. Rates of unmet need vary
      with family characteristics and health system factors, including maternal
      education, race/ethnicity, and length of well-child visits. CONCLUSION: Parents
      and pediatricians report high rates of discussion on many topics that are
      critical to healthy development in the first years of life. They also identify
      areas of need that largely address health supervision on developmental topics.
      Findings indicate that additional research is needed to understand issues related
      to specific topic areas as well as the dynamics of personal and system factors
      that determine what is discussed.

PMID- 15173462
TI  - Continuity of primary care clinician in early childhood.
AB  - OBJECTIVES: This study uses the first national data on well-child care for young
      children to 1) assess how many children have a specific clinician for well-child
      care; 2) identify the health insurance, health care setting, and child and family
      determinants of having a specific clinician; and 3) assess how parents choose
      pediatric clinicians. METHODS: Data from the National Survey of Early Childhood
      Health (NSECH), a nationally representative survey of health care quality for
      young children fielded by the National Center for Health Statistics in 2000, were
      used to describe well-child care settings for children aged 4 to 35 months.
      Parents reported the child's usual setting of well-child care, whether their
      child has a specific clinician for well-child care, and selection method for
      those with a clinician. Bivariate and logistic regression analyses are used to
      identify determinants of having a specific clinician and of provider selection
      method, including health care setting, insurance, managed care, and child and
      family characteristics. RESULTS: Nearly all young children aged 4 to 35 months in
      the United States (98%) have a regular setting, but only 46% have a specific
      clinician for well-child care. The proportion of young children who have a single
      clinician is highest among privately insured children (51%) and lowest among
      publicly insured children (37%) and uninsured children (28%). In multivariate
      logistic regression including health care and sociodemographic factors, odds of
      having a specific clinician vary little by health care setting. Odds are lower
      for children who are publicly insured (odds ratio [OR]: 0.7; 95% confidence
      interval [CI]: 0.45-0.97) and for Hispanic children with less acculturated
      parents (OR: 0.6; 95% CI: 0.39-0.91). Odds are higher for children in a health
      plan with gatekeeping requirements (OR: 1.4; 95% CI: 1.02-1.88). Approximately
      13% of young children with a specific clinician were assigned to that provider.
      Assignment rather than parent choice is more frequent for children who are
      publicly insured, in managed care, cared for in a community health center/public
      clinic, Hispanic, and of lower income and whose mother has lower education. In
      multivariate logistic regression, only lack of health insurance, care in a
      community health center, and managed care participation are associated with lack
      of choice. CONCLUSIONS: Anticipatory guidance is the foundation of health
      supervision visits and may be most effective when there is a continuous
      relationship between the pediatric provider and the parent. Only half of young
      children in the United States are reported to have a specific clinician for well
      child care. Low rates of continuity are found across health care settings.
      Furthermore, not all parents of children with a continuous relationship exercised
      choice, particularly among children in safety net health care settings. These
      provisional findings on a new measure of primary care continuity for children
      raise important questions about the prevalence and determinants of continuity.

PMID- 15173463
TI  - Assessing development in the pediatric office.
AB  - OBJECTIVE: To determine the proportion of children aged 10 to 35 months who were
      reported ever to have received a developmental assessment (DA) and to examine
      characteristics of the child, family, and health care setting associated with the
      receipt of a DA. METHODS: The National Survey of Early Childhood Health,
      conducted in 2000, is a survey of 2068 parents of children 4 to 35 months of age.
      Children were classified as having received a DA in response to 2 questions:
      whether the child's pediatric provider ever told parents that he or she was doing
      a "developmental assessment" and/or parents recalled explicit components of a DA,
      such as stacking blocks or throwing a ball. Parent-reported receipt of a DA was
      assessed in relationship to child and family, health care access, other measures
      of health care content and process, and measures of quality and satisfaction.
      RESULTS: Approximately 57% of children 10 to 35 months of age ever received a DA.
      Forty-two percent of parents recalled ever being told by their child's pediatric
      provider that a DA was being done. Thirty-nine percent recalled their child's
      being asked to perform specific tasks routinely included in a DA. Bivariate
      analysis indicates that receipt of a DA is not associated with child or family
      sociodemographic characteristics such as maternal education and household income,
      with the exception of race/ethnicity. Less acculturated Hispanic parents reported
      a DA more frequently than parents in other racial/ethnic groups (66% vs 56%). A
      smaller proportion of parents whose children who used community health centers
      reported their child's ever having received a DA compared with children who use
      other settings (51% vs 60%). Compared with other children, parents whose child
      ever received a DA reported more frequently than other parents that the time
      spent with the child's provider during the last well-child visit was adequate
      (94% vs 80%). They also reported longer visits (19 minutes vs 16 minutes), higher
      family-centered care ratings (mean: 71 vs 59), and higher satisfaction with well
      child care (8.9 vs 8.4). Receipt of a DA is also associated with the content of
      developmentally focused anticipatory guidance received. For each health
      supervision topic analyzed, frequency of discussion is higher for children who
      ever received a DA. In multivariate analysis, odds of receiving a DA are higher
      for children with longer visits with the provider (odds ratio: 1.03; 95%
      confidence interval: 1.01-1.05) and lower for children in community health
      clinics compared with a private office (odds ratio: 0.61; 95% confidence
      interval: 0.39-0.96), even accounting for total well-child visits to the
      pediatric provider. CONCLUSION: Although guidelines endorse the routine provision
      of DAs, parents of many children do not report receiving DAs. Children who
      receive assessments are more likely to receive other developmental services, and
      their parents are more likely to report greater satisfaction with care and rate
      the interpersonal quality of well-child care more favorably. The substantial
      number of children who do not receive these routinely recommended services raises
      important questions about the quality of care received.

PMID- 15173464
TI  - Routine assessment of family and community health risks: parent views and what
      they receive.
AB  - OBJECTIVE: To examine the prevalence of parent-provider discussions of family and
      community health risks during well-child visits and the gaps between which issues
      are discussed and which issues parents would like to discuss. METHODS: Data came
      from the National Survey of Early Childhood Health, a nationally representative
      sample of parents of 2068 children aged 4 to 35 months. The outcome measures were
      1) the reported discussions with pediatric clinicians about 7 family and
      community health risks and 2) whether the parent believes that pediatric
      clinicians should ask parents about each risk. RESULTS: Most parents believe that
      pediatric providers should discuss topics such as smoking in the household,
      financial difficulties, and emotional support available to the parent. However,
      with the exception of "household smoking," fewer than half of parents have been
      asked about these topics by their child's clinician. Parents of black and
      Hispanic children were more likely than parents of white children to be asked
      about several of these issues, as were parents of the youngest children and those
      with publicly financed health insurance. The greatest gap between parents' views
      and their reports of discussion with the clinician occur for parents of white
      children and older children. Among parents who hold the view that a topic should
      be discussed, parents of white and older children are less likely than others to
      report discussing some or all family and community health risks. CONCLUSION: The
      low frequency of discussions for many topics indicates potential unmet need. More
      universal surveillance of parents with young children might ensure that needs are
      not missed, particularly given that strong majorities of parents view family and
      community topics, with the exception of community violence, as appropriate for
      discussion in clinic visits.

PMID- 15173465
TI  - Parent report of reading to young children.
AB  - OBJECTIVE: The purpose of this study was to investigate the predictors and
      frequency of book-sharing activities in a nationally representative sample of
      families with young children and to examine the extent to which parents report
      that pediatric health care providers are addressing early literacy activities.
      METHODS: This study analyzed data from the 2000 National Survey of Early
      Childhood Health (NSECH), a telephone survey of 2068 parents of children aged 4
      to 35 months. Parents were queried about the frequency of reading with their
      child, whether their pediatric provider discussed reading in the past year, and,
      if not, whether a discussion of the importance of reading to their child would
      have been helpful. Descriptive statistics, bivariate analyses, and multivariate
      logistic regression to identify predictors of daily reading among parents of
      young children nationally were used. RESULTS: Approximately 52% of young children
      are reportedly read to every day by a parent. Significant predictors of daily
      reading include older child's age (19-35 months; odds ratio [OR]: 1.77; 95%
      confidence interval [CI]: 1.18-2.65, as compared with 4-9 months), maternal
      education greater than high school (OR: 2.00; 95% CI: 1.24-3.22), greater number
      of children's books in the home (OR: 1.01; 95% CI: 1.00-1.01), and discussion of
      reading by the pediatric provider (OR: 1.66; 95% CI: 1.23-2.24). Lower odds of
      daily reading are found for maternal full-time working status (OR: 0.68; 95% CI:
      0.49-0.95), black race/ethnicity (OR: 0.61; 95% CI: 0.41-0.91), Hispanic
      race/ethnicity (OR: 0.56; 95% CI: 0.37-0.86), Spanish language-dominant parents
      (OR: 0.37; 95% CI: 0.22-0.62), and >1 child in the household (2 children OR:
      0.68, 95% CI: 0.48-0.97; 3 children OR: 0.53, 95% CI: 0.35-0.82). Approximately
      37% of parents of young children stated that their child's pediatric provider had
      not discussed reading with them. Nearly half (47%) of these parents indicated
      that they would have found such a discussion helpful. CONCLUSIONS: Family context
      and daily reading routines are important for a child's early literacy
      development. This national study identifies how family characteristics and
      routines are associated with the family's literacy orientation. The analysis also
      indicates that a large percentage of parents with young children who do not read
      daily believe that it would be helpful to discuss the importance of reading with
      their child's pediatric provider.

PMID- 15173466
TI  - Parents' discipline of young children: results from the National Survey of Early
      Childhood Health.
AB  - OBJECTIVE: To examine the use and predictors of different discipline practices by
      parents of very young children using data from the 2000 National Survey of Early
      Childhood Health (NSECH). METHODS: NSECH is a nationally representative telephone
      survey of 2068 parents of young children between the ages of 4 and 35 months
      conducted by the National Center for Health Statistics. The survey includes
      questions about parents' use of 5 discipline practices: yelling, spanking, time
      out, toy removal, and explanations. chi2 analyses and logistic multivariate
      regression were used to examine associations between discipline practices and
      child, parent, and demographic factors. RESULTS: Among young children aged 19 to
      35 months, frequent parental use of discipline strategies ranged from 26%
      (spanking) to 65% (taking away toy or treat), 67% (yelling), 70% (using time
      out), and 90% (providing explanations). In multivariate analyses, child age
      predicts reports of more frequent spanking and yelling, and child developmental
      risk is associated with increased reports of yelling. Parent frustration predicts
      frequent use of every discipline practice, including a greater inclination to use
      aversive practices. Lower parental emotional well-being is associated with
      reports of frequent yelling and spanking. Black ethnicity and maternal age
      predict more frequent spanking, and Spanish-speaking parents reported less
      frequent use of time out and taking away a toy. CONCLUSION: Child age and
      developmental risk and parents' ethnicity, emotions, and mental health are
      closely associated with discipline practices in the first 3 years of life. These
      factors are important for pediatricians to recognize in providing anticipatory
      guidance about discipline.

PMID- 15173467
TI  - Insurance status and vaccination coverage among US preschool children.
AB  - BACKGROUND: Insurance status has been shown to have an impact on children's use
      of preventive and acute health services. The objective of this study was to
      determine the relationship between insurance status and vaccination coverage
      among US preschool children aged 19 to 35 months. METHODS: We linked data from 2
      national telephone surveys, the National Immunization Survey and the National
      Survey of Early Childhood Health, conducted during the first half of 2000.
      Children were considered up to date (UTD) when they had received at least 4
      diphtheria-tetanus-acellular pertussis/diphtheria-tetanus-pertussis vaccines, 3
      poliovirus vaccines, 1 MMR vaccine, 3 Haemophilus influenza vaccines, and 3
      hepatitis B vaccines at the time the interview was conducted. RESULTS: Among the
      735 children in our study sample, 72% were UTD. The vast majority (94%) reported
      some type of health insurance at the time of the survey. Children with private
      insurance were more likely to be UTD (80%) than those with public insurance (56%)
      or no insurance (64%). In a multivariate analysis that controlled for child's
      race/ethnicity; household income; maternal age/marital status/educational level;
      location of usual care; and Special Supplemental Nutrition Program for Women,
      Infants, and Children participation, insurance was no longer an independent
      predictor of vaccination. CONCLUSIONS: The disparity in vaccination coverage
      among publicly, privately, and uninsured children is dramatic, underscoring its
      importance as a marker for underimmunization, despite the multivariate findings.
      The Vaccines for Children Program, a partnership between public health and
      vaccination providers who serve uninsured children and those enrolled in
      Medicaid, is well suited to target and improve vaccination coverage among these
      vulnerable children.

PMID- 15173468
TI  - Satisfaction with health care for young children.
AB  - OBJECTIVES: The aims of this study are to 1) assess parent satisfaction with well
      child care for their young child and 2) identify how global satisfaction ratings
      and parent reports on the processes of care vary with child and family
      characteristics, health care received, and health system factors. METHODS: The
      National Survey of Early Childhood Health is a telephone survey that used a
      stratified random-digit-dial sampling design to achieve a nationally
      representative sample of 2068 children and 4 to 35 months. Parents provided
      global ratings of satisfaction with their child's well-child visits (range 0-100)
      and reported their satisfaction with information provided and the time spent with
      the provider. A subsample of parents whose child has a particular provider for
      well-child care (n = 930) also reported their likelihood of recommending their
      provider. RESULTS: The mean global satisfaction rating is 86.9 (standard error:
      6.1). Approximately 94% of parents of young children reported information
      satisfaction, 88% reported time satisfaction, and 79% would recommend their
      child's provider. Bivariate analysis shows lower satisfaction for uninsured
      children but few differences associated with insurance type or health care
      setting. In multivariate analyses including child and family factors and health
      system factors, Hispanic, Spanish-speaking mothers of young children have lower
      odds than non-Hispanic white mothers of reporting information (odds ratio [OR]:
      0.32; 95% confidence interval [CI]: 0.13-0.79) and time satisfaction (OR: 0.44;
      95% CI: 0.21-0.90). Parents of children who experienced missed or delayed care
      have lower odds of time satisfaction (OR: 0.27; 95% CI: 0.16-0.46) and have lower
      global satisfaction. Greater length of well-child visits is consistently
      associated with greater satisfaction on all 4 measures. CONCLUSION: Although most
      parents reported relatively high levels of satisfaction with well-child care,
      shorter length of well-child visits and experiencing missed or delayed care are
      the 2 factors consistently associated with lower satisfaction using each of the
      measures. Efforts to improve satisfaction ratings might focus on improving the
      delivery of well-child care and ensuring that parents get the time they need.

PMID- 15173469
TI  - Measuring the quality of preventive and developmental services for young
      children: national estimates and patterns of clinicians' performance.
AB  - OBJECTIVE: To generate a national picture of performance in the area of
      preventive and developmental services for children aged 4 to 35 months using 4
      composite quality measures in the areas of 1) anticipatory guidance and parental
      education, 2) screening for family psychosocial risks, 3) screening for smoking
      and drug and alcohol use in the home, and 4) provision of family-centered care.
      METHODS: Data from the National Survey on Early Childhood Health (N = 2068) were
      used to calculate the 4 composite performance measures, which, taken together,
      represent 23 topics included in the American Academy of Pediatrics health
      supervision guidelines. The reliability and degree of redundancy within and
      across these 4 measures were evaluated. Four methods for scoring these measures
      were used. Quality scores for subgroups of children were calculated, and logistic
      regression analysis was performed to examine the association of demographic,
      health, and health system variables with receiving recommended care. RESULTS:
      Regardless of the scoring method used, performance is highest in areas of family
      centered care and screening for smoking and drug and alcohol use in the home.
      Performance is lowest in the areas of anticipatory guidance and education and
      assessment for family psychosocial risks. Using a scoring method that takes into
      account parent preferences for guidance and beliefs about discussing psychosocial
      topics, composite quality measure scores ranged from 13.5% to 59.6% of parents of
      young children receiving recommended care. Overall, 94.0% of parents reported 1
      or more unmet needs for parenting guidance, education, and screening by pediatric
      clinician(s) in 1 or more of the content of care areas evaluated. Uninsured
      children and children aged 18 to 35 months are disproportionately represented
      among the 15.3% of children whose parents indicated an unmet need in each of the
      4 areas of care. Although the reliability of each composite measure was high, no
      single item in any composite was highly correlated with the remaining combined
      items. Performance on any 1 composite measure for a child was only somewhat
      predictive of performance for the other measures. There are significant
      variations in performance on the basis of child age, race, insurance status,
      maternal education, marital status, and parent language as well as other factors.
      CONCLUSIONS: National results using 4 complementary composite quality measures
      confirm the need for improving the quality of preventive and developmental
      services for young children in the United States. The 4 measures identify areas
      of care and subgroups of children for whom improvements in quality are most
      needed. The measures provide a parsimonious yet comprehensive assessment across
      distinct health supervision topics and 4 essential aspects of preventive and
      developmental services. Until valid measures of outcomes of preventive and
      developmental services are identified or 1 single process of care measure is
      shown to be highly predictive of these outcomes, assessing multiple aspects of
      recommended care will be necessary to assess performance of health care providers
      or systems of care.

PMID- 15173470
TI  - Financing childhood health supervision services in the 21st century.

PMID- 15173471
TI  - Mommy, who is my doctor?

PMID- 15173472
TI  - Small steps and big leaps: implications of the national survey of early childhood
      health for improving the quality of preventive and developmental care for young
      children.

PMID- 15173473
TI  - Cognitive function of children with cystic fibrosis: deleterious effect of early
      malnutrition.
AB  - OBJECTIVE: Patients who have cystic fibrosis (CF) and experience delayed
      diagnosis by traditional methods have greater nutritional insult compared with
      peers diagnosed via neonatal screening. The objective of this study was to
      evaluate cognitive function in children with CF and the influence of both early
      diagnosis through neonatal screening and the potential effect of early
      malnutrition. METHODS: Cognitive assessment data were obtained for 89 CF patients
      (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in
      either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of
      the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, Second
      Edition was administered to generate the Cognitive Skills Index (CSI) and
      cognitive factor scores (Verbal, Nonverbal, and Memory). RESULTS: Cognitive
      scores in the overall study population were similar to normative data (CSI mean
      [standard deviation]: 102.5 [16.6]; 95% confidence interval: 99.1-105.9). The
      mean (standard deviation) CSI scores for the screened and control groups were
      104.4 (14.4) and 99.8 (18.5), respectively. Significantly lower cognitive scores
      correlated with indicators of malnutrition and unfavorable family factors such as
      single parents, lower socioeconomic status, and less parental education. Our
      analyses revealed lower cognitive scores in patients with low plasma alpha
      tocopherol (alpha-T) levels at diagnosis. In addition, patients in the control
      group who also had vitamin E deficiency at diagnosis (alpha-T < 300 microg/dl)
      showed significantly lower CSI scores in comparison with alpha-T-sufficient
      control subjects and both deficient and sufficient alpha-T subsets of screened
      patients. CONCLUSION: Results suggest that prevention of prolonged malnutrition
      by early diagnosis and nutritional therapy, particularly minimizing the duration
      of vitamin E deficiency, is associated with better cognitive functioning in
      children with CF.

PMID- 15173474
TI  - Fetal infants: the fate of 4172 infants with birth weights of 401 to 500 grams-
      the Vermont Oxford Network experience (1996-2000).
AB  - OBJECTIVE: Improvement in the survival of extremely low birth weight infants
      requires that we evaluate the limits of our care and assess the impact of
      treatment on a population of infants who previously rarely survived. METHODS: A
      review was conducted of demographic and clinical data of infants who had birth
      weight 401 to 500 g and were entered in the Vermont Oxford Network Database
      between 1996 and 2000. RESULTS: A total of 4172 infants who weighed 401-500 g
      (mean gestational age: 23.3 +/- 2.1 weeks) were born at 346 participating
      centers. Overall, 17% survived until discharge. A total of 2186 (52%) died in the
      delivery room (DR), and 1986 (48%) were admitted to a neonatal intensive care
      unit (NICU). Compared with infants who died in the DR, infants who survived the
      DR and were admitted to the NICU were more likely to be female (58% vs 49%), to
      be small for gestational age (56% vs 11%), to have received prenatal steroids
      (61% vs 12%), and to have been delivered by cesarean section (55% vs 5%). Thirty
      six percent of NICU admissions survived to discharge. Mean gestational age of the
      690 NICU survivors was 25.3 +/- 2.0 weeks. These survivors experienced
      significant morbidity in the NICU. CONCLUSIONS: An appreciable number of these
      marginally viable fetal infants survive. They experienced a high rate of serious
      morbidities while in the NICU. There is very little information about long-term
      outcomes, as the medical and developmental status of few of these infants has
      been followed carefully. Parents should be made aware of the high incidence of
      serious problems, and concerted efforts should be made to follow the status of
      these infants.

PMID- 15173475
TI  - Long-term ocular prognosis in 327 children with congenital toxoplasmosis.
AB  - OBJECTIVE: Retinochoroiditis is the most frequent consequence of congenital
      toxoplasmosis. Early diagnosis and treatment are believed to reduce the risk of
      visual impairment. We report on the clinical evolution of ocular lesions and
      final visual function in a prospective cohort of congenitally infected children
      who were identified during monthly maternal prenatal screening. METHODS: The
      study included 327 congenitally infected children who were monitored for up to 14
      years at the Croix Rousse Hospital in Lyon, France. Data on date of maternal
      infection; time and type of therapy; antenatal, neonatal, and postnatal work-ups;
      and ocular status were analyzed. RESULTS: All mothers but 52 had been treated.
      Pyrimethamine and sulfadiazine was given in utero to 38% of children and after
      birth to 72% of newborns. Fansidar was given for an average duration of 337 days
      in all but 2 children. After a median follow-up of 6 years, 79 (24%) children had
      at least 1 retinochoroidal lesion. In 23 (29%) of them, at least 1 new event had
      been diagnosed up to 10 years after detection of the first lesions: reactivation
      of an existing lesion (1 case), new lesion in a previously healthy location (19
      cases), or both (3 cases). Fifty-five children had lesions in 1 eye; of the 45
      children for whom final visual acuity data were available, 31 (69%) had normal
      vision. Twenty-four children had lesions in both eyes; of the 21 for whom final
      visual acuity data were available, 11 had normal vision in both eyes. None had
      bilateral visual impairment. CONCLUSIONS: Clinicians, parents, and elder children
      with congenital infection should be informed that late-onset retinal lesions and
      relapse can occur many years after birth but that the overall ocular prognosis of
      congenital toxoplasmosis is satisfactory when infection is identified early and
      treated accordingly.

PMID- 15173476
TI  - Population-based newborn screening for genetic disorders when multiple mutation
      DNA testing is incorporated: a cystic fibrosis newborn screening model
      demonstrating increased sensitivity but more carrier detections.
AB  - OBJECTIVES: Newborn screening for cystic fibrosis (CF) provides a model to
      investigate the implications of applying multiple-mutation DNA testing in
      screening for any disorder in a pediatric population-based setting, where
      detection of affected infants is desired and identification of unaffected
      carriers is not. Widely applied 2-tiered CF newborn screening strategies first
      test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a
      single CFTR mutation (DeltaF508), systematically missing CF-affected infants with
      any of the >1000 less common or population-specific mutations. Comparison of CF
      newborn screening algorithms that incorporate single- and multiple-mutation
      testing may offer insights into strategies that maximize the public health value
      of screening for CF and other genetic disorders. The objective of this study was
      to evaluate technical feasibility and practical implications of 2-tiered CF
      newborn screening that uses testing for multiple mutations (multiple-CFTR
      mutation testing). METHODS: We implemented statewide CF newborn screening using a
      2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT
      then had multiple-CFTR-mutation testing. Infants who screened positive by
      detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe
      protocol) were then referred for definitive diagnosis by sweat testing. We
      compared the number of sweat-test referrals using single- with multiple-CFTR
      mutation testing. Initial physician assessments and diagnostic outcomes of these
      screened-positive infants and any affected infants missed by the screen were
      analyzed. We evaluated compliance with our screening and follow-up protocols. All
      Massachusetts delivery units, the Newborn Screening Program, pediatric health
      care providers who evaluate and refer screened-positive infants, and the 5
      Massachusetts CF Centers and their affiliated genetic services participated. A 4
      year cohort of 323 506 infants who were born in Massachusetts between February 1,
      1999, and February 1, 2003, and screened for CF at approximately 2 days of age
      was studied. RESULTS: A total of 110 of 112 CF-affected infants screened
      (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation
      screening; 2 false-negative screens did not show elevated IRT. A total of 107
      (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation
      screen, and 3 had positive screens on the basis of the failsafe protocol. In
      contrast, had we used single-mutation testing, only 96 (87%) of the 110 would
      have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had
      positive screens on the basis of the failsafe protocol, and an additional 6
      infants would have had false-negative screens. Among 110 CF-affected screened
      positive infants, a likely "genetic diagnosis" was made by the multiple-CFTR
      mutation screen in 82 (75%) versus 55 (50%) with DeltaF508 alone. Increased
      sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals
      for sweat testing and carrier identifications than testing with DeltaF508 alone.
      CONCLUSIONS: Use of multiple-CFTR-mutation testing improved sensitivity and
      postscreening prediction of CF at the cost of increased referrals and carrier
      identification.

PMID- 15173477
TI  - The cost of giving childhood vaccinations: differences among provider types.
AB  - OBJECTIVE: To describe costs to providers of delivering childhood immunizations.
      METHODS: We collected variable costs--costs that vary with the amount of services
      rendered--including cost of practitioner and staff time and supplies, using a
      cost accounting method, from 12 practices (4 pediatric practices, 4 family
      practices, and 4 public health agencies) in rural and urban areas in Colorado.
      For private practices, we estimated fixed costs--costs that do not vary with the
      amount of services, eg, rent and insurance). We also collected reimbursement
      information for vaccinations for private practices. RESULTS: Variable costs per
      shot (excluding vaccine cost) were 8.15 dollars for pediatric practices, 5.79
      dollars for family practices, and 5.41 dollars for public health agencies. Total
      costs per shot, including fixed costs, were 10.67 dollars for pediatric practices
      and 7.57 dollars for family practices. Average reimbursement for pediatricians
      and private family practices was 8.27 dollars and 6.68 dollars, respectively. For
      pediatric practices, average variable costs were barely exceeded by average
      reimbursement, and reimbursement was 22% less than average total costs. This
      contrasts with an earlier study of the rural practices investigated here, in
      which there was a comfortable margin between reimbursement and variable costs.
      CONCLUSION: The decline in the ratio of reimbursement to cost for private
      practices, particularly for pediatric practices, suggests that referral to public
      agencies by private providers for vaccinations may increase and that if
      vaccinations are not as frequently provided in the child's medical home, then the
      currently high childhood immunization rates may be in jeopardy.

PMID- 15173478
TI  - Headache and backache after lumbar puncture in children and adolescents: a
      prospective study.
AB  - OBJECTIVE: After lumbar puncture, many adults develop headaches or backaches.
      Postpuncture complaints are believed to be rare in children and adolescents, but
      their exact incidence is unclear because there is a paucity of data derived from
      general pediatric patients. In a prospective study of general pediatric and
      neuropediatric patients, we investigated the frequency of postlumbar puncture
      headaches or backaches and factors that might influence their occurrence.
      METHODS: Conducted over 12 months, the prospective study included 112 patients
      aged 2 to 16 years. We evaluated them for factors that might influence the rate
      of postpuncture complaints: age, gender, use of local anesthesia, cannula gauge,
      bevel orientation, number of puncture attempts, volume of cerebrospinal fluid
      (CSF) aspirated, and cell count in CSF. RESULTS: Twenty-seven percent of the
      patients experienced headaches (positional headache in 9%), and 40% developed
      backache. Frequency of complaints increased in relation to patients' age. In
      older children, girls reported complaints more frequently than did boys. Patients
      with higher cell counts in CSF had more frequent headaches than did patients
      without pleocytosis. Cannula gauge or bevel orientation did not influence
      outcome. CONCLUSION: The frequency of positional and nonpositional headaches
      after lumbar puncture is lower in children than in adults. Backaches contribute
      significantly to postpuncture morbidity. With puberty, the incidences of
      postpuncture complaints increase, and girls start to become more prone to develop
      postpuncture headaches. Recommendations regarding cannula gauge or bevel
      orientation that derive from studies in adults are not confirmed for children.

PMID- 15173479
TI  - Timing of initial surfactant treatment for infants 23 to 29 weeks' gestation: is
      routine practice evidence based?
AB  - OBJECTIVE: To describe the timing of initial surfactant treatment for high-risk
      preterm infants in routine practice and compare these findings with evidence from
      randomized trials and published guidelines. METHODS: Data from the Vermont Oxford
      Network Database for infants who were born from 1998 to 2000 and had birth
      weights 401 to 1500 g and gestational ages of 23 to 29 weeks were analyzed to
      determine the time after birth at which the initial dose of surfactant was
      administered. Multivariate models adjusting for clustering of cases within
      hospitals identified factors associated with surfactant administration and its
      timing. Evidence on surfactant timing from systematic reviews of randomized
      trials and from published guidelines was reviewed. RESULTS: A total of 47 608
      eligible infants were cared for at 341 hospitals in North America that
      participated in the Vermont Oxford Network Database from 1998 to 2000. Seventy
      nine percent of infants received surfactant treatment (77.6% in 1998, 79.4% in
      1999, and 79.6% in 2000). Factors that increased the likelihood of surfactant
      treatment were outborn birth, lower gestational age, lower 1-minute Apgar score,
      male gender, white race, cesarean delivery, multiple birth, or birth later in the
      study period. The first dose of surfactant was administered at a median time
      after birth of 50 minutes (60 minutes in 1998, 51 minutes in 1999, and 42 minutes
      in 2000). Over the 3-year study period, inborn infants received their initial
      dose of surfactant earlier than outborn infants (median time: 43 minutes vs 79
      minutes). Other factors associated with earlier administration of the initial
      surfactant dose were gestational age, lower 1-minute Apgar score, cesarean
      delivery, antenatal steroid treatment, multiple birth, and small size for
      gestational age. In 2000, 27% of infants received surfactant in the delivery
      room. There was wide variation among hospitals in the proportion of infants who
      received surfactant treatment in the delivery room (interquartile range: 0%-75%),
      in the median time of the initial surfactant dose (interquartile range: 20-90
      minutes), and in the proportion of infants who received the first dose >2 hours
      after birth (interquartile range: 7%-34%). Six systematic reviews of randomized
      trials of surfactant timing were identified. No national guidelines addressing
      the timing of surfactant therapy were found. CONCLUSION: Although the time after
      birth at which the first dose of surfactant is administered to infants 23 to 29
      weeks' gestation decreased from 1998 to 2000, in 2000 many infants still received
      delayed treatment, and delivery room surfactant administration was not routinely
      practiced at most units. We conclude that there is a gap between evidence from
      randomized controlled trials that supports prophylactic or early surfactant
      administration and what is actually done in routine practice at many units.

PMID- 15173480
TI  - A randomized, clinical trial of a home safety intervention based in an emergency
      department setting.
AB  - OBJECTIVE: To assess the effectiveness of an emergency department (ED)-based home
      safety intervention on caregivers' behaviors and practices related to home
      safety. METHODS: We conducted a randomized, clinical trial of 96 consecutive
      caregivers of children who were younger than 5 years and presented to an urban
      pediatric ED for evaluation of an acute unintentional injury sustained in the
      home. After completing a structured home safety questionnaire via face-to-face
      interview, caregivers were randomly assigned to receive either comprehensive home
      safety education and free safety devices or focused, injury-specific ED discharge
      instructions. Participants were contacted by telephone 2 months after the initial
      ED visit for repeat administration of the safety questionnaire. The pretest and
      posttest questionnaires were scored such that the accrual of points correlated
      with reporting of safer practices. Scores were then normalized to a 100-point
      scale. The overall safety score reflected performance on the entire
      questionnaire, and the 8 category safety scores reflected performance in single
      areas of home injury prevention (fire, burn, poison, near-drowning, aspiration,
      cuts/piercings, falls, and safety device use). The main outcome was degree of
      improvement in safety practices as assessed by improvement in safety scores.
      RESULTS: The intervention group demonstrated a significantly higher average
      overall safety score at follow-up than the control group (73.3% +/- 8.4% vs 66.8%
      +/-11.1) and significant improvements in poison, cut/piercing, and burns category
      scores. Caregivers in the intervention group also demonstrated greater
      improvement in reported use of the distributed safety devices. CONCLUSIONS: This
      educational and device disbursement intervention was effective in improving the
      home safety practices of caregivers of young children. Moreover, the ED was used
      effectively to disseminate home injury prevention information.

PMID- 15173481
TI  - Voluntary anonymous reporting of medical errors for neonatal intensive care.
AB  - OBJECTIVES: Medical errors cause significant morbidity and mortality in
      hospitalized patients. Specialty-based, voluntary reporting of medical errors by
      health care providers is an important strategy that may enhance patient safety.
      We developed a voluntary, anonymous, Internet-based reporting system for medical
      errors in neonatal intensive care, evaluated its feasibility, and identified
      errors that affect high-risk neonates and their families. METHODS: Health
      professionals (n = 739) from 54 hospitals in the Vermont Oxford Network received
      access to a secure Internet site for anonymous reporting of errors, near-miss
      errors, and adverse events. Reports used free-text entry in phase 1 (17 months)
      and a structured form in phase 2 (10 months). The number and types of reported
      events and factors that contributed to the events were measured. RESULTS: Of 1230
      reports--522 in phase 1 (17 months) and 708 in phase 2 (10 months)--the most
      frequent event categories were wrong medication, dose, schedule, or infusion rate
      (including nutritional agents and blood products; 47%); error in administration
      or method of using a treatment (14%); patient misidentification (11%); other
      system failure (9%); error or delay in diagnosis (7%); and error in the
      performance of an operation, procedure, or test (4%). The most frequent
      contributory factors were failure to follow policy or protocol (47%), inattention
      (27%), communications problem (22%), error in charting or documentation (13%),
      distraction (12%), inexperience (10%), labeling error (10%), and poor teamwork
      (9%). In 24 reports, family members assisted in discovery, contributed to the
      cause, or themselves were victims of the error. Serious patient harm was reported
      in 2% and minor harm in 25% of phase 2 events. CONCLUSIONS: Specialty-based,
      voluntary, anonymous Internet reporting by health care professionals identified a
      broad range of medical errors in neonatal intensive care and promoted
      multidisciplinary collaborative learning. Similar specialty-based systems have
      the potential to enhance patient safety in a variety of clinical settings.

PMID- 15173482
TI  - Impact of early newborn discharge legislation and early follow-up visits on
      infant outcomes in a state Medicaid population.
AB  - OBJECTIVE: Scant information exists on the effects of legislation mandating
      coverage of minimum postnatal hospital stays on infant health outcomes. There are
      also gaps in knowledge regarding the effectiveness of early follow-up visits for
      newborns. The objective of this study was to determine the impact of 1)
      legislation mandating coverage of minimum postnatal hospital stays and 2) early
      follow-up visits by the age of 4 days on infant outcomes during the first month
      of life. METHODS: A retrospective analysis was conducted of Ohio Medicaid claims
      data linked with birth certificate data for the period 1991-1998. The impact of
      the legislation was evaluated using interrupted time-series analysis of health
      related utilization. The effects of early follow-up visits for vaginally
      delivered newborns with short stays were analyzed using the day of the week on
      which the birth occurred (eg, Monday, Tuesday) as an instrumental variable to
      account for potential confounding. A total of 155,352 full-term newborns who were
      born to mothers who receive Medicaid were studied. The main outcomes measured
      were rehospitalizations, emergency department (ED) visits, and diagnoses of
      dehydration and infection within 10 and 21 days of birth. RESULTS: Few outcomes
      exhibited significant changes after legislation mandating coverage of minimum
      postnatal hospital stays. Rates of rehospitalization for jaundice within 10 days
      of birth fell from 0.78% to 0.47% in the year after legislation was introduced
      but leveled off after the legislation took effect. Rates of ED visits within 21
      days increased from 6.0% to 10.4% during periods of increasing short stay but
      fell to 8.0% during the year after introduction of the legislation and leveled
      off when the legislation took effect. Rates of all-cause rehospitalization,
      dehydration, and infection diagnoses showed no consistent relationship to Ohio's
      legislation. Using instrumental variable analysis, newborns who received early
      follow-up visits were significantly less likely to have rehospitalizations within
      the first 10 days of life than those who did not. CONCLUSIONS: In this state
      Medicaid population, legislation mandating coverage of minimum postnatal hospital
      stays was associated with reductions in the rates of rehospitalization for
      jaundice and ED visits. For newborns with short stays, early follow-up visits may
      reduce rehospitalizations in the early postpartum period.

PMID- 15173483
TI  - Evaluation of a new transcutaneous bilirubinometer.
AB  - OBJECTIVE: The objective of this study was to evaluate the Minolta/Hill-Rom Air
      Shields Transcutaneous Jaundice Meter model JM-103. METHODS: We studied a
      convenience sample of 849 newborns > or =35 weeks of gestation in 3 hospitals.
      These infants had total serum bilirubin (TSB) levels measured on clinical
      indication, and transcutaneous bilirubin (TcB) levels were obtained within 1 hour
      of the TSB levels. The population was 59.2% white, 29.8% black, 4.5% East Asian,
      3.8% Middle Eastern, 1.6% Indian/Pakistani, and 1.1% Hispanic. RESULTS: There was
      a close correlation between TSB and TcB values in all of the population groups:
      white (n = 503, r =.949); black (n = 253, r =.822); and East Asian,
      Indian/Pakistani, and Hispanic (n = 93, r =.926). In the black population, the
      correlation was less close than in the other groups, and differences between the
      TcB and TSB measurements tended to increase with rising TSB values. JM-103 values
      differed from TSB values by 3 mg/dL or more in 2% of white, 3.2% of other, and
      17.4% of black infants. In these black infants, the JM-103 value was always
      greater than the TSB value. CONCLUSIONS: We conclude that TcB measurements using
      the JM-103 jaundice meter correlate very closely with TSB levels over the range
      of TSB encountered in this study. Because only 3.3% of our infants had TSB values
      >15 mg/dL (257 micro mol/L), more data are needed in this range of TSB
      concentration. The correlation in black infants is not as close as in other
      groups, but because the tendency in blacks is for the JM-103 to overestimate
      serum bilirubin levels, dangerous clinical errors are unlikely to occur. The
      measurement technique is rapid and simple, and it is easy to perform repeated
      measurements over time, thus reducing the likelihood of error. TcB measurements
      with the JM-103 jaundice meter should obviate the need for most serum bilirubin
      levels in newborn infants > or =35 weeks of gestation, although serum bilirubin
      measurements are still required when treatment with phototherapy or exchange
      transfusion is being considered.

PMID- 15173484
TI  - Transcutaneous bilirubin measurements and serum total bilirubin levels in
      indigenous African infants.
AB  - OBJECTIVE: The objective of this study was to determine whether transcutaneous
      bilirubin (TcB) measurements correlate with serum total bilirubin (STB) levels in
      indigenous, darkly pigmented African newborns with varying degrees of skin
      pigmentation, some of which had developed kernicterus. METHODS: Jaundiced infants
      who were < or =2 weeks of age and admitted to Baptist Medical Center-Eku (Eku; n
      = 29) and Jos University Teaching Hospital (Jos; n = 98) in Nigeria were studied.
      TcB measurements using the BiliChek were made simultaneously with blood sampling
      for STB measurements by spectrophotometry before phototherapy. RESULTS: Using
      linear regression analysis, we found that measurements of TcB correlated well
      with those of STB with r values of.90 and.88 for Eku and Jos, respectively. Mean
      bias and imprecision of TcB measurements as compared with STB measurements for
      the total population was 0.5 +/- 7.6 mg/dL using the method of Bland and Altman.
      At STB > or 12 mg/dL, correlation (r =.84) and bias and imprecision (-1.2 +/- 8.6
      mg/dL) of measurements were only slightly poorer. Furthermore, when infants were
      grouped by degree of skin pigmentation, correlations of TcB and STB measurements
      remained strong. CONCLUSIONS: From these results, we can conclude that TcB
      measurements are a useful and reliable index for estimating STB levels in
      pigmented neonates, including those with hyperbilirubinemia and kernicterus. In
      the absence of reliable STB measurements, the relatively simple and noninvasive
      TcB measurements can be an important adjunct in directing phototherapy and
      exchange transfusions, thereby preventing bilirubin-induced morbidity and
      mortality in low-technology clinical environments.

PMID- 15173485
TI  - Brain perfusion in children: evolution with age assessed by quantitative
      perfusion computed tomography.
AB  - OBJECTIVE: The objective of this study was to assess the age-related variations
      of brain perfusion through quantitative cerebral perfusion computed tomography
      (CT) results in children without brain abnormality. METHODS: Brain perfusion CT
      examinations were performed in 77 children, aged 7 days to 18 years. These
      patients were admitted at our institution for both noncontrast and contrast
      enhanced cerebral CT. Only children whose conventional cerebral CT and
      clinical/radiologic follow-up, including additional investigations, were normal
      were taken into account for this study (53 of 77). RESULTS: The average regional
      rCBF amounts to 40 (mL/100 g per minute) for the first 6 months of life, peaks at
      approximately 130 (mL/100 g per minute) at approximately 2 to 4 years of age, and
      finally stabilizes at approximately 50 (mL/100 g per minute) at approximately 7
      to 8 years of age, with a small increase of rCBF values at approximately 12 years
      of age. The rCBF in the gray matter averages 3 times that in the white matter,
      except for the first 6 months of life. The global CBF represents 10% to 20% of
      the global cardiac output for the first 6 months of life, peaks at approximately
      55% by 2 to 4 years of age, and finally stabilizes at approximately 15% by 7 to 8
      years of age. Specific age-related evolution patterns were identified in the
      different anatomic areas of the cerebral parenchyma, which could be related to
      the development of neuroanatomic structures and to the emergence of corresponding
      cognitive functions. CONCLUSIONS: Quantitative perfusion CT characterization of
      brain perfusion shows specific age variations. Brain perfusion of each cortical
      area evolves according to a specific time course, in close correlation with the
      psychomotor development.

PMID- 15173486
TI  - Trends in the incidence of severe retinopathy of prematurity in a geographically
      defined population over a 10-year period.
AB  - OBJECTIVE: To examine trends in the incidence of severe (> or =grade 3)
      retinopathy of prematurity (ROP) in infants with birth weight of < or =1250 g in
      a geographically defined population over a 10-year period. METHODS: An
      observational study was conducted of all infants who had a birth weight < or
      =1250 g and were born to mothers who were resident in the county of
      Leicestershire, United Kingdom, during the period January 1, 1990, to December
      30, 1999. Cases were identified by the Trent Neonatal Survey. The incidence of
      severe ROP (> or =grade 3) was compared in 2 successive 5-year periods: 1990-1994
      and 1995-1999. RESULTS: Comparing the first 5-year period (1990-1994) with the
      second (1995-1999), the total number of live births fell (60 789 vs 56 564).
      However, there was a significant increase in the number of births with birth
      weight < or =1250 g (including live and dead; 615 vs 734; live births only: 455
      vs 556). Survival to 42 weeks of infants who were born at < or =1250 g was
      significantly better in the latter time period (203 vs 302; odds ratio [OR] for
      death: 0.54; 95% confidence interval [CI]: 0.39-0.75). The number of cases of
      severe ROP was 4 times higher during the second time period compared with the
      first (9 vs 36). A significantly increased risk for the development of severe ROP
      was seen during the second time period (OR: 2.92; 95% CI: 1.37-6.20). Even after
      allowing for the change in gestation induced by the improved survival during the
      second time period, the increased risk remained (OR: 2.81; 95% CI: 1.27-6.21).
      CONCLUSIONS: There is strong evidence that the incidence of severe ROP among
      infants with birth weight < or =1250 g increased in the latter half of the last
      decade. The increased risk seems to be independent of the increase in survival.

PMID- 15173487
TI  - Does valsalva retinopathy occur in infants? An initial investigation in infants
      with vomiting caused by pyloric stenosis.
AB  - OBJECTIVE: Retinal hemorrhages (RHs) are 1 manifestation of child abuse, and
      although they often are considered to be diagnostic of abuse in a young child,
      there are other potential causes. RHs have been described in association with
      valsalva maneuver, such as forceful vomiting or coughing. Our aim was to describe
      the incidence of RH in infants with vomiting caused by pyloric stenosis. METHODS:
      A prospective, descriptive study was conducted of infants who underwent
      pyloromyotomy for hypertrophic pyloric stenosis (HPS). Dilated retinal
      examinations were performed, and the findings were documented. RESULTS: A total
      of 100 infants with HPS were evaluated. Eighty-four infants were male, 92 were
      white, and 21 had a family history of pyloric stenosis. Thirty-seven examinations
      were performed in the operating room. Eighteen examinations were confirmed by a
      second investigator, and 3 children had dilated eye examinations documented
      independently by a pediatric ophthalmologist. No RHs were identified (0 of 100;
      95% confidence interval: 0%-3%). One patient had facial petechiae, and 2 had
      subconjunctival hemorrhage. Electrolyte levels were abnormal in 63 patients. In
      89 cases, the emesis was described as projectile. Patients varied in the number
      of episodes of emesis, with 30% of patients having >100 episodes of emesis before
      diagnosis. One patient had a respiratory arrest associated with vomiting in the
      emergency department and required bag-valve mask ventilation. CONCLUSIONS: No RHs
      were identified in 100 infants with vomiting caused by HPS. These results suggest
      that RHs do not result from forceful vomiting in infants.

PMID- 15173488
TI  - Serious bacterial infections in febrile infants 1 to 90 days old with and without
      viral infections.
AB  - OBJECTIVE: The risk of serious bacterial infection (SBI) in febrile infants who
      are classified as low risk (LR) or high risk (HR) by the Rochester criteria has
      been established. LR infants average a 1.4% occurrence of SBI, whereas HR infants
      have an occurrence of 21%. The occurrence of SBI in Rochester LR or HR infants
      with confirmed viral infections is unknown. The objective of this study was to
      determine the occurrence of SBI in Rochester LR and HR infants with and without
      viral infections. METHODS: All febrile infants who were 90 days or younger and
      evaluated at Primary Children's Medical Center between December 1996 and June
      2002 were eligible. Infants were classified as Rochester LR or HR, and discharge
      diagnoses were collected. Viral testing for enteroviruses, respiratory viruses,
      rotavirus, and herpesvirus was performed as indicated by study protocol, clinical
      presentation, and season of the year. Results of all bacterial cultures were
      reviewed. RESULTS: Of 1779 infants enrolled, 1385 (78%) had some form of viral
      diagnostic testing and 491 (35%) had 1 or more viruses identified. By the
      Rochester criteria, 456 (33%) infants were classified as LR and 922 (67%) infants
      as HR. For infants with viral infections, the occurrence of SBI was significantly
      lower than in infants without a viral infection (4.2% vs 12.3%). Rochester HR
      virus-positive (HR+) infants had significantly fewer bacterial infections than HR
      virus-negative (HR-) infants (5.5% vs 16.7%). When compared with HR- infants, HR+
      infants were less likely to have bacteremia, urinary tract infection, or soft
      tissue infections, and HR+ infants had a similar occurrence of bacteremia as LR
      infants (0.92% vs 1.97%). CONCLUSIONS: Febrile infants with confirmed viral
      infections are at lower risk for SBI than those in whom a viral infection is not
      identified. Viral diagnostic data can positively contribute to the management of
      febrile infants, especially those who are classified as HR.

PMID- 15173489
TI  - How informative are parent reports of attention-deficit/hyperactivity disorder
      symptoms for assessing outcome in clinical trials of long-acting treatments? A
      pooled analysis of parents' and teachers' reports.
AB  - OBJECTIVE: The validity of parent reports of children's attention
      deficit/hyperactivity disorder (ADHD) symptoms has been questioned, especially in
      clinical trials. Some advocate the exclusive use of teacher reports, maintaining
      that parent reports are not sensitive to changes in ADHD symptoms. This study
      compares the ability of parent and teacher reports to document change during
      clinical trials of long-acting treatments. METHODS: We conducted a literature
      search of Medline to identify any published clinical trials in pediatric ADHD
      that met the following criteria: 1) used a randomized design, 2) examined the
      efficacy of long-acting agents or standard formulations using 3-times-a-day
      dosing, and 3) used both parent and teacher reports of the same measure of ADHD
      symptoms as a study outcome. For each measurement of ADHD symptoms, we calculated
      effect sizes for parent and teacher reports. RESULTS: Three large, randomized,
      controlled clinical trials were identified (N = 1445 subjects). For every outcome
      for which teacher reports documented significant improvement, parent reports did
      also. Pooled analysis revealed a larger effect captured by the parent report
      relative to the teacher report. CONCLUSION: Results suggest that parent reports
      are at least as sensitive to detecting change in ADHD symptoms as teacher reports
      in clinical trials that assess the efficacy of long-acting agents. These results
      suggest that parent reports are informative for detecting change during treatment
      of children with ADHD.

PMID- 15173490
TI  - Range of neurologic disorders in patients with celiac disease.
AB  - OBJECTIVE: During the past 2 decades, celiac disease (CD) has been recognized as
      a multisystem autoimmune disorder. A growing body of distinct neurologic
      conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic
      neuropathies, and dementia have been reported, mainly in middle-aged adults.
      There still are insufficient data on the association of CD with various
      neurologic disorders in children, adolescents, and young adults, including more
      common and "soft" neurologic conditions, such as headache, learning disorders,
      attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The aim of
      the present study is to look for a broader spectrum of neurologic disorders in CD
      patients, most of them children or young adults. METHODS: Patients with CD were
      asked to fill in a questionnaire regarding the presence of neurologic disorders
      or symptoms. Their medical charts were reviewed, and those who were reported as
      having neurologic manifestations underwent neurologic examination and brain
      imaging or electroencephalogram if required. Their neurologic data were compared
      with that of a control group matched for age and gender. RESULTS: Patients with
      CD were more prone to develop neurologic disorders (51.4%) in comparison with
      control subjects (19.9%). These disorders include hypotonia, developmental delay,
      learning disorders and ADHD, headache, and cerebellar ataxia. Epileptic disorders
      were only marginally more common in CD. In contrast, no difference was found in
      the prevalence of tic disorders in both groups. Therapeutic benefit, with gluten
      free diet, was demonstrated only in patients with transient infantile hypotonia
      and migraine headache. CONCLUSION: This study suggests that the variability of
      neurologic disorders that occur in CD is broader than previously reported and
      includes "softer" and more common neurologic disorders, such as chronic headache,
      developmental delay, hypotonia, and learning disorders or ADHD. Future
      longitudinal prospective studies might better define the full range of these
      neurologic disorders and their clinical response to a gluten-free diet.

PMID- 15173491
TI  - The maternal lifestyle study: cognitive, motor, and behavioral outcomes of
      cocaine-exposed and opiate-exposed infants through three years of age.
AB  - OBJECTIVE: To evaluate the direct effects of prenatal cocaine exposure and
      prenatal opiate exposure on infant mental, motor, and behavioral outcomes
      longitudinally between 1 and 3 years old. METHODS: As part of a prospective,
      longitudinal, multisite study, the Bayley Scales of Infant Development II were
      administered to 1227 infants who were exposed to cocaine (n = 474), opiates (n =
      50), cocaine and opiates (n = 48), and neither substance (n = 655) at 1, 2, and 3
      years of corrected age by certified, masked examiners. Hierarchic linear modeling
      of the 1-, 2-, and 3-year scores was conducted using cocaine and opiate exposure
      as predictors with and without controlling for covariates. RESULTS: Overall
      retention was 88.4% and did not differ by cocaine or opiate exposure. Overall (at
      1, 2, and 3 years), cocaine-exposed infants scored 1.6 Mental Development Index
      points below infants who were not exposed to cocaine. Opiate-exposed infants
      scored 3.8 Psychomotor Development Index points below infants who were not
      exposed to opiates. Neither the cocaine nor the opiate effect remained
      significant after controlling for covariates. Neither cocaine nor opiate exposure
      was associated with the Behavioral Record Score during the examination. Low birth
      weight and indices of nonoptimal caregiving were associated with lower Mental
      Development Index, Psychomotor Development Index, and Behavioral Record Score
      scores for all groups of infants. CONCLUSIONS: In the largest at-risk sample
      observed longitudinally to date, infant prenatal exposure to cocaine and to
      opiates was not associated with mental, motor, or behavioral deficits after
      controlling for birth weight and environmental risks.

PMID- 15173492
TI  - Nonfatal and fatal firearm-related injuries among children aged 14 years and
      younger: United States, 1993-2000.
AB  - OBJECTIVE: To provide national estimates of fatal and nonfatal firearm-related
      (FA) injuries among children < or =14 years old and to examine the circumstances
      under which these injuries occurred. METHODS: For nonfatal FA injuries among
      children, we analyzed data on emergency department (ED) visits from the National
      Electronic Injury Surveillance System for 1993 through 2000. National estimates
      of injured children who were treated in hospital EDs were examined by selected
      characteristics, such as age, gender, race/ethnicity of the patient, primary body
      part affected, intent of the injury, the relationship of the shooter to the
      patient, where the injury occurred, and activity at the time of injury. For fatal
      FA injuries among children, we analyzed mortality data from the National Vital
      Statistics System for 1993 through 2000. Data from both sources were used to
      calculate case-fatality rates. RESULTS: From 1993 through 2000, an estimated
      22,661 (95% confidence interval [CI]: 16,668-28,654) or 4.9 per 100,000 (95% CI:
      3.6-6.2) children < or = 14 years old with nonfatal FA injuries were treated in
      US hospital EDs. Assaults accounted for 41.5% of nonfatal FA injuries, and
      unintentional injuries accounted for 43.1%. Approximately 4 of 5 children who
      sustained a nonfatal, unintentional FA injury were reportedly shot by themselves
      or by a friend, a relative, or another person known to them. During this period,
      5542, or 1.20 per 100,000 (95% CI: 1.17, 1.23), children < or =14 years old died
      from FA injuries; 1 of every 5 children who were wounded by a firearm gunshot
      died from that injury. Most FA deaths were violence related, with homicides and
      suicides constituting 54.7% and 21.9% of these deaths, respectively. For
      individuals < or =14 years old, the burden of morbidity and mortality associated
      with FA injuries falls disproportionately on boys, blacks, and children 10 to 14
      years old. Both fatal and nonfatal injury rates declined >50% during the study
      period. CONCLUSIONS: Although rates of nonfatal and fatal FA injuries declined
      during the period of study, FA injuries remain an important public health concern
      for children. Well-designed evaluation studies are needed to examine the
      effectiveness of potential interventions aimed at reducing FA injuries among
      children.

PMID- 15173493
TI  - Long-term effect of budesonide on hypothalamic-pituitary-adrenal axis function in
      children with mild to moderate asthma.
AB  - OBJECTIVE: To determine the safety of long-term (36 months) administration of an
      inhaled corticosteroid (budesonide) on hypothalamic-pituitary-adrenal (HPA) axis
      function in children with mild to moderate asthma. METHODS: This was an ancillary
      study of the Childhood Asthma Management Program (CAMP). Sixty-three children who
      had mild to moderate asthma and were enrolled in CAMP underwent evaluation of HPA
      axis function before and 12 and 36 months after receiving continuous therapy with
      either an inhaled anti-inflammatory agent (budesonide 400 microg/day or
      nedocromil 16 mg/day) or placebo. HPA axis function was assessed by serum
      cortisol levels 30 and 60 minutes after 0.25 mg of adrenocorticotrophic hormone
      (ACTH) and 24-hour urinary free cortisol excretion. RESULTS: There were no
      differences in serum cortisol levels after ACTH stimulation between treatment
      groups, regardless of time after ACTH administration or months of follow-up.
      Urinary cortisol excretion per body surface area was similar in both treatment
      groups at 36 months, after adjusting for age at randomization, race, gender, and
      clinic. Cumulative inhaled corticosteroid exposure did not influence serum
      cortisol response to ACTH or urinary free cortisol excretion at 36 months.
      CONCLUSIONS: We found no effects of chronic budesonide treatment at a dose of 400
      micro g/day on HPA axis function in children with mild to moderate asthma and
      demonstrated the absence of a cumulative effect on HPA axis function over a 3
      year period.

PMID- 15173494
TI  - Anxiety, depressive, and posttraumatic stress disorders among mothers of
      pediatric survivors of hematopoietic stem cell transplantation.
AB  - OBJECTIVE: To examine the prevalence and predictors of anxiety, depression, and
      posttraumatic stress disorder among mothers of children who underwent
      hematopoietic stem cell transplantation (HSCT). METHODS: A total of 111 mothers
      of children who survived HSCT completed self-report measures of psychological
      functioning at the time of HSCT and self-report measures and a structured
      psychiatric interview 18 months after HSCT. Demographic data and medical data
      were also collected. RESULTS: Approximately 20% of mothers had clinically
      significant distress reactions. When subthreshold posttraumatic stress disorder
      was included, nearly one third of mothers met the criterion for persistent
      distress. Mothers with 1 of the 4 psychiatric diagnoses reported a significantly
      lower quality of life, suggesting that the diagnoses had an impact on their
      general quality of life. Mothers who had 1 of the 4 diagnoses at 18 months were
      younger and had higher anxiety and depressive symptoms at the time of HSCT.
      CONCLUSIONS: A subset of mothers of children who survive HSCT may require
      psychological intervention. Mothers who are most at risk are younger and evidence
      anxiety and depressive symptoms at the time of transplantation.

PMID- 15173495
TI  - Low levels of tissue inhibitors of metalloproteinases with a high matrix
      metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio are present in
      tracheal aspirate fluids of infants who develop chronic lung disease.
AB  - OBJECTIVE: The pathogenesis of chronic lung disease (CLD) involves inflammation
      with proteolytic damage to lung extracellular matrix. Matrix metalloproteinases
      (MMPs) are zinc-dependent endopeptidases that, acting in concert with their
      tissue inhibitors, tightly orchestrate extracellular matrix morphogenesis and
      repair after injury. Imbalances in their levels relative to that of their
      inhibitors have been implicated in diseases characterized by matrix disruption
      and remodeling. We investigated the possibility that imbalances in MMP-9 and MMP
      2 relative to their tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2,
      respectively, in tracheal aspirates of preterm infants may be involved in the
      development of CLD. METHODS: Serial tracheal aspirates collected from birth until
      extubation in 49 ventilated preterm infants (24-32 weeks' gestations) were
      analyzed for MMP-2, MMP-9, TIMP-1, and TIMP-2. Data normalized by TA values of
      free secretory component of immunoglobulin A were compared for CLD (n = 22)
      versus no CLD (n = 27). Also, known clinical predictors of CLD (gestational age,
      birth weight, and sex) were assessed for both groups. Association of predictors
      with the outcome CLD was assessed by logistic regression. RESULTS: Mean
      gestational age was lower in CLD infants, but birth weight and gender were
      comparable for both groups. CLD infants had significantly lower TIMP-1 level with
      higher MMP-9/TIMP-1 ratio during the first 2 weeks of life and low TIMP-2 and MMP
      2 levels during the first 3 days of life compared with no-CLD infants. Logistic
      regression analysis indicated that the findings are predictive of CLD.
      CONCLUSIONS: We conclude that low tracheal aspirate levels of TIMPs, with a high
      MMP-9/TIMP-1 ratio early in life, are associated with subsequent development of
      CLD.

PMID- 15173496
TI  - Early childhood computer experience and cognitive and motor development.
AB  - OBJECTIVES: To explore the association between early computer experience (both
      accessibility and frequency of use) and cognitive and psychomotor development
      among young children. METHODS: The participants were 122 preschool children
      enrolled in a rural county Head Start program in the United States during 2001
      2002. The following tests were administered to the children: the Bender Visual
      Motor Gestalt Test; the Boehm Test of Basic Concepts, Third Edition Preschool;
      the Test of Gross Motor Development, Second Edition; and a short form of the
      Wechsler Preschool and Primary Scales of Intelligence-Revised. Information
      pertaining to family characteristics and children's early computer experience was
      collected from parents. Both bivariate and multivariate analyses were used to
      assess the association between early computer experience and cognitive and motor
      development. RESULTS: Of the participating children, 53% had a computer at home.
      Among families who had a computer, 83% had children's software on the computer.
      According to parents' reports, 29% of these children played on the home computer
      on a daily basis, and an additional 44% of the children played on the computer at
      least weekly. Of those families who did not have a home computer, 49% reported
      that their children had access to a computer somewhere outside home. Among these
      children, 10% had daily access to the computer and 33% had weekly access. The
      presence of a computer in the home was significantly associated with the family's
      income and the educational attainment of the parents. There was no gender
      difference in computer accessibility and frequency use among the participating
      children. Children who had access to a computer performed better on measures of
      school readiness and cognitive development, controlling for children's
      developmental stage and family socioeconomic status. The data in the current
      study did not suggest a relationship between computer experience and visual motor
      or gross motor skills among the participating children. CONCLUSION: The findings
      in the present study suggest that early computer exposure before or during the
      preschool years is associated with development of preschool concepts and
      cognition among young children. However, frequency of use did not reveal such a
      relationship; neither did the ownership of other child electronic or video games
      in the household.

PMID- 15173497
TI  - Usefulness of the American Academy of Pediatrics recommendations for identifying
      youths with hypercholesterolemia.
AB  - OBJECTIVE: To determine the usefulness of parent history of hypercholesterolemia
      and cardiovascular disease as a screening criterion for hypercholesterolemia in
      youths. METHODS: Data were available from a population-based survey of 3665
      Quebec youths aged 9, 13, and 16 years (81.2% of eligible subjects). Blood
      specimens were collected from 2475 subjects (54.8% of those eligible), and
      questionnaire data were obtained from 3048 parents (67.5% of those eligible).
      Lipids were measured in a Centers for Disease Control and Prevention standardized
      laboratory. Usefulness of parent history in identifying borderline/high low
      density lipoprotein cholesterol (LDL-C) (> or =2.8 mmol/L [> or =110 mg/dL]) and
      high LDL-C (> or =3.4 mmol/L [> or =130 mg/dL]) was assessed according to test
      performance statistics (sensitivity, specificity, positive predictive value, and
      negative predictive value). RESULTS: The prevalence of a positive parent history
      was 25.6%; 18.3% of subjects had borderline/high LDL-C, and 4.8% had high LDL-C.
      Sensitivity, specificity, positive predictive value, and negative predictive
      value of parent history were 33.1%, 76.0%, 23.7%, and 83.5%, respectively, for
      identifying borderline/high LDL-C; they were 40.7%, 75.1%, 7.7%, and 96.1% for
      identifying high LDL-C. Test performance statistics were not improved in
      subgroups defined according to age, gender, parent education, household income,
      family status, and family origin (French Canadian, other); neither were they
      improved by adding screening criteria (parent history of diabetes or
      hypertension, or youth overweight). CONCLUSION: Parent history screening criteria
      offer little improvement over random population screening in identifying youths
      with hypercholesterolemia.

PMID- 15173499
TI  - The changing face of pleural empyemas in children: epidemiology and management.
AB  - OBJECTIVE: Empyema remains a significant cause of morbidity in children. This
      study evaluates the changes that have affected the outcome in children with
      pleural empyema, including the emergence of resistant organisms, the introduction
      of the pneumococcal conjugate vaccine, and earlier treatment with video-assisted
      thoracoscopy (VATS). METHODS: A retrospective chart review was performed on all
      patients who were discharged with a diagnosis of empyema and community-acquired
      pneumonia over a 10-year period (1993-2002) at Texas Children's Hospital in
      Houston, Texas. Data collected included demographic information, clinical
      presentation, radiographic studies, laboratory data including culture results,
      and hospital course. RESULTS: A total of 230 charts were available for review.
      The mean age of the patients was 4.0 +/- 3.6 years. Of the pleural fluid cultures
      performed, 32% (69 of 219) were positive. An additional 27 patients had a cause
      identified by blood culture. The first penicillin-nonsusceptible Streptococcus
      pneumoniae was identified in 1995, and the first methicillin-resistant
      Staphylococcus aureus was identified in 1998. After the universal use of the
      pneumococcal conjugate vaccine, 3 major changes have occurred (1999-2000 vs 2001
      2002): 1) the number of patients admitted with empyema (per 10 000 admissions)
      has decreased from 23 to 12.6; 2) the prevalence of S pneumoniae has decreased
      from 66% (29 of 44) to 27% (4 of 15); and 3) S aureus has become the most common
      pathogen isolated (18% vs 60%), with 78% of those being methicillin resistant.
      The use of early VATS (<48 hours after admission) versus late VATS (>48 hours
      after admission) significantly decreased the length of hospitalization (11.49 +/-
      6.56 days vs 15.18 +/- 8.62 days). CONCLUSIONS: The microbiologic cause of
      empyema has changed with an increasing incidence of S aureus, particularly
      methicillin-resistant S aureus. The use of VATS for initial therapy of empyema
      results in decreased duration of fever and length of hospitalization.

PMID- 15173498
TI  - Risk of serious bacterial infection in young febrile infants with respiratory
      syncytial virus infections.
AB  - BACKGROUND: The evaluation of young febrile infants is controversial, in part
      because it is unclear whether clinical evidence of a viral infection
      significantly reduces the risk of serious bacterial infections (SBIs).
      Specifically, it remains unclear whether the risk of SBI is altered in a
      meaningful way in the presence of respiratory syncytial virus (RSV) infections.
      OBJECTIVE: The objective of this study was to determine the risk of SBI in young
      febrile infants who are infected with RSV compared with those without RSV
      infections. METHODS: We conducted a 3-year multicenter, prospective, cross
      sectional study. All febrile (> or =38 degrees C) infants who were < or =60 days
      of age and presented to any of 8 pediatric emergency departments from October
      through March 1998-2001 were eligible. General clinical appearance was evaluated
      using the Yale Observational Scale. We determined RSV status by antigen testing
      of nasopharyngeal secretions. We defined bronchiolitis as either wheezing alone
      or chest retractions in association with an upper respiratory infection. We
      evaluated infants with blood, urine, cerebrospinal fluid, and stool cultures.
      Urinary tract infection (UTI) was defined by single pathogen growth of > or =5 x
      10(4) cfu/mL, or > or =10(4) cfu/mL in association with a positive urinalysis in
      a catheterized specimen, or > or = 10(3) cfu/mL in a suprapubic aspirate.
      Bacteremia, bacterial meningitis, and bacterial enteritis were defined by growth
      of a known bacterial pathogen. SBI was defined as any of the above-mentioned 4
      bacterial infections. RESULTS: We enrolled 1248 patients, including 269 (22%)
      with RSV infections. The overall SBI status could be determined in 1169 (94%) of
      the 1248 patients, and the rate of SBIs was 11.4% (133 of 1169; 95% confidence
      interval [CI]: 9.6%-13.3%). The rate of SBIs in the RSV-positive infants was 7.0%
      (17 of 244; 95% CI: 4.1%-10.9%) compared with 12.5% (116 of 925; 95% CI: 10.5%
      14.8%) in the RSV-negative infants (risk difference: 5.5%; 95% CI: 1.7%-9.4%).
      The rate of UTI in the RSV-positive infants was 5.4% (14 of 261; 95% CI: 3.0%
      8.8%) compared with 10.1% (98 of 966; 95% CI: 8.3%-12.2%) in the RSV-negative
      infants (risk difference: 4.7%; 95% CI: 1.4%-8.1%). The RSV-positive infants had
      a lower rate of bacteremia than the RSV-negative infants (1.1% vs 2.3%; risk
      difference: 1.2%; 95% CI: -0.4% to 2.7%). No RSV-positive infant had bacterial
      meningitis (0 of 251; 95% CI: 0%-1.2%); however, the differences between the 2
      groups with regard to bacteremia and bacterial meningitis did not achieve
      statistical significance. CONCLUSIONS: Febrile infants who are < or =60 days of
      age and have RSV infections are at significantly lower risk of SBI than febrile
      infants without RSV infection. Nevertheless, the rate of SBIs, particularly as a
      result of UTI, remains appreciable in febrile RSV-positive infants.

PMID- 15173500
TI  - Pediatric patient safety in hospitals: a national picture in 2000.
AB  - OBJECTIVE: To describe potential patient safety events for hospitalized children,
      examine associated factors, and explore impacts of safety events. METHODS: The
      newly released Patient Safety Indicators (PSIs), developed by researchers at the
      Agency for Healthcare Research and Quality to identify potential in-hospital
      patient safety problems using administrative data, were applied to hospital
      discharge data. All 5.7 million discharge records for children younger than 19
      years from 27 states in the 2000 Healthcare Cost and Utilization Project were
      analyzed for PSI events. Prevalence of PSI events and associations with patient
      level and hospital-level characteristics were examined. Multivariate regression
      adjusting for patient severity of illness was used to estimate impacts of safety
      events in terms of excess length of stay, charges, and in-hospital mortality.
      RESULTS: The prevalence of pediatric patient safety events is significant. PSI
      events occurred more frequently in the very young and those on Medicaid
      insurance, some of the most vulnerable hospitalized children. Regression analysis
      found that almost all PSIs are associated with significant and substantial
      increases in length of stay, charges, and in-hospital death. Using the estimates
      derived here and the actual number of cases identified in the 2000 data, we
      estimate that patient safety events incurred >1 billion dollars in excess charges
      for children alone in 2000. CONCLUSIONS: Patient safety problems for hospitalized
      children occur frequently and with substantial impacts to our health care
      industry. Unmeasurable by this study are the additional "costs" and "burdens" of
      safety events that our patients are forced to handle. Additional work to describe
      and quantify better these outcomes in addition to ones measured here can help
      solidify the "business case" for patient safety efforts.

PMID- 15173501
TI  - Institutional review board practices regarding assent in pediatric research.
AB  - OBJECTIVE: To assess how Institutional Review Boards (IRBs) implement the assent
      requirement for research with children. METHODS: Telephone interviews were
      conducted with 188 chairpersons of IRBs from a range of institutions nationwide.
      Respondents were queried on 4 topics: 1) which children are considered capable of
      assent, 2) which information investigators must provide pediatric research
      subjects, 3) whether IRBs favor the enrollment of children who are capable of
      assent, and 4) how chairpersons view payment for children's research
      participation. RESULTS: Half of IRBs have a method that they require
      investigators to follow when determining which children are capable of assent,
      most commonly an age cutoff. Half of IRBs do not have a method, and the majority
      rely on investigators' clinical judgment. IRBs largely follow the adult research
      regulations when determining which information should be provided to an assenting
      child. A total of 58% of IRBs would enroll a child who is incapable of assent in
      a nonbeneficial study, even if children who are capable of assent could be
      enrolled instead. Almost half (46%) of chairpersons believe that it sometimes or
      always acceptable to offer incentive payments to children, and more than one
      third (35%) thought it acceptable to offer payment to the parents. CONCLUSION:
      When possible, IRBs follow the federal regulations for research with adults when
      implementing the assent requirement. For considerations that do not have analogs
      in the adult regulations, IRB practices vary widely. These data suggest that IRBs
      need guidance on how to implement the assent requirement in a way that provides
      appropriate protections for pediatric research subjects.

PMID- 15173502
TI  - Factors associated with difficult toilet training.
AB  - OBJECTIVE: To identify temperament and behavioral patterns in children with
      difficult toilet training and to compare those children with same-aged toilet
      trained children. METHODS: We compared 46 referred clinic patients who were
      difficult toilet trainers (DTT) with 62 comparison children (CC) using the Carey
      McDevitt Behavioral Style Questionnaire, the Parenting Scale, and a questionnaire
      of toilet-training history. RESULTS: CC were more likely to have easy
      temperaments (odds ratio [OR]: 33.51). DTT were more likely to be less adaptable
      (OR: 3.12), more negative in mood (OR: 2.79), less persistent (OR: 2.97), and
      lower in approach (OR: 1.85). DTT were more likely than CC to be constipated (OR:
      3.52), although 55% of CC were constipated. DTT were likely to hide to stool
      (74%) and to ask for pull-ups in which to leave stool (37%). Parenting styles did
      not differ between the groups. CONCLUSIONS: Although the referral population may
      be inherently biased, these data suggest that difficult toilet training is
      associated with difficult temperamental traits and constipation in affected
      children.

PMID- 15173503
TI  - Population-based surveillance for hospitalizations associated with respiratory
      syncytial virus, influenza virus, and parainfluenza viruses among young children.
AB  - OBJECTIVE: Respiratory syncytial virus (RSV), influenza virus, and parainfluenza
      viruses (PIV) cause significant morbidity in young children. Although only
      influenza virus infection and illness is currently vaccine-preventable, vaccines
      are under development for RSV and PIV. We established a prospective, active
      population-based surveillance network to provide precise estimates of
      hospitalization rates for viral acute respiratory illness (ARI) in young children
      and to measure the potential impact of enhanced vaccine usage on these rates.
      METHODS: Prospective, active population-based surveillance was conducted in young
      children who were hospitalized for ARI from October 1, 2000, to September 30,
      2001, in Monroe County, New York (Rochester area) and Davidson County, Tennessee
      (Nashville area). Eligible children younger than 5 years were those who resided
      in surveillance counties and were hospitalized for febrile or acute respiratory
      illness. Viral culture and polymerase chain reaction identified viruses from
      nasal and throat samples obtained from all surveillance children. We measured
      population-based rates of hospitalization for RSV, influenza virus, and PIV as
      well as demographic, clinical, and risk factor assessment for each virus.
      RESULTS: Of 812 eligible hospital admissions, 592 (73%) children were enrolled.
      Of the enrolled children, RSV was identified in 20%, influenza in 3%, PIV in 7%,
      other respiratory viruses in 36%, and no detectable virus in 39%. Population
      based rates of ARI hospitalizations in children younger than 5 years were 18 per
      1000. Virus-positive hospitalization rates per 1000 children were 3.5 for RSV,
      1.2 for PIV, and 0.6 for influenza virus. Younger age (particularly <1 year),
      black and Hispanic race/ethnicity, male gender, and presence of chronic
      underlying illness were associated with higher hospitalization rates.
      CONCLUSIONS: This study confirms that children younger than 5 years and
      particularly children younger than 1 year have a high burden of hospitalization
      from RSV, influenza, and PIV. The enhanced use of influenza vaccine and the
      development of RSV and PIV vaccines have the potential to reduce markedly the
      pediatric morbidity from ARIs.

PMID- 15173504
TI  - Intracerebral abscess in children: historical trends at Children's Hospital
      Boston.
AB  - OBJECTIVES: A previous study performed at Children's Hospital Boston describing
      the natural history of intracerebral abscess between 1945 and 1980 demonstrated a
      decline in mortality after 1970. This current study examines the occurrence of
      intracerebral abscess at Children's Hospital Boston between 1981 and 2000,
      inclusive, and compares the results with the previous study. Our objectives were
      to determine whether there had been a change in the predisposing factors, whether
      there were changes in the microbiology of intracerebral abscesses, and whether
      mortality rate had continued to decline. METHODS: To ensure that all occurrences
      of intracerebral abscess treated at Children's Hospital Boston between 1981 and
      2000 were identified, we searched 4 separately maintained databases for the
      keywords "brain" or "abscess" or the International Classification of Diseases,
      Ninth Revision code 324.x. This search yielded the names of 386 patients. Of
      these 386 patients, a solitary intracerebral abscess or multiple noncontiguous
      intracerebral abscesses could be confirmed in 54 patients on the basis of cranial
      imaging (computed tomography or magnetic resonance imaging) or autopsy reports.
      The complete retrospective review of the medical records of these 54 patients
      constitutes the basis for this study. RESULTS: Congenital heart disease was the
      most common predisposing factor during both eras. Compared with the previous era,
      important historical trends identified include a reduction in the number of
      abscesses that occurred in the settings of sinus or otitic infection (11% during
      1981-2000 vs 26% during 1945-1980), an increase in number of intracranial
      abscesses in infants (18% vs 7%) and in the setting of immunosuppression (16% vs
      1%), an increase in the number of children who were treated with antibiotics
      alone (22% vs 1%), a stable overall mortality rate (24% vs 27%), and the
      identification of Citrobacter and fungus as causes of intracranial abscess not
      observed during the previous era of 1945-1980. Citrobacter was observed only
      during the neonatal period. Fungi were the causative organisms predominantly in
      the setting of immunosuppression. CONCLUSIONS: Intracerebral abscess in children
      continues to be associated with high rates of neurologic impairment and death.
      Because earlier detection may reduce morbidity and mortality, intracranial
      abscess should be considered when evaluating children with new-onset neurologic
      signs or symptoms, especially in children who have acute immunosuppression and
      disseminated fungal disease or fungemia.

PMID- 15173505
TI  - Violence and suffering in television news: toward a broader conception of harmful
      television content for children.
AB  - Traditionally, the public and professional debate about the inappropriateness of
      media violence for children focuses mainly on the negative effects of violence in
      entertainment programming. However, since the terrorist attacks on September 11th
      and the recent coverage of the war in Iraq, the suitability of real-life news
      violence for children may be doubted more than ever. To draw attention to the
      potential harmful effects of violence presented in news programs, it is argued in
      the present article that health care professionals should advocate a broader
      conception of media violence than thus far has been used. On the basis of recent
      research, potential effects of violent news content, such as fear, aggression,
      and desensitization, are discussed and recommendations are provided on how to
      abate these outcomes.

PMID- 15173506
TI  - Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant
      cycle.

PMID- 15173507
TI  - Ethical concerns about federal approval of risky pediatric studies.
AB  - The US Federal Code limits research with healthy children to no more than a
      minimal risk of harm; it restricts research with children who have some disorder
      or condition to no more than a minor increase over minimal risk, unless potential
      harms are offset by potential benefits to them, as in therapeutic studies. Higher
      risk studies require "407 approval," named after the relevant section of the code
      describing requirements. Rarely used until recently, 407 approval requirements
      include Institutional Review Board approval and authorization by the Secretary of
      the Department of Health and Human Services after consultation with a panel of
      experts; a period for public comment; and assurances that there are adequate
      permission, consent, and assent. This 407-approval mechanism contains both
      procedural and interpretative ambiguities, which raise ethical concerns about 1)
      the expertise represented on advisory panels, 2) the scope of the information
      offered to the public for comment and its potential conflicts with investigators'
      intellectual property or commercial interests, 3) whether any upper level of risk
      exists, and 4) how it conforms with other policies such as the best interest of
      the child standard in the law or in medical decision making.

PMID- 15173508
TI  - Recent advances in the treatment of amblyopia.

PMID- 15173509
TI  - Primary care pediatrics: 2004 and beyond.

PMID- 15173510
TI  - Understanding toilet training difficulties.

PMID- 15173511
TI  - Fetal surgery for congenital diaphragmatic hernia.

PMID- 15173512
TI  - Cystic fibrosis newborn screening: shifting the key question from "should we
      screen?" to "how should we screen?".

PMID- 15173513
TI  - Is it time to reduce our phobia of inhaled corticosteroids?

PMID- 15173514
TI  - Unpredictable patterns of viral respiratory disease in children.

PMID- 15173515
TI  - So what's wrong with penicillin for strep throat?

PMID- 15173516
TI  - Fetal infants: thoughts about what to do.

PMID- 15173517
TI  - Cushing's syndrome after intra-articular and intradermal administration of
      triamcinolone acetonide in three pediatric patients.
AB  - BACKGROUND: Intra-articular and intradermal steroids are often used for their
      antiinflammatory effect. There is limited experience with intra-articular and
      intralesional administration of corticosteroids in the pediatric age group.
      DESIGN/METHODS: We performed a retrospective chart review of 3 pediatric patients
      who developed Cushing's syndrome after local administration of triamcinolone
      acetonide (TCA). RESULTS: Two females 9 and 17 years old, received intra
      articular injections of TCA. One patient received multiple injections of TCA into
      the interphalangeal joints (cumulative dose: 120 mg), whereas the other received
      a single injection of 40 mg, a dose that is considered to be in the therapeutic
      range, into the hip joint. The third patient, a 7-year-old female, received
      multiple intralesional injections of TCA. These patients developed signs and
      symptoms of hypercortisolism that appeared 4 to 6 weeks after local
      administration of TCA and lasted for 4 to 6 months after the last dose of TCA.
      TCA was detectable in the plasma and urine by the liquid chromatography/tandem
      mass spectrometry method 4 to 5 months after the last dose of the steroid.
      CONCLUSIONS: We noted evidence for Cushing's syndrome in 3 pediatric patients
      after intra-articular or intradermal administration of TCA. One of them had
      received a therapeutic dose of TCA. The possibility of hypothalamic-pituitary
      adrenal axis suppression should be considered in patients who have received intra
      articular or intradermal steroid injections, particularly in those who have had
      multiple or relatively high doses.

PMID- 15173518
TI  - Legalization of marijuana: potential impact on youth.
AB  - As experts in the health care of children and adolescents, pediatricians may be
      called on to advise legislators concerning the potential impact of changes in the
      legal status of marijuana on adolescents. Parents, too, may look to pediatricians
      for advice as they consider whether to support state-level initiatives that
      propose to legalize the use of marijuana for medical purposes or to decriminalize
      possession of small amounts of marijuana. This policy statement provides the
      position of the American Academy of Pediatrics on the issue of marijuana
      legalization, and the accompanying technical report (available online) reviews
      what is currently known about the relationship between adolescents' use of
      marijuana and its legal status to better understand how change might influence
      the degree of marijuana use by adolescents in the future.

PMID- 15173519
TI  - Sexual orientation and adolescents.
AB  - The American Academy of Pediatrics issued its first statement on homosexuality
      and adolescents in 1983, with a revision in 1993. This report reflects the
      growing understanding of youth of differing sexual orientations. Young people are
      recognizing their sexual orientation earlier than in the past, making this a
      topic of importance to pediatricians. Pediatricians should be aware that some
      youths in their care may have concerns about their sexual orientation or that of
      siblings, friends, parents, relatives, or others. Health care professionals
      should provide factual, current, nonjudgmental information in a confidential
      manner. All youths, including those who know or wonder whether they are not
      heterosexual, may seek information from physicians about sexual orientation,
      sexually transmitted diseases, substance abuse, or various psychosocial
      difficulties. The pediatrician should be attentive to various potential
      psychosocial difficulties, offer counseling or refer for counseling when
      necessary and ensure that every sexually active youth receives a thorough medical
      history, physical examination, immunizations, appropriate laboratory tests, and
      counseling about sexually transmitted diseases (including human immunodeficiency
      virus infection) and appropriate treatment if necessary. Not all pediatricians
      may feel able to provide the type of care described in this report. Any
      pediatrician who is unable to care for and counsel nonheterosexual youth should
      refer these patients to an appropriate colleague.

PMID- 15173520
TI  - Guidelines for pediatric cancer centers.
AB  - Since the American Academy of Pediatrics published guidelines for pediatric
      cancer centers in 1986 and 1997, significant changes in the delivery of health
      care have prompted a review of the role of tertiary medical centers in the care
      of pediatric patients. The potential effect of these changes on the treatment and
      survival rates of children with cancer led to this revision. The intent of this
      statement is to delineate personnel and facilities that are essential to provide
      state-of-the-art care for children and adolescents with cancer. This statement
      emphasizes the importance of board-certified pediatric hematologists/oncologists,
      pediatric subspecialty consultants, and appropriately qualified pediatric medical
      subspecialists and pediatric surgical specialists overseeing the care of all
      pediatric and adolescent cancer patients and the need for facilities available
      only at a tertiary center as essential for the initial management and much of the
      follow-up for pediatric and adolescent cancer patients.

PMID- 15173521
TI  - Prescribing therapy services for children with motor disabilities.
AB  - Pediatricians often are called on to prescribe physical, occupational, and speech
      language therapy services for children with motor disabilities. This report
      defines the context in which rehabilitation therapies should be prescribed,
      emphasizing the evaluation and enhancement of the child's function and abilities
      and participation in age-appropriate life roles. The report encourages
      pediatricians to work with teams including the parents, child, teachers,
      therapists, and other physicians to ensure that their patients receive
      appropriate therapy services.

PMID- 15173522
TI  - School-based mental health services.
AB  - More than 20% of children and adolescents have mental health problems. Health
      care professionals for children and adolescents must educate key stakeholders
      about the extent of these problems and work together with them to increase access
      to mental health resources. School-based programs offer the promise of improving
      access to diagnosis of and treatment for the mental health problems of children
      and adolescents. Pediatric health care professionals, educators, and mental
      health specialists should work in collaboration to develop and implement
      effective school-based mental health services.

PMID- 15173523
TI  - Is the glass 10% empty or 90% full?

PMID- 15173524
TI  - Heat wave and acute pancreatitis: very unusual cystic fibrosis presentation.

PMID- 15173525
TI  - Firearm injury prevention: failure of gun-safety education.

PMID- 15173526
TI  - Gastric residuals in prediction of necrotizing enterocolitis in very low birth
      weight infants.

PMID- 15173527
TI  - Inhaled nitric oxide and the societal perspective.

PMID- 15173528
TI  - Error in Munchausen by proxy defined.

PMID- 15173529
TI  - Does an isolated history of loss of consciousness or amnesia predict brain
      injuries in children after blunt head trauma?
AB  - BACKGROUND: A history of loss of consciousness (LOC) is frequently used as an
      indication for cranial computed tomography (CT) in the emergency department (ED)
      evaluation of children with blunt head trauma. OBJECTIVE: We sought to determine
      whether an isolated LOC and/or amnesia is predictive of traumatic brain injury
      (TBI) in children with blunt head trauma. METHODS: We prospectively enrolled
      children <18 years old presenting to a level I trauma center ED between July 1998
      and September 2001 with blunt head trauma. We evaluated the association of LOC
      and/or amnesia with 1) TBI identified on CT and 2) TBI requiring acute
      intervention. We defined the latter by a neurosurgical procedure, antiepileptic
      medication for >1 week, persistent neurologic deficits, or hospitalization for >
      or =2 nights. We then investigated the association of LOC and/or amnesia with TBI
      in those patients without other symptoms or signs of TBI ("isolated" LOC and/or
      amnesia). RESULTS: Of eligible children, 2043 (77%) were enrolled, 1271 (62%) of
      whom underwent CT; 1159 (91%) of these 1271 had their LOC and/or amnesia status
      known. A total of 801 (39%) of the 2043 enrolled children had a documented
      history of LOC and/or amnesia. Of the 745 with documented LOC and/or amnesia who
      underwent CT, 70 (9.4%; 95% confidence interval [CI]: 7.4%, 11.7%) had TBI
      identified on CT versus 11 of 414 (2.7%; 95% CI: 1.3%, 4.7%) without LOC and/or
      amnesia (difference: 6.7%; 95% CI: 4.1%, 9.3%). Of the 801 children known to have
      had LOC and/or amnesia (regardless of whether they underwent CT), 77 (9.6%; 95%
      CI: 7.7%, 11.9%) had TBI requiring acute intervention versus 11 of 1115 (1%; 95%
      CI: 0.5%, 1.8%) of those without LOC and/or amnesia (difference: 8.6%; 95% CI:
      6.5%, 10.7%). For those with an isolated LOC and/or amnesia without other signs
      or symptoms of TBI, however, 0 of 142 (95% CI: 0%, 2.1%) had TBI identified on
      CT, and 0 of 164 (95% CI: 0%,1.8%) had TBI requiring acute intervention.
      CONCLUSIONS: Isolated LOC and/or amnesia, defined by the absence of other
      clinical findings suggestive of TBI, are not predictive of either TBI on CT or
      TBI requiring acute intervention. Elimination of an isolated LOC and/or amnesia
      as an indication for CT may decrease unnecessary CT use in those patients without
      an appreciable risk of TBI.

PMID- 15173530
TI  - Epidemiology of a tuberculosis outbreak in a rural Missouri high school.
AB  - OBJECTIVES: 1) Demonstrate the importance of maintaining a tuberculosis (TB)
      control program even in low-incidence areas by studying a TB-contact
      investigation of a highly infectious high school student in rural Missouri, and
      2) discuss factors that perpetuated or contained this school-based outbreak.
      METHODS: A case review of the index patient, a 15-year-old high school student,
      established estimates of his level and duration of infectiousness. Contact
      investigations of his household (n = 5), high school (n = 781), and school bus (n
      = 67) were administered according to guidelines established by the Centers for
      Disease Control and Prevention. High school students were stratified further
      based on classroom exposure, and relative risks were calculated for each risk
      group. RESULTS: The case review revealed that the index patient had evidence of a
      pulmonary cavity on chest radiograph 6 months before his TB diagnosis. Of the 5
      household contacts, all were infected and 3 (60%) had developed active TB
      disease. Of the 781 high school students sought for TB screening, 559 (72%)
      completed testing, and 58 (10%) were PPD-positive. Sixty-seven bus riders were
      sought for testing and 7 (19%) were purified protein derivative (PPD)-positive,
      with 1 bus rider subsequently diagnosed with active disease. Risks were
      calculated based on classroom and bus exposure to the patient. The relative risks
      for a positive PPD were 3.2 for attending any class with the patient (n = 25),
      4.2 for classes with less ventilation (n = 21), and 5.7 for > or =3 classes (n =
      7) with the patient. A total of 62 students started treatment for latent TB
      infection, and 49 have completed it. Forty-two of these students received
      directly observed therapy through the local public health agency and the high
      school. CONCLUSION: This investigation demonstrated widespread adult-type
      transmission from a pediatric TB case with a 6-month delay in diagnosis. Several
      actions contributed to the success of this investigation, including rapidly
      mobilizing the public health system, centralizing follow-up, and on-site testing
      and treatment with directly observed therapy. Pediatricians need to maintain
      awareness of TB and risk factors in children, even in low-incidence areas. Prompt
      diagnosis would have reduced the severity of illness in the patient and
      potentially prevented widespread school-based transmission. Public health
      authorities must maintain an infrastructure to respond to large TB outbreaks.

PMID- 15173531
TI  - During toilet training, constipation occurs before stool toileting refusal.
AB  - BACKGROUND: Previous studies demonstrated that constipation and painful
      defecation are associated with stool toileting refusal (STR), but whether they
      are the result of STR or occur before this behavior is not known. OBJECTIVE: To
      determine whether constipation and painful defecation occur as a result of STR or
      occur before STR. METHODS: Three hundred eighty children between 17 and 19 months
      of age participated in a prospective longitudinal study of toilet training.
      Children were monitored with telephone interviews every 2 to 3 months until the
      completion of daytime toilet training. Information obtained in follow-up
      interviews included parents' reports on the presence and frequency of hard bowel
      movements, painful defecation, and child toilet training behaviors. Children were
      defined as completing daytime toilet training when they were experiencing <4
      urine accidents per week and < or =2 episodes of fecal soiling per month.
      Children were defined as having frequent hard bowel movements if the parents
      reported a hard bowel movement approximately once per week in > or =2 follow-up
      telephone interviews or more than once per week in 1 follow-up telephone
      interview. RESULTS: The mean age at the completion of daytime toilet training was
      36.8 +/- 6.1 months (range: 22-54 months). Ninety-three children (24.4%)
      developed STR. Parents of children who developed STR, in comparison with the rest
      of the sample, were more likely to report that the child had experienced hard
      bowel movements (67.7% vs 50.9%), frequent hard bowel movements (29.0% vs 14.3%),
      and painful defecation (41.9% vs 27.9%). Of the children who experienced both STR
      and hard bowel movements, 93.4% demonstrated constipation before the onset of
      STR. In that group, parents reported hard bowel movements at almost one-half of
      all follow-up telephone interviews before the onset of STR. Of the children who
      experienced both STR and painful defecation, 74.4% experienced the first episode
      of painful defecation before the onset of STR. Children with frequent hard bowel
      movements demonstrated a longer duration of STR (9.0 +/- 6.5 vs 4.8 +/- 3.0
      months). CONCLUSIONS: When hard bowel movements or painful defecation is
      associated with STR, the first episode of constipation usually occurs before the
      STR. The fact that hard bowel movements frequently occur before the onset of STR
      suggests that for many of these children constipation is a chronic problem that
      is not being treated effectively. Therefore, hard bowel movements and painful
      defecation are factors that potentially contribute to the STR and for the
      majority of children are not caused solely by the STR behavior. Additional
      studies are needed to determine whether earlier and more effective treatment of
      constipation could decrease the incidence of STR.

PMID- 15173532
TI  - Maternal depressive symptoms and infant health practices among low-income women.
AB  - OBJECTIVES: To determine the relationships between maternal depressive symptoms
      and the use of infant health services, parenting practices, and injury-prevention
      measures. METHODS: A prospective, community-based survey of women attending
      Philadelphia public health centers between February 2000 and November 2001 was
      conducted. Women were surveyed at 3 time points before and after parturition.
      Depressive symptoms were determined with the Center for Epidemiologic Studies
      Depression Scale at each time point. We studied 6 outcomes, clustered into 3
      categories: 1) infant health service use (adequate well-child care and ever being
      hospitalized); 2) parenting practices (breastfeeding for > or =1 month and use of
      corporal punishment); and 3) injury-prevention measures (having a smoke alarm and
      using the back sleep position). RESULTS: The sample consisted of 774 largely
      single (74%), uninsured (63%), African American (65%) women, with a mean age of
      24 +/- 6 years and a mean annual income of 8063 dollars. Forty-eight percent of
      women had depressive symptoms at 1 or 2 time points (ever symptoms) and 12% had
      depressive symptoms at all points (persistent symptoms). Compared with women who
      never had depressive symptoms (without symptoms), women with persistent symptoms
      were nearly 3 times as likely to have their child ever hospitalized (adjusted
      odds ratio: 2.89; 95% confidence interval: 1.61-5.07) and twice as likely to use
      corporal punishment (adjusted odds ratio: 1.90; 95% confidence interval: 1.08
      3.34). Mothers with persistent depressive symptoms were nearly three-quarters
      less likely to have smoke alarms in their homes (adjusted odds ratio: 0.28; 95%
      confidence interval: 0.11-0.70) and one-half as likely to use the back sleep
      position (adjusted odds ratio: 0.56; 95% confidence interval: 0.35-0.91),
      compared with women without symptoms. There was no association between maternal
      depressive symptoms and infant receipt of well-child care or the likelihood of
      breastfeeding for > or =1 month. CONCLUSIONS: Maternal depressive symptoms
      persisting from the prepartum to postpartum periods were associated with
      increased risks of infant hospitalization and use of corporal punishment and with
      lower likelihood of having a smoke alarm and using the back sleep position.
      Additional efforts are needed to identify and evaluate mothers with depressive
      symptoms to improve the health and safety of young infants.

PMID- 15173533
TI  - Association between evening admissions and higher mortality rates in the
      pediatric intensive care unit.
AB  - BACKGROUND: Previous research investigating the relationship between the time of
      admission and mortality rates has yielded inconsistent results and has not been
      conducted in the pediatric intensive care unit (PICU) patient population.
      OBJECTIVE: To determine whether an association between the time of admission
      (weekday versus weekend and daytime versus evening) and the risk of death exists
      among pediatric patients included in a cohort of children admitted to a national
      sample of PICUs. DESIGN/METHODS: We analyzed retrospectively a cohort of
      consecutive admissions to 15 PICUs included in the Pediatric Intensive Care Unit
      Evaluations database. The odds of death were analyzed by using mixed-effects,
      multivariate, logistic regression, with clustering at the hospital level. The
      primary independent variables were admission to the PICU on a weekend and
      admission to the PICU during evening hours. The severity of illness was adjusted
      by using the Pediatric Risk of Mortality III probability of death score.
      PATIENTS: All 20,547 emergency PICU admissions made between May 1995 and December
      2001 were included in the analyses. MAIN OUTCOME MEASURES: The primary outcome
      was death within 48 hours after admission to the PICU. RESULTS: Pediatric
      patients admitted to the PICU during evening hours had higher odds of death (odds
      ratio [OR]: 1.28; 95% confidence interval [CI]: 1.00-1.62) than did those
      admitted during daytime hours. Subgroup analyses revealed higher odds of death
      among patients admitted with shock (OR: 4.09; 95% CI: 1.65-10.1), with congenital
      cardiovascular disease (OR: 3.90; 95% CI: 1.37-11.1), or after cardiac arrest
      (OR: 1.80; 95% CI: 1.04-3.13). There was no association between mortality rates
      and the day of admission (weekend admissions versus weekday admissions).
      CONCLUSIONS: An increased risk of death exists for some pediatric patients
      admitted to the PICU during evening hours. It remains necessary to determine
      whether this finding results from differences in the structure of care, processes
      of care, or both.

PMID- 15173534
TI  - Severe acute respiratory syndrome among children.
AB  - OBJECTIVE: To study the epidemiologic, clinical, laboratory, and radiologic
      features, prognostic indicators, and short-term to medium-term outcomes for
      children with severe acute respiratory syndrome (SARS) and to validate the
      performance characteristics of a clinical case definition, calculated with
      respect to SARS-associated coronavirus (SARS-CoV) seroconversion. METHODS:
      Children <18 years of age, from a single-site outbreak, who satisfied a clinical
      case definition for SARS, with subsequent serologic confirmation, were treated
      according to a standard protocol and prospectively monitored. RESULTS: Forty-four
      children were included. The median age was 12 years. Forty-two children (95.5%)
      demonstrated an epidemiologic link. Fever, cough, malaise, coryza, sputum
      production, headache, myalgia, lymphopenia, and elevated lactate dehydrogenase
      levels were common presenting features. Radiographic findings were nonspecific,
      but high-resolution computed tomography of the thorax was an early diagnostic
      aid. A specific reverse transcription-polymerase chain reaction assay for SARS
      CoV yielded positive results for <50% of children. Of 9 children who developed
      hypoxemia, 8 were treated with methylprednisolone. Of 5 children who received
      intensive care, 3 required assisted ventilation. All children recovered, and
      serious adverse events in response to treatment were not observed. The outcomes
      at 3 to 6 months after disease onset, including exercise tolerance, pulmonary
      functions, and psychologic status, were favorable. An age of >12 years was
      associated with methylprednisolone therapy for severe illness. After exclusion of
      the only infant, an age of >12 years was associated with oxygen requirements.
      Sore throat, high neutrophil count at presentation, and peak neutrophilia were
      independent factors predicting severe illness. The clinical case definition
      demonstrated good sensitivity, specificity, and positive and negative predictive
      values (97.8%, 92.7%, 88%, and 98.7%, respectively) for diagnostic accuracy.
      CONCLUSIONS: Children are susceptible to SARS-CoV infection. Teenagers resemble
      adults with respect to disease progression and may develop severe illness. The
      short-term to medium-term outcomes are good. Sore throat and initial and peak
      neutrophilia seem to be predictors of severe illness. Our clinical case
      definition performed well in the epidemic.

PMID- 15173535
TI  - Psychiatric hospitalizations among children and youths with human
      immunodeficiency virus infection.
AB  - OBJECTIVE: Psychiatric manifestations of pediatric human immunodeficiency virus
      (HIV) infection have been described. However, data on severe sequelae requiring
      hospitalization among this population have not been reported. METHODS: The
      Pediatric Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (PACTG)
      219C is a prospective cohort study designed to examine long-term outcomes among
      HIV-infected children and HIV-uninfected infants born to HIV-infected women.
      Children with HIV infection who have enrolled in PACTG 219C are examined
      quarterly, with collection of clinical and laboratory data. Hospitalizations and
      diagnoses for all participants between September 2000 (when enrollment into PACTG
      219C was started) and December 2002 were reviewed. RESULTS: Among 1808 HIV
      infected participants who were <15 years of age at the last visit date, 25
      children had been hospitalized for psychiatric manifestations, 8 before
      enrollment into PACTG 219C. Seventeen children were hospitalized during 2757
      person-years of follow-up monitoring after entry into PACTG 219C, which
      represents an incidence of 6.17 cases per 1000 person-years (95% confidence
      interval: 3.59-9.87 cases per 1000 person-years). This was significantly higher
      than the incidence of 1.70 cases per 1000 person-years (95% confidence interval:
      1.67-1.72 cases per 1000 person-years) in the general pediatric population <15
      years of age, as reported in the 2000 National Hospital Discharge Survey,
      yielding a relative rate of 3.62 (95% confidence interval: 2.11-5.80). A total of
      32 HIV-infected children, regardless of age, were hospitalized because of
      psychiatric illnesses. The majority of patients were admitted because of
      depression (n = 16) or behavioral disorders (n = 8). Fifteen (47%) underwent
      multiple psychiatric hospitalizations. The median age at the first psychiatric
      hospitalization was 11 years (range: 4-17 years); all patients had been
      perinatally infected. Knowledge of HIV seropositivity status and having
      experienced a significant life event were both significantly associated with an
      increased risk of psychiatric hospitalization (hazard ratios of 6.13 and 3.04,
      respectively). No psychiatric hospitalizations were observed among the 1021 HIV
      uninfected members of the cohort. CONCLUSIONS: Children with HIV/AIDS are at
      increased risk for psychiatric hospitalizations during childhood and early
      adolescence, compared with the general pediatric population. Knowledge of HIV
      seropositivity status and recent significant life events were significantly
      associated with increased risks of admission in this population.

PMID- 15173536
TI  - Knowledge, attitudes, and beliefs of school nurses and personnel and associations
      with nonmedical immunization exemptions.
AB  - OBJECTIVES: We studied school personnel involved in the review of student's
      immunization status to determine whether personnel training, immunization-related
      knowledge, attitudes, and beliefs, use of alternative medicine, and sources of
      vaccine information were associated with the vaccination status of school
      children. METHODS: Surveys were mailed to a stratified and random sample of 1000
      schools in Colorado, Massachusetts, Missouri, and Washington. School personnel
      reported their training and perceptions of disease susceptibility/severity,
      vaccine efficacy/safety, key immunization beliefs, use of alternative medicine,
      confidence in organizations, sources, and credibility of vaccine information, and
      the rates of vaccine exemptors in their schools. Logistic regression analysis was
      used to explore associations between personnel factors and beliefs (independent
      variables) with the likelihood of a child having an exemption (dependent
      variable). Regression models were adjusted for clustering of children in schools,
      type of school (public versus private), and state. RESULTS: Surveys were returned
      by 69.6% of eligible participants. A child attending a school with a respondent
      who was a nurse was significantly less likely to be have an exemption than a
      child attending a school with a respondent who was not a nurse (odds ratio [OR]:
      0.39; 95% confidence interval [CI]: 0.28-0.56). The majority of respondents
      believed that children (95.6%) and the community (96.1%) benefit when children
      are vaccinated. Nurses were more likely than nonnurses to hold beliefs supporting
      the utility and safety of vaccination. Greater perceived disease susceptibility
      and severity and vaccine efficacy and safety were associated with a decreased
      likelihood of a child in the school having an exemption. Vaccine misconceptions
      were relatively common. For example, 19.0% of respondents were concerned that
      children's immune systems could be weakened by too many immunizations, and this
      belief was associated with an increased likelihood of a child in the school
      having an exemption (OR: 1.51; 95% CI: 1.00-2.28). Most respondents had a
      moderate amount or great deal of confidence in state health departments (91.4%),
      the Centers for Disease Control and Prevention (CDC) (93.9%), local health
      departments (88.8%), health care providers (88.5%), the Food and Drug
      Administration (73.6%), and the health care system (65.2%). Fewer respondents had
      a moderate amount or great deal of confidence in the media (17.4%). A child
      attending a school with a respondent who had a moderate amount or great deal of
      confidence in local and state health departments was less likely to have an
      exemption (OR: 0.47 and 0.44; 95% CI: 0.27-0.80 and 0.25-0.80, respectively) than
      a child attending a school with a respondent who did not have a moderate amount
      or great deal of confidence in local and state health departments. Confidence in
      other groups was not associated with the likelihood of a child in the school
      having an exemption. Nearly half (45.5%) of the respondents or their immediate
      family members had used some form of alternative medicine in the last 5 years. A
      child attending a school with a respondent who had (or had a family member[s]
      who) used an alternative medicine practitioner was more likely to have an
      exemption than a child attending a school with a respondent who had not used an
      alternative medicine practitioner. There were significant associations between
      sources used and perception of reliability for vaccine information with the
      likelihood of a child in the school having an exemption. Use of professional
      organizations, government resources, vaccine companies, and pharmacists for
      vaccine information were associated with a decreased likelihood of a child in the
      school having an exemption. Perceiving health departments and the CDC as a good
      or excellent source for vaccine information was associated with a decreased
      likelihood of a child in the school having an exemption. CONCLUSIONS: The
      training, knowledge, attitudes, and beliefs of school personnel who work with
      parents on immunrk with parents on immunization issues were associated with the
      likelihood of a child in the school having an exemption. Although respondents
      generally believed in vaccinations, misconceptions were common. Many school
      personnel seem to be unaware of the seriousness of some vaccine-preventable
      diseases and that unimmunized children are highly susceptible to diseases. These
      misperceptions were associated with an increased likelihood of a child having an
      exemption. This study of associations cannot determine causal associations.
      Nonetheless, the frequency of vaccine misconceptions among school personnel
      warrants vaccine communication programs for school employees who work with
      parents on immunization issues. An intervention study could determine whether
      such programs have an impact on parental decisions to claim exemptions for their
      children. Personnel without formal health care training who advice parents on
      immunization issues could be passing on misinformation to parents. Nurses or
      properly trained health personnel should be the primary school contacts for
      parents on immunization issues. Health departments and health care providers were
      used most often by school personnel for vaccine information. Providers,
      professional organizations, health departments, and the CDC were considered most
      credible. The CDC may be an underutilized source, given its high credibility;
      only 58.1% of respondents reported using the CDC for vaccine information. Greater
      visibility of CDC on vaccine information statements and communication efforts
      from the CDC directly to school personnel will likely be well received.
      Respondents who do not consider health departments and the CDC as credible
      sources were associated with a greater likelihood of a child in their school
      having an exemption. The CDC may need to consider working with other reliable
      sources to communicate with these personnel. Studies are needed to understand why
      some parents choose to forgo vaccination for children who do not have true
      medical contraindications to vaccines. School personnel trained in vaccine safety
      may serve as a valuable source of vaccine information for parents. Parents who
      have misconceptions about vaccines would likely benefit from discussions with
      health care providers. Additional public-information campaigns regarding
      misconceptions and the value of vaccination may be needed.

PMID- 15173537
TI  - Early extubation and nasal continuous positive airway pressure after surfactant
      treatment for respiratory distress syndrome among preterm infants <30 weeks'
      gestation.
AB  - OBJECTIVE: To test the hypothesis that preterm infants with infant respiratory
      distress syndrome who are treated with nasal continuous positive airway pressure
      (NCPAP) and surfactant administration followed by immediate extubation and NCPAP
      application (SURF-NCPAP group) demonstrate less need for mechanical ventilation
      (MV), compared with infants who receive MV after surfactant administration (SURF
      MV group). METHODS: A prospective randomized study was conducted, in which
      infants <30 weeks' gestation were randomized to the SURF-NCPAP group or the SURF
      MV group. RESULTS: At 7 days of life, no patient in the SURF-NCPAP group but 6
      patients (43%) in the SURF-MV group still were undergoing MV. The duration of
      oxygen therapy, NCPAP, and MV, the need for a second dose of surfactant, and the
      length of stay in the intensive care unit were significantly greater in the SURF
      MV group. CONCLUSIONS: The immediate reinstitution of NCPAP after surfactant
      administration for infants with infant respiratory distress syndrome is safe and
      beneficial, as indicated by the lesser need for MV and the briefer requirement
      for respiratory supports, compared with the institution of MV after surfactant
      treatment. Moreover, this strategy contributed to reducing the need for
      surfactant treatment and reducing the time and costs involved in keeping the
      infants in the neonatal intensive care unit.

PMID- 15173538
TI  - Plasma C-reactive protein levels among children with sleep-disordered breathing.
AB  - INTRODUCTION: Levels of C-reactive protein (CRP), an important serum marker of
      inflammation with major implications for cardiovascular morbidity and
      atherogenesis, are elevated among adult patients with sleep-disordered breathing
      (SDB). We hypothesized that elevated CRP plasma levels would also be present
      among children with SDB. METHODS: Eighty-one children (mean age: 9.3 +/- 3.7
      years) underwent polysomnographic evaluations. Samples for plasma CRP level and
      lipid profile determinations were drawn the next morning. RESULTS: Because plasma
      CRP levels were not normally distributed in this cohort, logarithmic
      transformation was applied. Log plasma CRP levels were significantly higher in
      the SDB group (obstructive apnea/hypopnea index [AHI] of > or =5), compared with
      the mild SDB group (AHI of > or =1 and <5) and the control group (AHI of <1).
      Significant positive correlations were found between log CRP levels and AHI (r
      =.53) and arousal index (r =.28), whereas an inverse correlation was found
      between the lowest nocturnal arterial oxygen saturation and log CRP levels (r = 
      .47). These correlations persisted after exclusion of outliers. Moreover, 94% of
      the children with elevated log CRP levels reported excessive daytime sleepiness
      and/or learning problems, compared with 62% of the children with normal log CRP
      levels. CONCLUSIONS: Plasma CRP levels were increased among some children with
      SDB and were correlated with AHI, arterial oxygen saturation nadir, and arousal
      index measures. These changes were particularly prominent among children who were
      sleepy or presented with neurobehavioral complaints. The intermittent hypoxemia
      and sleep fragmentation of SDB may underlie inflammatory responses, the magnitude
      of which may ultimately lead to the cardiovascular, cognitive, and behavioral
      morbidities of SDB.

PMID- 15173539
TI  - A brief screening questionnaire for infant sleep problems: validation and
      findings for an Internet sample.
AB  - OBJECTIVE: To develop and validate (using subjective and objective methods) a
      brief infant sleep questionnaire (BISQ) that would be appropriate for screening
      in pediatric settings. DESIGN: Two studies were performed to assess the
      properties of the BISQ. Study I compared BISQ measures with sleep diary measures
      and objective actigraphic sleep measures for clinical (N = 43) and control (N =
      57) groups of infants (5-29 months of age). The second study was based on an
      Internet survey of 1028 respondents who completed the BISQ posted on an infant
      sleep web site. RESULTS: In study I, BISQ measures were found to be correlated
      significantly with sleep measures derived from actigraphy and sleep diaries. BISQ
      measures (number of night wakings and nocturnal sleep duration) were the best
      predictors for distinguishing between clinical and control samples. High test
      retest correlations (r >.82) were demonstrated for BISQ measures for a subsample
      of 26 infants. Study II provided a developmental perspective on BISQ measures.
      The study demonstrated that BISQ measures derived from a large Internet survey
      provided developmental and sleep ecology-related findings that corresponded to
      the existing literature findings on sleep patterns in early childhood.
      CONCLUSIONS: The findings provide psychometric, clinical, and ecologic support
      for the use of the BISQ as a brief infant sleep screening tool for clinical and
      research purposes. Potential clinical cutoff scores are provided.

PMID- 15173540
TI  - Prospective longitudinal study of children with tic disorders and/or obsessive
      compulsive disorder: relationship of symptom exacerbations to newly acquired
      streptococcal infections.
AB  - BACKGROUND: It has been proposed that infection by group A beta-hemolytic
      streptococci (GABHS) can trigger acute symptom exacerbations among patients with
      Tourette's syndrome (TS) or obsessive-compulsive disorder (OCD), via autoimmune
      mechanisms. OBJECTIVE: To examine the temporal relationship between newly
      acquired GABHS infections (and other immunologic indices) and acute exacerbations
      of tics and obsessive-compulsive symptoms. METHODS: Pediatric patients (7-17
      years of age) with TS and/or OCD (N = 47) and healthy control subjects (N = 19)
      were prospectively monitored for newly acquired GABHS infections, nonspecific
      markers of acute inflammatory responses, and D8/17-reactive cells (a marker of
      rheumatic fever). Objective monthly ratings of tic and obsessive-compulsive
      symptom severity were used to determine the timing of symptom exacerbations.
      RESULTS: The overall rate of acute exacerbations of neuropsychiatric symptoms was
      0.56 exacerbations per patient per year. The average rate of new GABHS
      infections, using a stringent definition, was 0.42 infections per subject per
      year among patients, compared with 0.28 infections per subject per year for
      control subjects. The association between symptom exacerbations and new GABHS
      infections among patients was no greater than that expected on the basis of
      chance. At baseline, patients demonstrated significantly higher levels of D8/17
      reactive cells and neopterin, compared with control subjects, but there was no
      consistent pattern of change when exacerbation time points were compared with
      baseline or follow-up time points. CONCLUSIONS: The results suggest no clear
      relationship between new GABHS infections and symptom exacerbations in an
      unselected group of patients with TS and/or OCD.

PMID- 15173541
TI  - Heat stress and sudden infant death syndrome incidence: a United States
      population epidemiologic study.
AB  - OBJECTIVES: To determine the role of heat stress in sudden infant death syndrome
      (SIDS) by examining the SIDS rates during periods of extreme environmental
      temperatures in a period when most infants were placed prone for sleep. DESIGN: A
      retrospective study of SIDS rates and mortality rates attributable to excessive
      environmental heat in relationship to climatologic temperature was performed.
      Data were collected for each of 454 counties in 4 states (Arkansas, Georgia,
      Kansas, and Missouri) from May 1 to September 30, 1980, and were then summed to
      yield the mortality rates for each 5 degrees F (2.8 degrees C) temperature range.
      RESULTS: chi2 analyses revealed significant relationships for heat-related
      mortality rates and both the maximal daily temperature and mean daily temperature
      but demonstrated no such relationships for SIDS rates. No association between
      SIDS rates and heat-related mortality rates was found with Spearman's ranked
      correlation, for either the maximal daily temperature or the mean daily
      temperature. CONCLUSIONS: On the basis of our findings of no significant
      association between SIDS and either measure of temperature during periods of high
      heat stress-related death rates, it seems unlikely that the heat stress
      associated with the combination of prone sleep positions and elevated
      environmental temperatures has a significant role in the development of SIDS.

PMID- 15173542
TI  - Effects of growth hormone treatment on body proportions and final height among
      small children with X-linked hypophosphatemic rickets.
AB  - BACKGROUND: X-linked hypophosphatemic rickets (XLH) is characterized by rickets,
      disproportionate short stature, and impaired renal phosphate reabsorption and
      vitamin D metabolism. Despite oral phosphate and vitamin D treatment, most
      children with XLH demonstrate reduced adult height. OBJECTIVE: To determine the
      beneficial effects of recombinant human growth hormone (rhGH) therapy on body
      proportions and adult height among patients with XLH. METHODS: Three initially
      prepubertal short children (age, 9.4-12.9 years) with XLH were treated with rhGH
      for 3.1 to 6.3 years until adult height was attained. RESULTS: rhGH treatment led
      to sustained increases in standardized height for all children. The median adult
      height was 0.9 SD (range: 0.5-1.3 SD) greater than that at the initiation of rhGH
      treatment and exceeded the predicted adult height by 6.2 cm (range: 5.3-9.8 cm).
      However, longitudinal growth of the trunk was stimulated more than leg growth.
      During rhGH treatment, the standardized sitting height increased by 1.6 SD
      (range: 1.1-2.7 SD), compared with baseline values. In contrast, the median
      subischial leg length did not change consistently (median change: 0.3 SD; range: 
      0.1 to 0.6 SD). CONCLUSION: The increase in final height after rhGH treatment is
      of potential benefit for children with XLH. However, the exaggeration of
      disproportionate truncal growth observed for our prepubertal patients is a
      potential negative effect of treatment and should be confirmed with additional
      studies.

PMID- 15173543
TI  - Creating opportunities for parent empowerment: program effects on the mental
      health/coping outcomes of critically ill young children and their mothers.
AB  - OBJECTIVE: Increasing numbers of children in the United States (ie, approximately
      200 children per 100,000 population) require intensive care annually, because of
      advances in pediatric therapeutic techniques and a changing spectrum of pediatric
      disease. These children are especially vulnerable to a multitude of short- and
      long-term negative emotional, behavioral, and academic outcomes, including a
      higher risk of posttraumatic stress disorder (PTSD) and a greater need for
      psychiatric treatment, compared with matched hospitalized children who do not
      require intensive care. In addition, the parents of these children are at risk
      for the development of PTSD, as well as other negative emotional outcomes (eg,
      depression and anxiety disorders). There has been little research conducted to
      systematically determine the effects of interventions aimed at improving
      psychosocial outcomes for critically ill children and their parents, despite
      recognition of the adverse effects of critical care hospitalization on the
      nonphysiologic well-being of patients and their families. The purpose of this
      study was to evaluate the effects of a preventive educational-behavioral
      intervention program, the Creating Opportunities for Parent Empowerment (COPE)
      program, initiated early in the intensive care unit hospitalization on the mental
      health/psychosocial outcomes of critically ill young children and their mothers.
      DESIGN: A randomized, controlled trial with follow-up assessments 1, 3, 6, and 12
      months after hospitalization was conducted with 174 mothers and their 2- to 7
      year-old children who were unexpectedly hospitalized in the pediatric intensive
      care units (PICUs) of 2 children's hospitals. The final sample of 163 mothers
      ranged in age from 18 to 52 years, with a mean of 31.2 years. Among the mothers
      reporting race/ethnicity, the sample included 116 white (71.2%), 33 African
      American (20.3%), 3 Hispanic (1.8%), and 2 Indian (1.2%) mothers. The mean age of
      the hospitalized children was 50.3 months. Ninety-nine children (60.7%) were male
      and 64 (39.3%) were female. The major reasons for hospitalization were
      respiratory problems, accidental trauma, neurologic problems, and infections.
      Fifty-seven percent (n = 93) of the children had never been hospitalized
      overnight, and none had experienced a previous PICU hospitalization.
      INTERVENTIONS: Mothers in the experimental (COPE) group received a 3-phase
      educational-behavioral intervention program 1) 6 to 16 hours after PICU
      admission, 2) 2 to 16 hours after transfer to the general pediatric unit, and 3)
      2 to 3 days after their children were discharged from the hospital. Control
      mothers received a structurally equivalent control program. The COPE intervention
      was based on self-regulation theory, control theory, and the emotional contagion
      hypothesis. The COPE program, which was delivered with audiotapes and matching
      written information, as well as a parent-child activity workbook that facilitated
      implementing the audiotaped information, focused on increasing 1) parents'
      knowledge and understanding of the range of behaviors and emotions that young
      children typically display during and after hospitalization and 2) direct parent
      participation in their children's emotional and physical care. The COPE workbook,
      which was provided to parents and children after transfer from the PICU to the
      general pediatric unit, contained 3 activities to be completed before discharge
      from the hospital, ie, 1) puppet play to encourage expression of emotions in a
      nonthreatening manner, 2) therapeutic medical play to assist children in
      obtaining some sense of mastery and control over the hospital experience, and 3)
      reading and discussing Jenny's Wish, a story about a young child who successfully
      copes with a stressful hospitalization. OUTCOME MEASURES: Primary outcomes
      included maternal anxiety, negative mood state, depression, maternal beliefs,
      parental stress, and parent participation in their children's care, as well as
      child adjustment, which was assessed with the Behavioral Assessment System for
      Children (parent form). RESn (parent form). RESULTS: COPE mothers reported
      significantly less parental stress and participated more in their children's
      physical and emotional care on the pediatric unit, compared with control mothers,
      as rated by nurses who were blinded with respect to study group. In comparison
      with control mothers, COPE mothers reported less negative mood state, less
      depression, and fewer PTSD symptoms at certain follow-up assessments after
      hospitalization. In addition, COPE mothers reported stronger beliefs regarding
      their children's likely responses to hospitalization and how they could enhance
      their children's adjustment, compared with control mothers. COPE children, in
      comparison with control children, exhibited significantly fewer withdrawal
      symptoms 6 months after discharge, as well as fewer negative behavioral symptoms
      and externalizing behaviors at 12 months. COPE mothers also reported less
      hyperactivity and greater adaptability among their children at 12 months,
      compared with control mothers. One year after discharge, a significantly higher
      percentage of control group children (25.9%) exhibited clinically significant
      behavioral symptoms, compared with COPE children (2.3%). In addition, 6 and 12
      months after discharge, significantly higher percentages of control group
      children exhibited clinically significant externalizing symptoms (6 months,
      14.3%; 12 months, 22.2%), compared with COPE children (6 months, 1.8%; 12 months,
      4.5%). CONCLUSIONS: The findings of this study indicated that mothers who
      received the COPE program experienced improved maternal functional and emotional
      coping outcomes, which resulted in significantly fewer child adjustment problems,
      in comparison with the control group. With the increasing prevalence of attention
      deficit/hyperactivity disorder and externalizing problems among children and the
      documented lack of mental health screening and early intervention services for
      children in this country, the COPE intervention could help protect this high-risk
      population of children from developing these troublesome problems. As a result,
      the mental health status of children after critical care hospitalization could be
      improved. With routine provision of the COPE program in PICUs throughout the
      country, family burdens and costs associated with the mental health treatment of
      these problems might be substantially reduced.

PMID- 15173544
TI  - Effects of fluid and electrolyte management on amphotericin B-induced
      nephrotoxicity among extremely low birth weight infants.
AB  - OBJECTIVE: Greater use of invasive procedures and aggressive antimicrobial
      therapy predispose extremely low birth weight (ELBW) infants to systemic fungal
      sepsis. Despite its adverse effects (including renal and electrolyte
      disturbances), amphotericin B (amphoB) remains the preferred drug for fungal
      therapy. Multiple studies have indicated that sodium loading may prevent renal
      toxicity among animals and human adults. The effects of fluid and electrolyte
      management on amphoB-induced nephrotoxicity among ELBW infants have not been
      evaluated extensively. The purpose of this study was to examine the effects of
      fluid and electrolyte management on amphoB-induced nephrotoxicity among ELBW
      infants. DESIGN/METHODS: The medical records were reviewed for all ELBW infants
      (birth weights of < or =1250 g) who developed systemic fungal sepsis, requiring
      amphoB therapy, between January 1992 and December 2000. Demographic, clinical,
      and laboratory data were collected from the medical records for each patient.
      RESULTS: Fungal sepsis requiring amphoB treatment developed for 4.4% of ELBW
      infants (25 of 573 infants), with a gestational age of 25 +/- 1 weeks and a birth
      weight of 738 +/- 37 g, at a postnatal age of 16 +/- 2 days. Renal compromise, as
      manifested by low urine output and high creatinine levels, occurred for 44% of
      those infants (11 of 25 infants). There was no difference between the infants who
      developed renal compromise (renal compromise group [RCG], n = 11) and those who
      did not (no-renal-compromise group [NCG], n = 14) with respect to birth weight,
      gestational age, and risk factors predisposing the infants to fungal sepsis. The
      RCG demonstrated a decrease in urine output by 3.4 +/- 2 days and an increase in
      serum creatinine levels by 3.9 +/- 2 days after the initiation of amphoB therapy.
      Infants in the RCG had a significantly higher incidence of hyponatremia, compared
      with infants in the NCG (7 of 11 infants vs 0 of 14 infants), with no significant
      difference in the incidences of hypokalemia (2 of 11 infants vs 0 of 14 infants).
      Infants in the RCG, compared with infants in the NCG, had significantly lower
      mean daily sodium intakes in the 4 days before the initiation of amphoB therapy
      (2.6-2.9 mEq/kg per day vs 4.2-4.7 mEq/kg per day) and in the first 4 days of
      amphoB treatment (2.7-3.1 mEq/kg per day vs 4.5-5.6 mEq/kg per day). Mean daily
      sodium intakes were not statistically significantly different between the 2
      groups between day 5 and day 10 of amphoB therapy. Infants in the RCG tended to
      have lower mean daily potassium intakes in the 4 days before the initiation of
      amphoB therapy and during the first 4 days of amphoB therapy. Subsequently, the
      mean daily potassium intakes remained not statistically significantly different
      between the groups. Mean daily fluid intakes were not different between the
      groups. CONCLUSIONS: Conventional amphoB combined with adequate hydration and
      higher sodium intakes of >4 mEq/kg per day may provide effective protection
      against amphoB-induced nephrotoxicity among ELBW infants. Our data confirm the
      published results of animal and human adult studies and suggest that higher
      sodium intakes may prevent renal compromise during amphoB therapy among ELBW
      infants.

PMID- 15173545
TI  - Shifts in percentiles of growth during early childhood: analysis of longitudinal
      data from the California Child Health and Development Study.
AB  - OBJECTIVE: To document growth-velocity changes across major percentiles during
      the preschool years. DESIGN: Analyses of longitudinal data using height-for-age,
      weight-for-age, weight-for-height, and body mass index (BMI)-for-age percentiles
      were performed to examine crossing of major percentiles of the Centers for
      Disease Control and Prevention 2000 growth charts. The 5th, 10th, 25th, 50th,
      75th, 90th, and 95th percentiles were defined as the major percentiles. SETTING:
      Data from the California Child Health and Development Study were used. SUBJECTS:
      A total of 10,844 children up to 60 months of age, with 44,296 height and weight
      measurements, were included in our final analysis. RESULTS: For height-for-age,
      32% of children between birth and 6 months of age, 13% to 15% of children between
      6 and 24 months of age, and 2% to 10% of children between 24 and 60 months of age
      crossed 2 major percentiles. For weight-for-age, 39% of children between birth
      and 6 months of age, 6% to 15% of children between 6 and 24 months of age, and 1%
      to 5% of children between 24 and 60 months of age crossed 2 major percentiles. In
      contrast, for weight-for-height, 62% of children between birth and 6 months of
      age, 20% to 27% of children between 6 and 24 months of age, and 6% to 15% of
      children between 24 to 60 months of age crossed 2 major percentiles. Similar to
      the pattern observed for weight-for-height, 8% to 15% of children between 24 and
      60 months of age crossed 2 major BMI-for-age percentiles. During the preschool
      years, weight-for-height had the highest percentages of children who crossed 2
      major percentiles, and weight-for-age had the lowest percentages of children who
      crossed 2 major percentiles among these 3 indices. CONCLUSIONS: Shifts in growth
      rates were very common for children from birth to 6 months of age, somewhat less
      common for children 6 to 24 months of age, and least common for children 24 to 60
      months of age. Shifts in weight-for-height occurred more frequently than did
      other growth changes. Pediatricians must consider the prevalence of growth rate
      shifts during infancy and early childhood before they counsel parents regarding
      growth or refer children for additional evaluations of growth.

PMID- 15173546
TI  - Air pollution and sudden infant death syndrome.
AB  - BACKGROUND: Sudden infant death syndrome (SIDS) affects approximately 1 in 1000
      live births and is the most common cause of infant death after the perinatal
      period. OBJECTIVE: To determine the influence of air pollution on the incidence
      of SIDS. METHODS: Time-series analyses were performed to compare the daily
      mortality rates for SIDS and the daily air pollution concentrations in each of 12
      Canadian cities during the period of 1984-1999. Serial autocorrelation was
      controlled for by city, and then the city-specific estimates were pooled.
      Increased daily rates of SIDS were associated with increases, on the previous
      day, in the levels of sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon
      monoxide but not ozone or fine particles measured every sixth day. Effects
      persisted despite adjustments for season alone or the combination of daily mean
      temperature, relative humidity, and changes in barometric pressure for NO2 and
      SO2 but not carbon monoxide. RESULTS: Increases in both SO2 and NO2, equivalent
      to their interquartile ranges, were associated with a 17.72% increase in SIDS
      incidence. CONCLUSION: Ambient SO2 and NO2 may be important risk factors for
      SIDS.

PMID- 15173547
TI  - Legalization of marijuana: potential impact on youth.
AB  - This technical report provides historical perspectives and comparisons of various
      approaches to the legal status of marijuana to aid in forming public policy.
      Information on the impact that decriminalization and legalization of marijuana
      could have on adolescents, in addition to concerns surrounding medicinal use of
      marijuana, are also addressed in this report. Recommendations are included in the
      accompanying policy statement.

PMID- 15173548
TI  - Telemedicine: pediatric applications.
AB  - The newly developing field of telemedicine has the potential to benefit pediatric
      care by increasing access to pediatric specialists and services. This report
      explores the current uses and limitations of telemedicine in pediatrics.

PMID- 15173549
TI  - Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the
      region on chromosome 4 bearing gene(s) for underlying facets of metabolic
      syndrome.
AB  - Congenic BB.SHR (D4Got41-Npy-Tacr1; BB.4S) rats develop an incomplete metabolic
      syndrome with obesity, hyperleptinemia, and dyslipidemia compared with their
      progenitor strain, the diabetes-prone BB/OK rat. To narrow down the underlying
      gene(s), two subcongenic BB.SHR rat lines, briefly termed BB.4Sa and BB.4Sb, were
      generated. Male BB.4S (n = 20), BB.4Sa (n = 24), and BB.4Sb (n = 26) were
      longitudinally characterized for facets of the metabolic syndrome and analyzed
      for expression of genes located in the region of interest in liver and blood.
      Body weight gain was comparable, serum triglycerides and leptin were
      significantly increased, and total cholesterol and HDL-cholesterol ratio were
      decreased in BB.4S compared with both subcongenics. Serum insulin was
      significantly higher in BB.4S and BB.4Sa than in BB.4Sb. The adiposity index
      showed a graduated decrease from BB.6S to BB.4Sb. Obvious differences in relative
      expression were found in 6 of 10 genes in liver and in 2 of 9 genes in blood.
      Only one gene, the eukaryotic translation initiation factor 2alpha kinase 3
      (Eif2ak3 also called Perk or Pek), was significantly less expressed in liver and
      in blood of both subcongenic BB.4Sa and BB.4Sb compared with their "parental"
      BB.4S rats. Based on the phenotype and genotype in BB.4S and its subcongenic
      derivatives, the most important region on chromosome 4 can be said to lie between
      D4Got72 and Tacr1. Eif2ak3 is mapped in this region. Considering the function of
      Eif2ak3, it may be a candidate gene for the development of glucose intolerance
      found in both subcongenics but not in BB.4S. Allelic variants between BB/OK and
      SHR could influence Eif2ak3 function, possibly leading not only to glucose
      intolerance but also to the disturbances in hepatic and renal function found in
      human Wolcott-Rallison syndrome.

PMID- 15173550
TI  - Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice.
AB  - Systemic lupus erythematosus (SLE) is an autoimmune disorder with immune-complex
      deposition that affects multiple organs. Previous studies have suggested the
      involvement of oxidative stress and apoptosis in SLE, but no clear link to
      etiology has been established. Here we show that mice deficient in a
      transcription factor responsible for controlling the expression of numerous
      detoxification and antioxidant genes develop an autoimmune disease with multiple
      organ pathologies that closely resembles human SLE. Aged female mice with a
      knockout of nuclear factor, erythroid-derived 2, like 2 (nrf2) are prone to
      develop antibodies against double-stranded DNA and the Smith antigen as well as
      IgG, IgM, and C3 deposition in kidney, liver, heart, and brain. Prior to the
      development of autoimmune antibodies and organ pathology, oxidative damage occurs
      in the liver and kidney as indicated by the increased levels of the DNA oxidation
      marker 8-hydroxydeoxyguanosine and the later increase in the lipid peroxidation
      product malondialdehyde. Gene expression profiles demonstrate an early decrease
      in numerous antioxidant and detoxification genes in the livers and altered levels
      of cytokines and T and B cell-specific genes in the spleens of nrf2 knockout
      mice. These data strongly suggest that a deficiency in detoxification and
      increased oxidative stress can result in the development of a systemic autoimmune
      disease.

PMID- 15173551
TI  - Etomidate for procedural sedation in the emergency department.
AB  - OBJECTIVE: To review the current efficacy and safety evidence for the use of
      etomidate for procedural sedation in the emergency department (ED). DATA SOURCES:
      MEDLINE (1966-December 2003), EMBASE (1980-December 2003), PubMED (1966-December
      2003), and Cochrane Database of Systemic Reviews (up to December 2003) were
      searched for full-text reports published in English on the use of etomidate in
      humans. Search terms included etomidate, procedural sedation, conscious sedation,
      relocation, dislocation, abscess incision, abscess drainage, and cardioversion.
      STUDY SELECTION AND DATA EXTRACTION: Prospective and retrospective studies
      evaluating efficacy or safety endpoints using etomidate for procedural sedation
      in the ED were included. All studies were evaluated independently by both
      authors. For clinical outcomes (efficacy, safety), the definitions specified by
      each study were used. DATA SYNTHESIS: Three observational studies and 5
      prospective, randomized controlled trials were included in this review. Onset of
      action and time to recovery following etomidate were rapid and found to be
      comparable to that of propofol and thiopental but significantly faster than that
      of midazolam. The dose of etomidate for procedural sedation ranged from 0.15 to
      0.22 mg/kg. No significant hemodynamic effects were observed; however,
      respiratory depression resulting in oxygen desaturation to <90% or apnea appears
      to occur in approximately 10% of patients undergoing procedural sedation with
      etomidate with or without analgesia. The most prominent adverse effect reported
      with etomidate was myoclonus, occurring in 20-45% of patients. CONCLUSIONS:
      Etomidate is an appropriate and valuable agent for performing procedural sedation
      in the ED. The rapid onset and recovery time and relative lack of significant
      hemodynamic and respiratory effects may facilitate optimal and safe conditions
      for procedural sedation in the ED.

PMID- 15173552
TI  - Sotalol-induced depression.

PMID- 15173553
TI  - Persistence of medial hyalinosis of small vessels in an allograft after
      discontinuation of cyclosporine.

PMID- 15173554
TI  - Acute onset of severe dilated cardiomyopathy during bromocriptine therapy.
AB  - OBJECTIVE: To report a case of severe dilated cardiomyopathy (DCMP) in a patient
      on bromocriptine therapy for a microprolactinoma. CASE SUMMARY: A 31-year-old
      African American female, who had been receiving bromocriptine 5 mg orally daily
      for a microprolactinoma during the preceding month, developed severe DCMP. An
      echocardiogram showed a markedly dilated left ventricle with severe reduction in
      the left-ventricular ejection fraction in the absence of any other identifiable
      causes of DCMP such as a peripartum state, ethanol use, preceding systemic viral
      illness, chronic hypocalcemia, chronic hypophosphatemia, or chronic uncontrolled
      tachycardia. She improved substantially (both symptomatically and
      echocardiographically) after cessation of bromocriptine therapy and initiation of
      supportive treatment of congestive heart failure (CHF). She showed no recurrence
      of CHF at a follow-up visit 2 months after withdrawal of the supportive care. The
      patient was not rechallenged with bromocriptine due to the clinical/ethical
      gravity of this probable adverse effect. DISCUSSION: Although cardiopulmonary
      adverse effects have been reported with the use of cabergoline (another dopamine
      agonist), to the best of our knowledge, this is the first case report of severe
      life-threatening DCMP associated with bromocriptine therapy. Causality assessment
      using the Naranjo probability scale revealed that the adverse drug event was
      probable. CONCLUSIONS: Bromocriptine was probably associated with DCMP in a
      patient being treated for a microprolactinoma. Severe DCMP needs to be considered
      a potentially life-threatening but reversible adverse effect of bromocriptine
      therapy for microprolactinoma of the pituitary gland.

PMID- 15173555
TI  - Relationship between MMR vaccine and autism.
AB  - OBJECTIVE: To evaluate the proposed link between the administration of the
      measles, mumps, and rubella (MMR) vaccine and the development of autism. DATA
      SOURCES: A literature search utilizing MEDLINE (1966-November 2003), with the key
      terms measles, mumps, rubella, and autism, was conducted. Review of the
      references listed in the articles identified was also performed. DATA SYNTHESIS:
      Ten articles that specifically evaluated the possible relationship between the
      MMR vaccine and autism were identified. Review articles, commentaries, and
      evaluations of a link between gastrointestinal symptoms in autistic children and
      MMR immunization were excluded. CONCLUSIONS: Based upon the current literature,
      it appears that there is no relationship between MMR vaccination and the
      development of autism.

PMID- 15173557
TI  - Comparing dexmedetomidine prescribing patterns and safety in the naturalistic
      setting versus published data.
AB  - BACKGROUND: In clinical practice, new drugs may be used differently than the
      product labeling recommends. Furthermore, it often takes several years of use
      before adverse drug reactions (ADRs) are reported. OBJECTIVE: To compare
      prescribing patterns and safety of the newly released drug dexmedetomidine as
      observed in clinical practice with published data on the drug. METHODS:
      Information from a convenience sample of adults receiving dexmedetomidine as part
      of routine patient care at 10 institutions was retrospectively collected from
      June 27, 2001, to May 31, 2002. Investigators reviewed medical records daily and
      entered dosing information, patient demographics, and predefined categories of
      ADR severity and probability anonymously via the Internet on a secure server.
      RESULTS: Only 33% of the total sample (n = 136) of patients received a loading
      infusion of dexmedetomidine; however, maintenance dosing was usually within
      product labeling guidelines. Of note, 27.2% of patients received dexmedetomidine
      above the maximum dose and 33.8% received the drug beyond 24 hours. Some patients
      (15.4%) were never mechanically ventilated, while 59.5% received dexmedetomidine
      following extubation for an average of 11.3 hours. ADRs were reported in 30% of
      patients: 20% of the reactions required treatment or increased length of stay.
      Hypotension was the most common ADR, occurring in 22.7% of patients. Bradycardia
      was reported in 4.4% of patients. The rate and type of ADRs were similar in
      patients receiving dexmedetomidine >24 hours compared with the total population.
      CONCLUSIONS: Dexmedetomidine is prescribed within product labeling guidelines
      except for low use of a loading dose, some patients received the drug at doses
      above the maximum, and others received it for longer than 24 hours. Since ADR
      rates are similar to those of other published reports, dexmedetomidine maintained
      its expected safety profile in our patients.

PMID- 15173556
TI  - Delayed salicylate toxicity at 35 hours without early manifestations following a
      single salicylate ingestion.
AB  - OBJECTIVE: To report a case of delayed toxicity following a single ingestion of
      aspirin, where the initial concentrations were nearly undetectable and the
      patient was completely asymptomatic for the first 35 hours. CASE SUMMARY: A 14
      year-old white female was evaluated after a single ingestion of 120 tablets of
      aspirin 81 mg/tablet hours before arrival to the emergency department. She denied
      nausea, abdominal pain, tinnitus, or shortness of breath. She received one dose
      of activated charcoal. The first salicylate concentration (4 h after ingestion)
      was 1 mg/dL. At 35 hours, the patient became symptomatic (dizziness, tinnitus,
      epigastric discomfort). Her salicylate concentration at that time was 46 mg/dL. A
      second dose of activated charcoal was administered, and intravenous bicarbonate
      with potassium was started as a continuous infusion for 30 hours. DISCUSSION:
      While delayed salicylate toxicity is well reported in the literature, no report
      was found regarding concentrations increasing to toxicity 35 hours after
      ingestion. The delayed aspirin absorption may be due to salicylate-induced
      pylorospasm or the formation of pharmacobezoars. CONCLUSIONS: In cases with known
      salicylate ingestion, it is important to follow salicylate concentrations every 4
      hours until they are steadily decreasing according to a 4-hour half-life and the
      patient shows no symptoms of salicylate intoxication.

PMID- 15173558
TI  - Tobramycin bladder irrigation for treating a urinary tract infection in a
      critically ill patient.

PMID- 15173559
TI  - Unintentional intravenous infusion of Golytely in a 4-year-old girl.
AB  - OBJECTIVE: To report an accidental intravenous infusion of Golytely (polyethylene
      glycol and electrolyte solution; PEG-ELS) in a pediatric patient that did not
      result in systemic toxicity. CASE SUMMARY: A 4-year-old Hispanic girl presented
      to the emergency department after ingestion of approximately 24 tablets of 6
      mercaptopurine (6-MP) 2 hours earlier. She vomited twice after receiving syrup of
      ipecac at home. Upon arrival, her vital signs were temperature 36.2 degrees C,
      heart rate 102 beats/min, respiratory rate 42 breaths/min, and blood pressure
      115/67 mm Hg. Her physical examination was normal. The patient received activated
      charcoal 1 g/kg. Golytely administered through a nasogastric tube was ordered.
      Upon reevaluation, it was noted that the patient had received 391 mL of Golytely
      intravenously. The infusion was immediately stopped. There was no evidence of
      acidosis, renal failure, or ethylene glycol toxicity. She was admitted for
      observation and was discharged 36 hours later. DISCUSSION: As of April 29, 2004,
      accidental intravenous infusion of PEG-ELS has not been previously reported.
      Potential toxicity from Golytely is mainly related to the molecular weight of PEG
      in the formulation. PEG can theoretically be degraded to ethylene glycol. It is
      thus important to monitor acid-base status, renal function, and pulmonary
      function in these patients. CONCLUSIONS: When administered correctly, an infusion
      of PEG-ELS by nasogastric tube is a safe gastrointestinal decontamination
      technique used in toxicology; PEG-ELS is not indicated for intravenous
      administration. Protocols need to be implemented in the workplace to minimize
      errors in the delivery of treatment to patients. Fortunately, this patient did
      not have any toxicity from the intravenous infusion of Golytely.

PMID- 15173560
TI  - Plastidial alpha-glucan phosphorylase is not required for starch degradation in
      Arabidopsis leaves but has a role in the tolerance of abiotic stress.
AB  - To study the role of the plastidial alpha-glucan phosphorylase in starch
      metabolism in the leaves of Arabidopsis, two independent mutant lines containing
      T-DNA insertions within the phosphorylase gene were identified. Both insertions
      eliminate the activity of the plastidial alpha-glucan phosphorylase. Measurement
      of other enzymes of starch metabolism reveals only minor changes compared with
      the wild type. The loss of plastidial alpha-glucan phosphorylase does not cause a
      significant change in the total accumulation of starch during the day or its
      remobilization at night. Starch structure and composition are unaltered. However,
      mutant plants display lesions on their leaves that are not seen on wild-type
      plants, and mesophyll cells bordering the lesions accumulate high levels of
      starch. Lesion formation is abolished by growing plants under 100% humidity in
      still air, but subsequent transfer to circulating air with lower humidity causes
      extensive wilting in the mutant leaves. Wilted sectors die, causing large lesions
      that are bordered by starch-accumulating cells. Similar lesions are caused by the
      application of acute salt stress to mature plants. We conclude that plastidial
      phosphorylase is not required for the degradation of starch, but that it plays a
      role in the capacity of the leaf lamina to endure a transient water deficit.

PMID- 15173561
TI  - The peroxisome deficient Arabidopsis mutant sse1 exhibits impaired fatty acid
      synthesis.
AB  - The Arabidopsis Shrunken Seed 1 (SSE1) gene encodes a homolog of the peroxisome
      biogenesis factor Pex16p, and a loss-of-function mutation in this gene alters
      seed storage composition. Two lines of evidence support a function for SSE1 in
      peroxisome biogenesis: the peroxisomal localization of a green fluorescent
      protein-SSE1 fusion protein and the lack of normal peroxisomes in sse1 mutant
      embryos. The green fluorescent protein-SSE1 colocalizes with the red fluorescent
      protein (RFP)-labeled peroxisomal markers RFP-peroxisome targeting signal 1 and
      peroxisome targeting signal 2-RFP in transgenic Arabidopsis. Each peroxisomal
      marker exhibits a normal punctate peroxisomal distribution in the wild type but
      not the sse1 mutant embryos. Further studies reported here were designed toward
      understanding carbon metabolism in the sse1 mutant. A time course study of
      dissected embryos revealed a dramatic rate decrease in oil accumulation and an
      increase in starch accumulation. Introduction of starch synthesis mutations into
      the sse1 background did not restore oil biosynthesis. This finding demonstrated
      that reduction in oil content in sse1 is not caused by increased carbon flow to
      starch. To identify the blocked steps in the sse1 oil deposition pathway,
      developing sse1 seeds were supplied radiolabeled oil synthesis precursors. The
      ability of sse1 to incorporate oleic acid, but not pyruvate or acetate, into
      triacylglycerol indicated a defect in the fatty acid biosynthetic pathway in this
      mutant. Taken together, the results point to a possible role for peroxisomes in
      the net synthesis of fatty acids in addition to their established function in
      lipid catabolism. Other possible interpretations of the results are discussed.

PMID- 15173562
TI  - Type-B response regulators display overlapping expression patterns in
      Arabidopsis.
AB  - Two-component signaling systems, involving His kinases, His-containing
      phosphotransfer proteins, and response regulators, have been implicated in plant
      responses to hormones and environmental factors. Genomic analysis of Arabidopsis
      supports the existence of 22 response regulators (ARRs) that can be divided into
      at least two distinct groups designated type-A and type-B. Phylogenetic analysis
      indicates that the type-B family is composed of one major and two minor
      subfamilies. The expression of the type-B ARRs was examined by using both reverse
      transcription-PCR and beta-glucuronidase fusion constructs. The major subfamily
      of type-B ARRs showed particularly high expression in regions where cytokinins
      play a significant role, including cells in the apical meristem region and in
      young leaves that would be undergoing cell division. Multiple members within this
      same subfamily of type-B ARRs were expressed near the root tip with highest
      expression in the root elongation zone. beta-Glucuronidase-fusions to full-length
      ARR2, ARR12, and ARR19 were nuclear localized, consistent with a role in
      transcriptional regulation. These data suggest that differing expression levels
      of the type-B ARRs may play a role in modulating the cellular responses to
      cytokinin.

PMID- 15173563
TI  - Expression of the Isochrysis C18-delta9 polyunsaturated fatty acid specific
      elongase component alters Arabidopsis glycerolipid profiles.
AB  - A cDNA isolated from the prymnesiophyte micro-alga Isochrysis galbana, designated
      IgASE1, encodes a fatty acid elongating component that is specific for linoleic
      acid (C18:2n-6) and alpha-linolenic acid (C18:3n-3). Constitutive expression of
      IgASE1 in Arabidopsis resulted in the accumulation of eicosadienoic acid (EDA;
      C20:2n-6) and eicosatrienoic acid (ETrA; C20:3n-3) in all tissues examined, with
      no visible effects on plant morphology. Positional analysis of the various lipid
      classes indicated that these novel fatty acids were largely excluded from the sn
      2 position of chloroplast galactolipids and seed triacylglycerol, whereas they
      were enriched in the same position in phosphatidylcholine. EDA and ETrA are
      precursors of arachidonic acid (C20:4n-6), eicosapentaenoic acid (C20:5n-3), and
      docosahexaenoic acid (C22:6n-3) synthesized via the so-called omega6 Delta8
      desaturase and omega3 Delta8 desaturase biosynthetic pathways, respectively. The
      synthesis of significant quantities of EDA and ETrA in a higher plant is
      therefore a key step in the production of very long chain polyunsaturated fatty
      acid in oil-seed species. The results are further discussed in terms of
      prokaryotic and eukaryotic pathways of lipid synthesis in plants.

PMID- 15173564
TI  - Arabidopsis MPSS. An online resource for quantitative expression analysis.

PMID- 15173565
TI  - Della proteins and gibberellin-regulated seed germination and floral development
      in Arabidopsis.
AB  - RGA (repressor of ga1-3) and GAI (gibberellin insensitive) are negative
      regulators of plant hormone gibberellin (GA) signaling in Arabidopsis. The GA
      deficient mutant ga1-3 is a nongerminating, extreme dwarf that flowers late and
      produces male-sterile flowers. The rga and gai null alleles interact
      synergistically to rescue vegetative growth and floral initiation in ga1-3,
      indicating that RGA and GAI are major repressors for these processes. However,
      rga and gai in combination cannot rescue seed germination or floral development
      in ga1-3. RGA and GAI belong to the DELLA subfamily within the GRAS family of
      plant regulatory proteins. Three additional DELLA proteins RGL1, RGL2, and RGL3
      are present in Arabidopsis. Previous studies provided evidence that RGL2 and
      possibly RGL1 control seed germination. To investigate further the function of
      the RGL genes, we examined the expression profiles of all 5 DELLA protein genes
      by real-time PCR. RGA and, to a lesser extent, GAI mRNAs were expressed
      ubiquitously in all tissues, whereas RGL1, 2, and 3 transcripts were present at
      high levels only in germinating seeds and/or flowers and siliques. Using the
      newly isolated rgl1, rgl2, and rgl3 T-DNA insertion mutants, we demonstrated that
      RGL2 is the major repressor in seed germination. We further provided evidence
      that RGA, RGL1, and RGL2 are all involved in modulating floral development.
      Interestingly, RGL2 expression is regulated not only at the transcript level. We
      showed that RGL2 protein in imbibed seeds is rapidly degraded by GA treatment and
      that the F-box protein SLY1 is required for RGL2 degradation to occur.

PMID- 15173566
TI  - Functional annotation of the Arabidopsis genome using controlled vocabularies.
AB  - Controlled vocabularies are increasingly used by databases to describe genes and
      gene products because they facilitate identification of similar genes within an
      organism or among different organisms. One of The Arabidopsis Information
      Resource's goals is to associate all Arabidopsis genes with terms developed by
      the Gene Ontology Consortium that describe the molecular function, biological
      process, and subcellular location of a gene product. We have also developed terms
      describing Arabidopsis anatomy and developmental stages and use these to annotate
      published gene expression data. As of March 2004, we used computational and
      manual annotation methods to make 85,666 annotations representing 26,624 unique
      loci. We focus on associating genes to controlled vocabulary terms based on
      experimental data from the literature and use The Arabidopsis Information
      Resource-developed PubSearch software to facilitate this process. Each annotation
      is tagged with a combination of evidence codes, evidence descriptions, and
      references that provide a robust means to assess data quality. Annotation of all
      Arabidopsis genes will allow quantitative comparisons between sets of genes
      derived from sources such as microarray experiments. The Arabidopsis annotation
      data will also facilitate annotation of newly sequenced plant genomes by using
      sequence similarity to transfer annotations to homologous genes. In addition,
      complete and up-to-date annotations will make unknown genes easy to identify and
      target for experimentation. Here, we describe the process of Arabidopsis
      functional annotation using a variety of data sources and illustrate several ways
      in which this information can be accessed and used to infer knowledge about
      Arabidopsis and other plant species.

PMID- 15173567
TI  - From laboratory to field. Using information from Arabidopsis to engineer salt,
      cold, and drought tolerance in crops.

PMID- 15173568
TI  - A mutant of Arabidopsis lacking the triose-phosphate/phosphate translocator
      reveals metabolic regulation of starch breakdown in the light.
AB  - The chloroplast envelope triose-phosphate/phosphate translocator (TPT) is
      responsible for carbohydrate export during photosynthesis. Using measurements of
      carbohydrates, partitioning of assimilated 14CO2, photosynthetic gas exchange,
      and chlorophyll fluorescence, we show that a mutant of Arabidopsis lacking the
      TPT increases synthesis of starch compared to the wild type, thereby compensating
      for a deficiency in its ability to export triose-phosphate from the chloroplast.
      However, during growth under high light, the capacity for starch synthesis
      becomes limiting so that the chloroplastic phosphate pool is depleted, resulting
      in a restriction on electron transport, a reduction in the rate of
      photosynthesis, and slowed plant growth. Under the same conditions but not under
      low light, we observe release of 14C label from starch, indicating that its
      synthesis and degradation occur simultaneously in the light. The induction of
      starch turnover in the mutant specifically under high light conditions leads us
      to conclude that it is regulated by one or more metabolic signals, which arise as
      a result of phosphate limitation of photosynthesis.

PMID- 15173569
TI  - IAR4, a gene required for auxin conjugate sensitivity in Arabidopsis, encodes a
      pyruvate dehydrogenase E1alpha homolog.
AB  - The formation and hydrolysis of indole-3-acetic acid (IAA) conjugates represent a
      potentially important means for plants to regulate IAA levels and thereby auxin
      responses. The identification and characterization of mutants defective in these
      processes is advancing the understanding of auxin regulation and response. Here
      we report the isolation and characterization of the Arabidopsis iar4 mutant,
      which has reduced sensitivity to several IAA-amino acid conjugates. iar4 is less
      sensitive to a synthetic auxin and low concentrations of an ethylene precursor
      but responds to free IAA and other hormones tested similarly to wild type. The
      gene defective in iar4 encodes a homolog of the E1alpha-subunit of mitochondrial
      pyruvate dehydrogenase, which converts pyruvate to acetyl-coenzyme A. We did not
      detect glycolysis or Krebs-cycle-related defects in the iar4 mutant, and a T-DNA
      insertion in the IAR4 coding sequence conferred similar phenotypes as the
      originally identified missense allele. In contrast, we found that disruption of
      the previously described mitochondrial pyruvate dehydrogenase E1alpha-subunit
      does not alter IAA-Ala responsiveness or confer any obvious phenotypes. It is
      possible that IAR4 acts in the conversion of indole-3-pyruvate to indole-3-acetyl
      coenzyme A, which is a potential precursor of IAA and IAA conjugates.

PMID- 15173571
TI  - Salicylate accumulation inhibits growth at chilling temperature in Arabidopsis.
AB  - The growth of Arabidopsis plants in chilling conditions could be related to their
      levels of salicylic acid (SA). Plants with the SA hydroxylase NahG transgene grew
      at similar rates to Col-0 wild types at 23 degrees C, and growth of both
      genotypes was slowed by transfer to 5 degrees C. However, at 5 degrees C, NahG
      plants displayed relative growth rates about one-third greater than Col-0, so
      that by 2 months NahG plants were typically 2.7-fold larger. This resulted
      primarily from greater cell expansion in NahG rosette leaves. Specific leaf areas
      and leaf area ratios remained similar in both genotypes. Net assimilation rates
      were similar in both genotypes at 23 degrees C, but higher in NahG at 5 degrees
      C. Chlorophyll fluorescence measurements revealed no PSII photodamage in chilled
      leaves of either genotype. Col-0 shoots at 5 degrees C accumulated SA,
      particularly in glucosylated form. SA in NahG shoots showed similar tendencies at
      5 degrees C, but at greatly depleted levels. Catechol was not detected as a
      metabolite of the NahG transgene product. We also examined growth and SA levels
      in SA signaling and metabolism mutants at 5 degrees C. The partially SA
      insensitive npr1 mutant displayed growth intermediate between NahG and Col-0,
      while the SA-deficient eds5 mutant behaved like NahG. In contrast, the cpr1
      mutant at 5 degrees C accumulated very high levels of SA and its growth was much
      more inhibited than wild type. At both temperatures, cpr1 was the only SA
      responsive genotype in which oxidative damage (measured as thiobarbituric acid
      reactive substances) was significantly different from wild type.

PMID- 15173572
TI  - Biography of Juan Carlos Castilla.

PMID- 15173570
TI  - Methods for transcriptional profiling in plants. Be fruitful and replicate.

PMID- 15173573
TI  - ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the
      transcription factor TonEBP/OREBP.
AB  - High NaCl activates the transcription factor tonicity-responsive enhancer/osmotic
      response element-binding protein (TonEBP/OREBP), resulting in increased
      transcription of several protective genes, including the glycine betaine/gamma
      aminobutyric acid transporter (BGT1). High NaCl damages DNA, and DNA damage
      activates ataxia telangiectasia mutated (ATM) kinase through autophosphorylation
      on Ser-1981. TonEBP/OREBP contains ATM consensus phosphorylation sites at Ser
      1197, Ser-1247, and Ser-1367. The present studies test whether ATM is involved in
      activation of TonEBP/OREBP by high NaCl. We find that raising osmolality from 300
      to 500 mosmol/kg by adding NaCl activates ATM, as indicated by phosphorylation at
      Ser-1981. High urea and radiation also activate ATM, but they do not increase
      TonEBP/OREBP transcriptional activity like high NaCl does. Wortmannin, which
      inhibits ATM, reduces NaCl-induced TonEBP/OREBP transcriptional activation and
      BGT1 mRNA increase. Overexpression of wild-type TonEBP/OREBP increases ORE/TonE
      reporter activity much more than does overexpression of TonEBP/OREBP S1197A,
      S1247A, or S1367A. In AT cells (which express nonfunctional ATM), TonEBP/OREBP
      transcriptional and transactivating activity are further increased by expression
      of wild-type ATM but not of S1981A ATM. TonEBP/OREBP reciprocally
      coimmunoprecipitates with ATM kinase, demonstrating physical association.
      Additionally, antibody to ATM kinase supershifts TonEBP/OREBP bound to its
      cognate ORE/TonE DNA element. In AT cells, wortmannin further decreases high NaCl
      induced increase in transcriptional activity, consistent with participation of
      signaling kinase(s) in addition to ATM. In conclusion, signaling via ATM is
      necessary for full activation of TonEBP/OREBP by high NaCl, but it is not
      sufficient.

PMID- 15173574
TI  - The linker-loop region of Escherichia coli chaperone Hsp31 functions as a gate
      that modulates high-affinity substrate binding at elevated temperatures.
AB  - Precise control of substrate binding and release is essential for molecular
      chaperones to exert their protective function in times of stress. The mechanisms
      used are diverse and have been difficult to unravel. Escherichia coli heat-shock
      protein 31 (Hsp31) is a recent addition to the known complement of eubacterial
      chaperones. Crystallographic studies have revealed the presence of a hydrophobic
      bowl at the Hsp31 dimer interface and shown that the linker region connecting the
      two structural domains within each subunit is disordered. Together with a
      neighboring flexible loop, the linker caps a hydrophobic area adjacent to the
      bowl. Using a collection of Hsp31 mutants, we show that although both bowl and
      linker-loop-shielded residues participate in substrate binding, the latter are
      critical for protein capture at high temperature. Linker immobilization via an
      artificial disulfide bridge abolishes chaperone activity at elevated temperatures
      by precluding exposure of the underlying hydrophobic domain. We conclude that
      Hsp31 uses its linker-loop region as a thermally activated gate to control
      nonnative protein annealing to a high-affinity substrate-binding site. This
      simple yet efficient strategy to capture partially folded proteins under heat
      shock conditions may be shared by other folding modulators.

PMID- 15173576
TI  - Endocannabinoids: getting the message across.

PMID- 15173575
TI  - Activation of Aurora-A kinase by protein phosphatase inhibitor-2, a bifunctional
      signaling protein.
AB  - Aurora-A kinase is necessary for centrosome maturation, for assembly and
      maintenance of a bipolar spindle, and for proper chromosome segregation during
      cell division. Aurora-A is an oncogene that is overexpressed in multiple human
      cancers. Regulation of kinase activity apparently depends on phosphorylation of
      Thr-288 in the T-loop. In addition, interactions with targeting protein for
      Xenopus kinesin-like protein 2 (TPX2) allosterically activate Aurora-A. The Thr
      288 phosphorylation is reversed by type-1 protein phosphatase (PP1). Mutations in
      the yeast Aurora, Ipl1, are suppressed by overexpression of Glc8, the yeast
      homolog of phosphatase inhibitor-2 (I-2). In this study, we show that human I-2
      directly and specifically stimulated recombinant human Aurora-A activity in
      vitro. The I-2 increase in kinase activity was not simply due to inhibition of
      PP1 because it was not mimicked by other phosphatase inhibitors. Furthermore,
      activation of Aurora-A was unaffected by deletion of the I-2 N-terminal PP1
      binding motif but was eliminated by deletion of the I-2 C-terminal domain. Aurora
      A and I-2 were recovered together from mitotic HeLa cells. Kinase activation by I
      2 and TPX2 was not additive and occurred without a corresponding increase in T
      loop phosphorylation. These results suggest that both I-2 and TPX2 function as
      allosteric activators of Aurora-A. This implies that I-2 is a bifunctional
      signaling protein with separate domains to inhibit PP1 and directly stimulate
      Aurora-A kinase.

PMID- 15173577
TI  - A generalization of the Pi-theorem and dimensional analysis.
AB  - This article introduces a generalization of dimensional analysis and its
      corollary, the Pi-theorem, to the class of problems in which some of the
      quantities that define the problem have fixed values in all the cases that are of
      interest. The procedure can reduce the number of dimensionless similarity
      variables beyond the prediction of Buckingham's theorem. The generalized Pi
      theorem tells when and how large a reduction is attainable.

PMID- 15173579
TI  - Bacteria make tracks to the pole.

PMID- 15173578
TI  - Polyadenylation of rRNA in Saccharomyces cerevisiae.
AB  - In contrast to mRNAs, rRNAs are transcribed by RNA polymerase I or III and are
      not believed to be polyadenylated. Here we show that in Saccharomyces cerevisiae,
      at least a small fraction of rRNAs do have a poly(A) tail. The levels of
      polyadenylated rRNAs are dramatically increased in strains lacking the
      degradation function of Rrp6p, a component of the nuclear exosome. Pap1p, the
      poly(A) polymerase, is responsible for adenylating the rRNAs despite the fact
      that the rRNAs do not have a canonical polyadenylation signal. Polyadenylated
      rRNAs reside mainly within the nucleus and are in turn degraded. For at least one
      rRNA type, the polyadenylation preferentially occurs on the precursor rather than
      the mature product. The existence of polyadenylated rRNAs may reflect a quality
      control mechanism of rRNA biogenesis.

PMID- 15173580
TI  - beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF
      kappaB inhibitor IkappaBalpha.
AB  - In addition to their roles in desensitization and signaling of seven-membrane
      spanning receptors, beta-arrestins have been more recently implicated in
      regulating non-seven-membrane-spanning receptor pathways. By using a yeast two
      hybrid screen, we identified the inhibitor of NF-kappaB, IkappaBalpha, as a
      binding partner of beta-arrestin 1. Both beta-arrestin 1 and 2 interact with
      IkappaBalpha in transfected cells as assessed by immunoprecipitation experiments.
      Additionally, upstream kinases known to regulate the function of IkappaBalpha,
      such as IkappaB kinase alpha and beta and NF-kappaB-inducing kinase, were also
      shown to interact with beta-arrestin. Overexpression of either beta-arrestin 1 or
      beta-arrestin 2 led to marked inhibition of NF-kappaB activity, as measured by
      reporter gene activity. Inhibition of NF-kappaB activity was independent of the
      type of stimulus used for NF-kappaB activation. Conversely, suppression of beta
      arrestin 1, but not beta-arrestin 2, expression by using RNA interference led to
      a 3-fold increase in tumor necrosis factor-stimulated NF-kappaB activity as
      measured by NF-kappaB mobility-shift analysis. These data uncover a role of beta
      arrestins in the regulation of NF-kappaB-mediated gene regulation.

PMID- 15173581
TI  - DNA axial rotation and the merge of oppositely supercoiled DNA domains in
      Escherichia coli: effects of DNA bends.
AB  - We have examined the issue whether axial rotation of an intracellular DNA segment
      several thousand base pairs in length is associated with a large friction barrier
      against the merge of oppositely supercoiled DNA domains. The induction of a site
      specific recombinase was used to form intracellular DNA rings bearing different
      numbers of transcription units, and it was found that DNA rings with a single
      tetA gene and no other transcription units does not become excessively negatively
      supercoiled in Escherichia coli cells lacking DNA topoisomerase I. Thus, whereas
      oppositely supercoiled domains are generated in a tetA-bearing DNA ring through
      anchoring of the tetA transcripts to cell membrane, these domains appear to
      readily merge by means of axial rotation of the DNA segment connecting them. The
      diffusional merge of these oppositely supercoiled domains is not significantly
      affected by the presence of bent sequences in the intervening DNA segment.
      Examination of the effects of adding more transcription units to the tetA-bearing
      ring suggests, however, that DNA bends stabilized by bound protein molecules may
      significantly impede this process inside E. coli, as suggested by previous in
      vitro studies.

PMID- 15173582
TI  - Changing concentrations of CO, CH(4), C(5)H(8), CH(3)Br, CH(3)I, and dimethyl
      sulfide during the Southern Ocean Iron Enrichment Experiments.
AB  - Oceanic iron (Fe) fertilization experiments have advanced the understanding of
      how Fe regulates biological productivity and air-sea carbon dioxide (CO(2))
      exchange. However, little is known about the production and consumption of
      halocarbons and other gases as a result of Fe addition. Besides metabolizing
      inorganic carbon, marine microorganisms produce and consume many other trace
      gases. Several of these gases, which individually impact global climate,
      stratospheric ozone concentration, or local photochemistry, have not been
      previously quantified during an Fe-enrichment experiment. We describe results for
      selected dissolved trace gases including methane (CH(4)), isoprene (C(5)H(8)),
      methyl bromide (CH(3)Br), dimethyl sulfide, and oxygen (O(2)), which increased
      subsequent to Fe fertilization, and the associated decreases in concentrations of
      carbon monoxide (CO), methyl iodide (CH(3)I), and CO(2) observed during the
      Southern Ocean Iron Enrichment Experiments.

PMID- 15173583
TI  - Protection against lethal influenza virus challenge by RNA interference in vivo.
AB  - Influenza virus infection is responsible for hundreds of thousands of deaths
      annually. Current vaccination strategies and antiviral drugs provide limited
      protection; therefore, new strategies are needed. RNA interference is an
      effective means of suppressing virus replication in vitro. Here we demonstrate
      that treatment with small interfering RNAs (siRNAs) specific for highly conserved
      regions of the nucleoprotein or acidic polymerase inhibits influenza A virus
      replication in vivo. Delivery of these siRNAs significantly reduced lung virus
      titers in infected mice and protected animals from lethal challenge. This
      protection was specific and not mediated by an antiviral IFN response. Moreover,
      influenza-specific siRNA treatment was broadly effective and protected animals
      against lethal challenge with highly pathogenic avian influenza A viruses of the
      H5 and H7 subtypes. These results indicate that RNA interference is promising for
      control of influenza virus infection, as well as other viral infections.

PMID- 15173584
TI  - Stability and dynamics of crystals and glasses of motorized particles.
AB  - Many of the large structures of the cell, such as the cytoskeleton, are assembled
      and maintained far from equilibrium. We study the stabilities of various
      structures for a simple model of such a far-from-equilibrium organized assembly
      in which spherical particles move under the influence of attached motors. From
      the variational solutions of the many-body master equation for Brownian motion
      with motorized kicking we obtain a closed equation for the order parameter of
      localization. Thus, we obtain the transition criterion for localization and
      stability limits for the crystalline phase and frozen amorphous structures of
      motorized particles. The theory also allows an estimate of nonequilibrium
      effective temperatures characterizing the response and fluctuations of motorized
      asemblies.

PMID- 15173585
TI  - The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion
      promotes axonal regeneration and functional recovery.
AB  - Although there is no spontaneous regeneration of mammalian spinal axons after
      injury, they can be enticed to grow if cAMP is elevated in the neuronal cell
      bodies before the spinal axons are cut. Prophylactic injection of cAMP, however,
      is useless as therapy for spinal injuries. We now show that the phosphodiesterase
      4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier)
      overcomes inhibitors of regeneration in myelin in culture and promotes
      regeneration in vivo. Two weeks after a hemisection lesion at C3/4, with
      embryonic spinal tissue implanted immediately at the lesion site, a 10-day
      delivery of rolipram results in considerable axon regrowth into the transplant
      and a significant improvement in motor function. Surprisingly, in rolipram
      treated animals, there was also an attenuation of reactive gliosis. Hence,
      because rolipram promotes axon regeneration, attenuates the formation of the
      glial scar, and significantly enhances functional recovery, and because it is
      effective when delivered s.c., as well as post-injury, it is a strong candidate
      as a useful therapy subsequent to spinal cord injury.

PMID- 15173586
TI  - Crystal structure of nickel-containing superoxide dismutase reveals another type
      of active site.
AB  - Superoxide dismutases (SODs, EC 1.15.1.1) are ubiquitous enzymes that efficiently
      catalyze the dismutation of superoxide radical anions to protect biological
      molecules from oxidative damage. The crystal structure of nickel-containing SOD
      (NiSOD) from Streptomyces seoulensis was determined for the resting, x-ray
      reduced, and thiosulfate-reduced enzyme state. NiSOD is a homohexamer consisting
      of four-helix-bundle subunits. The catalytic center resides in the N-terminal
      active-site loop, where a Ni(III) ion is coordinated by the amino group of His-1,
      the amide group of Cys-2, two thiolate groups of Cys-2 and Cys-6, and the
      imidazolate of His-1 as axial ligand that is lost in the chemically reduced state
      as well as after x-ray-induced reduction. This structure represents a third class
      of SODs concerning the catalytic metal species, subunit structure, and oligomeric
      organization. It adds a member to the small number of Ni-metalloenzymes and
      contributes with its Ni(III) active site to the general understanding of Ni
      related biochemistry. NiSOD is shown to occur also in bacteria other than
      Streptomyces and is predicted to be present in some cyanobacteria.

PMID- 15173587
TI  - Modification of the erythroid transcription factor GATA-1 by SUMO-1.
AB  - The activity of transcription factors is tightly modulated by posttranslational
      modifications affecting stability, localization, and protein-protein
      interactions. Conjugation to SUMO is a reversible posttranslational modification
      that has been shown to regulate important transcription factors involved in cell
      proliferation, differentiation, and tumor suppression. Here, we demonstrate that
      the erythroid transcription factor GATA-1 is sumoylated in vitro and in vivo and
      map the single lysine residue involved in SUMO-1 attachment. We show that the
      nuclear RING finger protein PIASy promotes sumoylation of GATA-1 and dramatically
      represses its transcriptional activity. We present evidence that a
      nonsumoylatable GATA-1 mutant is indistinguishable from the WT protein in its
      ability to transactivate a reporter gene in mammalian cells and in its ability to
      trigger endogenous globin expression in Xenopus explants. These observations open
      interesting questions about the biological role of this posttranslational
      modification of GATA-1.

PMID- 15173588
TI  - Down-regulation of Smad7 expression by ubiquitin-dependent degradation
      contributes to renal fibrosis in obstructive nephropathy in mice.
AB  - Overexpression of transforming growth factor beta (TGF-beta) has been shown to
      play pathogenic roles in progression of renal fibrosis, and the severity of
      tubulointerstitial fibrosis correlates better with renal function than the
      severity of glomerulosclerosis. Smad proteins are signaling transducers
      downstream from TGF-beta receptors. Three families of Smad proteins have been
      identified: receptor-regulated Smad2 and Smad3, common partner Smad4, and
      inhibitory Smad7 (part of a negative-feedback loop). We investigated Smad
      mediated TGF-beta signaling pathway and regulatory mechanisms of inhibitory Smad7
      in unilateral ureteral obstruction (UUO) kidneys in mice, a model of progressive
      tubulointerstitial fibrosis. Compared with sham-operated kidneys, the level of
      Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas
      immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis
      were inversely increased. Furthermore, we demonstrated that both the degradation
      and ubiquitination activity of Smad7 protein were increased markedly in UUO
      kidneys compared with sham-operated ones. We also found that both Smurf1 and
      Smurf2 (Smad ubiquitination regulatory factors), which are E3 ubiquitin ligases
      for Smad7, were increased and that they interacted with Smad7 in UUO kidneys. Our
      results suggest that the reduction of Smad7 protein resulting from enhanced
      ubiquitin-dependent degradation plays a pathogenic role in progression of
      tubulointerstitial fibrosis.

PMID- 15173589
TI  - The LIM-homeodomain protein Lhx2 is required for complete development of mouse
      olfactory sensory neurons.
AB  - In mice, approximately 1,000 odorant receptor (OR) genes are expressed in
      olfactory sensory neurons (OSNs). Homeodomain sites can be recognized in the
      promoter and upstream regions of several OR genes. Here, using the yeast one
      hybrid system and electrophoretic mobility shift assay, we report that Lhx2, a
      LIM-homeodomain protein, binds to the homeodomain site in the mouse M71 OR
      promoter region. In Lhx2-deficient mice, the morphology of the olfactory
      epithelium is grossly normal. However, expression of OMP is abolished and that of
      GAP43 is severely reduced, indicating that no mature and few immature OSNs are
      produced. M71 and other OR genes also are not expressed. OSN development appears
      to be arrested between the terminal differentiation into neurons and the
      transition to immature neurons. Thus, Lhx2 is required for complete development
      of OSNs in mice.

PMID- 15173590
TI  - Total synthesis of (-)-spinosyn A.
AB  - A convergent, highly stereoselective total synthesis of (-)-spinosyn A (1) is
      described. Key features of the synthesis include the transannular Diels-Alder
      reaction of macrocyclic pentaene 11 and the transannular Morita-Baylis-Hillman
      cyclization of 12 that generates tetracycle 26. The total synthesis of (-)
      spinosyn A was completed by a sequence involving the highly beta-selective
      glycosidation reaction of 13 and glycosyl imidate 30.

PMID- 15173591
TI  - Antigen selection based on expression levels during infection facilitates vaccine
      development for an intracellular pathogen.
AB  - Vaccines effective against intracellular pathogens could save the lives of
      millions of people every year, but vaccine development has been hampered by the
      slow largely empirical search for protective antigens. In vivo highly expressed
      antigens might represent a small attractive antigen subset that could be rapidly
      evaluated, but experimental evidence supporting this rationale, as well as
      practical strategies for its application, is largely lacking because of technical
      difficulties. Here, we used Salmonella strains expressing differential amounts of
      a fluorescent model antigen during infection to show that, in a mouse typhoid
      fever model, CD4 T cells preferentially recognize abundant Salmonella antigens.
      To identify a large number of natural Salmonella antigens with high expression
      levels during infection, we used a quantitative in vivo screening strategy.
      Immunization studies with five particularly attractive candidates revealed two
      highly protective antigens that might permit the development of an improved
      typhoid fever vaccine. In conclusion, we have established a rationale and an
      experimental strategy that will substantially facilitate vaccine development for
      Salmonella and possibly other intracellular pathogens.

PMID- 15173592
TI  - Bilayers merge even when exocytosis is transient.
AB  - During exocytosis, the lumen of secretory vesicles connects with the
      extracellular space. In some vesicles, this connection closes again, causing the
      vesicle to be recaptured mostly intact. The degree to which the bilayers of such
      vesicles mix with the plasma membrane is unknown. Work supporting the kiss-and
      run model of transient exocytosis implies that synaptic vesicles allow neither
      lipid nor protein to escape into the plasma membrane, suggesting that the two
      bilayers never merge. Here, we test whether neuroendocrine granules behave
      similarly. Using two-color evanescent field microscopy, we imaged the lipid probe
      FM4-64 and fluorescent proteins in single dense core granules. During exocytosis,
      granules lost FM4-64 into the plasma membrane in small fractions of a second.
      Although FM4-64 was lost, granules retained the membrane protein, GFP-phogrin. By
      using GFP-phogrin as a probe for resealing, it was found that even granules that
      reseal lose FM4-64. We conclude that the lipid bilayers of the granule and the
      plasma membrane become continuous even when exocytosis is transient.

PMID- 15173593
TI  - CD4 on CD8(+) T cells directly enhances effector function and is a target for HIV
      infection.
AB  - Costimulation of purified CD8(+) T lymphocytes induces de novo expression of CD4,
      suggesting a previously unrecognized function for this molecule in the immune
      response. Here, we report that the CD4 molecule plays a direct role in CD8(+) T
      cell function by modulating expression of IFN-gamma and Fas ligand, two important
      CD8(+) T cell effector molecules. CD4 expression also allows infection of CD8
      cells by HIV, which results in down-regulation of the CD4 molecule and impairs
      the induction of IFN-gamma, Fas ligand, and the cytotoxic responses of activated
      CD8(+) T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell
      function, and infection of these cells by HIV provides an additional reservoir
      for the virus and also may contribute to the immunodeficiency seen in HIV
      disease.

PMID- 15173595
TI  - Hydrogen peroxide mediates plant root cell response to nutrient deprivation.
AB  - Potassium (K(+)) is an essential nutrient required by plants in large quantities,
      but changes in soil concentrations may limit K(+) acquisition by roots. It is not
      known how plant root cells sense or signal the changes that occur after the onset
      of K(+) deficiency. Changes in the kinetics of Rb(+) uptake in Arabidopsis roots
      occur within 6 h after K(+) deprivation. Reactive oxygen species (ROS) and
      ethylene increased when the plants were deprived of K(+). ROS accumulated in a
      discrete region of roots that has been shown to be active in K(+) uptake and
      translocation. Suppression of an NADPH oxidase in Arabidopsis (rhd2), which is
      involved in ROS production, prevented the up-regulation of genes that are
      normally induced by K(+) deficiency, but the induction of high-affinity K(+)
      transport activity was unchanged. Application of H(2)O(2) restored the expression
      of genes induced by K(+) deficiency in rhd2 and was also sufficient to induce
      high-affinity K(+) transport activity in roots grown under K(+)-sufficient
      conditions. ROS production is an early root response to K(+) deficiency that
      modulates gene expression and physiological changes in the kinetics of K(+)
      uptake.

PMID- 15173594
TI  - Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive
      choline transporter knockout mice.
AB  - Presynaptic acetylcholine (ACh) synthesis and release is thought to be sustained
      by a hemicholinium-3-sensitive choline transporter (CHT). We disrupted the murine
      CHT gene and examined CHT-/- and +/- animals for evidence of impaired cholinergic
      neurotransmission. Although morphologically normal at birth, CHT-/- mice become
      immobile, breathe irregularly, appear cyanotic, and die within an hour.
      Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are
      specifically lost in CHT-/- mouse brains. Moreover, we observe a time-dependent
      loss of spontaneous and evoked responses at CHT-/- neuromuscular junctions.
      Consistent with deficits in synaptic ACh availability, we also observe
      developmental alterations in neuromuscular junction morphology reminiscent of
      changes in mutants lacking ACh synthesis. Adult CHT+/- mice overcome reductions
      in CHT protein levels and sustain choline uptake activity at wild-type levels
      through posttranslational mechanisms. Our results demonstrate that CHT is an
      essential and regulated presynaptic component of cholinergic signaling and
      indicate that CHT warrants consideration as a candidate gene for disorders
      characterized by cholinergic hypofunction.

PMID- 15173596
TI  - Involvement of a bifunctional fatty-acyl desaturase in the biosynthesis of the
      silkmoth, Bombyx mori, sex pheromone.
AB  - The straight-chain C(10) to C(18) unsaturated aliphatic compounds containing an
      oxygenated functional group (aldehyde, alcohol, or acetate ester) derived from
      saturated C(16) or C(18) fatty acids are a major class of sex pheromone
      components produced by female moths. In the biosynthesis of these pheromone
      components, various combinations of limited chain-shortening and regio- and
      stereospecific desaturation reactions significantly contribute to the production
      of a vast number of the species-specific pheromone components in Lepidoptera.
      Biosynthesis of the silkmoth sex pheromone bombykol, (E,Z)-10,12-hexadecadien-1
      ol, involves two consecutive desaturation steps, the second of which is unique in
      that it generates a conjugated diene system from the Delta11-monoene C(16)
      intermediate. In experiments designed to characterize the acyl-CoA desaturases
      responsible for bombykol biosynthesis, we have cloned three cDNAs encoding
      desaturase family members from the pheromone gland of the inbred strain of the
      silkmoth, Bombyx mori. Transcript analyses by RT-PCR and subsequent functional
      assays using a Bac-to-Bac baculovirus expression system revealed that desat1 is
      the only desaturase gene prominently expressed during pheromonogenesis and that
      its gene product, B. mori Desat1, possesses both Z11 desaturation and Delta10,12
      desaturation activities. Consequently, we have concluded that B. mori Desat1 is
      not only a bifunctional desaturase involved in bombykol biosynthesis but that it
      is also the enzyme responsible for both desaturation steps.

PMID- 15173597
TI  - Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella
      formation but not global cilia assembly.
AB  - The functions of the proteins encoded by the Bardet-Biedl syndrome (BBS) genes
      are unknown. Mutations in these genes lead to the pleiotropic human disorder BBS,
      which is characterized by obesity, retinopathy, polydactyly, renal and cardiac
      malformations, learning disabilities, and hypogenitalism. Secondary features
      include diabetes mellitus and hypertension. Recently, it has been suggested that
      the BBS phenotypes are the result of a lack of cilia formation or function. In
      this study, we show that mice lacking the Bbs4 protein have major components of
      the human phenotype, including obesity and retinal degeneration. We show that
      Bbs4-null mice develop both motile and primary cilia, demonstrating that Bbs4 is
      not required for global cilia formation. Interestingly, male Bbs4-null mice do
      not form spermatozoa flagella, and BBS4 retinopathy involves apoptotic death of
      photoreceptors, the primary ciliated cells of the retina. These mutation data
      demonstrate a connection between the function of a BBS protein and cilia. To
      further evaluate an association between cilia and BBS, we performed homology
      comparisons of BBS proteins in model organisms and find that BBS proteins are
      specifically conserved in ciliated organisms.

PMID- 15173598
TI  - Plant-derived pyrrolizidine alkaloid protects eggs of a moth (Utetheisa ornatrix)
      against a parasitoid wasp (Trichogramma ostriniae).
AB  - Pyrrolizidine alkaloid (PA), sequestered by the moth Utetheisa ornatrix from its
      larval food plant, is transmitted by both males and females to the eggs. Males
      confer PA on the female by seminal infusion, and females pass this gift, together
      with PA that they themselves procured as larvae, to the eggs. Here we show that
      PA protects the eggs against parasitization by the chalcidoid wasp, Trichogramma
      ostriniae. Eggs laid subsequent to a first mating of an Utetheisa female receive
      most of their PA from the female. The amount they receive from the male is
      insufficient to provide for full protection. However, female Utetheisa are
      promiscuous and therefore likely to receive PA on a cumulative basis from their
      male partners.

PMID- 15173599
TI  - Inhibition of influenza virus production in virus-infected mice by RNA
      interference.
AB  - Influenza A virus infection is a major source of morbidity and mortality
      worldwide. Because the effectiveness of existing vaccines and antiviral drugs is
      limited, development of new treatment modalities is needed. Here, we show that
      short interfering RNAs (siRNAs) specific for conserved regions of influenza virus
      genes can prevent and treat influenza virus infection in mice. Virus production
      in lungs of infected mice is reduced by siRNAs given either before or after
      initiating virus infection, by using slow i.v. administration of small volumes
      containing siRNAs in complexes with a polycation carrier. Similar effects also
      are observed when mice are given DNA vectors i.v. or intranasally, from which
      siRNA precursors can be transcribed. Development of delivery systems that may be
      compatible with human use demonstrates the potential utility of siRNAs for
      prophylaxis and therapy of influenza virus infections in humans.

PMID- 15173600
TI  - From cell death to neuronal regeneration, effects of the p75 neurotrophin
      receptor depend on interactions with partner subunits.
AB  - In the adult mammalian central nervous system (CNS), growth of neuronal fibers is
      actively inhibited by myelin. The proteins myelin-associated glycoprotein (MAG),
      oligodendrocyte myelin glycoprotein (OMgP), and Nogo-66 have been identified as
      inhibitory components present in CNS myelin. All three proteins exert their
      inhibitory activity by binding to a neuronal receptor complex containing the Nogo
      66 receptor (NgR) and the neurotrophin (NT) receptor p75NTR. In their recent
      publication, Mi et al. identify the novel protein Lingo-1 as an interactor of
      p75NTR and NgR. The Lingo-1-NgR-p75NTR complex is shown to confer the inhibitory
      effects on nerve cell regeneration of Nogo-66, OMgP, and MAG by activating the
      small guanosine triphosphatase (GTPase) RhoA. Together with the recent finding
      that p75NTR interacts with the transmembrane protein sortilin to form a different
      receptor complex with cell death-promoting activity, the results of Mi et al.
      indicate that p75NTR exerts its diverse cellular functions by associating with
      function-specific co-receptors.

PMID- 15173601
TI  - Musculoskeletal ultrasonography: what is it and should training be compulsory for
      rheumatologists?

PMID- 15173603
TI  - Differential plague-transmission dynamics determine Yersinia pestis population
      genetic structure on local, regional, and global scales.
AB  - Plague, the disease caused by the bacterium Yersinia pestis, has greatly impacted
      human civilization. Y. pestis is a successful global pathogen, with active foci
      on all continents except Australia and Antarctica. Because the Y. pestis genome
      is highly monomorphic, previous attempts to characterize the population genetic
      structure within a single focus have been largely unsuccessful. Here we report
      that highly mutable marker loci allow determination of Y. pestis population
      genetic structure and tracking of transmission patterns at two spatial scales
      within a single focus. In addition, we found that in vitro mutation rates for
      these loci are similar to those observed in vivo, which allowed us to develop a
      mutation-rate-based model to examine transmission mechanisms. Our model suggests
      there are two primary components of plague ecology: a rapid expansion phase for
      population growth and dispersal followed by a slower persistence phase. This
      pattern seems consistent across local, regional, and even global scales.

PMID- 15173602
TI  - The systemic lupus erythematosus Tri-nation Study: absence of a link between
      health resource use and health outcome.
AB  - OBJECTIVE: Health consumption and health status in SLE in three countries with
      different health funding structures were compared. METHODS: Seven hundred and
      fifteen SLE patients (Canada 231, USA 269, UK 215) were surveyed semi-annually
      over 4 yr for health resource utilization and health status. Cross-country
      comparisons of (i) cumulative health expenditure (calculated by applying 2002
      Canadian prices to resources in all countries) and (ii) disease damage (Systemic
      Lupus International Collaborating Clinics/American College of Rheumatology Damage
      Index, SLICC/ACR DI) at study conclusion were performed after adjustment. Missing
      expenditure and damage data were managed through multiple imputation using best
      predictive regressions with all available data from all patients as potential
      covariates. RESULTS: Four hundred and eighty-five patients provided data at study
      entry and conclusion and at least four resource questionnaires (Canada 162, USA
      157, UK 166); 41 died (Canada 13, USA 18, UK 10); 189 withdrew, were lost to
      follow-up or provided data at entry and conclusion but fewer than four resource
      questionnaires (Canada 56, USA 94, UK 39). At conclusion, after imputation, in
      Canada, the USA and the UK respectively, mean cumulative costs per patient over 4
      yr [95% confidence interval (CI)] were $15,845 (13,509, 18,182), $20,244 (17,764,
      22,724) and $17,647 (15,557, 19,737) and mean changes in SLICC/ACR DI were 0.49
      (0.39, 0.60), 0.63 (0.52, 0.74) and 0.48 (0.39, 0.57). After adjustment for
      baseline differences, on average (95% CI), Canadian and British patients utilized
      20% (8%, 32%) and 13% (1%, 24%) less resources than patients in the USA
      respectively, but experienced similar health outcomes. CONCLUSION: Despite
      patients in the USA incurring higher health expenditures, they did not experience
      superior health outcomes.

PMID- 15173605
TI  - Making protein immunoprecipitates.
AB  - A wide variety of methods used in the study of signal transduction in eukaryotes
      rely on the ability to precipitate proteins from whole cell extracts.
      Immunoprecipitation and related methods of affinity purification are routinely
      used to assess binding partner interactions and enzyme activity in addition to
      the size of a protein, rates of protein synthesis and turnover, and protein
      abundance, thus making it a mainstay of a wide variety of protocols. This chapter
      will provide starting-point methods for immunoprecipitation of proteins under
      denaturing and nondenaturing conditions and the detection of protein-protein
      interactions by co-precipitation. The Notes section gives recommendations on how
      to troubleshoot potential problems that can arise while doing these
      methodologies.

PMID- 15173604
TI  - Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced
      antiproliferative and antiinflammatory properties.
AB  - Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, namely statins,
      exert pleiotropic actions beyond lipid-lowering effects. Their pharmacological
      activity on atherosclerotic plaque stability and vascular inflammation appears to
      be mediated, at least in part, by nitric oxide (NO). With the aim of enhancing
      the nonlipid-lowering properties of selected statins, we introduced a NO
      releasing moiety into the structure of pravastatin (NCX 6550) and fluvastatin
      (NCX 6553). NO release was evaluated as nitrosylhemoglobin adduct formation by
      using EPR spectroscopy in rat blood. Both compounds produced a linear time
      dependent increase in nitrosylhemoglobin formation, which is consistent with slow
      NO release kinetics. In PC12 cells, unlike their native statins, both compounds
      stimulated cGMP formation (NCX 6550, EC(50) = 2.3 +/- 0.2 microM; NCX 6553,
      EC(50) = 2.7 +/- 0.2 microM). Moreover, NCX 6550 potently inhibited cell
      proliferation in rat aortic smooth muscle cells (IC(50) = 2.2 +/- 0.3 microM)
      with a mechanism that involved both the polyamine and HMG-CoA reductase signaling
      pathways. Hence, mevalonate or putrescine partially reverted the effects of NCX
      6550 and their combination was fully effective. In RAW 264.7 murine macrophage
      cells stimulated with lipopolysaccharide (1 microg/ml), NCX 6550, but not
      pravastatin, significantly decreased inducible NO synthase and cyclooxygenase-2
      protein expression as well as nitrite accumulation. All together, the data show
      that the previously undescribed NO-releasing statins retain HMG-CoA reductase
      inhibitory activity and release bioactive NO slowly. Among the additional
      properties, compared with native statins, the NO-releasing statins show enhanced
      antiinflammatory effects. Thus, NO-releasing statins represent an interesting
      class of drugs having potential in the therapy of disorders associated with
      endothelial dysfunction and vascular inflammation.

PMID- 15173606
TI  - Signal transduction inhibitors in cellular function.
AB  - Signal transduction pathways mediate cell-cell interactions and integrate signals
      from the extracellular environment through specific receptors at the cell
      membrane. They play a pivotal role in regulating cellular growth and
      differentiation and in mediating many physiological and pathological processes,
      such as apoptosis, inflammation, and tumor development. The mitogen- activated
      protein kinases (MAPKs) constitute a cascade of phosphorylation events that
      transmit extracellular growth signals through membrane-bound Ras to the nucleus
      of the cell. In this chapter, detailed protocols for analyzing the kinase
      activities of the key components of the MAPKs pathway MEK1, ERK1, JNK, and p38
      MAPK are described. A brief introduction to the chemical inhibitors to the MAPKs
      pathway is provided in the method section of each kinase assay. Inhibitors of
      other signaling pathways are summarized in Table 1. The reporter assay of cyclin
      D1, a key downstream target gene of MAPKs pathway, is also described in detail.

PMID- 15173607
TI  - Two-dimensional gel electrophoresis for the identification of signaling targets.
AB  - Two-dimensional electrophoresis (2-DE) is a powerful technique to differentially
      display patterns of protein expression and posttranslational modifications,
      providing a good strategy to monitor molecular responses induced by the
      activation or inactivation of specific signaling pathways. In this chapter,
      optimized protocols for 2-DE using extracts from tissue culture are provided.
      Protocols for in-gel digestion of gel-resolved proteins, which allow protein
      identification by mass spectrometry are also discussed.

PMID- 15173608
TI  - A high-throughput mammalian cell-based transient transfection assay.
AB  - In eukaryotic organisms gene expression is regulated through a variety of
      upstream transacting factors (transcription factors) whose primary function
      appears to be the targeting of coregulatory protein complexes, which interact
      with basal transcription machinery to define the relative rate of transcription
      for a specific gene. Understanding the regulatory forces mediating transcription
      factor activity has been the focus of both academic and industrial research
      efforts over the past 15 yr, and in this time frame a variety of methodologies
      have been developed for reconstituting and assaying transcription factor
      activities in mammalian cell environments. Presented here is a high-throughput
      version of one of these methodologies that can be readily adapted to the
      screening of a variety of transcription factors. This technology utilizes co
      transfection of mammalian expression and luciferase reporter plasmids to
      reconstitute transcription events in a mammalian host cell. Included is a
      detailed protocol for the use of a 96-well plate format, along with a variety of
      cost-effective measures that can be implemented to facilitate the use of the
      technology in the average low budget academic laboratory.

PMID- 15173609
TI  - Determining protein half-lives.
AB  - Controlling the stability of cellular proteins is a fundamental way by which
      cells regulate growth, differentiation, survival, and development. Measuring the
      turnover rate of a protein is often the first step in assessing whether or not
      the function of a protein is regulated by proteolysis under specific
      physiological conditions. Over the years, procedures to determine the half-life
      of proteins in cultured eukaryotic cells have been well-established. This chapter
      describes in detail the two most frequently used methods, pulse-chase analysis
      and cycloheximide blocking, to determine a protein's half-life in yeast and
      cultured mammalian cells.

PMID- 15173611
TI  - Comparative phosphorylation site mapping from gel-derived proteins using a
      multidimensional ES/MS-based approach.
AB  - Understanding how phosphorylation regulates the behavior of individual proteins
      is critical to understanding signaling pathways. These studies usually involve
      knowledge of which amino acid residues are phosphorylated on a given protein and
      the extent of such a modification. This is often a rather difficult task in that
      most phosphoproteins contain multiple substoichiometric sites of phosphorylation.
      Here we describe the multidimensional electrospray (ES) mass spectrometry (MS)
      based phosphopeptide-mapping strategy developed in our laboratory. In the first
      dimension of the process, phosphopeptides present in a protein digest are
      selectively detected and collected into fractions during on-line liquid
      chromatography (LC)/ES/MS, which monitors for phosphopeptide-specific marker
      ions. This analysis generates a phosphorylation profile that can be used to
      assess changes in the phosphorylation state of a protein pointing to those
      phosphopeptides that require further investigation. The phosphopeptide-containing
      fractions are then analyzed in the second dimension by nano-ES with precursor-ion
      scan for the marker ion m/z 79. As the final step, direct sequencing of the
      phosphopeptides is performed by LC/ES/MS/MS. Merits and limitations of the
      strategy, as well as experimental details and suggestions, are described here.

PMID- 15173610
TI  - Assaying protein kinase activity.
AB  - Protein kinases, encoded by approx 2% of eukaryotic genes, represent one of the
      major classes of cell-regulatory molecules. Assessment of the catalytic activity
      of a specific protein kinase can be an important step in elucidating signal
      transduction pathways that affect cell behavior. As an example of approaches
      taken to measure protein kinase activity, this chapter presents methods useful
      for determination of the activity of the oncogenic protein-tyrosine kinase v-Src.
      Included are protocols for heterologous expression of the kinase in yeast
      Saccharomyces cerevisiae, immunoaffinity purification from yeast cell lysates,
      kinase reactions using incorporation of 32P into peptide substrates, and
      quantifying protein kinase activity. The Notes section discusses alternative
      approaches for assaying the activity of Src recovered from vertebrate cells and
      it gives recommendations for assaying the activity of the other protein kinases
      with respect to the substrate specifity and the composition of kinase reaction
      buffer.

PMID- 15173612
TI  - Studies of calmodulin-dependent regulation.
AB  - Methods are presented for purifying bovine testes calmodulin and the calmodulin
      regulated plasma-membrane calcium ATPase from human erythrocytes by calcium
      dependent affinity chromatography. The assay of CaM Kinase II using a synthetic
      peptide substrate is also described.

PMID- 15173613
TI  - Measurement of protein-DNA interactions in vivo by chromatin immunoprecipitation.
AB  - Elucidating mechanisms controlling nuclear processes requires an understanding of
      the nucleoprotein structure of genes at endogenous chromosomal loci. Traditional
      approaches to measuring protein-DNA interactions in vitro have often failed to
      provide insights into physiological mechanisms. Given that most transcription
      factors interact with simple DNA sequence motifs, which are abundantly
      distributed throughout a genome, it is essential to pinpoint the small subset of
      sites bound by factors in vivo. Signaling mechanisms induce the assembly and
      modulation of complex patterns of histone acetylation, methylation,
      phosphorylation, and ubiquitination, which are crucial determinants of chromatin
      accessibility. These seemingly complex issues can be directly addressed by a
      powerful methodology termed the chromatin immunoprecipitation (ChIP) assay. ChIP
      analysis involves covalently trapping endogenous proteins at chromatin sites,
      thereby yielding snapshots of protein-DNA interactions and histone modifications
      within living cells. The chromatin is sonicated to generate small fragments, and
      an immunoprecipitation is conducted with an antibody against the desired factor
      or histone modification. Crosslinks are reversed, and polymerase chain reaction
      (PCR) is used to assess whether DNA sequences are recovered immune-specifically.
      Chromatin-domain scanning coupled with quantitative analysis is a powerful means
      of dissecting mechanisms by which signaling pathways target genes within a
      complex genome.

PMID- 15173614
TI  - Characterization of protein-DNA association in vivo by chromatin
      immunoprecipitation.
AB  - Chromatin immunoprecipitation (ChIP) is one of the most powerful methods to
      identify and characterize the association of proteins with specific genomic
      regions in the context of intact cells. In this method, cells are first treated
      with formaldehyde to crosslink protein-protein and protein-DNA complexes in situ.
      Next, the crosslinked chromatin is sheared by sonication to generate small
      chromatin fragments, and the fragments associated with the protein of interest
      are immunoprecipitated using antibodies to the protein. Finally, protein-DNA
      crosslinks are reversed and the DNA is examined for the presence of particular
      sequences by quantitative polymerase chain reaction (PCR). Enrichment of specific
      sequences in the precipitate indicates that the sequences are associated with the
      protein of interest in vivo. The ChIP method described here is intended for
      studying protein-DNA association in the budding yeast Saccharomyces cerevisiae,
      but it can be easily implemented in other cell types, including fly, mammalian,
      and plant cells.

PMID- 15173615
TI  - Nonradioactive methods for detecting activation of Ras-related small G proteins.
AB  - Ras-related small GTPases serve as critical regulators for a wide range of
      cellular signaling pathways and are activated by the conversion of the GDP-bound
      state to the GTP-bound conformation. Until recently, measurement of the GTP-bound
      active form of Ras-related G proteins involved immunoprecipitation of 32P-labeled
      protein followed by separation of the labeled GTP/GDP bound to GTPase. A new
      method based on the large affinity difference of the GTP- and GDP-bound form of
      Ras proteins for specific binding domains of effector proteins in vitro has been
      developed. By using glutathione S-transferase (GST) fusion proteins containing
      these binding domains, the GTP-bound form of the GTPase can be precipitated from
      cell lysates. In principle, this method can be used for all members of the Ras
      superfamily. Here we describe a general procedure to monitor the GTP-bound form
      of Ras-related GTPases.

PMID- 15173616
TI  - Nucleocytoplasmic glycosylation, O-GlcNAc: identification and site mapping.
AB  - beta-O-linked N-acetylglucosamine (O-GlcNAc) is posttranslationally added to
      serine and threonine residues of many nuclear and cytoplasmic proteins found in
      metazoans. This modification is dynamic and responsive to numerous stimuli and
      conditions, suggesting an important role in many regulatory pathways. Moreover,
      the O-GlcNAc modification seems to compete with phosphorylation for sites of
      attachment, indicating a reciprocal relationship with phosphorylation. This
      chapter includes protocols for: (1) identifying the O-GlcNAc modification on
      proteins through immunoblotting, lectin affinity chromatography, and
      galactosyltransferase labeling; and (2) identifying and enriching for the sites
      of attachment using the mass spectrometry-based beta-elimination followed by
      Michael addition with dithiothreitol (BEMAD) technique.

PMID- 15173618
TI  - Assaying lipid phosphate phosphatase activities.
AB  - Lipid phosphate molecules such as phosphatidate, lysophosphatidate, and
      diacylglycerol pyro phosphate play roles as signaling molecules in prokaryotic
      and eukaryotic cells. The cellular processes by which lipid phosphate molecules
      signal may be attenuated through the action of lipid phosphate phosphatase
      enzymes. The levels of lipid phosphate phosphatase activities may be used as a
      marker of signaling events in the cell. In this chapter we describe enzymatic
      assays that are routinely used to measure the activities of phosphatidate
      phosphatase, lysophosphatidate phosphatase, and diacylglycerol pyrophosphate
      phosphatase. These activities are measured by following the release of water
      soluble radioactive inorganic phosphate from chloroform-soluble radioactive lipid
      phosphate substrate following a simple chloroform/methanol/ water phase
      partition.

PMID- 15173617
TI  - Techniques in protein methylation.
AB  - Proteins can be methylated on the side-chain nitrogens of arginine and lysine
      residues or on carboxy-termini. Protein methylation is a way of subtly changing
      the primary sequence of a peptide so that it can encode more information. This
      common posttranslational modification is implicated in the regulation of a
      variety of processes including protein trafficking, transcription and protein
      protein interactions. In this chapter, we will use the arginine
      methyltransferases to illustrate different approaches that have been developed to
      assess protein methylation. Both in vivo and in vitro methylation techniques are
      described, and the use of small molecule inhibitors of protein methylation will
      be demonstrated.

PMID- 15173619
TI  - Assaying phosphoinositide phosphatases.
AB  - The roles of phosphoinositide second messengers as signaling molecules in a vast
      array of cellular processes including cell growth, metabolism, vesicular
      transport, programmed cell death, and responses to extracellular signals are only
      beginning to be understood. The recent identification of novel phosphoinositide
      signaling molecules underscores the need for methodology with which to
      characterize the enzymes responsible for regulating cellular phosphoinositide
      levels. One of the ways in which cells control these lipids is through
      dephosphorylation by phosphoinositide phosphatases, which oppose and regulate the
      actions of phosphoinositide kinases. We describe herein two rapid and simple
      assays for characterizing phosphoinositide phosphatases that can be used to
      provide a basis for understanding the activity and specificity of these enzymes.

PMID- 15173620
TI  - Assaying phospholipase A2 activity.
AB  - Mammalian cells contain many structurally and functionally diverse phospholipases
      A2 (PLA2) that catalyze the hydrolysis of sn-2 fatty acid from membrane
      phospholipid. Assays are described for measuring the activity of Group IVA
      cytosolic PLA2alpha(cPLAalpha) and for secreted PLA2s (sPLA2) that are suitable
      for purified enzymes and for measuring activity in crude cell lysates and culture
      medium. The assay for cPLA2alpha involves measuring the calcium-dependent release
      of radiolabeled sn-2 arachidonic acid from small unilamellar vesicles of
      phosphatidylcholine. Methods are described for distinguishing cPLA2alpha activity
      in cell lysates from other PLA2s. sPLA2 activity is monitored using a
      fluorimetric assay that measures the continuous calcium-dependent formation of
      albumin-bound pyrene fatty acid from the sn-2 position of phosphatidylglycerol.

PMID- 15173621
TI  - Measurement and immunofluorescence of cellular phosphoinositides.
AB  - Phosphoinositides are a vitally important class of intracellular-signaling
      molecules that regulate cellular processes, including signaling through cell
      surface receptors, remodeling of the cytoskeleton, vesicle-mediated protein
      trafficking, and various nuclear functions. Methods for the analysis of in vivo
      phosphoinositide concentration, such as the one described in this chapter enable
      quantification of all phosphoinositides from a population of cells. This method
      involves metabolic labeling of cells with myo<-[2-3H] inositol, followed by lipid
      extraction, and quantification by high-performance liquid chromatography (HPLC).
      It provides improved efficiency and reproducibility when analyzing yeast, plant
      cells, and is applicable to animal cells as well. In addition, a technique for
      determining the intracellular location of phosphoinositides is described. When
      quantification and localization techniques are used in parallel, an investigator
      can identify cell, and even subcellular concentration changes. The technique
      described in this chapter uses immunodetection with antiphosphoinositide
      antibodies to determine the localization and relative concentrations of
      phosphinositides in fixed cells. The availability of antibodies allows an
      investigator to perform immunofluorescence and potentially immunoelectron
      microscopy of phosphoinositide localization on particular cellular, organellar,
      or vesicular membranes.

PMID- 15173622
TI  - Measuring dynamic changes in cAMP using fluorescence resonance energy transfer.
AB  - cAMP is a ubiquitous second messenger that controls numerous cellular events
      including movement, growth, metabolism, contraction, and synaptic plasticity.
      With the emerging concept of compartmentalization of cAMP-dependent signaling, a
      detailed study of the spatio-temporal intracellular dynamics of cAMP is required.
      Here we describe a new methodology for monitoring fluctuations of cAMP in living
      cells, based on the use of a genetically encoded biosensor. The regulatory and
      catalytic subunits of the main cAMP effector, the protein kinase A (PKA), fused
      with two suitable green fluorescent protein (GFP) mutants is used for measuring
      changes in fluorescence resonance energy transfer (FRET) that correlate with
      changes in intracellular cAMP levels. This method allows the study of cAMP
      fluctuations in living cells with high resolution both in time and in space.

PMID- 15173623
TI  - In vivo detection of protein-protein interaction in plant cells using BRET.
AB  - The emerging technique of bioluminescence resonance energy transfer (BRET) allows
      us to detect protein interactions in live cells and in real time, thus providing
      a new window into cellular signal transduction processes. We present experimental
      protocols for expressing fusion proteins between luciferase and fluorescent
      proteins that are the basis for BRET measurement, as well as for measuring and
      imaging BRET in a variety of cell types. Despite our focus on plant cells, the
      techniques described here are easily adaptable to other cell systems that have
      yet to benefit from the BRET technique.

PMID- 15173625
TI  - Assaying cytochrome C translocation during apoptosis.
AB  - Translocation of proteins from the mitochondrial intermembrane space to the
      cytoplasm is a critical event during apoptosis. There are several methods for
      assaying this event cited in the literature. In this chapter, we highlight
      separation of cytosolic and mitochondrial fractions of cultured cells using
      digitonin as the method for measuring cytochrome c release that, in our hands has
      been the simplest and most reproducible.

PMID- 15173624
TI  - Revealing protein dynamics by photobleaching techniques.
AB  - Green fluorescent proteins (GFPs) are widely used tools to visualize proteins and
      study their intracellular distribution. One feature of working with GFP variants,
      photobleaching, has recently been combined with an older technique known as
      fluorescence recovery after photobleaching (FRAP) to study protein kinetics in
      vivo. During photobleaching, fluorochromes get destroyed irreversibly by repeated
      excitation with an intensive light source. When the photobleaching is applied to
      a restricted area or structure, recovery of fluorescence will be the result of
      active or passive diffusion from fluorescent molecules from unbleached
      surrounding areas. Fluorescence loss in photobleaching (FLIP) is a variant of
      FRAP where an area is bleached, and loss of fluorescence in surrounding areas is
      observed. FLIP can be used to study the dynamics of different pools of a protein
      or can show how a protein diffuses, or is transported through a cell or cellular
      structure. Here, we discuss these photobleaching fluorescent imaging techniques,
      illustrated with examples of these techniques applied to proteins of the
      Saccharomyces cerevisiae pheromone response MAPK pathway.

PMID- 15173626
TI  - Morphological changes in woody stem of Prunus jamasakura under simulated
      microgravity.
AB  - When the four-week-old woody stem of Prunus jamasakura was grown under simulated
      microgravity condition on a three-dimensional clinostat, it bent at growth, and
      width of its secondary xylem decreased due to the reduction of fiber cell numbers
      and a smaller microfibril angle in the secondary cell wall, as reported in our
      previous paper. Gravity induces the development of the secondary xylem that
      supports the stem upward against the action of gravity. In this study,
      morphological changes of the tissues and cells were microscopically observed.
      Disorder was found in the concentric structure of tissues that organize the stem.
      The radial arrangement of the cells was also disturbed in the secondary xylem,
      and in the secondary phloem secondary cell walls of the bast fiber cells were
      undeveloped. These findings suggest that differentiation and development of the
      secondary xylem and the bast fiber cells are strongly controlled by terrestrial
      gravity. These tissue and cells functions to support the stem under the action of
      gravity. Furthermore, clinorotation induced disorder in the straight joint of
      vessel elements and the lattice-like structure of radial parenchyma cells, which
      is responsible for water transportation and storage, respectively. Gravity is an
      essential factor for keeping the division and differentiation normal in woody
      stem.

PMID- 15173627
TI  - Nitrate toxicity on visceral organs of Medaka fish, Oryzias latipes: aiming to
      raise fish from egg to egg in space.
AB  - Histological survey was made to determine nitrate toxicity on the Medaka fish,
      Oryzias latipes. In order to investigate the effects of short-term exposure to
      nitrate, one-month-old Medaka fish was exposed to NaNO3 at concentrations of 100
      and 125 mg NO3-N l-1 for 96 hours. At the end of the exposure period, survival
      rate was found to be 30% and 10%, for the 100 and 125 mg NO3-N l-1 exposure
      concentrations, respectively. Histological examination of the organs showed that
      disruption of cell alignment was a common feature in the gills, intestinal
      ampulla, liver and kidney. A long-term exposure experiment was also carried out,
      whereby Medaka fish was exposed to NaNO3 (100 and 125 mg NO3-N l-1) for three
      months from its egg stage. Eggs treated with NaNO3 hatched within 10 days after
      fertilization. At the end of the exposure period, survival rate in the 100 and
      125 mg NO3-N l-1 treatments were 40% and 30%, respectively. Fibrosis of the
      hepatic cells and curved spinal column were observed in the juveniles subjected
      to long-term nitrate exposure. The results of our experiments suggest that the
      high mortality resulting from short-term acute exposure to nitrate is caused by
      general dysfunction throughout the whole body. The chronic toxic effects
      attributed to nitrate, following long-term exposure, were likely to have resulted
      from nutrient deficiency caused by hepatic dysfunction.

PMID- 15173628
TI  - [Biology of size and gravity].
AB  - Gravity is a force that acts on mass. Biological effects of gravity and their
      magnitude depend on scale of mass and difference in density. One significant
      contribution of space biology is confirmation of direct action of gravity even at
      the cellular level. Since cell is the elementary unit of life, existence of
      primary effects of gravity on cells leads to establish the firm basis of
      gravitational biology. However, gravity is not limited to produce its biological
      effects on molecules and their reaction networks that compose living cells.
      Biological system has hierarchical structure with layers of organism, group, and
      ecological system, which emerge from the system one layer down. Influence of
      gravity is higher at larger mass. In addition to this, actions of gravity in each
      layer are caused by process and mechanism that is subjected and different in each
      layer of the hierarchy. Because of this feature, summing up gravitational action
      on cells does not explain gravity for biological system at upper layers. Gravity
      at ecological system or organismal level can not reduced to cellular mechanism.
      Size of cells and organisms is one of fundamental characters of them and a
      determinant in their design of form and function. Size closely relates to other
      physical quantities, such as mass, volume, and surface area. Gravity produces
      weight of mass. Organisms are required to equip components to support weight and
      to resist against force that arise at movement of body or a part of it. Volume
      and surface area associate with mass and heat transport process at body. Gravity
      dominates those processes by inducing natural convection around organisms. This
      review covers various elements and process, with which gravity make influence on
      living systems, chosen on the basis of biology of size. Cells and biochemical
      networks are under the control of organism to integrate a consolidated form. How
      cells adjust metabolic rate to meet to the size of the composed organism, whether
      is gravity responsible for this feature, are subject we discuss in this article.
      Three major topics in gravitational and space biology are; how living systems
      have been adapted to terrestrial gravity and evolved, how living systems respond
      to exotic gravitational environment, and whether living systems could respond and
      adapt to microgravity. Biology of size can contribute to find a way to answer
      these question, and answer why gravity is important in biology, at explaining why
      gravity has been a dominant factor through the evolutional history on the earth.

PMID- 15173629
TI  - The organization of the corticonuclear and olivocerebellar climbing fiber
      projections to the rat cerebellar vermis: the congruence of projection zones and
      the zebrin pattern.
AB  - The zonal organization of the corticonuclear and the olivocerebellar climbing
      fiber projections to the vermis of the cerebellum of the rat was compared to the
      pattern of zebrin-positive and zebrin-negative bands in material double-stained
      for zebrin II and for different anterograde tracers injected in subnuclei of the
      inferior olive, or retrograde tracers injected in the cerebellar and vestibular
      target nuclei of the Purkinje cells of the vermis. Projection zones A(1), A(X),
      X, B, C(X) in the vermis and A(2) (accessory A zone) and C(2) in the hemisphere
      were defined by their efferent corticonuclear and their afferent climbing fiber
      connections, and were found to share the same topographical framework with the
      zebrin pattern.

PMID- 15173630
TI  - Holoprosencephaly--topologic variations in a liveborn series: a general model
      based upon MRI analysis.
AB  - We present an MRI-based anatomic analysis of a series of 9 human brains,
      representing lobar, semilobar and alobar forms of holoprosencephaly. The analysis
      of these variable forms of the malformation is based upon a topologic systematics
      established in a prior analysis of a homogeneous set of semilobar malformations.
      This systematics has the dual advantage that it serves both as a uniform
      reference for qualitative description and as a quantitative descriptive base for
      mathematical correlations between parameters of topology and of growth and
      development. Within this systematics, the prosencephalic midline is divided from
      caudal to rostral into diencephalic (DD-right and left, subthalamus through
      suprachiasmatic junction with telencephalon), telencephalic (TT-right and left,
      suprachiasmatic border of telencephalon midline to hippocampal commissure) and
      diencephalic-telencephalic (DT-right and left-hippocampal commissure through
      temporal limb of choroid fissure) segments. The topologic abnormality of the
      initial semilobar series was expressed in an orderly rostral to caudal gradient
      along the TT segment. In each malformation, normal midline topology began with a
      small posterior corpus callosum. Although the topologic anomaly in the present
      series invariably also involved the TT segment, this involvement was not
      continuous and was variably associated with anomalies of the DD in 6 and
      unilaterally of the DT in 1 brain. In the present as well as with the earlier
      series of HPE malformations but not in "normative brains," total telencephalic
      growth is strongly correlated with the length of the midline telencephalic
      segment. We propose that this system of analysis will be sensitive to the
      developmental stage and locus of expression of genetic and non-genetic
      determinants of the formal origin of HPE. For all of the present series,
      karyotype anlyses were normal. Mutations in the Shh and Zic2 genes were excluded
      in 2 cases.

PMID- 15173631
TI  - Ultrastructural analysis of hippocampal pyramidal neurons from apolipoprotein E
      deficient mice treated with a cathepsin inhibitor.
AB  - Cultured hippocampal slices prepared from apolipoprotein E (apoE)-deficient mice
      were exposed to an inhibitor of cathepsins B and L and then processed for an
      ultrastructural analysis of neuronal features for pyramidal cell bodies. Electron
      microscopy showed that the nuclei of pyramidal cells from treated hippocampal
      slices were more eccentrically located than those from untreated slices. In
      addition, increased numbers of vesicles were associated with the Golgi complex
      while microtubules were less frequent in the proximal dendrites. Consistent with
      previous studies in rats, treated apoE-deficient slices had increased numbers of
      lysosomes and multivesicular bodies. Finally, there were reductions in the number
      of synapses around the cell body, a finding similar to that found in the brains
      from Alzheimer's disease patients. These results provide ultrastructural data
      indicating that partial lysosomal dysfunction in apoE-deficient brains rapidly
      induces characteristic features of the aged human brain.

PMID- 15173632
TI  - Harmaline-induced climbing fiber activation causes amino acid and peptide release
      in the rodent cerebellar cortex and a unique temporal pattern of Fos expression
      in the olivo-cerebellar pathway.
AB  - Cerebellar climbing fibers have a unique relationship with the dendritic tree of
      cerebellar Purkinje cells and have been proposed as a key input in establishing
      long-term plastic changes in the cerebellar cortex. Although both glutamate and
      aspartate and a number of neuropeptides have been implicated as climbing fiber
      released neurotransmitters/neuromodulators, the in vivo release of these
      substances during climbing fiber stimulation remains to be demonstrated. In the
      present study, climbing fibers were activated with harmaline and rats or mice
      were implanted with a microdialysis probe or a microperfusion probe,
      respectively, to measure amino acid or peptide release. Additional rats were
      euthanized at various timepoints post-harmaline injection and Fos
      immunocytochemistry was used to visualize the activation pattern of the inferior
      olive, cerebellar cortex and deep nuclei over time. Fos expression was first
      detected in the inferior olive at 15 min post-harmaline injection followed by
      expression in the deep cerebellar nuclei (30 min) and then in the cerebellar
      cortex (1 h). Between 2 and 6 h Purkinje cells expressing Fos were found in
      variable numbers in both the vermal and paravermal regions and there was a
      distinct parasagittal-banding pattern in the vermal region. Of several amino
      acids measured following harmaline administration only glutamate and aspartate
      levels increased significantly in the first dialysate sample compared to
      preharmaline levels and their release was blocked by prior lesion of the inferior
      olive. Citrulline also increased following climbing fiber stimulation, but this
      occurred in the second and third dialysate samples and may reflect nitric oxide
      production. Four peptides were examined in cerebellar microperfusates following
      climbing fiber stimulation. Only corticotropin releasing factor (CRF), calcitonin
      gene related peptide (CGRP) and bradykinin were significantly increased compared
      to pre-harmaline levels. These results suggest that glutamate, aspartate, CRF and
      CGRP are released from climbing fibers during activation of the olivocerebellar
      system.

PMID- 15173633
TI  - The contribution of the principal and spinal trigeminal nuclei to the receptive
      field properties of thalamic VPM neurons in the rat.
AB  - Primary sensory information from neurons innervating whisker follicles on one
      side of a rat's face is relayed primarily through two subnuclei of the brainstem
      trigeminal complex to the contralateral thalamus. The present experiments were
      undertaken to separate the contribution of the principal trigeminal nucleus (PrV)
      from that of the spinal trigeminal nucleus (SpV) to whisker evoked responses in
      the ventral posterior medial (VPM) nucleus in the adult rat thalamus.
      Extracellular single-unit responses of VPM neurons to controlled stimulation of
      the contralateral whiskers under urethane anesthesia were quantified in terms of
      receptive field size, modal latency, response probability and response magnitude.
      The SpV contribution to VPM cell responses was isolated by making kainic acid
      lesions of the PrV. The PrV contribution was ascertained by cutting the
      trigeminothalamic axons arising from SpV just before they cross the midline.
      After destruction of the PrV, the SpV pathway alone produced large receptive
      fields (mean: 9.04 whiskers) and long latency (mean: 11.07 ms) responses from VPM
      neurons. In contrast, PrV input alone (SpV disconnected) generated small
      receptive fields (mean: 1.06 whiskers) and shorter latency (mean: 6.74 ms)
      responses. With both pathways intact the average receptive field size was 2.4
      whiskers and peak (modal) response latency was 7.33 ms. The responses with both
      pathways intact were significantly different from either pathway operating in
      isolation. Response probability and magnitude followed the same trend. We
      conclude that normal responses of individual VPM neurons represent the
      integration of input activity transmitted through both PrV and SpV pathways.

PMID- 15173634
TI  - Localization and developmental expression of GABA(B) receptors in the rat
      olfactory bulb.
AB  - In this study, we investigated the distribution and developmental expression of
      the GABA(B) receptor subunits, GABA(B1) and GABA(B2), in the main and accessory
      olfactory bulbs of the rat. Antibodies raised against these subunits strongly
      labelled the glomerular layer, suggesting that olfactory and vomeronasal nerve
      fibers express functional GABA(B) receptors. Using postembedding immunogold
      cytochemistry, we found that GABA(B) receptors can be present at both
      extrasynaptic and presynaptic sites of olfactory nerve terminals, and in the
      latter case they are preferentially associated with the peripheral part of the
      synaptic specialization. Olfactory nerve fibers expressed GABA(B1) and GABA(B2)
      at early developmental stages, suggesting that GABA(B) receptors may play a role
      in olfactory development. Output and local neurons of the main and accessory
      olfactory bulbs were also labelled for GABA(B1) and GABA(B2), although the
      subcellular distribution patterns of the two subunits were not completely
      overlapping. These results indicate that presynaptically located GABA(B)
      receptors modulate neurotransmitter release from olfactory and vomeronasal nerve
      fibers and that, in addition to this presynaptic role, GABA(B) receptors may
      regulate neuronal excitability in infraglomerular circuits.

PMID- 15173635
TI  - The thalamic paraventricular nucleus relays information from the suprachiasmatic
      nucleus to the amygdala: a combined anterograde and retrograde tracing study in
      the rat at the light and electron microscopic levels.
AB  - The relationship between efferents of the hypothalamic suprachiasmatic nucleus
      (SCN) and neurons of the thalamic paraventricular nucleus (PVT) projecting to the
      amygdala was investigated in the rat using tract tracing in light and electron
      microscopy. Biotinylated dextran amine was used to label anterogradely SCN
      efferents. These fibers were found to reach the thalamic midline, terminating in
      PVT, through three pathways: anterodorsally through the preoptic region, dorsally
      through the periventricular hypothalamus, and through the contralateral medial
      hypothalamic and preoptic areas after crossing the midline in the optic chiasm.
      Preterminal and terminal-like elements labeled from the SCN were distributed
      throughout the rostrocaudal extent of PVT, with an anteroposterior gradient of
      density. Labeled terminal elements were densest in the dorsal portion of PVT
      beneath the ependymal lining and some of them entered the ependyma. Anterograde
      tracing of SCN fibers was combined with injections of retrograde tracers in the
      amygdala. Numerous retrogradely labeled cell bodies were seen throughout PVT,
      with a prevalence in its anterodorsal portion. Overlap was detected between
      puncta labeled from the SCN and retrogradely labeled neurons, especially in the
      anterodorsal sector of PVT, where numerous puncta were in close apposition to
      thalamo-amygdaloid cells. Electron microscopy revealed that boutons labeled from
      the SCN established synaptic contacts with dendritic profiles of PVT neurons
      labeled from the amygdala. The findings demonstrate that information processed in
      the biological clock is conveyed to the amygdala through PVT, indicating that
      this nucleus plays a role in the transfer of circadian timing information to the
      limbic system.

PMID- 15173636
TI  - Abnormal HNK-1 expression in the cerebellum of an N-CAM null mouse.
AB  - Human natural killer antigen-1 (HNK-1) is a carbohydrate epitope associated with
      sulfoglucuronylglycolipids and glycoproteins. Biochemical analyses have
      demonstrated associations between the HNK-1 epitope and isoforms of the neural
      cell adhesion molecule (N-CAM) family. In the cerebellum, HNK-1 is prominently
      expressed in Purkinje cell dendrites and Golgi cells. Purkinje cell expression of
      HNK-1 reveals an array of parasagittal stripes and transverse zones.
      Interestingly, the parasagittal expression pattern of HNK-1 is different from
      those reported with several other markers such as zebrin II/aldolase C and the
      small heat shock protein HSP25. N-CAM null knockout mice were used to explore the
      possible role of the HNK-1/N-CAM interaction during the topographical
      organization of the cerebellar cortex. N-CAM null mice have no N-CAM
      immunoreactivity but otherwise the cerebellum appears morphologically normal.
      Further, in the N-CAM null HNK-1 immunoreactivity is abolished from Purkinje cell
      dendrites but is retained on Golgi cells and neurons of the cerebellar nuclei.
      Despite the absence of N-CAM/HNK-1, parasagittal stripes and transverse zones in
      the cerebellum as revealed by using zebrin II immunocytochemistry appear normal.

PMID- 15173638
TI  - Radial glia-like cells at the base of the lateral ventricles in adult mice.
AB  - During development radial glia (RG) are neurogenic, provide a substrate for
      migration, and transform into astrocytes. Cells in the RG lineage are
      functionally and biochemically heterogeneous in subregions of the brain. In the
      subventricular zone (SVZ) of the adult, astrocyte-like cells exhibit stem cell
      properties. During examination of the response of SVZ astrocytes to brain injury
      in adult mice, we serendipitously found a population of cells in the walls of the
      ventral lateral ventricle (LV) that were morphologically similar to RG. The cells
      expressed vimentin, glial fibrillary acidic protein (GFAP), intermediate filament
      proteins expressed by neural progenitor cells, RG and astrocytes. These RG-like
      cells had long processes extending ventrally into the nucleus accumbens,
      ventromedial striatum, ventrolateral septum, and the bed nucleus of the stria
      terminalis. The RG-like cell processes were associated with a high density of
      doublecortin-positive cells. Lesioning the cerebral cortex did not change the
      expression of vimentin and GFAP in RG-like cells, nor did it alter their
      morphology. To study the ontogeny of these cells, we examined the expression of
      molecules associated with RG during development: vimentin, astrocyte-specific
      glutamate transporter (GLAST), and brain lipid-binding protein (BLBP). As
      expected, vimentin was expressed in RG in the ventral LV embryonically (E16, E19)
      and during the first postnatal week (P0, P7). At P14, P21, P28 as well as in the
      adult (8-12 weeks), the ventral portion of the LV retained vimentin
      immunopositive RG-like cells, whereas RG largely disappeared in the dorsal two
      thirds of the LV. GLAST and BLBP were expressed in RG of the ventral LV
      embryonically and through P7. In contrast to vimentin, at later stages BLBP and
      GLAST were found in RG-like cell somata but not in their processes. Our results
      show that cells expressing vimentin and GFAP (in the radial glia-astrocyte
      lineage) are heterogeneous dorsoventrally in the walls of the LV. The results
      suggest that not all RG in the ventral LV complete the transformation into
      astrocytes and that the ventral SVZ may be functionally dissimilar from the rest
      of the SVZ.

PMID- 15173637
TI  - High-resolution proteomic mapping in the vertebrate central nervous system: close
      proximity of connexin35 to NMDA glutamate receptor clusters and co-localization
      of connexin36 with immunoreactivity for zonula occludens protein-1 (ZO-1).
AB  - Combined confocal microscopy and freeze-fracture replica immunogold labeling
      (FRIL) were used to examine the connexin identity at electrical synapses in
      goldfish brain and rat retina, and to test for "co-localization" vs. "close
      proximity" of connexins to other functionally interacting proteins in synapses of
      goldfish and mouse brain and rat retina. In goldfish brain, confocal microscopy
      revealed immunofluorescence for connexin35 (Cx35) and NMDA-R1 (NR1) glutamate
      receptor protein in Mauthner Cell/Club Ending synapses. By FRIL double labeling,
      NR1 glutamate receptors were found in clusters of intramembrane particles in the
      postsynaptic membrane extraplasmic leaflets, and these distinctive postsynaptic
      densities were in close proximity (0.1-0.3 microm) to neuronal gap junctions
      labeled for Cx35, which is the fish ortholog of connexin36 (Cx36) found at
      neuronal gap junctions in mammals. Immunogold labeling for Cx36 in adult rat
      retina revealed abundant gap junctions, including several previously unrecognized
      morphological types. As in goldfish hindbrain, immunogold double labeling
      revealed NR1-containing postsynaptic densities localized near Cx36-labeled gap
      junction in rat inferior olive. Confocal immunofluorescence microscopy revealed
      widespread co-localization of Cx36 and ZO-1, particularly in the reticular
      thalamic nucleus and amygdala of mouse brain. By FRIL, ZO-1 immunoreactivity was
      co-localized with Cx36 at individual gap junction plaques in rat retinal neurons.
      As cytoplasmic accessory proteins, ZO-1 and possibly related members of the
      membrane-associated guanylate kinase (MAGUK) family represent scaffolding
      proteins that may bind to and regulate the activity of many neuronal gap
      junctions. These data document the power of combining immunofluorescence confocal
      microscopy with FRIL ultrastructural imaging and immunogold labeling to determine
      the relative proximities of proteins that are involved in short- vs. intermediate
      range molecular interactions in the complex membrane appositions at synapses
      between neurons.

PMID- 15173639
TI  - [Retinopathy of prematurity. Results of fundus examination performed in 94
      preterm infants].
AB  - PURPOSE: The purpose of this study was to evaluate the incidence and severity of
      retinopathy of prematurity (ROP) in infants of birth weight less than 1.500 g
      and/or under 32 weeks'gestation. METHODS: Ninety-four preterm infants were
      examined following the Royal College of Ophthalmologists guidelines and
      retinopathy was graded using the International Classification of ROP. Screening
      limits were 1 500 g birth weight or 32 weeks'gestational age. Fundus examinations
      for ROP were performed at 5 weeks'chronological age from birth. Pupil dilation
      was obtained with instillation of 1% tropicamide three times at 15-minute
      intervals. RESULTS: The 94 infants examined for ROP had a median gestational age
      of 292.3 weeks and a median birth weight of 1 110340 g. ROP was diagnosed in 21
      of 94 subjects (22.3%) by fundus examination. ROP stage 3 developed in one
      preterm infant, ROP stage 2 developed in five preterm infants, and ROP stage 1
      developed in 15 preterm infants. No premature babies developed stage 4 or stage 5
      ROP. The disease regressed spontaneously in all cases and none of the infants
      required cryo/laser therapy. In the most premature infants, 23-26
      weeks'gestation, 57% developed ROP and one developed severe ROP (stage 3). No
      disease more posterior to peripheral zone 2 was observed. The incidence of ROP
      was higher in infants exposed to greater than 21% oxygen (24.2%) than in infants
      who did not receive oxygen (17.8%). Oxygen, blood transfusion, and cardiopathy
      appear to be associated with an increased incidence of retinopathy of
      prematurity. CONCLUSIONS: ROP continues to be a common problem associated with
      prematurity in France. This study found a similar incidence of prethreshold ROP
      when compared to recent studies. The data showed that blood transfusion and
      cardiopathy may play a role in the development of ROP in premature infants.

PMID- 15173640
TI  - [Treating severe dry eye syndromes with autologous serum].
AB  - BACKGROUND: Dry eye syndrome with tear deficiency can be improved with artificial
      tears, which can be associated with topical anti-inflammatory agents. Autologous
      serum can provide the ocular surface with beneficial growth factors and vitamins.
      PATIENTS AND METHODS: Twenty-one patients suffering from severe dry eye due to
      Sjogren's syndrome were treated with 20% autologous serum for 2 Months. The
      Schirmer I test, break-up time, and fluorescein and lissamine green stainings
      were performed before and after treatment. Subjective complaints such as burning,
      foreign body sensation, dryness and photophobia were assessed by a questionnaire
      as well as a face score reflecting the current condition of patients' eyes.
      RESULTS: Lissamine green and fluorescein scores improved significantly as well as
      subjective symptoms of burning, foreign body sensation and dryness (p<0.05). The
      face score was significantly improved. Bacterial culture of serum delivered to
      the patients all remained negative. DISCUSSION: Autologous serum provides growth
      factors and vitamins that are useful for an altered ocular surface due to
      Sjogren's disease. However, some problems still remain: risk of contamination,
      arbitrary dilution of autologous serum, and a current lack of regulations for use
      of autologous serum. A close collaboration between ophthalmologists and the
      Etablissement Francais du Sang (French Blood Bank) is mandatory because
      autologous serum should be considered as a useful tool to treat severe ocular
      surface disorders. CONCLUSION: The use of autologous serum improved symptoms and
      objective signs caused by severe Sjogren's syndrome. Currently, a lack of clear
      regulations prevents its widespread use in severe ocular surface disorders.

PMID- 15173641
TI  - [Contusive retinal detachment: a retrospective review of 48 patients].
AB  - PURPOSE: Analysis of the epidemiological, clinical and therapeutic
      characteristics of retinal detachment after ocular blunt trauma. MATERIAL AND
      METHODS: We retrospectively reviewed 48 patients with isolated retinal detachment
      after ocular blunt trauma, studying their epidemiological characteristics (age,
      sex and trauma circumstances), their clinic details and the surgical techniques
      used. RESULTS: The average age of our patients was 39.3 Years; most were male
      (75%). Assault and home accidents were the most common cause of ocular trauma
      (83.2%). Total retinal detachment was noted in 47.9%. Of the retinal breaks
      found, dialysis at the ora serrata was observed in 22%, atrophic holes in 33.9%,
      retinal breaks in 40.6% and giant tears in 4.2%. Most of the breaks were situated
      at the lower temporal quadrant. Forty one out of the 48 patients were operated
      on, with surgical treatment consisting in episcleral surgery in 38 cases and
      vitreoretinal surgery in three cases. Complete anatomical success was achieved in
      92.7%. CONCLUSION: This survey shows that the prognosis of retinal detachment
      after ocular blunt trauma remains favorable given the young age and the absence
      of advanced vitreoretinal proliferation, but this should not affect the
      importance of prevention.

PMID- 15173642
TI  - [Botulinum toxin in infantile estropia: long-term results].
AB  - PURPOSE: To evaluate long term results of botulinum toxin in infantile esotropia.
      METHODS: Nineteen infants between 6 and 13 Months of age were treated with
      botulinum toxin injected into the medial recti. The amount of deviation, the
      different symptoms of infantile esotropia, and the need for surgery were studied.
      RESULTS: Esotropia reappears frequently with time. Dissociated vertical deviation
      and manifest/latent nystagmus are only partially improved. Surgery is usually
      mandatory over the long term. CONCLUSION: Despite some good results, a single
      botulinum toxin injection is less effective than incisional surgery in treating
      the different symptoms of infantile esotropia.

PMID- 15173643
TI  - [Analysis of 925 patients on long-term hydroxychloroquine or chloroquine
      treatment: results of ophthalmological screening].
AB  - PURPOSE: The aim of this 4-Year study was to analyze the population referred to
      our laboratory for the visual follow-up of hydroxychloroquine or chloroquine
      treatment. MATERIAL AND METHODS: We received 925 patients: 78% female, 22% male.
      For each patient, a 13-item criteria was filled out and regular exams were
      performed. The pathologies were divided in to 4 groups: rheumatoid polyarthritis
      (P), lupus (L), sarcoidosis (S), others (O). RESULTS: The pathologies were
      distributed as follows: 48% "P", 29% "L", 3% "S", 1% "P + L", 19% "O". Of these
      patients, 19% had less than 1 Year of treatment, 73% 1-10 Years and 8% more than
      10 Years. The screening exposed no retinal intoxications but 3% presented pre
      clinical intoxication (PCI) and 80% were allowed to continue their treatment. The
      most important statistical results were: 1) a significant relation between the
      PCI and the duration of the treatment (p<0.001); 2) a non-significant relation
      between the PCI and the daily dose (p=0.417); and 3) a significant relation
      between PCI and the cumulative dose (p=0.003). CONCLUSION: The results shows the
      advantage of the ERG in screening to prevent anti-malarial retinal toxicity. This
      study confirms that the cumulative dose seems to be more important than the daily
      dose, but we agree with the international consensus to respect a daily dose under
      6.5 mg/kg/d. The results also demonstrated that, with this large and diversified
      population, there is a need for prospective and multi-centric studies. With the
      above results, international standards should be established in order to obtain
      the most efficient screening for each category of patient.

PMID- 15173644
TI  - [Syphilitic chorioretinitis in the immunocompromised patient: a case report].
AB  - Syphilitic chorioretinitis is a rare manifestation of secondary syphilis. The
      Authors report a case of a patient tested positive for human immune deficiency
      virus. A 26-Year-old man presented with a history of suddenly blurred vision in
      the right eye. Because of a central scotoma, visual acuity was reduced to
      counting fingers. Slit-lamp examination found one-plus anterior chamber cells and
      one-plus vitreous cells. Results of ophthalmoscopic examination showed a large
      yellow lesion in the macular area with a papillar edema and peripheral
      vasculitis. Serum and cerebrospinal fluid were positive for syphilitic serology.
      Visual acuity improved to 20/20 after three courses of intravenous ceftriaxone
      (2g/day for 15 days). The fundus lesion resolved almost completely, resulting in
      slight pigmentary changes in the macular area. This case report highlights the
      need for syphilitic serology in cases of uveitis in immunocompromised patients.

PMID- 15173645
TI  - [Intrastromal epithelial cysts of the iris: two case studies].
AB  - AIM: Intrastromal epithelial cysts, congenital or acquired, are rare tumors of
      the anterior chamber. We report two cases, one in a 4-Month-old girl and one in a
      14-Year-old teenage girl. MATERIAL AND METHODS: In the infant case, a large cyst
      with a superior base obstructed the visual axis. The child had already developed
      amblyopia and intermittent esotropia, with normal ocular pressure. Aspiration of
      the cyst with complete excision was done without iridectomy. Two Years later, a
      secondary corectopia required an inferior iridectomy. Finally, 4 Years later,
      endophthalmitis developed on a corneal stitch, and the eye was enucleated. In the
      second case, the teenage girl had noticed a modification in her iris due to an
      inferior temporal iris cyst. The cyst was excised with a peripheral iridectomy.
      Despite a first complete excision, a recurrence the following Year was treated by
      Yag laser. One Year later, the clinical aspect was stable. COMMENTS AND
      CONCLUSION: These benign tumors present the problem of local extension and
      recurrence. Surgical treatment with iridectomy is often proposed despite eventual
      aesthetic or functional consequences. Yag laser may be a therapeutic alternative.
      The two operations reported here did not prevent recurrence. In conclusion,
      intrastromal epithelial cysts of the iris are rare and benign tumors that may
      induce local complications and lead to recurrence. Many treatments can be
      discussed for each case.

PMID- 15173646
TI  - [Post-traumatic endocapsular blood effusion].
AB  - A rare complication after extracapsular surgery of the cataract, blood effusion
      is often a fortuitous discovery when a drop in visual acuity occurs. The subject
      reported herein is a 76-Year-old patient who presented an endocapsular blood
      effusion with no liquid level 1 Year after the extracapsular surgery of the
      cataract, discovered while examining a decrease in visual acuity. Questioning led
      to the discovery of eye trauma due to Nd: YAG laser posterior capsulotomy 3
      Months before, which had progressed spontaneously and favorably for 2 Months,
      with a reduction of the effusion and better visual acuity. The bleeding seems to
      have come from a vascular injury due to a direct contusion, with blood possibly
      coming from the ciliary body, the iridocorneal angle, or the vitreous. The liquid
      effusion may have been caught at the back by the implant and enclosed in the area
      located between the capsular bag and the anterior hyaloid, without intravitreous
      diffusion. Most of reported cases in the literature discuss observations made on
      an intact posterior capsule, which appeared during or after close surgery. The
      treatment was simple supervision. Some Authors propose a Nd: YAG laser
      capsulotomy in case resorption is too slow.

PMID- 15173647
TI  - [Bilateral congenital aniridia: 5 case reports].
AB  - INTRODUCTION: Aniridia is a rare familial or sporadic disorder affecting not only
      the iris but also the cornea, angle structures, lens, optic nerve, and fovea.
      This disorder may be associated with many other systemic abnormalities such as
      urogenital malignancies. CASE REPORTS: A 44-Year-old man who complained of visual
      loss presented bilateral congenital aniridia with corneal dystrophy and dense
      cataract. His 12-Year-old daughter also presented visual loss with severe
      bilateral corneal dystrophy and total congenital cataract associated with
      aniridia. Two other daughters, 18 and 23 Years of age, and an 11-Year-old son had
      nystagmus with bilateral congenital cataract and ectopia lentis. Clinical and
      radiological investigations did not disclose evidence of extraocular
      abnormalities in this family. Three patients underwent cataract extraction
      without intraocular implantation and the aphakia was corrected with glasses. All
      three patients progressed well. DISCUSSION: This family provided a good
      illustration of the different clinical spectra of ocular involvement in
      congenital aniridia and its management difficulties, above all those of cataract
      surgery and correction of aphakia. CONCLUSION: Aniridia is a genetic disease with
      possible association with other ocular and systemic disorders, which may
      compromise visual and vital prognosis. Genetic advice is very important in such
      families.

PMID- 15173648
TI  - [Abducens nerve palsy in spontaneous intracranial hypotension].
AB  - Described by Schaltenbrand (1940), spontaneous intracranial hypotension is an
      unusual syndrome, sometimes revealed by an abducens nerve palsy motivating the
      patient to consult emergency ophthalmology services. The Authors report the case
      of a 50-Year-old Turkish woman who presented with diplopia due to a left abducens
      nerve palsy. These symptoms were associated with headache and nausea. Brain
      magnetic resonance imaging demonstrated diffuse pachymeningeal enhancement with
      gadolinium. A lumbar puncture showed low spinal fluid pressure (6 cm H2O),
      leading to the diagnosis of palsy by spontaneous intracranial hypotension. First,
      a classic treatment was prescribed with no result: increased water intake,
      corticoid therapy, and rest. Then a blood patch consisting of an injection of
      autologous blood by lumbar puncture between the third and fourth lumbar vertebrae
      to plug the spontaneous leak of spinal fluid, with success. A review of the
      literature provides information on the physiopathological mechanism, the clinical
      and imaging symptoms, and the treatment.

PMID- 15173649
TI  - [Hyphema with secondary hemorrhage: think about sickle cell disease].
AB  - The Authors report a case of a 13-Year-old white child who presented a grade I
      hyphema, anterior chamber inflammation after trauma. He presented a secondary
      hemorrhage with increased intraocular pressure that was not controlled within 48
      h, thus requiring surgical intervention. A hemoglobin electrophoresis and
      hemostasis test showed a sickle cell trait. After hemorrhage resorption, the
      ocular fundus showed substantial retinal hemorrhage. The final visual outcome was
      poor and attributed to optic atrophy. Sickle cell trait is a significant risk
      factor for secondary hemorrhage, increased intraocular pressure, and permanent
      visual impairement in children who have traumatic hyphemas following blunt
      trauma.

PMID- 15173650
TI  - [Fungal keratitis in a daily disposable soft contact lens wearer].
AB  - A case of fungal keratitis was diagnosed in a young female who had been wearing
      daily disposable soft contact lenses for 2 Years. No risk factor was demonstrated
      and specific treatment was effective. This case emphasizes that patients must be
      aware of the importance of hygiene as daily disposable contact lenses must be
      discarded daily.

PMID- 15173651
TI  - [Repeated pulse corticosteroid therapy in Vogt-Koyanagi-Harada disease. A case
      report].
AB  - Vogt-Koyanagi-Harada disease is an autoimmune bilateral uveitis that occurs in
      people with genetic sensitivity. Diagnosis was based on the association of ocular
      inflammatory manifestations such as diffuse choroiditis, with or without anterior
      uveitis, and extraocular manifestations such as meningismus, tegumentary or
      auditory findings. Intravenous pulses of corticosteroid followed by oral
      corticosteroid is the mainstay therapy. We present the case of a woman who showed
      a first improvement of symptoms with three consecutive daily pulses of
      corticosteroid, but none during the following oral therapy. A second phase of
      intravenous pulses of corticosteroid, a Month after the first one, induced great
      improvement in symptoms and retinal findings, whereas oral therapy seemed not to
      be effective. This case provides the opportunity for a discussion on the
      advantages of multiple pulses of corticosteroid at the acute phase of this
      disease, because of its vascular effects associated with anti-inflammatory
      effects.

PMID- 15173652
TI  - [Fourth-generation fluoroquinolone antibiotics: improving antibacterial
      prophylaxis and treatment].

PMID- 15173654
TI  - [Unconventional transmissible agents].
AB  - Ophthalmologists must take into account the possible emergence of unconventional
      transmissible agents in their daily practice. Official recommendations have been
      circulated; however, their routine application remains difficult, with technical
      and financial considerations limiting factors in the use of an ideal of one
      disposable medical device per patient. This review describes how these
      recommendations are followed and tries to provide insights into improving daily
      practice with these unconventional transmissible agents.

PMID- 15173655
TI  - [Transmission of conventional agents during outpatient care].
AB  - Outpatient care bring together in a single location a large number of patients
      potentially bearing conventional infectious agents (virus, bacteria, fungi,
      parasites). This report details the germs potentially involved. We emphasize
      adenovirus epidemic keratoconjunctivitis, which is particularly prevalent in
      ophthalmology outpatient care. We analyze the modes of contamination and the
      means to prevent iatrogenic infections.

PMID- 15173656
TI  - [Rules and regulations concerning contact lens-related infection].
AB  - Contact lens-related infectious keratitis is a potentially sight-threatening
      complication. Bacterial keratitis, mostly due to Gram-negative bacteria, is
      associated with poor lens hygiene, overnight wear, and contaminated lens care
      solutions. Contamination of the lens storage case may cause fungal keratitis.
      Acanthamoeba infection is related to the use of tap water or swimming while
      wearing soft lenses. Viruses are of less concern among contact lens wearers.
      Possible transmission of Creutzfeldt-Jakob disease by multi-patient trial lenses
      must be taken in account. To minimize these risk factors, regulations are applied
      at various levels: CE marking of contact lenses and care products as they are
      medical devices; contact lens fitting only by health care professionals;
      distribution of contact lenses by opticians and lens care solutions by opticians
      and pharmacists; hygienic management of trial lenses following official
      recommendations. Contact lens-related keratitis must be reported to health care
      Authorities.

PMID- 15173657
TI  - [Hygiene in ophthalmological care quality: in the operating room].
AB  - Ocular surgery has become more and more refined over the last century. However,
      infections occurring after surgical procedures are very often devastating and
      sight-threatening. This review provides a number of details on the environment of
      ocular surgery, mainly, the patient, staff, medical devices used and the
      operating room. Proper understanding of basic hygiene rules is mandatory on the
      part of all individuals involved in eye care and particularly in ocular surgery
      in order to decrease the ocular morbidity due to postoperative ocular infections.

PMID- 15173659
TI  - [Ultrabiomicroscopy and anterior segment masses].

PMID- 15173660
TI  - [Merkel cell carcinoma].
AB  - Merkel cell carcinoma is a neuroendocrine tumor of the skin, originating from
      neuroendocrine cells. A case report of Merkel cell carcinoma, discovered in a 77
      Year-old woman, was diagnosed and confirmed on a biopsy. Diagnostic and
      therapeutic orientations of this unusual but malignant tumor are described.

PMID- 15173661
TI  - Expression of vascular endothelial growth factor-A and vascular endothelial
      growth factor-C as prognostic factors for non-small cell lung cancer.
AB  - BACKGROUND: Understanding and controlling angiogenesis and lymphangiogenesis
      could lead to effective strategies for cancer treatment. The aim of our study was
      to clarify the clinical value of vascular endothelial growth factor-A (VEGF-A)
      and VEGF-C in non-small cell lung cancer (NSCLC). MATERIAL/METHODS: One hundred
      and fifty-three patients with NSCLCs were studied to investigate intratumoral
      expression of VEGF-A and VEGF-C by immunohistochemistry. Simultaneously, we
      evaluated tumor angiogenesis using CD34 immunostaining. RESULTS: Seventy-eight
      carcinomas (51.0%) were VEGF-A-positive, and 64 carcinomas (41.8%) were VEGF-C
      positive. There was no correlationship between VEGF-A expression and VEGF-C
      expression in NSCLCs. The frequency of hypervascular tumors was significantly
      higher in VEGF-A-positive NSCLCs than in VEGF-A-negative NSCLCs (p=0.0442), while
      there was no correlation between intratumoral VEGF-C expression status and tumor
      vascularity. Concerning survival of NSCLC patients, intratumoral expression of
      VEGF-A was one of the significant prognostic factors in NSCLC patients (relative
      risk=2.012, p=0.0101), especially in patients with adenocarcinomas (relative
      risk=3.816, p=0.0025). On the other hand, intratumoral expression VEGF-C was one
      of the significant prognostic factors in patients with squamous cell carcinomas
      (relative risk=3.946, p=0.0143). CONCLUSIONS: The present study demonstrated that
      intratumoral VEGF-A expression is one of the significant prognostic factors in
      patients with adenocarcinomas, and that intratumoral VEGF-C expression is one of
      the significant prognostic factors in patients with squamous cell carcinomas.
      These different functions of the VEGF family in relation to tumor histology might
      reflect the clinical behaviors of NSCLCs.

PMID- 15173662
TI  - Protective effects of green tea catechins on cerebral ischemic damage.
AB  - BACKGROUND: Green tea catechins possess potent antioxidative properties, and the
      preventive effects against various oxidative diseases have been reported. The
      purpose of this study is to examine preventive and protective effects of green
      tea catechins on various deteriorative processes following stroke.
      MATERIAL/METHODS: Male Wistar rats were given ad libitum water with or without
      0.25 and 0.5% tea catechin extract for 5 days prior to the operation and during
      the experiment. Right middle cerebral artery was occluded for 2 h, then
      reperfused for 22 h. Brain slices were stained with triphenyltetrazolim chloride
      to assess infarct area. Concentrations of plasma EGCg, and serum NOx were
      analyzed by HPLC. Detection of iNOS expression, neutrophil infiltration and
      peroxynitrite formation in the penumbra was performed by immunostain. Neurologic
      deficit was scored by posture reflex. RESULTS: Tea catechins dose-dependently
      reduced the brain infarct area and volume. Infarct volume was inversely
      correlated with plasma EGCg concentration. Dark staining for iNOS, neutrophils
      and peroxynitrite were observed in vessel wall of small arteries in control
      ischemic hemisphere, while in catechins (0.5%)-treated rats iNOS was detected
      slightly, and staining for neutrophils and peroxynitrite was not seen. Catechin
      ingestion blocked a 3-fold increase in serum NOx concentration in the jugular
      vein, and also reduced by 35% a 2-fold increase of plasma lipid peroxide level
      seen in control rats after reperfusion. Neurologic deficits were significantly
      alleviated by 0.5% catechin ingestion. CONCLUSIONS: Daily intake of green tea
      catechins efficiently protects the penumbra from irreversible damage due to
      cerebral ischemia, and consequent neurologic deficits.

PMID- 15173663
TI  - Acetylsalicylic acid-dependent inhibition of collagen biosynthesis and beta1
      integrin signaling in cultured fibroblasts.
AB  - BACKGROUND: Non-steroid anti-inflammatory drugs (NSAIDs) are known inhibitors of
      collagen biosynthesis in animal tissues and cell cultures. The mechanism of their
      action on collagen biosynthesis involves inactivation of prolidase, the enzyme
      that recovers proline from collagen degradation products for collagen re
      synthesis. In fibroblasts, prolidase activity is stimulated through a signal
      induced by an activated b1-integrin receptor that contributes to an increase in
      enzyme phosphorylation. To discover whether this is an underlying mechanism of
      acetylsalicylic acid-dependent inhibition of collagen biosynthesis in fibroblasts
      was the aim of this study. MATERIAL/METHODS: Control and acetylsalicylic acid
      treated confluent human skin fibroblasts were compared with respect to collagen
      biosynthesis ([3H]proline incorporation assay), prolidase activity (colorimetric
      assay) and the expressions of prolidase and some signaling proteins (Western
      immunoblot analysis). RESULTS: In cells treated with acetylsalicylic acid, a
      concomitant decrease in prolidase activity, prolidase phosphorylation (at the
      threonine residue), and collagen biosynthesis were observed. This was accompanied
      by a decrease in the expressions of SOS and phosphorylated MAP kinases, ERK1 and
      ERK2, but not FAK or Grab2. This suggests that a decrease in prolidase activity
      may contribute to a decrease in the biosynthesis of proline-containing proteins,
      such as collagen and SOS. A decrease in collagen biosynthesis decreases the
      interaction of the protein with the b1-integrin receptor (extracellular process),
      disturbing signaling (intracellular process). CONCLUSIONS: The inhibitory effect
      of acetylsalicylic acid on collagen biosynthesis in fibroblasts is coupled to the
      inhibition of prolidase phosphorylation (but not expression) and down-regulation
      of the intracellular signal transmitted by the b1-integrin receptor.

PMID- 15173664
TI  - PER-1 type beta-lactamase production in Acinetobacter baumannii is related to
      cell adhesion.
AB  - BACKGROUND: Recently, the dissemination of ESBL (PER-1) among Acinetobacter
      isolates was reported in Turkish hospitals. We investigated the presence and the
      association of various virulence determinants in 20 Acinetobacter baumannii
      isolates, of which 13 were blaPER-1 positive. MATERIAL/METHODS: Virulence tests
      were slime and hemolysin production, gelatinase and protease activity, biofilm
      formation, and Caco2 cell adhesion. RAPD analysis was also performed with ERIC
      primers. RESULTS: None of the strains was positive for slime or hemolysin
      production and gelatinase or protease activity. A total of 16 strains, five of
      which were PER-1 gene negative, formed a biofilm on polymer surfaces. There was
      no relation between the presence of the PER gene and biofilm formation. On the
      other hand, nine strains (all PER-1 gene positive) were positive in adhesion
      experiments to Caco2 cell lines. All PER-negative strains were negative for cell
      adhesion. CONCLUSIONS: This study indicates the existence of a relation between
      PER-1 gene and cell adhesion in Acinetobacter strains.

PMID- 15173665
TI  - Susceptibility of Desulfovibrio desulfuricans intestinal strains to sulfasalazine
      and its biotransformation products.
AB  - BACKGROUND: Desulfovibrio desulfuricans intestinal bacteria may contribute to
      toxic hydrogen sulfide production in the human gut. Our objective was to examine
      whether the D. desulfuricans strains isolated from the human body are susceptible
      to sulfasalazine (SAS) and the products of its biotransformation, i.e. 5
      aminosalicylic acid (5-ASA) and sulfapyridine (SP), in order to determine the
      relationship between the strains' susceptibility to SAS and their ability to
      reduce the azo bond within this drug. MATERIAL/METHODS: Six wild strains of D.
      desulfuricans (isolated from feces and biopsy specimens from patients with
      colitis ulcerosa, Crohn's disease, irritable bowel syndrome, colonic diverticula,
      primary biliary cirrhosis, or tubular adenomas of the colon) were cultured in the
      presence of SAS, 5-ASA, and SP. Growth inhibition coefficients were compared with
      coefficients of inhibition of the azo-bond reduction in SAS. RESULTS: The D.
      desulfuricans strains present in the human digestive tract were susceptible to a
      small degree to SAS and to 5-ASA and SP. CONCLUSIONS: The intestinal D.
      desulfuricans strains differed in their susceptibility to SAS and its
      biotransformation products. The strains showing higher susceptibility to SAS lost
      the ability to reduce the azo bond in this drug, which may be attributed to the
      lower metabolic activity of the bacteria. The presence of D. desulfuricans in the
      large intestines of patients with ulcerative colitis and the confirmed diversity
      of the biological activity of the isolated strains demonstrate the need for
      clinical examination of the role of these bacteria in the development of some
      inflammatory disorders.

PMID- 15173666
TI  - Loss of heterozygosity on chromosome arm 13q in larynx cancer patients: analysis
      of tumor, margin and clinically unchanged mucosa.
AB  - BACKGROUND: Loss of heterozygosity, frequently observed during the development of
      many tumor types, also occurs in larynx cancer. This disease has a very complex
      genetic background, with numerous alterations involving oncogenes and tumor
      suppressor genes. The upper parts of the respiratory-digestive tract are exposed
      to many carcinogens, which can result in the appearance of multiple tumors or
      primary tumor relapses. The examination of normal-appearing tissues makes it
      possible to recognize genetic events occurring at early stages. MATERIAL/METHODS:
      65 larynx cancer patients were examined for loss of heterozygosity (LOH) on the
      13q chromosomal arm, with the application of three microsatellite markers. The
      material from each patient consisted of blood, tumor, safe margin, and 1-2
      clinically unchanged mucosal samples. RESULTS: High frequencies of LOH in tumor
      tissues (49-64%) were observed in both studied chromosomal regions (13q14 and
      13q34). The frequency of LOH in safe margin ranged from 12 to 31%. In normal
      appearing mucosa, LOH was observed less frequently: 6-26% of informative cases.
      CONCLUSIONS: The data obtained from this investigation suggest that losses in the
      region of the 13q arm occur frequently during larynx cancer development.
      Moreover, they were observed not only in tumor tissues, but also in clinically
      unchanged mucosa. This could be a highly reliable predictor of the occurrence of
      relapse or second primary tumor in this anatomical site.

PMID- 15173667
TI  - Morphometric characteristics of cell nuclei of the precancerous lesions and
      laryngeal cancer.
AB  - BACKGROUND: The purpose of this study was to characterize normal epithelium,
      precancerous lesions and laryngeal squamous cell carcinoma (SCC) with the use of
      nuclear morphometry. The relationship between the morphometric parameters of the
      cell nuclei and the pathological lesions was analyzed. In addition, a
      morphometric comparison was performed among normal epithelium, precancerous
      lesions, and cancer of the larynx. MATERIAL/METHODS: Our research involved 12
      patients after total laryngectomy. All the postoperative histological specimens
      consisted of laryngeal SCC, precancerous lesions (dysplasia), keratosis with mild
      dysplasia, and normal epithelium. The cell nuclei of the SCC, dysplasia,
      keratosis, and the basal and superficial layers of the normal epithelium were
      measured. The nuclear parameters included area, equivalent diameter, length,
      breadth, perimeter, mean and integrated grey levels, convex area and convex
      perimeter, roundness, aspect ratio and fullness ratio. For each case, 500 nuclei
      were studied using a Polyvar Reicher microscope connected to a Quantimet 500
      computer system. RESULTS: The relationship between karyometrical parameters and
      pathological lesions was found to be statistically significant. We observed the
      largest nuclei in keratosis lesions and the smallest in basal layers of normal
      epithelium. In some cases there were no significant differences between dysplasia
      nuclei and the superficial layers of normal epithelium. CONCLUSIONS:
      Karyometrical parameters correlate with morphometrical lesions in the larynx and
      may be useful in the prediction of laryngeal neoplasm.

PMID- 15173668
TI  - An application of a genetic algorithm in conjunction with other data mining
      methods for estimating outcome after hospitalization in cancer patients.
AB  - BACKGROUND: We investigated which factors predicted the risk of in-hospital
      mortality in a general population of cancer patients with non-terminal disease
      and whether employing the genetic algorithm technique would be useful in this
      regard. MATERIAL/METHODS: A total of 201 cancer patients, including all cases of
      in-hospital mortality over a 2-year period, as well as a control group of
      subjects discharged during the same period, all having an Eastern Cooperative
      Oncology Group (ECOG) performance status of of < or =3 at the time of admission,
      were retrospectively evaluated. Indicators of in-hospital mortality were
      determined by multivariate logistic regression, recursive partitioning analysis,
      neural network, and genetic algorithm (GA) techniques. The performance of the
      different techniques were compared by a number of measures, including receiver
      operating curve (ROC) analysis. RESULTS: All four analysis methods selected a
      combination of six explanatory variables to explain the risk of in-hospital
      mortality: lactate dehydrogenase (LDH), alanine transaminase (ALT), hemoglobin
      (Hb), white blood cell counts (Wbc), type of cancer, and reason for admission.
      Compared with the other 3 methods, GA selected the least number of explanatory
      variables, i.e. LDH and reason for admission, with similar fraction of cases
      explained (78.6%), and yielded a fitness score of 0.52. CONCLUSIONS: LDH is an
      important indicator of in-hospital mortality for hospitalized cancer patients not
      in terminal stage. GA reliably predicted in-hospital mortality and was shown to
      be as efficient as the other data mining techniques employed in this study. Its
      use in a clinical setting for prognostication in oncology appears promising.

PMID- 15173669
TI  - Assessment of heat tolerance for post exertional heat stroke individuals.
AB  - BACKGROUND: The aim of this study was to evaluate the heat tolerance test, which
      was performed by individuals with high risk for heat injuries, for exposure
      duration and climatic conditions. MATERIAL/METHODS: Nineteen young (19+/-1 yr)
      post heat stroke males performed 2 separate tolerance tests consisting of
      identical treadmill walking (5km.h-1, 2% grade) for 120 min during hot (40
      degrees C, 40%RH) and comfort (20 degrees C, 50%RH) climate conditions.
      Physiological monitoring included rectal temperature (Tre), heart rate (HR), skin
      temperature and sweat rate (msw). Concomitantly, strain evaluation was assessed
      by the physiological strain index (PSI) and the cumulative heat strain index
      (CHSI). RESULTS: 14 subjects were categorized as heat tolerant (HT) and 5
      subjects as heat intolerant (HI). The comfort tolerance test was found as
      irrelevant for heat intolerance assessment. PSI after 60 min (PSI60) was unable
      to predict PSI after 120 min (PSI120) whereas there was not a high enough
      correlation between CHSI60 and CHSI120. CONCLUSIONS: It was concluded that
      tolerance to heat must be tested during heat stress and the test duration cannot
      be shorter than 120 min.

PMID- 15173670
TI  - Facilitating internal cardioversion of chronic atrial fibrillation with ibutilide
      -predictors of atrial defibrillation-threshold decrease.
AB  - BACKGROUND: Internal atrial cardioversion has been successfully used in the
      treatment of atrial fibrillation. The object of this study was to depict the
      effect of ibutilide on sinus rhythm restoration and internal atrial
      defibrillation threshold in patients with chronic atrial fibrillation.
      MATERIAL/METHODS: Twenty-four patients (14 men and 10 women, mean age 63.16+/
      8.55 years) with chronic atrial fibrillation were cardioverted using a single
      lead system. The distal coil of the defibrillator catheter was placed in the
      coronary sinus and the proximal coil at the junction of the superior vena cava
      and the high right atrium. Synchronized biphasic shocks were applied using a step
      up protocol from 1 to 30 joules until sinus rhythm was restored. In all patients
      with successful cardioversion, atrial fibrillation was reinduced and second
      cardioversion was attempted after intravenous administration of 1 mg ibutilide.
      RESULTS: Successful internal cardioversion was achieved in 22 (91.6%) and 23
      (95.83%) patients before and after ibutilide administration, respectively. The
      amount of energy given was reduced from 13.89+/-11.44 to 8.28+/-9.64 joules
      (p=0.0001). Variables associated with the reduction of the defibrillation
      threshold after ibutilide administration were: duration of the last episode of
      atrial fibrillation (p=0.008), time since the first episode of atrial
      fibrillation (p=0.002), body mass index (p=0.01), ejection fraction (p=0.025),
      male gender (p=0.001), and diameter of the left atrium (p=0.028). CONCLUSIONS:
      Internal atrial defibrillation after ibutilide administration is a safe and
      effective method for sinus rhythm restoration, with concurrent significant
      reduction of the atrial defibrillation threshold.

PMID- 15173671
TI  - Assessment of immunological parameters following a qigong training program.
AB  - BACKGROUND: Qigong is a type of Chinese psychosomatic exercise that integrates
      meditation, slow physical movements, and breathing, and to which numerous
      physical as well as mental benefits have been classically ascribed. The aim of
      the present study was to analyze the effects of a qigong program on various
      immunological parameters. MATERIAL/METHODS: 29 naive subjects participated in the
      study, of whom 16 were allocated to the experimental group and the rest to the
      control group. The experimental subjects underwent a qigong training program,
      conducted by a qualified instructor, consisting of half an hour of daily practice
      for one month. The day before the experiment commenced and the day after it
      finished, blood samples were drawn from all subjects for the quantification of
      immunological parameters (leukocytes, immunoglobulins, and complement). As
      statistical analysis, analysis of covariance (ANCOVA) was carried out. RESULTS:
      Statistically significant differences were found between the control and
      experimental groups, with the experimental group showing lower numbers of total
      leukocytes and eosinophils, number and percentage of monocytes, as well as
      complement C3 concentration. In addition, a similar result with a trend towards
      significance was observed in the number of eosinophils. CONCLUSIONS: These
      findings demonstrate that after one month of practicing qigong, significant
      immunological changes occurred between the experimental and control groups, with
      a consistently lower and broadly significant profile of these measures within the
      qigong practitioner group.

PMID- 15173672
TI  - Is pipelle biopsy really adequate for diagnosing endometrial disease?
AB  - BACKGROUND: The purpose of our research was to determine the reliability and
      accuracy of the Pipelle device in acquiring an adequate and representative
      endometrial sample and to compare it with D&C histology. MATERIAL/METHODS: A
      total of 127 women were prospectively included in the study. After Pipelle
      endometrial sampling, classic dilatation and curettage (D&C) was performed. The
      histological results of both techniques were compared to assess the accuracy of
      Pipelle sampling. Prior to endometrial sampling, transvaginal ultrasonography was
      performed to determine endometrial thickness and pathological lesions, and to
      exclude other pathologies confined to the pelvis. The outcome measures were
      specimen adequacy and comparability of histological diagnosis between the Pipelle
      specimen and the D&C specimen. RESULTS: Although no patient had a failed biopsy
      procedure, 13 patients had insufficient tissue in the D&C group, and 29 patients
      in the Pipelle group. In 100 of 127 patients (79%), the Pipelle endometrial
      histology results were in agreement with the D&C histology results. Pipelle
      biopsy was unable to diagnose 1 of 5 endometrial hyperplasia cases. CONCLUSIONS:
      The Pipelle device is a limited endometrial sampling technique for obtaining an
      adequate and representative endometrial sample. It should be reserved for those
      patients in whom there is only a minimal risk for endometrial carcinoma,
      hyperplasia and polyps. Any failure to obtain an endometrial specimen would
      suggest performing a full endometrial curettage, especially in anamnestically-
      and sonographically-determined patients at high risk for endometrial cancer.

PMID- 15173673
TI  - Myoid hamartoma of the liver--a novel variant of hamartoma developing in the
      hilar region and imitating a malignant liver tumor.
AB  - BACKGROUND: We report here an unusual variant of hepatic mesenchymal hamartoma
      exhibiting a marked myoid differentiation and clinically imitating hilar
      malignancy. CASE REPORT: A 17-year-old patient was admitted to the hospital with
      the suspicion of Klatskin's tumor. Three months before he had presented with
      jaundice and light stools. Imaging techniques demonstrated a solid lesion (3 cm)
      situated in liver segment IV. Biochemical tests detected an increased level of
      bilirubin, alkaline phosphatase, AspAt, ALAT, and slightly increased CA19-9.
      Diagnosed with perihilar malignancy, the patient underwent left-sided
      hemihepatectomy with hepaticojejunostomy. The liver resection specimen showed an
      unencapsulated solid hilar tumor (5x3x3.5 cm), consisting of eosinophilic spindle
      like cells with blunt-ended nuclei. Within the lesion we found numerous biliary
      ductules. Focally, numerous plasma cells and eosinophils were found, but no
      cystic spaces. There was no cellular atypia. Apart from the lesion the liver
      revealed intensified fibrosis of portal areas. Immunohistochemical studies
      demonstrated positivity of most spindle-like cells for SMActin, whereas only a
      few cells were CD34- and desmin-positive. Ki67 was positive in less than 5%
      cells. CONCLUSIONS: Given the indistinct border and heterogeneous morphology,
      with spindle-like myoid cells constituting most of the tissue, interspersed with
      biliary ductules, we suggest that this tumor is an unusual variant of mesenchymal
      hamartoma. As the mesenchymal component in this lesion was mainly represented by
      cells of muscular origin, we suggest classifying this lesion as an previously
      undescribed form of mesenchymal hamartoma, and propose the term, myoid hamartoma
      of the liver.

PMID- 15173674
TI  - Retroperitoneal abscess as a late complication following laparoscopic
      cholecystectomy.
AB  - BACKGROUND: Gallstone spillage during laparoscopic cholecystectomy is a
      relatively common occurrence. These intraperitoneal gallstones are considered to
      be harmless. Rarely, they may give rise to complications. Surgeons should
      retrieve spilled stones whenever possible. CASE REPORT: We report the case of a
      75-year-old man with retroperitoneal abscess that developed 6 years following
      laparoscopic cholecystectomy as a late complication. The cavity, though it
      drained purulent material, was sterile in culture. Gallstones were found in the
      drain effluent. To our knowledge this is the first case report in English of such
      a delayed complication caused by spilled gallstones. CONCLUSIONS: Every effort
      should be made to avoid perforation of the gall bladder during its dissection.
      Whether the procedure should be converted to open surgery to retrieve all the
      stones is subject to debate.

PMID- 15173675
TI  - Endogenous morphine: a role in wellness medicine.
AB  - The demonstration of the multiplicity of opiate receptor types has led to the
      understanding that, depending on their site of action, opioid peptides as well as
      opiate alkaloids may bind to more than one opiate receptor subtype. In addition
      to the two main mu opiate receptor subtypes, mu1 and mu2, our laboratory has
      demonstrated a third mu opiate receptor (mu3) that is selective for opiate
      alkaloids but insensitive to opioid peptides. Recently, the mu3 opiate receptor
      subtype has been cloned from human immune, vascular and neural tissues. This mu3
      story complements many biochemical reports; demonstrating morphine is an
      endogenous signaling molecule, functioning in the capacity of a neurotransmitter
      and hormone. Adding additional evidence to this hypothesis are the findings of
      morphine precursors in mammalian and invertebrate tissues. The reports published
      in this issue of MSM complement this story while advancing the hypothesis by
      placing opiate alkaloid signaling in limbic structures. The pharmacological
      characteristics of exogenous morphine find a role for explaining morphine action
      in an "emotional" and belief setting.

PMID- 15173676
TI  - A gravitational hypothesis of essential hypertension as a natural adaptation to
      increased gravitational stress caused by regular, prolonged sitting typical of
      modern life.
AB  - BACKGROUND: Spaceflight studies have demonstrated that adaptation to increased
      gravitational stress after prolonged microgravity includes sympathetic
      activation, water retention, and arterial pressure increase, i.e. is very similar
      to essential hypertension, which looks like an advanced stage of adaptation to a
      further increase in gravitational stress. MATERIAL/METHODS: Theoretical analysis
      and literature review were performed to develop an hypothesis of essential
      hypertension as adaptation to increased gravitational stress associated with
      prolonged sitting. RESULTS: Gravitation shifts blood downwards, and gravitational
      stress (GS) on the cardiovascular system in an upright position may be defined as
      the amount of work necessary to return the blood upwards and maintain adequate
      upper-body circulation calculated as the product of the gravitational potential
      (Ugr=g*h) and the mass of blood moved: GS =Ugr*Mshift. In a complex vascular
      network, this blood shift is actually a function of time, estimated in a first
      approximation as Mshift(t)=(Ugr*t)/Rd (Rd: the resistance to downward blood
      flow). Thus, gravitational stress is proportional to the time spent upright
      GS=Ugr*Mshift(t)=(Ugr2*t)/Rd=(g2*h2*t)/Rd. From this analysis, regular, prolonged
      sitting typical of modern life should cause a significant increase in
      gravitational stress on the cardiovascular system, requiring advanced
      antigravitational response with sympathetic hyperactivity, vasoconstriction,
      volume overload, and arterial hypertension. The hypertensive effect of prolonged
      sitting has been demonstrated in clinical studies. CONCLUSIONS: Essential
      hypertension may be explained as adaptation to increased gravitational stress
      caused by regular, prolonged sitting. This gravitational hypothesis of essential
      hypertension, supported by clinical data, offers a way to its complete healing
      through elimination of the primary factor of prolonged sitting.

PMID- 15173677
TI  - How about the effect of thiazolidinediones in diabetic nephropathy?

PMID- 15173678
TI  - Endogenous morphine and codeine in the brain of non human primate.
AB  - BACKGROUND: Morphine is the most used compound among narcotic analgesics. Apart
      from its presence in the poppy plant, morphine has been shown to be endogenously
      present in different tissues of mammals and lower animals. MATERIAL/METHODS: The
      presence of endogenous morphine and codeine was investigated by Gas
      Chromatography/ Mass Spectrometry (GC/MS) in the brain of non human primate. The
      release of endogenous morphine from monkey brain slices was studied in vitro in
      the presence of high potassium concentrations with and without calcium in the
      medium. RESULTS: Endogenous morphine, and its direct precursor codeine, was for
      the first time detected by GC/MS in the brain of non human primate. High
      potassium concentrations depolarized neurons releasing endogenous morphine
      twofold above basal line levels in a calcium dependent mechanism. CONCLUSIONS:
      This finding confirms the presence of the endogenous alkaloid throughout the
      phylogenesis of the nerve system of mammals and lower animals and indicates that
      endogenous morphine might function as a neuromodulator/neurotransmitter agent in
      the central nervous system (CNS) of non human primates.

PMID- 15173679
TI  - Commonalities in the central nervous system's involvement with complementary
      medical therapies: limbic morphinergic processes.
AB  - BACKGROUND: Currently, complementary and alternative medicine (CAM) are
      experiencing growing popularity, especially in former industrialized countries.
      However, most of the underlying physiological and molecular mechanisms as well as
      participating biological structures are still speculative. Specific and non
      specific effects may play a role in CAM. Moreover, trust, belief, and expectation
      may be of importance, pointing towards common central nervous system (CNS)
      pathways involved in CAM. MATERIAL/METHODS: Four CAM approaches (acupuncture,
      meditation, music therapy, and massage therapy) were examined with regard to the
      CNS activity pattern involved. CNS commonalities between different approaches
      were investigated. RESULTS: Frontal/prefrontal and limbic brain structures play a
      role in CAM. Particularly, left-anterior regions of the brain and reward or
      motivation circuitry constituents are involved, indicating positive affect and
      emotion-related memory processing--accompanied by endocrinologic and autonomic
      functions--as crucial components of CAM effects. Thus, trust and belief in a
      therapist or positive therapy expectations seem to be important. However, besides
      common non-specific or subjective effects, specific (objective) physiological
      components also exist. CONCLUSIONS: Non-specific CNS commonalities are involved
      in various CAM therapies. Different therapeutic approaches physiologically
      overlap in the brain. However, molecular correspondents of the detected CNS
      analogies still have to be specified. In particular, fast acting autoregulatory
      signaling molecules presumably play a role. These may also be involved in the
      placebo response.

PMID- 15173680
TI  - Music alters constitutively expressed opiate and cytokine processes in listeners.
AB  - BACKGROUND: Listening to music as a means of inducing a sense of calm and
      relaxation has been known for some time. Although these effects are robust,
      little research has been conducted into exploring the underlying neurochemical
      changes, which must occur to provide an individual with these objective
      sensations. MATERIAL/METHODS: In the current report we utilize an AB design to
      explore observed differences in blood plasma signaling molecules in pre- and post
      music listening groups when compared with controls. We focus chiefly on
      cytokines, as well as peripheral blood mononuclear cells and polymorphonuclear
      cells. We utilized reverse transcription followed by real-time polymerase chain
      reactions to determine relative mRNA expression for the mu opiate receptor gene.
      Using high pressure liquid chromatography coupled to electrochemical detection as
      well as nano electrospray ionization double quadrupole orthogonal acceleration
      time of flight-mass spectrometry we determined opiate alkaloid levels. RESULTS:
      Our findings are two-fold: with regard to mu opiate receptor expression,
      mononuclear cells showed a statistically significant increase in subjects in the
      music group compared to the control. Plasma morphine levels were found to be non
      significantly lower in subjects after listening to music when compared to control
      subjects whereas morphine 6 glucuronide levels increased slightly, suggesting
      morphine's conversion to morphine 6 glucuronide. IL- 6 levels were significantly
      lower as well whereas IL-1b, IL-10 and cortisol values were unchanged.
      CONCLUSIONS: Taken together, it appears that music-listeners exhibit plasma
      signal molecule changes consistent with the physiological changes associated with
      the reported actions of music, i.e, lower blood pressure.

PMID- 15173681
TI  - Mu opiate receptor subtypes.
AB  - The . opiate receptor gene (MOR) has at least 14 exons that can generate 15
      different splice variants. Recently, two new human MOR splice variants (hMOR-1O
      and hMOR-1X) have been identified and characterized. The two variants containing
      human MOR exons 1, 2, and 3 and a fourth alternative exon O, or exon X, are
      expressed in human brain tissue, and are selective for mu opioid binding in
      transfected cells. It is unclear; however, what the biologic role of these two
      novel human splice variants is in vivo. The mu3 opiate receptor subtype found in
      various human tissues where it is coupled to constitutive nitric oxide synthase
      derived nitric oxide release is characterized by its opiate alkaloid selectivity
      and its insensitivity to opioid peptides. The mu3 clone exhibits 100% identity to
      the mu1 receptor subtype in the center and conserved region, but with a truncated
      5'-end (position 503 of mu1 mRNA) (missing several hundred nucleotides). In
      addition, the 3'-end of the new clone contains the 3'-end of the mu1 receptor,
      followed by a new fragment of 263 bases, and then by a 202 bp fragment of the 3'
      end of the mu1 gene untranslated region. When mu3 is expressed in a heterologous
      system, the protein produced from this cDNA exhibits all of the expected
      biochemical characteristics of the mu3 receptor. The isolation of this novel
      splice variant adds support to the presence of morphinergic signaling in animals.

PMID- 15173682
TI  - The brain-gut axis in irritable bowel syndrome--clinical aspects.
AB  - Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI)
      disorder, affecting about 20% of the world's population. Chronic abdominal pain
      or discomfort relieved by defecation and associated with altered bowel habits are
      the mainstay in diagnosis. The pathophysiology of IBS remains unknown. This
      biopsychosocial disorder involves dysregulation of the nervous system, altered
      intestinal motility, and increased visceral sensitivity. All of these result from
      dysregulation of the bidirectional communication between the gut with its enteric
      nervous system and the brain (the brain-gut axis), modulated by various
      psychosocial and environmental factors (e.g. infection, inflammation). Numerous
      neurotransmitters are found in the brain and gut that regulate GI activities,
      including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT3 and 5-HT4
      receptors. The current approach to IBS patients is based on a positive diagnosis
      of the symptom complex, exclusion of underlying organic disease, and institution
      of a therapeutic trial. Traditional symptomatic treatment has included
      antidiarrheals, laxatives and bulking agents/fiber, low-dose tricyclic
      antidepressants, antispasmodics for pain, and "alternative" therapies (e.g.
      psychotherapy, hypnotherapy). The scientific evidence supporting this therapy is
      limited. Novel approaches include visceral analgesics and serotonin agonists and
      antagonists. In patients with severe diarrhea, 5-HT3 receptor antagonists (e.g.
      alosetron) and selective M3-type anticholinergics are indicated, in constipation
      5-HT4 agonists (e.g. tegaserod), and in pain alfa2-adrenergics (e.g. clonidine),
      cholecystokinin antagonists, kappa-opioid agonists (e.g. fedotozine), and
      neurokinin antagonists; some of these agents are still being investigated.
      Understanding the brain-gut axis is crucial in the development of effective
      therapies for IBS.

PMID- 15173683
TI  - Serial analysis of gene expression (SAGE): application in cancer research.
AB  - Serial analysis of gene expression (SAGE) is a powerful tool that allows digital
      analysis of overall gene expression patterns. SAGE provides quantitative and
      comprehensive expression profiling in a given cell population. Because SAGE does
      not require a preexisting clone, it can be used to identify and quantitate new as
      well as known genes. It works by isolating short fragments of genetic information
      from the genes expressed in the cell being studied. These short sequences, called
      SAGE tags, are linked together for efficient sequencing. SAGE is particularly
      well suited for organisms whose genome is not completely sequenced, because it
      does not require a hybridization probe for each transcript and allows new genes
      to be discovered. New modifications of SAGE now permit the analysis of gene
      expression in cell sub-populations or micro-anatomic structures, providing access
      to unexplored transcriptomes of normal and disease biology. Data derived using
      the SAGE technology have been used to identify tumor markers for a variety of
      cancers, including gastrointestinal cancer, lung and thyroid cancer, breast and
      ovarian cancer, neuroblastoma and glioblastoma, prostate cancer, and renal cell
      carcinoma. In this review we present an outline of the method and updated
      information on the applications of SAGE technology to various cancers.

PMID- 15173685
TI  - Hyperthermia in ischemic stroke.
AB  - Hyperthermia following ischemic stroke is a common but undesirable event whose
      pathophysiology and clinical importance are not fully recognized. Hyperthermia in
      ischemic stroke may result from the brain infarct itself; however, the progress
      of biochemical and inflammatory mechanisms associated with cerebral ischemia is
      also relevant. Consequently, the presence of hyperthermia accentuates ischemic
      mechanisms within the penumbra, an area of reversibly impaired neuronal function
      surrounding the infarct, contributing to conversion of the penumbra into an
      irreversible lesion. Therefore, hyperthermia following ischemic stroke seems to
      be an event both induced by and inducing brain infarct progression. Both clinical
      and experimental studies show hyperthermia-dependent exacerbation of ischemic
      brain damage and stroke outcome. The detrimental effects of hyperthermia in human
      stroke are associated in particular with increased body temperature within the
      first 24 hours of the disease. The common occurrence of superimposed infections
      in stroke patients may be an important peripheral cause of poststroke
      hyperthermia. Pharmacological antipyretic medication is recommended in every case
      of hyperthermia following ischaemic stroke, regardless of its cause, as any
      hyperthermia may worsen stroke outcome. There is currently no evidence from
      randomized trials to support the routine use of chemical or physical cooling
      therapy in acute stroke Further understanding of the mechanisms inducing
      hyperthermia and its contribution to an increase in the degree of injury during
      stroke may lead to new and important therapeutic approaches.

PMID- 15173684
TI  - Pesticides and oxidative stress: a review.
AB  - The purpose of this paper is to provide a brief review of the current state of
      our knowledge regarding pesticides and oxidative stress. To this end, we
      performed a search of the literature using Medline/Index Medicus, EMBASE/Excerpta
      Medica, and Chemical Abstracts; most of the relevant citations were studied and
      summarized. In order to better understand the nature of oxidative stress, the
      principles of free radical production and the body's normal defense system are
      discussed. The pesticides are categorized and discussed according to their
      ability to produce lipid peroxidation or alter body antioxidant status. It is
      concluded that stimulation of free radical production, induction of lipid
      peroxidation, and disturbance of the total antioxidant capability of the body are
      mechanisms of toxicity in most pesticides, including organophosphates, bipyridyl
      herbicides and organochlorines.

PMID- 15173686
TI  - [Organ donor and health policy: the anaesthesia and reanimation].
AB  - The possibility of tissues and organs transplantation is nowadays an ordinary
      surgical procedure for patients that do not have other way of treatment. Today
      the principal objective of the National Health Care System is the improvement in
      the transplantation activities. To achieve this objective it is necessary to
      sustain and promote donation, which is still the principal resource that can be
      used to satisfy the needs of the patients in waiting list for transplantation. In
      Italy much has been done by Institutions and physicians with excellent results,
      both in terms of number of donations and quality of transplantations. But it is
      still not sufficient. A non homogeneity is still observed between different
      Provinces, not only in terms of donation, but also in terms of number of
      transplantation. This situation does not contribute to guarantee the same level
      of accessibility to health care assistance, which patients deserve. To solve
      these problems the National Health Care Plan 2003-2005 has indicated, among the
      strategic objectives, a better utilization of organs and a more deep campaign of
      information for all citizens. It is important that all the Institutions and all
      the operators involved would give more attention to the donation process problems
      and would always be active and efficient. Only keeping a high level of
      involvement of the local coordinators and of the anaesthetists and intensive,
      pivotal figures in the process of donation, and reminding to all citizens the
      possibility of a "love sign", fruit of a decision born by a personal analysis, it
      will be possible to offer a possibility of life to the patients for whom up today
      no other treatments exists.

PMID- 15173687
TI  - Aims of sedation/analgesia.
AB  - The concept of analgo-sedation in intensive care medicine has changed
      considerably since the last decades. Deep sedation, keeping patients artificially
      unconscious, is not necessary anymore, it postpones weaning from mechanical
      ventilation, it provokes complications, and prolongs the length of ICU stay. On
      the other hand, recent surveys have shown that patients recall their intensive
      care experience still as stressing and painful. This need more awareness of
      patient's pain and the readiness to give analgesics particularly before painful
      procedures. The frightening environment of the ICU, sleep deprivation, pain and
      discomfort related not only to the actual dysfunctions, but even more to the
      stressing procedures of care and treatment, make a certain level of sedation
      necessary. But patients' discomfort may also originate from many other reasons,
      such as hypoxaemia, hypotension, cardiac failure, drugs overdose or withdrawal,
      or simply from an uncomfortable body position. These sometimes non-obvious
      reasons have to be carefully looked for in order to treat the problem
      effectively. Delirium and other mental problems are common in critically ill
      patients. They have to be diagnosed with particular attention and treated
      specifically. Sedatives must be carefully adapted to the individual needs and the
      actual situation. Modern modes of mechanical ventilation allows lower levels of
      sedation. Regularly repeated assessment of the sedation level (e.g. by Ramsay
      score) is mandatory; a sedation protocol seems advantageous. To avoid inadvertent
      accumulation and overdose, it is recommended to keep the patient at a sedation
      level at which communication is still possible. A daily interruption of the
      sedation has shown to shorten the duration of mechanical ventilation and the
      length of ICU stay.

PMID- 15173688
TI  - Non-invasive ventilation in COPD patients.
AB  - The authors briefly review the clinical applications of non-invasive ventilation
      (NIV) in patients with chronic obstructive pulmonary disease (COPD), mostly
      focusing on the application of NIV in the intensive care setting. After a short
      discussion of the main pathophysiologic aspects of NIV administration in patients
      with acute exacerbation of COPD, the most relevant clinical trials are shortly
      reviewed, particularly focussing on prospective randomised trials. NIV
      application is analysed both in its early administration, as a tool to prevent
      endotracheal intubation and its main complication, and as a technique alternative
      to endotracheal intubation in patients requiring mechanical ventilation. Finally,
      the main contraindications for NIV are reviewed and discussed.

PMID- 15173689
TI  - [Non invasive mechanical ventilation in acute cardiogenic pulmonary edema: is it
      all done?].
AB  - The aim of the paper is to critically analyse the results obtained by recent
      literature concerning the most important aspects of application of Non Invasive
      Mechanical Ventilation for the treatment of Acute Cardiogenic Pulmonary Edema,
      and to elaborate a definition of what is, on the whole, widely accepted, focusing
      the attention on those issues which still remain unanswered and therefore require
      further studies. MEDLINE was searched and the bibliography of a selected group of
      articles was perused. The literature was analysed and the information gathered
      has proved to address the questions in a systematic way. All studies concerning
      the use of a non invasive ventilation technique in the treatment of acute
      pulmonary edema or acute respiratory failure which included pulmonary edema have
      been considered. New physiological issues have been introduced on the
      pathogenesis of acute pulmonary edema. Even though very little non invasive
      ventilation has been performed outside intensive care units, a growing interest
      is rising in the opportunity of transferring this technique to a different
      setting which would include critically ill patients. No random controlled trials
      and studies have ever established whether positive pressure support is really
      better than continuous airway pressure, but several trials appear to have
      excluded the potential for high-risk in the use of assisted ventilation. General
      opinion has not yet confirmed foreseeable failures in non invasive ventilation at
      the time of patient admission. A good deal of favorable experimental evidence
      supports the use of non invasive ventilation in the acute pulmonary edema and
      guarantees safety when used in intensive care units. Very few trials have been
      carried out in order to explore application on severe pulmonary edema outside
      intensive care unit. A whole new world of old and new issues on patient selection
      criteria, ventilation times, type of ventilation and predictability of failure,
      could be discovered.

PMID- 15173690
TI  - Acute lung injury after pulmonary resection.
AB  - Primary Acute Lung Injury (ALI) after lung resection (or "post-pneumonectomy
      pulmonary edema") is a rare form of acute respiratory failure characterized by
      dyspnea, hypoxemia, diffuse infiltrates on chest radiogram, and rapid evolution
      often unresponsive to therapy. ALI occurs almost exclusively following
      pneumonectomy, within 3 days from surgery and without a preceding cause. Factors
      implicated in its pathogenesis may include excessive fluid administration,
      alveolar injury during one-lung ventilation, pulmonary hypertension, and impaired
      lymph drainage. There is no specific therapy. Suggested measures in the
      perioperative care include the meticulous maintenance of physiological stability,
      judicious fluid restriction, and the limitation of ventilatory volumes and
      pressures.

PMID- 15173691
TI  - Microvasculature in ventilator-induced lung injury: target or cause?
AB  - Clinicians managing acute lung injury must reconcile the competing objectives of
      ensuring adequate oxygen delivery and minimizing the adverse effects of
      ventilatory support. Judging from our experimental work, microvascular stresses
      appear to be a potent cofactor in the development of pulmonary edema as well as
      in the expression of lung damage resulting from an injurious pattern of
      ventilation. When the lung is ventilated with high pressure, raising pre
      capillary pressure or reducing post capillary pressure are both undesirable.
      Raising ventilation frequency may also have cost. Such observations imply that
      reducing the demands for blood flow and ventilation are important considerations
      in formulating a lung protective approach to mechanical ventilation of ARDS.

PMID- 15173692
TI  - Surgical approach to the intraabdominal infections.
AB  - AIM: The term intraabdominal infectioncomprises a broad of variety of
      pathological conditions which are characterized by signs of systemic infection as
      a response to an abdominal source of infection and ranges from a confined problem
      to a devastating disease regarding all organ systems. Septic abdomen is an
      interesting challenge in general surgery: to decide when and how to treat septic
      abdomen lacks of a general consensus and has not been standardized yet. METHODS:
      A total of 1 110 patients underwent surgical treatment for abdominal infection in
      a period of 10 years in the Department of Surgery of San Gerardo Hospital, Monza,
      Italy. We focused our attention on 94 patients who required re-exploration for
      residual or recurrent intra-abdominal infection. RESULTS: The procedure was
      associated with a mortality rate of 40%. The median number of re-explorations was
      5.1. CONCLUSION: Planned multiple relaparotomies with temporarily abdomen closure
      are performed only in a selected high mortality risk group of elderly patients
      with surgical evidence of diffuse peritonitis, presence of primary infectious
      process of more than 72 hours, and a APACHE II score > 20. Relaparotomy on demand
      is required instead in those patients who develop a clinical deterioration after
      a first safe surgical control of the source of infection. Lack of improvement is
      not considered a condition to reoperate. Early detection of persisting infection,
      < 24-36 hours, is an important prognostic factor of outcome.

PMID- 15173693
TI  - What can be done about acute renal failure?
AB  - Acute renal failure (ARF) complicates the clinical course of as many as 5% of all
      hospitalized patients with the critically ill and injured disproportionably at
      risk. Considerable effort has been expended to develop techniques to prevent ARF
      or to facilitate its resolution. However, to date, studies have failed to
      demonstrate that drugs can prevent onset or deterioration of renal function in
      the critically ill, and some studies have even suggested harm. Recent data
      suggest that NAC can reduce the incidence of ARF secondary to radio-contrast
      agents and improved techniques for RRT and, perhaps, new drugs aimed at improving
      cellular repair, will improve outcome from ARF in the future.

PMID- 15173694
TI  - Hemofiltration in the prevention of radiocontrast agent induced nephropathy.
AB  - AIM: The aim of the study was to investigate the role of hemofiltration in
      preventing contrast nephropathy in patients with renal failure. METHODS: We
      randomized 114 renal failure patients undergoing percutaneous coronary
      interventions (PCI) to either peri-procedural hemofiltration or saline hydration.
      RESULTS: Contrast nephropathy occurred in 5% of hemofiltration-treated patients
      and in 50% in controls (P<0.01). In-hospital event rate as well as in-hospital
      and 1-year mortality rates were lower in patients treated with hemofiltration.
      CONCLUSION: In patients with renal failure undergoing PCI, peri-procedural
      hemofiltration is effective for the prevention of contrast nephropathy, and is
      associated with improved in-hospital and long-term outcome.

PMID- 15173695
TI  - Pathophysiology and management of the flail chest.
AB  - Flail chest occurs when a series of adjacent ribs are fractured in at least 2
      places, anteriorly and posteriorly. This section of the chest wall becomes
      unstable and it moves inwards during spontaneous inspiration. The physiological
      impact of a flail chest depends on multiple factors, including the size of the
      flail segment, the intrathoracic pressure generated during spontaneous
      ventilation, and the associated damage to the lung and chest wall. Treatment
      varies with the severity of the physiologic impairment attributable to the flail
      segment itself. Immediate surgical fixation may decrease morbidity, but
      conservative treatment with positive pressure ventilation is preferred when
      multiple injuries to the intrathoracic organs are present.

PMID- 15173696
TI  - Blunt cardiac injury.
AB  - Blunt cardiac injury (BCI) is a common complication of chest trauma. With
      improvements in pre-hospital care and rapid regional transport, more patients
      with severe BCI may arrive at the hospital with signs of life. Prompt recognition
      and expeditious surgical and critical care treatment may increase the number of
      survivors. This paper reviews current clinical considerations in dealing with
      patients suffering BCI.

PMID- 15173697
TI  - [Cerebral oxygen consumption and ischemia in traumatic brain injury].
AB  - AIM: Clinical and experimental studies have shown a reduction of cerebral blood
      flow (CBF) and metabolic alterations following traumatic brain injury (TBI). The
      incidence of ischemia and the meaning of post-traumatic metabolic alterations are
      still unclear. METHODS: Revision of CBF and metabolic changes following TBI based
      on the literature and on our clinical experience. RESULTS: Cerebral ischemia and
      metabolic alterations are part of the secondary insults/damage leading to an
      increased damage following TBI. Global ischemia occurs early following TBI as
      shown by CBF measurements and by greater values of arterio-jugular difference of
      oxygen (AJDO(2)) during the 1(st) 24 hours postinjury. Post-traumatic ischemia
      should be defined based on the relationships between CBF and on the metabolic
      requirements of the brain. Regional ischemia occurs more frequently than global
      ischemia as shown by regional monitoring of cerebral oxygenation. Following TBI
      there is a transient phase of increased glycolitic activity followed by a more
      prolonged phase of reduced metabolic rate of glucose (CMRglc) and oxygen
      (CMRO(2)). The extent of CMRO(2) reduction is a marker of injury severity and it
      is associated with unfavorable outcome. CONCLUSION: Cerebral ischemia occurs
      following TBI and should be defined based on CBF value and the metabolic needs of
      the brain. Global monitoring of cerebral oxygenation adequacy should be combined
      with regional monitoring. The meaning of high AJDO(2) values should be
      reconsidered: if they can highlights potential ischemia they are also showing a
      still living brain with a partially preserved oxygen extraction capability.

PMID- 15173698
TI  - [Moderate hypothermia in traumatic brain injury: results of clinical trials].
AB  - The concept of neuroprotection' by hypothermia dates back to ancient times. This
      paper reviews the results of clinical trials using mild hypothermia (3235 degrees
      C) in patients with severe traumatic brain injury over the past decade. Induced
      hypothermia has been used in experimental models mostly to prevent or attenuate
      secondary neurological injury and has been used to provide neuroprotection in
      traumatic brain injury, both in animal models and clinical trials. Results from
      animal experiments largely confirm that hypothermia can provide protection for
      the injured brain; however, the results from clinical trials and from a number of
      meta-analyses have been conflicting. This paper reviews the evidence and explores
      possible reasons for the mixed results from clinical trials. Hypothermia is
      clearly effective in controlling intracranial hypertension. Early favourable
      results on neurological outcome and mortality were not confirmed in a subsequent
      multi-center trial. Subsequently, single-centre studies, with quicker induction
      of hypothermia and longer duration of cooling, again reported benefits on
      outcome. These differences may be explained by differences in study protocols
      (i.e. speed and duration of cooling, speed of re-warming), prevention of side
      effects and various supportive measures in the ICU. Although induced hypothermia
      appears to be a highly promising treatment in various forms of neurological
      injury including traumatic brain injury, the difficulties in realising its
      therapeutic potential are underscored by the negative results from a large multi
      center trial. Routine usage of hypothermia in traumatic brain injury can not
      currently be recommended.

PMID- 15173699
TI  - The pulmonary artery catheter in critically ill patients. Does it change outcome?
AB  - Initially described more than 30 years ago, the Pulmonary Artery Catheter (PAC)
      technique was becoming more and more used in the following years. This
      hemodynamic monitoring device can be used according 2 different therapeutic
      attitudes. The first one strives to achieve supranormal hemodynamic values,
      particularly in terms of cardiac index and oxygen consumption. However, this
      attitude has been demonstrated to be deleterious in the intensive care setting
      and is, to date, strongly questioned in the perioperative period. Conversely, the
      use of PAC to optimize the hemodynamic status in an individualized manner appears
      more seductive, even if the impact of a therapeutic attitude guided by
      standardized protocols has never been investigated. Although the PAC affords a
      continuous monitoring of a large panel of hemodynamic data, including tissue
      oxygenation parameters and estimation of left cardiac filling pressures, some
      pitfalls may occur in the measurement as well as in the interpretation of the
      data. Furthermore, because it is an invasive procedure, the safety of the PAC has
      been seriously questioned for several years. However, the recent study of Richard
      and coworkers clearly demonstrated that the use of PAC was not responsible for
      increased mortality in severely ill patients with circulatory shock and/or acute
      respiratory distress syndrome. The development of educational programs would
      allow to improve the quality of the collection and interpretation of hemodynamic
      parameters with the hope to enhance the efficiency of the PAC for the management
      of critically ill patients.

PMID- 15173700
TI  - Reduced compliance of left ventricle.
AB  - Diastolic function is essential for efficient systolic performance. A normal
      diastole allows left ventricle (LV) filling to occur under normal intracavitary
      pressure. It is an energy dependent process, as such affected by ischemia.
      Several factors influence diastolic function of the LV: the mitral valve area,
      the gradient between atrium and ventricle, LV relaxation and compliance, atrial
      compliance, the presence of sinus rhythm, the end-systolic volume.
      Echocardiography is the principal diagnostic tool to assess LV diastolic function
      noninvasively in clinical practice. Doppler evaluation allows to analyse each
      phase of LV diastole through measurement of transmitral and pulmonary veins flows
      velocities. Tissue Doppler echocardiography and color M-mode Doppler have also
      been introduced in the study of diastole. The use of echocardiography in the
      setting of diastolic dysfunction in ICU and operatory room has relevant
      implications in the management of haemodynamic instability, in vasoactive d rugs
      titration, in the detection of myocardial ischemia, and in performing prognostic
      stratification. These information can guide the management of cardiac patients
      undergoing cardiac and non cardiac surgery, in the perioperative phase, as well
      as in the management of critical ICU patients. On this basis evaluating the LV
      filling properties can contribute to improve the quality of treatments in such
      challenging situations.

PMID- 15173701
TI  - Hemodynamic-volumetric monitoring.
AB  - Maintenance of adequate cardiac preload is of paramount importance in the
      treatment of patients undergoing major surgical surgery and in the critically ill
      setting. The end point is to maintain the organ perfusion through volume
      replacement and therapy to optimize cardiac output, oxygen deliver. Various
      methods have been introduced into clinical practice to estimate cardiac preload.
      In the last 10 years the transpulmonary indicator dilution technique showed to be
      accurate as hemodynamic-volumetric monitoring. We briefly review the intra
      thoracic blood volume index as a preload index and the fluid responsiveness
      indexes, stroke volume variation and pulse pressure variation, available as novel
      parameters at the bed-side. The optimization of fluid balance and vasoactive
      drugs administration based on volumetric monitoring makes the transpulmonary
      indicator dilution technique a new option as an effective monitoring system where
      intravascular volume management is a primary objective.

PMID- 15173702
TI  - Pathophysiology of severe pulmonary hypertension in the critically ill patient.
AB  - Pulmonary hypertension (PH) is a threatening condition that can be associated
      with a great variety of both pulmonary and extrapulmonary diseases. In all forms
      of severe PH the pulmonary vascular bed looses its physiological features of a
      "high flow-low pressure system", putting an increased afterload on the right
      ventricle (RV). Acute pulmonary hypertension in the intensive care unit often
      represents a clinical problem secondary to acute respiratory failure, left heart
      failure, pulmonary embolism, or decompensation of prior PH by concurrent
      pulmonary or cardiovascular disease. Right ventricular failure (acute cor
      pulmonale) occurs when relevant increases in pulmonary vascular resistance
      overwhelm its compensatory mechanisms, both abruptly on a previously normal RV,
      or gradually on a chronic cor pulmonale. This review addresses the main
      pathophysiological aspects of severe PH, focusing on the hemodynamic derangements
      occurring in the setting of acute cor pulmonale, and emphasizing the role of
      ventricular interdependence (the way right ventricular failure greatly affects
      diastolic and systolic function of the left ventricle), the risk of RV ischemia
      (the end stage of RV failure) and systemic organ hypoperfusion (caused by
      antegrade and retrograde heart failure). The understanding of the peculiar
      features of this type of cardiovascular insufficiency is necessary to both
      provide effective monitoring and adequate supportive therapy.

PMID- 15173703
TI  - Modulating the pulmonary circulation: an update.
AB  - Pulmonary hypertension is a common finding in pulmonary circulatory disorders of
      different origin. Chronic pulmonary hypertension may develop due to either
      cardiopulmonary or systemic diseases whereas acute and acute-on-chronic pulmonary
      hypertension often occur in the course of cardiothoracic surgery. Right heart
      failure is the major risk particularly in the course of acute pulmonary
      hypertension. Thus, besides basic treatment of the underlying disease the use of
      vasodilators is a valuable therapeutic option to decrease right ventricular
      afterload, but intravenous vasodilators may provoke systemic arterial hypotension
      and impair gas exchange due to vasodilation of pulmonary shunt areas. Therefore,
      inhaled vasodilators such as nitric oxide and prostacyclin have been suggested
      for the treatment of pulmonary hypertension especially when concomitant hypoxemia
      is present due to a ventilation-perfusion mismatch. However, randomised
      controlled trials performed to evaluate long-term effects revealed different
      results: thus, in chronic pulmonary hypertension inhaled vasodilators improved
      outcome whereas the results for the treatment of the acute respiratory distress
      syndrome revealed beneficial effects only when used as a rescue and/or bridging
      therapy in severe hypoxemia. In cardiothoracic surgery, inhaled vasodilators have
      been shown to improve pulmonary circulation when severe pulmonary hypertension is
      present. Although effective in experimental studies no clear recommendation can
      be made in view to the use of other vasodilators such as phosphodiesterase
      inhibitors or endothelin antagonists. Likewise, the combination of different
      vasodilators merit further investigations to prove efficacy in randomised
      controlled trials.

PMID- 15173704
TI  - [Administration of inhaled nitric oxide in newborns].
AB  - The use of inhaled nitric oxide (iNO) in newborn hypoxemic respiratory failure is
      based on the evidence of selective pulmonary vasodilation, without systemic side
      effects. It is use in more than 34 weeks old newborns, with severe acute
      pulmonary hypertension and right-left extrapulmonary shunt. In the other cases
      (i.e. pneumonia, sepsis, ARDS), the therapeutic effect is less evident; no final
      data are available on the use of iNO in pre-term babies. The recommended dosage
      is 20 ppm, scaling down until 5 ppm and the 40 ppm should never be reached. The
      length of treatment is variable, usually no more than 7 days and the weaning
      should be progressive. In conclusion,the use of iNO in newborns with persistent
      pulmonary hypertension reduces the need of ECMO, but does not substantially
      modify the outcome.

PMID- 15173705
TI  - Coronary sinus retroperfusion: can forward progress still be achieved by using a
      backward technique?

PMID- 15173706
TI  - At the epicenter of severe acute respiratory syndrome.

PMID- 15173707
TI  - Gene transfer of tumor necrosis factor inhibitor improves the function of lung
      allografts.
AB  - BACKGROUND: Tumor necrosis factor is an important mediator of lung transplant
      acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor
      necrosis factor-alpha and -beta and inhibits their function. The objectives of
      this study were to demonstrate efficient in vivo gene transfer of a soluble type
      I tumor necrosis factor receptor fusion protein (sTNF-RI-Ig) and determine its
      effects on lung allograft acute rejection. METHODS: Three groups of Fischer rats
      (n = 6 per group) underwent recipient intramuscular transfection 24 hours before
      transplantation with saline, 1 x 10(10) plaque-forming units of control
      adenovirus encoding beta-galactosidase, or 1 x 10(10) plaque-forming units of
      adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received
      recipient intramuscular transfection with 1 x 10(10) Ad.sTNF-RI-Ig at the time of
      transplantation. Brown Norway donor lung grafts were stored for 5 hours before
      orthotopic lung transplantation. Graft function and rejection scores were
      assessed 5 days after transplantation. Time-dependent transgene expression in
      muscle, serum, and lung grafts were evaluated by using enzyme-linked
      immunosorbent assay of human soluble type I tumor necrosis factor receptor.
      RESULTS: Recipient intramuscular transfection with 1 x 10(10) plaque-forming
      units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered
      24 hours before transplantation compared with saline, beta-galactosidase, and
      Ad.sTNF-RI-Ig transfection at the time of transplantation (435.8 +/- 106.6 mm Hg
      vs 142.3 +/- 146.3 mm Hg, 177.4 +/- 153.7 mm Hg, and 237.3 +/- 185.2 mm Hg; P
      =.002,.005, and.046, respectively). Transgene expression was time dependent, and
      there was a trend toward lower vascular rejection scores (P =.066) in the Ad.sTNF
      RI-Ig group transfected 24 hours before transplantation. CONCLUSIONS: Recipient
      intramuscular Ad.sTNF-RI-Ig gene transfer improves allograft function in a well
      established model of acute rejection. Maximum benefit was observed when
      transfection occurred 24 hours before transplantation.

PMID- 15173708
TI  - Early results of endoscopic lung volume reduction for emphysema.
AB  - BACKGROUND: We determined the feasibility, safety, and short-term efficacy of
      bronchoscopic placement of a one-way endobronchial valve in selected
      bronchopulmonary segments as an alternative to surgical lung volume reduction.
      METHODS: A total of 21 patients with incapacitating emphysema who underwent this
      procedure were studied. All patients had placement of the endobronchial valves
      into the most emphysematous lung segments. We recorded any major complications or
      deaths attributed to the procedure and analyzed (1) improvements in the
      spirometric and functional parameters and quality of life and (2) the radiologic
      changes compared with the baseline data at 30 and 90 days. RESULTS: A total of 20
      patients had complete follow-up data. There was no mortality in the group
      studied. The forced expiratory volume at 1 second, forced expiratory volume at 1
      second (percentage of predicted), forced vital capacity, and forced vital
      capacity (percentage of predicted) all improved significantly at 90 days (0.73 +/
      0.26 L vs 0.92 +/- 0.34 L [P =.009]; 33.3% +/- 11.9% vs 42.2% +/- 15.0% [P
      =.006]; 1.94 +/- 0.62 L vs 2.25 +/- 0.61 L [P =.015]; and 63.3% +/- 17.6% vs
      73.9% +/- 17.1% [P =.012], respectively). The 6-minute walking distance improved
      at 30 and 90 days (251.6 +/- 100.2 m vs 306.3 +/- 112.3 m and 322.3 +/- 129.7 m;
      P =.012 and P =.003). The results of the 36-Item Short-Form Health Survey and the
      St George Respiratory Questionnaire showed significant improvements at 90 days.
      The Medical Research Council dyspnea grade also improved significantly at 30 and
      at 90 days (P =.006 and P =.003, respectively). CONCLUSIONS: Endobronchial valve
      placement is a safe procedure, with significant short-term improvements in
      functional status, quality of life, and relief of dyspnea in selected patients
      with emphysema. A larger study with long-term follow-up is therefore warranted.

PMID- 15173709
TI  - Visceral pleural invasion classification in non-small cell lung cancer: a
      proposal on the basis of outcome assessment.
AB  - OBJECTIVE: The definition of visceral pleural invasion in lung cancer TNM
      classification of the International Union Against Cancer lacks detail. The
      purpose of this study was to evaluate the significance of the extent of pleural
      involvement as a prognostic factor and to propose a refined TNM classification on
      the basis of visceral pleural invasion. METHODS: We reviewed 1653 consecutive
      patients with T1, T2, and T3 surgically resected non-small cell lung cancer for
      their clinicopathologic characteristics and prognoses. Visceral pleural invasion
      was classified by using the Japan Lung Cancer Society criteria: p0, tumor with no
      pleural involvement beyond its elastic layer; p1, tumor extension beyond the
      elastic layer but no exposure on the pleural surface; and p2, tumor exposure on
      the pleural surface. RESULTS: The 5-year survivals for patients with p1 or p2
      tumors of 3 cm or less were identical and significantly worse than those for
      patients with p0 tumors of the same size. Patients with p1 or p2 tumors of
      greater than 3 cm and patients with T3 cancers had essentially identical
      survivals. CONCLUSIONS: Visceral pleural invasion should be defined as tumor
      extension beyond the elastic layer of the visceral pleura, regardless of its
      exposure on the pleural surface. A tumor of 3 cm or less with visceral pleural
      invasion should remain classified as a T2 tumor, as presently occurs in the
      International Union Against Cancer staging system, and tumors of greater than 3
      cm with visceral pleural invasion should be upgraded to T3 status in the
      International Union Against Cancer TNM classification.

PMID- 15173710
TI  - Prognostic significance of vascular endothelial growth factor and cyclooxygenase
      2 expression in patients receiving preoperative chemoradiation for esophageal
      cancer.
AB  - OBJECTIVE: Both vascular endothelial growth factor and cyclooxygenase 2
      overexpression have been associated with poor prognosis in a variety of human
      malignancies. In this study we assessed the effect of preoperative chemotherapy
      and radiation on expression levels of vascular endothelial growth factor and
      cyclooxygenase 2 in patients with esophageal cancer and determined whether these
      markers were associated with treatment response and overall survival. METHODS:
      Expression levels of vascular endothelial growth factor and cyclooxygenase 2 were
      measured in a cohort of 46 patients with esophageal cancer receiving preoperative
      chemoradiation followed by surgical resection. Immunohistochemical stains were
      performed on both pretreatment biopsy specimens and posttreatment resection
      specimens for each patient. Differences in vascular endothelial growth factor and
      cyclooxygenase 2 expression before and after treatment were measured, and
      pretreatment expression levels were correlated with treatment response and
      overall survival. RESULTS: We found that preoperative chemotherapy and radiation
      induced expression of cyclooxygenase 2 in stromal cells and induced vascular
      endothelial growth factor expression in both tumor and stromal cells.
      Pretreatment vascular endothelial growth factor expression did not correlate with
      treatment response, and cyclooxygenase 2 expression correlated with treatment
      response only in the subset of patients with squamous cell carcinoma. Although
      patients whose tumors expressed high levels of vascular endothelial growth factor
      and cyclooxygenase 2 tended to have shorter overall survival times, this trend
      did not reach statistical significance. CONCLUSIONS: Neither vascular endothelial
      growth factor nor cyclooxygenase 2 are strong predictors of treatment response
      and survival in patients undergoing preoperative chemoradiation for esophageal
      cancer. This lack of prognostic significance might be explained by changes in the
      expression levels of these markers during treatment.

PMID- 15173711
TI  - Prognostic value of visceral pleural invasion in resected non-small cell lung
      cancer diagnosed by using a jet stream of saline solution.
AB  - OBJECTIVE: Visceral pleural invasion caused by non-small cell lung cancer is a
      factor in the poor prognosis of patients with that disease. We investigated the
      relationship between the diagnosis of visceral pleural invasion by using a jet
      stream of saline solution, which was previously reported as a new cytologic
      method to more accurately detect the presence of visceral pleural invasion, and
      prognosis. METHODS: From January 1992 through December 1998, 143 consecutive
      patients with peripheral non-small cell lung cancer that appeared to reach the
      visceral pleura underwent a surgical resection at the Department of Thoracic
      Oncology, National Kyushu Cancer Center. The surface of the visceral pleura in
      patients undergoing lung cancer resection was irrigated with a jet stream of
      saline solution. The diagnosis of visceral pleural invasion was determined by
      means of either a pathologic examination or by means of a jet stream of saline
      solution. In addition, a cytologic examination of the pleural lavage fluid
      obtained immediately after a thoracotomy was evaluated. RESULTS: Forty-nine (34%)
      resected tumors were identified as having visceral pleural invasion. The
      diagnosis of visceral pleural invasion in 31, 6, and 12 patients was determined
      by using a jet stream of saline solution alone, pathologic examination alone, or
      both, respectively. The visceral pleural invasion and positive findings of
      intrapleural lavage cytology were linked. Although there was no significant
      difference between the incidence of distant metastases in the patients with
      visceral pleural invasion and those without visceral pleural invasion, the
      incidence of local recurrence, especially regarding carcinomatous pleuritis
      (malignant pleural effusion, pleural dissemination, or both), in the patients
      with visceral pleural invasion was significantly higher than in those without
      visceral pleural invasion. The recurrence-free survival of patients with visceral
      pleural invasion was significantly shorter than that of patients without visceral
      pleural invasion (P =.004), even patients with stage I disease (P =.02). There
      was also a significant difference between the patients with or without visceral
      pleural invasion in the overall survival (P =.02). Visceral pleural invasion was
      independently associated with a poor recurrence-free survival on the basis of
      multivariate analyses (P =.03), as were sex (P =.03), age (P = 002), and the
      stage of the disease (P <.0001). CONCLUSIONS: This study confirmed that the jet
      stream of saline solution method in addition to ordinary pathologic examination
      was useful for detecting visceral pleural invasion, which is considered to be one
      of the causes of local recurrence, especially in carcinomatous pleuritis.

PMID- 15173712
TI  - Heterotopic en bloc tracheobronchial transplantation with direct
      revascularization in pigs.
AB  - OBJECTIVE: This article describes the application of a novel aortic tube
      technique for directly revascularized tracheobronchial transplantation with dual
      blood supply in pigs. METHODS: Eleven adult Large White pigs underwent
      heterotopic tracheal transplantation with a dual revascularization technique
      (inferior thyroid artery and bronchial artery). Seven tracheobronchial grafts
      were perfused ex vivo, and hemodynamic data were collected. RESULTS: At the last
      evaluation, 6 pigs had normally epithelialized mucus-producing allografts with
      correct morphologic conformation and cartilage viability. The histopathologic
      examination revealed homogeneous tissue regardless of biopsy site (trachea,
      carina, or bronchi), demonstrating the efficacy of the revascularization
      procedure. Four animals had early ischemic necrosis develop, 2 from acute
      rejection and 2 from technical mishap. One additional pig had acute rejection
      starting on the 14th postoperative day. The CD4(+)/CD8(+) ratio was maintained
      close to or above 0.8 in the subgroup with rejection and below 0.6 in the animals
      that were correctly immunosuppressed. Pressure-flow curves in 7 ex vivo
      tracheobronchial grafts showed a nonsignificant difference (P <.12) in vascular
      resistance between the bronchial artery territory (lower resistance) and the
      inferior thyroid artery territory. CONCLUSIONS: For the first time, a
      transplantation technique encompassing the entire trachea, carina, and stem
      bronchi has been made possible. By means of the dual inferior thyroid and
      bronchial artery axis, we were able to obtain a structurally healthy and
      functional graft to replace the main airway.

PMID- 15173713
TI  - Flow patterns in the aortic root and the aorta studied with time-resolved, 3
      dimensional, phase-contrast magnetic resonance imaging: implications for aortic
      valve-sparing surgery.
AB  - OBJECTIVE: Sparing the aortic valve has become a surgical option for patients who
      require repair of aortic root ectasia and have normal valve leaflets. Surgical
      approaches to valve sparing differ with regard to preservation of the native
      sinuses of Valsalva. The role of the sinuses and the importance of maintaining
      them remain controversial. METHODS: By using a time-resolved, 3-dimensional,
      phase-contrast magnetic resonance imaging technique, aortic root and aortic blood
      velocity data were acquired from 2 patients with Marfan syndrome 6 months after
      aortic valve-sparing surgery with straight Dacron grafts and contrasted with data
      from 6 normal volunteers. RESULTS: In normal aortas vortical blood flow became
      apparent in the individual sinuses after peak systole. The vortices filled the
      available space behind the valve leaflets and persisted until diastole, expanding
      and moving inward during aortic valve closure. In contrast, no vortices were
      observed in the postoperative patients with Marfan syndrome with negligible
      sinuses. CONCLUSIONS: Changes in supravalvular flow accompany loss of sinus
      architecture. Whether the presence, size, and velocity of supravalvular vortices
      affects the function or durability of the preserved aortic valve remains to be
      studied.

PMID- 15173714
TI  - Development of biologic coronary artery bypass grafting in a rabbit model:
      revival of a classic concept with modern biotechnology.
AB  - OBJECTIVE: We have developed a technique for biologic coronary artery bypass
      grafting, which is a revival of a classic concept with modern biotechnology.
      METHODS: Acute myocardial infarction was created by ligating the major branch of
      the circumflex artery in rabbits. Animals were divided into four groups: a
      nontreated group (group N), a group in which omentum was used to wrap the
      infarcted area (group G), a group in which a gelatin hydrogel sheet incorporating
      100 microg basic fibroblast growth factor was placed over the infarcted area
      (group F), and a group in which the infarcted area was similarly treated with
      basic fibroblast growth factor followed by omental wrapping (group FG). Cardiac
      function was subsequently assessed by echocardiography. Postmortem angiography
      through the gastroepiploic artery was done in groups G and FG. Infarct size and
      arteriolar density were evaluated. RESULTS: Group FG showed a better fractional
      area change than did the other groups (group N P <.001, group G P =.002, group F
      P <.001). Angiography revealed that communication from the gastroepiploic artery
      to the coronary artery was created through a rich bed of neovascularization in
      all 7 animals of group FG, whereas poor collaterals were recognized in only 2 of
      7 animals in group G. Infarct size was reduced to a greater extent in group FG
      than in groups F, G, and N (10% +/- 3%, 16% +/- 5%, 19% +/- 7%, 23% +/- 2%,
      respectively, group F P =.04, groups G and N P <.01). The number of arterioles 20
      to 100 microm in diameter was increased to a greater extent in group FG than in
      groups F, G, and N (23 +/- 5 arterioles/mm(2), 14 +/- 3 arterioles/mm(2), 10 +/-
      1 arterioles/mm(2), 4 +/- 2 arterioles/mm(2), respectively), with the differences
      being significant. CONCLUSIONS: These results show that bypass from the
      gastroepiploic artery to coronary arteries can be achieved without surgical
      anastomosis through slow release of basic fibroblast growth factor in this rabbit
      acute myocardial infarction model. This new revascularization concept, biologic
      coronary artery bypass grafting, could be applicable for revascularizing many
      tiny coronary vessels in patients who are difficult to treat with conventional
      surgery or catheter intervention.

PMID- 15173715
TI  - Hemodynamic and clinical outcomes with the Biocor valve in the aortic position:
      an 8-year experience.
AB  - OBJECTIVES: The aim of this study was to analyze the 8-year experience, survival,
      prosthetic complications, and hemodynamics of patients who received the Biocor
      valve, a new-generation tissue valve, in the aortic position. METHODS: From May
      1992 through May 2001, 257 consecutive patients (129 women and 128 men; mean age,
      75 +/- 6 years; age range, 45-91 years) received 258 aortic Biocor porcine
      prostheses. One female patient who received 2 Biocor valves in the aortic
      position during 2 consecutive operations was entered twice in the statistical
      analysis. Twelve (4.6%) patients had previous aortic valve operations.
      Preoperatively, 82 (32%) patients were in New York Heart Association functional
      class III or IV. Associated surgical procedures included coronary artery bypass
      grafting in 56 (21.7%) patients, aortic annular enlargement or aortoplasty in 20
      (8%) patients, and others in 8 (3%) patients. Echocardiography was performed in
      the majority of long-term survivors (91.6%). Follow-up included 1215 patient
      years and was 100% complete, with a median time of 5 patient-years (range, 0.4
      10.5 years). RESULTS: There were 16 (6.2%) early deaths. According to a
      univariate analysis, New York Heart Association functional class III or IV,
      concomitant procedures, ejection fractions of less than 40%, and urgent
      operations were identified as significant perioperative risk factors. At follow
      up, 75 patients died; 8-year actuarial Kaplan-Meier survival was 48% +/- 5%. At 8
      years, the actuarial freedom from valve-related death was 92% +/- 2.6%, the
      freedom from thromboembolism was 93% +/- 2%, the freedom from anticoagulant
      related hemorrhage was 95% +/- 2%, the freedom from endocarditis was 99% +/-
      0.6%, the freedom from paravalvular leak was 96% +/- 1.5%, the freedom from all
      valve-related complications was 78% +/- 4.5%, and the freedom from structural
      valve deterioration was 95% +/- 3.7%. At 8 years, the actuarial freedom from
      structural valve deterioration was 89% +/- 10% and 95.8% +/- 4% in patients
      younger and older than 65 years, respectively. At 10 years, in patients older
      than 65 years, the actual freedom from structural valve deterioration was 97.9%
      +/- 2.1%, and the freedom from reoperation was 97% +/- 1.3%. New York Heart
      Association status was I or II in 90% of patients at the end of follow-up. The
      mean echocardiographic follow-up time was 4.6 +/- 2 years. By using Doppler
      echocardiography, the peak and mean transprosthetic gradients were determined to
      be 30.8 +/- 9.3 mm Hg and 16.6 +/- 5.3 mm Hg, respectively. Mean mass/volume
      ratio and left ventricular end-diastolic volume were 1.37 +/- 0.17 g/mL and 63.4
      +/- 22.6 mL/m(2), respectively. The majority of patients showed a persistent left
      ventricular hypertrophy. CONCLUSION: The Biocor is an effective bioprosthesis
      with a low incidence of valve-related complications comparable with that of other
      second-generation bioprostheses. This stented porcine prosthesis provides
      satisfactory results in terms of hemodynamics, valve durability, and freedom from
      reoperation.

PMID- 15173716
TI  - Beating heart revascularization with or without cardiopulmonary bypass:
      evaluation of inflammatory response in a prospective randomized study.
AB  - OBJECTIVE: On-pump beating heart coronary artery surgery provides the opportunity
      to examine the isolated effect of cardiopulmonary bypass. This prospective
      randomized study compares the early clinical outcomes and inflammatory response
      of patients undergoing elective on-pump and off-pump beating heart coronary
      artery bypass grafting. METHOD AND PATIENTS: Thirty-seven consecutive patients
      undergoing elective coronary artery bypass grafting were recruited from a pool of
      73 patients, with 19 patients randomized to on-pump beating heart surgery and 18
      patients to off-pump coronary bypass surgery. Intraoperative events and
      postoperative outcomes were recorded. Plasma levels of interleukin-6, interleukin
      8, and interleukin-10, tumor necrosis factor-alpha, and vascular cell adhesion
      molecule-1 were measured before the operation, intraoperatively, after the
      operation, and 4, 24, and 48 hours thereafter. RESULTS: There was no significant
      difference in clinical outcomes between the 2 groups. The operating time was
      longer and consumption of platelets was greater for the on-pump beating heart
      group. There was no postoperative mortality or major complication in either
      group. There was significant elevation in the levels of interleukin-6,
      interleukin-8, and interleukin-10 and tumor necrosis factor-alpha during and
      immediately after the operations in the on-pump beating heart group when compared
      with the off-pump group. Levels of interleukin-8 (P =.01) and tumor necrosis
      factor-alpha (P =.0004) remained significantly elevated 4 hours after the
      operation in the on-pump beating heart group. The level of vascular adhesion
      molecule dropped significantly during the operation but was elevated 4 hours (P
      =.026) after the operation in the on-pump beating heart group. CONCLUSION: The
      use of cardiopulmonary bypass alone without global myocardial ischemia secondary
      to aortic crossclamping and cardioplegic cardiac arrest can trigger intense
      inflammatory responses.

PMID- 15173717
TI  - Clinical and angiographic results after mechanical connection for distal
      anastomosis in coronary surgery.
AB  - BACKGROUND: Sutureless anastomotic devices are of increasing interest in
      cardiovascular surgery. We investigated the stainless steel clip system of St
      Jude Medical/Anastomotic Technology Group (Maple Grove, Minn) to connect
      saphenous vein grafts with coronary arteries. METHODS: Forty-five patients were
      enrolled in this feasibility study performed on patients who had on-pump coronary
      artery bypass grafting, but 32 patients only received 1 distal anastomosis with
      this investigational device (2.5 mm [n = 14] and 2.0 mm [n = 18]). Thirteen were
      excluded because target vessels were too small, calcified, or tortuous. The
      system consists of an expandable clip mounted on a balloon catheter; delivery is
      obtained during balloon inflation. The main differences between the 2.5-mm and
      2.0-mm devices are different loading and deployment in smaller coronary arteries
      for the 2.0-mm device. RESULTS: A connecting device was deployed on the right
      coronary artery in 14 patients, the posterior descending branch in 12 patients,
      the obtuse marginal in 5 patients, and the posterolateral branch in 1 patient.
      Perfect hemostasis of the sutureless connector anastomosis was obtained in 28
      patients. Three connectors were removed because of minor leakage at the
      connection site, and 1 connector was removed because of mismanipulation after
      successful deployment. Hand-sewn anastomosis was performed at the same
      arteriotomy site. Intraoperative flow was assessed by the transit time method and
      averaged 71 +/- 24 mL/min. One patient died of neurologic injury; the connector
      was patent at autopsy. One patient had a perioperative myocardial infarction.
      There was no adverse cardiac event in the remaining patients. All patients
      underwent clinical follow-up after 6 and 12 months and 35 angiograms were
      available in 21 patients: after 3 and 6 months, 17 anastomoses were patent and
      the saphenous vein graft was occluded in 4 patients. CONCLUSIONS: The coronary
      connector system from St Jude Medical/Anastomotic Technology Group allows
      consistently uniform sutureless connection between the saphenous vein graft and
      coronary artery. Loading and deployment require careful training. This technology
      is under constant development and may give a significant boost to less invasive
      coronary revascularization techniques.

PMID- 15173718
TI  - Epicardial left ventricular lead placement for cardiac resynchronization therapy:
      optimal pace site selection with pressure-volume loops.
AB  - OBJECTIVES: Patients in heart failure with left bundle branch block benefit from
      cardiac resynchronization therapy. Usually the left ventricular pacing lead is
      placed by coronary sinus catheterization; however, this procedure is not always
      successful, and patients may be referred for surgical epicardial lead placement.
      The objective of this study was to develop a method to guide epicardial lead
      placement in cardiac resynchronization therapy. METHODS: Eleven patients in heart
      failure who were eligible for cardiac resynchronization therapy were referred for
      surgery because of failed coronary sinus left ventricular lead implantation.
      Minithoracotomy or thoracoscopy was performed, and a temporary epicardial
      electrode was used for biventricular pacing at various sites on the left
      ventricle. Pressure-volume loops with the conductance catheter were used to
      select the best site for each individual patient. RESULTS: Relative to the
      baseline situation, biventricular pacing with an optimal left ventricular lead
      position significantly increased stroke volume (+39%, P =.01), maximal left
      ventricular pressure derivative (+20%, P =.02), ejection fraction (+30%, P
      =.007), and stroke work (+66%, P =.006) and reduced end-systolic volume (-6%, P
      =.04). In contrast, biventricular pacing at a suboptimal site did not
      significantly change left ventricular function and even worsened it in some
      cases. CONCLUSIONS: To optimize cardiac resynchronization therapy with epicardial
      leads, mapping to determine the best pace site is a prerequisite. Pressure-volume
      loops offer real-time guidance for targeting epicardial lead placement during
      minimal invasive surgery.

PMID- 15173719
TI  - Determinants of postinfarction remodeling affect outcome and left ventricular
      geometry after surgical treatment of ischemic cardiomyopathy.
AB  - OBJECTIVE: To identify the effects of the time between myocardial infarction and
      surgery, the site of infarction, mitral involvement on ventricular geometry, and
      clinical outcome in the treatment of ischemic cardiomyopathy in patients with
      heart failure. METHODS: Sixty-nine consecutive patients with ischemic
      cardiomyopathy, indexed end-systolic volume > or =50 mL/m(2), ejection fraction <
      or =35%, and heart failure underwent surgery 81.9 +/- 100.8 months after
      myocardial infarction, using different techniques of ventricular restoration.
      Thirteen geometric parameters were studied pre- and postoperatively. Paired and
      unpaired t tests and general linear model for multivariate analysis were used to
      analyze subgroups. Logistic regression and Kaplan-Meier survival curves with
      pairwise log-rank were used to correlate covariates to clinical outcome. RESULTS:
      Longer time to surgery and posterior necrosis linearly correlated with higher
      left ventricular volumes (r(2) =.66) and diameters (r(2) =.40). High grade of
      mitral regurgitation was always present in posterior infarctions. Hospital
      mortality was 4.3%. Complicated postoperative course was predicted by mitral
      surgery (P =.004) and longer time to surgery (P =.04). Survival was significantly
      lower in the posterior infarction (P =.0002) and mitral surgery (P =.001)
      subgroups. At a mean follow-up of 1.9 +/- 1.3 years, functional status and
      geometrical restoration are influenced by the studied covariates. CONCLUSIONS:
      Longer time to surgery after myocardial infarction, its posterior location, and
      significant mitral regurgitation can affect left ventricular remodeling, surgical
      restoration, and clinical outcome in patients with ischemic cardiomyopathy.

PMID- 15173720
TI  - Eight-year results after aortic valve replacement with the Freestyle stentless
      bioprosthesis.
AB  - OBJECTIVES: We sought to describe the hemodynamic and clinical outcomes for the
      Freestyle aortic root bioprosthesis (Medtronic, Inc, Minneapolis, Minn) in a
      large multicenter cohort prospectively followed for 8 years. METHODS: A total of
      700 patients (651 [93%] >60 years of age) at 8 centers in North America were
      followed prospectively after aortic valve replacement with the Freestyle
      stentless bioprosthesis; the implant technique was subcoronary in 500, total root
      in 162, and root inclusion in 38. Follow-up was 3395 patient-years (4.9 +/- 2.3
      years per patient). Clinical and echocardiographic follow-up was prospectively
      obtained at yearly intervals. RESULTS: For the subcoronary, total root, and root
      inclusion groups, actuarial freedom from valve-related death was 96.8% (SE 3.0%),
      92.3% (SE 7.7%), and 90.9% (SE 11.2%), respectively, and freedom from structural
      deterioration was 98.6% (SE 2.0%), 100.0% (SE 0.0%), and 100.0% (SE 0.0%),
      respectively. Hemodynamics remained excellent at 6 years. Freedom from moderate
      or more aortic regurgitation was 86.0% (SE 5.1%), 98.7% (SE 3.9%), and 97.3% (SE
      6.6%), respectively. Gradients were slightly lower (P =.0009), and the effective
      orifice area (P =.02) and freedom from aortic regurgitation were slightly higher
      (P =.03) with total root than subcoronary implantation. CONCLUSIONS: The
      Freestyle stentless aortic root bioprosthesis is a versatile option for aortic
      valve replacement. Measures of clinical outcomes and prosthesis durability remain
      excellent in multicenter follow-up through 8 years in a population predominantly
      older than 60 years at the time of the operation.

PMID- 15173721
TI  - Risk factors for persistent pleural effusions after the extracardiac Fontan
      procedure.
AB  - OBJECTIVE: Pleural effusions after the Fontan operation contribute significantly
      to morbidity and prolonged hospitalization. This study investigates the
      association between selected preoperative, operative, and postoperative variables
      and persistent pleural effusions after the extracardiac Fontan procedure.
      METHODS: We conducted a retrospective study of extracardiac Fontan procedures.
      The variables analyzed as potential risk factors included age and weight at the
      time of the operation, anatomic diagnosis, preoperative oxygen saturation, mean
      pulmonary artery pressure, ventricular end-diastolic pressure, presence of an
      accessory source of pulmonary blood flow, presence of significant aortopulmonary
      collateral vessels, presence of fenestration, cardiopulmonary bypass time,
      conduit size, postoperative pulmonary artery pressure, use of angiotensin
      converting enzyme inhibitors, and presence of postoperative infection. The
      outcome measures evaluated were duration and volume of chest tube drainage after
      surgical intervention. RESULTS: From June 1997 to August 2002, 100 consecutive
      patients underwent the extracardiac Fontan procedure. The median age at operation
      was 3.1 years. The median duration of chest tube drainage was 10 days, and the
      median volume of drainage was 14.7 mL.kg(-1).d(-1). As determined by means of
      multivariate analysis, significant risk factors for pleural effusions lasting
      more than 2 weeks were lower preoperative oxygen saturation (P =.011) and the
      presence of postoperative infections (P =.003). Significant risk factors for
      pleural effusions draining at more than 20 mL.kg(-1).d(-1) were lower
      preoperative oxygen saturation (P =.005), smaller conduit size (P =.04), and
      longer duration of cardiopulmonary bypass (P =.004). CONCLUSIONS: Lower
      preoperative oxygen saturation, presence of postoperative infection, smaller
      conduit size, and longer duration of cardiopulmonary bypass were associated with
      persistent pleural effusions after the extracardiac Fontan procedure.
      Modifications of some of these risk factors might influence the duration and
      volume of pleural drainage after surgical intervention.

PMID- 15173723
TI  - Direct closure of the septum primum in atrioventricular canal defects.
AB  - OBJECTIVE: The objective of this study was to assess the safety of directly
      closing the septum primum during the correction of atrioventricular canal
      defects. METHODS: We performed a retrospective analysis of our experience with
      direct closure of the septum primum during the repair of atrioventricular canal
      defect. The series consisted of 28 consecutive patients presenting with a partial
      (15 patients) and complete (13 patients) atrioventricular canal defect. The cleft
      in the atrioventricular valve was closed completely in 25 patients and partially
      in 3 patients (those with a small left lateral leaflet). In complete
      atrioventricular canal, the ventricular septum defect was closed with a patch of
      polytetrafluoroethylene (Gore-Tex, W. L. Gore & Associates, Inc, Flagstaff, Ariz)
      or xenopericardium. Follow-up was complete and ranged from 3 to 21 months (median
      11 months). RESULTS: There were no early or late deaths and no surgical
      complications. The septum primum defect was closed completely in all patients as
      assessed by echocardiography. All the patients were in sinus rhythmus, and none
      had even a temporary complete atrioventricular block. The surgical result and
      heart rhythm have remained stable over time. CONCLUSIONS: Direct closure of the
      septum primum is an easy, quick, and safe procedure during repair of
      atrioventricular defects.

PMID- 15173722
TI  - Variability of plasma aprotinin concentrations in pediatric patients undergoing
      cardiac surgery.
AB  - OBJECTIVES: Infants and children undergoing cardiopulmonary bypass for repair of
      congenital heart defects are at substantial risk for excessive bleeding,
      contributing greatly to morbidity and mortality. Aprotinin significantly reduces
      bleeding and transfusion requirements in adults but is of indeterminate value for
      pediatric patients. The aim of this study was to determine plasma aprotinin
      concentrations in these patients with a functional aprotinin assay. METHODS:
      Thirty patients less than 16 years of age scheduled for cardiac surgery with
      aprotinin were enrolled. Aprotinin was administered as a 25,000 KIU/kg bolus,
      35,000 KIU/kg cardiopulmonary bypass prime, and 12,500 KIU.kg(-1).h(-1)
      continuous infusion. Blood samples for aprotinin concentrations (kallikrein
      inhibiting units/milliliter) were obtained before aprotinin; 5 minutes post
      bolus; 5 minutes after cardiopulmonary bypass initiation; 30 and 60 minutes on
      cardiopulmonary bypass; on discontinuation of aprotinin; 1 hour after aprotinin
      discontinuation; and 4 hours after permanent separation from cardiopulmonary
      bypass. For analysis, patients were grouped according to weight (<10 kg, 10-20
      kg, >20 kg). Differences between weight groups were assessed using an exact test
      for categoric variables and 1-way analysis of variance for continuous variables.
      RESULTS: Aprotinin concentrations differed significantly across weight groups.
      Five minutes after aprotinin bolus and initiation of cardiopulmonary bypass,
      there was significant correlation between weight and aprotinin concentration (r
      =.57, P =.003; r =.69, P =.001, respectively). CONCLUSION: A functional assay
      reveals significant variability in aprotinin concentration for pediatric patients
      using current weight-based aprotinin dosing. Additional investigation is
      necessary to determine target aprotinin concentration dosing regimens to provide
      better efficacy.

PMID- 15173724
TI  - Tricuspid valve replacement with a mitral homograft in children with rheumatic
      tricuspid valvulopathy.
AB  - OBJECTIVE: Tricuspid valve replacement in children is associated with a
      nonnegligible complication rate because of specific disadvantages of mechanical
      or biologic prostheses. The objective of this study was to examine the midterm
      clinical outcomes of tricuspid valve replacement with a mitral homograft in 8
      children with unreparable rheumatic tricuspid valve involvement. METHODS: Between
      1993 and 2003, tricuspid valve replacement with a mitral homograft was performed
      in 8 patients (2 male and 6 female patients; mean age, 14.2 years) with rheumatic
      tricuspid valve disease. All patients were in New York Heart Association class
      III or IV. In all patients with rheumatic valve disease, conservative operations
      had previously been performed on the tricuspid valve during concomitant left
      sided surgical intervention. Mean follow-up was 56 +/- 12 months and was
      complete. RESULTS: There were no operative or late deaths. All patients were
      alive at the most recent follow-up contact and were in New York Heart Association
      functional class I or II. None of the patients required homograft-related
      reoperation. At the most recent echocardiograhic examination, 6 patients had
      trivial residual tricuspid regurgitation, and 2 had mild tricuspid regurgitation.
      None of the patients had maximal transvalvular tricuspid gradients greater than 2
      mm Hg during their yearly follow-up visits. CONCLUSION: On the basis of our
      midterm results, tricuspid valve replacement with a mitral homograft in children
      seems to be a valuable alternative surgical option.

PMID- 15173725
TI  - Elimination of proinflammatory cytokines in pediatric cardiac surgery: analysis
      of ultrafiltration method and filter type.
AB  - OBJECTIVE: This study was undertaken to assess whether different filter types or
      ultrafiltration methods influence inflammatory markers in pediatric cardiac
      surgery. METHODS: Forty-one children younger than 5 years were prospectively
      randomized to groups A (polyamid filter with conventional ultrafiltration), B
      (polyamid filter with modified ultrafiltration), C (polysulfon filter with
      conventional ultrafiltration), and D (polysulfon filter with modified
      ultrafiltration). Interleukin 6, interleukin 10, tumor necrosis factor, terminal
      complement complex, and lactoferrin were measured before the operation (T0),
      before rewarming (T1), after ultrafiltration (T2), at 6 (T3) and 18 hours (T4)
      after the operation, and in the ultrafiltrate. RESULTS: All markers changed with
      both ultrafiltration methods, both filter types, and in all groups (except tumor
      necrosis factor) along the T0 to T4 observation time (P <.0001). Their patterns
      of changes were different for terminal complement complex, with less decrease
      after use of the polysulfon filter (P <.05), and among groups A through D for
      interleukin 6 (P =.01), with more decrease in group C than group A (P <.02).
      Interleukin 10 decreased with the polyamid filter (P <.001) but not with the
      polysulfon filter. In the ultrafiltrate, tumor necrosis factor was higher with
      the polysulfon filter than the polyamid filter (6.8 +/- 5 pg/mL vs 4.0 +/- 3.7
      pg/mL, P <.05). The ultrafiltrate/plasma ratio of interleukin 6 was higher with
      conventional ultrafiltration than modified ultrafiltration (0.018 +/- 0.017 vs
      0.004 +/- 0.007, P <.005). CONCLUSIONS: The polysulfon filter showed a filtration
      profile for inflammatory mediators superior to that of the polyamid filter for
      interleukin 6, tumor necrosis factor, and interleukin 10. Interleukin 6 was most
      efficiently removed by conventional ultrafiltration with a polysulfon filter, and
      tumor necrosis factor was best removed by modified ultrafiltration with a
      polysulfon filter, whereas other inflammatory mediators were not influenced by
      filter type or ultrafiltration method. Therefore combined conventional and
      modified ultrafiltration with a polysulfon filter may currently be the most
      effective strategy for removing inflammatory mediators in pediatric heart
      surgery.

PMID- 15173726
TI  - Evaluation of heart fatty acid-binding protein as a rapid indicator for
      assessment of myocardial damage in pediatric cardiac surgery.
AB  - OBJECTIVES: Perioperative myocardial damage is a major determinant of
      postoperative cardiac dysfunction for congenital heart disease. Heart fatty acid
      binding protein is reported to be a rapid marker of perioperative myocardial
      damage that peaks earlier than creatine kinase isoenzyme MB or cardiac troponin T
      in adults. The objective of this study was to assess the suitability of using
      serum concentrations of heart fatty acid-binding protein for evaluation of
      perioperative myocardial damage in pediatric cardiac surgery. METHODS: After
      institutional review board approval and informed consent, 100 children undergoing
      open procedures for congenital heart disease were prospectively enrolled in the
      study. Mean age at operation was 4.9 +/- 0.4 years. Serum concentrations of heart
      fatty acid-binding protein, creatine kinase isoenzyme MB, and cardiac troponin T
      were measured serially before operation and at 0, 1, 2, 3, and 6 hours after
      aortic declamping. Relationships between serum peak level of heart fatty acid
      binding protein and intraoperative and postoperative clinical variables were
      evaluated. RESULTS: Serum heart fatty acid-binding protein reached its peak level
      at 1 hour after declamping in 95 patients (95%), which was significantly earlier
      (P <.01) than serum creatine kinase isoenzyme MB or cardiac troponin T. In
      addition, serum heart fatty acid-binding protein level immediately after
      declamping correlated strongly with serum peak heart fatty acid-binding protein
      level (r = 0.91, P <.01). The serum peak level of heart fatty acid-binding
      protein correlated with those of creatine kinase isoenzyme MB (r = 0.77, P <.01)
      and cardiac troponin T (r = 0.80, P <.01). In the forward stepwise multiple
      regression analysis, age (P <.0001), aortic crossclamp time (P <.0001), the
      presence of a ventriculotomy (P <.001), and the lowest hematocrit level during
      cardiopulmonary bypass (P <.05) were significant intraoperative variables that
      influenced the release of heart fatty acid-binding protein. There were
      significant relationships between serum peak heart fatty acid-binding protein
      level and postoperative inotropic support, duration of intubation, and intensive
      care unit stay (P <.01 for each). CONCLUSIONS: Heart fatty acid-binding protein
      is a rapid marker for assessment of myocardial damage and clinical outcome in
      pediatric cardiac surgery. In particular, serum heart fatty acid-binding protein
      level immediately after aortic declamping may be a potentially useful prognostic
      indicator of myocardial damage as well as clinical outcome in pediatric cardiac
      surgery.

PMID- 15173727
TI  - The salvage potential of coronary sinus interventions: meta-analysis and
      pathophysiologic consequences.
AB  - OBJECTIVES: Intermittent coronary sinus occlusion has been described to be
      effective in salvaging ischemic myocardium. This meta-analysis aims to review the
      efficacy of intermittent coronary sinus occlusion and intermittent coronary sinus
      occlusion in combination with retroperfusion of arterial blood as methods of
      myocardial salvage. METHODS: A Medline search was performed to review the
      published literature on intermittent coronary sinus occlusion. The study
      inclusion criterion was a randomized, placebo-controlled trial with area of
      infarction (expressed as a percentage of the area at risk) as the primary end
      point. RESULTS: Seven experimental trials comprising 125 test animals were found
      that analyzed the effects of intermittent coronary sinus occlusion on ischemic
      damage during coronary occlusion. A further 5 studies comprising 88 animals were
      designed to evaluate the effect of intermittent coronary sinus occlusion in
      combination with retroperfusion of arterial blood on the infarct size. A meta
      analysis of the 7 studies analyzing the effect of intermittent coronary sinus
      occlusion revealed a significant reduction in infarct size of 29.3% in the
      treatment group compared with that in the placebo group (P <.001; 95% confidence
      interval, -40.9 to -17.7). A meta-analysis of the 5 trials analyzing the effect
      of intermittent coronary sinus occlusion in combination with retroperfusion
      revealed a reduction in infarct size of 39.4% in the treatment group compared
      with that in the placebo group (P <.001; 95% confidence interval, -48.9 to 
      29.9). Comparison between intermittent coronary sinus occlusion and intermittent
      coronary sinus occlusion in combination with retroperfusion of arterial blood
      showed no statistical difference (P =.19). An inverse relationship between
      achieved coronary sinus pressure increase per minute and infarct size could be
      found in the intermittent coronary sinus occlusion group (r = -0.92; P <.007),
      whereas in combination with retroperfusion, there was a negative correlation both
      between achieved coronary sinus pressure and the amount of the retroperfusate and
      myocardial salvage (r = -0.97; P <.004). CONCLUSIONS: The use of intermittent
      coronary sinus occlusion and intermittent coronary sinus occlusion in combination
      with retroperfusion of arterial blood significantly decreases ischemic damage
      during coronary occlusions. Intermittent coronary sinus occlusion in combination
      with retroperfusion exhibits no significant profit in salvaging the ischemic
      myocardium in comparison with that provided by intermittent coronary sinus
      occlusion alone.

PMID- 15173728
TI  - Load dependence of cardiac output in biventricular pacing: right ventricular
      pressure overload in pigs.
AB  - BACKGROUND: The effect of biventricular pacing on stroke volume is believed to be
      dependent on right ventricular/left ventricular delay, but effects in individual
      patients are unpredictable. This variability may reflect relative right and left
      ventricular volume and/or pressure overloads. Accordingly, we tested the
      hypothesis that the relation of cardiac output to right ventricular/left
      ventricular delay is load dependent in a pig model of pulmonary stenosis.
      METHODS: After median sternotomy in 6 anesthetized, domestic pigs, complete heart
      block was induced by ethanol ablation. During epicardial, atrial tracking DDD
      biventricular pacing, atrioventricular delay was varied between 60 and 180 ms in
      30-ms increments. Right ventricular/left ventricular delay was varied at each
      atrioventricular delay from +80 ms (right ventricle first) to -80 ms (left
      ventricle first) in 20-ms increments. Aortic flow, right ventricular pressure,
      peripheral arterial pressure, and electrocardiogram were measured in the control
      state and during pulmonary stenosis, created by tightening a snare around the
      pulmonary artery until cardiac output decreased by 50%. RESULTS: Atrioventricular
      and right ventricular/left ventricular delay had no effect on cardiac output
      during the control state, but during pulmonary stenosis there was a statistically
      significant (P =.0001, repeated-measures analysis of variance) right
      ventricular/left ventricular delay-related trend toward higher cardiac output
      with right ventricular pacing first. This effect was more pronounced when the
      optimal atrioventricular delay was determined first, resulting in a 20% increase
      in cardiac output when the optimal right ventricular/left ventricular delay was
      compared with simultaneous biventricular pacing. CONCLUSIONS: Optimized
      biventricular pacing in swine is associated with increased cardiac output during
      acute pulmonary stenosis, but not during the control state. Further studies are
      needed to determine whether specific types of right ventricular and left
      ventricular overload predictably affect the relation between right
      ventricular/left ventricular delay and cardiac output.

PMID- 15173729
TI  - Pharmacologic preconditioning of JTE-607, a novel cytokine inhibitor, attenuates
      ischemia-reperfusion injury in the myocardium.
AB  - BACKGROUND: Myocardial ischemia-reperfusion injury is a main cause of
      postoperative cardiac dysfunction, and a burst of proinflammatory cytokines, such
      as tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and
      interleukin 8, plays a pivotal role. Recently, JTE-607 has been reported as a
      potent inhibitor of the multiple inflammatory cytokines in the endotoxin shock
      mouse model. In this study we proved the hypothesis that JTE-607 might attenuate
      myocardial ischemia-reperfusion injury in a rat model. METHODS: The isolated rat
      hearts in the JTE-607 preconditioning group (J group, n = 8) or control group (C
      group, n = 8) were subjected to warm ischemia (37 degrees C) for 30 minutes,
      followed by 60 minutes of reperfusion with the Langendorff perfusion system.
      RESULTS: Left ventricular developed pressure and maximum dp/dt after reperfusion
      were significantly improved in the J group than in the C group (P <.01). Creatine
      phosphokinase leakage is significantly lower in the J group (P <.05). Moreover,
      the tissue cytokine levels, such as tumor necrosis factor alpha, interleukin 6,
      and interleukin 8, in the myocardium were significantly lower in the J group than
      in the C group (P <.05). CONCLUSION: These results suggested that the
      pharmacologic preconditioning of JTE-607 inhibits a burst of endogenous cytokines
      in the myocardium, resulting in the improvement of cardiac function after
      ischemia-reperfusion injury. Thus JTE-607 might be a novel therapeutic strategy
      for the protection of postoperative cardiac dysfunction in cardiac surgery.

PMID- 15173730
TI  - The effect of maternal hypothermic cardiopulmonary bypass on fetal lamb
      temperature, hemodynamics, oxygenation, and acid-base balance.
AB  - OBJECTIVE: To evaluate fetal-maternal temperature relationship and fetal
      cardiovascular and metabolic response during maternal hypothermic cardiopulmonary
      bypass in pregnant ewes. METHODS: Cardiopulmonary bypass was instituted in 9
      pregnant ewes, reaching 2 different levels of maternal hypothermia: 24 degrees C
      to 20 degrees C (deep hypothermia) in group A (5 cases) and less than 20 degrees
      C (very deep hypothermia) in group B (4 cases). Hypothermic levels were
      maintained for 20 minutes, then the rewarming phase was started. Fetal and
      maternal temperature, blood pressure, heart rate, electrocardiogram, blood gases,
      and acid-base balance were evaluated at different levels of hypothermia and
      during recovery. RESULTS: Fetal survival was related to maternal hypothermia: all
      group A fetuses survived, while 2 of 4 fetuses of group B in which maternal
      temperature was lowered below 18 degrees C died in a very deep acidotic and
      hypoxic status. Maternal temperature was always lower than fetal temperature
      during cooling; during rewarming the gradient was inverted. The start of
      cardiopulmonary bypass and cooling was associated with transient fetal
      tachycardia and hypertension; then, both fetal heart rate and blood pressure
      progressively decreased. The reduction of fetal heart rate was of 7 beats per
      minute for each degree of fetal cooling. Deep maternal hypothermia was associated
      with fetal alkalosis and reduction of Po(2). Very deep hypothermia, in particular
      below 18 degrees C, caused irreversible fetal acidosis and hypoxia. CONCLUSIONS:
      Deep maternal hypothermic cardiopulmonary bypass was associated with reversible
      modifications in fetal cardiovascular parameters, blood gases, and acid-base
      balance and therefore with fetal survival. On the contrary, fetuses did not
      survive to a very deep hypothermia below 18 degrees C.

PMID- 15173731
TI  - In vivo inhibition of neutrophil activity by a FAS (CD95) stimulating module:
      arterial in-line application in a porcine cardiac surgery model.
AB  - OBJECTIVE: Cardiac surgery with cardiopulmonary bypass is associated with
      aberrant neutrophil activation and potentially severe pathogenic sequelae. This
      experimental study was done to evaluate a leukocyte inhibition module that
      rapidly inactivates neutrophils through CD95 stimulation. METHODS: German
      landrace pigs (4 groups, each n = 5) underwent cardiac surgery without
      cardiopulmonary bypass (group I), with cardiopulmonary bypass (group II), with
      cardiopulmonary bypass plus a leukocyte filter (group III), and with
      cardiopulmonary bypass plus a leukocyte inhibition module (group IV). The
      leukocyte filter or leukocyte inhibition module was introduced into the arterial
      line of the heart-lung machine. RESULTS: Leukocyte counts were decreased by up to
      43% in group IV compared with values in group II (P =.023). In group IV, but not
      in groups I to III, no delay in spontaneous neutrophil apoptosis was observed
      after annexin V-propidium iodide staining. Late apoptotic (11.7%) or necrotic
      neutrophils (9.3%) were detected in 2 animals (group IV). Tumor necrosis factor
      alpha serum levels increased over time in groups I to III (>2-fold) but remained
      at baseline levels in group IV (P <.05). Interleukin 8-mediated chemotactic
      neutrophil transmigration activity increased over time in groups I to III but was
      totally abrogated in group IV at any time point. The perioperative increase of
      creatine kinase and creatine kinase MB levels was lower in groups III (1.5-fold
      and 1.3-fold, respectively) and IV (1.2-fold and 1.5-fold, respectively) compared
      with values in group II (both 1.9-fold). CONCLUSIONS: The leukocyte inhibition
      module downregulated cardiopulmonary bypass-related neutrophil activity and thus
      might be beneficial in cardiac surgery and other clinical settings with
      unappreciated neutrophil activation.

PMID- 15173732
TI  - Weaning of rotary blood pump recipients after myocardial recovery: a computer
      study of changes in cardiac energetics.
AB  - BACKGROUND: Weaning of patients from mechanical cardiac support after myocardial
      recovery has always involved multiple, interacting factors, particularly the
      training of the myocardium during reduction of pump flow. Rotary pumps offer
      training advantages when support flow is reduced, even to nearly zero. We report
      a computer analysis that evaluates the work required of the heart during partial
      unloading and removal of rotary pumps. METHODS AND RESULTS: A computer model of
      the assisted circulation, previously implemented in MATLAB (The MathWorks Inc,
      Natick, Mass), has been augmented with a model of the MicroMed DeBakey
      ventricular assist device (MicroMed Technology, Inc, Houston, Tex). Flow,
      pressure patterns, and external work (pressure-volume area, calculated as the
      area of the ventricular pressure-volume loop [external work] plus potential
      energy) were calculated for nonassisted and various continuously assisted
      patients. Under low-flow conditions, the heart imposes an oscillating forward
      backward flow through the non-occlusive rotary pump, causing an increase in
      ventricular work. Thus, an assist flow of 1 to 1.5 L/min requires work equivalent
      to that of the unsupported heart. At 60% contractility, the nonassisted pressure
      volume area is 1.10 Ws/beat, and the potential energy is 0.38 Ws/beat. At a Qpump
      of 1 L/min, the pressure-volume area is 1.21 Ws/beat, and the potential energy is
      0.37 Ws/beat. At a Qpump of 3 L/min, the pressure-volume area is 0.93 Ws/beat,
      and the potential energy is 0.29 Ws/beat. These conditions cannot be achieved
      with pulsatile systems. CONCLUSION: During weaning and retraining, an implanted
      rotary pump can provide a workload to the heart like that in the nonassisted
      situation, thus increasing the predictability of weaning and reducing the risk of
      reiterating heart failure.

PMID- 15173733
TI  - Myocardial blood supply through a direct left ventricle-coronary artery shunt is
      not aided by augmented coronary capacitance.
AB  - OBJECTIVES: Left ventricle-coronary artery shunting is proposed as an alternative
      means of myocardial revascularization when standard methods are not an option.
      During diastole, however, regurgitant coronary flow to the left ventricle
      decreases the efficacy of the left ventricle-coronary artery shunt. We
      investigated whether augmented coronary compliance would improve net forward
      shunt flow. METHODS: In 11 anesthetized pigs a specially designed stent was
      placed through the lateral wall of the left ventricle. Through an arterial graft,
      it was connected to the proximal left anterior descending coronary artery. A
      blind stump of the right internal thoracic artery (15 cm) was anastomosed to the
      distal left anterior descending coronary artery to serve as added coronary
      compliance chamber. Blood flow was measured in the coronary artery just distal
      from the left ventricle-coronary artery shunt, as well as in the shunt and in the
      compliance chamber entrance-exit. RESULTS: The left ventricle-coronary artery
      shunt decreased the net forward midcoronary flow to 53% +/- 18% (mean +/- SD) of
      native flow (8 +/- 4 vs 16 +/- 5 mL/min at baseline, P <.01). The augmented
      compliance did not significantly increase net forward coronary flow (61% +/- 25%
      of native flow, P <.01 vs baseline and P =.21 vs left ventricle-coronary artery
      shunt with normal compliance). The increase in systolic forward flow (53 +/- 23
      vs 37 +/- 19 mL/min with normal compliance) was accompanied by a similar increase
      in diastolic regurgitant flow (-26 +/- 20 vs -16 +/- 16 mL/min). CONCLUSION: In
      healthy pigs a left ventricle-coronary artery shunt decreased net forward
      coronary flow to 53% +/- 18% of native flow. Augmentation of coronary artery
      compliance did not improve shunt performance.

PMID- 15173734
TI  - Solid and gaseous cerebral microembolization during off-pump, on-pump, and open
      cardiac surgery procedures.
AB  - BACKGROUND: Neurocognitive dysfunction remains a limitation of cardiac surgery
      with cardiopulmonary bypass. Intraoperative cerebral microembolization is
      believed to be one of the most important etiologic factors. Using a new
      generation of transcranial Doppler ultrasonography, we compared the number and
      nature of intraoperative microemboli in patients undergoing on-pump and off-pump
      cardiac surgery procedures. METHODS: Bilateral continuous transcranial Doppler
      monitoring of the middle cerebral arteries was performed in 45 patients (15 off
      pump coronary artery bypass grafting, 15 on-pump coronary artery bypass grafting,
      and 15 open cardiac procedures). All recordings were performed using a multi
      range, multifrequency system to allow both measurement of the number and
      discrimination of the nature of microemboli in the 3 different groups. RESULTS:
      The median number (interquartile range) of microemboli in the off-pump coronary
      artery bypass grafting, on-pump coronary artery bypass grafting, and open
      procedure groups were 40 (28-80), 275 (199-472), and 860 (393-1321), respectively
      (P <.01). Twelve percent of microemboli in the off-pump coronary artery bypass
      grafting group were solid compared with 28% and 22% in the on-pump coronary
      artery bypass grafting and open procedure groups, respectively (P <.05). In the
      on-pump groups, 24% of microemboli occurred during cardiopulmonary bypass, and
      56% occurred during aortic manipulation (cannulation, decannulation, application,
      and removal of crossclamp or sideclamp). CONCLUSIONS: Cerebral microembolization
      is significantly reduced with avoidance of cardiopulmonary bypass. The majority
      of microemboli occurring during cardiac surgery are gaseous, with a higher
      proportion of solid microemboli in the on-pump group, and may have a different
      significance for cerebral injury than solid microemboli. The ability to reliably
      discriminate gas and solid microemboli may have an important role in the
      implementation of neuroprotective strategies.

PMID- 15173735
TI  - A bioabsorbable (polyglactin), nonrestrictive, external sheath inhibits porcine
      saphenous vein graft thickening.
AB  - OBJECTIVE: External, nonrestrictive, macro-porous polyester stents prevent
      neointima formation in porcine vein grafts and have been proposed as a
      therapeutic approach to the prevention of late vein graft failure. These stents
      are nonbiodegradable and therefore may promote long-term foreign body problems
      including infection and inflammation. The effect of external macro-porous
      biodegradable (polyglactin) sheaths on neointimal and medial thickening in
      porcine vein grafts was therefore investigated. METHODS: Bilateral saphenous vein
      carotid artery interposition grafting was performed in white Landrace pigs (n =
      8) with external placement of polyglactin (Vicryl) sheaths (8 mm in diameter) on
      1 side, with the contralateral side acting as a control. One month after surgery,
      grafts were explanted and wall dimensions measured on histological sections using
      computer-aided planimetry, and an immunocytochemical appraisal was carried out.
      RESULTS: All grafts were patent at explantation. Polyglactin sheaths
      significantly reduced intimal thickness, medial thickness, and the percentage of
      proliferating cells compared with unsheathed controls. There was a pronounced
      accumulation of macrophages, giant cells, endothelial cells, and microvessels
      within and surrounding the biodegradable sheath compared with controls.
      CONCLUSIONS: A nonrestrictive, biodegradable (polyglactin), external sheath
      reduces medial and intimal thickening in experimental saphenous vein grafts,
      possibly through inflammatory cell-mediated angiogenesis. If subsequent long-term
      studies confirm preservation of this beneficial effect, once the sheath
      biodegrades, this approach may have an advantage over the permanent polyester
      stent when applied clinically.

PMID- 15173736
TI  - Electrophysiologic and mechanical evidence of superiority of hyperpolarizing
      versus depolarizing cardioplegia in protection of endothelium-derived
      hyperpolarizing factor-mediated endothelial function: a study in coronary
      resistance arteries.
AB  - OBJECTIVE: The advantages of hyperpolarizing cardioplegia with potassium-channel
      openers versus depolarizing cardioplegia have been suggested but not demonstrated
      in coronary microarteries. This study examined the simultaneous electric and
      tonic alteration of coronary microarteries at the cellular level during and after
      exposure to depolarizing cardioplegia or hyperpolarizing cardioplegia, with
      emphasis on endothelium-derived hyperpolarizing factor-mediated relaxation and
      hyperpolarization. METHODS: Porcine coronary microarteries (diameter,
      approximately 200-400 microm) were incubated with depolarizing cardioplegia (20
      mmol/L KCl) or hyperpolarizing cardioplegia (10 micromol/L aprikalim) for 1 hour.
      Cellular membrane potential with a glass microelectrode in a coronary smooth
      muscle cell and isometric force of the muscle were simultaneously measured in a
      myograph. RESULTS: Depolarizing cardioplegia incubation produced a stable
      contraction (from 4.9 +/- 0.3 mN to 7.3 +/- 0.4 mN) and depolarization (from -51
      +/- 1 mV to -41 +/- 2 mV). In contrast, hyperpolarizing cardioplegia relaxed
      (from 4.8 +/- 0.3 mN to 3.5 +/- 0.3 mN) and hyperpolarized (from -51 +/- 2 mV to 
      56 +/- 1 mV) the smooth muscle. After exposure to depolarizing cardioplegia, the
      bradykinin-induced, endothelium-derived hyperpolarizing factor-mediated
      relaxation reduced from 66.2% +/- 5.0% to 18.4% +/- 3.7% (P <.001), and the
      membrane hyperpolarization reduced from 18 +/- 1 mV to 7 +/- 1 mV (P <.001) in
      the presence of indomethacin and N(G)-nitro-L-arginine. In contrast,
      hyperpolarizing cardioplegia did not affect the bradykinin-induced responses.
      CONCLUSIONS: In the coronary microarteries, exposure to hyperpolarizing
      cardioplegia preserves whereas depolarizing cardioplegia reduces the endothelium
      derived hyperpolarizing factor-mediated electric (hyperpolarization) and
      mechanical (relaxation) responses. Thus hyperpolarizing cardioplegia is superior
      to depolarizing cardioplegia in protecting the endothelial function in the
      coronary microcirculation.

PMID- 15173737
TI  - Higher bypass temperature correlates with increased white cell activation in the
      cerebral microcirculation.
AB  - OBJECTIVE: Cardiopulmonary bypass induces a systemic inflammatory response, which
      in turn promotes a cascade of leukocyte and endothelial cell activity. We
      investigated whether differences in bypass temperature and flow rate affect
      endothelial cell and leukocyte adhesion in the cerebral microcirculation.
      METHODS: Thirty-six piglets (13.0 +/- 1.1 kg) had a cranial window placed over
      the parietal cortex to evaluate the microcirculation by means of intravital
      microscopy. Animals were cooled to a temperature of 15 degrees C, 25 degrees C,
      or 34 degrees C on cardiopulmonary bypass with hematocrit levels of 20% or 30% by
      using pH-stat management, followed by 60 minutes of reduced flow (10, 25, or 50
      mL.kg(-1).min(-1)). Rhodamine staining was used to observe adherent and rolling
      leukocytes in postcapillary venules. RESULTS: Higher bypass temperature
      correlated with significantly more adherent and rolling leukocytes during the
      full 60 minutes of low-flow bypass (P <.05). Poisson regression revealed more
      adherent leukocytes at 34 degrees C than at 15 degrees C and at a flow rate of 10
      mL.kg(-1).min(-1) compared with a flow rate of 50 mL.kg(-1).min(-1). There was an
      inverse correlation between flow rate and the number of adherent and rolling
      leukocytes at 30, 45, and 60 minutes of low-flow bypass (P <.05). Temperature was
      a multivariable predictor of histologic score, with greater neurologic damage
      found after bypass at 34 degrees C (P <.01). CONCLUSIONS: Leukocyte activation in
      cerebral microcirculation is increased with higher temperature and lower flow
      rate, suggesting that these variables influence the inflammatory response during
      cardiopulmonary bypass.

PMID- 15173738
TI  - Optimal timing of cardiac transplantation after ventricular assist device
      implantation.
AB  - OBJECTIVE: We sought to determine the influence of the interval from ventricular
      assist device implantation to cardiac transplantation on end-organ function and
      posttransplantation survival. METHODS: United Network for Organ Sharing data on
      2692 heart transplantations performed in adult patients in the United States
      between October 1999 and March 2001 were reviewed. RESULTS: Seventeen percent
      (466) of adult heart transplant recipients were bridged to transplantation with a
      ventricular assist device. Almost half of patients with ventricular assist
      devices undergoing transplantation were upgraded to status 1A as a result of
      ventricular assist device-related complications occurring more than 30 days after
      ventricular assist device implantation. Creatinine and total bilirubin levels
      were less in patients undergoing transplantation after 2 to 4 weeks of mechanical
      support. One-year survival was higher in the nonventricular assist device than in
      the ventricular assist device group (85.7% vs 79.7%, P =.0004). Within the
      ventricular assist device group, survival was lower for patients undergoing
      transplantation within 2 weeks of ventricular assist device implantation compared
      with those undergoing transplantation later (74.2% vs 84.2 %, P =.03). One-year
      survival among patients supported with a ventricular assist device for more than
      30 days without complications was 91.4%. Multivariate analysis demonstrated a
      significant independent effect of the time interval from ventricular assist
      device implantation to transplantation on posttransplantation mortality and
      suggested that a period of lowest risk might exist between 1 and 3 months after
      implantation. CONCLUSIONS: Survival after cardiac transplantation is influenced
      by the time interval from ventricular assist device insertion to transplantation.
      Survival is significantly lower when performed within 2 to 4 weeks of ventricular
      assist device implantation.

PMID- 15173739
TI  - HLA sensitization in ventricular assist device recipients: does type of device
      make a difference?
AB  - BACKGROUND: We sought to (1) characterize the temporal pattern of T-cell panel
      reactive antibody during ventricular assist device support, (2) identify
      predictors of higher T-cell panel reactive antibody during ventricular assist
      device support, and (3) determine whether device type remained a predictor after
      accounting for nonrandom device selection. METHODS: Between December 1991 and
      August 2000, 239 patients received implantable ventricular assist devices, of
      whom 231 had T-cell panel reactive antibody measured. Panel reactive antibody was
      measured before implantation of the assist device, approximately 2 weeks after
      device implantation, irregularly thereafter depending on clinical events and
      length of support, and at transplantation. Longitudinal mixed modeling was used
      to characterize the temporal pattern of sensitization and its predictors during
      ventricular assist device support. To account for nonrandom factors in device
      selection when comparing HeartMate (Thermo Cardiosystems, Inc, Woburn, Mass) and
      Novacor (Baxter Healthcare Corp, Novacor Div, Oakland, Calif) devices, we
      propensity-matched patients according to baseline characteristics. RESULTS: T
      cell panel reactive antibody increased rapidly after implantation of the
      ventricular assist device and then immediately began to decrease. Predictors of
      higher T-cell panel reactive antibody during support with the assist device were
      a shorter interval from device implantation to T-cell panel reactive antibody
      measurement (P <.0001), female sex (P =.0004), younger age (P =.01), higher T
      cell panel reactive antibody before device implantation (P =.03), more
      perioperative red blood cell transfusions (P =.006), and an earlier date of
      device implantation (P =.001). In matched patients, device type was not a
      predictor of higher T-cell panel reactive antibody during ventricular assist
      device support (P =.8). CONCLUSIONS: HLA sensitization during ventricular assist
      device support is not constant but increases rapidly at implantation and then
      decreases. This temporal pattern of sensitization is influenced by patient
      factors and not by the type of device.

PMID- 15173740
TI  - Successful treatment of a Stanford type A dissection by percutaneous placement of
      a covered stent graft in the ascending aorta.

PMID- 15173741
TI  - The dilemma of skeletonized internal thoracic artery sequential bypass versus
      proximal pedicled in situ internal thoracic artery plus coronary-coronary free
      internal thoracic artery bypass for multiple lesions of the left anterior
      descending coronary artery.

PMID- 15173742
TI  - Activated recombinant factor VII for refractory bleeding during extracorporeal
      membrane oxygenation.

PMID- 15173743
TI  - Changes in platelet aggregation after suspension of aspirin therapy.

PMID- 15173744
TI  - Surgical pitfalls during explantation of a thoracic aortic endoprosthesis.

PMID- 15173745
TI  - Should heart transplantation be considered as a treatment option for patients
      aged 70 years and older?

PMID- 15173746
TI  - Superior vena cava stenosis: a delayed BioGlue complication.

PMID- 15173747
TI  - New technologies for the treatment of type A aortic dissection: a case report.

PMID- 15173748
TI  - Repair of a sinus of valsalva aneurysm that had ruptured into the pulmonary
      artery.

PMID- 15173749
TI  - Anatomic variations of the radial artery: significance when harvesting for
      coronary artery bypass grafting.

PMID- 15173750
TI  - Retrograde segmental aortic repair for type II thoracoabdominal aortic aneurysm.

PMID- 15173751
TI  - Resection of a pleomorphic carcinoma of the lung invading the descending aorta.

PMID- 15173752
TI  - Mediastinal parathyroidectomy with the da Vinci robot: presentation of a new
      technique.

PMID- 15173753
TI  - Congenital cystic adenomatoid malformation in a middle-aged woman with
      hemoptysis.

PMID- 15173754
TI  - Transhiatal esophagogastrectomy for an isolated ovarian cancer metastasis to the
      esophagus.

PMID- 15173755
TI  - Massive pneumoencephalus of late onset after an en bloc resection for lung
      cancer.

PMID- 15173756
TI  - Rupture of a chronic expanding hematoma of the thorax into lung parenchyma.

PMID- 15173757
TI  - Thyroid metastasis after resection of atypical bronchial carcinoid.

PMID- 15173758
TI  - An autopsy case of angiosarcoma arising around a woven Dacron prosthesis after a
      Cabrol operation.

PMID- 15173759
TI  - Thymolipoma with high production of carbohydrate antigen 19-9.

PMID- 15173760
TI  - The robotic, 2-stage, 3-field esophagolymphadenectomy.

PMID- 15173761
TI  - Obstruction of St Jude Medical valves in the aortic position.

PMID- 15173762
TI  - Prosthesis size and prosthesis-patient size are unrelated to prosthesis-patient
      mismatch.

PMID- 15173763
TI  - Epidemiologic contrast of predictors' trends for outcomes of coronary artery
      bypass grafting: heart failure versus ventricular function versus left main
      disease.

PMID- 15173764
TI  - Extracapsular lymph node involvement in esophageal cancer and number of involved
      nodes.

PMID- 15173765
TI  - Skeletonized bilateral internal thoracic arteries in patients with diabetes:
      additional advantages and concerns.

PMID- 15173766
TI  - A lost opportunity.

PMID- 15173767
TI  - Nuclear cardiology in randomized multicenter clinical trials.

PMID- 15173768
TI  - In retroSPECT: the prognostic value of nuclear cardiology-past, present, and
      future.

PMID- 15173769
TI  - Is it time for SPECT attenuation correction?

PMID- 15173770
TI  - Tomographic equilibrium radionuclide angiography: has its time arrived?

PMID- 15173771
TI  - Challenges and strategies in the provision of high-quality nuclear cardiology
      imaging services in office-based cardiology practice.

PMID- 15173772
TI  - The prognostic value of ECG-gated SPECT imaging in patients undergoing stress Tc
      99m sestamibi myocardial perfusion imaging.
AB  - BACKGROUND: The ability of stress radionuclide myocardial perfusion imaging to
      predict adverse cardiac events is well accepted. As left ventricular systolic
      function has also been shown to be an important prognostic indicator, the
      objective of this study was to determine whether electrocardiography (ECG)-gated
      single photon emission computed tomography (SPECT) functional data add additional
      power. METHODS AND RESULTS: In this study 3207 patients who underwent stress
      myocardial perfusion imaging with ECG gating, without early (</=60 days)
      revascularization, were studied. Subsequent nonfatal myocardial infarction and
      cardiac death were related to perfusion and ECG-gated SPECT ventricular function
      parameters. Cox proportional hazards regression analysis was used to evaluate the
      independent predictive value of these parameters, as well as their added utility
      over clinical and ECG parameters. Patients with abnormal perfusion images had an
      annual event rate of 5.1% compared with 1.6% for patients with normal images (P
      <.001). An abnormal gated SPECT wall motion score was associated with an annual
      event rate of 6.1% compared with 1.6% for a normal score (P <.001), and an
      abnormal left ventricular ejection fraction was associated with an event rate of
      7.4% compared with 1.8% for normal patients (P <.001). Abnormal ECG-gated SPECT
      results worsened outcome in both patients with normal perfusion images and those
      with abnormal perfusion images. Cardiac death was predicted by the number of
      territories with a perfusion defect and an abnormal ejection fraction, whereas
      myocardial infarction was predicted by the number of territories with a perfusion
      defect but not by ejection fraction. CONCLUSIONS: Ventricular function data from
      ECG-gated SPECT add important prognostic value to data obtained from perfusion
      imaging alone in predicting adverse cardiac events.

PMID- 15173773
TI  - Quantitative Tc-99m sestamibi attenuation-corrected SPECT: development and
      multicenter trial validation of myocardial perfusion stress gender-independent
      normal database in an obese population.
AB  - BACKGROUND: A gender-independent stress normal database and criteria for
      abnormality for attenuation-corrected rest-stress technetium 99m sestamibi same
      day myocardial perfusion imaging were developed by evaluation of 112 patients,
      validated against an obese population of 95 patients from four different clinical
      sites, and compared with conventional gender-matched database quantification of
      non-attenuation-corrected studies. METHODS AND RESULTS: These 95 validation
      patients (63 men) were used for prospective quantitative evaluation (mean weight,
      213 +/- 57 lb; mean body mass index, 32 +/- 9 kg/m(2)). This group included 21
      patients (12 men) with a lower than 5% likelihood of coronary artery disease
      (mean weight, 226 +/- 72 lb; mean body mass index, 34 +/- 13 kg/m(2)) and 74 who
      underwent cardiac catheterization within 2 months (35 with normal coronaries or
      coronary lesions <70%). These studies were processed twice, once by use of
      conventional reconstruction and gender-specific database quantification and a
      second time by use of attenuation correction and a single gender-independent
      attenuation-corrected normal database. The attenuation-corrected normal database
      and criteria for abnormality were developed by evaluation of 48 and 78 patients,
      respectively. No statistically significant differences were found when comparing
      attenuation-corrected perfusion distributions of normal men and women, whereas
      significant differences were found in the same uncorrected studies. Compared with
      quantitative analysis of the uncorrected studies, quantitative analysis of the
      attenuation-corrected studies by use of a gender-independent normal database
      demonstrated a significant improvement in normalcy rate (90% vs 52%, P =.006) and
      specificity (57% vs 29%, P =.015) in this obese population at no significant loss
      in sensitivity (90% vs 97%, P = not significant). CONCLUSION: Attenuation
      corrected studies can be quantified with a single gender-independent normal
      database and a single criterion for abnormality without loss of sensitivity and
      with significantly better specificity and normalcy rate.

PMID- 15173774
TI  - Clinical value of attenuation correction in stress-only Tc-99m sestamibi SPECT
      imaging.
AB  - BACKGROUND: Attenuation artifact remains a substantial limitation to confident
      interpretation of images and reduces laboratory efficiency by requiring
      comparison of stress and rest image sets. Attenuation-corrected stress-only
      imaging has the potential to ameliorate these limitations. METHODS AND RESULTS:
      Ten experienced nuclear cardiologists independently interpreted 90 stress-only
      electrocardiography (ECG)-gated technetium 99m sestamibi images in a sequential
      fashion: myocardial perfusion imaging (MPI) alone, MPI plus ECG-gated data, and
      attenuation-corrected MPI with ECG-gated data. Images were interpreted for
      diagnostic certainty (normal, probably normal, equivocal, probably abnormal,
      abnormal, and perceived need for rest imaging). With stress MPI data alone, only
      37% of studies were interpreted as definitely normal or abnormal, with a very
      high perceived need for rest imaging (77%). The addition of gated data did not
      alter the interpretations. However, attenuation-corrected data significantly
      increased the number of studies characterized as definitely normal or abnormal
      (84%, P <.005) and significantly reduced the perceived need for rest imaging
      (43%, P <.005). These results were confirmed by use of a nonsequential consensus
      interpretation of three readers. CONCLUSION: Attenuation correction applied to
      studies with stress-only Tc-99m ECG-gated single photon emission computed
      tomography images significantly increases the ability to interpret studies as
      definitely normal or abnormal and reduces the need for rest imaging. These
      findings may improve laboratory efficiency and diagnostic accuracy.

PMID- 15173775
TI  - Model dependence of gated blood pool SPECT ventricular function measurements.
AB  - BACKGROUND: Calculation differences between various gated blood pool (GBP) single
      photon emission computed tomography (SPECT) (GBPS) algorithms may arise as a
      result of different modeling assumptions. Little information has been available
      thus far regarding differences for right ventricular (RV) function calculations,
      for which GBPS may be uniquely well suited. METHODS AND RESULTS: Measurements of
      QBS (Cedars-Sinai Medical Center, Los Angeles, Calif) and BP-SPECT (Columbia
      University, New York, NY) algorithms were evaluated. QBS and BP-SPECT left
      ventricular (LV) ejection fraction (EF) correlated strongly with conventional
      planar-GBP LVEF for 422 patients (r = 0.81 vs r = 0.83). QBS correlated
      significantly more strongly with BP-SPECT for LVEF than for RVEF (r = 0.80 vs r =
      0.41). Both algorithms demonstrated significant gender differences for 31 normal
      subjects. BP-SPECT normal LVEF (67% +/- 9%) was significantly closer to values in
      the magnetic resonance imaging (MRI) literature (68% +/- 5%) than QBS (58% +/-
      9%), but both algorithms underestimated normal RVEF (52% +/- 7% and 50% +/- 9%)
      compared with the MRI literature (64% +/- 9%). For 21 patients, QBS correlated
      similarly to MRI as BP-SPECT for LVEF (r = 0.80 vs r = 0.85) but RVEF correlation
      was significantly weaker (r = 0.47 vs r = 0.81). For 16 dynamic phantom
      simulations, QBS LVEF correlated similarly to BP-SPECT (r = 0.81 vs r = 0.91) but
      QBS RVEF correlation was significantly weaker (r = 0.62 vs r = 0.82). Volumes
      were lower by QBS than BP-SPECT for all data types. CONCLUSIONS: Both algorithms
      produced LV parameters that correlated strongly with all forms of image data, but
      all QBS RV relationships were significantly different from BP-SPECT RV
      relationships. Differences between the two algorithms were attributed to
      differences in their underlying ventricular modeling assumptions.

PMID- 15173776
TI  - Automatic quantification of right ventricular function with gated blood pool
      SPECT.
AB  - BACKGROUND: Quantification of right ventricular (RV) function is clinically
      relevant for the risk stratification and follow-up of patients with a wide
      spectrum of disease. This can be achieved with electrocardiography-gated blood
      pool single photon emission computed tomography (GBPS). We aimed to evaluate the
      accuracy of the completely automatic QBS GBPS processing software as compared
      with equilibrium planar radionuclide angiography (RNA) and with a GBPS manual
      segmentation method (GBPS(35%)) for the measurement of global RV ejection
      fraction (EF), taking the first-pass RNA (FP-RNA) as the gold standard. In
      parallel, we compared the RVEF, RV end-diastolic volume (EDV), and RV end
      systolic volume (ESV) provided by QBS and GBPS(35%). METHODS AND RESULTS: The
      population included 85 patients with chronic post-embolic pulmonary hypertension.
      Twenty-one patients were excluded because of unsuccessful FP-RNA. Intraobserver
      and interobserver RVEF, RVEDV, and RVESV reproducibilities encountered with
      planar RNA, QBS, and GBPS(35%) were similar and compared favorably with those
      calculated with FP-RNA for RVEF. Mean RVEF was different between all methods.
      RVEF calculated with FP-RNA was better correlated to QBS (r = 0.68) and GBPS(35%)
      (r = 0.70) than to planar RNA (r = 0.59). RVEDV and RVESV with QBS were lower
      than with GBPS(35%), by 29% +/- 14% and 36% +/- 13%, respectively. RVEDV and
      RVESV with QBS were highly correlated to corresponding GBPS(35%) values: r = 0.88
      and r = 0.91, respectively. CONCLUSION: As opposed to FP-RNA, GBPS is highly
      successful for the quantification of RV function. Both QBS and GBPS(35%) provide
      RVEF values similarly well correlated to FP-RNA and performed better than planar
      RNA. RVEF, RVEDV, and RVESV provided by QBS and GBPS(35%) are highly correlated.
      All of these RV functional measurements require further validation versus a
      better gold standard before their accuracy can be established.

PMID- 15173777
TI  - Dipyridamole-induced abnormal Tl-201 lung uptake in patients with normal
      myocardial perfusion: a marker of increased left ventricular filling pressures.
AB  - BACKGROUND: The mechanism of dipyridamole-induced abnormal increased T1-201 lung
      uptake in patients without coronary artery disease is poorly understood. The
      purpose of this study was to evaluate the relation between dipyridamole-induced
      abnormal T1-201 lung uptake and left ventricular (LV) diastolic indexes using
      Doppler, color M-mode and Tissue Doppler modalities at rest, and at dipyridamole
      stress echocardiograpy (DSE) in patients with normal myocardial perfusion and LV
      function. METHODS AND RESULTS: 18 consecutive patients (mean age 64 +/- 7 years)
      with normal myocardial perfusion and increased lung T1-201 uptake on dipyridamole
      stress-redistribution single photon emission computed tomography (SPECT) were
      included in our study. These patients were compared with 18 age-matched control
      patients with normal perfusion and normal T1-201 lung uptake. All patients
      underwent DSE. A good correlation was found between the T-201 lung uptake, the
      peak early velocity of mitral inflow (E, r = 0.57) and estimated pulmonary
      capillary wedge pressure (PCWP = 1.24[E/Ea] + 1.9, r = 0.68). In patients with
      increased L/H ratio compared to control group, the E and the PCWP were
      significantly higher at baseline 81 +/- 18 vs 68 +/- 11 (cm/s) and 13 +/- 3 vs
      10.2 +/- 2 (mmHg). An additional significant increase of E to 91 +/- 23 (cm/s (P
      = 0.001)) and PCWP to 14.8 +/- 3 (P = 0.005) after dipyridamole administration
      was seen; in contrast to a nonsignificant change observed in control group. For
      the detection of a dipyridamole induced PCWP >12 mmHg, a L/H ratio of >/=50% had
      a sensitivity of 72% and a specificity of 83%, resulting in a positive and a
      negative predictive value of 81% and 75%, respectively. CONCLUSIONS: A
      dipyridamole-induced abnormal T1-201 lung uptake in patients with normal
      myocardial perfusion and systolic function is predictive of elevated filling
      pressures at rest and in response to dipyridamole administration, probably
      reflecting an intrinsic resting diastolic dysfunction and a further abnormal
      response to vasodilatation.

PMID- 15173778
TI  - Impact of photon energy recovery on the assessment of left ventricular volume
      using myocardial perfusion SPECT.
AB  - BACKGROUND: Photon energy recovery (PER) is a spectral deconvolution technique
      validated for scatter removal in patients and phantom studies. The purpose of
      this study was to examine the impact of PER on left ventricular volume
      measurement based on myocardial perfusion single photon emission computed
      tomography (SPECT). METHODS AND RESULTS: SPECT acquisitions were performed by use
      of a static cardiac phantom and in 25 patients after a rest injection of
      technetium 99m sestamibi by use of multiple energy windows (126-136, 137-144, and
      145-154 keV). Data were successively reconstructed with and without PER, by use
      of iterative reconstruction and post-processing filtering (Butterworth filter;
      order, 5; cutoff, 0.30 cycles/pixel). Image contrast was evaluated in
      reconstructed data, and volumes were calculated by use of QGS. PER increased
      reconstructed image contrast from 62% +/- 2.7% to 84.3% +/- 5.7% in the phantom
      studies (P <.0001) and from 49% +/- 2% to 73% +/- 2% in patients (P <.0001).
      Although it remained underestimated (P <.0001), phantom volume was higher after
      PER correction compared with uncorrected data (50.9 +/- 0.8 mL vs 44.6 +/- 1 mL,
      P <.0001). The error in volume measurement was decreased by PER correction (16.6%
      +/- 1.3% vs 27% +/- 1.7% [uncorrected data], P <.0001). In patients, left
      ventricular volume increased from 83 +/- 10 mL to 91 +/- 10 mL (P <.0001), and
      the PER-induced volume increase was correlated with the image contrast increase
      (r = 0.61, P =.001). Finally, the percentage of volume increase was higher in
      patients with small left ventricular volumes. CONCLUSIONS: PER has a significant
      impact on image contrast and left ventricular volume measurement by use of
      perfusion SPECT. PER improves the accuracy of phantom volume assessment. In
      patients, volume increase is correlated to image contrast increase and is higher
      in those with small ventricles.

PMID- 15173779
TI  - The historical and conceptual evolution of radionuclide assessment of myocardial
      viability.

PMID- 15173781
TI  - Role of molecular imaging in defining and denying death...

PMID- 15173782
TI  - Churg-Strauss syndrome and myocardial perfusion SPECT imaging.

PMID- 15173783
TI  - Correct identification of a myocardial perfusion SPECT lesion leads to early
      diagnosis of lung cancer.

PMID- 15173780
TI  - Advances in nuclear cardiology: preoperative risk stratification.

PMID- 15173785
TI  - Tools for endoscopic stricture dilation.

PMID- 15173786
TI  - Monitoring equipment for endoscopy.

PMID- 15173787
TI  - Can patient characteristics predict the outcome of endoscopic evaluation of iron
      deficiency anemia: a multiple logistic regression analysis.
AB  - BACKGROUND: The purpose of this study was to identify clinical and biochemical
      variables that predict the outcome of upper/lower endoscopy in outpatients with
      iron deficiency anemia and to determine which endoscopic procedure should be
      performed first. METHODS: Ninety-eight patients (74 women, 24 men; mean age 55
      years) with iron deficiency anemia referred from the hematology department were
      interviewed and responded to a questionnaire that included clinical and
      biochemical variables, and underwent EGD (with biopsies) and colonoscopy. The
      endoscopic findings were recorded as presence/absence of GI cancer, upper/lower
      GI tract lesions and bleeding/non-bleeding-associated GI lesions. A multiple
      logistic regression analysis was applied to identify variables significantly
      related with the outcome of the investigations. Multiple analyses were performed
      so that a Bonferroni correction for multiple testing removed significance except
      where p<0.01. RESULTS: A likely cause of iron deficiency anemia was found in
      86.7% of patients. The risk factors for GI malignancies were: male gender (OR
      7.5: 95% CI[1.7, 31.9]; p<0.01), advanced age (OR 1.1/y: 95% CI[1, 1.2]; p<0.01),
      and lower mean corpuscular volume (OR 1.1/unit: 95% CI[1, 1.2]; p<0.002). The
      risk factors for bleeding-related diseases were the following: greater age (OR
      1.1/y: 95% CI[1.1, 1.2]; p<0.001), absence of lower-GI tract symptoms (OR 4.7:
      95% CI[1.3, 16.6]; p<0.05), and a positive fecal occult blood test (OR 4.1: 95%
      CI[1.2, 14.3]; p<0.05). The risk factors for non-bleeding-related GI tract
      diseases were the following: negative fecal occult blood test (OR 4.5: 95%
      CI[1.16, 20]; p<0.05) and higher Hb level (OR 1.4/unit: 95% CI[1.1, 1.8];
      p<0.05). CONCLUSIONS: For non-hospitalized patients with iron deficiency anemia,
      colonoscopy should be the initial investigation in those greater than 50 years of
      age, particularly men, and those without upper-GI tract symptoms and with lower
      values for mean corpuscular volume and Hb. EGD should be performed first in
      younger patients, particularly those with a mild decrease in Hb and a negative
      fecal occult blood test.

PMID- 15173788
TI  - A risk score system for identification of patients with upper-GI bleeding
      suitable for outpatient management.
AB  - BACKGROUND: The aim of this study was to develop a risk score system for
      identification of patients with upper-GI hemorrhage who are suitable for
      outpatient management. METHODS: From a prospective cohort of 983 consecutive
      patients with upper-GI hemorrhage not associated with portal hypertension, 581
      cases that did not meet pre-established criteria for admission were selected, and
      a logistic regression analysis was performed to identify factors associated with
      two adverse outcomes: recurrent bleeding and/or the need for emergency surgery.
      The risk score system was developed by using the beta coefficients of the
      logistic model, and its performance was evaluated. The results of this model were
      combined with pre-established criteria for admission to build a simplified
      scoring system for identification of patients who can be managed safely on an
      outpatient basis. RESULTS: Chronic alcoholism, active malignancy, prior upper
      digestive tract surgery, wasting syndrome, hemodynamic compromise, duodenal ulcer
      as the cause of upper-GI hemorrhage, and hemorrhage of unknown cause were
      independently associated with a greater risk of unfavorable outcomes in the group
      that did not meet pre-established criteria for admission. The logistic model
      showed a high capacity for discrimination (C statistic: 0.87) and good
      calibration (p value for Hosmer-Lemeshow goodness-of-fit test, 0.62), with a
      sensitivity of 100% and specificity of 64%. The simplified score had a
      sensitivity of 100% and specificity of 29% for adverse outcomes, and sensitivity
      of 78% and specificity of 38% for mortality. CONCLUSIONS: The score system
      developed in this study may be helpful in deciding between hospitalization and
      outpatient management for patients with upper-GI hemorrhage, but it remains to be
      validated in patient groups other than those used for its development.

PMID- 15173789
TI  - Can clinical features predict the likelihood of finding abnormalities when using
      capsule endoscopy in patients with GI bleeding of obscure origin?
AB  - BACKGROUND: Capsule endoscopy is becoming the investigation of choice for GI
      bleeding of obscure etiology. This study examined whether clinical or other
      features predict an increased likelihood of finding a lesion in patients with
      this type of bleeding. METHODS: Clinical and other data were collected
      prospectively for 92 patients undergoing capsule endoscopy for GI bleeding of
      obscure origin. Patients were divided into two groups: those with overt bleeding
      (42 patients) and those with anemia alone (50 patients). The relationship between
      these data and the findings at capsule endoscopy was examined. RESULTS: A
      definite or probable cause of bleeding was found in 60 patients (angiodysplasias
      47, tumor 7, ulcer 3, gastric antral vascular ectasia 2). There was no difference
      between the two groups with respect to age, gender, mode of presentation,
      duration of bleeding, or need for transfusion. Lesions were found as often in
      patients who had only one preceding endoscopy and colonoscopy as in those who had
      multiple procedures. Colonic cleansing and cecal imaging by the capsule did not
      influence the result. Hospitalized patients were more likely to have an actively
      bleeding lesion detected. CONCLUSIONS: Capsule endoscopy is equally useful in
      patients with overt and occult GI bleeding of obscure origin. Capsule endoscopy
      should be performed early in the evaluation of these patients.

PMID- 15173790
TI  - The frequency of peptic ulcer as a cause of upper-GI bleeding is exaggerated.
AB  - BACKGROUND: Peptic ulcer disease is considered the cause of upper-GI bleeding in
      50% of cases. A recent decline in the proportion of cases of upper-GI bleeding
      because of a peptic ulcer was noted by us. The objectives of this study were to
      evaluate the frequency of peptic ulcer in patients with upper-GI bleeding and the
      proportion of bleeding peptic ulcers with a non-bleeding visible vessel. METHODS:
      Patients with upper-GI bleeding seen from December 1999 until April 2001 at a
      tertiary, university-affiliated medical center were studied prospectively. The
      Clinical Outcome Research Initiative (CORI) database was used to correlate the
      single institution data with nationwide data. Endoscopic data in the CORI
      database for patients who had endoscopy for upper-GI bleeding between December
      1999 and July 2001 were retrieved and analyzed. RESULTS: A total of 126 patients
      were included in the prospective study. The endoscopic findings were: peptic
      ulcer in 31.8%: 95% confidence interval (CI) [23.7%, 40.6%] of patients; a non
      bleeding visible vessel was present in 10%: 95% CI[2.8%, 23.7%] of these peptic
      ulcers. From the nationwide CORI database, data for 7822 patients with upper-GI
      bleeding were obtained. The endoscopic findings were: peptic ulcer in 20.6%:95%
      CI[19.7%, 21.5%] of patients with upper-GI bleeding; a non-bleeding visible
      vessel was present in 7.3%: 95% CI[6.1%, 8.6%] of the ulcers. CONCLUSIONS: The
      frequency of peptic ulcer in patients with upper-GI bleeding and the proportion
      of bleeding ulcers with a non-bleeding visible vessel are less than previously
      reported.

PMID- 15173791
TI  - Moderate level sedation during endoscopy: a prospective study using low-dose
      propofol, meperidine/fentanyl, and midazolam.
AB  - BACKGROUND: Propofol provides several benefits over benzodiazepine and narcotic
      agents as a sedative medication for endoscopic procedures, including faster
      recovery and improved patient satisfaction. However, its use generally has been
      limited to anesthesiologists because of the risks associated with deep sedation.
      METHODS: One hundred patients undergoing colonoscopy or EGD were sedated with low
      dose propofol, midazolam, and fentanyl (or meperidine). Depth of sedation was
      assessed at 2-minute intervals by an independent observer by using the American
      Society of Anesthesiologists criteria. Recovery time was determined by using
      paired neuropsychometric tests. A post-procedure satisfaction survey and 24-hour
      follow-up questionnaires were administered. RESULTS: For colonoscopy and EGD,
      respectively, the mean propofol dose was 98 mg and 79 mg, the mean midazolam dose
      was 0.9 mg and 0.8 mg, the mean fentanyl dose was 69 mcg and 63 mcg, and the mean
      meperidine dose was 42 mg (for both procedures). There were 628 assessments of
      the level of sedation performed during 74 colonoscopies and 101 assessments
      during 26 EGDs. The level of sedation was minimal in 77%, moderate in 21%, and
      deep in 2% of assessments. Nine of the 13 episodes of deep sedation were recorded
      during colonoscopy and 4 during EGD. In no instance was more than a single
      assessment of deep sedation recorded during one procedure. Ninety-eight percent
      of patients were satisfied with the sedation, and 71% returned to their usual
      activities within 2 hours of discharge. There was no serious adverse event.
      CONCLUSIONS: Endoscopic sedation with low-dose propofol, a narcotic agent, and
      midazolam produces a moderate level of sedation. The quality of sedation and
      measures of recovery are comparable with the results reported with standard-dose
      propofol.

PMID- 15173792
TI  - Detachable endoloop vs. elastic band ligation for bleeding esophageal varices.
AB  - BACKGROUND: Variceal bleeding is a serious complication with a mortality rate
      that ranges from 20% to 50%. Patients who have variceal hemorrhage usually are
      treated by endoscopic injection sclerotherapy or elastic band ligation to
      eradicate the varices. Endoloop ligation is a newly developed technique for
      achieving hemostasis and variceal eradication. This study compared endoloop
      ligation with elastic band ligation in patients with acute esophageal variceal
      bleeding. METHODS: Fifty patients with acute esophageal variceal bleeding were
      recruited: 25 were treated by elastic band ligation and 25 by endoloop ligation.
      RESULTS: Although the number of patients in whom bleeding recurred during a
      follow-up period of 6 months was smaller in the endoloop group (12%) vs. the band
      group (28%), this difference was not statistically significant. Furthermore, no
      statistically significant difference was found between the two groups with
      respect to the number of patients in whom variceal eradication was achieved, the
      number of treatment sessions required for variceal eradication, or the frequency
      of variceal recurrence. The total cost for variceal obliteration by endoloop
      ligation was 342 dollars per patient, whereas, the total cost of variceal
      eradication by elastic band ligation was 356 dollars per patient. The endoloop
      had certain technical advantages over band application: a better field of vision,
      tighter application, good results with junctional varices, and a lack of strain
      exerted by the device on the endoscope. CONCLUSIONS: Endoloop ligation is a
      promising new technique for management of patients with bleeding esophageal
      varices.

PMID- 15173793
TI  - Cardia-type metaplasia arising in the remnant esophagus after cardia resection.
AB  - BACKGROUND: Specialized intestinalized metaplasia in the distal esophagus
      (Barrett's esophagus) is a recognized precursor of esophageal adenocarcinoma, but
      its pathogenesis is incompletely understood. The aim of this study was to
      investigate the mucosal effects of esophagogastrostomy, an artificial interface
      between esophageal squamous and gastric oxyntic epithelium. METHODS: EGD was
      performed in 14 consecutive patients (median age 63 years, range 26-71 years) who
      had undergone esophagogastrostomy from 3 to 88 months earlier. Biopsy specimens
      were obtained in 13 patients from the anastomosis and, when present, columnar
      epithelium in the remnant esophagus. RESULTS: In 10 patients, EGD demonstrated
      tongue-shaped segments of columnar epithelium extending from 0.3 to 7 cm into the
      remnant esophagus. Biopsy specimens revealed cardia-type mucosa in all patients,
      whether at the anastomosis or proximally in esophageal segments of columnar
      epithelium. Magnification endoscopy of cardia-type mucosa visualized a long-oval,
      tubular, or ridged surface pattern. In 3 cases, complete intestinal metaplasia
      was observed within the cardia-type mucosa. CONCLUSIONS: The frequent
      transformation of squamous epithelium into cardia-type mucosa in the distal
      remnant esophagus after esophagogastrostomy supports the concept that cardia-type
      mucosa is a reflux-induced metaplasia that may give rise to the subsequent
      development of specialized intestinalized metaplasia.

PMID- 15173794
TI  - Mangafodipir-enhanced magnetic resonance cholangiography for the diagnosis of
      bile duct leaks.
AB  - BACKGROUND: The purpose of this prospective study was to assess the value of
      contrast-enhanced magnetic resonance cholangiography with mangafodipir trisodium
      perfusion for detection and localization of trauma-induced and postoperative bile
      duct leaks. METHODS: Eleven patients with suspected bile duct leaks after trauma
      (n=5) or surgery (n=6) were included. Patients with suspected leaks after
      cholecystectomy were excluded. All patients underwent contrast-enhanced magnetic
      resonance cholangiography with two-dimensional axial and three-dimensional
      coronal gradient-echo images acquired 1 to 3 hours after intravenous
      administration of mangafodipir trisodium perfusion. Contrast-enhanced magnetic
      resonance cholangiography findings were correlated with direct cholangiography
      obtained in all patients, including endoscopic retrograde (n=7) and percutaneous
      transhepatic cholangiography (n=4). RESULTS: Biliary tract enhancement was
      identified in all patients on contrast-enhanced magnetic resonance
      cholangiography. Peritoneal cavity fluid and bile collections that contained
      extravasated mangafodipir trisodium (increased signal intensity on gradient-echo
      sequences) were demonstrated in 6 patients. Direct cholangiography confirmed the
      presence of bile duct leaks in these 6 patients and the absence of bile duct
      leaks in 5 patients. There was no false-negative or false-positive contrast
      enhanced magnetic resonance cholangiography. CONCLUSIONS: Mangafodipir-enhanced
      magnetic resonance cholangiography is a noninvasive technique that can provide
      functional biliary information with excellent depiction of bile duct leaks.

PMID- 15173795
TI  - Macrocystic pancreatic cystadenoma: The role of EUS and cyst fluid analysis in
      distinguishing mucinous and serous lesions.
AB  - BACKGROUND: Benign pancreatic serous cystadenoma usually is morphologically
      distinguishable from mucinous cystadenomas, which require resection because of
      their malignant potential. A macrocystic variant of serous cystadenoma recently
      has been described, rendering this important distinction more difficult. The aim
      of this study was to determine the EUS and tumor marker characteristics of
      mucinous cystadenoma compared with macrocystic serous cystadenomas. METHODS:
      Medical records for consecutive patients seen between 1995 and 2002, with a
      histopathologic diagnosis of mucinous cystadenoma or macrocystic serous
      cystadenoma after surgery, who had undergone a detailed EUS examination,
      including EUS-guided FNA, were retrospectively reviewed. RESULTS: A resection
      specimen was available for 32 mucinous cystadenomas and 9 macrocystic serous
      cystadenomas. No significant differences were observed with regard to clinical
      data (age, gender, presence of symptoms), lesion size, and location within the
      pancreas. All mucinous cystadenomas had a discernible cyst wall (thickened, 66%;
      focal parietal nodules, 25%) compared with 56% of macrocystic serous cystadenomas
      (p<0.0001). A thick echo content also was more frequent in mucinous cystadenoma
      (56% vs. 11%; p=0.04; statistical significance removed by the Bonferroni
      correction). Microcysts were only observed in macrocystic serous cystadenomas
      (44%; p=0.0008). The combination of a cyst wall that is thickened and the absence
      of microcysts had a sensitivity of 100% and specificity of 78% for the diagnosis
      of mucinous cystadenoma compared with macrocystic serous cystadenoma. Although
      intracystic carbohydrate-associated antigen 72-4 and mucins M1 were non
      discriminatory, low carcinoembryonic antigen (<5 ng/mL) and carbohydrate
      associated antigen 19-9 (<50,000 U/mL) values were found in macrocystic serous
      lesions (respectively, 100% and 100%; p=0.0002 and p=0.0002). CONCLUSIONS:
      Although there is considerable overlap, helpful EUS characteristics that
      differentiate mucinous cystadenoma from macrocystic serous cystadenoma include a
      thick cyst wall and microcysts. These features, coupled with analysis of
      aspirated fluid for tumor markers (especially carcinoembryonic antigen), should
      help to confirm the diagnosis.

PMID- 15173796
TI  - A simple way of avoiding post-ERCP pancreatitis.
AB  - BACKGROUND: Pancreatitis occurs in up to 30% of patients who undergo ERCP. This
      study tested the hypothesis that post-ERCP pancreatitis can be avoided by
      initially accessing the bile duct with a soft-tipped Teflon tracer 0.035-inch
      guidewire. METHODS: A single endoscopist performed ERCP in 400 consecutive
      patients with pancreatobiliary disease who were randomized to two groups. In
      Group A (200 patients), the bile duct was first accessed by insertion of a soft
      tipped Teflon tracer (diameter 0.035 inch) guidewire through a 6F, double channel
      sphincterotome, followed by cannulation, injection of contrast, and
      sphincterotomy. In Group B (200 patients), the bile duct was opacified by using
      traditional methods of cannulation. RESULTS: No case of acute pancreatitis was
      detected in Group A, whereas, 8 cases were observed in Group B (6 mild, one
      moderate, one severe) (p < 0.01). In 9 patients in Group A vs. 39 in Group B (p <
      0.001), the serum amylase rose to more than 5 times the upper normal limit during
      the 24 hours after the procedure. There was no procedure-related mortality.
      CONCLUSIONS: Accessing the bile duct with a soft-tipped tracer guidewire prevents
      post-ERCP pancreatitis.

PMID- 15173797
TI  - White specks in the esophageal mucosa: An endoscopic manifestation of non-reflux
      eosinophilic esophagitis in children.
AB  - BACKGROUND: White specks in the esophageal mucosa have been observed in children
      with eosinophilic esophagitis. The aim of this study was to determine the
      relationship between white specks in the esophageal mucosa and allergic (non
      reflux) eosinophilic esophagitis. METHODS: Endoscopic data, pH probe results, and
      histopathology reports for children with esophageal endoscopic abnormalities seen
      during a 17-month period were reviewed. Eosinophilic esophagitis was grouped
      according to the number of eosinophils per high power field (non-allergic, <15
      eosinophils/high power field; allergic, > or =15 eosinophils/high power field).
      RESULTS: Of 1041 endoscopies performed during the study period, 153 revealed
      evidence of eosinophilic esophagitis. Of these 153, 61 had fewer than 15
      eosinophils/high power field and 92 had 15 or more eosinophils/high power field.
      At 31 of the 153 procedures, white specks were noted in the esophageal mucosa.
      The sensitivity of white specks in the esophageal mucosa for allergic
      eosinophilic esophagitis was only 30%, but the specificity was 95%. pH probe
      testing was performed in 21 patients with white specks and was normal in all.
      CONCLUSIONS: This report describes a new endoscopic finding associated with
      allergic eosinophilic esophagitis in children. Eosinophilic esophagitis tends to
      be severe when white specks are present (> or =15 eosinophils/high power field)
      and is not associated with pathologic gastroesophageal reflux, as demonstrated by
      pH probe testing.

PMID- 15173798
TI  - An evaluation of laparoscopic cholecystectomy after selective percutaneous
      transhepatic gallbladder drainage for acute cholecystitis.
AB  - BACKGROUND: The aim of this study was to evaluate the safety and usefulness of
      laparoscopic cholecystectomy after selective percutaneous transhepatic
      gallbladder drainage in patients with severe acute cholecystitis and patients
      with acute cholecystitis and severe comorbid disease. METHODS: According to
      whether percutaneous transhepatic gallbladder drainage was performed before
      surgery, 133 patients with acute cholecystitis were divided into a percutaneous
      transhepatic gallbladder drainage group (n=60) and non-percutaneous-transhepatic
      gallbladder-drainage group (n=73). Background factors, safety, and postoperative
      course were retrospectively evaluated and compared between these two groups.
      RESULTS: Compared with the non-percutaneous-transhepatic-gallbladder-drainage
      group, the percutaneous transhepatic gallbladder drainage group was significantly
      older (p=0.0009), had a higher frequency of comorbid disease (p=0.0252), and a
      worse American Society of Anesthesiology classification (p=0.0021). In individual
      statistical tests, body temperature (p=0.0288), white blood cell count
      (p=0.0175), and C-reactive protein value (p=0.0022) were significantly elevated
      in the percutaneous transhepatic gallbladder drainage group; however, for
      frequency of comorbid disease, body temperature, and white blood cell count,
      significance was removed by correction for multiple testing of data. There was no
      significant difference in gender distribution, history of upper abdominal
      surgery, or body mass index between the two groups. The duration of surgery was
      marginally but significantly longer in the percutaneous transhepatic gallbladder
      drainage group (p=0.0414; in a single statistical test; however, that
      significance was removed by correction for the multiple testing of data). Between
      the two groups, there was no significant difference in blood loss at surgery,
      frequency of postoperative complications, rate of conversion to open laparotomy,
      interval until oral feeding was resumed, and length of postoperative hospital
      stay. CONCLUSIONS: These data suggest that satisfactory outcomes can be achieved
      with selective pre-operative gallbladder drainage in older and sicker patients
      with acute cholecystitis.

PMID- 15173799
TI  - Prevention of post-ERCP pancreatitis: a comprehensive review.

PMID- 15173800
TI  - Autoimmune pancreatitis.

PMID- 15173801
TI  - Adenoma of the duodenal papilla.

PMID- 15173802
TI  - Large, flat colon cancer.

PMID- 15173803
TI  - Colonic muco-submucosal elongated polyp.

PMID- 15173804
TI  - Bile duct varices.

PMID- 15173805
TI  - Tracheoesophageal fistula.

PMID- 15173806
TI  - Polyp associated with rectal prolapse.

PMID- 15173807
TI  - Chewing gum bezoar.

PMID- 15173808
TI  - Pancreatic pseudocysts (Part I).

PMID- 15173809
TI  - Photodynamic therapy with green light and m-tetrahydroxyphenyl chlorin for
      intramucosal adenocarcinoma and high-grade dysplasia in Barrett's esophagus.
AB  - BACKGROUND: The eradication of early stage neoplastic lesions in Barrett's
      esophagus is imperative to prevent invasive adenocarcinoma. Early stage lesions
      have an extremely low risk of lymph node metastasis, thereby, making local
      treatment feasible. Photodynamic therapy destroys malignant cells by a
      photochemical effect. The aims of this study were to evaluate the efficacy and
      tolerance of photodynamic therapy with green light and a new photosensitizer,
      temoporfin or m-tetrahydroxyphenyl chlorin in patients with Barrett's esophagus
      and early stage neoplastic lesions. METHODS: Four days after injection of m
      tetrahydroxyphenyl chlorin, lesions were illuminated at a wavelength of 514 nm
      through non-circumferential windowed diffusers. Follow-up endoscopy with biopsies
      was performed at regular intervals. RESULTS: Fourteen lesions (7 high-grade
      dysplasia, 7 intramucosal adenocarcinoma) in 12 patients were treated. For all
      lesions, efficacy was 100% and squamous re-epithelialization was complete. Side
      effects were of moderate severity (one stricture). Mean follow-up was 34 (15)
      months (range 12-68 months). CONCLUSIONS: Green light photodynamic therapy with m
      tetrahydroxyphenyl chlorin can eradicate early stage neoplastic lesions in
      Barrett's esophagus and may be proposed as an alternative first-line therapy or a
      second-line therapy after failure of other endoscopic treatments. The efficacy
      and patient tolerance of the procedure justify further studies of the method in
      larger groups of patients.

PMID- 15173810
TI  - Initial experience with catheter probe US when using a multibending endoscope.
AB  - BACKGROUND: High-frequency catheter probe US provides detailed images when the
      scanning plane is perpendicular to the area of interest and the latter is within
      the focal zone. A multibending endoscope has been developed that has two bending
      sections that can be deflected independently. The aim of this study was to
      determine whether this new endoscope enhances high-frequency catheter probe US.
      METHODS: High-frequency catheter probe US was performed with the multibending
      endoscope in 33 patients with upper-GI lesions. The endoscope was carefully
      maneuvered until the scanning plane was perpendicular to the area of interest and
      the target area was within the focal zone of the probe. The effects of deflecting
      the second bending section on the image and on the rotating elements in the probe
      were evaluated. RESULTS: For 28 lesions, no improvement was observed with use of
      both bending sections. However, for 5 lesions, the US image was improved by use
      of the second bending section. These lesions were located in the stomach on the
      lesser or greater curve. In no instance did deflection of both bending sections
      result in uneven rotation of the mechanical elements in the probe. CONCLUSIONS:
      For certain lesions, US images obtained with a catheter probe can be improved by
      using an endoscope with a second bending section.

PMID- 15173811
TI  - Initial experience with a new peroral electronic pancreatoscope with an accessory
      channel.
AB  - BACKGROUND: A peroral electronic pancreatoscope was previously developed to
      improve visualization of the pancreatic duct, but this instrument had no
      accessory channel. METHODS: A new peroral electronic pancreatoscope (2.6-mm
      external diameter) with an accessory channel (0.5 mm) was developed. Peroral
      pancreatoscopy or cholangioscopy was performed with this new instrument in 11
      patients with various pancreatobiliary diseases. The clinical utility of the new
      peroral electronic pancreatoscope was assessed, and visualization with this new
      instrument was compared with that of the prototype. RESULTS: The resolution of
      the two instrument systems was nearly equal, with that provided by the new
      peroral electronic pancreatoscope being slightly better. The new peroral
      electronic pancreatoscope was inserted successfully into the pancreatic or bile
      duct in 9 of the 11 patients (82%). Observation of a predetermined target and
      juice collection with direct visualization was successful in 8 of the 9 patients
      (89%). CONCLUSIONS: The new peroral electronic pancreatoscope with an accessory
      channel was useful for clinical diagnosis of various pancreatobiliary diseases.
      Visualization is excellent. Pancreatic juice and other samples can be collected
      under direct visualization.

PMID- 15173812
TI  - Endoscopic minor papilla interventions in patients without pancreas divisum.
AB  - BACKGROUND: Endoscopic treatment through the minor papilla is well known in
      patients with pancreas divisum. However, there are few data concerning endoscopic
      minor papilla interventions in patients without pancreas divisum when access to
      the main pancreatic duct via the major papilla is technically difficult. METHODS:
      Records for 213 patients without pancreas divisum who, from April 2001 to June
      2003, underwent ERCP for various pancreatic diseases were retrospectively
      reviewed. Patients were included if they had endoscopic interventions via the
      minor papilla because access through the major papilla was not possible.
      OBSERVATIONS: Minor papilla papillotomy or fistulotomy with endoscopic
      interventions was successful in 10 (91%) of 11 patients. Of these 10 patients, 9
      had chronic pancreatitis and one had pancreatic ductal leak from previous
      pancreatic surgery. The reasons for the inability to access the main pancreatic
      duct to the tail of the gland via the major papilla included a distorted course
      of the main pancreatic duct (n=5), impacted stone (n=5), and stricture (n=8). In
      8 patients, there were two causes. No complication related to the minor papilla
      interventions was observed in any patient. CONCLUSIONS: Endoscopic minor papilla
      interventions are technically feasible in patients with pancreatic diseases but
      not pancreas divisum when access to the main pancreatic duct via the major
      papilla is not possible.

PMID- 15173813
TI  - The spectrum of GI strongyloidiasis: an endoscopic-pathologic study.
AB  - BACKGROUND: The aim of this study was a detailed endoscopic-pathologic assessment
      of patients with various forms of GI strongyloidiasis. METHODS: Six patients with
      a diagnosis of GI strongyloidiasis who underwent endoscopic evaluation during a 3
      year period (January 1998-January 2001) were included. Published information was
      reviewed in detail, focusing on the endoscopic features and the diagnostic
      approach to this parasitosis. OBSERVATIONS: Strongyloidiasis has a broad range of
      endoscopic features. In the duodenum, the findings included edema, brown
      discoloration of the mucosa, erythematous spots, subepithelial hemorrhages, and
      megaduodenum. In the colon, the findings included loss of vascular pattern,
      edema, aphthous ulcers, erosions, serpiginous ulcerations, and xanthoma-like
      lesions, and, in the stomach, thickened folds and mucosal erosions. A
      histopathologic diagnosis of strongyloidiasis was made in all cases. CONCLUSIONS:
      Strongyloidiasis can involve any segment of the GI tract. EGD with procurement of
      biopsy specimens from the duodenum was the most accurate method of diagnosis in
      this case series.

PMID- 15173814
TI  - Septic complications after injection of N-butyl-2-cyanoacrylate: report of two
      cases and review.

PMID- 15173815
TI  - Portal-hypertensive-gastropathy-like changes in a patient with secondary
      polycythemia: reversal of endoscopic and histopathologic changes with phlebotomy.

PMID- 15173816
TI  - GI stromal tumor unmasked by argon plasma coagulation of vascular ectasia.

PMID- 15173817
TI  - Melanoma seeding of an EUS-guided fine needle track.

PMID- 15173818
TI  - Chemical esophagitis after chromoendoscopy with Lugol's solution for esophageal
      cancer: case report.

PMID- 15173819
TI  - Aspiration of a capsule endoscope.

PMID- 15173820
TI  - Intraluminal radiotherapy and Nd:YAG laser photoablation for primary malignant
      melanoma of the esophagus.

PMID- 15173821
TI  - Unusual complications of argon plasma coagulation.

PMID- 15173822
TI  - Polo-like kinases and the orchestration of cell division.

PMID- 15173823
TI  - Modulation of signalling by Sprouty: a developing story.

PMID- 15173824
TI  - Gene regulation by riboswitches.

PMID- 15173825
TI  - Juxtamembrane autoinhibition in receptor tyrosine kinases.

PMID- 15173826
TI  - Plant trichomes: a model for cell differentiation.

PMID- 15173827
TI  - Dynamic microtubules lead the way for spindle positioning.

PMID- 15173828
TI  - Nuclear stress bodies: a heterochromatin affair?

PMID- 15173829
TI  - Gamma-secretase: proteasome of the membrane?

PMID- 15173830
TI  - Therapeutic potential of oral tolerance.

PMID- 15173831
TI  - Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40.

PMID- 15173832
TI  - Adhesion mechanisms regulating the migration of monocytes.

PMID- 15173833
TI  - Mathematical and computational models of immune-receptor signalling.

PMID- 15173834
TI  - Sick and tired: Does sleep have a vital role in the immune system?

PMID- 15173835
TI  - Hydrophobicity: an ancient damage-associated molecular pattern that initiates
      innate immune responses.

PMID- 15173836
TI  - Interactions between commensal intestinal bacteria and the immune system.

PMID- 15173837
TI  - GSK3 inhibitors: development and therapeutic potential.

PMID- 15173838
TI  - Antibody-targeted radiation cancer therapy.

PMID- 15173839
TI  - Targeted therapy for brain tumours.

PMID- 15173840
TI  - Antimalarial drug discovery: efficacy models for compound screening.

PMID- 15173841
TI  - Science, pharmacoeconomics and ethics in drug R&D: a sustainable future scenario?

PMID- 15173842
TI  - Microbubbles in medical imaging: current applications and future directions.

PMID- 15173843
TI  - A preliminary FMRI study of sustained attention in euthymic, unmedicated bipolar
      disorder.
AB  - The symptoms of bipolar disorder suggest dysfunction of anterior limbic networks
      that modulate emotional behavior and that reciprocally interact with dorsal
      attentional systems. Bipolar patients maintain a constant vulnerability to mood
      episodes even during euthymia, when symptoms are minimal. Consequently, we
      predicted that, compared with healthy subjects, bipolar patients would exhibit
      abnormal activation of regions of the anterior limbic network with corresponding
      abnormal activation of other cortical areas involved in attentional processing.
      In all, 10 unmedicated euthymic bipolar patients and 10 group-matched healthy
      subjects were studied with fMRI while performing the Continuous Performance Task
      Identical Pairs version (CPT-IP). fMRI scans were obtained on a 3.0 T Bruker
      system using an echo planar imaging (EPI) pulse sequence, while subjects
      performed the CPT-IP and a control condition to contrast group differences in
      regional brain activation. The euthymic bipolar and healthy subjects performed
      similarly on the CPT-IP, yet showed significantly different patterns of brain
      activation. Specifically, bipolar patients exhibited increased activation of
      limbic, paralimbic, and ventrolateral prefrontal areas, as well as visual
      associational cortices. Healthy subjects exhibited relatively increased
      activation in fusiform gyrus and medial prefrontal cortex. In conclusion, these
      differences suggest that bipolar patients exhibit overactivation of anterior
      limbic areas with corresponding abnormal activation in visual associational
      cortical areas, permitting successful performance of an attentional task. Since
      the differences occurred in euthymia, they may represent trait, rather than
      state, abnormalities of brain function in bipolar disorder.

PMID- 15173845
TI  - Nonstereotyped responding in positive schizotypy after a single dose of levodopa.
AB  - Stereotyped behavior and left-sided orientation biases, associated with the
      dopamine (DA) system, were observed in populations of the schizophrenia spectrum
      disorders. We investigated whether heightened DA concentrations influence both
      side biases and stereotyped responding in a visuo-motor computer task, in which
      90, 180, and 270 degrees rotated objects had to be brought into a target
      position. To account for the role of the schizophrenia spectrum, task performance
      was also analyzed as a function of healthy participants' high or low magical
      ideation (MI), a positive schizotypal feature. The first 36 participants (20
      women) remained substance free. In a second sample, 20 men received levodopa and
      20 men a placebo in a double-blind procedure. Results showed that high MI scorers
      responded more stereotyped than low MI scorers, without being specifically biased
      towards the left side. Rotation preferences toward one or the other side made
      high MI scorers less flexible for objects efficiently to be rotated into the
      opposite direction. This inflexibility may reflect impaired left hemisphere
      functioning. Unexpectedly, in the levodopa group, high MI scorers performed
      superior to low MI scorers. Since DA actions appear to follow an inverted U-shape
      function, the 'low' performing high MI scorers profited from the enhanced DA
      availability. Our observation in the levodopa group points to a dissociation
      between schizotypy and schizophrenia: while cognitive improvement in
      schizophrenia can occur after treatment with atypical neuroleptic agents, in our
      positive schizotypal participants a DA agonist resulted in improved task
      performance. This dissociation may point to protective neurochemical mechanisms
      preventing healthy schizotypes from developing full-blown psychotic symptoms.

PMID- 15173846
TI  - Accepting the East.

PMID- 15173844
TI  - The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in
      healthy individuals: implications for psychosis.
AB  - Recent advances in the understanding of brain cannabinoid receptor function have
      renewed interest in the association between cannabinoid compounds and psychosis.
      In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral,
      cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9
      tetrahydrocannabinol (Delta-9-THC) were characterized in 22 healthy individuals,
      who had been exposed to cannabis but had never been diagnosed with a cannabis
      abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also
      collected. Delta-9-THC (1) produced schizophrenia-like positive and negative
      symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria;
      (5) disrupted immediate and delayed word recall, sparing recognition recall; (6)
      impaired performance on tests of distractibility, verbal fluency, and working
      memory (7) did not impair orientation; (8) increased plasma cortisol. These data
      indicate that Delta-9-THC produces a broad range of transient symptoms,
      behaviors, and cognitive deficits in healthy individuals that resemble some
      aspects of endogenous psychoses. These data warrant further study of whether
      brain cannabinoid receptor function contributes to the pathophysiology of
      psychotic disorders.

PMID- 15173849
TI  - Magnetic semiconductors: engineering ferromagnetism.

PMID- 15173847
TI  - Materials science: a field about to explode?

PMID- 15173850
TI  - Nanostructured metals: retaining ductility.

PMID- 15173851
TI  - Coarsening dynamics: flowing complex shapes.

PMID- 15173852
TI  - Nanopores: flossing with DNA.

PMID- 15173854
TI  - Material witness: what's so pure about science?

PMID- 15173853
TI  - Nanowire synthesis: constructive destruction.

PMID- 15173855
TI  - Energy density of foods and beverages in the Australian food supply: influence of
      macronutrients and comparison to dietary intake.
AB  - OBJECTIVES: The energy density (ED) of the diet is considered an important
      determinant of total energy intake and thus energy balance and weight change. We
      aimed to compare relationships between ED and macronutrient content in individual
      food and beverage items as well as population diet in a typical Western country.
      DESIGN: Nutrient data for 3673 food items and 247 beverage items came from the
      Australian Food and Nutrient database (AusNut). Food and beverage intake data
      came from the 1995 Australian National Nutrition Survey (a 24-h dietary recall
      survey in 13 858 people over the age of 2). Relationships between ED and
      macronutrient and water content were analysed by linear regression with 95%
      prediction bands. RESULTS: For both individual food items and population food
      intake, there was a positive relationship between ED and percent energy as fat
      and negative relationships between ED and percent energy as carbohydrate and
      percent water by weight. In all cases, there was close agreement between the
      slopes of the regression lines between food items and dietary intake. There were
      no clear relationships between ED and macronutrient content for beverage items.
      Carbohydrate (mostly sucrose) contributed 91, 47, and 25% of total energy for
      sugar-based, fat-based, and alcohol-based beverages respectively. CONCLUSIONS:
      The relationship between ED and fat content of foods holds true across both
      population diets and individual food items available in the food supply in a
      typical Western country such as Australia. As high-fat diets are associated with
      a high BMI, population measures with an overall aim of reducing the ED of diets
      may be effective in mediating the growing problem of overweight and obesity.

PMID- 15173856
TI  - The effect of different nutritional feeds on the postprandial glucose response in
      healthy volunteers and patients with type II diabetes.
AB  - OBJECTIVE: Assessment of postprandial glycaemic response to four nutritional
      feeds with different macronutrient and fibre composition. DESIGN: A randomized,
      double-blind, crossover study. SETTING: University of Maastricht, the
      Netherlands. SUBJECTS: A total of 10 healthy volunteers and 10 patients with type
      II diabetes. INTERVENTIONS: Subjects received 200 kcal of four enteral nutrition
      products (two standard products and two diabetes-specific products). Fasting and
      postprandial plasma glucose were measured for 2 h. Peak glucose level and area
      under the curve were calculated. RESULTS: In healthy volunteers and diabetic
      patients, the feed with a low carbohydrate (CHO), high monounsaturated fatty acid
      (MUFA) and high fibre content significantly decreased peak glucose concentration
      and area under the curve compared to the feeds with standard composition.
      CONCLUSIONS: Special feeds with a low CHO, high MUFA and high fibre content
      improve glycaemic balance and therefore should be considered in diabetic patients
      who are in need of nutritional support.

PMID- 15173858
TI  - Multicenter randomized phase III trial of epirubicin plus paclitaxel vs
      epirubicin followed by paclitaxel in metastatic breast cancer patients: focus on
      cardiac safety.
AB  - The aim of the study was to evaluate cardiac safety of two different schedules of
      Epirubicin and Paclitaxel in advanced breast cancer patients enrolled into a
      multicenter randomized phase III trial. Patients received Epirubicin 90 mg m(-2)
      plus Paclitaxel 200 mg m(-2) (3-h infusion) on day 1 every 3 weeks for eight
      courses (arm A), or Epirubicin 120 mg m(-2) on day 1 every 3 weeks for four
      courses followed by four courses of Paclitaxel 250 mg m(-2) on day 1 every 3
      weeks (arm B). Left ventricular ejection fraction was evaluated by bidimesional
      echocardiography at baseline, after four and eight courses of chemotherapy and
      every 4 months during follow-up. Baseline median left ventricular ejection
      fraction was 60% in arm A and 65% in arm B; after four courses, figures were 57
      and 60%, respectively. After eight courses, the median left ventricular ejection
      fraction in arm A declined to 50% while no further reduction was detected in arm
      B by adding four courses of high-dose Paclitaxel. Seven episodes of congestive
      heart failure were observed during treatment in arm A. Present monitoring
      demonstrated that the risk of congestive heart failure or impairment in the
      cardiac function correlated only with the cumulative dose of Epirubicin; no
      impact on cardiotoxicity can be attributed to high-dose Paclitaxel.

PMID- 15173857
TI  - Antiangiogenic activity of aplidine, a new agent of marine origin.
AB  - The antineoplastic compound aplidine, a new marine-derived depsipeptide, has
      shown preclinical activity in vitro on haematological and solid tumour cell
      lines. It is currently in early phase clinical trials. The exact mechanism of
      action of this anticancer agent still needs to be clarified. We have previously
      reported that aplidine blocks the secretion of the angiogenic factor vascular
      endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting
      a possible effect on tumour angiogenesis. This study was designed to investigate
      the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic
      membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis
      elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9
      ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of
      patients, aplidine inhibited endothelial cell functions related to angiogenesis.
      It affected VEGF- and FGF-2-induced endothelial cell proliferation, inhibited
      cell migration and invasiveness assessed in the Boyden chamber and blocked the
      production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells.
      Finally, aplidine prevented the formation of capillary-like structures by
      endothelial cells on Matrigel. These findings indicate that aplidine has
      antiangiogenic activity in vivo and inhibits endothelial cell functional
      responses to angiogenic stimuli in vitro. This effect might contribute to the
      antineoplastic activity of aplidine.

PMID- 15173859
TI  - Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk
      of colorectal cancer.
AB  - Inflammation plays a key role in the development of colorectal cancers. We have
      investigated the relationship between PTGS2 (COX2) polymorphisms and colorectal
      cancer risk in a hospital based case-control study. We recruited 292 patients
      with colorectal cancer and 274 controls from new patients admitted to Bellvitge
      Hospital, Barcelona, Spain, from 1996 to 1998. Subjects responded to a
      questionnaire on risk factors. Genotypes of the eight more frequent polymorphisms
      of PTGS2 were determined. Two polymorphisms are located in the promoter sequence,
      one in the untranslated region of exon 1, one in exon 3, one in intron 5, two in
      the untranslated region of exon 10, and one downstream of the last
      polyadenylation (poly-A) signal. Associations were analysed with logistic
      regression models assuming a dominant effect for rare variants to increase
      statistical power. An association was detected between colorectal cancer and a
      polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio
      (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01. A nearby
      polymorphism downstream of the last poly-A signal also showed a nonsignificant
      increase in risk (OR 2.17, 95% CI 0.99-4.78, P=0.05). Analysis of haplotypes
      confirmed that individuals with these variants were at increased risk of
      colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97
      4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti
      inflammatory drugs and risk of colorectal cancer were also explored.

PMID- 15173861
TI  - Editorial.

PMID- 15173860
TI  - Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of
      NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of
      full-length TRAIL.
AB  - TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo-2L) is a
      promising novel anticancer agent that selectively induces apoptosis in tumour
      cells and the activity of which can be enhanced by combined treatment with chemo-
      or radiotherapy. For therapeutic purposes, the use of full-length TRAIL may be
      favourable to recombinant TRAIL based on its increased tumour cell killing
      potential, and the delivery of TRAIL at the tumour site by adenovirus vectors may
      provide an approach to overcome the short half-life of recombinant TRAIL and
      hepatocyte toxicity in vivo. Here, we constructed an adenoviral vector expressing
      full-length TRAIL (AdTRAIL) and studied the potential of chemo- and radiotherapy
      in enhancing AdTRAIL-induced apoptosis in non-small cell lung cancer (NSCLC) H460
      cells and normal cells and, in addition, investigated the mechanism of AdTRAIL
      induced apoptosis. AdTRAIL effectively killed H460 cells, which we previously
      showed to have a deficiency in mitochondria-dependent apoptosis by downstream
      activation of caspase-8 rather than caspase-9. Further analyses revealed that
      AdTRAIL induces death receptor- and mitochondria-dependent apoptosis that could
      be partially suppressed by Bcl2 overexpression. Combined treatment with
      doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX) and radiation strongly
      enhanced AdTRAIL-induced cytotoxicity in a synergistic way. Synergy was
      accompanied by the cleavage of Bid and an increase in caspase-8 processing that
      was abolished by Bcl2 overexpression, indicating that the Bid-mitochondrial
      amplification loop is functional in H460 cells. Moreover, combination treatment
      did not alter the tumour selectivity of AdTRAIL since normal human fibroblasts
      (NHFs) remained resistant under these conditions. These findings further indicate
      that the combined use of chemo/radiotherapy and adenovirus-produced full-length
      TRAIL may provide a valuable treatment option for NSCLC.

PMID- 15173862
TI  - Human Tissue-Temperature Rise During Ultrasound Treatments With the Aquaflex Gel
      Pad.
AB  - OBJECTIVE: To measure tissue-temperature rise in the lateral aspect of the ankle
      during 10-minute ultrasound treatments with ultrasound gel (gel), a gel pad with
      a thin layer of ultrasound gel on the top (gel/pad), and a gel pad with a thin
      layer of ultrasound gel on the top and the bottom coated with ultrasound gel
      (gel/pad/gel). DESIGN AND SETTING: We used a 1 x 3 repeated-measures, crossover
      design. The dependent variables were tissue-temperature change and time to peak
      temperature. The independent variable was the type of ultrasound coupling medium.
      Treatment orders were randomly assigned, and all possible orders were assigned 3
      times. A thermocouple was inserted through a 32-mm catheter at a depth of 1 cm
      into the target-tissue space, the posterior lateral aspect of the left ankle,
      halfway between the lateral malleolus and the Achilles tendon. Each treatment
      consisted of ultrasound delivered topically at 1 W/cm(2), 3 MHz, in the
      continuous mode for 10 minutes. SUBJECTS: Eighteen healthy, college-aged student
      volunteers (13 women, 5 men), with no history of ankle injury in the previous 6
      months. MEASUREMENTS: Intratissue temperature, measured every 30 seconds for 10
      minutes. RESULTS: Intratissue temperature increases during the 10-minute
      treatments were significantly greater for the ultrasound gel (7.72 degrees C +/-
      0.52 degrees C) and the gel/pad/gel (6.68 degrees C +/- 0.52 degrees C) than for
      the gel/pad (4.98 degrees C +/- 0.52 degrees C). CONCLUSIONS: When ultrasound is
      applied over bony prominences, a gel pad should be covered with ultrasound gel on
      both sides to ensure optimal heating.

PMID- 15173864
TI  - Comparison of Cervical Spine Motion During Application Among 4 Rigid
      Immobilization Collars.
AB  - OBJECTIVE: To quantify the cervical spine range of motion that occurred during
      application of 4 rigid cervical immobilization collars, the time of application,
      and the amount of active range of motion available after application. DESIGN AND
      SETTING: We evaluated the amount of cervical motion that occurred during
      application of 4 commonly used collars: NECLOC (NL), StifNeck (SN), StifNeck
      Select (SNS), and Rapid Form Vacuum Immobilizer (VI). Each clinician applied a
      properly sized collar to both a small- and medium-size model 3 times. After
      application, active range-of-motion testing was completed with the subject in the
      supine and seated positions. SUBJECTS: A total of 17 certified athletic trainers
      participated. MEASUREMENTS: We used 3-dimensional kinematic head and thorax data
      to calculate peak angular displacement, total linear distance, and total angular
      distance during application and peak angular displacement during supine and
      seated range-of-motion testing. Application time was calculated during each
      trial. RESULTS: Significant differences between collars were noted for
      application time, total linear distance, and total angular distance (P<.01). The
      SN and SNS were applied significantly faster and with significantly less total
      linear distance and total angular distance than the NL and the VI collars. The NL
      was applied significantly faster and with significantly less total linear
      distance and total angular distance than the VI. During supine and seated active
      range-of-motion tests, the SN and SNS permitted significantly less cervical
      flexion-extension, rotation, and lateral flexion than the NL and VI. CONCLUSIONS:
      Of the collars tested, the SN and SNS appear to be the optimal collars for use by
      certified athletic trainers. They were applied with the least motion in the
      fastest time and provided superior restriction during active range-of-motion
      testing.

PMID- 15173863
TI  - Influence of Pre-Exercise Muscle Temperature on Responses to Eccentric Exercise.
AB  - OBJECTIVE: We tested the hypothesis that altering the pre-exercise muscle
      temperature would influence the magnitude of muscle damage induced by eccentric
      exercise. SUBJECTS: Female students who had no experience in resistance training
      were placed into either a microwave treatment group (n = 10) or an icing
      treatment group (n = 10). DESIGN AND SETTING: Subjects in each group performed 12
      maximal eccentric actions of the forearm flexors of each arm on 2 separate
      occasions separated by 4 weeks. Before testing, the exercise arm was subjected to
      either passive warming (microwave) or control for the microwave treatment group
      or cooling (icing) or control for the icing treatment group. The control arm
      performed the same exercise protocol without treatment. Limbs were randomized for
      treatment or control and order of testing. Deep muscle temperature increased by
      approximately 3 degrees C after the microwave treatment and decreased
      approximately 5 degrees C after the icing treatment. MEASUREMENTS: We evaluated
      changes in maximal isometric force and indirect markers of muscle damage,
      including range of motion, upper arm circumference, muscle soreness, and plasma
      creatine kinase activity, in the microwave and control and icing and control
      groups using a 2-way, repeated-measures analysis of variance. RESULTS: All
      measures changed significantly (P <.01) after exercise, but neither of the
      treatments demonstrated significant effects on most of the variables compared
      with the control. CONCLUSIONS: These results suggest that pre-exercise cooling
      does not affect the magnitude of muscle damage in response to eccentric exercise.
      Similarly, pre-exercise passive muscle warming did not prove beneficial in
      attenuating indicators of muscle damage. Thus, any beneficial effects of warm-up
      exercise cannot be attributed to the effects of increased muscle temperature.

PMID- 15173865
TI  - Collegiate Football Players Display More Active Cervical Spine Mobility Than High
      School Football Players.
AB  - OBJECTIVES: To compare the active cervical spine range of motion and resting
      cervical spine alignment (sagittal plane) of collegiate and high school football
      players using the Cervical Range of Motion (CROM) Measurement System and to
      identify normative values for these populations. DESIGN AND SETTING: A 2 x 7
      factorial design for main effects was used to evaluate the influence of level of
      play (college, high school) on the cervical spine range of motion of football
      players. Data were collected during preparticipation physical examinations.
      SUBJECTS: A convenience sample of 189 unimpaired collegiate (n = 70, age = 19.5
      +/- 1.5 years) and high school (n = 119, age = 15.7 +/- 1.4 years) football
      players participated. MEASUREMENTS: Subjects were measured for active cervical
      spine range of motion using the CROM system and the manufacturer's recommended
      measurement techniques. RESULTS: Collegiate football players had increased active
      cervical spine range of motion for flexion, extension, left cervical rotation,
      and left lateral flexion (overall mean increase = 4.3 +/- 2 degrees ) compared
      with high school players. Collegiate players also assumed a more flexed resting
      sagittal-plane cervical spine posture (P =.001). CONCLUSIONS: Collegiate players
      generally displayed greater active cervical spine range of motion than high
      school players. The increased resting sagittal-plane cervical spine flexion
      alignment we report among the collegiate players suggests a change in the natural
      cervical spine lordosis, possibly due to a neutral-zone shift associated with
      combined increases in lower cervical spine flexion and upper cervical spine
      extension as an adaptation to football training or playing. Further study using
      radiographic or magnetic resonance imaging techniques is warranted. The CROM
      system is a useful tool for identifying aggregate hypomobile or hypermobile
      active cervical spine mobility among football players that might otherwise remain
      unrecognized during standard preparticipation physical examinations. In
      combination with manual segmental assessments of passive accessory intervertebral
      movements, CROM enables early identification of players with impaired or
      excessive cervical spine mobility, thus facilitating proactive injury-prevention
      intervention.

PMID- 15173866
TI  - Effectiveness of Glenohumeral-Joint Stability Braces in Limiting Active and
      Passive Shoulder Range of Motion in Collegiate Football Players.
AB  - OBJECTIVE: To determine the effectiveness of glenohumeral-joint stability braces
      in limiting active and passive shoulder abduction and external rotation in
      collegiate football players. DESIGN AND SETTING: A 2-factor, repeated-measures
      design was used. The independent variables were brace condition (Denison and Duke
      Wyre harness, Sawa shoulder brace) and force application (active, passive). The
      dependent variables were shoulder abduction (45 degrees braced limit) and
      external-rotation angular displacements. SUBJECTS: Fifteen National Collegiate
      Athletic Association Division I male college football players (age = 19.9 +/-
      1.37 years, height = 183.2 +/- 7.85 cm, mass = 89.9 +/- 14.79 kg) participated in
      the study. MEASUREMENTS: We used the PEAK Motus motion analysis system to measure
      angular displacements. RESULTS: Neither brace maintained the arm position at the
      45 degrees braced limit during active or passive shoulder abduction (motion
      ranged from 56.8 degrees to 73.0 degrees ). Although we did not use a priori
      external-rotation limits in this study, motion ranged from 71.6 degrees to 93.9
      degrees with the braces. A repeated-measures multivariate analysis of variance
      indicated no significant interaction effect (P =.41), but main effects were
      significant for brace condition and force application (P <.001). Reported
      differences are statistically significant. For abduction, the Denison and Duke
      Wyre harness resulted in 12.3 degrees (21%) greater angular displacement than the
      Sawa shoulder brace, and passive abduction resulted in 3.9 degrees (6%) more
      angular displacement than active abduction. For external rotation, the Denison
      and Duke Wyre harness resulted in 6.7 degrees (9%) more angular displacement than
      the Sawa shoulder brace, and passive external rotation resulted in 15.6 degrees
      (21%) more angular displacement than active external rotation. CONCLUSIONS:
      Preset, braced abduction motion limits were not realized during active and
      passive physiologic loading of the glenohumeral joint. However, protection
      against the vulnerable position of 90 degrees of abduction and external rotation
      was attained at a preset braced limit of 45 degrees of abduction (the exception
      was the Denison and Duke Wyre harness during passive external rotation). The Sawa
      shoulder brace was most effective for this purpose.

PMID- 15173867
TI  - Performance on the Balance Error Scoring System Decreases After Fatigue.
AB  - OBJECTIVE: To determine the immediate effects of a whole-body fatigue protocol on
      performance of the Balance Error Scoring System (BESS), a postural-stability test
      commonly used as part of a concussion-assessment battery. DESIGN AND SETTING:
      Subjects were assigned to a fatigue or control group and were assessed before and
      immediately after a 20-minute fatigue protocol or rest period. SUBJECTS: Fourteen
      fatigue subjects and 13 control subjects participated in this study. All subjects
      were male and free of vestibular disorders, and none had suffered a mild head
      injury or lower extremity injury in the preceding 6 months, as described through
      self-report. MEASUREMENTS: We measured performance on the BESS for 9 stance
      surface conditions and summed each condition to obtain a total score. Using the
      Borg scale, we also measured ratings of perceived exertion before, during, and
      after the fatigue protocol or rest period. RESULTS: We found a significant
      increase in total errors from pretest to posttest in the fatigue group (14.36 +/-
      4.73 versus 16.93 +/- 4.32), a significant decrease in errors in the control
      group (13.32 +/- 3.77 versus 11.08 +/- 3.88), and a significant difference
      between groups on the posttest. The rating of perceived exertion scores were
      significantly different between the fatigue and control groups at the middle
      (13.29 +/- 1.59 versus 6.23 +/- 0.83) and end (15.86 +/- 2.38 versus 6.15 +/-
      0.55) of the fatigue or rest period. CONCLUSIONS: The BESS error scores increased
      immediately after the fatigue protocol, demonstrating that balance ability
      diminished. Clinicians who use the BESS as part of their sideline assessment for
      concussion should not administer the test immediately after a concussion due to
      the effects of fatigue.

PMID- 15173868
TI  - Body-Weight Fluctuation in Collegiate Wrestlers: Implications of the National
      Collegiate Athletic Association Weight-Certification Program.
AB  - OBJECTIVE: To determine fluctuations in total body weight of the elite collegiate
      wrestler during the competitive season. DESIGN AND SETTING: The study period
      lasted 2 competitive seasons, beginning 1 month before the 1999-2000 and 2000-
      2001 competitive seasons and ending 1 month after the National Championships.
      SUBJECTS: Seventy-eight male subjects (age = 21.3 +/- 1.5 years, height = 154.1
      +/- 0.5 cm) from 4 major universities whose teams finished in the top 5 at both
      the 2000 and 2001 National Collegiate Athletic Association Division I National
      Wrestling Championships. MEASUREMENTS: Each subject was asked to report to the
      testing area 24 hours before, 1 hour before, and 24 hours after a competitive
      wrestling match, and weight was recorded to the nearest 0.1 lb (0.45 kg).
      Comparisons among the prematch weights, official weigh-ins, and postmatch weights
      were made using a randomized, 1-group, repeated-measures factorial analysis of
      covariance with an alpha level of.05. RESULTS: A significant difference (F(2,154)
      = 229.99, P <.0001) existed in subjects' weights 24 hours (73.93 +/- 11.62 kg)
      and 1 hour (72.53 +/- 11.66 kg) before a competitive match and 24 hours after
      (73.65 +/- 13.58 kg) a competitive match. Additionally, we computed 2 t tests to
      determine the difference among weight changes 24 hours and 1 hour before and 24
      hours after a competitive wrestling match. A significant difference was noted
      between body-weight changes 24 hours and 1 hour before the match (t(77) = 56.21,
      P <.0001). CONCLUSIONS: Elite collegiate wrestlers, like novice wrestlers,
      significantly reduce weight immediately before and gain weight after the
      competition.

PMID- 15173869
TI  - Influence of a Pre-Exercise Glycerol Hydration Beverage on Performance and
      Physiologic Function During Mountain-Bike Races in the Heat.
AB  - OBJECTIVE: To determine if pre-exercise hydration with and without glycerol
      differentially affects physiologic and performance responses during mountain-bike
      races in the heat. DESIGN AND SETTING: Testing (random, crossover, double-blind
      design) included the following 3 treatments administered in conjunction with a 30
      mile mountain-bike race consisting of three 10-mile (16-km) loops: (1) no water
      during exercise (NE): water consumed before the race and no water consumed during
      the race, (2) glycerol (G): mixture of water and glycerol consumed before the
      race and water via 2 water bottles consumed during the race, and (3) water (W):
      water consumed before the race and water via 2 water bottles consumed during the
      race. Subjects stopped for 8 minutes after each 10-mile loop for collection of
      data. SUBJECTS: Twelve heat-acclimated male mountain bikers with age = 24.5 +/-
      1.1 years, percentage of body fat = 14.3 +/- 1.0%, mass = 76.9 +/- 1.9 kg, height
      = 179 +/- 2 cm. MEASUREMENTS: We measured body weight, percentage of body fat,
      rectal temperature, blood lactate, blood glucose, urine volume, urine color,
      urine specific gravity, thirst sensation, thermal sensation, rating of perceived
      exertion, fluid consumption, heart rate, and sweat rate. Each subject completed
      the Environmental Symptoms Questionnaire. RESULTS: The G trial was less
      dehydrated than the NE and W trials postexercise. Pre-exercise urine volume was
      less in the G trial than in the NE and W trials, and postexercise thirst was less
      in the G trial than the NE and W trials. Postexercise Environmental Symptoms
      Questionnaire scores were lower in the G trial than the NE or W trials. It is
      noteworthy that, although not significant, the G trial performed 5 minutes faster
      on loop 3 than the NE and W trials. CONCLUSIONS: Lower Environmental Symptoms
      Questionnaire scores and percentage of dehydration may indicate decreased signs
      and symptoms of heat strain in the G trial. Based on the NE trial performance,
      adequate pre-exercise hydration, even without glycerol, may limit the detrimental
      effects of dehydration.

PMID- 15173870
TI  - Effects of Clinical Field-Experience Setting on Athletic Training Students'
      Perceived Percentage of Time Spent on Active Learning.
AB  - OBJECTIVE: Our purpose was to examine undergraduate athletic training students'
      perceptions of how time is utilized during clinical field experiences while
      enrolled in Commission on Accreditation of Allied Health Education Program
      (CAAHEP)-accredited athletic training programs and to determine the effects of
      clinical field-experience length and setting, academic standing, sex, clinical
      assignment, and National Collegiate Athletic Association level on active
      learning. DESIGN AND SETTING: Using the Athletic Training-Clinical Education Time
      Framework (AT-CETF) and Utilizing Time and Active Learning Survey, subjects
      completed a 1-day, self-reported observation of how their clinical field
      experience time was utilized. SUBJECTS: Program directors at 131 CAAHEP
      accredited athletic training programs were sent survey packages. Seventy-two
      (41%) male subjects and 105 (59%) female subjects from 25 institutions completed
      the survey packages. Eight of the 10 National Athletic Trainers' Association
      districts were represented in the study. MEASUREMENTS: The AT-CETF is a
      behavioral time-profiling framework that measures athletic training students'
      perceptions of utilization of clinical field-experience time based on the
      performance domains associated with the 1999 National Athletic Trainers'
      Association Board of Certification Role Delineation Study and literature related
      to time and learning. RESULTS: Subjects spent 51% of their clinical field
      experience time engaged in active learning, 9% in managerial activities, 17% in
      unengaged activities, and 23% in waiting activities. Multiple 2 x 2 x 3 analyses
      of variance (length of clinical field experience x academic standing x clinical
      field-experience setting) revealed a significant difference between the levels of
      clinical field-experience setting and the dependent variables of perceived
      percentage of active learning time and waiting time. A 2 x 3 analysis of variance
      (sex x clinical assignment) revealed a significant difference between the levels
      of clinical assignment and the dependent variable of perceived percentage of
      active learning time. CONCLUSIONS: The type of clinical field-experience setting
      and clinical assignment affects the amount of time spent in active learning.
      Therefore, profiling students' use of time may allow educators to identify
      clinical field-experience settings that maximize active learning time, expose
      students to their own unique learning situations, and offer students access to
      clinical field-experience settings aligned with their professional goals.

PMID- 15173871
TI  - Athletic Training Education Program Directors' Perceptions on Job Selection,
      Satisfaction, and Attrition.
AB  - OBJECTIVE: To determine the potential reasons for becoming a program director and
      reasons for leaving the program director position within athletic training
      education programs accredited by the Commission on Accreditation of Allied Health
      Education Programs (CAAHEP); in addition, to describe the most and least
      beneficial and satisfying aspects of the program director position. DESIGN AND
      SETTING: In 1999, we sent a validated survey to athletic training education
      program directors of CAAHEP-accredited athletic training education programs.
      SUBJECTS: Of 113 athletic training education program directors of accredited
      undergraduate programs, 83 participated, for a response rate of 73.4%.
      MEASUREMENTS: The survey consisted of open-ended questions regarding potential
      reasons for becoming a program director and possibly leaving the program
      direction position and most and least beneficial and satisfying aspects of the
      position. We used inductive content analysis to determine themes for the
      responses to the open-ended questions. Descriptive statistics, including
      percentages, were calculated to report the data. RESULTS: Academic environment
      was the primary theme for becoming an athletic training education program
      director and professional appointment was the primary theme for possibly leaving
      the position. Professional advancement and student growth and success were the
      primary themes for the most beneficial and satisfying aspects. Workload and
      student issues and discipline were the primary themes for the least beneficial
      and satisfying aspects. CONCLUSIONS: Factors that affect job selection,
      satisfaction, and attrition are related to academic environment, teaching,
      students, professional advancement, program development/advancement, workload,
      personal issues, and athletics.

PMID- 15173872
TI  - The Stress and Coping Responses of Certified Graduate Athletic Training Students.
AB  - OBJECTIVE: To assess the sources of stress and coping responses of certified
      graduate athletic training students. DESIGN AND SETTING: We interviewed certified
      graduate athletic training students 3 times over a 9-month period. We transcribed
      the interviews verbatim and used grounded theory analytic procedures to
      inductively analyze the participants' sources of stress and coping responses.
      SUBJECTS: Three male and 3 female certified graduate athletic training students
      from a postcertification graduate athletic training program volunteered to
      participate in this investigation. The participants were full-time graduate
      students, with a mean age of 23 years, who had worked an average of 1.5 years as
      certified athletic trainers at the time of the first interview. MEASUREMENTS: We
      used grounded theory analytic procedures to inductively analyze the participants'
      sources of stress and coping responses. RESULTS: A total of 6 general sources of
      stress and 11 coping dimensions were revealed. The stress dimensions were labeled
      athletic training duties, comparing job duties, responsibilities as student, time
      management, social evaluation, and future concerns. The coping responses were
      planning, instrumental social support, adjusting to job responsibilities,
      positive evaluations, emotional social support, humor, wishful thinking,
      religion, mental or behavioral disengagement, activities outside the profession,
      and other outcomes. CONCLUSIONS: Certified graduate athletic training students
      should be encouraged to use problem-focused (eg, seeking advice, planning) and
      emotion-focused (eg, positive evaluations, humor) forms of coping with stress.

PMID- 15173873
TI  - Splenic Artery Avulsion in a High School Football Player: A Case Report.
AB  - OBJECTIVE: To present the case of a high school football player who sustained
      avulsion of 2 branches of the splenic artery from his spleen as he was tackled
      and landed on the football. BACKGROUND: A high school football player was tackled
      and fell onto the football, left side first. He was examined by a certified
      athletic trainer and an internist. On evaluation, he had a positive Kehr sign,
      exquisite left upper abdominal quadrant tenderness, and complaint of nausea. He
      also exhibited signs of the onset of shock, including diaphoresis, a rapid pulse,
      and hypotension. He was immediately transported by ambulance to the local
      emergency facility. DIFFERENTIAL DIAGNOSIS: Splenic rupture, splenic laceration,
      splenic artery avulsion, or ruptured viscus. TREATMENT: Emergency surgery was
      performed, with removal of 2800 mL of blood and ligation of the 2 arterial
      branches avulsed from the spleen. The patient fully recovered within 6 weeks and
      was cleared to resume all sports activities. UNIQUENESS: Injury to the spleen in
      football is a known yet very uncommon injury. Even more unusual is the avulsion
      of splenic artery branches from the spleen. CONCLUSIONS: It is critical that
      athletic trainers and team physicians have an understanding of the mechanisms,
      signs, and symptoms of splenic injury. Because the spleen is a highly vascular
      organ, severe hemorrhage can be fatal in just minutes if not recognized and
      appropriately treated.

PMID- 15173874
TI  - Clearing a roadmap.

PMID- 15173875
TI  - Progress on new vaccine strategies for the immunotherapy and prevention of
      cancer.
AB  - In recent years, great strides in understanding and regulating the immune system
      have led to new hope for harnessing its exquisite specificity to destroy cancer
      cells without affecting normal tissues. This review examines the fundamental
      immunologic advances and the novel vaccine strategies arising from these
      advances, as well as the early clinical trials studying new approaches to treat
      or prevent cancer.

PMID- 15173876
TI  - Inhibit GSK-3beta or there's heartbreak dead ahead.
AB  - Numerous signaling pathways have been shown to mediate cardioprotection, but the
      end effectors that mediate protection are only beginning to be elucidated.
      Numerous cardioprotective drugs are shown to converge on glycogen synthase kinase
      3beta (GSK-3beta). The phosphorylation and inhibition of GSK-3beta lead to
      inhibition or delayed activation of the mitochondrial permeability transition, a
      key regulator of apoptosis.

PMID- 15173877
TI  - A fork in the road of cell differentiation in the kidney tubule.
AB  - The collecting ducts of the kidney are composed of intercalated cells
      (responsible for acid/base transport), principal cells (mediating salt and water
      absorption), and inner medullary cells, which mediate all three types of
      transport. Forkhead box (Fox) genes are a large family of transcription factors
      that are important in cell-type specification during organogenesis. In this
      issue, Blomqvist et al. find that mice lacking Foxi1 have no intercalated cells
      in the kidney. The collecting ducts of the null mice contained primitive cells
      that expressed both intercalated cell and principal cell proteins, yet the
      acid/base transport function of the kidney was disrupted and the mice exhibited
      distal renal tubular acidosis. These findings suggest that Foxi1 plays a critical
      role in determining cell identity during collecting duct development.

PMID- 15173878
TI  - The case of visceral fat: argument for the defense.
AB  - Increased plasma fatty acid concentrations may be responsible for many of the
      metabolic abnormalities associated with abdominal obesity. Excessive visceral fat
      is associated with insulin resistance and other metabolic risk factors for
      coronary heart disease. A study reported in this issue of the JCI evaluates the
      relative contribution of fatty acids released during lipolysis of visceral
      adipose tissue triglycerides to portal and systemic fatty acid flux in human
      subjects.

PMID- 15173879
TI  - Getting stents to go with the flow.
AB  - Implantation of expandable stents into stenotic arteries after percutaneous
      coronary intervention to relieve arterial narrowing has become a standard
      therapeutic tool. The improvement in vascular interventional technology, and
      especially stent technology, has, arguably, outstripped understanding of the
      biologic consequences of opening an obstructed artery. In the case of bifurcation
      stenoses, new evidence suggests that opening a stenotic subsidiary branch may
      create unfavorable hemodynamics in the stented main branch that can lead to in
      stent restenosis.

PMID- 15173880
TI  - Glycogen synthase kinase-3beta mediates convergence of protection signaling to
      inhibit the mitochondrial permeability transition pore.
AB  - Environmental stresses converge on the mitochondria that can trigger or inhibit
      cell death. Excitable, postmitotic cells, in response to sublethal noxious
      stress, engage mechanisms that afford protection from subsequent insults. We show
      that reoxygenation after prolonged hypoxia reduces the reactive oxygen species
      (ROS) threshold for the mitochondrial permeability transition (MPT) in
      cardiomyocytes and that cell survival is steeply negatively correlated with the
      fraction of depolarized mitochondria. Cell protection that exhibits a memory
      (preconditioning) results from triggered mitochondrial swelling that causes
      enhanced substrate oxidation and ROS production, leading to redox activation of
      PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively,
      receptor tyrosine kinase or certain G protein-coupled receptor activation elicits
      cell protection (without mitochondrial swelling or durable memory) by inhibiting
      GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or
      protein kinase A pathways. The convergence of these pathways via inhibition of
      GSK-3beta on the end effector, the permeability transition pore complex, to limit
      MPT induction is the general mechanism of cardiomyocyte protection.

PMID- 15173881
TI  - Development of antigen-specific ELISA for circulating autoantibodies to
      extracellular matrix protein 1 in lichen sclerosus.
AB  - Lichen sclerosus is a common, acquired chronic inflammatory skin disease of
      unknown etiology, although circulating autoantibodies to the glycoprotein
      extracellular matrix protein 1 (ECM1) have been detected in most patients' sera.
      We have examined the nature of ECM1 epitopes in lichen sclerosus sera, developed
      an ELISA system for serologic diagnosis, and assessed clinicopathological
      correlation between ELISA titer and disease. Epitope-mapping studies revealed
      that lichen sclerosus sera most frequently recognized the distal second tandem
      repeat domain and carboxyl-terminus of ECM1. We analyzed serum autoantibody
      reactivity against this immunodominant epitope in 413 individuals (95 subjects
      with lichen sclerosus, 161 normal control subjects, and 157 subjects with other
      autoimmune basement membrane or sclerosing diseases). The ELISA assay was highly
      sensitive; 76 of 95 lichen sclerosus patients (80.0%) exhibited IgG reactivity.
      It was also highly specific (93.7%) in discriminating between lichen sclerosus
      and other disease/control sera. Higher anti-ECM1 titers also correlated with more
      longstanding and refractory disease and cases complicated by squamous cell
      carcinoma. Furthermore, passive transfer of affinity-purified patient IgG
      reproduced some histologic and immunopathologic features of lichen sclerosus
      skin. This new ELISA is valuable for the accurate detection and quantification of
      anti-ECM1 autoantibodies. Moreover, the values may have clinical significance in
      patients with lichen sclerosus.

PMID- 15173882
TI  - Distal renal tubular acidosis in mice that lack the forkhead transcription factor
      Foxi1.
AB  - While macro- and microscopic kidney development appear to proceed normally in
      mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of
      cells lining the distal nephron. Northern blot analyses, cRNA in situ
      hybridizations, and immunohistochemistry demonstrate a complete loss of
      expression of several anion transporters, proton pumps, and anion exchange
      proteins expressed by intercalated cells of the collecting ducts, many of which
      have been implicated in hereditary forms of distal renal tubular acidosis (dRTA).
      In Foxi1-null mutants the normal epithelium with its two major cell types -
      principal and intercalated cells - has been replaced by a single cell type
      positive for both principal and intercalated cell markers. To test the functional
      consequences of these alterations, Foxi1(-/-) mice were compared with WT
      littermates in their response to an acidic load. This revealed an inability to
      acidify the urine as well as a lowered systemic buffer capacity and overt
      acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to
      altered cellular composition of the distal nephron epithelium, thereby denying
      this epithelium the proper gene expression pattern needed for maintaining
      adequate acid-base homeostasis.

PMID- 15173883
TI  - Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon
      receptor antisense oligonucleotide inhibitors.
AB  - Uncontrolled hepatic glucose production contributes significantly to
      hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated
      in the etiology of this condition; however, effective therapies to block glucagon
      signaling and thereby regulate glucose metabolism do not exist. To determine the
      extent to which blocking glucagon action would reverse hyperglycemia, we targeted
      the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2'
      methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO)
      inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood
      glucose, improved glucose tolerance, and preserved insulin secretion.
      Importantly, in addition to decreasing expression of cAMP-regulated genes in
      liver and preventing glucagon-mediated hepatic glucose production, GCGR
      inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP
      1) and insulin levels in pancreatic islets. Together, these studies identify a
      novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the
      dual action of decreasing hepatic glucose production and improving pancreatic
      beta cell function.

PMID- 15173884
TI  - Splanchnic lipolysis in human obesity.
AB  - Elevated FFA concentrations have been shown to reproduce some of the metabolic
      abnormalities of obesity. It has been hypothesized that visceral adipose tissue
      lipolysis releases excess FFAs into the portal vein, exposing the liver to higher
      FFA concentrations. We used isotope dilution/hepatic vein catheterization
      techniques to examine whether intra-abdominal fat contributes a greater portion
      of hepatic FFA delivery in visceral obesity. Obese women (n = 24) and men (n =
      20) with a range of obesity phenotypes, taken together with healthy, lean women
      (n = 12) and men (n = 12), were studied. Systemic, splanchnic, and leg FFA
      kinetics were measured. The results showed that plasma FFA concentrations were
      approximately 20% greater in obese men and obese women. The contribution of
      splanchnic lipolysis to hepatic FFA delivery ranged from less than 10% to almost
      50% and increased as a function of visceral fat in women (r = 0.49, P = 0.002)
      and in men (r = 0.52, P = 0.002); the slope of the relationship was greater in
      women than in men (P < 0.05). Leg and splanchnic tissues contributed a greater
      portion of systemic FFA release in obese men and women than in lean men and
      women. We conclude that the contribution of visceral adipose tissue lipolysis to
      hepatic FFA delivery increases with increasing visceral fat in humans and that
      this effect is greater in women than in men.

PMID- 15173885
TI  - Concentration-dependent regulation of thyrotropin receptor function by thyroid
      stimulating antibody.
AB  - Thyrotropin receptor (TSHR) Ab's of the stimulating variety are the cause of
      hyperthyroid Graves disease. MS-1 is a hamster mAb with TSHR-stimulating
      activity. To examine the in vivo biological activity of MS-1, mice were treated
      with purified MS-1 intraperitoneally and the thyroid response evaluated. MS-1
      induced a dose-dependent increase in serum thyroxine (T4), with a maximum effect
      after 10 proportional, variant g of MS-1 was administered. MS-1-secreting
      hybridoma cells were then transferred into the peritoneum of nude mice to study
      chronic thyroid stimulation. Serum MS-1 levels detected after 2 weeks were
      approximately 10-50 proportional, variant g/ml, and the serum TSH was suppressed
      in all animals. Serum triiodothyronine levels were elevated, but only in animals
      with low serum MS-1 concentrations. In addition, there was a negative correlation
      between serum T4 and the serum MS-1 concentrations. These in vivo studies
      suggested a partial TSHR inactivation induced by excessive stimulation by MS-1.
      We confirmed this inactivation by demonstrating MS-1 modulation of TSHR function
      in vitro as evidenced by downregulation and desensitization of the TSHR at
      concentrations of MS-1 achieved in the in vivo studies. Thus, inactivation of the
      TSHR by stimulating TSHR autoantibodies (TSHR-Ab's) in Graves disease patients
      may provide a functional explanation for the poor correlation between thyroid
      function and serum TSHR-Ab concentrations.

PMID- 15173886
TI  - Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1
      is critical for host inflammatory response in vivo.
AB  - The leukocyte integrin alpha(M)beta(2)/Mac-1 appears to support the inflammatory
      response through multiple ligands, but local engagement of fibrin(ogen) may be
      particularly important for leukocyte function. To define the biological
      significance of fibrin(ogen)-alpha(M)beta(2) interaction in vivo, gene-targeted
      mice were generated in which the alpha(M)beta(2)-binding motif within the
      fibrinogen gamma chain (N(390)RLSIGE(396)) was converted to a series of alanine
      residues. Mice carrying the Fibgamma(390-396A) allele maintained normal levels of
      fibrinogen, retained normal clotting function, supported platelet aggregation,
      and never developed spontaneous hemorrhagic events. However, the mutant
      fibrinogen failed to support alpha(M)beta(2)-mediated adhesion of primary
      neutrophils, macrophages, and alpha(M)beta(2)-expressing cell lines. The
      elimination of the alpha(M)beta(2)-binding motif on fibrin(ogen) severely
      compromised the inflammatory response in vivo as evidenced by a dramatic
      impediment in leukocyte clearance of Staphylococcus aureus inoculated into the
      peritoneal cavity. This defect in bacterial clearance was due not to diminished
      leukocyte trafficking but rather to a failure to fully implement antimicrobial
      functions. These studies definitively demonstrate that fibrin(ogen) is a
      physiologically relevant ligand for alpha(M)beta(2), integrin engagement of
      fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and
      the biological importance of fibrinogen in regulating the inflammatory response
      can be appreciated outside of any alteration in clotting function.

PMID- 15173887
TI  - Dynamic flow alterations dictate leukocyte adhesion and response to endovascular
      interventions.
AB  - Although arterial bifurcations are frequent sites for obstructive atherosclerotic
      lesions, the optimal approach to these lesions remains unresolved. Benchtop
      models of arterial bifurcations were analyzed for flow disturbances known to
      correlate with vascular disease. These models possess an adaptable geometry
      capable of simulating the course of arterial disease and the effects of arterial
      interventions. Chronic in vivo studies evaluated the effect of flow disturbances
      on the pattern of neointimal hyperplasia. Acute in vivo studies helped propose a
      mechanism that bridges the early mechanical stimulus and the late tissue effect.
      Side-branch (SB) dilation adversely affected flow patterns in the main branch
      (MB) and, as a result, the long-term MB patency of stents implanted in pig
      arteries. Critical to this effect is chronic MB remodeling that seems to
      compensate for an occluded SB. Acute leukocyte recruitment was directly
      influenced by the changes in flow patterns, suggesting a link between flow
      disturbance on the one hand and leukocyte recruitment and intimal hyperplasia on
      the other. It is often impossible to simultaneously maximize the total cross
      sectional area of both branches and to minimize flow disturbance in the MB. The
      apparent trade-off between these two clinically desirable goals may explain many
      of the common failure modes of bifurcation stenting.

PMID- 15173888
TI  - PKCbeta regulates ischemia/reperfusion injury in the lung.
AB  - Activation of PKCbetaII is associated with the response to ischemia/reperfusion
      (I/R), though its role, either pathogenic or protective, has not been determined.
      In a murine model of single-lung I/R, evidence linking PKCbeta to maladaptive
      responses is shown in the following studies. Homozygous PKCbeta-null mice and WT
      mice fed the PKCbeta inhibitor ruboxistaurin subjected to I/R displayed increased
      survival compared with controls. In PKCbeta-null mice, phosphorylation of
      extracellular signal-regulated protein kinase-1 and -2 (ERK1/2), JNK, and p38
      MAPK was suppressed in I/R. Expression of the immediate early gene, early growth
      response-1 (Egr-1), and its downstream target genes was significantly increased
      in WT mice in I/R, particularly in mononuclear phagocytes (MPs), whereas this
      expression was attenuated in PKCbeta-null mice or WT mice fed ruboxistaurin. In
      vitro, hypoxia/reoxygenation-mediated induction of Egr-1 in MPs was suppressed by
      inhibition of PKCbeta, ERK1/2, and JNK, but not by inhibition of p38 MAPK. These
      findings elucidate key roles for PKCbetaII activation in I/R by coordinated
      activation of MAPKs (ERK1/2, JNK) and Egr-1.

PMID- 15173889
TI  - CD28 ligation induces transplantation tolerance by IFN-gamma-dependent depletion
      of T cells that recognize alloantigens.
AB  - Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell
      expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined
      the mechanism of anti-CD28-mediated immunosuppression and found that anti-CD28
      mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28
      treatment prevented GVHD by selectively depleting alloantigen-activated donor T
      cells through apoptosis but spared the T cells that did not recognize recipient
      alloantigens. Overexpression of Bcl-x(L) did not protect T cells from depletion
      and did not affect GVHD prevention after anti-CD28 treatment. Depletion of
      activated T cells mediated through CD28 did not depend on the expression of death
      receptors Fas and TNF receptors type I and II, but both the depletion of
      activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality
      required donor-derived IFN-gamma production. This study demonstrates that
      agonistic Ab's specific for the CD28 costimulatory molecule may be used as novel
      therapeutic agents to abrogate pathogenic T cell responses by selective depletion
      of activated T cells.

PMID- 15173890
TI  - The clinical implication and molecular mechanism of preferential IL-4 production
      by modified glycolipid-stimulated NKT cells.
AB  - OCH, a sphingosine-truncated analog of alpha-galactosylceramide (alphaGC), is a
      potential therapeutic reagent for a variety of Th1-mediated autoimmune diseases
      through its selective induction of Th2 cytokines from natural killer T (NKT)
      cells. We demonstrate here that the NKT cell production of IFN-gamma is more
      susceptible to the sphingosine length of glycolipid ligand than that of IL-4 and
      that the length of the sphingosine chain determines the duration of NKT cell
      stimulation by CD1d-associated glycolipids. Furthermore, IFN-gamma production by
      NKT cells requires longer T cell receptor stimulation than is required for IL-4
      production by NKT cells stimulated either with immobilized mAb to CD3 or with
      immobilized "alphaGC-loaded" CD1d molecules. Interestingly, transcription of IFN
      gamma but not that of IL-4 was sensitive to cycloheximide treatment, indicating
      the intrinsic involvement of de novo protein synthesis for IFN-gamma production
      by NKT cells. Finally, we determined c-Rel was preferentially transcribed in
      alphaGC-stimulated but not in OCH-stimulated NKT cells and was essential for IFN
      gamma production by activated NKT cells. Given the dominant immune regulation by
      the remarkable cytokine production of ligand-stimulated NKT cells in vivo, in
      comparison with that of (antigen-specific) T cells or NK cells, the current study
      confirms OCH as a likely therapeutic reagent for use against Th1-mediated
      autoimmune diseases and provides a novel clue for the design of drugs targeting
      NKT cells.

PMID- 15173891
TI  - Receptor for advanced glycation end products (RAGE) regulates sepsis but not the
      adaptive immune response.
AB  - While the initiation of the adaptive and innate immune response is well
      understood, less is known about cellular mechanisms propagating inflammation. The
      receptor for advanced glycation end products (RAGE), a transmembrane receptor of
      the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel
      animal models with defective or tissue-specific RAGE expression, we show that in
      these animal models RAGE does not play a role in the adaptive immune response.
      However, deletion of RAGE provides protection from the lethal effects of septic
      shock caused by cecal ligation and puncture. Such protection is reversed by
      reconstitution of RAGE in endothelial and hematopoietic cells. These results
      indicate that the innate immune response is controlled by pattern-recognition
      receptors not only at the initiating steps but also at the phase of perpetuation.

PMID- 15173892
TI  - The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell
      malignancies.
AB  - The IL-12Rbeta2 gene is expressed in human mature B cell subsets but not in
      transformed B cell lines. Silencing of this gene may be advantageous to
      neoplastic B cells. Our objective was to investigate the mechanism(s) and the
      functional consequence(s) of IL-12Rbeta2 gene silencing in primary B cell tumors
      and transformed B cell lines. Purified tumor cells from 41 patients with
      different chronic B cell lymphoproliferative disorders, representing the
      counterparts of the major mature human B cell subsets, tested negative for IL
      12Rbeta2 gene expression. Hypermethylation of a CpG island in the noncoding exon
      1 was associated with silencing of this gene in malignant B cells. Treatment with
      the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine restored IL-12Rbeta2
      mRNA expression in primary neoplastic B cells that underwent apoptosis following
      exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation
      and increased the apoptotic rate of IL-12Rbeta2-transfected B cell lines in
      vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12Rbeta2
      transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through
      antiproliferative and proapoptotic effects, coupled with neoangiogenesis
      inhibition related to human IFN-gamma-independent induction of hMig/CXCL9. The IL
      12Rbeta2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12
      exerts direct antitumor effects on IL-12Rbeta2-expressing neoplastic B cells.

PMID- 15173893
TI  - Neurobiology of severe mental disorders: from cell to bedside 25th International
      Symposium of the Centre de recherche en sciences neurologiques, Universite de
      Montreal.

PMID- 15173894
TI  - Gene-environment interaction and the genetics of depression.
AB  - Depression is a group of brain disorders with varied origins, complex genetics
      and obscure neurobiology. Definitions of clinical phenotypes are not rooted in
      their neurobiology, and animal models of behavioural despair have considerable
      limitations. Nevertheless, investigation of subtle alterations in gene
      expression, of correlations between genotype and brain activity, and of
      environmental variables interacting with genetic variants have advanced research
      into the genetics of depression. Although the postgenomic era is still in its
      infancy, several milestones have already been reached: variation in gene
      expression has been confirmed to play a predominant role in individual
      differences; gene-environment interactions have been established in humans and in
      a nonhuman primate model; gene-phenotype correlations have been substantiated by
      functional neuroimaging; and the notion of gene networks that control brain
      development is increasingly recognized. Given the etiologic and psychobiologic
      complexity of mood disorders, it is not surprising that the identification of
      specific genetic factors is extremely difficult and continues to be among the
      last frontiers of gene hunting.

PMID- 15173895
TI  - Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of
      depression.
AB  - Major alterations of the hypothalamic-pituitary-adrenocortical (HPA) system that
      can be reversed by successful antidepressant therapy are often seen in depressed
      patients. Persuasive evidence points to the involvement of a dysfunctional
      glucocorticoid receptor (GR) system in these changes. Support for this also comes
      from studies of transgenic mice that express an antisense RNA, complementary to
      the GR mRNA, and have numerous neuroendocrine characteristics of human depression
      as well as altered behaviour. Many of these neuroendocrine and behavioural
      characteristics of the transgenic mice can be reversed by antidepressants. A
      possible explanation for this is that the antidepressant-induced increase in GRs
      renders the HPA axis more sensitive to glucocorticoid feedback. This new insight
      into antidepressant drug action suggests a novel approach to the development of
      antidepressant drugs.

PMID- 15173896
TI  - Implications of adult hippocampal neurogenesis in antidepressant action.
AB  - In the dentate gyrus of the hippocampus, cell birth and maturation into neurons,
      or neurogenesis, occur throughout the lifetime of animals and humans. Multiple
      factors have been shown to regulate adult neurogenesis, and a number of findings
      in this field have had a large impact on basic and clinical research in
      depression. It has been reported that both physical and psychosocial stress
      paradigms, as well as some animal models of depression, produce a decrease in
      hippocampal cell proliferation and neurogenesis. Conversely, long-term, but not
      short-term, treatment with different classes of antidepressant drug increases
      cell proliferation and neurogenesis. Patients with depressive disorders or post
      traumatic stress disorder have reduced hippocampal volume. Given this interaction
      of stress, depression and neurogenesis, a current hypothesis is that reduced
      adult hippocampal cell proliferation or neurogenesis may be involved in the
      pathophysiology of depression and that reversal or prevention of the decrease in
      neurogenesis may be one way in which the antidepressant drugs exert their
      effects. Research from this emerging field will further our understanding of the
      effects of stress and depression on the brain and the mechanism of action of
      antidepressant drugs.

PMID- 15173897
TI  - Impact of substance P receptor antagonism on the serotonin and norepinephrine
      systems: relevance to the antidepressant/anxiolytic response.
AB  - Substance P (neurokinin-1 [NK1]) receptor antagonists appear to be effective
      antidepressant and anxiolytic agents, as indicated in 3 double-blind clinical
      trials. In laboratory animals, they promptly attenuate the responsiveness of
      serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) neurons to
      agonists of their cell-body autoreceptors, as is the case for some antidepressant
      drugs that are currently in clinical use. Long-term, but not subacute, antagonism
      of NK1 receptors in rats increases 5-HT transmission in the hippocampus, a
      property common to all antidepressant treatments tested thus far. This
      enhancement seems to be mediated by a time-dependent increase in the firing rate
      of 5-HT neurons. Mice with the NK1 receptor deleted from their genetic code also
      have an increased firing rate of 5-HT neurons. Taken together, these observations
      strongly suggest that NK1 antagonists could become a new class of antidepressant
      and anxiolytic agents.

PMID- 15173898
TI  - What is the role of pharmacotherapy in tobacco cessation in patients with
      schizophrenia?

PMID- 15173901
TI  - Metals in perspective.

PMID- 15173902
TI  - Research profile. Professor Jan-Olof Levin.

PMID- 15173903
TI  - Advances in analytical technologies for environmental protection and public
      safety.
AB  - Due to the increased threats of chemical and biological agents of injury by
      terrorist organizations, a significant effort is underway to develop tools that
      can be used to detect and effectively combat chemical and biochemical toxins. In
      addition to the right mix of policies and training of medical personnel on how to
      recognize symptoms of biochemical warfare agents, the major success in combating
      terrorism still lies in the prevention, early detection and the efficient and
      timely response using reliable analytical technologies and powerful therapies for
      minimizing the effects in the event of an attack. The public and regulatory
      agencies expect reliable methodologies and devices for public security. Today's
      systems are too bulky or slow to meet the "detect-to-warn" needs for first
      responders such as soldiers and medical personnel. This paper presents the
      challenges in monitoring technologies for warfare agents and other toxins. It
      provides an overview of how advances in environmental analytical methodologies
      could be adapted to design reliable sensors for public safety and environmental
      surveillance. The paths to designing sensors that meet the needs of today's
      measurement challenges are analyzed using examples of novel sensors, autonomous
      cell-based toxicity monitoring, 'Lab-on-a-Chip' devices and conventional
      environmental analytical techniques. Finally, in order to ensure that the public
      and legal authorities are provided with quality data to make informed decisions,
      guidelines are provided for assessing data quality and quality assurance using
      the United States Environmental Protection Agency (US-EPA) methodologies.

PMID- 15173904
TI  - Characterization of physicochemical properties of beryllium aerosols associated
      with prevalence of chronic beryllium disease.
AB  - Little is known about the physicochemical properties of beryllium aerosols
      associated with increased risk of beryllium sensitization and chronic beryllium
      disease (CBD). Such information is needed to evaluate whether airborne mass of
      beryllium is the appropriate metric of exposure or alternatively to provide a
      scientific basis for using information on particle size, surface area, and
      chemistry to support an improved exposure limit based on bioavailability through
      the inhalation and dermal routes of exposure. Thus, we used a suite of analytical
      techniques to characterize aerodynamically size-fractionated beryllium particles
      and powders that have been associated in epidemiological studies with higher
      prevalence of CBD. Aerosol particles were sampled from the ventilation systems of
      production lines for powders of beryllium metal and beryllium oxide and for
      ingots of copper-beryllium alloy. End product powders from the metal and oxide
      production lines were also collected. Particles released during production of
      beryllium metal were found to be complex, having heterogeneous composition,
      including reactive species such as fluorine. Powders from beryllium metal
      production were of high purity with only a minor component of beryllium oxide.
      Both particles and powders from oxide production were high-purity oxide.
      Particles released during production of copper-beryllium alloy were
      heterogeneous, being predominantly copper oxides. Thus, all particles and powders
      contain at least some beryllium in the form of beryllium oxide. These data
      justify efforts to thoroughly characterize beryllium aerosol properties when
      performing exposure assessments. The data also suggest that differences in
      particle chemical composition, size, number, and surface area may influence
      bioavailability of beryllium and contribute to risk of CBD. However, a scientific
      basis does not yet exist to replace mass as the current metric of exposure.

PMID- 15173905
TI  - Levels of synthetic musk compounds in municipal wastewater for potential
      estimation of biota exposure in receiving waters.
AB  - We analyzed water samples from the confluence of three municipal sewage treatment
      effluent streams, surface water, and whole carp (Cyprinus carpio) for synthetic
      musks for a period of 7-12 months. The lipid content of each fish was determined
      and compared with the concentration of musks in the whole fish tissue. Enhanced
      methods were used for water sampling and musk extraction. The data presented here
      provide insight as to the relationship between concentrations of synthetic musks
      in the municipal effluent and associated biota. This study confirmed the presence
      of polycyclic and nitro musk compounds in sewage effluent, Lake Mead water, and
      carp. The concentrations were found to be considerably lower than previous
      studies conducted in other countries. This study also provides data for
      polycyclic and nitro musk compounds, as well as some of the nitro musk
      metabolites in sewage treatment plant effluent, lake water, and carp.

PMID- 15173906
TI  - A pilot study on the determination of perfluorooctanesulfonate and other
      perfluorinated compounds in blood of Canadians.
AB  - A pilot study was conducted to provide preliminary data on the concentrations of
      perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA) and
      perfluorooctanesulfonamide (PFOSA) in the blood of Canadians. A set of 56 human
      serum samples was collected from non-occupationally exposed Canadians and
      analyzed by microbore HPLC-negative ion electrospray tandem mass spectrometry.
      PFOS was the main component of perfluorinated organic compounds (PFCs) and was
      detected in all 56 blood specimens at an average concentration of 28.8 ng mL(-1)
      and a range from 3.7 to 65.1 ng mL(-1). The concentration of PFOA was an order of
      magnitude lower than that of PFOS and was found only in 16 samples (29%) at
      concentrations above the limit of quantification (LOQ). PFOSA was not detected at
      levels above the method detection limit (MDL) in any of the samples. The levels
      of PFCs observed in the sample group of non-occupationally exposed humans in
      Canada were similar to the levels reported in a previous US study with a similar
      sample pool size. Two distinct PFOS isomers in human serum were identified by
      accurate mass determination.

PMID- 15173907
TI  - Improved application of recombinant yeast assays on environmental samples by size
      exclusion chromatography.
AB  - The utility of HPLC with a size exclusion chromatography (SEC) column for the
      fractionation of environmental samples was examined to expand the applicability
      of recombinant yeast assays (RYAs) for the measurement of estrogenic activity in
      environmental samples. The elution of steroidal hormone standards through SEC was
      tested, and river water and sediment samples were subjected to SEC fractionation.
      The retention times of all estrogen standards were longer than those of the major
      components with absorbance at 230 nm of the environmental sample matrix. The
      estrogenic activity of SEC fractions of environmental samples from highly
      polluted sites was measured using RYA and revealed the existence of estrogenic
      compounds that could not be detected or quantified in extracted samples before
      fractionation. The fractions from environmental samples that corresponded to the
      retention time of estrone, 17[small beta]-estradiol, and estriol were analyzed
      with LC/MS/MS. These three estrogens were separated into three different
      fractions, and the concentration of estrone coincided with the estrogenic
      activity of the fraction in which it was detected. The profile of estrogenic
      activity of SEC fractions indicated the molecular size of the estrogenic
      compounds and the yeast growth inhibitors in samples.

PMID- 15173908
TI  - Simultaneous extraction of bromide, chloride, fluoride and sulfate from soils,
      waste- and building materials.
AB  - The simultaneous extraction of bromide, chloride, fluoride and sulfate was
      studied in soils, waste- and building materials. Acid, neutral and alkaline
      extractants were used; 0.01 mol l(-1) H(3)PO(4), milliQ-water and 0.01 mol l(-1)
      NaOH, respectively. The extracts were analysed by ion chromatography and ion
      selective electrode. Extracted concentrations were compared with the amount
      obtained by an alkaline smelt, as an approximation of the total extractable
      content. The results indicate that there is a significant difference in
      extraction behaviour between waste- and building materials and soils. Bromide and
      chloride were in general completely extracted from the former solid materials,
      but less than 10% and 50%, respectively, from soils. Fluoride is strongly bound
      in all investigated samples; less than 10% of the total content was extracted
      with any of the three extractants. The fraction of extracted sulfate varied
      between 4 and 87% of the total content, and was in general larger in waste- and
      building materials than in soils. Differences in extracted concentration between
      the 3 extractants occurred mainly for fluoride and sulfate. Extracted bromide was
      similar with all three extractants and extracted chloride showed differences for
      the various soil samples only. Increasing the NaOH concentration up to 1 mol l(
      1) resulted mainly in an increase of extracted amount of fluoride and for soils
      also in extracted amounts of bromide and sulfate. Although, the results show that
      the composition of the solid material strongly influences the final pH of the
      extract and the extracted amount of investigated anions, application of Milli-Q
      water as an extractant might be a very fruitful option within the development of
      the Dutch Building Materials Decree.

PMID- 15173909
TI  - How well should laboratories perform in proficiency tests.
AB  - The long-term performance of laboratories is examined using results from three
      proficiency testing programmes in the water and environmental monitoring sector.
      A medium term proficiency test pass rate of greater than approximately 75% is
      suggested as a minimum target for routine analysis to demonstrate fitness for
      purpose. This pass rate is proposed as a practical yardstick to be used by QA
      managers and accreditation bodies. This recommendation is contingent on a
      laboratory's continued and largely uninterrupted participation in a PT programme.

PMID- 15173910
TI  - Dermal exposure to monoterpenes during wood work.
AB  - The dermal exposure to the suspected allergenic monoterpenes [small alpha]
      pinene, [small beta]-pinene and [capital Delta](3)-carene was assessed with a
      patch sampling technique. The patch used was made of activated charcoal
      sandwiched between two layers of cotton cloth. Patches were fastened at 12
      different spots on a sampling overall and at the front of a cap to estimate the
      potential exposure of the body. Fastening two patches on a cotton glove, one
      patch representing the dorsal side and one patch representing the palm of the
      hand respectively, assessed the exposure on the hands. Sampling was carried out
      during collecting of pine and spruce boards in sawmills and during sawing of pine
      wood pieces in joinery shops respectively. The potential dermal exposure of the
      total body was 29.0-1 890 mg h(-1) with a geometric mean (GM) of 238 mg h(-1)
      during sawing. During collecting the GM was estimated to 100 mg h(-1) with a
      range of 12.2-959 mg h(-1). The hands had a mean exposure of 9.24 mg h(-1) during
      sawing and 3.25 mg h(-1) during collecting respectively. The good correlation
      between the mass of contamination on the individual body parts and the potential
      body exposure indicates that sampling can be performed on one body part to give a
      good estimation of the potential body exposure. Monoterpenes were detected at
      patches fastened underneath the protective clothing indicating a contamination of
      the skin of the worker. The patch used may overestimate the dermal exposure.

PMID- 15173911
TI  - High frequency monitoring of the coastal marine environment using the MAREL buoy.
AB  - The MAREL Iroise data buoy provides physico-chemical measurements acquired in
      surface marine water in continuous and autonomous mode. The water is pumped 1.5 m
      from below the surface through a sampling pipe and flows through the measuring
      cell located in the floating structure. Technological innovations implemented
      inside the measuring cell atop the buoy allow a continuous cleaning of the
      sensor, while injection of chloride ions into the circuit prevents biological
      fouling. Specific sensors for temperature, salinity, oxygen and fluorescence
      investigated in this paper have been evaluated to guarantee measurement precision
      over a 3 month period. A bi-directional link under Internet TCP-IP protocols is
      used for data, alarms and remote-control transmissions with the land-based data
      centre. Herein, we present a 29 month record for 4 parameters measured using a
      MAREL buoy moored in a coastal environment (Iroise Sea, Brest, France). The
      accuracy of the data provided by the buoy is assessed by comparison with
      measurements of sea water weekly sampled at the same site as part of SOMLIT
      (Service d'Observation du Milieu LIToral), the French network for monitoring of
      the coastal environment. Some particular events (impact of intensive fresh water
      discharges, dynamics of a fast phytoplankton bloom) are also presented,
      demonstrating the worth of monitoring a highly variable environment with a high
      frequency continuous reliable system.

PMID- 15173912
TI  - A field evaluation of a piezo-optical dosimeter for environmental monitoring of
      nitrogen dioxide.
AB  - Measurements of 8-hour time-weighted average NO(2) concentrations are reported at
      7 different locations in the region of Dunkirk over 5 consecutive days using
      PiezOptic monitoring badges previously calibrated for the range 0-70 ppb together
      with data from chemiluminescent analysers in 5 sites (4 fixed and one mobile).
      The latter facilities also provided data on ozone and NO concentrations and
      meteorological conditions. Daily averages from the two pairs of badges in
      different types of sampling cover in each site have been compared with data from
      the chemiluminescent analysers, and found largely to agree within error margins
      of +/-30%. Although NO(2) and ozone concentrations were low, rendering detailed
      discussion impossible, the general features followed expected patterns.

PMID- 15173913
TI  - The significance of KIT (CD117) in gastrointestinal stromal tumors.

PMID- 15173914
TI  - Endometrial adenocarcinoma: beliefs and scepticism.
AB  - The incidence of endometrial adenocarcinoma is high in North America and northern
      Europe, and low in Asia and Africa. This variance in frequency rates occurred in
      the late 1970s and its real cause has remained in question since. There is a
      widespread belief that endometrial adenocarcinomas associated with endometrial
      hyperplasia have a much better prognosis than those related to endometrial
      atrophy. This view is, in general terms, true but only because a high proportion
      of tumors arising from an atrophic endometrium are of serous/papillary, clear
      cell, or Grade 2-3 endometrioid carcinomas, in contrast to those developing from
      a hyperplastic endometrium, which are nearly all G1 endometrioid adenocarcinomas.
      These adenocarcinomas have, however, an excellent prognosis, no matter whether
      they are related to hyperplasia or atrophy, and taxonomically they form a single
      tumor group. In this regard, it is most reasonable to separate endometrial
      carcinomas into low- and high-grade tumors. The first are formed solely of G1 or
      "authentic" endometrioid adenocarcinomas, i.e., endometrioid neoplasms composed
      in their entirety of glandular elements without having traces of nonsquamous
      solid components. The high-grade tumors are formed of both endometrioid Grade 2-3
      adenocarcinomas and nonendometrioid carcinomas-all of particularly aggressive
      behavior. The question of grading endometrioid adenocarcinomas in a precise and
      reproducible way becomes obvious. It is also believed that endometrial
      adenocarcinomas associated with endometrial hyperplasia are estrogen-primed,
      while those related to endometrial atrophy are deprived of hormonal stimulation.
      However, as we have shown in this laboratory recently, estrogen stimulation may
      be very common in endometrial neoplasms developing in an atrophic endometrium.
      For indeed most, if not all, postmenopausal atrophic endometria harboring
      adenocarcinomas contain actively proliferating glands, with high Ki-67
      proliferation index, high epidermal growth factor receptor (EGFR) activity, high
      microvessel density (MVD), and rich in estrogen and progesterone receptors (ER
      and PR), indicative of a continuous low-level estrogenic stimulation. That there
      is a number of endometrial carcinomas that tend to develop in a milieu of
      antiestrogenic domination, following treatment for breast carcinoma, this may
      well represent a form of breast-endometrial hereditary disease and, certainly,
      merits further investigation.

PMID- 15173915
TI  - Differential expression of S100C in thyroid lesions.
AB  - Identification of new potential markers that may help in the diagnosis of benign
      and malignant thyroid lesions is needed. By comparative 2-dimensional gel
      electrophoresis of microdissected cells from tumors and normal thyroid tissue, we
      identified a new protein, S100C, which is highly expressed in papillary
      carcinomas. In order to validate this finding, we investigated the
      immunohistochemical expression and the potential role in diagnosis of these
      markers in 94 specimens representing the spectrum of malignant and benign thyroid
      lesions. Normal thyroid tissue was evaluated in 57 specimens. Galectin-3, a
      marker reported as specific for malignant lesions, was also evaluated in the same
      lesions. S100C protein was expressed in the nuclei of normal tissue, hyperplastic
      nodules, and follicular adenomas and carcinomas. Papillary carcinomas showed a
      strong, but cytoplasmic, pattern of staining. Galectin-3 immunostaining was
      strongly positive in papillary carcinomas, and negative in benign lesions,
      confirming its value in differential diagnosis. These findings suggest that
      immunohistochemical staining of S100C could be helpful in the pathological study
      of thyroid lesions, especially in cases in which follicular variants of papillary
      carcinoma and follicular carcinoma are considered in the differential diagnosis.

PMID- 15173916
TI  - Neuroendocrine in Barrett's mucosa and adenocarcinomas of the gastroesophageal
      junction.
AB  - We estimated the prevalence and prognostic significance of neuroendocrine (NE)
      cells in a series of 208 resection specimens containing gastroesophageal junction
      (GEJ) adenocarcinomas, with 56 specimens containing Barrett's mucosa.
      Immunohistochemically, chromogranin A (CGA) was positive in 49% (102/208) of GEJ
      adenocarcinomas and in 68% (38/56) of Barrett's mucosas. CGA in GEJ tumors
      correlated with pTNM stage. CGA in Barrett correlated with pTNM stage and tumor
      grade of the adjacent carcinoma. Patients with CGA in Barrett had better survival
      than patients without CGA in Barrett, with 5-year survival percentages of 56% and
      9%, respectively. In multi-variate analysis, CGA in Barrett was an independent
      prognostic factor for survival after surgery. Therefore CGA in Barrett adjacent
      to GEJ adenocarcinoma might be helpful in the assessment of patient outcome.

PMID- 15173917
TI  - Clinical implication of dermatopathic lymphadenopathy among Japanese: a report of
      19 cases.
AB  - To clarify the clinicopathologic and immunohistochemical features of
      dermatopathic lymphadenopathy not associated with mycosis fungoides among
      Japanese, 19 patients were studied. Seventy-four percent of the patients were
      more than 50 years old (median; 63 years, mean 61 years). Systemic symptoms such
      as fever were recorded in 68% and multicentric lymphadenopathy was noted in 83%
      of patients. An association of autoimmune disease or positivity of autoantibodies
      was recorded in 6 patients. Five patients showed cutaneous hypersensitivity
      reactions to a drug. Histologically, in addition to the dermatopathic
      lymphadenopathy, numerous immunoblasts were observed in 2 cases and sheet-like
      proliferation of mature plasma cells in 3 cases. Various atypical or malignant
      lymphoproliferative disorders exhibiting immunologic abnormalities such as
      angioimmunoblastic T-cell lymphoma or autoimmune disease-associated
      lymphadenopathy frequently occur in middle-aged and elderly patients. At least
      some of the patients with dermatopathic lymphadenopathy should be
      clinicopathologically differentiated from these lymphoproliferative disorders.

PMID- 15173918
TI  - Immunohistochemical expression of vascular endothelial growth factor (VEGF) and C
      KIT in cutaneous melanocytic lesions.
AB  - Vascular endothelial growth factor (VEGF) and C-KIT are involved in tumor
      progression in several human neoplasms. The aim of the present study has been to
      investigate their immunohistochemical expression in melanocytic lesions. We
      examined 11 compound nevi, 12 dysplastic nevi, and 18 melanomas. Immunostaining
      for VEGF was observed only in melanomas; c-kit expression was detected in
      melanomas (higher in radial than in vertical growth phase) and in nevi
      (predominantly in the junctional component). Our data indicate that assessment of
      VEGF expression might aid in the differential diagnosis between dysplastic nevi
      and melanomas. Moreover, VEGF might be a candidate for targeted therapy. The loss
      of c-kit expression might contribute to melanoma progression.

PMID- 15173919
TI  - Limitations in the interpretation of biopsies in patients with penile squamous
      cell carcinoma.
AB  - Surgeons often perform small or superficial penile biopsies that are difficult to
      classify definitely with regard to a benign or malignant nature, and if
      malignant, cannot always be accurately subclassified. Staging and therapeutic
      decisions rely on the identification, in these materials, of pathologic
      parameters related to prognosis. In this study, we evaluated the accuracy and
      completeness of pathologic information obtained from biopsies of 57 consecutive
      patients with squamous cell carcinoma (SSC) of the penis, and compared it with
      the information obtained from penectomies. Diagnostic accuracy was determined by
      recording discordances of critical factors in biopsies and penectomies. The
      evaluated parameters were as follows: cancer diagnosis, histologic type, tumor
      grade, depth of invasion (anatomical levels), and vascular invasion. Histologic
      subtypes of SCC were the following: usual 37, verruciform 11, mixed 7,
      pseudohyperplastic 1, and sarcomatoid 1. Grades were 1, 2, and 3 (well,
      moderately and poorly differentiated). Levels of invasion were lamina propria,
      corpus spongiosum, and corpus cavernosum in the glans; and lamina propria,
      dartos, and skin in the foreskin. In 2 patients with well-differentiated tumors a
      diagnosis of cancer could not be established in biopsy material. In 17 cases
      (30%) there was a biopsy-penectomy discordance of histologic types, especially of
      verruciform and mixed carcinomas. Biopsies failed to identify the correct
      histologic grade in 30% of the cases. A higher grade was usually identified in
      penectomy specimens. Because biopsies were superficial, the deepest point of
      invasion could not be determined in 91% of the cases. Vascular invasion was
      identified in biopsies in only 1 of 8 patients. In summary, biopsies were useful
      for cancer diagnosis except in 2 differentiated variants of penile squamous cell
      carcinoma. However, important pathologic parameters related to prognosis were
      missed on biopsy materials, and they were more accurately evaluated in penectomy
      specimens. We conclude that clinical and pathologic staging of penile cancer, at
      least in our material, cannot depend on biopsy information alone. Data from
      biopsies may be insufficient to make a decision whether to perform a groin
      dissection, or for prognostic evaluation in those patients in whom other
      treatment modalities (such as radiotherapy or chemotherapy) are being considered.

PMID- 15173920
TI  - The pathologist and the bomb: Averill A. Liebow in Hiroshima.

PMID- 15173921
TI  - A 'fly in the ointment': cutaneous infestation by Musca domestica.

PMID- 15173922
TI  - Nevus cells growing within a lymph vessel valve.

PMID- 15173923
TI  - Myoid hamartomas of the breast: report of 3 cases and review of the literature.
AB  - Hamartomas were first described by Albrecht in 1904, who defined them as tumor
      like malformations in which there was abnormal blending of the normal components
      of an organ. The myoid hamartoma is a rare benign lesion of the breast and has an
      uncertain origin, possibly in the walls of the blood vessels, muscularis
      mammillae of the areolae, and mainly in myoepithelium. We report 3 cases of myoid
      hamartomas of the breast, with the clinical, radiologic, and histopathological
      findings, and review the literature. The 3 lesions showed normal breast ducts and
      lobules, entrapped by a muscular stroma and some foci of mature adipose tissue.
      The muscular origin of part of the stroma was confirmed by strong reactiveness
      with smooth-muscle actin.

PMID- 15173924
TI  - Alveolar adenoma of the lung: a clinicopathologic, immunohistochemical, and
      molecular study of an unusual case.
AB  - We describe an alveolar adenoma of the lung with 3 previously unreported
      findings, which expand both the clinical and the morphologic spectrum of this
      rare tumor: presentation as a cystic nodule, foci of mature adipocytes, and S-100
      positivity of the mesenchymal cells. Furthermore, using a laser capture
      microdissection technique under microscope visualization, we analyzed multiple
      chromosomal loci in both the epithelial and mesenchymal components of the lesion,
      showing microsatellite alterations and loss of heterozygosity in the former but
      not in the latter.

PMID- 15173925
TI  - Pleomorphic rhabdomyosarcoma of the anterior abdominal wall following
      multimodality treatment for carcinoma of the rectum.
AB  - Postradiation sarcomas are rare, and the most commonly reported ones are
      malignant fibrous histiocytoma, osteosarcoma, angiosarcoma, fibrosarcoma,
      malignant peripheral nerve sheath tumor, and high-grade pleomorphic sarcoma, not
      otherwise specified. There are a few case reports of postradiation
      rhabdomyosarcomas following treatment of retinoblastoma, breast cancer,
      endometrial adenocarcinoma, and Hodgkin's disease. Secondary neoplasms following
      radiation and surgical treatment of rectal adenocarcinomas have not been reported
      in the English literature. We report a case of pleomorphic rhabdomyosarcoma of
      the anterior abdominal wall following treatment of rectal carcinoma, and we
      review the literature.

PMID- 15173926
TI  - Primary carcinoid tumor of the prostate with concurrent adenocarcinoma: a case
      report.
AB  - Prostatic adenocarcinomas commonly exhibit neuroendocrine differentiation as
      demonstrated by immunohistochemistry. However, true carcinoids of the prostate
      are rare. We describe herein a case of a primary carcinoid occurring
      synchronously with a conventional adenocarcinoma in the prostate of a 66-year-old
      man. The carcinoid measured 0.2 x 0.2 cm and did not show contiguity with
      adjacent conventional, moderately differentiated adenocarcinoma.
      Immunohistochemical stains for chromogranin and neuron-specific enolase were
      strongly immunoreactive in the carcinoid but not in the adenocarcinoma. Both
      neoplasms demonstrated positive staining for prostatic acid phosphatase and
      prostate-specific antigen. Owing to the relatively minute size of the carcinoid,
      the possibility that this tumor will impact negatively on the patient's overall
      prognosis is not anticipated.

PMID- 15173927
TI  - Collecting duct carcinoma exhibiting diastase-resistant PAS-positive globular
      cytoplasmic inclusions and rhabdoid features arising in adult polycystic kidney
      disease: a case report.
AB  - A 76-year-old man complained of lumbago, and a subsequent detailed examination
      revealed a mass in the left kidney. Macroscopically, multiple cysts were
      recognized in the bilateral kidney; the tumor proliferated predominantly in the
      renal medulla and showed a whitish color with focal necrosis and hemorrhage. A
      histologic examination of the surgically resected tumor showed various growth
      patterns, such as solid, tubular, and papillary, by tumor cells. The diagnosis of
      collecting duct carcinoma (CDC) was made. Furthermore, tumor cells contained
      globular inclusions resembling hyaline globules and large eosinophilic
      inclusions, resulting in rhabdoid features, in the cytoplasm. Histochemically,
      globular inclusions were positive for periodic acid-Schiff (PAS) with diastase
      pretreatment. Immunohistochemically, large esosinophilic inclusions were reactive
      for vimentin. Although these findings are rare in CDCs, they should be recognized
      in the pathologic spectrum of CDCs. Int J Surg Pathol 12(2):171-177, 2004

PMID- 15173928
TI  - Low-grade tubular myxoid renal tumors: a clinicopathological study of 3 cases.
AB  - We report 3 cases of a new renal cell tumor entity with a review of the
      literature. These 3 cases were retrieved from the files of this institution from
      1991 to 2002. The clinical data and all histologic slides were reviewed and an
      immunohistochemical study was performed. Patients were all females. Tumors were
      almost similar with well-defined margins. Tumor architecture was tubular and
      focally fusiform with an abundant myxoid stroma. Tumor cells were low cuboidal,
      slightly eosinophilic with low nuclear grade. Immunohistochemistry was in favor
      of a distal nephron differentiation. All patients were healthy after surgery. We
      describe 3 cases of a new clinicopathological entity entitled low-grade tubular
      myxoid renal tumor with a benign clinical course.

PMID- 15173929
TI  - Increased responsiveness of presumed 5-HT cells to citalopram in adult rats
      subjected to prolonged maternal separation relative to brief separation.
AB  - RATIONALE: Certain adverse events in childhood, such as loss of a parent or
      sexual abuse, are associated with an increased vulnerability to develop
      depression later in life. Prolonged, daily maternal separation of rat pups
      induces several behavioral, endocrine and neurochemical changes similar to those
      observed in human depression. OBJECTIVES: Because dysfunction of brain
      serotonergic systems has been implicated in the pathophysiology of depression,
      the effects of neonatal maternal separation on these systems was studied in adult
      rats. METHODS: Male rat pups were subjected to daily maternal separation for 180
      min (HMS180) from postnatal day 2 to day 14. Neonatal handled rats, i.e., pups
      undergoing daily 15-min separations during the same time period (HMS15), were
      chosen as a control group, since the 180-min separations involved handling of the
      pups, i.e., the pups were removed from the home cage during the separations. As
      adults, the effect of citalopram (0.05-0.80 mg/kg, intravenous) on the firing
      rate of 5-HT neurons in the dorsal raphe nucleus (DRN) was studied. RESULTS: The
      inhibitory effect of citalopram on serotonergic cell firing was significantly
      enhanced at doses of 0.1 mg/kg and 0.4 mg/kg in the HMS180 compared with that in
      the HMS15 rats. However, the number of binding sites and mRNA expression of the 5
      HT transporter and 5-HT(1A) receptors in the DRN did not differ between the two
      rearing groups. CONCLUSION: These findings suggest that early life stress gives
      rise to persistent changes in the function, but not the density or mRNA
      expression of central 5-HT(1A) receptors and/or 5-HT transporters.

PMID- 15173931
TI  - QTL analysis of fertility restoration in cytoplasmic male sterile pepper.
AB  - Fertility restoration of Peterson's cytoplasmic male-sterility in pepper
      (Capsicum annuum L.) is quantitative and environment-dependent. QTL analysis of
      fertility restoration was performed based on the test-cross progeny of 77013A (a
      strict cytoplasmic-genetic male sterile line) and a doubled haploid population of
      114 lines obtained from an F1 hybrid between Yolo wonder (a sterility maintainer
      line) and Perennial (a fertility-restorer line). The fertility of the test
      crossed lines was assessed under greenhouse and open field conditions using three
      criteria related to pollen or seed production. One major QTL for fertility
      restoration was mapped to chromosome P6. It was significant in all the
      environments and for all the traits, accounting for 20-69% of the phenotypic
      variation, depending on the trait. Four additional minor QTLs were also detected
      on chromosomes P5, P2, and linkage groups PY3 and PY1, accounting for 7-17% of
      the phenotypic variation. Most of the alleles increasing fertility originated
      from the restorer parent, except for two alleles at minor QTLs. Phenotypic
      analysis and genetic dissection indicated that breeding pepper for complete
      sterility of female lines and high hybrid fertility requires complex combinations
      of alleles from both parents and a strict control of the environment.

PMID- 15173930
TI  - Habituation of acoustic startle is disrupted by psychotomimetic drugs:
      differential dependence on dopaminergic and nitric oxide modulatory mechanisms.
AB  - RATIONALE: A deficit in attention and information processing has been considered
      a central feature in schizophrenia, which might lead to stimulus overload and
      cognitive fragmentation. It has been shown that patients with schizophrenia
      display a relative inability to gate incoming stimuli. Thus, patients repeatedly
      subjected to acoustic startle-eliciting stimuli habituate less to these stimuli
      than controls. Furthermore, schizophrenia-like symptoms can be induced by
      pharmacological manipulations in humans by psychotomimetic drugs, e.g.
      phencyclidine (PCP) and D-amphetamine (D-AMP). Recent studies show that the
      behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide
      synthase (NOS) inhibitors, suggesting that NO plays an important role in at least
      the pharmacological effects of PCP. OBJECTIVES: The first aim of the present
      study was to investigate if PCP, MK-801 and D-AMP impair habituation of acoustic
      startle in mice. Secondly, we examine the effect of the NOS inhibitor, L-NAME,
      and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in
      habituation. RESULTS: PCP (4 mg/kg), MK-801 (0.4 mg/kg) and D-AMP (5.0 mg/kg),
      impaired habituation of the acoustic startle response in mice. This effect was
      reversed by the NOS inhibitor, L-NAME. The typical antipsychotic, haloperidol,
      reversed the effects of PCP and D-AMP, but not that of MK-801. CONCLUSIONS: The
      finding that PCP, MK-801 and D-AMP impair habituation in mice is consistent with
      the idea that these treatments model certain filter deficits seen in
      schizophrenic patients. Furthermore, the present results suggest that NO is
      critically involved in these effects on habituation, whereas that of dopamine is
      less clear.

PMID- 15173932
TI  - Duodenal HFE expression and hepcidin levels determine body iron homeostasis:
      modulation by genetic diversity and dietary iron availability.
AB  - HFE affects the interaction of transferrin bound iron with transferrin receptors
      (TfR) thereby modulating iron uptake. To study genetically determined differences
      in HFE expression we examined individual HFE levels in C57BL/Sv129 mice and
      assessed their relationship to the regulation of iron homeostasis in the duodenum
      and the liver, and their regulation by diet. We found an up to 14-fold variation
      in inter-individual expression of HFE mRNA in the duodenum. Mice with high
      duodenal HFE mRNA expression presented with significantly higher levels of TfR
      and DMT-1 mRNAs and an increased IRP-1 binding affinity as compared to mice with
      low HFE levels. Duodenal HFE expression was positively associated with serum iron
      and liver HFE levels. Dietary iron supplementation decreased HFE in the duodenum
      but not in the liver. This was paralleled by reduced amounts of DMT-1 and FP-1 in
      the duodenum while the expression of DMT-1, FP-1, and hepcidin in the liver were
      increased with dietary iron overload. Duodenal and liver HFE levels are regulated
      by divergent penetration of as yet unelucidated modifier genes and to a much
      lesser extent by dietary iron. These measures control duodenal iron transport and
      liver iron homeostasis by modulating HFE expression either directly or via
      stimulation of iron sensitive regulatory molecules, such as hepcidin, which then
      exert their effects on body iron homeostasis.

PMID- 15173933
TI  - [Nodular erythema of both feet].

PMID- 15173934
TI  - Evolution and migration history of the Chinese population inferred from Chinese Y
      chromosome evidence.
AB  - Y-chromosomes from 76 Chinese men covering 33 ethnic minorities throughout China
      as well as the Han majority were collected as genetic material for the study of
      Chinese nonrecombinant Y-chromosome (NRY) phylogeny. Of the accepted worldwide
      NRY haplogroups, three (haplogroups D, C, O) were significant in this sample,
      extending previous assessments of Chinese genetic diversity. Based on geographic,
      linguistic, and ethnohistorical information, the 33 Chinese ethnic minorities in
      our survey were divided into the following four subgroups: North, Tibet, West,
      and South. Inferred from the distribution of the newly found immediate ancestor
      lineage haplogroup O*, which has M214 but not M175, we argue that the southern
      origin scenario of this most common Chinese Y haplogroup is not very likely. We
      tentatively propose a West/North-origin hypothesis, suggesting that haplogroup O
      originated in West/North China and mainly evolved in China and thence spread
      further throughout eastern Eurasia. The nested cladistic analysis revealed in
      detail a multilayered, multidirectional, and continuous history of ethnic
      admixture that has shaped the contemporary Chinese population. Our results give
      some new clues to the evolution and migration of the Chinese population and its
      subsequence moving about in this land, which are in accordance with the
      historical records.

PMID- 15173935
TI  - Effects of mild heat exposure on sleep stages and body temperature in older men.
AB  - The purpose of this study was to examine the effects of mild heat exposure on
      sleep stages and body temperature in older men. Ten healthy male volunteers with
      a mean age of 69.2 +/- 1.35 years served as subjects. The experiments were
      carried out under two different sets of conditions: 26 degrees C 50% relative
      humidity (RH) and 32 degrees C 50% RH. The subjects slept from 2200 hours to 0600
      hours with a cotton blanket and wearing short-sleeve pajamas and shorts on a bed
      covered by a sheet. Electroencephalogram, electro-occulogram and mental
      electromyogram recordings were made through the night. Rectal and skin
      temperatures were measured continuously. No significant differences were observed
      in sleep onset latency. In time spent in each sleep stage, wakefulness was
      significantly increased at 32 degrees C than at 26 degrees C. The total amount of
      wakefulness increased and rapid eye movement sleep (REM) decreased at 32 degrees
      C compared to 26 degrees C. The fall in rectal temperature was significantly
      suppressed and the mean skin temperature was significantly higher at 32 degrees C
      than at 26 degrees C. These results suggest that, for older men, even mild heat
      exposure during the nighttime sleep period may increase thermal load, suppress
      the decrease of rectal temperature, decrease REM, and increase wakefulness and
      whole-body sweat loss.

PMID- 15173936
TI  - New PTH assays and renal osteodystrophy.
AB  - Parathyroid hormone (PTH) levels have been used instead of bone histomorphometric
      analysis in renal failure, but the assessment of tetracycline-labeled bone biopsy
      remains the most reliable method to diagnose the different subtypes of renal
      osteodystrophy. The availability of the first-generation immunometric PTH assay
      (1(st) PTH-IMA) allowed the distinction between the different types of renal bone
      diseases. However, 1(st) PTH-IMA not only detects the intact hormone PTH(1-84),
      but also additional PTH truncated fragments. A second-generation immunometric PTH
      assay (2(nd) PTH-IMA) recognizes only PTH(1-84) and possible PTH fragments that
      are truncated at the carboxyl-terminus, but not PTH(7-84). In addition, whether
      assessment of the ratio PTH(1-84) and amino-terminally truncated PTH(1-84)
      fragments is a better predictor of bone turnover remains controversial. An
      initial study using the 2(nd) PTH-IMA suggested that the ratio between PTH(1-84)
      and amino-terminally truncated PTH(1-84) fragments more accurately predicts bone
      turnover in adult patients treated with hemodialysis. However, subsequent studies
      using the Scantibodies assay have failed to better predict the underlying bone
      disease in adults undergoing maintenance hemodialysis. Furthermore, a different
      2(nd) PTH-IMA (Immutopics) with similar, but not identical, in vitro
      characteristics did not show a superior predictive value of the ratio in
      pediatric patients treated with peritoneal dialysis. Although the 2(nd) PTH-IMA
      may provide important new insights into the physiology of parathyroid gland
      function, at present, measurement of PTH using either 1(st) or 2(nd) PTH-IMAs
      provides similar accuracy for predicting bone turnover in patients treated with
      dialysis. Thus, the current data do not yet support the claim that 2(nd) PTH-IMAs
      provide an advantage over 1(st) PTH-IMAs for the diagnosis of the different
      subtypes of renal bone diseases.

PMID- 15173937
TI  - Growth hormone therapy influences endothelial function in children with renal
      failure.
AB  - Endothelial dysfunction, an early step in atherogenesis, is prevalent in children
      with renal insufficiency. Endothelial dysfunction in growth hormone deficiency is
      reversed by growth hormone (rhGH) therapy. Renal failure induces growth hormone
      resistance at the receptor and post-receptor level, which can be overcome by rhGH
      therapy. This study investigates the influence of rhGH therapy in children with
      renal failure on flow-mediated dilation (FMD) of the brachial artery, a marker of
      endothelial function. We studied 8 patients, who were on rhGH for at least 6
      months, and 8 healthy children for comparison. FMD of the brachial artery was
      measured non-invasively as the percentage increase in diameter during post
      ischemic hyperemia. Patients were studied at baseline, after 4 weeks interruption
      of rhGH therapy, and 4 weeks after resumption of therapy. FMD was significantly
      lower in patients (4.7%) than healthy controls (13.8%) ( P=0.01). During the
      administration of rhGH, FMD was significantly higher (3.9%) than during
      interruption of the treatment (1.4%) ( P=0.04). Our data support the theory that
      a disturbance in the GH-IGF axis contributes to the endothelial dysfunction of
      renal failure. Treatment with rhGH not only improves growth but may also
      favorably influence the risk for atherogenesis.

PMID- 15173938
TI  - The longest use of liposomal amphotericin B and 5-fluorocytosine in neonatal
      renal candidiasis.
AB  - Bilateral fungal obstruction of the renal collecting system is rare in infancy.
      Treatment options include medical or surgical procedures. Reports of successful
      medical treatment with liposomal amphotericin B have been published but the
      duration of treatment is controversial. We report a 3-week-old preterm baby with
      myelomeningocele who had experienced acute renal failure related to bilateral
      renal fungus balls, which improved with percutaneous nephrostomy and 12 weeks of
      liposomal amphotericin B intravenously combined with 5-fluorocytosine orally for
      9 weeks.

PMID- 15173941
TI  - Management of stage I cervical sarcoma botryoides in childhood and adolescence.
AB  - Rhabdomyosarcomas are the most common soft tissue sarcomas in childhood. The
      botryoid variant arises in infancy from the vagina or urinary bladder and
      extremely rarely from the uterine cervix. Treatment regimes range from local
      excision of the tumour to radical hysterectomy with adjuvant multidrug therapy
      and/or radiotherapy. In cases of minimal cervical invasion, the less invasive
      local excision in combination with adjuvant chemotherapy has resulted in
      excellent survival rates with complete functional preservation of the bladder,
      rectum, vagina, and ovaries. We present here a 30-year literature review and a
      case report of a cervical sarcoma botryoides in a 5-year-old girl. CONCLUSION:
      based on the literature review and our own observation, we recommend minor
      surgical approaches in combination with chemotherapy as the treatment of choice
      for early stage I cervical rhabdomyosarcoma.

PMID- 15173942
TI  - Lipid fixation for fat staining in paraffin sections applied to lesions of
      atherosclerosis.
AB  - A new method to fix lipids for staining in paraffin sections was applied here to
      early lesions of atherosclerosis to test comparability with similar results using
      frozen-section fat stains. Small blocks of formalin-fixed human coronary artery
      were exposed to an emulsion of linoleic acid and lecithin in 70% ethylene glycol
      at 56 degrees C for 3 days. The unsaturated fatty acids partitioned into the
      tissue lipids for later fixation by chromic acid and could then be processed
      through paraffin-section for fat staining. Blocks of tissue from the same
      specimens were also processed for standard frozen-section fat staining. The types
      of early atherosclerotic lesions described by the American Heart Association
      Lesions Committee--types I, II, III, and IV--were demonstrated equally well using
      the two methods. Additional newly described patterns of lipid deposits were also
      revealed by both methods. The paraffin method showed no indication of omitting or
      adding anything compared with frozen sections. The surprising finding of
      unexpected patterns of lipid distribution in human coronary artery suggests that
      the method may prove to be useful. Those novel patterns were first observed with
      the more flexible paraffin method and later confirmed by the more tedious and
      demanding frozen-section method.

PMID- 15173943
TI  - Myofibrosarcoma.
AB  - Myofibrosarcomas are malignant tumours of myofibroblasts, which have been
      recognised for many years, but have become clearly defined only recently. They
      are low- or high-grade sarcomas that arise in soft tissue or bone in adults or
      children. Low-grade myofibrosarcomas are infiltrative tumours, usually in deep
      soft tissue, with a predilection for the head and neck region, which display a
      range of microscopic appearances from fasciitis-like to fibrosarcoma-like; all
      cases at least focally display nuclear pleomorphism. They express smooth-muscle
      actin and calponin, and some express desmin, but most lack h-caldesmon. Low-grade
      myofibrosarcomas can recur but rarely metastasise. Their differential diagnosis
      is from benign myofibroblastic proliferations, such as fasciitis and
      fibromatosis, as well as from fibrosarcoma and leiomyosarcoma. Pleomorphic
      myofibrosarcomas are high-grade pleomorphic sarcomas (malignant fibrous
      histiocytoma), which show ultrastructural evidence of myofibroblastic
      differentiation. They closely resemble malignant fibrous histiocytoma clinically
      and morphologically, but are more frequently actin positive. This article
      describes the low- and high-grade variants of myofibrosarcoma and other malignant
      tumours with myofibroblastic differentiation.

PMID- 15173944
TI  - Analysis of splice donor and acceptor function in a novel Ac-based gene trap
      construct.
AB  - In this study, an Ac-based gene trap construct was engineered to increase gene
      trapping efficiency by an effective use of triple acceptor sites preceding a
      reporter gene. The target of the engineering process was a synthetic intron
      preceding the GUS reporter. Two different gene trap constructs were designed. In
      one construct, three of the sequence elements serving as signals for recognition
      of an intron 3' boundary were systematically modified to allow for almost optimal
      acceptor site recognition, while these sequences remained unchanged in the other
      construct. To compare recognition of the engineered intron with that of the
      unmodified intron, tester constructs were transiently transformed into barley
      (Hordeum vulgare L.) tissue and the accuracy and efficiency of splicing was
      determined by mRNA mapping and reporter-gene expression frequency analysis. By
      employing this test system, we could show that systematic engineering of the
      intron sequence elements results in advanced intron recognition, compared to the
      unmodified intron, and that all three acceptor sites were activated, but with
      unequal frequency. The impact of our findings on reporter expression in a gene
      trap approach is discussed.

PMID- 15173945
TI  - Glyphosate inhibits the translocation of green fluorescent protein and sucrose
      from a transgenic tobacco host to Cuscuta campestris Yunk.
AB  - The parasitic plant Cuscuta campestris is dependent on its host for water,
      assimilates and amino acids. It can be controlled by the herbicide glyphosate,
      which inhibits 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), resulting in
      shikimate accumulation. In this study, C. campestris was parasitic on transgenic
      tobacco plants expressing green fluorescent protein (GFP) in the phloem. Changes
      in [14C]sucrose and GFP accumulation in the parasite were used as indicators of
      the herbicide's effect on translocation between the host and parasite. Host
      plants were treated with glyphosate 22 days after sowing. Shikimate accumulation
      in the parasite 1 day after glyphosate treatment (DAGT) confirmed EPSPS
      inhibition in C. campestris. No damage was visible in the host plants for the
      first 3 DAGT, while during that same time, a significant reduction in
      [14C]sucrose and GFP accumulation was observed in the parasite. Thus, we propose
      that the parallel reduction in GFP and sucrose accumulation in C. campestris is a
      result of a glyphosate effect on the parasite's ability to withdraw assimilates
      from the host.

PMID- 15173946
TI  - Surgical trauma: hyperinflammation versus immunosuppression?
AB  - BACKGROUND: Experimental and clinical studies have brought evidence that surgical
      trauma markedly affects the immune system, including both the specific and the
      non-specific immune response. MATERIALS AND METHODS: This report reviews the
      present knowledge on the mechanisms of surgical trauma-induced immune dysfunction
      and outlines experimental and clinical approaches to find effective treatment
      strategies. RESULTS: Major surgical trauma induces an early hyperinflammatory
      response, which is characterized by (1) pro-inflammatory tumour necrosis factor
      alpha (TNF), interleukin (IL)-1, and IL-6 cytokine release and (2) neutrophil
      activation and microvascular adherence, as well as (3) uncontrolled
      polymorphonuclear (PMN) and macrophage oxidative burst. The massive and
      continuous IL-6 release induces an acute phase response, but, more importantly,
      also accounts for the up-regulation of major anti-inflammatory mediators, such as
      prostaglandin (PG) E2, IL-10 and transforming growth factor (TGF)-ss. This
      results in surgical, trauma-induced, immunosuppression, as indicated by (1)
      monocyte deactivation, reflected by the lack of monocytic TNF- production upon
      lipopolysaccharide (LPS) stimulation, and (2) a shift of the Th1/Th2 ratio
      towards a Th2-dominated cytokine pattern. The imbalance between pro-inflammatory
      and anti-inflammatory cytokines and immuno-competent cells determines the
      phenotype of disease and should help the physician to compose the therapeutic
      strategy. In fact, recent clinical studies have shown that both the initial
      uncontrolled hyperinflammation and the continued cell-mediated immunosuppression
      represent primary targets to counteract post-surgery immune dysfunction. The
      balance between inflammatory and anti-inflammatory forces may be restored by
      interferon gamma (IFN-gamma) to counteract monocyte deactivation; the anti
      inflammatory PGE2 may be inhibited by indomethacin to attenuate
      immunosuppression; or the initial hyperinflammation may be targeted by
      administration of anti-inflammatory substances, such as granulocyte colony
      stimulating factor (G-CSF), hydoxyethyl starch, or pentoxifylline. CONCLUSIONS:
      When drawing up the therapeutic regimen the physician should not consider
      hyperinflammation versus immunosuppression, but hyperinflammation and
      immunosuppression, aiming at restoring an appropriate mediator- and immune cell
      associated balance.

PMID- 15173947
TI  - Prevalence and treatment of bleeding complications in chronic pancreatitis.
AB  - OBJECTIVES: As spontaneous major haemorrhage in patients with chronic
      pancreatitis is rare, limited data have been reported, and no evidence-based
      guidelines are currently available regarding the optimal treatment modality.
      PATIENTS AND METHODS: We report our experience with 36 patients with severe
      bleeding complications from a series of 541 patients presenting with chronic
      pancreatitis (representing a prevalence of 6.7% of admitted patients), treated in
      one surgical department over a period of 9.5 years, with a median follow-up of
      4.1 years. RESULTS: Haemorrhage was indirectly related to chronic pancreatitis in
      eight patients (22.2%) with ulcer or variceal bleeding. Three patients (8.4%)
      demonstrated spleen infarction or rupture. The most common causes of major
      haemorrhage were pseudoaneurysms in 25 patients (69.4%). Nine of them were
      treated with primary embolization. Sixteen patients with pseudoaneurysms
      underwent surgery. The only mortalities (8.3%) observed were from bleeding
      associated complications of pseudoaneurysms. Two patients died after surgery, and
      one after primary embolization. We observed a higher re-bleeding rate after
      surgery (25% vs 11% after embolization). The presence of haemorrhagic shock, and
      the amount of blood transfused, were significant determinants of hospital
      mortality. Patient age, pseudoaneurysm location, and treatment modality had no
      significant influence on mortality. CONCLUSIONS: Any haemodynamically stable
      patient with haemorrhage due to arterial pseudoaneurysms should undergo
      angiography with embolization when technically possible. If there are no other
      pancreas-related indications for surgery, embolization remains the definitive
      treatment. If embolization is not available or has failed, surgery is indicated,
      although perioperative morbidity will be higher.

PMID- 15173948
TI  - Fundus autofluorescence in carriers of X-linked recessive retinitis pigmentosa
      associated with mutations in RPGR, and correlation with electrophysiological and
      psychophysical data.
AB  - PURPOSE: To describe fundus autofluorescence (AF) in carriers of X-linked
      retinitis pigmentosa (XLRP) associated with mutations in RPGR (RP3), and to
      compare the findings on AF with ophthalmoscopy and with electrophysiological and
      psychophysical data. METHODS: Eleven carriers from two families with XLRP and
      mutations in RPGR underwent clinical examination including fundus photography,
      AF, full-field electroretinography, Goldmann kinetic perimetry and two-colour
      threshold perimetry (2CT perimetry). RESULTS: An abnormal AF pattern was found in
      9 of 11 carriers, with a radial pattern in 6 of 11. In 2CT perimetry patchy rod
      and cone sensitivity losses were seen in 7 of 8 carriers. Rods tended to be more
      affected than cones. The areas of sensitivity loss showed some correspondence
      with the abnormalities seen on AF. CONCLUSION: AF had a specific pattern in 9 of
      11 carriers from two families with mutations in RPGR. The result was independent
      of the family investigated. The radial pattern may be explained by random X
      inactivation early during embryogenesis subsequently preserved in all daughter
      cells and the centrifugal radial growth pattern of the developing neuroretina. AF
      may prove to be a rapid and easy clinical test to identify carriers of RP3.

PMID- 15173949
TI  - Pregnancy outcome in non-gynecologic cancer.
AB  - OBJECTIVE: The objective was to determine the prevalence of non-gynecologic
      cancer in pregnancy and its maternal and fetal outcome in a single tertiary
      center in the Eastern Province of Saudi Arabia. METHOD: Retrospective chart
      review was done of 54 patients with a diagnosis of non-gynecologic cancer in
      pregnancy at Dhahran Health Center from January 1990 to December 2001 using the
      Dhahran Health Information database. Maternal and fetal outcome were determined
      for 17 women with active cancer during pregnancy (Group I, 18 pregnancies) and
      for 44 women in cancer remission (Group II, 96 pregnancies). Seven women were
      pregnant during active cancer and during cancer remission. RESULTS: There were
      114 pregnancies in 54 women with cancer. The prevalence in pregnancy was
      1.5:1,000 (54 cancer in 70,987 pregnancies). Thyroid (33) and breast (11) cancer
      accounted for 75% of all cancer. Induced abortion, spontaneous abortion,
      stillbirth and low birth weights in Group I were: 5 (28%), 0 (0%), 1 (6%) and 2
      (11%), respectively, and in Group II were: 1 (1%), 11 (11%), 0 (0%) and 3 (3%),
      respectively. Live births for Group I, II and all patients with cancer were 12
      (66.7%), 84 (87.5%) and 96 (84.2%), respectively, with p =0.025 There were three
      maternity deaths among 17 women in Group I. None of 44 women in Group II died.
      CONCLUSION: The diagnosis of active cancer in pregnancy carries a significant
      increase in perinatal and maternal mortality. However, pregnancy during cancer in
      remission has favorable outcome, pregnancy in this group should not be
      discouraged.

PMID- 15173950
TI  - Labor analgesia for the morbidly obese parturient: an old problem--new solution.
AB  - INTRODUCTION: Morbid obesity is perhaps the most common nutritional disorder seen
      in pregnancy, and morbidly obese parturients have more pregnancy complication
      than normal body mass index (BMI) pregnant patients. Combined spinal epidural
      anesthesia (CSEA) has become a well-established alternative to epidural analgesia
      for labor pain in many institutions. However, due to lack of an appropriately
      long needle design, its advantages have not been routinely available to laboring
      morbidly obese patients. CASE REPORT: I herein, present a case of a morbidly
      obese parturient whose labor analgesia was managed with CSEA administered with
      the newly released, commercially available, CSEA needle set, specifically
      designed for morbidly obese patients.

PMID- 15173951
TI  - Prolactin-producing pituitary adenoma with incomplete neuronal transformation: an
      intermediate adenoma-neuronal tumor.
AB  - We present a unique case of a prolactin (PRL)-producing pituitary adenoma showing
      incomplete neuronal differentiation without ganglion cells. A 27-year-old man
      presented with nausea, headaches, and instability over the last 2 months.
      Clinical examination revealed obesity with no other endocrinological signs. His
      serum PRL levels were slightly elevated (38 ng/ml), whereas concentrations of the
      other adenohypophysial hormones were within normal range. Histology revealed an
      unusual pituitary adenoma containing many hypocellular areas with fibrillar
      appearance. The sizable tumor cells were polyhedral or elongated harboring an
      ovoid, vesicular nucleus with prominent nucleolus, lacking, however, the typical
      features of ganglion cells. By immunohistochemistry, many adenoma cells were
      positive for PRL. Immunostain for neurofilament protein revealed variable amounts
      of fibrils dispersed throughout the stroma, mostly in the hypocellular areas. In
      addition, neurofilament protein and chromogranin were strongly reactive in
      approximately 15% of the tumor cell population, whereas reactivity for
      synaptophysin was uniform throughout the tumor. These findings led to the
      conclusion that part of the tumor-cell population expressed a hybrid
      immunoprofile of adenoma-neuronal cell. Our case is the first PRL-producing
      pituitary adenoma showing incomplete neuronal differentiation lacking mature
      ganglion cells.

PMID- 15173952
TI  - Multifocal hydatid disease in a child.
AB  - One of the most serious helminth infections in humans with widespread occurrence
      is hydatid disease. Although the majority of the cases are referred in adults,
      many of them have to do with children. The hydatid cysts can occur in any organ
      of the human body and in rare cases in a combination of different sites. We
      present the case of a young boy with hydatid cysts in both lungs and in the upper
      pole of the left kidney. The rarity of this case is the unusual combination of
      the cyst development in these organs without the involvement of the liver.

PMID- 15173953
TI  - Observation of continuous spike-waves during slow sleep in children with
      myelomeningocele.
AB  - CASES: Two patients with myelomeningoceles (MMC) and shunt-treated hydrocephalus
      are reported. At 5 and 7 years respectively, when they began presenting mental
      deterioration and behavioural disorders, sleep EEG showed continuous spike-waves
      during slow sleep (CSWS). DISCUSSION: These are the first cases of CSWS described
      in patients with MMC. The mechanisms of CSWS are considered. The role of
      hydrocephalus and the thalamic injuries found in one of the patients is discussed
      in detail. The usefulness of monitoring sleep EEG in patients with hydrocephalus
      or thalamic lesions is stressed, considering the effects of CSWS on the cognitive
      competencies and the soft or subclinical course that epilepsy complicated with
      CSWS may follow.

PMID- 15173954
TI  - Current status of vesicoureteral reflux diagnosis.
AB  - In children, diagnostic imaging for vesicoureteral reflux (VUR) encompasses both
      radiologic and sonographic modalities. The former comprises voiding
      cystourethrography (VCUG), the most widespread method for examination for reflux,
      and radionuclide cystography (RNC). In RNC the radiation exposure is
      significantly less than in VCUG with continuous fluoroscopy, but the anatomic
      details depicted are much inferior. With the introduction of pulsed fluoroscopy,
      the radiation exposure of VCUG has been markedly curtailed. VCUG is the first
      imaging choice for the urethra. The sonographic diagnosis of VUR with the
      intravesical administration of an ultrasound (US) contrast agent-voiding
      urosonography (VUS)-is being used increasingly in the routine diagnostic imaging
      work-up of reflux. Various sonographic reflux examination methods had been tried
      in the past. The real breakthrough came with the availability of stabilized US
      contrast media. Further impetus came with the introduction of harmonic US
      imaging. The recent release of a second generation US contrast medium promises to
      make a further positive impact on VUS. The diagnostic accuracy of contrast
      enhanced VUS has been found to be comparable to radiologic methods. VUS is
      primarily performed in follow-up studies and as the primary reflux examination
      modality in girls.

PMID- 15173955
TI  - Feasibility and pharmacokinetic study of infusional dexrazoxane and dose
      intensive doxorubicin administered concurrently over 96 h for the treatment of
      advanced malignancies.
AB  - PURPOSE: Dexrazoxane administration prior to short infusion doxorubicin prevents
      anthracycline-related heart damage. Since delivery of doxorubicin by 96-h
      continuous intravenous infusion also reduces cardiac injury, we studied
      delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous
      infusion. METHODS: Patients with advanced malignancies received tandem cycles of
      concurrent 96-h infusions of dexrazoxane 500 mg/m2 and doxorubicin 165 mg/m2, and
      24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5
      microg/kg) and oral levofloxacin (500 mg) were administered daily until the white
      blood cell count reached 10,000 microl(-1). Plasma samples were analyzed for
      dexrazoxane and doxorubicin concentrations. RESULTS: Ten patients were enrolled;
      eight patients had measurable disease. Two partial responses were observed in
      patients with soft-tissue sarcoma. The median number of days of granulocytopenia
      (<500 microl(-1)) was nine and of platelet count <20,000 microl(-1) was seven.
      Six patients received a single cycle because of progression (one), stable disease
      (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction
      (two). Principal grade 3/4 toxicities included hypotension (two), anorexia
      (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with
      documented infection (three). One death from neutropenic sepsis occurred.
      Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged
      from 59.1 to 106.9 nM. CONCLUSIONS: These results suggest that tandem cycles of
      concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be
      administered with minimal cardiac toxicity, and have activity in patients with
      recurrent sarcomas. However, significant non-cardiac toxicities indicate that the
      cardiac sparing potential of this approach would be maximized at lower dose
      levels of doxorubicin.

PMID- 15173956
TI  - Mechanistic and antineoplastic evaluation of taurolidine in the DU145 model of
      human prostate cancer.
AB  - Taurolidine (TRD) was designed in the 1970s as a broad-spectrum antibiotic and is
      used clinically at high doses without systemic toxicity. We have found that this
      agent possesses cytotoxic activity in human tumor cell lines and antineoplastic
      activity in mice bearing i.p. human tumor xenografts. We now report the mechanism
      by which TRD induces cell death in DU145 human prostate tumor cells. The IC50 (3
      days) of TRD in this model was 16.8+/-1.1 microM. Cytotoxicity was associated
      with DNA debris and increased membrane phosphatidylserine externalization, both
      suggesting the induction of apoptosis. This was confirmed by the ability of TRD
      to induce PARP cleavage in these cells, an effect prevented by coexposure to the
      pan-caspase inhibitor zVAD-FMK. TRD exposure also resulted in the appearance of
      cytochrome c in the cytoplasm, procaspase 9 activation within 2 h of drug
      exposure and procaspase 8 activation 4 h after exposure. Parallel experiments
      revealed that cytochrome c appearance in the cytoplasm was not blocked by
      preexposure to zVAD-FMK, while activation of both procaspase 9 and procaspase 8
      was prevented. Finally, antineoplastic activity was assessed in mice bearing
      subcutaneous xenografts of DU145 cells. Initial studies quantitated the toxicity
      of three i.p. injections of TRD, administered as one injection on three alternate
      days per week, at doses ranging from 500 to 700 mg/kg per injection. The 500
      mg/kg dose produced about 7% mortality after three cycles and effectively
      inhibited tumor growth. Thus, TRD induced mitochondrial-mediated apoptosis in
      DU145 human prostate tumor cells and this effect could be exploited for
      therapeutic advantage.

PMID- 15173957
TI  - Tumor selective antivascular effects of the novel antimitotic compound ABT-751:
      an in vivo rat regional hemodynamic study.
AB  - Selective induction of vascular damage within a growing tumor is a potentially
      important approach in the search for potent anticancer therapeutics. Tubulin
      binding (antimitotic) agents destabilize cellular microtubules, suppress tumor
      growth, and exert antivascular effects with varying degrees of tumor selectivity
      in preclinical models. The tumor-selective, antivascular effects of ABT-751, a
      novel, orally active antimitotic agent, currently in phase II clinical
      development, were characterized in vivo in the present study. We developed an in
      vivo rat model designed to quantify acute changes in regional vascular resistance
      (VR) in both tumor and non-tumor vascular beds simultaneously. Tissue-isolated
      tumors (1 g) with blood flow supplied by a single epigastric artery were grown in
      rats. Subsequently, tumor blood flow was measured under anesthesia in solid
      tumors and also in mesenteric, renal, and normal epigastric arteries.
      Phenylephrine-induced (1 micromol/kg) increases in VR were not different between
      tumor and non-tumor epigastric arteries, suggesting that tumor vessels possess
      relatively normal vasoconstrictive function. ABT-751 (3, 10, and 30 mg/kg; i.v.)
      produced modest transient increases in mean arterial pressure with no effect on
      heart rate. Tumor VR increased to 75+/-36, 732+/-172, and 727+/-125% above
      baseline, respectively (P<0.05 for the 10 and 30 mg/kg doses), whereas VR in
      normal epigastric arteries was not significantly affected. Administration of ABT
      751 produced transient modest ( P<0.05) increases in mesenteric VR and no effect
      on renal VR. These results demonstrate that ABT-751 produces marked reductions in
      tumor blood flow in the intact rat at doses that exert negligible effects on
      normal vascular function.

PMID- 15173958
TI  - Acute panmyelosis with myelofibrosis: a clinicopathological study on 46 patients
      including histochemistry of bone marrow biopsies and follow-up.
AB  - Controversy continues whether acute panmyelosis with myelofibrosis (APMF) exists
      as a well-defined clinicopathological entity. Following exclusion of overt acute
      myeloid leukemia (AML), especially the megakaryoblastic subtype, a retrospective
      study was performed on 46 patients with clinical and morphological features
      suggesting the diagnosis of APMF. All patients had a bone marrow (BM) biopsy
      performed at onset, and 13 had follow-up examinations. Enzyme histochemical and
      immunohistochemical techniques were applied and BM features evaluated by a
      semiquantitative scoring system. Clinical findings consisted of pancytopenia
      associated with a left-shifted differential count of the peripheral blood (less
      than 5% blasts) and no or minor splenomegaly. During follow-up (median survival 9
      months) 35 patients developed severe BM insufficiency and 10 transformed into
      overt AML. Although myelofibrosis was a characteristic finding, other BM features
      proved to be heterogeneous. Cellularity was reduced in 13 and increased in 25
      specimens. Most prominent was a left-shifted, often macrocytic erythropoiesis and
      a maturation defect of the neutrophil series. In 15 patients an increase (less
      than 20%) in CD34+ progenitors, immature myelomonocytic cells, and
      megakaryoblasts was noted. Abnormalities of megakaryocytes (atypical microforms,
      clustering, dysplasia) were regularly present. The stroma showed an inflammatory
      reaction (perivascular plasmacytosis, lymphoid nodules, many macrophages, iron
      deposits) in about 50% of the samples. Sequential BM biopsies revealed an
      accumulation of lysozyme-expressing myelomonocytic and CD34+ progenitor cells
      suggesting an increase in blasts. In conclusion, APMF may not be a distinct
      entity, but includes hyperfibrotic myelodysplastic syndromes (MDS) either primary
      or secondary, a rare form of initial AML with fibrosis, and even cases of toxic
      myelopathy.

PMID- 15173959
TI  - Study of carpal bone morphology and position in three dimensions by image
      analysis from computed tomography scans of the wrist.
AB  - The morphology and positioning of the carpal bones were studied in three
      dimensions in 18 normal adults on computed tomography (CT) scans of the wrist.
      The digital data from each CT scan were processed to extract the carpal bones and
      to automatically characterize their geometry (geometric centroid, principal axes
      of inertia) using specific software tools. Biometric and angular parameters were
      defined for this purpose, and most of these parameters showed a normal
      distribution. The mean distance between the geometric centroid of the capitate
      and that of the triquetrum, expressed as a relationship to the length of the
      first principal axis of inertia of the capitate, was found to be the greatest
      (157.6%+/-8.4%), whereas the smallest mean distance was between the hamate and
      triquetrum (91.4%+/-7.3%). In the sagittal plane, the first principal axis of
      inertia of the bones of the first carpal row projected in front of the vertical
      axis of the orthogonal reference system, whereas the first principal axis of the
      capitate projected behind it. Measurements using this methodology are far more
      numerous than those from standard plain radiographs and have the additional
      advantage of being independent of the examiner. Future investigations on normal
      wrists should provide a normal range for each quantitative parameter, and
      comparative study of normal and pathologic wrist measurements should help to
      define the most relevant parameters for specific traumatic pathologies of the
      wrist.

PMID- 15173960
TI  - Development of the vermiform appendix during the fetal period.
AB  - This study aimed to determine the location and development of the vermiform
      appendix (VA) in terms of morphometry. It was carried out on 80 human fetuses
      that exhibited neither external pathology nor anomaly and whose gestational ages
      were between 10 and 40 weeks. The location of the VA and cecum was established.
      Total VA diameter, lumen diameter, wall thickness, serosa, muscularis and mucosa
      thickness were measured on microscope slides. The VA was almost always observed
      in the subcecal region during the fetal period. The length of the VA and the
      attachment length of the meso-appendix to the VA increased with the gestational
      age. Lymphocyte aggregation was first seen at the 17th week of the fetal period.
      Positive and meaningful correlation was found between gestational age and
      morphometric parameters of the VA. A significant difference was found between the
      genders in the thickness of mucosa, which was larger in girls (p<0.05). When the
      proximal, median and distal parts were compared, the thickness of serosa between
      the proximal and distal parts was also significantly different (p<0.05). The
      present study has revealed that the VA matures in the second trimester during the
      fetal period. Furthermore, the morphologic development of the VA is almost
      uniform from the proximal to distal part.

PMID- 15173961
TI  - [Botox. It is not about wrinkles].

PMID- 15173962
TI  - [Stem cells: science's challenge in the fight against diabetes].

PMID- 15173963
TI  - [Post-operative endophthalmitis. Developing guidelines to protect the
      ophthalmologist].

PMID- 15173964
TI  - [Experimental study on usefulness of silicone-fluorsilicone copolymer oil (SiFO)
      in vitreoretinal surgery].
AB  - PURPOSE: To evaluate the usefulness of silicone-fluorsilicone copolymer oil
      (SiFO) as an intraoperative tool and a vitreous substitute in vitreoretinal
      surgery. METHODS: Handling properties of SiFO were tested and compared with those
      of perfluorooctane (PFO). The transparency of both substances was measured by
      spectrophotometry and subjectively assessed. Their tendency to dispersion was
      observed during injection in balanced saline solution (BSS) and after mechanized
      and manual shaking. Ease of injection and aspiration through small-gauge
      instruments was evaluated. Ocular tolerance to SiFO and PFO was studied after
      intravitreal injection in rabbit eyes: intraocular pressure, anterior segment
      inflammatory response and dispersion were evaluated, and a histopathological
      study was performed. RESULTS: Injection and aspiration of SiFO were more
      difficult than those of PFO because of its higher viscosity. PFO dispersed
      progressively into small droplets as early as two days after intravitreal
      injection, whereas SiFO remained as a single bubble for 14 days.
      Histopathologically both substances induced an inflammatory response over the
      inferior retina, with microvacuolated macrophages and foreign body giant cells,
      which were larger in eyes wearing SiFO. CONCLUSIONS: SiFO may be useful as an
      intraoperative tool, although its main drawback is a more difficult injection and
      aspiration compared to PFO. It has been well tolerated as a short-term vitreous
      substitute, but further clinical studies are needed.

PMID- 15173965
TI  - [Preoperative eye-drop antibiotherapy in cataract surgery].
AB  - OBJECTIVE: To ascertain the effectiveness of various antibiotic eye-drops in
      eradicating the preoperative conjunctival bacteria of patients undergoing
      cataract surgery and to differentiate the failure of these treatments due to the
      lack of "in vitro" sensibility from other possible causes. METHODS: Retrospective
      study of the preoperative conjunctival flora of 4876 consecutive patients; "in
      vitro" sensibility was analysed by grouping bacteria into eight categories; the
      susceptibility percentages of the total conjunctival flora to five antibacterial
      agents were compared. The effectiveness of the eye-drop treatment with a single
      sensitive tested antibiotic (Aureomicin, Chloramphenicol, Gentamicin, Norfloxacin
      or Rifamicin) was evaluated in patients with pathogen bacteria. RESULTS: The "in
      vitro" sensibilities of Chloramphenicol (84.4%) and Rifampicin (83.9%) were
      similar (p < 0.01) and statistically higher than those of the other antibiotics.
      Nevertheless, the Chloramphenicol pathogen bacterium treatment failed in 21.2% of
      cases, in spite of being "in vitro" sensitive. Gentamicin presented the best
      effectiveness for eradicating Staphylococcus aureus and Gram (-) rods. Aureomicin
      had the best effectiveness against Streptococcus and Gram (-) diplococci.
      Rifamicin was the most effective for eradicating the whole predominant Gram (+)
      flora. The effectiveness of all five antibiotics decreased when there was more
      than one pathogen. CONCLUSIONS: None of the five antibiotic monotherapies
      maintains the patients' conjunctive free of pathogen bacteria 48 hours after
      finishing the treatment; however, there are bacterial patrons whose treatment
      could be optimised. The existence of polymicrobial flora decreases the
      effectiveness of the treatment.

PMID- 15173966
TI  - [Impact of cataract surgery upon functional capacity of the elderly].
AB  - PURPOSE: To determine the impact of cataract intervention on visual function of
      the elderly and on autonomy in daily activities, analyzing the influence of
      clinical and sociodemographic variables. METHODS: Observational and longitudinal
      study. 185 elderly patients having undergone cataract surgery were compared with
      179 elderly patients on a surgical waiting list. The first group was evaluated
      prior to surgery and at 4 months post-intervention. Control group patients were
      evaluated at the same times, without having received surgery. For all subjects,
      the state of visual function was determined by the Activities of Daily Vision
      Scale (ADVS). Degree of dependence in carrying out basic daily activities,
      cognitive state and self-perception of vision were also measured. Other variables
      were visual acuity, other ocular diseases and sociodemographic characteristics.
      RESULTS: Amongst the elderly patients having undergone surgery, the proportion of
      subjects able to carry out basic activities 4 months post-intervention (60.7%)
      was very similar to the initial pre-intervention figure (62.2%). However, in the
      control group, the proportion (63.1%) diminished significantly at the 4-month
      mark (48.8%) (p= 0.0001). Of the intervened subjects, 75.7% demonstrated improved
      self-perception of vision after 4 months as opposed to 15.4% of the non
      intervened patients (p= 0.00001). Post-intervention, the mean score on the ADVS
      rose from 51.0 S.D. 28.4 to 76.0 S.D. 25.4 (p < 0.001). In contrast, the control
      group's mean score dropped from 54.8 S.D. 24.8 to 46.5 S.D. 27.1 (p < 0.001).
      CONCLUSIONS: Cataract surgery in the elderly improves visual function and
      prevents loss of autonomy, delaying dependency in carrying out basic daily
      activities.

PMID- 15173967
TI  - [Idiopathic polypoidal choroidal vasculopathy].
AB  - PURPOSE: To evaluate the incidence, clinical features and evolution of polypoidal
      choroidal vasculopathy (PCV) in our population. METHODS: Retrospective study of
      patients diagnosed with exudative and/or hemorrhagic maculopathy including age
      related macular degeneration in the last two years and who have undergone a
      complete ophthalmologic exploration and videoangiography with fluorescein and
      indocyanine green. RESULTS: 250 patients were included in the study, 8 patients
      (3.2%) had clinical and angiographic criteria of PCV. The mean age was 68 years
      old, 62.5% were men and 85.7% were caucasian. Ninety percent of cases presented
      clinically as a predominantly hemorrhagic macular detachment. The initial
      clinical diagnosis before indocyanine green angiography was exudative age-related
      macular degeneration in 90% of cases. The mean visual acuity was 0.2 at baseline
      and after follow-up. Laser treatment was performed in 4 eyes, achieving good
      anatomic and visual acuity results in 2 of them; both eyes of one patient were
      treated by photodynamic therapy with poor angiographic and functional outcome.
      CONCLUSIONS: Polypoidal choroidal vasculopathy is a clinical entity which is
      relatively frequent among patients previously diagnosed with exudative
      maculopathy. Indocyanine green angiography increases the number of correct
      diagnoses. Treatment must be individualized depending on the location of the
      lesions and the severity of the disease.

PMID- 15173968
TI  - [Serpiginous choroiditis: clinical course and treatment].
AB  - PURPOSE: To evaluate the clinical evolution and treatment of serpiginous
      choroiditis in 11 diagnosed patients. METHODS: Retrospective study of 11 cases
      diagnosed with serpiginous choroiditis in our area, from 1980 to the present. We
      analyzed age at onset of symptoms, systemic diseases, ophthalmological symptoms
      at presentation, the location of lesions, initial and final visual acuity,
      recurrences, treatment regime and development of subretinal neovascularization. A
      complete ophthalmological examination and fluorescein angiograms were performed
      in all of them. RESULTS: The mean period of follow-up was 4 years. Average age
      was 56 years, predominantly in men (10/1). Five patients had known ischemic
      cardiopathy and systemic hypertension, one patient underwent a kidney transplant.
      All of them were treated with oral prednisone (1-1.5 mg/kg/daily) in the active
      stages. Three patients received triple therapy (prednisone, cyclosporine and
      azathioprine) that did not prevent the recurrences. Five patients developed a
      subretinal neovascularization, bilateral in three of them. CONCLUSIONS: The
      serpiginous choroiditis is a rare entity and the visual outcome prognosis is
      determined by the macular involvement. Men are predominantly affected in our
      series and corticosteroid treatment is effective in acute inflammatory episodes.
      Recurrences could not be prevented by triple therapy with immunosuppressive
      agents in our three patients.

PMID- 15173969
TI  - [Orbital manifestation of Wegener's granulomatosis].
AB  - CASE REPORT: Patient who consults for a recidivant orbital mass. Preliminary
      clinical and image studies suggested an initial differential diagnosis between a
      lachrymal gland tumor or an orbital located pseudotumor. However, the clinical
      evolution of the case required a re-evaluation of the preliminary diagnosis. The
      clinical, histologic and serologic findings were key in the final diagnosis.
      DISCUSSION: Wegener's granulomatosis is a necrotizing vasculitis. Classically it
      affects the upper airways, lungs and kidneys. Between 30% and 70% of patients
      present ophthalmic symptoms during the course of the illness. Ophthalmic
      affectation prior to systemic manifestations is less frequent and could delay
      final diagnosis.

PMID- 15173970
TI  - [Abadie - Lagrange. Twenty five years of verbal war].

PMID- 15173971
TI  - [Mary Cassat's cataracts (1845-1926)].

PMID- 15173972
TI  - Comparison of different cardiac MRI sequences at 1.5 T/3.0 T with respect to
      signal-to-noise and contrast-to-noise ratios - initial experience.
AB  - PURPOSE: To compare image quality, signal-to-noise (SNR) and contrast-to-noise
      ratios (CNR) of different MRI sequences for cardiac imaging at 1.5 T and 3.0 T in
      volunteers. MATERIAL AND METHODS: 10 volunteers (5 male, 5 female) with a mean
      age of 33 years (+/- 8) without any history of cardiac diseases were examined on
      a GE Signa 3.0 T and a GE Signa 1.5 T TwinSpeed Excite (GE Medical Systems,
      Milwaukee, WI, USA) scanner using a 4-element phased array surface coil (same
      design) on the same day. For tissue characterization ECG gated Fast Spinecho
      (FSE) T (1)- (Double IR), T (1)-STIR (Triple IR) and T (2)-weighted sequences in
      transverse orientation were used. For functional analysis a steady state free
      precession (SSFP - FIESTA) sequence was performed in the 4-chamber, 2-chamber
      long axis and short axis view. The flip angle used for the SSFP sequence at 3.0 T
      was reduced from 45 degrees to 30 degrees to keep short TR times while staying
      within the pre-defined SAR limitations. All other sequence parameters were kept
      constant. RESULTS: All acquisitions could successfully be completed for the 10
      volunteers. The mean SNR 3.0 T compared to 1.5 T was remarkably increased (p <
      0.05) for the T (2) - (160 % SNR increase), the STIR-T (1)- (123 %) and the T (1)
      (91 %) weighted FSE. Similar results were found comparing CNR at 3.0 T and 1.5
      T. The mean SNR achieved using the SSFP sequences was more than doubled by 3.0 T
      (150 %), but did not have any significant effect on the CNR. The image quality at
      3.0 T did not appear to be improved, and was considered to be significantly worse
      when using SSFP sequences. Artefacts like shading in the area of the right
      ventricle (RV) were found to be more present at 3.0 T using FSE sequences. After
      a localized shim had been performed in 5/10 volunteers at the infero-lateral wall
      of the left ventricle (LV) with the SSFP sequences at 3.0 T no significant
      increase in artefacts could be detected. CONCLUSIONS: In all cardiac FSE
      sequences, SNR and CNR at 3.0 T were found to be increased compared to 1.5 T
      without any major changes of the sequence parameters. The adjusted SSFP sequences
      fulfilled the expected increase in SNR at 3.0 T but showed no increase in CNR. On
      the contrary, the overall image quality did not change or was even found to be
      significantly lower for the SSFP and the FSE sequences at the free wall of the
      RV. Nevertheless, the results are encouraging for the use of 3.0 T for cardiac
      tissue characterization and new applications with progressing use of parallel
      imaging.

PMID- 15173973
TI  - [Transarterial embolization of the kidney: review of the literature].
AB  - The percutaneous transarterial total embolization of the kidney is a minimal
      invasive therapeutic procedure for radiological nephrectomy. The reported
      indications, technique, results and complications of percutaneous transarterial
      total renal embolization are reviewed. Aside from transient symptoms as part of
      the postembolization syndrome with a stated incidence of 47 % to 100 % of
      embolizations, other complications are relatively rare and occur in the range of
      0 % to 20 % with a mortality of up to 3.3 %. Technical success is high and not
      related to the diagnosis. However, clinical success depends on the underlying
      disease. Embolization of non-resectable renal tumors may improve the survival
      rate.

PMID- 15173974
TI  - [Magnetic resonance imaging in the diagnosis of benign and malignant pelvic
      tumors].
AB  - Magnetic resonance imaging (MRI) is an accepted imaging method for diagnosing
      diseases of the female pelvis. This review article describes the role of MR
      imaging for the diagnosis of benign and malignant pelvic tumors. Sagittal T2
      weighted fast spin echo sequences can be effectively applied to diagnose
      leiomyomas of the uterus and provide exact pretreatment measurements of size and
      localization. In the diagnostic work-up of endometrial carcinoma, fat-saturated,
      T1-weighted gradient echo sequences make it possible to determine precisely how
      deep myometrial infiltration extends and what tissue should be included in
      preoperative treatment planning. In cervical cancer staging, MRI permits both
      assessment of local tumor extent and determination of tumor volume for planning
      and monitoring radiotherapy. The usefulness of MRI in cervical cancer staging is,
      however, limited since not all early-stage cancer (FIGO stage IA and small stage
      IB tumors) can be detected. Hence, it appears that the use of MRI as a screening
      method for cervical cancer cannot be recommended. MRI can distinguish between
      benign and malignant ovarian tumors with high sensitivity and specificity.
      Standard and fat-saturated T1-weighted sequences usually can diagnose teratomas
      with a specificity of 100 %. Axial fat-saturated, contrast enhanced T1-weighted
      spin echo sequences are useful in the staging of malignant ovarian tumors since
      they facilitate evaluation of their internal structure and will disclose
      peritoneal metastases. Besides staging of ovarian cancer, MRI can be applied for
      localization and for monitoring treatment response.

PMID- 15173975
TI  - [Clinical evaluation of a software for automated localization of lung nodules at
      follow-up CT examinations].
AB  - PURPOSE: To evaluate a software algorithm for automated localization of pulmonary
      nodules at follow-up CT examinations of the chest and to determine factors
      influencing the rate of correctly matched nodules. MATERIALS AND METHODS: The
      "real-time automatic matching" (RAM) algorithm (Siemens LungCare trade mark
      software) was applied to 22 follow-up multirow-detector CT (MDCT) examinations in
      11 patients (Siemens Somatom VolumeZoom, tube voltage 120 kVp; effective tube
      current 20 mAs (n = 18) or 100 mAs (n = 4); 4 x 1 mm detector configuration, 1.25
      mm slice thickness; 0.8 mm reconstruction increment; standard lung kernel B50f)
      with a total of 190 lung nodules (mean diameter 6.7 +/- 3.5 mm, range 2 - 17 mm).
      The following nodule features were recorded: diameter, edge definition (well- or
      ill-defined), location (upper, middle or lower third; central or peripheral;
      right or left lung) and inspiration level (considered identical if the difference
      of diaphragm-apex distance between baseline and follow-up examination was < 5 %,
      otherwise it was considered different). A nodule was regarded as correctly
      localized if the marking box drawn by the software was visible on at least one
      slice together with the nodule and the center of the nodule was located inside
      the marking box. chi(2)-test was used to describe influence of nodule features on
      detection rate. Influence of nodule size was assessed using Mann-Whitney-U-Test.
      RESULTS: RAM correctly located 164 of 190 of all lung nodules (86.3 %). Detection
      rate did not depend on nodule location (left vs. right lung: p = 0.48; upper vs.
      middle vs. lower third: p = 0.96; peripheral vs. central: p = 0.47) or diameter
      (p = 0.30). Influence of inspiration level was highly significant (p < 0.001):
      nodules were detected in 100 % (146/146) for identical inspiration levels and in
      40.9 % (18/44) for different inspiration levels. The observation of a significant
      better localization of ill-defined nodules (p = 0.028) corresponds to a
      statistical artifact due to the inhomogeneous distributions of this specific
      feature in our data. CONCLUSION: RAM is a valuable tool for follow-up of lung
      nodules at CT. Only very different inspiration levels influenced detection rate.

PMID- 15173976
TI  - [Reference values of MRI flow measurements of the pulmonary outflow tract in
      healthy children].
AB  - PURPOSE: To provide reference values for MRI-based flow measurements in the main
      pulmonary artery in healthy children. MATERIALS AND METHODS: In 98 healthy
      children (age: 3 - 17 years, median: 11 years), the main pulmonary artery was
      examined using MRI-based flow measurements with high temporal resolution (9.6 ms
      per cardiac phase). RESULTS: The acceleration time revealed a distinct age
      dependency and varied between 90 and 155 ms (mean: 124 ms +/- 14). The relative
      acceleration time (related to the RR-interval) varied between 12.7 and 27 %
      (mean: 18 % +/- 2.6). The mean values and the standard deviations for the
      determined values were as follows: cardiac output (5.4 l/min +/- 1.4), cardiac
      output normalized to the body surface area (4.2 [l/min]/m(2) +/- 0.8), average
      systolic flow velocity (66 cm/s +/- 12), maximum systolic flow (309 ml/s +/- 79),
      mean flow (110 ml/s +/- 30), distensibility of the wall of the main pulmonary
      artery (79 % +/- 26), peak velocity (96 cm/s +/- 15), pressure gradient along the
      pulmonary valve (3.8 mm Hg +/- 1.2), stroke volume (63.2 ml +/- 17.9),
      acceleration volume (23.7 ml +/- 8.7), maximum acceleration of flow (4924 ml/s(2)
      +/- 1431), and reverse volume (0.2 ml +/- 0.3). CONCLUSIONS: The acquired values
      of reference are applicable to all pediatric patients and serve as a framework
      for the communication between the radiologist and the pediatric cardiologists.
      High temporal resolution of the measurement sequence is mandatory. Noticeable
      deviations of these values should induce additional (probably invasive)
      evaluation.

PMID- 15173977
TI  - [Commentary to: "The postnatal development of the frontal axial angle of the
      occipitoatlantal complex"].

PMID- 15173978
TI  - [The postnatal development of the frontal axial angle of the occipitoatlantal
      complex].
AB  - PURPOSE: The frontal axial angle of the occipitoatlantal complex in adults is
      well known. Clinical radiological investigations of the infantile cervical spine
      indicate other proportions. Extensive radiological studies concerning the
      postnatal development of the frontal axial angle are unknown. Knowledge about the
      special biomechanical relation of the infantile cervical spine is necessary for
      understanding several high cervical irritation syndromes in newborns. MATERIALS
      AND METHODS: To measure the occipitoatlantal angle C0/C1, 1016 AP radiographs of
      the upper cervical spine were investigated. The radiographs were obtained on
      female and male patients ranging from 0 - 10 years of age. RESULTS: The frontal
      axial angle C0/C1 is distinctly flatter in infants (153 degrees in newborns at
      the age of 0 to 3 months) and only approaches an adult state after the 10 th year
      of life. CONCLUSION: The distinctly flatter configuration of the frontal axial
      angle C0/C1 in newborns could be interpreted as constituting a different
      morphology for better adaptation to the biomechanical strain of the upper
      cervical spine during labor. The postnatal development of the frontal axial angle
      of the occipitoatlantal complex is illustrated.

PMID- 15173979
TI  - [Cranial sonography for newborn screening: a 10-year retrospective study in
      11,887 newborns].
AB  - We retrospectively analyzed the results of a sonographic cranial screening study,
      performed between 1985 and 1994 to determine the incidence of intracranial
      hemorrhage and cerebral anomalies based on obstetrical risk factors. In the
      Department of Obstetrics and Gynecology of the University Giessen, Giessen,
      Germany, 94.6 % (n = 11,887) of all children born during the study period were
      included and underwent sonographic cranial screening within the first 10 days
      after birth. Cerebral abnormalities were found in 653 (= 5.5 %) cases, and peri
      /intraventricular hemorrhages (PIVH, grade I-IV) in 303 cases. Periventricular
      leucomalacia, porencephaly, subarachnoidal hemorrhage and hydrocephaly were rare
      (< or = 0.2 %). The Apgar index proved to be a good prognostic factor,
      particularly at 1 and 5 minutes after birth (p < 0.0001). In contrast,
      correlation between PIVH and cardiotocography, arterial cord blood gases, and pH
      was poor. We did not observe a higher incidence of PIVH in newborns with growth
      retardation, preeclampsia and premature ruptures of membranes or prolonged labor.
      With decreasing gestational age, the frequency of PIVH increased progressively
      from 0.4 % at 39 weeks to 53.2 % at 27 weeks (p < 0.001). We also found a higher
      risk of intracranial hemorrhage in preterm newborns with amniotic infections
      (38.1 %, p < 0.001). In mature babies, we did not find a difference between the
      incidence of PIVH and delivery-modes; however, we noted a higher risk of PIVH
      Grade IV in preterm newborns with breech presentation for vaginal delivery versus
      caesarean section (38.5 % versus 7.4 %, p = 0.005). The incidence of PIVH over
      this 10 year time period did not increase despite an increasing number of preterm
      newborns over time. In conclusion, this study, which represents one of the
      largest patient cohorts studied for PIVH, indicates that neonatal sonographic
      cranial screening is an important tool to define quality control in obstetrics.

PMID- 15173980
TI  - [Erroneous X-ray dose measurements in paediatric cardiac investigations].
AB  - According to national and international rules the x-ray exposure of cardiac
      catheter examinations have to be measured. For a Philips Integris angiographic
      system used for paediatric heart catheterization we found severe errors in the
      indicated time of fluoroscopy and total dose area product ( DAP) both for
      fluoroscopy and radiography. Fluoroscopy times shorter than 6 seconds and DAPs
      smaller than 0.1 Gy cm (2) are ignored and not considered in the indicated total
      fluoroscopy time and the fluoroscopic and radiographic DAPs. This error leads to
      a systematic underestimation of the risk of radiation-induced cancer especially
      with infants and children.

PMID- 15173981
TI  - [Automatic exposure control to reduce the dose in subsecond multislice spiral CT:
      phantom measurements and clinical results].
AB  - PURPOSE: To investigate the potential of dose reduction in multislice spiral CT
      (MSCT) with automatic exposure control. MATERIALS AND METHODS: The study was
      performed on a Sensation 4 multislice scanner. This prototype implementation
      analyzed the distribution of the attenuation along the z-axis in the lateral and
      sagittal directions of the digital radiogram. Depending on this distribution of
      the attenuation, the tube current (mA) is defined for every tube rotation. In
      addition, the tube current was modulated during each tube rotation. First, a
      three step oval water phantom was measured to evaluate the potential of this
      method with respect to dose reduction and image quality. In a patient study (n =
      26), four different scan regions (shoulder, thorax, abdomen, pelvis) were
      examined and dose (mAs) and image quality evaluated in comparison to examinations
      with a standard protocol for these regions in adults and a weight-adjusted
      standard protocol in children. The image quality was classified in consensus as
      good, sufficient and poor image quality. RESULTS: By adapting and modulating the
      tube current, we substantially reduced the variation of noise in one spiral scan
      and in one scan region of our patient collective. The dose (average mAs) was
      reduced by 31 % to 66 % in children (mean 44 %) and between 35 % and 64 % in
      adults (mean 53 %), depending on the scan region. The image quality was
      substantially improved in regions with high attenuation and did not suffer in low
      attenuation regions. CONCLUSION: The dose can be reduced substantially by an
      automatic exposure control including angular tube current modulation with the
      same or improved image quality.

PMID- 15173982
TI  - [Software-assisted CT-postprocessing of the carotid arteries].
AB  - PURPOSE: A software assistant for automatic evaluation of CT-angiograms (CTA) was
      developed. It should enable the visualization of the vessel lumen and the
      quantitative evaluation of a stenosis. CTA examinations of patients with
      suspected carotid artery stenoses were used for the evaluation of the software
      assistant. MATERIALS AND METHODS: Twelve Patients with suspected high-grade
      stenosis of the carotid arteries underwent a CTA examination using a multislice
      CT scanner. The data were analyzed and evaluated using the new software
      assistant. The results were compared with the data of digital subtraction
      angiography (DSA) of these patients. RESULTS: The time of digital postprocessing
      with the new software-assistant took about six minutes on average. Contour
      extraction of the vessel, MIP and curved MPR (c-MPR) and orthogonal cross
      sectional images of the vessels were calculated, followed by an automatic
      quantification of stenosis by the use of the c-MPR. A good correlation was found
      between CTA and DSA data regarding the stenosis grade (r = 0.82). Furthermore,
      some information could be provided about the plaque morphology. CONCLUSION: The
      software-assisted detection and analysis of carotid artery stenosis with the new
      developed program is possible within a justifiable time. DSA- and CTA-data did
      not show a significant difference in stenosis grading. Further development of
      software tools could lead to a better characterization of plaque morphology.

PMID- 15173983
TI  - [Experimental in vitro study to evaluate a flat-panel detector system].
AB  - PURPOSE: To evaluate the contrast-detail performance of a flat-panel detector
      system, we performed a comparative study of this flat-panel system versus storage
      phosphor and conventional screen-film systems. MATERIALS AND METHODS: Bone models
      made of human humeri were prepared with foreign bodies, fracture lines and
      drilled holes to create artificial fractures, osteolyses or metastases. Immersed
      in a water bath, hard copy images of these models were acquired with the same
      exposure dose (55 kV; 3.2 mAs) on the flat-panel detector, two state-of-the-art
      storage phosphor systems (PCR, ADC) and two conventional screen-film systems
      (Insight, T-Mat). Using a standardized protocol with a 4-point scale for a
      lesion, 220 different images were analyzed as to their appearance by 5
      independent radiologists. The statistical significance of the differences between
      the used modalities and the observers was determined with a sign test. RESULTS:
      Especially the drilled holes showed differences between the modalities. The flat
      panel detector showed significantly slightly better results locally than the two
      storage phosphor systems. The same applied to the Insight screen-film systems,
      but the intraindividual differences between the modalities were not clinically
      relevant. CONCLUSION: Under the conditions of the chosen experimental design, the
      flat-panel detector showed results comparable to the conventional screen-film and
      the state of the art storage phosphor radiographs. The use in skeletal
      radiography is possible.

PMID- 15173984
TI  - [Iodine delivery rate of different concentrations of iodine-containing contrast
      agents with rapid injection].
AB  - PURPOSE: To determine how the concentration of iodinated contrast media for
      computed tomography studies affects the iodine delivery rate at various
      conditions. MATERIALS AND METHODS: Three nonionic, iodinated contrast agents that
      are marketed for computed tomography applications were administered through 1.1
      and 1.3 mm large peripheral vein catheters into a vein phantom with room
      temperature and with pre-heating of the agents at 37 degrees C using a power
      injector. Each injection applied 40 ml of contrast medium at a flow rate of four
      to eight ml/s. The iodine concentration of Iopromide, Iomeprol, and Iodixanol
      varied between 300 and 400 mg iodine per cc. The power injector used a pressure
      limit of 21 bar. For each experiment, the maximum iodine deliver rate was
      calculated from the highest possible flow rate recorded. RESULTS: Larger vein
      catheters and the higher contrast temperature yielded the highest flow rates.
      With the higher iodine concentrations, viscosity limited the injection speed of
      the achievable pressure limit. The highest iodine delivery rate was 2560 mg/s,
      using an agent with 320 mg/ml iodine content. With the more concentrated agent, a
      maximal iodine delivery rate of 2400 mg/s was achieved. CONCLUSION: Very high
      iodinated contrast agent concentrations do not increase the iodine delivery rate
      of rapid peripheral intravenous injections, since the high viscosity of such
      agents causes the injection pressure to increase more than the higher iodine
      concentration would compensate for. With lower injection velocities, the higher
      viscosity of highly concentrated contrast agents may remain without practical
      consequences.

PMID- 15173985
TI  - [Web-based training in radiology - student course in the Virtual University of
      Bavaria].
AB  - PURPOSE: The ninth version of the licensing regulation for medical doctors
      (Approbation Regulation (AR)) sets a benchmark in terms of practical experience,
      interdigitation of preclinical and clinical studies, interdisciplinary approach,
      economic efficiency, independence of students, added new teaching and learning
      modalities, and ongoing evaluation of the progress of the medical students. It is
      the aim to implement these major points of the AR in a model course for
      diagnostic radiology and radiation protection within the scope of the Virtual
      University of Bavaria and test them in practice. MATERIALS AND METHODS: In
      cooperation with residents and board certified radiologists, students developed
      the virtual course "Web-Based Training (WBT) Radiology" in diagnostic radiology
      and radiation protection for students in the first clinical semester. A
      representative target group taken from the student body was asked about the
      options to get access to the World Wide Web (Internet), and the satisfaction
      concerning configuration and content of the newly developed program. A comparison
      was made between the results of the final examination taken by students who made
      use of the virtual course in addition to conventional lessons and taken by
      students who did not subscribe to the virtual course and exclusively relied on
      conventional lessons. In addition, a pilot study was conducted in the winter
      semester 2002/03, which compared students taking either the traditional lessons
      or the new virtual course on the Internet. RESULTS: The virtual course-model had
      test results with a positive trend. All targeted students had Internet access.
      Constructive criticism was immediately implemented and contributed to rapid
      optimization. The learning success of the additive or alternative virtual course
      was in no way less than the learning success achieved with the conventional
      course. CONCLUSION: The learning success as measure of quality in teaching and
      the acceptance by students and teachers justify the continuation of this course
      model and its expansion. Besides enabling the learning in small study groups; the
      course "WBT Radiology" might not only help implementing the major points of the
      new AR but might also complement any deficiencies in the current education.
      Economic aspects may encourage their implementations.

PMID- 15173986
TI  - [Remote access to a web-based image distribution system].
AB  - PURPOSE: To assess different network and security technologies for remote access
      to a web-based image distribution system of a hospital intranet. MATERIALS AND
      METHODS: Following preparatory testing, the time-to-display (TTD) was measured
      for three image types (CR, CT, MR). The evaluation included two remote access
      technologies consisting of direct ISDN-Dial-Up or VPN connection (Virtual Private
      Network), with three different connection speeds of 64, 128 (ISDN) and 768 Kbit/s
      (ADSL-Asymmetric Digital Subscriber Line), as well as with lossless and lossy
      compression. RESULTS: Depending on the image type, the TTD with lossless
      compression for 64 Kbit/s varied from 1 : 00 to 2 : 40 minutes, for 128 Kbit/s
      from 0 : 35 to 1 : 15 minutes and for ADSL from 0 : 15 to 0 : 45 minutes. The
      ISDN-Dial-Up connection was superior to VPN technology at 64 Kbit/s but did not
      allow higher connection speeds. Lossy compression reduced the TTD by half for all
      measurements. CONCLUSIONS: VPN technology is preferable to direct Dial-Up
      connections since it offers higher connection speeds and advantages in usage and
      security. For occasional usage, 128 Kbit/s (ISDN) can be considered sufficient,
      especially in conjunction with lossy compression. ADSL should be chosen when a
      more frequent usage is anticipated, whereby lossy compression may be omitted. Due
      to higher bandwidths and improved usability, the web-based approach appears
      superior to conventional teleradiology systems.

PMID- 15173987
TI  - [Cavernous liver hemangioma].

PMID- 15173988
TI  - [Central nervous system manifestation of Wegener granulomatosis: diagnosis using
      contrast media-enhanced MRI enhancement].

PMID- 15173989
TI  - [Hamartoma as a rare cardiac tumor].

PMID- 15173990
TI  - [Retroperitoneal extension in lymphatic filariasis and chylura].

PMID- 15173991
TI  - Patented antiinflammatory plant drug development from traditional medicine.
AB  - Patents secured on antiinflammatory plant drugs derived from 38 plants are
      reviewed. An attempt has been made to compare the modern and traditional use of
      plant drugs and to establish the relevance of folk claims in developing modern
      drugs. The role of plant botanicals such as polysaccharides, terpenes,
      curcuminoids, alkaloids, etc. in alleviating inflammatory diseases including
      arthritis, rheumatism, acne skin allergy and ulcers is highlighted. Chemicals
      that alleviate swelling are derived from plants including grape, boswellia,
      turmeric, devil's claw and some essential oils such as clove, eucalyptus,
      rosemary, lavender, mint, myrrh, millefolia and pine have been patented and used
      as mixed formulations. Plants containing polysaccharides are the most potent in
      curing inflammatory diseases.

PMID- 15173992
TI  - In vitro anti-Helicobacter pylori potential of methanol extract of Allium
      ascalonicum Linn. (Liliaceae) leaf: susceptibility and effect on urease activity.
AB  - The crude methanol extract of the leaf of Allium ascalonicum was screened in
      vitro against fi ve strains of Helicobacter pylori (Hp) (ATCC 24376, UCH 97001,
      UCH 97009, UCH 98026 and UCH 99039) for antibacterial activity by the agar
      diffusion method in Mueller-Hinton agar supplemented with de fi brinated horse
      blood. All the strains were inhibited by the extract to varying degrees. The
      minimum inhibitory concentrations (MICs) of the extract against all the tested
      strains ranged from 6.25 to 12.5 mg/mL. The effects of increasing concentrations
      of the extract on the urease activity of three of the Helicobacter pylori strains
      were investigated further. The results showed that increasing the concentration
      of the extract decreased the urease activity of all the strains tested.
      Phytochemical screening of the plant showed that it contains alkaloids, cardiac
      glycosides and saponins. The anti-Hp activity observed is discussed in relation
      to the chemical constituents reportedly isolated from these plants and their
      traditional uses. The result of this work suggests that Allium ascalonicum has
      some therapeutic potential against Helicobacter pylori infection, which could be
      explored for patients with gastroduodenal disorders.

PMID- 15173993
TI  - Hepatoprotective effect of New Livfit, a polyherbal formulation, is mediated
      through its free radical scavenging activity.
AB  - The effect of New Livfit, a polyherbal formulation, was studied on pyrogallol
      induced hepatotoxicity in rats. Administration of pyrogallol 100 mg/kg, i.p.
      caused a significant increase in liver enzymes as well as a significant increase
      in lipid peroxidation. Simultaneous administration of oral New Livfit and
      pyrogallol prevented these changes in hepatic damage. The results of the study
      showed that New Liv fi t(R) exerted a hepatoprotective effect against pyrogallol
      induced liver toxicity, which was mediated through its free radical scavenging
      property.

PMID- 15173994
TI  - Antioxidant activity of three extracts of Morus nigra.
AB  - The antioxidant effect of three different extracts of Morus nigra fruit (fruit
      juice, hydroalcoholic and polyphenolic) on haemoglobin glycosylation,
      peroxidative damage to human erythrocytes, liver hepatooytes of rats and human
      low-density lipoprotein (LDL) were studied. The results show that all three
      extracts inhibited haemoglobin glycosylation induced by glucose to differing
      degrees. The haemolysis of human erythrocytes induced by hydrogen peroxide was
      also inhibited. The production of malondialdehyde (MDA) during peroxidative
      damage to plasma membranes of isolated rat hepatocytes induced by tert-butyl
      hydroperoxide (tBH) was also inhibited. Inhibition of lipid peroxidation of LDL
      induced by copper (II) ion was achieved during the study. The results suggest
      that Morus nigra fruit has a protective action against peroxidative damage to
      biomembranes and biomolecules.

PMID- 15173995
TI  - Effect of Amirkabiria odorastissima mozaffarian on the development and
      progression of fatty streaks in hypercholesterolemic rabbits.
AB  - New studies have introduced atherosclerosis as an inflammatory disease. Different
      factors affect the development of inflammation that can be linked to free
      radicals, hypertention, diabetes mellitus, genetic changes, hypercholesterolemia
      and some of the microorganisms. Using anti-inflammatory drugs can be useful in
      preventing atherosclerosis. Finding drugs from natural sources and without side
      effects can be useful. Amirkabiria odoratissima (umbelliferae) is from Iranian fl
      ora and is used traditionally as an anti-inflammatory drug. This study was
      designed to assess the effects of this plant on the development and progression
      of fatty streaks. Male rabbits were fed: (a) rabbit chow; (b) 1% cholesterol
      diet; (c) cholesterol diet supplemented with the plant; (d) normal diet
      supplemented with the plant. After 12 weeks, the animals were sacrificed and the
      aorta, right and left branches of coronary arteries were dissected and
      histologically processed. Before and after the end of the study, biochemical
      factors were measured. The amounts of cholesterol, LDL, HDL, triglyceride and
      fasting blood sugar (FBS) were determined by enzymatic methods, quantitative CRP
      was determined by turbidimetric methods, malondialdehyde (MDA) and antioxidant
      capacity were determined by speceterophotometric methods. The results indicate
      that there is a significant difference between the groups supplemented with
      herbal medicine and others (p < 0.05) in the mean grade of fatty streak of right
      and left coronary artery and aorta. At the end of the 12-week period cholesterol,
      LDL and CRP were significantly reduced in the groups which received herbal
      medicine (p < 0.05). The data suggests that Amirkabiria odoratissima Mozaffarian
      has beneficial effects to prevent development of fatty streak; however, further
      studies are needed to understand the mechanisms whereby this plant exerts its
      anti-atherosclerotic effects.

PMID- 15173996
TI  - Evaluation of the anticarcinogenic activity of Swertia chirata Buch.Ham, an
      Indian medicinal plant, on DMBA-induced mouse skin carcinogenesis model.
AB  - Considerable attention has been focused on plants which are sources of natural
      anti-oxidant compounds, because most of them have a modulatory role on
      physiological functions and biotransformation reactions involved in the
      detoxification process. Such compounds are likely to afford protection from
      cytotoxic, genotoxic and metabolic actions of environmental toxicant thereby
      reducing the risk for cancer. The present study reports the anticarcinogenic
      activity of Swertia chirata Buch.Ham, an Indian medicinal plant. All the four
      detoxification enzymes studied viz, GST, GPx, SOD and CAT were found to be
      activated in different degrees following treatment with infusion of Swertia
      chirata, its crude extract and a purified 'Amarogentin' rich extract. The
      activation of the enzymes was accompanied by significant reduction in lipid
      peroxidation and inhibition of incidence as well as multiplicity of
      Dimethylbenz(a)anthracene (DMBA) induced papillomas. The effect of S.chirata on
      apoptosis and cell proliferation was also studied in mice skin exposed to DMBA.
      Both the crude and purified extracts significantly inhibited cell proliferation
      and induced apoptosis. This is the fi rst report of its kind and the observation
      suggests the chemopreventive potential of Swertia chirata.

PMID- 15173997
TI  - Anti-plasmodial activity of some Kenyan medicinal plant extracts singly and in
      combination with chloroquine.
AB  - Sixty organic and aqueous extracts of eleven plants used for the control of
      malaria by local communities in Kisii District, Kenya were screened for in vitro
      anti-plasmodial activity. The plants selection was based on existing
      ethnobotanical information and interviews with local communities. The extracts
      were tested against chloroquine sensitive and resistant laboratory adapted
      strains of Plasmodium falciparum. The study revealed that 63.6% of the plants
      were active (IC50 < or = 100 microg/mL). Extracts of four plants, Ekebergia
      capensis, Stephania abyssinica, Ajuga remota and Clerodendrum myricoides gave
      IC50 values below 30 microg/mL against both chloroquine sensitive and resistant
      P. falciparum strains. Combination of extracts of E. capensis and C. myricoides
      with chloroquine against the multi-drug resistant P. falciparum isolate (V1/S)
      revealed synergistic effect. The plants which showed activity may be useful as
      sources for novel anti-plasmodial compounds.

PMID- 15173998
TI  - Analgesic properties of the aqueous and ethanol extracts of the leaves of
      Kalanchoe crenata (Crassulaceae).
AB  - The aqueous and ethanol extracts of the dry leaves of Kalanchoe crenata (300 and
      600 mg/kg) were evaluated for their analgesic properties on the pain induced by
      acetic acid, formalin and heat in mice and by pressure on rats. The ethanol
      extract of K. crenata at a dose of 600 mg/kg produced an inhibition of 61.13% on
      pain induced by acetic acid and 50.13% for that induced by formalin. An
      inhibition of 67.18% was observed on pain induced by heat 45 min after the
      administration of the extract. The aqueous extract administered at a dose of 600
      mg/kg produced a maximum effect of 25% on pain induced by pressure. These
      activities were similar to those produced by a paracetamol-codeine association,
      while indomethacin exhibited a protective effect only against the writhing test.
      Our results suggest that the leaves of K. crenata could be a source of analgesic
      compounds.

PMID- 15173999
TI  - Prevention of bone loss by oil extract of garlic (Allium sativum Linn.) in an
      ovariectomized rat model of osteoporosis.
AB  - The effects of oil extract of garlic (Allium sativum Linn.) on different primary
      and secondary osteoporotic marker changes were tested in an ovariectomized rat
      model of osteoporosis. Experiments were performed on three different rat models:
      sham-operated control, ovariectomized and ovariectomized supplemented with garlic
      oil. In ovariectomized group, there has been a significant increase in different
      relative organ weights compared to sham-operated control, while the uterine
      weight was found to be decreased. Supplementation with oil extract of garlic
      could effectively reverse these changes. Also low bone densities that developed
      in the ovariectomized group were significantly recovered in the garlic oil
      supplemented group. In our study, the development of high rate of bone turnover
      and osteoporosis in the ovariectomized animals were confirmed by significant
      alteration of serum alkaline phosphatase activity, serum tartrate resistant acid
      phosphatase activity, urinary excretion of calcium, phosphate, hydroxyproline and
      urinary calcium to creatinine ratio, when compared with the sham-operated control
      group. Garlic oil extract supplementation, apart from its unique influence in
      lowering blood cholesterol, could also prevent ovariectomy-induced rise in all
      the above-mentioned marker changes. The results of this study emphasize that oil
      extract of garlic possibly has a positive role in suppressing ovariectomy-induced
      bone resorption.

PMID- 15174000
TI  - Immunosuppressive and cytotoxic properties of Nigella sativa.
AB  - In this study the volatile oil of Nigella sativa seeds (NSVO) was investigated
      for its immunomodulating and cytotoxic properties. A rat model was designed to
      examine the effect of NSVO on selected immune components. Long-Evans rats were
      challenged with a specific antigen (typhoid TH) and treated with NSVO; and the
      changes produced in their serum antibody titre along with the splenocytes and
      peripheral immune cells were analysed. Antibody titre for the experimental animal
      was found to be 1280 as compared to the 2560 in the control rats. There was a
      significant (p < 0.05) decrease in splenocytes and neutrophils counts, but a rise
      in peripheral lymphocytes and monocytes in the experimental animals. To test the
      cytotoxicity of NSVO, a panel of five human cancer cell lines and a fibroblast
      line was used. The MTT assay was employed to estimate the cell mortality.
      Vinblastine sulphate and mitomycin C were used as the positive control. LC(50)
      values for NSVO were 155.02 +/- 10.4, 185.77 +/- 2.9, 120.40 +/- 20.5, 384.53 +/-
      12.1 and 286.83 +/- 23.3 micro g/ml respectively against the SCL, SCL-6, SCL
      37'6, NUGC-4 cancer lines and 3T6 fibroblast line. Results indicate that the NSVO
      could be considered as a potential immunosuppressive cytotoxic agent.

PMID- 15174001
TI  - Effect of Hypericum perforatum on marble-burying by mice.
AB  - The effect of Hypericum perforatum extract (LI 160) at a dose that exerts an
      antidepressive-like effect was studied in mice in the marble-burying test. Acute
      Hypericum perforatum (150, 300 and 500 mg/kg, p.o.) reduced immobility time in
      the forced swimming test. The number of marbles buried, but not locomotor
      activity, was reduced by acute treatment with Hypericum perforatum (150 and 300
      mg/kg, p.o.). However, this effect was not seen after chronic treatment (21 days)
      with Hypericum perforatum (300 mg/kg, p.o.). Thus, Hypericum perforatum extract,
      at antidepressant dose, exerts an acute anxiolytic drug effect on the marble
      burying test, which could indicate a potential anti-obsessive effect, although
      the development of tolerance could be an important drawback.

PMID- 15174002
TI  - Hypoglycaemic effect of stigmast-4-en-3-one and its corresponding alcohol from
      the bark of Anacardium occidentale (cashew).
AB  - Intravenous administration of the hexane extract of the bark of Anacardium
      occidentale (cashew) in normal, healthy dogs produced a significant lowering of
      the blood glucose levels. Pursuit of the hypoglycaemic principle(s) in the hexane
      extract resulted in the isolation and characterization of two compounds, stigmast
      4-en-3-ol (1) and stigmast-4-en-3-one (2). These compounds were purified by
      chromatographic methods and the structures were characterized by spectroscopic
      methods. Both compounds produced significant hypoglycaemic activity after
      intravenous administration at a dose of 1.3 mg/kg body weight. The bark of the
      cashew plant, A. occidentale, exhibited a hypoglycaemic effect probably due to
      the presence of these compounds.

PMID- 15174003
TI  - Chemoprotective effect of plant phenolics against anthracycline-induced toxicity
      on rat cardiomyocytes. Part II. caffeic, chlorogenic and rosmarinic acids.
AB  - The chemoprotective effects of caffeic (CA), chlorogenic (CHA) and rosmarinic
      (RA) acids were tested against the toxicity of doxorubicin (DOX) in neonatal rat
      cardiomyocytes and the iron-dependent DOX induced lipid peroxidation of heart
      membranes, mitochondria and microsomes. The protectivity of these acids was
      compared with dexrazoxan, used as an adjuvant during DOX chemotherapy. The
      cytoprotective effects were assessed by enzyme (LDH and ASAT) and troponin I
      leakage, secondly by intracellular ATP content. All hydroxycinnamic acids proved
      non-cytotoxic, and they stabilized both membranes and the energetic status of
      cardiomyocytes. After preincubation of cardiomyocytes with the test compounds
      (100, 200 microm; 1 h) the cardiomyocytes were treated with the toxic agent, DOX
      (100 microm; 8 h). The test compounds protected cardiomyocytes against DOX
      induced oxidative stress (RA > CHA > or = CA) on all monitored parameters.
      Substantial preservation of monolayer integrity of the cardiomyocytes by test
      compounds was also found microscopically. All the acids were more effective in
      the assays used than dexrazoxan. RA showed the most effective cytoprotectivity.
      All the acids significantly reduced the iron-dependent DOX induced lipid
      peroxidation of heart membranes, although of the test compounds, CHA was found to
      be the most effective (IC(50) = 8.04 +/- 0.74/6.87 +/- 0.52 micro m for
      microsomes/mitochondria).

PMID- 15174004
TI  - In vitro anti-mycobacterial activities of three species of Cola plant extracts
      (Sterculiaceae).
AB  - Extracts obtained from three Nigerian Sterculiaceae plants: Cola accuminata, C.
      nitida and C. milleni were screened for anti-mycobacterium properties using a
      slow growing Mycobacterium bovis ATCC 35738 (designated BCG Mexican and known to
      have some virulence in mouse and guinea pig) at 1000 microg/ml using the
      radiometric (BACTEC) method. The extracts were also tested against six fast
      growing ATCC strains of M. vaccae using the broth microdilution method. The
      methanol extracts from both leaves, stem bark and root bark of Cola accuminata
      and from the leaves and stem bark of C. nitida and C. milleni were not active at
      the highest concentration of 1000 microg/ml. Only the methanol extract of root
      bark for both C. nitida and C. milleni were found to be potent against both M.
      bovis and strains of M. vaccae. The minimum inhibitory concentration (MIC) of C.
      nitida against M. bovis is 125 microg/ml while the MIC of C. milleni against M.
      bovis is 62.5 microg/ml after at least 6 days of inhibition with growth index
      (GI) units lesser than or equal to the change in GI units inoculated with a 1/100
      of the BACTEC inoculum for a control vial. The minimum inhibitory concentration
      of C. milleni against the six ATCC strain of M. vaccae ranged from 62.5 microg/ml
      to 250 microg/ml while for C. nitida ranged from 500 microg/ml to above
      1000microg/ml. Evidently, C. milleni has the highest inhibitory activity against
      both M. bovis and strains of M. vaccae used. Rifampicin, the positive control
      used has strong activity against M. bovis at the tested concentration of 5 microg
      and 10 microg/ml and 4 to 8 microg/ml against the six strains of M. vaccae.

PMID- 15174005
TI  - Nimbidin suppresses functions of macrophages and neutrophils: relevance to its
      antiinflammatory mechanisms.
AB  - Nimbidin is a mixture of tetranortriterpenes and is the major active principle of
      the seed oil of Azadirachta indica A. Juss (Meliaceae) possessing potent
      antiinflammatory and antiarthritic activities. The present study revealed that
      nimbidin significantly inhibited some of the functions of macrophages and
      neutrophils relevant to the inflammatory response following both in vivo and in
      vitro exposure. Oral administration of 5-25 mg/kg nimbidin to rats for 3
      consecutive days significantly inhibited the migration of macrophages to their
      peritoneal cavities in response to inflammatory stimuli and also inhibited
      phagocytosis and phorbol-12-myristate-13-acetate (PMA) stimulated respiratory
      burst in these cells. In vitro exposure of rat peritoneal macrophages to nimbidin
      also inhibited phagocytosis and PMA stimulated respiratory burst in these cells.
      Nimbidin also inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production
      in lipopolysaccharide (LPS) stimulated macrophages following in vitro exposure,
      whereas interleukin 1 (IL-1) was only weakly inhibited. Probing the mechanism of
      NO inhibition revealed that nimbidin ameliorated the induction of inducible NO
      synthase (iNOS) without any inhibition in its catalytic activity. In addition,
      nimbidin also attenuated degranulation in neutrophils assessed in terms of
      release of beta-glucuronidase, myeloperoxidase and lysozyme. The results suggest
      that nimbidin suppresses the functions of macrophages and neutrophils relevant to
      inflammation. Thus nimbidin can be valuable in treating inflammation/inflammatory
      diseases.

PMID- 15174006
TI  - Antioxidative effects of 7-hydroxy-3-methoxy-cadalene extracted from Zelkova
      serrata on 4-(methylinitros amino)-1-(3-pyridyl)-1-butanone-induced oxidative
      stress in A/J mice.
AB  - Effects of 7-hydroxy-3-methoxy-cadalene (cadalene) extracted from Zelkova serrata
      on 4-(methylinitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced oxidative stress
      were examined using A/J mice. NNK (65 microg/ml water) was orally administered to
      20 mice for 7 weeks, followed by free feeding of a commercial diet, not
      containing cadalene, for 2 weeks. The control group was maintained without NNK
      and cadalene administration, and treatment groups with NNK and cadalene (6.25,
      25, 100 mg/kg feed) feeding for 25 weeks. The glutathione concentration of
      cadalene-treated (65 microg/ml water) group was significantly higher than that of
      the group treated only with NNK (p < 0.05). The results of our study strongly
      indicate that cadalene exerts antioxidative effect on NNK-induced lung
      tumorigenesis in A/J mice.

PMID- 15174007
TI  - Antioxidant and free radical scavenging activities of 5,7,3'-trihydroxy-3,6,4'
      trimethoxyflavone from Brickellia veronicaefolia.
AB  - The antioxidant and antiradical activities of 5,7,3'-trihydroxy-3,6,4'
      trimethoxyflavone or centaureidin isolated and characterized from Brickellia
      veronicaefolia were elucidated by heat-induced oxidation in a beta-carotene and
      linoleic acid system and by the 1,1-diphenyl-2-picrylhydrazyl decoloration test.
      The centaureidin (32.1%) exhibited antioxidative activity less than that of BHT
      (95.5%) and alpha-tocopherol (95.9%) on oxidation in a beta-carotene and linoleic
      acid system. A moderate antiradical effect (47.6%) compared with BHT (96.7%) and
      alpha-tocopherol (94.6%) in DPPH decoloration test was found.

PMID- 15174008
TI  - Hepatoprotective activity of Centaurium erythraea on acetaminophen-induced
      hepatotoxicity in rats.
AB  - The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was
      evaluated for hepatoprotective activity against acetaminophen-induced liver
      toxicity in rats. An oral dose of 300 mg/kg/day for 6 days or a single dose of
      900 mg/kg for 1 day exhibited a significant protective effect by lowering serum
      glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase
      (SGPT) and lactate dehydrogenase (LDH). The activity of the extract was supported
      by histopathological examination of liver sections.

PMID- 15174009
TI  - Time to move beyond nigrostriatal dopamine deficiency in Parkinson's disease.

PMID- 15174010
TI  - The dopamine transporter: importance in Parkinson's disease.
AB  - The dopamine transporter (DAT) may be the single most important determinant of
      extracellular dopamine concentrations. The importance of DAT in Parkinson's
      disease (PD) in which DAT may be reduced by 50 to 70% is unclear. We have
      examined the effects of methylphenidate (MPD), an inhibitor of DAT, administered
      alone or with levodopa, on parkinsonism measured with tapping and walking speeds,
      dyskinesia, subjective effects, and vital signs. MPD in oral doses of up to 0.4
      mg/kg was well tolerated. Administered alone, MPD produced no objective
      improvement of parkinsonism. MPD, 0.4 mg/kg orally, coadministered with 2-hour
      levodopa infusions at 0.5 or 1.0mg/kg/hr increased the percentage of patients
      responding to the 0.5mg/kg/hr dose and prolonged the response to levodopa
      infusions as measured by tapping and walking speeds. Dyskinesia was prolonged in
      proportion to the increase in antiparkinson actions but severity was not
      increased. MPD decreased the hypotensive response to levodopa. In conclusion, MPD
      appeared to have no effect given alone but potentiated the effects of levodopa,
      particularly doses at threshold for clinical effects. These observations indicate
      that the residual DAT is functional in PD and is a potential target for
      symptomatic therapy of PD.

PMID- 15174011
TI  - Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease.
AB  - We used positron emission tomography (PET) with (+)-[(11)C]dihydrotetrabenazine
      ([+]-[(11)C]DTBZ) to examine striatal monoaminergic presynaptic terminal density
      in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimer's disease
      (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at
      least 1 year before dementia (DLB/PD) and 14 developed dementia before
      parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential
      was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD
      compared to AD and control. Binding was lower in the DLB/PD group than the
      DLB/AD, but the differences reached only marginal significance in the caudate
      nucleus. No differences were found between AD and control groups though a few AD
      patients had binding values below the range of the controls. Subsequent
      neuropathological examination in one AD patient revealed both AD and DLB changes
      despite the absence of clinical parkinsonism. Both DLB groups had an anterior to
      posterior binding deficit gradient relative to controls, largest in posterior
      putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD
      group showed significant binding asymmetry only in posterior putamen. We conclude
      that PET with (+)-[(11)C]DTBZ differentiates DLB from AD, and decreased binding
      in AD may indicate subclinical DLB pathology in addition to AD pathology.

PMID- 15174012
TI  - Scrapie-specific neuronal lesions are independent of neuronal PrP expression.
AB  - In the transmissible spongiform encephalopathies (TSE), accumulation of the
      abnormal disease-specific prion protein is associated with neurodegeneration.
      Previous data suggested that abnormal prion protein (PrP) could induce neuronal
      pathology only when neurons expressed the normal form of PrP, but conflicting
      evidence also has been reported. Understanding whether neuronal PrP expression is
      required for TSE neuropathological damage in vivo is essential for determining
      the mechanism of TSE pathogenesis. Therefore, these experiments were designed to
      study scrapie pathogenesis in vivo in the absence of neuronal PrP expression.
      Hamster scrapie (strain 263K) was used to infect transgenic mice expressing
      hamster PrP in the brain only in astrocytes. These mice previously were shown to
      develop clinical scrapie, but it was unclear whether the brain pathology was
      caused by damage to astrocytes, neurons, or other cell types. In this electron
      microscopic study, neurons demonstrated TSE-specific pathology despite lacking
      PrP expression. Abnormal PrP was identified around astrocytes, primarily in the
      extracellular spaces of the neuropil, but astrocytes showed only reactive changes
      and no damage. Therefore, in this model the pathogenesis of the disease appeared
      to involve neuronal damage associated with extracellular astrocytic accumulation
      of abnormal PrP acting upon nearby PrP-negative neurons or triggering the release
      of non-PrP neurotoxic factors from astrocytes.

PMID- 15174013
TI  - Linkage and association with the NOS2A locus on chromosome 17q11 in multiple
      sclerosis.
AB  - A large body of research supports a multifactorial cause in multiple sclerosis
      (MS), with an underlying genetic susceptibility likely acting in concert with
      undefined environmental exposures. Here, we used a highly efficient multilocus
      genotyping assay to study single nucleotide polymorphisms representing variation
      in 34 genes from inflammatory pathways in a well-characterized MS familial data
      set. Evidence of transmission distortion was present for several polymorphisms.
      Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained
      significant after correction for multiple testing and were reproduced in a second
      independent African American MS data set. In addition, linkage to a NOS2A
      promoter region polymorphism, (CCTTT)(n), was present in a third data set of
      multicase MS families. Our results provide strong evidence for linkage and
      association to a new candidate disease gene on chromosome 17q11 in MS and suggest
      that variation within NOS2A or a nearby locus contributes to disease
      susceptibility.

PMID- 15174014
TI  - Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice.
AB  - Increasing evidence points to synaptic plasticity impairment as one of the first
      events in Alzheimer's disease (AD). However, studies on synaptic dysfunction in
      different transgenic AD models that overexpress familial AD mutant forms of
      amyloid precursor protein (APP) and/or presenilin (PS) have provided conflicting
      results. Both long-term potentiation (LTP) and basal synaptic transmission (BST)
      have been found to be both unchanged and altered in different models and under
      differing experimental conditions. Because of their more robust amyloid-beta
      (Abeta) deposition, double transgenic mice currently are used by several
      laboratories as an AD model. Here, we report that mice overexpressing APP
      (K670N:M671L) together with PS1 (M146L) have abnormal LTP as early as 3 months of
      age. Interestingly, reduced LTP paralleled plaque appearance and increased Abeta
      levels and abnormal short-term memory (working memory). BST and long-term memory
      (reference memory) are impaired only later (approximately 6 months) as amyloid
      burden increases. Abeta pathology across different ages did not correlate with
      synaptic and cognitive deficits, suggesting that Abeta levels are not a marker of
      memory decline. In contrast, progression of LTP impairment correlated with the
      deterioration of working memory, suggesting that percentage of potentiation might
      be an indicator of the cognitive decline and disease progression in the APP/PS1
      mice.

PMID- 15174015
TI  - Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD
      continuum.
AB  - The cholinergic denervation in Alzheimer's disease (AD) provides the rationale
      for treatments with anticholinesterases. The presence of this cholinergic lesion
      is solidly established in advanced AD. Whether it also exists in early disease
      remains unsettled. This question was addressed with thioflavin-S
      histofluorescence to identify neurofibrillary tangles (NFT) and two tau
      antibodies (AT8, Alz-50) to identify pre-tangle cytopathology in the nucleus
      basalis, the source of cortical cholinergic innervation. Methods for the
      concurrent visualization of tauopathy and choline acetyltransferase were used to
      determine if the cytopathology was selectively located within cholinergic
      neurons. Five elderly index cases who had died at the stage of mild cognitive
      impairment (MCI) or early AD were identified by longitudinal neuropsychological
      and behavioral assessments. They were compared to 7 age-matched cognitively
      normal subjects. NFT and AT8 (or Alz-50) immunostaining in cholinergic nucleus
      basalis neurons existed even in the cognitively normal subjects. The percentage
      of tauopathy-containing nucleus basalis neurons was greater in the cognitively
      impaired and showed a significant correlation with memory scores obtained 1-18
      months prior to death. These results show that cytopathology in cortical
      cholinergic pathways is a very early event in the course of the continuum that
      leads from advanced age to MCI and AD.

PMID- 15174016
TI  - The influence of time after stroke on brain activations during a motor task.
AB  - After stroke, the pattern of brain activation during performance of a motor task
      is related to outcome. Here, we compare this relationship in the early (10-14
      days) and late (at least 3 months) phases after first-ever stroke. A negative
      linear relationship between task-related brain activation, as measured by
      functional magnetic resonance imaging, and outcome is seen in several identical
      primary and nonprimary motor regions that is independent of time after stroke. In
      other words, patients with poorer outcome scores recruit more widely within motor
      related regions in both the early or late poststroke phase. However, in
      contralesional middle intraparietal sulcus, contralesional cerebellum, and
      ipsilesional rostral premotor cortex, this relationship is seen only in the early
      poststroke phase. Thus, patients with poorer outcome scores recruit these areas
      in only the early and not the late poststroke phase. These results suggest that
      there are differences in the cerebral implementation of action in patients with
      poor outcome that are dependent on the time since stroke. Thus, in those patients
      with the most to gain from rehabilitation, different therapeutic approaches may
      be required at different stages after stroke.

PMID- 15174017
TI  - Central nervous system abnormalities in asymptomatic young patients with Sbeta
      thalassemia.
AB  - Twenty-one children and young adults with sickle/beta-thalassemia without overt
      stroke were examined with magnetic resonance imaging and angiography (MRA),
      transcranial Doppler (TCD), visual (VEP) and median nerve somatosensory (SEP)
      evoked potential recordings, and neuropsychological testing (Wechsler
      Intelligence Scale [WISC-III]). Eight (38%) had silent infarction in the
      parietooccipital cortex, deep white matter, or basal ganglia, including two of
      three with previous seizures. Of 17 undergoing TCD, none had maximum middle
      cerebral artery (MCA) velocities greater than 126cm/sec, but 9 were abnormal,
      with low velocities and difficulty in tracking the MCA and/or asymmetry. Three
      patients had abnormal MRA, one of whom also had silent infarction. One patient
      had pathological VEP recordings, whereas all SEP recordings were normal. WISC-III
      was performed in all 11 children, 4 with silent infarction: all but 1 had IQ
      scores greater than 85 (mean, 97.7; standard deviation, 14.2). We conclude that
      Greek children and young adults with Sbeta-thalassemia and no history of clinical
      stroke have TCD abnormalities and silent infarction similar to those reported in
      children and adolescents with sickle cell anemia, but cognitive function is not
      necessarily compromised. International collaboration is needed to establish the
      risk factors for central nervous system sequelae in patients with sickle cell
      disease, including Sbeta-thalassemia, leading to evidence-based prevention.

PMID- 15174018
TI  - Role of cerebral lateralization in control of immune processes in humans.
AB  - Cerebral lateralization may be important in neural control of immune function.
      Animal studies have demonstrated differential effects of left and right brain
      lesions on immune function, but human studies are inconclusive. Here, we show
      that resections in the language dominant hemisphere of patients with epilepsy
      reduce lymphocytes, total T cells, and helper T cells. In contrast, resections in
      the language nondominant hemisphere increased the same cellular elements. T-cell
      responses to mitogens and microbial antigens were not differentially affected.
      Left/right arm histamine skin response ratios were altered in patients with left
      cerebral epileptic focus, and flare skin responses were reduced by left cerebral
      resections in contrast with an increase after right cerebral resections. The
      findings demonstrate a differential role of the left and right cerebral
      hemispheres on immune functions in humans.

PMID- 15174019
TI  - Somatic mosaicism in FSHD often goes undetected.
AB  - Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1A) is associated
      with contractions of the polymorphic D4Z4 repeat array on chromosome 4qter. The
      disease has a high frequency of new mutations of mitotic origin. Pulsed-field gel
      electrophoresis-based studies show that mitotic mutations leading to somatic
      mosaicism occur equally frequently in patients and parents. Nevertheless, somatic
      mosaicism in FSHD is mainly reported in asymptomatic parents by applying standard
      Southern analysis after linear gel electrophoresis. Explaining this apparent
      discrepancy, we here demonstrate that somatic mosaicism in FSHD patients goes
      largely undetected using the standard diagnostic technique, indicating that
      linear electrophoresis is unsuitable to identify mosaic patients. As a
      consequence, the phenotype of mosaic patient's offspring will be underestimated,
      whereas the recurrence risk in the symptomatic mosaic individuals will be
      overestimated. Moreover, somatic mosaicism may partly explain the observation of
      anticipation in de novo kindreds. Therefore, clinicians should always consider
      pulsed-field gel electrophoresis analysis in de novo FSHD families, in particular
      when the patient's phenotype is much milder than expected based on D4Z4 length
      proper.

PMID- 15174020
TI  - Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob
      disease: UK cases 1991-2002.
AB  - Human prion diseases can occur as an idiopathic disorder (sporadic Creutzfeldt
      Jakob disease) or can be acquired, as is the case for variant Creutzfeldt-Jakob
      disease. These disorders are characterized by the accumulation of a protease
      resistant form of the host-encoded prion protein termed PrP(Sc) in the brains of
      affected individuals. PrP(Sc) has been proposed to be the principal, if not sole,
      component of the infectious agent, with its accumulation in the central nervous
      system the primary event leading to neurodegeneration. A major question remains
      as to whether self-propagating structural differences in PrP(Sc) might account
      for the clinicopathological diversity evident in Creutzfeldt-Jakob disease and
      whether different prion protein types underlie the existence of different strains
      of causative agent. Here, we describe the results of a large-scale biochemical
      study of PrP(Sc) from autopsy-proved cases of variant Creutzfeldt-Jakob disease
      (n = 59) and compare these with cases of sporadic Creutzfeldt-Jakob disease (n =
      170) in the United Kingdom over the period 1991 to 2002. The results show PrP(Sc)
      in variant Creutzfeldt-Jakob disease to be remarkably stereotyped. In contrast,
      considerable heterogeneity in PrP(Sc) exists both between and within cases of
      sporadic Creutzfeldt-Jakob disease.

PMID- 15174021
TI  - A critical period for prevention of posttraumatic neocortical hyperexcitability
      in rats.
AB  - Penetrating cortical trauma frequently results in delayed development of
      epilepsy. In the rat undercut model of neocortical posttraumatic
      hyperexcitability, suppression of neuronal activity by exposing the injured
      cortex to tetrodotoxin (TTX) in vivo for approximately 2 weeks prevents the
      expression of abnormal hypersynchronous discharges in neocortical slices. We
      examined the relationship between neuronal activity during the latent period
      after trauma and subsequent expression of hyperexcitability by varying the timing
      of TTX treatment. Partially isolated islands of rat sensorimotor cortex were
      treated with Elvax polymer containing TTX to suppress cortical activity and
      slices obtained for in vitro experiments 10 to 15 days later. TTX treatment was
      either started immediately after injury and discontinued after a variable number
      of days or delayed for a variable time after the lesion was placed. Immediate
      treatment lasting only 2 to 3 days and treatment delayed up to 3 days prevented
      hyperexcitability. Thus, there is a critical period for development of
      hyperexcitability in this model that depends on cortical activity. We propose
      that the hyperexcitability caused by partial cortical isolation may represent an
      early stage of posttraumatic epileptogenesis. A hypothetical cascade of events
      leading to subsequent pathophysiological activity is likely initiated at the time
      of injury but remains plastic during this critical period.

PMID- 15174022
TI  - Long-term results of bilateral pallidal stimulation in Parkinson's disease.
AB  - We followed up 11 patients for up to 5 years after bilateral pallidal deep brain
      stimulation for advanced Parkinson's disease. Dyskinesias remained significantly
      reduced until the last assessment. The initial improvement of off-period motor
      symptoms and fluctuations, however, was not sustained and gradually declined.
      Beneficial effects of pallidal deep brain stimulation on activities of daily
      living in the on- and off-period were lost after the first year. Replacement of
      pallidal electrodes into the subthalamic nucleus in four patients could restore
      the initial benefit of deep brain stimulation and allowed a significant reduction
      of dopaminergic drug therapy.

PMID- 15174023
TI  - Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive
      dystonia.
AB  - Unstable GTP cyclohydrolase I (GCH) mutations in dopa-responsive dystonia (DRD)
      can exert a dominant-negative effect in the HeLa cell model, but in a batch of
      cells this effect could not be shown. Through differential display, we found a
      higher Hsc70 expression in the non-dominant-negative cells. We further
      demonstrated that ectopic expression of Hsp40/Hsp70 stabilized the GCH mutant
      G201E. Moreover, Hsp90 inhibitor geldanamycin destroyed the wild-type GCH level,
      and heat shock increased the synthesis of GCH protein. Therefore, the dominant
      negative effect produced by unstable proteins would be susceptible to the status
      of molecular chaperones, which could be the modifying genes and therapeutic
      targets for DRD and other genetic diseases.

PMID- 15174024
TI  - Functional brain changes in presymptomatic Huntington's disease.
AB  - Evidence suggests early structural brain changes in individuals with the
      Huntington's disease (HD) genetic mutation who are presymptomatic for the
      movement symptoms of the illness. The aim of this study was to investigate the
      presence of functional brain changes in this same population using functional
      magnetic resonance imaging. Subjects and matched controls underwent an functional
      magnetic resonance imaging "interference" protocol, a task known to be mediated
      in part by corticostriatal circuitry. In the setting of normal cognitive
      performance, presymptomatic HD subjects had significantly and specifically less
      activation in the left anterior cingulate cortex (BA 24, 32) compared with
      matched controls.

PMID- 15174026
TI  - The 14q restless legs syndrome locus in the French Canadian population.
AB  - A new restless legs syndrome locus on chromosome 14 recently has been reported in
      one family of Italian origin. Our study aimed to replicate this finding and
      determine the importance of this locus in the French Canadian population. Markers
      spanning the region were genotyped in 14 large families and linkage assessed
      using two-point and multipoint logarithm of odds scores. Possible linkage to this
      locus was found in one of our kindreds providing support for the existence of
      this locus and indicating that this locus may be responsible for a small fraction
      of French Canadian restless legs syndrome.

PMID- 15174025
TI  - Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel
      ATP1A2 mutation.
AB  - Alternating hemiplegia of childhood (AHC) is typically distinguished from
      familial hemiplegic migraine (FHM) by infantile onset of the characteristic
      symptoms and high prevalence of associated neurological deficits that become
      increasingly obvious with age. Expansion of the clinical spectrum in FHM recently
      has begun to blur the distinction between these disorders. We report a novel
      ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum
      between AHC and FHM syndromes, supporting a possible common pathogenesis in a
      subset of such cases. Mutation analysis in classic sporadic AHC patients and in
      an additional five kindreds in which linkage to the ATP1A2 locus could not be
      excluded failed to identify additional mutations.

PMID- 15174028
TI  - Preoperative response to levodopa is the best predictor of transplant outcome.

PMID- 15174027
TI  - Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity.
AB  - Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder
      that arises because of mutations in the ATM gene. The 5762ins137 A-->G point
      mutation activates a cryptic splice donor site resulting in a 137 bp intronic
      insert being aberrantly spliced into the ATM transcript. However, normal ATM
      transcript also is produced from this affected allele, albeit at significantly
      reduced levels. An exceptionally mild A-T phenotype occurs as a result of
      homozygosity for the 5762ins137 mutation because of relative preservation of ATM
      protein expression/kinase activity.

PMID- 15174030
TI  - Further evidence that interactions between CYP2D6 and pesticide exposure increase
      risk for Parkinson's disease.

PMID- 15174031
TI  - Increased beta-Secretase activity in cerebrospinal fluid of Alzheimer's disease
      subjects.

PMID- 15174037
TI  - Capillary electrophoresis of single mammalian cells.
AB  - Capillary electrophoresis (CE) has been established as powerful tool for single
      cell analysis. Newly developed sampling, separation and detection methods have
      allowed the investigation of single mammalian cells with CE despite their small
      size and complex composition. Advances in sample injection techniques include
      several novel methods for the injection of whole cells and sampling techniques
      for the study of cellular secretion. CE of single mammalian cells has been
      applied in a wide range of fields including protein analysis, neuroscience, and
      oncology. The development of new detection schemes in the analysis of single
      mammalian cells with CE has included studies of protein expression and the
      utilization of mass spectrometric and electrochemical detection. Subcellular
      mammalian cell analysis with CE also has been investigated.

PMID- 15174038
TI  - Chiral cyclodextrin-modified microemulsion electrokinetic chromatography.
AB  - Cyclodextrin (CD)-modified microemulsion electrokinetic chromatography (MEEKC) or
      CD-MEEKC has not previously been applied to the area of chiral separations.
      Herein, the results of investigations of various microemulsions with CD additives
      are presented. Two different microemulsions are explored: an ethyl acetate sodium
      dodecyl sulfate microemulsion, and a chiral dodecoxycarbonylvaline (DDCV)
      microemulsion. Each microemulsion is paired separately with a neutral CD
      (hydroxypropyl-beta-CD) and an anionic CD (sulfated-beta-CD). In addition, the
      chiral DDCV microemulsion is investigated in both the R- and S- form. By varying
      simple parameters such as buffer system, applied voltage, surfactant enantiomer,
      and type of cyclodextrin, dramatic improvements in the chiral separations were
      noted. Resolution was found to be highly dependent on buffer identity and
      concentration, and somewhat dependent on whether the CDs used were randomly or
      highly sulfated. Under optimized conditions, the resolution ranged from 0.8 to
      4.8, with plate counts ranging from 4000 to 26 000. Additionally, S- and R
      levetiracetam, which had never before been enantioseparated via capillary
      electrophoresis (CE) methodologies, were separated in less than 8 min, with a
      resolution of 1.1.

PMID- 15174039
TI  - Single-isomer sulfated alpha-cyclodextrins for capillary electrophoresis. Part 2.
      Hexakis(6-O-sulfo)-alpha-cyclodextrin: synthesis, analytical characterization,
      and initial screening tests.
AB  - The second member of the family of single-isomer sulfated alpha-cyclodextrins,
      the sodium salt of hexakis(6-O-sulfo)-alpha-cyclodextrin (HxS), has been
      synthesized, analytically characterized, and used as the resolving agent for the
      capillary electrophoretic separation of the enantiomers of nonionic, weak-acid
      and weak-base analytes present in our initial screening kit. HxS interacted less
      strongly with many of the analytes tested than the larger-ring analogs,
      heptakis(6-O-sulfo)-beta-cyclodextrin (HS) and octakis(6-O-sulfo)-gamma
      cyclodextrin (OS). For some of the analytes, the separation selectivities
      obtained with HxS were complementary to those observed with hexakis(2,3-di-O
      acetyl-6-O-sulfo)-alpha-cyclodextrin (HxDAS), HS, and OS. For all analytes, the
      effective mobilities and separation selectivities as a function of the background
      electrolyte concentration of HxS followed the trends that were found for HxDAS,
      HS, and OS.

PMID- 15174040
TI  - Open-tubular electrochromatographic characterization of synthetic peptides.
AB  - The open-tubular electrochromatographic (OT-CEC) migration behavior of a series
      of peptides, based on a common structural feature, has been characterized using
      two different types of chemically modified etched capillaries. The organic
      moieties immobilized onto the capillary inner surface were n-butylphenyl and
      cholesterol-10-undecenaoate, respectively. The structure-migration behavior of
      this set of peptides has been studied at several pH values and with methanol at
      different concentrations as an organic solvent modifier of the buffer electrolyte
      composition. By comparing the structural properties of the peptides, such as
      their amino acid sequences, charge-to-mass ratios and intrinsic hydrophobicities
      to their migrational behavior, the relative contribution of electrophoretic and
      chromatographic mobility to the overall migration times, elution order, and
      selectivity has been determined. Moreover, the experimental data provide
      important insight into procedures that can be used to modulate the separation of
      peptides in OT-CEC through variation of the composition of the electrolyte buffer
      as well as via the properties of the bonded organic moiety.

PMID- 15174041
TI  - Capillary electrophoresis of cationic random coil peptide standards: effect of
      anionic ion-pairing reagents and comparison with reversed-phase chromatography.
AB  - The present study compares a charge/hydrophobicity capillary electrophoresis (CE)
      approach to reversed-phase high-performance liquid chromatography (RP-HPLC) for
      the separation of three series of four synthetic, random coil peptide standards.
      Each series has peptides of the same positive charge (+1, +2 and +3 series) and
      length but differing in hydrophobicity. Complete resolution of the 12 peptides
      was achieved via a novel CE approach: a capillary zone electrophoresis (CZE) mode
      effected a separation of identically charged peptides; within each charged group
      of peptides, the addition of perfluorinated acid anionic ion-pairing reagents
      allowed resolution of the peptides through a mechanism based on peptide
      hydrophobicity which we have termed ioninteraction (II)-CZE. The peak capacity
      and peptide resolution of this CE approach was superior to that of RP-HPLC and
      stresses an important role for CE for peptide/proteomic applications.

PMID- 15174042
TI  - Selectivity of quadruplex DNA stationary phases toward amino acids in
      homodipeptides and alanyl dipeptides.
AB  - Series of dipeptides, including homodipeptides and alanyl dipeptides, were
      separated using quadruplex (G-quartet) DNA stationary phases in open-tubular
      capillary electrochromatography (OTCEC). The stationary phases were constructed
      by covalently attaching the DNA oligonucleotides to the inner capillary surface.
      Three different G-quartet forming oligonucleotides were investigated: the two
      plane G-quartet forming thrombin-binding aptamer, the four-plane analogue of the
      thrombin-binding aptamer, and a two-plane oligonucleotide identical to the
      thrombin-binding aptamer except for the replacement of the guanine by thymine in
      the central bridging loop of the G-quartet structure. Results were compared with
      results obtained using capillary electrophoresis on a bare capillary and OTCEC
      using an oligonucleotide with the same base composition as the thrombin-binding
      aptamer but in a different sequence that does not allow G-quartet formation as
      the stationary phase.

PMID- 15174043
TI  - Membrane-mediated capillary electrophoresis: interaction of cationic peptides
      with bicelles.
AB  - Electrokinetic capillary chromatography is applied to determine the membrane
      affinity of peptides using both 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC)
      micelles and DHPC/1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bicelles
      under controlled conditions. The effect of temperature and the bicelle q value in
      surface association with cationic peptides is studied. The cationic peptides
      selected have a well-defined membrane structure (indolicidin), induced secondary
      structure (melittin, magainin 2), or do not possess classical secondary structure
      (atrial natriuretic peptide (ANP) 1-28, 4-28, 5-27). Electrokinetic capillary
      chromatography facilitated by DMPC and DHPC additives provides a rapid means of
      estimating lipophilicity and screening for peptides that have membrane affinity.

PMID- 15174044
TI  - Determination of dissociation constants for a heparin-binding domain of amyloid
      precursor protein and heparins or heparan sulfate by affinity capillary
      electrophoresis.
AB  - Dynamic affinity capillary electrophoresis (ACE) was used for determining the
      binding constants between heparin-like glycosaminoglycans and the (96-110)
      heparin-binding domain of amyloid precursor protein (APP). The migration time
      shift of the (96-110) APP peptide was monitored as the concentration of heparin
      was increased in the background electrolyte. The compounds investigated included
      low-molecular-weight heparin, porcine mucosa heparin, and heparan sulfate. Change
      in mobility as a function of glycosaminoglycan concentration was plotted using
      both linear regression (Scatchard analysis) and nonlinear regression.
      Dissociation constants (K(d)) were determined and compared for both sets of
      analyses with the low-molecular-weight heparin giving the most reproducible
      results and best fit with a K(d) value of 3.9 microM.

PMID- 15174045
TI  - Peptide separations by slab gel electrophoresis in pluronic F127 polymer liquid
      crystals.
AB  - Proteomics and peptidomics could benefit from simple methods for high-resolution
      separation of oligopeptides analogous to slab gel electrophoresis of proteins.
      Gels of Pluronic F127 copolymer surfactant were investigated as media for slab
      gel electrophoresis of oligopeptides using a trypsin digest of myoglobin.
      Concentrated solutions of Pluronic F127 are fluid at low temperatures (</= 5
      degrees C), but become a gel-like micellar liquid crystal upon warming. Nucleic
      acids are well separated by electrophoresis in these gels as previously shown by
      Rill and Liu. Good separations of myoglobin tryptic peptides were accomplished by
      electrophoresis on slab gels of 24% Pluronic F127 or 15% polyacrylamide using the
      alkaline Laemmli buffer system (without sodium dodecyl sulfate). Labeling of
      peptides with the succinimidyl ester of Cascade Yellow (CY) prior to
      electrophoresis allowed sensitive detection with blacklight illumination at 365
      nm. Labeled tryptic peptides were identified by matrix-assisted laser
      desorption/ionization-time of flight (MALDI-TOF)-mass spectrometry. An inverse
      dependence of electrophoretic mobility on mass of peptides with charge Z = -1 was
      observed in both media. Two-dimensional (2-D) electrophoresis of myoglobin
      peptides on polyacrylamide, then on Pluronic media, at pH 8.3 indicated that the
      primary separation mechanism of most peptides was the same in both media. A few
      off-diagonal spots indicated that some peptides were preferentially retarded in
      Pluronic gels, perhaps due to hydrophobic effects. The ease of gel preparation
      and peptide recovery are advantages of Pluronic F127 gels for oligopeptide
      electrophoresis. The two media can be combined conveniently for 2-D
      electrophoresis, providing means to facilitate protein identification and
      peptidomics.

PMID- 15174046
TI  - High-performance liquid chromatography and capillary electrophoresis:
      methodological challenges for the determination of biologically relevant low
      aliphatic aldehydes in human saliva.
AB  - Tobacco smoke is involved in the pathogenesis of cardiovascular and respiratory
      diseases and also has a local toxic effect in the oral cavity. Low-aliphatic
      aldehydes, such as formaldehyde, acetaldehyde and acrolein, are among the main
      components of mainstream cigarette smoke and their local noxious and carcinogenic
      effects in the oral cavity and upper gastrointestinal tract are well-known.
      Although various studies have been performed so far to determine their content in
      cigarette smoke, none has included the direct measurement of these compounds in
      the saliva of smoking and nonsmoking subjects. Thus, in an attempt to verify
      whether typical chromatographic (high-performance liquid chromatography, HPLC)
      and/or electrophoretic (capillary electrophoresis, CE) techniques could be
      reliable methods for determining the levels of these analytes in human saliva, we
      submitted specimens obtained from a selected population of heavy, moderate, and
      nonsmoking subjects to HPLC and CE analyses. Both methods showed good
      reproducibility in terms of migration times and peak height and/or areas and had
      comparable linearity. Quantitative analyses performed on the specimens
      investigated evidenced a 3.5-fold increase of low-aliphatic aldehydes in saliva
      of nonsmoking subjects after they have smoked a single cigarette and a further 2
      fold increase of these compounds in saliva of smokers with a daily consumption of
      10 or more cigarettes.

PMID- 15174048
TI  - Orthogonal separations of nicotine and nicotine-related alkaloids by various
      capillary electrophoretic modes.
AB  - The migration behaviour of nicotine and related tobacco alkaloids was
      investigated using three different capillary electrophoretic (CE) modes. Novel
      separations were achieved both using microemulsion electrokinetic chromatography
      (MEEKC) and nonaqueous CE (NACE). Improved resolution compared to previous
      studies was obtained using free-solution CE (FSCE). Each technique resulted in
      different, orthogonal separation selectivity. The suitability of each method for
      application to the analysis of nicotine lozenges is discussed. The FSCE method
      was applied to the analysis of nicotine lozenges due to its compatibility with an
      established lozenge extraction solvent. The method used gave good injection
      precision and linearity. Good agreement of CE and high-performance liquid
      chromatography (HPLC) results was obtained. The CE method is therefore considered
      suitable for the quantitative determination of nicotine in nicotine lozenges.

PMID- 15174047
TI  - Determination of nitrate and nitrite in rat brain perfusates by capillary
      electrophoresis.
AB  - A fast and simple method for the direct, simultaneous detection of nitrite (NO(2)
      (-)) and nitrate (NO(3) (-)) in rat striatum has been developed using a capillary
      electrophoresis separation of low-flow push-pull perfusion samples. The method
      was optimized primarily for nitrite because nitrite is more important
      physiologically and is found at lower levels than nitrate. We obtained a complete
      separation of NO(2) (-) and NO(3) (-) in rat striatum within 1.5 min. Optimal CE
      separations were achieved with 20 mM phosphate, 2 mM cetyltrimethylammonium
      chloride (CTAC) buffer at pH 3.5. The samples were injected electrokinetically
      for 2 s into a 40 cm x 75 microm ID fused-silica capillary. The separation
      voltage was 10 kV (negative polarity), and the injection voltage was 16 kV
      (negative polarity). UV detection was performed at 214 nm. The limits of
      detection obtained at a signal-to-noise ratio (S/N) of 3 for nitrite and nitrate
      were 0.96 and 2.86 microM. This is one of the fastest separations of nitrite and
      nitrate of a biological sample ever reported. Interference produced by the high
      physiological level of chloride is successfully minimized by use of CTAC in the
      run buffer.

PMID- 15174049
TI  - What to do with "one-hit wonders"?

PMID- 15174050
TI  - Genome-based proteomics.
AB  - Protein-protein interactions play crucial roles in various biological pathways
      and functions. Therefore, the characterization of protein levels and also the
      network of interactions within an organism would contribute considerably to the
      understanding of life. The availability of the human genome sequence has created
      a range of new possibilities for biomedical research. A crucial challenge is to
      utilize the genetic information for better understanding of protein distribution
      and function in normal as well as in pathological biological processes. In this
      review, we have focused on different platforms used for systematic genome-based
      proteome analyses. These technologies are in many ways complementary and should
      be seen as various ways to elucidate different functions of the proteome.

PMID- 15174051
TI  - An investigation into the human serum "interactome".
AB  - The protein content of human serum is composed of a millieu of proteins from
      almost every type of cell and tissue within the body. The serum proteome has been
      shown to contain information that directly reflects pathophysiological states and
      represents an invaluable source of diagnostic information for a variety of
      different diseases. Unfortunately, the dynamic range of protein abundance,
      ranging from >> mg/mL level to << pg/mL level, renders complete characterization
      of this proteome nearly impossible with current analytical methods. To study low
      abundance proteins, which have potential value for clinical diagnosis, the high
      abundant species, such as immunoglobulins and albumin, are generally eliminated
      as the first step in many analytical protocols. This step, however, is
      hypothesized to concomitantly remove proteins/peptides associated with the high
      abundant proteins targeted for depletion. In this study, immunoprecipitation was
      combined with microcapillary reversed-phase liquid chromatography (microRPLC)
      coupled on-line with tandem mass spectrometry (MS/MS) to investigate the low
      molecular-weight proteins/peptides that associate with the most abundant species
      in serum. By this targeted isolation of select highly abundant serum proteins,
      the associated proteins/peptides can be enriched and effectively identified by
      microRPLC-MS/MS. Among the 210 proteins identified, 73% and 67% were not found in
      previous studies of the low-molecular-weight or whole-serum proteome,
      respectively.

PMID- 15174052
TI  - Low-molecular-weight human serum proteome using ultrafiltration, isoelectric
      focusing, and mass spectrometry.
AB  - Identification of the serum proteome is a daunting analytical task due to the
      complex nature of the sample which has an extremely large dynamic range of
      protein components. This report addresses this issue by using centrifugal
      ultrafiltration to enrich the low-molecular-weight (LMW) serum proteome while
      decreasing the amount of abundant high-molecular-weight proteins. Reduction of
      the complex nature of the sample was achieved by fractionation of the LMW serum
      proteins using solution-phase isoelectric focusing (IEF). Multiple enzyme
      digestions are performed and analyzed by liquid chromatography-tandem mass
      spectrometry (LC-MS/MS). Analysis of the tandem mass spectra resulted in the
      identification of 262 proteins belonging to LMW serum proteome. Our results
      demonstrate the effectiveness of this methodology to isolate and identify LMW
      proteins with improved confidence in the MS data acquired. In addition, our
      methodology can be combined with other multidimensional chromatography techniques
      performed on the peptide level to increase the number of identified proteins.

PMID- 15174053
TI  - Proteomic analysis of detergent-resistant membrane rafts.
AB  - A combined, detergent- and organic solvent-based proteomic method for the
      analysis of detergent-resistant membrane rafts (DRMR) is described. These
      specialized domains of the plasma membrane contain a distinctive and dynamic
      protein and/or lipid complement, which can be isolated from most mammalian cells.
      Lipid rafts are predominantly involved in signal transduction and adapted to
      mediate and produce different cellular responses. To facilitate a better
      understanding of their biology and role, DRMR were isolated from Vero cells as a
      Triton X-100 insoluble fraction. After detergent removal, sonication in 60%
      buffered methanol was used to extract, solubilize and tryptically digest the
      resulting protein complement. The peptide digestate was analyzed by
      microcapillary reversed-phase liquid chromatography-tandem mass spectrometry. Gas
      phase fractionation in the mass-to-charge range was employed to broaden the
      selection of precursor ions and increase the number of identifications in an
      effort to detect less abundant proteins. A total of 380 proteins were identified
      including all known lipid raft markers. A total of 91 (24%) proteins were
      classified as integral alpha-helical membrane proteins, of which 51 (56%) were
      predicted to have multiple transmembrane domains.

PMID- 15174054
TI  - On-line protein digestion and peptide mapping by capillary electrophoresis with
      post-column labeling for laser-induced fluorescence detection.
AB  - A nanoliter enzyme microreactor was developed for on-line capillary
      electrophoresis (CE) peptide mapping of proteins, allowing picomole quantities of
      proteins to be digested. The enzyme microreactor was formed by immobilizing
      trypsin onto a monolithic capillary column, which was prepared by in situ
      polymerization of glycidyl methacrylate and ethylene dimethacrylate in a
      capillary. Highly efficient digestion of three protein standards was
      demonstrated. The detection of peptide fragments in CE was enhanced by post
      column derivatization and laser-induced fluorescence detection. The microreactor
      has a volume of about 30 nL and is coupled with a separation capillary via a
      fluid joint for on-line digestion. The overall analysis, including digestion and
      separation, lasted only about 16 min. Column efficiencies > 300 000 plates/m were
      obtained for most peaks in the electropherogram of an on-line peptide mapping
      experiment of denatured alpha-lactalbumin under optimal conditions.

PMID- 15174055
TI  - Blue silver: a very sensitive colloidal Coomassie G-250 staining for proteome
      analysis.
AB  - A modified Neuhoff's colloidal Coomassie Blue G-250 stain is reported, dubbed
      "blue silver" on account of its considerably higher sensitivity, approaching the
      one of conventional silver staining. The main modifications, as compared to
      Neuhoff's protocol, were: a 20% increment in dye concentration (from 0.1% up to
      0.12%) and a much higher level of phosphoric acid in the recipe (from 2% up to
      10%). The "blue silver" exhibits a much faster dye uptake (80% during the first
      hour of coloration, vs. none with a commercial preparation from Sigma). Even at
      equilibrium (24 h staining), the "blue silver" exhibits a much higher sensitivity
      than all other recipes, approaching (but lower than) the one of the classical
      silver stain. Measurements of stain sensitivity after sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) of bovine serum albumin (BSA) gave
      a detection limit (signal-to-noise ratio > 3) of 1 ng in a single zone. The
      somewhat lower sensitivity of "blue silver" as compared to classical silvering
      protocols in the presence of aldehydes is amply compensated for by its full
      compatibility with mass spectrometry of eluted polypeptide chains, after a two
      dimensional map analysis, thus confirming that no dye is covalently bound (or
      permanently modifies) to any residue in the proteinaceous material. It is
      believed that the higher level of phosphoric acid in the recipe, thus its lower
      final pH, helps in protonating the last dissociated residues of Asp and Glu in
      the polypeptide coils, thus greatly favoring ionic anchoring of dye molecules to
      the protein moiety. Such a binding, though, must be followed by considerable
      hydrophobic association with the aromatic and hydrophobic residues along the
      polypeptide backbone.

PMID- 15174056
TI  - Proteomic analysis of carbonylated proteins in two-dimensional gel
      electrophoresis using avidin-fluorescein affinity staining.
AB  - A method for detecting carbonylated proteins in two-dimensional electrophoresis
      (2-DE) was developed using biotinylation and avidin-fluorescein isothiocyanate
      (FITC) affinity staining. The method was used to examine oxidatively modified
      proteins associated with oxidative stress. Carbonyl formation in proteins was
      first examined in a model system by subjecting bovine serum albumin (BSA) and
      ribonuclease A (RNase A) to metal-catalyzed oxidation (MCO). Carbonyl group
      formation was found to occur at multiple sites along with a small amount of
      polypeptide chain cleavage. In vivo studies were conducted in yeast cell cultures
      using 5 mM hydrogen peroxide to induce oxidative stress. Biotinylation of yeast
      protein was accomplished during extraction at 4 degrees C in a lysis buffer
      containing 5 mM biotin-hydrazide. Biotin-hydrazide forms a Schiff base with a
      carbonyl group on an oxidized protein that is subsequently reduced before
      electrophoresis. Proteins were separated by either 2-DE or sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE). Biotinylated species were detected
      using avidin-FITC affinity staining. Detection sensitivity with biotinylated
      proteins was five times higher than achieved by silver staining. The limit of
      detection with avidin-FITC staining approached 0.64 pmol of protein-associated
      carbonyls. Twenty carbonylated proteins were identified in the proteome of yeast
      following oxidative stress with hydrogen peroxide. Matrix-assisted laser
      desorption/ionization-mass spectrometry (MALDI-MS) analysis of tryptic peptides
      was used to identify peptides extracted from gels. Aconitase, heat shock protein
      SSA1 and SSC1, pyruvate decarboxylase isozyme 1, pyruvate kinase 1, enolase 1 and
      2, phosphoglycerate kinase, fructose-bisphosphate aldorase, and glyceraldehyde-3
      phosphate dehydrogenase were among the major targets of oxidative stress.

PMID- 15174057
TI  - Quantitative proteomic analysis of inorganic phosphate-induced murine MC3T3-E1
      osteoblast cells.
AB  - Cleavable isotope-coded affinity tag (cICAT) reagents were utilized to identify
      and quantitate protein expression differences in control and inorganic phosphate
      treated murine MC3T3-E1 osteoblast cells. Proteins extracted from control and
      treated cells were labeled with the light and heavy isotopic versions of cICAT
      reagents, respectively. The cICAT-labeled samples were combined, proteolytically
      digested, and the cICAT-derivatized peptides isolated using immobilized avidin
      chromatography. The cICAT-labeled peptides were resolved into 96 fractions by
      strong cation-exchange (SCX) liquid chromatography (LC). Analysis of the SCX-LC
      cICAT peptide fractions by microcapillary reversed-phase LC-tandem mass
      spectrometry resulted in the identification and quantitation of 7227 unique
      peptides corresponding to 2501 proteins, or roughly 9% of the proteins currently
      predicted to be encoded by the mouse genome. A false positive analysis indicated
      a 98% confidence in the peptide identifications. To corroborate changes in
      abundance measured by cICAT with those detectable in traditionally prepared cell
      lysate, we chose to analyze cyclin D1. Cyclin D1 has been previously identified
      as a phosphate-responsive gene and was likewise identified as a phosphate
      responsive protein in the current analysis. The 1.76-fold increase in abundance
      in cyclin D1 determined from cICAT corresponds well with the 2.41-fold increase
      as determined by Western blotting. These results demonstrate that quantitative
      proteomics is capable of providing a quantitative view of thousands of proteins
      in mammalian cells within a defined set of experiments.

PMID- 15174058
TI  - Intact mass measurements for unequivocal identification of hydrophobic
      photosynthetic photosystems I and II antenna proteins.
AB  - The purpose of this study was to determine the optimal experimental conditions
      necessary to allow rapid and accurate identification of highly hydrophobic
      proteins, such as the antenna proteins from photosystems I and II. The antenna
      proteins were derived from two different species, tomato and Arabidopsis, whose
      photosynthetic genome is well known. The separation techniques included sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by
      immunoblotting, microamino acid sequencing, reversed-phase high-performance
      liquid chromatography (RP-HPLC), intact mass measurements, and peptide mass
      fingerprinting by mass spectrometry. Immunoblotting was time-consuming, and
      success was limited due to cross-reactivity between these highly conserved
      sequences. The best results by far were achieved by separating intact proteins
      through hyphenation of reversed-phase liquid chromatography on-line to an
      electrospray ionization mass spectrometer (ESI-MS) and consequently identifying
      individual proteins from their intact mass measurements (IMMs), whereas peptide
      mass fingerprinting was hampered by the highly hydrophobic nature of these
      proteins. RP-HPLC-ESI-MS was superior in the quality of separation. Moreover, the
      high quality of mass spectra recorded during the RP-HPLC-ESI-MS analysis meant
      that the relative deviations of the molecular masses determined with a quadrupole
      ion trap mass analyzer ranged between 100 and 300 ppm. Thus, the correspondence
      between the intact mass values measured with those deduced from the DNA sequences
      allowed the different types of antenna proteins to be identified and assigned to
      their corresponding gene families. By utilizing this correlation, it was possible
      to spot gene products of previously cloned genes.

PMID- 15174059
TI  - Comparison of two glutaraldehyde immobilization techniques for solid-phase
      tryptic peptide mapping of human hemoglobin by capillary zone electrophoresis and
      mass spectrometry.
AB  - Stabilization of proteolytic enzymes, especially by immobilization, is of
      considerable interest because of their potential applications in medicine and the
      chemical and pharmaceutical industries. We report here a detailed comparison of
      two procedures for trypsin immobilization using the same homobifunctional agent,
      glutaraldehyde, for the purpose of peptide mapping. These methods include
      covalent coupling either to controlled pore glass (solid support) or via a cross
      linking reaction (without any solid support). The immobilized trypsin
      preparations were characterized by the determination of immobilization
      efficiency, which ranged from 68 to > 95%, and measurement of apparent kinetic
      parameters toward a synthetic peptide-like substrate. Batch digestions of whole
      denaturated human normal adult hemoglobin (HbA) were performed to obtain peptide
      maps by capillary zone electrophoresis (CZE). Migration time reproducibility of
      the CZE maps was excellent, with a mean relative standard deviation of 1.5%.
      Moreover, the two immobilized enzyme preparations showed excellent
      reproducibility for repeated digestions. Matrix-assisted laser
      desorption/ionization (MALDI)-mass spectrometry was also used for peptide mass
      mapping of denaturated HbA digested using the two immobilized trypsin
      preparations. Even though the two immobilized trypsin preparations do not behave
      identically, similar sequence coverages of 57% and 61% (for the two HbA chains
      merged) were achieved for the support-based and cross-linked trypsin
      preparations, respectively.

PMID- 15174060
TI  - Electronic gel protein transfer and identification using matrix-assisted laser
      desorption/ionization-mass spectrometry.
AB  - An electronic protein transfer technique is described for achieving the rapid and
      efficient recovery of sodium dodecyl sulfate (SDS)-protein complexes from
      polyacrylamide gels. This process involves the use of small-dimension capillaries
      in physical contact with a resolved protein band within the polyacrylamide gel,
      providing a large potential drop and high electric field strength at the
      capillary/gel interface. Several factors controlling the electronic protein
      transfer, including the applied electric field strength, the electrophoresis
      buffer concentration, and the capillary dimension, are studied to further enhance
      the use of field-amplification for sample stacking of extracted SDS-protein
      complexes. As a result of sample stacking, the extracted proteins from a 50 ng
      gel loading are present in a narrow ( approximately 80 nL) and highly
      concentrated (0.46 mg/mL or 3.3 x 10(-5) M for cytochrome c) solution plug. Three
      model proteins with molecular mass ranging from 14 kDa (cytochrome c) to 116 kDa
      (beta-galactosidase) are stained by Coomassie blue and electrophoretically
      extracted from gels with protein loadings as low as 50 ng. The capillary format
      of the electronic protein transfer technique allows direct deposition of
      extracted proteins onto a matrix-assisted laser desorption/ionization mass
      spectrometry (MALDI-MS) target. Various matrices and solvent compositions are
      evaluated for the analysis of extracted and concentrated SDS-protein complexes
      using MALDI-MS. The electronic protein transfer technique, when operated under
      optimized conditions, is demonstrated for the effective (>70% recovery), speedy
      (less than 5 min), and sensitive MS identification of gel resolved proteins (as
      low as 50 ng).

PMID- 15174061
TI  - Analysis of the sinusitis nasal lavage fluid proteome using capillary liquid
      chromatography interfaced to electrospray ionization-quadrupole time of flight-
      tandem mass spectrometry.
AB  - The nasal lavage fluids (NLFs) from four subjects with acute sinusitis were
      analyzed to investigate the amount of proteins expressed in this pathology at the
      beginning of the event (day 1) and after 6 days of treatment with antibiotics and
      a nasal steroid spray. The protein identification was performed with capillary
      liquid chromatography-electrospray-quadrupole time of flight-(LC-ESI-Q-TOF)-mass
      spectrometry. The samples collected on the first day contained high-abundant
      plasma proteins, such as albumin and immunoglobulins, glandular serous cell
      proteins (lysozyme, lactoferrin, and polymeric immunoglobulin receptor),
      epithelial keratins, and inflammatory cell proteins (myeloperoxidase, IL-16, and
      IL-17E). After six days of therapy, the complexity of the proteome was reduced to
      plasma proteins and lysozyme with no inflammatory markers. The presence of
      hemoglobin, however, suggested that significant squamous metaplasia with breaches
      in the epithelial barrier, or nasal steroid-related bleeding, had occurred. The
      proteomic approach presented here allowed us to identify, in the high complexity
      of acute sinusitis nasal secretions, the proteins that respond to a
      pharmacological treatment and that could be suitable as markers of this
      pathology.

PMID- 15174067
TI  - Enhanced axonal growth into a spinal cord contusion injury site in a strain of
      mouse (129X1/SvJ) with a diminished inflammatory response.
AB  - After injury in the adult central nervous system, invading and intrinsic cells
      contribute to the formation of a lesion site that is refractory to axonal growth.
      To test the hypothesis that the inflammatory response to trauma dictates the
      extent of axonal growth after spinal cord injury, the time course of lesion
      evolution was compared in two mouse strains with contrasting cellular responses
      to peripheral inflammatory challenge. Adult C57Bl/6 and 129X1/SvJ mice received
      identical contusion injuries to the mid-thoracic spinal cord and were allowed to
      recover for 6 hours to 9 weeks. Both strains responded with a rapid, transient
      increase in chemokine expression, but the magnitude of this early response was
      slightly reduced in the 129X1/SvJ mice. Morphological indicators of inflammation
      were similar during the first week postinjury. After 7 days postinjury, however,
      the cellular responses differed between strains. The C57Bl/6 lesion core was
      chronically occupied by macrophages, devoid of astrocytes, and contained few
      axonal profiles. In contrast, as the macrophage density decreased a network of
      astrocytic processes and axons of central and peripheral origin invaded the
      center of the lesion site in 129X1Sv/J mice. Growth of axons in the 129X1Sv/J
      mice was accompanied by increased extravascular laminin in the lesion core and a
      reduced expression of chondroitin sulfate proteoglycan glycosaminoglycan
      sidechains in the periphery of the lesion. These results demonstrate that the
      diminished chronic inflammatory response in 129X1/SvJ mice is associated with
      enhanced cellular repair and increased axonal growth after spinal cord injury.

PMID- 15174068
TI  - Distribution of the neuropeptide FF1 receptor (hFF1) in the human hypothalamus
      and surrounding basal forebrain structures: immunohistochemical study.
AB  - Neuropeptides with C-terminal RFamide and their receptors NPFF1 (FF1) and NPFF2
      (FF2) have been implicated in a wide variety of functions, including nociception
      and autonomic and neuroendocrine regulation. Recent studies indicate that the
      FF1, but not FF2, mRNA is highly expressed in the human hypothalamus. In the
      present study, localization of FF1 in the human hypothalamus and surrounding
      regions was studied immunohistochemically by using an antibody against human FF1
      (hFF1). Brain sections from healthy 30-50-year-old individuals were used for hFF1
      immunohistochemistry. The highest density of hFF1-stained cells was found in the
      posterior division of the bed nucleus of the stria terminalis and in the zona
      incerta. A moderate density of cells was observed in the perifornical nucleus,
      infundibular nucleus, tuberomammillary nucleus, and lateral tuberal nucleus. A
      lesser density was revealed in the dorsomedial hypothalamic nucleus, basal
      nucleus of Meynert, and anterior amygdaloid area. Only scattered hFF1 cells were
      found in the suprachiasmatic nucleus and hypothalamic paraventricular nucleus.
      hFF1 cells and fibers were absent in the supraoptic and mammillary nuclei. Single
      and double strands of hFF1-immunopositive punctate varicosities marked cellular
      processes of different caliber. The density of hFF1-immunostained fiber networks
      did not always coincide with that of hFF1-immunostained cells. hFF1
      immunoreactivity was also found in the wall of blood vessels within most brain
      areas studied. Localization of hFF1 in discrete regions of the hypothalamus and
      extended amygdala may provide important insights into the role of amidated
      neuropeptides in central autonomic and neuroendocrine control in the human brain.

PMID- 15174069
TI  - Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish
      ventral and lateral pallial histogenetic divisions in the developing mouse
      claustroamygdaloid complex.
AB  - We studied the lateral and ventral pallial divisions of the claustroamygdaloid
      complex by means of analysis of expression patterns of the developmental
      regulatory genes Tbr1, Dbx1, Neurogenin 2, Emx1, Cadherin 8, and Semaphorin 5A in
      mouse developing telencephalon, from embryonic day 12.5 until birth. Our results
      indicate that these genes help to distinguish distinct lateral and ventral
      pallial histogenetic divisions in the embryonic telencephalon. Tbr1 is broadly
      expressed in both lateral and ventral pallial histogenetic divisions (the
      lateroventral migratory stream plus the mantle) during early and intermediate
      embryonic development; its signal becomes weak in parts of the mantle during late
      embryonic development. Dbx1 is strongly and specifically expressed in progenitor
      cells (ventricular zone) of the ventral pallium during early embryonic
      development, but there is no signal of this gene in the rest of the pallium nor
      the subpallium. Neurogenin 2 and Semaphorin 5A are both expressed in a ventral
      subdivision of the lateroventral migratory stream (called by us the ventral
      migratory stream). Further, specific nuclei of the claustral complex and pallial
      amygdala show strong expression of Neurogenin 2 and/or Semaphorin 5A, including
      the ventromedial claustrum and endopiriform nuclei, the lateral and basomedial
      amygdalar nuclei, the anterior and posteromedial cortical amygdalar areas, plus
      the amygdalo-hippocampal area. We interpret these nuclei or areas of the
      claustroamygdaloid complex as possible derivatives of the ventral pallium. In
      contrast, during embryonic development the dorsolateral claustrum, the
      basolateral amygdalar nucleus, and the posterolateral cortical amygdalar area do
      not express or show weak expression of Neurogenin 2 or Semaphorin 5A, but express
      selectively and strongly Cadherin 8 plus Emx1, and may be derivatives of the
      lateral pallium. The lateral pallial and ventral pallial divisions of the
      claustroamygdaloid complex appear to have some different sets of connections,
      although this requires further investigation.

PMID- 15174070
TI  - Intrinsic differences in brain and spinal cord mitochondria: Implication for
      therapeutic interventions.
AB  - It is well known that regions of the CNS differentially respond to insults. After
      brain injury, cyclosporine A reduces damage but is ineffective following spinal
      cord injury. We address this disparity by assessing several parameters of
      mitochondrial physiology in the normal neocortex and spinal cord. In situ
      measurements of O(2) (-.) production, lipid peroxidation, and mitochondrial DNA
      oxidation revealed significantly higher levels in spinal cord vs. neocortical
      neurons. Real-time PCR demonstrated differences in mitochondrial transcripts
      coupled with decreases in complex I enzyme activity and respiration in spinal
      cord mitochondria. The threshold for calcium-induced mitochondrial permeability
      transition was substantially reduced in spinal cord vs. neocortex and modulated
      by lipid peroxidation. These intrinsic differences may provide a pivotal target
      for strategies to ameliorate neuronal damage following injury, and this imbalance
      in oxidative stress may contribute to the susceptibility of spinal cord motor
      neurons in neuropathologies such as amyotrophic lateral sclerosis.

PMID- 15174071
TI  - STAT3 phosphorylation in injured axons before sensory and motor neuron nuclei:
      potential role for STAT3 as a retrograde signaling transcription factor.
AB  - STAT3 is a latent transcription factor that is activated by plasma membrane
      growth factor receptor complexes. Conditional gene disruption data indicate that
      it contributes to the survival of cranial motor neurons after peripheral nerve
      lesion. In agreement, levels of activated STAT3 (Tyr705-phosphorylated STAT3)
      have been shown to increase in the nuclei of adult cranial motor neurons during
      their regeneration after the same injury. The data presented here demonstrate
      that STAT3 is similarly but not identically affected in sciatic motor neurons
      after sciatic nerve injury. In addition, we find that sensory neuron nuclei also
      display an analogous increase in activated STAT3, thereby supporting a role for
      STAT3 in the survival and regeneration of these cells. Most interesting, the
      present data indicate that peripheral nerve lesion leads to a very rapid
      activation of STAT3 in axons at the lesion site. This response increases during
      the first 24 hours after injury and extends back to the motor and sensory neurons
      such that phospho-STAT3-immunoreactive axons are first detected in the dorsal
      root ganglia and ventral spinal cord at the same postlesion time intervals at
      which the activated STAT3 is first detected in the neuronal nuclei. Together
      these data raise the possibility that axonal STAT3, activated at the injury site,
      acts as a retrograde signaling transcription factor, which promotes the survival
      and regeneration of both sensory and motor neurons.

PMID- 15174072
TI  - Lumbar commissural interneurons with reticulospinal inputs in the cat: morphology
      and discharge patterns during fictive locomotion.
AB  - The purpose of this study was 1). to characterize the morphology of lumbar
      commissural neurons (CNs) with reticulospinal inputs and 2). to quantitate their
      activity during locomotor rhythm generation. Intraaxonal recordings at the L4-7
      level of the spinal cord were obtained in 67 neurons in the decerebrate,
      paralyzed cat. Fourteen of them were subsequently nearly fully visualized
      following their intraaxonal injection with the tracer neurobiotin. All 14 were
      CNs with axons projecting across the midline of the spinal cord. Their somata
      were located mainly in lamina VIII and additionally in laminae VII-VI. Most of
      the lamina VIII CNs were excited monosynaptically from reticulospinal pathways.
      They were judged to be interneuronal CNs if they had no, or a short, rostral
      projection. These CNs commonly gave off multiple axon collaterals in and around
      their somata's segmental level. They projected mainly to laminae VIII-VII and
      some additionally to lamina IX. Some laminae VIII and the laminae VII-VI CNs were
      excited polysynaptically from reticulospinal pathways or were not excited. They
      were judged to be long propriospinal or ascending tract CNs because they had only
      an ascending axon. Most lamina VIII CNs discharged rhythmically during fictive
      locomotion evoked by stimulation of the mesencephalic locomotor region,
      exhibiting one peak per locomotor cycle. The peak was in phase with neurographic
      activity of either a left or a right hindlimb extensor nerve. These results
      suggested that lamina VIII CNs are reciprocally connected bilaterally at each
      segmental level. Such an arrangement suggests their participation in the
      generation and coordination of reciprocal and bilateral locomotor activity.

PMID- 15174073
TI  - Expression of the genes Emx1, Tbr1, and Eomes (Tbr2) in the telencephalon of
      Xenopus laevis confirms the existence of a ventral pallial division in all
      tetrapods.
AB  - To investigate the pallial organization and the exact location and extension of
      the ventral pallium in amphibians, we cloned a fragment of the homeobox
      XenopusTbr1 (xTbr1) gene and analyzed its expression compared with that of the
      genes xEomes (Tbr2) and xEmx1 in the telencephalon of the frog Xenopus laevis
      during embryonic and larval development. The expression of xEmx1 was also
      analyzed in the adult frog. We compared the expression patterns of these pallial
      marker genes with that of the subpallial gene xDistal-less-4 (xDll4). Our results
      indicate that the whole pallium of Xenopus expresses the T-box genes xTbr1 and
      xEomes (in proliferating cells and/or mantle) during embryonic and larval
      development, and the expression of these genes is topographically complementary
      to that of xDll4 in the subpallium. In addition to their massive expression in
      the pallium, both xTbr1 and xEomes are expressed in a few dispersed cells in the
      subpallium, which may represent immigrant cells of pallial origin, because these
      genes are not found in the subpallial proliferating cells. On the other hand,
      during development xEmx1 is expressed in a large part of the pallium
      (proliferating and postmitotic cells) except for an area adjacent to the pallio
      subpallial boundary, where xEmx1 is observed only in some mantle cells. This
      pallial area poor in xEmx1 expression and poor in expression of the subpallial
      gene xDll4, but expressing the pallial marker genes xTbr1 and xEomes, appears to
      represent the amphibian ventral pallium, comparable to that described in other
      vertebrates (Puelles et al. [2000] J. Comp. Neurol. 424:409-438). In the adult
      frog, the ventral pallium appears to include the rostral part of the lateral
      amygdalar nucleus as well as a large part of the medial amygdalar nucleus (as
      defined by Marin et al. [1998] J. Comp. Neurol. 392:285-312). In contrast, the
      caudal part of the previously termed lateral amygdalar nucleus shows strong xEmx1
      expression and may be a lateral pallial derivative. The possible homology of
      these amphibian amygdalar nuclei is discussed. Finally, expression of xTbr1,
      xEomes, and xEmx1 is observed in the mitral cell layer of the olfactory bulb from
      early developmental stages, further supporting that this structure is a pallial
      derivative.

PMID- 15174074
TI  - The temporospatial expression of peripheral myelin protein 22 at the developing
      blood-nerve and blood-brain barriers.
AB  - Peripheral myelin protein 22 (PMP22), also known as growth arrest-specific gene 3
      (gas3), is a tetraspan membrane protein whose misexpression is associated with
      demyelinating peripheral neuropathies. Although the function of PMP22 in Schwann
      cells is unknown, the protein is found at intercellular junctions of various
      epithelia and endothelia. To begin to elucidate the role of PMP22 at cell
      junctions, we examined the temporal expression and protein localization during
      development and maturation of the rat blood-nerve barrier (BNB) and blood-brain
      barrier (BBB). Developing and adult rat sciatic nerves and brains were
      coimmunostained for PMP22 and known junctional proteins including zonula
      occludens-1 (ZO-1), occludin, and claudin-5. Prior to the maturation of the BNB
      and BBB and detection of the tight junction protein occludin, PMP22 is present at
      ZO-1 positive endothelial junctions of the sciatic nerve and brain cortex. The
      subcellular localization of PMP22 in cultured brain endothelia was confirmed by
      internalization with ZO-1 after EGTA-induced disruption of cell junctions. In
      choroid epithelia, PMP22 is detected along with occludin and ZO-1 as early as
      embryonic day 15 (E15). In agreement, PMP22 message is elevated in P1 rat brain
      microvasculature and choroid epithelia, compared with total cortex. Additionally,
      neuroepithelial cell junctions in the embryonic rat brain are immunoreactive for
      PMP22, ZO-1, and beta-catenin but not occludin. Together, these studies identify
      PMP22 as an early constituent of intercellular junctions in the developing and
      mature rat BNB and BBB.

PMID- 15174075
TI  - Subcellular and subsynaptic localization of group I metabotropic glutamate
      receptors in the monkey subthalamic nucleus.
AB  - Both subtypes of group I metabotropic glutamate receptor, mGluR1 and mGluR5, are
      expressed postsynaptically in neurons of the subthalamic nucleus (STN), and their
      activation induces different physiological responses. To test whether these
      effects could be explained by a differential localization of the two group I
      mGluRs, we analyzed the subcellular and subsynaptic distribution of mGluR1a and
      mGluR5 in the monkey STN. Double-immunofluorescence and light microscopic
      analyses revealed that both group I mGluR subtypes were strongly coexpressed in
      the neuropil and neuronal perikarya. Astrocytic perikarya exhibited intense
      mGluR1a, but no detectable mGluR5, immunoreactivity. At the electron microscopic
      level, immunoperoxidase labeling for both mGluR1a and mGluR5 was localized mainly
      in dendrites. A significant proportion of the total pool of mGluR1a
      immunoreactive elements was accounted for by glial cell processes, whereas glial
      cell labeling was much less frequently encountered in sections immunostained for
      mGluR5. Preembedding immunogold labeling in STN dendrites revealed that 60-70% of
      the gold labeling for both mGluR subtypes was intracellular, whereas 30-40% was
      apposed to the plasma membrane. Of the plasma membrane-apposed particles, more
      than 90% were extrasynaptic; fewer than 10% were associated with symmetric or
      asymmetric synapses. Most of the synapse-associated labeling was found at the
      edges of both asymmetric and symmetric postsynaptic specializations. Some
      extrasynaptic gold particles were aggregated on parts of the plasma membrane
      tightly apposed by glial processes. These findings demonstrate that mGluR1a and
      mGluR5 exhibit a similar pattern of subsynaptic localization in monkey STN
      neurons, with both receptor subtypes exhibiting substantial extrasynaptic and
      perisynaptic localization.

PMID- 15174077
TI  - Development and morphology of class II Kenyon cells in the mushroom bodies of the
      honey bee, Apis mellifera.
AB  - Class II Kenyon cells, defined by their early birthdate and unique dendritic
      arborizations, have been observed in the mushroom bodies of evolutionarily
      divergent insects. In the fruit fly Drosophila melanogaster, Class II (also
      called clawed) Kenyon cells are well known for their extensive reorganization
      that occurs during metamorphosis. The present account reports for the first time
      the occurrence of mushroom body reorganization during metamorphosis in
      holometabolous insect species outside of the Diptera. In the honey bee, Apis
      mellifera, Class II Kenyon cells show signs of degeneration and undergo a subtle
      reshaping of their axons during metamorphosis. Unlike in Drosophila,
      reorganization of Class II Kenyon cells in the honey bee does not involve the
      loss of axon branches. In contrast, the mushroom bodies of closely related
      hymenopteran species, the polistine wasps, undergo a much more dramatic
      restructuring near the end of metamorphosis. Immunohistochemistry, dextran fills,
      and Golgi impregnations illuminate the heterogeneous nature of Class II Kenyon
      cells in the developing and adult honey bee brain, with subpopulations differing
      in the location of dendritic arbors within the calyx, and branching pattern in
      the lobes. Furthermore, polyclonal antibodies against the catalytic subunit of
      Drosophila protein kinase A (anti-DC0) label an unusual and previously
      undescribed trajectory for these neurons. The observed variations in morphology
      indicate that subpopulations of Class II Kenyon cells in the honey bee can likely
      be further defined by significant differences in their specific connections and
      functions within the mushroom bodies.

PMID- 15174078
TI  - Subcellular localization of GABAB receptor subunits in rat globus pallidus.
AB  - The inhibitory amino acid gamma-aminobutyric acid (GABA) is the major
      neurotransmitter in the globus pallidus. Although electrophysiological studies
      have indicated that functional GABA(B) receptors exist in rat globus pallidus,
      the subcellular localization of GABA(B) receptor subunits and their spatial
      relationship to glutamatergic and GABAergic synapses are unknown. Here, we use
      pre-embedding immunogold labeling to study the subcellular localization of
      GABA(B) receptor subunits, GABA(B1) and GABA(B2), in globus pallidus neurons and
      identified populations of afferent terminals. Immunolabeling for GABA(B1) and
      GABA(B2) was observed throughout the globus pallidus, with GABA(B1) more strongly
      expressed in perikarya and GABA(B2) mainly expressed in the neuropil. Electron
      microscopic analysis revealed that the majority of GABA(B1) labeling was
      localized within the cytoplasm, whereas most of GABA(B2) labeling was associated
      with the plasma membrane. At the subcellular level, both the GABA(B1) and
      GABA(B2) immunogold labeling was localized at pre- and postsynaptic sites. At
      asymmetric, putative excitatory, synapses, GABA(B1) and GABA(B2) immunogold
      labeling was found at perisynaptic sites of both pre- and postsynaptic
      specializations. Double immunolabeling, using the vesicular glutamate transporter
      2 (VGLUT2), revealed the glutamatergic nature of most immunogold-labeled
      asymmetric synapses. At symmetric, putative GABAergic, synapses, including those
      formed by anterogradely labeled striatopallidal terminals, GABA(B1) and GABA(B2)
      immunogold labeling was found in the main body of both pre- and postsynaptic
      specializations. These results demonstrate the existence of presynaptic GABA(B)
      auto- and heteroreceptors and postsynaptic GABA(B) receptors, which may be
      involved in modulating synaptic transmission in the globus pallidus.

PMID- 15174079
TI  - S-cone connections of the diffuse bipolar cell type DB6 in macaque monkey retina.
AB  - Previous studies of primate retinae have shown that diffuse bipolar (DB) cells
      contact all the cones in their dendritic field, suggesting there is no spectral
      selectivity in the functional input to DB cells. However, since short-wavelength
      sensitive (S) cones make up less than 10% of the total cone population,
      specialized connectivity with S-cones is difficult to detect. In the present
      study, the S-cone connectivity of a subtype of DB cells, the DB6 cell, was
      studied in macaque monkey retina. Pieces of macaque retina were processed with
      antibodies to CD15 to stain DB6 cells and antibodies to the S-cone opsin to
      identify S-cones. Immunoreactivity was visualized using immunoperoxidase or
      immunofluorescence. Some preparations were additionally processed with peanut
      agglutinin coupled to fluorescein to reveal medium- and long-wavelength sensitive
      (M/L) cones. The preparations were analyzed using conventional and deconvolution
      light microscopy. The majority of DB6 cells had one or two S-cones in their
      dendritic field and the majority of S-cones were located in the dendritic field
      of DB6 cells. On average, 80% of the S-cones and 81% of the M/L cones contacted
      DB6 cells. The average number of dendritic terminals at cone pedicles did not
      differ between the cone types. However, the total number of DB6 dendritic
      terminals receiving input from M/L-cone pedicles was about eight times higher
      than the total number of dendritic terminals at S-cone pedicles. In conclusion,
      DB6 cells make indiscriminate contact with all cone types, but receive their
      major input from M/L-cones and thus carry a "Yellow-ON" spectral signal.

PMID- 15174081
TI  - Peptidomics of CNS-associated neurohemal systems of adult Drosophila
      melanogaster: a mass spectrometric survey of peptides from individual flies.
AB  - Neuropeptides are important messenger molecules that influence nearly all
      physiological processes. In insects, they can be released as neuromodulators
      within the central nervous system (CNS) or as neurohormones into the hemolymph.
      We analyzed the peptidome of neurohormonal release sites and associated secretory
      peptidergic neurons of adult Drosophila melanogaster. MALDI-TOF mass
      spectrometric analyzes were performed on single organs or cell cluster from
      individual flies. This first peptidomic characterization in adult fruit flies
      revealed 32 different neuropeptides. Peptides not directly predictable from
      previously cloned or annotated precursor genes were sequenced by tandem mass
      spectrometry. These peptides turned out to be either intermediate products of
      neuropeptide processing or shorter versions of known peptides. We found that the
      peptidome of the CNS-associated neurohemal organs is tagma-specific in
      Drosophila. Abdominal neurohemal organs and their supplying peptidergic neurons
      contain the capa gene products periviscerokinins and pyrokinin-1, thoracic
      neurohemal organs contain FMRFamides, and the neurohemal release sites of the
      brain contain pyrokinin-1(2-15), pyrokinin-2, corazonin, myosuppressin, and sNPF
      as their major putative release products. Our results show that peptidomic
      approaches are well suited to study differential neuropeptide expression or
      posttranslational modifications in morphologically defined parts of the nervous
      system and in a developmental and physiological context in animals as small as
      Drosophila melanogaster.

PMID- 15174080
TI  - Differential expression of 5HT-1A, alpha 1b adrenergic, CRF-R1, and CRF-R2
      receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and
      catecholaminergic cells of the rat dorsal raphe nucleus.
AB  - The dorsal raphe nucleus (DR) has a topographic neuroanatomy consistent with the
      idea that different parts of this nucleus subserve different functions. Here we
      use dual in situ hybridization to describe the rostral-caudal neurochemical
      distribution of three major cell groups, serotonin (5-hydroxytryptamine; 5-HT),
      gamma-aminobutyric acid (GABA), and catecholamine, and their relative
      colocalization with each other and mRNA encoding four different receptor subtypes
      that have been described to influence DR responses, namely, 5HT-1A, alpha(1b)
      adrenergic (alpha(1b) ADR), and corticotropin-releasing factor type 1 (CRF-R1)
      and 2 (CRF-R2) receptors. Serotonergic and GABAergic neurons were distributed
      throughout the rostral-caudal extent of the DR, whereas catecholaminergic neurons
      were generally restricted to the rostral half of the nucleus. These phenotypes
      essentially represent distinct cell populations, because the neurochemical
      markers were rarely colocalized. Both 5HT-1A and alpha(1b) ADR mRNA were highly
      expressed throughout the DR, and the vast majority of serotonergic neurons
      expressed both receptors. A smaller percentage of GABAergic neurons also
      expressed 5HT-1A or alpha(1b) ADR mRNA. Very few catecholaminergic cells
      expressed either 5HT-1A or alpha(1b) ADR mRNA. CRF-R1 mRNA was detected only at
      very low levels within the DR, and quantitative colocalization studies were not
      technically feasible. CRF-R2 mRNA was mainly expressed at the middle and caudal
      levels of the DR. At midlevels, CRF-R2 mRNA was expressed exclusively in
      serotonin neurons, whereas, at caudal levels, approximately half the CRF-R2 mRNA
      was expressed in GABAergic neurons. The differential distribution of distinct
      neurochemical phenotypes lends support to the idea of functional differentiation
      of the DR.

PMID- 15174082
TI  - Distinct expression of phosphorylated N-methyl-D-aspartate receptor NR1 subunits
      by projection neurons and interneurons in the striatum of normal and amphetamine
      treated rats.
AB  - N-methyl-D-aspartate (NMDA) receptors are heteromeric assemblies of subunits (NR1
      and NR2A-D), and are enriched in the striatum. Receptor phosphorylation has
      recently been demonstrated on the NR1 subunit at three serine residues, 897, 896,
      and 890, which appear to correspond to the level of receptor activity. In this
      study, expression of phospho-specific NR1 subunits at serine 897 (pNR1S897),
      serine 896 (pNR1S896), or serine 890 (pNR1S890) in neurochemically identified
      neurons of the adult rat striatum was detected by using double-immunofluorescent
      labeling or combined in situ hybridization and immunohistochemistry. In both the
      dorsal and ventral striatum, pNR1S897 was expressed at high levels in projection
      neurons containing >55% dynorphin (striatonigral) and >90% enkephalin
      (striatopallidal) and in interneurons that were 100% positive for choline, >90%
      positive for parvalbumin, and >45% positive for somatostatin (co-containing
      neuropeptide Y and neuronal nitric oxide synthase). Low levels of pNR1S896 were
      present in a small portion of projection neurons (<15% for both populations of
      projection neurons) and were almost lacking in the three types of interneurons.
      Interestingly, pNR1S890 was exclusively expressed in most parvalbumin-containing
      interneurons (70-80%). Acute administration of a psychostimulant, amphetamine,
      increased the number of dynorphin-containing projection neurons and parvalbumin
      interneurons showing detectable levels of pNR1S896 and pNR1S890, respectively.
      These results demonstrate the distinct expression of phospho-NR1 subunits in
      different populations of striatal projection neurons and interneurons at variable
      levels in normal rats; they also demonstrate that phosphorylation of NR1, at
      least on serine 896 and 890 sites, is sensitive to drug exposure.

PMID- 15174083
TI  - Vanilloid receptor like 1 (VRL1) immunoreactivity in mammalian retina:
      colocalization with somatostatin and purinergic P2X1 receptors.
AB  - The distribution of vanilloid receptor like1 immunoreactivity (VRL1-IR) in the
      retinas of rat, cat, and monkey was studied by single- and double-labeling
      immunocytochemistry. The patterns were similar for all three species in that VRL1
      IR was most prominent in the inner plexiform layer, with scattered compact
      projections to the outer plexiform layer (OPL). VRL1-immunoreactive cell bodies
      were present throughout the rat retina, represented by amacrine cells in the
      inner nuclear layer and ganglion cell layer (GCL). In cat and monkey retinas,
      VRL1-immunoreactive cell bodies were restricted to the GCL in the inferior
      retina. Occasional cell bodies were associated with retinal blood vessels, but
      their identity as pericytes, glia, or neurons is uncertain. All VRL1
      immunoreactive cells and processes colocalized with somatostatin and purinergic
      P2X1 receptor-IR but not with tyrosine hydroxylase-IR. VRL1-immunoreactive
      processes in the OPL did not label with antisera against synaptic vesicle 2
      (SV2), suggesting that they were dendritic and did not derive from interplexiform
      cells. However, VRL1-immunoreactive processes in the far periphery toward the
      pars plana labeled for SV2, suggesting that these processes were presynaptic. The
      VRL1-immunoreactive cell bodies in the monkey GCL were not calbindin
      immunoreactive, demonstrating that they were not displaced H2 horizontal cells.
      The VRL1-immunoreactive cells in cat and monkey could represent biplexiform
      and/or associational ganglion cells that receive input in the OPL throughout the
      retina and direct output to the far periphery. The presence of P2X1 receptors and
      vanilloid receptor like 1 protein on somatostatin-containing neurons in mammalian
      retina adds to the growing complexity regarding the chemical control of retinal
      function that is likely to include the microcirculation.

PMID- 15174084
TI  - Estrogen modulates synaptic N-methyl-D-aspartate receptor subunit distribution in
      the aged hippocampus.
AB  - Estrogen interacts with N-methyl-D-aspartate (NMDA) receptors to regulate
      multiple aspects of morphological and functional plasticity. In hippocampus,
      estrogen increases both dendritic spine density and synapse number, and NMDA
      antagonists block these effects. Thus, estrogen-mediated hippocampal plasticity
      may be of particular importance in the context of age-related changes in
      endocrine status and cognitive performance. NR1 levels per synapse are increased
      in CA1 by estrogen in aged rats but not young rats, although no information is
      available on estrogen-induced synaptic alterations in other NMDA receptor
      subunits that might impact function. Therefore, the present study was designed to
      investigate the effect of estrogen on the synaptic and subsynaptic distributions
      of the NMDA receptor subunits, NR2A and NR2B in CA1 pyramidal cells, within the
      context of aging. Our results demonstrated that the overall synaptic levels of
      NR2A and NR2B are similar in young and aged female rats, regardless of estrogen
      treatment. However, in the aged CA1, estrogen restores NR2B levels back to young
      levels in the lateral portions of the active synaptic zone. Thus, estrogen may
      impact the mobility of NMDA receptors across the synapse and, in the process,
      restore a more youthful synaptic profile. These findings have important
      implications for the mechanism of estrogen-induced alterations in NMDA receptor
      mediated processes, particularly in the context of aging.

PMID- 15174085
TI  - Do central terminals of intact myelinated primary afferents sprout into the
      superficial dorsal horn of rat spinal cord after injury to a neighboring
      peripheral nerve?
AB  - In order to investigate whether normal myelinated primary afferent axons sprout
      into the territories of adjacent injured peripheral nerve fibers in the
      superficial dorsal horn of the spinal cord, adult rats underwent either
      sectioning of the saphenous or femoral nerves on one side, or else unilateral
      denervation of the skin of the posterior thigh. Two weeks later cholera toxin B
      subunit (CTb), which is normally transported selectively by myelinated somatic
      primary afferents, was injected into the ipsilateral (intact) sciatic nerve. The
      relationship between CTb, vasoactive intestinal peptide (VIP), and binding of
      Bandeiraea simplicifolia isolectin B4 (IB4) was then examined in the ipsilateral
      dorsal horn of the second to fifth lumbar spinal segments (L2-L5). Sectioning of
      the femoral or saphenous nerves resulted in a reduction of IB4 binding in laminae
      I-II in the medial third of the dorsal horn of L2, L3, and the upper part of L4.
      VIP-immunoreactivity was upregulated in exactly the same regions in which IB4
      binding was reduced. These correspond to the areas that were previously
      innervated by unmyelinated afferents in the sectioned nerves. CTb-labeling was
      detected in regions known to receive input from myelinated sciatic afferents:
      lamina I and a band extending from the inner part of lamina II (IIi) to lamina V
      in the L3-5 segments, and the deepest part of the dorsal horn in L2. Importantly,
      no CTb-labeling was detected in the outer part of lamina II (IIo) in the
      denervated areas. Sectioning of branches of the posterior cutaneous nerve of the
      thigh resulted in a reduction of IB4-binding and upregulation of VIP
      immunoreactivity in the lateral part of the superficial dorsal horn of caudal L4
      and L5. Again, CTb-immunoreactivity showed the normal sciatic pattern in L4-L5,
      with no labeling detected in lamina IIo in the denervated region. These results
      do not support the suggestion that the central terminals of intact myelinated
      afferents sprout into regions of lamina II occupied by adjacent nerves that have
      been axotomized peripherally.

PMID- 15174086
TI  - Differential expression of the mammalian homologue of fasciclin II during
      olfactory development in vivo and in vitro.
AB  - Developing olfactory sensory neurons are guided to the glomeruli of the olfactory
      bulb by an increasingly stringent process that is influenced by expression of
      odorant receptors, cell adhesion molecules (CAMs), and other kinds of signaling
      cascades. A fundamental feature of the projection is the connecting of broad
      zones in the epithelium to broad zones in the bulb, also termed rhinotopy. One
      molecule that parallels and may aid neurons in establishing rhinotopy is the
      mammalian homologue of fasciclin II (OCAM/mamFas II; also known as RNCAM and NCAM
      2), an immunoglobulin superfamily CAM that is differentially expressed in the
      developing and mature olfactory epithelium (OE): Axons elaborated by ventral and
      lateral epithelium express the protein at high levels, whereas dorsomedial axons
      express little or no OCAM/mamFas II. Our investigation has demonstrated that
      OCAM/mamFas II is detectable early in the development of the rat OE. mRNA is
      evident on RT-PCR and in situ hybridization by E12.5, and protein is apparent by
      immunohistochemistry by E13.5. By using a tissue culture system that separates
      ventral septal epithelium (OCAM/mamFas II-positive) from dorsal (OCAM/mamFas II
      negative), we find that explants maintain protein expression levels in vitro that
      are characteristic of the phenotype at the original location in vivo. At least
      some neurons are born in culture, suggesting that any cues that direct
      differential expression are also maintained in vitro. Finally, high OCAM/mamFas
      II expression correlates with increased growth and fasciculation of olfactory
      axons in vitro. These data and the similarity between OCAM/mamFas II, on the one
      hand, and fasciclin II and NCAM, on the other, suggest that OCAM/mamFas II might
      play a role in growth and fasciculation of primary olfactory axons during
      development of the projection.

PMID- 15174087
TI  - Olfactory receptor gene expression in tiger salamander olfactory epithelium.
AB  - Physiological studies of odor-elicited responses from the olfactory epithelium
      and bulb in the tiger salamander, Ambystoma tigrinum, have elucidated a number of
      features of olfactory coding that appear to be conserved across several
      vertebrate species. This animal model has provided an accessible in vivo system
      for observing individual and ensemble olfactory responses to odorant stimulation
      using biochemical, neurophysiological, and behavioral assays. In this paper we
      have complemented these studies by characterizing 35 candidate odorant receptor
      genes. These receptor sequences are similar to those of the large families of
      olfactory receptors found in mammals and fish. In situ hybridization, using RNA
      probes to 20 of these sequences, demonstrates differential distributions of
      labeled cells across the extent and within the depth of the olfactory epithelium.
      The distributions of cells labeled with probes to different receptors show
      spatially restricted patterns that are generally localized to different degrees
      in medial-lateral and anterior-posterior directions. The patterns of receptor
      expression in the ventral olfactory epithelium (OE) are mirrored in the dorsal
      OE. We present a hypothesis as to how the sensory neuron populations expressing
      different receptor types responding to a particular odorant may relate to the
      distribution patterns of epithelial and bulbar responses previously characterized
      using single-unit and voltage-sensitive dye recording methods.

PMID- 15174089
TI  - Role of caspases in the regulation of apoptotic pancreatic islet beta-cells
      death.
AB  - The homeostatic control of beta-cell mass in normal and pathological conditions
      is based on the balance of proliferation, differentiation, and death of the
      insulin-secreting cells. A considerable body of evidence, accumulated during the
      last decade, has emphasized the significance of the disregulation of the
      mechanisms regulating the apoptosis of beta-cells in the sequence of events that
      lead to the development of diabetes. The identification of agents capable of
      interfering with this process needs to be based on a better understanding of the
      beta-cell specific pathways that are activated during apoptosis. The aim of this
      article is fivefold: (1) a review of the evidence for beta-cell apoptosis in Type
      I diabetes, Type II diabetes, and islet transplantation, (2) to review the common
      stimuli and their mechanisms in pancreatic beta-cell apoptosis, (3) to review the
      role of caspases and their activation pathway in beta-cell apoptosis, (4) to
      review the caspase cascade and morphological cellular changes in apoptotic beta
      cells, and (5) to highlight the putative strategies for preventing pancreatic
      beta-cells from apoptosis.

PMID- 15174088
TI  - Hypoxia suppresses runx2 independent of modeled microgravity.
AB  - Bone loss is a consequence of skeletal unloading as seen in bed rest and space
      flight. Unloading decreases oxygenation and osteoblast differentiation/function
      in bone. Previously we demonstrated that simulation of unloading in vitro, by
      culturing differentiating mouse osteoblasts in a horizontal rotating wall vessel
      (RWV), results in suppressed expression of runx2, a master transcriptional
      regulator of osteoblast differentiation. However, the RWV is able to reproduce in
      a controlled fashion at least two aspects of disuse that are directly linked,
      model microgravity and hypoxia. Hypoxia in the RWV is indicated by reduced medium
      oxygen tension and increased expression of GAPDH and VEGF. To uncouple the role
      of model microgravity from hypoxia in suppressed runx2 expression, we cultured
      osteoblasts under modeled microgravity (oxygenated, horizontal RWV rotation),
      hypoxia (vertical RWV rotation), or both conditions (horizontal RWV rotation).
      The expression, DNA binding activity and promoter activity of runx2, was
      suppressed under hypoxic but not normoxic modeled microgravity RWV conditions.
      Consistent with a role for hypoxia in suppression of runx2, direct exposure to
      hypoxia alone is sufficient to suppress runx2 expression in osteoblasts grown in
      standard tissue culture plates. Taken together, our findings indicate that
      hypoxia associated with skeletal unloading could be major suppressor of runx2
      expression leading to suppressed osteoblast differentiation and bone formation.

PMID- 15174090
TI  - Role of RB and RB2/P130 genes in marrow stromal stem cells plasticity.
AB  - Marrow stromal cells (MSCs) are stem-like cells having a striking somatic
      plasticity. In fact, besides differentiating into mesenchymal lineages (bone,
      cartilage, and fat), they are capable of differentiating into neurons and
      astrocytes in vitro and in vivo. The RB and RB2/P130 genes, belonging to the
      retinoblastoma gene family, play a key role in neurogenesis, and for this reason,
      we investigated their role in neural commitment and differentiation of MSCs. In
      MSCs that were either uncommitted or committed toward neural differentiation, we
      ectopically expressed RB and RB2/P130 genes and analyzed their role in regulating
      the cell cycle, apoptosis and differentiation. In uncommitted MSCs, the activity
      of RB and RB2/P130 appeared limited to negatively regulating cell cycle
      progression, having no role in apoptosis and differentiation (toward either
      mesenchymal or neural lineages). On the other hand, in MSCs committed toward the
      neural phenotype, both RB and RB2/P130 reduced cell proliferation rate and
      affected the apoptotic process. RB protected differentiating cells from
      programmed cell death. On the contrary, RB2/P130 increased the percentage of
      cells in apoptosis. All of these activities were accomplished mainly in an HDAC
      independent way. The retinoblastoma genes also influenced differentiation in
      neural committed MSCs. RB2/P130 contributes mainly to the induction of generic
      neural properties, while RB triggers cholinergic differentiation. These
      differentiating activities are HDAC-dependent. Our research shows that there is a
      critical temporal requirement for the RB genes during neuronal differentiation of
      MSCs: they are not required for cell commitment but play a role in the maturation
      process. For the above reasons, RB and RB2/P130 may have a role in neural
      differentiation but not in neural determination.

PMID- 15174091
TI  - PDGF and FGF induce focal adhesion kinase (FAK) phosphorylation at Ser-910:
      dissociation from Tyr-397 phosphorylation and requirement for ERK activation.
AB  - A rapid increase in the tyrosine phosphorylation of focal adhesion kinase (FAK)
      has been extensively documented in cells stimulated by multiple signaling
      molecules, but very little is known about the regulation of FAK phosphorylation
      at serine residues. Stimulation of Swiss 3T3 cells with platelet-derived growth
      factor (PDGF) promoted a striking increase in the phosphorylation of FAK at Ser
      910, as revealed by site-specific antibodies that recognized the phosphorylated
      state of this residue. FAK phosphorylation at Ser-910 could be distinguished from
      that at Tyr-397 in terms of dose-response relationships and kinetics.
      Furthermore, the selective phosphoinositide 3-kinase (PI 3-kinase) inhibitors
      wortmannin and LY 294002 abrogated FAK phosphorylation at Tyr-397 but did not
      interfere with PDGF-induced FAK phosphorylation at Ser-910. Conversely, treatment
      with U0126, a potent inhibitor of MEK-mediated ERK activation, prevented FAK
      phosphorylation at Ser-910 induced by PDGF but did not interfere with PDGF
      induced FAK phosphorylation at Tyr-397. These results were extended using growth
      factors that either stimulate, fibroblast growth factor (FGF), or do not
      stimulate (insulin) the ERK pathway activation in Swiss 3T3 cells. FGF but not
      insulin promoted a striking ERK-dependent phosphorylation of FAK at Ser-910. Our
      results indicate that FAK phosphorylation at Tyr-397 and FAK phosphorylation at
      Ser-910 are induced in response to PDGF stimulation through different signaling
      pathways, namely PI 3-kinase and ERK, respectively.

PMID- 15174092
TI  - Drug-resistant breast carcinoma (MCF-7) cells are paradoxically sensitive to
      apoptosis.
AB  - The purpose of this study was to determine whether expression of tissue
      transglutaminase (TG2) and caspase-3 proteins in drug-resistant breast carcinoma
      MCF-7/DOX cells would render these cells selectively susceptible to apoptotic
      stimuli. Despite high resistance to multidrug resistance (MDR)-related drug,
      doxorubicin (> or =150-fold), the MCF-7/DOX cells were extremely sensitive to
      apoptotic stimuli. Thus, calcium ionophore, A23187 (A23187) and the protein
      kinase C inhibitor staurosporine (STS) each induced rapid and time-dependent
      apoptosis in MCF-7/DOX cells. The apoptosis induced by either agent was
      accompanied by caspase-3 activation and other downstream changes that are typical
      of cells undergoing apoptosis. The alterations upstream of caspase-3 activation,
      however, such as loss in mitochondrial membrane potential (DeltaPsi), release of
      cytochrome c, and activation of caspase-8, and caspase-9, were detected only in
      STS-treated cells. The A12387 failed to induce any of the caspase-3 upstream
      changes, implying that A23187-induced apoptosis may utilize one or more novel
      upstream pathways leading to the activation of caspase 3. In summary, these data
      demonstrate that MCF-7/DOX cells are much more sensitive to apoptotic stimuli
      than previously thought and that A23187-induced apoptosis may involve some novel,
      yet unidentified, upstream pathway that leads to the activation of caspase-3 and
      other downstream events.

PMID- 15174093
TI  - Decreased expression of peroxisome proliferator activated receptor gamma in cftr
      /- mice.
AB  - Some of the pathological manifestations of cystic fibrosis are in accordance with
      an impaired expression and/or activity of PPARgamma. We hypothesized that
      PPARgamma expression is altered in tissues lacking the normal cystic fibrosis
      transmembrane regulator protein (CFTR). PPARgamma mRNA levels were measured in
      colonic mucosa, ileal mucosa, adipose tissue, lung, and liver from wild-type and
      cftr-/- mice by quantitative RT-PCR. PPARgamma expression was decreased twofold
      in CFTR-regulated tissues (colon, ileum, and lung) from cftr-/- mice compared to
      wild-type littermates. In contrast, no differences were found in fat and liver.
      Immunohistochemical analysis of PPARgamma in ileum and colon revealed a
      predominantly nuclear localization in wild-type mucosal epithelial cells while
      tissues from cftr-/- mice showed a more diffuse, lower intensity labeling. A
      significant decrease in PPARgamma expression was confirmed in nuclear extracts of
      colon mucosa by Western blot analysis. In addition, binding of the PPARgamma/RXR
      heterodimer to an oligonucletotide containing a peroxisome proliferator
      responsive element (PPRE) was also decreased in colonic mucosa extracts from cftr
      /- mice. Treatment of cftr-/- mice with the PPARgamma ligand rosiglitazone
      restored both the nuclear localization and binding to DNA, but did not increase
      RNA levels. We conclude that PPARgamma expression in cftr-/- mice is
      downregulated at the RNA and protein levels and its function diminished. These
      changes may be related to the loss of function of CFTR and may be relevant to the
      pathogenesis of metabolic abnormalities associated with cystic fibrosis in
      humans.

PMID- 15174094
TI  - Chimeric molecule IL-6/soluble IL-6 receptor is a potent mitogen for fetal
      hepatocytes.
AB  - A novel recombinant molecule, termed IL-6c and consisting of a chimera of
      interleukin 6 (IL-6) and its soluble receptor is extremely potent in stimulating
      proliferation of hematopoietic progenitors. We investigated the effect of the IL
      6c on the proliferation and differentiation of E14 fetal hepatocytes. IL-6c, in a
      dose-dependent manner, stimulated proliferation of E14 fetal rat hepatocytes.
      Adult hepatocyte mitogens together with IL-6c showed no further effect on
      proliferation. Hematopoietic stem cells mitogens SCF and flt3 ligand (FL) were
      also mitogenic for fetal hepatocytes, but did not further enhance the effect of
      IL-6c on cell proliferation. IL-6c decreased expression of fetal markers alpha
      fetoprotein (AFP) and gamma-glutamyltranspeptidase, and induced expression of
      adult enzyme glucose-6-phosphatase (Gluc-6-P) in E14 hepatocytes. On the other
      hand, IL-6c strongly reduced, in a dose-dependant manner, expression of albumin
      and tyrosine aminotransferase (TAT). However, when the cells were grown for 3
      days with IL-6c, and IL-6c was removed for the next 5 days, expression of albumin
      and TAT returned to levels found in control cultures. In conclusion, IL-6c
      stimulated proliferation and affected gene expression in fetal hepatocytes in
      culture.

PMID- 15174096
TI  - Sensitivity of myofibroblasts to H2O2-mediated apoptosis and their antioxidant
      cell network.
AB  - During wound healing, the transition from granulation to scar tissue shows a
      decrease in myofibroblast cellularity. Previous results have correlated the
      disappearance of these cells with the induction of apoptotic cell death by some
      unknown stimuli. In contrast, hypertrophic scar appearance after wound healing is
      thought to be linked to a disorder of apoptotic function which induces
      myofibroblast persistence in granulation tissue. Oxidative stress being an
      important mediator of apoptosis, we have evaluated the apoptotic response of
      normal and pathological wound myofibroblasts (WMyo and HMyo respectively) in
      their interaction with two oxidative stress inducers: hydrogen peroxide, using a
      high concentration as a single dose, and sodium ascorbate which induced a
      continuous release of H2O2 at a low concentration. Our results showed that,
      according to the H2O2 treatment type, HMyo were more sensitive (after ascorbate
      treatment) or less sensitive (after H2O2 treatment) when compared to WMyo and Fb.
      We next assessed the presence of several molecules known to be involved in the
      antioxidant network protecting cells against H2O2 injury and found HMyo to have a
      higher level of activity of glutathione peroxidase and a lower level of activity
      of catalase than WMyo. These results can help explain the contradictory responses
      of myofibroblasts according to the oxidative stress treatment. This is the first
      study linking refractory oxidative stress mediated cell death to cellular
      phenotype in hypertrophic myofibroblasts, and indicates a pivotal role for the
      antioxidant enzyme system in this type of resistance.

PMID- 15174095
TI  - A low dose of daidzein acts as an ERbeta-selective agonist in trabecular
      osteoblasts of young female piglets.
AB  - The role of estrogens and estrogen-like molecules, including isoflavones, in
      regulating bone cell activities is essential in understanding the etiology and
      treatment of post-menopausal osteoporosis. Although estrogen replacement (HRT)
      has been the main therapy used to prevent and treat osteoporosis, there are
      concerns about its safety. Isoflavones have attracted attention to their
      potential roles in osteoporosis prevention and treatment. We have compared the
      effects of the isoflavone daidzein (1 nM), which has no effect on tyrosine
      kinases, and 17beta-estradiol (1 nM) on the development and function of cultured
      osteoblasts isolated from long bones of young female piglets. Daidzein increased
      ALP activity, osteocalcin secretion, and mineralization, while E2 increased only
      ALP activity. The content of ERbeta and osteoprotegerin secretion by control
      cells gradually increased during osteoblast differentiation, whereas the ERalpha
      and RANK-L content decreased. Daidzein enhanced only the nuclear ERbeta whereas
      estradiol increased both ERalpha and ERbeta. Daidzein and estradiol increased
      osteoprotegerin and RANK-L secretion. Daidzein had a more pronounced effect than
      did estradiol. Daidzein and estradiol increased the membrane content of RANK-L
      and the nuclear content of runx2/Cbfa1. Daidzein enhanced the nuclear content of
      progesterone and vitamin D receptors but not as much as did estradiol. All the
      effects of daidzein were blocked by ICI 182,780. We conclude that a low
      concentration of daidzein may exert its anti-resorptive action by increasing the
      activity of porcine mature osteoblasts via ERbeta, by regulating runx2/Cbfa1
      production, and by stimulating the secretion of key proteins involved in
      osteoclastogenesis, such as osteoprotegerin and RANK-ligand.

PMID- 15174097
TI  - Targeting of HLA-DR molecules transduces agonistic functional signals in
      cutaneous melanoma.
AB  - The role of human leukocyte antigens (HLA) class II molecules in transducing
      intracellular signals in immune cells is well established. Solid tumors of
      different histotype can also express HLA class II antigens; however, their
      intracellular signaling ability is essentially unknown. Due to the frequent
      expression of HLA class II molecules in primary and metastatic lesions, cutaneous
      melanoma was utilized to investigate whether the engagement of HLA-DR molecules
      transduces functional intracellular signal(s). Triggering of HLA-DR molecules by
      the anti-HLA-DR monoclonal antibody (mAb) L243 induced a significant (P < 0.05)
      and dose-dependent growth-inhibition of metastatic melanoma cells Mel 120, as
      well as their homotypic aggregation. Furthermore, an increase in tyrosine
      phosphorylation of multiple cellular proteins with a molecular weight ranging
      from 66 to 130 kD, including p125 focal adhesion kinase, was observed. Lastly,
      the engagement of HLA-DR molecules by mAb L243 inhibited activator protein-1-DNA
      binding. Thus, HLA-DR molecules expressed on melanoma cells can transduce
      functional intracellular signals. This finding is consistent with evidences
      obtained in hematological malignancies, and suggests the potential usefulness of
      HLA-DR molecules to set-up new approaches of targeted therapy in metastatic
      melanoma.

PMID- 15174098
TI  - Vinculin, VASP, and profilin are coordinately regulated during actin remodeling
      in epithelial cells, which requires de novo protein synthesis and protein kinase
      signal transduction pathways.
AB  - Transformation progression of epithelial cells involves alterations in their
      morphology, polarity, and adhesive characteristics, all of which are associated
      with the loss and/or reorganization of actin structures. To identify the
      underlying mechanism of formation of the adhesion-dependent, circumferential
      actin network, the expression and localization of the actin binding and
      regulating proteins (ABPs), vinculin, VASP, and profilin were evaluated.
      Experimental depolarization of epithelial cells results in the loss of normal F
      actin structures and the transient upregulation of vinculin, VASP, and profilin.
      This response is due to the loss of cell-cell, and not cell-substrate
      interactions, since cells that no longer express focal adhesions or stress fibers
      are still sensitive to changes in adhesion and manifest this in the altered
      profile of expression of these ABPs. Transient upregulation is dependent upon de
      novo protein synthesis, and protein kinase-, but not phosphatase-sensitive signal
      transduction pathway(s). Inhibition of the synthesis of these proteins is
      accompanied by dephosphorylation of the ribosomal S6 protein, but does not
      involve inhibition of the PI3-kinase-Akt-mTOR pathway. Constitutive expression of
      VASP results in altered cell morphology and adhesion and F-actin and vinculin
      structures. V12rac1 expressing epithelial cells are constitutively nonadhesive,
      malignantly transformed, and constitutively express high levels of these ABPs,
      with altered subcellular localizations. Transformation suppression is accompanied
      by the restoration of normal levels of the three ABPs, actin structures,
      adhesion, and epithelial morphology. Thus, vinculin, VASP, and profilin are
      coordinately regulated by signal transduction pathways that effect a
      translational response. Additionally, their expression profile maybe indicative
      of the adhesion and transformation status of epithelial cells.

PMID- 15174099
TI  - Expression of phospholipase C beta family isoenzymes in C2C12 myoblasts during
      terminal differentiation.
AB  - In the present work, we have analyzed the expression and subcellular localization
      of all the members of inositide-specific phospholipase C (PLCbeta) family in
      muscle differentiation, given that nuclear PLCbeta1 has been shown to be related
      to the differentiative process. Cell cultures of C2C12 myoblasts were induced to
      differentiate towards the phenotype of myotubes, which are also indicated as
      differentiated C2C12 cells. By means of immunochemical and immunocytochemical
      analysis, the expression and subcellular localization of PLCbeta1, beta2, beta3,
      beta4 have been assessed. As further characterization, we investigated the
      localization of PLCbeta isoenzymes in C2C12 cells by fusing their cDNA to
      enhanced green fluorescent protein (GFP). In myoblast culture, PLCbeta4 was the
      most expressed isoform in the cytoplasm, whereas PLCbeta1 and beta3 exhibited a
      lesser expression in this cell compartment. In nuclei of differentiated myotube
      culture, PLCbeta1 isoform was expressed at the highest extent. A marked decrease
      of PLCbeta4 expression in the cytoplasm of differentiated C2C12 cells was
      detected as compared to myoblasts. No relevant differences were evidenced as
      regards the expression of PLCbeta3 at both cytoplasmatic and nuclear level,
      whilst PLCbeta2 expression was almost undetectable. Therefore, we propose that
      the different subcellular expression of these PLC isoforms, namely the increase
      of nuclear PLCbeta1 and the decrease of cytoplasmatic PLCbeta4, during the
      establishment of myotube differentiation, is related to a spatial-temporal
      signaling event, involved in myogenic differentiation. Once again the subcellular
      localization appears to be a key step for the diverse signaling activity of
      PLCbetas.

PMID- 15174100
TI  - PAI-1 expression is required for epithelial cell migration in two distinct phases
      of in vitro wound repair.
AB  - Several proteases and their specific inhibitors modulate the interdependent
      processes of cell migration and matrix proteolysis as part of the global program
      of trauma repair. Expression of plasminogen activator inhibitor type-1 (PAI-1), a
      serine protease inhibitor (SERPIN) important in the control of barrier
      proteolysis and cell-to-matrix adhesion, for example, is spatially-temporally
      regulated following epithelial denudation injury in vitro as well as in vivo. PAI
      1 mRNA/protein synthesis was induced early after epidermal monolayer scraping and
      restricted to keratinocytes comprising the motile cohort closely recapitulating,
      thereby, similar events during cutaneous healing. The time course of PAI-1
      promoter-driven PAI-1-GFP fusion "reporter" expression in wound-juxtaposed cells
      approximated that of the endogenous PAI-1 gene confirming the location
      specificity of gene regulation in this model. ERK activation was evident within 5
      min after injury and particularly prominent in cells residing at the scrape-edge
      (suggesting a possible role in PAI-1 induction and/or the motile response) as was
      myosin light chain (MLC) phosphorylation. Indeed, MEK blockade with PD98059 or
      U0126 attenuated keratinocyte migration (by > or =60%), as did transient
      transfection of a dominant-negative ERK1 construct (40% decrease in monolayer
      repair), and completely inhibited PAI-1 transcript expression. Anti-sense down
      regulation of PAI-1 synthesis (by 80-85%), or addition of PAI-1 neutralizing
      antibodies also inhibited injury site closure over a 24 h period establishing
      that PAI-1 was required for efficient long-term planar motility in this system.
      PAI-1 anti-sense transfection or actinomycin D transcriptional blockade, in
      contrast, did not affect the initial migratory response suggesting that residual
      PAI-1 protein levels (at least in transfectant cells and actinomycin D-treated
      cultures) may be sufficient to support early cell movement. Pharmacologic
      inhibition of keratinocyte MEK signaling effectively ablated scrape-induced PAI-1
      mRNA expression but failed to attenuate wound-associated increases in cellular
      PAI-1 protein levels soon after monolayer injury. Collectively, these data
      suggest that basal PAI-1 transcripts may be mobilized for initial PAI-1 synthesis
      and, perhaps, the early motile response while maintenance of the normal rate of
      migration requires the prolonged PAI-1 expression that typically accompanies the
      repair response. To assess this possibility, scrape site closure studies were
      designed using keratinocytes isolated from PAI-1-/- mice. PAI-1-/- keratinocytes,
      in fact, had a significant wound healing defect evident even within the first 6 h
      following monolayer denudation injury. Addition of active PAI-1 protein to PAI-/-
      keratinocytes rescued the migratory phenotype that that approximating wild-type
      cells. These findings validate use of the present keratinocyte model to
      investigate injury-related controls on PAI-1 gene regulation and, collectively,
      implicate participation of PAI-1 in two distinct phases of epidermal wound
      repair.

PMID- 15174101
TI  - Significance of N-methyl-D-aspartate (NMDA) receptor-mediated signaling in human
      keratinocytes.
AB  - Increasing data suggest that glutamate might act as a cell-signaling molecule in
      non-neuronal tissues such as the skin. Here we demonstrate the presence of
      functional N-methyl-D-aspartate (NMDA)-type glutamate receptors in human
      keratinocytes. NMDA receptor expression strongly reflects the degree of cell-to
      cell contact. Wounding polarizes the expression of NMDA receptors in
      keratinocytes involved in re-epithelialization, and the process of re
      epithelialization is inhibited by NMDA receptor activation. We also demonstrate
      that squamous cell carcinomas lack NMDA receptors. Our data suggest that Ca2+
      entry through NMDA receptors influences the cycle of keratinocyte proliferation,
      differentiation, and migration during epithelialization. Moreover, NMDA receptor
      activation might play a role in contact-mediated inhibition of growth, a process
      that is absent during neoplastic pathology. This receptor may serve as a
      pharmacological target for modulating keratinocyte behavior and treating
      cutaneous disorders.

PMID- 15174102
TI  - Decreased expression of beta1-integrin and focal adhesion kinase in epithelial
      cells may initiate involution of mammary glands.
AB  - The mechanisms regulating involution of mammary glands after weaning are not
      clear, but engorgement with milk is a key trigger. Many cell types require to be
      anchored to an extracellular matrix (ECM) as a prerequisite for survival and this
      is achieved via intregrins binding to specific motifs and signalling their
      attachment, intracellularly, via focal adhesion kinase (FAK). We sought to
      determine firstly, if expression of beta1-integrin and FAK is reduced during the
      first stage of involution. Expression of beta1-integrin and FAK was significantly
      reduced at 6 h after sealing teats and this was accompanied with a decreased
      abundance of cytochrome C in mitochondria. Secondly, we sought to determine if
      expression of beta1-integrin and FAK was restored during the first, partially
      reversible stage of involution (at 24 h), but not during the second irreversible
      stage, which occurs after 72 h. Re-suckling restored full expression of the 80
      kDa fragment of FAK, but not of the 125 kDa protein or beta1-integrin at 24 h
      after weaning. Re-suckling did not restore expression of either peptide after 72
      h. Changes in expression of cytochrome C and pro-caspase-3 (apoptotic markers)
      were similar to that of the 80 kDa fragment of FAK. These data suggest that
      epithelial cells can restore partial contact with their basement membrane during
      the first, reversible stage, but not during the second irreversible stage of
      involution. We speculate that decreased contact between epithelial cells and
      their basement membrane initiates apoptosis in mammary glands at weaning. This
      process begins within 6 h of pup withdrawal.

PMID- 15174103
TI  - Opinions and trends in biomaterials education: report of a 2003 Society for
      Biomaterials survey.
AB  - The Society for Biomaterials (SFB) aims to serve its members through acting as a
      forum for the exchange of information and ideas. To aid in the practical
      development of the SFB and more specifically biomaterials education, all active,
      associate, and student members were surveyed. In general, the survey asked
      questions regarding respondent demographics, experiences and activities with the
      SFB, and opinions about biomaterials education. Perceptions and needs of
      biomaterials-related education and career-related training practices were a
      specific focus of the survey. A total of 140 individuals responded to the survey
      for a response rate of 18%. Members from industry felt that new hires, in
      general, should be better trained in product development, regulatory issues for
      new materials and devices, and in the relevant testing required. When asked what
      was missing from their professional education, many respondents commented that
      business training in areas such as negotiations, management, and understanding
      the needs outside of academia was lacking. Also, many respondents seemed to have
      trouble identifying with what they were supposed to know and felt a "lack of set
      professional knowledge." This study has raised many ideas and questions that
      require further discussion. The results should ultimately be useful for helping
      the SFB decide how best to focus future efforts in biomaterials education.

PMID- 15174104
TI  - Enhancing the biological activity of immobilized osteopontin using a type-1
      collagen affinity coating.
AB  - The covalent attachment of biomolecules onto surfaces represents a step toward
      the improvement of biomaterial properties by providing relevant biological
      signals of interest to the cell culture or tissue environment. The chemistries
      involved, however, often attach proteins to the surface in a random fashion,
      rather than the conformation or orientation most easily recognized by cells and
      other proteins both in vitro and in vivo. An alternative approach is to take
      advantage of natural interactions to both bind and orient a biomolecule
      "naturally," thereby enhancing its biological activity. Type 1 collagen has been
      shown to bind to osteopontin (OPN), a protein implicated in processes such as
      wound healing, endothelial cell survival, and angiogenesis. This study seeks to
      characterize, quantify, and exploit this interaction in order to present a more
      naturally recognized form of OPN to the environment surrounding a biomaterial.
      Binding of OPN to type 1 collagen was confirmed using Surface Plasmon Resonance
      (SPR). Radio-iodination of OPN showed that binding to collagen was dose-dependent
      and maximal in basic conditions. Principal component analysis of Time-of-Flight
      Secondary Ion Mass Spectrometry (ToF-SIMS) data identified differences in OPN
      immobilized via different techniques. Adhesion of bovine aortic endothelial cells
      on OPN immobilized using the affinity coating was also significantly enhanced
      compared to controls. Investigation into the in vivo relevance of this
      immobilization method is currently underway.

PMID- 15174105
TI  - Thermal residual stresses near the interface between plasma-sprayed
      hydroxyapatite coating and titanium substrate: finite element analysis and
      synchrotron radiation measurements.
AB  - Plasma-sprayed hydroxyapatite (HA) coatings on titanium alloy are often used in
      prosthetic implants. The metallic substrate gives the implant good mechanical
      strength which is combined with good biocompatibility and osteointegration of the
      ceramic coating. However, the interface between the HA coating and titanium alloy
      substrate is an area of critical weakness when compared with the interlamellar
      cohesive strength of the HA coating structure. Knowledge of the stresses in
      materials near the interface seems to be an important step in understanding why
      failure occurs. Synchrotron radiation, using Beamline BM16 at the European
      Synchrotron Radiation Facility (Grenoble, France), has been used to determine
      local stresses near the interface, down to 10 microm in resolution, between a
      plasma-sprayed HA coating and a titanium alloy substrate. This experimental
      determination of residual stresses is compared with the results found by a finite
      element analysis modeling the thermal effects of the plasma-spraying process.
      Residual stresses have been found in deposited ceramic near the interface due to
      a thermal properties mismatch of the materials. If the plane stress state is
      assumed, meaning the perpendicular component of residual stress is ignored
      (sigma(z) = 0), then the synchrotron residual stress measurements should be
      interpreted as mainly compressive in the ceramic coating. This is in
      contradiction with the coefficient of thermal expansion mismatch; therefore, the
      simplified plane stresses assumption seems to be inappropriate for the deposited
      morphology characterized by pores and a network of microcracks. The detailed
      finite element analysis model, taking into account the real morphology of the
      coating and the real three-dimensional stress field distribution, allowed the
      estimation of sigma(z), leading to a more accurate interpretation of synchrotron
      measurements, which is validated by the experimental results.

PMID- 15174106
TI  - In vivo evaluation of a novel electrically conductive polypyrrole/poly(D,L
      lactide) composite and polypyrrole-coated poly(D,L-lactide-co-glycolide)
      membranes.
AB  - This study evaluated the in vivo biocompatibility and biodegradation behavior of
      a novel polypyrrole (PPy)/poly(D,L-lactide) (PDLLA) composite and PPy-coated
      poly(D,L-lactide-co-glycolide) membranes. Test membranes were implanted
      subcutaneously in rats for 3-120 days. The biocompatibility was assessed by
      quantifying the alkaline and acid phosphatase secretion, the immunohistochemical
      staining of the ED-2-positive macrophages, and the histology at the
      tissue/material interface. The degradation was investigated using scanning
      electron microscopy. Pure PDLLA and poly(D,L-lactide-co-glycolide) membranes were
      used as references, whereas expanded polytetrafluoroethylene and a commercial
      styrene-butadiene rubber were used as controls. The enzyme activity of the PPy
      containing specimens was shown to be similar to that of the references. The
      histological findings were consistent with the enzymatic results, showing a mild
      to-moderate acute inflammation followed by a resolution of the inflammatory
      response with a decrease in inflammatory cells for each biodegradable membrane.
      The tissue reactions to the PPy, which was either in the form of nanoparticles or
      surface coating, were comparable to the response to the neighboring biodegradable
      materials. Elevated ED-2-positive macrophage populations appeared as early as day
      3 in the loose connective tissue surrounding the implants. The density of these
      populations was related to the degree of inflammation. Scanning electron
      microscopy showed that the degradation of the PPy/PDLLA composite was not
      affected by the presence of PPy.

PMID- 15174107
TI  - Impact of collagen structure on matrix trafficking by human fibroblasts.
AB  - Biodegradation of collagen biomaterial matrices and the deposition of new
      collagen extracellular matrix (ECM) are critical to the integration of in vitro
      bioengineered materials and tissues in vivo. In previous studies, we observed
      significant impact of collagen matrix structure on primary lung fibroblast
      behavior in vitro. In the present work, to begin to understand the mechanistic
      basis for our previous observation, the response of human fibroblasts (IMR-90) to
      the structural state of collagen matrices was studied with respect to cell
      proliferation, cell morphology, beta-galactosidase level, and transcript content
      for collagen (Col-1), matrix metalloproteinases (MMP-1, MMP-2), tissue inhibitors
      of matrix metalloproteinase (TIMP-1 and TIMP-2). Collagen digestion was assessed
      quantitatively by uptake of collagen-coated fluorescent beads incorporated in the
      preformed collagen matrix. Transcript levels related to the deposition of new ECM
      proteins varied as a function of the structure of the collagen matrix presented
      to the cells. Col-1 expression was 2-fold higher and expression for MMP-1, MMP-2,
      TIMP-1, and TIMP-2 increased for cells when grown on 156 microg/cm2 denatured
      collagen compared with cells grown on tissue culture (TC) plastic. On 156
      microg/cm2 nondenatured (native) collagen, Col-1 expression was decreased by half
      and MMP-2 was increased by 2.5-fold compared with cells grown on TC plastic. On
      78 microg/cm2 denatured collagen, Col-1 expression was 80% whereas the MMPs and
      TIMPs were increased by 1.25- to 2-fold compared with cells grown on TC plastic.
      On 78 microg/cm2 nondenatured collagen expression of all 5 transcripts was
      reduced 60-90% of the levels determined for the cells grown on TC plastic. Cell
      viability, based on cell morphology and beta-galactosidase activity, was improved
      on the denatured collagen. A higher level of collagen matrix incorporation was
      observed for cells grown on denatured collagen than on nondenatured collagen or
      TC plastic. These data suggest that tissue engineering matrices incorporating
      denatured collagen may promote more active remodeling toward new ECM in
      comparison to cells grown on nondenatured collagen or cells grown on TC plastic.

PMID- 15174108
TI  - Polyethylene glycol-grafted polystyrene particles.
AB  - Densely pegylated particles that can serve as a model system for artificial cells
      were prepared by covalently grafting amino polyethylene glycol (PEG, molecular
      weight 3400 or 5000) onto carboxyl polystyrene particles (PS-COOH) using
      carbodiimide chemistry. PEG-modified particles (PS-PEG) were characterized by
      determination of the PEG surface concentration, zeta-potential, size, and
      morphology. Under optimized grafting conditions, a dense "brush-like" PEG layer
      was formed. A PEG surface concentration of approximately 60 pmol/cm2,
      corresponding with an average distance between grafted PEG chains of
      approximately 17 A can be realized. It was shown that grafting of PEG onto PS
      COOH reduced the adsorption of proteins from human plasma (85 vol %) in phosphate
      buffered saline up to 90%.

PMID- 15174109
TI  - Electrochemical behavior of different preparations of plasma-sprayed
      hydroxyapatite coatings on Ti6Al4V substrate.
AB  - The corrosion behavior of four different preparations of plasma-sprayed
      hydroxyapatite (HA) coatings on Ti6Al4V substrates in static Hank's balanced salt
      solution was investigated using dc potentiodynamic and ac impedance techniques.
      Two different nominal thicknesses, 50 microm and 200 microm, and two different
      spraying conditions, were considered. The electrochemical impedance experiments
      proved this technique to be very suitable for the investigation of the
      electrochemical behavior of surgical implant alloys when they are coated with HA,
      which is characterized by the dissolution and passivation characteristics of the
      underlying metal substrate. Because the coatings are porous, ionic paths between
      the electrolytic medium and the base material can eventually be produced,
      resulting in the corrosion of the coated metal. Differences in the corrosion
      resistance of the coated materials were detected, and a relevant model for the
      description of the coating degradation in the biosimulating solution was
      proposed. The model consisted of the description of the coated system in terms of
      a two-layer model of the surface film. Significant differences in electrochemical
      behavior for similar nominal thicknesses of HA coatings obtained under different
      spraying conditions were found.

PMID- 15174110
TI  - A low-temperature biomimetic calcium phosphate surface enhances early implant
      fixation in a rat model.
AB  - The present study demonstrates increased early mechanical fixation of titanium
      implants coated with a new biomimetic apatite surface in a rat model. Male
      Sprague-Dawley rats received unilateral femoral medullary implants for periods of
      1-4 weeks. The strength of fixation of the implant to the host bone increased
      more rapidly in the group receiving apatite-treated implants compared with the
      control group as evidenced by the apatite group's 21-fold greater fixation
      strength at 1 week (p = 0.009), 4-fold greater fixation strength at 2 weeks (p =
      0.041), and 2-fold greater fixation strength at 4 weeks (p = 0.093) compared with
      the control. Fixation strength was correlated with bone-implant contact as
      determined from micro computed tomography assessment of the specimens (r2 =
      0.338, p = 0.011 in the control group and r2 = 0.543, p < 0.001 in the apatite
      group). Furthermore, for a given amount of bone-implant contact, the fixation
      strength was higher in the apatite group than in the control group (p = 0.011),
      suggesting that the bone formed a stronger bond to the apatite coating than to
      the titanium. This difference in bonding strength accounted for the difference in
      mechanical behavior.

PMID- 15174111
TI  - Development of photocrosslinkable hyaluronic acid-polyethylene glycol-peptide
      composite hydrogels for soft tissue engineering.
AB  - Hyaluronic acid (HA; also called hyaluronan) is a naturally derived,
      nonimmunogenic, nonadhesive glycosaminoglycan that has important roles in several
      wound-healing processes. In previous work, we created photocrosslinkable glycidyl
      methacrylate-HA (GMHA) hydrogel biomaterials that were cytocompatible,
      biologically active, and had a decreased rate of hyaluronidase degradation
      compared with native HA. The goal of the studies presented herein was to explore
      peptide conjugation techniques to further adjust the material and biological
      properties of the GMHA hydrogels. We conjugated GMHA with acrylated forms of
      polyethylene glycol (PEG) and PEG-peptides to yield GMHA-PEG-peptide composite
      hydrogels. By varying the reactant concentrations, we created stable hydrogels
      with high peptide conjugation efficiencies (up to 80%), controllable peptide
      concentrations (in the range of 1-6 micromol peptide per milliliter of hydrogel),
      and defined physicochemical properties (e.g., swelling ratio, enzymatic
      degradation rate). These composite hydrogels may prove to be a promising
      scaffolding biomaterial for a variety of soft tissue engineering applications.

PMID- 15174112
TI  - Viscoelastic characterizations of acellular dermal matrix (ADM) preparations for
      use as injectable implants.
AB  - Viscoelastic characteristics of acellular dermal matrix (ADM) preparations with
      various additives were analyzed with creep curves, stress-strain relationships,
      and the storage modulus with reference to those of ADM preparations crosslinked
      with glutaraldehyde. Creep curves for all ADM preparations were determined to
      comply with the Kelvin-Voigt model. The stress-strain plots of all ADM
      preparations compared were described as linear. The storage modulus of all ADM
      preparations was maintained at a nearly constant level throughout the range of
      oscillating frequencies applied. ADM preparations crosslinked with glutaraldehyde
      showed that both Young's modulus (E) for the spring part and retardation time
      (tau) in the Kelvin-Voigt model, and hence viscosity (eta) for the liquid part,
      increased with an increasing concentration of glutaraldehyde. Higher Young's
      modulus and viscosity and a greater extent of the "solid" response of ADM
      preparations crosslinked with glutaraldehyde might have been responsible for the
      longer persistence that was demonstrated after implantation. The increase in ADM
      concentration and the addition of various additives to ADM preparations,
      including alpha-hydroxy acid (citric acid, lactic acid, and glycolic acid) and
      hyaluronic acid, resulted in similar effects on the viscoelastic characteristics
      of the ADM preparations, but they were less efficacious than those crosslinked
      with glutaraldehyde. Among them, increasing ADM concentration to >200 mg/mL and
      addition of glycolic acid at a concentration of >2% improved the viscoelastic
      characteristics of the resulting ADM preparations so that their level of
      persistence was closer to that of material crosslinked with glutaraldehyde. On
      the contrary, the influence on viscoelastic characteristics of adding PVP greatly
      differed from that of hyaluronic acid and was only apparent when adding
      concentrations of PVP of >10%. Similarly, viscoelastic characteristics of the ADM
      preparations examined were also so sensitive to temperature that the persistence
      of ADM preparations after implantation at body temperature would deteriorate.

PMID- 15174113
TI  - Pegylated polystyrene particles as a model system for artificial cells.
AB  - Pegylated polystyrene particles (PS-PEG) were prepared as a model system for
      artificial cells, by modification of carboxyl polystyrene particles (PS-COOH)
      with homo- and hetero-bifunctional polyethylene glycols (PEG, MW 1500, 3400, and
      5000) containing an amino end group for immobilization and an amino, hydroxyl, or
      methoxy end group that is exposed at the surface after immobilization. Protein
      adsorption from human plasma dilutions (85 v %) onto PS-PEG with a PEG surface
      concentration higher than 40 pmol/cm2 was reduced up to 90-95% compared with
      protein adsorption onto PS-COOH with a final protein surface concentration of
      approximately 30 ng/cm2. Two-dimensional gel electrophoresis analyses showed that
      30% of the total amount of adsorbed proteins onto PS-PEG are dysopsonins (i.e.,
      nonadhesive proteins like albumin and apolipoproteins). For PS-COOH, <15% of the
      amount of adsorbed proteins are dysopsonins. In addition, the generation of
      terminal complement compound (TCC) by PS-PEG particles with a PEG surface
      concentration lower than approximately 55 pmol/cm2 is not significant. The low
      protein adsorption, the relatively high percentage of adsorbed dysopsonins, and
      the low level of complement activation may prevent the uptake of PS-PEG by the
      mononuclear phagocytic system (MPS) in vivo. Moreover, PS-PEG (PEG surface
      concentration > approximately 35 pmol/cm2) shows minimal interaction with
      cultured human umbilical vein endothelial cells (HUVEC), which mimics the
      endothelial lining of the blood vessel wall.

PMID- 15174114
TI  - Hemocompatibility of nitrogen-doped, hydrogen-free diamond-like carbon prepared
      by nitrogen plasma immersion ion implantation-deposition.
AB  - Amorphous hydrogenated carbon (a-C:H) has been shown to be a potential material
      in biomedical devices such as artificial heart valves, bone implants, and so on
      because of its chemical inertness, low coefficient of friction, high wear
      resistance, and good biocompatibility. However, the biomedical characteristics
      such as blood compatibility of doped hydrogen-free diamond-like carbon (DLC) have
      not been investigated in details. We recently began to investigate the potential
      use of nitrogen-doped, hydrogen-free DLC in artificial heart valves. In our
      experiments, a series of hydrogen-free DLC films doped with nitrogen were
      synthesized by plasma immersion ion implantation-deposition (PIII-D) utilizing a
      pulsed vacuum arc plasma source and different N to Ar (FN/FAr) gas mixtures in
      the plasma chamber. The structures and properties of the film were evaluated by
      Raman spectroscopy, Rutherford backscattering spectrometry (RBS), and X-ray
      photoelectron spectroscopy (XPS). To assess the blood compatibility of the films
      and the impact on the blood compatibility by the presence of nitrogen, platelet
      adhesion tests were conducted. Our results indicate that the blood compatibility
      of both hydrogen-free carbon films (a-C) and amorphous carbon nitride films are
      better than that of low-temperature isotropic pyrolytic carbon (LTIC). The
      experimental results are consistent with the relative theory of interfacial
      energy and surface tension including both dispersion and polar components. Our
      results also indicate that an optimal fraction of sp2 bonding is desirable, but
      an excessively high nitrogen concentration degrades the properties to an extent
      that the biocompatibility can be worse than that of LTIC.

PMID- 15174115
TI  - Prolonged ectopic calcification induced by BMP-2-derived synthetic peptide.
AB  - Bone morphogenetic protein-2 (BMP-2) promotes the formation and regeneration of
      bone and cartilage, and therefore constitutes the most promising candidate for a
      bone repair material. However, it also has a wide range of functions, such as in
      organogenesis and apoptosis. Therefore, we investigated a novel synthetic peptide
      corresponding to residues 73-92 of BMP-2. This peptide bound to a BMP-2-specific
      receptor and elevated both alkaline phosphatase activity and osteocalcin mRNA in
      the murine cell line, C3H10T1/2. The 73-92 peptide also induced ectopic
      calcification when conjugated to a covalently crosslinked alginate gel. Here we
      report that the 73-92 peptide-conjugated alginate gel showed prolonged ectopic
      calcification for up to 7 weeks in rat calf muscle. In contrast, rhBMP-2
      impregnated collagen gel showed maximum ectopic calcification at 3 weeks, and the
      calcified products that had formed disappeared after 5 weeks. Histological
      examination showed that the 73-92 peptide-conjugated alginate gel induced many
      osteoblast-like cells and few osteoclasts. In contrast, rhBMP-2-impregnated
      collagen gel induced many osteoclasts. These results suggest that the 73-92
      peptide on alginate gel remains active at the implanted site, continuously
      induces differentiation of osteoblast precursor cells into osteoblasts, and
      activates osteoblasts to promote ectopic calcification.

PMID- 15174116
TI  - Differential expression of osteogenic factors associated with osteoinductivity of
      human osteosarcoma cell lines.
AB  - Differential expression of multiple osteogenic factors may be responsible for the
      different osteoinductivity of osteosarcoma cell lines. We compared in vivo
      osteoinductivity of human osteosarcoma cell lines (Saos-2 vs. U-2 OS) in nude
      mice, and their in vitro expression of various osteogenic factors of protein
      level by quantitative immunocytochemistry and mRNA level by RT-PCR and/or in situ
      hybridization. Saos-2 cells, but not U-2 OS, were osteoinductive in vivo.
      Significantly higher expression (independent t-test, all p < 0.005) of osteogenic
      factors were observed in Saos-2 cells compared with U-2 OS, which included bone
      morphogenetic proteins (particularly BMPs-2, 3, 4, and 7), transforming growth
      factor-beta (TGF-beta), BMP receptor (BMPR)-1A, receptor-regulated Smads (R
      Smads), Smads 1, 2, and 5, and common-mediator Smad (Co-Smad), Smad 4. In
      contrast, U-2 OS cells expressed higher levels of inhibitory Smad 6 (I-Smad)
      protein than Saos-2 cells (p < 0.001). These results suggest that a combination
      of osteogenic factors (BMPs, TGF-beta, BMPRs, and R/Co-Smads) against I-Smad may
      play important roles in the Saos-2 cell osteoinductivity. This may have a
      clinical implication in selecting key osteogenic factors for combined therapy for
      bone defect diseases. The characterized cell lines can be used as positive and
      negative controls for the assessments of both in vitro and in vivo bone formation
      capabilities of designed tissues or biomaterials.

PMID- 15174117
TI  - Nanometer surface roughness increases select osteoblast adhesion on carbon
      nanofiber compacts.
AB  - Carbon nanofibers have exceptional theoretical mechanical properties (such as low
      weight-to-strength ratios) that, along with possessing nanoscale fiber dimensions
      similar to crystalline hydroxyapatite found in bone, suggest strong possibilities
      for use as an orthopedic/dental implant material. To determine, for the first
      time, cytocompatibility properties pertinent for bone prosthetic applications,
      osteoblast (bone-forming cells), fibroblast (cells contributing to callus
      formation and fibrous encapsulation events that result in implant loosening),
      chondrocyte (cartilage-forming cells), and smooth muscle cell (for comparison
      purposes) adhesion were determined on carbon nanofibers in the present in vitro
      study. Results provided evidence that, compared to conventional carbon fibers,
      nanometer dimension carbon fibers promoted select osteoblast adhesion. Moreover,
      adhesion of other cells was not influenced by carbon fiber dimensions. In fact,
      smooth muscle cell, fibroblast, and chondrocyte adhesion decreased with an
      increase in either carbon nanofiber surface energy or simultaneous change in
      carbon nanofiber chemistry. To determine properties that selectively enhanced
      osteoblast adhesion, similar cell adhesion assays were performed on polymer
      (specifically, poly-lactic-co-glycolic; PLGA) casts of carbon fiber compacts
      previously tested. Compared to PLGA casts of conventional carbon fibers, results
      provided the first evidence of enhanced select osteoblast adhesion on PLGA casts
      of nanophase carbon fibers. The summation of these results demonstrate that due
      to a high degree of nanometer surface roughness, carbon fibers with nanometer
      dimensions may be optimal materials to selectively increase osteoblast adhesion
      necessary for successful orthopedic/dental implant applications.

PMID- 15174118
TI  - PLA and PLGA microspheres of beta-galactosidase: Effect of formulation factors on
      protein antigenicity and immunogenicity.
AB  - The entrapment of beta-galactosidase (Escherichia coli) in PLA and PLGA
      microspheres using a double emulsion technique resulted to significant reduction
      of protein antigenicity. The extent of antigenicity loss depended on the
      conditions of microsphere preparation. Most of antigenicity loss occurred on the
      first emulsification step. Only the effects of microsphere preparation factors
      having an important influence on protein antigenicity, such as the type of
      organic phase (polymer solvent) and homogenization, could be predicted (on a
      qualitative basis) by antigenicity data obtained after the first emulsification
      step. The type of polymer and polymer solvent used to prepare the microspheres
      affected beta-galactosidase immunogenicity. The PLA microspheres prepared using
      ethyl acetate was the most immunogenic microsphere formulation, eliciting similar
      total antibody responses as the alum formulation of beta-gal. This formulation
      was the only microsphere formulation that induced an IgG1/IgG2a ratio lower than
      1, indicating an immune response biased towards a Th1 type. The results obtained
      indicate that large protein molecules with complex tertiary structure such as
      beta-galactosidase can be entrapped in PLA and PLGA microspheres with retention
      of protein immunogenic potential, providing that appropriate conditions of
      microsphere preparation are applied, and that the formulation of microspheres
      might influence the Th1/Th2 type of immune response against the encapsulated
      antigen.

PMID- 15174119
TI  - Influence of additive hyaluronic acid on the lubricating ability in the
      temporomandibular joint.
AB  - In synovial fluid, hyaluronic acid (HA) is an essential component for the
      lubrication of joints, thus preventing friction. The relationship between HA and
      joint friction is not unambiguously established yet. In the present study, the
      effect of the application of HA on the frictional coefficient in the
      temporomandibular joint was evaluated. After measuring the frictional coefficient
      in intact porcine joints (n = 10), the subsequent effect of phosphate-buffered
      saline (PBS) washing and gauze scouring and the application of HA was examined.
      Compared with the intact joint, the frictional coefficient was significantly
      larger after PBS washing and gauze scouring. Subsequent application of HA
      resulted in a significant decrease (50-75%) of the frictional coefficient.
      However, it did not recover to the same value as in the intact joints.
      Observations by scanning electron microscopy showed that after PBS washing, the
      amorphous layer of the articular cartilage was still intact, whereas it was
      partially collapsed after gauze scouring. In conclusion, the addition of HA did
      reduce the coefficient of friction under the experimental conditions in this
      study; the relevance to the clinical condition and the duration of the treatment
      effect in vivo require further investigation.

PMID- 15174121
TI  - Post-translational modifications: a challenge for proteomics and bioinformatics.

PMID- 15174120
TI  - Preparation of poly(ethylene glycol)-block-poly(caprolactone) copolymers and
      their applications as thermo-sensitive materials.
AB  - The polymerization of epsilon-caprolactone (epsilon-CL) was initiated by the
      terminal alcohol of methoxy poly(ethylene glycol) (MPEG) as an initiator via
      activated ring-opening polymerization in the presence of HCl. Et2O as a monomer
      activator. The molecular weights of the poly(epsilon-caprolactone) (PCL) in MPEG
      PCL diblock copolymers controlled with the feed ratio of epsilon-CL to MPEG. The
      polymerization was preceded by living fashion with no termination or chain
      transfer. This polymerization procedure offered MPEG-PCL diblock copolymers with
      well-defined structures. The gel-to-sol transitions of MPEG-PCL diblock copolymer
      solutions were also examined. The diblock copolymers synthesized with various
      MPEG and PCL lengths were dissolved in water at 80 degrees C in various
      concentrations. The polymer solutions formed gel at room temperature. The formed
      gel became fluids again by increasing the temperature. The gel-to-sol transition
      showed strong dependence on the length of the MPEG and PCL diblock segments. When
      the polymer solution was injected into rat, it became a gel at body temperature.
      The formed gel maintained for 1 month. We confirmed that MPEG-PCL diblock
      copolymers with well-defined structures served as new thermo-sensitive
      biomaterials.

PMID- 15174122
TI  - The RESID Database of Protein Modifications as a resource and annotation tool.
AB  - The RESID Database of Protein Modifications is a comprehensive collection of
      annotations and structures for protein modifications and cross-links including
      pre-, co-, and post-translational modifications. The database provides:
      systematic and alternate names, atomic formulas and masses, enzymatic activities
      that generate the modifications, keywords, literature citations, Gene Ontology
      (GO) cross-references, protein sequence database feature table annotations,
      structure diagrams, and molecular models. This database is freely accessible on
      the Internet through resources provided by the European Bioinformatics Institute
      (http://www.ebi.ac.uk/RESID), and by the National Cancer Institute--Frederick
      Advanced Biomedical Computing Center (http://www.ncifcrf.gov/RESID). Each RESID
      Database entry presents a chemically unique modification and shows how that
      modification is currently annotated in the protein sequence databases, Swiss-Prot
      and the Protein Information Resource (PIR). The RESID Database provides a table
      of corresponding equivalent feature annotations that is used in the UniProt
      project, an international effort to combine the resources of the Swiss-Prot,
      TrEMBL and PIR. As an annotation tool, the RESID Database is used in
      standardizing and enhancing modification descriptions in the feature tables of
      Swiss-Prot entries. As an Internet resource, the RESID Database assists
      researchers in high-throughput proteomics to search monoisotopic masses and mass
      differences and identify known and predicted protein modifications.

PMID- 15174123
TI  - Unimod: Protein modifications for mass spectrometry.
AB  - Unimod is a database of protein modifications for use in mass spectrometry
      applications, especially protein identification and de novo sequencing. It
      contains accurate and verifiable values, derived from elemental compositions, for
      the mass differences introduced by both natural and artificial modifications.

PMID- 15174124
TI  - Annotation of post-translational modifications in the Swiss-Prot knowledge base.
AB  - High-throughput proteomic studies produce a wealth of new information regarding
      post-translational modifications (PTMs). The Swiss-Prot knowledge base is faced
      with the challenge of including this information in a consistent and structured
      way, in order to facilitate easy retrieval and promote understanding by biologist
      expert users as well as computer programs. We are therefore standardizing the
      annotation of PTM features represented in Swiss-Prot. Indeed, a controlled
      vocabulary has been associated with every described PTM. In this paper, we
      present the major update of the feature annotation, and, by showing a few
      examples, explain how the annotation is implemented and what it means. Mod-Prot,
      a future companion database of Swiss-Prot, devoted to the biological aspects of
      PTMs (i.e., general description of the process, identity of the modification
      enzyme(s), taxonomic range, mass modification) is briefly described. Finally we
      encourage once again the scientific community (i.e., both individual researchers
      and database maintainers) to interact with us, so that we can continuously
      enhance the quality and swiftness of our services.

PMID- 15174125
TI  - PhosphoSite: A bioinformatics resource dedicated to physiological protein
      phosphorylation.
AB  - PhosphoSite is a curated, web-based bioinformatics resource dedicated to
      physiologic sites of protein phosphorylation in human and mouse. PhosphoSite is
      populated with information derived from published literature as well as high
      throughput discovery programs. PhosphoSite provides information about the
      phosphorylated residue and its surrounding sequence, orthologous sites in other
      species, location of the site within known domains and motifs, and relevant
      literature references. Links are also provided to a number of external resources
      for protein sequences, structure, post-translational modifications and signaling
      pathways, as well as sources of phospho-specific antibodies and probes. As the
      amount of information in the underlying knowledgebase expands, users will be able
      to systematically search for the kinases, phosphatases, ligands, treatments, and
      receptors that have been shown to regulate the phosphorylation status of the
      sites, and pathways in which the phosphorylation sites function. As it develops
      into a comprehensive resource of known in vivo phosphorylation sites, we expect
      that PhosphoSite will be a valuable tool for researchers seeking to understand
      the role of intracellular signaling pathways in a wide variety of biological
      processes.

PMID- 15174126
TI  - The Phosphorylation Site Database: A guide to the serine-, threonine-, and/or
      tyrosine-phosphorylated proteins in prokaryotic organisms.
AB  - The Phosphorylation Site Database [http://vigen.biochem.vt.edu/xpd/xpd.htm]
      provides ready access to information from the primary scientific literature
      concerning those proteins from prokaryotic organisms, i.e., the members of the
      domains Archaea and Bacteria, that have been reported to undergo covalent
      phosphorylation on the hydroxyl side chains of serine, threonine, and/or tyrosine
      residues. Where known, the sequence of the site(s) of phosphorylation and the
      functional consequences of phosphorylation also are included. Active links enable
      users to quickly access further information concerning the phosphoprotein of
      interest from PubMed, GenBank, SWISS-PROT, and PIR.

PMID- 15174127
TI  - Advances in the prediction of protein targeting signals.
AB  - Enlarged sets of reference data and special machine learning approaches have
      improved the accuracy of the prediction of protein subcellular localization.
      Recent approaches report over 95% correct predictions with low fractions of false
      positives for secretory proteins. A clear trend is to develop specifically
      tailored organism- and organelle-specific prediction tools rather than using one
      general method. Focus of the review is on machine learning systems, highlighting
      four concepts: the artificial neural feed-forward network, the self-organizing
      map (SOM), the Hidden-Markov-Model (HMM), and the support vector machine (SVM).

PMID- 15174129
TI  - Prediction of the subcellular localization of eukaryotic proteins using sequence
      signals and composition.
AB  - A tool called Locfind for the sequence-based prediction of the localization of
      eukaryotic proteins is introduced. It is based on bidirectional recurrent neural
      networks trained to read sequentially the amino acid sequence and produce
      localization information along the sequence. Systematic variation of the network
      architecture in combination with an efficient learning algorithm lead to a 91%
      correct localization prediction for novel proteins in fivefold cross-validation.
      The data and evaluation procedure are the same as the non-plant part of the
      widely used TargetP tool by Emanuelsson et al. The Locfind system is available on
      the WWW for predictions (http://www.stepc.gr/~synaptic/locfind.html).

PMID- 15174128
TI  - Predotar: A tool for rapidly screening proteomes for N-terminal targeting
      sequences.
AB  - Probably more than 25% of the proteins encoded by the nuclear genomes of
      multicellular eukaryotes are targeted to membrane-bound compartments by N
      terminal targeting signals. The major signals are those for the endoplasmic
      reticulum, the mitochondria, and in plants, plastids. The most abundant of these
      targeted proteins are well-known and well-studied, but a large proportion remain
      unknown, including most of those involved in regulation of organellar gene
      expression or regulation of biochemical pathways. The discovery and
      characterization of these proteins by biochemical means will be long and
      difficult. An alternative method is to identify candidate organellar proteins via
      their characteristic N-terminal targeting sequences. We have developed a neural
      network-based approach (Predotar--Prediction of Organelle Targeting sequences)
      for identifying genes encoding these proteins amongst eukaryotic genome
      sequences. The power of this approach for identifying and annotating novel gene
      families has been illustrated by the discovery of the pentatricopeptide repeat
      family.

PMID- 15174130
TI  - Fine-tuning the prediction of sequences cleaved by signal peptidase II: a curated
      set of proven and predicted lipoproteins of Escherichia coli K-12.
AB  - A curated set of 81 proven and 44 predicted lipoproteins of Escherichia coli K-12
      was defined with the combined use of a literature survey, a variety of predictive
      tools and human expertise. The well-documented Gram-negative proteome of E. coli
      K-12 was chosen to assess how the different approaches complement each other and
      to ensure a stable definition of a consistent set of lipoproteins. The results of
      detailed analysis of such proteins at the level of a single proteome are
      presented, corroborated and rationalized.

PMID- 15174131
TI  - Prediction of sequence signals for lipid post-translational modifications:
      insights from case studies.
AB  - In silico annotation techniques for post-translational modifications (PTMs) are
      important to generate biologically meaningful descriptions for sequences of
      experimentally uncharacterized proteins. Having previously contributed with
      predictors for lipid PTMs, we summarize our methodological experience. Rather
      than only looking for the sequence pattern in substrate sequences, a strategy
      aimed at creating a generalized model of substrate protein/enzyme interaction
      appears more appropriate since the number of known substrate sequences is small,
      and some of them are not sufficiently verified experimentally. Such a physical
      approach (in contrast to a mere textual analysis of substrate sequences) can also
      take into account other, heterogeneous biological data (mutations of substrate
      sequences, kinetic data, enzyme sequences/structures) with simple analytical
      expressions in the score function. Several lipid PTMs are encoded in the form of
      a small sequence region (with pronounced amino acid type preferences) that is
      connected to the substrate protein by a linker region with many conformationally
      flexible, hydrophilic residues. A score function composed of terms penalizing
      sequence properties known to be incompatible with productive substrate
      protein/enzyme complexes essentially unselects inappropriate queries. Also, we
      estimate the number of nonredundant sequences necessary for robust profile
      computation with statistical criteria, a number that is not reached in most cases
      of PTM prediction. Finally, we discuss the usage of evolutionary information in
      evaluating the functional importance of predicted PTMs in cases of motif
      conservation within sequence families.

PMID- 15174132
TI  - N-Terminal myristoylation predictions by ensembles of neural networks.
AB  - N-terminal myristoylation is a post-translational modification that causes the
      addition of a myristate to a glycine in the N-terminal end of the amino acid
      chain. This work presents neural network (NN) models that learn to discriminate
      myristoylated and nonmyristoylated proteins. Ensembles of 25 NNs and decision
      trees were trained on 390 positive sequences and 327 negative sequences.
      Experiments showed that NN ensembles were more accurate than decision tree
      ensembles. Our NN predictor evaluated by the leave-one-out procedure, obtained a
      false positive error rate equal to 2.1%. That was better than the PROSITE pattern
      for myristoylation for which the false positive error rate was 22.3%. On a recent
      version of Swiss-Prot (41.2), the NN ensemble predicted 876 myristoylated
      proteins, while 1150 proteins were predicted by the PROSITE pattern for
      myristoylation. Finally, compared to the well-known NMT predictor, the NN
      predictor gave similar results. Our tool is available under
      http://www.expasy.org/tools/myristoylator/myristoylator.html.

PMID- 15174133
TI  - Prediction of post-translational glycosylation and phosphorylation of proteins
      from the amino acid sequence.
AB  - Post-translational modifications (PTMs) occur on almost all proteins analyzed to
      date. The function of a modified protein is often strongly affected by these
      modifications and therefore increased knowledge about the potential PTMs of a
      target protein may increase our understanding of the molecular processes in which
      it takes part. High-throughput methods for the identification of PTMs are being
      developed, in particular within the fields of proteomics and mass spectrometry.
      However, these methods are still in their early stages, and it is indeed
      advantageous to cut down on the number of experimental steps by integrating
      computational approaches into the validation procedures. Many advanced methods
      for the prediction of PTMs exist and many are made publicly available. We
      describe our experiences with the development of prediction methods for
      phosphorylation and glycosylation sites and the development of PTM-specific
      databases. In addition, we discuss novel ideas for PTM visualization (exemplified
      by kinase landscapes) and improvements for prediction specificity (by using ESS-
      evolutionary stable sites). As an example, we present a new method for kinase
      specific prediction of phosphorylation sites, NetPhosK, which extends our earlier
      and more general tool, NetPhos. The new server, NetPhosK, is made publicly
      available at the URL http://www.cbs.dtu.dk/services/NetPhosK/. The issues of
      underestimation, over-prediction and strategies for improving prediction
      specificity are also discussed.

PMID- 15174134
TI  - Development of a mass fingerprinting tool for automated interpretation of
      oligosaccharide fragmentation data.
AB  - The bioinformatic tool GlycosidIQ was developed for computerized interpretation
      of oligosaccharide mass spectrometric fragmentation based on matching
      experimental data with theoretically fragmented oligosaccharides generated from
      the database GlycoSuiteDB. This use of the software for glycofragment mass
      fingerprinting obviates a large part of the manual, labor intensive, and
      technically challenging interpretation of oligosaccharide fragmentation. Using
      130 negative ion electrospray ionization-tandem mass spectrometry fragment
      spectra from identified oligosaccharide structures, it was shown that the
      GlycosidIQ scoring algorithms were able to correctly identify oligosaccharides in
      the great majority of cases (correct structure top ranked in 78% of the cases and
      an additional 17% were ranked second highest in the sample set).

PMID- 15174135
TI  - Prediction of disulfide-bonded cysteines in proteomes with a hidden neural
      network.
AB  - A hidden neural network-based method is used to predict the bonding state of
      cysteines starting from the residue sequence of the protein chain. The method
      scores as high as 89% and 86% per cysteine residue and per protein, respectively,
      and in this overcomes other predictors of the same category. We then explore the
      efficacy of our predictor in computing the disulfide content of the whole
      proteome of Escherichia coli (K12 and O157), Aeropirum pernix, Thermotoga
      maritima, and Homo sapiens. We find that the percentage of extracellular
      disulfide containing proteins is higher than that of intracellular one, and that
      the human proteome is by far the one with the highest content of sulfur-sulfur
      linkages in proteins.

PMID- 15174136
TI  - ProteoMod: A new tool to quantitate protein post-translational modifications.
AB  - Post-translational modifications (PTMs) are known to regulate biological
      processes by controlling protein function. The effect of a PTM on protein
      function depends critically on the position and the number of modifications.
      While there are convenient methods available to qualitatively examine
      modifications like phosphorylation, glycosylation, acetylation and methylation,
      methods available for their quantitative assessment are cumbersome. We have
      developed a new tool that allows quantitation of the number of phosphorylation
      events in proteins with ease. The "ProteoMod" tool depends on shifts in the
      isoelectric points of proteins upon post-translational change. The extent of
      shift exhibited upon phosphorylation is algorithmically converted into the number
      of phosphorylations conferred. The validity of ProteoMod was confirmed by
      examining proteins with previously known number of phosphorylations. The list of
      proteins examined included HSP27, HSP70 and tumor suppressor p53. The approach
      can also be applied to estimate modifications like acetylation, methylation and
      sialylation in proteins. We analyzed shifts in isoelectric points due to
      sialylation events in N-glycoproteins. Using influenza hemagglutinin we show that
      shifts in isoelectric points correlate with intracellular distribution of this
      model membrane protein. In addition to extending the application of two
      dimensional gel electrophoresis to quantitate modifications, our study also
      highlights its potential use in cell biology.

PMID- 15174137
TI  - Highly informative proteome analysis by combining improved N-terminal sulfonation
      for de novo peptide sequencing and online capillary reverse-phase liquid
      chromatography/tandem mass spectrometry.
AB  - Recently, various chemical modifications of peptides have been incorporated into
      mass spectrometric analyses of proteome samples, predominantly in conjunction
      with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS), to
      facilitate de novo sequencing of peptides. In this work, we investigate
      systematically the utility of N-terminal sulfonation of tryptic peptides by 4
      sulfophenyl isothiocyanate (SPITC) for proteome analysis by capillary reverse
      phase liquid chromatography/tandem mass spectrometry (cRPLC/MS/MS). The
      experimental conditions for the sulfonation were carefully adjusted so that SPITC
      reacts selectively with the N-terminal amino groups, even in the presence of the
      epsilon-amino groups of lysine residues. Mass spectrometric analyses of the
      modified peptides by cRPLC/MS/MS indicated that SPITC derivatization proceeded
      toward near completion under the experimental conditions employed here. The SPITC
      derivatized peptides underwent facile fragmentation, predominantly resulting in y
      series ions in the MS/MS spectra. Combining SPITC derivatization and cRPLC/MS/MS
      analyses facilitated the acquisition of sequence information for lysine
      terminated tryptic peptides as well as arginine-terminated peptides without the
      need for additional peptide pretreatment, such as guanidination of lysine amino
      group. This process alleviated the biased detection of arginine-terminated
      peptides that is often observed in MALDI MS experiments. We will discuss the
      utility of the technique as a viable method for proteome analyses and present
      examples of its application in analyzing samples having different levels of
      complexity.

PMID- 15174138
TI  - Functional protein nanoarrays for biomarker profiling.
AB  - The use of microarrays for parallel screening of nucleic acid profiles has become
      an industry standard. Similar efforts for screening protein-protein interactions
      are gaining momentum, however, they remain limited by the requirement for
      relatively large sample volumes. One strategy for overcoming this problem is to
      significantly decrease the size and consequently the sample volume of the protein
      interaction assay. We report here on our progress over the last two years in the
      construction of ultraminiaturized, functional protein capture assays. Each one
      micron spot in these array-based assays covers less than 1/1000(th) of the
      surface area of a conventional microarray spot while still maintaining enough
      antibodies to provide a useful dynamic range. These nanoarray assays can be read
      by conventional optical fluorescence microscopy as well as by novel label-free
      methods such as atomic force microscopy. The size reduction realized by
      functional protein nanoarrays also creates opportunities for novel applications
      including highly multiplexed single cell analysis and integration with
      microfluidics and other "lab-on-a-chip" technologies.

PMID- 15174139
TI  - Readout of protein microarrays using intrinsic time resolved UV fluorescence for
      label-free detection.
AB  - Detecting protein-protein interactions other than those of antibody-antigen pairs
      still represents a demanding and tedious task. In the present work, a novel
      method as an alternative to current molecular biology-based detection procedures
      is established. It solely relies on the change of fluorescence decay times of the
      protein's intrinsic fluorophores tryptophan and tyrosine due to protein-protein
      interaction. Unlike previously utilized related methods, no labelling of the
      binding partners is required. This opens the possibility to detect proteins and
      their natural interactions without perturbation due to chemical alteration. The
      technique uses immobilization of one of the protein partners onto solid supports,
      which allows performance of protein binding studies in the microarray format.
      Fluorescence lifetime experiments of proteins in their different binding states
      have been applied to protease/protease-substrate pairs, as well as to the
      tubulin/kinesin system. Different binding behavior of proteins in solution
      towards protein partners immobilized on protein microarrays was detected with
      regard to binding specificity and protein amount. This label-free method for
      analyzing protein microarrays offers broad applicability ranging from principal
      investigations of protein interactions to applications in molecular biology and
      medicine.

PMID- 15174140
TI  - Has the yo-yo stopped? An assessment of human protein-coding gene number.
AB  - Since the identification of approximately 25,000 proteins from the draft human
      genome assembly in 2001, estimates of the total have oscillated between 30,000
      and 70,000. The recently announced genome closure has not generated a consensus
      gene count despite this being a key parameter for many areas of biology including
      drug target discovery and characterization of the human proteome. Contrary to
      earlier predictions of constitutive under-detection for eukaryotic genes, the
      latest model organism updates have produced minor increases in the worm but fly
      and yeast gene numbers have decreased. The postdraft, precompletion interval has
      produced large increases in human transcript coverage, continuous improvements in
      genome assembly and refinements in automated genomic annotation. Notably these
      enhancements have resulted in an Ensembl human protein-coding gene number of
      22,184, a decrease of 1862 since the first release. Longitudinal database surveys
      indicate that redundancy-reduced human mRNA and protein collections are
      flattening out at approximately 28,000, although Ensembl maps approximately
      20,000 known sequences. Observations suggest high-throughput cloning projects are
      predominantly extending known genes or sampling new splice forms and novel
      protein discovery has slowed to a trickle. The hypothesis that substantial
      numbers of short proteins remain experimentally and computationally undetected in
      mammalian genomes is neither supported by sequence data nor by the extensive
      homology between mouse and human proteins. Aggregating the independent
      annotations for complete transcripts from seven completed human chromosomes
      extrapolates to approximately 25,000 genes. The inclusion of partial putative
      genes would increase this to above 30,000 but recent data suggest these represent
      predominantly nonprotein-coding transcripts. Mass spectrometry-based proteomics
      has already verified more than 10% of human genes but has not identified
      significant numbers of unpredicted proteins. The available data are thus
      converging to a basal protein-coding gene number well below 30,000, which could
      even be as low as 25,000.

PMID- 15174141
TI  - Prediction of protein-protein interactions based on surface patch comparison.
AB  - A method to predict if two proteins interact, based on their three-dimensional
      structures, is presented. It consists of five steps: (i) the surface of each
      protein, represented by the solvent accessible atoms, is divided into small
      patches; (ii) the shape of each patch is described by the atom distributions
      along its principal axes; (iii) the shape complementarity between two patches is
      estimated by comparing, through contingency table analysis, their atom
      distributions along their principal axes; (iv) given protein A, with nA surface
      patches, and protein B, with nB surface patches, nA x nB shape complementarity
      values are obtained; and (v) the distribution of the latter allows one to
      discriminate pairs of interacting and of noninteracting proteins. Only a few
      seconds are necessary to predict if two proteins interact, with accuracy close to
      80%, sensitivity over 70% and specificity close to 50%.

PMID- 15174142
TI  - Modulation of gene expression by hypoxia in human umbilical cord vein endothelial
      cells: A transcriptomic and proteomic study.
AB  - Hypoxia is a characteristic feature of many human pathologies, including cancer.
      The sustained proliferation rate of tumor cells leads to alterations of the tumor
      microenvironment, that progressively becomes more acidic, nutrient-deprived, and
      hypoxic. The reduced partial pressure of oxygen triggers the onset of an adaptive
      response, aimed at increasing the local oxygen concentration by several
      complementary actions. Although directly exposed to the blood stream, endothelial
      cells lining the vascular lumen in tumors also can be exposed to hypoxia and
      therefore can contribute to the onset of the adaptive response that leads to
      tumor angiogenesis. Aiming at getting a detailed insight into the oxygen
      dependent regulation of the transcriptional program of vascular endothelial cells
      and at identifying new relevant markers that may be used as targets for
      therapeutic intervention in tumor angiogenesis, we have performed a broad-range
      transcriptomic analysis, using the Affymetrix HG-U133A Gene Chips, of mRNA
      expression levels in human umbilical cord vein endothelial cells (HUVEC), exposed
      in vitro to hypoxia for different time periods. The transcriptomic analysis was
      complemented by a semiquantitative reverse transcriptase-polymerase chain
      reaction (RT-PCR) analysis of mRNA levels and alternative splicing for some
      selected extracellular matrix protein genes, and by a proteomic analysis, using
      two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and tandem mass
      spectrometry for protein separation and identification, of hypoxic and normoxic
      HUVEC whole-cell lysates and subcellular fractions. Our analysis confirmed
      previous findings on genes whose expression is regulated by oxygen concentration
      but also identified new genes (e.g., CXCR4, claudin 3, CD24, tetranectin, Del-1,
      procollagen lysyl hydroxylase 1 and 2) which are transcriptionally upregulated in
      hypoxic conditions.

PMID- 15174143
TI  - Two-dimensional maps and databases of the human macrophage proteome and
      secretome.
AB  - Macrophages exert a crucial, but still incompletely known, role in complex
      disorders such inflammatory, immunological, and infectious diseases. A
      differential proteomic approach should help to elucidate the macrophage
      dysfunctions involved in these diseases. With this goal in mind, we established
      the first two-dimensional maps of the human macrophage proteome and secretome.
      Intracellular and secreted proteins were extracted from monocyte-derived
      macrophages obtained from healthy donors (n = 16), and separated by two
      dimensional gel electrophoresis. Silver-stained gels were analyzed using
      Progenesis software. A high level of between-gel reproducibility was obtained,
      allowing us to generate two patterns specific of the macrophage proteome and
      secretome, respectively. A total of 127 and 66 distinct intracellular and
      secreted polypeptide spots, corresponding to 100 and 38 different proteins,
      respectively, were identified by matrix assisted laser desorption/ionisation-mass
      spectrometry. The two-dimensional reference maps and databases resulting from
      this study confirm that macrophages are involved in a wide range of biological
      functions, and that they provide a useful tool for a wide array of investigators
      involved in macrophage biology, allowing to investigate the macrophage protein
      changes associated with various disorders or environmental stimuli.

PMID- 15174144
TI  - Cross-species identification of proteins from proteome profiles of the marine
      oligotrophic ultramicrobacterium, Sphingopyxis alaskensis.
AB  - Sphingopyxis (formerly Sphingomonas) alaskensis is a model bacterium for studying
      adaptation to oligotrophy (nutrient-limitation). It has a unique physiology which
      is fundamentally different to that of the well studied bacteria such as
      Escherichia coli. To begin to identify the genes involved in its physiological
      responses to nutrient-limited growth and starvation, we developed high resolution
      two-dimensional electrophoresis (2-DE) methods and determined the identity of 12
      proteins from a total of 21 spots using mass spectrometric approaches and cross
      species matching. The best matches were to Novosphingobium aromaticivorans; a
      terrestrial, hydrocarbon degrading bacterium which was previously classified in
      the genus Sphingomonas. The proteins identified are involved in fundamental
      cellular processes including protein synthesis, protein folding, energy
      generation and electron transport. We also compared radiolabelled and silver
      stained 2-DE gels generated with the same protein samples and found significant
      differences in the protein profiles. The use of both methods increased the total
      number of proteins with differential spot intensities which could be identified
      from a single protein sample. The ability to effectively utilise cross-species
      matching from radiolabelled and silver-stained gels provides new approaches for
      determining the genetic basis of microbial oligotrophy.

PMID- 15174145
TI  - Characterization and location of post-translational modifications on chromogranin
      B from bovine adrenal medullary chromaffin granules.
AB  - Bovine chromoganin B (CGB)/secretogranin I, an acidic protein with a sequence of
      626 residues and an isoelectric point of 5.2 is a major member of the
      chromogranin/secretogranin (CG/Sg) family. The difference between the theoretical
      molecular mass (76 kDa) and the value estimated by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis results from post-translational modifications
      (glycosylation, phosphorylation and sulfation) and from the abundance of acidic
      residues (D 4.6%, and E 16.5%). Although the sequence of CGB is known, the
      structural analyses of the post-translational modifications have so far not been
      carried out. In the present study, using a combination of proteomic techniques
      including two-dimensional gel electrophoresis, Western blot, high-performance
      liquid chromatography purification, enzymatic digestion, sequencing, carbohydrate
      analysis, matrix-assisted laser desorption/ionization-time of flight and liquid
      chromatography mass spectrometry analysis, we have located 18 post-translational
      modifications on bovine CGB, isolated from adrenal medulla chromaffin granules.
      Furthermore, we have identified at the molecular level the presence of a mutation
      M/V on position 577 of natural CGB. All together these data reflect the complex
      structure of this protein marker of the neuroendocrine system.

PMID- 15174146
TI  - Proteomic analysis of mouse mammary terminal end buds identifies axonal growth
      cone proteins.
AB  - Ductal morphogenesis in the mouse mammary gland occurs mainly postnatally and is
      driven by specialized structures at the ends of the developing ducts, the
      terminal end buds (TEBs), which later regress once ductal growth is complete. To
      identify proteins that are specifically associated with migration of TEBs we
      developed a novel method of isolating TEBs, which eliminated the mammary stroma.
      The protein expression profile of the TEBs was then compared with that of
      isolates taken from the 4th inguinal mammary gland of adult virgin mice using two
      dimensional (2-D) gel electrophoresis and mass spectrometry (MS) analysis (matrix
      assisted laser desorption/ionization and quadrupole time of flight). Following
      construction of an integrated protein expression database, 44 protein features
      which showed differential expression levels between the two sets were chosen for
      MS analysis. Of these, 24 gave protein annotations whereas the other 20 produced
      unidentified peptides. Fourteen unequivocal proteins were identified from these
      24, whereas the remaining 10 matched more than one protein within a single 2-D
      gel feature. Several of the identified proteins were associated with the
      cytoskeleton and have previously been reported in axonal growth cones, suggesting
      that they may influence cell shape and motility within the advancing TEBs, in a
      similar fashion to migrating axons.

PMID- 15174147
TI  - Mapping of bovine skeletal muscle proteins using two-dimensional gel
      electrophoresis and mass spectrometry.
AB  - The large individual variation in meat quality seen both within and between
      animals is not fully understood. Consequently, our long-term goal is to identify
      reliable proteins which control or determine bovine meat quality. Using a
      proteomic approach, bovine skeletal muscle samples were analyzed by two
      dimensional gel electrophoresis (2-DE) using an immobilized pH 4-7 gradient in
      the first dimension and mass spectrometry. We first tested the reproducibility of
      the method. These experiments showed slightly greater intersample than
      intrasample variability. In order to evaluate the type of visualized proteins in
      2-DE, we initiated the construction of a protein reference map of bovine
      Semitendinosus muscle. In total, 129 protein spots corresponding to 75 different
      gene products were identified. Of these proteins, the largest portion is involved
      in metabolism (25.5%), cell structure (17%), cell defense (16%) and contractile
      apparatus (14.5%). One quarter of the identified proteins are represented by two
      or several protein spots and multiple isoforms of troponin T are present. Peptide
      mass fingerprint results indicate that these isoforms are partly generated by
      alternative splicing. The data presented here are an important step for further
      proteome analyses on bovine muscle. This may lead to progress in understanding
      the mechanisms controlling postmortem muscle metabolism and meat quality.

PMID- 15174148
TI  - Proteomic characterization of novel serum amyloid P component variants from human
      plasma and urine.
AB  - Serum amyloid P component (SAP) is a human plasma protein that has been widely
      studied for its influence on amyloid plaque formation and stabilization. SAP was
      characterized directly from human plasma and urine samples via novel affinity
      mass spectrometry-based proteomic technology that is able to readily discriminate
      between mass-altered protein variants. These analyses were able to identify
      several variants of SAP that have not been previously reported. These variants
      include microheterogeneity of the glycan structure, from the loss of one or both
      terminal sialic acid residues, as well as the loss of the C-terminal valine
      residue. Moreover, the analysis of urine allowed for the consistent
      identification of serum amyloid P component as a normal constituent of the urine
      proteome.

PMID- 15174149
TI  - Dispensable role for interferon-gamma in the burn-induced acute phase response: a
      proteomic analysis.
AB  - We examined the role of the pleiotropic cytokine interferon-gamma (IFN-gamma) in
      initiating the burn injury-induced acute phase response (APR). Two-dimensional (2
      D) electrophoresis was used to obtain serum protein profiles from wild-type (WT)
      and IFN-gamma knockout mice following sham-burn or 20% burn injury. Serum 2-D
      images from both groups of burn-injured mice were characterized by the
      upregulation of a similar panel of protein spots. These included the three major
      murine acute phase proteins haptoglobin, serum amyloid A, and serum amyloid P,
      that were identified by matrix-assisted laser desorption/ionization-time of
      flight (MALDI-TOF)-mass spectrometry. Furthermore, the changes in the levels of
      these protein spots were very similar between these two groups of mice, as
      determined by image analysis. Other features of burn-induced APR such as a
      decrease in total serum protein concentration, an elevated circulation level of
      the cytokine interleukin-6 (IL-6), and activation of the IL-6 signal transduction
      protein STAT3 were also evaluated and found to be similar between wild-type and
      IFN-gamma knockout mice. These results suggest a dispensable role of IFN-gamma in
      the induction of the hepatic APR in mice following burn injury.

PMID- 15174150
TI  - Proteomic analysis of adipocyte differentiation: Evidence that alpha2
      macroglobulin is involved in the adipose conversion of 3T3 L1 preadipocytes.
AB  - Adipogenesis is an important aspect of energy homeostasis. Here we have used a
      differential proteome mapping strategy to identify intracellular proteins that
      are differentially expressed during adipose conversion of 3T3 L1 preadipocytes.
      Two-dimensional gel electrophoresis analysis identified 8 proteins that are
      induced following hormone-evoked differentiation. In addition, we found that a
      alpha2 macroglobulin fragment was abundantly present in 3T3 L1 preadipocytes, but
      was virtually undetectable in fully differentiated adipocytes. Metabolic
      radiolabeling with (35S)methionine and Northern blot analysis indicated that the
      intracellular alpha2 macroglobulin fragment in preadipocytes was derived from the
      extracellular culture medium, not de novo synthesis. Incubation of preadipocytes
      with an antialpha2 macroglobulin polyclonal antibody caused depletion of the
      intracellular alpha2 macroglobulin fragments, and also enhanced spontaneous
      adipose conversion. These results suggest that intracellular alpha2 macroglobulin
      fragment inhibits adipocyte differentiation, and that hormone treatment induces
      differentiation at least in part by suppression of intracellular alpha2
      macroglobulin activity in 3T3 L1 preadipocytes.

PMID- 15174156
TI  - Chemical biology of the sugar code.
AB  - A high-density coding system is essential to allow cells to communicate
      efficiently and swiftly through complex surface interactions. All the structural
      requirements for forming a wide array of signals with a system of minimal size
      are met by oligomers of carbohydrates. These molecules surpass amino acids and
      nucleotides by far in information-storing capacity and serve as ligands in
      biorecognition processes for the transfer of information. The results of work
      aiming to reveal the intricate ways in which oligosaccharide determinants of
      cellular glycoconjugates interact with tissue lectins and thereby trigger
      multifarious cellular responses (e.g. in adhesion or growth regulation) are
      teaching amazing lessons about the range of finely tuned activities involved. The
      ability of enzymes to generate an enormous diversity of biochemical signals is
      matched by receptor proteins (lectins), which are equally elaborate. The
      multiformity of lectins ensures accurate signal decoding and transmission. The
      exquisite refinement of both sides of the protein-carbohydrate recognition system
      turns the structural complexity of glycans--a demanding but essentially mastered
      problem for analytical chemistry--into a biochemical virtue. The emerging medical
      importance of protein-carbohydrate recognition, for example in combating
      infection and the spread of tumors or in targeting drugs, also explains why this
      interaction system is no longer below industrial radarscopes. Our review sketches
      the concept of the sugar code, with a solid description of the historical
      background. We also place emphasis on a distinctive feature of the code, that is,
      the potential of a carbohydrate ligand to adopt various defined shapes, each with
      its own particular ligand properties (differential conformer selection). Proper
      consideration of the structure and shape of the ligand enables us to envision the
      chemical design of potent binding partners for a target (in lectin-mediated drug
      delivery) or ways to block lectins of medical importance (in infection, tumor
      spread, or inflammation).

PMID- 15174157
TI  - A new DNA analogue with expanded size and scope.

PMID- 15174158
TI  - A chemically designed enzymatic cleavage site for phosphoproteome analysis.

PMID- 15174159
TI  - Functional evaluation of carbohydrate-centred glycoclusters by enzyme-linked
      lectin assay: ligands for concanavalin A.
AB  - The affinities of the mannose-specific lectin concanavalin A (Con A) towards D
      glucose-centred mannosyl clusters differing in the anomeric configuration of the
      monosaccharide core, nature of the bridging functional groups and valency, have
      been measured by a competitive enzyme-linked lectin assay. Pentavalent thioether
      linked ligands (5 and 7) were prepared by radical addition of 2,3,4,6-tetra-O
      acetyl-1-thio-alpha-D-mannopyranose to the corresponding penta-O-allyl-alpha- or 
      beta-D-glucopyranose, followed by deacetylation. The distinct reactivity of the
      anomeric position in the D-glucose scaffold was exploited in the preparation of a
      tetravalent cluster (10) that keeps a reactive aglyconic group for further
      manipulation, including incorporation of a reporter group or attachment to a
      solid support. Hydroboration of the double bonds in the penta-O-allyl-alpha-D
      glucopyranose derivative and replacement of the hydroxy groups with amine
      moieties gave a suitable precursor for the preparation of pentavalent and 15
      valent mannosides through the thiourea-bridging reaction (17 and 20,
      respectively). The diastereomeric 1-thiomannose-coated clusters 5 and 7 were
      demonstrated to be potent ligands for Con A, with IC(50) values for the
      inhibition of the Con A-yeast mannan association indicative of 6.4- and 5.5-fold
      increases in binding affinity (valency-corrected values), respectively, relative
      to the value for methyl alpha-D-mannopyranoside. The tetravalent cluster 10
      exhibited a valency-corrected relative lectin-binding potency virtually identical
      to that of the homologous pentavalent mannoside 7. In sharp contrast, replacement
      of the 1-thiomannose wedges of 5 with alpha-D-mannopyranosylthioureido units (17)
      virtually abolished any multivalent or statistic effects, with a dramatic
      decrease of binding affinity. The 15-valent ligand 20, possessing classical O
      glycosidic linkages, exhibited a twofold increase in lectin affinity relative to
      the penta-O-(thioglycoside) 5; it is less efficient based on the number of
      mannose units. The results illustrate the potential of carbohydrates as
      polyfunctional platforms for glycocluster construction and underline the
      importance of careful design of the overall architecture in optimising
      glycocluster recognition by specific lectins.

PMID- 15174160
TI  - Biosynthesis of volatiles by the myxobacterium Myxococcus xanthus.
AB  - The volatiles emitted from cell cultures of myxobacterium Myxococcus xanthus were
      collected by use of a closed-loop stripping apparatus (CLSA) and analyzed by GC
      MS. Two new natural products, (S)-9-methyldecan-3-ol ((S)-1) and 9-methyldecan-3
      one (2), were identified and synthesized, together with other aliphatic ketones
      and alcohols, and terpenes. Biosynthesis of the two main components (S)-1 and 2
      was examined in feeding experiments carried out with the wild-type strain DK1622
      and two mutant strains JD300 and DK11017, which are impaired in the degradation
      pathway from leucine to isovaleryl-SCoA. Isovaleryl-SCoA is used as a starter,
      followed by chain elongation with two malonate units. Subsequent use of methyl
      malonate and decarboxylation leads to (S)-1 and 2. Furthermore, 3,3
      dimethylacrylic acid (DMAA) can be used by the mutant strain to form isovaleryl
      SCoA, which corroborates recent data on the detection of a novel variety of the
      mevalonate pathway giving rise to isovaleryl-SCoA from HMGCoA.

PMID- 15174161
TI  - Light-activated transcription and repression by using photocaged SERMs.
AB  - Recently developed methods to regulate the spatial and temporal patterning of
      genes in a light-directed manner hold promise as powerful tools for exploring the
      function of genes that act through their unique spatiotemporal patterning. To
      further explore the application of photocaged ligands of nuclear receptors to
      control gene expression patterning, the actions of photocaged analogues of
      selective estrogen-receptor modulators (SERMs) have been evaluated. Photocaged
      derivatives of hydroxytamoxifen (NB-Htam) and guanidine tamoxifen (NB-Gtam) have
      been synthesized that selectively antagonize ER alpha- and ER beta-mediated
      transcription at classic estrogen response elements (EREs) in response to light.
      When present only intracellularly, Htam and Gtam provide a similar transient
      repression response. When SERMs are allowed to diffuse out of the cell,
      transcription is recovered at a similar rate for Htam and Gtam (6.4 and 5.6 h(
      1)), but is notably faster than is observed with the covalently binding SERM
      tamoxifen aziridine (Taz) (3.8 h(-1)). This suggests that the duration of agonist
      action is controlled by ligand off-rates/diffusion and not by receptor turnover.
      Gtam activates ER beta-mediated transcription at AP1 sites in a similar way to
      what has previously been reported for Htam. NB-Gtam and NB-Tam provide a light
      activated transcription response at AP1-driven reporters, thus illustrating the
      unique ability of photocaged SERMs to simultaneously mediate light-activated
      transcription and repression.

PMID- 15174162
TI  - A novel bis-aziridinylnaphthoquinone with anti-solid tumor activity in which
      induced apoptosis is associated with altered expression of Bcl-2 protein.
AB  - Aziridine-containing compounds have been of interest as anticancer agents since
      the late 1970s. The design, synthesis, and study of aziridinylnaphthoquinone
      analogues to obtain compounds with enhanced activity/toxicity profiles are an
      ongoing research effort in our group. A series of bis-aziridinylnaphthoquinone
      derivatives has been prepared, and the cytotoxic activities of these synthetic
      bis-aziridinylnaphthoquinone derivatives has been investigated. The synthetic
      derivatives displayed significant cytotoxicity against human carcinoma cell lines
      and weak cytotoxic activities against skin fibroblasts (SF). The bis
      aziridinylnaphthoquinone 1 c was the most effective of the tested analogues at
      reducing the viability of Hep2 cells, with an LD(50) value of 5.23 microM, and
      also exhibited weak cytotoxic activity against SF cells, with an LD(50) value of
      54.12 microM. The DNA alkylation and DNA interstrand cross-linking abilities of 1
      c were also investigated. Bis-aziridinylnaphthoquinone 1 c was an effective agent
      for alkylation of DNA after chemical reduction in vitro, and its bifunctional
      alkylating moieties were able to cross-link DNA. We also report here our efforts
      to determine direct antitumor effects of 1 c on Hep2 cells. Growth arrest in Hep2
      cells was preceded by early induction of G(2)-M cell cycle arrest at 0.75 microM
      of 1 c after culture for 24 h, and was then followed by apoptosis after 60 h.
      This was associated with decreased expression of antiapoptotic bcl2 protein (by
      78 %) upon culture with 3.0 microM of 1 c after 60 h. Our results suggest that 1
      c is a novel antitumor aziridinylnaphthoquinone with therapeutic potential
      against solid tumors.

PMID- 15174163
TI  - Bacteria displaying interleukin-4 mutants stimulate mammalian cells and reflect
      the biological activities of variant soluble cytokines.
AB  - We describe a novel procedure that allows the rapid determination of cytokine
      activity on cells that express their cognate receptor. The four-helix bundle
      cytokine interleukin-4 (IL-4) was inducibly expressed as a fusion with the E.
      coli outer-membrane protein intimin, such that IL-4 was presented on the surfaces
      of the bacteria. Expression and accessibility of the cytokine on the cell
      exteriors were monitored by Western blotting and fluorescence microscopy, making
      use of two epitopes flanking the IL-4 component of the fusion protein. To
      demonstrate the biological activity of the immobilized cytokine, a Ba/F3-derived
      cell line stably transfected with both the bipartite human IL-4 receptor and an
      IL-4-specific luciferase reporter gene construct was employed. Bacterial cells
      displaying interleukin-4 elicited a specific, dose-dependent response in the
      reporter cells. Two variants of IL-4 with previously characterized (partial)
      antagonistic properties were also expressed as membrane-bound fusion proteins and
      were tested for their activity in the immobilized state. In comparison with
      bacteria displaying wild-type IL-4, E. coli clones presenting variants IL-4 Y124G
      and Y124D showed diminished or abolished activity, respectively, on murine
      reporter cells. The relative signaling potencies of the immobilized IL-4 variants
      thus closely mirror the agonistic properties of the corresponding soluble
      cytokines. This approach should be generally applicable for the mutational
      analysis of numerous signal mediators that trigger cellular responses through
      dimerization of transmembrane receptors.

PMID- 15174164
TI  - Rapid discovery of potent sulfotransferase inhibitors by diversity-oriented
      reaction in microplates followed by in situ screening.
AB  - Rapid diversity-oriented microplate library synthesis and in situ screening with
      a high-throughput fluorescence-based assay were used to develop potent inhibitors
      of beta-arylsulfotransferase IV (beta-AST-IV). This strategy leads to facile
      inhibitor synthesis and study as it allows protecting-group manipulation and
      product isolation from other library components to be avoided. Through repeated
      library formation, three aspects of inhibitor makeup, the identities of the two
      binding groups and the length of the linker between them, were independently
      optimized. Several potent inhibitors were obtained, one of which was determined
      to have an inhibition constant K(i) of 5 nM. This compound is the most potent
      beta-AST-IV inhibitor developed to date, with a K(i) value more than five orders
      of magnitude lower than the Michaelis constant K(m) for the substrate whose
      binding it inhibits.

PMID- 15174165
TI  - Mutational analysis of a key residue in the substrate specificity of a
      cephalosporin acylase.
AB  - beta-Lactam acylases are crucial for the synthesis of semisynthetic
      cephalosporins and penicillins. Unfortunately, there are no cephalosporin
      acylases known that can efficiently hydrolyse the amino-adipic side chain of
      Cephalosporin C. In a previous directed evolution experiment, residue Asn266 of
      the glutaryl acylase from Pseudomonas SY-77 was identified as being important for
      substrate specificity. In order to explore the function of this residue in
      substrate specificity, we performed a complete mutational analysis of position
      266. Codons for all amino acids were introduced in the gene, 16 proteins that
      could be functionally expressed in Escherichia coli were purified to homogeneity
      and their catalytic parameters were determined. The mutant enzymes displayed a
      broad spectrum of affinities and activities, pointing to the flexibility of the
      enzyme at this position. Mutants in which Asn266 was changed into Phe, Gln, Trp
      and Tyr displayed up to twofold better catalytic efficiency (k(cat)/K(m))than the
      wild-type enzyme when adipyl-7-aminodesacetoxycephalosporanic acid (adipyl-7
      ADCA) was used as substrate, due to a decreased K(m). Only mutants SY-77(N266H)
      and SY-77(N266M) showed an improvement of both catalytic parameters, resulting in
      10- and 15-times higher catalytic efficiency with adipyl-7-ADCA, respectively.
      Remarkably, the catalytic activity (k(cat)) of SY-77(N266M) when using adipyl-7
      ADCA as substrate was as high as when glutaryl-7-aminocephalosporanic acid
      (glutaryl-7-ACA) was used, and approaches commercially interesting activity. SY
      77(N266Q), SY-77(N266H) and SY-77(N266M) mutants showed a modest improvement in
      hydrolysing Cephalosporin C. Since these mutants also have a good catalytic
      efficiency when adipyl-7-ADCA is used and are still active towards glutaryl-7
      ACA, they can be regarded as broad substrate acylases. These results demonstrate
      that the combination of directed evolution for the identification of important
      positions, together with saturation mutagenesis for finding the optimal amino
      acid, is a very effective method for finding improved biocatalysts.

PMID- 15174166
TI  - Classifying enzymes from selectivity fingerprints.
AB  - Fingerprints of lipases and esterases have been recorded by using an array of
      chiral fluorogenic aliphatic esters of increasing chain length (C(4)-C(16)).
      Classification of the enzyme series was carried out with selectivity data by
      clustering and principal component analysis (PCA). Enzymes were classified on the
      basis of selectivity for chain length (C(4)-C(6) vs. C(10)-C(16)) and of middle
      chain-length (C(8)-C(10)) reactivity. A minimum set of nine substrates was
      defined by cluster analysis of relative reactivities of each substrate for the
      different enzymes. This selectivity-based analysis is general. It does not
      require a common reference substrate to react with all enzymes or vice versa, and
      is independent of knowing the exact concentration of active protein in the enzyme
      samples.

PMID- 15174167
TI  - A powerful antiradiation compound revealed by a new high-throughput screening
      method.
AB  - We present a new high-throughput screening method for the selection of powerful
      water-soluble antiradiation compounds. This method, which uses conventional
      immunoassay techniques, allowed the capacity of a given compound to protect
      thymidine from irradiation to be evaluated. By applying this assay to an
      antioxidant library, we showed for the first time that norbadione A, a well-known
      mushroom pigment, has pronounced atypical antiradiation properties.

PMID- 15174168
TI  - Comparative analysis of putative agonist-binding modes in the human A1 adenosine
      receptor.
AB  - A recent study reported a model of the human A(1) adenosine receptor and its
      agonist binding site, proposing two putative binding modes in the same binding
      site for the natural agonist, adenosine. The present work investigates the
      flexibility of this binding site by exhaustive exploration with the natural
      agonist and with three other adenosine derivatives: N6-cyclopentyladenosine
      (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and 5'-N
      ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for
      agonists that would explain the role in the binding process of the different
      substitutions allowed at the 2, N6, and 5' positions of adenosine. This problem
      was addressed through docking simulations, molecular dynamics studies, and
      estimations of the ligand-binding free energy with both the AUTODOCK scoring
      function and the linear interaction energy (LIE) approach. The results point to a
      single receptor-binding position that explains the effects of the different
      chemical modifications on the adenosine derivatives considered here.

PMID- 15174169
TI  - Two-dimensional multiarray formation of hepatocyte spheroids on a microfabricated
      PEG-brush surface.
AB  - A two-dimensional microarray of ten thousand (100 x 100) hepatocyte
      heterospheroids, underlaid with endothelial cells, was successfully constructed
      with 100 microm spacing in an active area of 20 x 20 mm on microfabricated glass
      substrates that were coated with poly(ethylene glycol) brushes. Cocultivation of
      hepatocytes with endothelial cells was essential to stabilize hepatocyte
      viability and liver-specific functions, allowing us to obtain hepatocyte
      spheroids with a diameter of 100 microm, functioning as a miniaturized liver to
      secret albumin for at least one month. The most important feature of this study
      is that these substrates are defined to provide an unprecedented control of
      substrate properties for modulating cell behavior, employing both surface
      engineering and synthetic polymer chemistry. The spheroid array constructed here
      is highly useful as a platform of tissue and cell-based biosensors and detects a
      wide variety of clinically, pharmacologically, and toxicologically active
      compounds through a cellular physiological response.

PMID- 15174170
TI  - A template-assembled synthetic protein surface mimetic of the von Willebrand
      factor A1 domain inhibits botrocetin-induced platelet aggregation.
AB  - Platelet adhesion, the initial step of platelet activation, is mediated by the
      interaction of von Willebrand factor (VWF) with its platelet receptor, the GPIb
      IX complex. The binding of VWF to GPIb-IX is induced either by increased shear
      stress or by exogenous modulators, such as botrocetin. At a molecular level, this
      interaction takes place between the A1 domain of VWF and the GPIb alpha chain of
      the GPIb-IX complex. We report here the design and functional characteristics of
      a VWF template-assembled synthetic protein (TASP), a chimeric four-helix-bundle
      TASP scaffold mimicking the surface of the A1 domain. Twelve residues located on
      helices alpha 3 and alpha 4 in the native A1 domain were grafted onto a surface
      formed by two neighboring helices of the TASP. VWF TASP was found to inhibit
      specifically botrocetin-induced platelet aggregation and to bind both botrocetin
      and GPIb alpha. However, in contrast to the native A1 domain, VWF TASP did not
      bind simultaneously to both ligands. Modeling studies revealed that the relative
      orientation of the alpha helices in VWF TASP led to a clash of bound botrocetin
      and GPIb alpha. These results demonstrate that a chimeric four-helix-bundle TASP
      as a scaffold offers a suitable surface for presenting crucial residues of the
      VWF A1 domain; the potential of the TASP approach for de novo protein design and
      mimicry is thereby illustrated.

PMID- 15174171
TI  - 1-Ethynylpyrene as a tunable and versatile molecular beacon for DNA.

PMID- 15174172
TI  - Residue- and sequence-selective binding of nonaromatic dipeptides by bis(beta
      cyclodextrin) with a functional tether.

PMID- 15174173
TI  - Drug identification through in vivo screening of chemical libraries.

PMID- 15174174
TI  - Microbial desaturation of bis(1-chloro-2-propyl) ether into a dichloro vinyl
      ether.

PMID- 15174175
TI  - Biosynthesis of carbapenem antibiotics: new carbapenam substrates for carbapenem
      synthase (CarC).

PMID- 15174177
TI  - Tetrahydrogestrinone: discovery, synthesis, and detection in urine.
AB  - Tetrahydrogestrinone (18a-homo-pregna-4,9,11-trien-17beta-ol-3-one or THG) was
      identified in the residue of a spent syringe that had allegedly contained an
      anabolic steroid undetectable by sport doping control urine tests. THG was
      synthesized by hydrogenation of gestrinone and characterized by mass spectrometry
      and NMR spectroscopy. We developed and evaluated sensitive and specific methods
      for rapid screening of urine samples by liquid chromatography/tandem mass
      spectrometry (LC/MS/MS) of underivatized THG (using transitions m/z 313 to 241
      and 313 to 159) and gas chromatography/high-resolution mass spectrometry
      (GC/HRMS) analysis of the combination trimethylsilyl ether-oxime derivative of
      THG (using fragments m/z 240.14, 254.15, 267.16, and 294.19). A baboon
      administration study showed that THG is excreted in urine.

PMID- 15174179
TI  - Post-source decay matrix-assisted laser desorption/ionization mass spectrometric
      study of tetracyclic 2,3-dihydro-1,5-benzothiazepines.
AB  - The fragmentation behavior of six tetracyclic 2,3-dihydro-1,5-benzothiazepine
      derivatives cationized with protons and silver ions under post-source decay (PSD)
      matrix-assisted laser desorption/ionization (MALDI) conditions is reported. The
      protonated adduct ions decompose into several structurally important fragment
      ions, including substituted cyclopropane and benzohydrothiazole cations.
      Elimination of Ag and H and/or AgH from the silver-cationized adduct ions of
      these ([M+Ag](+)) compounds was observed. It was also found that [M+Ag](+)
      produced silver-depleted fragment ions exclusively. Based on the PSD results a
      fragmentation pathway is proposed for the [M+H](+) and [M+Ag](+) precursor ions.

PMID- 15174178
TI  - Direct determination of endogenous melatonin in human saliva by column-switching
      semi-microcolumn liquid chromatography/mass spectrometry with on-line analyte
      enrichment.
AB  - An analytical method that enables direct and sensitive determination of
      endogenous melatonin (MLT) in human saliva was developed by means of column
      switching semi-microcolumn liquid chromatography (i.d.: 1-2 mm)/mass spectrometry
      (LC/MS). The system allows direct injection analysis of a 400-microL aliquot of
      saliva with minimal sample pretreatment (internal standard (IS) addition and
      vortex mixing) and a relatively short run-time (10 min). The system consists of
      three columns to attain large volume injection and on-line analyte enrichment. A
      pre-column packed with a silica-based mixed-functional C8 (4.0 mm i.d. x 20 mm)
      was used for on-line sample cleanup. MLT and an IS, the d7 isomer of MLT (d7
      MLT), were heart-cut by valve switching and enriched at the top of the
      intermediate trapping column packed with a silica-based C18 (4.0 mm i.d. x 10
      mm). Subsequently, the analytes were backflushed into a semi-micro C18 silica
      column (2.0 mm i.d. x 150 mm) for the final separation. MLT and IS were
      ascertained by positive electrospray ionization and selected ion monitoring
      (SIM). MLT was monitored based on its fragment ion at m/z 174.1 by in-source
      collision-induced dissociation (CID). The validation of this method revealed a
      detection limit of 2.5 pg mL(-1) at a signal-to-noise (S/N) ratio of 5. The
      linearity of the method was established in the ranges 5-250 and 100-2500 pg mL(
      1) with a coefficient of determination of greater than 0.998. Accuracies,
      evaluated at five levels in the range 5-1000 pg mL(-1), were between 81 and 108%
      with a relative standard deviation (RSD) ranging from 1.3-20%. The method was
      successfully applied for the endogenous saliva MLT monitoring of two healthy
      subjects.

PMID- 15174180
TI  - Semi-automated quantification of ivermectin in rat and human plasma using protein
      precipitation and filtration with liquid chromatography/tandem mass spectrometry.
AB  - Ivermectin is a parasiticide commonly used in humans and livestock. It is
      currently under development for the treatment of pediculosis of humans (head
      lice) that does not respond to established treatments. A liquid
      chromatography/turbo ion spray tandem mass spectrometry (LC/TIS-MS/MS) method for
      the determination of ivermectin in rat and human plasma has been developed that
      uses emamectin [4"-epi-(methylamino)-4"-deoxyavermectin] as the internal
      standard. Sample preparation involved protein precipitation and filtration of
      fortified plasma in the 96-well format. Chromatographic separation was
      accomplished using fast gradient conditions on a C8 stationary phase. The
      analytes were detected with the mass spectrometer operated in the positive ion,
      multiple reaction monitoring mode. The method exhibited good intra- and interday
      accuracy and precision, and was linear over a dynamic range of 1-2000 ng/mL. In
      rat plasma, intraday accuracy ranged between 84-93% for the low quality control
      (QC) sample (1.5 ng/mL), and between 91-109% for the remaining QCs. Intraday
      precision ranged between 4.9-15% for the low QC, and 0.8-6.3% for the remaining
      QCs. Interday accuracy ranged between 88-107%, and precision between 4.1-11%.
      Similar data was obtained using human plasma. An investigation of matrix effects
      indicated that the ionization efficiency of ivermectin was favored by the
      presence of an ammonium ion in an aqueous environment. The implications of this
      observation toward assay sensitivity are discussed.

PMID- 15174181
TI  - Fragmentation of biotinylated cyclic peptides.
AB  - Electrospray ionization coupled with tandem mass spectrometry (MS/MS) was used to
      determine the preferred binding site(s) of biotin NHS ester with a series of
      cyclic peptides with antibiotic properties. The peptides investigated are
      polymyxins, cyclic peptides produced by Bacillus polymyxa. In spite of the 1:1
      stoichiometry used in the labeling reaction, multiple biotin molecules were
      incorporated into intact polymyxin peptides. Given the amine specificity of the
      activated biotin and the large number of amino acids with primary amines in the
      polymyxins, it was not clear by inspection which binding sites were more reactive
      than others. MS/MS was used to characterize the structure of the biotinylated
      peptides. MS/MS spectra of cyclic peptides often lead to ambiguous structure
      determinations due to the potential for multiple ring openings which result in
      the generation of multiple ion series. The MS/MS spectra of polymyxin peptides
      are especially difficult to characterize due to the lack of variety in their
      amino acids; however, the added complexity of the biotin aided the elucidation of
      the fragmentation pathways. MS/MS spectra of the species with biotin additions
      were used to rationalize the preferential binding sites of these molecules.

PMID- 15174182
TI  - A modified internal lock-mass method for calibration of the product ions derived
      from sustained off-resonance irradiation collision-induced dissociation using a
      Fourier transform mass spectrometer.
AB  - A modified internal lock-mass calibration method is introduced for improving the
      mass measurement accuracy of the product ion spectra derived from sustained off
      resonance irradiation collision-induced dissociation (SORI-CID) Fourier transform
      ion cyclotron resonance (FTICR) mass spectrometry. This method involves an
      initial external calibration of the Fourier transform mass spectrometer to obtain
      the initial A- and B-terms for the equation (f(i) = A/(m/z)(i) + B). The A-term
      is adjusted by using an empirical relationship between the up-shift of the A-term
      and the pulse-gas duration, whereas the B-term is adjusted by using the mass of
      the unfragmented precursor ion from the SORI-CID mass spectrum of the unknown
      sample as internal lock-mass. These adjusted A- and B-terms are then used to
      provide exact mass SORI-CID calibration for the unknown sample. The modified
      internal lock-mass method achieved average mass measurement accuracy of
      approximately 3 ppm which is significantly better than that of the conventional
      internal lock-mass calibration ( approximately 9 ppm) and is approaching that of
      the internal calibration ( approximately 2 ppm) and requires no addition of
      internal calibrant or instrumental modifications.

PMID- 15174183
TI  - Electrospray ionization mass spectrometric analysis of nucleic acids using high
      throughput on-line desalting.
AB  - A rapid on-line desalting method utilizing ion-pair reversed-phase high
      performance liquid chromatography (IP-RP-HPLC) was employed in tandem with
      negative electrospray ionization mass spectrometry (ESI-MS) for the routine
      analysis of nucleic acids. Desalting was performed on a short 10 x 2.1 mm guard
      column packed with 3.5 microm C(18) sorbent. The HPLC system was connected in
      line to an orthogonal ESI-TOF mass spectrometer via a six-port, two-position
      switching valve, allowing desalting followed by mass analysis of nucleic acids.
      Duty cycle times for the method were as low as 1.5 min per sample. This allowed
      for the analysis of approximately 950 samples per 24-h time period, which is
      suitable for medium- to high-throughput applications. Average mass accuracy was
      determined to be 80 ppm for oligonucleotides up to 110 mer in length with
      external calibration. The method was utilized for synthetic oligonucleotide
      quality control and analysis of DNA genotyping fragments.

PMID- 15174184
TI  - An improved thin-layer chromatography/mass spectrometry coupling using a surface
      sampling probe electrospray ion trap system.
AB  - A combined surface sampling probe/electrospray emitter coupled with an ion trap
      mass spectrometer was used for the direct read out of unmodified reversed-phase
      C18 thin-layer chromatography (TLC) plates. The operation of the surface sampling
      electrospray ionization interface in positive and negative ionization modes was
      demonstrated through the direct analysis of TLC plates on which a commercial test
      mix comprised of four dye compounds viz., rhodamine B, fluorescein, naphthol blue
      black, and fast green FCF, and an extract of the caffeine-containing plant Ilex
      vomitoria, were spotted and developed. Acquisition of full-scan mass spectra and
      automated collection of MS/MS product ion spectra while scanning a development
      lane along the surface of a TLC plate demonstrated the advantages of using an ion
      trap in this combination. Details of the sampling system, benefits of analyzing a
      developed lane in both positive ion and negative ion modes, levels of detection
      while surface scanning, surface scan speed effects, and the utility of three
      dimensional data display, are also discussed.

PMID- 15174185
TI  - Development and validation of an isotope-dilution electrospray ionization tandem
      mass spectrometry method with an on-line sample clean-up device for the
      quantitative analysis of the benzene exposure biomarker S-phenylmercapturic acid
      in human urine.
AB  - An isotope-dilution electrospray ionization tandem mass spectrometry (ESI-MS/MS)
      method with an on-line sample clean-up device, for the quantitative analysis of
      human urine for the benzene exposure biomarker S-phenylmercapturic acid (SPMA),
      was developed and validated. The sample clean-up system was constructed from an
      autosampler, a reversed-phase C18 trap cartridge, a two-position switching valve,
      and controlling computer software and hardware. The sample clean-up system was
      interfaced via 1/20 splitting to the ESI source of a triple-quadrupole mass
      spectrometer using negative ion mode and multiple reaction monitoring for SPMA
      and the isotope-labeled internal standard. A strategy was adopted to acquire
      pooled blank urine matrix and quality control samples spiked with standards.
      Validated procedures and data on method specificity, detection limits, standard
      curves, precision and recovery, sample storage stability, and inter-laboratory
      comparison are presented. The analytical system was fully automated. No tedious
      manual sample clean-up procedures are required. With the selectivity and the
      sensitivity provided by ESI-MS/MS detection, the analytical system can be used
      for high-throughput and accurate determination of SPMA levels in human urine
      samples, as a biomarker for environmental as well as occupational benzene
      exposure.

PMID- 15174186
TI  - An unusual cleavage reaction of a peptide observed during dithiotreitol and
      tris(2-carboxyethyl)phosphine reduction: application to sequencing of HpTx2
      spider toxin using nanospray tandem mass spectrometry.
AB  - A recombinant peptidic spider toxin, HpTx2, was investigated directly by
      nanoelectrospray tandem mass spectrometry (MS/MS). This 30-residue toxin
      possesses a highly knotted structure with cystines arranged in close proximity.
      The low-energy collision-induced dissociation MS/MS spectrum of the [M+4H](4+)
      ion permitted characterization of the C-terminal sequence of HpTx2 up to Cys(26)
      that is involved in a disulfide bridge. Chemical pre-treatment with DTT or TCEP
      was then investigated, and it was found that an unexpected cleavage reaction of
      HpTx2 gave two smaller peptides which were completely sequenced by MS/MS
      experiments using a Qq-TOF mass spectrometer. This unusual hydrolysis reaction
      facilitated the determination of the complete sequence of the HpTx2 toxin.

PMID- 15174187
TI  - Rapid screening of plasma volume expanders in urine using matrix-assisted laser
      desorption/ionisation time-of-flight mass spectrometry.
AB  - The use of plasma volume expanders, especially those based on chemically modified
      polysaccharides such as hydroxyethyl starch, has found its way from the medical
      field to the athletic community in the everlasting drive for performance
      enhancement. As such, plasma volume expanders have been placed on the list of
      banned substances by the International Olympic Committee, and in turn require
      accurate and sensitive analytical tools for their detection in complex biological
      matrices. Here we present a relatively straightforward method for the detection
      of polysaccharide-based plasma volume expanders (PVE) in urine, based on the
      carefully controlled partial acid hydrolysis of urine (20 microL) in a total
      volume of 500 microL 4 M trifluoroacetic acid. Following the incubation (30 min
      at 100 degrees C) an aliquot of the hydrolysate is dried, re-suspended in the
      analytical matrix (e.g. 2,5-dihydroxybenzoic acid) and examined by matrix
      assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI
      TOFMS). The obtained mass spectrometric profile reveals a high number of
      characteristic peaks in the mass range between 500 and 3000 Da, a region that in
      urine samples devoid of PVE appears relatively clean, and thus allows the
      unambiguous identification of the presence of such PVE. This approach is fast
      (the mass profile can be obtained within 90 min), highly sensitive (the effective
      sample amount on the MALDI target is equivalent to 100 nL urine), needs little
      sample handling (four steps), requires no derivatisation and is devoid of
      interference from other biomolecules. The approach has been worked-out for
      hydroxy ethyl starch but can be applied to other polymer-derived plasma expanders
      such as dextran and probably the newly developed acetyl starch.

PMID- 15174188
TI  - Characterization of phenolic acids in black carrots (Daucus carota ssp. sativus
      var. atrorubens Alef.) by high-performance liquid chromatography/electrospray
      ionization mass spectrometry.
AB  - Phenolic acids were extracted from black carrot roots (Daucus carota ssp. sativus
      var. atrorubens Alef.) and a black carrot juice concentrate, and characterized by
      high-performance liquid chromatography/electrospray ionization mass spectrometry.
      Most of the compounds detected were identified as depsides composed of p
      coumaric, caffeic and ferulic acids. Additionally, three hydroxybenzoic acid
      derivatives and one quercetin glycoside were detected. 5-O-Caffeoylquinic acid
      (chlorogenic acid) represented the predominant compound amounting to 657 mg/kg in
      the roots and 5815 mg/kg in the concentrate. The specific fragmentation patterns
      of mono- and dihydroxycinnamoylquinic acids allowed the distinction of several
      stereoisomers. The presence of 4-O-caffeoylquinic acid and several further
      hydroxycinnamic acid esters, together with compounds not belonging to the depside
      type, is reported for the first time. The present study reveals that the phenolic
      profile of black carrots is even more complex than hitherto assumed and may
      contribute to pigment stability of extracts derived from the roots.

PMID- 15174189
TI  - Direct analysis of selected N-acyl-L-homoserine lactones by gas
      chromatography/mass spectrometry.
AB  - A rapid, simple and selective method involving direct separation by gas
      chromatography (GC) with electron ionization mass spectrometry (EI-MS) was
      employed to determine some N-acylhomoserine lactones (AHLs). Using GC/EI-MS,
      simultaneous separation and characterization of AHLs were possible without prior
      derivatization. Informative fragmentation patterns were obtained to identify the
      structures of N-acyl chains of AHLs. Electron ionization resulted in a common
      fragmentation pattern with the most abundant ion at m/z 143 and other minor peaks
      at m/z 71, 57, and 43. The presence of AHLs in extracts of Burkholderia cepacia
      strains was achieved in selected ion monitoring mode by using the prominent
      fragment at m/z 143.

PMID- 15174191
TI  - Investigation of chiral reactions: the structural detection of new hydrogenated
      isocinchona alkaloids from mixtures without isolation using electrospray
      ionization tandem mass spectrometry.
AB  - The reaction mixture for the hydrogenation of ethyl pyruvate on Pt-alumina
      catalyst modified with isocinchona alkaloids (alpha-ICN (I) and beta-ICN (II))
      was studied by electrospray ionization tandem mass spectrometry (ESI-MS/MS). It
      was established that part of the chiral modifiers themselves are converted into
      ions of m/z 299, 305 and 309 in the course of chiral hydrogenation. The
      experimental data allowed the determination of the probable structure of the ions
      mentioned. According to ESI-MS/MS spectra the structure of the new cinchona
      alkaloids was assumed: tetrahydro-isocinchonines (III-VI), decahydro
      isocinchonines (VII, VIII) and hydrogenated compounds of VII and VIII by scission
      of their C--N and C--O bonds (IX/1, IX/2, X). Fragmentation pathways are proposed
      for these new compounds.

PMID- 15174192
TI  - Unexpected observation of ion suppression in a liquid chromatography/atmospheric
      pressure chemical ionization mass spectrometric bioanalytical method.
AB  - Ion suppression is a well-known phenomenon in electrospray ionization (ESI) mass
      spectrometry. These suppression effects have been shown to adversely affect the
      accuracy and precision of quantitative bioanalytical methods using ion spray.
      Such suppression effects have not been as well defined in atmospheric pressure
      chemical ionization (APCI) and there is some debate whether these effects
      actually occur in the ionization process using APCI. Here an example is described
      where clear ion suppression was observed during studies on a model compound and
      three metabolites using APCI liquid chromatography/tandem mass spectrometry
      (LC/MS/MS).

PMID- 15174193
TI  - Ethylenediamine as a liquid chemical reagent to probe hydrogen bonding and host
      guest interactions with crown ethers in an ion trap tandem mass spectrometer.
AB  - Ethylenediamine (EDA) was used as a novel liquid chemical reagent to probe
      hydrogen bonding and host-guest interactions with crown ether derivatives in an
      ion trap mass spectrometer (ITMS). Selective ion/molecule reaction product ions
      were generated by reactions of EDA with oxygenated and aza-crown ethers. For the
      oxygenated crown ethers, glycols and dimethylglycols, ion/molecule reactions led
      to the formation of the protonated molecules ([M+H](+)) and adduct ions including
      [M+30](+), [M+44](+) and [M+61](+). The aza-crown ethers produced [M+H](+),
      [M+13](+) and [M+27](+) ions. Collisionally activated dissociation (CAD)
      experiments were applied to probe the binding strength of these ion/molecule
      reaction products. CAD results indicated that all these hydrogen-bonding
      complexes are weakly bound except for the [M+44](+) ion of 18-crown-6, since all
      the complexes dissociate to the protonated polyether and/or protonated EDA.
      Fragmentation of the [M+H](+) ions under CAD conditions indicates the extensive
      covalent bond cleavage of the protonated crown ether skeleton.

PMID- 15174194
TI  - Analytical characterization of a facile porous polymer monolithic trypsin
      microreactor enabling peptide mass mapping using mass spectrometry.
AB  - A simple and rapid single-step method is presented to fabricate an enzyme reactor
      using trypsin immobilized on a macroporous polymer monolith. A reactor produced
      in a capillary format is ready to use within 1 h of preparation. The monomers
      making up the monolith, including N-acryloxysuccinimide for covalent
      immobilization of the enzyme, are mixed with trypsin and introduced into the
      column by capillary force for polymerization/immobilization. The enzyme activity
      from column-to-column is reproducible below 5% relative standard deviation (RSD),
      while the reactor is durable for at least 20 weeks when stored at room
      temperature. The apparent kinetic constants V(max) and K(m) are of value similar
      to those obtained by free trypsin in solution. Enzymatic digestion of proteins
      was shown to be feasible on a time-scale of seconds and submicromolar
      concentrations enabling peptide mass mapping by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry.

PMID- 15174195
TI  - Non-linear and non-constant variance calibration curves in analysis of volatile
      organic compounds for testing of water by the purge-and-trap method coupled with
      gas chromatography/mass spectrometry.
AB  - Currently used operating conditions for analysing volatile organic compounds
      (VOCs) by purge-and-trap gas chromatography/mass spectrometry (GC/MS) produced
      non-linear calibration curves with non-uniform variance. Second-order polynomial
      models therefore had to be used in weighted regression analysis of measurements
      of replicates spiked at various concentrations. A transparent procedure based on
      a reported method of very low computational complexity allowed calculation of the
      parameters of second-order models, confidence bands of regression lines,
      prediction bands, and confidence intervals of discriminated analyte
      concentrations. Tolerance intervals were introduced for this last purpose.
      Critical, detection and quantification levels drawn from the calibration curves
      were compared with those calculated by the EPA method.

PMID- 15174197
TI  - Electrospray ionization mass spectral fragmentation mechanisms of DNA-recognizing
      polyamides containing N-methylpyrrole and N-methylimidazol.

PMID- 15174196
TI  - Surface-activated chemical ionization ion trap mass spectrometry in the analysis
      of 21-deoxycortisol in blood.

PMID- 15174199
TI  - Mass spectral studies of a sesquiterpene: 1(10),2,11(13)-eremophylatrien-12-oic
      acid.

PMID- 15174201
TI  - [70th anniversary of the O.O. Bogomolets Institute of Physiology of the National
      Academy of Science of Ukraine].
AB  - The brief history of creation and basic stages of development of the largest
      centre of science of the country and global physiological science--A.A.
      Bogomolets Institute of physiology of National Academy of Sciences of Ukraine is
      stated. The basic achievements of scientific divisions of Institute for the 70
      year's period in area of the most urgent problems of molecular physiology,
      neurophysiology, physiology of visceral systems are marked. Is covered many-sided
      and versatile scientific and publishing activity of the employees of Institute,
      the role of the outstanding scientists--physiologists and biophysicists of
      Institute in formation of national scientific schools is shown.

PMID- 15174202
TI  - [Role of nitric oxide and mitochondrial permeability pore in changes of oxygen
      consumption in the working skeletal muscle].
AB  - On anaesthetized dogs the role NO and mitochondrial permeability transition pore
      (MPTP) in the regulation of regional blood circulation, efficiency of oxygen
      using, and muscle contraction force was investigated. Under different frequency
      stimulation it was shown, that short-term (30") smoothly tetanic contraction (40
      Hz) is more economic for a skeletal muscle than short-term (30") single
      contractions (8 Hz) with respect to the efficiency of oxygen using. Injection NOS
      inhibitor L-NMMA (2.7 mg/kg, i.a.) resulted in pronounced fall of a functional
      hyperemia magnitude (P < 0.01), significant reduction of the muscle contractions
      force (P < 0.01), and efficiency of oxygen using (P < 0.01), in m.gastrocnemicus,
      in comparison with control. Pretreatment with an exogenous activator of MPTP
      phenilarsine oxide (PAO, 0.2 mg/kg, i.a.) caused a marked inhibition of an
      endothelium-dependent vessels dilation on skin-muscle region of rear limb. At the
      same time the muscle contractions force was significantly decreased (P < 0.01)
      and efficiency of oxygen using was diminished too (P < 0.01). This was
      accompanied by an appearance in blood from v. femoralis mitochondrial factor
      (MF), indicating MPTP activation. Preliminary injection of the exogenous NO donor
      sodium nitroprusside (0.2 mg/kg, i.v.) prevented considerably an inhibition of a
      dilation vessels reserve, a fall of muscle contractions force (P < 0.01) and
      considerably reduced oxygen cost (P < 0.01) of a m.gastercnemicus work also. The
      concentration of MF in blood from v. femoralis also was considerably reduced (P <
      0.001) that has been the evidence of MPTP inhibition. Thus, activation of MPTP
      and development of oxidative stress resulted in endothelium dysfunction, a force
      of muscle contraction diminishing and a significant decrease in efficiency of
      oxygen using. NO essentially reduced the negative effects of MPTP activation and
      was antagonist of oxidative damages development.

PMID- 15174203
TI  - [Study of the mechanism of action of novel fluoro-containing analogs of diazoxide
      on the vascular tonus].
AB  - On the isolated preparations of rat aorta it was shown that the new fluoro
      containing analogues of diazoxide (DiazoFp and DiazoFm) elicit vasodilatatory
      effects related to the activation of ATP-sensitive potassium channels. It was
      established that DiazoFp is a more powerful vasodilator than DiazoFm and
      diazoxide. It was proposed that DiazoFp action consists of two components: direct
      activation of sarcKATP channels and activation of sarcKATP channels, through
      activation of mitoKATP channels.

PMID- 15174204
TI  - [Acute myocardial ischemia-reperfusion injury: role of nitric oxide system].
AB  - In experiments on the closed-chest dogs it was shown that NOS inhibition resulted
      in the significant alterations of hemodynamic indices (coronary and peripheral
      vascular resistance, cardiac output and heart rate) under local myocardial
      ischemia/reperfusion in comparison with control experiments. At the first time it
      was shown that NOS inhibition activated the autophagic destruction of
      cardiomyocytes in the ischemic myocardium and could reduce an area of
      functionally active myocardium. L-arginine administration attenuated cardio- and
      hemodynamic disturbances, that substantially improved the course of
      ischemia/reperfusion, diminished the ultrastructural changes in myocardium and
      prevented development of autophagic programmed cell death.

PMID- 15174206
TI  - [Aging-related increase of sensitivity of the mitochondrial permeability
      transition pore to inductors in the rat heart].
AB  - An age-related increase in the sensitivity of the mitochondrial permeability
      transition pore (MPTP) to inductors of it's opening, Ca2+ ions and
      phenylarsineoxide (PAO) was studied in experiments in vitro on isolated heart
      mitochondria of adult and old rats. Two indices were measured
      spectrophotometrically (lambda = 520 nm) by a decrease in an optical density
      (OD), resulting from mitochondrial swelling and a release of mitochondrial
      unidentified substances (mitochondrial factor, MF) registered also
      spectrophotometrically in a range of waves lambda = 230-260 nm. Dose-dependent
      effect of Ca2+ (10(-7)-10(-4) mol/l) and PAO (10(-8)-10(-4) mol/l) on swelling of
      the mitochondria were observed in samples from both adult and old rats. Swelling
      of the mitochondria from the heart of old rats induced by application of the
      above inductors was more intensive than the respective effect in samples from
      adult rats. In samples from the heart of both adult and old rats Ca2+ ions within
      the tested concentration range (10(-7)-10(-4) mol/l) evoked the release of MF in
      a dose-dependent manner. Mitochondria from the heart of old rats were found to be
      capable of releasing some amounts of MF in the absence of the MPTP inductors PAO.
      When this inductor was applied in a 10(-9) to 10(-4) mol/l concentration range,
      isolated mitochondria from the heart of old rats released unidentified substances
      with the absorption peaks at two wavelength, lambda = 230 nm and lambda = 240-245
      nm. The former peak was found to be Cyclosporin A-insensitive, while the latter
      peak could be practically completely inhibited by this antibiotic. The
      concentrations of tested solutions (10(-7) mol/l CaCl2 and 10(-9) mol/l PAO), at
      which the release of the factor from the mitochondria of the old rat heart was
      observed, were significantly lower than those in adult rats. Our experimental
      data show that mitochondria isolated from the heart tissue of old rats
      demonstrate significantly higher sensitivity to inductors of MPTP-opening, Ca(2+)
      overload and PAO as compared to that typical of adult animals. A higher
      sensitivity of MPTP-opening in the heart of old rats was accompanied by a higher
      basal level of expression of mRNA of the bax gene, as compared to that found in
      adult animals. The expression of the bcl-2 gene showed no age group-related
      differences. It can be supposed that a proapoptotic agent, the Bax protein, is
      related to an increase in the sensitivity of the MPTP (in particular to that
      manifested in the processes of pore formation) in the course of aging.
      Antioxidants, melathonin and trolox, when applied in 10(-5) mol/l concentration,
      presented to a certain extent opening of the MPTP-induced by 10(-5) mol/l PAO in
      samples from adult and old rats. These findings can be used for correction of
      increased sensitivity of the MPTP to different inductors, which is typical of old
      rats. We conclude that physiological aging is accompanied by the mitochondrial
      dysfunction. The MF-released capability of the mitochondria from heart tissue of
      old rats observed both in the presence and absence of MPTP-opening inductors
      (probably related to a higher sensitivity of MPTP-opening) is one of the
      manifestation of such dysfunction.

PMID- 15174205
TI  - [Some mechanisms of the development of endothelial disfunction in aging].
AB  - Taking into consideration age-related changes in endothelium, the ability of
      endothelium to produce vasoactive substances has been studied in healthy subjects
      of various age. Under experimental conditions, the activity of constitutive and
      inducible NO-synthase has been studied as well. The clinical part of the study
      involved investigation of 38 healthy subjects aged 60-79. The study has been
      designed to investigate vasomotor function of the endothelium, the levels of
      endothelin-1, NO2, prostacyclin, thromboxan, the level of adhesive molecules and
      inhibitor of tissue plasminogen activator. The levels of endothelial and
      inducible NO-synthases in tissues of the myocardium and the aorta has been
      investigated in healthy rats of various age. The data obtained show a decrease in
      the production of relaxation factors: NO and prostacyclin with aging. An
      important mechanism of deterioration of NO-synthesizing function of the
      endothelium is a decrease in endothelial NOS activity. The synthesis of
      endothelial vasoconstricting agents increased with ageing. This in combination
      with decreased production of vasodilating substances results in deterioration of
      defence properties of the endothelium. The increase in titer of adhesive
      molecules and inhibitors of tissue plasminogen activator testifies to age
      dependent deterioration of anti-inflammatory and antithrombotic activities of the
      endothelium.

PMID- 15174207
TI  - [Systemic inflammatory process as an etiological factor in increase of
      atherogenic potential of plasma].
AB  - The aim of the study was to investigate the role of systemic inflammation in the
      development of the atherogenic plasma abilities and to prevent the systemic
      inflammatory process by using fenofibrate (F.). An experimental model of
      inflammation was produced in 2 groups of rabbits, one of them received F. The
      activity of the systemic inflammation, oxidative stress, disturbances of
      lipoprotein metabolism, and the character and mechanisms of F. action were
      determined during 8 weeks of investigation. Under the primary character of the
      inflammation, induced in rabbits by intravenous injection of pirogenal, it was
      determined the distinct interdependence between activity of the systemic
      inflammatory process, monocytes activation, oxidative stress intensity,
      antioxidative plasma potential, the appearance of the lipoprotein atherogenic
      forms, hypercholesterolemia and hypertriglyceridemia. This dependence was
      confirmed in rabbits, treated with F. These data show that treatment with F.
      prevents hypercholesterolemia and hypertriglyceridemia development and suppresses
      the activity of inflammatory process.

PMID- 15174208
TI  - [Characteristics of pain reaction and sensitivity in species of different genetic
      groups].
AB  - The development of a painful syndrome in two genetic lines of mice 57BL/6J and
      CBA/CaLac was investigated in experiments with the formalin test. It have been
      shown the influence of nociceptive stimulus on behaviour of animals, the presence
      of essential distinctions in painful behavioural reaction and other behavioural
      states, the difference in a painful threshold on electric stimulus between these
      both groups of animals. The nociceptive stimulus results in reduction of
      behaviour mobility states of animals and increases the passive behaviour states.
      The genetic line of mice 57BL/6J has shown higher values of intensity of painful
      reaction at the lower background painful sensitivity to electric stimulus, animal
      lines 57BL/6J were more mobile than animal lines CBA/CaLac. Such character of
      animal behaviour in lines C57BL/6J suggests the increased reactivity of nervous
      system of these animals, it may serve as a model for studying the cellular
      mechanisms of development of somatic pain for finding effective hypoanalgetic
      steps.

PMID- 15174209
TI  - [Evaluation of analgesia evoked by microwaves of low intensity in the point of
      acupuncture in mice with different genotypes].
AB  - It was investigated the duration of pain response-licking of a back paw after
      injection of a solution of formalin (5% on 0.025 ml) in a dorsal surface of a
      back paw and the level of analgesia evoked by microwaves of low intensity on the
      point of acupuncture E-36 applied during 10 minutes on injected back paw in mice
      of genotypes C57B1/6j (C57), CBA/CaLac (CBA) and white laboratory mice. It was
      shown that the mice C57 had the largest duration of pain response and the lowest
      level of analgesia (8.3%) when compared with mice CBA and white laboratory mice.
      The mice of a genotype NAA had the shortest duration of pain response, but an
      average level of analgesia (13.8%) in comparison with mice C57 and white
      laboratory mice. The white laboratory mice had average duration of pain response
      but the greatest level of analgesia (24.2%) in comparison with mice of a genotype
      C57 and CBA.

PMID- 15174210
TI  - [Structural organisation of CA1 zone in the hippocampus of rats in the
      experimental brain ischemia].
AB  - The dynamic of structural and ultrastructural changes of CA1 area of the
      hippocampus was examined in rats after 10 or 15 min of global ischemia (4 vessels
      occlusion, 4VO) followed by reperfusion. In the early period of reperfusion (15
      min, 2 h), the structural changes in synaptic terminals were observed, without
      any significant signs of neuronal damage. These changes consisted in (i) the
      increase of the relative number of perforated and multiple synapses, and (ii) the
      synaptic vesicles rearrangement. Clear neuronal damage appeared morphologically
      at 24 h, and then developed for 3-6 days and resulted in the delayed damage and
      death of the hippocampal neurons.

PMID- 15174211
TI  - [Effect of oxygen-glucose deprivation of different duration on rat hippocampal
      slice cultures].
AB  - We studied morphofunctional changes in organotypic hippocampal slice cultures
      (OHSC) subjected to oxygen-glucose deprivation (OGD) for 10, 30, and 60 min
      followed by normoxic reoxygenation for 1, 4, and 24 h. Cell viability was
      estimated using trypan blue (TB) staining, lactate dehydrogenase (LDH) assay, and
      MTT/formazan assay. Structural changes in CA1 area of OHSC were analyzed by light
      and electron microscopy. No significant signs of destruction were found in the
      cultures 1 h following 10 min OGD; moreover, clear increase in cell metabolic
      activity was determined by MTT/formazan assay. Ultrastructural analysis of CA1
      stratum radiatum revealed an increase in the number of glial processes and the
      number of perforated and multiple synapses as compared to the control, where
      simple synapses were relatively more numerous. 4 h following 10 min OGD,
      manifestations of cell damage in the cultures appeared and become profound at 24
      h after OGD. We suppose that mild (10 min) OGD leads to plastic changes in
      neurons and delayed cell damage. 30 and 60 min OGD resulted in more early and
      pronounced cell damage as compared to 10 min OGD. To conclude, clear dependence
      of cell damage on the duration of deprivation as well as reoxygenation was
      observed. The model of ischemic damage in the slice cultures appears convenient
      to be used to analyze properties and mechanisms of neural cell response to OGD
      and to test neuroprotective tools.

PMID- 15174212
TI  - [Electrophoretic lymphocyte motility in tonsils of patients with chronic
      tonsillitis].
AB  - The changes in the electrophoresis motility (EPM) of lymphocytes in the tonsils
      of patients with chronic tonsillitis were assessed using the method of
      microelectrophoresis. Tonsil lymphocytes of healthy volunteers were used as
      controls of these experiments. During this investigation it was shown that the
      average value of EPM of lymphocytes in the control group was -0.98 +/- 0.02
      mumol.cm.V-1.S-1. The absolute value of TPM of lymphocytes of the patients with
      chronic tonssillitis in average dropped 16% to a value of -0.82 +/- 0.02
      mumol.cm.V-1.S-1. The percent composition of lymphocytes, whose EPM was close to
      0, is higher in the group of patients with chronic tonsillitis, then in the
      control group. Mathematical analysis were conducted on the experimental data and
      on the basis of the results it was proposed that the drop of the absolute value
      of EPM during chronic tonsillitis is connected with the drop in the amount of
      active lymphocytes.

PMID- 15174213
TI  - [Ultrastructural characteristics of rat adrenal cortex cultured cells in the norm
      and after calcium ionophore A23187 and adrenocorticotropic hormone application].
AB  - The ultrastructure of a fasciculata-reticularis zone cells of a rat adrenal
      cortex in norm, and after application of adrenocorticotropic hormone (ACTH) and
      calcium ionophore A23187 was investigated. In the control it has been revealed
      three types of cells which differed on the ultrastructure. ACTH or ionophore
      A23187 application resulted in disappearance of a difference in ultrastructure of
      cells of different types, also all cells got morphological attributes of
      accelerated steroidogenesis. The probable role of cells with different types of
      ultrastructure for fasciculata-reticularis zone function, and also prospective
      participation of calcium ions in ACTH influences on ultrastructure of a
      fasciculata-reticularis zone is discussed.

PMID- 15174214
TI  - [State of lipid peroxidation and blood antioxidant system in rats with acute
      pneumonia].
AB  - The functional condition of prooxidant--antioxidant system in rat blood plasma in
      acute pneumonia, on the 4th full day after intranasal animals' infectioning, by
      Staphylococcus Aureus culture depending on sex was studied. The investigation of
      PLO indexes and AOS activity on the 4th full-day after animals' contamination
      with St. aureus culture, in blood plasma, in acute pneumonia, showed the increase
      of DK and MDA content, and oppression of AOS-SOD ferments and catalase activity.
      In males these changes were more expressed indicating an exhaustion of functional
      reserves of antioxidant system.

PMID- 15174215
TI  - Adherence to calcium channel blocker therapy in older adults: a comparison of
      amlodipine and felodipine.
AB  - The efficacy of dihydropyridine calcium channel blockers for treating
      hypertension appears to be similar, but a variety of factors, including patient
      characteristics, tolerability and pharmacokinetic properties, may influence
      treatment adherence and outcome. We aimed to evaluate treatment adherence in
      clinical practice among older hypertensive adults (50+ years) prescribed
      amlodipine or felodipine for the first time as part of the California Medicaid
      (Medi-Cal) program. We used a retrospective, matched, cohort-analysis design.
      Over 1 year, patients prescribed amlodipine were 21% less likely to discontinue
      study treatment than those prescribed felodipine. Discontinuation tended to occur
      early, with 20% and 30% of amlodipine and felodipine patients, respectively,
      discontinuing treatment after one prescription. A non-significant difference in
      favour of amlodipine was demonstrated for anti-anginal medication use among
      patients taking these drugs at baseline. This study suggests that use of
      amlodipine may be associated with improved adherence, compared with felodipine,
      among older out-patients in the Medi-Cal program.

PMID- 15174216
TI  - Echocardiographical characteristics of healthy young subjects with physiological
      mitral regurgitation.
AB  - We aimed to analyse the echocardiographical characteristics of healthy subjects
      and determine the causal mechanism of the development of physiological mitral
      regurgitation (PMR). A total of 130 healthy subjects were divided into two groups
      according to whether or not PMR was detected. There were no statistical
      differences between the two groups in terms of the mean values of the systolic
      and diastolic left ventricular internal diameters and the left atrial diameter.
      The mean values of the length and thickness of the anterior mitral valve (AMV)
      and the mitral annular diameter (MAD) from subjects in group 1 (with PMR) were
      statistically different from those of group 2 (without PMR). In conclusion, the
      AMV was slightly longer and thicker and the MAD was smaller in subjects with PMR
      than in subjects without PMR. The changes observed in the AMV and the mitral
      annulus may play a causal role in the development of PMR.

PMID- 15174217
TI  - Coronary flow reserve after coronary intervention in similar in patients with
      preserved viability in previous myocardial infarction and in those with angina
      pectoris.
AB  - The relationship between coronary flow reserve (CFR) and viability in the
      infarcted myocardium has not been fully clarified. We measured coronary blood
      flow velocity immediately after coronary intervention (with percutaneous
      transluminal coronary angioplasty [PTCA] or stenting) in 38 patients with
      previous myocardial infarction and preserved viability and 48 with angina
      pectoris. CFR was calculated and was similar between the two patient groups. No
      differences in the incidence of post-intervention CFR > 2.0 were detected; there
      were no differences in post-intervention CFR between patients with preserved
      myocardial viability and those with angina pectoris who underwent PTCA. Coronary
      stenting reduced the percentage diameter stenosis in both groups compared with
      PTCA and slightly increased the post-intervention CFR. No differences were,
      however, detected in post-intervention CFR between patients with preserved
      myocardial viability and those with angina pectoris who underwent additional
      stenting. These results reveal that in patients with preserved myocardial
      viability, post-intervention CFR was restored to values similar to those in
      patients with angina pectoris.

PMID- 15174218
TI  - Effectiveness of hyperbaric oxygen therapy in the treatment of complex regional
      pain syndrome.
AB  - In this double-blind, randomized, placebo-controlled study we aimed to assess the
      effectiveness of hyperbaric oxygen (HBO) therapy for treating patients with
      complex regional pain syndrome (CRPS). Of the 71 patients, 37 were allocated to
      the HBO group and 34 to the control (normal air) group. Both groups received 15
      therapy sessions in a hyperbaric chamber. Pain, oedema and range of motion (ROM)
      of the wrist were evaluated before treatment, after the 15th treatment session
      and on day 45. In the HBO group there was a significant decrease in pain and
      oedema and a significant increase in the ROM of the wrist. When we compared the
      two groups, the HBO group had significantly better results with the exception of
      wrist extension. In conclusion, HBO is an effective and well-tolerated method for
      decreasing pain and oedema and increasing the ROM in patients with CRPS.

PMID- 15174220
TI  - Relationship between cardiovascular risk indicators and types of obesity in
      overweight and obese women.
AB  - We aimed to evaluate the relationship between different types of obesity and
      cardiovascular risk indicators. A total of 623 overweight (body mass index [BMI]
      > 25 kg/m2), and 2559 obese (BMI > 30 kg/m2) women were divided into four groups
      according to their BMI and waist-to-hip ratio (WHR): simple overweight (BMI 25-30
      kg/m2 and WHR < 0.8, n = 371), abdominal adiposity (BMI 25-30 kg/m2 and WHR >
      0.8, n = 252), peripheral (pure) obesity (BMI > 30 kg/m2 and WHR < 0.8, n = 918)
      and central obesity (BMI > 30 kg/m2 and WHR > 0.8, n = 1641). The levels of the
      risk indicators measured (clinical, anthropometric and laboratory) were
      significantly higher in the central obesity group. Total body fat and abdominal
      fat accumulation seems to result in more serious hyperinsulinaemia and insulin
      resistance in central obesity. Measuring BMI and WHR in obese patients may reveal
      their risk for coronary heart disease.

PMID- 15174219
TI  - A new treatment modality for fibromyalgia syndrome: hyperbaric oxygen therapy.
AB  - Fibromyalgia syndrome (FMS) is characterized by longstanding multifocal pain with
      generalized allodynia/hyperalgesia. There are several treatment methods but none
      has been specifically approved for this application. We conducted a randomized
      controlled study to evaluate the effect of hyperbaric oxygen (HBO) therapy in FMS
      (HBO group: n = 26; control group: n = 24). Tender points and pain threshold were
      assessed before, and after the first and fifteenth sessions of therapy. Pain was
      also scored on a visual analogue scale (VAS). There was a significant reduction
      in tender points and VAS scores and a significant increase in pain threshold of
      the HBO group after the first and fifteenth therapy sessions. There was also a
      significant difference between the HBO and control groups for all parameters
      except the VAS scores after the first session. We conclude that HBO therapy has
      an important role in managing FMS.

PMID- 15174221
TI  - Electroencephalographical effects of sarpogrelate hydrochloride versus
      ticlopidine hydrochloride in elderly patients with peripheral atherosclerosis.
AB  - The aim was to determine the efficacy of sarpogrelate (a selective 5
      hydroxytryptamine-2-serotonergic receptor antagonist) on cerebrovascular function
      and mean blood pressure (mBP) in elderly patients (> 60 years old). Patients with
      peripheral circulatory disorders were studied using electroencephalogram (EEG)
      and mBP measurements before and after 2 years' treatment with either sarpogrelate
      (n = 31) or ticlopidine (n = 43). Ticlopidine had no significant effect on the
      whole brain. Sarpogrelate decreased the percentage of slow waves (%slow), but not
      significantly, and was associated with a smaller change in the percentage of slow
      waves (delta slow). In the anterior area, neither drug caused significant EEG
      changes. In the posterior area, sarpogrelate significantly decreased the %slow
      and increased the %alpha values, and was associated with a significantly higher
      delta alpha value than ticlopidine. The results suggest that sarpogrelate
      hydrochloride can suppress serotonin-induced pathological processes in peripheral
      circulatory disorders and may be recommended as an anti-platelet agent, even in
      elderly patients with subclinical arteriosclerosis.

PMID- 15174222
TI  - Detection of Grb-2-related adaptor protein gene (GRAP) and peptide molecule in
      salivary glands of MRL/lpr mice and patients with Sjogren's syndrome.
AB  - The pathogenesis of Sjogren's syndrome (SS) is poorly understood. In this study
      we used an in-house mouse spleen cDNA microarray to analyse genes in spleens from
      MRL/lpr (an SS mouse model) mice. We have previously demonstrated that GRAP genes
      were up-regulated in salivary glands of the same mice. The microarray analysis
      showed that seven out of 2304 genes were highly expressed in spleens from the
      MRL/lpr mice, one of which was the GRAP gene. In other words, the GRAP gene is
      highly expressed in the salivary glands and spleen of MRL/lpr mice. We also
      carried out immunohistochemical studies. Mouse and human Grb-2-related adaptor
      protein (GRAP) antigens were expressed on ductal cells and infiltrating
      lymphocytes in salivary glands of MRL/lpr mice and SS patients, but only weakly
      in controls (MRL/+ mice and individuals with salivary cysts). These results
      suggest that the GRAP gene might have a role in the pathogenesis of SS.

PMID- 15174223
TI  - Reperfusion strategy after regional ischaemia: comparative study of reperfusion
      conditions and compositions.
AB  - We investigated the effects of pressure, temperature and additives on aortic root
      reperfusion success. Cardiopulmonary bypass and heart arrest were initiated in
      mongrel dogs and sudden uncontrolled normothermic (group 1), pressure controlled
      substrate enriched normothermic (group 2a), pressure controlled unmodified
      normothermic (group 2b) and pressure controlled unmodified tepid (group 3)
      reperfusion compared. In group 1, the first cardiac rhythm was ventricular
      fibrillation, but dogs in the other groups showed spontaneous sinus rhythm.
      Recovery times were significantly longer and cardiac output levels significantly
      decreased in group 1 compared with the other groups. Prolonged lactate production
      and oxygen uptake failure were observed in group 1 compared with the other
      groups; oxidative stress markers and microscopic studies confirmed significant
      tissue injury in group 1. All parameters were similar between groups 2a, 2b and
      3, indicating that low reperfusion pressure in the first 2 min is the most
      effective component of reperfusion.

PMID- 15174224
TI  - Reperfusion strategy after regional ischaemia: simulation of emergency
      revascularization and effects of integrated cardioplegia on myocardial
      resuscitation.
AB  - We induced ischaemia in the left anterior descending artery of 16 dogs while the
      heart was beating, followed by cardiopulmonary bypass (CPB), aortic cross
      clamping and blood cardioplegia. Half of the dogs received integrated blood
      cardioplegia and sudden uncontrolled reperfusion (group A) while the others
      received the same cardioplegia followed by pressure-controlled tepid initial
      reperfusion (group B). The effects on myocardial cell metabolism, oxidative
      stress and ultrastructure were recorded. The recovery period was significantly
      longer and cardiac output levels after CPB significantly lower in group A
      compared with group B. Group A showed a failure to uptake and utilize oxygen
      during the recovery period and significant lipid peroxidation. Marked tissue
      oedema was seen in group A but mitochondrial and organelle integrity was almost
      normal in both groups. We conclude that integrated cardioplegia could partially
      resuscitate the myocardium in this model, and pressure controlled reperfusion
      during the first 2 min is needed as an adjunct procedure.

PMID- 15174225
TI  - Intra-articular injection of tenoxicam in rats: assessment of the local effects
      on the articular cartilage and synovium.
AB  - This study investigated the possible local adverse effects of intra-articular
      administration of tenoxicam in the rat knee joint. A total of 50 rats were given
      0.25 ml of a standard preparation of tenoxicam by injection into the right knee
      joint and 0.25 ml of 0.9% saline solution by injection into the left knee joint
      as a control. Groups of 10 rats were killed 24 h, 48 h, 7 days, 14 days and 21
      days after tenoxicam administration. Two rats were sham operated; one was killed
      on the first day and the other on the second day after this procedure. All the
      joints were prepared and sectioned for histological examination. Tissue loss and
      oedema were observed in the specimens obtained 24 h and 48 h after treatment with
      tenoxicam. No pathological changes were observed in the 7-day, 14-day and 21-day
      specimens, or in the control joints. Caution should be exercised when using intra
      articular tenoxicam for post-operative analgesia.

PMID- 15174226
TI  - A comparison of colour duplex ultrasonography after transurethral alprostadil and
      intracavernous alprostadil in the assessment of erectile dysfunction.
AB  - This study aimed to investigate whether transurethral alprostadil could be used
      for the diagnosis of erectile dysfunction using colour duplex ultrasound. The
      ultrasonography results were compared after transurethral and intracavernous
      alprostadil administration in 20 patients with erectile dysfunction. There were
      no significant differences in the mean peak systolic velocities (PSVs) between
      the two routes of administration, but the mean end diastolic velocities (EDVs)
      showed significant differences, with patients treated with transurethral
      alprostadil having higher EDVs. Linear regression analysis of the PSVs reached
      following the two routes of administration showed a moderate relationship, but
      linear regression analysis of the EDVs showed no relationship. We concluded that
      transurethral alprostadil was an inappropriate vasoactive drug to use with colour
      duplex ultrasonography for the evaluation of patients with erectile dysfunction
      because it required a longer scan time and it was less effective and less
      reliable than intracavernous alprostadil at stimulating complete corporeal smooth
      muscle relaxation.

PMID- 15174227
TI  - Change in serum concentrations of interleukin-2 and interferon-gamma during
      treatment of tuberculosis.
AB  - We aimed to investigate changes in serum concentrations of the cytokines
      interleukin (IL)-2 and interferon (IFN)-gamma during the clinical course of
      active tuberculosis, to establish the presence of cellular immunity before and
      after treatment. Blood samples were taken from 18 patients with active
      tuberculosis before and 2 months after therapy; IL-2 and IFN-gamma concentrations
      were evaluated. The mean serum IL-2 concentration before therapy was 164.5 pg/ml
      (range 12-980 pg/ml) and the concentration 2 months after therapy was 92.11 pg/ml
      (range 1-490 pg/ml). The mean serum IFN-gamma concentrations were 10.83 pg/ml
      (range 1-22.2 pg/ml) and 4.64 pg/ml (range 1-28.5 pg/ml), respectively. The
      decrease in concentrations of both cytokines after therapy was statistically
      significant. Further studies investigating the benefits of adding cytokines to
      drug treatment for tuberculosis are needed.

PMID- 15174228
TI  - Features of patients with influenza virus infection examined in the emergency
      department of a university hospital in north-western Japan.
AB  - We aimed to determine if there were any changes in the clinical features of
      patients infected with influenza during an influenza epidemic in north-western
      Japan. We retrospectively obtained data on influenza-infected patients from an
      electronic database set up in the emergency department. Patients were examined in
      the Department of Emergency Medicine, Kanazawa Medical University in 2001, 2002
      or 2003. The information collected included age, sex, time of visiting the
      emergency department, visiting method, grade of emergency, where they were when
      their symptoms started to develop, influenza-related complication(s) and outcome.
      The retrospective data collected for the 3 years analysed (2001-2003) were
      similar despite the influenza epidemic in the winter of 2002/2003. These results
      allow us to estimate the influenza-related total medical costs and total work
      burden for staff in the emergency department of a university hospital during any
      future influenza epidemics.

PMID- 15174230
TI  - [Recommendation of the Polish Neurologic Society and the Polish Neurosurgical
      Society regarding stroke prevention and therapy].

PMID- 15174229
TI  - Normal ranges of ulnar and radial deviation with reference to ulnar variance.
AB  - We aimed to determine the normal ranges of radial and ulnar deviation of the
      wrist in relation to the ulnar variance. A total of 102 healthy subjects (204
      wrists) were included in the study. The ranges of radial and ulnar deviation of
      the wrists were measured using a universal goniometer. Ulnar variance was
      assessed manually or radiographically, and recorded as ulna minus, ulna plus or
      ulna minus/plus. When the ranges of radial and ulnar deviation were compared with
      ulnar variance, ulnar deviation was greater in ulna minus subjects and radial
      deviation was greater in ulna minus/plus subjects. There was no significant
      difference in the total range of radio-ulnar deviation. The results of this study
      indicate that ulnar deviation is greater in ulna minus wrists, and we suggest
      that ulnar variance should be recorded alongside measurements of radial and ulnar
      deviation.

PMID- 15174231
TI  - [Open trial of the effectiveness of interferon beta 1a (Avonex) in multiple
      sclerosis. Clinical assessment using motor coordination tests].
AB  - OBJECTIVE: The aim of the study was to evaluate clinical efficacy and safety of
      interferon beta 1A (Avonex) in the Polish population of remitting-relapsing
      multiple sclerosis (RR MS) patients. MATERIAL AND METHODS: The study was
      organized as an open, multi-center trial with 126 RR MS patients. Intramuscular
      Avonex was administered once a week in the dose of 30 mcg. The treatment duration
      was 24 months. The annual relapse rate (ARR), proportion of relapse-free
      patients, the average change in EDSS scores between the baseline and the study
      completion, and the proportion of patients who deteriorated on the EDSS scale
      during the treatment were used as evaluation parameters. Additionally, to obtain
      quantitative data, the 9HPT and 25 FW test results were taken into account.
      RESULTS: A significant decrease in the ARR was noted in the course of treatment
      (from 1.47 in the 2-year period preceding the study to 0.38). The mean EDSS score
      for the whole group was higher by 0.13 on the study completion. However, patients
      without motor deficits (EDSS < 2.0) at baseline improved by 0.25 on the EDSS
      during the treatment, while those with motor deficits (EDSS 2.0 to 4.0)-
      deteriorated by 0.65. In the period under study 45.8% of the patients remained
      stable, 26.7% improved and 27.5% deteriorated on the EDSS. The mean duration of
      the 9HPT test performance increased by 0.67 sec for the dominant, and by 0.97 sec
      for the non-dominant hand from the baseline to post-treatment evaluation. But
      again, in patients without any motor deficits the mean time of 9HPT test
      performance was shorter post-treatment than at baseline for the dominant and non
      dominant hand, while in those with motor deficits it was longer for both hands on
      the study completion. The mean performance time on the 25 FW test was longer by
      0.74 sec on the study completion for the whole group, but in patients without
      motor deficits the increase in the 25 FW performance time was significantly
      smaller than in those with baseline EDSS scores ranging from 2.0 to 4.0. Avonex
      did not cause any significant abnormalities in laboratory parameters monitored
      during the treatment, and no significant side effects were observed except for
      flu-like symptoms following an Avonex injection. CONCLUSION: Results of this
      study confirmed a beneficial effect of 1FNb 1A (Avonex) in the dose of 30 mcg per
      week on the clinical status of MS patients. The findings indicate a better
      treatment outcome in patients with less pronounced neurological deficits at
      baseline.

PMID- 15174233
TI  - [Fractal analysis of MCA blood flow velocity fluctuations in migraine-
      preliminary report].
AB  - Many reports confirm the existence of long-range correlations between
      fluctuations of various physiological signals in healthy subjects and demonstrate
      disappearance of these correlations in pathological conditions. Blood flow
      velocity in intracranial vessels is changeable over time and depends on complex
      physiological regulatory mechanisms. The character of blood flow velocity
      fluctuations may indicate the presence of vascular disorders associated with
      various diseases. The aim of our study was to establish whether fluctuations in
      MCA blood flow velocity are fractal in physiological conditions and if so,
      whether this feature is lost in migraine, as the role of vasomotoric disturbances
      has been already evidenced in pathophysiology of this disease. The axial flow
      velocity changes averaged over a cardiac beat interval were monitored
      continuously via two channels through the temporal windows using a DWL Multi-DopT
      TCD device with 2-MHz probes. The examinations were performed in supine rest in
      two-hour periods in two groups: of 7 patients with clinically confirmed migraine
      with aura during headache-free intervals (15 recordings), and in the control
      group of 4 young, healthy volunteers (10 recordings). The results in the form of
      time series were analysed using the methods of fractal statistics.
      Multifractality in the recordings in physiological conditions was clearly
      confirmed, as well as its absence in the averaged recordings in the group of
      migraneurs. The findings justify a supposition that the breakdown of multifractal
      properties of MCA blood flow time series in migraine may result from the
      vasomotor disturbances present even during headache-free intervals. However,
      possible usefulness of this method in the diagnostics of migraine requires
      further investigation.

PMID- 15174232
TI  - [Open trial of the effectiveness of interferon beta 1a (Avonex) in the treatment
      of multiple sclerosis in Poland: MRI results].
AB  - OBJECTIVE: To assess the effect of interferon-beta 1A (IFNb 1A, Avonex) treatment
      on magnetic resonance (MR) image in patients with remitting-relapsing multiple
      sclerosis (RR MS) who participated in the Polish Avonex trial. PATIENTS AND
      METHODS: RR MS patients (N = 126) participated in a two-year randomized open
      trial of Avonex treatment administered in the dose of 30 mcg once a week. MRI was
      performed twice in each case: shortly before the patient's enrollment in the
      study and within a month from the study completion. Changes in T2-weighted lesion
      volume and T1-weighted gadolinium-enhanced lesion volume, as well as the number
      of new T2-weighted and T1-weighted gadolinium-enhanced lesions were measured.
      RESULTS: Over the two-year treatment period the mean volume of T2-weighted
      lesions decreased by 3.9% (p = 0.83) while that of T1-weighted gadolinium
      enhanced lesions decreased by 79% (p = 0.084%) as compared to the baseline MRI
      evaluation. The mean number of enhanced lesions after two years of Avonex therapy
      was reduced by 46.1% (p = 0.0035). The total number of enhanced lesions decreased
      by 49.8% (p = 0.0078). Both the number of new T2-weighted lesions, 3.7 per
      patient, and that of new T1-weighted gadolinium-enhanced lesions, 0.7 per
      patient, were comparable with the results obtained in other Avonex trials.
      CONCLUSION: The results confirmed that interferon beta-1a (Avonex) has a
      significant effect in MS patients, slowing down the progress of their disease.
      This effect is particularly visible in T1-weighted contrast-enhanced images,
      indicating an impact of the treatment particularly on the inflammatory stage of
      the demyelination process.

PMID- 15174234
TI  - [Chronic fatigue syndrome following tick-borne diseases].
AB  - The chronic fatigue syndrome (CFS) is characterized by a feeling of tiredness
      persisting for over 6 months, associated with a number of other symptoms
      including headaches, myalgia and arthralgia, memory and concentration impairment.
      Its cause is unknown, there are neither objective diagnostic methods, nor causal
      treatment of the condition. In view of hypotheses suggesting a relationship
      between CFS and infections, 86 patients with a history of borreliosis or tick
      borne encephalitis were examined. In 50% of these cases CFS could be identified.
      This clinical pattern was found in as many as 71% of the borreliosis patients,
      while only 24% of those with history of tick-borne encephalitis were diagnosed
      with CFS. Moreover, in the patients with a history of borreliosis after
      symptomatic treatment recommended for CFS, an amelioration was noted in as many
      as 61% of the cases. The findings suggest that the chronic fatigue syndrome is
      frequent among patients with a history of borreliosis.

PMID- 15174235
TI  - [Association of apoE polymorphism and treatment outcome in patients with
      traumatic brain injury].
AB  - A number of papers published in recent years indicate the importance of the
      apolipoprotein E gene (apoE) for the outcome of traumatic brain injury [TBI]. A
      majority of publications suggest that the presence of an epsilon 4 allele is
      associated with an unfavorable long-term outcome. A hypothesis has been recently
      posed that this phenomenon may be related to an increased risk of traumatic
      hypoxic brain damage or post-traumatic ischemic complications. The study group
      consisted of 95 consecutive TBI patients treated in the years 2000-2001 in the
      Neurotraumatology Clinic. The presence of apoE epsilon 4 was found in 16 cases.
      In the statistical analysis relationship was sought between the patient's age and
      state of consciousness at admission as assessed using the Glasgow Coma Scale, on
      the one hand, and on the other hand, treatment outcome at 6 months from injury,
      in patients differing in respect of apoE epsilon 4 presence. Although the number
      of apoE-negative patients was nearly five times as large as that of the apoE
      positive, regression coefficients in both groups were statistically significant.
      The obtained results indicate that the presence of apoE epsilon 4 contributes to
      a less favorable clinical TBI outcome than the absence of this allele.

PMID- 15174236
TI  - [Preliminary evaluation of risk and effectiveness of early choline alphoscerate
      treatment in craniocerebral injury].
AB  - Pharmacological treatment of craniocerebral injuries (CCI) to a large extent
      involves correction of metabolic disturbances resulting from primary and
      secondary mechanisms of trauma. Choline alphoscerate (CA), a substrate of
      phosphatydylocholine and a carrier of choline, plays a major role in
      phospholipidic transformation of the neuronal cell wall. OBJECTIVE: To goal of
      the study was to evaluate the risk and efficacy of early CA treatment in patients
      with CCI. MATERIAL: Twenty three CCI patients were treated with CA in the years
      2001-2002. In 8 cases an acute subdural haematoma with multiple hemorrhagic foci
      was diagnosed. Six patients were diagnosed with cerebral contusion with multiple
      hemorrhagic foci, while 9 patients suffered from concussion of the brain. The
      patients' condition was assessed at admission using the adult trauma score (ATS)-
      11 patients scored 8 points on the ATS, 4 patients scored 9, and 8 patients
      scored 11 points. METHODS: The inclusion criterion was the patient's clinical
      status at admission in the range 8-11 ATS points. CA was administered according
      to the following schedule: 1.0 g/d i.m. for 14 days, then 0.8 g/d orally for the
      next 28 days. AC (Gliatilin) produced by Italfarmaco was used in the study. The
      cost of this CA treatment was estimated by the producer at PLN 424. RESULTS:
      After three months of the treatment an improvement was noted in 96% of the
      patients. Fourteen patients were independent and professionally active, another
      five were independent, but did not work, while three patients required permanent
      care. One patient died because of pneumonia. No complications due to the CA
      treatment were observed in the group studied. CONCLUSIONS: Early treatment with
      CA is safe and as a component of complex pharmacotherapy has a beneficial effect
      on the treatment outcome in CCI patients.

PMID- 15174237
TI  - [Surgical treatment of invasive pituitary adenomas (somatotropinoma or
      corticotropinoma)].
AB  - AIM OF THE STUDY: To evaluate efficiency of the transcranial epidural approach in
      the treatment of invasive GH- or ACTH-secreting pituitary adenomas with extension
      to the cavernous sinus. MATERIAL AND METHODS: During the past two years (from
      January 2000 to December 2001) 14 patients with invasive GH- or ACTH-secreting
      pituitary adenomas extending to the cavernous sinus were operated on using the
      transcranial epidural approach. Our experience is based on an analysis of 12
      patients with GH-secreting tumors and 2 patients with ACTH-secreting adenomas.
      The patients' mean age was 45.36 years (range 28-66, SD +/- 10.26 years).
      Parasellar extension of the tumor was measured using the Knosp scale--in all the
      cases there was an extension to the cavernous sinus, in stage III (4 patients) or
      stage IV (10 patients). RESULTS: In none of the cases a total surgical removal of
      the invasive GH-secreting adenoma was attained (according the following cure
      criteria: basal serum GH level below 2.5 micrograms/l, OGTT < 1 microgram/l,
      normal sex- and age-related IGF-I level). In four patients the surgery resulted
      in a reduction of the basal serum GH level to below 5 micrograms/l (their
      postoperative mean serum IGF-I level was 530 micrograms/l--significantly lower,
      but still abnormal, p < 0.05). In a single case of a female patient the basal
      serum GH level was below 10 micrograms/l, while in other 7 patients the GH level
      remained above 10 micrograms/l. Remission (normalization of 24-hour urine-free
      cortisol (UFC) and its metabolites) was achieved in one patient with the Cushing
      disease. There were no complications involving case fatality. A transient
      deterioration of the third cranial nerve function observed in one patient
      disappeared within 3 months from the surgery. There was no deterioration of
      pituitary function and no cases of diabetes insipidus in our group. CONCLUSION:
      Transcranial epidural approach is an alternative to radiotherapy and/or prolonged
      medication in the treatment of invasive GH- or ACTH-secreting pituitary adenomas.

PMID- 15174238
TI  - [Fractal analysis of intracranial blood flow velocity fluctuations in continuous
      TCD recordings].
AB  - Many physiological signals fluctuate in an apparently irregular and complex
      manner. The fractal analysis of these changes often confirms the existence of
      long-range correlations in healthy subjects and demonstrate a lack of such
      correlations in pathological conditions. The authors discuss usefulness of the
      fractal statistics methods in the analysis of intracranial blood flow velocity
      changes averaged over a cardiac beat interval measured in humans, using
      transcranial Doppler ultrasonography (TCD). An assumption was made that fractal
      properties of blood velocity time series in healthy individuals result from a
      proper autoregulation of their cerebral blood flow and that in cases of vascular
      disturbances fractuality may disappear. A review of the literature is presented
      to provide a theoretical rationale for the proposed method.

PMID- 15174239
TI  - [Fusogens in the treatment of nervous system injury].
AB  - In the paper a new method is presented of injured nerve fibres repair by means of
      the so-called fusogens. This entirely novel approach to the treatment of injuries
      of the central nervous system and peripheral nerves in humans may be feasible in
      a near future. Unquestionable advantages of these substances include their easy
      applicability and no undesirable side effects. What remains to be established is
      their mode of operation and precise therapeutic indications.

PMID- 15174241
TI  - [Progressive atrophy of the globus pallidus--case report].
AB  - The authors report a case of atrophy of the globus pallidus in a woman aged 25
      years, diagnosed alive. The diagnosis was based to a large extent on MRI
      findings. Atrophy of the globus pallidus (AGP) is a rare disease, recognized
      mostly in neuropathological examination. Its etiopathogenesis has not been
      explained so far. Since no specific abnormalities have been detected in
      laboratory tests, the clinical diagnosis of AGP is only probable. However, AGP
      should be suspected if such extrapyramidal symptoms are present as dystonia,
      choreoathetosis, muscular rigidity, and characteristic localisation of lesions in
      MRI. At present only comprehensive symptomatic treatment is possible.

PMID- 15174240
TI  - [Transsphenoidal surgery of intrasellar and perichiasmatic tumors--personal
      experience].
AB  - Microsurgical transsphenoidal approach has been for decades an established
      standard surgical treatment of pituitary adenomas. Actually it offers a safe and
      rapid midline access to the sellar region with a minimal risk of injury to
      vascular vessels, the optic chiasm or nerves and the brain. Major limitations of
      this approach are due to the narrow and deep operating field, with the related
      possible complications of the pituitary insufficiency and the cerebrospinal fluid
      rhinorrhea. In this paper the authors present their own experience with
      transsphenoidal surgery they performed in over 1500 cases during the past 28
      years. The history and evolution of the microsurgery are described, including the
      operative technique, indications and counter-indications, as well as relative
      advantages and disadvantages of the transsphenoidal approach. Moreover, current
      modifications of the neurosurgical technique (extended transsphenoidal
      approaches) and their application in the treatment of non-glandular
      perichiasmatic tumors are outlined and discussed.

PMID- 15174242
TI  - [Diagnostic difficulties in Creutzfeldt-Jakob disease--case report].
AB  - The Creutzfeldt-Jakob disease (CJD) is rare spongiform encephalopathy. Its main
      symptoms are rapidly progressing dementia, myoclonic jerks, visual disturbances,
      ataxia, and pyramidal and extrapyramidal signs. A case of sporadic form of the
      CJD is reported, with blurred vision as one of the first symptoms. This symptom
      occurred shortly after vaccination against influenza, and was accompanied by
      other signs suggesting postvaccinal encephalitis. However, at a later stage of
      the disease typical changes were found in EEG recording and in magnetic resonance
      imaging (MRI). The presence of the 14-3-3 protein was detected in the patient's
      cerebrospinal fluid. The diagnosis of sporadic Creutzfeldt-Jakob disease was
      verified neuropathologically.

PMID- 15174243
TI  - [Multiple cerebral glioma or tumor dissemination via CSF pathways? Case report].
AB  - A case is presented of a 38-year-old female patient who developed bifocal
      metachronous cerebral glioma with the same histological appearance (glioblastoma
      multiforme). Two separate tumors were operated on within six months: the first
      one was localized in the left parieto-occipital area, and the other in the right
      temporal lobe. The tumor cells dissemination occurred probably via the CSF
      pathways: during the first operation the posterior horn of the left lateral
      ventricle was opened, and the second neoplastic lesion was situated also in the
      direct vicinity of CSF spaces (the Sylvian cistern). For all practical purposes,
      the case presented testifies to the necessity of intraoperative protection of the
      CSF spaces by separating any open CSF cisterns from the removed tumor mass with
      cotton pads. In case of diagnosing cerebral glioma, a possibility of the presence
      of multiple foci should be taken into account. It is especially important for the
      differentiation of multiple lesions occurring synchronically, where similarity of
      radiological features is seen in metastases, cerebral abscesses and demyelinating
      lesions.

PMID- 15174244
TI  - [Pseudocyst of the neck after traumatic avulsion of spinal C6-T2 nerve roots-
      case report].
AB  - A case is presented of an avulsion injury of the left brachial plexus in a woman
      who--after surgical reconstruction of the plexus--developed a liquid fistula from
      a giant pseudocyst localized in this area. A prolonged persistence of the
      pseudocyst resulted in a severe pain syndrome and symptoms of vascular disorders
      in the upper limb. Since results of local treatment (punctures, pressure
      dressings) were unsatisfactory, the authors decided to close the liquid fistula
      by suturing the damaged dural sac by means of laminectomy. The necessity of
      particular caution when operating in the area of intervertebral foramina is
      emphasized. The authors also point out that in case of any of cerebrospinal fluid
      leakage, special attention should be paid to stopping the escape of CSF.

PMID- 15174246
TI  - [Reflections on the multiple sclerosis and its treatment].

PMID- 15174247
TI  - [The effect of antiepileptic drug therapy on antioxidant enzyme activity and
      serum lipid peroxidation in young patients with epilepsy].
AB  - Changes in antioxidant defense mechanisms and the resulting increased lipid
      peroxidation are involved in the pathogenesis of epilepsy. Research findings
      concerning the effect of antiepileptic therapies on these processes are
      discordant. The aim of our study was to estimate, firstly, the activity of the
      following antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase
      (GSH-Px) and glutathione reductase (GSSG-R), and secondly, malondialdehyde (MDA)
      serum concentration in children and adolescents newly diagnosed with epilepsy and
      receiving either carbamazepine (CBZ) or valproate (VPA) monotherapy, or
      polytherapy. The study group included 90 young patients with epilepsy, aged 6
      months to 20 years. In 22 patients epilepsy was newly diagnosed; CBZ monotherapy
      was administered to 16 patients, VPA monotherapy--to 25, and polytherapy--in 27
      cases. The control group consisted of 61 non-epileptic patients aged 4-17 years.
      SOD, GSH-Px and GSSG-R activities and MDA concentration were measured using
      spectrophotometry. SOD activity was decreased in newly diagnosed epileptic
      children receiving VPA or CBZ monotherapy (p < 0.05), or polytherapy (p < 0.01)
      in comparison to relevant levels in non-epileptic patients. GSH-Px activity was
      increased in all the patients, but significantly in those receiving polytherapy
      (p < 0.05). While in patients newly diagnosed with epilepsy no change in GSSG-R
      activity was found, its level was slightly lower both in those receiving VPA
      monotherapy and polytherapy, but increased in those with CBZ monotherapy. MDA
      concentration was elevated in all the epileptic patients, significantly (p <
      0.05) both in VPA monotherapy and in polytherapy, while insignificantly--in newly
      diagnosed epilepsy and in CBZ monotherapy. Our results indicate that in the serum
      of children and adolescents with epilepsy the oxidants-antioxidants balance is
      modified by antiepileptic therapy.

PMID- 15174248
TI  - [Suppressing effect of the serotonin 5HT1B/D receptor agonist rizatriptan on
      calcitonin gene-related peptide (CGRP) concentration in migraine attacks].
AB  - Calcitonin gene-related peptide (CGRP) is one of the neuropeptides most abundant
      in the nervous tissue. Recent studies indicate that local cranial release of CGRP
      from the trigeminal nerve perivascular endings within arachnoidea plays an
      important role in the pathophysiology of migraine attacks and cluster headaches.
      Elevated CGRP levels in cranial venous blood (in the jugular vein) during an
      acute spontaneous migraine attack have been reported in rather few studies so
      far. Sumatriptan--a selective serotonin 5HT1B/D receptor agonist, highly
      effective in terminating migraine attacks, decreases the elevated CGRP level back
      to normal. The aim of our study was to determine the effect of rizatriptan (a
      drug from a new generation of triptans) on CGRP release in migraine attacks. In
      45 patients suffering from migraine attacks with and without aura, plasma CGRP
      levels were assessed during an attack twice: before treatment and two hours after
      rizatriptan administration. In the group under study the plasma CGRP level before
      treatment was significantly higher than that measured two hours after rizatriptan
      administration. The decrease in CGRP levels was associated with subsidence of the
      migraine attack. There was no difference between migraine patients with and
      without aura. These results suggest that triptans as serotonin 5HT1B/D receptor
      agonists decrease CGRP plasma concentration in migraine attacks.

PMID- 15174249
TI  - [Lipid peroxidation and antioxidant potential in patients with cervical spinal
      cord injury].
AB  - The aim of the study was to evaluate the intensity of oxygen-derived free
      radicals generation (expressed as the lipid peroxidation process), as well as
      antioxidant potential changes in patients with cervical spinal cord injury.
      Subjects in the study were 32 patients treated in the Neurosurgery and
      Neurotraumatology Clinic, Medical University in Bydgoszcz. Malondialdehyde (MDA)
      concentration and conjugated dienes (CD) level in the patients' blood plasma and
      erythrocytes, as well as their plasma antioxidant potential in reaction with a
      stable free radical--1.1-diphenyl-2-picryl-hydrazyl were assayed. Intensification
      of the lipid peroxidation process as well as a decrement of plasma antioxidant
      potential were found in the patients with cervical spinal cord injury. A strong
      correlation was also shown between severity of cervical spinal cord injury
      assessed using the ASIA impairment scale on the one hand and intensification of
      the lipid peroxidation process and plasma antioxidant potential decrease on the
      other hand.

PMID- 15174250
TI  - [Gastric myoelectric activity disturbance in patients with traumatic lesions of
      the brain stem].
AB  - The aim of the study was to evaluate effects of cranio-cerebral trauma on gastric
      myoelectric activity. Twenty four patients hospitalized in the Department of
      Neurotraumatology, Collegium Medicum of the Jagiellonian University were compared
      with a control group of 16 healthy volunteers matched for gender and age. Their
      gastric myoelectric activity was measured using standard cutaneous electrodes
      with Synectics, a Swedish system of data storage and analysis. Results of the
      study were analyzed at the Department of Pathophysiology, Collegium Medicum,
      Jagiellonian University. In the electrogastrography (EGG) recording of the
      control group the proportions of time with bradygastria (0.5-2 cpm), normogastria
      (2-4 cpm) and tachygastria (4-10 cpm) were 11.6 +/- 8%, 86.2 +/- 9% and 2.16 +/-
      1.5% respectively. The signal amplitude was 181 +/- 11.5 microV2. In patients
      with a severe head injury followed by intracranial hypertension III degree and
      cerebral coma (the Glasgow Coma Scale score 4-7 points), the proportion of
      bradygastria in the total recording time amounted to 46.5 +/- 8%. In these
      patients also the signal amplitude was found to increase up to 766 microV2 (p =
      0.0007). Our results indicate that in patients comatose due to a posttraumatic
      brainstem injury, the function of the brain-gut link is altered. There is a
      severe disorder of the upper gut motility, associated with gastric dysrhythmia-
      bradygastria resulting from an increased cholinergic output. This leads to
      intestinal feeding intolerance.

PMID- 15174251
TI  - [Multimodal intraoperative electrophysiological monitoring during
      cerebellopontine angle tumor surgery. Benefit or loss?].
AB  - In the Neurosurgery Department, Silesian University School of Medicine,
      continuous monitoring of selected neurophysiological functions of the central and
      peripheral nervous system was introduced in 1998 as a routine procedure in
      cerebellopontine angle surgery and some other operations performed in the
      petroclival region. Such benefits from this method as increased patient safety,
      availability of information about dynamic changes in the monitored structures,
      and the possibility of cranial nerves localization using stimulation in the
      operating area, are quite obvious. The paper presents results of a detailed
      statistical analysis of the amount of time required for preparation and for
      operating in 174 cerebellopontine angle tumor surgeries performed in the years
      1986-2002 with (group M) and without (group BM, before the year 1998)
      intraoperative monitoring. Subgroups distinguished according to the histological
      type of tumor were evaluated. Out of 95 procedures performed in group M, 57 were
      operations of acoustic neurinoma cases, 15 meningiomas, 8 cases of epidermal
      cyst, and 15 other growth processes in the cerebellopontine angle region. Among
      79 operations in group BM, there were 57 cases of acoustic neurinoma, 4 cases of
      meningioma, 8 cases of epidermal cyst, and 10 of other types of neoplastic
      growth. In group M as compared to group BM the pre-op. preparation time was found
      to be significantly longer in cases of the VIII-th nerve neurinoma, and of other
      tumors. No statistically significant differences in the amount of operating time
      in were found between any of the subgroups. Both radicality of tumor removal and
      facial nerve status have clearly improved since intraoperative monitoring was
      introduced.

PMID- 15174252
TI  - [Subsidence and its effects on the anterior plate stabilization in the course of
      cervical interbody spondylodesis. Part II. Clinical evaluation. Study design].
AB  - STUDY DESIGN: Subsidence is a common phenomenon in the process of interbody
      fusion. The paper presents a retrospective clinical and radiological evaluation
      of subsidence in a group of 23 patients after cervical corpectomy with mesh cage
      and plate stabilization. Subsidence magnitude and its impact on the stabilizing
      system and on the clinical and radiological outcome were estimated. MATERIAL AND
      METHOD: The mesh cage and cervical plate stabilization was preformed after one-
      (20 cases) or two-level (3 cases) corpectomy. The patients' mean age was 35 years
      (age range 18-72); 9 patients were aged over 50. Indications to corpectomy were:
      neurological impairment due to burst body fractures in 14 cases, multilevel
      spondylosis in 5, and OPLL in 2 patients. One patient had a kidney cancer
      metastasis. The mean follow-up period was 17 months (range 12-28 mo.). The
      patients' clinical status was evaluated using the ASIA scale in the post
      traumatic group, and the Odom criteria in spondylotic cases. In all the cases
      pain severity was estimated by the VAS scale. Magnitude of subsidence was
      measured on consecutive lateral x-rays during the follow-up. Bone fusion was
      confirmed after 3 months in lateral flexion-extension x-rays. Changes in the
      local and general cervical lordosis were evaluated during the follow-up. RESULTS:
      A 72-year-old patient died after 6 weeks due to causes unrelated to the surgery.
      In all the remaining patients bone fusion was attained. There were no cases of
      the clinical status deterioration during the follow-up. Subsidence of over 1 mm
      was found in 19 patients (86.4%). The mean value of subsidence was 2.2 mm, but in
      a group of older patients (aged over 50) it amounted to 2.8 mm. In 4 cases
      (18.1%) with hardware complications, i.e. a screw breakage or slipping, the mean
      subsidence magnitude was 4.3 mm. Local and general cervical lordosis were
      maintained during the follow-up period, even in the group with excessive
      subsidence. The screw breakage site was invariably the round hole of the plate.
      CONCLUSIONS: The subsidence phenomenon is seen in a majority of fused patients.
      Nevertheless, clinical and radiological results of the surgery are good. An
      excessive subsidence may result from hardware complications. In newly designed
      plates subsidence should be taken into account.

PMID- 15174253
TI  - [Cerebral venous thrombosis--clinical aspects and consequences].
AB  - The clinical picture of cerebral venous thrombosis (CVT) depends on the site of
      thrombosis in the venous system including superficial veins, deep veins and
      venous sinuses. Thrombotic changes may occur simultaneously in various parts of
      the venous system. Since CVT may have various causes, the knowledge of its
      etiology helps to make the diagnosis. In systemic diseases multiple intravascular
      clots may result, while in localized pathological conditions thrombosis maybe
      restricted to the lesion site. The clinical picture is often serious, leading to
      death, or to severe complications such as pulmonary embolism, and to distant
      complications--like epilepsy or intracranial hypertension being the cause of
      chronic headaches (lumbar puncture and CSF pressure measurement are helpful in
      the diagnosis of intracranial hypertension). In order to prevent complications of
      crucial importance is not only the proper diagnosis (with MRI and venography as
      the diagnostic techniques of choice), but also an early and prolonged treatment
      with anticoagulants. Heparin or fractionated heparin is recommended even though
      there is a possibility of cerebral haemorrhagic lesions.

PMID- 15174254
TI  - [Advances in the research on immunopathogenesis of myasthenia gravis].
AB  - Microscopic structure and immunologic function of the thymus gland are outlined,
      with an emphasis on its role in the process of T and B lymphocytes maturation.
      Other types of thymic cells are also described, including epithelial and myoid
      cells that presumably have a central role in initiation of an autoimmunologic
      process leading to myasthenic symptoms development. A detailed account is
      presented of issues concerning pathophysiology of myasthenia, the structure of
      nicotinic acetylcholine receptor (AchR) at neuromuscular junctions, and
      mechanisms underlying its destruction by autoantibodies. The role of T and B
      lymphocytes, of various cytokine types, of autoantibodies to various striated
      muscle antigens, as well as a possible role of genetic and bacterial factors in
      the development of myasthenia gravis are discussed. In conclusion it is stressed
      that since recent research findings go beyond the classic theory of myasthenia, a
      new consistent theory of the disease immunopathogenesis must be created in the
      future to place all the newly discovered phenomena in a logical conceptual
      structure.

PMID- 15174255
TI  - [The role of N-acetyltransferase polymorphism in the pathogenesis of Parkinson's
      disease].
AB  - Pathogenesis of many diseases is related to the influence of noxious
      environmental agents coupled with individual genetic sensitivity that depends on
      the function of detoxificating enzymes. One of the latter is N-acetyltransferase
      2 whose mutations lead to an impairment of the enzyme function. Genetically
      determined acetylation rate reduction with exposure to neurotoxins may contribute
      to the development of Parkinson's disease (PD). While both genetic and
      environmental factors are implicated in etiology of PD, genetic factors may play
      a crucial role in early-onset Parkinson's disease (in patients aged under 50).

PMID- 15174256
TI  - [Trigemino-autonomic cephalalgias. Report of two cases].
AB  - Trigemino-autonomic cephalalgias (TAC) constitute a rare group of primary
      headache conditions associated with unilateral fluctuating head pain and
      autonomic symptoms. These syndromes, including cluster headache, hemicrania
      continua, paroxysmal hemicrania and SUNCT, are much less prevalent than migraine
      and tension-type headache. The pathogenesis of TAC is unknown. Similar
      neuropeptide changes seen in all TAC syndromes suggest a shared underlying
      pathophysiology in these headaches. Some of them respond to the treatment with
      indomethacin and sumatriptan. Two patients suffering from one of the trigemino
      autonomic cephalalgias are presented in the paper.

PMID- 15174257
TI  - [The effect of chronic Vagus Nerve Stimulation (VNS) on the central conduction
      time assessed by multimodal evoked potentials in patients with drug resistant
      epilepsy: preliminary report].
AB  - Changes over time in evoked potentials of various modality (VEP, SSEP and BAEP)
      were analyzed in 3 patients, submitted to chronic Vagus Nerve Stimulation (VNS)
      due to drug resistant epilepsy. The aim of a study was to establish which
      cerebral structures are most prone to change their baseline electrophysiological
      status in consequence of chronic VNS. Evoked potentials were examined before the
      Vagus Nerve Stimulator implantation and at arbitrarily defined follow-ups several
      months after the implantation. Preliminary results obtained in a small group of 3
      patients suggest a possible prolongation of the central conduction time in the
      examined modalities of evoked potentials due to the VNS treatment. A hypothetical
      mechanism of antiepileptic VNS action might be related to the permanent
      stimulation of brainstem and cortical structures that limit seizures propagation
      through hyperpolarisation both at the cortical level and in subcortical
      structures.

PMID- 15174258
TI  - [Atlanto-occipital instability due to the transverse atlas ligament rupture.
      Report of a case with symptoms persisting for 21 years].
AB  - The authors describe a case of a judo sportsman with a cervical spine injury
      sustained 21 years earlier. The injury initiated characteristic sensations of
      severe generalized pain with paraesthesias recurring whenever he was hit on the
      top of the head. In February 2001 the patient fell on his head, which resulted in
      tetraplegia with a complete sensory loss. The symptoms disappeared after ten
      minutes. Plain radiography, CT and MRI performed after this episode revealed
      occipitalization of the atlas and C1-C2 instability due to a rupture of the
      transverse atlas ligament. The patient underwent surgery by the posterior
      approach: decompression of the foramen magnum, fixation of the occiput and C-2
      (with wiring and a bone graft). At one-year follow-up after the surgery the
      patient had limited movements of the neck without neurological symptoms. Plain
      radiograms confirmed stability of the occipitocervical fusion. There was no
      recurrence of the preoperative symptoms.

PMID- 15174259
TI  - [Intrathecal baclofen in severe spasticity due to multiple sclerosis].
AB  - Intrathecal administration of baclofen via programmable pump is a highly
      effective treatment method in severe spasticity resistant to oral medications.
      The authors describe a case of severe spasticity with tetraplegia and painful (>
      10 a day) muscle spasms in the upper and lower limbs and paraspinal muscles, in a
      patient with clinically definite diagnosis of multiple sclerosis (MS). The 34
      year-old female patient with a 15-year history of MS, suffering from lower limb
      spasticity with pes equinovarus since 1995, was treated with very good results
      with botulinum toxin injections of calf muscles (14 sessions of Dysport 1500iu
      till 2002). In the early 2002 she developed tetraplegia with severe, generalized
      and intractable spasticity. After 4 months of ineffective polytherapy (with high
      doses of oral baclofen, tizanidine, gabapentine, clonidine, diazepam) and the
      patient's enormous sufferings (she could neither sit up nor voluntarily change
      her position in bed), a programmable baclofen pump (Medtronic) was implanted. As
      soon as a few days after the surgery she could stand, sit and move voluntarily,
      her painful spasms disappeared, and her bladder catheter was removed. At a 6
      month follow-up the effect was stable--she was able to walk a long distance
      outdoors with the aid of a crutch. The daily dose of the drug is 500 micrograms.
      No side effects of complications were noted.

PMID- 15174260
TI  - [The hippocampus and neuro-transplantation].
AB  - A review of the author's histological and electron-microscopic studies of
      differentiation of hippocampal transplants with different levels of the
      graft/host integration. The grafts developing in the anterior eye chamber were
      the experimental model of complete isolation from the brain. The effects of
      various factors (age of the donor fetal tissue, host age and strain, degree of
      the integration with the recipient brain) on the growth and neural organization
      of grafts were studied. Analysis of fine structure of intraocular and
      intracortical grafts, as a rule, showed mature highly differentiated neurons and
      glia and normal density of typical synaptic contacts. However, morphological
      features suggesting both hyperactivity of some neurons and continuous growth of
      some neural processes were observed. The expression of nonsynaptic and transport
      metabolic interactions between the cells was increased. The observed
      ultrastructural deviations can be regarded as a compensatory adaptation of the
      tissue to the deficit of specific afferent signals. It was shown that in the
      absence of normal cellular targets, axons of the grafted neurons establish
      functional synaptic contacts with improper neural elements in the host brain.

PMID- 15174261
TI  - [The role of medial septal area in the neural control over hibernation].
AB  - Hibernation (winter sleep) is a kind of unique adaptive behavior of small mammals
      subjected to fine and complex central control. One of the most promising
      approaches to this problem is a search for the mechanisms providing brain control
      under conditions of a sharp decrease in temperature, (virtually, to zero) and
      metabolic rate. Studies conducted at the Laboratory of System Organization of
      Neurons under the supervision of Professor O.S. Vinogradova confirmed the
      hypothesis of the special role of the septohippocampal system in the control of
      winter sleep. Together with a brief characterization of hibernation in general,
      the data obtained at the Laboratory are also summarized in the review. The
      experimental evidence for the role of the medial septal area as a "sentry post"
      in hibernation is presented.

PMID- 15174262
TI  - [Specifics of monoaminergic regulation of the central nervous system of
      hibernating animals (Citellus undulatus)].
AB  - Seasonal features of open-field behavior of Yakut ground squirrels (Citellus
      undulatus) and changes in the brain MAO A activity were studied. It was found
      that all parameters of exploratory activity in the open field and holeboard test
      reached the values characteristic of summer animals very rapidly, within a few
      days or (in some cases) even within the first 24 hours after the arousal from
      hibernation in the middle of April. In autumn these parameters decreased to their
      minimum values 1.5-2 months prior to hibernation. Biochemical analysis showed
      that in April the activity of MAO A measured with serotonin as a substrate in the
      hippocampus was 1.8 times (p < 0.05) higher than the activity of MAO A with
      respect to noradrenaline. In contrast, in autumn the MAO A activity determined
      with noradrenaline as a substrate was 2.5 (p < 0.05) times higher than the
      activity a MAO A with respect to serotonin. Taken together, these data indicate
      that the seasonal features of the higher nervous activity of hibernating animals
      depend on the balance between serotonergic and noradrenergic systems in different
      periods of the annual cycle.

PMID- 15174263
TI  - [Double evoked responses to the electrical stimulation of Shaffer's collaterals
      in CA1 hippocampal field].
AB  - Double evoked responses to single current pulses applied to Shaffer's collaterals
      were observed in CAI hippocampal field in freely moving rats. The second response
      was an irregular population EPSP with constant latency sometimes accompanied by a
      population spike. The effect was observed in 22 of 54 tested rats (40.74%). In 10
      of these 22 animals (45.45%) the second response was evoked by a weak testing
      stimulus of at least of a single collateral, in the remaining 12 rats the second
      response appeared to stimulation with increased current or after potentiation of
      the stimulated pathways. The second responses were very sensitive to the
      functional state of an animal and were recorded at the state of rest or during
      sleep. The latencies of the second response measured from the beginning of the
      first response were very close in different animals and with low intraindividual
      variability indicating that the same circuits are involved in its generation. It
      is suggested that hippocampus can support dynamic processes such as reverberation
      of signals.

PMID- 15174264
TI  - [Theta rhythmicity in the medial septum: entraining by the GABA-ergic neurons].
AB  - The medial septal/diagonal band complex (MS/DB) is believed to play an important
      role in the generation and maintenance of the hippocampal theta rhythm, which has
      been implicated in the mnemonic and information-processing capacity of the brain.
      Although the physiological and morphological diversity of the septal neurons
      indicates their different functions, it is not known which cell type within the
      population contributes most critically to the theta rhythm. Here we review the
      chemical identity of different cell groups within the MS/DB complex, the
      anatomical connectivity between them, the electrophysiological properties of
      immunochemically-defined cell types, and their contribution to theta rhythmicity
      in the medial septum and the hippocampal theta rhythm. In order to better
      understand the mechanisms involved in rhythmic burst firing of the MS/DB neurons,
      a number of relevant theoretical models related to the generation/synchronization
      in neural networks are discussed.

PMID- 15174265
TI  - [Influence of experimental epileptogenesis on memory: the role of lipids in
      cognitive disorders].
AB  - Learning and memory disorders accompanying epileptogenesis were studied in rats
      with the use of two experimental models of epilepsy, picrotoxin kindling and
      kainic treatment. Rise of exploratory activity and decrease in animal's
      capability for experimental extinction of a response were characteristic of the
      initial stage of epileptogenesis. It was suggested that a dysfunction of brain
      hippocampal system can be responsible for cognitive disorders. To reveal their
      mechanisms, lipid contents were determined in the neocortex and hippocampus in
      appropriate periods after exposure to epileptogenic factors. Long-term changes in
      hippocampal lipid spectrum were found five days after the exposure to kainic
      acid. In particular, after sodium valproate treatment (the compensation of kainic
      effects), the total content of phospholipids in hippocampus was decreased. The
      hippocampal sphingomyelin level dropped as a result of picrotoxin kindling. The
      sphingomyelin changes suggest some recovery processes in hippocampal cells and
      point to an adaptive role of membrane lipids in the mechanisms of the damaging
      epiptogenous effects.

PMID- 15174266
TI  - [Dopaminergic regulation of theta activity of septohippocampal neuron in the
      awake rabbit].
AB  - The effects of dopamine reuptake blocker nomifensine and nonselective antagonist
      of dopamine receptors haloperidol on the theta rhythmicity of the medial septal
      neurons and hippocampal EEG were investigated in the rabbit. Bilateral
      intracerebroventricular infusion of nomifensine (9 micrograms in each
      ventriculus) produced an increase in both the rate of firing and the theta
      modulation of medial septal neurons; the theta power of the hippocampal EEG also
      augmented. The degree of neuronal theta stability (time constant of damping, tao
      theta) significantly increased. The frequency of rhythmic bursts in the neuronal
      firing also substantially elevated. The amplitude, regularity and frequency of
      theta waves in the hippocampal EEG also increased. The antagonist haloperidol
      (12.5 mg) caused the opposite effect. The theta activity of medial septal neurons
      and the theta power of the hippocampal EEG decreased after haloperidol injection.
      Theta rhythmicity of septal neurons significantly diminished, the rate of
      rhythmic bursts in the neuronal firing also decreased, although not
      substantially. The theta amplitude and regularity in the hippocampal EEG also
      decreased. Effects of both drugs built up rapidly and then gradually attenuated.
      Nomifensine infusion against the background of exposure to haloperidol provoked
      neither increasing neuronal firing rate, nor elevating theta activity. These
      finding suggest that dopaminergic system produces activation of the
      septohippocampal system in situations that require selective attention to
      functionally important information.

PMID- 15174267
TI  - [Interhemispheric asymmetry of the spatial-temporal potentials of the human
      cerebral cortex under various conditions of the formation of verbal
      conditioning].
AB  - It was shown on the basis of electrophysiological data in 60 healthy subjects
      that the interhemispheric brain asymmetry in the course of formation and
      actualization of the verbal set depends on the context of the cognitive activity.
      More complex cognitive activity results in a development of regional
      interhemispheric differences in the studied characteristics of the spatiotemporal
      organization of cortical potentials. These differences are most spectacular in
      the frontal areas of the cortex.

PMID- 15174268
TI  - [Study of trait anxiety in children with different profiles of lateral
      organization after early social deprivation].
AB  - School behavior and learning were examined in 68 right-, lefthanded, and
      ambidextral 10-12-year-old children earlier exposed to social deprivation.
      Socially deprived children revealed stress and high trait anxiety. "Imposed
      lefthandedness" is considered to be an important factor responsible for the high
      level of trait anxiety. In the group of socially deprived children persons with
      sanguinic temperament showed the lowest, and melancholies showed the highest
      levels of trait anxiety as compared to the control group.

PMID- 15174269
TI  - [Spectral power and cortical interactions in the beta2 rhythm in normal subjects
      and schizophrenic patients].
AB  - Spectral and coherence characteristics of the beta 2 rhythm (20-40 Hz) were
      compared in patients with acute schizophrenia (the first episode), patients with
      chronic schizophrenia (disease duration more than two years), and healthy
      subjects (control group) during cognitive task performance. Examination showed
      the "excessive" spectral power of this rhythm in the prefrontal cortical areas in
      patients with acute schizophrenia and its "insufficient" spectral power in all
      derivations of the right hemisphere in patients with the chronic form as compared
      to the controls. The similarity of the beta 2 spectral power distribution in
      different cortical areas measured by covariance method decreased with increase in
      psychopathologic manifestations. Coherent analysis revealed a substantially lower
      number of cortico-cortical functional connections in schizophrenic patients than
      in healthy subjects, absence of interhemispheric connections in patients with
      acute schizophrenia, and a slight increase in their number if patients with the
      chronic disease. However, as distinct from the controls revealing many inter- and
      intrahemispheric connections in all cortical areas, in schizophrenics the
      interhemispheric connections were observed only in the posterior cortical
      regions. The results point to a disorder of interhemispheric interaction in
      schizophrenia.

PMID- 15174270
TI  - [A geometrical model for the perceived line of orientation based on subjective
      evaluations and human VEP data].
AB  - A geometric model in proposed based on subjective dissimilarity estimates among
      differently oriented line segments in the frontal plane and on visual evoked
      potentials (VEP) recorded in respond to abrupt changes in the orientation of such
      a line segment. The orientations are represented by points constituting a clised
      planar curve, with interpoint distances corresponding to interstimulus
      dissimilarities. The angle of the radius-vertor connecting the center of the
      configuration with its circumference encodes the orientation of the line stimuli
      in the visual field, and two Cartesian axes drawn through the center are
      interpreted as two orientation-opponent channels in the neuronal network
      processing line orientation. The first channel (the ordinate axis) gives maximal
      positive and maximal negative responses to, respectively, vertical and horizontal
      orientations, whereas the second channel (the abscissa axis) gives maximal
      positive and maximal negative responses to, respectively, 45 and 135 degrees
      orientations. The VEP analysis shows that the activity of the first channel
      affects the interpeak amplitudes of both the P1-N2 (P130-N180) and N2-P2 (N180
      P230) components, whereas the second channel affects only the late component N180
      P230. We propose the hypothesis according to which outputs of the two channels
      are connected linearly (which is reflected in the city-block metric obtained when
      distances are computed directly from neuronal activity), but the growth rate of
      the overall output is inhibited nonlinearly when it reaches large absolute
      values. This inhibition effectively transforms the "true" city-block metric of
      the line orientation space into the Euclidean metric one obtains when distances
      are computed from subjective dissimilarity estimates. VEP amplitudes as
      intermediate characteristics of visual processing between neuronal activity and
      subjective estimates represent intermediate metric (between city-block and
      Euclidean).

PMID- 15174271
TI  - [Simulation model of the tuning mechanism in the visual cortex neuron for the
      perception of Y-shape images].
AB  - We performed an imitation simulation of receptive fields (RF) of cat cortical
      neurons in the primary visual cortex, which were able to detect symmetrical and
      asymmetrical Y-like figures. We investigated the models of the receptive fields
      of neurons sensitive to Y-like figures through either the convergence from half
      bar detectors or disinhibition mechanism. The model of an of the receptive fields
      of neurons sensitive to Y-like figures through either the convergence from half
      bar detectors or disinhibition mechanism. The model of an-like figure detector on
      the basis of convergence from the angle and orientation detectors was advanced.
      Tuning of the simulated receptive fields to Y-like figures was compared with
      their tuning to cross-like figures. It was shown that the detectors of asymmetric
      Y-like figures are also detectors of a cross, whereas the detectors of symmetric
      Y-like figures are more sensitive to Y-like figures than to crosses. The features
      of the model critical for sensitivity to Y-like figures (the shape, localization,
      and weight of the RF zones) were specified.

PMID- 15174272
TI  - [Long-term synaptic facilitation depends on RNA synthesis in LP11 neuron of
      sensitized Helix].
AB  - Effects of actinomycin D (transcription inhibitor) on neural mechanisms of
      nociceptive sensitization were studied in Helix lucorum LP11 command neurons of
      defensive behavior. In control snails, the sensitizing stimulation (three
      applications of 10% quinine solution with 15-min intervals) produced an increase
      in membrane excitability and two-phase changes in neural responses to tactile or
      chemical sensory stimuli. In the first (within one hour after the beginning of
      the sensitization) phase the responses were depressed; they were facilitated in
      the second phase (to 24r). Application of 20 microM actinomycin D to LPl1 neuron
      during sensitization of a snail semi-intact preparation did not affect the
      increase in membrane excitability and short-term depressions of neural responses
      but suppressed the long-term synaptic facilitation. Actinomycin D application 30
      min after the third sensitizing stimulus prevented neither increase in membrane
      excitability nor the long-term synaptic facilitation of the neural responses
      evoked by sensory stimuli. It is suggested that the long-term synaptic
      facilitation in Helix LPl1 neurons depends on the RNA synthesis in the critical
      time window (within one hour after the sensitization beginning), whereas membrane
      excitability changes do not depend on transcription within two-three hours.

PMID- 15174273
TI  - [The effects of Mexidol on food conditioning and synaptic fine structure of
      hippocampal field CA1 in rats exposed to a single acoustic stimulation with
      ultrasonic components].
AB  - The effect of exposure of rats to a complex acoustic signal with ultrasonic
      components on line structure of synapses of the CA1 field of the hippocampus was
      studied during a course treatment (two weeks) with broad-spectrum antioxidant
      Mexidol. Under the same conditions, the time course of food conditioning by a
      conditioned tone stimulus and acquisition of trace conditioned reflex (time
      interval counting) were studied in the same rat group. Rats non-exposed to stress
      against the background of Mexidol and without Mexidol treatment served as
      control. Analysis of fine structure of the vesicle redistribution in CA1 synapses
      revealed a reduction of the efficacy of synaptic transmission a day after the
      exposure to the complex acoustic stimulus. We found a negative effect of the
      complex acoustic stimulus on conditioning by tone and acquisition of time
      counting trace reflex by rats. This effect was shown to be normalized by the
      course Mexidol treatment. The results suggests the expediency of Mexidol
      application for prevention of cognitive disorders, which are frequent under
      stress-inducing conditions.

PMID- 15174275
TI  - [Induction of synthesis of Hsp104 of Saccharomyces cerevisiae in heat shock is
      controlled by mitochondria].
AB  - Heat shock protein Hsp104 of Saccharomyces cerevisiae functions as a protector of
      cells against heat stress. When yeast are grown in media containing
      nonfermentable carbon sources, the constitutive level of this protein increases,
      which suggests an association between the expression of Hsp104 and yeast energy
      metabolism. In this work, it is shown that distortions in the function of
      mitochondria appearing as a result of mutation petite or after exposure of cells
      to the mitochondrial inhibitor sodium azide reduce the induction of Hsp104
      synthesis during heat shock. Since the addition of sodium azide suppressed the
      formation of induced thermotolerance in the parent type and in mutant hsp104, the
      expression of gene HSP104 and other stress genes during heat shock is apparently
      regulated by mitochondria.

PMID- 15174274
TI  - [The influence of neonatal ketamine injection on pain sensitivity and audiogenic
      seizures in adult rats].
AB  - The remote effects of neonatal (on the 3d-to-9th postnatal days) ketamine
      injections (10 and 50 mg/kg in 20 microliters of distilled water, s.c.) were
      analyzed in adult Wistar, WAG/Rij, and KM (a strain with high audiogenic
      sensitivity) rats. Both ketamine and water injections increased pain sensitivity
      in adult rats. Neonatally injected water increased the mean score of seizures in
      Wistar and WAG/Rij, whereas ketamine water solution injected in the dose of 50
      mg/kg did not change the seizure intensity (as compared to the intact control).
      Consequently, ketamine significantly reduced the mean score of the audiogenic
      seizure fit without change in its latency. In highly sensitive KM rats the
      neonatally injected ketamine (50 mg/kg) significantly shortened the mean latency
      of the fit onset, and fit stages developed faster. Thus, the neonatal ketamine
      injection increased the audiogenic seizure susceptibility of brain structures in
      KM rats.

PMID- 15174276
TI  - [Role of moderate bacteriophage 139 in change in production of cholera toxin in a
      classic strain of Vibrio cholerae].
AB  - New data were obtained concerning cell sensitivity of pathogenic strains of
      cholera vibrions, which belong to the serogroup O1 of classical biovar, to the
      temperate bacteriophage K139, the native host of which is Vibrio cholerae O139.
      Molecular-genetic and biochemical studies showed that phage 139 integrated into
      the chromosome of strains V. cholerae O1 can change their toxigenic properties. A
      change in the production of cholera toxin (CT) in lysogens is associated both
      with an increase in the activity of the toxR regulatory gene and with a
      distortion of the structure of a chromosomal DNA region that contains a copy of
      the operon ctxAB encoding CT biosynthesis.

PMID- 15174277
TI  - [Instability of a cryptic plasmid in Sinorhizobium meliloti P108 during symbiosis
      of it with alfalfa Medicago sativa].
AB  - Instability of cryptic plasmids in Sinorhizobium meliloti laboratory strains
      SKhM1-188, DM7-R, and P108 as well as in their clones isolated from nodules of
      alfalfa grown during a long-term microvegetation experiment (120 days) was
      studied. The isolated clones of strains SKhM1-188 and DM7-R manifested stable
      inheritance of plasmids, whereas 12.7-14.0% of clones with changed plasmid
      profile were detected in a population of clones from strain P108. These
      segregants were designated as P108c. Segregants P108c exhibited significantly
      decreased symbiotic effectiveness, nitrogenase activity, and the competitiveness
      with respect to alfalfa, compared to the original strain P108. It was established
      that a 80-kb deletion occurred in a larger of two cryptic plasmids (240 and 230
      kb) of segregants P108c. It was concluded that genetic rearrangements are
      possible in rhizobial clones that did not undergo structural transformation and
      retained viability in the nodule during the natural vegetation period of alfalfa.

PMID- 15174278
TI  - [Comparison of genomes of new gigantic Pseudomonas aeruginosa phages from native
      populations from different regions].
AB  - To study the genome diversity of bacteriophages from geographically distant
      natural populations, new giant phi KZ-like Pseudomonas aeruginosa phages isolated
      in two different regions were compared with earlier known phages of three species
      (phi KZ, Lin68, EL). A broad spectrum of lytic activity was demonstrated for all
      phi KZ-like phages. Phages of the phi KZ species proved to be common in natural
      populations of various regions, while IL- and Lin68-related phages were extremely
      rare. Most phi KZ-related phages had unique DNA restriction patterns, but the
      differences between these were only minor, and the genomes did not contain
      nonhomologous fragments. The spectrum of capsid polypeptides proved to be
      conserved in each species, and was proposed as a character necessary and
      sufficient for express classification of phages with an accuracy of species.
      Phages isolated in different geographical regions showed no substantial
      difference. Some phages only slightly differing in DNA restriction pattern from
      phi KZ may be used to study the origin of phi KZ genes coding for orthologs of
      proteins of unrelated species (other phages, pathogenic bacteria, eukaryotes).

PMID- 15174279
TI  - [Sterilizing effect of the mutant allele sbr10 (l(1)ts403) in compound with null
      alleles in Drosophila melanogaster females].
AB  - In females of Df(1)v-L4/+(0/+) genotype, the presence of the wild-type allele of
      small bristles (sbr) gene in a single dose has no significant effect on their
      fecundity, whereas a reduced dose of the temperature-sensitive allele
      sbr10(l(1)ts403) causes a strong sterilizing effect in females Df(1)v-L4/sbr10
      (0/sbr10) at permissive temperature. We studied the contribution to this effects
      of the following factors: resorption of egg chambers, decreased oviposition,
      offspring death at the embryonic and larval stages, and reduced fecundity in
      females 0/sbr10. Sterilizing effect of the mutant sbr10 allele proved to be
      primarily caused by offspring lethality at the embryonic and first-instar larval
      stages. In 0/+ females, the majority of undeveloped eggs contained embryos that
      perished at the late developmental stages, whereas in females 0/sbr10, at least
      50% of undeveloped egg showed no visible signs of development or the embryo
      development was arrested at early stages of embryogenesis. The results obtained
      suggest insufficiency of the temperature-sensitive allele sbr10 in haploid state
      to ensure the reproductive functions of Drosophila melanogaster females.

PMID- 15174280
TI  - Determination of malathion and diazinon resistance by sequencing the Md alpha E7
      gene from Guatemala, Colombia, Manhattan, and Thailand housefly (Musca domestica
      L.) strains.
AB  - Organophosphate (OP) insecticides (parathion/diazinon) resistance in housefly
      (Musca domestica L.) is associated with the change in carboxylesterase activity.
      The product of alpha E7 gene, which is a member of alpha-esterase gene cluster,
      is probably playing a role in detoxification of the xenobiotic esters. In
      parathion/diazinon resistant M. domestica species Gly137 to Asp substitution was
      found in the active center of the product of alpha E7 gene. In malathion (an OP)
      resistant M. domestica strains Trp251 to Ser substitution was identified in the
      active center of the Md alpha E7. In our research, to understand the allelic
      diversity of the Md alpha E7, the gene was partially sequenced from four
      different housefly strains from different localities (Guatemala, Manhattan (USA),
      Colombia (USA) and Thailand). It was found out that; in Thailand strain one
      allele has Cys residue at the position of 251, the other allele contains a Trp
      for the same site. In Colombia strain, one allele has Asp137, the other allele
      contains a Gly residue at this point. The Manhattan and Guatemala strains have
      Asp137 and Trp251 residues on their both alleles at these two different
      positions.

PMID- 15174281
TI  - [Mutation of Indy(p115) increases the life expectancy of imago of Drosophila
      melanogaster depending on sex and genetic background].
AB  - The Indyp115 allele in heterozygous state almost doubles the life span of adult
      Drosophila melanogaster, and this effect largely depends on the strain used for
      obtaining heterozygotes. Male and female life span depends on Indyp115 to a
      different degree. Apart from Indyp115 heterozygotes, sexual dimorphism for life
      span was also observed in strain Hikone-AW, but not in OregonR and TM3 balancer.
      In heterozygotes Indyp115/OR, both the average life span and female reproductive
      period increased as compared to OR control. No substantial increase in female
      reproductive period in Indyp115/Hk heterozygotes was found. In homozygotes for
      allele Indyp115, we have previously revealed two phases of embryotic lethality
      and lethality at the larval and pupa stages. Thus, allele Indyp115 has a double
      and opposite effect on Drosophila viability. On the one hand, it extends the life
      span of adult flies, on the other, decreases survival at preimaginal stages.

PMID- 15174282
TI  - [Genetic control of mitosis. Mast(v40) protein--an element of checkpoints
      system?].
AB  - The effect of the mastv40 mutation was studied using neural ganglion cells of
      third-instar larvae of Drosophila melanogaster. The distributions of the cells by
      the interphase nucleus diameter and by the distance between the sister chromosome
      sets in anaphase were analyzed. Three following types of defects induced by the
      mutation were described: (1) Monopolar mitosis or, in the case of bipolar
      mitosis, an abnormally short distance between the sister chromosome sets in
      anaphase and early telophase. We believe that these abnormalities are caused by
      damage of the start and (or) motor mechanisms of centrosome separation at the
      beginning and in the end of mitosis. (2) Lagging and bridging of chromosomes in
      anaphase and early telophase. These defects seem to be related to the disruption
      of functioning of mitotic spindle microtubules and (or) their defective
      attachment to the appropriate kinetochores. (3) Unlimited division of aneuploid
      and polyploid cells, which may be explained either by inactivation of the
      checkpoint system controlling the genome ploidy or by checkpoint adaptation.
      Taken collectively, our results and literature data suggest that the MAST protein
      is an element of the checkpoint system and that division of aneuploid and
      polyploid cells results from inactivation of the checkpoints.

PMID- 15174283
TI  - [High level of polymorphism and autotetraploid origin of rare endemic species of
      Fabaceae, Oxytropis chankaensis Jurtz., inferred from allozyme data].
AB  - Using starch electrophoresis, we examined 19 enzyme systems presumably controlled
      by 35 loci in the rare endemic tetraploid species Oxytropis chankaensis Jurtz.
      (Fabaceae). Electrophoretic patterns and their genetic interpretation are
      presented. The isozyme data suggest tetrasomic inheritance in O. chankaensis.
      Three or four alleles at a particular locus were found in a number of individual
      plants, which indicate the autotetraploid origin of this species. Seventeen loci
      were shown to be polymorphic. As reliable gene markers for population systems, we
      recommend highly active polymorphic systems showing good allozyme separation (Ce
      2, Gpi-2, Gpt-2, Idh-2, Lap, Mdh-2, and Mdh-3). Parameters of allozyme
      variability proved to be very high for a rare species with a restricted range: P
      = 48.6%, Ap = 3.06, Hob = 0.173.

PMID- 15174284
TI  - [Genetic variability and interrelationship of Siberian and Far Eastern larches
      from RAPD-analysis data].
AB  - Genetic diversity of larches from six geographically isolated regions, Tomsk,
      Irkutsk, Ulan-Ude (Siberia), and Blagoveshchensk, Khabarovsk, Yuzhno-Sakhalinsk
      (Far East) was examined by means of RAPD analysis. Tree DNA samples were compared
      using 457 RAPD loci (97% of which were polymorphic), identified with 17 primers
      of random sequences. In the samples examined, 32 to 49% of the genes were in
      heterozygous state, mean expected heterozygosity (Hexp) varied from 0.1373 to
      0.1891, and the genetic distances (DN) for different sample pairs varied from
      0.0361 to 0.1802. The main population parameters were determined for Larix
      sibirica Ledeb., L. gmelinni (Rupr.) Rupr., and L. kamtschatica (Rupr.) Carr.
      Analysis of the genetic relationships showed that L. kamtschatica was
      characterized by highest genetic differentiation from the other larches examined,
      while larches from Primorskii krai were genetically close to L. sibirica.

PMID- 15174285
TI  - [Genealogic analysis of the resistance of winter wheat to common bunt].
AB  - Comparative genealogical analysis of North American (the United States and
      Canada) and Eastern European (Russia and Ukraine) winter wheat cultivars
      resistant and susceptible to common bunt has been performed. Analysis of variance
      applied to North American wheats has demonstrated that resistant and susceptible
      cultivars significantly differ from each other with respect to the contributions
      of common ancestors. The contributions of Oro (Bt4 and Bt7), Rio (Bt6), White
      Odessa (Bt1), and Florence (Bt3) to the resistant cultivars are significantly
      higher than their contributions to the susceptible ones. This demonstrates that
      the use of these resistance donors in wheat breeding for several decades has been
      effective. The contribution of PI-178383 (Bt8, Bt9, and Bt10) is considerably
      higher in the group of resistant cultivars bred after 1965. The mean
      contributions of Federation (Bt7) and Nebred (Bt4) are significantly higher in
      the group of resistant cultivars obtained before 1965; however, the differences
      in the contributions of these donors between new resistant and susceptible
      cultivars became nonsignificant. Among the Russian and Ukrainian cultivars, there
      are differences between groups of resistant and susceptible cultivars from
      different regions determined by the differences between the regional populations
      of the pathogen in racial composition. In the northern region, the contributions
      of the wheat grass (Agropyron glaucum) and the rye cultivar Eliseevskaya are
      significantly higher in the resistant cultivars; in the southern region, a local
      cultivar of the Odessa oblast is the prevalent resistant cultivar. In addition,
      cultivar Yaroslav Emmer is likely to be effective in the northern region; and
      foreign sources (Oro, Florence, Federation, and Triticum timopheevii), in the
      southern region. Very few sources of vertical resistance to common bunt are used
      for winter wheat breeding in Russia and Ukraine. The decrease in genetic
      diversity in favor of a few identical genes may cause adequate changes in the
      pathogen population and subsequent proliferation of the pathogen on the
      genetically identical substrate. A new interpretation of the resistance of line
      Lutescens 6028 as a source of new genes, Bt12 and Bt13, is suggested. Both
      genealogical and segregation analyses have shown that the genes determining the
      resistance of this line may be identical to those described earlier (Bt1, Bt3,
      Bt4, Bt6, and Bt7); and the high resistance of this line is determined by a
      combination of these genes.

PMID- 15174286
TI  - [Leaf proteins in transgenic tobacco plants, expressing dual-stranded RNA in
      viral infection].
AB  - Generation of transgenic tobacco plants, producing double-stranded RNA with no
      homology to tobacco genome sequences is reported. The RNA synthesis is mediated
      by a construct containing an inverted repeat of the pBR322 tetracycline
      resistance gene fragment under control of the 35S CaMV promoter. Analysis of the
      resistance of transgenic plants to the tobacco mosaic virus revealed the changes
      in the protein spectra of the infected plants. The 25- and 30-kDa proteins found
      were not detected in the extracts of normal plants. Amino acid sequencing of the
      30-kDa peptide with subsequent computer database search revealed the homology of
      this protein to the hydrolases belonging to the group of plant beta-glucanases.
      The role of the novel polypeptides in an increase of the resistance of transgenic
      plants to TMV, and also the possibility of the regulation of their expression by
      nonhomologous dsRNA are discussed.

PMID- 15174287
TI  - [Effective size of subpopulation of the early run sockeye salmon Oncorhynchus
      nerka from Azabach's Lake (Kamchatka): effect of density on variance of
      reproductive success].
AB  - Using Parensky's approach for estimating the number of breeding pairs, we
      determined effective subpopulation size Ne in early-run sockeye salmon
      Oncorhynchus nerka from Azabach'e Lake (Kamchatka) in 1977 through 1981. On
      average (over years and populations), biased sex ratio decreased Ne by 7% as
      compared to the number of fish on the spawning sites (Ni). High density reduced
      the Ne/Ni ratio by 62-66% because some fish were excluded from spawning.
      Dominance polygyny as compared to monogamy and random union of gametes could
      reduce Ne by about 17%.

PMID- 15174288
TI  - [Allelic variants of the tumor necrosis factor superfamily as markers of the
      severity of the course of chronic obstructive lung disease and bronchiectatic
      disease].
AB  - The distribution of allelic variants of genes of the TNF superfamily (TNFA and
      LTA) was studied in 172 patients with chronic obstructive pulmonary disease
      (COPD), bronchiectatic disease (n = 22), and in healthy individuals (n = 169).
      Analysis of the TNFA gene locus -308G-->A revealed no differences between the
      examined groups. Analysis of the LTA gene polymorphic locus +252A-->G showed that
      in patients with COPD, the frequency of the G allele was significantly higher
      than that in the control group (chi 2 = 3.98, p < 0.05). The presence of this
      allele in the genotype was correlated with the degree of COPD severity. Thus, in
      patients with stage II COPD, heterozygous AG genotype predominated (51.3%),
      whereas in patients with stage III COPD, the frequency of AG genotype was reduced
      to 32.7% at the expense of increased frequency of GG genotype (14.6%) (chi 2 =
      6.78, p < 0.05; OR = 4.6, CI 1.37-15.96). The distribution of combined TNFA and
      LTA genotypes was also studied. In the group of COPD patients, the proportion of
      individuals with a combination of normal GG TNFA genotype and heterozygous AG LTA
      genotype was significantly higher (28.5% versus 18.4% in control; chi 2 = 4.14, p
      < 0.05; OR = 1.75, CI = 1.01-3.04). Genotype combinations were characterized at
      various clinical stages of COPD and bronchiectatic disease (BED). Thus, we have
      shown for the first time ever that LTA gene alleles and their combinations with
      the polymorphic variants of the TNFA gene are associated with predisposition to
      COPD and severity of this disease.

PMID- 15174289
TI  - [Genetic structure of people from the Volga-Ural region and Central Asia from
      data of Alu-polymorphism].
AB  - Nine Alu loci (Ya5NBC5, Ya5NBC27, Ya5NBC148, Ya5NBC182, YA5NBC361, ACE, ApoA1,
      PV92, TPA25) were analyzed in six ethnic populations (Trans-Ural Bashkirs, Tatars
      Mishars, Mordovians-Moksha, Mountain Maris, Udmurts, and Komi-Permyaks) of the
      Volga-Ural region and in three Central Asian populations (Uzbeks, Kazakhs, and
      Uigurs). All Alu insertions analyzed appeared to be polymorphic in all
      populations examined. The frequency of insertion varied from 0.110 in Mountain
      Maris at the Ya5NBC5 locus to 0.914 in Tatars at the ApoA1 locus. The data on the
      allele frequency distribution at nine loci point to the existence of substantial
      genetic diversity in the populations examined. The value of the observed
      heterozygosity averaged over nine Alu insertions varied from 0.326 in Mountain
      Maris to 0.445 in Kazakhs and Uigurs. The level of the interpopulation genetic
      differences for the Volga-Ural population (Fst = 0.061) was higher than for the
      populations of Central Asia (Fst = 0.024), Europe (Fst = 0.02), and Southeastern
      Asia (Fst = 0.018). The populations examined were highly differentiated both in
      respect of linguistic characteristics and the geographical position. The data
      obtained confirmed the effectiveness of the marker system used for the assessment
      of genetic differentiation and the relationships between the ethnic groups.

PMID- 15174290
TI  - [Genetic archaeologic perspective on the origin of Yakuts].
AB  - Published data on two cases of linkage disequilibrium in Yakuts are analyzed.
      These are the disequilibria between loci HLA-A and HLA-B and between the mutation
      of gene SCA1 responsible for type 1 spinocerebellar ataxia and its flanking
      microsatellites D6S274 and D6S89. Both cases are regarded as consequences of the
      founder effect. The genetic archeological approach has been used to calculate the
      historical period when the mutant SCA1 gene and the HLA-A1?B17 haplotype spread
      in the population. It has been found that this was approximately 60-70
      generations (1500-1750 years) ago in both cases. The time of the segregation of
      haplotype HLA-A1?B17 has also been calculated for some other populations.
      Caucasoids have proved to be the oldest carriers of this gene, which agrees with
      the well-known notion that HLA-A1 originated in Indo-Europeans. The general
      distribution of HLA genes in Yakuts is similar to that in east-central Asian
      Mongoloids; therefore, it is concluded that that Yakuts are east-central Asian
      Mongoloids by origin, except for the founder that had haplotype A1?B17.
      Historically, the time of the appearance of this haplotype coincided with the
      period when Saks conquered east-central Asia; therefore, it is hypothesized that
      the aforementioned founder was a Sak.

PMID- 15174291
TI  - [Inheritance of stability of MN81330 common wheat samples to septoria blotch].
AB  - Wheat samples described in literature as resistant to septoria glume blotch were
      assessed for their response to inoculation with Septoria nodorum Berk. Three days
      after inoculation with the infectious agent, samples Klein Titan (k-41772), Mian
      Jang (k-61568), Walter (k-54585), Reisler (k-59505), Rempart (k-59493), PIN/BOW
      (k-62838), MN81330 (k-60785), Frondoso (k-46736), Sokrates (k-58179) were
      classified as resistant to infection. Seven days after inoculation, only samples
      Reisler and Mian Jang were regarded as resistant. The genetic control of glume
      blotch resistance was studied by hybridological analysis in sample MN81330.
      Resistance of this sample manifested in a longer latent period of the disease is
      controlled by two dominant complementary genes not linked to the gene Lr24
      responsible for resistance to brown rust, to the gene responsible for coleoptile
      coloration, and to minor genes that improve expression of the major ones.

PMID- 15174292
TI  - [Neurotensin: physiological properties and role in the regulation of organism
      function].
AB  - In review one can find summarized data about neurotensin structure, properties
      and physiological activity, presented in publications of last 30 years, from the
      time when this peptide has been discovered. The article contains data about
      neurotensin blood plasma level and its distribution in various organs and tissues
      in humans and different animal species. Main manifestations of neurotensin
      physiological activity are discussed as its participation in regulation of
      cardiovascular, digestive and endocrine systems and also in regulation of
      immunity and cell growth. From clinical point of view, obvious interest
      represents neurotensin ability to produce neuroleptical and antipsychotie effects
      after injecting into the brain ventricles.

PMID- 15174293
TI  - [Features and mechanisms of realization the respiratory influences of the
      extrapyramydal system structures].
AB  - In the publication the modern condition of the problem of suprabulbar regulation
      of breathing is analysed. The review on structure, neurochemistry and anatomic
      connections of the red nucleus and substantia nigra with the medullary
      respiratory center is submitted. The data on the respiratory effects of GABA and
      apomorphine microinjected into the red nucleus and substantia nigra as well as
      effects of their electrostimulation after the blockade of GABA and dopamine
      receptors in the respiratory center are discussed. The conceptual scheme of the
      mechanisms of realization the respiratory influences of the extrapyramydal system
      is offered.

PMID- 15174294
TI  - [EEG characteristics of bioelectrical activity of the brain in women with normal
      and complicated pregnancy].
AB  - Spectrum and coherent EEG analysis has been made at 109 pregnant women during 35
      36 weeks of gestation. It has been shown, that functional interhemispherical
      asymmetry of the brain is the sensible parameter of normal and complicated
      gestation. It has been found out that as for normal pregnancy prevailing
      activation in central and temple areas of the brain contralateral to the side of
      placenta placement in uterus is characteristic. The development of gestation
      complications accompanied by the inversion of interhemispherical asymmetry of EEG
      activation. It was pointed out that correlative relations of bioelectrical
      activity of the brain in women with normal gestation are the indicator of
      dominating of nervous centers of left hemisphere in the integrational process.

PMID- 15174296
TI  - [Desynchronization: mechanisms of development from molecular to systemic levels].
AB  - Striking progress in the field of molecular chronobiology has been made during
      the last years. It renders us to reconsider some traditional viewpoints
      concerning circadian system functioning. Not only we are able now to explain
      basic concept of how clock genes pass through transcriptional and post
      transcriptional pathways and how circadian system eventually "comes to life" at
      the cellular level, but we are also in position to speculate on how the whole
      organism constitutes its space-temporal order and how certain ultradians and
      infradians could be generated. Herein we propose a concept of multifuctorial
      genesis of chronomes and suggest terms such as "input rhythm" (or influencing
      rhythm) and "output rhythm" (or modulated rhythm). We stress on a viewpoint that
      the majority of investigated variables are multifuctorial by its nature because
      of vast net of regulatory mechanisms lied down in between the molecular basis of
      the clock and the output rhythms which are actually measurable by investigators.
      An attempt to follow down mechanisms of loss in the circadian temporal order
      (desynchronization) from the molecular level to that of a whole organism has been
      provided.

PMID- 15174295
TI  - [Functional significance of the thyroid gland].
AB  - On the basis of literature data and our own findings, the paper presents the
      current concepts of the production, secretion, transport, catabolism, mechanisms
      of action, and effects in the organism of thyroid hormones during eu-, hypo-, and
      hyperthyrosis. The nervous, humoral, and immune mechanisms of regulation of the
      secretory activity of the thyroid gland and changes in its functional activity in
      ontogenesis are discussed.

PMID- 15174300
TI  - [The future of Spain it depends on the science].

PMID- 15174297
TI  - [The endogenous allosteric regulators of receptors].
AB  - The literature data devoted to endogenous allosteric regulators of membrane bound
      receptors are summarized in the present review. The allosteric processes are
      classified to (i) cooperative interaction, (ii) nonspecific, (iii) functional,
      and (iv) specific regulations according to target topography in a receptor. The
      specific endogenous allosteric regulators are described for GABAA, NMDA,
      muscarinic, nicotinic, serotonin, and opioid receptors. Substances of different
      chemical structure (peptides, lipids, and polycyclics) are able both to activate
      or inhibit binding and function of respective receptors. Some pathological
      processes appear to depend on endogenous receptor modulators. The role of the
      regulators is speculated in terms of receptor homeostasis, in particular,
      counteraction of receptor tolerance and/or sensitisation during physiological
      pulsation in a ligand' level in synaptic cleft.

PMID- 15174298
TI  - [The experiments with laboratory animals from a bioethical point of view-
      history, modern time, perspectives].
AB  - The origin of laboratory animal science was called forth by violent development
      of experimental biology and medicine in the XIX century on the one hand, and on
      the other hand by the necessity to have standard healthy animals for experiments
      with strictly definite biological characteristics. With this aim in view
      management technology and animal use in experiments have been constantly
      improved. "Laboratory animal" notion has been formed by the end of the XIX
      century. At the beginning of laboratory animal science development ethical
      problems were not as urgent as they are now. It is established that the three Rs
      bioethical conception of W.M.S. Russel and R.L. Burch (1959) has influence on
      modern state and perspectives of the development of animal experimental methods.
      It is shown that the existence of laboratory animal protection laws and the
      reflection in them of compulsory ethical review of scientific project and
      statistics of used laboratory animals is absolutely necessary.

PMID- 15174301
TI  - Recent advances in chromaffin cell biology: summing up the last International
      Symposium on Chromaffin Cell Biology.
AB  - The International Symposium on Chromaffin Cell Biology (ISCCB) brings together a
      group of approximately 150 scientists from around the world who meet every 2
      years to discuss recent advances in our understanding of biogenesis and motion of
      secretory vesicles, synthesis, storage and release of secreted products
      (catecholamines, chromogranins, ATP), and mechanisms involving the excitation
      secretion coupling, membrane ion channels, intracellular calcium homeostasis and
      exocytosis. The development of new technologies that allow an accurate
      measurement of catecholamines, vesicle motion, exocytosis, etc. are also
      analyzed. The 12th ISCCB, organized by Ricardo Borges, took place on September 20
      26, 2003, in La Palma, Canary Islands, Spain. In this article we describe the
      most recent and significant contributions to the 12th ISCCB.

PMID- 15174302
TI  - The circadian timing system: making sense of day/night gene expression.
AB  - The circadian time-keeping system ensures predictive adaptation of individuals to
      the reproducible 24-h day/night alternations of our planet by generating the 24-h
      (circadian) rhythms found in hormone release and cardiovascular, biophysical and
      behavioral functions, and others. In mammals, the master clock resides in the
      suprachiasmatic nucleus (SCN) of the hypothalamus. The molecular events
      determining the functional oscillation of the SCN neurons with a period of 24-h
      involve recurrent expression of several clock proteins that interact in complex
      transcription/translation feedback loops. In mammals, a glutamatergic
      monosynaptic pathway originating from the retina regulaltes the clock gene
      expression pattern in the SCN neurons, synchronizing them to the light:dark
      cycle. The emerging concept is that neural/humoral output signals from the SCN
      impinge upon peripheral clocks located in other areas of the brain, heart, lung,
      gastrointestinal tract, liver, kidney, fibroblasts, and most of the cell
      phenotypes, resulting in overt circadian rhythms in integrated physiological
      functions. Here we review the impact of day/night alternation on integrated
      physiology; the molecular mechanisms and input/output signaling pathways involved
      in SCN circadian function; the current concept of peripheral clocks; and the
      potential role of melatonin as a circadian neuroendocrine transducer.

PMID- 15174303
TI  - Supramolecular complex formation in cell signaling and disease: an update on a
      recurrent theme in cell life and death.

PMID- 15174304
TI  - Optimization of a protocol for direct organogenesis of red clover (Trifolium
      pratense L.) meristems for breeding purposes.
AB  - A series of experiments were carried out in order to optimize a protocol for the
      direct organogenesis of Chilean red clover germplasm. A range of cultivars were
      used to analyze the effect of explant source (crown or stem meristems of
      vegetative plants), culture media and plant growth regulators. Our findings
      showed that stem meristems were easier to obtain, presented lower levels of
      contamination and a better development than crown meristems. The L2 medium showed
      better results than B5 and MS media for the cultivars and experimental lines
      studied. L2 medium supplemented with 0.003 mg/l of 4-amino-3,5,6
      trichloropicolinic acid and 1.0 mg/l of 6-benzylaminopurine gave consistently
      better results and will be applied in our breeding program to propagate, maintain
      and eliminate viruses from elite red clover clones.

PMID- 15174305
TI  - Impact of the training program on lipid profile and cardiac health.
AB  - The aim of this study was to investigate the effects of training programs on
      serum lipid profile and myocardial oxidative stress. Male Wistar rats (2 mo-old)
      were divided into three groups (n = 8): sedentary (S), loadless trained (T) and
      trained-overload 2% body weight (TL). T and TL were trained through swimming for
      9 weeks. T and TL rats had increased myocardial lipoperoxide (TBA) and lipid
      hydroperoxide (HP), whereas HP was higher in TL than in T animals. Superoxide
      dismutase (SOD) activities were lowest in TL. Myocardial glutathione peroxidase
      (GSH-Px) was lower in TL than in T and S rats. TL decreased HDL-cholesterol and
      increased LDL-cholesterol. The serum lactate dehydrogenase and TBA were
      increased, while SOD and GSH-Px activities were decreased in TL rats. Loadless
      training was able to improve HDL-cholesterol and to reduce LDL-cholesterol. In
      conclusion, the loadless training program induced beneficial effects on lipid
      profile, while overload training induced dyslipidemic profile that was associated
      with serum oxidative stress. The overload training program was deleterious
      relative to loadless training program, increasing myocardial oxidative stress.

PMID- 15174306
TI  - Effects of buthionine sulfoximine nifurtimox and benznidazole upon trypanothione
      and metallothionein proteins in Trypanosoma cruzi.
AB  - Proteins rich in sulfhydryl groups, such as metallothionein, are present in
      several strains of the parasite Trypanosoma cruzi, the etiological agent of
      Chagas' disease. Metallothionein-like protein concentrations ranged from 5.1 to
      13.2 pmol/mg protein depending on the parasite strain and growth phase.
      Nifurtimox and benznidazole, used in the treatment of Chagas' disease, decreased
      metallothionein activity by approximately 70%. T. cruzi metallothionein was
      induced by ZnCl2. Metallothionein from T. cruzi was partially purified and its
      monobromobimane derivative showed a molecular weight of approximately 10,000 Da
      by SDS-PAGE analysis. The concentration of trypanothione, the major glutathione
      conjugate in T. cruzi, ranged from 3.8 to 10.8 nmol/mg protein, depending on the
      culture phase. The addition of buthionine sulfoximine to the protozoal culture
      considerably reduced the concentration of trypanothione and had no effect upon
      the metallothionein concentration. The possible contribution of metallothionein
      like proteins to drug resistance in T. cruzi is discussed.

PMID- 15174307
TI  - Replicase mediated resistance against potato leafroll virus in potato Desiree
      plants.
AB  - Potato leafroll virus (PLRV) is a major menace for the potato production all over
      the world. PLRV is transmitted by aphids, and until now, the only strategy
      available to control this pest has been to use large amounts of insecticides.
      Transgenic approaches involving the expression of viral replicases are being
      developed to provide protection for plants against viral diseases. The purpose of
      this study was to compare the protection afforded by the differential expression
      of PLRV replicate transgene in potato plants cv. Desiree, Plants were genetically
      modified to express the complete sense PLRV replicase gene. Two constructions
      were used, one containing the constitutive 35SCaMV promoter and the other the
      phloem-specific RolA promoter from Agrobacterium rhizogenes. Transgenic plants
      were infected with PLRV in vitro, using infested aphids. In plants in which
      35SCaMV controlled the expression of the PLRV replicase gene, signs of infection
      were initially detected, although most plants later developed a recovery
      phenotype showing undetectable virus levels 40 days after infection. In turn,
      those plants with the RolA promoter displayed an initial resistance that was
      later overcome. Different molecular mechanisms are likely to participate in the
      response to PLRV infection of these two types of transgenic plants.

PMID- 15174308
TI  - Study of the expression of carotenoid biosynthesis genes in wild-type and
      deregulated strains of Xanthophyllomyces dendrorhous (Ex.: Phaffia rhodozyma).
AB  - The expression, at the mRNA level, of carotenoid biosynthetic genes from
      Xanthophyllomyces dendrorhous was studied by RT-PCR. The experimental conditions
      for the RT-PCR assay were standardized to quantify the relative transcript levels
      of idi, crtE, crtYB and crtI genes. This work attempted to correlate astaxanthin
      production with the transcript levels of carotenogenic genes in a wild-type
      strain (UCD 67-385) and two overproducer deregulated strains (atxS1 and atxS2).
      At 3 day cultures, the wild-type strain contained higher transcript levels from
      the crtE and crtYB genes on minimal medium than on rich medium. Similarly,
      carotenoid production was higher on minimal medium than on rich medium. However,
      carotenoid production in the atxS1 and atxS2 strains was not correlated with the
      transcript level of carotenogenic genes under the same experimental conditions.
      This result suggests that there is not a linear relationship between
      carotenogenic transcript levels and carotenoid biosynthesis.

PMID- 15174309
TI  - Age dependence of the levels of plasma norepinephrine, aldosterone, renin
      activity and urinary vanillylmandelic acid in normal and essential hypertensives.
AB  - In the present study the upper reference limits (URLs) for resting plasma
      norepinephrine, epinephrine, serum aldosterone, plasma renin activity,
      aldosterone/renin activity ratio, as well as urinary vanillylmandelic acid in
      healthy Egyptian normotensive subjects over a range of ages (5-60 yr) were
      established. There was a significant age effect on plasma norepinephrine, UVMA,
      serum aldosterone and PRA, whereas a single URL for plasma epinephrine level is
      satisfactory. In uncomplicated untreated essential hypertensive subjects (5-60
      yr), the average prevalence of elevation in the plasma norepinephrine,
      epinephrine and urinary vanillylmandelic acid above their corresponding URLs was
      85.10, 62.15 and 83.20%, respectively. This suggests that elevation in plasma
      catecholamine concentrations is more likely a common consequence than playing a
      possible role in the pathogenesis of hypertension, supported by insignificant
      correlation coefficients between the plasma catecholamine levels and resting
      systolic and diastolic blood pressure values (SBP & DBP) in all hypertensive age
      groups. Primary hyperaldosteronism was not detected among the normokalemic
      essential hypertensives at any age using aldosterone/plasma renin activity ratio
      as a primary screening method. In the present study, 7 statistically significant
      positive coefficient correlations are reported for SBP or DBP values with UVMA
      levels in hypertensive children and adolescents, serum aldosterone in old
      hypertensives, and PRA in adult hypertensives.

PMID- 15174311
TI  - [Infectious diseases in Russian Federation: problems and solutions].

PMID- 15174310
TI  - The acetyl xylan esterase II gene from Penicillium purpurogenum is differentially
      expressed in several carbon sources, and tightly regulated by pH.
AB  - The expression of the acetyl xylan esterase II (axeII) gene from Penicillium
      purpurogenum is repressed by glucose and induced by xylan, as well as to a small
      degree by xylose and xylitol. This gene is expressed at neutral pH, but not under
      alkaline or acidic conditions, in agreement with previous findings for other
      xylanolytic genes of this organism. This is the first report showing pH
      regulation of an axe gene.

PMID- 15174312
TI  - [HIV-infection in progress].

PMID- 15174313
TI  - [Antiretroviral therapy of acute HIV-infection].
AB  - AIM: To study efficacy of a short course of highly active antiretroviral therapy
      (HAART). MATERIAL AND METHODS: Acute HIV infection was verified in 16 infected
      subjected basing either on seroconversion (by immunoblotting) or a documented
      negative result 6-12 months before registration of a positive result for HIV
      antibodies. RESULTS: HAART was given to 12 patients (combivir + nevirapin). The
      number of CD+ lymphocytes (by median) 1 month after the treatment increased by
      185 cells/mcl, 3 months after the treatment--by 215 cells/mcl. After 1-month
      therapy viral load (median) diminished by 2.02 log10 copy/ml, after 3 months--by
      2.31 log10 copy/ml. 71% patients had HIV RNA under 400 copy/ml. Untreated
      patients showed changes neither in CD4+ lymphocytes number nor in viral load. The
      study continues. CONCLUSION: HAART is used at the stage of acute infection in the
      presence of psychic trauma provoked by establishment of HIV-infection diagnosis.
      Therefore, it is necessary to consult the patients for preparing them for
      treatment and to maintain compliance.

PMID- 15174314
TI  - [Secondary diseases in patients with HIV infection: 15-year follow-up].
AB  - AIM: To analyse the results of a 15-year study of opportunistic diseases in AIDS
      patients. MATERIAL AND METHODS: The spectrum of opportunistic diseases were made
      in AIDS patients in respect to clinical, laboratory and autopsy data for the
      periods: 1987-1992 (n = 27, 25 deaths--92.6%), 1993-1997 (n = 95, 58 deaths-
      61.8%), 1998-1999 (n = 70, 28 deaths--40%), 2000-2001 (n = 126, 31 deaths-
      24.6%), 2002 (n = 80, 32 deaths--40%). RESULTS: The spectrum of opportunistic
      diseases in AIDS patients was determined for the above time periods and causes
      underlying these diseases have been determined. CONCLUSION: Among opportunistic
      diseases associated with HIV infections most prevalent were the following:
      tuberculosis, cytomegaloviral infections, cerebral toxoplasmosis. Leading modern
      trends were identified: increasing morbidity of AIDS, tuberculosis, new AIDS
      cases at late stages with severe opportunistic diseases (2/3 of deaths).

PMID- 15174315
TI  - [Characteristics of tuberculosis running with HIV infection].
AB  - AIM: To analyse social, clinical, x-ray and immunological features of
      tuberculosis (TB) in 117 patients from the Moscow region with concurrent HIV
      infection. MATERIAL AND METHODS: The patients were divided into 3 groups
      depending on the time of TB and HIV-infection detection in relation to each
      other. Group 1 patients (20.5%) had suffered from TB for 2 years before detection
      of HIV-infection, group 2 patients (51%) were diagnosed simultaneously for 1-2
      years to have both diseases, group 3 patients (28%) had suffered from HIV
      infection for 2 years before the diagnosis of TB. RESULTS: It was established
      that the course of TB with associated HIV-infection depends not only on severity
      of immunodeficiency caused by HIV but also on characteristics of M. tuberculosis
      and social status of the patients. Most of TB/HIV patients were drug addicts,
      alcoholics, convicts. Unfavourable social status in the above patients, contact
      with TB (70%) and its realization in a penitentiary carry a high risk of drug
      resistant TB. High prevalence of destructive TB forms (64%), among them large
      caverns were in 77%, may result from M. tuberculosis resistance to
      antituberculous drugs and unfavourable social status of the patients. Reduction
      of the number of CD4-cells lowers the ability to form caverns and fibrosis and
      promotes dissemination of M. tuberculosis bacteria with formation of inflammation
      foci in different organs and systems. CONCLUSION: Four clinical models of TB/HIV
      onset and course are suggested.

PMID- 15174316
TI  - [Development and evaluation of the kit for detection of SARS-associated
      Coronavirus RNA].
AB  - AIM: To develop a diagnostic kit for detection of SARS (severe acute respiratory
      syndrome)-related coronavirus RNA based on reverse transcription and polymerase
      chain reaction and to estimate its specificity and sensitivity. MATERIAL AND
      METHODS: 68 virus and bacterial cultures, 240 clinical samples from people
      without SARS symptoms and also 22 RNA samples from patients with SARS symptoms
      received during the epidemic in Beijing were used. RESULTS: The specificity of
      the kit was determined using animal coronaviruses and other bacterial and viral
      strains, causing acute respiratory and intestinal infections, and was shown to be
      100%. The sensitivity of the kit in different clinical samples was 2.2 x 10(3)
      genome equivalents of recombinant SARS RNA in 1 ml of the specimen. The kit was
      evaluated in the Institute of Microbiology and Epidemiology of Beijing (China)
      using SARS-cov viral suspension and clinical samples from patients with suspected
      SARS. It was shown that kit was able to detect 10 TCID/50 ml of SARS-Cov virus.
      Testing of clinical samples from patients with suspected SARS showed that
      diagnostic sensitivity of the kit was 95%. Detection of the SARS-Cov RNA was more
      effective in feces compared to sputum 990 and 40%, respectively). CONCLUSION: The
      kit "AmpliSens SARS" for qualitative detection of SARS-related coronavirus RNA by
      reverse transcription and polymerase chain reaction (PCR) in nasopharyngeal
      wash/aspirates, naso/oropharyngeal swabs, plasma, and extract from feces has been
      developed in the Central Research Institute for Epidemiology of the RF Ministry
      of Health. The kit contains reagents for RNA isolation and purification, cDNA
      synthesis by reverse transcription of RNA, for PCR and for electrophoretic
      analysis of amplified products. The kit also contains recombinant positive and
      internal control samples allowing to control efficiency of analysis and showed
      good analytical and diagnostic characteristics.

PMID- 15174317
TI  - [Present-day Clinical characteristics of scarlatina].
AB  - AIM: To study present-day clinical manifestations of scarlatina. MATERIAL AND
      METHODS: The authors have reviewed 138 case histories of children with scarlatina
      treated outpatiently and 51 case histories of hospitalized scarlatina children as
      well as social and age characteristics of 1657 children and 108 adults
      hospitalized in the infectious hospital N 1 in 1962-2001. Official data on
      scarlatina morbidity in Moscow and Russia for 1991-2001 are presented. Antibiotic
      sensitivity of 414 cultures of group A streptococci (GAS) isolated in 1987-1995
      and 1996-2001 was investigated. RESULTS: Overall and seasonal scarlatina
      morbidities in 7-14-year-olds appeared to rise significantly. In the majority of
      cases scarlatina took a mild course but in the adults clinical picture of the
      disease was rather severe. GAS demonstrated high sensitivity (about 100%) to
      betalactamic antibiotics. The percentage of erythromycin-resistant streptococcal
      cultures increased more than 9-fold and reached 1.9% (1996-2001). There is a
      marked trend to a proportional increase of GAS cultures resistant to tetracycline
      and gentamycin. CONCLUSION: Recently, changes have occurred in scarlatina
      epidemiological and clinical features. Different sensitivity of GAS to
      antibiotics must be taken into consideration for prescription of etiotropic
      treatment and prevention of scarlatina at jobs.

PMID- 15174318
TI  - [Development of tests for assessment of efficiency of vaccination for rabies
      prophylaxis. ].

PMID- 15174319
TI  - [Diagnosis of structural changes] of the brain in patients with coronary and
      asymptomatic carotid atherosclerosis].
AB  - AIM: To compare echomorphostructure of atherosclerotic plaques and vascular
      stenosis degree with structural changes of the brain according to MR image in
      patients with combined atherosclerotic affection of coronary and carotid arteries
      in an asymptomatic course of carotid atherosclerosis. MATERIAL AND METHODS: MR
      imaging was made in 53 men aged 44 to 78 years with stenosing atherosclerotic
      affection of the internal carotid arteries. Vascular obstruction reached 30-80%.
      Neurological examination detected no signs of focal brain lesions. Hypertension,
      myocardial infarction, permanent atrial fibrillation were diagnosed in 19 (36%),
      20 (38%) and 12 (23%) patients, respectively. RESULTS: Ultrasound investigation
      has established that carotid arteries contain more frequently spongy and
      heterogenic plaques than dense and calcinated. MRI registered structural
      alterations of cerebral tissue of various degree in 96% cases. CONCLUSION:
      Significant correlations were established between ischemic affection of the brain
      with myocardial infarction, arterial hypertension, cardiac fibrillation, type of
      atherosclerotic plaque.

PMID- 15174320
TI  - [Preclinical diagnosis of renal damage in essential hypertension].
AB  - AIM: To study renal functional reserve and 24-h beta 2-microglobulinuria (B2-MGU)
      in patients with different stages of essential hypertension (EH) and to evaluate
      acceptability of these parameters as early markers of preclinical renal
      impairment in EH. METHODS: We examined 150 patients (mean age 42.1 +/- 3.4 years)
      with EH without overt clinical manifestations of hypertensive nephropathy. Renal
      functional reserve (RFR) was determined with the use of acute oral protein
      loading and was defined as an increase in endogenic creatinine clearance in
      percent. B2-MGU was evaluated by radioimmunoassay (RIO-BETA-2-MICRO kit).
      Radioimmunoassay detection of microalbuminuria (MAU) was performed with the use
      of the standard kit Albumin-RIA. RESULTS: RFR appeared to be significantly lower
      in patients with EH compared to the control group, and its level significantly
      decreased with aggravation of EH. Both B2-MGU and MAU were significantly higher
      in patients with EH and significantly increased with aggravation of EH.
      CONCLUSION: We suggest that, apart from MAU, RFR abnormalities and excessive B2
      MGU should be used as markers of preclinical renal impairment in EH.

PMID- 15174321
TI  - [The spectrum and activity of urinary Ig-proteinases as a marker of chronic
      pyelonephritis].
AB  - AIM: To study the activity of Ig-splitting proteinases of various classes in the
      urine in patients with chronic pyelonephritis. MATERIAL AND METHODS: Clinical,
      device and laboratory examinations were made in 50 patients (age 20-60 years).
      Admission and dynamic measurements were also made of the activity of serin, metal
      dependent and thiol Ig-splitting proteinases in the urine. RESULTS: Total
      proteolytic activity in the urine of the patients was higher than in healthy
      subjects. Thiol proteinase activity was detected in 98% cases. This activity was
      100 times higher in the patients than in healthy subjects. Significant
      differences were registered in the activity of serin proteinases. After the
      treatment the level of serin proteinases approached the normal value while thiol
      proteinase activity decreased significantly (2-fold, on the average) but remained
      high. If this activity was high, the patients (70%) had 1-2 exacerbations
      annually, in low activity exacerbations were absent. CONCLUSION: The activity of
      Ig-splitting proteinases of different classes is an important diagnostic and
      prognostic laboratory criterion of chronic pyelonephritis and can serve a
      criterion of treatment efficacy.

PMID- 15174322
TI  - [Potentialities of high-resolution computed tomography in diagnosis of pulmonary
      lesions after bone marrow transplantation in blood diseases].
AB  - AIM: To study characteristics of a skialogical picture of pulmonary parenchyma
      and roentgenomorphological signs of inflammatory changes before and after bone
      marrow transplantation (BMT); relationship between the data of high-resolution
      computed tomography (HRCT) and clinical data. MATERIAL AND METHODS: HRCT
      (computer tomograph of the third generation "Somatom CR-3") was made in fever,
      changes in physical examination in patients (n = 28) after BMT from November 2001
      to January 2003. BMT was made in myelomic disease, lymphogranulomatosis, acute
      leukemia, chronic myeloid leukemia, lymphosarcoma, autoimmune hemolytic anemia.
      RESULTS: Twenty four patients were examined before BMT. Of them, 18 patients had
      roentgenomorphological changes of the parenchyma, primarily, diffuse. Three
      patients were examined during conditioning, two cases had signs of toxic
      pulmonitis. One day after allo-BMT all the patients exhibited lowering of
      densitometric values of pulmonary tissue by 70 HU vs the baseline. Infectious
      affection of the lungs was diagnosed in 13 cases during day 0-100. From day 100
      after allo-BMT 7 recipients were observed. In 6 cases the changes resulted from
      transplant against host reaction. Infectious affection of pulmonary tissue was
      observed in 1 case. Characteristic x-ray picture of pulmonary stroma in secondary
      disease was determined. CONCLUSION: For early diagnosis of pneumonia in
      myelotoxic agranulocytosis it is necessary to make examination by HRCT before
      BMT. HRCT of the chest is indicated in even minor changes in the clinical
      picture. It is necessary to perform a control over water-electrolyte balance and
      active respiratory exercise in the course of conditioning. Viral pneumonias show
      the picture of metainflammatory changes for a long time. Fungal pneumonias tend
      to recurrence at "previous site". HRCT examination of the pulmonary tissue
      provides more information about pulmonary tissue in patients with secondary
      disease.

PMID- 15174323
TI  - [Efficacy oh the Rome criteria II in diagnosis of irritable bowel syndrome].
AB  - AIM: To study efficacy of the Rome criteria II in diagnosis of irritable bowel
      syndrome (IBS). MATERIAL AND METHODS: The examination was made of 288 consecutive
      patients with an IBS diagnosis admitted to the hospital from January to December
      2002. RESULTS: The IBS diagnosis was confirmed in the specialized hospital in 74
      (25.8%) of 288 patients admitted with this diagnosis. Of 61 patients, whose
      diagnosis met the Rome criteria, the IBS diagnosis was not confirmed in 7
      patients (11.4%). CONCLUSION: Out of 288 patients admitted to a
      gastroenterological hospital, 78.8% patients were diagnosed at the prehospital
      stage not basing on the Rome criteria and appeared erroneous in 70.1%. The
      analysis of the anxiety causes identified different intestinal diseases in 78.5%
      cases, the diagnosis of IBS was confirmed in the rest cases. Specificity of the
      Rome criteria II was 88.6%, sensitivity 82.4%. This provides a reliable diagnosis
      of IBS.

PMID- 15174324
TI  - [Exercise and nicotinic acid delayed action drug Enduracin: application in
      outpatient rehabilitation of patients with ischemic heart disease].
AB  - AIM: To evaluate efficacy of combined use of moderate exercise and nicotinic acid
      drug enduracin in patients with coronary heart disease (CHD) with moderate
      dyslipidemia (DE). MATERIAL AND METHODS: The effects of exercise therapy alone,
      enduracin alone and their combination on physical performance (PP), hemodynamics,
      blood lipid spectrum and clinical course of CHD were studied in 93 CHD patients
      with moderate DE. The results were evaluated clinically after 1-year treatment.
      RESULTS: Combined used of exercise and enduracin in CHD patients showed its
      efficacy manifesting in improvement of PP, hemodynamics at rest and exercise
      test, left ventricular systolic function, clinical course, reduction of DE.
      Enduracin + exercise appeared more efficient than their use in monotherapy.
      Enduracin monotherapy had a positive action on PP, arterial pressure and anginal
      attacks frequency. CONCLUSION: Enduracin is recommended as monotherapy and in
      combination with moderate exercise in outpatient rehabilitation and secondary
      prophylaxis of CHD patients with moderate dyslipidemia and angina pectoris to
      relieve myocardial ischemia under exercise, to raise PP, improve lipid
      composition of blood and prevent maladaptive left ventricular remodeling.

PMID- 15174325
TI  - [Efficacy of cytoprotective agent Mexicor in urgent cardiology].
AB  - AIM: To study efficacy of cytoprotector mexicor in patients with unstable angina
      (UA), acute myocardial infarction (MI), hypertensive crises (HC) in combined
      therapy with conventional drugs. MATERIAL AND METHODS: An open randomized study
      included 338 patients with acute forms of ischemic heart disease (IHD) and
      arterial hypertension running with crises. Combined therapy of 20 patients with
      UA, 90 patients with MI and 43 patients with HC (study groups) was supplemented
      with mexicor in a dose 6-9 mg/kg/day. The control matched patients (20, 86 and 79
      patients, respectively) received conventional treatment alone. The effects of the
      treatments were assessed by ultrasound investigation of the heart in M-, B- and
      Doppler modes, by ECG and arterial pressure 24-h monitoring, by activity of lipid
      peroxidation (LPO). RESULTS: Adjuvant therapy of urgent cardiological conditions
      with mexicor diminished oxidant stress, left ventricular dysfunction. In MI
      patients mexicor promoted reduction of the akinesia zones, recovery of disturbed
      segmentary contractility. In UA patients mexicor contributed to more pronounced
      decrease in the frequency, duration and severity of myocardial ischemia, enhanced
      stabilization of angina. In HC patients mexicor promoted earlier normalization of
      a 24-h AP profile and variability of cardiac rhythm, recurrence rate of HC
      decreased 2-fold. CONCLUSION: The addition of mexicor to conventional therapy of
      UA, MI, HC improves clinical course of these diseases, reduces oxidant stress,
      accelerates recovery of cardiac contractility and left ventricular diastolic
      function, normalization of central hemodynamics.

PMID- 15174326
TI  - [Methodological approaches to estimation of morning urge of arterial pressure in
      essential hypertensives].
AB  - AIM: To estimate the time intervals of a morning arterial pressure urge (MAPU)
      and MAPU characteristics in patients with essential hypertension (EH). MATERIAL
      AND METHODS: The study enrolled 70 patients (50 male and 20 female) with EH of
      the first (n = 41) and second (n = 20) degrees aged 34-65 years (mean age 50.4 +/
      0.9 years). The control group consisted of 9 healthy men. Morning dynamics of
      arterial pressure (AP) and heart rate (HR) was studied basing on the data of 24-h
      AP monitoring (Spacelabs-90207, USA). RESULTS: Dynamics of AP from nocturnal to
      diurnal patterns in both hypertensive and normotensive subjects falls into 3
      phases: a premorning urge (from 4-5 a.m. to waking up) with a characteristic slow
      rise in AP and HR; a morning urge (from waking up for 4-5 hours) with a
      characteristic forced AP and HR rise); a diurnal urge (from 11 a.m. to 13-14
      p.m.) with characteristic slowing down of AP and HR rise. Patients with EH of the
      first and second degree vs normotensive subjects had unfavourable changes in
      morning dynamics of AP and HR: a significant progressive growth of maximal
      systolic and diastolic pressure proportional to mean circadian AP levels; a rise
      of morning hours index of AP which characterizes amplitude-speed features of AP
      and HR. CONCLUSION: To characterize MAPU most completely it is recommended to
      estimate the following parameters: wave index (to assess AP conversion from one
      level to another), mean rate of AP change per hour (to prevent influence of
      random factors on the rate of MAPU); relative maximal values of AP (to estimate
      maximal AP values in morning hours and nocturnal mean AP).

PMID- 15174327
TI  - [Cytokines and cytokine therapy in gastrointestinal diseases].
AB  - AIM: To compare cytokine status in gastrointestinal diseases (GID) with reference
      to etiological factor, course, stage, therapy of the disease. MATERIAL AND
      METHODS: Enzyme immunoassay was used to examine cytokines in the peripheral
      blood, tissue homogenates of 560 GID patients. GID were represented by ulcer
      disease (UD), cholelithiasis, chronic hepatitis (CH), glutenic enteropathy (GE),
      Crohn's disease (CD), nonspecific ulcer colitis (NUC). RESULTS: In chronic
      recurrent GID (UD, cholelithiasis, GE) early exacerbation was characterized by
      elevated concentrations of IL-1 beta, IL-6, IL-8. Concentrations of IL-12, Inf
      alpha, g, TNF alpha reached maximum on the height of the disease. Intensification
      of regenerative processes raised concentrations of IL-4, IL-10. An overall level
      of serum cytokines averaged 190-780 pg/ml, reaching in some patients with active
      disease 1200-3000 pg/ml, in remission 30-110 pg/ml, in the control 40 pg/ml. In
      chronic progressive GID the levels of IL-1 beta, IL-2, IL-8, IL-6 reached 30-80
      pg/ml, IL-12, Inf gamma, TNF alpha--150-370 pg/ml. A rise in cytokines
      concentrations in inflammatory viral, bacterial, autoimmune GID was higher than
      in cancer, alcoholism-related diseases, metabolic disturbances. Basic therapy in
      patients with chronic recurrent GID led to a significant fall in concentration of
      serum cytokines. Therapy with monoclonal antibodies to TNF alpha was associated
      with transitory pronounced favourable changes in peripheral blood cytokine
      status. CONCLUSION: GID provoke elevation of serum and tissue cytokines,
      impairment of cytokine balance in correlation with the etiological factor,
      variants of the course, stage of the disease, on-going therapy.

PMID- 15174328
TI  - [Quality of life, clinical symptoms and nasal passability in patients with
      allergic rhinitis].
AB  - AIM: To examine correlations between quality of life, impairment of nasal
      passability and severity of clinical symptoms in patients with allergic rhinitis
      (AR). MATERIAL AND METHODS: The examination of 54 AR patients (41 females, 13
      males age 18-62 years, mean age 38 years) diagnosed seasonal AR in 19 and year
      round AR in 35 patients. Quality of life was assessed by RQLQ questionnaire.
      Nasal inspiratory peakflowmetry was used to assess nasal obstruction. AR symptoms
      were registered by self-control score method. RESULTS: Most parameters of quality
      of life of AR patients correlated significantly with severity of clinical
      symptoms, the degree of nasal passability. Positive changes in clinical symptoms,
      nasal peakflowmetry evidence correlated with improvement of life quality in the
      course of treatment with a present-day antihistamine drug fexofenadin (120
      mg/day) for 28 days. CONCLUSION: Quality of life in AR patients correlated with
      severity of clinical symptoms and the degree of nasal obstruction. Assessment of
      life quality should be included in the scheme of standard examination of AR
      patients.

PMID- 15174329
TI  - [Modern problems in clinical diagnosis of infectious diseases].

PMID- 15174330
TI  - [Modern methods immunological and genetical diagnostics in clinical practice].

PMID- 15174331
TI  - [Markers of chronic renal failure and assessment of renal function].

PMID- 15174332
TI  - [Self monitoring of arterial blood pressure as a method for changing patients
      attitude toward treatment of arterial hypertension].

PMID- 15174333
TI  - [Comparative sensitivity of different Cholinesterases of different origin to its
      inhibitors].

PMID- 15174334
TI  - [Activity, composition and distribution of pancreatic serine proteases in
      different taxonomy groups of hydrobionts. ].

PMID- 15174335
TI  - [Acid phosphatase of Ameba: Amoeba Proteus].

PMID- 15174336
TI  - [Regulatory influence of synthetic cationic peptides containing glutamic acid
      residues on functional activity of components of adenylate cyclase signal
      system].

PMID- 15174337
TI  - [Influence of glutamate and inhibitors of different pathways of free radicals
      synthesis on activity Na,K-atpase and accumulation of lipids peroxidation
      products in synaptosomes in rat cerebellum].

PMID- 15174338
TI  - [The dependence of force on the velocity frog Rana Temporaria blood vessel
      contraction].

PMID- 15174339
TI  - [Correlative relationship between rate of oxygen consumption, body temperature
      and activities of key antioxidant enzymes in liver of Mus Musculus].

PMID- 15174340
TI  - [Locomotion development of walruses Eumetopias Jubatus in early ontogenesis].

PMID- 15174341
TI  - [Effects of fast-wave Sleep deprivation in rats with hereditary audiogenic
      seizures].

PMID- 15174342
TI  - [Age related changes of physiology of mitral valve in humans. ].

PMID- 15174343
TI  - [Hypothalamo-hypophyseal-adrenal system response to oxidative stress in mice of
      different age].

PMID- 15174344
TI  - [Comparative morphological analysis of reindeer and cow ovaries].

PMID- 15174345
TI  - [The role of glycogen phosphorylase kinase in regulation of sarcoplasmic
      reticulum Ca-atpase of frog Rana Temporaria].

PMID- 15174346
TI  - [ Uncoupling agents influence on non-phosphorylating respiration in liver
      mitochondria of river lamprey and grass frog in autumn-winter period of metabolic
      depression].

PMID- 15174347
TI  - [Sensitivities of human and several animal species erythrocytes to colloidal
      osmotic lysis].

PMID- 15174348
TI  - [From diversity of molecular forms to functional specialization of oligomeric
      proteins, nicotinic acetylcholine receptor, acetylcholinesterase and Na+, K+
      ATPase].
AB  - The review is devoted to the issue of diversity of molecular forms of oligomeric
      proteins using as examples members of the three protein classes: nicotinic
      acetylcholine receptor, acetylcholinesterase, and Na,K-ATPase. The data are
      presented on the molecular structure of proteins, subunit compositions, and
      isoforms of subunits, as well as on some features of gene expression. Particular
      emphasis has been made on the functional specialization of different molecular
      forms of one and the same oligomeric protein. The three above proteins, which
      serve seemingly quite different cellular processes, demonstrate many common
      principles of molecular mechanisms of physiological function.

PMID- 15174349
TI  - [Polyploidy: significance for cardiomyocyte function and heart aerobic capacity].
AB  - Somatic polyploidy, defined as genome multiplication, was found in all
      differentiated mammalian tissues. The highest level of such a polyploidy was
      found in the myocardium. This phenomenon was shown to be associated with changes
      in the pattern of gene expression. Hence, polyploidization may create cells with
      new physiology. The effect of polyploidy on the heart function has never been
      studied. The aim of the present study was to investigate the effect of polyploidy
      on cardiomyocyte functioning and heart aerobic capacity. DNA and the total
      protein content, nucleolar activity reflecting the rate of rRNA synthesis and,
      consequently, ribosome biogenesis, were measured in ventricular myocytes isolated
      from the human and from 21 mammalian species by image cytometry and microscopic
      morphometry. The total protein content was estimated after staining slides with
      naphtol-yellow dye. For measurement of DNA and nucleolar area, staining with
      Hoechst and AgNO3 was applied. Cardiac aerobic capacity was evaluated by the
      heart mass to body mass ratio. A negative correlation between the heart index and
      the average cell ploidy was revealed (r = -0.79; P < 0.0001). The average genome
      number per myocyte was registered to be higher by approximately 35% in the
      sedentary mammals, with the heart index about 0.4% from body mass, than in the
      athletes with heart index about 0.6% of body mass. Polyploidization was shown to
      be associated with a sharp decrease in the protein/DNA ratio in cardiomyocytes.
      As a result, cardiomyocytes in the athletic mammals with poorly polyploid hearts
      have much higher protein content per genome than do cells in the sedentary
      species with highly polyploid hearts. Surprisingly, despite decreased protein/DNA
      ratio, the nucleolar area per genome significantly increased with
      polyploidization, indicating the imbalance between the cellular protein content
      and the rate of ribosome biogenesis. Such an imbalance should obviously impair
      cardiac function, because the additional genomes take some valuable space and
      biological resources from the cell, which could have been otherwise directed to
      the maintenance of cardiomyocyte contractile machinery. It is generally accepted
      that somatic polyploidy is associated with oxidative stress and energetic
      starvation. Thus, we suppose that additional genomes may serve for cardiomyocyte
      protection from oxidative damage in the hearts.

PMID- 15174351
TI  - [Localization of fibrillarin, 53 kDa protein and Ag-NOR proteins in the nuclei of
      giant antipodal cells of the wheat Triticum aestivum].
AB  - Distribution of nucleolar argentophylic proteins, fibrillarin and 53 kDa protein,
      in highly polyploid nuclei of antipodal cells of Triticum aestivum L. was studied
      at different stages of the embryo sac development. The main results are as
      follows. 1. Ag-NOR proteins and fibrillarin form clusters are distributed in the
      giant nucleoli, whereas 53 kDa protein is mainly localized on the nucleolar
      periphery. Ag-NOR proteins and fibrillarin are accumulated as globular nucleolar
      like particles--micronucleoli. 2. Dynamics of Ag-NOR proteins, fibrillarin and 53
      kDa protein depends on the proliferative activity of endosperm cells. In embryo
      sacs with non-dividing endosperm cells at interphase stages, Ag-NOR proteins and
      fibrillarin were observed only within nucleoli and micronucleoli. In embryo sacs
      with dividing endosperm cells, fibrillarin and 53 kDa protein formed
      heterogeneous globular bodies varying in size. Simultaneously, some argentophylic
      material was observed in giant chromosomes. This may be due, presumably, to a
      partial or complete disappearance of the nucleoli of antipods and transition of
      some nucleolar components into the peripheral material of giant polytene
      chromosomes. We suggest that giant nuclei of antipodal cells may undergo cyclic
      transformation similar to those in the nuclei of dividing cells.

PMID- 15174350
TI  - [Cell response of rat liver parenchyma to the infection by the intestinal
      protozoan pathogen Cryptosporidium parvum (Sporozoa, Coccidia)].
AB  - In the present work, the authors' previous studies of a "distant action", exerted
      by an intestinal pathogen (Cryptosporidium parvum) on the liver of experimentally
      infected baby rats, were extended to include shifts in the quantity of glycogen,
      protein and nuclear DNA in the host liver at different degrees of infection. One
      of the outcomes of this work is the discovery of a very quick response of
      hepatocytes and a high sensitivity of rat liver to parasitic invasion even at a
      weak intensity of infection. 85-90 h after oocyst feeding to rats, glycogen
      quantity in their livers was 2.5 times lower that in the control. This suggests
      that the infected host liver worked under energetic starvation conditions. The
      proposed coefficients of general infection (I) and infection with intracellular
      stages (F) made it possible to distinguish between the total abundance of
      parasites in the host intestine during the whole period of infection, and the
      number of feeding intracellular stages available by the moment of autopsy. The
      glycogen amount in rat hepatocytes does not depend on I, and negatively
      correlates with F. Unlike, the protein content in hepatocytes positively
      correlates with I, being independent of F. Despite the obvious deficiency of
      amino acids in the infected rats, as a consequence of cryptosporidiosis-induced
      malabsorption, the protein synthesis in their hepatocytes was not at all
      inhibited but, on the contrary, much activated. This is a most characteristic
      feature of the distant action of C. parvum on the liver of parasitized host. With
      C. parvum infection, the share of polyploid hepatocytes does not correlate with
      either I, or F. However, compared to the control, the mean values of relative
      numbers of polyploid cells in weakly, moderately, and heavily infected animals
      (according to I values) were higher by 20, 100 and 100%, respectively. In
      hepatocyte nuclei of C. parvum infected rats, the total area of nucleoli
      increases almost by 30%. The above changes are discussed in terms of both the
      liver compensatory response to the existing pathology (diarrhea), and the host
      parasite relationships. Studies into the distant action of an intestinal pathogen
      (C. parvum) on non-intestinal organs (liver) of the infected host may be
      qualified as a new and original approach to pathogenesis of protozoan infections
      (coccidioses sensu lato), to which young host specimens are known to be most
      susceptible.

PMID- 15174352
TI  - [The role of phosphoinositide signaling in the lower eukaryotes].
AB  - The recent achievements on phosphoinositide signaling in the unicellular
      eukaryotes have been reviewed. Special attention is paid to mechanisms of
      phospholipase C (PLC) activation and its interaction with both cell surface
      receptors and effector cytoplasm targets. We discuss the role of protein kinase C
      (PKC) in intracellular signaling, and the relationship between the PI-signal
      pathway key enzymes with protein kinases of cAMP-PKA and MAP-kinase pathways.

PMID- 15174353
TI  - [The influence of lectins on the aggregation of neutrophils and erythrocytes in
      healthy humans].
AB  - A study was made of the influence of some plant lectins on the aggregation of
      neutrophils and erythrocytes in healthy humans, and the state of carbohydrate
      determinants of glycoprotein receptors of these cells was characterized. These
      carbohydrate determinants, containing D-mannose, N-acetyl-D-glucosamin, and bD
      galactose, provide neutrophils aggregation in healthy persons. The surface
      receptors of erythrocytes have remains of bD-galactose, several N-acetyl-D
      glucosamin, N-acetyl-neyranimic acid, N-acetyl-D-galactosamin, L-fucose. Thus, in
      neutrophils and erythrocytes of healthy persons there is a definite composition
      of carbohydrate determinants of glycoproteins. Changes in these carbohydrate
      determinants are able to increase cells aggregation and, consequently, to disturb
      reological property of the blood, and to impair processes of microcirculation and
      thrombose stimulation.

PMID- 15174354
TI  - [Neutrophil activation in vitro].
AB  - Kinetics of spontaneous and induced reactions of Nitroblue tetrazolium (NBT)
      restoration by neutrophils was investigated in vitro. The index of activated
      neutrophils (IAN), commonly characterizing cell activation degree depending on
      the reaction time (t), was described by the equation: IAN = [NBT0](1-exp[-k1t]) +
      k0t; where (NBT0) is intracellular concentration of NBT, which reflects membrane
      permeability, k1 and k0--speed constants of the first and zero order reactions,
      characterizing, respectively, stimulation and spontaneous activities of enzymatic
      systems involved in NBT restoration. We detected the ability of heparin (2.0-7.5
      mkg/ml) or chondrotin sulphate (0.25-2.5 mkg/ml) to activate neutrophils and
      presumably to maintain in vivo their spontaneous activity. The values of kinetics
      equation parameters enable us to speculate about relative hyper-, hypo- and
      normal function of neutrophils, related to the functional state of the whole
      organism. The value of [NBT0] changes from 8 to 103 conventional units, and a
      high correlation exists between this index and the reaction speed constants,
      differing in stimulated and spontaneously activated cells. The latter are
      represented by neutrophils only, which, as shown before, produce active forms of
      oxygen, used, probably, not for phagocytosis needs. The share of such cells makes
      approximately 30-40% of the neutrophil recirculating pool, and positively
      correlates with [NBT0], (r = 0.58; P < 0.05). This is determined by a very high
      membrane permeability of this neutrophil subpopulation. The detected different
      spontaneous and stimulated ability, various membrane permeability and enzyme
      system activity confirm the neutrophil functional unequality, which defines their
      activation peculiarity.

PMID- 15174355
TI  - [Enhancement of fibroblast growth promoting activity of human blood after its
      irradiation in vivo (transcutaneously) and in vitro with visible and infrared
      polarized light].
AB  - Visible and infrared (IR) irradiation of laser and non-laser sources has a
      pronounced wound-healing effect promoting tissue repair without hyperproduction
      of connective tissue elements. This effect develops as a consequence of local and
      systemic light effects, but many aspects of their mechanism have been yet
      unclear. In the present work, we have shown that in 0.5 h after irradiation of a
      small area of the volunteers' body surface with polychromatic visible + IR light
      (400-3400 nm, 95% polarization, 12 J/cm2) the amounts of PDGF and TGF-beta 1 in
      the blood serum increase, on average, by 20 and 43%, respectively. This effect is
      preserved for at least 24 h to be recorded only in volunteers with the initially
      normal and decreased levels of the growth factors; the initially elevated content
      of PDGF-AB decreases. Addition of such a plasma (2.5%) to the nutrient medium of
      primary cultures of human embryonal fibroblasts stimulates cell proliferation, on
      average, by 10 and 17%, but only in the case if the initial growth-promoting (GP)
      blood activity was low. Similar changes occur in parallel experiments following
      irradiation of blood samples of the same volunteers in vitro, as well as at
      mixing irradiated and non-irradiated autologous blood at the ratio 1:10 (v/v),
      i.e. at modeling a situation in the vascular bed, when the transcutaneously
      photomodified blood contacts with the rest of its volume. Similar changes in the
      blood GP activity under conditions in vitro were recorded as well after 4-9 daily
      phototherapy sessions. This allows us to suggest that changes in GP activity of
      circulating blood of the irradiated volunteers may be, to a large extent, the
      consequence of effect exerted on the blood by small amounts of transcutaneously
      photomodified blood. The obtained results are discussed in terms of light effect
      on wound healing and scar tissue formation, with regard to the authors' previous
      data on much higher GP of the irradiated blood in respect to keratinocytes, the
      fast decrease in proinflammatory cytokine levels, and the increase in IFN-gamma
      content.

PMID- 15174356
TI  - [The function of leaf meristematic cells in Cotinus coggygria Scop].
AB  - Proliferation of leaf meristem cells and formation of multicellular glands and
      unicellular hairs in Cotinus coggygria were studied under conditions of complex
      stressors exerting influence on this species when introduced and grown in such a
      big industrial city as Voronezh. Variability in the length of dividing
      meristematic cells (from 7.5 to 30.0 microns) was detected. The chromosome number
      was calculated, and the mean length of chromosomes (1 micron) was determined. The
      modal chromosome number in the leaf meristem cells in 2 n = 30. However, along
      with these cells, aneuploid (2.7%), uninucleate polypoid (1.9%), binuclear (10%),
      and polynuclear (3%) cells were also observed. The length of trichomes initials,
      formed in the epidermis, was near 40 microns. These have a large nucleus and may
      have, presumably, a polyploid nature. It is assumed that a heterogeneous
      meristematic cell population, at the expense of selection into such a population,
      is able to provide an optimum combination of cells with different level ploidy
      and aneuploidy for more effective realization of gene function in the extremal
      environment conditions.

PMID- 15174357
TI  - Creating win-win relationships: strengthening the ties between technology
      managers and manufacturers.

PMID- 15174358
TI  - "Beyond 'broke'": three steps to improve how your hospital buys, uses, and
      repairs equipment.
AB  - By approaching problems in the hospital as an observational researcher, biomeds
      can begin to think about the problems in a different way, which may point toward
      opportunities to solve these problems. Of all of the people in the hospital,
      biomeds are in the best position to address these issues because they see how the
      products are used and what goes wrong. These three steps are just a starting
      point for moving beyond product repair and maintenance so biomeds can improve
      product use in their hospitals.

PMID- 15174359
TI  - The future of biomedical support: Web technology provides additional tools for
      today's BMET.
AB  - Biomeds have been and will continue to be on the cutting edge of health care
      technology. Whether it is working on the latest diagnostic imaging equipment,
      handling the network cabling for the IT department in a large hospital or
      repairing an infrared TV remote that fell out of a patient's bed, the BMET is
      able to work with many different and ever changing technologies. By taking
      advantage of some of the new Web-based technologies and combining them with the
      existing biomedical training and support programs currently available, today's
      BMET will be well prepared to meet the changes in health care technology.

PMID- 15174361
TI  - Identifying and fixing intermittent problems.

PMID- 15174360
TI  - The fundamentals of... video endoscopy systems.

PMID- 15174362
TI  - Coping with information fatigue syndrome.

PMID- 15174363
TI  - A case study ... how one facility saved money and created value.

PMID- 15174364
TI  - How one biomed prepared for the anatomy and physiology section of the exam.

PMID- 15174365
TI  - Understanding CAPA requirements in a software context.

PMID- 15174366
TI  - Medical virtual reality simulation: enhancing safety through practicing medicine
      without patients.

PMID- 15174368
TI  - A novel system for mild hypothermia.
AB  - Mild hypothermia has been shown to provide protective effects in patients with
      ischemia (e.g. acute stroke and heart attack), but traditional methods for
      inducing, maintaining, and reversing hypothermia are slow, difficult to
      administer and control, and uncomfortable for patients. An innovative method
      produces mild, wholebody hypothermia (32 degrees C to 34 degrees C) by use of an
      endovascular heat exchanger placed into the inferior vena cava. A closed-loop
      system accurately changes core body temperature with average cool-down rates of
      4.8 degrees C per hour, tight-target temperature control of +/- 0.1 degree C, and
      average rewarm rates of 1.9 degrees C per hour. By enhancing the mixing of blood
      in the vicinity of the heat exchanger, the disposable, small-diameter catheter
      efficiently exchanges heat between the closed-loop circulating fluid and the
      blood stream in response to body temperature. A control algorithm adapts to body
      physiology and thermal mass to mitigate temperature excursions. Flexible, bellow
      shaped segments along the length of the catheter allow precise maneuvering within
      blood vessels. Heparin, covalently bonded to the catheter, helps control
      thrombogenicity. This novel design has potential clinical applications in
      cerebrovascular surgery, acute stroke, acute myocardial infarction, cardiac
      arrest, and fever control.

PMID- 15174367
TI  - Integrated data acquisition system for medical device testing and physiology
      research in compliance with good laboratory practices.
AB  - In seeking approval from the US Food and Drug Administration (FDA) for clinical
      trial evaluation of an experimental medical device, a sponsor is required to
      submit experimental findings and support documentation to demonstrate device
      safety and efficacy that are in compliance with Good Laboratory Practices (GLP).
      The objective of this project was to develop an integrated data acquisition (DAQ)
      system and documentation strategy for monitoring and recording physiological data
      when testing medical devices in accordance with GLP guidelines mandated by the
      FDA. Data aquisition systems were developed as stand-alone instrumentation racks
      containing transducer amplifiers and signal processors, analog-to-digital
      converters for data storage, visual display and graphical user-interfaces, power
      conditioners, and test measurement devices. Engineering standard operating
      procedures (SOP) were developed to provide a written step-by-step process for
      calibrating, validating, and certifying each individual instrumentation unit and
      the integrated DAQ system. Engineering staff received GLP and SOP training and
      then completed the calibration, validation, and certification process for the
      individual instrumentation components and integrated DAQ system. Eight integrated
      DAQ systems have been successfully developed that were inspected by regulatory
      affairs consultants and determined to meet GLP guidelines. Two of these DAQ
      systems were used to support 40 of the pre-clinical animal studies evaluating the
      AbiCor artificial heart (ABIOMED, Danvers, MA). Based in part on these pre
      clinical animal data, the AbioCor clinical trials began in July 2001. The process
      of developing integrated DAQ systems, SOP, and the validation and certification
      methods used to ensure GLP compliance are presented in this article.

PMID- 15174369
TI  - [The increase in the variability of microsatellite-associated repeats in the
      genome of gamma-irradiated male mice is tissue specific].
AB  - The arbitrarily primed polymerase chain reaction (AP-PCR) was used to measure the
      level of polymorphism of microsatellite (MCS)-associated repeating sequences of
      spleen, lung, and brain DNA in the F1 progeny of male BALB/c mice exposed to
      acute gamma-radiation at doses of 50 cGy and 200 cGy 15 days before mating with
      unirradiated females. The variability of MCS-associated sequences in the genome
      of brain and lung cells was higher as compared to the spleen cells of the progeny
      of unirradiated males. In the progeny of irradiated males, a 20% increase in MCS
      polymorphism of spleen DNA was found as an increase in the frequency of "non
      parent" bands in DNA-fingerprints as against to the progeny of unirradiated
      males. Significant changes in this parameter were revealed for brain tissue and
      not for lung tissue only in the progeny of males exposed to 200 cGy. The results
      suggest a tissue-specific character of transmission of radiation-induced
      alterations in the genome of germ cells of male parents to the somatic cells of
      the progeny.

PMID- 15174370
TI  - [Induction of the Tn10 precise excision in E. coli cells after accelerated heavy
      ions irradiation].
AB  - The influence of the irradiation of different kinds on the induction of the
      structural mutations in the bacteria Escherichia coli is considered. The
      regularities of the Tn10 precise excision after accelerated 4He and 12C ions
      irradiations with different linear energy transfer (LET) were investigated. Dose
      dependences of the survival and relative frequency of the Tn10 precise excision
      were obtained. It was shown, that the relative frequency of the Tn10 precise
      excision is the exponential function from the irradiation dose. Relative
      biological efficiency (RBE), and relative genetic efficiency (RGE) were
      calculated, and were treated as the function of the LET.

PMID- 15174371
TI  - [Effect of phosphatidic acid on the radiation-initiated peroxidation of
      phosphatidylcholine in liposomes].
AB  - It was found that the incorporation of anionic dipalmitoyl phosphatidic acid
      (DPPA) into phosphatidylcholine (PC) liposomes up to 15 mol % was accompanied by
      the intensification of accumulation of diene conjugates (DC), which are primary
      products of lipid peroxidation (LPO), if the LPO was initiated by gamma
      irradiation of a 137Cs source. Monoethyl ester of DPPA, phosphatidylethanol
      (DPPEt), exerted a lesser influence at the same concentrations. Ca2+ ions
      inhibited the DC production not only in liposomes consisting of lipid mixture but
      in lipid membranes of PC alone as well. It was assumed that the electrostatic
      repulsion of negatively charged DPPA and DPPEt resulted in the loosening of
      polarside region of membrane hydrophobic layer and in consequence the access of
      hydroxyl radicals to hydrocarbon chains of PC. This assumption is in good
      agreement with the results of osmotic behavior of liposomes in hypertonic urea
      solution.

PMID- 15174372
TI  - [Chromosome aberrations in human lymphocytes at a various duration of cultivation
      after irradiation].
AB  - Human peripheral blood lymphocytes were exposed to 60Co gamma-rays (a dose of 3
      Gy) and cultivated during seven days in the presence of PHA and BrdU. It was
      shown that the metaphases of the first and second mitosises occurred during
      cultivation of the irradiated and unirradiated lymphocytes, being evidence about
      of irregularity of the coming into division of various fractions of lymphocytes.
      The time of cultivation did not influence a rate of aberrations in metaphases of
      the first and second mitosises of the irradiated lymphocytes. During the first
      and the subsequent mitosises the number of exchange chromosome aberrations
      decreased and reached a control level in metaphases of the fourth and fifth
      mitosises. The number of paired fragments at second and third mitosises increased
      a little and started to decrease only in metaphases of the fourth and fifth
      mitosises. The decrease in chromosome aberrations with prolongation of the
      cultivation of lymphocytes after irradiating is a consequence of elimination of
      cells with chromosome damages during sequential mitotic divisions.

PMID- 15174373
TI  - [Effect of external gamma-irradiation on the genetic apparatus of somatic cells
      of rat fetus].
AB  - Cytogenetic effects of different radiation dose rate and dose value were studied
      in fibroblasts of 20-day old rat fetuses and new-born ratlings. Quantitative and
      qualitative changes in the occurrence frequency in the spectrum of chromosome
      aberration types were revealed and changes in aneuploid fibroblast ratio were
      observed. The damages in the fibroblast chromosome structure of fetuses remain
      after birth (2-day-old ratling) and they were also observed in fetuses of the
      second generation.

PMID- 15174374
TI  - [Aging rate after continual low dose irradiation of drosophila strains with
      apoptosis deregulation].
AB  - In this article the results of investigations of interrelation between radio
      induced apoptosis in larvae nervous system and aging in imago are presented. It
      was shown that the apoptosis level of larvae nervous ganglion 2.5 folds increased
      after exposure to ionizing radiation (54 cGy). Irradiation of stocks with higher
      apoptosis induction sensitivity, bearing mutations of inhibitor apoptosis protein
      th (allele th1 and th4) and wild type strain Berlin leaded to elevation of
      activity at all ages and accordingly to decreasing of aging speed. Whereas in
      stocks with lower apoptosis induction sensitivity (with mutations of genes rpr,
      grim, hid, dArk and Dcp-1) this effect was not observed. The obtained results
      suggested that radiation-induced apoptosis could be one of the mechanisms
      preventing aging.

PMID- 15174375
TI  - [Modifying influence of iodine deficiency on radiation damage to the fetus
      (review)].
AB  - It known an oppressing action of radiation, including radioactive iodine isotopes
      on the reproductive system and fetus development. There are clinical data on a
      negative influence of iodine deficiency on the course of pregnancy and fetus
      development resulting from hormonal disfunction of thyroid gland and a mother
      fetus system. There are no data about a character and mechanisms of interaction
      of radiation and iodine endemia at the combined action on the gonads and fetus.
      The urgency of this problem is caused by the fact that many regions of the
      country are characterized to some extent by iodine deficiency in local food and
      water (in Russian Federation such regions make approximately 50% of territories),
      and the opportunity of radiation accidents at nuclear plants with contamination
      of the environment with products of nuclear division (significant part of which
      is radioactive iodine isotopes is an objective reality. The analysis of a few
      published and own experimental data allows us to conclude that the combined
      influence of an external gamma-irradiation and iodine deficiency on reproductive
      function has a synergic character.

PMID- 15174376
TI  - [Role of hematopoietic microenvironment in the mechanism of radioprotective
      action of interleukin-1 beta in long-term bone marrow cultures].
AB  - The influence of human interleukin-1 beta in different concentration on processes
      of postirradiation recovery of haemopoietic precursors (GM-CFC) and morphology of
      recognized elements of bone marrow were studied in long-term bone marrow cultures
      during 28 days after gamma-irradiation with a dose of 2 Gy. It was studied also
      the action of interleukin-1 beta on proliferation, the contents of GM-CFC and the
      induction of GM-CSF in non-irradiated cultures. It was shown that the injection
      of interleukin-1 beta increased proliferation and the content of GM-CFC and also
      raised an induction of GM-CSF in the non-irradiation cultures. The maximum
      increase of a level of GM-CSF, amount of GM-CFC and proliferation of GM-CFC was
      marked in 20 hours after the injection of cytokine. Under irradiation of long
      term bone marrow cultures the maximum stimulation effect to recovery of GM-CFC,
      total number of myelocaryocytes and the content of immature and mature
      granulocytes were observed after the injection of interleukin-1 beta in
      concentration of 0.005 microgram/ml 20 hours prior to radiation exposure. The
      data of this report suggest that one of the mechanisms of radioprotective action
      of interleukin-1 beta apparently is connected with stimulation action on
      hematopoietic microenvironment cellular elements that causes the release of GM
      CSF or/and other cytokines, and stimulation recovery of haemopoietic precursors.

PMID- 15174377
TI  - [Dependence of radioprotective activity of chitosan on its molecular mass].
AB  - The influence of chitosan molecular mass (70, 10 and 5 kDa) on its
      radioprotective efficiency in mice experiments was studied. It was shown that
      chitosans with molecular masses of 70 and 10 kDa had similar radioprotective
      properties. The survival of mice increased up to 73% and 87% respectively at
      intravenous injection 15-30 min before a whole-body exposure to 137Cs gamma
      radiation at a dose of 8 Gy (Cd97/30). Practically absolute loss of
      radioprotective activity occurred below a threshold of about 10 kDa. The results
      showed a high chitosan radioprotective activity in a wider range of molecular
      masses than it was supposed earlier.

PMID- 15174378
TI  - [Metallothionein content in tissue and neoplasms of mice under cadmium chloride
      administration and gamma irradiation. Increased radioresistance in mice with
      elevated level of metallothionein].
AB  - It was confirmed that the survival of gamma-exposed mice became higher after
      preliminarily subcutaneous injections of cadmium chloride. It is supposed that
      radioresistance of mice is connected with the induction of metallothionein
      proteins by cadmium chloride.

PMID- 15174379
TI  - [Long time combined action of cadmium and ultraviolet radiation on barley
      plants].
AB  - In a greenhouse experiment the development of biomass and grain yield was studied
      under a long-time combined action of medium-wave UV-radiation and cadmium
      (exposure levels of the agents were, respectively, 0.65-1.30 W/m2, 5 and 50 mg/kg
      of soil). The influence of the metal on the UV-radiation induced inhibition of
      the vegetative mass development was found to be dependent on the duration of
      stress: with increase in the exposure time the cadmium ability for cushioning
      negative effects of irradiation decreases. Simultaneously the contribution of the
      metal and its interaction with UV-radiation to the variability in the observed
      indicator (biomass) becomes much less significant than that of irradiation.
      Considerable independent of cadmium concentration reduction in the grain yield
      becomes evident at a rate of medium-wave UV-radiation intensity of 0.65 W/m2,
      whereas at UV-radiation exposure levels of 1.30 W/m2 and the heavy metal
      concentration of 50 mg/kg in soil practically total inhibition of grain
      productivity occurred. As for grain formation, relative effects of irradiation
      were somewhat higher than these of cadmium and its interaction with UV-radiation.

PMID- 15174380
TI  - [Acquired radioresistance of progeny of irradiated cells is accompanied by
      rearrangements in chromatin organization].
AB  - gamma-Irradiation action within a dose range of 0-20 Gy on parental djungarian
      hamster fiborblasts, DH-TK- cell line, and the progenies of these irradiated
      cells, surviving acute exposure to 20 Gy irradiation, PIC-20 cell line, was
      examined. The PICs were 3 times more radioresistant than the parental cells as
      calculated from D0. Using a method of anomalous viscosity time dependence (AVTD)
      it was revealed that starting (initial) level (in untreated cells) of chromatin
      compactness in radioresistant progenies was more than 1.4 times as high as for
      parental cells. The analysis of dose dependence has shown that irradiation with a
      dose of 5 Gy resulted in complete chromatin loop relaxation in radiosensitive DH
      TK- cells and partial one in radioresistant PIC-20 cells. Besides, the beginning
      of DNA-membrane complexes degradation following the irradiation with doses over
      15 Gy in DH-TK- cells was observed. It was shown that the increased state of
      relative chromatin relaxation in PIC-20 cells determines an increasing in
      reparation effectiveness that resulted in lower percent of residual damages in
      these cells. Using the Nosern hybridization method the expression level of mts 1,
      tag 7 and vseap 1 genes was studied. It is revealed that tag 7 and vseap 1 gene
      expression in radioresistant cells were correspondingly 6 and 10 times higher
      than in radiosensitive parental cells and the level of mts 1 gene expression was
      not changed. So, based on the results obtained we suggest that acquired
      radioresistance in progenies of irradiated cells is determined by rearrangements
      in chromatin structure and accompanied constitutive changes of gene expression.

PMID- 15174381
TI  - [Antineoplastic effect of glutapyrone in continual gamma-irradiation of rats].
AB  - In experiments on rats (290 animals) exposed to chronic gamma-radiation with the
      total dose of 10.0 Gy it was detected that prescription of synthetic
      pharmaceutical of the dihydropyridine class--glutapyrone--together with drinking
      water during 6 months reduced the rate of malignant neoplasms from 26.5% in the
      control group to 13% in the treated animals. In radiation-exposed rats that
      received glutapyrone there was a narrowing of spectrum of the emerged neoplasms
      (connectively-tissual tumors only) as compared to the animals of the radiated
      control group, where blastomas of epithelium and lymphoid origin were also
      revealed. Low toxicity of glutapyrone and its anticarcinogenic action show the
      potential for this preparation to be used in practice.

PMID- 15174382
TI  - [Radiation-induced and embryotoxic effects in experimental hyperthyroidism].
AB  - The purpose of this article was investigation the development of the posterity
      rat (line Wistar) in the postnatal ontogenesis after combined and separate action
      of gamma-radiation (1.25 Gy at 20 days) and hyperthyroidism, provoked by toxic
      thyroid doses of 100 mg thyroidin per rat. It was shown that hyperthyroidism did
      not affect physical development of the irradiated posterity, but in a long-time
      period (7 month) it was revealed a decrease in ability to the training of
      posterity rats after the combined action of the factors.

PMID- 15174383
TI  - [Evaluation of radon effects on lung cancer development].
AB  - In order to evaluate the effect of indoor exposure to radon and thoron on the
      development of lung cancer in the population of two towns of Sverdlovsk Region,
      epidemiologic studies were conducted using a multifactarial method of analysis.
      Both towns, Pervouralsk and Karpinsk, are located within the geological area with
      the gamma-radiation exposure dose ranging from 5 to 12 mu r/hr, and are
      characterized by an increased cancer incidence rate--323.1 and 364.6 cases per
      100,000 of population, respectively. The mean values of the voluminous indoor
      activity (VA) of radon in Pervouralsk and Karpinsk were 23 and 75 Bq/m3 (with
      maximal indices of radon VA being 395 and 739 Bq/m3), equivalent equilibrium
      concentrations (EEC) of residential radon and thoron were 0.6 and 2.5 Bq/m3
      (maximal indices of EEC of thoron being 5 and 13 Bq/m3), respectively. The
      results of multifactorial analysis of 22 different lung cancer risk factors
      carried out using the pattern recognition method proved that the contribution of
      thoron and radon in the development of lung cancer in the population of
      Pervouralsk and Karpinsk was not significant--0.5 and 0.6%, respectively. The
      calculations performed in a monofactorial model of risk evaluation BEIR VI gave
      different results--11-16% and 35-52% for the towns of Pervouralsk and Karpinsk,
      respectively. The discussion of the results provides arguments for the
      reliability and adequacy of the application of multifactorial method of radiation
      risk evaluation as compared to the traditionally applied monofactorial method.

PMID- 15174384
TI  - [Criteria for the assessment of radon potential risk in territories].
AB  - The detailed analysis of criteria used in the different countries for an
      assessment of radon potential risk in territories was made. Such criteria as
      radon flux density from earth surface, radon concentration in soil air, specific
      activity of 226Ra in superficial soils were chosen. The analysis has revealed
      that the most reliable criterion is the value of equilibrium radon concentration
      in the soil air. The method of measurement of this value is specified.

PMID- 15174385
TI  - [Potency of peroral and parenteral administration of Zinc-DTPA for decorporation
      of 241Am from the gastrointestinal tract].
AB  - An effect of cincacine at three doses (25, 150 and 300 mumol/kg) has been studied
      in rats receiving 241Am citrate intragastrically. The radionuclide was introduced
      every other day for 2 weeks. The total content was 925 kBq/kg. A cincacine
      administration leads to limitation of radionuclide accumulation in the major
      organs of deposition independent of the modes of intake. At gastrointestinal
      241Am intake peroral cincacine administration is more effective in limiting this
      radionuclide accumulation in skeleton but less effective in reduction of its
      accumulation in liver compared to parenteral cincacine. No reliable dependence of
      cincacine efficacy on dosage has been revealed. A morphology study of organs has
      shown that cincacine ingestion at a dose of 150 mumol/kg for 4 weeks and at a
      dose of 300 mumol/kg for 2 weeks produces a toxic effect on the small intestine
      mucosa. 25 mumol/kg is the optimum dose and per os administration of higher doses
      is not expedient.

PMID- 15174386
TI  - [Estimation of rate constant for dissolution of radioactive fuel particles].
AB  - Some theoretical of the experimental investigation of solubility of radioactive
      aerosols were examined. Filters, which were exposed during October-November 1987
      in Pripyat town, were studied. Measurements on 22 November 1987 showed that an
      activity in the air was 12.1-20.8 mBq/m3 for 137Cs, 34.9-89.3 mBq/m-3 for 144Ce,
      24.3-30.5 mBq/m-3 for 106Ru. Disperse structure of aerosol hot particles and the
      number of hot particles on each filter fragment was estimated by radiography. To
      determine a dissolution rate constant a static system with two 0.14 micron pore
      size membrane MFE filters (Dubna, Russia) enclosing fragments of Petryanov
      filters was selected. The composition was held in Gamble's solution lung fluid
      anf then in 0.1 mol/l HCl as dastic juice simulation. The activity of 90Sr,
      238Pu, 239 + 240Pu, 241Am and 244Cm in aerosol filters and solutions was measured
      by radiochemical methods. It was shown that leaching of radionuclides from
      aerosol hot particles in lung fluid simulation decreases in line 137Cs > 90Sr >>
      239 + 240Pu > or = 241Am, depending om particle diameter and time. Dissolution
      constants were presented. Dissolution of aerosol particles in 0.1 mol/l HCl is
      also shown (dissolution time was 3 days). A radionuclide transition to HCl
      solution decreases in line 90Am 241Am >> 137Cs > 239 + 240Pu. A transition degree
      reached 21% for 90Sr and extraction of 241Am was 3-17%.

PMID- 15174387
TI  - 2002 National Hospital Discharge Survey.
AB  - OBJECTIVES: This report presents national estimates of the use of non-Federal
      short-stay hospitals in the United States during 2002 and trend data for selected
      variables. Numbers and rates of discharges, diagnoses, and procedures are shown
      by age and sex. Average lengths of stay are presented for all discharges and for
      selected diagnostic categories by age and sex. METHODS: The estimates are based
      on medical abstract data collected through the 2002 National Hospital Discharge
      Survey. The survey has been conducted annually since 1965 by the National Center
      for Health Statistics. Diagnoses and procedures presented are coded using the
      International Classification of Diseases, 9th Revision, Clinical Modification
      (ICD-9-CM). RESULTS: Trends in the utilization of non-Federal short-stay
      hospitals show that the average age and age distribution of inpatients has
      changed dramatically from 1970 through 2002. In 1970, the average age of all
      inpatients was 40.7 years compared with 52.1 years in 2002. The percent of
      discharges aged 65 years and over comprised 20 percent of hospital discharges in
      1970 whereas they comprised 38 percent in 2002. During this same period, the
      percent of inpatients under 15 years of age declined from 13 to 8 percent and
      inpatients 15-44 years of age declined from 43 to 32 percent. The percent of
      inpatients aged 45-64 years was more stable during these 23 years. In 2002, there
      were an estimated 33.7 million hospital discharges, excluding newborn infants.
      The discharge rate was 1,174.6 per 10,000 population. The rate of respiratory
      disease diagnoses among persons 65 years and over was significantly higher than
      for other age groups and has risen since 1975. There were 42.5 million procedures
      performed on inpatients during 2002. About one-quarter of all procedures
      performed on females were obstetrical. Almost one-quarter of all procedures
      performed on males were cardiovascular.

PMID- 15174389
TI  - [Mites of the family Cheyletidae (Acari: Prostigmata): phylogeny, distribution,
      evolution and analysis of parasite-host relationship].
AB  - A modern system, phylogeny, distribution and host parasite relationships of
      cheyletid mites (Acari: Prostigmatal Cheyletidae) is shortly discussed. According
      to the phylogenetic hypothesis proposed by Bochkov and Fain (2001), the family
      Cheyletidae includes now 15 tribes: Acaropsellini, Bakini, Cheletogenini,
      Cheletosomatini, Chelonotini, Cheyletiini, Cheyletiellini, Cheyletini,
      Cheletomorphini, Criokerontini, Metacheyletiini, Niheliini, Ornithocheyletiini,
      Teinocheylini and one unnamed tribe including the genera Caudacheles and Alliea.
      The parasitic Cheyletidae were primarily free-living predators, frequently
      associated with nests of vertebrates. These mites, being predators, have numerous
      preadaptations to the parasitic mode of life and they possess high ecological
      plasticity. Therefore it was quite easy for these mites to adapt to parasitism on
      the vertebrates. According to our phylogenetical hypothesis, the parasitism on
      vertebrates has arisen independently in several phylogenetic lines of the
      cheyletids associated with nests of vertebrates. Such transition from nest
      predation to true parasitism probably occurred repeatedly and at different times.
      The cheyletid mites are more widely represented on birds than on mammals.
      Possibly, it is in relation with a more early origin of parasitism in the
      cheyletids associated with bird nests than in the cheyletids associated with
      mammal nests. An independent origin of the parasitism in many different cheyletid
      phyletic lines, arisen significantly later than the origin of such a parasitic
      group as myobiid mites, is probably the main reason, which could explain the
      recent mosaic distribution of the Cheyletidae among the mammalian taxa. Parasitic
      associations between cheyletids and vertebrates are more common than the
      associations between these mites and the invertebrates. In the invertebrates,
      these associations are generally restricted to a phoresy. The zoogeographical
      analysis showed that this family as whole is characterised by the extremely low
      endemisms. The most part of the free-living cheyletid mites are associated with
      Holarctic region (87%) and, therefore, this family, probably, originated there.

PMID- 15174388
TI  - [Long-term dynamics of the epizootic process in natural foci of ixodid tick
      borreliosis in mountain taiga forests of the Middle Ural].
AB  - During eleven spring-summer seasons (1992-2002), the dynamics of the epizootic
      process in natural foci of ixodid tick-borne borrelioses (ITBB) were studied in
      taiga forests of the Middle Ural (Perm Province, Russia). In these foci, Borrelia
      garinii and B. afzelii circulate, and their main vector is the Ixodes persulcatus
      tick. Main parameters of the epizootic process were calculated for each season.
      In four seasons (1993, 1996, 1999 and 2002), the parameters characterizing the
      abundance of unfed nymphs and adult ticks, as well as the prevalence of Borrelia
      in them, density of infected ticks, and approximate total number of Borrelia in
      them proved to increase essentially and simultaneously. These seasons were
      preceded by the years of population peaks in forest small mammals (1992, 1995,
      1998 and 2001), especially in the Clethrionomys glareolus vole, the dominant
      species in the local fauna of these mammals and the main reservoir host of
      Borrelia. Apparently, the possibility of horizontal transmission of the ITBB
      agents sharply increased in such years, and this resulted in the intensification
      of their dissemination.

PMID- 15174390
TI  - [Relationship of the flea Citellophilus tesquorum altaicus (Siphonaptera:
      Ceratophyllidae) with the plague agent].
AB  - Some aspects of relationships of the flea Citellophilus tesquorum altaicus and
      bacterium Yersinia pestis of two strains isolated from different parts of the
      Tuva natural plague focus were studied. Peculiarities of elimination and blood
      meal activity of fleas infected with two strains of the plague agent were not
      revealed. Differences in mortality and alimentary activity are considerably
      determined by the sex of insects. The ability of examined strains to form a
      proventriculus block was not identical in the strains examined. This ability was
      expressed higher in the strain I-3428, which originated from the same part of the
      natural focus as the insectarium flea culture, than in the strain I-3327. During
      the spring and first half of summer, the proventriculus block appeared more
      frequently in females. The increasing of the fraction of blocked individuals was
      observed in both sexes from spring to summer. As for the ability to transmit the
      plague agent, similar seasonal increasing was noted in males, but in females, the
      ability to inoculate the plague microbe was always maintained at the same level.

PMID- 15174391
TI  - [Fine structure of the female reproductive system in Sobolevicanthus gracilis and
      Cloacotaenia megalops (Cestoda: Cyclophyllidea)].
AB  - The fine structure of the female reproductive organs and ducts in two
      cyclophyllidean cestodes was studied by transmission electron microscopy. All the
      studied ducts (vitelline, fertilization and vaginal ducts, and oviducts) as well
      as the uterine and ootype walls have the luminal surface elevated to form apical
      cytoplasmic lamellae and are surrounded by bands of circular muscules, which are
      attached to the basement layer. The structure of the studied ducts epithelium
      corresponds to the pattern described in other ducts of the cestode genital
      system, namely a nucleate syncytial layer. An exception is the vagina
      Sobolevicanthus gracilis, in which the surface is lined with not numerous
      atypical microtriches. The comparison of our results and the data reported for
      other species is given. It is found out that in different species of cestodes
      forming oligolecital eggs, there are observed various uterine structures and
      diverse contacts between the eggs capsules and the uterine epithelium. The
      formation of special structures and contacts is the evolutionary way from the
      extrauterine type to more progressive intrauterine type of embryo development in
      cestodes.

PMID- 15174392
TI  - [The parasite fauna of the chub mackerel (Scombridae: Scomber japonicus Houttuyn,
      1782) in the central-eastern Atlantic (Atlantic coast of the Northern Africa and
      the Azores Archipelago banks)].
AB  - The parasite fauna of the chub mackerel Scomber japonicus Houtuym, 1782 was
      studied from the neritic areas of Morocco, Western Sahara, Mauritania and from
      the banks of the Azores Archipelago (the Great Meteor Bank, the Hyeres Bank and
      the Irving Bank) in 1994-2001. Twenty eight species of parasites of following
      group have been were found: Coccidia (1 species), Microsporidia (1), Myxosporea
      (4), Monogenea (4), Cestoda (5), Trematoda (5), Acanthocephala (1) and Nematoda
      (6). The differences between mackerel parasite fauna in the neritic areas and
      from of the Azores Archipelago banks were established. Peculiarities of the
      mackerel parasite fauna in two areas (Morocco--Western Sahara and Mauritania)
      corroborate the hypothesis that two populations of chub mackerel are available:
      "Sahara-Moroccan" and "Senegal-Mauritanian". Ontogenetic variability of parasite
      fauna was related to food demands of mackerel and its feeding habits in the areas
      Morocco and Mauritania. Kudoa histolytica has negative influence on the
      commercial value of S. japonicus. These parasites were localized in the muscles
      of mackerel from Mauritania (40%, TL = 20-25 cm). Parasites being dangerous for
      human health were presented by larvae of Bolbosoma sp. (occurred on the banks of
      the Azores Archipelago), Anisakis simplex and Contracaecum sp. (occurred in all
      areas investigated).

PMID- 15174393
TI  - [Variability and phenotypic structure of Proteocephalus torulosus (Cestoda:
      Proteocephalidea)--a parasite of cyprinid fishes].
AB  - Variability of 5 qualitative features of Proteocephalus torulosus from 6 fish
      species belonging to 5 genera of the subfamily Leuciscinae was studied.
      Itraspecific diversity is represented by 3 scolex forms, 2 types of proglottid
      structure, 3 proglottid shapes, and 2 variations of the female reproductive
      system characteristics. The parasite living in different host species form
      separate ecological forms differing in the number of phenotypes and their ratio.
      However, the same scolex and strobila phenotypes dominate in the range of the
      parasite. Two P. torulosus groupings have been recognised the European and Asian
      ones, which differ in the representation of the proglottid structure types.

PMID- 15174394
TI  - [Ecological succession of parasitic fauna of fishes in lakes].
AB  - Succession of fish parasite fauna in lakes (with example of Baltic shield) was
      investigated. At the middle oligotrophic stage, the fauna of parasites and fishes
      maintain a relative stability for a long period and characterised by maximum
      species diversity.

PMID- 15174395
TI  - [New data on Cyathocotyle bushiensis (Trematoda: Cyathocotylidae)].
AB  - Metacercariae of Cyathocotyle bushiensis Khan, 1962 (Digenea) were found in
      populations of seven species of gastropod snails collected from lakes and rivers
      in the south of West Siberia (Russia). This is the first record of C. bushiensis
      in Russia. Five species of snails, Lymnaea stagnalis, L. palustris, L. tumida,
      Planorbis planorbis (Pulmonata) and Viviparus viviparus (Prosobranchia) were
      recorded as new hosts for the metacercariae of C. bushiensis. The infection rate
      of Bithynia tentaculata and Opisthorchophorus (= Codiella) troscheli
      (Prosobranchia), the main hosts of C. bushiensis metacercariae, was analyzed in
      regard to the sex and shell length of molluscs. It was revealed that infection
      rate and mean intensity of metacercariae increases with the shell lengths.
      Drawings and descriptions of excysted metacercariae from naturally infected
      snails and adult worms from experimentally infected domestic ducklings are given.

PMID- 15174396
TI  - [Is good clinical practice a problem?].

PMID- 15174397
TI  - [Reorganization of psychiatry].

PMID- 15174398
TI  - [Day hospital treatment versus hospital admission in acute psychiatric illness].

PMID- 15174399
TI  - [New regulations on drug research].

PMID- 15174400
TI  - [Treatment of ischemic heart disease with the platelet aggregation inhibitor
      clopidogrel].

PMID- 15174401
TI  - [The ill physician].

PMID- 15174402
TI  - [Diagnostics: new methodological initiatives].

PMID- 15174403
TI  - [The Danish clinical guidelines (Klaringsrapporter, 1996-2001: Insufficient
      evidence presented for the diagnostic accuracy of recommended clinical
      biochemical tests].

PMID- 15174405
TI  - [Thrombolytic treatment of acute and subacute limb ischemia].

PMID- 15174404
TI  - [The free TRAM flap used for breast reconstruction: A retrospective study].

PMID- 15174406
TI  - [Are treatment effects or adverse effects of significance for the association
      between financing and conclusions in randomized trials?].

PMID- 15174407
TI  - [10-year follow-up study of mortality among users of hostels for homeless people
      in Copenhagen].

PMID- 15174408
TI  - [Lower extremity blood pressure determination].

PMID- 15174409
TI  - [Fatal outcome of pneumococcal pneumonia--a consequence of macrolide
      resistance?].

PMID- 15174410
TI  - [Condylomata lata--manifestations of secondary syphilis].

PMID- 15174411
TI  - [The sugar report and lipogenesis].

PMID- 15174412
TI  - [Evidence-based medicine--is it something to rely on?].

PMID- 15174413
TI  - [Reporting of adverse effects].

PMID- 15174414
TI  - [Economic prescription of drugs].

PMID- 15174416
TI  - [Congress participation].

PMID- 15174415
TI  - [Internal medicine patients again].

PMID- 15174417
TI  - [Rehabilitation works].

PMID- 15174418
TI  - [From observation to handling].

PMID- 15174419
TI  - [The Danish quality model--it is the will to want to be able to do].

PMID- 15174420
TI  - [Prevention of hospital incidents. Information about the Danish Patient Insurance
      Association's case records].

PMID- 15174421
TI  - [Lumbar disk prolapse surgery. Can intervention at an incorrect level be
      prevented?].

PMID- 15174422
TI  - [The pattern of treatment injuries and near misses in a surgery department. A
      review of a 1-year material].

PMID- 15174423
TI  - [Deep infection (purulent arthritis) following arthroscopic knee surgery in
      Denmark 1998-2000].

PMID- 15174424
TI  - [General practitioners' attitudes toward reporting and learning from adverse
      events. Experiences from focus group interviews].

PMID- 15174425
TI  - [Possibilities for quality improvement in general practice by learning from
      adverse events].

PMID- 15174426
TI  - [Cross-sectorial cooperation concerning concerning ambulatory care patients].

PMID- 15174427
TI  - [Quality control in the national health service. I. The decision to develop a
      Danish Quality Model].

PMID- 15174428
TI  - [Quality control in the national health service. II. Accreditation is a model].

PMID- 15174429
TI  - [Quality control in the national health service III. Accreditation in a European
      perspective].

PMID- 15174430
TI  - [Quality development in the national health service. IV. Standards for disease
      prevention and health promotion in hospitals].

PMID- 15174432
TI  - [Accreditation in a health technology assessment perspective].

PMID- 15174431
TI  - [Quality control in the national health service. Patients' experiences of
      hospitals' quality].

PMID- 15174433
TI  - [From my bosom].

PMID- 15174434
TI  - [Number recognition-will delay the work at the Institute of Pathology in
      Aalborg].

PMID- 15174435
TI  - [Recycling of disposable medical equipment].

PMID- 15174436
TI  - Security and privacy after September 11: the health care example.

PMID- 15174438
TI  - HIPAA: commercial interests win round two.

PMID- 15174437
TI  - Medical records and HIPAA: is it too late to protect privacy?

PMID- 15174439
TI  - Personal privacy and common goods: a framework for balancing under the national
      health information privacy rule.

PMID- 15174440
TI  - The power of pregnancy: examining constitutional rights in a gestational
      surrogacy contract.

PMID- 15174441
TI  - Conceivable sterilization: a constitutional analysis of a Norplant/Depo-Provera
      welfare condition.

PMID- 15174442
TI  - Cloning human organs: potential sources and property implications.

PMID- 15174443
TI  - From agape to organs: religious difference between Japan and America in judging
      the ethics of transplant.
AB  - This essay argues that Japan's resistance to the practice of transplanting organs
      from persons deemed "brain dead" may not be the result, as some claim, of that
      society's religions being not yet sufficiently expressive of love and altruism.
      The violence to the body necessary for the excision of transplantable organs
      seems to have been made acceptable to American Christians at a unique historical
      "window of opportunity" for acceptance of that new form of medical technology.
      Traditional reserve about corpse mutilation had weakened and, especially as
      presented by the theologian Joseph Fletcher, organ donation was touted as both
      expressive of agape and a way of "updating" Christianity via the ethics of
      Utilitarianism. Many Japanese, largely Buddhist and Confucian in their
      orientation, view these changed valorizations as neither necessary nor patently
      more ethical than those of their own traditions.

PMID- 15174444
TI  - PRHO learning and teaching.

PMID- 15174445
TI  - Best Paper Award 2003.

PMID- 15174446
TI  - A case-study of access deficit to stored multiplication facts: discrepancy
      between explicit and implicit tasks.

PMID- 15174447
TI  - Mechanisms underlying visuo-spatial amelioration of neglect after prism
      adaptation.

PMID- 15174448
TI  - Regular and irregular morphology and its relation with agrammatism: evidence from
      Spanish and Catalan.

PMID- 15174449
TI  - Supramodal representation of objects and actions in the human inferior temporal
      and ventral premotor cortex.

PMID- 15174450
TI  - The recovery of subject clitics in mild agrammatism: implications for treatment
      and linguistic analysis.

PMID- 15174451
TI  - Ipsilesional neglect for left imaginal space.

PMID- 15174452
TI  - The acquisition of arithmetic knowledge - an FMRI study.

PMID- 15174453
TI  - Joint attention for pointing but not grasping postures.

PMID- 15174454
TI  - The mental representation of ordinal sequences is spatially organized: evidence
      from days of the week.

PMID- 15174455
TI  - The bleeding edge of technology.

PMID- 15174456
TI  - Diet and DNA.

PMID- 15174457
TI  - Retrieval of episodic and semantic autobiographical memories in early Alzheimer's
      disease and semantic dementia.

PMID- 15174458
TI  - How viruses sabotage silencing.

PMID- 15174459
TI  - International sequencing consortium.

PMID- 15174460
TI  - Bone densitometry and fracture risk prediction.

PMID- 15174461
TI  - Do signers think differently? The processing of number parity in deaf
      participants.

PMID- 15174462
TI  - Implicit processing of global information in Balint's Syndrome.

PMID- 15174463
TI  - Lost in the middle. Attentional modulation of the pseudoneglect phenomenon in a
      "no hands" line bisection paradigm.

PMID- 15174464
TI  - Luminescence Literature. Electrochemiluminescence 1999-2002.

PMID- 15174465
TI  - A modest proposal: toward improved access to biotechnology research tools by
      implementing a broad experimental use exception.

PMID- 15174466
TI  - [After tumor therapy what possibilities exist for preservation of female
      fertility?].

PMID- 15174467
TI  - [Physical activity and prevention of disease].
AB  - Physical inactivity is one of the major risk factors for cardiovascular diseases.
      Regular physical activity conversely is effective in reducing all-cause
      mortality, cardiovascular morbidity and mortality. Risks and side-effects can be
      neglected, medical examination before training is strongly recommended.
      Counseling healthy persons and patients at any age for physical activity, and
      training prescription should be an essential part of physicians' work in general
      practice.

PMID- 15174468
TI  - [New treatment options for HIV-infected patients].

PMID- 15174470
TI  - WHA adopts landmark global strategy on diet and health. In a victory over the
      sugar lobby, health ministers finally approve global strategy to combat obesity
      epidemic.

PMID- 15174469
TI  - [Craniocerebral trauma. 2: Intra-axial injuries, secondary injuries].

PMID- 15174471
TI  - Hungarian government confronts "tipping" practices. Doctors can earn much-needed
      extra cash in tips from patients, but health care suffers as a result.

PMID- 15174472
TI  - UK opens embryonic stem cell bank.

PMID- 15174473
TI  - USA announces plan to expedite AIDS drug approvals.

PMID- 15174474
TI  - Dual-task interference of encoding and retrieval processes in healthy and
      impaired working memory.

PMID- 15174475
TI  - FDA follows NIH in review of staff consulting activities.

PMID- 15174477
TI  - The neural substrates of derivational morphological processing: an FRMI study.

PMID- 15174476
TI  - SARS under control, but lab-safety questions remain.

PMID- 15174478
TI  - Myriad loses rights to breast cancer gene patent.

PMID- 15174479
TI  - Japan makes progress in facing up to post-traumatic stress. Japan's "stiff upper
      lip" begins to quiver as peer pressure gives way to a new openness about PTSD.

PMID- 15174480
TI  - Verb-noun compounds in Italian: a multiple single-case study.

PMID- 15174481
TI  - Modulation of space-based and object-based neglect by perceptual parsing.

PMID- 15174482
TI  - Relevance of semantic features and category specificity.

PMID- 15174483
TI  - The role of semantic and symbolic representations in arithmetic processing:
      insights from simulated dyscalculia in a connectionist model.

PMID- 15174484
TI  - Effects of strategies of mental rotation performed by unilateral brain damaged
      patients.

PMID- 15174485
TI  - Neural correlates of successful declarative memory formation and retrieval: the
      anatomical overlap.

PMID- 15174486
TI  - The code of silence.

PMID- 15174487
TI  - The code of silence.

PMID- 15174488
TI  - The code of silence.

PMID- 15174489
TI  - Spine training. Spine surgery fellowships: perspectives of the fellows and
      directors.

PMID- 15174490
TI  - Spine and the law. US Supreme Court dismisses fraud on the Food and Drug
      Administration claim.

PMID- 15174491
TI  - Spine in the arts. The surrealists' spine.

PMID- 15174492
TI  - Employers shift rising health care costs to workers: no long-term solution in
      sight.
AB  - Despite concerns that an economic downturn would prompt employers to rein in
      rapidly rising health insurance premiums by radically reducing benefits, few have
      made dramatic benefit changes, according to findings from the Center for Studying
      Health System Change's (HSC) 2002-03 site visits to 12 nationally representative
      communities. Key employer changes focused on increasing patient cost sharing and
      revising family coverage policies. Few employers adopted innovative health
      benefit strategies or major design changes. Given employers' lack of confidence
      in alternative strategies and their unwillingness to restrict workers' choice of
      providers, employers will likely continue incremental cost-sharing increases in
      the face of ongoing premium increases.

PMID- 15174493
TI  - "Drug holidays" provide no benefits in HIV treatment.

PMID- 15174494
TI  - Cochlear implants may increase risk for bacterial meningitis.

PMID- 15174495
TI  - The origins of the Association of Program Directors in Radiology.

PMID- 15174496
TI  - Tuberculosis drug resistance: summary report for 2003.

PMID- 15174497
TI  - [Endourology and transitional cell carcinomas of the upper urinary system].

PMID- 15174498
TI  - [Treatment of upper urinary tract tumors. Report of our experience].
AB  - OBJECTIVES: The objective of this article is to perform a comprehensive
      exposition of the various non-endourological treatment options for upper urinary
      tract tumors in order to set the bases to choose the most adequate surgical
      indication depending on tumors' and patients' characteristics; we consider the
      various surgical approaches, and the historic evolution from the classic
      indication established by Albarran (radical nephroureterectomy with bladder cuff)
      to the current ones more conservative. We also consider the role of radiotherapy
      and chemotherapy in the treatment of these tumors. METHODS/RESULTS: We refer to
      the conclusions of various authors and their large series published in the
      literature, series considered classic already, and provide support adding our
      experience by reviewing 223 patients treated from 1977 to 2003 with a mean follow
      up of 45 months (maximum 238 months). CONCLUSIONS: We can state that it is
      acceptable to indicate less aggressive ways of treatment (nephroureterectomy
      without bladder cuff, distal or partial ureterectomy, and conservative
      operations) if the oncological radicality requirements are met, remembering that
      site, tumor grade and stage are determinant in the outcome.

PMID- 15174499
TI  - [Pathologic classification of upper urinary tract tumors].
AB  - OBJECTIVES: To do an update on the upper urinary tract tumors classification
      systems. METHODS/RESULTS: Bibliography review of the various classification
      systems appeared over the last years, comparing them and reviewing their
      associated problems. CONCLUSIONS: Current systematization advocated by WHO and
      ISUP are the most adequate for patient stratification. However, there are
      problems for coupling tumors with characteristics in the limit between some of
      their categories, so that we consider it will be convenient to review them.

PMID- 15174500
TI  - [Upper urinary tract tumor: differential diagnosis by radiological images].
AB  - To perform the adequate treatment of upper urinary tract lesions it is very
      important to have an exact diagnosis. When the suspicion of an upper tract
      urothelial tumor is established the initial evaluation is carried out by imaging
      diagnostic tests (intravenous urography, pyelography, and others). The
      association of radiological tests and urine cytologies allows us to get to a
      correct diagnosis in most cases. Upper urinary tract endoscopy solves some
      equivocal cases, but sometimes it is impossible to clarify the nature of the
      lesion in spite of a comprehensive diagnostic effort. Therapeutic decision should
      be individualized in these cases. The objective of this article is to describe
      the various features of upper tract urothelial tumors in a variety of available
      imaging tests, and to review all conditions that may have similar images,
      describing the characteristic radiological findings for each of them. We discuss
      about differential diagnosis and perform a critical evaluation of the diagnostic
      difficulties that occasionally present upper urinary tract diseases.

PMID- 15174501
TI  - [Urinary cytology in the diagnosis of upper urinary tract urothelial tumor].
AB  - OBJECTIVES: To review the current usefulness of urinary cytology in the diagnosis
      of upper urinary tract urothelial tumor in relation to conservative endoscopic
      treatment. METHODS: Bibliographic review of the published articles about urinary
      cytology of the upper urinary tract urothelial tumor and evaluation of the
      diagnostic efficacy obtained in various series. Review of the cytological
      diagnostic criteria for urothelial tumors. RESULTS: From 1960 to 2003, 26 series
      collecting results of the cytological diagnosis of urothelial tumors of the
      ureter and renal pelvis have been published. Results have been variable with a
      diagnostic accuracy between 23 and 100%. Such an ample variation depends on
      sampling techniques, preparation techniques, type of tumor, and the urologists
      and pathologist's experience. The collection of the sample by direct endoscopical
      visualization significantly proves the diagnostic efficacy of cytology for upper
      urinary tract urothelial tumors. CONCLUSIONS: Urine cytology selectively obtained
      from the upper urinary tract with endoscopical techniques is a reliable method in
      the diagnosis of renal pelvis and ureter neoplasias. Urine cytology has a
      sensitivity close to 90% and specificity between 98-100% for carcinoma in situ
      and high-grade urothelial neoplasias, so that it can contribute in the
      therapeutic decision making process in a very effective manner. Despite its low
      sensitivity, it may be useful in the diagnosis of low grade urothelial neoplasias
      when samples are selectively obtained by catheterization, and it has not been
      excelled by any of the biomarkers molecular tests yet.

PMID- 15174503
TI  - [Antegrade and retrograde endourological techniques. Equipment and methodology].
AB  - Low grade and stage upper urinary tract tumors may be treated endoscopically by
      antegrade or retrograde approach. The approach mainly depends on tumor size and
      site. Generally, retrograde ureteroscopy is used for small size tumors of the
      ureter and kidney, whereas the antegrade approach is indicated for bigger tumors
      in the upper ureter or kidney, or those tumors which cannot be adequately managed
      in a retrograde manner because of their site (lower calyx) or previous urinary
      diversion. This article presents the techniques of retrograde ureteroscopy and
      percutaneous antegrade resection, as well as the equipment needed for adequate
      endoscopic treatment of the upper urinary tract urothelial tumors.

PMID- 15174502
TI  - [Upper urinary tract tumors pathology (ureter, pelvis and renal calyces)].
AB  - OBJECTIVES: To show the pathologic characteristics of upper urinary tract tumors
      with special emphasis on the peculiarities due to anatomical site and secondary
      to endoscopic treatment. METHODS: Bibliographic review and presentation of our
      ten-year experience at the "Hospital Ramon y Cajal" Pathology Department in
      Madrid studying 203 urothelial tumors of the ureter, renal pelvis and calyces.
      RESULTS: More than 95% of the upper urinary tract tumors in adults have their
      origin in the urothelium, and most of them are either malignant or potentially
      malignant. Their biological behaviour is similar to bladder tumors, although they
      have some peculiarities due to their anatomical localization. Tumors at the renal
      calyces may be more aggressive due to their particular way of intrarenal
      dissemination. CONCLUSIONS: Anatomical localization and proper pathological study
      are the determinant factors to establish prognosis and possible adjuvant
      treatment for upper urinary tract tumors after endoscopic resection.

PMID- 15174504
TI  - [Protocol for percutaneous treatment of upper urinary tract urothelial tumors].
AB  - We develop the diagnostic methodology to select patients with upper urinary tract
      urothelial tumors who are candidates for percutaneous endoscopic treatment. This
      treatment is indicated for low grade and stage lesions in the pyelocalyceal
      system (> 3 cm), lumbar ureter (> 1-2 cm) and for failures of the retrograde
      approach. In this protocol, we emphasize the performance of intraoperative biopsy
      and pyelocalyceal mapping, as well as the need of a second look to rule out
      residual tumor.

PMID- 15174505
TI  - [Upper urinary tract urothelial tumor. Antegrade percutaneous management].
AB  - OBJECTIVES: Upper urinary tract tumors account for 2-4% of urinary tract tumors
      and 5% of urothelial tumors. The pyelocalyceal system (75%) and distal third of
      the ureter are the most frequent locolizations. Various series confirm a
      relatively benign course of low grade and stage tumors, with survivals around 80
      66% for pyelic and ureteral tumors respectively. Tumor grade and stage are the
      most important factors for patient outcome, more than type of treatment
      undertaken (classic radical nephroureterectomy vs. conservative surgery). With
      the development of endoscopic techniques and the use of new equipment, both
      ureteroscopy and nephroscopy have gained a relevant role in the study and
      treatment of upper urinary tract tumors in selected groups of patients.
      METHODS/RESULTS: We describe data from the literature about the nature of
      urothelial tumors, diagnostic methods, and indications of conservative
      management. We performed a retrospective chart review of patients undergoing
      endoscopical procedures (ureteroscopy and nephroscopy) to rule out upper urinary
      tract urothelial tumors at the Hospital Ramon y Cajal in Madrid between January
      1996 andJune 2003. We do a comparative analysis between our results and those
      referred in the literature and a previous study in our department published in
      1996. CONCLUSIONS: Both ureteroscopy and nephroscopy are effective and safe
      procedures in the diagnosis and treatment of suspicious-looking lesions of the
      urinary tract, with a low complication rate. Main indications are small,
      papillary, and low grade tumors, confined within the mucosa, with negative
      urinary cytolo,gy, in patients with associated comorbidity, solitary kidney or
      bilateral tumors.

PMID- 15174507
TI  - [Protocol for ureteroscopy in the diagnosis and treatment of the upper urinary
      tract transitional cell carcinoma].
AB  - Since Perez-Castro and Martinez-Pineiro initiated diagnostic and therapeutic
      ureteroscopy this technique has gained a place in the management of upper urinary
      tract tumors. Improvement of the equipment (rigid and flexible), better diagnosis
      and knowledge of outcomes and allows to treat a group of patients with
      transitional cell carcinoma of the ureter and pelvis by the conservative
      retrograde technique. In this article, we present an overview of indications and
      management of the upper urinary tract tumor by ureteroscopy.

PMID- 15174506
TI  - [Is there a risk of carcinoma dissemination in the percutaneous access for
      endoscopical treatment of upper urinary tract urothelial tumors?].
AB  - OBJECTIVES: The incidence of transitional cell carcinoma of the renal pelvis and
      ureter is low, and the standard treatment is nephroureterectomy with a bladder
      cuff. However, there are special circumstances, from both patient and tumor
      characteristics, which are subsidiary of a minimally invasive endoscopic
      treatment, such as percutaneous resection. Very satisfactory results have been
      obtained with this technique, which has been performed since 1985. Nevertheless,
      theoretically there exists a potential risk of disseminating tumor cells when
      performing this technique. The objective of this article is to review our
      experience, and that of other groups, performing percutaneous resection of upper
      urinary tract tumors, and to determine the incidence tumor dissemination.
      METHODS: We performed a bibliographic search in Medline (PubMed) and reviewed the
      articles about upper urinary tract tumors treated by percutaneous resection. We
      also evaluated the incidence of tumor dissemination related to surgery RESULTS:
      Published data show a very low incidence of tumor dissemination after endoscopic
      resection by a percutaneous approach. Theoretically tumor dissemination can be
      the result of dissemination to the blood or lymphatic circulation, or the implant
      of tumor cells in the contiguous or distant urothelial mucosa, or propagation of
      these tumor cells to the retroperitoneal space or the nephrostomy track.
      CONCLUSIONS: Percutaneous endoscopic resection of upper urinary tract urothelial
      tumors is a safe and effective technique that enables a minimally invasive and
      nephron sparing treatment. If some precautions are taken, this surgical technique
      does not involve a significant risk for tumor cell dissemination.

PMID- 15174508
TI  - [Overview of the results of the treatment of transitional cell carcinoma by
      ureteroscopy].
AB  - Conservative treatment of the transitional cell carcinoma of the upper urinary
      tract by ureteroscopy is currently a therapeutic approach which is accepted by
      urologists. Recurrences are frequent (0-65%), as well as in bladder tumors; the
      longer the follow-up of the series the higher the recurrence. Multifocality,
      history of bladder tumor or renal pelvis localization are prognostic factors for
      recurrence. The treatment of recurrences may be conservative or radical depending
      on grade, stage and multifocality.

PMID- 15174509
TI  - [Ureteroscopy in the follow-up protocol for upper urinary tract urothelial tumors
      treated endoscopically].
AB  - OBJECTIVES: To evaluate the role of ureteroscopy (rigid and flexible) in the
      follow-up protocol for transitional cell tumors treated conservatively in our
      department by endourological procedures, and to review the articles on this topic
      available in the literature. METHODS: From February 1997 to June 2003, 10
      patients (12 renal units) with upper urinary tract urothelial tumor treated
      conservatively by endourological procedures were followed by cytology,
      cystoscopy, retrograde ureteropyelography, and ureteroscopy (rigid and flexible),
      quarterly during the first year, semi-annually during the second year, and yearly
      thereafter in order to detect tumor recurrence. RESULTS: Mean follow-up was 31.9
      months (R 14-65). Two patients died: one because of a previous metacronous
      bladder tumor and the other after distant progression. One patient was lost to
      followup. A total of 42 ureteroscopies were performed (31 flexible and 11 rigid).
      Flexible ureteroscopy was performed in 6 patients and rigid ureteroscopy in
      three; neither was feasible in one patient so that follow-up was done by
      cytology, cystoscopy and urography. Tumor recurrence was detected in 2 patients
      but ureteroscopy did not inform about tumor stage. Flexible ureteroscopy failed
      in another patient in which rigid ureteroscopy was feasible. Although this latter
      was technically easier to perform, procedure discomfort was worse. CONCLUSIONS:
      The follow-up of transitional cell tumors of the upper urinary tract should be
      very strict because of the high risk of tumor relapse. Ureteroscopy, mainly
      flexible, is standing out as the most effective procedure to watch these tumors.

PMID- 15174510
TI  - [Chemoprophylaxis and endoscopical treatment of upper urinary tract tumors
      recurrences].
AB  - OBJECTIVES: Upper urinary tract tumors are a rare condition. We review our
      experience in the diagnosis of upper urinary tract tumors and their recurrences,
      emphasizing the management of recurrences. METHODS: From January 1980 to June
      2002 139 endourological procedures were carried out in 94 patients with the
      working diagnosis of upper urinary tract tumor. RESULTS: The overall treatment
      failure rate was 18.7 with ureteroscopy being the least efficient technique.
      CONCLUSIONS: In our experience, there is an indication for conservative
      endourological treatment in superficial low grade G1-2 tumors smaller than 2 cm.

PMID- 15174511
TI  - [Systematic review about the usefulness and prognostic value of the p53
      oncoprotein and proliferation marker Ki-67 for upper urinary tract transitional
      cell carcinoma].
AB  - OBJECTIVES: To perform a systematic review on the expression and prognostic value
      of the p 53 oncoprotein and Ki 67 proliferation marker in transitional cell
      carcinoma of the upper urinary tract. METHODS: A systematic review of cohort,
      prospective and retrospective studies from 1/1/1990 to 11/24/2003 has been
      undertaken, performing a bibliographic search both manual and electronic in the
      main databases. 632 works were found using the keywords "ureter, renal and pelvis
      tumor", and 14 with "ureter, renal and pelvis tumor, and immunohistochemical".
      RESULTS: 509 patients were studied; they were selected from 7 retrospective
      studies about the usefulness of p53 and Ki 67 in transitional cell carcinoma of
      the upper urinary tract published between 1995 and 2002 (three Spanish studies,
      three Japanese and one North American). Each one analyzes between 37 and 121
      cases, with a mean age of 66.8 years (range 63.0-74.7) and a predominance of male
      sex in 100% of the studies. The pyelocalyceal site was the most frequent in these
      series. Treatment is another issue taken into consideration in this papers, being
      nephroureterectomy the most frequently found. The p53 and Ki 67 percentage
      expression in various studies has been related to clinical and histological
      factors. Only 5 studies performed a multivariate analysis using Cox regression
      models. Three of them deal with Ki 67 and two with p53, although one of the p53
      studies associates cyclin E determinations. Only two out of three studies about
      Ki 67 were considered evaluable, because multivariate analysis was not performed
      in the other one. CONCLUSIONS: 1) There are a few studies and they are very
      heterogeneous in terms of design, selection criteria, follow-up, and use of
      prognostic variables. 2) The analyzed studies establish that oncoprotein p53 and
      proliferation marker Ki 67 are prognostic factors for transitional cell carcinoma
      of the upper urinary tract, and 3) To perform a meta-analysis was deemed not
      indicated because of the heterogeneicity of the studies found in our search.

PMID- 15174512
TI  - [The interest of PET (Positron Emission Tomography) for urothelial tumors].
AB  - OBJECTIVES: To study the state-of-the-art and potential applications of PET for
      urothelial tumors. METHODS: We introduce the basics of the PET technique and
      perform a systematic bibliographic review on the use of PET in these tumors.
      RESULTS: Clinical experience on PET in urothelial tumors is still limited. The
      main interest of this technique is detection and localization of lymph nodes and
      distant metastases. CONCLUSIONS: PET may be useful in staging, re-staging and for
      recurrences of upper urinary tract tumors, allowing avoiding more invasive
      diagnostic methods and more aggressive therapies; nevertheless more extensive
      clinical studies are necessary to support this indications.

PMID- 15174513
TI  - [Radical or conservative surgery for upper urinary tract transitional cell
      carcinomas (TCC)?].
AB  - OBJECTIVE: We expose the arguments supporting radical and conservative surgery
      based on international bibliography and our own experience, with special citation
      of endoscopic surgery (percutaneous and ureteroscopy). METHODS/RESULTS: We
      evaluate the criteria of multifocality, cell seeding and number of recurrences
      separately, as well as the diagnostic difficulties establishing tumor grade and
      stage, by connecting the various techniques and their results. CONCLUSION: the
      choice between radical or conservative surgery for upper urinary tract TCC is
      conditioned by precise indications and the surgical technique chosen does not
      influence the final outcome of low grade/stage tumors.

PMID- 15174515
TI  - Images in neuro-oncology: Dural metastases.

PMID- 15174514
TI  - Extensive distribution of liposomes in rodent brains and brain tumors following
      convection-enhanced delivery.
AB  - Liposomes labeled with various markers were subjected to local-regional
      administration with either direct injection or convection-enhanced delivery (CED)
      into rodent brains and brain tumor models. Direct injection of liposomes
      containing attached or encapsulated fluorochromes and/or encapsulated gold
      particles indicated that tissue localization of liposomes could be sensitively
      and specifically detected in the central nervous system (CNS). When CED was
      applied, liposomes achieved extensive and efficient distribution within normal
      mouse brains. Co-infusion of mannitol further increased tissue penetration of
      liposomes. Liposomes were also loaded with gadodiamide to monitor their CNS
      distribution in rats by magnetic resonance imaging (MRI). CED-infused liposomes
      were readily seen on MRI scans as large regions of intense signal at 2 h, and
      more diffuse regions at 24 h. Finally, labeled liposomes were infused via CED
      into tumor tissue in glioma xenograft models in rodent hosts. In intracranial U
      87 glioma xenografts, CED-infused liposomes had distributed throughout tumor
      tissue, including extension into surrounding normal tissue. Greater penetration
      was observed using 40 versus 90 nm liposomes, as well as with mannitol co
      infusion. To our knowledge, this is the first report of CED infusion of liposomes
      into the CNS. We conclude that CED of liposomes in the CNS is a feasible
      approach, and offers a promising strategy for targeting therapeutic agents to
      brain tumors.

PMID- 15174516
TI  - Recurrent glioependymal cyst of the posterior fossa: an unusual entity containing
      mixed glial elements. Case report.
AB  - Reports of glioependymal cysts in the posterior fossa are uncommon. There are
      only a few documented cases of posterior fossa glioependymal cysts and, to our
      knowledge, this is the first documented case of a recurrent posterior fossa
      glioependymal cyst. We discuss the clinical presentation, pathological features,
      and treatment options for this lesion. A 55-year-old woman with a 10-year history
      of a recurrent cytic lesion in the left cerebellar hemisphere, which required two
      operations, presented with diplopia, dizziness, and ataxia. Magnetic resonance
      imaging revealed a multiloculted cytic lesion in the left cerebellar hemisphere.
      Resection, through a suboccipital craniectomy, resulted in improvement of the
      patient's neurologic status. Microscopic examination of a surgical specimen
      revealed complex cysts lined by a single layer of ependyma-like cells and
      underlying gliotic parenchyma with florid reactive changes. Glioependymal cysts
      of the posterior fossa may present with symptoms of increased intracranial
      pressure and compression of local structures. Recurrence in this case may be
      partly explained by subtotal resection in the previous two operations and may
      also be associated with a florid, proliferative ependymal element. Definitive
      diagnosis is by microscopic examination of surgically resected specimens. Total
      extirpation of these cystic lesions is recommended.

PMID- 15174517
TI  - Primary dural mucosa-associated lymphoid tissue-type lymphoma: case report and
      review of the literature.
AB  - A 47-year-old Hispanic male presented with visual field disturbances, memory
      impairment, and a seizure. CT and MRI were consistent with meningioma. Both
      neurologic exam and routine laboratory tests were within normal limits. The
      patient underwent craniotomy and subtotal resection of the tumor. On H&E, the
      lesion was composed of a lymphoid mass with well-defined irregularly shaped
      follicles surrounded by a monomorphic population of small lymphocytes. Marginal
      zones stained for B-cell markers, CD20 and CD79a, one T-cell marker, CD43, and
      kappa light chains. While other markers did not stain the majority of tumor
      cells, they did identify other lymphoid and plasma cell elements. A diagnosis of
      marginal zone B-cell lymphoma of dura, mucosa-associated lymphoid tissue (MALT)
      type (extranodal) was made. MALT-type lymphomas are unusual in the nervous
      system; this is the first such case reported in a male and serves to emphasize
      the wide diversity of presentation of a neoplasm originally described in the GI
      tract and thus far described in the CNS only in females.

PMID- 15174518
TI  - Histopathological findings in autopsied glioblastoma patients treated by mixed
      neutron beam BNCT.
AB  - Since 1998, we have introduced a mixed epithermal- and thermal neutron beam for
      boron neutron capture therapy (BNCT) to improve the neutron beam distribution.
      Sixteen patients with malignant glioma (glioblastoma, n = 14; anaplastic
      ependymoma, n = 1; PNET, n = 1) were treated by BNCT in Japan. Of these, 9 died;
      3 due to cerebrospinal fluid (CSF) dissemination, 1 each of tumor invasion,
      meningitis, pneumonia, and unknown causes, and 2 patients died of local
      recurrence or radiation necrosis. The current postmortem study is comprised of 3
      patients with glioblastoma who were treated with BNCT employing an epithermal
      neutron beam and sodium borocaptate (BSH: Na2B12H11SH). None of the patients
      manifested local regrowth at the primary site. However, in 2 patients there was
      CSF dissemination; tumor cells were recognized throughout the subarachnoid space.
      In the other patient, tumor cells had massively invaded the ipsilateral- and
      contralateral hemisphere and brain stem from the bottom of the tumor cavity via
      the corpus callosum and cerebral peduncle. Our findings indicate that BNCT can
      achieve local control of glioblastoma at the primary site. However, to further
      improve the clinical outcome after BNCT, steps must be taken to prevent CSF
      dissemination.

PMID- 15174519
TI  - Intracranial chondrosarcoma: a case report and review of the literature.
AB  - OBJECTIVE AND IMPORTANCE: Chondrosarcomas rarely occur intracranially away from
      the skull base. We present a case of a supratentorial dural-based, low-grade
      classic chondrosarcoma and emphasize salient imaging findings that assist in its
      diagnosis. CLINICAL PRESENTATION: A 23-year-old female presented with new onset
      seizures. Multiple radiographic imaging studies identified a large left frontal
      mass with radiological findings that suggested the correct diagnosis.
      INTERVENTION: The patient underwent a left frontal craniotomy and gross total
      resection of the lesion and associated dura. CONCLUSION: Intracranial
      chondrosarcomas away from the skull based are extremely rare malignancies. As
      with other extra-axial masses, they often grow to a relatively large size before
      generating symptoms. Careful analysis of CT, MR, and angiographic imaging
      characteristics should suggest the correct diagnosis.

PMID- 15174520
TI  - Results of contemporary surgical management of radiation necrosis using frameless
      stereotaxis and intraoperative magnetic resonance imaging.
AB  - OBJECTIVE: Radiation necrosis is a well-known complication of radiotherapy for
      malignant brain tumors. Although surgery was once considered the mainstay of
      treatment, no recent reports have evaluated the use of intraoperative magnetic
      resonance imaging (IOMRI) and frameless stereotaxis during surgical resection of
      radiation necrosis. In this retrospective review, we evaluate the effectiveness
      of surgical resection using frameless stereotaxis and IOMRI for the treatment of
      radiation necrosis. METHODS: From October 1999 through February 2002, 11 patients
      who had malignant brain tumors underwent surgery for radiation necrosis. The
      diagnosis of radiation necrosis was based primarily on MRI and clinical
      suspicion. Frameless stereotaxis was used in all patients and IOMRI was used in
      nine. All patients underwent at least one radiation treatment before surgery and
      nine patients had multiple treatments. Patient outcome was based on changes in
      steroid dose, Karnofsky Performance Score (KPS), and neurologic deficit. RESULTS:
      Optimal resection as confirmed by IOMRI was achieved in all patients by the use
      of frameless stereotaxis alone; no additional resection was performed in any
      patient. For nine patients taking steroids (mean preoperative dose 24 mg/day)
      before treatment of necrosis, all had a substantial reduction in steroid dosage
      (mean postoperative dose 8 mg/day) after surgical treatment. Postoperatively, KPS
      improved in four patients, remained stable in four, and worsened in three. Three
      complications that resulted from surgery included wound infection, asymptomatic
      carotid dissection, and pulmonary embolism; thus, overall morbidity including
      both surgical complications and neurologic deterioration was 54%. CONCLUSIONS: In
      this review, frameless stereotaxis was helpful in guiding the surgeon; however,
      IOMRI did not provide any additional benefit for the surgical treatment of
      radiation necrosis. Surgical treatment of radiation necrosis was associated with
      high risks of complication or neurologic deficit. Given the success of medical
      therapies, including hyperbaric oxygen, we believe that surgical treatment of
      radiation necrosis should be reserved for symptomatic patients in whom medical
      therapy has failed.

PMID- 15174521
TI  - Choroid plexus papillomas: a single institutional experience.
AB  - OBJECTIVE: To determine the long-term outcome of resected choroid plexus
      papillomas (CPPs). METHODS: Medical records and histologic specimens were
      reviewed for 41 patients (19 male, 22 female; median age, 36 years; range, 6
      months to 74 years) with CPP seen between 1974 and 2000. Tumor locations were as
      follows: 76%, fourth ventricle; 17%, lateral ventricle, and 7%, third ventricle.
      Fifty-six percent had a gross total resection (GTR) and 44% had a subtotal
      resection (STR). Median follow-up was 6.5 years. RESULTS: Five-year local
      control, distant brain control, and overall survival were 84%, 92%, and 97%,
      respectively. Comparison of GTR and STR at 5 years showed a significant increase
      in local control (100% vs. 68%; P = 0.04) but not in overall survival (100% vs.
      94%). Even after STR, only 50% of patients required a subsequent resection for
      recurrence. Addition of radiation therapy to initial STR did not seem to
      influence outcomes. At first relapse, GTR was accomplished in 1 patient, and only
      STR was accomplished in the others. Addition of radiation therapy to STR in our
      study led to disease control in half the patients treated, and STR alone led to
      disease control in only a quarter of the patients. Second relapses were treated
      palliatively with radiation therapy. CONCLUSIONS: Surgical resection is the
      treatment of choice for CPPs. After initial STR, reoperations for recurrence are
      required only half the time. Therefore, there seems to be no role for radiation
      therapy after initial STR. For STRs at first relapse, local control outcome is
      poor.

PMID- 15174522
TI  - The risk for malignant primary adult-onset glioma in a large, multiethnic,
      managed-care cohort: cigarette smoking and other lifestyle behaviors.
AB  - PURPOSE: To determine the risk for malignant primary adult-onset glioma (MPAG)
      associated with cigarette smoking and other lifestyle behaviors in a large,
      multiethnic, managed-care cohort. METHODS: The study population included a cohort
      of 133,811 subscribers to the Kaiser Permanente Medical Care Program of Northern
      California who had received a multiphasic health checkup and questionnaire
      between 1977 and 1985, were at least 25 years old at their start of follow-up,
      and had no prior history of benign or malignant brain tumors. In this cohort,
      patients were followed for up to 21 years for the development of MPAG. RESULTS:
      Risk for MPAG among women increased with increasing packs of cigarettes smoked
      per day (p-for-trend = 0.04), adjusting for cigar and pipe smoking, patient age,
      sex, race, education, alcohol use and coffee consumption. A similar pattern was
      not observed for men. Individuals who smoked marijuana at least once a month,
      adjusting for cigarette smoking (packs smoked per day) and for the factors noted
      above, had a 2.8-fold (CI = 1.3-6.2) increased risk for MPAG. Relative risk for
      MPAG increased with increasing consumption of coffee (p-for-trend = 0.05).
      CONCLUSIONS: Cigarette smoking was associated with an increased risk for MPAG
      among women but not among men. Individuals who smoked marijuana at least once a
      month had an increased risk for MPAG, although no dose-response relation was
      observed. Drinkers of >7 cups of coffee per day had a 70% increased risk for MPAG
      and smaller risk elevation for lower consumption. Alcohol usage was not
      associated with an increased risk for MPAG.

PMID- 15174523
TI  - Spinal cord gangliogliomas: a review of 56 patients.
AB  - There have been only case reports concerning the management of intramedullary
      spinal cord gangliogliomas. We review our experience of 56 patients with respect
      to functional status, progression-free survival and long-term outcome. In this
      retrospective review, 56 patients, 35 males and 21 females ranging in age from 7
      months to 25 years (mean, 7.0 y), underwent surgical treatment for intramedullary
      gangliogliomas located throughout the spinal cord. Forty-six patients had gross
      total resection as confirmed by postoperative imaging studies, and 10 had radical
      subtotal resection. Only five patients underwent postoperative irradiation or
      chemotherapy after surgery at our center and therefore outcome was attributed to
      surgery alone. There were no operative deaths, and the 5-year actuarial survival
      rate was 88%. The progression-free survival rate at 5 years was 67%. Neurological
      function in the surviving patients at recent follow-up evaluation was stable or
      improved in 72%. Patients have a long survival following radical surgery. These
      tumors have an indolent course, and radiotherapy appears to be unnecessary.

PMID- 15174524
TI  - Maintenance therapy with 13-cis retinoid acid in high-grade glioma at complete
      response after first-line multimodal therapy--a phase-II study.
AB  - BACKGROUND: Approximately 5% of patients with malignant glioma achieve complete
      response (CR) after first-line combined modality treatment. Although these
      patients will invariably suffer from tumor recurrence, they usually do not
      receive any further treatment to maintain remission. According to in vitro and in
      vivo clinical studies, 13-cis retinoic acid (cRA) may be a promising agent for
      maintenance therapy in these patients. OBJECTIVE: We initiated a clinical study
      to evaluate the feasibility and toxicity of high-dose cRA as maintenance therapy
      in patients with high-grade glioma in complete remission after first-line
      multimodal treatment. METHODS: A prospective single-arm phase-II study in
      patients with CR after combined first-line therapy (neurosurgery, radio- and
      chemotherapy) was performed. Patients were treated with cRA at 60 mg/m2 BS from
      day 1 to 21 in four-weekly cycles with a dose escalation of up to 100 mg/m2 BS
      until tumor recurrence. Clinical controls were performed every 4 weeks, magnetic
      resonance imaging every 8 weeks. RESULTS: Twenty-three patients (10, grade IV;
      13, grade III) were evaluable using an intention-to-treat analysis. Treatment was
      well tolerated for up to 149 weeks with moderate dermatological symptoms in all
      patients. No grade 4 toxicities were observed. Median time to progression was 41
      weeks, median overall survival 74 weeks after inclusion in the protocol.
      DISCUSSION: There is an urgent need for strategies maintaining remission in
      patients with malignant glioma. Maintenance therapy with high-dose cRA is
      feasible and well tolerated over long periods of time. A controlled clinical
      trial to test the efficacy of cRA as a maintenance treatment in malignant glioma
      is warranted.

PMID- 15174526
TI  - Living doll paper doll.

PMID- 15174525
TI  - Nasopharyngeal carcinoma metastasis to the pituitary gland: a case report and
      literature review.
AB  - While nasopharyngeal carcinoma (NPC) commonly invades the skull base, true
      central nervous system metastasis is a rare phenomenon. We report a case of NPC
      metastasis to the pituitary gland and review the literature for similar events.
      Eight months after his definitive radiation therapy, our patient presented with
      symptoms of optic chiasm compression and panhypopituitarism. Medical imaging
      revealed a pituitary mass but demonstrated no evidence of skull base erosion or
      direct intracranial extension. Subsequent biopsy of the pituitary lesion was
      confirmed as NPC in origin with Epstein-Barr virus-encoded RNA in-situ
      hybridization studies. The patient was treated with high dose chemotherapy
      followed by autologous stem cell transplant, which produced short-term
      symptomatic relief and at least a 7 month survival.

PMID- 15174527
TI  - Risk factors for pain in children with severe cognitive impairments.
AB  - Diagnosing cause of pain in children with severe cognitive impairments is
      difficult due to their problems with communication. Identification of risk
      factors for specific pain etiologies might help professionals in this task. The
      aim of this study was to determine whether child-related characteristics increase
      risk for specific types of pain. Participants were the caregivers of 41 females
      and 53 males with moderate to profound mental retardation, who were aged 3 to 18
      years 8 months (mean 10:1, SD 4:4) but who communicated at the level of a typical
      child of 13.8 months (SD 10 months): 44 of the children had cerebral palsy (CP)
      and 59 a seizure disorder. Caregivers reported the cause of children's episodes
      of pain for four 1-week periods over 1 year. Logistic regression analyses were
      used to predict occurrence of specific types of pain using children's
      demographic, medical, and physical characteristics. Children had 406 episodes of
      pain due to accident, gastrointestinal conditions, musculoskeletal problems,
      infection, recurrent conditions, and common childhood causes. Results indicated
      that a unique set of risk factors predicted each pain type in this sample.
      Significant risk factors for pain included: lack of visual impairment and leg
      impairment (accidental pain); seizures, leg impairment, and greater number of
      medications (non-accidental pain); being male and tube fed (musculoskeletal
      pain); age <7 years, absence of CP, visual impairment, and less frequent medical
      monitoring (infection pain); being female and with arm impairment
      (gastrointestinal pain); and being tube fed and taking fewer medications (common
      childhood pains). In most cases, models were more specific than sensitive,
      indicating that the significant predictors are more useful for eliminating
      potential pain causes. These results suggest that population risk factors may be
      helpful in structuring diagnostic investigations for individual children with
      severe cognitive impairments.

PMID- 15174528
TI  - Sleep patterns and sleep disorders in children with autistic spectrum disorders:
      insights using parent report and actigraphy.
AB  - The present study sought to describe the profile of sleep disturbance reported in
      children with autistic spectrum disorders (ASDs) and to document any sleep
      disorders underlying reports of sleeplessness. Sixty-nine children aged 5 to 16
      years (mean 9 years 4 months, SD 2 years 7 months; 14 females) with an ASD were
      assessed by detailed sleep histories taken from parents, the Simonds and Parraga
      Sleep Questionnaire, a 2-week sleep diary, and actigraphs worn by the child for
      five nights. Parent-reported sleeplessness featured prominently (64%). Sleep
      disorders underlying the sleeplessness were most commonly behavioural (i.e. to do
      with inappropriate sleep-related behaviours), although sleep-wake cycle disorders
      and anxiety-related problems were also seen. In addition, the sleeplessness
      patterns of a large minority of children could not be classified by conventional
      diagnostic criteria. Sleep patterns measured objectively did not differ between
      those children with or without reported sleeplessness, but the sleep quality of
      all children seemed to be compromised compared with normal values.

PMID- 15174529
TI  - Relationship between motor proficiency, attention, impulse, and activity in
      children with ADHD.
AB  - The aim of this study was to investigate the relationship between motor
      performance, attention deficit, impulsiveness, and hyperactivity in children with
      attention-deficit--hyperactivity disorder (ADHD). Participants were 42 school
      aged children with ADHD (36 males, 6 females; mean age 8 years 2 months, SD 1
      year 2 months; range 6 years to 11 years), and 42 age- and sex-matched children
      without ADHD (mean age 8 years 3 months, SD 1 year 1 month; range 6 years to 11
      years). Motor abilities were assessed with the Bruininks-Oseretsky Test of Motor
      Proficiency. Attention and impulse control were measured with the Gordon
      Diagnostic System, and assessment of activity level was based on two Activity
      Level Rating Scales that were completed by parents and teachers. Analysis by t
      test revealed a significant difference between children with and without ADHD in
      fine and gross motor skills, impulse control, and attention. Stepwise regression
      indicated that attention, impulse control, and parent ratings of activity level
      were the three best predictors of gross motor skills for children with ADHD,
      accounting for 55.9% of the variance. Attention and impulse control were the two
      best predictors of fine motor skills, accounting for 45.7% of the variance.
      Attention and impulse control were consistently found to be important predictors
      of both fine and gross motor skills in children with ADHD. However, the fact that
      activity level was a predictor for gross motor proficiency but not for fine motor
      tasks suggests that different behavioral processes are involved in fine and gross
      motor performance to different extents.

PMID- 15174530
TI  - Validation of a parent report measure of cognitive development in very preterm
      infants.
AB  - Parental report may provide an inexpensive alternative to standardized
      assessments of children's development. We have adapted and validated a parental
      questionnaire on cognitive development for use with very preterm infants. Sixty
      four 2-year-olds (28 males, 36 females) born less than 30 weeks' gestation
      (median 28.5 weeks, range 23 to 31 weeks), median birthweight 980g (range 500 to
      1905g) were assessed using the Mental Development Index (MDI) of the Bayley
      Scales of Infant Development-II and the parental questionnaire. Significant
      correlations between parent report and MDI scores (r=0.54-0.68, p<0.001)
      indicated good concurrent validity. Diagnostic use of the parent report for
      predicting an MDI score of less than 70 was assessed by using receiver operating
      characteristic (ROC) curves. The optimal cut off produced equal sensitivity and
      specificity (81%), indicating good discriminatory power in diagnosing
      developmental delay. Test-retest reliability was demonstrated and accuracy of
      parent reporting was not affected by sociodemographic factors. Our questionnaire
      provides a valid outcome measure for use in randomized trials or large population
      surveys.

PMID- 15174531
TI  - Prenatal exposure to polychlorinated biphenyls and breastfeeding: opposing
      effects on auditory P300 latencies in 9-year-old Dutch children.
AB  - Effects of perinatal exposure to polychlorinated biphenyls (PCBs) on auditory
      P300 latencies and amplitudes were evaluated in children from a Rotterdam cohort.
      From this cohort of healthy, term babies, the 26 lowest and 26 highest prenatally
      PCB-exposed children from the breastfed and the formula-fed groups (n=104) were
      invited for P300 assessment when they were 9 years of age. For P300 assessment an
      auditory simple odd-ball paradigm was used. In the 83 participating children, 60
      assessments (32 males, 28 females) satisfied the measurement criteria and were
      included in the data analyses. After adjusting for confounding variables,
      children with high prenatal exposure were found to have longer P300 latencies
      than children with low prenatal exposure. Lactational exposure to PCBs through
      breastfeeding milk was not related to P300 latencies. P300 latencies were shorter
      in children breast-fed for at least 16 weeks than in children breastfed for 6 to
      16 weeks and formula-fed children. P300 amplitudes were not related to perinatal
      PCB exposure nor breastfeeding. Results of this exploratory study suggest that
      prenatal exposure to environmental levels of PCBs and related compounds delays
      mechanisms in the central nervous system that evaluate and process relevant
      stimuli, whereas breastfeeding accelerates these mechanisms.

PMID- 15174532
TI  - Effects of supramalleolar orthoses on postural stability in children with Down
      syndrome.
AB  - This study explored the effects of a flexible supramalleolar orthosis (SMO),
      indicated to decrease pronation associated with hypotonia, on postural stability
      in children with Down syndrome. Seventeen children with Down syndrome (nine
      males, eight females; mean age 5 years 10 months, SD 17.2 months; range 3 years 6
      months to 8 years) were tested three times in a 10-week period (weeks 1, 3, and
      10) using the Standing and the Walking, Running, and Jumping dimensions of the
      Gross Motor Function Measure (GMFM), and the Balance subtest of the Bruininks
      Oseretsky Test of Motor Proficiency (BOTMP). Range of motion measurements were
      used to explore the influence of joint laxity. Significant improvement was found
      with SMOs compared with shoes only in the Standing dimension (p=0.001) and the
      Walking, Running, and Jumping dimension (p=0.0001) of the GMFM, both at the time
      of fitting (week 3) and after 7 weeks of wearing SMOs (week 10). For the BOTMP
      Balance subtest, significant improvement (p=0.027) was seen only at the end of
      the 7-week study period. Amount of joint laxity did not influence response to
      orthotic intervention. This study showed that young children with Down syndrome
      showed immediate and longer-term (after 7 weeks of use) improvement in postural
      stability with the use of flexible SMOs.

PMID- 15174533
TI  - Remodeling of the proximal femur after varus osteotomy in children with cerebral
      palsy.
AB  - The purpose of this study was to determine and measure the factors that affect
      the remodeling of the proximal femur after varus osteotomy in children with
      spastic cerebral palsy (CP). Seventy-five varus proximal osteotomies were
      performed on 44 children (26 females, 18 males) for hip dysplasia. Thirty-nine
      patients had spastic CP and five had spastic diplegia; 35 patients used a
      wheelchair for mobility and nine could walk. Mean age at time of surgery was 8
      years (SD 4 years), range 2 years 6 months to 15 years. Preoperative, immediate
      postoperative, and follow-up (0 to 6 months, 6 months to <1 year, 1 year to <2
      years, 2 years to <4 years, 4 years to <6 years, and 6 years to <8 years)
      radiographs were reviewed. Neck-shaft angles were measured. Correlations to
      examine the relationship between age at time of surgery and ambulatory status
      with postoperative changes in neck-shaft angles were reviewed. Remodeling of the
      proximal femur does occur after varus osteotomy as long as the physes of the
      proximal femur show growth potential. Remodeling was quite variable between
      patients: children younger than 4 years old at the time of surgery remodeled more
      than children who were older than 4 years. Ambulatory status has little effect on
      the magnitude of remodeling. This study reinforces the need to follow these
      patients with periodic hip radiographs until completion of growth.

PMID- 15174534
TI  - Predicting low bone density in children and young adults with quadriplegic
      cerebral palsy.
AB  - Many children and young adults with cerebral palsy (CP) have diminished bone
      mineral density (BMD) and a propensity to fracture with minimal trauma. The aim
      of this study was to identify variables which are routinely assessed as part of
      standard clinical care and that might be used to identify those individuals with
      CP who are most likely to have low BMD. One hundred and seven participants (ages
      2 years 1 month to 21 years 1 month; mean age 10 years 11 months, SD 4 years 2
      months) with moderate to severe spastic CP were assessed in detail. This included
      gathering clinical data, taking anthropometric measures of growth and nutrition,
      as well as dual energy X-ray absorptiometry measures of BMD. Seventeen
      participants were ambulatory with assistance (Gross Motor Function Classification
      System [GMFCS] level III), and 90 were capable of little or no ambulation even
      with assistance (26 GMFCS level IV and 64 GMFCS level V). Weight z score proved
      to be the best predictor of BMD z score. Declining BMD z scores also correlated
      with increasing age and greater severity of involvement. It can be predicted,
      with reasonable reliability, that a 10-year-old non-ambulatory child with
      quadriplegic CP and a 'typical' weight z score of -2 will have a BMD z score that
      is at best -2. Prior fractures, use of anticonvulsants, and feeding difficulties
      further reduce predicted BMD.

PMID- 15174535
TI  - Secondary impairments in young adults with spina bifida.
AB  - The aim of this study was to examine the prevalence of secondary impairments in
      young adults with spina bifida and to relate the prevalence to the type of spina
      bifida and the level of lesion. This cross-sectional study is part of the ASPINE
      (Adolescents with Spina Bifida in the Netherlands) study. Data were collected on
      medical history, hydrocephalus (shunt: yes/no), neurological level of lesion
      (International Standards for Neurological and Functional Classification of Spinal
      Cord Injury), visual acuity (Landolt rings), spasticity (Modified Ashworth
      Scale), contractures (range of motion), scoliosis (deviation from perpendicular),
      ambulation (Hoffer criteria), pressure sores and blood pressure (physical
      examination), epilepsy, pain, incontinence and sexuality (questionnaire), and
      cognitive functioning (Raven Standard Progressive Matrices). In total, 179
      patients with spina bifida participated (41% male, age range 16 to 25 years, mean
      20 years 9 months, SD 2 years 11 months). These were 37 patients with spina
      bifida occulta, 119 patients with spina bifida aperta and hydrocephalus (AHC+)
      and 23 patients with spina bifida aperta without hydrocephalus (AHC-). Of our
      patient group, 73 had a high-level lesion (L2 and above), 68 a mid-level lesion
      (L3 to L5), and 38 a low-level lesion (S1 and below). Both subdivisions were
      strongly related with patients with higher lesions more often having
      hydrocephalus. Most secondary impairments were found for patients with AHC+, and
      patients with AHC- were mostly comparable to patients with spina bifida occulta.
      According to level of lesion, most medical problems were found in the high-level
      lesion group. However, all subgroups suffered from health problems.

PMID- 15174536
TI  - Congenital ocular motor apraxia associated with idiopathic generalized epilepsy
      in monozygotic twins.
AB  - Identical female twins (age 11 years) with congenital ocular motor apraxia and
      generalized idiopathic epilepsy are reported. Their presenting symptoms were a
      long history of abnormal head and eye movements. One twin developed partial
      sensory seizures. The patients underwent 16-channel EEG, electro-oculographic
      recordings, MRI of the brain, and genetic and metabolic investigations. EEG
      findings were consistent with idiopathic generalized epilepsy.
      Electrooculographic recordings of the saccades confirmed an inability to elicit
      horizontal saccades without preceding head movement; saccades to the left were
      better than saccades to the right. MR scans for one twin showed normal findings,
      however, for the twin who had meningitis they revealed asymmetry between the
      right and left temporal lobes but no specific abnormality. DNA analysis using a
      series of autosomal polymorphic markers confirmed the monozygocity of the twins.
      White blood cell enzyme analysis excluded Sandhoff disease, Tay-Sachs disease,
      GM1 gangliosidosis, metacromatic leucodystrophy, Gaucher disease, Niemann-Pick
      disease (A and B), and Krabbe leucodystrophy. Albumin and immunoglobulin (IgA,
      IgG, and IgM) levels were normal. It is concluded that autosomal recessive
      inheritance seems the most likely explanation here, as recent studies have found
      insertion and missense mutations of the aprataxin gene which have been related to
      an early onset form of ataxia with ocular motor apraxia and hypoalbuminaemia.

PMID- 15174537
TI  - The acidosis paradox: asphyxial brain injury without coincident acidemia.

PMID- 15174538
TI  - Attention deficits and subclinical epileptiform discharges: are EEG diagnostics
      in ADHD optional or essential?

PMID- 15174539
TI  - Anterior instability of the shoulder after trauma.

PMID- 15174540
TI  - Reconstruction of the posterior cruciate ligament. Indications and results.

PMID- 15174541
TI  - Acetabular revision with impacted morsellised cancellous bone grafting and a
      cemented cup. A 15- to 20-year follow-up.
AB  - This study presents the clinical and radiological results of 62 consecutive
      acetabular revisions in 58 patients, at a mean of 16.5 years follow-up (15 to
      20). The Kaplan-Meier survivorship for the cup with end-point revisions for any
      reason, was 79% at 15 years (95% confidence interval (CI); 67 to 91). Excluding
      two revisions for septic loosening at three and six years, and one revision of a
      well-fixed cup after 12 years in the course of a femoral revision, the
      survivorship was 84% at 15 years (95% CI; 73 to 95). At review there were no
      additional cases of loosening, although seven acetabular reconstructions showed
      radiolucent lines in one or two zones. Acetabular revision using impacted large
      morsellised bone chips (0.7 cm to 1.0 cm) and a cemented cup, is a reliable
      technique of reconstruction, when assessed at more than 15 years.

PMID- 15174542
TI  - Wear of the cup in the Charnley LFA in the young patient.
AB  - Since wear and loosening of the ultra-high-molecular-weight polyethylene cup are
      factors which limit the life of an arthroplasty we have attempted to identify
      factors associated with either low wear (0.02 mm/year or less) or high wear (0.2
      mm/year or more). In a series of 1434 Charnley low-friction arthroplasties (1092
      patients) 190 (13.2%) showed low wear while 149 (10.4%) showed high wear. We used
      chi-squared test to assess the significance of various factors. The significant
      factors of the low-wear group were female gender (p = 0.042), rheumatoid
      arthritis (p = 0.014), Charnley grade C (p = 0.03) and varus position of the stem
      (p = 0.003). The use of acetabular cement pressurisation (p = 0.07) and
      medialisation of the cup (p = 0.07) approached significance. In the high-wear
      group there was a predominance of men (p = 0.042) with osteoarthritis (p = 0.006)
      as the underlying hip pathology, and the stem in a valgus position (p = 0.023).
      Support of the cup by the rim of the acetabulum approached significance (p =
      0.07). There was no statistical significance between the two groups for revision
      for aseptic loosening of the stem or fracture of the stem (p = 0.49). There was a
      highly significant difference (p < 0.0001) between the two groups for revision
      for wear and aseptic loosening of the cup, 5.3% compared with 39%. Changes in the
      cup geometry are probably sufficient to explain the increasing incidence of
      loosening and revisions with the increasing depth of penetration of the cup.
      There is much to be gained from the use of a low-wearing ceramic-ultra-high
      molecular-weight combination. Tissue reaction to the polyethylene particles
      cannot be the cause of aseptic loosening of the stem.

PMID- 15174543
TI  - Failure rates for 4762 revision total hip arthroplasties in the Norwegian
      Arthroplasty Register.
AB  - We present the results for 4762 revision total hip arthroplasties with no
      previous infection in the hip, which were reported to the Norwegian Arthroplasty
      Register between 1987 and 2003. The ten-year failure rate for revised prostheses
      was 26% (95% CI 25 to 26). Cox regression analyses were undertaken separately for
      acetabular and femoral revision components. Cemented revision components without
      allograft was the reference category. For acetabular components, we found a
      significantly reduced risk of failure for uncemented revisions both with
      (relative risk (RR) = 0.66; 95% CI 0.43 to 0.99) and without (RR = 0.37; 95% CI
      0.22 to 0.61) allograft. For femoral components, we found a significantly reduced
      risk of failure for uncemented revisions, both with (RR = 0.27; 95% CI 0.16 to
      0.46) and without (RR = 0.22; 95% CI 0.11 to 0.46) unimpacted allograft. This
      reduced risk of failure also applied to cemented revision components with
      allograft (RR = 0.53; 95% CI 0.33 to 0.84) and with impaction bone grafting (RR =
      0.34; 95% CI 0.19 to 0.62). Revision prostheses have generally inferior results
      when compared with primary prostheses. Recementation without allograft, and
      uncemented revision with bone impaction, were associated with worse results than
      the other revision techniques which we studied.

PMID- 15174544
TI  - Computer-assisted revision total knee replacement.
AB  - A technique for performing allograft-augmented revision total knee replacement
      (TKR) using computer assistance is described, on the basis of the results in 14
      patients. Bone deficits were made up with impaction grafting. Femoral grafting
      was made possible by the construction of a retaining wall or dam which allowed
      pressurisation and retention of the graft. Tibial grafting used a mixture of
      corticocancellous and morsellised allograft. The position of the implants was
      monitored by the computer system and adjusted while the cement was setting. The
      outcome was determined using a six-parameter, quantitative technique (the Perth
      CT protocol) which measured the alignment of the prosthesis and provided an
      objective score. The final outcomes were not perfect with errors being made in
      femoral rotation and in producing a mismatch between the femoral and tibial
      components. In spite of the shortcomings the alignments were comparable in
      accuracy with those after primary TKR. Computer assistance shows considerable
      promise in producing accurate alignment in revision TKR with bone deficits.

PMID- 15174545
TI  - Reconstruction of the anterior cruciate ligament. Single- versus double-bundle
      multistranded hamstring tendons.
AB  - A total of 108 patients with unilateral instability of the knee, associated with
      rupture of the anterior cruciate ligament, was prospectively randomised for
      arthroscopic single- or double-bundle reconstruction of the ligament using
      hamstring tendons. The same post-operative rehabilitation protocol was used for
      all. The patients were followed up for a mean of 32 months (24 to 36). We
      measured the anterior laxity and joint position sense at different angles of
      flexion of the knee to determine whether both bundles in the double-bundle
      reconstruction contributed to the stability of the joint and proprioception. No
      significant difference was found between the two groups with regard to anterior
      laxity measured by the KT-2000 arthrometer with the knee at 20 degrees or 70
      degrees flexion nor with regard to proprioception. A notchplasty was required
      less often in the double- compared with the single-bundle reconstruction. We did
      not find any advantage in a double-bundle as opposed to a single-bundle
      reconstruction in terms of stability or proprioception.

PMID- 15174546
TI  - Osteochondral defects of the talus treated with autologous bone grafting.
AB  - We reviewed, retrospectively, 13 patients who had undergone open anterograde
      autologous bone grafting of the talus for symptomatic osteochondral defects of
      the dome of the talus. The mean age of the seven men and six women was 38.4
      years. The defects included the full thickness of articular cartilage, extended
      through the subchondral plate and were associated with subchondral cysts. Six
      patients (46%) were clinical failures requiring further surgery. Of the remaining
      seven, functional outcome results were obtained at a mean of 51.9 months after
      surgery. The mean outcome scores for the Musculoskeletal Outcomes Data Evaluation
      and Management System foot and ankle questionnaire and the American Orthopaedic
      Foot and Ankle Society ankle-hindfoot scale were 87.0 and 84.3, respectively.
      There was an overall 46.2% patient satisfaction rate. We believe that the
      technique of autologous bone grafting presented should be used with extreme
      caution, when considered as the primary treatment for the adult patient with a
      symptomatic advanced osteochondral defect of the talus.

PMID- 15174547
TI  - Results of isolated Lisfranc injuries and the effect of compensation claims.
AB  - The results of treatment of Lisfranc injuries are often unsatisfactory. This
      retrospective study investigated 46 patients with isolated Lisfranc injuries at a
      minimum of two years after surgery. Thirteen patients had a poor outcome and had
      to change employment, or were unable to find work as a result of this injury. The
      presence of a compensation claim (p = 0.02) and a delay in diagnosis of more than
      six months were associated with a poor outcome (p = 0.01). There was no
      association between poor functional outcome and age, gender, mechanism of injury
      or previous occupation. This study may have medico-legal implications on
      reporting the prognosis for such injuries, and highlights the importance of
      prompt diagnosis and treatment.

PMID- 15174548
TI  - Glenothoracic fusion. An adjunct to radical scapulectomy.
AB  - We describe a surgical procedure used to achieve glenothoracic fusion after one
      stage radical, near total scapulectomy for primary or secondary malignant lesions
      in six patients. The aim was complete excision of the lesion and preservation of
      the glenoid to provide a fulcrum for movement of the arm. Post-operative
      assessment involved determination of the range of movement and the application of
      the Musculoskeletal Tumour Society score and the Constant score to evaluate
      function. The results showed that a functional range of movement was attainable
      despite such radical surgery, although there was a considerable reduction in
      power and ability to lift.

PMID- 15174549
TI  - Correction of Madelung's deformity by the Ilizarov technique.
AB  - We present our experience with correction of Madelung's deformity by the Ilizarov
      technique. Seven patients (eight deformities) were treated by osteotomy of the
      radius with subsequent lengthening and angular correction. They were reviewed at
      a mean of 30 months (1.5 to 5.5 years). At the time of operation their mean age
      was 19 years (9 to 44). At follow-up all were free from pain and supination had
      improved by a mean of 34 degrees and pronation by 9 degrees. Flexion had
      increased in most cases with a median increase of 15 degrees, but only one
      patient gained further extension. Radial and ulnar deviation were increased by a
      mean of 6 degrees and 9 degrees, respectively. Radiographic measurements showed
      that the mean volar angulation had been reduced from 25 degrees to 11 degrees,
      ulnar inclination from 45 degrees to 30 degrees and carpal malalignment (volar
      translation) from 7 to 2 mm. The mean lengthening of the radius was 12 mm (6 to
      25). All the patients were satisfied with the functional and cosmetic results.

PMID- 15174550
TI  - Post-traumatic instability of the trapeziometacarpal joint of the thumb.
      Diagnosis and the results of reconstruction of the beak ligament.
AB  - In 28 patients with a solitary diagnosis of instability of the trapeziometacarpal
      joint because of a rupture of the anterior oblique ligament, reconstruction was
      carried out using a slip of the tendon of flexor carpi radialis. We were able to
      review 26 patients. The results after a follow-up of four years seven months
      showed that most (87%) had significant relief from pain and symptoms. Seventeen
      were graded as good to excellent. The mean grip strength recovered to 86% of the
      contralateral side. Most patients (81%) felt that they had subjective improvement
      and would have undergone the operation again. A lesser functional result was seen
      in those who developed a flexion deformity because of overtightening of the
      reconstruction. Increased awareness of this lesion can lead to an early and clear
      diagnosis so that the patient may be advised adequately. We describe a specific,
      diagnostic, clinical test which we have used consistently and successfully.

PMID- 15174551
TI  - Predictive value of the duration of sciatica for lumbar discectomy. A prospective
      cohort study.
AB  - The optimum timing of lumbar discectomy for sciatica is imprecise. We have
      investigated a number of prognostic factors in relation to the outcome of
      radiculopathy after lumbar discectomy. We recruited 113 consecutive patients of
      whom 103 (91%) were followed up at one year. We found a significant association
      between the duration of radiculopathy and the changes in the Oswestry Disability
      Index score (p = 0.005) and the low back outcome score (p = 0.03). Improvement in
      pain was independent of all variables. Patients with an uncontained herniated
      disc had a shorter duration of symptoms and a better functional outcome than
      those with a contained herniation. Our study suggests that patients with sciatica
      for more than 12 months have a less favourable outcome. We detected no variation
      in the results for patients operated on in whom the duration of sciatica was less
      than 12 months.

PMID- 15174552
TI  - Progression of scoliosis after spinal fusion in Duchenne's muscular dystrophy.
AB  - A consecutive series of 85 patients with Duchenne's muscular dystrophy who
      underwent spinal fusion over a period of 16 years was followed up with regard to
      the progression of the scoliosis and pelvic obliquity. Of 74 patients with
      adequate radiographic follow-up, 55 were instrumented with the Luque single-unit
      rod system and 19 with the Isola pedicle screw system; seven were instrumented to
      L3/4, 42 to L5, 15 to S1 and 10 to the pelvis with intrailiac rods. The mean
      period of follow-up was 49 months (SD 22) before and 47 months (SD 24) after
      operation. There was one peri-operative death and three cases of failure of
      hardware. The mean improvement in the Cobb angle was 26 degrees and in pelvic
      obliquity, 9.2 degrees. Fusion to L3/4 achieved a poorer correction of both
      curves while intrapelvic rods, achieved and maintained the best correction of
      pelvic obliquity. Fusion to S1 did not provide any benefit over more proximal
      fusion excluding the sacrum, with regard to correction and maintenance of both
      angles. The Isola system appeared to provide and maintain a slightly better
      correction of the Cobb angle.

PMID- 15174553
TI  - Factors affecting rates of infection and nonunion in intramedullary nailing.
AB  - We report a retrospective study over five years to determine the incidence of
      infection and nonunion after intramedullary nailing in fractures of 214 long
      bones; 122 femoral, 75 tibial and 17 humeral. The indications for nailing were
      trauma (n = 161), pathological fracture (n = 30) and nonunion (n = 23). There
      were 30 open fractures. The overall rates of deep infection and nonunion were
      3.8% and 14.2%, respectively. Using multiple logistic regression analysis, we
      determined the relationships between deep infection and nonunion and the pre- and
      peri-operative factors of age, ASA score, indication for nailing, the use of
      reaming, the use of antibiotics, whether the fracture was open and the operating
      time. Open fractures were found to be significantly associated with deep
      infection. The length of the operation may also affect the outcome. Opening of
      the fracture at the time of surgery and the ASA score were found to be
      significantly associated with the development of nonunion after intramedullary
      nailing. We have compared our findings with previously published data from large
      teaching hospital units.

PMID- 15174554
TI  - Hidden blood loss following hip and knee arthroplasty. Correct management of
      blood loss should take hidden loss into account.
AB  - Following total hip arthroplasty (THA) and total knee arthroplasty (TKR) only the
      'visible' measured blood loss is usually known. This underestimates the 'true'
      total loss, as some loss is 'hidden'. Correct management of blood loss should
      take hidden loss into account. We studied 101 THAs and 101 TKAs (with re-infusion
      of drained blood). Following THA, the mean total loss was 1510 ml and the hidden
      loss 471 ml (26%). Following TKA, the mean total loss was 1498 ml. The hidden
      loss was 765 ml (49%). Obesity made no difference with either operation. THA
      involves a small hidden loss, the total loss being 1.3 times that measured.
      However, following TKA, there may be substantial hidden blood loss due to
      bleeding into the tissues and residual blood in the joint. The true total loss
      can be determined by doubling the measured loss.

PMID- 15174555
TI  - Comparative analysis of risk factors for pathological fracture with femoral
      metastases.
AB  - A number of risk factors based upon mostly retrospective surgical data, have been
      formulated in order to identify impending pathological fractures of the femur
      from low-risk metastases. We have followed up patients taking part in a
      randomised trial of radiotherapy, prospectively, in order to determine if these
      factors were effective in predicting fractures. In 102 patients with 110 femoral
      lesions, 14 fractures occurred during follow-up. The risk factors studied were
      increasing pain, the size of the lesion, radiographic appearance, localisation,
      transverse/axial/circumferential involvement of the cortex and the scoring system
      of Mirels. Only axial cortical involvement >30 mm (p = 0.01), and circumferential
      cortical involvement >50% (p = 0.03) were predictive of fracture. Mirels' scoring
      system was insufficiently specific to predict a fracture (p = 0.36). Our results
      indicate that most conventional risk factors overestimate the actual occurrence
      of pathological fractures of the femur. The risk factor of axial cortical
      involvement provides a simple, objective tool in order to decide which treatment
      is appropriate.

PMID- 15174556
TI  - The influence of treatment on the pathology of club foot. CT study at maturity.
AB  - We performed CT to investigate how treatment may modify the basic skeletal
      pathology of congenital club foot. Two homogenous groups of patients treated by
      one of the authors (EI) or under his supervision were studied. The first included
      32 patients with 47 club feet reviewed at a mean age of 25 years and treated by
      manipulation, application of toe-to-groin plaster casts and an extensive
      posteromedial release. The second included 32 patients with 49 club feet reviewed
      at a mean age of 19 years and treated by the Ponseti manipulation technique,
      application of toe-to-groin plaster casts and a limited posterior release. At
      follow-up the shape of the subtalar, talonavicular and calcaneocuboid joints was
      found to be altered in many feet in both groups. This did not appear to be
      influenced significantly by the type of treatment performed. Correction of the
      heel varus and the increased declination angle of the neck of the talus was
      better in the club feet of the second group, whereas reduction of the medial
      subluxation of the navicular was better in the first. There was a marked increase
      in the external ankle torsion angle in the first group and a moderate increase of
      this angle in the second group, in which medial subluxation of the cuboid on the
      anterior apophysis of the calcaneum was always corrected. Equinus was corrected
      in both groups but three-dimensional CT reconstruction of the whole foot showed
      that cavus, supination and adduction deformities were corrected much better in
      the second group.

PMID- 15174557
TI  - Nancy nailing of diaphyseal forearm fractures. Single bone fixation for fractures
      of both bones.
AB  - We identified 25 children (10 girls and 15 boys) who had been treated with single
      bone intramedullary fixation for diaphyseal fractures of both forearm bones.
      Their mean age was 10.75 years (4.6 to 15.9). All had a good functional outcome.
      We conclude that in selected children, single bone intramedullary nailing is a
      suitable method of treatment for diaphyseal fractures of both bones of the
      forearm.

PMID- 15174558
TI  - Evolution of late presenting developmental dysplasia of the hip and associated
      surgical procedures after 14 years of neonatal ultrasound screening.
AB  - Between 1985 and 1998, 12,331 patients were included in the general neonatal
      ultrasound hip screening programme for developmental dysplasia of the hip (DDH).
      Patients who needed treatment (604) were compared with a second group of 73
      unscreened children treated conservatively and surgically for DDH. The incidence
      of Graf sonographic hip types IIc to IV varied throughout the observation period.
      Femoral and pelvic osteotomies were almost entirely restricted to the unscreened
      group of patients. The six to ten per year recorded in the period 1985 to 1990
      declined subsequently to three or less per year. The yearly admissions to
      hospital fell noticeably after six years of screening. Late presentations of DDH
      were reduced to three or less per year from 1990 to 1994, none between 1995 and
      1998 and one or two per year from 2000. We conclude that general neonatal
      sonographic hip screening can reduce significantly surgical procedures,
      hospitalisation and late presentation of DDH.

PMID- 15174559
TI  - Congenital absence (ankylosis) of the knee.
AB  - A congenital, unilateral, fixed flexion deformity in a neonate was diagnosed as a
      congenital absence of the knee. A single cartilage mass, with fusion of the lower
      femoral and upper tibial ossification centres, was demonstrated by imaging
      studies. This condition has been reported in the literature only once before.
      Surgery on our patient, which was performed at the age of two years, consisted of
      separation of the fused cartilaginous anlage and gradual correction of the
      deformity using an Ilizarov frame.

PMID- 15174560
TI  - Distal radio-ulnar joint subluxation following intramedullary nailing of the
      radius in a child.
AB  - We describe a patient with fractures of both bones of the forearm in whom
      flexible intramedullary nail fixation of the radius alone led to ulnar malunion
      and a symptomatic distal radio-ulnar joint subluxation. This was successfully
      treated by ulnar osteotomy.

PMID- 15174561
TI  - Fluorosis-induced hyperparathyroidism mimicking a giant-cell tumour of the femur.
AB  - We report the case of a young woman who, over a period of five years was
      diagnosed and treated for a giant-cell tumour of bone, osteomalacia and
      fluorosis. A review of the literature revealed a correlation between these three
      diagnoses, the primary pathology being fluorosis and the remaining symptoms being
      secondary manifestations. It is important to be aware of this association,
      especially in regions with endemic skeletal fluorosis.

PMID- 15174562
TI  - Wear debris from hip or knee replacements causes chromosomal damage in human
      cells in tissue culture.
AB  - Wear debris was extracted from 21 worn hip and knee replacements. Its mutagenic
      effects were tested on human cells in tissue culture using the micronucleus assay
      and fluorescent in situ hybridisation. The extracted wear debris increased the
      level of micronuclei in a linear dose-dependent manner but with a tenfold
      difference between samples. The concentration of titanium +/- vanadium and
      aluminium within the wear debris was linearly related both to the level of
      centromere-positive micronuclei in tissue culture, indicating an aneuploid event,
      and to the level of aneuploidy in vivo in peripheral blood lymphocytes. The
      concentration of cobalt and chromium +/- nickel and molybdenum in the wear debris
      correlated with the total index of micronuclei in tissue culture, both centromere
      positive and centromere-negative i.e. both chromosomal breakage and aneuploidy
      events. The results show that wear debris can damage chromosomes in a dose
      dependent manner which is specific to the type of metal. The results from studies
      in vitro correlate with those in vivo and suggest that the wear debris from a
      worn implant is at least partly responsible for the chromosomal damage which is
      seen in vivo.

PMID- 15174563
TI  - The expression and prognostic significance of bone morphogenetic protein-2 in
      patients with malignant fibrous histiocytoma.
AB  - We investigated the rates of expression of bone morphogenetic protein-2 (BMP-2)
      in 29 adult patients with high-grade malignant fibrous histiocytoma of soft
      tissue, using the BMP-2-specific monoclonal antibody, AbH3b2/17, and found that
      they ranged from 1.9% to 78.9%. The survival at five years of the groups
      expressing high (> or = 30%) and low (< 30%) levels of BMP-2 was 85.7% and 36.3%,
      respectively. Multivariable analysis showed that only BMP-2 had prognostic
      significance for continuous disease-free survival and for overall survival (p <
      0.05). Our findings indicate that over-expression of BMP-2 in malignant fibrous
      histiocytoma of soft tissue is the most reliable prognostic indicator of the
      parameters assessed.

PMID- 15174564
TI  - The effect of extracorporeal shock waves on a rat model of injury to tendo
      Achillis. A histological and biomechanical study.
AB  - The effects of extracorporeal shock waves (ESWT) on tendon healing were assessed
      by observing histological and biomechanical parameters in a rat model of injury
      to the tendo Achillis. The injury was created by inserting an 18-G needle through
      tendo Achillis in 48 adult Wistar albino rats. The animals were divided into
      three groups. The first group received radiation only after the operation. The
      second received no shock waves and the third had 500 15 KV shocks on the second
      post-operative day. All the rats were killed on the 21st day after surgery.
      Histopathological analysis showed an increase in the number of capillaries and
      less formation of adhesions in the study group compared with the control group (p
      = 0.03). A significantly greater force was required to rupture the tendon in the
      study group (p = 0.028). Our findings suggest a basis for clinical trials using
      ESWT.

PMID- 15174565
TI  - A prospective, randomised comparison of autologous chondrocyte implantation
      versus mosaicplasty for osteochondral defects in the knee.

PMID- 15174566
TI  - Reduction of blood loss using high-dose aprotinin in major orthopaedic surgery.

PMID- 15174567
TI  - Incidence and natural history of deep-vein thrombosis after total hip
      arthroplasty.

PMID- 15174568
TI  - Primary and revision lumbar discectomy.

PMID- 15174569
TI  - Effect of animal production on meat quality.

PMID- 15174570
TI  - Quality aspects of pork meat and its nutritional impact.

PMID- 15174571
TI  - Meat flavor: contribution of proteins and peptides to the flavor of beef.
AB  - While the majority of meat flavor is lipid in origin, the contribution of
      peptides and amino acids to overall meat flavor should not be overlooked. Amino
      acids and peptide levels have been shown to change with postmortem aging in
      muscle and with dry-curing, a process similar to PMA. Variation in protein,
      peptide, and amino acid composition have also been shown to occur with heating
      and with post-heating storage of meat. This makes a large pool of reactive
      components that may directly affect flavor or indirectly affect flavor by
      reacting with reducing sugars to form Maillard reaction products and Strecker
      degradation products that impact meat flavor. Further research in this area
      should continue with particular emphasis on natural peptide flavor enhancers,
      modulators, and potentiators.

PMID- 15174572
TI  - The effects of extended chilled storage on the odor and flavor of sheepmeat.

PMID- 15174573
TI  - Effect of electron beam irradiation on microbial growth, lipid oxidation and
      color of ground beef patties upon refrigerated storage.

PMID- 15174574
TI  - Enzymatic hydrolysis of lipids in muscle of fish and shellfish during cold
      storage.

PMID- 15174575
TI  - Temperature, color, and texture prediction models for surimi seafood
      pasteurization.

PMID- 15174576
TI  - The chemistry of quality enhancement in low-value fish.

PMID- 15174577
TI  - The interaction of disulfide flavor compounds with proteins in model systems.

PMID- 15174578
TI  - Gas chromatography-olfactometry analysis and its importance in food quality
      control. Influence of assessors' training and sampling methods on gas
      chromatography-olfactometry data.

PMID- 15174579
TI  - Screening for sensory quality in foods using solid phase micro-extraction tandem
      mass spectrometry.

PMID- 15174581
TI  - Quality modification of food by extrusion processing.

PMID- 15174583
TI  - Sensory and peptides characteristics of soy sauce fractions obtained by
      ultrafiltration.

PMID- 15174582
TI  - Stability of aseptic flavored milk beverages.

PMID- 15174580
TI  - Maillard reaction-based glycosylation of lysozyme.

PMID- 15174584
TI  - Quality assessment of a low-salt soy sauce made of a salty peptide or its related
      compounds.

PMID- 15174586
TI  - Flavor of vinegars. Especially on the volatile components.

PMID- 15174585
TI  - Quality characteristics of edible oils.

PMID- 15174587
TI  - Textural quality assessment for fresh fruits and vegetables.
AB  - Academically, quantitative measurement of texture is essential for the study of
      the chemical and physiological mechanisms of texture. Commercially, quantitative
      measurement of texture is essential to ensure the quality of produce at packout.
      The diversity of tissues involved, the variety of attributes required to fully
      describe textural properties, and the changes in these attributes as the product
      ripens and senesces contribute to the complexity of texture measurement. Texture
      is a human assessment of the structural elements of a food. It is generally
      accepted that texture relates primarily to mechanical properties, so instrumental
      measurements relate mainly to mechanical properties. Fruits and vegetables
      exhibit viscoelastic behavior under mechanical loading, which means that the
      force, distance, and time involved in loading determine the value of any
      measurement. Because of their viscoelastic character, every effort should be made
      to hold the speed of the test constant in manual texture measurements and the
      rate of loading should be specified and controlled in mechanized measurements.
      There are many types of mechanical loading: puncture, compression, shearing,
      torsion (twisting), extrusion, crushing, tension, bending, vibration, and impact.
      The most widely used texture measurement for fruits and vegetables, after manual
      squeezing of course, is the Magness-Taylor fruit firmness test, which measures
      the maximum force to puncture the product in a specified way. The Kramer shear or
      shear-compression test is widely used in the processed foods industry, but is
      less commonly used by horticulturists. Nondestructive methods are highly desired
      both for sorting and for postharvest research. Compression tests of excised
      tissue pieces are frequently used in research. Nondestructive testing using
      impact, vibrational behavior, light scattering, and optical methods are being
      investigated but none has been widely accepted to date. Multiple instrumental
      measurements may be necessary to adequately the diversity of textural attributes
      sensed by the human consumer.

PMID- 15174588
TI  - Irradiation of apple cider: impact on flavor quality.

PMID- 15174589
TI  - Fruit and vegetable edible wraps: application to partially dehydrated apple
      pieces.

PMID- 15174590
TI  - Quality of fresh citrus fruit.

PMID- 15174591
TI  - Evaluation of water washes for the removal of organophosphorus pesticides from
      Maine wild blueberries.

PMID- 15174592
TI  - Sugar quality in soft drink manufacture: the acid beverage floc problem.

PMID- 15174593
TI  - Influence of DNA on volatile generation from Maillard reaction of cysteine and
      ribose.

PMID- 15174594
TI  - Monitoring the dynamics of tissue oxygenation in vivo by phosphorescence
      quenching.

PMID- 15174595
TI  - Estimation of cerebral blood flow in a newborn piglet model of neonatal asphyxia.

PMID- 15174596
TI  - Measurement of the optical properties of the adult human head with spatially
      resolved spectroscopy and changes of posture.

PMID- 15174597
TI  - Partitioning of arterial and venous volumes in the brain under hypoxic
      conditions.

PMID- 15174598
TI  - Variability of PCO2 breath-by-breath in normal man.

PMID- 15174599
TI  - Spectral characteristics of spontaneous oscillations in cerebral haemodynamics
      are posture dependent.

PMID- 15174600
TI  - Nirs mediated CBF assessment: validating the indocyanine green bolus transit
      detection by comparison with coloured microsphere flowmetry.

PMID- 15174601
TI  - Simultaneous assessment of microvascular oxygen saturation and laser-Doppler flow
      in gastric mucosa.

PMID- 15174602
TI  - TSC and hemorrhagic shock.

PMID- 15174603
TI  - Comparison of the influence of xenon vs. isoflurane on ventilation-perfusion
      relationships in patients undergoing simultaneous aortocaval occlusion.

PMID- 15174604
TI  - Re-evaluation of the reliability of cytochrome oxidase--signal study of
      cardiopulmonary bypass.

PMID- 15174605
TI  - Acute respiratory distress syndrome in patients after blunt thoracic trauma: the
      influence of hyperbaric oxygen therapy.

PMID- 15174606
TI  - Changes in redox status of cerebral cytochrome oxidase during periods of
      hypoperfusion in patients undergoing cardiopulmonary bypass.

PMID- 15174607
TI  - The effect of ischemia and hypoxia on renal blood flow, energy metabolism and
      function in vivo.

PMID- 15174608
TI  - Oxygen and oxidative stress modulate the expression of uncoupling protein-5 in
      vitro and in vivo.

PMID- 15174609
TI  - Age-related alteration of brain function during cerebral ischemia.

PMID- 15174610
TI  - A micro-light guide system for measuring oxygen by phosphorescence quenching.

PMID- 15174611
TI  - A new approach to monitor spinal cord vitality in real time.

PMID- 15174612
TI  - How proton translocation across mitochondrial inner membranes drives the Fo rotor
      of ATP synthase.
AB  - It has been believed for some time that there are two major but alternative
      models for the selective transport of ions across membranes generally. On the one
      hand this transport is by way of transmembrane channels. These channels exist
      within macromolecular complexes which span the membrane and provide a hydrophilic
      pathway through which the ions can be translocated. Alternatively, carriers have
      been postulated which can dissolve in the lipid moiety of the membrane, are able
      to selectively co-ordinate ions, and then move from one side of the membrane to
      the other, before unloading the ion. Proton translocation across the inner
      mitochondrial membrane is intensely interesting, firstly because the process is
      tightly coupled to the synthesis of ATP, but additionally because the emerging
      picture of proton translocation incorporates features from both the classical
      mechanisms of ion transport. Thus there are two channels, one from either side of
      the membrane, both of which penetrate to the centre of the membrane. However
      neither of them individually spans the membrane, but they remain separated by a
      short distance in the plane of the membrane. Transport across this remaining gap
      involves a carrier that reversibly binds the ion. The mechanism for transport
      across this remaining region is not carrier-facilitated diffusion, nor any "flip
      flop" change of shape by the carrier. Rather it is an electrically driven
      rotation of the carrier, and the source of the electric field that drives this
      rotor is the transmembrane electric potential.

PMID- 15174613
TI  - Applications and benefits of a non-ionic surfactant and artificial oxygen
      carriers for enhancing post-thaw recovery of plant cells from cryopreservation.

PMID- 15174614
TI  - Novel injectable gels for the sustained release of protein C.

PMID- 15174615
TI  - Oxygen consumption and antioxidant status of plant cells cultured with oxygenated
      perfluorocarbon.

PMID- 15174616
TI  - Growth and antioxidant status of plant cells cultured with bovine haemoglobin
      solution.

PMID- 15174617
TI  - Preliminary study for the protein C purification using mini-antibodies produced
      from recombinant E. coli.

PMID- 15174618
TI  - Sensing improvement of protein C biosensor by sample circulation.

PMID- 15174619
TI  - Theoretical studies of IMAC interfacial phenomena for the production of protein
      C.

PMID- 15174620
TI  - Analysis of equilibrium adsorption isotherms for human protein C purification by
      immobilized metal affinity chromatography.

PMID- 15174621
TI  - Haemoglobin-enhanced mitosis in cultured plant protoplasts.

PMID- 15174622
TI  - Oxygen therapeutics ("blood substitutes") where are they, and what can we expect?

PMID- 15174623
TI  - Microvascular PO2 and blood velocity measurements in rat brain cortex during
      hemodilution with a plasma expander (Hespan) and a hemoglobin-based oxygen
      carrier (DCLHb).

PMID- 15174624
TI  - Steady-state MR imaging with MION for quantification of angiogenesis in normal
      brain and in brain tumors.

PMID- 15174625
TI  - A new intrinsic hypoxia marker in esophageal cancer.

PMID- 15174626
TI  - Lack of association between tumor oxygenation and cell cycle distribution or
      proliferation kinetics in experimental sarcomas.

PMID- 15174627
TI  - Genomic and phenomic correlations in the respiration of basal cell carcinomas.

PMID- 15174628
TI  - Influence of neuronally derived nitric oxide on blood oxygenation and cerebral
      pO2 in a mouse model measured by EPR spectrometry.

PMID- 15174629
TI  - Optical measurements of tissue oxygen saturation in lower limb wound healing.
AB  - This review has highlighted the role of oxygen in wound healing and in the
      mechanism of preventing infection. Optical measurements of tissue SO2 in wounds
      can provide valuable information, not only about the inflammatory state of the
      wound, but also about healing potential in ulcers and critical limb ischaemia.
      The technique is fast, non-invasive and can be used without the necessity for
      contact with the skin.

PMID- 15174630
TI  - Microcirculation assessment in vasculopathies: capillaroscopy and peripheral
      tissue oxygenation.

PMID- 15174631
TI  - The effects of food intake on muscle oxygen consumption: noninvasive measurement
      using NIRS.

PMID- 15174632
TI  - Oxygen as a regulator of tissue perfusion.

PMID- 15174633
TI  - The flux of oxygen within tissues.
AB  - Diffusive flux of oxygen through tissues which are essentially connective and
      have few cells, display reduced diffusion coefficients when compared to that
      through an equivalent lamina of water. In general even significant reductions can
      be explained in terms of the exclusions imposed on small molecular weight
      diffusates by the large hydrodynamic domains of the connective tissue components.
      An alternative way of explaining this large exclusion is to point to the very
      large microscopic viscosities which large interacting polymers impose upon the
      solvent (water). By contrast, the diffusive flux of oxygen through tissues
      composed of contiguously packed and actively respiring cells, shows an increased
      diffusive flux for oxygen when compared to that through an equivalent water
      lamina. This increase can be explained in terms of the substantial solubility of
      oxygen within the membrane phase of the cells. This high oxygen partition
      coefficient into cell lipids has several consequences. Firstly oxygen diffusion
      will be directed and two dimensional rather than random and three dimensional.
      Secondly this diffusion will be directed towards the oxygen-consuming sites which
      are located at lipid surfaces. Thirdly the aqueous oxygen partial pressure will
      be kept low (since re-supply is constrained while consumption is continuous).
      This low aqueous environment permits all of the cell soluble redox systems to be
      maintained efficiently at low metabolic cost, as well as minimising the risk of
      unscheduled oxidations. Viewed from this perspective, the high value found for
      oxygen partition coefficient into the erythrocyte membrane suggests that
      evolution of membrane structure and components may have been driven in part by
      the selective advantages of high oxygen solubility.

PMID- 15174635
TI  - Comparison of closed-circuit and Fick-derived oxygen consumption during
      anaesthesia for liver transplantation in patients.

PMID- 15174634
TI  - Epr spectroscopic evidence of free radical outflow from an isolated muscle bed in
      exercising humans: functional significance of decreasing intracellular PO2 vs.
      increasing O2 flux.

PMID- 15174636
TI  - A new miniature fiber oxygenator for small animal cardiopulmonary bypass.
AB  - Neurocognitive decline following cardiac surgery is an increasing problem,
      particularly affecting older patients. The use of cardiopulmonary bypass is a
      suspected cause. Research into pathophysiology and possible preventive measures
      requires the use of an animal model. Commercial oxygenators are too large and
      expensive for use in small animals. We describe a fiber oxygenator scaled for use
      in the rat. In vitro and in vivo testing show that it is able to support full gas
      exchange in this size of animal, and causes no allergic or toxic reactions.

PMID- 15174637
TI  - The effect of graded systemic hypoxaemia on hepatic tissue oxygenation.

PMID- 15174638
TI  - Modeling of oxygen diffusion and metabolism from capillary to muscle.

PMID- 15174639
TI  - [Neuropsychological functions and ADL disturbances: a review].

PMID- 15174640
TI  - [Functional performance measure (FPM)].

PMID- 15174641
TI  - [Assessment of motor and process skills (AMPS)].

PMID- 15174642
TI  - [Bayer ADL].

PMID- 15174643
TI  - [Behave-AD].

PMID- 15174644
TI  - [Cohen-Mansfield Agitation Inventory (CMAI)].

PMID- 15174645
TI  - [Clinical global assessment].

PMID- 15174646
TI  - [The Japanese version of Zarit Burden Interview (J-ZBI) and its short version (J 
      ZBI_8)].

PMID- 15174647
TI  - [Depressive state].

PMID- 15174648
TI  - [Psychotic symptoms in old age].

PMID- 15174649
TI  - [Agitation].

PMID- 15174650
TI  - [Hypersexuality. Hypersexuality in persons with dementia].

PMID- 15174651
TI  - [Sleep disturbance].

PMID- 15174652
TI  - [Delirium].

PMID- 15174653
TI  - [Seizures].

PMID- 15174654
TI  - [Mobility, falls and fractures].

PMID- 15174655
TI  - [Feeding problems].

PMID- 15174656
TI  - [Incontinence].

PMID- 15174657
TI  - [Death].

PMID- 15174658
TI  - [Epidemiological statistics of dementia in Japan].

PMID- 15174659
TI  - [Comparison of epidemiological data between Japan and other countries].

PMID- 15174660
TI  - [The Hisayama study].

PMID- 15174661
TI  - [Differential diagnosis between cerebrovascular dementia and Alzheimer disease].

PMID- 15174662
TI  - [Dementia of Alzheimer type and frontotemporal dementia].

PMID- 15174663
TI  - [Alzheimer type dementia and Huntington's disease].

PMID- 15174664
TI  - [Differential diagnosis of Alzheimer-type dementia and dementia with Lewy
      bodies].

PMID- 15174665
TI  - [Cerebral amyloid angiopathy].

PMID- 15174666
TI  - [Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL)].

PMID- 15174667
TI  - [Cerebral autosomal recessive arteriopathy with subcortical infarcts and
      leukoencephalopathy (CARASIL)].

PMID- 15174668
TI  - [Familial hemiplegic migraine].

PMID- 15174669
TI  - [Sneddon syndrome].

PMID- 15174670
TI  - [Intravascular lymphomatosis].

PMID- 15174671
TI  - [ApoE].

PMID- 15174672
TI  - [A molecular genetic overview of familial dementing disorders].

PMID- 15174673
TI  - [Tauopathy].

PMID- 15174674
TI  - [Association between mitochondrial dysfunction and degenerative dementia].

PMID- 15174675
TI  - [Triplet repeat disease and dementia].

PMID- 15174676
TI  - [Possibility of gene and restorative therapies for dementia].

PMID- 15174677
TI  - [Cognitive abilities of centenarians].

PMID- 15174678
TI  - [Animal model for Alzheimer's disease].

PMID- 15174679
TI  - [Development of Japan Stroke Scale (Higher Cortical Function) [JSS-H]].

PMID- 15174680
TI  - [Vaccine therapy for Alzheimer's disease].

PMID- 15174681
TI  - [Alzheimer disease with 'cotton wool' plaques].

PMID- 15174682
TI  - [Mild cognitive impairment (MCI)--overview].

PMID- 15174683
TI  - [Mild cognitive impairment (MCI)--concepts and classification].

PMID- 15174684
TI  - [Mild cognitive impairment (MCI)--risk factor].

PMID- 15174685
TI  - [Mild cognitive impairment (MCI)--pathophysiology].

PMID- 15174686
TI  - [Mild cognitive impairment (MCI)--neuroimaging].

PMID- 15174687
TI  - [Mild cognitive impairment (MCI)--diagnosis and differential diagnosis].

PMID- 15174688
TI  - [Mild cognitive impairment (MCI)--treatment and prognosis].

PMID- 15174689
TI  - [Mild cognitive impairment (MCI)--epidemiology].

PMID- 15174690
TI  - [The effect of KAIGO-HOKEN on care for the dementia people].

PMID- 15174691
TI  - [Treatment and care for people with dementia in hospital or institution--critical
      pass for dementia].

PMID- 15174692
TI  - [Home care and visiting nurse service for demented patients].

PMID- 15174693
TI  - [Respite care for the elderly].

PMID- 15174694
TI  - [Day care for elderly with dementia].

PMID- 15174695
TI  - [Nursing home care for elderly with dementia].

PMID- 15174696
TI  - [Elderly health care facility].

PMID- 15174697
TI  - [Daytime care for 'with dementia'].

PMID- 15174698
TI  - [Group home].

PMID- 15174699
TI  - [Social support network for patients with dementia].

PMID- 15174700
TI  - [Care manager].

PMID- 15174701
TI  - [Rehabilitationists in management of the dementias].

PMID- 15174702
TI  - [QOL of the welfare workers who are engaged in care for the demented].

PMID- 15174703
TI  - [Education for family caregivers].

PMID- 15174704
TI  - [Care to support the dignity of people with dementia].

PMID- 15174705
TI  - [Adult guardianship].

PMID- 15174706
TI  - [The concept of metabolic syndrome. Its history and disease concept].

PMID- 15174707
TI  - [Metabolic syndrome: epidemiology].

PMID- 15174708
TI  - [The concept of metabolic syndrome: Genetic mechanism involved in the disease].

PMID- 15174709
TI  - [The mechanism and physiopathology of metabolic syndrome. The role of obesity-
      abnormal production of adipocytokines].

PMID- 15174710
TI  - [Vascular dysfunctions in metabolic syndrome. 1) A risk for cerebrovascular
      disorders].

PMID- 15174711
TI  - [Vascular dysfunction in metabolic syndrome: 2) Risk for coronary artery
      disease].

PMID- 15174712
TI  - [Clinical diagnosis of metabolic syndrome. 1. Significance and target in the
      treatment of hyperlipemia].

PMID- 15174713
TI  - [Approaches in clinical management of metabolic syndrome. 2. Keypoints in testing
      for lipid metabolism anomalies and cardiovascular risk].

PMID- 15174714
TI  - [Approach in management of metabolic syndrome. 2. Significance and the target in
      the treatment of diabetes mellitus].

PMID- 15174715
TI  - [Approach in clinical management of metabolic syndrome. 4. Diagnosis of mild
      diabetes mellitus].

PMID- 15174716
TI  - [Approach in clinical management of metabolic syndrome. 5. Significance and
      target in the treatment of hypertension].

PMID- 15174717
TI  - [Approach in clinical management of metabolic syndrome. 6. A new approach in the
      therapy based on diverse actions of antihypertensive agents: in view of metabolic
      domino theory].

PMID- 15174718
TI  - [Approach in clinical treatment of metabolic syndrome. 7. The effect of weight
      reduction and its significance in obesity].

PMID- 15174719
TI  - [Approach in clinical management of metabolic syndrome. 8. Methods and effects of
      exercise therapy].

PMID- 15174720
TI  - [Approach in clinical management of metabolic syndrome. 9. Methods and effects of
      diet therapy].

PMID- 15174721
TI  - [Clinical management of metabolic syndrome: discussion].

PMID- 15174722
TI  - [Successful treatment with steroid pulse therapy for myeloproliferation and
      'Takotsubo' cardiomyopathy in a patient with angioimmunoblastic T cell lymphoma].

PMID- 15174723
TI  - [Protein-losing gastropathy after cytomegalovirus mononucleosis].

PMID- 15174724
TI  - [Brain abscess suggestive of the association between intracranial pressure and
      cerebral salt wasting].

PMID- 15174725
TI  - [Platelet recovery of idiopathic thrombocytopenic purpura after eradication of
      Helicobacter pylori: report of two cases].

PMID- 15174726
TI  - [Lymphomatoid granulomatosis treated with oral cyclophosphamide and prednisolone
      followed by CHOP].

PMID- 15174727
TI  - [Pancytopenia associated with hyperthyroidism].

PMID- 15174728
TI  - [Efficacy of hypotensive diuretics in general practice: evidence-based medicine].

PMID- 15174729
TI  - [Diagnosis and treatment of Brugada syndrome: the current status in Japan].

PMID- 15174730
TI  - [Recent findings in airway hyperreactivity].

PMID- 15174731
TI  - [Research on renal diseases in the post-genome era].

PMID- 15174732
TI  - [A molecular structure involved in the estrogenic disrupting action caused by
      dioxin receptors].

PMID- 15174733
TI  - The nature and importance of our prehistoric diet.
AB  - Because our digestive system has not basically changed since prehistoric times it
      is suggested that it would be best for our health if our diet conformed as nearly
      as possible to that of our hunter-gatherer ancestors. Reasons are given for
      indicating that their diet was mainly plant based and uncooked. The paper is
      necessarily speculative and comments and criticisms are invited.

PMID- 15174734
TI  - How the use of high nitrogen fertilisers depresses the mineral content of crops.

PMID- 15174735
TI  - Discovering the cure for arthritis.

PMID- 15174736
TI  - Health status, lifestyle and nutrient intake of home resident elderly in Bahrain.
AB  - The elderly are more susceptible to chronic diseases which reduce functional
      capacity. Researches on health and nutritional status, therefore, are needed to
      prevent and control these chronic diseases. The objective of this study was to
      find out the health, lifestyle, ability to carry out daily living tasks, and
      intake of nutrients among home-resident Bahraini elderly. Data were based on a
      cross-sectional community study of 201 Bahraini elderly aged 65 years, which were
      selected proportionally from all geographical regions of Bahrain (88 men and 113
      women). They were visited and interviewed at home by trained female workers,
      using a pre-tested questionnaire. There was no statistically significant
      difference between men and women in the history of chronic diseases. However, the
      proportion of chronic diseases was higher among women, except for peptic ulcer.
      Men were more likely to smoke (38.6%) than women (24.8%) (p = 0.0353). Dietary
      supplements were more common among men (19.3%) than women (12.4%). Mean nutrient
      intakes for energy, iron and calcium were below the USA Recommended Daily
      Allowances. Men had more capability to do daily activities without help than
      women. In conclusion, there is a need to establish a national plan of action to
      promote health and nutritional status among the elderly of Bahrain. This study
      can provide some baseline data for further in depth study of health status of
      Bahraini elderly.

PMID- 15174737
TI  - Dynamics of the iodine-goitrogen balance in the thyroid status of catfish from
      selected fresh and brackish water bodies.
AB  - The study was designed to investigate the dynamics of the goitrogen-iodine
      balance in Igbokoda brackish and Ogbese fresh water bodies in Ondo State,
      Nigeria. The parameters determined include iodine, thiocyanate, chloride,
      nitrate, calcium, magnesium hardness, calcium hardness, total hardness, and total
      coliform counts in water, sediment and/or fish (flesh and serum). The fish were
      subjected to a number of treatments (boiling with water or sodium chloride
      solution, frying or roasting) prior to analysis. The iodine level (microg I/100g)
      in the flesh of fish varied with size, treatment and location; it increased with
      size, was reduced by some treatments (boiling with either water or NaCl
      solution), while frying and roasting did not affect the level. The least values
      were 93.45 (Ogbese fish boiled with NaCl solution) and 160.94 (Igbokoda fish
      boiled with either water or NaCl solution). On the whole, Igbokoda (160.94
      314.08) had higher values than Ogbese (93.45-205.06). Serum iodine (microg
      I/100mL) was equally higher in Igbokoda (5.00-9.00) compared to Ogbese (2.80
      5.00). Only the large sized fish of Ogbese recorded a value of 5.00 micromol/L
      for thiocyanate while this parameter was not detected in other samples. The
      calculated I/goitrogen ratios (I/Ca, I/NO3, I/Cl and I/SCN) were higher for
      Igbokoda water than Ogbese water with the exception of I/Mg. This was equally
      reinforced by the total count of coliforms (goitrogenic), which was higher in
      Ogbese (3.0 x 10(3)) than in Igbokoda (2.7 x 10(3)). These results indicate that
      the Igbokoda brackish water body would be a better source of iodine than Ogbese
      fresh water body for the population dependent on them.

PMID- 15174738
TI  - Nutritional and sensory evaluation of nutritious porridge prepared using
      combinations of soy and sorghum grits.
AB  - A study was conducted to determine the acceptability of porridge developed from
      various proportions of soy and sorghum. Partially defatted soydhal was soaked in
      four salt solutions namely, sodium carbonate, sodium bicarbonate, sodium
      tripolyphosphate and sodium chloride. Soaked dhal was dried and made into grits.
      Soy and sorghum grits were mixed in three proportions i.e. 10:90, 20:80 and 30:70
      to develop nutritious porridge. Porridge prepared from wheat grits served as a
      control. The sensory evaluation of the developed porridge was done using a 9
      point hedonic scale. Porridge prepared using sodium carbonate soaked soydhal was
      found to fall in the 'like slightly' category whereas other three types of
      porridges as well as control porridge were 'liked moderately' by the panellists.
      Nutritional evaluation of the developed porridge demonstrated that protein, fat,
      crude fibre and ash contents increased significantly (P < 0.05) as the level of
      soy was increased from 10 to 20 and 30 per cent.

PMID- 15174739
TI  - Nutritional status of obese hypercholesterolemic adults.
AB  - The study was conducted to collect information regarding food and nutrient intake
      of hypercholesterolemic adults (male n = 30, female n = 20). The Body Mass Index
      (BMI) of the respondents indicated that 70% of them had a BMI more than 26. The
      food intake of the respondents was recorded for three consecutive days using 24
      hour dietary recall and questionnaire method. The intake of cereals, sugar and
      oil was significantly higher than the Recommended Dietary Intake (RDI) prescribed
      for Indians, whereas intake of pulses was at par with RDI. The consumption of
      green leafy and other vegetable and roots and tubers was significantly lower
      among both male and female respondents. The intake of protein was at par with
      recommended dietary allowance (RDA), but fat and energy intake were significantly
      higher in both male and female respondents. The subjects were given diet
      counselling and this received a good response from the respondents.

PMID- 15174740
TI  - Vitamin A status of pregnant Nigerian women: relationship to dietary habits and
      morbidity.
AB  - Vitamin A status of pregnant Nigerian women has been determined by measurement of
      retinol concentration in plasma samples obtained from pregnant subjects, using a
      spectrophotometric method. The relationship between vitamin A status, dietary
      habits and morbidity pattern was also examined. Two hundred (200) consecutive
      pregnant women registered for antenatal clinic at the Obafemi Awolowo University
      Teaching Hospitals Complex within a period of eight (8) weeks were recruited as
      subjects. The subjects were aged 15-43 years (mean 27.2 years), and were at
      different stages of pregnancy. Semi-structured questionnaires were administered
      on the subjects to obtain data on dietary habits, present health status and
      obstetric history. Vitamin A deficiency (plasma retinol concentration < 0.35
      micromol/L) is found in 17.5% of the subjects, while 37% and 45.5% have
      borderline (plasma retinol concentration 0.35-0.70 micromol/L) and normal (plasma
      retinol concentration > 0.70 micromol/L) vitamin A status respectively. There is
      a significant relationship between frequent micturition and vitamin A status (chi
      square = 0.39: P < 0.05). There is no relationship between maternal age and
      vitamin A status. Although about 80% of the subjects consumed red palm oil daily,
      about 64% would heat the oil to smoking for at least 10 minutes, before adding to
      stew during cooking. Green vegetables were also boiled in hot water before adding
      to sauce, while liver is consumed on just about three days per month. The
      findings reported in this study have further strengthened the claim that vitamin
      A deficiency is fairly prevalent in pregnant Nigerian women, underlining the need
      for prompt and effective intervention.

PMID- 15174741
TI  - The under utilization of honey in a deprived environment.
AB  - The study investigated the utilization of honey in the treatment and prevention
      of illness amongst 400 respondents in Oranfe Community, Ile-Ife, Osun State
      Nigeria. Data were collected by employing a structured and pretested open ended
      questionnaire. The data indicated that 21%, 17% and less than 5% of the
      respondents had used honey for wounds, respiratory tract infections and
      gastroenteritis respectively. Neither educational nor professional status had any
      significant influence on the usage of honey in the treatment and prevention of
      common illness (p > 0.05). The vast majority (55%) preferred refined sugar to
      honey. The study has some policy implications. The first is the need for an
      intensive nutrition education programme that will disseminate the health benefits
      of honey as a source of energy, essential nutrients and its antioxidant
      properties. The second is the need to promote its usage in clinical trials
      because of its antibacterial properties.

PMID- 15174742
TI  - Evaluation of a QIAamp DNA stool purification kit for Shiga-toxigenic Escherichia
      coli detection in bovine fecal swabs by PCR.
AB  - A commercial kit intended for Taq polymerase inhibitor removal was tested to
      detect Shiga-toxigenic Escherichia coli (STEC) by polymersase chain reaction
      (PCR) directly from cattle fecal samples. Forty-five samples were analysed for
      the presence of stx genes. Results were compared to those obtained by two other
      methods: amplification of DNA purified by a non-commercial procedure (heat lysis
      protocol), and amplification of DNA from samples cultured in solid media,
      commonly used in our lab. Identical numbers of positive samples (33/45, 73 %)
      were obtained with the QIAamp DNA stool purification kit and the culturing
      procedure, suggesting an adequate removal of inhibitors that interfere in PCR
      amplification from the feces. Besides, the number of positive samples detected
      using DNA purified by the non-commercial protocol was lower, 25/39 (64%) than
      that achieved by using the kit. In conclusion, the use of the QIAamp DNA stool
      purification kit provided a rapid stx gene detection by PCR in bovine fecal
      samples.

PMID- 15174743
TI  - [Influence of salinity and temperature on fatty acid composition of Pseudomonas
      fluorescens GNP-OHP-3 membrane].
AB  - The bacteria respond to environmental changes modifying their composition. One of
      the most important modifications is the variation on fatty acid composition of
      cellular membranes to maintain the homeoviscosity. The action of temperature,
      hydrostatic pressure and solvents on Pseudomonas putida has been thoroughly
      studied. In this paper, the combined action of the temperature and salinity on
      fatty acid composition of cellular membranes of Pseudomonas fluorescens GNP-OHP
      3, a bacterial strain isolated from a petroleum contaminated habitat, was
      studied. The modifications in the fatty acid composition of Pseudomonas
      fluorescens GNP-OHP-3 membrane were similar to those described for other members
      of Pseudomonas: an increase in saturated fatty acids and a decrease in
      unsaturated fatty acids were observed with the increase of the temperature.
      Variations of main fatty acids were in general erratic in the range of assayed
      saline concentrations. The variation of cyclopropane fatty acids could be
      expressed with mathematic equations that allowed to predict their percentage in
      relation to sodium chloride concentration.

PMID- 15174744
TI  - [Development of an antigen for the diagnosis of Kilham rat parvovirus by
      hemagglutination inhibition test].
AB  - An antigen of rat parvovirus (Kilham virus) was developed for the diagnosis of
      viral infection in rat colonies by using hemagglutination inhibition (HAI) test.
      Primary cell cultures from rat embryos were infected with Kilham rat virus.
      Infected cells obtained at different time post infection were scraped,
      centrifuged, concentrated one hundred times, sonicated and centrifuged again. The
      supernatants obtained were titrated by hemagglutination. The specificity was
      confirmed with positive and negative reference sera. Ninety eight serum samples
      were studied by using HAI test. The results coincided with those obtained in a
      reference laboratory. Kilham rat parvovirus antigen obtained from 5 days-infected
      cells was specific, sensitive, easy to prepare, with a high yield and it is
      useful to detect this virus in experimental and production rat colonies.

PMID- 15174745
TI  - [Isolation of Haemophilus influenzae serotypes from deep sites in sick children].
AB  - Haemophilus influenzae (Hi) is the causative agent of several human diseases such
      as sepsis, meningitis, celulitis, and osteoarthritis. We investigated the
      isolation of Hi serotypes from sterile sites in sick children. One hundred and
      seventy nine strains from 146 patients were studied, period 1996-2002, at the
      Microbiology Laboratory, Hospital de Ninos Superiora Sor Maria Ludovica,
      Argentina. The serotype distribution was:1 a, 112 b,1 c,1 d, 4 e, 3 f y 24 no
      typable. Since the beginning of universal Hi b vaccination in 1998, we have
      observed the fast decrease of serotype b and a relative increase of other
      serotypes.

PMID- 15174747
TI  - [Isolation of enterococci species causative of infections and sensitivity to
      antimicrobial drugs].
AB  - Between April 1, 1999 and June 30, 2000, 144 isolates of enterococci (one per
      patient) from cultures of several anatomic sites were collected. One hundred and
      nineteen (82.6%) E. faecalis, 11 (7.6%) E. faecium and 14 (9.7%) of other species
      (5 E. raffinosus, 4 E. avium, 3 E. casseliflavus, 1 E. pseudoavium, and 1 E.
      dispar) were associated with clinical infections. The most common sites of
      isolation were: the urinary tract 54.9%, abdominal cavity 12.5%, surgical wounds
      12.5%, abscesses 6.9% and diabetic foot 6.2%. High-level resistance to gentamicin
      or streptomycin or both was detected in 48.6% of the isolates. E. faecium and E.
      raffinosus were significantly more resistant than E. faecalis to ampicilin and
      imipenem. None of the strains exhibited beta-lactamase activity. One strain of E.
      faecium (0.7%) was resistant to vancomicin and teicoplanin (Van A phenotype) and
      two strains of E. casseliflavus (1.4%) showed low level of resistance to
      vancomicin (Van C phenotype). Because of these diverse antimicrobial resistance
      mechanisms, successful treatment and control of enterococcal infections with
      current antimicrobial agents are becoming increasingly difficult.

PMID- 15174748
TI  - [Methicillin resistance detection in Staphylococcus aureus: comparison between
      conventional methods and MRSA-Screen latex agglutination technique].
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen that
      has emerged over the last four decades, causing both nosocomial and community
      acquired infections. Rapid and accurate detection of methicillin resistance in S.
      aureus is important for the use of appropriate antimicrobial therapy and for the
      control of nosocomial spread of MRSA strains. We evaluated the efficiency of
      conventional methods for detection of methicillin resistance such as the disk
      diffusion, agar dilution, oxacillin agar screen test, and the latex agglutination
      test MRSA-Screen latex, in 100 isolates of S. aureus, 79 mecA positive and 21
      mecA negative. The MRSA-Screen latex (Denka Seiken, Niigata, Japon), is a latex
      agglutination method that detects the presence of PLP-2a, product of mecA gene in
      S. aureus. The PCR of the mecA gene was used as the "gold standard" for the
      evaluation of the different methods tested. The percentages of sensitivity and
      specificity were as follows: disk difusion 97 and 100%, agar dilution 97 and 95%,
      oxacillin agar screen test 100 and 100%, and MRSA-Screen latex, 100 and 100 %.
      All methods presented high sensitivity and specificity, but MRSA-Screen latex had
      the advantage of giving a reliable result, equivalent to PCR, in only 15 minutes.

PMID- 15174746
TI  - [Bact-Alert automatized system for blood cultures: 5 vs 7 days of incubation.
      First Argentine multicentre study].
AB  - Bact-Alert automatized system for blood cultures: 5 vs 7 days of incubation.
      First Argentine multicentre study. Between January and December 2001, we analyzed
      80,141 blood cultures by the Bact-Alert system (14,960 FAN aerobics, 3,855 FAN
      anaerobic, 11,114 standards aerobics, 11,367 standards anaerobic, 12,054
      pediatrics and 26,791 FAN pediatrics bottles) and 44.235 series from 27.615
      patients at eight hospitals of Buenos Aires city, one of La Plata city and three
      of the Buenos Aires province. A total of 13,657 blood cultures yielded a positive
      result. Only 181 of them had been detected as positive between the 5th and 7th
      day of incubation and only 26 (0.19%) had clinical significance (Staphylococcus
      aureus 3; coagulase negative staphylococci 2; Enterococcus faecalis 1;
      Streptococcus pneumoniae 2; Campylobacter spp 1; Escherichia coli 1; Enterobacter
      cloacae 1; Enterobacteraerogenes 1; Citrobacter freundii 1; Klebsiella pneumoniae
      1; Proteus mirabilis 1; Serratia marcescens 4; yeasts 7, including one strain of
      Cryptococcus neoformans). Of the total of contaminants, 38% were isolated by the
      anaerobic standard (65% were Propionibacterium spp and 29% coagulase negative
      staphylococci), 31.2% by the FAN aerobic (33.3% difphteroids and 28.9% Bacillus
      spp), 11.8% by the pediatric, 9% by FAN pediatric, 8.33% by aerobic standard and
      1.4% by FAN anaerobic bottle. Our results show that the prolonged incubation of
      blood cultures for more than 5 days using the Bact-Alert system is unnecessary.

PMID- 15174749
TI  - [Increase of rising activity of commercial yeasts by application of stress
      conditions during their propagation].
AB  - Rising activity determined as CO2 production of two commercial strains of
      Saccharomyces cerevisiae could be increased mainly in sweet bread doughs by
      introducing a "starvation/pulse feeding" schedule of sugar cane molasses during a
      fed-batch propagation. Such increase was strain dependent. Except for the
      trehalose intracellular level, other traits related to the yeast industrial
      performance were unaffected. Applicability of method for baker's yeast industrial
      production is discussed.

PMID- 15174750
TI  - Microbial dehalogenation of polychlorinated biphenyls in aerobic conditions.
AB  - From soils contaminated with polychlorinated biphenyls (PCBs) a strain of
      Alcaligenes sp. able to grow in a mineral medium with a commercial mixture of
      PCBs as carbon source was isolated. This strain consumed up to 200 ppm in seven
      days in laboratory conditions. After 24 h of incubation, some new congeners of
      PCBs could be recognized by mass spectrometry. Through the identification of
      these compounds it was possible to postulate examples of possible transformations
      by dechlorinations of penta- and tetra-chlorinated congeners into tri-chlorinated
      ones. The properties of the isolated strain are appropriate for bioremediation of
      contaminated areas and also for using in bioreactors in order to remove the
      xenobiotic chemical.

PMID- 15174752
TI  - Epidemiology and economic impact of rhinosinusitis.
AB  - Rhinosinusitis is highly prevalent in the United States, affecting an estimated
      16% of the adult population annually. The prevalence of the illness is increased
      in women and, relative to other US regions, in individuals living in the South.
      The direct costs associated with chronic rhinosinusitis are higher than the
      background costs in managed care patients because of increased office visits and
      medication prescriptions, and the indirect costs due to restricted activity days
      are enormous. Rhinosinusitis poses an immense economic burden in the United
      States. Data concerning the epidemiology and economic impact of the disease are
      reviewed.

PMID- 15174751
TI  - Inhibition of the growth of Ascosphaera apis by Bacillus and Paenibacillus
      strains isolated from honey.
AB  - The fungus Ascosphaera apis, the causative agent of chalkbrood disease in
      honeybee larvae, occurs throughout the world and is found in many beekeeping
      areas of Argentina. The potential as biocontrol agents of 249 aerobic spore
      forming bacterial antagonists isolated from honey samples was evaluated. Each
      isolate was screened against A. apis by a central disk test assay. Ten bacterial
      strains that showed the best antagonistic effect to A. apis were selected for
      further study and identified as Bacillus cereus (m363, mv86, mv81, mv75),
      Bacillus circulans (Fr231, m448b), Bacillus megaterium (m435), Bacillus pumilus
      (m354), Bacillus subtilis (m329), and Paenibacillus alvei (m321). For testing the
      efficiency of the selected strains, a paired culture test was used with 5
      replicates of each combination bacterial antagonist/A. apis strain, and 5
      replications for each control on 4 different culture media. The analysis of
      variance and posterior comparison of means according to LSD method showed that
      the best antagonists when using YGPSA medium were B. subtilis (m329) and B.
      megaterium (m435), and in the case of MYPGP medium the most efficient were B.
      circulans strains Fr 231 and m448b.

PMID- 15174753
TI  - Pathogenesis of chronic rhinosinusitis.
AB  - Chronic rhinosinusitis (CRS) is a multifactorial disease. Predisposing factors
      can be divided into environmental and non-host factors, such as pollution, viral
      infections, smoking, fungus, and bacteria; general host factors, including
      genetic factors and immune deficiency; and local host factors, including
      persistent focal inflammation within the ostiomeatal complex. Evidence suggests
      that the underlying bone in the ostiomeatal complex is actively involved in the
      disease process of CRS. The evidence concerning a broad range of predisposing
      factors for CRS is reviewed.

PMID- 15174754
TI  - Diagnosis of chronic rhinosinusitis.
AB  - Chronic rhinosinusitis is a multifactorial disease defined as inflammation of the
      nasal cavity and paranasal sinuses with a history of at least 12 weeks in
      duration. The major symptoms include facial pressure or pain, nasal obstruction,
      discharge or purulence, and hyposmia or anosmia. The minor symptoms include
      fever, halitosis, fatigue, and dental pain. Microorganisms play a significant
      role in the persistence and origination of the inflammatory process, although the
      exact role of these organisms in the pathogenesis of chronic rhinosinusitis is
      unclear. The clinical diagnosis relies heavily on the patient history and
      physical examination, which may include nasal endoscopy and computed tomography.
      Diagnostic techniques are here reviewed.

PMID- 15174755
TI  - Role of endoscopy in the management of chronic rhinosinusitis.
AB  - Endoscopy has multiple uses in both the medical and surgical management of
      chronic rhinosinusitis (CRS). This article reviews applications of endoscopy in
      preoperative evaluation and postoperative management of CRS. Before operation,
      nasal endoscopy is the standard for tissue sampling, evaluation of the mucosa,
      identifying structural alterations, and staging of allergic fungal sinusitis. As
      part of the surgical procedure, endoscopy may be used to minimize the time needed
      for postoperative debridement. Applications of endoscopy in in-office medical
      management of CRS include culturing the sinuses for fungus or bacteria, inserting
      a cannula for the delivery of drug therapy, and various minor manipulations
      following a surgical procedure. Perhaps the most important role for endoscopy in
      patients with CRS is in medical management, particularly in cases involving
      eosinophilic inflammation. Angled telescopes are important for visualizing areas
      often overlooked in sinuses that may otherwise appear to be normal, ie, the
      depths of the maxillary, frontal, or sphenoid sinus. Further use and research are
      likely to elicit more uses for this important technology.

PMID- 15174756
TI  - Imaging for staging of rhinosinusitis.
AB  - Although clinical judgment is sufficient to diagnose rhinosinusitis in many
      cases, a number of patients with recurrent or complicated sinus disease require
      imaging studies. Advances in the field of diagnostic imaging techniques such as
      computed x-ray tomography (CT) and magnetic resonance imaging have enhanced our
      understanding and management of the disease. Magnetic resonance imaging excels in
      displaying soft tissue resolution and is superior in demonstrating the presence
      of neoplasia and fungal sinusitis. but has limited advantages over CT scanning in
      demonstrating the regional anatomy (bony structure) and in the diagnosis of
      chronic rhinosinusitis. Computed tomography provides greater detailed information
      about the paranasal sinuses than do plain radiographic films. Rhinosinusitis
      staging systems utilizing CT techniques are reviewed. Although results from the
      Lund-Mackay system appear to be easily reproducible. there are still clinical
      challenges not addressed by this method of classification. Considering the
      patency of specific ostiomeatal channels and quantifying the volume of disease
      may add to the clinical value of future classification systems.

PMID- 15174757
TI  - Biopsy and specimen collection in chronic rhinosinusitis.
AB  - Biopsy, aspiration, swab, and irrigation of the nose and sinuses are methods used
      in specimen collection and culture when chronic rhinosinusitis is suspected.
      Biopsy may be indicated to identify the presence of fungal elements in the mucus
      or tissues, suspected neoplasm, or inflamed bone. Aspiration directly from the
      maxillary sinus is considered to be the gold standard for culture, but it is
      painful. Direct endoscopic-guided culture of the middle meatus appears to be a
      viable substitute, with swab and suction methods having similar rates of
      microbiological contamination. Topical delivery methods for irrigating sinus
      cavities may utilize spray bottles, nebulizers, or a bulb syringe; these have
      various degrees of efficacy in dispersing materials to the sinuses. Use of the
      bulb syringe appears to offer broad distribution with limited risk of sample
      contamination. Specimens must be handled carefully to avoid loss of fungal
      elements. Advantages and indications of various methods are reviewed.

PMID- 15174758
TI  - Etiology of chronic rhinosinusitis: the role of fungus.
AB  - Chronic rhinosinusitis is an inflammatory disorder with numerous predisposing
      factors, including genetics, pollution, anatomic anomalies, bacteria, and fungus.
      In some studies, fungi have been cultured from nearly 100% of patients with
      rhinosinusitis and nasal polyposis. T-cell sensitization to fungus with
      production of the T-helper 2 (Th2) cytokine interleukin-5 has been proposed as a
      key step in the initiation of the disease. Interleukin-5 also plays an important
      role in the effector phase of the disease through its effects on
      eosinophilopoesis and eosinophil survival. There is considerable controversy
      concerning the role of fungi as the cause of "chronic eosinophilic
      rhinosinusitis" and whether this even represents a distinct clinical entity.
      Further study is also required to define the optimal treatment for the disease.

PMID- 15174759
TI  - Treatment of the interarytenoid muscle with botulinum toxin for laryngeal
      dystonia.
AB  - The treatment of laryngeal dystonia with botulinum toxin has provided various
      degrees of relief to the majority of patients with adductor dysphonia; however, a
      significant number of patients have limited or no improvement with this type of
      therapy. It remains unclear why some patients respond to the routine
      administration of toxin to the thyroarytenoid muscles whereas others do not.
      Injections into the lateral cricoarytenoid muscles have provided an improved
      voice in some patients who were unresponsive to injections into the
      thyroarytenoid muscles. Fine-wire electromyography can demonstrate the particular
      dystonic activity of these muscles to help determine which muscle is
      predominantly involved. It can also demonstrate dramatic dystonic activity in the
      interarytenoid (IA) muscle in many patients. We present the results of 23
      patients treated with injections to the IA muscle after demonstration of dystonic
      IA activity. Ten have benefited from IA therapy. Five of these 10 patients did
      not have a good result from botulinum toxin until IA injections were added to the
      treatment plan. In 8 patients, IA therapy provided no improvement, and 5 patients
      were lost to adequate follow-up. According to fine-wire electromyography and
      clinical response, the IA muscle is an active dystonic muscle in some patients
      with laryngeal dystonia and should be treated with botulinum toxin in selected
      patients.

PMID- 15174760
TI  - Tremor laryngeal dystonia: treatment of the lateral cricoarytenoid muscle.
AB  - Tremor laryngeal dystonia is a clinical entity distinct from adductor laryngeal
      dystonia, according to perceptual, stroboscopic, and fine-wire electromyographic
      findings. Treatment with botulinum toxin has proven more difficult for tremor
      laryngeal dystonia than for adductor laryngeal dystonia, yet no treatment
      variations have been considered that might produce improved clinical results. We
      present 81 patients with a clinical presentation of tremor laryngeal dystonia who
      were treated with a variety of approaches with botulinum toxin. On the basis of
      both fine-wire electromyographic findings and clinical response, currently 44 of
      those patients are being followed up after at least 3 injections. Twenty-one
      patients (48%) are maintained on lateral cricoarytenoid injections, and 23 (52%)
      are maintained on thyroarytenoid muscle injections. The electromyographic
      findings of this group are presented along with their clinical outcome. According
      to our findings, the majority of patients with tremor laryngeal dystonia can be
      successfully treated with botulinum toxin if the practitioner includes injections
      to the lateral cricoarytenoid muscle as a treatment option.

PMID- 15174761
TI  - Capsaicin receptor expression in rat laryngeal innervation.
AB  - Capsaicin elicits a sensation of burning pain by selectively activating sensory
      neurons that convey information about noxious stimuli to the central nervous
      system. Vanilloid receptor subtype 1 (VRI) and the vanilloid receptor-like
      protein 1 (VRL-1) are activated, not only by capsaicin, but also by noxious heat
      and protons, and it has been suggested that they are polymodal nociceptors. We
      investigated the expression of VR1 and VRL-1 in the rat larynx and nodose
      ganglion using VR1 and VRL-1 immunohistochemical analysis with visualization by
      diaminobenzidine reaction. Fibers positive for VRL-1 were detected in the
      laryngeal epithelium and lamina propria. Cells positive for VRL-1 were
      distributed in the intralaryngeal ganglia. Half of the neurons in the nodose
      ganglion had VR-1 immunoreactivity, and almost 10% of the nodose ganglion neurons
      were positive for VRL-1. These findings suggest that these capsaicin receptors
      play an important role in the nociception of the laryngeal innervation.

PMID- 15174762
TI  - Combination of fascia transplantation and fat injection into the vocal fold for
      sulcus vocalis: long-term results.
AB  - Fat injection and fascia transplantation alone have been used to treat patients
      with sulcus vocalis. No information is available on the effectiveness of these
      two procedures used in concert to treat sulcus vocalis. The objectives of this
      study were to conduct the two procedures together and report the long-term
      results. This article assesses, retrospectively, the effectiveness of the
      combination treatment of fascia transplantation and fat injection (FTFI) in
      patients with sulcus vocalis (n = 22). Perceptual acoustic, phonatory function,
      and videolaryngostroboscopic data were evaluated before and after FTFI treatment
      in 18 patients. The mean follow-up time was 16.6 months. Sixteen patients had
      excellent results, 3 reported improvement, and 3 indicated no change. Phonatory
      function improved significantly in terms of phonation time, grade, roughness (p <
      .05), and breathiness (p < .001). The videolaryngostroboscopic rating showed
      significant improvement in vocal fold vibration amplitude and excursion of the
      mucosal wave (p < .05). Type 3 sulcus responded better to this treatment than did
      type 2 (sulcus vergeture). No postoperative complications were noted. The FTFI
      technique consists of an autogenous implant and delivers positive results. It may
      be considered as an option for patients with sulcus vocalis. It has been
      demonstrated to achieve excellent results in a majority of patients and to
      deliver a better prognosis than fat injection alone. Although resorption of fat
      and fascia is associated with FTFI, the FTFI procedure may be repeated multiple
      times.

PMID- 15174763
TI  - Revision single-stage laryngotracheal reconstruction in children.
AB  - In this report, we discuss indications, technique, outcome, and complications of
      revision single-stage laryngotracheal reconstruction (SSLTR), formulate
      guidelines to avoid or prevent procedure failure, and establish a protocol for
      the management of procedure failure. We retrospectively reviewed the charts of
      122 patients between the ages of 8 months and 9 years who underwent SSLTR between
      January 1992 and September 2001 in 2 tertiary care children's medical centers in
      different cities and assessed the outcomes of patients who underwent revision
      SSLTR. A total of 122 patients underwent SSLTR, of whom 48 patients underwent
      anterior and posterior grafting. Of the 122 patients, 13 had revision SSLTR; 8 of
      these 13 underwent the initial laryngotracheal reconstruction at another
      institution. Five patients had anterior grafting laryngotracheal reconstruction
      without stenting, 7 had anterior and posterior grafting with 1 to 21 days of
      endotracheal intubation, and I had cricotracheal resection and anastomosis. Of
      the 13 patients, 5 had anterior wall or graft collapse (grade IV stenosis), 4 had
      subglottic stenosis (grade IV), 2 had circumferential subglottic stenosis (grade
      III), and 2 had subglottic and glottic stenosis (grade IV). The overall success
      rate for all patients was 86% (105 of 122). The success rates for the 122
      patients were as follows: anterior grafting, 100%; anterior and posterior
      grafting, 83% (40 of 48); and revision cases, 70% (9 of 13). We conclude that
      laryngotracheal reconstruction with a costal cartilage rib graft should be
      considered the procedure of choice for the management of subglottic stenosis. We
      believe that patients in whom the first procedure fails should have a high chance
      of success with revision SSLTR if strict guidelines and protocols are followed.

PMID- 15174765
TI  - Extracorporeal shock wave lithotripsy of submandibular stones: evaluation after
      10 years.
AB  - The use of extracorporeal shock waves in the treatment of submandibular stones is
      a minimally invasive approach for the treatment of this disease. Its clinical
      significance has been determined in a long-term retrospective study, performed as
      follow-up to the short-term results. From 1989 to 1994, 197 patients (88 female,
      109 male; age range, 8 to 83 years) with symptomatic, sonographically detectable
      concretions of the submandibular gland were treated with extracorporeal shock
      wave lithotripsy. The review analysis was completed retrospectively in 2002 and
      included 191 patients with complete data. The period under review ranged from 8
      to 13 years, with an average of 10.5 years. Altogether, 67 of the 191 patients
      (35%) either were free of stones or had no more symptoms from the residual
      sialoliths. Another 15% had a significant improvement in their symptoms and
      required no further therapy. The remaining 95 patients (50%) had residual stones;
      they had no symptoms in the short review period, but have had symptoms since. The
      therapeutic success was not influenced by the stone size, but rather by the stone
      location within the gland. After therapy, no severe side effects were identified.
      Extracorporeal shock wave lithotripsy is a possible treatment for stones in the
      submandibular gland. In combination with other gland-preserving methods, it now
      forms part of a multitherapeutic approach that renders submandibulectomy
      unnecessary in the majority of cases.

PMID- 15174764
TI  - Recurrent syncope as presenting symptom of Burkitt's lymphoma at the carotid
      bifurcation.
AB  - Burkitt's lymphoma is rare outside of Africa, and head and neck manifestations of
      this disease are even more uncommon. We report a case of Burkitt's lymphoma
      localized at the bifurcation of the right common carotid artery in a 64-year-old
      man. The presenting symptoms were recurrent syncopes that necessitated a
      pacemaker, followed by a rapid onset of cranial nerve palsies. The tumor had
      infiltrated cranial nerves IX, X, XI, and XII and was resected by selective neck
      dissection. The patient was subsequently treated with a chemotherapeutic regimen
      consisting of a combination of cytosine arabinoside, vincristine, ifosfamide,
      prednisone, and an intrathecal application of methotrexate. He also underwent
      external-beam irradiation of the neck. The patient has been followed up for a
      period of 42 months and has no evidence of recurrent disease. Repeated diagnostic
      testing and a coordination of multiple disciplines can speed diagnosis and
      therapeutic management. The current literature is reviewed and discussed.

PMID- 15174766
TI  - Cellular neurothekeoma of the maxilla.
AB  - Neurothekeomas are uncommon benign soft tissue tumors of nerve sheath origin.
      They occur predominately in the head and neck or upper trunk of children and
      young adults. A 15-month-old boy presented with an enlarging mass of the right
      maxilla. Radiologic imaging demonstrated an expansile lesion of the nasomalar
      region. An incisional biopsy resulted in the diagnosis of neurothekeoma. This
      lesion should be considered as part of the differential diagnosis of pediatric
      soft tissue head and neck masses. We discuss the presentation, evaluation, and
      treatment of these rare benign lesions.

PMID- 15174767
TI  - Clinical features of bilateral progressive hearing loss associated with
      myeloperoxidase-antineutrophil cytoplasmic antibody.
AB  - In this study, we analyzed the clinical features, diagnostic criteria, treatment,
      and outcome of atypical bilateral progressive hearing loss associated with
      myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA). The evaluation
      was made by audiogram and laboratory data in 6 cases treated at Hokkaido
      University Hospital. We measured MPO-ANCA by enzyme-linked immunosorbent assay;
      the result was positive in all cases. The hearing loss developed bilaterally and
      progressed to total deafness within several weeks. The onset of hearing loss was
      not simultaneous in the 2 ears. Methylprednisolone pulse therapy was effective in
      9 ears. Three ears showed no improvement; 2 of the 3 ears had already exhibited
      total deafness at the first visit. After the treatment, the titer of MPO-ANCA
      decreased in all patients. The level of MPO-ANCA should be tested in patients
      with bilateral progressive hearing loss of unknown origin and can be used as a
      marker of the disease's activity.

PMID- 15174768
TI  - Large intraosseous hemangioma of the temporal bone in a child.
AB  - Hemangiomas of the temporal bone are extremely uncommon tumors, predominantly
      arising in the area of the geniculate ganglion and the internal auditory canal
      and affecting mainly middle-aged adults. We present a 6-year-old boy who had
      suffered from recurrent infections of the left ear associated with a slight
      conductive hearing loss, but without facial nerve dysfunction. Using high
      resolution computed tomography and gadolinium-enhanced magnetic resonance
      imaging, we detected an unusually large 32 x 32 x 24-mm mass of the left temporal
      bone occupying the entire mastoid. Histopathologically, a capillary hemangioma
      was diagnosed. The tumor was removed surgically by a transmastoid approach. We
      present a thorough review of the literature, focusing on the clinical and
      radiologic features, as well as the pathogenesis of intratemporal vascular
      lesions.

PMID- 15174769
TI  - Surgical management of special cases of intractable Meniere's disease: unilateral
      cases with intact canals and bilateral cases.
AB  - If a clinician seeks to allow patients with vertigo to return to work as soon as
      possible, it is very important to determine the appearance of vestibular symptoms
      during convalescence just after treatment, as well as the long-term results.
      Apprehensive patients with vertigo may undergo severe psychological torment if
      treatment requires long-term rest in bed before they can return to daily life. In
      this paper, we observed postoperative vestibular symptoms (subjective sensation
      and objective nystagmus) in 50 patients with intractable Meniere's disease,
      including cases from our previous preliminary report, during the period of
      convalescence just after endolymphatic sac drainage and steroid instillation
      surgery (EDSS). All symptoms were eliminated within 8 days after EDSS. There was
      no significant difference in the duration of any vestibular symptoms between
      bilateral (n = 8) and unilateral cases (n = 42). This result indicates that EDSS
      could be as safe a treatment for bilateral Meniere's disease as for unilateral
      disease. In unilateral cases with intact semicircular canal function (n = 17),
      postoperative evoked vestibular sensation, positional, and positioning (Dix
      Hallpike) nystagmus disappeared significantly earlier than in those with canal
      paresis (n = 25). This result indicates that EDSS could keep the vestibular
      peripheral function of patients with unilateral Meniere's disease with intact
      canals quite stable after surgery. Therefore, EDSS could be recommended as an
      initial, less-invasive surgical treatment for intractable Meniere's disease,
      especially in unilateral cases with intact canals and in bilateral cases.

PMID- 15174770
TI  - Controversies and criticisms on designs for experimental autoimmune
      labyrinthitis.
AB  - Although immune-mediated inner ear disease was reported around 25 years ago,
      numerous attempts to identify the inner ear antigens have been performed.
      Experimental animal models have been used to study the immune mechanisms involved
      in hearing loss and to develop new therapies. Because animal models of autoimmune
      labyrinthitis have been developed by means of different antigens, we cannot yet
      show a valid immunopathologic explanation. A critical analysis of the more
      relevant experimental models employed has been performed in order to validate the
      methodology. Comparison between these models and animals with spontaneous
      systemic autoimmune disease has raised more questions concerning the
      pathophysiology of autoimmune hearing loss. A new pathogenetic theory is
      suggested, involving the supporting cells of the organ of Corti.

PMID- 15174771
TI  - State and federal regulations for hearing.
AB  - Mandated federal and state requirements for hearing function prescribed for
      military and pilot performance, schoolchildren, and commercial and school bus
      drivers are summarized in the following review. The material is directed toward
      involved otolaryngologists, industrial physicians, and appropriate review boards
      for reference in licensure examinations or student hearing assessments.

PMID- 15174772
TI  - Otorhinolaryngological procedures in the fifteenth century in Anatolia.
AB  - The author of one of the earliest surgical books was Serefettin Sabuncuoglu (AD
      1385 to 1468?). He is the author of Cerrahiyyetul-Haniyye (Imperial Surgery),
      which was written in 1465. This book contains miniatures of surgical procedures,
      and there were many important and major new contributions to the surgical
      literature originally described by Sabuncuoglu himself. He described surgical
      management of nasal polyposis, nasal fracture, facial palsy, mandibular fracture
      and dislocation, hoarseness and constriction of the breath, tumors of the tonsil
      and uvula, laryngeal tumors, and goiter. The aim of this report is to describe
      his contributions to otorhinolaryngology.

PMID- 15174773
TI  - Palatal myoclonus associated with compression of the brain stem by an ectatic
      vertebral artery.

PMID- 15174774
TI  - Predictive value of sleep nasendoscopy in the management of habitual snorers.

PMID- 15174775
TI  - The number of authors of scientific publications.
AB  - As in most other scientific journals, the number of authors per paper published
      in Acta Paediatrica is gradually increasing. In the 2003 volume, the number of
      authors was six or more in about one-third of the Regular papers and Clinical
      observations. The editorial board has handled several conflicts of interest due
      to disputes about authorship. CONCLUSION: Editors of scientific journals should
      promote a policy with the aim of creating a true balance between authorship and
      originality of papers.

PMID- 15174776
TI  - Positive pressure ventilation at neonatal resuscitation: review of equipment and
      international survey of practice.
AB  - BACKGROUND: The equipment used to provide positive pressure ventilation to
      newborns needing resuscitation at delivery varies between institutions. Devices
      were reviewed and their use surveyed in a sample of neonatal centres worldwide.
      AIM: To determine which equipment is used to resuscitate newborns at delivery in
      a sample of teaching hospitals around the world. METHODS: A questionnaire was
      sent via e-mail to a neonatologist at each of 46 NICUs in 23 countries on five
      continents, asking which resuscitation equipment they used. If it was not
      returned, follow-up was by e-mail. RESULTS: Data were obtained from 40 (87%)
      centres representing 19 countries. Round face masks are used at 34 (85%) centres,
      anatomically shaped masks are used exclusively at six (15%) and a mixture of
      types are used at 11 (28%). Straight endotracheal tubes are used exclusively at
      36 (90%) centres: shouldered tubes are used infrequently at three of the four
      centres that have them. The self-inflating bag is the most commonly used manual
      ventilation device (used at 33 (83%) centres), the Laerdal Infant Resuscitator
      the most popular model. Flow-inflating bags are used at 10 (25%) centres. The
      Neopuff Infant Resuscitator is used at 12 (30%) centres. Varying oxygen
      concentrations are provided during neonatal resuscitation at half of the centres,
      while 100% oxygen is routinely used at the other half. CONCLUSIONS: This survey
      shows considerable variation in practice, reflecting this lack of evidence and
      consequent uncertainty among clinicians. Comparison of the two most popular
      manual ventilation devices, the Laerdal Infant Resuscitator and the Neopuff
      Infant Resuscitator, is urgently required.

PMID- 15174777
TI  - Up for grabs--authors are a dime a dozen: the problem of multiple authors.
AB  - AIM: To outline some of the major ethical problems related to multiple
      authorship. METHODS: A survey of the literature, data collected over the years,
      regarding multiple authors, e.g., definition, contribution, ethical behavior and
      guidelines, and personal experience were the primary inputs. RESULTS: Despite the
      efforts of a number of editors' organizations, there still is a major problem in
      the attribution of authors' credits to those who had nothing to do with the
      writing. CONCLUSIONS: The solution to this problem may be found in one of two
      ways: strict enforcement of standards of authorship by journal editors, i.e.,
      rejection of articles, no matter how good they may appear to be, because they
      violate these standards, and/or adoption of authorship standards as understood by
      commercial publishers.

PMID- 15174778
TI  - Iron status in a group of Norwegian children aged 6-24 months.
AB  - An adequate iron status is of vital importance for health and development in
      infancy and early childhood. Iron status was evaluated in a group of full-term
      Norwegian children followed longitudinally, at the ages of 6 mo (n = 278), 12 mo
      (n = 249) and 24 mo (n = 231) by measuring haemoglobin (Hb), mean cell volume
      (MCV) and serum ferritin. At 6, 12 and 24 mo of age, 3, 10 and 12%, respectively,
      had iron deficiency anaemia (IDA) defined as Hb <110 g/l in combination with
      ferritin <15 microg/l. With more restrictive criteria for defining IDA (Hb <110
      g/l or <105 g/l in combination with ferritin <12 microg/l), the prevalence
      decreased to 1-2% at 6 mo and 2-5% at 12 and 24 mo of age. If children with a
      history of fever in the previous month were excluded, the proportion of children
      with depleted iron stores (ferritin <10 microg/l) increased from 2 to 3% at 6 mo,
      from 5 to 7% at 12 mo and from 9 to 13% at 24 mo. CONCLUSION: Mild iron
      deficiency anaemia exists among otherwise healthy Norwegian infants and toddlers.
      The prevention and early treatment of iron deficiency should be a priority for
      the child health services.

PMID- 15174779
TI  - Zinc supplementation for four months does not affect plasma copper concentration
      in infants.
AB  - AIM: The aim of the present study, which was undertaken as a sub-study within a
      randomized controlled trial of zinc supplementation, was to evaluate the effect
      of prolonged zinc supplementation on copper status as assessed by hematological
      markers. METHODS: Plasma copper and zinc were estimated at baseline and after 120
      d of supplementation in a randomly selected infant subset (115) of the children.
      Of these, 61 children were in a zinc group (Z) getting 10 mg of elemental zinc,
      and 54 were in a control group (C) getting supplement without zinc. RESULTS:
      Baseline plasma zinc was comparable in the two groups; post-supplementation zinc
      was significantly higher (Z 93.0 +/- 3.6 vs C 60.6 +/- 8.0) in the zinc
      supplementation group. There was no significant difference in the mean/median
      copper levels between the zinc and control groups. The percentage of children
      with plasma copper <100 microg/dl was also not significantly different between
      groups (baseline Z 14.8%, C 11.1%; post-supplementation Z 18.0%, C 11.1%). There
      were no differences between the zinc and control groups after 120 d of
      supplementation in hemoglobin (Hgb), mean corpuscular volume (MCV), mean
      corpuscular hemoglobin concentration (MCHC), or number of lymphocytes or
      granulocytes. CONCLUSION: Zinc supplementation of 10 mg/d for 4 mo in this study
      did not affect copper status, as assessed by plasma copper concentration and
      hematological parameters, diagnostics of copper deficiency.

PMID- 15174780
TI  - N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to
      adolescence. Elevated levels at birth and in infants and children with heart
      diseases.
AB  - AIM: Determination of plasma levels of N-terminal pro-B-type natriuretic peptide
      (N-BNP) in infants and children with and without heart diseases. METHODS: Plasma
      N-BNP was measured in 78 infants and children without heart disease and in 55
      infants and children with heart disease causing volume and pressure overload.
      Heart diseases included chronic dilated cardiomyopathy, acute left ventricular
      dysfunction, and congenital cardiac anomalies resulting in left and right
      ventricular volume or pressure overload. The Mann-Whitney rank-sum test and the
      ANOVA for ranks test were used to compare two or more groups, respectively.
      RESULTS: N-BNP levels were elevated in the first days of life but were not
      significantly different in children from 4 mo to 15 y old. The upper limit in
      children older than 4 mo with no heart disease was 349 pg/ml. In patients with
      heart disease, N-BNP levels were significantly higher than in control children (p
      < 0.0001). CONCLUSION: N-BNP levels are elevated in the first days of life and
      are stable from age 4 mo to adolescence. Elevated N-BNP levels reflect cardiac
      dysfunction in infants and children.

PMID- 15174781
TI  - Gastric emptying in infants: epigastric impedance versus scintigraphy.
AB  - AIM: To compare epigastric impedance versus scintigraphy in monitoring the
      gastric emptying of the same adapted milk formula in infants. METHODS: Seven
      infants with clinical symptoms of gastric motility disease underwent scintigraphy
      with 99mTc sulphur colloid for the 90 min following the ingestion of the same
      adapted milk formula, in order to evaluate gastric emptying. A bio-impedance
      device, connected to a PC, was prepared for this purpose with four standard
      electrodes placed anteriorly on the upper part of the body. The obtained graphs
      were compared to those of the scintigraphic method. Statistical analysis was
      performed using Pearson correlation. The confidence limits were set at 95%.
      Parental consent was obtained before each analysis. RESULTS: The gastric emptying
      patterns obtained with epigastric impedance were closely correlated to those
      shown by the scintigraphy (r = 0.86 +/- 0.08; p < 0.05). A significant
      correlation between the gastric emptying velocity measured by the two techniques
      was found (r = 0.94; p = 0.002). CONCLUSIONS: Epigastric impedance in infants
      provided estimates of gastric emptying that were closely correlated with
      scintigraphy. However, the limits derived from the epigastric impedance suggest
      that, at the moment, the two methods should not be used interchangeably.

PMID- 15174782
TI  - Lung volume and the response to high volume strategy, high frequency oscillation.
AB  - BACKGROUND: Infants with severe respiratory failure are frequently transferred to
      high volume strategy, high frequency oscillation (HFO). Mean airway pressure
      (MAP) is then elevated, the aim being to open up atelectatic lungs and hence
      improve gas exchange. AIM: To test the hypothesis that lung volume prior to
      transfer would predict the response to high volume strategy HFO and identify
      which factors related to poor outcome (death). METHODS: Lung volume was assessed
      by measurement of functional residual capacity (FRC) and the response to HFO
      determined by the change in the alveolar arterial gradient (AaDO2) on transfer
      from conventional mechanical ventilation (CMV) to the optimal MAP on high volume
      strategy HFO. PATIENTS: Forty-two infants with a median gestational age of 28
      (range 23 to 40) wk were studied. RESULTS: FRC prior to transfer correlated
      significantly with the change in MAP necessary to optimize oxygenation (p =
      0.012), but not the change in AaDO2 in response to HFO. There were no significant
      differences in the lung volumes of survivors and non-survivors, but those who
      died were more immature (p = 0.0009) and had a smaller response to HFO (p =
      0.035). CONCLUSION: Lung volume prior to transfer to high volume strategy HFO
      might be helpful to guide oscillatory settings, but is a poor predictor of the
      response to high volume strategy HFO.

PMID- 15174783
TI  - Silent acetaminophen-induced hepatotoxicity in febrile children: does this entity
      exist?
AB  - Several descriptions of acetaminophen-associated liver injury caused by
      therapeutic or a dosage slightly above the recommended dosage have been
      described. Our hypothesis is that in sick febrile infants and children, who may
      also be calorie depleted, there might be an increased hepatic vulnerability to
      acetaminophen. AIM: (1) To correlate serum acetaminophen levels in febrile
      infants and children with the following parameters: aspartate aminotransferase
      (AST) levels, fever, vomiting and/or decreased caloric intake; and (2) to assess
      parental knowledge regarding the medication dosage and hazards of acetaminophen.
      METHODS: Healthy children with an acute febrile illness, who had received
      acetaminophen, were eligible to participate in the study. AST and acetaminophen
      levels were drawn, and a detailed questionnaire was completed for every child.
      RESULTS: 107 children participated in the study; 50 girls and 57 boys with ages
      ranging from 1 mo to 16 y (mean 33 mo). All serum acetaminophen levels were
      within the safety range. Although 32% of parents administered a single
      acetaminophen dose above 15 mg/kg and 46% gave a daily dose above 60 mg/kg/d, no
      significant differences were observed in the serum acetaminophen and AST levels
      compared to those who received the appropriate dose. In about 60% of cases, the
      high doses were recommended by a physician. Young age and high fever were
      associated with significantly higher acetaminophen levels. We could not find an
      association between acetaminophen levels and vomiting, decreased caloric intake
      and AST levels. Only 24 parents (22%) were aware of the possible toxicity of
      acetaminophen. CONCLUSIONS: No evidence of increased hepatic vulnerability to
      acetaminophen was noted in a cohort of febrile infants and children. Furthermore,
      significant numbers of parents and physicians were unaware of acetaminophen
      dangers.

PMID- 15174784
TI  - Lower leg growth suppression caused by inhaled glucocorticoids is not accompanied
      by reduced thickness of the cutis or subcutis.
AB  - BACKGROUND: Exogenous glucocorticoids suppress short-term lower leg growth in
      children as assessed by knemometry. The knemometric measurements, however, may be
      confounded by reductions in the thickness of the cutis and subcutis over the
      knee. AIM: To assess whether inhaled glucocorticoid-induced suppression of short
      term growth is accompanied by changes in the thickness of the cutis and subcutis.
      METHODS: The study was a randomized, controlled, crossover trial with 1 wk
      treatment, run-in and washout periods. Active treatment was inhaled budesonide
      200 microg twice daily. Short-term growth was assessed by knemometry, and the
      thickness of the cutis and subcutis over the knee, on the volar forearm and
      abdomen was measured by 20 MHz B-mode ultrasound. MATERIAL: Nineteen children
      with asthma aged 7 to 13 y. RESULTS: Lower leg growth was significantly reduced
      during budesonide treatment (0.27 mm/wk) compared to the treatment-free period
      (0.54 mm/wk) (p = 0.02, 95%: -0.50 to -0.05). Variations in the thickness of the
      cutis were seen during budesonide treatment (mean +/- SEM): -0.01 +/- 0.03 mm
      over the knee, -0.02 +/- 0.02 mm on the forearm and 0.01 +/- 0.02 mm on the
      abdomen. The variations in the total thickness of the cutis and subcutis were 
      0.05 +/- 0.12 mm, 0.06 +/- 0.12 mm and -0.06 +/- 0.10 mm during budesonide
      treatment. The variations in thickness of the cutis or subcutis were not
      statistically different during budesonide treatment and the treatment free period
      in any anatomical location. CONCLUSIONS: Short-term lower leg growth suppression
      induced by inhaled glucocorticoids is not confounded by variations in thickness
      of cutis or subcutis. The present observations further establishes knemometry as
      a reliable tool for assessment of the risk of growth suppression of inhaled
      glucocorticoids in children with asthma.

PMID- 15174785
TI  - Screening of coeliac disease in north Italian children with type 1 diabetes:
      limited usefulness of HLA-DQ typing.
AB  - AIM: To determine the contribution of HLA-DQA1* and HLA-DQB1* genes to the risk
      of coeliac disease (CD) in a cohort of children with type 1 diabetes mellitus
      (T1DM) from northern Italy. METHODS: Three hundred and fifty-seven children with
      T1DM, attending the Childhood Diabetes Unit of the University of Verona, have
      been regularly tested for serum IgA endomysial antibodies (EMA). All patients
      with positive EMA underwent small bowel biopsy to confirm the diagnosis of CD.
      HLA typing was performed in subjects with T1DM and CD, and in a control group of
      79 EMA-negative patients with T1DM. RESULTS: Of the 357 patients tested, 25 (7%)
      had CD. The frequency of HLA-DQA1*0501-DQB1*0201 (T1DM + CD 68% vs T1DM 62%) and
      of DQA1*0301-DQB1*0302 (T1DM + CD 40% vs T1DM 35%) haplotypes, between T1DM
      patients with and without CD, was statistically comparable. A trend towards a
      reduction of the risk of CD (p = 0.055, OR: 0.22, CI 0.05: 1.04) was observed in
      patients with T1DM (28% vs T1DM + CD 2%) who did not carry either the HLA
      DQA1*0501-DQB1*0201 or the DQA1*0301-DQB1*0302 haplotype. CONCLUSION: A high
      prevalence of HLA-DQA1* and -DQB1* susceptibility haplotypes for CD was observed
      both in EMA-negative diabetics and in those with associated CD. The
      implementation of screening programmes of CD in a T1DM population, based on the
      identification of HLA susceptibility haplotypes, seems to be of limited
      usefulness. Serial serologic screening of diabetic patients remains the advisable
      strategy.

PMID- 15174786
TI  - T cell receptor V gene usage by CD4+ and CD8+ peripheral blood T lymphocytes in
      immune thrombocytopenic purpura.
AB  - AIM: To identify T cell expansions, i.e. increased frequencies of T cells using a
      particular T cell receptor (TCR) V alpha or V beta gene segment, in patients with
      immune thrombocytopenic purpura (ITP). METHODS: The TCR repertoires of CD4+ and
      CD8+ peripheral blood lymphocytes of 16 patients with chronic ITP were analysed
      by staining with a panel of anti-TCR V alpha and V beta antibodies followed by
      flow cytometry. RESULTS: Four of the 16 patients exhibited a total of 6
      expansions of CD8+ T cells using a particular V beta segment, but no expansions
      were detected in the CD4+ subset. For three of the expansions where a follow-up
      blood sample after treatment with intravenous immunoglobulin was available, only
      one expansion remained. CONCLUSION: Overall T cell expansion frequency was the
      same as in healthy individuals. However, the presence of expansions that
      normalized with treatment suggests the presence of specific T cells implicated in
      the pathogenesis of ITP.

PMID- 15174787
TI  - Retrospective evaluation of long-term efficacy and safety of splenectomy in
      chronic idiopathic thrombocytopenic purpura in children.
AB  - AIM: To review the long-term efficacy and safety of splenectomy in children with
      chronic idiopathic thrombocytopenic purpura (cITP). PATIENTS AND METHODS: Data
      from 33 splenectomized children were retrospectively analysed (median follow up
      period: 18.8 y from the removal of the spleen). The median age of children at
      splenectomy was 12 y and the median ITP duration 3.3 y. Indications for
      splenectomy were: persistent severe thrombocytopenia with extensive purpura,
      epistaxis and/or gum bleeds, menorrhagia (n = 5) and severe or recurrent
      haemorrhage from various sites (n = 11). RESULTS: Eighty-five per cent of the
      patients showed an excellent (n = 26) or partial response to splenectomy. Five
      children (15%), all females, failed to respond. Of the responders, 25%
      experienced a transient recurrence of thrombocytopenia within 6 mo to 4 y from
      splenectomy. The mortality rate due to severe sepsis was 3%. However, the
      majority of the splenectomized patients have not so far suffered any severe or
      mild bacterial infection, despite incomplete vaccination and/or antibiotic
      prophylaxis. CONCLUSION: Splenectomy remains the only effective therapeutic
      modality for children with cITP, although it is associated with transient
      recurrence and rarely with post-splenectomy sepsis, which could be fatal.
      Nonetheless, splenectomy should be the last treatment option for the cITP
      patient, after all available therapeutic modalities have been exhausted and the
      child still remains profoundly thrombocytopenic and symptomatic.

PMID- 15174788
TI  - Neonatal respiratory morbidity risk and mode of delivery at term: influence of
      timing of elective caesarean delivery.
AB  - AIM: To establish whether the timing of delivery between 37 + 0 and 41 + 6 wk
      gestation influences neonatal respiratory outcome in elective caesarean delivery,
      following uncomplicated pregnancy, thus providing information that can be used to
      aid planning of elective delivery at term. METHODS: All pregnant women who were
      delivered by elective caesarean delivery at term during a 3-y period were
      identified from a perinatal database and compared retrospectively with pregnant
      women matched for week of gestation, who were vaginally delivered. Maternal
      characteristics, neonatal outcome, incidence of respiratory distress syndrome
      (RDS) and transient tachypnea of the newborn (TTN) were analysed. During this
      time, 1284 elective caesarean section deliveries occurred at or after 37 + 0 wk
      of gestation. RESULTS: Neonatal respiratory morbidity risk (odds ratio, OR),
      including RDS and TTN, was significantly higher in the infant group delivered by
      elective caesarean delivery compared with vaginal delivery (OR 2.6; 95% CI: 1.35
      5.9; p < 0.01). While TTN risk in caesarean delivery was not increased (OR 1.19;
      95% CI: 0.58-2.4; p > 0.05), the RDS risk was significantly increased (OR 5.85;
      95% CI: 2.27-32.4; p < 0.01). This RDS risk is greatly increased in weeks 37 + 0
      to 38 + 6 (OR 12.9; 95% CI: 3.57-35.53; p < 0.01). After 39 + 0 wk, there was no
      significant difference in RDS risk. CONCLUSIONS: Infants born by elective
      caesarean delivery at term are at increased risk for developing respiratory
      disorders compared with those born by vaginal delivery. A significant reduction
      in neonatal RDS would be obtained if elective caesarean delivery were performed
      after 39 + 0 gestational weeks of pregnancy.

PMID- 15174789
TI  - Whole blood interleukin 8 and plasma interleukin 8 levels in newborn infants with
      suspected bacterial infection.
AB  - AIM: To evaluate a new micro-method technique for measurement of interleukin 8 in
      detergent-lysed whole blood (whole blood IL-8) applicable to capillary blood
      sampling as a test for bacterial infections in neonates. METHODS: Whole blood IL
      8 was measured at the first suspicion of infection along with IL-8 determined in
      plasma (plasma IL-8), C-reactive protein and blood cultures in 154 consecutive
      newborn infants with clinical signs of bacterial infection. Only 20 microl of
      whole blood were required for the new assay. RESULTS: Blood culture-proven
      infections were diagnosed in six infants and clinical infection (defined as a
      combination of clinical and laboratory signs) in 20 infants. 1000 pg/ml was
      determined as the suitable threshold for whole blood IL-8 by ROC-curve analysis.
      At that threshold, whole blood IL-8 detected blood culture-proven infections with
      a sensitivity of 83% and a specificity of 67%. The areas under the ROC curves
      were similar for whole blood IL-8 and plasma IL-8. CONCLUSIONS: Compared with
      plasma IL-8, whole blood IL-8 offers the advantages that measurements of whole
      blood IL-8 require a smaller blood sample volume and are not altered by
      haemolysis. The diagnostic accuracy of whole blood IL-8 remains to be studied in
      more detail in the future.

PMID- 15174790
TI  - Plasma protein Z levels in healthy and high-risk newborn infants.
AB  - AIM: To evaluate plasma protein Z (PZ) levels in healthy and high-risk newborn
      infants. METHODS: A longitudinal observational study was conducted. Inclusion
      criteria were: healthy term and preterm newborns normal for gestational age and
      newborns belonging to one of the following groups: newborns small for gestational
      age (SGA), newborns affected by respiratory distress syndrome (RDS), newborns
      from mothers with pre-eclampsia. Newborns with sepsis, congenital malformation or
      haemorrhagic disorders were excluded. Plasma PZ levels, protein C (PC)
      concentration, PC activity and protein-induced vitamin K absence levels were
      measured. RESULTS: 53 newborns were enrolled into the study. PZ and PC antigen
      levels varied significantly among analysed subgroups on day 1 (p < 0.01): lower
      levels of these inhibitors were found in RDS newborns (group C), newborns from
      mothers affected by pre-eclampsia (group D) and SGA newborns (group E) than in
      healthy term and preterm newborns (groups A and B). CONCLUSION: PZ deficiency
      occurs in newborns affected by severe RDS, in newborns from pre-eclamptic mothers
      and in SGA newborns, probably owing to activated coagulation in the first two
      conditions and to reduced PZ synthesis in the last condition.

PMID- 15174791
TI  - The use of in-line intravenous filters in sick newborn infants.
AB  - AIM: This study assesses the improvement in outcome for newborn infants by
      decreasing major complications associated with intravenous fluid therapy by using
      an in-line filter, and evaluates the economical impact this might have in
      relation to daily changing of i.v. lines. METHODS: In a prospective controlled
      study, 88 infants were randomly assigned to receive either filtered (except for
      lipids, blood and blood products) or non-filtered infusions via a central
      catheter. Main outcome measures such as bacteraemia, phlebitis, extravasation,
      thrombosis, septicaemia and necrosis were all scored. The costs attributable to
      patients during a standard 8-day stay were also recorded. RESULTS: Significant
      reductions were found in major complications such as thrombi and clinical sepsis
      (control group (21), filter group (8); p < 0.05). Bacterial cultures of the
      filters showed a contamination rate on the upstream surface of 15/109 filters
      (14%). The mean costs of disposables were less in the filter group, showing a
      reduction from 31.17 euros to 23.79 euros. CONCLUSIONS: The use of this in-line
      filter leads to a significant decrease in major complications and substantial
      cost savings.

PMID- 15174792
TI  - Feeding problems in nursery children: prevalence and psychosocial factors.
AB  - AIM: In this study we analyze the prevalence of feeding problems in a sample of
      nursery children and examine the environmental and psychopathological factors
      related to such problems. METHODS: We used the Early Childhood Inventory-Parents
      Checklist to assess 851 Spanish children aged between 3 and 6 years from both
      urban and rural samples. This screens emotional and behavioural problems and is
      based on the Diagnostic and Statistical Manual of Mental Disorders-IV. We
      collected sociodemographic data and information about life events and the
      psychopathology of the children's parents (General Health Questionnaire-28).
      RESULTS: Our results showed that the prevalence of feeding problems was 4.8% and
      that there were no differences between gender. Sample subtype, socioeconomic
      level and family characteristics were not linked to feeding problems. Children
      with feeding problems had significantly more symptoms of psychological problems
      and somatic complaints and had experienced more life events in the previous 12
      months. The psychopathology of the mother, especially in terms of anxiety
      problems, increased the risk of feeding problems in children. CONCLUSION: When
      there are complaints of feeding problems in preschools, the psychological
      problems of children and their mothers should be taken into consideration during
      paediatric consultation, irrespective of gender or socioeconomic status.

PMID- 15174793
TI  - Duration of breastfeeding and breastfeeding problems in relation to length of
      postpartum stay: a longitudinal cohort study of a national Swedish sample.
AB  - AIM: To investigate the association between length of postpartum stay and
      duration of breastfeeding and breastfeeding problems, with special focus on early
      hospital discharge. METHODS: Swedish-speaking women were recruited from all
      antenatal clinics in Sweden during 3 wk evenly spread over 1 y in 1999 to 2000.
      In total, 3293 women (71% of those who were eligible) consented to participate in
      the study. Data were collected by questionnaires in early pregnancy, 2 mo and 1 y
      postpartum, and from the Swedish Medical Birth Register. For the purpose of this
      study, only data from the 2709 women (82%) who filled in the question about
      length of stay in the 2-mo questionnaire were analysed. Women were divided into
      six groups according to length of postpartum stay (day 1: < 24 h to day 6: > or =
      120 h). RESULTS: The median duration of any breastfeeding was 7 mo in women
      discharged on day 1, and 8 mo in women discharged on any of the following days; a
      non-significant difference (p = 0.66). Besides hospital policies regarding length
      of stay (residential area) and number of domiciliary visits, early discharge was
      associated with the following maternal characteristics, which could be divided
      into three categories: (1) older, multipara, many children; (2) positive
      experience of the first breastfeeding after birth; (3) low education, economic
      problems, smoking, lack of support from partner. Late discharge was associated
      with operative delivery, preterm birth and low infant birthweight. When these
      factors were controlled for by Cox regression analysis, no statistical
      differences were found between the six groups in the relative risk of
      discontinuing to breastfeed. Breastfeeding problems, such as engorgement and
      mastitis, did not differ, but women discharged on day 6 or later had fewer
      problems with sore or cracked nipples during the first week and more problems 4-8
      wk postpartum. CONCLUSION: Maternal characteristics may be more important
      predictors of the duration of breastfeeding than length of stay in hospital after
      the birth. The effect of domiciliary support needs further research.

PMID- 15174794
TI  - Sleep patterns in children and adolescents with functional recurrent abdominal
      pain: objective versus subjective assessment.
AB  - AIM: To document objective sleep patterns of children and adolescents with
      functional recurrent abdominal pain (RAP), and to compare them with subjective
      sleep assessments and sleep patterns of healthy controls. METHODS: Subjective
      sleep reports and sleep habit assessments were obtained from 25 adolescents with
      functional RAP and from 15 age- and gender-matched healthy volunteers, and were
      compared with continuous movement monitoring using the Actigraph for 7
      consecutive days. RESULTS: Abdominal pain before falling asleep was a unanimous
      complaint in the RAP group, with 29% reporting awakening from sleep by the pain.
      Only 25% of RAP patients assessed their sleep quality as good, compared with 87%
      of the control group. Objective sleep patterns measurements of the RAP patients
      were similar to those of the control group as well as to measurements observed in
      a large population of school-aged children and adolescents. CONCLUSION: This
      study of a small group of children and adolescents with functional RAP provides
      objective evidence that their sleep patterns do not differ from those of normal
      peers, despite their subjective complaints.

PMID- 15174795
TI  - Health-related fitness in Swedish adolescents between 1987 and 2001.
AB  - AIM: To assess trends in neuro-muscular and cardio-respiratory fitness and
      morphological fitness in Swedish adolescents between 1987 and 2001. METHODS:
      Comparison of data from two samples, one from 1987 (n = 479) and one from 2001 (n
      = 1470). Subjects underwent functional tests of muscular strength in the lower
      limbs, trunk and upper body, sub-maximal ergometrics, and measurement of body
      mass and height. RESULTS: Cardio-respiratory fitness showed only small changes
      between 1987 and 2001 among boys, with no changes in girls. Neuro-muscular
      fitness, as measured by three functional tests, was lower in 2001 compared to
      1987. The most pronounced changes in these functional tests were found in the arm
      hang test, while changes in lower body and trunk strength tests were less. Our
      results indicate that the difference in the prevalence of overweight in
      adolescents between 1987 and 2001 is mainly due to a large change in the most
      unfit group. The fittest group showed only marginal changes. CONCLUSION: We
      suggest that the differences in neuro-muscular fitness are at least partly due to
      differences in the amount and nature of physical activity, and that this might
      lead to consequences for health later in life.

PMID- 15174796
TI  - Oral anticoagulant treatment in children based on monitoring at home.
AB  - AIM: To evaluate the feasibility of home monitoring of oral anticoagulant
      treatment (OAT) in paediatric patients. METHODS: A total of 19 paediatric
      patients received OAT and then monitored their treatment at home with CoaguChek.
      Data on their International Normalized Ratio (INR) values were collected
      retrospectively from hospital records and from the notes kept by the families.
      The families of the patients were also asked to fill in a questionnaire. RESULTS:
      No thrombotic or haemorrhagic complications occurred during a total amount of
      44.7 follow-up years. INR: the proportion of INR values measured at home falling
      within the therapeutic range for the given patient varied from 33 to 86% (median
      69%). The questionnaire: all respondents were satisfied with home monitoring, and
      63% felt that a major advantage of home monitoring was that there was no need to
      perform venipuncture. While 47% of the respondents reported no disadvantages of
      home monitoring, 42% reported that they occasionally lacked confidence in their
      ability to conduct OAT correctly at home. CONCLUSION: Home monitoring of OAT is
      feasible and reasonably reliable in paediatric patients. However, it is crucial
      that healthcare professionals supervise the treatment and the families are
      provided with detailed and precise instructions on how to act in a variety of
      clinical situations.

PMID- 15174797
TI  - A descriptive survey of Swedish child health nurses' awareness of abuse and
      neglect. II. Characteristics of the children.
AB  - AIM: To determine whether children considered by child health nurses to be at
      risk of abuse or neglect differed from the general population in gender, age and
      health status, and whether such child characteristics were related to nurses'
      perceptions of case seriousness, or to reporting to the child protection services
      (CPS). METHODS: Questionnaires were sent to nurses in the preventive Child Health
      Services, 951 of whom identified a total of 6044 children aged 0 to 6 y as
      suspected of risk of maltreatment. RESULTS: Boys and older children were over
      represented among the identified children, possibly because the attention of the
      nurses was attracted by salient symptoms in older boys. Children with health
      problems and boys exposed to disturbed parenting/neglect were perceived as more
      serious cases than other children. Children aged 4-6 y were more likely to be
      reported to the CPS than children under 3 y of age. CONCLUSION: The findings
      raise the question whether possibly maltreated children who are very young,
      female or in good health run a particularly high risk of non-detection, of being
      considered non-serious cases and of not being reported to the CPS. The risk of
      going unnoticed may be higher for some children at risk of maltreatment than for
      others.

PMID- 15174798
TI  - A short-term follow-up of children with poor word production at the age of 18
      months.
AB  - AIM: (a) To study the stability of poor language development assessed by a new
      screening instrument based on parents' recognition of words their 18-mo-old
      children use; (b) to evaluate the predictability of the less-than-eight-words cut
      off used by Child Health Centres (CHCs) in Sweden at the present 18-mo check-up-
      an assessment based on parents' recall of their children's vocabulary. METHODS:
      All failures of the less-than-eight-words criterion, corresponding to about 10%
      of 1000 children from a community-based study, were followed up within half a
      year after the first assessment. The follow-up instrument was an extensive,
      internationally well-known and structured parent questionnaire, standardized for
      Swedish children. RESULTS: Almost half of the followed-ups performed below the
      10th percentile and more than two-thirds were found below the 20th percentile.
      Thus, after a few months about one-third of the children had caught up to a
      fairly normal level of performance. Two of the children who had recovered
      performed above median. More relaxed cut-off criteria were applied ad hoc,
      reducing the proportion of children with a fast recovery. CONCLUSION: Age of
      language assessment and/or the level of cut-off criterion presently used at
      Swedish CHCs should be reconsidered.

PMID- 15174799
TI  - Helicobacter heilmannii gastroduodenal disease and clinical aspects in children
      with dyspeptic symptoms.
AB  - AIM: To evaluate the occurrence and clinical characteristics of Helicobacter
      heilmannii infection among children presenting with dyspeptic symptoms. METHOD:
      Prospective cohort study of 580 patients. RESULTS: Of all examined dyspeptic
      children, 26.4% were infected with spiral-shaped organisms, and 0.9% of patients
      were found to be infected with spiral H. heilmannii-like organisms. CONCLUSION:
      In children with dyspeptic symptoms, the possible presence of gastroduodenal
      disease due to H. heilmannii should be considered. Further studies are needed to
      clarify H. heilmannii-related gastroduodenal pathology in the paediatric
      population.

PMID- 15174800
TI  - Acute hyperammonaemic encephalopathy in a female newborn caused by a novel, de
      novo mutation in the ornithine transcarbamylase gene.
AB  - A full-term female offspring of a first and uneventful pregnancy presented at 60
      h of life with irritability, tachypnea and respiratory alkalosis progressing to
      deep coma with clinically dominant circulatory failure, tachycardia and
      hypotension. Diagnosis of ornithine transcarbamylase (OTC) deficiency was made on
      the basis of hyperammonaemia, hypocitrullinaemia and extreme hyperexcretion of
      orotic acid. The baby was treated with peritoneal dialysis, arginine
      hydrochloride and adequate energy supply. DNA analysis revealed an as of yet
      unidentified missense mutation in the 6th exon of the OTC gene, resulting in a
      change of lysine to glutamine at position 210 (K210Q). Her parents were not found
      to carry this mutation, implying that this mutation may have occurred either de
      novo in the patient or in a parental germ cell. CONCLUSION: An acute neonatal
      form of OTC deficiency should be considered in the differential diagnosis of coma
      in female newborns.

PMID- 15174801
TI  - Acinar dysplasia: a rare cause of neonatal respiratory failure.
AB  - Acinar dysplasia is a rare cause of death in the first few hours of life, due to
      an absence of alveoli. This report presents the first case associated with
      additional major renal malformations. The diagnosis of acinar dysplasia was
      unexpectedly made at autopsy. CONCLUSION: Even in the presence of antenatally
      diagnosed severe anomalies, autopsy may reveal diagnostically important
      information.

PMID- 15174802
TI  - An unusual case of an atypical eating disorder masquerading as a serious multi
      systemic illness.
AB  - An early diagnosis and multidisciplinary team approach are mandatory in the
      management of eating disorders. Serious organic symptoms and nutritional effects
      can mimic a systemic illness, particularly in those with atypical presentations.
      A 15-y-old adolescent male presented with poor growth, low weight, abdominal pain
      and yellow pigmentation. Further bizarre multi-system symptomatology resulted in
      a protracted admission with multiple investigations. An initial diagnosis of
      teratoma proved negative on abdominal laparotomy. A multidisciplinary approach
      followed by a feeding challenge led to the diagnosis of an eating disorder. The
      disorder, although more common in girls and adolescents, is increasing in
      incidence in both males and younger children. CONCLUSION: Atypical eating
      disorders are potentially serious and life-threatening illnesses, and
      paediatricians and psychologists should be aware of unusual presentations.

PMID- 15174803
TI  - Henoch-Schonlein purpura associated with Kingella kingae bacteremia.

PMID- 15174805
TI  - Intermittent torsion of a wandering spleen in a child: the role of MRI in
      diagnosis.
AB  - Wandering spleen is a rare condition, particularly in children. We report a
      pediatric case of intermittent torsion of a wandering spleen. The preoperative
      diagnosis was made based on ultrasonography (US), computed tomography (CT), and
      magnetic resonance imaging (MRI). A detailed description of MRI findings is
      presented and the role of MRI in diagnosis is explored.

PMID- 15174804
TI  - MR findings in a case of exogastric stromal tumor of the stomach.
AB  - A case of gastrointestinal stromal tumor of stomach investigated with US, CT, and
      MRI is reported. On imaging, the neoplasm arises from the wall of the gastric
      fundus and appears well circumscribed and sharply demarcated from the adjacent
      structures. MRI provides an excellent means of evaluating the site and extension
      of this neoplasm and enables accurate surgical planning. The authors stress that
      there has been recently widespread scientific and clinical interest in GIST
      (gastrointestinal stromal tumor) because its principal pathogenetic defect has
      been identified and a specific molecular inhibitor of GIST has been developed.

PMID- 15174806
TI  - Thyroid enlargement due to extramedullary plasmacytoma.
AB  - We report the case of a 69-year-old woman presenting with a rapidly enlarging
      thyroid mass as the first extramedullary symptom of plasmacytoma. Extramedullary
      locations are found in less than 5% of patients with multiple myeloma and can
      arise in any tissue. If the patient presents with extramedullary lesions and the
      radiologist is unaware of the underlying disease process the masses can be
      mistaken for disseminated metastatic carcinoma or non-Hodgkin's lymphoma.

PMID- 15174807
TI  - Imaging of benign liver lesions.

PMID- 15174808
TI  - Non-invasive diagnosis of infracardiac total anomalous pulmonary venous return.

PMID- 15174809
TI  - Fenestral and cochlear otosclerosis.

PMID- 15174810
TI  - Detection and clearance of Syphacia obvelata infection in Swiss Webster and
      athymic nude mice.
AB  - Our routine health-surveillance program is based on use of the Swiss Webster
      mouse, with sentinels submitted for testing every 7 weeks. Athymic nude (nu/nu)
      mice are used as an adjunct method to detect pinworm infections. The premise for
      the use of the nude mouse was based on research that revealed the thymus as
      necessary to confer resistance to pinworm infections. In light of this finding,
      it was inferred that an athymic mouse would be more susceptible to pinworm
      infections than a euthymic mouse, and hence a better sentinel animal for pinworm
      detection. To test the validity of this assumption, the Syphacia obvelata
      detection ability of the athymic nude mouse was compared to that of the Swiss
      Webster. Our results indicate no significant temporal difference in the detection
      ability of the two genotypes of mice. A clearance study for the parasite was also
      performed, in which the majority of Swiss Webster mice cleared the infection
      whereas athymic nude mice did not. In light of our results, we conclude that use
      of the athymic nude mouse for Syphacia obvelata detection offered no significant
      advantage over the euthymic Swiss Webster mouse for our program.

PMID- 15174811
TI  - The implementation of robotic technology in an animal facility: a case study.
AB  - The benefits of a robotics system for waste disposal and cage sanitation in an
      animal care facility include a reduction of ergonomic concerns and an increase in
      production capability. A modular approach can further provide an ability to
      relocate the unit to new building construction. There are numerous considerations
      that can affect the design and operation of a robotic cagewash system. These
      include facility layout, existing animal husbandry procedures, equipment
      selection, and employee involvement. The implementation of the complete system in
      an animal facility requires communication and insight from all members of the
      animal care staff as well as novel solutions to attain full production and
      operation. The system itself contains many complex technical and mechanical
      functions, but a successful installation can only be fully achieved with teamwork
      and proper training.

PMID- 15174812
TI  - Beta 2 microglobulin and resistance to murine respiratory mycoplasmosis.
AB  - Mycoplasma pulmonis (MP) infection causes murine respiratory mycoplasmosis (MRM)
      in mice. This study was designed to determine whether C57BL/6 beta 2
      microglobulin knockout (KO) mice (B2m-/-) differed from C57BL/6 B2m(+/+) wild
      type (WT) mice in the early events of acute infection and to confirm previous
      studies that suggested loss of beta 2 microglobulin (B2m) expression was
      correlated with increased disease susceptibility. Experimentally infected mice
      were necropsied at various time points after infection. Quantitative cultures
      were performed on lung, trachea, and nares at each time point. Tissues were
      collected for histopathology. Both genotypes had marked clearance of MP from all
      sites within the first 24 h post-infection (p.i.). There were no differences
      between KO and WT mice in the ability to clear MP from the lung, nares, or
      trachea during the first 48 h p.i. During chronic infection, there was a
      significant difference among days p.i. for number of MP isolated from the lungs,
      nares, and trachea (P<0.05). There were significant differences (P<0.05) between
      genotypes for number of MP isolated from the lung. Numbers of MP isolated from KO
      mice were greater than from WT mice at day 10 through day 28 p.i. There was no
      significant overall difference between genotypes for number of MP isolated from
      the nares or trachea. However, increased numbers of MP were isolated from the
      nares of KO mice at days 21 and 28 p.i. and from the trachea of KO mice at days 7
      and 21 p.i. During chronic infection, KO mice had increased facial scratching and
      altered respiration as well as marked weight loss compared with those of WT mice.
      The KO and WT mice differed (KO more severe) with respect to the presence and
      extent of neutrophilic exudate in the lung. Differences approached significance
      for consolidation of lung parenchyma but not for lymphoid infiltration, tending
      to be more severe in KO mice. Loss of B2m does not appear to affect clearance of
      MP during the critical first 48 h of infection but does seem to affect chronic
      infection, which may be because of the loss of CD8(+) Tc1 cells, the CD1-B2m
      complex, or both.

PMID- 15174813
TI  - The effects of anesthesia on the clinical chemistry of New Zealand White rabbits.
AB  - The effects of four anesthetics on various plasma biochemical parameters were
      investigated in the New Zealand White rabbit. Fifty animals were assigned to five
      treatment groups (n = 10 per group): control (1 ml normal saline intravenously
      [i.v.]); ketamine (10 mg/kg i.v.) with either xylazine (3 mg/kg i.v.) or diazepam
      (2 mg/kg i.v.); pentobarbitone (30 mg/kg i.v.); and thiopentone (20 mg/kg i.v.).
      Plasma cholesterol, triglycerides, lactate dehydrogenase (LDH), sodium,
      potassium, chloride, calcium and phosphorus concentrations were measured by an
      autoanalyzer. Blood samples were obtained at six time-points: before injection
      and at 10, 30, 60, and 120 min and 24 h after injection of the anesthetic or
      saline. Plasma biochemical levels were compared to control group and baseline
      (time 0) levels. Plasma cholesterol concentrations significantly increased in the
      ketamine-diazepam (P<0.01) and pentobarbitone (P<0.05) groups, whereas plasma
      triglycerides significantly increased in the ketamine-xylazine (P<0.01) and
      ketamine-diazepam (P<0.01) groups. Plasma LDH significantly increased in the
      ketamine-diazepam group (P<0.001) and decreased in the pentobarbitone group
      (P<0.01). Plasma sodium levels significantly increased after ketamine-xylazine
      (P<0.05), ketamine-diazepam (P<0.05), and thiopentone (P<0.05) administration;
      plasma potassium significantly increased after ketamine-xylazine (P<0.05) and
      decreased in the pentobarbitone group (P<0.05); plasma chloride (P<0.01) and
      phosphorus (P<0.05) significantly increased after ketamine-diazepam treatment
      whereas plasma calcium levels increased (P<0.05) after ketamine-xylazine
      injection. From the results observed so far, we concluded that plasma levels of
      some biochemical parameters significantly increased or decreased after anesthetic
      administration. Therefore, caution is required in interpreting data on plasma
      biochemical parameters from anesthetized rabbits, particularly during the
      recovery period.

PMID- 15174814
TI  - Comparison of culture results from the feces and rectum of nonhuman primates with
      diarrhea.
AB  - The reliability of culture results from fecal samples versus direct culture of
      the rectum is compared in 10 cases of diarrhea in rhesus monkeys (Macaca
      mulatta). Of the 10 comparisons, 7 were the same; of the 3 that were not,
      suboptimal growth of fecal cultures on primary media plates accounted for the
      difference. The results suggest that rectal cultures are optimum for diagnosing
      bacterial causes of diarrhea, but fecal sampling may still serve as a useful
      alternative under certain circumstances including disease surveillance,
      identifying etiologies in group-housed animals, and when weighing the physiologic
      and regulatory ramifications of restraint.

PMID- 15174815
TI  - Use of body condition scoring to manage body weight in dogs.
AB  - The purpose of this study was to evaluate the use of a body condition scoring
      system as a tool to manage body weight in our dog colony. We believe that body
      condition extremes have a pronounced potential impact on pharmaceutical
      assessment studies. We selected animals from our colony for participation in a
      dietary management program based on body condition scoring and body weight.
      Dietary amount was adjusted according to the current and desired conditions of
      the animal. Animals were re-evaluated monthly, and diet was adjusted based on the
      progress the animal was making toward its goal. Retrospective analysis of the
      data showed that approximately 3 months of enrollment in the dietary management
      program was required to optimize body condition in our dogs. Nearly twice as many
      female than male animals were enrolled in the program for weight loss, and they
      were enrolled at a significantly younger age (784.3 days versus 1063.9 days,
      respectively, P = 0.02). Nearly six times as many female animals were enrolled
      for weight loss as weight gain. Conversely, twice as many males than females were
      enrolled for weight gain, but differences in age for these animals were not
      significant. There was a significant negative correlation (-0.68, P < 0.01)
      between age and rate of loss of body condition for female dogs. Body condition
      scoring was a less sensitive indicator of progress on the program than was body
      weight, with a 6.5% to 7.2% change in body weight seen for each incremental
      change in score. It took between 2 and 4 months for the body condition score to
      change by one increment. Correlations between change in body condition and body
      weight were poor, except in the group of male animals enrolled for weight loss
      (0.84, P < 0.01). We conclude that body condition scoring is useful for dietary
      management of a dog colony within the time frame we have described, with the
      caveat that correlations between weight change and body condition score change is
      somewhat variable. Older female dogs offered particular challenges for management
      of obesity.

PMID- 15174817
TI  - Validation of the Nonin 8600V Pulse Oximeter for heart rate and oxygen saturation
      measurements in rats.
AB  - This report validates the use and limitations of the Nonin Pulse Oximeter for
      measuring heart rate and oxygen saturation in rats. Eight anesthetized Sprague
      Dawley rats were intubated and catheterized. Oxygen saturation was directly
      measured from arterial blood by using a Radiometer OSM3 Hemoximeter adjusted for
      rat blood as well as indirectly by using the Nonin Pulse Oximeter. Oxygen
      saturation was changed by varying the level of inhaled oxygen. Heart rate was
      measured in two ways: 1) by using the signal from the Nonin Pulse Oximeter and 2)
      by counting the pressure pulses from the transduced blood pressure. There was
      excellent agreement between heart rate values measured by the Nonin Pulse
      Oximeter and that measured by counting the pulses from the arterial blood
      pressure recording. The Nonin Pulse Oximeter underestimated oxygen saturations by
      about 3% to 5% compared to the Hemoximeter. Overall, the pulse oximeter reflected
      important trends in oxygen saturations, making it a useful tool for laboratory
      animal medicine.

PMID- 15174816
TI  - Clinical and hematological effects of serial phlebotomy performed on laboratory
      beagles.
AB  - We conducted a study designed to mimic a typical pharmacokinetic study to gain a
      better understanding of a dog's response to multiple, frequent blood sampling at
      15% total blood volume. Ten dogs were randomly assigned to either a control group
      having sham venipuncture performed or to a blood collection group having 1.5% of
      their body weight (approximately 15% total blood volume) removed weekly for 4
      weeks. Both groups were monitored during a 2-week recovery period immediately
      after the 4-week collection period. Parameters evaluated were clinical signs,
      body weight, and hematological and serum biochemical analytes. There were minimal
      differences in red blood cell morphology between the two groups. Statistically
      significant differences in hematocrit between the two groups occurred on several
      days, and this finding was attributed to blood withdrawal in the blood collection
      group; however, this statistical difference was not deemed to be clinically
      significant. There were no statistically significant differences in body weight,
      total protein, reticulocyte count, mean corpuscular volume, mean corpuscular
      hemoglobin, or red cell distribution width. We conclude that removing 15% blood
      volume in laboratory beagles is compatible with maintaining the health and well
      being of the dog and can be acceptable in laboratory situations when it is
      scientifically justified.

PMID- 15174818
TI  - Infection with pinworms (Syphacia obvelata) does not affect the plasma
      corticosterone concentration in male, nonpregnant female, and pregnant female
      rats.
AB  - Pinworm infections are common in rodent colonies, but the effect of pinworms on
      the host hypothalamic-pituitary-adrenal (HPA) axis had not been investigated.
      Other parasites stimulate, inhibit, or have no effect on the HPA axis of their
      hosts. We studied the effect of Syphacia obvelata infection on plasma
      corticosterone concentrations in Sprague-Dawley rats. Blood samples were taken
      from male, female, and pregnant rats during an active infection, when all 21 rats
      examined harbored worms, and after 4 weeks of treatment with piperazine and
      ivermectin, when only 2 of the 23 rats examined harbored worms. Plasma
      corticosterone concentration was measured by radioimmunoassay, and all pinworms
      in the cecum and colon were counted. Plasma corticosterone concentration did not
      differ between infected and uninfected rats in any group of rats. Pinworms were
      much more abundant in pregnant rats than in male or nonpregnant female animals.
      Corticosterone was highest in pregnant females and lowest in males. In
      conclusion, infection with S. obvelata did not affect plasma corticosterone
      concentration in male, female, or pregnant rats, suggesting that such an
      infection does not invalidate studies of the HPA axis in these animals.

PMID- 15174819
TI  - Method for hand-feeding mouse pups with nursing bottles.
AB  - The purpose of this study was to establish a hand-feeding method for the mouse by
      using nursing bottles. Five different-sized nipples were tested. The largest
      nipple used for pups from 12 to 15 days of age was 5.5 mm in diameter and 10 mm
      long, with a tip of 1.5 mm in diameter. The size of the nipple was much larger
      than that of the mothers, and bloating due to air accumulation was observed in
      the artificially-reared pups. To prevent bloat, the nipple size was increased,
      and a piece of sponge was stuffed in the nipple. Among the 30 pups fed from 1 day
      of age, 26 were weaned and 4 died. Three pups died due to aspiration of milk into
      the lung, and the remaining one died due to bloating. The development of nursing
      bottles with nipples may be potentially useful for the studies of nutrition,
      behavior, immunology, psychology, and toxicology.

PMID- 15174820
TI  - Rodent analgesiometry: the hot plate, tail flick and Von Frey hairs.

PMID- 15174821
TI  - Pathophysiology of peripheral nerve injury: a brief review.
AB  - Clinicians caring for patients with brachial plexus and other nerve injuries must
      possess a clear understanding of the peripheral nervous system's response to
      trauma. In this article, the authors briefly review peripheral nerve injury (PNI)
      types, discuss the common injury classification schemes, and describe the dynamic
      processes of degeneration and reinnervation that characterize the PNI response.

PMID- 15174822
TI  - Mechanisms of injury in operative brachial plexus lesions.
AB  - OBJECT: The authors focus on injury mechanisms involved in 1019 operative
      brachial plexus injuries (BPIs) managed between 1968 and 1998 at Louisiana State
      University Health Sciences Center (LSUHSC). METHODS: Data regarding these
      mechanisms of injury were obtained via retrospective chart reviews of patients
      who had undergone operations at LSUHSC. Five main mechanisms of injury to the
      brachial plexus occurred in the series. These included 509 stretch/contusion
      injuries (49%) with four patterns of presentation in 366 patients: 208 C5-T1
      nerve injuries; 75 C5-7, 55 C5-6 injuries; and 28 involving the C8-T1 or C7-T1
      nerves. Stretch/contusion injury was followed in frequency by gunshot wound
      (GSW), resulting in 118 injuries (12%). Most of the 293 involved plexus elements
      had some gross continuity when surgically exposed. Seventy-one lacerations
      involved the brachial plexus (7%), including 83 sharp lacerations caused by
      knives or glass; 61 blunt transections due to automobile metal, fan, and motor
      blades, chain saws, or animal bites. Nontraumatic BPIs included 160 cases of
      thoracic outlet syndrome or 16% of the total of 1019 BPIs. There were 161 tumors
      (16%) of neural sheath origin including 55 solitary neurofibromas (34%), 32
      neurofibromas associated with von Recklinghausen disease (20%), 54 schwannomas
      (34%), and 20 malignant nerve sheath tumors (20%) removed. Obstetrical BPI was
      not included in the original series; however, the current literature is reviewed
      in this paper. CONCLUSIONS: The conclusion of this study is that the brachial
      plexus can be injured by multiple mechanisms of which stretch/contusion injury is
      the most frequently encountered, followed by GSWs.

PMID- 15174823
TI  - Penetrating injuries due to gunshot wounds involving the brachial plexus.
AB  - The authors review 118 operative brachial plexus gunshot wounds (GSWs), causing
      293 element injuries that were managed over a 30-year period at Louisiana State
      University Health Sciences Center (LSUHSC). Retrospective chart reviews were
      performed. Using the LSUHSC grading system for motor sensory function, each
      element's grades were combined and averaged. Most of the 293 injured elements
      were found to have gross continuity at operation and of 202 elements with
      complete neurological loss, only 16 (8%) exhibited total disruption. Of 293
      injuries, 128 elements with complete or incomplete loss were not only in
      continuity when explored but also had positive intraoperative nerve action
      potentials (NAPs). After neurolysis, 120 of 128 elements in continuity (94%)
      improved to greater than or equal to Grade 3 function. Elements not regenerating
      early usually required repair. One hundred fifty-six of 202 completely or
      incompletely injured elements (77%) required resection and suture or graft repair
      based on intraoperative NAPs. Neurolysis achieved greater than or equal to Grade
      3 results in 42 (91%) of 46 elements with complete loss. Suture repair resulted
      in good outcomes in 14 (67%) of 21 and in 73 (54%) of 135 undergoing graft
      repairs (1 to 3.5 cm length) and presenting with complete loss. Of 91 incomplete
      elements, intraoperative NAPs were positive in 82 (90%) and 78 of 82 had good
      results. Nine had negative NAPs and six elements required suture repair. Three
      required grafts with results of greater than or equal to Grade 3 in five (83%) of
      six and two (67%) of three, respectively. Based on 118 patient results with 293
      injured elements, guidelines for the management of GSWs were established as
      described in this paper.

PMID- 15174824
TI  - Infraclavicular brachial plexus stretch injury.
AB  - OBJECT: The authors report the surgery-related results obtained in 143 patients
      with stretch-induced infraclavicular brachial plexus injuries (BPIs). The entire
      series comprised 1019 operative BPIs managed at the Louisiana State University
      Health Sciences Center between 1968 and 1998. METHODS: Infraclavicular lesions
      represented 143 (28%) of the total of 509 stretch injuries involving both the
      infra- and supraclavicular brachial plexus, of which 366 (72%) were
      supraclavicular lesions. The operative approach is thoroughly outlined, and
      common patterns and combinations of involvement of nerves peculiar to the
      infraclavicular area are presented. Overall, the results of suture and graft
      repair were favorable for the lateral and posterior cord and their outflows.
      Repair of medial cord-median nerve also yielded acceptable results. The results
      of medial cord and medial cord-ulnar nerve, however, were poor. The incidence of
      associated injuries in the infraclavicular as opposed to the supraclavicular
      area, including shoulder dislocation and fracture and humeral fractures as well
      as vascular injuries including axillary artery injury was higher. Results of a
      literature search supported the finding that vascular injuries were increased due
      to the juxtaposition of vessels among the brachial plexus elements. CONCLUSIONS:
      Thus, although less common than their supraclavicular counterpart,
      infraclavicular stretch injury lesions when they occur are technically more
      difficult to treat and are associated with a higher incidence of vascular and
      dislocation/fraction injuries. Favorable results were obtained for lateral and
      posterior cord lesions and their outflows, with acceptable outcome after medial
      cord-median nerve stretch injury repair. The results of medial cord and medial
      cord to ulnar nerve, however, were poor.

PMID- 15174825
TI  - Nerve transfers for severe brachial plexus injuries: a review.
AB  - Nerve transfer procedures are increasingly performed for repair of severe
      brachial plexus injury (BPI), in which the proximal spinal nerve roots have been
      avulsed from the spinal cord. The procedure essentially involves the coaption of
      a proximal foreign nerve to the distal denervated nerve to reinnervate the latter
      by the donated axons. Cortical plasticity appears to play an important
      physiological role in the functional recovery of the reinnervated muscles. The
      author describes the general principles governing the successful use of nerve
      transfers. One major goal of this literature review is to provide a comprehensive
      survey on the numerous intra- and extraplexal nerves that have been used in
      transfer procedures to repair the brachial plexus. Thus, an emphasis on clinical
      outcomes is provided throughout. The second major goal is to discuss the role of
      candidate nerves for transfers in the surgical management of the common severe
      brachial plexus problems encountered clinically. It is hoped that this review
      will provide the treating surgeon with an updated list, indications, and expected
      outcomes involving nerve transfer operations for severe BPIs.

PMID- 15174826
TI  - Reinnervation of the biceps in C5-7 brachial plexus avulsion injuries: results
      after distal bypass surgery.
AB  - OBJECT: The authors report various techniques, and their results, after
      performing median and ulnar nerve transfers to reanimate the biceps muscle in C5
      7 avulsion-related brachial plexus injuries (BPIs). METHODS: Forty-three adult
      patients with BPIs of the upper-middle plexus underwent reinnervation of the
      biceps muscle; neurotization of the musculocutaneous nerve was performed using
      fascicles from the ulnar nerve (39 cases) and the median nerve (four cases). The
      different techniques included sectioning, rerouting, and direct suturing of the
      entire musculocutaneous nerve (35 cases); direct reinnervation of the motor
      branches of the musculocutaneous nerve (three cases); and reinnervation using
      small grafts to the motor fascicles that enter the biceps muscle (five cases).
      Elbow flexion recovery ranged from M2 to M4, according to the patient's age and
      the level of integrity of the hand. No surgery-related failure occurred. No
      significant difference in outcome was related to any of the technical variants.
      In patients younger than age 45 years and exhibiting a normal hand function a
      score of M4 or better was always achieved. On average, reinnervation occurred 6
      months after surgery. There was no clinical evidence of donor nerve dysfunction.
      CONCLUSIONS: When accurate selection criteria are met, the results after this
      type of neurotization have proved excellent.

PMID- 15174827
TI  - Restoration of hand function and so called "breathing arm" after intraspinal
      repair of C5-T1 brachial plexus avulsion injury. Case report.
AB  - This 9-year-old boy sustained a complete right-sided C5-T1 brachial plexus
      avulsion injury in a motorcycle accident. He underwent surgery 4 weeks after the
      accident. The motor-related nerve roots in all parts of the avulsed brachial
      plexus were reconnected to the spinal cord by reimplantation of peripheral nerve
      grafts. Recovery in the proximal part of the arm started 8 to 10 months later.
      Motor function was restored throughout the arm and also in the intrinsic muscles
      of the hand by 2 years postoperatively. The initial severe excruciating pain,
      typical after nerve root avulsions, disappeared completely with motor recovery.
      The authors observed good recruitment of regenerated motor units in all parts of
      the arm, but there were cocontractions. Transcranial magnetic stimulation
      produced response in all muscles, with prolonged latency and smaller amplitude
      compared with the intact side. There was inspiration-evoked muscle activity in
      proximal arm muscles--that is, the so-called "breathing arm" phenomenon. The
      issues of nerve regeneration after intraspinal reimplantation in a young
      individual, as well as plasticity and associated pain, are discussed. To the best
      of the authors' knowledge, the present case demonstrates, for the first time,
      that spinal cord surgery can restore hand function after a complete brachial
      plexus avulsion injury.

PMID- 15174828
TI  - Gracilis free muscle transfer for restoration of function after complete brachial
      plexus avulsion.
AB  - OBJECT: The authors report the functional outcomes after functioning free muscle
      transfer (FFMT) for restoration of the upper-extremity movement after brachial
      plexus injury (BPI). METHODS: The authors conducted a retrospective review of 36
      gracilis FFMT procedures performed in 27 patients with BPI between 1990 and 2000.
      Eighteen patients underwent a single gracilis FFMT procedure for restoration of
      either elbow flexion (17 cases) or finger flexion (one case). Nine patients
      underwent a double free muscle transfer for simultaneous restoration of elbow
      flexion and wrist extension (first muscle) and finger flexion (second muscle),
      combined with direct triceps neurotization. The results obtained in 29 cases of
      FFMT in which the follow-up period was 1 year are reported. Neurotization of the
      donor muscle was performed using the musculocutaneous nerve (one case), spinal
      accessory nerve (12 cases), or multiple intercostal motor nerves (16 cases). Two
      second-stage muscle flaps failed secondary to vascular insufficiency. Mean
      electromyography-measured reinnervation time was 5 months. At a minimum follow-up
      period of 1 year, five muscles achieved less than or equal to Grade M2, eight
      Grade M3, four Grade M4, and 12 Grade M5. Transfer for combined elbow flexion and
      wrist extension compared with elbow flexion alone lowered the overall results for
      elbow flexion strength. Seventy-nine percent of the FFMTs for elbow flexion alone
      (single transfer) and 63% of similarly innervated muscles transferred for
      combined motion achieved at least Grade M4 elbow flexion strength. CONCLUSIONS:
      Functioning free muscle transfer is a viable reconstructive option for
      restoration of upper-extremity function in the setting of severe BPI. It is
      possible to achieve good to excellent outcomes in terms of muscle grades with the
      simultaneous reconstruction of two functions by one FFMT, making restoration of
      basic hand function possible. More reliable results are obtained when a single
      FFMT is performed for a single function.

PMID- 15174829
TI  - Secondary deformities of the shoulder in infants with an obstetrical brachial
      plexus lesions considered for neurosurgical treatment.
AB  - OBJECT: The authors performed a prospective study in which magnetic resonance
      (MR) imaging was conducted in 26 consecutive infants (mean age 5.6 months, range
      2.7-14.5 months) in whom recovery from an obstetric lesion of the brachial plexus
      had been inadequate in the first 3 months of life. The purpose was to identify
      early secondary deformations of the shoulder in obstetrical brachial plexus
      lesions (OBPLs). METHODS: Features of the shoulders were analyzed according to a
      standardized MR imaging protocol in patients with OBPLs. Measurements were made
      of the appearance of the glenoid, glenoid version, and the position of the
      humeral head. The appearance of the glenoid on the affected side was normal in
      only 11 shoulders. In the remainder it was convex in eight and biconcave in seven
      cases. The degree of humeral head subluxation was significantly greater (p =
      0.001) in affected shoulders than in normal shoulders (152 and 170 degrees,
      respectively). The presence of abnormal glenoid retroversion and humeral head
      subluxation increased with age: there was a statistical difference (p = 0.001)
      between infants younger than 5 months of age and those who were older.
      CONCLUSIONS: Magnetic resonance imaging demonstrates shoulder-related anatomical
      and nerve root lesion, allowing evaluation of neural, osseous, and cartilaginous
      structures in younger children.

PMID- 15174830
TI  - Delayed central nervous system superficial siderosis following brachial plexus
      avulsion injury. Report of three cases.
AB  - Chronic subarachnoid hemorrhage may cause deposition of hemosiderin on the
      leptomeninges and subpial layers of the neuraxis, leading to superficial
      siderosis (SS). The symptoms and signs of SS are progressive and fatal.
      Exploration of potential sites responsible for intrathecal bleeding and
      subsequent hemosiderin deposition may prevent disease progression. A source of
      hemorrhage including dural pathological entities, tumors, and vascular lesions
      has been previously identified in as many as 50% of patients with SS. In this
      report, the authors present three patients in whom central nervous system SS
      developed decades after brachial plexus avulsion injury. They believe that the
      traumatic dural diverticula in these cases may be a potential source of bleeding.
      A better understanding of the pathophysiology of SS is important to develop more
      suitable therapies.

PMID- 15174831
TI  - Primary brachial plexus tumors: imaging, surgical, and pathological findings in
      25 patients.
AB  - OBJECT: The authors report on the treatment of primary brachial plexus tumors in
      25 patients at the University of California, San Francisco. They compare their
      findings with those obtained in similar series. METHODS: The authors reviewed the
      electronic and medical records, radiological images, operative reports, and
      pathological findings in 25 consecutive cases of primary brachial plexus tumors.
      Cases of metastatic lesions or adjacent neoplasms extending into and involving
      the brachial plexus were excluded. At presentation patients ranged in age from 19
      to 71 years (mean 47-15 years), and neurofibromatosis was present in eight
      patients (32%). Presenting signs and symptoms included palpable mass (60%),
      numbness/paresthesias (44%), radiating pain (44%), local pain (16%), and weakness
      (12%). Duration of symptoms ranged from 2 months to 10 years. Neuroimaging
      revealed lesions ranging widely in size (volume approximately 1 to 100 ml).
      Pathological diagnoses included schwannoma (15 [60%]), neurofibroma (five [20%]),
      malignant peripheral nerve sheath tumor (four [16%]), and desmoid tumor (one
      [4%]). CONCLUSIONS: Primary tumors arising in the brachial plexus are rare.
      Careful workup, surgical technique, and attention to pathological diagnosis
      optimize management.

PMID- 15174832
TI  - Uranyl-based metallamacrocycles: tri- and tetranuclear complexes with
      (2R,3R,4S,5S)-tetrahydrofurantetracarboxylic acid.
AB  - The trinuclear [UO2L]36- and tetranuclear [UO2L]48- metallamacrocycles, obtained
      by reaction of uranyl nitrate with the rigidly angular ligand (2R,3R,4S,5S)
      tetrahydrofurantetracarboxylic acid (H4L) in a basic medium, are in equilibrium
      in methanol solution. Depending on the counterion, one or the other can be
      selectively isolated in crystal form. These rare examples of supramolecules
      incorporating actinide ions confirm the high potential and unique features of
      uranyl as a building block. Uranyl complexation through both the tri- and
      bidentate sites of the ligand is at variance with previous assumptions resulting
      from molecular modeling in nuclear waste reprocessing studies.

PMID- 15174833
TI  - High-energy intermediate or stable transition state analogue: theoretical
      perspective of the active site and mechanism of beta-phosphoglucomutase.
AB  - A recent crystal structure of beta-phosphoglucomutase from Lactococcus lactis is
      reported to contain a five-coordinate phosphorus with five oxygen ligands that is
      a high-energy reaction intermediate during the phosphoryl transfer in the
      isomerization of beta-glucose 1-phosphate to beta-glucose 6-phosphate.
      Subsequently, it has been suggested that this structure is a transition state
      analogue with a five-coordinate magnesium with two oxygen and three fluorine
      ligands. Two layer ONIOM(B3LYP:PM3MM) calculations have been performed to address
      the nature of this intermediate and the mechanism of the phosphoryl transfer.
      These calculations provide evidence that (1) the observed crystal structure is
      consistent with a five-coordinate magnesium (a stable transition state analogue),
      not a five-coordinate phosphorus (a phosphorane) as a high-energy intermediate,
      (2) the active site is stabilized by the extensive hydrogen-bonding network, (3)
      the transfer of the phosphoryl group proceeds through a moderate barrier (14 kcal
      mol-1) five-coordinate phosphorus without a stable phosphorane or metaphosphate
      intermediate, (4) this concerted transition state is directly coupled to a proton
      transfer from the oxygen of glucose to the carboxylic group of aspartate 10, and
      (5) a stable glucose 1,6-bis-phosphoglucose intermediate is formed.

PMID- 15174834
TI  - Catalytic carbonylation of beta-lactones to succinic anhydrides.
AB  - A well-defined, highly active and selective catalyst for the synthesis of
      succinic anhydrides from CO and beta-lactones is reported. At 200 psi of CO, the
      catalyst [(N,N'-bis(3,5-di-tert
      butylsalicylidene)phenylenediamino)Al(THF)2][Co(CO)4] carbonylates beta
      propiolactones to succinic anhydrides in high yield. (R)-beta-Butyrolactone is
      carbonylated to (S)-methylsuccinic anhydride with clean inversion of
      stereochemistry, while cis-2,3-dimethyl-beta-propiolactone yields exclusively
      trans-2,3-dimethylsuccinic anhydride. These data are consistent with a mechanism
      involving nucleophilic attack by [Co(CO)4]- on the beta carbon of the lactone,
      followed by CO insertion and anhydride formation.

PMID- 15174835
TI  - Design of new chiral phase-transfer catalysts with dual functions for highly
      enantioselective epoxidation of alpha,beta-unsaturated ketones.
AB  - A new chiral ammonium bromide, 1-Br, possessing diarylmethanol functionality as a
      substrate recognition site has been designed as a promising, dual-functioning
      catalyst for the highly enantioselective epoxidation of alpha,beta-unsaturated
      ketones under mild phase-transfer conditions. For instance, vigorous stirring of
      a mixture of chalcone, 1-Br (3 mol %), and 13% NaOCl in toluene at 0 degrees C
      for 24 h gave rise to epoxy chalcone quantitatively with 96% ee. A variety of
      alpha,beta-unsaturated ketones can also be epoxidized with rigorous
      stereochemical control, clearly demonstrating the effectiveness and utility of
      the present system. Further, a successful single-crystal X-ray diffraction
      analysis of 1-PF6 uncovered its distinctive three-dimensional molecular
      architecture and provided useful information for postulating the transition
      state.

PMID- 15174836
TI  - AND/OR bimolecular recognition.
AB  - cis-Decalin (2) and perylene (3) are co-enclathrated by a self-assembled M6L4
      coordination cage (1) to give 1 superset(2.3) although each of them is not
      enclathrated. This phenomenon is termed as AND bimolecular recognition because
      enclathration occurs only if 2 and 3 coexist. Cage 1 also coenclathrates azulene
      (8) and 1,4-naphthoquinone (9) to give 1 superset(8.9). In this case, 1
      superset(8)2 and 1 superset(9)2 are formed by treating 1 with 8 and 9
      individually. This case is termed as OR bimolecular recognition because
      enclathration occurs if 8 or 9 exists. Accordingly, we have shown that the self
      assembled cage 1 experiences both AND and OR bimolecular recognition.

PMID- 15174837
TI  - Unexpected relationships between structure and function in alpha,beta-peptides:
      antimicrobial foldamers with heterogeneous backbones.
AB  - We describe our first effort to design antimicrobial alpha/beta-peptides based
      upon their helical folding behavior. alpha/beta-Peptide 3 (above), designed as a
      scrambled negative control, exhibited the most favorable activity profile,
      combining high antimicrobial activity with low hemolytic activity. This finding
      suggests that design principles focused primarily on structures that adopt
      globally amphiphilic structures may exclude productive possibilities from
      evaluation.

PMID- 15174838
TI  - Nanotube molecular transporters: internalization of carbon nanotube-protein
      conjugates into Mammalian cells.
AB  - The interactions between various functionalized carbon nanotubes and several
      types of human cancer cells are explored. We have prepared modified nanotubes and
      have shown that these can be derivatized in a way that enables attachment of
      small molecules and of proteins, the latter through a novel noncovalent
      association. The functionalized carbon nanotubes enter nonadherent human cancer
      cells as well as adherent cell lines (CHO and 3T3) and by themselves are not
      toxic. While the fluoresceinated protein streptavidin (MW approximately 60 kD) by
      itself does not enter cells, it readily enters cells when complexed to a nanotube
      biotin transporter and exhibits dose-dependent cytotoxicity. The uptake pathway
      is consistent with adsorption-mediated endocytosis. The use of carbon nanotubes
      as molecular transporters could be exploited for various cargos. The
      biocompatibility and unique physical, electrical, optical, and mechanical
      properties of nanotubes provide the basis for new classes of materials for drug,
      protein, and gene delivery applications.

PMID- 15174839
TI  - Silver(I) 1,3-butadiynediide and two related silver(I) double salts containing
      the C4(2-) dianion.
AB  - Ag2C4, the second silver carbide to be fully characterized, has been synthesized
      as a light-gray powder (contaminated with metallic silver) that is explosive at
      high temperature (130 degrees C) and sensitive to mechanical shock, rather like
      the well-known prototype Ag2C2. In the pair of hydrated double salts
      Ag2C4.6AgNO3.nH2O (n = 2, 3), the nearly linear, centrosymmetric 1,3-butadiyne
      1,4-diyl dianion C42-exhibits an unprecedented mu8-coordination mode, each
      terminal being capped by four sigma-bonded silver(I) atoms with pi-interaction to
      one of them.

PMID- 15174840
TI  - Controlling synthesis of BiIn dendritic nanocrystals by solution dispersion.
AB  - In this study, we report a novel and simple solution-phase route for one
      dimensional metal nanocrystals. BiIn nanocrystals were prepared by directly
      dispersing melting BiIn alloy at an appropriate solvent. The as-obtained BiIn
      nanocrystals with a dendritic shape possess a good crystalline phase. The
      morphology of the nanocrystals can be greatly modified by changing the reaction
      parameters. This strong UV emission might arise from the quantum-confined In2O3
      particles.

PMID- 15174841
TI  - Creation of a shikimate pathway variant.
AB  - The competition between the Escherichia coli carbohydrate phosphotransferase
      system and 3-deoxy-d-arabino-heptulosonate 7-phosphate (DAHP) synthase for
      phosphoenolpyruvate limits the concentration and yield of natural products
      microbially synthesized via the shikimate pathway. To circumvent this competition
      for phosphoenolpyruvate, a shikimate pathway variant has been created. 2-Keto-3
      deoxy-6-phosphogalactonate (KDPGal) aldolases encoded by Escherichia coli dgoA
      and Klebsiella pneumoniae dgoA are subjected to directed evolution. The evolved
      KDPGal aldolase isozymes exhibit 4-8-fold higher specific activities relative to
      that for native KDPGal aldolase with respect to catalyzing the condensation of
      pyruvate and d-erythrose 4-phosphate to produce DAHP. To probe the ability of the
      created shikimate pathway variant to support microbial growth and metabolism,
      growth rates and synthesis of 3-dehydroshikimate are examined for E. coli
      constructs that lack phosphoenolpruvate-based DAHP synthase activity and rely on
      evolved KDPGal aldolase for biosynthesis of shikimate pathway intermediates and
      products.

PMID- 15174842
TI  - Isolation and characterization of a carbene derivative of La@C82.
AB  - The photochemical reaction of La@C82 with 2-adamantane-2,3-[3H]-diazirine affords
      adduct 2, La@C82(Ad), in a quantitative and highly selective manner. The
      structure of compound 2 is confirmed by ESR, MS, and UV-vis-NIR spectroscopies,
      and the first X-ray crystallographic characterization of an endohedral
      monometallofullerene derivative is reported.

PMID- 15174843
TI  - Naked deltahedral silicon clusters in solution: synthesis and characterization of
      Si9(3-) and Si5(2-).
AB  - Elusive for over 100 years, deltahedral Zintl ions of silicon are finally
      synthesized and structurally characterized. The two clusters reported here, Si93-
      and Si52-, are analogous to known clusters of the heavier members of this group:
      Ge, Sn, and Pb.

PMID- 15174844
TI  - Osmabenzenes from the reactions of HC[triple bond]CCH(OH)C[triple bond]CH with
      OsX2(PPh3)3 (X = Cl, Br).
AB  - Treatment of OsX2(PPh3)3 (X = Cl, Br) with HCCCH(OH)CCH in THF produces
      OsX2(CH=C(PPh3)CH(OH)CCH)(PPh3)2, which reacts with PPh3 to give osmabenzenes
      [Os(CHC(PPh3)CHC(PPh3)CH)X2(PPh3)2]+.

PMID- 15174845
TI  - Efficient catalysis of Nazarov cyclization using a cationic iridium complex
      possessing adjacent labile coordination sites.
AB  - The dicationic Ir(III) complex [IrMe(CO)(dppe)(DIB)](BARF)2 having adjacent
      labile sites has been found to be a very effective catalyst for promoting the
      Nazarov cyclization of aryl vinyl and divinyl ketones. Spectroscopic evidence for
      a substate-catalyst complex before cyclization is presented. The efficiency of
      the cyclization is attributed to the electrophilicity of the Ir(III) complex and
      substrate activation via chelation.

PMID- 15174846
TI  - The structure and conformational behavior of sulfonium salt glycosidase
      inhibitors in solution: a combined quantum mechanical NMR approach.
AB  - We present the conformational analysis of an inhibitor of alpha-mannosidase,
      based on a novel sulfonium salt structure (1) that mimics the mannosyl cation
      intermediate. Because of the number of possible isomeric structures for 1, as
      well as its complex molecular structure, traditional conformational analysis by
      NMR was not applicable. Instead, a single experimentally consistent structure was
      obtained from finite perturbation quantum mechanical calculations of the NMR J
      couplings at the B3LYP/6-311G** level. Using a full relaxation matrix analysis,
      we showed that the quantum-predicted NMR structure was the only isomer that was
      consistent with the experimental NOE intensities. The results illustrate the
      potential for finite perturbation calculations to be useful in the analysis of
      complex charged molecules.

PMID- 15174847
TI  - Rare example of nucleophilic substitution at vinylic carbon with inversion:
      mechanism of methyleneaziridine formation by sodium amide induced ring closure
      revisited.
AB  - Intramolecular nucleophilic substitution of the C-Br bond of (E)- and (Z)-2
      bromobut-2-enylamines by the pendant nitrogen atom leads to 2-ethyleneaziridines
      by way of stereochemical inversion at the vinylic carbon atom. The
      stereochemistry of the products is unambiguously established by X-ray
      crystallography performed on two derivatives. These cyclizations represent some
      of the first examples of substitution with inversion in unactivated vinylic
      substrates. In conjunction with additional deuterium-labeling experiments, the
      accepted mechanism for this reaction is shown to be flawed.

PMID- 15174848
TI  - Enamines from terminal epoxides and hindered lithium amides.
AB  - A new reactivity mode of lithium amides with epoxides leads to hindered enamines.
      The reaction of some of these enamines with unactivated primary and secondary
      alkyl halides is described, which expands the range of electrophiles that one can
      use in the synthesis of mono-alkylated aldehydes.

PMID- 15174850
TI  - Low-temperature synthesis of hexagonal (Wurtzite) ZnS nanocrystals.
AB  - We report a low-temperature (150 degrees C) and simple synthesis of quasi
      monodispersed and uniform hexagonal (Wurtzite) ZnS nanocrystals in ethylene
      glycol medium. The samples structures were characterized with X-ray diffraction
      technique and transmission electron microscopy. It is believed that ethylene
      glycol medium plays a key role in forming hexagonal ZnS which is a stable phase
      at high temperatures.

PMID- 15174849
TI  - Antifungal cyclopentenediones from Piper coruscans.
AB  - Coruscanones A and B, two new antifungal cyclopentenedione derivatives, have been
      isolated from Piper coruscans and their structures elucidated by spectroscopic
      and chemical methods. Coruscanone A exhibits significant antifungal activity
      against Candida albicans and its azole-resistant strains and may serve as a
      template for a new class of antifungal agents.

PMID- 15174851
TI  - Metallic mesoporous nanocomposites for electrocatalysis.
AB  - We describe the fabrication, characterization, and applications of ultrathin,
      free-standing mesoporous metal membranes uniformly decorated with catalytically
      active nanoparticles. Platinum-plated nanoporous gold leaf (Pt-NPG) made by
      confining a plating reaction to occur within the pores of dealloyed silver/gold
      leaf is 100 nm thick and contains an extremely high, uniform dispersion of 3 nm
      diameter catalytic particles. This nanostructured composite holds promise as a
      prototypical member of a new class of fuel cell electrodes, showing good
      electrocatalytic performance at low platinum loading (less than 0.05 mg cm-2),
      while also maintaining long-term stability against coarsening and aggregation of
      catalytic nanoparticles.

PMID- 15174852
TI  - Ultrasensitive ATP detection using firefly luciferase entrapped in sugar-modified
      sol-gel-derived silica.
AB  - Firefly luciferase (FL) was entrapped in sol-gel-derived silica containing
      precursors based on covalent linkage of d-gluconolactone or d-maltonolactone to
      (aminopropyl)triethoxysilane to form N-(3-triethoxysilylpropyl)gluconamide or N
      (3-triethoxysilylpropyl)maltonamide. The enzyme was active and stable in this
      material and showed catalytic constants close to those in solution. As little as
      20 amol ATP could be detected with the entrapped FL, and the entrapped enzyme
      could be used over several cycles.

PMID- 15174853
TI  - Mechanism and stereochemistry of enzymatic cyclization of 24,30-Bisnor-2,3
      oxidosqualene by recombinant beta-amyrin synthase.
AB  - Recombinant beta-amyrin synthase from Pisum sativum converted 24,30-bisnor-2,3
      oxidosqualene into a 3:1:0.2 mixture of 29,30-bisnor-beta-amyrin, 29,30
      bisnorgermanicol, and 29,30-bisnor-delta-amyrin. Further, enzyme reactions with
      [23-13C]- and [23,23-2H]-labeled isotopomers demonstrated that the cyclization
      did not proceed through formation of a lupanyl primary cation with a five
      membered E-ring, but an electrophilic addition of the tetracyclic C-18 cation on
      to the terminal double bond directly generated a thermodynamically favored
      pentacyclic secondary cation with a less-strained six-membered E-ring.
      Interestingly, the formation of the three regioisomers suggested that the absence
      of the terminal methyl groups resulted in a structural perturbation in the
      folding conformation of the E-ring of the oleanyl cation at the active site of
      the enzyme.

PMID- 15174854
TI  - Binding causes the remote [5'-3H]thymidine kinetic isotope effect in human
      thymidine phosphorylase.
AB  - The remote 5'-3H V/K kinetic isotope effect (KIE) observed in human thymidine
      phosphorylase (6.1%) is significantly larger than can be explained by the
      reaction chemistry. One hypothesis connects the 5'-3H KIE in purine nucleoside
      phosphorylase to that enzyme's SN1 transition state. The transition state of
      thymidine phosphorylase, however, is an SN2 nucleophilic displacement. Here we
      report equilibrium binding isotope effects sufficiently large to explain the
      presence of this substantial KIE in thymidine phosphorylase.

PMID- 15174855
TI  - Highly efficient addition of activated methylene compounds to alkenes catalyzed
      by gold and silver.
AB  - A highly efficient intermolecular addition of 1,3-diketones to alkenes catalyzed
      by AuCl3/AgOTf was developed. A mechanistic rationale for the reaction has been
      proposed via a alpha-C-H activation.

PMID- 15174856
TI  - Electron spin dynamics in photoexcited diamagnetic and paramagnetic corroles.
AB  - Three corroles, which differ by their cavity's core, namely, diamagnetic free
      base tris(pentafluorophenyl)corrole and its gallium(III) complex and the
      paramagnetic oxo-chromium(V) complex, were studied by steady-state and time
      resolved electron paramagnetic resonance (EPR) spectroscopy. The magnetic and
      orientational parameters of the corroles, oriented in a nematic liquid crystal,
      were determined and interpreted in terms of their structure, geometry, and
      excited states spin dynamics. It was shown that both diamagnetic corroles,
      photoexcited to their triplet states, exhibit similar EPR line shapes, which is
      characterized by a negative zero-field splitting parameter, D, whose origin is
      due to molecular "stretching". Photoexcited Cr(V)O-corrole exhibits polarized
      ground-state EPR spectrum in emission mode. This polarization stems from the
      sequence of photophysical and photochemical reactions, involving the formation of
      the trip-quartet/trip-doublet composite states and their selective quenching via
      a charge transfer state.

PMID- 15174857
TI  - The role of ligand displacement in SmII-HMPA-based reductions.
AB  - Addition of HMPA to [Sm[N(SiMe(3))(2)](2)] produces a less reactive reductant in
      contrast to addition of HMPA to SmI(2). While the [Sm[N(SiMe(3))(2)](2)]-HMPA
      combination results in a more powerful reductant based on the redox potential,
      the observed decrease in reactivity is attributed to steric hindrance caused by
      the nonlabile ligand -N(SiMe(3))(2) and HMPA around the Sm metal. The importance
      of ligand displacement (exchange) in Sm(II)-HMPA-based reactions and insight into
      the mechanism of [Sm[N(SiMe(3))(2)](2)]-HMPA and SmI(2)-HMPA reductions are
      presented.

PMID- 15174858
TI  - Ruthenium-catalyzed cyclization of epoxide with a tethered alkyne: formation of
      ketene intermediates via oxygen transfer from epoxides to terminal alkynes.
AB  - Treatment of (o-ethynyl)phenyl epoxides with TpRuPPh(3)(CH(3)CN)(2)PF(6) (10 mol
      %) in hot toluene (100 degrees C, 3-6 h) gave 2-naphthols or 1-alkylidene-2
      indanones very selectively with isolated yields exceeding 72%, depending on the
      nature of the epoxide substituents. Surprisingly, the reaction intermediate
      proved to be a ruthenium-pi-ketene species that can be trapped efficiently by
      alcohol to give an ester compound. This phenomenon indicates a novel oxygen
      transfer from epoxide to its terminal alkyne catalyzed by a ruthenium complex. A
      plausible mechanism is proposed on the basis of reaction products and the
      deuterium-labeling experiment. The 2-naphthol products are thought to derive from
      6-endo-dig cyclization of (o-alkenyl)phenyl ketene intermediates, whereas 1
      alkylidene-2-indanones are given from the 5-endo-dig cyclization pathway.

PMID- 15174859
TI  - Solution structure of xDNA: a paired genetic helix with increased diameter.
AB  - We describe the structure in aqueous solution of an extended-size DNA-like duplex
      with base pairs that are approximately 2.4 A longer than those of DNA. Deoxy-lin
      benzoadenosine (dxA) was employed as a dA analogue to form hydrogen-bonded base
      pairs with dT. The 10mer self-complementary extended oligodeoxynucleotide 5'
      d(xATxAxATxATTxAT) forms a much more thermodynamically stable duplex than the
      corresponding DNA sequence, 5'-d(ATAATATTAT). NMR studies show that this extended
      DNA (xDNA) retains many features of natural B-form DNA, but with a few structural
      alterations due to its increased helical diameter. The results give insight into
      the structural plasticity of the natural DNA backbone and lend insight into the
      evolutionary origins of the natural base pairs. Finally, this structural study
      confirms the hypothesis that extended nucleobase analogues can form stable DNA
      like structures, suggesting that alternative genetic systems might be viable for
      storage and transfer of genetic information.

PMID- 15174860
TI  - Structural mimicry of retroviral tat proteins by constrained beta-hairpin
      peptidomimetics: ligands with high affinity and selectivity for viral TAR RNA
      regulatory elements.
AB  - An approach is described to the design of beta-hairpin peptidomimetic ligands for
      bovine immunodeficiency virus (BIV) Tat protein, which inhibit binding to its
      transactivator response element (TAR) RNA. A library of peptidomimetics was
      derived by grafting onto a hairpin-inducing d-Pro-l-Pro template sequences
      related to the RNA recognition element in Tat. One hairpin mimetic was identified
      that binds tightly (K(d) approximately 150 nM) to BIV TAR, and another that binds
      also to HIV-1 TAR RNA (K(d) approximately 1-2 microM). (In the same assay, the
      wild-type BIV Tat(65-81) peptide binds to BIV TAR with K(d) approximately 50 nM.)
      The high-affinity BIV-Tat mimetic was shown to adopt a stable beta-hairpin
      conformation in free solution by NMR methods. Amino acid substitutions in this
      mimetic were shown to impact on the hairpin structure and to disrupt binding to
      the RNA. This family of conformationally constrained peptidomimetics affords
      insights into the structural requirements for binding to TAR RNA and provides a
      basis for the design of new ligands with increased inhibitory activity and
      specificity to both BIV and HIV TAR RNAs.

PMID- 15174861
TI  - Multiple states of the Tyr318Leu mutant of dihydroorotate dehydrogenase revealed
      by single-molecule kinetics.
AB  - Dihydroorotate dehydrogenase (DHOD) from Escherichia coli is a monomeric membrane
      associated flavoprotein that catalyzes the oxidation of dihydroorotate to
      orotate. By using confocal fluorescence spectroscopy on the highly fluorescent
      Tyr318Leu DHOD mutant, we studied the catalytic turnover of single enzyme
      molecules through the characteristic on-off fluorescence signal, which
      corresponds to flavin mononucleotide (FMN) interconverting between the oxidized
      and reduced states during turnover. Our single-molecule data provide evidence of
      a distinct static heterogeneity in the enzymatic activity, with some molecules
      going through the on-off cycles 5-fold faster than others, however, there is no
      detectable dynamic disorder in DHOD turnover. When 0.1% reduced Triton X-100, a
      detergent that more closely simulates the natural membrane environment, is added,
      our data suggest the degree of static molecular heterogeneity is reduced. The
      observation of static heterogeneity suggests that the enzyme, which associates
      with the membrane in vivo, is present in distinct conformations that result in
      different catalytic efficiencies. The alternate conformations are most likely the
      result of the loss of van der Waals or other interactions between tyrosine 318
      and FMN in the catalytic site with the mutation of Tyr318Leu, which disrupts the
      native structure of wild-type DHOD.

PMID- 15174862
TI  - Efforts to expand the genetic alphabet: identification of a replicable unnatural
      DNA self-pair.
AB  - Six unnatural nucleotides featuring fluorine-substituted phenyl nucleobase
      analogues have been synthesized, incorporated into DNA, and characterized in
      terms of the structure and replication properties of the self-pairs they form.
      Each unnatural self-pair is accommodated in B-form DNA without detectable
      structural perturbation, and all are thermally stable and selective to roughly
      the same degree. Furthermore, the efficiency of polymerase-mediated mispair
      synthesis is similar for each unnatural nucleotide in the template. In contrast,
      the efficiency of polymerase-mediated self-pair extension is highly dependent on
      the specific fluorine substitution pattern. The most promising unnatural base
      pair candidate of this series is the 3-fluorobenzene self-pair, which is
      replicated with reasonable efficiency and selectivity.

PMID- 15174863
TI  - The hydrolysis of urea and the proficiency of urease.
AB  - We present the results of a computational study of the solution phase
      decomposition of urea, which provides insight into probable reaction pathways for
      the urease-catalyzed reaction. Calculations, which were used to derive
      thermodynamic parameters that were further used for a kinetic analysis, have been
      done at the solvent-corrected MP2/6-311++G** level. Both elimination and
      hydrolytic pathways have been considered. Elimination is favored for the solution
      phase reaction, which proceeds by H-bond coordination of a water molecule to the
      amine nitrogen atoms. The coordination of one water molecule greatly facilitates
      the reaction by allowing it to proceed through a cyclic six-member transition
      state. Aspects of the water-urea H-bond interactions have also provided insights
      into critical aspects of the hydrogen bond pattern in the urease active site. On
      the basis of a kinetic analysis, we have estimated the proficiency of urease and
      have predicted that it is the most proficient enzyme identified to date.

PMID- 15174864
TI  - Mechanistic studies of the isomerization of peroxynitrite to nitrate catalyzed by
      distal histidine metmyoglobin mutants.
AB  - Hemoproteins are known to react with the strong nitrating and oxidizing agent
      peroxynitrite according to different mechanisms. In this article, we show that
      the iron(iii) forms of the sperm whale myoglobin (sw Mb) mutants H64A, H64D,
      H64L, F43W/H64L, and H64Y/H93G catalyze the isomerization of peroxynitrite to
      nitrate. The two most efficient catalysts are H64A (k(cat) = (5.8 +/- 0.1) x
      10(6) M(-1) s(-1), at pH 7.5 and 20 degrees C) and H64D metMb (k(cat) = (4.8 +/-
      0.1) x 10(6) M(-1) s(-1), at pH 7.5 and 20 degrees C). The pH dependence of the
      values of k(cat) shows that HOONO is the species which reacts with the heme. In
      the presence of physiologically relevant concentrations of CO(2) (1.2 mM), the
      decay of peroxynitrite is accelerated by these metMb mutants via the concurring
      reaction of HOONO with their iron(iii) centers. Studies in the presence of free
      added tyrosine show that the metMb mutants prevent peroxynitrite-mediated
      nitration. The efficiency of the different sw metMb mutants correlates with the
      value of k(cat). Finally, we show that sw WT-metMb is nitrated to a larger extent
      than horse heart metMb, a result that suggests that the additional Tyr151 is a
      site of preferential nitration. Again, the extent of nitration of the tyrosine
      residues of the metMb mutants correlates with the values of k(cat).

PMID- 15174866
TI  - Structure-selectivity relationships and structure for a peptide-based
      enantioselective acylation catalyst.
AB  - Studies of analogues of a recently discovered enantioselective peptide-based
      catalyst for enantioselective acylation reactions have led to mechanistic insight
      and improved catalysts. Systematic replacement of each residue within the parent
      peptide with alanine of the appropriate stereochemistry allows for an unambiguous
      evaluation of the kinetic role of each amino acid side chain in the catalyst. The
      results of the alanine scan support a bifunctional catalysis mechanism at the
      heart of the origin of enantioselectivity. In addition, an experimentally derived
      solution structure of the peptide-based catalyst is presented that supports a key
      role for each residue within the peptide chain.

PMID- 15174865
TI  - Effect of side chains on turns and helices in peptides of beta3-aminoxy acids.
AB  - We have investigated, using NMR, IR, and CD spectroscopy and X-ray
      crystallography, the conformational properties of peptides 1-10 of beta(3)
      aminoxy acids (NH(2)OCHRCH(2)COOH) having different side chains on the beta
      carbon atom (e.g., R = Me, Et, COOBn, CH(2)CH(2)CH=CH(2), i-Bu, i-Pr). The beta N
      O turns and beta N-O helices that involve a nine-membered-ring intramolecular
      hydrogen bond between NH(i)(+2) and CO(i), which have been found previously in
      peptides of beta(2,2)-aminoxy acids (NH(2)OCH(2)CMe(2)COOH), are also present in
      those beta(3)-aminoxy peptides. X-ray crystal structures and NMR spectral
      analysis reveal that, in the beta N-O turns and beta N-O helices induced by
      beta(3)-aminoxy acids, the N-O bond could be either anti or gauche to the
      C(alpha)-C(beta) bond depending on the size of the side chain; in contrast, only
      the anti conformation was found in beta(2,2)-aminoxy peptides. Both diamide 1 and
      triamide 9 exist in different conformations in solution and in the solid state:
      parallel sheet structures in the solid state and predominantly beta N-O turn and
      beta N-O helix conformations in nonpolar solvents. Theoretical studies on a
      series of model diamides rationalize very well the experimentally observed
      conformational features of these beta(3)-aminoxy peptides.

PMID- 15174867
TI  - Organic spin clusters. A dendritic-macrocyclic poly(arylmethyl) polyradical with
      very high spin of S = 10 and its derivatives: synthesis, magnetic studies, and
      small-angle neutron scattering.
AB  - Synthesis and characterization of organic spin clusters, high-spin
      poly(arylmethyl) polyradicals with 24 and 8 triarylmethyls, are described.
      Polyether precursors to the polyradicals are prepared via modular, multistep
      syntheses, culminating in Negishi cross-couplings between four monofunctional
      branch (dendritic) modules and the tetrafunctional calix[4]arene-based
      macrocyclic core. The corresponding carbopolyanions are prepared and oxidized to
      polyradicals in tetrahydrofuran-d(8). The measured values of S, from numerical
      fits of magnetization vs magnetic field data to Brillouin functions at low
      temperatures (T = 1.8-5 K), are S = 10 and S = 3.6-3.8 for polyradicals with 24
      and 8 triarylmethyls, respectively. Magnetizations at saturation (M(sat))
      indicate that 60-80% of unpaired electrons are present at T = 1.8-5 K. Low
      resolution shape reconstructions from the small-angle neutron scattering (SANS)
      data indicate that both the polyradical with 24 triarylmethyls and its
      derivatives have dumbbell-like shapes with overall dimensions 2 x 3 x 4 nm, in
      agreement with the molecular shapes of the lowest energy conformations obtained
      from Monte Carlo conformational searches. On the basis of these shapes, the size
      of the magnetic anisotropy barrier in the polyradical, originating in magnetic
      shape anisotropy, is estimated to be in the milliKelvin range, consistent with
      the observed paramagnetic behavior at T >or= 1.8 K. For macromolecular
      polyradicals, with the elongated shape and the spin density similar to the
      polyradical with 24 triarylmethyls, it is predicted that the values of S on the
      order of 1000 or higher may be required for "single-molecule-magnet" behavior,
      i.e., superparamagnetic blocking (via coherent rotation of magnetization) at the
      readily accessible temperatures T > 2 K.

PMID- 15174868
TI  - Ladder-type pentaphenylenes and their polymers: efficient blue-light emitters and
      electron-accepting materials via a common intermediate.
AB  - A new route to ladder-type pentaphenylenes has been developed in which both good
      hole-accepting p-type and electron-accepting n-type materials can be prepared
      from a common intermediate. This key intermediate is a pentaphenylene diester 5
      obtained in high yield by Suzuki coupling of 2 equiv of fluorene boronates with
      2,5-dibromoterephthalate. Addition of aryllithium followed by ring closure with
      boron trifluoride produced a blue-emitting ladder-type pentaphenylene.
      Bromination followed by reductive polymerization with nickel(0) gave new high
      molecular mass polymers, which show efficient blue emission with a very small
      Stokes shift. These polymers bridge the gap in emission between polyfluorenes and
      fully ladder-type polyphenylenes. An alternative ring closure of the
      dibromopentaphenylene diester 14 with acid made a diketone that is a good
      electron-accepting material, as it displays a reversible two-electron reduction.
      The reduction onset potential of -0.875 V against Ag/Ag(+) corresponds to a
      lowest unoccupied molecular orbital (LUMO) energy level of 3.53 eV, comparable to
      the work function of magnesium, suggesting that this unit could be used to
      greatly increase the injection of electrons into polymers containing it in a
      light-emitting diode (LED) or solar cell. A red-emitting material was prepared by
      Suzuki coupling of the dibromopentaphenylene 10b with a perylene dye, thus
      offering the prospect of tuning the emission from pentaphenylene materials over
      the whole visible range by attachment of suitable dyes. Unoptimized single-layer
      organic LEDs that used 11b showed stable pure-blue emission with brightnesses of
      over 200 cd/m(2) at 7 V, with moderate efficiencies.

PMID- 15174869
TI  - A model for double asymmetric induction in the stereocontrolled reduction of
      glycosyl alpha-ketoesters with oxazaborolidines.
AB  - Experimental diastereoselectivities for the stereocontrolled reduction of
      glycosyl alpha-ketoesters into the corresponding alpha-hydroxyesters have
      recently been reported with unexpected results. The process is catalyzed by a
      chiral oxazaborolidine derivative (the so-called CBS catalyst) and represents the
      key step in the synthesis of glycosyl alpha-amino acids synthons, a class of
      compounds that allow preparation of natural glycopeptides analogues exhibiting
      potential therapeutic relevance. Good to very good diastereomeric excesses have
      been obtained for a series of reactions with different glucidic derivatives, but
      surprisingly, the major product obtained does not correspond to that predicted by
      using Corey's model. In the present work, we carry out a theoretical
      investigation of these reactions at the density functional level. Separated
      effects from the catalyst and from the glucidic derivative have been computed to
      rationalize the observed diastereoselectivities and the double asymmetric
      induction.

PMID- 15174870
TI  - Anion-directed self-assembly of coordination polymer into tunable secondary
      structure.
AB  - A bent-shaped bipyridine ligand containing a dendritic aliphatic side chain has
      been synthesized as a ligand and complexed with silver ion through a self
      assembling process. The resulting complexes were observed to self-assemble into
      supramolecular structures that differ significantly as a function of the
      counteranion size in the solid state, as confirmed by 1-D and 2-D X-ray
      diffraction experiments. The secondary structure of a cationic coordination chain
      appears to be dependent on the size of the counteranion. As the size of anion
      increases, the secondary structure of the coordination chain changes, from a
      helical chain, via a dimeric cycle, to a zigzag chain in the solid state.
      Interestingly, dilute solutions of the complexes exhibiting a columnar structure
      in polar solvents undergo spontaneous gelation and the resulting gels display a
      significant Cotton effect in the chromophore of the aromatic unit. These results
      represent a significant example that small variation in the anion size can
      provide a useful strategy to manipulate the secondary structure of linear chain
      and thereby solid-state supramolecular structure.

PMID- 15174871
TI  - Luminescent organoboron quinolate polymers.
AB  - The synthesis of well-defined luminescent organoboron polymers via a novel three
      step procedure starting from silylated polystyrene is reported. Highly selective
      borylation of poly(4-trimethylsilylstyrene) (PS-Si), followed by replacement of
      the bromine substituents in poly(4-dibromoborylstyrene) (PS-BBr) with substituted
      thienyl groups (R = H, 3-hexyl, 5-hexyl), and final introduction of the 8
      hydroxyquinolato moiety yields a series of new organoboron quinolate polymers in
      67-83% isolated yield. The hexyl-substituted polymers are highly soluble and
      solution-processable yielding thin films that efficiently emit light at 513-514
      nm upon excitation at 395 nm.

PMID- 15174872
TI  - Colloidal lithographic nanopatterning via reactive ion etching.
AB  - We report here a novel colloidal lithographic approach to the fabrication of
      nonspherical colloidal particle arrays with a long-range order by selective
      reactive ion etching (RIE) of multilayered spherical colloidal particles. First,
      layered colloidal crystals with different crystal structures (or orientations)
      were self-organized onto substrates. Then, during the RIE, the upper layer in the
      colloidal multilayer acted as a mask for the lower layer and the resulting
      anisotropic etching created nonspherical particle arrays and new patterns. The
      new patterns have shapes that are different from the original as a result of the
      relative shadowing of the RIE process by the top layer and the lower layers. The
      shape and size of the particles and patterns were dependent on the crystal
      orientation relative to the etchant flow, the number of colloidal layers, and the
      RIE conditions. The various colloidal patterns can be used as masks for two
      dimensional (2-D) nanopatterns. In addition, the resulting nonspherical particles
      can be used as novel building blocks for colloidal photonic crystals.

PMID- 15174873
TI  - Pincer complex-catalyzed allylation of aldehyde and imine substrates via
      nucleophilic eta1-allyl palladium intermediates.
AB  - Electrophilic allylic substitution of allylstannanes with aldehyde and imine
      substrates could be achieved by employment of palladium pincer complex catalysts.
      It was found that the catalytic activity of the pincer complexes is highly
      dependent on the ligand effects. The best results were obtained by employment of
      PCP pincer complexes with weakly coordinating counterions. In contrast to
      previous applications for electrophilic allylic substitutions via
      bisallylpalladium complexes, the presented reactions involve monoallylpalladium
      intermediates. Thus, employment of pincer complex catalysts extends the synthetic
      scope of the palladium-catalyzed allylic substitution reactions. Moreover, use of
      these catalysts eliminates the side reactions occurring in transformations via
      bisallylpalladium intermediates. The key intermediate of the electrophilic
      substitution reaction was observed by (1)H NMR spectroscopy. This intermediate
      was characterized as an eta(1)-allyl-coordinated pincer complex. Density
      functional theory (DFT) modeling shows that the electrophilic attack can be
      accomplished with a low activation barrier at the gamma-position of the eta(1)
      allyl moiety. According to the DFT calculations, this reaction takes place via a
      six-membered cyclic transition-state (TS) structure, in which the tridentate
      coordination state of the pincer ligand is preserved. The stereoselectivity of
      the reaction could be explained on the basis of the six-membered cyclic TS model.

PMID- 15174874
TI  - Evidence for epitaxial arrangement and high conformational order of an organic
      monolayer on Si(111) by sum frequency generation spectroscopy.
AB  - The structure of an octadecyl monolayer formed on a hydrogen-terminated Si(111)
      surface in neat octadecene was studied by infrared-visible sum frequency
      generation (SFG) spectroscopy. The SFG spectra in the CH vibration region were
      dominated by peaks corresponding to those of the methyl group, confirming that
      the monolayer is essentially in the all-trans conformation. The shapes of the
      spectra were strongly dependent on the azimuthal angle, and the strength of the
      asymmetric vibration mode obtained from the theoretical fitting shows threefold
      symmetry with respect to the azimuthal angle, suggesting the epitaxial
      arrangement of the monolayer with the Si(111) substrate. The orientation angle of
      the methyl group estimated from SFG anisotropy was in good agreement with the
      theoretical prediction.

PMID- 15174875
TI  - Solution-processible conjugated electrophosphorescent polymers.
AB  - We report the synthesis and photophysical study of a series of solution
      processible phosphorescent iridium complexes. These comprise bis-cyclometalated
      iridium units [Ir(ppy)(2)(acac)] or [Ir(btp)(2)(acac)] where ppy is 2
      phenylpyridinato, btp is 2-(2'-benzo[b]thienyl)pyridinato, and acac is
      acetylacetonate. The iridium units are covalently attached to and in conjugation
      with oligo(9,9-dioctylfluorenyl-2,7-diyl) [(FO)(n)] to form complexes [Ir(ppy
      (FO)(n))(2)(acac)] or [Ir(btp-(FO)(n))(2)(acac)], where the number of fluorene
      units, n, is 1, 2, 3, approximately 10, approximately 20, approximately 30, or
      approximately 40. All the complexes exhibit emission from a mixed triplet state
      in both photoluminescence and electroluminescence, with efficient quenching of
      the fluorene singlet emission. Short-chain complexes, 11-13, [Ir(ppy-(FO)(n)
      FH)(2)(acac)] where n = 0, 1, or 2, show green light emission, red-shifted
      through the FO attachment by about 70 meV, but for longer chains there is
      quenching because of the lower energy triplet state associated with polyfluorene.
      In contrast, polymer complexes 18-21 [Ir(btp-(FO)(n))(2)(acac)] where n is 5-40
      have better triplet energy level matching and can be used to provide efficient
      red phosphorescent polymer light-emitting diodes, with a red shift due to the
      fluorene attachment of about 50 meV. We contrast this small (50-70 meV) and short
      range modification of the triplet energies through extended conjugation, with the
      much more substantial evolution of the pi-pi* singlet transitions, which saturate
      at about n = 10. These covalently bound materials show improvements in efficiency
      over simple blends and will form the basis of future investigations into energy
      transfer processes occurring in light-emitting diodes.

PMID- 15174876
TI  - Monocyclopentadienylhydride derivatives of ruthenium: stereoselective proton
      transfer and proton-hydride exchange in an extremely short dihydrogen bond.
AB  - Diastereomerically pure complexes of formula CpRuCl(PP) and CpRuH(PP) with chiral
      ferrocenyl diphosphines were prepared and the selectivity of proton-transfer
      processes over the monohydride compounds with different acids was studied. With 1
      equiv of HBF(4) the cis-dihydrogen and trans-dihydride complexes were formed
      while with 3 equiv of CF(3)CO(2)H the trans-dihydride derivative was the only
      product. However, the use of 1 equiv of CF(3)CO(2)H led to a dihydrogen bonded
      complex with an extremely short RuH...HO(2)CF(3) interaction that exhibits proton
      hydride exchange. Using the labeled acid CF(3)CO(2)D, a stereoselective
      transference of the deuteron was demonstrated that implies the previous
      epimerization of the monohydride and the subsequent attack of the acid in the
      position previously occupied by the hydride.

PMID- 15174877
TI  - NMR analysis of surfaces and interfaces in 2-nm CdSe.
AB  - Solid-state NMR analysis on wurtzite 2-nm hexadecylamine-capped CdSe nanocrystals
      (CdSe-HDA) provides evidence of discrete nanoparticle reconstruction within the
      Se sublattice of the nanomaterial. The cadmium and selenium atoms are probed with
      (1)H-(113)Cd and (1)H-(77)Se cross-polarization magic angle spinning (MAS)
      experiments, which demonstrate five ordered selenium sites in the nanoparticle
      that can be assigned to contributions arising from different surface sites and a
      selenium site one layer down from the surface. Intriguingly, in these materials
      both HDA and thiophenol are observed to selectively bind to specific sites on the
      nanoparticle surface. 2D heteronuclear chemical shift correlation (HETCOR)
      experiments provide evidence for thiophenol selectively binding at surface
      vacancies. Analysis of the NMR provides a model of a 2-nm CdSe-HDA molecular
      surface.

PMID- 15174878
TI  - Characterization of complicated new polymorphs of chlorothalonil by X-ray
      diffraction and computer crystal structure prediction.
AB  - A simultaneous experimental and computational search for polymorphs of
      chlorothalonil (2,4,5,6-tetrachloro-1,3-benzenedicarbonitrile) has been
      conducted, leading to the first characterization of forms 2 and 3. The crystal
      structure prediction study, using a specifically developed anisotropic atom-atom
      potential for chlorothalonil, gave as the global minimum in the lattice energy a
      structure that was readily refined against powder diffraction data to the known
      form 1 (P2(1)/a). The structure of form 2 was solved and refined from powder
      diffraction data, giving a disordered structure in the Rm (166) space group (Z =
      3). It could also be refined against a P1 ordered model, starting from a low
      energy hypothetical sheet structure found in the computational search. This shows
      that the disorder could be associated with the stacking of ordered sheets. The
      disordered structure for form 2 was later confirmed by single-crystal X-ray
      diffraction. The structure of form 3, determined from single-crystal diffraction,
      contains three independent molecules in the asymmetric unit in P2(1) (4) (Z = 6).
      Powder diffraction showed that this single-herringbone structure was similar to
      two low-energy structures found in the search. Further analysis confirmed that
      form 3 has a similar lattice energy and contains elements from both these
      predicted structures, which can be considered as good approximations to the form
      3 structure.

PMID- 15174879
TI  - Molecular and electronic structures by design: tuning symmetrical and
      unsymmetrical linear trichromium chains.
AB  - The preparation, properties, and crystal structures of 12 trichromium extended
      metal atom chain (EMAC) compounds of the type Cr(3)(L)(4)X(2) (L = equatorial
      ligands dipyridylamide (dpa) or di-4,4'-ethyl-2,2'-pyridylamide (depa), and X =
      axial ligands, e.g., halide or pseudohalide ions) with large variations in metal
      metal distances are reported here. These complexes, which belong to a broad class
      of fundamentally interesting trinuclear molecules over which the electrons may or
      may not be delocalized, pose significant theoretical and experimental challenges
      which are dealt with in this report. Complexes with strongly donating axial or
      equatorial ligands tend to favor a symmetrical (D(4)) molecular structure, while
      more weakly donating ligands give rise to unsymmetrical (C(4)) structures; the
      physical properties of these two classes of compounds are discussed fully, and
      important comparisons with a reported DFT model of the electronic structures of
      the compounds are made.

PMID- 15174880
TI  - Polyaniline nanowires on Si surfaces fabricated with DNA templates.
AB  - It is essential to put individual, free-standing nanowires onto insulating
      substrates and integrate them to useful devices. Here we report a strategy for
      fabrication of conducting polymer nanowires on thermally oxidized Si surfaces by
      use of DNA as templates. The direct use of stretched and immobilized DNA strands
      as templates avoids the agglomeration of DNA caused by shielding of charges on
      DNA when polyaniline/DNA complexes formed in solution. Most importantly, the
      oriented DNA strands immobilized on the Si surface predetermine the position and
      the orientation of the nanowires. The approach described here is the first step
      toward uniting the programmable-assembly ability of DNA with the unique
      electronic properties of conducting polymers for high-density functional
      nanodevices. The conductivity of the nanowires is very sensitive to the proton
      doping-undoping process, suggesting that the nanowires hold great promise for
      sensitive chemical sensor applications.

PMID- 15174881
TI  - Molecular rectification: self-assembled monolayers in which donor-(pi-bridge)
      acceptor moieties are centrally located and symmetrically coupled to both gold
      electrodes.
AB  - Self-assembled monolayers (SAMs) obtained from 1-(10-acetylsulfanyldecyl)-4-[2-(4
      dimethylaminophenyl)vinyl]quinolinium iodide exhibit asymmetric current-voltage
      (I-V) characteristics. The rectification may be reversibly switched: it is
      suppressed when the film is exposed to HCl vapor, the intramolecular charge
      transfer axis being inhibited by protonation, but restored when exposed to NH(3).
      The behavior is intrinsic to the donor-(pi-bridge)-acceptor moiety, and ambiguity
      in the assignment has been excluded by matching the alkyl tails on the substrate
      and contacting STM tip to locate the chromophore midway between the electrodes:
      Au-S-C(10)H(21)//D-pi-A-C(10)H(20)-S-Au. Films contacted by gold tips exhibit
      rectification ratios of ca. 18 at +/-1 V, whereas those contacted by
      pentanethiolate (Au-S-C(5)H(11))- and decanethiolate (Au-S-C(10)H(21))-coated
      tips have corresponding ratios of ca. 11 and 5, respectively. The I-V curves are
      different, but when adjusted for thickness the current versus electric field
      dependence is indistinguishable. Seven dyes are reported: SAMs with sterically
      hindered D-pi-A moieties, in which the donor and acceptor are twisted out of
      plane, exhibit rectification, whereas those that are planar or have a weak donor
      acceptor combination do not.

PMID- 15174882
TI  - Role of Asp102 in the catalytic relay system of serine proteases: a theoretical
      study.
AB  - The role of Asp102 in the catalytic relay system of serine proteases is studied
      theoretically by calculating the free energy profiles of the single proton
      transfer reaction by the Asn102 mutant trypsin and the concerted double proton
      transfer reaction (so-called the charge-relay mechanism) of the wild-type
      trypsin. For each reaction, the reaction free energy profile of the rate
      determining step (the tetrahedral intermediate formation step) is calculated by
      using ab initio QM/MM electronic structure calculations combined with molecular
      dynamics-free energy perturbation method. In the mutant reaction, the free energy
      monotonically increases along the reaction path. The rate-determining step of the
      mutant reaction is the formation of tetrahedral intermediate complex, not the
      base (His57) abstraction of the proton from Ser195. In contrast to the single
      proton-transfer reaction of the wild-type, MD simulations of the enzyme-substrate
      complex show that the catalytically favorable alignment of the relay system (the
      hydrogen bonding network between the mutant triad, His57, Asn102, and Ser195) is
      rarely observed even in the presence of a substrate at the active site. In the
      double proton-transfer reaction, the energy barrier is observed at the proton
      abstraction step, which corresponds to the rate-determining step of the single
      proton-transfer reaction of the wild-type. Although both reaction profiles show
      an increase of the activation barrier by several kcals/mol, these increases have
      different energetic origins: a large energetic loss of the electrostatic
      stabilization between His57 and Asn102 in the mutant reaction, while the lack of
      stabilization by the protein environment in the double proton-transfer reaction.
      Comparing the present results with the single proton transfer of the wild-type,
      Asp102 is proven to play two important roles in the catalytic process. One is to
      stabilize the protonated His57, or ionic intermediate, formed during the
      acylation, and the other is to fix the configuration around the active site,
      which is favorable to promote the catalytic process. These two factors are
      closely related to each other and are indispensable for the efficient catalysis.
      Also the present calculations suggest the importance of the remote site
      interaction between His57 and Val213-Ser214 at the catalytic transition state.

PMID- 15174883
TI  - Methyl groups as probes for proteins and complexes in in-cell NMR experiments.
AB  - Studying protein components of large intracellular complexes by in-cell NMR has
      so far been impossible because the backbone resonances are unobservable due to
      their slow tumbling rates. We describe a methodology that overcomes this
      difficulty through selective labeling of methyl groups, which possess more
      favorable relaxation behavior. Comparison of different in-cell labeling schemes
      with three different proteins, calmodulin, NmerA, and FKBP, shows that selective
      labeling with [(13)C]methyl groups on methionine and alanine provides excellent
      sensitivity with low background levels at very low costs.

PMID- 15174884
TI  - Electron transport in two-dimensional arrays of gold nanocrystals investigated by
      scanning electrochemical microscopy.
AB  - This article reports the use of the scanning electrochemical microscope (SECM) to
      investigate the electronic properties of Langmuir monolayers of alkane thiol
      protected gold nanocrystals (NCs). A substantial increase in monolayer
      conductivity upon mechanical compression of the Au NC monolayer is reported for
      the first time. This may be the room temperature signature of the insulator to
      metal transition previously reported for comparable silver NC monolayers. Factors
      influencing the conductivity of the monolayer NC array are discussed.

PMID- 15174885
TI  - Enzyme-catalyzed bio-pumping of electrons into au-nanoparticles: a surface
      plasmon resonance and electrochemical study.
AB  - The enzyme glucose oxidase (GOx) is reconstituted on a flavin adenin dinucleotide
      (FAD, 1) cofactor-functionalized Au-nanoparticle (Au-NP), 1.4 nm, and the GOx/Au
      NP hybrid is linked to a bulk Au-electrode by a short dithiol, 1,4-benzenedithiol
      (2), or a long dithiol, 1,9-nonanedithiol (3), monolayer. The reconstituted
      GOx/Au-NP hybrid system exhibits electrical communication between the enzyme
      redox cofactor and the Au-NP core. Because the thiol monolayers provide a barrier
      for electron tunneling, the electron transfer occurring upon the biocatalytic
      oxidation of glucose results in the Au-NPs charging. The charging of the Au-NPs
      alters the plasma frequency and the dielectric constant of the Au-NPs, thus
      leading to the changes of the dielectric constant of the interface. These are
      reflected in pronounced shifts of the plasmon angle, theta(P), in the surface
      plasmon resonance (SPR) spectra. As the biocatalytic charging phenomenon is
      controlled by the concentration of glucose, the changes in the theta(P) values
      correlate with the concentration of glucose. The biocatalytic charging process is
      characterized by following the differential capacitance of the GOx/Au-NP
      interface and by monitoring the potential generated on the bulk Au-electrode. The
      charging of the GOx/Au-NPs is also accomplished in the absence of glucose by the
      application of an external potential on the electrode, that resulted in similar
      plasmon angle shifts. The results allowed us to estimate the number of electrons
      stored per Au-NP at variable concentrations of glucose in the presence of the two
      different thiol linkers.

PMID- 15174886
TI  - Electronic control of the regiochemistry in palladium-phosphine catalyzed
      intermolecular Heck reactions.
AB  - Density functional theory calculations of the transition-state structures and
      reaction barriers for the C-C coupling between monosubstituted eta(2)-olefins and
      eta(1)-vinyl for neutral [PdI(PH(3))(vinyl)(RCHCH(2))] and cationic
      [Pd(H(2)PCH(2)PH(2))(vinyl)(RCHCH(2))](+) (R = OMe, Me, and CN) depend mostly on
      the regiochemistry and not on the starting position of the olefin substituent.
      The regiochemistry is thus implicit in the electronic structure of the precursor
      complex. A selectivity index, Omega, based on electrostatic and frontier orbital
      interactions gives a good correlation with experiment for vinylations or
      arylations. The model correctly predicts that the regiochemistry for R = OMe, Me,
      and CN is the same for both neutral and cationic Pd complexes while for R =
      CH(2)OH the regiochemistry reverses. The latter is confirmed by explicit
      calculations of the transition-state energies. Selectivity indices are computed
      for 13 substituents: CO(2)Me, CN, CF(3), Ph, H, Me, CH(2)OH, CH(2)NMe(2), 2
      pyrolidone, CH(2)SiMe(3), OAc, OMe, and F. Cationic conditions systematically
      give larger Omega values and thus tend to favor coupling at the alpha carbon on
      the olefin. The Omega values are approximately additive and can be used to
      predict the regiochemistry for disubstituted olefins.

PMID- 15174888
TI  - Hormone replacement therapy and obstructive airway diseases.
AB  - Controversy exists as to the role of female reproductive hormones in asthma and
      COPD and, specifically, the effect of hormone replacement therapy (HRT) on these
      disorders. The differential incidence of asthma over the menstrual life cycle
      suggests an effect of female reproductive hormones on asthma; less data are
      available for COPD. Estrogen and progesterone have protean effects at the
      cellular level, consistent with potentially harmful and beneficial effects in
      lung disease. Large epidemiologic studies show an increased risk of development
      of asthma with the use of HRT but no consistent effects on COPD. Clinical and
      epidemiologic studies of exacerbations are limited, but suggest either a harmful
      effect or no effect of HRT on exacerbations of asthma and COPD. HRT appears to
      increase the risk of development of asthma but is not associated with the loss of
      lung function characteristic of COPD. Because the development of asthma is rare
      in postmenopausal women, the absolute increase in risk among women without asthma
      is modest. Physicians may wish to avoid HRT therapy in patients with difficult to
      control asthma and COPD. Clinical decisions to start or continue HRT among women
      without asthma or COPD should be based on the effects of HRT on more common
      diseases such as cardiovascular disease, breast cancer and osteoporosis, non
      vertebral fractures and colon cancer.

PMID- 15174889
TI  - Management of exercise-induced bronchospasm in children: the role of leukotriene
      antagonists.
AB  - This review assesses the evidence on the efficacy of leukotriene antagonists in
      the management of exercise-induced bronchospasm (EIB) in children. Only two
      randomized, double-blind, placebo-controlled, crossover studies have examined the
      effect of leukotriene antagonists in EIB in a pediatric setting. All other
      studies, including those comparing leukotriene antagonists with other agents such
      as beta(2)-adrenoceptor agonists (beta(2)-agonists) and inhaled corticosteroids,
      primarily involve adult patients. In children, not receiving other asthma
      medication, leukotriene antagonists can offer statistically significant
      protection from EIB compared with placebo. However, protection is not complete,
      as a significant proportion of children will continue to experience a >15%
      reduction in FEV(1). None of the studies involved children treated concurrently
      with other asthma medications; therefore, comments on additive therapy cannot be
      made. Despite evidence from only a few studies, leukotriene antagonists are seen
      to be well tolerated, efficacious, and of benefit to some children. In addition,
      current management for EIB with short-acting beta(2)-agonists is less than ideal.
      It is therefore concluded that in children with EIB, leukotriene antagonists are
      indicated on a trial basis with individualized therapy and follow-up to evaluate
      treatment response.

PMID- 15174890
TI  - Matrix metalloproteinases in the pathogenesis of asthma and COPD: implications
      for therapy.
AB  - While asthma is an inflammatory disorder of the airways involving mediators
      released from mast cells and eosinophils, inflammation alone is insufficient to
      explain the chronic nature of the disease. Recent progress in the understanding
      of disease pathogenesis has revealed that airway remodeling, which is at least in
      part due to an excess of extracellular matrix (ECM) deposition in the airway
      wall, plays a significant role in airflow obstruction. Matrix metalloproteinases
      (MMPs) have been suggested to be the major proteolytic enzymes to induce airway
      remodeling in asthma and COPD. It has been widely accepted that different
      inflammatory processes are involved in asthma and COPD with different
      inflammatory cells, mediators, and responses to treatments. Despite these
      different processes, airflow obstruction and airway remodeling characterize these
      two diseases. MMP-2 and -9 have been reported to be involved in the pathogenesis
      of airway remodeling in both diseases and MMP-12, in addition to these MMPs, in
      the pathogenesis of COPD. In this review, we discuss the current views on the
      role of MMPs in the pathogenesis of bronchial asthma and COPD. Anti-MMP therapy
      could theoretically be useful to prevent airway remodeling in asthma and COPD.
      However, to date no clinical data are available regarding the efficacy of anti
      MMP therapies in the treatment of patients with asthma and COPD.

PMID- 15174891
TI  - Epoprostenol in pregnant patients with secondary pulmonary hypertension: two case
      reports and a review of the literature.
AB  - Women who present with pulmonary hypertension during gestation have traditionally
      been persuaded to terminate their pregnancy. Historically, the mortality
      associated with this group is very high. Certain patients with a secondary cause
      of pulmonary hypertension are believed to share similar pathophysiology with
      primary pulmonary hypertension patients. Recently, new treatments have become
      available that have slowed disease progression. We present the successful
      treatment of two patients who presented during late gestation with moderate
      pulmonary hypertension. Both patients were managed with intravenous vasodilators
      and anticoagulants without complication. Each patient successfully delivered a
      healthy child via spontaneous vaginal delivery. The review of the historical
      management of similar patients including new insights into the etiology of
      pulmonary arterial hypertension is also included. It highlights the complexity
      involved in managing such patients and the requirement of a multidisiplinary team
      approach.

PMID- 15174892
TI  - Hydrofluoroalkane formulations of inhaled corticosteroids for the treatment of
      asthma.
AB  - Current international guidelines for the treatment of asthma advocate inhaled
      corticosteroids as first-line therapy for persistent symptoms. As
      chlorofluorocarbon (CFC)-based products are being phased out because of
      environmental concerns, new inhaler propellants, such as hydrofluoroalkane (HFA)
      134a, have been developed. The reformulation of existing corticosteroid compounds
      into HFA propellants has resulted in two distinct classes of corticosteroid
      aerosols consisting of HFA suspensions and HFA solutions. The new HFA
      formulations of flunisolide and beclomethasone dipropionate exist as solutions,
      whereas HFA preparations of fluticasone propionate, triamcinolone acetonide, and
      mometasone furoate are formulated as suspensions. HFA suspensions retain the same
      particle size, deposition, and efficacy profiles as their CFC counterparts. HFA
      solutions, however, exist as extra-fine aerosols which have been shown to
      penetrate more effectively into the peripheral regions of the lung. Comparisons
      of HFA solutions with their CFC counterparts have demonstrated equivalent
      efficacy when given in smaller doses. The safety profiles of both HFA suspensions
      and solutions, given at equivalent doses, are comparable to CFC formulations.
      Increasing evidence suggests that inflammation of the small airways plays an
      important role in the pathogenesis of asthma. Currently, the clinical
      implications of long-term treatment of the peripheral lung using an extra-fine
      inhaled corticosteroid aerosol remain uncertain. Future studies, involving
      histopathologic and clinical endpoints, will be necessary to determine whether
      treatment with HFA solutions offers significant advantages over currently
      available therapies.

PMID- 15174893
TI  - Etiopathogenesis and management of perennial allergic rhinitis: a state-of-the
      art review.
AB  - Perennial allergic rhinitis is an inflammatory disorder characterized by symptoms
      of nasal congestion, rhinorrhea, sneezing, and itching. The prevalence of
      allergic rhinitis is quite common and affects 20% or more of various populations.
      Some patients with allergic rhinitis are symptomatic only during the pollen
      season, while many others are allergic to multiple allergens including indoor
      allergens such as house dust mites, animal dander, cockroaches, and fungi, which
      lead to perennial symptoms. Immunoglobulin (Ig)-E is the proximate cause of
      perennial allergic rhinitis. Circulating IgE antibodies bind to the high affinity
      IgE receptor on mast cells and basophils. IgE antibodies, bound to the receptors
      crosslinked by allergen, initiate the secretion of inflammatory mediators
      including histamine, leukotrienes, and cytokines. These mediators can induce both
      acute and chronic changes that result in symptoms of allergy. Many therapies are
      approved for the treatment of allergic rhinitis including intranasal
      corticosteroids, antihistamines with or without decongestants, and nasal cromolyn
      sodium (sodium cromoglicate). Allergen avoidance is the mainstay of therapy for
      many patients but is not always practical. For those patients who have not
      responded to appropriate medications, allergen specific immunotherapy may also be
      effective.A number of studies with omalizumab have shown that it is effective in
      the treatment of seasonal allergic rhinitis induced by pollen such as ragweed and
      birch pollen. Omalizumab is a molecularly cloned humanized monoclonal antibody
      inhibiting human IgE. It binds specifically to the region of the IgE molecule
      that binds to the IgE receptor on the mast cell or basophils. Because omalizumab
      cannot bind IgE molecules that are already bound to the surface receptors on mast
      cells and basophils, it does not stimulate secretion of mediators from these
      cells. Omalizumab does not appear to stimulate an immune response against itself.
      It rapidly reduces free serum IgE levels by over 95% when administered at
      therapeutic doses and also results in the reduction of IgE receptors on mast
      cells and basophils. The combined effects of reduction of both free IgE in serum
      and the receptor density on the mast cells or basophils results in decreased
      allergen-stimulated mediator release. Preliminary studies in the treatment of
      perennial allergic rhinitis supports omalizumab's efficacy and safety. The
      compound has been well tolerated. Aside from urticarial reactions, adverse
      effects appear to be minimal. Omalizumab is the first of several new immune-based
      specifically targeted molecules that may prove to be extremely valuable in the
      treatment of perennial allergic rhinitis, as it is often unresponsive to
      traditional therapies.

PMID- 15174894
TI  - The effect of oral clarithromycin on bronchial airway inflammation in moderate-to
      severe stable COPD: a randomized controlled trial.
AB  - INTRODUCTION: COPD is characterized by bronchial neutrophilic inflammation.
      Clarithromycin is a macrolide antibiotic that has antibacterial and anti
      inflammatory properties. Macrolide antibiotics have been shown to improve airway
      inflammation in diffuse pan-bronchiolitis but their role in COPD is undetermined.
      The aim of the study was to determine if 3 months of therapy with modified
      release oral clarithromycin (Klaricid XL) 500 mg/day reduced bronchial airway
      inflammation in patients with moderate-to-severe stable COPD compared with
      placebo. METHODS: A prospective, double-blind controlled trial randomized
      patients with moderate-to-severe stable COPD to 3 months' therapy with oral
      modified-release clarithromycin 500 mg/day or placebo. Patients underwent saline
      sputum induction before and after treatment with clarithromycin. The effects of
      clarithromycin on sputum total cell and neutrophil counts, supernatant
      interleukin-8 (IL-8), leukotriene B(4) (LTB(4)), tumor necrosis factor (TNF)
      alpha, neutrophil elastase (NE), and neutrophil chemotaxis were assessed in
      comparison with placebo. RESULTS: Of a total of 67 patients included in the
      trial, 31 were treated with clarithromycin and 36 with placebo. The groups were
      similar in age, body mass index, history of smoking, and spirometry. Of 60
      evaluable patients, 26 and 34 completed 3 months' therapy with clarithromycin and
      placebo, respectively. Clarithromycin had no significant effect on sputum total
      cell count, neutrophil count, IL-8, LTB(4), TNFalpha levels or neutrophil
      elastase. However, clarithromycin did cause a small reduction in the neutrophil
      differential (p = 0.04 relative to placebo) and neutrophil chemotaxis (p = 0.058
      relative to placebo). CONCLUSIONS: Oral clarithromycin 500 mg/day administered
      for 3 months had no significant effect on sputum neutrophil numbers or cytokine
      levels in patients with moderate-to-severe stable COPD. However, clarithromycin
      did cause a small reduction in the neutrophil differential and neutrophil
      chemotaxis. Further studies may be warranted to determine the clinical
      significance of these findings.

PMID- 15174895
TI  - HIV pharmacogenomics: closer to personalized therapy?
AB  - Pharmacogenomics classically focuses on host nuclear genetic polymorphisms that
      can be used to predict adverse drug reactions (ADRs). Because ADRs are defined as
      any noxious, unintended, and undesired drug effects, loss of efficacy due to the
      development of antiretroviral drug resistance and both acute and cumulative
      adverse effects of antiretroviral therapy can be considered ADRs. In order to
      address these types of antiretroviral-associated ADRs, pharmacogenomic testing
      methods have expanded to include molecular assays that characterize extranuclear
      genetic material (e.g. HIV and mitochondrial genomes), as well as the host
      nuclear genetic material. Recent molecular advances permit high resolution
      resistance testing that detects loss of therapeutic efficacy through the use of
      phenotypic, genotypic and/or virtual phenotypic resistance testing. These assays
      use complex technical and interpretative methods to improve the therapeutic
      efficacy of antiretroviral therapy. The resistance assays demonstrate the utility
      of pharmacogenomic testing for patients undergoing lifelong and complex
      antiretroviral therapies. Future applications of antiretroviral-directed
      pharmacogenomic tests range from quantitative detection of mitochondrial
      depletion as an early surrogate marker for drug toxicity, to qualitative analysis
      of host immune haplotypes, and metabolic/transporter genetic polymorphisms for
      predicting disease progression. In summary, pharmacogenomic testing for HIV
      positive patients provides proof of principle that these tests can be used
      clinically to improve outcomes for patients undergoing complex and sustained drug
      regimens.

PMID- 15174896
TI  - Pharmacogenetics of antihypertensive drug responses.
AB  - The blood pressure (BP) response to any single antihypertensive drug is
      characterized by marked interindividual variation, and the known predictors of
      response are of limited value in identifying the optimum drug for an individual
      patient. Analysis of genetic variation has the potential to improve our
      understanding of determinants of antihypertensive drug response in order to
      individualize drug selection. Genetic variation can influence both
      pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug
      response. Classic pharmacogenetic investigations have identified variations in
      single genes that have a large effect on antihypertensive drug metabolism and are
      inherited in a Mendelian fashion. These include a polymorphism in the CYP2D6
      gene, encoding a cytochrome p450 family member involved in phase I drug
      metabolism, and polymorphisms in genes encoding enzymes involved in phase II drug
      metabolism, including N-acetyltransferase (NAT2), catechol-O-methyltransferase
      (COMT), and phenol sulfotransferase (P-PST, SULT1A1). Although these
      polymorphisms have major effects on the pharmacokinetic profiles of both commonly
      used antihypertensive drugs such as metoprolol (CYP2D6), and lesser used drugs
      such as hydralazine (NAT2), methyldopa (COMT), and minoxidil (SULT1A1), they have
      not been shown to influence variation in the antihypertensive effect of these
      drugs at conventional doses. Interest is now focused on identifying genetic
      polymorphisms that influence the pharmacodynamic determinants of antihypertensive
      response. Using a candidate gene approach, such polymorphisms have been
      identified in genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3
      and GNAS1), the beta(1)-adrenergic receptor (ADRB1), endothelial nitric oxide
      synthase (NOS3), and components of the renin-angiotensin-aldosterone system
      (angiotensinogen [AGT], angiotensin converting enzyme [ACE], the angiotensin type
      I receptor [AGTR1], and aldosterone synthase [CYP11B2]). These polymorphisms have
      been shown to influence the BP response to diuretics (ADD1, GNB3, NOS3, and ACE),
      beta-blockers (GNAS1 and ADRB1), ACE inhibitors (AGT, ACE, and AGTR1),
      angiotensin receptor blockers (ACE and CYP11B2), and clonidine (GNB3).An emerging
      consensus from these studies is that single gene effects on antihypertensive drug
      responses are small, and even the combined effects of all presently known
      polymorphisms do not account for enough variation in response to be clinically
      useful. New genome-wide scanning techniques may lead to the identification of
      genes previously unsuspected of influencing drug response. Additional
      requirements for pharmacogenetic approaches to become clinically useful are the
      characterization of the effects of haplotypes and multi-locus genotypes on drug
      response, and consideration of gene-by-environment interactions. Such studies
      will require huge sample sizes and novel statistical methods, but the theoretical
      and technical framework is in place to make this possible.

PMID- 15174897
TI  - The epithelial sodium channel in hypertension: genetic heterogeneity and
      implications for treatment with amiloride.
AB  - The epithelial sodium channel (ENaC) has a central role in sodium transport
      across membranes. It is expressed on the apical cell surface of renal tubular
      epithelia and also on other aldosterone-responsive epithelial cells. In the
      kidney, ENaC contributes to the regulation of blood pressure via changes in
      sodium balance and blood volume. Rare monogenetic disorders associated with
      hypertension have been described, such as Liddle syndrome, which gives rise to
      increased sodium reabsorption in the kidney via increased ENaC activity. There
      are many other variants in the genes encoding ENaC subunits, some of which occur
      with sufficient frequency as to be termed polymorphic variants. The Thr594Met
      polymorphism of the ENaC beta-subunit gene SCNN1B occurs exclusively in Black
      individuals, with a frequency of 6-8% in those with hypertension. It increases
      cAMP mediated ENaC sodium current in affected B lymphocytes, and has been
      associated with hypertension in a Black South London population. There is
      preliminary evidence that amiloride is effective as monotherapy in hypertensive
      individuals with the Thr594Met polymorphism and in patients with resistant
      hypertension, who have evidence of increased amiloride-sensitive sodium channel
      activity. If these preliminary studies are corroborated in larger studies, then
      amiloride may provide an important new strategy for blood pressure control in
      selected individuals.

PMID- 15174898
TI  - Genome-scale analysis of lung cancer progression.
AB  - Among cancers, lung cancer is the single biggest killer in the US. It is
      estimated that lung cancer was responsible for 171900 newly diagnosed cases of
      cancer in the US in 2003, and for 157200 deaths. Over many years, however, there
      has been little improvement in the clinical outcome of lung cancer, and any
      improvement in the incidence or mortality from lung cancer can largely be
      attributed to smoking cessation and not to the success of therapy. The
      histopathology of lung cancer reveals that it is a disease with many faces. Lung
      cancer is often nonresponsive to traditional therapy, leaving few, if any,
      alternatives in the management of the advanced stages of the disease. The
      molecular pathogenesis of lung cancer, only recently illuminated, involves
      numerous molecular and cell biological changes revealing a very complex disease
      progression. Large-scale mRNA expression analysis has been recently used to
      classify lung cancers molecularly. These techniques have been used successfully
      to differentiate lung cancer histotypes based on patterns of genes expressed. The
      use of protein analysis to this end has also been attempted, with limited
      correlation with RNA experiments. This likely reflects the limited sensitivity of
      the technologies and complex, poorly understood post-synthesis protein
      modifications. In any event, there have been great strides made in understanding
      the nature of lung cancer from a molecular perspective; these effects represent a
      great advancement in the diagnosis and prognosis of lung cancer. Moreover, these
      advances may lead to the improvement of patient survival by guiding the choice of
      more efficacious therapy.

PMID- 15174899
TI  - Diagnostic chimerism analysis after allogeneic stem cell transplantation: new
      methods and markers.
AB  - Analysis of chimerism after allogeneic hematopoietic cell transplantation is
      important for assessing engraftment and the early detection of graft failure. In
      addition, the monitoring of minimal residual disease and early detection of
      imminent relapse has also become an important issue. Novel transplant procedures,
      for example dose-reduced conditioning protocols, rely on chimerism analysis to
      guide intervention, i.e. the reduction of immunosuppression or infusion of donor
      lymphocytes. During the last 30 years, several methods for the analysis of
      chimerism after hematopoietic cell transplantation have been published.
      Currently, fluorescent in situ hybridization (XY-FISH) analysis of sex
      chromosomes after transplantation from a sex-mismatched donor or analysis of
      polymorphic DNA sequences, i.e. short tandem repeats (STR) or variable number of
      tandem repeats (VNTR), are the most widely used procedures used in the assessment
      of chimerism. Two major diagnostic fields can be defined for chimerism analysis:
      the period of engraftment and the detection of minimal residual disease. Although
      STR-PCR and FISH analysis are very useful in the diagnosis of engraftment and
      graft failure, they are only of limited use in the monitoring of minimal residual
      disease, largely because of its limited level of sensitivity (1-5% for the minor
      population). Several novel procedures to improve this level of detection have
      been reported in recent years. One focus has been the use of real-time PCR
      techniques based on analysis of the Y-chromosome or, more recently, single
      nucleotide polymorphism (SNPs). These procedures combine quantitative analysis
      with high sensitivity (10(-4) to 10(-6)), and hold great potential for the
      future. In addition, the combination of cell sorting based on leukemia-specific
      immunophenotype and STR-PCR has been successfully used for minimal residual
      disease detection. First clinical data using these procedures indicate that
      intervention (e.g. the reduction of immunosuppression or donor lymphocyte
      infusion) may be effective in the minimal residual disease situation, even in
      high risk diseases like acute myeloid leukemia and acute lymphoblastic leukemia.
      The optimal timing of these diagnostic interventions is a critical issue and has
      to be further optimized. Whether this will ultimately improve the survival of
      patients with leukemia after transplantation has to be shown in prospective
      studies.

PMID- 15174900
TI  - Genetically targeted cancer therapy: tumor destruction by PKR activation.
AB  - The is a double-stranded RNA-activated protein kinase (PKR) has been largely
      investigated for its key role in viral host defense. Although best characterized
      by its function in mediating the antiviral and antiproliferative effects of
      interferon (IFN), PKR is also implicated in transcriptional regulation, cell
      differentiation, signal transduction, and tumor suppression. However, recent
      findings identifying PKR as an important effector of apoptosis have led to an
      increased interest in PKR modulation as an antitumor strategy. PKR can either be
      up-regulated through direct induction by the transcription factor E2F-1, or it
      can be activated through direct protein-protein interactions with the melanoma
      differentiation-associated gene-7 (MDA7, IL-24). Additionally, the intracellular
      formation of double-stranded RNA by transfection with antisense RNA complementary
      to tumor-specific RNA sequences can induce PKR activation and apoptosis selective
      to these tumor cells. The growing application of viral vector-based gene
      therapies and oncolytic, replicating viruses that must elude viral defense in
      order to be effective, has also drawn attention to PKR. Oncolytic viruses, like
      the attenuated herpes simplex virus R3616, the vesicular stomatitis virus, or
      reovirus, specifically replicate in tumor cells only because the viral host
      defense in the permissive cells is suppressed. In this article we review the role
      of PKR as an effector of apoptosis and a target for tumor treatment strategies
      and discuss the potential of PKR-modifying agents to treat patients with cancer.
      Targeted gene therapy against cancer can be approached by activation of PKR with
      the down-regulation of protein synthesis and induction of apoptosis, or by
      suppression of PKR with the propagation of oncolytic virus. Since the PKR pathway
      can be modified by many routes, antitumor therapies combining oncolytic virus,
      gene therapies, and chemotherapy with PKR modifiers are likely to emerge in the
      near future as therapeutic options in the treatment of patients with cancer.

PMID- 15174901
TI  - Flow cytometric assay for genotyping cytochrome p450 2C9 and 2C19: comparison
      with a microelectronic DNA array.
AB  - INTRODUCTION: Cytochrome p450 (CYP) 2C9 and 2C19 metabolize a wide range of
      therapeutically important drugs. Genetic polymorphisms in the CYP2C9 and CYP2C19
      genes result in variations in drug response. To correlate the dose required for
      therapeutic drug efficacy with genotype, accurate and reliable methods for
      detecting single nucleotide polymorphisms (SNPs) of CYP2C9 and CYP2C19 are
      required. STUDY DESIGN: We evaluated two technologies for genotyping CYP2C9 (*2
      and *3 alleles) and CYP2C19 (*2 and *3 alleles). We developed a multiplexed flow
      cytometric assay based on the Luminex xMAP system and oligonucleotide-tagged
      Universal Array microspheres. The Luminex assay was compared with the eSensor DNA
      detection system, provided by Motorola Life Sciences. Genotypes determined by the
      two methods were confirmed by sequence analysis. RESULTS: Of the 101 whole-genome
      amplified DNA samples genotyped by the Luminex method, 15 (14.8%) were
      heterozygous and 1 was homozygous for the CYP2C9*2 polymorphism. For the CYP2C9*3
      polymorphism, 13 (12.9%) were heterozygous and 1 was homozygous. Two samples had
      the CYP2C9*2/*3 genotype. For CYP2C19*2, 17 (16.8%) of the samples were
      heterozygous and one was homozygous. The CYP2C19*3 polymorphism was not found.
      Genotypes determined by the Luminex assay were in complete concordance with the
      eSensor SNP assay results. A dilution study showed that 1.5 ng of nucleic acid
      was adequate for PCR and subsequent detection of SNPs by the Luminex assay. The
      within run and between run coefficients of variance (CVs) for allelic ratios
      determined by the Luminex procedure were found to be <or=4.1% and <or=9.1%,
      respectively, for the alleles present. CONCLUSION: Both the in-house Luminex
      method and the eSensor trade mark DNA detection system reproducibly and
      unambiguously genotyped SNPs of CYP2C9 and CYP2C19 in the samples tested.

PMID- 15174903
TI  - Cerebral ischemia after carotid intervention.
AB  - PURPOSE: To determine the incidence of symptomatic and asymptomatic cerebral
      ischemic lesions found on diffusion-weighted magnetic resonance imaging (DW-MRI)
      after carotid interventions. METHODS: A prospective study was conducted to assess
      new cerebral ischemic lesions using DW-MRI in symptomatic patients with carotid
      artery disease undergoing protected carotid artery stenting (CAS) or carotid
      endarterectomy (CEA). DW-MRI was performed before and after the intervention in
      44 patients (21 CAS and 23 CEA). Two experienced radiologists not involved in the
      carotid procedures or neurological assessment compared the postprocedural DW-MR
      images with those acquired before the intervention. RESULTS: Three (6.8%) of the
      44 patients suffered strokes: 1 major and 1 minor stroke after CEA and 1 minor
      stroke after CAS. DW-MRI showed 15 new hyperintense lesions in 2 (9%) of 23 CEA
      patients; 31 new hyperintense lesions were found in 9 (43%) of the 21 CAS
      patients. The majority of new lesions were located in the ipsilateral vascular
      territory; 2 CAS patients also showed 6 new hyperintense lesions in the
      cerebellum. The mean lesion load per patient was 2.52 cm(3) (range 0.31-4.74) in
      the CEA group and 1.74 cm(3) (0.03-9.72) in the CAS group (p=0.35). The volume of
      the individual lesions in CEA patients was 0.39 cm(3) (range 0.01-2.16) compared
      to 0.52 cm(3) (range 0.01-5.47) in the CAS group (p=0.23). Patients who were
      asymptomatic after the intervention had fewer lesions (p=0.03) and a smaller
      lesion load than symptomatic patients. CONCLUSIONS: Ischemic lesions were more
      frequently seen on DW-MRI after carotid stenting than after endarterectomy. The
      majority of the detected lesions did not cause neurological deficits.

PMID- 15174902
TI  - Novel intravascular ultrasound-guided method to create transintimal arterial
      communications: initial experience in peripheral occlusive disease and aortic
      dissection.
AB  - PURPOSE: To report our experience using a commercially available catheter-based
      system equipped with an intravascular ultrasound (IVUS) transducer to achieve
      controlled true lumen re-entry in patients undergoing subintimal angioplasty for
      chronic total occlusions (CTO) or aortic dissections. METHODS: During an 8-month
      period, 10 patients (6 men; mean age 73.4 years) with lower extremity (LE)
      ischemia from CTOs (n=7) or true lumen collapse from aortic dissections (n=3)
      were treated. Subintimal access and controlled re-entry of the CTOs were
      performed with a commercially available 6.2-F dual-lumen catheter, which
      contained an integrated 64-element phased-array IVUS transducer and a deployable
      24-G needle through which a guidewire was passed once the target lumen was
      reached. The occluded segments were balloon dilated; self-expanding nitinol
      stents were deployed. In the aortic dissections, fenestrations were performed
      using the same device, with the IVUS unit acting as the guide. The fenestrations
      were balloon dilated and stented to support the true lumen. RESULTS: Time to
      effective re-entry ranged from 6 to 10 minutes (mean 7) in the CTOs; antegrade
      flow was restored in all 7 CTOs, and the patients were free of ischemic symptoms
      at up to 8-month follow-up. In the aortic dissection cases, the fenestrations
      equalized pressures between the lumens and restored flow into the compromised
      vessels. There were no complications related to the use of this device in any of
      the 10 patients. CONCLUSIONS: Our preliminary results demonstrate the feasibility
      of using this catheter-based system for subintimal recanalization with controlled
      re-entry in CTOs and for aortic flap fenestrations in aortic dissections. This
      approach can improve the technical success rate, reduce the time of the
      procedure, and minimize potential complications.

PMID- 15174904
TI  - Spontaneous scalp arteriovenous fistula in a child with hartnup disease.
AB  - PURPOSE: To report the endovascular treatment of a spontaneous scalp
      arteriovenous fistula (AVF) in a child with Hartnup disease. CASE REPORT: A 6
      year-old girl with Hartnup disease presented with recurrent attacks of intense,
      migraine-like, right-sided headache; a tender, pulsatile small mass was observed
      in the scalp. Selective digital subtraction angiography revealed a high-flow
      scalp AVF fed by the frontal branch of the right superficial temporal artery
      draining via the scalp veins. Endovascular treatment was performed by direct
      puncture of the distal feeding artery and injection of 2 mL of a 50% mixture of N
      butyl-cyanoacrylate and Lipiodol. Serial arteriograms performed 6 months and 2
      years later documented complete resolution of the lesion. The patient has had no
      recurrence of clinical symptoms or local signs for recanalization. CONCLUSIONS:
      Scalp AVFs may progress in size, causing significantly disabling symptoms,
      particularly in children. We recommend endovascular treatment at the earliest
      possible stage.

PMID- 15174905
TI  - Intraoperative innominate and common carotid intervention combined with carotid
      endarterectomy: a "true" endovascular surgical approach.
AB  - PURPOSE: To report the technique of carotid endarterectomy (CEA) combined with
      retrograde balloon angioplasty and stenting of proximal "tandem" lesions in the
      supra-aortic trunk. TECHNIQUE: Intraoperative techniques in 34 patients with 23
      left common carotid artery (CCA) and 11 innominate artery lesions included
      general anesthesia, low-dose dextran, prosthetic patching, selective shunting, 8
      F sheath entry into the native CCA before the CEA, manual CCA sizing, and balloon
      expandable stent placement after predilation. The technique has a high procedural
      success rate (97%) and appears durable. Over a mean 34-month follow-up, 2 >70%
      ostial CCA restenoses were found at 24 months. CONCLUSIONS: Intraoperative
      innominate or left CCA balloon angioplasty/stenting combined with carotid
      endarterectomy is safe, effective, and durable.

PMID- 15174906
TI  - Thrombosis of a bifurcated endograft following lower-back microwave therapy.
AB  - PURPOSE: To describe an unusual case involving thrombosis in an aortic endograft
      limb following microwave therapy (MWT) for lumbar pain. CASE REPORT: A 77-year
      old man had successful repair of an abdominal aortic aneurysm with a Vanguard
      endograft. He had been free of complications during the 3-year follow-up. Five
      days after the 36-month surveillance angiogram, the patient was treated with MWT
      for chronic left-sided lumbar pain due to vertebral arthrosis. Immediately after
      this session, the patient presented with acute ischemia in the left lower limb.
      Computed tomographic angiography showed a thrombosis of the left limb of the
      endograft. A femorofemoral crossover bypass was performed. No complication was
      observed in later surveillance. CONCLUSIONS: It may be advisable to avoid MWT and
      other deep heating therapies in patients with endografts. This caution is
      applicable to other metallic stents.

PMID- 15174907
TI  - Endovascular stenting for stenoses in surgically reconstructed brachiocephalic
      bypass grafts: immediate and midterm outcomes.
AB  - PURPOSE: To report the use of endovascular stenting for treatment of patients
      with symptomatic obstruction of brachiocephalic surgical reconstructions.
      METHODS: Twenty-two patients (17 men; mean age 65+/-6 years) with 24 symptomatic
      obstructions of brachiocephalic Dacron bypass grafts (2 aorto-innominate, 9
      subclavian-carotid, and 11 carotid-subclavian) were treated with balloon
      expandable stents delivered via a percutaneous brachial access or surgical
      exposure of the common carotid artery. A distal protection device was utilized in
      the 9 patients with subclavian-carotid bypass grafts. All patients were followed
      by clinical and Doppler examinations. RESULTS: Procedural success was 100%; 1
      (4.5%) patient developed transient intraprocedural aphasia owing to intolerance
      to the distal protection balloon occlusion. All 22 patients reported complete
      relief of their presenting symptoms. Over a 29-month follow-up, 3 (13.6%)
      restenoses were found, but none was due to stent compression. CONCLUSIONS:
      Stenting for obstructed brachiocephalic reconstructions appears to be a safe,
      effective, and durable therapeutic strategy.

PMID- 15174908
TI  - Residual stenosis poststenting and subsequent decrease in the proximal reference
      diameter are correlated: excessive axial wall stress is a plausible explanation.
AB  - PURPOSE: To test the hypothesis that edge restenosis in stented lesions might be
      due to an increase in axial wall stress in the adjacent proximal vessel segment
      by examining whether the proximal reference diameters of conventionally stented
      lesions are reduced at follow-up and whether this reduction depends on the degree
      of residual stenosis poststenting. METHODS: The literature published in the past
      5 years dealing with restenosis following implantation of standard stents was
      screened for the availability of (1) reference vessel diameters poststenting, (2)
      mean residual stenosis poststenting, and (3) mean reference vessel diameters at
      follow-up in the same patients or groups of patients. Data collected from 11
      publications were pooled and used to compute the change in reference segment
      diameter over time. These differences were compared to the residual stenosis
      poststenting by nonlinear regression. RESULTS: The reduction in the mean
      reference diameters over time and the mean residual stenosis poststenting appear
      to be strongly correlated (r2 = 0.838), which supports the idea that the
      evolution of a stenosis adjacent to a stent margin depends on the severity of the
      residual stenosis. CONCLUSIONS: This finding indicates that edge restenosis might
      be due to excessive axial wall stress. It may also explain, at least partly, why
      edge restenosis is observed with catheter-based brachytherapy and radioactive or
      drug-eluting stents.

PMID- 15174910
TI  - Plasma homocysteine and restenosis after femoropopliteal angioplasty.
AB  - PURPOSE: To assess the relationship between plasma homocysteine levels and
      restenosis after femoropopliteal percutaneous transluminal angioplasty. METHODS:
      Over a 10-month period, 128 consecutive, symptomatic patients (72 men; median age
      70 years) having successful femoropopliteal angioplasty for atherosclerotic
      occlusive disease were prospectively enrolled in the study. Plasma homocysteine
      levels were determined the day before the procedure. The primary endpoint was
      restenosis >50%, documented by duplex sonography, at up to 12 months' follow-up.
      Cox proportional hazards analysis was used to determine the risk of restenosis in
      relation to pretreatment homocysteine levels. RESULTS: The restenosis rate at 12
      months was 46%. Median baseline plasma homocysteine levels were not different in
      patients with and without restenosis (15.4 versus 16.7 micromol/L, p=0.30).
      Compared to patients with homocysteine levels </=14 micromol/L (lower tertile,
      n=43), the hazard ratio of incident restenosis was 0.75 (95% CI 0.40 to 1.40) in
      patients with homocysteine levels from 14.1 to 19.6 micromol/L (middle tertile,
      n=42) and 0.64 (95% CI 0.33 to 1.22) in patients with homocysteine levels >/=19.7
      micromol/L (upper tertile, n=42) (p=0.38). Multivariate analysis showed that
      lesion length (p<0.0001) and lack of hypertension (p=0.0013) were associated with
      restenosis. CONCLUSIONS: Elevated plasma homocysteine levels are not associated
      with restenosis after femoropopliteal angioplasty. Therefore, plasma homocysteine
      cannot be considered as an important risk factor influencing the outcome after
      initially successful angioplasty in femoropopliteal arteries.

PMID- 15174909
TI  - Comparison of catecholamine hormone release in patients undergoing carotid artery
      stenting or carotid endarterectomy.
AB  - PURPOSE: To investigate the pattern of catecholamine response in patients
      undergoing carotid endarterectomy (CEA) or carotid artery stenting (CAS).
      METHODS: Adrenaline, noradrenaline, and renin levels were measured at 5 time
      points in 12 patients undergoing 13 CEAs (1 bilateral) and 13 patients undergoing
      unilateral CAS. Arterial blood samples were taken at the following time points:
      (1) after induction in CEA patients or 5 minutes following first contrast
      injection in CAS patients, (2) 5 minutes following ICA clamp release in surgical
      patients or deflation of the balloon in the CAS cohort, (3) 60 minutes following
      ICA clamp release in surgical patients or deflation of the balloon in the CAS
      cohort, and (4) 24 hours following the procedure. Intraoperative blood pressure
      and heart rate were recorded using radial arterial monitoring. Changes in
      adrenaline, noradrenaline, and renin levels are expressed as ratios versus
      baseline. RESULTS: Patterns of adrenaline and noradrenaline release were
      significantly different in patients undergoing CAS and CEA, with much higher and
      more variable surges of adrenaline and noradrenaline occurring in CEA patients.
      Adrenaline and noradrenaline levels increased significantly over baseline
      following carotid artery clamping in patients undergoing CEA (noradrenaline ratio
      before clamping: 1.54+/-1.25, 24 hours after unclamping: 8.38+/-16.35 [p<0.001];
      adrenaline ratio before clamping: 1.12+/-0.49, 60 minutes after unclamping:
      17.59+/-19.14 [p<0.001]). Conversely, in patients undergoing CAS, catecholamine
      levels remained unchanged (noradrenaline ratio before dilation: 0.96+/-0.23, 24
      hours after the procedure: 0.92+/-0.32 [p=NS]; adrenaline ratio before dilation:
      0.83+/-0.33, 60 minutes after balloon deflation: 0.56+/-0.32 [p=NS]).
      CONCLUSIONS: CAS is associated with a significantly less marked catecholamine
      response than CEA, which may reflect down-regulation of the sympathetic nervous
      system in response to carotid sinus stimulation during carotid angioplasty.

PMID- 15174911
TI  - Excessive carotid in-stent neointimal formation predicts late cardiovascular
      events.
AB  - PURPOSE: To examine if excessive in-stent neointimal formation causing a
      subcritical stenosis may indicate enhanced vascular reactivity in response to
      injury, thus predicting late cardiovascular events. METHODS: One hundred
      consecutive patients (64 men; median age 71 years) with high-grade internal
      carotid artery stenoses (68 asymptomatic, 32 symptomatic) underwent carotid
      artery stenting (CAS). High-sensitivity C-reactive protein (hs-CRP) was measured
      before CAS. Patients were monitored with duplex ultrasound for excessive in-stent
      neointimal formation (flow-compromising lumen diameter reduction >/=50%),
      critical restenosis (>/=70%), or the occurrence of late major adverse
      cardiovascular events (MACE) defined as myocardial infarction (MI), stroke, and
      death occurring later than 30 days poststenting. RESULTS: Over a median 23-month
      follow-up, excessive neointimal formation was observed in 14 (14%) patients,
      restenosis in 2 (2%), and 30 late MACE in 25 [25%: 4 MIs, 2 ipsilateral strokes
      (in the patients with restenosis), 8 contralateral strokes, and 16 cardiovascular
      deaths]. Cumulative MACE-free survival rates at 6, 12, and 24 months were 92%,
      84%, and 77%, respectively. Baseline hs-CRP levels were associated both with
      neointimal hyperplasia (p=0.024) and MACE (p=0.021). Patients with excessive
      neointimal formation exhibited a significantly increased adjusted risk for MACE
      (hazard ratio 3.56, p=0.010). CONCLUSIONS: Excessive in-stent neointimal
      formation after CAS indicates an increased risk for late MACE, potentially
      reflecting a state of exaggerated vascular reactivity in response to injury.
      Inflammation, which is associated both with neointimal hyperplasia and MACE,
      seems a common characteristic of different vascular pathologies.

PMID- 15174912
TI  - Coronary artery bypass surgery or percutaneous renal revascularization: which one
      first?

PMID- 15174913
TI  - Change in aneurysm diameter after stent-graft repair of ruptured abdominal aortic
      aneurysms.
AB  - PURPOSE: To compare the changes in aneurysm size following endovascular aneurysm
      repair (EVAR) for ruptured versus elective abdominal aortic aneurysms (AAA).
      METHODS: Aneurysm sac diameter was measured from computed tomographic (CT) scans
      in 14 hemodynamically stable patients (14 men; mean age 74+/-7 years, range 60 to
      83) prior to emergent stent-graft repair for ruptured AAA. The aneurysm diameter
      change was followed postprocedurally with serial CT and the outcomes compared to
      74 AAA patients (58 men; mean age 74+/-7 years, range 56 to 87) having elective
      EVAR in the same time period. The mean rate of sac decrease (mm/month) was
      calculated for each group. RESULTS: There were 3 postoperative deaths in the
      ruptured AAA cohort, leaving 11 patients available for follow-up analysis (mean
      16 months, range 2-49). Eight (73%) patients with ruptured AAA demonstrated
      significantly decreased (>5 mm) aneurysm diameters compared with 32 (43%)
      elective cases (p=0.07) followed a mean 20 months (range 3-51). The mean rate of
      sac diameter decrease was 1.50+/-1.03 mm/month in the rupture group versus 0.73+/
      0.86 mm/month in the elective group (p=0.04). CONCLUSIONS: This study suggests
      that ruptured AAAs treated with stent-graft experience sac regression at a higher
      rate compared with electively treated AAA. The reasons for these findings remain
      unclear.

PMID- 15174914
TI  - Stent-assisted angioplasty at the level of the common femoral artery bifurcation:
      midterm outcomes.
AB  - PURPOSE: To report the midterm outcome after stent-assisted angioplasty of
      occlusive disease at the common femoral artery bifurcation. METHODS: Between 1995
      and 2002, 27 consecutive patients (18 men; mean age 70 years, range 47-90)
      underwent angioplasty with stent implantation in 33 limbs; target sites included
      19 common femoral arteries, the origins of 2 superficial or 4 profunda femoris
      arteries, and 8 bypass anastomoses. RESULTS: Technical success was 100%. Patients
      were followed for a mean 30 months (95% CI 21 to 39), at which time the
      cumulative primary patency was 86% (95% CI 85% to 88%). At 3 years, 83% of the
      arteries were patent. Five restenoses were due to neointimal hyperplasia in 4
      cases (3 bypass grafts) and strut failure of the only balloon-expandable stent
      used in this series. Restenoses due to neointimal hyperplasia at bypass
      anastomoses (3/ 8) were more common than in native arteries (2/25) (p=0.078);
      cumulative primary patency for the bypass subgroup was 71% (95% CI 59% to 82%) at
      a mean 23-month follow-up; 75% and 60% of the anastomoses were patent after 1 and
      2 years, respectively. CONCLUSIONS: Angioplasty of obstructions in the common
      femoral artery and its bifurcation with implantation of self-expanding stents
      shows good midterm primary patency. Native artery lesions have a better outcome
      than stenoses at bypass anastomoses. The procedure does not preclude further
      endovascular interventions at the puncture site.

PMID- 15174915
TI  - Long-term outcome of infrainguinal percutaneous transluminal angioplasty.
AB  - PURPOSE: To evaluate the long-term outcome of infrainguinal percutaneous
      transluminal angioplasty (PTA). METHODS: Between 1991 and 1994, 77 patients (45
      men; mean age 70 years, range 41-85) underwent infrainguinal PTA for occlusive
      disease. Patient records and angiographic examinations were reviewed to extract
      data to a patient register. A long-term (mean 9.3 years) follow-up examination of
      survivors was performed, including physical evaluation, walking impairment
      questionnaire (WIQ), and duplex ultrasound. RESULTS: Cumulative primary and
      secondary patency rates, respectively, were 81% and 86% at 1 year, 65% and 73% at
      5 years, and 12% and 17% at 10 years. Patency rates were better for patients with
      claudication than critical ischemia (p=0.02). Stenoses had better primary patency
      than occlusions (p=0.001), but there was no difference between stenoses <2 cm
      versus >/=2 cm. At long-term follow-up, patients with patent vessels (50%) had
      better ankle-brachial indices (p=0.01) and less pain in their calves (p=0.04)
      compared to patients with non-patent vessels, but there was no difference in
      walking capacity or quality of life. Generalized femoral artery disease (p=0.03)
      and diabetes mellitus (p=0.03) predicted poor survival. CONCLUSIONS: Although the
      overall long-term patency of infrainguinal PTA is poor, the technique has a low
      morbidity and can be performed in selected patients with a reasonable long-term
      result.

PMID- 15174916
TI  - Fate of collateral vessels following subintimal angioplasty.
AB  - PURPOSE: To evaluate the fate of collateral vessels adjacent to and within the
      target lesion following subintimal angioplasty (SIA). METHODS: Pre and
      postprocedural angiograms were reviewed for 29 patients undergoing SIA of the
      lower extremity arteries over a 3-year period. The number of patent collateral
      vessels </=5 cm proximal to the occlusion (proximal segment) and </=5 cm distal
      to the occlusion (distal segment) were recorded pre and postprocedurally and
      compared. In addition, the number of collateral vessels that were re-opened
      within the recanalized segment following SIA was counted. RESULTS: The mean
      number of patent collaterals in the proximal segment was 1.9 (range 0-4)
      preprocedurally and 1.4 (range 0-4) postprocedurally (p<0.002). The mean number
      of patent collaterals in the distal segment was 1.9 (range 0-4) pre-procedurally
      and 1.0 (range 0-4) postprocedurally (p<0.0001). Previously absent collaterals
      within the recanalized segment were observed in 4 (14%) of 29 patients post-SIA.
      The mean number of collateral vessels within all 3 segments (proximal, treated,
      and distal) was 3.9 collaterals preprocedurally and 2.9 collaterals
      postprocedurally. CONCLUSIONS: Some collateral vessels are sacrificed during SIA,
      but the majority are preserved. In addition, SIA has the potential to open new
      collaterals within the occluded segment. These collaterals may play an important
      role should restenosis develop within the target segment.

PMID- 15174917
TI  - Controlled localized thrombolysis with the "turbo" trellis to treat acute
      arterial occlusions following major surgery.
AB  - PURPOSE: To present the management of acute arterial ischemia following major
      abdominal and orthopedic surgery using a percutaneous thrombectomy device and a
      low dose of thrombolytic agent. CASE REPORT: A 38-year-old woman with T-8
      paraplegia from a traumatic fall developed pelvic osteomyelitis, for which a left
      hemipelvectomy, hysterectomy, and partial vaginal resection were performed.
      Twelve hours after the procedure, the patient developed an ischemic left leg.
      Computed tomographic angiography demonstrated an occlusion of the left external
      iliac and common femoral arteries. A Turbo Trellis percutaneous thrombectomy
      device was used to lyse the left external iliac artery thrombosis using 1 mg of
      tissue plasminogen activator infused between the proximal and distal occluding
      balloons of the device. Total dispersion time was 5 minutes. There was complete
      thrombus removal without any significant bleeding complications. At 6 months, the
      artery remains widely patent. CONCLUSIONS: Combination therapy with mechanical
      thrombectomy devices and low dose thrombolytic agents can be used to treat acute
      arterial occlusions at a single setting. The increased speed of the Turbo Trellis
      may allow for smaller doses of thrombolytic agents and shorter treatment times.

PMID- 15174918
TI  - Two-stage combined endovascular and surgical approach for recurrent
      thoracoabdominal aortic aneurysm.
AB  - PURPOSE: To present a 2-stage combined endovascular and surgical approach for
      recurrent thoracoabdominal aortic aneurysm (TAAA). CASE REPORT: A 78-year-old man
      with previous surgical repairs of infrarenal abdominal and descending thoracic
      aortic aneurysms was referred for dysphagia due to an enlarging 9-cm aneurysm
      extending from the mid thoracic to the suprarenal aorta. Because no suitable
      endograft was available, an open repair was attempted, but the presence of a
      "frozen" chest made the redo procedure extremely difficult. A 2-stage treatment
      was thus decided upon. First, a retrograde bifurcated bypass graft was implanted
      from the abdominal aortic graft to the superior mesenteric and celiac arteries.
      Twenty days later, the TAAA was successfully excluded with a stent-graft, during
      which spinal fluid drainage was performed to prevent paraplegia. At 6 months,
      computed tomography showed patency of the endoprosthesis and visceral grafts. At
      1 year, the patient remains asymptomatic. CONCLUSIONS: This case illustrates that
      a 2-stage combined endovascular and surgical approach may be a safe and effective
      alternative to reoperation for recurrent TAAA.

PMID- 15174919
TI  - Comparison of MR angiography versus digital subtraction angiography as a basis
      for planning treatment of lower limb occlusive disease.
AB  - PURPOSE: To compare contrast-enhanced moving-bed magnetic resonance angiography
      (MRA) with digital subtraction angiography (DSA) for the ability to provide
      adequate information on which to construct a therapeutic strategy in patients
      suffering from peripheral arterial occlusive disease (PAOD). METHODS: A
      prospective study was conducted involving 48 consecutive patients (25 men; mean
      age 65.7+/-10.2 years) with PAOD who underwent MRA and DSA of the peripheral
      arteries on 2 consecutive days. Every leg was divided into 3 anatomical regions
      (suprainguinal, femoropopliteal, calf), and the sensitivity and specificity for
      the detection of significant (>70%) lesions, as well as the interobserver
      variability, were calculated. The potential differences in the therapeutic
      strategy based on the results of both modalities were evaluated. RESULTS: The MRA
      and DSA studies in the 48 study patients produced 864 arterial segments for
      interpretation. The sensitivity of MRA for the detection of significant lesions
      was 94.7% for the suprainguinal, 89.5% for the femoropopliteal, and 91.3% for the
      calf arteries. Corresponding specificity was 98.1%, 96.2% and 93.4%,
      respectively. The interobserver correlation for the detection of significant
      lesions by MRA and DSA was excellent (kappa>0.8) for all 3 segments, with
      slightly superior values for MRA. MRA and DSA agreed in the grading of 821
      (95.0%) segments. In 8 (16.7%) patients, MRA suggested an additional
      intervention, and in 3 (6.3%) patients, additional DSA was necessary for the
      final diagnosis. CONCLUSIONS: The accuracy of MRA for the detection of
      significant lesions is comparable to DSA. Basing the therapeutic strategy solely
      on the results of MRA can reduce the number of DSAs by three quarters, but at the
      risk of incurring lesion overestimation in approximately 17%.

PMID- 15174920
TI  - Health-related quality of life outcomes following elective open or endovascular
      AAA repair: a randomized controlled trial.
AB  - PURPOSE: To assess health-related quality of life outcomes after endovascular
      versus open abdominal aortic aneurysm repair. METHODS: Participants were randomly
      assigned to receive either endovascular or open abdominal aortic aneurysm (AAA)
      surgery according to a rate of 3 endovascular patients to 1 with open repair.
      Data on patient characteristics, operative aspects, and procedural and device
      related complications were compiled at a single center. Health-related quality of
      life was assessed before treatment and 1 and 3 months following operation using
      the Medical Outcomes Study Short-Form 36-item Health Survey (SF-36) and the
      EuroQol questionnaire. RESULTS: Between 1996 and 1999, 57 patients (54 men; mean
      age 69 years, range 52-82) underwent endovascular and 19 patients (16 men; mean
      age 68 years, range 52-81) underwent open AAA repairs. Preoperatively, comparable
      scores were recorded in both treatment groups. One month after operation,
      patients of both groups scored significantly lower on the SF-36 domains of Role
      Limitations due to physical problems and Pain compared to preoperative scores.
      Three months after operation, both groups had scores in all domains comparable to
      preoperative levels of functioning. There was a significant benefit for the
      endovascular group 1 month after operation in the SF-36 domains of Physical
      Functioning, Role Limitations due to physical problems, Vitality, and Pain; their
      score on the EuroQol Usual Activities item was also significantly better. After 3
      months, there were no longer differences between groups. CONCLUSIONS: Short-term
      health-related quality of life benefits were found after endovascular repair
      compared with standard open surgery.

PMID- 15174921
TI  - Exclusion of a crural pseudoaneurysm with a PTFE-covered stent-graft.
AB  - PURPOSE: To describe the successful endovascular treatment of an iatrogenic
      anterior tibial artery pseudoaneurysm with a polytetrafluoroethylene-covered
      stent-graft. CASE REPORT: A 58-year-old man was admitted to our hospital with
      pseudoarthrosis and malunion of the right distal tibia. Fibulotomy and
      intramedullary fixation were performed, which was complicated by a pseudoaneurysm
      of the anterior tibial artery. Under local anesthesia, a 4x31-mm Symbiot covered
      stent was successfully placed over the origin of the pseudoaneurysm. At 12
      months, the pseudoaneurysm remained excluded, and the anterior tibial artery was
      patent. CONCLUSIONS: Endovascular treatment of a crural artery pseudoaneurysm
      seems to be a feasible treatment option. Further experience with this technique
      is needed to validate its safety and long-term patency.

PMID- 15174922
TI  - Caffeine, priming, and tip of the tongue: evidence for plasticity in the
      phonological system.
AB  - A study was performed involving phonological priming and tip-of-the-tongue states
      (TOTs) in which participants took either 200 mg of caffeine or placebo. Results
      show a clear positive priming effect produced for the caffeine group when primed
      with phonologically related words. When primed with unrelated words, the caffeine
      subgroup produced a significant increase in the number of TOTs. This contrasting
      effect provides evidence that the positive priming of caffeine was not a result
      of caffeine's well-known alertness effects. For placebo, a significant negative
      effect occurred with the related-word priming condition. The results support the
      novel hypothesis that the blocking of A, adenosine receptors by caffeine induces
      an increased short-term plasticity effect within the phonological retrieval
      system.

PMID- 15174923
TI  - Personality and emotion: test of Gray's personality theory by means of an fMRI
      study.
AB  - Although it is known that there are fundamental personality differences in the
      behavioral responses to emotional stimuli, traits have scarcely been investigated
      in this context by means of functional imaging studies. To maximize the variance
      with respect to personality, the authors tested 12 control subjects and 12
      subjects who had sadomasochistic experiences with respect to the relationship
      between J. A. Gray's (1970) personality dimensions, the behavioral approach
      system (BAS) and the behavioral inhibition system (BIS), and brain activity in
      regions of interest. The BIS was associated with activity in numerous brain areas
      in response to fear, disgust, and erotic visual stimuli, whereas few associations
      could he detected between the BAS and brain activity in response to disgust and
      erotic stimuli.

PMID- 15174924
TI  - Tolerance to amphetamine hypophagia: a real-time depiction of learning to
      suppress stereotyped movements in the rat.
AB  - To analyze how tolerance develops to amphetamine-induced hypophagia, the authors
      recorded real-time licking responses in rats given chronic injections of the drug
      and access to milk for 30 min. Initially, licking was greatly reduced and
      occurred only late in the session. The acquisition of tolerance was characterized
      by a decrease in the latency to initiate licking, a gradual increase in the
      number of licks, and a reorganization of the temporal licking pattern such that
      licks were distributed throughout the session, interspersed with pauses. On post
      tolerance dose-response tests, licking was directly proportional to drug dose in
      some rats. The results support the view that tolerance to amphetamine hypophagia
      involves a behavioral adaptation to the motor effects of the drug.

PMID- 15174925
TI  - Intraventricular insulin and leptin reverse place preference conditioned with
      high-fat diet in rats.
AB  - The authors hypothesized that insulin and leptin, hormones that convey metabolic
      and energy balance status to the central nervous system (CNS), decrease the
      reward value of food, as assessed by conditioned place preference (CPP). CPP to
      high-fat diet was blocked in ad-lib fed rats given intraventricular insulin or
      leptin throughout training and test or acutely before the test. Insulin or leptin
      given only during the training period did not block CPP. Thus, elevated insulin
      and leptin do not prevent learning a food's reward value, but instead block its
      retrieval. Food-restricted rats receiving cerebrospinal fluid, insulin, or leptin
      had comparable CPPs. Results indicate that the CNS roles of insulin and leptin
      may include processes involving memory and reward.

PMID- 15174926
TI  - Temperament in the rat: sex differences and hormonal influences on harm avoidance
      and novelty seeking.
AB  - This study showed large and consistent individual differences in 64 rats (32
      males) in the hole board and canopy test, which are considered to measure
      exploration and anxiety, respectively. Nonestrous females were more active than
      males and nose poked more in the hole board. In the canopy test, nonestrous
      females, compared with males, showed greater intraindividual variability in time
      spent outside the protective canopy. Estrous females spent significantly more
      time outside the canopy. Gonadectomy reduced nose poking in males and hole board
      locomotion in both sexes. Principal-components analysis disclosed 2 temperamental
      dimensions reflecting harm avoidance and novelty seeking. More males had high
      levels of psychometric harm avoidance, and fewer males than females had a low
      harm-avoidance/high-novelty-seeking, sanguine profile.

PMID- 15174927
TI  - Circadian phase alteration by GABA and light differs in diurnal and nocturnal
      rodents during the day.
AB  - These studies investigated the circadian effects of light and gamma aminobutyric
      acid-A (GABAA) receptor activation in the suprachiasmatic nucleus (SCN) of the
      diurnal unstriped Nile grass rat (Arvicanthis niloticus). Microinjection of the
      GABAA agonist muscimol into the SCN during the day produced phase shifts that
      were opposite in direction to those previously reported in nocturnal rodents. In
      addition, light had no significant effect on the magnitude of muscimol-induced
      phase delays during the daytime. Injection of muscimol during the night, however,
      significantly inhibited light-induced phase delays and advances in a manner
      similar to that previously reported in nocturnal rodents. Therefore, the
      circadian effects of GABAA receptor activation are similar in diurnal and
      nocturnal species during the night but differ significantly during the day.

PMID- 15174928
TI  - D-cycloserine and the facilitation of extinction of conditioned fear:
      consequences for reinstatement.
AB  - Several recent studies have reported that D-cycloserine (DCS), a partial N-methyl
      D-aspartate agonist, facilitates extinction of learned fear in rats. Other
      studies have shown that representation of the unconditioned stimulus (US) can
      reinstate learned fear after extinction. This study examined whether this
      reinstatement effect occurs in Sprague-Dawley rats given DCS at the time of
      extinction. Results showed that saline-treated rats exhibited the reinstatement
      effect but DCS-treated rats did not (Experiments 1 and 2). This lack of
      reinstatement in DCS-treated rats was not due to residual effects of DCS on
      either US or context processing (Experiment 3). Overall, these results (a) raise
      questions about the mechanisms underlying DCS facilitation of extinction and (b)
      suggest that DCS might have substantial practical benefit.

PMID- 15174930
TI  - One-trial odor-reward association: a form of event memory not dependent on
      hippocampal function.
AB  - To examine whether the hippocampus is required for memory for unique experiences
      independent of their spatial or temporal context, the authors devised a novel
      task that requires rats to remember odor-reward associations formed within a
      single training trial. Unlike previous tests of 1-trial memory, in this task new
      associations with otherwise familiar stimuli must be formed, and accurate
      judgments cannot be based on relative familiarity or recency of the stimuli. The
      authors show that intact rats performed well on this novel test of event memory.
      Furthermore, rats with lesions of the hippocampus showed no impairments, even
      over long retention intervals. These data suggest that the hippocampus is not
      required for event-specific stimulus-reward associations and that other brain
      structures mediate this aspect of episodic memory.

PMID- 15174929
TI  - The role of claustrum in Pavlovian heart rate conditioning in the rabbit
      (Oryctolagus cuniculus): anatomical, electrophysiological, and lesion studies.
AB  - The role of the claustrum in Pavlovian heart rate (HR) conditioning was studied
      in the rabbit (Oryctolagus cuniculus) by (a) mapping claustral projections to the
      prefrontal cortex (PFC), (b) recording claustral single-unit discharge to sensory
      stimulation and conditioning stimuli during HR conditioning, and (c) assessing
      the effects of claustral damage on HR conditioning. Contralateral and ipsilateral
      claustral projections to the PFC were found. Claustral cells responded to
      nonsignal stimulation with increased discharge and also showed conditioned
      stimulus-evoked increases in discharge during Pavlovian HR conditioning.
      Moreover, claustral lesions diminished the magnitude of the HR-conditioned
      response without affecting the cardiac-orienting response to the conditioned
      stimulus or the cardiac-unconditioning response to the unconditioned stimulus,
      suggesting a role for the claustrum in associative learning.

PMID- 15174931
TI  - Effects of hippocampus and medial caudate nucleus lesions on memory for direction
      information in rats.
AB  - A delayed matching-to-sample task was designed to assess memory for direction
      information in rats. During the study phase, rats traversed a maze arm oriented
      in 1 of 3 directions. After a delay period, a test phase was presented that
      required a choice between the study phase direction and a foil direction. Once
      rats reached a learning criterion, probe trials suggested that normal rats favor
      the use of direction, rather than turning response, information and use
      vestibular feedback. Rats were then given hippocampus, medial caudate nucleus
      (MCN), or cortical control lesions. Unlike control rats, those with hippocampus
      and MCN lesions exhibited marked impairments when retested. However, all rats
      were able to learn a direction discrimination task. These results suggest that
      the hippocampus and MCN support processes associated with short-term memory for
      direction information.

PMID- 15174932
TI  - Selective lesioning of the cholinergic septo-hippocampal pathway does not disrupt
      spatial short-term memory: a comparison with the effects of fimbria-fornix
      lesions.
AB  - Rats receiving intrahippocampal injections of 192 IgG-saporin (SAP-HPC), fimbria
      fornix lesions (FF), or sham control surgeries were tested in a series of delayed
      matching (DMTP)- and nonmatching (DNMTP)-to-position tasks. The FF group was
      significantly impaired on a pretrained DNMTP task relative to the control and SAP
      HPC groups, which did not differ. All groups then acquired a matching-to-
      position rule at the same rate, and only the FF group showed a delay-dependent
      deficit when longer retention intervals were introduced for DMTP testing. Results
      demonstrate the importance of the fimbria-fornix fiber system in spatial short
      term memory but suggest that the cholinergic septohippocampal component of this
      pathway is not required for successful delayed matching (or nonmatching)-to
      position performance.

PMID- 15174933
TI  - Retrograde amnesia induced by drugs acting on different molecular systems.
AB  - The gamma aminobutyric acid-A (GABA-sub(A)) agonist, muscimol, the glutamate N
      methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonopentanoic
      acid (AP5), and the inhibitor of the extracellularly regulated kinases (ERKs), UO
      126, cause retrograde amnesia when administered to the hippocampus. In the
      present study, the authors found that they all cause retrograde amnesia for 1
      trial inhibitory avoidance, not only when infused into the dorsal CA1 region of
      the hippocampus, but also when infused into the basolateral amygdala or the
      entorhinal, parietal, and posterior cingulate cortices. The posttraining time
      course of the effect of each drug was, however, quite different across brain
      structures. Thus, in all of them, NMDA receptors and the ERK pathway are
      indispensable for memory consolidation, and GABA-sub(A) receptor activation
      inhibits memory consolidation: but in each case, their influence is interwoven
      differently.

PMID- 15174934
TI  - Evidence of a time-dependent long-term stage of memory for a spatial learning
      task in the chick (Callus gallus).
AB  - The generalizability of temporal parameters of memory formation previously
      observed for a passive avoidance task was investigated in a spatial task with day
      old chicks (Callus gallus). The percentage improvement in completion time over 2
      separate trials was measured, and chicks were found to complete the second trial
      faster at all times tested up to 2 hr, except at 55 min posttraining. In
      addition, retention at 120 min, but not at 30 min, posttraining was found to be
      impaired by protein synthesis inhibition. These findings are consistent with the
      timing of a long-term stage of memory formation following passive avoidance
      training, implying that there may be some hardwiring to the temporal
      characteristics of memory formation in this species.

PMID- 15174935
TI  - The control of feather pecking by serotonin.
AB  - Feather-pecking behavior in laying hens (Callus gallus) may be considered a
      behavioral pathology, comparable to human psychopathological disorders.
      Scientific knowledge on the causation of such disorders strongly suggests
      involvement of the serotonergic (5-hydroxytryptamine; 5-HT) system in feather
      pecking. Previously, chicks from a high-feather-pecking (HFP) line were found to
      display lower 5-HT turnover levels than chicks from a low-feather-pecking (LFP)
      line (in response to acute stress; Y. M. van Hierden et al., 2002). The present
      study investigated whether low 5-HT neurotransmission modulates feather pecking.
      First. S-15535, a somatodendritic 5-HT-sub(1A) autoreceptor agonist, was
      demonstrated to be an excellent tool for reducing 5-HT turnover in the forebrain
      of LFP and HFP chicks. Second, the most effective dose of S-15535 (4.0 mg/kg body
      weight) significantly increased severe feather-pecking behavior. The results
      confirmed the postulation that the performance of feather pecking is triggered by
      low 5-HT neurotransmission.

PMID- 15174936
TI  - Sexual dimorphism and the NMDA receptor in alloparental behavior in juvenile
      prairie voles (Microtus ochrogaster).
AB  - The prairie vole (Microtus ochrogaster) exhibits parental behavior in both males
      and females and extensive alloparenting in juveniles. The authors studied the
      effects on juvenile alloparenting of antagonists for the PCP, glycine, and
      glutamate sites on the N-methyl-D-aspartate (NMDA) receptor. In male voles, all 3
      drugs had an inverted-U dose-response curve. This change could not be attributed
      to fear of the pup or a nonspecific impairment of cognition, level of locomotor
      activity, or motor coordination. The PCP site antagonist had a U-shaped dose
      response curve in females, the opposite of that in males, but neither of the
      other drugs changed female alloparental behavior. Both male and female voles
      exhibit alloparental behavior, but its neurobiological underpinnings are sexually
      dimorphic in juveniles.

PMID- 15174937
TI  - Early and later adoptions differently modify mother-pup interactions.
AB  - Life events occurring during the perinatal period have strong long-term effects.
      In rats, prenatal stress, postnatal maternal separations, or adoptions at
      different periods are known to affect behavior and reactivity to stress in
      offspring. To determine the role of maternal factors on differential outcome
      adoptions, the authors investigated interactions between pups and the adopting
      mothers by assessing both pups' ultrasound emissions and maternal behavior. Early
      and late adoptions increased mother care at the moment of adoption and during
      mother-infant reunion after a separation procedure. However, although early
      adoption induced a decrease in pups' ultrasound emissions in response to a
      stressful separation, later adoptions enhanced it. Results suggest a sensitive
      period during which fostering may change pups' and dams' behavior.

PMID- 15174938
TI  - Hemispheric specialization in the primary auditory area of awake and anesthetized
      starlings (Sturnus vulgaris).
AB  - Although evidence exists for a lateralization of song production, few studies
      have focused on the perceptual aspect of lateralization in songbirds. In the
      present study, the authors recorded neuronal responses to a variety of species
      specific and artificial, nonspecific stimuli in both hemispheres of awake and
      anesthetized male starlings (Sturnus vulgaris). Recordings were made in the
      primary auditory area of the songbird brain, the Field L complex. The right
      hemisphere exhibited significantly more responsive units than the left hemisphere
      in awake birds, and this difference was significantly reduced in anesthetized
      birds. Furthermore, clear hemispheric specialization toward categories of
      behaviorally relevant stimuli and precise parameters of these stimuli were found.
      The main auditory area of the starling's brain thus appears to show some degree
      of lateralization.

PMID- 15174939
TI  - Brain pathways and behavioral responses to weak electric fields in parasitic sea
      lampreys (Petromyzon marinus).
AB  - The authors characterized the behavioral and brain responses of parasitic sea
      lampreys (Petromyzon marinus) to weak electric fields. Lampreys showed
      preferences for the cathodal end of the testing aquarium after electric
      stimulation. Within a range of cathodal fields (-0.1 to -30.0 mu-V/cm), lampreys
      exhibited increased active behaviors. In contrast, anodal fields decreased most
      active behaviors below baseline. Exposure to electric fields resulted in changes
      in Western blot patterns for the neuronal activity markers Fos, Fos-B. and Jun in
      whole-brain homogenate. Electric stimulation also increased Fos-B
      immunoreactivity in the octavolateral and the habenula-fasciculus retroflexus
      interpeduncular systems. These results confirm that the octavolateral system is
      associated with electroreception and suggest that the habenula-fasciculus
      retroflexus-interpeduncular system may be pan of the electroreceptive network.

PMID- 15174940
TI  - Peptide effects on social behavior: effects of vasotocin and isotocin on social
      approach behavior in male goldfish (Carassius auratus).
AB  - The authors measured the effects of centrally infused peptides on social approach
      behaviors in goldfish (Carassius auratus), a social teleost. Vasotocin (VT)
      inhibited approach responses toward the visual stimuli of conspecifics in the
      absence of aggressive or sexual olfactory contextual cues in males, and a V1
      receptor antagonist stimulated such responses, at least in males that were not
      highly social in baseline conditions, as did isotocin (IT). In the absence of
      social stimuli, VT did not affect activity, therefore indicating that the
      inhibition was not the result of nonspecific effects on arousal or motor
      functioning. These experiments indicate that VT and IT induce opposite effects on
      social approach responses in male goldfish and that endogenous VT, at least, is
      associated with levels of sociality.

PMID- 15174941
TI  - Comparison of operant escape and innate reflex responses to nociceptive skin
      temperatures produced by heat and cold stimulation of rats.
AB  - In behavioral tests, rats performed learned escape responses to thermal
      stimulation of the paws by 44.0. 47.0. or 0.3 degrees C. Licking, guarding, and
      jumping reflexes were evaluated at these temperatures. The frequency, latency,
      and duration of escape and reflex responses were compared and were related to
      hind-paw skin temperatures measured during stimulation of awake and anesthetized
      rats. The duration and latency of escape from heat were appropriately related to
      stimulus intensity. Escape occurred reliably for each intensity. Reflexes
      occurred unreliably and at long latency to 44.0 or 0.3 degrees C and were not
      appropriately related to heat intensity. The reflexes were relatively insensitive
      to thermal nociceptive stimulation other than heating of the skin at a high rate.

PMID- 15174942
TI  - Adenoviral vector-mediated rescue of the OMP-null behavioral phenotype:
      enhancement of odorant threshold sensitivity.
AB  - Mice from which the olfactory marker protein (OMP) gene has been deleted
      demonstrate a number of neurophysiologic and behavioral defects that suggest OMP
      is an important component in olfactory signal transduction and is critically
      involved in odor processing. Recently, the potential pleiotropic effects of gene
      deletion were addressed by adenoviral vector-mediated rescue of the
      neurophysiologic defects, in vivo. As a complement to this study, the authors
      used a recombinant adenoviral vector to transiently introduce OMP into olfactory
      sensory neurons of adult OMP-null mice and, using psychophysical methods,
      demonstrated the resulting reacquisition of behavioral function subsequent to
      gene replacement. The rescue of the OMP-null behavioral phenotype further
      supports the hypothesis that OMP is an important component in olfactory signal
      amplification and/or transduction processing.

PMID- 15174943
TI  - A comparison of GluR-A-deficient and wild-type mice on a test battery assessing
      sensorimotor, affective, and cognitive behaviors.
AB  - Previous studies have demonstrated a spatial working memory deficit in glutamate
      receptor (GluR)-A (GluR1) AMPA receptor subunit knockout mice. The present study
      evaluated male and female wild-type and GluR-A-/- mice on a test battery that
      assessed sensorimotor, affective, and cognitive behaviors. Results revealed a
      behavioral phenotype more extensive than previously described. GluR-A-/- mice
      were hyperactive, displayed a subtle lack of motor coordination, and were
      generally more anxious than wild-type controls. In addition, they showed a
      deficit in spontaneous alternation, consistent with previous reports of a role
      for GluR-A-dependent plasticity in hippocampus-dependent, spatial working memory.
      Although changes in motor coordination or anxiety cannot explain the
      dissociations already reported within the spatial memory domain, it is clear that
      they could significantly affect interpretation of results obtained in other kinds
      of behavioral tasks.

PMID- 15174944
TI  - Role of cyclic GMP in nitrous-oxide-induced anxiolytic-like behavior in the mouse
      light-dark exploration test.
AB  - Nitric oxide (NO) has been implicated in the anxiolytic-like behavioral effects
      of nitrous oxide (N2O). This study was conducted to determine whether NO
      activates a soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP)
      pathway in the behavioral response to N2O in the light-dark exploration test. In
      mice pretreated with an sGC inhibitor, the increased light-compartment activity
      normally induced by N2O was significantly attenuated. Pretreatment with a cGMP
      phosphodiesterase inhibitor antagonized the anxiogenic effect of 15% N2O and
      enhanced the anxiolytic effect of 25% N2O, implying that cGMP reduces anxiety.
      These preliminary findings suggest that a signaling pathway involving NO and cGMP
      may mediate the behavioral effects of N2O.

PMID- 15174945
TI  - The behavioral deficit observed following noncontingent shock in spinalized rats
      is prevented by the protein synthesis inhibitor cycloheximide.
AB  - Spinalized rats that receive shock when 1 hind limb is extended (contingent
      shock) exhibit an increase in flexion duration, a simple form of instrumental
      learning. Rats that receive shock independent of leg position (noncontingent
      shock) do not exhibit an increase in flexion duration and fail to learn when
      tested with contingent shock 24 hr later. It appears that noncontingent shock
      induces an intraspinal modification that inhibits the capacity to learn. The
      authors propose that the mechanisms that underlie this effect depend on de novo
      protein synthesis. To evaluate this hypothesis, the authors gave spinalized rats
      the protein synthesis inhibitor Cycloheximide (CXM) or saline intrathecally prior
      to, or immediately after, noncontingent shock exposure. Twenty-four hours later,
      rats were tested with contingent shock. Rats that received the vehicle and
      noncontingent shock failed to learn. CXM-treated shocked rats learned normally,
      suggesting that the learning deficit depends on protein synthesis within the
      spinal cord.

PMID- 15174947
TI  - Molecular biological design of novel antineoplastic therapies.
AB  - Novel therapies represent a new strategy for the development of anticancer
      agents. New targets derived from the knowledge of the molecular structure and
      genetic defects has been useful in developing anticancer drugs that prolong or
      stabilise the progression of tumours with minimal systemic toxicities. In this
      review, the mechanism of action and the most significant trials regarding
      monoclonal antibodies, tyrosine kinase inhibitors, angiogenesis and
      cyclooxygenase inhibitor-based therapies, farnesyl transferase inhibitors and
      proteasome inhibitors are discussed. The potential biological end points and
      toxicities are also described. In conclusion, novel therapies present a promising
      class of anticancer agents, acting through different mechanisms and offering a
      new perspective in the treatment of cancer.

PMID- 15174946
TI  - Chimpanzees (Pan troglodytes) are predominantly right-handed: replication in
      three populations of apes.
AB  - Population-level right-handedness has historically been considered a hallmark of
      human evolution. Even though recent studies in chimpanzees (Pan troglodytes) have
      demonstrated population-level right-handedness for certain behaviors, some have
      questioned the validity and consistency of these findings by arguing that
      reported laterality effects are specific to certain colonies of apes and to those
      chimpanzees reared by humans. The authors report evidence of population-level
      right-handedness in 3 separate colonies of chimpanzees. Moreover, handedness in
      the 3 colonies was unrelated to the proportion of subjects that were raised by
      humans. This is the strongest evidence to date that population-level handedness
      is evident in chimpanzees and is not an artifact of human rearing.

PMID- 15174948
TI  - Novel targeted agents in the treatment of lung cancer.
AB  - Lung cancer is the leading cause of cancer-related mortality in the US. Although
      an improvement in outcome is possible with the continued advancement of cytotoxic
      based treatment, clinical research is currently focused on utilising novel
      molecular targets with proven efficacy in preclinical models and a low toxicity
      profile. This is the result of advances in understanding of tumour biology and
      molecular pathways that have been implicated in cancer pathogenesis and
      progression. Novel agents targeting cell cycle regulation, angiogenesis and
      signal transduction pathways have reached clinical testing in lung cancer and are
      discussed in this review.

PMID- 15174949
TI  - Colon cancer angiogenesis and antiangiogenic therapy.
AB  - Metastatic development is the primary cause of cancer treatment failure and is
      responsible for most deaths from colorectal cancer. For the majority of patients,
      by the time primary colorectal cancers are diagnosed, sub-clinical or clinically
      relevant liver metastases have already occurred. The formation of liver
      metastases represents a highly selective sequence in which a subpopulation of
      cells, within a tumour, express genes that allow them to progress through
      distinct steps and spread to distant organs. Modification of gene expression in
      these cells leads to transformation, growth, angiogenesis, invasion,
      dissemination, survival in systemic circulation and attachment in the organ of
      metastases. Existing therapies directed at metastatic disease of the liver have
      had minimal impact on outcome. Contemporary treatment regimens are not likely to
      significantly alter the natural history of liver metastases. Consequently,
      understanding the molecular and biological mechanisms of colorectal cancer may
      allow for the development of therapeutic strategies designed to prevent and treat
      liver metastases. Standard chemotherapy regimens have had only minimal success in
      effectively treating metastatic colorectal cancer. This review focuses on the
      molecular and biological mechanisms of colorectal cancer angiogenesis. In
      addition, this report will evaluate the novel antiangiogenic therapeutic
      strategies targeting colorectal cancer and hepatic metastases.

PMID- 15174951
TI  - The potential of Na+/Ca2+ exchange blockers in the treatment of cardiac disease.
AB  - The Na(+)/Ca(2+) exchanger (NCX), a surface membrane antiporter, is the primary
      pathway for Ca(2+) efflux from the cardiac cell and a determinant of both the
      electrical and contractile state of the heart. Enhanced expression of NCX has
      recently been recognised as one of the molecular mechanisms that contributes to
      reduced Ca(2+) release, impaired contractility and an increased risk of
      arrhythmias during the development of cardiac hypertrophy and failure. The NCX
      has also been implicated in the mechanism of arrhythmias and cellular injury
      associated with ischaemia and reperfusion. Hence, NCX blockade represents a
      potential therapeutic strategy for treating cardiac disease, however, its
      reversibility and electrogenic properties must be taken into consideration when
      predicting the outcome. NCX inhibition has been demonstrated to be protective
      against ischaemic injury and to have a positive inotropic and antiarrhythmic
      effect in failing heart cells. However, progress has been impaired by the absence
      of clinically useful agents. Two drugs, KB-R7943 and SEA-0400, have been
      developed as NCX blockers but both lack specificity. Selective peptide inhibitors
      have been well characterised but are active only when delivered to the
      intracellular space. Gene therapy strategies may circumvent the latter problem in
      the future. This review discusses the effects of NCX blockade, supporting its
      potential as a new cardiovascular therapeutic strategy.

PMID- 15174952
TI  - Novel approaches to antifungal prophylaxis.
AB  - Antifungal prophylaxis represents a significant advance in the management of
      patients at risk from fungal infections in a variety of settings. Identification
      of patients at the highest risk and the utilisation of safe and effective drugs
      maximises the benefits of prophylaxis. Situations in which antifungal prophylaxis
      has been shown to be useful are bone marrow transplantation, liver and lung
      transplantation, surgical and neonatal intensive care units, secondary
      prophylaxis of fungal infections associated with HIV and neutropenia associated
      haematological malignancies and their treatment. New antifungal agents, such as
      the echinocandins and the new azoles, are available and have a potential role in
      antifungal prophylaxis. Future studies should evaluate which strategy is more
      useful; prophylaxis or pre-emptive therapy.

PMID- 15174950
TI  - Recent advances in natriuretic peptides in congestive heart failure.
AB  - Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are
      secreted by the heart and play important roles in the compensation of congestive
      heart failure with their vasodilating, natriuretic, antiproliferative, lusitropic
      and neurohumoral-modulating properties. Based on these beneficial properties,
      exogenous BNP was developed as a new treatment for congestive heart failure and
      approved in the US for acute decompensated heart failure. New therapeutic
      strategies for heart failure that are currently being investigated include
      chronic subcutaneous BNP administration and intermittent BNP infusions.
      Furthermore, strategies combining exogenous BNP with an inhibitor of the BNP
      degrading enzyme neutral endopeptidase could contribute to maximising the actions
      of BNP and reduce the amount of exogenous BNP needed.

PMID- 15174953
TI  - Immunotherapeutics for nosocomial infections.
AB  - Nosocomial or hospital-acquired infections are associated with prolonged
      hospitalisation and increased healthcare costs and resource utilisation.
      Continued advances in sophisticated medical procedures, an increase in the number
      of immunocompromised patients and a steady rise in the prevalence of antibiotic
      resistant organisms has renewed interest in the development of novel therapies
      that can treat nosocomial infections. This review focuses on novel immunological
      approaches to address this significant unmet medical need.

PMID- 15174954
TI  - Vaccines for the prevention of respiratory viral infections: problems and current
      status.
AB  - Acute respiratory virus infections cause the majority of lower respiratory tract
      illnesses and hospitalisations of infants and the elderly. The emergence of new
      respiratory viruses and a high probability that influenza will cause further
      pandemics highlights the necessity for developing better preventative strategies.
      Although there is a clear and pressing need for vaccines to prevent respiratory
      syncytial virus, rhinoviruses, coronaviruses, parainfluenza and human
      metapneumovirus, progress has been extremely slow. This review presents the
      current status of vaccine development for respiratory viral diseases and outlines
      novel approaches for the future.

PMID- 15174955
TI  - Cataract formation and prevention.
AB  - Cataract, a leading cause of blindness worldwide, is a multifactorial eye
      disease. In developing countries the incidence of cataract among young
      generations is not uncommon due to malnutrition, excess exposure to ultraviolet
      radiation and so on. In developed countries, age-related cataract affecting the
      population over 65 years of age is a major concern. Oxidative stress was
      suggested to inflict damage to the lens and induce opacification, and a variety
      of antioxidant nutrients were tested for the prevention or delay of cataract
      development. Although promising results were obtained in animal studies of
      various antioxidants, epidemiological studies on human populations do not seem to
      support their protective effects unequivocally. It is unlikely that age-related
      cataract in man, similar to the ageing process itself, will be prevented or
      delayed by therapeutic drugs in the foreseeable future. At present, keeping a
      health-conscious life style (i.e., no smoking) may be the most effective and
      least expensive strategy to prevent the onset of age-related cataract.

PMID- 15174956
TI  - Vascular biology support for the use of bevacizumab in colorectal cancer.
AB  - In colorectal cancer, increased expression of the angiogenesis promoter vascular
      endothelial growth factor correlates with invasiveness, vascular density,
      metastases, recurrence and prognosis. Bevacizumab is a recombinant humanised
      monoclonal antibody to vascular endothelial growth factor. In recent clinical
      trials, bevacizumab has been shown to prolong the time to disease progression and
      the survival of patients with colorectal cancer. In six patients with
      adenocarcinoma of the rectum, bevacizumab decreased tumour blood perfusion and
      volume, interstitial fluid pressure, the number of circulating endothelial cells
      and fluorodeoxyglucose uptake. Surgical specimens showed a marked response in all
      six patients with only microscopic disease in five of the patients. These effects
      of bevacizumab on the vascular biology of tumours probably underlie the
      progression and survival benefits observed in clinical trials of colorectal
      cancer.

PMID- 15174957
TI  - Intensive lipid-lowering therapy in coronary artery disease: implications of the
      REVERSAL and PROVE-IT trials.
AB  - Current international guidelines recommend that the goal of treatment with lipid
      lowering therapy in patients with established coronary artery disease (CAD)
      should be a low-density lipoprotein cholesterol level of < 100 mg/dl. The
      question that remains to be answered is whether more aggressive lowering of low
      density lipoprotein cholesterol levels below this target offers additional
      benefit and whether it can be tolerated. Two recently published related studies
      addressed this question by comparing intensive lipid lowering with atorvastatin
      (Lipitor, Pfizer) 80 mg/day with a moderate lipid-lowering regimen of pravastatin
      (Pravachol, Bristol-Myers Squibb) 40 mg/day. The first study, the Reversing
      Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) compared the effect of
      the two regimens on coronary artery atheroma burden and progression using
      intravascular ultrasound in patients with symptomatic CAD. The second study, the
      Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) was a
      clinical outcome trial in patients recently hospitalised with acute coronary
      syndromes. This article reviews the implications of these two studies in the
      management of patients with CAD. In addition, other ongoing trials and future
      directions are explored.

PMID- 15174958
TI  - Antibacterial drug discovery & development summit.
AB  - Over 100 senior researchers and managers from academic and industrial research
      organisations attended this 2-day annual international discovery summit on
      antibacterial R&D. A number of firms, particularly biotechnology firms, presented
      compounds that are advancing through clinical development. In addition, areas for
      basic research and development included metallo-beta-lactamases, ribosomal
      structural studies and phage-selected targets were described.

PMID- 15174959
TI  - Cutaneous gene therapy for haemophilia.

PMID- 15174960
TI  - Immunome-derived vaccines.
AB  - Immune response to a subset of antigens and epitopes derived from an infectious
      pathogen may be sufficient for competent protection; immune recognition of every
      potential epitope derived from the pathogen's genome does not appear to be
      required. The pneumococcal and hepatitis vaccines, both of which are subunit
      vaccines, illustrate this premise. Similarly, 'immunome-derived vaccines' are
      based on the concept that response to the subset of antigens and epitopes that
      interface with the host immune system (the immunome) and not the whole organism
      (represented by the proteome or genome) can be sufficient for protection.
      Competent immune responses to cancer are also probably restricted to the
      neoplasm's 'immunome', although the set of antigens that drive successful immune
      response to cancer cells has proven more difficult to uncover. Researchers are
      now using bioinformatics sequence analysis tools, epitope mapping tools,
      microarrays and high-throughput immunology assays to discover the components of
      the immunome, which are then used to compose these new vaccines. At least one
      immunome-derived vaccine is in clinical trials and many others are in the vaccine
      pipeline. Due to the rapid improvement of immunoinformatics tools and
      immunological assays, the era of immunome-derived vaccines has begun.

PMID- 15174961
TI  - What is regenerative medicine? Emergence of applied stem cell and developmental
      biology.
AB  - Regenerative medicine is an emerging, but still poorly defined, field of
      biomedicine. The ongoing 'regenerative medicine revolution' is based on a series
      of new exciting breakthrough discoveries in the field of stem cell biology and
      developmental biology. The main problem of regenerative medicine is not so much
      stem cell differentiation, isolation and lineage diversity, although these are
      very important issues, but rather stem cell mobilisation, recruitment and
      integration into functional tissues. The key issue in enhancing tissue and organ
      regeneration is how to mobilise circulating stem and progenitor cells and how to
      provide an appropriate environment ('niche') for their tissue and organo-specific
      recruitment, 'homing' and complete functional integration. We need to know more
      about basic tissue biology, tissue regeneration and the cellular and molecular
      mechanisms of tissue turnover (both cellular and extracellular components) at
      different periods of human life and in different diseases. Systematic in silico,
      in vitro and in vivo research is a foundation for further progress in
      regenerative medicine. Regenerative medicine is a rapidly advancing field that
      opens new and exciting opportunities for completely revolutionary therapeutic
      modalities and technologies. Regenerative medicine is, at its essence, an
      emergence of applied stem cell and developmental biology.

PMID- 15174962
TI  - Gene transfer to epidermal stem cells: implications for tissue engineering.
AB  - The skin is an attractive target for gene therapy because it is easily accessible
      and shows great potential as an ectopic site for protein delivery in vivo.
      Genetically modified epidermal cells can be used to engineer three-dimensional
      skin substitutes, which when transplanted can act as in vivo 'bioreactors' for
      delivery of therapeutic proteins locally or systemically. Although some gene
      transfer technologies have the potential to afford permanent genetic
      modification, differentiation and eventual loss of genetically modified cells
      from the epidermis results in temporary transgene expression. Therefore, to
      achieve stable long-term gene expression, it is critical to deliver genes to
      epidermal stem cells, which possess unlimited growth potential and self-renewal
      capacity. This review discusses the recent advances in epidermal stem cell
      isolation, gene transfer and engineering of skin substitutes. Recent efforts that
      employ gene therapy and tissue engineering for the treatment of genetic diseases,
      chronic wounds and systemic disorders, such as leptin deficiency or diabetes, are
      reviewed. Finally, the use of gene-modified tissue-engineered skin as a
      biological model for understanding tissue development, wound healing and
      epithelial carcinogenesis is also discussed.

PMID- 15174963
TI  - Biodegradable polyester elastomers in tissue engineering.
AB  - Tissue engineering often makes use of biodegradable scaffolds to guide and
      promote controlled cellular growth and differentiation in order to generate new
      tissue. There has been significant research regarding the effects of scaffold
      surface chemistry and degradation rate on tissue formation and the importance of
      these parameters is widely recognised. Nevertheless, studies describing the role
      of mechanical stimuli during tissue development and function suggest that the
      mechanical properties of the scaffold will also be important. In particular,
      scaffold mechanics should be taken into account if mechanical stimulation, such
      as cyclic strain, will be incorporated into strategies to grow improved tissues
      or the target tissue to be replaced has elastomeric properties. Biodegradable
      polyesters, such as polyglycolide, polylactide and poly(lactide-co-glycolide),
      although commonly used in tissue engineering, undergo plastic deformation and
      failure when exposed to long-term cyclic strain, limiting their use in
      engineering elastomeric tissues. This review will cover the latest advances in
      the development of biodegradable polyester elastomers for use as scaffolds to
      engineer tissues, such as heart valves and blood vessels.

PMID- 15174964
TI  - Use of Sertoli cell transplants to provide local immunoprotection for tissue
      grafts.
AB  - The recent success of allogeneic islet transplantation for the treatment of type
      I diabetes has renewed interest in cell therapy for diseases of secretory cell
      dysfunction. Unfortunately, widespread clinical use of cell transplantation is
      limited by tissue availability and the need for long-term immunosuppresion.
      Testicular Sertoli cells can confer local immunoprotection for co-transplanted
      cells and may provide a means of overcoming the obstacles associated with cell
      transplantation. Sertoli cell grafts protect islets in animal models of diabetes
      and can be transplanted into the brain to enhance regeneration and promote the
      survival of co-grafted tissues. This review describes the role that Sertoli cells
      normally play in testicular immunology, details the preclinical data using
      transplanted Sertoli cells in models of diabetes and Parkinson's disease and
      discusses some of the possible mechanisms involved in this phenomena, as well as
      the future of this technology.

PMID- 15174965
TI  - Role of interferons in the treatment of severe acute respiratory syndrome.
AB  - Severe acute respiratory syndrome (SARS) is caused by the SARS coronavirus (SCV).
      The disease appeared in the Guandong province of southern China in 2002. The
      epidemic affected > 8422 patients and caused 908 deaths in 29 countries on 5
      continents. Several treatment modalities were tried with limited success to treat
      SARS and a variety of experimental drugs are under development. Type I
      interferons (IFNs-alpha/beta) were suggested as potential candidates to treat
      SARS. Several animal and human coronaviruses, including SCV, were shown to be
      sensitive to IFNs both in vitro and in vivo. A pilot clinical report showed
      effectiveness of IFN-alpha for the treatment of SARS patients. This review
      summarises antiviral activities of IFNs with special regard to SARS, and reviews
      the published clinical and experimental data describing the use of IFNs for SARS.

PMID- 15174966
TI  - Interleukin-16 and peptide derivatives as immunomodulatory therapy in allergic
      lung disease.
AB  - The therapeutic potential of interleukin (IL)-16 and derived peptides in allergic
      asthma is considered, focusing on key interactions with CD4 and associated
      chemokine receptors. IL-16 is a pleiotropic cytokine that has multiple effector
      functions with putative roles in varied T cell-mediated inflammatory diseases,
      such as asthma, inflammatory bowel disease and atopic dermatitis. Both in vitro
      and in vivo, IL-16 downregulates antigen-driven T cell activation, T helper 2
      cytokine production and allergic airway inflammation. Peptides derived from the C
      terminal bioactive portion of IL-16 offer advantages related to their retained
      immunomodulatory properties and absence of signalling in and chemoattraction to T
      cells.

PMID- 15174967
TI  - Therapeutic potential of targeting IL-1 and IL-18 in inflammation.
AB  - Interleukin (IL)-1 and IL-18 are cytokines that play a major role in autoimmune
      and inflammatory human disease. Both cytokines drive a wide range of pro
      inflammatory effector networks in many cell types and use common signal
      transduction cascades. IL-1, IL-18 and other members of the IL-1 superfamily are
      expressed at elevated levels in tissue and fluid samples isolated from patients
      with many chronic inflammatory diseases. These cytokines are primary drivers in
      acute and chronic animal models of inflammation and their blockade has been shown
      to ameliorate disease in preclinical studies. Biological agents that target IL-1
      have demonstrated efficacy in patients with rheumatoid arthritis, and further
      agents targeting IL-1 or IL-18 neutralisation are in clinical development. The
      potential for such agents spans human disease where tissue destruction is a
      primary end point of cytokine action.

PMID- 15174968
TI  - Viral vectors for inducing CD8+ T cell responses.
AB  - CD8(+) T cells (T(CD8+)) can mediate protective immunity to intracellular
      pathogens and tumours. Viruses generate strong T(CD8+) responses and, therefore,
      represent attractive vectors for generating vaccines aimed at producing T(CD8+)
      mediated protective immunity. This review will examine the immunological
      properties of viruses that make them good candidates as vaccine vectors, as well
      as the manipulations of both vector and antigen that may be required to produce
      an effective vaccine. The areas addressed include virus infection of dendritic
      cells in vivo, stimulation of the innate immune response via intracellular and
      extracellular pattern recognition receptors, the effect of antigenic form on the
      pathways of antigen presentation and the requirement for elimination of viral
      genes that target various aspects of the innate and adaptive immune response.

PMID- 15174969
TI  - Regulation of haematopoiesis by growth factors - emerging insights and therapies.
AB  - Haematopoiesis is regulated by a wide variety of glycoprotein hormones, including
      stem cell factor, granulocyte-macrophage colony-stimulating factor,
      thrombopoietin and IL-3. These haematopoietic growth factors (HGFs) share a
      number of properties, including redundancy, pleiotropy, autocrine and paracrine
      effects, receptor subunit oligomerisation and similar signal transduction
      mechanisms, yet each one has a unique spectrum of haematopoietic activity.
      Ongoing studies with knockout mice have discovered previously unrecognised
      physiological roles for HGFs, linking haematopoiesis to innate immunity,
      pulmonary physiology and bone metabolism. The regulation of stem cells by HGFs
      within niches of the bone marrow microenvironment is now well recognised and
      similar mechanisms appear to exist in the regulation of other stem cell
      compartments. Alternative signalling strategies, other than tyrosine kinase
      activation and phosphotyrosine cascades, may account for some of the more subtle
      differences between HGFs. Accumulating evidence suggests that some, but not all,
      HGF receptors can transduce a genuine lineage-determining signal at certain
      points in haematopoiesis. Further studies, primarily at the receptor level, are
      needed to determine the mechanisms of instructive signalling, which may include
      phosphoserine cascades. Novel haematopoietic regulators, as well as the
      development of biological therapies, including growth factor antagonists and
      peptide mimetics, are also discussed.

PMID- 15174970
TI  - Hydrogels for oral delivery of therapeutic proteins.
AB  - In recent years there has been significant new interest in the development of
      transmucosal (mostly oral) pharmaceutical formulations for the delivery of
      therapeutic proteins. Emphasis has been given to the molecular design of new
      carriers for the delivery of insulin, calcitonin and various types of interferons
      for the treatment of diabetes, osteoporosis, multiple sclerosis and cancer. Most
      popular carriers include advanced designs of swollen hydrogels prepared from
      neutral or intelligent polymeric networks. In this review, the most successful of
      such systems are presented and their promise in the field described.

PMID- 15174971
TI  - Particle-mediated DNA vaccine delivery to the skin.
AB  - Particle-mediated DNA vaccines employ a physical, intracellular delivery device
      to achieve the deposition of plasmid DNA-based expression vectors directly into
      the interior of cells of the skin. The resultant bolus of transient antigen
      expression in keratinocytes and trafficking dendritic cells results in the
      induction of humoral and cellular immune responses in various animal models and
      humans, mimicking characteristics of live or live-vectored vaccines. Ultimately,
      DNA vaccine success in the clinic will depend on both the successful
      intracellular delivery of a plasmid vector and an immunostimulator or adjuvant to
      maximise humoral and cellular immune responses to the encoded antigen(s). To this
      end, recent DNA vaccine clinical trials are confirming the importance of an
      intracellular delivery system, while preclinical studies in animal models are
      demonstrating the feasibility of augmenting responses through the use of DNA
      encoded immunostimulators. Particle-mediated DNA vaccines represent a promising
      tool for developing candidate vaccines against some of the more difficult
      infectious, parasitic and oncologic disease targets.

PMID- 15174972
TI  - Vaccinia as a vector for gene delivery.
AB  - Gene therapy is a promising approach, yet so far it has shown limited
      effectiveness in many clinical trials, mainly due to insufficient gene
      transduction. Recombinant vaccinia virus (rVV) has been well developed as a gene
      delivery vector, initially for protein expression in mammalian cells. rVV has
      been further developed to express antigens in vivo in generating immunity for
      protection against specific infectious diseases and cancer. rVVs, as non
      replicating viral vectors, have been demonstrated for their great potential as
      vaccines, for their diminished cytopathic effects, high levels of protein
      expression and strong immunogenicity, and they are relatively safe in animals and
      in human patients. A number of clinical trials using rVVs as vaccines have shown
      promising results for treating infectious diseases and cancer. In the last few
      years, due to its exceptional ability to replicate in tumour cells, the Western
      Reserve strain vaccinia has been explored as a replicating oncolytic virus for
      cancer virotherapy. As more is learned about the functions of viral gene products
      in controlling the mammalian cell cycle and in disabling cellular defence
      mechanisms, specific viral functions can be augmented or eliminated to enhance
      antitumour efficacy and improve tumour cell targeting. General mechanisms by
      which this oncolytic virus achieves the antitumour efficacy and specificity are
      reviewed. Specifically, the deletion of the viral genes for thymidine kinase and
      vaccinia growth factor resulted in a vaccinia mutant with enhanced tumour
      targeting activity and fully retaining its efficiency of replication in cancer
      cells. Other potential strategies for improving this vector for gene delivery
      will also be discussed in this review.

PMID- 15174973
TI  - Gene therapy for renal disorders.
AB  - During the last 20 years there have been major improvements in renal replacement
      therapy, including dialysis and kidney transplantation; however, the treatment
      options for renal diseases are still limited. Gene therapy is a potential
      modality for many renal diseases for which we are as yet unable to offer specific
      treatment. This article reviews the recent data on gene therapy in animal models
      applicable to human renal diseases and evaluates its efficacy, safety and
      clinical relevance. Several approaches appear to be promising, including adeno
      associated viral vectors for long-term gene expression, electroporation for
      muscular gene delivery, ultrasound/microbubble-mediated gene targeting,
      macrophage-based gene therapy and small interfering RNAs.

PMID- 15174974
TI  - Antisense approaches in prostate cancer.
AB  - Patients with hormone refractory prostate cancer have limited treatment options
      and new therapies are urgently needed. Advances in the understanding of the
      molecular mechanisms implicated in prostate cancer progression have identified
      many potential therapeutic gene targets that are involved in apoptosis, growth
      factors, cell signalling and the androgen receptor (AR). Antisense
      oligonucleotides are short sequences of synthetic modified DNA that are designed
      to be complimentary to a selected gene's mRNA and thereby specifically inhibit
      expression of that gene. The antisense approach continues to hold promise as a
      therapeutic modality to target genes involved in cancer progression, especially
      those in which the gene products are not amenable to small molecule inhibition or
      antibodies. The current status and future direction of a number of antisense
      oligonucleotides targeting several genes, including BCL-2, BCL-XL, clusterin, the
      inhibitors of apoptosis (IAP) family, MDM2, protein kinase C-alpha, c-raf,
      insulin-like growth factor binding proteins and the AR, that have potential
      clinical use in prostate cancer are reviewed.

PMID- 15174975
TI  - Use of CpG oligodeoxynucleotides as immunoprotective agents.
AB  - Single-stranded oligodeoxynucleotides (ODNs) synthesised to express unmethylated
      'CpG motifs' mimic the ability of bacterial DNA to trigger the innate immune
      system. CpG ODNs stimulate cells that express Toll-like receptor 9, initiating an
      immunomodulatory cascade resulting in the activation of B and T lymphocytes,
      natural killer cells, monocytes, macrophages and dendritic cells. CpG ODNs
      improve the host's ability to resist infection by accelerating and improving the
      induction of an innate and then adaptive immune response, characterised by the
      production of Th1 and pro-inflammatory cytokines, chemokines and polyreactive
      antibodies. Studies in rodents and non-human primates demonstrate that CpG ODNs
      can protect the host against bacterial, viral, fungal and parasitic infections.
      CpG-induced protection develops rapidly but persists for only a few weeks.
      Preclinical and clinical trials suggest that CpG ODNs can be used safely to
      activate the human immune system.

PMID- 15174976
TI  - Application of Quillaja saponaria extracts as oral adjuvants for plant-made
      vaccines.
AB  - Extracts from the Quillaja saponaria tree are known to provide immune
      potentiating responses and, hence, can be useful as adjuvants. Partial
      purification from the crude (food-grade) extract results in Quil A, which is
      contained in several veterinary vaccines. Further purification can provide
      concentrated saponin fractions such as QS-21, which is currently under
      investigation as a potential adjuvant for use in humans. Purified saponins have
      proven safe and effective when injected and have significantly enhanced the
      efficacy of some oral vaccines under clinical investigation. Toxicity of the food
      grade extract from Quillaja saponaria has limited its use as a parenteral
      adjuvant; however, this toxicity seems to be abated when delivered orally. It is
      commonly used within the food and beverage industries and has no documented
      toxicity in humans at the present levels of consumption. Use of transgenic plants
      has been proposed as an alternative system for oral vaccine production and
      administration, and it is likely that an oral adjuvant will be required in most
      cases. Food-grade saponins have significant advantages for use with plant-made
      vaccines and are likely to provide a broad adjuvant effect due to the multiple
      saponin components. A review of the origin, production, biological activity,
      toxicity and use in the food industry is provided for Quillaja saponaria extract.
      Previous evaluation of this adjuvant in preclinical studies with plant made
      vaccines is discussed and a proposed level of experimental use in humans is
      provided.

PMID- 15174977
TI  - Therapeutic idiotype vaccines in B lymphoproliferative diseases.
AB  - The recognition of the surface immunoglobulin protein of the tumour B cells as a
      specific tumour antigen has prompted the development of vaccination strategies
      aimed at the induction of humoral and cellular antitumour responses. Results
      obtained in preclinical models of B lymphoproliferative diseases, as well as in
      initial clinical trials, have shown the immunogenic potential of the idiotype
      (Id) when administered in association with proper adjuvants. The definitive
      evidence for clinical efficacy of this therapeutic approach awaits ongoing
      randomised Phase III studies. Research efforts at present include identification
      of new vaccination settings to improve the clinical benefit of vaccine treatment,
      the establishment of more convenient methods to produce individual Id vaccines
      and the development of new strategies of vaccination, including genetic
      vaccination.

PMID- 15174978
TI  - Yersinia pestis (plague) vaccines.
AB  - Live attenuated and killed whole cell vaccines against disease caused by Yersinia
      pestis have been available since the early part of the last century. Although
      these vaccines indicate the feasibility of protecting against disease, they have
      a number of shortcomings. The live attenuated vaccine is highly reactogenic and
      is not licensed for use in humans. The killed whole cell vaccine, also
      reactogenic, provides poor protection against pneumonic plague and immunisation
      requires multiple doses of the vaccine. Against this background, a range of
      candidate vaccines, including rationally attenuated mutants, subunit vaccines and
      naked DNA vaccines have been described. Of these, an injected subunit vaccine is
      likely to offer the best near-term solution to the provision of a vaccine that
      protects against both bubonic and pneumonic plague.

PMID- 15174979
TI  - Novel biologic therapies for psoriasis.
AB  - There has been a recent explosion in knowledge regarding the central role of the
      immune system in the pathogenesis of psoriasis. Originally felt to be primarily a
      disorder of keratinocyte hyperproliferation, it has recently been classified as a
      T cell-mediated, autoimmune disease. Type 1 cytokines released predominantly from
      activated T lymphocytes are now considered to cause the psoriatic phenotype,
      including the epidermal and vascular changes. Armed with this new knowledge,
      pharmaceutical and biotechnology companies have developed more specific,
      immunologically directed interventions. These newer agents aim to be both more
      effective in clearing a condition that is associated with much morbidity and to
      be more selective, resulting in fewer toxic side effects than current therapies.
      This article gives an overview of the newer immunotherapeutic approaches from the
      points of view of safety, efficacy and mechanisms of action. The review also
      outlines the steps involved in the immune response leading to psoriasis and
      considers how each step could offer a target for therapeutic intervention.
      Infliximab, etanercept, alefacept and efalizumab are considered in detail.

PMID- 15174980
TI  - Long-term solutions for the problem of vaccine shortages.
AB  - During the past few years, vaccine shortage has been a serious problem affecting
      both developed and developing countries. The explanation is linked to the poor
      economic value associated with vaccines. Although every year the routine use of
      vaccines saves millions of lives, the economic value associated with them is
      negligible, especially if compared with the pharmaceutical market. This situation
      disincentives private investment, which prefers to focus on more profitable
      business. To overcome these problems, it is essential to recognise that the
      intangible value of vaccination (the value of being alive and healthy) represents
      the real value provided by vaccines. If the intangible value were to be included
      in the vaccine price, vaccines would become as attractive as other
      pharmaceuticals. While waiting for a long-term sustainable solution, public
      private partnerships represent a way to increase vaccine value awareness and to
      decrease the risk for vaccine manufacturers. This article will provide examples
      of how public-private partnerships both in developed and developing countries
      have been established to handle specific problems concerning vaccination.

PMID- 15174981
TI  - Medical radiation and the risk of cancer.

PMID- 15174982
TI  - The beginning of the end of warfarin?

PMID- 15174983
TI  - Research assessment: there must be an easier way.

PMID- 15174984
TI  - In search of sustainability.

PMID- 15174985
TI  - Patient attitudes to donation of embryos for research in Western Australia.
AB  - OBJECTIVE: To ascertain patients' attitudes to embryo donation for research
      purposes. DESIGN: Anonymous questionnaire survey. PARTICIPANTS AND SETTING: 235
      couples who had embryos in storage at Concept Fertility Centre on 30 March 2003
      that had been cryopreserved between 1 January 2000 and 30 June 2002. MAIN OUTCOME
      MEASURES: Participants' choices with regard to donating embryos to another
      couple, to research to improve in-vitro fertilisation (IVF) techniques or to stem
      cell research, and the likelihood of couples choosing to use a range of sources
      to help them with their decision. RESULTS: The response rate was 57%. Twenty-nine
      per cent of respondents (36/126) reported they would donate their embryos to
      research that would improve IVF techniques and 27% (34/126) reported they would
      donate their embryos to stem-cell research. Fifteen per cent (19/126) would
      donate their embryos to another infertile couple. Willingness to donate to
      research was not influenced by whether the couple had previous children, or age.
      Women and men with moderate to strong religious beliefs were less likely to
      donate to research. Over 90% of respondents indicated they would seek outside
      help to decide the fate of their embryos. CONCLUSION: This study suggests that
      about 30% of couples would donate their embryos to research, and highlights the
      need to provide support and information to help couples through their decision
      making process.

PMID- 15174986
TI  - Are current playground safety standards adequate for preventing arm fractures?
AB  - OBJECTIVE: To assess compliance with current standards of playgrounds where
      children have sustained a fall-related arm fracture. DESIGN, SETTING AND
      PARTICIPANTS: Between October 2000 and December 2002, a consecutive prospective
      series of 402 children aged under 13 years who fell from playground equipment and
      sustained an arm fracture was identified by emergency department staff in five
      Victorian hospitals. Trained field testers measured playground equipment height,
      surface type and depth, and surface impact attenuation factors to determine
      compliance with safety standards. MAIN OUTCOME MEASURES: Playground compliance
      with current Australian safety standards. RESULTS: Ninety-eight percent of
      playgrounds had a recommended type of surface material. The mean surface depth
      was 11.1 cm (SD, 5.0 cm) and the mean equipment height was 2.04 m (SD, 0.43 m).
      Although over 85% of playgrounds complied with recommended maximum equipment
      height and surface impact attenuation characteristics, only 4.7% complied with
      recommended surface depth. CONCLUSION: Playgrounds where children have sustained
      an arm fracture generally comply with all important safety recommendations except
      surface depth. Playground fall-related arm fracture requires specific
      countermeasures for prevention, distinct from head injury prevention guidelines.

PMID- 15174987
TI  - An outbreak of Legionnaires' disease at the Melbourne Aquarium, April 2000:
      investigation and case-control studies.
AB  - OBJECTIVE: To investigate the source and risk factors associated with Australia's
      largest outbreak of Legionnaires' disease. DESIGN AND SETTING: Epidemiological
      and environmental investigation of cases of Legionnaires' disease associated with
      visits to the Melbourne Aquarium; two case-control studies to confirm the
      outbreak source and to investigate risk factors for infection, respectively.
      PARTICIPANTS: Patients with confirmed Legionnaires' disease who visited the
      Melbourne Aquarium between 11 and 27 April 2000 were compared (i) with control
      participants from the community, and (ii) with control participants selected from
      other visitors to the Aquarium during this period. MAIN OUTCOME MEASURES: Risk
      factors for acquiring Legionnaires' disease. RESULTS: There were 125 confirmed
      cases of Legionnaires' disease caused by Legionella pneumophila serogroup 1
      associated with the Aquarium; 76% of patients were hospitalised, and four (3.2%)
      died. The Aquarium cooling towers were contaminated with this organism. Visiting
      the Aquarium was significantly associated with disease (odds ratio [OR], 207; 95%
      CI, 73-630). The case-control study indicated that current smoking was a dose
      dependent risk (multivariable OR for currently smoking > 70 cigarettes/week,
      13.5; 95% CI, 5-36), but chronic illness and duration of exposure at the site
      were not significant risks. CONCLUSIONS: This study showed an association between
      poorly disinfected cooling towers at the Aquarium and Legionnaires' disease in
      visitors, and confirmed current smoking as a critical risk factor. The rapid
      response, publicity, and widespread urinary antigen testing may have resulted in
      detection of milder cases and contributed to the relatively low apparent
      morbidity and mortality rates. The urinary antigen test allows rapid
      identification of cases and may be changing the severity of illness recognised as
      Legionnaires' disease and altering who is considered at risk.

PMID- 15174990
TI  - Ageing and healthcare costs in Australia: a case of policy-based evidence?
AB  - There have been dire predictions that population ageing will result in
      skyrocketing health costs. However, numerous studies have shown that the effect
      of population ageing on health expenditure is likely to be small and manageable.
      Pessimism about population ageing is popular in policy debates because it fits
      with ideological positions that favour growth in the private sector and seek to
      contain health expenditure in the public sector. It might also distract attention
      from the need to evaluate the appropriateness and effectiveness of current
      patterns of care. Pessimistic scenarios have stifled debate and limited the
      number of policy options considered. Policy making in Australia would be improved
      if we took a more realistic view of the effect of population ageing on health
      expenditure.

PMID- 15174989
TI  - Anonymity or transparency in reporting of medical error: a community-based survey
      in South Australia.
AB  - OBJECTIVES: To seek public opinion on the reporting of medical errors and the
      anonymity of healthcare workers who report medical errors. DESIGN AND
      PARTICIPANTS: A random, representative survey of 2005 South Australians in April
      2002, using telephone interviews based on a vignette provided. MAIN OUTCOME
      MEASURES: When a medical error occurs (i) whether the incident should be
      reported, and (ii) whether the report should disclose the healthcare worker's
      identity. RESULTS: (i) Most respondents (94.2%; 95% CI, 93.0%-95.2%) believed
      healthcare workers should report medical errors. (ii) 68.0% (95% CI, 65.5%-70.5%)
      of those in favour of reporting believed the healthcare worker should be
      identified on the report, while 29.2% (95% CI, 26.7%-31.7%) favoured anonymous
      reporting. CONCLUSIONS: Most respondents believed that, when a healthcare worker
      makes an error, an incident report should be written and the individual should be
      identified on the report. Respondents were reluctant to accept healthcare worker
      anonymity, even though this may encourage reporting.

PMID- 15174988
TI  - Detention for tuberculosis: public health and the law.
AB  - Non-compliance with treatment of pulmonary tuberculosis (TB) by an individual can
      put the community at risk of transmission of TB. Public health (detention) orders
      can be issued to detain non-compliant individuals, but this is a last resort and
      rarely used. Two recent cases in New South Wales illustrate the process of
      issuing a public health order in NSW, and some of the issues that may arise. The
      NSW law can also be applied to patients with severe acute respiratory syndrome
      (SARS) or HIV/AIDS. The other states and territories have similar laws, which
      often apply to a broader range of diseases and have fewer limits on issuing and
      extending orders.

PMID- 15174991
TI  - Complementary and alternative medicine--with a difference.

PMID- 15174992
TI  - The rise and rise of complementary and alternative medicine: a sociological
      perspective.
AB  - Major reasons for the growth in the use of complementary and alternative medicine
      (CAM), in Australia and elsewhere, are general societal changes rather than
      specific reasons internal to medicine. There are problems of definition of CAM,
      as well as the extent to which CAM modalities can be considered a unified
      paradigm. The general changes examined include the consumer and green movements,
      as well as postmodernism. The movement surrounding evidence-based healthcare may
      provide some answers, but will not settle the issue of compatibility. CAM is here
      to stay and will continue to present challenges for conventional medicine on how
      to respond.

PMID- 15174994
TI  - Bulk-billing GP clinics did not significantly reduce emergency department
      caseload in Mackay, Queensland.

PMID- 15174995
TI  - What explains falling asthma mortality?

PMID- 15174996
TI  - Central venous catheters: optimal patient care or convenience?

PMID- 15174997
TI  - Q fever in children: an emerging public health issue in Queensland.

PMID- 15174998
TI  - Border screening for SARS.

PMID- 15174999
TI  - Using AUDIT to classify patients into Australian Alcohol Guideline categories.

PMID- 15175000
TI  - Acute liver failure associated with the use of herbal preparations containing
      black cohosh.

PMID- 15175001
TI  - Central core disease mutations R4892W, I4897T and G4898E in the ryanodine
      receptor isoform 1 reduce the Ca2+ sensitivity and amplitude of Ca2+-dependent
      Ca2+ release.
AB  - Three CCD (central core disease) mutants, R4892W (Arg4892-->), I4897T and G4898E,
      in the pore region of the skeletal-muscle Ca2+-release channel RyR1 (ryanodine
      receptor 1) were characterized using a newly developed assay that monitored Ca2+
      release in the presence of Ca2+ uptake in microsomes isolated from HEK-293 cells
      (human embryonic kidney 293 cells), co-expressing each of the three mutants
      together with SERCA1a (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase 1a). Both
      Ca2+ sensitivity and peak amplitude of Ca2+ release were either absent from or
      sharply decreased in homotetrameric mutants. Co-expression of wild-type RyR1 with
      mutant RyR1 (heterotetrameric mutants) restored Ca2+ sensitivity partially, in
      the ratio 1:2, or fully, in the ratio 1:1. Peak amplitude was restored only
      partially in the ratio 1:2 or 1:1. Reduced amplitude was not correlated with
      maximum Ca2+ loading or the amount of expressed RyR1 protein. High-affinity
      [3H]ryanodine binding and caffeine-induced Ca2+ release were also absent from the
      three homotetrameric mutants. These results indicate that decreased Ca2+
      sensitivity is one of the serious defects in these three excitation-contraction
      uncoupling CCD mutations. In CCD skeletal muscles, where a mixture of wild-type
      and mutant RyR1 is expressed, these defects are expected to decrease Ca2+-induced
      Ca2+ release, as well as orthograde Ca2+ release, in response to transverse
      tubular membrane depolarization.

PMID- 15175003
TI  - Active-site-mediated elimination of hydrogen fluoride from a fluorinated
      substrate analogue by isopenicillin N synthase.
AB  - Isopenicillin N synthase (IPNS) is a non-haem iron oxidase that catalyses the
      formation of bicyclic isopenicillin N from delta-(L-alpha-aminoadipoyl)-L
      cysteinyl-D-valine (ACV). In this study we report a novel activity for the iron
      of the IPNS active site, which behaves as a Lewis acid to catalyse the
      elimination of HF from the fluorinated substrate analogue, delta-(L-alpha
      aminoadipoyl)-L-cysteinyl-D-beta-fluorovaline (ACbetaFV). X-Ray crystallographic
      studies of IPNS crystals grown anaerobically with ACbetaFV reveal that the
      valinyl beta-fluorine is missing from the active site region, and suggest the
      presence of the unsaturated tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D
      isodehydrovaline in place of substrate ACbetaFV. (19)F NMR studies confirm the
      release of fluoride from ACbetaFV in the presence of the active IPNS enzyme.
      These results suggest a new mode of reactivity for the IPNS iron centre, a
      mechanism of action that has not previously been reported for any of the iron
      oxidase enzymes.

PMID- 15175002
TI  - Identification of a novel receptor for an invertebrate oxytocin/vasopressin
      superfamily peptide: molecular and functional evolution of the
      oxytocin/vasopressin superfamily.
AB  - Annetocin is structurally related to an OT (oxytocin)/VP (vasopressin) family
      peptide, which has been isolated from the earthworm Eisenia foetida and has been
      shown to induce OT-like egg-laying behaviour. We now report the identification of
      an endogenous AnR (annetocin receptor). The deduced AnR precursor displays high
      sequence similarity with OT/VP receptors. Genomic analysis of the AnR gene
      revealed that the intron-inserted position is conserved between the AnR gene and
      the mammalian OT/VP receptor genes. These results indicate that AnR and mammalian
      OT/VP receptors share a common ancestor gene. Administration of annetocin to the
      AnR expressed in Xenopus oocytes induced a calcium-dependent signal transduction.
      Reverse transcriptase-PCR analysis and in situ hybridization showed that the AnR
      gene is expressed specifically in the nephridia located in the clitellum region,
      although the nephridia are distributed throughout the worm body. This result
      suggests that annetocin induces egg-laying behaviour through its action on the
      nephridia. This is the first description concerning the functional correlation
      between an invertebrate OT/VP-related peptide and egg-laying behaviour.

PMID- 15175004
TI  - Characterization of the first non-insect invertebrate functional angiotensin
      converting enzyme (ACE): leech TtACE resembles the N-domain of mammalian ACE.
AB  - Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that plays a major
      role in blood homoeostasis and reproduction in mammals. In vertebrates, both
      transmembrane and soluble ACE, containing one or two homologous active sites,
      have been characterized. So far, several ACEs from invertebrates have been
      cloned, but only in insects. They are soluble and display a single active site.
      Using biochemical procedures, an ACE-like activity was detected in our model, the
      leech, Theromyzon tessulatum. Annelida is the most distant phylum in which an ACE
      activity has been observed. To gain more insight into the leech enzyme, we have
      developed a PCR approach to characterize its mRNA. The approx. 2 kb cDNA has been
      predicted to encode a 616-amino-acid soluble enzyme containing a single active
      site, named TtACE (T. tessulatum ACE). Surprisingly, its primary sequence shows
      greater similarity to vertebrates than to invertebrates. Stable in vitro
      expression of TtACE in transfected Chinese-hamster ovary cells revealed that the
      leech enzyme is a functional metalloprotease. As in mammals, this 79 kDa
      glycosylated enzyme functions as a dipeptidyl carboxypeptidase capable of
      hydrolysing angiotensin I to angiotensin II. However, a weak chloride inhibitory
      effect and acetylated N-acetyl-SDKP (Ac SDAcKP) hydrolysis reveal that TtACE
      activity resembles that of the N-domain of mammalian ACE. In situ hybridization
      shows that its cellular distribution is restricted to epithelial midgut cells.
      Although the precise roles and endogenous substrates of TtACE remain to be
      identified, characterization of this ancestral peptidase will help to clarify its
      physiological roles in non-insect invertebrate species.

PMID- 15175005
TI  - Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine
      phosphatase activities.
AB  - Human PHOSPHO1 is a phosphatase enzyme for which expression is upregulated in
      mineralizing cells. This enzyme has been implicated in the generation of P(i) for
      matrix mineralization, a process central to skeletal development. PHOSPHO1 is a
      member of the haloacid dehalogenase (HAD) superfamily of Mg2+-dependent
      hydrolases. However, substrates for PHOSPHO1 are, as yet, unidentified and little
      is known about its activity. We show here that PHOSPHO1 exhibits high specific
      activities toward phosphoethanolamine (PEA) and phosphocholine (PCho). Optimal
      enzymic activity was observed at approx. pH 6.7. The enzyme shows a high specific
      Mg2+-dependence, with apparent K(m) values of 3.0 microM for PEA and 11.4 microM
      for PCho. These results provide a novel mechanism for the generation of P(i) in
      mineralizing cells from PEA and PCho.

PMID- 15175006
TI  - Glutamine availability up-regulates expression of the amino acid transporter
      protein ASCT2 in HepG2 cells and stimulates the ASCT2 promoter.
AB  - Glutamine transport into the human hepatoma cell line HepG2 is catalysed
      primarily by an ASCT2-type transporter identical in sequence with that cloned
      previously from JAR cells. An antibody raised against the C-terminus of the ASCT2
      protein was shown to recognize ASCT2 on Western blots. Using this antibody, it
      was found that variation in cell growth rate did not affect ASCT2 expression, but
      both growth rate and ASCT2 expression were significantly reduced by glutamine
      deprivation. Expression of a number of other proteins was shown to be unaffected
      under these conditions. The sequence of the 5'-flanking region of the ASCT2 gene
      was derived from the human genome database. A 907 bp fragment of this sequence
      was directionally ligated into a luciferase reporter vector and was shown to
      exhibit promoter activity when transfected into HepG2 cells. Promoter activity
      was greatly reduced when transfection was performed in glutamine-free medium and
      was restored when glutamine was added post-transfection. The absence of other
      essential amino acids did not affect promoter activity, and glutamine deprivation
      did not affect the MCT1 (monocarboxylate transporter 1) promoter. These results
      indicate that both ASCT2 promoter activity and ASCT2 protein expression in these
      cells are dependent on glutamine availability.

PMID- 15175007
TI  - Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on
      the pH gradient across the mitochondrial inner membrane.
AB  - The relationship between protonmotive force and superoxide production by
      mitochondria is poorly understood. To address this issue, the rate of superoxide
      production from complex I of rat skeletal muscle mitochondria incubated under a
      variety of conditions was assessed. By far, the largest rate of superoxide
      production was from mitochondria respiring on succinate; this rate was almost
      abolished by rotenone or piericidin, indicating that superoxide production from
      complex I is large under conditions of reverse electron transport. The high rate
      of superoxide production by complex I could also be abolished by uncoupler,
      confirming that superoxide production is sensitive to protonmotive force. It was
      inhibited by nigericin, suggesting that it is more dependent on the pH gradient
      across the mitochondrial inner membrane than on the membrane potential. These
      effects were examined in detail, leading to the conclusions that the effect of
      protonmotive force was mostly direct, and not indirect through changes in the
      redox state of the ubiquinone pool, and that the production of superoxide by
      complex I during reverse electron transport was at least 3-fold more sensitive to
      the pH gradient than to the membrane potential.

PMID- 15175008
TI  - Overexpression of inactive arylsulphatase mutants and in vitro activation by
      light-dependent oxidation with vanadate.
AB  - Arylsulphatases B (ASB) and A (ASA) are subject to a unique post-translational
      modification that is required for their function. The modification reaction,
      conversion of an active-site cysteine into a formylglycine, becomes saturated
      when these enzymes are overexpressed. We have removed the possibility of in vivo
      modification by expressing mutants of ASB and ASA in which the active-site
      cysteine is substituted with a serine. These mutants are expressed much more
      efficiently when compared with the native enzymes under identical conditions. The
      purified ASB mutant can then be converted into catalytically active ASB in vitro
      using vanadate and light.

PMID- 15175009
TI  - A proteome analysis of the arsenite response in cultured lung cells: evidence for
      in vitro oxidative stress-induced apoptosis.
AB  - Arsenite is well documented as a chemotherapeutic agent capable of inducing cell
      death. However, the cellular response at the molecular level has not been studied
      extensively. In the present study, we provide for the first time a proteomic
      analysis of rat LECs (lung epithelial cells) treated with arsenite, with the aim
      of identifying defence proteins, probably expressed to protect the cells during
      the course of arsenic-induced apoptosis. Comparative proteome analysis was
      conducted on LECs and LECs treated with 40 microM arsenite to identify global
      changes in their protein expression profiles. Over 1000 protein spots were
      separated by two-dimensional electrophoresis and visualized by silver staining.
      Seven proteins changed expression levels significantly and were identified by
      matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry and
      database searching. The proteins up-regulated were mostly HSPs (heat-shock
      proteins) and antioxidative stress proteins, including HSP70, aldose reductase,
      haem oxygenase-1, HSP27, ferritin light chain and alphaB-crystallin. The
      glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase was down-regulated.
      Pretreatment with the thiol antioxidants glutathione or N-acetylcysteine before
      arsenite insult effectively abrogated the induction of these defence proteins and
      sustained cell viability, whereas antioxidants were protective only at earlier
      time points if they were added to cells after arsenite. Taken together, our
      results demonstrate that high levels of arsenite cause oxidative stress-induced
      apoptosis.

PMID- 15175010
TI  - Kinetics of NO and O2 binding to a maleimide poly(ethylene glycol)-conjugated
      human haemoglobin.
AB  - The hypertensive effect observed with most cell-free haemoglobins has been
      proposed to result from NO scavenging. However, a newly developed PEG
      [poly(ethylene glycol)]-conjugated haemoglobin, MalPEG-Hb [maleimide-activated
      PEG-conjugated haemoglobin], is non-hypertensive with unique physicochemical
      properties: high O2 affinity, low co-operativity and large molecular radius. It
      is therefore of interest to compare the ligand-binding properties of MalPEG-Hb
      with unmodified cell-free HbA (stroma-free human haemoglobin). NO association
      rates for deoxy and oxyMalPEG-Hb and HbA were found to be identical. These
      results confirm the lack of correlation between hypertension and NO for a similar
      modified haemoglobin with high molecular radius and low p50 (pO2 at which
      haemoglobin is half-saturated with O2) [Rohlfs, Bruner, Chiu, Gonzales, Gonzales,
      Magde, Magde, Vandegriff and Winslow (1998) J. Biol. Chem. 273, 12128-12134]. The
      R-state O2 association kinetic constants were also the same for the two
      haemoglobins. However, even though the p50 of MalPEG-Hb is approx. half of that
      of HbA, the biphasic O2 dissociation rates measured at relatively high pO2 (150
      Torr) were 2-fold higher, giving rise to a 2-fold lower R-state equilibrium
      association constant for MalPEG-Hb compared with HbA. Thus the O2 affinity of
      MalPEG-Hb is higher only at pO2 values lower than the intersection point of the
      O2 equilibrium curves for MalPEG-Hb and HbA. In summary, the present studies
      found similar rates of NO binding to HbA and MalPEG-Hb, eliminating the
      possibility that the lack of vasoactivity of MalPEG-Hb is simply the result of
      reduced molecular reactivity with NO. Alternatively, the unique O2-binding
      characteristics with low p50 and co-operativity suggest that the 'R-state'
      conformation of MalPEG-Hb is in a more T-state configuration and restricted from
      conformational change.

PMID- 15175011
TI  - Mature bovine articular cartilage contains abundant aggrecan that is C-terminally
      truncated at Ala719-Ala720, a site which is readily cleaved by m-calpain.
AB  - Extracts of normal mature articular cartilage contain aggrecan molecules which
      bear the G1 domain (the N-terminal globular domain of aggrecan) and are C
      terminally truncated by proteolysis at a number of sites. A proportion of these
      molecules are generated by an aggrecanase and/or matrix-metalloproteinase
      mediated cleavage in the IGD (interglobular domain between the G1 and G2 domains
      of aggrecan). However, the proteinase(s) responsible for formation of the
      majority of the larger G1-G2 and glycosaminoglycan-bearing truncated species is
      (are) unknown. N-terminal sequencing of aggrecan core fragments generated by m
      calpain digestion of bovine aggrecan has identified four novel cleavage sites:
      one within the CS (chondroitin sulphate)-1 domain (at one or more of the bonds
      Ser1229-Val1230, Ser1249-Val1250, Ser1287-Val1288, Gly1307-Val1308 and Ser1346
      Val1347), two within the IGD (at bonds Ala474-Ala475 and Gly365-Gly366) and one
      within the KS (keratan sulphate) domain (at Ala719-Ala720). A new monoclonal
      antibody (SK-28) to the C-terminal neoepitope at M710VTQVGPGVA719 showed that
      aggrecan products generated by this cleavage are present in high abundance in
      mature bovine articular cartilage extracts. We conclude that m-calpain, or an
      unidentified proteinase with the capacity to cleave at the same site, is active
      during aggrecan biosynthesis/secretion by mature chondrocytes or in the matrix of
      mature bovine articular cartilage in vivo.

PMID- 15175012
TI  - Functional analysis of the green fluorescent protein-tagged inositol 1,4,5
      trisphosphate receptor type 3 in Ca(2+) release and entry in DT40 B lymphocytes.
AB  - We examined the function of GFP-IP(3)R3 (green fluorescent protein-tagged
      inositol 1,4,5-trisphosphate receptor type 3) in Ca(2+) release and entry using a
      mutant DT40 cell line (IP(3)R-KO) in which all three IP(3)R genes had been
      disrupted. GFP-IP(3)R3 fluorescence largely overlapped with the distribution of
      endoplasmic reticulum, whereas a portion of GFP-IP(3)R3 apparently co-localized
      with the plasma membrane. The application of IP(3) to permeabilized WT (wild
      type) DT40 cells induced Ca(2+) release from internal stores. Although this did
      not occur in IP(3)R-KO cells it was restored by expression of GFP-IP(3)R3. In
      intact cells, application of anti-IgM, an activator of the BCR (B-cell receptor),
      or trypsin, a protease-activated receptor 2 agonist, did not cause any Ca(2+)
      response in IP(3)R-KO cells, whereas these treatments induced oscillatory or
      transient Ca(2+) responses in GFP-IP(3)R3-expressing IP(3)R-KO cells, as well as
      in WT cells. In addition, BCR activation elicited Ca(2+) entry in WT and GFP
      IP(3)R3-expressing IP(3)R-KO cells but not in IP(3)R-KO cells. This BCR-mediated
      Ca(2+) entry was observed in the presence of La(3+), which blocks capacitative
      Ca(2+) entry. Thapsigargin depleted Ca(2+) stores and led to Ca(2+) entry in
      IP(3)R-KO cells irrespective of GFP-IP(3)R3 expression. In contrast with BCR
      stimulation, thapsigargin-induced Ca(2+) entry was completely blocked by La(3+),
      suggesting that the BCR-mediated Ca(2+) entry pathway is distinct from the
      capacitative Ca(2+) entry pathway. The present study demonstrates that GFP
      IP(3)R3 could compensate for native IP(3)R in both IP(3)-induced Ca(2+) release
      and BCR-mediated Ca(2+) entry.

PMID- 15175013
TI  - Purification of Drosophila DNA polymerase zeta by REV1 protein-affinity
      chromatography.
AB  - Studies on the biochemical properties of very-large-size eukaryotic DNA
      polymerases have been limited by the difficulty in obtaining sufficient purified
      forms of each enzyme. Our aim was to determine and elucidate the biochemical
      properties of one such polymerase, pol zeta (DNA polymerase zeta) from Drosophila
      melanogaster (Dmpol zeta). Using an REV1 (UV-revertible gene 1) protein-affinity
      column, we have isolated the enzyme directly from Drosophila embryos. Completely
      purified Dmpol zeta was found to have a molecular mass of approx. 240 kDa, and to
      be sensitive to aphidicolin and resistant to ddTTP (2',3'-dideoxythymidine-5
      triphosphate) and N-ethylmaleimide. The enzyme has a preference for
      poly(dA)/oligo(dT)(10:1) as a template primer and has high processivity for DNA
      synthesis. Moreover, Dmpol zeta showed significantly higher fidelity compared
      with Rattus norvegicus DNA polymerase, an error-prone DNA polymerase, in an M13
      forward mutation assay. The activities of bypassing pyrimidine dimers and (6-4)
      photoproducts and extending from mismatched primer-template termini in (6-4)
      photoproduct by Dmpol zeta were not detected. Drosophila REV7 interacted with
      Dmpol zeta in vitro, but did not influence the DNA synthesis activity of Dmpol
      zeta. The present study is the first report about characterization of purified
      pol zeta from multicellular organisms, and the second concerning the
      characterization of yeast pol zeta.

PMID- 15175014
TI  - Metformin inhibits mitochondrial permeability transition and cell death: a
      pharmacological in vitro study.
AB  - Metformin, a drug widely used in the treatment of Type II diabetes, has recently
      received attention owing to new findings regarding its mitochondrial and cellular
      effects. In the present study, the effects of metformin on respiration, complex 1
      activity, mitochondrial permeability transition, cytochrome c release and cell
      death were investigated in cultured cells from a human carcinoma-derived cell
      line (KB cells). Metformin significantly decreased respiration both in intact
      cells and after permeabilization. This was due to a mild and specific inhibition
      of the respiratory chain complex 1. In addition, metformin prevented to a
      significant extent mitochondrial permeability transition both in permeabilized
      cells, as induced by calcium, and in intact cells, as induced by the glutathione
      oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of
      cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl
      hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium
      iodide staining and cytochrome c release. We propose that metformin prevents the
      permeability transition-related commitment to cell death in relation to its mild
      inhibitory effect on complex 1, which is responsible for a decreased probability
      of mitochondrial permeability transition.

PMID- 15175015
TI  - Kinetics and control of oxidative phosphorylation in rat liver mitochondria after
      dexamethasone treatment.
AB  - The present investigation was undertaken in order to evaluate the contributions
      of ATP synthesis and proton leak reactions to the rate of active respiration of
      liver mitochondria, which is altered following dexamethasone treatment (1.5 mg/kg
      per day for 5 days). We applied top-down metabolic control analysis and its
      extension, elasticity analysis, to gain insight into the mechanisms of
      glucocorticoid regulation of mitochondrial bioenergetics. Liver mitochondria were
      isolated from dexamethasone-treated, pair-fed and control rats when in a fed or
      overnight fasted state. Injection of dexamethasone for 5 days resulted in an
      increase in the fraction of the proton cycle of phosphorylating liver
      mitochondria, which was associated with a decrease in the efficiency of the
      mitochondrial oxidative phosphorylation process in liver. This increase in proton
      leak activity occurred with little change in the mitochondrial membrane
      potential, despite a significant decrease in the rate of oxidative
      phosphorylation. Regulation analysis indicates that mitochondrial membrane
      potential homoeostasis is achieved by equal inhibition of the mitochondrial
      substrate oxidation and phosphorylation reactions in rats given dexamethasone.
      Our results also suggest that active liver mitochondria from dexamethasone
      treated rats are capable of maintaining phosphorylation flux for cellular
      purposes, despite an increase in the energetic cost of mitochondrial ATP
      production due to increased basal proton permeability of the inner membrane. They
      also provide a complete description of the effects of dexamethasone treatment on
      liver mitochondrial bioenergetics.

PMID- 15175017
TI  - Templated assembly of the pH-sensitive membrane-lytic peptide GALA.
AB  - Delivery of protein or nucleic acid therapeutics into intracellular compartments
      may require facilitation to allow these macromolecules to cross otherwise
      impermeant cellular membranes. Peptides capable of forming membrane-spanning
      channels hold promise as just such facilitators, although the requirement for
      peptide oligomerization to form these channels may limit their effectiveness.
      Synthetic molecules containing multiple copies of membrane-active peptides
      attached to a template molecule in a pre-oligomerized form have attracted
      interest for drug-delivery applications. Using three template designs, we
      synthesized multimeric versions of the pH-sensitive lytic peptide GALA and
      compared their performance to monomeric GALA. Template assembly stabilized helix
      formation: templated GALA retained alpha-helical structure even at neutral pH,
      unlike monomeric GALA. In membrane leakage assays, templated GALA retained the pH
      sensitivity of the monomer, with improved leakage for dimeric GALA. Surprisingly,
      trimeric GALA was less effective, particularly when synthesized with a larger and
      more flexible spacer. Surface plasmon resonance analysis indicated that
      reversible binding of templated GALA to lipid surfaces at acidic conditions was
      greatly reduced compared with monomeric GALA, but that the amount of irreversibly
      bound material was similar. We interpreted these results to indicate that
      templated peptides may cyclize into 'self-satisfied' oligomeric structures,
      incapable of further aggregation and subsequent pore formation. Future design of
      templated peptides must be carefully performed to avoid this unwanted
      consequence.

PMID- 15175018
TI  - Synthesis, radiolabeling and in vitro and in vivo characterization of a
      technetium-99m-labeled alpha-M2 peptide as a tumor imaging agent.
AB  - In an effort to develop a peptide-based radiopharmaceutical for the detection of
      breast cancer, we have prepared an analog of alphaM2 peptide, modified to
      incorporate an N3S chelate system. Mercaptoacetyltriglycine (MAG)(3)-derivatized
      alphaM2 peptide was prepared by solid-phase synthesis and radiolabeled with
      (99m)Tc by an exchange method. In vitro cell-binding on human breast cancer cell
      lines, MDA-MB-231 and MCF-7, indicated the affinity and specificity of (99m)Tc
      MAG(3)-alphaM2 toward breast cancer cells. Additionally, the radiolabeled peptide
      showed rapid internalization into human breast cancer cells. In vivo
      biodistribution in mice showed that the radiolabeled peptide cleared rapidly from
      the blood and most non-target tissues and was excreted significantly via the
      kidneys. Uptake of (99m)Tc-MAG(3)-alphaM2 in the tumor was moderate. The
      radiochemical and in vitro and in vivo characterization indicates that the
      radiolabeled peptide has certain favorable properties and it might be a useful
      radiopharmaceutical for the detection of breast cancer in vivo.

PMID- 15175016
TI  - Two conserved cysteine residues are critical for the enzymic function of the
      human platelet-derived growth factor receptor-beta: evidence for different roles
      of Cys-822 and Cys-940 in the kinase activity.
AB  - The platelet-derived growth factor receptor-beta (PDGFR-beta) has a number of
      conserved cysteine residues on its cytoplasmic domain. We have examined whether
      the cysteine residues play a role in the enzymic function of PDGFR-beta. We found
      that N-ethylmaleimide, which selectively alkylates free thiol groups of cysteine
      residues, completely inhibited the kinase activity of PDGFR-beta. We then
      identified, through site-directed mutagenesis, two conserved cysteine residues
      critical for the enzymic function of PDGFR-beta. Cys to Ser mutations for either
      Cys-822, positioned in the catalytic loop, or Cys-940, located in the C-terminal
      kinase subdomain, significantly reduced the activities of autophosphorylation and
      phosphorylation towards exogenous substrates. The non-reducing gel analysis
      indicated that neither of these cysteine residues contributes to the kinase
      activity by disulphide-bond formation. In addition, the individual mutation of
      Cys-822 and Cys-940 had no effect on protein stability or the binding of
      substrates or ATP, implying that these cysteine residues are involved in enzyme
      catalysis. Finally, proteolytic cleavage assays showed that the mutation of Cys
      940, but not Cys-822, induced a protein conformational change. Taken together,
      these results suggest that Cys-940 contributes to the catalytic activity of PDGFR
      beta by playing a structural role, whereas Cys-822 contributes through a
      different mechanism.

PMID- 15175019
TI  - A theta-defensin composed exclusively of D-amino acids is active against HIV-1.
AB  - The ability of certain theta-defensins, including retrocyclin-1, to protect human
      cells from infection by HIV-1 marks them as potentially useful molecules. Theta
      defensins composed of L-amino acids are likely to be unstable in environments
      that contain host and microbial proteases. This study compared the properties of
      two enantiomeric theta-defensins, retrocyclin-1, and RC-112. Although these
      peptides have identical sequences, RC-112 is composed exclusively of D-amino
      acids, whereas retrocyclin-1 contains only L-amino acids. We compared the ability
      of these peptides to protect JC53-BL human cells from infection by 30 primary HIV
      1 isolates. JC53-BL cells are modified HeLa cells that express surface CD4,
      CXCR4, and CCR5. They also contain reporter cassettes that are driven by the HIV
      1 LTR, and express beta-galactosidase and luciferase. The HIV-1 isolates varied
      in co-receptor specificity and included subtypes A, B, C, D, CRF01-AE, and G. RC
      112 was several fold more potent than retrocyclin-1 across the entire HIV-1
      panel. Although RC-112 bound immobilized gp120 and CD4 with lower affinity than
      did retrocyclin-1, surface plasmon resonance experiments performed with 1
      microg/mL of RC-112 and retrocyclin-1 revealed that both glycoproteins were bound
      to a similar extent. The superior antiviral performance of RC-112 most likely
      reflected its resistance to degradation by surface-associated or secreted
      proteases of the JC53-BL target cells. Theta-defensins composed exclusively of D
      amino acids merit consideration as starting points for designing microbicides for
      topical application to the vagina or rectum.

PMID- 15175020
TI  - Nonpeptide/peptide chimeric ligands for the nociceptin/orphanin FQ receptor:
      design, synthesis and in vitro pharmacological activity.
AB  - Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the G-protein coupled
      receptor referred to as N/OFQ peptide (NOP) receptor. NOP receptor activation by
      N/OFQ modulates several biological functions both at central and peripheral
      level. Structure activity relationship (SAR) studies demonstrated that the N/OFQ
      sequence can be divided into a N-terminal tetrapeptide 'message' crucial for
      receptor activation and a C-terminal 'address' important for receptor binding. On
      the basis of this message/address concept we synthesized some chimeric compounds
      in which we substituted the natural message domain with the nonselective
      nonpeptide NOP ligand (8-Naphthalen-1-yl-methyl-4-oxo-1-phenyl-1,3,8-triaza
      spiro[4,5]dec-3-yl)-aceticacid methyl ester (NNC 63-0532) and used as address
      domain the peptide sequences Thr-NH2, N/OFQ(5-9)-NH2, N/OFQ(5-13)-NH2 and N/OFQ(5
      17)-NH2. All the compounds were pharmacologically evaluated in the electrically
      stimulated guinea-pig ileum. NNC 63-0532 produced a concentration-dependent
      inhibition of the electrically induced twitches showing, in comparison with
      N/OFQ, lower potency and higher maximal effects. In addition, contrary to N/OFQ,
      the effects of NNC 63-0532 were insensitive to the NOP selective antagonist
      [Nphe1, Arg14, Lys15]N/OFQ-NH2 (UFP-101) while prevented by naloxone. Similar
      results were obtained with NNC 63-0532/Thr-NH2 and NNC 63-0532/N/OFQ(1-9)-NH2. On
      the contrary, the inhibitory effects of NNC 63-0532/N/OFQ(5-13)-NH2 and NNC 63
      0532/N/OFQ(5-17)-NH2 were slightly antagonized by UFP-101 while naloxone
      prevented the effects of the high but not of the low concentrations of the two
      ligands. These data indicate that it is possible to functionalize with the N/OFQ
      address sequence a nonpeptide NOP ligand for increasing its binding to the NOP
      receptor. Moreover, these results corroborate the idea that the 5-13 sequence
      represents the crucial core of the N/OFQ address domain.

PMID- 15175022
TI  - Roles for CD30 in the biology and treatment of CD30 lymphoproliferative diseases.

PMID- 15175023
TI  - Sculpting skin appendages out of epidermal layers via temporally and spatially
      regulated apoptotic events.
AB  - Complex skin appendages are built from the epidermal cells through various cell
      events. Here we used TUNEL and caspase-3 immuno-localization to examine apoptosis
      in feather morphogenesis. We deduced three modes. In Mode 1A, apoptosis occurs
      within the localized growth zone (LoGZ) to regulate growth (feather buds). In
      Mode 1B, morphogen secreting cells are present adjacent to LoGZ and apoptosis may
      work to remove such signaling centers (barb ridges). In Mode 2, keratinocytes
      apoptosed before terminal differentiation and left spaces between branches
      (marginal plate). In Mode 3A, keratinocytes cornified and flaked off to free skin
      appendages (feather sheath, pulp epithelium). In Mode 3B, keratinized apoptosed
      epithelial cells became permanent structures (rachis, ramus, barbules). Thus,
      different apoptotic modes can have different impacts on morphogenesis. We further
      tested effects of imbalanced Shh on apoptosis. Shh suppression reduced marginal
      plate apoptosis and caused abnormal differentiation of barbule plates. Shh over
      expression enhanced proliferation in barb ridges. Expression of Patched in the
      barbule plate epithelia implies a paracrine mechanism. The current work
      complements our recent work on LoGZ to show how adding and removing cell masses
      in temporally and spatially specific ways are coordinated to sculpt skin
      appendages from epidermal layers.

PMID- 15175024
TI  - Keratinocyte G2/M growth arrest by 1,25-dihydroxyvitamin D3 is caused by Cdc2
      phosphorylation through Wee1 and Myt1 regulation.
AB  - 1,25-dihydroxyvitamin D3 (1,25[OH]2VD3) has an antiproliferative effect on
      keratinocyte growth, and its derivatives are used for the treatment of psoriasis.
      It was reported previously that 1,25[OH]2VD3 induced cell cycle arrest not only
      at the G0/G1 phase but also at the G2/M phase. However, the mechanism of
      1,25[OH]2VD3-induced G2/M phase arrest in keratinocytes has not been fully
      understood. The addition of 10(-8) to 10(-6) M 1,25[OH]2VD3 to cultured normal
      human keratinocytes enhanced the expression of Myt1 mRNA preceding Wee1 mRNA; 10(
      6) M 1,25[OH]2VD3 unregulated Myt1 mRNA from 6 h to 24 h and Wee1 mRNA from 12 to
      48 h. Interestingly, the levels of phosphorylated Cdc2 were increased between 6 h
      and 48 h after 1,25[OH]2VD3 treatment, although the expression levels of Cdc2
      mRNA and its protein production were reduced. 1,25[OH]2VD3 also decreased the
      expression of cyclin B1, which forms a complex with Cdc2. These data indicated
      that the increase of Myt1 and Wee1 induced the phosphorylation of Cdc2 leading to
      G2/M arrest. In conclusion, the induction of Cdc2 phosphorylation due to the
      increase of Wee1 and Myt1 as well as the reduction of Cdc2 and cyclin B1 are
      involved in 1,25[OH]2VD3-induced G2/M arrest of keratinocytes.

PMID- 15175026
TI  - Dystroglycan in skin and cutaneous cells: beta-subunit is shed from the cell
      surface.
AB  - In skin, hemidesmosomal protein complexes attach the epidermis to the dermis and
      are critical for stable connection of the basal epithelial cell cytoskeleton with
      the basement membrane (BM). In muscle, a similar supramolecular aggregate, the
      dystrophin glycoprotein complex links the inside of muscle cells with the BM. A
      component of the muscle complex, dystroglycan (DG), also occurs in epithelia. In
      this study, we characterized the expression and biochemical properties of
      authentic and recombinant DG in human skin and cutaneous cells in vitro. We show
      that DG is present at the epidermal BM zone, and it is produced by both
      keratinocytes and fibroblasts in vitro. The biosynthetic precursor is efficiently
      processed to the alpha- and beta-DG subunits; and, in addition, a distinct
      extracellular segment of the transmembranous beta-subunit is shed from the cell
      surface by metalloproteinases. Shedding of the beta-subunit releases the alpha
      subunit from the DG complex on the cell surface into the extracellular space. The
      shedding is enhanced by IL-1beta and phorbol esters, and inhibited by
      metalloproteinase inhibitors. Deficiency of perlecan, a major ligand of alpha-DG,
      enhanced shedding suggesting that lack of a binding partner destabilizes the
      epithelial DG complex and makes it accessible to proteolytic processing.

PMID- 15175025
TI  - Signaling events during induction of plasminogen activator inhibitor-1 expression
      by sphingosylphosphorylcholine in cultured human dermal fibroblasts.
AB  - Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid metabolite that can
      enhance wound healing. In a search for effectors downstream of SPC in the wound
      healing process, we found that the expression of the gene for plasminogen
      activator inhibitor-1 (PAI-1) was significantly affected. ELISA and western blot
      analyses showed that SPC markedly induced PAI-1 production in human dermal
      fibroblasts cultured in vitro. Inhibition by pre-treatment with pertussis toxin
      (PTx), but not by tyrphostin A47 (a receptor tyrosine kinase inhibitor),
      indicated that PTx-sensitive G proteins were involved in SPC-induced PAI-1
      expression. SPC elicited a rapid and transient increase in intracellular calcium
      levels ([Ca2+]i), measured using laser scanning confocal microscopy, which was
      partly mediated through PTx-sensitive G proteins. Pre-treatment with
      thapsigargin, but not with EGTA, abolished SPC-induced PAI-1 expression,
      indicating the importance of Ca2+ release from internal stores. Phorbol-12
      myristate-13-acetate (PMA) induced the expression of PAI-1, and pre-treatment
      with Ro 31-8220 (a PKC inhibitor) markedly suppressed SPC-induced PAI-1
      expression. SPC-induced PAI-1 expression was also significantly suppressed by
      PD98059 (a specific MAPK kinase 1/2 inhibitor). Consistent with this result, SPC
      stimulated the phosphorylation of p42/44 extracellular signal-regulated kinase
      (ERK). Together, these results suggest that SPC induces PAI-1 production through
      a G protein-coupled calcium increase and downstream kinase signaling events in
      cultured human dermal fibroblasts.

PMID- 15175027
TI  - Health-related quality of life and hand eczema--a comparison of two instruments,
      including factor analysis.
AB  - Hand eczema is a disease of long duration, affecting the individual and society.
      The purpose of this study of 100 patients (51 females and 49 males) at an
      occupational dermatology clinic was to investigate whether the generic
      questionnaire Short Form-36 (SF-36), and the dermatology-specific Dermatology
      Life Quality Index (DLQI) are appropriate for assessing health-related quality of
      life (HRQL) in patients with hand eczema, and whether gender differences in HRQL
      could be detected. HRQL was affected by hand eczema, measured with both SF-36 and
      DLQI. The SF-36 showed more impaired HRQL for females than for males, in the
      mental health dimension, whereas no gender-related differences were detected with
      the DLQI. To compare the instruments we used factor analysis, with a polychoric
      correlation matrix as input, thus taking the ordinal aspect of the data into
      account. There was a high correlation between the instruments for physical
      health, but lower for mental health. In this context our interpretation of the
      factor analysis is that the SF-36 measures mental health better than the DLQI.
      The SF-36 therefore appears suitable for use in future studies for measuring
      HRQL, and gender differences in HRQL, in persons with reported hand eczema.

PMID- 15175028
TI  - Epidermal growth factor induces fibronectin expression in human dermal
      fibroblasts via protein kinase C delta signaling pathway.
AB  - Epidermal growth factor (EGF) and fibronectin are known to play an important role
      in wound healing. In this study, we demonstrated that EGF upregulates the
      expression of fibronectin mRNA and protein in human dermal fibroblasts.
      Actinomycin D, an RNA synthesis inhibitor, significantly blocked basal mRNA
      expression, but the addition of EGF compensated the blockage. Cycloheximide, a
      protein synthesis inhibitor, did not block this upregulation by EGF. In addition,
      the treatment with EGF significantly reduced the degradation rate of fibronectin
      mRNA. But EGF did not increase fibronectin promoter activity. EGF-mediated
      induction of fibronectin expression was inhibited by the treatment of fibroblasts
      with protein kinase C (PKC) inhibitor, Calphostin C and Rottlerin. The
      transfection of a dominant-negative mutant of PKCdelta into fibroblasts
      significantly reduced the induction of fibronectin protein expression by EGF. EGF
      enhanced PKCdelta protein expression and also translocated PKCdelta to the
      membrane. Rottlerin blocked the EGF-mediated reduction of mRNA degradation rate.
      These results indicate that EGF-mediated induction of fibronectin expression
      occurs at the post-transcriptional level and involves PKCdelta signaling pathway.

PMID- 15175029
TI  - Association analysis of cystatin A and zinc finger protein 148, two genes located
      at the psoriasis susceptibility locus PSORS5.
AB  - Psoriasis is a multifactorial hereditary skin disease. The searches for causative
      DNA variations have generated several susceptibility loci, but at present, the
      gene(s) involved has not been identified. In this article, we investigated
      whether cystatin A, an upregulated gene in psoriatic plaques and located at
      chromosome 3q21, is the disease-causing gene at the psoriasis susceptibility
      locus PSORS5. We also investigated association to a second gene located in this
      region, zinc finger protein 148. The two genes have been sequenced in a small
      case/control set in search for SNP markers, followed by family-based association
      analysis using the transmission disequilibrium test. We did not detect
      association with either of the genes.

PMID- 15175030
TI  - Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage
      to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population.
AB  - Ten genome-wide scans have been conducted over the past few years in the search
      for psoriasis susceptibility genes, but only one potential susceptibility region
      has been consistently replicated. A meta-analysis using the genome-search meta
      analysis method was undertaken combining the results of six of these psoriasis
      genome-wide studies. The results of this analysis revealed linkage to the major
      histocompatibility complex on chromosome 6p21 that includes the PSORS1 locus. In
      addition, linkage was also recorded to a region on chromosome 4q28-q31 previously
      identified only in a Chinese Hans population. Both these regions were
      statistically significant even after correction for multiple testing. A possible
      reason for the erratic replication of findings could be the large effect of the
      PSORS1 locus (6p21) masking the effect of other loci involved in psoriasis. To
      overcome this problem, we suggest that future studies condition on the effect of
      the PSORS1 locus.

PMID- 15175031
TI  - Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin
      deposition in allergen-challenged human atopic skin.
AB  - Anti-IL-5 monoclonal antibody (mepolizumab) reduces baseline bronchial mucosal
      eosinophils and deposition of extracellular matrix proteins in the reticular
      basement membrane in mild asthma. Here we report the effect of anti-IL-5, in the
      same patients, on allergen-induced eosinophil accumulation, tenascin deposition
      (as a marker of repair and remodelling) and the magnitude of the late-phase
      allergic cutaneous reaction. Skin biopsies were performed in 24 atopic subjects
      at allergen- and diluent-injected sites before 6 and 48 h after, three infusions
      of a humanized, monoclonal antibody against IL-5 (mepolizumab) using a randomized
      double-blind, placebo-controlled design. Anti-IL-5 significantly inhibited
      eosinophil infiltration in 6 h and 48 h skin biopsies as well as the numbers of
      tenascin immunoreactive cells at 48 h. In contrast, anti-IL-5 had no significant
      effect on the size of the 6 or 48 h late-phase cutaneous allergic reaction. This
      study (a) suggests that eosinophils are unlikely to cause the redness, swelling,
      and induration characteristic of the peak (6 h) late-phase cutaneous allergic
      reaction and (b) shows that decreases in tenascin positive cells at 48 h
      correlates with reduction of eosinophils, so providing further evidence of
      involvement in remodelling processes associated with allergic inflammation.

PMID- 15175032
TI  - BP230- and BP180-specific auto-antibodies in bullous pemphigoid.
AB  - Bullous pemphigoid is a subepidermal blistering disease associated with auto
      antibodies (auto-ab) to BP180 and BP230. We developed ELISAs utilizing
      baculovirus-encoded recombinant proteins of BP230 and BP180 and studied their
      diagnostic and prognostic values by assessing the profile of the auto-ab response
      in 127 patients with BP. 39 patients had focal involvement, whereas 88 had
      generalized disease; 51 individuals served as controls. The results indicate: (1)
      BP180 IgG reactivity was associated with an overall sensitivity of 0.953 and
      specificity of 0.940; (2) 105 of 127 BP patients also displayed BP230 auto
      reactivity, the global diagnostic performance of which, however, was moderate
      compared to BP180-auto-reactivity (sensitivity 0.815 vs 0.953, specificity 0.648
      vs 0.940); (3) 101 patients (79.5%) had concordant BP180 and BP230 reactivity;
      (4) the association between the presence of BP230 auto-reactivity and focal
      involvement was stronger than in generalized disease (odds ratio (OR) 17.7 vs
      10.2), independently from BP180 auto-ab profile; (5) correlation of total IgG
      with IgG1 and IgG4 was variable for both BP180 and BP230. Collectively, the
      global diagnostic properties of the BP180-ELISA outperform those of the BP230
      ELISA. Presence of BP230 auto-reactivity, however, supports the diagnosis of BP
      and might be indicative for the extent of the disease.

PMID- 15175033
TI  - Impaired sphingomyelinase activity and epidermal differentiation in atopic
      dermatitis.
AB  - A defective permeability barrier leads to the penetration of environmental
      allergens into the skin and initiates immunological reactions and inflammation
      crucially involved in the pathogenesis of atopic dermatitis (AD). Decreased
      stratum corneum ceramide content may cause the defect in permeability barrier
      function consistently found in AD. Acid and neutral sphingomyelinase (A- and N
      SMase) generate ceramides with structural and signal transduction functions in
      epidermal proliferation and differentiation. We determined epidermal SMase
      activities, DNA synthesis, involucrin, loricrin, filaggrin, and keratin
      expression in lesional and non-lesional skin of AD patients. We found decreased
      epidermal A-SMase activity in lesional and non-lesional skin, correlating with
      reduced stratum corneum ceramide content and disturbed barrier function. N-SMase
      activity was reduced in non-lesional skin and more significantly reduced in
      lesional skin, correlating with impaired expression of cornified envelope
      proteins and keratins, important for skin barrier function. Changes in
      involucrin, loricrin, filaggrin, keratin K 5 (basal) and K 16 (proliferation
      associated) were noticed in non-lesional and lesional skin, whereas changes in K
      10 (suprabasal), K 6 (proliferation associated), and K 17 (inflammation
      associated) were found only in lesional skin. In summary, reduction in SMase
      generating ceramides and impaired differentiation are involved in the defective
      barrier function found in AD.

PMID- 15175034
TI  - A comparative study of photoacoustic and reflectance methods for determination of
      epidermal melanin content.
AB  - Although epidermal melanin content has been quantified non-invasively using
      visible reflectance spectroscopy (VRS), there is currently no way to determine
      melanin distribution in the epidermis. We have developed a photoacoustic probe
      that uses a Q-switched, frequency-doubled Nd:YAG (neodymium, yttrium, aluminum,
      garnet) laser operating at 532 nm to generate acoustic pulses in skin in vivo.
      The probe contained a piezoelectric element that detected photoacoustic waves
      that were then analyzed for epidermal melanin content using a photoacoustic
      melanin index (PAMI). Melanin content was compared between results of
      photoacoustics and VRS. Spectra from human skin were fitted to a model based on
      diffusion theory that included parameters for epidermal thickness, melanin
      content, hair color and density, and dermal blood content. Ten human subjects
      with skin phototypes I-VI were tested using the photoacoustic probe and VRS. A
      plot of PAMI v. VRS showed a good linear fit with r2=0.85. Photoacoustic and VRS
      measurements are shown for a human subject with vitiligo, indicating that melanin
      was almost completely absent. We present preliminary modeling for photoacoustic
      probe design and analysis necessary for depth profiling of epidermal melanin.

PMID- 15175035
TI  - Ultraviolet a radiation-induced immediate iron release is a key modulator of the
      activation of NF-kappaB in human skin fibroblasts.
AB  - Ultraviolet A (UVA, 320-400 nm) radiation, an oxidizing component of sunlight,
      leads to an immediate increase in the labile iron in human skin fibroblasts.
      Exposure of skin fibroblasts to UVA radiation is also known to induce nuclear
      factor-kappaB (NF-kappaB) DNA-binding activity, although the underlying mechanism
      is unclear. We report here that in skin fibroblasts, the extent of NF-kappaB
      activation by UVA tightly correlates with the level of "UVA-induced" labile iron
      release as shown by both iron chelation and iron loading treatments. Furthermore,
      our data indicate that the slow kinetics of induction of NF-kappaB by UVA
      relative to other oxidants previously studied is due to a transient increase in
      permeability of nuclear membrane to proteins and occurs as a result of labile
      iron-mediated damage to nuclear membrane. Since in addition to iron chelators,
      lipid peroxidation inhibitors also decrease the UVA-mediated induction of NF
      kappaB, we propose that the rapid release of labile iron by UVA might act as a
      catalyst to exacerbate the generation of lipid secondary messengers in skin cell
      membranes that are responsible for induction of NF-kappaB. This novel role for
      iron in amplifying NF-kappaB mobilization in response to UVA-induced oxidative
      stress aids understanding of its involvement in UV-induced skin inflammation.

PMID- 15175036
TI  - Responses of black and white skin to solar-simulating radiation: differences in
      DNA photodamage, infiltrating neutrophils, proteolytic enzymes induced,
      keratinocyte activation, and IL-10 expression.
AB  - Black skin is more resistant to the deleterious effects of ultraviolet radiation
      than white skin. A higher melanin content and a different melanosomal dispersion
      pattern in the epidermis are thought to be responsible for this. Our purpose was
      to compare skin responses in black and white skin following exposure to solar
      simulating radiation (SSR) to further investigate the photoprotective properties
      of black skin. Six volunteers of skin phototype I-III (white) were exposed to
      (doses measured directly with a Waldmann UV detector device) 12,000-18,000 mJ per
      cm2 (2 MED) of SSR and compared with six volunteers of skin phototype VI (black)
      exposed to 18,000 mJ per cm2 (<1 MED) of SSR. The presence and distribution of
      skin pigment, DNA photodamage, infiltrating neutrophils, photoaging associated
      proteolytic enzymes, keratinocyte activation, and the source of interleukin 10
      (IL-10) in skin biopsies taken before and after exposure were studied. In all
      white skinned subjects, 12,000-18,000 mJ per cm2 of SSR induced DNA damage in
      epidermal and dermal cells, an influx of neutrophils, active proteolytic enzymes,
      and diffuse keratinocyte activation. Additionally, in three of the white skinned
      volunteers IL-10 positive neutrophils were found to infiltrate the epidermis.
      Except for DNA damage in the supra basal epidermis, none of these changes was
      found in black skinned subjects. Increased skin pigmentation appears to be
      primarily responsible for the observed differences in skin responses. Our data
      could provide an explanation as to why black skin is less susceptible to sunburn,
      photoaging, and skin carcinogenesis.

PMID- 15175037
TI  - Sunlight exposure and (sero)prevalence of epidermodysplasia verruciformis
      associated human papillomavirus.
AB  - Ultraviolet radiation (UVR) is associated with an increased risk of squamous cell
      carcinoma (SCC), which is in part due to immunomodulation. In addition, human
      papilloma virus (HPV), especially the epidermodysplasia verruciformis (EV)
      associated types, may be involved. In view of the capacity of UVR to impair host
      resistance to infections, we investigated the relationship between solar exposure
      and the prevalence of cutaneous HPV. In a case-control study on skin cancer (320
      controls and 156 patients) a lifetime-retrospective questionnaire on sun exposure
      was administered. The presence of DNA of HPV types 5, 8, 15, 20, 24, and 38 in
      plucked eyebrow hair and type-specific seroreactivity were assessed and analyzed
      in relation to estimated exposure. Sunburn episodes in the past, especially at
      age 13-20 y, appeared to be associated with an enhanced risk of EV-HPV DNA
      positivity. In contrast, a higher lifetime sun exposure was associated with a
      lower risk of HPV infection. These results indicate that UVR at erythematogenic
      doses increases the risk of EV-HPV infection, possibly due to impaired host
      resistance to HPV and/or a direct effect of UVR on viral replication. The
      favorable association between lifetime sun exposure and HPV prevalence, however,
      underscores the enigmatic role of HPV in skin carcinogenesis.

PMID- 15175038
TI  - In vivo oxygen radical generation in the skin of the protoporphyria model mouse
      with visible light exposure: an L-band ESR study.
AB  - Although oxygen radicals are thought to play a key role in the skin injury that
      is caused by protoporphyria, there is no direct evidence of generation of these
      radicals in vivo. This study measured the generation of oxygen radicals caused by
      visible light non-invasively in the skin of griseofulvin-induced protoporphyria
      model mice, using an in vivo electron spin resonance spectrometer equipped with a
      surface-coil-type resonator that could detect radicals within about 0.5 mm of the
      skin surface. A durable nitroxyl radical was administered intravenously as a
      probe. Light irradiation enhanced the decay of the nitroxyl signal in
      griseofulvin-treated mice, whereas light irradiation did not enhance the signal
      decay in control mice. The enhanced signal decay was completely suppressed by
      intravenous administration of hydroxyl radical scavengers, superoxide dismutase
      or catalase, or the intraperitoneal administration of desferrioxamine. The
      enhanced signal decay with illumination was reversible, and quickly responded to
      turning the light on and off. These observations suggest that the hydroxyl
      radical is generated via an iron-catalyzed reaction in the skin. This paper
      demonstrates, for the first time, the specific generation of oxygen radicals in
      response to light irradiation of the skin of protoporphyria model mice.

PMID- 15175039
TI  - Reduced fibroblast interaction with intact collagen as a mechanism for depressed
      collagen synthesis in photodamaged skin.
AB  - This report provides evidence from a number of different approaches (i.e.,
      comparison of cell shape in 1-microm sections of photodamaged versus healthy skin
      at the light microscopic level; comparison of cell shape and apposition to
      collagen fibrils in ultrathin sections of the same tissues examined by
      transmission electron microscopy, and fluorescence staining for adhesion site
      protein expression and actin filament architecture in frozen tissue sections)
      that dermal cells in healthy skin are attached to collagen fibrils over a large
      part of the cell border, have a flattened/spread (two-dimensional) appearance and
      have abundant actin in their cytoplasm. In contrast, cells in photodamaged skin
      are often in contact with fragmented collagen or amorphous debris rather than
      intact collagen, have a collapsed/elongated shape, and have a lower amount of
      actin. Collagen synthesis is reduced in severely photodamaged skin relative to
      collagen synthesis in corresponding sun-protected skin (N Engl J Med 329:530,
      1993). We hypothesize that fibroblasts in severely damaged skin have less
      interaction with intact collagen and as a result experience a reduction in
      mechanical tension. Decreased collagen synthesis is (presumed to be) the result.

PMID- 15175040
TI  - Green tea polyphenols prevent ultraviolet light-induced oxidative damage and
      matrix metalloproteinases expression in mouse skin.
AB  - Chronic exposure of solar ultraviolet (UV) light to human skin results in
      photoaging. UV-induced oxidative damage and induction of matrix
      metalloproteinases (MMP) have been implicated in this process. Because
      polyphenols from green tea (GTP) prevent other cutaneous adverse effects of UV
      radiation we hypothesized that UV irradiation-induced oxidative damage and
      induction of MMP might be prevented in vivo in mouse skin by oral administration
      of GTP. GTP was administered in drinking water (0.2%, wt/vol) to SKH-1 hairless
      mice, which were then exposed to multiple doses of UVB (90 mJ per cm2, for 2 mo
      on alternate days) following in vivo photoaging animal protocol. Treatment of GTP
      resulted in inhibition of UVB-induced protein oxidation in vivo in mouse skin, a
      hallmark of photoaging, when analyzed biochemically, by immunoblotting, and
      immunohistochemistry. GTP treatment also inhibited UVB-induced protein oxidation
      in vitro in human skin fibroblast HS68 cells, which supports in vivo
      observations. Moreover, oral administration of GTP also resulted in inhibition of
      UVB-induced expression of matrix degrading MMP, such as MMP-2 (67%), MMP-3 (63%),
      MMP-7 (62%), and MMP-9 (60%) in hairless mouse skin. These data suggest that GTP
      as a dietary supplement could be useful to attenuate solar UVB light-induced
      premature skin aging.

PMID- 15175041
TI  - Treatment with 5-fluorouracil and celecoxib displays synergistic regression of
      ultraviolet light B-induced skin tumors.
AB  - Standard chemotherapeutic agents used for the treatment of pre-cancerous skin
      lesions and non-melanoma skin cancers are not completely effective. Several
      studies have suggested that repeated inflammatory sunburn reactions, which
      include the induction of cyclooxygenase-2 (COX-2) and the subsequent production
      of prostaglandins, play a role in skin cancer development. COX-2 inhibition has
      been demonstrated to be a potent means of preventing skin cancer development in
      mice; however, COX-2 inhibitors alone are not effective as chemotherapeutic
      agents. Data in a variety of cancer types suggest greater efficacy in treating
      tumors with combination chemotherapies. Therefore, we hypothesized that a
      combination of the chemotherapeutic agent 5-fluorouracil (5-FU) and the COX-2
      inhibitor and anti-inflammatory drug celecoxib would act synergistically to
      regress tumors in a murine model of ultraviolet light B- (UVB-) induced
      carcinogenesis. We found that topical treatment with 5-FU and celecoxib together
      was up to 70% more effective in reducing the number of UVB-induced skin tumors
      than 5-FU treatment alone. Our data suggest that more effective chemotherapy
      regimens can be developed to treat the millions of pre-cancerous and cancerous
      skin lesions that arise every year, which could ultimately lead to a significant
      reduction in costs and cosmetic defects (scarring) associated with surgical
      interventions.

PMID- 15175042
TI  - Chromosomal aberration patterns differ in subtypes of primary cutaneous B cell
      lymphomas.
AB  - The diagnostic and prognostic importance of recurrent chromosomal aberrations in
      systemic B cell lymphoma is well documented. In contrast, limited data exist on
      genetic changes in primary cutaneous B cell lymphoma. In this study we
      investigated chromosomal aberration patterns in two types of primary cutaneous B
      cell lymphoma with a different clinical behavior. Twenty-two primary cutaneous B
      cell lymphomas, including nine follicle center cell lymphomas and 13 large B cell
      lymphomas of the leg, were analyzed by comparative genomic hybridization and in
      part by fluorescence in situ hybridization. The most frequent imbalances
      detectable were gains in 18q (eight of 22), 1q (six of 22), 7 (six of 22), 12q
      (six of 22), or Xp (four of 22), and losses in 6q (four of 22). In contrast to
      large B cell lymphomas of the leg, primary cutaneous follicle center cell
      lymphomas had fewer imbalances and lacked translocations affecting the IGH locus.
      Gains in 18q (eight of 13) and losses in 6q (four of 13) as well as breakpoints
      within the IGH locus (six of 11) were restricted to the large B cell lymphomas of
      the leg subtype. Translocation t(14; 18) was excluded in 16 primary cutaneous B
      cell lymphomas of both subtypes that were studied by fluorescence in situ
      hybridization. These results suggest that primary cutaneous follicle center cell
      lymphoma and large B cell lymphoma of the leg are characterized by different
      chromosomal aberration patterns, which in part might determine the different
      clinical course of these malignancies.

PMID- 15175043
TI  - GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression
      by binding to its promoter.
AB  - Sonic hedgehog (Shh) binds to its receptor patched (PTCH), leading to the
      activation and repression of target genes via the GLI family of zinc-finger
      transcription factors. Deregulation of the Shh pathway is associated with basal
      cell carcinoma (BCC) due to upregulation of GLI1 and GLI2. We recently
      demonstrated a positive feedback loop between GLI1 and GLI2, which revealed that
      GLI1 may be a direct target of GLI2. Using band shift and luciferase reporter
      assays, we now show that GLI2 binds the GLI-binding consensus sequence in the
      GLI1 promoter. These data suggest that GLI2 directly activates GLI1 and that
      retrovirally expressed GLI2 induces expression of endogenous GLI1 in human
      primary keratinocytes. Finally, using in situ hybridization, we show that GLI2 is
      expressed in the interfollicular epidermis and the outer root sheath of hair
      follicles in normal skin as well as in BCC tumor islands. These results suggest
      an important role for GLI2 in regulating epidermal proliferation and skin
      tumorigenesis.

PMID- 15175044
TI  - GBP-5 splicing variants: New guanylate-binding proteins with tumor-associated
      expression and antigenicity.
AB  - We have identified a new gene, gbp-5, with high homology to the guanylate binding
      proteins (GBP) belonging to the GTPase superfamily including the ras gene. gbp-5
      is transcribed at least into three splicing variants (gbp-5a, -5b, and -5ta)
      leading to two different proteins (GBP-5a/b, GBP-5ta). GBP-5ta is C-terminally
      truncated by 97aa and has therefore lost its isoprenylation site. Although RT-PCR
      results indicated expression of GBP-5 members in selected normal tissues, western
      blotting using two newly generated antibodies revealed that expression of both
      proteins is restricted to peripheral blood monocytes with GBP-5ta at lower
      levels. In contrast, cutaneous T-cell lymphoma (CTCL) tumor tissues (seven of
      seven) were positive solely for GBP-5ta, and four of four CTCL cell lines
      expressed both proteins. Eight of nine melanoma cell lines expressed GBP-5a/b and
      four of nine additionally low levels of GBP-5ta. SEREX retesting using CTCL sera
      indicated a higher immunogenicity for GBP-5ta (nine of 16) than for GBP-5a/b (two
      of 11). Treatment of CTCL cell lines with interferon-gamma did not alter protein
      expression of GBP-5ta or GBP-5a/b. The restricted expression pattern of both GBP
      5ta and GBP-5a/b and the pivotal role of many known members of the GTP-binding
      proteins in proliferation and differentiation suggest possible cancer-related
      functions of gbp-5.

PMID- 15175045
TI  - Implications of using the ND1 gene as a control region for real-time PCR analysis
      of mitochondrial DNA deletions in human skin.

PMID- 15175046
TI  - Molecular cloning of human dectin-2.

PMID- 15175052
TI  - UVA and NF-kappaB activity: ironing out the details.

PMID- 15175053
TI  - ROS: a step closer to elucidating their role in the etiology of light-induced
      skin disorders.

PMID- 15175054
TI  - Psoriasis genetics: the way forward.

PMID- 15175055
TI  - On the atrial response to focal discharges in man.
AB  - INTRODUCTION: Triggers and vulnerability are key factors for the occurrence of
      atrial fibrillation (AF). The aim of this study was to assess spatial dispersion
      of atrial refractoriness and vulnerability in response to both focal discharges
      as well as programmed electrical stimulation in patients undergoing ablation of
      atrial arrhythmogenic foci. METHODS AND RESULTS: Twenty-nine patients were
      studied, and 12 right atrial unipolar electrograms were recorded. Inducibility of
      AF was assessed by a pacing protocol that started with one extrastimulus,
      followed by more aggressive pacing until AF was obtained. Mean fibrillatory
      intervals were used to assess the local refractoriness of each recording site.
      Spatial dispersion of refractoriness was calculated as the coefficient of
      dispersion (CD value: standard deviation of the mean of all local mean
      fibrillatory intervals as a percentage of the overall mean fibrillatory
      interval). Based on our previous study, a CD value </= 3.0 was defined as normal,
      whereas a CD value >3.0 was considered enhanced spatial dispersion of
      refractoriness. Fifteen of 29 patients had normal dispersion of refractoriness
      (mean CD value 1.65 +/- 0.43), and AF was inducible with burst pacing only. These
      patients had focal discharges causing rapid atrial tachycardia with a focal
      activation pattern. Activation mapping of focal activity was possible in 14 of 15
      patients. Focal triggering of AF occurred in only 1 of 15 patients. Fourteen of
      29 patients had enhanced dispersion (mean CD value 4.2 +/- 0.72). AF was
      inducible with a single extrastimulus in 11 of 14 patients (P < 0.001). Focal
      triggering of AF occurred in all 14 patients. CONCLUSION: Spatial dispersion of
      atrial refractoriness determines whether focal atrial discharges trigger AF with
      disorganized activity or, alternatively, only rapid atrial tachycardia.

PMID- 15175056
TI  - Single-stage adenosine tilt testing in patients with unexplained syncope.
AB  - INTRODUCTION: We previously have shown that a 3-minute single-stage adenosine
      tilt test has a diagnostic yield comparable to a two-stage protocol consisting of
      a 30-minute drug-free tilt followed by a 15-minute isoproterenol tilt. In this
      study, we sought to further define the clinical utility of adenosine tilt testing
      in patients with unexplained syncope by prospectively evaluating test specificity
      and determining predictors of a positive test response. METHODS AND RESULTS: The
      specificity of single-stage adenosine tilt testing was determined using 30
      control subjects. To determine the diagnostic yield of this protocol, adenosine
      tilts were performed in 129 patients with unexplained syncope. The adenosine tilt
      test protocol had high specificity (100%) but a low overall diagnostic yield
      (18%). However, the yield was affected significantly by age. In patients </=40
      years of age, the tilt test was positive in 15 (41%) of 37 patients, which was
      significantly greater than the yield in patients between the ages of 41 and 64
      years (6/41 patients [15%], P = 0.012) and those >/=65 years of age (2/41
      patients [5%], P < 0.0001). CONCLUSION: These data support single-stage adenosine
      tilt testing in patients </=40 years of age because the diagnostic yield of the
      test is maximal in this group and the test can be completed in </=3 minutes.
      Conversely, the diagnostic yield of adenosine tilt testing in patients >40 years
      of age is low, suggesting that the clinical utility of this protocol is limited
      in these patients.

PMID- 15175057
TI  - Ablation of superior pulmonary veins compared to ablation of all four pulmonary
      veins:.
AB  - INTRODUCTION: Isolation of all pulmonary veins (PV) is advocated for treatment of
      paroxysmal atrial fibrillation (PAF). However, the superior PVs are responsible
      for most AF triggers, whereas the inferior PVs carry the higher risk for ablation
      induced ostial stenosis. The aim of this study was to compare a superior PV
      isolation approach with isolation of all PVs for treatment of PAF. METHODS AND
      RESULTS: Fifty-two patients with PAF were randomized to either left superior
      pulmonary vein (LSPV) isolation followed by additional isolation of the right
      superior pulmonary vein (RSPV) in case of AF recurrence (group A, n = 27) or
      isolation of all four PVs followed by a repeat procedure in case of recurrence
      (group B, n = 25). At 1-year follow-up, 11 patients (41%) in group A and 8
      patients (32%) in group B had AF relapse (P = 0.55). No significant differences
      in AF relapse were detected between groups at 3 and 12 months (log rank = 0.36, P
      = 0.54) and by Cox proportional hazards model analysis (P = 0.62). Nonsignificant
      PV stenosis was detected in two patients from group B. Total radiofrequency
      energy delivery and fluoroscopy and procedure times were lower in group A: 8.9 +/
      1.4 minutes vs 25.6 +/- 3.7 minutes (P < 0.001), 22.2 +/- 6.8 minutes vs 62 +/-
      10.3 minutes (P < 0.001), and 131.8 +/- 26.5 minutes vs 222.2 +/- 32.3 minutes (P
      < 0.001), respectively. CONCLUSION: A staged superior PVs isolation approach
      confers equal success rates but with reduced radiofrequency energy delivery and
      fluoroscopy and procedure times compared to isolation of all PVs at the initial
      ablation attempt.

PMID- 15175059
TI  - Clinical characteristics of subjects with the Brugada-type electrocardiogram:.
AB  - INTRODUCTION: The Brugada-type ECG, a terminal r' wave accompanied by ST segment
      elevation in the right precordial leads, is not a very rare condition. Most of
      the cases are men in Japan and elsewhere; however, information about the clinical
      features of these cases is lacking. The aim of this study was to determine the
      clinical characteristics of subjects with the Brugada-type ECG, specifically
      Japanese men. METHODS AND RESULTS: We extracted male Brugada-type ECG cases from
      3,374 men followed biennially from 1958 through 2001 in Nagasaki, Japan, and
      compared the clinical characteristics at diagnosis between these cases and four
      age-matched male controls for each case. A total of 34 cases with the Brugada
      type ECG were observed during follow-up. Body mass index (BMI) at diagnosis was
      significantly lower in Brugada-type ECG cases than in 136 controls (20.2 +/- 2.1
      kg/m(2) vs 21.8 +/- 2.8 kg/m(2), P = 0.003). The BMI trend in cases was always
      lower than that in controls throughout the 8-year observation period (from 4
      years before diagnosis to 4 years after diagnosis). Pulse rate at diagnosis was
      also somewhat lower in Brugada-type ECG cases than in controls (68.9 +/- 7.7
      beats/min vs 72.7 +/- 11.1 beats/min, P = 0.038). The significance disappeared
      after controlling for BMI (P = 0.131) or body weight (P = 0.153). CONCLUSION: The
      cases with the Brugada-type ECG had lower BMI than controls, leading to a clue to
      possible basic mechanisms of the Brugada-type ECG with a focus on this
      association.

PMID- 15175058
TI  - Clinical experience with a new detection algorithm for differentiation of
      supraventricular from ventricular tachycardia in a dual-chamber defibrillator.
AB  - INTRODUCTION: Inadequate therapy for supraventricular tachyarrhythmias (SVT) is a
      frequent problem of implantable cardioverter defibrillators (ICD). Dual-chamber
      ICDs have been developed to improve discrimination of SVT from ventricular
      tachycardia (VT). We investigated the positive predictivity, sensitivity, and
      specificity of a new algorithm, the SMART detection trade mark algorithm,
      incorporated in the Phylax AV (Biotronik) dual-chamber ICD. METHODS AND RESULTS:
      Two hundred nine patients (185 men, age 64 +/- 11 years) received a Phylax AV ICD
      with SMART detection trade mark activated. In 138 of these patients, 1,245
      sustained tachycardia episodes with a detailed electrogram were stored in the
      device during a follow-up period of 10 +/- 6 months. Episodes were correctly
      classified as ventricular fibrillation (VF, n = 178) in 52 patients, VT (n = 641)
      in 98 patients, and SVT (n = 385) in 48 patients by the algorithm. Forty-one true
      SVT episodes (3.3%) were misclassified as VT: atrial fibrillation (n = 7) and
      flutter (n = 1), sinus tachycardia (n = 12), and other SVT (n = 21). The positive
      predictivity for VF/VT was 94.5% (95% CI 92.7-95.8) uncorrected and 94.5% (95% CI
      92.9-95.8%) corrected with the generalized equation estimation (GEE) method. The
      positive predictivity for SVT was 100%. The specificity was 88.9% (95% CI 85.6
      91.6%) uncorrected and 89.0% (95% CI 85.6-91.6%) corrected with the GEE method
      with a sensitivity of 100%. CONCLUSION: The SMART detection trade mark algorithm
      was safe and reliable for the detection of all ventricular tachycardias. Although
      its specificity was high, it should be improved with regard to SVT to avoid
      inappropriate ICD therapies.

PMID- 15175060
TI  - Long-term outcome of patients who received implantable cardioverter
      defibrillators for stable ventricular tachycardia.
AB  - INTRODUCTION: Evidence is inconclusive concerning the role of implantable
      cardioverter defibrillators (ICDs) to treat patients with hemodynamically stable
      ventricular tachycardia (VT). The goal of this study was to estimate future risk
      of unstable ventricular arrhythmias in patients who received ICDs for stable VT.
      METHODS AND RESULTS: We reviewed complete ICD follow-up data from 82 patients
      (age 66.1 +/- 11.3 years; left ventricular ejection fraction 32.3%+/- 11.2%; mean
      +/- SD) who received ICDs for stable VT. During the follow-up period of 23.6 +/-
      21.5 months (mean +/- SD), 15 patients (18%) died, and 10 (12%) developed
      unstable ventricular arrhythmia, 8 of whom had the unstable arrhythmia as the
      first arrhythmia after ICD placement. Estimated 2- and 4-year survival in the
      whole group was 80% and 74%, respectively. Estimated 2- and 4-year probability of
      any VT and unstable VT was 67% and 77% and 11% and 25%, respectively. There were
      no differences in age, ejection fraction, sex, underlying heart disease, cycle
      length, symptoms, baseline electrophysiologic study results, or QRS
      characteristics of qualifying VT between patients who developed unstable
      ventricular arrhythmia and patients who did not. Twenty-nine patients (35%) had
      at least one inappropriate shock, and 11 (13%) underwent further surgery for ICD
      related complications. CONCLUSION: Patients who present with hemodynamically
      stable VT are at risk for subsequent unstable VT. ICD treatment offers potential
      salvage of patients with stable VT who subsequently develop unstable
      VT/ventricular fibrillation, although complications and inappropriate shocks are
      considerable. No predictors could be found for high and low risk for unstable
      arrhythmias. These findings support ICD treatment for stable VT survivors.

PMID- 15175061
TI  - Implantable cardioverter defibrillator therapy for ambulatory ventricular
      tachycardia: are we using an elephant gun?

PMID- 15175062
TI  - Vagal activity modulates spontaneous augmentation of ST elevation in the daily
      life of patients with Brugada syndrome.
AB  - INTRODUCTION: In Brugada syndrome, ventricular fibrillation (VF) occurs mainly
      during sleep, and Brugada ECG signs are intensified by parasympathomimetic drugs;
      therefore, vagal activity could be a precipitating factor of VF. The aim of the
      present study was to elucidate the relation between spontaneous augmentation of
      ST elevation and changes in autonomic nervous activities in the daily life of
      patients with Brugada syndrome. METHODS AND RESULTS: Twenty-three consecutive
      patients with Brugada syndrome were studied. Group VF(+) consisted of 7
      symptomatic patients and 3 asymptomatic patients with inducible VF; group VF(-)
      consisted of 13 asymptomatic patients without documented or inducible VF. Two
      channel unipolar lead (V(1) and V(2)) Holter ECG was recorded. Heart rate
      variability was analyzed by the maximum entropy method. Spontaneous augmentation
      of ST elevation (>/=1.5 mm/20 min) occurred more frequently during 24 hours in
      group VF(+) than in group VF(-) (5.7 +/- 2.5 times vs 2.3 +/- 2.4 times, P <
      0.01). ST elevation was significantly greater in group VF(+) than in group VF(-)
      (2.1 +/- 0.2 mm vs 1.8 +/- 0.2 mm, P < 0.05). Power of the high-frequency
      component (HF: 0.15-0.4 Hz) and RR interval increased progressively, and the
      ratio of low-frequency component (LF; 0.04- 0.15 Hz) to high-frequency component
      (LF/HF) gradually decreased toward the time of maximum ST elevation. During an
      entire day, daytime (0-5 P.M.), and nighttime (0-5 A.M.), both HF and LF/HF were
      not different between groups VF(+) and VF(-). CONCLUSION: In Brugada syndrome,
      spontaneous augmentation of ST elevation in daily life occurred along with an
      increase in vagal activity. ST elevation was augmented more in patients with VF
      than in those without VF under similar vagal tone.

PMID- 15175063
TI  - Detection of inadvertent catheter movement into a pulmonary vein during
      radiofrequency catheter ablation by real-time impedance monitoring.
AB  - INTRODUCTION: During radiofrequency ablation to encircle or isolate the pulmonary
      veins (PVs), applications of radiofrequency energy within a PV may result in
      stenosis. The aim of this study was to determine whether monitoring of real-time
      impedance facilitates detection of inadvertent catheter movement into a PV.
      METHODS AND RESULTS: In 30 consecutive patients (mean age 53 +/- 11 years) who
      underwent a left atrial ablation procedure, the three-dimensional geometry of the
      left atrium, the PVs, and their ostia were reconstructed using an electroanatomic
      mapping system. The PV ostia were identified based on venography, changes in
      electrogram morphology, and manual and fluoroscopic feedback as the catheter was
      withdrawn from the PV into the left atrium. Real-time impedance was measured at
      the ostium, inside the PV at approximately 1 and 3 cm from the ostium, in the
      left atrial appendage, and at the posterior left atrial wall. There was an
      impedance gradient from the distal PV (127 +/- 30 Omega) to the proximal PV (108
      +/- 15 Omega) to the ostium (98 +/- 11 Omega) in each PV (P < 0.01). There was no
      significant impedance difference between the ostial and left atrial sites. During
      applications of radiofrequency energy, movement of the ablation catheter into a
      PV was accurately detected in 80% of the cases (20) when there was an abrupt
      increase of >/=4 Omega in real-time impedance. CONCLUSION: There is a significant
      impedance gradient from the distal PV to the left atrium. Continuous monitoring
      of the real-time impedance facilitates detection of inadvertent catheter movement
      into a PV during applications of radiofrequency energy.

PMID- 15175064
TI  - Entrainment mapping of dual-loop macroreentry in common atrial flutter: new
      insights into the atrial flutter circuit.
AB  - INTRODUCTION: The aim of this study was to determine using entrainment mapping
      whether the reentrant circuit of common type atrial flutter (AFL) is single loop
      or dual loop. METHODS AND RESULTS: In 12 consecutive patients with
      counterclockwise (CCW) AFL, entrainment mapping was performed with evaluation of
      atrial electrograms from the tricuspid annulus (TA) and the posterior right
      atrial (RA) area. We hypothesized that a dual-loop reentry could be surmised from
      "paradoxical delayed capture" of the proximal part of the circuit having a longer
      interval from the stimulus to the captured beat compared with the distal part of
      the circuit. In 6 of 12 patients with CCW AFL, during entrainment from the septal
      side of the posterior blocking line, the interval from the stimulus to the last
      captured beat was longer at the RA free wall than at the isthmus position. In
      these six patients with paradoxical delayed capture, flutter cycle length (FCL)
      was 227 +/- 12 ms and postpacing interval minus FCL was significantly shorter at
      the posterior blocking line than at the RA free wall (20 +/- 11 ms vs 48 +/- 33
      ms, P < 0.05). In two of these patients, early breakthrough occurred at the
      lateral TA. A posterior block line was confirmed in all six patients in the sinus
      venosa area by intracardiac echocardiography. CONCLUSION: Half of the patients
      with common type AFL had a dual-loop macroreentrant circuit consisting of an
      anterior loop (circuit around the TA) and a posterior loop (circuit around the
      inferior vena cava and the posterior blocking line).

PMID- 15175065
TI  - Markers of myocardial damage, tissue healing, and inflammation after
      radiofrequency catheter ablation of atrial tachyarrhythmias.
AB  - INTRODUCTION: Radiofrequency ablation produces a localized endomyocardial
      necrosis that may result in release of biochemical markers reflecting myocardial
      cell damage, inflammation, and tissue reparation. The aim of this study was to
      determine the extent of rise and time course of markers of inflammation and
      tissue reparation in patients undergoing radiofrequency catheter ablation.
      METHODS AND RESULTS: Serial blood samples were taken from patients with AV nodal
      reentrant tachycardia (n = 5), Wolff-Parkinson-White syndrome (n = 3), and atrial
      flutter (n = 5) undergoing radiofrequency ablation. Blood was taken before
      ablation (day 0, baseline) and at day 1 and day 120 after ablation. The
      proinflammatory marker interleukin-6 (IL-6), troponin I (TNI), and myoglobin, as
      well as matrix metalloproteinase-9 (MMP-9), a marker for myocardial healing, were
      measured by enzyme-linked immunosorbent assay. Levels of IL-6, TNI, myoglobin,
      and MMP-9 were significantly elevated on day 1 after ablation compared to
      baseline levels. Seven of the 13 patients had troponin levels greater than the
      threshold of significant myocardial damage (>0.1 ng/mL) on day 1. Plasma levels
      of MMP-9 were still elevated on day 120 compared to values before ablation (P =
      0.021). CONCLUSION: Markers of inflammation, wound healing, and myocardial damage
      are increased in patients who undergo radiofrequency ablation. Levels of MMP-9, a
      marker for myocardial healing and repair, are still elevated 120 days after the
      procedure, suggesting that radiofrequency ablation induces tissue damage leading
      to a long-term process of reparation.

PMID- 15175066
TI  - Predictors of recurrence following catheter ablation of atrial fibrillation using
      an irrigated-tip ablation catheter.
AB  - INTRODUCTION: The aims of this study were to identify predictors of recurrence
      after catheter ablation of atrial fibrillation (AF) and to report the safety and
      efficacy of catheter ablation of AF using an irrigated-tip ablation catheter.
      METHODS AND RESULTS: Seventy-five consecutive patients (51 men [68%]; age 54 +/-
      13 years) with symptomatic drug-refractory paroxysmal (42 patients), persistent
      (21 patients), or permanent (12 patients) AF underwent catheter ablation of AF
      using an irrigated-tip ablation catheter and a standard ablation strategy, which
      involved electrical isolation of all pulmonary veins (PVs) and creation of a
      cavotricuspid linear lesion. At 10.5 +/- 7.5 months of follow-up following a
      single (n = 75) or redo ablation procedure (n = 11), 39 (52%) of the 75 patients
      were free of AF, 10 were improved (13%), and 26 had experienced no benefit from
      the ablation procedure (35%). Seventy-six percent of patients with paroxysmal AF
      were free from recurrent AF. The most significant complications were two episodes
      of pericardial tamponade, mitral valve injury in one patient, two strokes, and
      complete but asymptomatic PV stenosis in one patient. Cox proportional hazards
      multivariate regression analysis identified the presence of persistent AF,
      permanent AF, and age >50 years prior to the ablation are the only independent
      predictors of AF recurrence after the first PV isolation procedure. CONCLUSION:
      Catheter ablation of AF using a strategy involving isolation of all PVs and
      creation of a linear lesion in the cavotricuspid isthmus using cooled
      radiofrequency energy is associated with moderate efficacy and an important risk
      for complications. The best results of this procedure are achieved in the subset
      of patients who are younger than 50 years and have only paroxysmal AF.

PMID- 15175067
TI  - The restitution portrait: a new method for investigating rate-dependent
      restitution.
AB  - INTRODUCTION: Electrical restitution, relating action potential duration (APD) to
      diastolic interval (DI), was believed to determine the stability of heart rhythm.
      However, recent studies demonstrate that stability also depends on long-term APD
      changes caused by memory. This study presents a new method for investigation of
      rate- and memory-dependent aspects of restitution and for assessment of mapping
      models of APD. METHODS AND RESULTS: Bullfrog ventricular myocardium was paced
      with a "perturbed downsweep protocol." Starting from a basic cycle length (BCL)
      of 1,000 ms, the tissue was paced until steady state was achieved, followed by
      single beats of longer and shorter cycle lengths. BCL was decreased by 50 to 100
      ms and the process repeated. All APDs were plotted as a function of the preceding
      DI, which allowed simultaneous observation of dynamic, S1-S2, and two constant
      BCL restitution curves in a "restitution portrait." Responses were classified as
      1:1 (stimulus:response), transient 2:2, or persistent 2:2 (alternans) and were
      related to the slopes of the restitution curves. None of these slopes approached
      unity for the persistent 2:2 response, demonstrating that the traditional
      restitution condition does not predict alternans. The restitution portrait was
      used to evaluate three mapping models of APD. The models with no memory and with
      one-beat memory did not produce restitution portraits similar to the experimental
      one. A model with two-beat memory produced a qualitatively similar portrait.
      CONCLUSION: The restitution portrait allows a more comprehensive assessment of
      cardiac dynamics than methods used to date. Further study of models with memory
      may result in a clinical criterion for electrical instability.

PMID- 15175068
TI  - Transmural distribution of connexins in rodent hearts.
AB  - INTRODUCTION: Electrophysiologic heterogeneity across the ventricular wall is a
      result of differential transmural expression of various ion channel proteins that
      underlie the different action potential waveforms observed in epicardial,
      midmyocardial, and endocardial regions. Cardiac connexins mediate cell-to-cell
      communication, are critical for normal impulse propagation, and play a role in
      electrophysiologic remodeling in disease states. However, little is known about
      the transmural distribution of cardiac gap junction proteins. METHODS AND
      RESULTS: Connexin expression in epicardium, midmyocardium, and endocardium was
      assessed immunohistochemically in mouse and rat hearts. The total connexin
      protein content within different ventricular regions was measured by
      immunoblotting. Connexin43 is twice as abundant in midmyocardium and endocardium
      compared with epicardium in the mouse but not in the rat. Connexin45 is expressed
      equally across the left ventricular wall. CONCLUSION: Epicardial myocytes express
      significantly less Cx43 and therefore may be less well coupled than midmyocardial
      and endocardial myocytes. A transmural gradient of connexin43 expression across
      the left ventricular free wall likely results in differences in the stoichiometry
      of connexins expressed in different regions of the heart.

PMID- 15175069
TI  - Successful implantable cardioverter defibrillator placement in an ambulatory
      patient without thoracic venous access.
AB  - Evaluation of an individual requiring permanent cardiac pacing and implantable
      cardioverter defibrillator (ICD) function revealed no suitable thoracic vascular
      access for traditional device implantation. Because the patient refused cardiac
      surgery, a left femoral venous approach was used to introduce two extended
      length, active fixation leads that were positioned in the right atrium and
      ventricle. The leads were tunneled to the abdomen and connected to a dual-chamber
      ICD. A low defibrillation threshold and robust pacing and sensing parameters were
      observed at implant. All of these parameters were stable at 6-month follow-up. In
      addition, no negative effects of the predominantly abdominal shock vector were
      observed. This case suggests that femoral ICD placement should be considered
      before routinely referring such patients for open chest surgery.

PMID- 15175070
TI  - Ablation of atrioventricular nodal reentrant tachycardia in tricuspid atresia.
AB  - A 31-year-old woman with tricuspid atresia and a palliative Waterston shunt
      presented with intractable poorly tolerated supraventricular tachycardia.
      Electrophysiologic evaluation was consistent with AV nodal reentrant tachycardia.
      The fast pathway region was mapped electroanatomically during tachycardia and
      with constant rate ventricular pacing. Successful radiofrequency ablation was
      achieved by placement of lesions in an area adjacent and inferior to the His
      bundle electrogram on the left side of the septum.

PMID- 15175071
TI  - Implantable cardioverter defibrillator oversensing: what is the mechanism?

PMID- 15175072
TI  - Alternating wide and narrow QRS complex tachycardias: what is the mechanism?

PMID- 15175073
TI  - One method to reduce heart block risk during catheter ablation of
      atrioventricular nodal reentrant tachycardia.

PMID- 15175074
TI  - Catecholaminergic polymorphic ventricular tachycardia, recurrent syncope, and
      implantable loop recorder.

PMID- 15175075
TI  - Protein misfolding in neurodegenerative diseases.
AB  - A common pathogenic mechanism shared by diverse neurodegenerative disorders, like
      Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible
      spongiform encephalopathies, may be altered protein homeostasis leading to
      protein misfolding and aggregation of a wide variety of different proteins in the
      form of insoluble fibrils. Mutations in the genes encoding protein constituents
      of these aggregates have been linked to the corresponding diseases, thus a
      reasonable scenario of pathogenesis was based on misfolding of a neurone-specific
      protein that forms insoluble fibrils that subsequently kill neuronal cells.
      However, during the past 5 years accumulating evidence has revealed the
      neurotoxic role of prefibrillar intermediate forms (soluble oligomers and
      protofibrils) produced during fibril formation. Many think these may be the
      predominant neurotoxic species, whereas microscopically visible fibrillar
      aggregates may not be toxic. Large protein aggregates may rather be simply
      inactive, or even represent a protective state that sequesters and inactivates
      toxic oligomers and protofibrils. Further understanding of the biochemical
      mechanisms involved in protein misfolding and fibrillization may optimize the
      planning of common therapeutic approaches for neurodegenerative diseases,
      directed towards reversal of protein misfolding, blockade of protein
      oligomerization and interference with the action of toxic proteins.

PMID- 15175076
TI  - The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation
      and expression analysis.
AB  - Focal epilepsies in young patients are frequently associated with differentiated
      glioneuronal tumours. Dysplastic neurones represent a characteristic
      neuropathological feature of gangliogliomas, the most common entity encountered
      in this group. Here, we have analysed two major components of the reelin pathway
      involved in neuronal migration and cortical development, that is, p35 and
      disabled-1 (dab1), in gangliogliomas. Genomic structures of human dab1 and p35
      were identified 'in silico' using the HTGS databank, NCBI BLAST 2.1. DNA sequence
      analysis was carried out in gangliogliomas obtained from 29 epilepsy patients vs.
      peripheral blood DNA from non-affected control individuals (n = 100). Gene
      expression of dab1 and p35 was determined by real-time RT-PCR (reverse
      transcriptase polymerase chain reaction) in gangliogliomas (n = 14) vs. non
      neoplastic central nervous system tissue (n = 20). The human dab1 gene contains
      13 coding exons and is located on chromosome 1p31-32. A single coding exon
      constitutes the human p35 gene, which is located on chromosome 17q11.2. A novel
      homologueous genomic region on chromosome 2 has to be taken into account for
      future studies on p35. One ganglioglioma patient showed a unique polymorphism in
      the p35 gene. The single base exchange (C to A) at nucleotide 904 of the p35 cDNA
      (GenBank X80343, start ATG, codon 302) results in a leucine-isoleucine amino acid
      substitution. No mutations of the dab1 and p35 genes in gangliogliomas were
      observed. However, significantly lower levels of dab1 and p35 gene transcripts
      were detected in gangliogliomas compared to controls (dab1 28.24%, t-test P <
      0.001; p35 21.28%, t-test P < 0.001, in gangliogliomas vs. controls). Our data
      suggest that mutational events of dab1 and p35 are not involved in the molecular
      pathogenesis of gangliogliomas. A potential functional role of these
      developmentally regulated genes for the formation of epileptogenic glioneuronal
      lesions remains to be elucidated.

PMID- 15175077
TI  - IL-16 expression in lymphocytes and microglia in HIV-1 encephalitis.
AB  - IL-16 is a natural ligand for the CD4 molecule and is known for its chemotactic
      and anti-HIV-1 activities. We determined IL-16 expression in human brain tissue
      with HIV-1 encephalitis by specific immunocytochemistry and showed that
      infiltrating lymphocytes and activated microglia express IL-16. IL-16
      immunoreactivity was particularly pronounced in microglial nodules. In vitro,
      human foetal microglia and not astrocytes produce IL-16, and HIV-1 infection up
      regulates microglial IL-16 release in a Nef-dependent manner. These results
      support the notion that, in the brain, IL-16 is a macrophage-lineage specific
      modulator of the inflammatory response and HIV-1 expression. Recruitment of IL
      16+ T cells and microglia/macrophages may represent an innate response to HIV-1
      infection in the central nervous system that counterbalances viral stimulatory
      factors.

PMID- 15175078
TI  - Selective changes in nicotinic acetylcholine receptor subtypes related to tobacco
      smoking: an immunohistochemical study.
AB  - Increases in neuronal nicotinic receptors (nAChRs) in response to nicotine
      exposure have been reported in cell cultures, rodent brains, and in the brains of
      human smokers. The present study examines alterations in alpha4 and alpha7 nAChR
      subunit cellular expression in human hippocampus and entorhinal cortex from
      normal elderly individuals with known smoking history. There were significant
      increases in the intensity of alpha4 immunoreactive neuropil, but not the number
      of cell bodies, in many regions of hippocampus and entorhinal cortex in smokers
      compared to age-matched non-smokers and ex-smokers. There was also an increase in
      alpha7 immunoreactive perikarya in the granular cell layer of dentate gyrus in
      smokers but not other regions examined. There was, in contrast, a significant
      reduction in alpha7 immunoreactive astrocytes in smokers and ex-smokers compared
      to non-smokers. These findings suggest exposure to tobacco smoke acutely up
      regulates alpha4 receptors in axon terminals and dendrites but not perikarya,
      whereas tobacco smoking induced down-regulation of alpha7 expression on
      astrocytes is a long-term effect. As the alpha4 subunit decreases with ageing and
      degenerative diseases such as Alzheimer's disease, whereas alpha7 increases in
      astrocytes in Alzheimer's disease, the findings further indicate the therapeutic
      relevance of nicotinic agonists such as nicotine.

PMID- 15175079
TI  - Disturbed trafficking of dystrophin and associated proteins in targetoid
      phenomena after chronic muscle denervation.
AB  - Dystrophin and associated proteins form a complex with an important role at the
      sarcolemma. Expression of this protein complex is highly regulated during
      development and regeneration. In order to better understand assembling patterns
      of these proteins, we have studied their expression in targetoid-like phenomena
      found in human muscle after chronic denervation, a situation known to give rise
      to abnormal protein trafficking. In eight biopsies of patients with chronic
      denervation, mainly resulting from amyotrophic lateral sclerosis, we found a
      number of targetoid phenomena. Selective accumulation of a number of sarcolemmal
      and sarcoplasmatic proteins occurred in targetoid phenomena. The larger majority
      of them contained gamma-sarcoglycan (gammaSG), but none contained the
      developmental heavy chain myosin isoform. In a series of 166 targetoid phenomena
      which could be studied with 17 different antibodies recognizing sarcolemmal and
      cytoplasmatic proteins, a high level of colocalization of gammaSG with desmin and
      alpha-actinin was found. Colocalization rate was much lower with other proteins,
      including other members of the dystrophin-associated protein complex. These data
      show that selective changes in expression of otherwise closely related proteins
      occur during disturbed trafficking leading to target formation. Because members
      of the dystrophin-associated protein complex do not accumulate in a similar
      fashion within targets, we suggest that a complex molecular control of gene
      expression and trafficking of this complex is involved after chronic muscle
      denervation.

PMID- 15175080
TI  - Hypoxia-inducible factor 1alpha/vascular endothelial growth factor axis in
      astrocytomas. Associations with microvessel morphometry, proliferation and
      prognosis.
AB  - Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that promotes
      ischaemia-driven angiogenesis. The aim of this study was to determine the
      relation of HIF-1alpha to vascular endothelial growth factor (VEGF; an important
      angiogenic molecule in brain tumours), p53 expression, angiogenesis,
      proliferative potential and clinical outcome in a large series of diffuse
      astrocytomas. Expression of HIF-1alpha, VEGF, Ki-67 (a proliferation-associated
      marker) and p53 was determined immunohistochemically in 83 adult patients with
      supratentorial diffuse astrocytomas. Microvessels, highlighted by means of anti
      CD34 immunohistochemistry, were enumerated with computer-assisted image analysis.
      Although HIF-1alpha and VEGF were expressed in the majority of cases, their
      levels increased significantly with increasing grade and proliferative potential.
      HIF-1alpha positively correlated with microvessel counts and VEGF with total
      vascular area and the presence of rounder vessel sections. There was a positive
      correlation of VEGF with p53 expression in astrocytomas and anaplastic
      astrocytomas. In univariate analysis, both VEGF and HIF-1alpha were associated
      with shortened survival in the entire cohort, but lost significance when grades
      II/III and grade IV were analysed separately. Multivariate analysis revealed that
      the combination of HIF-1alpha with grade was a significant prognostic indicator.
      HIF-1alpha expression may be used to refine the prognostic information provided
      by grade in patients with diffuse astrocytomas. Its adverse prognostic effect is
      most likely mediated by hypoxia, the driving force for HIF-1alpha accumulation.

PMID- 15175081
TI  - Differential gene expression in human brain pericytes induced by amyloid-beta
      protein.
AB  - Cerebral amyloid angiopathy is one of the characteristics of Alzheimer's disease
      (AD) and this accumulation of fibrillar amyloid-beta (Alphabeta) in the vascular
      wall is accompanied by marked vascular damage. In vitro, Abeta1-40 carrying the
      'Dutch' mutation (DAbeta1-40) induces degeneration of cultured human brain
      pericytes (HBP). To identify possible intracellular mediators of Abeta-induced
      cell death, a comparative cDNA expression array was performed to detect
      differential gene expression of Abeta-treated vs. untreated HBP. Messenger RNA
      expression of cyclin D1, integrin beta4, defender against cell death-1,
      neuroleukin, thymosin beta10, and integrin alpha5 were increased in DAbeta1-40
      treated HBP, whereas insulin-like growth factor binding protein-2 mRNA expression
      was decreased. Corresponding protein expression was investigated in AD and
      control brains to explore a potential role for these proteins in pathological
      lesions of the AD brain. Cyclin D1 expression was increased in cerebral amyloid
      angiopathy and cells in a perivascular position, suggesting that the cell cycle
      may be disturbed during Abeta-mediated degeneration of cerebrovascular cells.
      Moreover, cyclin D1 expression, but also that of integrin beta4, defender against
      cell death-1, neuroleukin and thymosin beta10 was found in a subset of senile
      plaques, suggesting a role for these proteins in the pathogenesis of senile
      plaques.

PMID- 15175082
TI  - Neuropil and neuronal changes in hippocampal NADPH-diaphorase histochemistry in
      the ME7 model of murine prion disease.
AB  - Nitric oxide (NO) has been implicated in neurotoxicity and cerebral blood flow
      changes in chronic neurodegeneration, but its activity in the mammalian prion
      diseases has not been studied in detail. Nicotine adenine dinucleotide phosphate
      (NADPH)-diaphorase (NADPH-d) histochemistry is a simple and robust histochemical
      procedure that allows localization of the tissue distribution of NO synthases.
      The aim of the present study is to assess whether NADPH-d histochemical activity
      is altered in the hippocampus in the ME7 model of prion disease in C57BL/6J mice.
      At early and late stages after the initiation of the disease we assessed features
      of the NADPH-d positive cells and the neuropil histochemical activity in CA1 and
      dentate gyrus using densitometric analysis. In C57BL/6J mice 13 weeks
      postinjection of the prion agent ME7, when behavioural changes first become
      apparent, neuropil NADPH-d histochemical staining increases, whereas at late
      stages it decreases dramatically. Both type I and type II NADPH-d positive cells
      were found to survive throughout the hippocampal formation into the late stages
      of the disease, but diaphorase activity was reduced in dendritic branches and
      abnormal varicosities were present in both dendritic and axonal processes of
      NADPH-d positive type I cells. The pathophysiological implications of the results
      remain to be investigated but both blood flow alteration and NO neurotoxicity may
      be features of the disease.

PMID- 15175083
TI  - No evidence of hSNF5/INI1 point mutations in choroid plexus papilloma.
AB  - Choroid plexus carcinomas (CPC) have been shown to carry mutations in the
      hSNF5/INI1 gene on chromosomal arm 22q11.2. A recent study on choroid plexus
      papillomas (CPP) and CPC revealed frequent losses of chromosomal portions on the
      long arm of chromosome 22 (-22q). The region harbouring hSNF5/INI1 was affected
      in 47% of the CPP and 73% of the CPC, respectively. -22q occurred more frequently
      in adult than in infantile CPP suggesting different pathogenetic pathways for
      these tumours. These findings may indicate a potential tumour suppressor gene
      function of hSNF5/INI1 in a subset of choroid plexus tumours. In order to examine
      its potential role in the pathogenesis of choroid plexus tumours, we analysed
      exons 1-9 of hSNF5/INI1 by SSCP analysis in a series of 21 formalin-fixed and
      paraffin-embedded CPP. No alterations in migratory patterns were detected. These
      data indicate that somatic point mutations of hSNF5/INI1 do not play a role in
      the pathogenesis of CPP and that CPP and CPC may arise by two different molecular
      pathways.

PMID- 15175084
TI  - Ten years of EC-funded concerted actions on the neuropathology of prion disease:
      report on the final scientific meeting (31 October-2 November 2003, Baden near
      Vienna, Austria).

PMID- 15175085
TI  - Dural haemorrhage in non-traumatic infant deaths: an observation on Smith vs.
      Geddes.

PMID- 15175088
TI  - USP Veterinary Pharmaceutical Information Monographs--Anti-inflammatories.

PMID- 15175089
TI  - Age, performance and sleep deprivation.
AB  - Young subjects are frequently involved in sleep-related accidents. They could be
      more affected than older drivers by sleep loss and therefore worsen their driving
      skills quicker, or have a different perception of their level of impairment. To
      test these hypotheses we studied variations of reaction time (RT), a fundamental
      prerequisite for safe performing, as measured by lapses, i.e. responses > or =
      500 ms and self-assessment of performance and sleepiness after a night awake and
      after a night asleep in a balanced crossover design in young versus older healthy
      subjects. Ten young (20-25 years old) and 10 older volunteers (52-63 years old)
      were tested with and without 24 h of sleep deprivation. Without sleep
      deprivation, RTs were slower in older subjects than in the younger ones. However,
      after sleep deprivation, the RTs of young subjects increased while that of the
      older subjects remained almost unaffected. Sleepiness and self-perception of
      performance were equally affected in both age groups showing different perception
      of performance in the age groups. Our findings are discussed in terms of
      vulnerability to sleep-related accidents.

PMID- 15175090
TI  - Stimulus-induced brain lactate: effects of aging and prolonged wakefulness.
AB  - Both aging and sleep deprivation disturb the functions of the frontal lobes.
      Deficits in brain energy metabolism have been reported in these conditions.
      Neurons use not only glucose but also lactate as their energy substrate. The
      physiological response to elevated neuronal activity is a transient increase in
      lactate concentrations in the stimulated area. We have previously shown that
      cognitive stimulation increases brain lactate. To study the effect of prolonged
      wakefulness on the lactate response we designed an experiment to assess brain
      lactate levels during a 40-h sleep deprivation period in young (19-24 years old;
      n = 13) and in aged (60-68 years old; n = 12) healthy female volunteers. Brain
      lactate levels were assessed with proton MR-spectroscopy ((1)H MRS) during the
      performance of a silent word generation task. The (1)H MRS voxel location was
      individually selected, using functional magnetic resonance imaging, to cover the
      activated area in the left frontal lobe. The degree of sleepiness was verified
      using vigilance tests and self-rating scales. In the young alert subjects, the
      silent word generation test induced a 40% increase in lactate, but during the
      prolonged wakefulness period this response disappeared. In the aged subjects, the
      lactate response could not be detected even in the alert state. We propose that
      the absence of the lactate response may be a sign of malfunctioning of normal
      brain energy metabolism. The behavioral effects of prolonged wakefulness and
      aging may arise from this dysfunction.

PMID- 15175091
TI  - Waking up properly: is there a role of thermoregulation in sleep inertia?
AB  - We assume that alertness should be highest at the end of a sleep episode: it is
      not. There is always sleep inertia upon awakening, which can last minutes to
      hours, and whose underlying physiological mechanisms are largely unknown.
      Previously, we had found a functional relationship between the degree of distal
      vasodilatation (as measured by the distal-proximal skin temperature gradient
      (DPG) and sleepiness (as measured by subjective ratings), promoting rapid sleep
      onset. This led us to hypothesize that the dissipation of sleep inertia
      (sleepiness) would be associated with reverse thermoregulatory mechanisms, i.e.
      distal vasoconstriction. In two sets of experiments with either a nocturnal sleep
      episode (study 1) or an afternoon nap (study 2) we could show that vasodilatation
      of hands and feet increased after lights off and that this was reversed after
      lights on. The time course of the DPG was significantly and positively correlated
      with subjective sleepiness (KSS), reflecting similar temporal relationships in
      both studies 1 and 2. The extremities cooled at a rate very closely parallel to
      the decay of sleepiness [time constants for the exponential decline calculated
      for study 2: DPG, 0.286 +/- 0.048 h versus KSS, 0.332 +/- 0.050 h; NS],
      indicating redistribution of heat from the shell to the core during dissipation
      of sleepiness. There was no statistical evidence that the time course of sleep
      inertia and its thermophysiological correlates depend on sleep structure prior to
      awakening. The symmetry between the thermoregulatory processes initiating
      sleepiness and those dissipating it is striking. In order to directly test our
      hypothesis, further studies with thermophysiological interventions (e.g. cooling
      the extremities) are needed.

PMID- 15175092
TI  - The relationship of nightmare frequency and nightmare distress to well-being.
AB  - Nightmares can be defined as very disturbing dreams, the events or emotions of
      which cause the dreamer to wake up. In contrast, unpleasant dreams can be defined
      in terms of a negative emotional rating of a dream, irrespective of whether or
      not the emotions or events of the dream woke the dreamer. This study addresses
      whether frequency of unpleasant dreams is a better index of low well-being than
      is frequency of nightmares. A total of 147 participants reported their nightmare
      frequency retrospectively and then kept a log of all dreams, including
      nightmares, for 2 weeks, and rated each dream for pleasantness/unpleasantness.
      Anxiety, depression, neuroticism, and acute stress were found to be associated
      with nightmare distress (ND) (the trait-like general level of distress in waking
      life caused by having nightmares) and prospective frequency of unpleasant dreams,
      and less so with the mean emotional tone of all dreams, or retrospective or
      prospective nightmare frequency. Correlations between low well-being and
      retrospective nightmare frequency became insignificant when trait ND was
      controlled for, but correlations with prospective unpleasant dream frequency were
      maintained. The reporting of nightmares may thus be confounded and modulated by
      trait ND: such confounding does not occur for the reporting of unpleasant dreams
      in general. Thus there may be attributional components to deciding that one has
      been awoken by a dream, which can affect estimated nightmare frequency and its
      relationship with well-being. Underestimation of nightmare frequency by the
      retrospective questionnaire compared with logs was found to be a function of mean
      dream unpleasantness and ND.

PMID- 15175093
TI  - Spontaneous eyelid movements (ELMS) during sleep are related to dream recall on
      awakening.
AB  - The present study aimed to test whether spontaneous eyelid movements (ELMs)
      during stage 2 and rapid eye movement (REM) sleep are related to more frequent
      and vivid reports of visual mentation on awakening. Participants were awakened 15
      s after an ELM was observed during ongoing REM and stage 2 sleep and immediately
      asked for a mentation report and to rate the visual vividness of any imagery they
      could remember. These reports were compared with control reports collected after
      a period of ELM quiescence before awakening (noELM). Significantly greater
      frequencies of imagery reports were collected after ELM awakenings compared with
      noELM awakenings from stage 2, but not REM sleep. When imagery was reported,
      imagery ratings were not significantly different between ELM and noELM
      conditions, regardless of sleep stage. The average amount of electroencephalogram
      (EEG) arousal 15 s after stage 2 awakenings was significantly higher in the ELM
      compared with noELM conditions. In addition, within the stage 2 ELM condition,
      EEG arousal was significantly higher when visual imagery was reported compared
      with reports without imagery; suggesting that the observed increase in imagery
      reporting from the stage 2 ELM condition could have been mediated by the level of
      brain arousal. Such arousal possibly provides better conditions to attend and
      recall previous mental activity from NREM sleep. However, there was no
      ELM/arousal effect within REM sleep, possibly because this state is already at
      maximum sleeping levels of arousal, attention and resulting dream recall.

PMID- 15175094
TI  - Sleep deprivation in honey bees.
AB  - Rest at night in forager honey bees (Apis mellifera) meets essential criteria of
      sleep. This paper reports the effect of a 12-h total sleep deprivation (SD) by
      forced activity on the behaviour of these animals. The behaviour of sleep
      deprived animals is compared with that of control animals under LD [periodic
      alternation between light (L) and darkness (D)] 12 : 12 hours. SD for 12 h during
      the first D period resulted in a significant difference with respect to the
      parameter 'hourly amount of antennal immobility' between sleep-deprived and
      control animals during the remaining L and D periods. This difference did not
      occur in the L period following the deprivation night, but rather it became
      obvious at the beginning of the following D period. The increase of the amount of
      antennal immobility in sleep-deprived bees was accompanied by an increase of the
      duration of episodes of antennal immobility. Moreover, the latency from 'lights
      off' to the first episode of antennal immobility lasting 20 s or longer ('deep
      sleep latency') tended to be shorter in sleep-deprived than in control animals.
      Disturbing the bees during the day (L period) did not result in such differences
      between disturbed and control animals. Highest reaction thresholds in sleeping
      honey bees occur during long episodes of antennal immobility. We therefore
      conclude that honey bees compensate a sleep deficit by intensification
      (deepening) of the sleep process and thus that sleep in honey bees, like that in
      other arthropods and mammals, is controlled by regulatory mechanisms.

PMID- 15175095
TI  - The effects of bright-light therapy on actigraphical measured sleep last for
      several weeks post-treatment. A study in a nursing home population.
AB  - We investigated the time-course of nocturnal actigraphic measures, following the
      termination of bright-light therapy for sleep disturbances in demented nursing
      home patients. From an earlier study, 11 nursing home patients (86 +/- 9 years,
      Mini-Mental Status Examination score 12 +/- 4) with actigraphically measured
      sleep efficiency < 85%, were recruited to morning bright-light treatment (6000
      8000 lux) 2 h per day for 14 days. Actigraphic measures were registered at
      pretreatment, treatment and at four monthly post-treatment periods. Each
      actigraphic recording period consisted of seven consecutive days. Sleep improved
      substantially with treatment; sleep efficiency increased from 73% to 86% and
      total nocturnal wake time was reduced by nearly 2 h. During the 16 weeks post
      treatment period, actigraphic measures gradually returned to pretreatment levels.
      Sleep efficiency remained significantly higher than the pretreatment level 4
      weeks after treatment termination. Sleep onset latency remained significantly
      reduced up until 12 weeks post-treatment. This study supports previous findings
      of beneficial effects of bright-light therapy for sleep disturbances in demented
      nursing home patients. Furthermore, these results are the first to suggest that
      post-treatment effects of short-term bright-light therapy may last longer than
      previously assumed.

PMID- 15175096
TI  - Cortico-motoneurone excitability in patients with obstructive sleep apnoea.
AB  - A disordered neuromotor control of pharynx muscles may play a role in the genesis
      of obstructive sleep apnoea syndrome (OSAS). This raises the possibility of a
      dysfunction of projections descending from the cortex to segmental nuclei. With
      single pulse transcranial magnetic stimulation (TMS) we studied the physiology of
      the corticospinal projection to hand muscles in seven OSAS patients. At first, we
      compared them with nine age- and sex-matched normal controls in the wake state.
      The only abnormality was a lengthening of the central silent period (P < 0.001).
      This supports a steady imbalance of motor cortical interneurone activities
      towards a state of enhanced inhibition. Then we looked at changes of the motor
      evoked potential (MEP) size and latency, according to whether patients were
      awake, or in a non-rapid eye movement (REM) 2 sleep stage, or during a typical
      apnoea. During non-REM 2 sleep, the average MEP amplitude was significantly (P <
      0.05) smaller than in the awake state. The MEP latency was, in turn,
      significantly longer (P < 0.05). During apnoeas, the MEP size decreased, and the
      latency increased further (P < 0.05), indicating an extra depression of the
      cortico-motoneuronal activity. All TMS changes were detected outside the
      pharyngeal district, suggesting a widespread dysfunction of the cortico
      motoneuronal system in the OSAS, which is more evident during apnoeas.

PMID- 15175097
TI  - Neurobehavioral correlates of sleep-disordered breathing in children.
AB  - The effects of sleep-disordered breathing (SDB) on neurobehavioral function were
      examined in two matched groups of children from the general population. Thirty
      five children with polysomnographically confirmed SDB were matched for ethnicity,
      age, gender, maternal educational attainment, and maternal smoking, to healthy
      children with no evidence of SDB. Children with SDB had significantly lower mean
      scores on the Differential Ability Scales for General Conceptual Ability (similar
      to IQ) and for the Non-verbal Cluster. On the neuropsychology assessment battery
      (NEPSY), children with SDB scored significantly lower than the control group on
      the attention/executive function domain and two subtests within that domain, one
      measuring visual attention and the other executive function. In addition,
      children with SDB scored significantly lower than the controls on one subtest
      from the NEPSY language domain: Phonological Processing. This subtest measures
      phonological awareness, a skill that is critical for learning to read. No
      differences in behavior, as measured by the Child Behavior Checklist (CBCL) or
      the Conners' Parent Rating Scale, were found between the two groups. Using a
      novel algorithm to assess sleep pressure, we found that children with SDB were
      significantly sleepier than controls. Furthermore, total arousal index was
      negatively correlated with neurocognitive abilities, suggesting a role for sleep
      fragmentation in pediatric SDB-induced cognitive dysfunction.

PMID- 15175098
TI  - Does frequency of nocturnal urination reflect the severity of sleep-disordered
      breathing?
AB  - Nocturia is an often-described symptom of sleep-disordered breathing (SDB). The
      aim of our study was to determine the frequency of nocturnal urination among
      patients with different severity of SDB and to find out whether frequency of
      nocturnal urination reflects the severity of disease. A retrospective chart
      review was conducted among 1075 subjects of suspected SDB. Nocturia was assessed
      using standard questionnaire evaluating a frequency of nocturnal urination.
      Subjects were divided into four groups of SDB based on the polysomnographic
      evaluation. In primary snoring group, 51% subjects did not complain nocturia, 28%
      subjects reported one time, 16% subjects reported two to three times and 5%
      subjects reported more than three times urination per night. Among patients with
      mild obstructive sleep apnea syndrome (OSAS), nocturnal urination was not
      reported by 36% and was reported one time by 34%, two to three times by 15%, more
      than 3 times by 15%. The corresponding frequencies among patients with moderate
      OSAS were 40, 31, 17 and 12%, and with severe OSAS were 23, 22, 23 and 32%,
      respectively. The severe OSA group was significantly different from other groups
      as regards the frequency of nocturnal urination (P < 0.001) while other OSA
      groups did not show any significance. Nocturnal urination of more than three
      times was significantly more reported by severe OSA patients ( P < 0.001)
      (positive predictive value = 0.71, negative predictive value = 0.62).

PMID- 15175099
TI  - Abnormal sleep duration and motor vehicle crash risk.

PMID- 15175100
TI  - Forecasting the cytokine storm following systemic interleukin (IL)-2
      administration.
AB  - Extensive clinical experience has shown that systemic interleukin (IL)-2
      administration can induce complete or partial regression of renal cell cancer
      (RCC) metastases in 15 to 20 % of patients. Since IL-2 has no direct anti-cancer
      effects, it is believed that cancer regression is mediated either by a direct
      modulation of immune cell effector functions or through the mediation of soluble
      factors released as a result of IL-2 administration.We previously observed that
      transcriptional and protein changes induced by systemic IL-2 administration
      affect predominantly mononuclear phagocytes with little effect, particularly
      within the tumor microenvironment, on T cell activation, localization and
      proliferation. It further appeared that mononuclear phagocyte activation could be
      best explained by the indirect mediation of a secondary release of cytokines by
      IL-2 responsive cells either in the circulation or in peripheral tissues.To
      better characterize the cytokine outburst that follows systemic IL-2
      administration we followed the serum levels of 68 soluble factors in ten patients
      with RCC undergoing high dose (720,000 IU/kg intravenously every 8 hours) IL-2
      therapy. Serum was collected before therapy, 3 hours after the 1st and 4th dose
      and assayed on a multiplexed protein array platform. This study demonstrated that
      1) the serum concentration of more than half the soluble factors studied changed
      significantly during therapy; 2) changes became more dramatic with increasing
      doses; 3) subclasses of soluble factors displayed different kinetics and 4)
      cytokine patterns varied quantitatively among patients.This study shows that the
      cytokine storm that follows systemic IL-2 administration is complex and far
      reaching inclusive of soluble factors with disparate, partly redundant and partly
      contrasting effects on immune function. Therefore comparing in parallel large
      number of soluble factors, it sets a comprehensive foundation for further
      elucidation of "cytokine storm" in larger patient pools. Based on this analysis,
      we propose a prospective collection of serum samples in a larger cohort of
      patients undergoing IL-2 administration with the purpose of discerning patterns
      predictive of clinical outcome and toxicity.

PMID- 15175101
TI  - Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis
      in human microvascular endothelial cells through altered intracellular signaling.
AB  - The immunosuppressive agent cyclosporin A (CsA), a calcineurin inhibitor which
      blocks T cell activation has provided the pharmacologic foundation for organ
      transplantation. CsA exerts additional effects on non-immune cell populations and
      may adversely effect microvascular endothelial cells, contributing to chronic
      rejection, a long-term clinical complication and significant cause of mortality
      in solid-organ transplants, including patients with small bowel allografts.
      Growth of new blood vessels, or angiogenesis, is a critical homeostatic mechanism
      in organs and tissues, and regulates vascular populations in response to
      physiologic requirements. We hypothesized that CsA would inhibit the angiogenic
      capacity of human gut microvessels. Primary cultures of human intestinal
      microvascular endothelial cells (HIMEC) were used to evaluate CsA's effect on
      four in vitro measures of angiogenesis, including endothelial stress fiber
      assembly, migration, proliferation and tube formation, in response to the
      endothelial growth factor VEGF. We characterized the effect of CsA on
      intracellular signaling mechanisms following VEGF stimulation. CsA affected all
      VEGF induced angiogenic events assessed in HIMEC. CsA differentially inhibited
      signaling pathways which mediated distinct steps of the angiogenic process. CsA
      blocked VEGF induced nuclear translocation of the transcription factor NFAT,
      activation of p44/42 MAPK, and partially inhibited JNK and p38 MAPK. CsA
      differentially affected signaling cascades in a dose dependent fashion and
      completely blocked expression of COX-2, which was integrally linked to HIMEC
      angiogenesis. These data suggest that CsA inhibits the ability of microvascular
      endothelial cells to undergo angiogenesis, impairing vascular homeostatic
      mechanisms and contributing to the vasculopathy associated with chronic
      rejection.

PMID- 15175102
TI  - Expression of connexins in human preimplantation embryos in vitro.
AB  - Intercellular communication via gap junctions is required to coordinate
      developmental processes in the mammalian embryo. We have investigated if the
      connexin (Cx) isoforms known to form gap junctions in rodent preimplantation
      embryos are also expressed in human embryos, with the aim of identifying species
      differences in communication patterns in early development. Using a combination
      of polyA PCR and immunocytochemistry we have assessed the expression of Cx26,
      Cx31, Cx32, Cx40, Cx43 and Cx45 which are thought to be important in early rodent
      embryos. The results demonstrate that Cx31 and Cx43 are the main connexin
      isoforms expressed in human preimplantation embryos and that these isoforms are
      co-expressed in the blastocyst. Cx45 protein is expressed in the blastocyst but
      the protein may be translated from a generally low level of transcripts: which
      could only be detected in the PN to 4-cell embryos. Interestingly, Cx40, which is
      expressed by the extravillous trophoblast in the early human placenta, was not
      found to be expressed in the blastocyst trophectoderm from which this tissue
      develops. All of the connexin isoforms in human preimplantation embryos are also
      found in rodents pointing to a common regulation of these connexins in
      development of rodent and human early embryos and perhaps other species.

PMID- 15175103
TI  - Secretory carcinoma of breast in a 17-year-old male.
AB  - BACKGROUND: Secretory carcinoma of the male breast (juvenile carcinoma) is a rare
      neoplasm. Only a few cases have been reported in the literature. CASE REPORT: We
      report here a case in a 17-year old male presenting with recurrent breast
      swelling. CONCLUSIONS: Though considered an indolent neoplasm, secretory
      carcinoma does metastasise to lymph nodes and recur after local excision. Surgery
      in form of mastectomy with axillary clearance is the treatment of choice.

PMID- 15175104
TI  - Therapy of murine squamous cell carcinomas with 2-difluoromethylornithine.
AB  - Targeted overexpression of an ornithine decarboxylase (ODC) transgene to mouse
      skin (the K6/ODC mouse) significantly enhances susceptibility to carcinogenesis.
      While in most strain backgrounds the predominant tumor type resulting from
      initiation-promotion protocols is benign squamous papilloma, K6/ODC mice on a
      FVB/N background develop malignant squamous cell carcinomas (SCCs) rapidly and in
      high multiplicity after carcinogen treatment. We have investigated the utility of
      polyamine-based therapy against SCCs in this model using the ODC inhibitor 2
      difluoromethylornithine delivered orally. At a 2% concentration in drinking
      water, DFMO caused rapid tumor regression, but in most cases, tumors eventually
      regrew rapidly even in the presence of DFMO. The tumors that regrew were spindle
      cell carcinomas, an aggressive undifferentiated variant of SCC. At 1% DFMO in the
      drinking water, tumors also responded rapidly, but tumor regrowth did not occur.
      The majority of DFMO-treated SCCs were classified as complete responses, and in
      some cases, apparent tumor cures were achieved. The enzymatic activity of ODC,
      the target of DFMO, was substantially reduced after treatment with 1% DFMO and
      the high SCC polyamine levels, especially putrescine, were also significantly
      lowered. Based on the results of BrdUrd labeling and TUNEL assays, the effect of
      DFMO on SCC growth was accompanied by a significant reduction in tumor
      proliferation with no increase in the apoptotic index. These results demonstrate
      that SCCs, at least in the mouse, are particularly sensitive to polyamine-based
      therapy.

PMID- 15175106
TI  - Eradication of methicillin-resistant Staphylococcus aureus with an antiseptic
      soap and nasal mupirocin among colonized patients--an open uncontrolled clinical
      trial.
AB  - BACKGROUND: Aim of the study was to determine the clinical efficacy of a new
      antiseptic liquid soap (Stellisept scrub), based on the combination of
      undecylenamidopropyltrimonium methosulphate (4%) and phenoxyethanol (2%), for
      eradication of MRSA among colonized patients who do not receive antibiotic
      therapy. METHODS: Over two years 50 MRSA patients in 6 hospitals were observed.
      Treatment was defined as the daily application of Stellisept scrub for the
      antiseptic body and hair wash (at least 60 s) in combination with nasal
      mupirocin. A treatment cycle was a minimum of 5 days treatment. Screening was
      carried out at least 48 h after the treatment cycle was finished, with 24 h
      between each of the requested three or more samplings, which included the
      nasopharynx, groin, axilla, perineum and other MRSA-positive skin areas. RESULTS:
      Fifteen cases were retrospectively excluded (lack of outcome documentation,
      concomitant antibiotic therapy, open wounds). All 35 patients had colonization
      with MRSA before antiseptic treatment on the skin, in the groin (80%), the axilla
      (25.7%), the perineum (20%) or other skin areas (14.3%). Colonization at more
      than one skin sites was found in 34.3%. Nasal colonization was found in 21 of 28
      patients (75%), 7 patients were without nasal screening prior to the antiseptic
      treatment. After one treatment cycle MRSA was eradicated in 25 patients (71.4%),
      after a second cycle the total eradication rate was 91.4%, after a third cycle
      the rate increased to 94.2%. No patient discontinued the antiseptic treatment due
      to dermal intolerance of the product. CONCLUSIONS: Progressive eradication of
      MRSA carriage was observed with the antiseptic soap and mupirocin. The
      eradication rate was not biased by concomitant antibiotic treatment, screening
      during treatment or lack of evidence for colonization in contrast to other
      studies with other preparations.

PMID- 15175105
TI  - Liver-specific expression of the agouti gene in transgenic mice promotes liver
      carcinogenesis in the absence of obesity and diabetes.
AB  - BACKGROUND: The agouti protein is a paracrine factor that is normally present in
      the skin of many species of mammals. Agouti regulates the switch between black
      and yellow hair pigmentation by signalling through the melanocortin 1 receptor
      (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant
      regulatory mutations in the mouse agouti gene that cause the wild-type protein to
      be produced at abnormally high levels throughout the body. Mice harboring these
      mutations exhibit a pleiotropic syndrome characterized by yellow coat color,
      obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to
      hyperplasia and carcinogenesis in numerous tissues, including the liver. The goal
      of this research was to determine if ectopic expression of the agouti gene in the
      liver alone is sufficient to recapitulate any aspect of this syndrome. For this
      purpose, we generated lines of transgenic mice expressing high levels of agouti
      in the liver under the regulatory control of the albumin promoter. Expression
      levels of the agouti transgene in the liver were quantified by Northern blot
      analysis. Functional agouti protein in the liver of transgenic mice was assayed
      by its ability to inhibit binding of the alpha-melanocyte stimulating hormone
      (alphaMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were
      analyzed in control and transgenic mice. Control and transgenic male mice were
      given a single intraperitoneal injection (10 mg/kg) of the hepatocellular
      carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at
      36 or 40 weeks after DEN injection and the number of tumors per liver and total
      liver weights were recorded. RESULTS: The albumin-agouti transgene was expressed
      at high levels in the livers of mice and produced a functional agouti protein.
      Albumin-agouti transgenic mice had normal body weights and normal levels of blood
      glucose and plasma insulin, but responded to chemical initiation of the liver
      with an increased number of liver tumors compared to non-transgenic control mice.
      CONCLUSIONS: The data demonstrate that liver-specific expression of the agouti
      gene is not sufficient to induce obesity or diabetes, but, in the absence of
      these factors, agouti continues to promote hepatocellular carcinogenesis.

PMID- 15175107
TI  - Infection control and the significance of sputum and other respiratory secretions
      from adult patients with cystic fibrosis.
AB  - BACKGROUND: There is limited data available on the environmental and public
      health impact of the microbiological hazards associated with sputa from patients
      with cystic fibrosis [CF]. Pseudomonas aeruginosa, Burkholderia cenocepacia
      (formerly Burkholderia cepacia genomovar III), Staphylococcus aureus and
      Stenotrophomonas maltophilia are bacterial pathogens which are commonly found in
      the sputum of CF patients. A study was performed to ascertain the amount of
      sputum produced relating to microbial loading, as well as the diversity of
      bacteria present in a population of adult patients, with particular attention to
      pathogenic organisms. METHODS: Sputum from adult [>18 years old] CF patients [n =
      20], chosen randomly from a population of 138 CF patients, was collected over a
      24 h period on admission to the in-patient CF unit and enumerated quantitatively,
      as well as the sputa from 138 adult CF patients was examined qualitatively for
      the presence of infecting microflora. In addition, all different phenotypes from
      the sputum of each patient were identified phenotypically employing a combination
      of conventional identification methods [e.g. oxidase], as well as the API
      Identification schemes [API 20 NE, API 20 E]. RESULTS: This study demonstrated
      that patients with cystic fibrosis generate large numbers of bacteria in their
      sputum, approximating to 10(9) organisms per patient per day. Although these
      organisms are introduced to the environment from the respiratory tract mainly via
      sputum, relatively few represent true bacterial pathogens and therefore are not
      clinically important to the general public who are immunocompotent. The greatest
      risk of such environmental microbial loading is to other patients with CF and
      therefore CF patients should be made aware of the hazards of acquiring such
      organisms from the environment, as well as socializing with other CF patients
      with certain transmissible types, such as Pseudomonas aeruginosa and Burkholderia
      cenocepacia. CONCLUSIONS: Environmental health professionals should therefore be
      aware that CF patients are a greater risk to their peer grouping rather than to
      the general public or health care workers and that good personal hygiene
      practices with CF patients should be encouraged to minimize environmental
      contamination and potential acquisition.

PMID- 15175108
TI  - Interaction of atopy and smoking on respiratory effects of occupational dust
      exposure: a general population-based study.
AB  - BACKGROUND: For individual exposures, effect modification by atopy or smoking has
      been reported on the occurrence of occupational airway disease. It is unclear if
      effect modification can be studied in a general population by an aggregated
      exposure measure. Assess relationship between airway obstruction and occupational
      exposure using a job-exposure-matrix (JEM) classifying jobs into 3 broad types of
      exposure, and test for effect modification by atopy, and smoking. METHODS: Data
      from 1,906 subjects were analyzed, all participants of the European Community
      Respiratory Health Survey. Job titles were categorized by an a priori constructed
      job exposure matrix into three classes of exposure to respectively organic dust,
      mineral dust, and gases/ fumes. Relationships were assessed for 'current wheeze',
      bronchial hyperresponsiveness (BHR), 'current asthma' (wheeze+BHR), and 'chronic
      bronchitis' (morning phlegm or morning cough), and lung function. RESULTS:
      Subjects with organic dust exposure in their work environment more frequently had
      'current asthma' (OR 1.48, 95% C.I. 0.95;2.30), and a lower FEV1 (-59 mL, 95%
      C.I. -114;-4). The relationship was only present in asthmatic workers, and their
      risk was four-fold greater than in subjects with either atopy or exposure alone.
      Mineral dust exposure was associated with 'chronic bronchitis' (OR 2.22, 95% C.I.
      1.16;4.23) and a lower FEV1/FVC ratio (-1.1%, 95% C.I. -1.8;-0.3). We observed an
      excess risk in smokers, greater than the separate effects of smoking or mineral
      dust exposure together. CONCLUSION: Occupational exposure to organic dust is
      associated with an increased risk of asthma, particularly in atopics. Chronic
      bronchitis occurs more frequently among individuals exposed to mineral dust, and
      smoking doubles this risk.

PMID- 15175110
TI  - Computational studies of the effects of myocardial blood flow reductions on
      cardiac metabolism.
AB  - BACKGROUND: A computational model of myocardial energy metabolism was used to
      assess the metabolic responses to normal and reduced myocardial blood flow. The
      goal was to examine to what extent glycolysis and lactate formation are
      controlled by the supply of glycolytic substrate and/or the cellular redox
      (NADH/NAD+) and phosphorylation (ATP/ADP) states. METHODS: Flow was reduced over
      a wide range and for a sufficient duration in order to investigate the sequence
      of events that occur during the transition to a new metabolic steady state.
      RESULTS: Simulation results indicated multiple time-dependent controls over both
      glycolysis and lactate formation. CONCLUSIONS: Changes in phosphorylation state
      and glucose uptake only significantly affect the initial phase of the glycolytic
      response to ischemia, while glycogen breakdown exerts control over glycolysis
      during the entire duration of ischemia. Similarly, changes in the redox state
      affect the rates of lactate formation and release primarily during the initial
      transient phase of the response to the reductions in blood flow, while the rate
      of glycolysis controls the rate of lactate formation throughout the entire period
      of adaptation.

PMID- 15175112
TI  - A comparison of olanzapine and risperidone on the risk of psychiatric
      hospitalization in the naturalistic treatment of patients with schizophrenia.
AB  - BACKGROUND: Decreasing hospital admissions is important for improving outcomes
      for people with schizophrenia and for reducing cost of hospitalization, the
      largest expenditure in treating this persistent and severe mental illness. This
      prospective observational study compared olanzapine and risperidone on one-year
      psychiatric hospitalization rate, duration, and time to hospitalization in the
      treatment of patients with schizophrenia in usual care. METHODS: We examined data
      of patients newly initiated on olanzapine (N = 159) or risperidone (N = 112) who
      continued on the index antipsychotic for at least one year following initiation.
      Patients were participants in a 3-year prospective, observational study of
      schizophrenia patients in the US. Outcome measures were percent of hospitalized
      patients, total days hospitalized per patient, and time to first hospitalization
      during the one-year post initiation. Analyses employed a generalized linear model
      with adjustments for demographic and clinical variables. A two-part model was
      used to confirm the findings. Time to hospitalization was measured by the Kaplan
      Meier survival formula. RESULTS: Compared to risperidone, olanzapine-treated
      patients had significantly lower hospitalization rates, (24.1% vs. 14.4%,
      respectively, p = 0.040) and significantly fewer hospitalization days (14.5 days
      vs. 9.9 days, respectively, p = 0.035). The mean difference of 4.6 days
      translated to $2,502 in annual psychiatric hospitalization cost savings per
      olanzapine-treated patient, on average. CONCLUSIONS: Consistent with prior
      clinical trial research, treatment-adherent schizophrenia patients who were
      treated in usual care with olanzapine had a lower risk of psychiatric
      hospitalization than risperidone-treated patients. Lower hospitalization costs
      appear to more than offset the higher medication acquisition cost of olanzapine.

PMID- 15175111
TI  - Potential use of sugar binding proteins in reactors for regeneration of CO2
      fixation acceptor D-Ribulose-1,5-bisphosphate.
AB  - Sugar binding proteins and binders of intermediate sugar metabolites derived from
      microbes are increasingly being used as reagents in new and expanding areas of
      biotechnology. The fixation of carbon dioxide at emission source has recently
      emerged as a technology with potentially significant implications for
      environmental biotechnology. Carbon dioxide is fixed onto a five carbon sugar D
      ribulose-1,5-bisphosphate. We present a review of enzymatic and non-enzymatic
      binding proteins, for 3-phosphoglycerate (3PGA), 3-phosphoglyceraldehyde (3PGAL),
      dihydroxyacetone phosphate (DHAP), xylulose-5-phosphate (X5P) and ribulose-1,5
      bisphosphate (RuBP) which could be potentially used in reactors regenerating RuBP
      from 3PGA. A series of reactors combined in a linear fashion has been previously
      shown to convert 3-PGA, (the product of fixed CO2 on RuBP as starting material)
      into RuBP (Bhattacharya et al., 2004; Bhattacharya, 2001). This was the basis for
      designing reactors harboring enzyme complexes/mixtures instead of linear
      combination of single-enzyme reactors for conversion of 3PGA into RuBP. Specific
      sugars in such enzyme-complex harboring reactors requires removal at key steps
      and fed to different reactors necessitating reversible sugar binders. In this
      review we present an account of existing microbial sugar binding proteins and
      their potential utility in these operations.

PMID- 15175116
TI  - Genome SEGE: a database for 'intronless' genes in eukaryotic genomes.
AB  - BACKGROUND: A number of completely sequenced eukaryotic genome data are available
      in the public domain. Eukaryotic genes are either 'intron containing' or
      'intronless'. Eukaryotic 'intronless' genes are interesting datasets for
      comparative genomics and evolutionary studies. The SEGE database containing a
      collection of eukaryotic single exon genes is available. However, SEGE is derived
      using GenBank. The redundant, incomplete and heterogeneous qualities of GenBank
      data are a bottleneck for biological investigation in comparative genomics and
      evolutionary studies. Such studies often require representative gene sets from
      each genome and this is possible only by deriving specific datasets from
      completely sequenced genome data. Thus Genome SEGE, a database for 'intronless'
      genes in completely sequenced eukaryotic genomes, has been constructed.
      AVAILABILITY: http://sege.ntu.edu.sg/wester/intronless DESCRIPTION: Eukaryotic
      'intronless' genes are extracted from nine completely sequenced genomes (four of
      which are unicellular and five of which are multi-cellular). The complete dataset
      is available for download. Data subsets are also available for 'intronless'
      pseudo-genes. The database provides information on the distribution of
      'intronless' genes in different genomes together with their length distributions
      in each genome. Additionally, the search tool provides pre-computed PROSITE
      motifs for each sequence in the database with appropriate hyperlinks to InterPro.
      A search facility is also available through the web server. CONCLUSIONS: The
      unique features that distinguish Genome SEGE from SEGE is the service providing
      representative 'intronless' datasets for completely sequenced genomes.
      'Intronless' gene sets available in this database will be of use for subsequent
      bio-computational analysis in comparative genomics and evolutionary studies. Such
      analysis may help to revisit the original genome data for re-examination and re
      annotation.

PMID- 15175115
TI  - Paternal imprinting of the SLC22A1LS gene located in the human chromosome segment
      11p15.5.
AB  - BACKGROUND: Genomic imprinting is an epigenetic chromosomal modification in the
      gametes or zygotes that results in a non-random monoallelic expression of
      specific autosomal genes depending upon their parent of origin. Approximately 44
      human genes have been reported to be imprinted. A majority of them are clustered,
      including some on chromosome segment 11p15.5. We report here the imprinting
      status of the SLC22A1LS gene from the human chromosome segment 11p15.5 RESULTS:
      In order to test for allele specific expression patterns, PCR primer sets from
      the SLC22A1LS gene were used to look for heterozygosity in DNA samples from 17
      spontaneous abortuses using PCR-SSCP and DNA sequence analyses. cDNA samples from
      different tissues of spontaneous abortuses showing heterozygosity were subjected
      to PCR-SSCP analysis to determine the allele specific expression pattern. PCR
      SSCP analysis revealed heterozygosity in two of the 17 abortuses examined. DNA
      sequence analysis showed that the heterozygosity is caused by a G>A change at
      nucleotide position 473 (c.473G>A) in exon 4 of the SLC22A1LS gene. PCR-SSCP
      analysis suggested that this gene is paternally imprinted in five fetal tissues
      examined. CONCLUSIONS: This study reports the imprinting status of the SLC22A1LS
      gene for the first time. The results suggest imprinting of the paternal allele of
      this gene in five fetal tissues: brain, liver, placenta, kidneys and lungs.

PMID- 15175118
TI  - Inferior alveolar nerve injury caused by thermoplastic gutta-percha
      overextension.
AB  - Injuries to the inferior alveolar nerve following trauma resulting in a
      mandibular fracture are well documented and are a well-known risk when surgical
      procedures are planned for the mandible in the region of the inferior alveolar
      canal. Such injuries are relatively rare following endodontic therapy. This
      article reports a case of combined thermal and pressure injury to the inferior
      alveolar nerve, reviews the pathogenesis of such an injury and makes suggestions
      for its management.

PMID- 15175117
TI  - Prevalence of dental caries among 7- and 13-year-old First Nations children,
      District of Manitoulin, Ontario.
AB  - PURPOSE: Dental caries is a disease that, although decreasing in the non
      Aboriginal child population, remains high for Canadian Aboriginal and Native
      American children and adolescents. To address dental health issues in First
      Nations in the District of Manitoulin, Noojmowin Teg Health Centre initiated a
      multiphase collaborative research project with the department of community
      dentistry at the University of Toronto. The purpose of this paper was to identify
      the prevalence of dental caries in children 7 or 13 years of age and to compare
      these data with published data for the same age groups from other First Nations
      communities in Canada. METHODS: All children 7 or 13 years of age who were in
      elementary schools on a reserve in 7 First Nations communities were eligible for
      a dental health examination as part of the survey. Children attending school off
      the reserve in 6 of the communities were also eligible. RESULTS: A total of 66
      children (56% 7-year-old children, 62% girls) were examined. The mean caries
      score (deft+ DMFT) for 7-year-old children was 6.2; the mean decayed, extracted,
      filled permanent teeth (DMFT) score for 13-year-old children was 4.1. Overall,
      96% of children had 1 or more past or active carious lesion. CONCLUSION: Results
      indicate that dental caries is highly prevalent and increasing in severity in
      this population.

PMID- 15175114
TI  - TP73 allelic expression in human brain and allele frequencies in Alzheimer's
      disease.
AB  - BACKGROUND: The p73 protein, a paralogue of the p53 tumor suppressor, is
      essential for normal development and survival of neurons. TP73 is therefore of
      interest as a candidate gene for Alzheimer's disease (AD) susceptibility. TP73
      mRNA is transcribed from three promoters, termed P1-P3, and there is evidence for
      an additional complexity in its regulation, namely, a variable allelic expression
      bias in some human tissues. METHODS: We utilized RT-PCR/RFLP and direct cDNA
      sequencing to measure allele-specific expression of TP73 mRNA, SNP genotyping to
      assess genetic associations with AD, and promoter-reporter assays to assess
      allele-specific TP73 promoter activity. RESULTS: Using a coding-neutral BanI
      polymorphism in TP73 exon 5 as an allelic marker, we found a pronounced allelic
      expression bias in one adult brain hippocampus, while 3 other brains (two adult;
      one fetal) showed approximately equal expression from both alleles. In a tri
      ethnic elderly population of African-Americans, Caribbean Hispanics and
      Caucasians, a G/A single nucleotide polymorphism (SNP) at -386 in the TP73 P3
      promoter was weakly but significantly associated with AD (crude O.R. for AD given
      any -386G allele 1.7; C.I. 1.2-2.5; after adjusting for age and education O.R.
      1.5; C.I. 1.1-2.3, N= 1191). The frequency of the -386G allele varied by
      ethnicity and was highest in African-Americans and lowest in Caucasians. No
      significant differences in basal P3 promoter activity were detected comparing 
      386G vs. -386A promoter-luciferase constructs in human SK-NSH-N neuroblastoma
      cells. CONCLUSIONS: There is a reproducible allelic expression bias in mRNA
      expression from the TP73 gene in some, though not all, adult human brains, and
      inter-individual variation in regulatory sequences of the TP73 locus may affect
      susceptibility to AD. However, additional studies will be necessary to exclude
      genetic admixture as an alternative explanation for the observed associations.

PMID- 15175119
TI  - A closer look at diagnosis in clinical dental practice: part 3. Effectiveness of
      radiographic diagnostic procedures.
AB  - This article, the third in a series, uses the tools described in the first 2
      articles to examine some of the radiographic diagnostic procedures that are
      employed regularly in dental practice. With a general grounding in the meaning of
      terms such as sensitivity, specificity, thresholds, kappa coefficients, and
      predictive values, the reader should now be a more discerning user of the
      operating characteristic data for dental diagnostic procedures. By re-examining
      some of these procedures in terms of their effectiveness, accuracy and validity,
      dental practitioners should be able to use the procedures in a more targeted
      manner and gain the maximum benefit from their results. With a better
      understanding of the value of a diagnostic test, the clinician's decision-making
      process will be far better informed. For example, knowing that a certain
      radiographic view is associated with a 60% false-positive rate for identifying
      occlusal caries will preclude blind trust in the results and will help the
      informed clinician attribute a realistic weight to the radiographic findings.
      This article considers diagnostic procedures in common use in North American
      practice, with special emphasis on radiography.

PMID- 15175120
TI  - Salivary status in patients treated for head and neck cancer.
AB  - The objective of this study was to compare unstimulated salivary flow rate and
      residual salivary volume (the volume of saliva retained in the mouth after
      swallowing) in a group of 23 control subjects and a group of 25 patients who had
      received radiation treatment or had undergone removal of the salivary glands (or
      both) for head and neck cancer. As expected, the mean flow rate (+/- 0 standard
      deviation) in the patient group was significantly less than that in the control
      group (0.07 +/- 0.11 and 0.45 +/- 0 0.27 mL/min, respectively). However, the mean
      residual volumes were not significantly different between the 2 groups (0.70 +/-
      0 0.28 and 0.82 +/- 0 0.26 mL, respectively). The 25 patients were subdivided
      according to their self-reported assessment of the mouth as being not dry (3),
      somewhat dry (12) or very dry (10); mean residual volume of saliva was
      significantly lower, at 71% the level in control subjects, for the group with
      very dry mouth (p < 0.02). These results suggest that people who report that the
      mouth is dry may not have a complete lack of fluid in the mouth; rather, there
      may be localized areas of dryness, notably on the hard palate, where the salivary
      film is particularly thin and subject to fluid absorption or evaporation because
      of mouth breathing.

PMID- 15175113
TI  - The urine dipstick test useful to rule out infections. A meta-analysis of the
      accuracy.
AB  - BACKGROUND: Many studies have evaluated the accuracy of dipstick tests as rapid
      detectors of bacteriuria and urinary tract infections (UTI). The lack of an
      adequate explanation for the heterogeneity of the dipstick accuracy stimulates an
      ongoing debate. The objective of the present meta-analysis was to summarise the
      available evidence on the diagnostic accuracy of the urine dipstick test, taking
      into account various pre-defined potential sources of heterogeneity. METHODS:
      Literature from 1990 through 1999 was searched in Medline and Embase, and by
      reference tracking. Selected publications should be concerned with the diagnosis
      of bacteriuria or urinary tract infections, investigate the use of dipstick tests
      for nitrites and/or leukocyte esterase, and present empirical data. A checklist
      was used to assess methodological quality. RESULTS: 70 publications were
      included. Accuracy of nitrites was high in pregnant women (Diagnostic Odds Ratio
      = 165) and elderly people (DOR = 108). Positive predictive values were >/=80% in
      elderly and in family medicine. Accuracy of leukocyte-esterase was high in
      studies in urology patients (DOR = 276). Sensitivities were highest in family
      medicine (86%). Negative predictive values were high in both tests in all patient
      groups and settings, except for in family medicine. The combination of both test
      results showed an important increase in sensitivity. Accuracy was high in studies
      in urology patients (DOR = 52), in children (DOR = 46), and if clinical
      information was present (DOR = 28). Sensitivity was highest in studies carried
      out in family medicine (90%). Predictive values of combinations of positive test
      results were low in all other situations. CONCLUSIONS: Overall, this review
      demonstrates that the urine dipstick test alone seems to be useful in all
      populations to exclude the presence of infection if the results of both nitrites
      and leukocyte-esterase are negative. Sensitivities of the combination of both
      tests vary between 68 and 88% in different patient groups, but positive test
      results have to be confirmed. Although the combination of positive test results
      is very sensitive in family practice, the usefulness of the dipstick test alone
      to rule in infection remains doubtful, even with high pre-test probabilities.

PMID- 15175121
TI  - [Accidents and disasters, public health problems].

PMID- 15175122
TI  - [Placement of nasoenteral feeding tubes under electrocardiographic guidance in
      critically ill patients].
AB  - INTRODUCTION: Nasoenteral feeding is the preferred method to feed critically ill
      patients. Infusion of diet into duodenum instead of stomach is considered safer
      to avoid pulmonary aspiration. To place the tip of the tube inside duodenum, one
      can perform external maneuvers, aided by the tube's guidance, or use fluoroscopy
      and/or endoscopy. Spontaneous passage of the tip of the tube into duodenum, even
      with administration of pro-kinetic drugs, is achieved in <30% of cases.
      OBJECTIVE: Assessing helpfulness of electrocardiographic tracing in placement of
      a nasoduodenal tube in critically ill patients amenable to early enteral feeding.
      MATERIAL AND METHODS: From January, 2001 through January, 2002 at the Intensive
      Care Unit of Hospital Angeles del Pedregal (Mexico City), a nasoenteral tube was
      placed in all critically ill patients who were candidate for early enteral
      feeding, intending to leave the tip inside duodenum with the aid of ECG tracing.
      During passage of the tube through esophagus, the screen showed postive QRS; on
      entering stomach, trace became isoelectric and after crossing pylorus, QRS trace
      turned definitely negative. Once the procedure was over, an X-ray was taken to
      confirm that the tip of the tube as inside duodenum. RESULTS: This method was
      used in 100 consecutive patients. The tip of the tube reached the duodenum in 95
      of 100 patients. CONCLUSIONS: Placement of nasoduodenal tube with the aid of
      electrocardiographic tracing is a safe method that makes possible the tip of the
      tube to reach duodenum, or proximal jejunum in the majority of cases.

PMID- 15175123
TI  - [Detection of thyroid pathology during surgical exploration of the neck for
      primary hyperthyroidism].
AB  - OBJECTIVE: Our objective was to determine prevalence of incidental thyroid
      pathology during surgical treatment of primary hyperparathyroidism and to compare
      sensitivity and specificity of surgical neck exploration with histologic study of
      resected thyroid gland to confirm unsuspected pathologies. MATERIAL AND METHODS:
      This was prospective cohort study performed at the Specialty Hospital's
      Department of Endocrine Surgery at the Mexican Institute of Social Security's
      (IMSS's) Centro Medico de Occidente in Guadalajara, Jalisco State between 1995
      and 2003. All were submitted to bilateral neck exploration under general
      anesthesia. According to the surgeon's criteria, any suspected thyroid anomaly
      was resected for transoperative frozen sections as well as definite
      histopathologic study. RESULTS: Preoperatively from a total of 44 cases of
      hyperparathyroidism, only four cases with thyroid anomalies were detected with
      neck ultrasound and/or computer tomography (CT) scan; additionally, 13 patients
      had thyroid anomalies found during neck exploration according to surgeon
      criteria. All were biopsied. Final study revealed thyroid disease in 16 cases;
      three had well-differentiated thyroid carcinoma and the remaining 13 patients had
      different benign entities. In one case, the thyroid specimen was considered
      normal. Sensitivity and specificity of surgeon criteria were 100 and 96%,
      respectively, to establish thyroid disease during neck exploration for another
      purpose. CONCLUSIONS: Association of hyperparathyroidism and benign and malignant
      thyroid disease is a common phenomenon. Independently of the ability of
      preoperative imaging procedures to detect unsuspected findings, we suggest
      exploration neck bilaterally and resection of any suspicious lesion.

PMID- 15175124
TI  - [Experience in management of trauma-related acute abdomen at the "General Ignacio
      Zaragoza" Regional Hospital in Mexico City].
AB  - OBJECTIVE: To know the current state of surgical management of patients with
      abdominal trauma. MATERIAL AND METHODS: We carried out a retrospective,
      observational, transversal study involving patients with abdominal trauma with
      clinical files wtih trauma who required surgery during the period of April 1,
      1998 through March 30, 2003. RESULTS: There were 72 cases including nine male and
      33 female patients. Mechanism of lesion was divided into closed and penetrating
      trauma, the latter group of patients divided into individuals with blunt wounds
      or with gunshot wounds. Most frequent early postoperative complication was
      hemorrhage, while most frequent late postoperative complication was acute renal
      failure. Causes of death were hypovolemic shock in four patients followed by two
      cases each with the following pathologies: acute respiratory insufficiency
      syndrome; myocardial infarct, and septic shock. CONCLUSIONS: Abdominal trauma is
      a frequent pathology in our environment, males the most affected patients, with
      penetrating trauma main lesion cause. Prolonged surgical time required
      hemotransfusions, and infectious processes together with processes related with
      tissular hypoxia are the most common cause of complications and death.

PMID- 15175125
TI  - [Inguinal symptoms of acute abdomen].
AB  - INTRODUCTION: We describe a syndrome in which empty hernial sac, in its role of
      peritoneal recess, becomes distended with pus during or after general
      peritonitis, usually caused by acute appendicitis. Until 1998, only 14 pediatric
      cases were described in the literature. MATERIALS, METHODS, AND RESULTS: We
      presented here eight cases of patients who experienced inguinal symptoms. In
      four, appendectomy was performed; in four, this was secondary to necrotizing
      enterocolitis. Inguinal complaints, pain, and flogosis were present in first
      group, while pneumoperitoneum and visible duct vaginalis were present in second
      group. CONCLUSIONS: These cases demonstrated that persistent patent processus
      vaginalis may predispose to inguinal pathology secondary to intraabdominal sepsis
      and represent a unique complication.

PMID- 15175126
TI  - [Evaluation of hepatic resections in patients with benign and malignant lesions].
AB  - OBJECTIVE: To evaluate hepatic resections in patient with benign and malignant
      lesions during the years 1997 to 2002 at the Autonomous University Hospital
      Service of Maracaibo, Venezuela. MATERIALS: We carried out 18 hepatic resections
      for benign and/or malignant lesions; traumatic and infectious lesions were
      excluded. RESULTS: The female sex prevailed with 77.7% and age ranged between
      third and fourth decade. Three asymptomatic patients (16.6%) and 83.3%
      symptomatic; pain in upper hemiabdomen 80%. Ultrasonography was employed in 94.4%
      of cases, CT 83.3%, FNAB 27.7%, arteriography 22.2%, Echo-Doppler 16.6%,
      laparoscopy 11.1%, hepatic scintigraphy and ERCP, 5.5%. Minor resections
      represented 61.1%. Major hepatic resections represented 38.8%, with prevalence of
      left hepatectomy (33.3%). Blood loss was greatest in major hepatic resections
      with average of 1,242.9 +/- 827.8 ml. Pringles maneuver was carried out in 90%
      with duration average of 8.5 min; morbidity was 16.6%. Benign tumours prevailed
      with 66.6%. CONCLUSION: The technique of resection with intraparenchymatous
      identification of pedicles makes it the most successful technique for hepatic
      resections.

PMID- 15175127
TI  - [Endometriosis implant in cesarean section surgical scar].
AB  - INTRODUCTION: Abdominal wall endometrioma is a clinical entity characterized by
      presence of a tumor located somewhere inside a surgical scar, most frequently
      after cesarean section, although it has been described after hysterectomy or
      laparotomy. It is associated with episodes of periodic pain confirmed by
      histopathologic examination. Our objective was to describe a characteristic triad
      of periodic pain, tumor, and history of cesarean section in a group of patients.
      MATERIAL AND METHODS: We conducted a case series of 25 patients between January
      1994 and August 2002 who presented a triad consisting of periodic pain,
      associated with menses, history of cesarean section, and tumor inside a surgical
      scar confirmed as endometrium after histopathologic exam. RESULTS: Patients
      presenting the triad were subjected to surgical resection of the tumor including
      skin, adipose tissue, muscle, and peritoneum. Samples revealed endometrium after
      histopathologic examination. Patients presented 100% recovery after surgical
      treatment without relapse of symptoms during follow-up to date. CONCLUSIONS:
      Abdominal wall endometrioma can be identified by the triad described by Esquivel.
      Surgical treatment shows satisfactory results.

PMID- 15175129
TI  - [P-selectin as endothelial reactivity marker in patients with pre-eclampsia].
AB  - INTRODUCTION: Pre-eclampsia affects 5% of all pregnancies. The physiopathologic
      hallmark is altered endothelium function and platelet activation. Selectins are
      molecules involved with the regulation between these systems, P-selectin is a
      molecule expressed in platelet membrane. Our objective was to describe the role
      of P-selectin on endothelial reactivity in patients with pre-eclampsia compared
      with normal pregnancies. MATERIAL AND METHODS: Blood samples from 30 patients
      with severe pre-eclampsia (cases) were compared with patients with 30 normal
      pregnancies during labor (controls). Samples from both groups were analyzed using
      ELISA (Bender Med kit, Vienna, Austria) for determination of P-selectin. RESULTS:
      We compared main clinical, biochemical, and hematologic variables in both groups,
      identifying an outstanding difference in expression of P-selectin between them.
      CONCLUSIONS: P-selectin is a marker of endothelium activation in patients with
      severe pre-eclampsia.

PMID- 15175128
TI  - [Ureterocele in children].
AB  - INTRODUCTION: Ureterocele is cystic dilation of the terminal part of the ureter
      located within the bladder of the urethra or both. In the majority of cases, it
      is accompanied by a double-collector system and affects 6:1 female child
      patients. MATERIALS AND METHODS: We conducted an observational, longitudinal,
      transverse, descriptive, retrospective, and open study. Files of pediatric
      patients with diagnosed ureterocele from January 1, 1990 through December 31,
      2002 were reviewed. Age, sex, symptomatology, type of ureterocele, side effects,
      and laboratory and image studies were analyzed. RESULTS: There were 40 cases, 50%
      male, average age 20 months; first clinical manifestation was urinary tract
      infection in 87.5%. Ectopic type was found more frequently with 62.3% and
      orthotopic or simple, in 37.5%. First surgical intervention was reimplantation in
      80% of ectopic and in 66.7% in orthotopic cases. DISCUSSION: Ureterocele
      treatment depends to a great degree on status of affected kidney and capacity of
      functionality of the contralateral kidney. The spectrum of therapeutic modalities
      range from transureteral incision of ureterocele to nephrectomy and vesical
      reconstruction. Indication to proceed with endoscopy would be considered only in
      a patient with intravesical ureterocele with a simple collector system. We prefer
      to proceed in the majority of cases with ureteral reimplantation and resection of
      ureterocele.

PMID- 15175130
TI  - [Non-hypothermic J wave in subarachnoid hemorrhage].
AB  - Incidence of electrocardiographic abnormalities in subarachnoid hemorrhage
      secondary to aneurysm rupture is 50-100%. The most frequent electrocardiographic
      abnormalities described include acuminated, inverted or flat T waves, inverted T
      waves associated with prolonged QT interval, positive or negative ST segment
      levels, prominent U waves, PR segment enlargement, acuminated P waves, and
      pathologic Q waves. J point is the isoelectric union of QRS complex with ST
      segment. It represents the end of depolarization and the beginning of
      repolarization. Prominent and positive J point level is named J wave, considered
      pathognomonic of severe hypothermia, although it has also been described in other
      clinical entities not associated with hypothermia, such as hypercalcemia, Brugada
      syndrome, acute brain injury, cardiac arrest, and dysfunction of cervical
      sympathetic system. Non-hypothermic J wave is an infrequent electrocardiographic
      manifestation of subarachnoid hemorrhage. We describe a clinical case of non
      hypothermic J wave in a patient with subarachnoid hemorrhage.

PMID- 15175131
TI  - [Conversion to laparoscopic Roux-en-Y gastric bypass after vertical banded
      gastroplasty. A case report].
AB  - BACKGROUND: Vertical banded gastroplasty (VBG) is sometimes associated with
      gastroesophageal reflux disease (GERD) and long-time failure in weight loss. This
      situation is a problem; one therapeutic option is a Roux-en-Y gastric bypass
      (RYGBP). OBJECTIVE: To analyze the perspective of laparoscopic surgical treatment
      in a patient with persistent GERD after traditional bariatric surgery for morbid
      obesity management. CASE REPORT: A 48-year-old woman with morbid obesity, body
      mass index (BMI) of 46 kg/m(2), and high blood pressure underwent VBG (open
      surgery, Mason's technique) in 1996 and decreased her BMI to 32 kg/m(2). Six
      years after initial surgery, she developed severe GERD resistant to medical
      treatment (omeprazol 80 mg/day) that was confirmed by 24-h esophageal pH
      monitoring (48 DeMeester normal) and esophageal manometry (low esophageal
      sphincter pressure) 5 mmHg). During these years, she increased BMI from 32
      kg/m(2) to 40 kg/m(2). Laparoscopic conversion to RYGBP was performed. RESULTS:
      Postoperative evolution was satisfactory with disappearance of GERD. Control 24-h
      esophageal pH monitoring reported 4 DeMeester normal. At 12-month follow-up, she
      decreased BMI to 27 kg/m(2). CONCLUSIONS: Laparoscopic reoperative RYGBP is a
      viable surgical option in GERD treatment and obesity control.

PMID- 15175132
TI  - [Familial Mediterranean fever in Mexico City. A 20-year follow-up].
AB  - Familial Mediterranean fever (MFF) is an autosomic recessive, inherited
      inflammatory disease principally seen in persons from the Mediterranean area.
      Clinical findings include fever, abdominal pain, and pleuritis. The most severe
      complication of MFF is renal amyloidosis, manifested as nephrotic syndrome, which
      evolves into chronic renal failure. In this study, we described clinical
      findings, evolution, and response to treatment in 52 patients diagnosed with MFF
      living in Mexico City in whom the most important clinical features were fever and
      abdominal pain. Differing from previous reported series of patients from the
      Mediterranean area, patient developed renal amyloidosis during the 20-year follow
      up, which suggests that an environmental factor might have a significant
      influence in development of renal amyloidosis.

PMID- 15175133
TI  - [Calcium, the atom triggering life and cellular function].
AB  - Although during the last three decades phosphorylation and dephosphorylation
      systems have been pointed out as the mechanisms used by living cells to control
      biological processes, it seems that calcium dynamics is the phenomenon that
      precedes and controls protein activation by the introduction of phosphate groups
      into distinct protein structures. The process begins with activation of calcium
      channels that allows the influx of the ion, which once inside the cell leads to
      calcium-calmodulin complex, a molecule capable of triggering activation of
      distinct proteinkinases. Thus, the cell in addition to suffering a change in
      polarity enhances neuroconduction and release of different substances such as
      hormones and para-hormones, facilitates intra- and intercellular communication,
      and exerts determinant influence on phenotypic expression by means of promotion
      of immediate and mediate response genes. Ionic conformational calcium runs short-
      and long-term facilitation mechanisms, exerting its influence on control of
      memory through homosynaptic depression and hetersynaptic facilitation processes;
      triggers autophosphorylation of several enzymes leading and enhancing cellular
      activity and participates in signal transduction and decodification. Calcium
      influx rate activates certain groups of phosphatases capable of inhibiting
      autophosphorylation processes, only as a negative feedback mechanism. In
      addition, ionic calcium also participates in the "cross-activate" mechanism of
      proteinkinases A and G, influencing to production of systemic and central nervous
      system nitric oxide. On these bases, it is possible to guess that future
      pharmacologic interventions on calcium fluxes could be of invaluable importance
      in prevention and control of a number of distinct physiopathologic events.

PMID- 15175134
TI  - [Acute pancreatitis in childhood. Is it the same disease in adults? by Baeza
      Herrera C, et al].

PMID- 15175136
TI  - Hereditary angioedema: the rewards of studying a rare disease.

PMID- 15175139
TI  - Immunoglobulin E-bearing antigen-presenting cells in atopic dermatitis.
AB  - Human antigen-presenting cells (APCs) bind monomeric immunoglobulin E (IgE) via
      the high-affinity IgE receptor, Fc epsilon RI. Surface expression of this
      trimeric structure is strongly associated with the atopic status of the donors,
      and maximal levels are observed on Langerhans cells (LC) and inflammatory
      dendritic epidermal cells (IDEC) in atopic dermatitis (AD). Although
      intracellular expression of the Fc epsilon RI alpha-chain is induced by
      interleukin-4 (IL-4), the upregulation of surface levels on dendritic cells (DC)
      from atopics is due to enhanced expression of the Fc epsilon RI gamma-chain and
      stabilization by binding of its ligand IgE. A characteristic function of Fc
      epsilon RI-bearing APCs is the specific uptake and processing of IgE-bound
      allergens, which is followed by T-cell stimulation. In AD, DC-mediated
      presentation of aeroallergens penetrating the epidermis is thought to induce an
      IgE-mediated, delayed-type hypersensitivity reaction. In addition, different Fc
      epsilon RI-bearing APC subsets in AD skin might regulate inflammatory processes
      through the production of Th1/Th2-polarizing signals, proinflammatory cytokines,
      chemokines, and factors that are involved in the induction of tolerance.

PMID- 15175140
TI  - Dietary modification of atopic disease: Use of probiotics in the prevention of
      atopic dermatitis.
AB  - The increased prevalence of atopic diseases, atopic dermatitis, allergic
      rhinitis, and asthma has been described as an epidemic. New approaches in the
      fight against allergic diseases are called for, the target being the persistence
      of the atopic T helper 2-skewed immune responder pattern beyond infancy. Atopic
      dermatitis, the earliest of these conditions, might act as a portal for the
      development of IgE-mediated atopic manifestations. Abundant evidence implies that
      specific strains selected from the healthy gut microbiota exhibit powerful
      antipathogenic and anti-inflammatory capabilities, and several targets for the
      probiotic approach have emerged in atopic dermatitis: degradation/structural
      modification of enteral antigens, normalization of the properties of aberrant
      indigenous microbiota and of gut barrier functions, regulation of the secretion
      of inflammatory mediators, and promotion of the development of the immune system.
      Better understanding of the effects of different probiotic strains and deeper
      insight into the mechanisms of the heterogeneous manifestations of atopic disease
      are needed for the validation of specific strains carrying anti-allergic
      potential.

PMID- 15175142
TI  - Lessons from atopy patch testing in atopic dermatitis.
AB  - The exposure of atopic eczema (AE) patients to their relevant protein allergens
      (eg, from house dust mite, cat dander, grass pollen, or food allergens) can
      trigger an exacerbation or maintain the disease. Diagnostic procedures are needed
      to specify allergen avoidance recommendations for the individual patient. Skin
      prick tests and specific serum IgE tests might be helpful in pointing out
      potential trigger factors, but relevance needs to be confirmed (eg, with food
      provocation tests). The atopy patch test (APT) involves the epicutaneous
      application of intact protein allergens in a diagnostic patch test setting with
      an evaluation of the induced eczematous skin lesions after 24 to 72 hours. The
      APT targets the cellular component of AE and helps round out the AE test
      spectrum. As a number of apparently minor test modifications greatly influence
      the sensitivity, specificity, and reproducibility of the APT, the European Task
      Force on Atopic Dermatitis (ETFAD) has developed a standardized APT technique. It
      consists of purified allergen preparations in petrolatum, applied in 12-mm
      diameter Finn chambers mounted on Scanpor tape to non-irritated, non-abraded, or
      tape-stripped skin of the upper back. The APT is read at 48 and 72 hours
      according to the test criteria and reading key of the ETFAD for appearance of
      erythema, and number and distribution pattern of the papules. In contrast with
      skin prick tests, the APT might even detect a relevant sensitization in the
      absence of specific IgE. Many studies have been undertaken to objectify the
      sensitivity and specificity of the APT to show its diagnostic use in clinical
      practice.

PMID- 15175141
TI  - Keratinocytes in atopic dermatitis: inflammatory signals.
AB  - Atopic dermatitis (AD) is a chronic inflammatory skin disorder that usually
      predates the development of allergic airway disease. In most cases, this is
      thought to be an allergen-driven disease with prominent roles played by antigen
      presenting cells and effector Th2 cells. But keratinocytes, by virtue of their
      location, provide an important window to the environment and are also thought to
      contribute to the development of AD. In this review, we discuss several biologic
      attributes of keratinocytes that are relevant for AD: 1) intrinsic defects in
      barrier function, 2) production of inflammatory mediators that promote or
      maintain allergic inflammation, 3) keratinocyte apoptosis, 4) effects of
      staphylococcal toxins on keratinocytes, and 5) potential consequences of the
      expression of cosignaling molecules (eg, B7 family members) and receptors
      important for innate immune responses (eg, Toll receptors). Clearly, these
      findings have highlighted a more active role played by the epithelium than was
      previously recognized.

PMID- 15175145
TI  - Air pollution and otitis media: a review of evidence from epidemiologic studies.
AB  - Otitis media (main types: acute otitis media and otitis media with effusion) is
      one of the most common childhood infections, particularly before the age of 3
      years. The main causes are viral and/or bacterial ear infections, commonly
      accompanied by or following upper respiratory tract infection. Besides these
      infections, other risk factors, such as male sex, young age, genetic
      predisposition, low socioeconomic status, low vitamin A and C intake, and bottle
      feeding are discussed. There is indication that exposure to environmental tobacco
      smoke is a major environmental risk factor, although additional effects of the
      exposure to ambient air pollutants is uncertain. Although some studies reported
      statistically significant increased risk for otitis media in children with high
      exposure to ambient air pollutants, the risks were not consistent among the
      studies. Owing to the scarcity of available data, far-reaching conclusions cannot
      be drawn yet. However, the evidence of an increased risk for environmental
      tobacco smoke exposure and identified increased risk for ambient air pollution
      exposure in some studies should stimulate future research using otitis media as
      one of the major outcomes in air pollution epidemiology.

PMID- 15175144
TI  - Common respiratory manifestations of food allergy: a critical focus on otitis
      media.
AB  - Previous investigations have established the pathogenic role of food allergy in
      respiratory tract symptoms, which rarely occur in isolation. Specific foods have
      been implicated in these reactions. The role of food allergy in otitis media is
      controversial, probably uncommon, and further studies are needed. Food-induced
      asthma is more common in young pediatric patients, especially those with atopic
      dermatitis. Asthma induced by food allergy is considered a risk factor for fatal
      and near-fatal anaphylactic reactions. Moreover, food allergy can elicit airway
      hyperreactivity and asthmatic responses. Therefore, evaluation for food allergy
      should be considered among patients with recalcitrant or otherwise unexplained
      acute severe asthma exacerbations; asthma triggered by ingestion of particular
      foods; and asthma and other manifestations of food allergy (eg, anaphylaxis,
      moderate to severe atopic dermatitis).

PMID- 15175147
TI  - Dry eye: diagnosis and current treatment strategies.
AB  - One in four patients attending ophthalmic clinics report symptoms of dry eye,
      making it one of the most common complaints seen by ophthalmologists. Aqueous
      layer deficiency is the most common form of dry eye and is frequently caused by
      decreased secretion of tears by the lacrimal glands. Evaporative dry eye is often
      secondary to meibomian gland disease and results in a defective lipid layer. Tear
      replacement or preservation using artificial tears and/or punctal occlusion are
      the mainstay of treatment. Newer forms of therapy were designed to modify the
      underlying disease process. These include the use of topical cyclosporin A,
      autologous serum, and sodium hyaluronate drops, which suppress underlying
      inflammation, provide growth factors, and prevent the onset of squamous
      metaplasia in ocular surface epithelium. Hormonal therapy might have a role in
      the future of dry eye therapy.

PMID- 15175148
TI  - Ocular allergy treatment comparisons: azelastine and olopatadine.
AB  - Azelastine hydrochloride 0.05% and olopatadine hydrochloride 0.1% are topical
      ocular allergy treatments that have demonstrated multiple pharmacologic actions,
      including antihistamine, mast cell stabilization, and inhibition of
      proinflammatory mediators. In this article, the mechanisms of action, efficacy,
      and tolerability of these two agents on ocular signs and symptoms are examined.
      By studying the various target sites of drug action, an enhanced clinical
      response algorithm of these topical ocular agents can be implemented to maximize
      the response for patients suffering from ocular allergy.

PMID- 15175150
TI  - Propagating prions in fungi and mammals.
AB  - Prions constitute a rare class of protein, which can switch to a robust amyloid
      form and then propagate that form in the absence of a nucleic acid determinant,
      thereby creating a unique, protein-only infectious agent. Details of the
      mechanism that drives conversion to the prion form and then subsequent
      propagation of that form are beginning to emerge using a range of in vivo and in
      vitro approaches. Recent studies on both mammalian and fungal prions are
      providing a greater understanding of the structural features that distinguish
      prions from non-transmissible amyloids.

PMID- 15175149
TI  - Basic science and pathophysiology of ocular allergy.
AB  - Ocular allergy includes several clinical subtypes ranging from the mild seasonal
      allergic conjunctivitis to the potentially sight-threatening atopic
      keratoconjunctivitis. Current therapies, particularly for the severe forms of
      disease, need to be more localized and with fewer side effects. For this to be
      achieved, it requires a better understanding of the basic mechanisms involved. In
      this chapter, recent findings are discussed that suggest that it is important to
      take an integrated approach, including both immune and structural elements of the
      eye. This provides potential new strategies for therapy, addressing the influence
      of structural cells in disease. These might influence the immune processes that
      take place and, as the structural cells are precisely localized, topical
      application is likely to be effective.

PMID- 15175151
TI  - A unified nomenclature for protein subunits of mediator complexes linking
      transcriptional regulators to RNA polymerase II.

PMID- 15175152
TI  - Control of crosslinking by quaternary structure changes during bacteriophage HK97
      maturation.
AB  - Radical structural changes drive the maturation of the capsid of HK97, a lambda
      like, dsDNA bacteriophage of Escherichia coli. These include expansion from
      approximately 560 to approximately 660 A in diameter, metamorphosis from a round
      to an angular shape, and formation of covalent crosslinks between adjacent
      capsomers. Analogous transformations also occur in unrelated viruses and protein
      complexes. We find that expansion and crosslinking happen concurrently during
      maturation at low pH. Expansion causes residues on three different subunits to
      move up to 35 A to form 420 active sites that each catalyze the formation of a
      lysine-asparagine crosslink between adjacent subunits, making crosslink formation
      an indirect reporter of structural change. Intermediate crosslinking patterns
      support a previously proposed model of expansion, while hydrophobic properties
      aid in distinguishing discrete intermediates. A structure derived from cryo-EM
      images reveals the free intermediate conformation of penton arms, supporting our
      model for coordinated movement of hexons and pentons on the capsid lattice.

PMID- 15175153
TI  - A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by
      recruiting the degradation machinery.
AB  - Inherently unstable mRNAs contain AU-rich elements (AREs) in their 3'
      untranslated regions that act as mRNA stability determinants by interacting with
      ARE binding proteins (ARE-BPs). The mechanisms underlying the function of ARE and
      ARE-BP interactions in promoting mRNA decay are not fully understood. Here, we
      demonstrate that KSRP, a KH domain-containing ARE-BP, is an essential factor for
      ARE-directed mRNA decay. Some of the KH motifs (KHs) of KSRP directly mediate RNA
      binding, mRNA decay, and interactions with the exosome and poly(A) ribonuclease
      (PARN). The ability of KHs to promote mRNA decay correlates with their ability to
      bind the ARE and associate with RNA-degrading enzymes. Thus, KHs promote rapid
      mRNA decay by recruiting degradation machinery to ARE-containing mRNAs.

PMID- 15175154
TI  - The mRNA surveillance protein hSMG-1 functions in genotoxic stress response
      pathways in mammalian cells.
AB  - Members of the PI 3-kinase-related kinase (PIKK) family function in mitogenic and
      stress-induced signaling pathways in eukaryotic cells. Here, we characterize the
      newest PIKK family member, hSMG-1, as a genotoxic stress-activated protein kinase
      that displays some functional overlap with the related kinase, ATM, in human
      cells. Both ATM and hSMG-1 phosphorylate Ser/Thr-Gln-containing target sequences
      in the checkpoint protein p53 and the nonsense-mediated mRNA decay (NMD) protein
      hUpf1. Expression of hSMG-1 is required for optimal p53 activation after cellular
      exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA
      damage and increased sensitivity to ionizing radiation (IR). Moreover, IR
      exposure triggers hUpf1 phosphorylation at Ser/Thr-Gln motifs, and both ATM and
      hSMG-1 contribute to these phosphorylation events. Finally, NMD is suppressed in
      hSMG-1- but not ATM-deficient cells. These results indicate that hSMG-1 plays
      important roles in the maintenance of both genome and transcriptome integrity in
      human cells.

PMID- 15175156
TI  - Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian
      cells.
AB  - Using a substrate measuring deletion or inversion of an I-SceI-excised fragment
      and both accurate and inaccurate rejoining, we determined the impact of non
      homologous end-joining (NHEJ) on mammalian chromosome rearrangements. Deletion is
      2- to 8-fold more efficient than inversion, independent of the DNA ends
      structure. KU80 controls accurate rejoining, whereas in absence of KU mutagenic
      rejoining, particularly microhomology-mediated repair, occurs efficiently. In
      cells bearing both the NHEJ and a homologous recombination (HR) substrate
      containing a third I-SceI site, we show that NHEJ is at least 3.3-fold more
      efficient than HR, and translocation of the I-SceI fragment from the NHEJ
      substrate locus into the HR-I-SceI site can occur, but 50- to 100-fold less
      frequently than deletion. Deletions and translocations show both accurate and
      inaccurate rejoining, suggesting that they correspond to a mix of KU-dependent
      and KU-independent processes. Thus these processes should represent prominent
      pathways for DSB-induced genetic instability in mammalian cells.

PMID- 15175155
TI  - NXF-2, REF-1, and REF-2 affect the choice of nuclear export pathway for tra-2
      mRNA in C. elegans.
AB  - In C. elegans, tra-2 mRNA nuclear export is controlled by a 3'UTR element, the
      TRE. In the absence of TRA-1, the TRE retains tra-2 mRNA in the nucleus. The
      binding of TRA-1 to the 3'UTR overcomes this retention resulting in export of a
      TRA-1/tra-2 mRNA complex. Here, we find that, unlike most mRNAs, tra-2 mRNA exits
      the nucleus via an alternative pathway to NXF-1 that requires CRM1 activity.
      Inhibition of export by NXF-1 depends upon the TRE, CeNXF-2, CeREF-1, and CeREF
      2. Removal of the TRE or any one of these factors results in export of tra-2 by
      NXF-1. NXF-2 and REF-1 specifically bind the TRE, suggesting that they directly
      control tra-2 mRNA export. Furthermore, choice of proper export pathway affects
      tra-2 translational control. Therefore, tra-2 mRNA export is highly regulated and
      plays an important role in development by regulating the activity of tra-2 mRNA
      in the cytoplasm.

PMID- 15175157
TI  - Pin1 links the activities of c-Abl and p300 in regulating p73 function.
AB  - Activation of p73 upon genotoxic treatment triggers apoptosis of tumor cells
      lacking functional p53 and involves the activities of c-Abl and p300. Here, we
      demonstrate that conformational changes of p73 catalyzed by the prolyl isomerase
      Pin1 are crucial in this pathway. Lack of Pin1 reduces p73 stability, hampering
      its accumulation upon genotoxic stress. Indeed, we show that upon treatment with
      chemotherapeutic drugs c-Abl enhances the phosphorylation-dependent interaction
      between Pin1 and p73, and this in turn promotes p73 acetylation by p300.
      Consistently, the ability of c-Abl and p300 to increase p73 stability and
      transcriptional activity requires Pin1. As a consequence, Pin1 appears to be
      essential for activation of the apoptotic response by endogenous p73.

PMID- 15175158
TI  - Hierarchical recruitment of polycomb group silencing complexes.
AB  - Polycomb group (PcG) proteins maintain the transcriptional silence of target
      genes through many cycles of cell division. Here, we provide evidence for the
      sequential binding of PcG proteins at a Polycomb response element (PRE) in
      proliferating cells in which the sequence-specific DNA binding Pho and Phol
      proteins directly recruit E(z)-containing complexes, which in turn methylate
      histone H3 at lysine 27 (H3mK27). This provides a tag that facilitates binding by
      a Pc-containing complex. In wing imaginal discs, these PcG proteins also are
      present at discrete locations at or downstream of the promoter of a silenced
      target gene, Ubx. E(z)-dependent H3mK27 is also present near the Ubx promoter and
      is needed for Pc binding. The location of E(z)- and Pc-containing complexes
      downstream of the Ubx transcription start site suggests that they may inhibit
      transcription by interfering with assembly of the preinitiation complex or by
      blocking transcription initiation or elongation.

PMID- 15175159
TI  - Transcriptional interference between convergent promoters caused by elongation
      over the promoter.
AB  - Transcriptional interference with convergent transcription from face-to-face
      promoters is a potentially important form of gene regulation in all organisms.
      Using LacZ reporter studies, the mechanism of interference was determined for a
      pair of face-to-face prokaryotic promoters in which a strong promoter interferes
      5.6-fold with a weak promoter, 62 bp away. The promoters were variously
      rearranged to test different models of interference. Terminating transcription
      from the strong promoter before it reached the weak promoter dramatically reduced
      interference, indicating a requirement for the passage of the converging RNAP
      over the weak promoter. Based on in vitro experiments showing a slow rate of
      escape for open complexes at the weak promoter and their sensitivity to head-on
      collisions with elongating RNAP, a "sitting duck" model of interference is
      proposed and supported with in vivo permanganate footprinting. The model is
      further supported by the analysis of a second set of prokaryotic face-to-face
      promoters.

PMID- 15175160
TI  - Chromatin disassembly mediated by the histone chaperone Asf1 is essential for
      transcriptional activation of the yeast PHO5 and PHO8 genes.
AB  - Nucleosome loss from a promoter region has recently been described as a potential
      mechanism for transcriptional regulation. We investigated whether H3/H4 histone
      chaperones mediate the loss of nucleosomes from the promoter of the yeast PHO5
      gene during transcriptional activation. We found that antisilencing function 1
      (Asf1p) mediates nucleosome disassembly from the PHO5 promoter in vivo. We show
      that nucleosome disassembly also occurs at a second promoter, that of the PHO8
      gene, during activation, and we demonstrate that this is also mediated by Asf1p.
      Furthermore, we show that nucleosome disassembly is essential for PHO5 and PHO8
      activation. Contrary to the current dogma, we demonstrate that nucleosome
      disassembly is not required to enable binding of the Pho4p activator to its PHO5
      UASp2 site in vivo. Finally, we show that nucleosomes are reassembled over the
      PHO5 promoter during repression. As such, nucleosome disassembly and reassembly
      are important mechanisms for transcriptional activation and repression,
      respectively.

PMID- 15175161
TI  - Removal of promoter nucleosomes by disassembly rather than sliding in vivo.
AB  - Previous work demonstrated the removal of nucleosomes from the PHO5 promoter upon
      transcriptional activation in yeast. Removal could occur by nucleosome
      disassembly or by sliding of nucleosomes away from the promoter. We have now
      activated the PHO5 promoter on chromatin circles following excision from the
      chromosomal locus. Whereas sliding would conserve the number of nucleosomes on
      the circle, we found that the number was diminished, demonstrating chromatin
      remodeling by nucleosome disassembly.

PMID- 15175162
TI  - Structure and function of CRSP/Med2; a promoter-selective transcriptional
      coactivator complex.
AB  - The multi-subunit, human CRSP coactivator-also known as Mediator (Med)-regulates
      transcription by mediating signals between enhancer-bound factors (activators)
      and the core transcriptional machinery. Interestingly, different activators are
      known to bind distinct subunits within the CRSP/Med complex. We have isolated a
      stable, endogenous CRSP/Med complex (CRSP/Med2) that specifically lacks both the
      Med220 and the Med70 subunits. The three-dimensional structure of CRSP/Med2 was
      determined to 31 A resolution using electron microscopy and single-particle
      reconstruction techniques. Despite lacking both Med220 and Med70, CRSP/Med2
      displays potent, activator-dependent transcriptional coactivator function in
      response to VP16, Sp1, and Sp1/SREBP-1a in vitro using chromatin templates.
      However, CRSP/Med2 is unable to potentiate activated transcription from a vitamin
      D receptor-responsive promoter, which requires interaction with Med220 for
      coactivator recruitment, whereas VDR-directed activation by CRSP/Med occurs
      normally. Thus, it appears that CRSP/Med may be regulated by a combinatorial
      assembly mechanism that allows promoter-selective function upon exchange of
      specific coactivator targets.

PMID- 15175163
TI  - A set of consensus mammalian mediator subunits identified by multidimensional
      protein identification technology.
AB  - The Mediator is a multiprotein transcriptional coactivator that is expressed
      ubiquitously in eukaryotes from yeast to mammals and is required for induction of
      RNA polymerase II (pol II) transcription by DNA binding transcription factors. In
      the work described here, we exploit multidimensional protein identification
      technology (MudPIT) to carry out a proteomic analysis of the subunit composition
      of the mammalian Mediator complex. By comparing MudPIT data sets obtained from
      six independent Mediator preparations immunoaffinity purified through their Nut2
      (MED10), Med25 (MED9), Intersex (MED29), LCMR1 (MED19), AK007855 (MED28), or
      CRSP70 (MED26) subunits, we identify a set of consensus mammalian Mediator
      subunits. In addition, we identify as Mediator-associated proteins the CDK8-like
      cyclin-dependent kinase CDK11 and the TRAP240-like KIAA1025 protein (MED13L),
      which is mutated in patients with the congenital heart defect transposition of
      the great arteries (TGA).

PMID- 15175164
TI  - Antimony: an unlikely confounder in the relationship between well water arsenic
      and health outcomes in Bangladesh.
AB  - Recent in vitro studies have suggested a potential role for antimony as a
      confounder in human health studies related to arsenic in drinking water. We
      measured tube-well water concentrations of antimony and arsenic in the Pabna
      region of Bangladesh, where arsenic concentrations are known to be elevated and
      the concentrations of antimony have not yet been thoroughly documented. Two
      hundred forty-five tube-well water samples were collected from various regions in
      Pabna, Bangladesh, as part of an ongoing case-control study. Water samples were
      analyzed for arsenic and antimony concentrations by inductively coupled plasma
      mass spectrometry using U.S. Environmental Protection Agency method 200.8. The
      arsenic concentrations in the tube-well water samples ranged from < 1 microg/L to
      747 microg/L. All 245 water samples had antimony concentrations < 1 microg/L.
      Based on consideration of the concentrations used the in vitro studies compared
      with field-observed concentrations, our results do not support the hypothesis
      that antimony would be a significant confounder in observed relationships between
      arsenic exposure through drinking water and potential health outcomes in Pabna,
      Bangladesh.

PMID- 15175165
TI  - A tale of two diesels.
AB  - Two different samples of diesel exhaust particles (DEP) have been used by
      toxicologists interested primarily in cancer/genotoxicity or noncancer--such as
      pulmonary inflammation and asthma exacerbation--health end points. These are,
      respectively, a standard reference material, SRM 2975, from a heavy-duty diesel
      engine, and a sample collected by researchers at the Japanese National Institute
      for Environmental Studies from an automobile diesel engine. In this issue of
      Environmental Health Perspectives companion papers appear, by David DeMarini and
      co-workers and by Pramila Singh and co-workers, characterizing these samples and
      contrasting their Salmonella mutagenicity and pulmonary toxicity in mice. This
      commentary is a plea from an atmospheric chemist for more cooperation among
      toxicologists, analytical chemists, atmospheric chemists, and automotive and
      combustion engineers to provide a comprehensive assessment of health risks to
      humans exposed to contemporary diesel emissions and for greater quantities and
      more diverse types of DEP and ambient samples (i.e., SRMs) that can be shared and
      exhaustively characterized. This needs to be a continuing process as diesel
      engines, fuels, and exhaust components evolve in response to control regulations.

PMID- 15175166
TI  - Bioassay-directed fractionation and salmonella mutagenicity of automobile and
      forklift diesel exhaust particles.
AB  - Many pulmonary toxicity studies of diesel exhaust particles (DEPs) have used an
      automobile-generated sample (A-DEPs) whose mutagenicity has not been reported. In
      contrast, many mutagenicity studies of DEPs have used a forklift-generated sample
      (SRM 2975) that has been evaluated in only a few pulmonary toxicity studies.
      Therefore, we evaluated the mutagenicity of both DEPs in Salmonella coupled to a
      bioassay-directed fractionation. The percentage of extractable organic material
      (EOM) was 26.3% for A-DEPs and 2% for SRM 2975. Most of the A-EOM (~55%) eluted
      in the hexane fraction, reflecting the presence of alkanes and alkenes, typical
      of uncombusted fuel. In contrast, most of the SRM 2975 EOM (~58%) eluted in the
      polar methanol fraction, indicative of oxygenated and/or nitrated organics
      derived from combustion. Most of the direct-acting, base-substitution activity of
      the A-EOM eluted in the hexane/dichloromethane (DCM) fraction, but this activity
      eluted in the polar methanol fraction for the SRM 2975 EOM. The direct-acting
      frameshift mutagenicity eluted across fractions of A-EOM, whereas > 80% eluted
      only in the DCM fraction of SRM 2975 EOM. The A-DEPs were more mutagenic than SRM
      2975 per mass of particle, having 227 times more polycyclic aromatic hydrocarbon
      type and 8-45 more nitroarene-type mutagenic activity. These differences were
      associated with the different conditions under which the two DEP samples were
      generated and collected. A comprehensive understanding of the mechanisms
      responsible for the health effects of DEPs requires the evaluation of DEP
      standards for a variety of end points, and our results highlight the need for
      multidisciplinary studies on a variety of representative samples of DEPs.

PMID- 15175167
TI  - Sample characterization of automobile and forklift diesel exhaust particles and
      comparative pulmonary toxicity in mice.
AB  - Two samples of diesel exhaust particles (DEPs) predominate in health effects
      research: an automobile-derived DEP (A-DEP) sample and the National Institute of
      Standards Technology standard reference material (SRM 2975) generated from a
      forklift engine. A-DEPs have been tested extensively for their effects on
      pulmonary inflammation and exacerbation of allergic asthmalike responses. In
      contrast, SRM 2975 has been tested thoroughly for its genotoxicity. In the
      present study, we combined physical and chemical analyses of both DEP samples
      with pulmonary toxicity testing in CD-1 mice to compare the two materials and to
      make associations between their physicochemical properties and their biologic
      effects. A-DEPs had more than 10 times the amount of extractable organic material
      and less than one-sixth the amount of elemental carbon compared with SRM 2975.
      Aspiration of 100 micro g of either DEP sample in saline produced mild acute lung
      injury; however, A-DEPs induced macrophage influx and activation, whereas SRM
      2975 enhanced polymorphonuclear cell inflammation. A-DEPs stimulated an increase
      in interleukin-6 (IL-6), tumor necrosis factor alpha, macrophage inhibitory
      protein-2, and the TH2 cytokine IL-5, whereas SRM 2975 only induced significant
      levels of IL-6. Fractionated organic extracts of the same quantity of DEPs (100
      micro g) did not have a discernable effect on lung responses and will require
      further study. The disparate results obtained highlight the need for chemical,
      physical, and source characterization of particle samples under investigation.
      Multidisciplinary toxicity testing of diesel emissions derived from a variety of
      generation and collection conditions is required to meaningfully assess the
      health hazards associated with exposures to DEPs. Key words: automobile, diesel
      exhaust particles, forklift, mice, pulmonary toxicity, SRM 2975.

PMID- 15175168
TI  - Relationships between PCBs and thyroid hormones and retinol in female and male
      polar bears.
AB  - We studied the relationships between polychlorinated biphenyls (PCBs) and thyroid
      hormones (THs) and retinol within two groups of female polar bears (Ursus
      maritimus), females with cubs of the year (FWCOY) and females without cubs of the
      year (FWOCOY), and within a group of males. Concentrations of five of the six
      quantified PCB congeners, i.e., PCB-99, PCB-153, PCB-156, PCB-180, PCB-194 (sigma
      PCB5), correlated with each other, whereas the concentrations of PCB-118 did not
      correlate with the other congeners. sigma PCB5 and PCB-118 did not differ between
      the three different groups of polar bears, and the plasma levels ranged from 16.7
      to 203.2 ng/g wet weight (ww) for sigma PCB5 and from 0.09 to 0.93 ng/g ww for
      PCB-118. PCBs did not affect the retinol status in any of the three groups. In
      FWCOY, we found negative correlations between sigma PCB5 and the three TH
      variables free thyroxin (FT4) (r2 = 0.35), free triiodothyronine (FT3) (r2 =
      0.30), and the total T4:total T3 ratio (TT4:TT3) (r2 = 0.92). In FWOCOY, sigma
      PCB5 was negatively correlated to TT4 (r2 = 0.14) and positively correlated to
      TT3:FT3 (r2 = 0.31), whereas PCB-118 was positively correlated to FT3 (r2 = 0.21)
      and negatively correlated to TT3:FT3 (r2 = 0.26). In males, sigma PCB5 was
      negatively correlated to FT3 (r2 = 0.56) and positively correlated to FT4:FT3 (r2
      = 0.78), whereas PCB-118 was negatively correlated to FT4:FT3 (r2 = 0.53). Thus,
      PCBs affected five TH variables in the female polar bears (TT4, FT4, FT3,
      TT3:FT3, TT4:TT3), but PCBs affected only two TH variables in males (FT3,
      FT4:FT3). Female polar bears could be more susceptible to TH-related effects of
      PCBs than are males. PCBs also affected T3 to a larger degree than T4.

PMID- 15175169
TI  - Prediction of residential pet and cockroach allergen levels using questionnaire
      information.
AB  - We assessed the accuracy of questionnaire reports of cat and dog ownership and
      presence of cockroaches in predicting measured allergen concentrations in house
      dust. We collected dust samples in the homes of 932 newborns living in New
      England. Dust samples were taken from the main living area and the infant's
      bedding. Allergen content of house dust was measured by enzyme-linked
      immunosorbent assays (ELISA) and related to questionnaire information on past and
      current cat and dog ownership and presence of cockroaches. Allergen levels were
      dichotomized using the limit of detection and the following cut points: 1.0
      microg/g and 8.0 microg/g for cat, 2.0 microg/g and 10.0 microg/g for dog, and 2
      U/g and 8 U/g for cockroach allergen. For the upper cut point, both specificity
      and sensitivity of questionnaire-reported cat and dog ownership and presence of
      cockroaches were high. For the limit of detection and lower cut point,
      specificity was high (> 80%), whereas sensitivity was low, particularly for
      current cat and dog ownership (21-60%). Taking pet ownership during the preceding
      2 years into account increased the sensitivity by 10%, but it remained relatively
      poor. In conclusion, questionnaire-reported pet ownership and presence of
      cockroaches predicts allergen levels above the upper cut point but is a
      relatively poor measure of allergen exposure above the limit of detection and the
      lower cut point. Knowledge of past pet ownership can improve pet allergen
      exposure assessment by means of questionnaire. However, for epidemiologic
      purposes, measured concentrations of allergens are necessary.

PMID- 15175170
TI  - Cellular and humoral immune abnormalities in Gulf War veterans.
AB  - We examined 100 symptomatic Gulf War veterans (patients) and 100 controls for
      immunologic assays. The veterans and controls were compared for the percentage of
      T cells (CD3); B cells (CD19); helper:suppressor (CD4:CD8) ratio; natural killer
      (NK) cell activity; mitogenic response to phytohemagglutin (PHA) and pokeweed
      mitogen (PWM); level of immune complexes; myelin basic protein (MBP) and striated
      and smooth muscle autoantibodies; and antibodies against Epstein-Barr virus,
      cytomegalovirus, herpes simplex virus type 1 (HSV-1), HSV-2, human herpes Type 6
      (HHV-6), and Varicella zoster virus (VZV). The percentage of T cells in patients
      versus controls was not significantly different, whereas a significantly higher
      proportion of patients had elevated T cells compared with controls. The
      percentage of B cells was significantly elevated in the patients versus the
      controls. The NK cell (NK) activity was significantly decreased in the patients
      (24.8 +/- 16.5 lytic units) versus the controls (37.3 +/- 26.4 lytic units). The
      percentage of patients with lower than normal response to PHA and PWM was
      significantly different from controls. Immune complexes were significantly
      increased in the patients (53.1 +/- 18.6, mean +/- SD) versus controls (34.6 +/-
      14.3). Autoantibody titers directed against MBP and striated or smooth muscle
      were significantly greater in patients versus controls. Finally, the patients had
      significantly greater titers of antibodies to the viruses compared with the
      controls (p < 0.001). These immune alterations were detected 2-8 years after
      participation in the Gulf War. The immune alterations are consistent with
      exposure to different environmental factors. We conclude that Gulf War syndrome
      is a multifaceted illness with immune function alterations that may be induced by
      various factors and are probably associated with chronic fatigue syndrome.

PMID- 15175171
TI  - Natural variability and the influence of concurrent control values on the
      detection and interpretation of low-dose or weak endocrine toxicities.
AB  - While defining the no effect level for the 5 alpha-reductase inhibitor
      finasteride in the Hershberger assay, we encountered an inverted-U low-dose
      trophic effect on the prostate gland of the rat. Two attempts to confirm this
      observation were unsuccessful, and we concluded that the positive effect
      initially observed was associated with normal biologic variability. During the
      same period we attempted, unsuccessfully, to repeat our own observation of weak
      uterotrophic activity in the rat for the sunscreen 3-(4-methylbenzylidene)camphor
      (4MBC). Further evaluation led us to conclude that 4MBC is uterotrophic only when
      the control uterine weights are at the low end of their normally encountered
      range. This led us to reevaluate our earlier mouse uterotrophic assay data for
      bisphenol A (BPA). Originally we had concluded that BPA gave irreproducible
      evidence of weak uterotrophic activity, but upon ordering the eight experiments
      we had conducted, according to decreasing control uterine weight, we confirmed
      reproducible weak uterotrophic activity for BPA when the control uteri were at
      the low end of their normal range. In this article, we describe these
      observations, together with a reanalysis of the data associated with several
      reported instances of weak or low-dose endocrine effects that have proven
      difficult to confirm in independent laboratories. These include the activity of
      BPA on the CF1 mouse prostate; the activities of BPA, octylphenol, and
      nonylphenol on the rat testis; and the effect of polycarbonate caging on control
      mouse uterine weight. In all of these cases, variability among controls provides
      a major obstacle to data interpretation and confirmation. Our recommendations on
      experimental design are also presented, with a view to ending the current impasse
      on the reality, or otherwise, of low-dose or weak endocrine toxicities.

PMID- 15175172
TI  - Adipose tissue levels of organochlorine pesticides and polychlorinated biphenyls
      and risk of non-Hodgkin's lymphoma.
AB  - In this nested case-control study we examined the relationship between non
      Hodgkin's lymphoma (NHL) and organochlorine pesticide exposure. We used a data
      set originally collected between 1969 and 1983 in the U.S. Environmental
      Protection Agency National Human Adipose Tissue Survey. Adipose samples were
      randomly collected from cadavers and surgical patients, and levels of
      organochlorine pesticide residues were determined. From the original study
      population, 175 NHL cases were identified and matched to 481 controls; 173
      controls were selected from accident victims, and 308 from cases with a diagnosis
      of myocardial infarction. Cases and controls were mainly from cadavers (> 96%)
      and were matched on sex, age, region of residence within the United States, and
      race/ethnicity. Conditional logistic regression showed the organochlorine
      pesticide residue heptachlor epoxide to be significantly associated with NHL
      [compared with the lowest quartile: third quartile odds ratio (OR) = 1.82, 95%
      confidence interval (CI), 1.01-3.28; fourth quartile OR = 3.41, 95% CI, 1.89
      6.16]. The highest quartile level of dieldrin was also associated with elevated
      NHL risk (OR = 2.70; 95% CI, 1.58-4.61), as were higher levels of oxychlordane,
      p,p'-DDE [p,p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene], and ss-benzene
      hexachloride (ORs = 1.79, 1.99, and 2.47, respectively). The p-values for trends
      for these associations were significant. In models containing pairs of
      pesticides, only heptachlor epoxide and dieldrin remained significantly
      associated with risk of NHL. Limitations of this study include collection of
      samples after diagnosis and a lack of information on variables affecting
      organochlorine levels such as diet, occupation, and body mass index. Given the
      persistence of pesticides in the environment, these findings are still relevant
      today.

PMID- 15175173
TI  - Estradiol uptake, toxicity, metabolism, and adverse effects on cadmium-treated
      amphibian embryos.
AB  - The exposure of Bufo arenarum embryos to 25 micromol/L 17beta-estradiol (E2)
      resulted in 100% lethality within 48 hr, whereas 10 micromol//L E2 was the no
      observed effect concentration value for short-term chronic (7 days) exposure. The
      toxicity profile curves show that lethal effects were proportional to the E2
      concentration and the time of exposure. The E2 uptake resulted in 20.1 ng E2/mg
      embryo at 8 hr posttreatment, but 67.3% of this value was achieved during the
      first 30 min of incubation with this estrogen. Regarding metabolism, the embryos
      synthesize estrone (E1) from E2 by means of 17beta-hydroxysteroid dehydrogenase.
      Simultaneous treatments of Bufo arenarum embryos with 1 mg/L Cd2+ and 0.1, 1, or
      10 micromol/L E2 enhanced the lethality exerted by cadmium in 76.7, 80, and 83.3%
      of embryos, respectively. The results indicate that estrogenic endocrine
      disruptors could have an adverse effect on amphibian embryos and enhance the
      toxic effect of Cd on amphibian embryos. This study points to the possibility of
      using the AMPHITOX test as a screening method for potential endocrine disruption
      as well as the combined effects of chemical mixtures.

PMID- 15175174
TI  - Cytogenetic markers, DNA single-strand breaks, urinary metabolites, and DNA
      repair rates in styrene-exposed lamination workers.
AB  - The effect of occupational exposure to styrene on frequencies of chromosomal
      aberrations and binucleated cells with micronuclei and on single-strand break
      levels in peripheral blood lymphocytes was studied in 86 reinforced plastic
      workers and 42 control individuals (including 16 maintenance workers with
      intermittent, low-dose exposure). In these individuals, the irradiation-specific
      DNA repair rates and the repair rates of 8-oxoguanines were investigated. We
      assessed the exposure by measuring the concentrations of styrene in air and in
      blood and of mandelic acid, phenylglyoxylic acid, 4-vinyl phenol conjugates and
      regioisomeric phenyl hydroxyethyl mercapturic acids in urine. All these
      parameters correlated with one another. No clear relationship was found between
      the styrene exposure and the frequencies of chromosomal aberrations. Binucleated
      cells with micronuclei were moderately related to the parameters of styrene
      exposure. We found a negative correlation between all exposure parameters and
      single-strand breaks. The positive correlation between exposure parameters and
      DNA repair rates suggests that particular DNA repair pathways may be induced by
      styrene exposure.

PMID- 15175175
TI  - Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary
      hypertension.
AB  - Preexistent cardiopulmonary disease in humans appears to enhance susceptibility
      to the adverse effects of ambient particulate matter. Previous studies in this
      laboratory have demonstrated enhanced inflammation and mortality after
      intratracheal instillation (IT) and inhalation (INH) of residual oil fly ash
      (ROFA) in a rat model of pulmonary hypertension induced by monocrotaline (MCT).
      The present study was conducted to examine the effects of ROFA in this model on
      ventilatory function in unanesthetized, unrestrained animals. Sixty-day-old male
      CD rats were injected with MCT (60 mg/kg) or vehicle (VEH) intraperitoneally 10
      days before IT of ROFA (8.3 mg/kg) or saline (SAL) (control) or nose-only INH of
      ROFA [15 mg/m3 for 6 hr on 3 consecutive days or air (control)]. At 24 and 72 hr
      after exposure, rats were studied individually in a simultaneous gas uptake/whole
      body plethysmograph. Lungs were removed at 72 hr for histology. Pulmonary test
      results showed that tidal volume (VT) decreased 24 hr after IT of ROFA in MCT
      treated rats. Breathing frequency, minute volume (VE), and the ventilatory
      equivalent for oxygen increased in MCT- and VEH-treated rats 24 hr after IT or
      INH of ROFA and remained elevated 72 hr post-IT. O2 uptake (VO2) decreased after
      IT of ROFA in MCT-treated rats. Carbon monoxide uptake decreased 24 hr after IT
      of ROFA, returning to control values in VEH-treated rats but remaining low in MCT
      treated rats 72 hr post-IT. ROFA exposure induced histologic changes and
      abnormalities in several ventilatory parameters, many of which were enhanced by
      MCT treatment.

PMID- 15175176
TI  - Ultrafine particle deposition in subjects with asthma.
AB  - Ambient air particles in the ultrafine size range (diameter < 100 nm) may
      contribute to the health effects of particulate matter. However, there are few
      data on ultrafine particle deposition during spontaneous breathing, and none in
      people with asthma. Sixteen subjects with mild to moderate asthma were exposed
      for 2 hr, by mouthpiece, to ultrafine carbon particles with a count median
      diameter (CMD) of 23 nm and a geometric standard deviation of 1.6. Deposition was
      measured during spontaneous breathing at rest (minute ventilation, 13.3 +/- 2.0
      L/min) and exercise (minute ventilation, 41.9 +/- 9.0 L/min). The mean +/- SD
      fractional deposition was 0.76 +/- 0.05 by particle number and 0.69 +/- 0.07 by
      particle mass concentration. The number deposition fraction increased as particle
      size decreased, reaching 0.84 +/- 0.03 for the smallest particles (midpoint CMD =
      8.7 nm). No differences between sexes were observed. The deposition fraction
      increased during exercise to 0.86 +/- 0.04 and 0.79 +/- 0.05 by particle number
      and mass concentration, respectively, and reached 0.93 +/- 0.02 for the smallest
      particles. Experimental deposition data exceeded model predictions during
      exercise. The deposition at rest was greater in these subjects with asthma than
      in previously studied healthy subjects (0.76 +/- 0.05 vs. 0.65 +/- 0.10, p <
      0.001). The efficient respiratory deposition of ultrafine particles increases
      further in subjects with asthma. Key words: air pollution, asthma, deposition,
      dosimetry, inhalation, ultrafine particles.

PMID- 15175177
TI  - Chemical risks associated with consumption of shellfish harvested on the north
      shore of the St. Lawrence River's lower estuary.
AB  - Shellfish have the capacity to accumulate chemical contaminants found in their
      biotope and therefore present a potential risk for consumers. This study was
      conducted to assess the chemical risks associated with consumption of shellfish
      harvested on the north shore of the St. Lawrence River's lower estuary. A survey
      was carried out on 162 recreational harvesters, and shellfish were sampled for
      chemical contaminant analysis. We quantified 10 metals, 22 polycyclic aromatic
      hydrocarbons (PAHs), 14 polychlorinated biphenyls (PCBs), and 10 chlorinated
      pesticides. We subsequently evaluated cancer and noncancer risks for four
      consumption scenarios based on our survey results and published results. Soft
      shell clams (Mya arenaria) were by far the most consumed shellfish species. Of
      the 56 selected contaminants, 36 were detected in the 23 homogenates of soft
      shell clam meat. None of the contaminants found in the soft-shell clams were
      associated with intakes that exceed the main exposure limit recommendations
      proposed to prevent noncancer effects. However, several limits must be considered
      before drawing conclusions about the relative safety of shellfish consumption
      regarding this end point. Furthermore, inorganic arsenic and PCBs were present in
      sufficient concentrations to lead to cancer risks exceeding the level often
      considered acceptable for environmental exposure (1 x 10 (-4) to 1 x 10(-6)) in
      each of the four scenarios, even for the lowest observed scenario of 15 meals of
      soft-shell clams per year.

PMID- 15175178
TI  - Breast cancer risk and historical exposure to pesticides from wide-area
      applications assessed with GIS.
AB  - Pesticides are of interest in etiologic studies of breast cancer because many
      mimic estrogen, a known breast cancer risk factor, or cause mammary tumors in
      animals, but most previous studies have been limited by using one-time tissue
      measurements of residues of only a few pesticides long banned in the United
      States. As an alternative method to assess historical exposures to banned and
      current-use pesticides, we used geographic information system (GIS) technology in
      a population-based case-control study of 1,165 women residing in Cape Cod,
      Massachusetts, who were diagnosed with breast cancer in 1988-1995 and 1,006
      controls. We assessed exposures dating back to 1948 (when DDT was first used
      there) from pesticides applied for tree pests (e.g., gypsy moths), cranberry
      bogs, other agriculture, and mosquito control on wetlands. We found no overall
      pattern of association between pesticide use and breast cancer. We found modest
      increases in risk associated with aerial application of persistent pesticides on
      cranberry bogs and less persistent pesticides applied for tree pests or
      agriculture. Adjusted odds ratios for these exposures were 1.8 or lower, and,
      with a few exceptions, confidence intervals did not exclude the null. The study
      is limited by uncertainty about locations of home addresses (particularly before
      1980) and unrecorded tree pest and mosquito control events as well as lack of
      information about exposures during years when women in the study lived off Cape
      Cod and about women with potentially important early life exposures on Cape Cod
      who were not included because they moved away.

PMID- 15175179
TI  - Endocrine disruption and altered gonadal development in white perch (Morone
      americana) from the lower Great Lakes region.
AB  - High prevalences of gonadal intersex have been observed in wild fish populations
      in areas affected by domestic and industrial effluents. For this study, fish were
      collected in 1998 from the Cootes Paradise region of Hamilton Harbour in western
      Lake Ontario, Canada, to determine whether gonadal abnormalities, including
      intersex, were present in young of the year (YOY) fish. No gonadal abnormalities
      were observed in goldfish (Carassius auratus), common carp (Cyprinus carpio),
      gizzard shad (Dorosoma cepedianum), brown bullhead (Ictalurus ameiurus),
      pumpkinseed (Lepomis gibbosus), and bluegill (Lepomis macrochirus). However,
      intersex gonads were observed in 8 of 16 male white perch (Morone americana)
      examined in this survey. Subsequently, in 1999 and 2000 white perch estimated to
      be YOY to approximately 2 years of age were collected from Cootes Paradise and
      from two other sites in the lower Great Lakes region. Gonadal intersex was
      observed in male white perch collected from the Bay of Quinte (22-44%) and Lake
      St. Clair (45%), although the prevalence and the extent of the intersex condition
      were lower relative to the 83% prevalence in white perch collected in Cootes
      Paradise. Intersex was not observed in hatchery-reared white perch or in white
      perch collected from an uncontaminated reference site (i.e., Deal Lake) in the
      United States. An analysis of plasma collected in the spring of 2002 from male
      adult white perch in Cootes Paradise revealed high concentrations of
      vitellogenin, ranging from 49 to 1,711 microg/mL. These observations indicate
      that male white perch are exposed to estrogenic endocrine-disrupting substances
      that may be responsible for the induction of gonadal intersex.

PMID- 15175181
TI  - Mercury exposure aboard an ore boat.
AB  - Two maritime academy interns (X and Y) were exposed to mercury vapor after
      spilling a bottle of mercury on the floor in an enclosed storeroom while doing
      inventory aboard an ore boat. During a 3-day period, intern Y suffered transient
      clinical intoxication that resolved after he was removed from the environment and
      he showered and discarded all clothing. His initial serum mercury level dropped
      from 4 ng/mL to < 0.05 ng/mL. Intern X had an initial level of 11 ng/mL, which
      continued to rise to a maximum of 188.8 ng/mL. He complained of tremulousness,
      insomnia, and mild agitation and was hospitalized. He had showered and discarded
      all clothing except his footwear earlier than intern Y. Intern X's continued
      exposure due to mercury in the contaminated boots during the 2 weeks before
      hospitalization was presumed to be the cause. Removing his footwear led to
      resolution of his toxic symptoms and correlated with subsequent lowered serum
      mercury levels. Chelation was initiated as recommended, despite its uncertain
      benefit for neurologic intoxication. Mercury is used in the merchant marine
      industry in ballast monitors called king gauges. New engineering is recommended
      for ballast monitoring to eliminate this hazard.

PMID- 15175180
TI  - Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic
      treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds.
AB  - We evaluated the effect of chronic exposure to dioxin and dioxin-like compounds
      on the pancreas in female Harlan Sprague-Dawley rats. This investigation
      represents part of an ongoing National Toxicology Program initiative to determine
      the relative potency of chronic toxicity and carcinogenicity of polychlorinated
      dioxins, furans, and biphenyls. Animals were treated by gavage for up to 2 years
      with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3,4,4,5-pentachlorobiphenyl
      (PCB-126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a toxic-equivalency
      factor (TEF) mixture of these agents; control animals received corn oil-acetone
      vehicle alone. A complete necropsy was performed on all animals, and a full
      complement of tissues was collected and examined microscopically. Administration
      of each of the four compounds was associated with increased incidences of several
      nonneoplastic changes in the exocrine pancreas, including cytoplasmic
      vacuolation, chronic active inflammation, atrophy, and arteritis. Low incidences,
      but higher than those in the historical database, of pancreatic acinar adenoma
      and carcinoma were seen in the TCDD, PeCDF, and TEF-mixture groups. These results
      indicate that the pancreatic acini are target tissues for dioxin and certain
      dioxin-like compounds. Key words: carcinogenesis, dioxin, furans, inflammation,
      pancreas, polychlorinated biphenyls.

PMID- 15175182
TI  - Pesticide testing in humans: ethics and public policy.
AB  - Pesticide manufacturers have tested pesticides increasingly in human volunteers
      over the past decade. The apparent goal of these human studies is to establish
      threshold levels for symptoms, termed "no observed effect levels." Data from
      these studies have been submitted to the U.S. Environmental Protection Agency
      (EPA) for consideration in standard setting. There are no required ethical
      guidelines for studies of pesticides toxicity conducted in humans, no
      governmental oversight is exercised, and no procedures have been put in place for
      the protection of human subjects. To examine ethical and policy issues involved
      in the testing of pesticides in humans and the use of human data in standard
      setting, in February 2002 the Center for Children's Health and the Environment of
      the Mount Sinai School of Medicine convened an expert workshop for ethicists,
      physicians, toxicologists, and policy analysts. After a peer consensus process,
      participants developed a number of ethical and public policy recommendations
      regarding the testing of pesticides in humans. Participants also strongly
      encouraged active biomonitoring of every pesticide currently in use to track
      human exposure, particularly in vulnerable populations, and to assess adverse
      effects on health.

PMID- 15175183
TI  - The effect of disinfection by-products and mutagenic activity on birth weight and
      gestational duration.
AB  - Epidemiologic studies of disinfection by-products have traditionally focused on
      total trihalomethane (TTHM) concentration as a surrogate for maternal exposure
      during pregnancy. We used birth certificate data on 196,000 infants to examine
      the effect of third-trimester exposures on various indices of fetal development.
      We examined the effect of town-average concentrations of TTHM and additional
      exposure metrics in relation to mean birth weight, mean gestational age, small
      for gestational age (SGA) infancy, and preterm delivery. Trihalomethane data
      (TTHM, chloroform, and bromodichloromethane) from 1995-1998 were available for
      109 towns in Massachusetts. Data from 1997-1998 on haloacetic acid (total
      haloacetic acids, dichloroacetic acid, and trichloroacetic acid), 3-chloro-4
      (dichloromethyl)-5- hydroxy-2(5H)-furanone (MX), and mutagenicity were available
      for a limited number of towns. We observed reductions in mean birth weight (12-18
      g) for maternal trihalomethane exposures > the 90th percentile compared with
      those < the 50th percentile. Birth weight reductions were detected for chloroform
      exposures > 20 microg/L and TTHM exposures > 40 microg/L. Elevated
      trihalomethanes were associated with increases in gestational duration and a
      reduced risk of preterm delivery. We found evidence of an exposure-response
      effect of trihalomethanes on risk of SGA, with odds ratios (ORs) ranging from
      1.09 to 1.23 for bromodichloromethane exposures > 5 microg/L. Elevated mutagenic
      activity was associated with SGA [OR = 1.25; 95% confidence interval (CI), 1.04
      to 1.51] and mean birth weight (-27 g; 95% CI, -54 to -1). Although smaller in
      magnitude, our findings are consistent with previous studies reporting
      associations between trihalomethanes and SGA. These data also suggest a
      relationship between fetal development indices and mutagenic activity independent
      of exposure to trihalomethanes, haloacetic acids, and MX.

PMID- 15175184
TI  - Levels of lead in breast milk and their relation to maternal blood and bone lead
      levels at one month postpartum.
AB  - Despite the many well-recognized benefits of breast-feeding for both mothers and
      infants, detectable levels of lead in breast milk have been documented in
      population studies of women with no current environmental or occupational
      exposures. Mobilization of maternal bone lead stores has been suggested as a
      potential endogenous source of lead in breast milk. We measured lead in breast
      milk to quantify the relation between maternal blood and bone lead levels and
      breast-feeding status (exclusive vs. partial) among 310 lactating women in Mexico
      City, Mexico, at 1 month postpartum. Umbilical cord and maternal blood samples
      were collected at delivery. Maternal breast milk, blood, and bone lead levels
      were obtained at 1 month postpartum. Levels of lead in breast milk ranged from
      0.21 to 8.02 microg/L (ppb), with a geometric mean (GM) of 1.1 microg/L; blood
      lead ranged from 1.8 to 29.9 microg/dL (GM = 8.4 microg/dL); bone lead ranged
      from < 1 to 67.2 microg/g bone mineral (patella) and from < 1 to 76.6 microg/g
      bone mineral (tibia) at 1 month postpartum. Breast milk lead was significantly
      correlated with umbilical cord lead [Spearman correlation coefficient (rS) =
      0.36, p < 0.0001] and maternal blood lead (rS= 0.38, p < 0.0001) at delivery and
      with maternal blood lead (rS = 0.42, p < 0.0001) and patella lead (rS= 0.15, p <
      0.01) at 1 month postpartum. Mother's age, years living in Mexico City, and use
      of lead-glazed ceramics, all predictive of cumulative lead exposure, were not
      significant predictors of breast milk lead levels. Adjusting for parity, daily
      dietary calcium intake (milligrams), infant weight change (grams), and breast
      feeding status (exclusive or partial lactation), the estimated effect of an
      interquartile range (IQR) increase in blood lead (5.0 microg/dL) was associated
      with a 33% increase in breast milk lead [95% confidence interval (CI), 24 to
      43%], whereas an IQR increase in patella lead (20 microg/g) was associated with a
      14% increase in breast milk lead (95% CI, 5 to 25%). An IQR increase in tibia
      lead (12.0 microg/g) was associated with a 5% increase in breast milk lead (95%
      CI, -3% to 14%). Our results indicate that even among a population of women with
      relatively high lifetime exposure to lead, levels of lead in breast milk are low,
      influenced both by current lead exposure and by redistribution of bone lead
      accumulated from past environmental exposures.

PMID- 15175186
TI  - The oceans and human health.

PMID- 15175187
TI  - Connecting the oceans and human health.

PMID- 15175185
TI  - Association of FEV1 in asthmatic children with personal and microenvironmental
      exposure to airborne particulate matter.
AB  - Exposure to particulate matter (PM) air pollution has been shown to exacerbate
      children's asthma, but the exposure sources and temporal characteristics are
      still under study. Children's exposure to PM is likely to involve both combustion
      related ambient PM and PM related to a child's activity in various indoor and
      outdoor microenvironments. Among 19 children with asthma, 9-17 years of age, we
      examined the relationship of temporal changes in percent predicted forced
      expiratory volume in 1 sec (FEV1) to personal continuous PM exposure and to 24-hr
      average gravimetric PM mass measured at home and central sites. Subjects were
      followed for 2 weeks during either the fall of 1999 or the spring of 2000, in a
      southern California region affected by transported air pollution.
      FEV(subscript)1(/subscript) was measured by subjects in the morning, afternoon,
      and evening. Exposure measurements included continuous PM using a passive
      nephelometer carried by subjects; indoor, outdoor home, and central-site 24-hr
      gravimetric PM2.5 (PM of aerodynamic diameter < 2.5 microm) and PM10; and central
      site hourly PM10, nitrogen dioxide, and ozone. Data were analyzed with linear
      mixed models controlling for within-subject autocorrelation, FEV1 maneuver time,
      and exposure period. We found inverse associations of FEV1 with increasing PM
      exposure during the 24 hr before the FEV1 maneuver and with increasing multiday
      PM averages. Deficits in percent predicted FEV1 (95% confidence interval) for
      given PM interquartile ranges measured during the preceding 24-hr were as
      follows: 128 microg/m3 1-hr maximum personal PM, -6.0% (-10.5 to -1.4); 30
      microg/m3 24-hr average personal PM, -5.9% (-10.8 to -1.0); 6.7 microg/m3 indoor
      home PM2.5, -1.6% (-2.8 to -0.4); 16 microg/m3 indoor home PM10, -2.1% (-3.7 to 
      0.4); 7.1 microg/m3 outdoor home PM2.5, -1.1% (-2.4 to 0.1); and 7.5 microg/m3
      central-site PM2.5, -0.7% (-1.9 to 0.4). Stronger associations were found for
      multiday moving averages of PM for both personal and stationary-site PM. Stronger
      associations with personal PM were found in boys allergic to indoor allergens.
      FEV1 was weakly associated with NO2 but not with O3. Results suggest mixed
      respiratory effects of PM in asthmatic children from both ambient background
      exposures and personal exposures in various microenvironments.

PMID- 15175188
TI  - Access to environmental information.

PMID- 15175189
TI  - Testing toxic compounds in human subjects: ethical standards and good science.

PMID- 15175190
TI  - Testing toxic pesticides in humans: health risks with no health benefits.

PMID- 15175191
TI  - Toxicity of fragrances.

PMID- 15175192
TI  - Reconstructing the environment in Iraq.

PMID- 15175193
TI  - New centers for oceans and human health.

PMID- 15175194
TI  - The state of the oceans, part 2: Delving deeper into the sea's bounty.

PMID- 15175195
TI  - Risk assessment at the EPA: an agency self-exam.

PMID- 15175196
TI  - RoboLobsters: the beauty of biomimetics.

PMID- 15175198
TI  - A model of ischemically induced ventricular fibrillation for comparison of fixed
      dose and escalating-dose defibrillation strategies.
AB  - OBJECTIVES: Fixed- and escalating-dose defibrillation protocols are both in
      clinical use. Clinical observations suggest that the probability of successful
      defibrillation is not constant across a population of patients with ventricular
      fibrillation (VF). Common animal models of electrically induced VF do not
      represent a clinical VF etiology or reproduce clinical heterogeneity in
      defibrillation probability. The authors hypothesized that a model of ischemically
      induced VF would exhibit heterogeneous defibrillation shock strength requirements
      and that an escalating-dose strategy would more effectively achieve prompt
      defibrillation. METHODS: Forty-six swine were randomized to fixed, lower-energy
      (150 J) transthoracic shocks (group 1) or escalating, higher-energy (200 J-300 J
      360 J) shocks (group 2). VF was induced by balloon occlusion of a coronary
      artery. After 1 or 5 minutes of VF, countershocks with a biphasic waveform were
      administered. The primary endpoint was successful defibrillation (termination of
      VF for 5 seconds) with < or =3 shocks. RESULTS: VF was induced with occlusion or
      after reperfusion in 35 animals. Only five of 17 group 1 animals (29%, 95% CI =
      10 to 56) could be defibrillated with < or =3 shocks; 15 of 18 group 2 animals
      (83%, 95% CI = 59 to 96) were defibrillated with < or =3 shocks (p < 0.002 vs.
      group 1). Nine of the group 1 animals (75%) that could not be defibrillated with
      150-J shocks were rescued with < or =3 shocks ranging from 200 to 360 J.
      CONCLUSIONS: In this ischemic VF animal model, defibrillation shock strength
      requirements varied among individuals, and when defibrillation was difficult, an
      escalating-dose strategy was more effective for prompt defibrillation than fixed,
      lower-energy shocks.

PMID- 15175199
TI  - Does the lateral chest radiograph help pediatric emergency physicians diagnose
      pneumonia? A randomized clinical trial.
AB  - OBJECTIVES: To determine whether the addition of the lateral chest radiograph to
      the frontal view influences the pediatric emergency physician's diagnosis and
      management of patients with pneumonia. METHODS: A randomized clinical trial was
      conducted, involving 570 patients, 1-16 years of age, visiting a pediatric
      emergency department (ED) for whom frontal and lateral chest radiographs were
      ordered for the clinical suspicion of pneumonia. Pediatric emergency physicians
      reviewed the frontal film alone in group 1 and both the frontal and the lateral
      films in group 2. The interpretation of each radiograph was then compared with
      consensus interpretation by pediatric radiologists who interpreted both views.
      RESULTS: There were 604 eligible children; 34 families declined to participate.
      Three hundred three were randomized into group 1, whereas 267 were randomized
      into group 2. The clinicians' interpretations were equal in sensitivity for group
      1 at 91% and 87% in group 2 (p = 0.321) and equal in specificity for group 1 at
      58% and 57% in group 2 (p = 0.888). CONCLUSIONS: The addition of the lateral
      chest radiograph to the frontal view did not improve the sensitivity or
      specificity of pediatric emergency physicians in their diagnosis of pneumonia in
      children.

PMID- 15175200
TI  - Derivation and validation of a risk stratification model to identify coronary
      artery disease in women who present to the emergency department with potential
      acute coronary syndromes.
AB  - OBJECTIVES: To derive and validate a model to identify women who would benefit
      from further evaluation of chest pain after an initial negative emergency
      department (ED) evaluation for acute coronary syndrome (ACS). METHODS: The
      derivation and validation cohorts were comprised of women who presented to the ED
      with chest pain at two university hospitals. Patients were excluded if the
      initial electrocardiogram (ECG) or cardiac markers were consistent with ACS.
      Patients were followed for 30 days after the index visit to identify evidence of
      coronary artery disease (CAD), which was defined as a positive diagnostic study,
      myocardial infarction, or death. The authors performed a logistic regression
      analysis to identify significant predictors of CAD. A scoring system was
      developed based on the B-coefficient of these significant predictors. Levels of
      risk were assigned by summing and categorizing the cumulative risk score into low
      , moderate-, and high-risk groups. RESULTS: The derivation and validation sets
      were comprised of 733 and 2,440 women, respectively. From the derivation set
      predictors of CAD (score) were history of CAD (1), age > or = 60 years (1), and
      high clinical suspicion (3). Low risk was defined as a score = 0, moderate risk
      score = 1-2, high risk score > or = 3. In the validation set, the numbers of
      patients with evidence of CAD were four of 1,348 (0.30%), 18 of 498 (3.6%), and
      71 of 594 (11.9%) in the low-, moderate-, and high-risk groups, respectively.
      CONCLUSIONS: The risk of underlying CAD in women who present to the ED with
      potential ACS may be determined using a simple risk stratification score.

PMID- 15175201
TI  - Deferral of the rectal examination in blunt trauma patients: a clinical decision
      rule.
AB  - OBJECTIVES: To develop a clinical decision rule that would allow for the safe
      deferral of the digital rectal examination (DRE) in blunt trauma patients.
      METHODS: The authors reviewed the medical records of all adult blunt trauma
      patients meeting trauma team activation criteria over a 14-month period. The
      results of the DRE and six predictor variables-abnormal neurologic examination,
      abdominal tenderness, pelvic stability, blood at the urethral meatus, blood
      pressure < 90 mm Hg, and age over 65 years-were recorded. Patients with abnormal
      DREs had their discharge summaries reviewed for specific criteria to determine if
      the abnormal DRE was a true- or false-positive examination. Predictor variables
      were entered into a classification and regression tree (CART) analysis designed
      to predict true-positive abnormal DREs. RESULTS: Of the 579 patients, 53 had
      abnormal DREs, 34 of which were true positives. CART analysis retained three
      predictors, abnormal neurologic examination, blood at the urethral meatus, and
      age over 65 years, and accurately classified all patients with a true-positive
      abnormal DRE. The probability of a true-positive abnormal DRE in a patient with a
      normal neurologic examination, no blood at the urethral meatus, and age less than
      65 years is between 0% and 0.8%. CONCLUSIONS: Adult patients with blunt trauma
      and a normal neurologic examination, with no blood at the urethral meatus, and
      who are less than 65 years old have an exceedingly low likelihood of a true
      positive abnormal DRE. If validated, patients who meet these three criteria may
      have the DRE safely deferred.

PMID- 15175202
TI  - Prevalence and significance of nonthromboembolic findings on chest computed
      tomography angiography performed to rule out pulmonary embolism: a multicenter
      study of 1,025 emergency department patients.
AB  - OBJECTIVES: To evaluate the hypothesis that computed tomography (CT) angiography
      often yields a result interpreted as an alternative diagnosis to pulmonary
      embolism (PE) in emergency department (ED) patients. METHODS: This was a
      multicenter, retrospective, and secondary analysis of consecutive patients in
      three academic emergency departments. ED patients with symptoms suspicious for PE
      were included. CT angiography was ordered at the discretion of the treating
      physician; patients were identified by query of the electronic medical record.
      Board-certified radiologists gave CT readings, which were reviewed by two
      independent emergency physicians who categorized the non-PE findings into one of
      four acuity categories: A = requiring specific and immediate intervention, B =
      requiring specific action on follow-up, C = requiring no action, and D =
      indeterminate findings. RESULTS: The prevalence of PE among the 1,025 patients
      studied was 10% (95% CI = 8% to 12%). In the 921 patients without PE, the mean
      prevalences (ranges between sites) of concordant categorized non-PE findings
      were: A = 7% (range 3%-11%), B = 10% (7%-13%), C = 17% (10%-20%), D = 4% (0%-8%),
      and no ancillary finding = 41% (29% to 45%). The most common category A findings
      included infiltrate or consolidation suggesting pneumonia (81%), aortic aneurysm
      or dissection (7%), and mass suggesting undiagnosed malignancy (7%). The overall
      unweighted agreement was 80% (kappa = 0.72) and weighted agreement was 93%
      (kappa(w) = 0.84). CONCLUSIONS: In ED patients with suspected PE, the CT
      angiogram frequently provides evidence suggesting an important alternative
      diagnosis to PE. Pulmonary infiltrate suggesting pneumonia was the most common
      non-PE finding.

PMID- 15175203
TI  - Raising our HEADSS: adolescent psychosocial documentation in the emergency
      department.
AB  - OBJECTIVES: To determine the effectiveness of a chart stamp featuring the acronym
      "HEADSS" (Home, Education, Alcohol, Drugs, Smoking, Sex) at improving adolescent
      psychosocial documentation in the emergency department (ED) chart. METHODS: The
      study sample consisted of ten emergency physicians. The ED charts of 306
      adolescent patients (aged 13-18 years) completed by these physicians were
      surveyed. An analysis of ED chart psychosocial documentation was conducted that
      compared a six-week control phase (with no chart stamp) with a four-week
      intervention phase (with a chart stamp featuring the HEADSS acronym). Presenting
      complaints in the ED, psychosocial documentation in the ED, and information from
      past medical records were compared between the two groups. RESULTS: The ED charts
      surveyed consisted of 153 charts from each phase. HEADSS documentation ranged
      from 8% to 12% in the intervention phase and 0% to 7% in the control phase.
      Emergency physicians were more likely to document the topics of education (p =
      0.029), alcohol (p = 0.045), and smoking (p = 0.009) as well as whether the
      patient was interviewed alone (p = 0.0001) in the intervention phase charts.
      Documentation of a detailed psychosocial assessment (>4/6 HEADSS topics
      addressed; p = 0.003) was more likely during the intervention phase. CONCLUSIONS:
      The HEADSS stamp is useful in prompting psychosocial documentation in the ED
      chart. Further study is needed to determine whether routine use of the HEADSS
      stamp technique can improve the detection and management of adolescent
      psychosocial problems.

PMID- 15175204
TI  - Clinical variables associated with mortality in out-of-hospital patients with
      hemodynamically significant bradycardia.
AB  - OBJECTIVES: To estimate mortality rates and identify clinical variables
      associated with mortality among patients with hemodynamically unstable
      bradycardia in an urban emergency medical services (EMS) system. METHODS: This
      was a retrospective study conducted in a large, urban EMS system. Adult non
      cardiac arrest patients transported by advanced life support paramedics from
      March 1996 to February 1997 with a heart rate < or =60 beats/min and systolic
      blood pressure < or =90 mm Hg were included. Transcutaneous pacing was not
      available. Patients under age 18 years, pregnant, or presenting with vital signs
      absent were excluded from the study population. Multivariate analysis of the
      association of patient characteristics with 30-day mortality was conducted by
      using a Cox proportional hazards model. RESULTS: Of the 247 patients studied, 133
      (53.9%) received a fluid bolus, 37 (15.0%) were treated with atropine, and 17
      (6.9%) received dopamine. Fifty-one (20.7%) died in the 19-month follow-up period
      (15.6 per 100 person-years); 10.5% died on the same day, 15.8% within 30 days,
      and 17.8% within one year. Variables associated with 30-day mortality included
      wide QRS complex (adjusted risk ratio [RR] 2.6 [95% confidence interval (95% CI)
      = 1.3 to 5.2]), use of heart rate-lowering calcium channel blockers (adjusted RR
      2.1 [95% CI = 1.0 to 4.7]), and paramedic assessment of lack of patient
      improvement over the course of the call (adjusted RR 0.2 [95% CI = 0.1 to 0.6]).
      CONCLUSIONS: Out-of-hospital patients with hemodynamically unstable bradycardia
      have a high mortality rate. A wide QRS complex and use of heart rate-lowering
      calcium channel blockers were associated with 30-day mortality.

PMID- 15175205
TI  - Characteristics of household addresses that repeatedly contact 911 to report
      intimate partner violence.
AB  - OBJECTIVES: To determine whether households that generate several 911 calls
      differ in important ways from those that make a single call and to determine
      whether households that generate repeat 911 calls for intimate partner violence
      (IPV) experience more severe violence than those that do not. METHODS: All cases
      of police-documented IPV were reviewed and linked with their respective 911
      calls. Each incident report was reviewed to determine the relationship between
      the offender and victim, demographic characteristics of the offender and victim,
      weapon and substance involvement, prior incidents of IPV, and violence severity.
      RESULTS: Of the 1,505 IPV addresses identified during the 12-month study
      interval, 1,010 (67.1%) placed more than one phone call to report IPV. Sixty-nine
      percent of African American victims, 50.6% of white victims, and 36.8% of
      Hispanic victims were repeat callers (p < 0.001). There were no differences
      between addresses that generated repeat calls versus single calls with respect to
      offender alcohol or drug involvement, presence of children, victim age, or
      offender age. Sixty-seven percent of households with severe violence and 66.9% of
      households with minor violence generated repeat 911 calls (p = 0.98).
      CONCLUSIONS: Ethnic differences in 911 use for IPV exist between African
      Americans, whites, and Hispanics. However, unknown societal, economic, or
      cultural issues could have influenced this finding. Households that repeatedly
      contacted 911 during the study interval to report IPV were not more likely to
      experience severe violence than those that placed a single 911 call.

PMID- 15175206
TI  - Clinical pearls: headache and hypoglossal nerve palsy.

PMID- 15175207
TI  - Evidence-based medical decision making: deductive versus inductive logical
      thinking.

PMID- 15175208
TI  - Injury prevention research: quo vadis?

PMID- 15175209
TI  - Integrating the accreditation council for graduate medical education core
      competencies into the model of the clinical practice of emergency medicine.

PMID- 15175210
TI  - B-type natriuretic peptide for diagnosis of heart failure in emergency department
      patients: a critical appraisal.
AB  - The diagnosis of heart failure in the outpatient setting can be difficult. A
      rapid assay for B-type natriuretic peptide (BNP) has been advocated for the
      diagnosis of heart failure, using a single cutoff of 100 pg/mL. BNP is produced
      by both the right and left cardiac ventricles and is elevated in a variety of
      conditions, including heart failure, pulmonary hypertension, cor pulmonale,
      pulmonary embolism, left ventricular hypertrophy, renal failure, circulatory
      overload, acute coronary syndromes, atrial fibrillation, lung cancer, and sepsis.
      This multitude of causes of BNP elevation imposes limits on its diagnostic use
      for heart failure. The literature on the use of BNP testing for diagnosis of
      heart failure is reviewed, and improved guidelines for its interpretation are
      suggested.

PMID- 15175211
TI  - Pretest probability estimates: a pitfall to the clinical utility of evidence
      based medicine?
AB  - OBJECTIVES: The Bayesian application of likelihood ratios has become incorporated
      into evidence-based medicine (EBM). This approach uses clinicians' pretest
      estimates of disease along with the results of diagnostic tests to generate
      individualized posttest disease probabilities for a given patient. To date, there
      is minimum scientific validation for the clinical application of this approach.
      This study is designed to evaluate variability in the initial step of this
      process, clinicians' estimates of pretest probability of disease, to assess
      whether this approach can be expected to yield consistent posttest disease
      estimates. METHODS: This cross-sectional cohort study was conducted at an urban
      county teaching hospital by using a sample of emergency and internal medicine
      residents and faculty, as well as emergency department (ED) midlevel
      practitioners. Participants read clinical vignettes designed to raise
      consideration for common ED disorders and were asked to estimate the likelihood
      of the suggested diagnosis based on the history and physical examination findings
      alone. No information about laboratory results or imaging studies was provided.
      RESULTS: Mean pretest probability estimates of disease ranged from 42% (95%
      confidence interval [95% CI] = 36.6% to 47.4%) to 77% (95% CI = 72.9% to 81.1%).
      The smallest difference in pretest probability magnitude for a single vignette
      was 70% (range 30-100%; interquartile range [IQR] 64-80%), whereas the largest
      was 95% (range 3-98%; IQR 30-60%). CONCLUSIONS: Wide variability in clinicians'
      pretest probability estimates of disease may present a possible concern about
      decision-making models based on Bayes' theorem, because it may ultimately yield
      inconsistent posttest disease estimates.

PMID- 15175212
TI  - Participation in the academic associate program: effect on medical school
      admission rate.
AB  - OBJECTIVES: Several emergency medicine programs are using premedical students as
      research assistants for clinical research in the emergency department (ED). These
      programs have been shown to enhance faculty research productivity, but the
      effects of these programs on the students' goals have not been assessed. The
      authors evaluated the effect of the Academic Associate Program (AAP) on medical
      school acceptance rates. METHODS: From 1997 to 2002, premedical students who
      attended informational sessions about the AAP completed a 28-item survey
      including demographic information, educational experiences, career goals, grade
      point average (GPA), and prior research participation. Premedical students who
      had a career goal of becoming a physician were included in the study if they
      matriculated into medical school or changed their career plans by the fall of
      2003. Medical school acceptance was determined by contacting students or their
      parents via telephone and e-mail. Students enrolled in the AAP were compared with
      Association of American Medical Colleges (AAMC) data to determine whether they
      were more or less likely to be accepted into medical school. RESULTS: During the
      study period, 198 students enrolled in the AAP had attained a final disposition
      with respect to medical school matriculation. Students were a mean age of 22.4 +/
      3.0 years, 55% female, and 43% nonwhite. Most students (91%) were junior year or
      later with respect to educational level. Prior research experience included being
      an author on an abstract (25%), being an author on a manuscript (17%), and
      presenting research at a scientific meeting (14%). The mean GPA ( +/- standard
      deviation) for Academic Associates was 3.38 ( +/- 0.31). Medical school
      acceptance rates were 79% for students in the AAP (95% confidence interval [95%
      CI] = 73.1 to 84.5). This is higher than expected based on AAMC published data
      with a 49% (95% CI = 48.5 to 49.5) acceptance rate for students with a mean GPA
      of 3.46. CONCLUSIONS: Compared with AAMC data, students in the AAP have a higher
      medical school acceptance rate despite a slightly lower GPA. This finding
      suggests that participation in the program enhances a student's likelihood of
      matriculating in medical school.

PMID- 15175213
TI  - Factors affecting pain scores during female urethral catheterization.
AB  - OBJECTIVES: To compare pain and discomfort ratings of female patients undergoing
      urethral catheterization randomized to topical application of plain lubricant
      versus lidocaine gel prior to the procedure. METHODS: This was a prospective,
      randomized, double-blind study involving female patients requiring urethral
      catheterization at an urban university-based academic emergency department. A
      staff nurse blinded to the lubricant type injected 5 mL of sterile surgical
      lubricant or 2% lidocaine gel into the urinary meatus. After 1 minute, an 8-F
      (for specimen collection) or a 16-F (for continuous collection) catheter was
      inserted into the urethra. Each patient rated the pain of the procedure on a
      validated 0- to 100-mm visual analog scale. The Mann-Whitney U test was used to
      analyze associations between pain ratings, lubricant type, and catheter size.
      Logistic regression was used to identify the contribution of lubricant type,
      catheter size, age category, difficulty of insertion, preprocedural pain, and
      diagnosis of urinary tract infection to procedural pain rating. RESULTS: One
      hundred women were randomized to plain lubricant (n = 50) or lidocaine (n = 50).
      The overall mean ( +/- SD) pain score was 23.5 +/- 27.2 mm. No significant
      differences in pain ratings were found based on catheter size or lubricant type.
      Younger women, aged 18-59 years, experienced higher pain ratings than women aged
      60-101 (mean pain difference 14.4 mm; 95% CI = 4.3 to 24.5; p < 0.006). Multiple
      logistic regression identified preprocedural pain as the only predictor of higher
      pain rating after catheterization (OR 1.02; 95% CI = 1.002 to 1.039, p = 0.03).
      CONCLUSIONS: Catheter size and lubricant type did not affect the severity of pain
      after urethral catheterization in women.

PMID- 15175214
TI  - Comparison of topical anesthetics and lubricants prior to urethral
      catheterization in males: a randomized controlled trial.
AB  - Although male urethral catheterization in the emergency department (ED) is both
      common and painful, few studies have evaluated the use of topical anesthesia
      prior to catheterization. OBJECTIVES: To determine whether pretreatment of the
      urethra with topical lidocaine reduces the pain associated with urethral
      catheterization. METHODS: This was a prospective, double-blind, randomized
      clinical trial of 36 alert, cooperative male adult patients requiring urethral
      catheterization, without allergies to the study medications or contraindications
      to their use, from a suburban university-based ED. Patients in the experimental
      group had topical lidocaine 2% gel injected in their urethras, whereas control
      patients received intraurethral lubrication only. Standardized catheterization
      with a no. 16 Foley was performed followed by pain assessment. The primary
      outcome measured was pain of catheterization on a 100-mm visual analog scale.
      Other outcomes included ease of insertion and procedural bleeding. RESULTS: The
      authors evaluated 36 patients evenly distributed between study groups. Mean age
      was 62 years (range 22-85). Compared with controls, patients pretreated with
      lidocaine experienced significantly less pain of catheterization (38 +/- 28 mm
      vs. 58 +/- 30 mm; mean difference 20 mm; 95% confidence interval [95% CI] = 0.4
      to 32; p = 0.04) and less pain of injection (23 +/- 17 mm vs. 40 +/- 25 mm; mean
      difference 17 mm; 95% CI = 3 to 32 mm; p = 0.02). There were no differences in
      the number of attempts and incidence of adverse events between the groups.
      CONCLUSIONS: Use of topical lidocaine gel reduces the pain associated with male
      urethral catheterization in comparison with topical lubricants only.

PMID- 15175215
TI  - Emergency physician-verified out-of-hospital intubation: miss rates by
      paramedics.
AB  - OBJECTIVES: To prospectively quantify the number of unrecognized missed out-of
      hospital intubations by ground paramedics using emergency physician verification
      as the criterion standard for verification of endotracheal tube placement.
      METHODS: The authors performed an observational, prospective study of consecutive
      intubated patients arriving by ground emergency medical services to two urban
      teaching hospitals. Endotracheal tube placement was verified by emergency
      physicians and evaluated by using a combination of direct visualization,
      esophageal detector device (EDD), colorimetric end-tidal carbon dioxide
      (ETCO(2)), and physical examination. RESULTS: During the six-month study period,
      208 out-of-hospital intubations by ground paramedics were enrolled, which
      included 160 (76.9%) medical patients and 48 (23.1%) trauma patients. A total of
      12 (5.8%) endotracheal tubes were incorrectly placed outside the trachea. This
      comprised ten (6.3%) medical patients and two (4.2%) trauma patients. Of the 12
      misplaced endotracheal tubes, a verification device (ETCO(2) or EDD) was used in
      three cases (25%) and not used in nine cases (75%). CONCLUSIONS: The rate of
      unrecognized, misplaced out-of-hospital intubations in this urban, midwestern
      setting was 5.8%. This is more consistent with results of prior out-of-hospital
      studies that used field verification and is discordant with the only other study
      to exclusively use emergency physician verification performed on arrival to the
      emergency department.

PMID- 15175216
TI  - A calibrated paper clip is a reliable measure of two-point discrimination.
AB  - OBJECTIVES: The primary objective of this study was to compare two different
      instruments for assessing digital nerve function; a secondary aim was to
      determine interobserver agreement among emergency physicians by using static two
      point testing of digital nerve function. METHODS: This was a prospective,
      blinded, observational study of static two-point discrimination involving healthy
      volunteers aged 18-59 years. The authors compared two instruments (paper clip set
      or Disk-Criminator) to assess two-point discrimination of the index and long
      fingers of the dominant hand. For each subject, the initial investigator and
      initial testing instrument were randomized. Two-point testing was conducted at 4,
      5, and 6 mm by using six randomly selected stimuli (1 or 2 points) for each
      distal phalanx tested. The study was designed to detect a 25% difference in mean
      two-point distance with a power of 80%. RESULTS: Seventy-five subjects were
      entered into the study, of which two were excluded. Interinstrument agreement for
      a given investigator ranged from 77% to 84% for absolute agreement and 98% to
      100% within 2 mm. Weighted kappa values for interobserver differences of 2 mm or
      less was 0.79 to 1.00. There was no statistically significant difference between
      instruments. CONCLUSIONS: Using a clinically relevant threshold of 2 mm, the
      authors found that a properly calibrated set of paper clips performed as well as
      the Disk-Criminator.

PMID- 15175217
TI  - Evaluation of the educational utility of patient follow-up.
AB  - OBJECTIVES: To date, no studies in emergency medicine (EM) have addressed the
      educational value of the Residency Review Committee for Emergency Medicine's (RRC
      EM) requirement for patient follow-up (FU). The authors examined whether
      performance of patient FU improved EM resident education. METHODS: All EM
      resident FU encounters from September 25, 2001, through September 24, 2002, were
      documented and analyzed. All EM residents at a regional tertiary referral
      emergency department (ED) initiated patient FU encounters by entering information
      regarding patients' initial ED presentations into a Web-based follow-up system
      (WBFUS), subsequently entered FU information, and indicated whether they thought
      that the specific FU encounters improved their education (yes/no). Supervising
      faculty members then reviewed the residents' completed FU entries. Blinded to
      residents' responses regarding educational utility, faculty members evaluated
      whether they thought the specific FU encounters were educational for the
      residents (yes/no). Data entered into the WBFUS were then summarized as
      percentages. RESULTS: Eight hundred forty-seven FU encounters were completed by
      18 EM residents and 29 EM faculty. Ninety-three percent of the FU entries were
      deemed by at least one evaluator (resident or faculty) to have educational value.
      Residents found the act of performing FU educational in 81.3% of cases, whereas
      faculty thought 80.4% were educational for the resident. Although the residents
      and faculty agreed on the educational value in 75.4% of cases, the overall
      strength of the agreement was slight to fair (kappa statistic = 0.21).
      CONCLUSIONS: This study indicates that EM residents and faculty believe that the
      act of performing patient FU has educational value for EM residents; however, the
      interobserver agreement between residents and faculty was low.

PMID- 15175219
TI  - Global disparities in health care.

PMID- 15175220
TI  - Cation transport by the neuronal K(+)-Cl(-) cotransporter KCC2: thermodynamics
      and kinetics of alternate transport modes.
AB  - Both Cs(+) and NH(4)(+) alter neuronal Cl(-) homeostasis, yet the mechanisms have
      not been clearly elucidated. We hypothesized that these two cations altered the
      operation of the neuronal K(+)-Cl(-) cotransporter (KCC2). Using exogenously
      expressed KCC2 protein, we first examined the interaction of cations at the
      transport site of KCC2 by monitoring furosemide-sensitive (86)Rb(+) influx as a
      function of external Rb(+) concentration at different fixed external cation
      concentrations (Na(+), Li(+), K(+), Cs(+), and NH(4)(+)). Neither Na(+) nor Li(+)
      affected furosemide-sensitive (86)Rb(+) influx, indicating their inability to
      interact at the cation translocation site of KCC2. As expected for an enzyme that
      accepts Rb(+) and K(+) as alternate substrates, K(+) was a competitive inhibitor
      of Rb(+) transport by KCC2. Like K(+), both Cs(+) and NH(4)(+) behaved as
      competitive inhibitors of Rb(+) transport by KCC2, indicating their potential as
      transport substrates. Using ion chromatography to measure unidirectional Rb(+)
      and Cs(+) influxes, we determined that although KCC2 was capable of transporting
      Cs(+), it did so with a lower apparent affinity and maximal velocity compared
      with Rb(+). To assess NH(4)(+) transport by KCC2, we monitored intracellular pH
      (pH(i)) with a pH-sensitive fluorescent dye after an NH(4)(+)-induced alkaline
      load. Cells expressing KCC2 protein recovered pH(i) much more rapidly than
      untransfected cells, indicating that KCC2 can mediate net NH(4)(+) uptake.
      Consistent with KCC2-mediated NH(4)(+) transport, pH(i) recovery in KCC2
      expressing cells could be inhibited by furosemide (200 microM) or removal of
      external [Cl(-)]. Thermodynamic and kinetic considerations of KCC2 operating in
      alternate transport modes can explain altered neuronal Cl(-) homeostasis in the
      presence of Cs(+) and NH(4)(+).

PMID- 15175221
TI  - Cytoskeletal mechanics in adherent human airway smooth muscle cells: probe
      specificity and scaling of protein-protein dynamics.
AB  - We probed elastic and loss moduli in the adherent human airway smooth muscle cell
      through a variety of receptor systems, each serving as a different molecular
      window on cytoskeletal dynamics. Coated magnetic microbeads were attached to the
      cell surface via coating-receptor binding. A panel of bead coatings was
      investigated: a peptide containing the sequence RGD, vitronectin, urokinase,
      activating antibody against beta(1)-integrin, nonactivating antibody against
      beta(1)-integrin, blocking antibody against beta(1)-integrin, antibody against
      beta(1)-integrin, and acetylated low-density lipoprotein. An oscillatory
      mechanical torque was applied to the bead, and resulting lateral displacements
      were measured at baseline, after actin disruption by cytochalasin D, or after
      contractile activation by histamine. As expected, mechanical moduli depended
      strongly on bead type and bead coating, differing at the extremes by as much as
      two orders of magnitude. In every case, however, elastic and loss moduli
      increased with frequency f as a weak power law, f( x-1). Moreover, with few
      exceptions, data could be scaled such that elastic and frictional responses
      depended solely on the power law exponent x. Taken together, these data suggest
      that power law behavior represents a generic feature of underlying protein
      protein dynamics.

PMID- 15175222
TI  - Novel effect of NF-kappaB activation: carbonylation and nitration injury to
      cytoskeleton and disruption of monolayer barrier in intestinal epithelium.
AB  - Using monolayers of intestinal cells, we reported that upregulation of inducible
      nitric oxide synthase (iNOS) is required for oxidative injury and that activation
      of NF-kappaB is key to cytoskeletal instability. In the present study, we
      hypothesized that NF-kappaB activation is crucial to oxidant-induced iNOS
      upregulation and its injurious consequences: cytoskeletal oxidation and nitration
      and monolayer dysfunction. Wild-type (WT) cells were pretreated with inhibitors
      of NF-kappaB, with or without exposure to oxidant (H(2)O(2)). Other cells were
      transfected with an IkappaBalpha mutant (an inhibitor of NF-kappaB). Relative to
      WT cells exposed to vehicle, oxidant exposure caused increases in IkappaBalpha
      instability, NF-kappaB subunit activation, iNOS-related activity (NO, oxidative
      stress, tubulin nitration), microtubule disassembly and instability (increased
      monomeric and decreased polymeric tubulin), and monolayer disruption. Monolayers
      pretreated with NF-kappaB inhibitors (MG-132, lactacystin) were protected against
      oxidation, showing decreases in all measures of the NF-kappaB --> iNOS --> NO
      pathway. Dominant mutant stabilization of IkappaBalpha to inactivate NF-kappaB
      suppressed all measures of the iNOS/NO upregulation while protecting monolayers
      against oxidant insult. In these mutants, we found prevention of tubulin
      nitration and oxidation and enhancement of cytoskeletal and monolayer stability.
      We concluded that 1) NF-kappaB is required for oxidant-induced iNOS upregulation
      and for the consequent nitration and oxidation of cytoskeleton; 2) NF-kappaB
      activation causes cytoskeletal injury following upregulation of NO-driven
      processes; and 3) the molecular event underlying the destabilizing effects of NF
      kappaB appears to be increases in carbonylation and nitrotyrosination of the
      subunit components of cytoskeleton. The ability to promote NO overproduction and
      cytoskeletal nitration/oxidation is a novel mechanism not previously attributed
      to NF-kappaB in cells.

PMID- 15175223
TI  - Plasma and intracellular membrane inositol 1,4,5-trisphosphate receptors mediate
      the Ca(2+) increase associated with the ATP-induced increase in ciliary beat
      frequency.
AB  - An increase in intracellular free Ca(2+) concentration ([Ca(2+)](i)) has been
      shown to be involved in the increase in ciliary beat frequency (CBF) in response
      to ATP; however, the signaling pathways associated with inositol 1,4,5
      trisphosphate (IP(3)) receptor-dependent Ca(2+) mobilization remain unresolved.
      Using radioimmunoassay techniques, we have demonstrated the appearance of two
      IP(3) peaks occurring 10 and 60 s after ATP addition, which was strongly
      correlated with a release of intracellular Ca(2+) from internal stores and an
      influx of extracellular Ca(2+), respectively. In addition, ATP-dependent Ca(2+)
      mobilization required protein kinase C (PKC) and Ca(2+)/calmodulin-dependent
      protein kinase II activation. We found an increase in PKC activity in response to
      ATP, with a peak at 60 s after ATP addition. Xestospongin C, an IP(3) receptor
      blocker, significantly diminished both the ATP-induced increase in CBF and the
      initial transient [Ca(2+)](i) component. ATP addition in the presence of
      xestospongin C or thapsigargin revealed that the Ca(2+) influx is also dependent
      on IP(3) receptor activation. Immunofluorescence and confocal microscopic studies
      showed the presence of IP(3) receptor types 1 and 3 in cultured ciliated cells.
      Immunogold electron microscopy localized IP(3) receptor type 3 to the nucleus,
      the endoplasmic reticulum, and, interestingly, the plasma membrane. In contrast,
      IP(3) receptor type 1 was found exclusively in the nucleus and the endoplasmic
      reticulum. Our study demonstrates for the first time the presence of IP(3)
      receptor type 3 in the plasma membrane in ciliated cells and leads us to
      postulate that the IP(3) receptor can directly trigger Ca(2+) influx in response
      to ATP.

PMID- 15175224
TI  - Modulation of chloride secretory responses and barrier function of intestinal
      epithelial cells by the Salmonella effector protein SigD.
AB  - The Salmonella effector protein SigD is an inositol phosphate phosphatase that
      inhibits phosphatidylinositol 3-kinase-dependent signaling. Because epidermal
      growth factor (EGF) inhibits chloride secretion via phosphatidylinositol 3
      kinase, we explored whether Salmonella infection might modify the inhibitory
      effect of EGF. As expected, EGF inhibited chloride secretion induced by carbachol
      in T(84) epithelial cells. Infection with wild-type (WT) but not sigD(-) mutant
      S. typhimurium SL1344 decreased CCh-stimulated chloride secretion. Moreover, WT
      but not sigD(-) Salmonella reduced the inhibitory effect of EGF on carbachol
      stimulated chloride secretion. Complementation of sigD restored the ability of
      mutant Salmonella to reverse the inhibitory effect of EGF. EGF-induced EGF
      receptor phosphorylation was similar in cells infected with either WT or mutant
      Salmonella, and neither WT nor sigD(-) Salmonella altered recruitment of the p85
      subunit of phosphatidylinositol 3-kinase to EGF receptor, implying that SigD acts
      downstream of these signaling events. Furthermore, transepithelial resistance
      fell more rapidly in cells infected with WT vs. sigD(-) Salmonella, indicating an
      early role for SigD in reducing barrier function, perhaps via activation of
      protein kinase C. We conclude that the Salmonella bacterial effector protein SigD
      may play critical roles in the pathogenesis of disease caused by this
      microorganism.

PMID- 15175225
TI  - Human cytomegalovirus-induced host cell enlargement is iron dependent.
AB  - A hallmark of human cytomegalovirus (HCMV) infection is the characteristic
      enlargement of the host cells (i.e., cytomegaly). Because iron (Fe) is required
      for cell growth and Fe chelators inhibit viral replication, we investigated the
      effects of HCMV infection on Fe homeostasis in MRC-5 fibroblasts. Using the
      metallosensitive fluorophore calcein and the Fe chelator salicylaldehyde
      isonicotinoyl hydrazone (SIH), the labile iron pool (LIP) in mock-infected cells
      was determined to be 1.04 +/- 0.05 microM. Twenty-four hours postinfection (hpi),
      the size of the LIP had nearly doubled. Because cytomegaly occurs between 24 and
      96 hpi, access to this larger LIP could be expected to facilitate enlargement to
      approximately 375% of the initial cell size. The ability of Fe chelation by 100
      microM SIH to limit enlargement to approximately 180% confirms that the LIP plays
      a major role in cytomegaly. The effect of SIH chelation on the mitochondrial
      membrane potential (DeltaPsi(M)) and morphology was studied using the
      mitochondrial voltage-sensitive dye JC-1. The mitochondria in mock-infected cells
      were heterogeneous with a broad distribution of DeltaPsi(M) and were threadlike.
      In contrast, the mitochondria of HCMV-infected cells had a more depolarized
      DeltaPsi(M) distributed over a narrow range and were grainlike in appearance.
      However, the HCMV-induced alteration in DeltaPsi(M) was not affected by SIH
      chelation. We conclude that the development of cytomegaly is inhibited by Fe
      chelation and may be facilitated by an HCMV-induced increase in the LIP.

PMID- 15175226
TI  - Changes in spinal cord architecture after brachial plexus injury in the newborn.
AB  - Obstetric brachial plexus palsy is a devastating birth injury. While many
      children recover spontaneously, 20-25% are left with a permanent impairment of
      the affected limb. So far, concepts of pathology and recovery have focused on the
      injury of the peripheral nerve. Proximal nerve injury at birth, however, leads to
      massive injury-induced motoneuron loss in corresponding motoneuron pools and
      therefore limits the extent of functional recovery. In the present study, the
      role of spinal cord plasticity after injury and recovery from obstetric brachial
      plexus lesions was investigated. A selective injury to spinal roots C5 and C6 was
      induced in newborn Sprague-Dawley rats, leading to motoneuron loss in
      corresponding motoneuron pools. Recovery of extremity function was evaluated with
      different behavioural paradigms. Permanent changes of adjacent motoneuron pools
      were quantitatively evaluated by retrograde tracing and functional muscle
      testing. We report that the adjacent C7 motoneuron contribution to biceps muscle
      innervation increased four-fold after upper trunk lesions in newborns, thus
      compensating for the injury-induced motoneuron loss. These results indicate that,
      in obstetric brachial plexus palsy, changes in spinal cord architecture are an
      integral part not only of primary pathology but also of the subsequent recovery
      process. While present treatment is directed towards the restoration of neural
      continuity, future treatment strategies must recognize and take advantage of CNS
      participation in the injury and recovery process.

PMID- 15175227
TI  - GABAA receptor-dependent synchronization leads to ictogenesis in the human
      dysplastic cortex.
AB  - Patients with Taylor's type focal cortical dysplasia (FCD) present with seizures
      that are often medically intractable. Here, we attempted to identify the cellular
      and pharmacological mechanisms responsible for this epileptogenic state by using
      field potential and K+-selective recordings in neocortical slices obtained from
      epileptic patients with FCD and, for purposes of comparison, with mesial temporal
      lobe epilepsy (MTLE), an epileptic disorder that, at least in the neocortex, is
      not characterized by any obvious structural aberration of neuronal networks.
      Spontaneous epileptiform activity was induced in vitro by applying 4
      aminopyridine (4AP)-containing medium. Under these conditions, we could identify
      in FCD slices a close temporal relationship between ictal activity onset and the
      occurrence of slow interictal-like events that were mainly contributed by GABAA
      receptor activation. We also found that in FCD slices, pharmacological procedures
      capable of decreasing or increasing GABAA receptor function abolished or
      potentiated ictal discharges, respectively. In addition, the initiation of ictal
      events in FCD tissue coincided with the occurrence of GABAA receptor-dependent
      interictal events leading to [K+]o elevations that were larger than those seen
      during the interictal period. Finally, by testing the effects induced by baclofen
      on epileptiform events generated by FCD and MTLE slices, we discovered that the
      function of GABAB receptors (presumably located at presynaptic inhibitory
      terminals) was markedly decreased in FCD tissue. Thus, epileptiform
      synchronization leading to in vitro ictal activity in the human FCD tissue is
      initiated by a synchronizing mechanism that paradoxically relies on GABAA
      receptor activation causing sizeable increases in [K+]o. This mechanism may be
      facilitated by the decreased ability of GABAB receptors to control GABA release
      from interneuron terminals.

PMID- 15175228
TI  - Are there socioeconomic gradients in stage and grade of breast cancer at
      diagnosis? Cross sectional analysis of UK cancer registry data.

PMID- 15175229
TI  - Meta-analysis of parenteral nutrition versus enteral nutrition in patients with
      acute pancreatitis.
AB  - OBJECTIVE: To compare the safety and clinical outcomes of enteral and parenteral
      nutrition in patients with acute pancreatitis. DATA SOURCES: Medline, Embase,
      Cochrane controlled trials register, and citation review of relevant primary and
      review articles. STUDY SELECTION: Randomised controlled studies that compared
      enteral nutrition with parenteral nutrition in patients with acute pancreatitis.
      From 117 articles screened, six were identified as randomised controlled trials
      and were included for data extraction. DATA EXTRACTION: Six studies with 263
      participants were analysed. Descriptive and outcome data were extracted. Main
      outcome measures were infections, complications other than infections, operative
      interventions, length of hospital stay, and mortality. The meta-analysis was
      performed with the random effects model. DATA SYNTHESIS: Enteral nutrition was
      associated with a significantly lower incidence of infections (relative risk
      0.45; 95% confidence interval 0.26 to 0.78, P = 0.004), reduced surgical
      interventions to control pancreatitis (0.48, 0.22 to 1.0, P = 0.05), and a
      reduced length of hospital stay (mean reduction 2.9 days, 1.6 days to 4.3 days, P
      < 0.001). There were no significant differences in mortality (relative risk 0.66,
      0.32 to 1.37, P = 0.3) or non-infectious complications (0.61, 0.31 to 1.22, P =
      0.16) between the two groups of patients. CONCLUSIONS: Enteral nutrition should
      be the preferred route of nutritional support in patients with acute
      pancreatitis.

PMID- 15175230
TI  - Prospective cohort study of retinal vessel diameters and risk of hypertension.
AB  - OBJECTIVE: To examine the relation between diameters of the retinal arterioles
      and 10 year incidence of hypertension. DESIGN: Population based prospective
      cohort study. SETTING: Beaver Dam eye study. PARTICIPANTS: 2451 normotensive
      people aged 43 to 84 years. MAIN OUTCOME MEASURES: Diameters of retinal
      arterioles and venules measured from digitised photographs of the retina taken at
      baseline. Measurements summarised as the arteriole:venule ratio, with a lower
      ratio indicating smaller arteriolar diameters. Incident hypertension, defined as
      systolic blood pressure > or =140 mm Hg, diastolic blood pressure > or =90 mm Hg,
      or use of antihypertensive drugs during follow up. RESULTS: 721 participants
      developed hypertension over a 10 year period. Those with lower arteriole:venule
      ratio had a higher cumulative incidence of hypertension (incidences of 17.4%,
      24.1%, 31.0%, and 45.1%, respectively, for decreasing quarters of distribution of
      arteriole:venule ratio). After adjustment for age and sex, participants with
      arteriole:venule ratios in the lowest quarter had a threefold higher risk of
      hypertension (odds ratio 2.95, 95% confidence interval 2.77 to 3.88) than those
      with ratios in the highest quarter. This association remained significant after
      further adjustment for baseline systolic and diastolic blood pressure and other
      risk factors (1.82, 1.39 to 2.40, for lowest versus highest ratio quarters).
      CONCLUSIONS: Narrowed retinal arterioles are associated with long term risk of
      hypertension, suggesting that structural alterations of the microvasculature may
      be linked to the development of hypertension.

PMID- 15175231
TI  - Severe acute respiratory syndrome and its impact on professionalism: qualitative
      study of physicians' behaviour during an emerging healthcare crisis.
AB  - OBJECTIVE: To explore issues of medical professionalism in the context of severe
      acute respiratory syndrome (SARS), a new emerging health threat. DESIGN:
      Qualitative interviews analysed with grounded theory methodology. SETTING:
      University hospitals in Toronto, Canada, during the SARS outbreak in 2003.
      PARTICIPANTS: 14 staff physicians from divisions of infectious diseases, general
      internal medicine, and critical care medicine. RESULTS: Of 14 attending
      physicians, four became ill during the outbreak. Participants described their
      experiences during the outbreak and highlighted several themes about values
      inherent to medical professionalism that arose during this crisis including the
      balance between care of patients and accepted personal risk, confidentiality,
      appropriate interactions between physicians and patients, ethical research
      conduct, and role modelling of professionalism for junior doctors. CONCLUSION:
      Despite concerns raised by professional societies about the erosion of
      professionalism, participants in this study amply demonstrated the necessary
      qualities during the recent healthcare crisis. However, there were several
      examples of strained professional behaviour witnessed by the participants and
      these examples highlight aspects of medical professionalism that medical
      educators and professional organisations should address in the future, including
      the balance between personal safety and duty of care.

PMID- 15175233
TI  - Cryoprotectant-free cryopreservation of human spermatozoa by vitrification and
      freezing in vapor: effect on motility, DNA integrity, and fertilization ability.
AB  - Human spermatozoa can be successfully cryopreserved avoiding the use of
      cryoprotectants through vitrification at very high cooling rates (up to 7.2 x
      10(5) degrees C/min). This is achieved by directly plunging a copper cryoloop
      loaded with a sperm suspension into liquid nitrogen. After storage, vitrified
      spermatozoa are instantly thawed by melting in an agitated, warm medium. The goal
      of the present study was to compare the quality of spermatozoa cryopreserved
      using this rapid vitrification method with that of spermatozoa cooled relatively
      slowly by preexposure of the loaded cryoloop to liquid nitrogen vapor (-160
      degrees C) with speed in the range 150-250 degrees C/min) before immersion into
      liquid nitrogen. Both cooling modes led to comparable results in terms of the
      motility, fertilization ability, and DNA integrity of the warmed spermatozoa. In
      both cases, instant thawing by melting in a warm medium was essential for
      successful cryopreservation. Our findings suggest that optimal regimes for the
      cryoprotectant-free cryopreservation of spermatozoa need not be restricted to
      very fast cooling before storage in liquid nitrogen, a wide range of cooling
      rates being acceptable. Herein, we discuss the implications of this finding in
      the light of the physics of extra- and intracellular vitrification.

PMID- 15175232
TI  - Seminal plasma regulates corpora lutea macrophage populations during early
      pregnancy in mice.
AB  - In mice, exposure of the uterus to seminal plasma at mating initiates an
      inflammatory response within the endometrium, which is characterized by
      production of cytokines that recruit and activate leukocytes. We hypothesized
      that this seminal plasma-induced inflammatory response would extend to the ovary,
      increasing leukocyte abundance within corpora lutea and potentially enhancing
      progesterone synthesis. Female mice mated to males with their seminal vesicles
      surgically removed exhibited fewer macrophages within corpora lutea on the day
      after mating, compared with females mated to vasectomized or normal, intact
      males. The mean number of F4/80-positive macrophages and major histocompatibility
      complex (MHC) class II-positive activated macrophages was approximately 2-fold
      fewer in the absence of seminal vesicle fluid. The effects of seminal plasma on
      macrophage abundance subsided by Day 4 and were not accompanied by a change in
      serum progesterone levels during luteinization (Days 1, 2, or 4 after mating) or
      luteolysis (Days 6 or 9). In vitro secretion of progesterone from corpora lutea
      cultured with or without LH also did not differ between treatment groups. There
      was no effect of seminal plasma deficiency in males on the number of ovulated ova
      or corpora lutea in females. These results imply that seminal plasma exposure of
      the female reproductive tract at mating augments the macrophage population of
      newly formed corpora lutea, although these additional macrophages seem not to
      play a role in steroidogenesis and may instead be involved in tissue remodeling
      within corpora lutea.

PMID- 15175235
TI  - Protection of porcine oocytes against cell damage caused by oxidative stress
      during in vitro maturation: role of superoxide dismutase activity in porcine
      follicular fluid.
AB  - To elucidate the beneficial effects of porcine follicular fluid (pFF) added to
      maturation medium on the sustenance of cytoplasmic maturation responsible for the
      subsequent developmental competence after in vitro fertilization (IVF) of porcine
      oocytes, we focused on the antioxidative role of pFF in its function of
      protecting oocytes from reactive oxygen species (ROS)-induced cell damage.
      Porcine follicular fluid collected from small (2-6 mm) follicles had about 7.2
      fold higher levels of superoxide dismutase (SOD) activity than that of fetal
      bovine serum (FBS), and this activity was markedly blocked by the CuZn-SOD
      inhibitor, diethyldithiocarbamate (DETC). The interruption of meiotic progression
      and the increasing intracellular glutathione (GSH) content throughout the
      maturation period, as well as an outbreak of DNA damage in oocytes and cumulus
      cells were difficult to detect in oocytes cultured in a medium supplemented with
      10% pFF, even in the presence of ROS generated by the hypoxanthine-xanthine
      oxidase system, whereas cell damage encompassed by ROS was prominent in oocytes
      cultured with 10% FBS and 10% pFF plus 100 microM DETC. Similarly, significant
      enhancement to the degree of transformation of the sperm nucleus into the male
      pronucleus (MPN) after in vitro fertilization was shown by the addition of pFF to
      the maturation medium. The presence of DETC during in vitro maturation reduced
      the ability of oocytes to promote MPN formation to the same extent as oocytes
      matured with FBS. The proportion developing to the blastocyst stage was increased
      in oocytes that matured with pFF, but this developmental competence was
      significantly lowered by treatment with DETC (P < 0.05). These findings suggest
      that pFF plays a critical role in protecting oocytes from oxidative stress
      through a higher level of radical scavenging activity elicited from SOD
      isoenzymes, resulting in the enhancement of cytoplasmic maturation responsible
      for developmental competence postfertilization.

PMID- 15175234
TI  - The effects of long-term vitamin E treatment on gene expression and oxidative
      stress damage in the aging Brown Norway rat epididymis.
AB  - The male reproductive tract of the Brown Norway rat is profoundly affected by
      aging. In the epididymis, the site of sperm maturation and storage, aging results
      in histological and biochemical changes that are suggestive of oxidative stress.
      Vitamin E is a potent lipid-soluble antioxidant that ameliorates the oxidative
      stress load associated with some chronic disease conditions. To determine the
      effects of long-term (18-mo) vitamin E deficiency and supplementation on aging in
      the epididymis, we assessed gene expression changes using cDNA microarrays and
      lipid peroxidation using immunohistochemical detection of 4-hydroxynonenal (4
      HNE) in 24-mo-old rats. Plasma vitamin E levels were significantly lower in
      vitamin E-deficient animals and higher in vitamin E-supplemented animals compared
      with age-matched controls. Vitamin E deficiency resulted in increased expression
      of oxidative stress-related transcripts along the epididymis. This effect was
      most marked in the corpus epididymidis, where expression of glutathione S
      transferases pi, 8, and mu, as well as superoxide dismutase, increased by over
      50%. The effect of vitamin E supplementation on the expression of oxidative
      stress-related transcripts was primarily decreased expression; however, the
      magnitude of the gene expression changes was smaller than that observed for
      vitamin E deficiency. 4-HNE immunostaining was present throughout the epididymis
      in control animals. Vitamin E deficiency both increased the intensity and altered
      the distribution of 4-HNE staining, while vitamin E supplementation had no
      observable effect. In summary, we found that long-term vitamin E treatment alters
      the expression of oxidative stress-related transcripts. Moreover, long-term
      vitamin E deficiency exacerbates the effects of age on the accumulation of
      oxidative stress damage in the epididymis.

PMID- 15175236
TI  - Theca interna: the other side of bovine follicular atresia.
AB  - Currently, histological classifications of ovarian follicular atresia are almost
      exclusively based on the morphology of the membrana granulosa without reference
      to the theca interna. Atresia in the bovine small antral ovarian follicle has
      been redefined into antral or basal atresia where cell death commences initially
      within antral or basal regions of the membrana granulosa, respectively. To
      examine cell death in the theca interna in the two types of atretic follicles,
      bovine ovaries were collected and processed for immunohistochemistry and light
      microscopy. Follicles were classified as healthy, antral atretic, or basal
      atretic. Follicle diameter was recorded and sections stained with lectin from
      Bandeiraea simplicifolia to identify endothelial cells or with an antibody to
      cytochrome P450 cholesterol side-chain cleavage to identify steroidogenic cells
      and combined with TUNEL labeling to identify dead cells. The numerical density of
      steroidogenic cells within the theca interna was significantly reduced (P <
      0.001) in basal atretic follicles in comparison with other follicles. Cell death
      was greater in both endothelial cells (P < 0.05) and steroidogenic cells (P <
      0.01) of the theca interna of basal atretic follicles compared with healthy and
      antral atretic follicles. Thus, we conclude that the theca interna is susceptible
      to cell death early in atresia, particularly in basal atretic follicles.

PMID- 15175237
TI  - Zonadhesin assembly into the hamster sperm acrosomal matrix occurs by distinct
      targeting strategies during spermiogenesis and maturation in the epididymis.
AB  - Zonadhesin is the only sperm protein known to bind in a species-specific manner
      to the zona pellucida. The zonadhesin precursor is a mosaic protein with a
      predicted transmembrane segment and large extracellular region composed of cell
      adhesion, mucin, and tandem von Willebrand D domains. Because the precursor
      possesses a predicted transmembrane segment and localizes to the anterior head,
      the mature protein was presumed to be a sperm surface zona pellucida-binding
      protein. In this study of hamster spermatozoa, we demonstrate that zonadhesin
      does not localize to the sperm surface but is instead a constituent of the
      acrosomal matrix. Immunoelectron microscopy revealed that distinct targeting
      pathways during spermiogenesis and sperm maturation in the epididymis result in
      trafficking of zonadhesin to the acrosomal matrix. In round spermatids,
      zonadhesin localized specifically to the acrosomal membrane, where it appeared to
      be evenly distributed between the outer and inner membrane domains. Subsequent
      redistribution of zonadhesin resulted in its elimination from the inner acrosomal
      membrane and restriction to the outer acrosomal membrane of the apical and
      principal segments and the contents of the posterior acrosome. During sperm
      maturation in the epididymis, zonadhesin dissociated from the outer acrosomal
      membrane and became incorporated into the forming acrosomal matrix. These data
      suggest an important structural role for zonadhesin in assembly of the acrosomal
      matrix and further support the view that the species specificity of zona
      pellucida adhesion is mediated by egg-binding proteins contained within the
      acrosome rather than on the periacrosomal plasma membrane.

PMID- 15175239
TI  - Spam1 (PH-20) expression in the extratesticular duct and accessory organs of the
      mouse: a possible role in sperm fluid reabsorption.
AB  - A widely conserved sperm antigen, the sperm adhesion molecule 1 (SPAM1 or PH-20)
      is a glycosylphosphatidyl inositol-linked protein with multiple roles in
      mammalian fertilization. It has been shown to be dually expressed in testis and
      epididymis and this is conserved in the four species (mouse, rat, macaques,
      humans) that have been studied to date. Here, we report Spam1 RNA and protein
      expression in the murine vas deferens and efferent ducts. In situ hybridization
      and immunohistochemistry indicate that transcript and protein are distributed in
      the nonciliated epithelial cells and that the efferent ducts have the most
      intense staining of all three regions of the excurrent ducts. Spam1 products were
      also present in the accessory organs, the prostate, and seminal vesicles and its
      fluid. Using hyaluronic acid substrate gel electrophoresis, hyaluronidase
      activity at pH 7.0 was detected in the vas deferens but was absent from the
      efferent ducts, the prostate, and the seminal vesicles/fluid. This suggests that
      Spam1 may play a nonenzymatic role in these organs. In the efferent ducts, where
      Spam1 is enriched in the apical (but not basolateral) membrane of nonciliated
      cells, it is likely to play a role in sperm concentration, which is the
      established function of that organ.

PMID- 15175238
TI  - Developmental expression of 2489 gene clusters during pig embryogenesis: an
      expressed sequence tag project.
AB  - Identification of mRNAs that are present at early stages of embryogenesis is
      critical for a better understanding of development. To this end, cDNA libraries
      were constructed from germinal vesicle-stage oocytes, in vivo-produced four-cell-
      and blastocyst-stage embryos, and from in vitro-produced four-cell- and
      blastocyst-stage embryos. Randomly picked clones (10 848) were sequenced from the
      3' end and those of sufficient quality (8066, 74%) were clustered into groups of
      sequence similarity (>95% identity), resulting in 2489 clusters. The sequence of
      the longest representative expressed sequence tag (EST) of each cluster was
      compared with GenBank and TIGR. Scores below 200 were considered unique, and 1114
      (44.8%) did not have a match in either database. Sequencing from the 5' end
      yielded 12 of 37 useful annotations, suggesting that one third of the 1114 might
      be identifiable, still leaving over 700 unique ESTs. Virtual Northerns compared
      between the stages identified numerous genes where expression appears to change
      from the germinal vesicle oocyte to the four-cell stage, from the four-cell to
      blastocyst stage, and between in vitro- and in vivo-derived four-cell- and
      blastocyst-stage embryos. This is the first large-scale sequencing project on
      early pig embryogenesis and has resulted in the discovery of a large number of
      genes as well as possible stage-specific expression. Because many of these ESTs
      appear to not be in the public databases, their addition will be useful for
      transcriptional profiling experiments conducted on early pig embryos.

PMID- 15175241
TI  - Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1
      pathway.
AB  - The ATM protein kinase is activated by intermolecular autophosphorylation in
      response to DNA damage and initiates cellular signaling pathways that facilitate
      cell survival and reduce chromosomal breakage. Here, we show that NBS1 and BRCA1
      are required for the recruitment of previously activated ATM to the sites of DNA
      breaks after ionizing irradiation, and that this recruitment is required for the
      phosphorylation of SMC1 by ATM. To explore the functional importance of SMC1
      phosphorylation, murine cells were generated, in which the two damage-induced
      phosphorylation sites in SMC1 are mutated. Although these cells demonstrate
      normal phosphorylation and focus formation of ATM, NBS1, and BRCA1 proteins after
      IR, they exhibit a defective S-phase checkpoint, decreased survival, and
      increased chromosomal aberrations after DNA damage. These observations suggest
      that many of the abnormal stress responses seen in cells lacking ATM, NBS1, or
      BRCA1 result from a failure of ATM migration to sites of DNA breaks and a
      resultant lack of SMC1 phosphorylation.

PMID- 15175240
TI  - The loss of circadian PAR bZip transcription factors results in epilepsy.
AB  - DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), and TEF
      (thyrotroph embryonic factor) are the three members of the PAR bZip (proline and
      acidic amino acid-rich basic leucine zipper) transcription factor family. All
      three of these transcriptional regulatory proteins accumulate with robust
      circadian rhythms in tissues with high amplitudes of clock gene expression, such
      as the suprachiasmatic nucleus (SCN) and the liver. However, they are expressed
      at nearly invariable levels in most brain regions, in which clock gene expression
      only cycles with low amplitude. Here we show that mice deficient for all three
      PAR bZip proteins are highly susceptible to generalized spontaneous and
      audiogenic epilepsies that frequently are lethal. Transcriptome profiling
      revealed pyridoxal kinase (Pdxk) as a target gene of PAR bZip proteins in both
      liver and brain. Pyridoxal kinase converts vitamin B6 derivatives into pyridoxal
      phosphate (PLP), the coenzyme of many enzymes involved in amino acid and
      neurotransmitter metabolism. PAR bZip-deficient mice show decreased brain levels
      of PLP, serotonin, and dopamine, and such changes have previously been reported
      to cause epilepsies in other systems. Hence, the expression of some clock
      controlled genes, such as Pdxk, may have to remain within narrow limits in the
      brain. This could explain why the circadian oscillator has evolved to generate
      only low-amplitude cycles in most brain regions.

PMID- 15175242
TI  - Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle
      kinetics.
AB  - Tumor development is dependent upon the inactivation of two key tumor-suppressor
      networks, p16(Ink4a)-cycD/cdk4-pRB-E2F and p19(Arf)-mdm2-p53, that regulate
      cellular proliferation and the tumor surveillance response. These networks are
      known to intersect with one another, but the mechanisms are poorly understood.
      Here, we show that E2F directly participates in the transcriptional control of
      Arf in both normal and transformed cells. This occurs in a manner that is
      significantly different from the regulation of classic E2F-responsive targets. In
      wild-type mouse embryonic fibroblasts (MEFs), the Arf promoter is occupied by
      E2F3 and not other E2F family members. In quiescent cells, this role is largely
      fulfilled by E2F3b, an E2F3 isoform whose function was previously undetermined.
      E2f3 loss is sufficient to derepress Arf, triggering activation of p53 and
      expression of p21(Cip1). Thus, E2F3 is a key repressor of the p19(Arf)-p53
      pathway in normal cells. Consistent with this notion, Arf mutation suppresses the
      activation of p53 and p21(Cip1) in E2f3-deficient MEFs. Arf loss also rescues the
      known cell cycle re-entry defect of E2f3(-/-) cells, and this correlates with
      restoration of appropriate activation of classic E2F-responsive genes. Our data
      also demonstrate a direct role for E2F in the oncogenic activation of Arf.
      Specifically, we observe recruitment of the endogenous activating E2Fs, E2F1, and
      E2F3a, to the Arf promoter. Thus, distinct E2F complexes directly contribute to
      the normal repression and oncogenic activation of Arf. We propose that monitoring
      of E2F levels and/or activity is a key component of Arf's ability to respond to
      inappropriate, but not normal cellular proliferation.

PMID- 15175243
TI  - Asymmetric production of surface-dividing and non-surface-dividing cortical
      progenitor cells.
AB  - Mature neocortical layers all derive from the cortical plate (CP), a transient
      zone in the dorsal telencephalon into which young neurons are continuously
      delivered. To understand cytogenetic and histogenetic events that trigger the
      emergence of the CP, we have used a slice culture technique. Most divisions at
      the ventricular surface generated paired cycling daughters (P/P divisions) and
      the majority of the P/P divisions were asymmetric in daughter cell behavior; they
      frequently sent one daughter cell to a non-surface (NS) position, the
      subventricular zone (SVZ), within a single cell-cycle length while keeping the
      other mitotic daughter for division at the surface. The NS-dividing cells were
      mostly Hu+ and their daughters were also Hu+, suggesting their commitment to the
      neuronal lineage and supply of early neurons at a position much closer to their
      destiny than from the ventricular surface. The release of a cycling daughter cell
      to SVZ was achieved by collapse of the ventricular process of the cell, followed
      by its NS division. Neurogenin2 (Ngn2) was immunohistochemically detected in a
      certain cycling population during G1 phase and was further restricted during G2-M
      phases to the SVZ-directed population. Its retroviral introduction converted
      surface divisions to NS divisions. The asymmetric P/P division may therefore
      contribute to efficient neuron/progenitor segregation required for CP initiation
      through cell cycle-dependent and lineage-restricted expression of Ngn2.

PMID- 15175244
TI  - Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract.
AB  - Dysmorphogenesis of the cardiac outflow tract (OFT) causes many congenital heart
      defects, including those associated with DiGeorge syndrome. Genetic manipulation
      in the mouse and mutational analysis in patients have shown that Tbx1, a T-box
      transcription factor, has a key role in the pathogenesis of this syndrome. Here,
      we have dissected Tbx1 function during OFT development using genetically modified
      mice and tissue-specific deletion, and have defined a dual role for this protein
      in OFT morphogenesis. We show that Tbx1 regulates cell contribution to the OFT by
      supporting cell proliferation in the secondary heart field, a source of cells
      fated to the OFT. This process might be regulated in part by Fgf10, which we show
      for the first time to be a direct target of Tbx1 in vitro. We also show that Tbx1
      expression is required in cells expressing Nkx2.5 for the formation of the aorto
      pulmonary septum, which divides the aorta from the main pulmonary artery. These
      results explain why aortic arch patterning defects and OFT defects can occur
      independently in individuals with DiGeorge syndrome. Furthermore, our data link,
      for the first time, the function of the secondary heart field to congenital heart
      disease.

PMID- 15175245
TI  - Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary
      palate growth and morphogenesis.
AB  - Development of the mammalian secondary palate involves multiple steps of highly
      regulated morphogenetic processes that are frequently disturbed during human
      development, resulting in the common birth defect of cleft palate. Neither the
      molecular processes governing normal palatogenesis nor the causes of cleft palate
      is well understood. In an expression screen to identify new transcription factors
      regulating palate development, we previously isolated the odd-skipped related 2
      (Osr2) gene, encoding a zinc-finger protein homologous to the Drosophila odd
      skipped gene product, and showed that Osr2 mRNA expression is specifically
      activated in the nascent palatal mesenchyme at the onset of palatal outgrowth. We
      report that a targeted null mutation in Osr2 impairs palatal shelf growth and
      causes delay in palatal shelf elevation, resulting in cleft palate. Whereas
      palatal outgrowth initiates normally in the Osr2 mutant embryos, a significant
      reduction in palatal mesenchyme proliferation occurs specifically in the medial
      halves of the downward growing palatal shelves at E13.5, which results in
      retarded, mediolaterally symmetric palatal shelves before palatal shelf
      elevation. The developmental timing of palatal growth retardation correlates
      exactly with the spatiotemporal pattern of Osr1 gene expression during palate
      development. Furthermore, we show that the Osr2 mutants exhibit altered gene
      expression patterns, including those of Osr1, Pax9 and Tgfb3, during palate
      development. These data identify Osr2 as a key intrinsic regulator of palatal
      growth and patterning.

PMID- 15175246
TI  - Organization of cardiac chamber progenitors in the zebrafish blastula.
AB  - Organogenesis requires the specification of a variety of cell types and the
      organization of these cells into a particular three-dimensional configuration.
      The embryonic vertebrate heart is organized into two major chambers, the
      ventricle and atrium, each consisting of two tissue layers, the myocardium and
      endocardium. The cellular and molecular mechanisms responsible for the separation
      of ventricular and atrial lineages are not well understood. To test models of
      cardiac chamber specification, we generated a high-resolution fate map of cardiac
      chamber progenitors in the zebrafish embryo at 40% epiboly, a stage prior to the
      initiation of gastrulation. Our map reveals a distinct spatial organization of
      myocardial progenitors: ventricular myocardial progenitors are positioned closer
      to the margin and to the dorsal midline than are atrial myocardial progenitors.
      By contrast, ventricular and atrial endocardial progenitors are not spatially
      organized at this stage. The relative orientations of ventricular and atrial
      myocardial progenitors before and after gastrulation suggest orderly movements of
      these populations. Furthermore, the initial positions of myocardial progenitors
      at 40% epiboly indicate that signals residing at the embryonic margin could
      influence chamber fate assignment. Indeed, via fate mapping, we demonstrate that
      Nodal signaling promotes ventricular fate specification near the margin, thereby
      playing an important early role during myocardial patterning.

PMID- 15175248
TI  - The zebrafish Iroquois gene iro7 positions the r4/r5 boundary and controls
      neurogenesis in the rostral hindbrain.
AB  - Early brain regionalisation involves the activation of genes coding for
      transcription factors in distinct domains of the neural plate. The limits of
      these domains often prefigure morphological boundaries. In the hindbrain,
      anteroposterior patterning depends on a segmentation process that leads to the
      formation of seven bulges called rhombomeres (r). The molecular cues involved in
      the early subdivision of the hindbrain and in rhombomere formation are not well
      understood. We show that iro7, a zebrafish gene coding for a transcription factor
      of the Iroquois family, is expressed at the end of gastrulation in the future
      midbrain and hindbrain territories up to the prospective r4/r5 boundary. This
      territory is strictly complementary to the expression domain of another homeobox
      gene, vhnf1, in the caudal neural plate. We demonstrate that Iro7 represses vhnf1
      expression anterior to their common border and that, conversely, vHnf1 represses
      iro7 expression caudal to it. This suggests that the r4/r5 boundary is positioned
      by mutual repression between these two transcription factors. In addition, iro7
      is involved in the specification of primary neurons in the rostral hindbrain. In
      particular, it is essential for the formation of the Mauthner neurons in r4. We
      propose that iro7 has a dual function in the hindbrain of the zebrafish embryo:
      it is required for the proper positioning of the prospective r4/r5 boundary and
      it promotes neurogenesis in the anterior hindbrain.

PMID- 15175247
TI  - HUA ENHANCER3 reveals a role for a cyclin-dependent protein kinase in the
      specification of floral organ identity in Arabidopsis.
AB  - In plants, organs are generated post-embryonically from highly organized
      structures known as meristems. Cell division in the meristem is closely
      integrated with cell fate specification and organ formation. The presence of
      multiple cyclin-dependent kinases (CDKs) and their partner cyclins in plants and
      other multicellular organisms probably reflects the complexity of cell cycle
      regulation within developmental contexts. The Arabidopsis genome encodes at least
      eight CDKs and 30 cyclins. However, no mutants in any CDKs have been reported,
      and the function of the great majority of these genes in plant development is
      unknown. We show that HUA ENHANCER3 (HEN3), which encodes CDKE, a homolog of
      mammalian CDK8, is required for the specification of stamen and carpel identities
      and for the proper termination of stem cells in the floral meristem. Therefore,
      CDK8 plays a role in cell differentiation in a multicellular organism.

PMID- 15175249
TI  - Homotypic signalling regulates Gata1 activity in the erythroblastic island.
AB  - Gata1 is a transcription factor essential for erythropoiesis. Erythroid cells
      lacking Gata1 undergo apoptosis, while overexpression of Gata1 results in a block
      in erythroid differentiation. However, erythroid cells overexpressing Gata1
      differentiate normally in vivo when in the presence of wild-type cells. We have
      proposed a model, whereby a signal generated by wild-type cells (red cell
      differentiation signal; REDS) overcomes the intrinsic defect in Gata1
      overexpressing erythroid cells. The simplest interpretation of this model is that
      wild-type erythroid cells generate REDS. To substantiate this notion, we have
      exploited a tissue specific Cre/loxP system and the process of X-inactivation to
      generate mice that overexpress Gata1 in half the erythroid cells and are Gata1
      null in the other half. The results show that the cells supplying REDS are
      erythroid cells. This study demonstrates the importance of intercellular
      signalling in regulating Gata1 activity and that this homotypic signalling
      between erythroid cells is crucial to normal differentiation.

PMID- 15175250
TI  - The dachsous gene, a member of the cadherin family, is required for Wg-dependent
      pattern formation in the Drosophila wing disc.
AB  - The dachsous (ds) gene encodes a member of the cadherin family involved in the
      non-canonical Wnt signaling pathway that controls the establishment of planar
      cell polarity (PCP) in Drosophila. ds is the only known cadherin gene in
      Drosophila with a restricted spatial pattern of expression in imaginal discs from
      early stages of larval development. In the wing disc, ds is first expressed
      distally, and later is restricted to the hinge and lateral regions of the notum.
      Flies homozygous for strong ds hypomorphic alleles display previously
      uncharacterized phenotypes consisting of a reduction of the hinge territory and
      an ectopic notum. These phenotypes resemble those caused by reduction of the
      canonical Wnt signal Wingless (Wg) during early wing disc development. An
      increase in Wg activity can rescue these phenotypes, indicating that Ds is
      required for efficient Wg signaling. This is further supported by genetic
      interactions between ds and several components of the Wg pathway in another
      developmental context. Ds and Wg show a complementary pattern of expression in
      early wing discs, suggesting that Ds acts in Wg-receiving cells. These results
      thus provide the first evidence for a more general role of Ds in Wnt signaling
      during imaginal development, not only affecting cell polarization but also
      modulating the response to Wg during the subdivision of the wing disc along its
      proximodistal (PD) axis.

PMID- 15175251
TI  - Engrailed genes are cell-autonomously required to prevent apoptosis in
      mesencephalic dopaminergic neurons.
AB  - The neuropathological hallmark of Parkinson's disease is the loss of dopaminergic
      neurons in the substantia nigra pars compacta, presumably mediated by apoptosis.
      The homeobox transcription factors engrailed 1 and engrailed 2 are expressed by
      this neuronal population from early in development to adulthood. Despite a large
      mid-hindbrain deletion in double mutants null for both genes, mesencephalic
      dopaminergic (mDA) neurons are induced, become postmitotic and acquire their
      neurotransmitter phenotype. However, at birth, no mDA neurons are left. We show
      that the entire population of these neurons is lost by E14 in the mutant animals,
      earlier than in any other described genetic model system for Parkinson's disease.
      This disappearance is caused by apoptosis revealed by the presence of activated
      caspase 3 in the dying tyrosine hydroxylase-positive mutant cells. Furthermore,
      using in vitro cell mixing experiments and RNA interference on primary cell
      culture of ventral midbrain we were able to show that the demise of mDA neurons
      in the mutant mice is due to a cell-autonomously requirement of the engrailed
      genes and not a result of the missing mid-hindbrain tissue. Gene silencing in the
      postmitotic neurons by RNA interference activates caspase 3 and induces apoptosis
      in less than 24 hours. This rapid induction of cell death in mDA neurons suggests
      that the engrailed genes participate directly in the regulation of apoptosis, a
      proposed mechanism for Parkinson's disease.

PMID- 15175252
TI  - Chip-mediated partnerships of the homeodomain proteins Bar and Aristaless with
      the LIM-HOM proteins Apterous and Lim1 regulate distal leg development.
AB  - Proximodistal patterning in Drosophila requires division of the developing leg
      into increasingly smaller, discrete domains of gene function. The LIM-HOM
      transcription factors apterous (ap) and Lim1 (also known as dlim1), and the
      homeobox genes Bar and aristaless (al) are part of the gene battery required for
      the development of specific leg segments. Our genetic results show that there are
      posttranslational interactions between Ap, Bar and the LIM-domain binding protein
      Chip in tarsus four, and between Al, Lim1 and Chip in the pretarsus, and that
      these interactions depend on the presence of balanced amounts of such proteins.
      We also observe in vitro protein binding between Bar and Chip, Bar and Ap, Lim1
      and Chip, and Al and Chip. Together with the previous evidence for interactions
      between Ap and Chip, these results suggest that these transcription factors form
      protein complexes during leg development. We propose that the different
      developmental outcomes of LIM-HOM function are due to the precise identity and
      dosage of the interacting partners present in a given cell.

PMID- 15175254
TI  - Discrimination between lumenal and cytosolic sites of deglycosylation in
      endoplasmic reticulum-associated degradation of glycoproteins by using benzyl
      mannose in CHO cell lines.
AB  - Recent studies demonstrated that deglycosylation step is a prerequisite for
      endoplasmic reticulum (ER)-associated degradation of misfolded glycoproteins.
      Here, we report the advantages of using benzyl mannose during pulse-chase
      experiments to study the subcellular location of the deglycosylation step in
      Chinese hamster ovary (CHO) cell lines. Benzyl mannose inhibited both the ER-to
      cytosol transport of oligomannosides and the trimming of cytosolic-labeled
      oligomannosides by the cytosolic mannosidase in vivo. We pointed out the
      occurrence of two subcellular sites of deglycosylation. The first one is located
      in the ER lumen, and led to the formation of Man8GlcNAc2 (isomer B) in wild-type
      CHO cell line and Man4GlcNAc2 in Man-P-Dol-deficient cell line. The second one
      was revealed in CHO mutant cell lines for which a high rate of glycoprotein
      degradation was required. It occurred in the cytosol and led to the liberation of
      oligosaccharides species with one GlcNAc residue and with a pattern similar to
      the one bound onto glycoproteins. The cytosolic deglycosylation site was not
      specific for CHO mutant cell lines, since we demonstrated the occurrence of
      cytosolic pathway when the formation of truncated glycans was induced in wild
      type cells.

PMID- 15175253
TI  - The mitotic-to-endocycle switch in Drosophila follicle cells is executed by Notch
      dependent regulation of G1/S, G2/M and M/G1 cell-cycle transitions.
AB  - The Notch signaling pathway controls the follicle cell mitotic-to-endocycle
      transition in Drosophila oogenesis by stopping the mitotic cycle and promoting
      the endocycle. To understand how the Notch pathway coordinates this process, we
      have identified and performed a functional analysis of genes whose transcription
      is responsive to the Notch pathway at this transition. These genes include the
      G2/M regulator Cdc25 phosphatase, String; a regulator of the APC ubiquitination
      complex Hec/CdhFzr and an inhibitor of the CyclinE/CDK complex, Dacapo. Notch
      activity leads to downregulation of String and Dacapo, and activation of Fzr. All
      three genes are independently responsive to Notch. In addition, CdhFzr, an
      essential gene for endocycles, is sufficient to stop mitotic cycle and promote
      precocious endocycles when expressed prematurely during mitotic stages. In
      contrast, overexpression of the growth controller Myc does not induce premature
      endocycles but accelerates the kinetics of normal endocycles. We also show that
      Archipelago (Ago), a SCF-regulator is dispensable for mitosis, but crucial for
      endocycle progression in follicle epithelium. The results support a model in
      which Notch activity executes the mitotic-to-endocycle switch by regulating all
      three major cell cycle transitions. Repression of String blocks the M-phase,
      activation of Fzr allows G1 progression and repression of Dacapo assures entry
      into the S-phase. This study provides a comprehensive picture of the logic that
      external signaling pathways may use to control cell cycle transitions by the
      coordinated regulation of the cell cycle.

PMID- 15175255
TI  - Structural characterization of the N-glycan moiety and site of glycosylation in
      vitellogenin from the decapod crustacean Cherax quadricarinatus.
AB  - Glycosylation is of importance for the structure and function of proteins. In the
      case of vitellin (Vt), a ubiquitous protein accumulated into granules as the main
      yolk protein constituent of oocytes during oogenesis, glycosylation could be of
      importantance for the folding, processing and transport of the protein to the
      yolk and also provides a source of carbohydrate during embryogenesis. Vt from the
      crayfish Cherax quadricarinatus is synthesized as a precursor protein,
      vitellogenin (Vg), in the hepatopancreas, transferred to the hemolymph, and
      mobilized into the growing oocyte via receptor-mediated endocytosis. The gene
      sequence of C. quadricarinatus shows a 2584-amino-acid protein with 10 putative
      glycosylation sites. In this study a combined approach of lectin immunoblotting,
      in-gel deglycosylation, and mass spectrometry was used to identify the
      glycosylation sites and probe the structure of the glycan moieties using C.
      quadricarinatus Vg as a model system. Three of the consensus sites for N
      glycosylation-namely, Asn(152), Asn(160) and Asn(2493)-were glycosylated with the
      high-mannose glycans, Man(5-9)GlcNAc(2), and the glucose-capped oligosaccharide
      Glc(1)Man(9)GlcNAc(2).

PMID- 15175256
TI  - Tracking global patterns of N-linked glycosylation site variation in highly
      variable viral glycoproteins: HIV, SIV, and HCV envelopes and influenza
      hemagglutinin.
AB  - Human and simian immunodeficiency viruses (HIV and SIV), influenza virus, and
      hepatitis C virus (HCV) have heavily glycosylated, highly variable surface
      proteins. Here we explore N-linked glycosylation site (sequon) variation at the
      population level in these viruses, using a new Web-based program developed to
      facilitate the sequon tracking and to define patterns (www.hiv.lanl.gov). This
      tool allowed rapid visualization of the two distinctive patterns of sequon
      variation found in HIV-1, HIV-2, and SIV CPZ. The first pattern (fixed) describes
      readily aligned sites that are either simply present or absent. These sites tend
      to be occupied by high-mannose glycans. The second pattern (shifting) refers to
      sites embedded in regions of extreme local length variation and is characterized
      by shifts in terms of the relative position and local density of sequons; these
      sites tend to be populated by complex carbohydrates. HIV, with its extreme
      variation in number and precise location of sequons, does not have a net increase
      in the number of sites over time at the population level. Primate lentiviral
      lineages have host species-dependent levels of sequon shifting, with HIV-1 in
      humans the most extreme. HCV E1 and E2 proteins, despite evolving extremely
      rapidly through point mutation, show limited sequon variation, although two
      shifting sites were identified. Human influenza A hemagglutinin H3 HA1 is
      accumulating sequons over time, but this trend is not evident in any other avian
      or human influenza A serotypes.

PMID- 15175257
TI  - Myelin-associated glycoprotein (Siglec-4) expression is progressively and
      selectively decreased in the brains of mice lacking complex gangliosides.
AB  - Myelin-associated glycoprotein (MAG, Siglec-4) is a quantitatively minor membrane
      component expressed preferentially on the innermost myelin wrap, adjacent to the
      axon. It stabilizes myelin-axon interactions by binding to complementary ligands
      on the axolemma. MAG, a member of the Siglec family of sialic acid-binding
      lectins, binds specifically to gangliosides GD1a and GT1b, which are the major
      sialoglycoconjugates on mammalian axons. Mice with a disrupted Galgt1 gene lack
      UDP-GalNAc:GM3/GD3 N-acetylgalactosaminyltransferase (GM2/GD2 synthase) and fail
      to express complex brain gangliosides, including GD1a and GT1b, instead
      expressing a comparable amount of the simpler gangliosides GM3, GD3, and O-acetyl
      GD3. Galgt1-null mice produce similar amounts of total myelin compared to wild
      type mice, but as the mice age, they exhibit axon degeneration and dysmyelination
      with accompanying motor behavioral deficits. Here we report that Galgt1-null mice
      display progressive and selective loss of MAG from the brain. At 1.5 months of
      age, MAG expression was similar in Galgt1-null and wild-type mice. However, by 6
      months of age MAG was decreased approximately 60% and at 12 months of age
      approximately 70% in Galgt1-null mice compared to wild-type littermates.
      Expression of the major myelin proteins (myelin basic protein and proteolipid
      protein) was not reduced in Galgt1-null mice compared to wild type. MAG mRNA
      expression was the same in 12-month-old Galgt1-null compared to wild-type mice,
      an age at which MAG protein expression was markedly reduced. We conclude that the
      maintenance of MAG protein levels depends on the presence of complex
      gangliosides, perhaps due to enhanced stability when MAG on myelin binds to its
      complementary ligands, GD1a and GT1b, on the apposing axon surface.

PMID- 15175258
TI  - Exploiting different ways to die.

PMID- 15175259
TI  - The histone modification pattern of active genes revealed through genome-wide
      chromatin analysis of a higher eukaryote.
AB  - The covalent modification of nucleosomal histones has emerged as a major
      determinant of chromatin structure and gene activity. To understand the interplay
      between various histone modifications, including acetylation and methylation, we
      performed a genome-wide chromatin structure analysis in a higher eukaryote. We
      found a binary pattern of histone modifications among euchromatic genes, with
      active genes being hyperacetylated for H3 and H4 and hypermethylated at Lys 4 and
      Lys 79 of H3, and inactive genes being hypomethylated and deacetylated at the
      same residues. Furthermore, the degree of modification correlates with the level
      of transcription, and modifications are largely restricted to transcribed
      regions, suggesting that their regulation is tightly linked to polymerase
      activity.

PMID- 15175260
TI  - Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability.
AB  - Nonhomologous end joining (NHEJ) and homologous recombination (HR) represent the
      two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells.
      NHEJ repairs DSBs by ligation of cognate broken ends irrespective of homologous
      flanking sequences, whereas HR repairs DSBs using an undamaged homologous
      template. Although both NHEJ and HR have been clearly implicated in the
      maintenance of genome stability, how these apparently independent and
      mechanistically distinct pathways are coordinated remains largely unexplored. To
      investigate the relationship between HR and NHEJ modes of DSB repair, we
      generated cells doubly deficient for the NHEJ factor DNA Ligase IV (Lig4) and the
      HR factor Rad54. We show that Lig4 and Rad54 cooperate to support cellular
      proliferation, repair spontaneous DSBs, and prevent chromosome and single
      chromatid aberrations. These findings demonstrate a role for NHEJ in the repair
      of DSBs that occur spontaneously during or after DNA replication, and reveal
      overlapping functions for NHEJ and Rad54-dependent HR in the repair of such DSBs.

PMID- 15175261
TI  - Collaboration of homologous recombination and nonhomologous end-joining factors
      for the survival and integrity of mice and cells.
AB  - Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are
      mechanistically distinct DNA repair pathways that contribute substantially to
      double-strand break (DSB) repair in mammalian cells. We have combined mutations
      in factors from both repair pathways, the HR protein Rad54 and the DNA-end
      binding factor Ku80, which has a role in NHEJ. Rad54(-/-)Ku80(-/-) mice were
      severely compromised in their survival, such that fewer double mutants were born
      than expected, and only a small proportion of those born reached adulthood.
      However, double-mutant mice died at lower frequency from tumors than Ku80 single
      mutant mice, likely as a result of rapid demise at a young age from other causes.
      When challenged with an exogenous DNA damaging agent, ionizing radiation, double
      mutant mice were exquisitely sensitive to low doses. Tissues and cells from
      double-mutant mice also showed indications of spontaneous DNA damage. Testes from
      some Rad54(-/-)Ku80(-/-) mice displayed enhanced apoptosis and reduced sperm
      production, and embryonic fibroblasts from Rad54(-/-)Ku80(-/-) animals
      accumulated foci of gamma-H2AX, a marker for DSBs. The substantially increased
      DNA damage response in the double mutants implies a cooperation of the two DSB
      repair pathways for survival and genomic integrity in the animal.

PMID- 15175262
TI  - SV40 T antigen interacts with Nbs1 to disrupt DNA replication control.
AB  - Nijmegen breakage syndrome (NBS) is characterized by radiation hypersensitivity,
      chromosomal instability, and predisposition to cancer. Nbs1, the NBS protein,
      forms a tight complex with Mre11 and Rad50, and these interactions contribute to
      proper double-strand break repair. The simian virus 40 (SV40) oncoprotein, large
      T antigen (T), also interacts with Nbs1, and T-containing cells experience
      chromosomal hyperreplication in a manner dependent on T/Nbs1 complex formation. A
      substantial fraction of NBS-deficient fibroblasts reinitiate DNA replication in
      discrete regions, and wild-type Nbs1 corrects this defect. Similarly, synthesis
      of an N-terminal Nbs1 fragment induced DNA rereplication and tetraploidy, in NBS
      deficient but not NBS-proficient cells. Moreover, SV40 origin-containing DNA
      hyperreplicated in T-containing NBS-deficient cells by comparison with T
      containing, Nbs1-reconstituted derivatives. Thus, Nbs1 suppresses rereplication
      of cellular DNA and SV40 origin-containing replicons, and T targets Nbs1, thereby
      enhancing the yield of new SV40 genomes during viral DNA replication.

PMID- 15175263
TI  - Activated oncogenes promote and cooperate with chromosomal instability for
      neoplastic transformation.
AB  - Most cancer cells are aneuploid. The chromosomal instability hypothesis contends
      that aneuploidy is the catalyst for transformation, whereas the gene mutation
      hypothesis asserts that cancer is driven by mutations to proto-oncogenes and
      tumor-suppressor genes, with the aneuploidy a side effect of tumorigenesis.
      Because genotoxic stress induced by "culture shock" can obscure the transforming
      potential of exogenous genes, we cultured wild-type and p53(-/-) mouse embryo
      fibroblasts in a more physiological (serum-free) environment. Under these
      conditions, the cells were immortal and, more importantly, chromosomally stable.
      Expression of oncogenic H-RasV12 did not induce senescence, but sensitized these
      cells to p53-dependent apoptosis. In addition, H-RasV12 induced chromosomal
      instability, as well as accumulation and phosphorylation of p53. Significantly,
      whereas cells grown under standard conditions could be transformed by
      coexpression of H-RasV12 and E1A, the chromosomally stable cells were refractory
      to transformation, as measured by anchorage-independent growth and tumor
      formation in nude mice. These oncogenes required a third genetic alteration that
      abolished the p53 pathway to create a permissive environment that promotes rapid
      chromosomal instability and transformation. Oncogene-induced chromosomal
      instability and transformation was attenuated by antioxidants. These data
      indicate that chromosomal instability could be a catalyst for oncogenic
      transformation, and bring together aspects of the chromosomal instability
      hypothesis and the gene mutation hypothesis for tumorigenesis.

PMID- 15175264
TI  - Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type
      methylating agents requires the ATR kinase.
AB  - S(N)1-type alkylating agents represent an important class of chemotherapeutics,
      but the molecular mechanisms underlying their cytotoxicity are unknown. Thus,
      although these substances modify predominantly purine nitrogen atoms, their
      toxicity appears to result from the processing of O(6)-methylguanine ((6Me)G)
      containing mispairs by the mismatch repair (MMR) system, because cells with
      defective MMR are highly resistant to killing by these agents. In an attempt to
      understand the role of the MMR system in the molecular transactions underlying
      the toxicity of alkylating agents, we studied the response of human MMR
      proficient and MMR-deficient cells to low concentrations of the prototypic
      methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We now show that
      MNNG treatment induced a cell cycle arrest that was absolutely dependent on
      functional MMR. Unusually, the cells arrested only in the second G(2) phase after
      treatment. Downstream targets of both ATM (Ataxia telangiectasia mutated) and ATR
      (ATM and Rad3-related) kinases were modified, but only the ablation of ATR, or
      the inhibition of CHK1, attenuated the arrest. The checkpoint activation was
      accompanied by the formation of nuclear foci containing the signaling and repair
      proteins ATR, the S(*)/T(*)Q substrate, gamma-H2AX, and replication protein A
      (RPA). The persistence of these foci implied that they may represent sites of
      irreparable damage.

PMID- 15175265
TI  - Signaling hierarchy downstream of retinoic acid that independently regulates
      vascular remodeling and endothelial cell proliferation.
AB  - We previously demonstrated that during vascular morphogenesis, retinoic acid (RA)
      is required for the control of endothelial cell proliferation and capillary
      plexus remodeling. Herein, we investigate the mechanisms by which RA regulates
      these processes in the yolk sac. We found that although the enzyme required for
      RA production during early embryogenesis, retinaldehyde dehydrogenase-2 (Raldh2),
      was expressed in the visceral endoderm, RA receptors alpha1 and alpha2 were
      expressed in endothelial cells in the mesoderm, indicating that they are direct
      targets of RA. In Raldh2(-/-) embryos, there was down-regulation of TGF-beta1,
      fibronectin (Fn) and integrin alpha5, which was associated with decreased
      visceral endoderm survival and production of VEGF-A, Indian hedgehog (IHH), and
      bFGF. Exogenous provision of RA or Fn to Raldh2(-/-) explants in whole mouse
      embryo culture restored vascular remodeling, visceral endoderm survival, as well
      as integrin alpha5 expression and its downstream signaling that controls
      endothelial growth. Exogenous provision of visceral endoderm-derived factors
      (VEGF-A, IHH, and bFGF) failed to rescue endothelial cell proliferative control
      but collectively promoted vascular remodeling, suggesting that these processes
      are independently regulated via a signaling hierarchy downstream of RA.

PMID- 15175266
TI  - Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous
      and intermittent infusion in liver transplant patients.
AB  - BACKGROUND: Drug pharmacokinetics may be altered during liver transplantation.
      Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent
      killing and therefore continuous infusion might have pharmacodynamic advantages.
      OBJECTIVES: To determine the pharmacokinetics of CTX and desacetylcefotaxime
      (DCTX) in serum, bile and urine during continuous and intermittent infusion when
      performing liver transplantation. METHODS: Fifteen patients undergoing liver
      transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h
      following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000
      mg iv four times daily). Samples were collected during the first 48 h after liver
      transplantation. Concentrations of CTX and DCTX were determined by HPLC. RESULTS:
      During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest
      serum concentration was 5 mg/L in the CI group and levels were undetectable in
      the BI group. Target serum concentrations of > or =4 mg/L were reached for 100%
      of the dosing interval during CI and approximately 60% during BI. Post
      operatively, the mean concentration in serum after CI was 26 mg/L. The lowest
      serum concentration was 8 mg/L in the CI group and levels were undetectable after
      BI. The peroperative pharmacokinetics of CTX in this patient group were deranged
      and variable, mainly caused by an increased volume of distribution and decreased
      hepatic clearance. Metabolism was hampered, but DCTX area under the curve
      (AUC)/CTX AUC ratios varying between 0.7-0.9 were reached peroperatively. Post
      operatively, DCTX AUC/CTX AUC ratios were higher (1.1-1.4). Unchanged CTX in bile
      was approximately 0.1% of the administered dose, leading to concentrations >4
      mg/L throughout the dosing interval for both regimens. CONCLUSION: Although an
      intermittent bolus infusion of CTX 1000 mg produces t > target concentration for
      60% of the dosing interval during liver transplantation, serum concentrations may
      be insufficient during the reperfusion phase. Continuous infusion overcomes this.
      Post-operatively, CTX clearance is impaired by decreased metabolic clearance and
      there is substantial accumulation of DCTX. In bile, sufficient concentrations of
      CTX and its active metabolite are reached with both regimens.

PMID- 15175267
TI  - Activity of ertapenem against Neisseria gonorrhoeae.

PMID- 15175268
TI  - Subinhibitory concentrations of florfenicol enhance the adherence of florfenicol
      susceptible and florfenicol-resistant Staphylococcus aureus.

PMID- 15175269
TI  - Resistance rates of Staphylococcus aureus in relation to patient status and type
      of specimen.
AB  - OBJECTIVES: The aim of this study was to assess the impact of data stratification
      on the resistance rates of Staphylococcus aureus, with emphasis on the value of
      blood culture-based resistance data. MATERIALS AND METHODS: All S. aureus
      isolates from patients in the Vienna University Hospital (2140 beds), isolated
      between 1/1996 and 12/2002, were stratified by patient status (ICU patient,
      regular inpatient, outpatient). Four kinds of specimen [blood, respiratory tract
      (RT), wounds and urine] were defined for analysis. Oxacillin and eight other
      compounds were considered. RESULTS: In total, 10,575 first isolates per patient
      were detected, derived from ICU patients (n=1464), inpatients (n=4152), and
      outpatients (n=4959). From blood, wounds, RT and urine, 610, 1464, 2716 and 3370
      first isolates per patient, respectively, were available. The blood-MRSA-rate
      (19.93%) was similar to the MRSA-rate of RT- (OR: 0.98, 95% CI: 0.76-1.25), wound
      (OR: 0.89, 95% CI: 0.71-1.12), and urine-isolates (OR: 0.91, 95% CI: 0.72-1.14).
      Isolates from inpatients (OR: 0.59, 95% CI: 0.47-0.74) and outpatients (OR: 0.16,
      95% CI: 0.13-0.21), regardless of the specimen, showed lower MRSA-rates than
      blood-isolates, in contrast to isolates from ICU patients (OR: 1.12, 95% CI: 0.87
      1.44). For other compounds, the resistance rates of blood-isolates were not
      always representative for RT- (six of eight rates similar), wound- (7/8), or
      urine-isolates (5/8). Most importantly, RT-, wound- and urine-isolates were
      significantly more often resistant to ciprofloxacin. Resistance rates of blood
      isolates were more representative for isolates from inpatients (five of eight
      rates similar) than from ICU patients or outpatients (each 3/8). CONCLUSIONS: The
      resistance rates of blood culture isolates enable a good overall assessment of
      the resistance of other clinically significant isolates. However, resistance data
      derived from selected specimens must not be equated with the overall resistance
      situation in the hospital.

PMID- 15175270
TI  - Molecular study of vancomycin-resistant enterococci isolated from humans and from
      food in a cattle-rearing area of France.
AB  - OBJECTIVES: Study possible links between vancomycin-resistant enterococci strains
      isolated from human stool samples and from pork or poultry food products.
      METHODS: One hundred and eleven vancomycin-resistant enterococci strains (15 VanA
      and 96 VanC) were isolated from human stool samples and from pork or poultry food
      products. Characterization of the Tn1546-like element of the 15 VanA strains was
      realized by restriction analysis of PCR products and polymorphism study. The 96
      strains of VanC phenotype (75 Enterococcus gallinarum and 21 Enterococcus
      casseliflavus) were analysed by pulsed-field gel electrophoresis (PFGE). RESULTS:
      In the study described here, polymorphism of the Tn1546-like element enabled the
      establishment of five groups. Groups III, IV and V were found only in human
      strains. Groups I and II were found to occur in strains isolated from humans and
      from food, suggesting a possible transfer of the Tn1546-like element. The
      isolates from Group I harboured the whole Tn1546 element. In Group II, the five
      strains possessed a novel Tn1546-like element, characterized by a single
      nucleotide difference in the vanX gene and a deletion upstream from the
      nucleotide 164. Analysis by PFGE of the 75 E. gallinarum strains revealed 20
      different patterns. One pattern was shared by isolates from pork food and human
      samples. None of the 21 E. casseliflavus strains tested was found to share
      similar PFGE patterns. CONCLUSIONS: Results tend to support the possible transfer
      of the Tn1546-like element between strains of VanA phenotype. Concerning VanC
      phenotype strains, the transfer was not demonstrated.

PMID- 15175271
TI  - Disposition of voriconazole during continuous veno-venous haemodiafiltration
      (CVVHDF) in a single patient.
AB  - OBJECTIVES: To determine whether voriconazole dosage adjustment is required
      during continuous veno-venous haemodiafiltration (CVVHDF). METHODS: Voriconazole
      pharmacokinetics were studied in a critically ill patient under CVVHDF. The
      analysis was carried out for 12 h following a 6 mg/kg dose. Voriconazole
      concentrations were measured by HPLC in blood inlet and outlet lines and in
      dialysate. RESULTS: The total body clearance of voriconazole was 20.3 L/h, with a
      terminal half-life of 13.7 h and a distribution volume of 399 L. The estimated
      sieving coefficient was 0.53 and the filtration-dialysis clearance 1.2 L/h.
      CONCLUSIONS: CVVHDF does not significantly affect voriconazole disposition and
      requires no dosage adjustment.

PMID- 15175272
TI  - The intranuclear localization and function of YT521-B is regulated by tyrosine
      phosphorylation.
AB  - YT521-B is a ubiquitously expressed nuclear protein that changes alternative
      splice site usage in a concentration dependent manner. YT521-B is located in a
      dynamic nuclear compartment, the YT body. We show that YT521-B is tyrosine
      phosphorylated by c-Abl in the nucleus. The protein shuttles between nucleus and
      cytosol, where it can be phosphorylated by c-Src or p59(fyn). Tyrosine
      phosphorylation causes dispersion of YT521-B from YT bodies to the nucleoplasm.
      Whereas YT bodies are soluble in non-denaturing buffers, the phosphorylated,
      dispersed form is non-soluble. Non-phosphorylated YT521-B changes alternative
      splice site selection of the IL-4 receptor, CD44 and SRp20, but phosphorylation
      of c-Abl minimizes this concentration dependent effect. We propose that tyrosine
      phosphorylation causes sequestration of YT521-B in an insoluble nuclear form,
      which abolishes the ability of YT521-B to change alternative splice sites.

PMID- 15175273
TI  - Variation in USF1 shows haplotype effects, gene : gene and gene : environment
      associations with glucose and lipid parameters in the European Atherosclerosis
      Research Study II.
AB  - Upstream stimulatory factor 1 (USF 1), is a transcription factor controlling
      expression of several genes involved in lipid and glucose homeostasis and co
      localizes with familial combined hyperlipidemia (FCHL) and type 2 diabetes on
      chromosome 1q22-23. We sequenced USF1 in 24 UK FCHL probands, but found no rare
      or common cSNPs. Three common intronic single nucleotide ploymorphisms (SNP),
      306A>G, 475C>T and 1748C>T, were identified and their association was examined
      with fasting and postprandial lipids and after an oral glucose tolerance test
      (OGTT) in the European Atherosclerosis Research Study II offspring study. There
      were no significant differences in allelic frequencies of the SNPs between cases
      and controls. Individually none of the SNPs showed significant associations with
      any parameter. In haplotype analysis, compared with other haplotypes, 475C/1748T
      showed significantly higher and 475T/1748T showed lower peak glucose (P=0.004 and
      0.07, respectively) during the OGTT. There was significant case-control
      heterogeneity in the interaction of genotype with body mass index, on fasting low
      density lipoprotein with 306A>G and 1748C>T, and on borderline significance with
      fasting glucose with 475C>T (P=0.002, 0.0007 and 0.015, respectively).
      Furthermore, 475C>T showed interaction with both HSL-60C>G (case-control
      heterogeneity P=0.0002) on AUC TG and APOC3 -482C>T on plasma apoE levels
      (P=0.0012). Thus, in these healthy young men, variation in USF1 was the
      influencing feature of both glucose and lipid homeostasis showing case-control
      heterogeneity.

PMID- 15175274
TI  - Comparative high-resolution analysis of linkage disequilibrium and tag single
      nucleotide polymorphisms between populations in the vitamin D receptor gene.
AB  - A genome-wide map of single nucleotide polymorphisms (SNP) and a pattern of
      linkage disequilibrium (LD) between their alleles are being established in three
      main ethnic groups. An important question is the applicability of such maps to
      different populations within a main ethnic group. Therefore, we have developed
      high-resolution SNP, haplotype and LD maps of vitamin D receptor gene region in
      large samples from five populations. Comparative analysis reveals that the LD
      patterns are identical in all four European populations tested with two small
      regions of 1.3 and 5.7 kb at which LD is disrupted completely resulting in three
      block-like regions over which there is significant and extensive LD. In an
      African population the pattern is similar, but two additional LD-breaking spots
      are also apparent. This LD pattern suggests combined action of recombination
      hotspots and founder effects, but cannot be explained by random recombination and
      genetic drift alone. Direct comparison indicates that the tag SNPs selected in
      one European population effectively predict the non-tag SNPs in the other
      Europeans, but not in the Gambians, for this region.

PMID- 15175275
TI  - Ezrin-dependent regulation of the actin cytoskeleton by beta-dystroglycan.
AB  - Dystroglycan is part of an adhesion receptor complex linking the extracellular
      matrix to the actin cytoskeleton. Previous studies have implicated dystroglycan
      in basement membrane formation and as a crucial link between dystrophin and
      laminin in muscle. We report here a further novel function for dystroglycan which
      appears to be in addition to its role as an adhesion molecule. beta-dystroglycan
      has been localized to microvilli structures in a number of cell types where it
      associates with the cytoskeletal adaptor ezrin, through which it is able to
      modulate the actin cytoskeleton and induce peripheral filopodia and microvilli.
      Ezrin is able to interact with dystroglycan through a cluster of basic residues
      in the juxtamembrane region of dystroglycan, and mutation of these residues both
      prevents ezrin binding and the induction of actin-rich surface protrusions. These
      studies reveal novel functions and additional signalling roles for dystroglycan,
      raising the possibility of new avenues for therapeutic intervention in diseases
      such as Duchenne muscular dystrophy.

PMID- 15175276
TI  - The transforming growth factor-beta1 (TGFB1) gene is associated with chronic
      obstructive pulmonary disease (COPD).
AB  - Although cigarette smoking is the primary environmental risk factor, genetic risk
      factors likely influence the development of chronic obstructive pulmonary disease
      (COPD). Linkage analysis between short-tandem repeat markers on chromosome 19 and
      COPD phenotypes was followed by association analysis of single nucleotide
      polymorphisms in a gene on chromosome 19q [transforming growth factor-beta1
      (TGFB1)] and COPD phenotypes in a family-based sample and a case-control study
      (cases with severe COPD and control subjects with significant history of smoking
      but no COPD). Stratification by smoking status substantially improved the
      evidence of linkage to chromosome 19q for COPD phenotypes. Among former and
      current smokers in the Boston Early-Onset COPD Study, there was significant
      evidence of linkage between chromosome 19q and pre-bronchodilator (pre-BD) FEV(1)
      (LOD=3.30) and suggestive evidence of linkage between chromosome 19q and other
      COPD phenotypes. In these families, a SNP in the promoter region of TGFB1
      (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957)
      were significantly associated with pre- and post-BD FEV(1) (P<0.05). Among
      smokers in the COPD cases and control subjects, two SNPs in the promoter region
      of TGFB1 (rs2241712 and rs1800469) and one SNP in exon 1 of TGFB1 (rs1982073)
      were significantly associated with COPD (P</=0.02 in all cases). Chromosome 19q
      likely contains a genetic locus (or loci) that influences COPD through an
      interaction with cigarette smoking. We hypothesize that genetic variants in or
      near the TGFB1 gene influence the pathogenesis of COPD among cigarette smokers.

PMID- 15175277
TI  - Occupancy and synergistic activation of the FMR1 promoter by Nrf-1 and Sp1 in
      vivo.
AB  - Fragile X syndrome is due to mutation of the FMR1 gene. The most common mutation
      is an expansion of a CGG repeat in the 5' UTR that triggers dense DNA methylation
      and formation of a heterochromatin-like structure which lead to transcriptional
      silencing. In vitro experiments have identified several transcription factors,
      including Sp1, Nrf-1 and USF1/2, as potential regulators of normal FMR1 promoter
      activity. Using CpG methylation-deficient Drosophila cells, we demonstrate in
      vivo that Nrf-1 and Sp1 are strong, synergistic activators of an unmethylated
      human FMR1-driven reporter, while USF1/2 and Max repress this activation. In
      addition, analyses of transcription factor activity upon DNA methylation of the
      reporter show that Sp1 activity was largely intact when the promoter was densely
      methylated, but Nrf-1 transactivation was very sensitive to dense methylation.
      Notably, Nrf-1 transactivation was relatively insensitive to methylation of
      cytosines only at its binding site. FMR1 reporter activity is also reduced in
      HeLa cells after expression of a short interfering RNA directed against
      endogenous Nrf-1. Using chromatin immunoprecipitation, we demonstrate directly
      that Sp1 and Nrf-1 occupy the human FMR1 promoter in vivo and these interactions
      are disrupted in fragile X patient cells. In addition, we discover that Max
      resides at the FMR1 promoter and show that USF1/2 but not c-Myc are present at
      endogenous FMR1. These findings provide the first direct in vivo evidence
      identifying the specific transcription factors that regulate FMR1.

PMID- 15175278
TI  - An alternative strategy for adaptation in bacterial behavior.

PMID- 15175279
TI  - Reciprocal regulation of bioluminescence and type III protein secretion in Vibrio
      harveyi and Vibrio parahaemolyticus in response to diffusible chemical signals.

PMID- 15175280
TI  - Phage-host interaction: an ecological perspective.

PMID- 15175281
TI  - Cellular stoichiometry of the components of the chemotaxis signaling complex.
AB  - The chemotactic sensory system of Escherichia coli comprises membrane-embedded
      chemoreceptors and six soluble chemotaxis (Che) proteins. These components form
      signaling complexes that mediate sensory excitation and adaptation. Previous
      determinations of cellular content of individual components provided differing
      and apparently conflicting values. We used quantitative immunoblotting to perform
      comprehensive determinations of cellular amounts of all components in two E. coli
      strains considered wild type for chemotaxis, grown in rich and minimal media.
      Cellular amounts varied up to 10-fold, but ratios between proteins varied no more
      than 30%. Thus, cellular stoichiometries were almost constant as amounts varied
      substantially. Calculations using those cellular stoichiometries and values for
      in vivo proportions of core components in complexes yielded an in vivo
      stoichiometry for core complexes of 3.4 receptor dimers and 1.6 CheW monomers for
      each CheA dimer and 2.4 CheY, 0.5 CheZ dimers, 0.08 CheB, and 0.05 CheR per
      complex. The values suggest a core unit of a trimer of chemoreceptor dimers, a
      dimer (or two monomers) of kinase CheA, and two CheW. These components may
      interact in extended arrays and, thus, stoichiometries could be nonintegral. In
      any case, cellular stoichiometries indicate that CheY could be bound to all
      signaling complexes and this binding would recruit essentially the entire
      cellular complement of unphosphorylated CheY, and also that phosphatase CheZ,
      methylesterase CheB, and methyltransferase CheR would be present at 1 per 2, per
      14, and per 20 core complexes, respectively. These characteristic ratios will be
      important in quantitative treatments of chemotaxis, both experimental and
      theoretical.

PMID- 15175282
TI  - Identification of mdoD, an mdoG paralog which encodes a twin-arginine-dependent
      periplasmic protein that controls osmoregulated periplasmic glucan backbone
      structures.
AB  - Osmoregulated periplasmic glucans (OPGs) of Escherichia coli are anionic and
      highly branched oligosaccharides that accumulate in the periplasmic space in
      response to low osmolarity of the medium. The glucan length, ranging from 5 to 12
      glucose residues, is under strict control. Two genes that form an operon, mdoGH,
      govern glucose backbone synthesis. The new gene mdoD, which appears to be a
      paralog of mdoG, was characterized in this study. Cassette inactivation of mdoD
      resulted in production of OPGs with a higher degree of polymerization, indicating
      that OpgD, the mdoD product (according to the new nomenclature), controls the
      glucose backbone structures. OpgD secretion depends on the Tat secretory pathway.
      Orthologs of the mdoG and mdoD genes are found in various proteobacteria. Most of
      the OpgD orthologs exhibit a Tat-dependent secretion signal, while most of the
      OpgG orthologs are Sec dependent.

PMID- 15175283
TI  - The decrease in FlaA observed in a flaB mutant of Borrelia burgdorferi occurs
      posttranscriptionally.
AB  - The Lyme disease bacterium Borrelia burgdorferi is a motile spirochete with a
      flat-wave morphology. The periplasmic flagella, which are situated between the
      outer membrane sheath and cell cylinder, are essential for both the cell's wavy
      shape and motility. Here we focus on the structure and regulation of its
      periplasmic flagella. Previous studies have suggested that the periplasmic
      flagella consist of a polymer of the major filament protein FlaB and a minor
      protein, FlaA. We used immunoprecipitation methodology to present further
      evidence that FlaA is indeed a flagellar protein. In addition, in contrast to
      FlaA of the spirochete Brachyspira hyodysenteriae, B. burgdorferi FlaA did not
      impact the overall helical shape of the periplasmic flagella. We have previously
      shown that B. burgdorferi lacks the sigma factor-dependent cascade control of
      motility gene transcription found in other bacteria. To begin to understand
      motility gene regulation in B. burgdorferi, we examined the effects of an
      insertion mutation in flaB on the amounts of proteins encoded by motility genes.
      Of several motility gene-encoded proteins examined, only the amount of FlaA was
      decreased in the flaB mutant; it was 13% compared to the wild-type amount. Real
      time reverse transcriptase PCR analysis indicated that this inhibition was not
      the result of a decrease in flaA mRNA. In addition, protein stability analysis
      suggested that FlaA was turned over in the flaB mutant. Our results indicate that
      the lack of FlaB negatively influences the amount of FlaA found in the cell and
      that this effect is at the level of either translational control or protein
      turnover.

PMID- 15175285
TI  - A homologue of aliB is found in the capsule region of nonencapsulated
      Streptococcus pneumoniae.
AB  - The epidemiology, phylogeny, and biology of nonencapsulated Streptococcus
      pneumoniae are largely unknown. Increased colonization capacity and
      transformability are, however, intriguing features of these pneumococci and play
      an important role. Twenty-seven nonencapsulated pneumococci were identified in a
      nationwide collection of 1,980 nasopharyngeal samples and 215 blood samples
      obtained between 1998 and 2002. On the basis of multilocus sequence typing and
      capsule region analysis we divided the nonencapsulated pneumococci into two
      groups. Group I was closely related to encapsulated strains. Group II had a
      clonal population structure, including two geographically widespread clones able
      to cause epidemic conjunctivitis and invasive diseases. Group II strains also
      carried a 1,959-bp homologue of aliB (aliB-like ORF 2) in the capsule region,
      which was highly homologous to a sequence in the capsule region of Streptococcus
      mitis. In addition, strains of the two major clones in group II had an additional
      sequence, aliB-like ORF 1 (1,968 to 2,004 bp), upstream of aliB-like ORF 2.
      Expression of aliB-like ORF 1 was detected by reverse transcription-PCR, and the
      corresponding RNA was visualized by Northern blotting. A gene fragment homologous
      to capN of serotypes 33 and 37 suggests that group II strains were derived from
      encapsulated pneumococci some time ago. Therefore, loss of capsule expression in
      vivo was found to be associated with the importation of one or two aliB
      homologues in some nonencapsulated pneumococci.

PMID- 15175284
TI  - The type II protein secretion system of Legionella pneumophila promotes growth at
      low temperatures.
AB  - The gram-negative bacterium Legionella pneumophila grows in both natural and man
      made water systems and in the mammalian lung as a facultative intracellular
      parasite. The PilD prepilin peptidase of L. pneumophila promotes type IV pilus
      biogenesis and type II protein secretion. Whereas pili enhance adherence,
      Legionella type II secretion is critical for intracellular growth and virulence.
      Previously, we observed that pilD transcript levels are greater in legionellae
      grown at 30 versus 37 degrees C. Using a new pilD::lacZ fusion strain, we now
      show that pilD transcriptional initiation increases progressively as L.
      pneumophila is grown at 30, 25, and 17 degrees C. Legionella pilD mutants also
      had a dramatically reduced ability to grow in broth and to form colonies on agar
      at the lower temperatures. Whereas strains specifically lacking type IV pili were
      not defective for low-temperature growth, mutations in type II secretion (lsp)
      genes greatly impaired the capacity of L. pneumophila to form colonies at 25, 17,
      and 12 degrees C. Indeed, the lsp mutants were completely unable to grow at 12
      degrees C. The growth defect of the pilD and lsp mutants was complemented by
      reintroduction of the corresponding intact gene. Interestingly, the lsp mutants
      displayed improved growth at 25 degrees C when plated next to a streak of wild
      type but not mutant bacteria, implying that a secreted, diffusible factor
      promotes low-temperature growth. Mutants lacking either the known secreted acid
      phosphatases, lipases, phospholipase C, lysophospholipase A, or protease grew
      normally at 25 degrees C, suggesting the existence of a critical, yet-to-be
      defined exoprotein(s). In summary, these data document, for the first time, that
      L. pneumophila replicates at temperatures below 20 degrees C and that a bacterial
      type II protein secretion system facilitates growth at low temperatures.

PMID- 15175286
TI  - Methylation-independent aerotaxis mediated by the Escherichia coli Aer protein.
AB  - Aer is a membrane-associated protein that mediates aerotactic responses in
      Escherichia coli. Its C-terminal half closely resembles the signaling domains of
      methyl-accepting chemotaxis proteins (MCPs), which undergo reversible methylation
      at specific glutamic acid residues to adapt their signaling outputs to
      homogeneous chemical environments. MCP-mediated behaviors are dependent on two
      specific enzymes, CheR (methyltransferase) and CheB (methylesterase). The Aer
      signaling domain contains unorthodox methylation sites that do not conform to the
      consensus motif for CheR or CheB substrates, suggesting that Aer, unlike
      conventional MCPs, might be a methylation-independent transducer. Several lines
      of evidence supported this possibility. (i) The Aer protein was not detectably
      modified by either CheR or CheB. (ii) Amino acid replacements at the putative Aer
      methylation sites generally had no deleterious effect on Aer function. (iii) Aer
      promoted aerotactic migrations on semisolid media in strains that lacked all four
      of the E. coli MCPs. CheR and CheB function had no influence on the rate of
      aerotactic movements in those strains. Thus, Aer senses and signals efficiently
      in the absence of deamidation or methylation, methylation changes, methylation
      enzymes, and methyl-accepting chemotaxis proteins. We also found that chimeric
      transducers containing the PAS-HAMP sensing domain of Aer joined to the signaling
      domain and methylation sites of Tar, an orthodox MCP, exhibited both methylation
      dependent and methylation-independent aerotactic behavior. The hybrid Aear
      transducers demonstrate that methylation independence does not emanate from the
      Aer signaling domain but rather may be due to transience of the cellular redox
      changes that are thought to trigger Aer-mediated behavioral responses.

PMID- 15175287
TI  - Regulatory elements of the Staphylococcus aureus protein A (Spa) promoter.
AB  - Staphylococcal protein A (Spa) is an important virulence factor of Staphylococcus
      aureus. Transcription of the spa determinant occurs during the exponential growth
      phase and is repressed when the cells enter the postexponential growth phase.
      Regulation of spa expression has been found to be complicated, with regulation
      involving multiple factors, including Agr, SarA, SarS, SarT, Rot, and MgrA. Our
      understanding of how these factors work on the spa promoter to regulate spa
      expression is incomplete. To identify regulatory sites within the spa promoter,
      analysis of deletion derivatives of the promoter in host strains deficient in one
      or more of the regulatory factors was undertaken, and several critical features
      of spa regulation were revealed. The transcriptional start sites of spa were
      determined by primer extension. The spa promoter sequences were subcloned in
      front of a promoterless chloramphenicol acetyltransferase reporter gene. Various
      lengths of spa truncations with the same 3' end were constructed, and the
      resultant plasmids were transduced into strains with different regulatory genetic
      backgrounds. Our results identified upstream promoter sequences necessary for Agr
      system regulation of spa expression. The cis elements for SarS activity, an
      activator of spa expression, and for SarA activity, a repressor of spa
      expression, were identified. The well-characterized SarA consensus sequence on
      the spa promoter was found to be insufficient for SarA repression of the spa
      promoter. Full repression required the presence of a second consensus site
      adjacent to the SarS binding site. Sequences directly upstream of the core
      promoter sequence were found to stimulate transcription.

PMID- 15175288
TI  - Characterization and functional analysis of the poxB gene, which encodes pyruvate
      oxidase in Lactobacillus plantarum.
AB  - The pyruvate oxidase gene (poxB) from Lactobacillus plantarum Lp80 was cloned and
      characterized. Northern blot and primer extension analyses revealed that
      transcription of poxB is monocistronic and under the control of a vegetative
      promoter. poxB mRNA expression was strongly induced by aeration and was repressed
      by glucose. Moreover, Northern blotting performed at different stages of growth
      showed that poxB expression is maximal in the early stationary phase when glucose
      is exhausted. Primer extension and in vivo footprint analyses revealed that
      glucose repression of poxB is mediated by CcpA binding to the cre site identified
      in the promoter region. The functional role of the PoxB enzyme was studied by
      using gene overexpression and knockout in order to evaluate its implications for
      acetate production. Constitutive overproduction of PoxB in L. plantarum revealed
      the predominant role of pyruvate oxidase in the control of acetate production
      under aerobic conditions. The DeltapoxB mutant strain exhibited a moderate (20 to
      25%) decrease in acetate production when it was grown on glucose as the carbon
      source, and residual pyruvate oxidase activity that was between 20 and 85% of the
      wild-type activity was observed with glucose limitation (0.2% glucose). In
      contrast, when the organism was grown on maltose, the poxB mutation resulted in a
      large (60 to 80%) decrease in acetate production. In agreement with the latter
      observation, the level of residual pyruvate oxidase activity with maltose
      limitation (0.2% maltose) was less than 10% of the wild-type level of activity.

PMID- 15175289
TI  - Membrane restructuring by Bordetella pertussis adenylate cyclase toxin, a member
      of the RTX toxin family.
AB  - Adenylate cyclase toxin (ACT) is secreted by Bordetella pertussis, the bacterium
      causing whooping cough. ACT is a member of the RTX (repeats in toxin) family of
      toxins, and like other members in the family, it may bind cell membranes and
      cause disruption of the permeability barrier, leading to efflux of cell contents.
      The present paper summarizes studies performed on cell and model membranes with
      the aim of understanding the mechanism of toxin insertion and membrane
      restructuring leading to release of contents. ACT does not necessarily require a
      protein receptor to bind the membrane bilayer, and this may explain its broad
      range of host cell types. In fact, red blood cells and liposomes (large
      unilamellar vesicles) display similar sensitivities to ACT. A varying liposomal
      bilayer composition leads to significant changes in ACT-induced membrane lysis,
      measured as efflux of fluorescent vesicle contents. Phosphatidylethanolamine
      (PE), a lipid that favors formation of nonlamellar (inverted hexagonal) phases,
      stimulated ACT-promoted efflux. Conversely, lysophosphatidylcholine, a micelle
      forming lipid that opposes the formation of inverted nonlamellar phases,
      inhibited ACT-induced efflux in a dose-dependent manner and neutralized the
      stimulatory effect of PE. These results strongly suggest that ACT-induced efflux
      is mediated by transient inverted nonlamellar lipid structures. Cholesterol, a
      lipid that favors inverted nonlamellar phase formation and also increases the
      static order of phospholipid hydrocarbon chains, among other effects, also
      enhanced ACT-induced liposomal efflux. Moreover, the use of a recently developed
      fluorescence assay technique allowed the detection of trans-bilayer (flip-flop)
      lipid motion simultaneous with efflux. Lipid flip-flop further confirms the
      formation of transient nonlamellar lipid structures as a result of ACT insertion
      in bilayers.

PMID- 15175291
TI  - Functional dissection of Escherichia coli trigger factor: unraveling the function
      of individual domains.
AB  - In Escherichia coli, the ribosome-associated chaperone Trigger Factor (TF)
      promotes the folding of newly synthesized cytosolic proteins. TF is composed of
      three domains: an N-terminal domain (N), which mediates ribosome binding; a
      central domain (P), which has peptidyl-prolyl cis/trans isomerase activity and is
      involved in substrate binding in vitro; and a C-terminal domain (C) with unknown
      function. We investigated the contributions of individual domains (N, P, and C)
      or domain combinations (NP, PC, and NC) to the chaperone activity of TF in vivo
      and in vitro. All fragments comprising the N domain (N, NP, NC) complemented the
      synthetic lethality of Deltatig DeltadnaK in cells lacking TF and DnaK, prevented
      protein aggregation in these cells, and cross-linked to nascent polypeptides in
      vitro. However, DeltatigDeltadnaK cells expressing the N domain alone grew more
      slowly and showed less viability than DeltatigDeltadnaK cells synthesizing either
      NP, NC, or full-length TF, indicating beneficial contributions of the P and C
      domains to TF's chaperone activity. In an in vitro system with purified
      components, none of the TF fragments assisted the refolding of denatured d
      glyceraldehyde-3-phosphate dehydrogenase in a manner comparable to that of wild
      type TF, suggesting that the observed chaperone activity of TF fragments in vivo
      is dependent on their localization at the ribosome. These results indicate that
      the N domain, in addition to its function to promote binding to the ribosome, has
      a chaperone activity per se and is sufficient to substitute for TF in vivo.

PMID- 15175290
TI  - Mutational analysis of the Myxococcus xanthus Omicron4499 promoter region reveals
      shared and unique properties in comparison with other C-signal-dependent
      promoters.
AB  - The bacterium Myxococcus xanthus undergoes multicellular development during times
      of nutritional stress and uses extracellular signals to coordinate cell behavior.
      C-signal affects gene expression late in development, including that of
      Omega4499, an operon identified by insertion of Tn5 lac into the M. xanthus
      chromosome. The Omega4499 promoter region has several sequences in common with
      those found previously to be important for expression of other C-signal-dependent
      promoters. To determine if these sequences are important for Omega4499 promoter
      activity, the effects of mutations on expression of a downstream reporter gene
      were tested in M. xanthus. Although the promoter resembles those recognized by
      Escherichia coli sigma(54), mutational analysis implied that a sigma(70)-type
      sigma factor likely recognizes the promoter. A 7-bp sequence known as a C box and
      a 5-bp element located 6 bp upstream of the C box have been shown to be important
      for expression of other C-signal-dependent promoters. The Omega4499 promoter
      region has C boxes centered at -33 and -55 bp, with 5-bp elements located 7 and 8
      bp upstream, respectively. A multiple-base-pair mutation in any of these
      sequences reduced Omega4499 promoter activity more than twofold. Single base-pair
      mutations in the C box centered at -33 bp yielded a different pattern of effects
      on expression than similar mutations in other C boxes, indicating that each
      functions somewhat differently. An element from about -81 to -77 bp exerted a
      twofold positive effect on expression but did not appear to be responsible for
      the C-signal dependence of the Omega4499 promoter. Mutations in sigD and sigE,
      which are genes that encode sigma factors, reduced expression from the Omega4499
      promoter. The results provide further insight into the regulation of C-signal
      dependent genes, demonstrating both shared and unique properties among the
      promoter regions so far examined.

PMID- 15175292
TI  - Role of RepA and DnaA proteins in the opening of the origin of DNA replication of
      an IncB plasmid.
AB  - The replication initiator protein RepA of the IncB plasmid pMU720 was shown to
      induce localized unwinding of its cognate origin of replication in vitro. DnaA,
      the initiator protein of Escherichia coli, was unable to induce localized
      unwinding of this origin of replication on its own but enhanced the opening
      generated by RepA. The opened region lies immediately downstream of the last of
      the three binding sites for RepA (RepA boxes) and covers one turn of DNA helix. A
      6-mer sequence, 5'-TCTTAA-3', which lies within the opened region, was essential
      for the localized unwinding of the origin in vitro and origin activity in vivo.
      In addition, efficient unwinding of the origin of replication of pMU720 in vitro
      required the native positioning of the binding sites for the initiator proteins.
      Interestingly, binding of RepA to RepA box 1, which is essential for origin
      activity, was not required for the localized opening of the origin in vitro.

PMID- 15175293
TI  - Quorum sensing regulates type III secretion in Vibrio harveyi and Vibrio
      parahaemolyticus.
AB  - In a process known as quorum sensing, bacteria communicate with one another by
      producing, releasing, detecting, and responding to signal molecules called
      autoinducers. Vibrio harveyi, a marine pathogen, uses two parallel quorum-sensing
      circuits, each consisting of an autoinducer-sensor pair, to control the
      expression of genes required for bioluminescence and a number of other target
      genes. Genetic screens designed to discover autoinducer-regulated targets in V.
      harveyi have revealed genes encoding components of a putative type III secretion
      (TTS) system. Using transcriptional reporter fusions and TTS protein localization
      studies, we show that the TTS system is indeed functional in V. harveyi and that
      expression of the genes encoding the secretion machinery requires an intact
      quorum-sensing signal transduction cascade. The newly completed genome of the
      closely related marine bacterium Vibrio parahaemolyticus, which is a human
      pathogen, shows that it possesses the genes encoding both of the V. harveyi-like
      quorum-sensing signaling circuits and that it also has a TTS system similar to
      that of V. harveyi. We show that quorum sensing regulates TTS in V.
      parahaemolyticus. Previous reports connecting quorum sensing to TTS in
      enterohemorrhagic and enteropathogenic Escherichia coli show that quorum sensing
      activates TTS at high cell density. Surprisingly, we find that at high cell
      density (in the presence of autoinducers), quorum sensing represses TTS in V.
      harveyi and V. parahaemolyticus.

PMID- 15175295
TI  - Regulation of hypercompetence in Legionella pneumophila.
AB  - Although many bacteria are known to be naturally competent for DNA uptake, this
      ability varies dramatically between species and even within a single species,
      some isolates display high levels of competence while others seem to be
      completely nontransformable. Surprisingly, many nontransformable bacterial
      strains appear to encode components necessary for DNA uptake. We believe that
      many such strains are actually competent but that this ability has been
      overlooked because standard laboratory conditions are inappropriate for
      competence induction. For example, most strains of the gram-negative bacterium
      Legionella pneumophila are not competent under normal laboratory conditions of
      aerobic growth at 37 degrees C. However, it was previously reported that
      microaerophilic growth at 37 degrees C allows L. pneumophila serogroup 1 strain
      AA100 to be naturally transformed. Here we report that another L. pneumophila
      serogroup 1 strain, Lp02, can also be transformed under these conditions.
      Moreover, Lp02 can be induced to high levels of competence by a second set of
      conditions, aerobic growth at 30 degrees C. In contrast to Lp02, AA100 is only
      minimally transformable at 30 degrees C, indicating that Lp02 is hypercompetent
      under these conditions. To identify potential causes of hypercompetence, we
      isolated mutants of AA100 that exhibited enhanced DNA uptake. Characterization of
      these mutants revealed two genes, proQ and comR, that are involved in regulating
      competence in L. pneumophila. This approach, involving the isolation of
      hypercompetent mutants, shows great promise as a method for identifying natural
      transformation in bacterial species previously thought to be nontransformable.

PMID- 15175294
TI  - The type III secreted protein BopD in Bordetella bronchiseptica is complexed with
      BopB for pore formation on the host plasma membrane.
AB  - The cytotoxicity of Bordetella bronchiseptica to infected cells is known to be
      dependent on a B. bronchiseptica type III secretion system. Although BopB, BopN,
      BopD, and Bsp22 have been identified as type III secreted proteins, these
      proteins remain to be characterized. In this study, in order to clarify the
      function of BopD during Bordetella infection, a BopD mutant was generated.
      Although secretion of BopD into the culture supernatant was completely abolished
      by the bopD mutation, the secretion of other type III secreted proteins was not
      affected by this mutation. It has been reported that severe cytotoxicity,
      including cell detachment from the substrata, and release of lactate
      dehydrogenase (LDH) into the supernatant are induced in L2 cells by wild-type B.
      bronchiseptica infection, and these phenotypes are dependent on the type III
      secretion system. In contrast, neither cell detachment nor LDH release was
      induced in L2 cells infected with the BopD mutant. Furthermore, the hemolytic
      activity of the BopD mutant was greatly impaired compared with that of the wild
      type strain. On the basis of the results of coimmunoprecipitation assays with
      anti-BopB antibodies, we conclude that BopD has the ability to associate with
      BopB. Finally, we show that the BopD-BopB complex is responsible for the pore
      formation in the host plasma membrane that functions as the conduit for the
      transition of effector proteins into host cells.

PMID- 15175296
TI  - Genetic characterization of a multicomponent signal transduction system
      controlling the expression of cable pili in Burkholderia cenocepacia.
AB  - Cable pili are peritrichous organelles expressed by certain strains of
      Burkholderia cenocepacia, believed to facilitate colonization of the lower
      respiratory tract in cystic fibrosis patients. The B. cenocepacia cblBACDS operon
      encodes the structural and accessory proteins required for the assembly of cable
      pili, as well as a gene designated cblS, predicted to encode a hybrid sensor
      kinase protein of bacterial two-component signal transduction systems. In this
      study we report the identification of two additional genes, designated cblT and
      cblR, predicted to encode a second hybrid sensor kinase and a response regulator,
      respectively. Analyses of the deduced amino acid sequences of the cblS and cblT
      gene products revealed that both putative sensor kinases have transmitter and
      receiver domains and that the cblT gene product has an additional C-terminal HPt
      domain. Mutagenesis of the cblS, cblT, or cblR gene led to a block in expression
      of CblA, the major pilin subunit, and a severe decrease in cblA transcript
      abundance. Using transcriptional fusion analyses, the decrease in the abundance
      of the cblA transcript in the cblS, cblT, and cblR mutants was shown to be due to
      a block in transcription from the cblB-proximal promoter, located upstream of the
      cblBACDS operon. Furthermore, ectopic expression of either cblS or cblR in wild
      type B. cenocepacia strain BC7 led to a significant increase, while ectopic
      expression of cblT resulted in a dramatic decrease, in abundance of the CblA
      major pilin and the cblA transcript. Our results demonstrate that the B.
      cenocepacia cblS, cblT, and cblR genes are essential for cable pilus expression
      and that their effect is exerted at the level of transcription of the cblBACDS
      operon. These findings are consistent with the proposed function of the cblSTR
      gene products as a multicomponent signal transduction pathway controlling the
      expression of cable pilus biosynthetic genes in B. cenocepacia.

PMID- 15175297
TI  - Expression analysis of a highly adherent and cytotoxic small colony variant of
      Pseudomonas aeruginosa isolated from a lung of a patient with cystic fibrosis.
AB  - The heterogeneous environment of the lung of the cystic fibrosis (CF) patient
      gives rise to Pseudomonas aeruginosa small colony variants (SCVs) with increased
      antibiotic resistance, autoaggregative growth behavior, and an enhanced ability
      to form biofilms. In this study, oligonucleotide DNA microarrays were used to
      perform a genome-wide expression study of autoaggregative and highly adherent P.
      aeruginosa SCV 20265 isolated from a CF patient's lung in comparison with its
      clonal wild type and a revertant generated in vitro from the SCV population. Most
      strikingly, SCV 20265 showed a pronounced upregulation of the type III protein
      secretion system (TTSS) and the respective effector proteins. This differential
      expression was shown to be biologically meaningful, as SCV 20265 and other
      hyperpiliated and autoaggregative SCVs with increased TTSS expression were
      significantly more cytotoxic for macrophages in vitro and were more virulent in a
      mouse model of respiratory tract infection than the wild type. The observed
      cytotoxicity and virulence of SCV 20265 required exsA, an important
      transcriptional activator of the TTSS. Thus, the prevailing assumption that P.
      aeruginosa is subject to selection towards reduced cytotoxicity and attenuated
      virulence during chronic CF lung infection might not apply to all clonal
      variants.

PMID- 15175298
TI  - The arginine regulatory protein mediates repression by arginine of the operons
      encoding glutamate synthase and anabolic glutamate dehydrogenase in Pseudomonas
      aeruginosa.
AB  - The arginine regulatory protein of Pseudomonas aeruginosa, ArgR, is essential for
      induction of operons that encode enzymes of the arginine succinyltransferase
      (AST) pathway, which is the primary route for arginine utilization by this
      organism under aerobic conditions. ArgR also induces the operon that encodes a
      catabolic NAD(+)-dependent glutamate dehydrogenase (GDH), which converts l
      glutamate, the product of the AST pathway, in alpha-ketoglutarate. The studies
      reported here show that ArgR also participates in the regulation of other enzymes
      of glutamate metabolism. Exogenous arginine repressed the specific activities of
      glutamate synthase (GltBD) and anabolic NADP-dependent GDH (GdhA) in cell
      extracts of strain PAO1, and this repression was abolished in an argR mutant. The
      promoter regions of the gltBD operon, which encodes GltBD, and the gdhA gene,
      which encodes GdhA, were identified by primer extension experiments. Measurements
      of beta-galactosidase expression from gltB::lacZ and gdhA::lacZ translational
      fusions confirmed the role of ArgR in mediating arginine repression. Gel
      retardation assays demonstrated the binding of homogeneous ArgR to DNA fragments
      carrying the regulatory regions for the gltBD and gdhA genes. DNase I
      footprinting experiments showed that ArgR protects DNA sequences in the control
      regions for these genes that are homologous to the consensus sequence of the ArgR
      binding site. In silica analysis of genomic information for P. fluorescens, P.
      putida, and P. stutzeri suggests that the findings reported here regarding ArgR
      regulation of operons that encode enzymes of glutamate biosynthesis in P.
      aeruginosa likely apply to other pseudomonads.

PMID- 15175299
TI  - Transcriptome analysis of the ArgR regulon in Pseudomonas aeruginosa.
AB  - Arginine metabolism in pseudomonads with multiple catabolic pathways for its
      utilization as carbon and nitrogen sources is of particular interest as the model
      system to study control of metabolic integration. We performed transcriptome
      analyses to identify genes controlled by the arginine regulatory protein ArgR and
      to better understand arginine metabolic pathways of P. aeruginosa. We compared
      gene expression in wild-type strain PAO1 with that in argR mutant strain PAO501
      grown in glutamate minimal medium in the presence and absence of arginine. Ten
      putative transcriptional units of 28 genes were inducible by ArgR and arginine,
      including all known ArgR-regulated operons under aerobic conditions. The newly
      identified genes include the putative adcAB operon, which encodes a catabolic
      arginine decarboxylase and an antiporter protein, and PA0328, which encodes a
      hypothetical fusion protein of a peptidase and a type IV autotransporter. Also
      identified as members of the arginine network are the following solute transport
      systems: PA1971 (braZ) for branched-chain amino acids permease; PA2042 for a
      putative sodium:serine symporter; PA3934, which belongs to the family of small
      oligopeptide transporters; and PA5152-5155, which encodes components of an ABC
      transporter for a putative opine uptake system. The effect of arginine on the
      expression of these genes was confirmed by lacZ fusion studies and by DNA binding
      studies with purified ArgR. Only five transcriptional units of nine genes were
      qualified as repressible by ArgR and arginine, with three operons (argF, carAB,
      and argG) in arginine biosynthesis and two operons (gltBD and gdhA) in glutamate
      biosynthesis. These results indicate that ArgR is important in control of
      arginine and glutamate metabolism and that arginine and ArgR may have a redundant
      effect in inducing the uptake systems of certain compounds.

PMID- 15175300
TI  - Detection and characterization of conjugative degradative plasmids in xenobiotic
      degrading Sphingomonas strains.
AB  - A systematic survey for the presence of plasmids in 17 different xenobiotic
      degrading Sphingomonas strains was performed. In almost all analyzed strains, two
      to five plasmids with sizes of about 50 to 500 kb were detected by using pulsed
      field gel electrophoresis. A comparison of plasmid preparations untreated or
      treated with S1 nuclease suggested that, in general, Sphingomonas plasmids are
      circular. Hybridization experiments with labeled gene probes suggested that large
      plasmids are involved in the degradation of dibenzo-p-dioxin, dibenzofuran, and
      naphthalenesulfonates in S. wittichii RW1, Sphingomonas sp. HH69, and S.
      xenophaga BN6, respectively. The plasmids which are responsible for the
      degradation of naphthalene, biphenyl, and toluene by S. aromaticivorans F199
      (pNL1) and of naphthalenesulfonates by S. xenophaga BN6 (pBN6) were site
      specifically labeled with a kanamycin resistance cassette. The conjugative
      transfer of these labeled plasmids was attempted with various bacterial strains
      as putative recipient strains. Thus, a conjugative transfer of plasmid pBN6 from
      S. xenophaga BN6 to a cured mutant of strain BN6 and to Sphingomonas sp. SS3 was
      observed. The conjugation experiments with plasmid pNL1 suggested a broader host
      range of this plasmid, because it was transferred without any obvious structural
      changes to S. yanoikuyae B1, Sphingomonas sp. SS3, and S. herbicidovorans. In
      contrast, major plasmid rearrangements were observed in the transconjugants after
      the transfer of plasmid pNL1 to Sphingomonas sp. HH69 and of pBN6 to Sphingomonas
      sp. SS3. No indications for the transfer of a Sphingomonas plasmid to bacteria
      outside of the Sphingomonadaceae were obtained.

PMID- 15175302
TI  - Control of photosynthetic and high-light-responsive genes by the histidine kinase
      DspA: negative and positive regulation and interactions between signal
      transduction pathways.
AB  - We have deleted a gene for a sensor histidine kinase, dspA (or hik33), in the
      cyanobacterium Synechocystis sp. strain PCC6803. In low and moderate light, the
      mutant grew slowly under photoautotrophic conditions, with a doubling time of
      approximately 40 h, and had severely reduced photosynthetic oxygen evolution.
      When the mutant was maintained in low or moderate light in the presence of
      glucose, its growth rate was only somewhat lower than that of wild-type cells.
      However, the mutant was light sensitive and rapidly died in high light.
      Furthermore, levels of many transcripts encoding genes associated with
      photosynthesis were altered in the mutant relative to wild-type Synechocystis sp.
      strain PCC6803 both in low light and following exposure to high light. There was
      constitutive expression of several high-light-inducible genes, including hli,
      psbAIII, and gpx2; there was little increased accumulation of sodB mRNA in high
      light; and the cells failed to accumulate cpcBA and psaAB mRNAs in low light in
      the presence of glucose, although a normal decline in the levels of these mRNAs
      was observed during exposure to high light. These results suggest that DspA is
      involved in controlling sets of photosynthetic and high-light-responsive genes,
      either directly or indirectly. These and other results, some of which are
      presented in a companion paper (C.-J. Tu, J. Shrager, R. Burnap, B. L. Postier,
      and A. R. Grossman, J. Bacteriol. 186:3889-3902, 2004), suggest that DspA acts as
      a global regulator that helps coordinate cellular metabolism with growth
      limitations imposed by environmental conditions.

PMID- 15175301
TI  - Vibrio fischeri LuxS and AinS: comparative study of two signal synthases.
AB  - Vibrio fischeri possesses two acyl-homoserine lactone quorum-sensing systems, ain
      and lux, both of which are involved in the regulation of luminescence gene
      expression and are required for persistent colonization of the squid host,
      Euprymna scolopes. We have previously demonstrated that the ain system induces
      luminescence at cell densities that precede lux system activation. Our data
      suggested that the ain system both relieves repression and initially induces the
      lux system, thereby achieving sequential induction of gene expression by these
      two systems. Analysis of the V. fischeri genome revealed the presence of a
      putative third system based on the enzyme LuxS, which catalyzes the synthesis of
      the Vibrio harveyi autoinducer 2 (AI-2). In this study, we investigated the
      impact of V. fischeri LuxS on luminescence and colonization competence in
      comparison to that of the ain system. Similar to the ain system, inactivation of
      the AI-2 system decreased light production in culture, but not in the squid host.
      However, while an ainS mutant produces no detectable light in culture, a luxS
      mutant expressed approximately 70% of wild-type luminescence levels. A mutation
      in luxS alone did not compromise symbiotic competence of V. fischeri; however,
      levels of colonization of an ainS luxS double mutant were reduced to 50% of the
      already diminished level of ainS mutant colonization, suggesting that these two
      systems regulate colonization gene expression synergistically through a common
      pathway. Introduction of a luxO mutation into the luxS and ainS luxS background
      could relieve both luminescence and colonization defects, consistent with a model
      in which LuxS, like AinS, regulates gene expression through LuxO. Furthermore,
      while luxS transcription appeared to be constitutive and the AI-2 signal
      concentration did not change dramatically, our data suggest that ainS
      transcription is autoregulated, resulting in an over 2,000-fold increase in
      signal concentration as culture density increased. Taken together, these data
      indicate that V. fischeri LuxS affects both luminescence regulation and
      colonization competence; however, its quantitative contribution is small when
      compared to that of the AinS signal.

PMID- 15175303
TI  - Consequences of a deletion in dspA on transcript accumulation in Synechocystis
      sp. strain PCC6803.
AB  - A sensor histidine kinase of Synechococcus sp. strain PCC7942, designated nblS,
      was previously identified and shown to be critical for the acclimation of cells
      to high-light and nutrient limitation conditions and to influence the expression
      of a number of light-responsive genes. The nblS orthologue in Synechocystis sp.
      strain PCC6803 is designated dspA (also called hik33). We have generated a dspA
      null mutant and analyzed global gene expression in both the mutant and wild-type
      strains under high- and low-light conditions. The mutant is aberrant for the
      expression of many genes encoding proteins critical for photosynthesis, phosphate
      and carbon acquisition, and the amelioration of stress conditions. Furthermore,
      transcripts from a number of genes normally detected only during exposure of wild
      type cells to high-light conditions become partially constitutive in the low
      light-grown dspA mutant. Other genes for which transcripts decline upon exposure
      of wild-type cells to high light are already lower in the mutant during growth in
      low light. These results suggest that DspA may influence gene expression in both
      a positive and a negative manner and that the dspA mutant behaves as if it were
      experiencing stress conditions (e.g., high-light exposure) even when maintained
      at near-optimal growth conditions for wild-type cells. This is discussed with
      respect to the importance of DspA for regulating the responses of the cell to
      environmental cues.

PMID- 15175304
TI  - Structural basis for iron binding and release by a novel class of periplasmic
      iron-binding proteins found in gram-negative pathogens.
AB  - We have determined the 1.35- and 1.45-A structures, respectively, of closed and
      open iron-loaded forms of Mannheimia haemolytica ferric ion-binding protein A. M.
      haemolytica is the causative agent in the economically important and fatal
      disease of cattle termed shipping fever. The periplasmic iron-binding protein of
      this gram-negative bacterium, which has homologous counterparts in many other
      pathogenic species, performs a key role in iron acquisition from mammalian host
      serum iron transport proteins and is essential for the survival of the pathogen
      within the host. The ferric (Fe(3+)) ion in the closed structure is bound by a
      novel asymmetric constellation of four ligands, including a synergistic carbonate
      anion. The open structure is ligated by three tyrosyl residues and a dynamically
      disordered solvent-exposed anion. Our results clearly implicate the synergistic
      anion as the primary mediator of global protein conformation and provide detailed
      insights into the molecular mechanisms of iron binding and release in the
      periplasm.

PMID- 15175305
TI  - Extensive genomic diversity in pathogenic Escherichia coli and Shigella Strains
      revealed by comparative genomic hybridization microarray.
AB  - Escherichia coli, including the closely related genus Shigella, is a highly
      diverse species in terms of genome structure. Comparative genomic hybridization
      (CGH) microarray analysis was used to compare the gene content of E. coli K-12
      with the gene contents of pathogenic strains. Missing genes in a pathogen were
      detected on a microarray slide spotted with 4,071 open reading frames (ORFs) of
      W3110, a commonly used wild-type K-12 strain. For 22 strains subjected to the CGH
      microarray analyses 1,424 ORFs were found to be absent in at least one strain.
      The common backbone of the E. coli genome was estimated to contain about 2,800
      ORFs. The mosaic distribution of absent regions indicated that the genomes of
      pathogenic strains were highly diversified because of insertions and deletions.
      Prophages, cell envelope genes, transporter genes, and regulator genes in the K
      12 genome often were not present in pathogens. The gene contents of the strains
      tested were recognized as a matrix for a neighbor-joining analysis. The
      phylogenic tree obtained was consistent with the results of previous studies.
      However, unique relationships between enteroinvasive strains and Shigella,
      uropathogenic, and some enteropathogenic strains were suggested by the results of
      this study. The data demonstrated that the CGH microarray technique is useful not
      only for genomic comparisons but also for phylogenic analysis of E. coli at the
      strain level.

PMID- 15175306
TI  - Spreading factors of Mycoplasma alligatoris, a flesh-eating mycoplasma.
AB  - Mycoplasma alligatoris causes lethal invasive disease of alligators and caimans.
      A homolog of the nagH gene, encoding a hyaluronidase secreted by Clostridium
      perfringens, and a C. perfringens hyaluronidase nagI or nagK pseudogene were
      discovered in the M. alligatoris genome. The nagH gene was detected by PCR in the
      closest relative of M. alligatoris, Mycoplasma crocodyli, but not in 40 other
      species representing the Mycoplasma hominis, Mycoplasma pneumoniae, and
      Spiroplasma phylogenetic clusters. The hyaluronidase activity in the cellular
      fraction of M. alligatoris and M. crocodyli SP4 broth cultures was equivalent to
      10(-16) U of Streptomyces hyalurolyticus hyaluronidase CFU(-1). Negligible
      activity was present in the cell-free supernatant fraction. No chondroitinase
      activity was detected. There is also a novel homolog of the nanI gene, which
      encodes a sialidase secreted by C. perfringens, in the M. alligatoris genome. The
      signature YRIP and SXDXGXTW motifs and catalytic residues of the clostridial
      sialidase are conserved in the mycoplasmal gene, but the leader sequence
      necessary for its secretion by C. perfringens is absent. The gene was not
      detected by PCR in any other mycoplasma. Potent cell-associated sialidase
      activity was present in M. alligatoris colonies on agar but not in the cell-free
      supernatants of broth cultures or in M. crocodyli. The presence of hyaluronidase
      and sialidase in M. alligatoris is consistent with the rapid invasiveness and
      necrotizing effects of this organism, and the lack of sialidase in M. crocodyli
      is consistent with its comparatively attenuated virulence. This genetic and
      biochemical evidence suggests that the spreading factors hyaluronidase and
      sialidase, a combination unprecedented in mycoplasmas, are the basis of the
      virulence of M. alligatoris.

PMID- 15175307
TI  - CovS inactivates CovR and is required for growth under conditions of general
      stress in Streptococcus pyogenes.
AB  - The gram-positive human pathogen Streptococcus pyogenes (group A streptococcus
      [GAS]) causes diseases ranging from mild and often self-limiting infections of
      the skin or throat to invasive and life-threatening illnesses. To cause such
      diverse types of disease, the GAS must be able to sense adverse environments and
      regulate its gene expression accordingly. The CovR/S two-component signal
      transduction regulatory system in GAS represses about 15% of the GAS genome,
      including many genes involved in virulence, in response to the environment. We
      report that CovR is still able to repress transcription from several promoters in
      the absence of the putative histidine kinase sensor for this system, CovS. We
      also show that a phosphorylation site mutant (D53A) of CovR is unable to repress
      gene expression. In addition, we report that a strain with a nonpolar mutation in
      CovS does not grow at a low pH, elevated temperature, or high osmolarity. The
      stress-related phenotypes of the CovS mutant were complemented by expression of
      covS from a plasmid. Selection for growth of a CovS mutant under stress
      conditions resulted in isolation of second-site mutations that inactivated covR,
      indicating that CovR and CovS act in the same pathway. Also, at 40 degrees C in
      the wild-type strain, CovR appeared to be less active on the promoter tested,
      which is consistent with the hypothesis that it was partially inactivated by
      CovS. We suggest that under mild stress conditions, CovS inactivates CovR, either
      directly or indirectly, and that this inactivation relieves repression of many
      GAS genes, including the genes needed for growth of GAS under stress conditions
      and some genes that are necessary for virulence. Growth of many gram-positive
      bacteria under multiple-stress conditions requires alteration of promoter
      recognition produced by RNA polymerase association with the general stress
      response sigma factor, sigma(B). We provide evidence that for GAS, which lacks a
      sigB ortholog, growth under stress conditions requires the CovR/S two-component
      regulatory system instead. This two-component system in GAS thus appears to
      perform a function for which other gram-positive bacteria utilize an alternative
      sigma factor.

PMID- 15175309
TI  - Effects of perturbing nucleoid structure on nucleoid occlusion-mediated
      toporegulation of FtsZ ring assembly.
AB  - In Escherichia coli, assembly of the FtsZ ring (Z ring) at the cell division site
      is negatively regulated by the nucleoid in a phenomenon called nucleoid occlusion
      (NO). Previous studies have indicated that chromosome packing plays a role in NO,
      as mukB mutants grown in rich medium often exhibit FtsZ rings on top of diffuse,
      unsegregated nucleoids. To address the potential role of overall nucleoid
      structure on NO, we investigated the effects of disrupting chromosome structure
      on Z-ring positioning. We found that NO was mostly normal in cells with
      inactivated DNA gyrase or in mukB-null mutants lacking topA, although some
      suppression of NO was evident in the latter case. Previous reports suggesting
      that transcription, translation, and membrane insertion of proteins
      ("transertion") influence nucleoid structure prompted us to investigate whether
      disruption of these activities had effects on NO. Blocking transcription caused
      nucleoids to become diffuse, and FtsZ relocalized to multiple bands on top of
      these nucleoids, biased towards midcell. This suggested that these diffuse
      nucleoids were defective in NO. Blocking translation with chloramphenicol caused
      characteristic nucleoid compaction, but FtsZ rarely assembled on top of these
      centrally positioned nucleoids. This suggested that NO remained active upon
      translation inhibition. Blocking protein secretion by thermoinduction of a
      secA(Ts) strain caused a chromosome segregation defect similar to that in parC
      mutants, and NO was active. Although indirect effects are certainly possible with
      these experiments, the above data suggest that optimum NO activity may require
      specific organization and structure of the nucleoid.

PMID- 15175308
TI  - Genomic diversity of Burkholderia pseudomallei clinical isolates: subtractive
      hybridization reveals a Burkholderia mallei-specific prophage in B. pseudomallei
      1026b.
AB  - Burkholderia pseudomallei is the etiologic agent of the disease melioidosis and
      is a category B biological threat agent. The genomic sequence of B. pseudomallei
      K96243 was recently determined, but little is known about the overall genetic
      diversity of this species. Suppression subtractive hybridization was employed to
      assess the genetic variability between two distinct clinical isolates of B.
      pseudomallei, 1026b and K96243. Numerous mobile genetic elements, including a
      temperate bacteriophage designated phi1026b, were identified among the 1026b
      specific suppression subtractive hybridization products. Bacteriophage phi1026b
      was spontaneously produced by 1026b, and it had a restricted host range,
      infecting only Burkholderia mallei. It possessed a noncontractile tail, an
      isometric head, and a linear 54,865-bp genome. The mosaic nature of the phi1026b
      genome was revealed by comparison with bacteriophage phiE125, a B. mallei
      specific bacteriophage produced by Burkholderia thailandensis. The phi1026b genes
      for DNA packaging, tail morphogenesis, host lysis, integration, and DNA
      replication were nearly identical to the corresponding genes in phiE125. On the
      other hand, phi1026b genes involved in head morphogenesis were similar to head
      morphogenesis genes encoded by Pseudomonas putida and Pseudomonas aeruginosa
      bacteriophages. Consistent with this observation, immunogold electron microscopy
      demonstrated that polyclonal antiserum against phiE125 reacted with the tail of
      phi1026b but not with the head. The results presented here suggest that B.
      pseudomallei strains are genetically heterogeneous and that bacteriophages are
      major contributors to the genomic diversity of this species. The bacteriophage
      characterized in this study may be a useful diagnostic tool for differentiating
      B. pseudomallei and B. mallei, two closely related biological threat agents.

PMID- 15175310
TI  - Mutational analysis of transmembrane regions 3 and 4 of SecY, a central component
      of protein translocase.
AB  - The SecYEG heterotrimeric membrane protein complex functions as a channel for
      protein translocation across the Escherichia coli cytoplasmic membrane. SecY is
      the central subunit of the SecYEG complex and contains 10 transmembrane segments
      (TM1 to TM10). Previous mutation studies suggested that TM3 and TM4 are
      particularly important for SecY function. To further characterize TM3 and TM4, we
      introduced a series of cysteine-scanning mutations into these segments. With one
      exception (an unstable product), all the mutant proteins complemented the cold
      sensitive growth defect of the secY39 mutant. A combination of this secY mutation
      and the secG deletion resulted in synthetic lethality, and the TM3 and TM4 SecY
      cysteine substitution mutations were examined for their ability to complement
      this lethality. Although they were all positive for complementation, some of the
      complemented cells exhibited significant retardation of protein export. The
      substitution-sensitive residues in TM3 can be aligned to one side of the alpha
      helix, and those in TM4 revealed a tendency for residues closer to the cytosolic
      side of the membrane to be more severely affected. Disulfide cross-linking
      experiments identified a specific contact point for TM3 and SecG TM2 as well as
      for TM4 and SecG TM1. Thus, although TM3 and TM4 do not contain any single
      residue that is absolutely required, they include functionally important helix
      surfaces and specific contact points with SecG. These results are discussed in
      light of the structural information available for the SecY complex.

PMID- 15175311
TI  - Genes involved in formation of structured multicellular communities by Bacillus
      subtilis.
AB  - The spore-forming bacterium Bacillus subtilis is capable of assembling
      multicellular communities (biofilms) that display a high degree of spatiotemporal
      organization. Wild strains that have not undergone domestication in the
      laboratory produce particularly robust biofilms with complex architectural
      features, such as fruiting-body-like aerial projections whose tips serve as
      preferential sites for sporulation. To discover genes involved in this
      multicellular behavior and to do so on a genome-wide basis, we took advantage of
      a large collection of mutants which have disruptions of most of the
      uncharacterized genes in the B. subtilis genome. This collection, which was
      generated with a laboratory strain, was screened for mutants that were impaired
      in biofilm formation. This subset of mutated genes was then introduced into the
      wild strain NCIB 3610 to study their effects on biofilm formation in liquid and
      solid media. In this way we identified six genes that are involved in the
      development of multicellular communities. These are yhxB (encoding a putative
      phosphohexomutase that may mediate exopolysaccharide synthesis), sipW (encoding a
      signal peptidase), ecsB (encoding an ABC transporter subunit), yqeK (encoding a
      putative phosphatase), ylbF (encoding a regulatory protein), and ymcA (a gene of
      unknown function). Further analysis revealed that these six genes play different
      roles in B. subtilis community development.

PMID- 15175312
TI  - Intragenomic heterogeneity and intergenomic recombination among haloarchaeal rRNA
      genes.
AB  - More than one copy of rRNA operons, which code for both the small-subunit (SSU)
      and large-subunit (LSU) rRNA, are often found in prokaryotes. It is generally
      assumed that all rRNA operons within a single cell are almost identical. A
      notable exception is the extremely halophilic archaeal genus Haloarcula, most
      species of which are known to harbor highly divergent rRNA operons that differ at
      approximately 5% of the nucleotide positions in the SSU gene and at 1 to 2% of
      the nucleotide positions in the LSU gene. We report that such intragenomic
      heterogeneity is not unique to Haloarcula, as high levels of intragenomic
      sequence variation have been observed for the SSU genes of two other genera of
      extreme halophiles, Halosimplex and Natrinema. To investigate this in detail, the
      two rRNA operons of Halosimplex carlsbadense and the four operons of Natrinema
      sp. strain XA3-1 were cloned and completely sequenced. The SSU and LSU genes of
      H. carlsbadense show the highest levels of intragenomic heterogeneity observed so
      far in archaea (6.7 and 2.6%). The operons of Natrinema sp. strain XA3-1 have
      additional unusual characteristics, such as identical internal transcribed
      spacers, while one of four SSU genes is 5% divergent and all LSU genes differ
      from each other by 0.9 to 1.9%. The heterogeneity among the Natrinema sp. strain
      XA3-1 LSU genes is localized in hot spots, and one of these regions is shown to
      be the result of a recombination event with a distantly related halophile. This
      is the first example of interspecies recombination between rRNA genes in archaea,
      and the recombination occurred over one of the largest phylogenetic distances
      ever reported for such an event. We suggest that intragenomic heterogeneity of
      rRNA operons is an ancient and stable trait in several lineages of the
      Halobacteriales. The impact of this phenomenon on the taxonomy of extremely
      halophilic archaea is discussed.

PMID- 15175313
TI  - Involvement of the SppA1 peptidase in acclimation to saturating light intensities
      in Synechocystis sp. strain PCC 6803.
AB  - The sll1703 gene, encoding an Arabidopsis homologue of the thylakoid membrane
      associated SppA peptidase, was inactivated by interposon mutagenesis in
      Synechocystis sp. strain PCC 6803. Upon acclimation from a light intensity of 50
      to 150 microE m(-2) s(-1), the mutant preserved most of its phycobilisome
      content, whereas the wild-type strain developed a bleaching phenotype due to the
      loss of about 40% of its phycobiliproteins. Using in vivo and in vitro
      experiments, we demonstrate that the DeltasppA1 strain does not undergo the
      cleavage of the L(R)(33) and L(CM)(99) linker proteins that develops in the wild
      type exposed to increasing light intensities. We conclude that a major
      contribution to light acclimation under a moderate light regime in cyanobacteria
      originates from an SppA1-mediated cleavage of phycobilisome linker proteins.
      Together with changes in gene expression of the major phycobiliproteins, it
      contributes an additional mechanism aimed at reducing the content in
      phycobilisome antennae upon acclimation to a higher light intensity.

PMID- 15175314
TI  - Role of the anti-sigma factor SpoIIAB in regulation of sigmaG during Bacillus
      subtilis sporulation.
AB  - RNA polymerase sigma factor sigma(F) initiates the prespore-specific program of
      gene expression during Bacillus subtilis sporulation. sigma(F) governs
      transcription of spoIIIG, encoding the late prespore-specific regulator sigma(G).
      However, transcription of spoIIIG is delayed relative to other genes under the
      control of sigma(F), and after synthesis, sigma(G) is initially kept in an
      inactive form. Activation of sigma(G) requires the complete engulfment of the
      prespore by the mother cell and expression of the spoIIIA and spoIIIJ loci. We
      screened for random mutations in spoIIIG that bypassed the requirement for
      spoIIIA for the activation of sigma(G). We found a mutation (spoIIIGE156K) that
      resulted in an amino acid substitution at position 156, which is adjacent to the
      position of a mutation (E155K) previously shown to prevent interaction of SpoIIAB
      with sigma(G). Comparative modelling techniques and in vivo studies suggested
      that the spoIIIGE156K mutation interferes with the interaction of SpoIIAB with
      sigma(G). The sigma(GE156K) isoform restored sigma(G)-directed gene expression to
      spoIIIA mutant cells. However, expression of sspE-lacZ in the spoIIIA
      spoIIIGE156K double mutant was delayed relative to completion of the engulfment
      process and was not confined to the prespore. Rather, beta-galactosidase
      accumulated throughout the entire cell at late times in development. This
      suggests that the activity of sigma(GE156K) is still regulated in the prespore of
      a spoIIIA mutant, but not by SpoIIAB. In agreement with this suggestion, we also
      found that expression of spoIIIGE156K from the promoter for the early prespore
      specific gene spoIIQ still resulted in sspE-lacZ induction at the normal time
      during sporulation, coincidently with completion of the engulfment process. In
      contrast, transcription of spoIIIGE156K, but not of the wild-type spoIIIG gene,
      from the mother cell-specific spoIID promoter permitted the rapid induction of
      sspE-lacZ expression. Together, the results suggest that SpoIIAB is either
      redundant or has no role in the regulation of sigma(G) in the prespore.

PMID- 15175315
TI  - Cross-regulation in Vibrio parahaemolyticus: compensatory activation of polar
      flagellar genes by the lateral flagellar regulator LafK.
AB  - Gene organization and hierarchical regulation of the polar flagellar genes of
      Vibrio parahaemolyticus, Vibrio cholerae, and Pseudomonas aeruginosa appear
      highly similar, with one puzzling difference. Two sigma(54)-dependent regulators
      are required to direct different classes of intermediate flagellar gene
      expression in V. cholerae and P. aeruginosa, whereas the V. parahaemolyticus
      homolog of one of these regulators, FlaK, appears dispensable. Here we
      demonstrate that there is compensatory activation of polar flagellar genes by the
      lateral flagellar regulator LafK.

PMID- 15175316
TI  - The Escherichia coli tppB (ydgR) gene represents a new class of OmpR-regulated
      genes.
AB  - The EnvZ/OmpR two-component regulatory system plays a critical role in the
      Escherichia coli stress response. In this study, we examined the expression of a
      new OmpR-regulated gene, ydgR. Our results indicate that ydgR is equivalent to
      the Salmonella enterica serovar Typhimurium tppB gene and represents a new class
      of OmpR-regulated genes.

PMID- 15175317
TI  - The last gene of the fla/che operon in Bacillus subtilis, ylxL, is required for
      maximal sigmaD function.
AB  - ylxL was found to be the last gene of the fla/che operon in Bacillus subtilis and
      is cotranscribed with the gene for the flagellum-specific alternate sigma factor,
      sigma(D). The ylxL gene was disrupted by insertional mutagenesis, and the
      resultant mutant strain was found to be compromised for sigma(D)-dependent
      functions.

PMID- 15175318
TI  - The acidic nature of the CcmG redox-active center is important for cytochrome c
      maturation in Escherichia coli.
AB  - Cytochrome c biogenesis in Escherichia coli is a complex process requiring at
      least eight genes (ccmABCDEFGH). One of these genes, ccmG, encodes a thioredoxin
      like protein with unusually specific redox activity. Here, we investigate the
      basis for CcmG function and demonstrate the importance of acidic residues
      surrounding the redox-active center.

PMID- 15175319
TI  - A mutant allele of rpoD results in increased conversion of aminoimidazole
      ribotide to hydroxymethyl pyrimidine in Salmonella enterica.
AB  - An allele of rpoD (rpoD1181) that results in increased synthesis of the
      pyrimidine moiety of thiamine in Salmonella enterica was identified. The S508Y
      substitution caused by rpoD1181 is analogous to the S506F derivative of the
      Escherichia coli protein. The properties of this E. coli mutant protein have been
      well characterized in vitro. Identification of a metabolic phenotype caused by
      the rpoD1181 allele of S. enterica allows past in vitro results to be
      incorporated in continuing efforts to understand cellular processes that are
      integrated with the thiamine biosynthetic pathway.

PMID- 15175320
TI  - Resuscitation of a defective prophage in Salmonella cocultures.
AB  - Widely studied Salmonella enterica serovar Typhimurium strains ATCC 14028s and
      SL1344 harbor a cryptic ST64B prophage unable to produce infectious virions. We
      found that coculturing either strain with an isogenic sibling lacking the
      prophage leads to the appearance of active forms of the virus. Active phage
      originates from reversion of a +1 frameshift mutation at a monotonous G:C run in
      a presumptive tail assembly pseudogene.

PMID- 15175321
TI  - MacA, a diheme c-type cytochrome involved in Fe(III) reduction by Geobacter
      sulfurreducens.
AB  - A 36-kDa diheme c-type cytochrome abundant in Fe(III)-respiring Geobacter
      sulfurreducens, designated MacA, was more highly expressed during growth with
      Fe(III) as the electron acceptor than with fumarate. Although MacA has homology
      to proteins with in vitro peroxidase activity, deletion of macA had no impact on
      response to oxidative stress. However, the capacity for Fe(III) reduction was
      greatly diminished, indicating that MacA, which is predicted to be localized in
      the periplasm, is a key intermediate in electron transfer to Fe(III).

PMID- 15175322
TI  - Microarray analysis and functional characterization of the nitrosative stress
      response in nonmucoid and mucoid Pseudomonas aeruginosa.
AB  - The type strain of Pseudomonas aeruginosa, PAO1, showed great upregulation of
      many nitrosative defense genes upon treatment with S-nitrosoglutathione, while
      the mucoid strain PAO578II showed no further upregulation above its constitutive
      upregulation of nor and fhp. NO* consumption however, showed that both strains
      mount functional, protein synthesis-dependent NO*-consumptive responses.

PMID- 15175323
TI  - Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling
      pathway by binding to tuberin.
AB  - Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in
      either TSC1 or TSC2 tumor suppressor gene. TSC1 and TSC2 products, Harmatin and
      Tuberin, form the functional complex to serve as the negative regulator for
      insulin-induced phosphorylation of S6 kinase and elF4E-binding protein 1. High
      risk human papillomavirus (HPV) infection is the necessary cause for cervical
      cancer. E6 oncoprotein encoded by HPV plays a pivotal role in carcinogenesis by
      interference with the host intracellular protein functions. In this study, we
      show that HPV16 E6 interacts with tumor suppressor gene TSC2 product, Tuberin,
      and results in the phosphorylation of S6 kinase and S6 even in the absence of
      insulin. The overexpression of Tuberin overcomes the effect of E6 on S6 kinase
      phosphorylation. Binding with HPV16 E6 causes the proteasome-mediated degradation
      of Tuberin. A DILG motif and an ELVG motif located in the carboxyl-terminal of
      Tuberin are required for E6 binding. In addition, the Tuberin interaction region
      in E6 has been mapped in the amino-terminal portion of HPV16 E6, which is
      different from the binding domain with p53. These results provide a possible link
      between E6-induced oncogenesis and the insulin-stimulated cell proliferation
      signaling pathway.

PMID- 15175324
TI  - The sensitivity of G protein-activated K+ channels toward halothane is
      essentially determined by the C terminus.
AB  - G protein-activated K(+) channels (GIRKs or Kir3.x) are targets for the volatile
      anesthetic, halothane. When coexpressed with the m(2) acetylcholine (ACh)
      receptor in Xenopus oocytes, agonist-activated GIRK1(F137S)- and GIRK2-mediated
      currents are inhibited by halothane, whereas in the absence of ACh, high
      concentrations of halothane induce GIRK1(F137S)-mediated currents. To elucidate
      the molecular mechanism of halothane action on GIRK currents of different subunit
      compositions, we constructed deletion mutants of GIRK1(F137S) (GIRK1(Delta363*))
      and GIRK2 (GIRK2(Delta356)) lacking the C-terminal ends, as well as chimeric GIRK
      channels. Mutated GIRK channels showed normal currents when activated by ACh but
      exhibited different pharmacological properties toward halothane. GIRK2(Delta356)
      showed no sensitivity against the inhibitory action of halothane but was
      activated by halothane in the absence of an agonist. GIRK1(Delta363*) was
      activated by halothane more efficiently. Currents mediated by chimeric channels
      were inhibited by anesthetic concentrations that were at least 30-fold lower than
      those necessary to decrease GIRK2 wild type currents. Glutathione S-transferase
      pulldown experiments did not show displacement of bound Gbetagamma by halothane,
      indicating that halothane does not interfere with Gbetagamma binding. Single
      channel experiments revealed an influence of halothane on the gating of the
      channels: The agonist-induced currents of GIRK1 and GIRK2, carried mainly by
      brief openings, were inhibited, whereas higher concentrations of the anesthetic
      promoted long openings of GIRK1 channels. Because the C terminus is crucial for
      these effects, an interaction of halothane with the channel seems to be involved
      in the mechanism of current modulation.

PMID- 15175325
TI  - Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte
      differentiation.
AB  - Mice deficient in the Msx2 gene manifest defects in skull ossification and a
      marked reduction in bone formation associated with decreases in osteoblast
      numbers, thus suggesting that Msx2 is involved in bone formation. However, the
      precise role of Msx2 during osteoblast differentiation is not fully understood.
      In the present study, we investigated the role of Msx2 in the regulation of
      osteoblast differentiation in the multipotent mesenchymal cell lines C3H10T1/2
      and C2C12 and in murine primary osteoblasts. Introduction of Msx2 induced
      alkaline phosphatase activity in C3H10T1/2 and C2C12 cells and promoted the
      calcification of murine primary osteoblasts. This effect of Msx2 was also
      observed in mesenchymal cells isolated from Runx2-deficient mice. Interestingly
      the expression of Msx2 was induced by bone morphogenetic protein 2 treatment in
      Runx2-deficient mesenchymal cells. In contrast, Msx2 diminished peroxisome
      proliferator-activated receptor gamma (PPARgamma) expression and adipogenesis of
      the preadipocytic cell line 3T3-F442A. Moreover Msx2 inhibited the
      transcriptional activity of PPARgamma, CCAAT/enhancer-binding protein beta
      (C/EBPbeta), and C/EBPdelta and blocked adipocyte differentiation of mesenchymal
      cells induced by overexpression of PPARgamma, C/EBPalpha, C/EBPbeta, or
      C/EBPdelta. These data indicate that Msx2 promotes osteoblast differentiation
      independently of Runx2 and negatively regulates adipocyte differentiation through
      inhibition of PPARgamma and the C/EBP family.

PMID- 15175326
TI  - Functional roles of four conserved charged residues in the membrane domain
      subunit NuoA of the proton-translocating NADH-quinone oxidoreductase from
      Escherichia coli.
AB  - The H(+)(Na(+))-translocating NADH-quinone (Q) oxidoreductase (NDH-1) of
      Escherichia coli is composed of 13 different subunits (NuoA-N). Subunit NuoA
      (ND3, Nqo7) is one of the seven membrane domain subunits that are considered to
      be involved in H(+)(Na(+)) translocation. We demonstrated that in the Paracoccus
      denitrificans NDH-1 subunit, Nqo7 (ND3) directly interacts with peripheral
      subunits Nqo6 (PSST) and Nqo4 (49 kDa) by using cross-linkers (Di Bernardo, S.,
      and Yagi, T. (2001) FEBS Lett. 508, 385-388 and Kao, M.-C., Matsuno-Yagi, A., and
      Yagi, T. (2004) Biochemistry 43, 3750-3755). To investigate the structural and
      functional roles of conserved charged amino acid residues, a nuoA knock-out
      mutant and site-specific mutants K46A, E51A, D79N, D79A, E81Q, E81A, and
      D79N/E81Q were constructed by utilizing chromosomal DNA manipulation. In terms of
      immunochemical and NADH dehydrogenase activity-staining analyses, all site
      specific mutants are similar to the wild type, suggesting that those NuoA site
      specific mutations do not significantly affect the assembly of peripheral
      subunits in situ. In addition, site-specific mutants showed similar deamino-NADH
      K(3)Fe(CN)(6) reductase activity to the wild type. The K46A mutation scarcely
      inhibited deamino-NADH-Q reductase activity. In contrast, E51A, D79A, D79N, E81A,
      and E81Q mutation partially suppressed deamino-NADH-Q reductase activity to 30,
      90, 40, 40, and 50%, respectively. The double mutant D79N/E81Q almost completely
      lost the energy-transducing NDH-1 activities but did not display any loss of
      deamino-NADH-K(3)Fe(CN)(6) reductase activity. The possible functional roles of
      residues Asp-79 and Glu-81 were discussed.

PMID- 15175327
TI  - A proteomic study of SUMO-2 target proteins.
AB  - The SUMO family in vertebrates includes at least three distinct proteins (SUMO-1,
      -2, and -3) that are added as post-translational modifications to target
      proteins. A considerable number of SUMO-1 target proteins have been identified,
      but little is known about SUMO-2. A stable HeLa cell line expressing His6-tagged
      SUMO-2 was established and used to label and purify novel endogenous SUMO-2
      target proteins. Tagged forms of SUMO-2 were functional and localized
      predominantly in the nucleus. His6-tagged SUMO-2 conjugates were affinity
      purified from nuclear fractions and identified by mass spectrometry. Eight novel
      potential SUMO-2 target proteins were identified by at least two peptides. Three
      of these proteins, SART1, heterogeneous nuclear ribonucleoprotein (RNP) M, and
      the U5 small nuclear RNP 200-kDa helicase, play a role in RNA metabolism. SART1
      and heterogeneous nuclear RNP M were both shown to be genuine SUMO targets,
      confirming the validity of the approach.

PMID- 15175328
TI  - The kinase activity of Rip1 is not required for tumor necrosis factor-alpha
      induced IkappaB kinase or p38 MAP kinase activation or for the ubiquitination of
      Rip1 by Traf2.
AB  - The death domain kinase Rip1 is recruited to the tumor necrosis factor receptor
      type 1 and mediates the IkappaB kinase and p38 MAP kinase pathways. In response
      to tumor necrosis factor-alpha (TNF-alpha), we find Rip1 phosphorylated and
      ubiquitinated, suggesting that Rip1 phosphorylation may stimulate its
      ubiquitination. To address the contribution of the kinase activity of Rip1 to its
      ubiquitination and to TNF-alpha signaling, we introduced wild type Rip1 and a
      kinase-inactive form of Rip1, Rip1D138N, into rip1-/- murine embryonic fibroblast
      cells by retroviral infection. TNF-alpha-induced ubiquitination of Rip1 is
      observed in Rip1D138N cells, supporting the argument that Rip1
      autophosphorylation is not required for Rip1 ubiquitination. TNF-alpha-induced
      Ikk and p38 MAP kinase activation is normal, and the Rip1D138N cells are
      resistant to TNF-alpha-induced cell death, indicating that the kinase activity of
      Rip1 is not required to mediate its antiapoptotic functions. In the absence of
      Traf2, TNF-alpha-induced ubiquitination of Rip1 is impaired, suggesting that
      Traf2 may be the E3 ubiquitin ligase responsible for the TNF-alpha-dependent,
      ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is
      dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather
      than its phosphorylation is critical in signaling.

PMID- 15175329
TI  - N-acetylglucosamine 6-O-sulfotransferase-1 regulates expression of L-selectin
      ligands and lymphocyte homing.
AB  - Lymphocyte homing is initiated by the binding of L-selectin on lymphocytes to its
      ligands on high endothelial venules (HEV). Sialyl 6-sulfo Lewis X is a major
      capping group of L-selectin ligands. N-Acetylglucosamine (GlcNAc) 6-sulfation is
      essential for the ligand activity, and is catalyzed by GlcNAc 6-O
      sulfotransferases (GlcNAc6STs) of which GlcNAc6ST-1 and GlcNAc6ST-2 are expressed
      in HEV. Here, we report that mice deficient in GlcNAc6ST-1 were impaired in the
      elaboration of sialyl 6-sulfo Lewis X in HEV and that an epitope of L-selectin
      ligands recognized by the MECA-79 anti-body was greatly reduced or abolished in
      the abluminal aspect of HEV. Lymphocyte homing to peripheral lymph nodes,
      mesenteric lymph nodes, and Peyer's patches was significantly reduced in
      GlcNAc6ST-1 null mice. These results demonstrate that GlcNAc6ST-1 is involved in
      lymphocyte homing in vivo, and indicate that GlcNAc6ST-1 and -2 play
      complementary roles. The importance of GlcNAc6ST-1 is particularly high-lighted
      by its involvement in lymphocyte homing to Peyer's patches where GlcNAc6ST-2
      expression is undetectable.

PMID- 15175330
TI  - ATP synthase that lacks F0a-subunit: isolation, properties, and indication of
      F0b2-subunits as an anchor rail of a rotating c-ring.
AB  - In a rotary motor F1F0-ATP synthase, F0 works as a proton motor; the oligomer
      ring of F0c-subunits (c-ring) rotates relative to the F0ab2 domain as protons
      pass through F0 down the gradient. F0ab2 must exert dual functions during
      rotation, that is, sliding the c-ring (motor drive) while keeping the association
      with the c-ring (anchor rail). Here we have isolated thermophilic F1F0(-a) which
      lacks F0a. F1F0(-a) has no proton transport activity, and F0(-a) does not work as
      a proton channel. Interestingly, ATPase activity of F1F0(-a) is greatly
      suppressed, even though its F1 sector is intact. Most likely, F0b2 associates
      with the c-ring as an anchor rail in the intact F1F0; without F0a, this
      association prevents rotation of the c-ring (and hence the gamma-subunit), which
      disables ATP hydrolysis at F1. Functional F1F0 is easily reconstituted from
      purified F0a and F1F0(-a), and thus F0a can bind to its proper location on F1F0(
      a) without a large rearrangement of other-subunits.

PMID- 15175331
TI  - Determinants of function and substrate specificity in human UDP-galactose 4'
      epimerase.
AB  - UDP-galactose 4'-epimerase (GALE) interconverts UDP-galactose and UDP-glucose in
      the final step of the Leloir pathway. Unlike the Escherichia coli enzyme, human
      GALE (hGALE) also efficiently interconverts a larger pair of substrates: UDP-N
      acetylgalactosamine and UDP-N-acetylglucosamine. The basis of this differential
      substrate specificity has remained obscure. Recently, however, x-ray
      crystallographic data have both predicted essential active site residues and
      suggested that differential active site cleft volume may be a key factor in
      determining GALE substrate selectivity. We report here a direct test of this
      hypothesis. In brief, we have created four substituted alleles: S132A, Y157F,
      S132A/Y157F, and C307Y-hGALE. While the first three substitutions were predicted
      to disrupt catalytic activity, the fourth was predicted to reduce active site
      cleft volume, thereby limiting entry or rotation of the larger but not the
      smaller substrate. All four alleles were expressed in a null-background strain of
      Saccharomyces cerevisiae and characterized in terms of activity with regard to
      both UDP-galactose and UDP-N-acetylgalactosamine. The S132A/Y157F and C307Y-hGALE
      proteins were also overexpressed in Pichia pastoris and purified for analysis. In
      all forms tested, the Y157F, S132A, and Y157F/S132A-hGALE proteins each
      demonstrated a complete loss of activity with respect to both substrates. In
      contrast, the C307Y-hGALE demonstrated normal activity with respect to UDP
      galactose but complete loss of activity with respect to UDP-N
      acetylgalactosamine. Together, these results serve to validate the wild-type
      hGALE crystal structure and fully support the hypothesis that residue 307 acts as
      a gatekeeper mediating substrate access to the hGALE active site.

PMID- 15175332
TI  - Molecular characterization of the microsomal tamoxifen binding site.
AB  - Tamoxifen is a selective estrogen receptor modulator widely used for the
      prophylactic treatment of breast cancer. In addition to the estrogen receptor
      (ER), tamoxifen binds with high affinity to the microsomal antiestrogen binding
      site (AEBS), which is involved in ER-independent effects of tamoxifen. In the
      present study, we investigate the modulation of the biosynthesis of cholesterol
      in tumor cell lines by AEBS ligands. As a consequence of the treatment with the
      antitumoral drugs tamoxifen or PBPE, a selective AEBS ligand, we show that tumor
      cells produced a significant concentration- and time-dependent accumulation of
      cholesterol precursors. Sterols have been purified by HPLC and gas
      chromatography, and their chemical structures determined by mass spectrometric
      analysis. The major metabolites identified were 5alpha-cholest-8-en-3beta-ol for
      tamoxifen treatment and 5alpha-cholest-8-en-3beta-ol and cholesta-5,7-dien-3beta
      ol, for PBPE treatment, suggesting that these AEBS ligands affect at least two
      enzymatic steps: the 3beta-hydroxysterol-Delta8-Delta7-isomerase and the 3beta
      hydroxysterol-Delta7-reductase. Steroidal antiestrogens such as ICI 182,780 and
      RU 58,668 did not affect these enzymatic steps, because they do not bind to the
      AEBS. Transient co-expression of human 3beta-hydroxysterol-Delta8-Delta7
      isomerase and 3beta-hydroxysterol-Delta7-reductase and immunoprecipitation
      experiments showed that both enzymes were required to reconstitute the AEBS in
      mammalian cells. Altogether, these data provide strong evidence that the AEBS is
      a hetero-oligomeric complex including 3beta-hydroxysterol-Delta8-Delta7-isomerase
      and the 3beta-hydroxysterol-Delta7-reductase as subunits that are necessary and
      sufficient for tamoxifen binding in mammary cells. Furthermore, because selective
      AEBS ligands are antitumoral compounds, these data suggest a link between
      cholesterol metabolism at a post-lanosterol step and tumor growth control. These
      data afford both the identification of the AEBS and give new insight into a novel
      molecular mechanism of action for drugs of clinical value.

PMID- 15175333
TI  - Tyrosine 547 constitutes an essential part of the catalytic mechanism of
      dipeptidyl peptidase IV.
AB  - Human dipeptidyl peptidase IV (DPP-IV) is a ubiquitously expressed type II
      transmembrane serine protease. It cleaves the penultimate positioned prolyl bonds
      at the N terminus of physiologically important peptides such as the incretin
      hormones glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. In
      this study, we have characterized different active site mutants. The Y547F mutant
      as well as the catalytic triad mutants S630A, D708A, and H740L showed less than
      1% wild type activity. X-ray crystal structure analysis of the Y547F mutant
      revealed no overall changes compared with wild type apoDPP-IV, except the
      ablation of the hydroxyl group of Tyr(547) and a water molecule positioned in
      close proximity to Tyr(547). To elucidate further the reaction mechanism, we
      determined the crystal structure of DPP-IV in complex with diisopropyl
      fluorophosphate, mimicking the tetrahedral intermediate. The kinetic and
      structural findings of the tyrosine residue are discussed in relation to the
      catalytic mechanism of DPP-IV and to the inhibitory mechanism of the 2
      cyanopyrrolidine class of potent DPP-IV inhibitors, proposing an explanation for
      the specificity of this class of inhibitors for the S9b family among serine
      proteases.

PMID- 15175334
TI  - A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand
      for Toll-like receptor 4.
AB  - MD-2, a glycoprotein that is essential for the innate response to
      lipopolysaccharide (LPS), binds to both LPS and the extracellular domain of Toll
      like receptor 4 (TLR4). Following synthesis, MD-2 is either secreted directly
      into the medium as a soluble, active protein, or binds directly to TLR4 in the
      endoplasmic reticulum before migrating to the cell surface. Here we investigate
      the function of the secreted form of MD-2. We show that secreted MD-2
      irreversibly loses activity over a 24-h period at physiological temperature. LPS,
      but not lipid A, prevents this loss in activity by forming a stable complex with
      MD-2, in a CD14-dependent process. Once formed, the stable MD-2.LPS complex
      activates TLR4 in the absence of CD14 or free LPS indicating that the activating
      ligand of TLR4 is the MD-2.LPS complex. Finally we show that the MD-2.LPS
      complex, but not LPS alone, induces epithelial cells, which express TLR4 but not
      MD-2, to secrete interleukin-6 and interleukin-8. We propose that the soluble MD
      2.LPS complex plays a crucial role in the LPS response by activating epithelial
      and other TLR4(+)/MD-2(-) cells in the inflammatory microenvironment.

PMID- 15175335
TI  - Sulfhydryl oxidation, not disulfide isomerization, is the principal function of
      protein disulfide isomerase in yeast Saccharomyces cerevisiae.
AB  - Protein disulfide isomerase (PDI) is an essential protein folding assistant of
      the eukaryotic endoplasmic reticulum that catalyzes both the formation of
      disulfides during protein folding (oxidase activity) and the isomerization of
      disulfides that may form incorrectly (isomerase activity). Catalysis of thiol
      disulfide exchange by PDI is required for cell viability in Saccharomyces
      cerevisiae, but there has been some uncertainty as to whether the essential role
      of PDI in the cell is oxidase or isomerase. We have studied the ability of PDI
      constructs with high oxidase activity and very low isomerase activity to
      complement the chromosomal deletion of PDI1 in S. cerevisiae. A single catalytic
      domain of yeast PDI (PDIa') has 50% of the oxidase activity but only 5% of the
      isomerase activity of wild-type PDI in vitro. Titrating the expression of PDI
      using the inducible/repressible GAL1-10 promoter shows that the amount of wild
      type PDI protein needed to sustain a normal growth rate is 60% or more of the
      amount normally expressed from the PDI1 chromosomal location. A single catalytic
      domain (PDIa') is needed in molar amounts that are approximately twice as high as
      those required for wild-type PDI, which contains two catalytic domains. This
      comparison suggests that high (>60%) PDI oxidase activity is critical to yeast
      growth and viability, whereas less than 6% of its isomerase activity is needed.

PMID- 15175336
TI  - Mitotic cyclins stimulate the activity of c-Myb-like factors for transactivation
      of G2/M phase-specific genes in tobacco.
AB  - Myb transcription factors, which contain three imperfect repeats in the Myb
      domain, are evolutionarily conserved members of the Myb superfamily. Vertebrate
      Myb proteins with three repeats, c-Myb, A-Myb, and BMyb, play important roles at
      the G(1)/S transition in the cell cycle. In plants, this type of Myb protein
      controls the G(2)/M phase by activating or repressing the transcription of cyclin
      B genes and a variety of other G(2)/M phase-specific genes. In tobacco, two genes
      for Myb activators, NtmybA1 and NtmybA2, are transcriptionally controlled and are
      expressed specifically at the G(2)/M phase. As we showed here, in addition to the
      control at the transcriptional level, activity of NtmybA2 is also controlled at
      the post-translational level. We found that the transactivation potential of
      NtmybA2 is repressed by a regulatory domain located at its carboxyl terminus and
      that specific classes of cyclins A and B enhanced NtmybA2 activity possibly by
      relieving this inhibitory effect. Mutations at the 20 potential sites of
      phosphorylation by cyclin-dependent kinase (CDK) in NtmybA2 blocked the enhancing
      effects of the cyclins on NtmybA2 activity. Recombinant NtmybA2 was
      phosphorylated in vitro by a CDK fraction prepared from tobacco BY2 cells. The
      kinase activity for NtmybA2 in the CDK fraction was cell cycle-regulated in BY2
      cells, peaking at the G(2)/M phase when the level of transcripts of cyclin B is
      maximal. Taken together, our data suggest that NtmybA2 is phosphorylated by a
      specific cyclin/CDK complex(es) at G(2)/M and that this phosphorylation removes
      the inhibitory effect of its C-terminal region, thereby activating NtmybA2
      specifically at G(2)/M.

PMID- 15175337
TI  - Heme oxygenase-2 is activated by calcium-calmodulin.
AB  - The heme oxygenase family of enzymes catalyzes the metabolism of heme to
      biliverdin, ferrous iron, and carbon monoxide (CO). At least two isoforms exist,
      heme oxygenase-1 (HO1) and heme oxygenase-2 (HO2), which are encoded by separate
      genes. HO2 is selectively enriched in neurons, and substantial evidence suggests
      that HO2-derived CO functions as a neurotransmitter/neuromodulator. However, a
      molecular mechanism for the rapid activation of HO2 during neuronal activity has
      not been described. Through a yeast two-hybrid screen we identified calmodulin as
      a potential regulator of HO2 activity. Calmodulin binds with nanomolar affinity
      to HO2 in a calcium-dependent manner via a canonical 1-10 motif, resulting in a 3
      fold increase in catalytic activity. Mutations within this motif block calmodulin
      binding and calcium-dependent stimulation of enzyme activity in vitro and in
      intact cells. The calcium mobilizing agents ionomycin and glutamate stimulate
      endogenous HO2 activity in primary cortical cultures, establishing in vivo
      relevance. Calcium-calmodulin provides a mechanism for rapid and transient
      activation of HO2 during neuronal activity.

PMID- 15175339
TI  - Lipid phase coexistence favors membrane insertion of equinatoxin-II, a pore
      forming toxin from Actinia equina.
AB  - Equinatoxin-II is a eukaryotic pore-forming toxin belonging to the family of
      actinoporins. Its interaction with model membranes is largely modulated by the
      presence of sphingomyelin. We have used large unilamellar vesicles and lipid
      monolayers to gain further information about this interaction. The coexistence of
      gel and liquid-crystal lipid phases in sphingomyelin/phosphatidylcholine mixtures
      and the coexistence of liquid-ordered and liquid-disordered lipid phases in
      phosphatidylcholine/cholesterol or sphingomyelin/phosphatidylcholine/cholesterol
      mixtures favor membrane insertion of equinatoxin-II. Phosphatidylcholine vesicles
      are not permeabilized by equinatoxin-II. However, the localized accumulation of
      phospholipase C-generated diacylglycerol creates conditions for toxin activity.
      By using epifluorescence microscopy of transferred monolayers, it seems that
      lipid packing defects arising at the interfaces between coexisting lipid phases
      may function as preferential binding sites for the toxin. The possible
      implications of such a mechanism in the assembly of a toroidal pore are
      discussed.

PMID- 15175338
TI  - Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth
      muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle
      progression, and matrix metalloproteinase-9 expression.
AB  - Sialic acid-containing glycosphingolipids (gangliosides) have been implicated in
      the regulation of various biological phenomena such as atherosclerosis. Recent
      report suggests that exogenously supplied disialoganglioside (GD3) serves a dual
      role in vascular smooth muscle cells (VSMC) proliferation and apoptosis. However,
      the role of the GD3 synthase gene in VSMC responses has not yet been elucidated.
      To determine whether a ganglioside is able to modulate VSMC growth, the effect of
      overexpression of the GD3 synthase gene on DNA synthesis was examined. The
      results show that the overexpression of this gene has a potent inhibitory effect
      on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of
      PDGF. The suppression of the GD3 synthase gene was correlated with the down
      regulation of cyclinE/CDK2, the up-regulation of the CDK inhibitor p21 and
      blocking of the p27 inhibition, whereas up-regulation of p53 as the result of GD3
      synthase gene expression was not observed. Consistently, blockade of GD3 function
      with anti-GD3 antibody reversed VSMC proliferation and cell cycle proteins. The
      expression of the GD3 synthase gene also led to the inhibition of TNF-alpha
      induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by
      zymography and immunoblot. Furthermore, GD3 synthase gene expression strongly
      decreased MMP-9 promoter activity in response to TNF-alpha. This inhibition was
      characterized by the down-regulation of MMP-9, which was transcriptionally
      regulated at NF-kappaB and activation protein-1 (AP-1) sites in the MMP-9
      promoter. Finally, the overexpression of MMP-9 in GD3 synthase transfectant cells
      rescued VSMC proliferation. However, MMP-2 overexpression was not affected by
      cell proliferation. These findings suggest that the GD3 synthase gene represents
      a physiological modulator of VSMC responses that may contribute to plaque
      instability in atherosclerosis.

PMID- 15175340
TI  - NMR study of nucleotide-induced changes in the nucleotide binding domain of
      Thermus thermophilus Hsp70 chaperone DnaK: implications for the allosteric
      mechanism.
AB  - We present an NMR investigation of the nucleotide-dependent conformational
      properties of a 44-kDa nucleotide binding domain (NBD) of an Hsp70 protein.
      Conformational changes driven by ATP binding and hydrolysis in the N-terminal NBD
      are believed to allosterically regulate substrate affinity in the C-terminal
      substrate binding domain. Several crystal structures of Hsc70 NBDs in different
      nucleotide states have, however, not shown significant structural differences. We
      have previously reported the NMR assignments of the backbone resonances of the
      NBD of the bacterial Hsp70 homologue Thermus thermophilus DnaK in the ADP-bound
      state. In this study we show, by assigning the NBD with the ATP/transition state
      analogue, ADP.AlFx, bound, that it closely mimics the ATP-bound state. Chemical
      shift difference mapping of the two nucleotide states identified differences in a
      cluster of residues at the interface between subdomains 1A and 1B. Further
      analysis of the spectra revealed that the ATP state exhibited a single
      conformation, whereas the ADP state was in slow conformational exchange between a
      form similar to the ATP state and another state unique to the ADP-bound form. A
      model is proposed of the allosteric mechanism based on the nucleotide state
      altering the balance of a dynamic equilibrium between the open and closed states.
      The observed chemical shift perturbations were concentrated in an area close to a
      previously described J-domain binding channel, confirming the importance of that
      region in the allosteric mechanism.

PMID- 15175341
TI  - Death-associated protein 3 localizes to the mitochondria and is involved in the
      process of mitochondrial fragmentation during cell death.
AB  - Death-associated protein 3 (DAP3) was previously isolated in our laboratory as a
      positive mediator of cell death. It is a 46-kDa protein containing a GTP binding
      domain that was shown to be essential for the induction of cell death. DAP3
      functions downstream of the receptor signaling complex, and its death-promoting
      effects depend on caspase activity. Recent reports have suggested that DAP3 is
      localized to the mitochondria, but no functional significance of this
      localization has been reported so far. Here, we study the sub-cellular
      localization and cellular function of human DAP3 (hDAP3). We found that hDAP3 is
      localized to the mitochondria and, in contrast to cytochrome c, is not released
      to the cytoplasm following several cell death signals. Overexpression of hDAP3
      induced dramatic changes in the mitochondrial structure involving increased
      fragmentation of the mitochondria. Both the mitochondrial localization of hDAP3
      and its GTP-binding activity were essential for the fragmentation. The punctiform
      mitochondrial morphology was similar to that observed upon treatment of HeLa
      cells with staurosporine. In fact, reduction of endogenous hDAP3 protein by RNA
      interference partially attenuated staurosporine-induced mitochondrial fission.
      Thus, hDAP3 is a necessary component in the molecular pathway that culminates in
      fragmented mitochondria, probably reflecting its involvement in the fission
      process. These results, for the first time, provide a specific functional role
      for hDAP3 in mitochondrial maintenance.

PMID- 15175342
TI  - Poly(A)-binding protein-interacting protein 2, a strong regulator of vascular
      endothelial growth factor mRNA.
AB  - Expression of vascular endothelial growth factor (VEGF) is tightly regulated,
      particularly at the level of its mRNA stability, which is essentially mediated
      through the 3'-untranslated region (3'-UTR) of VEGF mRNA. To identify new protein
      partners regulating VEGF mRNA stability, we screened a cDNA expression library
      with an RNA probe corresponding to the entire VEGF mRNA 3'-UTR. We identified the
      "poly(A)-binding protein-interacting protein 2" (PAIP2) as a new VEGF mRNA 3'-UTR
      interacting protein. By RNA electromobility shift assays, we showed that PAIP2
      binds to two distinct regions of a domain encompassing base 1 to 1280 of the VEGF
      3'-UTR. Such in vitro interaction was confirmed using cell extracts in which
      PAIP2 expression is induced by tetracycline (Tet-on cells). Moreover, we
      demonstrated by RNA affinity purification as well as by ribonucleoprotein
      complexes immunoprecipitation, that PAIP2 interacts with VEGF mRNA in vivo. Using
      an in vitro RNA degradation assay, the half-life of VEGF 3'-UTR was found to be
      increased by overexpressing PAIP2. PAIP2 stabilizes endogenous VEGF mRNA in Tet
      on cells, leading to increased VEGF secretion. Moreover, RNAi-mediated knock-down
      of PAIP2 significantly reduces the steady-state levels of endogenous VEGF mRNA.
      We also showed, by in vitro protein-protein interactions and co
      immunoprecipitation experiments, that PAIP2 interacts with HuR, an already known
      VEGF mRNA-binding protein, suggesting cooperation of both proteins for VEGF mRNA
      stabilization. Hence, PAIP2 appears to be a crucial regulator of VEGF mRNA and as
      a consequence, any variation in its expression could modulate angiogenesis.

PMID- 15175343
TI  - STAT2 nuclear trafficking.
AB  - STAT2 is a transcription factor critical to the signal transduction pathway of
      type I interferons (e.g. IFNalpha). STAT2 resides primarily in the cytoplasm and
      is tyrosine-phosphorylated after IFNalpha binds to cell surface receptors. In
      response to tyrosine phosphorylation STAT2 rapidly localizes to the nucleus and
      acquires the ability to bind specific DNA targets in association with two other
      proteins, STAT1 and IFN regulatory factor-9 (IRF-9). To elucidate the mechanisms
      that regulate cellular localization of STAT2, we investigated STAT2 nuclear
      trafficking both prior to tyrosine phosphorylation and after phosphorylation.
      Prior to phosphorylation, STAT2 is primarily resident in the cytoplasm, however,
      we found that it dynamically shuttles between nuclear and cytoplasmic
      compartments. The nuclear translocation of latent unphosphorylated STAT2 was
      found to be dependent on its constitutive association with IRF-9, and the export
      of STAT2 from the nucleus was contingent upon the function of an intrinsic
      nuclear export signal within the carboxyl terminus of STAT2. STAT2 export could
      be inhibited with leptomycin B, indicating a nuclear export signal within STAT2
      is recognized by the CRM1 exportin carrier. In contrast, following tyrosine
      phosphorylation, STAT2 dimerizes with phosphorylated STAT1 and accumulates in the
      nucleus. In the absence of STAT1, STAT2 does not accumulate in the nucleus. In
      addition, subsequent to nuclear import of phosphorylated STAT2, it redistributes
      to the cytoplasm within an hour coordinate with its dephosphorylation in the
      nucleus. The regulation of STAT2 nuclear trafficking is distinct from the
      previously characterized STAT1 factor.

PMID- 15175344
TI  - Syntaxin/Munc18 interactions in the late events during vesicle fusion and release
      in exocytosis.
AB  - The SNARE proteins, syntaxin, SNAP-25, and VAMP, form part of the core machinery
      for membrane fusion during regulated exocytosis. Additional proteins are required
      to account for the speed, spatial restriction, and tight control of exocytosis
      and a key role is played by members of the Sec1/Munc18 family of proteins that
      have been implicated either in vesicle docking or fusion itself through their
      interactions with the corresponding syntaxin. Using amperometry to assay the
      kinetics of single vesicle fusion/release events in adrenal chromaffin cells, the
      effect of expression of syntaxin 1A mutants was examined. Overexpression of wild
      type syntaxin or its cytoplasmic domain had no effect on the kinetics of release
      during single exocytotic events although the cytoplasmic domain reduced the
      frequency of exocytosis. In contrast, expression of either an open syntaxin 1A or
      the I233A mutant resulted in increased quantal size and a slowing of the kinetics
      of release. The wild-type and mutant syntaxins were overexpressed to a similar
      extent and the only common defect shown by the syntaxin 1A mutants was reduced
      binding to Munc18-1. These results are consistent with a role for Munc18-1 in
      controlling the late stages of exocytosis by binding to and limiting the
      availability of syntaxin in its open conformation. Modification of the Munc18
      1/syntaxin 1A interaction would therefore be a key mechanism for the regulation
      of quantal size.

PMID- 15175345
TI  - Natural phosphatidylcholine is actively translocated across the plasma membrane
      to the surface of mammalian cells.
AB  - The cell surface of eukaryotic cells is enriched in choline phospholipids,
      whereas the aminophospholipids are concentrated at the cytosolic side of the
      plasma membrane by the activity of one or more P-type ATPases. Lipid
      translocation has been investigated mostly by using short chain lipid analogs
      because assays for endogenous lipids are inherently complicated. In the present
      paper, we optimized two independent assays for the translocation of natural
      phosphatidylcholine (PC) to the cell surface based on the hydrolysis of outer
      leaflet phosphoglycerolipids by exogenous phospholipase A2 and the exchange of
      outer leaflet PC by a transfer protein. We report that PC reached the cell
      surface in the absence of vesicular traffic by a pathway that involved
      translocation across the plasma membrane. In erythrocytes, PC that was labeled at
      the inside of the plasma membrane was translocated to the cell surface with a
      half-time of 30 min. This translocation was probably mediated by an ATPase,
      because it required ATP and was vanadate-sensitive. The inhibition of PC
      translocation by glibenclamide, an inhibitor of various ATP binding cassette
      transporters, and its reduction in erythrocytes from both Abcb1a/1b and Abcb4
      knockout mice, suggest the involvement of ATP binding cassette transporters in
      natural PC cell surface translocation. The relative importance of the outward
      translocation of PC as compared with the well characterized fast inward
      translocation of phosphatidylserine for the overall asymmetric phospholipid
      organization in plasma membranes remains to be established.

PMID- 15175346
TI  - Apolipoprotein E receptors are required for reelin-induced proteasomal
      degradation of the neuronal adaptor protein Disabled-1.
AB  - The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation
      of neuronal positioning in the developing brain by the secreted molecule Reelin.
      Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low
      density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the
      subsequent activation or relocalization of downstream targets like
      phosphatidylinositol 3 (PI3)-kinase and Nckbeta. Disruption of Reelin signaling
      leads to the accumulation of Dab1 protein in the brains of genetically modified
      mice, suggesting that Reelin limits its own action in responsive neurons by down
      regulating the levels of Dab1 expression. Here, we use cultured primary embryonic
      neurons as a model to demonstrate that Reelin treatment targets Dab1 for
      proteolytic degradation by the ubiquitin-proteasome pathway. We show that
      tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for
      its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents
      Dab1 degradation. The Reelin-induced Dab1 degradation also depends on apoER2 and
      very low density lipoprotein receptor in a gene-dose dependent manner. Moreover,
      pharmacological blockade of the proteasome prevents the formation of a proper
      cortical plate in an in vitro slice culture assay. Our results demonstrate that
      signaling through neuronal apoE receptors can activate the ubiquitin-proteasome
      machinery, which might have implications for the role of Reelin during
      neurodevelopment and in the regulation of synaptic transmission.

PMID- 15175347
TI  - The P2Y2 nucleotide receptor mediates vascular cell adhesion molecule-1
      expression through interaction with VEGF receptor-2 (KDR/Flk-1).
AB  - UTP stimulates the expression of pro-inflammatory vascular cell adhesion molecule
      1 (VCAM-1) in endothelial cells through activation of the P2Y(2) nucleotide
      receptor P2Y(2)R. Here, we demonstrated that activation of the P2Y(2)R induced
      rapid tyrosine phosphorylation of vascular endothelial growth factor receptor
      (VEGFR)-2 in human coronary artery endothelial cells (HCAEC). RNA interference
      targeting VEGFR-2 or inhibition of VEGFR-2 tyrosine kinase activity abolishes
      P2Y(2)R-mediated VCAM-1 expression. Furthermore, VEGFR-2 and the P2Y(2)R co
      localize upon UTP stimulation. Deletion or mutation of two Src homology-3-binding
      sites in the C-terminal tail of the P2Y(2)R or inhibition of Src kinase activity
      abolished the P2Y(2)R-mediated transactivation of VEGFR-2 and subsequently
      inhibited UTP-induced VCAM-1 expression. Moreover, activation of VEGFR-2 by UTP
      leads to the phosphorylation of Vav2, a guanine nucleotide exchange factor for
      Rho family GTPases. Using a binding assay to measure the activity of the small
      GTPases Rho, we found that stimulation of HCAEC by UTP increased the activity of
      RhoA and Rac1 (but not Cdc42). Significantly, a dominant negative form of RhoA
      inhibited P2Y(2)R-mediated VCAM-1 expression, whereas expression of dominant
      negative forms of Cdc42 and Rac1 had no effect. These data indicate a novel
      mechanism whereby a nucleotide receptor transactivates a receptor tyrosine kinase
      to generate an inflammatory response associated with atherosclerosis.

PMID- 15175348
TI  - Involvement of 3-phosphoinositide-dependent protein kinase-1 in the MEK/MAPK
      signal transduction pathway.
AB  - The phosphatidylinositide-3-OH kinase/3-phospho-inositide-dependent protein
      kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK)
      kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles
      in the regulation of cell survival and proliferation. Despite their importance,
      however, the cross-talk between these two pathways has not been fully understood.
      Here we report that PDK1 promotes MAPK activation in a MEK-dependent manner. In
      vitro kinase assay revealed that the direct targets of PDK1 in the MAPK pathway
      were the upstream MAPK kinases MEK1 and MEK2. The identified PDK1 phosphorylation
      sites in MEK1 and MEK2 are Ser222 and Ser226, respectively, and are known to be
      essential for full activation. To date, these sites are thought to be
      phosphorylated by Raf kinases. However, PDK1 gene silencing using small
      interference RNA demonstrates that PDK1 is associated with maintaining the steady
      state phosphorylated MEK level and cell growth. The small interference RNA
      mediated down-regulation of PDK1 attenuated maximum MEK and MAPK activities but
      could not prolong MAPK signaling duration. Stable and transient expression of
      constitutively active MEK1 overcame these effects. Our results suggest a novel
      cross-talk between the phosphatidylinositide-3-OH kinase/PDK1/Akt pathway and the
      Raf/MEK/MAPK pathway.

PMID- 15175349
TI  - Both triggering and amplifying pathways contribute to fuel-induced insulin
      secretion in the absence of sulfonylurea receptor-1 in pancreatic beta-cells.
AB  - In normal beta-cells glucose induces insulin secretion by activating both a
      triggering pathway (closure of K(ATP) channels, depolarization, and rise in
      cytosolic [Ca(2+)](i)) and an amplifying pathway (augmentation of Ca(2+) efficacy
      on exocytosis). It is unclear if and how nutrients can regulate insulin secretion
      by beta-cells lacking K(ATP) channels (Sur1 knockout mice). We compared glucose-
      and amino acid-induced insulin secretion and [Ca(2+)](i) changes in control and
      Sur1KO islets. In 1 mm glucose (non-stimulatory for controls), the triggering
      signal [Ca(2+)](i) was high (loss of regulation) and insulin secretion was
      stimulated in Sur1KO islets. This "basal" secretion was decreased or increased by
      imposed changes in [Ca(2+)](i) and was dependent on ATP production, indicating
      that both triggering and amplifying signals are involved. High glucose stimulated
      insulin secretion in Sur1KO islets, by an unsuspected, transient increase in
      [Ca(2+)](i) and a sustained activation of the amplifying pathway. Unlike
      controls, Sur1KO islets were insensitive to diazoxide and tolbutamide, which
      rules out effects of either drug at sites other than K(ATP) channels. Amino acids
      potently increased insulin secretion by Sur1KO islets through both a further
      electrogenic rise in [Ca(2+)](i) and a metabolism-dependent activation of the
      amplifying pathway. After sulfonylurea blockade of their K(ATP) channels, control
      islets qualitatively behaved like Sur1KO islets, but their insulin secretion rate
      was consistently lower for a similar or even higher [Ca(2+)](i). In conclusion,
      fuel secretagogues can control insulin secretion in beta-cells without K(ATP)
      channels, partly by an unsuspected influence on the triggering [Ca(2+)](i) signal
      and mainly by the modulation of a very effective amplifying pathway.

PMID- 15175350
TI  - A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571)
      resistance is associated with altered expression of Bcl-2.
AB  - The relationship between the Src kinase Lyn and Bcl-2 expression was examined in
      chronic myelogenous leukemia cells (K562 and LAMA84) displaying a Bcr/Abl
      independent form of imatinib mesylate resistance. K562-R and LAMA-R cells that
      were markedly resistant to induction of mitochondrial dysfunction (e.g. loss of
      mitochondrial membrane potential, Bax translocation, cytochrome c, and apoptosis
      inducing factor release) and apoptosis by imatinib mesylate exhibited a
      pronounced reduction in expression of Bcr/Abl, Bcl-x(L), and STAT5 but a striking
      increase in levels of activated Lyn. Whereas basal expression of Bcl-2 protein
      was very low in parental cells, imatinib-resistant cells displayed a marked
      increase in Bcl-2 mRNA and/or protein levels. Treatment of LAMA-R cells with the
      Src kinase inhibitor PP2 significantly reduced Lyn activation as well as Bcl-2
      mRNA and protein levels. Transient or stable transfection of LAMA84 or K562 cells
      with a constitutively active Lyn (Y508F), but not with a kinase-dead mutant
      (K275D), significantly increased Bcl-2 protein expression and protected cells
      from lethality of imatinib mesylate. Ectopic expression of Bcl-2 protected K562
      and LAMA84 cells from imatinib mesylate- and PP2-mediated lethality. Conversely,
      interference with Bcl-2 function by co-administration of the small molecule Bcl-2
      inhibitor HA14-1 or down-regulation of Bcl-2 expression by small interfering RNA
      or antisense strategies significantly increased mitochondrial dysfunction and
      apoptosis induced by imatinib mesylate and the topoisomerase inhibitor VP-16 in
      LAMA-R cells. In marked contrast, these interventions had little effect in
      parental LAMA84 cells that display low basal levels of Bcl-2. Together, these
      findings indicate that activation of Lyn in leukemia cells displaying a Bcr/Abl
      independent form of imatinib mesylate resistance plays a functional role in Bcl-2
      up-regulation and provide a theoretical basis for the development of therapeutic
      strategies targeting Bcl-2 in such a setting.

PMID- 15175351
TI  - Lipid peroxidation induced by DHA enrichment modifies paracellular permeability
      in Caco-2 cells: protective role of taurine.
AB  - Dietary enrichment with docosahexaenoic acid (DHA) has numerous beneficial
      effects on health. However, the intake of high doses of polyunsaturated fatty
      acids can promote lipid peroxidation and the subsequent propagation of oxygen
      radicals. The purpose of this study was to evaluate the effect of DHA on lipid
      peroxidation and tight junction structure and permeability in Caco-2 cell
      cultures. Moreover, the effects of taurine, a functional ingredient with
      antioxidant properties, were also tested. Differentiated Caco-2 cell monolayers
      were maintained in DHA-supplemented conditions with or without added taurine.
      Incubation with 100 microM DHA increased lipid peroxidation and paracellular
      permeability, in parallel with a redistribution of the tight junction proteins
      occludin and ZO-1. Taurine partially prevented all of these effects. The
      participation of reactive oxygen and nitrogen species in increased paracellular
      permeability was also examined using various agents that modify the formation of
      superoxide radical, hydrogen peroxide, nitric oxide, and peroxynitrite. We
      conclude that hydrogen peroxide and peroxynitrite may be involved in the DHA
      induced increase in paracellular permeability and that the protective role of
      taurine may be in part related to its capacity to counteract the effects of
      hydrogen peroxide.

PMID- 15175352
TI  - Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption
      and insulin sensitivity.
AB  - The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the
      regulation of cholesterol metabolism and insulin sensitivity were studied in
      mildly hypercholesterolemic noncoronary subjects (n = 263, 144 men and 119 women)
      divided into tertiles by baseline serum cholestanol-to-cholesterol ratio (< or =
      118.3 and > or = 147.7 10(2) x mmol/mol cholesterol), a surrogate marker of
      cholesterol absorption efficiency. The lowest cholestanol tertile was associated
      with high body mass index (BMI), plasma glucose, serum insulin and triglycerides,
      and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low
      HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P <
      0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest
      cholestanol tertile (P < 0.001) and was associated with low total and LDL
      cholesterol and absorption markers and with high synthesis markers (P < 0.05 for
      all). The 604E allele of the ABCG5 gene in men was associated with high BMI,
      plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05
      for all). In a subgroup of 71 men, the 604E allele was associated with insulin
      resistance measured with the hyperinsulinemic euglycemic clamp. In conclusion,
      low cholesterol absorption efficiency was associated with characteristics of the
      metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked
      to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin
      resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5
      gene.

PMID- 15175353
TI  - In vivo metabolism of LDL subfractions in patients with heterozygous FH on statin
      therapy: rebound analysis of LDL subfractions after LDL apheresis.
AB  - LDL can be subfractionated into buoyant (1.020-1.029 g/ml(-1)), intermediate
      (1.030-1.040 g/ml(-1)), and dense (1.041-1.066 g/ml(-1)) LDLs. We studied the
      rebound of these LDL-subfractions after LDL apheresis in seven patients with
      heterozygous familial hypercholesterolemia (FH) regularly treated by apheresis
      (58 +/- 9 years, LDL-cholesterol = 342 +/- 87 mg/dl(-1), triglycerides = 109 +/-
      39 mg/dl(-1)) and high-dose statins. Apolipoprotein B (apoB) concentrations were
      measured in LDL subfractions immediately after and on days 1, 2, 3, 5, and 7
      after apheresis. Compartmental models were developed to test three hypotheses: 1)
      that dense LDLs are derived from the delipidation of buoyant and intermediate
      LDLs (model A); 2) that dense LDLs are generated directly from LDL-precursors
      (model B); or 3) that a model combining both pathways (model C) is necessary to
      describe the metabolism of dense LDLs. In all models, it was assumed that apoB
      production and fractional catabolic rate (FCR) did not change with apheresis.
      Apheresis decreased buoyant, intermediate, and dense LDL-apoB by 60 +/- 12%, 67
      +/- 5%, and 69 +/- 11%, respectively. Models B and C, but not model A, described
      the rebound data. The model with the greatest biological plausibility (model C)
      was used to estimate metabolic parameters. FCR was 1.05 +/- 0.86 d(-1), 0.48 +/-
      0.11 d(-1), and 0.69 +/- 0.24 d(-1) for buoyant, intermediate, and dense LDLs,
      respectively. Dense LDL production was 17.3 +/- 0.2 mg/kg(-1)/d(-1), 58% of which
      was derived directly from LDL precursors (VLDL, IDL, or direct secretion), while
      42% was derived from buoyant and intermediate LDLs. Thus, our data indicate that
      in statin-treated patients with heterozygous FH dense LDLs originate from two
      sources. Whether this is also valid in other metabolic situations (with
      predominant small, dense LDLs) remains to be determined.

PMID- 15175354
TI  - Participation of macrophages in atherosclerotic lesion morphology in LDLr-/-
      mice.
AB  - Lystbeige (beige) mice crossed with LDL receptor-deficient (LDLr-/-) mice had a
      distinct atherosclerotic lesion morphology that was not observed in LDLr-/- mice.
      This morphology is often associated with a stable plaque phenotype. We
      hypothesized that macrophage expression of the beige mutation accounted for this
      distinct morphology. Cultured bone marrow-derived macrophages from LDLr-/- and
      beige,LDLr-/- mice were compared for their ability to accumulate cholesterol,
      efflux cholesterol, migrate in response to chemotactic stimuli through Matrigel
      coated membranes, and express matrix metalloproteinase 9 (MMP9). No differences
      in cholesterol metabolism were identified. Beige,LDLr-/- macrophage invasion in
      vitro appeared to be less than LDLr-/- macrophage invasion but did not achieve
      significance. Nevertheless, tumor necrosis factor-alpha-induced MMP9 expression,
      secretion, and enzymatic activity of beige,LDLr-/- macrophages were all
      significantly decreased compared with those of LDLr-/- macrophages (P < 0.05).
      For in vivo analyses of macrophage function, bone marrow transplantation (BMT)
      studies were performed. LDLr-/- mice and beige,LDLr-/- mice were irradiated and
      reconstituted with wild-type or beige bone marrow from mice expressing green
      fluorescent protein (GFP). Identification of GFP cells provided for direct
      identification of donor-derived cells within lesions. Only expression of the
      beige mutation in the BMT recipients altered the macrophage location and collagen
      content of the lesions. These results suggested that impaired macrophage function
      by itself did not account for the stable lesion morphology of beige,LDLr-/-
      double-mutant mice.

PMID- 15175355
TI  - Endothelial lipase is synthesized by hepatic and aorta endothelial cells and its
      expression is altered in apoE-deficient mice.
AB  - Both LPL and HL are synthesized in parenchymal cells, are secreted, and bind to
      endothelial cells. To learn where endothelial lipase (EL) is synthesized in adult
      animals, the localization of EL in mouse and rat liver was studied by
      immunohistochemical analysis. Furthermore, to test whether EL could play a role
      in atherogenesis, the expression of EL in the aorta and liver of apolipoprotein E
      knockout (EKO) mice was determined. EL in both mouse and rat liver was
      colocalized with vascular endothelial cells but not with hepatocytes. In
      contrast, HL was present in both hepatocytes and endothelial cells. By in situ
      hybridization, EL mRNA was present only in endothelial cells in liver sections.
      EL was also present at low levels in aorta of normal mice. We fed EKO mice and
      wild-type mice a variety of diets and determined EL expression in liver and
      aorta. EKO mice showed significant expression of EL in aorta. EL expression was
      lower in the liver of EKO mice than in normal mice. Cholesterol feeding decreased
      EL in liver of both types of mice. In the aorta, EL was higher in EKO than in
      wild-type mice, and cholesterol feeding had no effect. Together, these data
      suggest that EL may be upregulated at the site of atherosclerotic lesions and
      thus could supply lipids to the area.

PMID- 15175356
TI  - Phosphatidylcholine deficiency upregulates enzymes of triacylglycerol metabolism
      in CHO cells.
AB  - We studied the regulation of triacylglycerol (TAG) metabolism by
      phosphatidylcholine (PC) in CHO MT58 cells, which are deficient in PC synthesis
      because of a temperature-sensitive CTP:phosphocholine cytidylyltransferase. At
      the permissive growth temperature (34 degrees C), these cells contained 49% less
      TAG and 30% less PC than wild-type CHO K1 cells. Treatment with
      dipalmitoylphosphatidylcholine normalized both the PC and TAG levels. Despite low
      TAG levels, the incorporation of [14C]oleate into TAG was increased in CHO MT58
      cells. The in vitro de novo synthesis of TAG and the activity of diacylglycerol
      acyltransferase were 90% and 34% higher, respectively. Two other key enzyme
      activities in TAG synthesis, acyl-CoA synthetase and mitochondrial glycerol-3
      phosphate acyltransferase (GPAT), increased by 48% and 2-fold, respectively, and
      mitochondrial GPAT mRNA increased by approximately 4-fold. Additionally, TAG
      hydrolysis was accelerated in CHO MT58 cells, and in vitro lipolytic activity
      increased by 68%. These studies suggest that a homeostatic mechanism increases
      TAG synthesis and recycling in response to PC deficiency. TAG recycling produces
      diacylglycerol and fatty acids that can be substrates for de novo PC synthesis
      and for lysophosphatidylcholine (lysoPC) acylation. In CHO MT58 cells, in which
      de novo PC synthesis is blocked, lysoPC acylation with fatty acid originating
      from TAG may represent the main pathway for generating PC.

PMID- 15175357
TI  - Benzophenone-containing cholesterol surrogates: synthesis and biological
      evaluation.
AB  - Eight analogs of cholesterol (1) containing a benzophenone group have been
      synthesized as prospective photoaffinity labels for studies in cellular sterol
      efflux and HDL formation. Six of these compounds (4-9) have the photophore
      replacing different portions of the cholesterol alkyl side chain, and two (10 and
      11) have it attached via nitrogen at carbon 3. The suitability of these analogs
      as cholesterol surrogates was determined by examining their ability to replace
      [3H]1 in fibroblasts preequilibrated with [3H]1. All eight analogs were effective
      in replacing natural 1 in competition with [3H]1 for apolipoprotein A-I-induced
      efflux. These are the first compounds shown to replace cholesterol successfully
      in a complex pathway of multiple intracellular steps. The results suggest an
      unexpected tolerance of biological membranes regarding the incorporation of
      sterols of differing chemical structure.

PMID- 15175358
TI  - Effects of an n-3-deficient diet on brain, retina, and liver fatty acyl
      composition in artificially reared rats.
AB  - Rat pups born to dams fed a diet with 3.1% of total fatty acids as alpha
      linolenic acid (LNA) were fed, using an artificial rearing system, either an n-3
      deficient (n-3-Def) or an n-3-adequate (n-3-Adq) diet. Both diets contained 17.1%
      linoleic acid, but the n-3-Adq diet also contained 3.1% LNA. The percentage of
      brain docosahexaenoic acid (DHA) continuously decreased (71%) with time over the
      29 days of the experiment, with concomitant increases in docosapentaenoic acid
      (DPAn-6). In the retina, the percentage of DHA rose in the n-3-Adq group, with an
      apparent increased rate around the time of eye opening. However, there was a flat
      curve for the percentage of DHA in the n-3-Def group and a rising DPAn-6 with
      time. Liver DHA was highest at the time of birth in the n-3-Adq group but fell
      off somewhat over the course of 29 days. This decrease was more pronounced in the
      n-3-Def group, and the DPAn-6 rose considerably during the second half of the
      experiment. This method presents a first-generation model for n-3 deficiency that
      is more similar to the case of human nutrition than is the commonly employed two
      generation model.

PMID- 15175359
TI  - Evidence that hepatic lipase deficiency in humans is not associated with
      proatherogenic changes in HDL composition and metabolism.
AB  - The aim of the present study was to characterize the composition and metabolism
      of HDL in subjects with complete hepatic lipase (HL) deficiency. Analyses were
      carried out in three complete and three partial HL-deficient subjects as well as
      in eight normotriglyceridemic (NTG) and two hypertriglyceridemic controls.
      Complete HL deficiency was associated with hypertriglyceridemia and with a 3.5
      fold increase in HDL-triglyceride (TG) levels. The in vivo kinetics of
      apolipoprotein A-I (apoA-I) and apoA-II (d < 1.25 g/l) were studied in the fasted
      state using a primed-constant infusion of l-(5,5,5-D3)leucine for 12 h. Complete
      HL deficiency was associated with a reduced fractional catabolic rate of apoA-I
      in the HL-deficient female proband (-47%) and in her two brothers (-21%) compared
      with gender- and TG-matched controls. Total plasma and HDL from complete HL
      deficient patients were able to mediate normal cholesterol efflux from human skin
      fibroblasts labeled with [3H]cholesterol. Complete HL deficiency was also
      associated with normal levels of prebeta-migrating apoA-I-containing HDL
      separated by two-dimensional gel electrophoresis and with an accumulation of
      large HDL particles compared with NTG controls. These results suggest that HL
      activity is important for adequate HDL metabolism, although its presence may not
      be necessary for normal HDL-mediated reverse cholesterol transport.

PMID- 15175360
TI  - The APOA4 T347S variant is associated with reduced plasma TAOS in subjects with
      diabetes mellitus and cardiovascular disease.
AB  - Apolipoprotein A-IV (apoA-IV) has been postulated to be antiatherogenic.
      Transgenic APOA4/Apoe-/- mice are protected against atherosclerosis, with plasma
      apoA-IV displaying antioxidant activity in vitro. In humans, there is an inverse
      relationship between apoA-IV levels and risk of coronary heart disease (CHD).
      Furthermore, the APOA4 T347S rare allele has been associated with increased risk
      of CHD and reduced apoA-IV levels. Reduced total antioxidant status (TAOS) due to
      increased oxidative stress is implicated in the process of atherogenesis. Thus,
      this study aimed to examine the association between the APOA4 T347S variant and
      TAOS in diabetic patients with (n = 196) or without (n = 509) cardiovascular
      disease (CVD). A higher percentage of CVD patients were present in the lowest
      quartile of TAOS, compared with the rest (P = 0.04). Overall, there was no
      association between genotype and TAOS. However, in patients with CVD, homozygotes
      for the S347 allele had significantly lower TAOS compared with TT and TS subjects
      (31.2 +/- 9.89% and 42.5 +/- 13.04% TAOS, respectively; P = 0.0024), an effect
      that was not seen in the patients without CVD. This study offers direct support
      for an antioxidant capacity of apoA-IV, thus providing some explanation for the
      antiatherogenic role of apoA-IV and the higher CVD risk in S347 homozygotes.

PMID- 15175361
TI  - Bioconversion of 3beta-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat
      brain enzyme systems.
AB  - We have previously demonstrated that the rat brain contains three unconjugated
      bile acids, and chenodeoxycholic acid (CDCA) is the most abundantly present in a
      tight protein binding form. The ratio of CDCA to the other acids in rat brain
      tissue was significantly higher than the ratio in the peripheral blood,
      indicating a contribution from either a specific uptake mechanism or a
      biosynthetic pathway for CDCA in rat brain. In this study, we have demonstrated
      the existence of an enzymatic activity that converts 3beta-hydroxy-5-cholenoic
      acid into CDCA in rat brain tissue. To distinguish marked compounds from
      endogenous related compounds, 18O-labeled 3beta-hydroxy-5-cholenoic acid,
      3beta,7alpha-dihydroxy-5-cholenoic acid, and 7alpha-hydroxy-3-oxo-4-cholenoic
      acid were synthesized as substrates for in vitro incubation studies. The results
      clearly suggest that 3beta-hydroxy-5-cholenoic acid was converted to 3beta,7alpha
      dihydroxy-5-cholenoic acid by microsomal enzymes. The 7alpha-hydroxy-3-oxo-4
      cholenoic acid was produced from 3beta,7alpha-dihydroxy-5-cholenoic acid by the
      action of microsomal enzymes, and Delta4-3-oxo acid was converted to CDCA by
      cytosolic enzymes. These findings indicate the presence of an enzymatic activity
      that converts 3beta-hydroxy-5-cholenoic acid into CDCA in rat brain tissue.
      Furthermore, this synthetic pathway for CDCA may relate to the function of 24S
      hydroxycholesterol, which plays an important role in cholesterol homeostasis in
      the body.

PMID- 15175362
TI  - High-level expression of ABCG5 and ABCG8 attenuates diet-induced
      hypercholesterolemia and atherosclerosis in Ldlr-/- mice.
AB  - Transgenic mice expressing human ABCG5 (G5) and ABCG8 (G8) have decreased
      fractional absorption and increased biliary secretion of cholesterol, but their
      plasma cholesterol levels are unchanged (males) or modestly reduced (females). To
      determine whether increased expression of G5 and G8 can ameliorate
      hypercholesterolemia in mice lacking LDL receptors (LDLRs), we examined the
      effects of G5G8 transgene expression on cholesterol metabolism and
      atherosclerosis in Ldlr-/- mice. In chow-fed Ldlr-/- mice, the G5G8 transgene
      reduced fractional absorption of dietary cholesterol by 50% and increased biliary
      cholesterol levels by 60% but did not affect plasma cholesterol levels. On a
      Western diet (21% fat, 0.2% cholesterol), G5G8Tg; Ldlr-/- mice had a 30%
      reduction in the level of hepatic cholesterol and 45% lower plasma cholesterol
      levels than the Ldlr-/- mice. After 6 months on the Western diet, the
      atherosclerotic lesion area in the aortic root and arch was approximately 70%
      lower in the G5G8Tg;Ldlr-/- than in the Ldlr-/- mice and was correlated with the
      plasma cholesterol levels. These results demonstrate that increased expression of
      G5 and G8 attenuates diet-induced hypercholesterolemia in Ldlr-/- mice, resulting
      in a significant reduction in plasma levels of cholesterol and aortic
      atherosclerotic lesion area.

PMID- 15175363
TI  - Direction-dependent phasing of locomotor muscle activity is altered post-stroke.
AB  - A major contributor to impaired locomotion post-stroke is abnormal phasing of
      muscle activity. While inappropriate paretic muscle phasing adapts to changing
      body orientation, load, and speed, it remains unclear whether paretic muscle
      phasing adapts to reversal of locomotor direction. We examined muscle phasing in
      backward pedaling, a task that requires shifts in biarticular but not
      uniarticular muscle phasing relative to forward pedaling. We hypothesized that if
      paretic and neurologically intact muscle phasing adapt similarly, then paretic
      biarticular but not paretic uniarticular muscles would shift phasing in backward
      pedaling. Paretic and neurologically intact individuals pedaled forward and
      backward while recording electromyograms (EMGs) from vastus medialis (VM), soleus
      (SOL), rectus femoris (RF), semimembranosus (SM), and biceps femoris (BF).
      Changes in muscle phasing were assessed by comparing the probability of muscle
      activity in forward and backward pedaling throughout 18 pedaling cycles. Paretic
      uniarticular muscles (VM and SOL) showed phase-advanced activity in backward
      versus forward pedaling, whereas the corresponding neurologically intact muscles
      showed little to no phasing change. Paretic biarticular muscles were less likely
      than neurologically intact biarticular muscles to display phasing changes in
      backward pedaling. Paretic RF displayed no phase change during backward pedaling,
      and paretic BF displayed no consistent adaptation to backward pedaling. Paretic
      SM was the only muscle to display backward/forward phase changes that were
      similar to the neurologically intact group. We conclude that paretic uniarticular
      muscles are more susceptible and paretic biarticular muscles are less susceptible
      to direction-dependent phase shifts, consistent with altered sensory integration
      and impaired cortical control of locomotion.

PMID- 15175364
TI  - Independent and convergent signals from the pontomedullary reticular formation
      contribute to the control of posture and movement during reaching in the cat.
AB  - We have addressed the nature of the postural control signals contained within the
      discharge activity of neurons in the pontomedullary reticular formation,
      including reticulospinal neurons, during a reaching task in the cat. We recorded
      the activity of 142 neurons during ipsilateral reaching movements that required
      anticipatory postural adjustments (APAs) in the supporting limbs to maintain
      equilibrium. Discharge activity in 82/142 (58%) neurons was significantly
      increased before the onset of the reach. Most of these neurons discharged either
      in a phasic (22/82), tonic (10/82), or phasic/tonic (41/82) pattern. In each of
      these 3 groups, the onset of the discharge activity in some neurons was
      temporally related either to the go signal or to the onset of the movement. In
      many neurons, one component of the discharge sequence was better related to the
      go signal and another to the onset of the movement. Based on our previous
      behavioral study during the same task, we suggest that reticular neurons in which
      the discharge activity is better related to the go signal contribute to the
      initiation of the APAs that precede the movement. Neurons in which the discharge
      activity is better related to the movement signal might contribute to the
      initiation of the movement and to the production of the postural responses that
      accompany that movement. Together our results suggest the existence of neurons
      that signal posture and movement independently and others that encode a
      convergent signal that contributes to the control of both posture and movement.

PMID- 15175365
TI  - Blockade of glycine transporter-1 (GLYT-1) potentiates NMDA receptor-mediated
      synaptic transmission in hypoglossal motorneurons.
AB  - NMDA receptor (NMDAR)-mediated spontaneous miniature excitatory postsynaptic
      currents (mEPSCs) are potentiated by exogenously applied glycine. In this study,
      we have investigated the effect of blocking glycine uptake on NMDAR-mediated
      responses from hypoglossal motorneurons (HMs) of rats. We have used N[3-(4'
      fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS; 500 nM), an antagonist
      of glycine transporter-1 (GLYT1), to study the effect of blocking endogenous
      glycine uptake on NMDAR-mediated synaptic transmission. We show that the charge
      transfer of NMDAR-mediated mEPSCs was enhanced after NFPS application in neonate
      (P2-4) and juvenile rats (P8-11), but this enhancement was statistically
      significant only in the former group. Spontaneous and evoked EPSCs showed a
      significant increase in NMDAR-mediated charge transfer in both neonates and
      juveniles. The greater increase observed in spontaneous EPSCs may be due to
      increased release of glycine from glycinergic terminals in the absence of
      tetrodotoxin (TTX). Brief application of NMDA onto HMs showed that extrasynaptic
      NMDARs may be potentiated by NFPS only in the presence of extracellularly applied
      glycine. Immunohistochemistry of GLYT1 and -2 shows labeling throughout the
      hypoglossal nucleus. GLYT1 labeling is diffuse and becomes more intense and
      uniform during development consistent with its glial localization. In contrast,
      GLYT2 labeling is intense throughout the nucleus and increases in intensity with
      age. Our results demonstrate the glycine binding site of the NMDAR is not
      saturated in the brain stem slice during the first 2 wk of development. We
      suggest that modulation of glycine concentration by GLYT1 is an important
      mechanism to regulate NMDAR-mediated synaptic transmission.

PMID- 15175366
TI  - Functional connectivity between the red nucleus and the hippocampus supports the
      role of hippocampal formation in sensorimotor integration.
AB  - Experiments were carried out in urethane-anesthetized rats to evaluate the
      hypothesis that the red nucleus has functional connections with the hippocampal
      formation. Depth profiles of electrical stimulation in experiment 1 confirmed
      that stimulation administered to the red nucleus elicited theta field activity in
      the hippocampal formation with a linear relationship between stimulus intensity
      and theta frequency. Experiment 2 showed that microinfusion of local anesthetic
      procaine hydrochloride into the medial septum resulted in a reversible blockade
      of theta field activity elicited by electrical stimulation of the red nucleus. In
      experiment 3, the discharge activity of red nucleus cells was recorded during the
      field conditions of hippocampal synchrony (theta) and hippocampal asynchrony
      [large amplitude irregular activity (LIA)]. Analysis revealed that 26/46 (56%) of
      red nucleus cells were theta-related, whereas the remaining 20 (44%) were
      nonrelated. The majority of theta-related cells were classified as tonic theta
      on. A brief increase above the basal discharge rate of tonic theta-on red nucleus
      cells during LIA predicted the transition from LIA to theta with 400- to 500-ms
      latency. Furthermore, higher frequency transitional discharges predicted higher
      theta frequencies, whereas higher discharge rates during theta predicted shifts
      to higher theta frequencies. The results supported the conclusion that the red
      nucleus, traditionally associated with motor functions, is functionally connected
      with the neural circuitry involved in the generation of theta band oscillation
      and synchrony in the hippocampal formation, in agreement with the predictions of
      the sensorimotor integration model of hippocampal function.

PMID- 15175367
TI  - Role for raphe magnus neuronal responses in the behavioral reactions to
      colorectal distension.
AB  - The brain stem is necessary for the expression of behavioral reactions to noxious
      visceral inputs. Neurons in raphe magnus (RM) and the adjacent nucleus
      reticularis magnocellularis (NRMC) respond to visceral stimuli and can facilitate
      the behavioral reaction to visceral stimulation. To determine which RM and NRMC
      cells could play a role in generating the reaction to colorectal distension
      (CRD), the responses of RM and NRMC cells to multiple intensities of CRD were
      compared with simultaneously evoked cardiovascular and visceromotor reactions in
      halothane-anesthetized rats. Most neurons (89%) responded to CRD with one of
      three basic response patterns. For cells with a graded response pattern, the
      response magnitude increased with increasing stimulation intensity. For flat
      responding cells, the response magnitude was not different across suprathreshold
      stimulation intensities. Finally, neurons with a switch response pattern
      responded to low- and high-intensity CRD in opposing directions. Cells were
      either inhibited or excited by CRD in each of these categories. Responses of
      cells with both graded and switch response patterns were significantly correlated
      with CRD-evoked tachycardia, pressor reaction, and hunching. The activity of
      graded-responding cells have the greatest predictive value for CRD-evoked
      reactions. Flat-responding cells have nonlinear responses that may augment
      reactions to stimuli above the noxious threshold. Cells with switch type response
      patterns may contribute to differential reactions evoked by CRD stimuli within
      the noxious range. In sum, RM and NRMC neurons respond to CRD with a variety of
      patterns, each of which may contribute to the sculpting of CRD reactions in
      different ways.

PMID- 15175368
TI  - Optical mapping reveals developmental dynamics of Mg2+-/APV-sensitive components
      of glossopharyngeal glutamatergic EPSPs in the embryonic chick NTS.
AB  - To examine whether there are any differences in functional organization between
      the glossopharyngeal nerve (N. IX)- and vagus nerve (N. X)-projecting areas in
      the nucleus of the tractus solitarius (NTS), we performed optical recording of
      neural responses evoked by N. IX stimulation in 5- to 9-day-old embryonic chick
      brain stem preparations and compared the results with those in our previous
      studies concerning the N. X-related NTS. First, we investigated DL-2-amino-5
      phosphonovaleric acid (APV)/Mg2+ sensitivity of the glutamatergic excitatory
      postsynaptic potentials (EPSPs) in the N. IX-related NTS. In 7- to 9-day-old
      preparations, we found regional differences in the degree of both the APV-induced
      reduction and Mg2+-free-induced enhancement of the EPSPs. We constructed
      developmental maps of spatial patterns of the APV- and Mg2+-sensitive components
      and showed that functional expression of the N-methyl-D-aspartate (NMDA) receptor
      dynamically changed during development. Second, we studied initial expression of
      synaptic functions in the N. IX-related NTS. In 6-day-old preparations, although
      action potentials alone were usually detected in normal Ringer solution, small
      EPSPs were elicited in a Mg2+-free solution. This result suggests that the NMDA
      receptor-mediated synaptic function is latently generated in the N. IX-related
      NTS at the 6-day-old embryonic stage and that external Mg2+ regulates the onset
      of synaptic functions. Developmental patterns of APV/Mg2+ sensitivity and the
      stage of initial expression of the glossopharyngeal EPSP were similar to those of
      the N. X, suggesting that the developmental sequence of the synaptic function in
      the NTS is the same for the N. IX- and N. X-related NTS.

PMID- 15175369
TI  - Voltage-gated ion channels in nociceptors: modulation by cGMP.
AB  - In tissue or nerve injury, proinflammatory mediators are released that can
      modulate a variety of ion channels found in nociceptors. The changes in channel
      activity, which primarily occurs through changes in intracellular pathways, may
      lead to the pathological states of hyperalgesia and allodynia. To understand
      further the regulatory mechanisms underlying the changes in channel activity, we
      used whole cell patch-clamp recordings from capsaicin-sensitive nociceptive
      neurons in rat trigeminal ganglion neurons to examine how the cGMP-dependent
      pathways may regulate ion channel function. Addition of the 8-(4
      chlorophenylthio)-3',5' (CPT)-cGMP, a membrane permeant modulator of ion
      channels, decreased the number of evoked action potentials by 36% and inhibited
      the tetrodotoxin-resistant (TTX-R) sodium currents and IA potassium currents by
      37 and 32%, respectively. Delayed rectifier potassium (IK) currents were
      unaffected, suggesting that the effects of CPT-cGMP are unlikely to arise from a
      nonspecific effect on channel activity as a consequence of the adsorption of
      amphipathic CPT-cGMP molecules to the membrane's bilayer component. This
      conclusion was reinforced by the lack of changes in gramicidin A channel function
      in the presence of CTP-cGMP. In summary, the activation of the cGMP-dependent
      pathways reduces nociceptor excitability, in part, by decreasing the activity of
      voltage-gated TTX-R sodium channels. This pathway may be a target for efforts to
      produce selective analgesics.

PMID- 15175370
TI  - Brief trains of action potentials enhance pyramidal neuron excitability via
      endocannabinoid-mediated suppression of inhibition.
AB  - Depolarization-induced suppression of inhibition (DSI) is a form of retrograde
      signaling at GABAergic synapses that is initiated by the calcium- and
      depolarization-dependent release of endocannabinoids from postsynaptic neurons.
      In the neocortex, pyramidal neurons (PNs) appear to use DSI as a mechanism for
      regulating somatic inhibition from a subpopulation of GABAergic inputs that
      express the type 1 cannabinoid receptor. Although postsynaptic control of
      afferent inhibition may directly influence the integrative properties of
      neocortical PNs, little is known about the patterns of activity that evoke
      endocannabinoid release and the impact such disinhibition may have on the
      excitability of PNs. Here we provide the first systematic survey of action
      potential (AP)-induced DSI in the neocortex. The magnitude and time course of DSI
      was directly related to the number and frequency of postsynaptic APs with
      significant suppression induced by a 20-Hz train containing as few as three APs.
      This AP-induced DSI was mediated by endocannabinoids as it was prevented by the
      cannabinoid receptor antagonist AM251 and potentiated by the endocannabinoid
      transport inhibitor AM404. We also explored the effects of endocannabinoid
      mediated DSI on PN excitability. We found that single AP trains markedly
      increased PN responsiveness to excitatory synaptic inputs and promoted AP
      discharge by suppressing GABAergic inhibition. The time course of this effect
      paralleled DSI expression and was completely blocked by AM251. Taken together,
      our data suggest a role for endocannabinoids in regulating the output of cortical
      PNs.

PMID- 15175371
TI  - Dexterous finger movements in primate without monosynaptic corticomotoneuronal
      excitation.
AB  - It is generally accepted that the precision grip and independent finger movements
      (IFMs) in monkey and man are controlled by the direct (monosynaptic)
      corticomotoneuronal (CM) pathway. This view is based on previous observations
      that pyramidotomy causes near permanent deficits of IFMs. However, in addition to
      the direct CM pathway, pyramidotomy interrupts several corticofugal connections
      to the brain stem and upper cervical segments. Indirect (oligosynaptic) CM
      pathways, which are phylogenetically older, have been considered to be of little
      or no importance in prehension. In three adult macaque monkeys, complete
      transection of the direct CM pathway was made in C4/C5, which is rostral to the
      forelimb segments (C6-Th1). Electrophysiological recordings revealed lack of the
      direct lateral corticospinal tract (LCST) volley, monosynaptic extracellular
      field potentials in the motor nuclei, and monosynaptic CM excitation. However, a
      disynaptic volley, disynaptic field potentials and disynaptic CM excitation
      mediated via C3-C4 propriospinal neurons remained after the lesion. Thus the
      lesion interrupted the monosynaptic CM pathway and oligosynaptic LCST pathways
      mediated by interneurons in the forelimb segments. Precision grip and IFMs were
      observed already after 1-28 days postoperatively. Weakness in force and deficits
      in preshaping remained for an observation period of 3 mo. Indirect CM pathways
      may be important for neuro-rehabilitation.

PMID- 15175372
TI  - Brain state-dependency of coherent oscillatory activity in the cerebral cortex
      and basal ganglia of the rat.
AB  - The nature of the coupling between neuronal assemblies in the cerebral cortex and
      basal ganglia (BG) is poorly understood. We tested the hypothesis that coherent
      population activity is dependent on brain state, frequency range, and/or BG
      nucleus using data from simultaneous recordings of electrocorticogram (ECoG) and
      BG local field potentials (LFPs) in anesthetized rats. The coherence between ECoG
      and LFPs simultaneously recorded from subthalamic nucleus (STN), globus pallidus
      (GP), and substantia nigra pars reticulata (SNr) was largely confined to slow- (
      approximately 1 Hz) and spindle- (7-12 Hz) frequency oscillations during slow
      wave activity (SWA). In contrast, during cortical activation, coherence was
      mostly restricted to high-frequency oscillations (15-60 Hz). The coherence
      between ECoG and LFPs also depended on BG recording site. Partial coherence
      analyses showed that, during SWA, STN and SNr shared the same temporal coupling
      with cortex, thereby forming a single functional axis. Cortex was also tightly,
      but independently, correlated with GP in a separate functional axis. During
      activation, STN, GP, and, to a lesser extent, SNr shared the same coherence with
      cortex as part of one functional axis. In addition, GP formed a second,
      independently coherent loop with cortex. These data suggest that coherent
      oscillatory activity is present at the level of LFPs recorded in cortico-basal
      ganglia circuits, and that synchronized population activity is dynamically
      organized according to brain state, frequency, and nucleus. These attributes
      further suggest that synchronized activity should be considered as one of a
      number of candidate mechanisms underlying the functional organization of these
      brain circuits.

PMID- 15175373
TI  - Origin of orientation-dependent asymmetries in vestibulo-ocular reflexes evoked
      by caloric stimulation.
AB  - A caloric stimulus evokes primarily a horizontal vestibulo-ocular reflex (VOR)
      when subjects are in a supine or prone orientation with the horizontal
      semicircular canal plane oriented vertically. In both monkeys and humans, the
      magnitude of VOR eye movements is greater in the supine than in the prone
      orientation, indicating that some factor or factors, other than the
      conventionally accepted convective stimulation of the horizontal canals,
      contributes to the generation of the VOR. We used long-duration caloric
      irrigations and mathematical models of canal-otolith interactions to investigate
      factors contributing to the prone/supine asymmetry. Binaural caloric irrigations
      were applied for 7.5 or 9.5 min with subjects in a null orientation with
      horizontal canals in the earth-horizontal plane (control trial), or with the
      subject's pitch orientation periodically changing between null, supine, and prone
      positions with each orientation held for 30 s (caloric step trial). The control
      trial responses identified a small response attributable to a direct thermal
      effect on vestibular afferent activity that accounted for only 15% of the
      observed prone/supine asymmetry. We show that the gravito-inertial force
      resolution hypothesis for sensory integration of canal and otolith information
      predicts that the central processing of canal and otolith information produces an
      internal estimate of motion that includes both a rotational motion component and
      a linear acceleration component. These components evoke a horizontal angular VOR
      and linear VOR, which combine additively in the supine orientation, but subtract
      in the prone orientation, thus accounting for the majority of the observed
      prone/supine asymmetry.

PMID- 15175374
TI  - Afferent-induced changes in rhythmic motor programs in the feeding circuitry of
      aplysia.
AB  - A manipulation often used to determine whether a neuron plays a role in the
      generation of a motor program involves injecting current into the cell during
      rhythmic activity to determine whether activity is modified. We perform this type
      of manipulation to study the impact of afferent activity on feeding-like motor
      programs in Aplysia. We trigger biting-like programs and manipulate sensory
      neurons that have been implicated in producing the changes in activity that occur
      when food is ingested, i.e., when bites are converted to bite-swallows. Sensory
      neurons that are manipulated are the radula mechanoafferent B21 and the
      retraction proprioceptor B51. Data suggest that both cells are peripherally
      activated during radula closing/retraction when food is ingested. We found that
      phasic subthreshold depolarization of a single sensory neuron can significantly
      prolong radula closing/retraction, as determined by recording both from
      interneurons (e.g., B64), and motor neurons (e.g., B15 and B8). Additionally,
      afferent activity produces a delay in the onset of the subsequent radula
      opening/protraction, and increases the firing frequency of motor neurons. These
      are the changes in activity that are seen when food is ingested. These results
      add to the growing data that implicate B21 and B51 in bite to bite-swallow
      conversions and indicate that afferent activity is important during feeding in
      Aplysia.

PMID- 15175375
TI  - How retinal ganglion cells prevent synaptic noise from reaching the spike output.
AB  - Synaptic vesicles are released stochastically, and therefore stimuli that
      increase a neuron's synaptic input might increase noise at its spike output.
      Indeed this appears true for neurons in primary visual cortex, where spike output
      variability increases with stimulus contrast. But in retinal ganglion cells,
      although intracellular recordings (with spikes blocked) showed that stronger
      stimuli increase membrane fluctuations, extracellular recordings showed that
      noise at the spike output is constant. Here we show that these seemingly
      paradoxical findings occur in the same cell and explain why. We made
      intracellular recordings from ganglion cells, in vitro, and presented periodic
      stimuli of various contrasts. For each stimulus cycle, we measured the response
      at the stimulus frequency (F1) for both membrane potential and spikes as well as
      the spike rate. The membrane and spike F1 response increased with contrast, but
      noise (SD) in the F1 responses and the spike rate was constant. We also measured
      membrane fluctuations (with spikes blocked) during the response depolarization
      and found that they did increase with contrast. However, increases in fluctuation
      amplitude were small relative to the depolarization (<10% at high contrast). A
      model based on estimated synaptic convergence, release rates, and membrane
      properties accounted for the relative magnitudes of fluctuations and
      depolarization. Furthermore, a cell's peak spike response preceded the peak
      depolarization, and therefore fluctuation amplitude peaked as the spike response
      declined. We conclude that two extremely general properties of a neuron, synaptic
      convergence and spike generation, combine to minimize the effects of membrane
      fluctuations on spiking.

PMID- 15175376
TI  - Laminar specific distribution of lateral excitatory connections in the rat
      superior colliculus.
AB  - Premovement activities in neurons in the intermediate gray layer [stratum griseum
      intermediale (SGI)] of the mammalian superior colliculus (SC) are essential for
      initiation of orienting behaviors such as saccades. Our previous study
      demonstrated that burst activities are induced by synchronous activation of SGI
      neurons communicating within a local excitatory network, which depends on NMDA
      receptor-dependent synaptic transmission and release from GABAA inhibition.
      Furthermore, dual whole cell recordings from adjacent neurons in SGI revealed
      that application of 10 microM bicuculline (Bic) and reduction of extracellular
      Mg2+ concentration (to 0.1 mM) induce spontaneous depolarization that is
      synchronous between neuron pairs, suggesting the recruitment of a large number of
      neurons communicating through intense excitatory connections. In the present
      study, we investigated the properties of synchronous depolarization and the
      fundamental structure of the lateral excitatory network that recruits a neuronal
      population in SC to synchronous activation, by analyzing the synchronicity of
      spontaneous depolarization induced in the presence of Bic plus low Mg2+. We found
      that 1) spontaneous depolarization exhibits bidirectional horizontal propagation
      among the SGI neuron pairs; 2) induction of spontaneous depolarization is not
      caused by activation of intrinsic voltage-dependent conductances; 3) neurons
      exposed to low Mg2+ alone exhibit spontaneous depolarization, although in this
      case the depolarization is less synchronous; and 4) neurons exposed to Bic alone
      exhibit synchronous depolarization, but less frequently than those exposed to
      both Bic and low Mg2+. Analysis of the synchronicity of spontaneous
      depolarization indicates that the distribution of lateral excitatory connections
      is markedly different among layers of SC; the SGI neurons form extensive lateral
      excitatory connections, whereas they are sparse or limited within subsets of
      neurons in the stratum griseum superficiale (SGS). Wide-field vertical neurons in
      the stratum opticum have features intermediate between neurons in the SGS and
      SGI. Such differences in the structure of lateral excitatory connections may
      reflect the different way signal processing is achieved in each layer of SC.

PMID- 15175377
TI  - Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation
      by a cysteine-modifying reagent.
AB  - The cysteine-modifying reagent N-ethylmaleimide (NEM) is known to augment
      currents from native M-channels in sympathetic neurons and cloned KCNQ2 channels.
      As a probe for channel function, we investigated the mechanism of NEM action and
      subunit specificity of cloned KCNQ2-5 channels expressed in Chinese hamster ovary
      cells at the whole-cell and single-channel levels. Biotinylation assays and total
      internal reflection fluorescence microscopy indicated that NEM action is not
      caused by increased trafficking of channels to the membrane. At saturating
      voltages, whole-cell currents of KCNQ2, KCNQ4, and KCNQ5 but not KCNQ3 were
      augmented threefold to fourfold by 50 microm NEM, and their voltage dependencies
      were negatively shifted by 10-20 mV. Unitary conductances of KCNQ2 and KCNQ3 (6.2
      and 8.5 pS, respectively) were much higher that those of KCNQ4 and KCNQ5 (2.1 and
      2.2 pS, respectively). Surprisingly, the maximal open probability (P(o)) of KCNQ3
      was near unity, much higher than that of KCNQ2, KCNQ4, and KCNQ5. NEM increased
      the P(o) of KCNQ2, KCNQ4, and KCNQ5 by threefold to fourfold but had no effect on
      their unitary conductances, suggesting that the increase in macroscopic currents
      can be accounted for by increases in P(o). Analysis of KCNQ3/4 chimeras
      determined the C terminus to be responsible for the differential maximal P(o),
      channel expression, and NEM action between the two channels. To further localize
      the site of NEM action, we mutated three cysteine residues in the C terminus of
      KCNQ4. The C519A mutation alone ablated most of the augmentation by NEM,
      suggesting that NEM acts via alkylation of this residue.

PMID- 15175379
TI  - Chandelier cells control excessive cortical excitation: characteristics of
      whisker-evoked synaptic responses of layer 2/3 nonpyramidal and pyramidal
      neurons.
AB  - Chandelier cells form inhibitory axo-axonic synapses on pyramidal neurons with
      their characteristic candlestick-like axonal terminals. The functional role of
      chandelier cells is still unclear, although the preferential loss of this cell
      type at epileptic loci suggests a role in epilepsy. Here we report an examination
      of whisker- and spontaneous activity-evoked responses in chandelier cells and
      other fast-spiking nonpyramidal neurons and regular-spiking pyramidal neurons in
      layer 2/3 of the barrel cortex. Fast-spiking nonpyramidal neurons, including
      chandelier cells, basket cells, neurogliaform cells, double bouquet cells, net
      basket cells, bitufted cells, and regular-spiking pyramidal neurons all respond
      to stimulation of multiple whiskers on the contralateral face. Whisker
      stimulation, however, evokes small, delayed EPSPs preceded by an earlier IPSP and
      no action potentials in chandelier cells, different from other nonpyramidal and
      pyramidal neurons. In addition, chandelier cells display a larger receptive field
      with lower acuity than other fast-spiking nonpyramidal neurons and pyramidal
      neurons. Notably, simultaneous dual whole-cell in vivo recordings show that
      chandelier cells, which rarely fire action potentials spontaneously, fire more
      robustly than other types of cortical neurons when the overall cortical
      excitation increases. Thus, chandelier cells may not process fast ascending
      sensory information but instead may be reserved to prevent excessive excitatory
      activity in neuronal networks.

PMID- 15175378
TI  - Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y
      expression in the dorsomedial hypothalamus during lactation.
AB  - In several hyperphagic models, including lactation, in which hypothalamic
      melanocortin signaling is reduced, a novel expression of NPY mRNA in the
      dorsomedial hypothalamus (DMH) has been observed, suggesting that melanocortin
      signaling and the induced NPY in the DMH may constitute unique neurocircuitry in
      mediating energy balance. Using lactating rats as a model, the present study
      first showed that in the DMH abundant alpha-MSH and agouti-related protein fibers
      are in close apposition to NPY-positive cells. However, no NPY and MC4R (a
      melanocortin receptor) double-labeled neurons were observed. These data suggested
      that melanocortin input may synapse on presynaptic terminals that then synapse on
      DMH NPY cells. To study the function of DMH MC4Rs in energy balance, an MC3/4R
      selective agonist, melanotan II (MTII), was injected bilaterally into the DMH.
      MTII injection significantly suppressed feeding induced by 24 hr fasting or
      suckling-induced hyperphagia. Furthermore, MTII treatment greatly attenuated
      suckling-induced NPY expression in the DMH. MTII treatment also stimulated
      uncoupling protein 1 activity in the brown adipose tissue of suckling female
      rats, indicative of increased sympathetic outflow. In summary, the present study
      demonstrated that the melanocortin system in the DMH not only plays an important
      role in inducing NPY expression in the DMH of lactating rats but also in
      regulating energy homeostasis, at least in part, by modulating appetite and
      energy expenditure.

PMID- 15175380
TI  - A cholinergic synaptically triggered event participates in the generation of
      persistent activity necessary for eye fixation.
AB  - An exciting topic regarding integrative properties of the nervous system is how
      transient motor commands or brief sensory stimuli are able to evoke persistent
      neuronal changes, mainly as a sustained, tonic action potential firing. A
      persisting firing seems to be necessary for postural maintenance after a previous
      movement. We have studied in vitro and in vivo the generation of the persistent
      neuronal activity responsible for eye fixation after spontaneous eye movements.
      Rat sagittal brainstem slices were used for the intracellular recording of
      prepositus hypoglossi (PH) neurons and their synaptic activation from nearby
      paramedian pontine reticular formation (PPRF) neurons. Single electrical pulses
      applied to the PPRF showed a monosynaptic glutamatergic projection on PH neurons,
      acting on AMPA-kainate receptors. Train stimulation of the PPRF area evoked a
      sustained depolarization of PH neurons exceeding (by hundreds of milliseconds)
      stimulus duration. Both duration and amplitude of this sustained depolarization
      were linearly related to train frequency. The train-evoked sustained
      depolarization was the result of interaction between glutamatergic excitatory
      burst neurons and cholinergic mesopontine reticular fibers projecting onto PH
      neurons, because it was prevented by slice superfusion with cholinergic
      antagonists and mimicked by cholinergic agonists. As expected, microinjections of
      cholinergic antagonists in the PH nucleus of alert behaving cats evoked a gaze
      holding deficit consisting of a re-centering drift of the eye after each saccade.
      These findings suggest that a slow, cholinergic, synaptically triggered event
      participates in the generation of persistent activity characteristic of PH
      neurons carrying eye position signals.

PMID- 15175381
TI  - Distinct roles of Galpha(q) and Galpha11 for Purkinje cell signaling and motor
      behavior.
AB  - G-protein-coupled metabotropic glutamate group I receptors (mGluR1s) mediate
      synaptic transmission and plasticity in Purkinje cells and, therefore, critically
      determine cerebellar motor control and learning. Purkinje cells express two
      members of the G-protein G(q) family, namely G(q) and G11. Although in vitro
      coexpression of mGluR1 with either Galpha11 or Galpha(q) produces equally well
      functioning signaling cascades, Galpha(q)- and Galpha11-deficient mice exhibit
      distinct alterations in motor coordination. By using whole-cell recordings and
      Ca2+ imaging in Purkinje cells, we show that Galpha(q) is required for mGluR
      dependent synaptic transmission and for long-term depression (LTD). Galpha11 has
      no detectable contribution for synaptic transmission but also contributes to LTD.
      Quantitative single-cell RT-PCR analyses in Purkinje cells demonstrate a more
      than 10-fold stronger expression of Galpha(q) versus Galpha11. Our findings
      suggest an expression level-dependent action of Galpha(q) and Galpha11 for
      Purkinje cell signaling and assign specific roles of these two G(q) isoforms for
      motor coordination.

PMID- 15175382
TI  - Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell
      excitability involve multiple signaling mechanisms.
AB  - Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive
      functions is widely recognized, the nature of DA actions in the PFC remains
      controversial. A critical component in DA actions is its modulation of glutamate
      transmission, which can be different when specific receptors are activated. To
      obtain a clear picture of cellular mechanisms involved in these interactions, we
      studied the effects of DA-glutamate coactivation on pyramidal cell excitability
      in brain slices obtained from developmentally mature rats using whole-cell patch
      clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393
      induced concentration-dependent excitability increases, whereas bath application
      of the D2 receptor agonist quinpirole induced a concentration-dependent
      excitability decrease. The NMDA-mediated response was potentiated by SKF38393.
      This NMDA-D1 synergism required postsynaptic intracellular Ca2+ and protein
      kinase A (PKA) and was independent of membrane depolarization. On the other hand,
      the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist.
      Surprisingly, the D2-NMDA interaction was also blocked by the GABA(A) antagonists
      bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors
      on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons.
      In contrast, the D2-AMPA interaction involves inhibition of PKA and activation of
      phospholipase lipase C-IP3 and intracellular Ca2+ at a postsynaptic level. Thus,
      the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability
      are mediated by multiple intracellular mechanisms and by activation of GABA(A)
      receptors, depending on the glutamate receptor subtypes involved.

PMID- 15175383
TI  - Dynamic interaction of oscillatory neurons coupled with reciprocally inhibitory
      synapses acts to stabilize the rhythm period.
AB  - In the rhythmically active pyloric circuit of the spiny lobster, the pyloric
      dilator (PD) neurons are members of the pacemaker group of neurons that make
      inhibitory synapses onto the follower lateral pyloric (LP) neuron. The LP neuron,
      in turn, makes a depressing inhibitory synapse to the PD neurons, providing the
      sole inhibitory feedback from the pyloric network to its pacemakers. This study
      investigates the dynamic interaction between the pyloric cycle period, the two
      types of neurons, and the feedback synapse in biologically realistic conditions.
      When the rhythm period was changed, the membrane potential waveform of the LP
      neuron was affected with a consistent pattern. These changes in the LP neuron
      waveform directly affected the dynamics of the LP to PD synapse and caused the
      postsynaptic potential (PSP) in the PD neurons to both peak earlier in phase and
      become larger in amplitude. Using an artificial synapse implemented in dynamic
      clamp, we show that when the LP to PD PSP occurred early in phase, it acted to
      speed up the pyloric rhythm, and larger PSPs also strengthened this trend.
      Together, these results indicate that interactions between these two types of
      neurons can dynamically change in response to increases in the rhythm period, and
      this dynamic change provides a negative feedback to the pacemaker group that
      could work to stabilize the rhythm period.

PMID- 15175384
TI  - A novel mechanism for the facilitation of theta-induced long-term potentiation by
      brain-derived neurotrophic factor.
AB  - Brain-derived neurotrophic factor (BDNF) contributes to the induction of long
      term potentiation (LTP) by theta-pattern stimulation, but the specific processes
      underlying this effect are not known. Experiments described here, using BDNF
      concentrations that have minor effects on baseline responses, show that the
      neurotrophin both reduces the threshold for LTP induction and elevates the
      ceiling on maximal potentiation. The enhanced LTP proved to be as stable and
      resistant to reversal as that recorded under control conditions. BDNF markedly
      increased the facilitation of burst responses that occurs within a theta train.
      This suggests that the neurotrophin acts on long-lasting events that (1) are set
      in motion by the first burst in a train and (2) regulate the amplitude of
      subsequent bursts. Whole-cell recordings established that BDNF causes a rapid
      reduction in the size of the long-lasting afterhyperpolarization (AHP) that
      follows individual theta bursts. Apamin, an antagonist of type 2 small
      conductance Ca2+-activated potassium (SK2) channels, also reduced hippocampal
      AHPs and closely reproduced the effects of BDNF on theta-burst responses and LTP.
      The latter results were replicated with a newly introduced, highly selective
      inhibitor of SK2 channels. Immunoblot analyses indicated that BDNF increases SK2
      serine phosphorylation in hippocampal slices. These findings point to the
      conclusion that BDNF-driven protein kinase cascades serve to depress the SK2
      component, and possibly other constituents, of the AHP. It is likely that this
      mechanism, acting with other factors, promotes the formation and increases the
      magnitude of LTP.

PMID- 15175385
TI  - Dopamine modulates use-dependent plasticity of inhibitory synapses.
AB  - The release of the hormones oxytocin (OT) and vasopressin (VP) into the
      circulation is dictated by the electrical activity of hypothalamic magnocellular
      neurosecretory cells (MNCs). In the paraventricular nucleus of the hypothalamus
      (PVN), MNC neuronal activity is exquisitely sensitive to changes in input from
      inhibitory GABAergic synapses. To explore the hypothesis that efficacy at these
      synapses is dictated by the rate at which a given synapse is activated, we
      obtained whole-cell recordings from MNCs in postnatal day 21-27 male Sprague
      Dawley rat brain slices. IPSCs were elicited by electrically stimulating
      GABAergic projections from either the suprachiasmatic nucleus or putative
      interneuron populations immediately ventral to the fornix at 5, 10, 20, and 50
      Hz. Short-term plasticity was observed at 88% of the synapses tested. Of this
      group, synaptic depression was observed in 58%, and synaptic facilitation was
      observed in 41%. Identification of cells using a combined electrophysiological
      and immunohistochemical approach revealed a strong correlation between cell
      phenotype and the nature of the plasticity. Short-term facilitation was observed
      preferentially in OT cells (86%), whereas short-term depression was predominant
      in VP neurons (69%). We next examined the effects of dopamine, which increases
      MNC excitability, on short-term plasticity. Activation of presynaptic D(4)
      receptors decreased the frequency of miniature IPSCs and prevented the
      development of synaptic depression at higher rates of activity. Synaptic
      facilitation, however, was unaffected by dopamine. These findings demonstrate
      that, by lowering GABA release probability, dopamine confers high-pass filtering
      properties to the majority of inhibitory synapses onto MNCs in PVN.

PMID- 15175386
TI  - Removal of AMPA receptors (AMPARs) from synapses is preceded by transient
      endocytosis of extrasynaptic AMPARs.
AB  - AMPA receptors (AMPARs) are dynamically regulated at synapses, but the time
      course and location of their exocytosis and endocytosis are not known. Therefore,
      we have used ecliptic pHluorin-tagged glutamate receptor 2 to visualize changes
      in AMPAR surface expression in real time. We show that synaptic and extrasynaptic
      AMPARs respond very differently to NMDA receptor activation; there is a rapid
      internalization of extrasynaptic AMPARs that precedes the delayed removal of
      synaptic AMPARs.

PMID- 15175387
TI  - 2-aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel
      TRPV3.
AB  - Six of the mammalian transient receptor potential (TRP) ion channel subtypes are
      nonselective cation channels that can be activated by increases or decreases in
      ambient temperature. Five of them can alternatively be activated by nonthermal
      stimuli such as capsaicin [transient receptor potential vanilloid 1 (TRPV1)] or
      hypo-osmolarity (TRPV2 and TRPV4). No nonthermal stimuli have yet been described
      for TRPV3, a warmth-gated ion channel expressed prominently in skin
      keratinocytes. Here, we demonstrate that 2-aminoethoxydiphenyl borate (2-APB), a
      compound used to inhibit store-operated Ca2+ channels and IP3 receptors, produces
      robust activation of recombinant TRPV3 in human embryonic kidney 293 cells with
      an EC50 of 28 microm. 2-APB also sensitizes TRPV3 to activation by heat, even at
      subthreshold concentrations. In inside-out membrane patches from TRPV3-expressing
      cells, 2-APB increases the open probability of TRPV3. Also, whereas heat alone is
      capable of activating TRPV3-mediated currents in only a small proportion of
      primary mouse keratinocytes, 2-APB activates heat-evoked, TRPV3-mediated currents
      in the majority of these cells. Together, these findings identify 2-APB as the
      first known chemical activator of TRPV3 and enhance the notion that TRPV3
      participates in the detection of heat by keratinocytes.

PMID- 15175388
TI  - Identification of motifs involved in endoplasmic reticulum retention-forward
      trafficking of the GLT-1 subtype of glutamate transporter.
AB  - Glutamate transporters may exist as homomultimers, but little is known about the
      mechanisms that ensure proper assembly and surface expression. In the present
      study, we investigated the mechanisms that contribute to posttranslational
      processing of the GLT-1 subtype of glutamate transporter. An extracellular
      leucine-based motif was identified that after mutation to alanine (6L/6A GLT-1)
      prevented export of GLT-1 from the endoplasmic reticulum (ER) to the plasma
      membrane and displayed a glycosylation pattern characteristic of "immature"
      transporter. This 6L/6A variant had a selective dominant-negative effect on wild
      type GLT-1 expression and formed coimmunoprecipitable complexes with GLT-1.
      Mutation of two downstream arginine residues to alanine partially restored
      maturation and functional activity of the 6L/6A variant. The fact that this
      additional mutation rescued maturation of GLT-1 essentially excludes the
      possibility that the 6L/6A mutant variant is not appropriately processed because
      of simple misfolding. When the domain containing these motifs was introduced into
      a topologically similar location in the interleukin 2alpha receptor subunit (Tac
      protein), the mutations had a similar effect on protein maturation. Topological
      models place at least the leucine-based motif in an extracellular domain, which
      would face the lumen of the ER during assembly. On the basis of these data, we
      suggest that an evolutionarily conserved arginine-based motif functions as an ER
      retention signal and a lumenal leucine motif is required for suppression of this
      signal. Interestingly, a high percentage of variably spliced GLT-1 mRNAs lacking
      parts of this domain are found in the CNS, suggesting that GLT-1 expression may
      be regulated during assembly.

PMID- 15175389
TI  - Cytoplasmic polyadenylation element binding protein-dependent protein synthesis
      is regulated by calcium/calmodulin-dependent protein kinase II.
AB  - Phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB)
      regulates protein synthesis in hippocampal dendrites. CPEB binds the 3'
      untranslated region (UTR) of cytoplasmic mRNAs and, when phosphorylated,
      initiates mRNA polyadenylation and translation. We report that, of the protein
      kinases activated in the hippocampus during synaptic plasticity,
      calcium/calmodulin-dependent protein kinase II (CaMKII) robustly phosphorylated
      the regulatory site (threonine 171) in CPEB in vitro. In postsynaptic density
      fractions or hippocampal neurons, CPEB phosphorylation increased when CaMKII was
      activated. These increases in CPEB phosphorylation were attenuated by a specific
      peptide inhibitor of CaMKII and by the general CaM-kinase inhibitor KN-93.
      Inhibitors of protein phosphatase 1 increased basal CPEB phosphorylation in
      neurons; this was also attenuated by a CaM-kinase inhibitor. To determine whether
      CaM-kinase activity regulates CPEB-dependent mRNA translation, hippocampal
      neurons were transfected with luciferase fused to a 3' UTR containing CPE-binding
      elements. Depolarization of neurons stimulated synthesis of luciferase; this was
      abrogated by inhibitors of protein synthesis, mRNA polyadenylation, and CaMKII.
      These results demonstrate that CPEB phosphorylation and translation are regulated
      by CaMKII activity and provide a possible mechanism for how dendritic protein
      synthesis in the hippocampus may be stimulated during synaptic plasticity.

PMID- 15175390
TI  - Presynaptic mechanism underlying cAMP-dependent synaptic potentiation.
AB  - The adenylyl cyclase activator forskolin presynaptically facilitates synaptic
      transmission at many synapses, but the exact intracellular mechanism underlying
      this effect is not known. We studied this issue at the calyx of Held, where it is
      possible to make simultaneous presynaptic and postsynaptic whole-cell recordings.
      Bath application of forskolin or intracellular application of cAMP into
      presynaptic terminals strongly potentiated EPSCs. The forskolin-induced synaptic
      potentiation was associated with increases in release probability (P) and number
      of releasable synaptic vesicles (N). Forskolin had no effect on the peak
      amplitudes of presynaptic Ca2+ currents or K+ currents, suggesting that the main
      target of cAMP resides in downstream of Ca2+ influx. Intracellular application of
      the selective Epac agonist 8-(4-chlorophenylthio)-2'-O-methyl-cAMP into
      presynaptic terminals potentiated EPSCs, suggesting that Epac is the main target
      of cAMP-induced synaptic potentiation. We conclude that an increase in cAMP
      concentration in the nerve terminal facilitates transmitter release by increasing
      both release probability and number of releasable vesicles via activating the
      Epac pathway at the calyx of Held.

PMID- 15175391
TI  - Cocaine self-administration selectively decreases noradrenergic regulation of
      metabotropic glutamate receptor-mediated inhibition in dopamine neurons.
AB  - Stimulant drugs of abuse have several effects on neural activity, including
      altering the excitability of dopamine neurons via the noradrenergic and
      glutamatergic systems. Thus, an interaction between noradrenergic and
      glutamatergic systems may play a role in drug-seeking behavior. Although many of
      the direct pharmacological effects of psychostimulants on dopamine neuron
      physiology are well established, the neurophysiological bases of drug-seeking
      behavior have yet to be fully elucidated. The present study measured short-term
      (3 d) and long-term (14 d) access to cocaine, by self-administration or passive
      exposure, and the regulation of metabotropic glutamate receptor (mGluR)-mediated
      inhibition of dopamine cells in rat midbrain slices. The results indicated that
      alpha-adrenoreceptor modulation of the mGluR-mediated inhibition is selectively
      reduced in animals that self-administered cocaine for 3 d. This effect was not
      observed in slices from either yoked cocaine animals, which were given cocaine in
      an amount and pattern equal to that used for the self-administering animals, or
      saline control animals. However, after 14 d of cocaine, alpha-adrenoreceptor
      regulation of the mGluR-mediated inhibition was equally reduced in both self
      administering and yoked cocaine animals relative to saline controls. The results
      suggest that alpha-adrenoreceptor regulation of the mGluR-mediated inhibition is
      an adaptive cellular mechanism involved in early cocaine self-administration that
      is distinct from a direct pharmacological effect of cocaine on dopamine neurons.
      The noradrenergic system could therefore serve to alter the reward value of
      stimuli that have significant effects on dopamine neuron firing pattern through
      mGluRs.

PMID- 15175392
TI  - Neuronal avalanches are diverse and precise activity patterns that are stable for
      many hours in cortical slice cultures.
AB  - A major goal of neuroscience is to elucidate mechanisms of cortical information
      processing and storage. Previous work from our laboratory (Beggs and Plenz, 2003)
      revealed that propagation of local field potentials (LFPs) in cortical circuits
      could be described by the same equations that govern avalanches. Whereas modeling
      studies suggested that these "neuronal avalanches" were optimal for information
      transmission, it was not clear what role they could play in information storage.
      Work from numerous other laboratories has shown that cortical structures can
      generate reproducible spatiotemporal patterns of activity that could be used as a
      substrate for memory. Here, we show that although neuronal avalanches lasted only
      a few milliseconds, their spatiotemporal patterns were also stable and
      significantly repeatable even many hours later. To investigate these issues, we
      cultured coronal slices of rat cortex for 4 weeks on 60-channel microelectrode
      arrays and recorded spontaneous extracellular LFPs continuously for 10 hr. Using
      correlation-based clustering and a global contrast function, we found that each
      cortical culture spontaneously produced 4736 +/- 2769 (mean +/- SD) neuronal
      avalanches per hour that clustered into 30 +/- 14 statistically significant
      families of spatiotemporal patterns. In 10 hr of recording, over 98% of the
      mutual information shared by these avalanche patterns were retained.
      Additionally, jittering analysis revealed that the correlations between
      avalanches were temporally precise to within +/-4 msec. The long-term stability,
      diversity, and temporal precision of these avalanches indicate that they fulfill
      many of the requirements expected of a substrate for memory and suggest that they
      play a central role in both information transmission and storage within cortical
      networks.

PMID- 15175393
TI  - A specific synaptic pathway activates a conditional plateau potential underlying
      protraction phase in the Aplysia feeding central pattern generator.
AB  - A common feature in the architecture of neuronal networks is a high degree of
      seemingly redundant synaptic connectivity. In many cases, the synaptic inputs
      converging on any particular neuron all use the same neurotransmitter and appear
      to be fundamentally equivalent. Here, we analyze a striking counterexample in
      which such inputs are not equivalent and, as a result, play very different roles
      in the generation of the pattern of activity produced by the network. In the
      feeding central pattern generator of Aplysia, the pattern-initiating neuron B50
      elicits motor programs by exciting the plateauing neuron B31/B32 in two ways:
      directly and indirectly through neuron B63. All of the synaptic connections use
      ACh. Despite the direct input of B50 to B31/B32, the indirect pathway of exciting
      B31/B32 through B63 is required for B50 to elicit the B31/B32 plateau potential
      and the motor program. We dissect this requirement using the muscarinic
      cholinergic antagonist pirenzepine. Pirenzepine blocks the B50-elicited motor
      program, the plateau potential in B31/B32, and, notably, a slow component of the
      EPSP elicited in B31/B32 by B63 but not that elicited by B50. The muscarinic
      agonist oxotremorine restores the plateau potential in B31/B32 and eliminates the
      necessity for B63 in B50-elicited motor programs. Together, our analysis shows
      that the plateau potential in B31/B32 is not endogenous but conditional,
      furthermore conditional on one particular synaptic input, that from B63. Thus,
      among several inputs to B31/B32 that use the same transmitter, the input from B63
      is functionally distinct in its preferential access to the plateau potential that
      represents the committed step toward the initiation of a motor program.

PMID- 15175394
TI  - Elevated thalamic low-voltage-activated currents precede the onset of absence
      epilepsy in the SNAP25-deficient mouse mutant coloboma.
AB  - Recessive mutations in genes encoding voltage-gated Ca2+ channel subunits alter
      high-voltage-activated (HVA) calcium currents, impair neurotransmitter release,
      and stimulate thalamic low-voltage-activated (LVA) currents that contribute to a
      cortical spike-wave epilepsy phenotype in mice. We now report thalamic LVA
      current elevations in a non-Ca2+ channel mutant. EEG analysis of Coloboma (Cm/+),
      an autosomal dominant mutant mouse lacking one copy of the gene for a
      synaptosomal-associated protein (SNAP25) that interacts with HVA channels,
      reveals abnormal spike-wave discharges (SWDs) in the behaving animal. We compared
      the biophysical properties of both LVA and HVA currents in Cm/+ and wild-type
      thalamic neurons and observed a 54% increase in peak current density of LVA
      currents evoked at -50 mV from -110 mV in Cm/+ before the developmental onset of
      seizures relative to control. The midpoint voltage for steady-state inactivation
      of LVA currents in Cm/+ was shifted in a depolarized direction by 8 mV before
      epilepsy onset, and the mean time constant for decay of LVA Ca2+ currents at -50
      mV was also prolonged. No significant differences were found in recovery from
      inactivation of LVA currents or in HVA current densities and kinetics. Our data
      demonstrate that a non-Ca2+ channel subunit gene mutation leads to potentiated
      thalamic LVA currents that precede the appearance of SWDs and that altered
      somatodendritic HVA currents are not required for abnormal thalamocortical
      oscillations. We suggest that presynaptic release defects shared by these mutants
      lead to postsynaptic LVA excitability increases in thalamic pacemaker neurons
      that favor rebound bursting and absence epilepsy.

PMID- 15175395
TI  - Role of the alpha1G T-type calcium channel in spontaneous absence seizures in
      mutant mice.
AB  - Alterations in thalamic T-type Ca2+ channels are thought to contribute to the
      pathogenesis of absence seizures. Here, we found that mice with a null mutation
      for the pore-forming alpha1A subunits of P/Q-type channels (alpha1A-/- mice) were
      prone to absence seizures characterized by typical spike-and-wave discharges
      (SWDs) and behavioral arrests. Isolated thalamocortical relay (TC) neurons from
      these mice showed increased T-type Ca2+ currents in vitro. To examine the role of
      increased T-currents in alpha1A-/- TC neurons, we cross-bred alpha1A-/- mice with
      mice harboring a null mutation for the gene encoding alpha1G, a major isotype of
      T-type Ca2+ channels in TC neurons. alpha1A-/-/alpha1G-/- mice showed a complete
      loss of T-type Ca2+ currents in TC neurons and displayed no SWDs. Interestingly,
      alpha1A-/-/alpha1G+/- mice had 75% of the T-type Ca2+ currents in TC neurons
      observed in alpha1A+/+/alpha1G+/+ mice and showed SWD activity that was
      quantitatively similar to that in alpha1A-/-/alpha1G+/+ mice. Similar results
      were obtained using double-mutant mice harboring the alpha1G mutation plus
      another mutation also used as a model for absence seizures, i.e., lethargic
      (beta4(lh/lh)), tottering (alpha1A(tg/tg)), or stargazer (gamma2(stg/stg)). The
      present results reveal that alpha1G T-type Ca2+ channels play a critical role in
      the genesis of spontaneous absence seizures resulting from hypofunctioning P/Q
      type channels, but that the augmentation of thalamic T-type Ca2+ currents is not
      an essential step in the genesis of absence seizures.

PMID- 15175396
TI  - Functional integration of embryonic stem cell-derived neurons in vivo.
AB  - Pluripotency and the potential for continuous self-renewal make embryonic stem
      (ES) cells an attractive donor source for neuronal cell replacement. Despite
      recent encouraging results in this field, little is known about the functional
      integration of transplanted ES cell-derived neurons on the single-cell level. To
      address this issue, ES cell-derived neural precursors exhibiting neuron-specific
      enhanced green fluorescent protein (EGFP) expression were introduced into the
      developing brain. Donor cells implanted into the cerebral ventricles of embryonic
      rats migrated as single cells into a variety of brain regions, where they
      acquired complex morphologies and adopted excitatory and inhibitory
      neurotransmitter phenotypes. Synaptic integration was suggested by the expression
      of PSD-95 (postsynaptic density-95) on donor cell dendrites, which in turn were
      approached by multiple synaptophysin-positive host axon terminals.
      Ultrastructural and electrophysiological data confirmed the formation of synapses
      between host and donor cells. Ten to 21 d after birth, all EGFP-positive donor
      cells examined displayed active membrane properties and received glutamatergic
      and GABAergic synaptic input from host neurons. These data demonstrate that, at
      the single-cell level, grafted ES cell-derived neurons undergo morphological and
      functional integration into the host brain circuitry. Antibodies to the region
      specific transcription factors Bf1, Dlx, En1, and Pax6 were used to explore
      whether functional donor cell integration depends on the acquisition of a
      regional phenotype. Our data show that incorporated neurons frequently exhibit a
      lacking or ectopic expression of these transcription factors. Thus, the lack of
      an appropriate regional "code" does not preclude morphological and synaptic
      integration of ES cell-derived neurons.

PMID- 15175397
TI  - Modular premotor drives and unit bursts as primitives for frog motor behaviors.
AB  - Spinal cord modularity impacts on our understanding of reflexes, development,
      descending systems in normal motor control, and recovery from injury. We used
      independent component analysis and best-basis or matching pursuit wavepacket
      analysis to extract the composition and temporal structure of bursts in hindlimb
      muscles of frogs. These techniques make minimal a priori assumptions about drive
      and motor pattern structure. We compared premotor drive and burst structures in
      spinal frogs with less reduced frogs with a fuller repertoire of locomotory,
      kicking, and scratching behaviors. Six multimuscle drives explain most of the
      variance of motor patterns (approximately 80%). Each extracted drive was
      activated with pulses at a single time scale or common duration (approximately
      275 msec) burst structure. The data show that complex behaviors in brainstem
      frogs arise as a result of focusing drives to smaller core groups of muscles.
      Brainstem drives were subsets of the muscle groups from spinal frogs. The 275
      msec burst duration was preserved across all behaviors and was most precise in
      brainstem frogs. These data support a modular decomposition of frog behaviors
      into a small collection of unit burst generators and associated muscle drives in
      spinal cord. Our data also show that the modular organization of drives seen in
      isolated spinal cord is fine-tuned by descending controls to enable a fuller
      movement repertoire. The unit burst generators and their associated muscle
      synergies extracted here link the biomechanical "primitives," described earlier
      in the frog, rat, and cat, and to the elements of pattern generation examined in
      fictive preparations.

PMID- 15175400
TI  - Radionuclide imaging of infection.
AB  - Although our understanding of microorganisms has advanced significantly and
      antimicrobial therapy has become increasingly available, infection remains a
      major cause of patient morbidity and mortality. The role of radionuclide imaging
      in the evaluation of the patient suspected of harboring an infection varies with
      the situation. For example, in the postoperative patient, radionuclide imaging is
      complementary to CT and is used to help differentiate postoperative changes from
      infection. In the case of the painful joint replacement, in contrast,
      radionuclide studies are the primary diagnostic imaging modality for
      differentiating infection from other causes of prosthetic failure. Several
      tracers are available for imaging infection: (99m)Tc-diphosphonates, (67)Ga
      citrate, and (111)In- and (99m)Tc-labeled leukocytes. At the moment, in
      immunocompetent patients, labeled leukocyte imaging is the radionuclide procedure
      of choice for detecting most infections. There are, unfortunately, significant
      limitations to the use of labeled leukocytes. The in vitro labeling process is
      labor intensive, is not always available, and involves direct handling of blood
      products. For musculoskeletal infection, the need to frequently perform
      complementary marrow or bone imaging adds complexity and expense to the procedure
      and is an inconvenience to patients. Considerable effort has therefore been
      devoted to the search for alternatives to this procedure, including in vivo
      methods of labeling leukocytes, (18)F-FDG PET, and radiolabeled antibiotics. This
      article reviews the current status of nuclear medicine infection imaging and the
      potential of a murine monoclonal antigranulocyte antibody, fanolesomab, that is
      currently under investigation. Upon completion of this article, the reader will
      be familiar with the physical characteristics and uptake mechanisms of tracers
      currently approved for infection imaging, the indications for the uses of these
      tracers, and the characteristics and potential indications for a murine
      monoclonal antigranulocyte antibody under investigation.

PMID- 15175401
TI  - Incidence and characterization of patient motion in myocardial perfusion SPECT:
      Part 1.
AB  - Despite advances in (99m)Tc-based radiopharmaceuticals and multiple-detector
      gantries, patient motion in myocardial perfusion SPECT acquisitions is still
      problematic and may produce artifacts that mimic coronary artery disease.
      METHODS: A prospective cross-sectional study of 800 myocardial perfusion SPECT
      studies performed with (99m)Tc-based radiopharmaceuticals at 3 private nuclear
      medicine sites was used to determine the incidence, type, and location of
      visually detectable motion. The rotating cinematic display and sinograms of the
      ungated datasets were visually assessed by 2 experienced technologists unaware of
      the other observer's responses and the clinical outcome. RESULTS: Among the 800
      studies analyzed, 36% contained visually detectable motion. Motion was seen on
      31.5% of rest studies, compared with 40.5% of stress studies (P = 0.004). The
      most common type of motion detected was multiple bounce, which represented 47.6%
      of motion. Left anterior oblique and anterior were the most common specific
      locations in which patient motion was detected in the raw data. CONCLUSION: This
      investigation established the significant incidence of patient motion during
      (99m)Tc-based myocardial perfusion SPECT studies that, fully realized, has the
      potential to introduce artifacts leading to false-positive findings. Further
      investigation of the impact of various types and degrees of patient motion is
      recommended.

PMID- 15175402
TI  - Cardiac autonomic neuropathy in the diabetic patient: does 123I-MIBG imaging have
      a role to play in early diagnosis?
AB  - OBJECTIVES: In diabetes, extended adrenergic receptor stimulation with
      hyperglycemia and insulin deficiency is associated with cardiac autonomic
      dysfunction. Clinically evident diabetic cardiac autonomic neuropathy (CAN) is
      associated with a poor prognosis. Research studies indicate that autonomic
      function tests, which are traditionally used to diagnose diabetic CAN, are less
      sensitive than (123)I-metaiodobenzylguanidine (MIBG) imaging, particularly in the
      early stages of the disease. This established imaging technique makes use of the
      noradrenaline analog MIBG, which is radiolabeled with (123)I to assess the
      noradrenaline uptake-1 mechanism of the sympathetic nervous system. Although
      scintigraphic studies indicate that long-standing cardiac autonomic dysfunction
      is permanent, some authors have shown partial reversibility with early metabolic
      intervention. (123)I-MIBG imaging could therefore have an important clinical role
      to play in the early diagnosis and treatment monitoring of diabetic CAN. METHODS:
      A PubMed/MEDLINE Internet search was performed using MIBG, diabetes, and cardiac
      autonomic neuropathy as key words. CONCLUSION: The general expense of (123)I-MIBG
      imaging, together with the lack of commercial availability of this
      radiopharmaceutical in the United States, has limited the clinical use of this
      technique. As such, the clinical role of (123)I-MIBG imaging in the early
      diagnosis of diabetic CAN has yet to be validated and defined in most regions of
      the world, and further study is required.

PMID- 15175403
TI  - A better method of quality control for 99mTc-tetrofosmin.
AB  - The method of quality control (QC) described on the package insert for (99m)Tc
      tetrofosmin requires meticulous attention to technique for accurate radiochemical
      purity results. About 30 min are needed. Other proposed methods have been
      validated only with pertechnetate. We developed a convenient new method using
      silica cartridges. METHODS: A silica cartridge with 70:30 methanol:water was
      determined to be acceptable. The method was validated against sodium
      pertechnetate ((99m)TcO(4)), (99m)Tc-glucoheptonate, (99m)Tc-sulfur colloid, and
      low-purity (99m)Tc-tetrofosmin. The validations were made by using a small volume
      of concentrated (99m)TcO(4) with expired kits. Instant thin-layer chromatography
      (ITLC) showed 6 impurities after an hour or two. The effects of sample size and
      flow rate were determined. The precision of repeated tests was determined by
      comparison with the results of 8 replications on the same batch. The 2 methods
      were compared at a hospital and at 2 commercial nuclear pharmacies, for a total
      of 134 replications, with 21 preparations being of <90% radiochemical purity.
      RESULTS: Volumes between 25 and 100 micro L did not affect the silica-cartridge
      method but did affect the ITLC method. Flow rate is critical and must be < or =5
      mL/min with the silica cartridges. The SD and variance by ITLC were 7 and 51
      times larger, respectively. Using the package insert technique as the gold
      standard, all batches of <90% radiochemical purity were rejected and those of
      >90% radiochemical purity were accepted. Linear regression gave the following
      equation: ITLC = 1.0051 x silica cartridge (R = 0.99). One- and 2-binned chi(2)
      analyses gave P values > 0.999999. A 2 x 2 contingency table showed 100%
      sensitivity, accuracy, and specificity, with a Fisher's exact test P value of 5.7
      x 10(-25). Correlation was nearly perfect. CONCLUSION: According to the published
      rating criteria for alternate radiochemical purity tests (American Pharmacists'
      Association), the silica-cartridge method has a score of 90.2, versus 65.8 for
      ITLC. On the basis of published criteria for alternate radiochemical purity
      testing methods, the new method is clearly seen to be superior. Furthermore,
      alternate methods were validated only with free (99m)TcO(4) and colloidal
      impurities. We showed that these are not the significant radiochemical impurities
      with (99m)Tc-tetrofosmin and that those methods are not valid. This new method is
      fast, convenient, accurate, safe, and economical, but careful control of flow
      rate is required.

PMID- 15175404
TI  - Ventilator add-on for delivering PET tracer gases.
AB  - OBJECTIVES: The increasing use of PET for assessing cerebral blood flow, oxygen
      metabolism, and blood volume in critically ill patients has created a need for
      reliable technical solutions for delivering (15)O-tracer gases to mechanically
      ventilated subjects. Our objective was to create such a solution. METHODS: We
      designed a ventilator add-on unit that enables complex functional brain studies
      using labeled oxygen and carbon monoxide gases as tracers. The unit manages both
      steady-state and bolus inhalations, and the latter can be manually initiated
      using a remote trigger. All parts conducting breathing gases can be sterilized.
      The unit can be operated during both spontaneous pressure support breathing and
      volume-controlled ventilation. It supports the standard safety features and
      alarms of the ventilator and includes an overflow valve in the bolus reservoir.
      RESULTS: The count rate curves obtained using the new unit were similar to those
      from the standard bag-inhalation method. CONCLUSION: The unit we describe offers
      an economical and easily operated solution for providing uninterrupted ventilator
      treatment while performing PET brain studies, and the provided treatment meets
      intensive care criteria.

PMID- 15175411
TI  - Mechanisms underlying the evolution and maintenance of functionally heterogeneous
      18S rRNA genes in Apicomplexans.
AB  - In many species of the protist phylum Apicomplexa, ribosomal RNA (rRNA) gene
      copies are structurally and functionally heterogeneous, owing to distinct
      requirements for rRNA-expression patterns at different developmental stages. The
      genomic mechanisms underlying the maintenance of this system over long-term
      evolutionary history are unclear. Therefore, the aim of this study was to
      investigate what processes underlie the long-term evolution of apicomplexan 18S
      genes in representative species. The results show that these genes evolve
      according to a birth-and-death model under strong purifying selection, thereby
      explaining how divergent 18S genes are generated over time while continuing to
      maintain their ability to produce fully functional rRNAs. In addition, it was
      found that Cryptosporidium parvum undergoes a rapid form of birth-and-death
      evolution that may facilitate host-specific adaptation, including that of type I
      and II strains found in humans. This represents the first case in which an rRNA
      gene family has been found to evolve under the birth-and-death model.

PMID- 15175412
TI  - Adaptive evolution of the histone fold domain in centromeric histones.
AB  - Centromeric DNA, being highly repetitive, has been refractory to molecular
      analysis. However, centromeric structural proteins are encoded by single-copy
      genes, and these can be analyzed by using standard phylogenetic tools. The
      centromere-specific histone, CenH3, replaces histone H3 in centromeric
      nucleosomes, and is required for the proper distribution of chromosomes during
      cell division. Whereas histone H3s are nearly identical between species, CenH3s
      are divergent, with an N-terminal tail that is highly variable in length and
      sequence. Both the N-terminal tail and histone fold domain (HFD) are subject to
      adaptive evolution in Drosophila. Similarly, comparisons between Arabidopsis
      thaliana and Arabidopsis arenosa detected adaptive evolution, but only in the N
      terminal tail. We have extended our evolutionary analyses of CenH3s to other
      members of the Brassicaceae, which allowed the detection of positive selection in
      both the N-terminal tail and in the HFD. We find that adaptively evolving sites
      in the HFD can potentially interact with DNA, including sites in the loop 1
      region of the HFD that are required for centromeric targeting in Drosophila.
      Other adaptively evolving sites in the HFD can be localized on the structure of
      the nucleosome core particle, revealing an extended surface in addition to loop 1
      in which conformational changes might alter histone-DNA contacts or water
      bridges. The identification of adaptively evolving sites provides a structural
      basis for the interaction between centromeric DNA and the protein that is thought
      to underlie the evolution of centromeres and the accumulation of pericentric
      heterochromatin.

PMID- 15175413
TI  - TAHRE, a novel telomeric retrotransposon from Drosophila melanogaster, reveals
      the origin of Drosophila telomeres.
AB  - Drosophila telomeres do not have typical telomerase repeats. Instead, two
      families of non-LTR retrotransposons, HeT-A and TART, maintain telomere length by
      occasional transposition to the chromosome ends. Despite the work on Drosophila
      telomeres, its evolutionary origin remains controversial. Herein we describe a
      novel telomere-specific retroelement that we name TAHRE (Telomere-Associated and
      HeT-A-Related Element). The structure of the three telomere-specific elements
      indicates a common ancestor. These results suggest that preexisting transposable
      elements were recruited to perform the cellular function of telomere maintenance.
      A recruitment similar to that of a retrotransposal reverse transcriptase has been
      suggested as the common origin of telomerases.

PMID- 15175414
TI  - Gene expression, synteny, and local similarity in human noncoding mutation rates.
AB  - The human genome is organized with regard to many features such as isochores,
      Giemsa bands, clusters of genes with similar expression patterns, and contiguous
      regions with shared evolutionary histories (synteny blocks). In addition to these
      genomic features, it is clear that mutation rates also vary across the human
      genome. To address how mutation rates and genomic features are related, we
      analyzed substitution rates at three classes of putatively neutral noncoding
      sites (nongenic, intronic, and ancestral repeats) in approximately 14 Mb of human
      chimpanzee alignments covering human chromosome 7. Patterns of mutation rate
      variation inferred from substitution rate variation differ among the three site
      classes. In particular, we find that intronic mutation rates are strongly
      affected by the breadth of expression of the genes in which they reside, with
      broadly expressed genes exhibiting low mutation rates, probably as a consequence
      of the transcription-coupled repair process acting in the germ line. All site
      classes show significant local similarities in mutation rate at the megabase
      scale, and regional similarities in nongenic mutation rate covary with blocks of
      synteny between the human and mouse genomes, indicating that the evolutionary
      history of a genomic region is an important determinant of mutation rate.

PMID- 15175416
TI  - Complex evolution of gypsy in Drosophilid species.
AB  - In an endeavor to contribute to the comprehension of the evolution of
      transposable elements (TEs) in the genome of host species, we investigated the
      phylogenetic relationships of sequences homologous to the retrotransposon gypsy
      of Drosophila melanogaster in 19 species of Drosophila, in Scaptodrosophila
      latifasciaeformis, and in Zaprionus indianus. This phylogenetic study was based
      on approximately 500 base pairs of the env gene. Our analyses showed considerable
      discrepancy between the phylogeny of gypsy elements and the relationship of their
      host species, and they allow us to infer a complex evolutionary pattern that
      could include ancestral polymorphism, vertical transmission, and several cases of
      horizontal transmission.

PMID- 15175417
TI  - Isobolographic analysis for combinations of a full and partial agonist: curved
      isoboles.
AB  - Combinations of drugs are frequently used therapeutically to achieve an enhanced
      effect without using an excess quantity of either agent. If the drugs exert
      overtly similar action, e.g., two analgesics, the effect of the combination may
      be tested for additivity, i.e., an effect level that is achieved based on the
      individual drug potencies. But combinations of agonists will sometimes display
      either superadditive (synergistic) or subadditive responses. Whether the two
      agonists are both drugs, or a combination of a drug and an endogenous chemical,
      there is interest in characterizing the interaction to determine whether it
      departs from additivity because quantitative information of this kind, aside from
      its therapeutic importance, may also illuminate mechanism. A common method for
      this characterization uses the isobologram. This is a plot in rectangular
      coordinates of dose combinations (a,b) that produce the same effect level (often
      taken to be 50% of the maximum). In its usual form, this plot is constructed as a
      straight line (of additivity) connecting intercepts that represent the
      individually effective doses, e.g., ED50 values of each. This line is the
      reference for distinguishing additive from nonadditive interactions accordingly
      as the tested combination is on or off this line. Discussed here are the
      assumptions that underlie this linear plot. Specifically we show that a
      combination of drugs with a variable potency ratio, exemplified by a full and a
      partial agonist, lead to curvilinear isoboles of additivity that may erroneously
      be attributed to either synergism or subadditivity.

PMID- 15175418
TI  - Low sodium modifies the vascular effects of angiotensin-converting enzyme
      inhibitor therapy in healthy rats.
AB  - Low dietary sodium (LS) increases the effect of angiotensin-converting enzyme
      (ACE) inhibitor therapy in patients and experimental models, but mechanisms
      underlying this enhanced efficacy are largely unknown. Because the benefits of
      ACE inhibition are mediated to a considerable extent by their effect on the
      vasculature, we studied whether low sodium alters the vascular effects of ACE
      inhibition. Baseline functional and morphological characteristics, and
      endothelium-dependent and -independent dilatory responses were studied in
      isolated perfused small intrarenal and mesenteric arteries obtained from control
      rats (CON), rats on LS, lisinopril-treated rats (CON-LIS), or rats treated with
      lisinopril during LS (LS-LIS). We found, first, that LS-LIS compared with CON-LIS
      enhances blood pressure reduction. Second, interlobar renal arteries had
      increased lumen diameter and reduced adrenergic contractility in CON-LIS compared
      with CON, without additional effects of LS. In contrast, mesenteric arteries were
      not altered in CON-LIS compared with CON, but became triggered for increased
      myogenic and adrenergic constriction in LS-LIS. Third, LS-LIS decreased
      acetylcholine (ACh)-induced vasodilation in both mesenteric and renal arteries
      compared with CON-LIS. During the latter condition, opposite prostaglandins are
      involved in the endothelial function of the two different vascular beds, i.e.,
      increased involvement of contractile prostaglandins in ACh-induced vasodilatation
      in renal arteries, versus dilatory prostaglandins in mesenteric arteries. Whether
      cause or consequence of the enhanced blood pressure response, our data
      demonstrate a modifying effect of dietary sodium on vascular effects of ACE
      inhibition. These findings provide a rationale for further studies addressing the
      mechanism-of-actions of our therapies to find additional strategies to improve
      therapy response.

PMID- 15175419
TI  - Negative feedback regulation of nigrostriatal dopamine release: mediation by
      striatal D1 receptors.
AB  - The nigrostriatal dopamine system of the mammalian brain is necessary for normal
      voluntary motor activity. Dopamine exerts its effects by acting on two primary
      receptor subtypes: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors.
      Previous research has indicated that both subtypes are involved in the negative
      feedback regulation of dopamine release in the brain. However, the role of D1
      like receptors localized within the striatum remains controversial. Using in vivo
      microdialysis, we report that infusions of the D1/D5 antagonist SCH 23390 [R-(+)
      7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] (5-200
      microM) directly into the striatum increased dopamine release in a concentration
      dependent manner. Systemic administration of the novel, full D1/D5 agonist A
      77636 [(-)-(1R,3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2
      benzopyran] produced the opposite effect, a dose-dependent (0.75-3.0 mg/kg s.c.)
      decrease in striatal dopamine efflux. Infusions of SCH 23390 (5.0 microM)
      attenuated this decrease. These findings suggest that endogenous dopamine acts on
      D1-like receptors localized within the striatum to decrease nigrostriatal
      dopamine release. This negative feedback may be due to the activation of an
      inhibitory long-loop pathway. Knowledge of the circuitry underlying D1-mediated
      regulation of nigrostriatal neurons may have significance in current research on
      treatments for Parkinson's disease.

PMID- 15175420
TI  - Intratumoral administration of methotrexate bound to activated carbon particles:
      antitumor effectiveness against human colon carcinoma xenografts and acute
      toxicity in mice.
AB  - We previously developed a new formulation of methotrexate (MTX) that is adsorbed
      onto a suspension of activated carbon particles (MTX-CH) and reported the
      usefulness of local administration in murine tumors. The present study examines
      the effects of human colon carcinoma (LoVo) xenografts and the acute toxicity of
      MTX-CH compared with MTX aqueous solution (MTX-AQ) in mice. In therapeutic
      experiments, LoVo cells were implanted into the backs of BALB/c nude mice. When
      the cells had developed into tumors, we performed an intratumoral administration
      of a weekly dose of 30 mg/kg. The MTX concentration in the tumor was compared
      between the MTX-CH group and MTX-AQ group. In experiments on acute toxicity, MTX
      CH and MTX-AQ were injected subcutaneously in BDF1 mice, and intoxication
      symptoms, changes in body weight, and date of death were recorded. In the
      therapeutic experiments, intratumoral administration of MTX-CH was much more
      effective in suppressing the tumor growth compared with MTX-AQ. In experiments of
      acute toxicity, the death time of the MTX-CH group was delayed to a greater
      extent, and the 50% lethal dose (LD(50)) values of MTX-CH were lower than those
      of MTX-AQ. The LD(50) values of MTX-CH are 75 times higher than the efficacious
      dose of 30 mg/kg. The present results suggest that intratumoral administration of
      MTX-CH is useful for local therapy and the therapeutic dose of MTX-CH can be
      safely injected subcutaneously.

PMID- 15175421
TI  - Intrathecal protease-activated receptor stimulation produces thermal hyperalgesia
      through spinal cyclooxygenase activity.
AB  - Activation of protease-activated receptors (PARs) in non-neural tissue results in
      prostaglandin production. Because PARs are found in the spinal cord and increased
      prostaglandin release in the spinal cord causes thermal hyperalgesia, we
      hypothesized that activation of these spinal PARs would stimulate prostaglandin
      production and cause a cyclooxygenase-dependent thermal hyperalgesia. PARs were
      activated using either thrombin or peptide agonists derived from the four PAR
      subtypes, delivered to the lumbar spinal cord. Dialysis experiments were
      conducted in conscious, unrestrained rats using loop microdialysis probes placed
      in the lumbar intrathecal space. Intrathecal thrombin stimulated release of
      prostaglandin E (PGE)(2) but not aspartate or glutamate. Intrathecal delivery of
      the PAR 1-derived peptide SFLLRN-NH(2) and the PAR 2-derived peptide SLIGRL both
      stimulated PGE(2) release; PAR 3-derived TFRGAP and PAR 4-derived GYPGQV were
      inactive. Intrathecal thrombin had no effect upon formalin-induced flinching or
      tactile sensitivity but resulted in a thermal hyperalgesia. Intrathecal SFLLRN
      NH(2) and SLIGRL both produced thermal hyperalgesia. Consistent with their
      effects on spinal PGE(2), hyperalgesia from these peptides was blocked by
      pretreatment with the cyclooxygenase inhibitor ibuprofen. SLIGRL-induced
      hyperalgesia was also blocked by the selective inhibitors SC 58,560 [5-(4
      fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;
      cyclooxygenase (COX) 1] and SC 58,125 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3
      (trifluoromethyl)-1H-pyrazole; COX 2]. These data indicate that activation of
      spinal PAR 2 and possibly PAR 1 results in the stimulation of the spinal
      cyclooxygenase cascade and a prostaglandin-dependent thermal hyperalgesia.

PMID- 15175415
TI  - Phylogenomics of eukaryotes: impact of missing data on large alignments.
AB  - Resolving the relationships between Metazoa and other eukaryotic groups as well
      as between metazoan phyla is central to the understanding of the origin and
      evolution of animals. The current view is based on limited data sets, either a
      single gene with many species (e.g., ribosomal RNA) or many genes but with only a
      few species. Because a reliable phylogenetic inference simultaneously requires
      numerous genes and numerous species, we assembled a very large data set
      containing 129 orthologous proteins ( approximately 30,000 aligned amino acid
      positions) for 36 eukaryotic species. Included in the alignments are data from
      the choanoflagellate Monosiga ovata, obtained through the sequencing of about
      1,000 cDNAs. We provide conclusive support for choanoflagellates as the closest
      relative of animals and for fungi as the second closest. The monophyly of Plantae
      and chromalveolates was recovered but without strong statistical support. Within
      animals, in contrast to the monophyly of Coelomata observed in several recent
      large-scale analyses, we recovered a paraphyletic Coelamata, with nematodes and
      platyhelminths nested within. To include a diverse sample of organisms, data from
      EST projects were used for several species, resulting in a large amount of
      missing data in our alignment (about 25%). By using different approaches, we
      verify that the inferred phylogeny is not sensitive to these missing data.
      Therefore, this large data set provides a reliable phylogenetic framework for
      studying eukaryotic and animal evolution and will be easily extendable when large
      amounts of sequence information become available from a broader taxonomic range.

PMID- 15175422
TI  - Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion:
      role of P-glycoprotein as a barrier to in vivo ocular drug absorption.
AB  - Efflux pump like P-glycoprotein (P-gp) is known to be a major barrier to drug
      delivery. Functional P-glycoprotein has been recently identified in cornea and
      corneal cell lines. Thus, it is probable that P-glycoprotein may restrict in vivo
      ocular drug absorption, resulting in low ocular bioavailability. Experiments were
      designed using New Zealand albino (New Zealand White) rabbits to assess
      inhibitors of P-gp efflux to increase drug absorption. Anesthetized rabbits were
      given constant topical infusions of [(14)C]erythromycin in the presence and
      absence of inhibitors. Testosterone, verapamil, quinidine, and cyclosporine A
      were selected as P-gp inhibitors. Transport experiments were conducted in Madin
      Darby canine kidney cells transfected with the human mdr1 gene (MDCK-MDR1).
      Erythromycin exhibited significant efflux out of MDCK-MDR1 cells, suggesting that
      erythromycin is a good substrate for P-gp. Ocular pharmacokinetic studies were
      conducted using a topical single-dose infusion method. Maximum inhibition of P-gp
      mediated efflux was observed with 500 microM testosterone. Area under the curve
      (AUC)(0- infinity ) of erythromycin with 500 microM testosterone was almost 4
      times higher than AUC(0- infinity ) without any inhibitor. Rate of elimination
      (k(10)) for erythromycin and those with inhibitors was found to be similar (141
      +/- 23 min), suggesting that elimination pathways were not altered. All the
      inhibitors were found to be nontoxic. Verapamil also inhibited the efflux pump
      with moderate change in AUC(0- infinity ) and C(max) compared with control. Thus,
      P-gp is found to be active in vivo, and it restricts topical erythromycin
      absorption across the cornea, which can be inhibited by known P-gp inhibitors.
      Therefore, ocular bioavailability of P-gp substrates can be significantly
      enhanced by proper selection of P-gp inhibitors.

PMID- 15175423
TI  - Short-term cocaine treatment causes neuroadaptive changes in Galphaq and Galpha11
      proteins in rats undergoing withdrawal.
AB  - One of the characteristics of drug dependence is that a drug has to be
      administered repeatedly before withdrawal effects can be observed. We have
      previously shown that withdrawal after 14 days of cocaine treatment produces a
      supersensitivity of hypothalamic 5-hydroxytryptamine (serotonin) 2A (5-HT(2A))
      receptors, which is accompanied by increases in the levels of Galpha(q) and
      Galpha(11) proteins. Unfortunately, the exact duration of cocaine treatment
      necessary to induce alterations in G protein levels during cocaine withdrawal is
      unknown. The present study investigated the minimum cocaine treatment period
      required to produce changes in protein levels of membrane- and cytosol-associated
      Galpha(q) and Galpha(11) proteins in the hypothalamic paraventricular nucleus,
      amygdala, and frontal cortex. Rats were injected with cocaine (15 mg/kg i.p.,
      b.i.d.) for 0, 1, 3, 5, and 7 days and tested after 2 days of withdrawal. The
      levels of Galpha(q) and Galpha(11) proteins were increased in the paraventricular
      nucleus and the amygdala but not in the frontal cortex. Although 1 and 3 days of
      cocaine treatment were sufficient to maximally elevate the protein levels of
      Galpha(11) and Galpha(q) proteins in the amygdala, 5 days of treatment were
      required to maximally increase the levels of Galpha(11) and Galpha(q) proteins in
      the paraventricular nucleus. The data suggest that the amygdala shows a faster
      neuroadaptation to the effects of cocaine than the hypothalamic paraventricular
      nucleus. These findings provide insight into the relative importance of
      individual components of 5-HT(2A) receptor signal transduction system in
      regulating the overall sensitivity of this signaling in cocaine-treated rats.

PMID- 15175424
TI  - Development of a real-time polymerase chain reaction-based method for the
      measurement of relative allelic expression and identification of CYP2A13 alleles
      with decreased expression in human lung.
AB  - CYP2A13 is a human cytochrome P450 monooxygenase that is efficient in the
      metabolic activation of tobacco-specific nitrosamines. Sequence variations that
      affect CYP2A13 expression may contribute to interindividual differences in
      susceptibility to tobacco-related tumorigenesis. The aim of this study was to
      identify any impact of CYP2A13 single-nucleotide polymorphisms (SNPs) on CYP2A13
      expression in human lung. Expression levels of CYP2A13 mRNA in normal lung
      displayed significant interindividual variation (>50-fold). Preliminary sequence
      analysis of CYP2A13 RNA-polymerase chain reaction (PCR) products suggested that a
      7520C > G variation, located in the 3'-untranslated region, could be associated
      with low transcript abundance. Subsequently, we developed a method for the
      measurement of relative allelic expression, by taking advantage of the capability
      for melting-curve analysis in real-time PCR. Quantitative analyses using this
      method indicated that transcripts from the 7520G-containing alleles were >10-fold
      less abundant than those from the 7520C-containing alleles in 14 of 16 samples
      examined. The frequencies of the 7520C > G variation in anonymous White, African
      American, Hispanic, and Asian newborns from New York State were found to be 5.2,
      26.8, 17.7, and 4.3%, respectively. The 7520C > G SNP was previously known to be
      present in both CYP2A13(*)1H and (*)3 alleles. However, analyses of SNP
      distribution indicated that, in 15 of the 16 heterozygous DNA samples, the 7520C
      > G SNP belonged to new CYP2A13(*)1 haplotypes. These findings provide a basis
      for further studies that associate CYP2A13 haplotypes with incidences of smoking
      related lung tumors and for studies on the mechanisms of the low-expression
      phenotype of the 7520G-containing allele.

PMID- 15175425
TI  - beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate
      protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal
      neurons by different mechanisms.
AB  - We examined neuroprotective effects of beta-estradiol, dehydroepiandrosterone
      (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) against N-methyl-D-aspartate
      (NMDA)-induced neurotoxicity in primary cultured rat hippocampal neurons. All
      three steroids demonstrated neuroprotective effects. Time-course studies revealed
      that steroid cotreatment for only 15 min at the same time as exposure to NMDA,
      but neither pretreatment nor addition of steroids for 24 h after NMDA-mediated
      neuroprotective effects. This indicates that short-term actions of these steroids
      are critical for this process. Acute treatment with beta-estradiol dose
      dependently inhibited NMDA-induced intracellular Ca(2+) increases, which strongly
      correlated with its neuroprotective effect via L-type voltage-gated calcium
      channels. Acute treatment with DHEA, but not with DHEA-S, significantly inhibited
      nitric oxide (NO) production and Ca(2+)-sensitive NO synthase (NOS) activity
      caused by NMDA stimulation. An NOS inhibitor, N(G)-monomethyl-L-arginine acetate
      was also protective against NMDA-induced neurotoxicity. These data indicate that
      beta-estradiol may exert neuroprotective effects mainly by reducing Ca(2+)
      increases but that DHEA may act by inhibiting NOS activity. Treatment with the
      sigma-1 receptor (Sig-1R) antagonists rimcazole or BD1063 (1-[2-(3,4
      dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride) partially, but
      significantly, reversed the neuroprotective effect of DHEA-S against NMDA-induced
      neurotoxicity, whereas muscimol, a GABA-A-receptor agonist, did not. This
      suggests that the neuroprotective effect of DHEA-S may be mediated via Sig-1R, at
      least in part. Together, our data suggest that the neurosteroid family members
      beta-estradiol, DHEA, and DHEA-S exert neuroprotective effects through different
      nongenomic mechanisms.

PMID- 15175426
TI  - Obituary. Robert Simpson.

PMID- 15175427
TI  - Acetylation of the human DNA glycosylase NEIL2 and inhibition of its activity.
AB  - Post-translational modifications of proteins, including acetylation, modulate
      their cellular functions. Several human DNA replication and repair enzymes have
      recently been shown to be acetylated, leading to their inactivation in some
      cases. Here we show that the transcriptional coactivator p300 stably interacts
      with, and acetylates, the recently discovered human DNA glycosylase NEIL2,
      involved in the repair of oxidized bases both in vivo and in vitro. Lys49 and
      Lys153 were identified as the major acetylation sites in NEIL2. Acetylation of
      Lys49, conserved among Nei orthologs, or its mutation to Arg inactivates both
      base excision and AP lyase activities, while acetylation of Lys153 has no effect.
      Reversible acetylation of Lys49 could thus regulate the repair activity of NEIL2
      in vivo.

PMID- 15175428
TI  - Construction of oligonucleotide arrays on a glass surface using a
      heterobifunctional reagent, N-(2-trifluoroethanesulfonatoethyl)-N-(methyl)
      triethoxysilylpropyl-3-amine (NTMTA).
AB  - A rapid method for construction of oligonucleotide arrays on a glass surface,
      using a novel heterobifunctional reagent, N-(2-trifluoroethanesulfonatoethyl)-N
      (methyl)-triethoxysilylpropyl-3-amine (NTMTA), has been described. The
      heterobifunctional reagent, NTMTA, carries two different thermoreactive groups.
      The triethoxysilyl group on one end is specific towards silanol functions on the
      virgin glass surface, while the trifluoroethanesulfonyl (tresyl) group on the
      other end of the reagent reacts specifically with aminoalkyl- or mercaptoalkyl-
      functionalized oligonucleotides. Immobilization of oligonucleotides on a glass
      surface has been realized via two routes. In the first one (A), 5'- aminoalkyl-
      or mercaptoalkyl-functionalized oligonucleotides were allowed to react with NTMTA
      to form a oligonucleotide-triethoxysilyl conjugate which, in a subsequent
      reaction with unmodified (virgin) glass microslide, results in surface-bound
      oligonucleotides. In the second route (B), the NTMTA reagent reacts first with a
      glass microslide whereby it generates trifluoroethanesulfonate ester functions on
      it, which in a subsequent step react with 5'-aminoalkyl or mercaptoalkyl
      oligonucleotides to generate support-bound oligonucleotides. Subsequently, the
      oligonucleotide arrays prepared by both routes were analyzed by hybridization
      experiments with complementary oligonucleotides. The constructed microarrays were
      successfully used in single and multiple nucleotide mismatch detection by
      hybridizing these with fluorescein-labeled complementary oligonucleotides.
      Further more, the proposed method was compared with the existing methods with
      respect to immobilization efficiency of oligonucleotides.

PMID- 15175429
TI  - Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor
      components of the ramoplanin complex.
AB  - Ramoplanin is a potent antibiotic, first disclosed in 1984, that acts by
      inhibiting bacterial cell-wall biosynthesis. The original ramoplanin complex was
      shown to consist of a mixture of three closely related compounds, ramoplanin A1
      A3, of which ramoplanin A2 is the most abundant. The structure of ramoplanin A2
      was unambiguously established first through a series of extensive spectroscopic
      studies, allowing complete stereochemical assignments and subsequently providing
      a minor reassignment of the side-chain double-bond stereochemistry and, most
      recently, through total synthesis of authentic material. Here we report the total
      syntheses of the aglycons of the minor components of the ramoplanin complex, A1
      and A3, which unambiguously establish their structure and provide an expected
      structural revision for the lipid side-chain double-bond stereochemistry.

PMID- 15175430
TI  - Fluorescence-aided molecule sorting: analysis of structure and interactions by
      alternating-laser excitation of single molecules.
AB  - We use alternating-laser excitation to achieve fluorescence-aided molecule
      sorting (FAMS) and enable simultaneous analysis of biomolecular structure and
      interactions at the level of single molecules. This was performed by labeling
      biomolecules with fluorophores that serve as donor-acceptor pairs for Forster
      resonance energy transfer, and by using alternating-laser excitation to excite
      directly both donors and acceptors present in single diffusing molecules.
      Emissions were reduced to the distance-dependent ratio E, and a distance
      independent, stoichiometry-based ratio S. Histograms of E and S sorted species
      based on the conformation and association status of each species. S was sensitive
      to the stoichiometry and relative brightness of fluorophores in single molecules,
      observables that can monitor oligomerization and local-environment changes,
      respectively. FAMS permits equilibrium and kinetic analysis of macromolecule
      ligand interactions; this was validated by measuring equilibrium and kinetic
      dissociation constants for the interaction of Escherichia coli catabolite
      activator protein with DNA. FAMS is a general platform for ratiometric
      measurements that report on structure, dynamics, stoichiometries, environment,
      and interactions of diffusing or immobilized molecules, thus enabling detailed
      mechanistic studies and ultrasensitive diagnostics.

PMID- 15175431
TI  - Coevolution of gene expression among interacting proteins.
AB  - Physically interacting proteins or parts of proteins are expected to evolve in a
      coordinated manner that preserves proper interactions. Such coevolution at the
      amino acid-sequence level is well documented and has been used to predict
      interacting proteins, domains, and amino acids. Interacting proteins are also
      often precisely coexpressed with one another, presumably to maintain proper
      stoichiometry among interacting components. Here, we show that the expression
      levels of physically interacting proteins coevolve. We estimate average
      expression levels of genes from four closely related fungi of the genus
      Saccharomyces using the codon adaptation index and show that expression levels of
      interacting proteins exhibit coordinated changes in these different species. We
      find that this coevolution of expression is a more powerful predictor of physical
      interaction than is coevolution of amino acid sequence. These results demonstrate
      that gene expression levels can coevolve, adding another dimension to the study
      of the coevolution of interacting proteins and underscoring the importance of
      maintaining coexpression of interacting proteins over evolutionary time. Our
      results also suggest that expression coevolution can be used for computational
      prediction of protein-protein interactions.

PMID- 15175432
TI  - Waiting for plan B--the FDA and nonprescription use of emergency contraception.

PMID- 15175433
TI  - Health care for homeless persons.

PMID- 15175434
TI  - Planning for epidemics--the lessons of SARS.

PMID- 15175435
TI  - Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic
      colorectal cancer.
AB  - BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial
      growth factor, has shown promising preclinical and clinical activity against
      metastatic colorectal cancer, particularly in combination with chemotherapy.
      METHODS: Of 813 patients with previously untreated metastatic colorectal cancer,
      we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and
      leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two
      weeks) and 411 to receive IFL plus placebo. The primary end point was overall
      survival. Secondary end points were progression-free survival, the response rate,
      the duration of the response, safety, and the quality of life. RESULTS: The
      median duration of survival was 20.3 months in the group given IFL plus
      bevacizumab, as compared with 15.6 months in the group given IFL plus placebo,
      corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration
      of progression-free survival was 10.6 months in the group given IFL plus
      bevacizumab, as compared with 6.2 months in the group given IFL plus placebo
      (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of
      response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the
      response was 10.4 months in the group given IFL plus bevacizumab, as compared
      with 7.1 months in the group given IFL plus placebo (hazard ratio for
      progression, 0.62; P=0.001). Grade 3 hypertension was more common during
      treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs.
      2.3 percent) but was easily managed. CONCLUSIONS: The addition of bevacizumab to
      fluorouracil-based combination chemotherapy results in statistically significant
      and clinically meaningful improvement in survival among patients with metastatic
      colorectal cancer.

PMID- 15175436
TI  - Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.
AB  - BACKGROUND: The standard adjuvant treatment of colon cancer is fluorouracil plus
      leucovorin (FL). Oxaliplatin improves the efficacy of this combination in
      patients with metastatic colorectal cancer. We evaluated the efficacy of
      treatment with FL plus oxaliplatin in the postoperative adjuvant setting.
      METHODS: We randomly assigned 2246 patients who had undergone curative resection
      for stage II or III colon cancer to receive FL alone or with oxaliplatin for six
      months. The primary end point was disease-free survival. RESULTS: A total of 1123
      patients were randomly assigned to each group. After a median follow-up of 37.9
      months, 237 patients in the group given FL plus oxaliplatin had had a cancer
      related event, as compared with 293 patients in the FL group (21.1 percent vs.
      26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease
      free survival at three years was 78.2 percent (95 percent confidence interval,
      75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent
      confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log
      rank test). In the group given FL plus oxaliplatin, the incidence of febrile
      neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects
      was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during
      treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in
      each group died during treatment (death rate, 0.5 percent). CONCLUSIONS: Adding
      oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant
      treatment of colon cancer.

PMID- 15175437
TI  - Public health measures to control the spread of the severe acute respiratory
      syndrome during the outbreak in Toronto.
AB  - BACKGROUND: Toronto was the site of North America's largest outbreak of the
      severe acute respiratory syndrome (SARS). An understanding of the patterns of
      transmission and the effects on public health in relation to control measures
      that were taken will help health officials prepare for any future outbreaks.
      METHODS: We analyzed SARS case, quarantine, and hotline records in relation to
      control measures. The two phases of the outbreak were compared. RESULTS: Toronto
      Public Health investigated 2132 potential cases of SARS, identified 23,103
      contacts of SARS patients as requiring quarantine, and logged 316,615 calls on
      its SARS hotline. In Toronto, 225 residents met the case definition of SARS, and
      all but 3 travel-related cases were linked to the index patient, from Hong Kong.
      SARS spread to 11 (58 percent) of Toronto's acute care hospitals. Unrecognized
      SARS among in-patients with underlying illness caused a resurgence, or a second
      phase, of the outbreak, which was finally controlled through active surveillance
      of hospitalized patients. In response to the control measures of Toronto Public
      Health, the number of persons who were exposed to SARS in nonhospital and
      nonhousehold settings dropped from 20 (13 percent) before the control measures
      were instituted (phase 1) to 0 afterward (phase 2). The number of patients who
      were exposed while in a hospital ward rose from 25 (17 percent) in phase 1 to 68
      (88 percent) in phase 2, and the number exposed while in the intensive care unit
      dropped from 13 (9 percent) in phase 1 to 0 in phase 2. Community spread (the
      length of the chains of transmission outside of hospital settings) was
      significantly reduced in phase 2 of the outbreak (P<0.001). CONCLUSIONS: The
      transmission of SARS in Toronto was limited primarily to hospitals and to
      households that had had contact with patients. For every case of SARS, health
      authorities should expect to quarantine up to 100 contacts of the patients and to
      investigate 8 possible cases. During an outbreak, active in-hospital surveillance
      for SARS-like illnesses and heightened infection-control measures are essential.

PMID- 15175438
TI  - Obesity and the metabolic syndrome in children and adolescents.
AB  - BACKGROUND: The prevalence and magnitude of childhood obesity are increasing
      dramatically. We examined the effect of varying degrees of obesity on the
      prevalence of the metabolic syndrome and its relation to insulin resistance and
      to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial
      cohort of children and adolescents. METHODS: We administered a standard glucose
      tolerance test to 439 obese, 31 overweight, and 20 nonobese children and
      adolescents. Baseline measurements included blood pressure and plasma lipid, C
      reactive protein, and adiponectin levels. Levels of triglycerides, high-density
      lipoprotein cholesterol, and blood pressure were adjusted for age and sex.
      Because the body-mass index varies according to age, we standardized the value
      for age and sex with the use of conversion to a z score. RESULTS: The prevalence
      of the metabolic syndrome increased with the severity of obesity and reached 50
      percent in severely obese youngsters. Each half-unit increase in the body-mass
      index, converted to a z score, was associated with an increase in the risk of the
      metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95
      percent confidence interval, 1.16 to 2.08), as was each unit of increase in
      insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95
      percent confidence interval, 1.07 to 1.18 for each additional unit of insulin
      resistance). The prevalence of the metabolic syndrome increased significantly
      with increasing insulin resistance (P for trend, <0.001) after adjustment for
      race or ethnic group and the degree of obesity. C-reactive protein levels
      increased and adiponectin levels decreased with increasing obesity. CONCLUSIONS:
      The prevalence of the metabolic syndrome is high among obese children and
      adolescents, and it increases with worsening obesity. Biomarkers of an increased
      risk of adverse cardiovascular outcomes are already present in these youngsters.

PMID- 15175439
TI  - Clinical practice. Surveillance strategies after curative treatment of colorectal
      cancer.

PMID- 15175440
TI  - Hereditary hemochromatosis--a new look at an old disease.

PMID- 15175441
TI  - Images in clinical medicine. Paraesophageal hernia.

PMID- 15175442
TI  - Clinical problem-solving. Forgotten but not gone.

PMID- 15175443
TI  - Two steps forward in the treatment of colorectal cancer.

PMID- 15175444
TI  - A middle ground on public accountability.

PMID- 15175445
TI  - The FDA, politics, and plan B.

PMID- 15175446
TI  - The changing face and implications of childhood obesity.

PMID- 15175447
TI  - B-type natriuretic peptide in the evaluation of acute dyspnea.

PMID- 15175448
TI  - Estrogen plus progestin and colorectal cancer in postmenopausal women.

PMID- 15175449
TI  - Impaired mitochondrial activity and insulin-resistant offspring of patients with
      type 2 diabetes.

PMID- 15175450
TI  - Acute renal colic.

PMID- 15175451
TI  - Data safety and monitoring boards.

PMID- 15175452
TI  - Ischemic mitral regurgitation during temporary coronary-artery ligation.

PMID- 15175453
TI  - Images in clinical medicine. A calcified pelvic mass.

PMID- 15175454
TI  - Are we ready to ration psychiatric medications?

PMID- 15175456
TI  - Psychiatry and spirituality at the end of life: a case report.

PMID- 15175457
TI  - The problem: How many patients live in residential care facilities?

PMID- 15175458
TI  - Assessment of geriatric patients in the psychiatric emergency service.

PMID- 15175459
TI  - Cresting.

PMID- 15175460
TI  - Less is more: Virginia's Performance Outcomes Measurement System.

PMID- 15175461
TI  - An examination of leading mental health journals for evidence to inform evidence
      based practice.
AB  - OBJECTIVE: This study examined whether data needed to inform evidence-based
      practice can be found in leading mental health journals. METHODS: Research
      studies described in articles that were published in 12 leading mental health
      journals in 1999 were examined to determine whether they evaluated clinical
      interventions, used rigorous designs, were conducted in routine practice
      settings, and included well-defined diagnostic groups and heterogeneous samples.
      RESULTS: Twenty-seven percent (N=295) of the 1,076 articles that were reviewed
      described research that evaluated interventions. Of these 295 articles, 64
      percent evaluated pharmacologic interventions and 33 percent evaluated
      psychosocial or psychotherapeutic interventions. Of the articles that evaluated
      interventions, 60 percent described randomized designs, but samples were modest;
      25 percent of the studies reported 31 or fewer participants. Of the 295 articles,
      84 percent described studies conducted in specialty mental health settings; very
      few (4 percent) described studies conducted in public mental health or managed
      care environments, which are common practice settings. Most samples were
      diagnostically well defined, but evidence of treatments for diagnoses other than
      schizophrenia and mood disorders was limited. CONCLUSIONS: This systematic review
      suggested that data needed to inform and advance evidence-based practice does not
      have the prominent place it deserves in leading journals. Only a quarter of the
      research studies that were examined evaluated clinical interventions, and
      articles that described pharmacologic interventions were published twice as often
      as articles that described psychosocial or psychotherapeutic interventions.
      Rigorous research designs predominated, but sample sizes were modest. Evidence
      was scarce on treatment effectiveness in routine practice settings.

PMID- 15175462
TI  - Course of patients with histories of aggression and crime after discharge from a
      cognitive-behavioral program.
AB  - OBJECTIVE: Patients exhibiting aggressive or criminal behavior present a
      challenge to treaters and caregivers. After discharge from an inpatient facility,
      such patients are at high risk of rehospitalization and rearrest. A long-term
      behaviorally based cognitive skills program was developed and administered to a
      group of such high-risk inpatients. The authors report the results of a
      postdischarge follow-up of this group. METHODS: After patients entered the
      inpatient treatment program, their psychiatric and criminal histories were
      recorded, and a battery of psychological measures were administered, including IQ
      tests and the Hare Psychopathy Checklist. After discharge, multiple sources were
      used to obtain information about patients' outcomes. RESULTS: Eighty-five
      patients were followed for between six months and two years after discharge.
      Thirty-three of these patients (39 percent) remained stable in the community, 35
      (42 percent) were rehospitalized, and 17 (20 percent) were arrested. Several
      variables that were ascertained before discharge predicted rehospitalization or
      arrest rates: comorbid antisocial personality disorder, higher score on the
      Psychopathy Checklist, history of arrests for violent crimes, and history of a
      learning disability. In addition, patients who developed substance use problems
      or did not adhere to medication treatment after discharge were more likely to be
      rehospitalized or arrested. CONCLUSIONS: Arrest rates were low compared with
      those observed in studies with similar populations. Although this outcome may be
      attributable to the treatment program, this naturalistic study could not prove
      that. The predictors of poor outcome may be used to develop a follow-up treatment
      program that focuses more resources on patients who are at the highest risk.

PMID- 15175463
TI  - The STIRR model of best practices for blood-borne diseases among clients with
      serious mental illness.
AB  - OBJECTIVE: Persons with severe mental illness have a markedly elevated risk of
      several blood-borne infections, including HIV, hepatitis B, and hepatitis C.
      Prevention, early detection, and treatment of these disorders are crucial
      interventions for high-risk populations. However, because of a number of
      barriers, most clients with severe mental illness do not receive these basic best
      practice services. The authors describe a public health model intervention
      designed to deliver basic best-practice services for blood-borne diseases, as
      specified by the Centers for Disease Control and Prevention, to clients with
      severe mental illness and co-occurring substance use disorders. METHODS: The
      intervention, called STIRR (for screen, test, immunize, reduce risk, and refer),
      is brief (requiring approximately one hour per client) and is delivered at the
      site of mental health care by a mobile team of specialists. Clients are provided
      with risk screening, testing for HIV and hepatitis, immunization for hepatitis A
      and B, risk-reduction counseling, and treatment referral for blood-borne
      infections. Also described is a pilot study to evaluate this model in two
      publicly funded community mental health centers. RESULTS: At the first site, 137
      (79 percent) of clients with severe mental illness were tested and immunized. At
      the second site, more than two-thirds of the clients of a dual diagnosis team
      participated (67 clients, or 68 percent). Intervention costs per client ranged
      from 194 dollars to 262 dollars. CONCLUSION: S: The STIRR approach has the
      potential to provide a basic, best-practice package of interventions for high
      risk clients with severe mental illness.

PMID- 15175464
TI  - A prospective study of assault against staff by youths in a state psychiatric
      hospital.
AB  - OBJECTIVE: This study examined the frequency and nature of violence directed at
      staff in a state inpatient psychiatric hospital for children and adolescents.
      METHODS: A total of 215 assaults that occurred over a two-month period were
      examined by using information obtained from staff at the time of the assault and
      from the hospital database. Assaults were analyzed for situational
      characteristics of the incidents as well as the characteristics that best
      differentiated between assaultive and nonassaultive patients. RESULTS: Thirty
      three percent of all hospitalized patients were involved in an assaultive
      incident. A majority of the patients who assaulted staff were neither involved in
      the juvenile justice system nor psychotic. Although youths who were involved in
      repeat assaults were more likely to be male, gender did not differentiate between
      those who were assaultive toward staff and those who were not. Some type of
      verbal direction or redirection (typically minor) on the part of the staff
      preceded a majority (68 percent) of the assaults. CONCLUSION: Preconceived
      notions about why youths assault staff at psychiatric hospitals do not appear to
      be validated by these data, which suggest a more complex picture.

PMID- 15175465
TI  - Multiple stakeholder agreement on desired outcomes for adolescents' mental health
      services.
AB  - OBJECTIVES: This study identified desired outcomes for adolescent mental health
      services according to various stakeholders-adolescents, parents, and therapists
      and examined agreement across these groups of stakeholders. Potential correlates
      of agreement, including the youth, family, and treatment characteristics, were
      also tested. METHODS: Interviews were conducted with 170 adolescents aged 11 to
      18 years, their caregiver, and their psychotherapist when the adolescents entered
      community-based outpatient mental health services. Each participant reported up
      to three desired outcomes, which were coded into 30 outcome categories across
      five broad outcome domains. RESULTS: Although the most commonly reported desired
      outcome across all three stakeholder groups was to reduce anger and aggression,
      relatively poor agreement existed within the adolescent-parent-therapist triads
      on desired outcomes for individual youths. Almost two-thirds of the triads did
      not agree on even one of the desired outcomes for the adolescent's treatment, and
      most kappa statistics reflected poor agreement. Youths and therapists were each
      more likely than parents to report desired outcomes that were related to the
      family environment; youths were the least likely to report desired outcomes that
      were related to youth symptom reduction. Although many potential correlates of
      agreement were tested, only two variables were significantly associated with the
      likelihood that the individual triads would agree on treatment goals: youth
      anxiety disorder was associated with significantly greater agreement, whereas
      therapist cognitive-behavioral orientation was associated with significantly
      poorer agreement. CONCLUSIONS: Consistent with the research on adult mental
      health services, a lack of consensus was found among key stakeholders on desired
      outcome priorities for adolescent services. This lack of consensus may limit
      engagement in treatment and the effectiveness of care.

PMID- 15175466
TI  - Variations in use of second-generation antipsychotic medication by race among
      adult psychiatric patients.
AB  - OBJECTIVE: This study examined variations in the use of second-generation
      antipsychotic medication among African-American and non-Hispanic white patients
      in a national sample of adults who were treated by psychiatrists. METHODS: This
      study used data from studies of psychiatric patients and treatments that were
      conducted by the American Psychiatric Institute for Research and Education's
      (APIRE's) Practice Research Network (PRN). Psychiatrists provided detailed
      clinical data for 126 African-American patients and 574 white patients who were
      randomly selected and for whom antipsychotic medications were prescribed. The
      study assessed differences by race in the use of second-generation antipsychotic
      medication, adjusting for clinical, sociodemographic, and health-system
      characteristics, including patients' source of payment for treatment. RESULTS:
      African-American patients were less likely than white patients to receive second
      generation antipsychotic medications (49 percent compared with 66 percent). After
      the analysis statistically adjusted for clinical, sociodemographic, and health
      system characteristics, African-American patients remained less likely than white
      patients to receive second-generation antipsychotics. CONCLUSIONS: Because
      African Americans tended to receive medications that are not first-line
      recommended treatments and that have a greater risk of producing tardive
      dyskinesia and extrapyramidal side effects, African Americans could be expected
      to suffer diminished clinical status. This disparity may also contribute to lower
      rates of adherence and to more frequent emergency department visits and
      psychiatric hospitalizations among African Americans

PMID- 15175467
TI  - Effects of patient and health-system characteristics on community tenure of
      discharged psychiatric inpatients.
AB  - OBJECTIVE: The purpose of this study was to identify the differential effect of
      patient and health-system characteristics on length of stay in the community
      among recidivist psychiatric patients. METHODS: Data on demographic and clinical
      characteristics and mental health service utilization were collected for patients
      with at least one previous psychiatric hospitalization (N=1,972) who visited a
      psychiatric emergency department at a university hospital in Leuven, Belgium,
      between March 2000 and March 2002. Logistic regression analysis was used to
      compare the characteristics of patients with a short (less than two months),
      intermediate (two to 12 months), or long (12 months or longer) stay in the
      community between their last hospital discharge and referral to the psychiatric
      emergency department. RESULTS: One in three patients visited the psychiatric
      emergency department within 30 days of discharge from a psychiatric
      hospitalization, and 43 percent of the patients visited within 60 days of
      discharge. Patients with a short community stay were more likely to be unemployed
      and to have had a discharge against medical advice, a short previous
      hospitalization, no aftercare plan, and a history of two or more previous
      hospitalizations. Longer community stays were predicted by the presence of a
      personality disorder. CONCLUSIONS: For patients with a history of psychiatric
      hospitalization, early psychiatric recidivism may be more highly influenced by
      health-system characteristics than by the presence of severe mental illness.

PMID- 15175468
TI  - Prevalence of psychiatric disorders among National Health Insurance enrollees in
      Taiwan.
AB  - OBJECTIVE: About 96 percent of all residents of Taiwan were enrolled in the
      National Health Insurance (NHI) program in 2000. This study used claims data from
      the NHI database to determine the prevalence of and the demographic
      characteristics that are associated with psychiatric disorders. METHODS: A total
      of 200,432 persons, about 1 percent of Taiwan's population, were randomly
      selected from the NHI database. Persons under the age of 18 years and persons who
      were not eligible for NHI in 2000 were excluded, leaving 137,914 persons
      available for this study. Data for enrollees who had at least one service claim
      during 2000 for ambulatory or inpatient care for a principal diagnosis of a
      psychiatric disorder were classified into one of the psychiatric disorder
      categories according to ICD-9-CM diagnostic criteria. Data from the 2000 NHI
      study were compared with data from a 1985 community survey, the Taiwan
      Psychiatric Epidemiological Project, to determine how the prevalence of
      psychiatric disorders changed over the 15-year period. RESULTS: The one-year
      prevalence of any major psychiatric disorder, any minor psychiatric disorder, and
      any psychiatric disorder were 1.37 percent, 4.26 percent, and 5.30 percent,
      respectively. The differences in prevalence between the sexes were significant
      for five major and nine minor psychiatric disorders. The prevalence for eight
      psychiatric disorders were lower in the 2000 NHI study than in the 1985 community
      survey. However, the prevalence of schizophrenic disorder was found to be higher
      in the 2000 study and the prevalence of bipolar disorder was found to be the same
      in both studies. CONCLUSIONS: Because the prevalence of psychiatric disorders
      were generally lower in this study and in the 1985 community survey than those in
      other countries, it was concluded that both major and minor psychiatric disorders
      were undertreated in Taiwan. It is necessary for the public health department and
      the general population to emphasize mental illness education, prevention, and
      treatment in Taiwan.

PMID- 15175469
TI  - Consumer and advocacy perspectives: What do our patients think about their care?
      What can advocates tell us on behalf of patients and of persons who need
      treatment?

PMID- 15175470
TI  - Clinicians' adherence to an algorithm for pharmacotherapy of depression in the
      Texas public mental health sector.
AB  - This study evaluated clinicians' adherence to the major depressive disorder
      algorithm of the Texas Implementation of Medication Algorithms (TIMA) as a
      component of usual care in the Texas public mental health system. Data were
      collected from two Texas Department of Mental Health and Mental Retardation
      centers between April and December 2000. Clinician adherence measures included
      documentation of outcome measures, prescribing patterns (correct medications,
      therapeutic dosing, dosage increases, and appropriate medication changes), and
      visit frequency. Clinicians had consistently high adherence to appropriate drug
      regimens, at appropriate dosages. Variability in attempts to increase dosages
      when warranted, visit frequency, and documentation of patient outcome measures
      between clinicians were seen. The results suggest that implementation of
      medication algorithms is possible in the public mental health sector.

PMID- 15175471
TI  - Use of psychotropic medications by youths in therapeutic foster care and group
      homes.
AB  - This article examines the use of psychotropic medications among youths in
      residential community-based placements. Data are from a study funded by the
      National Institute of Mental Health of therapeutic foster care (June 1999 through
      May 2001) and group homes (January through June 2001). Data were collected from
      staff by means of in-person interviews. Many youths in both settings received
      psychotropic medications, and approximately one-half were taking multiple
      psychotropic medications. After the authors controlled for demographic and
      clinical factors, the youths in group homes were nearly twice as likely as the
      youths in therapeutic foster care to receive medication. However, residential
      setting was not related to polypharmacology. Additional work is needed to study
      the appropriateness of use and implications of such patterns for research on
      intervention outcomes.

PMID- 15175472
TI  - Use of psychiatric and medical health care by veterans with severe mental
      illness.
AB  - Risk behaviors and health care use among 396 initially hospitalized veterans with
      severe mental illnesses were examined. Health care use was abstracted from
      Veterans Affairs databases (March 1998 to June 2000) for one year after hospital
      discharge. Lifetime intravenous drug use was related to increased use of
      outpatient services, and current alcohol use was related to decreased health care
      use. Patients with posttraumatic stress disorder had greater use of medical
      outpatient services than patients with schizophrenia-spectrum disorders, although
      they had longer hospital stays. These results highlight that veterans with severe
      mental illness receive more treatment in medical than psychiatric health clinics.

PMID- 15175473
TI  - The health and well-being of black mothers who care for their adult children with
      schizophrenia.
AB  - This study compared the mental and physical health of two groups of black mothers
      aged 55 years and older: those who were providing care for their adult child with
      schizophrenia or schizoaffective disorder (N=30) and those who did not have a
      child with mental illness (N=263). The only demographic variable that was found
      to differ between the two groups was that the women who were providing care for
      their adult child with mental illness had more children than the women in the
      comparison group. Both groups of women had similar mental health status. However,
      the mothers who were providing care for their adult children with mental illness
      had higher rates of chronic health conditions, such as high blood pressure,
      arthritis, and eye problems.

PMID- 15175474
TI  - Psychiatrists' attitudes about and informed consent practices for antipsychotics
      and tardive dyskinesia.
AB  - This study provided representative data about the attitudes and behaviors of
      psychiatrists with respect to obtaining informed consent for antipsychotic
      medications. A cross-sectional representative survey of 617 psychiatrists,
      stratified by age and gender, was conducted by using a self-report questionnaire.
      The response rate was 72 percent (N=427). Demographic characteristics did not
      correlate with whether the respondents disclosed information about the potential
      side effect of tardive dyskinesia, which is associated with antipsychotic
      medications. Respondents' attitudes toward informed consent were a strong
      predictor of whether they disclosed information about antipsychotic medications
      and the risk of tardive dyskinesia. A total of 263 respondents (78 percent)
      routinely disclosed information about tardive dyskinesia.

PMID- 15175475
TI  - Reactions of staff members to the relocation of a psychiatric department to a new
      building.
AB  - This study, which was conducted in Israel, examined staff members' reactions to
      the relocation of three closed psychiatric wards to a new building. Participants'
      (N=61) levels of uncertainty were significantly higher before the relocation than
      they were after the relocation. In addition, a significant positive correlation
      was found between anxiety levels before the relocation and anxiety levels after
      the relocation. A significant positive correlation was also found between anxiety
      levels before the relocation and uncertainty levels before and after the
      relocation. No significant correlation was found between the perceived success of
      the relocation and the other study variables.

PMID- 15175477
TI  - The disease analogy and substance abuse.

PMID- 15175479
TI  - A protocol for the reduction of surgical errors.

PMID- 15175480
TI  - Creating a "no blame" culture: have we got the balance right?

PMID- 15175481
TI  - What matters more in patient care? Giving doctors shorter hours of work or a good
      night's sleep?

PMID- 15175482
TI  - Knowledge and action in stroke--are either good enough?

PMID- 15175483
TI  - Flexible rather than standardised approaches to communicating risks in health
      care.

PMID- 15175484
TI  - Safety from numbers: Identifying drug related morbidity using electronic records
      in primary care.

PMID- 15175485
TI  - Patients' problems with new medication for chronic conditions.
AB  - OBJECTIVES: To assess patients' adherence to new medication for a chronic
      condition (and whether non-adherence was intentional), patients' problems with
      their medication, and their further information needs. METHODS: A longitudinal
      survey with data collection at 10 days and 4 weeks was performed on 258 patients
      recruited from 23 community pharmacies in south east England. Patients were
      eligible to participate if they were starting a new chronic medication and were
      either 75 years or older or had one of the following chronic conditions: stroke,
      coronary heart disease, asthma, diabetes, and rheumatoid arthritis. At each time
      point a semi-structured telephone interview was conducted and a postal
      questionnaire was sent. MAIN OUTCOME MEASURES: Self-reported adherence, causes of
      non-adherence, problems with medication, information needs. RESULTS: Sixty seven
      (30%) of 226 patients still taking their medication at 10 days and 43 of 171
      (25%) still taking their medication at 4 weeks were non-adherent. At 10 days 55%
      of the non-adherence was unintentional and the remainder was intentional; these
      proportions were similar at 4 weeks. 138 of 208 (66%) participants still taking
      their new medication at 10 days reported at least one problem with it. 137 of 226
      patients (61%) expressed a substantial and sustained need for further information
      at 10 days and 88 of 171 (51%) at 4 weeks. Several patients who were adherent or
      reported no problems at 10 days were non-adherent or had problems at 4 weeks.
      CONCLUSIONS: A significant proportion of patients newly started on a chronic
      medication quickly become non-adherent, often intentionally so. Many have
      problems with their medication and information needs. Patients need more support
      when starting on new medication for a chronic condition and new services may be
      required to provide this.

PMID- 15175486
TI  - Comparison of two methods of presenting risk information to patients about the
      side effects of medicines.
AB  - OBJECTIVE: To determine whether the use of verbal descriptors suggested by the
      European Union (EU) such as "common" (1-10% frequency) and "rare" (0.01-0.1%)
      effectively conveys the level of risk of side effects to people taking a
      medicine. DESIGN: Randomised controlled study with unconcealed allocation.
      PARTICIPANTS: 120 adults taking simvastatin or atorvastatin after cardiac surgery
      or myocardial infarction. SETTING: Cardiac rehabilitation clinics at two
      hospitals in Leeds, UK. INTERVENTION: A written statement about one of the side
      effects of the medicine (either constipation or pancreatitis). Within each side
      effect condition half the patients were given the information in verbal form and
      half in numerical form (for constipation, "common" or 2.5%; for pancreatitis,
      "rare" or 0.04%). MAIN OUTCOME MEASURE: The estimated likelihood of the side
      effect occurring. Other outcome measures related to the perceived severity of the
      side effect, its risk to health, and its effect on decisions about whether to
      take the medicine. RESULTS: The mean likelihood estimate given for the
      constipation side effect was 34.2% in the verbal group and 8.1% in the numerical
      group; for pancreatitis it was 18% in the verbal group and 2.1% in the numerical
      group. The verbal descriptors were associated with more negative perceptions of
      the medicine than their equivalent numerical descriptors. CONCLUSIONS: Patients
      want and need understandable information about medicines and their risks and
      benefits. This is essential if they are to become partners in medicine taking.
      The use of verbal descriptors to improve the level of information about side
      effect risk leads to overestimation of the level of harm and may lead patients to
      make inappropriate decisions about whether or not they take the medicine.

PMID- 15175487
TI  - Indicators for preventable drug related morbidity: application in primary care.
AB  - AIM: To apply in practice a series of validated indicators for preventable drug
      related morbidity (PDRM). DESIGN: A pilot study to identify retrospectively
      potential PDRM events over a 2 year 3 month time frame using the MIQUEST computer
      software program. SUBJECTS AND SETTING: The electronic patient record of all
      patients aged 18 years and over in nine English general practices. OUTCOME
      MEASURES: The number of potential PDRM events identified, as defined by the
      indicators. RESULTS: Five hundred and seven potential PDRM events were identified
      from 49 658 electronic patient records, giving an overall incidence of 1.0%. A
      small number of the indicators (n = 4) accounted for approximately 60% of the
      events, while for many indicators few events were identified. The most common
      events related to the use of non-steroidal anti-inflammatory drugs in patients
      with congestive heart failure or hypertension, lack of monitoring in patients
      prescribed angiotensin converting enzyme inhibitors, and the use of hypnotic
      anxiolytic agents. CONCLUSIONS: A small number of indicators contributed to the
      majority of the PDRM events. Interrogation of electronic patient records in
      primary care using computerised queries shows potential for detecting PDRM.

PMID- 15175488
TI  - Improving prescribing using a rule based prescribing system.
AB  - OBJECTIVE: To test the hypothesis that the prescribing behaviour of doctors would
      improve after having experience with a computerised rule based prescribing
      system. DESIGN: A prospective observational study of changes in prescribing
      habits resulting from the use of a computerised prescribing system in (1) a
      cohort of experienced users compared with a new cohort, and (2) a single cohort
      at the beginning and after 3 weeks of computer aided prescribing. SETTING: 64 bed
      renal unit in a teaching hospital. INTERVENTION: Routine use of a computerised
      prescribing system by doctors and nurses on a renal unit from 1 July to 31 August
      2001. MAIN OUTCOME MEASURES: Number of warning messages generated by the system;
      proportion of warning messages overridden; comparison between doctors of
      different grades; comparison by doctors' familiarity with the system. RESULTS: A
      total of 51,612 records relating to 5995 prescriptions made by 103 users, of whom
      42 were doctors, were analysed. The prescriptions generated 15,853 messages, of
      which 6592 were warning messages indicating prescribing errors or problems.
      Doctors new to the system generated fewer warning messages after using the system
      for 3 weeks (0.81 warning messages per prescription v 0.42 after 3 weeks, p =
      0.03). Doctors with more experience of the system were less likely to generate a
      warning message (Spearman's rho = -0.90, p = 0.04) but were more likely to
      disregard one (Spearman's rho = -1, p<0.01). Senior doctors were more likely than
      junior doctors to ignore a warning message. CONCLUSIONS: Doctors are influenced
      by the experience of using a computerised prescribing system. When judged by the
      number of warning messages generated per prescription, their prescribing improves
      with time and number of prescriptions written. Consultants and registrars are
      more likely to use their clinical judgement to override warning messages
      regarding prescribed drugs.

PMID- 15175489
TI  - Will changes in primary care improve health outcomes? Modelling the impact of
      financial incentives introduced to improve quality of care in the UK.
AB  - OBJECTIVES: To estimate the total health gain from improving the quality of care
      among patients with cardiovascular disease in line with the quality indicator
      targets in the new contract for general practitioners (GPs) in the UK. DESIGN:
      Statistical modelling, applying population impact measures to estimate
      cardiovascular health gains from achieving treatment targets in the GP contract,
      taking into account current levels of treatment and control. MAIN OUTCOME
      MEASURES: Number of events prevented in the population over 5 years applied to a
      national general practice population of 10,000. RESULTS: The greatest health gain
      in those aged 45-84 years would come from reaching cholesterol reduction targets.
      This could prevent 15 events in people with coronary heart disease, seven events
      in those with a history of stroke, and seven events in those with diabetes.
      Achieving blood pressure control targets in hypertensive patients without the
      above conditions could prevent 15 cardiovascular events, with further benefits
      from reducing blood pressure in patients with high blood pressure and coronary
      heart disease, stroke, or diabetes. Achieving other targets would have smaller
      impacts because high levels of care are already being achieved or because of the
      low prevalence of conditions or associated event risk. CONCLUSION: It is possible
      to quantify the health gain to a practice population of achieving quality targets
      such as those set in the new GP contract. The amount of health gain is sensitive
      to current quality of care, prevalence of conditions, and risk factors, and to
      the size of change anticipated. Nevertheless, it appears that significant health
      gains could result from achieving the proposed quality targets.

PMID- 15175490
TI  - Comparison of health care professionals' self-assessments of standards of care
      and patients' opinions on the care they received in hospital: observational
      study.
AB  - OBJECTIVES: To compare the views of healthcare professionals and patients
      regarding compliance with standards of care concerning patient information.
      DESIGN: Self-rated questionnaire survey. SETTING: Nine wards in short stay French
      hospitals. PARTICIPANTS: 939 patients and 359 healthcare professionals
      (physicians, nurses, assistants and other professionals). MAIN OUTCOME MEASURE:
      Patients' and healthcare professionals' views of compliance with 20 standards of
      patient care described in the French accreditation manual. Comparison of the rank
      order of the standards within the two samples. RESULTS: The response rate was
      61.5% in the patient group and 85.8% in the healthcare professionals. The rank
      orders for the 20 items were similar in both groups (Spearman rank order
      correlation 0.6, p = 0.004). The two items ranked highest by healthcare
      professionals ("consent request for a surgical procedure" and "the doctors ask
      the visitors to leave the room before examining a patient") were also the two
      ranked highest by the patients. Three items were ranked low by both groups:
      "consent request for students to be present", "health education given to
      patients", and "possibility to express satisfaction during discharge". Patients
      were more satisfied with their pain management than were healthcare providers.
      Professionals were more satisfied with the social services than the patients.
      CONCLUSION: There are both similarities and differences between patients' and
      healthcare professionals' views of care. Accurate assessments of quality
      performed during the accreditation procedure require that both patients' and
      professionals' views be taken into account.

PMID- 15175492
TI  - Assessing risk: the role of probabilistic risk assessment (PRA) in patient safety
      improvement.
AB  - Morbidity and mortality due to "medical errors" compel better understanding of
      health care as a system. Probabilistic risk assessment (PRA) has been used to
      assess the designs of high hazard, low risk systems such as commercial nuclear
      power plants and chemical manufacturing plants and is now being studied for its
      potential in the improvement of patient safety. PRA examines events that
      contribute to adverse outcomes through the use of event tree analysis and
      determines the likelihood of event occurrence through fault tree analysis. It
      complements tools already in use in patient safety such as failure modes and
      effects analyses (FMEAs) and root cause analyses (RCAs). PRA improves on RCA by
      taking account of the more complex causal interrelationships that are typical in
      health care. It also enables the analyst to examine potential solution
      effectiveness by direct graphical representations. However, PRA simplifies real
      world complexity by forcing binary conditions on events, and it lacks adequate
      probability data (although recent developments help to overcome these
      limitations). Its reliance on expert assessment calls for deep domain knowledge
      which has to come from research performed at the "sharp end" of acute care.

PMID- 15175491
TI  - Effect of a scoring system and protocol for sedation on duration of patients'
      need for ventilator support in a surgical intensive care unit.
AB  - PROBLEM: Need for improved sedation strategy for adults receiving ventilator
      support. DESIGN: Observational study of effect of introduction of guidelines to
      improve the doctors' and nurses' performance. The project was a prospective
      improvement and was part of a national quality improvement collaborative.
      BACKGROUND AND SETTING: A general mixed surgical intensive care unit in a
      university hospital; all doctors and nurses in the unit; all adult patients (>18
      years) treated by intermittent positive pressure ventilation for more than 24
      hours. KEY MEASURES FOR IMPROVEMENT: Reduction in patients' mean time on a
      ventilator and length of stay in intensive care over a period of 11 months;
      anonymous reporting of critical incidents; staff perceptions of ease and of
      consequences of changes. STRATEGIES FOR CHANGE: Multiple measures (protocol
      development, educational presentations, written guidelines, posters, flyers,
      emails, personal discussions, and continuous feedback) were tested, rapidly
      assessed, and adopted if beneficial. EFFECTS OF CHANGE: Mean ventilator time
      decreased by 2.1 days (95% confidence interval 0.7 to 3.6 days) from 7.4 days
      before intervention to 5.3 days after. Mean stay decreased by 1.0 day (-0.9 to
      2.9 days) from 9.3 days to 8.3 days. No accidental extubations or other incidents
      were identified. LESSONS LEARNT: Relatively simple changes in sedation practice
      had significant effects on length of ventilator support. The change process was
      well received by the staff and increased their interest in identifying other
      areas for improvement.

PMID- 15175493
TI  - Organisational change theory and the use of indicators in general practice.
AB  - General practices are making greater use of indicators to help shape and develop
      organisational arrangements supporting the delivery of health care. Debate
      continues concerning what exactly such indicators should measure and how they
      should be used to achieve improvement. Organisational theories can provide an
      analytical backdrop to inform the design of indicators, critique their
      construction, and evaluate their use. Systems theory, organisational development,
      social worlds theory, and complexity theory each has a practical contribution to
      make to our understanding of how indicators work in prompting quality
      improvements and why they sometimes don't. This paper argues that systems theory
      exerts the most influence over the use of indicators. It concludes that a
      strategic framework for quality improvement should take account of all four
      theories, recognising the multiple realities that any one approach will fail to
      reflect.

PMID- 15175494
TI  - Clinicians, librarians and patient safety: opportunities for partnership.
AB  - Librarians could improve the safety of medical care through greater participation
      in patient safety initiatives. A librarian's expertise in accessing the evidence
      base could enhance the safety and appropriateness of care in a clinical
      environment. In addition, librarians could apply specific technical knowledge
      management skills to medicine. To realize improvements from these skill sets,
      healthcare leaders must consider ways of working with librarians to enhance
      patient safety.

PMID- 15175495
TI  - The problem of appraising qualitative research.
AB  - Qualitative research can make a valuable contribution to the study of quality and
      safety in health care. Sound ways of appraising qualitative research are needed,
      but currently there are many different proposals with few signs of an emerging
      consensus. One problem has been the tendency to treat qualitative research as a
      unified field. We distinguish universal features of quality from those specific
      to methodology and offer a set of minimally prescriptive prompts to assist with
      the assessment of generic features of qualitative research. In using these,
      account will need to be taken of the particular method of data collection and
      methodological approach being used. There may be a need for appraisal criteria
      suited to the different methods of qualitative data collection and to different
      methodological approaches. These more specific criteria would help to distinguish
      fatal flaws from more minor errors in the design, conduct, and reporting of
      qualitative research. There will be difficulties in doing this because some
      aspects of qualitative research, particularly those relating to quality of
      insight and interpretation, will remain difficult to appraise and will rely
      largely on subjective judgement.

PMID- 15175497
TI  - Ignaz Semmelweis and the birth of infection control.

PMID- 15175496
TI  - How safe is the safety paradigm?
AB  - This paper reviews safety initiatives in the health systems of the UK, Canada,
      Australia, and the US. Initiatives to tackle safety shortcomings involve public
      private collaborations. Patient safety agencies (to institute learning, action
      and safety culture), adverse event reporting and, to a lesser extent, safety
      related performance indicators are currently used to design safer health systems.
      Their benefits are mixed, but there is little debate as to their possible side
      effects. Foreseeable adverse effects of multiple safety organisations stem from
      them being too many, too vague, too narrowly focused, threatened by the medical
      practice environment, and too optimistic. Safety related performance indicators
      are most developed in the US but suffer from inadequacies of administrative data,
      underreporting, variable indicator definitions, "extended" use, and low
      sensitivity of the diagnosis coding system, and arguable preventability of the
      prescribed conditions. A critical appraisal of the implications of these
      deficiencies is important to assure the safety of current health system safety
      initiatives and to establish evidence based safety. It is necessary to embed
      health system safety (as well as patient safety) in the societal culture,
      structures, and policies which promote effective, user centred, high performance
      care while allowing for healthy innovation.

PMID- 15175498
TI  - Peer pressure.

PMID- 15175499
TI  - Breaking in a new function for casein kinase 2.
AB  - DNA damage response mechanisms help ensure the fidelity of chromosomal
      transmission, and the failure of such mechanisms might lead to premature aging
      and cancer. A new report has established that casein kinase 2 (CK2), a protein
      that functions in diverse cellular processes, controls the activity of the DNA
      repair protein XRCC1. These results indicate that CK2 is a key participant in the
      cellular response to DNA damage.

PMID- 15175500
TI  - The consequences of nuclear transfer for mammalian foetal development and
      offspring survival. A mitochondrial DNA perspective.
AB  - The introduction of nuclear transfer (NT) and other technologies that involve
      embryo reconstruction require us to reinvestigate patterns of mitochondrial DNA
      (mtDNA) transmission, transcription and replication. MtDNA is a 16.6 kb genome
      located within each mitochondrion. The number of mitochondria and mtDNA copies
      per organelle is specific to each cell type. MtDNA is normally transmitted
      through the oocyte to the offspring. However, reconstructed oocytes often
      transmit both recipient oocyte mtDNA and mtDNA associated with the donor nucleus.
      We argue that the transmission of two populations of mtDNA may have implications
      for offspring survival as only one allele might be actively transcribed. This
      could result in the offspring phenotypically exhibiting mtDNA depletion-type
      syndromes. A similar occurrence could arise when nucleo-cytoplasmic interactions
      fail to regulate mtDNA transcription and replication, especially as the
      initiation of mtDNA replication post-implantation is a key developmental event.
      Furthermore, failure of the donor somatic nucleus to be reprogrammed could result
      in the early initiation of replication and the loss of cellular mtDNA
      specificity. We suggest investigations should be conducted to enhance our
      understanding of nucleo-cytoplasmic interactions in order to improve NT
      efficiency.

PMID- 15175501
TI  - Epigenetic reprogramming during early development in mammals.
AB  - Epigenetic modifications serve as an extension of the information content by
      which the underlying genetic code may be interpreted. These modifications mark
      genomic regions and act as heritable and stable instructions for the
      specification of chromatin organisation and structure that dictate
      transcriptional states. In mammals, DNA methylation and the modification of
      histones account for the major epigenetic alterations. Two cycles of DNA
      methylation reprogramming have been characterised. During germ cell development,
      epigenetic reprogramming of DNA methylation resets parent-of-origin based genomic
      imprints and restores totipotency to gametes. On fertilisation, the second cycle
      is triggered resulting in an asymmetric difference between parental genomes.
      Further epigenetic asymmetry is evident in the establishment of the first two
      lineages at the blastocyst stage. This differentiative event sets the epigenetic
      characteristics of the lineages as derivatives of the inner cell mass (somatic)
      and trophectoderm (extra-embryonic). It is the erasure and subsequent re-tracing
      of the epigenetic checkpoints that pose the most serious obstacles to somatic
      nuclear transfer. Elaboration of the mechanisms of these interactions will be
      invaluable in our fundamental understanding of biological processes and in
      achieving substantial therapeutic advances.

PMID- 15175502
TI  - PKC signalling regulates tight junction membrane assembly in the pre-implantation
      mouse embryo.
AB  - Epithelial differentiation including tight junction (TJ) formation occurs
      exclusively within the trophectoderm (TE) lineage of the mouse blastocyst. Here
      we examine mechanisms by which TJ protein membrane assembly might be regulated by
      protein kinase C (PKC) in the embryo. To overcome the inherent staging asynchrony
      of individual blastomeres within intact embryos, we have used isolated inner cell
      masses (ICMs) from early blastocysts to induce epithelial differentiation in
      their outer cells responding to their new cell contact pattern. Two TJ proteins
      examined retain their order of membrane assembly in isolated ICMs in culture as
      during normal development (early-assembling ZO-2 and late-assembling ZO
      1alpha(+)), but this process is highly accelerated. Using six chemical modulators
      of PKC activity, we show here that PKC signalling is involved in the regulation
      of TJ membrane assembly. While indolactam-mediated PKC activation stimulates
      membrane assembly of both TJ proteins, TPA-mediated PKC activation stimulates
      only that of ZO-1alpha(+). The PKC inhibitors Ro-31-8220, Ro-31-8425 and Go 6983
      suppress the stimulatory effect of both PKC activators on membrane assembly to
      varying extents according to inhibitor and TJ protein examined. Go 6983 similarly
      inhibits ZO-2 and ZO-1alpha(+) membrane assembly. PKC inhibition by Go 6976
      appeared to stimulate TJ membrane assembly. Despite the broad PKC isotype
      specificity of the inhibitors used, these data suggest that the two TJ proteins
      are differently regulated by PKC isotypes or subfamilies. As Go 6983 uniquely
      affects aPKC (particularly PKCzeta) and we find that both PKCdelta and zeta
      relocate upon activator treatment to colocalise partially with the TJ proteins in
      isolated ICMs, we suggest that at least PKCdelta and zeta may play a central role
      in regulating TJ membrane assembly.

PMID- 15175503
TI  - A novel follicle culture system markedly increases follicle volume, cell number
      and oestradiol secretion.
AB  - This study reports a novel, simple method for culture of mouse follicles which
      results in follicles with cell numbers similar to in vivo fully grown follicles.
      Using this method, follicles (180-240 microm in diameter) were cultured in a 100
      microl inverted drop of medium without oil and compared with culture in upright
      drops with and without a mineral oil overlay. Follicles, isolated from C57BL/6 x
      CBA/ca crossbred and MF1 inbred mice, were cultured individually at 37 degrees C
      in 96-well round-bottomed suspension cell tissue culture plates for 6 days.
      Follicles grown in the inverted drop culture system reached a markedly higher
      final diameter (means+/-s.e.m.; 471 +/- 6.0 microm) as compared with the upright
      with oil (363 +/- 2.7 microm) and without oil (358 +/- 4.0) systems. There was no
      significant effect of mouse strain on follicle diameter. Follicular secretion of
      oestradiol and lactate into the medium was measured on days 2, 4 and 6 of
      culture. Secretion of oestradiol per follicle on day 6 was 2.49 +/- 0.45 ng in
      the inverted and 0.90 +/- 0.17 ng in the upright without oil system (P < 0.001).
      Follicular secretion of lactate on a per unit of follicle volume basis remained
      constant in the inverted system over days 2, 4 and 6 and was less (P < 0.001)
      than secretion in both the upright with and without oil systems. Follicle cell
      proliferation was markedly increased in the inverted as compared with the upright
      with oil system; the increases in cell numbers were significant on day 3 (P <
      0.01) and on all subsequent days (P < 0.001). These results are discussed in
      relation to the supply of oxygen to the follicle in culture.

PMID- 15175504
TI  - The cultured rodent follicle as a model for investigations of gonadotrophin surge
      attenuating factor (GnSAF) production.
AB  - Gonadotrophin surge-attenuating factor (GnSAF) bioactivity (the suppression of
      GnRH-induced but not basal LH and FSH secretion from pituitary gonadotrophs) is
      produced by granulosa cells in vitro. Previous studies to investigate this
      bioactivity used dispersed granulosa cells which lack some cell types and the
      structural components of the follicle in vivo. The aim of this study, therefore,
      was to investigate whether intact rodent follicle culture was a suitable model
      for the study of the production of GnSAF bioactivity, allowing GnSAF to be
      investigated in a more physiologically realistic environment while still
      retaining culture conditions from which, as with granulosa cell cultures,
      extraneous factors can be excluded. Follicles from 16-day-old rats and 21-day-old
      mice were cultured for 3-6 days in the presence or absence of FSH and/or LH. The
      follicle-conditioned medium, and matching samples of unconditioned culture medium
      were added to our established rat pituitary monolayer GnSAF bioassay. Both mouse
      and rat intact follicles produced GnSAF bioactivity, reducing GnRH-induced LH
      secretion significantly. GnSAF output from the mouse follicles was highest during
      days 1-3 of culture, when follicles were at an early antral stage of development,
      and fell on days 4-6 as the follicles grew to the mid antral stage. While the
      stimulatory effects of FSH on rat follicle GnSAF secretion was dose-dependent, LH
      alone did not increase GnSAF production. An antibody against human GnSAF blocked
      GnSAF bioactivity produced by rat follicles, and recognised proteins within the
      expected pI and molecular weight range for GnSAF in two-dimensional gels of rat
      follicle-conditioned medium, showing a good homology between rodent and human
      GnSAF proteins. In conclusion, the release of GnSAF bioactivity is principally
      from small follicles stimulated by FSH. Therefore, intact rodent follicle culture
      systems offer an excellent model for the investigation of factors controlling
      GnSAF production under relatively physiological conditions.

PMID- 15175505
TI  - Offspring produced from heterotopic ovarian allografts in male and female
      recipient mice.
AB  - Studies on human ovarian xenografts and mouse allografts indicate that the male
      hormonal milieu and exogenous gonadotrophin administration stimulate antral
      follicle growth. However, it is not known whether oocytes produced under these
      conditions are developmentally competent. The objective of our study was to
      evaluate the developmental competence of oocytes produced in heterotopic mouse
      ovarian grafts placed in male and female recipient mice. Gonadotrophins were 7.5
      IU pregnant mare serum gonadotrophin (PMSG) alone or 7.5 IU PMSG and 7.5 IU human
      chorionic gonadotrophin or were not given prior to oocyte collection. The
      developmental competence of oocytes was assessed by performing in vitro
      fertilisation and embryo transfer to recipients. When no gonadotrophins were
      given the cleavage rate was similar for oocytes collected from ovarian grafts in
      male and female recipients. Gonadotrophin treatment significantly (P < 0.05)
      increased two-cell formation by oocytes grown in female graft recipients but not
      in male recipients. Implantation rates, fetal development and the birth of live
      young were unaffected by the sex of the graft recipient or gonadotrophin
      treatment. Live offspring were produced from oocytes collected from ovarian
      grafts in male and female recipients treated with or without gonadotrophins. In
      conclusion, this work has shown that the hormonal environment of male mice can
      support the growth of oocytes in ovarian allografts and that these oocytes can
      produce live offspring.

PMID- 15175506
TI  - Gonadotropin requirements for dominant follicle selection in GnRH agonist-treated
      cows.
AB  - A study was conducted to examine the effects of gonadotropins on ovarian
      follicular development and differentiation in GnRH agonist (GnRHa)-treated
      cattle. Holstein cows were allotted into two pre-treatment groups: controls (n =
      5) and GnRHa-treated (n = 9). Ovaries were removed from control cows on day 5
      following a synchronized estrus. Treatment with GnRHa resulted in follicular
      arrest at <5 mm. Following follicular arrest, GnRHa-treated cows received a
      constant infusion of FSH for 96 h (GnRHa/FSH), with a randomly selected subset
      receiving hourly pulses of LH in addition to FSH during the last 48 h of infusion
      (GnRHa/FSH + LH). At the end of infusion, ovaries were removed, follicles were
      counted and measured, and follicular fluid samples were collected from large
      follicles (>10 mm). Differences in expression of mRNA for LH receptor, FSH
      receptor, cytochrome P450 side-chain cleavage, 3beta-hydroxysteroid
      dehydrogenase, cytochrome P450 17alpha-hydroxylase (P450c17) and cytochrome P450
      aromatase were determined in large follicles using in situ hybridization. The
      number of large follicles did not differ between GnRHa/FSH-treated and GnRHa/FSH
      + LH-treated cows (P = 0.64), but was greater than control animals (P < or =
      0.004). Follicular fluid concentrations of estradiol-17beta and androstenedione
      were highest in GnRHa/FSH + LH-treated cows (P < or = 0.04), intermediate in
      control cows, and lowest in GnRHa/FSH-treated cows. Hybridization intensity of
      P450c17 was greater in GnRHa/FSH + LH-treated versus control or GnRHa/FSH-treated
      cows (P < or = 0.03). These results indicate that while FSH can support bovine
      follicular growth >10 mm, LH increases androgen production and expression of
      P450c17.

PMID- 15175507
TI  - Cloning of a buffalo (Bubalus bubalis) prostaglandin F(2alpha) receptor: changes
      in its expression and concentration in the buffalo cow corpus luteum.
AB  - Acting primarily through its specific G protein-coupled receptor termed FPr,
      prostaglandin (PG) F(2alpha) induces regression of the corpus luteum (CL) at the
      end of a non-fertile oestrous cycle. This study was aimed at cloning a full
      length cDNA for FPr and determining its expression and protein concentrations
      during different stages of CL development in the water buffalo. Serum
      progesterone and StAR expression were determined to establish temporal
      relationships between indices of steroidogenesis and changes in FPr expression at
      different stages of CL development. In contrast to the dairy cow, the stage IV CL
      (day 20 of the oestrous cycle) did not appear to be functionally regressed in the
      buffalo. Molecular cloning of a cDNA encoding the buffalo FPr yielded a full
      length 2193 bp FPr cDNA containing a single open reading frame encoding a 362
      amino acid protein with seven putative membrane-spanning domains. The deduced
      buffalo FPr amino acid sequence possesses a high degree of identity with the
      other mammalian homologues. Steady state concentration of buffalo FPr transcript
      increased (P > 0.05) from stage I to stage II/III, and declined at 18 h post
      PGF(2alpha) injection. The FPr concentration expressed as fmol/microg of plasma
      membrane protein showed an increase (P > 0.05) from stage I (1.98 +/- 0.10),
      through stage II/III (2.42 +/- 0.48) to stage IV (2.77 +/- 0.18). High affinity
      FPr was observed in stage I (K(d) 4.86 nmol) and stage II/III (K(d) 6.28 nmol)
      while low affinity FPr (K(d) 19.44 nmol) was observed in stage IV. In conclusion,
      we have cloned a full length FPr cDNA from buffalo cow CL and observed that FPr
      mRNA expression, receptor number and affinity did not vary significantly (P >
      0.05) within the luteal phase of the oestrous cycle.

PMID- 15175508
TI  - Alterations in placental 11 beta-hydroxysteroid dehydrogenase (11 betaHSD)
      activities and fetal cortisol:cortisone ratios induced by nutritional restriction
      prior to conception and at defined stages of gestation in ewes.
AB  - In the placenta, cortisol is inactivated by NADP(+)- and NAD(+)-dependent
      isoforms of 11beta-hydroxysteroid dehydrogenase (11betaHSD). Decreased placental
      11betaHSD activities have been implicated in intrauterine growth restriction
      (IUGR) and fetal programming of adult diseases. The objective of this study was
      to investigate whether placental 11betaHSD activities and fetal plasma
      cortisol:cortisone ratios could be affected by nutritional restriction of ewes
      (70% maintenance diet) throughout gestation, for specific stages of gestation, or
      prior to mating. Chronic nutritional restriction from day 26 of gestation onwards
      decreased NAD(+)-dependent 11betaHSD activities by 52 +/- 4% and 45 +/- 6% on
      days 90 and 135 of gestation respectively. Although the decreases in enzyme
      activities were associated with fetal IUGR, the cortisol:cortisone ratio in fetal
      plasma was unaffected by chronic nutritional restriction throughout pregnancy.
      Nutritional restriction confined to early (days 26-45), mid- (days 46-90) and
      late gestation (days 91-135), or the 30 days prior to mating, had no significant
      effect on NAD(+)-dependent, placental 11betaHSD activities, nor was there
      evidence of IUGR. However, nutritional restriction at each stage of pregnancy and
      prior to mating was associated with significant decreases in the fetal plasma
      cortisol:cortisone ratio (3.2 +/- 0.7 in control fetuses; 1.0 to 1.6 in fetuses
      carried by nutritionally restricted ewes). We conclude that nutritional
      restriction of pregnant ewes for more than 45 consecutive days can significantly
      decrease NAD(+)-dependent placental 11betaHSD activities in association with
      IUGR. While the cortisol:cortisone ratio in fetal plasma is sensitive to
      relatively acute restriction of nutrient intake, even prior to mating, this ratio
      does not reflect direct ex vivo measurements of placental 11betaHSD activities.

PMID- 15175510
TI  - If it bleeds, it leads: the pathos derby.

PMID- 15175509
TI  - Effects of parity and body condition at parturition on endocrine and reproductive
      parameters of the cow.
AB  - The effect of parity (multiparous vs primiparous) and body condition score (BCS;
      <3.0 or > or =3.0, lean vs fat) at parturition on metabolic and endocrine
      profiles from 1 month before to 2 months after parturition were studied in 42
      Holstein cows grazing on improved pastures. BCS and milk production were
      determined every 2 weeks. Non-esterified fatty acids (NEFA), beta-hydroxy
      butyrate (BHB), insulin, IGF-I, leptin, thyroxine (T4) and 3,3',5-tri
      iodothyroinine (T3) were determined in plasma every 10 days. Progesterone was
      determined three times per week after parturition. Primiparous cows had a lower
      BCS during the early postpartum period and produced less milk than multiparous
      animals. Primiparous cows had higher NEFA concentrations and they presented more
      samples with BHB concentrations of >1 mmol/l than multiparous cows. Multiparous
      cows had higher T3, T4 and IGF-I concentrations, while fat cows had higher leptin
      and IGF-I concentrations. All hormone concentrations were diminished in the first
      week postpartum. Primiparous cows and fat cows presented a steeper decay of IGF-I
      and leptin around parturition than multiparous cows and lean cows. While thyroid
      hormones and IGF-I showed increasing concentrations from approximately day 30,
      leptin concentrations remained low until the end of the experimental period. The
      initiation of ovarian cyclicity was delayed in primiparous cows and especially in
      primiparous lean cows, consistent with longer intervals from parturition to first
      service and to conception. The endocrine signals most likely to inform the
      reproductive axis regarding a negative energy balance were IGF-I and leptin.

PMID- 15175512
TI  - GASP: picking off the pack of lies.
AB  - GASP is celebrating 25 years tackling Big Tobacco's packs of lies!

PMID- 15175514
TI  - USA: sex and the ciggie.

PMID- 15175513
TI  - UK: acting normal without smoking.

PMID- 15175515
TI  - Sri Lanka: exploiting the fallen.

PMID- 15175517
TI  - Australia: a career in cancer promotion?

PMID- 15175519
TI  - USA/Brazil: the flavour of things to come.

PMID- 15175520
TI  - Malaysia: racing round the hurdles.

PMID- 15175521
TI  - Community tobacco control leaders' perceptions of harm reduction.
AB  - OBJECTIVE: To investigate community tobacco control leaders' attitudes toward
      harm reduction approaches to tobacco use, in order to assess benefits and risks
      associated with these strategies. DESIGN: Cross sectional design involving
      qualitative outcomes from nine structured focus groups. SUBJECTS: 47 community
      tobacco control leaders in Minnesota working in the areas of public policy,
      clinical treatment of nicotine dependence and youth development participated.
      OUTCOME MEASURES: Participants discussed definitions of harm reduction; benefits
      and risks of harm reduction methods; and how funds for tobacco control research
      and programmes should be allocated. RESULTS: Results indicated inconsistency
      about the definition of harm reduction: most groups included a broad range of
      strategies that extended beyond those typically referenced in the scientific
      literature. Many participants stated that harm reduction might be beneficial,
      particularly for smokers who could not or would not quit. However, most also
      expressed concern about a number of risks, including delivering a mixed message
      about tobacco, inadvertently benefiting the tobacco industry, and causing
      unanticipated negative health effects. Participants were inclined to suggest
      public policy measures (for example, smoking bans, increased taxes) as means for
      reducing harm. CONCLUSIONS: Results indicate that even among tobacco control
      leaders there is a need for common terminology to describe harm reduction
      approaches and that public policy approaches to harm reduction are considered
      more dependable than strategies that involve pharmaceutical treatment or rely on
      the tobacco industry, such as product modification.

PMID- 15175523
TI  - Smoking, social class, and gender: what can public health learn from the tobacco
      industry about disparities in smoking?
AB  - OBJECTIVE: To discover how the tobacco industry considers social class and gender
      in its efforts to market cigarettes in the USA, particularly to socially
      disadvantaged young women. METHODS: A systematic on-line search of tobacco
      industry documents using selected keywords was conducted, and epidemiological
      data on smoking rates reviewed. RESULTS: The two largest cigarette manufacturers
      in the USA consider "working class" young adults to be a critical market segment
      to promote growth of key brands. Through their own market research, these
      companies discovered that socially disadvantaged young women do not necessarily
      desire a "feminine" cigarette brand. CONCLUSIONS: Considering the tobacco
      industry's efforts, alongside the persistent and growing disparities in cigarette
      smoking by social class, and the narrowing of differences in smoking by gender,
      it is concluded that additional tobacco control resources ought to be directed
      toward working class women.

PMID- 15175527
TI  - Reducing social inequalities in smoking: can evidence inform policy? A pilot
      study.
AB  - OBJECTIVE: To assess the potential contribution of evidence from existing
      systematic reviews of effectiveness to answering the question: what works in
      reducing social inequalities in smoking? DATA SOURCE: The Cochrane Library
      (2002/4). STUDY SELECTION: Systematic reviews of the effectiveness of community
      based tobacco control interventions, and all the primary studies included in one
      of these reviews. DATA EXTRACTION: Reviews and primary studies were assessed for
      intent to assess the social distribution of intervention effects, information
      about the social inclusiveness or targeting of interventions, baseline
      sociodemographic data collected on participants, and estimates of effect size
      stratified by sociodemographic variables. DATA SYNTHESIS: Only one review aimed
      to examine outcomes stratified by sex, age or socioeconomic status, and these
      aims were only achieved with respect to sex. Sociodemographic data about
      participants were frequently collected in primary studies, but not used to
      compare intervention effects between social groups. CONCLUSIONS: There may be
      scope for using existing research more effectively to contribute to evidence
      based policy to reduce social inequalities in smoking-by explicitly seeking
      stratified outcome data in new systematic reviews, by re-analysing original
      datasets, and/or by meta-analysis of individual participant data.

PMID- 15175526
TI  - Tobacco harm reduction: what do the experts think?
AB  - OBJECTIVE: To assess experts' opinions about the future of, and potential to
      improve individual and public health through "tobacco harm reduction" (THR), the
      use of novel nicotine containing products purporting to reduce the health risks
      from cigarette smoking. DESIGN: Semi-structured telephone interviews on nine
      topic areas, with qualitative content analysis of coded transcripts.
      PARTICIPANTS: 29 professionals with expertise related to tobacco and interest in
      THR, including prominent tobacco control advocates (7), pharmaceutical (3) and
      tobacco industry scientists/officials (5), non-industry scientists (12), and
      Congressional staff (2). RESULTS: Respondents agreed that harm reduction is at
      minimum theoretically plausible, that characteristics of "good" and "bad" THR
      products can be identified, that government regulation is essential but not
      likely in the foreseeable future, and that additional scientific data are very
      much needed. However, there was no consensus on specifics, such as preferred
      regulatory strategies or examples of ideal THR products. Disagreement was seen
      not only across but also within respondent categories. Mistrust of key
      stakeholders-for example, tobacco control advocates distrust of tobacco industry
      scientists and vice versa-was pervasive, and cited frequently as a barrier to
      regulation and collaboration. CONCLUSIONS: Continued dialogue and debate are
      essential as we enter a new and uncertain era of products purporting to reduce
      tobacco produced harm. Experts have concluded that effective government
      regulation is crucial to minimising the risks associated with THR and maximising
      potential benefits.

PMID- 15175528
TI  - Reducing tobacco addiction through tobacco product regulation.
AB  - Tobacco product regulation has the potential to help reduce tobacco attributable
      disease by reducing the toxicity of these products and by reducing the prevalence
      of tobacco use and addiction.

PMID- 15175530
TI  - Tobacco and transition: an overview of industry investments, impact and influence
      in the former Soviet Union.
AB  - OBJECTIVES: To quantify the contribution the tobacco industry has made to foreign
      direct investment (FDI) in the former Soviet Union (FSU) as an indicator of its
      political and economic leverage; to explore the impact this has had on production
      capacity and tobacco control in the region. DESIGN: Data on industry investment
      and its impact on cigarette production capacity were collated from industry
      journals, reports, and websites. Data on total FDI were obtained from the
      European Bank of Reconstruction and Development. RESULTS: By the end of 2000,
      transnational tobacco companies (TTCs) had invested over 2.7 billion US dollars
      in 10 countries of the FSU. Tobacco money as a proportion of FDI varies from 1%
      to over 30% in Uzbekistan. Cigarette production capacity in the factories
      receiving investments tripled from 146 to 416 billion cigarettes per annum and
      the TTCs' market share has increased from nothing to between 50-100% in the
      markets in which they invested. Findings suggest that the effectiveness of
      national tobacco control measures corresponds broadly to the nature of the
      political and economic transition in each country and the size of industry
      investment, which is determined in part by the political context. Thus more
      effective measures tend to be seen in democratic states with smaller or no
      industry investments while the least effective measures are seen in highly
      centralised, one party states with high levels of industry investment or those
      with limited governmental capacity. CONCLUSIONS: The entry of the TTCs at a time
      of major political and economic change left the FSU particularly vulnerable to
      industry influence. This influence was enhanced by the industry's significant
      contribution to FDI, their ability to take over existing state monopolies in all
      but the largest countries, and the lack of democratic opposition.

PMID- 15175531
TI  - Moving East: how the transnational tobacco industry gained entry to the emerging
      markets of the former Soviet Union-part I: establishing cigarette imports.
AB  - OBJECTIVES: To identify British American Tobacco's (BAT) reasons for targeting
      the former Soviet Union following its collapse in 1991 and the initial strategies
      BAT used to enter the region. DESIGN: Analysis of tobacco industry documents held
      at the Guildford BAT archive. RESULTS: Desire to expand to new markets was based
      in part on the decline in old markets. The large population, proximity to China,
      scope to expand sales to women and, in Central Asia, a young population with high
      growth rates made the former Soviet Union particularly attractive. High
      consumption rates and unfilled demand caused by previous shortages offered
      potential for rapid returns on investment. A series of steps were taken to
      penetrate the markets with the initial focus on establishing imports. The
      documents suggest that BAT encouraged the use of aid money and barter trade to
      fund imports and directed the smuggling of cigarettes which graduated from an
      opportunistic strategy to a highly organised operation. In establishing a market
      presence, promotion of BAT's brands and corporate image were paramount, and used
      synonymously to promote both the cigarettes and the company. The tobacco industry
      targeted young people and women. It used the allure of western products to
      promote its brands and brand stretching and corporate imagery to pre-empt future
      marketing restrictions. CONCLUSIONS: BAT used the chaotic conditions in the
      immediate post-transition period in the former Soviet Union to exploit
      legislative loopholes and ensure illegal cigarette imports. Governments of
      countries targeted by the tobacco industry need to be aware of industry tactics
      and develop adequate tobacco control policies in order to prevent the
      exploitation of vulnerable populations. Marketing restrictions that focus on
      advertising without restricting the use of brand or company promotions will have
      a limited impact.

PMID- 15175532
TI  - Moving East: how the transnational tobacco industry gained entry to the emerging
      markets of the former Soviet Union-part II: an overview of priorities and tactics
      used to establish a manufacturing presence.
AB  - OBJECTIVES: To explore how British American Tobacco (BAT), having established
      cigarette imports, responded to the opportunities for investment in cigarette
      manufacturing in the former Soviet Union (FSU). DESIGN: Analysis of documents
      held at the BAT archive in Guildford, UK. RESULTS: Considerable priority was
      attached to investing in the FSU. This led BAT to undertake a major
      organisational change and to intense competition to acquire assets. BAT used
      flawed economic arguments to persuade cash starved governments that its
      investment would reap economic rewards. It offered excise advice that
      disadvantaged governments while benefiting BAT, confused issues over pricing, and
      avoided competitive tendering. BAT targeted agriculture ministries, using its
      expertise in leaf production to differentiate itself from other potential
      investors. It subverted the principles of corporate social responsibility to
      promote itself as a business partner. BAT's task was made easier by the naivety
      of post-Soviet governments and by the international financial organisations'
      support for rapid economic reform. The latter permitted tobacco transnationals to
      penetrate markets before effective competitive tendering processes had been
      established, giving them the opportunity to minimise prices and establish
      monopolies. CONCLUSIONS: Many of the arguments employed when penetrating post
      Soviet markets were highly misleading but governments lacked expertise to realise
      this. There is a need to build tobacco control capacity in transition economies,
      within and outside government, to ensure that governments are better informed of
      the true economic and health impacts of tobacco. Rapid transition from socialist
      to market economies without establishing regulatory institutional structures may
      be dangerous when investing companies use business practices that fall short of
      international standards.

PMID- 15175534
TI  - Airway disease risk from environmental tobacco smoke among coffeehouse workers in
      Turkey.
AB  - OBJECTIVES: To examine the effect of ETS exposure on respiratory symptoms and
      pulmonary function and to compare workers in coffeehouses to those in other
      occupations in order to assess the risk of respiratory illness in this
      occupation. DESIGN: Cross sectional study. SETTING: The study area consisted of
      the three metropolitan districts of the city of Izmir, Turkey. 86 coffeehouses
      and 80 other small scale shops which had no known respiratory risk factor,
      located in the same area, were taken as the study group. SUBJECTS: 207 workers
      were assessed. MAIN OUTCOME MEASUREMENTS: Subjects answered a questionnaire about
      demographic and working characteristics, respiratory symptoms, and smoking
      behaviour. Physical examinations and spirometric measurements were carried out at
      the workplaces. RESULTS: There was a significant increase in respiratory symptoms
      in coffeehouse workers. Working in a coffeehouse showed a significant risk for
      chronic bronchitis (odds ratio (OR) 4.3). In coffeehouse workers, forced
      expiratory volume in one second (FEV(1)) decreased 5.1%, forced vital capacity
      (FVC) 3.4%, FEV(1)/FVC 1.6%, peak expiratory flow (PEF) 6.45%, and forced
      expiratory flow (FEF(25)) 7.2%, FEF(50) 10%, and FEF(25-75) 9.8%. Among workers
      who were described as having an "airway disease", coffeehouse workers were
      significantly greater in number. When age, body mass index, and smoking behaviour
      were controlled, working in a coffeehouse was strongly associated with "airway
      disease" compared to other workers (OR 5.35, 95% confidence interval 2.41 to
      11.87). CONCLUSIONS: Workers in coffeehouses showed significant increases in
      respiratory symptoms and decreased pulmonary function. All workers need to gain
      an awareness of these occupational risks and working conditions should be
      improved immediately.

PMID- 15175535
TI  - The effectiveness of tobacco sales ban to minors: the case of Finland.
AB  - OBJECTIVE: To evaluate the effects of the 1977 and 1995 tobacco sales bans on
      tobacco acquisition of minors. DESIGN: Biennial nationwide postal surveys
      (adolescent health and lifestyle survey, AHLS) in 1977-2003; annual classroom
      surveys (school health promotion survey, SHPS) in 1996-2003. SETTING AND
      PARTICIPANTS: Entire Finland-12, 14, 16, and 18 year olds (AHLS, n = 80 282);
      eighth and ninth graders (14-16 year olds) (SHPS, n = 226 681). MAIN OUTCOME
      MEASURES: Purchase of tobacco from commercial sources during the past month,
      purchase from different commercial (shop, kiosk, other outlet) and social
      sources, ease of buying tobacco, overall acquisition of tobacco products, daily
      smoking, tobacco experimenting. RESULTS: Decrease in tobacco purchase from
      commercial sources was small and short term after 1977 but large and permanent
      after 1995: purchase rate among 14 year old smokers diminished from 90% to 67% in
      2003, 16 year olds from 94% to 62%. Purchases in shops decreased most (14 year
      olds: from 39% to 14%; 16 year olds: from 76% to 27%); purchases in kiosks less.
      An increase was observed in obtaining tobacco from other outlets and friends
      (social sources). Only 2-3% of 14-16 year old smokers used commercial sources
      exclusively when obtaining tobacco. Daily smoking began to decrease after 2001,
      following an earlier decrease in those experimenting. No changes were observed
      among age groups not targeted by the ban. CONCLUSIONS: Legislation appears to
      have permanently changed tobacco sales practices and decreased purchases from
      commercial sources. Social sources need to be taken into account when controlling
      access to tobacco. Sales bans should be accompanied by other health promotion
      measures.

PMID- 15175536
TI  - Smoking behaviour and toxin exposure during six weeks use of a potential reduced
      exposure product: Omni.
AB  - OBJECTIVE: To determine smoking behaviour, acceptability, and toxin exposure when
      smokers switch to the potential reduced exposure product-Omni cigarette. DESIGN:
      12 week randomised, crossover study of Omni versus own cigarettes. PARTICIPANTS:
      19 light/ultralight and 15 regular smokers. OUTCOMES: Cigarettes/day, smoking
      topography, craving, withdrawal symptoms, urinary cotinine plus its glucuronide
      (total cotinine), nicotine plus its glucuronide (total nicotine), and carcinogen
      metabolites (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol plus its glucuronides
      and 1-hydroxypyrene). RESULTS: When switched to Omni, smokers smoked the same
      number of cigarettes/day, smoked Omni cigarettes less intensely (total puff
      volume = -11%) and had slightly lower total cotinine (-18%) levels than their own
      cigarettes, but had a slightly greater carbon monoxide boost/cig (+21%). Craving
      and withdrawal ratings were similar with Omni and own cigarettes. Carcinogen
      metabolite levels were somewhat but not significantly lower with Omni. About half
      of smokers rated Omni as better for their health and about two thirds stated it
      was weaker and worse tasting than their own cigarettes. CONCLUSIONS: Although
      Omni may be an adequate behavioural and pharmacological substitute for
      traditional cigarettes, it may not decrease carcinogen exposure and may increase
      carbon monoxide. Replications with larger sample sizes and longer follow up are
      needed. These results indicate the need for regulation of reduced exposure and
      reduced risk claims.

PMID- 15175538
TI  - Nicotine delivery capabilities of smokeless tobacco products and implications for
      control of tobacco dependence in South Africa.
AB  - OBJECTIVES: Smokeless tobacco (SLT) use is popular among black South African
      women and children. The study sought to determine the nicotine delivery
      capability of popular industrialised and traditional SLT brands in South Africa,
      and to provide information for policy action by regulatory authorities. DESIGN:
      Laboratory chemical analysis of four industrialised and one traditional SLT
      products commercially available, using previously published analytical methods.
      Potential for dependence was inferred from nicotine delivery capabilities
      determined by the percentage free base nicotine. MEASUREMENTS: Moisture, pH,
      total nicotine, and percentage free base nicotine. RESULTS: Total nicotine
      content was between 6-16 mg/g. The pH varied between 7-10 and this correlated
      with percentage free base nicotine, which ranged between 10-99%. The nicotine
      delivery capability of the traditional product was lower than that of the
      industrialised products except for the recently introduced portion bag snus,
      which had comparable total nicotine but the lowest pH and percentage free base
      nicotine. The most popular SLT brands showed the highest percentage free base
      nicotine ever reported for any industrialised SLT or cigarette brands. Small cans
      contained higher nicotine than the large cans of the same brand tested. Findings
      from the study support a potential for limited "product graduation" by users.
      CONCLUSIONS: South African SLT users are mostly exposed to potentially very
      highly addictive levels of nicotine that may favour tobacco dependence and its
      consequent health risks. The increasing use of SLT by women of childbearing age
      support the need for intensified policy action to control its use.

PMID- 15175537
TI  - Exposure to environmental tobacco smoke (ETS) and determinants of support for
      complete smoking bans in psychiatric settings.
AB  - OBJECTIVE: To measure environmental tobacco smoke (ETS) exposure in psychiatric
      settings and to assess determinants of support for complete smoking bans. DESIGN:
      Cross sectional study SETTING: Dutch psychiatric hospitals, outpatient care
      institutions, and sheltered home facilities. SUBJECTS: A random sample of 540
      treatment staff, 306 attendants/nurses, and 93 patients. MAIN OUTCOME MEASURES:
      Self reported ETS exposure, current smoking policy, compliance with smoking
      policy, beliefs about smoking bans. RESULTS: 87% of respondents were exposed to
      tobacco smoke in psychiatric institutions; 29% said that on an average day they
      were exposed to "a lot of smoke". Although ETS originates mainly from smoking
      patients, both non-compliance from patients and employees with existing bans
      resulted in non-smokers being exposed to ETS. Due to non-compliance, ETS exposure
      was quite high when there is a general smoking ban (designated areas option).
      Only with a complete ban was compliance good and employees sufficiently protected
      from ETS exposure. Psychiatrists, psychologists, physicians, attendants, and
      nurses were most concerned about resistance from patients, partly because of the
      fear of infringing on patients' freedom to smoke. CONCLUSIONS: Complete smoking
      bans are the only way to fully protect those working in psychiatry from ETS
      exposure, mainly because general smoking bans are not sufficiently complied with.
      Communication strategies to improve compliance with complete bans are crucial to
      protect those working in psychiatry from ETS. Compliance could be improved by
      addressing the belief that the ban will effectively result in less ETS exposure
      and the issue of patients' freedom to smoke versus employees' right to work in a
      smoke-free environment.

PMID- 15175539
TI  - The cost effectiveness of pharmacological smoking cessation therapies in
      developing countries: a case study in the Seychelles.
AB  - OBJECTIVE: To examine the incremental cost effectiveness of the five first line
      pharmacological smoking cessation therapies in the Seychelles and other
      developing countries. DESIGN: A Markov chain cohort simulation. SUBJECTS: Two
      simulated cohorts of smokers: (1) a reference cohort given physician counselling
      only; (2) a treatment cohort given counselling plus cessation therapy.
      INTERVENTION: Addition of each of the five pharmacological cessation therapies to
      physician provided smoking cessation counselling. MAIN OUTCOME MEASURES: Cost per
      life-year saved (LYS) associated with the five pharmacotherapies. Effectiveness
      expressed as odds ratios for quitting associated with pharmacotherapies. Costs
      based on the additional physician time required and retail prices of the
      medications. RESULTS: Based on prices for currently available generic medications
      on the global market, the incremental cost per LYS for a 45 year old in the
      Seychelles was 599 US dollars for gum and 227 dollars for bupropion. Assuming US
      treatment prices as a conservative estimate, the incremental cost per LYS was
      significantly higher, though still favourable in comparison to other common
      medical interventions: 3712 dollars for nicotine gum, 1982 dollars for nicotine
      patch, 4597 dollars for nicotine spray, 4291 dollars for nicotine inhaler, and
      1324 dollars for bupropion. Cost per LYS increased significantly upon application
      of higher discount rates, which may be used to reflect relatively high
      opportunity costs for health expenditures in developing countries with highly
      constrained resources and high overall mortality. CONCLUSION: Pharmacological
      cessation therapy can be highly cost effective as compared to other common
      medical interventions in low mortality, middle income countries, particularly if
      medications can be procured at low prices.

PMID- 15175541
TI  - The effectiveness of workplace smoking cessation programmes: a meta-analysis of
      recent studies.
AB  - OBJECTIVE: Using meta-analytic procedures, we compare the effectiveness of recent
      controlled trials of worksite smoking cessation during the 1990s with a previous
      meta-analysis of programmes conducted in the 1980s. DATA SOURCES: ABI/Inform,
      BRS, CHID, Dissertation Abstracts International, ERIC, Medline, Occupational
      Health and Safety Database, PsycInfo, Smoking and Health Database, SSCI, and
      Sociological Abstracts. STUDY SELECTION: Controlled smoking cessation
      interventions at the workplace with at least six months follow up published from
      1989 to 2001 and reporting quit rates (QRs). DATA EXTRACTION: Two reviewers
      independently scanned titles/abstracts of relevant reports, and we reached
      consensus regarding inclusion/exclusion of the full text reports by negotiation.
      A third reviewer resolved disagreements. Two reviewers extracted data according
      to a coding manual. Consensus was again reached through negotiation and the use
      of a third reviewer. DATA SYNTHESIS: 19 journal articles were found reporting
      studies conforming to the study's inclusion criteria. Interventions included self
      help manuals, physician advice, health education, cessation groups, incentives,
      and competitions. A total of 4960 control subjects were compared with 4618
      intervention subjects. The adjusted random effects odds ratio was 2.03 (95%
      confidence interval 1.42 to 2.90) at six months follow up, 1.56 (95% CI 1.17 to
      2.07) at 12 months, and 1.33 (95% CI 0.95 to 1.87) at more than 12 months follow
      up. Funnel plots were consistent with strong publication bias at the first two
      follow ups but not the third. In Fisher et al's 1990 study, the corresponding ORs
      were 1.18, 1.66, and 1.18. CONCLUSIONS: Smoking cessation interventions at the
      worksite showed initial effectiveness, but the effect seemed to decrease over
      time and was not present beyond 12 months. Compared to the Fisher (1990)
      analysis, the effectiveness was higher for the six month follow up.
      Disappointingly, we found methodological inadequacies and insufficient reporting
      of key variables that were similar to those found in the earlier meta-analysis.
      This prevented us from determining much about the most effective components of
      interventions. It is advisable for researchers conducting studies in the future
      to report data on attrition and retention rates of participants who quit, because
      these variables can affect QRs.

PMID- 15175543
TI  - Public attitudes about tobacco smoke in workplaces: the importance of workers'
      rights in survey questions.

PMID- 15175544
TI  - Financial implications of cigarette smoking among individuals with schizophrenia.

PMID- 15175551
TI  - Perivascular innervation of penetrating brain parenchymal arterioles.
AB  - We investigated the functional heterogeneity of cerebral pial arteries that are
      extrinsically innervated versus penetrating brain parenchymal arterioles (PA)
      that are intrinsically innervated by comparing myogenic activity and reactivity
      to neurotransmitter. Pial middle cerebral arteries (MCA, n = 6) and PA (n = 6)
      that branched off the MCA and penetrated the brain tissue were isolated from male
      Wistar rats and studied in vitro under pressurized conditions for reactivity to
      serotonin (5-hydroxytryptamine, 5-HT), noradrenaline (NA), and indolactam-V (IL
      V), a protein kinase C (PKC) agonist. In a separate group of vessels from the
      same locations (n = 12), perivascular nerve density was determined after staining
      for protein gene product 9.5 (PGP 9.5). PAs were significantly smaller than MCAs,
      and possessed greater myogenic tone at all pressures studied. MCAs reacted to
      both 5-HT and NA with concentration-dependent contraction, however, PA had little
      to no response to either neurotransmitter. The percent constriction to 5-HT and
      NA for MCA versus PA at the maximum concentration was: 31 +/- 6% versus 1.0 +/-
      1.0% and 13 +/- 5% versus 2.6 +/- 1.8% (P < 0.01). However, both types of vessels
      contracted with similar reactivity to PKC activation with IL-V (41 +/- 4% versus
      37 +/- 7%, ns). Perivascular nerve density correlated with reactivity such that
      MCAs were densely innervated with varicose fibers within the adventitia; however,
      PA had very few or no adventitial fibers. The differential response to
      neurotransmitter suggests that there is significant heterogeneity in the cerebral
      circulation. It appears that in PA, the dominant vasoconstricting stimulus is
      intrinsic myogenic tone and that the role of neurotransmitter and intrinsic
      innervation is beyond that of controlling CBF.

PMID- 15175552
TI  - Effects of sodium selenate treatment on altered responses of left and right atria
      from streptozotocin-induced diabetic rats.
AB  - Experiments were designed to determine whether experimental diabetes alters
      inotropic and chronotropic effects of adrenergic, adenosinergic, and cholinergic
      agonists and whether the observed changes are prevented by sodium selenate
      therapy. Thirty-two rats were divided into four groups of eight subjects each.
      Diabetes induced by streptozotocin caused significant decreases in isoproterenol
      invoked contraction of the left atria with preservation of the right atrial
      chronotropic responses. The diminished response of the left atrial muscle to
      isoproterenol did not respond to treatment with sodium selenate. The left atria
      adenosine-induced direct- and indirect inotropic responses were diminished in the
      diabetic rats. After treatment with sodium selenate the direct response was
      completely normalized, but the indirect response was only partially corrected.
      Adenosine-induced negative chronotropic effects are accompanied by changed
      responses in diabetic right atria that are corrected after treatment. The
      carbachol-induced inotropic and chronotropic responses were not altered in tests
      of the acetylcholine system. We conclude that in diabetic rats, sodium selenate
      treatment reverses the deficits of adenosine-induced negative inotropic responses
      of left and right atria, but not those of isoproterenol-induced positive
      inotropic responses.

PMID- 15175553
TI  - Pressor responsiveness to intravenous quinpirole is blunted in malnourished,
      conscious rats: central vs. peripheral and spinal mechanisms.
AB  - In conscious rats, intravenous treatment with the dopamine D2-like receptor
      agonist quinpirole, elicited a pressor effect, which is attributed to central
      dopamine D2 receptor-mediated activation of sympathetic outflow associated with
      arginine vasopressin release. This prominent central effect is opposed to
      peripheral sympathoinhibitory and spinal depressor effects. The present study
      investigated the effects of pre- and postnatal undernutrition on the central
      pressor responsiveness to quinpirole. Malnourished (MalN) rats were obtained by
      feeding dams a multideficient diet (providing 8% protein) during pregnancy and
      nursing. At 90 days of age, MalN rats weighed significantly less than control
      (CNT) rats born to dams fed standard commercially diet (23% protein) during
      pregnancy and nursing. Baseline mean arterial pressure and heart rate in MalN
      rats were comparable to those of CNT. Intravenous treatment with quinpirole (0.3
      mg/kg) in MalN conscious rats induced a pressor effect, which was significantly
      reduced in both magnitude and duration, when compared with CNT rats. In both
      groups studied, pressor response to quinpirole was fully abolished by the
      peripheral and central dopamine D2 receptor antagonist, metoclopramide (5 mg/kg,
      i.v.) whereas was significantly enhanced after pretreatment with either
      intravenous (0.5 mg/kg) or intrathecal (40 microg per rat at T9-T10 level)
      domperidone, a dopamine D2 receptor antagonist that does not cross the blood
      brain barrier. However, even under peripheral and spinal dopamine D2 receptor
      blockade, maximum pressor effect of quinpirole remained significantly reduced in
      MalN when compared with CNT rats. Neither the maximum pressor nor the
      bradycardiac responses to intravenous phenylephrine or arginine vasopressin
      differed between CNT and MalN rats. This study shows that undernutrition imposed
      during fetal life and suckling blunted the pressor response to quinpirole in
      conscious rats. This blunted response appears mainly related to desensitization
      of brain dopamine D2 receptors rather than enhanced peripheral and/or spinal
      dopamine D2 receptor-mediated depressor effect or vascular hyporesponsiveness to
      alpha1-adrenoceptor and vasopressin receptor stimulation.

PMID- 15175554
TI  - Roles of NF-kappaB and SP-1 in oxidative stress-mediated induction of platelet
      derived growth factor-B by TNFalpha in human endothelial cells.
AB  - Platelet-derived growth factor-B (PDGF-B) is upregulated by proinflamatory
      stimuli in the early stages of atherosclerosis. However, its mechanisms are not
      fully elucidated. In the present study, by using the antioxidant N-acetylcysteine
      (NAC), we investigated in human umbilical vein endothelial cells (HUVECs) the
      roles of oxidative stress in PDGF-B expression induced by tumor necrosis factor
      alpha (TNFalpha) and its underlying mechanisms. Exposure of HUVECs to TNFalpha
      (200 U/ml) for 24 hours caused significant increases of both the PDGF-B
      expression and its promoter/enhancer activity, which were abolished by NAC (20
      mmol/L). Accordingly, a prolonged oxidative stress was induced by TNFalpha and
      that was prevented by pretreatment with NAC. Electrophoresis mobility shift assay
      (EMSA) and Western blot analysis showed that both the nuclear factor-kappaB (NF
      kappaB) and the specificity protein-1 (SP-1) were activated by TNFalpha. However,
      NAC only partially inhibited the TNFalpha-induced activation of NF-kappaB, but
      abolished the activation of SP-1. Mutation of the NF-kappaB binding site resulted
      in a moderate reduction in the TNFalpha-induced activity of PDGF-B
      promoter/enhancer, whereas mutation of SP-1 binding site resulted in an absence
      of induction by TNFalpha. These results suggest that oxidative stress mediates
      the TNFalpha-induced expression of PDGF-B in HUVECs through redox-sensitive
      transcription factors, predominantly the SP-1 and possibly, to some extent of NF
      kappaB.

PMID- 15175555
TI  - NO donor-activated PKC-delta plays a pivotal role in ischemic myocardial
      protection through accelerated opening of mitochondrial K-ATP channels.
AB  - Nitric oxide (NO) can activate protein kinase C (PKC) and the activation of
      mitochondrial ATP-sensitive potassium (K-ATP) channels is cardioprotective.
      However, interactions among NO, PKC, and mitochondrial K-ATP channels remain
      vague. To clarify the cardioprotective mechanism induced by nicorandil, we
      compared its ability to activate PKC isoforms with that of the mitochondrial K
      ATP channel opener, diazoxide. We induced myocardial infarction in rats by 30
      minutes of ischemia followed by reperfusion, then assessed the infarct size 3
      weeks later. We also examined the translocation of PKC isoforms in the isolated
      perfused rat heart. Nicorandil and diazoxide reduced infarct size, and the effect
      of nicorandil, but not of diazoxide attenuated by the PKC inhibitor,
      chelerythrine, or by the NO quencher, carboxy PTIO. Immunoblotting revealed that
      nicorandil translocated PKC-delta to the mitochondria, and that this was
      inhibited by carboxy PTIO. The protective effect of nicorandil against myocardial
      infarction partly depended on the translocation of PKC-delta to the mitochondria,
      which we attributed to the NO donor effect of nicorandil. The PKC-delta-
      dependent activation of mitochondrial K-ATP channel opening might be synergistic
      with its direct effect, making nicorandil an efficient opener of such channels.

PMID- 15175556
TI  - Sustaining excessive nitric oxide upregulates protein expression of nitric oxide
      synthase via soluble guanylyl cyclase: an in vivo study in rats.
AB  - The aim of this study was to elucidate whether upregulation of the endothelial NO
      synthase (eNOS)/nitric oxide (NO) pathway is associated with downregulation of
      the NO/soluble guanylyl cyclase (sGC) pathway. To produce acutely or chronically
      excessive NO, lipopolysaccharide (LPS) was administered intraperitoneally to rats
      in a single dose of 4 mg/kg (LPS-single group) or in stepwise doses of 0.5, 1.0,
      and 2.0 mg/kg every other day (LPS-repeated group). At 24 hours after the
      treatment, in the thoracic aorta from the LPS-single group, both relaxations in
      response to sodium nitroprus-side (SNP), an NO donor, and acetylcholine (ACh) and
      protein levels of sGC and eNOS remained unchanged. In contrast, in the LPS
      repeated group, the SNP-induced relaxation and sGC protein expression
      significantly decreased, while the ACh-induced relaxation and eNOS protein
      expression significantly increased compared with the non-treated control. All
      these changes in the relaxations and protein levels were restored by treatment
      with NOX-100, an NO scavenger. Furthermore, similar alteration in vascular
      function observed in the LPS-repeated group occurred in rats receiving SNP via
      subcutaneous using osmotic pumps (0.4 mg/h). These results indicate that
      persistent excessive NO exposure induces upregulation of the eNOS/NO pathway in
      the endothelium together with downregulation of the NO/sGC pathway.

PMID- 15175557
TI  - Intrapericardial delivery enhances cardiac effects of sotalol and atenolol.
AB  - Targeting drugs to the heart by intrapericardial (i.p.c.) delivery may be a
      promising strategy to obtain higher drug efficiencies with lesser side effects.
      We examined whether i.p.c. delivery of sotalol and atenolol in rats offers
      advantages over intravenous (i.v.) application. Following sustained IPC infusion
      of sotalol or atenolol, pericardial fluid levels exceeded plasma levels 97 and
      134 times respectively (P < 0.01) resulting in 3.8 and 4.7 times higher overall
      left ventricular tissue drug levels (P < 0.05). In a second experiment, the
      effects of the i.p.c. or i.v. beta-blocker infusions on nitroprusside-induced
      tachycardia were studied in conscious rats. For both drugs, i.p.c. infusion of
      0.03 mg/kg.h produced similar antitachycardiac effects as the 1 mg/kg.h i.v.
      dose. In a third set of studies, dP/dt max challenged by dobutamine infusion was
      assessed to study ventricular contractile function after i.v. and i.p.c. sotalol
      in anesthetized rats. i.p.c. sotalol infusion attenuated the dobutamine response
      curve to a greater extent than i.v. (P < 0.01). In conclusion, i.p.c. infusion of
      sotalol and atenolol results in high cardiac tissue concentrations with low
      systemic drug levels. Similar antitachycardiac effects can be obtained at a 10-
      to 30-fold lower dose compared with i.v. delivery. Also, depression of
      ventricular contractility is acquired at a substantially lower i.p.c. sotalol
      dose. Thus, beta-blocking properties of sotalol and atenolol can be greatly
      enhanced by applying them i.p.c.

PMID- 15175558
TI  - Effect of a synthetic matrix metalloproteinase inhibitor (ONO-4817) on neointima
      formation in hypercholesterolemic hamsters.
AB  - Degradation of extracellular matrix (ECM) proteins plays an important role in the
      development of vascular remodeling. We investigated the alteration of matrix
      metalloproteinases (MMPs) on the development of neointima formation and the
      effect of a newly synthesized MMP inhibitor using hypercholesterolemic hamsters.
      Endothelial injury was achieved by a catheter in the hamster carotid artery. Two
      weeks after the injury, neointima was detected in all hamsters. Oral
      administration (twice a day) of ONO-4817 was started 2 hours before injury and
      continued for the next 2 weeks. The neointimal area, with appearance of maze-like
      structures, was markedly reduced by 52.4 +/- 8.4% by treatment with ONO-4817 at a
      dose of 20 mg/kg per day. The treatment by ONO-4817 (20 mg/kg per day)
      significantly reduced the indexes of histone H1 on day 1, 5, and 10 and the BrdU
      index of intimal smooth muscle cells on day 5 and 10, but not on day 1. Whereas
      DNA synthesis was not reduced by ONO-4817, in vitro SMC migration on the other
      hand was reduced dose dependently. According to the results of western-blotting
      analysis, the expressions of MMPs were increased 1 week after injury. Especially,
      MMP-12 was not detected in hamsters without cholesterol diet, but it was much
      increased after injury in hypercholesterolemic hamsters. Additionally, active
      form of MMP-12 increased in the injured artery of hypercholesterolemic hamsters.
      In conclusion, inhibition of MMPs results in the suppression of neointima
      following vascular injury via both prevention of SMC migration and SMC
      proliferation of late phase in hypercholesterolemic hamsters. MMP-12 plays an
      important role on vascular stenosis in hypercholesterolemia and ONO-4817 could be
      a useful compound for the therapy for this field.

PMID- 15175559
TI  - Postprandial increase in plasma concentrations of remnant-like particles: an
      independent risk factor for restenosis after percutaneous coronary intervention.
AB  - Postprandial increase in remnant lipoprotein concentrations has been suggested as
      an important atherogenic factor. However, the influence of these remnants on the
      development of restenosis after percutaneous coronary intervention (PCI) remains
      to be examined. The present study was designed to address this point. In 60
      consecutive patients with successful PCI, the influences of possible risk factors
      on the development of restenosis, including remnant-like particles (RLP)
      cholesterol (RLP-C) and triglyceride (RLP-TG), were examined. While mean
      concentrations of RLP-C and RLP-TG were normal in fasting state, postprandial
      change in RLP-C concentrations was a significant and independent risk factor for
      restenosis after PCI. The calculated cut-off index (COI) for the change was +64%.
      When the patients were divided into 2 groups according to this COI, minimal lumen
      diameter (MLD) and reference coronary diameter were comparable before and
      immediately after PCI between the high- (COI < 64%) and the low- (COI < 64%)
      responders. However, follow-up coronary angiography 3 to 6 months after PCI
      demonstrated that MLD, late loss, and loss index were all worse in the high
      responders compared with the low responders. These results indicate that post
      prandial increase in RLP-C concentrations is an independent risk factor for
      restenosis after successful PCI, even in patients with normal fasting RLP-C
      levels.

PMID- 15175560
TI  - Effects of terbutaline on peripheral vascular resistance and arterial compliance.
AB  - In a double blind, randomized placebo-controlled crossover study we characterized
      how terbutaline affects the mean and short-term fluctuations of peripheral
      vascular resistance and arterial compliance. The study was carried out in six
      young and healthy male subjects in the supine and upright positions by recording
      continuously electrocardiography and finger arterial blood pressure. On average,
      large intravenous terbutaline doses reduce maximally by 50% the mean systolic
      diastolic pressure decay time (windkessel time), by 30% the mean vascular
      resistance, and by 20% the mean arterial compliance. Terbutaline reduces
      differently the beat-to-beat variability of peripheral vascular resistance and
      arterial compliance. The effects can be explained by beta-adrenoceptor activation
      that mediates smooth muscle relaxation in small resistance arteries and large
      conduit arteries. Differences between vascular resistance and compliance lowering
      actions could be explained by differences in the beta-adrenoceptor-mediated
      vascular relaxation and sympathetically mediated vascular contraction between
      small and large arteries.

PMID- 15175561
TI  - Formulation dependent pharmacokinetics--does the dosage form matter for
      nifedipine?
AB  - This was an open-label, randomized, 3-way crossover study that compared in 25
      healthy male subjects, the pharmacokinetics of a single 60-mg dose of nifedipine
      GITS tablet versus (1) 20-mg doses of nifedipine prolonged action tablets given
      q12h for a total of two doses and (2) 2 x 10 mg doses of nifedipine capsules
      given q8h for a total of three doses. Following capsule administration, there was
      a rapid rise in plasma concentration of drug achieving a peak concentration of
      196(35) ng/mL (mean and coefficient of variation) within 0.7 (105) hours and an
      AUC(infinity) of 973(39) ng.hr/mL. After nifedipine PA there was also a rapid
      rise in plasma concentration of drug achieving a Cmax of 85.5 (36) ng/mL with a
      tmax of 1.7(58) hours and an AUC(infinity) of 879(46) ng.hr/mL. For the
      nifedipine GITS formulation, there was a lag in the plasma concentration time
      profile for approximately 2 to 3 hours, then it rose gradually achieving a Cmax
      of of 686(54) 30.5(63) ng/mL with a tmax of 15.0(50) hours and an AUC(infinity)
      ng.hr/mL. The AUC(infinity) and Cmax were significantly (P = 0.0001) greater in
      the capsule and PA formulations than for the GITS; however, the tmax for the GITS
      formulation was significantly (P = 0.001) longer than for the other formulations.
      This study suggests marked formulation-dependent pharmacokinetics, which may have
      important clinical implications.

PMID- 15175562
TI  - ATP-sensitive potassium channels are involved in adenosine-induced reduction of
      blood pressure variability in spontaneously hypertensive rats.
AB  - With a computerized analysis system, blood pressure was recorded continuously in
      conscious unrestrained spontaneously hypertensive rats. The effects of different
      adenosine receptor agonists and ATP-sensitive potassium channel opener and
      blocker on blood pressure variability in spontaneously hypertensive rats were
      studied. It was found that adenosine, 5'-N-cyclopropyl-carboxamidoadenosine
      (CPCA, a selective adenosine A2-receptor agonist) and pinacidil (a nonselective
      ATP-sensitive potassium channel opener) decreased blood pressure variability when
      one of them was used alone, whereas N -cyclopentyladenosine (CPA, a selective
      adenosine A1-receptor agonist) had no significant effects on blood pressure
      variability. When pretreated with glibenclamide (a nonselective ATP-sensitive
      potassium channel blocker), the inhibitory effects of adenosine and CPCA on blood
      pressure variability were significantly prevented. By itself, however,
      glibenclamide had no influence on blood pressure variability. These results
      suggest that the effect of adenosine on blood pressure variability in
      spontaneously hypertensive rats is due to activation of ATP-sensitive potassium
      channels mediated by adenosine A2-receptor.

PMID- 15175563
TI  - 17-beta estradiol attenuates hypoxic induction of HIF-1alpha and erythropoietin
      in Hep3B cells.
AB  - Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that
      regulates expression of several hypoxia-inducible genes, including erythropoietin
      (EPO), by binding to hypoxia response elements (HREs) in their
      promoters/enhancers. Previously, we have shown that 17-beta estradiol (E2-beta)
      attenuates hypoxic induction of EPO in rats. We hypothesized that this response
      is mediated by E2-beta-induced attenuation of HIF-1alpha activity/expression. To
      test this hypothesis, we performed reporter gene assays in Hep3B cells to assess
      E2-beta effects on hypoxia-induced activity of a reporter gene driven by the HRE
      from a cloned EPO-enhancer element. Immunocytochemistry and Western blots were
      additionally used to determine effects of E2-beta on hypoxic increases in HIF
      1alpha and EPO immunoreactivity. Finally, we examined potential influences of E2
      beta on HIF-1alpha mRNA levels by real-time PCR. Consistent with our hypothesis,
      E2-beta (100 pM) inhibited hypoxic increases in HRE-mediated reporter gene
      activity. Furthermore, the estrogen-receptor antagonist ICI 182,780 (25 microM)
      eliminated these inhibitory effects of E2-beta. E2-beta similarly attenuated
      hypoxic induction of both EPO and HIF-1alpha protein in an estrogen-receptor
      dependent manner, but was without effect on HIF-1alpha mRNA expression. These
      findings suggest a role for E2-beta to attenuate EPO expression by interfering
      with hypoxic increases in HIF-1alpha protein through an estrogen receptor
      dependent mechanism.

PMID- 15175564
TI  - Effects of trimetazidine on left ventricular function in patients with type 2
      diabetes and heart failure.
AB  - Congestive heart failure and type 2 diabetes have a deleterious prognosis when
      combined. Trimetazidine, a metabolic agent with anti-ischemic properties, reduces
      fatty acid beta-oxidation via decreased 3-ketoacyl-coenzyme-A thiolase activity
      thereby facilitating energy production via the glycolytic pathway. OBJECTIVES: To
      assess myocardial function by Tissue Doppler Imaging (TDI) after one month of
      trimetazidine (Vastarel) added-on conventional treatment in patients with type 2
      diabetes and heart failure. METHODS: Twenty diabetic patients with ischemic heart
      failure (mean age 66 years; NYHA class II-III) were randomized to trimetazidine
      (60 mg daily) or placebo in a double-blind crossover design. Exercise tolerance,
      2-dimensional echocardiograms, and TDI (rest and exercise) were studied before
      and during treatment. RESULTS: Changes in exercise tolerance did not differ in
      the two groups. Ejection fraction at rest and moderate exercise only improved
      significantly with trimetazidine when analyzed for the first treatment period.
      TDI velocities did not change significantly during treatment periods. CONCLUSION:
      In this early pilot investigation of the effects of trimetazidine in patients
      with diabetes and heart failure there were only weak signs of improved systolic
      myocardial function at rest and exercise. The present observations indicate the
      need of further research to explore the effect of trimetazidine during longer
      treatment period or with more selected patient population.

PMID- 15175565
TI  - Attenuated inhibition of L-type calcium currents by troglitazone in fructose-fed
      rat cardiac ventricular myocytes.
AB  - We recently reported that troglitazone, an insulin-sensitizing agent, inhibited l
      type Ca current (ICa,L) more effectively in streptozotocin (STZ)-induced diabetic
      ventricular myocytes than in age-matched control myocytes. However, whether this
      agent would effectively inhibit ICa,L in an animal model of hyperinsulinemia is
      unknown. Using whole-cell voltage-clamp techniques, ICa,L was measured in
      ventricular myocytes isolated from 12 to 16 weeks on fructose-enriched feeding
      and age-matched control rats. Under control conditions, fructose-fed myocytes did
      not differ from control myocytes in membrane capacitance, current density, or
      voltage-dependent properties of ICa,L. Troglitazone inhibited ICa,L in both
      control and fructose-fed myocytes in a concentration-dependent manner. However,
      this inhibition was less in fructose-fed than in control myocytes; the half
      maximum inhibitory concentrations of troglitazone measured at a holding potential
      of -50 mV were 16.9 and 9.8 micromol/L, respectively. Contrary to the STZ-induced
      diabetic rat, the suppressive effect of troglitazone on cardiac ventricular ICa,L
      was attenuated in fructose-fed rats. Persistent elevation of plasma insulin
      concentration may play a role in these processes.

PMID- 15175567
TI  - Atrial fibrillation in rats induced by rapid transesophageal atrial pacing during
      brief episodes of asphyxia: a new in vivo model.
AB  - Non-pharmacological in vivo models of atrial fibrillation (AF) have been
      developed in large animals only. We aimed to develop and characterize a new small
      animal non-pharmacological in vivo model of AF. AF was induced by transesophageal
      atrial burst pacing during 35 seconds periods of asphyxia in anesthetized male
      Sprague-Dawley rats. AF was reproducibly induced in 81% of the rats. The presence
      of AF was associated with an increased heart rate, and a decreased blood
      pressure. Treatment with amiodarone, D,L-sotalol, flecainide, and propranolol all
      reduced duration of AF, whereas verapamil treatment was associated with a marked
      profibrillatory effect. Increasing gap junction intracellular communication using
      the antiarrhythmic peptide analogue AAP10 did not affect AF duration. Basal
      plasma level of epinephrine and norepinephrine were increased 5- to 20-fold
      relative to values reported by others, but unchanged following 35 seconds of
      asphyxia. The results from our study demonstrate that the rat model shares
      several clinical key characteristics with human AF: (1) hemodynamic response to
      AF; (2) increased autonomic tone; (3) antiarrhythmic effects of clinically used
      drugs; (4) profibrillatory effect of verapamil. Relative to existing models of AF
      in larger animals, this model offers rapid, predictive, and inexpensive testing
      of antiarrhythmic/profibrillatory effects of new drugs.

PMID- 15175566
TI  - Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous
      fibrinolysis in healthy smokers.
AB  - Blood flow and plasma fibrinolytic factors were measured on five occasions in
      both forearms of eight otherwise healthy male smokers during unilateral brachial
      artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8
      pmol/min), and the endothelium-independent vasodilator, sodium nitroprusside (2
      to 8 microg/min). On the first occasion, intra-arterial vitamin C was co-infused
      at 25 mg/min. On subsequent occasions, subjects attended after 28 and 35 days
      treatment with oral vitamin C (1 g daily) or placebo in a double-blind randomized
      crossover design still smoking but with and without acute smoke inhalation (3
      cigarettes over 30 minutes). Basal plasma ascorbate concentrations increased from
      37 +/- 6 micromol/L to 105 +/- 11 micromol/L following oral vitamin C
      supplementation (P = 0.002). Substance P caused dose-dependent increases in
      forearm blood flow (P < 0.001, ANOVA) and t-PA release (P < 0.05, ANOVA) that was
      unaffected by acute recent smoke inhalation, intra-arterial vitamin C, or oral
      vitamin C administration (p = ns). Likewise there were no effects on sodium
      nitroprusside-induced vasodilatation (p = ns). Neither acute local intra-arterial
      nor prolonged oral vitamin C supplementation reverses smoking-related endothelial
      dysfunction and impaired endogenous t-PA release. We conclude that the adverse
      vascular actions of smoking are not principally mediated through oxidative
      stress.

PMID- 15175568
TI  - Nonfatal and fatal drownings in recreational water settings--United States, 2001
      2002.
AB  - Drowning is the seventh leading cause of unintentional injury deaths for all ages
      and the second leading cause of all injury deaths in children aged 1-14 years.
      Many of these injuries occur in recreational water settings, including pools,
      spas/hot tubs, and natural water settings (e.g., lakes, rivers, or oceans). To
      examine the incidence and characteristics of nonfatal and fatal unintentional
      drownings in recreational water settings, CDC analyzed 2001-2002 data from the
      National Electronic Injury Surveillance System All Injury Program (NEISS-AIP) and
      National Vital Statistics System (NVSS) death certificate data from 2001. This
      report summarizes that analysis, which indicated that, during 2001-2002, an
      estimated 4,174 persons on average per year were treated in U.S. hospital
      emergency departments (EDs) for nonfatal unintentional drowning injuries in
      recreational water settings. Approximately 53% of persons required
      hospitalization or transfer for more specialized care. During 2001, a total of
      3,372 persons suffered fatal unintentional drownings in recreational settings.
      Nonfatal and fatal injury rates were highest for children aged < or =4 years and
      for males of all ages. To reduce the number of drownings, environmental
      protections (e.g., isolation pool-fences and lifeguards) should be adopted;
      alcohol use should be avoided while swimming, boating, or water skiing or while
      supervising children; and all participants, caregivers, and supervisors should be
      knowledgeable regarding water-safety skills and be trained in cardiopulmonary
      resuscitation (CPR).

PMID- 15175569
TI  - Enhanced enforcement of laws to prevent alcohol sales to underage persons--New
      Hampshire, 1999-2004.
AB  - In 1984, the National Minimum Drinking Age Act (Public Law 98-363) was passed,
      requiring states to raise to 21 years the minimum age to purchase and publicly
      possess alcohol. Although the law has contributed to substantial reductions in
      underage drinking and alcohol-related motor-vehicle crashes, alcohol use and
      binge drinking rates among youths remain high in the United States, and efforts
      by youths to purchase alcohol from licensed establishments frequently are
      successful. To reduce alcohol sales to persons aged <21 years in Concord (2000
      population: 40,687), New Hampshire, the Concord Police Department (CPD) and New
      Hampshire Liquor Commission (NHLC) conducted a pilot program of enhanced law
      enforcement with quarterly compliance checks of alcohol licenses during March
      2002-February 2004. This report summarizes the results of that program, which
      indicated that enhanced enforcement 1) resulted in a 64% reduction in retail
      alcohol sales to underage youths and 2) was temporally associated with declines
      in alcohol use and binge drinking among Concord high school students. These
      findings emphasize the potential effectiveness of enhanced enforcement of minimum
      drinking age laws to reduce consumption of alcohol by underage youths.

PMID- 15175570
TI  - Breast cancer--screening data for assessing quality of services--New York, 2000
      2003.
AB  - The New York State Breast and Cervical Cancer Screening Program (NYSBCCSP) is
      funded in part through the National Breast and Cervical Cancer Early Detection
      Program (NBCCEDP). A total of 292 mammography facilities participate in NYSBCCSP.
      In 1998, NYSBCCSP began reviewing the clinical outcomes of clients screened
      through the program to identify facilities that might need more intensive
      assessment of quality assurance and corrections of deficiencies. This report
      describes the quality assurance process of NYSBCCSP, which provides methods for
      monitoring and assessing the quality of clinical care by program providers. These
      outcome-based methods can be useful to other programs and providers of breast
      cancer screening.

PMID- 15175571
TI  - National laboratory inventory for global poliovirus containment--United States,
      November 2003.
AB  - In anticipation of the interruption of wild poliovirus (WPV) transmission, the
      United States has joined 122 other poliomyelitis-free countries in taking steps
      to minimize the risk for reintroducing WPV from laboratories to communities. In
      October 2002, a nationwide survey of laboratories and biomedical institutions
      (e.g., universities) that oversee multiple laboratories was conducted to identify
      those that might be holding WPV-containing materials and to establish a national
      inventory of institutions and laboratories retaining such materials. A total of
      32,429 laboratories and biomedical institutions listed in multiple databases were
      mailed letters to alert laboratories of the impending global eradication of polio
      and encourage disposal of unneeded WPV-containing materials. The national
      inventory is a list of institutions and laboratories whose staff will be kept
      informed of eradication progress and appropriate WPV-containment procedures. This
      report summarizes use of the survey to create the national inventory.

PMID- 15175572
TI  - Update: measles among children adopted from China.
AB  - As of May 24, 2004, investigators have identified 10 confirmed measles cases
      associated with adoptees who traveled to the United States from China during
      March 2004. No cases have been reported since April 18, and all the ill persons
      have recovered without complications. CDC is now recommending that the temporary
      suspension of adoptions from the affected orphanage in China be ended and
      standard adoption procedures be resumed.

PMID- 15175582
TI  - Cover to cover: 2003 Journal reader survey.

PMID- 15175583
TI  - Boomer ready initiative: identification of wellness needs.

PMID- 15175584
TI  - Medicare reform opens door for preventive nutrition services.

PMID- 15175585
TI  - Medicare prescription drug/reform act: medicine chest or Pandora's box?

PMID- 15175586
TI  - Weight cycling and immunocompetence.

PMID- 15175587
TI  - Nutrient contributions of dairy foods in the United States, Continuing Survey of
      Food Intakes by Individuals, 1994-1996, 1998.
AB  - OBJECTIVE: This study was designed to quantify the impact of dairy foods on
      nutrient intakes in the United States. SUBJECTS: Data were from 17959 respondents
      to the 1994-1996, 1998 Continuing Survey of Food Intakes by Individuals (CSFII).
      Statistical analyses Nutrient intakes were quantified by quartile of dairy food
      intake. Also, dairy intakes were compared in people who met vs did not meet
      intake recommendations for select nutrients. Finally, the direct contribution of
      dairy foods/ingredients to calcium and lipid intakes was determined. SAS and
      SUDAAN software were used. Data were weighted. Energy intake was a covariable in
      regression models. RESULTS: Intake of all micronutrients examined, except vitamin
      C, was higher with increasing quartile of total dairy and milk intake,
      controlling for energy intake. Calcium was the only micronutrient positively
      associated with cheese intake. Fat intake either did not differ or was lower
      among people in quartile 2, 3, or 4 vs quartile 1 of total dairy and milk intake,
      whereas fat was higher as quartile of cheese intake increased. Dietary
      cholesterol was lower as intakes of any of the dairy categories increased; the
      opposite was true for saturated fat. Dairy foods/ingredients directly contributed
      an average of 51% of dietary calcium, 19% of total fat, 32% of saturated fat, and
      22% of cholesterol. CONCLUSIONS: Total dairy and milk intakes were associated
      with higher micronutrient intakes without adverse impact on fat or dietary
      cholesterol. Results reinforce the strong nutritional profile of dairy-rich
      diets, although results with saturated fat and with cheese suggest that it would
      be useful to modify product composition and/or eating patterns to optimize
      nutritional contributions of dairy products.

PMID- 15175588
TI  - Frequent intentional weight loss is associated with lower natural killer cell
      cytotoxicity in postmenopausal women: possible long-term immune effects.
AB  - OBJECTIVE: Weight-loss attempts are likely to become more frequent as the
      prevalence of obesity rises. Repeated cycles of loss and gain are a common
      consequence of failed weight-loss attempts. The question of whether this pattern
      has negative health effects is unresolved. The objective of this research was to
      investigate associations between weight-loss history and current measures of
      immune function. DESIGN: The study design was a cross-sectional study. SUBJECTS:
      One hundred fourteen healthy, overweight, sedentary, postmenopausal women were
      recruited for an exercise intervention study and were currently weight stable.
      METHODS: History of intentional weight loss was assessed by questionnaire. Flow
      cytometry was used to measure natural killer cell (NK) cytotoxicity at four
      effector-to-target (E:T) ratios and for enumerating and phenotyping lymphocytes.
      Multiple linear regression analysis was used to investigate associations between
      weight loss within the past 20 years and current immune function. RESULTS: Women
      who reported ever intentionally losing >or=10 pounds had lower measured NK
      cytotoxicity than those who did not (24.7%+/-12.1% vs 31.1%+/-14.7%,
      respectively, at E:T 25:1; P=.01). Increasing frequency of previous intentional
      weight loss was associated with lower NK cytotoxicity (P=.003, trend). As an
      independent predictor, longer duration of recent weight stability was associated
      with higher NK cytotoxicity (21.6%+/-11.9%, 24.4%+/-11.0%, and 31.9%+/-14.4% for
      <or=2, >2 to <or=5, and >5 years of weight stability, respectively; P=.0002,
      trend). The frequency of weight loss episodes was also associated with
      differences in the number and proportion of NK cells. CONCLUSIONS: This study
      provides evidence that frequent intentional weight loss may have long-term
      effects on immune function.

PMID- 15175589
TI  - Weight-control behaviors among adolescent girls and boys: implications for
      dietary intake.
AB  - OBJECTIVE: To examine associations between healthful and unhealthful weight
      control behaviors and dietary intake among adolescents. DESIGN: Cross-sectional
      survey (Project EAT [Eating Among Teens]).Subjects/Setting The study population
      included 4144 middle and high school students from Minneapolis/St. Paul public
      schools from diverse racial and socioeconomic backgrounds. Statistical analyses
      Dietary intake patterns were compared across adolescent girls and boys reporting
      unhealthful, only healthful, or no weight-control behaviors in unadjusted
      analyses and analyses adjusted for sociodemographic factors and energy intake.
      RESULTS: Among girls, mean intakes differed across weight-control behaviors for
      all foods and nutrients examined. P values ranged from P=.006 to P<.001. Girls
      using unhealthful weight-control behaviors had significantly lower intakes of
      fruit; vegetables; grains; calcium; iron; vitamins A, C, and B-6; folate; and
      zinc than girls using only healthful weight-control behaviors. Compared with
      girls reporting no weight-control behaviors, girls using unhealthful weight
      control behaviors had lower intakes of grains, calcium, iron, vitamin B-6,
      folate, and zinc. In contrast to the girls, boys reporting unhealthful weight
      control behaviors did not have poorer dietary intakes than boys not using weight
      control behaviors or using only healthful behaviors. Among boys, there were no
      significant differences in mean intakes of vegetables; grains; calcium; iron;
      vitamins A, C, and B-6; folate; and zinc. Furthermore, boys using unhealthful
      weight-control behaviors had higher fruit intakes (P=.002) than boys reporting no
      weight-control behaviors. CONCLUSIONS: Adolescent girls who engage in unhealthful
      weight-control behaviors are at increased risk for dietary inadequacy. The
      findings demonstrate a need for interventions to prevent unhealthful weight
      control behaviors in adolescent girls, and to promote healthful weight-control
      behaviors when indicated.

PMID- 15175590
TI  - Dietary sources of nutrients among US adults, 1994 to 1996.
AB  - OBJECTIVE: To identify major food sources of 30 nutrients and dietary
      constituents among US adults during 1994 to 1996, and to compare them with those
      identified for 1989 to 1991. DESIGN: A total of 6419 foods were assigned to 112
      food groups based on similarities in nutrient content or use. These foods
      included 3778 food mixtures disaggregated by the US Department of Agriculture's
      (USDA) FoodLink computerized research tool, so ingredients could be assigned to
      the appropriate groups and nutrient values ascribed accordingly.Subjects/setting
      Single 24-hour dietary recalls from a nationally representative sample of 10019
      adults aged 19 years or older in USDA's 1994 to 1996 Continuing Survey of Food
      Intakes by Individuals were used. Statistical analyses performed The population
      proportion formula was used to determine weighted nutrient intakes by food
      groups. Results were tabulated in descending rank order for food groups providing
      at least 1% of total nutrient intake. RESULTS: Dietary food sources found for
      1994 to 1996 were fairly consistent with 1989 to 1991 results for the rank order
      and proportion these sources made to total nutrient intakes. Remarkable changes
      were seen in the higher proportion of energy from alcoholic beverages, in the
      shifts in the proportion of total fat and fatty acids from oil (higher ranked)
      and margarine (lower ranked), and in the lower proportion of vitamins and
      minerals from ready-to-eat cereals. CONCLUSIONS: Despite changes in survey
      methodology, the food supply, and eating patterns, food sources of nutrients
      among US adults in 1994 to 1996 and 1989 to 1991 were similar. The 1994 to 1996
      data are the first known national population estimates for dietary sources of
      vitamin A (retinol equivalents), selenium, caffeine, and theobromine among US
      adults.

PMID- 15175591
TI  - Hypovitaminosis D in acutely injured pediatric burn patients.
AB  - PROBLEM: The prevalence of vitamin D insufficiency, its etiology, and associated
      sequelae among acutely injured burn patients is unknown. OBJECTIVE: This study
      assessed vitamin D and endocrine status, as well as the effect of anabolic
      agents, in pediatric patients who had sustained burns in excess of 25% total body
      surface area (TBSA). SUBJECTS: Sixty-nine patients with a mean TBSA burn of
      50.6+/-2.2% (range 27% to 94%) and full thickness injury of 41.3+/-3.0% (range 0%
      to 94%) were studied. Subjects ranged in age from 0.6 to 18 years (mean, 5.8+/
      0.6 years). Main outcome measures Blood samples were obtained for serum 25
      hydroxyvitamin D (D25), 1,25-dihydroxyvitamin D (D1,25), albumin, cortisol,
      triiodothyronine (T3), tetraiodothyronine (T(4)), thyroid stimulating hormone
      (TSH), and parathormone (PTH). RESULTS: Two hundred eighty morning blood samples
      of D25 and D1,25 demonstrated that 45% and 26.2% were low and 8.9% and 11% were
      very low, respectively. At least one low D25 or D1,25 level occurred in 62.3% of
      all subjects. Very low levels were noted in 23.2% of all patients. There was an
      increased incidence of hyperparathyroidism in patients with very low serum D25.
      Vitamin D25 and D1,25 levels were lower in subjects with larger burns or
      inhalation injury, as well as those treated with thyroxine or oxandrolone. Serum
      albumin, cortisol, T(4), and TSH were not correlated with concentration of
      vitamin D. CONCLUSIONS: Demonstration of a high incidence of low serum vitamin D
      indicates vitamin D status may be significantly compromised in burned children.
      It is unclear why vitamin D deficiency exists in this population. The most
      effective way to improve vitamin D status remains elusive at this time.

PMID- 15175592
TI  - Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United
      States: The 1987, 1992, and 2000 National Health Interview Survey results.
AB  - OBJECTIVE: To describe trends in use of specific vitamin and mineral (VM)
      supplements. DESIGN: The nationally representative National Health Interview
      Survey queried adult respondents about their use of VM supplements in 1987, 1992,
      and 2000. Statistical analysis Trends in use of VM supplements from 1987 to 2000
      were determined using linear contrasts. RESULTS: The percentage of adults using
      any VM supplement daily increased from 23.2% (1987) to 23.7% (1992) to 33.9%
      (2000). This pattern was consistent for both sexes, all race/ethnic groups, and
      adults aged >or=25 years. The increase in the percentage of daily users of
      multivitamins, vitamin A, and vitamin E was 10.5, 1.2, and 7.3 percentage points,
      respectively, from 1987 to 2000. Increases in daily use of vitamin C (3.3
      percentage points) and calcium (6.1 percentage points) occurred between 1992 and
      2000. All trend analyses were significant at P<.001. In the 2000 National Health
      Interview Survey personnel queried the use of nonvitamin/nonmineral supplements
      for the first time. At that time, 6.0% of respondents reported using them daily.
      CONCLUSION: The increasing trend in supplement use over time and the notable use
      of nonvitamin/nonmineral supplements in 2000 indicates the continued need to
      monitor the use of all types of dietary supplements for purposes of dietary
      surveillance and nutrition-related research.

PMID- 15175593
TI  - Supplement use among US adults: implications for the dietetics professional.

PMID- 15175594
TI  - 2000-2001 food label and package survey: an update on prevalence of nutrition
      labeling and claims on processed, packaged foods.
AB  - The food label is an important tool for improving the public's understanding of
      the health benefits of following a nutritious diet. The Center for Food Safety
      and Applied Nutrition (CFSAN) of the Food and Drug Administration (FDA) has
      continued to study food labels with its Food Label and Package Survey (FLAPS).
      Data from the 2000-2001 FLAPS characterize various aspects of the labeling of
      processed, packaged foods, including nutrition labeling and various types of
      label claims. The FDA used a multistage, representative sample of food products
      from the Information Resources Inc (IRI) 1999 supermarket database as the basis
      for the FLAPS sample. The final FLAPS database consists of 1281 foods. An
      estimated 98.3% of FDA-regulated processed, packaged foods sold annually have
      nutrition labels, with an additional 1.7% of products exempt from nutrition
      labeling requirements. Health claims (4.4%), structure/function claims (6.2%),
      and nutrient content claims (49.7%) were identified on food labels. In addition
      to the resource this survey provides to CFSAN in assessing health and nutrition
      information on the food label, registered dietitians and other health
      professionals can use FLAPS data to assist consumers in choosing a more
      nutritious diet to improve their health and well-being.

PMID- 15175595
TI  - Facilitating transdisciplinary teamwork in dietetics education: a case study
      approach.
AB  - Teamwork, emphasized by the transdisciplinary approach, has been strongly linked
      to the development of a culture of patient safety. However, the vast majority of
      health care education is one-dimensional, ie, focused on one discipline, taught
      by practitioners of the same discipline, with students of the same discipline. In
      an effort to address this one-dimensional view of health care education, a case
      study assignment was developed to facilitate professional interaction between
      graduate physical therapy and graduate nutrition students. The objectives were
      threefold: (a). to increase student understanding of the role of another
      discipline, (b). to increase student ability to obtain and analyze information
      from a consultant relative to a patient case, and (c). to increase student
      communication skills across disciplines. For the assignment, physical therapy
      students were assigned one case scenario and one nutrition student to interview
      individually. The nutrition students acted as consultants in a clinical setting.
      The interactive assignment was considered an effective learning tool for
      facilitating interprofessional learning by the faculty based on student comments
      reporting increased understanding of the role of the other discipline, increased
      communication skills, and an understanding of the barriers to transdisciplinary
      interaction. Future studies, both quantitative and qualitative, may further
      identify effects of instructional activities designed to facilitate
      transdisciplinary health care.

PMID- 15175596
TI  - Conjugated linoleic acid: health implications and effects on body composition.
AB  - Conjugated linoleic acid (CLA) is attracting interest because of its purported
      effects on body composition, specifically a reduction in body fat mass and an
      increase in lean body mass. Other reported beneficial health-related effects of
      CLA include anticarcinogenic, antiatherogenic, antidiabetogenic, and immune
      modulating properties. Because research on CLA has been almost exclusively in
      animals and the mechanism(s) by which CLA exerts its effects remain largely
      unknown, scientists are extremely cautious about making definitive statements
      about CLA. Despite the limited research on CLA in human subjects, numerous
      Internet websites and health food stores sell CLA supplements or CLA-containing
      products as weight loss or ergogenic aids. The increasing popularity of CLA as a
      dietary supplement makes it important that dietitians and health professionals
      are aware of CLA and are able to provide the public with science-based
      information regarding CLA.

PMID- 15175597
TI  - Research and professional briefs: characterizing process control of fluid
      viscosities in nursing homes.
AB  - Swallowing impairment with advancing age is a major health care problem,
      especially among nursing home residents. An estimated 40% to 60% of nursing home
      residents have signs of swallowing disorders or dysphagia. The high number of
      nursing home residents with dysphagia is, at least in part, caused by patients
      with swallowing disorders being more likely to be discharged to institutional
      care. Aging alone does not result in swallowing disorders. Conditions that
      contribute to swallowing problems include dementia, cerebral vascular accidents,
      Parkinson's disease, neuromuscular disorders, and some medications. This article
      discusses the health-related rationale for thickened liquids and fluid
      viscosities, reviews each phase of the study, and concludes with the practical
      implications of the study for clinical dietitians.

PMID- 15175598
TI  - Self-reported dieting experiences of women with body mass indexes of 30 or more.
AB  - Self-reported information on dieting experiences of 149 women with a body mass
      index (BMI) of 30 to 70 was gathered to refute the notion that obese women have
      made few serious attempts to lose weight and to see whether women with higher
      BMIs report more frequent dieting than women with lower BMIs. Participants
      completed questionnaires about lifetime dieting experiences and provided
      demographic information, including heights and weights. Statistical comparisons
      among categorical variables were made using chi(2) tests. Women with higher BMIs
      tended to start dieting before age 14 (P<.001) and had dieted more frequently
      (P<.01) than women with lower BMIs. Negative memories of dieting far outnumbered
      positive or neutral ones. When a patient has a history of dieting failure,
      dietetics professionals should consider focusing on improvements in metabolic
      fitness through lifestyle changes for chronic disease risk reduction rather than
      encouraging continued attempts to lose weight.

PMID- 15175599
TI  - Portion size of common foods predicts energy intake among preschool-aged
      children.
AB  - This study evaluated the relationship of food intake behaviors to total energy
      intake among children aged 2 to 5 years old (N=5447) who participated in the
      Continuing Survey of Food Intakes by Individuals, 1994-1996, 1998 (CSFII 94-96,
      98). Food intake behaviors examined were portion size for 10 commonly eaten
      foods, number of eating occasions per day, and number of foods consumed per day.
      Using regression models, we examined these eating behaviors as predictors of
      energy intakes with adjustment for body weight. Eating behaviors and body weight
      were positively related to energy intake, together explaining 38% to 39% of the
      variability. Portion size alone accounted for 17% to 19% of the variance in
      energy intake, whereas body weight predicted only 4%. Feeding recommendations
      should highlight the importance of age-appropriate portion sizes and provide
      guidance on the frequency of eating and number of foods consumed.

PMID- 15175600
TI  - Vitamin D intake in the United States.
AB  - Mean intake of vitamin D in the United States was estimated from food and food
      plus supplements and compared with recommended intake levels. US men, nonpregnant
      and nonlactating women, and nonbreastfeeding children aged 1 year and older who
      participated in the Third National Health and Nutrition Examination Survey
      (NHANES III, 1988-1994) or the Continuing Survey of Food Intakes by Individuals
      1994-1996, 1998 (CSFII 1994-1996, 1998) were included in the estimates. Intake of
      vitamin D from food sources and dietary supplements was not meeting recommended
      levels. The lowest intakes of vitamin D from food were reported by female
      teenagers and female adults. The highest intakes of vitamin D from food sources
      were reported by male teenagers. Dairy products were the primary sources of both
      vitamin D and calcium. Additional food fortification as well as dietary and
      supplement guidance are needed for the general population.

PMID- 15175601
TI  - Position of the American Dietetic Association and Dietitians of Canada: nutrition
      and women's health.
AB  - It is the position of the American Dietetic Association (ADA) and Dietitians of
      Canada (DC) that women have specific nutritional needs and vulnerabilities and,
      as such, are at unique risk for various nutrition-related diseases and
      conditions. Therefore, the ADA and the DC strongly support research, health
      promotion activities, health services, and advocacy efforts that will enable
      women to adopt desirable nutrition practices for optimal health. Women are at
      risk for numerous chronic diseases and conditions that affect the duration and
      quality of their lives. Although women's health-related issues are multifaceted,
      nutrition has been shown to influence significantly the risk of chronic disease
      and to assist in maintaining optimal health status. Dietetics professionals
      strongly support research, health promotion activities, health services, and
      advocacy efforts that will enable women to adopt desirable nutrition practices
      for optimal health.

PMID- 15175603
TI  - The history and development of advanced practice nursing: lessons for dietetics.

PMID- 15175607
TI  - Where can I find summer food safety resources?

PMID- 15175610
TI  - Antibiotic susceptibility of glutaraldehyde-tolerant Mycobacterium chelonae from
      bronchoscope washing machines.
AB  - BACKGROUND: Contamination of bronchoalveolar lavage fluid is a major problem in
      the world. Although 2% glutaraldehyde (GA) is widely used as a disinfectant for
      bronchoscope cleaning, recently, GA-tolerant mycobacteria have been isolated,
      which makes this problem more complicated. METHODS: We studied the susceptibility
      to GA and antibiotics of mycobacteria isolated from bronchoscope washing machines
      in our hospital. We also studied the minimum inhibitory concentrations of GA and
      antibiotics with pump inhibitors. RESULTS: Twenty-nine mycobacteria were
      isolated, of which 26 were Mycobacterium chelonae. Among 18 isolates of M
      chelonae, excluding 8 isolates in which some results were not reproducible, 50%
      (9 of 18) were 2% GA-tolerant. One hundred percent (9 of 9) of the GA-tolerant
      isolates and 11% (1 of 9) of the GA-sensitive isolates were either resistant or
      intermediately resistant to 2 or 3 classes of antibiotics. Efflux pump inhibitors
      did not influence the susceptibility to GA and antibiotics. CONCLUSIONS: It was
      suggested that there might be an association of GA tolerance with antibiotic
      resistance in M chelonae. There may a different mechanism(s) other than that
      involving efflux pumps with regard to GA tolerance and antibiotic resistance in M
      chelonae. When bronchoscopy-related mycobacterial infections are suspected,
      physicians and clinical microbiologists should exercise care in handling GA
      tolerant mycobacteria, which may be resistant to multiple antibiotics.

PMID- 15175611
TI  - Enteric gram-negative bacilli bloodstream infections: 17 years' experience in a
      neonatal intensive care unit.
AB  - OBJECTIVE: To assess the occurrence of enteric gram-negative bacilli (EGNB)
      bloodstream infections (BSI) in a neonatal intensive care setting during a 17
      year period in which a consistent antibiotic treatment program was in place. To
      document infections, outbreaks, or epidemics, emergence of antibiotic resistance,
      clinical correlates, and outcomes of the most prevalent EGNB (Escherichia coli,
      Klebsiella pneumoniae, and Enterobacter cloacae). METHODS: This study analyzed
      demographic, clinical, and bacteriologic information from 360 infants born 1986
      2002 who developed 633 blood culture-proven BSI. A total of 121 EGNB were
      isolated (E coli, K pneumoniae, and E cloacae). Early-onset BSI were discovered
      within 48 hours from birth, and late-onset BSI were those that occurred
      thereafter. Suspected early-onset BSI were treated with ampicillin and
      gentamicin, suspected late-onset BSI with vancomycin and gentamicin. Antibiotics
      were changed on the basis of organism antimicrobial susceptibility. RESULTS:
      Early-onset BSI were noted in 52 of 21,336 (244/100,000) live births (1986-1991),
      40 of 20,402 (196/100,000) live births (1992-1997), and 25 of 17,926
      (139/100,000) live births (1998-2002). Of these cases, 39 were caused by E coli
      and 4 by K pneumoniae. Antibiograms for E coli isolated during the last 5 years
      of the study showed an increase in antibiotic resistance that coincided with
      obstetric group B streptococcus antepartum antibiotic prophylaxis. Group B
      streptococcus declined from 41 to 4 cases from the first to the last period. Late
      onset BSI increased from 111 to 230 cases from the first to the second 6-year
      study period and declined modestly (171 cases) during the last. Fifteen percent
      (78 cases) of late-onset BSI were caused by EGNB, 5% by other gram-negative
      bacilli, 67% primarily by coagulase-negative staphylococcus, and 13% by fungus.
      Nonspecific clinical and hematologic signs of late-onset BSI were similar across
      EGNB species, but necrotizing enterocolitis was often associated with E coli,
      whereas pneumonia and prolonged thrombocytopenia characterized K pneumoniae
      infections. No outbreaks or epidemics were observed, and strains of EGNB with
      evidence of extended spectrum beta-lactamase production were never isolated.
      CONCLUSION: Antepartum antibiotic prophylaxis may have increased antibiotic
      resistance in E coli isolates from early-onset BSI but has dramatically decreased
      group B streptococcus infections. Late-onset BSI caused by EGNB increased, but
      without changes in antibiotic susceptibility. In spite of medical advances, E
      coli, K pneumoniae, and E cloacae remain responsible for significant morbidity
      and mortality, especially in very low birth weight infants.

PMID- 15175612
TI  - Inappropriate use of urinary catheters in elderly patients at a midwestern
      community teaching hospital.
AB  - BACKGROUND: An estimated 4 million patients per year in the United States are
      subjected to urinary catheterization. Approximately 25% of patients who are
      hospitalized have an indwelling urinary tract catheter placed at some time during
      their hospital stay and nosocomial urinary tract infections develop in 5% per
      day, with associated bacteremia in 4% of patients. OBJECTIVE: We sought to assess
      the prevalence and the appropriateness of the use of urinary catheters at a
      community teaching hospital in medical patients age 65 years and older. METHODS:
      We randomly selected 285 charts from a total of 2845 patients admitted during the
      year 2000 who were 65 years and older and had an indwelling urinary tract
      catheter inserted during the first 24 hours after admission. We excluded patients
      who had a urinary catheter placed before admission and patients admitted for
      operation. RESULTS: On chart review we found an appropriate indication for
      catheterization for 46% of these patients. A physician or nurse explicitly
      documented the reason for catheter placement in only 13%. No order for
      catheterization was written in 33% of the charts. Mean duration of catheter use
      was 3 days. CONCLUSIONS: Less than half of urinary catheterizations in this
      teaching hospital were indicated and even fewer had an explicit indication
      recorded in the chart. Other investigators have had similar findings at other
      hospitals. Interventions are needed to decrease the inappropriate use of urinary
      catheters.

PMID- 15175613
TI  - Comparative in vitro and in vivo study of nine alcohol-based handrubs.
AB  - BACKGROUND: Hygienic hand disinfection using alcohol-based handrubs (AHRs) is an
      alternative method to conventional handwashing in hospital wards. Because a
      documented choice of such products would consider data from in-care evaluation,
      we designed a comparative study of 9 AHRs both in vitro and in vivo in actual
      care conditions. METHODS: The bactericidal activity of AHRs was first measured in
      vitro against 4 hospital strains exhibiting multiple antibiotic resistance:
      Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa, and
      Enterobacter aerogenes. In a second time, AHRs were tested in an intensive care
      unit for antibacterial activity against the cutaneous flora of personnel hands
      and for acceptance by the care personnel. RESULTS: The 9 AHRs could be classified
      in 3 groups on the basis of their in vitro activity: products of the first group
      showed a bactericidal activity higher than 4 log(10) against the 4 strains. Only
      1 of these products presented simultaneously an effective antibacterial activity
      against the cutaneous flora of care personnel hands and a good acceptance by the
      care personnel. CONCLUSION: The in vitro study allowed the differentiation of the
      AHRs tested on the basis of bactericidal activity, but evaluation in an in-care
      situation allowed further discrimination through both antibacterial activity and
      acceptance. Thus, the combination of in vitro and in vivo evaluations should
      provide helpful arguments in the choice of AHRs.

PMID- 15175614
TI  - Nosocomial infections among pediatric hematology/oncology patients: results of a
      prospective incidence study.
AB  - BACKGROUND: Nosocomial infections (NI) are an important clinical complication in
      adult and children patients at the different hospital wards. NI cause
      considerable morbidity and mortality and are associated with prolonged hospital
      stay and increased health care costs. OBJECTIVE: The objective of this study was
      to describe the incidence of NI in pediatric patients with neoplastic disease as
      a first step toward improving infection control policies. METHODS: A prospective
      surveillance study from March through May 2001 was performed in the pediatric
      hematology/oncology unit at the University Hospital in Barcelona. The Centers for
      Disease Control and Prevention criteria were used as standard definition for NI.
      NI rates were calculated as a density incidence rate (per 100 patient-days).
      RESULTS: Fifty-one patients were admitted during the study period. Twelve
      patients had a total of 18 NI. The incidence of NI was 1.77 per 100 patient-days.
      Patients with acute lymphoblastic leukemia had the highest NI rate (2.71 per 100
      patient-days). The most frequent episodes of NI were bacteremia (55.5%) and fever
      of unknown origin (16.6%). The most frequently isolated microorganisms were gram
      positive bacteria (78.6%). Coagulase-negative Staphylococci were the most common
      isolates in bacteremias (70%). The extrinsic risk factors related with the
      highest incidence rates of NI per 100 patient-days were central venous
      catheterization (1.7 infections) and parenteral nutrition (3.2 infections).
      CONCLUSIONS: Extrinsic risk factors associated with NI have been identified in
      this high-risk population. These findings suggest the need to evaluate the
      infection control measures to reduce the morbidity and mortality in a
      hematology/oncology unit.

PMID- 15175615
TI  - Nosocomial pneumonia in the intensive care unit of a Brazilian university
      hospital: an analysis of the time span from admission to disease onset.
AB  - BACKGROUND: In addition to controversies as to the definition of nosocomial
      pneumonia (NP) because of the lack of a widely accepted diagnostic standard,
      there has been no agreement concerning the time span from hospital admission to
      disease onset. This study aims at both estimating the time span, in hours, from
      admission to the occurrence of suspected NP and investigating risk factors that
      might influence this time span. METHODS: This is a cohort study, and subjects
      were patients with nosocomial infection acquired in the intensive care unit of
      Edgard Santos University Hospital (HUPES/ICU) in Salvador, Brazil, from January
      1995 to December 1997. Patients were observed from admission to 48 hours after
      discharge from the intensive care unit. The time span from admission to
      occurrence of suspected NP, the reason for admission, patient's origin, history
      of surgery, general anesthesia, mechanical ventilation, and use of antibiotic
      were analyzed and given a multivariate analysis using Cox regression model.
      RESULTS: Among 246 patients with nosocomial infection, 198 (80.5%) were suspected
      cases of NP, whereas 48 patients (19.5%) were not classified as such. The mean
      time, in hours, for the NP-free time span was 85.1 +/- 3.5 hours, and the median
      time was 72 hours when estimated by Kaplan-Meier method. Patients admitted from
      surgical heart procedures who had been given general anesthesia, mechanical
      ventilation, and antibiotics showed statistically significant shorter mean time
      spans from admission to NP occurrence when compared with the other patients. Age
      >or=50 years, use of mechanical ventilation, and use of antibiotics were
      associated with NP. CONCLUSIONS: Our finding for the estimated mean NP-free time
      span at the HUPES/ICU is somewhat in accordance with the literature (48 to 72
      hours). Patients at HUPES/ICU might be considered as showing early NP, because
      they were diagnosed before the 5th day after admission. Preventive measures to NP
      should be reviewed and intensified at the HUPES/ICU, especially as related to
      mechanical ventilation.

PMID- 15175616
TI  - Dissemination of nosocomial multiple-aminoglycoside-resistant Staphylococcus
      aureus caused by horizontal transfer of the resistance determinant (aacA/aphD)
      and clonal spread of resistant strains.
AB  - BACKGROUND: The multiple-aminoglycoside-resistant gene aacA/aphD exists as a
      transposable genetic element (Tn4001) in gram-positive cocci. Here we describe
      our retrospective investigation of the mechanism responsible for the
      dissemination of Tn4001 among staphylococci present in clinical isolates
      collected in our university hospital. At its peak, about 80% of the total
      isolates of methicillin-resistant Staphylococcus aureus showed multiple
      aminoglycoside resistance, and all harbored aacA/aphD. METHODS: Clonal
      relatedness was analyzed by pulsed field gel electrophoresis after SmaI
      endonuclease digestion of the genomic DNA from isolates collected in 1991 and
      1997. To detect Tn4001 on the chromosome and conjugative plasmids, specific
      sequences from aacA/aphD and the insertion sequence IS256, whose inverted
      sequence flanks aacA/aphD, were amplified by polymerase chain reaction. RESULTS:
      Pulsed field gel electrophoresis of genomic DNA, plasmid analysis, and polymerase
      chain reaction detection of the resistance determinant all indicated the presence
      of disseminated clones that had survived among hospitalized patients through
      acquisition of conjugative plasmids harboring aacA/aphD. Furthermore, aacA/aphD
      also disseminated among nosocomial strains other than S aureus as a consequence
      of the self-transferability of Tn4001. CONCLUSIONS: The nosocomial prevalence of
      multiple-aminoglycoside-resistant staphylococci is the result of both horizontal
      and interspecific transfer of aacA/aphD and the clonal spread and survival of
      resistant strains.

PMID- 15175617
TI  - Is seroprevalence of HTLV-I/II among blood donors in Lebanon relevant?
AB  - Human T-cell lymphotropic virus type I (HTLV-I) is associated with certain
      hematologic and neurologic disorders. Seroprevalence studies demonstrated that
      the distribution of HTLV-I is heterogeneous worldwide and not specific to 1
      region. Because blood is one of the major routes of transmission of the virus,
      blood banks of several countries routinely screen all blood donations for HTLV-I.
      The aim of the present study was to assess the seroprevalence rate of HTLV-I/II
      antibodies among Lebanese blood donors. Between August 2001 and March 2002,
      consecutive blood samples of 3529 blood donors were collected at blood banks of 4
      major hospitals in Lebanon. Initial enzyme-linked immunosorbent assay (ELISA)
      screening resulted in 23 (0.7%) positive samples, of which 12 (0.3%) were
      reconfirmed positive by ELISA. Further analysis by Western blot resulted in 2
      (0.06%) positive samples, of which 1 tested positive for HTLV-I by PCR (0.028%).
      Although its very low prevalence among Lebanese blood donors does not support
      routine screening of Lebanese blood donors for HTLV-I, screening of blood donors
      from other nationalities may be exercised, especially those from HTLV-I endemic
      areas.

PMID- 15175618
TI  - Disinfection and the prevention of infectious disease: no adverse effects?

PMID- 15175619
TI  - The benefits of surface disinfection.

PMID- 15175620
TI  - Validation of a multicenter computer-based surveillance system for hospital
      acquired bloodstream infections in neonatal intensive care departments.
AB  - Automated systems can facilitate surveillance for health care-associated
      infections. The New York Antimicrobial Resistance Project (NYARP) electronically
      monitors trends in bloodstream infections from 6 medical centers in New York, NY.
      To validate NYARP's data, episodes of health care-associated bloodstream
      infections detected by this system were compared with those obtained by an
      infection control practitioner performing an unrelated study in 2 participating
      neonatal intensive care departments. The sensitivity (84%), specificity (99%),
      and positive (84%) and negative (99%) predictive values of NYARP were excellent
      when coagulase-negative staphylococcal bloodstream infections were removed.

PMID- 15175621
TI  - Evaluation of a patient education model for increasing hand hygiene compliance in
      an inpatient rehabilitation unit.
AB  - BACKGROUND: Transmission of microorganisms from the hands of health care workers
      is the main cause of health care-acquired infections. Recent studies on bacterial
      contamination of hands by medical care specialty found the highest bacterial
      contamination on the hands of health care workers from rehabilitation units. The
      objective of this study is to determine the effect of a patient education model
      on hand hygiene (HH) compliance in a rehabilitation unit. METHODS: A 6-week pre-
      and post-intervention study with a 3-month follow-up using a patient education
      model was conducted in a 24-bed inpatient rehabilitation unit located in an acute
      care hospital. Thirty-five patients were enrolled in the intervention phase of
      the study after agreeing to ask all health care workers who had direct contact
      with them, "Did you wash/sanitize your hands?" Compliance with the program was
      measured through soap/sanitizer usage per resident-day before, during, and after
      the intervention. RESULTS: Usage increased from 5 HH per resident-day during the
      preintervention to 9.7 HH per resident-day during the intervention (P <.001), 6.7
      HH per resident-day postintervention (6 weeks) (P <.001), and 7.0 HH per resident
      day at 3 months (P <.001). CONCLUSIONS: Patient education increased HH compliance
      in an inpatient rehabilitation unit by 94% during the 6-week intervention, 34%
      during the 6 week post intervention, and 40% at 3-month follow-up. This program
      empowers patients with responsibility for their own care and provides ongoing HH
      education.

PMID- 15175622
TI  - Clinical nurse specialists and nurse practitioners: complementary roles for
      infectious disease and infection control.
AB  - BACKGROUND: The escalation of infectious diseases worldwide heralds an
      unprecedented need for nurses with advanced practice graduate preparation.
      OBJECTIVE: To describe how a graduate program prepares clinical nurse specialists
      and nurse practitioners in infectious diseases or infection control to provide
      distinct yet complementary care for patients with contagious disease and
      potentially antimicrobial-resistant infections. RESULTS: The University of
      Washington School of Nursing launched a new master of nursing program for
      infectious disease and infection control to reduce the threat of infectious
      diseases and multiple-resistant organisms.

PMID- 15175623
TI  - The anergy panel: an ineffective tool to validate tuberculin skin testing.

PMID- 15175624
TI  - The use of systematic reviews and meta-analyses in infection control and hospital
      epidemiology.
AB  - Systematic review is a type of research that attempts to identify and summarize
      all of the evidence related to a specific research question. It can be thought of
      as a "pause" in the process of conducting research in a particular area, in which
      the following questions are asked: Based on all of the available evidence, what
      do we know about this specific question so far, and what future studies should be
      conducted to clarify areas of uncertainty? The systematic review arose as an
      alternative to the traditional narrative review-which allows authors to pick and
      choose the studies they discuss and the depth at which they discuss them-a
      process prone to bias. By adhering to a prospectively defined protocol that
      specifies how studies should be identified, evaluated, and statistically combined
      (the statistical process is a component of systematic review and is called "meta
      analysis"), systematic reviews reduce the bias inherent to traditional narrative
      reviews. Systematic reviews are an increasingly common form of published
      research, and several of the approximately 1000 such studies that are published
      annually focus on topics important to infection control professionals.
      Consequently, it is essential that infection control professionals and hospital
      epidemiologists be able to understand and evaluate the quality of this useful
      research design. This article discusses the essential elements of a systematic
      review, provides a framework for evaluating the quality of such an article, and
      will help the infection control professional and hospital epidemiologist in
      determining whether the results of such reviews should change clinical practice.

PMID- 15175625
TI  - A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of
      chronic lymphocytic leukemia B cells.
AB  - The progressive rise of mature CD5+ B lymphocytes, despite the low proportion of
      proliferating cells, has led to the notion that B cell chronic lymphocytic
      leukemia (B-CLL) is primarily related to defective apoptosis. The
      microenvironment likely plays a prominent role because the malignant cells
      progressively accumulate in vivo, whereas they rapidly undergo spontaneous
      apoptosis when cultured in vitro. To assess microenvironment-mediated survival
      signals, B-CLL cells were cultured with a murine fibroblast cell line, Ltk-, with
      and without an agonistic antibody to CD40. Spontaneous apoptosis was associated
      with the loss of Akt and NF-kappaB activities. Interactions with fibroblasts
      sustained a basal level of Akt and NF-kappaB activities, which was dependent on
      phosphatidylinositol-3 kinase (PI3K). Constitutive activity of the PI3K pathway
      in B-CLL cells when cultured with fibroblasts prevented the downregulation of the
      prosurvival Bcl-2 family protein Bcl-xL and the caspase inhibitor proteins FLIPL
      and XIAP, and consequently caspase-3 activation and apoptosis. CD40 crosslinking
      in B-CLL cells did not further prevent murine fibroblasts-mediated apoptosis but
      induced cell proliferation, which was associated with an increase of Akt and NF
      kappaB activation compared with cells cultured with fibroblasts alone. The PI3K
      pathway seems to play a pivotal role in B-CLL cell survival and growth.

PMID- 15175626
TI  - Constitutive activation of PI3K is involved in the spontaneous proliferation of
      primary acute myeloid leukemia cells: direct evidence of PI3K activation.

PMID- 15175627
TI  - ETV6 (TEL) gene amplification in a myelodysplastic syndrome with excess of
      blasts.

PMID- 15175629
TI  - Respiratory development in preterm infants.
AB  - OBJECTIVE: This study examined the development of respiration during the preterm
      and early post-term periods and the effects of other biological and environmental
      variables, including sleep state, on this development. STUDY DESIGN: Weekly 2
      hour sleep observations and respiration recordings were obtained on 134 preterm
      infants from the time they were no longer critical until hospital discharge; a
      follow-up observation was conducted 1 to 3 months later. RESULTS: All respiratory
      variables, except length of respiratory pauses in quiet sleep, decreased although
      the rate of this decrease slowed after term for four variables. Respiratory
      variables, except variability of respiratory pauses lengths and periodic
      respiration, differed by sleep state. Covariates, except methylxanthine
      treatment, had minor effects. Four variables showed hospital-related differences,
      but cisapride treatment helped to explain the differences in three variables.
      CONCLUSIONS: Much development of respiration occurs in the early weeks after
      birth and reflects both neural maturation and effects of other biological and
      environmental factors, especially medications.

PMID- 15175628
TI  - Does making newborn follow-up appointments from the hospital improve compliance?
AB  - OBJECTIVE: To test a system of arranging the first newborn follow-up appointments
      made from the hospital prior to discharge. METHODS: Prospective randomized study
      of 328 term healthy newborns divided into control and intervention groups. As
      there were multiple practices, we checked for clustering in the two groups and
      then compared them for patient compliance with the first newborn appointment. We
      also compared the control and intervention groups for compliance with regard to
      insurance status. RESULTS: There was difference between the control and
      intervention group in timeliness for the first appointment (control, 84.9%,
      intervention group, 94.2%, p=0.0062). There was also improvement in privately
      insured patients (control 89.1%, intervention 96.5%, p=0.0263), as well as in
      Medicaid+noninsured patients (control 64.7%, intervention 90.2%, p=0.0245).
      DISCUSSION: We conclude that arranging for follow-up appointments from the
      hospital is a worthwhile inexpensive intervention that could significantly
      improve patient compliance with the first newborn visit.

PMID- 15175630
TI  - National Institute of Child Health and Human Development (NICHD) conference on
      kernicterus: a population perspective on prevention of kernicterus.
AB  - This paper reviews barriers to the prevention of kernicterus. Reports of
      kernicterus cases persist. We do not know why kernicterus continues to occur or
      how best to prevent it. We need evidence for key recommendations that make
      clinical guidelines usable by practitioners caring for newborns, especially for
      practitioners providing ambulatory care in the first week of life. Data on
      prevalence and incidence, mortality and morbidity are essential for launching a
      kernicterus public health campaign. Modeling cost-effectiveness requires data on
      costs and benefits of alternative strategies for managing hyperbilirubinemia and
      preventing kernicterus and on parental preferences concerning follow-up in the
      first days of life. Understanding how existing patterns of care obstruct
      preventive care involves exploration of the roles of clinicians, health-care
      organizations, parents, and payers and purchasers of health care. Lastly,
      discovering how to motivate change in existing practices can provide the guidance
      needed to prevent kernicterus in the US.

PMID- 15175632
TI  - Effect of changes in body posture on vasoactive hormones in pre-eclamptic women.
AB  - The aim of this study was to determine the normality or otherwise of neurohormone
      indices, particularly the sympathetic nervous system, in pre-eclamptic patients
      and document whether changes in body posture magnify any differences between pre
      eclamptic and normal women. We studied 11 women with pre-eclampsia and compared
      them with 17 matched normotensive pregnant women and eight nonpregnant women.
      Measurements of arterial pressure, heart rate and neurohormones were carried out
      with subjects in the left lateral position, then supine, left lateral, with
      upright posture and finally with assumption of the left lateral position again.
      Main outcome measures were arterial pressure, heart rate and hormones (plasma
      norepinephrine, renin activity, natriuretic peptides and endothelin-1). We
      observed that plasma norepinephrine levels were higher in pre-eclamptic than
      normotensive pregnant women and this was most obvious in the upright position.
      Plasma renin activity was likewise higher in pre-eclamptic than normotensive
      pregnant women, again most obvious with upright posture. Plasma natriuretic
      peptides and endothelin-1 levels were similar in pre-eclamptics and normotensive
      pregnant women. These data strengthen the premise that pre-eclampsia is
      associated with sympathetic overactivity as reflected by plasma norepinephrine
      levels, most obviously observed in the upright position.

PMID- 15175633
TI  - Effect of ingesting sour milk fermented using Lactobacillus helveticus bacteria
      producing tripeptides on blood pressure in subjects with mild hypertension.
AB  - Angiotensin-converting enzyme (ACE) is important in the regulation of blood
      pressure (BP). Two tripeptides that inhibit ACE, isoleucyl-prolyl-proline (Ile
      Pro-Pro) and valyl-prolyl-proline (Val-Pro-Pro), have been isolated from certain
      sour milks. The aim of the study reported was to evaluate the effect on BP in
      subjects with mild hypertension of a new sour milk containing tripeptides. The
      initial number of subjects was 60 (36 men, 24 women). Among the criteria for
      inclusion in the study were systolic BP (SBP) between 140 and 180 mmHg and/or
      diastolic BP (DPB) between 90 and 110 mmHg, without antihypertensive drug
      therapy. There were two study periods with a washout period between. All subjects
      were given 1.5 dl per day of a placebo (regular sour milk) or of the active
      product, a milk that had been fermented with Lactobacillus helveticus bacteria
      and contained 2.4-2.7 mg of Ile-Pro-Pro and 2.4-2.7 mg of Val-Pro-Pro per 1.5 dl.
      In the first phase, SBP fell 16 mmHg from baseline in the active group, 2 mmHg
      more than in the placebo group (P=0.0668) and no difference in DBP (P=0.92).
      There was a statistically significant downward trend both in SBP and DBP
      (P=0.0001). During the second phase, SBP fell 11 mmHg in the active group
      (P=0.008). The reduction in SBP was significantly larger in active than placebo
      group (P=0.012). In the crossover analysis combining both phases, SBP fell on
      average 2.6+/-15.9 mmHg more on the active product compared with the placebo
      product, but this difference was not statistically significant (P=0.3111). The
      difference in DBP, 1.0+/-8.3 mmHg between the two test products was not
      significant either (P=0.4431). In conclusion, the ingestion of sour milk
      fermented by L. helveticus bacteria and that containing ACE inhibitory
      tripeptides seems to lower BP modestly.

PMID- 15175634
TI  - Retention of heterozygosity at chromosome 7p22 and 11q13 in aldosterone-producing
      tumours of patients with familial hyperaldosteronism not remediable by
      glucocorticoids.

PMID- 15175635
TI  - Autonomic nervous function, arterial stiffness and blood pressure in patients
      with Type I diabetes mellitus and normal urinary albumin excretion.
AB  - Type I diabetic patients (DM-1) with an elevated urinary albumin excretion
      (UAE>30 mg/24 h) have a high cardiovascular risk. However, DM-1 patients with
      normal UAE have incipient abnormalities of the cardiovascular and nervous
      systems, such as elevations of blood pressures, increases in arterial stiffness
      and deterioration of autonomic nervous function. We studied the
      interrelationships of these abnormalities in normoalbuminuric DM-1 patients. In
      76 patients, we performed two cardiovascular reflex tests (deep in- and
      expiration test (IE test) and lying-to-standing test (LS test)), and determined
      aortic pulse wave velocity (PWV), local arterial compliances of the common
      carotid, femoral and brachial arteries, and 24-h blood pressures. The DeltaRRmax
      value of the LS test was associated with aortic PWV (negatively) and the
      compliance coefficients of the carotid, femoral and brachial arteries. Per 100-ms
      increase in DeltaRRmax, pulse wave velocity decreased by 0.39 m/s, compliance
      coefficients of the carotid, femoral and brachial arteries increased by 0.06,
      0.08 and 0.05 mm2/kPa, respectively. These associations were independent of age,
      24-h mean arterial pressure and 24-h heart rate. Increases in arterial stiffness
      were associated with increases in 24-h systolic and pulse pressure (per 1 m/s
      increase in PWV, systolic and pulse pressure increased by 2.1 and 1.7 mmHg,
      respectively). In normoalbuminuric DM-1 patients, deterioration of autonomic
      nervous function is associated with an increase in arterial stiffness, which, in
      turn, was associated with, and may cause, increased systolic and pulse pressure.
      These findings suggest that preventive strategies targeting autonomic dysfunction
      may reduce cardiovascular morbidity in diabetes.

PMID- 15175636
TI  - The effects of androgen depletion on human erectile function: a prospective study
      in male-to-female transsexuals.
AB  - The objective of the study was to determine the effects of androgen depletion on
      erectile function in a population of male-to-female transsexuals. The erectile
      function of 25 consecutive male-to-female transsexuals on androgen depletion
      treatment and scheduled for surgical gender reassignment was prospectively
      evaluated using medical and sexual history, physical examination, total serum
      testosterone, International Index of Erectile Function (IIEF-15) questionnaire,
      penile colour-coded Doppler ultrasonography (CDU) after pharmacological
      stimulation and nocturnal penile tumescence (NPT) test. All but one had
      undetectable or low testosterone. Subjective erectile function, according to IIEF
      15 scores, and penile CDU findings did not correlate with testosterone levels,
      whereas NPT test findings correlated well with testosterone levels. These
      findings would suggest that nocturnal erections are androgen-dependent whereas
      sexually induced erections are androgen-independent. It can also be assumed that
      testosterone is important but not essential for male erectile function and that
      other androgen-independent pathways can be responsible for sexually induced
      erections.

PMID- 15175638
TI  - Validity of the Arabic version of the sexual health inventory for men among
      Egyptians.
AB  - The objective of this study is to assess the validity of Arabic version of the
      abridged International Index of Erectile Function among a sample from the
      Egyptian populace. Two groups were included in this study. Group A included 68
      patients complaining of erectile dysfunction (ED) >1 y, who failed oral treatment
      and accepted intracavernous self-injection. All patients of group A were
      previously clinically diagnosed as having ED. Group B included 68 men not
      complaining of ED and not suffering from any major chronic or acute illness. The
      mean (s.d.) age of all 136 patients was 52+/-5.7 y. Candidates of both groups
      were requested to complete the Sexual Health Inventory for Men (SHIM)
      questionnaire. Cronbach's alpha coefficient was used to assess the internal
      consistency of the SHIM. The items of maintenance ability, erection confidence,
      maintenance frequency, erection firmness and intercourse satisfaction showed an
      overall ICC of 0.92. Internal consistency for the whole scale was 0.91. In
      conclusion, the Arabic version of the SHIM administered to 136 Egyptian men
      proved to be reliable and valid. It also showed a high degree of specificity and
      sensitivity among the Egyptian population.

PMID- 15175637
TI  - Cardiovascular effects of sildenafil in hypertensive men with erectile
      dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase
      (PDE5).
AB  - Erectile dysfunction (ED) is frequent in patients with essential hypertension
      (EH); a likely common pathogenetic pathway could be a reduced ability of
      arteriolar vascular smooth muscle (VSM) to relax. Increasing intracellular levels
      of cGMP reduce the contractile status of VSM; on the contrary, type 5 cGMP
      specific phosphodiesterase (PDE5, codified by PDE5A gene) regulates cGMP levels
      through its clearance. The PDE5A gene represents a good candidate for the
      intermediate phenotype EH/ED: genetic variants of the PDE5A may predispose to EH
      and ED and could affect the local and systemic response to sildenafil
      administration. Thus, a functionally relevant portion of PDE5 5'-flanking
      promoter region was analyzed by PCR and direct sequencing in patients with EH and
      idiopathic ED. The sequences obtained showed a T/G polymorphism at position 
      1142, near an AP1 regulatory element, that was not apparently associated with the
      intermediate phenotype. We also studied the relationship between this
      polymorphism and the effects of oral sildenafil on blood pressure (BP) and heart
      rate (HR) in men with ED. Sildenafil caused a significant decrease of BP, but had
      no effects on HR; statistical analysis showed no differences in BP and HR
      variations among PDE5A genotypes. In conclusion, our data showed no correlations
      of a novel polymorphism of the PDE5A promoter gene with the intermediate
      phenotype EH/ED and the BP and HR response to sildenafil administration. Further
      studies are necessary to define the role of this polymorphism and to study the
      genetic predisposition for EH with ED.

PMID- 15175639
TI  - The reliability and validity of Arizona sexual experiences scale in Turkish ESRD
      patients undergoing hemodialysis.
AB  - Although sexuality was the fifth most important life stressor cited by dialysis
      patients, sexual dysfunctions (SD) receive a very limited attention in the follow
      up of these patients. The main aim of the present study was to investigate the
      reliability and validity of the Arizona Sexual Experiences Scale (ASEX) for end
      stage renal disease (ESRD) patients undergoing hemodialysis (HD) in Turkey. The
      instrument's reliability and validity were assessed in 43 ESRD outpatients
      undergoing dialysis. All patients were assessed at baseline and at 6 months. ASEX
      showed good internal consistency (Cronbach's alpha's 0.89 and 0.90) and test
      retest reliability (r=0.88, P<0.001). Convergent validity of ASEX was measured by
      means of the scales' correlation with the psychiatrists' assessment for the
      presence of SD (r=0.53, P<0.001). The results of receiver operating
      characteristics analysis for criterion validity revealed that ASEX scores could
      discriminate well (0.85+/-0.06 (95% confidence interval, 0.73-0.90), P<0.001)
      between patients with 'no SD (n=26)' and 'with SD (n=17)'. A total ASEX score of
      < or =11 was found to be the best cutoff point (sensitivity=100%,
      specificity=52%) for screening in this group of patients. The findings of this
      study indicate that the ASEX is a valid and reliable instrument for use in
      clinical trials on sexual functioning of ESRD patients undergoing HD.

PMID- 15175640
TI  - Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent
      restenosis in hypercholesterolemic rabbits and monkeys.
AB  - In-stent restenosis results exclusively from neointimal hyperplasia due to
      mechanical injury and a foreign body response to the prosthesis. Inflammation
      mediated by monocyte chemoattractant protein-1 (MCP-1) might therefore underlie
      in-stent restenosis. We recently devised a new strategy for anti-MCP-1 gene
      therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into
      skeletal muscles. We used this strategy to investigate the role of MCP-1 in
      experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys.
      Transfection of the mutant MCP-1 gene suppressed monocyte infiltration/activation
      in the stented arterial wall and markedly reduced the development of neointimal
      hyperplasia. This strategy also suppressed local expression of MCP-1 and
      inflammatory cytokines. Therefore, inhibition of MCP-1-mediated inflammation is
      effective in reducing experimental in-stent restenosis. This strategy might be a
      useful form of gene therapy against human in-stent restenosis.

PMID- 15175641
TI  - Muscle stem cells can act as antigen-presenting cells: implication for gene
      therapy.
AB  - Research has shown that the use of a muscle-specific promoter can reduce immune
      response and improve gene transfer to muscle fibers. We investigated the
      efficiency of direct and ex vivo gene transfer to the skeletal muscles of 6- to 8
      week-old mdx mice by using two adenoviral vectors: adenovirus (AD) encoding the
      luciferase gene under the cytomegalovirus (CMV) promoter (ADCMV) and AD encoding
      the same gene under the muscle creatine kinase (MCK) promoter (ADMCK). Direct
      intramuscular injection of ADMCK triggered a lower immune response that enabled
      more efficient delivery and more persistent expression of the transgene than did
      ADCMV injection. Similarly, ex vivo gene transfer using ADCMV-transduced muscle
      derived stem cells (MDSCs) induced a stronger immune response and led to shorter
      transgene expression than did ex vivo gene transfer using ADMCK-transduced MDSCs.
      This immune response was due to the release of the antigen after MDSC death or to
      the ADCMV-transduced MDSCs acting as antigen-presenting cells (APCs) by
      expressing the transgene and rapidly initiating an immune response against
      subsequent viral inoculation. The use of a muscle-specific promoter that
      restricts transgene expression to differentiated muscle cells could prevent MDSCs
      from becoming APCs, and thereby could improve the efficiency of ex vivo gene
      transfer to skeletal muscle.

PMID- 15175642
TI  - Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces
      hypertension and attenuates its cardiovascular injuries.
AB  - Gene therapy of hypertension requires long-term expression of a therapeutic gene
      to achieve stable reduction of blood pressure. Human tissue kallikrein (HK)
      cleaves kininogen to produce a potent vasoactive peptide kinin, which plays an
      important role in the regulation of the cardiovascular and renal functions. In
      the present study, we have delivered human kallikrein cDNA with an rAAV vector to
      explore the potential therapeutic effects of kallikrein on hypertension and
      related secondary complications. A single tail vein injection of the rAAV-HK
      vector into the adult spontaneously hypertensive rats resulted in a significant
      reduction (12.0+/-2.55 mmHg, P<0.05, n=6, ANOVA) of the systolic blood pressure
      from 2 weeks after vector injection, when compared with the control rAAV-lacZ
      vector-injected rats. Weekly blood pressure monitoring showed stable hypertension
      reduction effect throughout the course of the 20-week experiments. In addition,
      total urine microalbumin contents decreased as a result of rAAV-HK treatment.
      Histological analysis of various tissues showed remarkable amelioration of
      cardiovascular hypertrophy, renal injury and collagen depositions in the rAAV
      treated group. Finally, persistent expression of the transgene product HK was
      confirmed by the enzyme-linked immunosorbent assay and reverse transcription
      polymerase chain reaction. We conclude that rAAV-mediated HK delivery rendered a
      long-term and stable reduction of hypertension and protected against renal
      injury, cardiac remodeling in the spontaneously hypertensive rat model. Further
      studies are warranted for the development of a gene therapy strategy for human
      hypertension.

PMID- 15175643
TI  - TCR beta polymorphisms and multiple sclerosis.
AB  - A total of 267 families with two or more siblings with multiple sclerosis (MS)
      were genotyped with 14 restriction fragment length polymorphisms at the TCR beta
      locus. A nonparametric linkage analysis of the data showed no evidence for
      linkage to this locus (mlod=0.11). No significant allelic or haplotype
      transmissions were observed in the total sample of 565 patients. After
      stratification for the presence of HLA DRB1*15, an association was observed
      between the BV25S1*1-BV26S1*1-BV2S1*1 haplotype and MS (P=0.00089). This was not
      significant upon correction for multiple comparisons. It was also not significant
      when the haplotype frequency in affected individuals was compared to a normal
      control sample (P=0.77). Furthermore, the associated haplotype was followed-up in
      an independent sample of 97 nuclear families with a single DRB1*15-positive child
      with MS. The BV25S1*1-BV26S1*1-BV2S1*1 haplotype did not show significant
      evidence for transmission distortion but the same trend was seen (P=0.21). There
      were no significant associations observed in the DRB1*15-negative patients and no
      detectable difference was seen in the DRB1*15-positive BV25S1*1-BV26S1*1-BV2S1*1
      association when comparing different subgroups based on clinical course of MS.
      These results show no evidence for linkage and fail to establish an association
      between MS susceptibility and the TCR beta locus.

PMID- 15175644
TI  - Expression levels for many genes in human peripheral blood cells are highly
      sensitive to ex vivo incubation.
AB  - Monitoring of gene and protein expression in peripheral blood cells has
      significant potential for improving the diagnosis and therapy of many human
      diseases. As genomic-scale microarray and proteomic technologies are applied to
      peripheral blood, it is important to consider the variables that may affect
      interpretation of data. Here we report experiments performed to identify genes
      that are particularly sensitive to ex vivo handling prior to RNA extraction for
      gene expression microarrays or quantitative real-time RT-PCR assays. We examined
      Affymetrix gene expression in samples from eight normal individuals where blood
      was processed for RNA either immediately after blood draw or the next day
      following overnight incubation. These studies identified hundreds of genes that
      are sensitive to ex vivo handling of blood, and suggest that this is an important
      variable to consider when designing and interpreting human PBMC experiments.

PMID- 15175645
TI  - Conservation of the genomic structure and receptor-mediated signaling between
      human and rat IL-24.
AB  - IL-24/MDA-7 is a new member of the IL-10 family of cytokines, which signals
      through two heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL
      20R2). Previously, we identified a rat gene named mob-5, which encodes a secreted
      protein that shares a high degree of homology with human IL-24. Expression of mob
      5 and its putative cell surface receptors was shown to be upregulated by
      oncogenic ras. Here we show that not only do rat mob-5 and human IL-24 share a
      strikingly similar genomic structure but also that the rat MOB-5 protein can bind
      to and signal through the human IL-24 receptors. Like human IL-24, binding of the
      rat MOB-5 protein to the human IL-24 receptors leads to activation of the
      JAK/STAT pathway, which in turn supports receptor-dependent survival and
      proliferation of Ba/F3 cells. Furthermore, using human colon cancer cell lines
      with somatic knockout of either the mutant or the wild-type k-ras allele, we
      demonstrate that the human IL-24 receptors also are upregulated by oncogenic ras.
      Taken together, these results provide strong experimental evidence that MOB-5 is
      indeed the rat homolog of human IL-24.

PMID- 15175646
TI  - Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype.
AB  - Interleukin-12 (IL-12), a heterodimeric cytokine, is important in the generation
      of a Th1-biased immune response. Several polymorphisms have been described in
      IL12B, the gene encoding the p40 subunit of IL-12. A bi-allelic polymorphism
      within the IL12B promoter region has been reported to show association with
      diseases as diverse as severe childhood asthma and fatal cerebral malaria. In
      order to define the molecular basis for these disease associations, we
      investigated the secretion of IL-12 by human monocyte-derived dendritic cells.
      Homozygotes for the IL12B promoter polymorphism showed a 10-fold difference in
      median p70 secretion in response to CD40 ligation. Remarkably, this difference
      resulted from the inability of most allele 1 homozygotes to secrete heterodimeric
      IL-12. In contrast, most of the donors homozygous for allele 2 had detectable
      secretion. These findings are important for the understanding of the highly
      complex regulation of IL-12 secretion, and its consequent impact on disease
      susceptibility, in humans.

PMID- 15175647
TI  - Synergistic interaction of two independent genetic loci causes extreme elevation
      of serum IgA in mice.
AB  - Understanding the molecular regulation of immunoglobulin A (IgA) expression is
      important as it plays an essential role in the first-line defence through mucosal
      secretions. Using inbred mouse strains, we identified two independent and
      dominant acting genetic loci that synergistically cause a 40-fold upregulation in
      serum IgA levels when introduced into the murine strain C57Bl/6J (B6). The first
      locus on chromosome 12 appears to be mainly responsible for the natural four-fold
      higher IgA levels in C3HeB/FeJ (C3H) compared to B6 mice. A second independent,
      chemically induced mutation on chromosome 5 caused a two-fold elevation when
      transferred from C3H into B6 mice. Both loci in concert effect a 40-fold
      elevation against the B6 genetic background. We determined the chromosomal
      localization of the two loci simultaneously by a one-step mapping process. The
      chemically induced mutation was identified within the immunoglobulin joining
      chain (IgJ) gene on chromosome 5. The major serum IgA modifier between the C3H
      and B6 was located on chromosome 12. This modifier region was mapped to a 350 kb
      region containing several immunoglobulin heavy-chain genes and the Ig alpha
      germline switch gene. We speculate that by interfering with both IgA expression
      and distribution, synergistic regulation of IgA is achieved.

PMID- 15175648
TI  - Allele-specific quantification of HLA-DQB1 gene expression by real-time reverse
      transcriptase-polymerase chain reaction.
AB  - In addition to coding region polymorphism, allele-specific variation in the
      upstream regulatory region of the HLA-DQB1 gene has been detected. Reporter gene
      assays and transfection studies have indicated that HLA-DQB1 promoter
      polymorphism may be of functional significance. The aim of this study was to
      utilize real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for
      allele-specific quantification of HLA-DQB1 expression and to analyze cell
      specific HLA-DQB1 expression in vivo. For the allele-specific quantification of
      DQB1 gene products, a real-time RT-PCR set of primer pairs (n=27) and probes
      (n=5) targeting exon 2 variability was established. The robustness and integrity
      of the assay system were confirmed by using recombinant DQB1 exon 2 plasmid
      clones as active exogenous controls. Sensitivity and reproducibility were
      assessed by serial dilution and allelic mixing analyses. In application to the
      study of allele-specific expression of DQB1 gene products during cytokine-driven
      maturation of monocyte-derived dendritic cells, differential patterns of allelic
      expression in heterozygous individuals were observed for DQB1*0301, compared to
      DQB1*0501 and DQB1*0602. At maximum, 1.9-fold (*0301/*0501) and 2.5-fold
      (*0301/*0602) higher induction was seen for DQB*0301. In conclusion, HLA-DQB1
      expression can be analyzed by real-time RT-PCR suitable for cell- and allele
      specific detection of HLA-DQB1 transcripts in homo- and heterozygous
      combinations.

PMID- 15175649
TI  - CD14 promoter polymorphism -159C>T is associated with susceptibility to chronic
      Chlamydia pneumoniae infection in peripheral blood monocytes.
AB  - Chlamydia pneumoniae uses peripheral blood monocytes (PBMC) for systemic
      dissemination and has been linked to atherogenesis by inflammation mediated via
      TLR2/4 and CD14. We found 12.8% of 610 coronary artery disease (CAD) patients of
      Central European background to be chronically infected with C. pneumoniae based
      on the repeated detection of chlamydial DNA in PBMC. Among those the -159C>T CD14
      promoter polymorphism was more frequent (OR 1.7, 95% CI 1.08-2.65, P=0.0224) than
      among C. pneumoniae-negative subjects matched for age and gender. The Arg753Gln
      TLR2 and Asp299Gly TLR4 polymorphisms were not related to chlamydial infection.
      Susceptibility for chronic chlamydial infection of PBMC in CAD patients appears
      associated with the CD14-159C>T promoter polymorphism encoding for enhanced CD14
      expression.

PMID- 15175650
TI  - Recruitment of the NuA4 complex poises the PHO5 promoter for chromatin remodeling
      and activation.
AB  - The remodeling of the promoter chromatin structure is a key event for the
      induction of the PHO5 gene. Two DNA-binding proteins Pho2 and Pho4 are critical
      for this step. We found that the NuA4 histone acetyltransferase complex is
      essential for PHO5 transcriptional induction without affecting Pho4 translocation
      upon phosphate starvation. Our data also indicate that NuA4 is critical for the
      chromatin remodeling event that occurs over the PHO5 promoter prior to
      activation. Using Chromatin IP analysis, we found that Esa1-dependent histone H4
      acetylation at the PHO5 promoter correlates with specific recruitment of the NuA4
      complex to this locus under repressing conditions. We demonstrate that the
      homeodomain transcriptional activator Pho2 is responsible for this recruitment in
      vivo and interacts directly with the NuA4 complex. Finally, we show that Pho4 is
      unable to bind the PHO5 promoter without prior action of NuA4. These results
      indicate that, before induction, NuA4 complex recruitment by Pho2 is an essential
      event that presets the PHO5 promoter for subsequent binding by Pho4, chromatin
      remodeling and transcription.

PMID- 15175651
TI  - TREK-1, a K+ channel involved in neuroprotection and general anesthesia.
AB  - TREK-1 is a two-pore-domain background potassium channel expressed throughout the
      central nervous system. It is opened by polyunsaturated fatty acids and
      lysophospholipids. It is inhibited by neurotransmitters that produce an increase
      in intracellular cAMP and by those that activate the Gq protein pathway. TREK-1
      is also activated by volatile anesthetics and has been suggested to be an
      important target in the action of these drugs. Using mice with a disrupted TREK-1
      gene, we now show that TREK-1 has an important role in neuroprotection against
      epilepsy and brain and spinal chord ischemia. Trek1-/- mice display an increased
      sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty
      acids, which is impressive in Trek1+/+ mice, disappears in Trek1-/- mice
      indicating a central role of TREK-1 in this process. Trek1-/- mice are also
      resistant to anesthesia by volatile anesthetics. TREK-1 emerges as a potential
      innovative target for developing new therapeutic agents for neurology and
      anesthesiology.

PMID- 15175652
TI  - Dynein and kinesin share an overlapping microtubule-binding site.
AB  - Dyneins and kinesins move in opposite directions on microtubules. The question of
      how the same-track microtubules are able to support movement in two directions
      remains unanswered due to the absence of details on dynein-microtubule
      interactions. To address this issue, we studied dynein-microtubule interactions
      using the tip of the microtubule-binding stalk, the dynein stalk head (DSH),
      which directly interacts with microtubules upon receiving conformational change
      from the ATPase domain. Biochemical and cryo-electron microscopic studies
      revealed that DSH bound to tubulin dimers with a periodicity of 80 A,
      corresponding to the step size of dyneins. The DSH molecule was observed as a
      globular corn grain-like shape that bound the same region as kinesin. Biochemical
      crosslinking experiments and image analyses of the DSH-kinesin head-microtubule
      complex revealed competition between DSH and the kinesin head for microtubule
      binding. Our results demonstrate that dynein and kinesin share an overlapping
      microtubule-binding site, and imply that binding at this site has an essential
      role for these motor proteins.

PMID- 15175653
TI  - A subset of human 35S U5 proteins, including Prp19, function prior to catalytic
      step 1 of splicing.
AB  - During catalytic activation of the spliceosome, snRNP remodeling events occur,
      leading to the formation of a 35S U5 snRNP that contains a large group of
      proteins, including Prp19 and CDC5, not found in 20S U5 snRNPs. To investigate
      the function of 35S U5 proteins, we immunoaffinity purified human spliceosomes
      that had not yet undergone catalytic activation (designated BDeltaU1), which
      contained U2, U4, U5, and U6, but lacked U1 snRNA. Comparison of the protein
      compositions of BDeltaU1 and activated B* spliceosomes revealed that, whereas
      U4/U6 snRNP proteins are stably associated with BDeltaU1 spliceosomes, 35S U5
      associated proteins (which are present in B*) are largely absent, suggesting that
      they are dispensable for complex B formation. Indeed,
      immunodepletion/complementation experiments demonstrated that a subset of 35S U5
      proteins including Prp19, which form a stable heteromeric complex, are required
      prior to catalytic step 1 of splicing, but not for stable integration of U4/U6.U5
      tri-snRNPs. Thus, comparison of the proteomes of spliceosomal complexes at
      defined stages can provide information as to which proteins function as a group
      at a particular step of splicing.

PMID- 15175655
TI  - Two-substrate association with the 20S proteasome at single-molecule level.
AB  - The bipartite structure of the proteasome raises the question of functional
      significance. A rational design for unraveling mechanistic details of the highly
      symmetrical degradation machinery from Thermoplasma acidophilum pursues
      orientated immobilization at metal-chelating interfaces via affinity tags fused
      either around the pore apertures or at the sides. End-on immobilization of the
      proteasome demonstrates that one pore is sufficient for substrate entry and
      product release. Remarkably, a 'dead-end' proteasome can process only one
      substrate at a time. In contrast, the side-on immobilized and free proteasome can
      bind two substrates, presumably one in each antechamber, with positive
      cooperativity as analyzed by surface plasmon resonance and single-molecule cross
      correlation spectroscopy. Thus, the two-stroke engine offers the advantage of
      speeding up degradation without enhancing complexity.

PMID- 15175654
TI  - Heme regulates gene expression by triggering Crm1-dependent nuclear export of
      Bach1.
AB  - Bach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes,
      both of which are known to be transcriptionally induced by heme. To test the
      hypothesis that heme regulates the activity of Bach1, we expressed wild type and
      mutated versions of Bach1 together with or without its heterodimer partner MafK
      in human 293T and GM02063 cells and examined their subcellular localization.
      Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1, whereas
      treating cells with hemin resulted in nuclear exclusion of Bach1. While the
      cadmium-inducible nuclear export signal (NES) of Bach1 was dispensable for the
      heme response, a region containing two of the heme-binding motifs was found to be
      critical for the heme-induced nuclear exclusion. This region functioned as a heme
      regulated NES dependent on the exporter Crm1. These results extend the regulatory
      roles for heme in protein sorting, and suggest that Bach1 transduces metabolic
      activity into gene expression.

PMID- 15175656
TI  - Positive and negative regulation of SMC-DNA interactions by ATP and accessory
      proteins.
AB  - Structural maintenance of chromosomes (SMC) proteins are central regulators of
      higher-order chromosome dynamics from bacteria to humans. The Bacillus subtilis
      SMC (BsSMC) homodimer adopts a V-shaped structure with an ATP-binding catalytic
      domain at each end. We report here that two small proteins, ScpA and ScpB,
      associate with the catalytic domains of BsSMC in an ordered fashion and suppress
      its ATPase activity. When combined with a 'transition state' mutant of BsSMC that
      poorly hydrolyzes ATP, ScpA promotes stable engagement of two catalytic domains
      in an ATP-dependent manner. In solution, this occurs intramolecularly and closes
      the DNA-entry gate of an SMC dimer. ScpB further stabilizes this conformation and
      prevents BsSMC from binding to double-stranded DNA (dsDNA). In contrast, when the
      mutant BsSMC is first allowed to interact with dsDNA, subsequent addition of ScpA
      leads to assembly of large nucleoprotein complexes, possibly by stabilizing
      intermolecular engagement of the catalytic domains from different SMC dimers. We
      propose that the ATP-modulated engagement/disengagement cycle of SMC proteins
      plays both positive and negative roles in their dynamic interactions with dsDNA.

PMID- 15175660
TI  - 'Urology: Today's Advances, Tomorrow's Clinical Practice', Cannes, November 2003.
      Current thinking in prostatic diseases: insights into dual 5alpha-reductase
      inhibitor therapy in BPH and prostate cancer.

PMID- 15175661
TI  - Whole-mount prostate sections reveal differential endoglin expression in stromal,
      epithelial, and endothelial cells with the development of prostate cancer.
AB  - Endoglin is a nonsignaling receptor for transforming growth factor that
      contributes to the action of this growth factor in diverse cell types. It may
      also exhibit a function of its own. Endoglin levels vary with disease states and
      is a marker of new blood vessels. We studied endoglin expression in whole-mount
      prostate sections from 64 patients with localized prostate cancer, assessing
      reactivity in the epithelium, the stroma, and blood vessels. Cells in
      normal/benign acini were negative but significantly immunoreactive (P<0.001) in
      both prostatic intraepithelial neoplasia (PIN; 52% of cases) and malignant areas
      (77% of cases). In tumors, this involved less than 25% of malignant cells in 59%
      of specimens. The endoglin-stained stroma was detected mainly in areas
      surrounding PIN acini and tumors. Endoglin antibodies detected more microvessels
      than von Willebrand Factor antibodies in all prostatic areas (P<0.01). In
      addition, the number of microvessels increased with the development of cancer and
      correlated with Gleason score (P<0.01). Changes in endoglin expression in PIN and
      malignant cells, the surrounding stroma, and related blood vessels, suggest that
      endoglin function may be altered in prostate cancer.

PMID- 15175657
TI  - PRMT3 is a ribosomal protein methyltransferase that affects the cellular levels
      of ribosomal subunits.
AB  - The mammalian protein arginine methyltransferase 3 (PRMT3) catalyzes the
      formation of asymmetric (type I) dimethylarginine in vitro. As yet, natural
      substrates and cellular pathways modulated by PRMT3 remain unknown. Here, we have
      identified an ortholog of PRMT3 in fission yeast. Tandem affinity purification of
      fission yeast PRMT3 coupled with mass spectrometric protein identification
      revealed that PRMT3 associates with components of the translational machinery. We
      identified the 40S ribosomal protein S2 as the first physiological substrate of
      PRMT3. In addition, a fraction of yeast and human PRMT3 cosedimented with free
      40S ribosomal subunits, as determined by sucrose gradient velocity
      centrifugation. The activity of PRMT3 is not essential since prmt3-disrupted
      cells are viable. Interestingly, cells lacking PRMT3 showed an accumulation of
      free 60S ribosomal subunits resulting in an imbalance in the 40S:60S free
      subunits ratio; yet pre-rRNA processing appeared to occur normally. Our results
      identify PRMT3 as the first type I ribosomal protein arginine methyltransferase
      and suggest that it regulates ribosome biosynthesis at a stage beyond pre-rRNA
      processing.

PMID- 15175662
TI  - Role of zinc in the pathogenesis and treatment of prostate cancer: critical
      issues to resolve.
AB  - The most consistent and persistent biochemical characteristic of prostate cancer
      (PCa) is the marked decrease in zinc and citrate levels in the malignant cells.
      This relationship provides compelling evidence that the lost ability of the
      malignant cells to accumulate zinc is an important factor in the development and
      progression of prostate malignancy. In addition, this relationship provides a
      rational basis for the concept that restoration of high zinc levels in malignant
      cells could be efficacious in the treatment and prevention of PCa.
      Epidemiological studies regarding dietary zinc effects on PCa have been
      conflicting and confusing. The purpose of this presentation is to present a
      current state of information regarding zinc relationships in the pathogenesis and
      treatment of PCa. We also hope to bring more attention to the medical and
      research community of the critical need for concerted clinical and basic research
      regarding zinc and PCa.

PMID- 15175663
TI  - Computerised triage in a prostate assessment clinic.
AB  - An MS Office package has been developed to score IPSS, take a patient history,
      compare flows with nomograms and decide on interim management. This is based on
      these scores, residual volume and laboratory results. A clearly formatted GP
      letter is produced. The patient uses a touch screen to answer questions on the
      IPSS and other medical history. These questions and responses are stored in Excel
      spread sheets. Clinic staff then enter results of flow studies, urinalysis, U&E
      and PSA. Excel Visual Basic creates a detailed printout for the notes and the MS
      Office mail merge facility creates a summary printout, which also serves as a
      letter to the GP. Excel allows embedding of formulae and program code to
      implement the rules for management. Based on these rules, the program either
      generates a request for an urgent appointment in the clinic or recommends the use
      of either an alpha blocker (if not contraindicated by medical history) or 5 alpha
      reductase inhibitors in the interim period before they are reviewed in clinic. A
      total of 139 patients have been seen and the computer decisions compared with
      those of a consultant urologist. Agreement was found in 106, disagreement in 33.
      However, 21 of the 33 involved computer oversensitivity to flow results. We do
      not anticipate difficulty improving this and are investigating using an
      artificial neural network. Of the other 12 patients, the urologist departed from
      the fixed rules for IPSS, creatinine, PSA and residual urine when only one
      variable was slightly abnormal. To conclude, this novel user-friendly system
      shows great potential in the management of prostate outpatients. Some tuning is
      needed, with particular respect to uroflow results.

PMID- 15175664
TI  - Impact of biochemical failure on long-term clinical outcome after radical
      prostatectomy for prostate cancer in Japan.
AB  - Detailed information is needed to understand the impact of biochemical failure
      (bF) on long-term outcome after definitive therapy for prostate cancer. In all,
      223 consecutive men treated with radical retropubic prostatectomy were followed
      and long-term clinical outcome was investigated. Pathological examination
      revealed more locally advanced tumors in this study compared with the typical
      cohorts seen in the Western series. The Cox proportional hazards model indicates
      pretreatment prostate-specific antigen levels and risk group stratification to be
      a significant predictors for bF (P<0.05), but not for overall survival. Seminal
      vesicle involvement was a significant predictor of systemic progression, cancer
      death and overall survival (P<0.05). Positive surgical margin and bF were also
      found to be independent predictors of overall survival (P<0.05). In contrast to
      reports from Western countries, this study found a significant correlation
      between bF after radical prostatectomy and overall survival. This may reflect
      years-later detection of prostate cancer in Japan compared with Western series.
      Biochemical failure may ultimately be translated into decreased overall survival
      after sufficient follow-up.

PMID- 15175665
TI  - Clinical characteristics of African-American men with hereditary prostate cancer:
      the AAHPC Study.
AB  - INTRODUCTION: The African-American Hereditary Prostate Cancer (AAHPC) Study was
      designed to recruit African-American families fulfilling very stringent criteria
      of four or more members diagnosed with prostate cancer at a combined age at
      diagnosis of 65 years or less. This report describes the clinical characteristics
      of a sample of affected AAHPC family members. METHODS: In all, 92 African
      American families were recruited into the study between 1998 and 2002. Complete
      clinical data including age and PSA at diagnosis, number of affected per family,
      stage, grade, and primary treatment were available on 154 affected males.
      Nonparametric Wilcoxon two-sample tests and Fisher's exact test (two-tailed),
      were performed to compare families with 4-6 and >6 affected males with respect to
      clinical characteristics. RESULTS: The mean number of affected men per family was
      5.5, with a mean age at diagnosis of 61.0 (+/-8.4) years. Age at diagnosis, PSA
      and Gleason score did not show significant differences between the two groups of
      families. Based on the Gleason score, 77.2% of affected males had favorable
      histology. Significantly, there were marked differences between the two groups in
      the frequency of node-positive disease (P=0.01) and distant metastases
      (P=0.0001). Radical prostatectomy was the preferred primary therapy for 66.2% of
      all affected men followed by 20.8% who chose radiation therapy. CONCLUSIONS: Our
      findings suggest that affected males who carry the highest load of genetic
      factors are at the highest risk for early dissemination of disease, thus efforts
      at early diagnosis and aggressive therapeutic approaches may be warranted in
      these families. Since the primary therapy choices in our study favored definitive
      treatment (87.0%) when compared to the 1983 and 1995 SEER data in which 28 and
      64% received definitive treatment, respectively, it appears that affected African
      American men in multiplex families may be demonstrating the reported psycho
      social impact of family history on screening practices and treatment decisions
      for prostate cancer.

PMID- 15175666
TI  - Playing catch-up.

PMID- 15175667
TI  - Sanofi takeover jeopardizes Aventis biotech deals.

PMID- 15175668
TI  - EGFR inhibitors square off at ASCO.

PMID- 15175669
TI  - China ramps up efforts to commercialize GM rice.

PMID- 15175670
TI  - New EU antitrust law burdens licensing.

PMID- 15175671
TI  - Startups hope federal study fixes SBIR flaws.

PMID- 15175673
TI  - Oligo oligarchy-the surprisingly small world of aptamers.

PMID- 15175674
TI  - Surge in US patents on botanicals.

PMID- 15175675
TI  - Chasing 'transgenic' shadows.

PMID- 15175676
TI  - Drugs in crops (continued).

PMID- 15175677
TI  - Preprocessing of oligonucleotide array data.

PMID- 15175678
TI  - ELSI and bioterrorism countermeasures?

PMID- 15175679
TI  - Response to Preprocessing of oligonucleotide array data.

PMID- 15175680
TI  - Biotechnology as religion.

PMID- 15175681
TI  - Diversifying in biotech.

PMID- 15175683
TI  - Public biotechnology 2003-the numbers.

PMID- 15175684
TI  - Industrial biotechnology-a chance at redemption.

PMID- 15175685
TI  - An image worth a thousand lives?

PMID- 15175686
TI  - Genome sequence of an omnipotent fungus.

PMID- 15175687
TI  - From alpha to omega-producing essential fatty acids in plants.

PMID- 15175688
TI  - The best of both worlds in plant protection.

PMID- 15175689
TI  - A mightier mouse with human adaptive immunity.

PMID- 15175691
TI  - Apomixis technology development-virgin births in farmers' fields?
AB  - Apomixis is the process of asexual reproduction through seed, in the absence of
      meiosis and fertilization, generating clonal progeny of maternal origin. Major
      benefits to agriculture could result from harnessing apomixis in crop plants.
      Although >400 apomictic plant species are known, apomixis is rare among crop
      plants, and the transfer of apomixis to crop varieties by conventional breeding
      has been largely unsuccessful. Because apomictic and sexual pathways are closely
      related, de novo engineering of apomixis might be achieved in sexually
      reproducing crops. Early consideration of issues relating to biosafety and
      intellectual property (IP) management can facilitate the acceptance and
      deployment of apomixis technology in agriculture.

PMID- 15175696
TI  - Managing innovation: university-industry partnerships and the licensing of the
      Harvard mouse.

PMID- 15175701
TI  - Bio-ontologies-fast and furious.

PMID- 15175700
TI  - Computer security in academia-a potential roadblock to distributed annotation of
      the human genome.

PMID- 15175702
TI  - A bean counter's take on human resources.

PMID- 15175703
TI  - Harvesting biotechnology.

PMID- 15175704
TI  - Biotech business Down Under.

PMID- 15175705
TI  - Farmers to pharmas.

PMID- 15175706
TI  - Biodiscovery--from reef to outback.

PMID- 15175707
TI  - Gaining medical momentum.

PMID- 15175708
TI  - Future outlook.

PMID- 15175709
TI  - Proteomic diagnostics tested.

PMID- 15175710
TI  - A question of priority.

PMID- 15175711
TI  - NASA devolves control of Cassini observations to research teams.

PMID- 15175712
TI  - Double check casts doubt on statistics in published papers.

PMID- 15175713
TI  - Korean bioethicists call for inquiry into stem-cell work.

PMID- 15175714
TI  - Fossil hunters bristle over plans for US tour.

PMID- 15175715
TI  - Scientists deny ethical breach at Kenyan orphanage.

PMID- 15175716
TI  - Overseas aid policy needs better science input, inquiry finds.

PMID- 15175717
TI  - Researchers seize moment to make tobacco data public.

PMID- 15175718
TI  - Pressured staff 'lose faith' in patent quality.

PMID- 15175719
TI  - Brands in peril as Brazil strives to keep AIDS drugs free.

PMID- 15175721
TI  - Proteomics and cancer: running before we can walk?

PMID- 15175722
TI  - Tortoise conservation: one of a kind.

PMID- 15175723
TI  - Cultural weight dragging at Asian giants' feet.

PMID- 15175725
TI  - Turing's war work counts for more than computers.

PMID- 15175724
TI  - Ecological and political costs of river diversion.

PMID- 15175731
TI  - When symmetry breaks down.

PMID- 15175732
TI  - Physics: the atomic wrist-watch.

PMID- 15175733
TI  - Gene regulation: a reason for reading nonsense.

PMID- 15175734
TI  - Theoretical immunology: parasitic turncoat.

PMID- 15175735
TI  - Global change: hydrocarbon-driven warming.

PMID- 15175736
TI  - Neurobiology: a matter of balance.

PMID- 15175738
TI  - Behavioural genetics: all in the family.

PMID- 15175741
TI  - Endangered species: where leatherback turtles meet fisheries.
AB  - The dramatic worldwide decline in populations of the leatherback turtle
      (Dermochelys coriacea) is largely due to the high mortality associated with their
      interaction with fisheries, so a reduction of this overlap is critical to their
      survival. The discovery of narrow migration corridors used by the leatherbacks in
      the Pacific Ocean raised the possibility of protecting the turtles by restricting
      fishing in these key areas. Here we use satellite tracking to show that there is
      no equivalent of these corridors in the North Atlantic Ocean, because the turtles
      disperse actively over the whole area. But we are able to identify a few 'hot
      spots' where leatherbacks meet fisheries and where conservation efforts should be
      focused.

PMID- 15175742
TI  - Endangered species: Pan-Atlantic leatherback turtle movements.
AB  - The overall extent of habitat use by leatherback turtles in the North Atlantic,
      and hence their possible interactions with longline fisheries, is unknown. Here
      we use long-term satellite telemetry to reveal that leatherbacks range throughout
      the North Atlantic, indicating that closing limited areas to longline fisheries
      will probably have only partial success in reducing turtle bycatch. Although
      turtles dive very deeply on occasion (one descended to a maximum depth of 1,230
      metres, which represents the deepest dive ever recorded for a reptile), they
      generally restrict their diving to less than 250 metres, which increases the
      chance that they will encounter longline hooks.

PMID- 15175743
TI  - Activity-dependent homeostatic specification of transmitter expression in
      embryonic neurons.
AB  - Neurotransmitters are essential for interneuronal signalling, and the
      specification of appropriate transmitters in differentiating neurons has been
      related to intrinsic neuronal identity and to extrinsic signalling proteins. Here
      we show that altering the distinct patterns of Ca2+ spike activity spontaneously
      generated by different classes of embryonic spinal neurons in vivo changes the
      transmitter that neurons express without affecting the expression of markers of
      cell identity. Regulation seems to be homeostatic: suppression of activity leads
      to an increased number of neurons expressing excitatory transmitters and a
      decreased number of neurons expressing inhibitory transmitters; the reverse
      occurs when activity is enhanced. The imposition of specific spike frequencies in
      vitro does not affect labels of cell identity but again specifies the expression
      of transmitters that are inappropriate for the markers they express, during an
      early critical period. The results identify a new role of patterned activity in
      development of the central nervous system.

PMID- 15175744
TI  - The structure of the high-energy spin excitations in a high-transition
      temperature superconductor.
AB  - In conventional superconductors, lattice vibrations (phonons) mediate the
      attraction between electrons that is responsible for superconductivity. The high
      transition temperatures (high-T(c)) of the copper oxide superconductors has led
      to collective spin excitations being proposed as the mediating excitations in
      these materials. The mediating excitations must be strongly coupled to the
      conduction electrons, have energy greater than the pairing energy, and be present
      at T(c). The most obvious feature in the magnetic excitations of high-T(c)
      superconductors such as YBa2Cu3O6+x is the so-called 'resonance'. Although the
      resonance may be strongly coupled to the superconductivity, it is unlikely to be
      the main cause, because it has not been found in the La2-x(Ba,Sr)(x)CuO4 family
      and is not universally present in Bi2Sr2CaCu2O8+delta (ref. 9). Here we use
      inelastic neutron scattering to characterize possible mediating excitations at
      higher energies in YBa2Cu3O6.6. We observe a square-shaped continuum of
      excitations peaked at incommensurate positions. These excitations have energies
      greater than the superconducting pairing energy, are present at T(c), and have
      spectral weight far exceeding that of the 'resonance'. The discovery of similar
      excitations in La2-xBa(x)CuO4 (ref. 10) suggests that they are a general property
      of the copper oxides, and a candidate for mediating the electron pairing.

PMID- 15175745
TI  - Quantum magnetic excitations from stripes in copper oxide superconductors.
AB  - In the copper oxide parent compounds of the high-transition-temperature
      superconductors the valence electrons are localized--one per copper site--by
      strong intra-atomic Coulomb repulsion. A symptom of this localization is
      antiferromagnetism, where the spins of localized electrons alternate between up
      and down. Superconductivity appears when mobile 'holes' are doped into this
      insulating state, and it coexists with antiferromagnetic fluctuations. In one
      approach to describing the coexistence, the holes are believed to self-organize
      into 'stripes' that alternate with antiferromagnetic (insulating) regions within
      copper oxide planes, which would necessitate an unconventional mechanism of
      superconductivity. There is an apparent problem with this picture, however:
      measurements of magnetic excitations in superconducting YBa2Cu3O6+x near optimum
      doping are incompatible with the naive expectations for a material with stripes.
      Here we report neutron scattering measurements on stripe-ordered
      La1.875Ba0.125CuO4. We show that the measured excitations are, surprisingly,
      quite similar to those in YBa2Cu3O6+x (refs 9, 10) (that is, the predicted
      spectrum of magnetic excitations is wrong). We find instead that the observed
      spectrum can be understood within a stripe model by taking account of quantum
      excitations. Our results support the concept that stripe correlations are
      essential to high-transition-temperature superconductivity.

PMID- 15175746
TI  - A three-dimensional optical photonic crystal with designed point defects.
AB  - Photonic crystals offer unprecedented opportunities for miniaturization and
      integration of optical devices. They also exhibit a variety of new physical
      phenomena, including suppression or enhancement of spontaneous emission, low
      threshold lasing, and quantum information processing. Various techniques for the
      fabrication of three-dimensional (3D) photonic crystals--such as silicon
      micromachining, wafer fusion bonding, holographic lithography, self-assembly,
      angled-etching, micromanipulation, glancing-angle deposition and auto-cloning-
      have been proposed and demonstrated with different levels of success. However, a
      critical step towards the fabrication of functional 3D devices, that is, the
      incorporation of microcavities or waveguides in a controllable way, has not been
      achieved at optical wavelengths. Here we present the fabrication of 3D photonic
      crystals that are particularly suited for optical device integration using a
      lithographic layer-by-layer approach. Point-defect microcavities are introduced
      during the fabrication process and optical measurements show they have resonant
      signatures around telecommunications wavelengths (1.3-1.5 microm). Measurements
      of reflectance and transmittance at near-infrared are in good agreement with
      numerical simulations.

PMID- 15175748
TI  - Geochemical evidence from the Sudbury structure for crustal redistribution by
      large bolide impacts.
AB  - Deformation and melting of the crust during the formation of large impact craters
      must have been important during the Earth's early evolution, but such processes
      remain poorly understood. The 1.8-billion-year-old Sudbury structure in Ontario,
      Canada, is greater than 200 km in diameter and preserves a complete impact
      section, including shocked basement rocks, an impact melt sheet and fallback
      material. It has generally been thought that the most voluminous impact melts
      represent the average composition of the continental crust, but here we show that
      the melt sheet now preserved as the Sudbury Igneous Complex is derived
      predominantly from the lower crust. We therefore infer that the hypervelocity
      impact caused a partial inversion of the compositional layering of the
      continental crust. Using geochemical data, including platinum-group-element
      abundances, we also show that the matrix of the overlying clast-laden Onaping
      Formation represents a mixture of the original surficial sedimentary strata,
      shock-melted lower crust and the impactor itself.

PMID- 15175747
TI  - Release of methane from a volcanic basin as a mechanism for initial Eocene global
      warming.
AB  - A 200,000-yr interval of extreme global warming marked the start of the Eocene
      epoch about 55 million years ago. Negative carbon- and oxygen-isotope excursions
      in marine and terrestrial sediments show that this event was linked to a massive
      and rapid (approximately 10,000 yr) input of isotopically depleted carbon. It has
      been suggested previously that extensive melting of gas hydrates buried in marine
      sediments may represent the carbon source and has caused the global climate
      change. Large-scale hydrate melting, however, requires a hitherto unknown
      triggering mechanism. Here we present evidence for the presence of thousands of
      hydrothermal vent complexes identified on seismic reflection profiles from the
      Voring and More basins in the Norwegian Sea. We propose that intrusion of
      voluminous mantle-derived melts in carbon-rich sedimentary strata in the
      northeast Atlantic may have caused an explosive release of methane--transported
      to the ocean or atmosphere through the vent complexes--close to the
      Palaeocene/Eocene boundary. Similar volcanic and metamorphic processes may
      explain climate events associated with other large igneous provinces such as the
      Siberian Traps (approximately 250 million years ago) and the Karoo Igneous
      Province (approximately 183 million years ago).

PMID- 15175749
TI  - Doubling the estimate of invertebrate biomass in a rainforest canopy.
AB  - Forest canopies represent the functional interface between 90% of the Earth's
      terrestrial biomass and the atmosphere and include some of the most threatened of
      all terrestrial ecosystems. However, we lack even a basic understanding of how
      the biomass of plants and animals is distributed throughout forest canopies, even
      though this information is vital for estimating energy flow, carbon cycling,
      resource use and the transfer of materials within this ecosystem. Here we measure
      the biomass of invertebrates living in a common rainforest epiphyte, describe a
      striking relationship between fern size and the biomass of animals within the
      ferns, and reveal that one large epiphyte may contain an invertebrate biomass
      similar to that found in the whole of the rest of the tree crown on which it is
      growing. Using these data, we show that including the fauna of these epiphytes--a
      neglected component in rainforest ecosystems--can more than double our estimate
      of the total invertebrate biomass in an entire rainforest canopy.

PMID- 15175750
TI  - Unusually dynamic sex roles in a fish.
AB  - Sex roles are typically thought of as being fixed for a given species. In most
      animals males compete for females, whereas the females are more reluctant to
      mate. Therefore sexual selection usually acts most strongly on males. This is
      explained by males having a higher potential reproductive rate than females,
      leading to more males being sexually active (a male-biased operational sex
      ratio). However, what determines sex roles and the strength of sexual selection
      is a controversial and much debated question. In this large-scale field study, we
      show a striking temporal plasticity in the mating competition of a fish (two
      spotted goby, Gobiusculus flavescens). Over the short breeding season fierce male
      male competition and intensive courtship behaviour in males were replaced by
      female-female competition and actively courting females. Hence, sex role reversal
      occurred rapidly. This is the first time that a shift in sex roles has been shown
      in a vertebrate. The shift might be explained by a large decline in male
      abundance, strongly skewing the sex ratio towards females. Notably, the sex role
      reversal did not occur at an equal operational sex ratio, contrary to established
      sex role theory.

PMID- 15175751
TI  - Transient cross-reactive immune responses can orchestrate antigenic variation in
      malaria.
AB  - The malaria parasite Plasmodium falciparum has evolved to prolong its duration of
      infection by antigenic variation of a major immune target on the surface of the
      infected red blood cell. This immune evasion strategy depends on the sequential,
      rather than simultaneous, appearance of immunologically distinct variants.
      Although the molecular mechanisms by which a single organism switches between
      variants are known in part, it remains unclear how an entire population of
      parasites within the host can synchronize expression to avoid rapidly exhausting
      the variant repertoire. Here we show that short-lived, partially cross-reactive
      immune responses to parasite-infected erythrocyte surface antigens can produce a
      cascade of sequentially dominant antigenic variants, each of which is the most
      immunologically distinct from its preceding types. This model reconciles several
      previously unexplained and apparently conflicting epidemiological observations by
      demonstrating that individuals with stronger cross-reactive immune responses can,
      paradoxically, be more likely to sustain chronic infections. Antigenic variation
      has always been seen as an adaptation of the parasite to evade host defence: we
      show that the coordination necessary for the success of this strategy might be
      provided by the host.

PMID- 15175752
TI  - Positive selection at sites of multiple amino acid replacements since rat-mouse
      divergence.
AB  - New alleles become fixed owing to random drift of nearly neutral mutations or to
      positive selection of substantially advantageous mutations. After decades of
      debate, the fraction of fixations driven by selection remains uncertain. Within
      9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each
      other at two nucleotide sites and 1,982 codons with three differences. At codons
      where rat-mouse divergence involved two non-synonymous substitutions, both of
      them occurred in the same lineage, either rat or mouse, in 64% of cases; however,
      independent substitutions would occur in the same lineage with a probability of
      only 50%. All three non-synonymous substitutions occurred in the same lineage for
      46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs
      of prokaryotic genomes also shows clumping of multiple non-synonymous
      substitutions in the same lineage. This pattern cannot be explained by correlated
      mutation or episodes of relaxed negative selection, but instead indicates that
      positive selection acts at many sites of rapid, successive amino acid
      replacement.

PMID- 15175753
TI  - Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and
      fat body.
AB  - In Drosophila melanogaster, ageing is slowed when insulin-like signalling is
      reduced: life expectancy is extended by more than 50% when the insulin-like
      receptor (InR) or its receptor substrate (chico) are mutated, or when insulin
      producing cells are ablated. But we have yet to resolve when insulin affects
      ageing, or whether insulin signals regulate ageing directly or indirectly through
      secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin
      signalling is inhibited in certain tissues, or when repressed in adult worms, and
      this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref.
      6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO,
      the equivalent of nematode daf-16 and mammalian FOXO3a. We demonstrate here that
      dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral
      fat body. We further show that this limited activation of dFOXO reduces
      expression of the Drosophila insulin-like peptide dilp-2 synthesized in neurons,
      and represses endogenous insulin-dependent signalling in peripheral fat body.
      These findings suggest that autonomous and non-autonomous roles of insulin
      signalling combine to control ageing.

PMID- 15175754
TI  - Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3
      gene.
AB  - Transcription by RNA polymerase II in Saccharomyces cerevisiae and in humans is
      widespread, even in genomic regions that do not encode proteins. The purpose of
      such intergenic transcription is largely unknown, although it can be regulatory.
      We have discovered a role for one case of intergenic transcription by studying
      the S. cerevisiae SER3 gene. Our previous results demonstrated that transcription
      of SER3 is tightly repressed during growth in rich medium. We now show that the
      regulatory region of this gene is highly transcribed under these conditions and
      produces a non-protein-coding RNA (SRG1). Expression of the SRG1 RNA is required
      for repression of SER3. Additional experiments have demonstrated that repression
      occurs by a transcription-interference mechanism in which SRG1 transcription
      across the SER3 promoter interferes with the binding of activators. This work
      identifies a previously unknown class of transcriptional regulatory genes.

PMID- 15175755
TI  - Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in
      Drosophila.
AB  - In eukaryotic cells, messenger RNAs harbouring premature termination codons
      (PTCs) are rapidly degraded by a conserved post-transcriptional mechanism
      referred to as nonsense-mediated mRNA decay (NMD), which prevents the synthesis
      of truncated proteins that could be deleterious for the cell. Studies in yeast
      and mammals indicate that degradation by means of this pathway can occur from
      both the 5' end of the message (involving decapping and 5'-to-3' exonucleolytic
      digestion by XRN1) or the 3' end (through accelerated deadenylation and exosome
      mediated 3'-to-5' decay). Here we show that, contrary to expectation, degradation
      of PTC-containing messages in Drosophila is initiated by endonucleolytic
      cleavage(s) in the vicinity of the nonsense codon. The resulting 5' fragment is
      rapidly degraded by exonucleolytic digestion by the exosome, whereas the 3'
      fragment is degraded by XRN1. This decay route is shown for several PTC
      containing reporters, as well as an endogenous mRNA that is naturally regulated
      by NMD. We conclude that, despite conservation in the NMD machinery, PTC
      containing transcripts are degraded in Drosophila by a mechanism that differs
      considerably from those described in yeast and mammals.

PMID- 15175756
TI  - Cyclic electron flow around photosystem I is essential for photosynthesis.
AB  - Photosynthesis provides at least two routes through which light energy can be
      used to generate a proton gradient across the thylakoid membrane of chloroplasts,
      which is subsequently used to synthesize ATP. In the first route, electrons
      released from water in photosystem II (PSII) are eventually transferred to NADP+
      by way of photosystem I (PSI). This linear electron flow is driven by two
      photochemical reactions that function in series. The cytochrome b6f complex
      mediates electron transport between the two photosystems and generates the proton
      gradient (DeltapH). In the second route, driven solely by PSI, electrons can be
      recycled from either reduced ferredoxin or NADPH to plastoquinone, and
      subsequently to the cytochrome b6f complex. Such cyclic flow generates DeltapH
      and thus ATP without the accumulation of reduced species. Whereas linear flow
      from water to NADP+ is commonly used to explain the function of the light
      dependent reactions of photosynthesis, the role of cyclic flow is less clear. In
      higher plants cyclic flow consists of two partially redundant pathways. Here we
      have constructed mutants in Arabidopsis thaliana in which both PSI cyclic
      pathways are impaired, and present evidence that cyclic flow is essential for
      efficient photosynthesis.

PMID- 15175759
TI  - Introductory matters.

PMID- 15175762
TI  - Crystal structure of a self-splicing group I intron with both exons.
AB  - The discovery of the RNA self-splicing group I intron provided the first
      demonstration that not all enzymes are proteins. Here we report the X-ray crystal
      structure (3.1-A resolution) of a complete group I bacterial intron in complex
      with both the 5'- and the 3'-exons. This complex corresponds to the splicing
      intermediate before the exon ligation step. It reveals how the intron uses
      structurally unprecedented RNA motifs to select the 5'- and 3'-splice sites. The
      5'-exon's 3'-OH is positioned for inline nucleophilic attack on the
      conformationally constrained scissile phosphate at the intron-3'-exon junction.
      Six phosphates from three disparate RNA strands converge to coordinate two metal
      ions that are asymmetrically positioned on opposing sides of the reactive
      phosphate. This structure represents the first splicing complex to include a
      complete intron, both exons and an organized active site occupied with metal
      ions.

PMID- 15175764
TI  - Routine microbiological screening in septic patients in a cardiac surgical
      intensive care unit.
AB  - INTRODUCTION: Patients in a surgical intensive care unit (ICU) have a high
      incidence of nosocomial infections which often lead to septic shock and death.
      Since specific antibiotic treatment is often difficult, it is recommended that
      routine nose/throat swabs be obtained in order to have a better idea of the
      causative agent when a systemic inflammatory response occurs in a given patient.
      MATERIALS AND METHODS: In 1435 patients in a cardiac surgical ICU, routine
      nose/throat swabs were taken thrice a week and tested for microorganisms and
      systemic inflammation. Blood cultures were also obtained. Antibiotic treatment
      was given to cover the microbes from the nose/throat swabs. Alternatively, an
      empirical antibiotic therapy was given to patients whose swabs had tested
      negative. RESULTS: Of the 86 patients with systemic inflammation, 29 had blood
      cultures positive for microbes. Of these, 18 received a specific antibiotic
      therapy based on their positive nose/throat cultures prior to the return of the
      blood cultures from the laboratory. However, only 11 patients tested positive for
      the same microbes on routine swabs and blood cultures. While positive routine
      swabs are quite specific to sepsis when there is a systemic inflammatory
      response, routine swabs are not a suitable screening tool due to their low
      sensitivity. CONCLUSION: Routine nose/throat swabs led to earlier specific
      antibiotic treatment in only 22 % of patients with clinical signs of systemic
      inflammation. In 36 % of cases, the organisms detected in the routine swabs and
      blood cultures were not identical. Hence, we believe that routine swabs are of
      limited value in instituting earlier, specific antibiotic therapy in septic
      patients.

PMID- 15175761
TI  - Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.
AB  - Calorie restriction extends lifespan in organisms ranging from yeast to mammals.
      In yeast, the SIR2 gene mediates the life-extending effects of calorie
      restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1),
      activates a critical component of calorie restriction in mammals; that is, fat
      mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and
      represses genes controlled by the fat regulator PPAR-gamma (peroxisome
      proliferator-activated receptor-gamma), including genes mediating fat storage.
      Sirt1 represses PPAR-gamma by docking with its cofactors NCoR (nuclear receptor
      co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone
      receptors). Mobilization of fatty acids from white adipocytes upon fasting is
      compromised in Sirt1+/- mice. Repression of PPAR-gamma by Sirt1 is also evident
      in 3T3-L1 adipocytes, where overexpression of Sirt1 attenuates adipogenesis, and
      RNA interference of Sirt1 enhances it. In differentiated fat cells, upregulation
      of Sirt1 triggers lipolysis and loss of fat. As a reduction in fat is sufficient
      to extend murine lifespan, our results provide a possible molecular pathway
      connecting calorie restriction to life extension in mammals.

PMID- 15175765
TI  - Deep hypothermic circulatory arrest in adults undergoing aortic surgery: local
      experience.
AB  - INTRODUCTION: The aim of our study was to evaluate the efficacy and safety of
      deep hypothermic circulatory arrest (DHCA) as a method of cerebral protection
      during aortic surgery. MATERIALS AND METHODS: We carried out a retrospective
      review of 59 consecutive patients (48 men, 11 women) undergoing elective or
      emergency aortic surgery requiring DHCA from January 1999 to April 2002 in 2
      tertiary care hospitals. Data regarding demographics, clinical characteristics,
      operation type, duration of circulatory arrest, nasopharyngeal temperatures, use
      of retrograde cerebral perfusion and central nervous system (CNS) morbidity and
      perioperative mortality were collected and analysed. RESULTS: There were 47 (79.7
      %) operations for aortic dissections and 12 (20.3 %) for aortic aneurysms. The
      mean duration of circulatory arrest was 42 +/- 23 minutes. The lowest
      nasopharyngeal temperature at the time of arrest was 16.5 degrees +/- 1.9 degrees
      C. Eight (13.6 %) patients had a new irreversible neurologic deficit
      postoperatively. These patients had a mean circulatory arrest time of 50 +/- 28
      minutes. Temporary neurologic dysfunction occurred in 8 (13.6 %) patients. Intra
      hospital mortality was 22 %. The mean circulatory arrest time for patients who
      died was 54 +/- 24 minutes. CONCLUSION: DHCA is a simple and effective method of
      CNS protection in aortic surgery with satisfactory outcomes. With increased
      surgical and anaesthetic experience, as well as selective use of adjuncts of
      cerebral protection, reductions in mortality and neurological morbidity will
      likely be achieved in the future.

PMID- 15175766
TI  - Hand-assisted laparoscopic living donor nephrectomy.
AB  - INTRODUCTION: Laparoscopic living donor nephrectomy (LDN) for renal
      transplantation is increasingly being performed to improve donor outcomes, by
      reducing perioperative morbidity without adversely impacting on allograft
      function in the recipient. We report our initial experience with hand-assisted
      LDN. MATERIALS AND METHODS: From March 2002 to January 2003, 10 hand-assisted
      LDNs were performed in 2 institutions. Potential donors were evaluated for
      suitability, which included a renal angiogram. Only donors with uncomplicated
      vascular arrangements of the left kidney were offered this technique. During
      surgery, dissection of the donor kidney was performed laparoscopically, aided by
      the surgeon 's non-dominant hand inserted into the abdominal cavity through a
      hand-assist device via a 7-cm abdominal incision. The graft was subsequently
      delivered through the incision. RESULTS: The mean operating time was 163.5 +/- 32
      minutes and the mean warm ischaemic time was 2.16 +/- 0.72 minutes. There were no
      conversions to the open nephrectomy technique or requirement for perioperative
      transfusions. Postoperatively, patients returned to normal diet by 1.8 +/- 0.8
      days and needed opiate analgesia up to a maximum of 48 hours. On average, the
      patients started ambulation at 2.1 +/- 0.9 days and were discharged 4 +/- 1.5
      days after surgery. There were no significant complications other than 3
      superficial wound infections. All grafts had immediate graft function. Serum
      creatinine levels of all recipients fell within 24 hours and reached baseline at
      a mean of 5.7 +/- 4.6 days. CONCLUSIONS: Hand-assisted LDN is safe, feasible and
      can be performed with minimal morbidity. It also allows for excellent allograft
      function.

PMID- 15175767
TI  - Rising trend of anterior cruciate ligament injuries in females in a regional
      hospital.
AB  - INTRODUCTION: We see a rising trend in the number of anterior cruciate ligament
      (ACL) injuries in females over the past 4 years (1999 to 2002). This article
      seeks to identify and examine the rising trend in the number of ACL injuries in
      females in our institution over this period. MATERIALS AND METHODS: Two hundred
      and fifty-nine patients with ACL reconstructions were identified and their
      casenotes were retrieved from the medical records office. Of these, 13 were
      females. RESULTS: The number of ACL reconstructions has increased from 9 cases to
      144 cases a year from 1999 to 2002. Over this period, 13 female cases (3 in 2001
      and 10 in 2002) with an age range of 13 to 38 years were performed in our
      institution. Their injuries were mainly sustained from a bad landing or during
      pivoting on 1 leg. There were 8 patients (61.5 %) with prior conditioning and
      experience and 5 without (38.5 %). The mean number of years of prior training was
      4.4 years. Of these 8, 4 were netball players. All were competitive players
      either at the school or club level and they were all playing as goal attackers.
      CONCLUSION: Linear regression analysis shows a significant increase in the number
      of ACL reconstructions performed for females in our institution over this time
      period. Netball was a common sport in our series. This suggests a likely
      relationship between netball and ACL injuries. All the patients were playing as
      goal attackers. The area of court covered and frequency of jump-stop and sudden
      deceleration activities could be a cause.

PMID- 15175768
TI  - Extended-spectrum beta-lactamases in clinical isolates of Escherichia coli and
      Klebsiella spp. in a Singapore hospital: clinical spectrum.
AB  - INTRODUCTION: The rising prevalence of extended-spectrum beta-lactamases in gram
      negative bacillary pathogens is an important clinical problem resulting from the
      extensive use of broad-spectrum antibiotics. The emergence of the extended
      spectrum beta-lactamases increases the possibility that traditional, empiric
      antimicrobial regimens may be ineffective. The aims of this study are: to
      determine the epidemiologic characteristics and clinical outcome of patients
      diagnosed with infection caused by Klebsiella spp. and Escherichia coli producing
      extended-spectrum beta-lactamases; to define a subgroup of patients who may
      benefit from early, empiric therapy; and to determine the local antibiotic
      sensitivity pattern in order to improve antibiotic utilisation in our hospital.
      MATERIALS AND METHODS: A 4-month retrospective review of patients hospitalised in
      Changi General Hospital between November 2000 and February 2001 who were
      diagnosed with infection caused by isolates of Klebsiella spp. or Escherichia
      coli producing extended-spectrum beta-lactamases. RESULTS: During the study
      period, 44 % of Klebsiella spp. and 16.1 % of Escherichia coli isolates were
      reported as producers of the extended-spectrum beta-lactamases. Sixty-eight
      patients were assessed to have clinically significant infection caused by 75
      isolates. Most of them were elderly, had multiple medical problems and were
      recently treated with beta-lactam antibiotics. There was a trend toward better
      outcome in patients who received adequate initial, empiric therapy. CONCLUSION:
      Patients with infections caused by extended-spectrum beta-lactamase producing
      Enterobacteriaceae have certain identifiable, common clinical characteristics. In
      our institution, only carbapenems remain effective against all isolates of
      Klebsiella spp. or Escherichia coli producing extended-spectrum beta-lactamases.
      Further research is necessary to define a group of patients who can benefit from
      an early, broad-spectrum, empiric therapy.

PMID- 15175769
TI  - Salivary immunoglobulin A and lysozyme in patients with psoriasis.
AB  - INTRODUCTION: We compared the salivary immunoglobulin A (IgA) and lysozyme
      concentration and secretion rates among mild and severe psoriasis patients and
      controls in Singapore. MATERIALS AND METHODS: Fifty-one psoriasis patients and 24
      controls participated in the study. None of the patients were on
      immunosuppressive therapy. The Psoriasis Area and Severity Index (PASI) was used
      to assess the severity of psoriasis. Patients were divided into mild and severe
      groups by the median PASI score. Each subject contributed a 5-minute unstimulated
      salivary sample. Enzyme-linked immunosorbent assay method was used to determine
      the salivary IgA and lysozyme levels. RESULTS: Psoriasis patients had lower
      concentration and secretion rate of IgA (geometric mean [GM], 97.5 micro g/mL and
      32.3 micro g/min) and lysozyme (GM, 127.6 micro g/mL and 42.1 micro g/min) than
      controls (IgA GM 256.3 micro g/mL, 79.1 micro g/min; lysozyme GM 180.9 micro
      g/mL, 55.8 micro g/min) [P = 0.000 (IgA concentration), P = 0.000 (IgA secretion
      rate), P = 0.015 (lysozyme concentration) and P = 0.150 (lysozyme secretion
      rate)]. However, no significant differences were observed between mild and severe
      patients for both IgA and lysozyme concentrations and secretion rates. PASI score
      showed negative, but non-significant, correlations with either log salivary IgA
      (r = -0.22, P = 0.13) or log lysozyme (r = -0.09, P = 0.53) secretion rates.
      CONCLUSION: Psoriasis patients had lower concentrations and secretion rates of
      salivary IgA and lysozyme compared to controls. However, among patients, the
      salivary IgA and lysozyme levels are variable and not related to severity of
      psoriasis.

PMID- 15175770
TI  - Cyclosporin in the treatment of severe atopic dermatitis: a retrospective study.
AB  - INTRODUCTION: The aims of this study were to determine the clinical profile of
      patients with atopic dermatitis who were treated with cyclosporin, and to assess
      the treatment duration, dose and response to cyclosporin therapy. MATERIALS AND
      METHODS: Casenotes of patients with atopic dermatitis treated with cyclosporin
      from January 2000 to February 2002 were analysed. RESULTS: There were 15 patients
      (9 males and 6 females) (age range, 1 to 58 years). All had severe disease. The
      mean initiating dose of cyclosporin was 2.8 mg/kg/day and the mean maximum dose
      was 3.3 mg/kg/day. Average duration of treatment was 6 months. Rapid improvement
      was seen within the first 2 weeks and maximum benefit was attained at a mean of
      10 weeks. At the end of treatment, 73 % of patients had improved from severe to
      none, mild or moderate disease. Five patients had a flare of eczema during
      therapy, 3 related to decrease in dose of medication. All patients relapsed
      within 3 months of cessation of cyclosporin. One patient with borderline
      hypertension developed worsening of blood pressure, which returned to baseline
      after cessation of cyclosporin and treatment with atenolol. No patient had
      sustained rises in serum creatinine. CONCLUSION: Cyclosporin is very useful in
      patients with severe, recalcitrant atopic dermatitis who have failed conventional
      therapy. It offers rapid relief of an otherwise disabling skin disease, but its
      effect is not long-lasting and relapses occur in almost all cases if followed up
      for long enough.

PMID- 15175771
TI  - Characteristics and acute rehabilitation of Guillain-Barre syndrome in Singapore.
AB  - INTRODUCTION: The objectives of this study are to describe the demographics,
      clinical characteristics, complications and functional outcomes in patients with
      Guillain-Barr e syndrome (GBS) or the Miller-Fisher syndrome (MFS) variant
      admitted to our institution. We also aim to identify prognostic outcome
      indicators. MATERIALS AND METHODS: A retrospective review of the case records of
      all patients discharged from our hospital with a diagnosis of GBS or MFS over a 2
      year period was performed. The clinical characteristics charted included the
      time of symptom onset to nadir. The Modified Barthel Index (MBI) and Expanded
      Grading Scale (EGS) for GBS were the functional outcome measures used. RESULTS:
      Thirty-one cases were reviewed and 8 (25.8 %) had the MFS variant. Twenty-two (71
      %) patients were male, with a mean age of 42.3 years. Weakness and numbness (74
      %) were the most common initial symptoms; 9 (29 %) patients were paraparetic and
      7 (22.6 %) were tetraparetic. Ten (32.3 %) patients had respiratory involvement
      and 8 (25.8 %) had urinary retention. Intravenous immunoglobulin (IVIG) was
      prescribed in 13 (41.9 %) patients. The mean duration to disease nadir was 8.1
      days. The mean MBI scores at nadir and discharge were 54.7 and 77.3,
      respectively, and this gain was highly significant (P <0.01). The majority (84 %)
      of patients were employed at admission and although most returned to work, 63 %
      (17/27) of the patients had residual symptoms or signs 3 months after discharge.
      CONCLUSION: The clinical characteristics and complication frequency closely
      follows that previously described in Western populations, although our cohort was
      younger and had a higher proportion of the MFS variant. Predictors of a poorer
      functional outcome include a high EGS score at nadir, tetraparesis, respiratory
      involvement, urinary retention and the need for nasogastric enteral feeding.
      Patients who had MFS or received IVIG had greater functional gains. Good
      functional outcomes occurred in a large majority of patients.

PMID- 15175772
TI  - Interleukin-2 levels in chronic schizophrenia patients.
AB  - INTRODUCTION: Most research in interleukin activity in schizophrenia has been in
      Caucasian populations. We examined interleukin-2 (IL-2) levels and their relation
      to the duration of the illness, psychopathology and treatment effects, in chronic
      schizophrenia patients of Asian origin. MATERIALS AND METHODS: Thirty chronic
      schizophrenia patients were recruited for the study and their demographic data
      and medication dosage were noted. Symptom severity was scored on the Positive And
      Negative Syndrome scale for Schizophrenia (PANSS) and blood sampling done. Ten
      healthy Chinese males were recruited as controls. Phytohaemagglutinin-stimulated
      production of serum levels of IL-2 were measured by enzyme-linked immunosorbent
      assay. RESULTS: IL-2 levels (1327 +/- 596.2) of all 30 patients were
      significantly lower than that of the Chinese controls (2420 +/- 342.5). This
      effect was noted throughout the entire duration of the illness. Ethnic and age
      differences in IL-2 levels were not found. There was, however, a negative
      correlation with the duration of the illness and a positive correlation with the
      dosage of medication. CONCLUSIONS: The results of this study of a population of
      mostly Chinese patients with schizophrenia replicate an important finding. Data
      such as this has not been reported previously on Asians of this racial group.

PMID- 15175773
TI  - Hemifacial spasm in Singapore: clinical characteristics and patients '
      perceptions.
AB  - INTRODUCTION: The aim of this study was to determine the clinical characteristics
      and patients ' perception of hemifacial spasm (HFS) in Singapore. MATERIALS AND
      METHODS: A clinical survey of 137 consecutive patients with HFS seen in our
      Botulinum Toxin Clinic over a 15-month period was undertaken. RESULTS: Forty-six
      men and 91 women were interviewed. Their mean age at onset of HFS was 48 years.
      The median disease duration was 60 months (range, 2 to 360 months). Left-sided
      spasm was common in 51.8 % of patients, and the orbicularis oculi was the first
      muscle to be affected in 86.1 % of them. The majority (65 %) had the spasm
      aggravated by stress and anxiety. In fact, 32 patients perceived stress and
      anxiety as a possible aetiology of HFS. Stroke was a main concern in 17 patients
      and 7 patients thought the spasm was a sign of demonic possession or a bad omen.
      The spasm embarrassed 75.2 % of the patients, rendered 65 % of them depressed,
      affected the vision in 60.6 % of them and compromised their work performance in
      35.8 %. Overall, treatment was delayed by a median interval of 6 months from
      onset of symptoms (range, 0 to 132). More than half (53.3 %) tried traditional
      therapies (acupuncture or herbal medicine), while only 48.2 % had botulinum toxin
      as the initial treatment. All patients eventually received botulinum toxin
      injections and more than 90 % showed improvement at 1 month posttreatment.
      CONCLUSIONS: The clinical characteristics and patients ' perception of HFS in
      Singapore were presented. HFS affects patients both psychosocially and
      functionally. Effective treatment with botulinum toxin exists and should be
      provided early to the patients.

PMID- 15175774
TI  - Molecular adsorbent recirculating system (MARS).
AB  - INTRODUCTION: Molecular adsorbent recirculating system (MARS) for albumin liver
      dialysis has been used as a bridge to liver transplantation in patients with
      fulminant hepatic failure (FHF). This review examines the available data on its
      clinical use, its technical aspects and present gaps in knowledge. METHODS: Peer
      reviewed journals and monographs on the subject were covered. RESULTS: FHF is
      associated with elevation in various substances including bilirubin, ammonia,
      lactate, free fatty acids and aromatic amino acids. Some of these toxic
      metabolites, such as ammonia and bilirubin, are believed to be central to the
      clinical manifestations of hepatic encephalopathy and acute renal failure. MARS
      ameliorates both biochemical and clinical manifestations of FHF by removing both
      water-soluble and protein-bound toxins. Among the benefits of MARS is the
      attenuation of severe cerebral oedema and raised intracranial pressure found in
      FHF, possibly through reduction in high concentrations of these toxins. Although
      MARS has been shown to be useful in FHF, its clinical efficacy in subfulminant
      hepatic failure and less severe forms of acute liver failure (ALF) remains
      uncertain. The current literature also suggests that it may be beneficial to
      treat cases of acute-on-chronic liver failure (AoCLF). Deranged systemic
      chemistries can be similarly ameliorated, but the impact of MARS on the natural
      history of AoCLF remains uncertain. The difficulty lies in being able to
      accurately quantify residual liver function and variability in the course of
      acute intercurrent events. The broader question is whether MARS can favourably
      change the natural history of ALF and FHF. For this, large multi-centre,
      randomised controlled trials are needed. Furthermore, it is also uncertain how
      hepatic excretory-assist devices, such as MARS, compare with bio-artificial liver
      assist devices which have both synthetic and excretory hepatic functions in ALF
      treatment in intensive care unit patients. Nevertheless, MARS has proven to be a
      valuable homeostatic tool that may be useful in restoring the biochemical and
      clinical status quo in much the same way that continuous veno-venous
      haemofiltration and mechanical ventilation provide temporary artificial organ
      support while these organs are in distress. This is the evolving concept of multi
      organ support therapy. Other major unresolved issues with MARS include the timing
      of initiation of albumin liver dialysis, the clinical and/or biochemical
      parameters to base this decision on, the intensity of MARS therapy (continuous
      versus intermittent) and the saturation capacity of the system for different
      metabolites in intermittent MARS. CONCLUSIONS: MARS is an effective and, thus
      far, safe homeostatic tool in treating FHF. More studies are needed to delineate
      its role as a homeostatic tool in less severe forms of ALF, including that which
      occurs in multi-organ failure and in AoCLF. Other studies need to focus on the
      optimal timing of initiation of and intensity of MARS albumin liver dialysis. The
      larger issue is to compare MARS with bio-assist liver devices in treating the
      whole spectrum of ALF.

PMID- 15175775
TI  - Marijuana in pregnancy.
AB  - INTRODUCTION: The prevalence of recreational drug abuse among young adults,
      including women, has increased markedly over the last 2 decades. Nearly 90 % of
      these women are of childbearing age. Marijuana remains the drug most commonly
      used for recreational purposes in pregnancy. However, there appears to be an
      absence of uniform guidelines for obstetric and anaesthetic management of
      pregnant patients with a history of marijuana abuse. MATERIALS AND METHODS: A
      Medline search for articles highlighting drug abuse in pregnancy, with particular
      emphasis on marijuana abuse in pregnancy, the drug 's impact on the fetus and
      implications for administration of obstetrical anaesthesia was performed.
      RESULTS: Because the pharmacological actions of marijuana are complex and include
      a unique blend of effects, the clinical picture could be very unpredictable, the
      diagnosis often difficult, and management at times controversial. CONCLUSION: In
      the absence of uniform anaesthetic guidelines for pregnant patients with a
      history of drug abuse, including abuse of marijuana, the decision regarding
      administration of peripartum analgesia or anaesthesia should be individualised
      and conducted on a case-by-case basis.

PMID- 15175776
TI  - Thoracic myelopathy secondary to ligamentum flavum ossification.
AB  - INTRODUCTION: Focal ossification of the ligamentum flavum (OLF) is a rare cause
      of thoracic myelopathy. The lower thoracic spine is most frequently affected and
      the patients present initially with posterior column disturbances followed by
      progressively increasing spastic paraparesis. The pathogenesis of OLF has not
      been conclusively established. MATERIALS AND METHODS: Five patients with thoracic
      myelopathy due to OLF underwent decompressive laminectomy and excision of the
      ligamentum flavum. Magnetic resonance (MR) images consistently revealed a linear
      or beak-like excrescence, uniformly hypodense on T1- and T2-weighted images,
      situated posterior to the thecal sac. A comparison of the preoperative
      neurological status and at followup was done using the Japanese Orthopaedic
      Association and Nurick scores modified for thoracic myelopathy. RESULTS:
      Decompressive laminectomy with excision of the OLF resulted in significant
      improvement in motor weakness and gait in 4 (1 excellent, 2 good, and 1 fair)
      patients who had slow-onset, but progressive compression, OLF. The patient who
      had acute traumatic spinal injury did not recover despite decompression and
      rehabilitation. All improved in their gait and spasticity, but 4 patients had
      persistent sensory deficit. CONCLUSION: OLF can significantly contribute to a
      spatial reduction of the thoracic spinal canal, resulting in slowly progressive
      paraparesis or acute paraplegia after trauma to the back. The T2-weighted
      sagittal image of MR imaging is the modality of choice for screening the
      longitudinal extent of OLF, with increased diagnostic accuracy when combined with
      computed tomographic myelogram. Neurological improvement usually occurs following
      decompression laminectomy with or without excision of the OLF. However, the
      persistence of residual numbness or weakness at follow-up may be due to
      irreversible changes within the cord as a result of severe thecal compression and
      the delay between the onset of initial symptoms/signs and surgical decompression.
      Prognosis remains poor for acute myelopathy with pre-existing OLF, despite
      surgery.

PMID- 15175777
TI  - A case of Maffucci 's syndrome with pleural effusion: ten-year follow-up.
AB  - INTRODUCTION: Maffucci 's syndrome (MS) is a congenital non-hereditary mesodermal
      dysplasia characterised by numerous mesenchymal neoplasias in the form of
      enchondromas with secondary bone deformities and multiple soft tissue
      haemangiomas that may have phlebolitis. CLINICAL PICTURE: A 23-year-old male
      patient presented with non-productive cough, dyspnoea, chest pain and back pain.
      Chest X-ray showed unilateral pleural effusion and multiple enchondromas of the
      ribs. On physical examination, there were mobile, multiple, bluish-coloured
      lesions probably cavernous haemangiomas on bilateral chest walls. In addition,
      there were multiple nodular lesions on the extremities especially accumulated on
      the fingers. The patient was diagnosed as Maffucci 's syndrome according to
      computed tomography (CT) of the thorax, conventional radiography of the skeletal
      system, magnetic resonance (MR) imaging, Th4-Th11 intercostal and right upper
      extremity angiography and physical examination findings. TREATMENT: As the
      patient rejected any diagnostic intervention, he was monitored with CT. OUTCOME:
      During the last 6 years of follow-up, the lesion that was detected on the rib
      adjacent to the basal segments of the left lung showed significant progression
      and was accepted as chondrosarcoma. CONCLUSION: To our knowledge, this is the
      first case of Maffucci ' s syndrome with pleural effusion. In this case report,
      the probable mechanism of pleural effusion was discussed.

PMID- 15175778
TI  - Uncommon benign intrascrotal tumours.
AB  - INTRODUCTION: Benign intrascrotal tumours are rare. CLINICAL PICTURE: Three
      patients with bilateral paratesticular leiomyomas, an adenomatoid tumour of the
      testis and a left paratesticular dermoid cyst coexisting with a synchronous left
      paratesticular epidermal cyst are presented. These tumours were discrete, hard
      and smooth lesions, in which the diagnosis of malignancy could not be safely
      excluded preoperatively even with ultrasonography. TREATMENT AND OUTCOME: The
      first patient had orchiectomy with contralateral testicular preserving surgery,
      the second patient underwent orchiectomy and the third had conservative
      testicular surgery. CONCLUSION: Awareness of these benign tumours may allow for
      testicular preservation.

PMID- 15175779
TI  - A case of metastatic squamous cell carcinoma of the hypopharynx manifesting as
      acute abdomen.
AB  - INTRODUCTION: Squamous cell head and neck cancers are usually confined to local
      and regional sites but occasionally, patients may present with rare
      manifestations of distant metastases. CLINICAL PICTURE: A 23-year-old female was
      treated with concurrent chemo-radiotherapy for stage IVA post-cricoid squamous
      cell carcinoma. A month later, she presented with acute abdomen and was found to
      have extensive peritoneal nodules at laparotomy. Intestinal obstruction soon
      followed. TREATMENT: She was managed conservatively for the intestinal
      obstruction and given weekly paclitaxel. OUTCOME: She continued to deteriorate
      and succumbed shortly after the diagnosis of carcinomatosis peritoneii.
      CONCLUSION: This rare and aggressive presentation reminds us to be cognizant of
      relapsed head and neck cancers manifesting atypically, and the need for more
      aggressive search of distant disease in at least some subgroups of head and neck
      cancer.

PMID- 15175780
TI  - A rare case of porphyria.
AB  - INTRODUCTION: Congenital erythropoietic porphyria is one of the rare forms of an
      intriguing group of metabolic disorders known as porphyrias. Less than 200 cases
      have been reported in the literature. CLINICAL PRESENTATION: We report the case
      of a 27-year-old gentleman who had the clinical profile suggestive of porphyria,
      now presenting with anaemia. The type of porphyria was found to be congenital
      erythropoietic porphyria by biochemical assay and cause for anaemia was
      haemolysis, a well-known association with the erythropoietic porphyrias.
      TREATMENT: The management of porphyrias is essentially symptomatic. He was
      treated with blood transfusions and haematinics. CONCLUSION: The patient improved
      symptomatically and he is on regular followup. With the development of gene
      therapy, a specific cure for this rare type of porphyria is expected in the near
      future.

PMID- 15175781
TI  - Plantar dislocation of lateral tarsometatarsal joint: a case of subtle Lisfranc
      injury.
AB  - INTRODUCTION: We present a rare case of plantar dislocation of the cuboid, fourth
      and fifth metatarsal joints. Fracture-dislocation in the midfoot region may be
      subtle and difficult to recognise at the emergency department. CLINICAL PICTURE:
      A 16-year-old girl presented with lateral foot pain and swelling following a fall
      from a height of 3 m. Initial radiograph revealed a third metatarsal shaft
      fracture; however, additional views reviewed a plantar direction of fourth and
      fifth metatarsal dislocation from the cuboid. TREATMENT: Open reduction and
      internal fixation with Kirschner wires followed by immobilisation in plaster was
      performed. OUTCOME: She made an uneventful recovery and the wires had since been
      removed. CONCLUSION: This case was unusual in that there was lateral
      tarsometatarsal disruption with neither diastasis between the first and second
      metatarsals nor injury to either the first or second tarsometatarsal joints. The
      plantar direction of dislocation was also unusual as these injuries are usually
      dorsal.

PMID- 15175782
TI  - An unusual cause of pulmonary haemorrhage in a patient with rheumatoid arthritis.
AB  - INTRODUCTION: Pulmonary haemorrhage is a rare presentation of strongyloides
      hyperinfection. CLINICAL PICTURE: A 69-year-old female patient with rheumatoid
      arthritis on methotrexate and prednisolone presented with severe community
      acquired pneumonia. Intravenous trimethoprim/ sulfamethoxazole (bactrim) and high
      dose hydrocortisone for Pneumocystis carinii pneumonia were commenced. She
      developed pulmonary haemorrhage 2 weeks later and bronchoalveolar lavage cytology
      revealed helminthic larvae identified as strongyloides. TREATMENT AND OUTCOME:
      Despite treatment with ivermectin and albendazole with rapid tailing down of
      hydrocortisone, she succumbed to her illness. CONCLUSIONS: Strongyloides
      hyperinfection should be considered in an immunocompromised patient on high dose
      corticosteroid presenting with pulmonary haemorrhage. Prognosis remains dismal as
      supported by our case report and current literature.

PMID- 15175783
TI  - Supernumerary testicle in a case of polyorchidism.
AB  - INTRODUCTION: The presence of more than 2 testicles is called polyorchidism. It
      is a rare anomaly. Less than 100 cases have been reported in the literature.
      CLINICAL PICTURE: A 51-year-old man complained of a painless right groin lump for
      a year. Physical examination revealed a discrete ovoid non-tender, firm but
      mobile lump. No cough impulse was demonstrated. Sonography demonstrated a soft
      tissue structure within the tunica vaginalis inferior to the deep inguinal ring.
      It demonstrated similar echotexture and vascular flow as the normal testis, but
      smaller in size. The findings were compatible with a diagnosis of polyorchidism.
      TREATMENT: The patient was not keen for surgery and was followed up
      conservatively. CONCLUSION: Differential diagnosis of a solid extratesticular
      mass should include polyorchidism.

PMID- 15175784
TI  - A case of cystic leiomyoma mimicking an ovarian malignancy.
AB  - INTRODUCTION: We report an unusual case of a large cystic, pedunculated uterine
      leiomyoma mimicking a primary malignant ovarian tumour on sonography and computed
      tomography (CT). CLINICAL PICTURE: A 56-year-old post-menopausal woman presented
      with a right pelviabdominal mass. Sonography and CT examination showed a large
      extrauterine mass arising from the right adnexa and extending into the abdomen.
      The mass was predominantly cystic with a solid component at the periphery. A
      preoperative diagnosis of a primary malignant ovarian tumour was made. TREATMENT:
      The patient underwent laparotomy. The large mass was found to arise from the
      uterine fundus; the ovary was not involved. The mass was resected, followed by
      total hysterectomy and bilateral salpingo-oophorectomy. Histology was that of a
      leiomyoma with extensive cystic degeneration. OUTCOME: The patient made an
      uneventful recovery. CONCLUSION: A pedunculated, subserosal uterine leiomyoma
      with extensive cystic degeneration can mimic an ovarian tumour on imaging and
      should be considered in the differential diagnosis of an adnexal mass.

PMID- 15175785
TI  - Dapsone hypersensitivity syndrome masquerading as a viral exanthem: three cases
      and a mini-review.
AB  - INTRODUCTION: We report 3 cases of dapsone hypersensitivity syndrome due to anti
      malarial chemoprophylactic treatment with maloprim, in military servicemen,
      presenting like a viral exanthem. CLINICAL PICTURE: Three male military recruits
      presented with fever and rash, 6 to 8 weeks after commencing on weekly doses of
      maloprim. TREATMENT: A course of topical and systemic corticosteroids and oral
      antihistamines were started. OUTCOME: All cases showed gradual resolution of
      fever, rash and eventual normalisation of liver function test. CONCLUSION: A high
      index of suspicion was required before this uncommon syndrome can be recognised.
      Early institution of corticosteroid therapy and discontinuation of maloprim are
      the mainstays of treatment.

PMID- 15175786
TI  - Head and neck cancer after foreign body ingestion.
AB  - INTRODUCTION: Ingestion of a foreign body is a common occurrence in our
      population. We present 2 cases that illustrate an unusual outcome of an otherwise
      usual occurrence. CLINICAL PICTURE: Two patients who presented with a history of
      ingestion of fish bones were worked up. The radiological findings were suspicious
      of a foreign body and both underwent examination under general anaesthesia. The
      endoscopic findings were normal. After further evaluation for persistent
      calcifications with computed tomography, a thyroid malignancy was found in the
      first patient and tongue cancer in the second patient. TREATMENT: The first
      patient underwent elective hemithyroidectomy and the second underwent wide
      excision of the tumour with neck dissection. OUTCOME: Both recovered uneventfully
      with regular follow-up in the outpatient clinic. CONCLUSION: There should be a
      high index of suspicion in patients with persistent calcifications.

PMID- 15175787
TI  - A case of ductal carcinoma in situ of breast with Poland syndrome.
AB  - INTRODUCTION: A 51-year-old woman was diagnosed with a rare case of multi-focal
      ductal carcinoma in situ (DCIS) of the breast associated with Poland syndrome.
      CLINICAL PICTURE: Physical examination showed mild hypoplasia of the left breast
      with microcalcifications on mammogram. Intraoperatively, there was complete
      absence of the pectoralis major, which precluded the insertion of a breast
      implant. TREATMENT AND OUTCOME: She underwent a skin-sparing mastectomy and
      autologous microsurgical free flap reconstruction with deep inferior epigastric
      perforator (DIEP) flap. Postoperative recovery was uneventful with no evidence of
      recurrence at 6 months. CONCLUSION: This is the first reported case of DCIS of
      the breast with Poland syndrome. We performed a skin-sparing mastectomy with
      immediate DIEP flap recontruction. Patient recovered well postoperatively with no
      evidence of recurrence at 6 months.

PMID- 15175788
TI  - A case of right loin pain: septic ovarian vein thrombosis due to Campylobacter
      fetus bacteraemia.
AB  - INTRODUCTION: Septic ovarian venous thrombosis is an uncommon condition.
      Diagnosis is often not immediately apparent clinically and there are many that
      mimic this condition. We described an unusual case of septic ovarian vein
      thrombosis associated with Campylobacter fetus (C. fetus) bacteraemia. CLINICAL
      PICTURE: A 46-year-old female presented with fever and acute right loin pain.
      Right ovarian venous thrombosis was demonstrated on sonography and confirmed with
      computed tomography and magnetic resonance imaging. C. fetus was isolated from
      the blood. TREATMENT AND OUTCOME: The patient was given antibiotics and
      anticoagulation therapy with good response. CONCLUSION: Septic ovarian vein
      thrombosis should be considered as a differential diagnosis in female patients
      presenting with fever associated with lower abdominal pain. C. fetus bacteraemia
      also predisposes to thrombophlebitis, including septic ovarian vein thrombosis.
      When they are diagnosed in a timely manner and treated appropriately, the
      response is good and potential serious complications, including thromboembolism,
      and death could be averted. Radiological imaging is useful in the diagnostic work
      up of this condition.

PMID- 15175789
TI  - Refining clinical practice: transforming science research into the art of
      medicine.
AB  - This article traces the development of modern day breast cancer treatment from
      1896 when observations were made on the positive response of patients to
      oophorectomy. The oestrogen receptor was defined and tamoxifen was discovered to
      be an effective anti-oestrogen. The genes related to breast cancer, BRCA1 and
      BRCA2, were found to confer high risks of breast and ovarian cancer on women with
      these genes. The application of functional genomics to breast tumours would
      result in a more accurate classification of cancers and hopefully more specific
      therapy and better clinical outcomes. An important off-shoot of anti-oestrogen
      research has resulted in a new class of drugs called selective oestrogen receptor
      modulators for treatment of osteoporosis and dyslipidemia.

PMID- 15175790
TI  - Low density lipoprotein receptor-related protein: regulation of the plasma
      membrane proteome.
AB  - Proteins in the plasma membrane anchor the cell within its microenvironment and
      sense changes occurring outside the cell. The anchoring interactions are cell
      type-specific and may involve adjacent cells or extracellular matrix proteins
      (ECMPs). In development, wound healing, and in various forms of pathology,
      including thrombosis and atherosclerosis, the microenvironment of the cell may
      change rapidly and dramatically. How the cell responds is strongly dependent on
      the protein composition of its plasma membrane, which we refer to as the plasma
      membrane proteome. Processes that regulate the plasma membrane proteome may alter
      cellular response. Low density lipoprotein receptor-related protein-1 (LRP-1) is
      a member of the LDL receptor family; however, LRP-1 and other less well studied
      members of this gene family demonstrate multiple activities unrelated to lipid
      homeostasis. LRP-1 binds and internalizes numerous, structurally diverse ligands,
      delivering most but not all these ligands to lysosomes for degradation. The
      intracellular tail of LRP-1 binds signaling adaptor proteins and thus may
      function in cell signaling. Biological activities of LRP-1 include antigen
      presentation, phagocytosis, removal of apoptotic cells, and regulation of
      vascular permeability. This review focuses on an emerging view of LRP-1 activity,
      in which LRP-1 regulates the protein composition of the plasma membrane and
      thereby "models" or "landscapes" the cell surface. In some cases, plasma membrane
      modeling results from the binding to bifunctional ligands or intracellular
      adaptor proteins, so that LRP-1 is bridged to another plasma membrane protein and
      the entire complex undergoes endocytosis. Membrane proteins already known to be
      subject to this form of regulation include urokinase-type plasminogen activator
      receptor, amyloid precursor protein, tissue factor, and alpha(V)-containing
      integrins. LRP-1 also controls the plasma membrane proteome by regulating
      maturation and transport of proteins in the secretory pathway. At the same time,
      LRP-1 serves as a receptor for specific ECMPs, including fibronectin and
      thrombospondin. Although ECMP-binding to LRP-1 results in endocytosis and
      catabolism, these receptor-ligation events also may be coupled, directly or
      indirectly, to cell-signaling. Based on these novel activities, LRP-1 emerges as
      a protein capable of modeling the interface of the cell with its
      microenvironment.

PMID- 15175791
TI  - New nonlipid effects of statins and their clinical relevance in cardiovascular
      disease.
AB  - Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins,
      have been demonstrated to reduce cardiovascular morbidity and mortality in
      patients with a wide range of cholesterol levels. Numerous cholesterol
      independent effects of statins that may limit atherosclerosis are probably
      related to inhibition of the geranylgeranylation of GTP-binding intracellular
      signaling proteins and involve: improved vasoreactivity, mostly through increased
      NO bioavailability; decreased expression of proinflammatory cytokines
      (interleukin-6, interleukin-1 beta, tumor necrosis factor alpha), C-reactive
      protein, chemokines, matrix metalloproteinases, and tissue factor with the
      subsequent inhibition of thrombin generation; reduced platelet activity;
      increased thrombomodulin expression; enhanced fibrinolysis, regulation of
      angiogenesis and immunomodulation. However, the clinical relevance of multiple
      protective effects induced by statins has not been clarified yet.

PMID- 15175792
TI  - Therapeutic effect of diagnostic ultrasound on enzymatic thrombolysis. An in
      vitro study on blood of normal subjects and patients with coronary artery
      disease.
AB  - If delivered at elevated intensity, ultrasound potentiates enzymatic clot
      dissolution; however, an elevated acoustic intensity damages vascular wall and
      favors reocclusion. This study's aim was to investigate whether exposure to high
      frequency, low-intensity ultrasound - generated by a diagnostic scanner -enhances
      enzymatic thrombolysis, and if this effect differs in clots from blood of normal
      subjects and of patients with coronary artery disease (CAD). Venous blood samples
      were drawn from 10 healthy volunteers and from 10 CAD patients on chronic medical
      treatment, which also included aspirin. Each sample generated 2 radiolabelled
      clots, which were positioned in 2 in vitro models filled with human plasma
      recirculating at 37 degrees. One clot was exposed to acetyl salicylic acid (60
      microg/ml), tissue plasminogen activator (3 microg/ml) and heparin (1 IU/ml),
      while the other was exposed to the same medications plus ultra-sound (2.5 MHz,
      mechanical index = 1.0) for 3 hours. Enzymatic thrombolysis was measured as
      solubilization of radiolabel. Normal subjects and patients did not significantly
      differ as to coagulation parameters, weight, volume and density of the clots, and
      fibrinolytic activity (p = 0.794). Ultrasound exposure did not influence
      thrombolysis in clots of normal subjects (p = 0.367), while it enhanced the
      dissolution of clots of CAD patients (p = 0.013). The enhancement was equal to
      51% at 5 minutes, 32% at 15 minutes, 27% at 30 minutes, 20% at 1 hour and 19% at
      3 hours (p < 0.05). Diagnostic ultrasound enhances enzymatic dissolution of clots
      generated from the blood of CAD patients, likely due to chronic treatment and in
      particular to aspirin.

PMID- 15175793
TI  - Comparison between ticlopidine and clopidogrel in patients with ST-segment
      elevation myocardial infarction treated with coronary stenting.
AB  - Controversy still surrounds the question, which antiplatelet drug should be added
      to aspirin in patients undergoing coronary stent implantation. The aim of the
      current study was to compare ticlopidine and clopidogrel in a consecutive series
      of patients with ST-segment elevation myocardial infarction (STEMI) treated with
      primary stenting. Our population is represented by 883 consecutive patients with
      STEMI undergoing primary stenting from April 1997 to October 2001. All clinical,
      angiographic, and follow-up data were prospectively collected. A total of 523
      patients on clopidogrel were compared with 360 patients on ticlopidine after
      primary stenting. Except for age and statin therapy, no difference in demographic
      and clinical characteristics was observed between the two groups. Patients on
      clopidogrel had a higher rate of successful reperfusion (80.7% vs 73.1%, p =
      0.008). No difference was observed between the two groups at both 30-day and 1
      year follow-up. These data were confirmed after correction for age, successful
      reperfusion and statin therapy. This study shows no difference in long-term
      clinical outcome between clopidogrel and ticlopidine as adjunctive antiplatelet
      therapy in patients with STEMI undergoing stent implantation.

PMID- 15175794
TI  - Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin
      generation and platelet activation in healthy volunteers.
AB  - The objectives were to investigate whether activation of the extrinsic
      coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition
      of thrombin generation and platelet activation by melagatran, the active form of
      the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized,
      parallel-group study, volunteers (20 per group) received a 5-hour intravenous
      (i.v.) infusion to achieve steady-state melagatran plasma concentrations of
      approximately 0.5 micromol/L, with a single i.v. bolus of rFVIIa (90 microg/kg)
      or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin
      complex, fibrinopeptide A, beta-thromboglobulin, and thrombin-activatable
      fibrinolysis inhibitor were quantified for venous and shed blood. Activated
      partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin
      potential, thrombus precursor protein (TpP), and plasmin-alpha(2)-antiplasmin
      complex concentrations were determined in venous blood. Shed blood volume was
      measured. Melagatran reduced markers of thrombin generation and platelet
      activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT,
      and TpP in venous blood. All other parameters were unaffected. In conclusion,
      rFVIIa did not reverse the anticoagulant effects of high constant concentrations
      of melagatran. However, the potential value of higher, continuous or repeated
      doses of rFVIIa or its use with lower melagatran concentrations has not been
      excluded.

PMID- 15175795
TI  - The effects of long-term diet and omega-3 fatty acid supplementation on
      coagulation factor VII and serum phospholipids with special emphasis on the R353Q
      polymorphism of the FVII gene.
AB  - The aim of the present study was to investigate the effect of long-term diet and
      very long chain n-3 fatty acids (VLC n-3) intervention on plasma coagulation
      factor VII (FVII), choline-containing phospholipids (PC) and triglycerides (TG),
      especially related to the R353Q polymorphism of the FVII gene. The present
      investigation included 219 subjects from the Diet and Omega-3 Intervention Trial
      on atherosclerosis (DOIT), a 2x2 factorial designed study in elderly men with
      long-standing hypercholesterolemia. The subjects were randomly allocated to
      receive placebo capsules (corn oil) (control), placebo capsules and dietary
      advice ("Mediterranean type" diet), VLC n-3 capsules, or VLC n-3 capsules and
      dietary advice combined. The R353Q genotype and the levels of FVIIc, FVIIag,
      FVIIa, PC, and TG at baseline and after 6 months were determined. Diet
      intervention was followed by a significant reduction of 5.1% in the levels of
      FVIIag and 2.4 mU/ml in FVIIa (95% CI -7.4, -2.9, and -3.8, -1.1, respectively)
      (both p<0.001) compared to the no diet group, independent of genotype. No effects
      of diet intervention on FVIIc, PC or TG were observed. After VLC n-3
      supplementation the TG levels were significantly reduced compared to placebo
      (p=0.01), whereas all FVII levels and PC remained unchanged. Dietary advice
      towards a "Mediterranean type" diet, but not VLC n-3 supplementation, was shown
      to reduce the levels of FVIIag and FVIIa after 6 months, independent of genotype.
      The results indicate the dietary advice to be more favourable in reducing this
      risk factor for CVD as compared to specific VLC n-3 supplementation.

PMID- 15175796
TI  - The Ser460Pro mutation in recombinant protein S Heerlen does not affect its APC
      cofactor and APC-independent anticoagulant activities.
AB  - Protein S is a vitamin K-dependent plasma protein that functions as an APC
      cofactor, but also exhibits anticoagulant activity in the absence of APC. The
      Heerlen polymorphism of protein S is characterized by a Ser460Pro substitution
      and lacks glycosylation at Asn458. It is associated with decreased protein S
      levels due to selective deficiency of free protein S Heerlen. To understand the
      lack of thrombotic complications associated with the protein S Heerlen mutation,
      we compared recombinant protein S Heerlen, wild type (wt) protein S and plasma
      derived protein S. wt-Protein S and protein S Heerlen each bound 1:1 to C4BP with
      dissociation constants of 0.27 and 0.33 nM, respectively. Both wt-protein S and
      protein S Heerlen, either free or in complex with C4BP, were equally active as
      prothrombinase inhibitors in the absence of APC. All three protein S preparations
      stimulated APC-catalyzed inactivation of normal FVa, FVa Leiden and FVIIIa to the
      same extent. If extrapolated to plasma, it is not likely that the decreased free
      protein S levels in carriers of the protein S Heerlen mutation are compensated by
      an increased anticoagulant activity of protein S Heerlen-C4BP complexes. It is
      possible that an unrecognized plasma factor selectively enhances the
      anticoagulant activity of protein S Heerlen. If not, the reduction of free
      protein S levels in heterozygous protein S Heerlen-carriers combined with (low)
      normal total protein S levels apparently minimally affects the total
      anticoagulant activity of protein S (APC-cofactor and APC-independent activity)
      and hence is not associated with increased risk of venous thrombosis.

PMID- 15175797
TI  - Plasma homocysteine concentration is not associated with activated protein C
      resistance in patients investigated for hypercoagulability.
AB  - Homocysteine and activated protein C (aPC) resistance are known risk factors for
      thromboembolism, but how elevated homocysteine influences thrombogenicity is not
      fully understood. The possibility that homocysteine may exert a pro-thrombotic
      effect by inducing aPC resistance has been addressed, with conflicting
      conclusions. The aim of this study is to evaluate the possible relationship of
      serum homocysteine concentration to aPC resistance in a cohort of patients
      investigated for hypercoagulability. Laboratory records from 1011 consecutive
      patients referred to the Haemostasis Laboratory at the Health Sciences Centre
      (Winnipeg, Canada) were reviewed from February 1997 to November 2002.
      Homocysteine levels, normalized aPC sensitivity ratio (aPC-SR), and Factor V
      Leiden genotype were recorded for all 1011 patients. 394 patients had aPC-SR
      determined by mixing the patient plasma in 4 parts FV deficient plasma (FV
      deficient-mix assay), and 617 patients had aPC-SR calculated without mixing (neat
      assay). Homocysteine did not significantly influence the aPC-SR when using the FV
      deficient assay. When aPC-SR was measured using the neat assay, homocysteine was
      found to correlate inversely with the degree of aPC resistance. The mean aPC-SR
      of FV Leiden-negative subjects measured using the neat assay was substantially
      lower than the expected normalized value of 1.0 that was obtained when aPC-SR was
      measured with the FV-deficient-mix assay. aPC resistance is common in patients
      being evaluated for possible hypercoagulability. In these patients, elevated
      plasma homocysteine levels is not associated with aPC resistance regardless of FV
      Leiden genotype suggesting that this is not the mechanism by which homocysteine
      exerts a prothrombotic effect.

PMID- 15175798
TI  - Warfarin dosing and cytochrome P450 2C9 polymorphisms.
AB  - Two cytochrome P450 2C9 (CYP2C9) polymorphisms, CYP2C9*2 and *3, metabolize
      warfarin inefficiently. We assessed the extent to which these polymorphisms
      explain very low warfarin dose requirements and hemorrhagic complications after
      excluding non-genetic determinants of warfarin dosing. In this retrospective
      observational study, 73 patients with stable warfarin doses for > or =1 month and
      International Normalized Ratios (INR) of 2.0-3.0 were enrolled from our
      Anticoagulation Clinic. Seventeen patients required < or =2 mg (low-dose), 41
      required 4-6 mg (moderate-dose), and 15 required > or =10 mg (high-dose) of daily
      warfarin. CYP2C9 genotyping was assessed by PCR amplification and restriction
      enzyme digestion analysis of DNA isolated from circulating leukocytes. The CYP2C9
      polymorphisms independently predicted low warfarin requirements after adjusting
      for Body Mass Index, age, acetaminophen use, and race (OR 24.80; 95% CI 3.83
      160.78). At least one polymorphism was present in every patient requiring < or
      =1.5 mg of daily warfarin, and 88%, 37%, and 7% of the low-, moderate-, and high
      dose groups, respectively. All homozygotes and compound-heterozygotes for the
      variant alleles were in the low-dose group. Rates of excessive (INR>6.0)
      anticoagulation (and bleeding) were 4.5 (6.0), 7.9 (7.9), and 14.7 (0) per 100
      patient-years in the wild-types, heterozygotes, and compound
      heterozygotes/homozygotes, respectively. In conclusion, CYP2C9*2 or *3 compound
      heterozygotes and homozygotes have low warfarin requirements even after excluding
      liver disease, excessive alcohol or acetaminophen consumption, low body weight,
      advancing age, and drug interactions. These polymorphisms increase the rate of
      excessive anticoagulation, but this risk does not appear to be associated with
      higher bleeding rates when anticoagulation status is closely monitored.

PMID- 15175799
TI  - Levels of annexin IV and V in the plasma of pregnant and postpartum women.
AB  - Annexin (Anx) V is pivotal in the maintenance of pregnancy by preventing the
      activation of blood coagulation. The homology of the amino acid sequence between
      Anx IV and Anx V is highest in Anx family proteins. However, little is known
      about the roles of Anx IV in pregnancy. The aim of this study is to clarify the
      roles of circulating Anx IV and Anx V in normal pregnancy. Subjects were non
      pregnant women (n = 50), 120 pregnant women, and maternal subjects just after
      delivery (n = 53) or postpartum (n = 67). Anx IV in the plasma of non-pregnant
      women was at a concentration 20 times that of Anx V. The plasma levels of Anx IV
      suddenly increase after delivery, but Anx V levels remain low during this period.
      Anx IV and Anx V exert similar levels of anticoagulant activity. Anx IV protein
      was expressed on the basal surface of syncytiotrophoblasts; Anx V protein, on the
      apical surface of syncytiotrophoblasts. These results suggest that Anx IV enters
      the maternal bloodstream just after delivery and might play a role in preventing
      disseminated intravascular coagulopathy, and that Anx V helps to prevent clotting
      in the placenta during pregnancy.

PMID- 15175800
TI  - Transition from argatroban to oral anticoagulation with phenprocoumon or
      acenocoumarol: effects on prothrombin time, activated partial thromboplastin
      time, and Ecarin Clotting Time.
AB  - Treatment with the direct thrombin inhibitor argatroban (ARG) is often followed
      by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol
      (AC) are frequently used in Europe. The standard monitoring test for VKA, pro
      thrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the
      International Normalized Ratio (INR) obtained during combined treatment does not
      reflect the true effect of the VKA. A similar interference of the VKA on the
      activated partial thromboplastin time (aPTT), a monitoring assay for direct
      thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone
      or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was
      investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of
      either 1.0, 2.0 or 3.0 microg/kg/min ARG (days 1, 3, 4 and 5) before initiation
      of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A
      linear relationship (INR(ARG+VKA) = intercept + slope * INR (VKA alone)) was
      observed between the INR measured "on" and "off" ARG. The slope depended on the
      argatroban dose and on the International Sensitivity Index (ISI) of the PT
      reagent, the steepest slope (i.e., the largest difference between INR (ARG+VKA)
      and INR (VKA alone)) was seen with the highest ARG dose and the PT reagent with
      an ISI of 2.13. There was a close correlation between plasma levels of ARG and
      aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased
      sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation
      of the ECT induced by argatroban. In conclusion, ARG at doses up to 2
      microg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA,
      as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is
      necessary to monitor ARG in the critical transition period, the ECT which is not
      influenced by VKA can be used as an alternative to the aPTT.

PMID- 15175801
TI  - Admission fibrinolytic profile predicts clot lysis resistance in stroke patients
      treated with tissue plasminogen activator.
AB  - Endogenous fibrinolysis inhibitors may be involved in t-PA resistance, decreasing
      stroke thrombolysis benefits. We aim to determine the impact of pretreatment
      levels of plasminogen activator inhibitor (PAI-1), lipoprotein(a), thrombin
      activatable fibrinolysis inhibitor (TAFI) and homocysteine on arterial
      recanalization and outcome. Forty-four consecutive patients with acute proximal
      middle cerebral artery occlusion were studied, including assessment of
      transcranial Doppler artery patency. The neurological status was determined by
      NIH Stroke Scale (NIHSS) and long-term outcome with modified Rankin Scale (mRS).
      Patients who recanalized after t-PA infusion had lower PAI-1 levels than those
      who remained occluded. Similarly, patients who achieved dramatic clinical
      recovery at 12 hours exhibited significantly lower PAI-1 levels as those
      independent (mRS< or =2) at third month. We observed a trend towards lower
      lipoprotein p(a) in patients who achieved recanalization at 1 hour, whereas no
      relation was found between TAFI or homo-cysteine levels and recanalization. After
      a regression model was applied the only independent predictor of thrombolysis
      resistance was baseline PAI-1>34 ng/ml, such that high PAI-1 levels interfere
      with tPA-induced recanalization in stroke, predicting a higher susceptibility
      towards clot-lysis resistance and poor out-come.

PMID- 15175802
TI  - Erythrocyte sodium/lithium countertransport is associated with thrombotic and
      fibrinolytic factors in 58-year-old men.
AB  - The metabolic syndrome, in which insulin resistance is the core feature, is
      associated both with dysregulation of thrombosis/fibrinolysis and erythrocyte
      sodium/lithium countertransport (SLC). To investigate this further we designed a
      cross-sectional study to examine whether factors involved in coagulation- and
      fibrinolysis systems were associated with SLC independently of insulin resistance
      in 93 58-year-old men. SLC was in univariate analysis positively correlated with
      PAI-1 activity (r = 0.35, p <0.01), tPA antigen (r = 0.38, p <0.01), von
      Willebrand factor (r = 0.25, p <0.05), protein S (r = 0.26, p <0.05), and C (r =
      0.30, p <0.01), and negatively associated with tPA activity(r = -0.28, p <0.01).
      Since these correlations could be influenced by the components of the metabolic
      syndrome itself, a separate analysis with adjustment for glucose infusion rate
      (GIR), plasma insulin, body fat, sagittal diameter of the abdomen (SD) and log
      serum triglyceride concentration (TG) was conducted. Then SLC was associated with
      tPA antigen independent of GIR, plasma insulin, body fat, SD and TG. SLC was also
      associated with protein C independent of GIR, insulin, body fat and SD but not
      TG. In conclusion, we found a relationship between SLC and the fibrinolytic
      system that was not related to the metabolic syndrome.

PMID- 15175803
TI  - Interaction of platelets with liposomes containing dodecapeptide sequence from
      fibrinogen.
AB  - Liposomes with a covalently bound synthetic peptide containing the dodecapeptide
      sequence HHLGGAKQAGDV, the putative platelet interaction site at gamma(400-411)
      of fibrinogen (dodecapeptide-liposomes), were prepared. These liposomes enhanced
      platelet aggregation and specifically adhered to platelets activated on the
      collagen surface. Dodecapeptide-liposomes released encapsulated materials upon
      interacting with platelets activated on the collagen surface. The rate of content
      release was dependent on the peptide surface density, indicating that the
      interaction between the dodecapeptide-liposomes and platelets activated on the
      collagen surface induces clustering of the surface-coupled ligands at the binding
      site on the receptor matrix to facilitate release of the internal contents
      through the liposome membranes. The level of lipid mixing between the
      dodecapeptide-liposomes and platelets activated on the collagen surface was
      relatively low, however it was increased in liposome preparations containing octa
      arginine, the (R)8 GDV sequence, while content release was maintained at the same
      level as that of the dodecapeptide-liposomes. The level of content release and
      lipid mixing for liposome preparations containing the RGD sequence as a ligand
      (RGD-liposomes) upon interacting with platelets activated on the collagen surface
      was extremely low. Both the level of the content release and lipid mixing,
      however, were enhanced in liposome preparations containing octa-arginine, the
      (R)8 RGD sequence. Dodecapeptide-liposomes and RGD-liposomes were not
      internalized by activated platelets. On the other hand, liposomes containing (R)8
      PPQ, (R)8 RGD, or (R)8 GDV were internalized by activated platelets, and the
      extent of internalization was inversely related to ligand affinity to the target.

PMID- 15175804
TI  - GPIb is involved in platelet aggregation induced by mucetin, a snake C-type
      lectin protein from Chinese habu (Trimeresurus mucrosquamatus) venom.
AB  - Mucetin (Trimeresurus mucrosquamatus venom activator, TMVA) is a potent platelet
      activator purified from Chinese habu (Trimeresurus mucrosquamatus) venom. It
      belongs to the snake venom heterodimeric C-type lectin family and exists in
      several multimeric forms. We now show that binding to platelet glycoprotein (GP)
      Ib is involved in mucetin-induced platelet aggregation. Antibodies against GPIb
      as well as the GPIb-blocking C-type lectin echicetin inhibited mucetin-induced
      platelet aggregation. Binding of GPIb was confirmed by affinity chromatography
      and Western blotting. Antibodies against GPVI inhibited convulxin- but not
      mucetin-induced aggregation. Signalling by mucetin involved rapid tyrosine
      phosphorylation of a number of proteins including Syk, Src, LAT and PLC gamma 2.
      Mucetin-induced phosphorylation of the Fc gamma chain of platelet was greatly
      promoted by inhibition of alpha(IIb)beta(3) by the peptidomimetic EMD 132338,
      suggesting that phosphatases downstream of alpha(IIb)beta(3) activation are
      involved in dephosphorylation of Fc gamma. Unlike other multimeric snake C-type
      lectins that act via GPIb and only agglutinate platelets, mucetin activates
      alpha(IIb)beta(3). Inhibition of alpha(IIb)beta(3) strongly reduced the
      aggregation response to mucetin, indicating that activation of alpha(IIb)beta(3)
      and binding of fibrinogen are involved in mucetin-induced platelet aggregation.
      Apyrase and aspirin also inhibit platelet aggregation induced by mucetin,
      suggesting that ADP and thromboxane A2 are involved in autocrine feedback.
      Sequence and structural comparison with closely related members of this protein
      family point to features that may be responsible for the functional differences.

PMID- 15175805
TI  - Triflamp, a snake venom metalloproteinase, reduces neutrophil-platelet adhesion
      through proteolysis of PSGL-1 but not glycoprotein Ib alpha.
AB  - Triflamp, a metalloproteinase isolated from Trimeresurus flavo-viridis, inhibits
      heterotypic adhesion between platelets and neutrophils. Coincubation studies
      demonstrate that direct interaction of triflamp with neutrophils is sufficient to
      inhibit the formation of neutrophil-platelet complexes. Its anti-adhesive effect
      is in a concentration- and incubation time-dependent manner. Triflamp reduces the
      expression of P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils and
      glycoprotein (GP) Ibalpha on platelets as probed by flow cytometry and Western
      blot. Moreover, triflamp disrupts P-selectin-mediated adhesion by cleaving PSGL-1
      from the neutrophil surface. There are obvious differences regarding PSGL-1
      proteolysis by triflamp and cathepsin G. Besides the NH2-terminus of PSGL-1,
      other sites are truncated by triflamp. The inhibitory effect of triflamp on PSGL
      1 expression was prevented by pretreatment with a metalloproteinase inhibitor,
      phenanthroline. However, triflamp-treated platelets fully keep the ability for
      binding to PAF- or fMLP-stimulated neutrophils. Our results indicate that
      degradation of platelet GPIb alpha by triflamp does not interfere with neutrophil
      platelet adhesion. Its effect on neutrophil PSGL-1 appears to be a critical
      factor for its inhibition on neutrophil-platelet interaction.

PMID- 15175806
TI  - Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions
      with recombinant P-selectin glycoprotein ligand-1.
AB  - The binding of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) to platelet P
      selectin is central to post-angioplasty restenosis. Although intracoronary stents
      limit the mechanical component of restenosis, they cause marked thrombo
      inflammation and neointimal proliferation leading to greater late luminal loss.
      We sought to demonstrate that P-selectin antagonism, using recombinant PSGL-1
      (rPSGL-Ig), is effective in reducing platelet-leukocyte reactions and in-stent
      restenosis in double-injured porcine coronary arteries. Two weeks after initial
      injury by angioplasty to the coronary arteries, stents were implanted at the
      injury-induced lesion site, 15 min after an i.v. bolus administration of a
      vehicle or rPSGL-Ig (1 mg/kg). Four weeks later, adhesion of (51)Cr-platelets and
      (111)In-neutrophils and histomorphometric analyses were performed. In-stent
      residual lumen was almost 3 fold larger in rPSGL-Ig-treated arteries (3.1 +/- 0.4
      mm(2)) as compared to control (1.1 +/- 0.2 mm(2)), which correspond to 64%
      vascular stenosis in control with no change in rPSGL-Ig animals. For a similar
      injury score, in-stent neointima was significantly reduced by 30 to 40% in the
      rPSGL-Ig group and quantitative coronary angiography showed a significant 35%
      reduction in late lumen loss. These effects of rPSGL-Ig were associated with a
      respective 70% and 53% reduction in platelet and neutrophil adhesion. In
      conclusion, pretreatment with rPSGL-Ig reduces thrombo-inflammatory responses,
      neointimal proliferation, and in-stent restenosis. P-selectin antagonism offers a
      promising therapy to improve clinical outcomes of coronary stenting.

PMID- 15175807
TI  - Protective role of interleukin-6 in coagulatory and hemostatic disturbance
      induced by lipopolysaccharide in mice.
AB  - Although the role of interleukin (IL)-6 in inflammatory diseases has been
      previously examined, its role in hemostasis, fibrinolysis, and coagulation during
      inflammation remains to be established. The present study elucidated the role of
      IL-6 in hemostatic and coagulatory changes during severe inflammation induced by
      intraperitoneal administration of lipopolysaccharide (LPS: 1 mg/kg) using IL-6
      null (-/-) mice. After LPS challenge, IL-6 (-/-) mice revealed significant
      prolongation of prothrombin time and activated partial thromboplastin time and a
      significant decrease in platelet counts as compared with wild type mice. LPS
      treatment induced marked pulmonary hemorrhage with neutrophilic inflammation in
      IL-6 (-/-) mice, in contrast, only mild neutrophilic infiltration in WT mice
      confirmed by macroscopic and histological findings. The protein levels of
      proinflammatory mediators, such as IL-1 beta, macrophage inflammatory protein
      (MIP)-1 alpha, MIP-2, macrophage chemoattractant protein-1,
      granulocyte/macrophage-colony-stimulating factor, and keratinocyte
      chemoattractant in the lungs were significantly greater in IL-6 (-/-) mice than
      in WT mice after LPS challenge. These results directly indicate that IL-6 is
      protective against coagulatory and hemostatic disturbance and subsequent
      pulmonary hemorrhage induced by bacterial endotoxin, at least partly, via the
      modulation of proinflammatory processes.

PMID- 15175808
TI  - Enhancement of neovascularization with cord blood CD133+ cell-derived endothelial
      progenitor cell transplantation.
AB  - The endothelial progenitor cells (EPCs) are responsible for postnatal
      vasculogenesis in physiological and pathological neovascularization and have been
      used for attenuating ischemic diseases. However, EPCs from umbilical cord blood
      (CB) were not well understood and the homing mechanisms of EPCs remain unclear.
      To determine the potential application of CB-derived EPCs, we established a
      culture system to induce the differentiation of CB cells into EPCs. Purified CB
      CD133(+) cells proliferated and, after further vascular endothelial growth factor
      receptor 2 (VEGFR-2) antibody purification, differentiated into EPCs expressing
      endothelial markers, such as VE-cadherin, VEGFR-2, CD31, von Willebrand factor
      (vWF) and Weibel-Palade bodies. These cells could also take up acetylated lower
      density lipoprotein (Ac-LDL) and bind Ulex europaeus agglutinin-1 (UEA-1). When
      expanded EPCs were transplanted via tail vein into nude mice, they incorporated
      into capillary networks in ischemic hindlimb, augmented neovascularization, and
      improved ischemic limb salvage. In addition, in ischemic tissue, there were
      elevated expressions of VEGF and stromal derived factor 1 alpha (SDF-1 alpha),
      both of which had chemotactic effect on EPCs. Moreover, P-/E-selectins was found
      on mouse ischemic endothelium and P-selectin glycoprotein ligand-1 (PSGL-1) on CB
      derived EPCs. Neutralizing antibody against PSGL-1 blocked the homing of EPCs to
      ischemic area by 61%. These results demonstrate that CB CD133(+) cell-derived
      EPCs can be applied for therapeutic neovascularization in ischemic diseases, and
      reveal important roles of chemoattractants and adhesive molecules in the homing
      of EPCs.

PMID- 15175809
TI  - Encapsulation of a plasminogen activator speeds reperfusion, lessens infarct and
      reduces blood loss in a canine model of coronary artery thrombosis.
AB  - In the present study, a polymer-encapsulated plasminogen activator was
      investigated as an alternative to restore blood flow more effectively than free
      plasminogen activator. While current fibrinolytic agents have limited efficacy,
      attributable to delayed onset of sustained reperfusion and bleeding
      complications, encapsulated plasminogen activators have shown promise in
      addressing these shortcomings. A polymer-encapsulated plasminogen activator could
      offer an effective formulation with a prolonged shelf-life. In this study,
      coronary artery thrombosis was produced in the anesthetized dog by the injection
      of thrombin + whole blood, and then one of five randomly selected formulations
      was administered intravenously: saline, blank microcapsules, free streptokinase
      (FREE SK), streptokinase and blank microcapsules (FREE SK + BLANK), or
      streptokinase entrapped in polymer microcapsules (MESK). MESK significantly
      accelerated the time to reperfusion compared to FREE SK or FREE SK + BLANK.
      Additionally, substantial reductions were observed in residual clot mass, infarct
      mass, reocclusion episodes, fibrinogen depletion and blood loss with MESK
      compared to FREE SK. The results of this study demonstrate that MESK accelerates
      thrombolysis and the restoration of blood flow compared to identical dosages of
      FREE SK while also reducing systemic fibrinogenolysis and blood loss.
      Microencapsulation may produce an improved dosage form for restoring arterial
      blood flow and reducing bleeding complications with thrombolytic therapy.

PMID- 15175810
TI  - In proven deep vein thrombosis, a low positive D-Dimer score is a strong negative
      predictor for associated malignancy.
AB  - D-Dimer measurements are being increasingly used for negative prediction of deep
      vein thrombosis (DVT). At our institution, clinical score, D-Dimer assay,
      plethysmography and, if necessary, Doppler ultrasound are used to secure the
      diagnosis. We collected the data from 100 consecutive patients proven to have
      DVT. We examined their medical case notes at diagnosis for concurrent clinical
      conditions and one year later to look for documented evidence of malignancy.
      Twenty-two of the 66 patients with D-Dimers greater than 1000 ng/ml were
      diagnosed with a cancer compared with only 2 of the 34 patients with a presenting
      D-Dimer score of less than 1000 ng/ml. We propose that a D-Dimer score of less
      than 1000 ng/ml in proven DVT is a strong negative predictor for malignancy (p =
      0.0025).

PMID- 15175811
TI  - INR calibration of Owren-type prothrombin time based on the relationship between
      PT% and INR utilizing normal plasma samples.
AB  - Prothrombin time (PT) is clinically important and is used to monitor oral
      anticoagulant therapy. To obtain PT results in international normalized ratio
      (INR), the current standardization procedure is complex and involves reference
      reagents. The PT of diluted plasma samples can be determined with a combined
      thromboplastin (the Owren-type procedure), but not necessarily with a plain
      thromboplastin (the Quick-type procedure). Owren-type PT procedures can
      therefore, as an alternative to the INR calibration, be calibrated with diluted
      normal plasma to give PT results in percent of normal PT activity (PT%). The
      present study explored if a plasma-based calibration of an Owren-type PT
      procedure can be used to obtain results in INR. The approach was to establish a
      relationship between PT% and INR by multi-center analysis of 365 samples from
      healthy individuals and patients on warfarin treatment. INR values were obtained
      by manual Quick-type reference procedure and PT% values by various automated
      Owren-type procedures. A relationship INR = (1/PT% + 0.018)/0.028 was found. A
      calibration procedure, based on the relationship, was investigated. Calibrators
      were the median PT of 21 normal plasma at dilutions representing 100%, 50%, 25%,
      12.5% and 6.25% of normal PT activity. These were assigned INR values of 1.00,
      1.36, 2.07, 3.05 and 6.36. Calibration of various Owren-type assays was
      repeatedly performed by 5 expert laboratories during 3 consecutive years. The INR
      values of certain lyophilised or frozen control plasmas were determined. The
      frozen control plasmas had externally assigned INR values according to WHO guide
      lines. Within the laboratory, CV was typically below 3%. No appreciable
      difference among the results of the different laboratories or the three assay
      occasions was found. Externally assigned and INR values were essentially
      identical to those found. These and other results indicated that the calibration
      procedure was reproducible, precise and accurate. Thus, an Owren-type PT assay
      can be calibrated with normal plasma samples to give results in INR and the
      investigated calibration procedure can be proposed for this purpose.

PMID- 15175812
TI  - Validation of a risk score identifying patients with acute pulmonary embolism,
      who are at low risk of clinical adverse outcome.
AB  - A clinical predictive model that accurately identifies patients with pulmonary
      embolism who are at low risk of adverse medical outcomes may be useful for
      management decisions, such as outpatient treatment. We aimed to externally
      validate a previously derived prognostic score identifying emergency ward
      patients with acute pulmonary embolism at low risk of 3-month complications. One
      hundred and ninety-nine consecutive patients with proven pulmonary embolism were
      included from the emergency centres of three teaching and general hospitals.
      Adverse outcomes, such as death, major bleed, or recurrent venous
      thromboembolism, were recorded during a 3-month follow-up. We retrospectively
      computed the prognostic score for each patient and determined its predictive
      accuracy at different threshold values. The overall 3-month risk of adverse event
      after the diagnosis of pulmonary embolism was 9.5%. At a threshold of 2 points,
      eight patients with scores at or below the cut-off (5%; 95% CI 2.6-9.6) and 11
      patients with scores above this cut-off (27.5%; 95% CI 16.1-42.8) presented a
      complication. The negative predictive value for an adverse out-come was 95.0%
      (95% CI 90.4-97.4). The receiver operating characteristic curve derived from the
      score distribution had an area of 0.77 (95% CI 0.65-0.89). This compared
      favourably with the characteristics of the derivation study. We conclude that the
      Geneva risk score has an acceptable predictive accuracy to identify patients with
      pulmonary embolism at low risk for 3-month adverse outcomes. Whether this score
      remains accurate and useful in clinical practice should be determined in a
      prospective multicentre validation study.

PMID- 15175813
TI  - Rapid D-dimer test combined a clinical model for deep vein thrombosis. Validation
      with ultrasonography and clinical follow-up in 383 patients.
AB  - An optimal approach to the diagnosis of deep vein thrombosis (DVT) in lower limbs
      in the emergency department is still unknown. In this prospective cohort study,
      we aimed to evaluate the accuracy of the widely available plasma D-dimer test
      (VIDAS) and establish the usefulness of combining D-dimer testing with a clinical
      model to reduce the need for serial ultra-sonographies and improve the diagnostic
      strategy of DVT. We performed a cohort study in 383 consecutive outpatients
      referred to the emergency department of Hospital La Princesa, with clinical
      suspicion of DVT. The patients were stratified into three pre-test probability
      categories using an explicit clinical model (Wells score), and underwent a
      quantitative automated ELISA D-dimer assay (VIDAS D-Dimer bioMerieux). Patients
      were managed according to the diagnostic strategy based on clinical probability
      and compression ultrasonography (CU). Patients for whom DVT was considered a high
      pre-test probability with negative ultrasonographic findings in the initial CU,
      returned the following week for repeat ultrasonography. All patients with DVT
      excluded did not receive anticoagulant therapy, and were followed up for three
      months to monitor the development of venous thromboembolic complications. DVT was
      confirmed in 102 patients (26.6%): 95 in the initial test, four in the second
      test, and three who developed venous thromboembolic complications in the three
      month follow-up period. The calculated D-dimer cut-off level was 1 micro g/ml.
      One hundred patients (98%) with DVT had positive D-dimer. D-dimer had a
      sensitivity of 98% and a negative predictive value of 98.6%. Among the high
      probability patients with positive D-dimer tests and initial negative CU, 9.75%
      had DVT on repeat CU at one week. The study results suggest that the addition of
      VIDAS D-dimer to this diagnostic algorithm could improve the management of
      patients with suspected DVT in daily practice. A diagnostic approach of DVT based
      on D-dimer (cut-off > or =1 microg/ml) as the first diagnostic tool for the
      exclusion of DVT, and the clinical probability model as the tool that identifies
      those patients requiring a second ultrasonography is useful and suitable for
      daily medical practice.

PMID- 15175814
TI  - Acquired thrombopathia related to montelukast therapy.

PMID- 15175815
TI  - Accidental overdosage of recombinant factor VIIa due to mistaken package size.

PMID- 15175816
TI  - Low pressure giant pulmonary artery aneurysm: a novel source of recurrent
      pulmonary embolism?

PMID- 15175817
TI  - Neuropharmacological treatment of refractory idiopathic thrombocytopenic purpura:
      roles of circulating catecholamines and serotonin.

PMID- 15175818
TI  - The frequency of P475S polymorphism in von Willebrand factor-cleaving protease in
      the Chinese population and its relevance to arterial thrombotic disorders.

PMID- 15175819
TI  - Hemochromatosis gene (HFE) polymorphisms are not associated with peripheral
      arterial disease.

PMID- 15175820
TI  - Prevalence of and major risk factors for adult bronchial asthma in Taipei City.
AB  - BACKGROUND AND PURPOSE: The prevalence of bronchial asthma has been on the rise
      worldwide, but the prevalence of adult asthma in Taiwan has not been reported.
      The objective of this study was to determine the current 1-year and lifetime
      asthma prevalence rates, and to identify major risk factors for adult asthma in
      Taiwan. METHODS: A cluster sampling was conducted in 1999, where 21 clusters and
      4549 adults (age > or = 18 years) were selected randomly. Face-to-face interviews
      were conducted with a total of 2076 adults (45.6%; men/women, 987/1089) using a
      questionnaire designed to assess asthma and asthma-like symptoms adapted from the
      American Thoracic Society with minor modifications to include information about
      current asthma status. RESULTS: The results showed that 50 cases had a previous
      diagnosis of asthma and 94 had been classified as probably having asthma with
      intermittently audible wheezing. The lifetime prevalence rate of asthma in adults
      in Taipei City was 7.8%. Seventy three out of 144 patients had asthmatic symptoms
      or wheezing in the past 12 months. The 1-year prevalence of asthma was 4.1%. A
      multiple logistic regression model showed the odds ratio (95% confidence
      interval) of a history of maternal asthma to be 5.8 (2.77 to 12.18), that of
      allergic rhinitis to be 3.2 (2.03 to 5.16), that of paternal asthma to be 2.2
      (0.91 to 5.21), that of older age (> or = 50 years) to be 2.0 (1.25 to 3.19), and
      that of smoking habit to be 1.7 (1.02 to 2.72). CONCLUSIONS: The lifetime
      prevalence rate of adult bronchial asthma in Taipei City was 7.8% and related to
      both genetic and environmental factors, which included maternal or paternal
      history of asthma, history of allergic rhinitis, older age (> or = 50 years), and
      smoking habits.

PMID- 15175821
TI  - Identification and initial characterization of small cells in adult cartilage and
      bone marrow.
AB  - BACKGROUND AND PURPOSE: Small cells in the range of less than 5 microm have been
      suspected to lie dormant and to be dispersed throughout the parenchyma of every
      tissue in the body. In bone marrow, small mesenchymal stem cells with rapidly
      renewing properties and differentiation potentials have been found. The aim of
      this study was to isolate and identify small cells from normal and osteoarthritic
      cartilages and compare their properties with those of small stem cells in bone
      marrow. METHODS: Small cells were isolated from cartilages and bone marrow.
      Characterization of these small cells was performed by hematoxylin and eosin
      staining and bromodeoxyuridine labeling. Scanning electron and atomic force
      microscopy were used for ultrastructural investigation and analysis of the cells.
      RESULTS: Small cells (< or = 5 microm) from both cartilages and bone marrow were
      shown to have mitotic activity on the basis of bromodeoxyuridine labeling, with
      the same replication time of 18 to 20 hours for population doubling.
      Ultrastructural and atomic force microscopy revealed these cells had spherical
      shape and were about 0.2 to 2.2 microm in diameter. CONCLUSIONS: This study
      demonstrated the presence of small cells in adult cartilage and bone marrow,
      which were about 0.2 to 2.2 microm in diameter and exhibited proliferation
      potential. These cells were able to be activated and differentiate into
      chondrocytes, and might have differentiation potential similar to small stem
      cells in bone marrow and thus play an important role in cartilage regeneration.

PMID- 15175822
TI  - Prevalence of perinuclear antineutrophil cytoplasmic antibody in patients with
      Graves' disease treated with propylthiouracil or methimazole in Taiwan.
AB  - BACKGROUND AND PURPOSE: Antineutrophil cytoplasmic antibody (ANCA)-mediated
      vasculitis can be induced by propylthiouracil (PTU) and methimazole (MMI) for the
      treatment of Graves' disease. This study investigated the prevalence of ANCA
      positivity and its clinical correlates in Taiwanese patients with Graves' disease
      treated with PTU or MMI. METHODS: Eighty nine patients with Graves' disease who
      were currently being treated with PTU (n = 47) or MMI (n = 42) were included in
      the study. Sera were screened for ANCA by indirect immunofluorescence. The
      antigenic specificity of myeloperoxidase or proteinase-3 was measured by enzyme
      linked immunosorbent assay. Thyroid autoantibodies against microsomal antibodies
      (AMA) and thyroglobulin antibodies were detected by indirect passive
      hemagglutination assays, and thyroid autoantibodies against thyrotropin receptor
      were detected by a radioreceptor assay. The correlations among ANCAs, clinical
      manifestations, gender, duration of treatment, and thyroid autoantibodies were
      analyzed by logistic regression. RESULTS: 20.2% of patients with Graves' disease
      receiving PTU and MMI were seropositive for ANCA; all of them were perinuclear
      ANCA (p-ANCA)-positive. The frequency of p-ANCA-positive status in the PTU
      treatment group was significantly higher than in the MMI treatment group (31.9%
      vs 7.1%; p = 0.01). The mean duration of PTU treatment was 25 +/- 16 months, and
      was 30 +/- 21 months for the MMI treatment. In the PTU treatment group, the
      average duration of treatment in p-ANCA-positive patients was significantly
      longer than in p-ANCA negative patients (32.9 +/- 16.3 vs 19.6 +/- 12.1 months, p
      = 0.04). In addition, the prevalence of AMA positivity was significantly lower in
      p-ANCA-positive patients than in p-ANCA negative patients (53.3% vs 90.6%; p =
      0.01). CONCLUSIONS: Only p-ANCA positivity was found in long-term treatment with
      PTU and MMI in Graves' disease. A higher frequency of p-ANCA positivity was found
      in the PTU treatment group than in the MMI treatment group. However, the presence
      of AMA was less frequent in p-ANCA-positive patients compared to p-ANCA-negative
      patients treated with PTU.

PMID- 15175823
TI  - Outpatient drug expenditures and prescription policies for diseases with high
      cost to the National Health Insurance system in Taiwan.
AB  - BACKGROUND AND PURPOSE: The high cost of drugs, particularly those used to treat
      upper respiratory tract infections, is an increasingly important problem for the
      National Health Insurance system in Taiwan. This study proposed a new
      classification scheme for reimbursing drug cost and estimated its impact on
      expenditures and health care utilization. METHODS: Data were obtained from the
      National Health Research Institutes' year 2000 computer file of the National
      Health Insurance Academic Research Database in Taiwan. Two factors were used to
      classify medications: 1) urgency of medications required; and 2) patient's self
      care ability. RESULTS: Among the 10 diseases with the highest number of
      outpatient department (OPD) visits, 7 were upper respiratory diseases. Acute
      upper respiratory infections (URIs) and acute nasopharyngitis were the 2 diseases
      with the highest number of OPD visits. Drug expenditure for acute URIs is about
      6% of total expenditure for drugs. Medications suitable for URIs patients' self
      care accounted for 42.8% of the total cost of prescribed drugs for these
      illnesses, and treatment medications unsuitable for patients' self-care accounted
      for 48.6%. Other medications used for URIs could not be grouped into these
      categories. The total expenditure for acute nasopharyngitis was about 1.3% of
      total expenditure for drugs. Medications suitable for self-care in patients with
      nasopharyngitis accounted for 51.8% of the total cost of medication prescribed
      for this illness, and medications unsuitable for patients' self-care accounted
      for 36.8%. CONCLUSIONS: Reducing the medications suitable for patients' self-care
      and enforcing different levels of payment rates on medications unsuitable for
      patients' self-care may reduce the excessive use of OPD drugs, improve the
      appropriateness of utilization for acute URIs and the common cold, and allow
      medical resources to be distributed more efficiently.

PMID- 15175824
TI  - Chronic hepatitis B virus infection and dyslipidemia.
AB  - BACKGROUND AND PURPOSE: The association of chronic hepatitis B virus (HBV)
      infection and decreased levels of high-density lipoprotein cholesterol (HDL-C)
      has been well documented. However, the relationship between dyslipidemia and
      asymptomatic chronic HBV infection is still unclear. METHODS: In 1997, 1330
      medical center employees (405 men and 925 women) were recruited to evaluate the
      effects of chronic HBV infection on serum lipid profile, including total
      cholesterol (TC), HDL-C, low-density lipoprotein cholesterol, and triglycerides
      (TG). Among these patients, 195 were found to have chronic HBV infection and 35
      (17.9%) of them were found to have elevated alanine aminotransferase (ALT).
      Multiple linear regression analyses were used to evaluate the effects of chronic
      HBV infection on serum lipids. RESULTS: The most significant finding was that
      levels of TC and HDL-C were decreased by 5.8 and 2.7 mg/dL respectively, among
      patients with asymptomatic chronic HBV infection (serum ALT < 40 U/L). After
      controlling for other determinants, male gender, old age, higher body mass index
      (BMI) and waist-to-hip ratio, current smoking, and hepatitis B surface antigen
      negative status with ALT > or = 40 U/L were associated with lower serum HDL-C and
      higher TG levels. However, moderate to heavy alcohol drinking, physically active
      lifestyle, and lower BMI were associated with higher levels of HDL-C.
      CONCLUSIONS: Asymptomatic chronic HBV infection was associated with lower serum
      levels of TC and HDL-C. Elevation of ALT was also an indicator of lower levels of
      HDL-C in patients with chronic hepatitis B and lower serum HDL-C and higher TG
      levels in patients without HBV infection. These findings also indicated the need
      to monitor the risk of atherosclerotic diseases in patients with asymptomatic
      chronic HBV infection, especially those with lower HDL-C levels.

PMID- 15175826
TI  - Validation of the Taiwan Birth Registry using obstetric records.
AB  - BACKGROUND AND PURPOSE: Birth certificates are a major source of population-based
      data often used in maternal and child health research, but their value depends
      upon the level of accuracy of the data. The purpose of this study was to assess
      the validity of the birth registry data in Taiwan. METHODS: Obstetric records of
      a total of 2779 infants born at a municipal hospital in Taipei between 1995 and
      1997 were abstracted and linked to the Taiwan Birth Registry (TBR). Concordance
      was presented by agreement percentages for various birth characteristics
      including gender, birth order, birth weight, and gestational age. Concordance was
      further assessed using Cohen's k and sensitivity/specificity for both birth
      weight and gestational age, with both variables categorized according to their
      customary definitions. RESULTS: Missing data for specific items in the TBR ranged
      from 0% (gender) to 1.6% (birth order). The birth registry accurately reported
      all 4 selected items, with the highest and lowest concordance percentage noted
      for gender (99.0%) and gestational age (88.3%), respectively. The level of
      agreement indicated by the Cohen's k statistic ranged from 0.92 to 0.96 for birth
      weight and gestational age when both variables were treated as categorical
      variables. CONCLUSIONS: The TBR showed a low rate of missing information and high
      levels of validity for the elements frequently used in maternal and child health
      research in Taiwan.

PMID- 15175825
TI  - Comparison of histidine-tryptophan-ketoglutarate and Euro-Collins solutions for
      lung preservation using the minipig in situ warm ischemia model.
AB  - BACKGROUND AND PURPOSE: Reperfusion injury remains a common problem in lung
      transplantation. This study compared the effect of lung preservation with
      histidine-tryptophan-ketoglutarate (HTK), a relatively low potassium solution,
      and Euro-Collins (EC) solution by using a minipig in situ model of warm ischemia.
      METHODS: The left lungs of 5 minipigs were selectively flushed with EC solution.
      HTK was used for flush perfusion in 6 other minipigs. After 60 minutes of warm
      ischemia, the left lungs were reperfused. Hemodynamics, aerodynamics, and
      arterial blood gas were measured after the blood flow and ventilation of the
      contralateral lungs were temporally blocked. Bronchoalveolar lavage fluid (BALF)
      analysis, lung wet-to-dry weight ratio (W/D ratio) and histological analysis were
      done before perfusion (right lung) and 2 hours after reperfusion (left lung).
      RESULTS: This in situ model of warm ischemia induced significantly increased
      pulmonary arterial pressure, pulmonary vascular resistance, BALF albumin contents
      and neutrophil counts, histological injury score, lung W/D ratio and tissue
      myeloperoxidase assay. The HTK perfusion group had a significantly lower degree
      of lung injury than the EC perfusion group. CONCLUSIONS: Lung preservation with
      HTK solution resulted in better lung function after reperfusion than preservation
      by EC solution in this minipig model.

PMID- 15175827
TI  - Acute hepatitis B virus superinfection in a Taiwanese patient with chronic
      hepatitis C.
AB  - Acute hepatitis B superimposed on patients with chronic hepatitis C is a rarely
      observed event, especially in hepatitis B virus (HBV)-prevalent areas where
      chronic HBV infection is usually acquired perinatally or at early infancy. The
      interactive relationship between HBV and hepatitis C virus (HCV) and clinical
      outcome in such patients remains controversial. We report a case of acute HBV
      superinfection which occurred during follow-up of chronic HCV infection in a 66
      year-old woman. The patient developed hepatic decompensation at the acute stage.
      Unlike previously reported cases in Taiwanese, in which the patient either died
      of fulminant hepatic failure or subsequently relapsed with HCV viremia, this
      chronic hepatitis C patient with acute HBV superinfection had virologic remission
      with undetectable HBV DNA and HCV RNA during 9 months of follow-up.

PMID- 15175828
TI  - Gastrocolocutaneous fistula in a child with congenital short bowel syndrome: a
      rare complication of percutaneous endoscopic gastrostomy.
AB  - Gastrocolocutaneous fistula is a rare major complication of percutaneous
      endoscopic gastrostomy (PEG). We report a case of this complication in a 2-year
      old boy with congenital short bowel syndrome with dilated bowel loops who
      underwent PEG insertion. Fever developed and stool-like substance was discharged
      from the gastrostomy tube 1 year later. Further upper gastrointestinal study and
      panendoscopy revealed a gastrocolonic and colocutaneous fistula. He underwent
      laparotomy to close the fistula. The recovery was uneventful and he was
      discharged 10 days after surgery. This case suggests that a previous history of
      abdominal surgery or dilated bowel loops should be a relative contraindication to
      PEG procedure. Open surgical gastrostomy is recommended for such patients.

PMID- 15175829
TI  - Ludwig's angina following herpetic gingivostomatitis in a toddler with tetralogy
      of Fallot.
AB  - Ludwig's angina is a rare but potentially lethal cellulitis of the submandibular
      space that occurs most often in young adults with predisposing odontogenic
      infection. In contrast to adult cases, most children with Ludwig's angina have no
      initiating factor. We report a case of Ludwig's angina in a 15-month-old boy
      which developed after an episode of herpetic gingivostomatitis. Under close
      monitoring of respiratory status, the condition was successfully managed with
      antibiotic treatment. This case illustrates that Ludwig's angina can develop in
      association with herpetic gingivostomatitis, which is a common and usually self
      limited disease in pediatric patients. Prompt recognition and aggressive
      management of this rare and severe secondary bacterial infection are the keys to
      avoiding unnecessary morbidity and mortality.

PMID- 15175830
TI  - Trisomy 18 in monozygotic twins with discordant phenotypes.
AB  - The incidence of trisomy 18 in monozygotic twins is approximately 1 per million.
      We report a pair of liveborn monozygotic twins with trisomy 18. Both twins had
      esophageal atresia with tracheoesophageal fistula (type C) and intrauterine
      growth retardation. Twin A had cleft lip, choanal atresia and perimembranous
      ventricular septal defect. Twin B had hypoplastic left heart syndrome. The twins
      died without aggressive intervention at the age of 2 months and 52 hours,
      respectively. These 2 babies had significantly discordant phenotypes, which
      suggests an epigenetic or environmental effect. Bioethical considerations remain
      important in the care of babies with multiple congenital anomalies.

PMID- 15175831
TI  - Metabolic syndrome and its contribution to coronary artery disease in non
      diabetic subjects.
AB  - BACKGROUND AND PURPOSE: People with the metabolic syndrome are at increased risk
      for developing diabetes mellitus and coronary artery disease (CAD). This study
      assessed the 5 risk factors of metabolic syndrome in non-diabetic individuals
      with angiographically-documented CAD. METHODS: To estimate the CAD risk
      associated with metabolic syndrome, we examined the 5 components of metabolic
      syndrome, defined by the National Cholesterol Education Program-Adult Treatment
      Panel (NCEP-ATP) III, including blood pressure (> or = 130/85 mm Hg), fasting
      glucose (> or = 110 mg/dL), fasting triglycerides (> or = 150 mg/dL), high
      density lipoprotein (HDL) cholesterol level (men < 40 mg/dL; women < 50 mg/dL),
      and abdominal obesity (waist circumference defined by the Department of Health,
      Taiwan: men > 90 cm; women > 80 cm) among 139 non-diabetic patients with
      angiographically-documented CAD and 139 age- and gender-matched non-diabetic
      control subjects. RESULTS: Metabolic syndrome was found to be more prevalent in
      subjects with CAD than subjects without CAD (51.8% vs 18.7%; p < 0.001). Multiple
      logistic regression analysis showed that hypertension was the strongest predictor
      of CAD, followed by higher fasting glucose and lowered HDL cholesterol. These 5
      factors accounted for 41.3% of total risk for CAD without diabetes. CONCLUSIONS:
      Our data revealed that the prevalence of metabolic syndrome was higher in this
      group of patients with angiographically-diagnosed CAD without diabetes than in
      controls.

PMID- 15175832
TI  - Clinical holistic medicine: when biomedicine is inadequate.
AB  - The modern physician is using pharmaceuticals as his prime tool. Unfortunately,
      this tool is much less efficient than you might expect from the biochemical
      theory. The belief in drugs as the solution to the health problems of mankind,
      overlooking important existing knowledge on quality of life, personal
      development, and holistic healing seems to be one good reason why approximately
      every second citizen of our modern society is chronically ill. The biomedical
      paradigm and the drugs are certainly useful, because in many situations we could
      not do without the drugs (like antibiotics), but curing infections or diseases in
      young age is not without consequences, as the way we perceive health and medicine
      is influenced by such experiences. When we get a more severe disease in midlife,
      we also believe drugs will make us healthy again. But at this age, the drugs do
      not work efficiently anymore, because we have turned older and lost much of the
      biological coherence that made us heal easily when we were younger. Now we need
      to assume responsibility, take learning, and improve our quality of life. We need
      a more holistic medicine that can help us back to life by allowing us to access
      our hidden resources. The modern physician cannot rely solely on drugs, but must
      also have holistic tools in his medical toolbox. This is the only way we can
      improve the general health of our populations. Whenever NNT (Number Needed to
      Treat) is 2 or higher, the likelihood of the drug to cure the patient is less
      than 50%, which is not satisfying to any physician. In this case, he must
      ethically try something more in order to cure his patients, which is the
      crossroads where both traditional manual medicine and the tools of a scientific
      holistic medicine are helpful.

PMID- 15175833
TI  - Clinical holistic medicine: tools for a medical science based on consciousness.
AB  - Biomedicine focuses on the biochemistry of the body, while consciousness-based
      medicine--holistic medicine--focuses on the individual"s experiences and
      conscious whole (Greek: holos, whole). Biomedicine perceives diseases as
      mechanical errors at the micro level, while consciousness-based medicine
      perceives diseases as disturbances in attitudes, perceptions, and experiences at
      the macro level--in the organism as a whole. Thus, consciousness-based medicine
      is based on the whole individual, while biomedicine is based on its smallest
      parts, the molecules. These two completely different points of departure make the
      two forms of medicine very different; they represent two different mind sets and
      two different frames of reference or medical paradigms. This paper explains the
      basic tools of clinical holistic medicine based on the life mission theory and
      holistic process theory, with examples of holistic healing from the holistic
      medical clinic.

PMID- 15175834
TI  - Clinical holistic medicine: induction of spontaneous remission of cancer by
      recovery of the human character and the purpose of life (the life mission).
AB  - The recovery of the human character and purpose of life with consciousness-based
      medicine seems to be able to induce spontaneous remissions in several diseases.
      On two different occasions, we observed breast tumors reduced to less than half
      their original diameters (clinically judged) during a holistic session, when
      working with the patients in accordance with the holistic process theory of
      healing, the life mission theory, and the theory of human character. One tumor
      was histologically diagnosed as malign breast cancer prior to the session, while
      the other was under examination. As both patients had the affected regions of the
      breast surgically removed immediately after the session, we are unable to
      determine if they were actually healed by the holistic treatment. We find it
      extremely interesting that the size of a tumor can be reduced dramatically within
      a few hours of holistic treatment, when the patient is highly motivated for
      personal development. The reduction of tumor size is in accordance with the
      holistic view that many types of cancer are caused by emotional and existential
      disturbances. From a holistic perspective, cancer can be understood as a simple
      disturbance of the cells, arising from the tissue holding on to a trauma with
      strong emotional content. This is called "a blockage", where the function of the
      cells is changed from their original function in the tissue to a function of
      holding emotions. The reduction of the tumor in the two cases happened when old
      painful emotions were identified in the tissues, in and around the tumor, and
      processed into understanding; when the patients finally did let go of negative
      beliefs and attitudes that had kept the feeling(s) repressed to that part of the
      body, the tumor first softened and then disappeared, presumably by apoptosis. We
      believe that the consciousness-based/holistic medical toolbox has a serious
      additional offer to cancer patients, and we will therefore strongly encourage the
      scientific society to explore these new possibilities. Our holistic medical
      research meets both ethical dilemmas and practical difficulties, as it obviously
      is important for the research in induced spontaneous remissions that surgery and
      chemotherapy is not used before it is absolutely necessary. On the other hand, is
      it important for the patient"s survival that they receive any well-documented
      treatment as soon as possible. An additional aspect for the patient who is able
      to cure her own cancer is that she is much less likely to get cancer again and
      much better prepared to deal with other diseases and challenges in life. Knowing
      that one can fight even cancer gives a strong belief in life and the need to
      improve quality of life. The high incidence of secondary cancers and the physical
      and emotional wounds from the biomedical treatment seem to justify a focus on
      prevention and additional holistic treatment modules. To support the patient in
      learning the mastery of coherence of body and life, using the crisis of cancer to
      recover the human character and the purpose of life, seems turning a personal
      potential disaster into the greatest gift of all. When it comes down to it, life
      is not just about surviving; what is more important is to live fully, to learn
      from the great challenges of life, and to obtain the optimal quality of life
      while being here.

PMID- 15175835
TI  - The performance of( 18)F-fluorodeoxyglucose positron emission tomography in small
      solitary pulmonary nodules.
AB  - Solitary pulmonary nodule (SPN, intraparenchymal lung mass <3 cm) is often a
      diagnostic challenge. This study was performed to evaluate the diagnostic
      accuracy of( 18)F-fluorodeoxyglucose positron emission tomography (FDG PET) in
      radiologically indeterminate SPN < or =10 mm on spiral CT. Between August 1997
      and March 2001, we identified all patients with radiologically indeterminate SPNs
      < or =10 mm who were referred for FDG PET imaging at the VU University Medical
      Centre. All PET scans were retrospectively reviewed by an experienced nuclear
      medicine physician. PET was considered positive in cases with at least moderately
      enhanced focal uptake, and otherwise as negative. Lesions were considered benign
      on the basis of histology, no growth during 1.5 years or disappearance within at
      least 6 months. Thirty-five patients with 36 SPNs < or =10 mm in diameter at
      clinical presentation were identified (one patient had two metachronous lesions).
      In 13 of 14 malignant nodules and in two of 22 benign nodules, diagnosis was
      confirmed by histology. Prevalence of malignancy was 39%. PET imaging correctly
      identified 30 of 36 small lesions. One lesion proved to be false negative on PET
      (CT: 10 mm), and in five lesions, PET scans proved to be false positive.
      Specificity was 77% (17/22; 95% CI: 0.55-0.92), sensitivity 93% (13/14; 95% CI:
      0.66-1.0), positive predictive value 72% (13/18; 95% CI: 0.46-0.90) and negative
      predictive value 94% (17/18; 95% CI: 0.73-1.0). This retrospective study suggests
      that FDG PET imaging could be a useful tool in differentiating benign from
      malignant SPNs < or =10 mm in diameter at clinical presentation. Such results may
      help in the design of larger prospective trials with structured clinical work-up.

PMID- 15175836
TI  - Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe1-Tyr3-octreotide
      versus 111In-pentetreotide in patients with advanced neuroendocrine tumours.
AB  - PURPOSE: For the internal radiotherapy of neuroendocrine tumours, the
      somatostatin analogue DOTATOC labelled with 90Y is frequently used [90Y-DOTA-Phe1
      Tyr3)-octreotide (SMT487-OctreoTher)]. Radiation exposure to the kidneys is
      critical in this therapy as it may result in renal failure. The aim of this study
      was to compare cumulative organ and tumour doses based upon dosimetric data
      acquired with the chemically identical 86Y-DOTA-Phe1-Tyr3-octreotide (considered
      as the gold standard) and the commercially available 111In-pentetreotide.
      METHODS: The cumulative organ and tumour doses for the therapeutic administration
      of 13.32 GBq 90Y-DOTA-Phe1-Tyr3-octreotide (three cycles, each of 4.44 GBq) were
      estimated based on the MIRD concept (MIRDOSE 3.1 and IMEDOSE). Patients with a
      cumulative kidney dose exceeding 27 Gy had to be excluded from subsequent therapy
      with 90Y-DOTA-Phe1-Tyr3-octreotide, in accordance with the directives of the
      German radiation protection authorities. RESULTS: The range of doses (mGy/MBq 90Y
      DOTA-Phe1-Tyr3-octreotide) for kidneys, spleen, liver and tumour masses was 0.6
      2.8, 1.5-4.2, 0.3-1.3 and 2.1-29.5 (86Y-DOTA-Phe1-Tyr3-octreotide), respectively,
      versus 1.3-3.0, 1.8-4.4, 0.2-0.8 and 1.4-19.7 (111In-pentetreotide), with wide
      inter-subject variability. Despite renal protection with amino acid infusions,
      estimated cumulative kidney doses in two patients exceeded 27 Gy. CONCLUSION:
      Compared with 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide
      overestimated doses to kidneys and spleen, whereas the radiation dose to the
      tumour-free liver was underestimated. However, both dosimetric approaches
      detected the two patients with an exceptionally high radiation burden to the
      kidneys that carried a potential risk of renal failure following radionuclide
      therapy.

PMID- 15175837
TI  - Imaging features of low-grade central osteosarcoma of the long bones and pelvis.
AB  - PURPOSE: To determine the age and gender distribution and imaging features of low
      grade central osteosarcoma (LGCOS) of the long bones and pelvis and to discuss
      our findings in the context of lesions for which LGCOS has been mistaken.
      MATERIALS AND METHODS: We reviewed 99 cases of LGCOS collected between 1919 and
      2002 from our institution and pathology consultation files. Adequate imaging was
      available in 70 cases (36 radiographs only, 17 radiographs/CT, 12
      radiographs/MRI, 2 radiographs/CT/MRI, 2 CT only, 1 MRI only, 5 bone scans).
      RESULTS: Patient average age was 30.1+/-14.2 years, with a slight female
      predominance. The femur and tibia were the most common long bones involved (29
      and 20 each) with the majority of these tumors arising around the knee, followed
      by the fibula, radius, humerus and ulna (four, three, two and one case each).
      Flat bones were involved in six cases (three pelvis, one rib, two scapulae).
      Short tubular bones were involved in five cases (two metatarsal, two phalanges,
      one clavicle). The lesion extended to the end of the affected long bone in 22 of
      59 cases. Lesions were large at presentation (mean 7.9+/-4.6 cm, range 2-24).
      Four radiographic patterns were identified: lytic with varying amounts of thick
      and coarse trabeculation ( n=22), predominantly lytic with few thin, incomplete
      trabecula ( n=21), densely sclerotic ( n=17) and mixed lytic and sclerotic (
      n=10). Lesions were benign-appearing overall with focally aggressive features. CT
      or MRI demonstrated cortical breech or extension into the soft tissues in all
      cases. CONCLUSIONS: LGCOS has a variable appearance on radiographs. A frequent
      pattern is a slow-growing large intracompartmental fibro-osseous lesion with
      varying amounts of septal ossification associated with focal areas of aggression.
      A homogeneously sclerotic pattern was also noted. Imaging with CT or MRI was
      helpful in every instance in our series in identifying areas of soft tissue
      extension or cortical disruption suggestive of a low-grade malignancy.

PMID- 15175838
TI  - Blade consolidation of multiple atrial septal defects: a novel approach to
      transcatheter closure.
AB  - The Amplatzer atrial septal defect occlusion device has gained popularity for the
      nonoperative closure of secundum-type defects. We describe a case of multiple
      atrial septal defects that were "consolidated" into a single defect using blade
      atrial septostomy for successful closure with single Amplatzer device.

PMID- 15175839
TI  - Effect of Cu(II) on the electrochemically initiated reaction of thiols with N, N
      diethyl- p-phenylenediamine: methodology for the indirect voltammetric
      determination of Cu(II).
AB  - The effect of Cu(II) on the determination of homocysteine via its
      electrochemically initiated reaction with N, N-diethyl-p-phenylenediamine is
      examined. The presence of copper inhibited the detection process for homocysteine
      owing to a complexation reaction occurring. This provided an indirect route for
      the sensitive and selective determination of Cu(II), which produced a linear
      response over the range from 2.5 to 500 microM and a limit of detection of 2.5
      microM. The detection pathway was examined in the presence of metallic and
      inorganic ions, with negligible interference observed.

PMID- 15175841
TI  - Withdrawal-induced c-Fos expression in the rat centromedial amygdala 24 h
      following a single morphine exposure.
AB  - RATIONALE: An opiate antagonist was found to induce motivational withdrawal signs
      24 h or even up to 48 h after a single dose of morphine in rats. OBJECTIVE: The
      present study was undertaken to determine whether such a withdrawal state would
      modify the neuronal activity in the brain. METHODS: A conditioned place aversion
      was established following a one-trial paradigm in rats undergoing a single
      exposure to morphine (10 mg/kg) 24 h prior to naloxone administration (0.5
      mg/kg). Subsequently, the expression of the protein product of c-fos gene (c-Fos)
      following naloxone administration was measured within the extended amygdala.
      RESULTS: A significant increase in c-Fos immunoreactivity was seen in the
      centromedial amygdala (CMA), but not in the bed nucleus of the stria terminalis
      (BST) and the shell (AcbSh) of the nucleus accumbens (Acb) in rats treated with
      both morphine and naloxone. Further examination of the distribution of c-Fos
      positive neurons along the rostrocaudal axis within CMA showed that the positive
      neurons distributed throughout this brain area and the caudal level of its
      central division (the central nucleus of the amygdala, CeA) exhibited the most
      robust labeling. CONCLUSIONS: Neuronal activity can be increased by naloxone at a
      dose that produces conditioned place aversion 24 h after a single morphine
      exposure. CMA, particularly the caudal level of its central division, was of high
      sensitivity. The current data also suggest a possible involvement of CMA in
      negative motivational component of precipitated withdrawal from acute morphine
      dependence.

PMID- 15175842
TI  - Relationship of body surface area with bone density and its risk of osteoporosis
      at various skeletal regions in women of mainland China.
AB  - The aim of this study was to investigate the relationship between body surface
      area (BS) and bone mineral density (BMD) and the associated osteoporosis risk at
      various skeletal regions in women from mainland China. BMD was measured at the
      posteroanterior (PA) spine (L1-L4), supine lateral spine (L2-L4) including
      volumetric BMD (vBMD), hip including femoral neck, trochanter and total hip, and
      forearm, including radius + ulna ultradistal (R + UUD), 1/3 site (R + U1/3) and
      total region (R + UT) using a dual-energy X-ray absorptiometry (DXA) fan-beam
      bone densitometer (Hologic QDR 4500A) in 3418 females aged from 18 to 75 years.
      Data analysis revealed a positive correlation between BS and BMD at the various
      skeletal regions (r = 0.114-0.373, all P = 0.000), but no correlation with vBMD
      (r = 0.000, P = 0.934). Using the stepwise regression model, BMDs at various
      skeletal regions were dependent variables while height, weight, body mass index
      (BMI), BS and projective bone area (BA) were independent variables; BS was
      determined to be the most important variable that affected the PA spine, hip and
      forearm BMDs. Subjects were divided into three groups according to size: large BS
      group (LBSG), intermediate BS group (IBSG) and small BS group (SBSG). The BMD at
      different skeletal regions of subjects between groups exhibited a significant
      gradient difference, with LBSG > IBSG > SBSG, but this was not seen for vBMD. On
      the fitting curves where BMD varied with age at the PA spine, femoral neck, total
      hip and R + UUD, BMDs of LBSG were 6.93-9.29% higher than those of IBSG and 12.1
      16.9 % higher than those of SBSG, whereas those of SBSG were 6.12-9.59% lower
      than those of IBSG at various skeletal regions, respectively. The prevalence
      rates and risks of osteoporosis of LBSG were significantly lower than those of
      SBSG and IBSG, whereas those of IBSG were obviously lower than those of SBSG at
      various skeletal regions, respectively, presenting a gradient difference among
      the three study groups, LBSG < IBSG < SBSG. Our study shows that the relationship
      between BS and BMD exceeds that between BMD and height or weight in women in
      mainland China. When areal BMD is employed, those with a larger BS have higher
      areal BMD and lower risks of osteoporosis while, conversely, those with a smaller
      BS have lower areal BMD, and therefore higher risk for osteoporosis. However,
      when vBMD is used, these differences diminish or even disappear.

PMID- 15175843
TI  - Effects of physical activity and dietary calcium intake on bone mineral density
      and osteoporosis risk in a rural Thai population.
AB  - The objective of the study was to determine the effects of modifiable risk
      factors on bone mineral density in postmenopausal Thai women. Dietary calcium
      intake (g/day), energy expenditure (kcal/day), and sunlight exposure (h/day) were
      assessed in 129 rural Thai women aged 63 years (range 50 to 84 years). Bone
      mineral density (BMD) at the femoral neck, lumbar spine, and distal radius were
      measured by dual-energy X-ray absorptiometry (DXA). The average dietary calcium
      intake was 236 +/- 188 g/day (mean +/- SD), while the energy expenditure was
      2,118 +/- 656 kcal/day with 1.1 +/- 1.7 h of sunlight exposure. In multiple
      linear regression analysis, dietary calcium intake, energy expenditure, and years
      since menopause were significant and independent predictors of BMD at various
      sites. The three factors together accounted for between 35% and 45% of the
      variance of BMD. The prevalence of osteoporosis (defined as BMD T-scores < or =
      2.5) was 33% at the femoral neck, 42% at the lumbar spine, and 35% at the distal
      radius. The risk of osteoporosis was higher in women with lower dietary calcium
      intake (< or =138 mg/day; prevalence rate ratio [PRR], 1.4; 95% confidence
      interval [CI], 1.0 to 1.9), lower energy expenditure (< or =1,682 kcal; PRR, 1.7;
      95% CI, 1.2 to 2.3), and greater years since menopause (> or =6 years; PRR, 2.6;
      95% CI, 1.2 to 5.8). The population attributable risk fraction of osteoporosis
      risk due to the three factors was 70%. These results suggest that in the Thai
      population, low dietary calcium intake and low physical activity together with
      advancing years since menopause were independent risk factors for low BMD.

PMID- 15175844
TI  - The importance of bisphosphonate therapy in maintaining bone mass in men after
      therapy with teriparatide [human parathyroid hormone(1-34)].
AB  - Teriparatide, the active fragment of human parathyroid hormone (hPTH 1-34), is an
      anabolic agent for the treatment of osteoporosis. Important questions remain
      regarding management strategy beyond the recommended 18- to 24-month course of
      teriparatide treatment. We followed 21 men for up to 2 years after discontinuing
      teriparatide. Twelve men (57%) chose treatment with bisphosphonate immediately
      after teriparatide withdrawal, while 9 (43%) opted for no pharmacologic agent. At
      the end of 1 year lumbar spine bone density increased an additional 5.1+/-1.0% in
      the bisphosphonate group, while it declined by 3.7+/-1.7% in those on no
      medication (P<0.002). In six men who delayed initiation of bisphosphonate until 1
      year after teriparatide withdrawal, their subsequent gains in the second year,
      2.6+/-1.7%, still placed them below the peak gains they achieved on teriparatide.
      In contrast, the 12 men who began bisphosphonates immediately and continued
      treatment for the entire 2-year post-PTH period had continued gains at the lumbar
      spine, 8.9+/-1.5% above their post-PTH values (P=0.002). For the 4-year period,
      including 2 years of teriparatide and 2 years of bisphosphonate, the total gains
      at the lumbar spine were 23.6+/-2.9%. Men, who received bisphosphonate in only
      the 2nd year post-teriparatide, had cumulative gains of 11.1+/-3.4%. Three men
      who did not receive any bisphosphonate at any time during the post-PTH period had
      cumulative gains of only 5.5+/-3.7%. These findings suggest that the use of
      bisphosphonates following teriparatide is an important component of any strategy
      utilizing this anabolic drug for osteoporosis in men. The immediate use of
      bisphosphonates after teriparatide withdrawal may help to optimize gains in bone
      density at the lumbar spine.

PMID- 15175845
TI  - Smoking and fracture risk: a meta-analysis.
AB  - Smoking is widely considered a risk factor for future fracture. The aim of this
      study was to quantify this risk on an international basis and to explore the
      relationship of this risk with age, sex and bone mineral density (BMD). We
      studied 59,232 men and women (74% female) from ten prospective cohorts comprising
      EVOS/EPOS, DOES, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, Hiroshima and
      two cohorts from Gothenburg. Cohorts were followed for a total of 250,000 person
      years. The effect of current or past smoking, on the risk of any fracture, any
      osteoporotic fracture and hip fracture alone was examined using a Poisson model
      for each sex from each cohort. Covariates examined were age, sex and BMD. The
      results of the different studies were merged using the weighted beta
      coefficients. Current smoking was associated with a significantly increased risk
      of any fracture compared to non-smokers (RR=1.25; 95% Confidence Interval
      (CI)=1.15-1.36). Risk ratio (RR) was adjusted marginally downward when account
      was taken of BMD, but it remained significantly increased (RR=1.13). For an
      osteoporotic fracture, the risk was marginally higher (RR=1.29; 95% CI=1.13
      1.28). The highest risk was observed for hip fracture (RR=1.84; 95% CI=1.52
      2.22), but this was also somewhat lower after adjustment for BMD (RR=1.60; 95%
      CI=1.27-2.02). Risk ratios were significantly higher in men than in women for all
      fractures and for osteoporotic fractures, but not for hip fracture. Low BMD
      accounted for only 23% of the smoking-related risk of hip fracture. Adjustment
      for body mass index had a small downward effect on risk for all fracture
      outcomes. For osteoporotic fracture, the risk ratio increased with age, but
      decreased with age for hip fracture. A smoking history was associated with a
      significantly increased risk of fracture compared with individuals with no
      smoking history, but the risk ratios were lower than for current smoking. We
      conclude that a history of smoking results in fracture risk that is substantially
      greater than that explained by measurement of BMD. Its validation on an
      international basis permits the use of this risk factor in case finding
      strategies.

PMID- 15175846
TI  - Cost-effectiveness of risedronate for the treatment of osteoporosis and
      prevention of fractures in postmenopausal women.
AB  - Randomized, double-blind, controlled studies have shown that treatment with
      risedronate reduces the risk of vertebral fracture in postmenopausal women with
      established vertebral osteoporosis. They also show that the drug decreases the
      risk of non-vertebral fractures in women with osteoporosis. The aim of this study
      was to investigate the cost-effectiveness of risedronate in postmenopausal women
      with osteoporosis. A Markov model was applied to a UK setting. Treatment effects
      were computed by meta-analysis of randomized, controlled trials and given over 5
      years to subjects aged between 60 and 80 years. Quality-adjusted life years
      (QALYs) and life years gained were used as outcome measures. Intervention with
      risedronate was cost-effective in women aged 60 years and older. Cost savings
      were also found for postmenopausal women aged 70 years and older with established
      vertebral osteoporosis (a prior spine fracture and BMD T-score < or =-2.5 SD).
      This treatment was cost-effective for women aged 65 years and older who had a
      prior vertebral fracture and a BMD T-score at the threshold of osteoporosis ( T
      score=-2.5 SD), and in women with a T-score < or =-2.5 SD, but without a prior
      vertebral fracture. In women aged 60-80 years and at the threshold of
      osteoporosis ( T-score=-2.5 SD) but without a prior vertebral fracture, treatment
      exceeded the threshold for cost-effectiveness. However, if an additional,
      independent risk factor was assumed (e.g., corticosteroid use) treatment became
      cost-effective.

PMID- 15175847
TI  - Effect of a case-finding strategy for osteoporosis on bisphosphonate prescribing
      in primary care.
AB  - Case-selection strategies have been advocated for identifying patients who would
      benefit from primary care to prevent osteoporosis. However, the effectiveness of
      this approach is unclear. To address this question, we performed a randomized
      control trial to determine whether a case-selection strategy to identify patients
      with clinical risk factors for osteoporosis, combined with open access to dual X
      ray absorptometry (DXA) scans, influences bisphosphonate prescribing in ten GP
      practices in Avon. Practices were randomized to two groups: the first identified
      women aged 45-75 years at high risk of osteoporosis and provided open access to
      DXA scans for 12 months; the second had no case-finding strategy and no DXA scan
      access. Bisphosphonate prescribing was ascertained by searching computerized
      patient records every 3 months during the intervention and a subsequent 6-month
      follow-up period. Overall, the number of subjects in each practice who were
      prescribed bisphosphonates increased by 50% (p<0.001), and the proportion of
      bisphosphonates prescribed as aminobisphosphonates increased 3-fold (p<0.001).
      The magnitude of these changes was similar in both groups. However, of the
      patients prescribed bisphosphonates, approximately twice as many in group 1, as
      compared with group 2, had a previously documented low-trauma fracture, as
      assessed at the end of the 12-month intervention period (p=0.01). Furthermore, at
      study's end, of the 30 patients in group 1 receiving bisphosphonates who had
      received DXA scans, 80% had osteoporosis as defined by t-score<-2.5. We conclude
      that use of a case-selection strategy for osteoporosis in primary care, combined
      with open access to DXA scans, appears to target bisphosphonate therapy to those
      at high risk of osteoporotic fractures. In contrast, the overall rate of
      bisphosphonate prescribing is unaffected by this intervention.

PMID- 15175848
TI  - Low levels of 25-hydroxy vitamin D are associated with elevated parathyroid
      hormone in healthy adolescent females.
AB  - This study aimed to investigate the relationship between 25-hydroxyvitamin D
      [25(OH)D)] and parathyroid hormone (PTH) levels in adolescent females residing in
      a northern climate. Concern regarding vitamin D status in this population is due
      to limited sunlight exposure in northern latitudes, decreased outdoor
      recreational activities, as well as decreased conversion in black girls from
      increased skin pigmentation. In this cross-sectional analysis, serum samples were
      assayed for 25(OH)D using competitive protein binding (CPB) assay and PTH with
      immuno-radiometric (RIA) procedures. Four hundred postmenarcheal females (12-18
      years) residing in northeastern Ohio were recruited. Subjects were excluded if
      they had a history of bone, kidney, or liver disease, or used medications that
      affect bone. The primary goal was to determine serum 25(OH)D concentrations in
      relation to circulating PTH levels in a population of adolescent girls. The
      Spearman correlation test was used to compare PTH and 25(OH)D. Fit multiple split
      models were run to determine change in slope of the regression line when 25(OH)D
      and PTH were plotted. Analysis of variance was determined using modeled means
      with differences by race and season in the final model. Unadjusted mean serum
      25(OH)D and PTH levels were 55.0+/-30.4 nmol/l and 39.4+/-20.6 ng/l,
      respectively. Blacks had lower 25(OH)D and higher PTH compared with non-blacks
      (P<0.0001), especially during the winter months. Decreasing 25(OH)D was inversely
      correlated with PTH (r=-0.314) (P<0.0001), and at concentrations of 25(OH)D < or
      =90 nmol/l, an increase in PTH was observed. Adolescents are at risk for
      decreased serum 25(OH)D concentrations, especially black girls. We found that the
      widely used cutoff for vitamin D deficiency is associated with increasing PTH
      levels and is below the inflection point for a change in the slope of the
      regression line. Our results support the need for further research to establish
      optimal vitamin D status in adolescent girls.

PMID- 15175849
TI  - Anterior subluxation after reduction of a posterior traumatic sterno-clavicular
      dislocation: a case report and a review of the literature.
AB  - Sternoclavicular dislocations represent a rare injury. Based on our clinical
      experience with a patient showing an anterior subluxation after reduction of a
      posterior traumatic dislocation, we review the literature. The emergent reduction
      of the dislocation is mandatory, always keeping in mind the potentially
      devastating neurovascular complications. If the treatment of a residual anterior
      instability remains controversial, a residual posterior instability should be
      treated by a surgical procedure. The optimal treatment depends mainly on each
      surgeon's choice and practice.

PMID- 15175851
TI  - Osteochondral lesion located at the lateral femoral condyle reconstructed by the
      transplantation of tissue-engineered cartilage in combination with a periosteum
      with bone block: a case report.
AB  - We report herein the successful treatment of a patient with an osteochondral
      defect extending to the edge of the lateral femoral condyle by transplantation of
      tissue-engineered cartilage made ex vivo using atelocollagen gel covered by
      periosteum with a bone block to reconstruct the normal contour of the femoral
      condyle.

PMID- 15175850
TI  - Clinical and functional results after the rehabilitation period in minimally
      invasive unicondylar knee arthroplasty patients.
AB  - The objective of the present study was to analyze the clinical and functional
      outcome after minimally-invasive implantation of a Repicci-type unicompartmental
      sledge prosthesis . In 29 patients with primary unicompartmental knee
      osteoarthritis, 29 replacements of the medial compartment and four of the lateral
      compartment were performed using the minimally-invasive technique with the metal
      backed and the all-polyethylene versions of the Repicci sledge prosthesis.
      Electromyography (EMG) of standardized locations was measured with the MyoSystem
      2000 and analyzed with Myoresearch software. Gait analysis was performed with a
      six-camera motion analysis system and force platforms. Established clinical and
      quality of life (SF-36) scores were used to compare patients with 11 healthy age
      matched individuals. The Repicci sledge prosthesis led postoperatively to
      functional results that were in the range of healthy joints, and superior to
      sledge prostheses of a different design. Gait and balance parameters were
      comparable to the control group, whilst electromyographically lower amplitudes
      were found in the patients than the controls and in the operated legs as compared
      to the non-operated legs. Many parameters of quality of life and activity were
      comparable to age-matched healthy individuals, and quality of life was superior
      to total knee replacement. When implanted using a minimally-invasive technique
      and with suitable patient selection, the Repicci sledge led to functional results
      comparable to those of healthy joints and gait parameters comparable to those of
      healthy individuals. The level of evidence is Level III, retrospective cohort
      study.

PMID- 15175852
TI  - Renal transplantation in amyloidosis: effects of HLA matching and donor type on
      recurrence of primary disease.
AB  - The aim of this study is to evaluate the effect of HLA-matching and donor type on
      recurrence of amyloidosis after renal transplantation. The study includes 30
      patients with systemic amyloidosis who received kidney transplants between 1985
      and 2001. Donor source and HLA tissue typing of the donor and recipient were
      evaluated in each case. Of the 30 patients, 20 developed a recurrence of
      amyloidosis in their allografts, as confirmed by biopsy. The time from
      transplantation to diagnosis of amyloidosis in the graft ranged from 18 months to
      10 years. Of the 20 patients with recurrence, 18 had received their grafts from
      living related donors (LRDs), and 2 had received their grafts from cadaveric
      donors (P < 0.01). There was a strong correlation between amyloidosis recurrence
      and degree of HLA-DR matching (P < 0.05). Furthermore, in the recipients of LRD
      grafts, the risk of amyloidosis recurrence was much higher if the donor-recipient
      pair were HLA-identical than if they were not perfectly matched (P < 0.01). The
      incidence of amyloidosis recurrence in our patients was significantly higher than
      the rates reported for other series. Most of the cases in previous reports
      involved cadaveric grafts. The higher rate of amyloidosis recurrence in our
      patients may be explained by the high proportion of LRD grafts and by genetic
      susceptibility.

PMID- 15175854
TI  - Development and validation of a PCR-based marker assay for negative selection of
      the HMW glutenin allele Glu-B1-1d (Bx-6) in wheat.
AB  - Polymorphisms between the coding sequences of high-molecular-weight (HMW)
      glutenin x-type genes at the Glu-1 locus were used to amplify Glu-1B x-type
      specific PCR fragments. PCR analysis in a wheat cultivar subset carrying
      different Glu-1B x-type alleles resulted in PCR fragments that differed in size
      for Glu-B1-1d (B-x6) and non -Glu-B1-1d (B-x6) genotypes. Subsequent sequencing
      analysis revealed a 15-bp in-frame insertion in the coding regions of all Glu-B1
      1d (B-x6) genotypes which allowed the development of a B-x6-specific PCR assay
      for high-throughput allele sizing by ion-pair reversed-phase high-performance
      liquid chromatography. The assay was validated in a set of 86 German wheat
      cultivars, and genotyping data unequivocally verified the presence of HMW
      glutenin subunits GLU-B1-1D (Bx-6) + GLU-B1-2A (By-8) by means of sodium dodecyl
      sulphate-polyacrylamide gel electrophoresis. These results demonstrate that the
      PCR assay can be applied for the detection and negative selection of the 'poor
      breadmaking quality' Glu-B1-1d (B-x6) alleles in wheat breeding programs.

PMID- 15175853
TI  - [The evaluation of balloonkyphoplasty for osteoporotic vertebral fractures. An
      interdisciplinary concept].
AB  - BACKGROUND DATA: Patients with osteoporotic vertebral compression fractures
      frequently complain of pain and a loss of function and mobility. Such fractures
      are associated with an increased mortality. The common treatment with bed rest,
      bracing or osteosynthesis does not lead to satisfying results. With two new
      surgical techniques, vertebroplasty and kyphoplasty, an internal stabilisation of
      osteoporotic vertebral fractures is possible. METHODS: All patients were treated
      by kyphoplasty. With a minimal invasive dorsal approach, an inflatable bone tamp
      is placed in the fractured vertebral body. This tamp can restore the vertebral
      body height and create a cavity, which is filled with bone cement under low
      pressure. The advantage of kyphoplasty compared to vertebroplasty is the
      restoration of the vertebral height and a decreased cement leakage rate. We
      performed a prospective, interdisciplinary study with a follow-up of 12 months.
      We treated 192 vertebral fractures in 102 patients. Augmentation was performed
      with polymethylmethacrylate in 138 cases and with a new injectable calcium
      phosphate-cement in 54 vertebral bodies. Outcome data were obtained with two
      different spine-scores and by the radiomorphometric evaluation of x-rays before
      and after treatment. RESULTS: We noticed a significant improvement in pain and
      function in 89% of the patients. All patients showed a regain of vertebral height
      of on average 17%. In 7% of all treated vertebral bodies, we noticed cement
      leakage, which was, however, far below the rates published for vertebroplasty (20
      70%). There were two complications, bleeding due to an unknown coagulopathy and a
      violation of the myelon by malpunction. CONCLUSION: Kyphoplasty is a reliable and
      minimally invasive method for stabilizing fractured osteoporotic vertebral
      bodies. Improvement of pain and function and a regain in height of the treated
      vertebral body can be accomplished.

PMID- 15175855
TI  - [Albrecht von Graefe (1828-1870) Notes on the cover picture].

PMID- 15175856
TI  - [Philosophizing about the mysteries of the brain. Overview of neurophilosophy].
AB  - The article portrays the field of "neurophilosophy" as the transdisciplinary
      reflection on questions of the brain and consciousness. Its central issues and
      basic assumptions are reviewed which belong in particular to the fields of
      neuroontology, neuroepistemology, neuroanthropology, and neuroethics. The article
      outlines the opportunities and limitations of this research.

PMID- 15175857
TI  - [Gadolinium enhancement of the cauda equina following ischemia of the lumbar
      cord].
AB  - Enhancement of the cauda equina is a well-recognized finding, in particular in
      patients with inflammatory diseases of the peripheral nervous system. However, we
      report an unusual case of a woman with an ischemic lesion in the lumbar
      intumescence who developed enhancement of the cauda equina 18 days after disease
      onset. Seventy-six days after the onset of illness, contrast uptake was no longer
      detectable. Severe injury to the motor neurons in the lumbar intumescence was
      evident clinically and electromyographically. We propose that the enhancement of
      the cauda equina was due to blood-nerve barrier disruption during Wallerian
      degeneration following ischemic injury to the motor neurons of the lumbar cord.

PMID- 15175858
TI  - [Monoaminergic transmitters in the cerebrospinal fluid of patients with acute,
      chronic, and intermittent pain. Interface between pain and depression?].
AB  - BACKGROUND AND STUDY PURPOSE: Pain and depression share similar neurobiological
      characteristics, and it is a common clinical observation that pain and depression
      may coincide in the same patient. They also appear to influence each other in the
      process of chronification. Furthermore, there is a complex coupling of pain and
      depression by monoaminergic transmitter system. PATIENTS AND METHODS: On the
      basis of these findings, norepinephrine (NE), epinephrine (E), dopamine (DOP), 5
      hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and vanillylmandelic
      acid (VMA) concentrations were determined in the cerebrospinal fluid (CSF) in
      patients with acute (20), chronic (27), and episodic pain syndrome (44) in a
      prospective study. The biochemical parameters were correlated to self-assessment
      pain and depression scores. The control group consisted of 13 pain-free patients
      with diseases affecting the muscular system. RESULTS: Patients with chronic and
      episodic pain syndromes had significantly more depressive and psychovegetative
      symptoms compared to patients with acute pain. In patients with acute pain, DOP
      was significantly higher than in controls and chronic and episodic pain patients.
      In addition DOP was positively correlated to self-assessment pain score
      (p*<0.05). In patients with chronic and episodic pain, NE and 5-HIAA were
      positively correlated to the duration of disease and were significantly lower
      than in the control group. In neither of these two groups could significant
      correlations be established between these parameters and pain or depression self
      assessment scores. In all groups, positive correlations were seen between the
      neurotransmitter and their metabolites. CONCLUSION: The pathological decrease of
      NE and 5-HIAA in the CSF points to the crucial role of noradrenergic and
      serotonergic transmitter systems in the generation, modulation, and perpetuation
      of chronic and episodic pain syndromes. It indicates that antidepressants are
      effective drugs in these diseases. However, a discriminative neurochemical
      pattern between pain and depression could not be established. The demonstration
      of polyvalent correlations between different neurotransmitters is indicative of
      complex neurobiological coupling between cortical, limbic, and hypothalamic
      neuronal networks on the one hand and the nociceptive descending system on the
      other hand in the genesis of pain and depression.

PMID- 15175859
TI  - Angiomyogenesis for cardiac repair using human myoblasts as carriers of human
      vascular endothelial growth factor.
AB  - This study investigated the potential of human skeletal myoblast carrying human
      VEGF(165) for angiomyogenesis for cardiac repair. A porcine heart model of
      chronic infarction was created in 18 female swine by coronary artery ligation.
      The animals were randomized into: group 1, DMEM injected ( n=6), group 2,
      myoblast transplanted ( n=5) and group 3, VEGF(165) myoblast transplanted ( n=7).
      Three weeks later 5 ml DMEM containing 3x10(8) myoblast carrying exogenous genes
      were injected into 20 sites in left ventricle intramyocardially in groups 2 and
      3. Group 1 animals were injected 5 ml DMEM without cells. Animals were kept on 5
      mg/kg cyclosporine per day for 6 weeks. Regional blood flow was measured using
      fluorescent microspheres. The heart was explanted between 6-12 weeks after
      transplantation for histological studies. Histological examination showed
      survival of lac-z expressing myoblasts in host tissue. Capillary density at low
      power field (x100) was 57.13+/-4.20 in group 3 which was significantly higher
      than the other groups. Regional blood flow was significantly improved 6 and 12
      weeks after transplantation, which was 2.41+/-0.11 and 3.39+/-0.11 ml(-1) min(-1)
      g(-1), respectively, in group 3. Left ventricular ejection fraction increased
      from 31.25+/-4.09% to 43.0+/-2.68% at 6 weeks in group 3. Human myoblasts are
      potential transgene carriers for the myocardium, in addition to strengthening the
      weakened myocardium through myogenesis.

PMID- 15175860
TI  - Nonviral DNA vectors for immunization and therapy: design and methods for their
      obtention.
AB  - The use of plasmid DNA for vaccination and therapy is a relatively novel
      technology, with advantages and limitations as with other gene transfer
      techniques. The technology is based on DNA vectors designed for administering
      genes coding for relevant proteins into a given organism, fulfilling requirements
      of the regulatory agencies that once properly formulated and delivered the
      desired vaccine/therapeutic effect can be achieved. Starting from conventional
      plasmid DNA vectors currently tested in clinical trials, improvement resulted in
      bacterial element-less vectors, increasing the complexity of the developmental
      process. The present review focuses on systems described for generating these
      nonviral DNA vectors for immunization and therapy from bacterial hosts
      (conventional and conditionally replicating plasmids, nonreplicating minicircles,
      and linear dumbbell-shaped expression cassettes) in vivo or in vitro.
      Additionally, nontherapeutic genetic sequences with a negative or positive effect
      according to the specific application are described, bringing a better
      comprehension of the technology's state of the art.

PMID- 15175862
TI  - Autoantigens of the nuclear pore complex.
AB  - The nuclear envelope (NE) is one of many intracellular targets of the autoimmune
      response in patients with autoimmune liver disease, systemic lupus erythematosus,
      and related conditions. In eukaryotic organisms the NE consists of five
      interconnected regions: an outer nuclear membrane (ONM) that is continuous with
      the endoplasmic reticulum, an intermembrane or perinuclear space, an inner
      nuclear membrane (INM) with a unique set of integral membrane proteins, the
      underlying nuclear lamina, and the pore domains that are regions where the ONM
      and INM come together. The pore domains are sites of regulated continuity between
      the cytoplasm and nucleus that are occupied by supramolecular structures, termed
      nuclear pore complexes (NPCs). Human autoantibodies identified to date bind to
      specific components in three of the five NE compartments. Autoantigen targets
      include the lamins A, B, and C of the nuclear lamina, gp210, p62 complex
      proteins, Nup153, and Tpr within the NPC, and LBR, MAN1, LAP1, and LAP2 that are
      integral proteins of the INM. Autoantibodies to these NE targets have been shown
      to be correlated with various autoimmune diseases such as primary biliary
      cirrhosis, other autoimmune liver diseases and systemic rheumatic diseases. Now
      that the proteome of the NE is more clearly defined, other autoantibodies to
      components in this cell compartment are likely to be defined.

PMID- 15175864
TI  - Lack of association of polymorphisms of the lymphotoxin alpha gene with
      myocardial infarction in Japanese.
AB  - Vascular inflammation plays an important role in the development of myocardial
      infarction (MI). Lymphotoxin alpha (LTA) is a cytokine with multiple functions in
      regulation of the immune system and inflammatory reactions. The aim of this study
      was to examine whether polymorphisms of the LTA gene are associated with the risk
      of MI in Japanese men and women. A case-control association study was performed
      for the 252A-->G and 804C-->A polymorphisms of the LTA gene and the prevalence of
      MI. The study population comprised 3,689 unrelated Japanese individuals (2,486
      men, 1,203 women), including 1891 patients with MI (1,493 men, 398 women) and
      1798 control subjects (993 men, 805 women). Among the control subjects 257
      individuals (108 men, 149 women) who had none of the conventional risk factors
      for coronary artery disease (CAD) were defined as low-risk controls. Genotypes
      for the two polymorphisms were determined with a fluorescence-based allele
      specific DNA primer assay system. Among all study subjects the 252A-->G and 804C-
      >A polymorphisms exhibited linkage disequilibrium. No association of either
      polymorphism with MI was detected in men or in women in comparisons with total
      control or low-risk control subjects. However, each of the two polymorphisms was
      associated with the prevalence of type 2 diabetes mellitus both in men with MI
      and in those without MI in a recessive genetic model. No association was detected
      between the polymorphisms and other conventional risk factors for CAD. The LTA
      gene thus does not appear to be a susceptibility locus for MI in Japanese men or
      women, although it might affect susceptibility to type 2 diabetes in Japanese
      men.

PMID- 15175865
TI  - [Excimer laser. Treatment of iatrogenic hypopigmentation following skin
      resurfacing].
AB  - As skin resurfacing has become more common, the number of patients developing
      post-treatment hypopigmentation has increased. No effective treatment for this
      complication has been developed. Some hypopigmented disorders, including
      vitiligo, have been treated with the excimer laser. We used the XeCl excimer
      laser to successfully treat a 78-year-old woman with perioral leukoderma
      following CO(2) laser skin resurfacing. The repigmentation was stable for at
      least 16 months. Larger prospective studies of this new therapeutic intervention
      are recommended to evaluate its efficacy and long-term stability.

PMID- 15175866
TI  - [The moat technique. A two-step surgical technique for extensive basal cell
      carcinomas of the lip].
AB  - Surgery of large basal cell carcinomas (BCC) in problematic locations is
      sometimes challenging. A two-step surgical treatment of extensive BCC of the
      upper lip with the moat technique as an alternative to temporary wound closure
      will be illustrated using the example of two patients: In the first step, only
      the safety margin around the tumor is removed. After micrographic examination
      proves the lateral margins to be tumor-free, the tumor itself with all layers of
      the upper lip is removed in a second step. The defect is then closed with
      advancement flaps. If tumor resection does not involve all layers, the
      histopathologic interpretation of the base is first possible after complete
      surgical closure. The moat technique offers several advantages: The infection
      risk is minimized and the patient can eat and drink with an intact lip while
      resection margins are processed overnight. Tumor-free tissue is spared through
      the step-by-step procedure; the extent of plastic surgery is thus reduced and
      good functional and cosmetic results can be achieved. In addition, the
      perioperative period is less complicated.

PMID- 15175861
TI  - Neurodegenerative disorders associated with diabetes mellitus.
AB  - More than 20 syndromes among the significant and increasing number of
      degenerative diseases of neuronal tissues are known to be associated with
      diabetes mellitus, increased insulin resistance and obesity, disturbed insulin
      sensitivity, and excessive or impaired insulin secretion. This review briefly
      presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down
      syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of
      mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome,
      Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative
      phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive
      megaloblastic anemia syndrome as well as their respective relationship to
      malignancies, cancer, and aging and the nature of their inheritance (including
      triplet repeat expansions), genetic loci, and corresponding functional
      biochemistry. Discussed in further detail are disturbances of glucose metabolism
      including impaired glucose tolerance and both insulin-dependent and non-insulin
      dependent diabetes caused by neurodegeneration in humans and mice, sometimes
      accompanied by degeneration of pancreatic beta-cells. Concordant mouse models
      obtained by targeted disruption (knock-out), knock-in, or transgenic
      overexpression of the respective transgene are also described. Preliminary
      conclusions suggest that many of the diabetogenic neurodegenerative disorders are
      related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial
      nutrient metabolism, which coincide with aberrant protein precipitation in the
      majority of affected individuals.

PMID- 15175867
TI  - [Antitumoral action of interferons and interleukins in combination with
      radiotherapy. Part II: radiobiological and immunologic strategies].
AB  - BACKGROUND: Combined tumor treatment with cytokines, e. g., interferons (IFN),
      and radiotherapy was initially of phenomenological nature but has increasingly
      been based on a radiobiological rationale. However, an improved understanding of
      the complex interactions of the cytokine network within the immune system
      warrants the rationale for such studies to be reviewed. METHODS: Based on
      published clinical studies, the results of treatment with interferons in
      combination with radiotherapy are reviewed. New strategies for antitumoral
      application of cytokines, illustrated by interleukin-(IL-)2 and IL-12 in
      preclinical and clinical studies, are presented. RESULTS: The initially high
      expectations regarding the antitumoral action of IFN-alpha, IFN-beta and IFN
      gamma in combination with radiotherapy have, with few exceptions, not been
      fulfilled. In particular, toxicity has been a problem after systemic application.
      Recent advances in immunology, however, have emphasized the importance of local
      interactions between antigen-presenting cells and effector cells such as natural
      killer (NK) cells and cytotoxic T-lymphocytes in the immune reaction against
      tumors. Preclinical studies with IL-2 und IL-12 have shown efficacy mainly
      against early metastases, but immune reactions against primary tumors have also
      been observed. Furthermore, the method and timing of the application have proven
      to be critical. CONCLUSION: A few positive clinical studies give cause for hope
      that a therapeutic benefit may be achieved by targeted, local application of
      cytokines. Recent preclinical studies indicate the importance of cellular
      cytokine production in the interaction between the components of the immune
      system. Gene therapy might contribute to reduce the toxicity associated with
      cytokine treatment.

PMID- 15175868
TI  - Verification of IMRT: techniques and problems.
AB  - PURPOSE: IMRT (intensity-modulated radiotherapy) verification techniques are
      reviewed together with investigations demonstrating the intrinsic verification
      problems. MATERIAL AND METHODS: Different IMRT verification procedures for either
      class solutions or individual patients are demonstrated. Among the latter are
      techniques like fluence or three-dimensional (3-D) dose distribution verification
      within a transfer phantom. Different radiographic films and absolute dose probes
      are investigated for their suitability. Finally, Monte Carlo techniques
      (XVMC/VEF) are used for error detection and IMRT verification. RESULTS: During
      introduction of clinical IMRT for head and neck (H and N) tumors, we concurrently
      applied fluence, relative, and absolute dose measurement. While fluence and
      relative dose are in rather good agreement with calculations, absolute dose is
      always low when compared to the TPS (TMS 6.1A, Nucletron B.V.) by 5-7%. This
      deviation seems to depend not on the number of segments, but can strongly depend
      on MLC misalignment. Further investigations have revealed the importance of a
      detailed commissioning of the TPS down to the small-field range using diamond or
      diode probes and its detailed verification. In addition, simple tests have shown
      that dose calculation approximations in the IMRT option of TMS are one major
      source of the dose deviation. XVMC/VEF does not use such approximations.
      CONCLUSION: The procedure starts with a detailed TPS commissioning and
      verification process. Different verification methods are recommended during
      clinical IMRT implementation phase, in order to locate sources of error. Later
      on, a minimal program could consist of a fluence or relative dose verification
      procedure with few films and absolute dose measurement, followed by an intensive
      MLC quality assurance (QA). Inverse Monte Carlo systems, like IMCO(++)/IKO or
      Hyperion, seem to be able to reduce the effort.

PMID- 15175869
TI  - Applicability and dosimetric impact of ultrasound-based preplanning in high-dose
      rate brachytherapy of prostate cancer.
AB  - BACKGROUND AND PURPOSE: Analyses of permanent brachytherapy seed implants of the
      prostate have demonstrated that the use of a preplan may lead to a considerable
      decrease of dosimetric implant quality. The authors aimed to determine whether
      the same drawbacks of preplanning also apply to high-dose-rate (HDR)
      brachytherapy. PATIENTS AND METHODS: 15 patients who underwent two separate HDR
      brachytherapy implants in addition to external-beam radiation therapy for
      advanced prostate cancer were analyzed. A pretherapeutic transrectal ultrasound
      was performed in all patients to generate a preplan for the first brachytherapy
      implant. For the second brachytherapy, a subset of patients were treated by
      preplans based on the ultrasound from the first brachytherapy implant. Preplans
      were compared with the respective postplans assessing the following parameters:
      coverage index, minimum target dose, homogeneity index, and dose exposure of
      organs at risk. The prostate geometries (volume, width, height, length) were
      compared as well. RESULTS: At the first brachytherapy, the matching between the
      preplan and actual implant geometry was sufficient in 47% of the patients, and
      the preplan could be applied. The dosimetric implant quality decreased
      considerably: the mean coverage differed by -0.11, the mean minimum target dose
      by -0.15, the mean homogeneity index by -0.09. The exposure of organs at risk was
      not substantially altered. At the second brachytherapy, all patients could be
      treated by the preplan; the differences between the implant quality parameters
      were less pronounced. The changes of prostate geometry between preplans and
      postplans were considerable, the differences in volume ranging from -8.0 to 13.8
      cm(3) and in dimensions (width, height, length) from -1.1 to 1.0 cm. CONCLUSION:
      Preplanning in HDR brachytherapy of the prostate is associated with a substantial
      decrease of dosimetric implant quality, when the preplan is based on a
      pretherapeutic ultrasound. The implant quality is less impaired in subsequent
      implants of fractionated brachytherapy.

PMID- 15175863
TI  - Nuclear factor-kappaB: its role in health and disease.
AB  - Nuclear factor-kappaB (NF-kappaB) is a major transcription factor that plays an
      essential role in several aspects of human health including the development of
      innate and adaptive immunity. The dysregulation of NF-kappaB is associated with
      many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer,
      diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral
      infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a
      major mediator of some human genetic disorders. Appropriate regulation and
      control of NF-kappaB activity, which can be achieved by gene modification or
      pharmacological strategies, would provide a potential approach for the management
      of NF-kappaB related human diseases. This review summarizes the current knowledge
      of the physiological and pathophysiological functions of NF-kappaB and its
      possible role as a target of therapeutic intervention

PMID- 15175870
TI  - On the actual state of industrial quality assurance procedures with regard to
      (106)Ru ophthalmic plaques.
AB  - BACKGROUND: In radiotherapy of intraocular tumors, e. g., in the case of malign
      choroid melanomas, episcleral brachytherapy with (106)Ru ophthalmic plaques has
      proven to be successful. In a study, the authors reported on the discovery of the
      following shortcomings in industrial quality assurance, which are relevant to
      therapy, during the course of an internal clinical acceptance test of (106)Ru
      ophthalmic plaques, manufactured by the company Bebig from Berlin, Germany. This
      consisted of inconsistent dose rate specifications in the manufacturer's
      certificate, covering a range of 111% and with the risk of leakage of the
      plaques. Bebig was called upon to adapt state-of-the-art production methods with
      regard to (106)Ru ophthalmic plaques. MATERIAL AND METHODS: In the meantime,
      Bebig has modernized production of (106)Ru ophthalmic plaques and adopted all the
      quality assurance procedures proposed by the authors. Moreover, the requested
      traceability of the calibration of activity and dose rate of the (106)Ru
      ophthalmic plaques to standards of the federal authorities in charge of
      measurement procedures has been implemented. RESULTS: In the year 2002, Bebig
      updated, among other things, the ASMW (GDR) calibration of the dose rate of the
      (106)Ru ophthalmic plaques from the years 1987-1989 by a calibration of the NIST
      (USA). The current NIST calibration, together with the new equipment for the
      measurement of the depth dose curves, led to the consequence that the new NIST
      2001 dose rate values show, in the mean, a deviation of 0.75 times (plaque type
      CCC) up to 2.06 times (plaque types CCX, CCY, and CCZ) compared to the dose rate
      values that had been indicated so far in Bebig's certificate, based on the ASMW
      1987 calibration. For the 95% confidence interval, Bebig estimated the
      measurement uncertainty to be +/- 25%. If one takes into consideration the
      minimal and maximal values in such 95% confidence intervals, it follows that the
      new NIST 2001 dose rate values deviate between 0.56 times (plaque type CCC) and
      2.58 times (plaque types CCX, CCY, and CCZ) from the Bebig certificate (ASMW
      calibration 1987). As regards leakage, no objections arose in the case of the
      (106)Ru ophthalmic plaques produced according to the new quality standards.
      CONCLUSION: Legislation has to make sure that the use of radioactive material on
      humans be, among other things, permitted as a matter of principle only, if the
      dose rate calibration can be traced to standards of a federal authority of
      measurement procedures. Furthermore, special leakage tests for radiation sources
      which come into direct contact with body fluids should be established. A
      historical retrospect reveals that the greatest changes have taken place in the
      indication of the dose rates of (125)I sources. Since the beginning of the use of
      (125)I sources in brachytherapy in the late 1960s, the dose rate indications, so
      far, have had to be reduced in small steps over a period of about 35 years by
      nearly a factor of 2. As regards the (106)Ru ophthalmic plaques, the NIST 2001
      calibration has resulted in a comparable reduction of the dose rate indications
      of up to a factor of 2 within the period of about several months. Thus, in the
      previous history of radiotherapy this case must be regarded as unique, because
      for the first time ever, an urgently needed recalibration has been protracted for
      such an unduly long period of time.

PMID- 15175871
TI  - Intraoperative radiotherapy of soft tissue sarcoma of the extremity.
AB  - PURPOSE: Evaluation of treatment outcome after intraoperative radiotherapy (IORT)
      +/- external-beam irradiation (EBRT) in patients with localized soft tissue
      sarcoma of the extremity at high risk for local recurrence after limb-sparing
      surgery. PATIENTS AND METHODS: 28 patients treated between 1989 and 1999 were
      evaluated retrospectively. Patients presented with locally recurrent (n = 17), T2
      (n = 20), high-grade (n = 26), or incompletely resected tumors (n = 11). All
      patients underwent limbsparing surgery and IORT (median dose of 15 Gy) given
      either with high-dose-rate brachytherapy or a linear accelerator. 25 patients
      received additional EBRT with a mean of 50.6 Gy (range: 30.6-60 Gy). The mean
      follow-up time was 4.3 years (95% confidence interval [CI]: 3.0-5.6 years).
      RESULTS: The 5-year overall and distant disease-free survival rates were 66% and
      54%, respectively. The overall actuarial recurrence rate after 5 years is 16%
      (95% CI: 1%, 31%). The crude rate after 8 years is 18%. Surgical margin status,
      primary versus recurrent tumor and tumor stage did not show any statistically
      significant influence (univariate analysis) on local recurrence rates. Patients
      with T1 tumors exhibited a borderline significant (p = 0.053) better distant
      disease-free survival (83%) compared to T2 tumors (43%). Five (24%) grade 3-4
      late side effects were observed. CONCLUSION: In patients with high-risk soft
      tissue sarcomas, IORT +/- EBRT after limb-preserving surgery achieves high local
      control rates. The risk of normal tissue toxicities is comparable to conventional
      limb-sparing treatment.

PMID- 15175872
TI  - [Early loss of teeth after treatment for childhood leukemia].
AB  - BACKGROUND: Only few reports of effects of radiotherapy in childhood on the
      dental apparatus are available in the literature. The basis for early loss of
      teeth appears to be a reduction of the root surface area after radiation
      exposure. These effects in the periodontium are a consequence of combined
      radiochemotherapy usually applied for treatment of childhood neoplasia.
      Chemotherapy alone also results in changes of periodontal development. CASE
      REPORT: A 33-year-old patient is reported, who, at the age of 11 years, received
      high-dose chemotherapy and radiotherapy of neuroaxis and cranium for acute
      lymphatic leukemia with relapse. The patient consulted the Implant Section of the
      Department of Oral and Maxillofacial Surgery because of severe dental changes and
      tooth loss despite adequate dental care and oral hygiene. Radiation doses given
      to the superior maxilla and mandible at the age of 11 were estimated to be in the
      range of 8-25 Gy. CONCLUSION: Intense, life-long dental care and follow-up of
      patients cured from malignant disease in childhood must hence be postulated in
      order to minimize dental treatment sequelae by supportive measures, but also to
      initiate timely adequate dental and prosthetic management.

PMID- 15175873
TI  - Effect of the hypoxic cell sensitizer isometronidazole on local control of two
      human squamous cell carcinomas after fractionated irradiation.
AB  - BACKGROUND AND PURPOSE: Hypoxia of clonogenic tumor cells is a major reason for
      radioresistance and hence local failure in radiotherapy. The objective of the
      present study was to test the efficacy of the hypoxic cell sensitizer
      isometronidazole (ISO) during fractionated irradiation in two different human
      squamous cell carcinomas. MATERIAL AND METHODS: Local control was evaluated for
      FaDu (radiobiological hypoxic fraction [rHF] 7%) and GL tumors (rHF 0.1%) after
      single-dose (SD) irradiation under ambient conditions and after 30 fractions
      within 6 weeks (30 f/6 w). ISO was applied 60 min before SD irradiation at a
      concentration of 100 mg/kg body weight (b.w.) or 750 mg/kg b.w. in both tumors.
      During fractionated irradiation, ISO was applied daily 60 min before each
      fraction (100 mg/kg b.w., in FaDu also 750 mg/kg b.w.). RESULTS: 100 mg/kg b. w.
      ISO did not improve local control after SD irradiation or 30 f/6 w in both tumor
      models. Application of 750 mg/kg b. w. ISO significantly decreased the SD-TCD(50)
      in FaDu tumors (dose-modifying factor [DMF] = 1.2; p = 0.01) but not in the
      better oxygenated GL tumor. ISO at 750 mg/kg b.w. also significantly improved
      local control of FaDu tumors after 30 fractions in 6 weeks (DMF = 1.2; p = 0.01),
      indicating that hypoxic clonogenic cells in FaDu tumors are not only present
      before start of irradiation but also limit the efficacy of treatment during a
      fractionated course of radiotherapy. CONCLUSION: ISO at a concentration of 750
      mg/kg b.w. shows an efficacy as a hypoxic cell sensitizer in severely hypoxic
      FaDu tumors but not in less hypoxic GL tumors. This supports the principle of
      hypoxic cell sensitization and improvement of local control of hypoxic tumors by
      nitroimidazole derivatives. However, doses of 750 mg/kg b. w. before each
      fraction may be difficult to achieve in the clinical situation. This, in light of
      the fact that other well-tolerable hypoxic cell sensitizers such as nimorazole
      with clinically proven efficacy at daily oral doses of < 3 g are available,
      limits the potential usefulness of ISO for radiation oncology.

PMID- 15175874
TI  - Oxygenation of tumor recurrences following fractionated radiotherapy of primary
      tumors. Studies on the rhabdomyosarcoma R1H of the rat.
AB  - BACKGROUND AND PURPOSE: Tumor oxygenation is well recognized as a major factor of
      tumor response to radiotherapy. In this respect, a number of studies have
      examined the response of primary tumors, whereas little is known about the
      oxygenation of tumor recurrences after radiotherapy. It was the aim of this study
      to investigate the oxygenation of tumor recurrences after preceding irradiation
      of the primary tumor. MATERIAL AND METHODS: Tumor oxygenation in primary tumors
      and recurrences of rat rhabdomyosarcomas R1H was measured by using pO(2) probes
      and Eppendorf pO(2) histography. Primary tumors were irradiated at a (60)Co
      radiotherapy facility with a total dose of 75 Gy, given in 30 fractions over 6
      weeks. Oxygenation was measured in R1H tumors before and directly after
      completion of irradiation. In R1H recurrences oxygenation was determined, when
      they reached the same size as the previously treated primary tumors (V(o) = 3.1
      +/- 0.5 cm(3)). Additionally, tumor microvessel density and the intercapillary
      distance of tumor blood vessels were determined on histological sections using a
      counting grid. RESULTS: Tumor oxygenation in R1H recurrences was significantly
      lower when compared to primary R1H tumors. In primary tumors a median pO(2) of 17
      +/- 7 mmHg was measured. By contrast, the median pO(2) in R1H recurrences was
      only 5 +/- 5 mmHg (p < 0.05). The high frequency of pO(2) values < 5 mmHg
      indicated that R1H recurrences were significantly more hypoxic (58 +/- 5%) in
      comparison to primary tumors (22 +/- 4%). The histological sections of the R1H
      recurrences showed a higher heterogeneity in their tissue structure than primary
      nonirradiated tumors. The morphometric studies demonstrated a reduced microvessel
      density (91 +/- 21/9.04 mm(2) in the tumor periphery; p = 0.0001) compared with
      recurrent tumors (68 +/- 26) and an enhanced mean distance of tumor blood
      vessels, especially in the center of the R1H recurrences (184 +/- 20 vs. 243 +/-
      70 mm; p = 0.0001). CONCLUSION: In R1H rhabdomyosarcomas tumor oxygenation in
      recurrent tumors following radiation therapy is significantly lower than in
      primary tumors. This observation has to be taken into account in cases of tumor
      recurrences where repeated radiotherapy, chemotherapy or combined treatment
      modalities are used.

PMID- 15175875
TI  - Recognizing evidence for what it is.

PMID- 15175876
TI  - Intercellular communication within the rat anterior pituitary: relationship
      between LH-RH neurons and folliculo-stellate cells in the pars tuberalis.
AB  - The distribution of LH-RH-positive nerve fibers in the median eminence was
      demonstrated in the 1970s and 1980s. A few LH-RH fibers have been reported to be
      present in the adjacent pars tuberalis of the pituitary, but their functional
      significance has not been clarified and still remains enigmatic. Adult male
      Wistar-Imamichi rats were separated into two groups: one for immunohistochemistry
      of LH-RH and S-100 protein (for the identification of folliculo-stellate cells)
      and the other for electron microscopy. For both immunohistochemistry and electron
      microscopy, the specimens obtained contained the pituitary gland connected with
      the hypothalamus. Numerous LH-RH-positive fibers were observed as tiny lines with
      several varicosities both on the primary vascular plexus and in the hypothalamus
      corresponding to the posterior half of the portal vein area. LH-RH-positive
      fibers were also noted around S-100-positive cells in the pars tuberalis. Weakly
      reactive S-100 cells were scattered in the pars tuberalis in the midsagittal
      plane, while clusters of strong reactive elements occurred 100-300 microm from
      the center. Similar observations were made using fluorescence
      immunohistochemistry for LH-RH and S-100, and at the electron-microscopic level.
      At the posterior portion of the portal vein system, bundles of the LH-RH
      immunoreactive fibers invaded the pars tuberalis and terminated on agranular
      cells. Gap junctions were clearly seen among agranular cells corresponding to
      folliculo-stellate cells. It is postulated that the LH-RH message might be
      transmitted not only by the established hypophyseal portal vein system but also
      via the folliculo-stellate cells in the pars tuberalis to aid in the modulation
      of LH release.

PMID- 15175877
TI  - Trichomonas vaginalis: cytochemical localization of a NTPDase1 and an ecto-5'
      nucleotidase and effects of adenine nucleotides on cellular viability.
AB  - Nucleoside triphosphate diphosphohydrolase 1 (NTPDase1), which hydrolyzes
      extracellular ATP and ADP, and ecto-5'-nucleotidase, which hydrolyzes AMP, are
      characterized for Trichomonas vaginalis. Ultrastructural cytochemical microscopy
      showed NTPDase1 and ecto-5'-nucleotidase activities on the surface of the
      parasites. High levels of extracellular adenine nucleotides and adenosine did not
      exert cytolytic effects in intact cells of T. vaginalis. Our results suggest that
      these enzymes are relevant for the survival of the parasite during exposure to
      extracellular nucleotides. Since the ecto-localization of these enzymes is
      essential for the maintenance of adenosine extracellular levels, this nucleoside
      could be important for the purine salvage pathway in the parasite.

PMID- 15175878
TI  - Allozyme analysis of genetic variation and polymorphism in Eubothrium salvelini
      and E. crassum (Cestoda: Pseudophyllidea) from alpine lakes.
AB  - The genetic structure of the most abundant species in the genus Eubothrium, E.
      crassum and E. salvelini, was studied by allozyme analysis in order to provide a
      consistent diagnosis for these morphologically similar species, as well as to
      assess their genetic relatedness. The proportion of fixed allelic differences
      (56.3%, 9 of 16 loci) between the species falls within the range accepted for
      valid species. A strict host specificity of E. crassum and E. salvelini for their
      typical host (lake trout, Arctic charr, respectively) was found in the French
      localities examined (Lake Annecy, Lake Bourget). For E. salvelini, polymorphism
      with the established allelic profile was found in the acid phosphatase (ACP)
      system. No significant deviation from the Hardy-Weinberg equilibrium expectations
      for ACP were found in either of the E. salvelini populations, which suggests
      predominantly cross-fertilization of these hermaphrodites. Analysis of the
      standardized variance in allelic frequencies demonstrated almost no among
      population differentiation (estimator theta of Fst = -0.03) between E. salvelini
      populations.

PMID- 15175879
TI  - Argas persicus sensu stricto does occur in Australia.
AB  - The status of Argas persicus in Australia has been a matter of controversy for
      over 25 years. Although early records of A. persicus sensu stricto are common, a
      major revision of the genus indicated that these records refer to A. robertsi,
      first described in 1968 from northern Australia, and to an "undescribed" member
      of the complex occurring in the south. Here, we show that A. persicus sensu
      stricto does occur in southern Australia and is the only species of Argas in the
      area recorded from poultry. Another undescribed species belonging to the A.
      persicus complex, from crows' nests near Lake Eyre in South Australia, was also
      discovered. This information is of considerable epidemiological significance, as
      A. persicus sensu stricto is a major vector for a number of highly pathogenic
      diseases of poultry, not all of which have yet been recorded from Australia.

PMID- 15175880
TI  - CDX-2, cytokeratin 7 and cytokeratin 20 immunohistochemical expression in the
      differential diagnosis of primary adenocarcinomas of the sinonasal tract.
AB  - Because the histopathological features of some primary adenocarcinomas of the
      sinonasal tract may show considerable overlap, we assessed the diagnostic value
      of a panel of immunohistochemical markers in the distinction between these
      malignancies. Paraffin-embedded tumour tissue sections from a series of 39
      primary adenocarcinomas of the sinonasal tract, including 25 cases of intestinal
      type adenocarcinoma (ITAC), 10 cases of salivary gland-type carcinoma and 4 cases
      of tubulopapillary low-grade adenocarcinoma were immunostained for CDX-2,
      cytokeratin 7 and cytokeratin 20. Diffuse nuclear staining for CDX-2 was
      identified in 80% of ITACs, while all non-ITACs were negative. Staining for
      cytokeratin 20 was positive in 84% of ITACs, including all cases negative for CDX
      2, but negative in all other adenocarcinomas. Cytokeratin 7 was consistently
      positive in 88% of ITACs and in 100% of non-ITACs. Normal sinonasal epithelia
      expressed cytokeratin 7, but not CDX-2 and cytokeratin 20. Staining for CDX-2 and
      cytokeratin 20 has potential use in separating ITACs from other primary malignant
      glandular neoplasms of the nasal cavities and paranasal sinuses.

PMID- 15175881
TI  - Morphometric analysis of the lung vasculature after extracorporeal membrane
      oxygenation treatment for pulmonary hypertension in newborns.
AB  - Persistent pulmonary hypertension in the newborn (PPHN) is characterised by
      increased medial and adventitial thickness in the lung vasculature. This study
      describes morphometry of lung vasculature after extracorporeal membrane
      oxygenation (ECMO) in newborns with PPHN, due to meconium aspiration syndrome,
      sepsis or idiopathic persistent pulmonary hypertension of the newborn (i-PPHN).
      Three groups were studied: newborns with PPHN treated with ECMO (n=9), newborns
      with PPHN not treated with ECMO (n=12) and age-matched controls without PPHN
      (n=11). In pulmonary arteries with an external diameter of less than 150 microm,
      arterial media, adventitia and total wall thickness, expressed as a percentage of
      the external diameter, and their cross-sectional areas were calculated. Newborns
      with PPHN, compared with controls, demonstrated increased percentage of media
      thickness, adventitia thickness and total wall thickness, and increased medial,
      adventitial and total wall cross-sectional area. Newborns treated with ECMO,
      compared with those not treated so, showed a decreased percentage of media
      thickness and medial cross-sectional area in arteries with an external diameter
      less than 75 microm, and decreased percentage of media thickness and decreased
      medial, adventitial and total wall cross-sectional area in arteries with an
      external diameter of 75-150 microm. ECMO for persistent PPHN, due to meconium
      aspiration syndrome, sepsis or i-PPHN, reduces the abnormal morphometry of small
      pulmonary arteries. The underlying mechanisms contributing to this improved
      morphometry are yet unknown.

PMID- 15175882
TI  - Pseudoaneurysm after total pharyngolaryngectomy with jejunal graft insertion: two
      different presentations.
AB  - Pharyngeal reconstruction after total pharyngolaryngectomy using a jejunal graft
      is now a common procedure in head and neck oncological surgery. The vascular
      supply of this graft comes from the anastomosis between a branch of the mesentric
      artery and a branch of the external carotid artery. We report two cases of
      pseudoaneurysm, one at the site of ligation of the lingual artery and the other
      at the site of arterial anastomosis. One presented with dramatic hematemesis and
      was managed by the interventional radiologist, and the second presented with a
      pulsating neck mass and required a surgical revision. In both cases, the jejunal
      graft survived.

PMID- 15175884
TI  - Tortuous internal carotid artery indenting the piriform sinus: a case report.
AB  - A case of tortuous internal carotid artery bulging and partially obliterating the
      piriform sinus, causing a sensation of fullness and abnormal throat, accompanied
      by choking spells in a 57-year-old patient is presented. Endoscopic examination
      and computerized tomographic angiography were useful in establishing the
      diagnosis. This rare anomaly should be recognized in order to prevent possible
      fatal hemorrhages during further surgical interventions of the piriform sinus.

PMID- 15175883
TI  - Reconstruction of the hypopharynx with U-shaped pectoralis major myocutaneous
      flap after total pharyngo-laryngectomy.
AB  - Resection of the whole circumference of the pharynx and esophagus is usually
      reconstructed with gastric pull-up, jejunum free graft or free forearm flap. The
      aim of this study was to assess the use of pectoralis major myocutaneous flap for
      closure of total pharyngeal defect. In 11 patients with hypopharynx and larynx
      cancer, total pharyngo-laryngectomy and excision of the cervical part of the
      esophagus and neck dissections were performed; the defects were closed with
      pectoralis major myocutaneous flaps. The skin island was sutured to prevertebral
      muscles, forming a letter U shape. Good healing was obtained in six patients, and
      five patients developed fistula that closed spontaneously within 3-4 weeks. The
      use of U-shaped pectoralis major myocutaneous flap, suturing it to prevertebral
      muscles, gives good functional results, and it is a simple and time-saving second
      choice method of reconstruction of the pharynx after total pharyngo-laryngectomy.

PMID- 15175885
TI  - Maternal-fetal status of copper, iron, molybdenum, selenium and zinc in insulin
      dependent diabetic pregnancies.
AB  - OBJECTIVE: The objective was to assess the status of essential trace elements
      such as copper, iron, molybdenum, selenium and zinc in insulin-dependent diabetic
      pregnancies at term and to compare the data with a control group. Fetal-maternal
      ratios of the elements and copper:zinc ratio were also computed in the control
      and study populations. METHODOLOGY: Samples from maternal vein, umbilical artery
      and umbilical vein of diabetic and control women were collected at the time of
      spontaneous delivery or cesarean section and activities of trace elements
      evaluated by atomic absorption spectrophotometry. RESULTS: Cu, Fe, Mo, Se and Zn
      concentrations in maternal venous blood averaged 2,156, 2,020, 13, 102 and 656
      microg/l in control women (n=17) while in the diabetic group (n=14), the
      corresponding values for the trace elements averaged 3,135, 3,675, 15, 85 and 628
      microg/l respectively. Values for copper and molybdenum were significantly higher
      (p<0.05) in the study group compared to control while those of zinc, iron and
      selenium were not significantly different (p>0.05). Iron and molybdenum values
      were significantly higher (p<0.05) and that of zinc significantly lower (p<0.05)
      in umbilical arterial samples of diabetic group compared to controls. In the case
      of molybdenum, copper the values were significantly higher (p<0.05) in umbilical
      venous samples of diabetic group compared to that of control. Significant
      differences in Cu:Zn ratio of maternal venous and umbilical samples and fetal
      maternal ratios of some elements were noted between control and study group as
      well. CONCLUSION: We speculate that altered status of some essential trace
      elements and altered antioxidant mineral ratio observed in insulin dependent
      diabetic patients could have deleterious influences on the health of the mother
      as well as the fetus and newborn.

PMID- 15175886
TI  - The value of uterine artery Doppler ultrasound in the prediction of severe
      complications in a risk population.
AB  - AIM: The aim of this prospective study was to assess the role of uterine artery
      color Doppler waveform analysis in the prediction of adverse pregnancy outcome
      such as preeclampsia, intrauterine growth retardation, placental abruption or a
      combination of outcome parameters in risk pregnancies (n=52). METHODS: Various
      uterine artery Doppler ultrasound parameters (resistance index (RI)>0.58, RI>0.7
      and uni/bilateral or bilateral notching) were tested. The mean time of delivery
      was 37+1 weeks' gestation. Six newborns (12%) were delivered before 34 weeks of
      gestation. The mean birth weight was 2,910 g. Dystrophic fetuses (<10%
      percentile) were registered in 7 cases (13%). In 11 of the 52 women (21%) a
      cesarean section was performed because of abnormal fetal heart recording.
      RESULTS: Preeclampsia was diagnosed in 4 cases (8%). In 4 cases (8%) an
      intrauterine fetal death was diagnosed. Placental abruption did not occur. The
      sensitivity of notching for the prediction of preeclampsia and for the prediction
      of a severe pregnancy complication was 75 and 69% with relative risks of 2.7 and
      2.0. The sensitivity of notching in the uterine arteries for developing an
      intrauterine growth retardation (IUGR) was 71% with a relative risk of 2.2. The
      sensitivity of RI>0.58 in the uterine arteries for developing an IUGR was 67%
      with a relative risk of 5.4. The sensitivity of RI>0.58 for the prediction of
      preeclampsia, of intrauterine death and for the prediction of a severe pregnancy
      complication was 50, 75 and 80% with relative risks of 2.7, 8.1 and 10.9
      respectively. CONCLUSION: The results of this study suggest that Doppler
      ultrasound of the uterine artery in the second trimester of gestation is a useful
      method to predict abnormal outcomes in risk pregnancies, with high negative
      predictive values.

PMID- 15175887
TI  - Dorsolateral dislocation of the proximal interphalangeal joint: closed reduction
      and early active motion or static splinting; a retrospective study.
AB  - INTRODUCTION: In a follow-up examination 50 patients who had sustained dorsal
      dislocations of the proximal interphalangeal (PIP) joint, the results of two
      conservative therapy regimens, either immobilisation or early motion, were
      investigated. The patients were assigned randomly. The inclusion criteria were:
      adult patients over the age of 18 with isolated, acute, closed dorsolateral
      dislocation of the PIP joint. MATERIALS AND METHODS: In group A, 25 patients were
      treated by closed reduction and immobilisation with a short-arm cast including
      both interphalangeal joints for 4 weeks. In group B, 25 patients were treated by
      dorsal block splinting of the PIP joint following reduction. The finger was
      released in extension with daily active exercise of the PIP joint. RESULTS: In
      group A, 9 patients showed a normal range of motion, whereas a limitation of
      extension of 10 deg and more was seen in 16 patients. All PIP joints were
      clinically stable, and 19 patients were satisfied. Two patients complained of a
      limitation of extension, 3 of limitation of extension and pain, and 1 of pain and
      swelling. In group B, only 2 of 25 patients showed a limitation of extension of
      10 deg and more, whereas 23 patients showed a normal range of motion. Instability
      of one collateral ligament was seen in 2 cases. Palmar instability did not occur,
      and 18 patients were satisfied. One patient complained of instability, pain and
      lack of extension during hard work, 1 of pain in combination with instability, 2
      of pain and 3 of swelling of the joint. CONCLUSION: Early active motion after
      dorsolateral dislocation of the PIP joint produces significantly superior results
      regarding the active range of motion and pinch power than static splinting.

PMID- 15175888
TI  - Infliximab as a therapy for non-Crohn's enterocutaneous fistulae.
AB  - BACKGROUND: Persistent enterocutaneous fistulae are associated with high
      morbidity and mortality and are surgically challenging to repair. Anti-TNF alpha
      antibody (Infliximab) promotes healing of fistulae associated with active
      inflammatory bowel disease (IBD). We report three patients with persistent
      fistulae, not associated with IBD that healed following single infusion of
      infliximab. PATIENTS: Patient 1 was a 31-year-old woman who had a
      panproctocolectomy and ileostomy in 1985 for ulcerative colitis. Twelve years
      after surgery she developed a strangulated parastomal hernia and required
      extensive resection of the small bowel. Postoperatively, she developed an
      enterocutaneous fistula within the midline wound. Radiological studies showed no
      evidence of ongoing active inflammatory bowel disease. The fistula remained
      patent for 3 years after which a single infusion (5 mg/kg) of Infliximab was
      administered. The fistula healed within 1 week and remained closed thereafter.
      Patient 2 was a 48-year-old man who had a polya gastrectomy for a large
      perforated duodenal ulcer. Four days after surgery a large left subdiaphragmatic
      collection was drained under CT guidance. A week later a high-output fistula (500
      to 1000-ml/day) developed from the midline wound. Six weeks later a single
      infusion of Infliximab (5 mg/kg) was administered. The output from the fistula
      was reduced to 50 ml/day on the day 2, and the fistula healed within 3 weeks. It
      remains closed 2 years later. Patient 3 was a 27-year-old man who had a
      pancreatic necrosectomy for acute pancreatitis in 1996. Over the next year he had
      further laparotomies for post-operative complications. As a result, he developed
      a fistula from the small bowel that was confirmed on sinogram. The fistula
      continued to discharge intermittently for the next 2 years at which time he was
      considered for Infliximab therapy. The fistula healed within 10 days of treatment
      and remains closed 6 months later. CONCLUSION: These cases suggest that TNF alpha
      inhibition can accelerate the healing of chronic enterocutaneous fistulae not
      associated with IBD. Further studies are required to assess the effectiveness of
      this treatment formally in this problematic condition.

PMID- 15175889
TI  - Prognostic significance of microsatellite instability in sporadic colorectal
      cancer.
AB  - BACKGROUND AND AIMS: Colorectal cancers exhibiting microsatellite instability
      (MSI) appear to have unique biological behavior. The influence of MSI on the
      prognosis of sporadic colorectal cancers is controversial and requires further
      investigation. The aim of this study was to analyze the association between MSI
      status and clinicopathological features and prognosis in sporadic colorectal
      cancer patients. PATIENTS AND METHODS: Of the 322 consecutive colorectal cancer
      patients operated upon at the Seoul National University Hospital between January
      and December 1998, we examined the clinicopathological features and prognosis of
      248 patients with sporadic primary colorectal cancer. The MSI status of these 248
      patients has been reported in a previous study. Of the 248 patients, 23 (9.3%)
      had MSI+ tumors. The patients' clinicopathological parameters were obtained from
      their medical records, and follow-up and survival data were obtained from medical
      records and phone calls. RESULTS: MSI+ sporadic colorectal cancers were found
      predominantly in the proximal colon ( p<0.001) and were associated with poor
      differentiation ( p=0.030), a lower preoperative serum carcinoembryonic antigen
      (CEA) level ( p=0.012), and less frequent systemic metastasis ( p=0.034) than MSI
      tumors. Low tumor grade ( p=0.022), low tumor T-stage ( p=0.002), no lymph node
      metastasis ( p<0.001), no systemic metastasis ( p<0.001), adjuvant chemotherapy (
      p<0.001) and MSI+ status ( p=0.038) were independent favorable prognostic factors
      for survival in sporadic colorectal cancer patients. CONCLUSION: MSI status was
      an independent favorable prognostic factor for survival in sporadic primary
      colorectal cancer patients.

PMID- 15175890
TI  - The use of ureteral stents and suprapubic catheter in vesicoureteric reflux
      surgery.
AB  - The use of ureteric stents in reimplantation surgery is important. The younger
      the patient, the more important the stenting of ureters post reimplantation
      becomes, because even minimal oedema following surgery will produce ureteric
      obstruction unless stents are in place. JJ stents are now the preferred method of
      choice in ureteric reimplantation surgery, but in the past the patient required
      another admission to hospital and general anaesthetic to have the stents removed
      endoscopically. We describe a technique whereby the stents are attached to the
      suprapubic catheter and are therefore removed prior to the patient's discharge
      from hospital, thus obviating the need for a second admission and second
      anaesthetic for the stent removal. We have studied 23 patients with this
      technique and find that it is a reliable and safe method to use.

PMID- 15175891
TI  - Why nut? The aspiration of hazelnuts has become a public health problem among
      small children in the central and eastern Black Sea regions of Turkey.
AB  - Our objective was to determine the significance of hazelnuts as the causative
      agent in pediatric foreign body aspirations in the main hazelnut production
      region of the world. We conducted a 10-year retrospective review of patients
      admitted to the pediatric surgery department in a 900-bed university hospital. Of
      135 children with foreign body aspiration, hazelnut aspiration was identified in
      35 (26%). All patients were younger than 5 years of age, and 32% of the hazelnut
      aspirations occurred during late summer, coinciding with the hazelnut harvest. We
      conclude that hazelnut aspiration is a public health problem in our region in
      children younger than 5 years of age, particularly during harvest-time. Hazelnut
      aspiration can be prevented by a well-defined public education program and
      precautionary measures taken by government and civil organizations.

PMID- 15175892
TI  - Assessment of coronary artery stent patency by electron-beam CT.
AB  - Following coronary angioplasty and stent implantation, restenosis remains common
      and its outcome difficult to predict. We set out to determine the diagnostic
      accuracy of electron-beam computed tomography (EBCT) for the non-invasive
      detection of stent obstruction. In a prospective, blinded investigation, we
      included 152 coronary artery segments in 117 patients treated with a stent
      implant. All segments were evaluated by a dynamic EBCT study that depicted
      contrast bolus passage distal to the stent and a CT angiographic study of the
      entire coronary arteries. It was found that delayed contrast enhancement in the
      distal segment correlated with angiographic stent obstruction (Spearman's rank
      correlation, P=0.008), while all other indicators of stent occlusion did not
      correlate with angiographic diagnosis. However, direct comparison of patients
      with obstruction of less vs. more than 75% of luminal diameter did not yield any
      statistically significant differences of distal enhancement delay, and for the
      detection of >90% occlusion, the sensitivity was 72% at a specificity of 60%.
      Although delayed contrast enhancement distal to the stent upon EBCT did correlate
      with angiographical obstruction, the correlation did not suffice to appear
      clinically satisfactory.

PMID- 15175893
TI  - Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs,
      docetaxel and paclitaxel, assessed employing primary human hepatocytes.
AB  - PURPOSE: The induction of cytochrome P450 (CYP) 3A4 by drugs and other
      xenobiotics is a common cause of serious drug interactions. The aim of this study
      was to comparatively examine the effects of paclitaxel and docetaxel, two
      structurally related taxane anticancer agents, on the activity and expression of
      hepatic CYP3A4. METHODS: Employing primary cultures of human hepatocytes from
      multiple donors, we investigated the differences in the magnitude of CYP3A4
      induction and relative accumulation of paclitaxel and docetaxel. The CYP3A4
      activity of intact hepatocytes was measured as the rate of testosterone 6beta
      hydroxylation. The CYP3A4-specific immunoreactive protein and mRNA levels were
      measured employing Western blot and Northern blot analysis, respectively.
      Furthermore, employing cell-based reporter gene assay in CV-1 cells, we evaluated
      the capacity of paclitaxel and docetaxel to activate human pregnane X receptor
      (hPXR), an orphan nuclear receptor that plays a key role in the transcriptional
      regulation of CYP3A4. RESULTS: In concurrence with previous reports, we observed
      that paclitaxel potently induced CYP3A4 activity and expression in hepatocytes
      treated for 48-96 h. However, docetaxel did not increase the activity or the
      CYP3A4 immunoreactive protein levels for treatment periods up to 96 h. A marginal
      increase in the CYP3A4 mRNA levels was observed in cells treated with higher
      levels (5 and 10 microM) of docetaxel. Furthermore, while paclitaxel effectively
      activated hPXR (the half-maximal effective concentration, EC50, being about 5.2
      microM), docetaxel weakly activated hPXR, and moreover the activation occurred
      only at high concentrations relative to paclitaxel. A comparison of the cellular
      concentrations of paclitaxel and docetaxel, in the cell culture models employed
      for evaluating CYP3A4 induction and hPXR activation, revealed that the
      intracellular paclitaxel levels were three-fold higher than that of docetaxel.
      Thus, it appears that both pharmacokinetic (drug concentration) and
      pharmacodynamic differences (hPXR activation) may account for the observed
      differences in CYP3A induction by paclitaxel and docetaxel. CONCLUSION: Our
      studies suggest that docetaxel has markedly reduced propensity to cause drug
      interactions that may entail hepatic CYP3A4 induction.

PMID- 15175894
TI  - Long-term follow-up of young patients with essential thrombocythemia treated with
      pipobroman.

PMID- 15175895
TI  - Distribution of ABO blood groups in acute leukaemias and lymphomas.
AB  - We studied the distribution of ABO blood groups in Hodgkin's lymphoma, non
      Hodgkin's lymphoma, acute myeloid leukaemia and acute lymphoblastic leukaemia, in
      children up to the age of 12 years, in a hospital-based retrospective study.
      Blood group data were recorded from the case records of all the patients in a
      tertiary care centre with the diagnosis of Hodgkin's lymphoma, non-Hodgkin's
      lymphoma, acute myeloid leukaemia and acute lymphoblastic leukaemia, during the
      period 1987-1997. There were 63 Hodgkin's lymphoma, 78 non-Hodgkin's lymphoma,
      116 acute myeloid leukaemia and 522 acute lymphoblastic leukaemia patients. We
      assessed the distribution of ABO blood groups and the difference in the
      distribution from the source population. In Hodgkin's lymphoma, there were 45.6%
      [95% confidence interval (CI): 6.8-84.5] more patients with B blood group. In
      acute lymphoblastic leukaemia, there were 14.3% (95% CI: 3.2-25.2) more patients
      with O blood group. In Hodgkin's lymphoma and non-Hodgkin's lymphoma patients,
      there were 56.5% (95% CI: 19.9-85.4) and 52.9% (95% CI: 18.1-82.6) less patients
      with A blood group, respectively. This shows that the relationship between the
      ABO blood groups and haematological malignancies merits further investigation in
      a population-based prospective study. This is the first study of its kind in any
      Indian population.

PMID- 15175897
TI  - Endoscopic management of early postoperative biliary ascariasis in patients with
      biliary tract surgery.
AB  - Bile leak and residual stones are well known complications of biliary tract
      surgery. In endemic areas of ascariasis, invasion of the biliary tract by
      roundworms during the early postoperative period is an infrequent but serious
      complication. The present study describes the endoscopic management of
      postoperative biliary ascariasis in 19 consecutive patients. There were 5 men and
      14 women with a mean age of 33.3 +/- 6.3 years. All patients had undergone
      cholecystectomy, with choledocholithotomy and placement of a T-tube in 13 (68.4%)
      patients. Eight (42.1%) patients including two with T-tubes were acutely sick at
      referral. Altogether, 16 (84.2%) patients had widened papillae due to previous
      endoscopic sphincterotomy (3 patients) or recent dilatation of the sphincter of
      Oddi by Bake's dilators (13 patients). All patients with a T-tube in situ had
      undergone unsuccessful attempts to remove the worms by flushing saline through
      the T-tube. Endoscopic retrograde cholangiopancreatography was performed 4 to 16
      days after biliary tract surgery and revealed roundworms in the common bile duct
      in 10 patients, in the hepatic ducts in 2, or in both ducts in 7. Three patients
      had coexisting biliary leakage: from the cystic duct stump in two and from a T
      tube track in one. Endoscopic treatment consisted of extracting the worms from
      the biliary tree and placing stents in those with coexisting leakage. Endoscopic
      success was defined as complete worm extraction and resolution of biliary leakage
      and was achieved in all patients. Complications occurred in one (5.3%) patient.
      We concluded that endoscopic management is an effective, safe approach for
      extracting ascarids from the biliary tree during the early postoperative period.
      It reduces the hospital stay, avoids T-tube-related complications, and permits a
      postoperative complication to be treated using a nonsurgical method.

PMID- 15175898
TI  - Identification of the nonrecurrent laryngeal nerve during thyroid surgery: 20
      year experience.
AB  - The nonrecurrent laryngeal nerve, which is rarely observed during thyroidectomy,
      is at high risk for damage. During a 20-year period 6000 thyroidectomies were
      performed at our institution, and during these operations inferior laryngeal
      nerves were routinely identified in all the patients with a standard procedure
      based on the usual anatomic landmarks. A nonrecurrent laryngeal nerve was
      observed on the right side in 31 cases (0.51%), with no anatomic anomalies found
      on the left side. The nerve anomaly was diagnosed preoperatively in five
      patients. A vocal cord deficit, caused by a nerve lesion, was observed in four
      cases (12.9%). Our results suggest that the best way to avoid morbidity is
      routine identification of the nerve. This can be done by carefully identifying
      all the thyroid structures and being suspicious of the presence of the
      abnormality when the inferior laryngeal nerve is not found in a classic position.

PMID- 15175899
TI  - Surgical treatment of portal vein cavernous transformation.
AB  - The aim of this study was to explore the treatment of portal cavernous
      transformation (PVCT). The surgical treatment of 18 patients with PVCT was
      studied retrospectively. Eight patients underwent mesocaval shunt with artificial
      grafts, two patients had splenectomy and disconnection, three patients had a
      central splenorenal shunt, and six patients had a distal splenorenal shunt. There
      were no deaths or hepatic encephalopathy after operation. Bleeding recurred in
      two patients (disconnection in one, mesocaval shunt in one). The individualized
      choice of shunt is ideal for treating PVCT, and the combined procedures of shunt
      and disconnection are useful. The Rex shunt will be the focus of PVCT surgery in
      the future.

PMID- 15175900
TI  - Vascular endothelial growth factor expression and neovascularization in Barrett's
      carcinoma.
AB  - Angiogenesis is essential for tumor growth and metastasis. An association between
      microvessel density, a measure of tumor angiogenesis, and conventional prognostic
      variables has been shown for many tumor entities. For Barrett's carcinoma, the
      results are controversial. Immature vessels formed in tumors are structurally and
      functionally different from those in mature vessels. The relation between mature
      and immature vessels as a prognostic factor for Barrett's carcinoma has not been
      assessed. Specimens from 45 R0-resected Barrett's carcinomas were immunostained
      for vascular endothelial growth factor (VEGF), CD 31, and smooth muscle alpha
      actin to discriminate between mature and immature vessels. VEGF staining was
      evaluated quantitatively by measuring optical density with a new computer-based
      program and expressed as a percentage of the staining (juvenile placental tissue)
      on control slides. The neovascularization coefficient (i.e., the relation between
      mature and immature vessels) was estimated with an interactive analytic computer
      program. The median survival of the study group was 45.7 months. The
      neovascularization coefficient correlated with the histopathologic classification
      ( p < 0.001). Survival time in patients with a low neovascularization coefficient
      was significantly better than the survival time in patients with a high
      neovascularization coefficient ( p = 0.021). VEGF expression did not correlate
      with clinicopathologic data ( p > 0.05) or with patient survival ( p > 0.05). The
      tumors with a high neovascularization coefficient did not have significantly
      elevated VEGF expression. Based on a strong quantitative computer evaluation
      program, the present study indicates that neovascularization has an important
      impact on the survival of patients with Barrett's carcinoma. However, VEGF does
      not appear to be the vascular growth factor stimulating neovascularization in
      Barrett's carcinoma patients.

PMID- 15175901
TI  - Microscopic liver metastasis: prognostic factor for patients with pT2 gallbladder
      carcinoma.
AB  - Hepatic metastasis is the most frequent mode of recurrence of advanced
      gallbladder cancer after radical resection. The aims of this study were to
      clarify the clinical significance of microscopic liver metastasis from pT2
      gallbladder cancer and to clarify whether partial hepatectomy can prevent hepatic
      recurrence in patients with microscopic liver metastasis. The subjects included
      20 patients with pT2 tumors who underwent radical surgery and partial hepatectomy
      with lymph node dissection. Microscopic liver metastasis was defined as a distant
      metastatic nodule including cancer cell nests in the lumen of the portal vein and
      discrete nodular lesions in the liver, all less than 5 mm in diameter. Cox's
      proportional hazard regression was used to analyze factors that contributed to
      outcomes. Microscopic metastases were detected in the resected livers from 5 of
      20 patients. There were more metastatic lesions within 1 cm of the gallbladder
      bed than were located 1 to 2 cm away from it. Microscopic liver metastases showed
      a strong correlation with the extent of blood vessel invasion around the primary
      tumor and were frequently detected in patients with a primary tumor localized on
      the hepatic side and with more than 3 cm of subserosal invasion. In four of five
      patients with microscopic liver metastases, recurrence was found in the remnant
      liver, which led to death within 15 months after the initial operation.
      Microscopic liver metastasis, operative curability, and lymph node metastasis
      were assessed as independent prognostic factors. A large proportion of patients
      with microscopic liver metastasis suffered from hepatic recurrence. Our results
      suggest that partial hepatectomy alone cannot prevent hepatic recurrence in
      patients with microscopic liver metastasis.

PMID- 15175902
TI  - Changes in liver enzymes after surgery in anti-hepatitis C virus-positive
      patients.
AB  - The aim of this study was to assess the influence of surgical intervention on
      changes in liver enzymes in patients with antibodies to hepatitis C virus (HCV).
      Of 623 patients who underwent laparotomy in our department during the 2 years
      between January 2000 and December 2001, a group of 39 (6.3%) who were positive
      for the HCV antibody were enrolled in this study. Serum levels of aspartate
      aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase
      (ALP), lactate dehydrogenase (LDH), and cholinesterase (ChE) were the standard
      liver tests performed. The antibody to HCV was measured in serum using an ELISA
      kit that can detect antibodies against the combined epitopes. The postoperative
      elevated values of AST and ALP in the anti-HCV-positive group were significantly
      higher than those in the anti-HCV-negative group ( p < 0.05). The postoperative
      decreased values of ChE in the anti-HCV-positive group were significantly greater
      than those in the anti-HCV-negative group ( p < 0.02). The postoperatively
      decreased ratios of ChE in the anti-HCV positive group were significantly greater
      than those in the anti-HCV negative group ( p < 0.0001). Using multivariate
      logistic regression modeling, testing positive for the antibody to HCV was
      independently and significantly associated with abnormal levels of ALT and ALP (
      p = 0.035 and 0.018, respectively). Monitoring liver enzymes such as ChE, ALT,
      and ALP might be effective for evaluating liver function after surgery in anti
      HCV-positive patients.

PMID- 15175905
TI  - The paradox of T-cell-mediated antitumor immunity in spite of poor clinical
      outcome in human melanoma.
AB  - Human melanoma is hardly ever curable at an advanced stage, but overwhelming
      evidence from untreated or vaccinated patients indicates that this tumor is
      highly antigenic and frequently immunogenic. Here, we review recent results
      indicating that CD8(+) T cell-mediated antitumor immunity is activated at the
      systemic and tumor level in the early clinical stages (AJCC stages I and II) and
      continues to be promoted, in a fraction of patients, even in metastatic disease
      (stages III and IV). This evidence was obtained by looking at frequency,
      differentiation phenotype, and function of antitumor T cells in periphery and
      tumor site of melanoma patients. On the other hand, the paradox of immunity in
      spite of poor clinical evolution of the disease, points toward a model of
      concurrent evolution of immunity and tumor escape. As melanoma progresses to
      metastatic disease, powerful mechanisms of tumor evasion from immune recognition,
      and of immunosuppression, are activated, thus tilting the balance between
      immunity and escape in favor of tumor resistance to host defense. Nevertheless,
      recent developments in our understanding of regulation of T cell-mediated
      immunity can provide clues to the prospects for improved immunotherapy
      approaches. By integrating the information from basic research in immunology,
      from murine tumor models, and from trials of immunotherapy, we discuss how the
      most relevant steps of the antitumor response should be manipulated with greater
      efficacy by future clinical trials.

PMID- 15175906
TI  - WT1 peptide vaccination combined with BCG-CWS is more efficient for tumor
      eradication than WT1 peptide vaccination alone.
AB  - A Wilms' tumor gene WT1 is expressed at high levels not only in most types of
      leukemia but also in various types of solid tumors, including lung and breast
      cancer. WT1 protein has been reported to serve as a target antigen for tumor
      specific immunotherapy both in vitro in human systems and in vivo in murine
      models. We have shown that mice immunized with WT1 peptide or WT1 cDNA could
      reject a challenge from WT1-expressing tumor cells (a "prophylactic" model).
      However, it was not examined whether WT1 peptide vaccination had the potency to
      reject tumor cells in a "therapeutic" setting. In the present study, we
      demonstrated for the first time that WT1 peptide vaccination combined with
      Mycobacterium bovis bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) was
      more effective for eradication of WT1-expressing tumor cells that had been
      implanted into mice before vaccination (a "therapeutic" model) compared with WT1
      peptide vaccination alone. An intradermal injection of BCG-CWS into mice,
      followed by that of WT1 peptide at the same site on the next day, generated WT1
      specific cytotoxic T lymphocytes (CTLs) and led to rejection of WT1-expressing
      leukemia or lung cancer cells. These results showed that BCG-CWS, which was well
      known to enhance innate immunity, could enhance WT1-specific immune responses
      (acquired immunity) in combination with WT1 peptide vaccination. Therefore, WT1
      peptide vaccination combined with BCG-CWS may be applied to cancer immunotherapy
      in clinical settings.

PMID- 15175907
TI  - T-cell-mediated lysis of B cells induced by a CD19xCD3 bispecific single-chain
      antibody is perforin dependent and death receptor independent.
AB  - A recently developed bispecific antibody construct, directed against CD19 and CD3
      (bscCD19xCD3), induces T-cell-mediated lysis of allogeneic and autologous B cells
      in a specific and highly efficient manner. Since knowledge of the molecular
      mechanisms underlying this lysis is limited, a study on bscCD19xCD3-activated T
      cell-effector pathways was performed. BscCD19xCD3-induced lysis of target B-cell
      lines Nalm-6, Daudi, and Raji and of autologous primary B cells is caused by the
      perforin-dependent granule-exocytosis pathway but not by the death ligands FasL,
      TRAIL, or TNF-alpha. When activated by bscCD19xCD3 and Raji cells, T cells
      express FasL mRNA, but incubation of Raji cells with cell-free supernatants from
      cytotoxicity experiments caused an upregulation of c-Flipl, possibly accounting
      for the cells' insensitivity toward death-receptor-mediated lysis. In addition to
      granule exocytosis, Raji cells are lysed by at least one mechanism independent of
      perforin, which requires transport through the T cell's Golgi apparatus.

PMID- 15175908
TI  - Histological study on mast cells in conjunctiva of NC/Nga mice.
AB  - PURPOSE: To investigate the pathological findings in conjunctiva of NC/Nga mice,
      which develop atopic dermatitis spontaneously, we focused our study on the
      density of mast cells as determined by histological methods. METHODS: NC/Nga mice
      were divided into five groups; the 4W-group comprised four 4-week-old mice
      without treatment, the 10W-group comprised four 10-week-old mice without
      treatment, the 16W-group comprised four 16-week-old mice without treatment, the
      Dx group comprised three 16-week-old mice undergoing topical 0.1% dexamethasone
      (Dx) ointment treatment, and the FK506 group comprised three 16-week-old mice
      undergoing topical 0.1% FK506 ointment treatment. For the histological
      examination, the lids and eyeballs of the mice were removed and fixed with
      Carnoy's solution and thin sections were made. The Carnoy-fixed specimens were
      stained with toluidine blue or H&E and examined histologically. Toluidine blue
      stained tissue sections were examined for the density per square millimeter of
      mast cells, which were identified as metachromatic cells in the conjunctival
      tissue and lid cutaneous tissue by light microscopy. RESULTS: Mast cell density
      in the conjunctiva was 8.6 +/- 8.2 cells/mm(2) in the 4W-group, 29.2 +/- 22.0
      cells/mm(2) in the 10W-group, 41.0 +/- 21.1 cells/mm(2) in the 16W-group, 22.7 +/
      17.1 cells/mm(2) in the Dx group, and 33.6 +/- 27.7 cells/mm(2) in the FK506
      group. Mast cell density increased significantly with age among the 4W-, 10W-,
      and 16W-groups ( P < 0.001). The mast cell density of lid cutaneous tissue was
      higher than the conjunctival mast cell density. Mast cell density was
      significantly higher in the 16W-group than in the Dx group, but not significantly
      higher than in the FK506 group. CONCLUSIONS: An increase in mast cell density
      with age indicates that NC/Nga mice develop atopic keratoconjunctivitis-like
      signs. Dexamethasone ointment has a suppressive effect on the increase in mast
      cell density.

PMID- 15175909
TI  - Analysis of COL8A2 gene mutation in Japanese patients with Fuchs' endothelial
      dystrophy and posterior polymorphous dystrophy.
AB  - PURPOSE: To determine whether Japanese patients with Fuchs' endothelial corneal
      dystrophy (FECD) and posterior polymorphous dystrophy (PPMD) carry mutations in
      the COL8A2 gene, and to investigate the possible pathogenicity of the COL8A2 gene
      in these corneal dystrophies. METHODS: DNA analysis of the COL8A2 gene was
      performed in 15 unrelated Japanese patients with FECD, and 5 patients with PPMD
      using polymerase chain reaction and direct sequencing. Mutation screenings were
      also performed in 36 unrelated normal volunteers as controls, as well as slit
      lamp and specular microscopy. RESULTS: Two types of heterozygous missense
      mutations of the COL8A2 gene (R155Q and T502M) in 5 of 15 FECD probands (R155Q,
      3/30 chromosomes, 10.0%; T502M, 3/30 chromosomes, 10.0%) were found. No mutation
      was detected in the coding region of the COL8A2 gene in the remaining 10 patients
      with FECD nor in any of the 5 patients with PPMD. These two mutations were also
      found in normal Japanese volunteers (R155Q, 5/72 chromosomes, 6.9%; T502M, 11/70
      chromosomes, 15.7%). The chromosomal frequency of the two mutations was not
      significant between the patients and normal controls. CONCLUSIONS: The R155Q and
      T502M mutations of COL8A2 may not be the causative defect in the Japanese FECD
      and PPMD patients examined in this study.

PMID- 15175910
TI  - Differential regulation of focal adhesion kinase and paxillin phosphorylation by
      the small GTP-binding protein Rho in human corneal epithelial cells.
AB  - PURPOSE: Lysophosphatidic acid (LPA), which activates the small guanosine
      triphosphate (GTP)-binding protein Rho, was previously shown to promote migration
      of the rabbit corneal epithelium in culture. The signaling pathway responsible
      for this effect of LPA was examined in this study with a human corneal epithelial
      (HCE) cell line. METHODS: The activation of Rho was detected with a pull-down
      assay. Tyrosine phosphorylation of paxillin and of focal adhesion kinase (FAK)
      were examined both by immunofluorescence staining and by immunoprecipitation and
      immunoblot analyses. Expression of integrins alpha5 and beta1 was evaluated by
      immunoblot analysis. RESULTS: Incubation of cells with LPA (10 micro M) for 2 min
      resulted in marked activation of Rho, and this effect was blocked by pretreatment
      with the Rho inhibitor exoenzyme C3 (2 micro g/ml) for 24 h. Tyrosine
      phosphorylation of both paxillin and FAK was detected in HCE cells under basal
      conditions by immunofluorescence staining, immunoprecipitation, and immunoblot
      analyses. LPA induced a concentration- and time-dependent increase in the
      tyrosine phosphorylation of paxillin, which was maximal at a concentration of 10
      micro M and a time of 2 min. Exoenzyme C3 inhibited LPA-induced paxillin
      phosphorylation. Neither LPA nor exoenzyme C3 affected tyrosine phosphorylation
      of FAK or expression of integrins alpha5 and beta1. CONCLUSIONS: LPA induces Rho
      activation and the consequent tyrosine phosphorylation of paxillin in HCE cells,
      and these effects likely contribute to the promotion of corneal epithelial
      migration by this agent.

PMID- 15175911
TI  - Changes in the s-wave of multifocal electroretinograms in eyes with primary open
      angle glaucoma.
AB  - PURPOSE: To determine whether the s-wave is present in the multifocal
      electroretinogram (mfERG) and whether it is altered in eyes with primary open
      angle glaucoma (POAG). METHODS: A Visual Evoked Response Imaging System was used
      to record mfERGs from 15 eyes of 15 normal adults, as control eyes, and from 15
      eyes of 15 patients with POAG. The stimulus consisted of 37 hexagonal stimulating
      elements with luminances of 200 cd/m(2) (white), 66.6 cd/m(2) (gray), and 4
      cd/m(2) (black). The white or black element was presented at five different base
      periods (bpds) from 13.3 to 213.3 ms according to a binary m-sequence. In the
      intervals between the white and black (or white) elements, gray elements were
      inserted at 75 Hz. The changes in the amplitude and implicit time of the s-wave
      of the all-trace waveform of the first-order kernel of the mfERG were compared
      with the mean deviation (MD) of retinal sensitivity in the whole visual field
      measured with a Humphrey Field Analyzer. RESULTS: The s-wave was present as a
      positive wavelet on the descending limb of the first-order kernel response of the
      mfERGs of all eyes with POAG. The s-wave amplitude increased with prolongation of
      the bpd, as occurs in normal eyes. The mean amplitudes of the s-waves at bpds of
      53.3 and 106.7 ms were significantly smaller in the eyes with POAG than in the
      control eyes. The correlation between the s-wave amplitude and the severity of
      disturbance in the entire visual field indicated by the MD was not significant in
      eyes with POAG. CONCLUSIONS: The characteristics of the s-wave in glaucomatous
      eyes were the same as those in the control eyes, but the amplitude of the s-waves
      in POAG eyes was significantly lower than that in the control eyes. This suggests
      that ganglion cells may be involved in the development of the s-wave. When
      comparing the s-wave with static perimetry, more local responses of the s-wave
      and more local retinal sensitivity in the static perimetry will be appropriate.

PMID- 15175912
TI  - Amplitude of the s-wave of multifocal electroretinograms can indicate local
      retinal sensitivity in glaucomatous eyes.
AB  - PURPOSE: To determine whether the amplitude of the s-wave on a multifocal
      electroretinogram (mfERG) is correlated with the degree of visual field
      depression in eyes with glaucoma. METHODS: Twenty patients (20 eyes) with
      glaucoma,ages 46 to 69 years, were studied. Twenty healthy volunteers (20 eyes)
      with normal intraocular pressure and with no eye diseases served as controls. The
      retinal sensitivities of the upper and lower visual fields of the glaucomatous
      eyes were determined with a Humphrey Field Analyzer. The severity of retinal
      sensitivity depression was rated as mild (Group A), intermediate (Group B), or
      severe (Group C). To record the s-wave, mfERGs were elicited by pseudorandom
      stimulation, with the stimulus alternating according to a binary m-sequence for
      base periods (bpds) of 13.3, 26.7, 53.3, 106.7, and 213.3 ms. The mfERGwaves
      recorded from the upper and lower visual field were summed separately. RESULTS:
      In the control group, the s-wave in the summed mfERG was observed in all visual
      field halves at all bpds 53.3 ms or longer. The s-wave amplitude at a bpd of
      213.3 ms was significantly larger than that at a bpd of 53.3 ms ( P < 0.05). The
      s-wave was also present in the glaucoma patients' eyes, and the s-wave amplitude
      increased as the bpd increased. At bpds of 53.3, 106.7, and 213.3-ms, the mean s
      wave amplitudes in Groups B and C were significantly smaller than those in the
      control group ( P < 0.05, 0.01, and 0.05, respectively). At bpds of 53.3 and
      106.7 ms, the mean amplitude of the s-waves in Group C was significantly smaller
      than that in Group A ( P < 0.05). At a bpd of 106.7 ms, a significant correlation
      was observed between the retinal sensitivity and the s-wave amplitude ( P <
      0.05). CONCLUSIONS: The significant correlation between the retinal sensitivity
      and the amplitude of the swave at a bpd of 106.7 ms supports the suggestion that
      the s-wave originates from the retinal ganglion cells and their axons. The
      amplitude of the s-wave may serve as an objective indicator of the severity of
      retinal ganglion cell damage.

PMID- 15175913
TI  - Ultrastructural changes in rat eyes with experimental Vogt-Koyanagi-Harada
      disease.
AB  - PURPOSE: To determine whether the ultrastructural changes in the eyes of an
      animal model of Vogt-Koyanagi-Harada (VKH) disease are similar to those in human
      eyes with VKH disease. METHODS: Pigmented rats derived by crossing brown Norway
      and Lewis rats were immunized with tyrosinase-family proteins, and the eyes were
      enucleated after different postinoculation times. The eyes were fixed in
      glutaraldehyde or formaldehyde and prepared for light or electron microscopy
      (EM). RESULTS: EM showed that thickening of the choroid resulted from the
      invasion of many lymphocytes and epithelioid-like cells. The melanocytes were
      surrounded by lymphocytes and lost their normal spindle shape. Neutrophils and
      eosinophils were also present in the choroid. These findings are very similar to
      the changes reported in eyes from patients with VKH disease or sympathetic
      ophthalmia. CONCLUSIONS: The similarity of the ultrastructural changes in this
      model to those in human VKH disease indicate that this animal model can serve as
      a histopathological model of human VKH disease.

PMID- 15175914
TI  - Autosomal dominant cone-rod dystrophy with R838H and R838C mutations in the
      GUCY2D gene in Japanese patients.
AB  - PURPOSE: To describe the clinical phenotypes of two Japanese families with
      autosomal dominant cone-rod dystrophy (CORD) caused by an R838H or R838C
      mutation. METHODS: Complete ophthalmological examinations were performed on three
      affected individuals from two Japanese families with autosomal dominant CORD. One
      family had an R838H mutation, and the other family had an R838C mutation in the
      GUCY2D gene. The tests included best-corrected visual acuity, slit-lamp and
      fundus examinations, fundus photography, electroretinography, Goldmann kinetic
      perimetry, and automated light- and dark-adapted static perimetry. RESULTS: The
      three patients showed essentially normal fundus or little pigmentary change in
      the maculae by indirect ophthalmoscopy, and only fluorescein angiography revealed
      clear atrophy of the retinal pigmented epithelium around the fovea. Central or
      paracentral scotoma was detected by the Goldmann kinetic visual field test.
      Electroretinography as well as light-adapted and dark-adapted two-color perimetry
      showed more severe impairment of cone than of rod function. The clinical features
      in our patients resembled those in Caucasian families with R838H or R838C
      mutations. CONCLUSIONS: The R838H and R838C mutations in GUCY2D cause CORD in the
      Japanese population. These mutations can cause a similar clinical phenotype in
      other races.

PMID- 15175915
TI  - Cytotoxicity of triamcinolone on cultured human retinal pigment epithelial cells:
      comparison with dexamethasone and hydrocortisone.
AB  - PURPOSE: Triamcinolone acetonide (TA) is a corticosteroid that can be used in the
      treatment of cystoid macular edema (CME) and other ocular inflammatory
      conditions. This study aims to investigate the degree of cytotoxic effect of TA
      on human retinal pigment epithelium (ARPE19 cell line) and to compare the
      relative toxicity of TA with two other corticosteroids, hydrocortisone (HC) and
      dexamethasone (DEX), over a range of concentrations and durations of exposure.
      METHODS: The ARPE19 cell line was cultured and maintained in a 1 : 1 mixture of
      Dulbecco's modified Eagle's medium and HAMS F12 medium containing 3 mM l
      glutamine supplemented with 10% fetal bovine serum, penicillin G, and
      streptomycin sulfate. Following an initial overnight incubation, corticosteroids
      (0.01-1 mg/ml) or vehicle (benzyl alcohol, 0.025%), diluted in culture medium,
      was added to the ARPE19 culture (5000 cells/well) on Day 0. Subsequently the
      culture medium containing corticosteroid or vehicle was refreshed daily. After 1,
      3, and 5 days, the proliferated amount of cells with and without corticosteroid
      treatment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5
      diphenyltetrazolium bromide (MTT) assay. All samples were read in triplicate,
      with n = 4 in all cases. The final results were analyzed using analysis of
      variance. RESULTS: TA, DEX, and HC caused a significant reduction in cell numbers
      throughout the whole range of concentrations when cells were exposed to them for
      more than one day. The action of the corticosteroids, apart from TA, was
      biphasic. There was an initial rise in cell proliferation in the presence of DEX
      and HC at 0.01-0.1 mg/ml on Day 1. Log-linear plots of DEX and HC concentrations
      against percent viability (mean % +/- SD) showed a significantly higher total
      viable cell percentage versus TA: 120.5 +/- 1.8% and 134.9 +/- 4.1% in the
      presence of DEX, and 110.0 +/- 15.3% and 118.3 +/- 9.0% in the presence of HC.
      The LD(50) values of the three corticosteroids show that, regardless of the
      duration of exposure, TA was the most toxic, with relative toxicity of TA > DEX >
      HC, equivalent to a ratio of 1.0 : 1.6 : 1.8, after one day of incubation. The
      vehicle alone had no effect. CONCLUSIONS: The present study demonstrated the
      degree of cytotoxicity of TA compared with DEX and HC. The results provide a
      profile of this drug relative to other common corticosteroids. Further studies
      are planned to characterize its effects and the degree of influence on cells of
      different ocular regions in order to show the full cytotoxicity of TA.

PMID- 15175916
TI  - Effects of topical phenylephrine on blood flow in the posterior segments of
      monkey and aged human eyes.
AB  - PURPOSE: The aim of this study was to evaluate the effects of topical 5%
      phenylephrine on circulation in the optic nerve head (ONH) of cynomolgus monkeys
      and in the central retinal artery (CRA) of aged patients. METHODS: In five
      monkeys, ONH tissue blood velocity (NB(ONH)), determined using the laser speckle
      method, and intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR)
      were measured 2 h after a single unilateral instillation and after a 7-day twice
      daily unilateral instillation of phenylephrine. In 20 aged patients (mean age:
      70.4 years), the CRA circulation indices were determined by color Doppler imaging
      (CDI), and IOP, BP, and PR were measured before and after four serial unilateral
      instillations at 30-min intervals of phenylephrine. RESULTS: In the monkeys,
      there was no significant change in IOP, BR, or PR, while NB(ONH) decreased 2 h
      after a single instillation ( P = 0.080) and after a 7-day instillation ( P =
      0.043). In theaged patients, IOP in the phenylephrine-treated eyes significantly
      increased ( P = 0.022), while the CDI indices, BR, and PR did not. In this CDI
      assessment, the statistical power to detect significant changes (P < 0.05) in the
      resistive index was estimated as 4.8% of the standard deviation. CONCLUSIONS:
      Topical phenylephrine decreased the ONH tissue blood velocity in monkeys,
      suggesting possible risks regarding circulation in the posterior portion of the
      eye. However, these effects were not observed in the CRA circulation in the
      patients.

PMID- 15175917
TI  - Correlation between indocyanine green angiographic findings and histopathology of
      polypoidal choroidal vasculopathy.
AB  - PURPOSE: To analyze the histopathology of polypoidal choroidal vasculopathy (PCV)
      and choroidal neovascularization (CNV) developing from PCV, the authors evaluated
      correlations between pathological findings and the findings of preoperative
      indocyanine green angiography (IA). METHODS: Two specimens were obtained during
      CNV excision associated with PCV. PCV tissue was excised with the CNV. The
      specimens were examined by light microscopy. RESULTS: In one case, IA revealed
      polypoidal lesions exhibiting hyperfluorescence in both the early and the late
      phase, and in the affected area, abnormally dilated vessels were identified
      histologically underneath relatively healthy retinal pigment epithelium (RPE). In
      the other case, the polypoidal lesions seen on IA showed early hyperfluorescence
      and late isofluorescence, and dilated vessels were observed under the RPE;
      perivascular amorphous material was present. The RPE adhered to the side of the
      choroid, and there was CNV under the neurosensory retina in both cases. The CNV
      had numerous vascular lumens, was not surrounded by the RPE, and exhibited few
      fibrous components. CONCLUSIONS: IA findings vary depending on the condition of
      the RPE located above the PCV and the extent of amorphous material around the
      PCV.

PMID- 15175918
TI  - Transretinal electrical stimulation with a suprachoroidal multichannel electrode
      in rabbit eyes.
AB  - PURPOSE: Several approaches for placing an electrode device for visual prosthesis
      have been previously proposed. In this study, we investigated if transretinal
      stimulation from the suprachoroidal space can elicit an electrical evoked
      potential (EEP) in albino rabbits. METHODS: A flat electrode array (polyimide
      plate, platinum electrode) was developed and used for this study. After
      performing a scleral incision at 2-2.5 mm from the limbus and placing an
      anchoring suture, the array was inserted into the suprachoroidal space in the
      posterior portion of the eye by direct observation under a microscope. A platinum
      wire was implanted into the vitreous space as a reference electrode. For
      electrical stimulation, a biphasic pulse was used. When the electrode was
      stimulated, the EEP was recorded. RESULTS: When the electrical stimulation from
      the suprachoroidal space was applied, the EEP could be recorded with an epidural
      electrode, and the threshold was 66.0 +/- 32.1 micro A (420 micro C/cm(2))
      [corrected]. placement of the array and the electrical stimulation. CONCLUSIONS:
      Transretinal electrical stimulation from the suprachoroidal space could elicit
      EEP, suggesting that this approach may be useful for a retinal prosthesis system.

PMID- 15175919
TI  - Time-frequency analysis of electronystagmogram signals in patients with
      congenital nystagmus.
AB  - PURPOSE: To evaluate the usefulness of the short-time Fourier transform (STFT) in
      the analysis of temporal congenital nystagmus characteristics. METHODS: We
      carried out an observational case series in patients with congenital nystagmus.
      An electronystagmogram (ENG) recording was performed for 300 s in 13 consecutive
      subjects with congenital nystagmus (age: 7-68 years). Digitized ENG signals (12
      bits, 100 Hz) were divided into 2-s segments with a Hanning window, and a Fourier
      transform was carried out for each segment. The power spectrum obtained for each
      segment was graphically reconstructed as a function of time. The results were
      compared among the patients. RESULTS: Clear periodicity in the time-frequency
      distribution was observed in 3 of the 13 patients (23%). One of the three
      patients was diagnosed with periodic alternating nystagmus, but the other two
      patients showed periodicity without alternation of beat direction. No significant
      difference was observed in clinical characteristics, except for sex, between
      patients who showed periodicity and those who did not. CONCLUSIONS: Some patients
      with congenital nystagmus showed clear periodicity in the nystagmus waveform
      without alternation of beat direction. The STFT is a useful tool to evaluate the
      temporal characteristics of congenital nystagmus in clinics.

PMID- 15175920
TI  - Cutaneous anthrax on eyelids.
AB  - BACKGROUND: Ophthalmologists should be aware of the signs and symptoms of
      anthrax, although it is a rare disease in humans. We report our successful
      treatment of three patients with cutaneous lesions in the periorbital area.
      CASES: In this study, we report on the treatment of three female patients who
      were initially diagnosed as having preseptal cellulitis. OBSERVATIONS: Gram
      positive robs were revealed in the microscopic examination of scrapings taken
      from the lesions. Bacillus anthracis was found in only two of the three scraping
      material cultures. Intravenous penicillin G was administered in all cases. Black
      and necrotic eschar, which is characteristic of anthrax, developed on the eyelids
      of all three patients during treatment. At the final examinations of the patients
      after the completion of treatment, we recognized the development of
      cicatrisation, lagophthalmos, and slight ectropion in the upper eyelid of the
      first patient, and, in the second patient, restriction of upper eyelid movement
      and development of a corneal scar from exposure keratopathy and ectropion. The
      cutaneous lesions healed without any eyelid pathology in the third patient.
      CONCLUSION: Although it is a rare disease in humans, anthrax should be considered
      in the differential diagnosis of preseptal and orbital cellulitis.

PMID- 15175921
TI  - Nocardia keratitis in a human immunodeficiency virus patient.
AB  - BACKGROUND: The development of Nocardia keratitis in a patient with human
      immunodeficiency virus infection is rare, and we could find no cases reported in
      the literature. CASE: A 48-year-old woman who had human immunodeficiency virus
      infection presented with decreased visual acuity, redness, and irritation in the
      right eye. OBSERVATIONS: Initially, the diagnosis was fungal keratitis, and she
      was treated with 0.3% amphotericin B eye drops and oral fluconazole for 1 month
      without improvement. Then, all former drugs were discontinued, and a corneal
      scraping was carried out. The culture result disclosed Nocardia asteroides, and
      after treatment with 10% sulfacetamide eye drops and oral trimethoprim
      sulfamethoxazole, the keratitis subsided dramatically. CONCLUSIONS: The treatment
      result for Nocardia keratitis in a human immunodeficiency virus patient was
      favorable after intensive use of 10% sulfacetamide eyedrops. Nocardia keratitis
      should be kept in mind as a possible causative organism when antifungal therapy
      fails in a keratitis case.

PMID- 15175922
TI  - Switch to latanoprost monotherapy from combined treatment with beta-antagonist
      and other antiglaucoma agents in patients with glaucoma or ocular hypertension.
AB  - PURPOSE: To investigate the effects on intraocular pressure (IOP) and the
      occurrence of adverse events upon switching directly to latanoprost monotherapy
      from multiple drug therapy, including a beta-antagonist, for glaucomatous eyes.
      METHODS: Patients with primary open-angle glaucoma or ocular hypertension and
      receiving long-term therapy with two or three topical ocular hypotensive drugs
      (including one topical beta-antagonist) were switched to latanoprost monotherapy
      for 12 weeks without any intervening washout period. Observations were performed
      before switching (baseline) and at weeks 4, 8, and 12 after switching to
      latanoprost monotherapy. RESULTS: Of the 29 enrolled patients, 26 (90%) completed
      this protocol. Three patients had excessive IOP elevation, and these patients
      were withdrawn. The switch to latanoprost monotherapy was followed by a
      significant ( P < 0.0001) mean reduction of 3.9 mmHg at week 12 in per-protocol
      cases ( n = 26) and a significant ( P = 0.0016) mean reduction of 2.8 mmHg at
      last postswitch visit in patients in the intent-to-treat analysis group ( n =
      29). Adverse ocular events other than IOP elevation were mild. CONCLUSIONS: The
      switch to latanoprost monotherapy in glaucoma patients receiving multiple drug
      therapy resulted in an additional, significant IOP reduction.

PMID- 15175923
TI  - Symmetry analysis for detecting early glaucomatous changes in ocular hypertension
      using optical coherence tomography.
AB  - PURPOSE: To compare symmetry analysis of the retinal nerve fiber layer (RNFL) in
      ocular-hypertensive, normal, and glaucomatous eyes using optical coherence
      tomography (OCT). METHODS: Thirty-three consecutive ocular-hypertensive patients
      (33 eyes), 25 normal volunteers (25 eyes), and 35 open-angle glaucoma patients
      (35 eyes) were enrolled in this study. Circular OCT scans were obtained using a
      diameter of 3.4 mm around the optic disc. RNFL thickness was measured, and a
      symmetry analysis was performed using symmetry ratios. To calculate the symmetry
      ratios, the circle was divided into the superior and inferior hemiretina. The
      superior hemiretina was further subdivided into three (area I, temporal 45
      degrees; area II, superior 90 degrees; and area III, nasal 45 degrees ) or five
      (with areas 1-5, each spanning 36 degrees ) zones. The symmetry ratios were
      defined as the ratios comparing the RNFL thickness within each of the zones with
      that in the analogous zone in the inferior hemiretina. RESULTS: RNFL thickness
      measurements could distinguish glaucomatous eyes from other groups, but could not
      distinguish ocular-hypertensive from normal eyes. However, the symmetry analysis
      revealed differences between ocular-hypertensive and normal eyes in area II (mean
      +/- SD, 0.77 +/- 0.16 vs. 0.85 +/- 0.12, P = 0.0379). CONCLUSIONS: Early
      glaucomatous RNFL changes might exist in some areas of ocular-hypertensive eyes,
      and a symmetry analysis may be a useful method for detecting these changes.

PMID- 15175924
TI  - Time-of-flight secondary ion mass spectrometry can replace histochemistry
      demonstration of fatty acids in the retina.
AB  - PURPOSE: The purpose of this study was to demonstrate fatty acids in the rat
      retina and to show that time-of-flight secondary ion mass spectrometry (TOF-SIMS)
      can replace histochemistry. METHODS: Five normal 3-month-old Wistar Kyoto rats
      were used. The eyes were enucleated under pentobarbital anesthesia, immediately
      put into liquid nitrogen without any fixation, then cut into semithin sections,
      which were covered by OCT compound. Serial semithin sections were cut to 8- micro
      m thickness with a cryoultramicrotome and air-dried. They were placed on a
      silicon plate and air-dried for 1 h for analysis with TOF-SIMS. Before the
      specimens were analyzed, the molecular weight of the secondary ion for each
      molecular substance was measured with the use of commercial samples. These values
      were used for calculating the count of the secondary ion for each molecular
      substance. The molecular weights of the secondary ions of maleic acid, palmitic
      acid, oleic acid, stearic acid, arachidonic acid, and docosahexaenoic acid were
      determined in the photoreceptor cells. RESULTS: Of the fatty acids in the
      photoreceptor cells, maleic acid had the highest count, followed in descending
      order by palmitic, oleic, docosahexaenoic, stearic, and arachidonic acids.
      CONCLUSIONS: TOF-SIMS can demonstrate the presence of fatty acids in the retina,
      replacing histochemical techniques.

PMID- 15175926
TI  - Convergence accommodation to convergence (CA/C) ratio in patients with
      intermittent exotropia and decompensated exophoria.
AB  - PURPOSE: To evaluate the convergence accommodation to convergence (CA/C) ratio in
      strabismic patients and to clarify its clinical implications. METHODS: Seventy
      eight consecutive patients (mean age: 12.9 +/- 6.0 years) with intermittent
      exotropia and decompensated exophoria who showed binocular fusion at least at
      near viewing were recruited. The CA/C ratio was estimated by measuring
      accommodative responses induced by horizontal prisms with different magnitudes
      under accommodation feedback open-loop conditions. The CA/C ratios were compared
      with accommodative convergence to accommodation (AC/A) ratios and other clinical
      parameters. RESULTS: A linear regression analysis indicated that the mean (+/-SD)
      CA/C ratio was 0.080 +/- 0.043 D/prism diopter or 0.48 +/- 0.26 D/meter angle.
      There was no inverse or reciprocal relationship between CA/C and AC/A ratios. The
      patients with lower CA/C ratios tended to have smaller tonic accommodation under
      binocular viewing conditions and larger exodeviation at near viewing.
      CONCLUSIONS: The CA/C ratio, like the AC/A ratio, is an independent parameter
      that characterizes clinical features. A lower CA/C may be beneficial for the
      vergence control system to compensate for ocular misalignment with minimum
      degradation of accommodation accuracy.

PMID- 15175925
TI  - Recovery of visual field loss due to central retinal artery occlusion.
AB  - BACKGROUND: The recovery of the visual field in eyes with central retinal artery
      occlusion (CRAO) has rarely been reported, because the patient has difficulty in
      central fixation during perimetry testing due to poor visual acuity. We describe
      the recovery of the central visual field in eyes with atypical CRAO. CASES: Two
      patients who showed sudden visual loss underwent ophthalmic examinations,
      including fluorescein fundus angiography and Humphrey central 30-2 perimetry.
      OBSERVATIONS: Both patients had good visual acuity at presentation, with normal
      retinal color in the area of the papillomacular bundle surrounded by a mild
      retinal whitening in one case and by scattered cotton-wool patches in the other.
      They were considered on the basis of angiographic findings to have central
      retinal artery occlusion. The mean deviation of the Humphrey central 30-2
      perimetry gradually improved during the initial 70 days after the onset of
      symptoms in both patients. CONCLUSIONS: Although the mechanism remains to be
      clarified, a certain degree of visual field recovery may be seen in some cases of
      retinal artery occlusion. More patients with CRAO should be studied with follow
      up perimetry.

PMID- 15175927
TI  - Merkel cell carcinoma of the eyelid: report of a case with immunohistochemical
      study.

PMID- 15175928
TI  - Sacral nerve stimulation for treatment of fecal incontinence in a patient with
      muscular dystrophy: report of a case.
AB  - Fecal incontinence is a common condition that causes major impairment of social
      life. Sacral nerve stimulation is a promising treatment in idiopathic fecal
      incontinence when conventional treatments have failed. However, new indications
      for sacral nerve stimulation are emerging. The present case shows that sacral
      nerve stimulation for treatment of fecal incontinence may be justified in other
      diseases in which fecal incontinence is a major problem.

PMID- 15175929
TI  - A wide-range integrative yeast expression vector system based on Arxula
      adeninivorans-derived elements.
AB  - An Arxula adeninivorans integration vector was applied to a range of alternative
      yeast species including Saccharomyces cerevisiae, Debaryomyces hansenii,
      Debaryomyces polymorphus, Hansenula polymorpha and Pichia pastoris. The vector
      harbours a conserved A. adeninivorans-derived 25S rDNA sequence for targeting,
      the A. adeninivorans-derived TEF1 promoter for expression control of the reporter
      sequence, and the Escherichia coli-derived hph gene conferring resistance against
      hygromycin B for selection of recombinants. Heterologous gene expression was
      assessed using a green fluorescent protein (GFP) reporter gene. The plasmid was
      found to be integrated into the genome of the various hosts tested; recombinant
      strains of all species exhibited heterologous gene expressions of a similar high
      level.

PMID- 15175930
TI  - Interactive image enhancement of CR and DR images.
AB  - There is continual pressure on the radiology department to increase its
      productivity. Two important links to productivity in the computed/digital
      radiography (CR/DR) workflow chain are the postprocessing step by technologists
      and the primary diagnosis step by radiologists, who may apply additional image
      enhancements to aid them in diagnosis. With the large matrix size of CR and DR
      images and the computational complexity of these algorithms, it has been
      challenging to provide interactive image enhancement, particularly on full
      resolution images. We have used a new programmable processor as the main
      computing engine of enhancement algorithms for CR or DR images. We have mapped
      these algorithms to the processor, maximally utilizing its architecture. On a 12
      bit 2688 x 2688 image, we have achieved the execution time of 465A ms for
      adaptive unsharp masking, window/level, image rotate, and lookup table operations
      using a single processor, which represents at least an order of magnitude
      improvement compared to the response time of current systems. This kind of
      performance facilitates rapid computation with preset parameter values and/or
      enables truly interactive QA processing on radiographs by technologists. The fast
      response time of these algorithms would be especially useful in a real-time
      radiology setting, where the radiologist's waiting time in performing image
      enhancements before making diagnosis can be greatly reduced. We believe that the
      use of these processors for fast CR/DR image computing coupled with the seamless
      flow of images and patient data will enable the radiology department to achieve
      higher productivity.

PMID- 15175931
TI  - Computer-assisted bone age assessment: graphical user interface for image
      processing and comparison.
AB  - The current study is part of a project resulting in a computer-assisted analysis
      of a hand radiograph yielding an assessment of skeletal maturity. The image
      analysis is based on features selected from six regions of interest. At various
      stages of skeletal development different image processing problems have to be
      addressed. At the early stage, feature extraction is based on Lee filtering
      followed by the random Gibbs fields and mathematical morphology. Once the fusion
      starts, wavelet decomposition methods are implemented. The user interface
      displays the closest neighbors to each image under consideration. Results show
      the sensitivity of different regions to both stages of development and certain
      feature sensitivity within each region. At the early stage of development, the
      distal features are more reliable indicators, whereas at the stage of epiphyseal
      fusion, a larger dynamic range of middle features makes them more sensitive. In
      the current study, a graphical user interface has been designed and implemented
      for testing the image processing routines and comparing the results of
      quantitative image analysis with the visual interpretation of extracted regions
      of interest. The user interface may also serve as a teaching tool. At the later
      stage of the project it will be used as a classification tool.

PMID- 15175932
TI  - Pneumocystis jiroveci isolates with dihydropteroate synthase mutations in
      patients with chronic bronchitis.
AB  - Since mutations in the dihydropteroate synthase (DHPS) gene possibly associated
      with sulfonamide resistance have been reported in patients with Pneumocystis
      jiroveci (previously carinii) pneumonia, and since P. jiroveci colonization has
      been recently demonstrated in patients with chronic pulmonary diseases, the
      present study aimed to investigate the possible occurrence of P. jiroveci DHPS
      mutations in patients with chronic bronchitis. P. jiroveci colonization was
      detected in 15 of 37 non-selected patients with chronic bronchitis by amplifying
      the large subunit of the mitochondrial gene of the ribosomal RNA using nested
      PCR. DHPS mutations were demonstrated using touchdown PCR and restriction enzyme
      analysis in two of eight patients with chronic bronchitis and in two of six
      patients from the same region who had AIDS-associated Pneumocystis pneumonia. In
      all cases, mutations were observed in subjects with no prior exposure to
      sulfonamides. These data could have important implications for public health,
      since (i) P. jiroveci colonization could speed the progression of chronic
      bronchitis, and (ii) these patients, who are customary sputum producers, could
      represent a reservoir for sulfonamide-resistant strains with the potential
      ability to transmit them to immunocompromised hosts susceptible to Pneumocystis
      pneumonia.

PMID- 15175934
TI  - The middle-arm fistula: A new native arteriovenous vascular access for
      hemodialysis patients.
AB  - Dialysis access procedures and complications are important causes of morbidity
      and hospitalization for chronic hemodialysis patients. The number of complicated
      subjects on dialysis is increasing, and creating a successful native
      arteriovenous fistula for these patients is a challenge. The classic Brescia
      Cimino fistula may not be the best first choice for a native vascular access. We
      describe the surgical technique of middle-arm fistula (MAF) for hemodialysis. A
      total of 112 surgical procedures were performed on 106 patients with primary
      unassisted 24- and 48-month patency rates of 93% and 83%, respectively, and a
      very low incidence of complications. Our approach was found to be a useful method
      in patients with comorbid factors.

PMID- 15175933
TI  - Vertebral osteomyelitis and epidural abscess in a patient receiving enfuvirtide.

PMID- 15175935
TI  - Endovascular abdominal aortic aneurysm repair in the octogenarian.
AB  - The aim of this study was to analyze patient outcomes following endovascular
      repair of infrarenal abdominal aortic aneurysms (EAR) among patients 80 years of
      age or older. In this study, reporting standards of the Ad Hoc Committee for
      Standardized Reporting Practices for Endovascular Aortic Aneurysm Repair of the
      Society of Vascular Surgery/American Association for Vascular Surgery (SVS/AAVS)
      were followed. Between August 8, 1996 and February 12, 2001 EAR was performed in
      31 patients (29 male and 2 female) with an average age of 83 +/- 3 years and an
      average maximum aneurysm diameter of 59 +/- 7 mm. Overall technical success was
      90% (28/31) with a single acute conversion and a 6% (2/32) incidence of major
      morbidity. There were no in-hospital deaths, but two patients (6%) died within 30
      days of intervention. Four endoleaks, two type I and two type II, were observed
      within the first 30 days after endograft implantation and three new type II
      endoleaks were noted after implant periods that exceeded 1 month. Average follow
      up was 16 months, with a single aneurysm-related death that occurred after late
      conversion to open repair, 2 years following initial endovascular treatment.
      Kaplan-Meier analysis revealed 3-, 12-, and 24-month estimated survivals of 93%
      (+/-5), 75% (+/-8), and 68% (+/-10), respectively. Clinical success rates were
      90% (+/-5), 90% (+/-5), and 72% (+/-17) at 12, 24, and 36 months, respectively.
      We conclude that, in the octogenarian with mild to moderate medical
      comorbidities, endovascular aneurysm repair provides an alternative to open AAA
      repair with low operative morbidity and good clinical success rates. Elevated
      SVS/AAVS medical comorbidity scores were not associated with increased operative
      mortality rates, but they did show a trend toward decreased mid-term survival.
      Careful consideration of life expectancy and the probability of rupture, as with
      traditional AAA repair, should dictate necessity for intervention.

PMID- 15175936
TI  - Protein stability and mutations in the axial methionine loop of a minimal
      cytochrome c.
AB  - The minimal mono-heme ferricytochrome c from Bacillus pasteurii, containing 71
      amino acids, has been further investigated through mutagenesis of different
      positions in the loop containing the iron ligand Met71. These mutations have been
      designed to sample different aspects of the loop structure, in order to obtain
      insights into the determinants of the stability of the iron(III) environment. In
      particular, positions 68, 72 and 75 have been essayed. Gln68 has been mutated to
      Lys to provide a suitable alternate ligand that can displace Met71 under
      denaturing conditions. Pro72 has been mutated to Gly and Ala to modify the range
      of allowed backbone conformations. Ile75, which is in van der Waals contact with
      Met71 and partly shields a long-lived water molecule in a protein cavity, has
      been substituted by Val and Ala to affect the network of inter-residue
      interactions around the metal site. The different contributions of the above
      amino acids to protein parameters such as structure, redox potential and the
      overall stability against unfolding with guanidinium hydrochloride are analyzed.
      While the structure remains essentially the same, the stability decreases with
      mutations. The comparison with mitochondrial c-type cytochromes is instructive.

PMID- 15175937
TI  - FTIR spectroelectrochemical study of the activation and inactivation processes of
      [NiFe] hydrogenases: effects of solvent isotope replacement and site-directed
      mutagenesis.
AB  - The kinetics of the activation and anaerobic inactivation processes of
      Desulfovibrio gigas hydrogenase have been measured in D(2)O by FTIR
      spectroelectrochemistry. A primary kinetic solvent isotope effect was observed
      for the inactivation process but not for the activation step. The kinetics of
      these processes have been also measured after replacement of a glutamic residue
      placed near the active site of an analogous [NiFe] hydrogenase from Desulfovibrio
      fructosovorans. Its replacement by a glutamine affected greatly the kinetics of
      the inactivation process but only slightly the activation process. The
      interpretation of the experimental results is that the rate-limiting step for
      anaerobic inactivation is the formation from water of a micro-OH(-) bridge at the
      hydrogenase active site, and that Glu25 has a role in this step.

PMID- 15175940
TI  - Novel interleukin 1beta polymorphism increased the risk of gastric cancer in a
      Korean population.
AB  - BACKGROUND: Polymorphisms in the gene for interleukin 1beta (IL-1B) have been
      found to increase the risks of gastric cancer and its precursors in response to
      Helicobacter pylori infection in white populations. however, there has been no
      independent confirmation of the role of IL-1B markers in gastric cancer patients
      from Asian populations. Moreover, there have been conflicting data regarding the
      effect of IL-1B-511/-31 on the risk of gastric cancer or its precursors in Asian
      populations. Therefore, we assessed an additional polymorphism in the promoter
      region of IL-1B at position-1473 with the IL-1B-511/-31 polymorphisms in a Korean
      population. METHODS: In a case-control study, including 331 gastric cancer cases
      and 433 controls, we assessed the association between the three polymorphisms and
      the risk of gastric cancer. All genotyping was performed in duplicate. To assess
      the DNA-binding activity of IL-1B-1473 in vitro, we performed an electrophoretic
      mobility shift assay (EMSA). RESULTS: When cases were divided according to the
      histologic type of the tumor, a significant difference in genotype frequencies
      for IL-1B-1473 was observed only between intestinal-type cases and controls (odds
      ratio [OR], 1.8; 95% confidence interval [CI], 1.0-3.5 and OR 2.1 and 95% CI, 1.1
      4.2 in the CG and GG genotypes, respectively). In the cases, there was a
      deviation from Hardy-Weinberg equilibrium in the IL-1B-511/-31 loci confined to
      the intestinal type, due to the excess of heterozygotes. The IL-1B-1473G allele
      showed decreased binding to nuclear extract, indicating a wearker promoter
      activity on EMSA. CONCLUSIONS: We identified a novel single-nucleotide
      polymorphism, 1473C-->G, in the IL-1B promoter that was significantly associated
      with gastric cancer among Koreans. Our results also suggest that the association
      between IL-1B polymorphism and an increased risk of gastric cancer may depend on
      the histologic type of gastric cancer.

PMID- 15175938
TI  - Cadherins: an integral role in inflammatory bowel disease and mucosal
      restitution.
AB  - The intestinal epithelium is characterized by rapid cellular turnover with
      continuous proliferation of multipotential stem cells within Lieberkuhn's crypts,
      cellular migration along the crypt-villus axis, cellular differentiation,
      polarization, apical apoptosis, and luminal shedding. These processes are
      critical for the development and maintenance of normal intestinal epithelial
      architecture and function and involve complex cell-cell and cell-substratum
      interactions, which are mediated by epithelial (E)-cadherin and the integrins,
      respectively. This review outlines the role of E-cadherin and its cytoplasmic
      binding proteins, the catenins, as well as the interplay with other mucosal
      adhesion and restitution molecules during physiological processes in the
      intestinal epithelium mediating embryogenesis, cellular differentiation, cellular
      migration, and mucosal repair, as well as what is known about the dysregulation
      of assembly of the E-cadherin-catenin adhesion complex in inflammatory bowel
      disease.

PMID- 15175939
TI  - Perforating veins in recurrent esophageal varices evaluated by endoscopic color
      Doppler ultrasonography with a galactose-based contrast agent.
AB  - BACKGROUND: We evaluated the usefulness of endoscopic color Doppler
      ultrasonography (ECDUS) with Levovist, a galactose-based contrast agents, for
      detecting veins in the esophageal wall in patients with recurrent esophageal
      varices after endoscopic therapies. METHODS: We compared vessel images detected
      prior to the use of contrast with those detected by enhanced ECDUS in 29 patients
      with recurrent esophageal varices. After the pre-contrast ECDUS examination, all
      29 patients received Levovist intravenously, at a concentration of 300 mg/ml. A
      7.5-ml dose of the contrast agent was injected at a slow infusion rate, of 1
      ml/min. The perforating veins detected by ECDUS were classified, according to
      flow direction, into three different types. Type 1 showed inflow from the
      paraesophageal veins to the esophageal varices. Type 2 showed outflow from the
      esophageal varices to the paraesophageal veins, while type 3 was a mixed type
      with both inflow and outflow. For comparison, 26 patients without recurrent
      esophageal varices were studied. RESULTS: Color flow images of perforating veins
      were obtained in 9 (31.0%) of the 29 patients with recurrent esophageal varices
      with pre-contrast ECDUS. The detection rate of perforating veins in the patients
      with recurrent esophageal varices (31.0%) was significantly higher than that in
      patients without recurrent esophageal varices (0 of 26; 0%) with pre-contrast
      ECDUS. Color flow images of perforating veins were detected in 22 (75.9%) of the
      29 patients with recurrent esophageal varices after Levovist contrast. On the
      other hand, color flow images of perforating veins were not detected in any of
      the 26 patients without recurrent esophageal varices after Levovist contrast.
      Type 1 perforating veins were recognized in 6 (20.7%) of the 29 patients, type 2
      in 2 (6.9%) of the 29, and type 3 in 1 (3.4%) of the 29 prior to the use of
      contrast. After the enhanced ECDUS, type 1 perforating veins were recognized in
      13 (44.8%) of the 29 patients, type 2 in 6 (20.7%) of the 29, and type 3 in 3
      (10.3%) of the 29. All color-flow images detected with pre-contrast ECDUS were
      enhanced after Levovist contrast. CONCLUSIONS: Perforating veins can be detected
      at a high rate by ECDUS with Levovist in patients with recurrent esophageal
      varices after endoscopic therapy.

PMID- 15175941
TI  - Increased expression of matrix metalloproteinase-7 in invasive early gastric
      cancer.
AB  - BACKGROUND: Matrix metalloproteinase-7 (MMP-7), a proteolytic enzyme, is
      suspected to play an important role in the progression of various cancers. To
      clarify the clinical importance of MMP-7, we retrospectively analyzed MMP-7
      expression in gastric epithelial tumors. METHODS: We tested 201 lesions (from 172
      patients) of surgically or endoscopically resected gastric epithelial tumors
      (gastric cancer, 158 lesions; gastric adenoma, 32 lesions; hyperplastic polyp, 11
      lesions). MMP-7 expression was immunohistochemically examined. Sections with
      immunostaining signals in more than 30% of tumor cells were judged to show
      positive expression. RESULTS: MMP-7 was expressed in 33.3% (67/201) of all
      lesions. MMP-7-positive tumors were significantly more frequent in diffuse-type
      adenocarcinomas (62.2%; 28/45) compared with intestinal-type lesions (31.9%;
      36/113; P < 0.001). Cancers invading the submucosa or deeper (60.5%; 46/76) were
      showed positivity significantly more frequently than mucosal cancers (22.0%;
      18/82; P < 0.001). MMP-7-positive lesions increased with the progression of
      gastric epithelial tumors, including adenomas, mucosal cancers, and cancers
      invading the submucosal layer or deeper (P < 0.001). MMP-7 expression occurred
      significantly more often in lymphatic invasion-positive cancers (65.1%; 41/63)
      than in lymphatic invasion-negative cancers (24.2%; 23/95; P < 0.001).
      CONCLUSIONS: The MMP-7-positive rate increased with the progression of gastric
      epithelial tumors, such as adenoma, mucosal cancer, and cancer invading the
      submucosal layer or deeper. MMP-7 was significantly associated with aggressive
      pathological phenotypes of cancer. The detection of the MMP-7 protein may be
      useful in pretherapeutic diagnosis.

PMID- 15175942
TI  - The clinical characteristics and outcome of intraabdominal abscess in Crohn's
      disease.
AB  - BACKGROUND: We aimed to elucidate the incidence and natural course of abdominal
      abscess complicating Crohn's disease (CD). METHODS: Of 352 patients with CD who
      were observed at our hospital between 1985 and October 2001, we studied 35
      patients (9.9%) with abscesses in the mid-abdominal region (the abdominal wall,
      peritoneal cavity, retroperitoneum, and subphrenic region). RESULTS: The
      cumulative incidence of complication with an abscess was 9% and 25%,
      respectively, 10 and 20 years after CD onset. Of the 35 CD patients with abscess,
      60% had had surgery by the time of the present study. The age when the abscess
      developed was 30.1 +/- 8.1 years, and the duration of illness from the onset of
      CD until development of an abscess was 10.8 +/- 6.3 years (range, 0-29 years).
      The location of involvement was: abdominal wall, n = 14 (40%); peritoneal cavity,
      n = 10 (29%); retroperitoneum or iliopsoas, n = 9 (26%); and subphrenic region, n
      = 2 (6%). In terms of location of abscess, it occurred most often on the right
      side (65.7%). Almost all abscesses occurred near the site of an anastomosis.
      Diseased segments of the bowel responsible for abscess formation were categorized
      radiographically as showing mild stenosis (6.5%), intermediate stenosis and/or
      simple fistula (41.9%), and severe stenosis and/or multiple fistulas (51.6%).
      Conservative treatment (including drainage of abscess) alone was effective in 7
      patients (20%) and surgery was needed in 28 patients (80%). During the 5.3-year
      follow-up after treatment for the abdominal abscess, 9 of the 35 patients (26%)
      had recurrence of an abscess, mostly within 3 years. CONCLUSIONS: Abscess
      formation was noted in about 10% of patients with CD, with 46% of abscesses
      occurring in a diseased bowel segment near an anastomotic site. Of the diseased
      bowel segments responsible for abscess formation, half had neither severe
      stenosis nor multiple fistulas. Almost all patients underwent surgery for the
      abscess, and, in more than a quarter of the patients, there was recurrence within
      a few years after surgery.

PMID- 15175943
TI  - Effect of mutation in the hepatitis C virus nonstructural 5B region on HCV
      replication.
AB  - BACKGROUND: We have reported that the presence of a mutation at the hepatitis C
      virus (HCV) nonstructural protein 5B (NS5B), defined as a change in amino acids
      at sites specific for a different reported genotype, was related to complete
      response (CR) to interferon (IFN) therapy in patients with chronic hepatitis C
      (CHC) with genotype 1b. The present study assessed the impact of the NS5B
      mutation on the replication of HCV in these patients. METHODS: Genotype-specific
      mutations of HCV NS5B were determined by direct sequencing. We measured HCV-RNA
      titers in serum by real-time detected polymerase chain reaction (PCR), and serum
      HCV core protein levels (as a marker of HCV-RNA replication) were measured using
      an enzyme immunoassay in patients with CHC genotype 1b. RNA-dependent RNA
      polymerase (RdRp) activity was measured by Behrens' method in liver cirrhosis
      patients infected with HCV (n = 13) and in those infected with hepatitis B virus
      (HBV; n = 2). RESULTS: The titers of HCV-RNA (n = 44) and the levels of HCV core
      protein (n = 41) were significantly lower in patients with the HCV genotype 1b
      mutant compared with wild-type HCV (P < 0.05). RdRp activity in liver tissue did
      not show any correlation with the HCV NS5B mutation. CONCLUSIONS: HCV NS5B
      genotype-specific mutations in HCV genotype 1b may influence HCV replication.

PMID- 15175944
TI  - Efficacy of interferon retreatment after relapse for chronic hepatitis C patients
      with biochemical response after first interferon therapy.
AB  - BACKGROUND: With respect to interferon (IFN) treatment for chronic hepatitis C,
      normalization of alanine aminotransferase (ALT) as well as clearance of hepatitis
      C virus (HCV)-RNA after IFN therapy is important. It has been shown that the
      incidence of hepatocellular carcinoma (HCC) in patients with normal ALT is
      significantly lower than that in those with elevated ALT after IFN therapy. We
      assessed the efficacy of IFN retreatment for chronic hepatitis C patients who had
      a biochemical response (BR) after the first IFN therapy and reelevated ALT during
      follow up, by a case control study. METHODS: Fifteen patients (case group; group
      1) enrolled in this study showed a BR after the first IFN therapy and reelevated
      ALT during follow up. Next, we retrospectively selected 30 patients (control
      group; group 2) with no response (NR) after the first IFN therapy. Group 2
      patients were matched 1 : 2 with group 1 patients for sex and age. All patients
      were given intramuscular injections of human lymphoblastoid IFN alpha daily (6
      MU) for 8 weeks and then three times a week for 16 weeks. We compared the
      clinical and biological differences between group 1 patients and group 2
      patients. Virological response (VR) was defined when serum HCV-RNA showed
      negativity more than 6 months after the completion of IFN therapy. BR was defined
      when ALT values remained normal during more than 6 months in spite of positive
      serum HCV-RNA, by reverse-transcription nested polymerase chain reaction, 3 and 6
      months after the completion of IFN therapy. NR was defined as any response except
      for VR or BR. RESULTS: The rate of patients showing VR in this study was 6.7%
      (1/15) in group 1 and 13.3% (4/30) in group 2. There was no significant
      difference between the groups with respect to VR. BR occurred in 73.3% (11/15) of
      patients in group 1, but in only 3.3% (1/30) of patients in group 2 (P = 0.0002).
      CONCLUSIONS: We conclude that IFN retreatment is one of the effective strategies
      with which to achieve BR again in HCV-positive patients who had a BR after their
      first IFN therapy and reelevation of ALT during follow up.

PMID- 15175946
TI  - Analysis of serum catalase activities in pancreatic diseases.
AB  - BACKGROUND: Active oxygen species are thought to be involved in the exacerbation
      of acute pancreatitis. Therefore, it would be reasonable to speculate that the
      activity of catalase is increased in the severe form of acute pancreatitis. The
      aim of the present study was to diagnose the severity of acute pancreatitis,
      using catalase activity, and to examine the usefulness of this measurement for
      this diagnosis. METHODS Catalase could be measured quickly in 87 patients with
      pancreatic disease, using automatic analyzers, and using kits based on UV rate
      assay methods. RESULTS: In pancreatic disease, catalase activity was higher in
      acute pancreatitis, particularly in the early stage of the disease. It could be
      used to diagnose the severity of acute pancreatitis almost as early as the
      criteria of the Japanese Ministry of Health and Welfare (MHW). When we set 330
      U/l as the cutoff value, its sensitivity of diagnosis was 76.9% in the first 4
      days of the disease and its specificity was 100%. CONCLUSIONS: As catalase
      activity can be measured quickly using automatic analyzers, serum catalase
      activity is useful for evaluation of the severity of acute pancreatitis.

PMID- 15175945
TI  - Inhibition of cell invasion and morphological change by troglitazone in human
      pancreatic cancer cells.
AB  - BACKGROUND: We have recently demonstrated that peroxisome proliferator activated
      receptor (PPAR) gamma activation by its selective ligand, troglitazone, potently
      inhibited cell proliferation in human pancreatic cancer cells. The present study
      was performed to clarify the role of PPARgamma in cell invasion/motility in human
      pancreatic cancer cells. METHODS: Cell invasive activity was assessed by an in
      vitro invasion assay, using a Transwell chamber, and by a wound-healing assay, in
      the human pancreatic cancer cell lines, PK-1 and PK-9. Cell morphology and actin
      structure were evaluated by phase-contrast and fluorescence microscopy. RESULTS:
      PPARgamma activation by troglitazone inhibited cell invasion and cell migration
      in PK-1 and PK-9 cells. We also examined the effect of troglitazone on cell
      morphology and actin structure because of its effect on cell motility. The size
      of PK-1 and PK-9 cells that had been incubated with troglitazone became smaller,
      and the in shape changed from flat to spindle, followed by round. The
      troglitazone-induced cell rounding was reversible by replacement with
      troglitazone-free medium. Rhodamine-phalloidin staining revealed a decreased
      number of actin filaments in PK-1 cells treated with troglitazone. In cells
      treated with mycalolide B, an actin depolymerizing agent, troglitazone failed to
      induce cell rounding. CONCLUSIONS: These results suggest that PPARgamma
      activation by troglitazone inhibited cell motility and changed cell morphology
      through modulating actin organization.

PMID- 15175947
TI  - Inflammatory tumor in pancreatic tail induced by endoscopic ablation with
      cyanoacrylate glue for gastric varices.
AB  - A 65-year-old Japanese man was hospitalized with back pain in April 1998. At age
      63 years, endoscopic ablation with cyanoacrylate glue had been performed for
      bleeding gastric varices. At the time of the present admission, a low-density
      mass (about 23 mm in diameter) was seen in the tail of the pancreas, and splenic
      vein occlusion and collateral veins were revealed on computed tomography. A
      hypoechoic tumor (about 22 mm in diameter) and splenic vein occlusion were
      clearly visualized on the pancreas tail via endoscopic ultrasonography. Venous
      phase of the splenic arteriogram revealed a completely occluded splenic vein in
      the hilus of the spleen. Thus, the patient was diagnosed with pancreatic cancer
      (stage I: T2N0M0). A surgical resection of the pancreatic tumor was performed,
      and a pancreatic tail resection with part of stomach around the pancreas tail,
      and splenectomy, were selected for this patient, in June 1998. Histopathological
      examination of the resected tumor revealed capsuled abscess formation with
      foreign body reaction between the stomach and the pancreas tail, and necrosis was
      present in the pancreas around the abscess. There were some deposits of
      cyanoacrylate glue in the tumor. The mass was considered to be an inflammatory
      tumor. In summary, this case of inflammatory pancreas tumor is a novel
      complication after endoscopic obliterative therapy with cyanoacrylate glue.

PMID- 15175948
TI  - Rectal cancer associated with chronic lymphocytic leukemia.
AB  - It has been reported that chronic lymphocytic leukemia (CLL) often occurs
      concomitantly with other malignant neoplasms. However, because CLL is rare in
      Japan, there are only a limited number of reports of the occurrence of malignant
      neoplasia in Japanese patients with CLL. We report here the simultaneous
      occurrence of rectal cancer and CLL in a 57-year-old man. Because the clinical
      stage of CLL was Rai system I, we decided, in accordance with the National Cancer
      Institute-Sponsored Working Group guidelines, to monitor him without therapy for
      CLL until evidence of disease progression, and we performed abdominoperineal
      resection of the rectum for the cancer. The small rectal tumor was associated
      with aggressive lymphangiosis carcinomatosa, and multiple nodal metastases were
      observed in the pool of CLL cells. He died of rectal cancer 7 months after the
      operation, and autopsy revealed extensive metastases of the cancer. Cellular and
      humoral immunity is often impaired in patients with CLL, and the defective
      immunity in this patient may have had an etiological role in the development and
      rapid progression of the cancer. In the follow-up of CLL patients, we must always
      be aware of the possible existence of a second malignant disease. Particular
      attention should be paid to those with defective immunity, and screening should
      be performed, especially for pulmonary and gastrointestinal malignancies.

PMID- 15175949
TI  - Successfully treated idiopathic rectosigmoid perforation 7 years after renal
      transplantation.
AB  - Colon perforation (CP) is still a critical complication after renal
      transplantation (RT), and idiopathic perforation is extremely rare. Here we
      describe a successfully treated case of idiopathic rectosigmoid perforation that
      occurred 7 years after RT. In our research this is the tenth reported case of
      idiopathic CP after RT and the second case that has occurred in the rectosigmoid.
      The patient was a 51-year-old Japanese male RT recipient still receiving
      immunosuppressive medication. He was admitted to the hospital for sudden onset of
      abdominal pain during defecation. Emergency laparotomy was performed 5 h after
      the onset, and a longitudinal 1.5 cm perforation with a clear margin was observed
      in the rectosigmoid, 8 cm above the peritoneal reflection. Hartmann's operation
      was performed. Macroscopic and histological examination did not reveal any
      specific findings that may have caused perforation, so the case was diagnosed as
      idiopathic rectosigmoid perforation.

PMID- 15175950
TI  - PBC-AIH overlap syndrome with concomitant ITP and Hashimoto's disease with
      positivity for anti-centromere antibody.
AB  - We report a case of primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH)
      overlap syndrome with concurrent idiopathic thrombocytopenic purpura (ITP) and
      Hashimoto's disease with positivity for anticentromere antibody. The patient was
      a 64-year-old woman with symptoms of jaundice and general fatigue. About 30 years
      earlier, she had been diagnosed as having ITP and had undergone splenectomy. As
      part of her present history, she had exhibited liver dysfunction in 1995, during
      the follow-up of Hashimoto's disease, and a liver biopsy led to the diagnosis of
      PBC. In March 2000, she was admitted to hospital because of general fatigue and
      jaundice. Blood tests revealed: total protein (TP), 6.6 g/dl; gamma-globulin
      (glb), 35.9%; total bilirubin (T-bil), 9.41 mg/dl; direct bilirubin (D-bil), 7.52
      mg/dl; aspartate aminotransferase (AST), 957 U/l; alanine aminotransferase (ALT),
      651 U/l; alkaline phosphatase (ALP), 595 U/l; gamma-guanosine triphosphate (GTP),
      129 U/l; IgG, 2620 mg/dl; IgM, 223 mg/dl; hepatitis B surface antigen (HBsAg),
      negative; anti-hepatitis C virus (HCV), negative; antinuclear antibody, positive;
      antimitchondrial antibody (AMA), negative (by the immunofluorescence [IF]
      method); and anti-pyruvate dehydrogenase complex (PDC)-E2 antibody, positive (by
      Western blotting). Anticentromere antibody (ACA), which is an alternative
      diagnostic marker for PBC, was detected in this patient. Prednisolone was
      administered after admission and liver function test results improved markedly.
      The liver biopsy in 1995 had revealed infiltration of lymphocytes and plasma
      cells in the portal areas with fibrous expansion and periportal necrosis.
      Destructive cholangitis was observed, as well as scattered epitheloid cell
      granulomas in some portal areas. Liver biopsy after the steroid treatment
      revealed alleviated necrotic inflammatory responses of hepatocytes, while the
      destructive cholangitis persisted. This is a very rare case of PBC-AIH overlap
      syndrome accompanied by ITP and Hashimoto's disease which provides a possible
      insight into the mechanisms and interplay of autoimmune diseases.

PMID- 15175951
TI  - Gene expressions of proinflammatory cytokines in the colonic mucosa in a patient
      with amebic colitis.

PMID- 15175952
TI  - Multiple tuberculous abscesses of the liver and the brain in a patient with acute
      leukemia.

PMID- 15175953
TI  - Acute hepatic failure due to hepatic involvement by chronic lymphocytic leukemic
      cells in a patient with chronic hepatitis B.

PMID- 15175954
TI  - Controversy in polymorphisms of interleukin-1beta in gastric cancer risks.

PMID- 15175955
TI  - Serum markers for predicting the severity of acute pancreatitis.

PMID- 15175956
TI  - [Clinical trials and studies of the German Society for Paediatric Oncology and
      Haematology (GPOH) and the European Directive for the Implementation of Good
      Clinical Practice in the Conduct of Clinical Trials].

PMID- 15175957
TI  - Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with
      unilateral nonmetastatic Wilms Tumor.
AB  - BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since
      the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP
      trials and studies largely focus on the issue of preoperative therapy to
      facilitate surgery of a shrunken tumor and to treat metastasis as early as
      possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020
      patients with a newly diagnosed renal tumor were registered. 847 of them had a
      histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173
      tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear
      cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative
      chemotherapy in benign tumors was given to 1.3 % of the patients. The main
      objective of the trial was the randomized question, if the postoperative two drug
      chemotherapy for stage I in intermediate risk or anaplasia can be reduced from
      conventional 3 courses to an experimental 1 course without loss of efficacy.
      RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive
      preoperative chemotherapy. The histology in this group of patients was of
      intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7
      %) high risk. The stage distribution of the tumors was stage I in 315 (61 %),
      stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %)
      patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was
      measured in 487 patients before and in 402 after preoperative chemotherapy. The
      median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction
      depends on the histological subtype. The event free survival (EFS) after 5 years
      was 91 % for all patients with unilateral Wilms tumor without distant metastasis.
      Randomisation was done in 43.7 % for stage I patients and there was no difference
      in EFS for both treatment arms (90 versus 91 %). The EFS is identical for
      patients with stage I and II N- (0.92), as well as for stage II N+ and III
      (0.82). The tumor volume after chemotherapy is a prognostic factor for
      intermediate risk tumors with the exception of epithelial and stromal predominant
      tumors. These two subtypes often present as large tumors, they do not shrink
      during preoperative chemotherapy but they still have an excellent prognosis. On
      the other hand the prognosis of patients with blastemal predominant subtype after
      preoperative chemotherapy is worse than in any other patient group of
      intermediate risk tumors. There are less blastemal predominant tumors compared to
      primary surgery, but they are chemotherapeutic resistant selected by the
      preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor
      without metastasis have an excellent prognosis. The post-operative chemotherapy
      in stage I can be reduced to 4 weeks without worsening treatment outcome. The
      reduction of the tumor volume could be identified as a helpful marker for
      stratification of post-operative treatment. Post-chemotherapy blastemal
      predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal
      anaplasia has a better prognosis than diffuse anaplasia and will be classified as
      intermediate risk tumor.

PMID- 15175959
TI  - The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease:
      evolution in the tradition of the DAL/GPOH studies.
AB  - Today it is possible to cure more than 90 % of children and adolescents with
      Hodgkin's disease with a combination of radiotherapy and chemotherapy. Since the
      DAL-HD 82 study, the main scientific focus has been on avoiding late effects such
      as the OPSI syndrome, late complications involving the heart, lungs, thyroid
      and/or gonads particularly sterility in men and premature onset of menopause in
      women, and the prevention of secondary malignancies. The GPOH-HD 2003 study will
      introduce FDG-PET to the initial diagnostic program and the assessment of
      response to therapy in order to evaluate further possibilities for reducing
      therapy. In this context, the central review of all clinical and radiological
      findings, systematically done since the DAL-HD 90 study, will be increasingly
      relevant in maintaining standardised stage classification and therapy group
      assignment which was established by the preceding studies. Continuing in the
      direction of the earlier studies, the indications for radiotherapy will be
      restricted even further. In the early stages (treatment group 1) patients with CR
      or a negative FDG-PET at the end of chemotherapy will receive no radiotherapy in
      order to reduce the risk of a secondary malignancy. In a randomized comparison,
      procarbazine will be replaced by dacarbazine in the COPP cycles to determine
      whether sterility in men and premature onset of menopause in women can be avoided
      by elimination of procarbazine while retaining the same clinical efficacy.
      Finally, relapse therapy is to be tailored according to the time of relapse, the
      initial therapy group, and the patient's response to the relapse therapy with
      more patients receiving autologous transplantation in order to further improve
      the results of relapse treatment.

PMID- 15175958
TI  - Impact of surgery, chemotherapy and irradiation on long term outcome of
      intracranial malignant non-germinomatous germ cell tumors: results of the German
      Cooperative Trial MAKEI 89.
AB  - Malignant non-germinomatous intracranial germ cell tumors (MNGGCTs) are a
      heterogenous group of neoplastic lesions. Their treatment concept follows a
      multimodal concept that may include tumor resection for local tumor control,
      craniospinal irradiation to cover leptomenigeal tumor spread and chemotherapy to
      eliminate systemic tumor dissemination. A Platinum-based chemotherapy proven to
      be highly effective in testicular and non-testicular malignant germ cell tumors
      in adults as well as in children has also been chosen for intracranial sites.
      While therapeutic concepts have been thoroughly evaluated for children and
      adolescents with extracranial nongonadal GCTs, no such detailed long term follow
      up data are available for intracranial MNGGCTs. This paper reports on the long
      term outcome of 41 patients with intracranial malignant non-germinomatous GCTs
      enrolled into the German prospective protocol MAKEI 89. The analysis focuses on
      the impact of surgery, radio- and chemotherapy. PATIENTS AND METHODS: Between
      January 1989 and January 1994, 41 patients with malignant intracranial non
      germinomatous GCTs were registered. Patients were compared in respect to protocol
      (n = 27) and non-protocol treatment (n = 14). Estimated were with chi (2) and
      Fisher exact test the impact of surgery, chemotherapy and irradiation on outcome.
      RESULTS: The estimated (Kaplan-Meier) 5-year event free survival (EFS) of
      patients treated according to protocol recommendations was 0.59 +/- 0.06 (n =
      27), compared to an EFS of 0.37 +/- 0.33 for patients with different treatments
      (n = 14) (p = 0.70, log-rank). The 5-year relapse-free survival rate (RFS) was
      0.74 +/- 0.06 in protocol patients and 0.38 +/- 0.33 in non-protocol patients
      (median observation time of 112 months after diagnosis for surviving patients) (p
      = 0.14, log-rank). Surgery, complete or incomplete had no significant impact on
      survival (p = 0.12). Radiotherapy, in terms of craniospinal irradiation had a
      significant influence on survival (p = 0.035) as well as a cumulative cisplatin
      dose >/= 400 mg/m (2) (p = 0.002). CONCLUSION: Cisplatin chemotherapy and
      craniospinal irradiation with tumor boost are of significant influence on long
      term survival in patients with MNGGCTs. The exclusion of major surgery at
      diagnosis using modern advances in neurosurgery or related tumor resection after
      neoadjuvant chemotherapy will allow a further reduction of treatment related
      mortality and long lasting morbidity. The analysis reveals that, given effective
      treatment, intracranial malignant non-germinomatous GCTs should not longer carry
      a poor prognosis.

PMID- 15175960
TI  - Congenital erythrocytosis and polycythemia vera in childhood and adolescence.
AB  - Polycythemia vera - the most frequent form of a primary erythrocytosis in adult
      patients - represents an extremely rare disease in pediatric and juvenile
      patients as do congenital primary and secondary erythrocytoses. Frequently, in
      patients with these diseases clinical problems do not occur before adulthood.
      Systematic data on clinical and laboratory evaluations as well as on treatment
      regimens are sparse. In addition, in the majority of cases with congenital
      erythrocytosis, the etiology is unknown. For those reasons, a protocol (PV-ERY-KA
      03) for the systematic collection of clinical, hematological, biochemical,
      biological as well as treatment data of children and adolescents with
      polycythemia vera or congenital erythrocytosis including the hemoglobinopathies
      with high affinity hemoglobin, familial 2,3-BPG deficiencies, and those of
      unknown origin, has been developed. These data are combined with molecular
      analyses which focus initially on EPO-receptor and vHL-gene examination, but will
      later be extended into presently unexplored pathophysiologic regulatory circuits.
      In addition, pathophysiologic changes due to the erythrocytosis will be studied.
      The co-ordinated medical care for patients with those rare diseases within a
      collaborative trial accompanied by scientific projects is aimed at the
      improvement of the treatment of these patients as well as to a better
      understanding of the underlying biological processes.

PMID- 15175961
TI  - Hematopoietic stem cell transplantation for mucopolysaccharidoses and
      leukodystrophies.
AB  - The only effective treatment for selected metabolic diseases is a successful
      allogeneic hematopoietic stem cell transplantation (HCT). Best results with HCT
      are obtained when performed early in the course of the disease. Hence, timely
      identification and referral are critical. Also, early identification of affected
      patients during the newborn period via screening may be invaluable, particularly
      for the infantile onset rapidly progressive forms of diseases. Rapid availability
      of a donor graft is often crucial for these patients. Preliminary experience
      suggests that results after umbilical cord blood (UCB) transplant may be
      comparable to those after marrow transplants. UCB grafts have certain benefits of
      rapid availability and even reduced risk of GvHD. Hence, UCB transplant
      represents an alternative to marrow HCT. Related haploidentical HCT, possibly
      with very high doses of CD34+ cells, may also represent an option. However,
      expertise has been developed in very few transplant centers and no large reports
      are available of its use for patients with inherited metabolic diseases.

PMID- 15175962
TI  - Long-time survival after unrelated bone marrow transplantation in children and
      adolescents and targeted therapy with CD25 blockade to prevent GVHD.
AB  - To evaluate longtime survival after matched unrelated donor (MUD) transplantation
      a group of patients (n = 10) with intensified GVHD prophylaxis were compared to
      patients receiving matched sibling (MSD) transplantation (n = 10); all
      transplantations were done between 1989 and 1995 in the same institution. A
      murine monoclonal antibody against CD25 was assessed in addition to standard GVHD
      prophylaxis for reducing GVHD in children with advanced leukemia after MUD BMT
      (group I). We compared the incidence of GVHD, relapse and survival under
      prophylaxis with either anti-CD25 (group I, n = 10) or MSD BMT without anti-CD25
      (group II, n = 10) with respect to known risk factors of transplant related
      morbidity, mortality and outcome. 3/10 leukemia patients in both groups were in
      CR3 or in relapse at time of transplant. Whereas incidence of acute GVHD grade
      III and IV was significantly higher in group I compared to group II (0.4 vs.
      0.0), no differences in engraftment, or chronic GVHD were seen between both
      groups. In addition, overall (0.5 vs. 0.6) and leukemia free survival (0.5 vs.
      0.6) was not different after 8 respectively 10 years from transplant. Murine anti
      CD25 therapy may have contributed to matching outcome of MUD vs. MSD marrow
      transplants in children with advanced leukemia. In conclusion, the use of anti
      CD25 in modulation of CD25+ regulatory and effector T cells in allo- and leukemia
      recognition merrits further exploration of its potential to improve both
      tolerance and leukemia control. Since the outcome of children with leukemia that
      received intensified GVHD prophylaxis in MUD BMT was similar to children with MSD
      transplants, MUD BMT has to be considered as an equivalent therapeutic option for
      patients, who have no HLA-identical sibling donor.

PMID- 15175963
TI  - Characterization of CD34+ progenitor-derived dendritic cells pulsed with tumor
      cell lysate for a vaccination strategy in children with malignant solid tumors
      and a poor prognosis.
AB  - BACKGROUND: Children and adolescents with primary multifocal, refractory or
      relapsed malignant extracranial solid tumors still have a poor prognosis inspite
      of intensive standard radio-/chemotherapy. Here complementary immunomodulatory
      treatment modalities may prove beneficial as consolidation therapy following
      cytoreduction. Neuroblastoma, Ewing tumor and soft tissue sarcoma cells have
      principally been shown to be susceptible towards both cytotoxic and humoral
      effector mechanisms. Yet in vivo they are not capable of inducing an effective
      antitumor response which has been attributed to low level MHC expression and lack
      of costimulatory surface molecules. Professional antigen - presenting cells such
      as dendritic cells (DCs) in contrast are capable of activating unprimed T cells
      and are therefore ideal tools for vaccine generation. RESULTS: Here we
      demonstrate that DCs may be generated from CD34+ progenitor cells to clinical
      scale in a three to four week cell culture process including an initial expansion
      and subsequent differentiation and maturation steps. DCs derived from CD34+
      progenitors express the expected marker profile and are highly effective in
      stimulating allogeneic T cell effectors. We also demonstrate that they
      effectively take up fluorescence-labelled tumor cell lysate. DISCUSSION: Having
      established a cell culture process for clinical scale DC production utilizing
      CD34+ progenitors as the cellular source we discuss the role of CD34+ derived DCs
      in clinical vaccination protocols. The rationale for a phase I/II DC dose
      escalation study for high risk pediatric patients with extracranial solid tumors
      assessing safety, immunological and clinical efficacy of serial combined
      intranodal and subcutaneous injections of tumor cell lysate-pulsed autologous DCs
      is delineated.

PMID- 15175964
TI  - [Out-patient palliative care of children with cancer and their families].
AB  - Pediatric palliative care is still in its beginning. Most children with life
      threatening disorders succumb with incomplete symptom control under in-patient
      conditions. Due to the limited number of patients and large hospital-home
      distances the realization of out-patient concepts of palliative care especially
      for children and adolescents with cancer is purposeful and beneficial. In a pilot
      project such an a aforementioned concept of pediatric palliative care proved
      successfully working despite insufficient conditions. Guidelines of pediatric
      palliative care are to be defined at short notice in order to ascertain autonomy
      and mobility of patients aiming at highest possible quality of life. The recently
      initiated program of integrating ambulatory and in-patient care within the
      regulations set forth in Germany's last health care system reform offers the
      chance of palliative home care of children in their terminal phase of life.

PMID- 15175965
TI  - [Emotional development - what determines it - what disturbs it?].
AB  - By asking for the determining factors in developmental psychology we exemplify
      the vicissitudes of scientific perspectives during the past century, in which the
      factors viewed as primarily responsible (for development) changed several times -
      depending on the "zeitgeist". In actual fact one must assume a continuous
      interaction of genetics, externally caused alterations and milieu effects. To
      this science can only contribute by means of statistical probability, which in a
      single case would have to be translated into no more than a statement of risks
      and chances.

PMID- 15175968
TI  - [Behavioural disorders in Alzheimer's disease. Data from a populational study].
AB  - AIMS: The purpose of this work was to study the characteristics of the
      behavioural disorders (non-cognitive or neuropsychiatric symptoms) presented by
      subjects with Alzheimer's disease from a sample of the population together with
      their relation to the cognitive and functional impairment suffered by these
      patients. PATIENTS AND METHODS: NEDICES is a longitudinal populational study
      based on the census of neurological diseases in subjects above the age of 64. In
      2001, a study was conducted of the situation of 83 subjects who had started
      suffering from Alzheimer's disease between 1994 and 1997. Due to death and a
      number of other reasons, only 32 of them could be examined. Patients were
      administered a structured interview with scales referring to the cognitive state,
      functional capacity, severity of the dementia and the presence and severity of
      neuropsychiatric disorders. RESULTS: All the patients studied presented some non
      cognitive symptom. Apathy was the most frequent (93.8%), followed by irritability
      (81.1%), anxiety (75.0%), dysphoria (71.8%) and agitation-aggressiveness (56.2%).
      The least frequent were deliria (50.2%), altered nocturnal behaviour and aberrant
      motor activity (37.6%), altered appetite and eating, and hallucinations (24.9%),
      disinhibition (21.8%) and euphoria (21.6%). The degree of cognitive impairment
      and the presence of non-cognitive symptoms exerted a similar and independent
      effect on functional capacity. Only 56.3% of the patients were treated with some
      kind of anticholinesterase or psychotropic medication. CONCLUSIONS: Our census
      based populational study confirmed the high prevalence rate of non-cognitive
      symptoms in patients with Alzheimer's disease. These data confirm the notion that
      these symptoms are intrinsic manifestations of the disease.

PMID- 15175966
TI  - [Non-conventional therapies in childhood cancer: guidelines for distinguishing
      non-harmful from harmful therapies: a report of the SIOP Working Committee on
      Psychosocial Issues in Pediatric Oncology].
AB  - This is the 11th official document of the SIOP Working Committee on Psychosocial
      Issues in Pediatric Oncology, instituted in 1991. There is a tendency for some
      physicians to make blanket statements against the use of non-proven,
      nonconventional therapies, even when these therapies are not harmful. There is an
      equal and opposite tendency on the part of many parents to do all that they
      possibly can for their children, including using any non-conventional therapy
      they feel might do some good. The health care team must open a healthy dialogue
      with parents that will lead to a clear distinction between those complementary
      therapies that are harmful and those that are not, indeed, might even be helpful
      psychologically if not therapeutically.

PMID- 15175969
TI  - [Neurological complications in a series of 205 orthotopic heart transplant
      patients].
AB  - INTRODUCTION: A heart transplant is the only effective therapeutic option open to
      many patients with severe heart failure and performing such an intervention is
      not free of complications. Little is known about the risk factors for
      neurological complications after a heart transplant. AIMS: The aim of this study
      was to identify the risk factors for neurological complications following a heart
      transplant and, more especially, those associated with epileptic seizures,
      encephalopathy, cerebrovascular accidents (CVA) and headaches. PATIENTS AND
      METHODS: We conducted a retrospective review of the records of 205 orthotopic
      heart transplant patients and collected clinical, haemodynamic and laboratory
      data before, during and after the intervention, using a standardised protocol.
      RESULTS: 95 patients (48%) presented neurological complications. Their
      frequencies were as follows: encephalopathy (16.6%), epileptic seizures (13.6%),
      neuromuscular disorders (10.6%), headaches (10.6%), CVA (10.1%), psychiatric
      disorders (2.2%) and infection of the central nervous system (2.2%). The risk
      factors for encephalopathy were post-transplant renal failure (RR: 4.6; CI 95%:
      1.4-15), post-transplant hepatic failure (RR: 5.6; CI 95%: 1.5-22) and pre
      transplant haemodynamic instability (RR: 4.3; CI 95%: 1.3-14); for epileptic
      seizures they were a cardiac index of < or = 2 L/min/m2 (RR: 23.8; CI 95%: 2-247)
      and extracorporeal circulation time > or = 115 min (RR: 11.3; CI 95%: 1-79); and
      for CVA the risk factor was post-transplant hepatic failure (RR: 12.9; CI 95%:
      2.5-66). CONCLUSIONS: Neurological complications often occur after a transplant
      and are transient. Perioperative haemodynamic instability giving rise to cerebral
      ischemia and the metabolic disorders secondary to multiple organ failure are
      determining factors of encephalopathy, epileptic seizures and CVA.

PMID- 15175970
TI  - [Traumatic brain injury and ischemic stroke: a delayed sequela?].
AB  - INTRODUCTION: Although the conventional risk factors of ischemic stroke are
      numerous and the physiopathological mechanisms are well known, we believe that
      there may be other less common factors that have received less attention by
      researchers but are nonetheless just as important. AIMS: The aim of this study
      was to determine whether there is a long-term relationship between suffering
      severe traumatic brain injury (TBI) and the occurrence of ischemic stroke.
      PATIENT AND METHODS: A retrospective study was performed to examine 140 cases of
      severe TBI attended over the last 10 years and the delayed presentation (that is,
      more than a year later) of an ischemic stroke. A fundamental requirement was the
      absence of any other known risk factors and the location of the cerebral infarct
      had to be ipsilateral and adjacent to the injured area of the brain. RESULTS:
      Only three patients were detected who presented a late post-traumatic medium
      sized stroke located in the cortico-subcortical region of the carotid territory,
      and who were diagnosed within an interval of time ranging between 11 and 16
      months. CONCLUSIONS: Based on the physiopathology put forward to account for the
      aetiological factors of diseases such as Parkinson, Alzheimer or post-traumatic
      epilepsy, we found reasons to consider severe TBI to be another predisposing
      factor of delayed ischemic stroke, with all the implications this involves in
      medical-legal matters. More extensive case mixes will be needed in order to
      confirm our proposition.

PMID- 15175971
TI  - [Linkage analysis in an extended multigenerational family segregating for
      idiopathic epilepsy].
AB  - INTRODUCTION: Linkage analyses enable us to identify the loci that bestow
      susceptibility to certain diseases which are assumed to have a genetic aetiology
      by determining the cosegregation of alleles of specific markers within families.
      AIMS: The aim of this study was to determine whether there is generalised
      idiopathic epilepsy (GIE) susceptibility in the 8q22.1 -q24.23, 16p13.3 and
      21q22.3 regions within an extended multigenerational family belonging to the
      Paisa community in Antioquia, a genetic isolate located in Colombia segregating
      for GIE with a strong capacity for detecting linkage. PATIENTS AND METHODS: A
      family with a number of individuals affected by idiopathic epilepsy who visited
      the Instituto Neurologico de Antioquia was selected for study. An affected
      individual was required to have been diagnosed by a neurologist as suffering from
      non-myoclonic idiopathic epilepsy or partial idiopathic epilepsy. All patients
      suspected of suffering from idiopathic epilepsy were submitted to video
      monitoring in order to characterise the seizures electroencephalographically.
      RESULTS: Of the 106 individuals in this family that were included in the family
      tree, 76 were genotyped, 15 of whom were affected by generalised clonic tonic
      seizures and six were considered to be possibly affected. Results of the lod
      score were significantly negative for all the markers in relation to each model
      that was considered. CONCLUSIONS: The possibility of the genes located in the
      8q22.1 -q24.23, 16p13.3 and 21q22.3 regions being responsible for the familial
      aggregation of GIE in this family was ruled out, which is in accordance with
      claims made in previous studies conducted on other families.

PMID- 15175972
TI  - [Neurosonological findings in the carotid artery in a sample of patients with
      lacunar infarction].
AB  - INTRODUCTION: Carotid stenosis has been reported as being associated to lacunar
      infarcts (LI) with variable frequency, but the aetiopathogenic relation between
      them is still subject to some controversy. AIMS: Our aim was to describe the
      prevalence of carotid disorders in a neurosonological study of a sample of
      patients with LI. PATIENTS AND METHODS: We analysed the results of the
      neurosonological study conducted on patients with clinical-radiological criteria
      of LI who were admitted to our Stroke Unit during the period of study. RESULTS:
      We studied 140 patients, and results were normal in only 42% of the cases.
      Stenosis > 50% was found in 10% of the cases and plaque without stenosis in 40.3%
      of the patients. In patients without plaque there was an increase in the tunica
      intima-media thickness in 7.2% of the cases. CONCLUSION: In most of the patients
      with LI there were anomalies in the study of the carotid performed using
      ultrasound scanning.

PMID- 15175973
TI  - [SENTREP test: two lists of sentences of equal length to check the attention and
      the presence of linguistic maturity problems].
AB  - INTRODUCTION: Comparing the syntactic complexity of the sentences, in addition to
      its length, may help detect the linguistic weaknesses of Spanish-speaking
      subjects. OBJECTIVES: The test consists of two lists of sentences of similar
      length: a list of sentences of well-controlled length, based on the repetition of
      bisyllabic words (such as the ones suggested by Kagan & Klein) and adding length
      to the sentences in two syllables steps; and a parallel list where a series of
      linguistic complexities are included (negatives, persons, numbers, tenses,
      composite or multiple verbs, relatives, etc) where length increases one syllable
      at a time. MATERIAL AND METHODS: We administered this test to 41, 44, 62 and 18
      student aged 6, 9, 12 and 15 at a upper-class school in Bogota; and to parallel
      groups of 20 gifted students (in a school for gifted children near Bogota) and 40
      disabled Hispanic non-readers attending an independent special program. RESULTS:
      Below a certain developmental level (the age of 9) student must face complexity
      as one more difficulty that diminishes the length of the repeated sentence. On
      the contrary: after this age, their mastery of the structure of language acts as
      a leading thread that allows the repetition of longer and longer sentences, much
      longer than their simple attention span. CONCLUSIONS: This diagnostic approach
      adds an unexpected approach to the very quick observation and detection of both
      attentional and linguistic problems.

PMID- 15175974
TI  - [Acute polyneuropathy and encephalopathy caused by arsenic poisoning].
AB  - INTRODUCTION: Acute arsenic toxicity is a multisystemic disease with pleural and
      pericardial effusions, gastrointestinal symptoms and pancytopenia. The most
      frequent neurological complication of inorganic arsenic intoxication is a distal
      symmetrical polyneuropathy. CASE REPORT: We report here a patient who developed a
      systemic illness followed with severe acute polyneuropathy. Electrophysiological
      findings suggested a Guillain-Barre syndrome (GBS). Finally an acute
      encephalopathy appeared which led to reconsideration of the diagnosis. A 24-hour
      heavy metal urine, nail and hair analysis was performed. A diagnosis of arsenic
      toxicity was made. Instead of chelating therapy patient died due to respiratory
      failure. CONCLUSIONS: A misdiagnosis of GBS in inorganic arsenic polyneuropathy
      is not infrequent. Atypical progression compels to rule out arsenic or heavy
      metal intoxication. In our case the appearance of the encephalopathy was the key
      to the diagnosis. It has been suggested that axonal degeneration and segmental
      demyelination might be equally prominent pathological features of the neuropathy,
      depending on the dosage and the length of time of exposure to arsenic. The exact
      pathophysiology of arsenic polyneuropathy remains unclear and a interference with
      pyruvate oxidation has been postulated.

PMID- 15175975
TI  - [Idiopathic catastrophic epileptic encephalopathy: an untreatable convulsive
      malady in infancy].
AB  - AIM: To present a case of catastrophic childhood epileptic syndrome with
      multifocal status epilepticus. CASE REPORT: A 4 years old boy with a multifocal
      status epilepticus of unknown origin which could only be controlled along some
      days with thiopentone enough to cause electrical suppression, and relapsed again
      after having stopped it. CONCLUSION: But for very high doses of barbiturates, any
      antiepileptic drug could control or improve the convulsions. MRI, initially
      normal, was followed by a progressive cerebral and cerebellar atrophy and the boy
      survived with heavy neurological secuelae.

PMID- 15175976
TI  - [Bilateral anterior opercular syndrome as a manifestation of a non-convulsive
      epileptic state].
AB  - INTRODUCTION: Foix-Chavany-Marie syndrome, or bilateral anterior opercular
      syndrome, is characterised by facio-pharyngo-glosso-masticatory diplegia with
      'automatic-voluntary dissociation', which consists in the abolition of voluntary
      movements while involuntary movements and reflexes are preserved. It is produced
      by bilateral involvement of the anterior or frontal opercular region. In adults
      it is related to ischemic lesions. In childhood it presents congenitally in
      perisylvian dysplasias and as an acquired disorder in encephalitis or can be
      episodic in symptomatic or idiopathic epilepsies such as benign rolandic
      epilepsy. CASE REPORT: A 13-year-old patient who presented, over five straight
      days, four episodes of facial dysplegia, anarthria, dysphagia, drooling,
      paralysis of the upper limbs, while involuntary facial expression was normal and
      the corneal, cough and gag reflexes were preserved. The first three come to an
      end spontaneously at 2, 4 and 20 hours, respectively; the fourth episode
      concluded an hour and a half after onset, following administration of intravenous
      phenytoin for 5 minutes. Computerised axial tomography and magnetic resonance
      images of the brain, as well as the interictal electroencephalograms (EEG), were
      normal. Administration of oxcarbazepine was started but at 8 months was stopped
      after a normal EEG during nocturnal sleep was obtained. After 15 months, the
      patient has not presented any more episodes. CONCLUSIONS: The paroxysmal
      character of the disorder together with normal interictal periods, the normality
      of the neuroimages, and the speedy recovery achieved after the administration of
      phenytoin support the notion of an epileptic origin. We believe that we are
      dealing with a bilateral anterior opercular syndrome due to a non-convulsive
      epileptic state, compatible with the presentation of benign rolandic epilepsy.

PMID- 15175978
TI  - [Memory-linked morphological changes].
AB  - INTRODUCTION: It has been suggested that storing information in the brain takes
      place by means of changes in synaptic communication efficiency, which is known as
      neuronal plasticity. Plastic events include changes in the function, structure,
      distribution and number of synapses, and it has been suggested that these plastic
      events could be related to learning and memory. DEVELOPMENT: In this work we will
      review some studies that report structural changes in which experience and
      learning intervene. In particular, structural changes have been observed in a
      region of the brain called the hippocampus, which plays a crucial role in the
      learning and memory of spatial tasks. It has been claimed that the appearance of
      new synapses after learning a spatial task is linked to the formation of long
      term memory and that the functioning of NMDA-type glutamate receptors is needed
      for both learning and the formation of new synapses to take place. CONCLUSIONS:
      Understanding the cellular mechanisms involved in the formation of memory is of
      utmost importance to be able to check the memory deficiencies that arise from
      injuries or as a consequence of old age and neurodegenerative diseases.

PMID- 15175977
TI  - [Donepezil therapy in patients with vascular and post-traumatic cognitive
      impairment: some clinical observations].
AB  - INTRODUCTION: Donepezil is a procholinergic drug that slows down cognitive and
      functional impairment in patients with Alzheimer's disease. Little research has
      been carried out to study its effect in other types of neurobehavioural
      disorders. AIMS: The purpose of this study was to describe the response to
      donepezil therapy in patients with neurobehavioural disorders due to vascular and
      post-traumatic causes. CASE REPORTS: Donepezil was administered to four patients
      with mild cognitive impairment due to vascular causes, to two patients with
      vascular dementia and to two patients with post-traumatic dementia. Following an
      average time of four months, the effects exerted on the cognitive, functional and
      behavioural areas were evaluated. One patient did not tolerate the drug and
      another suffered an episode of congestive heart failure that gave rise to a
      moderate neurobehavioural exacerbation. Two patients underwent a moderate
      improvement, three patients showed a slight improvement and no changes were
      observed in one patient. In general, memory, attention, depression, apathy and
      psychotic traits tended to improve. Aggressiveness/irritability tended to get
      worse. The functional repercussions of these changes were negligible or
      inexistent. CONCLUSIONS: Treatment with donepezil improved cognition and conduct
      in patients with neurobehavioural disorders due to vascular or post-traumatic
      causes. These results will have to be confirmed and expanded by means of
      controlled studies, and research must continue into the characteristics of
      responding patients and the relevance of their responses.

PMID- 15175980
TI  - [Nerve growth factor in neurodegeneration and neurorestorative therapy].
AB  - AIMS: The purpose of this work was to gather the information currently available
      about the content of nerve growth factor (NGF) in experimental models of
      neurodegeneration and in neurodegenerative diseases, including Alzheimer's,
      Parkinson's and Huntington's diseases, as well as to analyse how NGF content is
      affected by the application of different neurorestorative therapies (transplant
      and trophic therapy) in these neurological entities. DEVELOPMENT: Neurotrophins
      are proteins that promote the differentiation, growth and survival of many
      populations of peripheral neurons and the central nervous system during
      development and adulthood. NGF is the best known and most widely researched
      member of this family, which is also made up of the growth factor derived from
      the brain and neurotrophins 3, 4/5, 6 and 7. In the last few decades, significant
      progress has been made in the knowledge available about the biological role
      played by these factors, their molecular characterisation and regulation, as well
      as their signalling mechanisms. Yet, little is known about the role played by the
      neurotrophic factors in neurodegenerative diseases or whether the levels of these
      factors are modified following the use of neurorestorative treatment.
      CONCLUSIONS: Neurodegenerative disorders, especially Parkinson and Alzheimer, are
      accompanied by modifications in the levels of NGF that depend on the extent to
      which the disease has progressed. A model of the changes in NGF content during
      neurodegenerative processes is also proposed.

PMID- 15175979
TI  - [Psychosurgery and the neurosurgical treatment of pain: a systematic review of
      the experience gained in these kinds of treatment].
AB  - INTRODUCTION: Psychosurgery and the neurochemical treatment of pain (NTP) are
      therapeutic options restricted to patients who show resistance to medical
      treatments. Surgical techniques have been perfected over the last few decades.
      AIMS: Our aim was to conduct a systematic review of the studies dealing with
      psychosurgery and NTP reported in the literature, based on the standards of
      quality used in evidence-based medicine. DEVELOPMENT: Following screening and
      selection, nine of the 178 papers found (MEDLINE, 1990-2002) were selected for
      the study: three referring to the treatment of neuropathic pain and six about the
      treatment of obsessive-compulsive disorder (OCD). The objectives were the
      therapeutic results in all cases, the study of the anatomical-functional bases in
      three of them and the description of side effects in five. After adapting the
      standards of quality used in evidence-based medicine (there are no standards for
      papers about surgery), one was classified in group B, six in group C and two as C
      D. The three papers about the treatment of pain reported a significant
      improvement in the pain scales in 40-77% of patients. As regards the treatment of
      OCD, results showed an overall improvement of the scales in 20.4-70% of the
      patients with an improvement above 50%. The side effects are also described.
      CONCLUSIONS: Data published support the indication of psychosurgery and NTP for
      selected patients with neuropathic pain and OCD. The methodological limitations
      of the papers prevent us from drawing conclusions about the other diseases for
      which these techniques have been indicated.

PMID- 15175981
TI  - [Guidelines for the treatment of spasticity in adults using Botulinum toxin].
AB  - AIMS: The introduction of Botulinum toxin type A (BTA) in the treatment of
      spasticity in adults was a large step forward in neurology and it is currently
      seen as the first choice treatment in focal spasticity. In an attempt to achieve
      the optimisation of this therapeutic resource, different clinical guidelines have
      been drawn up which include reviews of the evidence available about the
      indications and use of BTA. Spasticity is characterised by the presence of
      involuntary muscular hyperactivity that is often associated to pain, deformity
      and functional disability. From the clinical point of view, the advantages of BTA
      are obvious (ease of use and dosage determination, long lasting effects,
      reversibility should the response be inappropriate, etc.) and far outweigh its
      drawbacks. It can only be used after a proper selection of patients, of the
      therapeutic aims and of the muscular areas to be treated, and a tailor-made
      programme of rehabilitation must also be drawn up. Increasing experience in its
      use suggests that its early administration is effective in preventing or reducing
      the complications arising from spasticity. CONCLUSIONS: BTA is effective in the
      treatment of spasticity and plays a significant role if the clinical objectives
      involve functional aspects. At present a large amount of well-documented
      experience concerning its indications, effects and safety in clinical practice is
      already available.

PMID- 15175982
TI  - [Peripheral neuropathy in Anderson-Fabry disease: its physiology, evaluation and
      treatment].
AB  - AIMS: The purpose of this study was to review the peripheral neurological aspects
      of Anderson-Fabry disease (AFD). DEVELOPMENT: AFD is a disease caused by
      lysosomal deposits that was first reported in 1898. This entity has begun to
      attract renewed interest in recent years because of the progress made in
      diagnostic techniques and the appearance of enzyme replacement therapy. This
      pathological condition is transmitted by recessive inheritance linked to the X
      chromosome and results from a deficiency of the enzyme alpha-galactosidase A,
      which leads to the accumulation of glycosphingolipids in endothelial and
      perithelial cells, as well as those of the smooth muscles in blood vessels, the
      dorsal root ganglia and other structures in the central and peripheral nervous
      systems. Symptoms during childhood include: neuropathic pain that is
      predominantly distal in the four limbs (and expresses itself as severe attacks
      that are often linked to changes in temperature and exercise that interfere with
      daily activities), hypohidrosis and angiokeratomas. The most serious
      complications appear during adulthood and include: kidney failure, heart failure
      and strokes. CONCLUSION: The arrival of enzyme replacement therapy is the first
      part of a chain in the treatment of AFD, where gene therapy and substrate
      inhibition therapy are beginning to emerge as real therapeutic alternatives. In
      spite of all this, at present, the management of painful symptoms is not at all
      satisfactory for patients and therefore further study and a deeper understanding
      of the mechanisms involved will allow more specific and effective therapeutic
      measures to be developed with which to provide patients with greater relief.

PMID- 15175983
TI  - [Vestibular nerves and nuclei throughout history].
AB  - Throughout the evolution of the concepts concerning the peripheral nerves,
      different ideas have dominated at different moments in history. The studies and
      demonstrations conducted in an attempt to further our knowledge of our own
      constitution and working at the same time enabled us to gain a better
      understanding of the make-up and specific functioning of the vestibular nerves,
      together with their central connecting elements in the brainstem: the vestibular
      nuclei. It may be that the first references to vestibular nerves are now lost in
      time, yet the Ancient Greeks already attempted to understand their functional
      nature by carrying out studies essentially focused on neuroanatomical aspects,
      but heavily influenced by philosophical concepts. It was not until the 18th
      century that researchers came to understand that there were differences between
      the vestibular nerve and the cochlear nerve --until then they were believed to be
      one single nerve. Another century went by before attempts were made to clarify
      the role it plays in balance and not in hearing. The differences between the
      distinct vestibular nuclei situated between the medulla oblongata and the pons
      were established in the 19th and 20th centuries when a number of authors, backed
      by previous microscopic studies, contributed to clarifying the fuzzy limits of
      cells separating the four classic nuclear groups and four others taken as being
      accessory.

PMID- 15175985
TI  - [Brain metastases as the first manifestation of an ovarian adenocarcinoma].

PMID- 15175986
TI  - [Treating patients with acute stroke in a rural area. The role played by primary
      health care].

PMID- 15175987
TI  - [Syphilitic meningomyelitis in a patient with AIDS].

PMID- 15175988
TI  - [Basilar stenosis with repeated transient ischemic attacks: a case that responded
      well to anticoagulation therapy].

PMID- 15175989
TI  - Antibiotics.

PMID- 15175990
TI  - Introduction: antimicrobial resistance among pediatric respiratory tract and
      nosocomial pathogens.

PMID- 15175991
TI  - Antimicrobial resistance among pediatric respiratory tract infections: clinical
      challenges.
AB  - Considerable development of antimicrobial resistance has occurred in the major
      pediatric bacterial pathogens, Streptococcus pneumoniae, Haemophilus influenzae,
      and Moraxella catarrhalis. However, most of the respiratory infections that
      children suffer are viral and self-limiting, and only a small percentage of them
      will develop secondary bacterial infections with the pathogens listed. The
      challenge for rational antibiotic use is to determine which patients can be
      treated conservatively and which require antimicrobial intervention to avoid
      prolonged discomfort or development of permanent sequelae. The basis for rational
      use of antibiotic in the era of resistance in these major pathogens is to avoid
      overuse of antimicrobial agents, tailor treatment to identified pathogens as much
      as possible, and base empiric treatment on the disease being treated and the
      susceptibility of the probable pathogens at breakpoints based on pharmacokinetic
      and pharmacodynamic parameters. With appropriate dosing regimens based on these
      parameters and despite development of resistance, amoxicillin is still one of the
      most active oral agents against S. pneumoniae and non-beta-lactamase producing
      strains of H. influenzae, whereas amoxicillin-clavulanate is active against beta
      lactamase-producing strains of H. influenzae and M. catarrhalis. Parenteral
      ceftriaxone and oral and parenteral fluoroquinolones are active against all 3
      species, but fluoroquinolones should be used with utmost caution when all other
      options have been considered because of concerns about toxicity and development
      of resistance. Introduction of a 7-valent conjugate pneumococcal vaccine in the
      United States in 2000 reduced the prevalence of invasive pneumococcal disease in
      children younger than 2 years old, but, as of 2001, had not had a major impact on
      decreasing antimicrobial resistance.

PMID- 15175992
TI  - Clinical challenges of nosocomial infections caused by antibiotic-resistant
      pathogens in pediatrics.
AB  - Antibiotic resistance in nosocomial infections is an ever-increasing problem as
      health care institutions provide care for children with more complicated medical
      and surgical problems. Several mechanisms of antibiotic resistance are reviewed
      for both gram-negative and gram-positive nosocomial pathogens. These adaptive
      resistance mechanisms allow organisms to survive in an environment of extensive
      antibiotic use and result in clinically significant infections. Mobile genetic
      elements have facilitated the rapid spread of antibiotic resistance within and
      among species. The clinical challenge faced by many practitioners is to
      understand these mechanisms of antibiotic resistance and to develop strategies
      for successfully treating infection caused by resistant pathogens. Nosocomial
      outbreaks caused by resistant organisms are described, and an approach to empiric
      therapy based on presumed pathogens, site of infection, and local resistance
      patterns is discussed.

PMID- 15175993
TI  - Controlling healthcare-associated infections: the role of infection control and
      antimicrobial use practices.
AB  - Healthcare-associated infections are a major cause of morbidity and mortality in
      pediatric patients in the United States and throughout the world. Overall rates
      of infection range widely depending on the pediatric population, with the highest
      rates being in patients in neonatal intensive care units, followed by those in
      pediatric intensive care units, immunocompromised patients, and those undergoing
      surgical procedures. Risk factors for healthcare-associated infection include
      intrinsic and extrinsic factors. The major intrinsic factors are age, birth
      weight, underlying diseases, and immune status. The major extrinsic factors are
      presence of invasive devices and procedures. The major risk factors for
      healthcare-associated infection caused by antimicrobial-resistant pathogens are
      either the transmission of pathogens from person to person (directly or
      indirectly, usually via the hands of healthcare workers) or the emergence of
      resistance after exposure to antimicrobials. Preventing healthcare-associated
      infections caused by antimicrobial-resistant pathogens requires a comprehensive
      approach that includes: 1) preventing infections through the use of vaccines and
      prophylaxis; 2) minimizing the use of invasive devices; 3) understanding and
      fully implementing (and complying with) current guideline recommendations for the
      prevention of infections; and 4) using antimicrobials judiciously. Implementing
      such a comprehensive program will reduce healthcare-associated infections, reduce
      the prevalence of antimicrobial-resistant pathogens, improve patient outcomes,
      and reduce health care costs.

PMID- 15175994
TI  - Promoting appropriate antibiotic use for pediatric patients: a social ecological
      framework.
AB  - During the 1990s, the number of prescriptions for antibiotics for children and
      adolescents finally decreased after more than a decade of alarming increases. The
      Centers for Disease Control and Prevention (CDC) and many other groups have
      designed and implemented interventions to promote appropriate prescribing of
      antibiotics, and these efforts appear to have contributed to recent decreases in
      rates of such prescribing. In this article, we describe the various types of
      interventions that the CDC and others are using to encourage appropriate use of
      antibiotics. A social ecological framework is used to describe the various
      factors contributing to prescribing and using antibiotics, as well as the
      interventions used for targeting these factors. Although most efforts promoting
      appropriate use of antibiotics have focused on reducing such use for viral
      infections, future efforts also should include a focus on ensuring the use of
      targeted agents when antibiotics are indicated.

PMID- 15175995
TI  - Penicillin: its discovery and early development.
AB  - In August 1928, Alexander Fleming returned from a vacation to his usually messy,
      disordered laboratory. In one of the Petri dishes that had not been touched by
      the Lysol, he noticed an unusual phenomenon: separate colonies of staphylococci
      and, near the dish's edge, a colony of mold approximately 20 mm in diameter. The
      finding proved to be a watershed in the history of medicine. This discovery lay
      dormant for some time before other researchers took up the challenge to
      investigate its clinical possibilities. Two investigators at Oxford, Sir Howard
      Walter Florey and Ernst Boris Chain, brought penicillin's potential for medical
      use to fruition and, along with Fleming, shared the 1945 Nobel Prize for
      Medicine. The discovery and development of penicillin represent one of the most
      important developments in the annals of medical history. This article presents a
      brief overview of the events that occurred in the progress from discovery to
      implementation as a therapeutic agent.

PMID- 15175996
TI  - Sir Alexander Fleming: Scottish researcher who discovered penicillin.
AB  - The discovery and development of penicillin changed the entire direction of
      approaches to treating infectious diseases and saved the lives of millions of
      people. Indeed, the development of penicillin was a watershed event in the battle
      against infectious diseases, and the individual who discovered it, Sir Alexander
      Fleming, remains a prominent individual in the annals of medical history. This
      article focuses primarily on the personal life of Alexander Fleming, an
      individual who had a remarkable diversity of interests and who made many
      contributions to science and medicine.

PMID- 15175997
TI  - A widening prospect: Imatinib and novel applications of targeted therapy.

PMID- 15175998
TI  - Role of KIT and platelet-derived growth factor receptors as oncoproteins.
AB  - KIT and platelet-derived growth factor receptors (PDGFRs) play critical oncogenic
      roles in a broad spectrum of hematologic and solid tumors. These receptor
      tyrosine kinases, as well as ABL and BCR-ABL, are inhibited by imatinib. Tumors
      caused by chromosomal translocations that lead to overexpression of PDGFR ligand,
      resulting in continuous activation of wild-type PDGFRs, are likely to respond to
      imatinib, as are malignancies caused by gene amplification and overexpression of
      wild-type PDGFR or KIT receptors. Malignancies linked to chromosomal
      translocations that express PDGFR or KIT fusion protein-tyrosine kinases are also
      likely to respond to imatinib. Malignant cell responses to imatinib depend on
      whether any of these tyrosine kinase activities play essential roles in the
      oncogenesis of a given tumor, as well as the precise molecular mechanism
      underlying oncogenesis. For example, imatinib efficacy for malignancies arising
      from constitutively activating point mutations in tyrosine kinases depends on the
      exact location of the mutation in the kinase molecule.

PMID- 15175999
TI  - Platelet-derived growth factor receptor inhibition to treat idiopathic
      hypereosinophilic syndrome.
AB  - Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders
      characterized by peripheral blood and tissue eosinophilia leading to end-organ
      damage. Hypereosinophilic syndrome can be fatal, particularly in patients with
      endomyocardial fibrosis, and treatment has traditionally been palliative or
      preventive. The disease shares features with myeloproliferative disorders, such
      as chronic myeloid leukemia, including responsiveness to hydroxyurea and
      interferon. The tyrosine kinase inhibitor imatinib, a highly effective treatment
      for chronic myeloid leukemia, has shown efficacy in normalizing eosinophil counts
      and resolving signs and symptoms in some HES patients. Fusion of the Fip1-like 1
      gene (FIP1L1) and the platelet-derived growth factor receptor alpha gene (PDGFRA)
      was discovered in the majority of patients with imatinib-sensitive HES, and all
      patients with the fusion responded to imatinib. The product of this fusion gene,
      FIP1L1-PDGFRalpha, is a constitutively active protein-tyrosine kinase capable of
      transforming hematopoietic cells. The efficacy of relatively low imatinib
      concentrations in HES, mediated by inhibition of FIP1L1-PDGFRalpha kinase
      activity, causally implicates FIP1L1-PDGFRA in the pathogenesis in certain HES
      patients.

PMID- 15176000
TI  - Increasing tumor uptake of anticancer drugs with imatinib.
AB  - Solid malignancies often exhibit high interstitial fluid pressure (IFP), which
      causes poor uptake of anticancer drugs. While there are several mechanisms that
      regulate IFP in tumors, activation of platelet-derived growth factor receptor,
      which is expressed in various cell types within the tumor microenvironment, has
      been observed to play an important role in elevating IFP. In preclinical studies,
      treatment with imatinib, which inhibits both alpha- and beta-platelet-derived
      growth factor receptors, as well as KIT, ABL, ARG, and BCR-ABL tyrosine kinases,
      has been shown to decrease tumor IFP and concomitantly augment uptake of
      chemotherapeutic drugs, thereby enhancing the efficacy of chemotherapy. This
      review discusses preclinical studies showing the ability of imatinib to lower IFP
      and increase drug uptake within solid tumors, as well as the scientific rationale
      for clinical use of imatinib as combination therapy for chemotherapy.

PMID- 15176001
TI  - Combination docetaxel and platelet-derived growth factor receptor inhibition with
      imatinib mesylate in prostate cancer.
AB  - The burden of metastatic disease in prostate cancer is largely distributed to
      bone in the form of osteoblastic metastases. Interactions between malignant
      epithelial cells of prostate cancer and the bone microenvironment are implicated
      in the progression of prostate cancer. Because prostate cancer cells in bone
      metastases express the platelet-derived growth factor receptor (PDGFR), it is
      possible that inhibition of PDGFR can be an effective means of altering the
      clinical course of prostate cancer. Preclinical data suggest that preferential
      expression of PDGFRs in endothelial cells of tumor vasculature in experimental
      prostate cancer bone metastases is an important target for combination therapy
      incorporating the PDGFR inhibitor imatinib mesylate. Clinical trials combining
      imatinib and docetaxel are under way in the metastatic and neoadjuvant settings.
      Clinical and translational data from these studies are likely to provide
      additional insights into the role of imatinib in combination therapy for prostate
      cancer.

PMID- 15176002
TI  - Molecularly targeted treatment for dermatofibrosarcoma protuberans.
AB  - Traditionally, treatment for dermatofibrosarcoma protuberans (DFSP), a rare
      cutaneous tumor that is locally aggressive, has been limited to wide surgical
      excision with negative margins. Although not usually metastatic, DFSP has
      significant potential for recurrence and interference in local structures. The
      pathogenesis of DFSP stems from a chromosomal rearrangement involving chromosomes
      17 and 22, in which the collagen 1alpha1 gene is fused to the gene for platelet
      derived growth factor (PDGF) B-chain. The resultant deregulated expression of
      PDGFB leads to continuous activation of the PDGF receptor beta (PDGFRbeta)
      protein-tyrosine kinase that promotes DFSP tumor cell growth. Imatinib is a
      potent and specific inhibitor of several protein-tyrosine kinases, including the
      PDGFRs. Preclinical investigations and clinical reports have shown the efficacy
      of imatinib in DFSP. Imatinib may provide an alternative for the treatment of
      unresectable or partially resectable tumors, thereby possibly improving the
      effectiveness of surgery.

PMID- 15176005
TI  - A new nursing role: what do you think?

PMID- 15176006
TI  - Why did AARP back the medicare drug plan?

PMID- 15176007
TI  - May you live in interesting times.

PMID- 15176008
TI  - Hate mail and cultural diversity.

PMID- 15176009
TI  - Preparing nurses for the 21st century: reenvisioning nursing education and
      practice.
AB  - Significant advances in biomedical science and in the complexity of health care,
      coupled with a worsening nursing shortage and numerous reports of unsafe and
      inadequate patient care, have prompted concerns about both nursing education and
      nursing practice. Beginning in 2000, the American Association of Colleges of
      Nursing (AACN) made a thorough study of nursing education, regulation, and
      practice issues. Input and consultation were sought from AACN members, nursing
      practice leaders, regulators, and other health professionals. Results of this
      work indicated the need for a new nursing professional, the clinical nurse
      leader, who could effectively coordinate, manage and evaluate care for groups of
      patients in complex health systems. Master's-degree education is proposed for
      piloting the preparation of clinical nurse leaders. Close coordination with nurse
      executives and administrators to develop the new education program and new models
      for care delivery is planned. Critical components of the pilot testing will be
      evaluation of the patient and nurse outcomes associated with the use of clinical
      nurse leaders and focused work to develop a new legal scope and credentials for
      them.

PMID- 15176010
TI  - The clinical nurse leader: a response from practice.
AB  - In October 2003, over 200 nurse leaders from education and practice met at the
      invitation of the American Association of Colleges of Nursing. A newly released
      white paper, describing the role of the clinical nurse leader, was discussed at
      the conference. This article outlines a response to that white paper from one
      practice setting. The article shares information about another role, that of team
      coordinator, that is similar to clinical nurse leader and has been implemented at
      an integrated not-for-profit health care system in 5 hospitals. The comparison of
      the team coordinator role to the clinical nurse leader role might assist in
      visualizing such a role in practice. Although the roles are not identical, many
      of the driving forces for change were similar; these included the need to meet
      the changing demands for improved patient outcomes and nurse retention. The team
      coordinator role has 4 domains of practice that are crosswalked against the
      clinical nurse leader 15 core competencies. An evaluation of the team coordinator
      role showed changes that need to be made, such as placing more emphasis on
      clinical progression of patients. Lessons learned are shared, including keeping
      the scope of the role manageable, providing documentation standards for new
      roles, and the leadership required of the nursing executive to implement change.

PMID- 15176011
TI  - An academic-service partnership: ideas that work.
AB  - The current environment of a growing shortage of nurses, larger baccalaureate
      nursing student enrollments, and resource scarcity requires creative solutions if
      we are to meet the current and future needs for nurses. When a regional medical
      center and a state university college of nursing pool their creativity, talent,
      and resources, everyone wins. The partnership created by the two organizations
      has resulted in nine shared initiatives: (1) feedback through the performance
      based development system, (2) a computerized medical record system, (3) summer
      internships; (4) the Leadership Initiative for Nursing Education (LINE)
      Institute, (5) the Helene Fuld Leadership grant, (6) the registered nurse
      refresher course, (7) the cooperative education program, (8) supplying clinical
      faculty, and (9) the nursing summer academy. Lessons learned by those in both
      organizations point to the importance of trust, risk-taking, and the joint
      responsibility of education and service for preparing the next generation of
      nurses for clinical practice.

PMID- 15176012
TI  - Appreciative inquiry and leadership transitions.
AB  - In times of accelerated change accompanied by leadership transitions,
      appreciative inquiry (AI) and sensemaking skills are necessary. AI is a
      philosophy, a model of change, and a set of tools and techniques that support
      discovery, dreaming, design, and creation of a vision that inspires people in an
      organization to move toward a collective destiny. Sensemaking involves sizing up
      a situation to create a framework for decision-making, creating a context for
      communication, linking with others, and focusing on what is and what could be.
      Sensemaking can be facilitated by applying appreciative leadership techniques. In
      this article, the story of the University of Utah College of Nursing's and the
      faculty's experience with an AI process illustrates the application of the AI
      leadership strategy to navigating organizational change and a leadership
      transition.

PMID- 15176013
TI  - Value and vulnerability: reflections on joint appointments.
AB  - For more than 20 years, joint appointments between nursing education and nursing
      service have been recommended as a strategy to foster excellence in nursing
      education and nursing practice, bridge the theory-practice gap, and promote
      clinically relevant research. This article discusses the termination of a joint
      appointment initiative after research that had demonstrated its success in terms
      of benefits to both agencies and satisfaction for the incumbents in the
      positions. It presents the value and vulnerability of joint academic-clinical
      agency joint appointments based on critical analysis of the academic literature
      juxtaposed with our research and subsequent experience with four joint
      appointments between a faculty of nursing and a home-care agency. Top-level
      administrative support and understanding of the potential of such positions are
      crucial for the nurses involved, and the positions themselves become vulnerable
      in times of change and fiscal restraint.

PMID- 15176014
TI  - Strengths and weaknesses of faculty teaching performance reported by
      undergraduate and graduate nursing students: a descriptive study.
AB  - The purpose of this study was to describe the patterns of strengths and
      weaknesses of faculty teaching performance as reported by undergraduate and
      graduate nursing students on a narrative section of a university faculty
      evaluation form. The study used a descriptive, retrospective, qualitative design.
      The summary forms represented a convenience sample of undergraduate and graduate
      nursing course sections (N = 317) taught by full-time and part-time nursing
      faculty from spring 1998 through fall 2002, including summer sessions. Course
      sections represented didactic and clinical education experiences. Content
      analysis was used to interpret the recorded comments representing strengths and
      weaknesses in faculty performance from students' perspectives. Patterns and
      associated themes were derived. Faculty performance strengths included patterns
      such as being a knowledgeable and strategic teacher, creating a positive learning
      environment, demonstrating professionalism, displaying scholarly traits, and
      being supportive. Weaknesses included patterns such as poor delivery of content,
      acting disorganized, being inaccessible, displaying weak teaching skills, being
      dishonorable, being unprofessional, and displaying negative traits. Implications
      for continuous quality improvement in teaching/learning processes are presented.

PMID- 15176015
TI  - Retention of African-American students in baccalaureate nursing programs: are we
      doing enough?
AB  - With the increasing minority population in the United States, much attention has
      been given to the lack of diversity among health care professionals, specifically
      nursing. Since the 1960s, the federal government has provided financial resources
      to institutions of higher education whose purpose was to diversify the health
      care profession. Historically, these resources have supported initiatives that
      primarily focused on the recruitment of minority students into higher education.
      These efforts temporarily increased the enrollment of students from varying
      racial and ethnic backgrounds. However, without established retention initiatives
      in place, the attrition rates for students from diverse backgrounds far exceeded
      the enrollment rates. Consequently, the nursing workforce continues to be a
      predominantly White female profession. In order for schools of nursing to create
      a workforce reflective of its patient population, both nursing education and
      institutions of higher education must be committed to implementing initiatives to
      increase the retention and graduation rates of minority students.

PMID- 15176016
TI  - Nurses' use of the media to provide public health information during a hepatitis
      A outbreak.

PMID- 15176017
TI  - Recruiting knowledge, not just nurses.
AB  - The importance of the definition of nurse as a "knowledge worker" and the utility
      of knowledge as a recruitment policy for building a strong nursing workforce are
      discussed. The method used is the implementation of a statewide merit-based
      scholarship program targeting academically excellent students. At the University
      of Vermont, which educates roughly half of the state's nursing students,
      applications to the College of Nursing are up 83 percent, and entering class size
      is up 92 percent. Most significantly, Scholastic Assessment Test (SAT) scores
      have improved 4 percent, reversing an 8-year trend. In conclusion, merit
      scholarships are an effective means of building intellectual capacity and
      attracting academically stronger candidates to the nursing profession.

PMID- 15176021
TI  - Anal cytology for anal cancer screening: is it time yet?

PMID- 15176022
TI  - p27(Kip1) expression and grading of breast cancer diagnosed on cytological
      samples.
AB  - The progressive reduction in p27(Kip1) (p27) protein immunohistochemical staining
      with increasing histological grading is a well-established finding occurring in
      breast cancer, and its role as diagnostic complement and prognostic marker has
      been thoroughly evaluated. To clarify whether this test may be applied to breast
      cytopathology, we performed p27 immunostaining on fresh fine-needle cytology
      (FNC) samples from 10 benign and 40 malignant breast lesions. On average, p27
      immunostaining was significantly lower in carcinomas than in benign lesions (P <
      0.005). In particular, among carcinomas, p27 immunostaining progressively reduced
      from well-to poorly differentiated lesions (G1 vs. G2, P < 0.05; G1 vs. G3, P <
      0.001; G2 vs. G3; P < 0.001). A similar trend was noted in a subgroup of 20
      matched FNCs and histological samples of breast carcinomas, when p27
      immunostaining on FNCs was stratified according to the histological grading (G1
      vs. G2, P = 0.18; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05). In addition, p27
      immunostaining on FNCs showed a good positive correlation with that on histology
      (Spearman R = 0.58; P < 0.01), with a diagnostic concordance between samples of
      85%, by using the standard 50% positive cell cutoff. Taken in concert, our data
      suggest that p27 immunostaining is a reliable marker of tumor cell
      differentiation in breast cytopathology as well as in histopathology.
      Accordingly, staining FNCs for p27 may be an useful complement in addition to
      cytological grading in the preoperative assessment of breast cancer.

PMID- 15176023
TI  - Airborne fungal spores, pollen grains, and vegetable cells in routine
      Papanicolaou smears.
AB  - The objective was to demonstrate the presence of airborne fungal spores, pollen
      grains, and vegetable cells in smears and establish their significance.
      Microscopic examination was of smears stained by the Papanicolaou technique. We
      found several types of airborne spores (Alternaria, Exserohilum, Aspergillus,
      Cladosporium, Epicoccum, Curvularia, and Ascosmycete), pollen grains (Lilium,
      bullrush, Pinus, Acacia, hazelnut, and oak), and several types of vegetable
      cells. The existence of these structures may be due to intrinsic or to extrinsic
      contamination of the sample. Anemophilous fungi spores and pollen grains have
      been shown to possess great allergenic capacity. Pollen grains and vegetable
      cells may be mistaken for certain microorganisms or malignant cells.

PMID- 15176024
TI  - Pitfalls in the cytological classification of borderline leprosy in the Ridley
      Jopling scale.
AB  - This is a blinded, retrospective, correlative study of classification of leprosy
      by cytomorphology, clinical examination, and bacterial density. One hundred
      consecutive adequate aspirates from skin lesions of leprosy were studied. The
      Ridley-Jopling (R-J) five-group classification system was used. May-Gruenwald
      Giemsa (MGG) and Ziehl-Neelsen (Z-N) stains were employed. Complete clinical,
      cytological, and bacteriological concordance was found in 88 patients. One-step
      mismatch in classification was seen in 12 patients with cytomorphological
      features of borderline-borderline (BB/mid-borderline) leprosy. Cytomorphological
      features of BB leprosy in aspirates from skin lesions should alert the
      cytopathologist to the possibility that the bacteriological index (BI) may vary
      widely. Appropriate steps must be taken to ensure accurate reporting of BI.

PMID- 15176025
TI  - Interobserver agreement of a probabilistic approach to reporting breast fine
      needle aspirations on ThinPrep.
AB  - We have previously demonstrated the accuracy and reproducibility of a
      probabilistic/categorical approach for reporting breast fine-needle aspiration
      (FNA). However, the interobserver agreement in the application of this approach
      has not been assessed. Twenty breast FNA cases (each on one ThinPrep slide) were
      pulled from the cytology files of Beth Israel Deaconess Medical Center. The cases
      included benign epithelial proliferative lesions (6), DCIS (4), and infiltrating
      carcinoma (10), as shown by subsequent histology. Six pathologists with 14-25 yr
      of experience in interpreting breast FNA and 0-8 yr of experience with ThinPrep
      preparations rendered diagnoses according to the probabilistic approach. The
      kappa statistic for the unremarkable/proliferative, atypical, suspicious, and
      positive categories were 0.64, 0.08, 0.43, and 0.75, respectively (P < 0.001 for
      all except for the atypical category [P = 0.09]). Spearman's rho correlating the
      individual pathologist's diagnosis and the histologic diagnosis ranged from 0.51
      (P = 0.02) to 0.78 (P < 0.0001). This was not correlated with the pathologists'
      years of experience interpreting breast FNA (P = 1.0) or with their years using
      ThinPrep preparations for breast FNA (P = 0.96). In conclusion, the interobserver
      agreement was excellent for the positive category in the probabilistic approach,
      poor for the atypical category, and fair to good for the other categories. The
      specific level of experience interpreting breast FNA or using ThinPrep among
      experienced pathologists did not seem to influence their accuracy in reporting
      the cases in our study.

PMID- 15176026
TI  - Invasive mammary carcinoma with osteoclast-like giant cells diagnosed by fine
      needle aspiration biopsy: review of the cytologic literature and distinction from
      other mammary lesions containing giant cells.
AB  - Invasive carcinoma with osteoclast-like giant cells is an unusual type of mammary
      adenocarcinoma with few cases reported in the cytology literature. We present the
      cytologic findings in a case of invasive cribriform carcinoma of the breast
      containing osteoclast-like giant cells diagnosed by fine-needle aspiration
      biopsy. The smears displayed three-dimensional cohesive cluster cells of uniform
      epithelial cells admixed with numerous multinucleated giant cells that
      morphologically resembled osteoclasts. Core biopsy confirmed the cytologic
      diagnosis. Immunohistochemical studies indicated that the multinucleated giant
      cells were of histocytic origin. Knowledge of the bland cytologic pattern and the
      admixture of giant cells seen in invasive cribriform carcinoma with osteoclast
      like giant cells should avoid making a false negative diagnosis on aspiration
      biopsy.

PMID- 15176027
TI  - Hepatocellular carcinoma diagnosed by fine-needle aspiration of the parotid
      gland.
AB  - Hepatocellular carcinoma rarely metastasizes to the salivary glands. We report a
      case of a 47-yr-old man who presented with a right parotid lesion that was
      diagnosed by fine-needle aspiration (FNA) biopsy as a metastatic lesion
      suggestive of hepatocellular carcinoma with similar findings in a subsequent
      intraoral incisional biopsy. The patient's serum alpha-fetoprotein level was
      within normal limits at the time of diagnosis. CT scan revealed a mass in the
      liver, but a liver biopsy was not performed. The patient deteriorated rapidly and
      died about 4 mo later. An autopsy confirmed the presence of hepatocellular
      carcinoma with distant metastases to unusual sites, including the parotid gland,
      orbit, and calvarium, bypassing more common sites such as the lungs. This is the
      second known reported case in which hepatocellular carcinoma presented as a
      salivary gland metastasis. In both cases the diagnosis was made by FNA biopsy,
      illustrating the utility of this method for diagnosing uncommon metastatic
      salivary gland lesions.

PMID- 15176028
TI  - Mammary myofibroblastoma: report of two cases with fine-needle aspiration
      cytology and review of the cytology literature.
AB  - Fine-needle aspirates from two histologically, immunohistochemically, and
      ultrastructurally confirmed mammary myofibroblastomas (MM) of two elderly women
      revealed abundant, randomly arranged single and clustered benign spindle-shaped
      mesenchymal cells with scant cytoplasm and elongated or oval nuclei displaying a
      finely granular chromatin pattern and inconspicuous nucleoli. In one case a few
      cells showed inconspicuous nuclear grooves. The aspirated tumor cells from the
      other case stained positively with desmin and CD34 antibodies and negatively with
      cytokeratin and S-100 protein antibodies, in keeping with an MM. A review of the
      literature was briefly presented.

PMID- 15176029
TI  - Identification of cytomegalovirus in a liquid-based gynecologic sample using
      morphology, immunohistochemistry, and DNA real-time PCR detection.
AB  - The viral cytopathic effects of cytomegalovirus (CMV) are rarely encountered in
      conventional cervical vaginal smears and have never been reported in a liquid
      based gynecologic sample (SurePath). We present results of a liquid-based
      gynecologic sample (SurePath) from an asymptomatic patient with classic CMV
      associated granular or dense cyanophilic intracytoplasmic and intranuclear
      inclusion bodies with a clear surrounding zone. These inclusions were
      immunohistochemically positive for CMV. The patient also had human papilloma
      virus (HPV)-associated koilocytes that showed a unique perinuclear immunostaining
      pattern suggesting coinfection with both CMV and HPV. CMV amplification using
      real-time polymerase chain reaction (PCR) of DNA extracted from the liquid-based
      sample confirmed the morphologic and immunohistochemical findings of CMV
      infection. These observations suggest that a liquid-based preparation can be used
      to assess CMV infection morphologically, immunohistochemically, and by real-time
      PCR.

PMID- 15176030
TI  - Papillary thyroid carcinoma with an adenoid cystic pattern: report of a case with
      fine-needle aspiration cytology and immunocytochemistry.
AB  - Although fine-needle aspiration (FNA) cytologic features of conventional
      papillary thyroid carcinoma (PTC) and some of its variants have been documented
      in the literature, PTC with an adenoid cystic pattern has not so far been
      described. A 35-year-old woman presented with solitary cold nodule in the right
      lobe of thyroid. FNA smears from the nodule showed features of PTC such as
      papilliform clusters, monolayered sheets, psammoma bodies, increased frequency of
      nuclear grooves, and intranuclear cytoplasmic inclusions. In addition, there were
      areas of follicular formation and light-pink to deep-purple hyaline globules with
      a laminated appearance and surrounded by neoplastic cells, reminiscent of adenoid
      cystic carcinoma. These globules were present in 53% of the follicles.
      Immunocytochemical staining for thyroglobulin yielded positive cytoplasmic
      reaction in the neoplastic cells. Histopathology of the thyroidectomy specimen
      confirmed the cytodiagnosis of PTC. The hyaline globules were present focally and
      were light pink to deep purple with a laminated appearance resembling psamomma
      bodies. The colloid and follicular cells were positive for thyroglobulin but the
      hyaline globules were negative. Von Kossa staining for calcium revealed positive
      reaction in the psamomma bodies and some of the hyaline globules, indicating that
      the globules may be the beginning of psammoma bodies. Thus, FNA cytology was
      useful in diagnosing an unusual variant of PTC.

PMID- 15176031
TI  - Cytologic diagnosis of endosalpingiosis with pregnant women presenting in
      peritoneal fluid: a case report.
AB  - The cytologic appearance of endosalpingiosis in peritoneal fluid cytology smears
      has not been extensively described. We report a case of endosalpingiosis in a 29
      year-old pregnant female who presented with peritoneal fluid. Dense papillary
      epithelial clusters with indistinct ciliated cells were found in the Papanicolaou
      stained smears. However, long and delicate cilia were obvious in papillary
      cluster with scanning electron microscopy. Cell nuclei were oval, with finely
      dispersed chromatin and uniform nuclear membrane. Peritoneal fluid cytology with
      these findings may be helpful to suggest the probable preoperative diagnosis of
      endosalpingiosis or benign glandular inclusions involving the pelvic peritoneum.

PMID- 15176032
TI  - Prevalence and typing of HPV DNA by hybrid capture II in women with ASCUS, ASC-H,
      LSIL, and AGC on ThinPrep Pap tests.
AB  - Testing for human papillomavirus (HPV) DNA is now a viable option for the
      management of women with atypical squamous cells of undetermined significance
      (ASCUS). The utility of reflexive HPV DNA testing for women with a cytologic
      diagnosis of atypical glandular cells-not otherwise specified (AGC-NOS), ASCUS
      subtypes, and low-grade squamous intraepithelial lesion (LSIL) has not been well
      established. In the present investigation, reflex Hybrid Capture II HPV DNA
      testing results were evaluated for HPV prevalence and type in 371 women with
      abnormal cytologic diagnoses of ASCUS-not otherwise specified (ASCUS-NOS), ASCUS
      suspicious for low-grade squamous intraepithelial lesion (ASCUS-L), atypical
      squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H),
      AGC-NOS, and LSIL on ThinPrep Pap tests. Positive high-risk HPV DNA was
      identified in 53.6% of the study samples, including ASCUS-NOS 40.2% ASCUS-L
      71.4%, ASC-H 37.5%, LSIL 88.6%, and AGC-NOS 0%. We conclude that reflex HPV DNA
      testing appears to not be useful for colposcopy triage for cytologic diagnoses of
      LSIL or AGC-NOS.

PMID- 15176033
TI  - Nikolay Ivanovich Pirogoff (1810-1881).

PMID- 15176034
TI  - Alternative approaches for regional ulnar nerve blockade: a cadaveric study.
AB  - Wrist blockade is a safe and effective alternative to general anesthesia in
      surgery of hand injuries. With regard to the ulnar nerve, the volar approach is
      used, where the needle passes through or medial to the flexor carpi ulnaris
      tendon; however, the ulnar artery is at risk because the needle may accidentally
      penetrate it, causing profuse bleeding. Alternatively, the wrist may be
      approached medially, the ulnar approach, and the needle tip placed posterior to
      the flexor carpi ulnaris tendon. To determine which of these methods may be
      preferable for avoiding ulnar artery injury, needles were inserted into the wrist
      area of cadaver hands (n = 57) using the volar and ulnar approaches; detailed
      dissection of the region around the inserted needles was subsequently carried
      out. The position of the ulnar nerve relative to the ulnar artery and injury to
      the artery was documented. Damage to the ulnar artery using the volar approach
      was 36.8% (21/57 cases) compared to no (0%) injury observed using the ulnar
      approach. At the level of the wrist crease just proximal to the pisiform bone,
      the ulnar nerve was medial to the artery in 92.9% (53/57) of cases, medial and
      posterior in 5.3% (3/57), and anterior to the artery in 1.8% (1/57) of cases.
      This study suggests that in cases where ulnar artery pulsation is not reliable,
      the ulnar approach may be preferable for ulnar nerve blockade due to an increased
      incidence of ulnar artery penetration with the volar approach.

PMID- 15176035
TI  - Changes in bone architecture in the femoral head and neck in osteoarthritis.
AB  - This study analyses changes in the bony architecture of the femoral head and neck
      in osteoarthritis. Five osteoarthritic hips were obtained from female patients
      undergoing total hip replacement and were compared to non-arthritic control
      specimens from the dissecting room. Analysis was carried out on a coronal bony
      slice of the femoral head and on a transverse section of the upper femoral neck.
      The results indicated that in the region of the compressive trabeculae the
      intertrabecular areas were generally smaller in the osteoarthritic specimens and
      that the inferior part of the cortex of the femoral neck had thickened. Our data
      thus quantified changes consistent with the thickening of compressive trabeculae
      reported by others and with thickening of the region of the femoral neck on which
      they converge. We found less trabecular bone in non-weight-bearing regions of the
      lower femoral head and in the medulla of the upper neck in the osteoarthritic
      specimens consistent with loss of tensile trabeculae. Scanning electron
      microscopy suggested that bone resorption activity was higher in the subchondral
      and non-weight-bearing regions of the osteoarthritic femoral heads than in the
      controls.

PMID- 15176036
TI  - Anatomy and blood supply of the subgaleal fascia flap.
AB  - The subgaleal fascia (SGF) is a distinct layer in the temporal fossa situated
      between the superficial fascia and galea aponeurotica and the temporal fascia
      covering the superficial surface of the temporal muscle. The SGF is used most
      frequently for otologic reconstruction. Reviewing the literature, however, showed
      many contradictory findings about dissection of an independent SGF layer, its
      blood supply, and the possibility of harvesting it as part of a combined flap.
      Our study, carried out on ten fresh cadavers, presents a detailed view of the
      blood supply of the SGF to develop a safe method of harvesting an inferior-based
      SGF. Our systematic plane-by-plane approach, associated with a transparent grid
      applied on each dissection, allowed us to quantify the branches from each plane
      and to localize precisely their entering sites from a reference "zygomatic
      point." The SGF had no ascending axial vascular supply entering from its base;
      according to our results, therefore, the SGF could not be harvested alone as an
      inferior pedicled flap down to the zygomatic arch. It may be feasible, however,
      to harvest a SGF flap when a strip of the superficial fascia is associated with
      its middle third. Therefore, we suggest that an average height of 5.4 cm of
      superficial fascia should be included in an inferior-based pedicle of a SGF.

PMID- 15176037
TI  - Surface anatomy of the inferior epigastric artery in relation to laparoscopic
      injury.
AB  - The inferior epigastric artery (IEA) is at risk of injury in laparoscopic
      surgery. Current descriptions of the course of the IEA do not provide surface
      landmarks useful to the surgeon. This study aimed to define surface relations and
      propose guidelines for safer trocar placement. The posterior surfaces of the
      anterior abdominal walls of 30 preserved cadavers were dissected. The surface
      anatomy of 60 IEAs and their branches were defined. At the level of the anterior
      superior iliac spine (ASIS), the IEA is 38% +/- 18% (95% confidence interval
      [CI]) from the midline to the ASIS. At the mid-inguinal point the relation is 40%
      +/- 17% and at the umbilicus 40% +/- 22%. The pattern of branches is highly
      variable. Although giving guidelines for trocar insertion can be treacherous, we
      found the following to be of value: 1) the midline is avascular; 2) the main stem
      of the IEA will be avoided if trocars are inserted more than two-thirds of the
      distance along a horizontal line between the midline and the ASIS; and 3) IEA
      branches are least frequently found in the lowest part of the abdomen lateral to
      the artery.

PMID- 15176038
TI  - Anomalous branch of the left common carotid artery.
AB  - A previously unreported anomalous branch of the left common carotid artery (LCCA)
      was observed during dissection at the Zagreb Medical School. The anomalous branch
      arose from the anterior surface of the LCCA approximately 2 cm superior to the
      aortic arch, and subsequently bifurcated into a right and left branch. We
      describe its anatomic features. Clinical implications are also discussed.

PMID- 15176039
TI  - Post-mastectomy chylous fistula: anatomical and clinical implications.
AB  - A chylous fistula after a modified radical mastectomy is a rare occurrence;
      however, major anatomical variations in the termination of the thoracic duct may
      occur, rendering it susceptible to injury. High output chylous fistulae are
      difficult to manage and have local, metabolic, and immunologic complications with
      a mortality rate varying from 12.5-50%. Herein such a case of postmastectomy
      chylous fistula and its management are discussed. A 56-year-old postmenopausal
      woman with invasive duct carcinoma of the left breast underwent modified radical
      mastectomy with complete axillary clearance (Level I, II, III nodes). The
      operative procedure was uneventful. On the commencement of a normal diet,
      however, the patient started exuding milky fluid from the axillary drain and
      analysis of the fluid revealed biochemical features compatible with chyle. After
      2 weeks of failed conservative management, the axilla was re-explored. A
      continuous flow of clear fluid was observed originating from a single major
      lymphatic trunk inferior to the axillary vein in the region of the former Level
      II nodes. The leak was controlled by the application of multiple mass ligatures
      using 2-0 silk suture. A part of the pectoralis major muscle was rotated and
      sutured over the area of the leak as additional reinforcement. Suturing a muscle
      flap over the leak has been described previously and functions theoretically by
      causing fibrosis. The chylous fistula in the present case was managed
      successfully with mass ligatures and muscle flap reinforcement.

PMID- 15176040
TI  - Unusual variation of the inferior attachment of the pectoralis minor muscle.
AB  - An unusual inferior attachment of pectoralis minor muscle was found on the right
      side of a male cadaver. The tendinous attachment, originating only from the 5th
      rib, was detected during the routine practical dissections. There were no other
      associated features in the thoracic region of this cadaver. We believe that this
      variation that has not been reported previously in the literature, should be
      taken into consideration by the surgeons.

PMID- 15176041
TI  - Malunion of the ulnar styloid as a cause of ulnar wrist pain.
AB  - We present a case of ulnar wrist pain that had been wrongly attributed to non
      union of the ulnar styloid. Surgical exploration revealed an ulnar styloid
      malunion that had caused pain by impinging on the triquetrum and a triangular
      fibrocartilage complex (TFC) lesion. There was no fracture of the distal radius
      and no associated carpal instability or disruption of the distal radio-ulnar
      joint. Treatment by resection of the ulnar styloid and re-attachment of the TFC
      provided a satisfactory outcome.

PMID- 15176042
TI  - Topographic approach to the study of the human body.
AB  - Recent developments in medical imaging techniques such as ultrasound, computed
      tomography (CT), and magnetic resonance imaging (MRI) have been explosive. These
      modalities provide 3D information about the human body and assess tissue damage
      in various pathological conditions. To complement the diagnostic usefulness of
      these imaging techniques, we have designed a system of topographic coordinates
      based on the principles of global projection cartography in which lines of
      latitude and longitudes are assigned to the surface of the human body. We
      designated the median sagittal plane as corresponding to the Greenwich Meridian
      (zero longitude) in global cartography. From the median sagittal plane (M0),
      vertical lines of longitude or "great circles" divide the body into 12 zones that
      are 30 degrees apart. Parallel lines of latitude are assigned according to
      surface anatomy landmarks. Studying the 3D reconstruction of anatomical
      structures is important for: 1) devising a system of coordinates; 2) allowing
      biomedical measurements to be made; and 3) drawing maps that may be useful in
      some clinical procedures (e.g., biopsies).

PMID- 15176044
TI  - Great cardiac vein variations.
AB  - A novel variation in the relationship of the great cardiac vein to the circumflex
      artery was observed in an otherwise normal cadaver heart. Vessels originated and
      terminated normally, but in their midcourse they were twisted around each other
      such that each made one complete loop around the other. This variation did not
      seem to be involved in any pathologies. Variations in the course of the great
      cardiac vein have been little studied until recently, but their simplicity
      emphasizes the uniqueness of our intertwined case. Commonly, the great cardiac
      vein varies with respect to presence, location, and the superficial or deep
      relationship of single crossings of the anterior interventricular and circumflex
      arteries. Although rare, the intertwined variation described in the present case
      may have important basic science implications for understanding mechanisms of
      vasculo-angiogenesis, and clinical implications for catheter-based procedures and
      surgeries in the region of the coronary sulcus. Also, a review of great cardiac
      vein variations is presented herein.

PMID- 15176043
TI  - Magnetic resonance microscopy versus light microscopy in human embryology
      teaching.
AB  - A study was carried out on the application of magnetic resonance microscopy (MRM)
      in teaching prenatal human development. Human embryos measuring 8 mm, 15 mm, 18.5
      mm, and 22 mm were fixed in a 4% paraformaldehyde solution and sections obtained
      with magnetic resonance imaging (MRI) were compared to those prepared for light
      microscopy (LM), using the same embryos. The MRM and LM slices were of a similar
      quality. In the MRM sections, embryonic organs and systems were clearly visible,
      particularly the peripheral and central nervous systems, and the cardiovascular
      and digestive systems. The digitalization and clarity of the MRM images make them
      an ideal teaching aid that is suitable for students during the first years of a
      health-science degree, particularly medicine. As well as providing students with
      their first experience of MRM, these images allow students to access, at any
      time, all embryos used, to assess changes in the positions of different organs
      throughout their stages of development, and to acquire spatial vision, an
      absolute requirement in the study of human anatomy. We recommend that this
      technique be incorporated into the wealth of standard embryonic teaching methods
      already in use.

PMID- 15176046
TI  - Endothelin A receptor blockade does not alter PSA secretion in prostate cancer
      cell lines.
AB  - BACKGROUND: Some men treated with atrasentan (ABT-627), an endothelin A (ETA)
      receptor inhibitor, had declines in their serum PSA levels. It is our hypothesis
      that this decrease is due to anti-tumoral activity and not a reduction in PSA
      secretion at the cellular level. METHODS: Two PSA secreting prostate cancer cell
      lines (LAPC4 and LNCaP) were treated with atrasentan and an ETB receptor
      antagonist (A192621) in varying concentrations (10(-6)-10(-10) M) and PSA levels
      were measured in the culture media. RESULTS: LNCaP and LAPC4 cells both express
      ETA receptors. Neither the ETA or ETB antagonist altered PSA secretion, while
      addition of DHT, a positive control, produced a marked increase in PSA secretion.
      CONCLUSIONS: Blockade of the ETA receptor does not affect the secretion of PSA in
      prostate cancer cell lines.

PMID- 15176047
TI  - Interleukin-6 protects LNCaP cells from apoptosis induced by androgen deprivation
      through the Stat3 pathway.
AB  - BACKGROUND: Elevated expression of interleukin-6 (IL-6) is implicated in the
      progression of hormone refractory prostate cancer. Previous studies demonstrated
      that IL-6 promotes androgen-independent growth of prostate cancer cells. In this
      study, the effect of IL-6 on apoptosis induced by androgen deprivation was
      investigated. METHODS: The effect of IL-6 on apoptosis induced by androgen
      deprivation in LNCaP cells was examined by cell death ELISA and Western blot
      using cleaved poly (ADP-ribose) polymerase (PARP) and caspase-9, as well as Bcl
      xL and phosphorylated Bad. The Stat3 in IL-6-mediated anti-apoptosis in prostate
      cancer cells was examined using either dominant-negative or constitutively
      activated Stat3 mutants. RESULTS: Overexpression of IL-6 renders androgen
      sensitive LNCaP human prostate cancer cells more resistant to apoptosis induced
      by androgen deprivation. LNCaP cells undergo apoptosis after 72 hr of androgen
      deprivation, an outcome is largely absent in clones overexpressing IL-6 as
      measured by cell death ELISA and chromatin degradation assays. IL-6 over
      expressing cells resulted in a significant decrease in the expression of cleaved
      PARP and cleaved caspase-9 as well as an increase in the expression of Bcl-xL and
      phosphorylated Bad. Addition of IL-6 antibody completely abolished the anti
      apoptotic activity of IL-6. This protective effect of IL-6 was reversed by the
      expression of a dominant-negative Stat3 mutant, Stat3F. Furthermore, ectopic
      expression of a constitutively active Stat3 antagonized androgen deprivation
      induced cell death of LNCaP cells. CONCLUSION: These results indicate that IL-6
      protects androgen sensitive LNCaP cells from apoptosis induced by androgen
      deprivation, and Stat3 activation play an important role in IL-6-mediated anti
      apoptosis in prostate cancer cells.

PMID- 15176048
TI  - Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer
      cells to androgen deprivation.
AB  - BACKGROUND: Early in the malignant transformation of prostate epithelial cells,
      the apoptotic response to androgen deprivation (AD) is lost and the principle
      response is a slowing of cell growth. In this study, we tested whether
      interruption of MDM2 function using antisense MDM2 oligonucleotide (AS) affects
      the apoptotic response of prostate cancer cells to AD. METHODS: Wild type LNCaP
      cells and MDM2-overexpressing (LNCaP-MST) cells were treated with AS alone or in
      combination with AD. Protein levels of MDM2, p53, and p21 were determined by
      Western blotting. Cell viability was measure by trypan blue staining. Apoptotic
      cell death was confirmed by cell morphological changes, annexin V/propidium
      iodide staining and caspase-3 + 7 activity. Overall cell survival was quantified
      by clonogenic assay. RESULTS: AS inhibited MDM2 expression to a greater extent in
      LNCaP cells, as compared to LNCaP-MST cells. AS enhanced the expression of p53
      and p21 in both cell lines. The growth inhibitory and cell death effects of AS +
      AD were generally greater than AS alone in LNCaP cells. Treatment of LNCaP cells
      with AS + AD for 72 hr caused a significant increase in cell death (66%) over AD
      alone (13%), AS alone (33%), or AD + AS + R1881 (34% with synthetic androgen
      replacement) that was attributable mainly to apoptosis. Clonogenic survival
      reflected the same pattern. CONCLUSIONS: Our results suggest that the apoptotic
      response of prostate cancer to AD is strongly influenced by MDM2 expression.
      Antisense MDM2 has broad potential as a therapeutic agent to sensitize prostate
      cancer cells to AD therapy by enhancing apoptotic cell death.

PMID- 15176049
TI  - Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce
      durable remission of metastatic androgen-independent prostate cancer: a Phase 2
      trial.
AB  - BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in American
      men, yet treatment of its metastatic androgen-independent form remains
      inadequate. This mandates development of new therapies such as immunotherapy. In
      this Phase 2 trial, we determined the efficacy of antigen presenting cells (APCs)
      loaded with PA2024, a recombinant fusion protein containing prostatic acid
      phosphatase (PAP) and GM-CSF. METHODS: We enrolled 21 patients with
      histologically documented androgen-independent prostate carcinoma that could be
      evaluated by radionuclide bone scan or computed tomography scan. APC8015 was
      prepared from a leukapheresis product; it contained autologous CD54-positive
      PA2024-loaded APCs with admixtures of monocytes, macrophages, B and T cells.
      APC8015 was infused intravenously twice, 2 weeks apart. Two weeks after the
      second infusion, patients received three subcutaneous injections of 1.0 mg of
      PA2024 1 month apart. We monitored patients' physical condition, immune response,
      and laboratory parameters. RESULTS: Nineteen patients could be evaluated for
      response to treatment. The median time to progression was 118 days. Treatment was
      tolerated reasonably well; most adverse effects were secondary to APC8015 and
      were NCI Common Toxicity Criteria Grade 1-2. Four of the 21 patients reported
      Grade 3-4 adverse events. Two patients exhibited a transient 25-50% decrease in
      prostate-specific antigen (PSA). For a third patient, PSA dropped from 221 ng/ml
      at baseline to undetectable levels by week 24 and has remained so for more than 4
      years. In addition, this patient's metastatic retroperitoneal and pelvic
      adenopathy has resolved. PBMC collected from patients for at least 16 weeks
      proliferated upon in vitro stimulation by PA2024. For the patient with responsive
      disease, PBMC could be stimulated for 96 weeks. CONCLUSIONS: This study
      demonstrates a definite clinical response of androgen-independent prostate cancer
      to APC immunotherapy. Currently we are studying this mode of therapy in Phase 3
      trials.

PMID- 15176050
TI  - A prostate stem cell antigen-derived peptide immunogenic in HLA-A24- prostate
      cancer patients.
AB  - BACKGROUND: We attempted to identify prostate stem cell antigen (PSCA)-derived
      peptides immunogenic in HLA-A24+ prostate cancer patients. METHODS: Peripheral
      blood mononuclear cells (PBMCs) were stimulated in vitro with each of three
      different PSCA-derived peptides, which were prepared based on the HLA-A24 binding
      motif, and their peptide-specific and HLA-A24-restricted anti-tumor responses
      were examined. Plasma levels of immunoglobulin G (IgG) against PSCA peptides were
      measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among three PSCA
      peptides, the PSCA 76-84 peptide most effectively induced peptide-specific
      cytotoxic T lymphocytes (CTLs) from PBMCs of HLA-A24+ prostate cancer patients.
      Cytotoxicity was dependent on peptide-specific and CD8+ T cells. The PSCA 76-84
      peptide-stimulated PBMCs showed a significant level of cytotoxicity against
      prostate cancer cells in an HLA-A24-restricted manner. IgG reactive to the PSCA
      76-84 peptide was detected in half of patients. CONCLUSIONS: The PSCA 76-84
      peptide should be considered for use in clinical trials of immunotherapy for HLA
      A24+ patients.

PMID- 15176051
TI  - P704P, P712P, and P775P: A genomic cluster of prostate-specific genes.
AB  - BACKGROUND: Discovery of prostate cancer- and tissue-specific genes will lead to
      an increased understanding of the molecular events associated with the malignant
      transformation and tumorigenesis of prostate cells. Such understanding will
      likely result in the development of promising new markers for screening,
      diagnosis, and prognosis, as well as potential therapeutic approaches for
      combating this disease. METHODS: A PCR-based subtraction method was combined with
      a high-throughput microarray screening approach to identify prostate tissue-
      and/or cancer-specific genes. Northern blot and quantitative real-time PCR were
      used to confirm prostate specificity. Bioinformatics analysis was performed to
      determine gene localization and to identify the open reading frame of novel
      genes. RESULTS: Three novel cDNA clones, P704P, P712P, and P775P, were identified
      and characterized to be specific for normal and malignant prostate tissues.
      Furthermore, P712P mRNA expression was found to be androgen responsive in LNCaP
      cells. Sequences for all three cDNAs were localized to an 80 kb genomic region on
      chromosome 22. Attempts to identify full-length transcripts did not reveal any
      apparent open reading frames, indicating that P704P, P712P, and P775P may belong
      to a novel class of transcripts with specific patterns of gene expression that do
      not code for translated proteins. CONCLUSIONS: A genomic cluster of prostate
      specific genes with no apparent open reading frame has been discovered using a
      high-throughput approach combining subtraction with microarray. This may
      represent an important genomic region having possible connections to prostate
      biology with potential applications in prostate diagnostics and therapy.

PMID- 15176052
TI  - Characterization and comparative analyses of transcriptomes from the normal and
      neoplastic human prostate.
AB  - BACKGROUND: The prostate gland is a highly specialized organ with functional
      attributes that serve to enhance the fertility of mammalian species. Pathological
      processes affecting the prostate include benign prostate hypertrophy and prostate
      carcinoma; diseases that account for major morbidity and mortality in middle-aged
      and elderly men. To facilitate studies of biological processes uniquely
      represented in the prostate and assess molecular alterations associated with
      prostate carcinoma, we sought to establish the diversity of gene expression in
      the normal and neoplastic prostate through the compilation and analysis of a
      prostate transcriptome. METHODS: We assembled and annotated ESTs derived from
      prostate cDNA libraries that were either produced in our laboratory or available
      from public sequence repositories such as CGAP, dbEST, and Unigene.
      Determinations of differential gene expression between the normal prostate, other
      normal tissues, and neoplastic prostate tissues was performed using statistical
      algorithms. Confirmation of differential expression was performed by quantitative
      PCR and Northern analysis. RESULTS: A total of 99,448 high-quality ESTs were
      assembled and annotated to produce a prostate transcriptome comprised of 24,580
      distinct TUs. Comparative analyses of gene expression levels identified 61 TUs
      with exclusive expression in the prostate and 45 TUs with high levels of
      expression in the prostate relative to at least 25 other normal tissues (P >
      0.99). Comparative analyses of ESTs derived from neoplastic prostate tissues
      identified 75 genes with dysregulated expression in cancer (P > 0.99).
      CONCLUSIONS: The human prostate expresses a diverse repertoire of genes that
      reflect a functionally complex organ. The identification of genes with prostate
      restricted or enhanced expression may provide additional insights into the
      biochemical processes that interact to form the developmental, signaling, and
      metabolic pathways of the normal and neoplastic gland.

PMID- 15176053
TI  - Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor
      grades.
AB  - BACKGROUND: Polo-like kinase 1 (PLK1) is known to be one of the key players in
      the regulation of mitosis of both normal and malignant transformed cells.
      Moreover, several studies reported an overexpression of PLK1 in human
      malignancies compared to the corresponding tissue of origin. METHODS: In this
      study, expression of PLK1 was investigated by immunohistochemistry in 78 tissue
      specimens of prostate carcinoma and in adjacent normal prostate tissue as well as
      in benign prostate hyperplasia. PLK1 expression was semiquantitavely scored and
      subsequently correlated to clinicopathological parameters and patient prognosis.
      RESULTS: No significant PLK1 expression was observed in normal prostate glandular
      epithelium and stroma. Specimens of benign prostate hyperplasia were PLK1
      negative as well. In contrast, 52.6% of all prostate carcinomas showed strong
      expression of PLK1. High grade intraepithelial lesions, if present, stained
      almost invariably in the same manner as the respective invasive tumors.
      Expression of PLK1 correlated positively with Gleason grade (P = 0.011). No other
      significant correlations of PLK1 expression with either tumor stage, WHO tumor
      grade, preoperative PSA, age, or resection margins could be established. In an
      analysis for differences in PSA-relapse-free survival time, PLK1 expression was
      not a prognostic marker. CONCLUSIONS: These results demonstrate a high rate of
      PLK1-positivity in prostate cancer which suggests involvement of PLK1 in
      tumorigenesis and progression in this tumor entity. Therefore, targeted
      strategies focussing on PLK1 inhibition might represent a promising new
      chemotherapeutic approach in prostate cancer.

PMID- 15176054
TI  - Prostein expression is highly restricted to normal and malignant prostate
      tissues.
AB  - BACKGROUND: Prostein is a recently described molecule expressed at the mRNA level
      in a prostate-specific manner. A murine monoclonal antibody was developed,
      characterized, and used to evaluate the expression of prostein protein in
      prostatic, other normal tissue and tumor samples. METHODS: The murine anti
      prostein monoclonal antibody 10E3-G4-D3 was generated using recombinant prostein.
      ELISA, FACS, and Western analyzes were used to characterize 10E3-G4-D3.
      Immunohistochemistry was used to characterize the expression of prostein in
      tissues. RESULTS: 10E3-G4-D3 specifically recognizes a linear intracellular
      epitope of prostein. IHC analysis demonstrates that prostein is expressed in the
      vast majority of normal and malignant prostatic tissues, regardless of grade and
      metastatic status. No protein expression is detected in a panel of approximately
      4,700 normal and malignant tissue samples representing the great majority of
      essential tissues and tumors. CONCLUSIONS: Prostein is exquisitely specific for
      prostate tissues, indicating a potential clinical utility of 10E3-G4-D3 as a
      diagnostic biomarker, and support the use of prostein as a novel target for
      development of prostein-specific antibody and T-cell based therapeutic strategies
      for prostate cancer.

PMID- 15176055
TI  - Molecular alterations associated with LNCaP cell progression to androgen
      independence.
AB  - BACKGROUND: There is no effective therapy currently available for androgen
      independent (AI) prostate cancer (CaP). This is largely due to lack of
      information about the molecular mechanisms by which androgen-dependent tumor
      cells progress to androgen independence. In this study, we investigated molecular
      alterations occurring in AI LNCaP cells. METHODS: We established and
      characterized three AI LNCaP sublines that exhibited a wide range of cytogenetic
      alterations. In order to understand why androgen-sensitive LNCaP cells can
      survive in an androgen-deprived environment, we analyzed the expression of
      signaling proteins associated with proliferation and survival of AI cells. In
      addition, gene expression profiling was performed to gain insight into molecular
      alterations in these LNCaP sublines. RESULTS: These LNCaP sublines exhibited
      heightened levels of androgen receptor (AR), HER2, MAPK, serine 473
      phosphorylated Akt, and Bcl-2, implicating these proteins as mediators of AI
      growth. Gene expression profiling identified a common set of 66 genes that were
      differentially expressed in all three sublines compared to the parental LNCaP
      cells. Of these, 32 were apparently androgen regulated, while the remainder
      comprised an expression signature specific for androgen independence. CONCLUSION:
      We have developed AI LNCaP cell models and identified several genes that are
      specifically expressed in these models. Elucidating the relative importance of
      these genetic changes will help define the molecular mechanism by which CaP
      progresses to androgen independence.

PMID- 15176056
TI  - NMR spectroscopic characterization of metoprolol/cyclodextrin complexes in
      aqueous solution: cavity size dependency.
AB  - The inclusion complex formation of a water-soluble beta(1)-selective
      adrenoreceptor antagonist Metoprolol (Met) with alpha-cyclodextrin (alpha-CyD),
      beta-cyclodextrin (beta-CyD), gamma-cyclodextrin (gamma-CyD), and 2-hydroxypropyl
      beta-cyclodextrin (HP-beta-CyD) in aqueous solution was studied by ultraviolet
      (UV), circular dichroism (CD), and nuclear magnetic resonance (NMR)
      spectroscopies and the modes of interaction were assessed. Continuous variation
      plots revealed that Met forms the inclusion complexes with alpha-CyD, beta-CyD,
      and HP-beta-CyD in a stoichiometry of 1:1, whereas gamma-CyD forms the 2:1
      complex where two Met molecules are included in one gamma-CyD cavity. NMR
      spectroscopic studies, including ROESY and GROESY techniques, clearly indicated
      that alpha-CyD with the small cavity includes the methoxyethylbenzene moiety of
      Met molecule shallowly in the cavity, depositing the benzene and the methoxy
      moieties around the secondary and primary sides, respectively, of the cavity. In
      the case of the beta-CyD complex, the methoxyethylbenzene moiety is more deeply
      included in the cavity, and it is feasible that Met may be able to enter from
      both primary and secondary hydroxyl sides of the cavity, forming the 1:1 complex.
      On the other hand, two Met molecules are included probably in an antiparallel
      orientation in the large gamma-CyD cavity, and the benzene moieties of Met are in
      contact with each other.

PMID- 15176057
TI  - A study of phase separation in peptide-loaded HPMC films using T(zero)-modulated
      temperature DSC, atomic force microscopy, and scanning electron microscopy.
AB  - Despite the widespread use of drug-loaded polymeric systems, there is still
      considerable uncertainty with regard to the nature of the distribution of the
      drug within the polymer matrix. The aim of this investigation was to develop
      thermal and microscopic techniques whereby the miscibility and spatial
      distribution of a model peptide, cyclosporin A (CyA), in hydroxypropyl
      methylcellulose (HPMC) films may be studied. The new technique of T(zero)
      modulated temperature differential scanning calorimetry (T(zero) MTDSC), scanning
      electron microscopy (SEM), and pulse force mode atomic force microscopy (PFM-AFM)
      were used in conjunction to study films prepared using a solvent evaporation
      process, with a solvent extraction study performed to elucidate the nature of the
      observed phases. T(zero) MTDSC studies showed glass transitions for both the HPMC
      and CycA, with the T(g) for the HPMC and CycA seen for the mixed systems. SEM
      showed two spherical phases of differing electron density. PFM-AFM also showed
      spheres of differing adhesion that increased in size on addition of drug. Pixel
      intensity analysis indicated that the smaller spheres corresponded to CycA.
      Exposure of the films to dichloromethane, in which CycA is soluble but HPMC is
      not, resulted in the presence of voids that corresponded well to the spheres
      suggested to correspond to the drug. It was concluded that the system had
      undergone extensive or complete phase separation, and that the thermal and
      microscopic techniques outlined above are an effective means by which this issue
      may be studied.

PMID- 15176058
TI  - Thiomers in noninvasive polypeptide delivery: in vitro and in vivo
      characterization of a polycarbophil-cysteine/glutathione gel formulation for
      human growth hormone.
AB  - This study was aimed at investigating the potential of a new polycarbophil
      cysteine (PCP-Cys)/glutathione (GSH) gel formulation to enhance the permeation of
      the model drug human growth hormone (hGH) across nasal mucosa in vitro and in
      vivo. The aqueous nasal gel contained PCP-Cys, GSH, and hGH in a final
      concentration of 0.3%, 0.5%, and 0.6% (m/v), respectively. In vitro permeation
      studies were performed in Ussing chambers on freshly excised bovine nasal mucosa
      using fluorescence-labeled dextran (molecular mass: 4.3 kDa; FD-4) and hGH (FITC
      hGH). The release profile of FITC-hGH from the gel formulation and an unmodified
      PCP control formulation was determined. Furthermore, in vivo studies in rats were
      performed comparing the PCP-Cys/GSH/hGH gel with PCP/hGH control gel and
      physiological saline. The permeation of FD-4 and FITC-hGH across the nasal mucosa
      was improved two-fold and three-fold, respectively, in the presence of PCP
      Cys/GSH. The PCP-Cys/GSH/hGH gel and the PCP/hGH control gel showed the same
      biphasic and matrix-controlled drug release. The nasal administration of the PCP
      Cys/GSH/hGH gel formulation to rats resulted in a significantly increased and
      prolonged hGH plasma concentration-time profile versus unmodified PCP gel and
      physiological saline. According to these results, PCP-Cys gels might represent a
      promising new strategy for systemic nasal polypeptide delivery.

PMID- 15176059
TI  - Improving the filterability and solid density of ranitidine hydrochloride Form 1.
AB  - Ranitidine hydrochloride Form 1 produced by the original method (Price et al.,
      1978 US patent) has poor filtration and drying characteristics, which make it
      less desirable commercially in comparison with Form 2. This article shows that
      the operating parameters have significant influence on the final properties of
      Form 1. In terms of filterability and solid bulk density, it was found that at a
      higher temperature (approximately 48 degrees C), the viscosity of the slurry
      decreased and improved product quality as compared with operating at room
      temperature (approximately 25 degrees C). It was found that the rapid addition of
      acid to the ranitidine base increased product density but led to higher residual
      solvent inclusion. The presence of excess ranitidine base in the solution and
      also the manner of reactant addition had a significant influence on the onset of
      nucleation and the rate of crystallization. The best results in terms of
      filterability and bulk solid density were obtained using an initial pH of 5.3 and
      then increasing it to 6.3-6.4 after the onset of nucleation.

PMID- 15176060
TI  - TOPS-MODE approach for the prediction of blood-brain barrier permeation.
AB  - The blood-brain barrier permeation has been investigated by using a topological
      substructural molecular design approach (TOPS-MODE). A linear regression model
      was developed to predict the in vivo blood-brain partitioning coefficient on a
      data set of 119 compounds, treated as the logarithm of the blood-brain
      concentration ratio. The final model explained the 70% of the variance and it was
      validated through the use of an external validation set (33 compounds of the 119,
      MAE = 0.33), a leave-one-out crossvalidation (q(2) = 0.65, S(press) = 0.43),
      fivefold full crossvalidation (removing 28 compounds in each cycle, MAE = 33,
      RMSE = 0.43) and the prediction of +/- values for an external test set (85.7% of
      good prediction). This methodology evidenced that the hydrophobicity increase the
      blood-brain barrier permeation, while the polar surface and its interaction with
      the atomic mass of compounds decrease it; suggesting the capacity of the TOPS
      MODE descriptors to estimate brain penetration potential of new drug candidates.
      Finally, by the present approach, positive and negative substructural
      contributions to the brain permeation were identified, and their possibilities in
      the lead generation and optimization processes were evaluated.

PMID- 15176061
TI  - Sustained release of cisplatin from multivesicular liposomes: potentiation of
      antitumor efficacy against S180 murine carcinoma.
AB  - Cisplatin was encapsulated into multivesicular liposomes (MVLs) and the
      entrapment efficiency, size distribution, and in vitro drug release
      characteristics of the cisplatin-MVLs were studied. Pharmacokinetics, tissue
      distribution, and therapeutic efficacy of cisplatin-MVLs were compared against
      injection of cisplatin solution into mice inoculated with the murine carcinoma
      180 (S180) tumor. The results showed that the cisplatin-MVLs were capable of high
      drug loading (0.148:1 mg cisplatin/mg lipid) and high encapsulation efficiency
      (>80%). The mean diameter of cisplatin-MVLs was 17 microm. In vitro studies of
      cisplatin-MVLs in saline solution showed that they sustained release of
      encapsulated drug for >7 days. Cisplatin-MVLs showed higher drug accumulation in
      the liver, spleen, and tumor regions than cisplatin solution, as well as higher
      plasma concentrations and a longer circulation time. The therapeutic efficacy of
      the cisplatin-MVL preparation against S180 tumor-bearing mice is significantly
      higher than that of cisplatin solution.

PMID- 15176062
TI  - Evaluation of different parameters that affect droplet-size distribution from
      nasal sprays using the Malvern Spraytec.
AB  - The applicability of laser diffraction (Spraytec) for characterizing the droplet
      size distribution (DSD) from nasal sprays was examined to understand the
      relationship between physical properties of nasal formulations and their spray
      characteristics. The impact of actuation force (3-7 kg), rheological properties
      from carboxymethylcellulose (CMC) and carbopol 934PNF, the influence of
      surfactant (Tween 80), actuation distance, and different nasal-pump designs on
      the aerosol DSD of nasal sprays were investigated using Spraytec((R)) with the
      eNSP actuation station (InnovaSystems, Moorestown, NJ). Spray-pattern analysis
      was performed by monitoring the emitted nasal spray containing a dye or a
      fluorescent marker. Parameters for DSD and spray pattern included: Dv(10),
      Dv(50), Dv(90), polydispersity, minimum and maximum diameters, plume area, and
      ovality. Increasing actuation distance from 1.5 to 6 cm from the laser beam
      decreased Dv(50) values by 17-27% for commercial nasal-spray products. Spray
      pattern analysis revealed a power law relationship between viscosity and surface
      area for CMC formulations. However, this relationship could not be obtained for
      carbopol formulations, which was attributed to differences in their rheological
      behavior. The addition of surfactant (0.5-5% Tween 80) to a 2% CMC solution
      decreased the Dv(50) values (16-26%) and altered the rheological properties
      (e.g., changes in viscosity and appearance of the thixotropic system). Briefly,
      the characteristic of nasal aerosol generation is dependent on a combination of
      actuation force, viscosity, rheological properties, surface tension, and pump
      design. The Spraytec with the eNSP actuation station provides an efficient and
      reliable way of monitoring the effects of formulation variables on DSD from nasal
      aerosols.

PMID- 15176063
TI  - Variation of peptide transporter (PepT1 and HPT1) expression in Caco-2 cells as a
      function of cell origin.
AB  - Caco-2 cell cultures are a widely used in vitro model for the small intestinal
      drug transport, although large differences have been reported for actively
      transported substrates from different laboratories. Therefore, we compared three
      different Caco-2 clones: (1) from the American Culture Tissue Collection (ATCC),
      (2) from the German Cancer Research Center (DKFZ) in Heidelberg, and (3) from the
      University Hospital in Marburg in different passage numbers regarding their
      morphology, multilayers, and tight junction formation, as well as expression of
      the peptide transporters, HPT1 and PepT1. We determined tight junction formation
      by measurement of the transepithelial electrical resistance, multilayer formation
      by confocal laser scanning microscopy, the expression of PepT1 and HPT1 by RT
      PCR, indirect immunofluorescence and the permeability of the PepT1 substrate,
      cephradine. Morphology and TEER-values varied strongly between the different
      clones. The expression of PepT1 and HPT1 increased in the following order: HD >
      ATCC > MR. Indirect immunofluorescence revealed a heterogeneous distribution of
      the transporters in ATCC-cells, whereas it was homogeneous in HD-cells. Only a
      very weak expression was found in MR-cells. While in ATCC-cells expression of
      transporters decreased with increasing passage number, it increased in HD-cells.
      Expression levels were congruent with the transport of cephradine. Expression of
      PepT1 and HPT1 was strongly affected by the culture conditions. Under identical
      culture conditions, Heidelberg (HD) Caco-2 cells seemed to be an appropriate in
      vitro cell culture model for the transport of actively transported drugs, because
      interpassage changes are low and the transporter distribution was homogeneous
      throughout the monolayer.

PMID- 15176064
TI  - Preparation of tributyrin emulsion and characterization of the binding of the
      emulsion particles to low-density lipoprotein in vitro.
AB  - Tributyrin has been shown to be an effective antitumor agent alone or in
      combination with other chemotherapeutic agents in vitro. Because tributyrin
      exists as an oil, it could be formulated as an emulsion to facilitate its
      delivery. The aim of this study was to develop a tributyrin emulsion with
      affinity to low-density lipoprotein (LDL). The tributyrin emulsion was prepared
      by sonication. Sizes of the different fractions of the emulsion particles
      separated by ultracentrifugation were determined. Cholesterol was found to
      decrease the particle size slightly because of its condensing effect. The
      emulsion monolayer prepared was proved to bind effectively with LDL in vitro. The
      dissociation constant and binding maximum to LDL of the emulsion fraction 1 with
      smaller particle sizes were 0.1236 microM and 0.4140 mmol/mol, and that of the
      fraction 2 with larger particle sizes were 0.0635 microM and 0.2654 mmol/mol,
      respectively. These results suggested that the binding ability of tributyrin
      emulsion depended on the component of the monolayer as well as the size of the
      emulsion particles. The potential pharmaceutical applications of this tributyrin
      emulsion are discussed.

PMID- 15176065
TI  - Water distribution studies within microcrystalline cellulose and chitosan using
      differential scanning calorimetry and dynamic vapor sorption analysis.
AB  - The objective of the study was to assess and compare the interaction and
      distribution of water within microcrystalline cellulose (MCC) and chitosan by
      differential scanning calorimetry (DSC) and dynamic vapor sorption analysis. The
      amounts of nonfreezing and freezing water in hydrated samples were determined
      from melting endotherms obtained by DSC. After accounting for the percent
      crystallinity of MCC and chitosan, no statistically significant difference was
      observed in their ability to bind water molecules per repeating unit at the
      minimum water content at which freezing water is evident. Exposure of chitosan to
      water for 30 min was sufficient to achieve equilibration at 61% w/w actual water
      content. The moisture sorption profiles were analyzed according to the GAB and
      Young and Nelson equations. The adsorbed monolayer, externally adsorbed moisture,
      and internally absorbed moisture were not statistically different for MCC and
      chitosan after accounting for the amorphous content of the polymers. These
      studies suggest that chitosan can act as a "molecular sponge," and thus aid in
      the production of beads by extrusion and spheronization.

PMID- 15176066
TI  - Prediction of sun protection factors and UVA parameters of sunscreens by using a
      calibrated step film model.
AB  - At the stage of screening of new sun protection formulations, quick and
      inexpensive methods for estimation of the ultraviolet (UV) screening performance
      are highly desirable. It has been shown recently that apart from measurements of
      sun protection factors in vitro, calculations using a calibrated step film model
      are also a possibility. In the present investigation, further evidence for the
      usefulness of the step film model in terms of prediction of the sun protection
      factor is shown. In addition, it is demonstrated that parameters, which
      characterize the protection in the UVA range such as the UVA/UVB ratio and the
      critical wavelength can be calculated in good accordance with experimental data.
      Although with less accuracy, the estimation of UVA protection factors is also
      possible, if the photodegradation some filters undergo upon irradiation is taken
      into consideration.

PMID- 15176067
TI  - Characterization of the drug release process by investigation of its temperature
      dependence.
AB  - Temperature-dependent drug release from disintegrating tablets made of NaCl
      containing agglomerated micronized cellulose (AMC) granules has been studied to
      characterize the release process. Release measurements on tablets compacted at
      three different compaction pressures; 50, 100, and 200 MPa, were performed at
      seven different temperatures; 6, 23, 33, 43, 50, 55, and 63 degrees C using the
      recently developed alternating ionic current method. Tablets compacted at
      different compaction pressures showed similar release rates. The release process
      was found to be diffusion-controlled, and the activation energy of the diffusion
      coefficient was comparable to that obtained for diffusion in pure water. The
      results show that the AMC granules in contact with water swell to a size and
      shape that is only slightly affected by their compaction history and the ion
      diffusion operates mainly within liquid-filled pores within the AMC granules. By
      using the temperature dependence of the release process, it was possible to reach
      this conclusion without any assumptions concerning the number and radii of the
      granules into which the tablets disintegrated. Further, the magnitude of the
      effective diffusion coefficient was found to be approximately 7.5 x 10(-10)
      cm(2)/s, which is approximately four orders of magnitude lower than for
      unhindered diffusion of Na(+) and Cl(-) in water but similar to the diffusion
      coefficient for protons and OH(-) ions in microcrystalline cellulose.

PMID- 15176068
TI  - Solid-state solubility influences encapsulation and release of hydrophobic drugs
      from PLGA/PLA nanoparticles.
AB  - Biodegradable nanoparticles formulated from poly(D,L-lactide-co-glycolide) (PLGA)
      and polylactide (PLA) polymers are being extensively investigated for various
      drug delivery applications. In this study, we hypothesize that the solid-state
      solubility of hydrophobic drugs in polymers could influence their encapsulation
      and release from nanoparticles. Dexamethasone and flutamide were used as model
      hydrophobic drugs. A simple, semiquantitative method based on drug-polymer phase
      separation was developed to determine the solid-state drug-polymer solubility.
      Nanoparticles using PLGA/PLA polymers were formulated using an emulsion-solvent
      evaporation technique, and were characterized for size, drug loading, and in
      vitro release. X-ray powder diffraction (XRD) and differential scanning
      calorimetry (DSC) were used to determine the physical state of the encapsulated
      drug. Results demonstrated that the solid-state drug-polymer solubility depends
      on the polymer composition, molecular weight, and end-functional groups (ester or
      carboxyl) in polymer chains. Higher solid-state drug-polymer solubility resulted
      in higher drug encapsulation in nanoparticles, but followed an inverse
      correlation with the percent cumulative drug released. The XRD and DSC analyses
      demonstrated that the drug encapsulated in nanoparticles was present in the form
      of a molecular dispersion (dissolved state) in the polymer, whereas in
      microparticles, the drug was present in both molecular dispersion and crystalline
      forms. In conclusion, the solid-state drug-polymer solubility affects the
      nanoparticle characteristics, and thus could be used as an important
      preformulation parameter.

PMID- 15176069
TI  - Tolerability and improved protective action of idebenone-loaded pegylated
      liposomes on ethanol-induced injury in primary cortical astrocytes.
AB  - The potential therapeutic advantages of the encapsulation of idebenone within
      pegylated liposomes were investigated in vitro on primary cortical astrocytes of
      rats. In particular, both the concentration-dependent effects and the therapeutic
      effectiveness toward excitotoxic injury, elicited by chronic treatment with
      ethanol (100 microM) for 12 days, were evaluated. The following parameters were
      taken into consideration to assay free or liposomally entrapped idebenone: lactic
      dehydrogenase release, respiratory capacity measured by tetrazolium salt
      conversion, glutamine synthetase, and the levels of constitutive and inducible 70
      kDa heat shock proteins. To evaluate the effects on astrocytes, three different
      drug concentrations were used (0.5 microM, 5 microM, and 50 microM). At the
      highest concentration used (50 microM), a toxic effect of the free and
      liposomally entrapped drug was observed. Toxic effects seem to be due to a
      cellular membrane perturbation, as demonstrated by (45)Ca(2+) permeation. The
      therapeutic effect of free or liposomally entrapped idebenone on ethanol-induced
      injury of primary cortical astrocytes was evaluated as a function of the drug
      concentration. The drug liposome formulation was much more effective than the
      free drug in counteracting the ethanol-induced damage in astrocytes, i.e., 10
      times-lower doses of liposomally entrapped idebenone are able to provide a
      greater protective action than the free drug. The improved action of idebenone
      loaded liposomes is probably due to the greater drug bioavailability at the
      cellular level.

PMID- 15176070
TI  - Aerodynamic sizing of metered dose inhalers: an evaluation of the Andersen and
      Next Generation pharmaceutical impactors and their USP methods.
AB  - The particle sizing performance of a Next Generation Pharmaceutical Impactor
      (NGI) was compared to that of an Andersen cascade impactor (ACI). A single lot of
      Vanceril MDIs containing beclomethasone dipropionate (BDP) was used throughout.
      MDIs were sampled into NGI and ACI in accordance with USP recommendations, at
      30.0 and 28.3 L/min, respectively, following 1, 2, 6, and 30 actuations with or
      without a silicone cup or stage coating, to determine the apparent particle size
      distributions (PSD) of BDP. The mass balance and the statistical comparability of
      drug deposits were assured on a "per actuation basis" across all experiments,
      demonstrating "good cascade impactor practices." Interstage deposition or "wall
      losses" in NGI were found to be lower than those in ACI, although their
      determination was laborious in NGI. The PSD profiles for Vanceril from a single
      actuation were distinguishable between NGI and ACI, when uncoated collection
      surfaces were used, most specifically for drug mass <4-microm aerodynamic
      diameter (p < 0.05). Silicone coating of collection surfaces and an increased
      number of actuations were shown to result in PSD profile shifts for both NGI and
      ACI. Such effects were most pronounced for NGI, although coating the collection
      surfaces and/or increasing the number of actuations improved drug retention
      significantly on the upper stages of NGI, and thereby, minimized the effects of
      particle bounce of BDP from Vanceril MDIs. PSD profiles from a single actuation
      could be determined reliably in either of these impactors, provided that coated
      collection surfaces were employed; also, cumulative % mass undersize profiles
      were similar between instruments. However, small differences in PSD profiles
      still existed to support NGI's design claims for reduced "overlap" in its stage
      collection efficiency curves.

PMID- 15176071
TI  - The molecular formula and proposed structure of the iron-dextran complex,
      imferon.
AB  - The first iron-dextran complex was discovered in 1953, when we attempted to
      synthesize an analog of ferritin, by substituting polysaccharide for its protein
      shell. This new complex soon became the most widely used parental therapy for
      hypochromic anemia in humans. No molecular formula has been proposed, but Cox has
      attributed an outline structure to it. The present article proposes a structure
      greatly different from the Cox model, by having a polynuclear beta-ferric
      oxyhydroxide core, closely similar or identical to Akaganeite, chelated firmly by
      an encircling framework of dextran gluconic acid chains and surrounded by a
      removable outer sheath of colloidal dextran gluconic acid. The molecular weight
      of the iron-dextran core molecule, including its chelated framework, has been
      determined by gel filtration and analysis and its molecular formula (1.3)
      calculated. Also, these new data and existing electron photomicrographic, X-ray
      diffraction and crystallographic studies, have enabled a molecular weight,
      formula, and model structure to be proposed for its complex (2), which includes
      the outer sheath. The 480 iron atoms in both the core molecule and its sheathed
      complex are close to the number calculated from the core's unit cell dimensions
      and volume.

PMID- 15176072
TI  - Probing structural changes of proteins incorporated into water-in-oil emulsions.
AB  - The applicability of different techniques, that is, Differential Scanning
      Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), and intrinsic
      tryptophan fluorescence, for probing the structural changes of proteins in the
      water-in-oil emulsions are investigated using nondefatted bovine (BSA) and human
      serum albumin (HSA) as model proteins. FTIR shows that the overall secondary
      structure of the proteins changes to some extent, 12% for BSA and 9% for HSA,
      when these are incorporated into the emulsion. There was no evidence of changes
      in the distribution of secondary structural elements apart from the changes in
      overall secondary structure. A blue shift of 12 to 14 nm in the fluorescence
      emission maximum was observed for proteins in the emulsion and 3 to 11 nm in the
      simulated interior of the aqueous phase, thus indicating structural changes
      around the tryptophan residues. DSC scans indicated that the domains in the
      proteins change because the shape of the transition peaks changes, when the
      proteins were incorporated into the emulsions. The total enthalpy decreases for
      BSA and HSA when these are incorporated into the emulsion, and some changes to
      the transition temperatures are observed. All the applied techniques supplement
      each other to give a more complete picture of the structural changes in proteins
      in intact water-in-oil emulsions.

PMID- 15176073
TI  - How to photostabilize molsidomine tablets.
AB  - Different methods of photostabilization are presented for the very light
      sensitive molsidomine tablets. The incorporation of photostabilizers such as
      light absorber or pigments into the tablets considerably improved the
      photostability. Nevertheless, photodegradation was still detected after 12 h of
      intense light stress. Pigments are superior to colorants or ultraviolet
      absorbers. The use of titanium dioxide needs to be considered carefully.
      Preblending the pigment with the drug substance is very helpful for taking full
      advantage of its photostabilizing properties. Surface-treated titanium dioxide
      with reduced photocatalytic activity was less suitable than untreated. That was
      due to a change of particle agglomeration and adhesion behavior, which was
      demonstrated by scanning electron microscopy pictures. However, only the
      protection of the tablets by a cover, either by blistering or film coating, gave
      a photostable drug product.

PMID- 15176074
TI  - Rapid dissolution of high-potency danazol particles produced by evaporative
      precipitation into aqueous solution.
AB  - High-potency danazol particles with high dissolution rates were produced by
      evaporative precipitation into aqueous solution (EPAS). Aqueous suspensions
      formed by EPAS were centrifuged to remove the nonadsorbed surfactant. The
      resulting surfactant-coated drug particles had extremely high drug-to-surfactant
      ratios greater than 5, corresponding to potencies (wt drug/wt drug + wt
      surfactant) as high as 93%. The mechanism of the high dissolution rates was
      characterized as a function of surfactant adsorption, particle size and surface
      area, drug crystallinity, and the contact angle for water on the drug surface.
      For danazol stabilized by polyvinyl pyrrolidone (PVP) alone or with sodium lauryl
      sulfate (SLS), small particle diameter and high surface area led to high
      dissolution rates with approximately 90% drug dissolved in 2 min. The
      crystallinity of the danazol was typically 80%. The properties of the particles
      and the dissolution rates were mostly unchanged under a 2-week thermal cycling
      stress test.

PMID- 15176075
TI  - Impact of excipient particle size on measurement of active pharmaceutical
      ingredient absorbance in mixtures using frequency domain photon migration.
AB  - A system of dual-component powder mixtures, varying in excipient particle size
      and concentration of active pharmaceutical ingredient (API), is analyzed using
      frequency domain photon migration (FDPM) techniques. The results show that the
      FDPM-measured absorption coefficient increases linearly with increasing API
      concentration whereas the isotropic scattering coefficient shows no sensitivity
      to changes in API concentration. It is further seen that the absorption
      coefficient of blends, owing to the API, is not only linearly dependent on its
      concentration, but that this relationship is furthermore related to the excipient
      particle size. Finally, a comparison between near-infrared absorbance and FDPM
      measured isotropic scattering as a function of reciprocal particle size is made
      to highlight FDPM as a powerful particle sizing tool without need for
      calibration. Overall, this study presents FDPM as a comprehensive method for
      detection of API concentration independent of excipient particle size.

PMID- 15176076
TI  - Prediction of human pharmacokinetic profile in animal scale up based on
      normalizing time course profiles.
AB  - The aim of the present study was to develop a method for predicting the
      concentration-time profile in humans based on pharmacokinetic data for animals.
      The method is based on the assumptions that concentration-time profiles of a drug
      are similar among species and "normalized curves" from a variety of animal
      species including humans can be superimposed. Normalized curves are obtained by
      normalizing the time axis with the MRT (mean residence time) and the
      concentration axis with dose/Vdss, where Vdss is the volume of distribution at
      steady state. The concentration-time profile in humans after intravenous
      injection can be simulated using the normalized curve for an animal and the
      predicted values of clearance (CL) and Vdss for humans. Although the general idea
      of our method is similar to the Dedrick plots, ours is superior in that it
      enables the use of predicted CL and Vdss values from any method. Our method was
      applied to some drugs using actual published data sets, and the assumption of the
      similarity of concentration-time profiles among species was found to be
      acceptable for these drugs. The results for the prediction of concentration-time
      profiles for humans were also acceptable. This method can be applied to any drug
      on the assumption that normalized curves from a variety of species can be
      superimposed.

PMID- 15176077
TI  - Effects of benzyl-, phenethyl-, and alpha-naphthyl isothiocyanates on P
      glycoprotein- and MRP1-mediated transport.
AB  - The objective of this investigation was to evaluate the effects of two dietary
      isothiocyanates (ITCs), benzyl- (BITC) and phenethyl isothiocyanate (PEITC), and
      one synthetic ITC, alpha-naphthyl isothiocyanate (1-NITC), on the P-glycoprotein
      (P-gp)- and multidrug-resistance protein 1 (MRP1)-mediated efflux of daunomycin
      (DNM), determine whether PEITC is a substrate of P-gp and/or MRP1, and elucidate
      the mechanism(s) involved in the inhibition of transport. BITC, PEITC, and 1-NITC
      significantly increased the 2-h accumulation of DNM in MCF-7/ADR (P-gp
      overexpression), PANC-1 (MRP1 overexpression), and human colon adenocarcinoma
      Caco-2 cells (except for 1-NITC). The accumulation of (14)C-PEITC was not changed
      in Caco-2, human breast cancer MDA435/LCC6 and MDA435/LCC6MDR1 (P-gp
      overexpression) cells in the absence and presence of the P-gp inhibitor
      verapamil, but significantly increased with the MRP inhibitor MK571 in PANC-1
      cells. The isocyanate and amine metabolites had no effect on DNM accumulation in
      any cell line. After 2- and 24-h ITC treatments, cellular concentrations of
      glutathione (GSH) in PANC-1 and Caco-2 cells were depleted by BITC and PEITC, but
      not by 1-NITC; glutathione-S-transferase activity exhibited small changes. Our
      results suggest that (1) BITC, PEITC, and 1-NITC inhibit the P-gp- and MRP1
      mediated efflux of DNM; (2) PEITC and/or its conjugates do not represent P-gp
      substrates; (3) BITC and PEITC, but not 1-NITC, inhibit MRP1 through the
      depletion of intracellular GSH, which acts as a cosubstrate for DNM efflux via
      MRP1; and (4) PEITC and/or its conjugates are MRP1 substrates so binding
      interactions with DNM represent a second potential mechanism involved in MRP1
      inhibition.

PMID- 15176078
TI  - Influenza vaccine powder formulation development: spray-freeze-drying and
      stability evaluation.
AB  - The purpose of this study was to develop a spray-freeze-drying (SFD) process for
      preparing an influenza vaccine dry powder formulation suitable for epidermal
      powder immunization. After preformulation of two types of flu vaccines, their dry
      powder formulations were prepared by SFD. Powder properties and physical
      stability were determined using particle size analysis, tap density measurement,
      scanning electron microscopy, optical microscopy, and moisture content analysis.
      Chemical and biochemical stability of vaccine antigens was determined by sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis, single radial immunodiffusion
      assay, and in vivo immunogenicity in a mouse model. We demonstrated that SFD
      could produce high-density particles-a critical parameter for effective skin
      penetration. From the stability perspective, the stress posed by SFD was mild
      because the antigen in the dry powder retained its stability, potency, and
      immunogenicity. Among several formulations screened, we noted that formulation
      composition has a significant role in the powder's long-term physical and
      biochemical stability. One formulation, in particular, containing sub-unit
      vaccine (45 microg of antigen in 1 mg of powder) with a tertiary mixture of
      trehalose, mannitol, and dextran, exhibited excellent overall stability,
      including acceptable biochemical stability after being exposed to a highly humid
      environment. After all, we have not only demonstrated the suitability of SFD to
      prepare powders for epidermal powder immunization but also developed a systematic
      formulation development strategy that allowed the optimization of an influenza
      vaccine dry powder formulation. More important, this study led to the selection
      of a formulation system that had been successfully tested in a human clinical
      study.

PMID- 15176079
TI  - Characterization and biological evaluation of a microparticle adjuvant
      formulation for plasmid DNA vaccines.
AB  - We describe the physiochemical characterization and immunological evaluation of
      plasmid DNA vaccine formulations containing a nonionic triblock copolymer
      adjuvant (CRL1005) in the presence and absence of a cationic surfactant,
      benzalkonium chloride (BAK). CRL1005 forms particles of 1-10 microns upon warming
      above its phase-transition temperature (approximately 6-8 degrees C) and the
      physical properties of the particles are altered by BAK. DNA/CRL1005 vaccines
      formulated with and without BAK were evaluated in rhesus macaques to determine
      the effect of CRL1005 and BAK on the ability of plasmid DNA to induce a cellular
      immune response. Immunogenicity results indicate that the addition of CRL1005 to
      human immunodeficiency virus-1 gag plasmid DNA formulated in phosphate-buffered
      saline leads to an enhancement in the gag-specific cellular immune response.
      Moreover, the addition of BAK to human immunodeficiency virus-1 gag plasmid
      DNA/CRL1005 formulations produces an additional enhancement in gag-specific
      cellular immunity. In vitro characterization studies of DNA/CRL1005 formulations
      indicate no detectable binding of DNA to CRL1005 particles in the absence of BAK,
      suggesting that the enhancement of cellular immunity induced by DNA/CRL1005
      formulations is not due to enhanced DNA delivery. In the presence of BAK,
      however, results indicate that BAK binds to CRL1005 particles, producing cationic
      microparticles that bind DNA through electrostatic interactions. If BAK is
      present at the phase-transition temperature, it reduces the particle size from
      approximately 2 microns to approximately 300 nm, presumably by binding to
      hydrophobic surfaces during particle formation. Zeta potential measurements
      indicate that the surface charge of CRL1005-BAK particles changes from positive
      to negative upon DNA binding, and DNA bound to the surface of CRL1005-BAK
      particles was visualized by fluorescence microscopy. These results indicate that
      the addition of BAK to DNA/CRL1005 formulations leads to the formation of
      approximately 300 nm CRL1005-BAK-DNA particles that enhance the cellular immune
      response in rhesus monkeys.

PMID- 15176081
TI  - Progression of hair cell ejection and molecular markers of apoptosis in the avian
      cochlea following gentamicin treatment.
AB  - Aminoglycoside treatment induces caspase-dependent apoptotic death in inner ear
      sensory hair cells. The timing of apoptotic signaling in sensory hair cells
      following systemic aminoglycoside treatment has not been characterized in vivo.
      We administered a single subcutaneous injection of the aminoglycoside gentamicin
      (300 mg/kg) to 12-16-day-old chicks and used immunocytochemical techniques to
      document the following responses in affected hair cells: T-cell restricted
      intracellular antigen-related protein (TIAR) translocation from the nucleus to
      the cytoplasm, cytochrome c release from the mitochondria, caspase-3 activation,
      nuclear condensation, and an orderly progression of hair cell ejection from the
      proximal end of the basilar papilla. Hair cells in the proximal tip exhibited
      TIAR translocation from the nucleus and aggregation into punctate granules in the
      cytoplasm 12 hours after injection and the response progressed distally.
      Cytochrome c release from the mitochondria into the cytoplasm and caspase-3
      activation were observed in affected hair cells immediately prior to and during
      ejection. Hair cell ejection occurred between 30 and 54 hours after injection,
      beginning in the proximal tip and progressing distally. Nuclear condensation
      accompanied ejection while the loss of: 1) membrane integrity; 2) phalloidin
      labeling of F-actin; and 3) TO-PRO-1 labeling of nuclear contents occurred within
      48 hours following ejection. Our results present a timeline of aminoglycoside
      induced inner ear sensory hair cell apoptotic death that includes an 18-hour
      window between the initial apoptotic response and the later stages of programmed
      death signaling that accompany ejection and a gradual breakdown of hair cells
      following ejection.

PMID- 15176082
TI  - Expression of VIP and/or PACAP receptor mRNA in peptide synthesizing cells within
      the suprachiasmatic nucleus of the rat and in its efferent target sites.
AB  - The suprachiasmatic nucleus (SCN) contains the predominant circadian pacemaker in
      mammals. Considerable evidence indicates that VPAC(2) and PAC(1), receptors for
      vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating
      peptide (PACAP), play critical roles in maintaining and entraining circadian
      rhythms. Retinal projections to the rat SCN contain PACAP and terminate mostly in
      the ventral SCN, the site of VIP neurons. The incidence of VPAC(2) and PAC(1)
      mRNAs within distinct neuronal populations of the rat SCN has been determined
      using double-label in situ hybridization. VPAC(2) mRNA was detected in almost all
      arginine-vasopressin (AVP) neurons of the dorsomedial SCN and in 41% of the VIP
      neurons; somatostatin (SST) neurons, predominantly in dorsomedial and
      intermediate regions, showed a decreased incidence (23%). PAC(1) mRNA was present
      in nearly half of the VIP and SST neurons (45% and 40%, respectively) and in one
      third of the AVP neurons (32%). Cells expressing VPAC(2) mRNA also were detected
      in diencephalic areas that receive VIP-immunoreactive SCN efferents, such as the
      peri-suprachiasmatic region, lateral subparaventricular zone, parvocellular
      hypothalamic paraventricular subdivisions, dorsomedial hypothalamic nucleus, and
      anterior thalamic paraventricular and paratenial nuclei. The extensive
      distribution of PAC(1) mRNA within the SCN suggests that actions of PACAP are not
      restricted to the predominantly retinorecipient region. The presence of VPAC(2)
      mRNA in nearly half the VIP neurons, in almost all the AVP neurons, and at sites
      receiving VIP-immunoreactive SCN efferents suggests that the SCN VIP neurons are
      coupled and/or autoregulated and also influence the AVP-containing dorsomedial
      SCN and distal sites via VPAC(2).

PMID- 15176083
TI  - Localization of the GABAB receptor 1a/b subunit relative to glutamatergic
      synapses in the dorsal cochlear nucleus of the rat.
AB  - Metabotropic gamma-aminobutyric acid receptors (GABA(B)) are involved in pre- and
      postsynaptic inhibitory effects upon auditory neurons and have been implicated in
      different aspects of acoustic information processing. To understand better the
      mechanisms by which GABA(B) receptors mediate their inhibitory effects, we used
      pre-embedding immunocytochemical techniques combined with quantification of
      immunogold particles to reveal the precise subcellular distribution of the
      GABA(B1) subunit in the rat dorsal cochlear nucleus. At the light microscopic
      level, GABA(B1) was detected in all divisions of the cochlear complex. The most
      intense immunoreactivity for GABA(B1) was found in the dorsal cochlear nucleus,
      whereas immunoreactivity in the anteroventral and posteroventral cochlear nuclei
      was very low. In the dorsal cochlear nucleus, a punctate labeling was observed in
      the superficial (molecular and fusiform cell) layers. At the electron microscopic
      level, GABA(B1) was found at both post- and presynaptic locations.
      Postsynaptically, GABA(B1) was localized mainly in the dendritic spines of
      presumed fusiform cells. Quantitative immunogold immunocytochemistry revealed
      that the highest concentration of GABA(B1) in the plasma membrane was in
      dendritic spines, followed by dendritic shafts and somata. Thus, the most intense
      immunoreactivity for GABA(B1) was observed in dendritic spines with a high
      density of immunogold particles at extrasynaptic sites, peaking around 300 nm
      from glutamatergic synapses. This is in contrast to GABAergic synapses, in which
      GABA(B1) was only occasionally found. Presynaptically, receptor immunoreactivity
      was detected primarily in axospinous endings, probably from granule cells, in
      both the active zone and extrasynaptic sites. The localization of GABA(B1)
      relative to synaptic sites in the DCN suggests a role for the receptor in the
      regulation of dendritic excitability and excitatory inputs.

PMID- 15176084
TI  - Development of neuromuscular junctions in the mouse esophagus: morphology
      suggests a role for enteric coinnervation during maturation of vagal myoneural
      contacts.
AB  - The time course of establishment of motor endplates and the subsequent
      developmental changes in their enteric and vagal innervation were examined in
      esophageal striated muscle of perinatal and adult C57/Bl6 mice by using
      immunocytochemistry and confocal laser scanning microscopy. Nicotinic
      acetylcholine receptors were visualized with alpha-bungarotoxin; vagal motor
      nerve terminals with antisera against vesicular acetylcholine transporter; and
      enteric nerve fibers with antisera against neuronal nitric oxide synthase,
      vasoactive intestinal peptide, and galanin. Because the various stages of
      esophageal striated myogenesis advance caudocranially, i.e., more mature stages
      are found cranial to immature stages, longitudinal cryosections through the
      esophagus were investigated. Synaptogenesis was divided into several distinct
      stages. 1) Mononucleated cells express acetylcholine receptors over their entire
      surface. 2) They start to cluster receptors without nerve fiber contacts. 3) The
      first nerve contact on a growing receptor cluster is made by a vagal nerve
      terminal, followed by an enteric terminal. 4) Vagal terminals grow until they
      match the size of endplate areas, and one to three enteric terminals intertwine
      with them on every receptor cluster. 5) After vagal terminals have covered the
      whole endplate area, enteric terminals are withdrawn from the majority of motor
      endplates. In a minority of endplates, enteric coinnervation persists through
      adulthood. The enteric innervation of all developing motor endplates, shortly
      after vagal terminals have contacted them, and the removal of enteric nerve
      fibers from the majority of mature motor endplates suggest a major role of
      enteric nerve fibers during maturation of esophageal neuromuscular junctions.

PMID- 15176085
TI  - The role of pigment cells in the brain of ascidian larva.
AB  - The functions of melanin in the pigment cells, the ocellus and the otolith, of
      ascidian larvae were studied by their swimming behavior and cell morphology with
      and without 1-phenyl-2-thiourea (PTU), an inhibitor of vertebrate tyrosinase.
      Melanin formation in both the otolith and the ocellus of PTU-treated larvae at 12
      hours of development was completely inhibited. These larvae were unable to swim
      because of abnormal tail development, but expression of rhodopsin in the outer
      segments of the photoreceptor was normal. In the PTU-treated larvae at 15 hours
      of development, melanin formation in the ocellus was inhibited, but that in the
      otolith seemed to be normal. The photic behavior of these larvae was normal, as
      was rhodopsin expression in the outer segments. However, the treated larvae lost
      upward swimming behavior. Synchrotron radiation X-ray fluorescence images showed
      that metallic elements of K, Ca, and Zn in the statocyte of larva were greatly
      decreased by PTU treatment, which may result in lowering the specific gravity of
      the pigment mass. SEM observations showed that the statocyte of Ciona
      intestinalis was supported by three parts, a foot-piece of the statocyte itself
      and two fibrous spring-like structures produced from protuberances. All three
      structures were synaptotagmin-positive. Movement of the statocyte would be
      detected by these three structures and thus would be responsible for the
      gravitational orientation.

PMID- 15176086
TI  - Differential expression pattern and steroid hormone sensitivity of SNAP-25 and
      synaptoporin mRNA in the telencephalic song control nucleus HVC of the zebra
      finch.
AB  - Gonadal steroid hormones play an important role in the process of sexual
      differentiation of brain areas and behavior such as singing and song learning in
      songbirds. These hormones affect behavior controlling circuits on both the gross
      morphological and ultrastructural levels. Here we study whether the expression of
      genes coding for synaptic proteins is sensitive to gonadal steroid hormones and
      whether such altered expression coincides with changes in brain area size. We
      treated adult male zebra finches with the aromatase inhibitor fadrozole, to
      reduce estrogen synthesis and analyzed the mRNA expression of the synaptic
      proteins synaptoporin (SPO) and synaptosomal-associated protein 25 kDa (SNAP-25)
      in song control areas and surrounding tissues of adult male zebra finches. SPO
      and SNAP-25 are differently expressed throughout the song system. Generally, the
      telencephalic song nuclei expressed SNAP-25 at high intensity whereas SPO
      expression was area-specific. Elevated levels of SNAP-25 mRNA were present in the
      nucleus hyperstriatalis ventrale pars caudale (HVC) and in the robust nucleus of
      the archistriatum (RA). SPO mRNA was found in moderate levels in the HVC, in low
      levels in the lateral nucleus magnocellularis (lMAN) and Area X, and was absent
      in the RA. The treatment significantly increased the mRNA level of SPO in the
      HVC, whereas SNAP-25 expression level was not affected. These expression patterns
      are not explained by the decrease of HVC volume after treatment. The decreased
      HVC size is not area-specific but correlates with an overall reduction in size
      and an overall increase in cell density of the forebrain.

PMID- 15176087
TI  - Age-related changes in the expression of axonal and glial group I metabotropic
      glutamate receptor in the rat substantia nigra pars reticulata.
AB  - Neuronal systems undergo many significant changes during the course of brain
      development. To characterize the developmental changes in the substantia nigra
      pars reticulata (SNr) associated with the expression of group I metabotropic
      glutamate receptors (mGluRs), we used the immunoperoxidase and immunogold methods
      at the electron microscope level to determine whether the subcellular and
      subsynaptic patterns of distribution of mGluR1a and mGluR5 differ between young
      (P14-P18) and adult (>2 months) rats. The SNr of young rats contained a
      significantly higher density of labeled unmyelinated axons for both receptor
      subtypes. In addition, mGluR5-immunoreactive glial processes were very abundant
      in young rats but absent in the adults. On the other hand, the relative
      proportion of immunoreactive dendrites was the same for both age groups. Analysis
      of immunogold-labeled rat SNr revealed similar proportions of plasma membrane
      bound mGluR1a and mGluR5 in adult (59.8 and 19.4%, respectively) and young (60.6
      and 18.4%, respectively) rats. The pattern of subsynaptic localization of mGluR1a
      also remained the same between young and adults. However, the proportion of
      extrasynaptic mGluR5 decreased, whereas proportions of gold particles associated
      with symmetric synapses increased in adults. The results of this study
      demonstrate significant differences in the expression of group I mGluRs in the
      SNr of young and adult rats. These findings support a role for group I mGluRs
      during development and emphasize the importance of using brain tissue from age
      matched subjects when attempting to correlate functional data from young rat
      brain slices with immunocytochemical localization of group I mGluRs.

PMID- 15176088
TI  - Pretectal and tectal afferents to the dorsal lateral geniculate nucleus of the
      turtle: an electron microscopic axon tracing and gamma-aminobutyric acid
      immunocytochemical study.
AB  - The pretectal and tectal projections to the dorsal lateral geniculate nucleus
      (GLd) of two species of turtle (Emys orbicularis and Testudo horsfieldi) were
      examined under the electron microscope by using axonal tracing techniques
      (horseradish peroxidase or biotinylated dextran amine) and postembedding gamma
      aminobutyric acid (GABA) immunocytochemistry. After injection of tracer into the
      pretectum, two types of axon terminals were identified as those of
      pretectogeniculate pathways. Both contained pleomorphic synaptic vesicles and
      were more numerous in the inner part of the nucleus. They could be distinguished
      on the bases of size and shape of their synaptic vesicles, type of synaptic
      contact, and level of GABA immunoreactivity. One type had a higher density of
      immunolabeling and established symmetric synaptic contacts, whereas the other,
      less densely immunolabeled, made asymmetric synaptic contacts. In both cases,
      synaptic contacts were mainly with relay cells and occasionally with
      interneurons. We suggest that these two types of pretectogeniculate terminals
      originate in two separate pretectal nuclei. After injection of tracer into the
      optic tectum, a single population of GABA-immunonegative tracer-labeled terminals
      was identified as belonging to the tectogeniculate pathway. These were small, had
      smooth contours, contained very small round synaptic vesicles, and established
      asymmetric synaptic contacts with long active zones, predominantly with relay
      cells and less frequently with interneurons, in the inner part of the nucleus. In
      addition, a population of GABA-negative and occasionally GABA-positive terminals,
      labeled by tracer injected into either the pretectum or the tectum, was
      identified as retinal terminals; these were presumably labeled by the retrograde
      transport of tracer in collateral branches of visual fibers innervating both the
      GLd and the pretectum or tectum. Comparison of the present ultrastructural
      findings in turtles with those previously reported in mammals shows that the
      cytological features, synaptic morphology, and immunochemical properties of the
      pretectogeniculate and tectogeniculate terminals of both groups share many
      similarities. Nevertheless, the postsynaptic targets of these two categories of
      terminals display some pronounced differences between the two groups, which are
      discussed in terms of their possible functional significance.

PMID- 15176089
TI  - Nestin promoter/enhancer directs transgene expression to precursors of adult
      generated periglomerular neurons.
AB  - The subventricular zone (SVZ) is a major neurogenic region in the adult brain.
      Cells from the SVZ give rise to two populations of olfactory bulb interneurons:
      the granule cells and periglomerular (PG) cells. Currently, little is known about
      the signaling pathways that direct these newly generated neurons to become either
      granule or PG neurons. In the present study, we used the nestin promoter and
      enhancer to direct expression of the tetracycline transactivator (tTA). We
      generated two independent strains of nestin-tTA transgenic animals and crossed
      founder mice from both lines to mice containing a tetracycline-regulated
      transgene (mCREB) whose expression served as a marker for the activity of the
      nestin-tTA transgene. mCREB expression occurred in a subset of proliferating
      cells in the SVZ and rostral migratory stream in both lines. Surprisingly, in
      both lines of nestin-tTA mice transgene expression in the olfactory bulb was
      limited to PG neurons and was absent from granule cells, suggesting that this
      nestin promoter construct differentiates between the two interneuronal
      populations. Transgene expression occurred in several subtypes of PG neurons,
      including those expressing calretinin, calbindin, GAD67, and tyrosine
      hydroxylase. These results suggest that a unique subset of SVZ precursor cells
      gives rise to PG, and not granule cells. The ability to express different
      transgenes within this subpopulation of neuronal precursors provides a powerful
      system to define the signals regulating the differentiation and survival of adult
      generated neurons in the olfactory bulb.

PMID- 15176090
TI  - Harnessing the HGP of public health.

PMID- 15176091
TI  - The code of silence.

PMID- 15176093
TI  - The code of silence.

PMID- 15176092
TI  - The code of silence.

PMID- 15176094
TI  - The code of silence.

PMID- 15176095
TI  - [Gramicidin S and a history of antibiotic research in Russia (on the 90th
      birthday of the State Prize laureate, professor M.G. Brazhnikova and 60 years
      since the first use of gramicidin S during the Great Patriotic War].

PMID- 15176096
TI  - [Effect of perfluoroorganic compounds on growth of streptomycetes and
      biosynthesis of antibiotic daunorubicin].
AB  - The use of perfluoroorganic compounds, i.e. perfluorodecalin and "Perftoran", a
      blood substitute with the gas transfer function, known as "blue blood"
      (containing 3 vol. % of perfluoromethylcyclohexylpiperidin and 7 vol. % of
      perfluorodecalin as emulsion with the average particle size of 0.07 microns) in
      biotechnology for intensification of the Streptomyces purpurogeniscleroticus
      growth under submerged conditions was shown promising for the first time. An
      increase of the biomass output and higher yields of daunorubicin were also
      demonstrated.

PMID- 15176097
TI  - [Growth and morphological characteristics of industrial strains of
      Bifidobacterium and Lactobacillus cultivated in hydrolysate-milk and hydrolysate
      soybean media].
AB  - Growth features of industrial strains of Bifidobacterium adolescentis MC-42, B.
      bifidum 1, B. longum B-379, Lactobacillus acidophilus, L. delbrueckii subsp.
      bulgaricus 8-79 and L. plantarum 8PA3 cultivated in hydrolysate-milk or
      hydrolysate-soybean media (HMM and HSM respectively) were analysed comparatively.
      The bacterial cells were investigated morphometrically with atom strength
      microscopy. It was shown that HSM vs HMM provided a higher growth rate of the
      strains (shortened growth phases and higher growth rates) that was more evident
      for the bifidobacteria as compared to the lactobacilli. At the same time, the
      morphological features of the bacterial cells slightly depended on the medium
      composition and were mainly defined by the genus.

PMID- 15176098
TI  - [Experimental and clinical study of the effect of antibiotics, oxytocin and their
      combinations on resistance of pathogens causing acute suppurative-inflammatory
      diseases of lungs and pleura].

PMID- 15176100
TI  - ["Swedish Bitter"--elixir of youth and longevity].

PMID- 15176099
TI  - [Efficacy and safety of cefoperazone/sulbactam in the treatment of children with
      mucoviscidosis during exacerbation of the bronchopulmonary process].
AB  - The use of cefoperazone/sulbactam in combination with amikacin in the treatment
      of 20 patients with mucoviscidosis and exacerbation of bronchopulmonary
      pathological process resulted in marked positive dynamics of the clinical and
      functional indices of the lungs state. The bacteriological effect with respect to
      the main pathogens in the cases of mucoviscidosis was strain-dependent:
      eradication of 10 (83.4%) out of 12 Staphylococcus aureus strains and only 3
      (15.8%) out of 19 Pseudomonas aeruginosa strains. The most frequent adverse
      reaction was diarrhea (5 children) successfully corrigated by loperamide.
      Discontinuation of the drug use was required in 3 patients because of
      macrohematuria (1 child) and allergic eruption.

PMID- 15176101
TI  - [Gramicidin S: characteristics of a producer, cultivation conditions, and
      interactions with a producer].

PMID- 15176102
TI  - [Structural and functional characteristics of gramicidin S in connection with its
      antibiotic activity].

PMID- 15176103
TI  - [Mechanism of biological activity of macrolide antibiotics--inhibitors of F0F1
      ATPase].

PMID- 15176104
TI  - Learning to lead. Interview by Lynne Pearce.

PMID- 15176105
TI  - The Bristol approach.

PMID- 15176106
TI  - School for scandal.

PMID- 15176107
TI  - Cutting remarks.

PMID- 15176108
TI  - Intimate strangers.

PMID- 15176109
TI  - Do you really know what we do all day?

PMID- 15176110
TI  - Music and the reduction of post-operative pain.
AB  - BACKGROUND: The prevention and treatment of post-operative pain, and the
      promotion of comfort are the challenges facing practitioners working in the
      recovery room setting. Surgical pain produces autonomic, psychological,
      immunological and behavioural responses that can delay or inhibit normal healing.
      Nurses spend more time with patients experiencing pain than any other healthcare
      professional. Therefore, they are in an ideal position to consider other pain
      relieving strategies to complement the analgesics currently used. CONCLUSION: The
      studies reviewed cannot prove that music is effective in reducing post-operative
      pain, because the research methodology in the majority is poor. Patients,
      experience of listening to music post-operatively was positive, aiding
      distraction and increasing comfort. This shows the difference between
      inconsistent results for the objective measures of pain and what the patient is
      reporting.

PMID- 15176111
TI  - Care maps: atypical antipsychotics. Introduction.

PMID- 15176112
TI  - Clinical decision-making: theory and practice.
AB  - Nurses have to make important clinical decisions in their everyday practice. This
      article provides an introduction to the theory of clinical decision-making,
      describes the type of decisions that nurses make and outlines the different
      approaches that can be used to make a decision.

PMID- 15176113
TI  - [Micro RNA--members of non-coding RNA family].

PMID- 15176114
TI  - [Proteins that recognize DNA strand breaks and their role in cellular stress
      response].

PMID- 15176116
TI  - [Role of mitochondria in cell damage].

PMID- 15176115
TI  - [Poly(ADP-ribose) polymerase and its function in DNA repair].

PMID- 15176117
TI  - [Structure and function in PDZ domains].

PMID- 15176118
TI  - [Short-chain monocarboxylic acids transport through plasma membrane].

PMID- 15176119
TI  - [Bacterial systems of sugar transport].

PMID- 15176120
TI  - [Therapeutic applications of dendrimers].

PMID- 15176121
TI  - [Plant receptor histidine kinases and multistep phosphate relay to response
      regulators].

PMID- 15176122
TI  - [Report from the 39th Conference of the Polish Biochemical Association, Gdansk 16
      20 September 2003].

PMID- 15176123
TI  - [Report on the FEBS Course--recombinant DNA technology and protein expression].

PMID- 15176124
TI  - Advantageous and disadvantageous impacts of tourism development on the living of
      Li ethnic minority villagers in Hainan Island, China.
AB  - Around the Mt. Wuzhishan in Hainan Island, China, tourism development has been
      rapidly progressed by the government and private companies since the 1980s,
      especially since the late 1990s, and consequently the living conditions of the Li
      ethnic minority people in Shuiman village, located in its center, have been
      drastically changing. As expected by the government, the villagers' income has
      increased by means of wage labors, selling the local products to the tourists,
      and compensatory payments for crops grown in the customary land when its use
      right was transferred to the company. Various changes in their lifestyle have
      contributed to the release from poverty and the overall improvement in basic
      human needs and primary health care. The villagers' flexible decision-makings on
      their living and environment use, with application of their traditional knowledge
      for resource uses, have been effective for sustainable human-environment
      relations, though further changes due to orders and requests of the government
      and companies may lead to environmental deterioration. Furthermore, inter
      household differentiation in income and the perception on tourism development and
      agricultural development has been enlarged. These situations are discussed from
      the viewpoint of community-based sustainable development.

PMID- 15176125
TI  - Sweating and tympanic temperature during warm water immersion compared between
      Vietnamese and Japanese living in Hanoi.
AB  - The present study compared between Japanese and Vietnamese subjects living in
      Hanoi, the local evaporation rate by sweating and the tympanic temperature during
      legs immersion in warm water. Seven Vietnamese and seven Japanese (who had lived
      in Hanoi for 1-2 years) participated in the experiments, which were performed in
      April, 2001 in Hanoi (Vietnam). It was found that the tympanic temperature at
      which subjects started to sweat in the forearm was significantly higher in
      Vietnamese than in Japanese. In addition, the local amount of evaporation was
      significantly lower in Vietnamese subjects. We discussed the physiological reason
      for such different thermoregulatory responses in terms of different levels of set
      point in the core temperature between Vietnamese and Japanese. It was concluded
      that the Vietnamese inhabitant commenced the sweating at higher tympanic
      temperature to identical warm stimuli and had lower sweating rate and higher
      tympanic temperature during the 40 min immersion of both legs to warm water than
      the Japanese inhabiting Hanoi for 1-2 years.

PMID- 15176126
TI  - A study on the prevalence of upper extremity repetitive strain injuries among the
      handloom weavers of West Bengal.
AB  - Handloom is one of the oldest cottage industries in India, particularly in West
      Bengal, where a considerable number of rural people are engaged in weaving.
      Purposes of the present investigation were to clarify the prevalence of
      repetitive strain injuries in upper extremities among the handloom weavers and to
      identify the risk factors leading to its development. Fifty male handloom weavers
      were randomly selected from the population. A questionnaire (Kourinka et al.,
      1987) method including Borg scale assessment of pain, checklist analyses of the
      work, and time-motion studies for analyzing the repetitiveness/non-repetitiveness
      of the job were implemented. The time-motion analyses demonstrated that weaving
      occupied over 50% of the work cycle time for majority of subjects, and thus could
      be regarded as a repetitive activity. Statistical analyses revealed a highly
      significant correlation between the intensity of pain feeling and the
      repetitiveness on one hand, and the year of experience as a weaver on the other.
      By contrast, no significant relationship was observed between chronological ages
      of weavers and the pain intensity. These results suggested that highly repetitive
      works engaged for a long time could increase the intensity of the pain felt and
      would lead to repetitive strain injuries.

PMID- 15176127
TI  - Inter-generation differences in foot morphology: aging or secular change?
AB  - Inter-generation differences in foot dimensions were examined using ANCOVA to
      determine whether aging or secular change is the more important causal factor. In
      examining the results, bone size was assumed not to change after the end of
      linear growth, while foot arches were assumed to become flatter rather than
      higher if there were any changes in skeletal structure. Changes in overall body
      build according to age were examined using statistical data collected by the
      government through population-follow-up. Secular changes in foot length (FL) and
      foot breadth, diagonal (FB) as well as the changes with age in FB were examined
      using data measured at ages younger than 50 years. The effects of overall body
      build were examined using the body mass index (BMI). Compared to the 1970 group
      (birth year: 1960-78) of the same FL, the 1930 group (birth year: 1909-39) had
      larger foot circumferences, wider breadth measurements, higher dorsal arches and
      ball, and greater toe 5 angle, but had shorter fibular instep lengths and shorter
      5th metatarsal bones. The 1930 groups tended to have larger FB than the 1970
      group of the same foot circumference. No inter-generation differences were
      observed in the heights at the medial and lateral malleoli, toe 1 angle, or the
      relationship between FB and heel breadth. These findings are discussed in terms
      of the effects of weight increase after the end of linear growth, changes in
      skeletal structure, overall body build as young adults, socioeconomic status
      during the growth period, as well as differential growth rates of foot bones. The
      conclusions are 1) changes in foot length and longitudinal arches due to aging
      are negligible, 2) the large circumferences, breadths, and higher dorsal arches
      and ball of the 1930 group for their foot length are better explained by their
      robust bones than by the increase in soft tissue after the end of linear growth,
      and 3) the larger FB of the 1930 group for their foot circumference is partly
      explained by their shorter fibular instep length. As a whole, factors affecting
      growth (secular change) are more important than changes after the end of growth
      (aging) in the inter-generation differences in foot morphology.

PMID- 15176128
TI  - Effects of complex aural stimuli on mental performance.
AB  - The objective of this study is to investigate the effect of complex aural stimuli
      on mental performance. A series of experiments were designed to obtain data for
      two different analyses. The first analysis is a "Stimulus" versus "No-stimulus"
      comparison for each of the four dependent variables, i.e. quantitative ability,
      reasoning ability, spatial ability and memory of an individual, by comparing the
      control treatment with the rest of the treatments. The second set of analysis is
      a multi-variant analysis of variance for component level main effects and
      interactions. The two component factors are tempo of the complex aural stimuli
      and sound volume level, each administered at three discrete levels for all four
      dependent variables. Ten experiments were conducted on eleven subjects. It was
      found that complex aural stimuli influence the quantitative and spatial aspect of
      the mind, while the reasoning ability was unaffected by the stimuli. Although
      memory showed a trend to be worse with the presence of complex aural stimuli, the
      effect was statistically insignificant. Variation in tempo and sound volume level
      of an aural stimulus did not significantly affect the mental performance of an
      individual. The results of these experiments can be effectively used in designing
      work environments.

PMID- 15176129
TI  - Patients Ombudsmen--a different approach to improve quality in health services.

PMID- 15176130
TI  - Patient Ombudsmen in seven European countries: an effective way to implement
      patients' rights?

PMID- 15176131
TI  - Terminal sedation: a legal approach.

PMID- 15176132
TI  - Cross-border access to health care within the European Union: recent developments
      in law and policy.

PMID- 15176133
TI  - European Court of Human Rights. ECHR 2003/7 Case of McGlinchey and others v. The
      United Kingdom, 29 April 2003, no.50390/99 (Second Section).

PMID- 15176134
TI  - European Court of Justice. CJEC 2003/4, Case C-192/01, Comission/Denmark.

PMID- 15176135
TI  - Lights! Camera! Action.

PMID- 15176136
TI  - Registered nurses and substance misuse or abuse: RNABC's role.

PMID- 15176137
TI  - Continence promotion and management.

PMID- 15176138
TI  - Milestone study seeks long-term solution to Canada's nursing crisis.

PMID- 15176140
TI  - Achilles tendon rupture: still not fully understood.

PMID- 15176139
TI  - Venous thromboembolism registry: a route to improved patient outcomes.

PMID- 15176141
TI  - Nasal polyps.
AB  - Nasal polyps are as common as adult onset asthma and unilateral polyps require
      histological examination. Medical therapy with corticosteroids should be tried
      before surgery. The anatomy should be demonstrated with computed tomography
      before endoscopic surgery.

PMID- 15176142
TI  - New aspects of pathogenesis of juvenile angiofibroma.
AB  - For over 150 years the aetiology of juvenile angiofibroma has been addressed in
      numerous theories, but actual details remained unknown. Interesting new findings,
      reviewed here, are beginning to elucidate the aetiology of this fascinating
      tumour.

PMID- 15176143
TI  - Assessment and management of dysphagia.
AB  - Swallowing problems are common in hospital inpatients and may affect morbidity
      and mortality. Accurate assessment of dysphagia is important, allowing optimal
      management and minimizing potential complications. This article considers the
      methods of swallow assessment available and ways in which problems can be
      addressed.

PMID- 15176144
TI  - Discitis.
AB  - Discitis is not an uncommon condition and can be potentially life threatening if
      diagnosed late. This article reviews recent publications and discusses the
      clinical presentation, pathoaetiology, diagnosis, treatment and pitfalls.

PMID- 15176145
TI  - Intensive insulin therapy in type 1 and type 2 diabetes.
AB  - Intensive insulin regimens can produce substantial clinical benefits for patients
      with type 1 and type 2 diabetes, but they are associated with an increased
      incidence of hypoglycaemia. This article discusses such regimens and whether the
      risk of hypoglycaemia can be reduced by using the new basal insulin analogue,
      insulin glargine.

PMID- 15176146
TI  - Hirsutism: diagnosis and management.
AB  - Hirsutism can be a source of great distress and social embarrassment and in some
      cases can indicate underlying endocrine or malignant disease. More is known about
      the metabolic consequences of hyperandrogenism including risk of developing
      cardiovascular disease, insulin resistance or diabetes. Full assessment is vital
      in light of the potential health consequences of hirsutism.

PMID- 15176147
TI  - An evaluation by doctors in training of a pilot programme of physician
      assistants.
AB  - New grades of health-care workers have been introduced to support trainee doctors
      and facilitate the implementation of the New Deal and the European Working Time
      Directive. This study surveyed the views of junior doctors regarding their
      experience of one such new post, called a physician assistant, and found trainees
      generally positive, welcoming this innovation.

PMID- 15176148
TI  - Emergency management of collapsed infants.

PMID- 15176149
TI  - Neurogenic T waves after subdural haematoma.

PMID- 15176150
TI  - Bilateral simultaneous spontaneous rupture of the Achilles tendon.

PMID- 15176152
TI  - Pain management: re-education is needed.

PMID- 15176151
TI  - Bilateral concurrent rupture of the Achilles tendon in the absence of risk
      factors.

PMID- 15176153
TI  - Aggression and violence in the NHS.

PMID- 15176154
TI  - Situation critical? Nosocomial infections and antibiotic resistance on intensive
      care.

PMID- 15176155
TI  - The saga of insecticide exposure with an increased risk of melanoma.

PMID- 15176156
TI  - Modification of Burow's triangle.

PMID- 15176157
TI  - New insights into imiquimod's mechanisms of action.
AB  - Imiquimod, an immune response modifier with potent antiviral and antitumor
      properties, has been reported to be effective in the treatment of various
      cutaneous neoplasms. Besides stimulating the production of pro-inflammatory
      cytokines through Toll-like receptors on the surface of dendritic cells of
      monocyte-macrophage lineage, novel antiapoptotic mechanisms have been identified.

PMID- 15176158
TI  - Rosacea: where are we now?
AB  - Advances continue to be made in the classification and treatment of rosacea, a
      chronic dermatologic syndrome. A new empiric classification system identifies 4
      rosacea subtypes (erythematotelangiectatic, papulopustular, phymatous, and
      ocular) that may aid in more precise diagnosis. Several new therapies have
      recently been approved for treatment of rosacea. Azelaic acid 15% gel is a new
      first-tier topical agent proven effective in reducing inflammatory lesions and
      erythema. New formulations of metronidazole and sulfacetamide 10%/sulfur 5% that
      offer cosmetic or tolerability advantages are now available. Intense pulsed light
      therapy has demonstrated effectiveness in reducing flushing, erythema, and
      telangiectases, with greater tolerability than existing laser systems. Other
      treatments under investigation include low-dose doxycycline hyclate (which may
      provide greater safety than existing oral antibiotics), benzoyl
      peroxide/clindamycin gel, and tacrolimus ointment (for steroid-induced rosacea).
      With this expanded armamentarium of medical and light-based therapies, clinicians
      can now implement a multifaceted approach to treatment, crafting new treatment
      combinations to address the unique and evolving features of rosacea in each
      individual patient.

PMID- 15176159
TI  - Intralesional immunotherapy for warts using a combination of skin test antigens:
      a safe and effective therapy.
AB  - Warts are a common dermatologic problem. There are many treatments available.
      Intralesional injection of a skin test antigen has been shown to be efficacious
      at eradicating all warts when only a part of one wart is injected. The aim of
      this study was to determine whether injection of the combination of Candida
      albicans, mumps, and Trichophyton skin test antigens was more efficacious than
      and as safe as single antigen injection. Seventy-one percent of subjects had
      resolution of their warts with the injection of the combination of skin test
      antigens in this open label single arm study.

PMID- 15176160
TI  - Long-term fat preservation.
AB  - The injection of autologous free fat obtained by suction-assisted lipectomy for
      the correction of soft tissue defects is a common procedure in plastic surgery.
      However, unpredictable partial absorption of the injected fat often necessitates
      repeated harvesting and injection. Fat preservation for future re-injection is
      indicated to avoid repeated fat harvesting procedures. A previous study has shown
      that fat obtained by suction can be preserved by freezing for at least 2 weeks.
      The purpose of the present study was to investigate the effect of freezing
      autologous free fat for 7 months on the take of the fat graft. Human fat obtained
      by suction-assisted lipectomy was centrifuged and stored in a domestic
      refrigerator at -18 degrees C for 7 months. After thawing, the fat was injected
      into the scalp of 10 nude mice, which served as the study group. In the control
      group (n = 10), fresh fat was injected. Fifteen weeks later, the fat grafts were
      dissected out. Volumes, weights, and histological parameters were compared
      between the groups. The injected fat survived in both the study and the control
      groups but the histological parameters were significantly inferior in the frozen
      fat. The weight of the frozen fat was also significantly less compared with the
      fresh fat. The volume of the frozen fat was inferior but not significantly. Based
      on this in vivo experiment, it is suggested to refrain from using fat that has
      been frozen for 7 months or longer. The longest period and the optimal conditions
      for fat preservation should be further investigated.

PMID- 15176161
TI  - Etanercept for the treatment of psoriasis: combination therapy with other
      modalities.
AB  - Etanercept is a self-administered medication that has FDA approval for the
      treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic
      arthritis, and ankylosing spondylitis. Etanercept is a human fusion protein of
      the tumor necrosis factor receptor (TNFR) and the Fc region of IgG1 that binds to
      and presumably inhibits the pro-inflammatory and pro-proliferative activity of
      the tumor necrosis factor (TNF). A recent multisite, randomized, double-blind,
      placebo-controlled study conclusively demonstrates that etanercept as monotherapy
      effectively treats patients with moderate-to-severe plaque psoriasis. This effect
      is dose-responsive, with the etanercept 50 mg twice-weekly dose significantly
      more effective than the 25 mg twice-weekly dose in reducing the Psoriasis Area
      and Severity Index (PASI) score over both 12 and 24 weeks of continuous therapy.
      Nevertheless, clinical trials do not instruct the dermatologist on how to
      practically integrate etanercept into a patient's pre-existing treatment regimen.
      Many psoriasis patients are already on other systemic therapies or have a medical
      history that necessitates a tailored approach to their therapy. Further, in some
      patients, etanercept at 25 mg twice weekly is ineffective in maximally clearing a
      patient of psoriasis. Below are cases that demonstrate how etanercept can be
      combined with other medications in order to both maximize clinical efficacy and
      minimize potential risk.

PMID- 15176162
TI  - Off-label uses and side effects of infliximab.
AB  - Infliximab was first approved by the FDA in 1998 as a treatment of moderately-to
      severely active Crohn's disease in patients who have an inadequate response to
      conventional therapies, and fistulizing Crohn's disease. In November 1999 the FDA
      approved it for use in rheumatoid arthritis with methotrexate, and further
      expanded this indication in December 2000. It appears to be a promising agent in
      the treatment of a variety of inflammatory diseases, psoriasis in particular. A
      MEDLINE search was performed for "infliximab" in February of 2004, and the 1,116
      articles found were reviewed. Approximately 200 articles were identified that
      contained references to the treatment with infliximab of skin disease, off-label
      uses, systemic diseases with cutaneous manifestations, and systemic and cutaneous
      side effects. These articles were reviewed and their contents summarized.
      Infliximab has been proven in well-controlled trial trials to ameliorate
      inflammatory bowel disease, rheumatoid arthritis, psoriasis, psoriatic arthritis,
      and ankylosing spondylitis. Anecdotal reports report it useful in treating the
      cutaneous manifestations and associations of inflammatory bowel disease, Behcet's
      disease, graft versus host disease, Sjogren's syndrome, refractory sarcoidosis,
      and a variety of other conditions. Its notable side effects include an increased
      risk of the induction of infections (e.g., tuberculosis). Infliximab is a very
      promising medication in the treatment of inflammatory dermatological conditions
      and should be used in larger scale trials of more diseases.

PMID- 15176163
TI  - Antiandrogen oligonucleotides: active principles in hair- and skin-derived
      culture cells.
AB  - Most drugs used for treatment of androgen-related dermatological disorders are
      not completely satisfactory in terms of clinical efficacy and potential secondary
      effects. There is, therefore, a need for a new generation of specific
      antiandrogens. This paper focuses on an oligonucleotide antisense pharmacological
      strategy. Acceptor sites were first disclosed by mapping the human Androgen
      Receptor (AR) mRNA conformation using an mRNA walking approach, oligonucleotide
      binding, and S1 protection assays. Antisense-sensitive regions were localized by
      RNAse H degradation and AR in vitro translation inhibition. Oligonucleotides were
      then designed and assessed, in primary cultures of human hair dermal papillae and
      skin derived fibroblasts, for their capability to down-regulate AR expression.
      Some of them were able to inhibit more than 60 to 80% of the AR expression. These
      could be a new class of antiandrogen oligonucleotides pharmacologically active in
      hair and skin derived cells, suitable for the treatment of dermatological
      disorders.

PMID- 15176164
TI  - The IFRA: working towards the continually-improved safety of fragrance
      ingredients and the importance of a partnership with the dermatological
      community.
AB  - The relationship between the fragrance industry and the dermatological community
      in the past has not always been perceived as one of partnership. IFRA, the
      International Fragrance Association, has started a series of initiatives to
      underline the industry's commitment to market safe products that limit any
      unavoidable risk to the minimum while at the same time enabling the consumer to
      choose from a variety of fragranced products. This article describes current
      projects and future initiatives.

PMID- 15176165
TI  - Follicular mycosis fungoides: successful treatment with oral bexarotene.
AB  - Follicular mycosis fungoides, a subtype of cutaneous T-cell lymphoma, is often
      difficult to treat. We present a case of a female with follicular mycosis
      fungoides who showed an excellent response to low-dose (150 mg/m2) oral
      bexarotene (Targretin). To our knowledge, this is the first reported case of
      follicular mycosis fungoides demonstrating a response to bexarotene.

PMID- 15176166
TI  - Serum sickness due to infliximab in a patient with psoriasis.
AB  - Infliximab is a chimeric, murine-human, monoclonal antibody against tumor
      necrosis alpha which has shown great efficacy in the treatment of psoriasis.
      Serum sickness, which is an immune complex mediated syndrome consisting of a
      cutaneous eruption, fever, arthritis, edema, and lymphadenopathy, has been
      described in several patients receiving infliximab for the treatment of Crohn's
      disease. However, to our knowledge, this type of reaction has not been well
      described in a patient treated with infliximab for psoriasis. We describe a
      patient who developed serum sickness while receiving infliximab for psoriasis and
      discuss the pathogenesis, diagnosis, and treatment of serum sickness. We believe
      that with the increasing use of infliximab for psoriasis, more cases of serum
      sickness will occur. Therefore, awareness of this adverse effect is essential.

PMID- 15176167
TI  - Solitary mastocytoma successfully treated with a moderate potency topical
      steroid.
AB  - We report a case of solitary mastocytoma in a child which was successfully
      treated with a topical steroid of moderate potency. The patient was an 18-month
      old girl who presented with localized oval shape yellowish to hyperpigmented
      lesion on the medial aspect of her right forearm noticed accidentally by the
      parents since the age of 6 months. The lesion was observed to get urticated
      mainly after bathing, toweling, and scratching of the area, associated with
      reddening and itching confined to the lesion (Figure 1). No other area of the
      body was affected with any similar lesion. Examination of the skin revealed a
      yellow-tan oval shape patch 1 x 3 cm in diameter which was firm to the touch with
      intact overlying skin. The lesion became swollen and itchy when it was rubbed
      vigorously (positive Darier's sign). Systemic examination was unremarkable. The
      patient investigations including complete blood count, routine biochemical data,
      plasma histamine level, and urinalysis were within normal levels. Skin biopsy was
      cancelled because the parents refused, so our clinical diagnosis was solitary
      mastocytoma even though it was not confirmed histologically. We started the
      patient on a moderate potency corticosteroid (betamethasone valerate 0.1% cream)
      twice a day for six weeks after which the lesion became softer with a weak
      Darier's sign. This treatment was continued for another four months which led to
      resolution of the lesion with residual hyperpigmentation, negative Darier's sign,
      and no signs of atrophy (Figure 2). Follow up of the patient for another 8 weeks
      without treatment did not reveal any recurrence of the lesion.

PMID- 15176168
TI  - Lupus erythematosus and lichen planus overlap syndrome.
AB  - A case of lupus erythematosus (LE) and lichen planus (LP) overlap syndrome in a
      71-year-old woman is presented. This disease displays characteristics of both LE
      and LP. The clinical, histologic, and immunopathologic features of this disorder
      are reviewed.

PMID- 15176169
TI  - Counter-regulatory balance: atopic dermatitis in patients undergoing infliximab
      infusion therapy.
AB  - Atopic dermatitis has been characterized as an autoimmune or auto-allergic
      phenomenon in which environmental allergens resembling human proteins activate
      auto-reactive T-cells to release pro-inflammatory cytokines of the T-helper 2
      (Th2) cytokine profile (IL-4, IL-5, IL-10, and IL-13). Infliximab is a chimeric
      IgG1 monoclonal antibody that blocks the effects of the inflammatory cytokine
      tumor necrosis factor (TNF)-alpha. Infliximab has been shown to benefit greatly
      patients suffering from diseases associated with a Th1 profile (IL-1, TNF-alpha,
      and IFN-mu), such as psoriasis, Crohn's disease and rheumatoid arthritis. Some
      researchers have suggested that disrupting the Th1-Th2 balance by downregulating
      Th1 cytokines may result in manifestations of Th2 disease. Consistent with this
      hypothesis, we present the cases of three patients who exhibited vivid
      manifestations of atopic dermatitis after the inception of infliximab induction
      therapy.

PMID- 15176170
TI  - Palmar erythema due to topiramate.
AB  - Topiramate is an anti-convulsant often used off-label for the treatment of
      several conditions, including obesity and schizophrenia. This case report
      describes palmar erythema as a side effect in a patient using topiramate for
      paranoid schizophrenia.

PMID- 15176171
TI  - Does sunscreen cause melanoma? Researchers now strongly say no.

PMID- 15176172
TI  - Health technology assessment and its influence on health-care priority setting.
AB  - In this article, we review the development of health technology assessment (HTA)
      in England and Wales, France, The Netherlands, and Sweden, and we summarize the
      reaction to these developments from a variety of different disciplinary and
      stakeholder perspectives (political science, sociology, economics, ethics, public
      health, general practice, clinical medicine, patients, and the pharmaceutical
      industry). We conclude that translating HTA into policy is a highly complex
      business and that, despite the growth of HTA over the past two decades, its
      influence on policy making, and its perceived relevance for people from a broad
      range of different perspectives, remains marginal.

PMID- 15176173
TI  - Health technology assessment in England and Wales.
AB  - In this study, we describe the current state of the Health Technology Assessment
      (HTA) system in England and Wales. This system rests on a distinction between
      assessment and appraisal and has three main strands: researcher-led HTA, the
      research and development program, and the HTA-NICE (National Institute for
      Clinical Excellence) process. We outline the pressures for HTA and how it has
      evolved in the British National Health Service. We discuss how HTA priorities are
      chosen, how HTA information is collected and assessed, how HTA evidence is used,
      and we make some observations about its impact. In our discussion, we consider
      some limitations of the HTA system, its possible divergence from evidence-based
      health care, its centralization, and some of the key challenges for managing HTA
      driven policy. But we remain hopeful that HTA can contribute to better and more
      explicit decision-making within England and Wales.

PMID- 15176174
TI  - Overview of health technology assessment in France.
AB  - Health technology assessment (HTA) in France covers a variety of activities
      performed for different customers (e.g., health professionals in the field and
      policy makers in government) for the benefit of patients. To promote the
      improvement of quality in health care, France has set up a series of distinct
      agencies that report to the Ministry of Health but are also accountable to their
      other customers. We place particular emphasis on ANAES (National Agency for
      Accreditation and Evaluation in Health) whose main remit is HTA. We show how the
      diversity of HTA activities and their decentralization suggests tight
      collaboration among all the different bodies which perform HTA or are closely
      involved with HTA, and we provide examples of such collaboration.

PMID- 15176175
TI  - Technology assessment, priority setting, and appropriate care in Dutch health
      care.
AB  - This article provides a critical analysis of the impact of health technology
      assessment (HTA) on priority setting in The Netherlands. It describes the limited
      steering powers of the Dutch government; its complex interactions with insurers,
      health-care providers, and patients; and the role of HTA in this context as an
      attempt to rationalize the debate about cost-effectiveness issues. HTA has been
      drawn upon for decision making on the health insurance package. Also, HTA
      findings have been linked to the national guideline development programs of the
      medical community. However, these impacts by no means have been straightforward.
      We argue that the political nature of the priority-setting debate asks for a
      broader approach to what constitutes HTA, and how it should be drawn upon in
      priority setting. Suggestions are made on how to do justice to the social
      dynamics of decision making and the behavior of stakeholders in health-care
      systems.

PMID- 15176176
TI  - Health technology assessment and priority setting for health policy in Sweden.
AB  - This article describes the development of health technology assessment (HTA) in
      Sweden, its influence on decision making, and its link with priority setting.
      Sweden has a well established governmental HTA body, the Swedish Council on
      Technology Assessment in Health Care (SBU), and an increasing number of
      regional/local HTA organizations. HTA has had an impact on clinical practice and
      is used to some extent in policy decisions. Several initiatives have now been
      taken to develop processes for open priority setting of health-care services.
      With the establishment of a new agency to undertake reimbursement decisions on
      pharmaceuticals, and greater patient and public involvement in decision making,
      it seems inevitable that HTA will play a more important role in priority setting
      in the near future.

PMID- 15176177
TI  - Health technology assessment in four countries: response from political science.
AB  - Four studies, each on health technology assessment (HTA) in a different country,
      are presented in this volume. Conveying differing levels of sensitivity to
      political aspects of HTA, their storylines are similar in terms of the importance
      of the institutional structures that produce HTA and mediate its influence on
      health policy decision making. Regarding the internal politics of HTA, the latter
      appears to have developed in a relatively depoliticized environment, supported by
      a dense and varied web of institutional sites for funding, production, and
      consumption of HTA, buffered from the capricious impacts of electoral politics.
      Regarding external politics, HTA in all the countries began with relatively
      politically innocuous studies of technologies recognized to be of major import to
      national health systems or researcher-initiated studies. However, with increased
      focus in health systems on explicit determination of health benefits baskets, the
      role of HTA has become more high profile. This means that political
      accountability for the entire HTA process will increase. The implication is that
      future management of HTA programs will require self-conscious attention to the
      building of institutions capable of handling the delicate process of integrating
      science and politics in health policy.

PMID- 15176178
TI  - Health technology assessment: a sociological commentary on reflexive innovation.
AB  - This study provides a sociological commentary on the current debates within
      health technology assessment (HTA), specifically in response to the approaches
      taken in France, The Netherlands, Sweden, and the United Kingdom. It argues that
      HTA is part of a wider reflexive innovation system that seeks to order current
      and prospective technologies. The study discusses the socio-political process of
      HTA priority setting, the rhetorical role of HTA, the localised and contingent
      use of HTA, and the policy gap between guidelines and practice. It argues for the
      development of new types of methodologies for assessment and for a stronger
      social embedding of HTA practice.

PMID- 15176179
TI  - Health technology assessment and policy from the economic perspective.
AB  - This article comments on the four country papers in this volume from an economic
      perspective. Different phases of the decision-making process, which can be
      supported by Health Technology Assessment (HTA), are considered. For each of
      these, there is large cross-country variation in the way in which HTA influences
      policy. Furthermore, economic themes regarding the relevance of HTA evidence for
      policy making, the position of cost-effectiveness in relation to other criteria
      vis-a-vis reimbursement decisions, the use of a cost per quality-adjusted life
      year threshold, and the incorporation of economic considerations in practice
      guidelines are discussed.

PMID- 15176180
TI  - Ethical perspectives on health technology assessment.
AB  - This study analyses why ethical aspects play a minor role in health technology
      assessment (HTA) studies, even when comprehensive approaches of technology
      assessment are advocated. Technology is often regarded as a value-neutral tool.
      At the same time, bioethics is dominated by an engineering model. Ethical
      contributions to evaluation of medical technology should go beyond issues of
      application in clinical practice and focus also on the definition of problems,
      the demarcation of technical and nontechnical issues, and the morally problematic
      implications of technologies.

PMID- 15176181
TI  - Health technology assessment and public health: a commentary.
AB  - This article reviews the developments in HTA in four countries, France, The
      Netherlands, Sweden, and United Kingdom, in relation to public health. It
      emphasizes that the majority of assessments made are concerned with individual
      clinical care rather than with the optimization of health. Possible reasons for
      the neglect of public health issues are that these are inherently more complex
      than the assessment of individual procedures or drugs. They are usually
      multisectoral, politically charged, and often considered mundane and "common
      sense" and, thus, not requiring evaluation (although when evaluations are done
      they are often counterintuitive). Unless more emphasis is given to the
      development and evaluation of public health measures, it is unlikely that there
      will be any major advances in health status. Possible areas for future assessment
      should include such issues as smoking, drug and other substance misuse,
      nutrition, and health inequalities. However, it is unlikely that these major
      areas of concern will be included in the future unless the methods of choice for
      priorities of development and assessment are changed to include measures that
      improve health status rather than only clinical services.

PMID- 15176182
TI  - View of health technology assessment from the swampy lowlands of general
      practice.
AB  - This article seeks to comment on the approaches to health technology assessment
      (HTA) outlined in the four main country studies in this volume. It is written
      from the perspective of a general practitioner working in an inner city area in
      the United Kingdom and argues that, from the point of view of the clinician, HTA
      delivers considerably less than it promises. The problems center on the
      inevitability of judgment by both politicians and clinicians and the conflicting
      foundations of these judgments. Within political decision-making, the needs of
      the population inevitably outweigh the needs of the individual; within clinical
      decision making, the opposite is the case. Attempting a scientific rationality,
      HTA struggles with the impossibility of holding the balance between the two.
      These difficulties are further compounded by the implications of ever-increasing
      expectations of perfect health and the effects of multinational commercial
      pressures.

PMID- 15176183
TI  - Health-care technology assessment: a clinical perspective.
AB  - Health technology assessment needs to relate to contemporary questions which
      concern public health-care systems: how to keep people healthy, how to focus on
      the needs of those with chronic disabilities and integrate care between the
      hospital and the community, how to encourage and audit effective teamwork, and
      how to establish a consensus about what is effective and affordable. Clinicians
      have an ethical responsibility to practice efficiently and economically, for
      profligacy in the care of one patient may mean that another is treated
      inadequately. For similar reasons, clinicians need to play a full role in the
      management of services. Advice from health technology assessment is vital and
      needs to be accurate, relevant, timely, clear, and accessible. As well as being
      concerned about what works, we need also to eliminate from practice what does
      not. Regular audit and appraisal of practice against the evidence base should be
      useful in this respect. Alternative approaches to management, such as the
      provision of care as opposed to aggressive treatments, need to be evaluated, and
      health technology assessment needs to consider how services are delivered, not
      just specific treatments.

PMID- 15176184
TI  - Perspectives on health technology assessment: response from the patient's
      perspective.
AB  - Health technology assessment (HTA) involves values and judgments, but there have
      been few attempts to seek the views of members of the public or to ensure that
      they have access to the results. Patients and citizens can make an important
      contribution to HTA by determining priorities for assessment, designing and
      conducting assessments and appraisals, receiving and using the findings, and
      engaging in debates about policy priorities and rationing. Those responsible for
      HTA should make greater efforts to involve the public and ensure that the
      findings are accessible to patients for use when making treatment choices.

PMID- 15176185
TI  - Pharmaceutical industry's perspective on health technology assessment.
AB  - This article presents the pharmaceutical industry's perspective on health
      technology assessment (HTA) with specific comments on the HTA systems in England
      and Wales, France, The Netherlands, and Sweden. The comments are focused on the
      following main themes: (i) The contributions of the HTA system to overall
      efficiency in the health-care system, (ii) HTA as a cost-driver for industry,
      patients, government, and society, and (iii) The various implementation barriers
      that currently exist for a successful implementation of HTA results.

PMID- 15176186
TI  - Temporal transformation of periodic incoherent ultrashort light pulses by chirped
      fiber gratings.
AB  - The analogy between free-space propagation of optical beams and light-pulse
      reflection from linearly chirped fiber gratings is used to analyze the Lau effect
      in the temporal domain. The coherence conditions that are satisfied in the
      spatial domain for obtaining, at certain fixed locations, periodic fringes
      patterns are reformulated for guided light propagation. In this analogy, spatial
      periodic irradiance distributions are transformed in periodic sequences of light
      pulses. An optical setup is proposed to produce sharp pulse trains, with minimal
      distortion effects, that have repetition frequencies that are different from
      those associated with the input periodic optical signal. Some numerical results
      are given to illustrate this approach.

PMID- 15176187
TI  - Phase noise and phase modulation in optical coherence tomography.
AB  - The signal in optical coherence tomography is often modulated either in phase or
      by use of the Doppler modulation generated by a depth-scanning mechanism. The
      effect of each type of modulation on the signal's amplitude is evaluated. The
      advantages of each type of modulation in terms of immunity to phase noise and
      penetration depth are discussed in relation to two envelope detection schemes,
      i.e., lock-in detection and rms-to-dc conversion. Phase noise due to drifts and
      demodulation instabilities causes distortion of the signal envelope and can be
      responsible in part for the speckle appearance of the image.

PMID- 15176188
TI  - Spatiotemporal approach for real-time absolute shape measurements by use of
      projected fringes.
AB  - A spatiotemporal approach for fast absolute shape measurements is formulated. In
      principle, the Takeda method is used in combination with the reduced temporal
      phase-unwrapping scheme to calculate the absolute phase. Three different
      measurements are performed: a flat surface, steps, and a curved beam with varying
      cross sections. The performance in standard deviation is improved, and the
      success rate is approximately the same as that obtained with a strict temporal
      solution for which a four-bucket phase algorithm is used. The multichannel
      approach is also used. Then only one static image is needed. It should therefore
      be possible to measure objects in motion.

PMID- 15176189
TI  - Total internal reflection ellipsometry: principles and applications.
AB  - A concept for a measurement technique based on ellipsometry in conditions of
      total internal reflection is presented. When combined with surface plasmon
      resonance (SPR) effects, this technique becomes powerful for monitoring and
      analyzing adsorption and desorption on thin semitransparent metal films as well
      as for analyzing the semitransparent films themselves. We call this technique
      total internal reflection ellipsometry (TIRE). The theory of ellipsometry under
      total internal reflection combined with SPR is discussed for some simple cases.
      For more advanced cases and to prove the concept, simulations are performed with
      the Fresnel formalism. The use of TIRE is exemplified by applications in protein
      adsorption, corrosion monitoring, and adsorption from opaque liquids on metal
      surfaces. Simulations and experiments show greatly enhanced thin-film sensitivity
      compared with ordinary ellipsometry.

PMID- 15176190
TI  - Time-resolved multidistance near-infrared spectroscopy of the adult head:
      intracerebral and extracerebral absorption changes from moments of distribution
      of times of flight of photons.
AB  - We report on multidistance time-resolved diffuse reflectance spectroscopy of the
      head of a healthy adult after intravenous administration of a bolus of
      indocyanine green. Intracerebral and extracerebral changes in absorption are
      deduced from moments (integral, mean time of flight, and variance) of the
      distributions of times of flight of photons (DTOFs), recorded simultaneously at
      four different source-detector separations. We calculate the sensitivity factors
      converting depth-dependent changes in absorption into changes of moments of DTOFs
      by Monte Carlo simulations by using a layered model of the head. We validate our
      method by analyzing moments of DTOFs simulated for the assumed changes in
      absorption in different layers of the head model.

PMID- 15176191
TI  - Measurement of the local optical properties of turbid media by differential path
      length spectroscopy.
AB  - We report on the development of an optical-fiber-based diagnostic tool with which
      to determine the local optical properties of a turbid medium. By using a single
      fiber in contact with the medium to deliver and detect white light, we have
      optimized the probability of detection of photons scattered from small depths.
      The contribution of scattered light from greater depths to the signal is measured
      and subtracted with an additional fiber, i.e., a collection fiber, to yield a
      differential backscatter signal. Phantoms demonstrate that, when photons have
      large mean free paths compared with the fiber diameter, single scattering
      dominates the differential backscatter signal. When photons have small mean free
      paths compared with the fiber diameter, the apparent path length of the photons
      that contribute to the differential backscatter signal becomes approximately
      equal to 4/5 of the fiber diameter. This effect is nearly independent of the
      optical properties of the sample under investigation.

PMID- 15176192
TI  - Laser spectral characterization in multiphoton microscopy.
AB  - Spectral and temporal characterization is a fundamental task when a tunable
      Ti:sapphire ultrafast laser system is operated for multiphoton microscopy
      applications. In the present paper simple procedures are reported that perform
      laser-peak-emission wavelength and bandwidth measurements without the need of any
      further instrumentation but a simple and inexpensive diffraction grating, by
      taking advantage of the confocal microscope imaging capabilities.

PMID- 15176193
TI  - High-order correlations from rough-surface scattering.
AB  - It is proposed to apply an optical setup of a randomly weak rough dielectric film
      on a reflecting metal substrate for the measurement of high-order correlations
      from rough-surface scattering. The angular amplitude and intensity correlations
      are measured. Because of multiple scattering, when the input laser beam size is
      comparatively small or close to the travel pass length inside the film, C(2) and
      C(3) are measured by subtraction of the amplitude correlation from the intensity
      correlation.

PMID- 15176194
TI  - Excitation-emission fluorimeter based on linear interference filters.
AB  - We describe the design, properties, and performance of an excitation-emission
      (EE) fluorimeter that enables spectral characterization of an object
      simultaneously with respect to both its excitation and its emission properties.
      Such devices require two wavelength-selecting elements, one in the optical path
      of the excitation broadband light to obtain tunable excitation and the other to
      analyze the resulting fluorescence. Existing EE instruments are usually
      implemented with two monochromators. The key feature of our EE fluorimeter is
      that it employs lightweight and compact linear interference filters (LIFs) as the
      wavelength-selection elements. The spectral tuning of both the excitation and the
      detection LIFs is achieved by their mechanical shift relative to each other by
      use of two computer-controlled linear step motors. The performance of the LIF
      based EE fluorimeter is demonstrated with the fluorescent spectra of various dyes
      and their mixtures.

PMID- 15176195
TI  - Local near-field enhancement of random Sb-SiN films.
AB  - Local near-field enhancement of random Sb-SiN films has been studied. Specimens
      consisting of a random Sb-SiN film and an optical recording layer were prepared
      and exposed to a focused laser beam. Laser-induced ablation occurred on the
      recording layer adjacent to random Sb-SiN film much faster and at much lower
      power than on a single recording layer. These results indicate that an optical
      field can be enhanced by random Sb-SiN films. The enhanced field was subsequently
      investigated by scanning near-field optical microscopy, and the pictures revealed
      that the enhanced field was localized.

PMID- 15176196
TI  - Digital image encryption and watermarking by phase-shifting interferometry.
AB  - A method for both image encryption and watermarking by three-step phase-shifting
      interferometry is proposed. The image to be hidden is stored in three
      interferograms and then can be reconstructed by use of one random phase mask,
      several specific geometric parameters, and a certain algorithm. To further
      increase the security of the hidden image and confuse unauthorized receivers,
      images with the same or different content can be added to the interferograms, and
      these images will have no or only a small effect on the retrieval of the hidden
      image, owing to the specific property of this algorithm. All these features and
      the utility of this method for image retrieval from parts of interferograms are
      verified by computer simulations. This technique uses intensity maps as decrypted
      images for delivery, and both encryption and decryption can be conveniently
      achieved digitally. It is particularly suitable for the remote transmission of
      secret information via the Internet.

PMID- 15176197
TI  - Generation of nanosized optical beams by use of butted gratings with small
      numbers of periods.
AB  - We have devised an optical high-throughput nanosized beam-generating structure
      consisting of butted gratings with small numbers of periods. We analyzed the
      structure of these grating by the transverse resonance method. We then
      demonstrated that it is possible to achieve a beam spot of 45 nm x 60 nm (FWHM)
      with this structure for the optical heads used in ultrahigh-density recording,
      such as those used in laser-assisted magnetic recording storage.

PMID- 15176198
TI  - Wind-flow measurement over the Subaru Telescope.
AB  - Wind flows over the 8.2-m Subaru Telescope at Mauna Kea in Hawaii were analyzed
      with a correlation method. Three or four wind flows were detected from our
      measurements. Spatial and temporal resolution of the wind-flow analysis across
      the 8.2 m pupil were investigated experimentally. A three-dimensional
      spatiotemporal-frequency analysis was also applied to the wind-flow data.

PMID- 15176199
TI  - Atmospheric transmittance of an absorbing gas. 6. OPTRAN status report and
      introduction to the NESDIS/NCEP community radiative transfer model.
AB  - Since the publication of the Optical Path Transmittance (OPTRAN) algorithm [Appl.
      Opt. 34, 8396 (1995)], much of the code and implementation has been refined and
      improved. The predictor set has been expanded, an objective method to select
      optimal predictors has been established, and the two-interpolation method has
      been discarded for a single-interpolation method. The OPTRAN coefficients have
      been generated for a wide range of satellites and instruments. The most
      significant new development is the Jacobian-K-matrix version of OPTRAN, which is
      currently used for operational direct radiance assimilation in both the Global
      Data Analysis System and the ETA Data Analysis System at the National
      Oceanographic and Atmospheric Administration, National Weather Service, National
      Centers for Environmental Prediction Environmental Modeling Center. This paper
      documents these improvements and serves as a record of the current status of the
      operational OPTRAN code.

PMID- 15176200
TI  - Preliminary measurements with an automated compact differential absorption lidar
      for the profiling of water vapor.
AB  - The design and preliminary tests of an automated differential absorption lidar
      (DIAL) that profiles water vapor in the lower troposphere are presented. The
      instrument, named CODI (for compact DIAL), has been developed to be eye safe, low
      cost, weatherproof, and portable. The lidar design and its unattended operation
      are described. Nighttime intercomparisons with in situ sensors and a radiosonde
      are shown. Desired improvements to the lidar, including a more powerful laser,
      are also discussed.

PMID- 15176201
TI  - Optical influence of ship wakes.
AB  - The optical variations observed within ship wakes are largely due to the
      generation of copious amounts of air bubbles in the upper ocean, a fraction of
      which accumulate as foam at the surface, where they release scavenged
      surfactants. Field experiments were conducted to test previous theoretical
      predictions of the variations in optical properties that result from bubble
      injection in the surface ocean. Variations in remote-sensing reflectance and size
      distribution of bubbles within the ship-wake zone were determined in three
      different optical water types: the clear equatorial Pacific Ocean, moderately
      turbid coastal waters, and very turbid coastal waters, the latter two of which
      were offshore of New Jersey. Bubbles introduced by moving vessels increased the
      backscattering in all cases, which in turn enhanced the reflectance over the
      entire visible and infrared wave bands. The elevated reflectance had different
      spectral characteristics in the three locations. The color of ship wakes appears
      greener in the open ocean, whereas little change in color was observed in near
      coastal turbid waters, consistent with predictions. Colorless themselves, bubbles
      increase the reflected radiance and change the color of the ocean in a way that
      depends on the spectral backscattering and absorption of the undisturbed
      background waters. For remote observation from aircraft or satellite, the foam
      and added surfactants further enhance the reflectance to a degree dependent on
      the illumination and the viewing geometry.

PMID- 15176202
TI  - Analysis of direct solar ultraviolet irradiance measurements in the French Alps.
      Retrieval of turbidity and ozone column amount.
AB  - Direct ultraviolet spectral solar irradiance is regularly obtained by the
      difference between global and diffuse irradiances at the French Alpine station of
      Briancon; the data of years 2001 and 2002 are analyzed in this paper. Comparison
      with modeled values is used for cloud screening, and an average UV-A aerosol
      optical depth is used as an index of turbidity; it is found to be around 0.05 for
      the clear winter days and around 0.2 in summer. Langley plots are used to verify
      the instrument calibration; they confirm the expected uncertainty smaller than
      5%. The ozone total column amount is estimated with an uncertainty between -3 and
      Dobson units; comparisons with TOMS (Total Ozone Mapping Spectrometer) overpass
      values shows agreement within the expected uncertainties of both instruments.

PMID- 15176203
TI  - Two-point source interferometric grating writing.
AB  - A novel grating-writing interferometer is demonstrated. This interferometer is
      compact, stable, and tunable well over 1000 nm and does not suffer from the
      inherent path-length differences that are present in other methods. It allows for
      high-quality gratings to be inscribed by preventing light from unwanted orders
      from affecting the fringe pattern. This technique is used to introduce a novel
      method of apodization based on removing the Fresnel end reflections in a grating.
      The experimental evidence proves the concept and shows that the technique is
      potentially useful for Bragg-grating inscription.

PMID- 15176204
TI  - One-wavelength tuning method for a tunable optical filter based on a cascaded
      polarization interference filter.
AB  - A one-wavelength tuning method is proposed to solve the tuning difficulty in a
      tunable optical filter based on cascaded cells. This method ensures that the
      optical path difference variation of all of the cells for the tuning is less than
      one wavelength and lowers the relative tuning accuracy requirement. Simulations
      show that different cells have different cross talk and loss deterioration when
      they undergo an error in optical path difference between the O-ray and the E-ray.
      An optimal error ratio in each cell is obtained. Under the error ratio, the
      deterioration from the random error in every cell is further simulated.

PMID- 15176205
TI  - Multiwavelength switching of Raman fiber ring laser incorporating composite
      polarization-maintaining fiber Lyot-Sagnac filter.
AB  - A multiwavelength switching laser is demonstrated by a precise and fast tuning of
      a composite Lyot-Sagnac comb filter based on multisegment polarization
      maintaining fibers. Broadband multiwavelength output is generated by cascaded
      Raman Stokes waves between 1.12 and 1.58 microns in a fiber-ring cavity with a
      wave-division-multiplexed coupler. Theoretical and experimental analysis of
      stable multiwavelength output operation for various Raman gain fibers and the
      electro-optic switching and flexible space tuning of interleaved wavebands are
      performed.

PMID- 15176206
TI  - Programmable broadband radio-frequency transversal filter with compact fiber
      optics and digital microelectromechanical system-based optical spectral control.
AB  - To the best of our knowledge, for the first time a programmable broadband rf
      transversal filter is proposed that operates on the principle of broadband
      optical spectral control implemented with a spatial light modulator input rf
      signal time delay and weight selection over a near-continuous signal space.
      Specifically, the filter uses a chirped fiber Bragg grating in combination with a
      two-dimensional digital micromirror device to enable a programmable rf filter. As
      a first step, a two-tap rf notch filter is demonstrated with a tuning range of
      0.563-6.032 GHz with a 25-dB notch depth at test notch frequencies of 845 and 905
      MHz. The proposed filter can find applications in diverse fields such as radar,
      communications, medicine, and test and measurement.

PMID- 15176207
TI  - Beam cleanup and image restoration with a photorefractive polymeric composite.
AB  - We demonstrate, for the first time to our knowledge, the use of a photorefractive
      polymeric composite to clean a phase-distorted laser beam and reconstruct a badly
      distorted image. Advantageous qualities including relatively high figures of
      merit, ease of processability, and low cost make this class of materials
      attractive when compared with their inorganic crystalline counterparts. In
      addition, we used four-wave-mixing and holographic techniques to obtain an
      internal diffraction efficiency of approximately 31% at 54.5 V/micron and a two
      beam-coupling gain coefficient of gamma = 17 cm-1 at 54.5 V/micron under our
      experimental conditions.

PMID- 15176208
TI  - Tunability of a 946-nm Nd:YAG microchip laser by use of a double-cavity
      configuration.
AB  - We observed the tunability of a 946-nm Nd:YAG microchip laser by using a double
      cavity configuration. We shifted the lasers wavelength from 938 to 946 nm by
      changing the thickness of the air gap. In addition, differences in reflectivity
      of the output mirror yielded the tunable range of the 946-nm band, with the
      center oscillation wavelength maintained at 946.1 nm.

PMID- 15176209
TI  - Unidirectional single-frequency operation of a Nd:YVO4 ring laser with and
      without a Faraday element.
AB  - We demonstrate high-performance unidirectional and single-frequency ring-laser
      operation based on a diode-side-pumped Nd:YVO4 bounce amplifier, obtained in a
      ring system both with and without a Faraday rotating element. Ring-laser
      operation with intracavity Faraday unidirectional element produces 15-W cw output
      in a TEM00 and single-longitudinal mode with beam propagation parameter M2 < 1.1
      with 35-W diode pumping. A novel non-Faraday-based ring laser uses a polarization
      dependent output coupler and asymmetric polarization state in the birefringent
      Nd:YVO4 gain medium and is demonstrated to produce highly unidirectional (1200:1)
      single-frequency output of 14 W in a TEM00 mode with beam propagation factor M2 <
      1.2 at 30 W of diode pumping.

PMID- 15176210
TI  - K(+)-Na+ ion-exchanged waveguides in Er(3+)-Yb3+ codoped phosphate glasses using
      field-assisted annealing.
AB  - Buried channel waveguides were fabricated in Er(3+)-Yb3+ codoped phosphate
      glasses with use of the thermal two-step ion-exhange method. The K(+)-Na+ ion
      exchange process was first carried out in pure KNO3 molten bath, and then field
      assisted annealing (FAA) was used to make the buried waveguides. The fluorescence
      properties of bulk glasses and channel waveguides were characterized, and the
      waveguide properties were studied. The formation mechanism of buried waveguides
      was analyzed, and the improved gain characteristics of the waveguide amplifiers
      with use of different FAA temperatures were measured. The maximum net gain of the
      waveguide amplifiers at 1.534-microns wavelength was measured to be approximately
      3.4 +/- 0.1 dB/cm with 120-mW pump power at 975-nm wavelength.

PMID- 15176211
TI  - Reference-frequency generation by Raman-enhanced four-photon mixing.
AB  - Reference-frequency generation for optical fiber instrumentation is now
      restricted to the frequency bands in which the reference materials have well
      resolved absorption lines. We study analytically and experimentally the
      possibility of generating reference wavelengths by use of Raman-enhanced four
      photon mixing in an optical fiber. We show that it is possible to generate
      efficiently frequencies that are 10-40 nm away from the absorption bands of the
      usual reference materials: acetylene (12C2H2), hydrogen cyanide (HCN), and
      similar or derived species. As a demonstration we use an acetylene cell to
      generate reference frequencies that cover the whole C (1530-1565 nm) and some
      part of the L (1565-1625 nm) transmission bands of the optical fiber.

PMID- 15176212
TI  - Distortions of the extinction coefficient profile caused by systematic errors in
      lidar data.
AB  - The influence of lidar data systematic errors on the retrieved particulate
      extinction coefficient profile in clear atmospheres is investigated.
      Particularly, two sources of the extinction coefficient profile distortions are
      analyzed: (1) a zero-line offset remaining after subtraction of an inaccurately
      determined signal background component and (2) a far-end incomplete overlap due
      to poor adjustment of the lidar system optics. Inversion results for simulated
      lidar signals, obtained with the near- and far-end solutions, are presented that
      show advantages of the near-end solution for clear atmospheres.

PMID- 15176213
TI  - [Cancer and demographic transition].
AB  - Two phenomena, one of which relates to the area of human reproduction and the
      other to the frequency, distribution, and control of disease in a population have
      emerged in the previous century and continue intensively to develop nowadays.
      Both these phenomena are directly related to the changes which are occurring in
      the incidence and prevalence of malignant tumours, as well as to mortality from
      them and to the opportunities for cancer control. The first of these phenomena
      has been denominated as the demographic, and the second as the epidemiological
      transition. The commonly accepted definition of the demographic transition is
      currently applied to designate a sustainable change in the type of population
      reproduction, when an initial and abrupt acceleration of population growth is
      replaced by its rapid deceleration with a subsequent stabilization of a
      population and a sharp change in its age structure. Demographic transition
      develops in a brief historical space of time and has the character of a global
      process. Population ageing and disequilibrium between the younger and older
      generations are the most important consequences of the demographic transition,
      and must inevitably influence the strategy and implementation of national cancer
      control programs. As life expectancy increases, so does the certainty that people
      will become more and more prone to diseases that are more common among older age
      groups, i.e. noncommunicable diseases and cancer in particular, rather than being
      affected by epidemics of infectious diseases. This situation is known as the
      epidemiological transition and reflects spectacular shifts in the pattern and
      causes of death and morbidity that have taken place in the vast majority of
      countries over the previous century. Epidemiological transition results in
      accession by poor countries to the problems of the rich, and leads to the "double
      burden" of disease in countries whose economies are undergoing transition,
      because of the still continuing burden of endemic infectious diseases. Russia is
      entering the final stages both of the demographic and the epidemiological
      transition, a period when numerous reasons, increasing demands on the systems of
      social protection and public health are inevitable. During the years 1992 to
      2001, cancer incidence increased from 271.8 up to 313.9 per 100,000 population,
      i.e. a growth of over 16% and an annual rate of growth of 1.7%. According to the
      global estimates provided by the International Agency for Research on Cancer the
      number of new cancer cases in the year 2000 exceeded 10 million, and the number
      of deaths from cancer reached 6.2 million. The annual growth rate of global
      cancer incidence during the last 25-30 years was higher than the global
      population growth rate. Analysis of data available from population based cancer
      registries in Russia and abroad confirms the conclusion that cancer is mainly the
      fate of people belonging to the older age groups. Given the levels of exposure to
      specific carcinogens and genetic predisposition factors, the incidence of cancer
      should be considered as an exponential function of age. The unfeasibility of
      attempts to change, in the foreseeable future, the rate and trend of demographic
      transition and demographic ageing, in particular, is obvious. It would therefore
      be more feasible to envisage their probable consequences and to adapt the limited
      resources of national health and social support services to the needs of cancer
      control, which will significantly increase in the near future.

PMID- 15176214
TI  - [Terra incognita in cancer epidemiology: occupational cancer among women].

PMID- 15176215
TI  - [Why doesn't overall survival improve in patients with disseminated solid
      tumors?].

PMID- 15176216
TI  - [Role of Ki-67 antigen in tumor proliferation--its structure and functions].

PMID- 15176217
TI  - [Allelic distribution of the CYP1A1 in lung cancer patients, middle-aged tissue
      donors and in elderly people without cancer].
AB  - The genetic polymorphism of metabolizers of tobacco smoke carcinogens can
      influence individual susceptibility to lung cancer. The study was concerned with
      the Mspl-polymorphism of the CYP1A1 gene responsible for encoding aryl
      hydrocarbon hydroxylase. It also plays a role in the activation of polycyclic
      aromatic hydrocarbons (PAH). The CYP1A1 alleles and genotype distribution in 146
      lung cancer patients was compared with that in 230 healthy donors. Another
      control group consisted of 259 "cancer-resistant" subjects, i.e. tumor-free
      smokers and non-smokers aged 75 and more. The CYP1A1 allele incidence (19%) in
      patients with squamous lung cancer was significantly higher than in the control
      cohorts (11%) which is consistent with the leading role of PAH in the etiology of
      this pathology.

PMID- 15176218
TI  - [Genetic polymorphism of steroidogenic enzymes and steroid receptor level in
      tumors of the reproductive system].
AB  - The strategy of therapy and prognosis of reproductive system neoplasia generally
      depend on the steroid receptor status of tumor. The causes of formation of
      steroid receptor-free tumors are to be investigated. The genetic polymorphism of
      CYP19 (aromatase), CYP17 (17-hydroxylase; 17,20-lyase), CYP1B1 (4-estrogen
      hydroxylase) and COMT (catechol-O-methyl transferase) was studied in a total of
      254 patients with breast and endometrial cancer, with particular reference to the
      association of certain polymorphisms and receptor status of tumor. It was found
      that the lack of estrogen receptor (ER) in breast tumor was due to a deficit in
      the A3A6 allele (p(0.01), while the absence of progesterone receptors was
      associated with a lower incidence of the A1A1 and A1A2 variants (p = 0.022) of
      tetranucleotide repeats in the CYP19 gene. In the same patients, receptor
      negative tumors occurred more often (p = 0.032) than in combinations of higher
      level of 4-hydroxylase estradiol of S-allele in position 48 (Gly/Arg) of the
      CYP1B1 gene. Moreover, endometrial carcinoma patients tended to reveal (p =
      0.058) an increased ratio of A6A7-CYP19 to allele A1-containing variant. No other
      distinctions between R(+) and R(-) tumors were identified. It is suggested that
      peculiar polymorphisms of steroidogenic enzymes may moderately influence the
      genesis of R(-) neoplasms which may be associated with either the rate of
      estrogen biosynthesis or, as in the case of CYP1B1, with formation of genotoxic
      derivatives of estrogens. The latter point is to be investigated further.

PMID- 15176219
TI  - [Expression of Hsp70 and Hdj1 chaperone proteins in human tumor cells].
AB  - Heat shock proteins (Hsp), or "stress proteins", play an important role in
      maintenance of cellular homeostasis both under normal conditions and during
      cellular stress. We tested malignant female urogenital and breast tumors for
      Hsp70 and Hdj1 (Hsp40) chaperones. Immunoenzyme procedure (based on Hsp70 and ATP
      interaction) was used to assay Hsp70 levels. Hsp70 and Hdj1 expression was higher
      in malignant cells than in benign ones. We were the first to demonstrate the
      feasibility of using Hdj1 expression as a novel prognostic factor for neoplastic
      disease.

PMID- 15176220
TI  - [Chemoimmunotherapy with dacarbazine and aranose combined with interferon-alpha
      in disseminated cutaneous melanoma].
AB  - Aranoza and dacarbazine (DTIC) monotherapy and in combinations with aranoza and
      interferon-alpha (IPHN-alpha) as well as DTIC and IPHN-alpha was given to 175
      patients (89 males and 86 females, aged 23-78) with disseminated skin melanoma.
      The effectiveness of aranoza and DTIC monotherapy was practically identical.
      Total response to DTIC used in combination with IPHN-alpha increased
      insignificantly: 25.6%--in combination vs. 19.5% DTIC alone (p > 0.05). IPHN
      alpha was most effective when used with aranoza (total objective response--31.7%
      vs. aranoza alone--16%). The best results were reported in cases heretofore
      untreated with cytostatic drugs. Total response (complete or partial remission)
      was recorded in 63% vs. 4.5% (p < 0.05) of patients who had received
      chemotherapy. In cases of aranoza+ IPHN-alpha treatment, complete and partial
      remission was reported in metastasis of the skin, subcutaneous fat, peripheral,
      retroperitoneal and abdominal (mesenteric) lymph nodes and lungs. There was no
      relapse of metastasis of the liver, intestinal tract, bones, breast or ovary.

PMID- 15176221
TI  - [Results of a multicenter, phase-II clinical trial of Dicarbamin used to shield
      leukopoiesis in cancer patients with immunosuppression due to chemotherapy].

PMID- 15176222
TI  - [The hemoprotective effect of Dicarbamin in ovarian cancer patients receiving
      chemotherapy].
AB  - The effect of dicarbamin on the hemopoetic cells of the bone marrow of ovarian
      cancer patients receiving myelosuppressive combination chemotherapy
      (cyclophosphamide + carboplatin) is discussed.

PMID- 15176223
TI  - [Expression of estrogen and progesterone receptors and oncoprotein HER-2 as a
      marker for clinical course and outcome in endometrioid adenocarcinoma of the
      uterine body (immunohistologic study)].
AB  - A retrospective immunohistological assay identified estrogen (ER) (72%) and
      progesterone (PR) (71%) receptor content in tumors from 76 patients with
      endometroid cancer (ER+ PR(+)--63.2%; ER- PR(-)--22.3%; ER+ PR- 9.2%; ER- PR+ 
      5.3%). Pattern R+ involved well differentiated cells, slight invasion of the
      myometrium and infrequent spreading to the regional lymph nodes, as compared with
      cases of unidentified ER or PR. Five-year survival in patients with ER+ PR+
      tumors was 83% vs. 53% in cases without steroid hormone receptor expression (p =
      0.04). HER 2 overexpression was found in 31.6% of tumors involving a decrease in
      total survival from 73 to 54.2% (p = 0.04). No significant correlation was
      established between ER and PR, on the one hand, and HER 2 expression, on the
      other. HER 2 overexpression leveled off the prognostic value of steroid receptor
      expression to a considerable degree; relapse incidence in patients with HER 2
      overexpression in ER+ PR+ tumors rose 9-26.7% while five-year survival dropped 88
      60% (p = 0.03). A distinct correlation between ER and PR expression (r = 0.96)
      was reported by D.C. Alfred et al. and verified by the H-scor procedure (R.A. Mc
      Clelland et al.). This procedure for steroid receptor expression determination is
      as the first unsophisticated, yet informative, method.

PMID- 15176224
TI  - [Results of a phase I-II clinical trial of Emoxyl, a novel antineoplastic
      anthracycline].
AB  - Emoxyl (ruboxyl) is a product of chemical modification of daunorubicin mediated
      by a stable free radical. The drug was given to 63 patients with different
      malignancies stages I-II. Inhibition of hemopoiesis (leukopenia and
      thrombocytopenia) was identified as the dose-limiting toxicity level. Alopecia or
      cardiotoxicity were not reported. A daily single dose of 100 mg/m2, 5 days,
      repeated in cycles after 3 weeks, proved the safest and most effective. Out of 55
      cases evaluated for immediate effect, complete remission (breast cancer, small
      cell cancer of the lung, Kaposi's sarcoma)--3; partial remission (breast cancer-
      2; non-Hodgkin's lymphoma--1)--3, and stabilization--26.

PMID- 15176225
TI  - [Mechanisms of the development of anemia in stomach cancer].
AB  - Structural and metabolic statuses of erythrocytes were evaluated using cytophoto-
      and interferometry, fine-layer chromatography, scanning and transmission electron
      microscopy, electrophoresis and fluorescent probing in 48 stomach cancer
      patients. Structural and metabolic disorders were detected in mature erythrocytes
      in patients with and without anemia. Changes in the structure and metabolism of
      peripheral blood erythrocytes taking place prior to quantitative changes were
      identified. Anemia development pathways were dependent on enhanced hemolysis of
      circulating erythrocytes and influx of immature cells from the bone marrow. The
      changing statuses of the membranes and metabolism appeared to play quite a role
      in erythrons being damaged by tumor process. Dysfunctional erythrocytes of
      stomach cancer patients need to be corrected by membrane-stabilizing and 
      repairing drugs.

PMID- 15176226
TI  - [Correlation of cytologic and DNA ploidy evidence and prognosis in childhood
      Wilm's tumor].
AB  - A retrospective evaluation of the clinical features, cytological, biological
      (DNA) and histological data on 29 children with Wilms' tumor. Two prognosis
      related groups were identified: (1) good outcome (17)--all children, aged 4-15,
      had survived by end of follow-up; (2) bad outcome (12)--all children died within
      4 months--4 years. Cytological examination by fine-needle biopsy of smears was
      carried out prior to preoperative neoadjuvant therapy in all 29 patients; in
      addition, print smears from resected tumor were taken from 21. Blastemal,
      stromal, epithelial and anaplastic cells levels were estimated by the semi
      quantitative procedure (0, 1+, 2+, 3+). DNA ploidy was determined by image
      cytometry after destaining slides and re-staining them according to Feulgen. It
      was shown that favorable outcome could be expected when fine-needle biopsy of
      print smears identified DNA diploidy and marked drug-related pathomorphosis
      involving fewer blastemal cells and signs of cell dystrophy and tumor necrosis.
      When anaplastic and aneuploid cells were detected, matched by the absence of
      therapeutic pathomorphosis, outcome was poor.

PMID- 15176227
TI  - [An improved procedure for autologous gene-modified cancer vaccine preparation
      for active specific immunotherapy of disseminated solid tumors].
AB  - Resected material was used from 108 patients with disseminated skin melanoma and
      47 patients suffering metastasized renal tumors to test procedures of tumor cell
      culture preparation and to search the best parameters. Gene tag 7 transfer,
      liposome delivery and electroporation were employed to stimulate immunogenic
      tumor cells. The transfer results were evaluated by expression of beta
      galactosidase and EGFP genes whose products were detected microscopically.
      Transfer efficiency was boosted by 30% due to selecting suitable parameters of
      tumor cell modification. Maximum effectiveness was attained by individualized
      choice of the parameters. Yet, undoubtedly, the best way of cell isolation was
      mechanical fragmentation of tumor. To speed up cell production, DMEM/F12 medium
      should be recommended. It should contain cattle embryonic serum (20%),
      conditioned medium of cultured fibroblasts of human embryonic lungs (20%),
      transferin, insulin and selenium (standard dose).

PMID- 15176228
TI  - [The effect of Dicarbamin on tumor hemopoietic cell differentiation in Friend's
      erythroblastoma (histologic and electron microscopic investigation)].

PMID- 15176229
TI  - [Immunohistochemical investigation of estrogen and progesterone receptors in
      breast tumors].
AB  - Estrogen (ER) and progesterone (PR) receptor levels were assayed in 344 breast
      tumors. The following 4 patterns were identified: ER+ PR(+)--61%; ER+ PR- 24%; ER
      PR(+)--15% and ER- PR(-)--35%. While no correlation was found between
      histological pattern, on the one hand, and the ER/PR ratio and age, on the other,
      there was one between estrogen and progesterone receptor content, on the one
      hand, and age, tumor size and metastatic spread to regional lymph nodes, on the
      other (p > 0.001).

PMID- 15176230
TI  - [Perspectives of improvement of chemotherapy effectiveness in disseminated solid
      tumors].

PMID- 15176231
TI  - [Taxanes in the adjuvant and neoadjuvant therapy of breast cancer].

PMID- 15176232
TI  - [Perspectives in antineoplastic therapy of breast cancer with brain metastasis].

PMID- 15176233
TI  - [Two nosocomial outbreaks of sepsis caused by Serratia marcescens, which occurred
      in July 1999 and January 2002--Tokyo].
AB  - Two nosocomial outbreaks of sepsis caused by Serratia marcescens, which occurred
      in Tokyo were the following cases. CASE A: In July 1999, 10 inpatients admitted
      to the third floor ward of the General Hospital A, developed sudden onset of high
      fever, coagulation disorders (disseminated intravascular coagulation), and acute
      renal failure, of which 5 died. Twenty-one strains of Serratia marcescens were
      isolated from the inpatient's blood and urine, nurse fingers and environmental
      samples from floor and cooling tower. Serratia infection was strongly suspected
      as the cause of sepsis. These cases were defined as "inpatients who developed
      fever 38 degrees C or more during July 26 to 29 and from whom S. marcescens was
      isolated by blood culture". Ten isolates were detected from the blood. In order
      to investigate the background of S. marcescens isolation in the hospital and to
      compare molecular and biochemical characteristics of S. marcescens, cultures were
      attempted from samples of other inpatients and staffs and hospital environment.
      Those were classified into 9 groups by various different typings: biotyping with
      Api Rapid 20; susceptibility typing of antimicrobial agents tested; pulsed-field
      gel electrophoresis (PFGE) typing of SpeI- or Xba I-restricted chromosome. All 10
      isolates causing sepsis were found to be in the same group. CASE B: In January
      2002, 24 inpatients, admitted to Neurosurgical Hospital B, developed sudden onset
      of high fever, of which 7 died. S. marcescens was isolated from a towel,
      environmental samples and inpatients. These cases were defined as "inpatients who
      developed fever of 38.5 degrees C and S. marcescens isolated by blood culture".
      Twelve strains were isolated from the blood samples in 12 cases. In order to
      investigate the background of S. marcescens isolation in the hospital, cultures
      were attempted from other inpatient's urine and environmental samples from
      medical tape, Tshake and a towel. These isolates were classified into 3 groups by
      the previous typings; biotyping with Api Rapid 20; susceptibility typing of
      antimicrobial agents tested; and PFGE typing. All 12 isolates in 12 cases were
      found to be in the same group. These cases of 2 nosocomial outbreaks of sepsis
      were defined as "in-patient who developed high fever and S. marcescens isolated
      by blood culture". However in both cases transmission routes of Serratia
      infection remain unknown by field investigation.

PMID- 15176234
TI  - [Epidemiological study of Arbekacin-resistant, methicillin resistant
      Staphylococcus aureus in Saitama Medical School Hospital].
AB  - Arbekacin-resistant, methicillin-resistant Staphylococcus aureus was frequently
      isolated in Saitama Medical School Hospital during 1996 and 1998. The minimum
      inhibitory concentration for ABK was 8 micrograms/ml in 14 strains, 16
      micrograms/ml in 6 strains, and 32 micrograms/ml in 2 strains. The maximum
      isolation rate of these resistant strains in one month was 8%. Use of ABK in the
      hospital did not increase during the same period. The infection control team
      (ICT) of the hospital recognized the increase of resistant strains and started
      intervention for the hospital staff. The ICT instructed the staff of each ward to
      follow standard precautions for the prevention of nosocomial infections and the
      risk of ABK-resistant MRSA was explained repeatedly. Thereafter, the isolation
      rate decreased to 3%. An epidemiological study was done using 22 strains of ABK
      resistant MRSA that were isolated in this period. The strains originated from
      different patients and from 10 different wards, which were designated as wards A
      to J. Eight strains were isolated from surgical ward A, followed by the other
      wards (ward B: 3, C: 2, D: 2, E: 2, F: 1, G: 1, H: 1, I: 1, J: 1). The specimens
      from which ABK-resistant MRSA were isolated were as follows,: sputum: 4, wound:
      4, decubitus ulcer: 4, urine: 2, pus: 2, blood :1, central venous catheter: 1,
      drainage tube: 1, tracheal aspirate: 1, skin: 1, stool: 1. Several investigations
      were done using these strains. Sensitivity tests for ABK, VCM, MINO, LVFX, FOM,
      IPM were performed by the standard method of the Japan Society for Chemotherapy.
      Coagulase types were determined. Production of toxic shock syndrome toxin-1 (TSST
      1), enterotoxin, and beta-lactamase was assayed. Pulse-field gel electrophoresis
      (PFGE) using Sma I was also done and differences were compared. Seven of the 8
      strains from ward A showed the same drug sensitivity profile and biological
      phenotype. Two of the 3 strains from ward B and 2 strains from ward C were also
      identical by these methods. Six of the 8 strains from ward A were also identical
      by PFGE. These 6 isolates showed the same drug sensitivity pattern, same
      coagulase type, and same production of TSST-1 and enterotoxin. Two other strains
      from ward B, one strain from ward F, and one from ward I also showed the same
      PFGE pattern, drug sensitivity profile, and toxin profile as the 6 strains from
      ward A. Our data show that the same strains were transmitted around the hospital
      during the study period, although serious nosocomial infections due to ABK
      resistant MRSA were avoided. Thus, intervention by the ICT in each ward was
      effective. ABK-resistant MRSA should be recognized as an important hospital
      pathogen and should be surveyed consistently.

PMID- 15176235
TI  - [A nosocomial outbreak of diarrhea caused by toxin A-negative, toxin B-positive
      Clostridium difficile in a cancer center hospital].
AB  - Between February and July 2001, 15 patients were diagnosed as Clostridium
      difficile-associated diarrhea in a ward of hematological neoplasm and lung cancer
      in a cancer center hospital. Of these 15 patients, 10 had malignant lymphoma, and
      12 and 11 had exposure to antimicrobial agents and cancer chemotherapy,
      respectively, before the onset of diarrhea. Toxin A-positive, toxin B-positive
      (A+ B+) C. difficile was recovered from five patients and the remaining 10
      patients suffered from diarrhea caused by toxin A-negative, toxin B-positive (A-
      B+) strains. All of the 10A- B+ isolates represented an identical banding pattern
      by PCR ribotyping and classified into one type (two subtypes) by pulsed field gel
      electrophoresis typing, indicating that a nosocomial outbreak of diarrhea caused
      by A- B+ C. difficile occurred among the patients hospitalized on this ward.
      Detection of toxin A in stool specimens by a toxin A detection kit was performed
      on 14 patients. Although two patients who carried A+ B+ strains were positive for
      toxin A assay, toxin A detection test was negative in 12 patients including 10
      patients with A- B+ C. difficile infection. Diagnosis of C. difficile-associated
      diarrhea by combination of toxin A assay in feces and culture of C. difficile
      could successfully lead to recognition of an outbreak caused by A- B+ C.
      difficile in a cancer center hospital.

PMID- 15176236
TI  - [Laboratory evaluation of commercial immunoblot assay kit for serodiagnosis of
      Echinococcus infections using sera from patients with alveolar hydatidosis in
      Hokkaido].
AB  - Using serum specimens from patients with alveolar hydatidosis (AH) in Hokkaido,
      we assessed the usefulness of "Echinococcus Western Blot IgG" (the French
      immunoblot assay, FIA), which has recently been launched from Ldbio Diagnostics
      (Lyon, France) as new commercial immunoblot assay kit of immunodiagnosis of
      Echinococcus infections. Eighty serum specimens were used for the present study:
      64 preoperative sera and nine postoperative sera, which were taken from AH
      patients in Hokkaido, and seven sera from persons who were ELISA (enzyme-linked
      immunosorbent assay)--positive in mass screening which was conducted for checking
      on Echinococcus infections in Hokkaido since 1982. When the 64 preoperative sera
      were examined by the Western blotting method (the Hokkaido method of Western
      blotting, HWB) which had been carried out at Hokkaido Institute of Public Health
      between 1987 and 1993, it was found that 53 cases were positive and six cases
      were quasi-positive, i.e. the rate of the positive cases including quasi-positive
      cases was 92.2%. From immunostaining patterns, HWB-positive sera could be grouped
      in two types: the complete type, which showed a pattern of multiple bands
      containing the 55 and 66 kDa bands, and the incomplete type, which showed
      patterns of only few bands containing the AH-specific polysaccharide antigen
      named C antigen. Forty-three of the 53 HWB-positive sera were of the complete
      type and the residue was of the incomplete type. On the other hand, when the 64
      preoperative sera were examined by FIA, 60 sera (93.8%) were judged to be
      positive and the others as negative sera. On the basis of the interpretation of
      immunostaining patterns described in the instruction manual, 47 (78.3%) of the 60
      positive sera were regarded as pattern P3, five (8.3%) as pattern P4, and eight
      (13.3%) as pattern P5. All of the complete-type sera were regarded as P3,
      indicating high antibody titers. Contrarily, most of the incomplete-type or quasi
      positive sera resulted in other patterns such as P4 and P5, indicating low
      antibody titers. Of 5 HWB-negative sera, two were FIA-positive (which showed P3
      and P5 patterns respectively), however their immunoreactions were significantly
      low. Therefore, apart from interpretation of pathological conditions of cases
      with exceedingly low antibody titers, FIA may be able to give a serologically
      clear interpretation to HWB-quasi-positive cases, indicating that it is a highly
      sensitive and useful method for immunodiagnosis of Echinococcus infections.

PMID- 15176238
TI  - [Current status and management of progressive renal disease].

PMID- 15176237
TI  - [Primary pulmonary cryptococcosis exhibiting the radiological characteristics of
      bronchiolitis obliterans organizing pneumonia].
AB  - A 31-year-old male was admitted to Toranomon Hospital because of a cough and
      bilateral patchy infiltrates shown on the chest radiograph. He had been well
      prior to admission. Chest CT scan revealed patchy areas of air-space
      consolidation with air-bronchogram and adjacent ground-glass opacities,
      suggestive of bronchiolitis obliterans organizing pneumonia (BOOP).
      Transbronchial lung biopsy specimen confirmed the formation of epithelioid cell
      granulomas without necrosis and the coexistence of organizing pneumonia. The
      titer of serum cryptococcal antigen increased to 1:256. According to these
      findings, a diagnosis of primary pulmonary cryptococcosis was made, although
      cryptococci were neither recognized in the specimen nor cultured from the
      bronchial lavaged fluid. Chest radiograph showed spontaneous regression in a
      short period of time. However, itraconazole was administered for the prolonged
      cough, and the symptom disappeared. The titer of serum cryptococcal antigen
      decreased to 1:16 after the therapy. Pulmonary cryptococcosis should be
      considered as one of the differential diagnoses when chest CT scan shows combined
      air-space consolidation and ground-glass opacities.

PMID- 15176239
TI  - [Differential diagnosis of kidney diseases: an approach in the diagnosis of
      kidney diseases].

PMID- 15176240
TI  - [Evaluation and diagnostic methods for renal dysfunction. 2. Urinalysis].

PMID- 15176241
TI  - [Evaluation and diagnosis of renal dysfunction. 3. Kidney function tests].

PMID- 15176242
TI  - [Evaluation and diagnosis of renal dysfunction. 4. Renal biopsy].

PMID- 15176243
TI  - [Evaluation and diagnosis of renal dysfunction. 5. Database construction through
      renal disease networks].

PMID- 15176244
TI  - [Advances in the treatment of progressive renal dysfunction. 1. Rapidly
      progressive glomerular nephritis].

PMID- 15176245
TI  - [Advance in the treatment of progressive renal dysfunction. 2. Nephrotic
      syndrome].

PMID- 15176246
TI  - [Advances in the treatment of progressive renal dysfunction. 2. IgA nephropathy].

PMID- 15176248
TI  - [Advances in the treatment of progressive renal dysfunction. 5. Diabetic
      nephropathy].

PMID- 15176247
TI  - [Advances in the treatment of progressive renal dysfunction. 4. Renal dysfunction
      associated with hypertension].

PMID- 15176249
TI  - [Advances in the treatment of progressive renal dysfunction. 6.Indications for
      adrenal cortex steroids for the treatment of various renal diseases].

PMID- 15176250
TI  - [Advances in the treatment of progressive renal dysfunctions. 7.
      Immunosuppressive agents used to treat renal dysfunctions and their indication].

PMID- 15176251
TI  - [Advances in the treatment of progressive renal dysfunction. 8. Diet therapy of
      progressive renal dysfunction].

PMID- 15176252
TI  - [Current topics. 1. Molecular mechanism involved in proteinuria].

PMID- 15176253
TI  - [Current topics. 2. Regeneration medicine and the kidney].

PMID- 15176254
TI  - [Medical networking to prevent kidney failure and life-time education:
      discussion].

PMID- 15176255
TI  - [Two patients of HELLP syndrome complicated with acute renal failure].

PMID- 15176256
TI  - [Polyarthritis caused by intravesical Bacillus Calmette-Guerin (BCG)
      immunotherapy for bladder cancer].

PMID- 15176257
TI  - [Behcet disease with exacerbation in summer and late coronary stent occlusion].

PMID- 15176258
TI  - [Neurosyphilis accompanied by Charcot spine].

PMID- 15176259
TI  - [Chlamydia psittaci infection in home delivery service].

PMID- 15176260
TI  - [Increases in the incidence of diabetic nephropathy and its management].

PMID- 15176261
TI  - [Nervous system disturbances associated with allergic diseases].

PMID- 15176262
TI  - [Environmental pollution and allergy].

PMID- 15176263
TI  - [Oral hypersensitivity syndrome and latex allergy].

PMID- 15176264
TI  - [Community nursing practice: a partly clear situation].

PMID- 15176265
TI  - ["Redefining the competences of each professional". Interview by Helene
      Delmotte].

PMID- 15176266
TI  - ["Allowing the right to retreat". Interview by Helene Delmotte].

PMID- 15176267
TI  - Scare stories twist cleanliness facts.

PMID- 15176268
TI  - Plans to foil health tourists must not damage nurse-patient trust.

PMID- 15176269
TI  - Should families take care of older relatives?

PMID- 15176270
TI  - 'This is the kind of nurse I want to be'.

PMID- 15176271
TI  - An innovative bank for practice nurses.

PMID- 15176272
TI  - How I coped with ... being a patient.

PMID- 15176273
TI  - Improving awareness of the impact of psoriasis on lifestyle.
AB  - The purpose of Psoriasis Awareness Week 2004 is to improve understanding of the
      condition and its effect on people's lives. This year's message is about being
      positive. It is aimed at promoting a balanced view of living with psoriasis to
      people with the condition, health professionals, families, carers, friends, and
      employers.

PMID- 15176274
TI  - What you need to know about ... anorexia nervosa.

PMID- 15176275
TI  - The impact of rheumatoid arthritis on patients' sex lives.
AB  - Rheumatoid arthritis is a chronic systemic disease that has the potential to
      affect all aspects of patients' lives, including their sexual activities and
      relationships. This article reports on a review of the literature assessing the
      problems that patients experience and whether they are addressed by health
      professionals. The literature indicates that many patients experience problems
      and that symptoms such as fatigue and pain impact negatively on sexual function.
      Some relationships suffer as a result but most partners are sympathetic. Poor
      communication between patient and health professionals is a common problem that
      needs to be addressed.

PMID- 15176276
TI  - Improving the monitoring and assessment of fluid balance.
AB  - This article reports on a project conducted by final-year students on a
      preregistration nursing programme. The students explored the potential to improve
      practice in a clinical area relevant to the trust at which they undertook their
      clinical placements. It is seen as innovative because it encourages partnership
      working between the educational institution and the NHS, helps to prepare
      students for their forthcoming registered nurse status and provides information
      of real practical value to the trust, enabling it to change and improve an
      important aspect of care.

PMID- 15176277
TI  - Strategies for avoiding pitfalls in clinical decision-making.
AB  - This article is the first in a series of four exploring how nurses make
      decisions. It distinguishes clinical judgement from the process of decision
      making and looks at the sorts of decisions nurses make and what can go wrong.

PMID- 15176278
TI  - Improving the identification and control of hypertension.

PMID- 15176279
TI  - Effective bowel management for patients after spinal cord injury.
AB  - After loss of ability to ambulate, the loss of voluntary control of bowel
      function has been described as the second most distressing aspect of life
      following spinal cord injury (SCI) (Glickman and Kamm, 1996). It may be the most
      distressing for the newly injured person (Rogers, 1991). The significance of this
      loss and the importance of effective management are emphasised by DeLisa and
      Kirshblum (1997) who suggest that 'establishing an effective bowel programme is
      critical because incontinence may interfere with a patient's physical,
      psychological, social, recreational, and sexual function'.

PMID- 15176280
TI  - Commissioning continence services--turning policy into action.
AB  - Incontinence of urine and faeces is a major issue in health care today. The
      financial cost is enormous with the NHS purchasing an annual 80 m Pounds worth of
      absorbent products alone (Euromonitor, 1999). But the financial cost is only part
      of the equation. Incontinence also has a considerable impact on the quality of
      life of those who experience it. The nature and impact on quality of life varies
      among individuals. However, where expert services are available cure rates can
      exceed 50 per cent (Royal College of Physicians, 1995). This suggests that
      specialist continence services have a vital role to play in helping patients
      improve their incontinence or manage their continence problems more effectively.

PMID- 15176281
TI  - Addressing the needs of teenagers with continence problems.
AB  - Adolescence refers to the period of great physical and emotional change
      experienced by 11 to 19-year-olds. A recent report aims to raise the profile of
      adolescent health (British Medical Association, 2003), and it is important to
      understand the impact of continence problems at a time in life when self-image is
      so important and wetting and soiling are particularly distressing. This article
      considers the specific needs of teenagers and ways of encouraging them to seek
      treatment.

PMID- 15176282
TI  - Disposable pull-ups versus disposable nappies for children with a disability.
AB  - Most children are expected to be dry by the age of three years (Lukeman, 1997).
      However, children with physical and/or learning disabilities may have difficulty
      achieving continence and will have an ongoing need for absorbent products.
      Historically these were disposable nappies. In recent years, the disposable pull
      up style pad (Fig 1) has proved popular as an alternative design.

PMID- 15176283
TI  - Establishing a bowel dysfunction service within primary care.
AB  - Seeking professional help for the symptoms of incontinence is extremely difficult
      for many people. Even patients consulting a hospital specialist for bowel
      problems have difficulties reporting faecal incontinence as one of their symptoms
      (Johanson and Lafferty, 1996).

PMID- 15176284
TI  - The prevalence of stress urinary incontinence in women.

PMID- 15176285
TI  - An evaluation of two body-worn continence products in an NHS trust.
AB  - In October 2002 Southend Hospital NHS Trust in Essex undertook a trial of a two
      piece disposable body-worn pad system (TENA Comfort Mini Extra) and a disposable
      absorbent one-piece body-worn pull-up (TENA Pants), with a view to converting the
      whole trust to using these products. The trial was successful and it was agreed
      by the commodity advisory group that these products should be standardised across
      the hospital.

PMID- 15176286
TI  - The link between absorbent pads and pressure management products.
AB  - Very little is known about the relationship between pressure management products
      (also known as pressure-relieving devices or pressure-redistributing devices) and
      absorbent continence products. However, a new project will focus on this little
      investigated yet important area of nursing research. The project is being carried
      out as part of a new award scheme that aims to enhance nursing research capacity
      by funding nurses to carry out doctoral level research (Box 1). A strong
      association between poor mobility and continence problems has been identified
      (Sgadari et al, 1997; Jirovec and Wells, 1990; McGrother et al, 1990; Ouslander
      et al, 1987) and reduced mobility is considered to be one of the intrinsic risk
      factors for the development of pressure ulcers (RCN, 2001). However, the
      relationship between incontinence and the development of pressure ulcers is not
      fully understood.

PMID- 15176287
TI  - Contracts of employment.

PMID- 15176288
TI  - [Role of neurotrophin and neuropeptides in bronchial asthma].
AB  - Asthma represents a chronic inflammatory process of the airways. The
      neurothrophin (NGF) and neuropeptides such as substance P (SP), neurokinin A
      (NKA), and calcitonin gene-related peptide (CGRP) play important role in
      stimulation of airways inflammation in asthmatics. NGF stimulates the
      differentiation and the migration of mast cells to bronchi epithelium.
      Furthermore, NGF stimulates mast cell degranulation and mediator upregulation and
      release. It also influences activity of basophils, eosinophils, neurophils,
      macrophages and T-cells. In addition, its important role in releasing of
      hyperresponsiveness has been proved. Neuropeptides such as CGRP and SP stimulate
      migration and degranulation of eosinophils and influence on airway responsiveness
      in asthmatics. This review article discusses the neuropeptides and NGF actions
      and mechanisms in the pathogenesis of asthma.

PMID- 15176289
TI  - [Efficiency of lymphocytes adhesion to endothelial cells of distinct tissue
      origin from children with asthma].
AB  - Lymphocytes extravasation is determined by their adhesion to the endothelial
      cells. The process goes along with high degree selectivity and is limited to
      lymph nodes and lymphatic tissue. It comes to uncontrolled extravasation to the
      tissues of involved organs in diseases with allergic origin as well in
      inflammation. Most information concerning adhesive interactions comes from
      researches dealing with normal lymphocytes. However, this phenomenon plays also
      crucial role in inflammation, metastasis and other pathologies. The aim of the
      work was to search for the possible distinct efficacy of adhesive interactions
      between peripheral blood lymphocytes from children with asthma and endothelial
      cells isolated from lung, skin and intestine. Isolated peripheral blood
      leukocytes were overlayered into endothelial cell monolayer. After washing the
      unbound cells, adhering lymphocytes were collected with endothelial cells. For
      quantifying the percentage of the particular cell populations cytofluorometric
      method was applied. The results are presented as a number of adhering lymphocytes
      per one endothelial cell. It has been shown that lymphocytes from asthmatic
      children have significantly greater adhesive potential towards endothelial cell
      lines from lungs and skin as compared with adhesion to endothelium of intestine
      origin. However, their B lymphocytes subpopulation demonstrated significantly
      higher percentage of cells adhering to all endothelial cell lines tested, as
      compared with B lymphocytes from normal controls. There were not statistically
      different adhesion efficiencies of T lymphocytes and NK cells. These findings
      indicate that local, tissue specific adhesive leukocyte-endothelial interactions
      may be of some importance in pathogenesis of allergic diseases.

PMID- 15176290
TI  - [Subclasses of immunoglobulin G in children with atopic bronchial asthma].
AB  - We examined immunoglobulin G (IgG) and its subclasses IgG1-IgG4 in the group of
      asthmatic children aged from 6 to 16 (n = 50) before of specific (mite)
      immunotherapy and in control group (n = 150) The results showed isolated decrease
      of IgG2 (22%) and connected with deficiency of other subclasses (16%). After
      immunotherapy during 3 years we showed deficiency of IgG subclasses in 60%
      children with asthma. In our opinion IgG should be examined before decision about
      immunotherapy because its deficiency in spite of good results of immunotherapy
      may be conductive for recurrent respiratory tract infections. In these cases
      immunocorrection methods should be considered.

PMID- 15176291
TI  - [Exhaled nitric oxide (NO) in asthma patients with acute exacerbation].
AB  - In recent years there has been an upsurge in interest in exhaled markers of
      inflammation, and nitric oxide (NO) in particular. The aim of the study was to
      evaluate the exhaled NO in monitoring anti-inflammatory therapy in asthma
      patients with acute exacerbation. The study was conducted in the group of 12
      asthma patients, during acute asthma exacerbation treated with oral
      corticosteroids. NO was measured in exhaled air by means of chemiluminescence
      (model 280i nitric oxide analyzer, Sievers Instruments, Inc, USA. During 15 days
      of study a significant decrease in exhaled NO was observed. In our study the
      improvement of this inflammation marker correlated with clinical markers of
      disease control (the need for rescue beta 2-agonist use). The significant
      decrease in exhaled NO was started long before than increase in spirometric
      parameters. Treatment of airway inflammation in asthma with systemic and inhaled
      corticosteroids reduces levels of NO in exhaled air. Measurement of exhaled NO is
      non-invasive, safe and causes no inconvenience to the patients' method to
      monitoring of anti-inflammatory therapy.

PMID- 15176292
TI  - [Exhaled nitric oxide (NO) in patients with respiratory tract diseases].
AB  - Nitric oxide (NO) is highly active molecule playing a key role in physiological
      as well as in pathological processes in the organism. Asthmatic patients show an
      increased expression of inducible nitric oxide synthase (iNOS) in airway
      epithelial cells and an increased level of NO in exhaled air. The aim of the
      study was to evaluate the exhaled NO in different groups of allergic patients and
      healthy volunteers. The study was conducted in the group of 94 patients and
      healthy subjects. NO was measured in exhaled air by means of chemiluminescence
      (model 280 nitric oxide analyzer. Sievers Instruments, Inc, USA. Healthy,
      nonsmoking subjects had exhaled NO levels of 10-20 ppB and smoking was one of the
      factors reduces exhaled NO. Exhaled NO was elevated in asthma patients. The
      patients with stable COPD have been shown to have exhaled NO on the same level
      that healthy smoking subjects. We observed, that the study patients with
      pollinosis who did not have asthma symptoms had increased levels of exhaled NO
      during pollen season. Measurement of exhaled NO is an easy, non-invasive
      procedure that can be used to monitor the level of airway inflammation.

PMID- 15176293
TI  - [Plasma antioxidative activity in patients with pulmonary tuberculosis].
AB  - Plasma antioxidative activity was determined by spectrophotometric method by
      estimation of plasma volume resulting in inhibition of free radical reaction rate
      by 50%. The study comprised 40 patients with pulmonary tuberculosis (25 men, 15
      women) aged 19-77 years (mean 48.5). Every patient had infiltrative pulmonary
      tuberculosis diagnosed. After 1-month therapy with tuberculostatic drugs vitamins
      C and E were added in 15 patients in a daily dose of 1.0 g and 600 mg
      respectively. The control group consisted of 16 clinically healthy subjects (12
      men, 4 women) aged 28-57 years (mean 42.5). Decrease in plasma antioxidative
      activity was found in patients as compared to the controls before as well as
      after therapy with tuberculostatic drugs. However, in patients with added
      vitamins (after 1-month tuberculostatic therapy) increase in plasma antioxidant
      activity was observed.

PMID- 15176294
TI  - [Analysis of some immunological parameters in pulmonary tuberculosis].
AB  - The role of humoral response in immunity to tuberculosis (TB) is unclear, and
      clinical studies have yield inconsistent conclusions. The aim of this study was
      to evaluate number of the lymphocytes B, concentrations of immunoglobulins A, G,
      M (IgA, IgG, IgM), circulating immune complexes (KI), components C3 and C4 of
      complement, the expression of Fc and C3 receptors on monocytes isolated from
      peripheral blood. We performed evaluation in four groups: healthy volunteers (n =
      24), patients with active tuberculosis before treatment (n = 36), TB patients
      after 2-month therapy (n = 20), and patients with inactive tuberculosis (n = 28).
      We estimated lymphocytes B, KI and the FcR, C3R expression on the surface of
      monocytes by Jondal method in evaluated groups. Monocytes were isolated from
      peripheral blood by Boyum method. The C3, C4, and IgA, IgG, IgM concentrations by
      nephelometry were tested. We found that in active TB before treatment the
      lymphocytes B number was significantly lower and the IgA, IgG, KI, C3, C4
      concentrations and FcR, C3R expression were significantly higher in comparison to
      healthy controls. The levels of IgM in tested groups of patients were normal.
      After 2-month therapy the C3 concentration was significantly lower and the IgA,
      IgG, KI levels and FcR, C3R expression were significantly higher than in healthy
      group; the lymphocytes B and C4 levels were comparable with the control values.
      In an inactive TB, KI and FcR, C3R expressions remained significantly increased
      in the level the same before the antituberculosis treatment; the remains
      parameters were comparable with the values obtained from the healthy groups. The
      obtained results suggested that the immunoreactivity changes in active TB. Two
      month antituberculosis treatment recovers some of parameters tested. In inactive
      TB, the restitution of immunoreactivity is not entirely occur; the KI levels and
      the FcR and C3R expression remain increased.

PMID- 15176295
TI  - [The effect of air pollution on pulmonary function in young men from different
      regions of Poland].
AB  - The aim of study was to evaluate possible influence of air pollution on pulmonary
      function in the population of 1278 healthy non-smoking young men (18-23 years
      old) from different parts of Poland. Poland was divided into three regions
      depending on different concentration of SO2, NO2 and airborne particulate matter
      (PM10) in the air: region 1 comprised North Poland--agricultural areas with the
      lowest concentrations of pollution, region 2 comprised Central Poland--big
      agglomerations with moderate air pollution, region 3 comprised South Poland--big
      agglomerations and industrial centres with the highest pollution level. Subjects
      were divided further according to a study place (North Group--subjects from
      region 1, Central Group--subjects from region 2 and South Group--subjects from
      region 3). Spirometry and bodypletysmography were performed at rest by using of
      mobile lab PNEUMOBIL (Jaeger). The results of the study were statistically
      analysed with the use computer packet Statistica. RESULTS OF THE STUDY:
      Significant decrease of medium values of pulmonary function test (PFT) was
      observed in the non-smokers from the region of increased air pollution (South
      Group) in comparison to the non-smokers from the region of low pollution level
      (North Group).

PMID- 15176296
TI  - [Assessment of drug therapy in chronic pulmonary obstructive disease].
AB  - Several national and international groups of experts have published guidelines
      for chronic obstructive pulmonary disease (COPD) diagnosis and treatment. But
      little is known about standards of care in real clinical practices. AIM: Of this
      study was to compare diagnosis and drug therapy in local medical practices
      against classical Polish Phthisiopneumonological Society standards for COPD
      management. Data has been collected in Pneumonology Dpt. Medical University of
      Gdansk from COPD patients referred between September 2001 and May 2002. One
      hundred and five consecutive cases have been included into study group. In local
      medical practices spirometry for COPD diagnosis and staging was used in only 42%
      of cases. In stable COPD theophilline was used as a first line bronchodilatator.
      During exacerbation treatment was much closer to guidelines recommendation. Large
      majority of patients, 87% of study group, was on combined inhaled
      bronchodilatators. CONCLUSIONS: Spirometry usage in COPD care fell below
      standards recommendation. Stable COPD treatment was not satisfactory. National
      program of guidelines implementations should be created.

PMID- 15176297
TI  - [Transthoracic fine-needle lung biopsy with linear transducer and bioptic channel
      monitored ultrasonographically].
AB  - From 1999 to 2002 81 transthoracic fine-needle lung biopsies (TFNB) were
      performed with use of linear transducer (3.5 MHz) and bioptic channel, monitored
      ultrasonographically. The procedure was applied in 70 patients with peripheral
      lesions on chest X-ray or CT, which needed histopathological examination. Our
      study showed that linear transducer with bioptic channel is useful in monitoring
      needle path and material aspiration during transthoracic fine-needle biopsy.
      Application of this equipment makes the procedure safe for patients and the
      percentage of observed complications is low. Specificity and sensitivity of the
      procedure is comparable to other imaging techniques.

PMID- 15176298
TI  - [Total and specific IgE and immediate skin tests in the prognosis of atopic
      dermatitis].
AB  - The possibility of forecasting of atopic dermatitis (AD) course is limited. The
      aim of the study was to determine the prognostic usefulness of determination of
      total and specific IgE concentrations and the results of immediate skin tests in
      AD patients. The study included 480 adult patients with AD. Immediate skin tests
      with extracts of 18 aeroallergens and 10 food allergens were performed by PRICK
      method. Total IgE concentration and concentration of specific IgE (sIgE) against
      13 aeroallergens and 12 food allergens were determined by the FAST method. For
      the assessment of the degree of pathologic process intensity the occurrence was
      determined of selected AD features according to Hanifin and Rajka exerting direct
      effect on the severity of the disease, urticaria, extensive cutaneous lesions and
      remission of the disease. The results were subjected to statistical analysis. In
      patients in whom total IgE concentration was significantly increased and/or
      hypersensitivity was found to aeroallergens, coexistence of atopic diseases of
      the airways, ectodermal defect, urticaria and extensive skin lesions was more
      frequently observed. Extensive skin lesions were also more frequent in patients
      with hypersensitivity to food allergens. The studies performed demonstrated that
      the diagnostic tests discussed are useful for prognostication of AD course. The
      presence of SIgE, positive results of immediate skin tests and high total IgE
      concentration prognosticate a more severe course of the disease.

PMID- 15176299
TI  - [Early intervention of specialist in children with bronchial asthma as a result
      of Prevention Program of Allergic Diseases in children].
AB  - Nowadays allergic diseases are one of the most important challenges in medicine
      because of healthful and economical consequences. Early diagnosis and correct
      treatment of allergic diseases, especially bronchial asthma have become a very
      important problem. For this purpose, prophylactic and treatment allergic programs
      are created. In this paper authors describe results of prophylactic program for
      allergic disease in children in Lodz district in years 2000-2001. Program
      improved access to specialists and allowed early diagnosis of bronchial asthma
      and other allergic diseases in children.

PMID- 15176300
TI  - [Possibilities in the differential diagnosis of brain neoplasms using the long
      and short time sequences of proton magnetic resonance spectroscopy].
AB  - Currently to perform proton magnetic resonance spectroscopy (1H MRS) with single
      voxel spectroscopy (SVS) technique long and/or short echo time sequences are used
      in order to provide complementary information. PURPOSE: The aim of the study was
      to compare the usefulness of STEAM (time echo, TE, 20 ms) and PRESS (TE 136 ms)
      sequences in the evaluation of brain neoplasms. MATERIALS AND METHOD: 15 healthy
      volunteers and 19 patients with brain tumors were examined using 1, 5 T MR
      scanner. MRI was performed with a standard protocol for brain neoplasms. 1H MRS
      with the SVS technique was performed after magnetic resonance imaging (MRI) using
      STEAM 20 and PRESS 136 sequences (voxel size 1 to 8 cc). RESULTS: In the STEAM
      sequence besides basic metabolites visible in PRESS as N-acetylaspartate, choline
      and creatine peaks of myoinositol and glutamate were visualized. Data obtained
      with short TE sequences in conjunction with long TE data were useful and in 5
      cases necessary to identify the tumor type. These results were confirmed by
      pathology. CONCLUSIONS: The use of short TE sequences enables to visualize
      metabolites important for the diagnosis and differentiation of the tumor type.
      The combined information drawn out from both long and short TE spectra is also
      important.

PMID- 15176301
TI  - [Interleukin-6 and interleukin-12 blood levels in patients with chronic B-cell
      lymphocytic leukemia].
AB  - B-cell chronic lymphatic leukaemia (B-CLL) is characterized by proliferation and
      accumulation of small B-lymphocytes, which are monoclonal in organ. The changes
      in IL-6 and IL-12 concentrations usually occur during the course of B-CLL. IL-6
      and IL-12 seem to be positive kinetic regulators of stem cells. Therefore the
      purpose of our study was to examine the changes in concentrations of IL-6 and IL
      12 in blood plasma, culture supernatant and isolated and broken lymphocytes from
      patients with B-CLL. The study was performed in I (n = 12) and III (n = 12) stage
      of disease according to Rai's classification--20 males and 4 females (aged 45-65)
      and in 12 healthy volunteers blood donors 35-55 years old. The study was approved
      by the local ethics committee. The measurement of concentrations of IL-6 was
      performed using the IL-6 immunoenzyme set of ELISA, R&D Systems Europe (UK) in
      plasma, culture supernatant and broken leukaemic cells. The results showed a
      significant increase in IL-6 and IL-12 concentration in blood plasma, culture
      supernatant and inside of the lymphocytes at I and III stage of B-CLL with regard
      to control groups. An increase of IL-6 and IL-12 concentrations in blood plasma
      and culture supernatant may suggest higher secretions by lymphocytes these
      interleukins during the course of B-CLL. An increase of IL-12 in broken leukaemic
      cells could be characteristic for the biochemistry of malignant lymphocytes.

PMID- 15176304
TI  - [Mucoepidermoid carcinoma of the lung--case reports].
AB  - Two patients, a young woman and a young man, with mucoepidermoid carcinoma of the
      lung, who were diagnosed at the Department of Phthisiopneumonology in Zabrze
      Silesian Medical University in Katowice are described. The principal method of
      diagnostics in the presented cases were bronchofiberoscopy followed by the
      histopathological examination of the lesions. There are no cases of massive
      bleeding as the side effect of this procedures described. This type of carcinoma
      of the lung is mostly found in young patients, usually without any risk factors
      of lung cancer, what confirms the rule, that all pulmonological symptoms of
      unknown origin should be verified by bronchoscopy, because other methods of
      diagnostics, including TC of chest-like in our patient, may be false-negative.
      The method of choice in the treatment of mucoepidermoid carcinoma is surgery. One
      should avoid a through bronchoscope resection, as it may be only partial.
      Metastases, mostly found in the local lymph nodes, are rarely described.

PMID- 15176303
TI  - [Addison's diseases caused by adrenal tuberculosis--case report].
AB  - A case of adrenal tuberculosis with acute Addison's disease is described. The
      disease manifested acute as suprarenal crisis. Metastatic and autoimmunological
      (antisuprarenal antibodies were not found) etiology was excluded. Computed
      tomography demonstrated calcifications in both, enlarged adrenals. After
      antituberculosis treatment and corticosteroid therapy we observed significant
      improvement in our patient's condition.

PMID- 15176302
TI  - [Assessment of surgical treatment in patients with severe depressed left
      ventricular function].
AB  - The aim of the study was to analyze perioperative risk factors, with special
      attention to cardioprotective techniques. Additionally we compared effectiveness
      of standard risk scales (Cleveland and Canadian) and own risk scale (modified by
      inclusion Graham, Chambers, Davies classification of distal coronary arteries) in
      investigated group. The obtained data indicate that cardioprotective techniques
      have no impact on clinical results but there are some important factors which
      influence surgical treatment: age (over 75 years), ejection fraction less than
      20% and poor distal parts of coronary vessels. The regression model results were
      used to calculate predictive value of Cleveland or Canadian risk scale (measured
      area under ROC curve). Effectiveness of anticipation: mortality (Cleveland and
      Canadian), complications, ICU and hospital stay in patients with severely
      depressed left ventricular function achieved 71%, 70%, 70%, 71%, 69%,
      respectively. After including Graham, Chambers, Davies classification of distal
      coronary arteries predictive value improved 3-4% and thereby raised to 74%, 73%,
      74%, 74% and 72%.

PMID- 15176305
TI  - [Role of tumor necrosis factor-alpha in allergic inflammation and airway
      hyperresponsiveness].
AB  - TNF-alpha is a potent multifunctional cytokine that plays a central role in the
      pathogenesis of many inflammatory diseases such as asthma and allergic rhinitis.
      This proinflammatory cytokine is produced by a variety of cells in the airways
      and is released via the IgE-dependent activation of mast cells. The elevated
      levels of TNF-alpha can be detected in the airways, bronchoalveolar lavage (BAL)
      fluid and nasal lavage from asthmatic and rhinitic patients. Leucocytes and
      monocytes isolated from BAL fluid of asthmatics were shown to release more TNF
      alpha than cells from control subjects. Recent research indicates that TNF-alpha
      maybe associated with acquired airway hyperresponsiveness a pathophysiological
      hallmark of asthma. It was suggested that TNF-alpha upregulates adhesion
      molecules and is directly responsible for transendothelial migration of
      inflammatory cells a central feature underlying the inflammatory response. A
      direct chemotactic effect has also been attributed to TNF-alpha. This cytokine is
      a chemoatractant for neutrophils and monocytes, can also induce transepithelial
      migration of neutrophils through production of IL-8.

PMID- 15176306
TI  - [Role of intra cellular adhesion molecule-1 (ICAM-1) and its soluble form (sICAM)
      in chronic airway inflammation].
AB  - Mucosal inflammation is the feature of both bronchial asthma and allergic
      rhinitis with evident of tissue eosinophilia, mast cells, eosinophils and T
      lymphocytes activation. The initial phase of cell recruitment is the margination
      and adhesion of leucocytes to the endothelium, prior to their transendothelial
      migration under a directed chemotactic stimulus. This adhesion occurs through
      specific ligand-receptor couplets involving leucocyte-endothelial adhesion
      molecules. One of these cell adhesion molecules is ICAM-1, an important early
      marker of immune activation and response. Its ligand, leukocyte function
      associated antigen one (LFA-1) is expressed on neutrophils, eosinophils and T
      cells. ICAM-1 was found to be expressed on epithelial and endothelial cells in
      rhinitis patients and in bronchial biopsies obtained from asthmatics also after
      allergen challenge. Circulating forms of these adhesion molecules have been
      identified in the peripheral blood, bronchoalveolar lavage (BAL) fluid and nasal
      lavage in patients with asthma and rhinitis. Systemic and local up-regulation of
      sICAM-1 suggests a function role for this soluble form of ICAM in the allergic
      inflammation.

PMID- 15176307
TI  - [Severe acute respiratory syndrome (SARS)--new, unknown disease?].
AB  - Severe Acute Respiratory Syndrome (SARS) caused by new corona--virus SARS-Co-V
      was not identified at humans and animals up to this time. A characteristic
      feature of this disease is biphasic course. First high fever, parainfluenza
      syndrome followed by increasing respiratory distress. The main role in
      transmission is droplet way, things contaminated by excreta, blood transfusion is
      not excluded. Pathomorphological changes are: bronchial epithelial denudation,
      loss of cilia, squamous metaplasia, a giant cells infiltrate of macrophages in
      the alveoli, haemophagocytosis, atrophy white pulp of the spleen. Diagnosis is
      based on clinical picture and epidemiological data supported by positive
      serology, PCR or presence virus in cell culture. In treatment ribavirin, steroids
      and mechanical ventilation are used.

PMID- 15176308
TI  - [The value of measuring the serum level of soluble interleukin-2 receptors in
      lung cancer patients].
AB  - This article is a review of recent reports dealing with the usefulness of
      measuring serum soluble interleukin-2 receptors (sIL-2R) level to assess the
      immunological status in lung cancer patients. The main function of sIL-2R is a
      regulation of the immune response by binding IL-2 what results in blocking the
      biological functions of this cytokine. By the competition with cell surface
      interleukin-2 receptors (IL-2R), sIL-2R act as immunosuppressive factor
      inhibiting IL-2R related lymphoblast growth. It is still not clear, why elevated
      levels of sIL-2R are reported both in immunodeficiency and immunostimulation
      state. In lung cancer patients the positive correlation between values of
      concentrations of sIL-2R and more progressive course of the disease is reported.
      The level of sIL-2R may be used as valuable prognostic marker both in patients
      treated with chemotherapy and in the case of operable tumors.

PMID- 15176309
TI  - [Role of the State Sanitary Inspection in supervision over nosocomial
      infections].
AB  - Suitably conducted monitoring of nosocomial infections in Polish health care
      centers would be a proof of the quality of medical services for the Polish
      society. However, because of some organizational and financial negligence from
      previous years, the Ministry of Health services are implementing practical and
      scientific rules of the nosocomial infections monitoring, through the
      implementation of systemic solutions, recommendations and suitable procedures.
      The State Sanitary Inspection has prepared a modern amendment of the act of
      communicable diseases and infections, which will help with proper enforcement of
      reliable reports and registers conducted by professional groups and existing
      committees for nosocomial infection control. We can expect that suitably
      conducted, hospital antibiotic policy, the use of medical science in the above
      mentioned scope, reliable comparing analyses, as well as drug resistance
      monitoring will bring clearly defined effects, such as: reduction of expenditures
      on health care, as well as lessening of hospitalization duration.

PMID- 15176310
TI  - [Fluoroquinolones interactions with nonsteroidal anti-inflammatory drugs].
AB  - Fluoroquinolones and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely
      prescribed in clinical use. Many of NSAIDs are over-the-counter (OTC) drugs,
      taken without doctor's prescription. It increases risk of adverse effects.
      Neurological side effects have to be taken under consideration during concomitant
      use of fluoroquinolones and NSAIDs. This article is a review of the different
      mechanisms responsible for quinolones interactions with NSAIDs.

PMID- 15176311
TI  - [Osmotic demyelination syndrome--can we avoid it?].
AB  - Osmotic demyelination syndrome is an iatrogenic disease related to
      inappropriately rapid correction of plasma osmolar disorders. The precise
      mechanism of injury is still unknown. Focal demyelination may appear in pontine
      (central pontine myelinosis, CPM) and extrapontine locations (extrapontine
      myelinosis, EPM), determining clinical manifestations of the disease. Modern
      techniques of radiological imaging like MRI play important role in demyelination
      syndrome diagnosis. The knowledge of conditions associated with an increased risk
      of osmotic demyelination syndrome and careful management of osmotic disturbances
      according to current standards may contribute to improved prognosis in this
      disease.

PMID- 15176312
TI  - [The Matthew effect in the medical publications].

PMID- 15176313
TI  - Neurogenic inflammation of the bladder.
AB  - Current evidence suggests multiple and redundant pathways through which the
      nervous system can initiate, amplify, and perpetuate inflammation. Many of the
      processes initiated by neurogenic inflammation have the capacity to recruit the
      participation of additional sensory nerves. These observations indicate that
      effective strategies for prevention or treatment of neurogenic inflammation of
      the bladder will entail or require intervention at multiple points. It has been
      observed that pain management in the future will be based on selective
      intervention tailored to the specific processes modulating pain perception in
      individual patients. It is exciting to contemplate the same approach to
      prevention and treatment of neurogenic bladder inflammation.

PMID- 15176314
TI  - Urine-induced apoptosis in cultured bladder urothelial cells.

PMID- 15176315
TI  - Bacillus of Calmette and Guerin modulates nuclear factor kappa beta in two
      urothelial carcinoma cell lines.

PMID- 15176316
TI  - Induction of urothelial cell proliferation by fibroblast growth factor-7 in RAG1
      deficient mice.
AB  - Fibroblast growth factor-7 (FGF-7, keratinocyte growth factor, KGF) is a 163
      amino acid glycoprotein synthesized and secreted by mesenchymal cells (e.g.
      fibroblasts/fibrocytes) in epithelial organs, thereby functioning as a paracrine
      mediator of epithelial cell proliferation. In the urinary bladder, FGF-7 is
      transported from the lamina propria across the urothelial basement membrane to
      where it ultimately binds to splice variants of the FGFR2 receptor present on the
      basolateral surface of transitional epithelial cells. We administered 100
      micrograms/ml (i.p.) recombinant FGF-7 (rFGF-7) to RAG1-deficient mice (n = 3)
      for 7 days and observed a striking expansion of the urinary bladder urothelium.
      This expansion was characterized by a layer of stratified urothelium > 20 cells
      thick and by positive immunostaining for the proliferation marker Ki-67. In
      contrast, RAG1-deficient mice (n = 3) that received only buffer injection did not
      exhibit detectable urothelial expansion. rFGF-7 was detected by immunoblot
      analyses in the serum, but not in the urine, from RAG1-deficient mice that
      received the recombinant protein. Mice that have a targeted disruption in the
      gene encoding the V(D)J recombination activation gene RAG1 have small lymphoid
      organs with no mature B and T lymphocytes, due to the inability of cell
      progenitors to perform V(D)J recombination. The biological activity of FGF-7 in
      RAG-1 mice indicates that immuno-dependent mechanisms are not required for the
      induction of urothelial cell proliferation by this epithelial cell-specific
      growth factor.

PMID- 15176317
TI  - Development of a recombinant FimCH vaccine for urinary tract infections.

PMID- 15176318
TI  - Intravesicular pain mapping.
AB  - The lack of success with the physician-only approach to bladder pain and
      interstitial cystitis demonstrates the need for a fresh new method. Such an
      approach, in which the patient becomes an integral part of the operating team,
      verifying that the operative findings are the source of the pain and that
      treatment of these areas will lead to the resolution of the pain, needs to be
      examined further.

PMID- 15176319
TI  - A hypothesis for the etiology of interstitial cystitis.

PMID- 15176320
TI  - Pentosanpolysulfate (Elmiron) is a potent inhibitor of mast cell histamine
      secretion.

PMID- 15176321
TI  - The efficacy of intravesicular sterile sodium chondroitin sulfate 0.2% in
      potassium tested positive patients with interstitial cystitis.

PMID- 15176322
TI  - Cystectomy causes immunosuppression in bladder cancer.

PMID- 15176323
TI  - The fate of urinary bladder smooth muscle after outlet obstruction--a role for
      the sarcoplasmic reticulum.

PMID- 15176324
TI  - Alteration of collagen three-dimensional architecture in noncompliant human
      urinary bladder.

PMID- 15176325
TI  - Modulation of angiogenesis: experimental strategies and potential therapeutic
      applications.

PMID- 15176326
TI  - Methods of testing urethral resistance in the female rat.
AB  - Development of an animal model of stress urinary incontinence is dependent on a
      measure of urethral resistance, such as leak point pressure (LPP). However,
      animals will not cough or perform Valsalva maneuvers upon request. The aim of
      this study was to use urodynamics to compare bladder pressures during spontaneous
      voids (SV), anesthetized LPP measurement, and induced sneezing in female rats. A
      suprapubic catheter was implanted in the bladder dome of 10 female rats. Two days
      later, the rats were tested urodynamically under urethane anesthesia. The bladder
      was emptied and filled with saline. The abdomen was then depressed manually to
      increase abdominal pressure while bladder pressure was measured. The bladder
      pressure when leakage occurred was taken as LPP. In addition, the rats were
      stimulated to sneeze by cutting off a whisker and using it to tickle the nostril.
      Both peak pressure and increase in pressure during LPP (43.4 +/- 3.6 and 33.1 +/-
      3.8 cm H2O, respectively) were significantly higher than pressures during both SV
      (30.4 +/- 3.8 and 19.3 +/- 3.4 cm H2O, respectively) and sneeze (9.5 +/- 0.7 and
      2.6 +/- 0.5 cm H2O, respectively). The time course of a sneeze (0.6 +/- 0.2 sec)
      was significantly shorter than the time course of both LPP (4.4 +/- 0.5 sec) and
      SV (6.9 +/- 1.3 sec). No rat leaked from a sneeze unless the sneeze triggered an
      SV. LPP triggered a SV in 5 rats and sneeze triggered a SV in 6 rats. With
      urodynamic measurement, it is possible to easily distinguish between LPPs, SVs,
      and sneezes. LPP can provide a quantifiable measure of decreased urethral
      resistance, whereas induced sneezes can provide a diagnostic test for severe
      incontinence.

PMID- 15176327
TI  - Virtual reality surgical simulation for lower urinary tract endourologic surgery.

PMID- 15176328
TI  - Autologous muscle transfer for reconstruction of the lower urinary tract.
AB  - The recent experimental results of using functioning muscle transfer to the
      bladder have been shown to be useful for some clinical indications. LDDM proved
      to be a viable option for the treatment of patients with an acontractile bladder
      due to traumatic or congenital lower motor neuropathy. A logical development for
      complete bladder substitution would be to combine the well-vascularized and
      contractile latissimus dorsi muscle transplant with cultivated and expanded
      autologous urothelial cells. A scaffolding, such as bioabsorbable polymer,
      alginate, or small intestinal sumucosa, may be useful to convey the in vitro
      created urothelial layer onto the muscle and to avoid osteogenesis. Experimental
      studies are necessary, however, to rule out whether these materials induce
      fibrosis, leading to stiffness of the neobladder wall, and thereby reducing
      contractile function and voiding capability of the transferred muscle.

PMID- 15176329
TI  - Effectiveness of denuding the intestinal mucosa by submucosal injection in the
      porcine model.

PMID- 15176330
TI  - Urinary diversion in the management of chronic perineal skin ulceration in spinal
      cord injured patients following sphincterotomy.
AB  - Carefully tailored urinary diversion offers an excellent alternative in the
      spinal cord injured patient with chronic urine leakage and pressure sores
      following sphincterotomy.

PMID- 15176331
TI  - The artificial urinary bladder.

PMID- 15176332
TI  - Comparison of the breaking strength of polyglactin mesh in urine, serum, and cell
      culture media.

PMID- 15176333
TI  - Growth of cultured human urothelial cells into stratified urothelial sheet
      suitable for autografts.

PMID- 15176334
TI  - Future perspectives in bladder reconstruction.

PMID- 15176335
TI  - Legal and ethical requirements for physician communication and Americans with
      Disabilities Act basics.

PMID- 15176336
TI  - The best concept for medical records in recent MEMRI.

PMID- 15176337
TI  - Getting to the top. United Physicians group proves self-management works.

PMID- 15176338
TI  - You can beat practice start-up stress ... with a little help.

PMID- 15176340
TI  - Physician candidates: three newcomers and two legislative veterans vie for
      elected office.

PMID- 15176339
TI  - MDCH team prepares for tough budget grind. Interview by Jennifer Higgins.

PMID- 15176341
TI  - FAQs about automated external defibrillators.

PMID- 15176342
TI  - Liability considerations. Re: Use of automated external defibrillators.

PMID- 15176343
TI  - SCI nurses make waves for healthy people with disabilities 2010: focus on health
      promotion and preventing secondary complications.

PMID- 15176344
TI  - The perimenopause experience for women with spinal cord injuries.
AB  - When health questions or concerns arise, nurses are often the first care
      providers contacted by women with spinal cord injuries (SCIs). This highlights
      the importance of nurses' understanding of specific health issues such as the
      perimenopause transition, along with understanding the symptoms and changes that
      women with SCI may experience throughout the conversion into menopause. Women
      aged 35 to 55 years old, with an SCI of any level or degree of completeness, no
      history of salpingo-oophorectomy or hysterectomy, and who receive care at a SCI
      model system in the mountain states, were mailed a questionnaire regarding
      symptoms associated with perimenopause, self-rated severity scores of various
      symptoms, and different options for treatment of the symptoms related to
      perimenopause. The 230 (62%) women who responded reported the following symptoms
      associated with perimenopause: menstrual cycle changes (60%), sleep disturbance
      (43%), night sweats (40%), hot flashes (39%), and decreased sex drive (38%).
      Subjective severity of these symptoms varied, but no significant differences were
      noted between women with tetraplegia and paraplegia, whether neurologically
      complete or incomplete. Perimenopause presents a unique challenge for women with
      SCI because the symptoms may mimic or mask other conditions associated with SCI,
      such as autonomic dysreflexia, infections, impaired temperature regulation, and
      spinal cord cysts. Care providers, and women with SCI, should carefully monitor
      their symptoms during perimenopause and the treatment plan should reflect a joint
      decision between the woman and her provider.

PMID- 15176345
TI  - How a woman's sexual adjustment after sustaining a spinal cord injury impacts
      sexual health interventions.
AB  - This qualitative study describes the female experience of sexual adjustment after
      spinal cord injury (SCI) in relation to the need for sexual health intervention.
      Ten women with SCI were interviewed using a predetermined, semistructured set of
      questions. Audiotaping and field notes were utilized to gather data. The
      investigators used consensus validation to complete data analysis, and all
      research findings were reviewed by the study participants for validation.
      Clinical findings indicated that there were a series of phases that women go
      through in sexual adjustment that affect when and how interventions were
      effective in meeting their sexual health needs. Women also identified the use of
      peers and support groups as essential adjuncts to professional intervention.

PMID- 15176346
TI  - Delegation decision-making by registered nurses who provide direct care for
      patients with spinal cord impairment.
AB  - Delegation and coordination of patient care are critical skills for registered
      nurses (RN). Most educational programs and clinical experiences in nursing school
      have not prepared nurses to function in a delegation decision-making capacity.
      Nurses caring for individuals with spinal cord impairment (SCI) are especially
      challenged to provide partial or total assistance to meet the requisite care
      needs of this patient population. Hospital length of stay has decreased for
      individuals with SCI. RNs employed in long-term care (LTC) facilities have found
      admissions of patients with SCI occur more frequently with the onset of managed
      care and the increased longevity of Americans. Capitated markets within managed
      care require a nursing care delivery model that safely and judiciously uses
      nursing personnel to their fullest potential. Conger's (1993) Delegation Decision
      Making Model (DDMM) utilizes all levels of personnel to their maximum potential
      while staying within the confines of individuals state nurse practice acts. The
      ability of RNs to direct the health care team is crucial to affect positive
      patient outcomes. The purpose of this descriptive comparative study was to
      ascertain baseline information on nurse delegation decision-making knowledge, job
      satisfaction, and level of comfort with this skill for RNs practicing in hospital
      and LTC settings. After reading a case study on a patient with SCI, RNs in the
      hospital and LTC facilities used Conger's (1993) DDMM. Scores for delegation
      decision-making were determined using the Nursing Assessment Decision Grid.
      Delegation knowledge scores were the same for RNs practicing in the hospital and
      LTC settings. Of interest was that RNs practicing in LTC settings cited learning
      delegation skills "on the job" 50% of the time compared to hospital nurses who
      reported learning these skills on the job 19% of the time. Additional research in
      the area of nurse delegation with this patient population needs to be
      investigated to support the findings of this study.

PMID- 15176347
TI  - The Vancouver General Hospital acute spine journal club: a success story.

PMID- 15176348
TI  - Closing the gap between practice and research.

PMID- 15176349
TI  - Breaking through the glass ceiling: women in executive leadership positions--Part
      I.
AB  - Women have had their share of difficulties climbing the corporate ladder in their
      chosen professional roles. Excellent role models exist for nurses to look up to
      as role models for leadership and executive level positions. Nurses and women
      must strive to achieve their goals of attaining executive/management level
      positions in their respective organizations. The glass ceiling still exists;
      however, women are slowly eroding that glass barrier and reaching their
      professional goals. In reviewing the struggles that men in nursing have
      encountered in a predominantly female profession, one realizes that stereotypical
      attitudes do cross gender lines. The authors conclude that executive level
      positions need to be opened more to women, just as the nursing profession must be
      more welcoming to men. The profession of nursing will only become stronger with
      gender diversity. Women encounter barriers when aspiring to executive level
      positions. In the next issue of SCI Nursing, the authors will report on what the
      evidence says about women in leadership roles, and the challenges they have and
      will continue to face.

PMID- 15176351
TI  - The legislative process: in review.

PMID- 15176350
TI  - Strategies for coping with the noncompliant adolescent spinal cord injury patient
      -Part I.

PMID- 15176352
TI  - Pregnancy for women with spinal cord injury.

PMID- 15176353
TI  - Strategies for a successful retirement.

PMID- 15176354
TI  - Disease management.

PMID- 15176355
TI  - Continued competence--a reflective practice approach.

PMID- 15176356
TI  - Nurses identify barriers to teaching patients about their medications.

PMID- 15176357
TI  - Bar codes on drugs to reduce errors.

PMID- 15176358
TI  - [On aging].

PMID- 15176359
TI  - [A philosophy of aging].
AB  - "What I pretend is to speak with lesser words about those immense words. To be
      more sincere: I would like to speak with immense words about those immense
      words"; so spoke J.A. Marina in one of his books, The Sentimental Labyrinth.
      There are few people as appropriate as he to lead us into a philosophy about old
      age. There are few occasions where wisdom and simplicity go hand in hand in a
      manner so tight and prolific as is the case with Marina's words. Let us take
      advantage of him.

PMID- 15176360
TI  - [Economic, social, and political impact of aging].
AB  - Aging is a social question, but it is also a political and economic issue of the
      utmost importance because it effects our economy and the collection of taxes in
      our societies and it questions our system of values, especially when we bear in
      mind that individualism, isolationism and people's loneliness predominate today.
      All of these factors demand forceful political measures separated from short term
      electoral slogans but having a vision for the future. This text is adapted from
      the report the author gave at the Menendez Pelayo International University.

PMID- 15176361
TI  - [Dependence in aging. Studies and research].
AB  - The study of a dependency to age has generated different research and
      investigation which have very different but necessary viewpoints, since an aging
      dependency requires a multidisciplinary collaboration and awareness. The studies
      summarized here were carried out between the years 2000 and 2004; they
      demonstrate aspects which the future law on dependency should bear in mind. At
      the present time, a panel of experts has been formed which is drawing up draft of
      that law. Another one of the topics dealt with is the heterogeneity of the norms
      applied by social services in the different autonomous communities which are the
      ones which must respond to the dependency to age, providing knowledge and
      treatment of this dependency.

PMID- 15176362
TI  - [Frail elderly].
AB  - The author analyzes diverse perspectives about old age throughout our history in
      order to define the concept of "the fragile elderly person". The author explains
      what this term means, its characteristics and some useful instruments nurse need
      be aware of in order to provide better care. The author provides us with an
      explanation about an integrated geriatrics evaluation, along with its usefulness,
      advantages and possible inconveniences.

PMID- 15176363
TI  - [Accidental falls among institutionalized elderly. Assessment of risks and
      interventions].
AB  - There is an extensive known bibliographic file which lists a multitude of risk
      factors in falls by the elderly in nursing homes; these include postural
      hypertension, walking and balance alterations, muscular weakness, cognitive and
      functional alterations, visual problems, etc. There is also a long list of
      manners to evaluate these risks and of interventions available for their
      treatment. This quantity of information inhibits the establishment of an
      effective clinical practice because it is impossible to try to identify or
      intervene in all of them. The objective of this article is to identify the most
      frequently described risk factors in the bibliographical review which the author
      carried out, to establish an effective form of identifying them and an efficient
      manner of intervention for them.

PMID- 15176364
TI  - [Universal access. A necessity of the 21st Century society].
AB  - This article deals with the current reality in our society to have universal
      accessibility, with the importance to provide information about accessibility to
      all citizens and with the necessity to legislate, project, construct and
      rehabilitate in a way that facilitates living for each individual, with or
      without a handicap; which definitely means "make life more human".

PMID- 15176365
TI  - [Humanizing options of retirement].
AB  - This article is a personal reflection by the new retired President of the Royal
      Foundation for the Handicapped. From a one hundred percent humanistic position,
      the author proposes to take advantage of his retirement in order to dig deeper
      into all those values and possibilities which, on occasions, the jarring rhythm
      of working life has made up set aside.

PMID- 15176366
TI  - [Open letter to the conscience of a society].
AB  - From a personal viewpoint, the author reflects about the changes in values which
      have come about in our society and which seriously damage the oldest, the most
      dependent and the most disfavored of its members.

PMID- 15176367
TI  - [What can we expect in the future?].

PMID- 15176368
TI  - Sponsorship of educational programmes in Nigerian medical and pharmacy schools by
      pharmaceutical companies: possible risk implication for public health.

PMID- 15176369
TI  - Gene symbol: ATP7A. Disease: Menkes disease.

PMID- 15176373
TI  - [Laparoscopic nephroureterectomy for upper urinary tract urothelial tumors].
AB  - OBJECTIVES: We present our 11 year experience with 15 laparoscopic
      nephroureterectomy procedures for upper urinary tract urothelial tumor.
      METHODS/RESULTS: The tumor site was pyelocalyceal in 9 cases, ureteral in 4, and
      multifocal in one. All cases were urothelial tumors grade II or III; stage was Ta
      T1 in 9 cases, T2 in three, T3 in two, and T4 in one. Transperitoneal approach
      was performed in 14 cases, whereas only one retroperitoneal. Hand assisted
      laparoscopy was performed in five cases. Seven specimens were extracted after
      morcellation without any recorded tumor seeding attributable to this manoeuvre.
      We recorded one case of sudden death due to pulmonary embolism 48 hours after the
      procedure, one case of intestinal obstruction secondary to an ileal loop hernia
      through the parietal orifice of one of the trocars, and one case of unstable
      angina pectoris. Two patients died because of disease progression, one of them
      after bladder recurrence. CONCLUSIONS: We think that hand assisted laparoscopy is
      a good indication for nephroureterectomy for upper urinary tract urothelial
      tumor. We propose a new procedure to avoid possible tumor cell spilling at the
      time of ureterectomy, which simplifies the operation very much at the same time.

PMID- 15176374
TI  - Monitoring the effect of PDT on in vivo oxygen saturation and microvascular
      circulation.

PMID- 15176375
TI  - [Hepatosplenic candidiasis in acute myeloid leukemia].
AB  - Chronic diseminated candidiasis--mainly its hepatosplenic form- is one of the
      most characteristic invasive infection due to Candida in haematological patients.
      A case is presented of a 31 year old man admitted to the Clinical Department with
      acute mieloid leukosis M2, showing febrile neutropenia after induction and
      consolidation chemotherapy. Hepatoesplenic candidiasis was diagnosed and
      confirmed by computered axial tomography (CAT) and hepatic biopsy; amphotericin B
      followed by liposome encapsuled amphotericin B up to complete a total dose of 4 g
      was used for treatment. The patient was discharged waiting for bone marrow
      transplantation. Early suspicion of hepatosplenic candidiasis helps to select a
      rapid diagnosis method and an effective treatment.

PMID- 15176376
TI  - "Follicular stem cell carcinoma: histologic, immunohistochemical,
      ultrastructural, and clinical characterization in 30 days".

PMID- 15176377
TI  - Nonhuman primates might be highly susceptible to cross-species infectivity by
      human alpha-herpesviruses.

PMID- 15176378
TI  - Qigong commentary.

PMID- 15176379
TI  - Gene  symbol: ATP7B. Disease: Wilson's disease.

PMID- 15176381
TI  - Gene symbol: HBMS. Disease: Porphyria, acute intermittent.

PMID- 15176382
TI  - Gene Symbol: COCH. Disease: DFNA9.

PMID- 15176383
TI  - A bad fit: the GP contract that doesn't measure up with PCTs.

PMID- 15176384
TI  - Gene Symbol: MUTYH. Disease: Autosomal recessive colorectal polyposis.

PMID- 15176385
TI  - Gene Symbol: VMD2. Disease: Best vitelliform macular dystrophy (VMD2).

PMID- 15176386
TI  - Public perception ideas. What they really really want.

PMID- 15176387
TI  - Gene Symbol: FECH. Disease: Porphyria, erythropoietic.

PMID- 15176388
TI  - Damned if they do: the HIV dilemma Labour can't dodge.

PMID- 15176389
TI  - Gene Symbol: CASR. Disease: Hyperparathyroidism.

PMID- 15176390
TI  - Public perception ideas. The vision thing.

PMID- 15176391
TI  - Gene Symbol: ars. Disease: Mal de Meleda.

PMID- 15176392
TI  - Gene Symbol: ED1. Disease: Ectodermal dysplasia, anhidrotic.

PMID- 15176393
TI  - Gene Symbol: FECH. Disease: Porphyria, erythropoietic.

PMID- 15176394
TI  - Infrared complex refractive index measurements and simulated reflection mode
      infrared absorption spectroscopy of shock-compressed polymer thin films.
AB  - Thin film interference effects complicate the interpretation of reflection-mode
      infrared absorption spectra obtained in shock-compressed thin film materials and
      must be carefully accounted for in any analysis attempting to unravel shock
      induced energy transfer or reactivity. We have calculated such effects for
      spectrally simple model systems and also, to the extent possible, for real
      systems such as polymethylmethacrylate (PMMA) and nitrocellulose (NC). We have
      utilized angle-dependent infrared (IR) reflectometry to obtain the ambient
      spectral complex index for PMMA and NC for use in the calculations and to
      interpret experiments. A number of counter-intuitive spectral effects are
      observed versus film thickness and during uniaxial shock compression: absorption
      band shifts, changes of shape, and changes in both absolute and relative peak
      intensities. The film thickness effects can be predicted by thin film
      interference alone, while additional assumptions are required to predict the
      effects due to shock compression. Since it is very difficult to obtain the
      complex index in the shock state, we made very simple assumptions regarding the
      change in vibrational spectra upon shock load-ing. We illustrate general thin
      film interference effects that could be expected and compare them to experimental
      results for the antisymmetric NO2 stretch mode of NC.

PMID- 15176395
TI  - How beneficiaries fare under the new Medicare drug bill.
AB  - The Medicare Prescription Drug Improvement and Modernization Act (MMA) provides
      the largest benefit expansion in Medicare's history while enacting major changes
      to the program's structure. Offering $410 billion in new drug benefits will
      certainly help many beneficiaries now struggling with the costs of prescriptions,
      particularly those with low incomes. It is difficult to determine, however,
      whether beneficiaries will be better off in the long run. The drug benefits will
      not grow with the needs of beneficiaries, and other changes that prove to be
      unworkable or that place some beneficiaries at risk will create added costs. In
      the meantime, favorable treatment of private plans will create new inequities.
      Additional legislation and carefully crafted regulations could mitigate a number
      of these issues; in the meantime, they will require close scrutiny.

PMID- 15176396
TI  - Operative mortality is lower in busier hospitals.

PMID- 15176397
TI  - Diabetes management program focuses on primary care practices.

PMID- 15176398
TI  - Increasing cases of drug-resistant gonorrhea prompt new CDC treatment
      recommendations for gay and bisexual men.

PMID- 15176399
TI  - GAO chief states case for health care reform.

PMID- 15176400
TI  - HIV in sub-Saharan Africa.

PMID- 15176401
TI  - New guidelines offer hope for UK patients with MS.

PMID- 15176402
TI  - Viral proteins cause cell death in HIV-associated dementia.

PMID- 15176403
TI  - Mitochondrial fusion protein mutated in CMT2A.

PMID- 15176404
TI  - Mitochondria back in the spotlight in Parkinson's disease.

PMID- 15176405
TI  - Step forwards for spinal-cord repair.

PMID- 15176407
TI  - Left temporoparietal junction performs social reasoning.

PMID- 15176406
TI  - Presenilin dysfunction leads to memory and plasticity defects.

PMID- 15176408
TI  - Mutations in ROBO3 cause HGPPS.

PMID- 15176409
TI  - Mind moves onscreen: brain-computer interface comes to trial.

PMID- 15176410
TI  - [Long-term treatment of phantom- and stump pain with Botulinum toxin type A over
      12 months. A first clinical observation].
AB  - Recently we were able to describe the successful treatment of phantom pain and
      stump pain with botulinum toxin A in a first pilot study. This case report over a
      1-year period now demonstrates that long-term treatment for this indication is
      possible. We injected 4 x 25 IU of botulinum toxin A (Botox) into trigger points
      of the stump muscles of a lower limb amputee who suffered from severe phantom and
      stump pain. With four injections performed every 3 months, the patient became
      almost completely pain-free, and his intrathecal morphine therapy could be
      reduced to 40% of the initial dose. Intrathecal clonidine was eliminated
      completely, as were the oral analgesics. A surgical treatment suggested for the
      stump pain was no longer necessary, and we suppose that botulinum toxin can also
      improve the tolerance of artificial limbs in cases of stump pain.

PMID- 15176412
TI  - Oral malodor: a review.

PMID- 15176411
TI  - [On the vestiges of Heinrich Frenkel (1860-1931)--Pioneer of neurorehabilitation.
      Annotation to the cover picture].
AB  - Heinrich Simon Frenkel or Frenkel-Heiden(1860-1931) is almost completely
      forgotten as a founder of neurorehabilitation and little is known about his life.
      Frenkel's main contribution, "The treatment of tabetic ataxia by meansof
      systematic exercise: An exposition of the principles and practice of compensatory
      movement treatment", was reprinted several times in English (1902, 1905, 1917).
      Frenkel exerted great influence among his contemporaries, including his direct
      student Otfrid Foerster (1873-1941) who became one of the most important
      neurologists and neurosurgeons of the 20th century. A floor mosaic, preserved in
      the historic building of the "Medizinische Poliklinik" in Munich, is an exact
      copy of the pattern of traces that Frenkel had published in 1900 for
      proprioceptive gait exercises in tabes dorsalis.

PMID- 15176413
TI  - Neuropathic pain: from mechanisms to treatment strategies.

PMID- 15176414
TI  - [Relation between nitric oxide, nitric oxide synthase and angiogenesis in tumor].

PMID- 15176415
TI  - [Current status of gene therapy of laryngeal cancer].

PMID- 15176418
TI  - Cellular basis and mechanism underlying normal and abnormal myocardial
      repolarization and arrhythmogenesis.
AB  - Regional differences in repolarization characteristics of distinct cell types are
      responsible for the inscription of the J wave and T wave of the electrocardiogram
      (ECG). Amplification of these electrical heterogeneities contributes to the
      development of a variety of cardiac arrhythmias. This brief review examines the
      ionic and cellular basis for these heterogeneities and their role in the Brugada
      and long-QT syndromes. Both cases involve an accentuation of transmural
      dispersion of repolarization (TDR). In the case of the Brugada syndrome. TDR is
      accentuated as a result of a preferential abbreviation of the right ventricular
      epicardial action potential, whereas in the long-QT syndrome, accentuation of TDR
      is secondary to a preferential prolongation of the action potential of the M
      cell.

PMID- 15176419
TI  - Genetic defects, ionic currents and electrocardiographic alterations.
AB  - Most experimental data on the kinetic properties of cardiac ion channels and
      their modification by genetic defects have been obtained in expression systems
      (e.g., Xenopus oocyte), away from the cellular environment where these channels
      function to generate the cardiac action potential. In this article, we describe
      the use of computational biology (computer simulations) in integrating such
      information on single ion channels into models of the functioning cardiac cell.
      We use this approach to mechanistically relate molecular processes to whole-cell
      electrophysiological function and its manifestation in electrocardiographic
      waveforms. Examples are provided from the congenital long QT syndrome and the
      Brugada syndrome.

PMID- 15176416
TI  - [Postexposure prevention after occupational exposure to HBV, HCV and HIV].

PMID- 15176420
TI  - Electrical remodeling and arrhythmias in long-QT syndrome: lessons from genetic
      models in mice.
AB  - Mutations in cardiac voltage-gated K+ channels cause long-QT syndrome (LQTS) and
      sudden death. We have created a mouse with a long-QT phenotype by overexpression
      of truncated K+ channels in the heart and have investigated the phenotype of
      these mice. These mice have long-QT phenotype, and spontaneous and inducible
      arrhythmias. Optical mapping of Kv1DN mice revealed spatial and temporal
      dispersion of repolarization that underlies the arrhythmias. Here I review our
      attempts to abolish arrhythmias in this model by crossbreeding with Kv4DN and
      Kv2DN mice or direct injection of adenoviral or adeno-associated viral vectors
      expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. Our published work
      suggests that the viral vectors rescue the phenotype at the cellular level, while
      crossbreeding with Kv4DN mice attenuates the spontaneous and inducible
      arrhythmias.

PMID- 15176421
TI  - Cardiac channelopathies: from men to mice.
AB  - During recent years, genetic manipulations in the mouse aimed to settle animal
      models of cardiac channelopathies. Among this group of diseases, the genetically
      heterogeneous long-QT (LQT) syndrome has instigated several models. Models of the
      LQT1 syndrome have been obtained by invalidation of Kcnq1 encoding a voltage
      dependent K+ channel alpha-subunit, LQT2 syndrome by invalidation of Merg also
      encoding a voltage-dependent K+ channel alpha-subunit, LQT3 by knocking-in a gain
      of-function deletion (delta KPQ) of the Scn5A cardiac Na+ channel gene, LQT4 by
      invalidating the ankyrin B gene. LQT5 by invalidating the Kcne1 K+ channel beta
      subunit and the Andersen syndrome by invalidation of the KCNJ2 gene encoding for
      a cardiac inward rectifier K+ channel. Among these LQT models, the LQT3 and LQT4
      mice exhibit spontaneous or exercise-induced life-threatening arrhythmias
      characteristics of long-QT patients. In addition, a model for the SCN5A-linked
      Brugada syndrome and for the inherited Lenegre disease has been established by
      heterozygous knock-out of Scn5A. These mice demonstrate progressive cardiac
      conduction defect similar to that observed in Lenegre patients and an increased
      susceptibility to arrhythmias as found in Brugada patients. In the future, the
      mouse model should prove instrumental to investigate the myocardial remodeling
      that is likely to result from gene invalidation either in man or in mice.

PMID- 15176422
TI  - Genetic basis of drug-induced arrhythmias.
AB  - Drug-induced torsade de pointes arrhythmia (TdP) is frequently seen in patients.
      This proarrhythmia is not restricted to anti-arrhythmics but includes a variety
      of drugs. A genetic predisposition is an attractive explanation for this clinical
      problem. In this review, we: 1) explain the arrhythmogenic mechanisms of TdP, 2)
      provide data for a genetic cause based upon mutations in the long QT or in
      cytochrome genes responsible for drug metabolism, and 3) present pathology-based
      electrical remodeling as an alternative explanation. It can be concluded that the
      current evidence for a genetic basis for drug-induced TdP is weak.

PMID- 15176423
TI  - Modulation of HERG potassium channel function by drug action.
AB  - Repolarization of cardiomyocytes is mainly performed by the rapid component of
      the delayed rectifier potassium current, I(Kr), which is encoded by the human
      ether-a-go-go-related gene (HERG). Inhibition of HERG potassium currents by class
      III antiarrhythmic drugs causes lengthening of the cardiac action potential,
      which produces a beneficial antiarrhythmic effect. Conversely, excessive
      prolongation of the action potential by a wide variety of antiarrhythmic and non
      antiarrhythmic drugs may lead to acquired long-QT syndrome, which is associated
      with a risk for 'torsade de pointes'-arrhythmias and sudden cardiac death. As a
      result, this undesirable side effect has prompted the withdrawal of several drugs
      from the market. Recent studies on HERG channel inhibition provide significant
      insights into the molecular factors that determine state-, voltage-, and use
      dependency of HERG current block. In addition, crucial properties of the putative
      drug binding site in HERG have been identified. The broad diversity in response
      to pharmacologic treatment among individuals is likely to depend on a combination
      of multiple factors from the fields of arrhythmia genetics, physiology and
      pharmacology. In conclusion, the increasing understanding of the molecular
      mechanisms that underlie HERG channel block by antiarrhythmic and non
      antiarrhythmic drugs may improve prevention and treatment of drug-induced long-QT
      syndrome.

PMID- 15176424
TI  - Drug-induced QT interval prolongation: regulatory perspectives and drug
      development.
AB  - Drug-induced torsade de pointes is a modern, iatrogenic challenge. This
      potentially fatal tachyarrhythmia is associated with many non-antiarrhythmic
      (including noncardiovascular) drugs, leading to a number of effective drugs being
      withdrawn from the market. Others have attracted severe prescribing restrictions
      while some new chemical entities have experienced difficulties in gaining
      regulatory approval. Since QT interval prolongation, a surrogate of torsade, is a
      mechanism-based concentration-dependent pharmacological effect, it is usually
      possible to characterise a drug for this toxicity during its development. The
      physicochemical and other pharmacological properties of a QT-prolonging drug
      modulate its clinical risk of torsade de pointes. Apart from these properties,
      the torsadogenic potential of a drug is also influenced clinically by a number of
      genetic and non-genetic factors. The former include polymorphisms of enzymes that
      metabolise the drug or its pharmacological target. Major non-genetic factors are
      the dose of the drug, co-medications especially metabolic inhibitors or other QT
      prolonging drugs, presence of electrolyte imbalance and co-morbidity especially
      liver or cardiac disease, including pre-existing prolongation of the QT interval
      or bradycardia. Drug development programmes should be aimed at characterising the
      potency of a drug to prolong the OT interval and its interactions with these
      genetic and non-genetic variables, if valuable drugs are to gain approval and
      continue to be prescribed effectively and safely. Physicians too have an
      important role by ensuring that they adhere to prescribing information and
      monitor the patients as recommended.

PMID- 15176425
TI  - Four potassium channel mutations account for 73% of the genetic spectrum
      underlying long-QT syndrome (LQTS) and provide evidence for a strong founder
      effect in Finland.
AB  - BACKGROUND: Mutations in five cardiac voltage-gated ion channel genes, including
      KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited
      long-QT syndrome (LQTS). Typically, each family carries its own private mutation,
      and the disease manifests with varying phenotype and incomplete penetrance, even
      within particular families. We had previously identified 14 different LOTS
      causing mutations in 92 Finnish families. AIM: In order to complete the
      characterization of Finnish spectrum of LOTS genes, we conducted a systematic
      search for mutations in the five LOTS genes among 188 additional unrelated
      probands. METHODS: The screening was performed by denaturing high-performance
      liquid chromatography (dHPLC) and DNA sequencing. RESULTS: Nineteen novel and 12
      previously described mutations were identified. Collectively, these data extend
      the number of molecularly defined affected Finnish LOTS families and patients at
      present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1
      G589D and IVS7-2A > G, HERG R176W and L552S) together account for as much as 73%
      of all established Finnish LQTS cases. CONCLUSIONS: The extent of genetic
      homogeneity underlying LOTS in Finland is unique in the whole world, providing a
      major advantage for screening and presymptomatic diagnosis of LOTS, and
      constituting an excellent basis to study the role of genetic and non-genetic
      factors influencing phenotypic variability in this disease.

PMID- 15176426
TI  - Beta-adrenergic receptor polymorphism in human cardiovascular disease.
AB  - Beta-adrenoceptors are polymorphic. Two common polymorphisms in the beta1
      adrenoceptor (Ser49Gly and Arg389Gly) and three in the beta2-adrenoceptor
      (Arg16Gly, Gln27Glu, and Thr164Ile) appear to influence receptor function. In
      vitro studies of agonist-stimulation have shown that the Gly49 beta1-adrenoceptor
      and the Gly16 beta2-adrenoceptors are more susceptible to down-regulation, while
      the Glu27 beta2-adrenoceptor variant seems to be resistant. Whereas the Arg389
      beta1-adrenoceptor demonstrates increased responsiveness to agonist stimulation
      in vitro, the Ile164 beta2-adrenoceptor variant, on the other hand, exhibits a
      decreased responsiveness. Although several studies in humans (ex vivo and in
      vivo) do support those functional effects, the literature on the phenotypic
      consequences of these beta-adrenoceptor polymorphisms in vivo is still far from
      being conclusive. At present, it appears that these beta-adrenoceptor
      polymorphisms are very likely not disease-causing genes, but might be risk
      factors, might modify disease and/or might influence progression of disease.

PMID- 15176428
TI  - Genes, exercise and sudden death: molecular basis of familial catecholaminergic
      polymorphic ventricular tachycardia.
AB  - Familial catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare
      arrhythmogenic disease manifesting with exercise- or stress-induced ventricular
      arrhythmias, syncope, and even sudden death. CPVT is inherited as an autosomal
      dominant or autosomal recessive trait, usually with high penetrance. We
      characterized in detail the clinical, structural and electrocardiographic
      findings in this disorder and by use of genome-wide linkage analysis, mapped the
      disease-causing gene to chromosome 1q42-q43. Thereafter, we and others
      demonstrated point mutations of the cardiac ryanodine receptor gene (RyR2) to
      underlie this life-threatening disease. In addition, RyR2 mutations were
      identified in patients affected with a variant form of arrhythmogenic right
      ventricular dysplasia (ARVD2), a phenotypically distinct disease entity.
      Identification of the causal mutations has enabled molecular diagnosis in the
      affected families, which is of major importance in identifying individuals at
      risk of an arrhythmia. Recently, several groups have delineated the functional
      effects of the RyR2 mutations associated with CPVT and ARVD2. The results are
      slightly contradictory, and further studies are thus needed to clarify the exact
      molecular mechanisms leading to arrhythmia induction.

PMID- 15176427
TI  - Molecular determinants of altered contractility in heart failure.
AB  - Heart failure remains a leading cause of mortality in the Western world. An
      important hallmark of heart failure is reduced myocardial contractility.
      Alterations in intracellular Ca2+ handling play a major role in the
      pathophysiology of these contractile abnormalities. Several defects in the
      excitation-contraction (EC) coupling system have been identified in patients with
      heart failure. Alterations in the density and function of proteins relevant for
      EC coupling have been reported. Chronic stimulation of the beta-adrenergic
      signaling pathway leads to protein kinase A (PKA) hyperphosphorylation of the
      cardiac ryanodine receptor (RyR2), which dissociates FKBP12.6 from RyR2, thereby
      altering channel gating and promoting diastolic sarcoplasmic reticulum (SR) Ca2+
      release. This may deplete the SR Ca2+ stores, which may reduce myocardial
      contractility. Clinical studies have demonstrated that beta-adrenergic receptor
      blockers reduce morbidity and mortality in all grades of congestive heart
      failure. Our experimental data indicate that beta-blockers reverse RyR2
      hyperphosphorylation and normalize channel gating, which is associated with
      increased contractility in heart failure. In conclusion, chronic hyperactivity of
      the beta-adrenergic signaling pathway impairs intracellular Ca2+ handling, which
      leads to reduced contractility in patients with heart failure.

PMID- 15176429
TI  - A missense mutation in CASQ2 is associated with autosomal recessive catecholamine
      induced polymorphic ventricular tachycardia in Bedouin families from Israel.
AB  - Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is characterized
      by episodes of syncope, seizures or sudden death, in response to physical
      activity or emotional stress, and affects mainly young children with
      morphologically normal hearts. We have recently described an autosomal recessive
      form of the disorder in seven families from a Bedouin tribe in the north of
      Israel, and mapped the disease-causing gene to chromosome 1p13-1p21. Direct
      sequencing of the calsequestrin 2 (CASQ2), a candidate gene from within the
      linkage interval, revealed a negatively charged aspartic acid change to a
      positively charged histidine at position 307 of the protein. CASQ2 serves as the
      major calcium reservoir within cardiac myocytes. This mutation occurs in a highly
      conserved residue of the protein. The implication of the calcium release cascade
      in this disease, may lead to a better understanding of the pathophysiologic
      events underlying ventricular tachycardia, and to the use of drugs directly
      involved in intracellular calcium control for the treatment of the CPVT patients.

PMID- 15176430
TI  - Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and genetic
      heterogeneity.
AB  - Due to its varied and variable phenotypes, Andersen-Tawil syndrome (ATS) holds a
      unique place in the field of channelopathies. Patients with ATS typically present
      with the triad of periodic paralysis, cardiac arrhythmias, and developmental
      dysmorphisms. Although penetrance of ATS is high, disease expression and severity
      are remarkably variable. Mutations in KCNJ2 are the primary cause of ATS with 21
      mutations discovered in 30 families. These mutations affect channel function
      through heterogeneous mechanisms, including reduced PIP2-related channel
      activation and altered pore function. Aside from KCNJ2-based ATS, the genetic
      basis of this disease in nearly 40% of cases is unknown. Other ATS genes likely
      share a common pathway or function with Kir2.1 or facilitate the activity of this
      ion channel. In this review, we explore hypotheses explaining the pathogenesis,
      expression, and variability of ATS.

PMID- 15176431
TI  - Gene transfer techniques for cardiac arrhythmias.
AB  - Therapy for cardiac arrhythmias is inadequate, based on current options. Gene
      therapy has shown tremendous potential to investigate pathophysiology and
      potential therapies for cardiac diseases. The current work reviews the
      possibilities for application of in vivo gene transfer to treatment of common
      arrhythmias, including vector selection, delivery technique, and data on in vivo
      gene transfer for rate control in atrial fibrillation and for pacemaking
      activity. Arrhythmia gene therapy is a field in its infancy, and future human
      applications are dependent on solutions to the problems discussed in this review.

PMID- 15176432
TI  - Gene therapy for heart failure.
AB  - Despite our continued advances in the management of coronary artery disease,
      there have been no significant reductions in the morbidity or mortality related
      to end-stage heart failure. The syndrome of heart failure represents a common
      endpoint for several disease processes, however, at the molecular level there are
      certain biochemical similarities common to all failing myocardium. Targeting
      these derangements with gene therapy represents a promising option in the
      treatment of heart failure. In this review, we will discuss the common
      biochemical changes that occur in the failing heart, novel therapeutic targets,
      including the beta-adrenergic receptor system and intracellular calcium
      regulation, and the vectors and transfer methodology responsible for delivering
      these transgenes to the myocardium.

PMID- 15176433
TI  - Family and population strategies for screening and counselling of inherited
      cardiac arrhythmias.
AB  - Family screening in inherited cardiac arrhythmias has been performed in The
      Netherlands since 1996, when diagnostic DNA testing in long QT syndrome (LQTS)
      and hypertrophic cardiomyopathy (HCM) became technically possible. In
      multidisciplinary outpatient academic clinics, an adjusted protocol for genetic
      counselling, originally derived from predictive testing in Huntington's disease,
      is being used. 1110 individuals, including 842 relatives of index patients, were
      informed about their risks, and most were tested molecularly and/or clinically
      for carriership of the disease present in their family. Of 345 relatives who were
      referred for cardiologic follow-up, 189 are being treated, because of an
      increased risk of life-threatening arrhythmias. Evaluation of the psychological
      and social consequences of family screening for inherited arrhythmias can be
      performed by using the adapted criteria of Wilson and Jungner, i.e., from a point
      of view of public health. Preliminary results of psychological research show that
      parents of children at risk for LQTS show high levels of distress. Many other
      aspects have to be evaluated yet, making final conclusions about the feasibility
      of family screening difficult, particularly in HCM. Clinical guidelines are
      urgently needed. Population screening by molecular testing, for instance in
      athletic preparticipation screening, will become possible in the future and has
      its own prerequisites for success.

PMID- 15176434
TI  - Overexpression of LIM kinase 1 renders resistance to apoptosis in PC12 cells by
      inhibition of caspase activation.
AB  - LIM kinases (LIMKs) regulate actin polymerization by phosphorylating cofilin and
      are predominantly expressed in neural tissue. In this study, the effect of LIMK1
      overexpression in PC12 cell apoptosis was investigated. PC12 cells overexpressing
      the wild-type LIMK1 were more resistant to serum-withdrawal-induced cell death
      and the level of caspase 3 activation in these cells was lower than in the
      control PC12 cells or than in the PC12 cells expressing a mutant LIMK1 lacking
      the kinase domain. The inhibition of JNK activation was observed in the PC12
      cells overexpressing the wild-type LIMK1 after serum withdrawal. These results
      suggest that the LIMK1 might allow resistance to apoptosis in PC12 cells by
      inhibiting JNK activation.

PMID- 15176435
TI  - Involvement of opioid receptor subtypes in both stimulatory and inhibitory
      effects of the opioid peptides on prolactin secretion during pregnancy.
AB  - 1. We have previously demonstrated the existence of a dual neuromodulatory
      regulation of prolactin secretion by the opioid system. In the present work, we
      evaluated the opioid receptor subtypes involved in both the stimulatory and the
      inhibitory regulation of prolactin secretion in pregnant rats. 2. Specific opioid
      agonists and antagonists were administered intracerebro ventricular (i.c.v.) to
      rats on day 3 and on day 19 pregnancy in rats of pretreated with mifepristone.
      Blood samples were obtained after decapitation at 12.00 and 18.00 h. Serum
      prolactin levels were measured by RIA. 3. The mu-selective agonist DAMGO and beta
      endorphin caused a significant increase in serum prolactin secretion on day 3 of
      pregnancy, during the diurnal surge and intersurge period. Pretreatment with
      naloxone prevented the increase on prolactin levels induced by DAMGO. The
      administration of U-50,488, a kappa-selective agonist or DPDPE, a delta-selective
      agonist, did not modify serum prolactin concentration while the mu1-antagonist
      naloxonazine reduced significantly serum prolactin levels. On day 19 of
      pregnancy, the release of prolactin induced by mifepristone was significantly
      increase by naloxonazine, while the kappa-antagonist nor-binaltorfimine induced
      only a small but significant increase. No effect was observed after
      administration of the delta-antagonist naltrindole. 4. We conclude that the mu
      opioid receptor seems to be more specifically involved in both the stimulatory
      and inhibitory regulation by the opioid system on prolactin secretion during
      pregnancy. The increase on serum prolactin levels on day 3 after administration
      of DAMGO and beta-endorphin may suggest the participation of other regulatory
      mechanisms as the dopaminergic and serotoninergic systems. On day 19, only the
      endogenous ligands delta did not participate in the regulation of prolactin
      secretion, while the participation of the kappa-opioid receptor was significantly
      less effective than the endogenous ligand mu. Our results provide evidences of an
      important role of the opioid system through specific receptors on the regulation
      of prolactin secretion during early and late pregnancy.

PMID- 15176436
TI  - Uptake and efflux of quinacrine, a candidate for the treatment of prion diseases,
      at the blood-brain barrier.
AB  - 1. A clinical trial of quinacrine in patients with Creutzfeldt-Jakob disease is
      now in progress. The permeability of drugs through the blood-brain barrier (BBB)
      is a determinant of their therapeutic efficacy for prion diseases. The mechanism
      of quinacrine transport across the BBB was investigated using mouse brain
      endothelial cells (MBEC4). 2. The permeability of quinacrine through MBEC4 cells
      was lower than that of sodium fluorescein, a BBB-impermeable marker. The
      basolateral-to-apical transport of quinacrine was greater than its apical-to
      basolateral transport. In the presence of P-glycoprotein (P-gp) inhibitor,
      cyclosporine or verapamil, the apical-to-basolateral transport of quinacrine
      increased. The uptake of quinacrine by MBEC4 cells was enhanced in the presence
      of cyclosporine or verapamil. 3. Quinacrine uptake was highly concentrative, this
      event being carried out by a saturable and carrier-mediated system with an
      apparent Km of 52.1 microM. Quinacrine uptake was insensitive to Na+-depletion
      and changes in the membrane potential and sensitive to changes in pH. This uptake
      was decreased by tetraethylammonium and cimetidine, a substrate and an inhibitor
      of organic cation transporters, respectively. 4. These findings suggest that
      quinacrine transport at the BBB is mediated by the efflux system (P-gp) and the
      influx system (organic cation transporter-like machinery).

PMID- 15176438
TI  - Detection of cannabinoid CB1, adenosine A1, muscarinic acetylcholine, and GABA(B)
      receptor-dependent G protein activity in transducin-deactivated membranes and
      autoradiography sections of rat retina.
AB  - 1. Several G-protein-coupled receptors (GPCRs) have been localized to various
      layers of the vertebrate retina, using autoradiographic and immunohistochemical
      techniques, but the functional data concerning G protein activation are limited.
      Here, we establish optimized assay conditions to detect receptor-dependent G
      protein activity in membranes and tissue sections of the rat retina. 2. Agonist
      stimulated [35S]GTPgammaS-binding responses were characterized for the Gi/o
      linked adenosine A1, cannabinoid CB1, m2/m4 muscarinic acetylcholine, and GABA(B)
      receptors. Initial assumption was that G protein activity under "basal
      conditions" is high due to enrichment and activity of rhodopsin and transducin in
      this tissue. 3. We found that pretreatment of retina membranes with hydroxylamine
      (10 mM), a rhodopsin-inactivating drug, substantially (up to 60%) reduced basal G
      protein activity, thereby improving signal-to-noise ratio to detect agonist
      stimulated G protein activation for all studied receptors. [35S]GTPgammaS
      autoradiography revealed that hydroxylamine specifically reduced basal binding in
      the transducin-enriched photoreceptor layer. In contrast, hydroxylamine did not
      affect GPCR signaling in brain membranes, indicating specific action on retinal
      transducin. 4. For all studied receptors, [35S]GTPgammaS autoradiography allowed
      localization of G protein activity to different retinal layers, with the bulk of
      signal detected in the ganglion cell layer. Strongest responses were observed for
      adenosine and muscarinic receptor agonists. Additional G protein activity was
      detected in the inner plexiform layer. 5. Responses to all tested agonists were
      reversed in the presence of appropriate receptor-selective antagonists,
      indicating receptor-mediated G protein activation.

PMID- 15176439
TI  - Hyperbaric oxygen enhances the expression of prion protein and heat shock protein
      70 in a mouse neuroblastoma cell line.
AB  - 1. Cellular prion protein, PrP(C), is a ubiquitous glycoprotein strongly
      expressed in neurons with an as yet unknown biological function. In previous
      studies, we demonstrated that PrP(C) could be regulated by heat shock stress,
      implying that it might be a stress-responsive protein. Hyperbaric oxygen (HBO)
      administration is a well-defined model for the study of oxidative stress. 2. This
      study investigated the effect of HBO on PrP(C) and Hsp 70 expression in mouse
      neuroblastoma cell lines (N18), assessing the expression of PrP(C) and Hsp 70
      using RT-PCR and Western blotting. HBO administration resulted in a time- and
      dose-dependent increase in PrP(C) and Hsp70 expression in N18 cells at both mRNA
      and protein levels, with a concomitant upregulation of c-Jun N-terminal kinase
      (JNK). 3. Under HBO treatment, luciferase reporter constructs of the rat PrP(C)
      promoter, containing the heat shock element (HSE) also present in Hsp70,
      expressed higher luciferase activity (3- to 10-fold) than those constructs
      without HSE. 4. In summary, these data suggest that PrP(C) and Hsp 70 may be
      regulated by HBO, through the activation of JNK. Thus, the activated heat shock
      transcriptional factor 1, phosphorylated by JNK interacted with HSE in the
      promoter of PrP(C) resulted in increased gene expression. These findings are
      vital for future therapeutic approaches in transmissible spongiform
      encephalopathies and the understanding of the function of the PrP(C).

PMID- 15176437
TI  - Secretin: hypothalamic distribution and hypothesized neuroregulatory role in
      autism.
AB  - 1. This study aims (1) to determine whether secretin is synthesized centrally,
      specifically by the HPA axis and (2) to discuss, on the basis of the findings in
      this and previous studies, secretin's possible neuroregulatory role in autism. 2.
      An immunocytochemical technique with single-cell resolution was performed in 12
      age/weight-matched male rats pretreated with stereotaxic microinjection of
      colchicine (0.6 microg/kg) or vehicle into the lateral ventricle. Following 2-day
      survival, rats were anesthetized and perfused for immunocytochemistry. Brain
      segments were blocked and alternate frozen 30-microm sections incubated in rabbit
      antibodies against secretin, vasoactive intestinal peptide, glucagon, or
      pituitary-adenylate-cyclase-activating peptide. Adjacent sections were processed
      for Nissl stain. Preadsorption studies were performed with members of the
      secretin peptide family to demonstrate primary antibody specificity. 3.
      Specificity of secretin immunoreactivity (ir) was verified by clear-cut
      preadsorption control data and relatively high concentrations and distinct
      topographic localization of secretin ir to paraventricular/supraoptic and
      intercalated hypothalamic nuclei. Secretin levels were upregulated by colchicine,
      an exemplar of homeostatic stressors, as compared with low constitutive
      expression in untreated rats. 4. This study provides the first direct
      immunocytochemical demonstration of secretinergic immunoreactivity in the
      forebrain and offers evidence that the hypothalamus, like the gut, is capable of
      synthesizing secretin. Secretin's dual expression by gut and brain secretin
      cells, as well as its overlapping central distribution with other stress
      adaptation neurohormones, especially oxytocin, indicates that it is stress
      sensitive. A neuroregulatory relationship between the peripheral and central
      stress response systems is suggested, as is a dual role for secretin in
      conditioning both of those stress-adaptation systems. Colchicine-induced
      upregulation of secretin indicates that secretin may be synthesized on demand in
      response to stress, a possible mechanism of action that may underlie secretin's
      role in autism.

PMID- 15176440
TI  - Implantation of tumoral XC cells induces chronic, endothelin-dependent, thermal
      hyperalgesia in mice.
AB  - 1. We describe here the alterations in the nociceptive sensitivity of Swiss CD1
      mice receiving an intraplantar (i.pl.) administration of XC Rous sarcoma-virus
      transformed rat fibroblasts (XC cells). 2. Histological studies reveal that XC
      cells remain at the injection site 2-3 weeks after implantation, a time at which
      an inflammatory reaction is also detected. No tumoral growth was found and 5
      weeks after inoculation neither XC cells nor inflammatory reaction were observed.
      3. Measures to different types of noxious stimuli were performed. At week 1 after
      XC cell inoculation, hyperalgesia to thermal, but not mechanical, stimuli as well
      as to capsaicin injection is present in the implanted paw. At week 5 after XC
      cell implantation, only thermal hyperalgesia is present, and this enhanced
      reactivity persisted for even 25 weeks after the disappearance of XC tumoral
      cells. 4. Pharmacological studies on thermal hyperalgesia were conducted at two
      different stages, week 1 and week 5 after XC cell inoculation. The systemic
      administration of morphine (1-10 mg/kg i.p. (intraperitoneal); 30 min before
      testing) prevents this thermal hyperalgesic reaction both at week 1 and week 5.
      The endothelin type A (ETA) receptor antagonist BQ-123 (10 nmol; i.pl.; 90 min
      before testing) abolishes both the early (week 1) and the late (week 5) thermal
      hyperalgesia. In contrast, the selective endothelin type B (ETB) receptor
      antagonist, BQ-788 (10 nmol; i.pl.; 90 min before) abolishes thermal hyperalgesia
      only at week 1, but not at week 5 after XC cell inoculation. 5. It might be
      concluded that endothelins are probably involved in this type of long-term
      thermal hyperalgesia produced by the transitory presence of the XC tumoral cell
      line.

PMID- 15176441
TI  - Induction of Fos immunoreactivity in oxytocin neurons in the paraventricular
      nucleus after female odor exposure in male rats: effects of sexual experience.
AB  - 1. We examined whether oxytocin (OT) neurons in the paraventricular nucleus of
      the hypothalamus (PVN) were activated by estrus female odor and sexual contact in
      sexually naive and experienced Long-Evans rats. 2. Male rats were not presented
      to anesthetized estrus females (control) or presented to the females without
      (exposure to the female odor without sexual contact) or with direct contact
      (exposure to the female odor with sexual contact). 3. Exposure to the female odor
      with sexual contact significantly increased OT neurons with Fos-ir in both males.
      Exposure to the female odor without contact increased OT neurons with Fos
      immunoreactive cells (Fos-ir) in sexually experienced males but not in naive
      males, suggesting that the female odor without sexual contact activated the
      oxytocinergic neuronal system in the PVN in the experienced males. 4. Therefore,
      exposure to the estrus female odor itself may exert different effects on sexually
      naive and experienced males.

PMID- 15176442
TI  - Solubilization of serotonin1A receptors heterologously expressed in Chinese
      hamster ovary cells.
AB  - 1. The serotonin1A (5-HT1A) receptors are members of a superfamily of seven
      transmembrane domain receptors that couple to G-proteins. They appear to be
      involved in various behavioral and cognitive functions. 2. We report here, for
      the first time, the solubilization of 5-HT1A receptors stably expressed in
      Chinese Hamster Ovary (CHO) cells using the zwitterionic detergent CHAPS in
      presence of NaCl followed by polyethylene glycol (PEG) precipitation. We show by
      ligand-binding assay that the 5-HT1A receptor solubilized this way is
      functionally active. We have optimized the efficiency of solubilization with
      respect to total protein and NaCl concentration. 3. Our results show that careful
      control of salt and protein concentration is crucial in optimal solubilization of
      membrane receptors heterologously expressed in cells in culture. The effective
      solubilization of important neurotransmitter receptors such as 5-HT1A receptors
      which are present in very low amounts in the native tissue may represent an
      important step in characterizing membrane receptors expressed in mammalian cells
      in culture.

PMID- 15176443
TI  - Nurses--one body, one voice.

PMID- 15176444
TI  - Herbal product use and perioperative patients.
AB  - IT IS VITAL for perioperative team members to assess the effects of increasingly
      used herbal and nontraditional medications on a patient's surgical course. THIS
      LITERATURE REVIEW provides a knowledge base so nurses can appropriately assess
      the possible effects of herbal medication use by perioperative patients. THE
      HISTORY OF HERBAL REMEDY USE, existing regulatory guidelines, effects on consumer
      safety, and socioeconomic and insurance issues are discussed. Additionally, the
      role of an herbal medicine practitioner is explored. Finally, the eight most
      commonly used herbal medications are examined, particularly in regard to
      perioperative patients.

PMID- 15176445
TI  - Educating nurses into the perioperative arena.
AB  - PROVIDING PERIOPERATIVE experience for those new to the OR is a vital necessity,
      especially because many nursing schools provide limited OR experiences. AN
      ALTERNATIVE to a traditional course is a condensed version that incorporates the
      material for a 10-week course into a two-weekend format that encompasses both
      didactic and laboratory experiences. RESPONSE TO THIS CONDENSED program has been
      so positive that it has edged out the 10-week program in the curriculum.

PMID- 15176446
TI  - Length stay, discharge disposition, and hospital charge predictors.
AB  - THIS STUDY EXPLORED the effect of patient, clinical, and treatment factors on
      length of stay (LOS), discharge disposition, and total acute care hospital
      charges for older adults undergoing elective total hip arthroplasty or total knee
      arthroplasty. A CAUSATIVE RETROSPECTIVE DESIGN was used, and data analysis
      included descriptive statistics, multiple regression, and logistic regression.
      SIGNIFICANT DIFFERENCES in predictor variables (ie, age, gender, living
      arrangement, comorbidities, postoperative complications) were found between
      patients who were discharged to home and those who were discharged to another
      facility. Only postoperative complications contributed significantly to LOS.
      Total surgical time and postoperative complications contributed significantly to
      hospital charges.

PMID- 15176447
TI  - Reaching out to future generations--introduction at the high school level.
AB  - THE NEXT GENERATION of potential health care workers needs to be educated about
      the joys of perioperative nursing. BY EDUCATING HIGH SCHOOL students, AORN
      members can ensure that they spread the message operative nursing at a grassroots
      level. AORN'S PERIOPERATIVE NURSING: Introduction at the High School Level Task
      Force has created resources members can use to educate high school students,
      faculty members, and career counselors about what perioperative nurses do.

PMID- 15176448
TI  - Recognizing professional and volunteer activities.
AB  - RECOGNITION OF ACHIEVEMENT is key for organizations seeking to retain both
      employees and volunteers. ORGANIZATIONS CAN MAINTAIN high levels of enthusiasm
      among employees or volunteers by offering tasks that provide value as well as
      satisfaction. AORN SEEKS TO ENSURE that its members receive the recognition that
      they deserve.

PMID- 15176449
TI  - Protecting patients from potential injuries.

PMID- 15176450
TI  - Protect your patient--it is never too late to reposition.

PMID- 15176451
TI  - AORN bariatric surgery guideline.

PMID- 15176452
TI  - Improving verbal communication in clinical care.

PMID- 15176453
TI  - The nursing shortage and the Nurse Reinvestment Act.

PMID- 15176454
TI  - Inhibin: actions and signalling.
AB  - Inhibin is best known as a reproductive hormone that inhibits release of follicle
      stimulating hormone (FSH) from the pituitary gland. Over the last decade or so a
      number of other biological roles have emerged, putting inhibin more in the class
      of a growth factor. Despite this, little is known of the signalling pathways for
      this protein. This minireview summarises the pertinent aspects of inhibin biology
      and focuses on four potential signalling mechanisms through which inhibin might
      influence cellular function, namely subunit availability, receptor assembly, co
      receptors and signalling through inhibin-specific signalling pathways.

PMID- 15176455
TI  - Involvement of nitric oxide in angiogenic activities of vascular endothelial
      growth factor isoforms.
AB  - We compared effects of vascular endothelial growth factor-121 (VEGF121) and
      vascular endothelial growth factor-165 (VEGF165) on generation of NO in HUVEC and
      the involvement of NO in VEGF121- and VEGF165-induced angiogenesis. VEGF
      stimulated synthesis of NO within seconds, reaching peak concentrations of 450 +/
      25 and 180 +/- 15 nmol/l for VEGF121, and VEGF165, respectively. The VEGF121
      increased NO production for about 40 s while VEGF165-stimulated NO release lasted
      only for about 20 s. Accordingly, cGMP elevation was stronger in VEGF121- than in
      VEGF165-treated cells. The VEGF121 was a very weak mitogen but strong
      chemoattractant for HUVEC, whereas VEGF165 potently induced both cell
      proliferation and migration. NO appeared to be involved in the endothelial
      migration and morphogenesis but not in the proliferation. NO was also a
      permissive molecule for VEGF121- but not for VEGF165-induced capillary sprouting
      in spheroid culture. In conclusion, VEGF121 is a stronger stimulator of
      endothelial nitric oxide synthase (eNOS) activity, and angiogenic potential of
      VEGF121 is more reliant on NO contribution.

PMID- 15176456
TI  - The osteoinductive activity of bone morphogenetic protein (BMP) purified by
      repeated extracts of bovine bone.
AB  - Native bone morphogenetic proteins (BMPs) extracted from bone have been used
      clinically to stimulate bone regeneration and repair. However, preparation of
      purified BMP is a laborious process. This study investigated the yield, activity
      and cost effectiveness of repeatedly extracting the same bone matrix to produce
      purified BMP. While repeated extraction was able to increase the yield 62% the
      activity of the partially purified BMP in later extracts decreased both in vitro
      and in vivo. This decline in activity appears to be due to an increase in non-BMP
      contaminants, such as collagen, in the extracts. When the first three extracts
      were combined and processed together activity was equivalent to that of the first
      extract. A simple analysis based on the cost of reagents used and the time
      required for purification indicates that separate processing of the extracts is
      inefficient while combining the first and second extracts and processing them
      together would result in a small cost saving. Based on this study we would
      recommend that the demineralized bone matrix be extracted no more than twice and
      that the extracts be combined for further processing.

PMID- 15176457
TI  - Effects of local application of growth and differentiation factor-5 (GDF-5) in a
      full-thickness cartilage defect model.
AB  - Our purpose in this study was to investigate the effects of growth and
      differentiation factor-5 (GDF-5) on cartilage and subchondral bone in a rabbit
      model harboring an osteochondral defect for a period of 6 months. Absorbable
      composites were implanted in adult rabbits (18 controls, 18 animals with collagen
      I matrix, and 18 animals with matrix plus GDF-5). After 4, 8, or 24 weeks the
      specimens were studied by histology, microcomputed tomography (microCT) and flow
      cytometric analysis (FACS). Implantation of GDF-5 resulted in an improved
      histological appearance. This was the result of significantly improved defect
      filling at 4 and 8 weeks. At 24 weeks, however, there was no difference between
      the groups. The histological examination disclosed a predominance of
      fibrocartilage, and remodeled subchondral bone was also observed. MicroCT
      documented normal bone density in all groups, excluding subchondral sclerosis. At
      24 weeks, FACS analysis revealed high apoptotic activity in the GDF-5-treated
      group. As far as we are aware, this is the first report of the effects of GDF-5
      in a full-thickness cartilage defect model. We assume that recombinant GDF-5
      contained on the carrier is probably able to accelerate the regeneration of the
      osteochondral defect owing to its availability. However, control of the protein
      delivery may require further investigation.

PMID- 15176458
TI  - Erythropoiesis from adult but not fetal blood-derived CD133+ stem cells depends
      strongly on interleukin-3.
AB  - We have shown previously that erythropoiesis in cultures from fetal blood depends
      less on interleukin-3 (IL3) than erythropoiesis from adult blood. This paper
      explores if this is due to different proportions of stem cell sub-populations
      with different IL3 requirement, or to different IL3 requirement on fetal and
      adult stem cells in general. The CD133 (AC133) antigen is found on half of all
      CD34+ cells with erythropoietic potential and is thought to mark a primitive stem
      cell sub-population. This work compares the IL3 requirements of CD133+ and CD133
      CD34+ cells derived from fetal (12-20 weeks) and adult blood. Erythropoiesis was
      monitored using flow cytometry and colony counting. Erythropoiesis from adult
      CD133+ but not CD133-CD34+ cells was dramatically delayed (6-8 days) in the
      absence of IL3. In cultures from fetal blood, both CD133+ and CD133-CD34+ cells
      showed only a small dependency on IL3. The ratio of erythroid colony-forming
      CD133+ cells to erythroid colony-forming CD34+ cells was 0.5-0.6 in adult and 0.2
      0.4 in fetal blood. The differential IL3 dependency of erythropoiesis from fetal
      and adult blood CD133+ and CD133-CD34+ stem cells may be relevant for the choice
      and preparation of stem cells for clinical purposes.

PMID- 15176459
TI  - Functional localization of proprotein-convertase furin and its substrate TGFbeta
      in EGF receptor-expressing gastric chief cells.
AB  - Furin, a proprotein-convertase, is distributed in the upper third layer and the
      lower quarter region of the rat gastric gland. We previously identified the upper
      furin-positive cells as parietal cells, and here, we identify the lower furin
      positive cells as chief cells. Chief cells express three isoforms of transforming
      growth factor beta (TGFbeta), whose precursor requires cleavage by furin for its
      activation. When the chief cell mass was decreased in rats by adrenalectomy,
      pepsinogen-, furin-, and TGFbeta-positive cells were also reduced. Stimulation of
      mouse chief cell primary-cultures with transforming growth factor alpha
      (TGFalpha) induced an increase in the expression of furin and TGFbeta mRNAs and
      in the formation of mature TGFbeta. Since parietal cells are known to express a
      high level of the epidermal growth factor (EGF) -family growth factors and chief
      cells strongly express EGF receptors (EGF-R), we suggest that chief cells receive
      the EGF-R signal from parietal cells in a paracrine fashion and regulate parietal
      cell mass by controlling the formation of mature TGFbeta.

PMID- 15176460
TI  - Activin A: a possible marker for liver transplant outcome.

PMID- 15176461
TI  - Expression of insulin-like growth factors (IGF)-1 and -2, IGF-binding proteins-2
      and -3, and receptors for growth hormone, IGF type-1 and -2 and insulin in the
      gastrointestinal tract of neonatal calves.
AB  - Growth hormone (GH), insulin-like growth factors (IGFs) and insulin influence
      post-natal gastrointestinal development and function. We have measured by real
      time PCR the mRNA levels of IGF-1 and -2, IGF-binding proteins (IGFBPs)-2 and -3,
      and receptors for GH, IGF type-1 and -2, and insulin in esophagus, rumen, fundus,
      pylorus, duodenum, jejunum, ileum and colon of calves on days 1 and 5 of life.
      Levels of mRNA of measured traits were different (P < 0.05) at different
      gastrointestinal sites. Furthermore, mRNA levels of IGFs, IGFBPs and of receptors
      for GH and IGF type-1 and -2 and insulin differed (P < 0.05) on days 1 and 5.
      Differences in mRNA abundance of IGFs, IGFBPs and of receptors for GH, IGFs, and
      insulin among gastrointestinal sites on days 1 and 5 of life suggest site
      specific functional importance and demonstrate that changes are the consequence
      of ontogenetic development and/or due to feeding.

PMID- 15176462
TI  - Neurodegenerative diseases: pathology and the advantage of single-cell profiling.
AB  - The aggregation of neuronal proteins as inclusions is emerging as a common
      mechanistic theme in neurodegenerative diseases. The presence of these "disease
      specific" pathologic changes in the brains of patients with neurodegenerative
      diseases assist pathologists in the diagnosis and characterization of dementing
      illnesses. However, these same inclusions may provide valuable clues toward
      understanding common pathologic roots and shared abnormalities in protein folding
      across disorders. Such an investigation will likely provide insights into disease
      mechanisms underlying neurodegenerative disorders characterized by abundant
      filamentous lesions. This review focuses on two themes: (i) Neurodegenerative
      disorders are characterized by shared and distinct histopathological and
      biochemical abnormalities, and (ii) the presence of abnormal protein aggregates
      may alter a gene, and hence protein expression in inclusion-bearing neurons
      predisposes them to dysfunction and eventual neuronal degeneration. The
      pathologic features of neurodegenerative diseases are first discussed followed by
      a rationale behind sampling mRNA species from single cells rather than from whole
      brain homogenates to explore disease mechanisms.

PMID- 15176463
TI  - Single-cell gene expression analysis: implications for neurodegenerative and
      neuropsychiatric disorders.
AB  - Technical and experimental advances in microaspiration techniques, RNA
      amplification, quantitative real-time polymerase chain reaction (qPCR), and cDNA
      microarray analysis have led to an increase in the number of studies of single
      cell gene expression. In particular, the central nervous system (CNS) is an ideal
      structure to apply single-cell gene expression paradigms. Unlike an organ that is
      composed of one principal cell type, the brain contains a constellation of
      neuronal and noneuronal populations of cells. A goal is to sample gene expression
      from similar cell types within a defined region without potential contamination
      by expression profiles of adjacent neuronal subpopulations and noneuronal cells.
      The unprecedented resolution afforded by single-cell RNA analysis in combination
      with cDNA microarrays and qPCR-based analyses allows for relative gene expression
      level comparisons across cell types under different experimental conditions and
      disease states. The ability to analyze single cells is an important distinction
      from global and regional assessments of mRNA expression and can be applied to
      optimally prepared tissues from animal models as well as postmortem human brain
      tissues. This focused review illustrates the potential power of single-cell gene
      expression studies within the CNS in relation to neurodegenerative and
      neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia,
      respectively.

PMID- 15176464
TI  - Proteomics for protein expression profiling in neuroscience.
AB  - As the technology of proteomics moves from a theoretical approach to a practical
      reality, neuroscientists will have to determine the most appropriate applications
      for this technology. Neuroscientists will have to surmount difficulties
      particular to their research, such as limited sample amounts, heterogeneous
      cellular compositions in samples, and the fact that many proteins of interest are
      rare, hydrophobic proteins. This review examines protein isolation and protein
      fractionation and separation using two-dimensional electrophoresis (2-DE) and
      mass spectrometry proteomic methods. Methods for quantifying relative protein
      expression between samples (e.g., 2-DIGE, and ICAT) are also described. The
      coverage of the proteome, ability to detect membrane proteins, resource
      requirements, and quantitative reliability of different approaches is also
      discussed. Although there are many challenges in proteomic neuroscience, this
      field promises many rewards in the future.

PMID- 15176465
TI  - Gene expression profiling of seizure disorders.
AB  - Seizure disorders affect a significant percentage of the population, and
      researchers worldwide continue to work toward a better understanding of what
      initiates, propagates, and results from aberrant and excessive neuronal
      excitation. During the past two decades, one aspect of this research effort has
      been to describe the effects of seizure activity upon neuronal gene expression,
      with hopes of identifying the molecular mechanisms that underlie subsequent
      changes in cell function and survival. Here we review this body of work from the
      perspective of how these gene profiling efforts have evolved, starting with one
      by-one analyses of specific gene targets to the more recent use of DNA
      microarrays to survey literally thousands of genes simultaneously. With regard to
      the latter, we present some of our own work that suggests that molecular
      mechanisms contributing to normal brain development are reiterated during seizure
      induced network reorganization.

PMID- 15176467
TI  - Folate-regulated changes in gene expression in the anterior neural tube of folate
      binding protein-1 (Folbp1)-deficient murine embryos.
AB  - Inactivation of the murine folate binding protein-1 (Folbp1) has been shown to
      play a vital role in embryonic development. Nullizygous embryos (Folbp1-/-) have
      significant malformations of the neural tube, craniofacies, and conotruncus, and
      invariably die in utero by gestational day (E) 10. Administration of 25 mg x kg(
      1) x day(-1) folinic acid to dams prior to and throughout gestation rescues the
      majority of embryos from premature death; however, a portion of surviving embryos
      develops neural tube defects. Using antisense RNA amplification and cDNA
      microarrays, we examined the expression of approximately 5700 genes in the
      anterior neural tube of gestational day 9 Folbp1-/- embryos that were
      supplemented with folinic acid. Genes that appear to be folate regulated include
      transcription factors, G-proteins, growth factors, methyltransferases, and those
      that are related to cell proliferation. The potential impact of such changes
      during neural tube closure is considered in light of the phenotype of Folbp1-/-
      embryos.

PMID- 15176468
TI  - Methodological considerations regarding single-cell gene expression profiling for
      brain injury.
AB  - Genomic microarrays are rapidly becoming ubiquitous throughout a wide variety of
      biological disciplines. As their use has grown during the past few years, many
      important discoveries have been made in the fields of central nervous system
      (CNS) injury and disease using this emerging technology. In addition, single-cell
      mRNA amplification techniques are now being used along with microarrays to
      overcome many of the difficulties associated with the cellular heterogeneity of
      the brain. This development has extended the utility of gene expression profiling
      and has provided researchers with exciting new insights into the neuropathology
      of CNS injury and disease at a molecular and cellular level. New methodological,
      standardization, and statistical techniques are currently being developed to
      improve the reproducibility of microarrays and facilitate the analysis of large
      amounts of data. In this review, we will discuss the application of these
      techniques to experimental, clinically relevant models of traumatic brain injury.

PMID- 15176466
TI  - Mining microarrays for metabolic meaning: nutritional regulation of hypothalamic
      gene expression.
AB  - DNA microarray analysis has been used to investigate relative changes in the
      level of gene expression in the CNS, including changes that are associated with
      disease, injury, psychiatric disorders, drug exposure or withdrawal, and memory
      formation. We have used oligonucleotide microarrays to identify hypothalamic
      genes that respond to nutritional manipulation. In addition to commonly used
      microarray analysis based on criteria such as fold-regulation, we have also found
      that simply carrying out multiple t tests then sorting by P value constitutes a
      highly reliable method to detect true regulation, as assessed by real-time
      polymerase chain reaction (PCR), even for relatively low abundance genes or
      relatively low magnitude of regulation. Such analyses directly suggested novel
      mechanisms that mediate effects of nutritional state on neuroendocrine function
      and are being used to identify regulated gene products that may elucidate the
      metabolic pathology of obese ob/ob, lean Vgf-/Vgf-, and other models with
      profound metabolic impairments.

PMID- 15176469
TI  - Proteomic analysis of neuronal hypoxia in vitro.
AB  - We used high-throughput Western blotting to identify proteins that are up- or
      down-regulated by neuronal hypoxia in vitro. Exposure to hypoxia for 24 h
      produced > or = 1.5-fold increases in the expression of 10/700 proteins (1.4%)
      and decreases in the expression of 16/700 proteins (2.3%). Up-regulated proteins
      included Arc, doublecortin/calmodulin kinase-like 1, integrin alpha(v), and
      fibronectin; down-regulated proteins included nuclear autoantigenic sperm
      protein, protein kinase C-related kinase 2, and E2F transcription factor 1. The
      prominence of cytoskeleton-related proteins among those showing altered
      expression highlights the role of the cytoskeleton in neuronal responses to
      hypoxia.

PMID- 15176470
TI  - Comprehensive proteome expression profiling of undifferentiated versus
      differentiated neural stem cells from adult rat hippocampus.
AB  - Adult neural stem cells can be isolated from various regions of the rat brain and
      seem to have multilineage differentiation potential. In this study, we
      investigated the hypothesis that global protein expression of adult neural stem
      cells isolated from rat hippocampus is changed during in vitro differentiation.
      After 2 days of differentiation, we separated total protein extracts by two
      dimensional gel electrophoresis and used mass spectrometry and gel-matching for
      identification. We detected a differential expression in 367 regulated protein
      spots, of which 128 could be identified. Regulated proteins included participants
      in transcription and DNA metabolism; signal transduction and Ca2+-signaling; MAP
      kinase pathways; cytoskeletal rearrangement; regulation of cell cycle,
      proliferation, and survival; protein biosynthesis, folding, and degradation; and
      glycine and glutamate metabolic pathways. These results suggest a massive
      reorganization of the stem cell proteomic profile upon differentiation and
      indicate potential cellular targets mediating the differentiation of neural stem
      cells.

PMID- 15176471
TI  - Combining brain imaging with microarray: isolating molecules underlying the
      physiologic disorders of the brain.
AB  - Many diseases of the nervous system cause dysfunction by impairing neuronal
      physiology more than by altering brain anatomy--including age-related cognitive
      decline, most psychiatric disorders, and even the earliest stages of Alzheimer's
      disease. The absence of clear anatomical markers makes it difficult to identify
      targeted cells, which in turn impedes attempts to isolate the pathogenic
      molecules that cause physiologic disruption. Here we show how brain imaging and
      microarray can be used as complimentary techniques that together can characterize
      the cellular and molecular aspects of this class of diseases.

PMID- 15176472
TI  - Modulation of sciatic nerve expression of class 3 semaphorins by nerve injury.
AB  - Beginning with the unexpected finding by cDNA array analysis that neuropilin-2 is
      induced in sciatic nerve distal to a transection, we document, for the first
      time, up-regulation in the axotomized adult peripheral nervous system of class 3
      semaphorins and their receptors, which are known to play prominent roles in
      axonal guidance during neural development. Previously, we described the use of
      cDNA arrays to screen for novel peripheral nervous system axotomy-induced
      candidate neurotrophic proteins. A novel finding of that prior study was
      substantial induction of neuropilin 2 (NP2) mRNA in the axotomized nerve
      segments. Following up on that initial observation, we have now used real-time
      quantitative reverse transcription-polymerase chain reaction to demonstrate
      induction of genes encoding neuropilin 1 (NP1), which, like NP2, serves as a
      coreceptor for members of the class 3 semaphorin family of axonal guidance
      molecules and of five of the six known class 3 semaphorins (Sema3A, Sema3B,
      Sema3C, Sema3E, and Sema3F, but not Sema3D) in crushed or transected sciatic
      nerves.

PMID- 15176473
TI  - Expression profile analysis of neurodegenerative disease: advances in specificity
      and resolution.
AB  - Microarray technology has become a common tool for developing expression
      profiles. Initially used in the analysis of cells lines and homogeneous tissues,
      this platform has been applied to more diverse tissues, such as the brain.
      Several neural disorders have already been profiled by microarrays using
      relatively large amounts of tissue. This data has unveiled many genes with
      differential expression between normal and diseased tissue that could potentially
      be used as gene markers for these afflictions. Because of the heterogeneity of
      the CNS, it is likely that small differences between gene expression in these
      studies would be enhanced by the sampling of a subset of cells based on these
      newly characterized gene markers. Subtraction of normal, unaffected cells from
      the sample may also result in a more accurate profile of a diseased cell.
      Expression profile studies from several neuropathological states are presented,
      with emphasis placed on those studies using small samples of cellular material
      and those using specialized methods of cell isolation and RNA amplification.

PMID- 15176474
TI  - Large-scale analysis of gene expression in epilepsy research: is synthesis
      already possible?
AB  - DNA microarrays are now popular tools for large-scale studies of gene expression
      in the brain in both physiologic and pathologic conditions. Here, we review the
      few available papers describing the use of microarrays in experiments relevant to
      temporal lobe epilepsy. Review of the data indicates that products of genes
      regulated during epileptic processes belong to a variety of functional classes,
      including signal transduction, transcription regulation, protein synthesis and
      degradation, basic metabolism, and structural proteins. There is surprisingly
      little overlap in gene lists from different studies. This might be related to the
      limited sensitivity of microarrays or to differences in the experimental setup,
      such as the use of different animal models, time points, and microarrays. Despite
      obvious problems with interpretation of the vast amount of information derived
      from microarray experiments, these data are potentially excellent tools for
      creating new hypotheses about events occurring during circuitry reorganization in
      the brain that results in lowered seizure threshold and epilepsy.

PMID- 15176475
TI  - The effects of ketamine vary among inbred mouse strains and mimic schizophrenia
      for the P80, but not P20 or N40 auditory ERP components.
AB  - N-methyl-D-aspartate (NMDA) antagonists produce behavioral and
      electrophysiological effects similar to schizophrenia. The mouse P20, N40, and
      P80 event related potential (ERP) components were analyzed for genetic variance
      among inbred strains and ketamine-induced differences to model abnormalities in
      the P50, N100, and P200 in schizophrenia. Ketamine increased P20/N40 amplitude
      and decreased P80 amplitude. Therefore, the effects of ketamine in mice are
      inconsistent with alterations in the corresponding P50 and N100 in schizophrenia,
      suggesting that NMDA receptor dysfunction may not underlie abnormalities of these
      components in schizophrenia. However, the effects of ketamine on the mouse P80
      were consistent with P200 ERP changes in schizophrenia and support the hypothesis
      that NMDA dysfunction may contribute to some neuronal abnormalities in
      schizophrenia. The current study lays the groundwork for defining the role of
      NMDA-mediated transmission for specific aspects of neuronal processing that vary
      with genetic background. Future studies could use transcription profiling to
      clarify such interactions between genetic background, specific neuronal circuits,
      and transmitter systems.

PMID- 15176476
TI  - Suppression subtractive hybridization and microarray identification of estrogen
      regulated hypothalamic genes.
AB  - The gonadal steroid estrogen is a pleiotropic hormone that has multiple effects
      on numerous cellular functions. One of estrogen's major targets is the brain,
      where the steroid not only affects growth, differentiation, and survival of
      neurons, but also regulates cell excitability. Because estrogen modulates
      multiple, overlapping signaling pathways, it has been difficult to scrutinize the
      transcriptional activity of the steroid. Therefore, we still lack a global
      picture of how different genes interact and are regulated by estrogen. Herein we
      report the use of suppression subtractive hybridization followed by custom
      microarray analysis of thousands of genes that are differentially expressed
      during the negative feedback phase of the female reproductive cycle. We have
      found a number of key transcripts that are regulated by estrogen and contribute
      to the alteration in synaptic transmission and hence excitability of hypothalamic
      neurons (e.g., GABA neurons). These include gec-1, GABA(B)R2, PI3 kinase subunit
      p55gamma, and a number of proteins containing pleckstrin homology domains that
      are critical for plasma membrane targeting. Studies are underway to refine our
      analysis to individual nuclei and individual cells. However, what has emerged
      from this highly sensitive microarray analysis is that estrogen affects neuronal
      plasticity in hypothalamic neurons not only by transcription of new membrane
      proteins (e.g., receptors and channels), but also by altering expression of
      downstream signaling molecules and proteins involved in neurosecretory pathways.

PMID- 15176477
TI  - Genomic portraits of the nervous system in health and disease.
AB  - As the human genome project moves toward its goal of sequencing the entire human
      genome, gene expression profiling by DNA microarray technology is being employed
      to rapidly screen genes for biological information. In this review, we will
      introduce DNA microarray technology, outline the basic experimental paradigms and
      data analysis methods, and then show with some examples how gene expression
      profiling can be applied to the study of the central nervous system in health and
      disease.

PMID- 15176478
TI  - Using the gene ontology for microarray data mining: a comparison of methods and
      application to age effects in human prefrontal cortex.
AB  - One of the challenges in the analysis of gene expression data is placing the
      results in the context of other data available about genes and their
      relationships to each other. Here, we approach this problem in the study of gene
      expression changes associated with age in two areas of the human prefrontal
      cortex, comparing two computational methods. The first method,
      "overrepresentation analysis" (ORA), is based on statistically evaluating the
      fraction of genes in a particular gene ontology class found among the set of
      genes showing age-related changes in expression. The second method, "functional
      class scoring" (FCS), examines the statistical distribution of individual gene
      scores among all genes in the gene ontology class and does not involve an initial
      gene selection step. We find that FCS yields more consistent results than ORA,
      and the results of ORA depended strongly on the gene selection threshold. Our
      findings highlight the utility of functional class scoring for the analysis of
      complex expression data sets and emphasize the advantage of considering all
      available genomic information rather than sets of genes that pass a predetermined
      "threshold of significance."

PMID- 15176479
TI  - Experimental strategy to identify genes susceptible to oxidative stress in nigral
      dopaminergic neurons.
AB  - Neuropathological evidence from both human and experimental models of Parkinson's
      disease (PD) firmly supports a significant role for oxidative stress (OS) in the
      death of dopaminergic (DA) neurons in substantia nigra. Largely unknown are the
      genes underlying selective susceptibility of nigral DA neuron to OS and how they
      effect nigral DA cell death. The major barriers to high-throughput identification
      of candidate genes are the paucity of nigral DA neurons as well as the dilution
      effect of non-DA cells both in primary cultures and brain tissues. To overcome
      these barriers, we have developed a DA cell line model, SN4741, appropriate for
      cDNA microarray analysis. Candidate genes were selected from both the microarray
      analysis and the molecular implication of their pathological mechanisms (i.e.,
      decreased mitochondrial complex I activity and proteasomal dysfunction) of PD.
      Subsequent secondary validation tests were devised to characterize genes
      including clone #45 that may underlie selective vulnerability of nigral DA neuron
      to OS.

PMID- 15176480
TI  - Effects of antidepressant drug imipramine on gene expression in rat prefrontal
      cortex.
AB  - We have investigated gene expression changes produced by acute and chronic daily
      treatment with a prototypical antidepressant, imipramine, using DNA microarrays.
      The analysis of similarities in gene expression patterns among functionally
      related genes revealed four expression profile cluster areas that showed a highly
      significant overrepresentation of several functional classes. Genes encoding for
      proteins involved in cAMP metabolism, postsynaptic membrane proteins, and proto
      oncogenes were overrepresented in different cluster areas. Furthermore, we found
      that serine proteases as a group were similarly regulated by chronic
      antidepressant treatment. Our data suggest that cAMP metabolism, synaptic
      function, and protein processing by serine proteases may be important targets of
      antidepressant treatment and potential objects for antidepressant drug
      development.

PMID- 15176481
TI  - Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal
      cortex are decreased in schizophrenia.
AB  - Microarray expression studies have reported decreased mRNA expression of
      histidine triad nucleotide-binding protein (HINT1) and cytosolic malate
      dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals
      with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the
      DLPFC have reported increased and decreased expression in individuals with
      schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the
      DLPFC in individuals with schizophrenia and controls were measured by real-time
      quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in
      situ hybridization. The Q-PCR results were compared by analysis of covariance
      between individuals with schizophrenia and controls. Gene expression levels for
      HINT1, MDH1, and SERPINI1 were significantly different between the groups. The
      male individuals with schizophrenia compared to male controls showed reductions
      by 2.8- to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in
      mRNA abundance for MDH1 (P = 0.006), HINT1 (P = 0.050), and neuroserpin (P =
      0.005) in DLPFC of male individuals with schizophrenia is consistent with prior
      reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there
      were no significant interactions with gender, gene expression between female
      patients and the female control group did not differ. These results confirm
      earlier reports and suggest abnormalities of specific genes related to metabolic
      and protease activities in the DLPFC might be considered as part of a molecular
      pathway in male patients with schizophrenia.

PMID- 15176483
TI  - Gene expression of transcription factors in the rat brain after morphine
      withdrawal.
AB  - Multiple approaches have been performed to elucidate the molecular mechanisms
      underlying drug withdrawal in opioid-dependent animals. Opiate withdrawal
      represents a state of neuronal hyperexcitability in the brain that leads to
      alterations in a number of second-messenger systems which, in turn, induce
      expression of transcription factors. Whereas earlier studies have primarily
      demonstrated an early and transient transcriptional activation of members of the
      Fos, Jun, and Krox families, recent microarray studies investigating the delayed
      response could additionally identify several transcriptional repressors such as
      cAMP response element modulator (CREM), IkappaB, silencer factor B, helix-loop
      helix proteins, or glucocorticoid-induced leucine zipper, indicating the attempt
      of the brain to re-establish homeostasis after withdrawal-induced excitation.

PMID- 15176482
TI  - Links between the pathology of Alzheimer's disease and vascular dementia.
AB  - The major neuropathological lesions defining Alzheimer's disease (AD) include
      neurofibrillary tangles and amyloid plaques, which are mainly composed of
      abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous
      neuropathological and neuroimaging studies indicate that at least one-third of AD
      cases are complicated by some degree of vascular pathology, whereas in a similar
      proportion of patients clinically diagnosed with vascular dementia, AD pathology
      is also present. Many classical vascular risk factors such as hypertension,
      diabetes mellitus, and hypercholesterolemia have recently been shown also to
      increase the risk of AD. Growing evidence suggests that vascular pathology lowers
      the threshold for the clinical presentation of dementia at a given level of AD
      related pathology and potentially directly promotes AD lesions such as A beta
      plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid
      precursor protein (APP), which is the precursor to the amyloid beta peptide and
      damages the blood-brain barrier (BBB), affecting A beta peptide clearance from
      the brain. Recognition of the importance of these vascular risk factors for AD
      related dementia and their treatment will be beneficial not only for preventing
      cardiac, cerebral, and peripheral complications of vascular disease, but also
      will likely have a direct impact on the occurrence of sporadic AD in older
      subjects. In this paper, we review some of the links between vascular risk
      factors and AD pathology and present data on the direct effect of ischemia on
      cognitive function and A beta deposition in a mouse model of AD.

PMID- 15176484
TI  - A molecular description of brain trauma pathophysiology using microarray
      technology: an overview.
AB  - It has been estimated that 50% of human transcriptome, the collection of mRNA in
      a cell, is expressed in the brain, making it one of the most complex organs to
      understand in terms of genomic responses to injury. The availability of genome
      sequences for several organisms coupled with the increasing affordability of
      microarray technologies makes it feasible to monitor the mRNA levels of thousands
      of genes simultaneously. In this paper, we provide an overview of findings using
      both cDNA- and oligonucleotide-based microarray analyses after experimental
      traumatic brain injury (TBI). Specifically, the utility of this methodology as a
      means of cataloging the biochemical sequelae of brain trauma and elucidating
      novel genes or pathways for further study is discussed. Furthermore, we offer
      future directions for the continued evaluation of microarray results and discuss
      the usefulness of microarray techniques as a testing format for determining the
      efficacy of mechanism-based therapies.

PMID- 15176485
TI  - Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum
      of stress-related signaling.
AB  - While specific components of normal brain aging and Alzheimer's disease (AD)
      appear to be genetically determined, it is not well understood whether AD is due
      to accelerated aging or if AD represents an independent disease entity
      superimposed upon senescence. Using gene expression profiling, significant
      alterations in brain-specific transcription patterns have been observed between
      AD and age-matched controls. In AD, although a general depression in brain
      genetic output has been reported, there are robust increases in the expression of
      potentially neuropathological genes. The data in this study show increases in the
      RNA abundance patterns for a stress-response, proinflammatory, apoptotic, and
      angiogenic gene family that occur during the transition from fetal to aged, and
      again during the transformation from aged to AD brain. Significantly up-regulated
      RNAs include those encoding stress-induced factors (HSP70), transcriptional
      repressors (DAXX), pentraxins (SAP), proapoptosis factors (FAS and DAXX), and
      several inflammatory markers (betaAPP, CEX1, NF-IL6, NF-kappaBp100,
      cyclooxygenase-2, IL-1alpha and IL-1beta precursors and cPLA2). These findings
      support the hypothesis that there is a continuum of stress-related gene
      expression as the brain ages and an advancement of inflammatory, apoptotic, and
      angiogenic gene signaling that correlates with the transition to AD.

PMID- 15176486
TI  - Anatomical methods for voxelation of the mammalian brain.
AB  - Voxelation allows high-throughput acquisition of three-dimensional gene
      expression patterns in the brain through analysis of spatially registered voxels
      (cubes). The method results in multiple volumetric maps of gene expression
      analogous to the images reconstructed in biomedical imaging techniques. An
      important issue for voxelation is the development of approaches to anchor
      correctly harvested voxels to the underlying anatomy. Here, we describe
      experiments to identify fixation and cryopreservation protocols for improved
      registration of harvested voxels with neuroanatomical structures.
      Paraformaldehyde fixation greatly reduced RNA recovery as judged by ribosomal RNA
      abundance. However, gene expression signals from paraformaldehyde-fixed samples
      were not appreciably diminished as judged by average signal-noise ratios from
      microarrays, highlighting the difficulties of accurate quantitation of cross
      linked RNA. Additional use of cryoprotection helped to improve further RNA
      recovery and signal from fixed tissue. It appears that the best protocol to
      provide the necessary resolution of neuroanatomical information in voxelation
      entails a controlled dose of fixation and thorough cryoprotection, complemented
      by histological staining.

PMID- 15176487
TI  - Derangement of hypothetical proteins in fetal Down's syndrome brain.
AB  - The success of the Human Genome Project (HGP) enables prediction of proteins by
      computer programs from nucleic acid sequences and for which there is no
      experimental evidence. Clues for function of hypothetical proteins are provided
      by sequence similarity with proteins of known function in model organisms. The
      availability of this bulk of new data is of immediate importance to Down's
      syndrome (DS) research. DS is the most common human chromosomal abnormality
      caused by an extra copy of chromosome 21 and is characterized by somatic
      anomalies and mental retardation. In addition, overexpression of chromosome 21
      genes is directly or indirectly responsible for mental retardation and other
      phenotypic abnormalities of DS. To allow insight into how trisomy 21 represents
      the phenotype of DS, we constructed a two-dimensional protein map and
      investigated expression of 8 hypothetical proteins in fetal DS (n = 7) and
      control (n = 7) brains (cortex). Two-dimensional electrophoresis (2-DE) with
      subsequent in-gel digestion of spots and matrix-assisted laser
      desorption/ionization (MALDI) spectroscopic identification followed by
      quantification of spots with specific software was applied. Quantitative analysis
      of hypothetical protein FLJ10849, hypothetical protein FLJ20113, and activator of
      hsp90 ATPase homologue 1 (AHA1) revealed levels comparable between DS and
      controls. By contrast, expression levels of hypothetical protein KIAA1185,
      hypothetical protein 55.2 kDa, hypothetical protein 58.8 kDa, actin-related
      protein 3beta (ARP3beta), and putative GTP-binding protein PTD004 were
      significantly decreased (P < 0.05) in fetal DS brain, and domain analysis
      suggests involvement in cytoskeleton, signaling, and chaperone system
      abnormalities.

PMID- 15176488
TI  - Neuroproteomics: expression profiling of the brain's proteomes in health and
      disease.
AB  - The term "proteome" describes the protein complement of a genome. Proteomes of
      cells are dynamic and are directly affected by environmental factors, such as
      stress and/or drug treatment, or as a result of aging and disease. One of the
      distinct advantages of proteomic analysis, not attainable with RNA expression
      data, is the ability to fractionate the cell's proteins into various
      subpopulations. In neuroscience, "neuromics" (proteomics in the central nervous
      system) is in its infancy, with a paucity of studies in the context of the brain.
      One of the objectives of this review is to illustrate the potential of neuromics
      to profile differences in the distribution of thousands of proteins as a function
      of disease markers. We have previously used this approach to determine the
      effects of varied postmortem interval in examining human brain tissue and to
      identify biomarkers. Here we review proteomic studies of schizophrenia,
      Alzheimer's disease, and Parkinson's disease. Experimental results regarding
      Parkinson's disease are presented to illustrate the potential of neuromics to
      identify pathways of pathogenesis and novel therapeutic targets.

PMID- 15176489
TI  - Onset of action for the relief of allergic rhinitis symptoms with second
      generation antihistamines.
AB  - Onset of action for relief of allergic rhinitis symptoms is of clinical
      significance to both the physician and the patient. Using either subjective or
      objective methods, the onset of action after a single, oral dose of an
      antihistamine can be measured. Multicenter studies, outdoor studies, and pollen
      challenge systems have been used to measure the onset of action. A literature
      search from 1985 to May 2002 was performed. All published, randomized, placebo
      controlled clinical studies pertaining to the onset of action for relief of
      allergic rhinitis symptoms after a single, oral dose of a second-generation
      antihistamine (not combined with a decongestant) including cetirizine,
      desloratadine, fexofenadine, and loratadine, were reviewed. The onset of action
      for cetirizine ranged from 59 minutes to 2 hours and 6 minutes and for loratadine
      onset of action ranged from 1 hour and 42 minutes to none identified during the
      duration of the study. Cetirizine had a shorter onset of action than loratadine
      for all comparisons. Fexofenadine had an onset of action within 60 minutes. The
      literature search did not reveal any published onset of action studies for
      desloratadine. The onset of action for a given second-generation antihistamine
      depends on how it is defined and subsequently measured.

PMID- 15176490
TI  - Antihistamine onset of action: the importance to the patient.
AB  - Although some older antihistamines have a relatively slow onset of action, modern
      agents indicate an efficacy between 1 and 3 hours of administration. For patients
      who use antihistamines regularly, a short onset of action is relatively
      unimportant. When antihistamines are used as needed, either because of poor
      compliance or in accordance with emerging therapeutic guidelines, antihistamines
      with a short onset of action are preferable.

PMID- 15176491
TI  - Interactions between rhinitis and asthma.
AB  - Allergic rhinitis is present in up to 75% of patients with asthma, and in
      longitudinal follow-up, patients with allergic rhinitis are three times more
      likely to develop asthma as compared with subjects without allergic rhinitis. In
      experimental nasal challenges with allergen followed by nasal biopsies at 24
      hours, there is positive staining for interleukin-5, eotaxin, intracellular
      adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin.
      Concurrently obtained bronchial biopsy specimens show eosinophils and
      intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E
      selectin. There is increasing evidence for bone marrow stimulation by either
      seasonal or experimental allergen exposure resulting in an increase in bone
      marrow and peripheral blood progenitors for eosinophils/basophils. These cells
      then could populate the nose and lungs. From a therapeutic perspective,
      intranasal beclomethasone dipropionate and flunisolide have been reported to
      reduce the symptoms of asthma in patients with ragweed-induced allergic rhinitis.
      Conversely, high-dose orally inhaled budesonide has been shown to reduce some of
      the symptoms of allergic rhinitis. Finally, first reported in 1968 and then not
      until 1997, there is evidence that allergen vaccine immunotherapy, when
      administered to children with allergic rhinitis, may prevent the development of
      asthma or at least reduce its likelihood of occurring.

PMID- 15176492
TI  - New thoughts on sinus headache.
AB  - Sinus headache is not a recognized entity by allergy, otolaryngology, or
      neurological organizations. Headache is a minor feature in the diagnosis of acute
      rhinosinusitis and is not validated as a symptom in chronic sinusitis. Sinus
      headaches are self-diagnosed due to weather triggers, bilateral and
      frontomaxillary location, and the presence of vasomotor signs and symptoms, all
      of which can accompany the migraine. Over 90% of self-diagnosed and doctor
      diagnosed sinus headaches meet the International Headache Society criteria for
      migraines, and those migraines misdiagnosed as sinus headaches respond to
      sumatriptan better than placebo because migraines respond to triptans. Sinus
      headaches are usually severely disabling migraines, misdiagnosed and mistreated,
      with 61% of patients receiving antibiotic prescriptions for noninfectious causes,
      thus failing the patients and, in addition, contributing to a serious public
      health problem.

PMID- 15176493
TI  - Celiac disease presenting as urticaria.
AB  - Celiac sprue is a chronic malabsorptive disorder that occurs in predisposed
      individuals secondary to ingestion of gluten. An increase of atopic or
      immunologic disorders has been reported in the setting of gluten enteropathy. The
      incidence of urticaria and celiac sprue is unknown but appears to be rare.

PMID- 15176494
TI  - Rhinitis and rhinologic headaches.
AB  - Rhinologic headache, a headache of nasal origin, generally has been attributed to
      past facial trauma causing nasal mucosa-septal contact points. Patients who have
      not knowingly experienced nasal trauma may have contact points caused by mucosal
      inflammation or anatomic abnormalities (septal spurs, septal deviation, and
      enlarged turbinates) and can develop rhinologic headaches. A population of 66
      such patients was studied to classify the type of patient susceptible to such
      headaches and to examine the type of underlying inflammation or anatomic
      abnormality responsible for creating their mucosal contact points. Most patients
      were women with a mean age at the time of initial presentation of 40 years. VMR
      was the most frequent cause of nasal inflammation, either alone or in combination
      with allergic rhinitis. Generally, headache symptoms improved with treatment of
      the underlying nasal inflammation in the majority of patients.

PMID- 15176495
TI  - Direct cost assessments in subjects with seasonal allergic rhinitis living in
      Ankara, Turkey.
AB  - The characteristics of seasonal allergic rhinitis (SAR) including the severity at
      initial presentation and cost estimates are not established for Turkey. The aim
      of this study was to document the clinical features and direct cost of subjects
      with SAR when diagnosed and followed according to international treatment
      guidelines and to determine the effectiveness of treatment in relation to the
      regional pollen count in our country. The clinical features of SAR were
      determined cross-sectionally in 175 patients living in Ankara, Turkey. The direct
      medical cost analysis obtained by a symptom-medication score method was performed
      prospectively in a subgroup of patients evaluated at the beginning of the pollen
      season (n = 37). Airborne Gramineae pollen grains were counted also in the same
      period. SAR was mild in 12.6% of cases, moderate in 51.4% of cases, and severe in
      36% of cases. Regional pollen counts were correlated with the number of patient
      visits and the initial severity of SAR. Mean cost of SAR per person without a
      comorbid disorder during a Gramineae pollen season for Ankara was 79.0 +/- 3.3
      dollars, where it reached a mean of 138.60 +/- 0.5 dollars in the presence of
      asthma and/or conjunctivitis. No difference was observed among disease severity
      groups by means of total direct cost (p > 0.05). Regional pollen counts influence
      the initial severity of SAR in our country. Appropriate treatment seemed to
      induce effective symptom control. Hence, education of both public and primary
      care physicians about the international guidelines might provide better cost
      effective management of SAR.

PMID- 15176496
TI  - Concurrent use of intranasal and orally inhaled fluticasone propionate does not
      affect hypothalamic-pituitary-adrenal-axis function.
AB  - Two double-blind, randomized, placebo-controlled, parallel group safety and
      efficacy studies included evaluation of the hypothalamic-pituitary-adrenal (HPA)
      axis effects of concurrent treatment with intranasal and orally inhaled
      fluticasone propionate (FP). In the first study, patients with asthma who were >
      or =12 years of age were assigned randomly to receive twice-daily doses (either
      88 or 220 microg) of orally inhaled FP delivered from a metered-dose inhaler
      (MDI). In the second study, patients were assigned randomly to receive either
      orally inhaled FP 250 microg or orally inhaled FP 250 microg/salmeterol 50 microg
      delivered via the Diskus device. In both studies, patients with rhinitis were
      allowed to continue the use of intranasal FP at their usual dosing. Treatment
      periods were 26 weeks and 12 weeks for the MDI and Diskus studies, respectively.
      HPA-axis effects were assessed using response to short cosyntropin stimulation
      testing. The number and percentage of patients with an abnormal cortisol
      response, defined as a morning plasma cortisol of <5 microg/dL, a poststimulation
      peak of <18 microg/dL, or a poststimulation rise of <7 microg/dL, were summarized
      in two subgroups: patients who used intranasal FP and those who did not. The
      concurrent administration of intranasal FP and orally inhaled FP via an MDI or
      Diskus or via Diskus with salmeterol was not associated with HPA-axis effects
      compared with orally inhaled FP alone. The results of these two studies suggest
      that concurrent use of intranasal FP with orally inhaled FP administered via MDI
      or Diskus for treatment of comorbid rhinitis and asthma does not increase the
      risk of HPA-axis abnormalities.

PMID- 15176497
TI  - Total and biologically active serum-soluble CD154 in patients with chronic
      idiopathic urticaria.
AB  - The pathogenesis of chronic idiopathic urticaria (CIU) is not understood
      completely; however, autoimmunity has been implicated. Because membrane and
      soluble forms of CD154 have been reported to be increased, in several autoimmune
      diseases, we have quantified the soluble CD154 (sCD154) molecule by a sandwich
      enzyme-linked immunosorbent assay in serum samples of 32 patients with CIU (aged
      32 +/- 12 years) and compared them with 32 age- and sex-matched nonallergic
      controls. A marked increase was observed in patients with CIU as compared with
      controls (4.8 +/- 2.6 ng/mL versus 2.9 +/- 0.9 ng/mL; p < 0.0005). No significant
      differences were found between groups of patients with positive or negative
      autologous serum skin test. A biological assay to determine sCD154 showed that
      patients with positive autologous serum skin test have the highest levels (4.9 +/
      1.2 ng/mL) of biologically active sCD154 as compared with their negative
      counterparts (2.2 +/- 1.3 ng/mL; p < .001) and controls (0.6 +/- 0.3 ng/mL; p <
      0.001). Active sCD154 can be derived from mast cell activation or other
      leukocytes. It is concluded that active sCD154 may be involved in the immune
      activation observed in patients with CIU.

PMID- 15176498
TI  - Results of an on-line survey of patients with hereditary angioedema.
AB  - Hereditary angioedema (HAE) is a rare but potentially fatal disease. An on-line
      survey was conducted of 63 patients in order to analyze the current clinical
      status of these patients. Sixty percent (n = 38) had type 1 HAE, 16% (n = 10) had
      type 2 HAE, and 24% (n = 15) did not know their type. The mean and median ages of
      onset of symptoms were predominantly in the teenage years. The diagnosis was
      typically made from 3.8 to 7.8 years after the onset of symptoms. The most common
      symptoms were abdominal pain and swelling (70%), swelling of extremities (45%),
      and throat closure (25%). Allergy-like symptoms were present in only 11.7% (n =
      7) of patients; hypotension occurred in only one patient (1.6%). The patients
      averaged 4.7 emergency room visits per year. Nearly one-quarter of the patients
      were treated for anaphylaxis in the emergency room. There was a high level of
      dissatisfaction among the patients with the current management of the disease.

PMID- 15176499
TI  - Ladybug hypersensitivity: report of a case and review of literature.
AB  - For years, allergists have known that inhalant allergens arise from insects such
      as flies, beetles, moths, cockroaches, and mites. Now, it is becoming evident
      that the Asian ladybeetle Harmonia axyridis possibly should be added to this
      list. Several cases have been reported recently in the literature describing
      patients suffering from allergic respiratory symptoms including rhinitis,
      conjunctivitis, and asthma related to exposure to ladybugs. These patients reveal
      positive skin-prick testing with ladybug extract and immunoglobulin E
      immunoblotting with the sera showing at least two distinct allergenic proteins.
      This species infests homes in very large numbers in the fall and winter months
      and stay there in a hibernation-like state until the warm weather arrives with
      early spring. We discuss avoidance measures, which are the key to successful
      treatment.

PMID- 15176500
TI  - [Which vaccination planning? An evolutionary and necessary reflection].

PMID- 15176501
TI  - [Is HIV more and more resistant?].

PMID- 15176502
TI  - [Septic shock: new treatment].

PMID- 15176503
TI  - [Vaccinations: why the vaccination schedule is no longer fixed].

PMID- 15176504
TI  - [What vaccination has brought].
AB  - The vaccines have improved obviously and constantly the struggle against
      infectious diseases. When the immunisations have been well applied some diseases
      fell down dramatically: i.e. diphtheria, poliomyelitis and smallpox which was
      eradicated. Actually some efficacious vaccines as measles or rubella vaccines
      could eliminate the diseases. Nevertheless in many developed countries the
      immunisation coverage is not properly reached and the diseases are always
      circulating, with a shift of age towards adults, with more severe diseases or new
      epidemiology (i.e. pertussis). However measles have been eliminated from some
      countries as Finland, Sweden, United States. The adverse events of vaccines are
      nowadays enhanced and discourage immunisation among some doctors or patients. The
      benefit-risk ratio has to be made very clear to avoid a lack or a denial of
      immunisation after false fears about risk of some vaccines. An improvement of
      surveillance and of correct information is highly required.

PMID- 15176505
TI  - [Children immunization in France: an update].
AB  - Vaccines are essential to prevent, control (as for poliomyelitis) or eradicate
      (as for smallpox) infectious diseases. In some cases, when a curative treatment
      is not available or efficient, they are the only way to fight the spread of the
      disease, by prevention. The national recommended childhood immunization schedule
      may vary each year and in each country (changes in infections characters,
      outbreaks, new vaccines availability...). In this review, new patterns in
      childhood vaccination in France are discussed.

PMID- 15176506
TI  - [What is the best way to administer vaccines in children?].

PMID- 15176507
TI  - [Adult immunization in France: an update].
AB  - French immunisation schedule recommends tetanus and poliomyelitis vaccine every
      10 years and influenza every year after the age of 65. Several other vaccinations
      related to occupational health are implemented. Travellers or immunocompromised
      people who could be exposed to infections need some other vaccinations, too.
      Pneumoccocal vaccine coverage is insufficient. Reinforcing diphteria immunization
      is considered, using a recently licensed combined vaccine. Maintenance of
      immunity against "childhood infectious diseases" preventable with vaccinations is
      a new challenge; measles, rubella and pertussis occur now quite often in adults:
      the risk of complications is higher in these ages (measles), or expose to
      specific risk (rubella in pregnant women); adults may even become the source of
      the contamination of younger people (many infants affected with whooping cough
      have contracted the disease from their own parents). The immunisation against
      these diseases should be prosecuted in adults. Related with the development of
      more efficacious new vaccines, the indications of pneumococcus, meningococcus or
      varicella vaccines should be defined in some populations of adults. Immunization
      policy of adults should be revised in order to continue the vaccination program
      of childhood. Some infections that may affect adults should be prevented by
      improving vaccine application. A real adult immunisation schedule and
      recommendations should be set up towards populations at risk of preventable
      infections. The implementation of these recommendations should be reinforced.

PMID- 15176508
TI  - [Should France continue to use BCG?].
AB  - In the context of the decrease of tuberculosis incidence, a re-assessment of the
      French BCG vaccination policy has been undertaken. The synthesis of the data
      available, done by the National Institute for Public Health Surveillance (InVS)
      has led to the conclusion of the absence of justification of the current policy
      of re-vaccinating children with a negative tuberculin skin test. Data from
      studies and from the results of the experiences from several countries having
      discontinued primovaccination confirm the effectiveness of BCG vaccination on
      childhood tuberculosis, mainly on extra-pulmonary cases. Base on these data and
      on the estimation carried out by InVS of the impact of the discontinuation in
      France of BCG re-vaccination and primovaccination, it was decided to discontinue
      the policy of re-vaccination and of routine tuberculin testing. A
      multidisciplinary expertise aimed at studying the relevancy, the feasibility and
      the acceptability of various options of reducing the target-population of
      primovaccination is on-going.

PMID- 15176509
TI  - [Why are boosters no longer necessary for protection against hepatitis B?].
AB  - Immunisation induces both antibody-producing-cells and memory cells. Although
      antibodies progressively decline over time, long-term follow-up studies of
      infants, children and adults vaccinated against hepatitis B have indicated that
      low or undetectable antibody responses years after vaccination are not associated
      to the development of chronic hepatitis. This is associated to the rapid
      development of anamnestic responses, reflecting persistence of hepatitis B memory
      cells. This resulted into a change of initial recommendations, which now
      highlight that booster doses are unnecessary in immunocompetent persons after a
      complete course of vaccination.

PMID- 15176510
TI  - [Meningococcal vaccination: which one? When? Why?].
AB  - Two kinds of meningococcal vaccines are available for invasive meningococcal
      infections (IMI) prevention, non conjugated polysaccharide vaccines anti A+C or
      anti A+C+W135+Y and conjugated polysaccharide vaccines anti-C. The last one have
      the advantage of being effective from 2 months of age. Vaccination should to be
      used in four circumstances: for subjects remaining in close contact with an IMI
      case; for pilgrims going to Mecca (A+C+W135+Y vaccine must be used); for
      travelers to a location with active transmission of IMI and close contacts with
      local population; in case of "mass" vaccination decided by health authorities.
      Generalised vaccination of all of one or more age groups has been done for
      serotype C in some European countries, because of high incidence. Effectiveness
      of this kind of intervention should be weighted with the risk of immunoselection
      of another serotype and with the possibility of a spontaneous decrease of the
      incidence.

PMID- 15176511
TI  - [Vaccinations for the travellers].
AB  - Immunisations for the traveller include, before specific vaccine, a correct
      immunisation schedule according to national recommendations with appropriate
      boosters and hepatitis B immunisation. The yellow fever vaccine is required to
      entry in countries of endemic area and quadrivalent ACYW135 meningococcal vaccine
      for entry in Saudi Arabia. Hepatitis A immunisation could be performed at 1 year
      of age and is recommended for travellers in tropical areas and children
      vaccination control the disease both in the patient and in the contacts.
      Meningococcal A+C vaccines are required for travellers in meningitis-prone areas
      of tropical Africa during the dry season (December to June), and quadrivalent
      ACYW135 is useful only in Burkina-Faso and Niger. Typhoid and rabies vaccines are
      required for ambulatory travellers in endemic areas, as Japanese encephalitis in
      south-west Asia. In central Europe, tick-borne encephalitis vaccination is
      recommended for patients travelling in forest areas during spring and summer.

PMID- 15176512
TI  - [Vaccines pharmacovigilance].
AB  - The pharmacovigilance of vaccines has the particularity of concerning medications
      with a preventative target, used in healthy subjects, who are often young. Their
      individual benefit is deferred and unknown, whereas their risk is immediate.
      Certain undesirable effects are linked to the antigen of live attenuated vaccines
      (post-MMR lymphocytic meningitis). Other non-specific effects are linked to other
      different components of the vaccines (macrophage and aluminium myofasciitis).
      Undesirable events susceptible to being due to the vaccination are identified and
      managed according to standardised procedures of pharmacovigilance, that is to
      say, based on "spontaneous notification", generation of an alert, confirmed or
      not by studies of pharmaco-epidemiology. The studies of pharmaco-epidemiology:
      have made evident oedematous reactions with cyanosis or purpura, with the
      vaccines containing the Haemophilus b valence, and the absence of an association
      with sudden death of the newborn; have excluded the existence of an elevated risk
      of demyelinisation or auto-immune disease associated with vaccination against
      hepatitis B, without being able to exclude a slight risk; go against the finding
      of an association between Crohn's disease and/or autisim and the MMR vaccination.
      Only their frequently encountered undesirable effects are well identified at the
      moment of commercialisation. Post-marketing surveillance of vaccines (declaration
      to the regional pharmacovigilance centres) allow the detection of possible rare
      and serious effects and the evaluation of the real vaccination risk. Thus it must
      be intensive and systematic.

PMID- 15176513
TI  - [Medical practice and the POEM].

PMID- 15176514
TI  - [Anaesthesia--local, regional and general].

PMID- 15176515
TI  - [Risk factors, prevention and cancer screening].

PMID- 15176516
TI  - [Amenorrhoea].

PMID- 15176517
TI  - [Pain in children: sedation and analgesia].

PMID- 15176518
TI  - A randomized controlled trial of osteopathic manipulative treatment following
      knee or hip arthroplasty.
AB  - CONTEXT: Preliminary study results suggest that osteopathic manipulative
      treatment (OMT) may reduce pain, improve ambulation, and increase rehabilitation
      efficiency in patients undergoing knee or hip arthroplasty. OBJECTIVE: To
      determine the efficacy of OMT in patients who recently underwent surgery for knee
      or hip osteoarthritis or for a hip fracture. DESIGN: Randomized controlled trial
      involving hospital and postdischarge phases. SETTING: Hospital-based acute
      rehabilitation unit. PATIENTS: A total of 42 women and 18 men who were
      hospitalized between October 1998 and August 1999. INTERVENTION: Patients were
      randomly assigned to groups that received either OMT or sham treatment in
      addition to standard care. Manipulation was individualized and performed
      according to study guidelines regarding frequency, duration, and technique. MAIN
      OUTCOME MEASURES: Changes in Functional Independence Measure (FIM) scores and in
      daily analgesic use during the rehabilitation unit stay; length of stay;
      rehabilitation efficiency--defined as the FIM total score change per
      rehabilitation unit day; and changes in Medical Outcomes Study Short Form-36
      scores from rehabilitation unit admission to 4 weeks after discharge. RESULTS: Of
      19 primary outcome measures, the only significant difference between groups was
      decreased rehabilitation efficiency with OMT (2.0 vs 2.6 FIM total score points
      per day; P = .01). Stratified analyses demonstrated that poorer OMT outcomes were
      confined to patients with osteoarthritis who underwent total knee arthroplasty
      (length of stay, 15.0 vs 8.3 days; P = .004; rehabilitation efficiency, 2.1 vs
      3.4 FIM total score points per day; P < .001). CONCLUSION: The OMT protocol used
      does not appear to be efficacious in this hospital rehabilitation population.

PMID- 15176519
TI  - Assessing the ability of medical students to perform osteopathic manipulative
      treatment techniques.
AB  - While osteopathic and allopathic medicine share many commonalities, there are key
      practice-based differences that uniquely characterize the two professions. For
      osteopathic medicine, one such defining feature is the use of osteopathic
      manipulative treatment (OMT). Unfortunately, while various treatment modalities
      are taught in osteopathic medical schools, there has been relatively little work
      done to establish standardized evaluation protocols. The purpose of this
      investigation was to explore the use of OMT assessment in the context of a
      multistation standardized patient examination. Analysis of performance data from
      121 fourth-year osteopathic medical students indicated that the ability to do OMT
      can be reliably and validly assessed using a combination of simulated patient
      encounters, trained osteopathic physician raters, and an objective rating tool.
      Additional studies that incorporate a larger sample of students and focus on
      modifications to the assessment tool and rating protocols are warranted.

PMID- 15176520
TI  - Joint clinical clerkships for osteopathic and allopathic medical students: New
      England's experience.
AB  - Although combined osteopathic and allopathic medical programs are well
      established for graduate medical education and continuing medical education,
      little has been published in the literature about such integration at the
      undergraduate level. The authors describe the preliminary efforts of a joint
      clinical clerkship program with students from regional osteopathic and allopathic
      medical schools at a major community teaching hospital in New England.
      Osteopathic principles and practice are consistently reinforced, exposing
      students from both medical backgrounds to them. It is hoped that this pilot
      program serves as a model for developing similar combined programs throughout the
      United States.

PMID- 15176521
TI  - Metastatic renal cell carcinoma-associated pleural effusion after coronary artery
      bypass grafting.
AB  - Pleural effusions after coronary artery bypass grafting (CABG) occur in up to 89%
      of patients undergoing the procedure. Effusions present days to months after
      surgery, and fluid characteristics relate to timing factors. Most of the
      effusions are left-sided and resolve spontaneously. Pleural effusions requiring
      treatment occur in a small percentage of patients who have undergone CABG. Post
      CABG pleural effusions in temporal relation to malignant effusions are not widely
      reported. This report describes a 50-year-old man presenting with a malignant
      left-sided pleural effusion 3 months after CABG, with characteristics resembling
      a late post-CABG effusion.

PMID- 15176522
TI  - Internal and external environmental influences in allergic diseases.
AB  - Allergy defines the hypersensitivity reactions caused by allergen-specific
      immunoglobulin E binding to mast cells, being cross-linked by subsequent allergen
      exposure, and releasing mediators of immediate hypersensitivity that initiate
      inflammatory cascades. Allergic diseases have both genetic and environmental
      components. Growing concern about allergic disease comes from the observed
      increase in incidence and prevalence and association with the development of
      asthma. This risk appears to be compounded by Western lifestyle, including indoor
      environment, diet, air pollution, and psychological stress. With increasing
      understanding of these mechanisms, new and improved modes of therapy are being
      developed to manage and possibly prevent allergic sensitization.

PMID- 15176523
TI  - Inflammatory responses in allergic rhinitis: traditional approaches and novel
      treatment strategies.
AB  - Allergic rhinitis (AR) is associated with decreased learning, performance and
      productivity at work and school, as well as a reduced quality of life. With a
      staggering annual economic impact between 6 billion dollars and 8 billion
      dollars, AR affects 20% of the adult population and up to 40% of children.
      Effective therapy for allergic rhinitis requires understanding the
      pathophysiology of the disease, as well as the role of various inflammatory
      mechanisms. As such, various classes of medication are at the physicians'
      disposal to treat patients with allergic rhinitis. Among these are second
      generation antihistamines and anticholinergic agents, intranasal corticosteroids,
      and mast cell stabilizers. Recently, montelukast, a leukotriene receptor
      antagonist, has been added to the modes of therapy approved by the US Food and
      Drug Administration for allergic rhinitis. For patients refractive to standard
      pharmacologic intervention, immunotherapy has shown some promising results. As
      newer strategies emerge, treatment regimens for allergic rhinitis should continue
      to improve not only daytime symptoms, but also nighttime symptoms and sleep with
      the fewest possible adverse effects.

PMID- 15176524
TI  - [Improving the surgeon's image: introduction].
AB  - The number of medical students who aspire to become surgeons has been decreasing
      in recent years. With a vicious spiral in the decreasing number and the growing
      deterioration of surgeons' working conditions, there is fear of deterioration of
      surgical care and subsequent disintegration of overall health care in Japan. The
      purpose of this issue is to devise a strategy for improving surgeons' image and
      their working conditions to attract future medical students. However, we cannot
      expect a quick cure for the problem of the decreasing number of applicants for
      surgery since this issue is deeply related to many fundamental problems in the
      health care system in Japan. The challenge for surgical educators in coming years
      will be to solve the problem of chronic sleep deprivation and overwork of surgery
      residents and to develop an efficient program to meet the critical educational
      needs of surgical residents. To solve this problem it is necessary to ensure well
      motivated surgical residents and to develop an integrated research program. No
      discussion of these issues would be complete without attention to the allocation
      of scarce medical resources, especially in relation to financial incentives for
      young surgeons. The authors, who are conscientious representatives of this
      society, would like to highlight these critical problems and issues that are
      particularly relevant to our modern surgical practice, and it is our sincere hope
      that all members of this society fully recognize these critical issues in the
      Japanese health care system to take leadership in improving the system. With the
      demonstration of withholding unnecessary medical conducts we may be able to
      initiate a renewal of the system and eventually to fulfill our dreams of Japan
      becoming a nation that can attract many patients from all over the world.
      Furthermore, verification of discipline with quality control and effective
      surgical treatment is needed to avoid criticism by other disciplines for being a
      self-centered field. The Japanese Surgical Society appears to be the only medical
      society that is capable of leading a revolution in the health care system of this
      country with its autonomy and self-discipline. It is timely for the Japanese
      Surgical Society to consider a modification of its stated mission by adding "to
      improve the care of the surgical patient" as dictated by the American College of
      Surgeons.

PMID- 15176525
TI  - [To be a good expert surgeon].
AB  - The clinical and scientific level of Japanese surgeons leads the world needless
      to say, in the field of early gastric cancer, supported by double-contrast
      roentgenogram, endoscopy and surgical procedure including lymph node dissection
      with good outcomes. Surgical skills of Japanese surgeons have been improved by
      watching of cine or videotaped programs at the academic assemblies, breaking
      through apprenticeship. Ambitious young surgeons could freely learned excellent
      technical procedure from the pictures. Young surgeon must be an ever-thinking
      surgeon to get any hint on the film. Even though medical examinations and
      treatments including surgical procedures are on the way of standardization
      through EBM, manuals, guidelines and DPC payment system, medical doctors
      including surgeons must critically continue to think and seek for better
      treatment for the patients. Since the every patient differs in terms of age. sex,
      stage of disease, complicated conditions and social background, the treatment
      should be different, patient to patient, as tailor made fashion. Unless any
      progress is made, science and arts of medicine will decline. As another advice
      for a young surgeon from my experience you should write an operation protocol of
      every procedure by your self, even if that operation is the first experience or
      you joined as an assistant. After you wrote, you read the protocol by your
      instructor. Then you learn many knowledge and surgical know-how. Certainly, the
      book of the protocols will be your valuable treasure. Furthermore, you should not
      aim to be a skillful surgeon, but to be a good surgeon performing reliable and
      gentle operations for the patients.

PMID- 15176526
TI  - [Medical resource utilization and allocation in Japan--evaluation of surgical
      expenditures].
AB  - We evaluated the appropriateness of medical cost allocation in Japan from the
      global aspect especially the percentage of the national budget for medical cost
      to gross national product (GDP). Base on OECD-Health Data in 2002, Japan was
      ranked high in the world in terms of medical services but was ranked the second
      lowest in terms of the percentage of medical cost to GDP (7.6%) among G7 advanced
      countries. In addition, at surgical departments, allocated medical cost is mostly
      used for surgical supplies and instruments, and only negligibly for doctor's fee.
      Unless this situation is improved, the surgical department in Japan will decline.
      Improvement measures should be taken without delay.

PMID- 15176527
TI  - [Evidence-based surgical therapy: the significance of randomized controlled
      trials].
AB  - Evidence-based medicine supplies the information to solve clinical questions but
      there are specific problems of randomized controlled trials in surgery. First,
      placebo-controlled trials are need to determine the placebo effects, but patients
      sometimes refuse the placebo surgery. Furthermore, it remains difficult to decide
      on standard surgical procedures because the participating surgeons vary in skill
      and experience. However, randomized controlled trials are essential for the
      further development of a high-quality surgical standard.

PMID- 15176528
TI  - [A new residency program for Japanese surgical specialties].
AB  - Medical education, in general, should be a continuous and life-long persistent
      training for the purposes to be reached through the education of humanity and
      medical techniques which are the arts based on the sciences whichever originated
      from the western or eastern world histories. These training started from the
      student life through the termination of medical profession, especially in the
      field of surgery, the medical doctors are the only existence to be allowed to
      insult human body even for the purpose of treatment. These facts should be
      learned through well-trained experienced teachers with ethics, theories and
      evidence based medicine. The new training curriculum for 5 years program of the
      surgical specialties in Japan has built up and started just two years ago to be
      successful supported not only by medical teachers but also by the government and
      civilian economical foundations. A sort of national board of medical specialties
      is necessary system to develop general medical care system with effective
      specializations.

PMID- 15176529
TI  - [What basic surgical research brings to surgical clinics].
AB  - In this article, author describes the present problems of surgical clinics and
      the importance of basic research by young surgeons to improve the clinical
      outcomes of surgery.

PMID- 15176530
TI  - [The role and leadership of the Japan Surgical Society in the future reforms in
      surgery].
AB  - Changes in medical sciences medical technologies, and medical care system of
      Japan during the last decade are quick and drastic. Surgery seems to be losing
      its glory, and carrier as a surgeon seems no more appealing nor attractive to the
      graduates from the medical school. In order to recover its attractiveness and
      former glory, education and training system of surgery in medical school,
      curriculum and training system in surgical residency and continuing education
      should be revisited and reorganized. Also, critical evaluation of surgical care,
      and reform in fee schedules for each surgical procedures and operations are
      inevitable and it is also important that these informations should freely be
      accessible by patients as requested. The Japan Surgical Society is the oldest and
      the most prestigious society of surgery in Japan, and the society should take
      leadership and actively participate in future reforms in surgery.

PMID- 15176531
TI  - [A small heart hospital in downtown of Tokyo].

PMID- 15176532
TI  - [What we can learn from a case of medical malpractice].

PMID- 15176533
TI  - Hepatitis E virus and acute-on-chronic liver failure.

PMID- 15176534
TI  - Non-biliary mishaps during laparoscopic cholecystectomy.
AB  - BACKGROUND: The most important complications of laparoscopic cholecystectomy (LC)
      are biliary tract injuries. Non-biliary complications can be equally devastating,
      but have received less attention in literature. METHODS: The case files of 1748
      patients who underwent LC over a period of seven years (1997-2003) in our
      department were retrospectively reviewed to identify non-biliary complications
      and their management. RESULTS: Nine patients (0.5%) sustained significant non
      biliary injury while undergoing LC. The commonest was duodenal perforation during
      dissection of the Calot's triangle (3 cases). Other complications included
      diaphragmatic injury (2 cases), and small bowel injury while inserting the
      umbilical port, right external iliac artery injury during insertion of Veress
      needle, portal vein injury during dissection, and liver laceration while using a
      delivery system to extract the gall bladder (1 each). All these complications
      were detected and managed intra-operatively. During the same period, 10 patients
      sustained biliary injury. CONCLUSION: Intra-operative non-biliary injuries during
      LC occur as frequently as biliary injuries, and can be life-threatening and
      difficult to manage.

PMID- 15176535
TI  - Superimposed acute hepatitis E infection in patients with chronic liver disease.
AB  - BACKGROUND: The natural history of infection with hepatitis E virus (HEV) in
      patients with chronic liver disease (CLD) is not well described. Our study aims
      to document the presentation, course and outcome of HEV superinfection in
      patients with CLD. METHODS: Over an 18-month period, ten patients with CLD were
      diagnosed to have HEV superinfection by detection of anti-HEV IgM antibodies in a
      setting of acute worsening. These patients were tested for HBsAg, IgM anti-HBc,
      anti-hepatitis C virus antibodies and IgM anti-hepatitis A virus antibodies, and
      were followed-up. RESULTS: The etiology of underlying CLD in the 10 patients (9
      men; mean [SD] age 42.4 [10.3] years) was alcohol in five patients, hepatitis B
      in two, hepatitis C in one and cryptogenic in two. Seven patients presented for
      the first time with recent-onset liver decompensation (median duration 27 days,
      range 7-45). All 10 had ascites and 7 had hepatic encephalopathy. Four patients
      developed renal failure during the course of illness. The median (range)
      bilirubin, ALT and albumin levels at presentation were 18.6 (4.9-32.6) mg/dL, 105
      (28-6610) IU/L and 32 (29-41) g/L, respectively. At 8 weeks, only one patient had
      normalization of serum bilirubin or ALT levels. Three patients (30%) died,
      including two of renal failure and one of massive upper GI bleed. CONCLUSIONS:
      Superinfection with HEV in patients with CLD causes severe liver decompensation,
      which is frequently complicated with hepatic encephalopathy and renal failure.
      Acute hepatitis E in these patients has a protracted course with high morbidity
      and mortality.

PMID- 15176536
TI  - A randomized trial of oral refeeding compared with jejunal tube refeeding in
      acute pancreatitis.
AB  - BACKGROUND: Relapse of pain during refeeding in acute pancreatitis may have a
      relation to the route of refeeding. AIM: To compare the efficacy of oral
      refeeding with jejunal tube refeeding in patients with acute pancreatitis, and
      determine the frequency of refeeding pain and factors associated with it.
      METHODS: Consecutive patients with acute pancreatitis, severe enough to stop oral
      feeding for 48 hours, were randomized to receive either oral or jejunal tube
      refeeding. The feeds were similar in calorie, lipid and protein content (400 Kcal
      on day 1, 1000 Kcal on day 2, 1400 Kcal on day 3, 1500 Kcal on day 4, and 1700
      Kcal on day 5). Clinical and biological factors (serum amylase, lipase, C
      reactive protein) and Balthazar CT severity index were recorded. Frequency of
      pain relapse and factors associated with it were analyzed. RESULTS: 28 patients
      with acute pancreatitis (biliary 14, alcohol 9, idiopathic 3, post-ERCP 2) were
      included. Fifteen patients received oral and 13 received enteral tube refeeding.
      Four patients in the oral group and none in the enteral tube group had relapse of
      pain (p=0.06). The factors associated with refeeding pain were longer duration of
      initial pain (p<0.02) and higher CT severity index (p<0.02). Pain relapse
      increased the total hospital stay (p<0.004) and hospital stay after the first
      attempt at feeding (p<0.001). CONCLUSIONS: Jejunal tube refeeding may reduce the
      frequency of pain relapse as compared to oral refeeding although the difference
      was not significant in this study. Longer duration of pain and higher CT severity
      index score were associated with occurrence of refeeding pain.

PMID- 15176537
TI  - Transcatheter embolization as primary treatment for visceral pseudoaneurysms in
      pancreatitis: clinical outcome and imaging follow up.
AB  - BACKGROUND: Pseudoaneurysm formation is an uncommon but fatal complication of
      pancreatitis. The morbidity and mortality associated with surgical management is
      high. Transcatheter embolization is a definitive minimally invasive form of
      treatment. AIM: To review our experience with transcatheter embolization as a
      therapeutic modality for pseudoaneurysms complicating pancreatitis. METHODS: This
      retrospective analysis included data of 30 patients (mean age 37 years, range 25
      to 65; 24 men) with visceral pseudoaneurysms secondary to pancreatitis, who
      underwent diagnostic angiography and transcatheter embolization, during the
      period March 1993 to February 2003. RESULTS: In 29 patients the pseudoaneurysms
      were successfully isolated from the circulation, and hemostasis was achieved. Re
      bleeding occurred in one patient, for which re-embolization was done. Twenty-nine
      patients improved clinically. One patient in whom the pseudoaneurysm was
      successfully embolized died due to septicemic shock. CONCLUSION: Endovascular
      embolization is a safe and effective non-surgical modality of treatment for
      visceral pseudoaneurysms complicating pancreatitis.

PMID- 15176538
TI  - Hepatitis E virus is responsible for decompensation of chronic liver disease in
      an endemic region.
AB  - BACKGROUND: Hepatitis A virus infection in patients with previously stable
      chronic liver disease is associated with liver decompensation. Whether infection
      with hepatitis E virus (HEV) also does so is not known. METHODS: We studied 32
      patients with decompensated liver disease and definite evidence of underlying
      cirrhosis for evidence of recent HEV infection. RESULTS: Of 32 patients, 14 (44%)
      had detectable IgM anti-HEV in their serum. In comparison, only 3 of 48 (6%)
      patients with stable cirrhosis and no recent decompensation had such antibodies
      (p<0.0001). Of the 14 patients with evidence of recent HEV infection, 11 had
      history of prodrome. The etiology of cirrhosis in these patients was: hepatitis B
      6, hepatitis C 2, both hepatitis B and C 2, Wilson's disease 1, autoimmune 1 and
      cryptogenic 2. Two of these 14 patients died. Twelve patients survived, as
      compared to 9 of 18 patients without evidence of recent HEV infection (p<0.01).
      CONCLUSION: HEV infection is a frequent cause of decompensation in patients with
      liver cirrhosis in HEV-endemic regions.

PMID- 15176539
TI  - Psychological abnormalities in patients with irritable bowel syndrome.
AB  - Irritable bowel syndrome (IBS) is a group of functional bowel disorders with
      different pathophyiological mechanisms but some common clinical features. It can
      be conceptualized within the biopsychosocial model of illness as a dysregulation
      of brain-gut axis and its relationships with psychosocial and environmental
      variables. Using advanced neuro-imaging techniques, it has been found that some
      brain centers (anterior cingulate cortex, limbic system, locus ceruleus) are
      active in mediating gut signals and that visceral hyperalgesia mediates
      perceptual sensitivity. Using new criteria for diagnosing psychosocial components
      of somatic illnesses, persistent somatization has been found as one of the main
      psychological factors that contributes to persistence of symptoms and poor
      treatment outcome in patients with IBS. Other psychological variables influencing
      symptom reporting have been identified in the constructs of health-care seeking,
      abuse, somatosensory amplification, and alexithymia. From a psychological
      viewpoint, IBS may be conceived as an abnormal cognitive processing of emotional
      and visceral stimuli, a tendency to perceive somatic stimuli as evidence of
      symptoms of disease, and to seek repeated and often unnecessary medical care.

PMID- 15176540
TI  - Primary biliary cirrhosis and autoimmune hepatitis overlap syndrome.
AB  - Primary biliary cirrhosis and autoimmune hepatitis are chronic immune-mediated
      liver disorders. An overlap syndrome is now recognized with mixed biochemical,
      serological and histological features. We report a 55-year-old lady with overlap
      syndrome, which presented with jaundice, pruritus and associated renal failure.
      She succumbed to her illness.

PMID- 15176541
TI  - Hemobilia as presenting manifestation of polyarteritis nodosa.
AB  - Polyarteritis nodosa (PAN) is a multisystem necrotizing inflammatory vasculitis
      of medium-sized muscular arteries. Hepatobiliary complications secondary to
      thrombosis or aneurysm formation in PAN are rare and are associated with poor
      outcome. We describe an 18-year-old man with PAN who presented with hemobilia
      secondary to rupture of a hepatic artery aneurysm, which was successfully managed
      with coil embolization followed by immunosuppressive therapy.

PMID- 15176542
TI  - Heparin therapy for mistaken cardiac diagnosis in Boerhaave's syndrome.
AB  - We describe two patients with Boerhaave's syndrome who presented with chest pain
      mimicking cardiac pain and received heparin therapy. One patient developed large
      intramural esophageal hematoma as a complication of heparin therapy. The other
      patient had no hematoma and his course was dominated by esophageal rupture. Both
      were managed conservatively.

PMID- 15176543
TI  - Takayasu arteritis presenting as chronic mesenteric ischemia.
AB  - We report a 40-year-old man with Takayasu arteritis involving the abdominal
      aorta, who presented with chronic mesenteric ischemia. The diagnosis was made by
      aortogram, which showed tight superior mesenteric artery (SMA) stenosis. The
      patient underwent successful balloon angioplasty of the SMA following
      corticosteroid treatment. He is asymptomatic 9 months later; repeat aortogram
      showed no stenosis.

PMID- 15176544
TI  - Giant mesenteric cyst of abdomen herniating into scrotum.
AB  - Cystic mesenteric tumors are rare abdominal neoplasms. We report a 55-year-old
      man with recurrent benign mesothelioma arising from the left colonic mesentery
      and extending into the scrotal sac. He recovered well after excision of the
      abdominal and scrotal mass.

PMID- 15176545
TI  - Spontaneous gall bladder perforation: a rare entity in infants.
AB  - Spontaneous gall bladder perforation in infants is rare. We report a 3-month-old
      male infant who presented with progressive abdominal distension, low-grade fever,
      bilateral hydrocele and acholic stools. Ultrasonography showed free fluid in the
      peritoneal cavity, which was bile-stained on paracentesis. Surgical exploration
      revealed sterile biliary peritonitis and a gangrenous gall bladder. Partial
      cholecystectomy with external biliary drainage resulted in satisfactory recovery.

PMID- 15176547
TI  - Lactose malabsorption in apparently healthy adults in northern India, assessed
      using lactose hydrogen breath test.

PMID- 15176546
TI  - Cholecysto-hydatid cyst fistula.
AB  - A 27-year-old woman developed recurrent hydatid of liver. CT scan showed
      unilocular cysts in segments IV and VII. Intraoperatively, there was a fistulous
      communication between the gall bladder and the cyst in segment IV. Partial
      pericystectomy along with cholecystectomy was done for the segment IV cyst;
      percutaneous aspiration, instillation and re-aspiration using hypertonic saline
      was done for the cyst in segment VII. This was followed by albendazole treatment.

PMID- 15176548
TI  - Comparison of different staining methods with rapid urease test for rapid
      identification of Helicobacter pylorlin gastric biopsies.

PMID- 15176549
TI  - Laparoscopic cholecystectomy in a patient with situs inversus.

PMID- 15176550
TI  - Gastric outlet obstruction caused by gastrostomy tube balloon.

PMID- 15176551
TI  - A lawyer, thinking of the neuro fraternity, reflects upon recent judicial
      decisions.
AB  - This article presents a general review of medico-legal issues that have recently
      come before the Judges, e.g. consent, negligence, warning the patient of the
      risks and the convincing expert.

PMID- 15176552
TI  - Should airguns be banned?
AB  - In this article, we express concerns regarding the availability of airguns, the
      injuries that they cause and their abuse as weapons of assault. We wish to
      stimulate debate on this topic and report a 5-year retrospective analysis of all
      airgun injuries to the head and neck, presenting to Alder Hey Children's
      Hospital, Liverpool, from June 1998 to June 2003. We identified 16 patients who
      suffered such injuries with ages ranging from 5 to 15 years. The majority of
      cases were violent assaults, which is not in accordance with previous published
      reports. All of these occurred in public places outside the home. Most incidents
      occurred through the spring and summer period. Six patients required overnight
      stay in hospital. Nine patients required operative procedures to remove the
      airgun pellets. Two patients had serious eye injuries resulting in loss of
      vision. Two patients had penetrating neck injuries requiring exploration of the
      wound. The remaining group had either skin-penetrating injuries with lodgement of
      fragments in subcutaneous tissues or non-skin penetrating injuries. This study
      highlights serious injuries arising from the abuse of airguns as weapons of
      assault. Airguns are readily available to people without license. Recent
      legislation has increased the minimum age at which airguns can be carried in a
      public place, but we believe that stricter legislation is required to produce a
      reduction in the number of airgun-related injuries.

PMID- 15176553
TI  - Relationship between shunt-dependent hydrocephalus after subarachnoid haemorrhage
      and duration of cerebrospinal fluid drainage.
AB  - Subarachnoid haemorrhage (SAH) patients in Fisher group 3 have a high risk of
      vasospasm and chronic hydrocephalus. We have provided cisternal irrigation
      combined with a head-shaking method for preventing vasospasm in SAH patients. We
      investigated 76 SAH patients in Fisher group 3 who received cisternal irrigation
      with head-shaking to evaluate the relationship between the occurrence of
      hydrocephalus and various clinical factors, including duration of cerebrospinal
      fluid (CSF) drainage. Chronic hydrocephalus occurred in 25 patients (33%). The
      occurrence of hydrocephalus was associated with longer duration of CSF drainage
      (median, 13 days versus 9 days). By logistic regression analysis using
      significant factors, including age, preoperative neurological grade and Glasgow
      Outcome Scale, only the duration of drainage was independently associated with
      the occurrence of hydrocephalus (Odds ratio = 1.18 per day; 95% confidence
      interval, 1.02- 1.36). These results indicate that long duration of CSF drainage
      for preventing vasospasm may increase the occurrence of hydrocephalus.

PMID- 15176554
TI  - The impact of care on carers of patients treated for aneurysmal subarachnoid
      haemorrhage.
AB  - Over the last decade there has been an increasing awareness that psychosocial
      problems may persist in patients who have made apparently good recoveries after
      aneurysmal subarachnoid haemorrhage (ASAH). The caregivers of these patients are
      often relatives and it is becoming apparent that these carers frequently suffer
      psychosocial stress with associated morbidity. Previous studies have looked
      primarily at patients and few have included carers. We exclusively studied carers
      using simple validated questionnaires. We measured the effect on general and
      psychosocial health of the carers of patients treated for ASAH, 2-3 years after
      discharge. The majority of the carers (88.1%) were close relatives; 53.8% were
      experiencing social or emotional stress and 46.4% of these felt completely
      overwhelmed. The level of stress correlated positively with management
      complications, but not site of aneurysm or other aspects of treatment. We
      conclude that there is an argument for priority assistance for those carers
      predicted to be vulnerable to stress.

PMID- 15176555
TI  - Perioperative evaluation of carotid endarterectomy by 3D-CT angiography with
      refined reconstruction: preliminary experience of CEA without conventional
      angiography.
AB  - Three-dimensional CT angiography (3D-CTA) was employed for perioperative
      evaluation of carotid endarterectomy (CEA) as an alternative to conventional
      angiography. A total of 62 carotid arteries were examined before and after CEA,
      26 with an early 3D-CT system and 36 with multidetector helical CT allowing
      sophisticated reconstruction by a personal workstation. In addition to patients
      who had undergone conventional angiography at other institutes, 10 subjects
      underwent CEA on the basis of 3D-CTA findings alone. The findings provided
      detailed information with an excellent view of carotid stenoses. Volume rendering
      images comprehensively visualized lesions and surrounding structures as well as
      calcifications, which were also well depicted by maximum intensity projection
      images. Evaluation of the cerebral circulation is one problem that still requires
      solution, although cerebral vessels were delineated by 3D-CTA. One patient
      experienced transient hemiparesis, but no significant permanent deficit. We
      conclude that 3D-CTA is a safe and accurate modality that is a practical
      alternative to conventional perioperative angiography.

PMID- 15176556
TI  - A prospective study on the clinical effect of surgical treatment of normal
      pressure hydrocephalus: the value of hydrodynamic evaluation.
AB  - The effect of surgical treatment of patients with normal pressure hydrocephalus
      (NPH) is reported to be variable. Candidates for surgery have often been selected
      using hydrodynamic tests; however, the predictive value of such tests remains
      uncertain. Seventeen patients with idiopathic NPH underwent continuous
      computerized intracranial pressure (ICP) monitoring and a steady state lumbar
      infusion test determining the resistance to cerebrospinal outflow (R(out)). The
      patients were treated surgically and clinically re-examined approximately 6
      months postoperatively using a new NPH score. The effect of surgical treatment
      was good. The R(out) was positively correlated with the clinical state of the
      patients before treatment. After surgery, the R(out) correlated well with the
      improvement in gait and NPH score. Ventricular size was negatively correlated
      with hydrodynamic variables before treatment. Surgery reduced the ventricular
      size only slightly and the degree of reduction was linked to the R(out). ICP
      measurements could not predict outcome in NPH cases.

PMID- 15176557
TI  - Cardiopulmonary haemodynamic changes after severe head injury.
AB  - Haemodynamic studies were performed by pulmonary artery catheter in 15 patients
      with severe head injury. To our knowledge, few data are available about the
      detailed haemodynamic changes after head injury using pulmonary artery catheter.
      All patients were assessed by the Glasgow Coma Scale, computed tomography and
      intracranial pressure monitoring. We divided the patients into hypotensive and
      normotensive groups. All patients showed a high pulmonary vascular resistance and
      a high pulmonary capillary wedge pressure, probably due to pulmonary
      vasoconstriction. In the hypotensive group, the two major changes were a marked
      decrease of the cardiac index and a slight increase of systemic vascular
      resistance. The low cardiac index was the result of heart failure secondary to
      myocardial dysfunction. In contrast, the normotensive group was characterized by
      a high systemic vascular resistance that was induced by generalized
      vasoconstriction. Increased intracranial pressure is initially associated with an
      increase of the cardiac index and systemic vascular resistance, so patients with
      severe head injury also suffer from profound circulatory disturbance.

PMID- 15176558
TI  - Posterior midline approach for large anterior/anterolateral foramen magnum
      tumours.
AB  - The standard surgical approaches described for excision of anterior or
      anterolaterally placed foramen magnum (FM) tumours are the far lateral approach,
      the extreme lateral approach and the transoral approach. In general the posterior
      midline approach is considered not suitable for these lesions. We have operated
      on 27 patients with benign anterior/anterolaterally placed FM tumours in the last
      8 years. Thirteen of these were operated via the posterior midline approach. All
      these 13 patients had large or giant tumours displacing the cervicomedullary
      region posteriorly and laterally. This allowed adequate access through this
      approach with minimal handling of neural tissue. For small lesions, the far
      lateral approach was used. Most of the patients improved significantly
      neurologically. We recommend the standard midline posterior approach for
      large/giant FM tumours as the tumour size itself provides enough working space
      for the surgeon. For small lesions, the far lateral approach is preferred.

PMID- 15176559
TI  - Orbital lymphangioma and its association with intracranial venous angioma.
AB  - Orbital lymphangioma is an uncommon, benign cystic lesion, generally manifest in
      childhood. It usually presents with a slowly progressive proptosis, displacement
      of the globe, ptosis and restriction of eye movements. Occasionally, focal
      lesions may remain asymptomatic. Spontaneous intraorbital haemorrhage may cause
      acute proptosis, compressive optic neuropathy and loss of vision. An 8-year-old
      girl presented with progressive left proptosis and a unilateral soft tissue mass
      at the supraorbital frontal region. Multiple intracranial venous angiomas were
      seen on MRI. Surgical decompression of the optic nerve was performed because of
      progressive decrease in visual acuity. We review the relevant literature; rarity
      of the orbital lymphangioma and its association with non-contiguous intracranial
      vascular anomalies were emphasized.

PMID- 15176560
TI  - A thoracic complication of ventriculoperitoneal shunt: symptomatic hydrothorax
      from intrathoracic migration of a ventriculoperitoneal shunt catheter.
AB  - Thoracic complications of ventriculoperitoneal (VP) shunt are very rare. We
      report an unusual case of VP shunt intrathoracic migration, associated with
      symptomatic hydrothorax. The patient was successfully managed with revision. We
      reviewed the 10 cases reported in the literature and discussed the mechanism of
      shunt-tip migration.

PMID- 15176561
TI  - Langerhans' cell histiocytosis of the temporal lobe and pons.
AB  - Intracerebral Langerhans' cell histiocytosis (LCH) is rare and tends to involve
      the hypothalamus. The authors report a rare case of LCH in the temporal lobe that
      subsequently was followed by a brainstem lesion. This appears to be the first
      case of temporal lobe and brainstem LCH that has been treated successfully and
      published. A 24-year-old man complained of cacosmia and nausea with a slight
      headache. He had a left temporal LCH, which was removed completely, but developed
      a brainstem lesion a year later. The pontine LCH was treated with radiosurgery.
      The follow-up period was 4 years without any neurological or radiological
      symptoms or signs. The 12 cases of solitary intracranial non-hypothalamic LCH
      reported previously are reviewed. Gamma knife radiosurgery effectively controlled
      the local growth of the pontine LCH without adverse effect.

PMID- 15176562
TI  - Adcon -L gel and intraoperative hypotension during lumbar discectomy.
AB  - This case report describes an intraoperative hypotensive event associated
      temporally with application of topical Adcon -L gel during lumbar surgery.
      Documented serum cardiac and immunological markers suggest a non-anaphylactoid
      aetiology. The aetiology of this phenomenon is discussed with reference to
      available literature.

PMID- 15176563
TI  - Cystic trochlear nerve neurinoma mimicking intrinsic brainstem tumour.
AB  - Trochlear nerve neurinomas are very rare with less than 20 surgically proved
      cases reported in the literature. A case of histologically proved cystic
      trochlear nerve neurinoma, which was mimicking an intrinsic brainstem tumour is
      reported here. The tumour was totally excised. The clinical features and surgical
      management are described and the literature reviewed.

PMID- 15176564
TI  - Sigmoid sinus thrombosis in a child after closed head injury.
AB  - Sigmoid sinus thrombosis in children following a closed head injury is rare. The
      authors report such a case with the clinical presentation, radiological findings
      and current literature.

PMID- 15176565
TI  - Candida albicans spondylodiscitis.
AB  - Candida spondylodiscitis is a rare complication of a haematogenous dissemination
      of a candida infection, that usually affects immunocompromised patients. We
      present a case of a Candida albicans spondylodiscitis in a patient in whom a
      bacterial origin was suspected because of the antecedent of a Staphylococcus
      aureus bacteriaemia. After unfavourable evolution with initial antibiotic
      treatment, the correct diagnosis was reached after culture of the material
      obtained from surgical debridement. The clinical, diagnostic features, and the
      literature are reviewed.

PMID- 15176566
TI  - Complete surgical excision of intramedullary schwannoma at the craniovertebral
      junction in neurofibromatosis type-2.
AB  - Intramedullary spinal schwannomas are extremely rare. We describe a case of a 13
      year-old female who was found to have an intramedullary schwannoma at
      craniovertebral junction along with incidental bilateral acoustic neuromas, which
      was excised completely. To our knowledge, this is the first report of a case of
      intramedullary schwannoma in association with NF-2 located at the craniovertebral
      junction. The literature has been reviewed with emphasis on radiological imaging,
      histopathological diagnosis and technique to achieve complete microsurgical
      excision.

PMID- 15176567
TI  - Vascular threat in base of skull fractures.

PMID- 15176568
TI  - Spinal cord infarction caused by malignant intramedullary glioma: the traps of
      epidemiology and travel history.

PMID- 15176569
TI  - Endovascular treatment of anterior communicating artery aneurysms.

PMID- 15176570
TI  - [In reference to "Factors that influence early breast-feeding cessation among
      working women"].

PMID- 15176571
TI  - [Seroprevalence of Chlamydia trachomatis among Mexican women].

PMID- 15176572
TI  - [Compensated sex: a practice at the heart of young Mexican women's
      vulnerabilities (STI/HIV/AIDS)].
AB  - OBJECTIVE: To discuss the risks for Mexican young women who engage in sexual
      relations in exchange for social or economic benefits, also known as compensated
      sex (CS), with the objective of exploring its possible public health
      implications. MATERIAL AND METHOD: This is a qualitative study conducted in
      youths 15 to 25 years of age in Cuernavaca, Morelos, Mexico, between September
      2001 and December 2002. The theoretical framework included sociology of
      knowledge, post-structuralism, and gender studies. Research methods consisted of
      six focal groups and eight interviews with young subjects identified or self
      declared as having practiced CS. RESULTS: To conceal their CS practices as a way
      to obtain social or economic benefits, young girls disguise it as "courtship" and
      subject themselves to rules and behaviors that restrain them in terms of condom
      use and expose them to sexually transmitted infections (STI). CONCLUSIONS:
      Although CS itself may not necessarily constitute a risky practice, the courtship
      context in which young women tend to develop these practices exposes them to a
      greater risk of STIs.

PMID- 15176573
TI  - Prevalence and determinants of male partner violence against Mexican women: a
      population-based study.
AB  - OBJECTIVE: To determine the prevalence of and risk factors for violence against
      women, inflicted by their male partners, in a representative sample of women
      residing in the metropolitan area of Cuernavaca Morelos, Mexico. MATERIAL AND
      METHODS: A population-based study was conducted from June to September 1998,
      among 1,535 women aged 15 to 49 years. Principal components analysis was used to
      determine the domains of violence that served as the dependent variable.
      Polynomial logistic regression models were used to estimate odds ratios (OR),
      with 95% confidence intervals (CI). RESULTS: Prevalence of low-moderate level
      violence was 35.8%, while prevalence of severe violence was 9.5%. The lifetime
      prevalence of reported rape was 5.9%. The main factors associated with violence
      were socio-economic status (OR=0.57; 95% CI=0.34-0.95); education level, both of
      the women studied (test for trend p=0.01) and of the male partner (test for trend
      p=0.002); number of years living with partner (OR=2.63; 95% CI=1.55-4.45),
      alcohol use (OR=2.56; 95% CI=2.02-3.25), illegal drug use by partner (OR=6.17;
      95% CI=2.37-16.03); violence during childhood (OR=3.40; 95% CI=2.23-5.18), and a
      history of rape (OR=5.89; 95% CI=2.78-12.5). CONCLUSIONS: Study findings confirm
      that violence against women is a prevalent phenomenon in Mexico. Awareness
      raising campaigns about male partner violence should bring this important issue
      to the front of public discussion. Such efforts will help assure that future
      generations do not experience partner violence to the extent that contemporary
      Mexican women do.

PMID- 15176574
TI  - [The social representation guiding parental decisions to face drug consumption of
      their teenage children].
AB  - OBJECTIVE: To identify the social representation guiding decisions of parents of
      teenage drug users to face consumption of their children. MATERIAL AND METHODS: A
      qualitative study using free lists, characterization questionnaires, and in-depth
      interviews was performed among 60 systematically selected parents of young drug
      users who were receiving treatment in Centros de Integracion Juvenil. Data
      analysis included correlations and interpretive analysis. RESULTS: Three stages
      were identified: 1) discovery of the addiction, characterized by parental
      disappointment; 2) permanence: The highest in duration, resource investment, and
      losses; and 3) withdrawal: Featured by seeking health services. CONCLUSIONS: The
      representation that guided parental decisions was "the offer of a better world",
      which stemmed from the social, cultural, and family context that revolves around
      consumption and that was sustained by two beliefs: "Learning from mistakes" and
      "where there is a will there is a way".

PMID- 15176575
TI  - [Onset of alcohol and tobacco use and transition to other drug use among students
      from Morelos, Mexico].
AB  - OBJECTIVE: To estimate the cumulative probability of occurrence of first use of
      alcohol and tobacco, and the risk of transition to illegal drugs (marijuana,
      cocaine, and heroine, among others), in adolescents and young adults, in Morelos
      State, Mexico. MATERIAL AND METHODS: A cross-sectional study was conducted during
      schoolyear 1998-1999, among 13 293 students aged 11-24 years, selected from
      public schools by probabilistic multistage sampling. Data were collected on
      sociodemographic, health status, and substance abuse variables, using a validated
      self-applied questionnaire. Data were restructured to assemble a synthetic cohort
      for discrete time survival analysis. Associations were assessed with hazard rates
      and 95% confidence intervals obtained by means of multivariate Cox regression
      models. RESULTS: Sixty percent of males started drinking alcohol at 17 years of
      age, and smoking tobacco at 18 years of age, on average. Women started using
      alcohol and tobacco one year after men. Utilization of illicit drugs occurred at
      19 years of age on average in 5% of women and 13% of men. Nine out of every 100
      illicit drug users started directly using illicit drugs without previous use of
      alcohol and/or tobacco. In general, alcohol or tobacco users were at greater risk
      of starting drug use than nonusers (RR=6.72; 95 % confidence interval [CI]=4.13
      10.93). CONCLUSIONS: Study findings suggest that interventions to decrease drug
      abuse should go together with efforts to delay initiation of alcohol and tobacco
      use. The innovative method used in this study yields epidemiologic evidence
      relating early use of alcohol and tobacco with initiation of illegal drugs in
      Mexican students.

PMID- 15176576
TI  - [Epidemiology of congenital hypothyroidism in Mexico].
AB  - OBJECTIVE: To describe the epidemiological characteristics of congenital
      hypothyroidism (CH) in newborns (NB) detected by the Ministry of Health of Mexico
      (SSA). MATERIAL AND METHODS: A cross-sectional study was conducted. Thyroid
      stimulating hormone (TSH) was quantified in 1,379,717 blood samples of NB (from
      umbilical cord or heel prick), collected in Guthrie cards, between January 2001
      and December 2002, in medical units of the SSA. The samples with TSH > or = 15
      microUI/ml for cord blood and > or = 10 microUI/ml for heel blood were considered
      suspicious and were submitted for confirmation by thyroid hormone profile and/or
      scintigraphy. When the results were positive, the case was registered as
      confirmed CH and the clinical and demographic data were recorded in specific
      formats. Statistical analysis was performed using descriptive statistics.
      RESULTS: The prevalence of CH was 4.12 x 10,000 NB, with female predominance
      (66.84%). Regional variations in the prevalence were observed, the highest in
      Quintana Roo (8.13 x 10,000 NB) and the lowest in Sinaloa (0.62 x 10,000 NB).
      Abnormalities included 57.46% of ectopic glands, 35.91% of athyrosis, and 6.63%
      abnormal thyroid function conditions. The main clinical features were umbilical
      hernia (43.73%) and jaundice (41.58%). A total of 151 (17.12%) suspicious NB were
      not confirmed because of incomplete or inaccurate identification data, death of
      the NB, parent refusal, and change of address. CONCLUSIONS: CH was present in
      1:2,426 NB, with a female predominance (2:1); an ectopic thyroid was the most
      common finding, and its prominent clinical features were umbilical hernia and
      jaundice.

PMID- 15176577
TI  - [RAPD-PCR characterization of Pseudomonas aeruginosa strains obtained from cystic
      fibrosis patients].
AB  - OBJECTIVE: To characterize P. aeruginosa strains isolated from bronchoalveolar
      lavage fluid of cystic fibrosis (CF) patients over a 3 year period. MATERIAL AND
      METHODS: A prospective follow-up study was carried out in a population of cystic
      fibrosis patients. The random amplified polymorphic DNA (RAP.D) technique was
      used to amplify DNA of P. aeruginosa strains isolated from bronchoalveolar lavage
      fluid samples of five CF patients from the Servicio de Neumologia y Cirugia del
      Torax del Instituto Nacional de Pediatria (Mexico City Chest Clinic of the
      National Pediatrics Institute) in Mexico City, between June 1996 and June 2002.
      Amplification patterns were established for each isolate to accurately identify
      all strains and to carry out an epidemiological analysis of P. aeruginosa among
      the selected CF patients. RESULTS: Eighteen different DNA amplification patterns
      were defined and used to identify each P. aeruginosa strain isolated from the
      different bronchoalveolar lavage samples. No correlation was observed between the
      different P. aeruginosa strain genotypes and mucoid or non-mucoid phenotypes, as
      strains with different phenotypes showed similar amplification patterns. Several
      strains with different amplification patterns were identified in samples obtained
      from the same patient, suggesting coinfection with ore than one P. aeruginosa
      strain. Two siblings with CF shared similargenotypes, suggesting the occurrence
      of cross- contamination. Similar genotypes of P. aeruginosa strains were isolated
      throughout the study period. CONCLUSION: Genotypic characterization of P.
      aeruginosa strains in CF patients allows more accurate epidemiological analyses
      of this important host-agent relationship.

PMID- 15176578
TI  - [Evaluation of integrated management of childhood illness against malnutrition in
      urban areas of Nayarit, Mexico].
AB  - OBJECTIVE: To assess the association between coverage of the Integrated
      Management of Childhood Illness (IMCI) strategy and the prevalence of stunting in
      children 6 to 36 months of age. MATERIAL AND METHODS: A cross-sectional study was
      conducted in two urban areas of Nayarit, Mexico, in August 2002. Anthropometry,
      health care for mothers and their children, morbidity and socioeconomic data were
      collected by means of household interviews. Statistical analyses were performed
      with chi-squared tests, Fisher's exact test, and logistic regression. RESULTS:
      IMCI coverage rates were as follows: immunization 97%, vitamin A supplementation
      66.9%, deworming with albendazole 91.5%, nutritional surveillance 50%, maternal
      health education 25.5%, maternal health care 24.4%, and 2.5% overall. The
      prevalence of stunting was 4.9%, and was statistically associated with incomplete
      courses of vitamin A supplementation and albendazole deworming. CONCLUSIONS:
      Coverage of IMCI components varied according to their feasibility and time of
      implementation. The associations between IMCI and failure to thrive highlight the
      importance of obtaining more information about its effects on the nutritional
      status of children. This will help to improve prevention strategies against child
      malnutrition.

PMID- 15176579
TI  - [Health in a Mexico in transition].

PMID- 15176580
TI  - [Mexico's mortality statistics: deaths registered in 2002].

PMID- 15176581
TI  - [Avian influenza: should we be concerned?].

PMID- 15176582
TI  - [Classification of mental retardation in child neurology].

PMID- 15176583
TI  - [New challenge for social activities in the Japanese Society of Child Neurology-
      establishment of Social Activity and Public Relations Committee: introductory
      remarks].
AB  - The Japanese Society of Child Neurology newly established Social Activity and
      Public Relations Committee for the purpose of flexible response to the social
      event publicity. The committee consists of more than 36 members and is divided
      into the following sub-committees: Sub-committee 1 is intended to support the
      management and care of patients with developmental disabilities from infancy to
      adolescence, Sub-committee 2 devoted to the acquisition of research grants and
      the communication of basic scientific research, and Sub-committee 3 to coordinate
      and support medical-educational relationship. These three sub-committees achieved
      many of their goals during their stated first year of existence.

PMID- 15176584
TI  - [Social support by an academic meeting].
AB  - This report is made for the Japanese Society of Child Neurology to determine the
      social problems regarding handicapped children and youngsters. In 2002, Social
      Activity and Public Relations Committee was organized in the Society, and
      immediately pointed out some social problems, such as medical care for severely
      handicapped children in special schools.

PMID- 15176585
TI  - [Driving license of patients with epilepsy, management of their oral drugs and
      suppositories by non-medical professionals, and the role of pediatric
      neurologists].
AB  - In June 2002, the following new driving regulations were enforced in Japan: 1. A
      person with epilepsy may be granted a driving license after a seizure-free period
      of two years. 2. A person with simple partial seizures that would not impair
      driving safety may be granted a driving license if no other seizures that may
      impair driving safety have occurred over a period of at least one year. 3. A
      person with seizures occurring only in sleep may be granted a driving license if
      no seizures have occurred in waking over a period of at least two years. 4. In
      case that the above requirements are going to be met within 6 months, driving
      should be prohibited for 6 months. 5. A person with epilepsy is recommended to
      apply for a license to drive heavy and/or public vehicles only after a seizure
      free period of 5 years without medication. The committee for legal problems of
      the Japan Epilepsy Society proposed a guideline for non-medical teaching or
      caring professionals to give children with epilepsy antiepileptic medication or
      to insert suppositories, if needed, at schools or care institutions. The
      guideline indicated the following preconditions as important: 1. There must be a
      wish and consent of the patient or his/her family. 2. Drugs or suppositories are
      usually taken or used at home and regarded as a safe procedure. 3. Attending
      doctor should provide clear information about the use and risk of the medication
      or suppository. 4. Privacy of the patient should be protected. Pediatric
      neurologists are expected to play an important role on these issues.

PMID- 15176586
TI  - [Actions to improve daily medical care for children with severe neurological
      impairment in school and community life].
AB  - With an increasing number of children with severe neurological impairment living
      in their houses, there is growing demand for daily medical care such as tube
      feeding and sputum suctioning in schools and community life. On the basis of
      activities of many neuro-pediatricians in many districts. Social Activity and
      Public Relations Committee made a detailed statement about this problem, and
      appealed to the government and other related institutions, which promoted
      governmental activity on this problem. The system of neuro-pediatricians'
      participation to schools should be improved. Medical support in community life
      requires further discussion and proposal.

PMID- 15176587
TI  - [Asking for cooperation with parents and special staff].
AB  - There is no doubt that the purpose of pediatric neurologic medicine is to improve
      the quality of life of children with neurologic diseases and disabilities by
      medical care based on scientific evidence. It is also necessary to help these
      children to live in their families and society from a professional viewpoint. The
      course of social activity of the Japanese Society of Child Neurology will be
      decided by Social Activity and Public Relations Committee, to which appropriate
      information should be provided by accumulation of social activities of individual
      members. This paper illustrates the individual activity through my own
      experience.

PMID- 15176588
TI  - [Current state of research funds and research facilities of the members of the
      Japanese Society of Child Neurology].
AB  - The state of research funds and research facilities was analyzed by a
      questionnaire sent to members of the Council of the Japanese Society of Child
      Neurology. Research funds were most frequently about 5 million yen, and only 10%
      of the responder received 10 million yen or more. Still, many of them replied
      that they were satisfied with their research funds. Research funds of the
      Japanese Society of Child Neurology are considered to be in a critical condition.
      Most of the responders wanted information about research funds and a campaign to
      raise them organized by the Society.

PMID- 15176589
TI  - [Cooperation between medicine and education].
AB  - In cooperation between medicine and education, a reciprocal understanding is
      important. For this reason, we researched the needs of medical and educational
      professionals by questionnaires. Many child neurology specialists agreed that
      their medical profiled are unveiled in public about attending developmental
      disabilities. Some educational professionals felt it necessary to be given to
      offer medical informations of students such as treatments and/or diagnosis of
      their disease, to attend to seminars and lectures on developmental disabilities,
      and to obtain consultations of doctor more easily. From the above results, we
      propose an ideal cooperation between medicine and education.

PMID- 15176590
TI  - [The move from institution to community of the physically and mentally disabled
      children in public supporting system in Japan].

PMID- 15176591
TI  - [Guidelines for medical examination of children with mental retardation in
      pediatric clinics which are specialized for developmental disorders-
      recommendation based on the current selection and usefulness of diagnostic
      examinations for children with mental retardation and/or pervasive developmental
      disorder].
AB  - We assessed the present status of choice and usefulness of medical examinations
      of children with mental retardation (MR) and/or pervasive developmental disorder
      (PDD). Children with severe MR received more examinations than those with mild
      MR. Many abnormal findings were demonstrated by MRI in cases of severe MR. Cases
      of PDD without MR rarely showed abnormal results. Cases of PDD with MR underwent
      fewer examinations, but showed more abnormal results. We presented guidelines
      regarding medical examinations for children with MR in pediatric clinics which
      are specialized for developmental disorders, including psychological tests,
      hearing tests, EEG, genetic tests and neuroimaging. Physicians should select
      appropriate medical examinations based on evidence. The goal of testing is to
      provide useful information concerning medical treatment, therapeutic rearing, and
      education, and to support patients and their families in cooperation with
      relevant facilities.

PMID- 15176592
TI  - [Informed consents for family of children with mental retardation in pediatric
      clinics].

PMID- 15176593
TI  - [Evaluation of appropriate medical testing of developmental delay/mental
      retardation].

PMID- 15176594
TI  - [Evaluation of the child with mental retardation with or without autism].

PMID- 15176595
TI  - [Clinical neurophysiological study of verbal and non-verbal sound perception:
      normal development of P300 event-related potential to different sound stimuli].
AB  - Developmental changes of P300 event related potential were evaluated in healthy
      children and adults aged from 7 to 29 years old, adopting 2 pairs of oddball
      stimuli: a non-verbal sound (tone burst: TB) pair and a verbal sound (VS) pair.
      P300 was evident for the target stimuli. In adult subjects, P300 was dominant at
      Pz for both stimuli. Peak latency of P300 was significantly longer for VS than
      for TB in both groups. P300 amplitude of the child group was higher than that of
      the adult group, however, there was no difference in P300 amplitude between
      stimuli conditions. Developmental changes of P300 from each stimuli condition
      were simulated by a quadratic equation. The age showing the shortest P300 peak
      latency was younger for TB (20.3 years) than for VS (23.6 years). The P300 peak
      latency reduced around 10 years old more rapidly for VS than for TB. In
      conclusion, there was no difference of the dominancy of P300 between the stimuli.
      The developmental changes of P300 were regulated by several components of the
      sound stimuli, such as their frequency.

PMID- 15176596
TI  - [Assessment of social networks between developmental physicians and welfare
      facilities/specialists for children with intellectual disabilities in Japan].
AB  - The social networks between Japanese child neurologists and welfare
      facilities/specialists for children with mental retardation (MR) were assessed. A
      total of 113 physicians answered our mail-in questionnaire. Most of the doctors
      had various connections with nursery homes for children with MR or severe motor
      and intellectual disabilities (SMID) and with public health centers, and often
      collaborated with teachers of schools and kindergartens. On the other hand, most
      physicians had little relation with residential and vocational facilities for
      adults with MR, and with specialists in residential or community care. There was
      a statistical correlation between the number of facilities or collaborated
      specialists and the number of persons seen by each physician; however, the
      physicians' experience and affiliations had no relation. In view of 'social
      participation', physicians who usually see children with developmental disorders
      can play an important role in decision making of their life-style with their
      families.

PMID- 15176597
TI  - [A study of the relationship between initial febrile seizures and human herpes
      virus 6, 7 infections].
AB  - The DNA detection of human herpes virus (HHV) 6, 7 was performed in the patients
      who visited to the Nakano children's hospital because of their initial febrile
      seizures (FS). Those patients included 35 boys and 21 girls under 3 years of age
      (mean: 1 year 4 months). DNAs of HHV 6, 7 in the mononuclear cells extracted from
      peripheral blood were detected in 84% of the patients. This study proved that at
      least 34% of initial FS are caused by HHV 6 or 7 infections. Forty-seven percents
      of the patients who were clinically diagnosed as exanthema subitum showed complex
      type FS. In conclusion, HHV 6 and 7 infections are often related to the
      occurrence of initial FS, which may be in part caused by their direct invasion to
      the central nervous system.

PMID- 15176598
TI  - [A case of severe mental retardation with blepharophimosis, ptosis,
      microphthalmia, microcephalus, hypogonadism and short stature--the difference
      from Ohdo blepharophimosis syndrome].
AB  - We report a case of 13-year-old girl with short stature, microcephalus,
      blepharophimosis, ptosis, bilateral microphthalmia (more prominent in the right),
      hypogonadism, other minor anomalies, and severe mental retardation. Her mother
      had two spontaneous abortions. She was born as the second baby of dizygotic
      twins. The first baby died of diaphragm hernia and heart failure. Her body
      height, body weight and head circumference were below -3 SD. She did not have
      epicanthus inversus, hypoplastic teeth, heart anomalies, seizures, muscle
      weakness, and hearing loss. She was able to handle her wheelchair, but could
      neither understand nor speak meaningful words. When she looked at something in
      front of herself, she turned her face up and lifted the left eyelid with her own
      fingers. She had no somatic change of puberty. Laboratory and radiological
      examinations demonstrated a normal karyotype, normal bone age, findings of
      Chilaiditi syndrome, and absence of brain malformation on cranial CT. The serum
      levels of LH and FSH were high for age and those of estradiol and progesterone
      were low, suggesting immaturity of ovarian function. These findings suggested the
      ovarian functions might not get maturations. Hypogonadism has previously been
      reported in female cases of the blepharophimosis, ptosis and epicanthus inversus
      syndrome (BPES) type I, but not in those with the Ohdo blepharophimosis syndrome
      (OBS). Our case's condition differs from BPES because of the presence of mental
      retardation and the absence of epicanthus inversus. We also discuss the
      distinction from OBS, a disease entity of unknown etiology presenting with a
      variety of complications.

PMID- 15176599
TI  - [The characteristic features of the N30 and N20 components of the short latency
      somatosensory evoked potential in median nerve stimulation in diplegic patients-
      comparison with other types in cerebral palsy].

PMID- 15176600
TI  - Mimics of brain tumor on neuroimaging: part I.
AB  - Brain tumor is a distinct pathological entity that differs from other diseases,
      including cerebrovascular, demyelinating, inflammatory, infectious, and various
      miscellaneous diseases. Insidious onset and gradual progression of signs and
      symptoms are common in patients with brain tumors, whereas the onset of
      cerebrovascular diseases is usually acute or sudden. Patients with demyelinating,
      inflammatory, or infectious diseases show subacute onset. Differentiation of
      brain tumors from other disorders is usually possible from the clinically and
      radiologically characteristic features. However, in some diseases other than
      brain tumors, an atypical clinical course and/or radiological findings may
      suggest or simulate those of brain tumors. The diagnosis of brain tumor is
      confirmed histopathologically, and appropriate therapies are given to the patient
      based on the histopathological type and grade of the tumor. In order to obtain a
      specimen for histopathological examination, surgical intervention is required.
      Other diseases are usually diagnosed clinically and radiologically. Invasive
      procedures should be avoided in making a diagnosis. Therefore, differentiation of
      brain tumors from other diseases is a critical issue for neuroimaging. Detailed
      inspection of images is necessary, and characteristic findings, and additional
      imaging methods, such as diffusion-weighted imaging, are often helpful for the
      differential diagnosis. We assess the imaging findings of diseases simulating
      brain tumors and review the literature.

PMID- 15176601
TI  - Efficacy of multi-slice helical CT venography for the diagnosis of deep venous
      thrombosis: comparison with venous sonography.
AB  - OBJECTIVE: The purpose of this study was to assess the efficacy of contrast
      enhanced multi-slice helical CT (MSCT) venography for the diagnosis of deep
      venous thrombosis (DVT) in comparison with venous sonography. MATERIALS AND
      METHODS: MSCT was used to obtain contiguous, 5-mm thick axial CT images from the
      diaphragm to the ankles of 27 patients after intravenous injection of contrast
      material. These patients were clinically suspected of having DVT. The same
      patients underwent venous sonography before CT examination. The detectability of
      DVT with MSCT venography was compared with that with venous sonography. RESULTS:
      MSCT venography detected DVT in 21 patients, but venous sonography did so in only
      17. MSCT venography detected DVT missed by venous sonography in five patients,
      while venous sonography detected DVT missed by MSCT venography in one patient.
      CONCLUSION: MSCT venography can be expected to make a valuable contribution to
      the diagnosis of DVT and to the prophylaxis of pulmonary embolism.

PMID- 15176602
TI  - A trial to measure local lung volume changes during respiration with CT.
AB  - PURPOSE: To evaluate changes in volume and the CT attenuation value of the
      pulmonary lobes and peripheral small lung tissue at full inspiration and
      expiration. MATERIALS AND METHODS: We designated (1000+CT insp)/(1000+CT
      exp)(1000+CT insp)/(1000+CT exp) as CT volume ratio, a new parameter to represent
      volume changes in lung tissue, and V insp/V exp as actual volume ratio: CT insp,
      exp: CT attenuation value of measured lung at inspiration and expiration; V insp,
      exp: actual lung volume measured with CT at inspiration and expiration. Ten
      normal healthy volunteers were investigated with 5 mm collimation CT in the
      supine position. RESULTS: The CT volume ratio and actual volume ratio of each
      lung lobe were well correlated. The CT volume ratios of small lung tissues were
      significantly larger in the dependent region than in the nondependent region when
      measured in the supine position at five levels, except at the level of the aortic
      arch (P<0.05). CONCLUSION: We advocated a new parameter (CT volume ratio) for
      representing lung tissue volume changes during respiration. The CT volume ratio
      might be a new noninvasive method to measure local volume changes in lung during
      respiration.

PMID- 15176603
TI  - Comparison between tissue harmonic imaging and liver-specific late-phase contrast
      enhanced pulse-inversion imaging in the detection of hepatocellular carcinoma and
      liver metastasis.
AB  - PURPOSE: To assess whether liver-specific late-phase contrast-enhanced pulse
      inversion (CE-PI) ultrasound imaging improves the detection of hepatocellular
      carcinoma (HCC) and liver metastasis in comparison with non-enhanced tissue
      harmonic imaging (THI). SUBJECTS AND METHODS: Twenty-one patients with HCC or
      liver metastasis were studied using standardized ultrasound harmonic settings.
      Sweeps through the hepatic lobes were done by THI, followed by late-phase CE-PI
      after Levovist injection. The number and segmental location of nodules detected
      by each method were recorded and compared with dynamic helical computed
      tomography (CT) as a reference. RESULTS: Sensitivity for the presence of the
      disease, metastasis or HCC, on a patient basis for each method was 81.0% for THI
      and 90.5% for CE-PI. Among the 78 metastatic nodules on reference CT, 31 true
      positive, three false-positive, and 47 false-negative nodules were found by THI,
      while CE-PI depicted 54 true-positive, 12 false-positive and 24 false-negative
      lesions. Sensitivity in the detection of individual lesion was 51.8% for THI and
      76.8% for CE-PI (p=0.0273). A total of 58 HCC nodules were detected on CT; 36
      true-positive, 15 false-positive, and 22 false-negative lesions were found by
      THI; while CE-PI depicted 43 true-positive, six false-positive, and 15 false
      negative lesions. Sensitivity in the detection of individual HCC was 42.9% by THI
      and 57.2% by CE-PI (p=0.2249 NS). CONCLUSION: In patients with liver metastasis,
      CE-PI statistically improved the sensitivity of lesion detection compared with
      THI. Conversely, CE-PI did not improve the sensitivity of lesion detection in
      patients with HCC.

PMID- 15176604
TI  - Quantitative evaluation of changes in irradiated lung fields after stereotactic
      irradiation by the Polygon Method.
AB  - PURPOSE: To evaluate areas of change in lung after thoracic stereotactic
      irradiation (STI). MATERIALS AND METHODS: We developed a method of evaluation
      named the Polygon Method, to measure the irradiated lung fields of 12 lung tumors
      treated by STI. Before treatment, each targeted field was divided into several
      circular zones of 2 cm in width centered at the tumor on high resolution computed
      tomography, and the areas of each zone before and after treatment were compared.
      RESULTS: Six months after treatment, the areas of the zone within 2 cm from the
      tumor decreased, and the mean ratio of areas after and before STI was 0.849
      (range, 0.515 to 1.052, p=0.0254). By contrast, the areas of zones located at 4
      to 6, 6 to 8, 8 to 10, and more than 10 cm from the tumor tended to increase,
      with mean ratios of 1.059, 1.058, 1.089 (p=0.0374), and 1.084, respectively.
      CONCLUSION: After thoracic STI, volume loss in the lung is limited to the field
      in close proximity to the tumor, while compensatory expansion of the lung occurs
      in fields distant from the tumor.

PMID- 15176605
TI  - Postoperative irradiation in cervical cancer: prognostic factors and outcome.
AB  - PURPOSE: The aim of this study was to evaluate prognostic factors and outcomes in
      patients with cervical cancer who underwent hysterectomy followed by pelvic
      irradiation. METHODS: This was a retrospective chart review of 140 patients with
      carcinoma of the cervix. The indications for irradiation were an incidental
      finding of invasive cancer, positive lymph nodes, parametrial extension of tumor,
      and positive or close margins. RESULTS: The 10-year cause-specific and overall
      survival rates were 72% and 69%, respectively. Recurrences developed at the
      following sites: five in the pelvis, four in the pelvis and with distant
      metastasis, and 13 with distant metastasis. Parametrial extension of tumor was
      the only significant prognostic factor for developing recurrent disease
      (p=0.004). Complications were grade 3 in 10 and grade 4 in 18. Leg edema occurred
      in patients undergoing radical hysterectomy and lymph node dissection, but not in
      patients undergoing simple hysterectomy (p=0.01), and was more likely if
      irradiation was begun within six weeks of surgery compared with starting
      irradiation after six weeks (p=0.02). CONCLUSION: Pelvic irradiation produced
      pelvic control of disease in 94%. Distant metastasis was the most common site of
      failure. Chronic toxicity was greatest if irradiation was begun less than six
      weeks postoperatively.

PMID- 15176606
TI  - Role of preoperative helical CT before laparoscopic cholecystectomy: evaluation
      of gallbladder and peritoneal adhesion.
AB  - OBJECTIVE: The purpose of this study was to assess the value of preoperative
      helical CT for the detection of adhesion of the gallbladder or surrounding
      peritoneum. SUBJECTS AND METHODS: Dynamic-enhanced helical CT of the abdomen was
      obtained before laparoscopic cholecystectomy in 47 patients. Images were
      reconstructed with a 5-mm interval. Appearances on CT images were correlated with
      operative findings, and useful findings for predicting gallbladder or peritoneal
      adhesion were determined by univariate and multivariate analysis. RESULTS:
      Patients with gallbladder or peritoneal adhesion often have gallbladder wall
      thickening, gallbladder wall enhancement, and increased density of the
      pericholecystic fat more frequently than patients without adhesion on both
      precontrast and postcontrast CT. Each of these findings was significant on
      univariate analysis. On multivariate analysis, increased density of the
      pericholecystic fat and focal attenuation increase in the liver were significant
      factors for predicting gallbladder or peritoneal adhesion. CONCLUSION: Increased
      density or stranding of pericholecystic fat and transient focal hepatic
      attenuation increase at dynamic arterial-phase CT indicates gallbladder and
      peritoneal adhesion.

PMID- 15176607
TI  - CT and MRI findings of xanthoma in the orbitofrontal region.
AB  - We report the imaging features of a rare case of xanthoma in the floor of the
      anterior cranial fossa involving the frontal bone and orbit. A 42-year-old man
      presented with a history of proptosis, headache, and hyperlipidemia. Computed
      tomography demonstrated a well-circumscribed, homogenous, expansive mass with
      isodensity to brain parenchyma. On magnetic resonance imaging, the tumor showed
      high signal intensity relative to brain white matter on T1-weighted images, with
      heterogeneously high signal intensity on T2-weighted images. Histological
      examination established a diagnosis of xanthoma.

PMID- 15176608
TI  - Postmortem computed tomographic (PMCT) demonstration of fatal hemoptysis by
      pulmonary tuberculosis--radiological-pathological correlation in a case of
      rupture of Rasmussen's aneurysm.
AB  - We report a case of fatal hemoptysis resulting from the rupture of a Rasmussen's
      aneurysm. Postmortem computed tomography (PMCT) clearly showed the air-fluid
      level within a tuberculous cavity and fluid-filled trachea. In this case, PMCT
      was useful as a screening tool to detect the cause of death as asphyxia from
      hemoptysis. It became a guideline for the following autopsy, as well as evidence
      to explain the importance of autopsy to the family.

PMID- 15176609
TI  - A case of sclerosing hemangioma surrounded by emphysematous change.
AB  - A 44-year-old woman presented with high-grade fever. Chest radiography showed a
      30 mm solitary pulmonary mass in the left lower lobe. Chest CT revealed a well
      defined solid mass in the left lower lobe. On contrast-enhanced CT, the mass
      showed homogeneity and mild enhancement. There was an emphysematous portion in
      the surrounding lung parenchyma. The patient underwent partial lobectomy of the
      left lower lobe. The final diagnosis of sclerosing hemangioma with abundant
      vasculature was confirmed pathologically. Pulmonary sclerosing hemangioma is a
      rare benign neoplasm. Some cases have been reported in which sclerosing
      hemangioma is surrounded by air spaces. We suggest that the air spaces around the
      tumor were formed by not only peritumoral bleeding but also a check-valve effect
      of the compressed bronchus.

PMID- 15176610
TI  - CT assessment of pulmonary emphysema using teleradiology.
AB  - PURPOSE: The present study assessed the usefulness of CT for diagnosis of
      pulmonary emphysema (PE) using teleradiology. METHODS: We reviewed 95 cases (56
      men and 39 women, ranging in age from 18 to 89 years) who had undergone CT
      examination between June 2002 and January 2003. CT images were transmitted via
      ISDN by DICOM to our hospital, and displayed in 4-image and 1-image format for
      reading on an image viewer. RESULTS: In 72 of the total 95 cases, both 1-image
      and 4-image displays were normal, and no PE was detected. Of the remaining 23
      patients, PE was found in 22 on 4-image display and in all 23 on 1-image display.
      The same grade and subtype were observed on 4-image and 1-image displays in 19
      cases. On the other hand, difference in diagnosis between the two types of
      display was obtained in four cases, in which mild low attenuation areas (LAAs)
      such as grade 1 or grade 2 centrilobular emphysema were found on the 1-image
      display but not seen on the 4-image display. CONCLUSIONS: The diagnosis of PE can
      be made by CT examination using teleradiology even in cases of mild lesions,
      when, for example, LAAs were found on the 1-image display but not seen on the
      other one. Therefore, teleradiology enables rapid diagnosis even in medical
      institutions where no expert chest radiologist is present.

PMID- 15176611
TI  - Sciart frame up.

PMID- 15176612
TI  - Bias to experience approaching motion in a three-dimensional virtual environment.
AB  - We used two-frame apparent motion in a three-dimensional virtual environment to
      test whether observers had biases to experience approaching or receding motion in
      depth. Observers viewed a tunnel of tiles receding in depth, that moved
      ambiguously either toward or away from them. We found that observers exhibited
      biases to experience approaching motion. The strengths of the biases were
      decreased when stimuli pointed away, but size of the display screen had no
      effect. Tests with diamond-shaped tiles that varied in the degree of pointing
      asymmetry resulted in a linear trend in which the bias was strongest for stimuli
      pointing toward the viewer, and weakest for stimuli pointing away. We show that
      the overall bias to experience approaching motion is consistent with a
      computational strategy of matching corresponding features between adjacent
      foreshortened stimuli in consecutive visual frames. We conclude that there are
      both adaptational and geometric reasons to favor the experience of approaching
      motion.

PMID- 15176613
TI  - Estimation of lifted weight and produced effort through perception of point-light
      display.
AB  - It has been shown that human observers can estimate the weight of a box from the
      observation of a point-light display of a lifting motion. We asked observers to
      report the weight of the box and the effort produced by five lifters ranging in
      size and strength to determine if observers can perceive lifter size. In
      experiment 1, five or six weights from each of five lifters were shown to
      fourteen observers in a random order. Observers showed less error in estimating
      the amount of effort each lifter produced than in estimating the actual weight of
      the box. In experiment 2, the lifters were presented individually to forty
      observers to remove any effect observing a previous lift might have had on
      estimating the subsequent lift by a different lifter. The results showed an
      improvement in estimated weight but not in estimated effort. In experiment 3, the
      actual size of the lifters was given to thirty-four observers, and the
      estimations of both weight and effort improved. In experiment 4, observers did
      not improve when observing practice trials and estimating either only weight or
      only effort. The results from the four experiments suggest that observers are
      more sensitive to lifter's effort than to the weight lifted, and that observers
      tend to use changes in the velocity profile of the lift when making their
      estimates.

PMID- 15176614
TI  - Confusion of space and time in the flash-lag effect.
AB  - The apparent lagging of a short flash in the relation to a moving object, the
      flash-lag effect (FLE), has so far been measured mainly in terms of illusory
      spatial offset. We propose a method of measuring the perceived temporal
      asynchrony of the FLE separately from its perceived spatial offset. We presented
      a moving stimulus that changed its colour at a certain moment. The observer
      indicated, in two different tasks, where and when the colour change occurred in
      relation to a stationary reference flash. Results show that the perceived time of
      the colour change was not congruent with the perceived location of the colour
      change: the colour change is perceived simultaneously with the flash, but is
      shifted in position. The presentation of the reference in the form of a flash is
      not critical for the occurrence of the FLE, because the same effect was obtained
      with a constantly visible reference signal, the position of which or time when it
      changed its colour were varied. The observer was not able to ignore the
      irrelevant dimension of the reference signal: the apparent time of the colour
      change was influenced by the position of the reference signal, and the apparent
      location of the colour change was influenced by the presentation time of the
      reference signal. The observer's inability to separate the spatial and temporal
      aspects of the moving stimulus clearly imposes certain limits on theories that
      are attempting to explain the FLE exclusively in terms of the perceived space and
      time.

PMID- 15176615
TI  - Facilitated processing of visual stimuli associated with the body.
AB  - Recent work on tactile perception has revealed enhanced tactile acuity and
      speeded spatial-choice reaction times (RTs) when viewing the stimulated body site
      as opposed to viewing a neutral object. Here we examine whether this body-view
      enhancement effect extends to visual targets. Participants performed a speeded
      spatial discrimination between two lights attached either to their own left index
      finger or to a wooden finger-shaped object, making a simple distal--proximal
      decision. We filmed either the finger-mounted or the object-mounted lights in
      separate experimental blocks and the live scene was projected onto a screen in
      front of the participants. Thus, participants responded to identical visual
      targets varying only in their context: on the body or not. Results revealed a
      large performance advantage for the finger-mounted stimuli: reaction times were
      substantially reduced, while discrimination accuracy was unaffected. With this
      finding we address concerns associated with previous work on the processing of
      stimuli attributed to the self and extend the finding of a performance advantage
      for such stimuli to vision.

PMID- 15176616
TI  - Visual and haptic discrimination of symmetry in unfamiliar displays extended in
      the z-axis.
AB  - We investigated, in two experiments, the discrimination of bilateral symmetry in
      vision and touch using four sets of unfamiliar displays. They varied in
      complexity from 3 to 30 turns. Two sets were 2-D flat forms (raised-line shapes
      and raised surfaces) while the other two were 3-D objects constructed by
      extending the 2-D shapes in height (short and tall objects). Experiment 1 showed
      that visual accuracy was excellent but latencies increased for raised-line shapes
      compared with 3-D objects. Experiment 2 showed that unimanual exploration was
      more accurate for asymmetric than for symmetric judgments, but only for 2-D
      shapes and short objects. Bimanual exploration at the body midline facilitated
      the discrimination of symmetric shapes without changing performance with
      asymmetric ones. Accuracy for haptically explored symmetric stimuli improved as
      the stimuli were extended in the third dimension, while no such a trend appeared
      for asymmetric stimuli. Unlike vision, haptic response latency decreased for 2-D
      shapes compared with 3-D objects. The present results are relevant to the
      understanding of symmetry discrimination in vision and touch.

PMID- 15176617
TI  - Gender differences in perception of self-orientation: software or hardware?
AB  - We evaluated the contribution of attentional strategy to the perception of self
      orientation with and without a body tilt in the median plane. Reinking et al
      (1974 Journal of Personality and Social Psychology 30 807-811) found that the
      frame dependence of females on the rod-and-frame test could be mediated by
      instructions prompting them to focus on internal cues (ie arising from inside of
      the body). Here, we measured the influence of attentional instructions on the
      perception of the morphological horizon. Eleven females and thirteen males
      estimated their morphological horizon in an upright and a 45 degrees body tilt in
      the median plane under three instruction conditions. All participants first
      performed without attentional instructions. Then, participants performed under
      both internal and external attentional instructions. For females, but not for
      males, perception of morphological horizon was more footward in the supine than
      in the upright orientation. Although instructions did not eliminate gender
      differences, internal instructions allowed females to reduce their perceptual
      bias in the supine orientation.

PMID- 15176618
TI  - The effect of colour congruency on shape discriminations of novel objects.
AB  - Although visual object recognition is primarily shape driven, colour assists the
      recognition of some objects. It is unclear, however, just how colour information
      is coded with respect to shape in long-term memory and how the availability of
      colour in the visual image facilitates object recognition. We examined the role
      of colour in the recognition of novel, 3-D objects by manipulating the congruency
      of object colour across the study and test phases, using an old/new shape
      identification task. In experiment 1, we found that participants were faster at
      correctly identifying old objects on the basis of shape information when these
      objects were presented in their original colour, rather than in a different
      colour. In experiments 2 and 3, we found that participants were faster at
      correctly identifying old objects on the basis of shape information when these
      objects were presented with their original part-colour conjunctions, rather than
      in different or in reversed part-colour conjunctions. In experiment 4, we found
      that participants were quite poor at the verbal recall of part-colour
      conjunctions for correctly identified old objects, presented as grey-scale images
      at test. In experiment 5, we found that participants were significantly slower at
      correctly identifying old objects when object colour was incongruent across study
      and test, than when background colour was incongruent across study and test. The
      results of these experiments suggest that both shape and colour information are
      stored as part of the long-term representation of these novel objects. Results
      are discussed in terms of how colour might be coded with respect to shape in
      stored object representations.

PMID- 15176619
TI  - Who is doing what to whom? Young infants' developing sense of social causality in
      animated displays.
AB  - In two different experiments a visual habituation/dishabituation procedure was
      used to test groups of 3-10-month-old infants for their ability to discriminate
      the role reversal of two abstract figures (discs of different colors) chasing
      each other on a computer screen. Results of the first experiment point to a
      reliable age effect. Only 8-10-month-old infants tended to dishabituate to a role
      reversal between chaser and chasee. A second experiment shows that in
      dishabituating to the role reversal, 8-10-month-olds do base this discrimination
      on relational information between the two discs and not merely on the contrast
      between their respective vitality or discrete dynamic. By the age of 8-10 months,
      infants demonstrate sensitivity to information specifying what one disc does to
      the other, at a distance. These findings point to important changes in perceptual
      cognitive development and are discussed in the context of a well described key
      transition in social-cognitive development occurring at around 9 months of age.

PMID- 15176620
TI  - Correlations among within-channel and between-channel auditory gap-detection
      thresholds in normal listeners.
AB  - We obtained data on within-channel and between-channel auditory temporal gap
      detection acuity in the normal population. Ninety-five normal listeners were
      tested for gap-detection thresholds, for conditions in which the gap was bounded
      by spectrally identical, and by spectrally different, acoustic markers. Separate
      thresholds were obtained with the use of an adaptive tracking method, for gaps
      delimited by narrowband noise bursts centred on 1.0 kHz, noise bursts centred on
      4.0 kHz, and for gaps bounded by a leading marker of 4.0 kHz noise and a trailing
      marker of 1.0 kHz noise. Gap thresholds were lowest for silent periods bounded by
      identical markers--'within-channel' stimuli. Gap thresholds were significantly
      longer for the between-channel stimulus--silent periods bounded by unidentical
      markers (p < 0.0001). Thresholds for the two within-channel tasks were highly
      correlated (R = 0.76). Thresholds for the between-channel stimulus were weakly
      correlated with thresholds for the within-channel stimuli (1.0 kHz, R = 0.39; and
      4.0 kHz, R = 0.46). The relatively poor predictability of between-channel
      thresholds from the within-channel thresholds is new evidence on the separability
      of the mechanisms that mediate performance of the two tasks. The data confirm
      that the acuity difference for the tasks, which has previously been demonstrated
      in only small numbers of highly trained listeners, extends to a population of
      untrained listeners. The acuity of the between-channel mechanism may be relevant
      to the formation of voice-onset time-category boundaries in speech perception.

PMID- 15176621
TI  - Homicidal and dyadic falls from a height: rarities in Singapore.
AB  - A review of homicidal falls from a height, over a ten-year-period (1991-2000),
      demonstrated the rarity of such deaths in Singapore, despite the high frequency
      of fatal falls from a height that prevails in the city-state. During that time,
      there were four cases (involving five individuals) of pure homicide and nine
      episodes (involving 19 individuals) of dyadic death involving vertical
      deceleration from a considerable height in the approximate range of 17-31 m (6-11
      floors) and 17-50 m (6-18 floors), respectively. The index cases were gleaned
      from a total of 533 homicides and 3,963 fatal falls from a height. Hence, the
      corresponding ten-year prevalence rates of homicidal falls were 0.9% in terms of
      all homicidal deaths and 0.1% in relation to all fatal falls, and 3.6% and 0.5%
      for dyadic falls, respectively. The majority of victims were children, with
      almost equal numbers of males and females, aged between two months and six years
      for pure homicides and between 20 months and 13 years for homicide-suicides. Over
      a third (9/24) of these subjects attained the maximum Injury Severity Score (ISS)
      of 75. With respect to the dyadic deaths, the majority of the perpetrators (6/9)
      were females, comprising four mothers and two live-in maids. It would appear that
      strained or broken relationships, probable or actual mental illness, or a
      combination of both factors, had largely predisposed them to these tragic events
      which may, potentially, carry diplomatic implications when foreign nationals are
      involved.

PMID- 15176622
TI  - British military forensic psychiatry.
AB  - Military psychiatry has recently generated a lot of interest. In contrast there
      is virtually no literature on military forensic psychiatry. The first section of
      the paper is a brief review of British military psychiatric services and recent
      data on the prevalence of mental illness in British armed forces personnel. The
      second section summarizes the relevant aspects of the British military judicial
      and penal systems including the practice of summary justice, the court martial
      system, and sentencing and corrective training. The third section of the paper
      addresses issues which are particular to forensic psychiatry, including mental
      defences in relation to the military, the military offences of malingering and
      impersonation, risk assessment in military contexts and the notion of
      'temperamental unsuitability' to military service.

PMID- 15176623
TI  - Fatal poisoning in Jamaica: a coroner's autopsy study from the University
      Hospital of the West Indies.
AB  - This study reviewed cases of fatal poisoning in a coroner's autopsy series at the
      University Hospital of the West Indies and represented the first such study
      reported from Jamaica. The autopsy protocols of all coroner's autopsies performed
      over the 20-year period January 1980 to December 1999 were reviewed
      retrospectively; 22 (1.0%) cases were identified and relevant clinical and
      pathological data analysed. There were 13 males and nine females (M:F ratio
      1.4:1) with an age range of 2 - 69 years (mean +/- SD = 27 +/- 16.1 years). The
      20 - 29 year group was most commonly affected and five patients (22.7%) were
      children (< 18 years of age). Pesticides (herbicides/ insecticides) were
      implicated in nine (41%) cases: paraquat was the most common, found in six (27%)
      cases. Prescription drugs were the next most prevalent group with six (27%)
      cases, followed by anti-psychotic drugs in four (18%) cases. Cocaine and ackee
      were each implicated in two (9%) cases. The manner of death was suicidal in 14
      (64%) cases and accidental in eight (36%) cases. Seven patients had documented
      psychiatric illnesses, six of whom committed suicide. Autopsy findings were
      largely non-specific. The relatively small number of cases was consistent with
      the low incidence of fatal poisoning in Jamaica.

PMID- 15176624
TI  - An autopsy study on medico-legal evaluation of post-mortem scavenging.
AB  - After death a body may be mutilated in various ways. Animal scavenging is one of
      the causes. This scavenging creates difficulties with the interpretation of
      various medico-legal questions such as identity of the victim and cause of death
      and, as a consequence, criminal charges against the perpetrator cannot be framed
      or proven. The present study was undertaken to find out the incidence of
      scavenging in the Saurashtra region (part of west India) and also to see how it
      affects the interpretation of medico-legal evidence. We are of the opinion that
      scavenging does affect various medico-legal parameters and knowledge of this fact
      and careful autopsy examinations helped us to reach a logical conclusion. A study
      comprising 13 cases observed during a period of one year is presented.

PMID- 15176625
TI  - A study of homicidal deaths in Delhi.
AB  - A meticulous post-mortem review was undertaken in the department of forensic
      medicine at the Maulana Azad Medical College (MAMC) to find out trends in
      homicides during the period 1992-1996. Standard procedures for autopsies and a
      review of the inquest papers were carried out. Out of 3,886 medico-legal
      autopsies performed in the department during the said period, only 232 cases
      (5.9%) were homicidal deaths. The commonest age group of the victims was 21-30
      years (38%). Males were victimized three times more often than females. The
      incidence of crime was slightly more at night than in the daytime, though evenly
      distributed during the winter and summer seasons. In our series, sharp weapon
      injuries were the most common type (34.9%) followed by blunt force injuries
      (15.9%). Defence wounds were present in 35 cases (15%). Violent rage/quarrel was
      the motive in 61 cases (29%).

PMID- 15176626
TI  - Homicide and affective disorder.
AB  - The background, offence characteristics and psychiatric diagnosis were reviewed
      of 115 referrals of offenders charged with homicide made by procurators fiscal to
      the State Hospital, Carstairs, Scotland's only special secure hospital. A
      retrospective casenote review was performed using a structured questionnaire. A
      higher percentage of mental illness and substance misuse (11% and 40%) was
      recorded than that reported by Gillies in 1976. The results are discussed in the
      context of comparable studies and, in particular, the National Confidential
      Inquiry into Suicide and Homicide by People with Mental Illness and the
      Discussion Paper on Insanity and Diminished Responsibility published by the
      Scottish Law Commission.

PMID- 15176627
TI  - The nearest relative in mental health law.
AB  - This article considers the concept of the 'nearest relative' in mental health law
      in England and Wales and argues, inter alia, for its retention in a way that
      avoids violation of the European Convention on Human Rights and the Human Rights
      Act 1998. It looks, first, at the meaning of nearest relative and then focuses on
      his/her role today, including its link with advance directives for mental health
      care, and on the tension between nearest relatives and approved social workers
      and the law. The problem exposed by JT v. United Kingdom in relation to the Human
      Rights Act 1998 and its implications for the future are considered. The impact of
      the Mental Health Bill (2002) on the nearest relative is discussed and
      recommendations to improve the present law are then suggested.

PMID- 15176628
TI  - Interobserver variability in analysis of asbestos fibres and asbestos bodies in
      human lung tissue.
AB  - Two different methods of quantifying asbestos fibre burden were assessed and the
      counts obtained were compared with semi-quantitative asbestos body counts in
      corresponding tissue sections. Comparison of the two methods found significantly
      different asbestos fibre counts between specimens. Each technique showed wide
      limits of agreement for reproducibility and interobserver variability as assessed
      by Bland-Altman plots, such that a repeated count could not necessarily be
      expected to lie within the same exposure category. Asbestos body counts in tissue
      sections were reproducible with good correlation between observers. Asbestos body
      and asbestos fibre counts showed correlation in some samples but not others.
      Counting of asbestos bodies is a valuable screening technique as the finding of
      asbestos bodies is accepted as a marker of significant asbestos exposure. When no
      asbestos bodies are identified asbestos fibres estimations may be useful in
      proving asbestos exposure. Different techniques are not interchangeable and each
      laboratory should establish a background range from unexposed individuals.

PMID- 15176629
TI  - Circumstances of crime in homicidal deaths.
AB  - Homicide patterns vary from country to country, influenced by many factors. In
      the two-year period from January 1998 to December 1999, 82 homicide victims were
      autopsied. The sex ratio was about three males for one female. The largest number
      of victims was found in the age group 21-30 years. Assaults with blunt weapons
      were the most common means. Acquaintances committed 34% of homicides. In contrast
      to males, the killing of a female by a stranger was rare. Revenge was the most
      common reason followed by arguments. In 40.2% of cases, the location of crime was
      outdoors, 37.8% were at the victim's house and in 9.7% of cases, the crime was
      committed at another domicile such as the offender's house, lodgings or a
      relative's house. In 14.7% of cases, the dead bodies were located away from the
      scene of crime.

PMID- 15176630
TI  - Forensic medical aspects of male-on-male rape and sexual assault in greater
      Manchester.
AB  - Male-on-male rapes and sexual assaults comprise fewer than 10% of such assaults
      reported to the police, and so many physicians seldom encounter them. This paper
      provides an overview of the nature of sexual assault encountered by males,
      ensuing injuries, and comparisons with male-on-female assault cases. The
      retrospective epidemiological study was on two cohorts seen at St. Mary's Sexual
      Assault Referral Centre, Manchester. The participants were Centre clients seen
      between October 1986 and mid-May 2003; 376 male eases (370 individual clients)
      and 7,789 female cases (7,403 individual clients). The main outcome measure was
      the presence of injury (abrasion, laceration, or bruise) to defined body areas.
      The results showed that 66% of male cases (when assault type was known) had been
      raped, significantly fewer than in female cases, (p 0.00, a 0.05, O.R. 0.474, 95%
      C.I. 0.357 to 0.63). Eighteen per cent of male cases that had a forensic medical
      examination presented with an anal injury, significantly more than in females (p
      0.00, a 0.05, O.R. 6.101, 95% C.I. 4.216 to 8.829). Significantly fewer males
      than females sustained injuries to other body areas. The conclusion was that
      males were significantly more likely (six times) than females to receive at least
      one injury to the anal area. Even so, males are five times more likely to have no
      anal injury.

PMID- 15176631
TI  - Fatality following a sternal bone marrow aspiration procedure: a case report.
AB  - A 58-year-old man was admitted to hospital for the investigation and treatment of
      pancytopaenia and anaemic heart failure but four days later he died following a
      sternal bone marrow aspiration procedure. The autopsy revealed a significant
      haemopericardium as a result of a puncture wound of the heart. The thickness the
      body of the sternum was 2 to 3 mm. No other significant pathology was noted and
      death was ascribed to a haemopericardium due to a puncture wound of the heart
      associated with bone marrow aspiration. An inquest was held at which the doctor
      who undertook the procedure was found not to be negligent.

PMID- 15176632
TI  - Suicide by a transvestite or sexual asphyxia? A case report.
AB  - Autoerotic asphyxial activity may at times result in unexpected death. Although
      the majority of deaths that occur during autoerotic asphyxial episodes are
      accidental, the possibility of suicide must always be entertained. In the case
      presented here, a 22-year-old married male was found hanging by his neck in his
      bedroom, which was locked from the inside. He was suspended by a 'lungi' (male
      wrap-around cloth) from the ceiling fan hook in his room, with his feet touching
      the ground. He was dressed in a brassiere, panties, and silver anklets. There was
      no evidence of previous perverse behaviour, and investigation disclosed no
      evidence of previous autoerotic sexual activity, homosexual behaviour, drug abuse
      or suicidal ideation.

PMID- 15176633
TI  - A fatal impaling injury in a road traffic accident: a case report.
AB  - A 17-year old, thin-built male was sitting in a bus on the right side of the rear
      seat. The same side of the bus accidentally hit some iron rods, meant for
      construction work, projecting from the tail end of a small truck. The incident
      happened when the bus driver tried to manoeuvre the bus towards the left side of
      the truck, standing at a red traffic light intersection. One of the iron-rods
      entered the bus through the glass window next to which the victim had been
      sitting and penetrated his chest cavity from the side, lacerating both the lungs
      and exiting through the left shoulder blade. The individual died on his way to
      hospital.

PMID- 15176634
TI  - Occlusion of a coronary ostium by an ingrowing endocardial vegetation: a case
      report.
AB  - A 21-year-old primi, with a period of gestation of 35 weeks, was found collapsed
      in the toilet of a maternity hospital in Colombo, Sri Lanka. She had been
      admitted five days previously and echocardiography had detected a tight aortic
      stenosis with grade I aortic regurgitation. At autopsy, the heart showed
      multiple, large (> 10mm), friable vegetations on a stenosed, bicuspid aortic
      valve. A 5 mm long part of a vegetation had extended into the ostium of the left
      main coronary artery and caused an obstruction. Histopathology showed scattered
      fibrosis and focal inflammatory cell infiltrate in the myocardium. The
      vegetations on the valve cusp were composed of colonies of bacteria, fibrin
      exudate and polymorphs. The cause of death was acute myocardial infarction in a
      pregnant woman due to occlusion of the left coronary artery by an infective
      endocarditis vegetation. A medline search of the past 25 years failed to find a
      similar case.

PMID- 15176635
TI  - Law and science. Civil law. Clinical negligence.

PMID- 15176636
TI  - Performing research with people who are not capable of giving their informed
      consent to research is sometimes justified.

PMID- 15176637
TI  - Helping motives in late modern society: values and attitudes among nursing
      students.
AB  - This article reports a follow-up study of Norwegian nursing students entitled
      'The helping motive an important goal for choosing nursing education'. It
      presents and discusses a significant ambiguity within the altruistic helping
      motive of 301 nursing students in the light of classical and modern virtue
      ethics. A quantitative longitudinal survey design was used to study socialization
      and building professional identity. The follow-up study began after respondents
      had completed more than two-and-a-half years of the three-year educational
      programme. Data were collected using a questionnaire with closed questions,
      supplemented by 18 semi-structured, in-depth, audiotaped interviews. A motive
      such as 'desire for human contact/to help others' appeared to be highly
      significant. The research questions employed were: What motivates nursing
      students at the end of their studies to help other people? What does helping
      others mean for nursing students? Factor analysis revealed two factors. Factor 1
      can be expressed as an altruism factor and factor 2 can be interpreted as an
      'acknowledgement-from-the-patient factor' that in fact indicates an ambiguity
      within the helping motive itself. Findings from the interviews also reveal
      ambiguous helping motives. On one hand the students want to be altruistic and on
      the other they wish to receive positive feedback from patients when giving help.
      The findings indicate that this positive feedback is essential to the students in
      order for them to provide altruistic care.

PMID- 15176638
TI  - Exploring the heart of ethical nursing practice: implications for ethics
      education.
AB  - The limitations of rational models of ethical decision making and the importance
      of nurses' human involvement as moral agents is increasingly being emphasized in
      the nursing literature. However, little is known about how nurses involve
      themselves in ethical decision making and action or about educational processes
      that support such practice. A recent study that examined the meaning and
      enactment of ethical nursing practice for three groups of nurses (nurses in
      direct care positions, student nurses, and nurses in advanced practice positions)
      highlighted that humanly involved ethical nursing practice is also simultaneously
      a personal process and a socially mediated one. Of particular significance was
      the way in which differing role expectations and contexts shaped the nurses'
      ethical practice. The study findings pointed to types of educative experiences
      that may help nurses to develop the knowledge and ability to live in and navigate
      their way through the complex, ambiguous and shifting terrain of ethical nursing
      practice.

PMID- 15176639
TI  - A longitudinal study on the development of moral judgement in Korean nursing
      students.
AB  - This longitudinal study examined the development of moral judgement in 37 nursin
      students attending a university in Suwon, Korea. The participants completed the
      Korean version of the Defining Issues Test to allow analysis of their level of
      moral judgement. The development of moral judgement was quantified using 'the
      moral development score' at each stage (i.e. the six stages detailed by Kohlberg)
      and the 'P(%) score' (a measure of the overall moral judgement level). The
      results were as follows: (1) the moral development score for stage 5A was
      consistently the highest across the four years of the students' course, showing
      significant differences in some sociodemographic factors including home, birth
      order and monthly income; and (2) the P(%) score was higher in fourth-year (47.47
      +/- 11.21) than in first-year (46.13 +/- 9.73) students. There was no significant
      difference in the P(%) score according to sociodemographic factors. Further
      studies will examine in detail the correlation between curriculum and moral
      judgement development. We suggest that courses in ethics education should be made
      more relevant.

PMID- 15176640
TI  - Nurses' voices: policy, practice and ethics.
AB  - This article deals with nurses' ethical concerns raised by the consequences of
      changes in governmental and institutional policies on nursing practice and
      patient care. The aims of this project were to explore perspectives of registered
      nurses who provide or manage direct patient care on policies that affect nursing
      and patient care, and to provide input to policy makers for the development of
      more patient-centred policies. Four focus groups were conducted with a total of
      36 registered nurse participants. The project team identified major themes that
      emerged in the analysis of transcripts of the focus group discussions. The four
      major themes were: effects of policy focused on cost containment, effects on
      quality of care, effects on patient education and access to needed services, and
      effects on nurses and nursing. The participants identified primarily negative
      effects of changes in national health policy and legislation that influence
      institutional policies on patient care and nursing practice. The effects of
      identified policy changes raised concerns about meeting nurses' ethical
      obligations to patients and families. Participants specified key points for
      consideration by legislators and other policy makers. They viewed nurses who are
      involved in direct patient care as a critical resource for legislators and other
      policy makers in the development of public and institutional policies that affect
      nursing and patient care.

PMID- 15176641
TI  - Nurses' professional care obligation and their attitudes towards SARS infection
      control measures in Taiwan during and after the 2003 epidemic.
AB  - This study investigated the relationship between hospital nurses' professional
      care obligation, their attitudes towards SARS infection control measures, whether
      they had ever cared for SARS patients, their current health status, selected
      demographic characteristics, and the time frame of the data collection (from May
      6 to May 12 2003 during the SARS epidemic, and from June 17 to June 24 2003 after
      the SARS epidemic). The study defines 172 nurses' willingness to provide care for
      SARS patients as a professional obligation regardless of the nature of the
      disease. A conceptual model was developed and tested using ordinal logistic
      regression modelling. The findings showed that nurses' levels of agreement with
      general SARS infection control measures and the lack of necessity for
      quarantining health care workers who provided care for SARS patients were
      statistically significant predicators of the nurses' fulfilling of their
      professional care obligation. Suggestions and study limitations are discussed.

PMID- 15176642
TI  - Euthanasia education for health professionals in Turkey: students change their
      opinions.
AB  - The purpose of this study was to investigate the impact of euthanasia education
      on the opinions of health sciences students. It was performed among 111 final
      year students at the College of Health Sciences, Dokuz Eylul University, Izmir,
      Turkey. These students train to become paramedical professionals and health
      technicians. Fifteen hours of educational training concerning ethical values and
      euthanasia was planned and the students' opinions about euthanasia were sought
      before and after the course. Statistical analyses of the data were performed with
      the related samples t-test by means of the Epi-Info program. Significant changes
      were shown in the students' opinions on people's right to decide about their own
      life, euthanasia in unconscious patients, and reasons for their objection to
      euthanasia after completing the course. The results of this study suggest that
      education can significantly change a person's approach to euthanasia.

PMID- 15176644
TI  - Nursing ethics: cross-border challenges and leadership.

PMID- 15176643
TI  - Research involving children: some ethical issues.
AB  - In a Norwegian study on how children aged 7-12 years cope during a period of
      serious illness within the family and on their quality of life at this time,
      several ethical questions became apparent. These were mainly concerned with the
      vulnerability of children during research, with their ability to make autonomous
      decisions, and with considerations regarding how to respect their right to
      confidentiality during the research process. In this article we approach these
      questions using our experience from this previous study, discussing them within
      the framework of theories of ethics and relevant research ethical guidelines.
      Finally, we discuss our experience in the light of the overall purpose of this
      article: how to deal with the ethical dilemmas that may appear during research
      involving young children.

PMID- 15176645
TI  - Ethics committees reform in Belgium.

PMID- 15176646
TI  - Country profile: Mongolia.

PMID- 15176647
TI  - Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid
      peptide with anti-angiogenic properties, in healthy men.
AB  - AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6,
      an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS:
      Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of
      single and repeated doses. In the single dose phase, successive groups of 5
      subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous
      injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects
      received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5
      subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total).
      In each group, 4 subjects received active treatment, the remainder placebo.
      Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h
      after the first of the repeated doses, and up to 24 h after the last of the
      repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH
      5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose
      regimens of A6 were safe and well-tolerated, both systemically and locally. Time
      to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax
      and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454
      10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300
      mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no
      evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was
      94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD
      13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger
      production of anti-A6 IgG antibodies within 14 days of the first dose.
      CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg,
      were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it
      was eliminated, mainly unchanged, in urine. Plasma concentrations were dose
      proportional. A6 did not trigger an early immunogenic response.

PMID- 15176648
TI  - Initiation of antihypertensive therapy among new users of cyclooxygenase-2
      selective and nonselective NSAIDs.
AB  - BACKGROUND: The comparative effects of cyclooxygenase-2- (COX-2) selective
      inhibitors and nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) on
      blood pressure are debated. Clinicians have been concerned about the need for
      antihypertensive treatment following therapy with these agents. OBJECTIVE: To
      compare initiation of antihypertensive treatment among new users of the COX-2
      selective inhibitor rofecoxib and of nonselective NSAIDs in clinical practice.
      METHODS: Retrospective cohort study using the MediPlus (UK) database that covers
      1.8 million patients throughout the UK. Patients included were at least 50 years
      of age, had at least 1 prescription for either diclofenac, ibuprofen, naproxen or
      rofecoxib (drugs of interest, DOIs), and had no prescription for any NSAID, COX-2
      inhibitor, or antihypertensive treatment during the 6 months prior to their
      first/index prescription date. A subset of patients, classified as chronic and
      persistent new users, had at least 3 prescriptions of the index prescription DOI
      and did not switch to another DOI during the 6-month follow-up period. Logistic
      regression analysis, adjusted for potential predictors, was used to assess
      initiation of new antihypertensive treatment. RESULTS: 18,737 suitable patients
      were identified (diclofenac 7,861, ibuprofen 8,423, naproxen 1,556 and rofecoxib
      897). Those using rofecoxib were older and more likely to be female than those
      using NSAIDs. During the 6 months following the index prescription, 7.0% of all
      new users and 11.5% of chronic and persistent new users initiated
      antihypertensive treatment. After adjusting for potential predictors there were
      no statistically significant differences in the risk of initiating
      antihypertensive treatment between new or chronic and persistent new users of
      rofecoxib, diclofenac, ibuprofen and naproxen (p > 0.05). CONCLUSION: The results
      of this study did not indicate any significant differences in the initiation of
      antihypertensive therapy among patients who were prescribed rofecoxib and NSAIDs,
      even after multiple prescriptions.

PMID- 15176649
TI  - Population-based pharmacokinetics of the soluble TNFr etanercept: a clinical
      study in 43 patients with ankylosing spondylitis compared with post hoc data from
      patients with rheumatoid arthritis.
AB  - OBJECTIVE: The purpose of this study was to evaluate the pharmacokinetics of
      etanercept in patients with ankylosing spondylitis (AS) in a phase 3 study.
      METHODS: Serum etanercept concentrations were analyzed from samples obtained at
      weeks 4 and 12 from 43 patients with AS (median age: 45 years; median body
      weight: 75 kg; white/non-white: 40/3; male/female: 34/9) receiving 25 mg
      subcutaneously twice weekly for 12 weeks. A population pharmacokinetics analysis
      using NONMEM was conducted to estimate individual etanercept pharmacokinetic
      parameters. Initially, appropriate base and covariate population pharmacokinetic
      models were built based on data from 10 prior clinical studies of etanercept
      administered subcutaneously or intravenously to healthy subjects (n = 53) and to
      patients with rheumatoid arthritis (RA) (n = 212). The influence of demographic
      characteristics on the pharmacokinetics of etanercept was thoroughly evaluated.
      The stability of the final model was evaluated using both internal
      (bootstrapping) and external (data splitting) validation approaches. Finally, the
      selected final population covariate model was used to estimate the Bayesian
      pharmacokinetic parameters for the patients with AS. RESULTS: The data from the
      10 prior clinical studies were optimally fitted to a 2-compartment linear
      population covariate model. Both age (< 17 years) and body weight (< 60 kg) were
      found to be important covariates on clearance. Both bootstrapping and data
      splitting validated the population model. The mean Bayesian-predicted etanercept
      clearance and steady-state trough concentration were 0.072 l/h and 2,004 ng/ml,
      respectively. The pharmacokinetic parameters of etanercept in the patients with
      AS were similar to those observed in the patients with RA. CONCLUSIONS: The
      pharmacokinetics of etanercept in patients with AS were similar to those in
      patients with RA. The AS disease state does not appear to alter the disposition
      of etanercept.

PMID- 15176650
TI  - Epidemiological assessment of 160 cases of insulin overdose recorded in a
      regional poisons unit.
AB  - OBJECTIVE: Overdoses with insulin are common, and cases of hypoglycemic coma can
      be fatal and cause cerebral defects. However, data published on this topic are
      rare, consisting mostly of case reports or reports in a small number of patients.
      The present investigation analyzes inquiries made to a regional poisons unit
      involving overdoses with insulin. PATIENTS AND METHODS: A total of 175,890
      inquiries for the years 1995-2003 (until September) were evaluated. 160 inquiries
      were received by telephone concerning insulin overdoses, and a standardized
      questionnaire was sent to the physicians asking for follow-up information. The
      cases were analyzed in regard to etiology, type of insulin used, concomitant
      substances being taken by the patient, symptoms and clinical outcome. RESULTS: Of
      the 160 inquiries investigated, 53.1% of the patients were female, 43.1% male and
      in 3.8% the sex of the patient was unknown. The average age was 44.7 years. 89.4%
      involved suicidal or parasuicidal cases, 5.0% were accidental overdoses and 1.9%
      involved cases of criminal overdose (3.7% were for other reasons). Rapidly acting
      insulins (57.8%) were used more commonly than long-acting formulations (42.8%).
      Benzodiazepines were the most frequently ingested concomitant medication (37.5%)
      with ethanol 15.6%, antihypertensive drugs 12.5% and antidepressants 10.0%. Most
      patients presented with a delay of 2-3 hours after insulin administration
      (15.0%). Almost 50% of the patients presented within the first 6 hours. According
      to the Poisoning Severity Score, no symptoms were observed in 16.8% of the
      patients, minor symptoms in 36.8%, major symptoms in 25.2% and serious symptoms
      in 21.3%. Information concerning the clinical outcome (75 cases) showed that a
      full recovery occurred in most patients (94.7%), but in 2.7% there were cerebral
      defects and 2.7% of the patients died. CONCLUSIONS: The etiology of overdoses
      with insulin was mainly deliberate self-poisoning. Physicians should take into
      account that long-acting insulin formulations and concomitant substances were
      frequently used. For overdoses with insulin, relatively high rates of serious
      symptoms and deaths were observed.

PMID- 15176651
TI  - Interference of Uzara glycosides in assays of digitalis glycosides.
AB  - OBJECTIVE: Presentation of a case report and pharmacokinetic investigation in
      healthy volunteers on the potential interference between cardiac glycosides and
      glycosides of Uzara, a herbal antidiarrheal preparation. METHODS: Pharmacokinetic
      pilot investigation of apparent digitoxin and digoxin serum concentrations in 4
      healthy volunteers after single-dose administration of 30 drops Uzara
      (approximately 1.5 ml approximately = 22 mg glycosides). RESULTS: Maximal
      apparent serum concentrations of digitoxin between 198.0 microg/l and 919.8
      microg/l (therapeutic range: 10-25 microg/l) occurred at 4-8 hours after
      administration. The terminal half-life of the glycosides was 8.87 +/- 2.20 hours.
      For digoxin, maximal apparent serum concentrations ranged between 1.4 microg/l
      and 6.34 microg/l (therapeutic range: 0.9-2.0 microg/l) at 6 hours post dosing.
      CONCLUSIONS: Administration of a single dose of an Uzara preparation, an over-the
      counter product, results in false high serum concentrations of digitoxin and
      digoxin. As described in the manufacturers Summary of Product Characteristics,
      this preparation should not be given to patients with cardiac failure or
      arrhythmia who require treatment with cardiac glycosides because of the
      demonstrated pharmacological actions of uzara glycosides.

PMID- 15176652
TI  - Dose-proportional pharmacokinetics of a methylphenidate extended-release capsule.
AB  - OBJECTIVE: To assess the dose-proportionality of the 10 mg, 20 mg and 30 mg
      methylphenidate extended-release (MPH ER) capsule formulations in healthy adults.
      MATERIALS: Metadate CD (methylphenidate HCl, USP) extended-release capsules (10,
      20 and 30 mg) were obtained from Celltech Manufacturing Inc. (Rochester, NY,
      USA). METHODS: This was a single-center, single-dose, fasted, randomized, open
      label, 3-way crossover study with a 1-week washout period between doses, in 24
      healthy male and female subjects, aged 21-40 years. MPH plasma concentration-time
      data were used to calculate the pharmacokinetic parameters for each treatment.
      The 20 mg capsule, the first FDA-approved dosage strength, was used as reference
      treatment. RESULTS: Twenty-three subjects completed all 3 study periods.
      Regardless of the dose, MPH ER capsules exhibited similar PK profiles as
      evidenced by a biphasic absorption profile, consisting of a sharp initial
      increase followed by a second increase in MPH plasma levels, all occurring at the
      same times. All 90% confidence intervals for the 10:20 mg and 30:20 mg dose
      normalized geometric mean ratios were within the 80-125% FDA limits for
      bioequivalence. This was true for Cmax (maximum observed concentration), AUC(0
      last) (area under the plasma concentration curve from time 0 to the last
      measurable time point) and AUC(0-inf) (area under the plasma concentration curve
      from time 0 to infinity). Adverse events were mild and the number and types of
      adverse events experienced by subjects did not differ among the 3 dosages.
      CONCLUSION: Data collected from this study demonstrate the dose proportionality
      of the new 10 mg and 30 mg dosage strengths of MPH ER capsules with the 20 mg
      capsule. The availability and predictability of these dosage strengths should
      facilitate dose titration of ADHD patients.

PMID- 15176653
TI  - Bioavailability of anthocyanidin-3-glycosides following consumption of elderberry
      extract and blackcurrant juice.
AB  - Pharmacokinetic parameters and the bioavailability of several dietary
      anthocyanins following consumption of blackcurrant juice and elderberry extract
      were compared exploratorily in 6 healthy volunteers. They were given a single
      oral dose of either 137 ml of blackcurrant juice (144.8 mg total anthocyanins) or
      30 ml of elderberry extract (147.3 mg total anthocyanins). Within 7 hours, the
      urinary excretion of total anthocyanins (i.e. the sum of all assayed
      anthocyanidin glycosides) was 0.04% and 0.37% of the administered dose following
      blackcurrant juice and elderberry extract ingestion, respectively.
      Pharmacokinetic parameters based on non-compartmental methods for plasma and
      urine concentrations exhibited higher variability in urinary excretion after
      ingestion of elderberry extract. Anthocyanin absorption was significantly greater
      following the intake of elderberry extract than after the intake of blackcurrant
      juice as shown by the 5.3- and 6.2-fold higher estimates of dose-normalized Cmax
      and AUC(0-tZ) of total anthocyanins, respectively. The geometric means of t(1/2)
      were not significantly different following elderberry extract (1.74 h) and
      blackcurrant juice ingestion (1.73 h, p > 0.05). The urinary excretion rate of
      intact anthocyanins was fast, appeared to be monoexponential for both
      blackcurrant juice and elderberry extract. However, in order to evaluate the
      contribution of anthocyanins to the health-protecting effects of blackcurrant
      juice and elderberry extract it will be necessary to perform further studies on
      the unchanged glycosides and their in vivo metabolites in human plasma and urine.

PMID- 15176654
TI  - Bioequivalence of pravastatin tablet formulations assessed in Korean males.
AB  - AIM: Determination of the bioequivalence of 2 pravastatin tablet formulations
      manufactured in Korea. PATIENTS AND METHODS: Twenty-three healthy male Korean
      volunteers received each of the 2 pravastatin formulations at a dose of 20 mg in
      a 2 x 2 crossover study. There was a 1-week washout period between doses. Plasma
      concentrations of pravastatin were monitored using high-performance liquid
      chromatography over a period of 8 hours after administration. AUC(0-8h) (the area
      under the plasma concentration-time curve from time zero to the last measured
      time in plasma, 8 h) was calculated using the linear-log trapezoidal method. Cmax
      (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled
      from the plasma concentration-time data. Analysis of variance was carried out
      using logarithmically transformed AUC(0-8h) and Cmax and untransformed tmax.
      RESULTS: The point estimates and 90% confidence intervals for AUC(0-8h)
      (parametric) and Cmax (parametric) were 1.067 (0.968 to approximately 1.176) and
      1.074 (0.999 to approximately 1.155), respectively, satisfying the bioequivalence
      criteria of the European Committee for Proprietary Medicinal Products and the US
      Food and Drug Administration guidelines. The corresponding value of tmax was
      0.000 (-0.250 to approximately 0.250). CONCLUSION: These results indicate that
      the 2 medications of pravastatin are bioequivalent and, thus, may be prescribed
      interchangeably.

PMID- 15176655
TI  - Possible mechanisms of gender bias in SLE: a new hypothesis involving a
      comparison of SLE with atopy.
AB  - The prevalence of systemic lupus erythematosus (SLE) is far higher in females
      than in males, and numerous investigations of this gender bias have been
      performed from several perspectives. Sex hormones, particularly estrogens, may be
      significant in causing the gender discrepancy. This article discusses the
      possible importance of estrogens in regulating the expression of and responsivity
      to autoantigens in SLE and in atopic disorders, which are associated with
      hyperreactivity to exogenous antigens. Estrogens seem to play an important role
      in the overexpression of endogenous autoantigens, such as human endogenous
      retroviruses (HERV), and this may be related to the existence of a gender bias in
      the incidence of SLE but not atopy.

PMID- 15176656
TI  - Chloroquine gestational use in systemic lupus erythematosus: assessing the risk
      of child ototoxicity by pure tone audiometry.
AB  - The objective of this study was to assess child chloroquine ototoxicity after its
      use during the gestational period in systemic lupus erythematosus (SLE). Nineteen
      children over four years old were evaluated: nine were exposed to chloroquine
      diphosphate (CDP) during gestation and 10 were born from mothers that did not
      take this drug before conception or anytime during pregnancy (CONTROL). Pure tone
      audiometry was performed in all children and high and low frequency threshold
      means were compared to evaluate the hearing status. All nine mothers taking CDP
      were exposed to this drug at least during the first trimester of pregnancy (56%
      during the whole gestational period) and the mean time of CDP use was 6.1 +/- 2.9
      months. No significant difference was found in children of CDP and CONTROL groups
      regarding age (7.6 +/- 4.4 versus 12.3 +/- 7.2 years; P = 0.10, respectively) and
      gender (P = 0.65). Pure tone high frequency thresholds, which are the first to be
      affected by ototoxic drugs, presented within normal limits in children exposed or
      not to CDP (8.5 +/- 5.0 versus 7.4 +/- 3.6 dBHL; P = 0.55, respectively).
      Likewise, the mean hearing thresholds at low frequencies were also similar in
      both groups (11.4 +/- 4.5 versus 11.9 +/- 3.0 dBHL; P = 0.66). In conclusion,
      child in utero exposure to chloroquine diphosphate does not seem to induce
      hearing impairment as measured by pure tone audiometry, reinforcing its safe use
      during pregnancy of lupus patients.

PMID- 15176657
TI  - Modulation of urinary CR1 in systemic lupus erythematosus.
AB  - The decline in the levels of erythrocyte complement receptor 1 (ECR1) in systemic
      lupus erythematosus (SLE) has been widely reported. The most probable cause for
      this decline is excessive proteolytic shedding of CR1 from the cell surface.
      Similarly a decline in glomerular CR1 (GCR1) has also been reported in SLE.
      Because CR1 is excreted in urine it is imperative to study the relationship of
      urinary CR1 (uCR1) with ECR1 and GCR1, and their overall correlation with disease
      activity. We have determined the levels of uCR1, ECR1 and GCR1 in SLE patients
      and compared them with normal controls and minimal change disease (MCD) patients.
      We found a significant decline in both uCR1 and GCR1 in SLE but not in MCD;
      levels of uCR1 in MCD were either comparable to those of controls or higher.
      Immunofluorescence for GCR1 was very high in MCD. We did not find any correlation
      between ECR1, uCR1 and kidney function tests on divariate scatter analyses. The
      correlation coefficient for uCR1 and GCR1 was highly significant and positive.
      Our findings thus suggest that uCR1 reflects the levels of GCR1 expression, which
      decline drastically in SLE. Therefore we envisage uCR1 as a potential marker for
      glomerular involvement in SLE.

PMID- 15176658
TI  - Quality of life in paediatric lupus.
AB  - Paediatric systemic lupus erythematosus (SLE) is associated with significant
      morbidity and has biopsychosocial implications resulting from the disease and its
      treatment. The aim of this study was to identify domains of quality of life (QOL)
      impacted by SLE in children. Children with SLE and their parents were asked a
      single open-ended question related to lupus. Themes derived from children's
      responses focused primarily on coping and maintaining control of their life
      despite SLE. Themes from the parents' responses were twofold: a) efforts to cope
      with their child having SLE; and b) appreciation/sadness in connection with their
      children's coping process. Qualitative exploration of different facets of QOL in
      these children is critical for the understanding of specific factors that
      assist/ease the coping process and formulating interventions for improving
      children's/family's self-efficacy and disease management.

PMID- 15176659
TI  - IgA and IgG tissue transglutaminase antibodies in systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) and coeliac disease (CD) are diseases of an
      autoimmune origin that share the human leukocyte HLA-B8 and HLA-DR3
      histocompatibility antigens, yet the co-association of CD with SLE is mainly
      based on case reports. Thus, the real prevalence of CD in SLE is unclear. The aim
      of this study was to determine the prevalence of antitissue transglutaminase
      (anti-tTG) in SLE and the relation between SLE and CD. In this case-control
      study, 100 patients with SLE, and 120 healthy subjects were studied. Sera from
      all participants were analysed for the presence of IgA and IgG anti-tTG
      antibodies using a human recombinant tissue transglutaminase (tTG) immuno
      enzymatic assay. Anti-tTG positive patients and controls were further tested for
      antiendomysial (EMA) antibodies by an indirect immunofluorescence and HLA typing
      (DQalpha1*0501-DQbeta1*0201 allele determination). Subjects who had EMA or the
      mentioned allele, underwent duodenal biopsy to confirm a possible diagnosis of
      CD. Anti-tTG antibodies (IgA or IgG isotypes) were found in three of the 100 SLE
      patients (overall prevalence of 3%): one had the IgA and two the IgG isotypes.
      Only 1 of 120 healthy subjects (0.8%) had a low positive reaction for IgA anti
      tTG. Only the IgA anti-tTG positive SLE patient was diagnosed as having CD based
      on a positive IgA-EMA and small bowel biopsy findings. The two IgG anti-tTG
      positive SLE patients and the IgA anti-tTG positive healthy subject were
      classified as false positives (EMA negative and HLA DQalpha1*0501-DQbeta1*0201
      allele negative). In conclusion, anti-tTG antibodies were found at a low rate in
      SLE patients and mostly did not indicate the presence of CD. Thus, serological
      screening for CD is not recommended in SLE, unless a clinical suspicion of CD is
      present.

PMID- 15176660
TI  - Antiphospholipid antibodies in primary Sjogren's syndrome: prevalence and
      clinical significance in a series of 74 patients.
AB  - The aim of this study is to determine prevalence, clinical significance of
      antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL),
      anti-beta2GP1 and lupus anticoagulant (LA) in a cohort of 74 patients with
      primary Sjogren's syndrome (pSS) according to revised European criteria. aPL were
      found in 25 (34%) patients; IgG in 23 (12 had low titres, six moderate titres and
      five high titres) and IgM in five (three and two had respectively moderate and
      high titres). Eight (11%) patients were found to have LA; anti-beta2GP1
      antibodies were detected only in three (4%) patients. Only two patients with LA,
      aPL and beta2GP1 had recurrent venous thrombosis. One patient with moderate
      titres of aPL exhibited recurrent spontaneous foetal losses. Peripheral
      neuropathies without cryoglobulinemia were more frequent in the aPL group. Other
      systemic involvements of pSS were the same in both groups with or without aPL.
      Patients with aPL have more concurrent immunological diseases such as thyroiditis
      and primary biliary cirrhosis and a higher prevalence of hypergammaglobulinemia
      (P < 0.05). Even if aPL prevalence reached 30% in pSS, titres were usually low,
      with a close correlation with hypergammaglobulinemia but not with
      antiphospholipid syndrome, which is related to positivity of both LA and aPL.

PMID- 15176661
TI  - Complement-fixing properties of antinuclear antibodies distinguish drug-induced
      lupus from systemic lupus erythematosus.
AB  - The immunofluorescence antinuclear antibody (ANA) test has been widely used to
      monitor autoimmune disease, but its value for diagnostic purposes is compromised
      by low specificity and high prevalence in disease-free individuals. The capacity
      of autoantibodies to fix serum complement proteins when bound to antigen is an
      important effector function because this property is associated with acute and
      chronic inflammatory processes. The current study evaluates the complement-fixing
      properties of antinuclear antibodies (CANA) in three well-defined and clinically
      related patient groups: systemic lupus erythematosus (SLE), drug-induced lupus
      (DIL) and drug-induced autoimmunity (DIA). Of 20 patients diagnosed with SLE, 90%
      displayed complement-fixing ANA while this feature was present in only two of 18
      patients with DIL and no patients with DIA without associated disease even though
      the mean ANA titres were similar among these patient groups. CANA was
      significantly correlated with anti-Sm activity. Because SLE but not DIL or DIA
      can be a life-threatening disease associated with complement consumption in vivo,
      these results demonstrate that measurement of CANA is a diagnostically useful
      tool and may have immunopathologic implications.

PMID- 15176662
TI  - Increased frequency of GM-CSF secreting PBMC in patients with active systemic
      lupus erythematosus can be reduced by immunoadsorption.
AB  - An objective was to determine the frequency of GM-CSF secreting peripheral blood
      mononuclear cells (PBMC) in patients with active systemic lupus erythematosus
      (SLE) and their relation to other cytokine secreting PBMC, activation markers on
      lymphocytes/monocytes, clinical manifestations and anti-dsDNA antibodies. A
      second objective was to further investigate the influence of immunoadsorption
      (IA) therapy on these parameters. The number of GM-CSF, interleukin-1beta (IL
      1beta), IL-6, interferon-gamma (INF-gamma) or tumour necrosis factor-alpha (TNF
      alpha) secreting PBMC was assessed by ELISPOT assay in 10 patients with active
      SLE. Further, the expression of activation markers on lymphocytes and monocytes
      was determined by flow cytometry. Three courses of IA were performed in the
      patients. Seventeen healthy, age- and sex-matched volunteers served as controls.
      GM-CSF secreting PBMC were significantly increased whereas INF-gamma secreting
      cells were decreased in SLE patients. The expression of CD71 (transferrin
      receptor) on CD4+ T-cells and of the costimulatory molecule CD86 on B-lymphocytes
      was significantly increased in SLE patients. GM-CSF secreting PBMC and CD4+/CD71+
      T-cells correlated with anti-dsDNA antibody titres and decreased towards levels
      of controls during IA. Disease activity and anti-dsDNA autoantibody titres were
      significantly reduced after the treatment. Our results demonstrate significant
      alterations of cellular and humoral immunity in SLE patients. The impaired
      immunity can be modulated by IA. Thus IA may prove an immunomodulatory
      therapeutic option in addition to the mere depletion of anti-dsDNA
      autoantibodies.

PMID- 15176663
TI  - Is there an ethnic difference in the prevalence of lupus cystitis? A report of
      six cases.
AB  - Lupus cystitis was rare but frequently resulted in obstructive uropathy and had a
      strong association with gastrointestinal (GI) symptoms. We treated six patients
      with systemic lupus erythematosus (SLE) and obstructive uropathy from January
      1996 to December 2001 in a university hospital. Evidence of cystitis was obtained
      from cystoscopic biopsy or the presence of thickened bladder wall in image study.
      Similar to other reports, five patients had GI manifestations such as abdominal
      pain, nausea/vomiting, diarrhoea or ileus. In addition, mesenteric
      lymphadenopathy or pancreatitis was noted in three patients. Two patients had
      been treated for idiopathic thrombocytopenic purpura (ITP), four and 20 years
      ago, respectively. All six patients had antibodies to double-stranded DNA
      (dsDNA). Five patients each had antibodies to cardiolipin (IgG aCL) or SSA. The
      high prevalence of anti-SSA had also been reported in Chinese lupus patients with
      intestinal pseudo-obstruction, a clinical manifestation frequently associated
      with bilateral ureterohydronephrosis. Two patients died of intractable infection
      after the surgical procedures for persistent ureterohydronephrosis and both
      patients had antibodies to ribosomal P proteins. Lupus cystitis might not be so
      rare in Chinese patients with SLE. The diagnosis should be kept in mind when
      lupus patients have urinary and/or GI symptoms.

PMID- 15176664
TI  - Acquired ichthyosis associated with systemic lupus erythematosus.
AB  - Acquired ichthyosis is an uncommon disease, it is characterized by symmetric
      scaling of the skin, which ranges from minor roughness and dryness to the
      desquamation of large plaques. It has been associated with various systemic
      diseases, although malignant conditions, especially Hodgkin's lymphoma are the
      most commonly cited. Drugs, HIV infection and autoimmune diseases such as
      dermatomyositis and mixed connective tissue disease have also been associated,
      and it has only rarely been found among patients with systemic lupus
      erythematosus (SLE). Herein, we report a patient with active SLE who developed a
      generalized acquired ichthyosis corroborated with skin biopsy, which completely
      disappeared after treatment. The association of autoimmune conditions with
      acquired ichthyosis could indicate that an abnormal host immune response,
      probably against components of the granular cell layer in particular the
      keratohyalin granules, may have a role in the pathogenesis. Thus, this finding
      may be a relevant cutaneous marker for an autoimmune origin.

PMID- 15176665
TI  - Tuberculosis in Turkish patients with systemic lupus erythematosus: increased
      frequency of extrapulmonary localization.
AB  - The objective was to investigate the frequency and characteristics of
      tuberculosis (TB) in patients with systemic lupus erythematosus (SLE). We
      reviewed the charts of 556 patients with SLE who were followed up between 1978
      and 2001 in our lupus clinic. Patients who developed TB after the diagnosis of
      SLE were identified (SLE/TB+). Ninety-six consecutive patients with SLE who did
      not develop TB during the follow-up were evaluated as a control group (SLE/TB-).
      Clinical, laboratory and management characteristics of these two groups of
      patients were recorded according to a predefined protocol, and compared. Of the
      556 patients evaluated, 20 patients (3.6%) with TB were identified. Nine of the
      20 patients (45%) had extrapulmonary TB (vertebral involvement in three patients,
      meningeal in two, and joint and soft tissue in four). Arthritis and renal
      involvement were significantly high in the SLE/TB+ group (P = 0.045, P = 0.009,
      respectively). The mean daily dose of prednisolone before the diagnosis of TB and
      the cumulative dose of prednisolone were significantly higher in the SLE/TB+
      group compared to the SLE/TB- group (27 +/- 22 g versus 16 +/- 16 g, 24 +/- 45 mg
      versus 11 +/- 8.5 mg, respectively). In conclusion, we found an increased
      frequency of TB infection and a high prevalence of extrapulmonary TB in a large
      cohort of SLE patients. The mean daily dose of prednisolone before the diagnosis
      of TB and the cumulative dose of prednisolone, which possibly related to disease
      severity, were important determinants for the increased risk of TB in these
      patients with SLE.

PMID- 15176666
TI  - Anti-SS-A/Ro reactivity in patients with Vogt-Koyanagi-Harada syndrome.

PMID- 15176667
TI  - Solar UV-B radiation is linked to the geographic variation of mortality from
      systemic lupus erythematosus in the USA.

PMID- 15176668
TI  - Attitudes toward aging: a comparative analysis of young adults from the United
      States and Germany.
AB  - Social and cultural attitudes toward aging provide a framework for assessing
      one's own aging experiences as well as one's attitudes toward older men and
      women. Ageism, or prejudicial attitudes and discriminatory practices toward older
      adults (Butler, 1980), has been found to be widespread around the world. This
      study focuses on a comparative analysis of the attitudes of young adults from
      Germany and the United States. Specifically, the purpose of this study was to
      evaluate similarities and differences in the anxiety associated with four
      measurable dimensions associated with ageism: fear of old people, psychological
      concerns associated with aging, concern over changes in physical appearance as a
      result of aging, and fear of losses associated with aging. The second purpose of
      this study was to evaluate the age at which young adults from these two countries
      might consider themselves to be "old." The findings indicate significant country
      and gender differences across the dimensions. German participants tended to view
      aging much more negatively than American participants did. However, Americans
      considered themselves to be "old" at a much younger age than Germans. Gender
      differences indicated that women in both countries were more concerned with age
      related changes in their physical appearance than were men. Analyses of the
      results are discussed in relation to the influence of ageism and negative
      cultural stereotypes of aging on people's self-image across the life span.

PMID- 15176669
TI  - Life satisfaction across the life course: evaluations of the most and least
      satisfying decades of life.
AB  - In a recent American study, the decades from ages 20 to 59 were most frequently
      chosen to be the most satisfying. However, one third of the elderly evaluated a
      decade in old age to be the most satisfying (Field, 1996). The present study was
      undertaken to investigate whether this finding could be replicated in a larger,
      representative sample of elderly Danes. Four cohorts born with an interval of
      five years, 62 to 77 years old (N = 3207) were asked to point out the most and
      the least satisfying decades of life. The years from 30 to 39 were most
      frequently chosen as the most satisfying decade, followed by the adjoining
      decades. A decade in old age was chosen as the least satisfying by 24% of the
      participants, while only 8.5% of the participants evaluated old age as the most
      satisfying period of life. Further analyses were made to examine conditions
      related to evaluating the present decade as the most or the least satisfying.

PMID- 15176670
TI  - Perceptions of help given to healthy older mothers by adult daughters: ways of
      initiating help and types of help given.
AB  - Older mother-adult daughter dyads (N = 43) addressed two issues pertaining to the
      ways in which help is initiated (offered, requested, and imposed help) and type
      of help given (instrumental help, advice, and emotional support) a) mothers'
      reasoning about these aspects of help, and b) daughters' understanding of
      mothers' feelings. Both groups noted that mothers were most comfortable with
      offered help; however, mothers indicated equal comfort with requested or imposed
      help, while daughters felt mothers were more comfortable with requested help than
      imposed help. Mothers and daughters both felt that mothers were less comfortable
      receiving additional instrumental help or advice than emotional support. Reasons
      given for mothers' feelings indicated that mothers saw both positive and negative
      elements in the help given by their adult daughters. Overall, daughters
      demonstrated a good understanding of mothers' feelings about the helping
      relationship.

PMID- 15176671
TI  - Work related attitudes of naval officers before and after retirement.
AB  - Prospective expectations for retirement and retrospective accounts of past work
      experiences are typically used in cross-sectional empirical studies of
      retirement. Unfortunately, little is known about the accuracy of such accounts.
      Therefore, in the present longitudinal study, we built on the work of Beehr and
      Nielson (1995) by examining the consistency of these accounts over time using
      data from 672 military retirees over a four- to five-year period. Mixed evidence
      for the consistency of these attitudes across time was found. Specifically, our
      results are much weaker than Beehr and Nielson's results, thus suggesting that
      longer time intervals between measurements may erode the accuracy of prospective
      estimates and retrospective accounts. Results are discussed in terms of the
      uniqueness of the military retirement and how civilian retirement and military
      retirement are becoming similar.

PMID- 15176672
TI  - Cognitive algebra of love through the adult life.
AB  - The study was aimed at characterizing the exact algebraic structure of the love
      schema in order to trace possible changes in the conceptualization of love
      throughout the adult life cycle, notably as regards the weight attributed to the
      three components of love: passion, intimacy, and commitment. The methodological
      framework was the Functional Theory of Cognition. Irrespective of the gender and
      age of the participants (from 18 to 93), the structure of the love schema was
      shown to obey an equal-weight-averaging rule; the love schema was conceived as a
      strictly compensatory schema. Irrespective of age and gender, passion was the
      most important factor (w = .51), followed by intimacy (.29) and commitment (.20).
      The relationship between overall love value and degree of passion (or intimacy or
      commitment) was not conceived as a linear one, but as an exponential one. The
      weight of passion was shown to decline over age, and the weight of commitment was
      shown to increase over age. This change was, however, very limited and observed
      in elderly participants only.

PMID- 15176673
TI  - The British hypothesis revisited.

PMID- 15176674
TI  - Bigger numbers needed!

PMID- 15176675
TI  - The hepatopulmonary syndrome: NO way out?

PMID- 15176676
TI  - The yin and the yang of p27Kip1 as a target for cancer therapy.

PMID- 15176677
TI  - Effects of p27Kip1 on cell cycle status and viability in A549 lung adenocarcinoma
      cells.
AB  - p27Kip1 is a cyclin-dependent kinase inhibitor, it negatively regulates G1
      progression and is reported to modulate apoptosis. Phosphorylation of this
      protein is thought to regulate its intracellular localisation and affect its
      stability. The aim of this study was to regulate p27Kip1 expression levels, and
      to examine how this protein affects cell cycle status and modulates viability in
      A549 lung adenocarcinoma cells. In addition, the association between
      phosphorylation status of p27Kip1 and its intracellular localisation was
      investigated, using expression vectors with cDNA of p27Kip1 or mutants in which
      the phosphorylation sites had been mutated. Although overexpression of p27Kip1
      reduced cell cycle progression, its removal did not change cell cycle status.
      Modest induction of p27Kip1 rescued adenovector-induced apoptosis and its removal
      with short interfering RNA increased spontaneous cell death. It was also observed
      that p27Kip1 localised mainly in the cytoplasm, and forced expression of p27Kip1
      cDNA with the substitution of serine (S) 10, threonine (T) 157 and T198 to
      glutamate (phosphor-mimetic) induced its cytoplasmic localisation. In conclusion,
      p27Kip1, when expressed physiologically, exists mainly in the cytoplasm, has
      little effect on cell cycle status and contributes viability in A549 lung
      adenocarcinoma cells. It was also surmised that intracellular localisation of
      p27Kip1 dominates its function and that its localisation was partly determined by
      its phosphorylation.

PMID- 15176678
TI  - Suppression of matrix metalloproteinase production from nasal fibroblasts by
      macrolide antibiotics in vitro.
AB  - It is well known that low-dose and long-term administration of macrolide
      antibiotics favourably modify the clinical status of chronic airway inflammatory
      diseases. However, the therapeutic mode of action of macrolide antibiotics is not
      well understood. The present study aimed to examine the influence of macrolide
      antibiotics, roxithromycin (RXM) and josamycin (JM) on matrix metalloproteinase
      (MMP) production from nasal polyp fibroblasts (NPF) in vitro. NPF, at a
      concentration of 2.5 x 10(5) cells x mL(-1), were stimulated with tumour necrosis
      factor (TNF)-alpha in the presence of various concentrations of RXM or JM for 24
      h. MMP-2 and -9 levels in culture supernatants were analysed by ELISA, and MMP
      mRNA expression was examined by RT-PCR. The influence of RXM on nuclear factor
      (NF)-kappaB and activator protein (AP)-1 activation was also examined. Addition
      of RXM (but not JM) at 5.0 and 7.5 microg x mL(-1) significantly suppressed the
      production of MMP-2 and -9 from NPF induced by TNF-alpha stimulation. RXM also
      suppressed MMP mRNA expression through the inhibition of NF-kappaB and AP-1
      activation. The present results suggest that the suppressive activity of
      roxithromycin on MMP-2 and -9 production is, in part, responsible for the
      therapeutic action of macrolides on chronic airway inflammatory diseases.

PMID- 15176679
TI  - Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic
      fibrosis patients.
AB  - In this European study, the phenotype in 68 patients, homozygous or compound
      heterozygous for the G85E mutation, was investigated. Each index case was
      compared with two cystic fibrosis (CF) patients from the same clinic, matched for
      age and sex: one with pancreatic sufficiency (PS) and one with pancreatic
      insufficiency (PI). When comparing 31 G85E/F508del and F508del/F508del patients,
      there were no differences in median age at diagnosis, mean sweat chloride value,
      most recent weight for height, most recent forced expiratory volume in one second
      % predicted, prevalence of chronic Pseudomonas aeruginosa colonisation and
      typical CF complications. However, PI was less frequent in the G85E/F508del
      group. Comparison of 55 G85E patients (with second mutation known and not
      classified as mild) with PS controls (n=44) showed that the G85E patients had a
      significantly higher sweat chloride, more often failure to thrive at diagnosis,
      higher prevalence of PI, worse current weight for height, higher prevalence of
      chronic P. aeruginosa colonisation and liver cirrhosis. Pulse-chase experiments
      revealed that G85E cystic fibrosis transmembrane conductance regulator failed to
      mature on a M470 as well as on a V470 background. Therefore, G85E is a class II
      mutation. Although there is variability in its clinical presentation, G85E
      mutation results in a severe phenotype.

PMID- 15176680
TI  - Impact of sputum bacteria on airway inflammation and health status in clinical
      stable COPD.
AB  - Chronic obstructive pulmonary disease (COPD) is characterised by sputum
      production, bacterial colonisation, neutrophilic bronchial airway inflammation
      and poor health status. The aim of this study was to determine the impact of
      sputum potentially pathogenic microorganisms (PPMs) on bronchial airway
      inflammation, health status and plasma fibrinogen levels in subjects with
      moderate-to-severe COPD during the clinical stable state. Sputum total cell and
      neutrophil counts, supernatant interleukin-8, leukotriene B4, tumour necrosis
      factor-alpha and neutrophil elastase levels, neutrophil chemotaxis and plasma
      fibrinogen levels were estimated. Health status was determined using the St
      George's Respiratory Questionnaire and the 36-item Short-Form Health Survey
      questionnaire. Twenty-seven (40%) subjects had PPMs and 40 (60%) non-PPMs in
      their sputum. Both groups were of similar age, body mass index, smoking history
      and lung function. The PPMs group showed significantly higher levels of
      interleukin-8, leukotriene B4, tumour necrosis factor-a, neutrophil elastase and
      increased neutrophil chemotaxis. They also exhibited worse health status and
      raised plasma fibrinogen levels compared to the non-PPMs group. In conclusion,
      subjects with clinically stable moderate-to-severe chronic obstructive pulmonary
      disease who had potentially pathogenic microorganisms in their sputum
      demonstrated an exaggerated airway inflammatory response, poorer health status
      and increased plasma fibrinogen levels than those who had nonpotentially
      pathogenic microorganisms.

PMID- 15176681
TI  - Inhaled corticosteroids and the risk of a first exacerbation in COPD patients.
AB  - The role of inhaled corticosteroids (ICS) in asthma is well established, but
      their benefit in the management of chronic obstructive pulmonary disease (COPD)
      is still controversial. The current study assessed whether ICS are effective in
      preventing a first exacerbation of COPD. A cohort of newly treated COPD patients
      was formed from the Administrative Databases of Saskatchewan Health. The outcome
      was the occurrence of a first moderate or severe exacerbation from 1990-1999.
      Moderate exacerbations involved prescriptions for an antibiotic and an oral
      corticosteroid on the same day. Severe exacerbations were hospitalisations with a
      primary discharge diagnosis of COPD. A nested case-control design was used and
      matched on year of birth and cohort entry. Rate ratios (RR) were further adjusted
      for use of other medication and other confounders. There were 995 exacerbations
      among 4,455 subjects. The rate of a first exacerbation was increased with any use
      of ICS in the year prior to the index date (RR: 1.27; 95% CI: 1.08-1.48) and with
      current use (RR: 1.51; 95% CI: 1.22-1.87), and it increased with increasing daily
      doses of ICS. Inhaled corticosteroids do not seem to be beneficial in reducing
      the risk of a first exacerbation of chronic obstructive pulmonary disease.

PMID- 15176682
TI  - Impact of preventing exacerbations on deterioration of health status in COPD.
AB  - Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with
      worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe
      (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced
      exacerbation frequency and the rate of deterioration in health status as compared
      with placebo. The present study analysed these data to test whether the effect of
      FP on health status was attributable to its effect on exacerbations. Rates of
      deterioration in St George's Respiratory Questionnaire (SGRQ) total score were
      obtained for 613 patients with moderate to severe COPD followed for a maximum of
      3 yrs. Exacerbation rates were skewed and could not be normalised, therefore,
      patients were stratified into three exacerbation groups: none, infrequent (<1.65
      exacerbations x yr(-1)) and frequent (>1.65 exacerbations x yr(-1)). There were
      91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with
      frequent exacerbations. Frequent exacerbations were independently associated with
      a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in
      health status (p=0.0003). Exacerbation frequency and rate of decline in forced
      expiratory volume in one second were independently related to the rate of
      deterioration in SGRQ score. Statistical modelling showed the beneficial effect
      of fluticasone propionate on deterioration in health status to be largely due to
      its effect on exacerbation frequency.

PMID- 15176683
TI  - Differential effects of emphysema on skeletal muscle fibre atrophy in hamsters.
AB  - Patients afflicted with emphysema demonstrate altered peripheral skeletal muscle
      fibre composition and atrophy. It is unknown whether these alterations are
      general to all skeletal muscles independent of function, phenotype or oxidative
      capacity. Therefore, the purpose of this investigation was to determine whether
      emphysema induces alterations in muscle fibre composition or atrophy in
      respiratory and locomotory muscles with diverse fibre types and metabolic
      profiles. Fibre composition and cross-sectional area were measured in selected
      hindlimb muscles and diaphragm of hamsters following saline (control, n=7) or
      elastase (emphysema, n=15) instillation. Excised lung volume increased 145% with
      emphysema. Fibre composition was largely unaltered, with the exception of a 13%
      reduction in IIB fibres in the tibialis anterior muscle of emphysema animals.
      Type I fibre size was also mainly unaltered, except for a diminished cross
      sectional area in plantaris muscle. However, fibre cross-sectional area of fast
      twitch types IIA, IIX and/or IIB fibres was reduced in the caudal biceps femoris,
      vastus lateralis, tibialis anterior, gastrocnemius and plantaris muscles of
      emphysema animals. In contrast, there was a trend for emphysema to increase the
      cross-sectional area of type IIA fibres in the diaphragm. These data demonstrate
      that emphysema-induced atrophy primarily affects locomotory muscles, independent
      of phenotype or oxidative capacity.

PMID- 15176684
TI  - Peak or plateau maximal inspiratory mouth pressure: which is best?
AB  - There is no clear evidence as to how maximal inspiratory mouth pressure (PI,max)
      should be measured, although plateau pressures sustained for 1 s and measured at
      residual volume (RV) are usually recommended. Peak and plateau PI,max were
      measured at RV and at functional residual capacity (FRC) in 533 healthy subjects
      (aged 10-90 yrs) in order to comparably test all PI,max measurements for their
      predictors, reproducibility and normal values. Plateau pressures accounted for
      82.0-86.3%, of peak pressures. Peak and plateau pressures measured at FRC
      accounted for 84.3-90.5% of pressures at RV, and were highly correlated. Age was
      negatively predictive and weight and body mass index positively predictive of
      PI,max, but regression parameters were low. All PI,max measurements were
      comparable when calculating regression parameters, between-subject variability
      and reproducibility. In conclusion, peak and plateau maximal inspiratory mouth
      pressure are comparably useful for the assessment of inspiratory muscle strength
      and can be reliably measured at functional residual capacity and at residual
      volume. Regression equations are of low impact in predicting normal values due to
      the weak influence of demographic and anthropometric factors and to the high
      unexplained between-subject-variability. Age-related 5th percentiles can indicate
      the lower limit of the normal range.

PMID- 15176685
TI  - Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients
      with asthma.
AB  - A randomised double-blind placebo-controlled study was designed to evaluate the
      effects of a semisynthetic macrolide antibiotic, clarithromycin, on bronchial
      hyperresponsiveness to methacholine in patients with a diagnosis of asthma. Adult
      asthma patients undergoing treatment with budesonide 400 microg b.i.d. and
      salbutamol 200 microg p.r.n. less than twice weekly were studied. Arm A (16
      males/six females, aged 48 +/- 16 yrs) received clarithromycin 250 mg b.i.d. for
      8 weeks, arm B (eight males/12 females, aged 42 +/- 12 yrs) clarithromycin 250 mg
      t.id. and arm C (six males/15 females, aged 41 +/- 16 yrs) placebo dextrose
      tablets. Bronchial hyperresponsiveness was quantified by measurement of the
      provocative dose of methacholine causing a 20% fall in forced expiratory volume
      in one second (PD20). Median (interquartile range) PD20 in the three groups
      before and after treatment with clarithromycin were: arm A: 0.3 (0.1-1) and 1.3
      (0.6-2) mg; arm B: 0.4 (0.1-0.9) and 2 (2-2) mg; and arm C: 0.4 (0.1-0.9) and 0.3
      (0.1-0.6) mg, respectively. Serum free cortisol levels were determined and
      remained unchanged from baseline in the clarithromycin-treated patients. It is
      concluded that clarithromycin reduces the degree of bronchial hyperresponsiveness
      in patients with asthma.

PMID- 15176686
TI  - Relationship between guideline treatment and health-related quality of life in
      asthma.
AB  - The aim of this study was to compare the health-related quality of life (HRQL) of
      asthma patients treated according to the 1997 National Institute of Health (NIH)
      international asthma guideline and that of asthmatics receiving non-guideline
      treatment. The suitability of 146 asthmatics' medication regimes was determined
      according to the 1997 NIH asthma guideline. Quality of life was assessed on a
      seven-point scale using the Asthma Quality of Life questionnaire. Just over half
      of the patients were not currently using the treatment considered necessary for
      controlling their asthma. Patients treated according to the guideline (n=72) had
      a significantly higher overall HRQL than patients with non-guideline treatment
      (5.7 versus 5.3). The differences were also significant for the subscales
      measuring symptoms and environmental exposure, but not for activities or
      emotional function. An association between non-guideline treatment and a poorer
      health-related quality of life in asthma patients treated in general practice was
      observed. This study supports the role of evidence-based guidelines in daily
      practice. Further studies are needed to determine if guideline treatment is
      responsible for the increase in health-related quality of life observed in this
      work.

PMID- 15176687
TI  - Asthma severity and medical resource utilisation.
AB  - Asthma represents a growing public health problem and the cost of asthma has been
      rising in many countries. The aim of this study was to estimate the direct and
      indirect cost of asthma among adult patients in Italy, and to assess the
      relationship between healthcare resource use and asthma severity according to the
      Global Initiative for Asthma (GINA) classification system. A multicentre cross
      sectional study was conducted in 16 Italian hospital-based specialised asthma
      clinics. Data collection was based on self-administered questionnaires and took
      place during the period May 1-November 30, 1999, and 500 consecutive patients
      with asthma, aged 18-55 yrs, were enrolled during regularly scheduled visits.
      Direct costs (drugs, physician visits, emergency service use and
      hospitalisation), indirect costs (loss of paid workdays) and total costs were
      determined in euros (Euros) for 1999. Patients with more severe disease, as
      classified by the GINA guideline, exhibited more night-time and daytime symptoms
      and were more limited in performing normal daily activities. The mean total cost
      of asthma per patient per year was estimated to be Euros 1,260; drug costs
      accounted for 16%, physician costs 12%, emergency service and hospitalisation
      costs 20% and indirect costs 52% of the mean cost. Stratified by severity, the
      total annual cost per patient amounted to Euros 720, Euros 1,046, Euros 1,535 and
      Euros 3,328 for patients with intermittent, mild persistent, moderate persistent
      and severe persistent asthma, respectively. Asthma severity, as determined by the
      Global Initiative for Asthma classification, is significantly associated with
      symptoms, limitations in normal daily activities, asthma-related medical resource
      utilisation and both direct and indirect costs. Asthma control is not only a
      clinical but also an economic imperative.

PMID- 15176688
TI  - Effect of peak expiratory flow data quantity on diagnostic sensitivity and
      specificity in occupational asthma.
AB  - Serial peak expiratory flow records are recommended in the first-line
      investigation of suspected occupational asthma. The effects of sequentially
      reducing the numbers of working weeks, consecutive days at work and readings
      taken per day on diagnostic sensitivity and specificity were investigated, using
      good quality peak expiratory flow records from 81 workers with independently
      confirmed occupational asthma and 60 asthmatics without occupational exposure.
      Sensitivity was 81.8% for records of 4 weeks' duration and 70% for those of 2
      weeks' duration (specificity 93.8 and 82.4% respectively). The sensitivity fell
      to 56.7% if there were only 2 consecutive workdays in each work period. Although
      best at 8 readings x day(-1), sensitivity and specificity were acceptable with
      four daily readings (82.4 and 87%). The effect of defining a record as being of
      adequate quality if it was of > or = 2.5 weeks' duration, with > or = 4 readings
      x day(-1) and > or = 3 consecutive workdays in each work period, was tested in
      records not used in the initial data reduction process. The sensitivity and
      specificity respectively of adequate records were 78.1 and 91.8 versus 63.6 and
      83.3% for inadequate records. Peak expiratory flow records for the diagnosis of
      occupational asthma should be interpreted with caution if they do not satisfy the
      suggested minimum data quantity criteria.

PMID- 15176689
TI  - Increased long-term mortality in heart failure due to sleep apnoea is not yet
      proven.
AB  - Previous small-scale studies of the effect of sleep-disordered breathing (SDB) on
      prognosis in congestive heart failure (CHF) are either lacking or conflicting.
      The aim of this study was to assess the impact of the presence and type of SDB on
      mortality in a patient group with severe CHF referred to a specialised heart
      failure centre. Out of 78 patients ((mean +/- SD) 53 +/- 9 yrs, left ventricular
      ejection fraction 19.9 +/- 7.2% and pulmonary capillary wedge pressure 16.5 +/-
      8.3 mmHg) followed-up over a median period of 52 months, 29% had no apnoea (CHF
      N), 28% had obstructive sleep apnoea (CHF-OSA) and 42% had central sleep apnoea
      (CHF-CSA). At 52 months, their overall mortality was 40%, and combined mortality
      and transplantation was 72%. Mortality rates were similar between the three
      apnoea groups. Survivors had a similar prevalence of SDB (71%) as the
      nonsurvivors (70%). Although a significant increase in mortality was evident at
      500 days in those patients with either CHF-SDB or CHF-CSA as compared with CHF-N,
      this was not significant at final follow-up (52 months) using Kaplan Meier
      analysis. Multivariate analysis identified transplantation but not SDB type or
      severity as a significant predictor of survival. In conclusion, sleep-disordered
      breathing impacts upon early (500 day), but not long-term (52 month), mortality
      in a specialised heart failure centre.

PMID- 15176690
TI  - Nontuberculous mycobacteria in non-HIV patients: epidemiology, treatment and
      response.
AB  - Recent international guidelines published in 1997 and 1999 have proposed
      diagnostic and treatment criteria for disease caused by nontuberculous
      mycobacteria (NTM). In this paper, the epidemiological data, diagnostic criteria,
      treatment regimens and outcomes from 117 HIV-negative patients who had a positive
      culture for NTM between 1995-1999 are reviewed. The authors wished to identify
      factors associated with improved outcome in these patients. A total of 71
      patients were believed to have a clinical disease caused by NTM, as defined by
      international criteria. A total of 72% patients were found to have had pulmonary
      disease. There was a rise in infections between 1995-1999, with a peak in
      infections in 1997. The most striking rise was in Mycobacterium avium
      intracellulare complex infections (1995: 33% infections; 1996: 36% infections;
      1997: 41% infections; 1998: 61% infections; 1999: 57% infections). There was a
      link between deprivation and number of positive NTM isolates (34.4% isolates
      occurred in the areas of lowest Carstairs deprivation index versus 20.6% isolates
      from areas of least deprivation). There was a significant association between
      appropriate therapy, defined by American Thoracic Society and British Thoracic
      Society guidelines, and successful outcome (74%) in contrast to those who
      received inappropriate treatment prior to the publication of these guidelines.
      Nontuberculous mycobacteria infections remain a significant problem in non-HIV
      patients. Adherence to published guidelines may improve patient outcomes.

PMID- 15176691
TI  - Exercise testing in pulmonary arterial hypertension and in chronic heart failure.
AB  - Exercise capacity is reduced in pulmonary arterial hypertension and in chronic
      left heart failure, but it is not known whether the cardiopulmonary exercise
      testing profile is different in the two conditions at the same severity of
      functional limitation. Nineteen patients with pulmonary arterial hypertension and
      19 with chronic heart failure underwent a 6-min walk test and symptom-limited
      maximal incremental cycle ergometry. The patients with pulmonary arterial
      hypertension and chronic heart failure did not differ in New York Heart
      Association Functional Class (mean +/- SEM 2.8 +/- 0.1 versus 2.8 +/- 0.2), 6-min
      walking distance (395 +/- 30 versus 419 +/- 20 m), peak work-rate, oxygen
      consumption, ventilation and cardiac frequency. However, patients with pulmonary
      arterial hypertension exhibited higher dyspnoea scores (5.8 +/- 0.6 versus 3.8 +/
      0.5) higher ventilatory equivalents for carbon dioxide (58 +/- 3 versus 44 +/- 3
      at the anaerobic threshold) and lower peak oxygen pulse (5.9 +/- 0.4 versus 8.7
      +/- 0.5 mL x beat(-1), or 53 +/- 4 versus 64 +/- 4% of the predicted value). It
      is concluded that the cardiopulmonary exercise testing profile in pulmonary
      arterial hypertension differs from that in chronic heart failure by showing more
      dyspnoea at comparable work-rates, related to greater reductions in ventilatory
      efficiency and stroke volume.

PMID- 15176692
TI  - Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline
      in cirrhotic rats.
AB  - Inhibition of tumour necrosis factor-alpha (TNF-alpha), levels of which are
      increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory
      state, mainly by decreasing the vascular overproduction of nitric oxide.
      Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular
      dilatation and increased alveolar to arterial oxygen tension difference (PA
      a,O2), is mainly related to pulmonary over-production of NO by macrophages
      accumulated in lung vessels. Since TNF-alpha is a potent activator of macrophagic
      inducible nitric oxide synthase (NOS), the aim of this study was to investigate
      whether TNF-alpha inhibition prevented hepatopulmonary syndrome and hyperdynamic
      circulatory state in rats with cirrhosis. TNF-alpha was inhibited by 5 weeks of
      pentoxifylline (10 mg x kg body weigh(-1) x day(-1)) in rats with cirrhosis
      induced by common bile duct ligation. Cardiac output, pulmonary and systemic
      vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium-99m
      labelled albumin macroaggregates (which reflects intrapulmonary vascular
      dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats.
      Blood TNF-alpha concentrations and pulmonary intravascular macrophage
      sequestration, as assessed by morphometric analysis and radioactive colloid
      uptake, were decreased with pentoxifylline. Pentoxifylline also prevented
      increases in aorta and lung NOS activities and inducible NOS expression. Thus
      pentoxifylline prevents development of hyperdynamic circulatory state and
      hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis
      factor-alpha on vascular nitric oxide synthase and intravascular macrophages.
      These results support an important role for tumour necrosis factor-alpha in the
      genesis of hepatopulmonary syndrome.

PMID- 15176693
TI  - Effect of saliva contamination on induced sputum cell counts, IL-8 and eosinophil
      cationic protein levels.
AB  - Excessive salivary contamination of induced sputum samples prevents the
      satisfactory examination of lower airway inflammation. The effects of salivary
      contamination on different sputum fluid phase measures and the levels of salivary
      contamination preventing analysis are not defined. The present study sought to
      examine this by investigating the effect of increasing salivary contamination on
      induced sputum samples. Sputum and saliva samples from subjects with asthma and
      healthy controls were collected, and treated with dithiothreitol (DTT). Saliva
      was then added to aliquots of dispersed sputum in increasing proportions (0% to
      100%). The effect of increasing saliva contamination was assessed on sputum total
      cell count, viability, differential cell count and fluid phase levels of
      interleukin (IL)-8, eosinophil cationic protein (ECP) and total protein. The
      addition of saliva to induced sputum reduced total cell counts and absolute cell
      counts but did not change the differential cell count. Levels of fluid phase ECP
      and IL-8 were significantly reduced with increased salivary contamination. There
      was a progressive reduction in ECP and IL-8, which reached significance at 70%
      and 80% saliva contamination, respectively. IL-8 levels corrected for total
      protein showed no change with increasing saliva concentrations. Induced sputum
      differential cell counts expressed as the proportion of nonsquamous cells are
      robust measures that are not influenced by salivary contamination. Studies
      reporting total and absolute cell counts and fluid phase mediator levels require
      control for squamous contamination.

PMID- 15176694
TI  - Functional residual capacity measurements in healthy infants: ultrasonic flow
      meter versus a mass spectrometer.
AB  - Accurate, reproducible and portable bedside monitoring of lung volume could
      potentially facilitate the early recognition of both under and overinflation of
      the lungs in ventilated and nonventilated subjects. This study asked whether a
      prototype portable ultrasonic flow meter provided valid and reliable measurements
      of functional residual capacity (FRCUS) when compared to those obtained using a
      mass spectrometer (FRCMS) in nonventilated healthy infants. Paired, randomised
      measurements of FRCMS and FRCUS were obtained using the sulphur hexafluoride
      (SF6) multiple-breath washout technique in 23 healthy infants with a median
      (range) postnatal age of 34.6 (1.3-92.6) weeks and weight of 8.3 (3.9-11.7) kg.
      FRCUS was on average 5.7%, (95% CI: 1.0-10.4%) less than FRCMS equating to a
      difference of approximately 1 mL x kg(-1). The 95% limits of agreement (LA)
      between the two techniques were relatively wide (95% LA: -17.5% to 29%), although
      in keeping with previously reported within-patient variability for lung volume
      measurements. There was no significant difference between the within subject
      coefficient of variation for FRCMS (3.7%) and FRCUS (5.2%). The ultrasonic flow
      meter used in this study provides repeatable measurements of functional residual
      capacity in spontaneously breathing healthy infants that approximate those
      obtained during mass spectrometry.

PMID- 15176695
TI  - Report of a workshop: quantitative computed tomography scanning in longitudinal
      studies of emphysema.
AB  - It has been reported that quantitative computed tomography (CT) scanning of the
      lungs showed decreased progression of emphysema in a randomised clinical trial in
      patients with severe alpha1-antitrypsin (alpha1-AT) deficiency receiving monthly
      intravenous augmentation therapy with human alpha1-AT. Comparable results were
      not obtained using rate of decline of forced expiratory volume in one second.
      Accordingly, the Alpha-1 Foundation convened a workshop to explore the
      feasibility of using quantitative CT data as a primary outcome variable in trials
      of drugs for treating alpha1-AT deficiency. This report reviews the following:
      the principles for the use of modern CT scanners for quantifying emphysema; the
      methods and data on validation by comparison with measurements of severity of
      emphysema in inflation-fixed specimens of lungs; and the possibility of
      decreasing radiation dosage from CT to make it safe and ethically possible to use
      CT in longitudinal studies. The workshop concluded that it is feasible, safe and
      ethically possible to use computed tomography in longitudinal studies of
      emphysema. It recommended that the primary end-point should be a significant
      shift in the 15th percentile of lung density.

PMID- 15176696
TI  - Multidetector CT-generated virtual bronchoscopy: an illustrated review of the
      potential clinical indications.
AB  - Multidetector computed tomography-generated virtual bronchoscopy (VB) is a recent
      technical development that allows visualisation of the lumen and wall of the
      trachea and proximal part of the bronchial tree. A dynamic image is produced that
      resembles what is seen with fibreoptic bronchoscopy (FB). Although the technique
      has not yet reached daily clinical practice and it can never replace FB,
      performing VB can be useful in well-defined clinical situations. In this paper,
      the value and limitations of virtual bronchoscopy will be reviewed, to illustrate
      the potential role of virtual bronchoscopy in the evaluation of trachea and
      bronchial tree pathology.

PMID- 15176697
TI  - Pulmonary infiltrates in Costello Syndrome.
AB  - This paper reports on a patient with diffuse pulmonary infiltrates directly
      related to Costello Syndrome. This congenital disorder is characterised by
      multiple congenital abnormalities, such as psychomotor retardation, short
      stature, redundant skin, papillomata, curly hair, relative macroencephaly,
      distinctive face and various defects of internal organs. This study is the first
      to document the histopathological findings in the lungs. Most conspicuous was the
      depositing of abnormal collagen and elastic fibres and the development of
      endogenous lipid pneumonia.

PMID- 15176698
TI  - Cough, fatigue and fever.

PMID- 15176699
TI  - Amfepramone does not cause primary pulmonary hypertension.

PMID- 15176700
TI  - Declaration of conflicts of interest.

PMID- 15176701
TI  - Acute exacerbation of idiopathic pulmonary fibrosis.

PMID- 15176702
TI  - [Obstructive sleep apnea and internal medicine].

PMID- 15176703
TI  - Interferon therapy: the other face of the medal.

PMID- 15176704
TI  - [Pathophysiological significance and clinical utility of circulating
      osteoprotegerin].
AB  - Osteoprotegerin (OPG) belongs to the tumor necrosis factor receptor superfamily
      and acts as a decoy receptor for the receptor activator of NF-kappaB ligand
      (RANKL), preventing its binding to RANK. Since 1997, the RANKL/RANK/OPG system
      has been intensively investigated in the fields of bone, immune and
      cardiovascular system pathophysiology. Specific anti-OPG antibodies have been
      developed, allowing for the measurement of OPG and, more recently, of soluble
      RANKL in both physiological and pathological conditions, often yielding
      unexpected results. When considering circulating OPG measurements, it should be
      borne in mind that this receptor is ubiquitously expressed, and that circulating
      levels do reflect the production by a number of tissues. Moreover, strikingly
      different values of circulating OPG have been reported. The aim of this paper is
      to summarize the available data on circulating OPG levels in a number of
      conditions; the pathophysiological significance and potential clinical utility
      will be emphasized.

PMID- 15176705
TI  - [Liver transplantation].
AB  - Liver transplantation represents the first choice treatment for patients with
      fulminant acute hepatitis and for patients with chronic liver disease and
      advanced functional failure. Patients in the waiting list for liver
      transplantation are classified according to the severity of their clinical
      conditions (evaluated using staging systems mostly based on hematochemical
      parameters related to liver function). This classification, together with the
      blood group and the body size compatibility, remains the main criterion for organ
      allocation. The main indications for liver transplantation are cirrhosis (mainly
      HCV-, HBV- and alcohol-related) and hepatocellular carcinoma emerging in
      cirrhosis in adult patients, biliary atresia and some inborn errors of metabolism
      in pediatric patients. In adults the overall 5-year survival ranges between 60
      and 70%, in both American and European series. Even better results have been
      reported for pediatric patients: in fact, the 5-year survival rate for children
      ranges between 70 and 80% in the main published series. In this study we
      evaluated the main medical problems correlated with liver transplantation such as
      immunosuppressive treatment, acute and chronic rejection, infectious
      complications, the recurrence of the liver disease leading to transplantation,
      and cardiovascular and metabolic complications.

PMID- 15176706
TI  - [High-protein diets and obesity].
AB  - An increased protein intake is one of the most common approaches to the dietary
      management of obesity. The authors analyze the issues related to protein
      requirement in normal-weight and obese subjects, to the use and to the usefulness
      of high-protein diets in the treatment of obesity. Caution with these diets is
      recommended in view of their only slight effect on weight and fat loss and owing
      to the scarce evidence of significant effects on satiety and energy intake.
      Furthermore, the risks of harmful outcomes may be correlated to an excessive
      protein intake. Moreover, these diets do not allow patients to adopt those
      nutritional behavior rules which are essential to maintain the weight and fat
      loss and, consequently, significantly reduce the cardiovascular and metabolic
      risks related to obesity.

PMID- 15176707
TI  - [Relationship between the obstructive sleep apnea syndrome and internal
      medicine].
AB  - Twelve to twenty-five percent of human population suffer from sleep disorders and
      sleep-related breathing disorders have a frequency of 5-10%. The association
      between sleep-related breathing disorders and several diseases, mainly
      cardiovascular and dysmetabolic, is well known. The aim of this study was to
      assess the prevalence of this association in a group of 620 patients, aged
      between 18 and 78 years and referred to the Laboratory of Respiratory
      Pathophysiology of the Umberto I Hospital of Rome. All patients had a clinical
      history of a sleep-related breathing disorder and answered a specific
      questionnaire. One-hundred-and-thirty-seven patients (120 males and 17 females,
      mean age 64 years), whose questionnaire was suggestive of a sleep-related
      breathing disorder, underwent clinical assessment including blood tests, lung
      function tests, blood-gas analysis, ECG and nocturnal polysomnography, either as
      in- or as out-patients. The main associated pathologies were: arterial
      hypertension (54.7%), chronic obstructive pulmonary disease (17.9%), obesity
      (63.1%), dyslipidemia (41%), type 2 diabetes mellitus (6.3%), gastroesophageal
      reflux (27.3%) and cardiac arrhythmias (4.2%); 95 patients with obstructive sleep
      apnea syndrome were treated, on the basis of the polysomnography outcomes and
      according to the Italian Association of Sleep Medicine Guidelines, either with
      preventive strategies for risk factor reduction, or with medical (positive
      pressure ventilation, oxygen, assessment of the best drug medication) and/or ear,
      nose end throat surgical therapies. In most patients, the improvement in the
      sleep-related breathing disorder was associated with an improvement in their
      systemic pathology, in particular cardiovascular disease, suggesting the need of
      a deeper consideration and comprehension of nocturnal apneas.

PMID- 15176708
TI  - [Idiopathic retroperitoneal fibrosis: a case report without increased levels of
      acute-phase reactants. Noninvasive diagnosis and treatment].
AB  - We report a case of benign idiopathic retroperitoneal fibrosis in a 39-year-old
      male, who was successfully treated with immunosuppressive drugs only. Advances in
      imaging techniques, especially in magnetic resonance imaging, often permit an
      accurate diagnosis in retroperitoneal fibrosis, avoiding open biopsy or biopsy by
      means of image-guided techniques. In addition, the modern medical approach with
      immunosuppressive drugs is based on evidence of disease regression following the
      medical therapy and is frequently effective. Hence, it is possible to avoid
      conventional surgery or laparoscopy. In the present case the response to
      immunosuppressive treatment was objectively assessed by means of enhanced
      computed tomography, magnetic resonance and nuclear medicine (Ga-67), showing an
      important decrease in the extent of the disease at follow-up. Our case shows the
      important role of the specialist in Internal Medicine in the treatment of this
      uncommon connective tissue disease.

PMID- 15176709
TI  - Adult idiopathic subglottic stenosis: a diagnostic and therapeutic challenge.
AB  - A 22-year-old woman presented with effort dyspnea unresponsive to
      bronchodilators. Harsh respiratory sounds were audible at the neck. Thoracic and
      cardiac evaluation was normal. Spirometry revealed an obstructive ventilatory
      defect, and the flow-volume loop indicated upper airway obstruction. Bronchoscopy
      and tracheal computed tomography revealed a stenosis of the subglottic larynx. A
      biopsy specimen of the stenotic area of the trachea showed a normal mucosa and
      non-specific chronic inflammation. The tracheal stenosis was managed by means of
      endobronchial laser therapy, which led to the resolution of the patient's
      symptoms. As we could not identify any specific pathogenetic process, our final
      diagnosis was idiopathic subglottic tracheal stenosis.

PMID- 15176710
TI  - Pulmonary sarcoidosis during interferon therapy: a rare or underestimated event?
AB  - Interferon (IFN)-alpha with or without ribavirin is the treatment of choice for
      patients with chronic HCV-related hepatitis. Cough and dyspnea during IFN therapy
      are often regarded as a side effect and not as a possible sign of the onset of a
      pulmonary interstitial disease. It may therefore be claimed that the likelihood
      that patients treated with IFN develop sarcoidosis is being underestimated.
      Although they are not conventionally classified as etiopathologic agents of
      sarcoidosis, the IFNs have been proven to be capable of triggering macrophages
      and of promoting the expression of class II HLA antigens. It is therefore
      possible that IFN-alpha treatment could trigger macrophages and promote the
      polarization of the immune response towards Th1 in the presence of particular
      susceptibility conditions, thus starting the series of events that lead to the
      onset of sarcoidosis. We describe a case of pulmonary sarcoidosis in a 33-year
      old patient treated with IFN-alpha2b and ribavirin for chronic HCV-related
      hepatitis after 6 months of therapy. The case we report here brings forth the
      issue of a possible underestimation of the real incidence of sarcoidosis during
      IFN therapy and highlights the need for more attention to and a more careful
      evaluation of respiratory symptoms manifesting in treated patients.

PMID- 15176711
TI  - [Celiac disease: presentation of a typical case and an atypical case].

PMID- 15176713
TI  - Control of beta-catenin/Tcf-directed transcription in medulloblastoma.
AB  - The beta-catenin, glycogen synthase kinase 3beta (GSK-3beta), and adenomatous
      polyposis coli (APC) gene products interact to form a network that influences the
      rate of cell proliferation. Medulloblastoma occurs as part of Turcot's syndrome
      and patients with Turcot's syndrome, who develop medulloblastomas, have been
      shown to harbor germline APC mutations. While APC mutations have been
      investigated and not identified in sporadic medulloblastomas, the status of the
      beta-catenin and GSK-3beta genes has not been evaluated in this tumor. This study
      shows that 3 of 67 medulloblastomas harbor beta-catenin mutations, each of which
      converts a GSK-3beta phosphorylation site from serine to cysteine. The beta
      catenin mutation seen in the tumors was not present in matched constitutional DNA
      in the 2 cases where matched normal DNA was available. A loss of heterozygosity
      (LOH) analysis of 32 medulloblastomas with paired normal DNA samples was
      performed with 4 microsatellite markers flanking the GSK-3beta locus; LOH with at
      least one marker was identified in 7 tumors. Sequencing of the remaining GSK
      3beta allele in these cases failed to identify any mutations. Taken together,
      these data suggest that activating mutations in the beta-catenin gene may be
      involved in the development of a subset of medulloblastomas. The GSK-3beta gene
      does not appear to be a target for inactivation in this tumor.

PMID- 15176712
TI  - Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide
      as second-line and oral temozolomide as third-line treatment for advanced
      neuroblastoma over one year of age.
AB  - Children affected by advanced neuroblastoma have a discouraging prognosis, but
      intensive induction chemotherapy may increase the complete response rate. The
      combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first
      time as front-line regimen in patients with stage 4 neuroblastoma over the age of
      1 y. Similarly, second-line treatment for children with relapsed neuroblastoma,
      particularly after high-dose chemotherapy, has been unsatisfactory. The
      combination of topotecan and cyclophosphamide was studied in resistant or
      relapsed solid tumors. Furthermore, there is a need for effective palliative
      treatment in patients failing therapy. Temozolomide, a new dacarbazine analog
      with optimal oral bioavailability, is being used in an ongoing phase II study as
      an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma
      have entered the ICE study; 15/16 (94%) major responses after induction were
      observed and 6/16 (37%) evaluable patients are disease free after a median of 51
      mo. Twenty-one patients with relapsed/refractory disease (of whom 13
      neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients
      responded. Forty-one patients entered the temozolomide study (of whom 16 had
      neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%)
      evaluable patients. Intensive induction with ICE resulted in a faster response
      with high response rate; a larger study with longer follow-up is needed to
      confirm a survival advantage. Second-line treatment was effective in obtaining
      remissions, some of them long lasting. Third-line treatment did not elicit
      measurable responses in neuroblastoma, but achieved prolonged freedom from
      disease progression and excellent palliation in several patients.

PMID- 15176715
TI  - Clinical biochemical genetics in the twenty-first century.
AB  - Genetic disorders are recognized to play an increasing role in pediatrics. Close
      to 10% of diseases among hospitalized children have been ascribed to Mendelian
      traits inherited as single gene defects, not a surprising figure considering that
      approximately 1000 inborn errors of metabolism (IEM) have been identified to
      date, primarily through the detection of endogenous metabolites abnormally
      accumulated in biological fluids and tissues. The laboratory discipline that
      covers the biochemical diagnosis of IEM is known as clinical biochemical
      genetics, and is defined as one concerned with the evaluation and diagnosis of
      patients and families with inherited metabolic disease, monitoring of treatment,
      and distinguishing heterozygous carriers from non-carriers by metabolite and
      enzymic analysis of physiological fluids and tissues. The biochemical genetics
      laboratory differs from the clinical chemistry laboratory in the extent of
      interpretation necessary to make its results meaningful to the clinician. While
      dramatic advances in molecular genetics have greatly changed the landscape of
      diagnostic options for many genetic disorders, a biochemical approach remains the
      dominant force for the diagnosis and monitoring of IEM. Owing to the
      stereotypical clinical presentation of many of these disorders, a major role of
      the biochemical genetics laboratory is to analyze ever more complex metabolic
      profiles to reach a preliminary diagnosis, which then needs to be confirmed by
      enzymic and/or molecular studies in vitro. Accordingly, the role of biochemical
      genetics in the pediatric practice of the 21st century is to provide a
      multicomponent screening process that can be divided into four major components:
      (i) at-risk screening (prenatal diagnosis); (ii) newborn screening (testing of
      presymptomatic patients); (iii) high-risk screening (testing of symptomatic
      patients); and (iv) postmortem screening (metabolic autopsy). The focus of our
      laboratory is to apply state-of-the-art technology such as tandem mass
      spectrometry to bring as many as possible IEM within the boundaries of newborn
      screening programs, and to investigate the role played by individual disorders in
      maternal complications of pregnancy, pediatric acute/fulminant liver failure, and
      sudden and unexpected death in early life.

PMID- 15176714
TI  - Inborn errors of metabolism: an update on epidemiology and on neonatal-onset
      hyperammonemia.
AB  - Inborn errors of metabolism (IEM) are a highly heterogeneous group of genetic
      conditions and represent a relevant cause of morbidity and mortality in the
      pediatric population. IEM, which are individually rare but collectively numerous,
      are well-recognized entities of the generic class of "rare" diseases. Since the
      first descriptions by Garrod at the beginning of the 20th century, several
      hundred new disorders have been defined, as new biochemical and molecular
      diagnostic tools became available. The clinical pictures of single diseases are
      extremely diverse, ranging from acute life-threatening manifestations to chronic
      late-onset forms, with single or multiorgan involvement. Mental retardation and
      progressive neurological impairment often characterize the clinical course. One
      of the principles to prevent high morbidity and mortality rates is early
      recognition followed by prompt therapeutic intervention. Therefore, a small
      number of treatable IEM is subject to neonatal mass screening. More recently, an
      innovative technique, based on tandem mass spectrometry, has expanded the range
      of neonatal screening to several additional disorders. Owing to the extreme
      heterogeneity, as well as to the increasing number of new disorders, exhaustive
      and updated epidemiological data on the overall occurrence of IEM are lacking. A
      national retrospective study was conducted to define the epidemiological profile
      of IEM in Italy and to estimate the costs related to the disease burden. Other
      relevant issues of our investigations focused on creating protocols of treatment
      for neonatal IEM, and on the development of new methods for the biochemical
      diagnosis.

PMID- 15176716
TI  - Indications for surgical treatment of epilepsy in childhood: a clinical and
      neurophysiological approach.
AB  - Resistant epilepsy is defined as the persistence of unacceptable seizures,
      despite correct drug treatment, or control of seizures at the cost of excessive
      side effects. About 30% of partial seizures are resistant to treatment; many of
      them is potentially a candidate for surgical treatment. Selection of patients is
      based fundamentally on precise identification of the epileptogenic area and on
      the evaluation that possible removal of that area will not be followed by serious
      neurological or neuropsychological deficits, or by onset of seizures in another
      part of the brain. To this end, careful clinical, neurophysiological and
      functional studies are conducted. Compared with adults, video
      electroencephalographic (EEG) study of seizures in childhood is more difficult
      because of the lack of patient cooperation and, therefore, the lack of every
      subjective element in the seizures. Furthermore, the criteria for defining drug
      resistance in childhood are still under discussion, as many epilepsies are age
      dependent and seizures stop with growth. Despite this, the age at time of surgery
      has been steadily decreasing, in the conviction that the persistence of
      intractable partial epilepsy is detrimental to cognitive development and can
      damage brain areas that are apparently healthy. The clinical and EEG criteria for
      epilepsies that are secondary to some specific disorders have been defined, e.g.
      hemimegalencephalia and focal cortical dysplasias often produce epilepsy with
      onset in the first days of life characterized by partial seizures and subintrant
      spasms, EEG record of focal or hemispheric burst suppression and drug resistance
      that can be defined within the first months of life. Prolonged video-EEG
      monitoring is always necessary to establish congruence between the area in which
      the seizure originates and the brain lesion evidenced at neuroimaging. Correct
      monitoring of seizures means close cooperation between neurologist,
      neurophysiology technician and the patient, if the child is at least 5-6 y old.
      Absence of cooperation also limits the use of in-depth recording.
      Neuropsychological assessment of the child can be of great help in defining the
      area damaged by the epileptogenic site as well as the state of the other brain
      areas. Close cooperation between neurologist, radiologist, neuropsychologist and
      brain surgeon is necessary for a case-by-case assessment of indication for
      surgical treatment.

PMID- 15176717
TI  - Advances in computer-assisted single-photon emission computed tomography (SPECT)
      for epilepsy surgery in children.
AB  - Epilepsy surgery has emerged as an important option in the treatment of children
      with epilepsy that is refractory to antiepileptic drug management. The
      cornerstone of successful surgery is accurate localization of the brain region of
      seizure onset. Traditional techniques of seizure onset localization, e.g. surface
      electroencephalography (EEG) recording and magnetic resonance imaging (MRI),
      allow accurate localization in a significant number of patients. When the focus
      of seizure onset is not apparent from these non-invasive techniques, other
      methods of localization, e.g. intracranial EEG recording, may be needed before
      resection of the focus. Single-photon emission computed tomography (SPECT) is a
      nuclear medicine blood-flow technique that has been used to identify a region of
      epileptogenic brain associated with low blood flow in the resting state
      (interictal SPECT) or increased blood flow at the time of seizure activity (ictal
      SPECT). This report describes the validation and utility of a computer-assisted
      method of subtracting the interictal from the ictal SPECT scans and co
      registering the difference image on the MRI. This method, called subtraction
      ictal SPECT co-registered on MRI (SISCOM), is used in guiding the location and
      the extent of intracranial electrode implantation, or in obviating the need for
      the implantation in some cases.

PMID- 15176718
TI  - The genetic basis of immune and autoimmune responses.
AB  - HLA class I and class II molecules play a major role in the presentation of
      short, pathogen-derived peptides to T cells, a process that initiates the
      adaptive cellular and humoral immune responses. However, the factors governing a
      cell's ability to respond or not to particular peptides are still not completely
      understood. Taking the example of a viral infection, in tissues infected with a
      virus, viral particles are taken up by antigen-presenting cells and uncoated. The
      viral DNA or RNA enters the nucleus, where it replicates. mRNA enters the cytosol
      and is transcribed into proteins. These proteins are degraded in proteasomes and
      the resulting peptides (8-10 residues) are loaded onto class I molecules for
      export to the surface of the cells. In the meantime, the groove of the class II
      molecules is also preparing to accommodate peptides (12-24 residues) generated by
      the endocytic protein-processing pathway. The surface of the infected cell then
      becomes adorned with peptide-loaded human leukocyte antigen (HLA) molecules. CD4+
      T helper lymphocytes engage class II molecules and elicit responses from B cells,
      which will ultimately lead to antibody production, whereas CD8+ T lymphocytes
      become cytotoxic T cells. As a consequence, the virus is eliminated from the
      body. However, certain mysteries and challenges remain. How can, as an exception
      to this rule, an autoimmune response be the escape from the perfect machinery?
      This review offers some hypotheses on how to see the problem through to its
      solution.

PMID- 15176719
TI  - The genetic basis for measles vaccine failure.
AB  - The US measles epidemics of 1989-1991 included a series of outbreaks resulting
      from vaccine failure. A series of studies was launched aimed at elucidating the
      mechanisms of this vaccine failure. A meta-analysis of the literature examining
      epidemics in vaccinated populations was conducted, which showed that the
      secondary vaccine failure rate (development of the disease despite an initial or
      primary vaccine success) is no more than 0.2%. The overwhelming proportion of
      measles vaccine failure was due to primary vaccine failure (failure to ever
      generate antibody from antigenic stimulation). This comparison of two
      geographically distinct communities revealed that 10% of children previously
      vaccinated against measles lacked antibody on follow-up and that these vaccine
      failures clustered in families. A study of monozygotic and dizygotic twins
      revealed a high degree of heritability of measles vaccine antibody level.
      Subsequent studies found associations with both class I and class II alleles in
      these population-based studies. In the future, detection of the specific peptides
      that interact with human leukocyte antigen (HLA) molecules may serve as the basis
      for improved vaccines and address vaccine failure that results from cold-chain
      problems, immaturity of the immune system, malnutrition and maternal immunity.

PMID- 15176720
TI  - Insight into B cell development and differentiation.
AB  - The main topic of this article is B cell development and differentiation, with a
      special focus on the mechanisms and molecules that regulate the expression of
      humoral immunity. Molecular epidemiological analysis was performed on the genes
      responsible for the X-linked agammaglobulinemia (XLA) phenotype of the majority
      of Italian patients and their distinct mutations were characterized. Mutations in
      Bruton's tyrosine kinase (BTK), a member of Tec Family of protein tyrosine
      kinases, have been found to be mainly responsible for XLA disease. The exact
      function of BTK in signal transduction is not yet known; thus, the specific role
      of BTK in receptor-dependent calcium signaling and the pro-antiapoptotic
      regulatory activity was addressed by transfecting RAMOS-1, a BTK-deficient human
      Burkitt's/B cell leukemia line with wild-type and mutant constructs. This work
      may provide clues about critical sites in the molecule and give support for gene
      therapy as a potential successful approach to XLA. Another aspect of this
      research is the identification and dissection of the molecular events that are
      likely to be directly related to the ability to express various isotypes of
      immunoglobulin with differing function and certain B cell immunodeficiency,
      mainly common variable disease and non-X-linked hyperIgM. B cell development and
      maturation steps in different compartments of the immune system are tracked by
      the analysis of cell-surface molecules and components of the signal transduction
      pathways, i.e. CD40, CD30, CD27, CD38, CD22 and CD24. A few components involved
      in B cell development, maturation and differentiation and their specific
      functional role are at least partially known, but these are far from fitting into
      an understandable pathway at present.

PMID- 15176721
TI  - B cell-dependent T cell development.
AB  - T and B cells are thought to develop independently. While it is widely recognized
      that T cells help B cells in the production of antibodies to protein antigens,
      less well understood is whether or how B cells contribute to T cell development
      and function. Defects in cell-mediated immunity in individuals with B cell
      deficiency and in B cell-deficient mice suggest that B cells contribute to T cell
      function. The question of whether T cell development is B cell dependent was
      revisited using two novel mouse strains: mice with monoclonal T cells (MT) and
      mice with monoclonal compartments of both B and T cells (MBT). It was found that
      T cell development and thymocyte selection is modified by the presence of B
      cells. These results suggest that B cells, or B cell products, contribute to
      thymocyte selection and T cell development.

PMID- 15176722
TI  - How common is attention-deficit/hyperactivity disorder? Towards resolution of the
      controversy: results from a population-based study.
AB  - Attention-deficit/hyperactivity disorder (AD/HD) is a common behavioral disorder
      among children, yet there is uncertainty about many aspects of AD/HD, including
      its precise frequency of occurrence, presence of comorbid conditions, long-term
      outcomes and the impact of treatment on long-term outcome. The objectives of the
      studies described in this paper were to address these important questions about
      AD/HD. The study subjects were from a population-based birth cohort, and included
      all children born in Rochester, Minnesota, from 1976 to 1982, who remained in the
      community after the age of 5 y (n = 5718). Complete medical and school records
      were available for all members of the birth cohort, including detailed
      information about AD/HD symptoms, psychometric test and questionnaire results,
      medical and non-medical treatments, and long-term academic and psychosocial
      outcomes. This information was used to identify 375 subjects from the birth
      cohort with AD/HD, based on well-defined research criteria. The estimated
      cumulative incidence of AD/HD at the age of 19y was 7.5% (95% confidence interval
      6.5-8.4). Data from these 375 subjects with AD/HD will be used in ongoing studies
      of this disorder.

PMID- 15176723
TI  - Memory development and intellectual disabilities.
AB  - Neuropsychological research has permitted different cognitive profiles among
      subjects with intellectual disabilities (ID) of different etiology to be defined.
      For example, numerous authors have stressed that the typical language profile for
      people with Down's syndrome (DS) consists of poor production with greater
      compromise of morphosyntax than of lexical abilities, but relatively preserved
      comprehension. Children with Williams' syndrome (WS) often show marked impairment
      in certain visuospatial abilities (especially praxic-constructive) and relative
      preservation of both productive and receptive language, at least concerning the
      phonological elements. These observations seem to support a theoretical approach
      that considers ID not as a mere slowing of normal cognitive development, but as
      distinct, individual profiles that can be qualitatively specified. The importance
      of this approach was shown in several recent studies of memory, especially
      implicit memory in subjects with ID. Neuropsychological studies suggest
      insufficient development of the mnemic function in ID at different levels of
      articulation. Long-term memory has been extensively investigated in people with
      ID both in the explicit and in the implicit component. According to recent
      studies, people with ID should show a diffuse impairment of declarative mnesic
      abilities and a relative preservation of implicit memory. The focus of this study
      is on the characteristics of long- and short-term memory in children with ID and,
      particularly, with DS and WS. The results are relevant to knowledge on the
      qualitative aspects of the anomalous cognitive development in mentally retarded
      people and the neurobiological substrate underlying this development.

PMID- 15176724
TI  - A mitochondrial ATPase 6 mutation is associated with Leigh syndrome in a family
      and affects proton flow and adenosine triphosphate output when modeled in
      Escherichia coli.
AB  - A multidisciplinary strategy was used to identify the molecular defect in a
      family with Leigh syndrome (LS). The propositus presented severe developmental
      delay, an ataxic-spastic gait and seizures. She died at 3.5 y of age from
      cardiorespiratory arrest. Postmortem examination disclosed pathological features
      typical of LS. A 12-y-old sister is affected with the same disease. Respiratory
      chain enzyme complex activities in skeletal muscle biopsy were normal. Adenosine
      triphosphate (ATP) synthesis during oxidative phosphorylation in skin fibroblasts
      mitochondria showed a severely hampered ATP production. Mitochondrial DNA
      sequencing revealed a new mutation in the ATPase 6 gene (T9176G). Site-directed
      mutagenesis in Escherichia coli strains was used to measure H+ pumping and ATP
      synthesis. Results were comparable to findings obtained in human cells. These
      data corroborate the use of E. coli strains as a feasible "animal" model for
      functional studies in pathogenic mutations of the ATPase 6 gene.

PMID- 15176725
TI  - Functional studies of frataxin.
AB  - Mitochondria generate adenosine triphosphate (ATP) but also dangerous reactive
      oxygen species (ROS). One-electron reduction of dioxygen in the early stages of
      the electron transport chain yields a superoxide radical that is detoxified by
      mitochondrial superoxide dismutase to give hydrogen peroxide. The hydroxyl
      radical is derived from decomposition of hydrogen peroxide via the Fenton
      reaction, catalyzed by Fe2+ ions. Mitochondria require a constant supply of Fe2+
      for heme and iron-sulfur cluster biosyntheses and therefore are particularly
      susceptible to ROS attack. Two main antioxidant defenses are known in
      mitochondria: enzymes that catalytically remove ROS, e.g. superoxide dismutase
      and glutathione peroxidase, and low molecular weight agents that scavenge ROS,
      including coenzyme Q, glutathione, and vitamins E and C. An effective defensive
      system, however, should also involve means to control the availability of pro
      oxidants such as Fe2+ ions. There is increasing evidence that this function may
      be carried out by the mitochondrial protein frataxin. Frataxin deficiency is the
      primary cause of Friedreich's ataxia (FRDA), an autosomal recessive degenerative
      disease. Frataxin is a highly conserved mitochondrial protein that plays a
      critical role in iron homeostasis. Respiratory deficits, abnormal cellular iron
      distribution and increased oxidative damage are associated with frataxin defects
      in yeast and mouse models of FRDA. The mechanism by which frataxin regulates iron
      metabolism is unknown. The yeast frataxin homologue (mYfh1p) is activated by
      Fe(II) in the presence of oxygen and assembles stepwise into a 48-subunit
      multimer (alpha48) that sequesters >2000 atoms of iron in a ferrihydrite mineral
      core. Assembly of mYfhlp is driven by two sequential iron oxidation reactions: a
      fast ferroxidase reaction catalyzed by mYfh1p induces the first assembly step
      (alpha --> alpha3), followed by a slower autoxidation reaction that promotes the
      assembly of higher order oligomers yielding alpha48. Depending on the ionic
      environment, stepwise assembly is associated with the sequestration of < or = 50
      75 Fe(II)/subunit. This Fe(II) is initially loosely bound to mYfh1p and can be
      readily mobilized by chelators or made available to the mitochondrial enzyme
      ferrochelatase to synthesize heme. However, as iron oxidation and mineralization
      proceed, Fe(III) becomes progressively inaccessible and a stable iron-protein
      complex is produced. In conclusion, by coupling iron oxidation with stepwise
      assembly, frataxin can successively function as an iron chaperon or an iron
      store. Reduced iron availability and solubility and increased oxidative damage
      may therefore explain the pathogenesis of FRDA.

PMID- 15176726
TI  - A single-institution Wilms' tumor and localized neuroblastoma series.
AB  - Since January 1980, 120 children affected by Wilms' tumor have been treated at
      Bambino Gesu, mostly with multimodality treatment according to Societe
      Internationale d'Oncologie Pediatrique (SIOP) protocols, including chemotherapy,
      surgery and radiotherapy in selected cases. This treatment approach emphasizes
      the role of preoperative (neoadjuvant) chemotherapy as opposed to the approach
      favored by the National Wilms' Tumor Study, which is focused on optimizing
      postoperative chemotherapy after primary surgery. Thus, using SIOP guidelines,
      staging occurs at the time of surgery, after chemotherapy administration. These
      differences will constitute the baseline for a comparison between the two
      experiences. Bilaterality, nephroblastomatosis, partial nephrectomy in unilateral
      Wilms' tumor and thrombosis of the vena cava are the main topics discussed. For
      the present study, the analysis was restricted to 98 consecutive cases diagnosed
      until December 1999, for whom at least 24 mo of follow-up is available. The more
      recent experience of treating resectable neuroblastoma in cooperative studies
      dates back to 1979, when the first Italian Cooperative Group Neuroblastoma
      protocol was introduced. This experience was continued within the frame of the
      first Localized Neuroblastoma European Study Group protocol (LNESG 94), and will
      be compared to North American Cooperative Group approaches and outcomes.
      Preoperative evaluation of surgical risk factors, intraoperative complications
      and their management, and long-term outcome will be discussed.

PMID- 15176727
TI  - Wilms' tumor and neuroblastoma.
AB  - Significant differences exist between the European and North American treatment
      protocols for Wilms' tumor and neuroblastoma. There are variations in biopsy
      technique, timing and extent of initial surgery, chemotherapy protocols and
      dosage routines, as well as the type of salvage therapy. With the consolidation
      of the two major North American study groups into a single entity (Children's
      Oncology Group), the European and North American study groups represent the only
      remaining large-scale venues for treatment comparison. It is important to study
      and understand the variation in treatment protocols in order to maintain an open
      forum of scientific investigation that will lead to improving the care and
      outcome of children with cancer. It is anticipated that the unification of the
      North American groups will lead to greater interest and scientific cooperation
      with the European study group. This paper will serve as a forum for such a
      discussion at a local level.

PMID- 15176728
TI  - Demography of the cereal rust mite Abacarus hystrix (Acari: Eriophyoidea) on
      quack grass.
AB  - Demography parameters of the cereal rust mite Abacarus hystrix (Nalepa) on quack
      grass were studied to investigate its potential capacity of population increase
      in conditions of initially low density. The experiment was maintained under
      laboratory conditions at a constant temperature of 19.5-20.5 degrees C and 94 +/-
      1% RH. Life-history data were used to calculate duration of developmental stages,
      survival of adults and rates of population increase. A new method of estimation
      of age-dependent fecundity is proposed. On average, eggs required 7.98 (n = 33,
      95% CI: 7.68-8.21) days to develop into adults. Life expectancy of females was
      longer than that of males (9.72 and 5.41 days, respectively). The mean sex ratio,
      expressed as the proportion of females, was 0.80 (n = 122, CI: 0.71-0.86). The
      reproductive output for females was age-dependent and daily egg production
      reached a peak (3.83 eggs/day, CI: 2.50-5.15) on the 5th day, and then decreased
      steeply. The net reproductive rate (R0) was 10.12 female progeny per female per
      generation, the generation time (T) was 11.31 days, the intrinsic rate of
      increase (r) was 0.20 female progeny per female per day, and the finite rate of
      increase (lambda) was 1.23 female progeny per day. These estimates showed that A.
      hystrix has a great potential capacity for rapid population increase when
      colonising new hosts and its density is low. Therefore, we conclude that the
      population of the cereal rust mite on quack grass may rapidly build up to very
      high densities and can be a reservoir population, which may easily disperse and
      infest other, including cultivated, grasses.

PMID- 15176729
TI  - Does Tetranychus urticae (Acari: Tetranychidae) use flying insects as vectors for
      phoretic dispersal?
AB  - Whether the spider mite Tetranychus urticae uses flying insects as vectors for
      phoretic dispersal was experimentally tested. Two bean plants were placed in a
      microcosm, and a mite population was introduced onto one of the plants. Either
      Phaenicia cuprina Wiedemann (Diptera: Calliphoridae) or Helicoverpa armigera
      Hubner (Lepidoptera: Noctuidae) was then introduced into the microcosms as a
      hypothetical vector insect. T. urticae populations on the second bean plant were
      monitored to detect any evidence of phoretic dispersal. Instances of dispersal
      were detected at extremely low frequency, suggesting that phoretic dispersal of
      T. urticae mediated by winged insects is probably rare in the wild.

PMID- 15176731
TI  - State-dependent and odour-mediated anemotactic responses of the predatory mite
      Phytoseiulus persimilis in a wind tunnel.
AB  - Anemotaxis in the predatory mite Phytoseiulus persimilis (both well-fed and
      starved), has previously been studied on a wire grid under slight turbulent
      airflow conditions yielding weak, yet distinct, gradients in wind speed and odour
      concentration (Sabelis and Van der Weel 1993). Such conditions might have
      critically influenced the outcome of the study. We repeated these experiments,
      under laminar airflow conditions on a flat surface in a wind tunnel, thereby
      avoiding variation in wind speed and odour concentration. Treatments for starved
      and well-fed mites were (1) still-air without herbivore-induced plant volatiles
      (HIPV) (well-fed mites only), (2) an HIPV-free air stream, and (3) an air stream
      with HIPV (originating from Lima bean plants infested by two-spotted spider
      mites, Tetranychus urticae). Well-fed mites oriented in random directions in
      still-air without HIPV. In an air stream, starved mites always oriented upwind,
      whether plant odours were present or not. Well-fed mites oriented downwind in an
      HIPV-free air stream, but in random directions in an air stream with HIPV. Only
      under the last treatment our results differed from those of Sabelis and Van der
      Weel (1993).

PMID- 15176730
TI  - Genetic analysis and cross-resistance spectrum of a laboratory-selected
      chlorfenapyr resistant strain of two-spotted spider mite (Acari: Tetranychidae).
AB  - A laboratory susceptible strain of Tetranychus urticae was selected with
      chlorfenapyr resulting in a resistant strain. After 12 cycles of exposure, the
      resistance ratio (RR) calculated from the LC50s of susceptible and selected
      strain was 580. The resistant strain was screened with 16 currently used
      acaricides for cross-resistance. Cross-resistance was detected with amitraz (RR =
      19.1), bifenthrin (RR = 1.3), bromopropylate (RR = 7.5), clofentezine (RR = 29.6)
      and dimethoate (RR = 17.6). No cross-resistance was detected with the new
      molecules acequinocyl, bifenazate and spirodiclofen. Mortality caused by
      chlorfenapyr in the F1 progeny from reciprocal crosses between both strains
      indicated that the mode of inheritance was incomplete recessive. Mortality in F2
      progeny indicated that the resistance was under the control of more than one
      gene. Synergist experiments with S,S,S-tributylphosphorotrithioate (DEF),
      piperonylbutoxide (PBO) and diethylmaleate (DEM), which are inhibitors of
      esterases, monooxygenases and glutathion-S-transferases respectively, suggested a
      major role of esterases in the resistance to chlorfenapyr.

PMID- 15176732
TI  - Reproductive compatibility between mite populations previously identified as
      Euseius concordis (Acari: Phytoseiidae).
AB  - The objective of the present research is to study the reproductive compatibility
      between populations of predatory mites previously identified as Euseius concordis
      (Chant) based on morphological characteristics. Colonies of these mite
      populations were established in the lab with specimens collected from different
      localities and host plants. Reproductive compatibility was evaluated through
      crosses and backcrosses within and between populations and the subsequent
      observation of females' oviposition, over a period of 10 days. The levels of
      oviposition obtained in the crosses between individuals from the same population
      were higher than those obtained in the crosses between individuals from different
      populations. Results indicate the occurrence of post-mating reproductive
      incompatibility between the mite population from Petrolina and the other
      populations studied. Crosses and backcrosses between populations involving female
      mites from Petrolina did not produce offspring, although endospermatophores were
      present inside the spermathecas of those females. Oviposition was reduced, and
      only sons were obtained, in crosses between populations with males from
      Petrolina. Crosses of females from Pontes e Lacerda and males from Jaguariuna and
      vice versa produced only male progeny. Our results established that the
      populations originating from Arroio do Meio, Pontes e Lacerda, Jaguaruna and
      Vicosa, are reproductively compatible. However, the latter populations and the
      population from Petrolina are genetically isolated. Based on these results we
      suggest that more cytological and genetic studies are needed to establish if this
      reproductive isolation represents a species barrier.

PMID- 15176733
TI  - Biology of three species of Agistemus (Acari: Stigmaeidae): life table parameters
      using eggs of Panonychus citri or pollen of Malephora crocea as food.
AB  - The biology and life table parameters of Agistemus industani Gonzalez, A. cyprius
      Gonzalez, and A. floridanus Gonzalez (Acari: Stigmaeidae) were studied under
      laboratory conditions using two food sources: Panonychus citri (McGregor) eggs or
      ice plant, Malephora crocea (Jacquin) Schwantes pollen at 25 degrees C. The
      larval, protonymph, deutonymph, and adult stages of A. industani fed on citrus
      red mite eggs. All active stages of A. industani, except the larva, fed on all P.
      citri stages and the larval stage could not feed on P. citri adults. All immature
      stages of A. industani fed on M. crocea pollen. Agistemus cyprius larvae fed on
      P. citri eggs and larvae or ice plant pollen. The nymphal stages fed on P. citri
      eggs, larvae, and protonymphs but not deutonymphs or adults while A. cyprius
      deutonymphs and adults fed on all P. citri stages. Adult and nymphal stages of A.
      cyprius fed on ice plant pollen and successfully completed their development
      while A. floridanus did not. Agistemus floridanus larvae fed only on P. citri
      eggs, while the other stages fed on P. citri eggs, larvae, and protonymphs. The
      developmental times from egg to adult for A. industani and A. cyprius when fed M.
      crocea pollen were 11.3 and 13.4 days, respectively. Agistemus floridanus was
      unable to complete its life cycle on a diet of only M. crocea pollen. Agistemus
      industani, A. cyprius, and A. floridanus completed development from egg to adult
      in 11.7, 13.8, and 10.8 days, respectively, when fed P. citri eggs. The intrinsic
      rate of increase (r(m)) values for A. cyprius and A. industani were 0.0311 and
      0.1201 per day on the pollen diet. The net reproductive rate (Ro) was 3.58 for A.
      cyprius and 10.07 for A. industani with generation times (T) of 45.2 and 35.1
      days, respectively, on the ice plant pollen diet. The r(m) values for A. cyprius,
      A. floridanus, and A. industani on the P. citri egg only diet were: 0.0562,
      0.1001, and 0.1031 per day, respectively. The Ro values for each species fed P.
      citri eggs only were: 6.36, 7.90, and 18.70 for A. cyprius, A. floridanus, and A.
      industani and the generation times (T) for each of the three species were: 35.2,
      29.9 and 37.8 days, respectively.

PMID- 15176734
TI  - Anti-tick effects of Melinis minutiflora and Andropogon gayanus grasses on plots
      experimentally infested with Boophilus microplus larvae.
AB  - Our objective in this trial was to investigate the anti-tick effects of molasses
      grass (Melinis minutiflora) and gamba grass (Andropogon gayanus) against
      Boophilus microplus, using buffel grass (Cenchrus ciliaris) as a control. During
      a 3-year-period fieldwork was carried out in the tropical, subhumid climate at
      Progreso, Municipality of Jiutepec, Morelos, Mexico. Experimental plots were
      established for three treatments with six replicates under a random factorial
      design in order to evaluate each of the four seasons. Additional work was
      developed for two more consecutive autumn seasons to evaluate the anti-tick
      effects of these grasses. Once the plots were established they were infested with
      5000 B. microplus larvae and sampled by dragging flannel cloths. The anti-tick
      effects were measured by counting the number of larvae recovered from each of the
      experimental plots. Both grasses, M. minutiflora and A. gayanus, demonstrated
      anti-tick effects; however, M. minutiflora grass had the greatest anti-tick
      effects through the seasons studied and in the three consecutive autumns
      evaluated.

PMID- 15176735
TI  - On molecular taxonomy: what is in a name?
AB  - Gene sequences of small portions of the genome are often used for premature
      detailed taxonomic changes, neglecting polyphasic taxonomy, which should also
      consider phenotypical characteristics. Three examples are given: (i) Recently,
      members of the genera Eperythrozoon and Haemobartonella have been moved,
      correctly so, from the Rickettsiales to the Mycoplasmatales, but were assigned to
      the genus Mycoplasma, mostly on the basis of 16S rRNA sequence analysis. Not only
      is the 16S rRNA sequence similarity between 'classical' Mycoplasma and these
      species of Eperythrozoon and Haemobartonella less than that between some other
      well-recognised bacterial genera, but their biological differences amply justify
      their classification in different genera of the Mycoplasmatales. Furthermore, the
      move creates considerable confusion, as it necessitates new names for some
      species, with more confusion likely to come when the 16S rRNA sequences of the
      type species of Eperythrozoon, a name which has priority over Mycoplasma, will be
      analysed. (ii) In the Rickettsiales, members of the genera Anaplasma, Ehrlichia,
      Cowdria, Neorickettsia and Wolhbachia are so closely related phylogenetically on
      the basis of 16S rRNA sequences, and for some also of groESL operon sequences,
      that they have recently been fused, correctly so, into one family, the
      Anaplasmataceae, while the tribes Ehrlichieae and Wolbachieae have been
      abolished. Sequence diversity within the 'classical' genus Ehrlichia has led to
      classifying E. phagocytophila (including E. equi and the agent of human
      granulocytic ehrlichiosis), E. platys and E. bovis in the genus Anaplasma, while
      others have been retained in Ehrlichia, which also includes Cowdria ruminantium.
      E. sennetsu and E. risticii have been transferred to the genus Neorickettsia. 16S
      rRNA and GroEL sequences of 'classical' Anaplasma and some members of 'classical'
      Ehrlichia do show a close relationship, but differences in citrate synthase gene
      sequences, the GC content of this gene, and sequences of the gene encoding the
      beta-subunit of RNA polymerase, not to speak of the phenotypical differences, do
      not justify the fusion into one genus. Because of the phylogenetical diversity in
      Ehrlichia it is recommended that a new genus name be created for the E.
      phagocytophila genogroup (and E. platys and E. bovis). (iii) One of the
      conclusions of studies on the phylogeny of ticks of the subfamilies
      Rhipicephalinae and Hyalomminae, based on nucleotide sequences from 12S rRNA,
      cytochrome c oxidase I, the internal transcribed spacer 2, 18S rRNA, as well as
      morphological characters, is that Boophilus should be considered as a subgenus of
      Rhipicephalus. While Boophilus and Rhipicephalus are undoubtedly close, the
      obviously important morphological and biological differences between the genera
      Rhipicephalus and Boophilus are thus overruled by similarities in the sequences
      of a number of genes and this leads to considerable confusion. Polyphasic
      taxonomy amply justifies maintaining Boophilus as a separate genus,
      phylogenetically near to Rhipicephalus. This note is a plea for a cautious and
      balanced approach to taxonomy, taking into account molecular genotypical
      information, as far as is possible from different genes, as well as phenotypical
      characteristics.

PMID- 15176736
TI  - Uterine mast cells: a new hypothesis to understand how we are born.
AB  - Birth is the result of complex, well-defined, and coordinated events, that are
      tightly regulated by endocrine, nervous, and immune responses, and take place
      primarily in the female reproductive tract. Various mechanisms and mediators
      involved in pregnancy, labor, and delivery, are highly conserved among different
      mammalian species and mast cells emerge as potential and crucial participants in
      these processes, as it is discussed in this review.

PMID- 15176737
TI  - Genetic stability in rice micropropagation.
AB  - An efficient clonal propagation procedure for six rice varieties cultivated in
      Argentina was developed by using shoot tip cultures, and the genetic stability of
      the micropropagated plants was verified by isozyme analysis. One week old
      seedlings obtained on MS medium were sectioned and subcultured on MS medium
      (0.75% agar) supplemented with different combination and concentrations of
      cytokinins (BAP and KIN) and auxins (2,4-D and NAA). After four weeks of culture,
      multiple shoots were obtained. The best response was observed on MS supplemented
      with BAP 5 mg l(-1). Shoot clumps were multiplied in MS liquid medium containing
      BAP 5 mg l(-1). Profuse rooting was obtained after transfer to MS medium lacking
      growth regulators and with sucrose 8% (w/v). Complete plants were successfully
      transferred to soil and grown to maturity. ADH and EST patterns of
      micropropagated rice plants showed polymorphisms compared with plants of the
      original varieties. However, the zymograms of the seed derived progeny of the
      micropropagated plants were similar to that of the original varieties. These
      results indicate the maintenance of the genetic stability in the sexual progeny
      of micropropagated plants.

PMID- 15176738
TI  - Tissue alterations in the Guinea pig lateral prostate following antiandrogen
      flutamide therapy.
AB  - The flutamide antiandrogenic effects on the Guinea pig male prostate morphology
      in puberal, post-puberal and adult ages were evaluated in the present study.
      Daily-treated group animals received flutamide subcutaneous injection at a dose
      of 10 mg/Kg body weight for 10 days. The control group animals received a
      pharmacological vehicle under the same conditions. The lateral prostate was
      removed, fixed and processed for light and transmission electron microscopy. The
      results revealed an increase of the acinus diameter in the treated puberal
      animals and straitness in the stromal compartment around the acini. The
      epithelial cells exhibited cubic phenotype. In the post-puberal and adult
      animals, a decrease of the acinus diameter was observed, as well as an increase
      of the smooth muscle layer and presence of the folds at epithelium. The
      ultrastructural evaluation of the secretory cells in the treated group
      demonstrated endomembrane enlargement, mainly in the rough endoplasmic reticulum
      and Golgi apparatus. In addition, a decrease of the microvilli and alterations in
      the distribution patterns and density of the stromal fibrillar components were
      observed. In conclusion, the flutamide treatment exerts tissue effects on the
      lateral prostate, promoting stroma/epithelium alterations.

PMID- 15176739
TI  - Bacteriostatic action of synthetic polyhydroxylated chalcones against Escherichia
      coli.
AB  - In previous work the bacteriostatic action of trihydroxylated chalcones against
      Staphylococcus aureus ATCC 25 923 was investigated. In this work the action of
      2',4',2-(OH)3-chalcone, 2',4',3-(OH)3-chalcone and 2',4',4-(OH)3-chalcone against
      Escherichia coli ATCC 25 922 was evaluated. Growth kinetic curves of E. coli were
      made in nutritive broth added with increasing drug concentrations. The specific
      growth rates of the microorganisms were calculated by a kinetic turbidimetric
      method, which was previously probed and the minimal inhibitory concentrations
      (MIC's) were evaluated by a mechanism of action proposed. The MICs of 2',4',3
      (OH)3-chalcone and 2',4',2-(OH)3-chalcone were 46 microg/ml and 122 microg/ml,
      respectively. The 2',4',4-(OH)3-chalcone was inactive. The MIC value of 2',4',3
      (OH)3-chalcone (46 microg/ml), more active than 2',3-(OH)2-chalcone (72.2
      microg/ml) may be due to the introduction of an electron donating group (-OH) at
      position 4' in the aromatic A-ring, which activates the region that includes the
      2'-hydroxyl neighbor group and the alpha,beta-unsaturated carbonyl group.

PMID- 15176740
TI  - Influence of genotype and explant source on indirect organogenesis by in vitro
      culture of leaves of Melia azedarach L.
AB  - In vitro regeneration of shoots from leaf explants of the Paradise tree (Melia
      azedarach L.) was studied. Three different portions (proximal portion, distal
      portion and rachis of the leaflets) of three developmental stages (folded, young
      still expanding and completely expanded) of leaves of 10-15 year old plants of
      seven genotypes were cultured on Murashige and Skoog (1962) medium (MS)
      supplemented with 1 mg x l(-1) benzylaminopurine (BAP) + 0.1 mg x l(-1) kinetin
      (KIN) + 3 mg x l(-1) adenine sulphate (ADS). The rachis of the leaflets of the
      completely expanded leaves was found to be the most responsive tissue, in most of
      the genotypes employed. Shoot regeneration occurred in leaf explants of all the
      genotypes tested. The best genotype for shoot regeneration was clone 4. Rooting
      was induced on MS medium supplemented with 2.5 mg x l(-1) 3-indolebutyric acid,
      IBA, (4 days) followed by subculture on MS lacking growth regulators (26 days).
      Complete plants were transferred to soil.

PMID- 15176741
TI  - Molecular analysis of the community structure of nitrifying bacteria in a
      continuous-flow bioreactor.
AB  - We herein report the diversity and relative abundance of chemolithotrophic
      nitrifying bacteria in a continuous-flow bioreactor using 16S-ribosomal RNA
      quantitative dot-blot hybridizations. About 14.9% of the total bacterial
      population, determined by epifluorescence microscopy in the bioreactor suspended
      phase, was represented by nitrifying bacteria. Of this fraction, ammonia- and
      nitrite-oxidizing bacteria accounted for 10% and 90%, respectively, the latter
      group being mostly Nitrospira-like. On the other hand, the nitrifiers
      adhesion/colonization capacity on polyethylene surfaces as evaluated by scanning
      electron microscopy and hybridizations analyses was 12.6% of the total bacterial
      community adhered. Finally, in spite of the relatively small contribution of
      nitrifiers to the total bacterial abundance in the bioreactor, we determined a
      mean ammonia removal rate of 170.48 +/- 8.29 mg N l(-1) d(-1); thus, the low
      percentage of ammonia-oxidizing bacteria, was not limiting the bioreactor
      performance.

PMID- 15176742
TI  - Quantification of nitrification and denitrification rates in algae and duckweed
      based wastewater treatment systems.
AB  - Nitrification and denitrification rates at three different depths (0.1, 0.45 and
      0.9m from the water surface) in two series of four algae and duckweed based waste
      stabilisation ponds (ABPs and DBPs) were measured using nitrate reduction
      techniques in laboratory batch incubations. The effects of temperature and BOD5
      loading were investigated. In situ measurements over the ponds' depths were also
      done for confirmation of laboratory results. Higher dissolved oxygen (DO)
      concentrations in ABPs, especially during the warm season, favoured higher
      nitrification in ABPs over DBPs. Organic surface loading also affected the rate
      of nitrification in the ponds. Nitrification rates did not increase along the
      treatment line despite the decrease in organic matter content. Adsorption of
      nitrifiers to available suspended particles and subsequent sedimentation was
      assumed to be the main reason for the similar nitrification rates in most ponds.
      In both systems, the presence of DO in the water column resulted in very low
      denitrification rates (5-45 mg-N m(-2)d(-1)). Higher denitrification rates (160
      560 mg-N m(-2)d(-1)) were measured in the sediments when anoxic conditions
      prevailed in the overlaying water. The absence of nitrite or nitrate accumulation
      suggested sufficient nitrite and nitrate diffusion within the water column to
      allow full denitrification. The nitrification and denitrification rates in both
      systems were higher at high temperature. The range of nitrogen loss via
      denitrification in ABPs and DBPs corresponded to 15-25% of total influent
      nitrogen.

PMID- 15176743
TI  - Enhancement of the natural organic matter removal from drinking water by
      nanofiltration.
AB  - Finnish surface waters are abundant in natural organic matter. Natural organic
      matter can be removed from drinking water in a water treatment process by
      coagulation and filtration. The standard treatment operations are not able to
      remove the smallest molar mass fraction of organic matter and the intermediate
      molar mass matter is only partly removed. The removal of residual natural organic
      matter from drinking water by nanofiltration was evalueted in this study. Three
      different nanofiltration membranes were compared in filtering six pre-treated
      surface waters. The total organic carbon content of the feed waters varied from
      2.0 to 4.2 mg l(-1). Other water quality parameters measured were conductivity,
      alkalinity, hardness, UV-absorbance, SUVA, E2/E3 value and molecular size
      distribution by high-performance size-exclusion chromatography. The natural
      organic matter removal efficiencies of the membranes were good and varied between
      100% and 49%, and between 85% and 47% according to molecular size distribution
      and total organic carbon measurements, respectively. Removal of different
      molecular size fractions varied from 100% to 56%, 100% to 54% and 88% to 19%,
      regarding high molar mass, intermediate molar mass and low molar mass organic
      matter, respectively. The Desal-5 DL membrane produced the highest natural
      organic matter removals.

PMID- 15176744
TI  - Application of a kinetic fractionation of trace elements (Cd, Cu and Pb) in
      unpolluted soil samples.
AB  - The hazard due to the presence of large amounts of trace metals in some soils is
      strongly related to the speciation of these metals. The aim of this work was to
      apply an operationally defined fractionation based on kinetics which could
      distinguish "labile" (quickly extracted) and "non labile or slowly labile i.e.
      slowly extracted) cations, using the extraction kinetics of trace metals by EDTA.
      This kinetic fractionation has been applied to ten soil samples from Burgundy
      (France), which are known to be unpolluted. Copper, lead and cadmium were
      determined using this fractionation procedure. According to this fractionation,
      cadmium was found to be more mobile than copper or lead, both in terms of the
      labile concentration and the kinetic constants.

PMID- 15176745
TI  - Removal of arsenic from water using hardened paste of Portland cement.
AB  - Portland cement has been used as a new low-cost adsorbent for the removal of
      arsenic from the water environment. In the batch experiments conducted at an
      initial concentration of 0.2 mg l(-1) of arsenate, it was found that up to 95% of
      arsenate could be removed. Kinetic profiles were developed for various
      conditions. The effect of adsorbent dose, effects of common ions such as Ca2+,
      Mg2+, Fe3+/Fe2+, 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- 15176746
TI  - Oxidation pathways for ozonation of azo dyes in a semi-batch reactor: a kinetic
      parameters approach.
AB  - In this study ozone and the H2O2/O3 oxidation system are used to decolorize
      aqueous solutions of Orange II (Or-II) and Acid Red 27 (AR-27). Investigations
      are carried out in a semi-batch bubble column reactor. A system of series
      parallel reactions is proposed to describe the mechanism of dye oxidation. The
      stoichiometric ratio for the first reaction is found to be 1 mol dye per mol O3,
      while the overall ozone demand for both reactions one and two is found to be 5
      and 6 moles for Or-II and AR-27 respectively. Molecular and radical kinetics are
      compared: a radical scavenger, t-butanol, can be added to ensure only the
      molecular reaction of ozone, or hydrogen peroxide can be supplied through a
      peristaltic pump, to initiate radical reactivity. Results reveal that colour
      removal is ensured by direct ozone attack. For both dyes, TOC removal
      efficiencies of 50 - 60 % are obtained by the action of the hydroxyl free
      radical. However, this is not improved by addition of H2O2, thus demonstrating
      that organic species alone ensure HO degrees radical production during ozonation.
      Both the mass transfer and the ozone reactivity with the dyes are considered to
      evaluate the kinetic parameters for the molecular pathway.

PMID- 15176747
TI  - Leaching of organic contaminants from storage of reclaimed asphalt pavement.
AB  - Recycling of asphalt has been promoted by rapid increases in both the use and
      price of petroleum-based bitumen. Semi-volatile organic compounds in leachates
      from reclaimed asphalt pavement, measured in field samples and in laboratory
      column test, were analysed through a GC/MS screen-test methodology. Sixteen PAH
      (polyaromatic hydrocarbons) were also analysed in leachates from the column
      study. The highest concentrations of semi-volatile compounds, approximately 400
      microg l(-1), were measured in field samples from the scarified stockpile.
      Naphthalene, butylated hydroxytoluene (BHT) and dibutyl phthalate (DBP) were the
      most dominant of the identified semi-volatiles. The occurrence of these compounds
      in urban groundwater, also indicate high emission rates and persistent structures
      of the compounds, making them potentially hazardous. Car exhausts, rubber tires
      and the asphalt material itself are all probable emission sources, determined
      from the organic contaminants released from the stockpiles. The major leaching
      mechanism indicated was dissolution of organic contaminants from the surface of
      the asphalt gravels. In the laboratory column test, the release of high-molecular
      weight and more toxic PAH was higher in the leachates after two years than at the
      commencement of storage. The concentrations of semi-volatiles in leachates, were
      also several times lower than those from the field stockpile. These results
      demonstrate the need to follow up laboratory column test with real field
      measurements.

PMID- 15176748
TI  - Uptake of aniline and nitrobenzene from aqueous solution by organo-zeolite.
AB  - Adsorption mechanisms of toxic non-ionic organic contaminants (NOCs), aniline and
      nitrobenzene, with natural-zeolite and organo-zeolite (OZ) were investigated in
      both batch and continuous systems. In batch tests, the adsorption capacity of
      aniline and nitrobenzene onto natural zeolite surface is very low or almost nil
      but becomes significant upon modifying the zeolite surface by
      hexadecyltrimethylammonium (HDTMA). A partitioning mechanism is proposed to be
      responsible for the adsorption of NOCs onto OZ. The effectiveness of the
      partitioning mechanism is directly connected with hydrophobic properties of the
      NOCs. The column tests were carried out as an indicator for continuous system.
      The breakthrough curves were constructed for OZ/NOC system and the adsorption
      capacity of NOCs onto OZ under the present conditions were determined as 2.36 and
      3.25 mg per gram of OZ, for aniline and nitrobenzene, respectively. A schematic
      model is proposed to account for the adsorption of NOCs onto OZ.

PMID- 15176749
TI  - Feasibility of biological aerated filters (BAFs) for treating landfill leachate.
AB  - Ammonia can be removed from landfill leachate using aerobic biological treatment
      processes. The biological aerated filter (BAF) combines biological treatment and
      subsequent biomass separation in one reactor providing a small footprint
      alternative to conventional systems. Leachate from an operational landfill was
      found to be aerobically treatable using the OECD recommended Modified Zahn
      Wellens test. This leachate was used as feed to a pilot-scale BAF at influent
      chemical oxygen demand (COD) and ammoniacal-nitrogen concentrations of 765 mg l(
      1) and 568 mg l(-1) respectively. During an initial period of stable operation
      without pH control, 33 %w/w of influent ammonia was removed. The reactor pH was
      9.2 with little conversion to total oxidized nitrogen (< 45 mg l(-1)), this
      removal was accounted for primarily by air stripping. In a second period of
      stable operation, the reactor pH was reduced to pH 7.2 and ammonia removal
      increased to 97 %w/w with a concomitant increase in effluent nitrite
      concentration to an average of 524 mg l(-1). Biological aerated filters (BAFs)
      can be used to nitrify landfill leachates though onward denitrification of
      nitrite-nitrogen and COD polishing is required to reach typical discharge consent
      standards.

PMID- 15176750
TI  - Biodegradation of C5+ hydrocarbons by a mixed bacterial consortium from a C(5+)
      contaminated site.
AB  - C5+, a mixture of benzene, toluene, xylene, styrene, dicyclopentadiene (DCPD),
      naphthalene and other compounds, is a byproduct of polyethylene production and
      has been introduced into the environment via accidental release. The degradation
      of C5+ was studied using a defined consortium of 11 distinct bacterial strains
      isolated from C(5+)-contaminated soil. Vigorous growth of individual strains on
      C5+ was no prediction of dominance in the consortium, when the latter was grown
      under the same conditions. The defined consortium was able to degrade benzene,
      toluene, styrene and naphthalene, and to codegrade m-xylene in the presence of
      toluene or naphthalene. It was unable to degrade DCPD, which was inhibitory when
      degradation of pairs of C5+ components was examined. The complete C5+ mixture
      appeared to be the best substrate for the consortium.

PMID- 15176751
TI  - Transportation of reclaimed wastewater through a long pipe: inhibition of
      sulphide production by nitrite from the secondary treatment.
AB  - The agricultural reuse of reclaimed wastewater has become a necessity in places
      with water shortages. Frequently, this involves the operation of long
      transportation pipelines, like in the South Tenerife reuse system, whose main
      element is a completely filled 61 km long gravity pipe in cast iron. Sulphide
      generation, which could contribute to pipe corrosion, is a usual process taking
      place during transportation if anaerobic conditions prevail. In the Wastewater
      Treatment Plant of Santa Cruz (Tenerife, Spain) a partial nitrification process
      was achieved by increasing the mean residence time through the aeration step at
      low dissolved oxygen concentration. Such conditions, combined with the right
      temperature and a free ammonia concentration above 1 mg l(-1), inhibited
      nitratation and favoured nitritation, which led to concentrations of NO2-N above
      8 mg l(-1) in the secondary effluent. During the transportation, nitrite
      inhibited the appearance of anaerobic conditions, and, consequently, no sulphide
      generation occurred. At the same time, a nitrite reduction process took place
      with a first order kinetics and a rate coefficient of 0.052 h(-1)' at 25 degrees
      C. A parallel behaviour between the nitrite depletion and the oxidation-reduction
      potential evolution along the pipeline was also observed.

PMID- 15176752
TI  - The use of waterworks sludge for the treatment of vegetable oil refinery industry
      wastewater.
AB  - Water treatment works using coagulation/flocculation in the process stream will
      generate a waste sludge. This sludge is termed as ferric, alum, or lime sludge
      based on which coagulant was primarily used. The works in Adana, Turkey uses
      ferric chloride. The potential for using this sludge for the treatment of
      vegetable oil refinery industry wastewater by coagulation has been investigated.
      The sludge acted as a coagulant and excellent oil and grease, COD and TSS removal
      efficiencies were obtained. The optimum conditions were a pH of 6 and a sludge
      dose of 1100 mg SS l(-1). The efficiency of sludge was also compared with alum
      and ferric chloride for the vegetable oil refinery wastewater. At doses of 1300
      1900 mg SS l(-1), the sludge was as effective as ferric chloride and alum at
      removing oil and grease, COD, and TSS. In addition, various combinations of
      ferric chloride and waterworks sludge were also examined. Under the condition of
      12.5 mg l(-1) fresh ferric chloride and 1000 mg SS l(-1) sludge dose, 99% oil and
      grease 99% TSS and 83% COD removal efficiencies were obtained.

PMID- 15176753
TI  - Convergent and discriminative validity of interview and questionnaire measures of
      personality disorder in mentally disordered offenders: a multitrait-multimethod
      analysis using confirmatory factor analysis.
AB  - Measures of personality disorder from the International Personality Disorder
      Examination, Personality Diagnostic Questionnaire, and Millon Clinical Multiaxial
      Inventory (MCMI-II) were obtained from detained male mentally disordered
      offenders (N = 156), and convergent and discriminant validity were examined by
      confirmatory factor analysis of the multitrait-multimethod matrix. Hierarchical
      comparisons of models varying in their specification of trait and method variance
      established the appropriateness of a model supporting both convergence and
      discrimination across methods, but these were variable across constructs and
      measures. Convergence was good for avoidant, schizoid, and antisocial disorders,
      but poor for histrionic, narcissistic, and obsessive-compulsive disorders.
      Avoidant, schizoid, and schizotypal disorders were not clearly distinguishable
      from each other. Measurement error attributable to method variance was
      substantial for all instruments and for most disorders. The commonly alleged
      superiority of interview over questionnaire methods was not supported, and the
      MCMI-II demonstrated proportionately more "true" variance. However, assessment
      methods may be differentially sensitive to different kinds of personality
      disorder problems.

PMID- 15176754
TI  - Personality characteristics of partner violent men: a Q-sort approach.
AB  - Our objective was to develop a personality profile of men who are violent toward
      their partners. A total of 52 experienced clinicians described either a current
      male patient who was violent toward his partner (and only toward his partner) or
      who was maritally distressed but nonviolent using the Shedler-Westen Assessment
      Procedure-200 (SWAP-200), a Q-sort instrument designed to harness the judgments
      of clinicians. Partner-violent patients showed significantly higher scores on the
      SWAP-200 antisocial and borderline personality disorder scales. In contrast,
      patients who were maritally distressed evidenced higher scores on the SWAP-200
      obsessive, avoidant, and high-functioning depressive scales. The men who were
      violent toward their partners were more antisocial and emotionally dysregulated,
      which is consistent with theory, and less obsessive, which has not been
      theoretically explored. The groups did not differ on theoretically important
      dimensions of personality including paranoid, dependent, and hostile features.

PMID- 15176755
TI  - Does treatment really make psychopaths worse? A review of the evidence.
AB  - We aimed to evaluate critically the evidence behind the perceived inverse
      association between the degree of psychopathy as reflected by a high score on the
      Hare Psychopathy Checklist-Revised (PCL-R) and treatment response. A literature
      search with the key identifiers of PCL-R (or its derivatives) and treatment
      response produced 24 studies that were then systematically evaluated. This showed
      that only three studies were of an appropriate research design to answer the
      question and of these, none met our standard for an acceptable study. We conclude
      therefore that the commonly held belief of an inverse relationship between high
      scores on the PCL-R and treatment response has not been established.

PMID- 15176756
TI  - Retrospective measures of childhood abuse: concurrent validity and reliability in
      a nonclinical sample with borderline features.
AB  - This study evaluated the psychometric properties of retrospective reports of
      childhood sexual and physical abuse by comparing two assessment formats,
      interview and questionnaire, and looking at both the concurrent validity and test
      retest reliability over 2 years. Nonclinical participants completed the Family
      Experiences Interview (FEI; Ogata et al., 1990) and the Family Experiences
      Questionnaire (FEQ; Wheelock, Lohr, & Silk, 1997) at age 18 and the FEQ again at
      age 20. Both assessments evaluate individuals for sexual and physical abuse
      before age 18, and the two have similar formats and wording. There were no
      significant differences in the reported frequency of childhood abuse on the
      interview versus on the questionnaire when given at the same point in time, and
      the agreement between the two measures was high. The test-retest reliability in
      childhood abuse reports was moderate. Taken together, these results suggest that
      interview and questionnaire reports of childhood abuse are roughly equivalent.

PMID- 15176757
TI  - Childhood maltreatment associated with adult personality disorders: findings from
      the Collaborative Longitudinal Personality Disorders Study.
AB  - Adverse childhood experiences such as abuse and neglect are frequently implicated
      in the development of personality disorders (PDs); however, research on the
      childhood histories of most PD groups remains limited. In this multisite
      investigation, we assessed self-reported history of abuse and neglect experiences
      among 600 patients diagnosed with either a PD (borderline, schizotypal, avoidant,
      or obsessive-compulsive) or major depressive disorder without PD. Results
      indicate that rates of childhood maltreatment among individuals with PDs are
      generally high (73% reporting abuse; 82% reporting neglect). As expected,
      borderline PD was more consistently associated with childhood abuse and neglect
      than other PD diagnoses. However, even when controlling for the effect of
      borderline PD, other PD diagnoses were associated with specific types of
      maltreatment.

PMID- 15176758
TI  - Effectiveness of atypical antipsychotic medications in reducing violent behavior
      among persons with schizophrenia in community-based treatment.
AB  - This study prospectively compared the effectiveness of atypical antipsychotic
      medications to that of conventional neuroleptics in reducing violent behavior
      among patients with schizophrenia under "usual care" conditions in the community.
      Participants (n = 229) were adults with schizophrenia spectrum disorders
      receiving inpatient or outpatient services in public sector mental health systems
      in North Carolina. Subjects were followed for 2 years in an observational study
      using multiple methods of data collection at 6-month intervals to assess
      treatment, sociodemographic characteristics, clinical features, and violence
      outcomes. Treatment with atypical antipsychotic medications (clozapine,
      risperidone, or olanzapine) was found to significantly reduce the risk of violent
      behavior, whereas treatment with conventional neuroleptics did not have this same
      beneficial effect. A cumulative effect on reduced violence was attributable to
      consistent compliance with atypical antipsychotic medications over a 2-year
      period. Concurrent reductions in psychotic symptoms, substance abuse, and adverse
      medication side effects were found to mediate the association between adherence
      with atypicals and lower violence risk. Treatment with atypical antipsychotic
      medications should be considered as an important component of violence risk
      management for schizophrenia patients at risk for violent behavior.

PMID- 15176759
TI  - Psychotic motivation and the paradox of current research on serious mental
      illness and rates of violence.
AB  - Persuasive empirical support exists for a positive association between serious
      mental illness (SMI) and rates of violence; a great deal of support is also
      present for the clinical impression that psychotic symptoms sometimes motivate
      "symptom-consistent" violence. We propose that the issue of the motivation for
      violence in the SMI population can be considered independently of the issue of
      the association between SMI and violence rates. We review much of the current
      literature on the association between SMI and violence in a framework that
      emphasizes motivational influences unique to the SMI population. We conclude that
      the contribution of psychotic motivation to rates of violence in the SMI
      population is a major research issue. Furthermore, we believe that recognition of
      the independence of motivational influences and violence rates, and consideration
      of the impact of treatment on violence, may help explain the paradox of current
      research: Delusions and hallucinations may motivate violent behavior, but this
      psychotic motivation may not be reflected in the actual rate of violence.

PMID- 15176760
TI  - Schizophrenia, delusional symptoms, and violence: the threat/control override
      concept reexamined.
AB  - In 1994 Link and Stueve identified a number of symptoms--called threat/control
      override (TCO) symptoms--that were significantly more than others related to
      violence. This was confirmed by some, but not all, following studies. The
      contradictory results could be due to remarkable differences in sample
      compositions, sources used, and definitions and periods of recorded violence, but
      they are mainly due to problems defining the TCO symptoms. To reexamine the
      validity of the TCO concept from an exclusively psychopathological position, we
      compared in a retrospective design a sample of male offenders with schizophrenia
      not guilty by reason of insanity (n = 119) with a matched sample of nonoffending
      schizophrenia patients (n = 105). We could find no significant differences
      regarding the prevalence of TCO symptoms in the two groups during the course of
      illness. The only statistically significant discriminating factors were social
      origin and substance abuse. Yet, taking into account the severity of offenses,
      TCO symptoms emerged as being associated with severe violence. This effect is
      primarily attributable to the comparatively unspecific threat symptoms. Control
      override, to be seen as more or less typical for schizophrenia, showed no
      significant association with the severity of violent behavior.

PMID- 15176761
TI  - Interpersonal trauma and posttraumatic stress disorder in patients with severe
      mental illness: demographic, clinical, and health correlates.
AB  - This study's purpose was to evaluate the prevalence and correlates of
      posttraumatic stress disorder (PTSD) in persons with severe mental illness.
      Standardized assessments of interpersonal trauma and PTSD were conducted in 782
      patients with severe mental illness receiving services in one of five inpatient
      and outpatient treatment settings. Analyses examined the prevalence of PTSD and
      the demographic, clinical, and health correlates of PTSD diagnosis. The overall
      rate of current PTSD in the sample was 34.8 percent. For demographic
      characteristics, the prevalence of PTSD was higher in patients who were younger,
      white, homeless, and unemployed. For clinical and health variables, PTSD was more
      common in patients with major mood disorders (compared to schizophrenia or
      schizoaffective disorders), alcohol use disorder, more recent psychiatric
      hospitalizations, more health problems, more visits to doctors for health
      problems, and more nonpsychiatric hospitalizations over the past year. The
      results support prior research documenting the high rates of PTSD in patients
      with severe mental illness and suggest that PTSD may contribute to substance
      abuse, psychiatric and medical comorbidity, and psychiatric and health service
      utilization.

PMID- 15176762
TI  - Comorbid personality disorders and substance use disorders of mentally ill
      homicide offenders: a structured clinical study on dual and triple diagnoses.
AB  - Comorbid substance use disorders (SUDs) increase the risk of homicide by persons
      with major mental disorders (MMDs). However, there are no published data from
      clinical interviews or lifetime objective documents on the prevalence of lifetime
      personality disorder (PD) or SUD among a comprehensive sample of mentally ill
      homicide offenders. Therefore, a nationally representative sample of men with MMD
      (n = 90) who had committed or attempted homicide was assessed using the research
      version of the Structured Clinical Interview for DSM-IV Axis I and Axis II
      Disorders. Lifetime documents, records, and questionnaires from persons who knew
      the subjects since childhood were used. Seventy-eight percent of the mentally ill
      homicide offenders were diagnosed with schizophrenia, 17 percent with
      schizoaffective disorder, and 5 percent with other psychosis. A lifetime SUD was
      detected in 74 percent and alcohol use disorder in 72 percent. PD accounted for
      51 percent, in 47 percent as antisocial personality disorder (APD). All subjects
      diagnosed with PD had SUD. Only 25 percent of the subjects had neither SUD nor
      PD. Among persons with dual diagnoses (MMD and SUD), about two-thirds had PD or
      APD. These results indicated that there were two-thirds major diagnostic
      categories of psychotic homicide offenders: about one-half had triple diagnosis
      (APD + SUD + MMD), one-quarter had "pure" dual diagnosis (SUD + MMD), and one
      quarter had "pure" MMD. The fourth possible category, "APD + MMD but no SUD," was
      not found. The prevention of severe violence by persons with MMD necessitates
      effective treatments for those with dual diagnosis who also have a history of
      APD.

PMID- 15176763
TI  - Psychotic symptoms among male adolescent detainees in The Netherlands.
AB  - This study investigated the prevalence of psychotic symptoms among incarcerated
      boys as well as the relationship between these symptoms and violent offending and
      criminal recidivism. The presence of psychotic symptoms was assessed in a
      representative sample of 204 incarcerated boys aged 12-18 using the Diagnostic
      Interview Schedule for Children (DISC-2.3). Seventy-two percent of the study
      participants had committed a violent index offense and 30 percent were criminal
      recidivists. Thirty-four percent (95% confidence interval [CI]: 27-41%) were DISC
      2.3 psychosis screen positive: 25% (95% CI: 19-31%) reported at least one
      pathognomonic of schizophrenia symptom and 9% (95% CI: 6-14%) reported at least
      three non-pathognomonic psychotic symptoms. In addition, 33 percent (95% CI: 26
      40%) reported one or two isolated, atypical psychotic symptoms. The presence of
      psychotic symptoms was not associated with violent offending or criminal
      recidivism. The high prevalence rate of psychotic symptoms among incarcerated
      boys calls for increased attention to diagnosis and treatment of psychosis. To
      obtain conclusive answers regarding the relationship between psychosis and
      violent offending, additional studies are needed in general population samples.

PMID- 15176764
TI  - Which executive skills should we target to affect social functioning and symptom
      change? A study of a cognitive remediation therapy program.
AB  - This study examined the link between executive function and functional outcome in
      schizophrenia to identify useful psychological intervention targets and explore
      how executive function changes affect social functioning and symptoms.
      Participants from two randomized controlled trials (n = 63) with poor social
      functioning, positive and negative symptoms, and cognitive impairment completed
      seven measures of executive function. Three cognitive factors were extracted:
      verbal working memory, response inhibition speed, and stimulus-driven responding.
      Participants received individual cognitive remediation therapy (CRT) (n = 18), a
      control therapy (occupational therapy activities) (n = 14), or treatment as usual
      (n = 19). Only the CRT group improved on verbal working memory. No group improved
      on the other factors. Although verbal working memory was significantly associated
      with social functioning and symptom severity 3 months after baseline, change in
      this factor did not predict change in either functional outcome. There was a
      significant interaction between group and the stimulus-driven responding factor,
      and for the CRT group only, a change to a more externally focused responding
      style was associated with reduced social problems and symptoms. Regardless of
      treatment type, increased response inhibition speed was associated with reduced
      negative symptoms. Stimulus-driven responding and response inhibition speed may
      therefore make useful targets for intervention.

PMID- 15176765
TI  - Supportive therapy for schizophrenia: possible mechanisms and implications for
      adjunctive psychosocial treatments.
AB  - This article posits that the positive findings for supportive therapy (ST) in
      recent trials may indicate an important but undervalued aspect of psychosocial
      interventions for schizophrenia. In developing this thesis, we consider the
      possible mechanisms underlying the beneficial effects of ST observed in recent
      trials of cognitive behavioral therapy for schizophrenia. We place this evidence
      in the context of a review of psychological models of mental health, the
      therapeutic alliance, and research on social cognition and social support in
      schizophrenia. We conclude this article by describing a new theoretically driven
      intervention for schizophrenia, functional cognitive-behavioral therapy (FCBT),
      which improves functional outcomes by integrating evidence-based advances in
      cognitive behavioral therapy with the strengths of ST approaches.

PMID- 15176766
TI  - Coping style in schizophrenia: associations with neurocognitive deficits and
      personality.
AB  - It is widely recognized that persons with schizophrenia tend to cope with stress
      in a relatively avoidant and ineffectual manner. Less is understood, however,
      about the factors that affect coping style in schizophrenia. To determine the
      extent to which various neurocognitive deficits and personality dimensions are
      related to coping style in schizophrenia, measures of visual memory, verbal
      memory, executive function, neuroticism, and extroversion were correlated with
      concurrent self-reports of preference for a range of active and avoidant coping
      strategies. Participants were 71 persons with schizophrenia spectrum disorders
      enrolled in outpatient psychiatric care. Stepwise multiple regressions indicated
      that neurocognition and personality were independently related to coping style.
      Specifically, higher levels of various forms of neurocognitive impairment and
      neuroticism predicted greater reliance on passive avoidant strategies and reduced
      reliance on active problem solving. Higher levels of extroversion were related to
      greater social support seeking. Implications for understanding the genesis of
      psychosocial dysfunction and for the development of rehabilitative interventions
      are discussed.

PMID- 15176767
TI  - Needs-based planning for persons with schizophrenia residing in board-and-care
      homes.
AB  - Data available from a recent planning project provided an opportunity to examine
      impairment and service needs of individuals with schizophrenia spectrum diagnoses
      living in a large board-and-care program. When first implemented, this minimum
      support custodial program was assumed to be adequate for discharged long-term
      inpatients with schizophrenia and other chronic mental illnesses. However, the
      needs assessments indicated considerable heterogeneity in resident level of
      impairment. When a validated planning template was applied to assign residents to
      an appropriate level of care, almost one-quarter were assigned to independent
      living with minimal support, one-third to community living with intensive
      support, and 40 percent to residential or inpatient treatment. The authors
      conclude that this program is not able to meet the varying needs of residents.
      Despite a common diagnosis, many can function in more independent settings, while
      others need more treatment and rehabilitation than they are currently provided.

PMID- 15176768
TI  - Hallucination focused integrative treatment: a randomized controlled trial.
AB  - Improvements in psychopathology, subjective burden, and coping with voices after
      hallucination focused integrative treatment (HIT) were studied in chronic
      schizophrenic patients with persistent (> 10 years), drug-refractory auditory
      hallucinations. In a randomized controlled trial, routine care was compared with
      HIT pre- and posttreatment at a 9-month interval. Independent raters used
      semistructured interviews to assess burden, symptoms, and coping. Within-group
      improvements in both burden and psychopathology were most significant in the
      experimental group (p < 0.05) after treatment. HIT patients showed change in
      applied coping strategies, but it did not reach statistical significance. Type
      and (change in) number of coping strategies did not seem related to outcome. The
      results suggest that HIT is a cost-effective practice that positively affects
      mental state in general, subjective burden, quality of life, and social
      functioning.

PMID- 15176769
TI  - Followup of psychotic outpatients: dimensions of delusions and work functioning
      in schizophrenia.
AB  - We studied three characteristics or dimensions of delusions in schizophrenia
      patients living in the community, including their influence on work and community
      functioning. The 149-patient sample included 57 delusional schizophrenia and
      nonschizophrenia outpatients, 50 nondelusional outpatient controls, and 42
      delusional inpatient controls. The data indicated the strength and prominence of
      acute-phase psychopathology on characteristics of delusions, with large
      significant differences in intensity of delusions between the acute inpatient
      phase and the postacute inpatient and outpatient phases. Contrary to some views,
      the data indicate that the overall presence of any delusions in general, and the
      various dimensions of delusions, both influence work performance and community
      functioning, with the greater part of the variance due to the presence of
      delusions in general. Despite their outpatient status, delusional outpatients
      showed surprisingly poor self-monitoring about whether others would regard their
      delusional ideation as unrealistic. Schizophrenia and affectively disordered
      patients with high emotional commitment to their delusions showed significantly
      poorer work functioning and were significantly more likely to be rehospitalized
      (p < 0.05), indicating the important impact on functioning of patients' feelings
      of immediacy and urgency about their unrealistic beliefs.

PMID- 15176770
TI  - Correlates of the affective impact of auditory hallucinations in psychotic
      disorders.
AB  - While many who hear auditory hallucinations (AHs) experience them as unpleasant,
      some do not. Little is known about the correlates of AHs that are not unpleasant,
      or of the characteristics of those who hear them. To better understand this
      symptom, we used a comprehensive structured interview schedule to study 199
      subjects who had experienced AHs. Subjects' responses to AHs were combined into
      two indexes: one assessing total affective impact and the other assessing the
      affective direction (positive or negative). Subjects who had grandiose delusions
      experienced their AHs more positively. AHs that were more frequent, lasted
      longer, and were louder were experienced more negatively. AHs heard in the second
      person and those related to people with whom the subjects had personal
      relationships were more positive than those heard in the third person. Many other
      aspects of AHs were unrelated to total affective impact or direction. It is
      argued that the positive evaluation of voices by subjects requires greater
      attention than it has received previously. Implications for assessment, clinical
      practice, and research are discussed.

PMID- 15176771
TI  - Clinical and etiopathogenic specificities of the French concept of psychose
      hallucinatoire chronique compared to schizophrenia.
AB  - The French concept of psychose hallucinatoire chronique (PHC) is characterized by
      late-onset psychosis, occurring predominantly in females. Symptoms are rich and
      frequent hallucinations but almost no dissociative features or negative symptoms.
      This diagnosis is classified among schizophrenia disorders (paranoid type)
      according to DSM-IV. PHC may also describe a group of patients with original
      clinical presentation and etiopathogenic factors. We compared 38 female PHC
      patients with two groups of female schizophrenia patients, matched for age at
      interview for the first group (n = 35), and duration of the disorder for the
      second group (n = 36). PHC subjects were relatively older patients with
      homogeneous clinical features characterized by predominantly positive symptoms
      without deterioration and fewer relatives with schizophrenia than schizophrenia
      patients. This first controlled study underscores clinical, phenomenological, and
      possibly etiopathogenic factors that characterized the PHC patients, even when
      the impact of late onset and late age at interview were taken into account. This
      study provides evidence that PHC may be a possible diagnosis in clinical
      practice, although it is difficult to reach a conclusion on its relationship with
      schizophrenia.

PMID- 15176773
TI  - First person account: The clogs.

PMID- 15176772
TI  - Absence of additional cognitive impairment in schizophrenia patients during
      maintenance electroconvulsive therapy.
AB  - This study examines the cognitive impairment profile of schizophrenia patients
      during maintenance electroconvulsive therapy (M-ECT). Ten schizophrenia patients
      treated with M-ECT and ten control patients matched for diagnosis, sex, and age
      who had never been treated with ECT were assessed with a comprehensive
      neuropsychological battery. M-ECT patients did not show a higher level of memory,
      attention, or frontal function impairment than the control group. The absence of
      additional memory dysfunction may favor the functional adaptation of these
      patients during M-ECT.

PMID- 15176774
TI  - Chemoselective cross metathesis of bishomoallylic alcohols: rapid access to
      fragment a of the cryptophycins.
AB  - [reaction: see text] The racemic or enantioselective allylation of in situ formed
      beta,gamma-unsaturated aldehydes provides efficient access to bishomoallylic
      alcohols from readily available 2-vinyloxiranes. These products, when subjected
      to modified Grubbs cross metathesis conditions, afforded terminally homologated
      products in moderate to good yields with high E selectivity and without
      degradation of the enantiomeric excess. The compounds obtained through this two
      step sequence yield fragments of an important and pharmacologically active family
      of cryptophycins.

PMID- 15176775
TI  - Synthesis of multitopic verdazyl radical ligands. Paramagnetic supramolecular
      synthons.
AB  - [structure: see text] The syntheses of several verdazyl radical and diradicals
      containing pyridine-based multitopic coordination sites are described. These
      compounds were designed to be paramagnetic analogues of oligopyridine
      metallosupramolecular building blocks.

PMID- 15176776
TI  - TRAM linker: a safety-catch linker for the traceless release of acrylamides.
AB  - [reaction: see text] A novel safety-catch linker for the solid-phase synthesis of
      small-molecule libraries containing electrophilic reactive groups has been
      developed. Upon cleavage from solid support, the linker generates a Michael
      acceptor (an acrylamide) on each library member. Utilization of a two-resin
      system in the final cleavage step provides crude products in high purity,
      allowing direct use in biological assays following filtration and evaporation.

PMID- 15176777
TI  - Stereoselection in radical cyclization of beta-alkoxyvinyl sulfoxides: synthesis
      of tetrahydrofuranyl allyl carbinols.
AB  - [reaction: see text] Tetrahydrofuranyl allyl carbinols may be prepared
      stereoselectively via radical cyclization of beta-alkoxyvinyl sulfoxides,
      Pummerer rearrangement, and reaction with allylstannane.

PMID- 15176778
TI  - Photodimers of a soluble tetracene derivative. excimer fluorescence from the head
      to-head isomer.
AB  - [reaction: see text] Irradiation of 5,12-didecyloxytetracene (1) leads to
      photodimers P(1) (planosymmetric) and P(2) (centrosymmetric). P(1) is
      characterized by naphthalene excimer fluorescence, whereas P(2) emits naphthalene
      monomer fluorescence.

PMID- 15176779
TI  - Copper(I)-catalyzed intramolecular asymmetric [2 + 2] photocycloaddition.
      Synthesis of both enantiomers of cyclobutane derivatives.
AB  - [reaction: see text] A simple approach for asymmetric induction in Cu(I)
      catalyzed [2 + 2] photocycloaddition, where asymmetric catalysts or chiral
      auxiliaries were inefficient, has been developed using the concept of chirality
      transfer from the readily available 2, 3-di-O-cyclohexylidine-(R)-(+)
      glyceraldehyde. An anion-induced cleavage of the tetrahydrofuran ring of the
      resulting oxa-bicyclo[3.2.0]heptanes led to a convenient access to the
      synthetically useful cis-1,2-disubstituted cyclobutanes in enantiomerically pure
      form.

PMID- 15176780
TI  - Iron(III) porphyrin catalyzed aziridination of alkenes with bromamine-T as
      nitrene source.
AB  - [reaction: see text] Iron(III) porphyrin complexes Fe(Por)Cl are effective
      catalysts for aziridination of alkenes using bromamine-T as the nitrene source.
      The catalytic system can operate under mild conditions with alkenes as limiting
      reagents. The aziridination reaction is general and suitable for a wide variety
      of alkenes, including aromatic, aliphatic, cyclic, and acyclic olefins, as well
      as alpha,beta-unsaturated esters. For 1,2-disubstituted olefins, the reactions
      proceeded with moderate to low stereospecificity.

PMID- 15176781
TI  - Addition of electrophilic and heterocyclic carbon-centered radicals to glyoxylic
      oxime ethers.
AB  - [reaction: see text] Stabilized primary radicals can be formed from alkyl halides
      in an atom transfer process with Et(3)B. This process depends on the strength of
      the carbon-halogen bond and the stability of the resulting primary radical.
      Radicals formed from benzyl iodide and ethyl iodoacetate add to glyoxylic oxime
      ethers; however, more electrophilic radicals do not. Glyoxylic oxime ethers are
      also good radical acceptors for heterocyclic carbon-centered secondary radicals,
      giving novel alpha-amino acid derivatives.

PMID- 15176782
TI  - Facile sonochemical synthesis of graphite intercalation compounds.
AB  - [reaction: see text] Graphite intercalation compounds (GICs) are useful as
      powerful reducing agents in organic chemistry and are typically prepared by
      anaerobic solid-state reactions at high temperatures for 1-8 h. We have been able
      to prepare KC(8) in situ in toluene using ultrasound in less than 5 min. This
      allows for a convenient approach to reductive chemical syntheses involving GICs.

PMID- 15176783
TI  - Novel porphyrin-fullerene assemblies: from rotaxanes to catenanes.
AB  - [reaction: see text] Titration of porphyrin-fullerene rotaxanes with DABCO or
      4,4'-bipyridine led to photo- and redoxactive catenanic architectures, which upon
      photoexcitation undergo a sequence of short-range energy and electron transfer
      events to give a long-lived charge-separated radical-pair state.

PMID- 15176784
TI  - Tetrakis-heteroleptic complexation at porphyrins: a convenient route to diversely
      functionalized aggregates.
AB  - [structure: see text] Using a novel tetraphenanthrolinated porphyrin building
      block and heteroleptic bisphenanthroline complexation, copper-instructed
      multicomponent assemblies exhibiting distinct electrochemical and photoactive
      behavior were accessed.

PMID- 15176785
TI  - Electrophilic substitution of dibromoparacyclophane: a route to novel
      paracyclophane phosphine ligands.
AB  - [reaction: see text] The regioselective functionalization of 4,12
      dibromoparacyclophane via electrophilic aromatic substitution is reported for the
      first time. The functionalization of the paracyclophane backbone allows the
      development of a new family of paracyclophane-based phosphines (named ParaPhos)
      that opens the possibility of improved catalyst development and tuning while
      retaining all the catalysis potential of the PhanePhos family of ligands.

PMID- 15176786
TI  - Interesting behavior of alpha,beta-unsaturated oximes in intramolecular [4 + 2]
      cycloaddition reactions.
AB  - [structure: see text] Intramolecular [4 + 2] cycloaddition using alpha,beta
      unsaturated oximes was explored. The reactions proceeded under unusually facile
      conditions to furnish the nitrones. The latter were subsequently reacted with
      DMAD to afford [3 + 2] cycloaddition products.

PMID- 15176787
TI  - Expedient protocol for solid-phase synthesis of secondary and tertiary amines.
AB  - [reaction: see text] An expedient solid-phase synthetic approach to secondary and
      tertiary amines was developed. The protocol employs conversion of resin-bound
      amino alcohols to the corresponding iodides, followed by iodide displacement with
      primary or secondary amines or with unprotected amino alcohols. This two-step
      procedure, affording products in good to excellent yields, is suitable for solid
      phase synthesis of polyamines.

PMID- 15176788
TI  - Stereoselective ketal-tethered intramolecular diels-alder cycloadditions. An
      approach to the 2-oxadecalin spiroketal core of antifungal agent fusidilactone C.
AB  - [reaction: see text] An approach toward the 2-oxadecalin spiroketal core of
      fusidilactone C via a rare ketal-tethered intramolecular Diels-Alder
      cycloaddition is described here. This intramolecular Diels-Alder cycloaddition is
      highly endo-selective and overall depended upon the nature of solvents and Lewis
      acids. We also observed some remarkable rate acceleration in MeOH.

PMID- 15176789
TI  - Samarium diiodide coupling of enones: a remarkable cascade sequence.
AB  - [reaction: see text] Treatment of cyclic enones with SmI(2) in THF/MeOH (4:1) led
      to tricyclic diol products in one step and, in the case of enone 7, gave the
      tetracycle 13 as a single diastereoisomer in up to 67% yield.

PMID- 15176790
TI  - Effect of binding and conformation on fluorescence quenching in new 2',7'
      dichlorofluorescein derivatives.
AB  - [structure: see text] Symmetrical and unsymmetrical 2',7'-dichlorofluorescein
      (DCF) derivatives have been synthesized by means of Mannich reactions and an
      aromatic Claisen rearrangement. NMR and fluorescence spectroscopic studies reveal
      the correlation between the conformations, the photoinduced electron transfer
      mechanism, and fluorescent intensities of these DCF derivatives. Two quenching
      nitrogen atoms cooperatively and reversibly suppress the fluorescence of the
      chromophore.

PMID- 15176791
TI  - Psymberin, a potent sponge-derived cytotoxin from Psammocinia distantly related
      to the pederin family.
AB  - [structure: see text] Bioassay-guided fractionation of the sponge Psammocinia sp.
      afforded psymberin (1) possessing 5S,8S,9S,11R,13R,15S,16R,17R stereochemistry.
      Psymberin exhibits structural similarities to the pederin family metabolites. The
      potent cytotoxicty and unique structural features of 1 make it a promising lead
      for therapeutic development.

PMID- 15176792
TI  - Microbiological transformations 57. Facile and efficient resin-based in situ SFPR
      preparative-scale synthesis of an enantiopure "unexpected" lactone regioisomer
      via a Baeyer-Villiger oxidation process.
AB  - [reaction: see text] The microbiological Baeyer-Villiger oxidation of (-)
      bicyclo[3.2.0]hept-2-en-6-one allowed exclusive formation of the "unexpected"
      lactone regioisomer in 84% yield, high chemical purity, and enantiopure form.
      Substrate (25 g) was transformed in a 1 L bubble column reactor, following a in
      situ substrate feeding/product removal methodology, which afforded high
      volumetric productivity (1.2 g L(-)(1) h(-)(1)). This illustrates the high
      "sustainable chemistry" advantages of such a process, simply conducted in aqueous
      medium, at room temperature and using atmospheric oxygen.

PMID- 15176793
TI  - Copper(I) thiolate catalysts in asymmetric conjugate addition reactions.
AB  - [structure: see text] Full conversion and enantioselectivities up to 83% have
      been obtained in the conjugate addition reactions of diethyl zinc to Michael
      acceptors catalyzed by well-defined (chiral) copper(I) aminoarenethiolates.
      Interesting differences between organozinc or Grignard reagents have been found:
      for cyclic enones R(2)Zn reagents afford better results, whereas earlier work
      showed that RMgX reagents react more selectively with acyclic enones.

PMID- 15176794
TI  - Hydrogen bonding patterns of calix[4]arenes with thiourea functionalities in
      solution and in the solid state.
AB  - [structure: see text] We have synthesized a number of calix[4]arene derivatives
      presenting thiourea functional groups at their upper rims by the condensation of
      a 1,3-di(p-amino)calix[4]arene with alkyl isothiocyanates. Mono- and dithiourea
      substituted calix[4]arenes were prepared selectively in good yields, and
      homocoupling of the former led to calix[4]arene dimers with a thiourea linker. X
      ray crystallography revealed interesting intra- and intermolecular hydrogen
      bonding patterns. (1)H NMR data and computational studies also provided some
      insight into the hydrogen bonding patterns.

PMID- 15176795
TI  - Supramolecular recognition and structural elucidation of inclusion complexes of
      an achiral carbene precursor in beta- and permethylated beta-cyclodextrin.
AB  - [structure: see text] Inclusion of achiral carbene precursor endo-8
      azibicyclo[3.2.1]octan-3-ol (1) in chiral beta-cyclodextrin (7-Cy) and tri-O
      methyl-beta-cyclodextrin (TRIMEB) leads to 1:1 complexes 1@7-Cy and 1@TRIMEB,
      respectively. The combined methods of induced circular dichroism, NMR
      spectroscopy, and X-ray structure determination were employed for the first time
      for structural elucidation of the complexes in solution and the solid state.
      Significantly different orientations of 1 were observed. Compared with 1@7-Cy,
      1@TRIMEB exhibits a different guest orientation and an association constant one
      twentieth lower.

PMID- 15176796
TI  - 2'-O-[2-(guanidinium)ethyl]-modified oligonucleotides: stabilizing effect on
      duplex and triplex structures.
AB  - [structure: see text] Oligonucleotides with a novel 2'-O-[2-(guanidinium)ethyl]
      (2'-O-GE) modification have been synthesized using a novel protecting group
      strategy for the guanidinium group. This modification enhances the binding
      affinity of oligonucleotides to RNA as well as duplex DNA (DeltaT(m) 3.2 degrees
      C per modification). The 2'-O-GE modified oligonucleotides exhibited exceptional
      resistance to nuclease degradation. The crystal structure of a palindromic duplex
      formed by a DNA oligonucleotide with a single 2'-O-GE modification was solved at
      1.16 A resolution.

PMID- 15176797
TI  - Structural diversity of peroxidase-catalyzed oxidation products of o
      methoxyphenols.
AB  - [reaction: see text] The biocatalytic oxidation of o-methoxyphenolic compounds
      led to a variety of oligophenols (dimers to pentamers) and some of their
      oxidation products. The reaction was carried out in an aqueous medium at room
      temperature with hydrogen peroxide as the terminal oxidant in a facile and green
      route to potentially bioactive compounds. Detailed structural information on the
      products of peroxidase-catalyzed oxidation of o-methoxyphenols is presented for
      the first time.

PMID- 15176798
TI  - Palladium-catalyzed ring expansion reaction of (Z)-1-(1,3
      butadienyl)cyclobutanols with aryl iodides. stereospecific synthesis of (Z)-2-(3
      aryl-1-propenyl)cyclopentanones.
AB  - [reaction: see text] A novel type of cascade ring expansion process has been
      developed by the palladium-catalyzed reaction of (Z)-1-(1,3
      butadienyl)cyclobutanols with aryl iodides. The reaction proceeds in a
      stereospecific manner to produce (Z)-2-(3-aryl-1-propenyl)cyclopentanones. It has
      also been found that regioselective alpha-arylation of alkenyl cyclopentanones
      proceeds to afford the alpha-arylated cyclopentanones.

PMID- 15176799
TI  - Synthesis of carboxamides by LDA-catalyzed Haller-Bauer and Cannizzaro reactions.
AB  - [reaction: see text] The first direct synthesis of N-alkylcarboxamides and N,N
      dialkylcarboxamides by Haller-Bauer (HB) and Cannizzaro-type reactions has been
      realized. Lithium N,N-diisopropylamide (LDA) catalyst was successfully used in
      not only the HB reaction of benzylic ketones with lithium N-alkylamides to give
      the corresponding carboxamides and hydrocarbons but also in the Cannizzaro-type
      reaction of aldehydes with lithium N-alkylamides or lithium N,N-dialkylamides to
      give the corresponding carboxamides and alcohols.

PMID- 15176800
TI  - Suzuki-Miyaura coupling catalyzed by polymer-incarcerated palladium, a highly
      active, recoverable, and reusable Pd catalyst.
AB  - [reaction: see text] Suzuki-Miyaura coupling using a highly efficient and
      reusable polymer-incarcerated palladium (PI Pd) is described. Various coupling
      reactions proceeded smoothly using PI Pd with phosphine ligands, and the catalyst
      could be recovered by simple filtration and reused several times without loss of
      activity.

PMID- 15176801
TI  - 4-metalated condensed pyrimidines: their preparation and reaction with aldehydes
      under Barbier-type conditions.
AB  - [reaction: see text] The organometallic intermediate obtained from halogen-metal
      exchanges of 4-iodo-6-phenylthieno[2,3-d]pyrimidine under Barbier-type conditions
      was reacted with aldehydes to form the corresponding alcohols in moderate yields.
      The reaction involving an organolithium intermediate proceeded only at low
      temperature, whereas the reaction involving a magnesium ate intermediate also
      proceeded at room temperature. A crystal structure confirms that the expected
      constitutional alcohol isomer is formed, where no migration has taken place. The
      conditions were also suitable for 9-benzyl-6-iodopurine.

PMID- 15176802
TI  - Lanthanide-promoted ethylation of Schiff bases by triethylaluminum.
AB  - [reaction: see text] Schiff bases of aromatic aldehydes and anilines that fail to
      react with triethylaluminum are smoothly alkylated at room temperature in the
      presence of lanthanide catalysts. The alkylation takes place selectively at the
      vinylic carbon atom.

PMID- 15176803
TI  - B(C6F5)3-catalyzed allylation of propargyl acetates with allylsilanes.
AB  - [reaction: see text] An efficient method for the B(C(6)F(5))(3)-catalyzed
      allylation of secondary propargylic alcohol derivatives with allylsilanes has
      been developed. This method allows for the facile synthesis of a variety of 1,5
      enynes in good to high yields with a number of functionalities, such as nitro,
      chloro, ester, and boronic ester, being tolerated under the reaction conditions.

PMID- 15176804
TI  - A concise total synthesis of (+/-)-1-epiaustraline.
AB  - [reaction: see text] A concise total synthesis of 1-epiaustraline 3 is described
      that utilizes a diastereoselective Birch reduction of an electron-deficient
      pyrrole and a chelation-controlled vinyl Grignard addition to an aldehyde to
      introduce the C7 stereocenter. The C1 and C2 stereocenters were set through an
      OsO(4)-catalyzed dihydroxylation.

PMID- 15176805
TI  - Preparation, characterization, and FET properties of novel
      dicyanopyrazinoquinoxaline derivatives.
AB  - [structure: see text] A series of the title dicyanopyrazinoquinoxaline
      derivatives have been prepared and characterized by using single-crystal X-ray
      structure analysis and redox potential measurements. They have strong electron
      accepting properties due to the pyrazinopyrazine skeletons as well as the cyano
      groups. Substituents can be easily introduced at the benzene ring and control the
      HOMO-LUMO energy gap and the molecular packing. They show clear n-type transistor
      properties in the FET devices.

PMID- 15176806
TI  - Syntheses and properties of donor-acceptor-type 2,5-diarylthiophene and 2,5
      diarylthiazole.
AB  - [structure: see text] Syntheses of differently substituted 2,5-diarylthiophenes
      and 2,5-diarylthiazoles are carried out with the palladium-catalyzed C-H
      substitution reaction using AgF as an activator. Remarkably strong
      photoluminescence is observed in 2,5-diarylthiophene. Differences between the
      physical properties of liquid crystalline characteristics and cyclic
      voltammograms of thiophene and thiazole are also studied.

PMID- 15176807
TI  - Zn(II)/amine-catalyzed coupling reaction of alkylidenemalonates with propargyl
      alcohol: a one-pot synthesis of methylenetetrahydrofurans.
AB  - [reaction: see text] A metal-catalyzed tandem 1,4-addition/cyclization between
      propargyl alcohol and a Michael acceptor, such as alkylidene malonate, has been
      developed. In the presence of catalytic amounts of zinc triflate [Zn(OTf)(2)] and
      triethylamine (Et(3)N), various 2-alkylidene-1,3-dicarbonyl compounds reacted
      with propargyl alcohol to give 3- or 4-methylene tetrahydrofurans in excellent
      yields.

PMID- 15176808
TI  - Microwave-accelerated SPOT-synthesis on cellulose supports.
AB  - [reaction: see text] We demonstrate that microwave irradiation can dramatically
      accelerate reaction rates for spatially addressable library synthesis on planar
      membrane supports. The development of a robust support/linker system, microwave
      assisted synthesis of small molecule test libraries, and methods for solid-phase
      scale-up on cellulose are described.

PMID- 15176809
TI  - SimplePHOX, a readily available chiral ligand system for iridium-catalyzed
      asymmetric hydrogenation.
AB  - [reaction: see text] New Ir-SimplePHOX complexes Ir-6-Ir-9 catalyze the
      quantitative, highly enantioselective hydrogenation of a range of
      unfunctionalized and functionalized olefins. Synthesis, catalytic results, and X
      ray crystal structures are presented here.

PMID- 15176810
TI  - Unprecedented in situ oxidative ring cleavage of isoxazolidines:
      diastereoselective transformation of nitronic acids and derivatives into 3
      hydroxymethyl 4-nitro tetrahydrofurans and pyrrolidines.
AB  - [reaction: see text] Nitronic acids undergo an intramolecular 1,3-dipolar
      cycloaddition to unactivated double bonds, and the resulting isoxazolidines
      spontaneously evolve by an unprecedented in situ oxidative ring cleavage. The
      extension of this transformation to silyl nitronates results in a general
      diastereoselective construction of hydroxymethyl nitro functionalized tetrahydro
      furans and -pyrrolidine having up to four consecutive stereogenic centers.

PMID- 15176811
TI  - Discovery of the chemical function of glycosidases: design, synthesis, and
      evaluation of mass-differentiated carbohydrate libraries.
AB  - [reaction: see text] Discovery of the catalytic chemical function of the many
      putative glycosidases coded in genomes currently relies on individual testing of
      possible substrates, usually as their p-nitrophenol conjugate. Herein, we present
      an alternative chemical proteomics approach using a synthetic mass-differentiated
      heat-stable substrate library with mass spectrometry readout. Library components
      do not serve as reaction inhibitors and both primary and secondary enzyme
      substrates can be delineated.

PMID- 15176812
TI  - Efficient and Z-selective cross-metathesis of conjugated enynes.
AB  - [reaction: see text] The generation of a conjugated alkynyl alkylidene has been
      achieved using an allyl ether moiety as an intramolecular catalyst delivery
      vehicle. The reaction of this intermediate with alkenes and alkynes yields
      conjugated enynes with Z-selectivity.

PMID- 15176813
TI  - Biomimetic total synthesis of litseaverticillols B, E, I, and J and structural
      reassignment of litseaverticillol E.
AB  - [reaction: see text] The first total synthesis of litseaverticillols B (1), E
      (2), I (4), and J (5) as well as the structural reassignment of litseaverticillol
      E (2) have been achieved by means of a biomimetic sequence of transformations
      during which a [4 + 2]-initiated reaction cascade and an ene reaction, both
      involving singlet oxygen ((1)O(2)), formed key steps. The reassignment of the
      structure of litseaverticillol E (3) to include an allylic hydroperoxide provides
      strong support for our biogenetic hypothesis.

PMID- 15176814
TI  - Total synthesis of cochleamycin A.
AB  - [reaction: see text] Cochleamycin A (1) was synthesized in 2.4% overall yield via
      a 23-step linear sequence starting from 3-butene-1-ol. Key features of the
      synthesis include the synthesis of (Z)-1,3-diene 21 via a Stille coupling of 4
      and 5 and a transannular Diels-Alder reaction of macrocycle 26 to provide the
      complete carbon skeleton of 1.

PMID- 15176815
TI  - Radical-mediated silyl- and germyldesulfonylation of vinyl and (alpha
      fluoro)vinyl sulfones: application of tris(trimethylsilyl)silanes and
      tris(trimethylsilyl)germanes in Pd-catalyzed couplings.
AB  - [reaction: see text] Radical-mediated silyl- and germyldesulfonylations of
      various vinyl and (alpha-fluoro)vinyl sulfones with tris(trimethylsilyl)silane
      and germanium hydrides provide access to vinyl and (alpha-fluoro)vinyl silanes
      and germanes. Upon oxidative treatment with hydrogen peroxide in basic aqueous
      solution, the vinyl tris(trimethylsilyl)silanes and -germanes undergo Pd
      catalyzed cross-couplings with aryl halides.

PMID- 15176816
TI  - Dynamic kinetic resolution of atropisomeric amides.
AB  - [reaction: see text] Using L-proline as catalyst in the asymmetric aldol reaction
      and a series of benzamides and naphthamides, we have accomplished a dynamic
      kinetic resolution that simultaneously establishes the stereochemistry of the
      atropisomeric amide's chiral axis and a stereogenic center. The
      enantioselectivities ranged from 82% to 95% and the diastereoselectivities from
      2.1:1 to 7.0:1.

PMID- 15176817
TI  - Assignment of absolute stereochemistry and total synthesis of (-)-spongidepsin.
AB  - [structure: see text] An enantioselective total synthesis of (-)-spongidepsin (2)
      and elucidation of the absolute stereochemistry of its four stereocenters are
      described. Spongidepsin (2), a 13-membered depsipeptide isolated from the Vanuatu
      marine sponge Spongia sp., has shown potent antitumor properties against a
      variety of NCI tumor cell lines. Our synthesis is convergent, and the absolute
      stereochemistry of four of the five chiral centers was assigned through
      synthesis.

PMID- 15176818
TI  - alpha,5-didehydro-3-picoline diradicals from skipped azaenediynes: computational
      and trapping studies of an aza-Myers-Saito cyclization.
AB  - [reaction: see text] On the basis of density functional calculations, the
      isomerization of skipped azaenediynes (C-alkynyl-N-propargylimines) to azaenyne
      allenes and subsequent rapid aza-Myers-Saito cyclization to alpha,5-didehydro-3
      picoline were predicted. We prepared the N-propargylimine of 1-phenyl-3
      tri(isopropyl)silylprop-2-yn-1-one, which undergoes proto-desilylation and
      isomerization to an azaenyne allene when treated with tetrabutylammonium
      fluoride. In the presence of 1,4-cyclohexadiene, this azaenyne allene affords 6
      phenyl-3-picoline and other products corresponding to the trapping of an alpha,5
      didehydro-3-picoline diradical.

PMID- 15176819
TI  - Using stereoelectronic effects to explain selective reactions of 4-substituted
      five-membered ring oxocarbenium ions.
AB  - [reaction: see text] The utility of the inside attack model to predict and
      analyze the stereoselectivities of nucleophilic additions to complex five
      membered ring oxocarbenium ions is demonstrated in a systematic study of C-4
      substituted acetals.

PMID- 15176820
TI  - Synthesis and evaluation of polyhydroxylated near-infrared carbocyanine molecular
      probes.
AB  - [reaction: see text] A new near-infrared (NIR) fluorescent molecular probe
      derived from indocarbocyanine dye and galactose was prepared, and the procedure
      was optimized. The presence of a nonionic polyhydroxyl moiety between hydrophobic
      groups enhances solubility and possibly minimizes aggregation in aqueous
      solutions. The structural framework of this molecule provides multivalent sites
      for labeling diverse molecules.

PMID- 15176821
TI  - Palladium-catalyzed decarboxylation and decarbonylation under hydrothermal
      conditions: decarboxylative deuteration.
AB  - [reaction: see text] Decarboxylation of free carboxylic acid was performed by
      Pd/C catalyst under hydrothermal water (250 degrees C/4 MPa). Under the
      hydrothermal conditions of deuterium oxide, decarbonylative deuteration was
      observed to give fully deuterated hydrocarbons from carboxylic acids or
      aldehydes.

PMID- 15176822
TI  - New asymmetric halo aldol reaction provides a novel approach to biologically
      important chiral cyclothers and cycloamines.
AB  - [reaction: see text] A new asymmetric halo aldol reaction has been developed by
      reacting cyclopropyl carbonyl derived enolates with aldehydes. The absolute
      structure was unambiguously confirmed by X-ray structural analysis. Eight
      examples were reported with good yields and up to complete control of
      diastereomeric excesses. These halo aldol products have been readily cyclized in
      the presence of weak bases to produce chiral 2,3-disubstituted tetrahydrofuran
      derivatives in good yield without any observed epimerization.

PMID- 15176824
TI  - Metal-catalyzed di-tert-butylsilylene transfer: synthesis and reactivity of
      silacyclopropanes.
AB  - Metal-catalyzed di-tert-butylsilylene transfer was developed as a mild,
      operationally simple, functional-group-tolerant method for silacyclopropane
      formation. Di-tert-butylsilylene was transferred from cyclohexene
      silacyclopropane 1 to an alkene through the use of a metal salt.
      Silacyclopropanation occurred at temperatures as low as -27 degrees C when AgOTf
      or AgOC(O)CF(3) were used as catalysts. Complex silacyclopropanes were formed
      stereospecifically and diastereoselectively from functionalized alkenes.
      Silacyclopropanes reacted with various carbonyl compounds, including aldehydes,
      ketones, formate esters, and formamides, in an overall process that efficiently
      converts alkenes into oxasilacyclopentanes with defined stereochemistry.

PMID- 15176825
TI  - Stereoselective conjugate addition of benzyl phenylsulfonyl carbanions to enoates
      derived from d-mannitol.
AB  - The conjugate addition of benzylic phenylsulfonyl carbanions (2a'-d') to enoates
      derived from d-(+)-mannitol (E- or Z-1a-c) was studied using THF and THF/HMPA as
      solvent. Under kinetic conditions (-78 degrees C), enoate E-1a,b led to a mixture
      of syn-(R,S) and anti-(S,S) adducts (55/45), and syn-(R,S) adducts were the main
      product obtained ( approximately 90/10) from enoate Z-1a. Under thermodynamic
      conditions (-78 degrees C to room temperature) syn-(R,S) adducts were also
      preferentially formed ( approximately 90/10), despite the geometry at the double
      bond in the acceptor. Enoate 1c (E/Z = 57/43), bearing an additional benzyl group
      at the alpha-position, also reacted with carbanions 2'a,b, under thermodynamic
      conditions, leading to syn-adducts in excellent de (control at the three newly
      generated stereogenic centers). The adducts were quantitatively transformed into
      the corresponding beta-gamma-disubstituted gamma-butyrolactones and
      alpha,beta,gamma-trisubstituted gamma-butyrolactones. (1)H NMR studies (NOE and J
      coupling) of these lactones allowed us to determine their configuration at the
      newly generated chiral centers. The reduction of the C-S bond in adducts syn
      (R,S) with Na/Hg, followed by treatment of the resulting products in aqueous acid
      media, led to enantioenriched beta-benzyl-gamma-hydroxymethyl-gamma
      butyrolactones. The conformational equilibrium of enoates E- and Z-1b was
      evaluated by theoretical calculations (ab initio, MP2/6-31G), and a mechanistic
      rationale was proposed to explain the observed stereoselectivities.

PMID- 15176826
TI  - Synthesis and X-ray crystal structure of the dolabellaauricularia peptide
      dolastatin 18.
AB  - A previously synthesized unit of dolastatin 10 (1), dolaphenine (Doe, 3), was
      converted in four steps to tripeptide 10. Subsequent condensation with carboxylic
      acid 11 (four steps from Meldrum's acid) provided a practical synthesis of the
      cancer cell growth inhibitor dolastatin 18 (2, Dhex-(S)-Leu-(R)-N-Me-Phe-Doe).
      The synthesis of dolastatin 18 (2) confirmed the R stereochemistry of the N-Me
      Phe unit as originally assigned and unusual among amino acid components of the
      sea hare Dolabella auricularia. An X-ray crystal structure determination of
      dolastatin 18 was also completed.

PMID- 15176827
TI  - Experimental and theoretical evidence of basic site preference in polyfunctional
      superbasic amidinazine: N(1),N(1)-dimethyl-N(2)-beta-(2-pyridylethyl)formamidine.
AB  - The gas-phase basicity (GB) of the flexible polyfunctional N(1),N(1)-dimethyl
      N(2)-beta-(2-pyridylethyl)formamidine (1) containing two potential basic sites
      (the ring N-aza and the chain N-imino) is obtained from proton-transfer
      equilibrium constant measurements, using Fourier-transform ion-cyclotron
      resonance mass spectrometry. Comparison of the experimental GB obtained for 1
      with those reported for model amidines and azines indicates that the chain N
      imino in the amidine group is the favored site of protonation. Semiempirical
      (AM1) and ab initio calculations (HF, MP2, and DFT), performed for 1 and its
      protonated forms, confirm this interpretation. These results are in contrast to
      those found previously for N(1),N(1)-dimethyl-N(2)-azinylformamidines (containing
      the amidine function directly linked to the azinyl ring), in which the ring N-aza
      is the most basic site in the gas phase. The separation of the two potential
      basic sites in 1 by the ethylene chain interrupts the resonance conjugation
      between the two functions and changes their relative basicities and, thus, the
      preferable site of protonation. It also increases the chelation effect against
      the proton and the gas-phase basicity of 1 in such a magnitude that consequently
      1 may be classified as a superbase (GB = 241.1 kcal mol(-)(1)). A transition
      state corresponding to the internal transfer of the proton (ITP) between the ring
      N-aza and the chain N-imino in 1 is investigated at the DFT(B3LYP)/6-31G level.
      The energy barrier calculated for the ITP between the two basic sites is small
      and vanishes when zero-point vibrational terms and thermal corrections are
      applied to obtain the enthalpy or Gibbs energy of activation for the proton
      transfer. Additional calculations at the DFT(MPW1K)/6-31G level confirm this
      behavior. This indicates that the quantum-chemical ITP in 1 has a single-well
      character. The proton is located on the N-imino site, and the H-bond is formed
      with the N-aza site.

PMID- 15176828
TI  - Synthesis and application of a new bisphosphite ligand collection for asymmetric
      hydroformylation of allyl cyanide.
AB  - A series of mono- and bidentate phosphites was prepared with (S)-5,5',6,6'
      tetramethyl-3,3'-di-tert-butyl-1,1'-biphenyl-2,2'-dioxy [(S)-BIPHEN] as a chiral
      auxiliary and screened in the asymmetric hydroformylation of allyl cyanide. These
      hydroformylation results were compared with those of two existing chiral ligands,
      Chiraphite and BINAPHOS, whose utility in asymmetric hydroformylation has been
      previously demonstrated. Bisphosphite 11 with a 2,2'-biphenol bridge was found to
      be the best overall ligand for asymmetric hydroformylation of allyl cyanide with
      up to 80% ee and regioselectivities (branch-to-linear ratio, b/l) of 20 with
      turnover frequency of 625 [h(-)(1)] at 35 degrees C. BINAPHOS gave
      enantioselectivities up to 77% ee when the reaction was conducted in either
      acetone or neat but with poor regioselectivity (b/l 2.8) and activities 7 times
      lower than that of 11. The product of allyl cyanide hydroformylation using (R,R)
      11 was subsequently transformed into (R)-2-methyl-4-aminobutanol, a useful chiral
      building block. Single-crystal X-ray structures of (S,S)-11 and its rhodium
      complex 19 were determined.

PMID- 15176829
TI  - Palladium-catalyzed enantioselective allylic alkylation of thiocarboxylate ions:
      asymmetric synthesis of allylic thioesters and memory effect/dynamic kinetic
      resolution of allylic esters.
AB  - The palladium-catalyzed allylic alkylation of KSAc and KSBz with racemic cyclic
      and acyclic allylic esters by using N,N'-(1R,2R)-1,2-cyclohexandiylbis[2
      (diphenylphosphino)-benzamide] as ligand frequently gave the corresponding
      allylic thioesters with high ee values and yields. The reaction of the cyclic
      allylic carbonates with KSAc in the presence of H(2)O was accompanied by a
      partial palladium-catalyzed enantioselective "hydrolysis" of the substrates with
      formation of the corresponding enantioenriched allylic alcohols. The degree of
      the "hydrolysis" was strongly dependent on the solvent and the thiocarboxylate
      ion. Highly selective kinetic resolutions (KRs) were observed in the palladium
      catalyzed reaction of the racemic cyclohexenyl and cycloheptenyl acetates with
      KSAc. While the KR of the cyclohexenyl acetate is characterized by a selectivity
      factor S = 72 +/- 19, that of the cycloheptenyl acetate afforded (R)
      cycloheptenyl acetate of >or=99% ee in 48% yield and (S)-cycloheptenyl
      thioacetate of 98% ee in 50% yield. The palladium-catalyzed reaction of the
      racemic cyclopentenyl acetate with KSAc showed a strong "memory effect" (ME),
      that is, both enantiomers reacted with different enantioselectivities. The ME was
      probed by studying the palladium-catalyzed reactions of both the matched acetate
      of >or=99% ee and the mismatched acetate of >or=99% ee with KSAc. The acetates
      not only reacted with different enantioselectivities and rates but also suffered
      an unexpected and concomitant palladium-catalyzed racemization in the presence of
      the chiral ligand. This led in the case of the mismatched acetate to a temporary
      dynamic kinetic resolution (DKR) that featured a racemization of the mismatched
      acetate by the chiral catalyst. Studies of the palladium-catalyzed reaction of
      the racemic cyclopentenyl acetate, carbonate, and naphthoate with KSAc in the
      presence of the chiral ligand also showed the ME to be strongly dependent on the
      nucleofuge. This also allowed the synthesis of (S)-cyclopentenyl thioacetate of
      92% ee in high yield from the racemic cyclopentenyl naphthoate.

PMID- 15176830
TI  - Highly regio- and chemoselective palladium-catalyzed propargylallylation of
      activated olefins: a novel route to 1,7-enyne derivatives.
AB  - An efficient method for the synthesis of 1,7-enyne derivatives via phosphine
      palladium-catalyzed three-component assembling of activated olefins, allylic
      chlorides, and allenylstannanes is described. Substituted arylethylidene
      malononitriles 1a-g (RCH=C(CN)(2): R = C(6)H(5) (1a), p-ClC(6)H(4) (1b), p
      OMeC(6)H(4) (1c), p-NO(2)C(6)H(4) (1d), 1-naphthyl (1e), 2-furyl (1f), and 2
      thienyl (1g)) undergo propargylallylation with allylic chlorides 2a-e (allyl
      chloride (2a), methallyl chloride (2b), 4-chloropent-2-ene (2c), cinnamyl
      chloride (2d), and 3-chlorocyclohexene (2e)) and n-tributylallenylstannane (n
      Bu(3)SnCH=C=CH(2), 3a) in the presence of Pd(PPh(3))(4) in toluene to afford the
      corresponding 1,7-enyne derivatives 4a-m in good to excellent yields. The
      catalytic reaction is highly regioselective, with the propargyl group adding to
      the carbon where the R group is attached and the allyl group adding to the carbon
      connected to the CN groups of activated olefins 1a-g. The present catalytic
      reaction is successfully extended to substituted arylethylidene-1,3-indanediones
      5a-j (RCH = (1,3-indanedione): R = C(6)H(5) (5a), p-ClC(6)H(4) (5b), p-BrC(6)H(4)
      (5c), p-OMeC(6)H(4) (5d), p-NO(2)C(6)H(4) (5e), p-CNC(6)H(4) (5f), p-biphenyl
      (5g), 1-naphthyl (5h), 2-thienyl (5i), and 2-benzo[b]furane-2-yl (5j)) and
      substituted 2,2-dimethyl-5-(arylethylidene)-1,3-dioxane-4,6-diones 7a,b (RCH =
      (1,3-dioxane-4,6-dione): R = p-NO(2)C(6)H(4) (7a), p-OMeC(6)H(4) (7b)). The three
      component assembling of these substrates with allylic chlorides (2a,b,d,e) and n
      tributylallenylstannane (n-Bu(3)SnCH=C=CH(2), 3a) proceeds smoothly to afford the
      corresponding 1,7-enyne derivatives 6a-m and 8a-d in good to excellent yields.
      The catalytic propargylallylation can be further applied to the activated dienes,
      C(6)H(5)CH=CH=CR(2) (R(2) = (CN)(2) (9a), 1,3-indanedione (9b), 2,2-dimethyl-1,3
      dioxane-4,6-dione (9c)), with allylic chlorides (2a,b,d) and allenylstannane 3a
      to give regio- and chemoselective 1,2-addition products 10a-h in good to
      excellent yields. A plausible mechanism based on an eta(1)-allenyl eta(3)-allyl
      palladium intermediate is proposed to account for the catalytic three-component
      reaction.

PMID- 15176831
TI  - Most stable conformation of the cyclopropane ring attached at a carbon atom in a
      1,2-dicarba-closo-dodecaborane(12) system.
AB  - We obtained two crystal structures of electronically interesting dicarba-closo
      dodecaborane(12)s (hereafter, "carboranes") substituted with a cyclopropyl group
      at a caged carbon atom, i.e., C-cyclopropyl-o-carborane (4) and C-cyclopropyl-o
      carboranylphenylmethanol (9), at 123 K. In these C-cyclopropyl-o-carboranes, the
      cyclopropyl group adopted a slightly twisted perpendicular conformation with
      respect to the electron-deficient carbon-carbon (C-C) bond axis in the o
      carborane cage. In contrast, it has previously been shown that a phenyl group
      substituted at the caged carbon atom, i.e., C-phenyl-o-carborane (3), is almost
      parallel to this axis at both 150 and 199 K. In other words, the pi system of the
      phenyl ring adopted an almost bisected conformation in 3. The preferred
      conformation of the cyclopropane ring in these C-cyclopropyl-o-carboranes was
      compared among the solid, the solution, and the gaseous states and was retained
      under the present conditions. Moreover, we found that the C-C bond length in the
      o-carborane cage not only varied along the rotation of the cyclopropyl group in 4
      but also was longer than that in 3, which bears a phenyl group at the dominant
      conformation. These phenomena may be related to homoconjugations between the
      caged o-carborane system that serves as an electron acceptor and the
      homoconjugative substituent that serves as an electron donor. In these C
      cyclopropyl-o-carboranes, two types of homoconjugations would result in a
      slightly twisted perpendicular conformation and 4 would be more strongly
      stabilized than would the phenyl derivative 3. On the basis of these studies, we
      propose the existence of a third type of strongly stabilizing interactive
      geometry for a cyclopropane ring in an o-carborane system.

PMID- 15176832
TI  - Electrochemical charging of a fullerene-functionalized self-assembled monolayer
      on au(111).
AB  - A fullerene derivative 10 with a terminal thiol group dissolves easily in common
      organic solvents and forms a densely packed self-assembled monolayer on gold
      surfaces. The functionalization of C(60) is based on the 1,3-dipolar
      cycloaddition of the azomethine ylide generated in situ from the corresponding
      aldehyde and N-methylglycine. The monolayers were characterized by grazing angle
      reflectance FTIR spectroscopy, scan tunneling microscopy, and cyclic voltammetry.
      The cyclic voltammogram of a SAM of 10 showed two well-resolved reversible
      cathodic waves corresponding to the first two one-electron reductions of the
      fullerene fragment.

PMID- 15176833
TI  - A stereochemical surprise at the late stage of the synthesis of fully N
      differentiated heparin oligosaccharides containing amino, acetamido, and N
      sulfonate groups.
AB  - The glucosamine residues in heparin-like glycosaminoglycans have been found to
      exist as amines, acetamides, and N-sulfonates. To develop a completely general,
      modular synthesis of heparin, three degrees of orthogonal nitrogen protection are
      required. Reported herein is a strategy for the synthesis of fully N
      differentiated heparin oligosaccharides in the context of target octasaccharide
      1, which contains an N-acetate, N-sulfonates, and a free amine. The protecting
      group scheme used in the synthesis blocked the N-acetate as a N-diacetate, the N
      sulfonates as azido groups, and the amine as a N-CBz; free hydroxyls were masked
      as benzyl ethers and O-sulfonates as acetate esters. Disaccharide and
      tetrasaccharide modules were synthesized using this strategy; however, the union
      of tetrasaccharide trichloroacetimidate 4 with disaccharide acceptor 5
      unexpectedly formed the undesired beta-linked glycoside in addition to the alpha
      linkage anticipated for iduronic acid nucleophiles, resulting in an inseparable
      6:1 alpha/beta mixture of products. Detailed studies into the basis for this
      unexpected result were conducted and are also reported.

PMID- 15176834
TI  - Intramolecular hydroboration of unsaturated phosphine boranes.
AB  - Homoallylic phosphine boranes undergo intramolecular hydroboration upon
      activation by triflic acid. The reaction occurs via an intermediate B
      trifluorosulfonyloxyborane complex such as 15, followed by S(N)1-like or S(N)2
      like displacement of the triflate leaving group, apparently leading to the
      formation of a four-center transition state. In the case of trisubstituted double
      bonds, as in the substrates 29 and 32, ionic hydrogenation of the alkene competes
      with internal hydroboration.

PMID- 15176835
TI  - On-resin native chemical ligation for cyclic peptide synthesis.
AB  - A novel cysteine derivative, N(alpha)-trityl-S-(9H-xanthen-9-yl)-l-cysteine [Trt
      Cys(Xan)-OH] has been introduced for peptide synthesis, specifically for
      application to a new strategy for the preparation of cyclic peptides. The
      following steps were carried out to synthesize the cyclic model peptide cyclo(Cys
      Thr-Abu-Gly-Gly-Ala-Arg-Pro-Asp-Phe): (i). side-chain anchoring of Fmoc-Asp-OAl
      via its free beta-carboxyl as a p-alkoxybenzyl ester to a solid support; (ii).
      stepwise chain elongation of the peptide by standard Fmoc/tBu solid-phase
      chemistry; (iii). removal of the N-terminal Fmoc group; (iv). coupling of Trt
      Cys(Xan)-OH; (v). selective Pd(0)-promoted cleavage of the C-terminal allyl
      ester; (vi). coupling of the C-terminal residue, i.e., H-Phe-SBzl, preactivated
      as a thioester; (vii). selective removal of the N(alpha)-Trt and S-Xan protecting
      groups under very mild acid conditions; (viii). on-resin cyclization by native
      chemical ligation in an aqueous milieu; and (ix). final acidolytic cleavage of
      the cyclic peptide from the resin. The strategy was evaluated for three supports:
      poly[N,N-dimethacrylamide-co-poly(ethylene glycol)] (PEGA), cross-linked
      ethoxylate acrylate resin (CLEAR), and poly(ethylene glycol)-polystyrene (PEG-PS)
      graft resin supports. For PEGA and CLEAR, the desired cyclic product was obtained
      in 76-86% overall yield with initial purities of approximately 70%, whereas for
      PEG-PS (which does not swell nearly as well in water), results were inferior.
      Solid-phase native chemical ligation/cyclization methodology appears to have
      advantages of convenience and specificity, which make it promising for further
      generalization.

PMID- 15176836
TI  - Photochemistry of fluorinated heterocyclic compounds. An expedient route for the
      synthesis of fluorinated 1,3,4-oxadiazoles and 1,2,4-triazoles.
AB  - The photochemistry of some 3-N-alkylamino-5-perfluoroalkyl-1,2,4-oxadiazoles in
      the presence of nitrogen nucleophiles such as ammonia and primary and secondary
      aliphatic amines has been investigated. The primary photolytic intermediate from
      the cleavage of the ring O-N bond follows two distinct and competing pathways
      leading to (i). 5-perfluoroalkyl-1,3,4-oxadiazoles, through the ring contraction
      ring expansion photoisomerization route favored by the presence of the base or
      (ii). 5-perfluoroalkyl-1,2,4-triazoles, through the intervention, as an internal
      nucleophile, of the exocyclic N-alkylamino moiety of the oxadiazole followed by
      the attack of the external nitrogen nucleophile and subsequent heterocyclization.
      Some comments on the photoreactivity of fluorinated oxadiazoles and on the
      applications of these photoprocesses in the synthesis of target fluorinated
      structures are emphasized. In this context, irradiations of 3
      perfluoroalkanoylamino-4-phenylfurazan in the presence of primary aliphatic
      amines are reconsidered as feasible one-pot synthetic methodologies toward
      fluorinated heterocycles. X-ray analysis of two representative products 1-methyl
      3-methylamino-5-perfluoroheptyl-1,2,4-triazole and 2-methylamino-5
      trifluoromethyl-1,3,4-oxadiazole confirmed the proposed structures and furnished
      interesting information on the crystal packing of these fluorinated five-membered
      heterocycles.

PMID- 15176837
TI  - Synthesis of optically pure (+)-puraquinonic acid and assignment of absolute
      configuration to natural (-)-puraquinonic acid. Use of radical cyclization for
      asymmetric generation of a quaternary center.
AB  - An asymmetric aldol reaction between aldehyde 31 and imide 32, followed at a
      later stage by ring-closing metathesis (38 --> 40), are key reactions used to
      make optically pure allylic alcohol 40. Radical cyclization of the derived Stork
      bromo acetals gives lactol ethers 43, which were degraded to generate a
      quaternary center carrying a methoxycarboxyl group (44 --> 47). Compound 47 was
      converted into (+)-puraquinonic acid; and comparison with a natural sample
      established that the configuration of the natural compound is 2R (1).

PMID- 15176838
TI  - A practical total synthesis of hapalosin, a 12-membered cyclic depsipeptide with
      multidrug resistance-reversing activity, by employing improved segment coupling
      and macrolactonization.
AB  - A practical total synthesis of hapalosin, a compound with multidrug resistance
      reversing activity, has been carried out using an unprecedented
      macrolactonization strategy. One of the features of the new approach is the
      straightforward and fully stereocontrolled access to the key gamma-amino beta
      hydroxy carboxylic acid subunit via an efficient acetate aldol addition reaction
      with N-methyl alpha-aminoaldehydes, which relies on a camphor-derived chiral
      lithium acetate enolate reagent. The scope of this aldol reaction is investigated
      and its potential application to the synthesis of other structurally related,
      biologically relevant compounds illustrated. Remarkably, the chiral tether in the
      resulting gamma-amino aldol adducts sterically protect the carbonyl group, thus
      avoiding intramolecular cyclization during the amino group deprotection and the
      subsequent segment coupling event. After successful segment coupling and smooth,
      clean release of the chiral auxiliary, a new macrolactonization protocol, based
      on the principle of double activation of both reactive sites, is applied, which
      leads to the 12-membered macrolactone hapalosin in unprecedented chemical
      efficiency.

PMID- 15176839
TI  - Ozonolysis of 1,4-cyclohexadienes in the presence of methanol and acid. Mechanism
      and intermediates in the conversion of 1,4-cyclohexadiene derivatives to beta
      keto esters.
AB  - Conditions for the preparation of beta-keto esters directly from 1,4
      cyclohexadiene derivatives are described. This procedure is a further step in the
      application of the synthetic methodology, which consists of the combination of
      Birch reduction of available benzene derivatives followed by ozonolysis. In this
      work, the syntheses of derivatives of dimethyl gamma-keto-alpha-aminoadipate and
      dimethyl beta-keto glutamate from the corresponding 1,4-cyclohexadiene
      derivatives are described. The latter compounds are prepared from phenylalanine
      and phenylglycine, respectively. The study of the ozonolysis of simple alkyl
      derivatives of 1,4-cyclohexadiene in the presence of methanol, both in the
      presence and absence of acid, helped to establish the mechanism of this reaction.
      The proximity of the two double bonds, which are cleaved, leads to the
      intermediate formation of 1,2-dioxolane derivatives that could be identified by
      NMR spectroscopy. It is shown that regardless of the regioselectivity of the
      cleavage of the primary ozonide, which is formed, all 1,2-dioxolane derivatives
      can lead to beta-keto esters. This is due to the equilibrium between these
      dioxolanes in the presence of methanol and acid.

PMID- 15176840
TI  - A short asymmetric synthesis of (+)-lyoniresinol dimethyl ether.
AB  - A short, efficient synthesis of the lignan (+)-lyoniresinol dimethyl ether is
      described. The synthesis is achieved by asymmetric photocyclization of an achiral
      dibenzylidenesuccinate to a chiral aryldihydronaphthalene. (-)-Ephedrine is used
      as a chiral auxiliary to bias the atropisomeric equilibrium in the
      dibenzylidenesuccinate prior to the photochemical reaction. The synthesis of the
      title compound was accomplished in five steps, and the final product was
      recrystallized to constant melting point and rotation.

PMID- 15176841
TI  - Fmoc-based synthesis of peptide alpha-thioesters using an aryl hydrazine support.
AB  - C-Terminal peptide thioesters are key intermediates in the
      synthesis/semisynthesis of proteins and of cyclic peptides by native chemical
      ligation. They are prepared by solid-phase peptide synthesis (SPPS) or
      biosynthetically by protein splicing techniques. Until recently, the chemical
      synthesis of C-terminal alpha-thioester peptides by SPPS was largely restricted
      to the use of Boc/Benzyl chemistry due to the poor stability of the thioester
      bond to the basic conditions required for the deprotection of the N(alpha)-Fmoc
      group. In the present work, we describe a new method for the SPPS of C-terminal
      thioesters using Fmoc/t-Bu chemistry. This method is based on the use of an aryl
      hydrazine linker, which is totally stable to conditions required for Fmoc-SPPS.
      When the peptide synthesis has been completed, activation of the linker is
      achieved by mild oxidation. This step converts the acyl hydrazine group into a
      highly reactive acyl diazene intermediate which reacts with an alpha-amino acid
      alkyl thioester (H-AA-SR) to yield the corresponding peptide alpha-thioester in
      good yield. This method has been successfully used to prepare a variety of
      peptide thioesters, cyclic peptides, and a fully functional Src homology 3 (SH3)
      protein domain.

PMID- 15176842
TI  - Stereoselective synthesis of atropisomeric korupensamines A and B utilizing
      planar chiral arene chromium complex.
AB  - Naphthyl tetrahydroisoquinoline alkaloids, atropisomeric korupensamines A and B
      and ent-korupensamine B, were synthesized by syn-selective cross-coupling of a
      planar chiral arene chromium complex with naphthylboronic acid and subsequent
      axial isomerization or tricarbonylchromium migration to the inverted arene face
      as a key step. Palladium(0)-catalyzed cross-coupling of planar chiral arene
      chromium complex 12 with naphthylboronic acid 9 gave syn-biaryl coupling product
      13. syn-Biaryl chromium complex 13 was heated in 1:1 mixture of di-n-butyl ether
      and 1,2-dichloroethane to give a face-inverted anti-biaryl chromium complex 14
      without axial isomerization. Korupensamine A was synthesized from the syn-biaryl
      chromium complex 13 via o-formyl syn-biaryl chromium complex 10, and ent
      korupensamine B was prepared from the face-inverted anti-biaryl chromium complex
      14. On the other hand, difluoro-substituted syn-biaryl chromium complex 40 with a
      formyl group afforded anti-biaryl chromium complex 41 containing a rotated
      central bond by heating in xylene. The chromium-complexed fluorine atom was
      easily substituted with an isopropoxy group by nucleophilic substitution. Use of
      these reactions allowed (+)-2-bromo-3,5-difluorobenzaldehyde chromium complex
      (37) as a single chiral source to be converted to atropisomeric korupensamines A
      and B, respectively.

PMID- 15176843
TI  - A survey of acid catalysis and oxidation conditions in the two-step, one-flask
      synthesis of meso-substituted corroles via dipyrromethanedicarbinols and pyrrole.
AB  - The reaction of dipyrromethanedicarbinols with pyrrole leading to meso
      substituted corroles was investigated to determine whether mild acid catalysts
      [Dy(OTf)(3), Yb(OTf)(3), Sc(OTf)(3), and InCl(3)] known to provide porphyrins
      from dipyrromethanecarbinol species while suppressing undesired reversibility
      (resulting in scrambling) are applicable to reactions affording corrole, and to
      explore the requirements of the oxidation step. We examined a model reaction
      leading to meso-triphenylcorrole (TPC) to survey the effect of acid catalyst,
      acid concentration, ratio of pyrrole to dipyrromethanedicarbinol, oxidant,
      oxidant quantity, and reaction time on the yield of TPC (by UV-vis) in reactions
      performed at room temperature in CH(2)Cl(2). Key to this survey was a
      modification of the well-known spectrophotometric method for monitoring reactions
      leading to porphyrin. The survey revealed that TPC could be prepared via a subset
      of the mild acid catalysts [Dy(OTf)(3) and Yb(OTf)(3)], and a preparative-scale
      reaction afforded an isolated yield of TPC of 49%, devoid of porphyrin.
      Suppression of reversible processes was further demonstrated by the synthesis of
      three corroles bearing different meso substituents in defined locations in
      isolated yields ranging from 50% to 80%. The reaction conditions were applicable
      to a dipyrromethanedicarbinol bearing electron-withdrawing pentafluorophenyl
      substituents-provided that the reaction time of the condensation step was
      increased. We identified circumstances under which DDQ can cause severe
      interference with the detection and isolation of some corroles, we found that the
      yield and purity of the corrole depend on judicious selection of oxidation
      conditions, and we assessed the sensitivity toward light of dilute solutions of
      the corroles prepared in this study.

PMID- 15176844
TI  - Microcionamides A and B, bioactive peptides from the philippine sponge Clathria
      (Thalysias) abietina.
AB  - Microcionamides A (1) and B (2) have been isolated from the Philippine marine
      sponge Clathria (Thalysias) abietina. These new linear peptides are cyclized via
      a cystine moiety and have their C-terminus blocked by a 2-phenylethylenamine
      group. Their total structures, including absolute stereochemistry, were
      determined by a combination of spectral and chemical methods. Compound 1 was
      shown to slowly isomerize about the C-36/C-37 double bond when stored in DMSO.
      Microcionamides A (1) and B (2) exhibited significant cytotoxicity against the
      human breast tumor cells lines MCF-7 and SKBR-3 and displayed inhibitory activity
      against Mycobacterium tuberculosis H(37)Ra.

PMID- 15176845
TI  - Asymmetric hydrogenation of o-alkoxy-substituted arylenamides.
AB  - A series of (2-alkoxyaryl)glycinols have been prepared in up to 97.8% ee by
      asymmetric hydrogenation with cationic rhodium Me-BPE or Me-DuPhos complexes.
      Others have shown that the presence of ortho substituents on related alpha
      arylenamides causes a decrease in enantioselectivity. However, in this study it
      was found that o-alkoxy alpha-arylenamides were reduced with high
      enantioselectivity irrespective of substituent size.

PMID- 15176846
TI  - Formation and electrochemical properties of a 1,4-diphosphafulvene including
      formal dimerization of phosphaallene.
AB  - Reactions of sterically protected 2-bromo-3-phenyl-1-phosphapropenes with bases
      such as tert-butyllithium and potassium tert-butoxide successfully afforded a
      bulky 1,4-diphosphafulvene (Mes = 2,4,6-tBu(3)C(6)H(2)) through a novel and
      formal dimerization pathway of 1-phosphaallene, together with small amounts of 3
      phenyl-1-phosphaallene and 3,4-diphosphanylidenecyclobutene. The structure of the
      1,4-diphosphafulvene was confirmed by X-ray crystallography indicating somewhat
      flattened phosphorus atoms due to the bulky Mes groups. The electrochemical
      properties of the 1,4-diphosphafulvene were investigated to show promising
      suitability as an electron donor, and indeed, it afforded a charge-transfer
      complex with TCNQ. Preparation and structural elucidation of an alkoxy
      functionalized 1-phosphaallene was also performed, and the effect of the alkoxy
      group on the 1-phosphaallene moiety was characterized.

PMID- 15176847
TI  - An Ireland-Claisen approach to lignans: synthesis of the putative structure of 5
      epi-eupomatilone-6.
AB  - A novel Ireland-Claisen approach to the putative structure of eupomatilone-6 is
      described. The rearrangement established the C3 and C4 stereocenters and
      concomitantly generated a vinyl epoxide. The C5 oxygen was installed by
      cyclization of the pentenoic acid carboxyl group onto the vinyl epoxide in an
      S(N)2' fashion to afford the C5-epi stereochemistry. The natural C5
      stereochemistry was accessed via a substrate directed dihydroxylation.

PMID- 15176848
TI  - N-vinyl-2-oxazolidinones: efficient chiral dienophiles for the [4 + 2]-based de
      novo synthesis of new N-2-deoxyglycosides.
AB  - Under smooth Eu(fod)(3)-catalyzed conditions, the inverse-electron demand hetero
      Diels-Alder reactions between enantiopure N-vinyl-2-oxazolidinones 1a-f and
      representative beta,gamma-unsaturated alpha-ketoesters proceed with a high degree
      of endo and facial diastereoselectivity. The elucidation of the stereostructure
      of these adducts, performed by X-ray analysis or chemical correlation, shows that
      the endo-selective cycloaddition process is facially controlled in favor of the
      (2S,4S)-adduct when starting from a (4S)-dienophile or vice versa. The specific
      interest of the adducts 10a-e, derived from (E)-4-tert-butoxymethylene pyruvic
      acid methyl ester 9, has been exemplified by the two-step and highly
      stereoselective transformation of these adducts into the new and valuable N-2
      deoxyglycosyl-oxazolidinones 12a-e, isolated in a pure diastereo- and
      enantiomeric form.

PMID- 15176849
TI  - Theoretical study of the nucleophilic 5-endo-trigonal cyclization of 1,1-difluoro
      1-alkenes.
AB  - The nucleophilic 5-endo-trigonal cyclization of 1,1-difluoro-1-alkenes has been
      studied at the B3LYP/6-31+G(d) level in an Onsager continuum model for DMF. The
      reaction takes an addition-elimination path. Both the transition-state structures
      and the IRC analyses suggest the delocalization of the negative charge to highly
      electronegative two fluorine atoms during the addition reaction is the origin of
      the high reactivity of 1,1-difluoro-1-alkenes. Judging from the activation
      energies, both dichloro and dibromo counterparts are much less reactive for 5
      endo-trigonal cyclization. In these substrates, the cyclization reaction is
      promoted by chlorine or bromine atom with their good leaving-group ability, and
      the addition of oxyanion to the pi-bond occurs along with the simultaneous
      elimination of halogen atom. The study on the cyclizations of beta-monofluoro-o
      hydroxystyrenes and beta-bromo-beta-fluoro counterparts shows that one fluorine
      atom is not enough to delocalize the negative charge in the addition step.

PMID- 15176850
TI  - Reactions of TFDA with ketones. synthesis of difluoromethyl 2,2
      difluorocyclopropyl ethers.
AB  - The sequential reaction of 2 equiv of difluorocarbene (generated from
      trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) by treatment with catalytic
      fluoride ion) with a series of electron-rich aromatic ketones and alpha,beta
      unsaturated ketones leads to the formation of difluoromethyl 2,2
      difluorocyclopropyl ethers in good yield.

PMID- 15176851
TI  - A catalytic asymmetric synthesis of chiral glycidic acid derivatives through
      chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid
      derivatives.
AB  - A novel and practical asymmetric synthesis of chiral glycidic acid derivatives
      involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key
      intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl
      (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a
      catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)
      7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and
      amides were epoxidized by the use of the same procedure to give the corresponding
      chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher
      enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of
      (E)-stilbene derivatives were observed and were proposed to be attributed to a
      dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates
      and those of the lactone moieties in the binaphthyl dioxirane.

PMID- 15176852
TI  - New resolution of 2-formyl-1,4-dhp derivatives using CIDR methodology. Facile
      access to new chiral tricyclic thiolactam.
AB  - (R)- and (S)-alpha-phenylethylamine (alpha-PEA: 7) have been used separately to
      resolve successfully a racemate 2-formyl-1,4-DHP derivative 4. The process was
      based on the difference of the solubility of both Schiff bases (6) since one of
      them crystallized out from the solution. These imines obtained by condensation of
      (R)-alpha-PEA (7) or (S)-alpha-PEA (7) with aldehyde (rac-4) were separated and
      analyzed by X-ray diffraction, and their exposition to an hydrochloric hydrolysis
      conditions led to the enantiopure (4R)-4 or (4S)-4 in excellent yields. Separate
      condensation of other chiral (8 and 13) and racemic (18) amino thiols as
      auxiliary with rac-4, (4S)-4, or (4R)-4 is accompanied by an in situ
      crystallization-induced dynamic resolution, whereby one distereomer of thiazole
      template selectively precipitates and can be isolated by simple filtration in 76
      82% yield with dr > 99. The thiazole species isolated from this process resulted
      from an amino aldehyde condensation followed by a spontaneous thiol-imine
      cycloaddition. Finally, the racemate (+/-)-(4R,2'R)-19 and the diastereomerically
      pure homologous (4S,2'R)-23 and (4R,2'S)-20 (obtained in good yields (79-82%)
      from 2-aminoethanethiol (18) and 2-formyl-1,4-DHP derivative rac-4, (4S)-4, or
      (4R)-4, respectively) were converted conveniently in a one-pot procedure into
      newly tricyclic thiolactams in the DHP series in racemic ((+/-)-(6R,9bR)-21, 72%
      yield)) and enantiopure ((6S,9bR)-24, 71% yield); (6R,9bS)-24, 70% yield) forms.

PMID- 15176853
TI  - Triplet diphenylcarbenes protected by (trimethylsilyl)ethynyl groups.
AB  - (2,4,6-Tribromophenyl)(4-tert-butyl-2,6-dimethylphenyl)diazomethane (1a) was
      shown to be stable enough to survive Sonogashira coupling reaction conditions at
      an elevated temperature and gave not only a para-monosubstituted product, (4
      trimethylsilylethynyl-2,6-dibromophenyl)(4-tert-butyl-2,6
      dimethylphenyl)diazomethane (1b), but also a disubstituted one, [2,4
      bis(trimethylsilylethynyl)-6-bromophenyl](4-tert-butyl-2,6
      dimethylphenyl)diazomethane (1c), and a trisubstituted product, [2,4,6
      tris(trimethylsilylethynyl)phenyl](4-tert-butyl-2,6-dimethylphenyl)diazomethane
      (1d). Triplet diphenylcarbenes (DPCs) generated by photolysis of those
      ethynylated diphenyldiazomethanes were characterized by ESR and UV-vis
      spectroscopies at low temperature and laser flash photolysis techniques in
      solution at room temperature. Although ESR data indicated that ethynyl groups at
      the ortho positions are likely to stabilize triplet DPCs both sterically and
      electronically more effectively than o-bromine groups, kinetic studies suggested
      that the stability of triplet DPCs is not increased by o-ethynyl groups, as
      opposed to o-bromine groups. It is likely that triplet DPCs decay by interacting
      with the o-ethynyl groups.

PMID- 15176854
TI  - Theoretical designs of singlet localized 1,3-diradicals.
AB  - Spin preference and S-T gaps of localized 1,3-diradicals were studied by an
      orbital phase theory and theoretical calculations. The orbital phase theory was
      applied to rationalize thermodynamic and kinetic stabilities of diradicals. We
      theoretically designed some singlet localized 1,3-diradicals, substituted
      trimethylenes, which are more stable than the lowest triplets. Some diradicals
      with the four-membered rings, 2,4-disilacyclobutane-1,3-diyls, were designed and
      shown to have singlet ground states and to be more stable than the sigma-bonded
      isomers, 2,4-disilabicyclo[1.1.0]butanes. The ab initio calculations supported
      predictions of the stable carbon-centered localized singlet 1,3-diradicals.

PMID- 15176855
TI  - Efficient crystallization-induced dynamic resolution of alpha-substituted
      carboxylic acids.
AB  - Herein we present a novel route to enantiomerically enriched chiral alpha
      substituted carboxylic acids by crystallization-induced dynamic resolution (CIDR)
      of their diastereomeric salts with chiral amines. Thus, the racemic alpha-bromo
      acid 3 is converted reliably with (1R,2S)-2-amino-1,2-diphenylethanol in the
      presence of a catalytic amount of tetrabutylammonium bromide into its R
      enantiomer 4 in 90% yield with 88% ee. Similarly, the racemic alpha-thiobenzoyl
      acid 5 could be resolved to 90% ee in 74% yield. Further enrichment to
      enantiomeric homogeneity could be achieved in both cases by crystallization. In a
      telescoped, two-step process, S-alpha-thiobenzoyl acid 6 (>or=99.6% ee) was
      prepared from the racemic bromide 3 in 63% yield. State-of-the-art parallel
      experimentation enabled rapid screening for suitable dynamic resolution
      conditions. Kinetic studies defined the influence of temperature,
      tetrabutylammonium bromide concentration, molarity, and solvent polarity on the
      resolution rate, product yield, and enantiomeric excess.

PMID- 15176856
TI  - New stereoselective preparation of (Z)-3-perfluoroalkyl-3-magnesiated enoates by
      an iodine-magnesium exchange reaction.
AB  - (Z)-Ethyl-3-perfluoroalkyl-3-magnesiated crotonates were prepared from (Z)-ethyl
      3-perfluoroalkyl-3-iodo enoates by iodine-magnesium exchange reaction with
      isopropylmagnesium bromide in THF at -78 degrees C. These new reagents reacted
      with a range of electrophiles, leading to polyfunctional products bearing a
      perfluoroalkyl group.

PMID- 15176857
TI  - A novel and highly efficient synthetic route to unsymmetrical organoselenides
      using cesium bases.
AB  - A new and convenient one-pot method for the preparation of unsymmetrical
      selenides has been developed. In the presence of cesium hydroxide, molecular
      sieves, and DMF, benzeneselenol undergoes direct alkylation with various alkyl
      halides for the synthesis of alkyl phenyl selenides in moderate to excellent
      yields. Another method to prepare unsymmetrical organoselenides was also
      completed by coupling terminal alkynes with benzeneselenyl bromide. As an
      application, the synthesis of a selenopeptide was also accomplished. Furthermore,
      this methodology was extended to the synthesis of an organoselenide on solid
      support.

PMID- 15176858
TI  - Benzotriazolyl-mediated 1,2-shifts of electron-rich heterocycles.
AB  - The anion formed from the lithiation of 1-[(methylthio)methyl]-1H-benzotriazole 1
      with n-BuLi adds to heteroaryl ketones to give 2-benzotriazolyl alcohols 3a-m.
      Thermolysis of 3a-g in the presence of zinc bromide induces a 1,2-shift of
      heteroaromatic groups to form ketones 4a-g. By contrast, in the rearrangement of
      2-benzotriazolyl alcohols 3h,i,k-m migration of the phenyl group rather than the
      corresponding heteroaromatic groups occurred to give ketones 4h,i,k-m.

PMID- 15176859
TI  - Palladium-catalyzed conversion of beta,gamma-unsaturated silyl sulfinates into
      (E)-alkenes: asymmetric synthesis of polypropionate fragments.
AB  - At low temperature, 1-alkoxy-1,3-dienes add to sulfur dioxide activated by a
      Lewis or protic acid generating zwitterionic intermediates that can be quenched
      by enoxysilanes. The resulting beta,gamma-unsaturated silyl sulfinates can be
      desilylated by 1:1 Pd(OAc)(2)/PPh(3) catalyst, liberating the corresponding
      beta,gamma-unsaturated sulfinic acids that undergo smooth and highly
      stereoselective retro-ene eliminations of sulfur dioxide. The method has been
      applied to generate enantiomerically pure polypropionate fragments.

PMID- 15176860
TI  - Cyclopentane construction by Rh-catalyzed intramolecular C-h insertion: relative
      reactivity of a range of catalysts.
AB  - The preparation and Rh-mediated cyclization of the alpha-diazoester 1 are
      outlined, and its utility in determining the elements that contribute to the
      reactivity of the intermediate Rh-carbenoid is presented. The rate of
      disappearance of diazo ester 1 catalyzed by several representative Rh(II)
      complexes was determined. The observed relative rate constants for the reaction
      of the Rh(II) complexes with 1 varied over a range of >10(7). The reactivity of
      the Rh-carbenoid intermediate was explored using the ratio of the sum of (3 + 4 +
      5) to 2 (cyclization vs elimination), the ratio of 3 to the sum of (4 + 5)
      (chemoselectivity), and the ratio of 4 to 5 (diastereoselectivity). It is
      striking that these four measures of reactivity were found to be independent of
      each other.

PMID- 15176861
TI  - The photochemical addition of 2,2,2-trifluoroethanol to methoxy-substituted
      stilbenes.
AB  - The excited-state lifetime of the trans-stilbene chromophore in acetonitrile is
      prolonged by methoxy substituents in the meta positions. The long-lived singlet
      excited state of trans-3,5-dimethoxystilbene (trans-2d) is quenched upon the
      addition of 2,2,2-trifluoroethanol (TFE), and the Markovnikov ether is observed
      as the major product from steady-state irradiations. The results indicate that
      the reaction pathway proceeds through a carbocation intermediate.

PMID- 15176862
TI  - Cross silyl benzoin additions catalyzed by lanthanum tricyanide.
AB  - From a screen of (cyanide)metal complexes, an improved catalyst for the cross
      silyl benzoin addition was discovered. Several M(CN)(3) complexes (M = Ce, Er,
      Sm, Y, Yb, La) were evaluated and lanthanum tricyanide was identified as the
      optimal catalyst. The catalyst, prepared in situ from LaCl(3), effects the
      selective coupling of aryl and alkyl acylsilanes with aryl, heteroaryl,
      alpha,beta-unsaturated, and aliphatic aldehydes. The reactions occur at ambient
      temperature in less than 5 min to provide, depending on the workup, alpha-hydroxy
      or alpha-silyloxy ketones in 48-93% isolated yield.

PMID- 15176864
TI  - Antibodies and genetically engineered related molecules: production and
      purification.
AB  - Antibodies and antibody derivatives constitute 20 % of biopharmaceutical products
      currently in development, and despite early failures of murine products, chimeric
      and humanized monoclonal antibodies are now viable therapeutics. A number of
      genetically engineered antibody constructions have emerged, including molecular
      hybrids or chimeras that can deliver a powerful toxin to a target such as a tumor
      cell. However, the general use in clinical practice of antibody therapeutics is
      dependent not only on the availability of products with required efficacy but
      also on the costs of therapy. As a rule, a significant percentage (50-80%) of the
      total manufacturing cost of a therapeutic antibody is incurred during downstream
      processing. The critical challenges posed by the production of novel antibody
      therapeutics include improving process economics and efficiency, to reduce costs,
      and fulfilling increasingly demanding quality criteria for Food and Drug
      Administration (FDA) approval. It is anticipated that novel affinity-based
      separations will emerge from the development of synthetic ligands tailored to
      specific biotechnological needs. These synthetic affinity ligands include
      peptides obtained by synthesis and screening of peptide combinatorial libraries
      and artificial non-peptidic ligands generated by a de novo process design and
      synthesis. The exceptional stability, improved selectivity, and low cost of these
      ligands can lead to more efficient, less expensive, and safer procedures for
      antibody purification at manufacturing scales. This review aims to highlight the
      current trends in the design and construction of genetically engineered
      antibodies and related molecules, the recombinant systems used for their
      production, and the development of novel affinity-based strategies for antibody
      recovery and purification.

PMID- 15176865
TI  - Industrial potential of organic solvent tolerant bacteria.
AB  - Most bacteria and their enzymes are destroyed or inactivated in the presence of
      organic solvents. Organic solvent tolerant bacteria are a relatively novel group
      of extremophilic microorganisms that combat these destructive effects and thrive
      in the presence of high concentrations of organic solvents as a result of various
      adaptations. These bacteria are being explored for their potential in industrial
      and environmental biotechnology, since their enzymes retain activity in the
      presence of toxic solvents. This property could be exploited to carry out
      bioremediation and biocatalysis in the presence of an organic phase. Because a
      large number of substrates used in industrial chemistry, such as steroids, are
      water-insoluble, their bioconversion rates are affected by poor dissolution in
      water. This problem can be overcome by carrying out the process in a biphasic
      organic-aqueous fermentation system, wherein the substrate is dissolved in the
      organic phase and provided to cells present in the aqueous phase. In
      bioprocessing of fine chemicals such as cis-diols and epoxides using such
      cultures, organic solvents can be used to extract a toxic product from the
      aqueous phase, thereby improving the efficiency of the process. Bacterial strains
      reported to grow on and utilize saturated concentrations of organic solvents such
      as toluene can revolutionize the removal of such pollutants. It is now known that
      enzymes display striking new properties in the presence of organic solvents. The
      role of solvent-stable enzymes in nonaqueous biocatalysis needs to be explored
      and could result in novel applications.

PMID- 15176866
TI  - Criteria to design green enzymatic processes in ionic liquid/supercritical carbon
      dioxide systems.
AB  - Five different ionic liquids (ILs) based on quaternary ammonium cations, with
      functional side chains ((3-hydroxypropyl)-trimethyl-, (3-cyanopropyl)-trimethyl-,
      butyl-trimethyl-, (5-cyanopentyl)-trimethyl- and hexyl-trimethyl-) associated
      with the same anion (bis(trifluoromethane)sulfonyl amide)), were synthesized, and
      their suitability for Candida antarctica lipase B (CALB)-catalyzed ester
      synthesis in IL/supercritical carbon dioxide (scCO(2)) biphasic systems was
      assayed. Catalytic efficiency of the system has been analyzed as a function of
      both enzyme properties and mass-transfer phenomena criteria. First, the
      suitability of these ILs as enzymic reaction media was tested for the kinetic
      resolution of rac-phenylethanol. All ILs were found to be suitable media for
      enzyme catalysis, the best catalytic parameter (5.3 U/mg specific activity, 94.9%
      selectivity) being obtained for the (5-cyanopentyl)-trimethylammonium. Second,
      enzyme stability in all of the ILs was studied at 50 degrees C over a period of
      50 days, and data were analyzed by a two-step kinetic deactivation model. All of
      the ILs were shown to act as stabilizing agents with respect to hexane, producing
      an increase in the free energy of deactivation (to 25 kJ/mol protein) and an
      improvement in the half-life time of the enzyme (2000-fold), which agrees with
      the observed increased hydrophobicity of the cation alkyl side chain (measured by
      Hansen's solubility parameter, delta). By using two different CALB-IL systems
      with different hydrophobicity in the cation, continuous processes to synthesize
      six different short chain alkyl esters (butyl acetate, butyl propionate, butyl
      butyrate, hexyl propionate, hexyl butyrate, and octyl propionate) in scCO(2) at
      10 MPa and 50 degrees C were carried out. Both rate-limiting parameters
      (synthetic activity and scCO(2)-ILs mass-transfer phenomena) were related with
      the delta-parameter of the ILs-alkyl chain and reagents.

PMID- 15176867
TI  - Modeling the quorum sensing regulatory network of human-pathogenic Pseudomonas
      aeruginosa.
AB  - The biochemical network underlying quorum sensing in human-pathogenic Pseudomonas
      aeruginosa is one of the best characterized. Mathematical modeling is required to
      untangle the complexity of its architecture and dynamics. We present a
      qualitative model of the P. aeruginosa quorum-sensing network including
      interactions between the las and rhl modules, the signaling molecule PQS and the
      regulatory proteins Mvfr and VfR. Simulations exemplify the model to reproduce
      natural network behavior and suggest quorum-sensing responses to pharmacological
      interference.

PMID- 15176868
TI  - Selective leakage of host-cell proteins during high-cell-density cultivation of
      recombinant and non-recombinant Escherichia coli.
AB  - Significant leakage of host-cell proteins into the culture medium occurred during
      high-cell-density cultivation of E. coli. Identification of these medium proteins
      revealed almost exclusively a periplasmic origin. Release of periplasmic proteins
      into the culture medium was observed throughout the entire cultivation of
      recombinant or non-recombinant cells. Leakage was intensified, however, in the
      final part of high-cell-density cultures (>100 g L(-)(1) dry cell mass) or when a
      temperature upshift was used for induction of recombinant protein synthesis.
      After temperature upshift, formation rates and residual cellular concentrations
      of periplasmic proteins declined with individual rates; e.g., the cellular
      content of the large periplasmic dipeptide binding protein DppA (57.4 kDa)
      started to decline about 4 h after the temperature upshift, whereas the smaller
      periplasmic d-galactose/d-glucose binding protein MglB (33.4 kDa) was already
      lost during the first hour after the upshift. In addition to periplasmic
      proteins, the osmotic-shock-sensitive heat-shock protein DnaK was found in
      significantly higher proportion in the cell-free medium of the temperature
      challenged culture than other cytoplasmic proteins. Cell lysis was not observed
      even after prolonged cultivation. Thus, loss of a subset of cellular proteins of
      mainly periplasmic origin ordinarily occurs during cultivation and is intensified
      through stressful conditions in high-cell-density cultures. The selective release
      of cellular proteins of periplasmic origin offers the opportunity to simplify the
      downstream processing of recombinant proteins directed to the periplasm of E.
      coli.

PMID- 15176869
TI  - Improvement of cellulose-degrading ability of a yeast strain displaying
      Trichoderma reesei endoglucanase II by recombination of cellulose-binding
      domains.
AB  - To improve the cellulolytic activity of a yeast strain displaying endoglucanase
      II (EGII) from the filamentous fungus Trichoderma reesei QM9414, the genes
      encoding the cellulose-binding domain (CBD) of EGII, cellobiohydrolase I (CBHI)
      and cellobiohydrolase II (CBHII) from T. reesei QM9414, were fused with the
      catalytic domain of EGII and expressed in Saccharomyces cerevisiae. Display of
      each of the recombinant EGIIs was confirmed using immunofluorescence microscopy.
      In the case of EGII-displaying yeast strains in which the CBD of EGII was
      replaced with the CBD of CBHI or CBHII, the binding affinity to Avicel and
      hydrolytic activity toward phosphoric acid swollen Avicel were similar to that of
      a yeast strain displaying wild-type EGII. On the other hand, the three yeast
      strains displaying EGII with two or three tandemly aligned CBDs showed binding
      affinity and hydrolytic activity higher than that of the yeast strain displaying
      wild-type EGII. This result indicates that the hydrolytic activity of yeast
      strains displaying recombinant EGII increases with increased binding ability to
      cellulose.

PMID- 15176870
TI  - Enhanced isoamyl acetate production upon manipulation of the acetyl-CoA node in
      Escherichia coli.
AB  - Coenzyme A (CoA) and its thioester derivative acetyl-Coenzyme A (acetyl-CoA)
      participate in over 100 different reactions in intermediary metabolism of
      microorganisms. Earlier results indicated that overexpression of upstream rate
      limiting enzyme pantothenate kinase with simultaneous supplementation of
      precursor pantothenic acid to the culture media increased intracellular CoA
      levels significantly ( approximately 10-fold). The acetyl-CoA levels also
      increased ( approximately 5-fold) but not as much as that of CoA, showing that
      the carbon flux from the pyruvate node is rate-limiting upon an increase in CoA
      levels. In this study, pyruvate dehydrogenase was overexpressed under elevated
      CoA levels to increase carbon flux from pyruvate to acetyl-CoA. This coexpression
      did not increase intracellular acetyl-CoA levels but increased the accumulation
      of extracellular acetate. The production of isoamyl acetate, an industrially
      useful compound derived from acetyl-CoA, was used as a model reporter system to
      signify the beneficial effects of this metabolic engineering strategy. In
      addition, a strain was created in which the acetate production pathway was
      inactivated to relieve competition at the acetyl-CoA node and to efficiently
      channel the enhanced carbon flux to the ester production pathway. The synergistic
      effect of cofactor CoA manipulation and pyruvate dehydrogenase overexpression in
      the acetate pathway deletion mutant led to a 5-fold increase in isoamyl acetate
      production. Under normal growth conditions the acetate pathway deletion mutant
      strains accumulate intracellular pyruvate, leading to excretion of pyruvate.
      However, upon enhancing the carbon flux from pyruvate to acetyl-CoA, the
      excretion of pyruvate was significantly reduced.

PMID- 15176871
TI  - Development and validation of a kinetic model for enzymatic saccharification of
      lignocellulosic biomass.
AB  - A multireaction kinetic model was developed for closed-system enzymatic
      hydrolysis of lignocellulosic biomass such as corn stover. Three hydrolysis
      reactions were modeled, two heterogeneous reactions for cellulose breakdown to
      cellobiose and glucose and one homogeneous reaction for hydrolyzing cellobiose to
      glucose. Cellulase adsorption onto pretreated lignocellulose was modeled via a
      Langmuir-type isotherm. The sugar products of cellulose hydrolysis, cellobiose
      and glucose, as well as xylose, the dominant sugar prevalent in most
      hemicellulose hydrolyzates, were assumed to competitively inhibit the enzymatic
      hydrolysis reactions. Model parameters were estimated from experimental data
      generated using dilute acid pretreated corn stover as the substrate. The model
      performed well in predicting cellulose hydrolysis trends at experimental
      conditions both inside and outside the design space used for parameter estimation
      and can be used for in silico process optimization.

PMID- 15176872
TI  - Serial 13C-based flux analysis of an L-phenylalanine-producing E. coli strain
      using the sensor reactor.
AB  - With the aid of the recently developed Sensor reactor system, a series of three
      subsequent (13)C labeling experiments was performed mirroring the l-phenylalanine
      (l-Phe) production phase of a recombinant E. coli strain that was cultivated
      under industry-like conditions in a 300 L bioreactor. On the basis of the data
      from NMR labeling analysis, three subsequent flux patterns were successfully
      derived monitoring the l-Phe formation during an observation window from 14 to
      23.3 h process time. Linear programming was performed to identify optimal flux
      patterns for l-Phe formation. Additionally, flux sensitivity analysis was used to
      identify the most promising metabolic engineering target. As a result, high rates
      of phosphoenolpyruvate (PEP) to pyruvate (PYR) conversion were identified as the
      most important reason for deterioration of the l-Phe/glucose yield from 20 to
      finally 11 mol %. Considering the characteristics of the enzyme kinetics
      involved, the working hypothesis was formulated that phosphoenolpyruvate synthase
      activity was increasingly hampered by rising oxaloacetate and 2-oxoglutarate
      concentrations, while at the same time pyruvate kinase activity arose due to
      activation by fructose 1,6-diphosphate. Hence, pps overexpression should be
      performed to optimize the existing production strain.

PMID- 15176873
TI  - Effect of binary combinations of selected toxic compounds on growth and
      fermentation of Kluyveromyces marxianus.
AB  - The inhibitory effects of various lignocellulose degradation products on glucose
      fermentation by the thermotolerant yeast Kluyveromyces marxianus were studied in
      batch cultures. The toxicity of the aromatic alcohol catechol and two aromatic
      aldehydes (4-hydroxybenzaldehyde and vanillin) was investigated in binary
      combinations. The aldehyde furfural that usually is present in relatively high
      concentration in hydrolyzates from pentose degradation was also tested.
      Experiments were conducted by combining agents at concentrations that
      individually caused 25% inhibition of growth. Compared to the relative toxicity
      of the individual compounds, combinations of furfural with catechol and 4
      hydroxybenzaldehyde were additive (50% inhibition of growth). The other binary
      combinations assayed (catechol with 4-hydroxybenzaldehyde, and vanillin with
      catechol, furfural, or 4-hydroxybenzaldehyde) showed synergistic effect on
      toxicity and caused a 60-90% decrease in cell mass production. The presence of
      aldehydes in the fermentation medium strongly inhibited cell growth and ethanol
      production. Kluyveromyces marxianus reduces aldehydes to their corresponding
      alcohols to mitigate the toxicity of these compounds. The total reduction of
      aldehydes was needed to start ethanol production. Vanillin, in binary
      combination, was dramatically toxic and was the only compound for which
      inhibition could not be overcome by yeast strain assimilation, causing a 90%
      reduction in both cell growth and fermentation.

PMID- 15176874
TI  - Modeling the inhibitor activity and relative binding affinities in enzyme
      inhibitor-protein systems: application to developmental regulation in a PG-PGIP
      system.
AB  - Within a number of classes of hydrolytic enzymes are certain enzymes whose
      activity is modulated by a specific inhibitor-protein that binds to the enzyme
      and forms an inactive complex. One unit of a specific inhibitor-protein activity
      is often defined as the amount necessary to inhibit one unit of its target enzyme
      by 50 %. No objective quantitative means is available to determine this point of
      50 % inhibition in crude systems such as those encountered during purification.
      Two models were derived: the first model is based on an irreversible binding
      approximation, and the second, or equilibrium, model is based on reversible
      binding. The two models were validated using the inhibition data for the
      polygalacturonase-polygalacturonase-inhibiting protein (PG-PGIP) system. Theory
      and experimental results indicate that the first model can be used for inhibitor
      protein activity determination and the second model can be used for inhibitor
      protein activity determination as well as for comparison of association constants
      among enzymes and their inhibitor-proteins from multiple sources. The models were
      used to identify and further clarify the nature of a differential regulation of
      expression of polygalacturonase-inhibiting protein in developing cantaloupe
      fruit. These are the first relations that provide for an objective and
      quantitative determination of inhibitor-protein activity in both pure and crude
      systems. Application of these models should prove valuable in gaining insights
      into regulatory mechanisms and enzyme-inhibitor-protein interactions.

PMID- 15176875
TI  - Pilot-plant-scale outdoor mixotrophic cultures of Phaeodactylum tricornutum using
      glycerol in vertical bubble column and airlift photobioreactors: studies in fed
      batch mode.
AB  - Pilot-scale (0.19 m column diameter, 2 m tall, and 60 L working volume) outdoor
      vertical bubble column (BC) and airlift photobioreactors (a split-cylinder (SC)
      and a draft-tube airlift device (DT)) were compared for fed-batch mixotrophic
      culture of the microalga Phaeodactylum tricornutum UTEX 640. The cultures were
      started photoautotrophically until the onset of a quasi-steady-state biomass
      concentration of 3.4 g L(-)(1). After this, the cultures were supplemented with
      organic nutrient (glycerol 0.1 M) and a reduced nitrogen source, resulting in an
      immediate growth rate boost, which was repeated with successive additions of
      nutrients in all three photobioreactors. During this period the biomass
      productivity was enhanced compared to photoautotrophic cultures in the three
      reactors, although differences were found among them. These could be attributed
      to the different hydrodynamic behavior influencing the transport phenomena inside
      the cultures. A 25.4 g L(-)(1) maximum biomass concentration was attained in the
      SC. Further additions of nutrients did not promote any more growth. The
      consumption of glycerol was quantitative in the first additions but slowed at
      high biomass concentration, suggesting that a minimum amount of light is needed
      to sustain growth. No significant effect of the supplied organic nutrient on
      carotenoids and chlorophylls content was observed, although it had a profound
      effect on the fatty acid composition. Eicosapentaenoic acid (EPA) content was
      increased up to 3% (DW) in mixotrophic growth, giving a productivity of 56 mg L(
      )(1) d(-)(1), a significant increase compared to the photoautotrophic control,
      which yielded a maximum EPA content of 1.9% (DW) and a productivity of 18 mg L(
      )(1) d(-)(1). The maximum biomass and EPA volumetric yields obtained in this work
      are comparable with those reported for commercial photoautotrophic monoculture of
      large quantities of P. tricornutum in closed continuous-run tubular loop
      bioreactors with tubes that are typically less than 0.08 m in diameter. When the
      comparison is established in terms of productivities based on the land area
      occupied, the vertical airlift and bubble-column bioreactors are extraordinarily
      more productive.

PMID- 15176876
TI  - Production of phytase (myo-inositolhexakisphosphate phosphohydrolase) by
      Aspergillus niger van Teighem in laboratory-scale fermenter.
AB  - The growth and production pattern of phytase by a filamentous fungus, Aspergillus
      niger van Teighem, were studied in submerged culture at varying agitation rates
      and controlled and uncontrolled pH conditions. Allowing the initial culture to
      grow under neutral condition with subsequent decline in pH resulted in increased
      phytase productivity. A maximum of 141 nkat/mL phytase was obtained when the
      broth pH was maintained at pH 2.5 as compared to 17 nkat/mL units at controlled
      pH 5.5. The culture morphology and rheological properties of the fermentation
      broth significantly varied with the agitation rate. The volumetric oxygen
      transfer coefficient was determined at different phases of fungal growth during
      batch fermentation using static gassing out and dynamic gassing out methods. The
      oxygen transfer coefficient (k(L)a) of the fermenter was found to be 125 h(-)(1)
      at 500 rpm as compared to 38 h(-)(1) at 200 rpm. The oxygen transfer rates at
      different phases of growth were significantly affected by cell mass concentration
      and fungal morphology. During the course of fermentation there was a gradual
      decline of k(L)a from 97 h(-)(1) on day 2 to 63 h(-)(1) on day 6 of fermentation,
      after which no significant change was observed. The degree of agitation
      considerably influenced the culture morphology where shear thinning of
      filamentous fungus was observed with the increase in agitation.

PMID- 15176877
TI  - Effect of washing on yield in one- and two-step steam pretreatment of softwood
      for production of ethanol.
AB  - Two-step steam pretreatment of softwood on laboratory scale has previously been
      shown to result in higher yields than one-step steam pretreatment. In this study,
      these results are verified on a larger scale. In an industrial process filtration
      and washing of the material between the two pretreatment steps are difficult
      without release of pressure. A worst case without filtration or washing was thus
      investigated to determine the influence of poor washing on the yield of sugars
      and the formation of byproducts. Steam pretreatment with SO(2) impregnation was
      investigated using three different procedures. One-step steam pretreatment was
      performed at 215 degrees C for 5 min. Two different kinds of two-step steam
      pretreatment were performed at 190 degrees C for 2 min in the first step and at
      210 degrees C for 5 min in the second step. In one case the slurry obtained after
      the first pretreatment step was separated into a liquid and a solid phase, where
      the water-insoluble solid material was washed with water and then used for
      pretreatment in the second step. In the other case of two-step steam
      pretreatment, neither separation nor washing was performed. The pretreated
      material was evaluated using both enzymatic hydrolysis and fed-batch simultaneous
      saccharification and fermentation. Both two-step steam pretreatment process
      configurations investigated resulted in higher yields of ethanol (300 L/ton) than
      one-step steam pretreatment (227 L/ton). Separation and washing of the material
      between the pretreatment steps in the two-step steam pretreatment process did not
      improve the overall sugar yield, although the formation of sugar degradation
      products was reduced.

PMID- 15176878
TI  - Microfluidic PDMS (polydimethylsiloxane) bioreactor for large-scale culture of
      hepatocytes.
AB  - Microfluidics could provide suitable environments for cell culture because of the
      larger surface-to-volume ratio and fluidic behavior similar to the environments
      in vivo. Such microfluidic environments are now used to investigate cell-to-cell
      interactions and behaviors in vitro, emulating situations observed in vivo, for
      example, microscale blood vessels modeled by microfluidic channels. These
      emulated situations cannot be realized by conventional technologies. In our
      previous works, microfluidic channels composed of two PDMS
      (poly(dimethylsiloxane)) layers were successfully used for Hep G2 cell culture.
      To achieve physiologically meaningful functions in vitro, a culture with a larger
      number of cells and higher density must be performed. This will require
      bioreactors with larger surface areas for cell attachment and sufficient amounts
      of oxygen and nutrition supply. For those purposes, we fabricated a bioreactor by
      stacking 10 PDMS layers together, i.e., four cell culture chambers, and a chamber
      dedicated to the oxygen supply inserted in the middle of the 10-stacked layers.
      The oxygen supply chamber is separated from the microfluidic channels for the
      culture medium perfusion by thin 300-microm PDMS walls. The high gas permeability
      of PDMS allows oxygen supply to the microfluidic channels through the thin walls.
      On the basis of the measurement of glucose consumption and albumin production, it
      is shown that cellular activity exhibits a gradual increase and saturation
      throughout the culture. We clearly observed that in the case of the microfluidic
      bioreactor for large-scale cultures, the oxygen chamber is indispensable to
      achieve longer and healthy cultures. In the present bioreactor, the cell density
      was found to be about 3-4 x 10(7) cells/cm(3), which is in the same order of
      magnitude as the conventional macroscale bioreactors. Consequently, by stacking
      single culture chambers and oxygen chambers in between, we could have a scalable
      method to realize the microfluidic bioreactor for large-scale cultures.

PMID- 15176879
TI  - Lipase-catalyzed ethanolysis of borage oil: a kinetic study.
AB  - Ethanolysis of borage oil catalyzed by two commercial lipases (from Pseudomonas
      cepacia and Candida antarctica) was studied using two different methodologies.
      Multiresponse models derived from a generalized Michaelis-Menten mechanism were
      utilized to describe the rates of formation of ethyl esters of the primary fatty
      acids present in the precursor oil. The relative rate constants determined for
      each of the fatty acid residues indicated that both lipases discriminate against
      release of gamma-linolenic acid residues under the reaction conditions studied.
      However, both lipases also released some of the residues located at the sn-2
      position, indicating that for the experimental conditions studied, both lipases
      are nonspecific. Moreover, inactivation of Novozym 435 was rapid. Because the
      half-life of this enzyme (ca. 2.2 h) is comparable to the half-life of the
      reaction, the intrinsic reaction rate and enzyme deactivation must both be
      considered in modeling the kinetics.

PMID- 15176880
TI  - Recovery of ammonium lactate and removal of hardness from fermentation broth by
      nanofiltration.
AB  - Nanofiltration (NF) was investigated as an alternative to desalting
      electrodialysis (ED) and ion exchange for the recovery of ammonium lactate from
      fermentation broth. Three commercial NF membranes, NF45, NF70, and NTR-729HF,
      were characterized with 50 mM NaCl, MgSO(4), and glucose solutions. NF45 membrane
      was selected because it showed the lowest rejection of monovalent ion, the
      highest rejection of divalent ion, and the highest rejection of nonpolar
      molecule. Effects of the operating pressure were investigated in a range of 100
      400 psig, on the flux, lactate recovery, and glucose and magnesium removal from a
      real fermentation broth containing about 1.0 M of ammonium lactate. The flux and
      recovery rate increased linearly with the pressure. However, lactate rejection
      also increased with the pressure, lowering the recovery yield. More magnesium
      ions and glucose were rejected as the pressure was increased, and at 400 psig,
      for example, magnesium ion was almost completely rejected, highlighting the
      chance of obviating the necessity of ion exchange to remove hardness, by using NF
      instead of desalting ED. Membrane fouling was not so severe as expected,
      considering the complex nature and a rather high concentration of the
      fermentation broth treated.

PMID- 15176881
TI  - Enantioselective affinity chromatography of a chiral drug by crystalline and
      carrier-bound antibody fab fragment.
AB  - An antibody Fab fragment, ENA5His, capable of enantioselective affinity
      chromatographic separation of a chiral drug, finrozole, was stabilized against
      organic solvents by chemical cross-linking. High concentration of methanol is
      needed to release the bound drug from the antibody fragment. However, in native
      form the antibody fragment is unstable at these conditions. We used cross-linked
      protein crystal technology to stabilize the antibody fragment molecule.
      Glutaraldehyde cross-linked ENA5His crystals (CLAC) packed in a column separated
      pure enantiomers from the racemic mixture of the drug. CLAC was totally stable at
      the elution conditions, enabling reuse of the immunoaffinity column packed with
      CLAC. However, the specific drug enantiomer binding capacity of CLAC was only 50%
      of the corresponding capacity of immobilized ENA5His. We were also able to cross
      link immobilized ENA5His by glutaraldehyde. This method produced a protein matrix
      with high activity and stability in the elution conditions.

PMID- 15176882
TI  - In situ and Ex situ adsorption and recovery of betalains from hairy root cultures
      of Beta vulgaris.
AB  - Various adsorbents were screened for in situ recovery of betalain pigments
      effluxed from hairy root cultures of red beet, Beta vulgaris. Alumina/silica
      (1:1) appeared ideal, showing in situ adsorption of 97% in a unit time of 30 min
      accounting for in situ recovery of 71.39% of the total betalaine effluxed. Other
      adsorbents such as Amberlite series (XAD-2 and -4), cyclodextrin, maltodextrin,
      dextrin white, and starches such as wheat starch and corn starch exhibited very
      poor in situ adsorption properties. Pretreatment of adsorbents with methanol
      significantly improved the adsorption capacities of some of the adsorbents, with
      a highest adsorption of 97.2% for alumina followed by alumina/silica (1:1) and
      higher adsorption by XAD-2 and -4. Complete in situ adsorption equilibrium was
      reached in 20 min for a solution containing 2.5 mg mL(-)(1) of betalain in
      adsorbents alumina, silica, and a mixture of alumina and silica. In situ betalain
      adsorption parameters for alumina/silica were determined using the Langmuir
      isotherm model where the adsorption capacity was found to be 0.174 mg g(-)(1) and
      the adsorption energy was 0.9 at pH 5.5 and 25 degrees C. Desorption of pigments
      from the adsorbents was invariably highest in poor adsorbents, indicating their
      poor adsorption energy for betalaines. Similarly, recovery by desorption was low
      in those adsorbents having high adsorption capacity, indicating that adsorbents
      such as activated ones with highest adsorption capacity with zero desorption
      property were unsuitable for the recovery of effluxed pigments. Ex situ recovery
      of betalain done using various combinations of alumina/silica and processed sand
      and different column geometries indicated that alumina with processed sand at a
      2:1 ratio (w/w) and a minimum column material of 2 cm height and 2 cm diameter
      was good enough to cause 97% pigment adsorption from a solution containing 1.6 mg
      mL(-)(1). Desorption and recovery of pigments ex situ from columns were affected
      by various elution mixtures, where a gradient elution with ascending levels of
      HCl/ethanol in water resulted in 100% recovery of adsorbed pigments in a
      significantly lesser volume of eluent in a short period of 1 h. Different pigment
      flow rates of 0.2, 0.3, and 3.1 mL s(-)(1) through a column of alumina/processed
      sand indicated that a pigment equilibrium concentration of 0.18 mg mL(-)(1) at
      flow rates of 0.02 and 0.3 mL s(-)(1) resulted in a breakthrough at 110 and 14
      min adsorbing 16.9 and 16.91 mg g(-)(1) betalain, respectively. From the
      breakthrough curves, the column capacities for respective flow rates were
      calculated as 8.86 and 9.6 mg g(-)(1), and the higher flow rates resulted in
      earlier breakthrough with lower capacity. Observations made in the present study
      are useful to develop a process for the on-line recovery of betalains effluxed
      from hairy roots.

PMID- 15176883
TI  - Theoretical investigation of axial and local particle size distribution on
      expanded bed adsorption process.
AB  - The general rate model was developed and solved to describe protein adsorption in
      an expanded bed. The model takes into account axial variation of bed porosity,
      particle size distribution (PSD), external and intraparticle mass transfer, and
      dispersion in liquid and solid phase. The analysis of the influence of the model
      parameters on dynamic capacity (DC) was investigated. The simulation results
      showed that major impact on dynamic capacity is exerted by intraparticle mass
      transfer (particle diameter and pore diffusivity). The external mass transfer
      resistance and dispersion parameters have secondary effect on DC. The replacement
      of axial PSD by the mean particle diameter results in error in calculation of DC,
      which increases remarkably with the increase of mean particle diameter. The PSD
      can promote a very slow approaching of plateau concentration by breakthrough
      curves. It was shown also that axial bed porosity variation could be replaced by
      average porosity with negligible error for DC calculations.

PMID- 15176884
TI  - Partitioning and characterization of tyrosine-tagged green fluorescent proteins
      in aqueous two-phase systems.
AB  - The green fluorescent protein GFPuv has been genetically engineered to
      investigate the influence of N-terminal tyrosine extensions in aqueous two-phase
      systems. Fusions in the N-terminus affected the protein expression, and tags
      containing three tyrosines and prolines influenced the expression favorably. This
      effect is probably due to changes in mRNA stability, because the amounts of
      corresponding mRNAs correlated with the amounts of GFPuv proteins. The
      partitioning was investigated in two different aqueous two-phase systems, a two
      polymer system composed of EO30PO70/dextran and a PEG/salt system with potassium
      phosphate. Partitioning in the PEG/salt system generally was more favorable than
      in the EO30PO70/dextran system. Tags with three tyrosines resulted in higher
      partitioning toward the EO30PO70- and PEG-rich phases, respectively. The effect
      of adding proline residues to the tag was also investigated, and the partitioning
      effect of the tag was enhanced when prolines were included in the tags with three
      tyrosines. The best tyrosine tag, Y3P2, increased the partition coefficient 5
      times in the PEG/salt system. Thermoseparation of the EO30PO70 phase allowed
      recovery of 83% Y3P2-GFPuv protein in a water phase.

PMID- 15176885
TI  - Metastable states of water and ice during pressure-supported freezing of potato
      tissue.
AB  - Different ice modifications were obtained during freezing processes at several
      pressure levels from atmospheric pressure up to 300 MPa. In the pressure range
      between 210 and 240 MPa, a metastable ice I modification area was observed, as
      the nucleation of ice I crystals in the thermodynamically stable region of ice
      III was reached. A significant degree of supercooling was obtained before
      freezing the tissue water to ice III, which has to be considered when designing
      pressure-supported freezing processes. The effect of supercooling phenomenon on
      the phase transition time is discussed using a mathematical model based on the
      solution of the heat transfer governing differential equations. Phase transition
      and freezing times for the different freezing paths experimented are compared for
      the processes: freezing at atmospheric pressure, pressure-assisted freezing, and
      pressure-shift freezing. Different metastable states of liquid water are defined
      according to their process-dependent stability.

PMID- 15176886
TI  - Modeling of monolith-supported affinity chromatography.
AB  - Ceramic monoliths have been used successfully as active support for affinity
      chromatography (1). A mathematical model was developed to simulate the adsorption
      elution experimental behavior of asparaginase in an agarose-coated monolith
      support. The computer-based model allows precise determination of experimental
      parameters. Because of the simple geometry of ceramic monoliths used as support,
      the mathematical model can be used to design adsorption/elution cycles for the
      large throughput separation of biomolecules.

PMID- 15176887
TI  - Supercritical carbon dioxide extraction of griseofulvin from the solid matrix
      obtained after solid-state fermentation.
AB  - Globally there is an increasing concern to minimize the use of organic solvents,
      particularly the chlorinated ones because of their suspected human
      carcinogenicity. The use of ecofriendly carbon dioxide as an alternative to
      organic solvents would be appropriate in the perspective of green technology.
      Supercritical carbon dioxide (SC-CO(2)) extraction is suitable for extraction of
      nonpolar compound with molecular weights less than 400. Griseofulvin is an
      antifungal antibiotic having a molecular weight of 353, making it amenable to SC
      CO(2) extraction. This work brings out the potential of supercritical carbon
      dioxide extraction (SCFE) for downstream processing of griseofulvin from the
      solid matrix obtained after solid-state fermentation (SSF). The optimized
      conditions for SCFE of griseofulvin from dried media after SSF were a flow rate
      of 0.4 L/min, temperature of 60 degrees C, and contact time of 90 min (30 min
      static + 60 min dynamic) at a pressure of 450-455 bar.

PMID- 15176888
TI  - Different properties of the lipases contained in porcine pancreatic lipase
      extracts as enantioselective biocatalysts.
AB  - The porcine pancreatic lipase (PPL) extracts contain a mixture of several
      lipases. Their fractioning was performed by sequential adsorption via interfacial
      activation on supports with different hydrophobicity. A protein of 25 KDa was
      preferentially adsorbed on octyl-Sepharose, another protein of 33 kDa was mainly
      adsorbed on octadecyl-Sepabeads support, and the PPL was mainly adsorbed on the
      support bearing phenyl groups. The different immobilized preparations showed
      different properties and different response due to change in the experimental
      conditions. Thus, in the hydrolysis of (+/-)-2-hydroxy-4-phenylbutyric acid ethyl
      ester [(+/-)-1] to produce the corresponding acid [2], the octyl-25KDa
      preparation showed the best enantioselectivity (E) value (E = 7) at pH 5 and 25
      degrees C, whereas the phenyl-PPL was the most enantioselective (E = 10) at pH 5,
      4 degrees C, and 10% dioxane. Using different preparations at different pHs it
      was possible to resolve (+/-)-2-O-butyryl-2-phenylacetic acid [(+/-)-3] with a
      high E value (E > 100); for example, with octadecyl-33 KDa enzyme at pH 8.

PMID- 15176889
TI  - Use and optimization of a dual-flowrate loading strategy to maximize throughput
      in protein-a affinity chromatography.
AB  - The effect of an alternate strategy employing two different flowrates during
      loading was explored as a means of increasing system productivity in Protein-A
      chromatography. The effect of such a loading strategy was evaluated using a
      chromatographic model that was able to accurately predict experimental
      breakthrough curves for this Protein-A system. A gradient-based optimization
      routine is carried out to establish the optimal loading conditions (initial and
      final flowrates and switching time). The two-step loading strategy (using a
      higher flowrate during the initial stages followed by a lower flowrate) was
      evaluated for an Fc-fusion protein and was found to result in significant
      improvements in process throughput. In an extension of this optimization routine,
      dynamic loading capacity and productivity were simultaneously optimized using a
      weighted objective function, and this result was compared to that obtained with
      the single flowrate. Again, the dual-flowrate strategy was found to be superior.

PMID- 15176890
TI  - Affinity adsorption of plasmid DNA.
AB  - The development of a protein-mediated dual functional affinity adsorption of
      plasmid DNA is described in this work. The affinity ligand for the plasmid DNA
      comprises a fusion protein with glutathione-S-transferase (GST) as the fusion
      partner with a zinc finger protein. The protein ligand is first bound to the
      adsorbent by affinity interaction between the GST moeity and gluthathione that is
      covalently immobilized to the base matrix. The plasmid binding is then enabled
      via the zinc finger protein and a specific nucleotide sequence inserted into the
      DNA. At lower loadings, the binding of the DNA onto the Fractogel, Sepharose, and
      Streamline matrices was 0.0078 +/- 0.0013, 0.0095 +/- 0.0016, and 0.0080 +/-
      0.0006 mg, respectively, to 50 microL of adsorbent. At a higher DNA challenge,
      the corresponding amounts were 0.0179 +/- 0.0043, 0.0219 +/- 0.0035, and 0.0190
      +/- 0.0041 mg, respectively. The relatively constant amounts bound to the three
      adsorbents indicated that the large DNA molecule was unable to utilize the
      available zinc finger sites that were located in the internal pores and binding
      was largely a surface adsorption phenomenon. Utilization of the zinc finger
      binding sites was shown to be highest for the Fractogel adsorbent. The adsorbed
      material was eluted with reduced glutathione, and the eluted efficiency for the
      DNA was between 23% and 27%. The protein elution profile appeared to match the
      adsorption profiles with significantly higher recoveries of bound GST-zinc finger
      protein.

PMID- 15176891
TI  - Transport of polymeric nanoparticle gene carriers in gastric mucus.
AB  - Nanoparticle transport through mucosal barriers is often restricted owing to
      mucoadhesion and the highly viscoelastic nature of mucus gels, which may limit
      efficient drug and gene delivery. We formulated sub-200 nm particulates from
      poly(d,l-lactic-co-glycolic) acid (PLGA) and the cationic surfactant
      dimethyldioctadecylammonium bromide (DDAB). Subsequently, anionic DNA was
      condensed to the surface to obtain gene carriers with transfection rates 50-fold
      higher than those of naked DNA in vitro. Using the method of multiple particle
      tracking (MPT), we measured the transport rates of dozens of individual PLGA
      DDAB/DNA nanoparticles in real time in reconstituted pig gastric mucus (PGM) that
      possessed physiologically relevant rheological properties. The average transport
      rate of PLGA-DDAB/DNA nanoparticles was 10-fold higher than those of similar size
      polystyrene nanoparticles. Improved transport rates, stability in mucus, and
      ability to transfect cells make PLGA-DDAB/DNA nanoparticles candidates for
      mucosal DNA vaccines and gene therapy.

PMID- 15176892
TI  - High-titer adenovirus vector production in 293S cell perfusion culture.
AB  - Human 293S cells culture for recombinant adenovirus production is traditionally
      carried out in batch at a maximum of 6 x 10(5) cells/mL. A previous report
      demonstrated that fed-batch, applied to the adenovirus/293S cells system,
      improves the volumetric production of viral proteins by increasing the cell
      density at which cells can be infected, up to 2 x 10(6) cells/mL, without
      reducing the per-cell yield of product. To increase this cell density limit, the
      adenovirus production was performed in a perfusion system where the cells were
      separated by means of a tangential flow filtration device. 293S cell growth to 14
      x 10(6) cells/mL was achieved in 10 days, at a medium renewal rate of 1 volume of
      medium per reactor volume and day (VVD). For adenovirus production, three 293S
      cell cultures were perfused at 1 VVD in parallel and infected at an average
      density of 8 x 10(6) cells/mL. One of the cultures was set at 37 degrees C and
      the two others at 35 degrees C. After a rapid initial cell loss, the average cell
      density stabilized at 5.75 x 10(6) cells/mL, 12 h postinfection, which was 8
      times higher than the cell density in the batch control. This allowed the
      production of 3.2 x 10(9) infectious viral particles/mL (IVP/mL) at 37 degrees C
      and 7.8 x 10(9) IVP/mL at 35 degrees C, this last result being 5.5 times higher
      than the control. To our knowledge, this nonconcentrated titer is the highest
      value that has ever been published for adenovirus vector production. These
      observations lead to the conclusion that perfusion is an efficient tool to
      maintain, at high cell density, a specific production rate level sufficient to
      increase significantly the adenovirus volumetric production. Furthermore, it
      shows that perfusion at 35 degrees C can improve viral titer by 2.4-fold compared
      to 37 degrees C, in accordance with a previous study on adenovirus batch
      production.

PMID- 15176893
TI  - HPCE monitoring of the N-glycosylation pattern and sialylation of murine
      erythropoietin produced by CHO cells in batch processes.
AB  - Using capillary electrophoresis coupled to laser-induced fluorescence (HPCE-LIF),
      it was possible to profile N-linked oligosaccharides from EPO, including species
      containing sialic acid, during the course of batch cultures performed either in
      serum-free or serum-containing medium. Although an unusual high heterogeneity of
      the N-linked oligosaccharides was observed by both SDS-PAGE and HPCE analysis,
      the patterns of mEPO glycans after desialylation by mild acid hydrolysis were
      found to be quite constant over the course of the cultures either with or without
      serum supplementation. In contrast, when the protein was analyzed by HPCE without
      acidic desialylation, fingerprints of N-linked oligosaccharides changed with time
      in serum-containing conditions. This phenomenon appeared to be mainly due to the
      desialylation of mEPO as a result of a sialidase activity released upon cell
      lysis. These results demonstrate that though a higher EPO titer was obtained in
      serum supplemented conditions, sialylation of EPO was severely affected by the
      presence of serum in the culture medium.

PMID- 15176894
TI  - Population balance approach to modeling hairy root growth.
AB  - Though numerous models have been developed to describe the growth of microbial
      cell cultures, far fewer models are available to describe the growth of hairy
      root cultures. Here a population balance model is proposed to simulate the growth
      of hairy roots. The model accounts for the increase in biomass due to elongation
      of a branch by cell division as well as the formation of new branches. The model
      incorporates the fact that although the likelihood of the formation of a new
      lateral branch is a maximum at a specific age of the parent branch, lateral
      branches can form over a distribution of ages of the parent branch. Model
      parameters are estimated using the genetic algorithm based on experimental data
      for batch and continuous bioreactors. The model proposed here may provide a
      better understanding of the increase in biomass of hairy root cultures.

PMID- 15176895
TI  - High-level expression of proteins in mammalian cells using transcription
      regulatory sequences from the Chinese hamster EF-1alpha gene.
AB  - High-level expression of a recombinant protein in Chinese hamster ovary (CHO)
      cells typically requires the laborious and time-consuming procedure of stepwise
      gene amplification. We hypothesized that use of transcription control regions
      from a highly expressed gene in CHO cells to drive expression of a gene of
      interest might reduce the requirement for gene amplification. To this end, we
      cloned a 19 kb DNA fragment containing the Chinese hamster elongation factor
      1alpha (EF-1alpha) gene, as well as 12 kb of 5' flanking sequence and 4 kb of 3'
      flanking sequence. Expression vectors containing 5' and 3' flanking sequences
      from the Chinese hamster EF-1alpha (CHEF1) gene were constructed and, after
      insertion of six different reporter genes, transfected into CHO cells. For
      comparison, CHO cells were also transfected with the same six reporter genes
      inserted into commercial vectors utilizing either the immediate early promoter
      from cytomegalovirus (CMV) or the human EF-1alpha promoter. The striking result
      from these studies was that average expression levels from pooled, stable
      transfectants of CHEF1 vectors were 6- to 35-fold higher than expression levels
      from commercial vectors that utilize the CMV or the human EF-1alpha promoters. We
      also used a CHEF1 vector to express a secreted and a membrane-bound protein in
      stably transfected non-CHO cell lines. CHEF1-driven expression of secreted
      alkaline phosphatase (SEAP) in three of four cell lines tested (HEK 293, K562,
      L1.2, and HCT 116) was 13- to 280-fold greater than that from a commercial vector
      employing the CMV promoter. After transfection of four different cell lines of
      hematopoietic origin (K562, L1.2, JY, and Jurkat), the CHEF1 vector was found to
      express the chemokine receptor CCR4 at >10-fold higher levels than that driven
      from a commercial vector utilizing the CMV promoter. Results from these
      experiments suggest that the CHEF1 vectors will be useful for high-level protein
      expression not only in CHO cells, but also in a variety of other mammalian cell
      lines.

PMID- 15176896
TI  - Development of auxotrophic agrobacterium tumefaciens for gene transfer in plant
      tissue culture.
AB  - Auxotrophic strains of Agrobacterium tumefaciens were generated for use in liquid
      co-culture with plant tissue for transient gene expression. Twenty-one auxotrophs
      were recovered from 1,900 tetracycline-resistant insertional mutants generated
      with a suicide vector transposon mutagenesis system. Twelve of these auxotrophs
      were characterized on a nutrient matrix. Isolates were screened for growth in
      plant cell and root culture, and three auxotrophs were identified that had
      limited growth: adenine (ade-24), leucine (leu-27), and cysteine (cys-32). Ade-24
      displayed poor T-DNA delivery in a transient expression test delivering GUS from
      a binary vector, while cys-32 displayed the best ability to deliver DNA of these
      three auxotrophs. The growth yield of cys-32 on cysteine was assessed to provide
      a quantitative basis for co-culture nutrient supplementation. The utility of cys
      32 for delivering T-DNA to plant tissues is demonstrated, where an 85-fold
      enhancement in GUS expression over wild-type A. tumefaciens was achieved.

PMID- 15176897
TI  - Rapid protein anchoring into the membranes of Mammalian cells using oleyl chain
      and poly(ethylene glycol) derivatives.
AB  - The cell membrane is an important interface for communication with extracellular
      events, and incorporation of bioactive substances, such as antibodies and
      receptors, into the cell membrane may enhance the potential abilities of cells.
      Gene manipulation, chemical modification of membrane proteins, and cell surface
      painting using a GPI anchor have been performed to introduce substances into cell
      membranes. Furthermore, many lipid anchors have also been used to modify lipid
      membranes such as liposomes. In this study, we have focused on developing an easy
      and rapid method for anchoring of substances including macromolecular proteins
      into the membranes of living mammalian cells. We employed a single oleyl chain
      derivative coupled with hydrophilic poly(ethylene glycol) (PEG90, the
      ethyleneoxide (EO) unit is 90) to facilitate solubilization in water. This water
      soluble derivative was designated Biocompatible Anchor for Membrane (BAM). Some
      proteins (streptavidin, EGFP and an antibody) were coupled with BAM90 at the
      distal terminal of PEG and rapidly (within a few minutes) anchored into the
      membranes of various cells (NIH3T3, 32D, Ba/F3, hybridoma 9E10). However, the
      anchored BAM90 disappeared from the cell membranes within 4-5 h in serum-free
      culture media, and moreover, the retention time of anchoring was shortened (1-2
      h) in culture medium containing 10% FBS. We further prepared a
      dioleylphosphatidylethanolamine (DOPE)-PEG derivative (DOPE-BAM80, the EO unit is
      80) as a double oleyl chain derivative for comparison with the single oleyl chain
      derivative, BAM90. The retention time of anchored DOPE-BAM80 was longer than that
      of BAM90 and more than 8 h in culture media with and without 10% serum.
      Furthermore, the treatment time of DOPE-BAM80 for anchoring was nearly as short
      (within a few minutes) as that of BAM90. In addition, both types of BAMs, BAM90
      and DOPE-BAM80, showed no cytotoxicity. Therefore, DOPE-BAM80 is useful for
      protein anchoring to cells. Although the utilization of BAM90 is considered to be
      limited, it is expected to useful in restricted environments, for example, in
      tissues such as the cornea, peritoneum, bladder, and various mucosae, which are
      less exposed to serum. Thus, we suggest the possibility that both types of BAM
      can be applied to cell surface engineering.

PMID- 15176898
TI  - Human mesenchymal stem cells tissue development in 3D PET matrices.
AB  - Human mesenchymal stem cells (hMSCs) are attractive cell sources for engineered
      tissue constructs with broad therapeutic potential. Three-dimensional (3D) hMSC
      tissue development in nonwoven poly(ethylene terephthalate) (PET) fibrous
      matrices was investigated. HMSCs were seeded onto 3D PET scaffolds and were
      cultured for over 1 month. Their proliferation rates were affected by seeding
      density but remained much lower than those of 2D controls. Compared to 2D
      surfaces, hMSCs grown in 3D scaffolds secreted and embedded themselves in an
      extensive ECM network composed of collagen I, collagen IV, fibronectin, and
      laminin. HMSCs were influenced by the orientation of adjacent PET fibers to
      organize the ECM proteins into highly aligned fibrils. We observed the increased
      expressions of alpha(2)beta(1) integrin but a slight decrease in the expression
      of alpha(5)beta(1) integrin in 3D compared to 2D culture and found that
      alpha(V)beta(3) was expressed only in 2D. Paxillin expression was down-regulated
      in 3D culture with a concomitant change in its localization patterns. We
      demonstrated the multi-lineage potentials of the 3D tissue constructs by
      differentiating the cells grown in the scaffolds into osteoblasts and adipocytes.
      Taken together, these results showed that hMSCs grown in 3D scaffolds display
      tissue development patterns distinct from their 2D counterparts and provide
      important clues for designing 3D scaffolds for developing tissue engineered
      constructs.

PMID- 15176899
TI  - Flow cytometric application of helper adenovirus (HAd) containing GFP gene
      flanked by two parallel loxP sites to evaluation of 293 cre-complementing cell
      line and monitoring of HAd in Gutless Ad production.
AB  - Gutless adenoviruses (GAds), namely, all gene-deleted adenoviruses, were
      developed to minimize their immune responses and toxic effects for a successful
      gene delivery tool in gene therapy. The Cre/loxP system has been widely used for
      GAd production. To produce GAd with a low amount of helper adenovirus (HAd) as
      byproduct, it is indispensable to use 293Cre cells expressing a high level of Cre
      for GAd production. In this study, we constructed the HAd containing enhanced
      green fluorescent protein gene flanked by two parallel loxP sites (HAd/GFP). The
      use of HAd/GFP with flow cytometry allows one to select 293Cre cells expressing a
      high level of Cre without using conventional Western blot analysis. Unlike
      conventional HAd titration methods such as plaque assay and end-point dilution
      assay, it also allows one to monitor rapidly the HAd as byproduct in earlier
      stages of GAd amplification. Taken together, the use of HAd/GFP with flow
      cytometry facilitates bioprocess development for efficient GAd production.

PMID- 15176901
TI  - Molecular dynamics simulations to determine the effect of supercritical carbon
      dioxide on the structural integrity of hen egg white lysozyme.
AB  - In this study, various molecular dynamics simulations were conducted to
      investigate the effect of supercritical carbon dioxide on the structural
      integrity of hen egg white lysozyme. The analyses of backbone root-mean-square
      deviation, radius of gyration, and secondary structure stability all show that
      supercritical CO(2) exhibits the ability to increase the stability of this
      protein, probably as a result of the solvent with less polarity, where
      hydrophobic interactions stabilizing the native structure are weakened and
      simultaneously the local hydrogen bonds are strengthened, resulting in
      stabilization of the secondary structures. The hydrophobic cores in the alpha-
      and beta-domains also play an important role in preventing this protein from
      thermal unfolding. As supercritical CO(2) has been attractive for biomedical
      applications because of the advantages of mild critical condition,
      nonflammability, nontoxity, and the purity of the resulting products, the
      structural stabilizing effect found in this study strongly suggests that it is
      possible to increase the thermostability of hen egg white lysozyme by
      pretreatment with supercritical CO(2), leading to better industrial applications
      of this protein.

PMID- 15176900
TI  - Starch gelatinization in coiled heaters.
AB  - A gelatinizing model food derived from a 5% w/w cross-linked waxy maize starch
      suspension was simulated in coiled heaters to assess the impact of centrifugal
      forces on flow and heat transfer. For four coil diameters (D = 0.25, 1, 2.5, and
      infinity m) and three flow rates (w = 0.5, 1, and 2 m/s), heat transfer, viscous
      development, and the severity of channeling were evaluated. Increasing curvature
      proved to suppress channeling as a result of more uniform heating and
      gelatinization. The maximum attainable viscosity was also higher, implying a
      lower starch consumption for a target viscosity. Higher flow rates necessitated
      longer heaters, and the maximum viscosity decreased. Moderate product velocities
      are therefore recommended.

PMID- 15176902
TI  - Pressure shift freezing of pork muscle: effect on color, drip loss, texture, and
      protein stability.
AB  - Cylindrical specimens (50 mm diameter and 160 mm length) of fresh pork muscle
      (boneless rib portions) packed in plastic bags were frozen by pressure shift
      freezing (PSF) at 100, 150, and 200 MPa, air blast freezing (ABF), and liquid
      immersion freezing (LIF). Temperature and phase transformations of the muscle
      tissue were monitored during the freezing process at three locations: center,
      midway between the center and the surface, and near the surface. Pork muscle
      quality changes [color, drip loss (both thawing and cooking), texture (shear
      force), and protein stability (DSC thermal profiles)] were evaluated after
      thawing the frozen samples at room temperature (20 degrees C). Employing
      pressures above 150 MPa caused very significant (P < 0.01) color changes in pork
      muscle during the PSF process. The PSF process reduced thawing drip loss of pork
      muscle but did not cause obvious changes in total drip loss following thawing and
      subsequent cooking. PSF at 150 and 200 MPa resulted in considerable denaturation
      of myofibrillar proteins of pork muscle. The PSF process also caused an increase
      in the pork muscle toughness as compared with that of unfrozen, ABF, and LIF
      samples.

PMID- 15176903
TI  - Effect of NaBH4 concentration and reaction time on physical properties of
      glutaraldehyde-polymerized hemoglobin.
AB  - The US is about 1.5 days away from exhausting its entire blood supply. Hence,
      there is an urgent need for the development of universal blood substitutes. One
      such blood substitute is glutaraldehyde-polymerized bovine hemoglobin. Despite
      the commercial development of glutaraldehyde-polymerized bovine hemoglobin-based
      blood substitutes, there has been little published work on the effect of reaction
      conditions on the physical properties of the polymerized hemoglobin dispersion.
      In this study, the effect of varying the concentration of the quenching agent
      NaBH(4), glutaraldehyde concentration, and reaction time on the physical
      properties of PolyHb dispersions was studied by measuring the absolute molecular
      weight distribution, as well as oxygen-binding properties such as P(50), Hill
      coefficient, and methemoglobin level (MetHb) of these dispersions. Bovine
      hemoglobin was polymerized with glutaraldehyde using a parallel synthetic
      approach. Asymmetric flow field-flow fractionation (AFFF) coupled with multi
      angle static light scattering (MASLS) was used to measure the absolute molecular
      weight distribution of the PolyHb dispersions. In general, high glutaraldehyde
      concentrations (20-30 times the molar concentration of hemoglobin) adversely
      affected the oxygen-binding properties of PolyHb dispersions, while NaBH(4)
      concentrations (up to 300 times the molar concentration of hemoglobin) and
      reaction times (up to 24 h) did not appear to have any effect on the oxygen
      binding properties of PolyHb dispersions.

PMID- 15176904
TI  - Oxidized mono-, di-, tri-, and polysaccharides as potential hemoglobin cross
      linking reagents for the synthesis of high oxygen affinity artificial blood
      substitutes.
AB  - Various oxidized mono/di/tri/poly saccharides were studied as potential
      hemoglobin (Hb) cross-linkers in order to produce oxygen carriers with high
      oxygen affinities (low P(50)'s) and high molecular weights (therefore lower
      macromolecular diffusivities compared to tetrameric Hb). Such physical properties
      were desired to produce polymerized hemoglobins (PolyHbs) with oxygen release
      profiles similar to that of human blood, as was demonstrated in work by Winslow
      (1). In this present study, bovine hemoglobin was cross-linked with a variety of
      oxidized (ring-opened) saccharides, which resulted in cross-linked Hb species
      ranging in size from 64 to 6400 kDa (depending on the particular oxidized
      saccharide used in the reaction) and P(50)'s ranging from 6 to 15 mmHg. A
      parallel synthetic approach was used to synthesize these carbohydrate-hemoglobin
      conjugates, and asymmetric flow field-flow fractionation (AFFF) coupled with
      multi-angle static light scattering (MASLS) was used to measure the absolute
      molecular weight distribution of these PolyHb dispersions. Cross-linking
      reactions were conducted at two pHs (6 and 8), with larger cross-linked Hb
      species produced at pH 8 (where hydrolysis was most likely to occur between
      glycosidic bonds linking adjacent saccharide rings) rather than at pH 6. The
      largest molecular weight species formed from these reactions consisted of Hb
      cross-linked with ring-opened lactose, maltose, methylglucopyranoside, sucrose,
      trehalose, and 15 kDa and 71 kDa dextran at high pH (pH 8). The most promising Hb
      cross-linker was methylglucopyranoside, which resulted in very large cross-linked
      Hb species, with low P(50)'s and lower methemoglobin (metHb) levels compared to
      the other Hb cross-linking reagents.

PMID- 15176905
TI  - Flow cytometric screening of cDNA expression libraries for fluorescent proteins.
AB  - Fluorescence-activated cell sorting (FACS) was applied for quantitative screening
      of cDNA expression libraries in bacteria for rare fluorescent protein encoding
      cDNAs. Rare fluorescent cells, observed at a frequency of 1 in 200,000 bacteria
      in a cDNA expression library constructed from Astrangia lajollaensis, were
      detected, enriched, and purified by sorting, yielding three distinct green
      fluorescent proteins. Two of the isolated fluorescent proteins were found to be
      2.5-fold brighter in whole cell fluorescence than the widely used and already
      optimized EGFP variant and possessed a novel cysteine-containing chromophore.
      FACS can possess significant advantages in the screening of cDNA libraries in
      bacteria, since desired genes may occur at low frequencies and possess unexpected
      properties. This strategy provides a high-throughput, quantitative approach for
      isolating fluorescent proteins from a more diverse range of organisms and should
      be extendable to proteins that are not intrinsically fluorescent with the use of
      available fluorescent indicators.

PMID- 15176907
TI  - Optimization of enzymatic gas-phase reactions by increasing the long-term
      stability of the catalyst.
AB  - Enzymatic gas-phase reactions are usually performed in continuous reactors, and
      thus very stable and active catalysts are required to perform such
      transformations on cost-effective levels. The present work is concerned with the
      reduction of gaseous acetophenone to enantiomerically pure (R)-1-phenylethanol
      catalyzed by solid alcohol dehydrogenase from Lactobacillus brevis (LBADH),
      immobilized onto glass beads. Initially, the catalyst preparation displayed a
      half-life of 1 day under reaction conditions at 40 degrees C and at a water
      activity of 0.5. It was shown that the observed decrease in activity is due to a
      degradation of the enzyme itself (LBADH) and not of the co-immobilized cofactor
      NADP. By the addition of sucrose to the cell extract before immobilization of the
      enzyme, the half-life of the catalyst preparation (at 40 degrees C) was increased
      40 times. The stabilized catalyst preparation was employed in a continuous gas
      phase reactor at different temperatures (25-60 degrees C). At 50 degrees C, a
      space-time yield of 107 g/L/d was achieved within the first 80 h of continuous
      reaction.

PMID- 15176906
TI  - Reduction of active elastase concentration by means of immobilized inhibitors: a
      novel therapeutic approach.
AB  - The inhibitory power of three different active Nylon membranes, separately loaded
      with three different protease inhibitors, was studied with the aim of reducing
      the increased elastase concentration occurring during hemodialysis or
      extracorporeal blood circulation in patients undergoing cardiopulmonary bypass.
      Chemical grafting was carried out to make the inert Nylon membrane suitable for
      the immobilization of the inhibitors. The behavior of immobilized alpha(1)
      antitrypsin, bovine pancreatic trypsin inhibitor (BPTI), or elastatinal was
      separately studied. alpha(1)-Antitrypsin and BPTI were covalently immobilized by
      means of a diazotization process, whereas elastatinal was covalently attached via
      a condensation process mediated by glutaraldehyde. The inhibitory power of each
      membrane type was studied as a function of the amount of immobilized inhibitor
      and temperature. All active membranes have shown good inhibitory power. The most
      efficient membrane was that loaded with alpha(1)-antitrypsin, the less efficient
      that with BPTI.

PMID- 15176908
TI  - Optimizing iron supplement strategies for enhanced surfactin production with
      Bacillus subtilis.
AB  - Supplement of Fe(2+) into fermentation medium was utilized as a tool to optimize
      the iron-mediated enhancement of surfactin production from Bacillus subtilis ATCC
      21332. Up to 3000 mg L(-)(1) of surfactin was produced using an iron-enriched
      minimal salt (MS) medium amended with an optimal Fe(2+) dosage of 4.0 mM, leading
      to 8-fold and 10-fold increase in cell concentration and surfactin yield,
      respectively, as compared to those without Fe(2+) supplement. In addition to
      resulting in an optimal production yield of surfactin, a supplement of 4.0 mM of
      Fe(2+) also propelled maximum overall surfactin production rate to a highest
      value of 24 mg L(-)(1) h(-)(1). Our results also show that production of
      surfactin followed a growth-associated kinetic model. The best yield coefficient
      estimated from the model was ca. 162 mg surfactin (g dry cell)(-)(1). The
      supernatant of the iron-enriched culture of B. subtilis ATCC 21332 exhibited the
      ability to emulsify kerosene and achieved a maximum emulsion index (E(24)) of 80%
      for culture supplemented with 4.0 mM of Fe(2+). Comparison of emulsion index and
      the corresponding surfactin production indicates that the emulsification activity
      was essentially contributed by surfactin.

PMID- 15176909
TI  - Enantioselective synthesis of phenylacetamides in the presence of high organic
      cosolvent concentrations catalyzed by stabilized penicillin G acylase. Effect of
      the acyl donor.
AB  - Immobilization of penicillin G acylase on glyoxyl agarose and its further
      hydrophilization by physicochemical modification with ionic polymers has made it
      possible to perform the direct condensation between (+/-)-2-hydroxy-2
      phenylethylamine [(+/-)-1] and different acyl donors in the presence of high
      concentrations of organic cosolvent (up to 90%) in the reaction medium. Using 50
      mM phenyl acetic acid and these drastic reaction conditions, too harsh for any
      other PGA preparation, we have achieved an almost quantitative transformation
      (more than 99%) of 10 mM (+/-)-1 into the corresponding amide. Remarkably, the
      enantioselectivity of the enzyme immobilized on the amine was strongly dependent
      on the acyl donor employed. Thus, using phenylacetic acid (2), the
      enantioselectivity was almost negligible (1.3 favoring the S isomer), whereas
      using S-mandelic acid [(S)-4], the E factor reached a value of 21 (also favoring
      the S isomer). By using R-mandelic acid [(R)-4], we observed a different
      enantioselectivity (E was 3.6 favoring the R). At 4 degrees C, the E value
      reached a value higher than 100 when (S)-4 was used as the acyl donor. The
      reaction performed under these conditions allowed us to produce (2S,2'S)-N-2'
      hydroxy-2'-phenyl)-2-hydroxyphenylacetamide [(2S,2'S)-7] with a diasteromeric
      excess higher than 98%.

PMID- 15176910
TI  - Effect of process variables on photosynthetic algal hydrogen production.
AB  - Chlamydomonas reinhardtii is a green alga that can use the sun's energy to split
      water into O(2) and H(2). This is accomplished by means of a two-phase cycle, an
      aerobic growth phase followed by an anaerobic hydrogen production phase. The
      effects of process variables on hydrogen production are examined here. These
      variables include cell concentration, light intensity, and reactor design
      parameters that affect light transport and mixing. An optimum cell concentration
      and light intensity are identified, and two reactor designs are compared. The
      maximum hydrogen production observed in this study was 0.29 mL of hydrogen per
      milliliter of suspension. This was measured at atmospheric pressure during a 96 h
      production cycle. This corresponds to an average hydrogen production rate of 0.12
      mmol/mL.h.

PMID- 15176911
TI  - Advanced monitoring and supervision of biological treatment of complex dairy
      effluents in a full-scale plant.
AB  - The operation of a wastewater treatment plant treating effluents from a dairy
      laboratory was monitored by an advanced system. This plant comprises a 12 m(3)
      anaerobic filter (AF) reactor and a 28 m(3) sequential batch reactor (SBR)
      coupled in series and is equipped with the following on-line measurement devices:
      biogas flow meter, feed and recycling flow meters, temperature sensor, dissolved
      oxygen analyzer, and redox meter. Other parameters such as chemical oxygen demand
      (COD), volatile fatty acids (VFA), etc. were determined off-line. The plant has
      been in operation for 634 days, the influent flow rate being 6-8 m(3)/d. COD
      concentration of the influent ranged between 8 and 12 kg COD/m(3), resulting in
      COD values in the effluent around 50-200 mg/L. The behavior of the system was
      studied using the set of measurements collected by the data acquisition program
      especially developed for this purpose. Monitoring of variables such as anaerobic
      reactor temperature permitted the detection and prevention of several failures
      such as temperature shocks in the AF reactor. Besides, off-line measurements such
      as the alkalinity or the VFA content, together with the on-line measurements,
      provided immediate information about the state of the plant and the detection of
      several anomalies, such as organic overloads in the SBR, allowing the
      implementation of several fast control actions.

PMID- 15176912
TI  - Effects of light intensity distribution on growth of Rhodobacter capsulatus.
AB  - For cultivation of photosynthetic cells under defined light intensity
      distributions, the repeated batch culture, in which a part of culture broth
      containing grown cells was repeatedly replaced at predetermined time intervals
      with a fresh medium to keep the cell concentration constant at an initial value,
      was employed. By use of this method the effects of the light intensity
      distribution on the growth characteristics of Rhodobacter capsulatus were
      studied. Unexpected decreases in the specific growth rate were observed in
      culture of R. capsulatus at high cell concentrations and a long light path
      length. Big differences in the light intensities of lightly and darkly
      illuminated portions in photobioreactors, which reflects the light intensity
      distribution, seemed to cause this phenomenon, which must be taken into
      consideration for stable growth of photosynthetic cells.

PMID- 15176914
TI  - Quality and costs of community-based residential supports for people with mental
      retardation and challenging behavior.
AB  - A longitudinal matched-groups design was used to examine the quality and costs of
      community-based residential supports to people with mental retardation and
      challenging behavior. Two forms of provision were investigated: noncongregate
      settings, where the minority of residents had challenging behavior, and
      congregate settings, where the majority of residents had challenging behavior.
      Data were collected for 25 people in each setting. We collected information
      through interviewing service personnel in each type of setting on the costs of
      service provision, the nature of support provided, and the quality of life of
      residents. We also conducted observations in each setting. Results suggest that
      noncongregate residential supports may be more cost effective than congregate
      residential supports.

PMID- 15176915
TI  - Statewide longitudinal survey of psychotropic medication use for persons with
      mental retardation: 1994 to 2000.
AB  - The use of psychotropic medication with persons who have mental retardation was
      surveyed. Data were collected on a large sample of Oklahomans in both 1994 and
      2000. Analysis revealed that the use of antidepressant medication increased
      dramatically over the course of the study, apparently as a function of increased
      use of SSRI medications. Antipsychotic medication did not change dramatically,
      but a shift to the newer atypical antipsychotic medications was noted. In a
      separate analysis of persons who moved from an institutional setting to a
      community-based setting, evidence suggested an increased use of psychotropic
      medication.

PMID- 15176916
TI  - Effects of risperidone on destructive behavior of persons with developmental
      disabilities: III. Functional analysis.
AB  - Functional analyses were conducted during a double-blind, placebo-controlled
      study of the atypical antipsychotic medication risperidone with 13 individuals.
      Risperidone was effective in reducing destructive behavior (compared to placebo)
      for 10 participants. For 7 of these responders, an undifferentiated pattern of
      responding occurred across their baseline functional analysis conditions (i.e., a
      similar rate of responding across conditions), and risperidone treatment produced
      nonspecific reductions of their destructive behavior across functional analysis
      conditions. For the remaining 3 responders, a differentiated pattern of
      responding occurred across their baseline functional analysis conditions (i.e.,
      an elevated rate of responding occurred in a specific condition), and risperidone
      treatment produced function-specific reductions of their destructive behavior.

PMID- 15176917
TI  - Effects of topiramate in adults with Prader-Willi syndrome.
AB  - Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with
      behavioral manifestations, including hyperphagia, compulsive behavior, self
      injury, and mild to moderate mental retardation. In an 8-week open-label study,
      we evaluated adjunctive therapy with the anticonvulsant topiramate in 8 adults
      with Prader-Willi syndrome. Appetite was measured by a 1-hour access to food four
      times throughout the study and quantified with a visual analogue scale.
      Topiramate did not significantly change calories consumed, Body Mass Index, or
      increase self-reported appetite. In addition, there were no significant changes
      in compulsions. Surprisingly, topiramate treatment resulted in a clinically
      significant improvement in the self-injury (i.e., skin-picking) that is
      characteristic of this syndrome. Potential benefits of topiramate for self-injury
      should be evaluated further in controlled trials.

PMID- 15176918
TI  - Early predictors of language in children with and without Down syndrome.
AB  - Predictors of productive and receptive language development in 39 children with
      intellectual disabilities (17 with Down syndrome) and their parents were
      identified. Children were in the prelinguistic or first stage of productive
      language acquisition (Brown, 1973). The Down syndrome and non-Down syndrome
      groups were matched on several variables, including IQ, CA, and vocabulary level.
      After controlling for initial language level, we attempted to identify unique
      early predictors of language measured 6 months later. Results indicate that Down
      syndrome negatively affected language development. Additionally, frequency of
      optimal parental responding predicted later productive language above and beyond
      etiology. Finally, canonical vocal communication and commenting predicted later
      productive language only in children without Down syndrome.

PMID- 15176919
TI  - Sleep problems in individuals with Angelman syndrome.
AB  - Prevalence of severe sleep problems and its association with other variables were
      investigated with 109 individuals who have Angelman syndrome. Severe settling
      problems, frequent night waking, and early waking were found in 2%, 37%, and 10%
      of the individuals, respectively. Sleep problems were persistent in this sample.
      No statistically significant associations were found between presence of a severe
      sleep problem and other variables (e.g., epilepsy, age, living environment, cause
      of genetic disorder, parents' and caregivers' coping strategies). Most parents
      reported adverse effects of their child's sleep problems on their own well-being.
      Implications for analysis and treatment of sleep problems in individuals with
      Angelman syndrome are discussed.

PMID- 15176920
TI  - [Lactose intake and bowel inflammatory disease: invert the tendency?].

PMID- 15176921
TI  - [Lactose malabsorption in patients with inflammatory bowel disease without
      activity: would it be necessary to exclude lactose products in the diet of all
      patients?].
AB  - INTRODUCTION: There are inflammatory bowel disease (IBD) patients avoid lacteal
      products without evidence of lactose malabsorption, probably because of incorrect
      patient perceptions and arbitrary advice from physicians and diet books. AIM: To
      evaluate the prevalence of lactose malabsorption in patients with IBP. METHOD: In
      18 patients with Crohns disease and 24 with ulcerative colitis and 25 controls
      the prevalence of lactose intolerance, as measured by lactose breath hydrogen
      tests. RESULTS: Observed deficiencies of absorption of the lactose in 7 (16.6%)
      patients with IBP and 5 (20%) subjects control. CONCLUSIONS: Not all the patients
      with IBD are intolerant to the lactose by the suppression of the lacteal produts
      must not be generalized in the diet of these patients.

PMID- 15176922
TI  - [Tuberculosis in Santiago de Compostela from 1999 to 2002. An epidemiological
      study].
AB  - OBJECTIVE: The purpose of this study was to determine the epidemiological
      characteristics of tuberculosis (TB) in the Public Health System District of
      Santiago de Compostela (population : 386125) from 1999 to 2002. METHODS:
      Inclusion criteria were: 1). microbiological and/or pathological diagnosis of TB
      in any specimen, and 2). patient younger 35 years old with recent medical history
      of TB. Mantoux test positive, and pleural effusion with linfocitosis and
      adenosine deaminase >47 IU/ml. RESULTS: 946 patients were included (568 men and
      378 women), with ages ranging from 2 months to 96 years. The incidence of TB was
      60.9/100000 in 1999, 67.6/100000 in 2000, 61.9/100000 in 2001 and 54.6/100000 in
      2002. The incidence rate of tuberculous meningitis was 1.03/100000 in 1999 and
      2000, 0.77/100000 in 2001 and 0.51/100000 in 2002. The percentage of cases
      associated with HIV was 3.4% in 1999, 1.9% in 2000, 2.4% in 2001 and 2002. We
      found an increase in the rate of males over 55 years of age; with incidence per
      100000 inhabitants of 122.4 in 1999, 142.8 in 2000, 115 in 2001 and 119 in 2002,
      whereas in females the incidence was 40.6 in 1999, 60.9 in 2000, 54.1 in 2001 and
      39.1 in 2002. CONCLUSIONS: In last four years the incidence of tuberculosis has
      decreased but remains high in males over 55 years old.

PMID- 15176923
TI  - [Anti-hypertensive effect of eprosartan in diabetic patients].
AB  - OBJECTIVE: Diabetes mellitus seems to induce an special difficulty to control the
      high blood pressure. This effect is more severe on the SBP. Previous reports
      suggest that a new angiotensin receptor blocker, eprosartan, might have a higher
      efficacy to reduce SBP. It has been evaluated the BP decrease obtained with
      eprosartan in a group of diabetics patients compared to non diabetic patients.
      MATERIAL AND METHODS: 81 patients were recruited of whom 65 have ended follow-up.
      34 patients were diabetics (mean age 66.7+/-10.7 years, 15 men and 19 women) and
      31 were non diabetics control patients (mean age 61.8+/-12,8 years, 13 men and 18
      women). All patients were treated with (600 mg) once daily. The doses was
      ingested in the morning. They were made three follow up visits (1, 3 and 6 mo
      after the first visit). RESULTS: SBP was significantly decreased both in
      diabetics (baseline 170.9+/-12.0, final 139.1+/-13.0 mmHg, p < 0.001) and in non
      diabetics group (baseline 169.9+/-18.0, final 142.0+/-13.3 mmHg, p < 0.001). DBP
      was also reduced in both groups (diabetics: baseline 92.9+/-9.7, final 78.4+/-8.5
      mmHg, p < 0.001; non diabetics: baseline 95.6+/-7.9, final 79.1+/-7.4 mmHg, p <
      0.001). Differences between the groups were not significant in any visit. Final
      BP reduction reached was -31.7/-14.6 mmHg in diabetics vs -27,6/-16,5 mmHg in non
      diabetics patients (difference is not significant) Pulse pressure changes were
      not different between the two groups (diabetics, 17.8+/-14.5, vs non diabetics,
      11.1+/-13.2 mmHg). Two diabetic patients need a second drug to achieve BP goal
      and no one in non diabetic group. No adverse effects were reported. CONCLUSIONS:
      Eprosartan seems to be an effective drug to reduce SBP, DBP and pulse pressure
      with the same effectiveness in diabetics and non diabetic patients.

PMID- 15176924
TI  - [CA 19.9 and HDL-cholesterol behaviour in a sporadic colorectal carcinoma
      sample].
AB  - BACKGROUND AND OBJECTIVE: We have carried out a comparative prediction analysis
      in sporadic colorectal carcinoma of plasmatic lipids and currently tumor markers
      used in this neoplasia (carcinoembrionary antigen - CEA, CA 19.9 and sialic acid 
      SA). PATIENTS AND METHODS: Transversal hospital-based case-control study. Sample
      was composed by 53 sporadic colorectal neoplasia patients just before surgery and
      40 non matched controls. A 90 per cent of cases were at Dukes A and B stages. A
      multivariable model was fitted with non-conditional logistic regression.
      Confidence intervals were calculated at 95 per cent of confidence. Model
      sensibility and specificity were performed at 50 per cent cutting point. We also
      explored possible interactions. RESULTS: All three tumor markers (CEA, CA 19.9
      and SA) were elevated in cases (p<0.01). Multivariable model included: Total
      cholesterol (TC) (OR= 0.69; CI: 0.50-0.96) high density lipoprotein fraction
      (HDL) (OR = 0.30; CI: 0.11-0.83) very low density lipoprotein fraction (VLDL) (OR
      = 2.21; CI = 1.07-4.55) years of age (OR = 1.11; CI = 0.98-1.26) CA 19.9 (OR =
      1.20; CI = 1.02-1.42) and alkaline phosphatase (OR = 1.09; CI = 1.01 - 1.19). No
      interactions were found out. Model sensibility reached 96.23% and a specificity
      of 92.50%. CONCLUSIONS: HDL showed a similar diagnostic strength than CA 19.9 in
      this sporadic colorectal carcinoma sample but with an inverse OR. This
      multivariable model is going to be validated.

PMID- 15176925
TI  - [Atheroembolic disease and pulmonary haemorrhage].
AB  - The cholesterol embolism syndrome is a multisystemic disease resulting from
      cholesterol crystal emboli deriving from ulcerous atherosclerotic plaques of the
      aorta or large arteries. Cholesterol crystal embolization can affect multiple
      organ, including the skin, kidney, brain, eyes, gastrointestinal tract and
      extremities, and mimic other systemic diseases like vasculitis. Cholesterol
      crystal embolization of lungs has been described and should be included in the
      differential diagnostic of pulmonary-renal syndromes. The diagnosis of
      cholesterol embolism should be considered in elderly patients with pre-existing
      atherosclerotic disease who develop renal failure and clinical features of
      peripheral cholesterol crystal embolization in association with precipitating
      event, without the need for histological demonstration of cholesterol clefts.
      This syndrome is associated with high morbidity and mortality but recent reports
      suggest that an aggressive therapeutic management with patient-tailored
      supportive measures, avoids precipitating factors, and the use of corticosteroids
      may be associated with a favorable clinical outcome.

PMID- 15176926
TI  - [Statin-induced rhabdomyolysis and renal failure: also with fluvastatine].
AB  - Hydroximetilglutaril-coenzima A reductase inhibitors (statin) have the potential
      to cause rhabdomyolysis. However, fluvastatin is rarely associated with
      rhabdomyolysis when compared to other statins. Differences in biochemical and
      pharmacokinetic properties between fluvastatin and the other statins have been
      invocated in order to explain the apparent comparative safety of fluvastatin. We
      present a case of rhabdomyolysis with acute renal failure in a patient receiving
      fluvastatin and, following the Karch-Lasagne algorithm, we present evidence that
      this case was an adverse reactions to fluvastatin.

PMID- 15176927
TI  - [Amebic colitis in an immunocompetent host].
AB  - Amebic colitis is a low prevalence illness in developed countries. Its diagnosis
      is infrequent and is usually made in certain groups of risk. Images studies are
      not useful in differential diagnosis with other illnesses as Inflammatory Bowel
      Disease (IBS). Next clinical note shows the problems in the diagnosis of amebic
      colitis in an immunocompetent host without risk factors.

PMID- 15176928
TI  - [Nodular secondary syphilis in a HIV patient mimicking cutaneous lymphoma].
AB  - We report the case of a 61-year old man who, already for a month, had infiltrated
      plaques on the chest, back, neck and face as well as axilar lymphadenopathy,
      bearing a striking resemblance to lymphoma. During his stay in the hospital he
      had fever, sore throat, macules on the palms and soles and a depapilated plaque
      on the tongue and alopecia. A test for syphilis confirmed the diagnosis. The HIV
      serology was also positive. The nodular secondary syphilis is an unusual form
      that was first documented more than 20 years ago. Since then, only a few cases
      have been reported in which the first diagnosis included lymphoreticular
      malignancy. This form of secondary syphilis was found in the HIV-infected as well
      as non-infected patients. We discuss the atypical clinical course, the
      inappropriate serological reactions and the therapy in HIV infected patients with
      secondary syphilis.

PMID- 15176930
TI  - [From tuberculosis to pulmonary aspergilloma. Apropos of a case].

PMID- 15176929
TI  - [Eoshinophilia: a practical approach].
AB  - In this first part of this paper we review the definition of eosinophilia and
      their classification according to the degree of elevation of eosinophils/microL.
      Aetiological factors related with eosinophilia were described in three groups of
      patients: a). autochthonous non-infected by HIV; b). HIV-infected; and c).
      arrived from tropical countries (imported eosinophilia). We included an
      algorithmic approach to the diagnosis, including the diagnostic studies that
      should be performed in patients with or without organ involvement. Pathological
      consequences of eosinophilia are indicated in the next part of the paper.
      Finally, therapeutical options used in patients with eosinophilia are reviewed,
      with an special emphasis on antihelminthic therapies and the management of the
      hypereosinophilic syndromes.

PMID- 15176931
TI  - [Epididymo-orchitis as the first manifestation of tuberculous reactivation].

PMID- 15176932
TI  - [Melkersson-Rosenthal syndrome, about one case with bilateral facial paralysis].

PMID- 15176933
TI  - [Deep venous thrombosis of the neck associated with lung cancer].

PMID- 15176934
TI  - [Renal metastasis from non-small cell lung carcinoma].

PMID- 15176935
TI  - [Jejunitis ulcerative chronic: disease in its own right?].

PMID- 15176936
TI  - [Does antithyroidal drug dose influence relapse of treated Graves-Basedow
      disease?].

PMID- 15176937
TI  - The immunization imperative.

PMID- 15176938
TI  - Progenics to develop HIV vaccine.

PMID- 15176940
TI  - Towards a Chlamydia vaccine. Interview by Kelly McCauley.

PMID- 15176941
TI  - A chimeric live attenuated vaccine against Japanese encephalitis.
AB  - Japanese encephalitis is a disease of the CNS, endemic in Asia and Oceania. The
      disease is refractory to drug treatments and whilst the rural economies remain
      heavily dependent on agriculture, conditions for propagation of the disease will
      persist. Thus, there is a need for effective vaccines. Although some currently
      exist, they have their shortcomings. ChimeriVax-JE (Acambis Inc.) is a chimeric,
      live attenuated vaccine which expresses protective Japanese encephalitis antigens
      and to date has proven to be safe, effective and well-tolerated in clinical
      trials. It therefore appears to be a cost-effective prophylactic vaccine against
      this debilitating disease.

PMID- 15176942
TI  - A review of the efficacy, immunogenicity and tolerability of a combined hepatitis
      A and B vaccine.
AB  - Hepatitis A and B are two of the most common vaccine-preventable liver diseases
      and continue to be a significant cause of morbidity and mortality worldwide, with
      their severity related to the individual's age upon initial infection. Twinrix
      (GlaxoSmithKline), a combined vaccine providing protection against both hepatitis
      A and B, has been available in more than 72 countries worldwide since 1997. This
      paper provides a critical review of clinical data on the efficacy, immunogenicity
      and tolerability of the combined vaccine, with particular focus on the clinical
      benefits of dual vaccination.

PMID- 15176943
TI  - Vaccination as a treatment for breast or ovarian cancer.
AB  - The immune system recognizes breast and ovarian cancer cells but whether it is
      effective in controlling these cancers in patients has yet to be proven. The
      challenge with vaccination strategies is to break tolerance so that the patient's
      immune system will recognize cancer cells. The success of vaccines depends on the
      identification of appropriate tumor antigens, establishment of effective
      immunization strategies and their ability to circumvent inhibitory immune
      mechanisms.

PMID- 15176944
TI  - Vaccines for conformational disorders.
AB  - Neurodegenerative disorders are becoming increasingly common and an ever greater
      healthcare burden, as the average age in Western populations rises. Many of these
      are conformational disorders, which are characterized by the accumulation of a
      host protein that undergoes a structural change increasing its beta-sheet
      content, rendering it toxic. The most common of these illnesses is Alzheimer's
      disease. Prion diseases are also conformational disorders, which are currently
      less common than Alzheimer's disease, however, these illnesses have no treatment
      and are universally rapidly fatal. The emergence of new variant Creutzfeldt-Jakob
      disease has raised the possibility of a large population at risk for this
      illness, as well as causing great concern regarding the safety of blood bank
      supplies. Recently, immune modulation has emerged as a highly promising
      therapeutic strategy for both Alzheimer's and prion diseases. We and others have
      demonstrated in both Alzheimer's and prion disease animal models that vaccination
      can dramatically improve the course of the illness. A human trial of an
      Alzheimer's disease vaccine using A beta1-42 was halted due to toxicity in a
      minority of patients (6%). However, recent data suggests that patients with a
      humoral response to A beta benefited cognitively from the vaccine. Toxicity in
      this human trial has been linked to excessive cell-mediated immunity. Novel
      vaccine strategies are under development for both Alzheimer's disease and
      prionoses which are predicted to have few or no significant side effects, while
      being efficacious.

PMID- 15176945
TI  - Varicella zoster virus: vaccination and implications in children with renal
      failure.
AB  - The varicella zoster virus is associated with significant disease in those with
      chronic kidney disease, both pre- and postrenal transplantation. With the advent
      of the varicella vaccine, the opportunity to prevent significant morbidity and
      mortality exists. Despite the secondary immune defects associated with renal
      failure, the varicella vaccine has been demonstrated to be immunogenic, safe and
      efficacious in pediatric patients with kidney disease.

PMID- 15176946
TI  - Developing an improved vaccine against tuberculosis.
AB  - Despite the availability of a vaccine for over 80 years, the tuberculosis
      epidemic continues to be a major cause of mortality and morbidity throughout the
      world. The factors contributing to the resurgence of tuberculosis and the
      possible explanations for the failure of the current vaccine, bacille Calmette
      Guerin, are discussed. The nature of protective immunity to Mycobacterium
      tuberculosis and how this relates to the development of new candidate vaccines is
      then considered. The issues surrounding the progression of the most promising
      candidates into Phase I clinical trials are also discussed.

PMID- 15176947
TI  - Vaccines against Francisella tularensis--past, present and future.
AB  - Francisella tularensis is a facultative intracellular bacterial pathogen capable
      of causing a spectrum of human diseases collectively called tularemia. The
      pathogen is highly infectious and some strains can cause rapidly lethal infection
      especially when inhaled. The latter were developed as biological weapons in the
      past and nowadays cause concern as potential bioterrorism agents. A live
      attenuated strain of the pathogen was developed more that 40 years ago and
      remains the sole prophylactic measure against the pathogen. Research to develop
      better live and subunit vaccines is under way. The former will require an
      understanding of the virulence factors of F. tularensis and a facile means of
      mutating them and the latter will require identification of the protective
      antigens of the pathogen. The current vaccine and its potential replacements are
      the focus of this review.

PMID- 15176948
TI  - Current status and future prospects for a vaccine against schistosomiasis.
AB  - Schistosomiasis remains an intractable problem in many parts of the world.
      Whereas the schistosome parasites cause little in the way of disease, their eggs
      become trapped in tissues of the host and elicit powerful and potentially
      damaging immune responses that are responsible for the pathology. Despite nearly
      four decades of effort there is still no effective vaccine against
      schistosomiasis, although a single vaccine candidate is undergoing clinical
      trials at present. Animal models have revealed much about disease progression and
      pathology. However, problems remain in identifying appropriate protective
      antigens to elicit immune responses that will attack the parasite but will not
      cross-react with egg antigens and thus increase the chance of developing severe
      chronic disease in individuals that have already been infected. This review
      summarizes the life-cycle of the parasite, current knowledge of pathogenesis and
      acquired immunity based on animal studies and observations in humans and the
      status of efforts in the vaccine development field.

PMID- 15176949
TI  - A novel outer-membrane anion channel (porin) as part of a putatively two
      component transport system for 4-toluenesulphonate in Comamonas testosteroni T-2.
AB  - Inducible mineralization of TSA (4-toluenesulphonate) by Comamonas testosteroni T
      2 is initiated by a secondary transport system, followed by oxygenation and
      oxidation by TsaMBCD to 4-sulphobenzoate under the regulation of TsaR and TsaQ.
      Evidence is presented for a novel, presumably two-component transport system
      (TsaST). It is proposed that TsaT, an outer-membrane porin, formed an anion
      selective channel that works in co-operation with the putative secondary
      transporter, TsaS, located in the inner membrane. tsaT was identified as a 1017
      bp ORF (open reading frame) on plasmid pTSA upstream of the TSA-catabolic genes
      in the tsa operon. Expression of tsaT was regulated by TsaR, the transcriptional
      activator of the tsa regulon. The presence of tsaT was concomitant with the
      presence of the tsa operon in different TSA-degrading isolates. tsaT was
      expressed in Escherichia coli and was detected in the outer membrane. A 22-amino
      acid leader peptide was identified. Purified protein reconstituted in lipid
      bilayer membranes formed anion-selective channels with a single-channel
      conductance of 3.5 nS in 1 M KCl. Downstream of tsaT, a constitutively expressed
      720-bp ORF (tsaS) was identified. tsaS coded for a hydrophobic protein predicted
      to have six transmembrane helices and which is most likely localized in the
      cytoplasmic membrane. tsaS is adjacent to tsaT, but showed a different
      transcriptional profile.

PMID- 15176950
TI  - Cloning, expression in Escherichia coli and characterization of the recombinant
      Neu5Acalpha2,6Galbeta1,4GlcNAc-specific high-affinity lectin and its mutants from
      the mushroom Polyporus squamosus.
AB  - Lectin from the mushroom Polyporus squamosus (PSL) has a unique carbohydrate
      binding specificity for sialylated glycoconjugates containing
      Neu5Acalpha2,6Galbeta1,4Glc/GlcNAc trisaccharide sequences of asparagine-linked
      glycoproteins. In the present study, we elucidate the molecular basis for its
      binding specificity as well as establish a consistent source of this useful
      lectin using a bacterial expression system. cDNA cloning revealed that PSL
      contains a ricin B chain-like (QXW)(3) domain at its N-terminus that is composed
      of three homologous subdomains (alpha, beta and gamma). A recombinant lectin was
      expressed in Escherichia coli as a fully active, soluble form. It agglutinated
      rabbit erythrocytes and showed the highest affinity for
      Neu5Acalpha2,6Galbeta1,4GlcNAc, but not for the sialyl alpha2,3-linked isomer. We
      also investigated the structure-function relationship of PSL. A monomeric C
      terminal deletion mutant lacking 40% of the lectin's molecular mass retained
      sugar-binding activity, indicating that the carbohydrate-binding sites are
      situated in the N-terminal portion of the lectin, whereas the C-terminal portion
      probably functions in oligomerization and structural stabilization. Mutant
      constructs that have single amino acid substitutions in the putative sugar
      binding sites, based on sequence alignment with the ricin B-chain, indicate that
      the beta and gamma subdomains are most probably sugar-binding sites. The
      recombinantly expressed lectin will be a valuable reagent for the detection of
      the Neu5Acalpha2,6Galbeta1,4GlcNAc sequence of asparagine-linked glycans.

PMID- 15176951
TI  - Identification of the growth hormone-releasing peptide binding site in CD36: a
      photoaffinity cross-linking study.
AB  - The GHRPs (growth hormone-releasing peptides) are a class of small synthetic
      peptides known to stimulate GH release through binding of a G-protein-coupled
      receptor (designated GHS-R). We have found that hexarelin, a hexapeptide member
      of the GHRPs, binds to another protein identified as CD36, a scavenger receptor
      that is expressed in various tissues, including monocytes/macrophages and the
      endothelial microvasculature. CD36 is involved in the endocytosis of oxLDL
      (oxidized low-density lipoprotein) by macrophages, and in the modulation of
      angiogenesis elicited by thrombospondin-1 through binding to endothelial cells.
      To define the binding domain for hexarelin on CD36, covalent photolabelling of
      CD36 followed by enzymic and chemical degradation of the photoligand-receptor
      complex was performed. A 8 kDa photolabelled fragment corresponding to the CD36
      (Asn132-Glu177) sequence has been identified as the hexarelin-binding site.
      Chemical cleavage of this fragment with CNBr resulted in the release of the free
      ligand, suggesting that Met169 is the contact point for the ligand within the
      receptor binding pocket. We conclude that the binding domain for hexarelin on
      CD36 overlaps with that for oxLDL, which corresponds to residues Gln155-Lys183 of
      CD36. Hence hexarelin might interfere with the CD36-mediated uptake of modified
      lipoproteins by macrophages. This may contribute, at least in part, to the anti
      atherosclerotic effect of GHRPs in apolipoprotein E-deficient mice.

PMID- 15176952
TI  - Drug interactions between mycophenolate and cyclosporine.

PMID- 15176953
TI  - Proactive psychosocial management of children and their families with chronic
      liver disease awaiting transplant.

PMID- 15176954
TI  - The value of the PRISM scores in comparing pediatric liver transplant outcomes.

PMID- 15176955
TI  - Withdrawal of immunosuppression in liver transplantation: lessons learned from
      PTLD.

PMID- 15176956
TI  - Solid organ transplantation in HIV-infected recipients.
AB  - HIV is generally regarded as an acceptable reason to exclude a potential
      recipient from consideration for transplantation. Most of the data in the
      literature regarding transplantation of HIV sero-positive individuals pertains to
      the time prior to the administration of Highly Active Anti-Retroviral Therapy
      (pre-HAART). This data, therefore, provides little guidance for the management of
      HIV-positive individuals in the current era. The development of HAART has
      resulted in a decreased mortality. With prolonged survival more HIV-infected
      individual are developing end stage organ disease from co-existing conditions
      such as HCV and HBV, and diseases common in the general population such as
      diabetes mellitus and hypertension. This has lead to clinicians, researchers and
      patients to actively investigate the role of solid organ transplantation in HIV
      infected individuals. In this article We review the literature to date in liver
      and renal transplantation, including more recent data in patients receiving
      HAART.

PMID- 15176957
TI  - Impact of liver transplantation on HRQOL in children less than 5 years old.
AB  - Our primary goal was to assess health related quality of life (HRQOL) at
      transplantation and 1 yr after transplantation in pediatric liver transplant
      patients aged less than 5 years. We conducted a prospective longitudinal study of
      HRQOL in pediatric liver transplant recipients, aged less than 5 years to define
      the impact of liver transplantation on HRQOL and identify factors that predict
      HRQOL after transplantation. The infant toddler health status questionnaire
      (ITHQ) was completed at the time of listing for liver transplantation and at 6
      and 12 months after liver transplantation. The primary outcome measures were the
      subscale scores that comprise ITHQ. The mean age (+/-s.e.m.) of the enrolled
      patients (n = 45) at transplantation was 1.4 (+/-1.2) yr. Thirty-eight (84%) of
      the enrolled patients completed the study. The highest mean baseline scores of
      78.6 (+/-3.3) were for global mental health (GlobalMH). ITHQ subscale scores
      increased steadily after transplantation. The greatest increase was in the first
      6 months after transplant. At 1 yr after transplantation, there were significant
      increases in all of the ITHQ subscale scores except for GlobalMH. ITHQ subscales
      were similar for patients who received LDLT compared with those who received
      cadaver donor liver transplantation (CDLT) at baseline and a year after
      transplant. Time elapsed as transplantation was a significant predictor of
      functional health in all of the models generated. Scores for general health (GH),
      global health (GGH), parental time-impact (PT) and parental time-emotion (PE)
      were higher for male children. Family cohesion (FC) improved with time elapsed
      since transplant and increased number of inpatient days. HRQOL improves after
      transplantation in all of our patients irrespective of the donor type. Functional
      health scores were higher in patients with normal serum bilirubin at 1 yr post
      transplant. Assessment of HRQOL should be an integral part of care for liver
      transplant patients and their caregivers.

PMID- 15176958
TI  - Liver transplantation in infants weighing under 7 kilograms: management and
      outcome of PICU.
AB  - Liver transplantation (LT) is an established treatment for children with acute
      and chronic liver failure. Some reports suggest that infants under the age of 1
      yr and children weighing under 13 kg are high-risk groups associated with less
      satisfactory results. This report describes our experience during the pediatric
      intensive care unit stay of 16 infants weighing <7 kg who received LT. We
      reviewed the records of 16 infants with median age 7.4 months and median weight
      5.8 kg, who received 18 liver allografts, nine whole and nine reduced. We also
      reviewed the use of adrenergic agonist agents, anti-infectious agents,
      antihypertensive agents, diuretics, immunosuppression protocol, sedation
      analgesia agents, others agents (prostaglandin E(1), heparin and dipyridamole),
      diagnosis and management of rejection episodes, follow-up examination, nutrition
      and outcome. Mean peri-operative blood transfusions were 204 mL/kg, 188 mL/kg of
      plasma and 36 mL/kg of platelets; mean operative time was 5 h. Primary abdominal
      wound closure was possible in nine patients. Median initial intensive care unit
      stay was 18 days. Reasons for an initial stay of more than 18 days were
      retransplantation (1), gastrointestinal bleeding (2), paralytic ileus and
      atelectasis (2), septic shock (2), diaphragmatic paralysis, renal impairment and
      acute respiratory distress syndrome (2). Mean requirement for artificial
      ventilation was 168 h. Mean use of dobutamine, prostaglandin E(1) and dopamine
      was 3.3, 7.5 and 8.8 days, respectively. Parenteral nutrition was started at a
      mean of 48 h and oral food intake was started at a mean of 72 h. The most
      frequent complications were infection, atelectasis, gastrointestinal bleeding,
      acute renal failure and hepatic artery thrombosis. Four children required six re
      explorations and two received retransplantation. Mean overall survival rate was
      82% and graft survival was 72%. Weight alone (under 7 kg) should not be
      considered as a contraindication for LT. The survival rate of children post-LT is
      excellent regardless of graft type.

PMID- 15176959
TI  - Non-compliance in children post-liver transplant. Who are the culprits?
AB  - Although non-compliance in pediatric liver transplants is known to be a major
      cause of late graft loss and patient mortality, follow-up seems inconsistent. As
      liver transplant becomes a luxury because of the shortage of organs, the need to
      maximize graft and patient survival by intense monitoring becomes a necessity.
      When evaluating children with elevated liver enzymes post-transplant, early or
      late non-compliance should always be suspected. The risk of non-compliance in
      children with chronic illness varies from 10 to 89%. In a study by Sudan et al.
      non-compliance was one of the leading causes of late mortality in children age 10
      17 yr. Although it is well documented that teenagers have a high rate of non
      compliance, the rate in the younger children has not been documented. In our
      series, we found that parental non-compliance comprises the majority of our
      problems with liver dysfunction, hospitalization, and graft loss. The purpose of
      this study was to evaluate the incidence of non-compliance in children post-liver
      transplant. A retrospective chart review of patient records from admissions and
      outpatient records was performed for documentation of elevated enzymes and low
      immunosuppressive levels. From July 1987 to December 2002, our program performed
      266 liver transplants in 234 children, with 1-yr graft survival of 84% and 1-yr
      patient survival of 90%. Our overall patient survival was 85% with 77% graft
      survival. There were 40 children with documented non-compliance with mild to
      severe liver dysfunction in this study. Twenty-eight of these children were
      younger than 10 yr [28 of 40 (46%) <5 yr], and 12 (30%) were older than 10 yr at
      the time of rejection. In 10 of 40 children, there was one documented incident of
      non-compliance, while 26 of 40 had two to four incidents, and four had five or
      more documented events. Our children (50%) came from two-parent households. The
      remaining 50% were from single households. In 27 of 40 (68%) children, rejection
      was confirmed by liver biopsy. In children on cyclosporine (Neoral; Novartis,
      East Hanover, NJ, USA) with a known history of non-compliance and low
      immunosuppressive levels, C2 monitoring was performed to verify absorption.
      Admission for drug monitoring and verification of non-compliance was accomplished
      in 32 of 40 (80%). Four of the 40 children (10%) were retransplanted, and one
      child had died. In conclusion, non-adherence to medications remains a major
      source of graft loss and morbidity post-transplant. We found that non-compliance
      crosses all socio-economic and cultural groups and that flexibility of clinic
      hours, shortened time between visits, and decreased numbers and times of
      medication will increase adherence.

PMID- 15176960
TI  - Perioperative management in pediatric heart transplantation from 1988 to 2001:
      anesthetic experience in a single center.
AB  - Pediatric cardiac transplantation is currently an accepted option for end-stage
      heart disease and congenital cardiac malformations. This report focuses on the
      anesthetic perioperative management in 12 yr. From 1988 to 2001 we performed 90
      heart transplantations in 88 children, infants and neonates. The pediatric heart
      transplant program of the children's heart center at our university hospital
      started in June 1988 with the transplantation of a 2-yr-old boy who was suffering
      from congenital heart disease. Since then, 88 transplants have been performed. We
      divided our patients into two groups. Group 1 ranged from 1988 to 1996 and Group
      2 from 1997 to 2001. The patient characteristics have not significantly changed
      over the years in our institution. At the time of transplantation, mean age of
      the patients was 2.6 +/- 4.3 yr from the period of 1988-1996 and 2.5 +/- 4.1 yr
      from 1997 to 2001. Since 1988, 90 transplants (Tx) in 88 patients have been
      performed. Two patients needed re-Tx within 2 days after the initial operation
      because of primary graft failure. Indications for Tx were congenital heart
      disease (n = 67) and cardiomyopathy (n = 21). In the subgroup of the patients
      suffering from congenital heart disease there were 46 with the diagnosis of HLHS,
      followed by endocardial fibroelastosis (n = 7); the remaining 14 patients had
      other complex cardiac malformations and some underwent corrective palliative
      cardiac surgery before Tx. Sixty-three patients were younger than 1 yr of age and
      only five children were older than 10 yr. Twenty-three percent of the patients on
      the waiting list died before Tx was possible. The overall survival rate was 79%
      at 1 yr and 73% at 5 and 10 yr. Infants with HLHS had a lower probability of
      survival after 5 yr compared with other diagnosis (69% vs. 84%). Until now 21
      patients have died after Tx. The duration of anesthesia, time of CPB and the age
      at the time of surgery decreased over the years. It is always a challenge for the
      anesthesiologist to treat these patients with pulmonary hypertension as one of
      the most critical risks in this group of patients. The preventive therapy with
      vasodilators as well as the availability of mechanical assist devices before and
      after heart transplantation reduces the effects of transitional pulmonary
      hypertension and prevents the development of post-operative right heart failure.

PMID- 15176961
TI  - Sirolimus for pediatric liver transplant recipients with post-transplant
      lymphoproliferative disease and hepatoblastoma.
AB  - Sirolimus is a promising immune suppressive agent, with the potential to reduce
      calcineurin inhibitor associated nephrotoxicity, halt progression of chronic
      rejection and prevent tumor proliferation. The aim of this study was to review
      the experience using sirolimus in pediatric liver transplant recipients at a
      single center. Database and medical charts of all pediatric liver transplant
      recipients receiving sirolimus at the Hospital for Sick Children in Toronto were
      reviewed. Eight patients received sirolimus between October, 2000 and September,
      2002. Indications for using sirolimus were post-transplant lymphoproliferative
      disease (PTLD) (n = 6) and hepatoblastoma (n = 2). Two patients with PTLD
      concurrently had renal impairment and chronic rejection. Sirolimus dosages ranged
      between 1.5 and 5 mg once daily. Median duration of follow-up was 17 months.
      Persistently elevated liver transaminase levels in the two children with chronic
      rejection decreased during sirolimus therapy. Recurrence of PTLD occurred in one
      patient. Two patients were diagnosed with acute cellular rejection after
      transition to maintenance sirolimus monotherapy. Resolution of adverse effects
      including mouth sores (n = 3), leg swelling (n = 2) and hyperlipidemia (n = 3)
      occurred either spontaneously or with dose reduction. Sirolimus was discontinued
      in four patients because of persisting bone marrow suppression, interstitial
      pneumonitis, life-threatening sepsis and refractory diarrhea. Children with PTLD
      or hepatoblastoma may benefit from immune suppression with sirolimus after liver
      transplantation. Further multi-center, prospective, randomized controlled trials
      will be instrumental to further the knowledge of long-term efficacy, safety and
      tolerability of sirolimus for selected children following liver transplantation.

PMID- 15176962
TI  - Echocardiographic changes and risk factors for left ventricular hypertrophy in
      children and adolescents after renal transplantation.
AB  - Long-term consequences of cardiac alteration in children with chronic renal
      failure and after renal transplantation are largely unknown. In chronic uremia,
      cardiomyopathy manifests itself as systolic dysfunction, concentric left
      ventricular hypertrophy (LVH) or left ventricular dilatation. The correction of
      uremic state by renal transplantation leads to normalization of left ventricular
      contractility, regression of LVH and improvement of cavity volume and so dialysis
      patients with uremic cardiomyopathy would benefit from renal transplantation. We
      studied 73 patients, aged 17 yr or less, who underwent renal transplantation in
      our center. This cross-sectional study was performed 4.6 yr (median) after
      transplantation. Of the total, 48 were males and 25 were females. Transthoracic
      echocardiographic examination was performed for all cases. The effects of
      clinical, demographic, biochemical and therapeutic data on echocardiographic
      parameters were assessed. Multivariate analysis was used to assess the relation
      between the risk factors and the left ventricular muscle mass index. The most
      common echocardiographic abnormalities were the LVH (47.9%), left atrial
      enlargement (31.5%) and left ventricular dilatation and systolic dysfunction
      (13.7% for each). The pretransplant dialysis, arteriovenous fistula, acute
      rejection, cumulative steroid dose per square meter surface area, post-transplant
      hypertension, anemia and graft dysfunction were significant risk factors for LVH
      by univariate analysis. The significant factors by multivariate analysis were
      pretransplant dialysis, post-transplant hypertension and anemia. From this study
      we may conclude that LVH is a common problem among renal transplant children and
      adolescents. Early transplantation, control of hypertension and correction of
      anemia may be beneficial regarding left ventricular function and structure.

PMID- 15176963
TI  - Evaluation of catch-up growth after liver transplantation in children with
      biliary atresia.
AB  - Orthotopic liver transplantation (Tx) has improved survival in infants with
      extrahepatic biliary atresia (BA) when portoenteroanastomosis fails. Symptoms
      leading to Tx include liver failure, poor quality of life and growth failure. The
      objective of the study was to determine catch-up growth in children with BA.
      Medical records and growth data of 36 patients (24 girls) who received a Tx due
      to BA were analyzed. Thirty-two patients completed 3 yr and 15 patients 7 yr of
      follow-up after Tx. At Tx, the median age was 2.7 yr (range 0.7-12.6) and mean
      height Z score (+/-s.d.) was -1.56 (+/-1.3). Patients were divided in two groups
      according to age at Tx: group I (n = 10), younger than 1.0 yr, and group II (n =
      26) older than 1.0 yr. Median age (range) at Tx in group I was 0.8 yr (0.7-1.0)
      and in group II it was 3.35 yr (1.25-12.6). Thirteen patients (nine in group I)
      were receptors of living related donors. We evaluated linear growth, liver and
      renal function, immunosuppressive regimen and allograft rejection episodes. We
      did not find any significant differences in allograft or renal function,
      immunosuppressive therapy and number of acute rejection episodes or height Z
      score at Tx, second and third year post-Tx between both groups. The mean height Z
      score at Tx in group I was -1.61 and in group II -1.54; at the second year, group
      I -0.66 and group II -1.08; at the third year, group I -0.17 and group II -0.85;
      and at the seventh year (total group) -0.3. However, the height gain at the third
      year was better in group I than in group II (p < 0.01, t-test). Height Z score at
      the third year improved more than 1 SDS in seven out of eight patients in group I
      and in only nine out of 24 in group II (odds ratio 11.6). We also found a
      correlation between height gain at the third year and age at Tx (r-0.65) and
      between height gain at the third year and height Z score at Tx (r-0.54) (Pearson,
      p < 0.05). Children with BA who are transplanted before 12 months of age
      presented better catch-up growth without change survival and morbidity.
      Orthotopic liver Tx improves survival and also enables height gain in these
      children.

PMID- 15176964
TI  - Comparison of the outcomes of allogeneic bone marrow transplantation from
      partially mismatched related donors, matched sibling donors, and matched
      unrelated donors in Japanese pediatric patients: a single center result.
AB  - Human leukocyte antigen-disparity is an essential factor in selecting a suitable
      donor for allogeneic bone marrow transplantation (BMT), and selection criteria
      may differ between countries or races and between adults and children. We
      investigated the usefulness of partially mismatched related donors (PMRD) for
      Japanese children in comparison with matched sibling donors (MSD) and matched
      unrelated donors (MUD). Eighteen patients were transplanted from PMRD, who
      consisted of 12 parents, five siblings, and one cousin. Five of these 18 patient
      donor pairs were serologically two-loci mismatched and 13 were one-locus
      mismatched. The probability of engraftment from PMRD was not different from that
      using BMT from MSD (n = 59) or MUD (n = 28). Severe acute graft-versus-host
      disease (GVHD) (>/=grade III) developed more frequently in PMRD (25.5 +/- 11.0%)
      than in MSD (0.0%), but was seen just as often as in MUD (21.9 +/- 7.9%). The
      probabilities of chronic GVHD in PMRD (56.7 +/- 14.3%) and MUD (41.7 +/- 11.4%)
      were significantly higher than that in MSD (18.7 +/- 5.7%, p = 0.01). However,
      there was no difference in the probability of event-free survival among the three
      groups. We conclude that PMRD (up to two-loci mismatch) could become suitable
      donors in BMT to the same extent as MUD for pediatric patients in Japan.

PMID- 15176965
TI  - Complete immunosuppressive withdrawal as a uniform approach to post-transplant
      lymphoproliferative disease in pediatric liver transplantation.
AB  - Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease
      (PTLD) in pediatric liver transplant recipients is associated with a high
      mortality (up to 60%) and the younger age groups, who are predominantly EBV
      naive, are at highest risk for development of this disease. The aim of this study
      is to assess, in this high-risk group, patient outcome and graft loss to
      rejection when complete withdrawal of immunosuppressive agents (IMS) is
      instituted as the mainstay of treatment in addition to the use of standard
      therapy. A retrospective analysis of 335 pediatric patients whose liver
      transplants were performed by our team between September 1988 and September 2002,
      was carried out through review of computer records, database and patient charts.
      Fifty patients developed either EBV or PTLD; 80% were < or =2 yr of age. Of these
      50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed
      with EBV infection, 14 of whom had positive tissue for EBV. Fifty-eight percent
      of patients who developed PTLD and 51.6% of patients with EBV received antibody
      for induction or treatment of rejection prior to onset of disease. Forty-six
      patients (92%) received post-transplant antiviral prophylaxis with ganciclovir or
      acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and
      Cytogam (in addition to one of the former agents) in 44%. In those with PTLD,
      treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation
      (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection
      and was held as long as there was no allograft rejection. Eight patients have
      remained off IMS for a mean of 1535.5 +/- 623 days. Of the 21 patients who were
      restarted on IMS for acute rejection, 18 responded to steroids and/or
      reinstitution of low-dose calcineurin inhibitors. The mean time to rejection
      while off IMS in this group was 107.43 +/- 140 days (range: 7-476). Two patients
      were re-transplanted for chronic rejection; one had chronic rejection that
      existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in
      those with PTLD and 6% in those with EBV disease. The cause of death was related
      to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or
      chronic rejection. PTLD is associated with high mortality in the pediatric
      population. Based on this report, we advocate aggressive management of PTLD that
      is composed of early cessation of IMS, the use of antiviral therapy, and
      chemotherapy when indicated. Episodes of rejection that occur after stopping IMS
      can be successfully treated with standard therapy without graft loss to acute
      rejection.

PMID- 15176966
TI  - Studies of Pediatric Liver Transplantation 2002: patient and graft survival and
      rejection in pediatric recipients of a first liver transplant in the United
      States and Canada.
AB  - Studies of Pediatric Liver Transplantation (SPLIT) is a cooperative research
      network comprising 38 pediatric liver transplant centers in North America. Data
      from the 1092 patients who have received a first liver transplant since 1995 were
      analyzed for factors influencing patient survival, graft survival and acute
      rejection. The 3, 12, 24 and 36 month Kaplan-Meier estimates of patient/graft
      survival were 90.9/85.5, 86.3/80.2, 84.3/76.0, and 83.8/75.3% respectively.
      Univariate analysis identified initial diagnosis, type of graft (whole vs. living
      and cadaveric technical variant), growth failure and continuous hospitalization
      or ICU admission prior to transplantation as significantly influencing patient
      and graft survival. Subsequent multivariate analysis identified as risk factors
      for death: fulminant liver failure (RR = 3.05, p < 0.05), cadaveric technical
      variant grafts (RR = 1.95, p < 0.05), continuous hospitalization pre-transplant
      (RR = 1.79, p < 0.05), height deficit >2 s.d. from mean (RR = 3.22, p < 0.05).
      Risk factors for graft loss included: fulminant liver failure (RR = 2.27, p <
      0.05), cadaveric technical variant grafts, (RR = 1.97, p < 0.05). Eleven percent
      of the 1092 patients were re-transplanted; vascular complications, particularly
      hepatic artery thrombosis (8.3% overall; 36.3% of graft failures), were
      responsible for the majority of re-transplants. Infection was the single most
      important cause of death (40 of 141, 28.4%) and was a contributing cause in 55
      (39%), particularly with bacterial or fungal organisms. The cumulative Kaplan
      Meier estimates of first rejection at 3, 12, 24 and 36 months were 44.8, 52.9,
      59.1, and 60.3%. Initial immunosuppression with tacrolimus reduced the
      probability of rejection (RR = 0.62, p < 0.05). Eleven percent of rejections were
      steroid-resistant; chronic rejection led to 7 of 121 (5.8%) re-transplants. The
      SPLIT registry, in compiling data from a large number of centers, reflects the
      current outcomes for pediatric liver transplants in North America.

PMID- 15176967
TI  - Studies of Pediatric Liver Transplantation: 2002 update. An overview of
      demographics, indications, timing, and immunosuppressive practices in pediatric
      liver transplantation in the United States and Canada.
AB  - Studies of Pediatric Liver Transplantation (SPLIT) was initiated in 1995 for the
      purpose of collecting comprehensive data from children undergoing liver
      transplantation. As of May 31, 2002, 1761 children were registered in SPLIT from
      38 participating centers in the United States and Canada. This report focuses on
      the demographics, primary diagnoses, clinical indications for transplant, and
      probability of obtaining liver transplantation for the 1187 children receiving a
      liver transplant after registration in SPLIT. Demographic information is also
      provided for the 1092 children who received their first ever liver
      transplantation. For this cohort, we also describe immunosuppressive practices at
      the time of transplant, and how the use of different medications changes with
      time.

PMID- 15176968
TI  - Successful treatment of a child with fulminant liver failure and coma caused by
      Amanita phalloides intoxication with albumin dialysis without liver
      transplantation.
AB  - FLF is a life-threatening disease. Hepatic coma exerts dramatic impact on patient
      survival. At present, LTx is the treatment modality of choice that provides
      significant improvement in outcome of most patients with FLF. Multiple attempts
      have been made to reduce mortality and improve the patient's condition. One of
      the new options is AD - MARS. We present the case of a 11-yr-old boy with FLF and
      hepatic coma who avoided the scheduled LTx because of rapid neurological and
      biochemical improvement immediately after three MARS sessions.

PMID- 15176969
TI  - Early graft failure due to a veno-occlusive disease after a pediatric living
      donor liver transplantation.
AB  - A 10-month-old boy with biliary atresia after Kasai procedure underwent a living
      donor liver transplantation (LDLT). Five days after the LDLT, high fever and
      increased ascites followed by poor bile drainage was accompanied by elevation of
      serum liver enzymes. Liver biopsy showed occlusion of the central veins by fibro
      edematous endothelium and submassive necrosis of the parenchyma. Veno-occlusive
      disease (VOD) was suspected, and re-LDLT was urgently performed because of
      deterioration of hepatic failure. There are few cases of VOD after liver
      transplantation and this is the first one in an infant after LDLT.

PMID- 15176970
TI  - EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined
      liver and small bowel transplantation.
AB  - A 4-year-old boy presented 14 months after liver and small bowel transplantation
      with fever, diarrhea, elevated liver enzymes, thrombocytopenia and
      autoantibodies. Total gammaglobulins level was normal but the level of plasma
      IgA1 was very high. The blood PCR for Epstein-Barr virus (EBV) was negative. The
      ileal biopsy disclosed a lymphoplasmacytic infiltration. The EBER probe was
      negative on the small bowel biopsies. The child was considered as suffering from
      a non-EBV-induced posttransplant lymphoproliferative disorder (PTLD). The high
      IgA level was presumed to be secreted by proliferating plasma cells in the
      transplanted bowel. Immunosuppression was reduced; but the efficacy was
      incomplete and an anti-CD20 antibody was added. There was complete resolution of
      symptoms and normalization of the IgA level. As IgA1 is mostly of intestinal
      origin, this unusual presentation of PTLD should lead to a high suspicion of a
      small bowel proliferating process.

PMID- 15176971
TI  - Expression and functional effects of Eph receptor tyrosine kinase A family
      members on Langerhans like dendritic cells.
AB  - BACKGROUND: The Eph receptors are the largest receptor tyrosine kinase family.
      Several family members are expressed in hematopoietic cells. Previously, the
      expression of a member of this family, EphA2, was identified on dendritic like
      cells in tonsils. We therefore specifically examined the expression of EphA2 on
      in vitro generated dendritic cells. RESULTS: In this study, expression of the
      EphA2 receptor was identified on in vitro generated Langerhans like dendritic
      cells compared to in vitro generated dendritic cells. We show that ligand induced
      engagement of the EphA2 receptor leads to receptor autophosphorylation indicating
      a functional receptor signaling pathway in these cells. We also observe
      phosphorylation and dephosphorylation of distinct proteins following ligand
      activation of EphA receptors. In co-stimulation assays, receptor-ligand
      interaction reduces the capacity of the Langerhans like dendritic cells to
      stimulate resting CD4+ T cells. CONCLUSION: Engagement of EphA receptor tyrosine
      kinases on Langerhans like dendritic cells induces signaling as shown by tyrosine
      phosphorylation and dephosphorylation of distinct proteins. Furthermore this
      engagement renders the cells less capable of stimulating CD4+ T cells.

PMID- 15176972
TI  - Variations in genome-wide gene expression in identical twins - a study of primary
      osteoblast-like culture from female twins discordant for osteoporosis.
AB  - BACKGROUND: Monozygotic twin pairs who are genetically identical would be
      potentially useful in gene expression study for specific traits as cases and
      controls, because there would be much less gene expression variation within pairs
      compared to two unrelated individuals. However the twin pair has to be discordant
      for the particular trait or phenotype excluding those resulting from known
      confounders. Such discordant monozygotic twin pairs are rare and very few studies
      have explored the potential usefulness of this approach. RESULTS: We studied
      genome-wide gene expression in primary osteoblast-like culture from marrow
      aspirates obtained from three pairs of monozygotic twins. We used the latest
      Affymetrix microchip contains probe sets for more than 20,000 genes. Two pairs
      were discordant for bone mineral density at the hip by more than one standard
      deviation, and the third pair was unrelated concordant and used as control. Only
      1.5% on average of genes showed variation in expression within pairs as compared
      to 5% between pairs or over 15% from the literature. Importantly we identified
      several groups of genes showing variations within the discordant pairs and not
      within the concordant pair such as chondroitin beta 1,4 N
      acetylgalactosaminyltransferase, inhibin beta A, interleukin 1 beta and colony
      stimulating factor 1 macrophage. These genes are known to have potential roles in
      bone physiology relating to bone density, osteoporosis and osteoarthritis.
      CONCLUSION: Using the example of osteoblast-like cells in our monozygotic
      discordant twins for osteoporosis, we identified genes showing differential
      expression. Although without further experiment, we cannot confirm or conclude
      these are genes definitely related to bone physiology, we believe we have shown
      the potential and cost-effectiveness of further gene expression studies in
      discordant monozygotic twin pairs. A replication study for confirmation is
      essential.

PMID- 15176973
TI  - Microtubule self-organisation by reaction-diffusion processes causes collective
      transport and organisation of cellular particles.
AB  - BACKGROUND: The transport of intra-cellular particles by microtubules is a major
      biological function. Under appropriate in vitro conditions, microtubule
      preparations behave as a 'complex' system and show 'emergent' phenomena. In
      particular, they form dissipative structures that self-organise over macroscopic
      distances by a combination of reaction and diffusion. RESULTS: Here, we show that
      self-organisation also gives rise to a collective transport of colloidal
      particles along a specific direction. Particles, such as polystyrene beads,
      chromosomes, nuclei, and vesicles are carried at speeds of several microns per
      minute. The process also results in the macroscopic self-organisation of these
      particles. After self-organisation is completed, they show the same pattern of
      organisation as the microtubules. Numerical simulations of a population of
      growing and shrinking microtubules, incorporating experimentally realistic
      reaction dynamics, predict self-organisation. They forecast that during self
      organisation, macroscopic parallel arrays of oriented microtubules form which
      cross the reaction space in successive waves. Such travelling waves are capable
      of transporting colloidal particles. The fact that in the simulations, the
      aligned arrays move along the same direction and at the same speed as the
      particles move, suggest that this process forms the underlying mechanism for the
      observed transport properties. CONCLUSIONS: This process constitutes a novel
      physical chemical mechanism by which chemical energy is converted into collective
      transport of colloidal particles along a given direction. Self-organisation of
      this type provides a new mechanism by which intra cellular particles such as
      chromosomes and vesicles can be displaced and simultaneously organised by
      microtubules. It is plausible that processes of this type occur in vivo.

PMID- 15176974
TI  - Detection of chromosomal regions showing differential gene expression in human
      skeletal muscle and in alveolar rhabdomyosarcoma.
AB  - BACKGROUND: Rhabdomyosarcoma is a relatively common tumour of the soft tissue,
      probably due to regulatory disruption of growth and differentiation of skeletal
      muscle stem cells. Identification of genes differentially expressed in normal
      skeletal muscle and in rhabdomyosarcoma may help in understanding mechanisms of
      tumour development, in discovering diagnostic and prognostic markers and in
      identifying novel targets for drug therapy. RESULTS: A Perl-code web client was
      developed to automatically obtain genome map positions of large sets of genes.
      The software, based on automatic search on Human Genome Browser by sequence
      alignment, only requires availability of a single transcribed sequence for each
      gene. In this way, we obtained tissue-specific chromosomal maps of genes
      expressed in rhabdomyosarcoma or skeletal muscle. Subsequently, Perl software was
      developed to calculate gene density along chromosomes, by using a sliding window.
      Thirty-three chromosomal regions harbouring genes mostly expressed in
      rhabdomyosarcoma were identified. Similarly, 48 chromosomal regions were detected
      including genes possibly related to function of differentiated skeletal muscle,
      but silenced in rhabdomyosarcoma. CONCLUSION: In this study we developed a method
      and the associated software for the comparative analysis of genomic expression in
      tissues and we identified chromosomal segments showing differential gene
      expression in human skeletal muscle and in alveolar rhabdomyosarcoma, appearing
      as candidate regions for harbouring genes involved in origin of alveolar
      rhabdomyosarcoma representing possible targets for drug treatment and/or
      development of tumor markers.

PMID- 15176975
TI  - How many novel eukaryotic 'kingdoms'? Pitfalls and limitations of environmental
      DNA surveys.
AB  - BACKGROUND: Over the past few years, the use of molecular techniques to detect
      cultivation-independent, eukaryotic diversity has proven to be a powerful
      approach. Based on small-subunit ribosomal RNA (SSU rRNA) gene analyses, these
      studies have revealed the existence of an unexpected variety of new phylotypes.
      Some of them represent novel diversity in known eukaryotic groups, mainly
      stramenopiles and alveolates. Others do not seem to be related to any molecularly
      described lineage, and have been proposed to represent novel eukaryotic kingdoms.
      In order to review the evolutionary importance of this novel high-level
      eukaryotic diversity critically, and to test the potential technical and
      analytical pitfalls and limitations of eukaryotic environmental DNA surveys
      (EES), we analysed 484 environmental SSU rRNA gene sequences, including 81 new
      sequences from sediments of the small river, the Seymaz (Geneva, Switzerland).
      RESULTS: Based on a detailed screening of an exhaustive alignment of eukaryotic
      SSU rRNA gene sequences and the phylogenetic re-analysis of previously published
      environmental sequences using Bayesian methods, our results suggest that the
      number of novel higher-level taxa revealed by previously published EES was
      overestimated. Three main sources of errors are responsible for this situation:
      (1) the presence of undetected chimeric sequences; (2) the misplacement of
      several fast-evolving sequences; and (3) the incomplete sampling of described,
      but yet unsequenced eukaryotes. Additionally, EES give a biased view of the
      diversity present in a given biotope because of the difficult amplification of
      SSU rRNA genes in some taxonomic groups. CONCLUSIONS: Environmental DNA surveys
      undoubtedly contribute to reveal many novel eukaryotic lineages, but there is no
      clear evidence for a spectacular increase of the diversity at the kingdom level.
      After re-analysis of previously published data, we found only five candidate
      lineages of possible novel high-level eukaryotic taxa, two of which comprise
      several phylotypes that were found independently in different studies. To
      ascertain their taxonomic status, however, the organisms themselves have now to
      be identified.

PMID- 15176976
TI  - The three-dimensional organization of telomeres in the nucleus of mammalian
      cells.
AB  - BACKGROUND: The observation of multiple genetic markers in situ by optical
      microscopy and their relevance to the study of three-dimensional (3D) chromosomal
      organization in the nucleus have been greatly developed in the last decade. These
      methods are important in cancer research because cancer is characterized by
      multiple alterations that affect the modulation of gene expression and the
      stability of the genome. It is, therefore, essential to analyze the 3D genome
      organization of the interphase nucleus in both normal and cancer cells. RESULTS:
      We describe a novel approach to study the distribution of all telomeres inside
      the nucleus of mammalian cells throughout the cell cycle. It is based on 3D
      telomere fluorescence in situ hybridization followed by quantitative analysis
      that determines the telomeres' distribution in the nucleus throughout the cell
      cycle. This method enables us to determine, for the first time, that telomere
      organization is cell-cycle dependent, with assembly of telomeres into a telomeric
      disk in the G2 phase. In tumor cells, the 3D telomere organization is distorted
      and aggregates are formed. CONCLUSIONS: The results emphasize a non-random and
      dynamic 3D nuclear telomeric organization and its importance to genomic
      stability. Based on our findings, it appears possible to examine telomeric
      aggregates suggestive of genomic instability in individual interphase nuclei and
      tissues without the need to examine metaphases. Such new avenues of monitoring
      genomic instability could potentially impact on cancer biology, genetics,
      diagnostic innovations and surveillance of treatment response in medicine.

PMID- 15176977
TI  - Cutaneous horns: are these lesions as innocent as they seem to be?
AB  - BACKGROUND: Cutaneous horns (cornu cutaneum) are uncommon lesions consisting of
      keratotic material resembling that of an animal horn. Cutaneous horn may arise
      from a wide range of the epidermal lesions, which may be benign, premalignant or
      malignant. PATIENTS AND METHODS: In this respective study, we describe our
      experience of eleven patients with cutaneous horn treated at our centre between
      January 2000 and January 2004. The clinical, pathological and treatment details
      were extracted from the case records. Data is presented as frequency
      distribution. RESULTS: There were 8 male and 3 female patients with a median age
      of 57 years. Most of the lesions were located on the ear, hand and scalp.
      Surgical resection was carried out in all the lesions. There were two cases of
      squamous cell carcinoma, and one case of basal cell carcinoma, other 8 cases were
      benign. None of the lesions recurred and no adjuvant treatment was given to any
      of the malignant lesions. CONCLUSION: Cutaneous horn is a clinical diagnosis that
      refers to a conical projection above the surface of the skin. The lesions
      typically occurs in sun exposed areas, particularly the face, ear, nose,
      forearms, and dorsum of hands. Even though our 60% of the cutaneous horns are
      benign possibility of skin cancer should always be kept in mind.

PMID- 15176978
TI  - Non-destructive on-chip cell sorting system with real-time microscopic image
      processing.
AB  - Studying cell functions for cellomics studies often requires the use of purified
      individual cells from mixtures of various kinds of cells. We have developed a new
      non-destructive on-chip cell sorting system for single cell based cultivation, by
      exploiting the advantage of microfluidics and electrostatic force. The system
      consists of the following two parts: a cell sorting chip made of poly
      dimethylsiloxane (PDMS) on a 0.2-mm-thick glass slide, and an image analysis
      system with a phase-contrast/fluorescence microscope. The unique features of our
      system include (i) identification of a target from sample cells is achieved by
      comparison of the 0.2-microm-resolution phase-contrast and fluorescence images of
      cells in the microchannel every 1/30 s; (ii) non-destructive sorting of target
      cells in a laminar flow by application of electrostatic repulsion force for
      removing unrequited cells from the one laminar flow to the other; (iii) the use
      of agar gel for electrodes in order to minimize the effect on cells by
      electrochemical reactions of electrodes, and (iv) pre-filter, which was
      fabricated within the channel for removal of dust contained in a sample solution
      from tissue extracts. The sorting chip is capable of continuous operation and we
      have purified more than ten thousand cells for cultivation without damaging them.
      Our design has proved to be very efficient and suitable for the routine use in
      cell purification experiments.

PMID- 15176979
TI  - Investigation of clusters of giardiasis using GIS and a spatial scan statistic.
AB  - BACKGROUND: Giardia lamblia is the most frequently identified human intestinal
      parasite in Canada with prevalence estimates of 4-10%. However, infection rates
      vary by geographical area and localized 'pockets' of high or low infection rates
      are thought to exist. Water-borne transmission is one of the major routes of
      infection. Sources of contamination of drinking water include humans, domestic
      and wild animals. A previous study in southern Ontario, Canada, indicated a
      bivariate association between giardiasis rates and livestock density and/or
      manure use on agricultural land; however these variables were not significant
      when the variable 'rural' was added to the model. In that study, urban areas were
      defined as those with a minimum of 1,000 persons and a population density of at
      least 400 persons per Km2; all other areas were considered rural. This paper
      investigates the presence of local giardiasis clusters and considers the extent
      to which livestock density and manure application on agricultural land might
      explain the 'rural' effect. A spatial scan statistic was used to identify spatial
      clusters and geographical correlation analysis was used to explore associations
      of giardiasis rates with manure application on agricultural land and livestock
      density. RESULTS: Significant (P < 0.05) high rate spatial clusters were
      identified in a number of areas. Results also showed significant (P < 0.05)
      associations between giardiasis rates and both livestock density and manure
      application on agricultural land. However, the associations were observed in only
      two regions. CONCLUSIONS: There is evidence that giardiasis clusters in space in
      southern Ontario. However, there is no strong evidence to suggest that either
      livestock density or manure application on agricultural land plays an important
      role in the epidemiology of giardiasis in the study area. Therefore these factors
      do not seem to explain the higher rates of giardiasis reported in rural areas.
      The spatial scan statistics methodology used in this study has an important
      potential use in disease surveillance for confirming or refuting cluster alarms.

PMID- 15176980
TI  - A second-generation anti TB vaccine is long overdue.
AB  - Mycobacterium bovis BCG vaccine significantly reduces the risk of tuberculosis by
      50% and continues to be used to prevent tuberculosis around the world. However,
      it has been shown to be ineffective in some geographical regions. The existence
      of different BCG strains was described more than 60 years ago, these vary in
      their antigenic content but the genetic mutations in BCG strains have yet been
      shown to affect their protection. After the declaration of tuberculosis as a
      global emergency in 1993, current research attempts to develop a novel more
      effective vaccine. Using new technologies, recombinant, auxotroph, DNA, subunit
      and phylogenetically closely related mycobacteria, naturally or genetically
      attenuated, have been used as vaccines in animal models, but their protective
      efficacy, is less than that offered by the current BCG vaccine. Today it is
      mandatory that a major effort be made to understand how different BCG vaccine
      strains influence immune response and why in some cases vaccines have failed, so
      we can rationally develop the next generation of tuberculosis vaccines to reduce
      the prevalence from 10% to less than 2 % for developed countries.

PMID- 15176981
TI  - The obligation of physicians to medical outliers: a Kantian and Hegelian
      synthesis.
AB  - BACKGROUND: Patients who present to medical practices without health insurance or
      with serious co-morbidities can become fiscal disasters to those who care for
      them. Their consumption of scarce resources has caused consternation among
      providers and institutions, especially as it concerns the amount and type of care
      they should receive. In fact, some providers may try to avoid caring for them
      altogether, or at least try to limit their institutional or practice exposure to
      them. DISCUSSION: We present a philosophical discourse, with emphasis on the
      writings of Immanuel Kant and G.F.W. Hegel, as to why physicians have the moral
      imperative to give such "outliers" considerate and thoughtful care. Outliers are
      defined and the ideals of morality, responsibility, good will, duty, and
      principle are applied to the care of patients whose financial means are meager
      and to those whose care is physiologically futile. Actions of moral worth,
      unconditional good will, and doing what is right are examined. SUMMARY: Outliers
      are a legitimate economic concern to individual practitioners and institutions,
      however this should not lead to an evasion of care. These patients should be
      identified early in their course of care, but such identification should be
      preceded by a well-planned recognition of this burden and appropriate staffing
      and funding should be secured. A thoughtful team approach by medical practices
      and their institutions, involving both clinicians and non-clinicians, should be
      pursued.

PMID- 15176982
TI  - A comparison of random draw and locally neutral models for the avifauna of an
      English woodland.
AB  - BACKGROUND: Explanations for patterns observed in the structure of local
      assemblages are frequently sought with reference to interactions between species,
      and between species and their local environment. However, analyses of null
      models, where non-interactive local communities are assembled from regional
      species pools, have demonstrated that much of the structure of local assemblages
      remains in simulated assemblages where local interactions have been excluded.
      Here we compare the ability of two null models to reproduce the breeding bird
      community of Eastern Wood, a 16-hectare woodland in England, UK. A random draw
      model, in which there is complete annual replacement of the community by
      immigrants from the regional pool, is compared to a locally neutral community
      model, in which there are two additional parameters describing the proportion of
      the community replaced annually (per capita death rate) and the proportion of
      individuals recruited locally rather than as immigrants from the regional pool.
      RESULTS: Both the random draw and locally neutral model are capable of
      reproducing with significant accuracy several features of the observed structure
      of the annual Eastern Wood breeding bird community, including species relative
      abundances, species richness and species composition. The two additional
      parameters present in the neutral model result in a qualitatively more realistic
      representation of the Eastern Wood breeding bird community, particularly of its
      dynamics through time. The fact that these parameters can be varied, allows for a
      close quantitative fit between model and observed communities to be achieved,
      particularly with respect to annual species richness and species accumulation
      through time. CONCLUSION: The presence of additional free parameters does not
      detract from the qualitative improvement in the model and the neutral model
      remains a model of local community structure that is null with respect to species
      differences at the local scale. The ability of this locally neutral model to
      describe a larger number of woodland bird communities with either little
      variation in its parameters or with variation explained by features local to the
      woods themselves (such as the area and isolation of a wood) will be a key
      subsequent test of its relevance.

PMID- 15176983
TI  - Crowding: risk factor or protective factor for lower respiratory disease in young
      children?
AB  - BACKGROUND: To study the effects of household crowding upon the respiratory
      health of young children living in the city of Sao Paulo, Brazil. METHODS: Case
      control study with children aged from 2 to 59 months living within the boundaries
      of the city of Sao Paulo. Cases were children recruited from 5 public hospitals
      in central Sao Paulo with an acute episode of lower respiratory disease. Children
      were classified into the following diagnostic categories: acute bronchitis, acute
      bronchiolitis, pneumonia, asthma, post-bronchiolitis wheezing and wheezing of
      uncertain aetiology. One control, crudely matched to each case with regard to age
      (<2, 2 years old or more), was selected among healthy children living in the
      neighborhood of the case. All buildings were surveyed for the presence of
      environmental contaminants, type of construction and building material. Plans of
      all homes, including measurements of floor area, height of walls, windows and
      solar orientation, was performed. Data were analysed using conditional logistic
      regression. RESULTS: A total of 313 pairs of children were studied. Over 70% of
      the cases had a primary or an associated diagnosis of a wheezing illness.
      Compared with controls, cases tended to live in smaller houses with less adequate
      sewage disposal. Cases and controls were similar with respect to the number of
      people and the number of children under five living in the household, as well the
      number of people sharing the child's bedroom. After controlling for potential
      confounders, no evidence of an association between number of persons sharing the
      child's bedroom and lower respiratory disease was identified when all cases were
      compared with their controls. However, when two categories of cases were
      distinguished (infections, asthma) and each category compared separately with
      their controls, crowding appeared to be associated with a 60% reduction in the
      incidence of asthma but with 2 1/2-fold increase in the incidence of lower
      respiratory tract infections (p = 0.001). CONCLUSION: Our findings suggest that
      household crowding places young children at risk of acute lower respiratory
      infection but may protect against asthma. This result is consistent with the
      hygiene hypothesis.

PMID- 15176984
TI  - Self-esteem, stress and self-rated health in family planning clinic patients.
AB  - BACKGROUND: The independent effects of stress on the health of primary care
      patients might be different for different types of clinic populations. This study
      examines these relationships in a low-income female population of patients
      attending a family planning clinic. METHODS: This study investigated the
      relevance of different sources of personal stress and social support to self
      rated health, adjusting for mental health, health behavior and demographic
      characteristics of subjects. Five hundred women who attended family planning
      clinics were surveyed and 345 completed the form for a response rate of 72
      percent. RESULTS: Multiple logistic regression analysis revealed that liking
      oneself was related to good self-rated health (Odds ratio = 7.11), but stress or
      support from children, parents, friends, churches or spouses were not
      significant. White non-Hispanic and non-white non-Hispanic respondents had lower
      odds of reporting good self-rated health than Hispanic respondents (odds ratios
      were 2.87 and 2.81, respectively). Exercising five or more days per week also was
      related to good self-rated health. Smoking 20 or more cigarettes per day, and
      obese III were negatively related to good self-rated health (odds ratios were.19
      and.22, respectively with corresponding p-values equal to.0043 and.0332).
      CONCLUSIONS: Among younger low-income women, addressing low self-esteem might
      improve health status.

PMID- 15176985
TI  - The expression of HSP83 genes in Leishmania infantum is affected by temperature
      and by stage-differentiation and is regulated at the levels of mRNA stability and
      translation.
AB  - BACKGROUND: Exposure of Leishmania promastigotes to the temperature of their
      mammalian hosts results in the induction of a typical heat shock response. It has
      been suggested that heat shock proteins play an important role in parasite
      survival and differentiation. RESULTS: Here we report the studies on the
      expression of the heat shock protein 83 (HSP83) genes of Leishmania infantum.
      Confirming previous observations for other Leishmania species, we found that the
      L. infantum HSP83 transcripts also show a temperature-dependent accumulation that
      is controlled by a post-transcriptional mechanism involving sequences located in
      the 3'-untranslated region (3'-UTR). However, contrary to that described for L.
      amazonensis, the accumulation of the HSP83 transcripts in L. infantum is
      dependent on active protein synthesis. The translation of HSP83 transcripts is
      enhanced during heat shock and, as first described in L. amazonensis, we show
      that the 3'-UTR of the L. infantum HSP83 gene is essential for this translational
      control. Measurement of the steady-state levels of HSP83 transcripts along the
      promastigote-to-amastigote differentiation evidenced a specific profile of HSP83
      RNAs: after an initial accumulation of HSP83 transcripts observed short after (2
      h) incubation in the differentiation conditions, the amount of HSP83 RNA
      decreased to a steady-state level lower than in undifferentiated promastigotes.
      We show that this transient accumulation is linked to the presence of the 3'-UTR
      and flanking regions. Again, an 8-fold increase in translation of the HSP83
      transcripts is observed short after the initiation of the axenic differentiation,
      but it is not sustained after 9 h. CONCLUSIONS: This transient expression of
      HSP83 genes could be relevant for the differentiation of Leishmania, and the
      underlying regulatory mechanism may be part of the developmental program of this
      parasite.

PMID- 15176986
TI  - Osteoporosis and the global competition for health care resources.
AB  - Global aging superimposed on existing infectious diseases and trauma will
      aggravate competition for health care resources to diagnose and treat
      osteoporosis. Efforts to implement public health measures are needed, but the
      targeted approach to assessment and treatment of high-risk individuals must also
      be refined. Increases in the elderly population worldwide will cause a dramatic
      rise in osteoporotic fractures, but other age-related diseases will increase as
      well. Changes will be superimposed on existing public health problems (e.g.,
      malaria, alcoholism), and these acute health care needs will take priority in
      some areas. Societies in most parts of the world may have to limit osteoporosis
      control to broad public health measures, and such efforts (e.g., calcium and
      vitamin D supplementation) should be supported. In these regions, clinical
      decision-making will generally be limited to treating patients with fractures
      (who presumably have already failed any public health measures in place), or in a
      few wealthy countries, to patients with low bone density identified by case
      finding. Case-finding approaches will vary with the resources available, although
      unselective (mass) screening by bone densitometry is largely ineffective and
      unaffordable anywhere. The key to clinical decision-making on behalf of
      individuals will be an assessment of absolute fracture risk, and the tools needed
      to predict the risk of an osteoporotic fracture over the next 10 years are now
      being developed. These include bone density measures, but also incorporate other
      risk factors (e.g., fracture history, corticosteroid use), which may allow
      extension of fracture risk prediction to nonwhite populations and to men. Even
      with a universal risk prediction tool, cost-effective treatment thresholds will
      vary by country based on the level of fracture risk in the region and on the
      resources available for health care. To better compete for these resources,
      efforts should be made to lower the cost of osteoporosis interventions.
      Additionally, evidence is needed that these interventions are really effective in
      reducing fractures in the community.

PMID- 15176987
TI  - A single-dose placebo-controlled study of AMG 162, a fully human monoclonal
      antibody to RANKL, in postmenopausal women.
AB  - The safety and bone antiresorptive effect of a single subcutaneous dose of AMG
      162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal
      women. AMG 162 is a potent antiresorptive agent for diseases such as
      osteoporosis. INTRODUCTION: RANKL is an essential osteoclastic differentiation
      and activation factor. MATERIALS AND METHODS: The bone antiresorptive activity
      and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated
      in postmenopausal women in this randomized, double-blind, placebo-controlled,
      single-dose, dose escalation study. Six cohorts of eight to nine women were
      randomly assigned to receive a single subcutaneous injection of either AMG 162 or
      placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg.
      Subjects were followed up to 6 months in all cohorts and 9 months in the three
      highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX;
      Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP,
      Ostase) were assessed as bone turnover markers. RESULTS AND CONCLUSIONS: Forty
      nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a
      dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6
      months) decrease in urinary NTX. At 6 months, there was a mean change from
      baseline of -81% in the 3.0 mg/kg AMG 162 group compared with -10% in the placebo
      group; serum NTX changes were -56% and 2%, respectively. BALP levels did not
      decrease remarkably until after 1 month, indicating that the effect of AMG 162 is
      primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to
      approximately 3-fold after 4 days in the 3.0 mg/kg dose group, but returned
      toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease
      >10% on average in any group, and no subject had values below 2 mmol/liter. AMG
      162 was well tolerated. No related serious adverse events occurred. No clinically
      meaningful laboratory changes, other than those described above, were observed.
      In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent
      rapid and sustained decrease from baseline in bone turnover and could be an
      effective and convenient treatment for osteoporosis.

PMID- 15176988
TI  - Prevention of bone loss in paraplegics over 2 years with alendronate.
AB  - To assess the effects of long-term treatment of bone loss with alendronate in a
      group of paraplegic men, 55 patients were evaluated in a prospective randomized
      controlled open label study that was 2 years in duration comparing alendronate
      and calcium with calcium alone. Bone loss was stopped at all cortical and
      trabecular infralesional sites (distal tibial epiphysis, tibial diaphysis, total
      hip) with alendronate 10 mg daily. INTRODUCTION: Bone loss after spinal cord
      injury (SCI) leads to increased fracture risk in the lower limbs of paraplegics.
      The aim of this study was to document long-term treatment of bone loss with
      alendronate in a group of paraplegic men with complete motor lesion after SCI.
      MATERIALS AND METHODS: Sixty-five men with complete motor post-traumatic
      medullary lesion between T1 and L2 with total motor and sensory loss (Frankel
      classification, stage A) or with total motor and partial sensory loss (Frankel
      classification, stage B) after SCI were included in this prospective randomized
      controlled open label study that was 2 years in duration. The patients were
      randomized to either the treatment group with alendronate 10 mg daily and
      elemental calcium 500 mg daily or to the control group with elemental calcium 500
      mg daily alone. The primary endpoint was defined as the effect over 24 months of
      alendronate and calcium compared with calcium alone on the BMD values at the
      distal tibial epiphysis (as a surrogate for trabecular bone in the paralyzed
      zone). The secondary endpoints were changes in BMD at supra- and infralesional
      sites of measurement. Biochemical markers of bone turnover were assessed.
      RESULTS: Fifty-five subjects, 0.1-29.5 years post-SCI, completed the study over
      24 months. BMD at the distal tibial epiphysis significantly decreased from
      baseline in the calcium group (-10.8 +/- 2.7% at 24 months, p < 0.001), whereas
      it remained stable in the alendronate plus calcium group (-2.0 +/- 2.9% at 24
      months, p = not significant versus baseline), leading to a significant intergroup
      difference over time (p = 0.017). At the tibial diaphysis, similar significant
      results were observed. At the ultradistal radius and the radial shaft, BMD did
      not change significantly from baseline in either treatment group. At the total
      hip, BMD decreased significantly in the calcium group (-4.1 +/- 1.6%, p = 0.038)
      but remained stable in the alendronate plus calcium group (+0.43 +/- 1.2%), with
      a significant intergroup difference (p = 0.037). At the lumbar spine, BMD
      increased significantly (p < 0.0001) from baseline in both groups. Biochemical
      markers of bone resorption were significantly decreased with alendronate versus
      baseline and control. Alendronate and calcium were generally safe and well
      tolerated. CONCLUSIONS: In paraplegic men, SCI bone loss was stopped at all
      measured cortical and trabecular infralesional sites over 24 months with
      alendronate 10 mg daily.

PMID- 15176989
TI  - A potentially deleterious role of IGFBP-2 on bone density in aging men and women.
AB  - The role of the IGFs and IGFBPs on age-related changes in BMD in adult men and
      women is not well understood. Studying an age-stratified community based sample
      of 344 men and 276 women, we found higher IGFBP-2 levels to be associated with
      lower BMD. IGFBP-2, which increases with age in both men and women, was the
      strongest, most consistent predictor of BMD among the IGF/IGFBPs studied.
      INTRODUCTION: Insulin-like growth factors (IGFs) and their binding proteins
      (IGFBPs) are important regulators of tissue growth and metabolism, but their
      association with BMD in adult men and women is controversial. MATERIALS AND
      METHODS: In an age-stratified, random sample of the community population, we
      examined the role of serum levels of IGF-I, IGF-II, and IGFBP-1, -2, and -3 on
      BMD of the proximal femur (total hip), lateral spine, midshaft, and ultradistal
      radius as measured by DXA. We explored the association before and after
      adjustment for potential confounders, including age, bioavailable estradiol and
      testosterone, sex hormone binding globulin (SHBG), and measures of total fat and
      skeletal muscle mass. RESULTS: We studied 344 men (age, 23-90 years) and 276
      women (age, 21-93 years; 166 postmenopausal) not on hormone replacement or oral
      contraceptives. In both men and women, IGF-I and IGFBP-3 levels fell with
      advancing age, whereas IGFBP-2 levels tended to rise with age. There was an
      inverse association of IGFBP-2 with BMD at most skeletal sites in men and both
      premenopausal and postmenopausal women, whereas lower IGF-I and IGFBP-3 were
      associated with lower BMD in men and postmenopausal women only. Lower IGF-II was
      associated with lower BMD in men only. There were no associations between IGFBP-1
      and BMD in either sex. After adjustment for age, in most cases, we found no
      further associations between IGF-I, IGF-II, or IGFBP-3 and BMD. In contrast,
      after age adjustment, higher IGFBP-2 remained a predictor of lower BMD in men and
      postmenopausal women at all sites except for the lateral spine (for men: r = 
      0.21, -0.20, and -0.19, all p < 0.001; and for postmenopausal women: r = -0.34, 
      0.24, and -0.25, all p < 0.01, for the total hip, midshaft, and ultradistal
      radius, respectively). IGFBP-2 remained an independent negative predictor of BMD
      in men, postmenopausal women, and all women combined after additional adjustment
      for bioavailable sex steroids, but not at all sites after adjustment for SHBG and
      muscle mass. In premenopausal women, IGFBP-2 had similar associations as seen in
      postmenopausal women, but they were weaker and not statistically robust.
      CONCLUSIONS: Among the IGF/IGFBPs in our study, IGFBP-2 was a key negative
      predictor of BMD among men and women, particularly postmenopausal women. Our
      findings suggest a potential role of the IGF/IGFBP system in regulating bone loss
      in aging men and women and identify a previously under-recognized, potentially
      deleterious role for IGFBP-2, a known inhibitor of IGF action that increases with
      age in both sexes. Whether the action of the IGF/IGFBP system on bone metabolism
      is mediated partly through its effects on muscle mass or SHBG deserves further
      study.

PMID- 15176990
TI  - Diabetes is associated independently of body composition with BMD and bone volume
      in older white and black men and women: The Health, Aging, and Body Composition
      Study.
AB  - The association between type 2 diabetes, BMD, and bone volume was examined to
      determine the effect of lean and fat mass and fasting insulin in the Health,
      Aging, and Body Composition Study, which included white and black well
      functioning men and women 70-79 years of age (N = 2979). Diabetes predicted
      higher hip, whole body, and volumetric spine BMD, and lower spine bone volume,
      independent of body composition and fasting insulin. INTRODUCTION: The purpose of
      this study was to determine if the association between type 2 diabetes and higher
      BMD observed in older white women is seen in elderly white men and blacks and to
      evaluate if higher BMD in diabetic individuals is accounted for by lean mass, fat
      mass, or fasting insulin differences. MATERIALS AND METHODS: In the Health,
      Aging, and Body Composition Study, which included white and black well
      functioning men and women 70-79 years of age (N = 2979), 19% of participants had
      diabetes at baseline. Of those with diabetes, 57% were men, and 62% were black.
      Multivariate linear regression models examined independent effects of diabetes,
      lean mass, fat mass, visceral fat, and fasting insulin on BMD and bone volume
      while adjusting for relevant covariates. RESULTS AND CONCLUSIONS: Fasting
      insulin, visceral fat, and volumetric spine BMD, assessed by CT, and lean mass,
      fat mass, and total hip and whole body BMD, assessed by DXA, were higher (p < or
      = 0.05 for all) for those with diabetes. Hip BMD was higher in white men (0.99 +/
      0.14 versus 0.93 +/- 0.14 g/cm2, p < 0.001), black men (1.06 +/- 0.17 versus
      1.00 +/- 0.15 g/cm2, p < 0.001), white women (0.83 +/- 0.13 versus 0.76 +/- 0.13
      g/cm2, p < 0.001), and black women (0.90 +/- 0.15 versus 0.85 +/- 0.15 g/cm2, p <
      0.001) with diabetes compared with those without diabetes, although the
      relationship was attenuated by body composition. In multiple regression models,
      diabetes was an independent predictor of higher hip, whole body, and volumetric
      spine BMD in all participants (p < or = 0.001), but lower spine volume (p = 0.01)
      and higher hip BMD for each race-gender group (p < or = 0.01). Type 2 diabetes
      was associated with a 4-5% higher total hip BMD in all race-gender groups of
      elderly adults, independent of body composition and fasting insulin levels.

PMID- 15176991
TI  - Lifestyle influences on 9-year changes in BMD in young women.
AB  - The effects of dietary calcium intake and physical activity on longitudinal
      changes in BMD over a mean of 9.4 years were examined in 62 healthy young women.
      Proximal femur BMD declined, lumbar spine BMD increased, and physical activity
      was associated with BMD change at intertrochanter and total hip sites.
      INTRODUCTION: Maximizing premenopausal BMD is an important strategy for the
      prevention of osteoporosis and resultant fractures later in life. MATERIALS AND
      METHODS: Young women who previously participated in a placebo-controlled 2-year
      calcium intervention study at a mean age of 18.5 +/- 0.3 years were remeasured at
      27.8 +/- 1.0 years of age. DXA (Hologic QDR 1000W) was used to measure changes in
      BMD, and lifestyle factors were ascertained by questionnaire. RESULTS AND
      CONCLUSIONS: Early decline in BMD at the neck of femur (-3.3%/decade) and the
      converse gain in BMD at the lumbar spine (+4.3%/decade) and intertrochanter
      (+1.9%/decade) suggest site-specific changes in BMD in young premenopausal women.
      No effect of previous calcium supplementation was seen on current BMD or changes
      in BMD (p > 0.10). Lifestyle predictors of change in BMD were determined using
      hierarchical regression analysis after forced correction for the covariates
      baseline BMD and previous calcium supplementation. Physical activity was
      positively associated with change in BMD at total hip and intertrochanter sites
      (beta-coefficients, beta = 0.26 and 0.26 respectively; p < 0.05). Calcium intake
      was negatively associated with change in BMD at the lumbar spine (beta = -0.27, p
      < 0.05). Parity was negatively associated with change in BMD at all sites (beta =
      -0.40 to -0.26, p < 0.05). These data show that BMD is already declining at the
      proximal femur in these healthy young women. Physical activity assists in
      maintenance of BMD at some sites and thus may contribute to lifelong fracture
      prevention. There was no positive association between calcium intake and change
      in BMD.

PMID- 15176992
TI  - Loss of regularity in the curvature of the thoracolumbar spine: a measure of
      structural failure.
AB  - Departure from regularity (smoothness) in the curvature of the spine was
      quantified and correlated with the number of fractures, deficits in height, BMD,
      and identified women with vertebral fractures. INTRODUCTION: Differences in
      anterior and posterior vertebral heights (VHs) form the thoracolumbar curvature
      needed for stability in bipedal gait. Modest differences in VHs within and
      between adjacent vertebrae allow the spine curve to change its trajectory gently.
      Large differences in VHs, as occur following a fracture, produce abrupt changes
      in the direction of the curve, producing a departure from regularity (i.e.,
      irregularity or loss of smoothness). MATERIALS AND METHODS: VHs and BMD were
      measured using DXA in 697 Lebanese women 20-87 years of age. Regularity of the
      spinal curvature was measured by comparing the ratio of the anterior to the
      posterior VHs of one vertebra to this ratio of adjacent vertebrae. If these
      ratios are similar, there is a smooth transition in the trajectory of the spinal
      curve. Departure from this regularity (smoothness) was measured at each pair of
      adjacent vertebrae in each individual and expressed as the spinal curvature
      irregularity index (SCII) for the entire thoracolumbar spine. RESULTS AND
      CONCLUSIONS: In premenopausal women, the mean SCII was 8.5% (range, 4-15%); that
      is, regularity was 91.5%. Only 0.8% of women had a SCII >17%. In postmenopausal
      women, the mean SCII was 10% (range, 4-36%) and was correlated with age (r =
      0.25), height (r = -0.21), BMD (r = -0.13), and the number of deformities
      assessed by quantitative vertebral morphometry (QVM; r = 0.31-0.60; all p <
      0.001). About 5% of women had an SCII >17%, and this group had 3- to 9-fold more
      deformities (as defined by QVM) than women with SCII <17%, reduced lumbar spine
      BMD (-1.01 SD), and 2- to 4-fold greater height deficits (-0.5 SD) than women
      with deformities (by QVM). The SCII is a robust method of identifying structural
      failure that is easy to compute and does not require controls.

PMID- 15176993
TI  - Macrophage inflammatory protein-1alpha induces hypercalcemia in adult T-cell
      leukemia.
AB  - Hypercalcemia is observed in >80% of ATL. Serum MIP-1alpha levels were elevated
      in all 24 ATL with hypercalcemia but undetectable in all 10 patients with humoral
      hypercalcemia of malignancy with solid tumors and in 34 of 37 ATL without
      hypercalcemia. We propose that serum MIP-1alpha is a clinical hallmark for
      hypercalcemia in ATL. INTRODUCTION: High serum cytokines levels are not always
      associated with hypercalcemia in patients with adult T-cell leukemia (ATL),
      suggesting that other factors are involved in the pathogenesis of ATL patients
      with hypercalcemia. This study was designed to determine the role of macrophage
      inflammatory protein-1alpha (MIP-1alpha), a chemokine recently described as an
      osteoclast stimulatory factor, in ATL-associated hypercalcemia. MATERIALS AND
      METHODS: We measured serum interleukin (IL)-1beta, IL-6, TNF-alpha, parathyroid
      hormone-related protein (PTHrP), and MIP-1alpha levels in ATL patients by enzyme
      linked immunosorbent assays. FACScan was used to measure the expression of RANKL
      on ATL cells. Osteoclast formation in cocultures of ATL cells and peripheral
      blood mononuclear cells (PBMCs) was evaluated by TRACP staining. RESULTS: High
      serum MIP-1alpha levels were noted in all 24 ATL patients with hypercalcemia and
      in 3 of 37 ATL patients without hypercalcemia. The elevated levels of MIP-1alpha
      and calcium in ATL patients decreased after effective chemotherapy, emphasizing
      the role of MIP-1alpha in ATL hypercalcemia. ATL cells spontaneously produced MIP
      1alpha. MIP-1alpha significantly enhanced human monocyte (precursor cells of
      osteoclasts) migration and induced RANKL expression on ATL cells. ATL cell
      induced osteoclast formation from PBMCs was inhibited by anti-MIP-1alpha antibody
      and osteoprotegerin. CONCLUSION: Our results suggest that MIP-1alpha can induce
      RANKL on ATL cells in autocrine fashion and that RANKL seems to mediate the
      hypercalcemic effect of MIP-1alpha in ATL. We propose that MIP-1alpha is the
      clinical hallmark of hypercalcemia in ATL and could be a potentially useful
      therapeutic target.

PMID- 15176994
TI  - Imbalance of osteoclastogenesis-regulating factors in patients with celiac
      disease.
AB  - Celiac disease is an autoimmune disorder characterized by atrophy of the
      intestine villi triggered by ingestion of gluten in genetically susceptible
      individuals. The association between celiac disease and low BMD has been
      recognized, but the mechanisms of disturbance are poorly understood. We show
      imbalance of cytokines relevant to bone metabolism in celiac patients' sera and
      the direct effect of these sera on in vitro bone cell activity. INTRODUCTION:
      Celiac disease is associated with mineral metabolism derangement and low BMD. We
      investigated whether imbalance of serum factors in celiac patients could affect
      human bone cell activity in vitro. MATERIALS AND METHODS: We studied two groups
      of celiac patients--one on a gluten-free diet and another before the diet--both
      with decreased bone mass. Patients were investigated for bone turnover markers,
      and their sera were used for culturing bone cells from healthy donors and
      evaluate changes in cell activity. RESULTS: The N-terminal telopeptide of
      procollagen type I and interleukin (IL)-6 were higher than normal in patients not
      on the gluten-free diet. IL-1beta and TNF-alpha/beta were normal in all patients.
      IL-12 was reduced in all patients, whereas IL-18 was reduced only in patients on
      the diet. The RANKL/osteoprotegerin (OPG) ratio was increased in patients not on
      the gluten-free diet. Persistently increased osteoclast numbers were obtained
      from peripheral blood mononuclear cells of healthy donors on incubation with sera
      of patients not on the gluten-free diet versus control sera and sera from
      patients on the diet. In human osteoblasts from healthy individuals, IL-18 was
      reduced on incubation with sera from all patients, whereas OPG expression was
      lower when sera from patients not on the diet were used. Proliferation, alkaline
      phosphatase, and nodule mineralization were increased in osteoblast cultures
      containing sera from all celiac patients, either on or not on the gluten-free
      diet. CONCLUSIONS: We conclude that bone loss in celiac disease might also be
      caused by a cytokine imbalance directly affecting osteoclastogenesis and
      osteoblast activity.

PMID- 15176995
TI  - Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype
      phenotype correlation, functional analysis, and structural consequences.
AB  - Three novel missense mutations of SQSTM1 were identified in familial PDB, all
      affecting the UBA domain. Functional and structural analysis showed that disease
      severity was related to the type of mutation but was unrelated to the
      polyubiquitin-binding properties of the mutant UBA domain peptides. INTRODUCTION:
      Mutations affecting the ubiquitin-associated (UBA) domain of Sequestosome 1
      (SQSTM1) gene have recently been identified as a common cause of familial Paget's
      disease of bone (PDB), but the mechanisms responsible are unclear. We identified
      three novel SQSTM1 mutations in PDB, conducted functional and structural analyses
      of all PDB-causing mutations, and studied the relationship between genotype and
      phenotype. MATERIALS AND METHODS: Mutation screening of the SQSTM1 gene was
      conducted in 70 kindreds with familial PDB. We characterized the effect of the
      mutations on structure of the UBA domain by protein NMR, studied the effects of
      the mutant UBA domains on ubiquitin binding, and looked at genotype-phenotype
      correlations. RESULTS AND CONCLUSIONS: Three novel missense mutations affecting
      the SQSTM1 UBA domain were identified, including a missense mutation at codon 411
      (G411S), a missense mutation at codon 404 (M404V), and a missense mutation at
      codon 425 (G425R). We also identified a deletion leading to a premature stop
      codon at 394 (L394X). None of the mutations were found in controls. Structural
      analysis showed that M404V and G425R involved residues on the hydrophobic surface
      patch implicated in ubiquitin binding, and consistent with this, the G425R and
      M404V mutants abolished the ability of mutant UBA domains to bind polyubiquitin
      chains. In contrast, the G411S and P392L mutants bound polyubiquitin chains
      normally. Genotype-phenotype analysis showed that patients with truncating
      mutations had more extensive PDB than those with missense mutations (bones
      involved = 6.05 +/- 2.71 versus 3.45 +/- 2.46; p < 0.0001). This work confirms
      the importance of UBA domain mutations of SQSTM1 as a cause of PDB but shows that
      there is no correlation between the ubiquitin-binding properties of the different
      mutant UBA domains and disease occurrence or extent. This indicates that the
      mechanism of action most probably involves an interaction between SQSTM1 and a
      hitherto unidentified protein that modulates bone turnover.

PMID- 15176996
TI  - Osteoclast differentiation by RANKL requires NF-kappaB-mediated downregulation of
      cyclin-dependent kinase 6 (Cdk6).
AB  - This study investigated the involvement of cell cycle factors in RANKL-induced
      osteoclast differentiation. Among the G1 cell cycle factors, Cdk6 was found to be
      a key molecule in determining the differentiation rate of osteoclasts as a
      downstream effector of the NF-kappaB signaling. INTRODUCTION: A temporal arrest
      in the G1 phase of the cell cycle is a prerequisite for cell differentiation,
      making it possible that cell cycle factors regulate not only the proliferation
      but also the differentiation of cells. This study investigated cell cycle factors
      that critically influence differentiation of the murine monocytic RAW264.7 cells
      to osteoclasts induced by RANKL. MATERIALS AND METHODS: Growth-arrested RAW cells
      were stimulated with serum in the presence or absence of soluble RANKL (100
      ng/ml). Expressions of the G1 cell cycle factors cyclin D1, D2, D3, E, cyclin
      dependent kinase (Cdk) 2, 4, 6, and Cdk inhibitors (p18 and p27) were determined
      by Western blot analysis. Involvement of NF-kappaB and c-jun N-terminal kinase
      (JNK) pathways was examined by overexpressing dominant negative mutants of the
      IkappaB kinase 2 (IKK(DN)) gene and mitogen-activated protein kinase kinase 7
      (MKK7(DN)) gene, respectively, using the adenovirus vectors. To determine the
      direct effect of Cdk6 on osteoclast differentiation, stable clones of RAW cells
      transfected with Cdk6 cDNA were established. Osteoclast differentiation was
      determined by TRACP staining, and cell cycle regulation was determined by BrdU
      uptake and flow cytometric analysis. RESULTS AND CONCLUSION: Among the cell cycle
      factors examined, the Cdk6 level was downregulated by RANKL synchronously with
      the appearance of multinucleated osteoclasts. Inhibition of the NF-kappaB pathway
      by IKK(DN) overexpression, but not that of the JNK pathway by MKK7(DN)
      overexpression, caused the decreases in both Cdk6 downregulation and
      osteoclastogenesis by RANKL. RAW cells overexpressing Cdk6 resist RANKL-induced
      osteoclastogenesis; however, cell cycle regulation was not affected by the levels
      of Cdk6 overexpression, suggesting that the inhibitory effect of Cdk6 on
      osteoclast differentiation was not exerted through cell cycle regulation. These
      results indicate that Cdk6 is a critical regulator of RANKL-induced osteoclast
      differentiation and that its NF-kappaB-mediated downregulation is essential for
      efficient osteoclast differentiation.

PMID- 15176997
TI  - Characterization of a novel bipotent hematopoietic progenitor population in
      normal and osteopetrotic mice.
AB  - Several reports indicate that osteoclasts and B-lymphocytes share a common
      progenitor. This study focuses on the characterization of this bipotent
      progenitor from the bone marrow of the osteopetrotic oc/oc mouse, where the
      bipotent progenitor population is amplified, and of normal mice. INTRODUCTION:
      Osteoclasts have a myelomonocytic origin, but they can also arise in vitro from
      pro-B-cells, suggesting that a subset of normal pro-B-cells is uncommitted and
      may reorient into the myeloid lineage representing a B-lymphoid/osteoclastic
      progenitor. The aim of this study was to characterize this progenitor population.
      MATERIALS AND METHODS: The osteopetrotic oc/oc mouse was used as a choice model
      because it displays an increased number of both osteoclasts and pro-B-cells in
      the bone marrow. Our results have been confirmed in normal littermates. Bone
      marrow cells from these animals were analyzed by flow cytometry. After sorting,
      the cells were cultured under different conditions to assess their
      differentiation capacity. RESULTS: Pro-B-cells from oc/oc and normal mice include
      an unusual biphenotypic population expressing markers from the B-lymphoid (CD19,
      CD43, CD5) and the myeloid (F4/80) lineages. This population also expresses
      progenitor markers (CD34 and Flt3) and is uncommitted. After sorting from the
      oc/oc bone marrow, this population is able to differentiate in vitro into
      osteoclast-like cells in the presence of RANKL and macrophage colony-stimulating
      factor (M-CSF), into dendritic-like cells in the presence of
      granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4,
      and TNFalpha, and into immature B-cells when seeded onto ST2 cells in the
      presence of IL-7. CONCLUSION: Our results show the existence of a novel bipotent
      biphenotypic hematopoietic progenitor population present in the bone marrow that
      has retained the capacity to differentiate into myeloid and B-lymphoid cells.

PMID- 15176998
TI  - The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in
      ovariectomized rats without changing bone formation.
AB  - Chloride channel activity is essential for osteoclast function. Consequently,
      inhibition of the osteoclastic chloride channel should prevent bone resorption.
      Accordingly, we tested a chloride channel inhibitor on bone turnover and found
      that it inhibits bone resorption without affecting bone formation. This study
      indicates that chloride channel inhibitors are highly promising for treatment of
      osteoporosis. INTRODUCTION: The chloride channel inhibitor, NS3736, blocked
      osteoclastic acidification and resorption in vitro with an IC50 value of 30
      microM. When tested in the rat ovariectomy model for osteoporosis, daily
      treatment with 30 mg/kg orally protected bone strength and BMD by approximately
      50% 6 weeks after surgery. Most interestingly, bone formation assessed by
      osteocalcin, mineral apposition rate, and mineralized surface index was not
      inhibited. MATERIALS AND METHODS: Analysis of chloride channels in human
      osteoclasts revealed that ClC-7 and CLIC1 were highly expressed. Furthermore, by
      electrophysiology, we detected a volume-activated anion channel on human
      osteoclasts. Screening 50 different human tissues showed a broad expression for
      CLIC1 and a restricted immunoreactivity for ClC-7, appearing mainly in
      osteoclasts, ovaries, appendix, and Purkinje cells. This highly selective
      distribution predicts that inhibition of ClC-7 should specifically target
      osteoclasts in vivo. We suggest that NS3736 is inhibiting ClC-7, leading to a
      bone-specific effect in vivo. RESULTS AND CONCLUSION: In conclusion, we show for
      the first time that chloride channel inhibitors can be used for prevention of
      ovariectomy-induced bone loss without impeding bone formation. We speculate that
      the coupling of bone resorption to bone formation is linked to the acidification
      of the resorption lacunae, thereby enabling compounds that directly interfere
      with this process to be able to positive uncouple this process resulting in a net
      bone gain.

PMID- 15176999
TI  - Role of TAFII-17, a VDR binding protein, in the increased osteoclast formation in
      Paget's Disease.
AB  - In contrast to normal OCL precursors, pagetic OCL precursors express MVNP and
      form OCL at physiologic concentrations of 1,25(OH)2D3, as do normal OCL
      precursors transfected with the MVNP gene. Using a GST-VDR chimeric protein, we
      identified TAFII-17 as VDR binding protein expressed by pagetic OCL precursors
      and MVNP transduced normal OCL precursors. TAF(II)-17 was in part responsible for
      the increased 1,25(OH)2D3 responsivity of pagetic OCL precursors. INTRODUCTION:
      Pagetic osteoclasts (OCLs) and their precursors express measles virus
      nucleocapsid protein (MVNP) and form large numbers of OCLs at low concentrations
      of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Similarly, normal OCL precursors
      transfected with MVNP also form OCLs at low concentrations of 1,25(OH)2D3. These
      results suggest that expression of MVNP in OCL precursors enhances vitamin D
      receptor (VDR)-mediated gene transcription. MATERIALS AND METHODS: To determine
      the mechanism for the increased OCL formation capacity of pagetic OCL precursors
      in response to 1,25(OH)2D3, lysates from pagetic and MVNP-transduced normal OCL
      precursors were incubated with a GST-VDR chimeric protein. RESULTS: A 17-kDa
      peptide that bound VDR was detected in MVNP-transduced cells and pagetic OCL
      precursors treated with 1,25(OH)2D3. This peptide was identified as TAFII-17, a
      component of the TFIID transcription complex. Expression of increased levels of
      TAFII-17 in cells allowed TAFII-17 to bind to VDR at low concentrations of
      1,25(OH)2D3. An antisense oligonucelotide (AS-ODN) to TAFII-17 significantly
      decreased OCL formation in response to 1,25(OH)2D3 in pagetic but not normal
      marrow cultures by approximately 40%. Transfection of TAFII-17 or MVNP into
      NIH3T3 cells increased VDR transcriptional activity as measured by DR-3 reporter
      assays. CONCLUSION: These data show that expression of the MVNP gene in OCL
      precursors results in increased levels of TAFII-17. TAFII-17 can bind VDR at low
      concentrations of 1,25(OH)2D3. These results suggest that MVNP expression in
      Paget's OCL precursors increases expression of a component(s) of the VDR
      transcription complex that can increase OCL formation.

PMID- 15177000
TI  - Continuous parathyroid hormone induces cortical porosity in the rat: effects on
      bone turnover and mechanical properties.
AB  - We examined the time course effects of continuous PTH on cortical bone and
      mechanical properties. PTH increased cortical bone turnover and induced
      intracortical porosity with no deleterious effect on bone strength. Withdrawal of
      PTH increased maximum torque to failure and stiffness with no change in energy
      absorbed. INTRODUCTION: The skeletal response of cortical bone to parathyroid
      hormone (PTH) is complex and species dependent. Intermittent administration of
      PTH to rats increases periosteal and endocortical bone formation but has no known
      effects on intracortical bone turnover. The effects of continuous PTH on cortical
      bone are not clearly established. MATERIALS AND METHODS: Eighty-four 6-month-old
      female Sprague-Dawley rats were divided into three control, six PTH, and two PTH
      withdrawal (WD) groups. They were subcutaneously implanted with osmotic pumps
      loaded with vehicle or 40 microg/kg BW/day human PTH(1-34) for 1, 3, 5, 7, 14,
      and 28 days. After 7 days, PTH was withdrawn from two groups of animals for 7 (7d
      PTH/7d-WD) and 21 days (7d-PTH/21d-WD). Histomorphometry was performed on
      periosteal and endocortical surfaces of the tibial diaphysis in all groups.
      microCT of tibias and mechanical testing by torsion of femora were performed on
      28d-PTH and 7d-PTH/21d-WD animals. RESULTS AND CONCLUSIONS: Continuous PTH
      increased periosteal and endocortical bone formation, endocortical osteoclast
      perimeter, and cortical porosity in a time-dependent manner, but did not change
      the mechanical properties of the femur, possibly because of addition of new bone
      onto periosteal and endocortical surfaces. Additionally, withdrawal of PTH
      restored normal cortical porosity and increased maximum torque to failure and
      stiffness. We conclude that continuous administration of PTH increased cortical
      porosity in rats without having a detrimental effect on bone mechanical
      properties.

PMID- 15177001
TI  - Risk factors for incident vertebral fractures in men and women: the Rotterdam
      Study.
AB  - Low BMD and prevalent vertebral fractures are known risk factors for incident
      vertebral fractures. In 3001 men and women from the Rotterdam Study, prevalent
      nonvertebral fractures, early menopause, current smoking, and walking aid use
      were also strong risk factors for incident vertebral fractures. INTRODUCTION:
      Thus far, age, low BMD, and prevalent vertebral fractures are the only well-known
      risk factors for incident vertebral fractures. Therefore, our aim was to
      investigate other potential risk factors for incident vertebral fractures in the
      elderly. MATERIALS AND METHODS: This study was based on the Rotterdam Study, a
      large prospective population-based cohort study among men and women > or =55
      years of age. For 3001 subjects, spinal radiographs were obtained at baseline and
      again approximately 6.3 years later. These follow-up radiographs were scored for
      vertebral fractures using the McCloskey-Kanis method. Whenever a vertebral
      fracture was detected, the radiograph was compared with the baseline radiograph.
      If this fracture was not already present at baseline, it was considered incident.
      At baseline, information on potential risk factors was obtained. RESULTS: Low BMD
      and prevalent vertebral fractures were strong risk factors for incident vertebral
      fractures in both men and women (RR 2.3 [1.6-3.3] and 2.2 [0.9-5.0] for men and
      RR 2.1 [1.6-2.6] and 4.1 [2.5-6.7] for women, respectively). For women, age,
      early menopause (< or =45 years of age; RR 1.0 [1.1-3.5]), current smoking (2.1
      [1.2-3.5]), and walking aid use (2.5 [1.1-5.5]) were additional independent risk
      factors. For men, only a history of nonvertebral fractures was a significant
      independent risk factor (OR 2.4 [1.2-4.8]). CONCLUSION: Apart from low BMD and
      prevalent vertebral fractures, prevalent nonvertebral fractures are associated
      with an increased incident vertebral fracture risk in men. In women, early
      menopause, current smoking, and walking aid use are additional independent risk
      factors for incident vertebral fractures.

PMID- 15177002
TI  - Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling
      pathway in MC3T3-E1 osteoblasts.
AB  - Androgens have important effects on the bone metabolism. However, the effect and
      mechanism of androgen action on the osteoblasts remains unknown. Here we showed
      that androgens increase phosphorylation and nuclear translocation of Akt. siRNA
      AR prevented androgen-induced Akt activation in MC3T3-E1 cells. This suggests
      that nongenomic androgen activation of Akt is mediated by androgen receptor in
      osteoblasts. INTRODUCTION: Androgens have important effects on the human skeleton
      in both males and females. However, the mechanism of androgen action on bone
      metabolism remains unknown. The aims of this study were to determine the effect
      and mechanism of androgen action on the osteoblast cells. MATERIALS AND METHODS:
      Here we showed that 5alpha-dihydrotestosterone (DHT) accelerates cell growth of
      the MC3T3-E1 cell line in a time- and dose-dependent manner. The specific
      phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 and kinase
      deficient Akt mutant can repress the androgen effect on MC3T3-E1 cells. Western
      blot analysis showed that DHT, 17beta-estradiol, and testosterone (T) induce a
      rapid and transient phosphorylation of Akt in MC3T3-E1 cells. This activation
      reached to a plateau after 15 minutes and gradually diminished after 60 minutes
      of DHT treatment. RESULTS: Fluorescence microscopy showed a distinct increase in
      immunostaining intensity in the nuclear interior after androgen treatment but no
      change in the subcellular distribution of Akt when the cells were pretreated with
      hydroxyflutamide (HF) or LY294002. In addition, small interfering RNA against
      androgen receptor (siRNA-AR) prevented DHT-induced Akt phosphorylation and cell
      growth. CONCLUSION: These findings represents the first physiological finding to
      indicate how steroid hormones such as androgens can mediate the nuclear
      localization of Akt/PKB in osteoblasts that has previously mainly been linked to
      growth factor-induced events occurring at the plasma membrane level.

PMID- 15177003
TI  - Sclerotic metaphyseal lines in a child treated with pamidronate:
      histomorphometric analysis.

PMID- 15177004
TI  - Severe malignant osteopetrosis caused by a GL gene mutation.
AB  - Infantile malignant autosomal recessive osteopetrosis is a genetically
      heterogeneous disease caused by the inability of OCLs to resorb and remodel bone,
      resulting in generalized osteosclerosis and obliteration of marrow spaces and
      cranial foramina. The classical clinical features are pathological fractures,
      visual impairment, and bone marrow failure. Two human genes have been described
      as the cause of this form of osteopetrosis: the T-cell immune-regulator-1
      (TCIRG1) gene, which is mutated in >50% of the patients, and the chloride channel
      7 (ClCN7) gene, which accounts for approximately 10% of cases. We report the
      clinical, radiographic, and histopathologic findings of the first human
      osteopetrosis case caused by a mutation in the grey-lethal (GL) gene. The
      patient, a 9-day-old male infant, presented with a very severe osteopetrotic
      phenotype including substantial hepatosplenomegaly since birth, cytopenia, and
      progressive major liver failure. Skeletal radiographs revealed a generalized
      increase in bone density with loss of corticomedullary differentiation.
      Histopathologic bone examination showed the typical osteopetrotic changes, with
      absence of resorptive activity, and osteoclasts, slightly decreased in number,
      with evident morphological alterations.

PMID- 15177005
TI  - Chondrosarcoma in association with primary hyperparathyroidism.
AB  - We describe two female patients, 66 and 36 years of age, with both primary
      hyperparathyroidism and chondrosarcoma. Case 1 had a chondrosarcoma of the right
      scapula, and case 2 had chondrosarcoma of the left proximal tibia. Both patients
      underwent surgical resection of their chondrosarcoma and subsequent parathyroid
      surgery. Histological analysis of the excised parathyroid in case 1 showed a
      parathyroid carcinoma and in case 2 showed a parathyroid adenoma. Including these
      two patients, there is now a total of six cases that have been reported in the
      literature describing the association between hyperparathyroidism and bone
      malignancy. We believe that this small number makes it unlikely that there is an
      association between these two conditions, although we speculate that there may be
      an underlying genetic basis.

PMID- 15177017
TI  - PbX marks the spot.
AB  - Pbx and Meis proteins act as cofactors to various transcription factors, but
      their exact functions have been unclear. A report by Berkes et al. in Molecular
      Cell now demonstrates that Pbx and Meis may penetrate repressive chromatin to
      mark specific genes for activation.

PMID- 15177018
TI  - Colinearity loops out.
AB  - Modulation of chromatin structure has long been proposed to underlie the colinear
      regulation of Hox genes during animal development. In a recent paper, Chambeyron
      and Bickmore explore this possibility in retinoic acid-induced ES cells. They
      show that, while chromatin remodeling confers transcriptional competence to the
      gene cluster, subsequent sequential extrusion of genes from their chromosome
      territory may determine their coordinated expression in time.

PMID- 15177019
TI  - REF-ereeing the cytoplasmic fate of mRNA via nuclear export.
AB  - The C. elegans sex-determining gene tra-2 is subject to multiple forms of
      regulation. A report in the June 4 issue of Molecular Cell now shows that
      proteins associated with the tra-2 mRNA determine its pathway of nuclear export
      and influence its cytoplasmic fate. These findings demonstrate an additional
      level of control and link nuclear export to the regulation of sexual development.

PMID- 15177020
TI  - E2F3-a novel repressor of the ARF/p53 pathway.
AB  - The Arf tumor suppressor is a key component of the p53 tumor surveillance
      pathway, and its expression is activated by abnormal proliferation signals. In a
      recent paper, Lees and coworkers investigate the regulation of Arf expression by
      E2Fs and demonstrate that in normal cells E2F3 is a pivotal repressor of Arf.

PMID- 15177021
TI  - GPI-anchor synthesis: Ras takes charge.
AB  - A new study shows that Ras2 regulates GPI-anchor synthesis in the ER.
      Reciprocally, the targeted enzyme GPI-GlcNAc transferase regulates Ras2 signal
      output. This novel intersection of Ras2 signaling and an ER-localized protein
      complex has interesting implications for Ras function.

PMID- 15177022
TI  - Putting the squeeze on mechanotransduction.
AB  - Both mechanical and chemical stimuli guide tissue function. In a recent paper,
      Tschumperlin et al. proposed that pressure acting on airway epithelium elicits
      mechanotransduction not by directly altering biochemical signaling but by
      regulating extracellular fluid volume to modulate ligand-receptor interactions.

PMID- 15177023
TI  - CLIP-170 family members: a motor-driven ride to microtubule plus ends.
AB  - CLIP-170 family proteins regulate microtubule plus end dynamics. Two reports
      published in this issue of Developmental Cell show that Bik1 and tip1p, the CLIP
      170-like proteins of budding and fission yeast, are carried to microtubule plus
      ends by kinesin motor proteins. These findings indicate a complex interplay
      between microtubule-associated proteins and suggest a novel mechanism by which
      kinesin proteins stabilize microtubules.

PMID- 15177024
TI  - Formation and remodeling of epithelial polarity.
AB  - Polarity is a fundamental property of all eukaryotic cells that underlies many
      developmental processes. A recent EMBO workshop (March 27-31) organized by Thomas
      Lecuit, Norbert Perrimon, and Keith Mostov brought cell and developmental
      biologists together on the Mediterranean coast near Marseille, France, to share
      views on how epithelium polarity is established and remodeled during development
      and disease. Participants witnessed and celebrated the emerging convergence of
      intellectual and experimental approaches to address how individual cells acquire
      polarity and form polarized tissues in the context of developing embryos.

PMID- 15177025
TI  - Genomic cis-regulatory architecture and trans-acting regulators of a single
      interneuron-specific gene battery in C. elegans.
AB  - Gene batteries are sets of coregulated genes with common cis-regulatory elements
      that define the differentiated state of a cell. The nature of gene batteries for
      individual neuronal cellular subtypes and their linked cis-regulatory elements is
      poorly defined. Through molecular dissection of the highly modular cis-regulatory
      architecture of individual neuronally expressed genes, we have defined a
      conserved 16 bp cis-regulatory motif that drives gene expression in a single
      interneuron subtype, termed AIY, in the nematode Caenorhabditis elegans. This
      motif is bound and activated by the Paired- and LIM-type homeodomain proteins CEH
      10 and TTX-3. Using genome-wide phylogenetic footprinting, we delineated the
      location, distribution, and evolution of AIY-specific cis-regulatory elements
      throughout the genome and thereby defined a large battery of AIY-expressed genes,
      all of which represent direct Paired/LIM homeodomain target genes. The identity
      of these homeodomain targets provides novel insights into the biology of the AIY
      interneuron.

PMID- 15177026
TI  - Maternal control of vertebrate development before the midblastula transition:
      mutants from the zebrafish I.
AB  - Maternal factors control development prior to the activation of the embryonic
      genome. In vertebrates, little is known about the molecular mechanisms by which
      maternal factors regulate embryonic development. To understand the processes
      controlled by maternal factors and identify key genes involved, we embarked on a
      maternal-effect mutant screen in the zebrafish. We identified 68 maternal-effect
      mutants. Here we describe 15 mutations in genes controlling processes prior to
      the midblastula transition, including egg development, blastodisc formation,
      embryonic polarity, initiation of cell cleavage, and cell division. These mutants
      exhibit phenotypes not previously observed in zygotic mutant screens. This
      collection of maternal-effect mutants provides the basis for a molecular genetic
      analysis of the maternal control of embryogenesis in vertebrates.

PMID- 15177027
TI  - Maternal control of development at the midblastula transition and beyond: mutants
      from the zebrafish II.
AB  - Many maternal factors in the oocyte persist in the embryo. They are required to
      initiate zygotic transcription but also function beyond this stage, where they
      interact with zygotic gene products during embryonic development. In a four
      generation screen in the zebrafish, we identified 47 maternal-effect and five
      paternal-effect mutants that manifest their phenotypes at the time of, or after,
      zygotic genome activation. We propagated a subset of 13 mutations that cause
      developmental arrest at the midblastula transition, defects in cell viability,
      embryonic morphogenesis, and establishment of the embryonic body plan. This
      diverse group of mutants, many not previously observed in vertebrates,
      demonstrates a substantial maternal contribution to the "zygotic" period of
      embryogenesis and a surprising degree of paternal control. These mutants provide
      powerful tools to dissect the maternal and paternal control of vertebrate
      embryogenesis.

PMID- 15177028
TI  - Major molecular differences between mammalian sexes are involved in drug
      metabolism and renal function.
AB  - Many anatomical differences exist between males and females; these are manifested
      on a molecular level by different hormonal environments. Although several
      molecular differences in adult tissues have been identified, a comprehensive
      investigation of the gene expression differences between males and females has
      not been performed. We surveyed the expression patterns of 13,977 mouse genes in
      male and female hypothalamus, kidney, liver, and reproductive tissues. Extensive
      differential gene expression was observed not only in the reproductive tissues,
      but also in the kidney and liver. The differentially expressed genes are involved
      in drug and steroid metabolism, osmotic regulation, or as yet unresolved cellular
      roles. In contrast, very few molecular differences were observed between the male
      and female hypothalamus in both mice and humans. We conclude that there are
      persistent differences in gene expression between adult males and females. These
      molecular differences have important implications for the physiological
      differences between males and females.

PMID- 15177029
TI  - Ext1-dependent heparan sulfate regulates the range of Ihh signaling during
      endochondral ossification.
AB  - Exostosin1 (Ext1) belongs to a family of glycosyltransferases necessary for the
      synthesis of the heparan sulfate (HS) chains of proteoglycans, which regulate
      signaling of several growth factors. Loss of tout velu (ttv), the homolog of Ext1
      in Drosophila, inhibits Hedgehog movement. In contrast, we show that reduced HS
      synthesis in mice carrying a hypomorphic mutation in Ext1 results in an elevated
      range of Indian hedgehog (Ihh) signaling during embryonic chondrocyte
      differentiation. Our data suggest a dual function for HS: First, HS is necessary
      to bind Hedgehog in the extracellular space. Second, HS negatively regulates the
      range of Hedgehog signaling in a concentration-dependent manner. Additionally,
      our data indicate that Ihh acts as a long-range morphogen, directly activating
      the expression of parathyroid hormone-like hormone. Finally, we propose that the
      development of exostoses in the human Hereditary Multiple Exostoses syndrome can
      be attributed to activation of Ihh signaling.

PMID- 15177030
TI  - Cell cycle control of kinesin-mediated transport of Bik1 (CLIP-170) regulates
      microtubule stability and dynein activation.
AB  - CLIPs are microtubule plus end-associated proteins that mediate interactions
      required for cell polarity and cell division. Here we demonstrate that budding
      yeast Bik1, unlike its human ortholog CLIP-170, is targeted to the microtubule
      plus end by a kinesin-dependent transport mechanism. Bik1 forms a complex with
      the kinesin Kip2. Fluorescently labeled Bik1 and Kip2 comigrate along individual
      microtubules. Bik1 exists in distinct intracellular pools: a stable pool at the
      spindle pole body that is depleted during cell cycle progression, a soluble pool
      from which Bik1 can be recruited during microtubule initiation, and a dynamic
      plus end pool maintained by Kip2. Kip2 stabilizes microtubules by targeting Bik1
      to the plus end and Kip2 levels are controlled during the cell cycle. As with
      Bik1, the targeting of dynein to the microtubule plus end requires Kip2. These
      findings reveal a central role for Kip2-dependent transport in the cell cycle
      control of microtubule dynamics and dynein-dependent motility.

PMID- 15177031
TI  - Tea2p kinesin is involved in spatial microtubule organization by transporting
      tip1p on microtubules.
AB  - The positioning of growth sites in fission yeast cells is mediated by spatially
      controlled microtubule dynamics brought about by tip1p, a CLIP-170-like protein,
      which is localized at the microtubule tips and guides them to the cell ends. The
      kinesin tea2p is also located at microtubule tips and affects microtubule
      dynamics. Here we show that tea2p interacts with tip1p and that the two proteins
      move with high velocity along the microtubules toward their growing tips. There,
      tea2p and tip1p accumulate in larger particles. Particle formation requires the
      EB1 homolog, mal3p. Our results suggest a model in which kinesins regulate
      microtubule growth by transporting regulatory factors such as tip1p to the
      growing microtubule tips.

PMID- 15177032
TI  - Sequential roles of Cdc42, Par-6, aPKC, and Lgl in the establishment of
      epithelial polarity during Drosophila embryogenesis.
AB  - How epithelial cells subdivide their plasma membrane into an apical and a
      basolateral domain is largely unclear. In Drosophila embryos, epithelial cells
      are generated from a syncytium during cellularization. We show here that polarity
      is established shortly after cellularization when Par-6 and the atypical protein
      kinase C concentrate on the apical side of the newly formed cells. Apical
      localization of Par-6 requires its interaction with activated Cdc42 and dominant
      active or dominant-negative Cdc42 disrupt epithelial polarity, suggesting that
      activation of this GTPase is crucial for the establishment of epithelial
      polarity. Maintenance of Par-6 localization requires the cytoskeletal protein
      Lgl. Genetic and biochemical experiments suggest that phosphorylation by aPKC
      inactivates Lgl on the apical side. On the basolateral side, Lgl is active and
      excludes Par-6 from the cell cortex, suggesting that complementary cortical
      domains are maintained by mutual inhibition of aPKC and Lgl on opposite sides of
      an epithelial cell.

PMID- 15177033
TI  - Ezrin is essential for epithelial organization and villus morphogenesis in the
      developing intestine.
AB  - Ezrin, Radixin, and Moesin (the ERM proteins) supply regulated linkage between
      membrane proteins and the actin cytoskeleton. The study of mammalian ERM proteins
      has been hampered by presumed functional overlap. We have found that Ezrin, the
      only ERM detected in epithelial cells of the developing intestine, provides an
      essential role in configuring the mouse intestinal epithelium. Surprisingly,
      Ezrin is not absolutely required for the formation of brush border microvilli or
      for the establishment or maintenance of epithelial polarity. Instead, Ezrin
      organizes the apical terminal web region, which is critical for the poorly
      understood process of de novo lumen formation and expansion during villus
      morphogenesis. Our data also suggest that Ezrin controls the localization and/or
      function of certain apical membrane proteins that support normal intestinal
      function. These in vivo studies highlight the critical function of Ezrin in the
      formation of a multicellular epithelium rather than an individual epithelial
      cell.

PMID- 15177034
TI  - Lumen morphogenesis in C. elegans requires the membrane-cytoskeleton linker erm
      1.
AB  - Epithelial tubes are basic building blocks of complex organs, but their
      architectural requirements are not well understood. Here we show that erm-1 is a
      unique C. elegans ortholog of the ERM family of cytoskeleton-membrane linkers,
      with an essential role in lumen morphogenesis. ERM-1 localizes to the luminal
      membranes of those tubular organ epithelia which lack stabilization by cuticle.
      RNA interference (RNAi), a germline deletion, and overexpression of erm-1 cause
      cystic luminal phenotypes in these epithelia. Confocal and ultrastructural
      analyses indicate that erm-1 functions directly in apical membrane morphogenesis,
      rather than in epithelial polarity and junction assembly as has been previously
      proposed for ERMs. We also show that act-5/cytoplasmic actin and sma-1/beta-H
      spectrin are required for lumen formation and functionally interact with erm-1.
      Our findings suggest that there are common structural constraints on the
      architecture of diverse organ lumina.

PMID- 15177035
TI  - A two-step mechanism for myotome formation in chick.
AB  - The study of the morphogenetic cell movements underlying myotome formation in the
      chick embryo has led to the emergence of highly controversial models. Here we
      report a real-time cell lineage analysis of myotome development using
      electroporation of a GFP reporter in newly formed chick somites. Confocal
      analysis of cell movements demonstrates that myotome formation involves two
      sequential steps. In a first phase, incremental myotome growth results from a
      contribution of myocytes derived solely from the medial border of the
      dermomyotome. In a second phase, myocytes are produced from all four borders of
      the dermomyotome. The relative distribution of myocytes demonstrates that the
      medial and the lateral borders of the somite generate exclusively epaxial and
      hypaxial muscles. This analysis also identified five myotomal regions,
      characterized by the origin of the myocytes that constitute them. Together, our
      results provide a comprehensive model describing the morphogenesis of the early
      myotome in higher vertebrates.

PMID- 15177036
TI  - Activation of stress-responsive promoters by ionizing radiation for deployment in
      targeted gene therapy.
AB  - Radiotherapy is one of the principal modalities of cancer treatment, but the
      delivery of a curative dose of ionizing radiation (IR) to the tumour is
      frequently limited by the need to protect the normal tissues within the
      irradiated area from radiation damage. This problem could be circumvented if
      tumour cells could be selectively sensitized to killing by IR. One way to achieve
      this goal would be to transduce the tumour cells with expression vectors carrying
      toxin genes under the control of promoters that are inactive unless induced by
      IR. For this approach to be successful, two parameters must be met: (i) the
      expression vector has to be delivered to the tumour or its immediate vicinity
      (e.g. its vasculature) and (ii) the promoter driving the expression of the toxin
      gene has to have negligible basal activity, yet has to be activated by clinically
      achievable doses of IR. Several vectors that fulfil these criteria are currently
      reaching clinical trials. In this review, we examine the response of mammalian
      cells to IR, and the current status of radiation-induced suicide gene therapy
      that is dependent on this response.

PMID- 15177037
TI  - High frequency of nucleotide misincorporations upon the processing of double
      strand breaks.
AB  - Base substitutions were detected as a consequence of double-strand break (DSB)
      repair in plants. The fidelity of processing free DNA ends was analyzed using a
      stop-codon inactivated beta-glucuronidase (uidA) reporter gene. Circular and
      linear plasmids carrying the inactive gene were delivered to Nicotiana
      plumbaginifolia protoplasts or Nicotiana tabacum leaves. Processing of breaks
      which occurred in close proximity (5-9 bp) to termination codons led to
      occasional reversions and subsequent gene reactivation. In contrast, the repair
      of breaks occurring at a greater distance from the stop-codon resulted in a
      significantly lower number of reversions. The data suggest that the error prone
      processing of the free ends involves partial degradation and re-synthesis of the
      DNA repair substrate.

PMID- 15177039
TI  - The isoflavonoids genistein and quercetin activate different stress signaling
      pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and
      histone H2AX.
AB  - The ataxia-telangiectasia mutated (ATM) protein kinase is activated in response
      to ionizing radiation (IR) and activates downstream DNA-damage signaling
      pathways. Although the role of ATM in the cellular response to ionizing radiation
      has been well characterized, its role in response to other DNA-damaging agents is
      less well defined. We previously showed that genistein, a naturally occurring
      isoflavonoid, induced increased ATM protein kinase activity, ATM-dependent
      phosphorylation of p53 on serine 15 and activation of the DNA-binding properties
      of p53. Here, we show that genistein also induces phosphorylation of p53 at
      serines 6, 9, 20, 46, and 392, and that genistein-induced accumulation and
      phosphorylation of p53 is reduced in two ATM-deficient human cell lines. Also, we
      show that genistein induces phosphorylation of ATM on serine 1981 and
      phosphorylation of histone H2AX on serine 139. The related bioflavonoids,
      daidzein and biochanin A, did not induce either phosphorylation of p53 or ATM at
      these sites. Like genistein, quercetin induced phosphorylation of ATM on serine
      1981, and ATM-dependent phosphorylation of histone H2AX on serine 139; however,
      p53 accumulation and phosphorylation on serines 6, 9, 15, 20, 46, and 392
      occurred in ATM-deficient cells, indicating that ATM is not required for
      quercetin-induced phosphorylation of p53. Our data suggest that genistein and
      quercetin induce different DNA-damage induced signaling pathways that, in the
      case of genistein, are highly ATM-dependent but, in the case of quercetin, may be
      ATM-dependent only for some downstream targets.

PMID- 15177038
TI  - The kinase activity of DNA-PK is required to protect mammalian telomeres.
AB  - The kinase activity of DNA-dependent protein kinase (DNA-PK) is required for
      efficient repair of DNA double-strand breaks (DSB) by non-homologous end joining
      (NHEJ). DNA-PK also participates in protection of mammalian telomeres, the
      natural ends of chromosomes. Here we investigate whether the kinase activity of
      DNA-PK is similarly required for effective telomere protection. DNA-PK proficient
      mouse cells were exposed to a highly specific inhibitor of DNA-PK phosphorylation
      designated IC86621. Chromosomal end-to-end fusions were induced in a
      concentration-dependent manner, demonstrating that the telomere end-protection
      role of DNA-PK requires its kinase activity. These fusions were uniformly
      chromatid-type, consistent with a role for DNA-PK in capping telomeres after DNA
      replication. Additionally, fusions involved exclusively telomeres produced via
      leading-strand DNA synthesis. Unexpectedly, the rate of telomeric fusions induced
      by IC86621 exceeded that which occurs spontaneously in DNA-dependent protein
      kinase catalytic subunit (DNA-PKcs) mutant cells by up to 110-fold. One
      explanation, that IC86621 might inhibit other, as yet unknown proteins, was ruled
      out when the drug failed to induce fusions in DNA-PKcs knock-out mouse cells.
      IC86621 did not induce fusions in Ku70 knock-out cells suggesting the drug
      requires the holoenzyme to be effective. ATM also is required for effective
      chromosome end protection. IC86621 increased fusions in ATM knock-out cells
      suggesting DNA-PK and ATM act in different telomere pathways. These results
      indicate that the kinase activity of DNA-PK is crucial to reestablishing a
      protective terminal structure, specifically on telomeres replicated by leading
      strand DNA synthesis.

PMID- 15177040
TI  - AHNAK interacts with the DNA ligase IV-XRCC4 complex and stimulates DNA ligase IV
      mediated double-stranded ligation.
AB  - AHNAK is a high molecular weight protein that is under-expressed in several
      radiosensitive neuroblastoma cell lines. Using immunoaffinity purification or
      purified proteins, we show that AHNAK interacts specifically with the DNA ligase
      IV-XRCC4 complex, a complex that functions in DNA non-homologous end-joining.
      Furthermore, AHNAK and the DNA ligase IV-XRCC4 complex co-immunoprecipitate
      demonstrating an in vivo interaction. This interaction is specific and is not
      observed with other DNA ligases nor with other components of the DNA non
      homologous end-joining machinery. We characterised AHNAK as a protein that
      stimulates the double-stranded (DS) ligation activity of DNA ligase IV-XRCC4. We
      show that AHNAK has weak DNA-binding activity and forms a stable complex with the
      DNA ligase IV-XRCC4 complex on DNA. AHNAK is also able to link two DNA molecules
      to a similar extent to that previously reported for Ku. Together, these findings
      demonstrate new activities for AHNAK, and raise the possibility that it may
      function to modulate DNA non-homologous end-joining.

PMID- 15177041
TI  - New immunoaffinity-LC-MS/MS methodology reveals that Aag null mice are deficient
      in their ability to clear 1,N6-etheno-deoxyadenosine DNA lesions from lung and
      liver in vivo.
AB  - The mouse alkyladenine DNA glycosylase (Aag) initiates base excision repair with
      a broad substrate range that includes the highly mutagenic exocyclic etheno DNA
      base adduct 1,N6-ethenodeoxyadenosine ((epsilon)dA). Previous attempts to
      determine the in vivo role of Aag in (epsilon)dA repair were complicated by
      technological difficulties in measuring low levels of (epsilon)dA in genomic DNA.
      Here we describe the development of a new method for (epsilon)dA detection in
      genomic DNA that couples an immunoaffinity purification with LC-MS/MS analysis
      and that utilizes an isotopically labeled internal standard. We go on to describe
      the application of this method to measuring the in vivo repair of (epsilon)dA
      base lesions in liver and lung tissue of wild type and Aag null mice. Our results
      demonstrate that while Aag clearly represents the major DNA repair enzyme for the
      in vivo removal (epsilon)dA bases, these lesions can also be eliminated from the
      genome via an alternative mechanism.

PMID- 15177042
TI  - Identification of DNA-PKcs phosphorylation sites in XRCC4 and effects of
      mutations at these sites on DNA end joining in a cell-free system.
AB  - Nonhomologous end joining (NHEJ) is the principal mechanism for repairing DNA
      double-strand breaks in mammalian cells. NHEJ requires at least three protein
      components: the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku
      protein, and the DNA ligase IV/XRCC4 (DNL IV/XRCC4) complex. Although DNA-PKcs
      phosphorylates several sites within itself and these other proteins, the
      significance of phosphorylation at individual sites is not yet understood. Here
      we investigate the effects of DNA-PKcs-mediated phosphorylation at two sites in
      XRCC4. One is a previously described site at serine 260; the other is a newly
      mapped site at serine 318. XRCC4 bearing mutations at these sites was co
      expressed with DNL IV, the resulting complexes were purified, and activity was
      tested in a cell-free end-joining system reconstituted from recombinant and
      purified proteins. Substitution of alanine for serine 260 or 318, which prevents
      phosphorylation at these positions, or aspartate for serine 260, which mimics
      constitutive phosphorylation, had no significant effect on overall end-joining
      activity. In the assay system used, DNA-PKcs is not essential, but when present,
      arrests the reaction until phosphorylation occurs, in effect establishing a
      reaction checkpoint. Mutations at serines 260 and 318 did not affect
      establishment or release from the checkpoint. Results demonstrate that DNA-PKcs
      mediated phosphorylation of XRCC4 serine 260 and serine 318 does not directly
      control end-joining under the conditions tested.

PMID- 15177044
TI  - 8-OxoG retards the activity of the ligase III/XRCC1 complex during the repair of
      a single-strand break, when present within a clustered DNA damage site.
AB  - Ionising radiation produces clustered DNA damage. Recent studies have established
      that the efficiency of excision of a lesion within clustered damage sites is
      reduced. This study presents evidence that the repair of clustered DNA damage is
      compromised, relative to that of the isolated lesions, since the lifetime of both
      lesions is extended by up to eight fold. Simple clustered damage sites, comprised
      of a single-strand break, one or five bases 3' or 5' to 8-oxoG on the opposite
      strand, were synthesised in oligonucleotides and repair carried out in XRS5
      nuclear extracts. The rate of repair of the single-strand break within these
      clustered damage sites is reduced, mainly due to inhibition of the DNA ligase
      III/XRCC1 complex. The single-strand break, present as an isolated lesion, is
      repaired by short-patch base excision repair, however the mechanism of repair of
      the single-strand break within the clustered damage site is asymmetric. When the
      lesions are 5' to each other, the single-strand break is rejoined by short-patch
      repair whereas the rejoining of the single-strand break occurs by long-patch type
      repair when the lesions are 3' to one another. The retardation of DNA ligase
      III/XRCC1 complex, following addition of one base, is responsible for the
      initiation of long-patch base excision repair when the lesions are 3' to each
      other. The lesions within the cluster are processed sequentially, the single
      strand break being repaired before excision of 8-oxoG, limiting the formation of
      double-strand breaks to <2%. Stalled processing of clustered DNA damage is
      suggested to have implications for mutation induction by radiation.

PMID- 15177043
TI  - The yeast Rad7/Rad16/Abf1 complex generates superhelical torsion in DNA that is
      required for nucleotide excision repair.
AB  - Nucleotide excision repair (NER) in eukaryotes removes DNA base damage as an
      oligonucleotide in a complex series of reactions. The nature of the dual incision
      reactions on either side of the damaged base has been extensively investigated.
      However, the precise mechanism of cleavage of the phosphodiester backbone of the
      DNA by the NER endonucleases and how this relates to removal of the damage
      containing oligonucleotide during the excision process has not been determined.
      We previously isolated a stable heterotrimeric complex of Rad7/Rad16/Abf1 from
      yeast which functions in the conserved global genome repair (GGR) pathway. GGR
      removes lesions from DNA that is not actively transcribing. We have shown
      previously that the Rad7/Rad16/Abf1 heterotrimer is required to observe DNA
      repair synthesis and oligonucleotide excision during in vitro NER, but not needed
      to detect NER-dependent incision in such reactions. Here we report that this
      protein complex generates superhelicity in DNA through the catalytic activity of
      the Rad16 component. The torsion generated in the DNA by this complex is
      necessary to remove the damage-containing oligonucleotide during NER--a process
      referred to as excision. We conclude that in yeast the molecular mechanism of NER
      includes the generation of superhelical torsion in DNA.

PMID- 15177045
TI  - Identification of specific amino acid residues in the E. coli beta processivity
      clamp involved in interactions with DNA polymerase III, UmuD and UmuD'.
AB  - Variants of a pentapeptide sequence (QL[S/F]LF), referred to as the eubacterial
      clamp-binding motif, appear to be required for certain proteins to bind
      specifically to the Escherichia coli beta sliding clamp, apparently by making
      contact with a hydrophobic pocket located at the base of the C-terminal tail of
      each beta protomer. Although both UmuC (DNA pol V) and the alpha catalytic
      subunit of DNA polymerase III (pol III) each bear a reasonable match to this
      motif, which appears to be required for their respective interactions with the
      clamp, neither UmuD not UmuD' do. As part of an ongoing effort to understand how
      interactions involving the different E. coli umuDC gene products and components
      of DNA polymerase III help to coordinate DNA replication with a DNA damage
      checkpoint control and translesion DNA synthesis (TLS) following DNA damage, we
      characterized the surfaces on beta important for its interactions with the two
      forms of the umuD gene product. We also characterized the surface of beta
      important for its interaction with the alpha catalytic subunit of pol III. Our
      results indicate that although UmuD, UmuD' and alpha share some common contacts
      with beta, each also makes unique contacts with the clamp. These findings suggest
      that differential interactions of UmuD and UmuD' with beta impose a DNA damage
      responsive conditionality on how beta interacts with the translesion DNA
      polymerase UmuC. This is formally analogous to how post-translational
      modification of the eukaryotic PCNA clamp influences mutagenesis. We discuss the
      implications of our findings in terms of how E. coli might coordinate the actions
      of the umuDC gene products with those of pol III, as well as for how organisms in
      general might manage the actions of their multiple DNA polymerases.

PMID- 15177046
TI  - Stereoselective excision of thymine glycol lesions by mammalian cell extracts.
AB  - Thymine glycols (Tg) are major pyrimidine oxidation products produced by chemical
      agents and ionizing radiation. Recent improvements in purification procedures
      gave us the opportunity to examine the incision of DNA duplexes containing a
      single (5S,6R)- or (5R,6S)-Tg lesion by mouse NTH1 DNA glycosylase and mammalian
      cell nuclear extracts. Time course experiments and steady state enzyme kinetics
      indicated that mNTH1 discriminates between the cis-Tg isomers. In addition, a
      variety of mammalian cell nuclear extracts showed a similar discrimination
      between the cis-Tg isomers. Trapping of Schiff base intermediates with sodium
      borohydride demonstrated that a single protein-DNA complex was formed in the
      presence of the nuclear extracts. The electrophoretic mobility of trapped
      complexes formed with both Tg isomers was identical to one another and similar to
      that of the complex formed with recombinant mNTH1. These results suggest that
      among all Tg-active DNA glycosylases, NTH1 is the major enzyme in mammalian cell
      nuclear extracts responsible for incision of duplexes containing cis-Tg isomers.

PMID- 15177047
TI  - A role for DNA polymerase V in G --> T mutations from the major benzo[a]pyrene N2
      dG adduct when studied in a 5'-TGT sequence in E. coli.
AB  - Benzo[a]pyrene (B[a]P), a potent mutagen/carcinogen, is metabolically activated
      to (+)-anti-B[a]PDE, which induces a full spectrum of mutations (e.g. GC --> TA,
      GC --> AT, etc.) principally via its major adduct [+ta]-B[a]P-N2-dG. Recent
      findings suggest that different lesion bypass DNA polymerases may be involved in
      different mutagenic pathways, which is the subject of this report. [+ta]-B[a]P-N2
      dG built into a plasmid in a 5'-TGT sequence gives approximately equal numbers of
      G --> T and G --> A mutations when host E. coli are UV irradiated prior to
      transformation, so this sequence context was chosen to investigate what DNA
      polymerases are involved in G --> T versus G --> A mutations. G --> T mutations
      decline (>10-fold) if E. coli either are not UV-irradiated or are deficient in
      DNA polymerase V ((delta)umuD/C), demonstrating a role for damage-inducible DNA
      Pol V in a G --> T pathway. G --> T mutations are not affected by transformation
      into E. coli deficient in either DNA polymerases II or IV. While the work herein
      was in progress, Lenne-Samuel et al. [Mol. Microbiol. 38 (2000) 299] built the
      same adduct into a plasmid in a 5'-GGA sequence, and showed that the frequency of
      G --> T mutations was similar in UV-irradiated and unirradiated host E. coli
      cells, suggesting no involvement by damage-inducible, lesion bypass DNA
      polymerases (i.e., not II, IV or V); furthermore, a role for DNA Pol V was
      explicitly ruled out. The easiest way to reconcile the findings of Lenne-Samuel
      et al. with the findings herein is if two G --> T mutagenic pathways exist for
      [+ta]-B[a]P-N2-dG, where sequence context dictates which pathway is followed. In
      contrast to the G --> T mutations, herein G --> A mutations from [+ta]-B[a]P-N2
      dG in the 5'-TGT sequence context are shown not to be affected by UV-irradiation
      of host E. coli, and are not dependent on DNA Pol V, or Pol II, Pol IV, or the
      damage-inducible, but SOS-independent UVM system. Published studies, however,
      have shown that G --> A mutations are usually enhanced by UV-irradiation of host
      E. coli prior to the introduction of plasmids either site-specifically modified
      with [+ta]-B[a]P-N2-dG or randomly adducted with (+)-anti-B[a]PDE; both findings
      imply the involvement of a lesion-bypass DNA polymerase. These disparate results
      suggest the existence of two G --> A mutagenic pathways for [+ta]-B[a]P-N2-dG as
      well, although confirmation of this awaits further study. In conclusion, a
      comparison between the evidence presented herein and published findings suggests
      the existence of two distinct mutagenic pathways for both G --> T and G --> A
      mutations from [+ta]-B[a]P-N2-dG, where in each case one pathway is not damage
      inducible and not dependent on a lesion-bypass DNA polymerase, while the second
      pathway is damage-inducible and dependent on a lesion-bypass DNA polymerase.
      Furthermore, DNA sequence context appears to dictate which pathway (as defined by
      the involvement of different DNA polymerases) is followed in each case.

PMID- 15177048
TI  - Ubc9 is required for damage-tolerance and damage-induced interchromosomal
      homologous recombination in S. cerevisiae.
AB  - Ubc9 is an enzyme involved in the conjugation of small ubiquitin related modifier
      (SUMO) to target proteins. A Saccharomyces cerevisiae ubc9 temperature sensitive
      (ts) mutant showed higher sensitivity to various DNA damaging agents such as
      methylmethanesulfonate (MMS) and UV at a semi-permissive temperature than wild
      type cells. The sensitivity of ubc9ts cells was not suppressed by the
      introduction of a mutated UBC9 gene, UBC9-C93S, whose product is unable to
      covalently bind to SUMO and consequently fails to conjugate SUMO to target
      proteins. Diploid ubc9ts cells were more sensitive to various DNA damaging agents
      than haploid ubc9ts cells suggesting the involvement of homologous recombination
      in the sensitivity of ubc9ts cells. The frequency of interchromosomal
      recombination between heteroalleles, his1-1/his1-7 loci, in wild-type cells was
      remarkably increased upon exposure to MMS or UV. Although the frequency of
      spontaneous interchromosomal recombination between the heteroalleles in ubc9ts
      cells was almost the same as that of wild-type cells, no induction of
      interchromosomal recombination was observed in ubc9ts cells upon exposure to MMS
      or UV.

PMID- 15177049
TI  - An integrated mechanistic model for transcription-coupled nucleotide excision
      repair.
AB  - Preferential repair of the transcribed strand of active genes is usually
      attributed to a coupling protein that dislodges RNA polymerase stalled at a
      damage site and recruits repair enzymes. Experimental observations of the effect
      of transcription on preferential repair in Escherichia coli are contradictory and
      inexplicable by this model. In this study, it is argued that the multiple
      conformations displayed by a stalled RNA polymerase result in two sub-pathways
      for repair: Mfd coupled and direct. Together with the fact that RNA polymerase
      recruits the repair enzymes in a promoter dependent manner, an integrated
      mechanistic model is proposed that is capable of explaining the effect of
      transcription on preferential repair reported in literature. The quantitative
      behavior of the model is illustrated by describing the various reactions using a
      biochemical network. The implications of the model on the mechanism for
      transcription-coupled repair in higher organisms are briefly discussed.

PMID- 15177050
TI  - How bioinformatics can help reverse engineer human aging.
AB  - To study human aging is an enormous challenge. The complexity of the aging
      phenotype and the near impossibility of studying aging directly in humans oblige
      researchers to resort to models and extrapolations. Computational approaches
      offer a powerful set of tools to study human aging. In one direction we have data
      mining methods, from comparative genomics to DNA microarrays, to retrieve
      information in large amounts of data. Afterwards, tools from systems biology to
      reverse engineering algorithms allow researchers to integrate different types of
      information to increase our knowledge about human aging. Computer methodologies
      will play a crucial role to reconstruct the genetic network of human aging and
      the associated regulatory mechanisms.

PMID- 15177051
TI  - Role of immune responsiveness and DNA repair capacity genes in ageing.
AB  - The genetic factors that determine immune responsiveness and DNA repair capacity
      are reviewed as major elements influencing the life span. Within this framework
      two sets of new data obtained in mice and humans are reported and discussed. As
      to the first set, the role of immune response genes was investigated in Biozzi
      mice genetically selected for high (H) or low (L) antibody response. After 15-20
      generations of assortative mating, H and L mice exhibited almost complete
      intraline homozygosity and interline polymorphism including distinct H-2
      haplotypes, such as q in H and s in L mice. In order to analyze the impact of
      quantitative trait loci (QTL) on the antibody response as well as on the DNA
      repair capacity in cells of the immune system independently of the selected H-2
      haplotype, congenic Hq and Hs as well as Lq and Ls mice were produced and
      analysed. Both the antibody response and DNA repair capacity were found to be
      independent of the H-2 haplotype and determined by QTL. As to the second set of
      data, DNA repair was also studied in irradiated peripheral blood mononuclear
      cells (PBMC) from ageing humans. The levels of ku 70, ku 80, DNA-PKcs,
      phosphorylated ku 80 as well as the DNA-binding activity of the ku70/ku 80
      heterodimer were determined in the cytoplasmic and nuclear extracts obtained,
      before and after irradiation, from young and elderly subjects. The results of
      this study suggest that the decreased DNA repair capacity in PBMC from elderly
      subjects may be related to impaired migration of the phosphorylated ku 80 from
      the cytoplasm to the nucleus. This finding helps to elucidate questions related
      to the impairment of DNA repair during ageing.

PMID- 15177052
TI  - The pharmacogenomics of Alzheimer's disease.
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder mostly affecting
      geriatric patients worldwide. The high emotional and economic impact of AD on
      patients, families, and the society has made AD one of the paramount geriatric
      syndromes. Efforts to find disease-modifying therapy have not yet been rewarding.
      Despite our increasing appreciation of the role of genetics in AD pathogenesis,
      pharmacogenomic approaches to uncover drug targets have not been extensively
      explored. The current knowledge of the genetics of both familial and non-familial
      (sporadic) AD, and the emerging data on the effect of Apolipoprotein E (ApoE)
      alleles on the response to AD therapeutic agents, is evidence that the potential
      utility of pharmacogenomics may not be limited to the familial AD (FAD) but
      provide answers for AD as a whole. The apparent inability of presently available
      drugs to alter the course of AD could be a signal that it is time to change the
      way we think about AD therapeutics.

PMID- 15177053
TI  - Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity.
AB  - Dehydroepiandrosterone (DHEA) is an abundantly produced adrenal steroid whose
      biological role has never been clarified. DHEA is a potent uncompetitive
      inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH) and as a
      consequence lowers NADPH levels and reduces NADPH-dependent oxygen-free radical
      production. Overproduction of oxygen-free radicals, or oxidative stress,
      upregulates inflammation and cellular proliferation and is believed to play a
      critical role in the development of cancer, atherosclerosis, and Alzheimer's
      disease, as well as the basic aging process. Both in vitro and in vivo
      experimental studies strongly indicate that DHEA and related steroids inhibit
      inflammation and associated epithelial hyperplasia, carcinogenesis, and
      atherosclerosis, at least in part, through the inhibition of G6PDH and oxygen
      free radical formation. Recent epidemiological findings in Sardinian males
      bearing the Mediterranean variant of G6PDH deficiency are consistent with the
      hypothesis that reduced G6PDH activity has a beneficial effect on age-related
      disease development and longevity. Clinical trials with DHEA are encumbered by
      the high oral doses required as well as the conversion of DHEA into active
      androgens. The use of less androgenic congeners as well as non-oral formulations
      may facilitate testing of this class of compounds.

PMID- 15177054
TI  - Energy restriction controls aging through neuroendocrine signal transduction.
AB  - Since the work of McCay in 1935, demonstrating the effect of energy restricted
      diet on the lifespan of rats, many studies have confirmed these findings in
      different species. Several mechanisms have been suggested, including among
      others, growth retardation, diminished apoptosis, decreased oxidative damage,
      altered glucose utilization, changes in gene expression, enhanced stress
      responsiveness and hormesis. There is some evidence that energy restriction (ER)
      exerts important metabolic effects on the aging process and longevity through
      intra- and intercellular signal transduction transmitters, with several signaling
      pathways mediating its beneficial action.

PMID- 15177055
TI  - Sarcolemmal K(ATP) channels in ageing.
AB  - This review highlights some recent research addressing sarcolemmal K(ATP)
      channels in ageing. These channels are abundant in cardiac myocytes where they
      are essential in coupling the cellular metabolic state with membrane
      excitability. The opening of sarcolemmal ATP-sensitive K+ (K(ATP)) channels
      occurs during ischaemia and protect the heart against injury. Age-dependent
      changes in the myocardial susceptibility to ischemia have been observed in
      different species, including humans. Recent research has demonstrated that ageing
      is associated with decrease in numbers of sarcolemmal K(ATP) in hearts from
      females, but not males. This phenomenon seems to be associated with age-dependent
      decrease in concentration of circulating estrogens. In the heart, SUR2A, a
      regulatory subunit of K(ATP) channels, is present in excess over Kir6.2, a pore
      forming K(ATP) channel subunit. The consequence of this is that SUR2A is a
      subunit that controls the number of sarcolemmal K(ATP) channels. Estrogens
      specifically up-regulate SUR2A and, thereby, control the number of sarcolemmal
      K(ATP) channels. Age-dependent loss of sarcolemmal K(ATP) channels creates a
      cardiac phenotype more sensitive to ischaemia, which may explain, at least in
      part, an ageing-associated decrease of myocardial tolerance to stress that occurs
      in elderly women.

PMID- 15177056
TI  - Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders.
AB  - Although olfaction is the primal sense in animals, its importance in humans is
      underappreciated. Extensive literature demonstrates that aging is accompanied by
      olfactory loss and hyposmia/anosmia which is also a feature of several
      neurodegenerative disorders. Alzheimer's and Parkinson's diseases are
      characterized by severe olfactory deficits, while problems of olfactory
      discrimination are less prominent features in several other disorders. Olfactory
      loss is accompanied by structural abnormalities of the olfactory epithelium, the
      olfactory bulb and the central olfactory cortices. This review summarizes our
      present knowledge about the pathological changes in the olfactory system during
      aging and in various neurodegenerative diseases.

PMID- 15177057
TI  - Cell-matrix interactions in aging: role of receptors and matricryptins.
AB  - Extracellular matrix (ECM) has been a central topic in aging research for several
      years. Cell-matrix interactions extend the interest in this topic both for normal
      tissue homeostatic regulation as well as for its dysregulation in age-related
      diseases. A relatively new extension of this ever-increasing field of aging
      research concerns the recognition of the original biological activities exhibited
      by proteolytic fragments of matrix macromolecules. A number of such matricryptins
      were recently identified, some of them endowed with harmful effects for tissue
      function. Some of the breakdown products exert a positive feedback effect by
      upregulating the biosynthesis of the original macromolecule synthesis and/or the
      expression of degrading enzymes. This results in vicious circles which might well
      be involved in tissue aging. The examples detailed in this review concern
      fibronectin (FN) and elastin. A number of fibronectin fragments (Fn-fr) were
      shown to exhibit diverse activities including increasing tissue degradation,
      inflammation and tumor progression. Elastin degradation products acting as
      agonists on the elastin-laminin receptor can trigger harmful effects such as up
      regulation of proteases and free radical production. Both macromolecules are at
      the center of autoamplifying vicious circles of potential importance for age
      dependent modification of tissue function.

PMID- 15177058
TI  - Is there a connection between estrogen and Parkinson's disease?
AB  - Increasing evidence suggests that estrogens may protect the nigrostriatal
      dopaminergic pathway affected in Parkinson's disease (PD). Animal studies show
      that estrogens influence the synthesis, release, and metabolism of dopamine and
      can modulate dopamine receptor expression and function. Some clinical studies
      suggest that PD symptoms may be exacerbated after menopause and delayed or
      alleviated with hormone replacement therapy, but others have failed to observe
      positive estrogenic effects. The conflicting findings suggest that several
      variables, including age, estrogen dose and formulation, and timing and length of
      dosing period, may determine whether benefits are seen and the nature of these
      benefits. Further investigation is therefore needed for the relationship between
      estrogens and the nigrostriatal dopaminergic system.

PMID- 15177059
TI  - Occupational and environmental risk factors for Parkinson's disease.
AB  - The etiology of Parkinson's disease (PD) remains obscure. Current research
      suggests that a variety of occupational and environmental risk factors may be
      linked to PD. This paper provides an overview of major occupational and
      environmental factors that have been associated with the development of PD and
      tries to assess current thinking about these factors and their possible
      mechanisms of operation. While clear links to rural living, dietary factors,
      exposure to metals, head injury, and exposure to infectious diseases during
      childhood have not been established, there is general agreement that smoking and
      exposure to pesticides affect the probability of developing PD.

PMID- 15177061
TI  - Fluoxetine-induced tremor: clinical features in 21 patients.
AB  - We report a cohort of 21 patients (12 females and nine males), with a mean age of
      42.4 years, who developed tremor after receiving fluoxetine at a mean dose of
      25.7 mg per day. The mean latency period for tremor appearance was 54.3 days.
      Severity was found to be mild. In all patients, tremor was postural, with
      P<0.0005, compared to patients with rest tremor and P<0.05 compared to
      action/intention-tremor patients. The frequency range was 6-12 Hz/s. After
      fluoxetine was discontinued, tremor disappeared in 10 patients after a mean
      latency period of 35.5 days. In the remaining 11 patients, tremor persisted up to
      the end of the observation period (a mean of 449 days). We believe that this
      tremor phenomenon is due to the involvement of the red nucleus and the inferior
      olivary nucleus through their projections to the thalamus and the spinal cord.

PMID- 15177060
TI  - Effects of fibroblast growth factor and glial-derived neurotrophic factor on
      akinesia, F-DOPA uptake and dopamine cells in parkinsonian primates.
AB  - Parkinson's disease (PD) is a common neurodegenerative disorder that produces
      progressive disability despite symptomatic treatment. Several strategies,
      including stereotaxic brain lesions, deep brain stimulation, transplants of
      dopamine cells and administration of neurotrophic factors, have been proposed to
      improve efficacy and to counteract the progression of the disease. We here report
      the effects of repetitive intracerebral infusion of basic fibroblast growth
      factor (bFGF) and glial-derived neurotrophic factor, up to 1 year, in Cynomolgus
      monkeys with long standing asymmetric parkinsonism produced by unilateral
      intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
      The treatment with neurotrophic factors was initiated when the parkinsonian
      deficits were stable, 6 months after the administration of MPTP. The evaluation
      of the response to the neurotrophic factors was performed by blind observers
      using: clinical scales that measured global motor deficit, motor ability in both
      hands, apomorphine-induced rotation, determination of the levels of monoamine
      metabolites in cerebrospinal fluid, and 6-F18-fluoro-l-DOPA (F-DOPA) uptake in
      the striatum and histology. Both factors, but bFGF more so, improve motor
      behavior, dopamine metabolism, striatal F-DOPA uptake, and the number of dopamine
      neurons. The procedure is well tolerated and provides a strong background for
      efficacy and safety of this treatment in patients with PD.

PMID- 15177063
TI  - Clinical and electromyographic assessment of essential tremor treatment.
AB  - It is a matter of debate whether beta-blockers or primidone have a better
      influence on essential tremor. It is also controversial whether essential tremor
      with synchronous electromyographic activity is influenced by the administration
      beta-blockers, while tremor with alternating electromyographic activity is
      influenced by primidone. The aim of this study was to reevaluate the effects of
      beta-blockers and primidone on essential tremor. We also aimed to evaluate the
      differential effects of beta-blockers and primidone on tremor with synchronous or
      alternating electromyographic activity and on tremor in different limb positions.
      One hundred patients (57 female, 43 male) with essential tremor were included in
      this study. According to the electromyographic pattern recorded from the
      antagonistic muscles, the patients were subdivided into group with synchronous
      (SYN) and group with alternating (ALT) activity. After the initial clinical and
      electromyographic examinations the patients were randomly assigned first to
      treatment with propranolol (180 mg daily), or to treatment with primidone (500 mg
      daily) for 30 days. After a washout period of 20 days the patients were assigned
      to the other treatment. Our results revealed that the effects of propranolol and
      primidone on essential tremor and on SYN or ALT tremor were similar. Differences
      between both drugs existed as regards to better primidone influence on the
      kinetic and intention tremors and to tremor localized outside the limbs. In
      conclusion it is better to treat patients with kinetic and intention essential
      tremor and tremor localized outside the limbs with primidone.

PMID- 15177062
TI  - Elevated glial brain-derived neurotrophic factor in Parkinson's diseased nigra.
AB  - We show the cellular distribution of immunoreactivity (IR) for brain-derived
      neurotrophic-factor (BDNF), neurotrophin-3 (NT-3) and tyrosine kinase receptors
      TRKB and TRKC in idiopathic Parkinson's disease (IPD) and controls at post
      mortem. In both groups, nigral neurons, astrocytes, ramified and amoeboid
      microglia expressed all antigens. Caudate-putamen neurons expressed all antigens
      except BDNF with similar distribution between groups. In IPD nigra, increased
      numbers of BDNF-IR and, less frequently, NT-3-IR ramified glia surrounded
      fragmented neurons, accompanied by BDNF-IR in surrounding neuropil. Amoeboid
      microglia were abundant only in IPD nigral scars. In IPD, glia might up-regulate
      neurotrophins in response to signals released from failing nigral neurons.

PMID- 15177064
TI  - The effect of COMT inhibition with entacapone on cardiorespiratory responses to
      exercise in patients with Parkinson's disease.
AB  - The inhibition of catechol-O-methyltransferase (COMT) may impair catecholamine
      clearance resulting in unwanted cardiac and hemodynamic events. We therefore
      studied the effects of entacapone, an inhibitor of peripheral COMT, on
      cardiorespiratory and plasma noradrenaline (NA) responses to exercise and on
      respiratory muscle strength in l-dopa treated patients with Parkinson's disease
      (PD). A randomized, double-blind, cross-over study with two 1week treatment
      periods was performed in 15 PD patients. The test battery included analysis of
      hemodynamics, gas exchange parameters and plasma NA during a maximal exercise
      test, assessment of maximal static airway pressures and pre- and post-exercise
      motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). The first
      test was done after withholding l-dopa overnight ('run-in' test, off-phase). The
      second and third tests were done in on-phase after 1week treatment with either
      entacapone 200mg or placebo given with each dose of l-dopa. No differences in
      maximal work load, plasma NA, or in cardiorespiratory responses to either maximal
      or work rate standardized submaximal exercise were observed between entacapone
      and placebo, except for O(2) pulse, which was slightly lower (p < 0.05) after
      entacapone at submaximal exercise level. Maximal airway pressures were similar
      between the study treatments and run-in. Exercise had no effect on motor UPDRS
      after either study treatment or during the run-in test. No serious adverse events
      were observed. The results of this study suggest that entacapone does not change
      the work capacity, work efficiency or respiratory muscle strength in l-dopa
      treated PD patients with mild to moderate disease severity, and that its use with
      l-dopa seems to be safe in conditions of maximal physical effort. However, data
      from the long-term use of COMT inhibitors are needed to confirm these findings.

PMID- 15177065
TI  - Apomorphine delays simple reaction time in Parkinsonian patients.
AB  - BACKGROUND: Parkinsonian patients have difficulty in the preparation and
      execution of movements, which translate into delayed performance of simple
      reaction time (SRT) paradigms. OBJECTIVE: To examine short-term effects of an
      acute subcutaneous injection of the dopamine agonist apomorphine on the results
      of a SRT task. METHODS: We studied a SRT paradigm in 26 non-fluctuating
      idiopathic Parkinsonian patients, before and 30, 60, 90 min after administration
      of apomorphine. RESULTS: The reaction time (RT) was significantly delayed after
      apomorphine injection. We found no significant change in movement time (MT).
      CONCLUSION: Delay of RT and the lack of response of MT to apomorphine
      administration may result from the sedative effects of apomorphine,
      overstimulation of postsynaptic dopaminergic receptors with subsequent inhibition
      of prefrontal cholinergic neurotransmission, and at least partial binding of
      apomorphine to presynaptic dopaminergic autoreceptors, which cause inhibition of
      locomotor activity. We suggest that future studies testing the capacity for
      reaction in Parkinsonian patients should consider the exact timing of the
      delivery of dopamine substituting drugs prior to the test.

PMID- 15177066
TI  - Kinetic tremor during tracking movements in patients with Parkinson's disease.
AB  - This study was undertaken to analyse kinetic tremor during a compensatory
      tracking task performed with the index fingers. Patients with Parkinson's disease
      (PD) (n=21) and control subjects (n=30) were tested using a laser system
      transducing displacement. All participants underwent a clinical examination. Nine
      characteristics quantifying the tracking task and tremor were applied to the
      processed displacement or velocity signal. The discriminating power of each
      characteristic was evaluated using differences between group means (p values),
      maximum percentage discrimination, and number of outliers in the patient group.
      All nine characteristics showed significant differences between means of the two
      groups using Welch-modified t-tests for unequal variances. The most
      discriminating characteristics reflected differences in the frequency
      distribution of the movement (proportional power in the 3-4Hz range, harmonicity
      and median frequency). These differences were rarely visible and did not
      correlate highly with tremor amplitude or with clinical ratings of tremor.
      Control subjects had residual spectral power from the tracking oscillations
      leaking above 3Hz, while most patients had a small 'kinetic tremor' in the 7-12Hz
      range. The maximum discrimination was moderate, 63% in the best case. Combining
      representative information about proportional power during posture (recorded in
      the same subjects) and tracking gave a much higher discrimination (90%) with
      respect to the 96.7th percentile of the control group. These results suggest that
      information coming from postural and kinetic tremors can be combined to isolate a
      subclinical feature of PD symptomatology. This feature could be used to re
      evaluate the classic distinction made between the akineto-rigid and tremulous
      forms of PD and is independent of tremor amplitude.

PMID- 15177067
TI  - Analyses of nursing home residents with Parkinson's disease using the minimum
      data set.
AB  - This study profiles over 79,000 nursing home residents with Parkinson's disease
      (PD) at admission using the 'minimum data set'. Results show that residents with
      PD averaged 79.7 years of age at admission and 48.4% were male. They tended to be
      physically dependent, as well as cognitively impaired. More than one in three had
      fallen in the prior 30 days. There was a high prevalence of dementia and
      depression. Ninety percent of these residents did not receive active or passive
      range of motion care and less than 10% had been recently evaluated by a licensed
      mental health specialist. To enhance the quality of life for nursing home
      residents with PD, appropriate and adequate rehabilitative, mental health, and
      cognitive care need to be implemented.

PMID- 15177068
TI  - Prosecution after an outbreak of subacute aluminum intoxication in a hemodialysis
      center.
AB  - Criminal prosecution of physicians for the death of patients has been
      extraordinarily rare, but there seems to be a rising trend. This case report
      describes the medical and judicial implications of criminal prosecution of two
      doctors at a hemodialysis clinic in the Netherlands Antilles that had to stand
      trial over the death of 10 dialysis patients. The patients died of subacute
      aluminum intoxication when aluminum leached from the cement lining of a newly
      installed water distribution pipe into the water supply of the dialysis center
      that did not make use of a water treatment system (WTS). Data of the case history
      of the dialysis patients, the criminal prosecution, preliminary judicial inquiry,
      the defense arguments and verdicts are reviewed. The prosecutor first decided to
      dismiss the case, but after an appeal by the families, the Court of Appeal
      decided to pursue prosecution for gross negligence. It held that the dialysis
      center should have used a WTS and also held that the dialysis staff reacted
      insufficiently on extra alarms on the dialysis machines in the two days after the
      new water distribution pipe was put in use. From June 6, 1998 until January 1999
      a preliminary judicial inquiry was performed in The Netherlands and on Curacao.
      After a cross-examination of 13 court-appointed experts by the prosecutor and the
      investigative judge, the prosecutor charged the two physicians of gross
      negligence manslaughter for not testing the composition of the water after the
      construction at the water distribution network. A prison sentence with probation
      of 6 months was demanded. The District Court disagreed on all issues with the
      prosecutor, but nevertheless held the medical director of Diatel guilty for
      performing hemodialysis without a WTS. In May 2000, the Court of Appeal held that
      it was not allowed to rule on the omission to install a WTS because this issue
      was not included in the charge and overturned the conviction. Medical personnel
      in charge of potentially dangerous procedures should be prepared for unexpected
      changes in the quality of their treatment. Because court-appointed experts might
      have an extraordinary role in the decision making process, guidelines should be
      prepared to ensure the trustworthiness of their testimony.

PMID- 15177069
TI  - Control region sequences for East Asian individuals in the Scientific Working
      Group on DNA Analysis Methods forensic mtDNA data set.
AB  - The Scientific Working Group on DNA Analysis Methods (SWGDAM) mitochondrial DNA
      (mtDNA) population data set is used to infer the relative rarity of mtDNA
      profiles obtained from evidence samples and of profiles used to identify missing
      persons. In this study, the East Asian haplogroup patterns in the SWGDAM data
      sets were analyzed in a phylogenetic context to determine relevant single
      nucleotide polymorphisms (SNPs) and to describe haplogroup distributions for
      Asians (n = 753; with a breakdown of individuals from China n = 356, Korea n =
      182, Japan n = 163, and Thailand n = 52). We focus on the patterns observed in
      the SWGDAM Chinese data set and refer to interesting differences in the smaller
      subgroup data sets for the other East Asian populations (Japanese, Korean, and
      Thai). A total of 218 SNPs were observed in the data set, including 37 observed
      positions not previously reported. In the largest of the East Asian SWGDAM data
      sets (Chinese), these SNPs ranged from having 1 to 29 changes in the phylogenetic
      tree, with site 16519 being the most variable. On average there were 4.5 changes
      for a character on the tree. The most variable sites (with 14 or more changes
      each listed from fastest to slowest) observed were 16519 (L = 29), 16311 (L =
      27), 152 (L = 24), 146 (L = 21), 16172 (L = 17), 16189 (L = 17), 195 (L = 16),
      16362 (L = 15), 16093 (L = 14), 16129 (L = 14) and 150 (L = 14). These rapidly
      changing sites are consistent with other published analyses. Only 28 SNPs are
      needed to identify all clusters containing 1% (n = 7) or more individuals in the
      East Asian data set. All 36 haplogroups previously observed in East Asian
      populations were also seen in the SWGDAM data sets and include: A, B, B4, B4a,
      B4b, B5a, B5b, C, D, D4, D4a, D4b, D5, D5a, F, F1, F1a, F1b, F1c, F2a, G2, G2a,
      M, M7a1, M7b, M7b1, M7b2, M7c, M8a, M9, M10, N9a, R, R9a, Y, and Z. Haplogroups
      A, B4a, D4, and F1a were the most commonly observed clusters in the Chinese data
      set (the largest of the data sets) with each of these occurring in more than 6%
      of the samples in the data set. The next most common haplogroups in the Chinese
      data set include the clusters C, M7b1, and N9a with each observed at frequencies
      greater than or equal to 4%. European Caucasian, and African haplogroups were
      rarely observed within the East Asian data sets. The various analyses revealed
      that the data set was similar to published East Asian data sets such as those
      from Han Chinese.

PMID- 15177070
TI  - Ultrastructural changes during in situ early postmortem autolysis in kidney,
      pancreas, liver, heart and skeletal muscle of rats.
AB  - Many morphological studies of the postmortem interval were carried out under
      conditions in which the tissue was incubated in vitro after extirpation. However,
      the extirpation affects cell viability. We examined the ultrastructural changes
      in the kidney, pancreas, liver, heart and skeletal muscle of male Wistar rats
      occurring postmortem in situ. In each organ, cell edema (cell swelling),
      appearance of amorphous dense deposits in the mitochondria, loss of glycogen
      granules, dilation of the endoplasmic reticulum, clumping and margination of
      nuclear chromatin, and/or condensation of nuclear chromatin were observed, but
      the duration of the period of ultrastructural change was organ specific. Most of
      the ultrastructural changes occurred earlier in kidney. In hepatocytes, the
      morphological degeneration occurred later than in the renal tubule epithelium and
      earlier than that in the myocardium. Of the five organs we examined, skeletal
      muscle showed the greatest delay in postmortem change. In the distal tubule
      epithelium and pancreatic acinar cells, two forms of nuclear change were seen:
      one resembled necrotic change and the other resembled apoptotic change. The
      effect of lysosomes and hydrolytic enzymes was not as great as previous findings.

PMID- 15177071
TI  - Quantitative analysis of cresol and its metabolites in biological materials and
      distribution in rats after oral administration.
AB  - We investigated kinetics of p-cresol, m-cresol, and their glucuronide and sulfate
      metabolites in blood and organs of rats. We established a quantitative analysis
      method for the measurement of the concentrations of cresols. Endogenous beta
      glucuronidase, an enzyme which hydrolyses the glucuronide, existed in rat organs,
      and it influenced the procedures for cresol hydrolysis of sulfatase. It was
      necessary for the quantitative analysis of cresol sulfate in organs to add the
      saccharolactone (d-saccharic acid 1,4-lactone) as an inhibitor for beta
      glucuronidase. On the other hand, endogenous sulfatase did not interfere in the
      quantitative analysis of the glucuronide. It was found that cresol administered
      via the stomach tube diffuses directly through gastric and small intestinal walls
      because the unconjugate cresol concentrations were extremely high not only in the
      liver, but also in the spleen. The unconjugates of cresol in the liver, spleen
      and kidney were detected in high concentrations even when the unconjugates were
      not detected in the blood. m-Cresol was easily metabolized to sulfate, and the p
      cresol to glucuronide in rats. The concentration ratios of m-cresol to p-cresol
      in blood and organs were different from the rate of the cresol soap solution that
      was administered. The pharmacokinetics was different between p-cresol and m
      cresol in rats.

PMID- 15177072
TI  - Polymorphisms of six Y-chromosome STRs in a Chinese population.
AB  - The polymorphic short tandem repeat (STR) loci of six Y-chromosome markers were
      investigated in 112 unrelated Chinese males using a multiplex polymerase chain
      reaction (PCR). Allele and haplotype frequencies for the Y-specific STR loci
      DYS19, DYS385, DYS389II, DYS390, DYS391 and DYS393 were analyzed by the Y-PLEX 6
      Kit. The commonest allele for each locus was: DYS19, allele 15; DYS385, allele
      12; DYS389II, allele 28; DYS390, allele 23; DYS391, 10; and DYS393, allele 12.
      Gene diversity value was calculated from the allelic frequency for each locus.
      The DYS385 locus proved to be highly polymorphic (0.890), DYS391 showed the
      lowest value (0.489), and the other loci showed values ranging from 0.646 to
      0.897. A total of 99 haplotypes were observed in six Y-specific STR loci, the
      haplotype diversity was raised to 0.999. The results revealed that a set of six Y
      specific STR loci were able to discriminate most of the male individuals in the
      Chinese population.

PMID- 15177073
TI  - Endogenous gamma-hydroxybutyric acid levels in postmortem blood.
AB  - The goal of this study was to determine how the postmortem interval and duration
      of storage of blood at 4 degrees C affect endogenous gamma-hydroxybutyric acid
      (GHB) levels in blood. Forty-three autopsy cases of non-users of GHB were
      involved. The postmortem interval ranged from 8 to 132 h. Blood samples were
      collected and stored without any preservatives at 4 degrees C for 1 day up to 15
      months until analysis. In some cases, samples were also stored at -20 degrees C
      for 10 days to 7 months to determine GHB levels at autopsy. Blood GHB
      concentrations were measured by headspace gas chromatography after GHB was
      converted to gamma-butyrolactone. Blood GHB concentrations ranged from 0 to 43.0
      microg/ml and averaged 9.80 microg/ml. A positive correlation was observed
      between concentration and postmortem interval (r = 0.571) but no correlation was
      found between concentration and storage interval at 4 degrees C. In 14 blood
      samples stored at -20 and 4 degrees C for 10 days, GHB concentrations were 4.55+/
      3.88 and 6.06+/-4.27 microg/ml, respectively. In another eight blood samples
      stored at -20 and 4 degrees C for 1-7 months, GHB concentrations were 3.77+/-2.76
      and 5.49+/-2.97 microg/ml, respectively. A large portion of endogenous GHB
      detected in blood of corpses may be produced during the interval between death
      and autopsy, rather than during storage of blood at 4 degrees C until analysis.
      In an additional experiment, it was suggested that glycolysis by bacteria may
      enhance endogenous GHB production.

PMID- 15177074
TI  - Analysis of two types of novel alleles in the DXS10011 locus.
AB  - A population study of the short tandem repeat locus DXS10011 was carried out in a
      sample of 104 unrelated Japanese individuals (56 males, 48 females). Thirty-six
      different alleles were distinguished. The power of discrimination was 0.933
      (male) and 0.997 (female). Sequence analysis of alleles was examined for 34
      samples. The sequence structures of the alleles were classified into three types:
      A, B and C. Type A had a regular repeat structure of the repeat region:
      (GAAA)(n). Types A and B differed in the base sequence of the repeat region. As
      an A (adenine) insertion in 5' upstream of (GAAA)(n) repeat unit was type C, this
      type was differentiated from type A.

PMID- 15177075
TI  - The application of a variable-pressure scanning electron microscope with energy
      dispersive X-ray microanalyser to the diagnosis of electrocution: a case report.
AB  - We describe here a case of accidental electrocution. A 48-year-old male was found
      dead in his room. At autopsy, there was a current mark on the right thumb and big
      toe. Histological examination revealed that the skin wound had the
      characteristics of a current mark, including vacuolation and elongation of the
      cell nuclei. We could also identify titanium metallization on the skin surface of
      the current mark using a variable-pressure scanning electron microscope (VP-SEM)
      equipped with energy dispersive X-ray microanalyser (EDX). The autopsy finding
      and the subsequent investigation support the conclusion that the cause of his
      death was electrocution. Our result shows that the VP-SEM with EDX is a useful
      tool for the forensic diagnosis of electrocution.

PMID- 15177076
TI  - Influence of lung fixation technique on the state of alveolar expansion-a
      histomorphometrical study.
AB  - Lungs removed at necropsy normally collapse due to the loss of negative pleural
      pressure leading to a quite unnatural appearance of both gross and histological
      specimens. In order to demonstrate the influence of post-mortem lung retraction
      on the degree of alveolar expansion, a histomorphometrical analysis was performed
      in lungs from a 9-month-old healthy infant. Tissue specimens from the right lung
      were obtained at autopsy and routinely fixed after retraction ('routinely fixed
      lung'), whereas the left lung was fixed in situ before opening the thoracic cage
      ('in situ fixed lung'). The size of the alveoli as well as the thickness of the
      alveolar walls were measured using an automatic image processing and analysis
      system (Leica QWIN) in both lungs. The mean alveolar size was 8.7 x 10(3)
      microm(2) in the routinely fixed lung (alveoli, n=1.1576) and 10.9 x 10(3)
      microm(2) in the in situ fixed lung (alveoli, n = 841). In contrast, the diameter
      of the alveolar walls showed no significant difference in both lungs. The average
      thickness of the alveolar walls was 7.9 microm (measuring sites, n = 1.190) in
      the routinely fixed lung and 8.1 microm in the in situ fixed lung (measuring
      sites, n = 1.027), respectively. The results provide evidence of significantly
      reduced aeration in the retracted and routinely fixed lung which could be of
      special forensic interest in cases of suspicious infanticide, stillbirth or
      infant death by drowning or suffocation.

PMID- 15177077
TI  - Application of the linear interaction energy method (LIE) to estimate the binding
      free energy values of Escherichia coli wild-type and mutant arginine repressor C
      terminal domain (ArgRc)-l-arginine and ArgRc-l-citrulline protein-ligand
      complexes.
AB  - Protein-ligand binding free energy values of wild-type and mutant C-terminal
      domain of Escherichia coli arginine repressor (ArgRc) protein systems bound to L
      arginine or L-citrulline molecules were calculated using the linear interaction
      energy (LIE) method by molecular dynamics (MD) simulation. The binding behaviour
      predicted by the dissociation constant (K(d)) calculations from the binding free
      energy values showed preferences for binding of L-arginine to the wild-type ArgRc
      but not to the mutant ArgRc(D128N). On the other hand, L-citrulline do not favour
      binding to wild-type ArgRc but prefer binding to mutant ArgRc(D128N). The
      dissociation constant for the wild-type ArgRc-L-arginine complex obtained in this
      study is in agreement with reported experimental results. Our results also
      support the experimental data for the binding of L-citrulline to the mutant
      ArgRc(D128N). These showed that LIE method for protein-ligand binding free energy
      calculation could be applied to the wild-type and the mutant E. coli ArgRc-L
      arginine and ArgRc-L-citrulline protein-ligand complexes and possibly to other
      transcriptional repressor-co-repressor systems as well.

PMID- 15177078
TI  - The signature molecular descriptor. 3. Inverse-quantitative structure-activity
      relationship of ICAM-1 inhibitory peptides.
AB  - We present a methodology for solving the inverse-quantitative structure-activity
      relationship (QSAR) problem using the molecular descriptor called signature. This
      methodology is detailed in four parts. First, we create a QSAR equation that
      correlates the occurrence of a signature to the activity values using a stepwise
      multilinear regression technique. Second, we construct constraint equations,
      specifically the graphicality and consistency equations, which facilitate the
      reconstruction of the solution compounds directly from the signatures. Third, we
      solve the set of constraint equations, which are both linear and Diophantine in
      nature. Last, we reconstruct and enumerate the solution molecules and calculate
      their activity values from the QSAR equation. We apply this inverse-QSAR method
      to a small set of LFA-1/ICAM-1 peptide inhibitors to assist in the search and
      design of more-potent inhibitory compounds. Many novel inhibitors were predicted,
      a number of which are predicted to be more potent than the strongest inhibitor in
      the training set. Two of the more potent inhibitors were synthesized and tested
      in-vivo, confirming them to be the strongest inhibiting peptides to date. Some of
      these compounds can be recycled to train a new QSAR and develop a more focused
      library of lead compounds.

PMID- 15177079
TI  - A method for quantifying and visualizing the diversity of QSAR models.
AB  - Feature selection is one of the most commonly used and reliable methods for
      deriving predictive quantitative structure-activity relationships (QSAR). Many
      feature selection algorithms are stochastic in nature and often produce different
      solutions depending on the initialization conditions. Because some features may
      be highly correlated, models that are based on different sets of descriptors may
      capture essentially the same information, however, such models are difficult to
      recognize. Here, we introduce a measure of similarity between QSAR models that
      captures the correlation between the underlying features. This measure can be
      used in conjunction with stochastic proximity embedding (SPE) or multi
      dimensional scaling (MDS) to create a meaningful visual representation of
      structure-activity model space and aid in the post-processing and analysis of
      results of feature selection calculations.

PMID- 15177080
TI  - Homology modeling of rho-crystallin from bullfrog (Rana catesbeiana) lens.
AB  - rho-Crystallins are major protein component found in the eye lenses of frogs of
      the genus Rana. Structural analysis has indicated that frog rho-crystallins
      belong to aldo-keto reductase superfamily (AKRs) which include aldehyde and
      aldose reductases, prostaglandin F synthase and several detoxification enzymes.
      Members of AKRs catalyze the oxidation-reduction reaction over a range of
      substrates using NAD(P)(H) as a cofactor. In spite of higher structural
      similarity with AKRs and cofactor binding affinity, the rho-crystallins were
      found to be catalytically inactive. This study presents comparative or homology
      modeling of rho-crystallin from bullfrog (Rana catesbeiana) in presence and
      absence of cofactor NADP and a competitive inhibitor, testosterone. The predicted
      models are explored to examine the catalytic cleft, cofactor binding affinity
      characteristics and substrate binding pocket.

PMID- 15177081
TI  - A practical approach to docking of zinc metalloproteinase inhibitors.
AB  - Forty zinc-dependent metalloproteinase/ligand complexes with known crystal
      structures were re-docked using five docking/scoring approaches (DOCK, FlexX,
      DrugScore, GOLD, and AutoDock). Correct geometry of the coordination bonds
      between the ligand's zinc binding group (ZBG) and the catalytic zinc is important
      for docking accuracy and scoring reliability. More than 75% of docked poses with
      RMSD less than 2A were found to have appropriate ZBG binding, but for poor ZBG
      binding, about 95% of poses failed to dock correctly. Elimination of poses with
      inappropriate zinc binding resulted in better binding energy predictions that
      were further improved by dividing the ligands into subsets according to the ZBG
      (carboxylates, hydroxamates, and phosphorus containing groups). After a subset re
      scoring using the regression functions obtained for individual subsets, DrugScore
      was able to explain 77% and the consensus scoring scheme X-CSCORE even 88% of
      variance in binding energies. The approach combining ZBG-based pose selection and
      subset re-scoring improved the hit rate in virtual screening for
      metalloproteinase inhibitors for all tested methods by 4-16%.

PMID- 15177082
TI  - The distribution of the unoccupied volume in glassy polymers.
AB  - The aim of this paper is to present an improved method to describe the unoccupied
      volume in glassy polymers. The method is able to treat atoms with non-spherical
      symmetry. The fineness of the raster points scanning the unit cell can be as
      small as 0.01 nm. This method was used to determine the unoccupied volume of
      molecular dynamic simulations of poly(amide imide) unit cells by probing it with
      a tracer atom. Since the reachable unoccupied volume strongly depends on the
      tracer radius, we used tracer radii between 0.03 and 0.17 nm. The poly(amide
      imide)s were used in the present work because they are well characterized,
      especially there already exist free volume data determined by positron lifetime
      experiments.

PMID- 15177084
TI  - Beyond the monoamine hypothesis: mechanisms, molecules and methods.
AB  - The first effective antidepressants (monoamine oxidase inhibitors and tricyclic
      antidepressants) relied on their ability to augment serotonin and noradrenaline
      levels at the synapse. Forty years later, the same biological model led to the
      supremacy of the serotonergic hypothesis to explain not only the pathophysiology
      of depressive illness, but also the neuropharmacological basis for obsessive
      compulsive disorder, phobias, posttraumatic stress disorder, and even generalized
      anxiety disorder. It could be argued that the blinkered view of depression as a
      solely serotonergic phenomenon has not only restrained and limited research into
      other potential systems, but has also slowed down the discovery of putative
      antidepressant drugs. While some might argue that the hypothalamic-pituitary
      adrenal (HPA) axis explains an individual's sensitivity to depression, there are
      others who equally claim that the most likely explanations are to be found in the
      neuropsychopharmacology of the immune system or even through reductions in
      hippocampal volume. There is a richness of possibilities regarding the mechanisms
      for antidepressant activity embracing theoretical, pharmacological and clinical
      data. However, the methods by which putative antidepressants are assessed and
      their clinical efficacy demonstrated are not always robust. That current clinical
      comparisons of antidepressants rarely show major differences in efficacy between
      existing molecules could be taken as an indication that "all drugs are the same"
      or perhaps, more insightfully, as an indication that the ubiquitous Hamilton
      depression (HAM-D) rating scales are not sensitive to inter-drug differences,
      even though pronounced pharmacodynamic differences between molecules are easily
      demonstrated. Any advances in the development of new antidepressants will have to
      find not only original compounds but also unique psychometric tests by which the
      drugs can be assessed in a sensitive, reliable, and valid manner.

PMID- 15177085
TI  - The hippocampus and depression.
AB  - The effect of depression on the hippocampus has become the focus of a number of
      structural and functional neuroimaging studies. In the past two decades, advances
      in neuroimaging techniques now allow the examination of subtle changes in both
      regional structure and function that are associated with the pathophysiology of
      depression. Many studies using 3-dimensional magnetic resonance imaging (MRI)
      volumetric measurement have reported decreases in hippocampal volume among
      depressed subjects compared with controls, whereas other studies have not found
      any volume loss. Differences among studies have been discussed. In some studies,
      the volume loss appears to have functional significance including an association
      with memory loss. Furthermore, we have found a trend towards loss of 5-HT(2A)
      receptors in the hippocampus using positron emission tomography (PET) to detect
      regional changes in [18F]altanserin binding. Functional imaging extends the
      sensitivity and specificity of structural imaging and will lead to a better
      understanding of affective disorders.

PMID- 15177086
TI  - Pathophysiology of depression: the concept of synaptic plasticity.
AB  - Neuronal plasticity or remodeling is most often discussed with regard to cellular
      and behavioral models of learning and memory. However, neuronal plasticity is a
      fundamental process by which the brain acquires information and makes the
      appropriate adaptive responses in future-related settings. Dysfunction of these
      fundamental processes could thereby contribute to the pathophysiology of mood
      disorders, and recovery could occur by induction of the appropriate plasticity or
      remodeling. These possibilities are supported by preclinical and clinical studies
      demonstrating that there are structural alterations that occur in response to
      stress and in patients with mood disorders. Moreover, antidepressant treatment
      may oppose these effects by regulation of signal transduction and gene expression
      pathways linked to neuronal plasticity. These findings comprise a novel
      conceptual framework for future studies of the etiology of mood disorders and for
      the development of novel therapeutic interventions.

PMID- 15177087
TI  - Synaptic plasticity and tianeptine: structural regulation.
AB  - Stress-induced structural and cellular alterations in the hippocampus can
      contribute to the pathophysiology of depression. The reversal of these
      alterations may be a mechanism by which antidepressants achieve their therapeutic
      effect. The aim of the present study was therefore to investigate the effect of
      tianeptine on stress-induced structural changes and alterations in cerebral
      metabolites. To this end, psychosocially stressed male tree shrews were treated
      with tianeptine. A combination of in vivo and postmortem methods was used to
      evaluate the antidepressant treatment on the preservation of neuronal plasticity.
      It was found that all stress-induced effects were prevented by the administration
      of tianeptine. It is concluded that these findings provide experimental evidence
      for recent theories that impairment of neuronal viability and neuroplasticity
      might be important causal factors in mood disorders, suggesting tianeptine as a
      potential stimulator of neural resilience.

PMID- 15177088
TI  - Structural plasticity and tianeptine: cellular and molecular targets.
AB  - The hippocampal formation, a structure involved in declarative, spatial and
      contextual memory, undergoes atrophy in depressive illness along with impairment
      in cognitive function. Animal model studies have shown that the hippocampus is a
      particularly sensitive and vulnerable brain region that responds to stress and
      stress hormones. Studies on models of stress and glucocorticoid actions reveal
      that the hippocampus shows a considerable degree of structural plasticity in the
      adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and
      repeated stress causes remodeling of dendrites in the CA3 region, a region that
      is particularly important in memory processing. Both forms of structural
      remodeling of the hippocampus are mediated by adrenal steroids working in concert
      with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA
      and NMDA receptors are also involved in neuronal death that is caused in
      pyramidal neurons by seizures, head trauma, and ischemia, and alterations of
      calcium homeostasis that accompany age-related cognitive impairment. Tianeptine
      (tianeptine) is an effective antidepressant that prevents and even reverses the
      actions of stress and glucocorticoids on dendritic remodeling in an animal model
      of chronic stress. Multiple neurotransmitter systems contribute to dendritic
      remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working
      synergistically with glucocorticoids. This review summarizes findings on
      neurochemical targets of adrenal steroid actions that may explain their role in
      the remodeling process. In studying these actions, we hope to better understand
      the molecular and cellular targets of action of tianeptine in relation to its
      role in influencing structural plasticity of the hippocampus.

PMID- 15177089
TI  - A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the
      short-term treatment of depression.
AB  - A meta-analysis was performed to compare the efficacy of tianeptine and selective
      serotonin reuptake inhibitors (SSRI) in the short-term treatment of depression.
      Consecutive selection and inclusion processes allowed five studies to be
      selected: two studies on tianeptine versus fluoxetine, two studies on tianeptine
      versus paroxetine, and one study on tianeptine versus sertraline. A total of 1348
      patients were included in the five studies; 681 subjects received an SSRI and 667
      tianeptine. A strict step-by-step methodology was applied in order to legitimize
      this meta-analysis and to interpret the results. Considering all the patients or
      those with a Montgomery-Asberg Depression Rating Scale (MADRS) inclusion score
      greater than 28, none of the assessed parameters (MADRS total score and responder
      rate) revealed any significant difference between the two treatment groups.
      Further analysis based on clinical global impression (CGI) items found no
      significant difference, except for CGI item 3 (therapeutic index), where a
      tendency (P=0.06 or 0.07 depending on the methodology) was found in favor of
      tianeptine. All in all, this study confirmed that tianeptine is at least as
      effective as SSRI, with a trend for a better acceptability profile in the
      treatment of depressed patients.

PMID- 15177095
TI  - Hazardous properties of paint residues from the furniture industry.
AB  - The objective of this study was to screen nine excess paint residues for
      environmental hazard and to evaluate their disposability in a non-hazardous or
      hazardous-waste landfill. These residues were produced in the process of spray
      painting furniture. Residues were classified according to their leaching and
      ecotoxicological properties. Leaching properties were determined with the
      European standard SFS-EN 12457-2 leaching-test. The toxicity of the leaching-test
      eluates was measured with plant-, bacteria- and enzyme-inhibition bioassays.
      Total organic carbon, formaldehyde and solvent concentrations in the solid wastes
      and in the leaching-test eluates were analysed. It seemed likely that leached
      formaldehyde caused very high acute toxicity in leaching-test eluates of the dry
      booth residues. This hypothesis was based on the fact that the formaldehyde
      concentrations in the leaching-test eluates of the dry-booth residues were 62-75
      times higher than the EC50 value reported in the literature for formaldehyde. The
      results of the water-curtain booth residues showed that the samples with the
      highest TOC and aromatic solvent concentrations were also the most toxic. The
      studied excess paint residues were complex organic mixtures and contained large
      amounts of compounds not identifiable from chemical data. Therefore, the
      evaluation of the hazard based solely on available chemical data is unlikely to
      be sufficient, as evidenced by our study. Our results show that harmful compounds
      remain in the solid waste and the toxicity results of their leaching-test eluates
      show that toxicity may leach from residues in contact with water at landfill
      sites. They also confirm the benefit of combining chemical and ecotoxicological
      assays in assessing the potential environmental hazard of complex organic
      mixtures found in wastes.

PMID- 15177096
TI  - Advanced sludge treatment affects extracellular polymeric substances to improve
      activated sludge dewatering.
AB  - The management of wastewater sludge, now often referred to as biosolids, accounts
      for a major portion of the cost of the wastewater treatment process and
      represents significant technical challenges. In many wastewater treatment
      facilities, the bottleneck of the sludge handling system is the dewatering
      operation. Advanced sludge treatment (AST) processes have been developed in order
      to improve sludge dewatering and to facilitate handling and ultimate disposal.
      The authors have extensively reported lab-scale, semi-pilot and pilot
      investigations on either thermal and thermochemical processes, or chemical
      oxidation using hydrogen peroxide. To understand the action of these advanced
      sludge technologies, the essential role played by extracellular polymeric
      substances (EPS) needs to be understood. EPS form a highly hydrated biofilm
      matrix, in which the micro-organisms are embedded. Hence they are of considerable
      importance in the removal of pollutants from wastewater, in bioflocculation, in
      settling and in dewatering of activated sludge. The present paper reviews the
      characteristics of EPS and the influence of thermochemical and oxidation
      mechanisms on degradation and flocculation of EPS. Experimental investigations on
      waste activated sludge are conducted by the authors to evaluate the various
      literature findings. From the experiments, it is concluded that AST methods
      enhance cake dewaterability in two ways: (i) they degrade EPS proteins and
      polysaccharides reducing the EPS water retention properties; and (ii) they
      promote flocculation which reduces the amount of fine flocs.

PMID- 15177097
TI  - Poly(ethylene glycol dimethacrylate-n-vinyl imidazole) beads for heavy metal
      removal.
AB  - Poly(ethylene glycol dimethacrylate-n-vinyl imidazole) [poly(EGDMA-VIM)] hydrogel
      (average diameter 150-200 microm) was prepared by copolymerizing ethylene glycol
      dimethacrylate (EGDMA) with n-vinyl imidazole (VIM). The copolymer hydrogel bead
      composition was characterized by elemental analysis and found to contain 5 EGDMA
      monomer units each VIM monomer unit. Poly(EGDMA-VIM) beads had a specific surface
      area of 59.8 m2/g. Poly(EGDMA-VIM) beads were characterized by swelling studies
      and scanning electron microscopy (SEM). These poly(EGDMA-VIM) beads with a
      swelling ratio of 78% were used for the heavy metal removal studies. Chelation
      capacity of the beads for the selected metal ions, i.e., Cd(II), Hg(II) and
      Pb(II) were investigated in aqueous media containing different amounts of these
      ions (10-750 mg/l) and at different pH values (3.0-7.0). Chelation rate was very
      fast. The maximum chelation capacities of the poly(EGDMA-VIM) beads were 69.4
      mg/g for Cd(II), 114.8 mg/g for Pb(II) and 163.5 mg/g for Hg(II). The affinity
      order on molar basis was observed as follows: Hg(II) > Cd(II) > Pb(II). Chelation
      behavior of heavy metal ions could be modelled using both the Langmuir and
      Freundlich isotherms. pH significantly affected the chelation capacity of VIM
      incorporated beads. Chelation of heavy metal ions from synthetic wastewater was
      also studied. The chelation capacities are 45.6 mg/g for Cd(II), 74.2 mg/g for
      Hg(II) and 92.5 mg/g for Pb(II) at 0.5 mmol/l initial metal concentration.
      Regeneration of the chelating-beads was easily performed with 0.1 M HNO3. These
      features make poly(EGDMA-VIM) beads potential candidate adsorbent for heavy metal
      removal.

PMID- 15177098
TI  - Removal of phosphate from aqueous solutions by electro-coagulation.
AB  - The aim of this paper was to investigate the feasibility of the removal of
      phosphate from aqueous solution by electro-coagulation (EC). The current density
      (CD) between 2.5 and 10 mA cm(-2) and duration in the limits of 5-20 min were
      tried for different concentrations. In order to determine optimal operating
      conditions, the EC process used for the phosphate removal was examined in
      dependence with the CD, initial concentrations and time. The results of the
      experimental batch processing showed high effectiveness of the EC method in
      removing phosphate from aqueous solutions.

PMID- 15177099
TI  - Technological parameters of the ammonolysis of waste 1,2-dichloropropane.
AB  - The ammonolysis of waste 1,2-dichloropropane (DCP) using liquid ammonia has been
      investigated. The influence of temperature, molar ratio of NH3/1,2
      dichloropropane and reaction time was examined. The highest yield of the
      synthesis was achieved at a temperature of 140 degrees C, for the reaction time
      of 3 h and the molar ratio of NH3/1,2-dichloropropane as 20:1. Under these
      conditions the degree of 1,2-dichloropropane conversion amounted to 97.1 mol% and
      the selectivity of transformation to 1,2-diaminopropane (DAP) in relation to
      consumed 1,2-dichloropropane was 25.3 mol%, whereas in relation to consumed
      ammonia 17.9 mol%. The remaining 1,2-dichloropropane reacts to form
      polypropyleneamines.

PMID- 15177100
TI  - Degradation of aldrin in adsorbed system using advanced oxidation processes:
      comparison of the treatment methods.
AB  - In this study, Fenton, UV/Fenton, UV/H2O2, UV/Fe2+ advanced oxidation processes
      have been applied for degradation of aldrin adsorbed on Na-montmorillonitte and
      activated carbon. Aldrin adsorbed on Na-montmorillonitte was degraded more
      efficiently than that of on activated carbon. For example, in UV/Fenton technique
      95% of aldrin was removed from Na-montmorillonitte while 50% degradation was
      observed on activated carbon. Degradation of aldrin adsorbed on Na
      montmorillonitte has also been achieved effectively using UV/Fe2+ technique
      despite the absence of H2O2. All AOPs but Fenton have been observed nearly
      equally effective for degradation of aldrin on Na-montmorillonitte sorbent.
      Fenton reaction exhibited least activity in degradation aldrin adsorbed on Na
      montmorillonitte. The experiments with activated carbon sorbent indicated that
      phenyl groups in activated carbon structure and aldrin molecules exhibited
      competitive behavior on reaction with OH* radicals. The results of infrared
      spectroscopy support this assumption. The degradation efficiency of aldrin using
      activated carbon sorbent was determined in the following order: UV/Fenton >
      UV/H2O2 > Fenton > UV/Fe2+.

PMID- 15177101
TI  - Electrodialytic removal of cadmium from wastewater sludge.
AB  - This paper presents for the first time laboratory results demonstrating
      electrodialytic removal of Cd from wastewater sludge, which is a method
      originally developed for soil remediation. During the remediation a stirred
      suspension of wastewater sludge was exposed to an electric dc field. The
      liquid/solid (ml/g fresh sludge) ratio was between 1.4 and 2. Three experiments
      were performed where the sludge was suspended in distilled water, citric acid or
      HNO3. The experimental conditions were otherwise identical. The Cd removal in the
      three experiments was 69, 70 and 67%, respectively, thus the removal was
      approximately the same. Chemical extraction experiments with acidic solutions
      showed that 5-10 times more Cd could be extracted from decomposed sludge than
      from fresh sludge. It is likely that the mobilization of Cd during decomposition
      of the sludge contributes to the efficient removal of Cd by the electrodialytic
      method. Extraction experiments and electrodialytic remediation using distilled
      water as enhancement agent showed that 0.3% Cd could be extracted from decomposed
      sludge during 1 week in closed flasks, whereas 69% was removed during 2 weeks of
      electrodialytic remediation in a stirred solution in contact with atmospheric
      air. A combination of aerobic decomposition and electrodialytic treatment could
      be a promising method for Cd removal from wastewater sludge, and thus Cd could be
      removed without the addition of chemicals to the sludge.

PMID- 15177102
TI  - Effect of metal spiking on different chemical pools and chemically extractable
      fractions of heavy metals in sewage sludge.
AB  - A laboratory experiment was conducted to study the effect of metal spiking and
      incubation on some properties and sequentially extractable chemical pools of some
      heavy metals (F1, two extractions with 0.1 M Sr(NO3)2; F2, one extraction with 1
      M NaOAc (pH 5.0); F3, three extractions with 5% NaOCl (pH 8.5) at 90-95 degrees
      C; F4, three extractions with 0.2 M oxalic acid + 0.2 M ammonium oxalate + 0.1 M
      ascorbic acid (pH 3.0); and F5, dissolution of sample residue in HF-HClO4
      (residual fraction,) and also 1 M CaCl2 and 0.005 M DTPA extractable heavy metals
      in sewage sludge. Metal spiking and incubation decreased pH and easily oxidizable
      organic C content of sludge but increased electrical conductivity. Metal spiking
      and incubation increased F1 fraction of all heavy metals, F2 fraction of Ni, Pb,
      Cu, and Cd, F3 fraction of Pb, Cu, and Cd, F4 or reducible fraction of Ni, Cu,
      and Cd and residual fraction of Zn and Pb, but decreased F2 fraction of Zn, F3 of
      Zn and Ni, F4 fraction of Zn and F5 fraction of Ni, Cu, and Cd. Metal spiking and
      incubation increased 1 M CaCl2 and 0.005 M DTPA extractable amounts of all heavy
      metals in sludge except for 0.005 M DTPA extractable Zn, which registered only
      very marginal decrease.

PMID- 15177103
TI  - Effect of experimental variables on the inertization of galvanic sludges in clay
      based ceramics.
AB  - The incorporation of several industrial wastes in ceramic matrixes had been
      attempted as an effective low expense technique for the fixation of metallic
      species in usable products or simply to reduce the residue volume for further
      disposal. However, the dominant mechanism of the inertization process and the
      relevant influent parameters are still unknown, mostly due to the complexity of
      the systems. This work reports the effect of several processing parameters such
      as the mixing time, the calcination temperature and duration, the relative amount
      of sludge, and the physical aspect of the sample (powdered or pressed pellets) on
      the fixing level of relevant species (SiO2), SO4(2)-, Zn, Ni, Ca, Cu, Cr) by
      leaching in different media (aqueous, acetate, and citrate). Statistical tools
      were used to define the relevance of each experimental variable on the
      inertization process of the used galvanic sludge. The relative amount of sludge
      in the mixture, the calcination temperature and the agglomeration state of the
      sample were found to be the most influent parameters of the inertization process.
      The incipient reaction between sludge and ceramic matrix components points out
      for the dominance of a macro-encapsulation mechanism.

PMID- 15177104
TI  - Examination of cadmium sorption characteristics for a boreal soil near Fairbanks,
      Alaska.
AB  - The objective of this research was to better understand cadmium (Cd) mobility in
      an organic-rich, boreal soil. Cadmium was selected for the study because of its
      tendency to be more mobile in soils than other heavy metals, such as lead or
      mercury. The release of metals from soil is a concern for northern regions where
      soils are gradually warming, resulting in an increased rate of natural organic
      matter (NOM) decomposition and soil erosion. Soil samples were collected from
      three principle soil horizons at a research site in the Caribou-Poker Creeks
      Research Watershed (CPCRW), near Fairbanks, Alaska. A dilute Cd solution was
      added to the soil and the soil solution was allowed to mix for 72 h. The soil
      solution was then passed through a 75 microm sieve and a 0.3 microm filter.
      Particulate samples retained on the sieve and filter were analyzed by atomic
      absorption (AA) to determine how much Cd was bound to the different size
      particles. The NOM in each particle size fraction was analyzed by pyrolysis-gas
      chromatography/mass spectrometry (py-GC/MS) to determine the nature of the NOM
      present. Our results showed that the concentration of Cd was almost equal for the
      different particle sizes in each horizon. That is, the amount of Cd associated
      with particles larger than 75 microm was nearly the same, on a per mass basis, as
      the amount of Cd associated with particles ranging in size between 0.3 and 75
      microm. Since the mass ratio of Cd to solids normally increases as particle size
      decreases, this result suggested unusual sorption behavior. Based on the Cd
      distribution among the particles and the percentage of NOM in each particle size
      range, it is believed that NOM is a primary factor influencing the sorption
      behavior of Cd in the boreal soil tested.

PMID- 15177105
TI  - Acid deposition and critical load analysis in Agra, India.
AB  - The deposition of sulphur (161.1 eq.ha(-1) per year), nitrogen(49.9 eq.ha(-1) per
      year), and ammonium (176.8 eq.ha(-1) per year) from the atmosphere were
      calculated for both wet and dry deposition in Agra region of India. Seven
      sampling sites located at Bichpuri, Bah, Fatehabad, Shamsabad, Nunhai, Dayalbagh,
      and St. John's College were used. The values for critical load of sulphur and
      nitrogen for soil with respect to Hibiscus (Hibiscus rosa-sinensis) and Black
      siris (Albizzia odoratissima) were calculated. The methodology employed involved
      the steady state mass balance (SSMB) method. The values of actual acidity were
      compared with the RAINS-Asia model. On comparing the acidity, it was found that
      the values computed by RAINS-Asia model are higher for this area.

PMID- 15177106
TI  - Recovery of isopropyl alcohol from waste solvent of a semiconductor plant.
AB  - An important waste solvent generated in the semiconductor manufacturing process
      was characterized by high isopropyl alcohol (IPA) concentration over 65%, other
      organic pollutants and strong color. Because of these characteristics, IPA
      recovery was deemed as a logic choice for tackling this waste solvent. In the
      present work, an integrated method consisting of air stripping in conjunction
      with condensation and packed activated carbon fiber (ACF) adsorption for dealing
      with this waste solvent. The air stripping with proper stripping temperature
      control was employed to remove IPA from the waste solvent and the IPA vapor in
      the gas mixture was condensed out in a side condenser. The residual IPA remaining
      in the gas mixture exiting the side condenser was efficiently removed in a packed
      ACF column. The air stripping with condensation was able to recover up to 93% of
      total IPA in the initial waste solvent. The residual IPA in the gas mixture,
      representing less than 3% of the initial IPA, was efficiently captured in the
      packed ACF column. Experimental tests were conducted to examine the performances
      of each unit and to identify the optimum operating conditions. Theoretical
      modeling of the experimental IPA breakthrough curves was also undertaken using a
      macroscopic model. The verified breakthrough model significantly facilitates the
      adsorption column design. The recovered IPA was found to be of high purity and
      could be considered for reuse.

PMID- 15177107
TI  - Role of the mixing conditions and composition of galvanic sludges on the
      inertization process in clay-based ceramics.
AB  - Hydroxide-metal sludges from electroplating industry are a potential source of
      environmental contamination due to their high content of heavy metals. The
      incorporation of these residues in a ceramic matrix can be a promising way to
      suppress the harmful effect of metals normally present in those sludges. This
      work reports the role of the mixing time between the waste and ceramic materials
      and of the calcination step on the fixing level of several metal-containing
      species (Al, Zn, Ni, Fe, Ca, Cu, Cr) after sequential leaching in different media
      (aqueous, acetate and citrate). A strong and/or long mixing process will promote
      the deagglomeration of the coarser agglomerates and then will increase the
      reactivity of remaining grains towards the ceramic material during the
      calcination. As a consequence, inertization is improved for fired samples. With
      non-calcined samples leaching increases as a result of increasing
      dispersability/availability of species.

PMID- 15177109
TI  - A rapid rosetting method for separation of hemocyte sub-populations of Drosophila
      melanogaster.
AB  - Hemocytes, cellular elements of the innate immune system in insects, play a
      crucial role in the cellular and humoral immune response. Although a significant
      amount of information has been collected on their differentiation and function,
      our understanding of hemocyte development is far from complete. Their
      characterisation is mostly based on morphological criteria. However, molecular
      markers were recently identified, defining functional subsets by the aid of
      monoclonal antibodies. Isolated subsets of hemocytes, in sufficient quantity and
      purity could help to analyse their development in vitro and also to further
      define their molecular characteristics. Here we describe an antibody-based
      rosetting technique for the physical separation of Drosophila hemocyte sub
      populations. We have applied anti-hemocyte antibodies coupled to sheep red blood
      cells for separation. The method relies on the formation of rosettes between
      hemocytes and sheep erythrocytes, sensitised with discriminative anti-hemocyte
      monoclonal antibodies. Using this method the rosetting and non-rosetting
      hemocytes can be separated from each other by gradient centrifugation. Rosette
      forming cells from the pellet and non-rosetting cells from the interface can be
      isolated in high recovery. The method can be used for functional and molecular
      characterisation of hemocyte sub-populations. The procedure is sensitive,
      reproducible and easy to perform.

PMID- 15177110
TI  - Phenoloxidase and QX disease resistance in Sydney rock oysters (Saccostrea
      glomerata).
AB  - QX is a fatal disease in Sydney rock oysters (Saccostrea glomerata) that results
      from infection by the protistan parasite, Marteilia sydneyi. Since 1997, the New
      South Wales Fisheries Service has bred S. glomerata for resistance to QX disease.
      The current study shows that the QX resistance breeding program has selected
      oysters with enhanced phenoloxidase (PO) activities. The third generation of QX
      selected oysters was compared to S. glomerata that had never been selected for
      disease resistance. PO enzyme assays showed that oysters bred for resistance had
      significantly higher PO activities than the non-selected population. There was no
      difference between populations in the activities of a variety of other enzymes.
      Native polyacrylamide gel electrophoresis identified a novel form of PO in QX
      selected oysters that contributes to their enhanced PO activities. This novel
      form of PO may represent a specific QX disease resistance factor.

PMID- 15177111
TI  - Single base oligodeoxyguanosine upregulates Fas ligand release by nonspecific
      cytotoxic cells.
AB  - Nonspecific cytotoxic cells (NCC) are a type of teleost NK-like cell. In the
      present study a novel stimulus secretion model is described for catfish NCC
      utilizing single base oligodeoxyguanosine. Binding of guanosine 20-mers (dG20) to
      NCC up-regulated expression of cytosolic FasL detected by an anti-human FasL
      monoclonal antibody (mab). In vitro treatment of purified NCC with dG20 produced
      a 7-fold increase in expression of soluble Fas ligand (sFasL) after 3 h. Antibody
      binding to NCC was saturable and approximately 30-35% of total NCC were positive
      for sFasL expression. The teleost FasL equivalent produced programmed cell death
      of appropriate FasR positive targets. Supernatants from dG20 activated NCC
      produced hypoploidy and annexin-V binding by FasR bearing HL-60 cells. Treatment
      of activated supernatants with immobilized anti-FasL mab neutralized these
      activities. These studies demonstrated that an NK like cell (NCC) produces and
      secretes sFasL following binding by single base oligodeoxyguanosine.

PMID- 15177112
TI  - Effect of environmental temperature on rainbow trout (Oncorhynchus mykiss) innate
      immunity.
AB  - Phagocytosis, complement lytic activity and opsonization capacity of rainbow
      trout plasma as well as the ability of phagocytes to recognize foreign particles
      were studied at different temperatures. Respiratory burst (RB) activity and
      opsonization capacity were assessed as chemiluminescence emission from diluted
      whole blood of fish which were acclimatized for 57 days at temperatures between 5
      and 20 degrees C. RB activity was higher at higher acclimatization and in vitro
      assay temperatures. The peak time of RB was significantly delayed in fish kept at
      lower temperatures (5-10 degrees C) as compared to fish kept at 15 or 20 degrees
      C temperatures. Opsonization capacity of plasma decreased in fish acclimatized at
      low temperatures and was also affected by in vitro assay temperature. The
      importance of glucan receptors in RB activity increased in fish kept at higher
      temperatures and was also affected by the in vitro assay temperature. The higher
      acclimation temperatures increased the lytic activity of both total and
      alternative complement pathways.

PMID- 15177113
TI  - An immunohistochemical study on complement component C3 in juvenile Atlantic
      halibut (Hippoglossus hippoglossus L.).
AB  - The complement systems of fish are well developed and play an important role in
      the immune response. Complement C3 is the central protein of all three activation
      pathways, being the major opsonin of the complement system and essential for the
      generation of the membrane attack complex. Very little is known about the
      development of the complement system in fish. In this study, we detect the
      presence of C3 in halibut larvae from the age of 37 degrees d post hatching until
      1050 degrees d (i.e. 5-99 d post hatching) using immunohistochemistry with
      specific antibodies produced against the beta-chain of halibut C3. At the
      different stages of larval maturation, C3 was detectable in yolksac, muscle,
      liver, brain, chondrocytes, spinal chord, eye, heart, stomach, intestines,
      oesophagus, pharynx and kidney. Our findings suggest a role of complement in the
      formation and generation of different organs, besides its important functions in
      the immune defence against invading pathogens.

PMID- 15177114
TI  - Characterization of the molecular chaperone calnexin in the channel catfish,
      Ictalurus punctatus, and its association with MHC class II molecules.
AB  - Folding and assembly of MHC molecules in mammals occurs in the endoplasmic
      reticulum (ER), but has not been studied in teleosts. Calnexin (CNX) is an ER
      chaperone that associates with glycoproteins bearing a monoglucosylated N-linked
      oligosaccharide side chain. Here we report the first identification and
      characterization of a full-length CNX cDNA clone in a teleost, and the
      association of the CNX chaperone with MHC class II in a channel catfish T cell
      line. The 1.8 kb CNX clone encodes a protein of 607 amino acids that is 72%
      identical to the consensus sequence of mammalian CNXs. The association of CNX
      with class II is of particular interest because the native MHC class II alpha
      chain of Ictalurus punctatus does not bear any N-linked oligosaccharide consensus
      glycosylation sequences. Thus the assembly of class II molecules in the catfish
      probably proceeds via different steps than occurs in mammals.

PMID- 15177115
TI  - Role of Mtd/Bok in normal and neoplastic B-cell development in the bursa of
      Fabricius.
AB  - B-cell development in the bursa of Fabricius is accompanied by extensive
      apoptotic cell death. Apoptosis, however, is suppressed during c-myc-induced
      neoplasia. The experiments described here suggest that Mtd/Bok may drive
      apoptosis during normal development, and that this activity is blocked during myc
      induced tumorigenesis. Bursal Mtd/Bok expression increases during development,
      correlating with the onset of intense, spontaneous apoptosis after hatching. Two
      isoforms of Mtd/Bok were characterized: WT-chMtd/Bok, found predominantly in the
      mitochondria and a less abundant form, lacking the presumptive transmembrane
      domain, Mtd/Bok deltaTM, found predominantly in the cytosol. Over-expression of
      Mtd/Bok deltaTM in a bursal lymphoma-derived cell line, DT40, reduced
      mitochondrial function and sensitized DT40 cells to apoptotic stimuli, while WT
      chMtd/Bok had a diminished phenotype in these cells. In contrast, retroviral
      transduction of bursal stem cells with WT-chMtd/Bok ablated normal stem cell
      function in transplantation experiments, and produced extensive apoptosis in myc
      induced pre-neoplastic bursal populations, but not in tumor cells.

PMID- 15177116
TI  - Gene expression profiling of bovine macrophages in response to Escherichia coli
      O157:H7 lipopolysaccharide.
AB  - The aim of this study was to identify changes in bovine macrophage gene
      expression in response to treatment with Escherichia coli 0157:H7
      lipopolysaccharide (LPS), utilizing a human gene microarray. Bovine cDNA from
      control and LPS-treated primary macrophages hybridized to greater than 5644
      (79.8%) of the non-control gene targets on a commercially available microarray
      containing greater than 7075 targets (Incyte Genomics, St. Louis, MO). Of these
      target sequences, 44 were differentially expressed upon exposure to LPS,
      including 18 genes not previously reported to exist in cattle. These included a
      pentaxin-related gene, CASP8, TNF-induced genes, interferon-induced genes, and
      inhibitors of apoptosis. Using the human microarray, cDNA from bovine LPS-treated
      and control macrophages consistently hybridized to targets known to be expressed
      constitutively by macrophages, as expected given the predicted cDNA sequence
      homology. That this human system was accurately estimating levels of bovine
      transcripts was further verified by real-time quantitative reverse transcriptase
      polymerase chain reaction (RTQ-PCR) using bovine-specific primers. This first
      report of bovine-human cross-species expression profiling by microarray
      hybridization demonstrates the utility of this technique in bovine gene
      expression and discovery.

PMID- 15177117
TI  - Expression of the third complement component (C3) and carboxypeptidase N small
      subunit (CPN1) during mouse embryonic development.
AB  - Complement regulatory proteins prevent excessive complement system activation and
      deposition, which can lead to host tissue damage, including fetal loss during
      pregnancy. To further understand the regulation of complement during development,
      we examined the expression of the complement protein, C3, and the active subunit
      of carboxypeptidase N (CPN1), the complement anaphylatoxin regulator. RNA and
      protein analyses indicated that CPN1 expression occurred as early as 8.5 days
      post coitus (dpc) and continued through birth. At 10.5 and 13.5 dpc, in situ
      hybridization revealed CPN1 RNA in erythroid progenitor cells. At 16.5 dpc,
      expression of CPN1 was also detected in hepatocytes. In comparison to CPN1, C3
      RNA expression occurred later (after 13.5 dpc). Moreover, C3 expression was
      limited to the liver erythroid progenitor cells at 16.5 dpc. These results
      demonstrated that mouse embryos contain RNA and protein for both C3 and CPN1, and
      CPN1 expression precedes that of C3 by several days.

PMID- 15177118
TI  - Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities.
AB  - Low-density lipoprotein (LDL) cholesterol is an established risk factor for
      coronary heart disease (CHD). In the presence of oxidative stress LDL particles
      can become oxidized to form a lipoprotein species that is particularly
      atherogenic. Indeed, oxidized LDL (oxLDL) is pro-inflammatory, it can cause
      endothelial dysfunction and it readily accumulates within the arterial wall.
      Several factors may influence the susceptibility of LDL to oxidation, including
      its size and composition, and the presence of endogenous antioxidant compounds,
      such as alpha-tocopherol. Individuals with type 2 diabetes or the metabolic
      syndrome have high levels of oxidative stress and consequently are at an
      increased risk for cardiovascular events. Reducing oxidative stress has been
      proposed as a potential approach to prevent CHD and antioxidant vitamins have
      been employed with encouraging results in experimental models of atherosclerosis.
      However, clinical trials have not demonstrated consistent beneficial effects of
      antioxidants on cardiovascular outcomes. Statins (3-hydroxy-3-methylglutaryl
      coenzyme A reductase inhibitors) are the first-line choice for lowering total and
      LDL cholesterol levels and they have been proven to reduce the risk of CHD.
      Recent data suggest that these compounds, in addition to their lipid-lowering
      ability, can also reduce the production of reactive oxygen species and increase
      the resistance of LDL to oxidation. It may be that the ability of statins to
      limit the oxidation of LDL contributes to their effectiveness at preventing
      atherosclerotic disease.

PMID- 15177119
TI  - Interrelationship between non-invasive measurements of atherosclerosis: flow
      mediated dilation of brachial artery, carotid intima-media thickness and pulse
      wave velocity.
AB  - Flow-mediated dilation (FMD) of the brachial artery, carotid intima-media
      thickness (IMT) and pulse wave velocity (PWV) have been shown to be good
      surrogate markers of clinical atherosclerosis. We determined the interrelation
      between these measurements, and examined whether their combination would be of
      clinical significance. One hundred and thirty-five consecutive subjects (79
      women/56 men) were enrolled, including 110 patients with risk factors for
      atherosclerosis, and 33 patients with atherosclerotic disease such as coronary
      heart disease, stroke or arteriosclerosis obliterans. IMT and plaque formation of
      the carotid artery and FMD of the brachial artery were assessed using
      ultrasonography. Brachial-ankle PWV (baPWV) was measured using an automated
      device (form ABI/PWV, Colin). Age, FMD, IMT and PWV were significantly correlated
      with each other. Multivariate analysis revealed an independent correlation
      between the parameters except for FMD, and all four parameters were independently
      correlated with each other in subjects <70 years. Next, we classified the
      subjects by tertile according to the values of FMD, IMT and PWV. Each of the
      worst tertiles was associated with a higher prevalence of atherosclerotic disease
      and carotid plaques compared to the other tertiles. Moreover, subjects with the
      worst tertiles of all three measurements had a markedly higher prevalence of
      atherosclerotic disease and carotid plaques. These results suggest that FMD, IMT
      and PWV are related to each other, but the combination of these measurements will
      be of stronger clinical relevance.

PMID- 15177120
TI  - Aortic glutathione metabolic status: time-dependent alterations in fat-fed
      rabbits.
AB  - Little is known about the vascular metabolic status of glutathione (GSH), which
      is crucial in cell antioxidant protection, in experimental conditions like high
      fat diet-induced atherosclerosis. This issue was, therefore, investigated in two
      groups of seven rabbits fed a 0.5% cholesterol-, 5% lard- and 5% peanut oil
      enriched diet for 18 and 80 days, which, respectively, raised the plasma values
      of total cholesterol by factors of about 12 and 37, and those of triglycerides by
      factors of 3 and 13; rabbits fed a standard diet for the same periods served as
      controls. Total GSH and the activities of the GSH level-maintaining enzymes
      glutathione reductase (GSSG-Red), gamma-glutamylcysteine synthetase (gamma-GCS)
      and gamma-glutamyl transpeptidase (gamma-GT) were specifically assessed in the
      aortic tissue, which was also assayed for fluorescent damage products of lipid
      peroxidation (FDPL). Sudan red staining of the aortic intima surface was also
      performed in two other groups of six controls and six fat-fed rabbits. After 18
      days of fat feeding, a significant decrement of aortic GSSG-Red activity,
      associated with gamma-GCS activation, increased GSH levels and normal gamma-GT
      activity, was observed; FDPL were only moderately enhanced, and atherosclerotic
      lesions did not occur. After 80 days of atherogenic diet, aortic GSH content was
      significantly decreased in concomitance with a marked depression of gamma-GT
      activity, while GSSG-Red and gamma-GCS activities were not significantly changed
      with respect to 18 days of fat feeding; FDPL underwent further considerable
      augmentation, and extensive Sudan red-stained atherosclerotic lesions were
      evident. Thus, short-term fat feeding induces gamma-GCS-dependent GSH
      biosynthesis of the rabbit aorta; prolonged high-fat intake and hyperlipidemic
      burden result instead in vascular gamma-GT dysfunction with GSH depletion,
      eventually favoring oxidative atherogenic effects.

PMID- 15177121
TI  - Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo)
      A1 from human macrophage foam cells.
AB  - High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an
      independent risk factor for coronary artery disease. Here, we show that TGRL
      inhibit the efflux of cholesterol from 'foam cell' macrophages to lipid-poor
      apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol
      transport and promote the formation of atherosclerotic lesions. Human (THP-1)
      monocyte-derived macrophages were pre-incubated (48 h) with acetylated low
      density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to
      apoA1. Pre-incubation of macrophage 'foam cells' with TGRL (0-200 microg/ml, 0-24
      h) inhibited the efflux of exogenously radiolabelled ([3H]), endogenously
      synthesised ([14C]) and cellular cholesterol mass to lipid-poor apoA1, but not
      control medium, during a (subsequent) efflux period. This inhibition is dependent
      upon the length of prior exposure to, and concentration of, TGRL employed, but is
      independent of changes in intracellular triglyceride accumulation or turnover of
      the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol
      efflux, major proteins involved in this process--namely apoE, ABCA1, SR-B1 and
      caveolin-1--were unaffected by TGRL pre-incubation, suggesting that exposure to
      these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic
      pathway.

PMID- 15177122
TI  - Variations in lipid and apolipoprotein concentrations in human leg lymph: effects
      of posture and physical exercise.
AB  - We studied the variations in the concentrations of cholesterol, triglycerides,
      phospholipids, apolipoproteins (apos) (A-I, A-II, B, C-III, E), free glycerol and
      albumin in human prenodal leg lymph during the 24 h cycle. Lymph was collected
      continuously for up to 96 h from nine healthy males on a low-fat isocaloric diet.
      In three free-living subjects, all lipid and apolipoprotein concentrations
      underwent synchronous variations, rising during the night and decreasing during
      the day. In three subjects who remained in supine rest for 48 h, the amplitude of
      circadian variation was much smaller. In three who alternated periods of supine
      rest with upright exercise, the highest concentrations occurred during rest.
      Lipid, apolipoprotein and albumin concentrations were inversely related to lymph
      flow rate. Free glycerol, much of which in tissue fluid is derived from local
      adipocytes, did not follow this pattern. On multiple regression, concentrations
      in lymph were related independently to the corresponding concentration in plasma
      (positive) and to lymph flow rate (negative) or lymph albumin concentration
      (positive). These results show that lipoprotein concentrations in human tissue
      fluid are determined only partly by their concentrations in plasma. They are also
      strongly affected by hemodynamic factors via their effects on fluid transport.

PMID- 15177123
TI  - Association of antibodies to chlamydial lipopolysaccharide with the endovascular
      presence of Chlamydophila pneumoniae in carotid artery disease.
AB  - Atherosclerotic lesions often harbor Chlamydophila pneumoniae (C. pneumoniae).
      The objective of the present study was to examine whether serological tests are
      able to predict individual endovascular infection. Endarterectomy specimens from
      70 patients with severe carotid artery stenosis were stained
      immunohistochemically for C. pneumoniae. Antibody titers to C. pneumoniae were
      measured in serum with a recombinant ELISA recognizing chlamydial
      lipopolysaccharide (cLPS) and with microimmunofluorescence (MIF). C. pneumoniae
      antigens were detected in 64 (91%) carotid artery specimens. Serum IgG antibodies
      to C. pneumoniae were detected in 43% of patients by cLPS-ELISA and in 77% by MIF
      test. Detection of C. pneumoniae positive cells within atherectomy specimens was
      strongly correlated to seroprevalence (P = 0.002) and to titers (P = 0.003) of
      cLPS-IgG antibodies, but not to results of the MIF-test. We conclude that cLPS
      IgG antibodies hold promise as a surrogate marker to identify individuals with
      high endovascular antigen load.

PMID- 15177124
TI  - Guidelines for the diagnosis and management of heterozygous familial
      hypercholesterolemia.
AB  - Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein
      metabolism characterized by very high plasma concentrations of low density
      lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature
      coronary heart disease (CHD). FH is a public health problem throughout the world.
      There are 10,000,000 people with FH worldwide, mainly heterozygotes, and
      approximately 85% of males and 50% of females with FH will suffer a coronary
      event before 65 years old if appropriate preventive efforts are not implemented.
      Early identification of persons with FH and their relatives, and the early start
      of treatment are essential issues in the prevention of premature cardiovascular
      disease (CVD) and death in this population. However, guidelines for the general
      population formally exclude FH from their diagnostic and treatment
      recommendations. These guidelines have been elaborated by a group of
      international experts with the intention to answer the main questions about
      heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis
      and management of these patients.

PMID- 15177125
TI  - Coronary artery calcification and cardiovascular risk factors: impact of the
      analytic approach.
AB  - Coronary artery calcification (CAC) may help identify novel risk factors for
      coronary atherosclerosis. However, analysis of CAC is challenging because of the
      distribution of CAC in the population. This has resulted in difficulty in
      interpreting and comparing results across studies. We applied several analytic
      approaches to CAC data in order to determine the impact of analytic methods on
      the association with established cardiovascular risk factors in 914 asymptomatic
      subjects in the Study of Inherited Risk Factors for Coronary Atherosclerosis.
      Multivariable analyses included: (1) linear regression of different
      transformations of CAC scores; (2) tobit regression of the log of (CAC + 1); (3)
      logistic regression using CAC zero as a cut-point; and (4) ordinal logistic
      regression using CAC categories. Linear regression of the log CAC scores and
      logistic regression of CAC zero cut-point failed to detect associations with some
      risk factors. In contrast, linear and tobit regression of the log (CAC + 1) and
      ordinal regression of CAC categories identified more associations and provided
      consistent results. Commonly applied methods of CAC analysis may fail to detect
      associations with cardiovascular risk factors. We present analytic approaches
      that are likely to provide consistent results and recommend the use of at least
      two distinct multivariable methods.

PMID- 15177126
TI  - Alcohol consumption and inflammatory markers in older adults: the Cardiovascular
      Health Study.
AB  - OBJECTIVE: We sought to determine the relation of alcohol intake and systemic
      inflammation in a population-based sample of older adults. METHODS AND RESULTS:
      As part of the Cardiovascular Health Study (CHS), 5865 adults aged 65 years and
      older reported their intake of beer, wine, and liquor. We determined white blood
      cell count (WBC), factor VIII coagulant activity (factor VIIIc), and levels of C
      reactive protein (CRP), fibrinogen, and albumin as markers of systemic
      inflammation. Among participants without confirmed cardiovascular disease,
      alcohol consumption was inversely associated with WBC, factor VIIIc, and
      fibrinogen level, and positively associated with albumin concentration in
      multivariate analyses. We found no consistent modification of these results by
      sex, obesity, or beverage type. The relation of alcohol use and CRP levels was
      significantly modified by apoE genotype (P interaction 0.03), with a positive
      association among participants with an apoE4 allele (P = 0.05), but a trend
      toward an inverse association among those without an apoE4 allele (P = 0.15).
      CONCLUSIONS: Alcohol intake is associated with lower levels of inflammatory
      markers in older adults free of cardiovascular disease.

PMID- 15177127
TI  - A genome-wide scan of serum lipid levels in the Old Order Amish.
AB  - Elevated serum low density lipoprotein cholesterol (LDL-C) and triglyceride (TG)
      and decreased high density lipoprotein cholesterol (HDL-C) levels are established
      risk factors for cardiovascular disease (CVD). To identify quantitative trait
      loci influencing lipid levels, we conducted genome-wide linkage analyses of total
      serum cholesterol (TSC), HDL-C, ln-transformed TG (LNTG) and LDL-C levels in 612
      individuals from 28 families of the Amish Family Diabetes Study (AFDS). Subjects
      were genotyped for 373 microsatellite markers covering all 22 autosomes and the X
      chromosome at an average density of 9.7 centimorgans. All lipid traits exhibited
      moderate estimated heritability (h2 +/- S.E.): TSC, 0.63 +/- 0.11; HDL-C, 0.54 +/
      0.08; LNTG, 0.37 +/- 0.08; LDL-C, 0.62 +/- 0.10. The highest logarithm of the
      odds (LOD) score observed was 2.47 (P = 0.0003), at 3p25 for LDL-C. LOD scores
      exceeding 2.0 (P < 0.001) were also observed at 2p23 (LOD = 2.17) and 19p13 (LOD
      = 2.23) for LDL-C, and at 11q23 (LOD = 2.03) for LNTG. Three additional regions
      exhibited LOD scores greater than 1.5, corresponding to a P-value of <0.005. Many
      of the regions suggestively linked in this genome-wide scan contain genes
      encoding proteins with established roles in lipid metabolism, including
      apolipoproteins, peroxisome proliferater-activated receptor-gamma and the LDL
      receptor.

PMID- 15177128
TI  - Non-invasive assessment of microvascular endothelial function by laser Doppler
      flowmetry in patients with essential hypertension.
AB  - The aim of the study was to investigate the endothelium-dependent vasodilation in
      the forearm skin using two non-invasive laser Doppler applications in patients
      with essential hypertension (EHT) and in normotensive (NT) control subjects. The
      effect of two consecutive doses of acetylcholine (ACh) and that of sodium
      nitroprusside (SNP) on the skin microcirculation, and thereafter the
      postocclusive reactive hyperaemic (PORH) response, were measured in 25 patients
      with essential hypertension and also in 25 control normotensive healthy subjects.
      The plasma von Willebrand factor (vWF) level and activity were also determined.
      The average peakflow in PORH was 287 +/- 31.5% (x +/- S.E.M.) in EHT and 410.28
      +/- 35.08% in NT (P < 0.01). The average hyperaemic response to the two doses of
      ACh-iontophoresis was 206.36 +/- 33.97 and 568.76 +/- 54.23% in EHT and 444.24 +/
      80.28 and 804.12 +/- 93.07% in NT (P < 0.01, 0.05). The response to SNP was
      similar in the two groups. The vWF levels were 122.5 +/- 13.2 and 89.6 +/- 8.1%
      (P = 0.0595, NS), the activities were 80.8 +/- 5.5 and 68.9 +/- 6.1% (P = 0.157,
      NS) in EHT and in NT, respectively. These results demonstrate that essential
      hypertension is associated with endothelial dysfunction in the skin
      microcirculation of the forearm.

PMID- 15177129
TI  - In vivo oxidizability of LDL in type 2 diabetic patients in good and poor
      glycemic control.
AB  - We aimed to determine if increased non-enzymatic glycosylation of the LDL was
      sufficient to increase the susceptibility to in vivo oxidation of the LDL
      particles. Twenty-two type 2 diabetic patients (11 males and 11 females) were
      included in this study. They were enrolled on the basis of good [glycated
      hemoglobin (HbA1c) < 7%] and poor glycemic control [(HbA1c) > 8%]. LDL were
      isolated by sequential ultracentrifugation and analyzed by capillary
      electrophoresis (CE) for diene conjugate content and for electronegativity. The
      glyc-LDL levels were increased in all diabetic type 2 patients, peaking in the
      diabetic subjects in poor diabetic control (17.3 +/- 8.07%). The LDL content of
      diene conjugates was similar between the two groups (6.65 +/- 0.77% for the
      patients with good glycemic control versus 6.88 +/- 0.74% for those with poor
      glycemic control; P = 0.49) as was the electrophoretic mobility ((-1.14544 +/-
      0.089) x 10(-4) cm2/(V s) for the patients with good glycemic control and (
      1.13666 +/- 0.073) x 10(-4) cm2/(V s) for those with poor glycemic control; P =
      0.80). The susceptibility to in vivo oxidation of LDL from type 2 diabetic
      patients in poor glycemic control did not differ from that of well-controlled
      diabetic patients. LDL glycosylation was not able to increase the oxidizability
      of LDL in the diabetic patients with poor glycemic control.

PMID- 15177130
TI  - Polymorphism in the promoter region of the apolipoprotein A5 gene is associated
      with an increased susceptibility for coronary artery disease.
AB  - Although triglycerides (TG) are a major risk factor for coronary artery disease
      (CAD), their exact role is still controversial. Recently, a T/C polymorphism in
      the promoter region of the apoA5 gene at position 1131 has been found that is
      associated with an increased plasma TG concentration. We investigated the role of
      this polymorphism in 308 Hungarian patients with CAD referred to coronary bypass
      surgery, and in 310 controls recruited from the same area. The prevalence of the
      apoA5-1131C allele was significantly higher among CAD patients than among
      controls (10.9% versus 5.7%; P < 0.001, Odds ratio (OR) = 1.99 (1.30-3.04)).
      Controls carrying the rare C allele had in average 23.0% (P < 0.001), subjects
      with CAD 13.8% (P < 0.001) higher TG levels compared to common allele
      homozygotes. The polymorphism was not associated with other conventional CAD risk
      factors or laboratory data of the patients. In logistic regression models
      adjusted for age, gender, presence of diabetes, BMI, smoking, LDL-C, HDL-C and
      hypertension a significantly increased risk of developing CAD was found in
      patients carrying the apoA5-1131C allele (P < 0.001; OR = 1.98 (1.14-3.48)),
      suggesting that this allele variant is an independent genetic risk factor for
      CAD.

PMID- 15177131
TI  - Epicardial coronary artery constriction to cold pressor test is predictive of
      cardiovascular events in hypertensive patients with angiographically normal
      coronary arteries and without other major coronary risk factor.
AB  - Epicardial coronary endothelial dysfunction independently predicts cardiovascular
      events in patients with coronary risk factors. This study was designed to
      evaluate outcome of hypertensive patients on the basis of their epicardial
      coronary function assessed by cold pressor test (CPT). Control subjects (n = 68,
      48.8 +/- 7.6 years) and hypertensive patients (n = 83, 51.3 +/- 7.9 years) with
      angiographically normal coronary arteries and without other major coronary risk
      factor underwent epicardial coronary reactivity assessment to CPT using
      quantitative angiography. Cardiovascular events were recorded with a mean follow
      up of 115 months (range 84-132). In control subjects, dilation occurred in 88.2%,
      no change in 11.8% (mean diameter change: +14.6 +/- 9.3%). In hypertensive
      patients, dilation occurred in 13.3%, no change in 25.3% (mean diameter change
      for both: +10.9 +/- 11.2%), and constriction in 61.4% (mean diameter change: 
      12.7 +/- 3.4%). Endothelium-independent dilation was normal in control subjects
      and hypertensive patients. In control subjects, there were three cardiovascular
      events in two subjects (2.9%). In hypertensive patients, there were 17
      cardiovascular events in 12 patients (14.5%, P < 0.01 versus control subjects),
      with 15 cardiovascular events in the 10/51 patients (19.6%) with coronary artery
      constriction, and two cardiovascular events in the 2/32 patients (6.3%) with no
      change or dilation (P < 0.05). In conclusion, in hypertensive patients with
      angiographically normal coronary arteries and without other major coronary risk
      factors, epicardial coronary artery dysfunction assessed by the cold pressor test
      is predictive of long-term cardiovascular events.

PMID- 15177132
TI  - Looking at non-genomic vascular effects of aldosterone.

PMID- 15177133
TI  - The role of the A54T polymorphism of the intestinal fatty acid binding protein
      for lipid levels, insulin sensitivity and carotid atherosclerosis.

PMID- 15177134
TI  - Re-calculated Hardy-Weinberg values in papers published in Atherosclerosis
      between 1995 and 2003.

PMID- 15177135
TI  - Serum butyrylcholinesterase activity in hyperlipidaemia.

PMID- 15177136
TI  - Significant increase in antibodies against oxidized LDL particles (IgoxLDL) in
      three-month old infants who received milk formula.

PMID- 15177137
TI  - Does TNF-alpha blockade cause plaque rupture?

PMID- 15177138
TI  - Definition of the acronym PRIME.

PMID- 15177139
TI  - Pathophysiology of severe malaria in children.
AB  - Over the past decade there has been a growing recognition that the
      rationalization of severe malaria in children into the two major syndromes of
      cerebral malaria and severe malaria anaemia is much too simplistic. Indeed, it
      has become apparent that death from severe malaria may arise from a wider
      spectrum of pathophysiological disorders with many features in common with the
      derangements seen in sepsis syndromes. Amongst these derangements acidosis has
      emerged as a central feature of severe malaria and the major predictor of a fatal
      outcome. We review the improved understanding of the pathophysiology of severe
      malaria through a series of clinical scenarios that reflect more accurately the
      clinical diversity of severe malaria in African children. Current therapeutic
      challenges are discussed and research priorities are highlighted.

PMID- 15177140
TI  - The effects of rainfall and evapotranspiration on the temporal dynamics of
      Anopheles gambiae s.s. and Anopheles arabiensis in a Kenyan village.
AB  - The population dynamics of the larval and adult life stages of the malaria vector
      Anopheles gambiae Giles were studied in Miwani, western Kenya, in relation to
      meteorological conditions. Larval density within a habitat, the number of larval
      habitats and sibling species composition were investigated as determinants of
      larval population dynamics. Female vector densities inside local houses and
      sibling species composition were investigated as determinants of adult population
      dynamics. Larval densities were estimated using a modified area-sampling method.
      Within the habitats, all instars showed a highly aggregated distribution, with
      the exception of second instars. A longitudinal study on the larval populations
      of A. gambiae s.l. in two different types of habitat (dirt track and ditch) was
      carried out, using a novel sampling procedure. A. gambiae s.s. and Anopheles
      arabiensis, the two sibling species occurring sympatrically in the study area,
      showed some spatial segregation between the two types of habitat. Rainfall was
      significantly correlated with the number of A. gambiae s.l. larval habitats
      during the first 6 weeks of study taking 1 week time lag into account, while over
      the entire 5-month study period correlations were less clear. With 1 week time
      lag, rainfall was also significantly correlated with the number of female A.
      gambiae s.l. collected from CDC-light traps in the study houses. Both larval and
      adult populations showed a significant increase in the proportion of A. gambiae
      s.s. within the mixed population of A. gambiae s.s. and A. arabiensis over time.
      Although not significantly correlated, the ratio of rainfall over
      precipitation/potential evapotranspiration (P/PE), indicative of the humidity
      conditions in the area, was probably the driving force of this increase.

PMID- 15177141
TI  - Changing epidemiology of American cutaneous leishmaniasis (ACL) in Brazil: a
      disease of the urban-rural interface.
AB  - American cutaneous leishmaniasis (ACL) was first reported from the south-western
      region of the state of Rio Grande do Norte in 1987. Sao Miguel municipality and
      adjacent areas have accounted for 90% of the American cutaneous leishmaniasis
      cases in the region since then. A population survey conducted in Sao Miguel and
      adjacent areas was undertaken to identify individuals with a history of ACL. The
      incidence of ACL, distribution by age and gender, clinical characteristics,
      family clustering, relationship to animals, association with skin test responses,
      and development of mucosal lesions were determined. Males and females were
      equally likely to be infected by Leishmania. Thirty-eight percent of the
      individuals tested were found to be Montenegro skin test positive. No difference
      in the Montenegro skin test was observed with gender, but the response increased
      with age. Among the 140 ACL cases treated in a 4-year period in Sao Miguel, five
      (3.6%) developed mucosal involvement. Sandflies capable of transmitting
      Leishmania were captured inside households and in the areas surrounding them. The
      high density of sandfly species potentially able to transmit Leishmania species
      and the age distribution of cases of cutaneous leishmaniasis suggest that
      transmission of the parasite occurred inside or in close proximity to houses.

PMID- 15177142
TI  - Application of field methods to assess isometamidium resistance of trypanosomes
      in cattle in western Ethiopia.
AB  - This study assessed the degree of isometamidium resistance of trypanosomes
      infecting cattle in the upper Didessa valley of western Ethiopia. An initial
      prevalence study was conducted to identify sites with a high risk of
      trypanosmosis in cattle. The trypanosome prevalence varied widely, with two
      sites, Kone (21.3%) and Village 1 settlement (15%) having a relatively high
      prevalence based on the phase-contrast buffy-coat technique (BCT). In the highest
      risk area, the Kone settlement, an isometamidium block treatment study was
      conducted from April to June 2001. A total of 300 cattle were included in this
      study, 100 from each of three villages (Cheleleki, Kolu and Burka). At day minus
      14 of the study, all 300 cattle were treated with diminazene aceturate at 7 mg/kg
      body weight. Subsequently, these cattle were ear-tagged and randomly assigned
      into two groups, 50 controls and 50 for isometamidium treatment in each village.
      Fourteen days later (day 0), the 50 treatment cattle were given isometamidium
      chloride at 1 mg/kg body weight. Both groups of cattle were then examined for
      trypanosome parasites using BCT every 14 days until 84 days. The two indices used
      in assessing isometamidium resistance, namely the proportion of infections during
      an 8-week follow-up period and the ratio of mean hazards in an isometamidium
      treated versus untreated group, provided consistent results across the three
      villages. In Burka village, both indices demonstrated the presence of
      isometamidium resistance trypanosome infections while in Cheleleki and Kolu
      villages, both indices did not indicate significant levels of resistance. There
      were significant differences between the Kaplan-Meier survival estimates of the
      control and treatment groups in Cheleleki (P < 0.01) and Kolu (P < 0.05) but not
      in Burka (P > 0.05).

PMID- 15177143
TI  - Trypanosoma cruzi: cloning and characterization of two genes whose expression is
      up-regulated in metacyclic trypomastigotes.
AB  - The differentiation of epimastigotes into metacyclic trypomastigotes
      (metacyclogenesis) involves the transformation of a replicative non-infective
      form of Trypanosoma cruzi into a non-replicative infective stage. The study of
      genes with stage-specific expression may provide insight into the mechanisms
      involved in the regulation of gene expression in this parasite. We cloned and
      characterized two genes whose expression is up-regulated in metacyclic
      trypomastigote, those encoding metacyclin-II (Met-II) and metacyclin-III (Met
      III). Nucleotide sequence analysis identified no sequence similarity with
      sequences available from genetic databases. The deduced amino acid sequences of
      the genes indicated that Met-III encodes a basic polypeptide whereas Met-II
      encodes an acidic polypeptide. Northern and Western blot analyses showed that Met
      II and Met-III were expressed by metacyclic trypomastigotes, but not by
      epimastigotes. Antisera directed against the recombinant Met-II and Met-III
      proteins recognized two polypeptides on Western blots: a 16-kDa and a 24-kDa
      polypeptide. Immunocytochemistry analysis using electron microscopy showed that
      metacyclin-II is localized mainly at the kinetoplast whereas metacyclin-III is
      localized at the nucleus of the parasite. Southern blot analysis, using genomic
      DNA and T. cruzi chromosomes separated by pulsed-field gel electrophoresis,
      indicated that these genes were present as single copies on different chromosomes
      of T. cruzi Dm28c.

PMID- 15177144
TI  - Malaria dispersal among islands: human mediated Plasmodium falciparum gene flow
      in Vanuatu, Melanesia.
AB  - A comparison of human and Plasmodium falciparum gene flow patterns in the model
      island system of Vanuatu, the limit of malaria in the Pacific reveals that human
      movement is essential for long, but not short distance P. falciparum gene flow.
      This suggests that long distance movement of humans may accelerate the evolution
      and spread of drug resistance and therefore exacerbate the global malaria
      problem.

PMID- 15177145
TI  - Idiopathic thrombocytopenic purpura due to vivax malaria in the Brazilian Amazon.
AB  - We describe a rare case of idiopathic thrombocytopenic purpura (ITP) triggered by
      Plasmodium vivax infection. The patient developed thrombocytopenia and bleeding
      associated with three episodes of malaria, and became dependent on corticosteroid
      therapy. The mechanisms by which this parasite evokes thrombocytopenia remain
      obscure.

PMID- 15177146
TI  - Circulating levels of the neuropeptide hormone somatostatin may determine hepatic
      fibrosis in Schistosoma mansoni infections.
AB  - The neuropeptide hormone somatostatin reduces fibrosis and Schistosoma-caused
      clinical morbidity in the rodent model. In our study we aimed to delineate an
      association between fibrosis and the inability to generate critical levels of
      endogenous somatostatin in S. mansoni infected subjects. In June 2001, 85
      subjects from the district dispensary at Richard Toll in the Medical Region of
      Saint-Louis, Senegal, were selected. Fifty-seven subjects were infected with S.
      mansoni of whom 32 were suffering from severe morbidity (SM). Twenty-eight
      subjects showed an inactive disease status with no evident infection at the
      actual time of study. All subjects were classified according to age, sex,
      occupation, height, weight, and parasite eggs per gram. All 85 participated in a
      water contact and morbidity questionnaire, underwent a clinical examination and
      donated 5ml of peripheral blood for detecting plasma levels of somatostatin.
      Ultrasonography detected fibrosis grade in all the subjects. To address whether
      inherent somatostatin levels determined clinically evident disease severity (epg,
      hepatomegaly, splenomegaly, hematemesis, ascites), the mean somatostatin values
      of the inactive disease status group and severe morbidity group were compared.
      Low somatostatin levels were depicted in subjects with severe morbidity symptoms
      associated with schistosomiasis as compared to exposed but inactive disease
      status subjects residing in the same region. Logistic regression analysis
      indicated that with decreasing somatostatin values the probability of severe
      morbidity increased with age being a confounding factor. To address whether
      inherent somatostatin levels determined fibrosis and if this association was
      significant, plasma somatostatin levels of non-fibrotics (ultrasonographic
      grading A), and fibrotics (ultrasonographic grading B-E) were compared. In all
      age groups as well as in adults alone, mean somatostatin levels were higher in
      the non-fibrotic group as compared to the fibrotics group, the difference being
      significant. The group B comprised of borderline fibrotic cases, therefore a
      separate analysis was done between groups A (non-fibrotics) and groups C, D
      (confirmed fibrotics). Mean somatostatin values were higher in the non-fibrotic
      group as compared to the fibrotics group, the difference being borderline
      significant. In schistosomiasis patients, circulating levels of somatostatin by
      binding to hepatic stellate cells (HSC) may modulate fibrosis. This phenomenon is
      regulated by age whereas gender and prior treatment have no effect on this
      association. Host specific somatostatin levels may create a 'preset environment'
      status that can determine progression to severe fibrosis.

PMID- 15177147
TI  - IL4-589C/T polymorphism and IgE levels in severe malaria.
AB  - Previous studies identified an allelic variant of the IL4 promoter region (IL4
      589T) that appears to enhance the transcriptional activity of IL4, and is
      associated with increased IgE levels. Total serum IgE levels are elevated in
      malaria endemic regions, and higher in children with severe malaria. Here, we
      investigated the relationship of the IL4-589C/T polymorphism with severity of the
      disease in a case-control study of severe malaria in Burkina Faso, West Africa.
      No association between the IL4-589T and severe malaria was observed. No
      difference in Plasmodium falciparum-specific IgE was detected between severe and
      uncomplicated malaria patients. Among children with severe malaria, total IgE
      levels were significantly elevated in those carrying the IL4-589T allele (P =
      0.018). In children with uncomplicated malaria, no significant difference was
      found. These results raise the possibility that there is a relationship between
      susceptibility to severe malaria, IgE production and genetic variation in the IL4
      region, which merits further investigation in other epidemiological settings.

PMID- 15177148
TI  - Symptom overlap for malaria and pneumonia--policy implications for home
      management strategies.
AB  - Malaria and pneumonia are the leading causes of child death in Sub-Saharan Africa
      (SSA). Integrated management of childhood illness (IMCI) at health facilities is
      presumptive: fever for malaria, and cough/difficult breathing with fast breathing
      for pneumonia. Of 3671 Ugandan under-fives at 14 health centres, 30% had symptoms
      compatible both with malaria and pneumonia, necessitating dual treatment. Of 2944
      "malaria" cases, 37% also had "pneumonia". The Global Fund and Roll Back Malaria
      are now supporting home management of malaria strategies across SSA. To
      adequately treat the sick child, these community strategies need to address the
      malaria-pneumonia symptom overlap and manage both conditions.

PMID- 15177149
TI  - Entry lesions in bancroftian filarial lymphoedema patients--a clinical
      observation.
AB  - The prevalence of entry lesions in limbs was significantly higher in limbs with
      filarial lymphoedema (80.88%) than in normal limbs (42.86%, P = 0.000012). Among
      the various entry lesions in the lymphoedematous limbs, the prevalence of web
      space intertrigo was significantly higher in those who had acute
      dermatolymphangioadenitis (ADLA) than those who did not have ADLA (P = 0.04).
      Entry lesions were present only in 25% of those not using footwear, while 84.3%
      of those using footwear regularly or irregularly had these lesions (P = 0.01).
      None of the patients with good limb hygiene had ADLA, while 64% of those with
      fair to poor limb hygiene had ADLA (P = 0.02). Since the majority of the entry
      lesions were asymptomatic, training of patients and health care givers to
      specifically look for and treat these along with advice for good limb hygiene
      practices should form an important component of foot care programme for optimum
      filarial morbidity management.

PMID- 15177150
TI  - A procedure for isolating and freezing metacyclic Trypanosoma brucei gambiense
      forms in the field.
AB  - An adaptation of a modified procedure using anion-exchange centrifugation was
      evaluated to isolate and freeze in field conditions a high number of bloodstream
      forms of Trypanosoma brucei gambiense for direct in vitro culture. Pellets of
      trypanosomes were obtained from 62 patients in Central Africa. The presence of
      trypanosomes was detected in all 62 eluates. The isolation system was efficient.
      Preliminary results of in vitro culture of 10 thawed samples of trypanosomes were
      highly promising because no fungal or bacterial contamination was noticed even
      after 2 weeks of culture.

PMID- 15177151
TI  - Efficacy of measles vaccine interlinked with potency and storage.

PMID- 15177153
TI  - Practical application of aqueous two-phase partition to process development for
      the recovery of biological products.
AB  - The practical application of aqueous two-phase systems (ATPS) to process
      development has been exploited for several years for the recovery of biological
      products. Unfortunately, this has not resulted in an extensive presence of the
      technique in commercial processes. Some of the main identified reasons for such
      situation involve the full understanding of the mechanism governing phase
      formation and the behaviour of solute partitioning in ATPS processes, the cost of
      phase forming polymers and the necessary extended time to understand the
      technique for process development. In this review paper, some of the practical
      disadvantages attributed to ATPS are addressed. The practical approach exploited
      to design ATPS processes, the application to achieve process integration, the
      increasing use for the recovery of high-value products and the recent development
      of alternative low cost ATPS, are discussed. It is proposed that the potential
      trend in the application of ATPS processes for the recovery of biological
      products will involve the recovery of high-value bio-particulate products with
      medical applications. This proposed trend in the application of ATPS will address
      the urgent need to rapidly and economically bring new biopharmaceutical products
      to market using scaleable and efficient bioprocess technology.

PMID- 15177154
TI  - Optimization of bovine serum albumin sorption and recovery by hydrogels.
AB  - Aqueous two-phase systems are composed of aqueous solutions of either two water
      soluble polymers, usually polyethylene glycol (PEG) and dextran (Dx), or a
      polymer and a salt, usually PEG and phosphate or sulfate. Partitioning of
      proteins in such systems provides a powerful method for separating and purifying
      mixtures of biomolecules by extraction. If one of the phase forming polymers is a
      crosslinked gel, then the solution-controlled gel sorption may be considered as a
      modification of aqueous two-phase extraction. Since PEG/dextran systems are
      widely used in aqueous two-phase extraction and dextran gels (Sephadex) are
      common chromatographic media, we choose a PEG/dextran gel system as a model
      system in this study. The partitioning behavior of pure bovine serum albumin
      (BSA) in PEG/dextran gel systems is investigated to see the effects of variations
      in PEG and NaCl concentrations on the partition coefficient K. By making use of
      the Box-Wilson experimental design, K is shown to be maximized at 9.8 (%, w/w)
      PEG and 0.2 M NaCl concentrations, respectively, as 182.

PMID- 15177155
TI  - Aggregation and denaturation of antibodies: a capillary electrophoresis, dynamic
      light scattering, and aqueous two-phase partitioning study.
AB  - Protein denaturation and aggregation are well-known problems in the
      pharmaceutical industry. As the protein aggregates, it loses its biological
      activity and creates problems in its administration to patients. In this paper,
      we explore the use of aqueous two-phase systems, capillary zone electrophoresis,
      and dynamic light scattering for the monitoring of protein denaturation and
      aggregation. Our studies focus on human IgG and HSA. Capillary zone
      electrophoresis was used to monitor changes in the charge to size ratio of the
      proteins upon denaturation and dynamic light scattering was used to detect the
      presence of any aggregates and to monitor the size of the proteins. The
      information obtained from aqueous two-phase partitioning is similar to that
      obtained from capillary zone electrophoresis. The simplicity of aqueous two-phase
      system and its low cost (compared to the other analytical techniques) suggest
      that it can be routinely used for the quality control of some pharmaceutical
      preparations.

PMID- 15177156
TI  - N-terminal tagged lactate dehydrogenase proteins: evaluation of relative
      hydrophobicity by hydrophobic interaction chromatography and aqueous two-phase
      system partition.
AB  - The hydrophobic contributions of 17 individual peptides, fused to the N-terminal
      of Bacillus stearothermophilus lactate dehydrogenase (LDH) were studied by
      hydrophobic interaction chromatography (HIC) and aqueous two-phase system (ATPS).
      The constructs were sequenced from a protein library designed with a five-amino
      acid randomised region in the N-terminal of an LDH protein. The 17 LDH variants
      and an LDH control lacking the randomised region were expressed in Escherichia
      coli. HIC and ATPS behaviour of the proteins indicated significant differences in
      protein hydrophobicity, even though the modifications caused only 1% increase in
      protein molecular weight and 2% variation in isoelectric points. HIC and ATPS
      results correlated well (R(2) = 0.89). Protein expression was clearly affected by
      N-terminal modification, but there was no evidence that the modification affected
      protein activity. A GluAsnAlaAspVal modification resulted in increased protein
      expression. In most cases, HIC and ATPS results compared favourably with those
      predicted on the basis of 34 amino acid residue hydrophobicity scales; assuming
      exposure of tag residues to solution. Exceptions included LeuAlaGlyValIle and
      LeuTyrGlyCysIle modifications, which were predicted, assuming full solution
      exposure, to be more hydrophobic than observed.

PMID- 15177157
TI  - Bioprocess intensification: a potential aqueous two-phase process for the primary
      recovery of B-phycoerythrin from Porphyridium cruentum.
AB  - A process for the primary recovery of B-phycoerythrin from Porphyridium cruentum
      exploiting aqueous two-phase systems (ATPS) was developed in order to reduce the
      number of unit operations and benefit from an increased yield of the protein
      product. The evaluation of system parameters such as poly(ethylene glycol) (PEG)
      molecular mass, concentration of PEG as well as salt, system pH and volume ratio
      was carried out to determine under which conditions the B-phycoerythrin and
      contaminants concentrate to opposite phases. PEG 1450-phosphate ATPS proved to be
      suitable for the recovery of B-phycoerythrin because the target protein
      concentrated to the top phase whilst the protein contaminants and cell debris
      concentrated in the bottom phase. An extraction ATPS stage comprising volume
      ratio (Vr) equal to 1.0, PEG 1450 24.9% (w/w), phosphate 12.6% (w/w) and system
      pH of 8.0 allowed B-phycoerythrin recovery with a purity of 2.9 (estimated as the
      relation of the 545-280 nm absorbances). The use of ATPS resulted in a primary
      recovery process that produced a protein purity of 2.9 +/- 0.2 and an overall
      product yield of 77.0% (w/w). The results reported demonstrated the practical
      implementation of ATPS for the design of a primary recovery process as a first
      step for the commercial purification of B-phycoerythrin produced by P. cruentum.

PMID- 15177158
TI  - Surfactant-aided size exclusion chromatography.
AB  - The flexibility and selectivity of size exclusion chromatography (SEC) for
      protein purification can be modified by adding non-ionic micelle-forming
      surfactants to the mobile phase. The micelles exclude proteins from a liquid
      phase similar to the exclusion effect of the polymer fibers of the size exclusion
      resin. This surfactant-aided size exclusion chromatography technology (SASEC) is
      demonstrated on the separation of two model proteins; bovine serum albumin (BSA)
      and myoglobin (Myo). The effect of the added surfactants on the distribution
      behavior of the proteins is predicted adequately by a size exclusion model
      presented in this paper.

PMID- 15177159
TI  - Optimized extraction by cetyl trimethyl ammonium bromide reversed micelles of
      xylose reductase and xylitol dehydrogenase from Candida guilliermondii
      homogenate.
AB  - The intracellular enzymes xylose reductase (XR, EC 1.1.1.21) and xylitol
      dehydrogenase (XD, EC 1.1.1.9) from Candida guilliermondii, grown in sugar cane
      bagasse hydrolysate, were separated by reversed micelles of cetyl trimethyl
      ammonium bromide (CTAB) cationic surfactant. An experimental design was employed
      to optimize the extraction conditions of both enzymes. Under these conditions
      (temperature = 5 degree C, hexanol: isooctane proportion = 5% (v/v), 22 %,
      surfactant concentration = 0.15M, pH = 7.0 and electrical conductivity = 14 mScm(
      1)) recovery values of about 100 and 80% were achieved for the enzymes XR and XD,
      respectively. The purity of XR and XD increased 5.6- and 1.8-fold, respectively.
      The extraction process caused some structural modifications in the enzymes
      molecules, as evidenced by the alteration of K(M) values determined before and
      after extraction, either in regard to the substrate (up 35% for XR and down 48%
      for XD) or cofactor (down 29% for XR and up 11% for XD). However, the average
      variation of V(max) values for both enzymes was not higher than 7%, indicating
      that the modified affinity of enzymes for their respective substrates and
      cofactors, as consequence of structural modifications suffered by them during the
      extraction, are compensated in some extension. This study demonstrated that
      liquid-liquid extraction by CTAB reversed micelles is an efficient process to
      separate the enzymes XR and XD present in the cell extract, and simultaneously
      increase the enzymatic activity and the purity of both enzymes produced by C.
      guilliermondii.

PMID- 15177160
TI  - Liquid-liquid extraction of xylitol dehydrogenase from Candida guilliermondii
      homogenate by reversed micelles.
AB  - The intracellular enzyme xylitol dehydrogenase (XD, EC 1.1.1.9) from Candida
      guilliermondii, grown in sugarcane bagasse hydrolysate, was separated by reversed
      micelles of BDBAC [N-benzyl-N-dodecyl-N-bis (2-hydroxyethyl) ammonium chloride]
      cationic surfactant. An experimental design was employed to evaluate the
      influence of the following factors on the enzyme separation: temperature, co
      solvent concentration and surfactant concentration. The results showed that just
      the temperature did not show significant effect on XD recovery. A model was used
      to represent the activity recovery and fit the experimental data. Under optimized
      conditions, the recovery of total activity was about 121%, and the purity
      increased 2.3-fold.

PMID- 15177161
TI  - Bromelain partitioning in two-phase aqueous systems containing PEO-PPO-PEO block
      copolymers.
AB  - Bromelain is an enzymatic complex obtained from pineapple (Ananas comosus) fruits
      and stem. Thermoseparation of bromelain by poly(ethylene oxide) (PEO)-
      poly(propylene oxide) (PPO)- poly(ethylene oxide) (PEO) block copolymers aqueous
      solutions was studied. Triblock copolymers with different EO percentages and
      different molecular mass were evaluated. Copolymer solutions at different pH
      values, buffer concentrations and copolymer concentrations were investigated. It
      was found that cloud point temperature increases as a function of %EO and
      decreases with copolymer molecular mass, copolymer concentration and buffer
      concentration. The results showed that all the studied factors influenced enzyme
      partition. The best conditions were copolymer with 10% EO and molecular mass of
      2000 g/mol, temperature of 25 degrees C, copolymer concentration of 5% (w/w), pH
      6.0 and salt concentration of 15 mM. Enzyme activity recovery around 79.5%,
      purification factor around 1.25 and activity partition coefficient around 1.4
      were obtained.

PMID- 15177162
TI  - Purification of hyperthermophilic archaeal amylolytic enzyme (MJA1) using
      thermoseparating aqueous two-phase systems.
AB  - Purification of a recombinant, thermostable alpha-amylase (MJA1) from the
      hyperthermophile, Methanococcus jannaschii, was investigated in the ethylene
      oxide-propylene oxide random copolymer (PEO-PPO)/(NH(4))(2)SO(4), and
      poly(ethylene glycol) (PEG)/(NH(4))(2)SO(4) aqueous two-phase systems. MJA1
      partitioned in the top polymer-rich phase, while the remainder of proteins
      partitioned in the bottom salt-rich phase. It was found that enzyme recovery of
      up to 90% with a purification factor of 3.31 was achieved using a single aqueous
      two-phase extraction step. In addition, the partition behavior of pure
      amyloglucosidase in polymer/salt aqueous two-phase systems was also evaluated.
      All of the studied enzymes partitioned unevenly in these polymer/salt systems.
      This work is the first reported application of thermoseparating polymer aqueous
      two-phase systems for the purification of extremophile enzymes.

PMID- 15177163
TI  - Mass transfer in aqueous two-phases system packed column.
AB  - The behavior of xylanase extraction in a packed column using polyethylene glycol
      (PEG) 4000 and dipotassium phosphate was studied. The possibility of using the
      packed column in continuous operations for enzyme extraction was studied since
      the previous work had only addressed the semi-continuous extraction of enzyme.
      The influence of several kinds of packings, Raschig rings, glass spheres and
      polystyrene rings were studied as well the superficial velocity ratio of the salt
      and the PEG phases. Packed column showed a good efficiency of overall mass
      transfer coefficient, around three times higher than sieve plate column, for
      xylanase extraction. The best selectivity was obtained with the polystyrene ring
      where 94% of xylanase was recovery to the polymeric whereas just 3% of
      contaminant was recovery to this phase. The residence time distribution was
      adjusted by the Model of Reactors in Series.

PMID- 15177164
TI  - Effect of electrostatic energy on partitioning of proteins in aqueous two-phase
      systems.
AB  - An attempt has been made to adopt a different approach to evaluate the effect of
      a protein's charge on its partitioning behaviour in PEG/salt aqueous two-phase
      systems (ATPS). This has been done using a computer methodology (DelPhi) that
      allows the calculation of the electrostatic solvation energy that charged
      proteins present in a particular media such as aqueous polymer-salt systems. This
      calculation was done for the protein in each of the phases and a correlation was
      investigated that related the electrostatic energy difference of the protein in
      each of the phases and its partition coefficient in ATPS. Such correlation
      resulted in a statistical model that also included the effect of molecular weight
      and a shape factor at each particular pH. A global correlation which included the
      effect of pH was also found. All the correlations were statistically evaluated
      and gave good results.

PMID- 15177165
TI  - Inexpensive one-step purification of polypeptides expressed in Escherichia coli
      as fusions with the family 9 carbohydrate-binding module of xylanase 10A from T.
      maritima.
AB  - A novel inexpensive affinity purification technology is described based on
      recombinant expression in Escherichia coli of the polypeptide or protein target
      fused through its N-terminus to TmXyn10ACBM9-2 (CBM9), the C-terminal family 9
      carbohydrate-binding module of xylanase 10A from Thermotoga maritima. Measured
      association constants (K(a)) for adsorption of CBM9 to insoluble allomorphs of
      cellulose are between 2 x 10(5) and 8 x 10(6) M(-1). CBM9 also binds a range of
      soluble sugars, including glucose. As a result, a 1M glucose solution is
      effective in eluting CBM9 and CBM9-tagged fusion proteins from a very inexpensive
      commercially-available cellulose-based capture column. A processing site is
      encoded at the C-terminus of the tag to facilitate its rapid and quantitative
      removal by Factor X(a) to recover the desired target protein sequence following
      affinity purification. Fusion of the CBM9 affinity tag to the N-terminus of green
      fluorescent protein (GFP) from the jellyfish, Aquorin victoria, is shown to yield
      >200 mgl(-1) of expressed soluble fusion protein that can be affinity separated
      from clarified cell lysate to a purity of >95% at a yield of 86%.

PMID- 15177166
TI  - Decontamination of surfaces by lysozyme encapsulated in reverse micelles.
AB  - Cells and enzymes can be used to decontaminate soil, water supplies, personal
      equipment, weapons and hospital equipment that have been exposed to bacteria,
      toxins or viruses. One of the problems associated with the use of microorganisms
      and enzymes for decontamination purposes is that the presence of water is not
      acceptable for some applications such as electronic equipment. One way of
      circumventing this problem is to allow the enzyme to distribute between a water
      phase and an organic phase-containing surfactant and then use the encapsulated
      enzyme in reverse micelles directly into the device to be clean. Reverse micelles
      were used to deliver the enzyme (lysozyme) to the cell-surface interface. They
      serve as a way to increase the local concentration of lysozyme and decrease the
      amount of water delivered. Specifically, we explored the lysis by free lysozyme
      and lysozyme encapsulated in reverse micelles of Klebsiella pneumoniae and
      Staphylococcus epidermidis attached to steel, glass, and hydroxyapatite. These
      two bacteria have been selected because they are known to be pathogenic and
      because of their differences in cell wall structure. Lysozyme was added to the
      surfaces in either reverse micelles or as a free solution and was tested under
      conditions of stirring and no stirring. Stirring was implemented to study the
      interplay between mass transfer limitations and surface roughness. We have shown
      that free lysozyme or lysozyme encapsulated in reverse micelles is capable of
      decontaminating surfaces of different texture. Lysis of the cells is slower when
      the encapsulated enzyme is used but lysis is more complete.

PMID- 15177167
TI  - Recovery in aqueous two-phase systems of lutein produced by the green microalga
      Chlorella protothecoides.
AB  - In this study the potential use of aqueous two-phase system (ATPS) to establish a
      viable process for the recovery of lutein from the green microalga Chlorella
      protothecoides is evaluated. The partitioning behaviour of lutein, a
      representative model of natural compounds of commercial interest, was
      investigated in a polyethylene glycol (PEG)-phosphate system. An evaluation of
      system parameters including PEG molecular mass, the concentrations of PEG,
      phosphate and product concentration was conducted, to estimate conditions under
      which lutein partitions preferentially to the top phase whilst cell debris
      partition to the opposite phase. The necessary addition of ethanol to the ATPS
      for the dissolution of lutein affected the phase formation and such effect was
      evaluated using the change in the volume ratio produced. ATPS extraction
      comprising Vr = 1.0, PEG 8000 22.9% (w/w) and phosphate 10.3% (w/w), pH 7.0
      provided the conditions for the concentration of lutein into the upper phase and
      the cell debris preferentially to the bottom phase. The use of ATPS resulted in a
      primary recovery process to obtain lutein with an overall product yield of 81.0
      +/- 2.8%. The findings reported here demonstrate the potential of ATPS for the
      further development of a prototype process to recover lutein from C.
      protothecoides as a first step for the generic application of this technique.

PMID- 15177168
TI  - Quantification of solid cell material by detection of membrane-associated
      proteins and peptidoglycan.
AB  - Quantification of solid cell material (cell debris) is necessary for the
      optimisation of the efficiency of bioseparations. Cell debris can be quantified
      by detection of a component present in the cell wall that can act as a marker for
      cell debris. Membrane-associated proteins have previously been used as a marker
      for cell debris. This marker was quantified by SDS-PAGE with densiometry. In this
      paper cell debris quantification methods are presented that are faster and more
      accurate, i.e. membrane-associated protein quantification with the Protein 50
      Labchip of Agilent Technologies, or that make use of peptidoglycan as marker for
      cell debris, i.e. a spectrophotometric muramic acid assay.

PMID- 15177169
TI  - Polyelectrolyte complexes as a tool for purification of plasmid DNA. Background
      and development.
AB  - The demand for highly purified plasmids in gene therapy and plasmid-based
      vaccines requires large-scale production of pharmaceutical-grade plasmid. Plasmid
      DNA was selectively precipitated from a clarified alkaline lysate using the
      polycation poly(N,N'-dimethyldiallylammonium) chloride which formed insoluble
      polyelectrolyte complex (PEC) with the plasmid DNA. Soluble PECs of DNA with
      polycations have earlier been used for cell transformation, but now the focus has
      been on insoluble PECs. Both DNA and RNA form stable PECs with synthetic
      polycations. However, it was possible to find a range of salt concentration where
      plasmid DNA was quantitatively precipitated whereas RNA remained in solution. The
      precipitated plasmid DNA was resolubilised at high salt concentration and the
      polycation was removed by gel-filtration.

PMID- 15177170
TI  - Characterization of supermacroporous monolithic polyacrylamide based matrices
      designed for chromatography of bioparticles.
AB  - Supermacroporous monolithic acrylamide (AAm)-based cryogels were prepared by
      radical cryo-polymerizaton (polymerization in the moderately frozen system) of
      AAm with functional monomers and cross-linker N,N'-methylene-bis-acrylamide
      (MBAAm). Electron microscopy studies revealed supermacroporous structure of the
      developed cryogels with pore size of 5-100 microm. Cryogel porosity depended on
      cryo-polymerization conditions. More than 90% of the monolithic bed volume is the
      interconnected supermacropores filled with water and less than 10% of the
      monolithic volume is pore walls. The total protein binding capacity (lysozyme in
      the case of immobilized metal affinity chromatography (IMAC) column and bovine
      serum albumin (BSA) in the case of anion-exchange (AE) column) was independent of
      the flow rates till 600 cm/h. Chromatographic behavior of E. coli cells when a
      cell suspension was applied to ion-exchange cryogel columns depended on both the
      density of functional ligand and the porosity of the cryogel.

PMID- 15177171
TI  - ATPS applied to extraction of small molecules - polycetides - and simultaneous
      clarification of culture media with filamentous microorganisms.
AB  - Aqueous two-phase systems (ATPS) were applied for extraction of small molecules
      (polycetides) - retamycin, an anthracyclin, and two red pigments, rubropunctamin
      and monascorubramin - from the whole culture media of Streptomyces olindensis and
      Monascus purpureus. ATPS allows, in one step, the separation of the small
      hydrophobic molecules in the PEG rich phase, from the filamentous microorganisms,
      which remains in the salt phase. Through experimental designs, the main variables
      and their levels were defined, as follows: for retamycin extraction, PEG 6000
      (10%, w/w), phosphate at 20% (w/w) and pH 6.0 led to the higher partition
      coefficient, K(r) = 8.2, and yield = 91.3%; for red pigments, the statistical
      analysis indicate PEG 6000 (20%, w/w) and phosphate at 15% (w/w), for a high
      partition coefficient, (K(pig) = 113 and 150).

PMID- 15177172
TI  - Application of polyethylene glycol-based aqueous biphasic reactive extraction to
      the catalytic oxidation of cyclic olefins.
AB  - Glutaric acid and 1,2,3,4-butanetetracarboxylic acid (BTCA) have been synthesized
      by sodium tungstate catalyzed oxidation of the cyclic olefins: cyclopentene and
      1,2,3,6-tetrahydrophthalic anhydride (THPA), using hydrogen peroxide in a
      polyethylene glycol (PEG)-2000/NaHSO(4) aqueous biphasic system (PEG-ABS). The
      production of glutaric acid and BTCA was found to increase from the monophasic to
      the biphasic regimes, and was found to be greatest at short tie-line lengths
      (TLLs), close to the system's critical point, yielding glutaric acid and BTCA in
      73.1 and 82.5% yield, respectively. The results imply that mutual mixing or
      contact of the components is important, because the product dicarboxylic acids
      were found to increase from the monophasic side to the critical point and
      decrease from the critical point to more divergent regimes. The two reactions
      were compared with adipic acid synthesis from cyclohexene in terms of the cyclic
      olefin structure, and the partitioning of the dicarboxylic acid product in the
      ABS.

PMID- 15177173
TI  - Effects of speciation on partitioning of iodine in aqueous biphasic systems and
      onto ABEC resins.
AB  - Polyethylene glycol (PEG)-aqueous biphasic systems (ABS) and PEG-grafted aqueous
      biphasic extraction chromatographic (ABEC) resins have been shown to remove
      inorganic species from environmental and nuclear wastes. The partitioning
      behavior of several iodide species (iodide, iodine, triiodide, iodate, and 4-iodo
      2,6-dimethylphenol (I-DMP)) have been studied for PEG (MW 2000)-salt systems and
      ABEC resins. Iodide partitioning to PEG-rich phases or onto ABEC resins can be
      enhanced by derivatization with 2,6-dimethylphenol to form 4-iodo-2,6
      dimethylphenol or by addition of I(2) to form triiodide. Conversely, iodide
      partitioning to the PEG-rich phase or onto ABEC resins is reduced by oxidation of
      iodide to IO(3)(-). Partitioning studies of iodide, iodate, and iodine in a PEG
      ABS are compared to results using ABEC resins.

PMID- 15177174
TI  - Evaluation of viscosities of aqueous two-phase systems containing protein.
AB  - The dynamic viscosities of aqueous polyethylene glycol, aqueous bovine serum
      albumin, and polyethylene glycol-bovine serum albumin-water solutions were
      measured at temperatures of 15, 20, 25, 30 and 35 degree C. To estimate the
      viscosity values of polyethylene glycol-bovine serum albumin-water solutions, a
      one parameter Grunberg-like model which was satisfactorily used earlier by the
      present author for polyethylene glycol-dextran-water solutions was employed. The
      disposable parameter a for our temperature range was estimated as 3.71. The
      relative errors varying from 0.29 to 18.98 in absolute value indicates that the
      Grunberg-like model works perfectly for polymer-protein solutions as well.

PMID- 15177175
TI  - Separation and purification of methoxypoly(ethylene glycol) grafted red blood
      cells via two-phase partitioning.
AB  - Alloimmunization to donor blood group antigens remains a significant problem in
      transfusion medicine. To attenuate the risk of alloimmunization, we have
      pioneered the membrane grafting of methoxypoly(ethylene glycol) (mPEG) to produce
      immunocamouflaged red blood cells (RBC). Grafting of the mPEG was accomplished
      using cyanuric chloride activated mPEG (CmPEG; M(r) = 5000), benzotriazole
      carbonate methoxyPEG (BTCmPEG; M(r) = 2000, 5000 or 20000); or N
      hydroxysuccinimidyl ester of mPEG propionic acid (SPAmPEG; M(r) = 5000, or
      20000). Because of the heterogeneity of grafting, a crucial tool in developing
      the stealth RBC is an ability to purify the modified RBC from unmodified
      (immunogenic) donor cells. As demonstrated, a (5, 4) dextran:PEG aqueous two
      phase polymer partitioning system cleanly separated the immunologically silent
      mPEG-grafted human RBC from control or lightly modified cells. Cell mixing
      experiments employing varying ratios of mPEG-modified and control RBC confirmed
      the purification efficacy of the phase partitioning system. Proportional changes
      in PEG-rich phase partitioning were achieved by increasing either the quantity of
      surface mPEG or the mPEG molecular weight. The biological viability of purified
      mPEG-RBC (BTCmPEG; [M(r) = 20000) was demonstrated by their normal in vivo
      survival at immunoprotective grafting concentrations (<or=2 mmol/L). The
      effective immunocamouflaging of RBC antigens coupled with efficient purification
      of the immunocamouflaged population provides encouragement for the further
      development of the stealth erythrocyte.

PMID- 15177177
TI  - DNA polymerase-eta as a reverse transcriptase: implications for mechanisms of
      hypermutation in innate anti-retroviral defences and antibody SHM systems.

PMID- 15177178
TI  - Immunoglobulin diversification in DT40: a model for vertebrate DNA damage
      tolerance.
AB  - Studies of recombination in vertebrates have rather lagged behind those in yeast
      and bacteria in large part due to the relative genetic intractability of
      vertebrate model systems. Immunoglobulin diversification in the chicken cell line
      DT40 provides a powerful combination of a physiological recombination process
      coupled with facile genetic modification. The immunoglobulin variable regions of
      DT40 constitutively diversify by a combination of gene conversion, in which
      sequence changes are templated from one of a number of upstream pseudogenes or by
      non-templated point mutation. Both of these events are initiated by abasic sites
      in the variable region DNA generated following the targeted deamination of
      cytidine by activation induced deaminase. Recent work has shown that the two
      outcomes, gene conversion and somatic mutation, are likely to reflect alternate
      pathways for the processing of these abasic sites. In this review I will discuss
      the current data on avian Ig gene diversification and examine how the
      immunoglobulin loci of DT40 may provide a useful model system for studying the
      mechanisms and interactions of vertebrate recombination and pathways of DNA
      damage tolerance.

PMID- 15177179
TI  - Aphidicolin-resistant and -sensitive base excision repair in wild-type and DNA
      polymerase beta-defective mouse cells.
AB  - Several DNA polymerases (Pols) can add complementary bases at the gap created
      during the base excision repair (BER). To characterize the BER resynthesis step,
      the repair of a single abasic site by wild-type and Pol beta-defective mouse cell
      extracts was analysed in the presence of aphidicolin, a specific inhibitor of
      replicative Pols. We show that there is a competition between distributive and
      processive Pols for the nucleotide addition at the primer terminus. In wild-type
      cell extracts, the initial nucleotide insertion involves mainly Pol beta but the
      elongation step is carried out by a replicative Pol. Conversely, in Pol beta-null
      cell extracts the synthesis step is carried out by a replicative Pol without any
      switching to an auxiliary polymerase. We present evidence that short-patch repair
      synthesis occurs even in the absence of both Pol beta and replicative Pols.
      Exogeneously added purified human Pol lambda was unable to stimulate this back-up
      synthesis.

PMID- 15177180
TI  - Quiescent murine cells lack global genomic repair but are proficient in
      transcription-coupled repair.
AB  - The majority of the cells in the body, including stem cells, exist in a quiescent
      state, so it is in quiescent cells where most DNA damage occurs. It has been
      uncertain whether or not this damage is repaired or fixed into mutations during
      quiescence or if proliferation is required for both. Prior to the development of
      transgenic mice, it was difficult to distinguish between these two possibilities,
      as cells had to proliferate to form colonies before mutations could be detected.
      Transgenes, however, can be shuttled out of quiescent mouse cells directly, and
      the level of DNA damage and mutation can be measured. Such measurements show that
      both mutation and repair are absent at a non-transcribed transgene in quiescent
      cells, although both are initiated when these cells are induced to proliferate.
      Conversely, the repair of transcriptionally active genes proceeds independently
      of proliferation in the same cells, as shown by the differential survival of wild
      type and XPA-/- cells. We infer from these results that global genomic DNA repair
      (GGR) is not active during cellular quiescence but that transcription-coupled
      repair (TCR) is, suggesting that GGR is restricted to S, whereas TCR remains
      active throughout the cell cycle.

PMID- 15177181
TI  - Spontaneous and cisplatin-induced recombination in Escherichia coli.
AB  - To measure cisplatin (cis-diaminodichloroplatinum(II))-induced recombination, we
      have used a qualitative intrachromosomal assay utilizing duplicate inactive lac
      operons containing non-overlapping deletions and selection for Lac+ recombinants.
      The two operons are separated by one Mb and conversion of one of them yields the
      Lac+ phenotype. Lac+ formation for both spontaneous and cisplatin-induced
      recombination requires the products of the recA, recBC, ruvA, ruvB, ruvC, priA
      and polA genes. Inactivation of the recF, recO, recR and recJ genes decreased
      cisplatin-induced, but not spontaneous, recombination. The dependence on PriA and
      RecBC suggests that recombination is induced following stalling or collapse of
      replication forks at DNA lesions to form double strand breaks. The lack of
      recombination induction by trans-DDP suggests that the recombinogenic lesions for
      cisplatin are purine-purine intrastrand crosslinks.

PMID- 15177182
TI  - Mutations in the nucleotide-binding domain of MutS homologs uncouple cell death
      from cell survival.
AB  - After genotoxic insult, the decision to repair or undergo cell death is pivotal
      for undamaged cell survival, and requires a highly controlled coordination of
      both pathways. Disruption of this regulation results in tumorigenesis and failure
      of cancer therapy. Mismatch repair (MMR) proteins have a unique role by
      contributing to both pathways, though direct evidence for their function in the
      DNA damage response is ambiguous. We report separation of function mutants in the
      ATPase domains of yeast MutS homologous (MSH) proteins that uncouple MMR
      dependent DNA repair from damage response to cisplatin. While mutations in the
      ATPase domain have devastating effects on the mutation rate of the cell, ATPase
      processing is mostly dispensable for the cell death phenotype; only limited
      processing by the MSH6 subunit is required in DNA damage response. Different DNA
      binding patterns and nucleotide sensitivity of Msh2/Msh6-DNA adduct and protein
      mismatch complexes, respectively, suggest that the presence of different DNA
      lesions influences the requirement for ATP. Limited proteolysis of purified
      protein gives first indications for differences in nucleotide-induced
      conformational changes in the presence of platinated DNA. Structural modeling of
      bacterial MutS proteins reinforces nucleotide-dependent differences in structures
      that contribute to the distinction between DNA damage response and repair. Our
      results demonstrate the uncoupling of MMR-dependent damage response from repair
      and present first indications for the involvement of distinct conformational
      changes in MSH proteins in this process. These data present evidence for a
      mechanism of MMR-dependent damage response that differs from MMR; these results
      have strong implications for the chemotherapeutic treatment of MMR-defective
      tumors.

PMID- 15177183
TI  - Immortalized mouse cell lines that lack a functional Rev3 gene are hypersensitive
      to UV irradiation and cisplatin treatment.
AB  - The catalytic subunit of polymerase zeta is encoded from the Rev3 gene. The
      enzyme is conserved through eukaryotic evolution and its main function appears to
      be translesion synthesis (TLS) over damaged bases that stall DNA replication. In
      non-vertebrate cells, inactivation of polymerase zeta results in a moderate
      hypersensitivity to DNA damage but no proliferative defect in the absence of
      exogenous damage. Mouse embryos that lack Rev3 however have a severe growth
      defect and are aborted at midgestation. This has suggested that polymerase zeta
      may be involved in vital processes in mammalian cells. Here we describe the
      establishment of immortalized mouse fibroblast cell lines that lack a functional
      Rev3 gene. These were established from homozygously Rev3-targeted mouse embryos
      that were also heterozygously targeted at the p53 locus, but the cell lines lost
      the wild type p53 allele during transformation. Cell lines in which the Rev3 gene
      is targeted on both alleles grow more slowly than control lines and the
      deficiency is also associated with an increased frequency of cells at the G2/M
      phase of the cell cycle and augmented apoptosis. Targeted cells are
      hypersensitive to UV irradiation and cisplatin treatment and arrest at the S or
      G2/M phase of the cell cycle if exposed to these treatments. Thus, although vital
      for murine embryonic development, polymerase zeta activity is not essential for
      continuous proliferation of transformed mammalian cells that lack p53. It does,
      however, appear to play an important role in allowing mammalian cells to tolerate
      DNA damage.

PMID- 15177184
TI  - Biochemical characterization of the ataxia-telangiectasia mutated (ATM) protein
      from human cells.
AB  - Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that
      plays a central role in controlling the cellular response to ionizing radiation
      and other DNA-damaging agents. ATM is a 3056 amino acid polypeptide that is
      present in low abundance in the nucleus of human cells. Here, we describe the
      purification and characterization of ATM from the nuclear fraction of HeLa cells.
      Microgram quantities of highly stable, kinase-active ATM were prepared. Purified
      ATM was phosphorylated on serine 1981 and was active towards a variety of known
      ATM substrates, including p53 and the Bloom Syndrome helicase, BLM. The protein
      kinase activity of ATM was selectively inhibited by wortmannin, caffeine and
      LY294002 and was stimulated by charged biological polymers, including single
      stranded M13 DNA (ssDNA), sheared double-stranded calf thymus DNA, heparin
      sulfate and poly ADP-ribose (PAR), raising the possibility that charged
      structures may contribute to regulation of ATM activity. However, chemical
      inhibition of the formation of poly ADP-ribose in cells had no effect on the
      activation of ATM-dependent pathways by ionizing radiation. Using gel filtration
      chromatography, we also show that purified ATM, as well as ATM in crude nuclear
      extracts from unirradiated and irradiated cells elutes with an estimated native
      molecular weight of approximately 600 kDa. Moreover, dephosphorylation of serine
      1981 did not affect the apparent molecular weight of ATM in irradiated extracts.
      Our results suggest that phosphorylation of serine 1981 alone may not directly
      regulate the subunit composition of ATM.

PMID- 15177185
TI  - The Hog1 MAP kinase pathway and the Mec1 DNA damage checkpoint pathway
      independently control the cellular responses to hydrogen peroxide.
AB  - The DNA damage checkpoint pathway and the MAP kinase pathway respond to various
      forms of environmental as well as endogenous stresses through signal transduction
      mechanisms involving protein kinases. Both pathways are intertwined in mammalian
      cells, but potential crosstalk between these two pathways in budding yeast has
      not been examined yet. We show that the Rad53 checkpoint kinase and the Hog1 MAP
      kinase of Saccharomyces cerevisiae become phosphorylated upon exposure to
      hydrogen peroxide, indicative of activation of the DNA damage checkpoint and MAP
      kinase pathways in response to oxidative stress. Rad53 kinase is equally
      activated in wild type and in hog1-Delta cells. Likewise, the activation of Hog1
      MAP kinase is not dependent on Mec1 kinase, the central checkpoint kinase in
      budding yeast. Mutants in either pathway are sensitive to hydrogen peroxide and
      the double mutants exhibit a near perfectly additive phenotype. These data
      demonstrate that the DNA damage checkpoint pathway and the MAP kinase pathway
      respond to oxidative stress independently of each other and suggest that these
      two stress signaling pathways are activated by different types of insults induced
      by hydrogen peroxide.

PMID- 15177186
TI  - PAF, ceramide and pulmonary edema: alveolar flooding and a flood of questions.

PMID- 15177187
TI  - A role for ezrin in a neglected metastatic tumor function.

PMID- 15177188
TI  - Danger signals: a time and space continuum.

PMID- 15177189
TI  - Homing alone? CD18 in infectious and allergic disease.

PMID- 15177190
TI  - RNA repair using spliceosome-mediated RNA trans-splicing.

PMID- 15177191
TI  - Methods for targeting biologicals to specific disease sites.
AB  - Cytokines are mediators of cell communication. Their therapeutic use requires
      frequent high doses to achieve effective local biological levels. However, the
      clinical use of some cytokines is limited because of their pleiotropism, which
      can result in unwanted side effects. Here, we review novel protein engineering
      technologies that overcome these limitations and enable the targeting of
      cytokines to specific sites. One such technology uses antibody-based recognition
      to direct the cytokine to a particular tissue, and another creates encapsulated
      latent cytokines that are released only at the site of disease. The latter method
      requires the overexpression of matrix-metalloproteinases, thereby exploiting the
      severity of the pathological process to regulate drug delivery. Because these
      technologies are based on the expression of fusion proteins, their application
      can be extended to other biologicals and can be delivered by gene therapy.

PMID- 15177192
TI  - VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS?
AB  - Since Charcot recognized the devastating disorder amyotrophic lateral sclerosis
      (ALS) in 1874, many theories have been proposed to explain its pathogenesis, but
      it remains as deadly and incurable as ever. Three years ago it was reported that
      reduced levels of vascular endothelial growth factor (VEGF) caused ALS-like
      motoneuron degeneration in mice. Recent evidence indicates that insufficient VEGF
      is also a risk factor for ALS in humans. Although VEGF was once considered to be
      only a specific angiogenic factor, emerging evidence indicates that it also
      displays important neuroprotective activity. These insights have primed
      widespread interest in developing VEGF-based therapies for (moto)neuron
      degenerative disorders, raising new hope for the treatment of ALS and other
      neurodegenerative diseases.

PMID- 15177193
TI  - Therapeutic and diagnostic implications of Hsp90 activation.
AB  - The molecular chaperone heat-shock protein 90 (Hsp90) is involved in the
      stabilization and conformational maturation of many signaling proteins that are
      deregulated in cancers. Hsp90 inhibition results in the proteasomal degradation
      of these client proteins and leads to potent antitumor activity. The Hsp90
      inhibitor 17-allylaminogeldanamycin (17-AAG) is presently in clinical trials.
      Recent work has identified the role of Hsp90 in multiple signal transduction
      pathways and revealed that the molecular mechanism of tumor selectivity by Hsp90
      inhibitors is the result of an activated, high-affinity conformation of Hsp90 in
      tumors. This review discusses these recent advances in the understanding of tumor
      Hsp90 for the treatment and diagnosis of cancer. In addition, the role of Hsp90
      in non-oncological diseases will also be discussed.

PMID- 15177194
TI  - The viral infectivity factor (Vif) of HIV-1 unveiled.
AB  - The viral infectivity factor (Vif) of HIV type-1 (HIV-1) is essential for
      efficient viral replication, yet was, until recently, enigmatic. This resulted
      from the complexity and cellular specificity of its function and the
      correspondingly complex systems that are required for its investigation. These
      limitations have been overcome and Vif function has been rapidly elucidated, with
      implications for the development of drugs to block its activity. These studies
      have revealed a novel component of the innate immune system, APOBEC3G, that
      lethally hypermutates retroviruses, including HIV-1. For HIV-1, the competition
      between the virus and APOBEC3G is tipped in favor of the invader by Vif, which
      binds to APOBEC3G and triggers its polyubiquitination and rapid degradation,
      thereby preventing its entry into progeny virions.

PMID- 15177195
TI  - A Deweyan case for the study of uncertainty in health geography.
AB  - John Dewey long ago challenged the philosophical tradition by arguing that
      uncertainty is a central, but undertheorized, trait of existence. His challenge
      to philosophy is also a challenge to the social sciences, including those that
      focus on health. In this paper, I set out to accomplish two goals. One is to
      present Dewey's view on uncertainty and thereby develop an argument for an
      underappreciated theoretical construct. The second is to explore the congruence
      of uncertainty and health geography with a focus on uncertainty's meaning and
      validity for inquiry in a health geography context. I begin with an explication
      of Dewey's position on uncertainty and assess it within a larger philosophical
      milieu. I then discuss various implications of this view for health geography and
      argue that the Deweyan case for uncertainty fits the discipline well. In the
      final part of the paper, I share an analysis of assisted living for older persons
      that displays different forms of uncertainty playing important roles in the
      health and place experience. I conclude that Dewey's philosophical position on
      uncertainty is a potentially important avenue for further inquiry into health and
      place.

PMID- 15177196
TI  - Medical practice variations in hospital care; time trends of a spatial
      phenomenon.
AB  - A persistent finding in health services research is that health care delivery and
      hospital utilisation in the Western world varies widely between areas, both
      within and between countries. Most studies have concentrated on cross-sectional
      variations in medical practice. The aim of this article is to investigate whether
      or not small area variation changed through time. We used hospital discharge
      rates in the Netherlands for 12 diagnostic or surgical categories to indicate
      medical practice patterns. The data cover a time span of almost two decades: 1980
      1997. First, it was found that in most cases regions are consistently above or
      below the national trend in the study period. Second, the analysis revealed a
      statistically significant decline of regional variation in hospital discharges in
      general during the 1980s and the 1990s. In all but one medical category the
      results of the separate analyses point towards a downward trend. In one-third of
      the medical categories this downward trend was statistically significant.
      Potential parallel changes in regional disparities in need for care, e.g.
      morbidity or age composition of regional populations or changes in regional
      differences in care supply are discussed.

PMID- 15177197
TI  - Obesity rates, income, and suburban sprawl: an analysis of US states.
AB  - In a decade of economic growth and rising income, obesity has risen dramatically.
      This is puzzling when researchers have found that there is an inverse relation
      between income and obesity. This paper argues that new location patterns produced
      by suburban sprawl are an important cause of rising obesity rates. New location
      patterns are such that work, school and social activities are not as easily
      accessible by foot. Changes in sprawl then drive changes in the causes of obesity
      identified by medical researchers (e.g., low activity levels). We define sprawl
      as increases in the amount of developed land, holding population constant.
      Determinants and outcomes are analyzed on a population basis. We use state-level
      data from the 1990s on obesity to show that states that increased the amount of
      developed land (holding population constant) showed larger increases in obesity.
      As a result, town planning efforts to reduce sprawl may be justified not only on
      aesthetic grounds but also based on efforts to reduce the costs associated with
      treating medical conditions related to obesity.

PMID- 15177199
TI  - Mapping the determinants of health inequalities in social space: can Bourdieu
      help us?
AB  - Considerable research effort has been devoted to describing and explaining, at a
      variety of spatial scales, geographical inequalities in health outcomes within
      the developed world. Following Bourdieu, we argue that structures of the social
      world may be revealed in different kinds of 'social' space. We outline the
      relational thinking that underlies these ideas. We then 'map', using
      correspondence analysis (on which Bourdieu himself drew), the structure of social
      space according to the differential availability of some forms of capital, across
      four study areas in north-west England. We use logistic regression analysis to
      explain variation in psychological morbidity (GHQ-score) and then portray the
      significant predictors of morbidity using multiple correspondence analysis. The
      area of residence of the survey respondents is used to associate them with
      particular locations in these social spaces.

PMID- 15177198
TI  - Physician supply, physician diversity, and outcomes of primary health care for
      older persons in the United States.
AB  - This study examines effects of physician supply and diversity on hospitalization
      for ambulatory care sensitive conditions (ACSH). Data are from 31 metropolitan
      areas in the 1984-1990 United States Longitudinal Study of Aging, and the Area
      Resource File. Discrete-time hazard models estimate ACSH risk. High ACSH risk may
      indicate problems with the accessibility or quality of primary care. Results show
      low supply areas have high risk. Adequate supply areas have significantly lower
      risk. Areas with greater supply have high risk, which may indicate supplier
      induced hospitalization. Greater physician diversity reduces ACSH risk. Results
      support policies promoting physician placement in underserved areas, and those
      that educate minority physicians.

PMID- 15177200
TI  - Place, discourse and vulnerability--a qualitative study of young adults living in
      a Swedish urban poverty zone.
AB  - This paper presents findings from a qualitative study of young adults living in a
      relatively deprived metropolitan area in Sweden. The analysis of interview data
      yielded four separate types of neighbourhood discourses, each related to a major
      hegemonic 'discourse of the problematic area'. The discursive model was used to
      disclose different patterns of vulnerability, at both the individual and the
      community level. The discourses are suggested to function as mechanisms through
      which the spatial context, defined in structural and relational terms, could be
      linked to health and well-being.

PMID- 15177201
TI  - Physician accessibility: an urban case study of pediatric providers.
AB  - Social disparity in the spatial distribution of healthcare providers in urban
      areas is a recognized problem. However, efforts to quantify the problem have been
      hampered by a lack of satisfactory measurements and methods. We revive and
      enhance a strategy based on provider density, proposed nearly three decades ago.
      The method avoids the border-crossing problem associated with provider-population
      ratios, yet reports spatial accessibility in intuitive units that are easily
      compared across diverse populations and geographies. We find racial and
      socioeconomic disparities in our case city, Washington, DC, despite a citywide
      overabundance of primary care providers for children.

PMID- 15177202
TI  - Exploring the interface between complementary and alternative medicine (CAM) and
      rural general practice: a call for research.

PMID- 15177203
TI  - Drug delivery systems for vitreoretinal diseases.
AB  - The eye has an environment that is specific unto itself in terms of
      pharmacokinetics: the inner and outer blood-retinal barriers separate the retina
      and the vitreous from the systemic circulation and vitreous body, which
      physiologically has no cellular components, occupies the vitreous cavity, an
      inner space of the eye, and reduces practical convection of molecules.
      Considering this, development of a drug delivery system (DDS) is becoming
      increasingly important in the treatment of vitreoretinal diseases not only to
      facilitate drug efficacy but also to attenuate adverse effects. The DDS has three
      major goals: enhances drug permeation (e.g., iontophoresis and transscleral DDS),
      controls release of drugs (e.g., microspheres, liposomes, and intraocular
      implants), and targets drugs (e.g., prodrugs with high molecular weight and
      immunoconjugates). Comprehensive knowledge of these should lead to development of
      innovative treatment modalities.

PMID- 15177204
TI  - Relationship between posterior capsule opacification and intraocular lens
      biocompatibility.
AB  - The type of healing process that occurs in response to cataract surgery and
      intraocular lens (IOL) implantation is dependent on a complex set of variables.
      Their interactions determine whether or not optical clarity is restored as a
      result of this procedure. In this process, wound healing entails cells undergoing
      either epithelial-mesenchymal transition, resulting in the generation of
      fibroblastic cells and accumulation of extracellular matrix, or lenticular
      structure formation. Such desperate cellular behaviors are regulated by the
      localized release of different cytokines, including transforming growth factor
      beta and fibroblast growth factors, which can result in post-operative capsular
      opacification. Other factors affecting the biological and mechanical outcome of
      IOL implantation are its composition, surface properties and shape.

PMID- 15177205
TI  - Dark adaptation and the retinoid cycle of vision.
AB  - Following exposure of our eye to very intense illumination, we experience a
      greatly elevated visual threshold, that takes tens of minutes to return
      completely to normal. The slowness of this phenomenon of "dark adaptation" has
      been studied for many decades, yet is still not fully understood. Here we review
      the biochemical and physical processes involved in eliminating the products of
      light absorption from the photoreceptor outer segment, in recycling the released
      retinoid to its original isomeric form as 11-cis retinal, and in regenerating the
      visual pigment rhodopsin. Then we analyse the time-course of three aspects of
      human dark adaptation: the recovery of psychophysical threshold, the recovery of
      rod photoreceptor circulating current, and the regeneration of rhodopsin. We
      begin with normal human subjects, and then analyse the recovery in several
      retinal disorders, including Oguchi disease, vitamin A deficiency, fundus
      albipunctatus, Bothnia dystrophy and Stargardt disease. We review a large body of
      evidence showing that the time-course of human dark adaptation and pigment
      regeneration is determined by the local concentration of 11-cis retinal, and that
      after a large bleach the recovery is limited by the rate at which 11-cis retinal
      is delivered to opsin in the bleached rod outer segments. We present a
      mathematical model that successfully describes a wide range of results in human
      and other mammals. The theoretical analysis provides a simple means of estimating
      the relative concentration of free 11-cis retinal in the retina/RPE, in disorders
      exhibiting slowed dark adaptation, from analysis of psychophysical measurements
      of threshold recovery or from analysis of pigment regeneration kinetics.

PMID- 15177206
TI  - [Is endoscopy useful in infertility treatment?].

PMID- 15177207
TI  - [Effects of HRT on the risks of breast cancer and cardiovascular disease: the
      validity of the epidemiological evidence].
AB  - Publication of the findings of the Women's Health Initiative, in July 2002, the
      second link of the triptych made up of the Collaborative Reanalysis, in 1997, and
      the Women Million Study, in 2003, shortly after the WHI, seems to have tolled the
      knell of HRT, by claiming that women using HRT and combined therapy, have an
      increased risk of breast cancer and cardiovascular disease. As a result, the risk
      benefit ratio would be reversed to the detriment of HRT. Over and above the
      legitimate questioning on the validity of these studies, such as calling into
      question their indisputable biases, especially the detection bias and hereby
      analysed in its spoiling the three randomised essays-there is the crucial
      question: can epidemiology make any headway in elucidating the hormonal aetiology
      of breast cancer? Indeed, given the low relative risks that have been observed,
      on the one hand, coupled with a whole set of methodological limitations, it is
      impossible to distinguish between bias and causation as alternative explanations
      for the observed associations. Above all, what emerges from this investigation is
      that, as far as HRT effects especially on breast cancer are concerned,
      epidemiological evidence only is inadequate, and collaborative research between
      histopathology and epidemiology is necessary.

PMID- 15177208
TI  - [Secondary debulking surgery and intraperitoneal chemotherapy in advanced or
      recurrent epithelial ovarian cancer].
AB  - OBJECTIVE: The aim of this study was to evaluate the indications and the results
      of secondary cytoreduction surgery with intraperitoneal (i.p.) paclitaxel
      chemotherapy in advanced or recurrent epithelial ovarian cancer. PATIENTS AND
      METHODS: In a retrospective study, records were reviewed for 13 patients who
      received i.p. paclitaxel therapy (175 mg/m2) during secondary cytoreductive
      surgery or surgery for recurrent disease. All these patients were initially
      treated with optimal debulking surgery (macroscopic persistent residual disease)
      and systemic chemotherapy. RESULTS: Nine patients were operated for secondary
      cytoreductive surgery (group I) and four patients operated for recurrent disease
      (group II). Postoperative residual disease was absent or microscopic in 69% (n =
      9). Median hospital stay was 16 days. Hematologic toxicity grade III-IV was
      reported by 12 patients (92%). Operative mortality was 7.7% (n = 1). Median
      follow-up was 22.7 months. The median overall survival was 25.5 months. The
      median disease-free survival was 8.5 months. The median disease-free survival for
      group I and II were respectively 11.7 months and 4.2 months (P = 0.3).
      Progression of disease after completion of treatment was documented in 62% (n =
      8): six patients for group I and two patients for group II. DISCUSSION AND
      CONCLUSION: Secondary cytoreduction surgery associated with intraperitoneal
      chemotherapy is feasible after adjuvant systemic chemotherapy for patients with
      recurrent or suboptimally resected ovarian cancer. Results on loco-regional
      control for recurrent disease are poor. Intraperitoneal chemotherapy should be
      discussed during a two-step surgical strategy, as secondary cytoreductive
      surgery.

PMID- 15177209
TI  - [Maternal and fetal consequences of increased gestational weight gain in women of
      normal prepregnant weight].
AB  - OBJECTIVE: To study the effects of increased gestational weight gain in women of
      normal prepregnant weight. PATIENTS AND METHODS: We compared 174 patients gaining
      more than 18 kg to 174 patients gaining between 9 and 15 kg. Body mass index was
      normal for every woman included in the study. RESULTS: Weight gain > or =18 kg
      was associated with increased risk of vascular complications (5.2% vs. 1.1%, P <
      0.05) but not with increased risk of mellitus diabetes (5.2% vs. 4.0%, NS).
      Weight gain > or =18 kg prolonged labor length (414.4 +/- 147 min vs. 376.5 +/-
      166.4 min, P < 0.05) and increased the rate of cesarean section (19.5% vs. 10.3%,
      P < 0.05). Neonatal outcome was similar in both groups, mean birth weight was
      greater (3413.6 +/- 427.0 g vs. 3163.4 +/- 495.1 g, P < 0.05) and the frequency
      of infants weighing more than 4000 g at birth was increased (8.0% vs. 4.0%, P <
      0.05) among women gaining more than 18 kg. CONCLUSION: Excess weight gain in
      pregnancy affects gestational and delivery outcomes and results in higher
      frequency of fetal macrosomia. These results confirm recommendations on weight
      gain in pregnancy as guidelines for pregnant women.

PMID- 15177210
TI  - [Histological diagnosis after Pap smears detecting cancer or high-grade lesion of
      the cervix].
AB  - OBJECTIVE: The aim of the study is to analyze the histological-cytological
      correlations for Pap smears having detected cancer or high-grade squamous intra
      epithelial lesion (HSIL) of the cervix. PATIENTS AND METHOD: The study about 311
      women is retrospective. The average age is 36.4 years. Group 1 (histological
      diagnosis of high-grade or invasive lesion) includes 244 women (77.5%). Group 2
      (histological diagnosis other than high-grade or invasive lesion) includes 37
      women (11.9%) with a presumed diagnosis of HSIL. Group 3 (absence of histological
      follow-up) includes 30 women (9.6%) with a presumed diagnosis of HSIL. RESULTS:
      In group 1, the presumed cytological diagnosis is HSIL in 229 cases, squamous
      carcinoma in 11 cases and adenocarcinoma in two cases. In this group, the average
      delay between the Pap smear and the first histology is equal to two months. It is
      longer than 6 months in seven cases. The diagnosis of cancer or high-grade lesion
      is confirmed histologically on a first biopsy of the cervix in 196 cases, a
      second or a third biopsy in 10 cases, an endocervical curettage in six cases and
      a surgical specimen in 32 cases. In the group 2, the histological diagnosis is
      normal-benign in 14 cases (presumed cytological false positives) and condyloma
      CIN 1 in 23 cases (presumed overevaluations). DISCUSSION AND CONCLUSION: Results
      highlight benefits of interactive exchanges between clinicians and pathologists,
      and the necessity of review of discordant cases by several pathologists in due
      time, with written comments and coding of the conclusions of the review.
      Histological follow-up is late or not done in some women.

PMID- 15177211
TI  - [Health behaviour of women attending child health clinics in health centers at
      Abidjan, Ivory Coast].
AB  - OBJECTIVE: To describe the health behaviour of women attending child health
      clinics in four health centres (HC) in the Yopougon and Abobo districts of
      Abidjan, Cote d'Ivoire, in March 2000. PATIENTS AND METHODS: Cross-sectional
      survey among women who came for infant consultations in the HC. Anonymous
      questionnaires filled in through interviews by social workers about the last
      pregnancy, delivery, and family planning (FP). RESULTS: Two hundred and forty-six
      women were interviewed in 1 month. The age (median: 25 years) and parity (median:
      two liveborn children) were comparable in the four HCs. A median of four prenatal
      consultations had been performed during the last pregnancy. The search of albumin
      and sugar in urine had been performed in >90% of women, like tetanus toxoid
      immunisation, anti-malaria and anti-anaemia prophylaxis. Blood group was checked
      in half of the women, syphilis infection status and haemoglobin level in less
      than one third. According to the HC, 3-23% of the women delivered at home. If
      delivery occurred in a HC, median duration between admission and delivery was 116
      min while median stay at the HC after delivery was 11 h. Only 14% of the women
      had attended at least one post-partum consultation and 8.5% a FP consultation.
      CONCLUSION: Our observations have shown a relatively good management of pregnancy
      in these HC of Abidjan and some failures regarding delivery, post-partum follow
      up and infant feeding.

PMID- 15177212
TI  - [Oxygen embolism after hydrogen peroxide irrigation of a breast abscess].
AB  - We report the case of oxygen embolism after inappropriate hydrogen peroxide
      irrigation of a breast abscess in a young patient. The issue proved to be both
      rapid and favourable.

PMID- 15177213
TI  - [Adolescence and pornography].
AB  - It is difficult to define pornography; it always proceeds from censure. Any
      representation of sexual relations forbidden by the law is considered as
      pornography. How can we evaluate its impact on teenagers? What are the possible
      consequences? Which image of woman is carried through pornography?

PMID- 15177214
TI  - [Pregnancy, low-back pain and pelvic girdle pain].
AB  - Prevalence and factors influencing pelvic joint and low-back pain during
      pregnancy are hereby reported. They can be associated with considerable
      disabilities as far as daily activities are concerned. They may be reduced by
      appropriate measures. Disc herniation rarely occurs during pregnancy and can be
      treated by oral or epidural steroid administration. Surgical intervention is
      scarcely indicated. In these cases MRI may be used, but only after the first
      trimester. Though uncommon, osteoporosis leading to vertebral or hip pain and
      fracture can occur during pregnancy and breastfeeding. Women concerned may have a
      pre-existing bone disease revealed by the physiological bone loss that occurs
      during pregnancy and breastfeeding. Other factors may influence bone mineral
      density variation such as osteomalacia, steroid or heparin administration. The
      relationship between transient osteoporosis of the hip and osteoporosis is
      discussed. Bone investigations and bone mineral density measurement after
      delivery are required.

PMID- 15177215
TI  - [Benefits of ultrasonography in the delivery room].
AB  - Ultrasonography should benefit many pathological events which occur in delivery
      rooms. The authors analyse the scarce literature about this subject and propose
      indications in which this complementary examination seems to be interesting.

PMID- 15177216
TI  - [Conservative treatment of endometrial cancer and atypical hyperplasia].
AB  - Endometrial carcinoma is the most frequent pelvic cancer encountered in women.
      The discovery of an endometrial carcinoma in a woman seeking pregnancy cannot be
      considered as exceptional. The medical alternative to the classic radical
      surgical treatment is studied in a review. Treatment with progestins might be
      considered and discussed with the couple in special indications. The oncologic
      risk to which this treatment exposes is limited. However, the application and the
      surveillance of this therapeutic protocol must obey strict rules, in order to
      recognize without delay any resistance to treatment. The spontaneous fertility of
      such patients seems weak, most probably because of their age, but assisted
      reproductive techniques (ART) could be considered in particular cases. Secondary
      hysterectomy is controversial, but a recent tendency is to widen this practice is
      becoming apparent.

PMID- 15177217
TI  - [Are there still contra-indications to epidural anaesthesia in obstetrics?].

PMID- 15177218
TI  - [There are no longer contraindications to the use of epidural anaesthesia in
      obstetrics].

PMID- 15177219
TI  - [There are still contraindications to the use of epidural anaesthesia in
      obstetrics].

PMID- 15177221
TI  - [Recommendation of good practice: Therapeutic strategies, with or without the
      assistance of medicine-based treatment, for stopping smoking (May 2003)].

PMID- 15177222
TI  - [Vaginal mucocele after vaginal tape, diagnosis and management. Gynecol Obstet
      Fertil 2003; 31 : 1013-17].

PMID- 15177223
TI  - [Lymphadenectomy in stage I endometrial neoplasms. Gynecol Obstet Fertil 2003; 31
      : 1004-1012].

PMID- 15177224
TI  - [Acceptability of misoprostol at home for voluntary drug-induced abortion.
      Gynecol Obstet Fertil 2004; 32 : 26-33].

PMID- 15177226
TI  - Non-traumatic lower limb vascular complications in endurance athletes. Review of
      literature.
AB  - OBJECTIVES: To review the importance, clinical features, investigations,
      management and prognosis of non-traumatic vascular injuries, affecting the lower
      limbs of endurance athletes. DESIGN: Review of literature. MATERIALS AND METHODS:
      A literature search was conducted from Medline, Pubmed, the National Electronic
      Library for Health, Google and Yahoo search engines for related articles and case
      reports regarding non-traumatic vascular complications involving the lower limb
      of endurance athletes. CONCLUSIONS: Non-traumatic vascular complications
      affecting the lower limbs include endofibrosis, stenosis/kinking of iliac
      arteries, dissection of external iliac artery, adductor canal syndrome, popliteal
      entrapment syndrome, chronic exertional compartment syndrome and effort-induced
      venous thrombosis. These are important as they affect athletes at the peak of
      their career and can be confusing to diagnose. The management is relatively well
      documented and produces good results in short term but the long term results are
      not known.

PMID- 15177227
TI  - Therapeutic angiogenesis in peripheral arterial disease: can biotechnology
      produce an effective collateral circulation?
AB  - The physiological processes of angiogenesis, vasculogenesis and arteriogenesis
      contribute to the growth of collateral vessels in response to obstructive
      arterial disease causing lower limb or myocardial ischaemia, but in clinical
      practice the endogenous angiogenic response is often suboptimal or impaired, e.g.
      by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis
      is an application of biotechnology to stimulate new vessel formation via local
      administration of pro-angiogenic growth factors in the form of recombinant
      protein or gene therapy, or by implantation of endothelial progenitor cells that
      will synthesize multiple angiogenic cytokines. Numerous experimental and clinical
      studies have sought to establish 'proof of concept' for therapeutic angiogenesis
      in PAD and myocardial ischaemia using different treatment modalities, but the
      results have been inconsistent. This review summarises the mechanisms of
      angiogenesis and the results of recent trials evaluating the efficacy and safety
      of different gene therapy, recombinant protein and cellular-based treatment
      approaches to enhance collateral vessel formation.

PMID- 15177228
TI  - Is ultrasound more accurate than axial computed tomography for determination of
      maximal abdominal aortic aneurysm diameter?
AB  - OBJECTIVE(S): Clinical assessment of maximal abdominal aortic aneurysm (AAA)
      diameter assumes clinical equivalency between ultrasound (US) and axial computed
      tomography (CT). Three-dimensional (3D) CT reconstruction allows for the
      assessment of AAA in the orthogonal plane and avoids oblique cuts due to AAA
      angulation. This study was undertaken to compare maximal AAA diameter by US,
      axial CT, and orthogonal CT, and to assess the effect that AAA angulation has on
      each measurement. METHODS: Maximal AAA diameter by US (US(max)), axial CT
      (axial(max)), and orthogonal CT (orthogonal(max)) along with aortic angulation
      and minor axis diameters were measured prospectively. Spiral CT data was
      processed by Medical Media Systems (West Lebanon, NH) to produce computerized
      axial CT and reformatted orthogonal CT images. The US technologists were blinded
      to all CT results and vice versa. RESULTS: Thirty-eight patients were analyzed.
      Mean axial(max) (58.0 mm) was significantly larger (P<0.05) than US(max) (53.9
      mm) or orthogonal(max) (54.7 mm). The difference between US(max) and
      orthogonal(max) (0.8 mm) was insignificant (P>0.05). When aortic angulation was
      <==25 degrees, axial(max) (55.3 mm), US(max) (54.3 mm), and orthogonal(max) (54.1
      mm) were similar (P>0.05); however, when aortic angulation was >25 degrees,
      axial(max) (60.1 mm) was significantly larger (P<0.001) than US(max) (53.8 mm)
      and orthogonal(max) (55.0 mm). The limits of agreement (LOA) between axial(max)
      and both US(max) and orthogonal(max) was poor and exceeded clinical acceptability
      (+/-5 mm). The variation between US(max) and orthogonal(max) was minimal with an
      acceptable LOA of -2.7 to 4.5 mm. CONCLUSION: Compared to axial CT, US is a
      better approximation of true perpendicular AAA diameter as determined by
      orthogonal CT. When aortic angulation is greater than 25 degrees axial CT becomes
      unreliable. However, US measurements are not affected by angulation and agree
      strongly with orthogonal CT measurements.

PMID- 15177229
TI  - Endoluminal repair of abdominal aortic aneurysm-contemporary Australian
      experience.
AB  - OBJECTIVE: An audit was established in November 1999 by the Australian Government
      Department of Health and Ageing to determine the mid- to long-term safety and
      efficacy of endoluminal graft repair (ELG) of abdominal aortic aneurysm (AAA).
      The audit has been undertaken by the Australian Safety and Efficacy Register for
      New Interventional Procedures-Surgical (ASERNIP-S). This study reviews
      contemporary Australian practice, based on audit data supplied to ASERNIP-S.
      DESIGN OF STUDY: This study is a prospective voluntary register (audit) of
      Australian data obtained from the private and public sector. Data were collected
      for ELG repairs performed between 1 November 1999 and 16 May 2001. Follow-up is
      continuing. Results. Seventy-nine vascular surgeons have contributed data on 950
      patients (816 male, 134 female, of median age 75.5 (range 36-94)). The mean
      aneurysm size was 57.5 mm (+/-10.2) and 44% of procedures were performed on
      aneurysms less than 55 mm in diameter. Fifty four percent of patients were
      considered suitable for open repair. Most ELG procedures were performed in an
      angiography or endovascular suite, under general anaesthetic using an open
      technique via the femoral arteries. Perioperative mortality was 1.7%, mostly from
      cardiac causes. Prior to discharge 7.2% of patients experienced an endoleak and
      18.6% had systemic complications. The average length of stay was 7.4 days (median
      5 days). Unsuccessful exclusion of the aneurysm occurred in 6.7% of cases.
      CONCLUSIONS: Endovascular repair of AAAs is a well accepted procedure and is
      performed by the majority of vascular surgeons in Australia. Australian surgeons
      are taking a rather aggressive approach to the management of aortic aneurysms,
      particularly in the moderate to higher risk patient groups. Mortality rates are
      low, given the elderly population in question and morbidity rates acceptable.
      ASERNIP-S is continuing to collect follow-up data for this patient cohort.

PMID- 15177230
TI  - The impact of endovascular treatment on in-hospital mortality following non
      ruptured AAA repair over a decade: a population based study of 16,446 patients.
AB  - OBJECTIVES: We hypothesised that over the past decade, the nation-wide outcome of
      infrarenal abdominal aortic aneurysm (AAA) repair has improved with the
      introduction of endovascular treatment. The aim of the study was to identify
      endovascularly-treated patients in a national registry and to assess the impact
      on in-hospital mortality of non-ruptured AAA repair, if any, after the
      introduction of endovascular repair. MATERIALS AND METHODS: We retrospectively
      studied the nation-wide outcome of non-ruptured AAA repair over the past decade.
      Variables studied were age and gender of the patients, hospital size and type and
      the year in which treatment was performed and the outcome on in-hospital
      mortality. The in-hospital mortality of non-ruptured AAA repair in 16,446
      patients in the 10-year period from 1991 to 2000 was 7.3% (6.2-8.2%). In the
      15,589 (95%) patients that underwent conventional treatment, in-hospital
      mortality was 7.6% (7.0-8.1%), whereas in the endovascular group it was 1.9% (0.6
      3.5%). In the multivariate analysis, age and endovascular repair were the most
      important independent predictors of in-hospital mortality. CONCLUSION: With the
      limitations of a national registry aside, the introduction of endovascular
      aneurysm repair seems to have had a small but significant impact on in-hospital
      mortality following infrarenal AAA repair.

PMID- 15177231
TI  - Outcome after abdominal aortic aneurysm repair. Difference between men and women.
AB  - OBJECTIVES: To evaluate short- and long-term outcome after open repair for
      ruptured and non-ruptured abdominal aortic aneurysm (AAA) with special emphasis
      on the difference between men and women. DESIGN: Single center retrospective
      study. Time and cause of death were determined from hospital charts, the National
      Bureau of Statistics and the Department for National Health and Welfare.
      Materials. Eight hundred and forty-six patients were followed-up, 597 were
      operated on for non-ruptured and 249 for ruptured aneurysms. METHODS: Case
      fatality was analyzed by multiple logistic regression considering year of
      surgery, age at surgery, and gender as covariates. The mortality rate for
      patients surviving 60 days after surgery was compared with the mortality in the
      general population by calculating the standardised mortality ratio (SMR).
      Mortality was also stratified according to gender and type of surgery. RESULTS:
      The SMR for patients surviving 60 days after surgery was significantly increased.
      SMR was significantly higher for women than for men. There was no statistically
      significant difference in SMR between patients operated for rupture compared to
      those operated for non-ruptured aneurysms. CONCLUSIONS: Women with AAA have a
      poorer outcome than women in the general population. This finding may relate to
      the large number of risk factors present in this patient sub-group.

PMID- 15177232
TI  - Preoperative risk stratification in patients undergoing elective infrarenal
      aortic aneurysm surgery: evaluation of five risk scoring methods.
AB  - OBJECTIVE: To evaluate five risk scoring methods in predicting the immediate
      postoperative outcome after elective open repair of abdominal aortic aneurysm
      (AAA). DESIGN: Retrospective evaluation of the Eagle score, Glasgow aneurysm
      score, Leiden score, modified Leiden score and Vanzetto score in a consecutive
      series of patients. PATIENTS: Two hundred and eighty-six consecutive patients
      undergoing elective infrarenal aortic aneurysm repair. RESULTS: Nine patients
      (3.1%) died in hospital and another 35 (12%) experienced severe postoperative
      complications. For the Glasgow aneurysm score, Leiden score, modified Leiden
      score and Vanzetto score receiver operating characteristics (ROC) curve analysis
      for prediction of in-hospital mortality showed area under the curve (AUC) of
      0.749 (p=0.01), 0.777 (p=0.008), 0.788 (p=0.006) and 0.794 (p=0.005),
      respectively. The Eagle risk score was less accurate for predicting in-hospital
      mortality. The risk-scoring systems did not perform well in predicting post
      operative complications, but multivariate analysis showed that the modified
      Leiden score was an independent predictor of postoperative complications.
      CONCLUSION: All scoring systems predict, with reasonable accuracy, the risk of in
      hospital death in patients undergoing elective open repair of AAA, whereas the
      accuracy in predicting severe postoperative complications is less.

PMID- 15177233
TI  - Long-term prognostic value of asymptomatic cardiac troponin T elevations in
      patients after major vascular surgery.
AB  - BACKGROUND: Cardiac troponin T (cTnT) is a sensitive and specific marker for
      myocardial injury, but elevations of cTnT without clinical evidence of ischemia
      and persistent or new electrocardiographic (ECG) abnormalities are common in
      patients undergoing major vascular surgery. We explored the long-term prognostic
      value of cTnT levels in these patients. METHODS: A follow-up study was conducted
      between 1996-2000 in 393 patients who underwent successful aortic or
      infrainguinal vascular surgery and routine sampling of cTnT. Patients were
      followed until May 2003 (median of 4 years [25th-75th percentile, 2.8-5.3
      years]). Total creatine kinase (CK), CK-MB, and cTnT were routinely screened in
      all patients, and included sampling after surgery and the mornings of
      postoperative days 2, 3 and 7. Electrocardiograms were also routinely evaluated
      for sign of ischemia. An elevated cTnT was defined as serum concentrations >/=0.1
      ng/ml in any of these samples. All-cause mortality was evaluated during long-term
      follow-up. RESULTS: Eighty patients (20%) had late death. The incidence of all
      cause mortality (41% vs. 17%; p<0.001) was significantly higher in patients with
      an elevated cTnT level compared to patients with normal cTnT. After adjustment
      for baseline clinical characteristics, the association between an elevated cTnT
      level and increased incidence of all-cause mortality (adjusted hazard ratio, 1.9;
      95% CI, 1.1-3.1) persisted. Elevated cTnT had significant prognostic value in
      patients with and without renal dysfunction, abnormal levels of CK-MB, and in
      patients with transient ECG abnormalities. CONCLUSIONS: Elevated cTnT levels are
      associated with an increased incidence of all-cause mortality in patients
      undergoing major vascular surgery.

PMID- 15177234
TI  - ACE inhibitors increase type III collagen synthesis: a potential explanation for
      reduction in acute vascular events by ACE inhibitors.
AB  - INTRODUCTION: Large trials have shown that angiotensin converting enzyme
      inhibitor (ACE-I) therapy reduces the risk of myocardial infarction and stroke.
      Acute vascular events are thought to be initiated by plaque rupture. Animal
      models of atherosclerosis show an increase in extra cellular matrix when given
      ACE-I therapy. ACE-I therapy could influence collagen synthesis, one of the major
      constituents of the atherosclerotic cap. METHODS: A nested case-control study was
      performed within the Huntingdon Aneurysm Screening Project. Subjects were
      assessed for arterial disease, drug history and smoking. Blood samples were taken
      for a measure of collagen synthesis, the amino-terminal propeptide of type III
      procollagen (PIIINP), lipid levels, iron metabolism and cotinine levels. RESULTS:
      Information was available for 420 subjects. Thirty-five were taking ACE-I therapy
      and 385 were not. Mean serum PIIINP level was 3.5 microg/l (sd 1.3 microg/l,
      range: 1.7-16.5 microg/l. There was a marked increase in mean collagen turnover
      between subjects taking ACE-I therapy compared to those not. Mean PIIINP level
      for cases and controls was 4.26 microg/l (95% CI: 3.73-4.79 microg/l) versus 3.61
      microg/l (95% CI: 3.48-3.75 microg/l). No differences were found for patients
      taking other antihypertensive drugs. After adjusting for age, weight, height,
      lipid levels and ferritin, PIIINP levels remained significantly higher in cases
      than controls: 4.14 microg/l (95% CI: 3.72-4.57 microg/l) versus 3.62 microg/l
      (95% CI: 3.49-3.75 microg/l) (P-value 0.02). DISCUSSION: These results suggest
      that ACE-I therapy up-regulates collagen synthesis, and could improve plaque
      stabilisation. This may provide an explanation for the decrease in acute vascular
      events observed in patients on ACE-I therapy.

PMID- 15177235
TI  - Effects of atherosclerotic plaque on the enlargement of an experimental model of
      abdominal aortic aneurysm in rabbits.
AB  - PURPOSE: Abdominal aortic aneurysm (AAA) usually is associated with
      atherosclerosis. We attempted to create an abdominal aortic aneurysm with
      atherosclerotic plaque in rabbits to investigate the relationship between
      atherosclerosis and enlargement of AAA. METHODS: An isolated segment of rabbit
      abdominal aorta was perfused with pancreatic elastase. Animals were fed a
      cholesterol-enriched diet to induce atherosclerotic plaque formation. Eight
      animals received perfusion with elastase and were fed a cholesterol-enriched diet
      (group EC), eight animals received perfusion with elastase and were fed a normal
      diet (group EN), eight animals received perfusion with saline and were fed a
      cholesterol-enriched diet (group SC), and eight animals received perfusion with
      saline and were fed a normal diet (group SN). Four animals served as a sham
      group. Each animal was killed after aortography at 4 or 12 weeks. The perfused
      segment was excised and examined histologically. RESULTS: No animal treated with
      saline and fed normal diet (groups SN) developed either an aneurysm or
      atherosclerosis. Atherosclerotic plaque was observed in animals fed the
      cholesterol-enriched diet (groups SC and EC) at 4 weeks, and the plaque had
      thickened further by 12 weeks. All animals treated with elastase (groups EN and
      EC) developed an AAA. Maximum internal diameter in groups EN and EC (4.1 mm) was
      equal at 4 weeks, but at 12 weeks, the diameter was less for group EC than for
      group EN (4.0 mm versus 4.8 mm, P<0.05). CONCLUSION: Cholesterol-enriched diet
      following the intra-luminal perfusion of an isolated aortic segment with elastase
      produced an AAA with atherosclerotic plaque in rabbits. It is likely that the
      thickened intima with atheroma suppressed continued enlargement of the aneurysm
      in this model.

PMID- 15177236
TI  - Assessment of graded intestinal hypoperfusion and reperfusion using continuous
      saline tonometry in a porcine model.
AB  - OBJECTIVE: To evaluate effects of graded intestinal hypoperfusion and reperfusion
      on intestinal metabolic parameters as assessed by a modified continuous saline
      tonometry technique. MATERIALS: Twelve barbiturate-anaesthetized female pigs.
      METHODS: Measurements were performed prior to and during three predefined levels
      of superior mesenteric mean arterial blood pressure (P(SMA) 70, 50 and 30 mmHg,
      respectively, each 80 min long), obtained by an adjustable clamp around the
      origin of the superior mesenteric artery, and during reperfusion. We continuously
      measured jejunal mucosal perfusion (laser Doppler flowmetry), jejunal tissue
      oxygen tension (PO(2TISSUE); microoximetry) and intramucosal PCO(2) (continuous
      saline tonometry) and calculated net intestinal lactate production, mesenteric
      oxygenation, PCO(2) gap (jejunal mucosal PCO(2)-arterial PCO(2)) and pHi.
      RESULTS: At P(SMA) 70 and 50 mmHg mesenteric oxygen uptake and net lactate
      production remained unaltered, in spite of decreased oxygen delivery. At these
      P(SMA) levels PCO(2) gap increased, while pHi and PO(2TISSUE) decreased. At
      P(SMA) 30 mmHg pronounced increases in PCO(2) gap and mesenteric net lactate
      production as well as marked decreases in PO(2TISSUE) and pHi were demonstrated.
      Data indicate absence of anaerobic conditions at an intestinal perfusion pressure
      (IPP)> or =41 mmHg, a pHi> or =7.22 or PCO(2) gap< or =15.8 mmHg. CONCLUSIONS:
      Continuous saline tonometry detected intestinal ischemia as induced by graded
      reductions in IPP. A threshold could be defined above which intestinal ischemia
      does not occur.

PMID- 15177237
TI  - Basic fibroblast growth factor mediates carotid plaque instability through
      metalloproteinase-2 and -9 expression.
AB  - OBJECTIVE(S): We hypothesized that basic fibroblast growth factor (bFGF) may
      exert a role in carotid plaque instability by regulating the expression of matrix
      metalloproteinases (MMP). METHODS: Plaques obtained from 40 consecutive patients
      undergoing carotid endarterectomy were preoperatively classified as soft or hard.
      Serum bFGF was pre- and postoperatively measured. The release of MMP-2 and MMP-9
      in the blood serum, and the activity, production and expression in the carotid
      specimens was analyzed. Specific anti-bFGF inhibition tests were performed in
      vitro on human umbilical artery smooth muscle cells (HUASMC) to evaluate the role
      of bFGF in the activity, production and expression of MMP-2 and -9. RESULTS:
      Twenty-one (53%) patients had a soft carotid plaque and 19 (48%) a hard plaque.
      Preoperative bFGF serum levels were higher in patients with soft plaques [soft=34
      (28-39) pg/mL and hard=20 (17-22) pg/mL-p<0.001] and postoperatively returned to
      normal values (when compared to 10 healthy volunteers). The serum levels of MMP-2
      in patients' with soft plaques were higher than those in patients' with hard
      plaques [soft=1222 (1190-1252) ng/mL and hard=748 (656-793)ng/mL-p<0.0001]. MMP-9
      serum values were 26 (22-29) ng/mL for soft plaques and 18 (15-21) ng/mL for hard
      plaques (p<0.0001). We found increased activity, production and expression of MMP
      2 and -9 in soft plaques compared to hard plaques (p<0.001). In vitro inhibition
      tests on HUASMC showed the direct influence of bFGF on the activity, production
      and expression of MMP-2 and -9 (p<0.001). CONCLUSIONS: bFGF seems to exert a key
      role in carotid plaque instability regulating the activity, production and
      expression of MMP thus altering the physiologic homeostasis of the carotid
      plaque.

PMID- 15177238
TI  - Risk factors for complications after carotid endarterectomy--a population-based
      study.
AB  - OBJECTIVES: The overall benefit of carotid endarterectomy (CEA) is dependent on
      the outcome from the procedure. However, many reports are from selected centres
      and not population-based. The aim of this study was to assess the 30-day
      complication rate for a whole country and also to determine independent risk
      factors for serious complications. MATERIALS AND METHODS: One thousand five
      hundred and eighteen CEA were retrospectively reviewed, covering principally all
      the CEAs in Sweden, during a three year period. Indications for surgery were;
      minor stroke 34%, TIA 34%, amaurosis fugax 18%, asymptomatic 11% and others 3%.
      Data were collected from the Swedish Vascular Registry (Swedvasc). Combined
      cohort and case-control methodology was used. RESULTS: Registered complications
      were; 43 permanent strokes, 32 transient strokes (<30 days), 18 TIA/amaurosis
      fugax and 22 deaths (seven fatal stokes). In the cohort study, the 30-day
      permanent stroke and death rate were 4.3% (65/1518). Significant risk factors in
      multivariate analyses were the indication for surgery (minor stroke vs. other
      indications) (p=0.02, RR=1.38), diabetes (p=0.02, RR=1.41), cardiac disease
      (p<0.01, RR 1.43) and operation at a university hospital (p=0.02, RR=1.39). In
      the case-control study comparing the 65 cases of permanent stroke and/or death
      with 130 matched controls the only significant risk factor was contralateral
      occlusion (p<0.01, OR=5.27). One patient (1/130) with a permanent stroke was
      wrongly reported as a local neurological complication (facial paresis).
      CONCLUSION: This national audit demonstrated population-based data on
      complication rates after CEA well comparable with previous randomised trials. The
      validity of the Swedvasc data was confirmed. Combined cohort and case-control
      methodology was useful in analysing risk factors for serious perioperative
      complications.

PMID- 15177239
TI  - The effect of long saphenous vein stripping on deep venous reflux.
AB  - BACKGROUND: The addition of long saphenous vein (LSV) stripping to sapheno
      femoral junction (SFJ) disconnection and multiple stab avulsions (MSAs) in the
      course of varicose vein (VV) surgery is associated with a significant reduction
      in recurrence, and a significant improvement in quality of life. It is
      hypothesised that these benefits relate, at least in part, to a favourable effect
      of stripping on deep venous reflux. OBJECTIVE: To examine the effect of long
      saphenous vein (LSV) stripping on deep venous reflux (DVR). METHODS: This was
      prospective study of 62 consecutive patients (77 limbs) CEAP class 2-6,
      undergoing SFJ disconnection and MSAs, with and without successful stripping of
      the LSV to the knee. A duplex ultrasound examination was performed pre
      operatively and at a median (IQR) of 24 (23-25) months post-operatively.
      Completely stripped limbs were defined as those in whom complete stripping of the
      LSV to the knee was confirmed on post-operative duplex. Reflux >/=0.5 s. was
      considered pathological. RESULTS: Pre-operatively, 32 (42%) limbs had deep venous
      reflux (DVR). Post-operative duplex at 24 months revealed that the LSV had been
      completely stripped in 29 (38%) limbs. In patients with pre-operative DVR,
      complete stripping was associated with a significant reduction in the prevalence
      of superficial femoral vein (SFV) (p<0.001) and popliteal vein (PV) (p=0.016),
      McNemar test) on post-operative duplex. By contrast, in patients without pre
      operative DVR, incomplete stripping was associated the development of SFV
      (p=0.031) and PV (p=0.008) reflux. CONCLUSIONS: Complete LSV stripping abolishes
      DVR in a significant proportion of limbs, whereas failure to strip is frequently
      associated with the development of new DVR. These data support for routine
      stripping and suggest that the benefits of stripping may relate, at least in
      part, to a favourable impact on deep venous function.

PMID- 15177240
TI  - Arterial perforation (by balloon) during subintimal angioplasty.

PMID- 15177241
TI  - An unusual presentation of a rare nerve cell tumour.
AB  - We present a rare case of a schwannoma in a pre/para-aortic position resembling a
      thrombosed saccular abdominal aortic aneurysm.

PMID- 15177242
TI  - Managing respiratory care services.
AB  - Managing in a health care environment is not for the frail of heart or weak of
      spirit. Health care is a system in crisis that is exacerbated because it got
      there by doing what once made it successful. From 1900 to 2004, focus of health
      care has shifted from controlling infectious diseases to episodic care and to
      present-day chronic and perspective care. The system has moved from issues of
      mortality, to morbidity, to mobility, to quality of life, to feeling good and,
      finally, to looking good. Managing the delivery of health care, if you choose to
      accept it, is not an impossible mission, but it will be a challenging job.
      Obviously, the focus of managers is how the system can be designed to innovate
      and improve care. Organizations and professions must change not only structures
      and processes, but national priorities for improvement with better methods of
      disseminating and applying knowledge. Managers of respiratory care departments
      must foster the use of information technology in clinical care, must create
      payment policies that encourage innovation and tested performance, and must
      enhance education programs to strengthen and retain the health care work forces.

PMID- 15177243
TI  - Leadership, leadership, wherefore art thou leadership?
AB  - Leadership is an elusive concept. Although no one best definition exists, some
      common characteristics, such as charisma and influence, tend to dominate most
      discussions on leadership qualities and traits. This article presents an overview
      of the findings of and pitfalls in research on leadership, in its varied and
      multifaceted contexts. It explores both personal and contextual attributes of
      leadership.

PMID- 15177244
TI  - Practitioner competency assessment and career ladders as a recruiting and
      retention tool.
AB  - The assessment of competency for respiratory care practitioners involves a
      thorough understanding of what defines competence, the development of a well
      planned, continuous process that starts with new employee orientation, and a
      clearly communicated set of staff expectations. Career ladders are a tool that
      can be used to aid staff retention and recruitment, thereby reducing multiple
      costs associated with a high employee turnover rate, and to encourage
      professional development and accountability while achieving important
      departmental objectives.

PMID- 15177245
TI  - Managing multidisciplinary departments.
AB  - Today there a shortage of qualified health care professionals, and the current
      reshaping of the health care delivery system demands that quality care be
      provided at a lower cost. Many health care managers are finding that that they
      must re-think and change their traditional departmental concepts to become a
      multidisciplinary service. How department managers may better manage a
      multidisciplinary department in this new and changing work environment is the
      topic of this discussion.

PMID- 15177246
TI  - Labor and productivity measures.
AB  - Respiratory care directors are now becoming experts in staffing models that are
      unique to services provided through allied health professionals. The basic human
      resource management tenets of attract, retain, and motivate remain at the core of
      management focus; however, time standards, volumes, staffing variables, and
      flexible budgets are the current twists added to the litany of labor management
      terms. Optimizing resource consumption and establishing measurable patient
      outcomes to justify staff use will also be part of the manager's challenges
      related to health care delivery in the twenty-first century.

PMID- 15177247
TI  - Respiratory care protocol development and impact.
AB  - Respiratory care (RC) protocols are widely regarded as the most appropriate
      method for properly allocating and delivering most forms of respiratory therapy.
      The use of protocols has increased steadily over the past 15 years, but, despite
      the successes and modest implementation of RC protocols across the country, there
      is room for improvement in adopting RC protocols for the effective use of
      respiratory care services. It also seems that many physicians have yet to be won
      over, and RC managers need to take the first step toward protocol development and
      implementation. This article addresses some of the issues surrounding the
      development of respiratory care protocols and the impact that their
      implementation may have based on experience gained to date.

PMID- 15177248
TI  - Quality and performance improvement in respiratory care.
AB  - An essential responsibility of the modern respiratory care manager is to
      establish and monitor a particular level of quality and service being provided by
      a department. Focusing on quality and performance improvement fosters an
      environment that empowers and encourages all employees to be innovative and
      resolve roadblocks that limit organizational performance. This article discusses
      the issues regarding quality and performance improvement that arise in the daily
      operations of a respiratory care department.

PMID- 15177249
TI  - Balanced scorecard for methodology for total performance improvement.
AB  - Health care organizations are complex adaptive systems, a set of connected or
      interdependent parts or agents that include caregivers, patients, and processes.
      Consequently, health care organizations are prone to problems and are not always
      predictable environments. Fundamental changes are needed in the organization and
      in the delivery of health care in the United States. This article presents a
      proven method of instituting and tracking the changes that can ensure a
      respiratory care department is delivering the appropriate level of care.

PMID- 15177250
TI  - Managing new technologies in respiratory care.
AB  - Capital equipment and technology administration, as outlined in this article, is
      one of many responsibilities for managers of respiratory care. Planning for 1, 5,
      and 10 years, strategic budgeting, and systematic evaluation of existing and
      future devices will assist in creating a successful equipment and technology
      program. A successful capital equipment and technology program will enable
      respiratory care practitioners to treat patients effectively with the proper
      tools for success.

PMID- 15177251
TI  - Medicolegal aspects of respiratory care and leadership responsibilities.
AB  - This article introduces clinicians and managers to general legal principles. The
      purpose of the article is to present an overview of health care law to those
      involved in the clinical practice and management of respiratory care.

PMID- 15177254
TI  - Embryogenesis of the peripheral nervous system.
AB  - Embryogenesis is a complex, wide-ranging event. Key processes may proceed
      simultaneously in different portions of the embryo, or sequentially, with phase
      offsets as waves of maturation pass outward from an initial point toward the
      periphery. The molecular signals used to pattern the body commonly serve multiple
      functions and reiterate as the body plan progresses. This article therefore
      presents first the anatomic model of the peripheral nervous system, so that the
      final goal is clear. It then reviews the terminology needed to describe
      embryogenesis. The article's first section reviews neural development. The main
      portion of the article addresses the maturation of the fetal nervous system in
      terms of the evolving gross morphology and the molecular signals that pattern
      these changes.

PMID- 15177255
TI  - Basic pathology of the peripheral nerve.
AB  - Peripheral nerve pathology encompasses a complex array of disease processes that
      are poorly understood. This article provides a substrate for communication
      between pathologists and radiologists who are involved in the diagnosis and
      treatment of patients with peripheral neuropathy. The article is organized into
      sections on normal histology, routine morphologic techniques used in the study of
      peripheral nerve, and the basic disease patterns, followed by a brief discussion
      of selected neuropathies.

PMID- 15177256
TI  - Clinical presentations of peripheral neuropathies.
AB  - This article addresses the clinical presentations of different peripheral
      neuropathies. The topic is discussed briefly with emphasis on the most important
      clinical features. MR imaging of the peripheral nerves is a rapidly advancing
      field, and it is hoped that the basic understanding of the clinical presentations
      of peripheral neuropathies will encourage radiologists to get more involved in MR
      imaging of the peripheral nerves.

PMID- 15177257
TI  - The brachial plexus: normal anatomy, pathology, and MR imaging.
AB  - The brachial plexus is the most technically and anatomically challenging area of
      the peripheral nervous system for diagnostic imaging. Marked improvements in
      spatial and contrast resolution of plexus images have resulted from the use of
      phased-array technology and newer MR pulse sequence designs. This article
      presents case material incorporating these improvements and discusses the primary
      factors that continue to limit MR image quality, such as inhomogenous fat
      suppression, motion artifacts, and small vessels that mimic or obscure plexus
      components, and potential solutions and imaging alternatives. Brachial plexus
      anatomy and its appearance on multiplanar MR images are reviewed. The morphologic
      features and MR signal characteristics that have been found useful in
      distinguishing between normal and abnormal plexus components,and in detecting
      neuropathic lesions, are addressed in the context of clinical indications for
      plexus imaging as follows: mass involving the plexus, traumatic injury,
      entrapment syndrome, posttreatment evaluation, and miscellaneous conditions.

PMID- 15177258
TI  - Anatomic and functional digital subtraction periangioneurography of the brachial
      plexus, its terminal branches, and the carotid sheath.
AB  - Correct localization of perineural compressions and adhesions is essential for
      effective pain relief in the use of local anesthetics, anti-inflammatory drugs,
      and neurolytic agents for lysis of adhesion by hydraulic distention, blunt
      dissection, or formal surgery. This article presents a method of entering and
      navigating the neurovascular sheath of the brachial plexus, the perinueral space
      of its terminal branches, and the carotid sheath using a catheter/guidewire
      system for imaging, testing motor function, administering pharmaceuticals, and
      lysing adhesions.

PMID- 15177260
TI  - The carpal tunnel: ultrasound display of normal imaging anatomy and pathology.
AB  - Ultrasound successfully displays the normal anatomy and pathology of the median
      nerve in the carpal tunnel. This article reviews the sonographic characteristics
      of carpal tunnel anatomy, including the superficially situated median nerve, the
      contained tendons and vessels, and the boundary-forming fibro-osseous landmarks.
      It emphasizes ultrasound evaluation of the median nerve and the criteria for
      diagnosis of compressive neuropathy in carpal tunnel syndrome. The techniques for
      performing sonography for carpal tunnel syndrome are detailed. Ultrasonic imaging
      is more comfortable for patients, less time-consuming, and less expensive than MR
      imaging, and achieves equal accuracy in skilled hands.

PMID- 15177259
TI  - Diagnosis of carpal tunnel syndrome: electrodiagnostic and MR imaging evaluation.
AB  - In clinically classic carpal tunnel syndrome (CTS) without symptoms or signs to
      suggest other disorders that can mimic CTS, it remains somewhat controversial as
      to whether performing nerve conduction studies is necessary or cost-effective. MR
      imaging reliably depicts normal carpal tunnel anatomy. It can also identify
      pathologic nerve compression and mass lesions, such as ganglion cysts, that
      compress nerves. Currently, MR imaging is most commonly used to image patients
      with ambiguous electrodiagnostic studies and clinical examinations. MR diffusion
      weighted imaging of peripheral nerves might prove to be the most sensitive
      imaging sequence for the detection of early nerve dysfunction. Electrodiagnostic
      studies are likely to remain the pivotal diagnostic examination in patients with
      suspected CTS for the foreseeable future. With advances in both software and
      hardware, however, high-resolution MR imaging of peripheral nerves will become
      faster, cheaper, and likely more accurate, possibly paving the way for an
      expanded role in the diagnosis of this common syndrome.

PMID- 15177261
TI  - MR neurography: diagnostic utility in the surgical treatment of peripheral nerve
      disorders.
AB  - Advances in MR imaging have improved the visualization of normal and pathologic
      peripheral nerve structures in various clinical settings. Peripheral nerve
      imaging has the potential to dramatically change the diagnosis and treatment of
      peripheral nerve pathology and lead to an improved understanding of peripheral
      nerve pathophysiology. Currently, MR imaging serves as a problem-solving tool
      when additional anatomic information is needed to clarify ambiguous
      electrodiagnostic and clinical examinations. The next major advance in MR imaging
      of peripheral nerves will likely be the transition from anatomic to physiologic
      imaging with higher resolution as better phased-array surface coils and higher
      field-strength magnets become available. Finally, MR neurography should remain
      complementary to the clinical examination and electrodiagnostic studies in the
      evaluation of peripheral nerve disorders.

PMID- 15177262
TI  - Vesicular trafficking of hepatic apolipoprotein B100 and its maturation to very
      low-density lipoprotein particles; studies from cells and cell-free systems.
AB  - A cell-free system was established to study the process by which apolipoprotein
      (apo)B100-containing lipoproteins exit the endoplasmic reticulum (ER). ApoB was
      found in COPII vesicles with physical properties distinct from those containing
      other secreted proteins. When lipid synthesis in rat hepatoma cells was
      stimulated by fatty acid addition, fully lipidated apoB-lipoproteins of very low
      density lipoprotein density were absent from the vesicles, but instead formed in
      a post-ER compartment. These data suggest that the COPII machinery in cells of
      hepatic and intestinal origin has evolved to sequester secreted cargoes with
      unique properties compared with those in other tissues, and that final lipidation
      occurs after a protein quality-control checkpoint is passed in the ER.

PMID- 15177263
TI  - Phenomics, lipodystrophy, and the metabolic syndrome.
AB  - The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes
      strongly related to cardiovascular disease that includes central obesity with
      hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the
      MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance
      syndrome" often are used interchangeably. The successful translation to clinical
      medicine of molecular genetic research on other rare monogenic metabolic
      disorders has stimulated the evaluation of such rare monogenic forms of insulin
      resistance as partial lipodystrophy resulting from mutations in either LMNA or
      PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin
      resistance using a range of diagnostic methods--an approach sometimes called
      "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular
      disease, which, in turn, may uncover new pathways and targets for interventions
      for the common MetS, diabetes, and atherosclerosis.

PMID- 15177264
TI  - Assembly and patterning of vertebrate blood vessels.
AB  - The mechanisms that regulate blood vessel assembly at appropriate sites in the
      organism are poorly understood, yet understanding this regulation is critical to
      the ability to design therapeutics around vessel production in vivo. Classic
      embryologic studies have yielded descriptive analyses of vascular pattern
      formation, and they show that angioblasts and endothelial cells respond to
      environmental cues to assemble at precise embryologic sites. The present study
      incorporated a genetic model, the mouse, into these studies to obtain mechanistic
      information regarding vessel assembly and patterning. The data show that both
      embryo-derived and stem-cell-derived mouse angioblasts respond to host cues in
      the avian embryo and pattern properly, and also highlight a critical role for the
      vascular endothelial cell growth factor signaling pathway in these patterning
      events.

PMID- 15177265
TI  - Shear-induced reorganization of endothelial cell cytoskeleton and adhesion
      complexes.
AB  - Endothelial cells undergo profound morphologic changes in response to alterations
      in shear stresses that are imposed on them by blood flow, and these responses
      have important implications for physiologic and pathophysiologic function of
      blood vessels. Shear-induced changes in cell morphology represent a unique mode
      of cell motility: elongation of the cells in the direction of shear stress is
      achieved by a reorientation and assembly of F-actin stress fibers at the basal
      cell surface that ultimately protrudes the upstream and downstream limits of the
      plasma membrane. Shape change is also accommodated by dramatic reorganization of
      cell-substrate and cell-cell junctional complexes. Both of these structures are
      sites of mechanotransduction, which raises intriguing questions concerning how
      shear-induced regulation of endothelial cell physiology is integrated with cell
      morphologic responses.

PMID- 15177266
TI  - Calmodulin kinase and L-type calcium channels; a recipe for arrhythmias?
AB  - L-type Ca2+ channels (LTCCs) are the main portal for Ca2+ entry into cardiac
      myocytes. These ion channel proteins open in response to cell membrane
      depolarizations elicited by action potentials, and LTCC current (I(Ca)) flows
      during the action potential plateau, to increase cellular Ca2+ (Ca2+(i)) and
      trigger myocardial contraction. I(Ca) is also implicated in the genesis of
      cardiac arrhythmias under conditions such as heart failure and cardiac
      hypertrophy, in which the action potential plateau and QT interval are prolonged.
      This article reviews recent findings about the molecular regulation of LTCCs by
      the Ca2+-dependent signaling molecule, calmodulin kinase II (CaMKII), and
      compares this form of regulation with regulation by calmodulin-binding domains
      and beta-adrenergic receptor agonists. LTCC dysregulation is discussed in the
      context of new results showing that CaMKII can be a proarrhythmic signal in
      disease conditions in which Ca2+(i) is disordered and cardiac repolarization is
      excessively prolonged.

PMID- 15177267
TI  - Modulation of atherogenesis by chemokines.
AB  - Migration of leukocytes into the vasculature-which involves the concerted effort
      of many molecules, including chemokines-is a requisite step for atherogenesis.
      The three chemokines that have been implicated most strongly in atherogenesis are
      monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8)/growth-regulated
      oncogene alpha (Gro-alpha), and fractalkine. Although all three chemokines appear
      to impact atherogenesis by attenuating monocyte/macrophage accumulation in the
      lesion, the precise mechanism of action of each of the chemokines, as well as
      their interactive role in atherosclerosis, have not been elucidated. This review
      focuses on the latest findings that describe the individual roles of MCP-1, IL
      8/Gro-alpha, and fractalkine on macrophage recruitment in atherosclerosis.
      Furthermore, based on present knowledge of the participation of these three
      chemokines and their receptors in monocyte/macrophage recruitment, a possible
      interactive role of these chemokines in atherogenesis is explored.

PMID- 15177268
TI  - Co-stimulation and plaque-antigen-specific T-cell responses in atherosclerosis.
AB  - Atherosclerosis is a chronic inflammatory disease of the arterial wall, and T
      cell-mediated immune responses to plaque antigens are a prominent component of
      the inflammatory process. In addition to antigen stimulation, T-cell responses
      require co-stimulatory signals, the best defined of which are delivered by B7
      family molecules on antigen-presenting cells binding to CD28 on T cells. T-cell
      co-stimulation directly influences the CD40/CD154 immunoregulatory pathway, which
      is well known to influence atherosclerosis. This review discusses recent progress
      in understanding the role of B7 family molecules in atherosclerosis, and T-cell
      co-stimulation as an important link between innate immunity and adaptive immune
      responses to plaque antigens.

PMID- 15177269
TI  - Hearing sensitivity and the risk of incident falls and fracture in older women:
      the study of osteoporotic fractures.
AB  - PURPOSE: To determine if age-related hearing loss may be related to bone health.
      Decreased vestibular function has been associated with hearing loss. We
      hypothesized that hearing loss would be related to an increased risk of falling
      and osteoporotic fracture in 6480 women aged 65 years or older enrolled in the
      Study of Osteoporotic Fractures. We further hypothesized that decreased bone
      mineral density would be associated with hearing loss. METHODS: Hearing
      sensitivity was ascertained via screening audiometry, and was classified as
      normal, mild loss, or significant loss. Incident non-spine fractures and falls
      were ascertained every 4 months for an average 6.7 years and 3 years,
      respectively. RESULTS: The age-adjusted annual fall rate did not differ
      significantly by hearing category, nor did the risk of incident fracture.
      Adjustment for confounding factors had no effect on our results. Age- and BMI
      adjusted mean calcaneal bone mineral density (g/cm2) was 0.380 in the normal
      hearing group, 0.375 in the mild loss group, and 0.371 in the significant loss
      group (p = 0.02). There were no significant differences in total hip bone mineral
      density across hearing categories. CONCLUSIONS: Our results do not support the
      hypothesis that hearing loss is a risk factor for fracture or falls [corrected]

PMID- 15177270
TI  - Hip fractures and Alzheimer's disease in elderly institutionalized Canadians.
AB  - PURPOSE: To examine the associations among Alzheimer's disease, hip fractures,
      and falls in elderly Canadians > or = 65 years of age (n=1513) who participated
      in the National Population Health Survey for Health Institutions between 1994 and
      1995. METHODS: The survey was designed to provide health-related information for
      residents of Canadian health institutions. Logistic regression analysis was used
      to assess the association between hip fractures and Alzheimer's Disease (AD).
      Covariates assessed included osteoporosis, age, sex, medications, and comorbid
      conditions. We did an additional analysis confined to participants who fell, in
      an attempt to tease out the contribution of falling to the relation between AD
      and hip fractures. RESULTS: The adjusted odds ratio relating Alzheimer's disease
      to hip fracture was 2.18 (95% CI: 1.26-3.79). Among those who reported falling,
      the adjusted odds ratio relating Alzheimer's disease to hip fracture was 1.78
      (95% CI: 1.01-3.14). CONCLUSIONS: The most important finding in this study is the
      independent relation between Alzheimer's disease and hip fractures.

PMID- 15177271
TI  - Predictors of falling cholesterol levels in older adults: the Cardiovascular
      Health Study.
AB  - PURPOSE: To estimate 4-year change in serum total cholesterol levels in a
      population-based sample of older adults and identify independent predictors of
      cholesterol decline. METHODS: Prospective study of 2837 adults aged 65 years and
      older with serum cholesterol measured in 1992-1993 and 1996-1997. RESULTS: Mean
      serum cholesterol levels declined 6.3 mg/dl between the two examinations.
      Declines were greater in white (-7.3 mg/dl) than black (-1.4 mg/dl) participants
      and in those in good/excellent health (-0.9 mg/dl) vs. fair/poor health (-3.1
      mg/dl; both p < 0.01). Factors associated with greater decline on multivariate
      analysis included age, male gender, and higher white cell count, albumin, and
      baseline cholesterol. Cholesterol levels declined 2.0 mg/dl per 6 year increment
      in baseline age and 6.8 mg/dl more in men than women after adjustment for other
      factors. C-reactive protein levels were unrelated to cholesterol change.
      CONCLUSION: Declining cholesterol levels were associated with male gender,
      advanced age, weight loss, and white blood cell count but not with C-reactive
      protein levels. The role of declining cholesterol synthesis, due to as yet
      undefined age-related changes or to cytokine-mediated reductions related to
      illness, should be examined to help clarify the mechanisms of the sometimes
      marked declines in cholesterol levels observed at advanced ages.

PMID- 15177272
TI  - Case-finding for depressive and exhausted mood in the general population:
      reliability and validity of a symptom-driven diagnostic scale. Results from the
      prospective MONICA/KORA Augsburg Study.
AB  - PURPOSE: Depressed and exhausted mood warrants epidemiological scrutiny as a
      cardiovascular risk factor. We evaluated the reliability and validity of a
      symptom-driven diagnostic scale. METHODS: To assess a depressed mood, items were
      derived from an extended battery of psychosocial questionnaires in a population
      based study including 11,949 subjects aged 25 to 74 years. RESULTS: Eight items
      from the 24-item von Zerssen checklist were extracted by factor analysis
      resulting in an approximately normally distributed scale (range 0-24; mean=8.23,
      SD 4.76). Median for men was 8.00 and 10.00 for women. Its internal consistency
      was high (Cronbach's alpha 0.88). Test-retest reliability of a sub-sample was
      0.83. Determining concurrent validity, correlation coefficients against a single
      depression questionnaire in 8237 subjects (p < 0.001) and SF-36 subscales
      (vitality and mental health) (both p < 0.0001) in 4226 subjects proved to be
      significant. Construct validity was confirmed by significant associations (all p
      < 0.001) with sleeping complaints, social isolation, and unhappiness. Test values
      for men above the 80th percentile exhibited significant hazard ratios for
      subsequent total mortality (80th percentile: HR 2.17, 95% CI: 1.31-13.55).
      CONCLUSION: The scale comprises eight items describing motivational depletion,
      decreased vitality, irritability, and an anxious mood with sufficient internal
      and external reliability, concurrent and construct validity. Its normal
      distribution allows a graduated analysis of different thresholds. The instrument
      may be particularly useful to identify exhausted and depressed mood of otherwise
      apparently healthy subjects in the general population.

PMID- 15177273
TI  - Limitations and potential uses of census-based data on ethnicity in a diverse
      community.
AB  - PURPOSE: Information on ethnicity, socioeconomic status, and social class has
      value in epidemiologic research and in measurement of the quality of health care
      but it is difficult to obtain for large populations. This evaluation assessed the
      potential usefulness of ethnicity data based on address geocoding to the 2000
      census. METHODS: We compared ethnicity based on the geocoding data with ethnicity
      from hospitalization records and birth certificates of a large health maintenance
      organization. RESULTS: Of 117,209 members with black ethnicity recorded at the
      time of a hospitalization, the mean percentage of blacks in their geocoded block
      was only 37%. Among the 62,661 individuals recorded as Asian at the time of a
      hospitalization, the mean percentage of Asians in their geocoded block was only
      24%. Among the 47,328 individuals who lived in a census block that had 50% or
      more blacks, 81% were recorded as black at the time of a hospitalization. Among
      the 24,424 individuals who lived in a census block that had 50% or more Asians,
      38% were recorded as being Asian at the time of a hospitalization. CONCLUSIONS:
      In our population, information on ethnicity derived from geocoding at the block
      level cannot be used to infer the ethnicity of Asian or black individuals.

PMID- 15177274
TI  - Descriptive epidemiology of health problems in Vaslui district, Romania.
AB  - PURPOSE: To describe the characteristics of morbidity in one district of Romania
      and to identify specific priority areas for preventive measures or further
      research. METHOD: A descriptive retrospective study, cases being identified using
      routinely collected data on morbidity from a district public health authority.
      Study population was defined as those resident in Vaslui district, an area
      characterized by lower socioeconomic development located in the north-eastern
      region of Romania (Moldova). The main outcome measures were occurrence and
      prevalence rates of events and patterns of hospital utilization over the study
      period (1996-2001). RESULTS: The overall occurrence rate was 46,779.1 per 100,000
      person-years with a declining trend over the 6-year study period. The highest
      values were amongst children. The most common causes were respiratory diseases
      (36.3%) and digestive diseases (31.4%) followed by infectious/parasitic diseases
      (5.8%), nervous system/sense organs diseases (5.6%) and skin/subcutaneous
      diseases (5.0%). The point prevalence rate increased steadily from 8.4% in 1996
      to 12.5% in 2001, the picture being dominated by anemia in children and
      cardiovascular diseases (i.e., hypertension, ischemic cardiopathy) in adults. The
      leading cause for hospitalization remains respiratory diseases followed by
      cardiovascular and digestive diseases (39.5% of all diagnoses). CONCLUSIONS: The
      results suggest a number of prevention priorities amongst Vaslui residents such
      as respiratory diseases especially in children less than 1 year of age and adults
      over 65 years, chronic cardiovascular diseases in adults or digestive diseases in
      the whole population. This work can be used as a starting point for other
      observational studies on health information systems as well as on broader
      determinants of health within this community.

PMID- 15177275
TI  - A method for imputing missing data in longitudinal studies.
AB  - PURPOSE: In a cohort in which racial data are unknown for some persons, race
      specific persons and person-years are imputed using a model-based iterative
      allocation algorithm (IAA). METHODS: An EM algorithm-based approach to address
      misclassification in a censored data regression setting can be adapted to
      estimate the probability that a person of unknown race is white. The
      corresponding race-specific person-years are obtained as a by-product of the
      estimation procedure. Variance estimates are computed using the bootstrap. The
      proposed approach is compared with the proportional allocation method (PAM).
      RESULTS: In an occupational cohort where racial data were missing for 41% of the
      workers, the age-time-race-specific person-years were estimated within a relative
      variation of approximately 20%, using the IAA. The deaths were less reliably
      estimated. The standardized mortality ratios (SMRs) for all-cause mortality
      estimated using the IAA and the PAM were more similar for the non-white workers
      than for a smaller subgroup of white workers. CONCLUSIONS: The IAA provides a
      method to reliably estimate race-specific person-year denominators in cohort
      studies with missing racial data. This method is applicable to other incompletely
      observed non-time-dependent categorical covariates. Internal cohort rates or SMRs
      can be computed and modeled, with bootstrap confidence intervals that account for
      the uncertainty in the determination of race.

PMID- 15177276
TI  - Excess mortality related to diabetes mellitus in elderly Medicare beneficiaries.
AB  - PURPOSE: To determine whether diabetes remains an important contributor to
      mortality among the elderly. METHODS: A 5% national sample of Medicare claims was
      utilized to create a retrospective cohort study. Participants were 148,562
      persons with at least one hospitalization or two outpatient visits for diabetes
      in 1994, who were alive on January 1, 1995, were > or =65 years old, and were not
      in managed care in 1994; and 148,562 age, gender, and race matched controls
      without diabetes. Deaths were ascertained through 1999. Survival and proportional
      hazards analysis were used to calculate rates and relative risks. RESULTS: The
      mortality rate was 100.2/1000 person years (PY) among seniors with diabetes
      compared with 60.6/1000 PY without diabetes (age adjusted relative risk
      (RR)=1.83, 95% CI: 1.81-1.86). Non-white minorities had a similar RR associated
      with diabetes (Hispanic 2.37, Asian 1.95, Native American 2.38, blacks 1.64) as
      whites (1.86). The mortality risk associated with diabetes decreased with
      increasing age, but remained significantly elevated even among those aged 85
      years and older. In contrast, the absolute excess mortality attributed to
      diabetes increased with age. CONCLUSION: The excess mortality associated with
      diabetes amongst all older ages suggests that greater attention to optimal
      diabetes treatment and prevention is needed.

PMID- 15177278
TI  - Characterization and biological activities of recombinant human plasminogen
      kringle 1-3 produced in Escherichia coli.
AB  - Angiogenesis, the formation of new capillaries from preexisting blood vessels, is
      involved in many pathological conditions, for example, tumorigenesis, diabetic
      retinopathy, and rheumatoid arthritis. Angiostatin, which contains the kringle 1
      4 domains of plasminogen, is known to be a potent inhibitor of angiogenesis and a
      strong suppressor of various solid tumors. In this study, we expressed
      recombinant protein containing the kringle 1-3 domains of human plasminogen in
      Escherichia coli and investigated its biological activities. The protein was
      successfully refolded from inclusion bodies and purified at a 30% overall yield,
      as a single peak by HPLC. The purified recombinant protein had biochemical
      properties that were similar to those of the native form, which included
      molecular size, lysine-binding capacity, and immunoreactivity with a specific
      antibody. The recombinant protein was also found to strongly inhibit the
      proliferation of bovine capillary endothelial cells in vitro, and the formation
      of new capillaries on chick embryos. In addition, it suppressed the growth of
      primary Lewis lung carcinoma and B16 melanoma in an in vivo mouse model. Our
      findings suggest that the recombinant kringle 1-3 domains in a prokaryote
      expression system have anti-angiogenic activities, which may be useful in
      clinical and basic research in the field of angiogenesis.

PMID- 15177279
TI  - A novel carrier molecule for high-level expression of peptide antibiotics in
      Escherichia coli.
AB  - Peptide antibiotics are often hard to express in engineered bacteria at high
      level. According to the properties of peptide antibiotics, a heterologous protein
      PaP3.30, encoded by ORF30 of Pseudomonas aeruginosa bacteriophage PaP3, was
      selected as a carrier molecule. The gene of the carrier molecule was constructed
      into the plasmid pQE-32 to give rise to the vector pQE-PaP30 for expression of
      peptide antibiotics in Escherichia coli. A his-tagged fusion protein was
      genetically constructed with a peptide antibiotic at its carboxy terminus. The
      novel carrier molecule was used for high-level expression of six peptide
      antibiotics with different sizes and isoelectric points in E. coli, which are
      hPAB-beta, MSI-78, Melletin, hBD-1, Cecropin A, and an ovine anion peptide. And
      further, one of six peptide antibiotics, hPAB-beta (an analog of a human peptide
      antibiotic), was taken as an example for studies of recovery of interesting
      products from the fusion partner, purification and antimicrobial activity
      evaluation. The results indicated that the expressed fusion protein existed as an
      inclusion body in the cytoplasm and the expression amounts of six peptide
      antibiotic fusions are all higher than 34% of the total cell protein. The
      expression products could be easily purified by Ni-NTA chromatography. Cyanogen
      bromide was used to cut at the methionine linker between the carrier and hPAB
      beta peptide. hPAB-beta was recovered from the fusion partner and purified to
      homogeneity with High S cation-exchange and Bio-gel P6 gel chromatography. The
      bactericidal activities of the purified recombinant hPAB-beta against P.
      aeruginosa are 31-64 microg/ml, and against Staphylococcus aureus are > or = 128
      microg/ml, being comparable to that of the chemical synthesis peptide. These
      results show that the carrier molecule can result in high-level expression of
      peptide antibiotics, and expression products can be easily recovered from their
      fusion partner and retain their bioactivity.

PMID- 15177280
TI  - Expression and purification of rat recombinant aminopeptidase B secreted from
      baculovirus-infected insect cells.
AB  - Aminopeptidase B (Ap-B) is a ubiquitous enzyme and its physiological function
      still remains an open question. This Zn2+ -exopeptidase catalyzes the amino
      terminal cleavage of basic residues of peptide or protein substrates, indicating
      a role in precursor processing. In addition, the enzyme exhibits a residual
      capacity to hydrolyze leukotriene A4 (LTA4) into the pro-inflammatory lipid
      mediator leukotriene B4 (LTB4) in vitro. This potential bi-functional nature of
      Ap-B is supported by a close structural relationship with LTA4 hydrolase, which
      hydrolyzes LTA4 into LTB4, in vivo, and exhibits an aminopeptidase activity, in
      vitro. Structural studies are necessary for the detailed understanding of the bi
      functional enzymatic mechanism of Ap-B. In this study, we report cDNA cloning,
      baculovirus expression, and purification of the rat Ap-B (rAp-B). The Ap-B cDNA
      was constructed from extracted rat testes total RNA and introduced into the pBAC1
      baculovirus transfer vector to generate recombinant baculoviruses. rAp-B
      expression, with or without COOH-hexahistidine tag, was tested in two different
      insect cell hosts (Sf9 and H5). The enzyme is secreted into the insect cell
      culture medium, which allowed a rapid purification of the protein. The His-tagged
      rAp-B was purified using metal affinity resin while the native recombinant rAp-B
      was partially purified using a single step DEAE Trisacryl ion exchange column.
      Although the recombinant rAp-B exhibits biochemical properties equivalent to
      those of the rat testes purified protein, the presence of the histidine-tag seems
      to partially inhibit the exopeptidase activity. However, this report shows that
      baculovirus-infected cells are a useful system to produce rat Ap-B for use in
      studying enzymatic mechanisms in vitro and 3D structure.

PMID- 15177281
TI  - Purification of a recombinant membrane protein tagged with a calmodulin-binding
      domain: properties of chimeras of the Escherichia coli nicotinamide nucleotide
      transhydrogenase and the C-terminus of human plasma membrane Ca2+ -ATPase.
AB  - A Ca2+ -dependent calmodulin-binding peptide (CBP) is an attractive tag for
      affinity purification of recombinant proteins, especially membrane proteins,
      since elution is simply accomplished by removing/chelating Ca2+. To develop a
      single-step calmodulin/CBP-dependent purification procedure for Escherichia coli
      nicotinamide nucleotide transhydrogenase, a 49 amino acid large CBP or a larger
      149 amino acid C-terminal fragment of human plasma membrane Ca2+ -ATPase (hPMCA)
      was fused C-terminally to the beta subunit of transhydrogenase. Fusion using the
      49 amino acid fragment resulted in a dramatic loss of transhydrogenase expression
      while fusion with the 149 amino acid fragment gave a satisfactory expression.
      This chimeric protein was purified by affinity chromatography on calmodulin
      Sepharose with mild elution with EDTA. The purity and activity were comparable to
      those obtained with His-tagged transhydrogenase and showed an increased
      stability. CBP-tagged transhydrogenase contained a 4- to 10-fold higher amount of
      the alpha subunit relative to the beta subunit as compared to wild-type
      transhydrogenase. To determine whether the latter was due to the CBP tag, a
      double-tagged transhydrogenase with both an N-terminal 6x His-tag and a CBP-tag,
      purified by using either tag, gave no significant increase in purity as compared
      to the single-tagged protein. The reasons for the altered subunit composition are
      discussed. The results suggest that, depending on the construct, the CBP-tag may
      be a suitable affinity purification tag for membrane proteins in general.

PMID- 15177282
TI  - High-throughput screening for soluble recombinant expressed kinases in
      Escherichia coli and insect cells.
AB  - We have constructed a dual expression vector for the production of recombinant
      proteins in both Escherichia coli and insect cells. In this vector, the
      baculoviral polyhedrin promoter was positioned upstream of the bacteriophage T7
      promoter and the lac operator. This vector, designated pBEV, was specifically
      designed to exploit the advantages that both hosts would provide. This vector
      also facilitates one-stop cloning, thereby simplifying the expression process for
      automation, and the development of a high-throughput method for protein
      expression. Utilizing the multi-system vector pBEV, a high-throughput process was
      developed with expression in deep-well blocks and purification in micro-titer
      plates enabling the identification of expression and solubility in both E. coli
      and insect cells. In this study, using pBEV, we have successfully expressed and
      purified multiple human kinases produced in E. coli and insect cells. Our results
      validate expression screening as a strategy to rapidly triage proteins
      identifying the optimum expression system and conditions for production.

PMID- 15177283
TI  - High-level expression of human cytochrome P450 1A2 by co-expression with human
      molecular chaperone HDJ-1(Hsp40).
AB  - Human cytochrome P450 (CYP) 1A2 is of great interest because of its important
      roles in the oxidation of numerous drugs and carcinogens. HDJ-1, a molecular
      chaperone in human, is known to assist the correct folding of unfolded proteins.
      To achieve high yield of recombinant human CYP1A2 in Escherichia coli, the CYP1A2
      encoding gene was co-expressed with the chaperone HDJ-1 under the control of an
      inducible tac promoter in bicistronic format. Expression level of CYP1A2 in the
      bicistronic construct reached up to 520 nmol/liter culture within 16 h at 37
      degrees C, which is 3.4-fold increase compared to the expression yield of CYP1A2
      alone without HDJ-1. By co-expression with HDJ-1, the catalytic activity of
      CYP1A2 was also increased 5.5-fold. The activity increase seems to be associated
      with the increase of CYP production at whole cell level. The present over
      expression system may be useful for rapid production of large amounts of active
      human CYP1A2 in E. coli.

PMID- 15177284
TI  - Cloning, expression, and purification of the 27 kDa (MPT51, Rv3803c) protein of
      Mycobacterium tuberculosis.
AB  - A limited number of proteins of Mycobacterium tuberculosis have been
      characterized so far for their use as potential candidates for diagnosis and
      vaccine studies. This study was aimed at cloning, expression, and purification of
      a 27 kDa protein (otherwise known as the MPT51 or Rv3803c protein) of M.
      tuberculosis. The Rv3803c gene was PCR amplified using primers that contain
      specific restriction sites. The amplified product was inserted initially into
      pTOPO and then sub-cloned into pET15b and pET24d vectors, such that the
      recombinant protein is predicted to contain an N-terminal or a C-terminal
      histidine tag, respectively. The recombinant plasmids were introduced into
      Escherichia coli BL21 (DE3) and the recombinant proteins were purified from the
      cytosolic fractions of the E. coli sonicates by nickel-NTA chromatography. The
      purity, molecular mass, and the conformation of the proteins were determined by
      high performance liquid chromatography (HPLC), matrix assisted laser desorption
      ionization-time-of-flight (MALDI-TOF), and circular dichroism (CD) studies,
      respectively. The purified proteins were found to be immunogenic and useful for
      immunodiagnostic studies of tuberculosis by enzyme linked immunosorbent assay
      (ELISA), with a sensitivity of 71% and specificity of 95%.

PMID- 15177285
TI  - High-level expression of a fungal pyranose oxidase in high cell-density fed-batch
      cultivations of Escherichia coli using lactose as inducer.
AB  - Expression of a recombinant pyranose oxidase (P2O) from the basidiomycete
      Trametes ochracea has been increased 10-fold in shaking flask cultures of
      Escherichia coli BL21(DE3) harboring plasmid pSE33 by optimizing the composition
      of the culture medium using an experimental design approach. Inexpensive lactose
      was used as a medium component and inducer of expression of the P2O gene, which
      is under the control of a trc promoter. The expression system was studied in
      detail in batch and fed-batch cultivations with the aim to improve the expression
      level of active recombinant protein and to minimize the formation of inclusion
      bodies. In batch cultivations, the highest specific P2O activity of 0.9 U (mg of
      soluble protein)(-1) was measured in oxygen-limited cultures grown at 25 degrees
      C. The highest overall volumetric productivity of 33 mg of active P2O per liter
      and hour (corresponding to 345U (L h)(-1)) has been determined in a high-density
      fed-batch process with a feed-forward exponential feeding strategy. During the
      fed-batch process, lactose was added intermittently to the culture. A final
      biomass concentration of 33 g L(-1) (based on cell dry weight) was obtained.
      Compared to shaking flask cultures in not optimized culture media, the overall
      volumetric P2O productivity has been improved by a factor of 110 using the fed
      batch strategy and the optimized culture medium. Recombinant P2O was expressed in
      the cytoplasm with 9% of the total soluble protein being active P2O. In terms of
      physical and enzyme kinetic properties, the purified recombinant P2O was found to
      be similar to the previously published data of P2O isolated from its original
      host.

PMID- 15177286
TI  - High-level expression of clostridial sialidase using a ferredoxin gene promoter
      based plasmid.
AB  - A "large" sialidase isozyme (NanI) from Clostridium perfringens is a
      representative microbial sialidase with broad substrate specificity, being used
      for the analysis of sialoglycoconjugates. It is also a possible virulence factor.
      However, purification of the native enzyme in a large quantity is not practical
      due to its low productivity. To obtain the enzyme in a satisfactory yield, a gene
      encoding the NanI was transcriptionally fused to the fdx gene promoter (P(fdx))
      in a shuttle-vector, pFF, and transformed into C. perfringens 13. The resultant
      strain released the enzyme into the culture medium, as the original strain does.
      The enzyme activity increased during the first 6 h of culture and thereafter
      remained at maximal levels. The maximal activity was approximately 3000-fold
      compared with that of the original strain, and 15-fold compared with that of
      recombinant Escherichia coli, which possesses extra copies of the tRNA gene for
      selected rare codons. This suggests the usefulness of a P(fdx)-based plasmid for
      expressing AT-rich genes in C. perfringens. The enzyme was successfully purified
      by two-step procedure with a specific activity of 2860 U/mg using 2'-(4
      methylumbelliferyl)-alpha-D-N-acetylneuraminic acid and a yield of 1.69 mg of
      NanI per 100 ml of culture. The method described here can facilitate purification
      of NanI in enough quality and quantity to analyze the role of
      sialoglycoconjugates in cells and the pathogenic importance of NanI sialidase.

PMID- 15177287
TI  - Purification of green fluorescent protein overexpressed by a mutant recombinant
      Escherichia coli.
AB  - Green fluorescent protein was purified from sonicated recombinant Escherichia
      coli and its mutant obtained after exposure to UV light. The latter overexpresses
      green fluorescent protein. The two-step procedure consisted of a two-phase
      aqueous extraction with PEG/salt and precipitation of the proteins from PEG phase
      by free Zn2+. The recoveries of green fluorescent protein were 73 and 83% in the
      cases of recombinant E. coli and its mutant, respectively. The corresponding fold
      purifications were 24 and 9, respectively. In both cases, the purified protein
      showed a single band on SDS-PAGE corresponding to 28 kDa.

PMID- 15177288
TI  - Cloning, overexpression, and characterization of a serine/threonine protein
      kinase pknI from Mycobacterium tuberculosis H37Rv.
AB  - Protein phosphorylation-dephosphorylation is the principal mechanism for
      translation of external signals into cellular responses. Eukaryotic-like
      serine/threonine kinases have been reported to play important roles in bacterial
      development and/or virulence. The PknI protein is one of the 11 eukaryotic-like
      serine/threonine kinases in Mycobacterium tuberculosis H37Rv. From the
      bioinformatic studies, PknI protein has been shown to have an N-terminal
      cytoplasmic domain followed by a transmembrane region and an extracellular C
      terminus suggestive of a sensor molecule. In this study, we have cloned,
      overexpressed, and characterized the entire coding region and the cytoplasmic
      domain of PknI as a fusion protein with an N-terminal histidine tag, and used
      immobilized metal affinity chromatography for purification of recombinant
      proteins. The purified recombinant proteins were found to be functionally active
      through in vitro phosphorylation assay and phosphoamino acid analysis. In vitro
      kinase assay of both proteins revealed that PknI is capable of
      autophosphorylation and showed manganese-dependent activity. Phosphoamino acid
      analysis indicated phosphorylation at serine and threonine residues. Southern
      blot analysis with genomic DNA highlighted the conserved nature of pknI among the
      various mycobacterial species. In silico analysis revealed a close homology of
      PknI to Stk1 from Streptococcus agalactiae, shown to have a role in virulence and
      cell segregation of the organism.

PMID- 15177289
TI  - Functional expression, purification, and characterization of the extra stable
      human placental alkaline phosphatase in the Pichia pastoris system.
AB  - Human placental alkaline phosphatase was successfully cloned in the yeast system
      Pichia pastoris. The recombinant enzyme was over-expressed as a secreted protein
      in the cultured medium. The enzyme was extremely stable, which resulted in a
      total recovery of the enzyme activity after the purification process. The
      purified enzyme preparation was apparently homogeneous as examined by the
      polyacrylamide gel electrophoresis, analytical gel-permeation chromatography, and
      analytical ultracentrifugation. The final enzyme preparation showed a
      purification of 803-fold from the culture medium with a specific activity of 578
      U/mg of protein. Fluorescence spectroscopic analyses showed multiple unfolding
      steps in the urea denaturation process of the homodimeric recombinant enzyme.
      Extensive conformational change of the enzyme in urea was detected by the
      analytical ultracentrifugation and the size-exclusive chromatography. The
      quaternary structure of the enzyme is quite stable. No indication of dissociation
      was observed after extensive tertiary structural changes.

PMID- 15177290
TI  - Increased peptide deformylase activity for N-formylmethionine processing of
      proteins overexpressed in Escherichia coli: application to homogeneous rubredoxin
      production.
AB  - Deformylation of the initiator N-formylmethionine does not always proceed to
      completion for proteins overexpressed in Escherichia coli. To overcome this
      limitation, the def gene encoding the Escherichia coli peptide deformylase was
      cloned into the plysS plasmid under the tetracycline (Tc) promoter control. The
      efficiency of this constitutive level of peptide deformylase expression was
      demonstrated for the case of the rubredoxins from both mesophilic and
      hyperthermophilic organisms which normally retain a majority of their N-formyl
      terminal form. Indicating the potential structural/functional significance of
      residual formylation, the presence of a highly solvent exposed N-formyl group in
      rubredoxin is discernable in the amide NMR chemical shifts for the active site
      metal-coordinating cysteines more than 21A away.

PMID- 15177291
TI  - The effect of variation within inhibitory domains on the activity of pea protease
      inhibitors from the Bowman-Birk class.
AB  - We have investigated the properties of variant pea seed protease inhibitors,
      homologous to the anti-carcinogenic Bowman-Birk inhibitor (BBI) from soybean but
      differing most significantly in amino acid sequences at the two independent sites
      of protease inhibition. The pea protease inhibitors were expressed, using
      Aspergillus niger, with yields of up to 23 mg secreted recombinant protein per
      litre of media. The recombinant proteins showed protease inhibitory activity and
      were deduced to be disulphide-bonded correctly; limited post-translational
      processing had occurred at the amino-terminal ends of all proteins. Differences
      in trypsin and chymotrypsin specific inhibitory activities, and in inhibition
      constants, were observed in studies of the two recombinant variants and BBI.

PMID- 15177292
TI  - Expression, purification, and sequence analysis of catalase-1 from the soil
      bacterium Comamonas terrigena N3H.
AB  - Catalases are essential components of the cellular equipment to cope with
      oxidative stress. We have purified and characterize herein the most abundant heme
      containing catalase-1 from the soil bacterium Comamonas terrigena N3H. This
      oxidative stress-induced enzyme was isolated from exponential phase cells grown
      in the presence of peroxyacetic acid. We have used consecutive steps of
      hydrophobic, molecular sieve, and ion exchange chromatography to achieve a high
      state of purity for this metalloenzyme. The purified sample of catalase exhibited
      a specific catalytic activity of 55,900 U/mg, allosteric behavior in peroxidic
      reaction, a broad pH optimum, and a rather atypical electronic spectrum. The
      sample of highest purity was subjected to mass spectrometry analysis. The
      molecular weight of the subunit of this homodimeric protein was determined as
      55,417 Da. The Qq-TOF mass analysis method allowed us to sequence short tryptic
      fragments of this catalase. Five such fragments with a total length of 57 amino
      acids together with several enzymatic properties allowed the classification of
      this hydroperoxidase as belonging to clade III of monofunctional catalases. The
      highest sequence similarity is with the catalase from Vibrio fischeri. The
      presented results imply the significance of this inducible enzyme in the
      prevention of toxic effects of oxidative stress for bacterial cells.

PMID- 15177293
TI  - Overexpression, purification, and characterization of ATP-NAD kinase of
      Sphingomonas sp. A1.
AB  - The NAD kinase gene (nadK) of Sphingomonas sp. A1 was cloned and then
      overexpressed in Escherichia coli, and the gene product (NadK) was purified from
      the E. coli cells through five steps with a 25% yield of activity. NadK was a
      homodimer of 32 kDa subunits, utilized ATP or other nucleoside triphosphates, but
      not inorganic polyphosphates, as phosphoryl donors for the phosphorylation of
      NAD, most efficiently at pH 8.0 and 50-55 degrees C, and was designated as ATP
      NAD kinase (NadK). NadK showed no NADH kinase activity and was slightly inhibited
      by NADP(H). Precursors for NAD biosynthesis such as quinolinic acid, nicotinic
      acid mononucleotide, nicotinic acid adenine dinucleotide, and nicotinic acid had
      no effect on the NadK activity, as observed in the cases of the NAD kinases of
      Micrococcus flavus, Mycobacterium tuberculosis, and E. coli. Taken together with
      the report that the NAD kinase of Bacillus subtilis is activated by quinolinic
      acid [J. Bacteriol. 185 (2003) 4844], it is indicated that the regulatory
      patterns of NAD kinases differ even among bacterial NAD kinases.

PMID- 15177294
TI  - Expression, production, and characterization of full-length vitronectin in
      Escherichia coli.
AB  - Vitronectin (VN) is one of the primary adhesive proteins in serum and serves to
      promote the attachment and spreading of a wide variety of cell types to tissue
      culture plastic. In this study, the pGEX2t expression vector was used to express
      full-length human VN as a GST-tagged fusion protein in Escherichia coli. GST/VN
      production was induced with IPTG and the protein was found to localize to
      inclusion bodies. The inclusion bodies were isolated from cell lysates, washed
      once with 2 M urea and Triton X-100, and then solubilized with 8 M urea in the
      presence of a reducing compound. Solubilized GST/VN was purified by heparin
      affinity chromatography and refolded by dialysis against phosphate buffered
      saline. Approximately 40 mg of GST/VN was recovered from 1L of bacterial culture.
      Purified GST/VN migrated at the predicted molecular mass on SDS-PAGE and was
      recognized by both anti-GST and anti-VN antibodies. GST/VN bound to heparin and
      promoted cell adhesion, spreading, and growth to a similar extent as that
      observed with plasma-derived VN. As such, the production of recombinant VN in
      bacteria represents a rapid and convenient method to produce large quantities of
      VN for cellular studies.

PMID- 15177295
TI  - Cloning, expression, and purification of soluble human interleukin-4 receptor in
      Streptomyces.
AB  - Interleukin-4 (IL-4) is a pleiotropic cytokine which plays a pivotal role in
      shaping immune responses and mediating important proinflammatory functions in
      asthma. This cytokine exerts its biological effects through binding to its
      receptor (IL-4R) complex, with the alpha chain as the high-affinity binding
      subunit. Soluble IL-4R (sIL-4R) lacks the transmembrane and cytoplasmic domains,
      so it cannot induce cellular activation. By acting as a decoy to circulating IL-4
      and neutralizing its activity, the high specificity and affinity of sIL-4R make
      it ideal as an IL-4 antagonist. In this study, a sIL-4R cDNA encoding the
      extracellular domain of IL-4R alpha chain was cloned into a Streptomyces
      Escherichia coli shuttle plasmid pSGLgpp and expressed secretly in Streptomyces
      lividans TK 24. On SDS-PAGE gel, the expressed sIL-4R protein showed a Mw of 24
      kDa, agreeable with the predicted size. The N-terminal sequence of the protein
      was also determined, confirming its identity and indicating that no degradation
      occurred at the N-terminus. With DEAE-Sepharose Fast Flow and Superdex HR 75
      columns, the protein was purified and used on HPLC analysis, the purity reaching
      about 90%. The results of the ligand-binding blot and ELISA showed that such
      protein has biological activity of binding with ligand IL-4.

PMID- 15177296
TI  - High-level expression and single-step purification of leucyl-tRNA synthetase from
      Aquifex aeolicus.
AB  - Aquifex aeolicus leucyl-tRNA synthetase is the only known heterodimeric LeuRS,
      consisting of two subunits with molecular masses of 74.0 and 33.5 kDa, and named
      alphabeta-LeuRS. The gene encoding alpha subunit was cloned into pSBET-b vector.
      Synthetic oligonucleotide encoding six histidine residues was also inserted in
      front of alpha subunit. PSBET-b vector contains argU gene, which encodes a rare
      Escherichia coli tRNA(Arg)(AGA/AGG). The argU gene helps A. aeolicus LeuRS, which
      contains AGA/AGG codons in exceptionally high frequency, express well in E. coli.
      The gene encoding beta subunit was inserted into pET-15b vector. E. coli BL21
      CodonPlus (DE3) cells were transformed with the two recombinant plasmids to
      produce alphabeta-LeuRS with a His6 tag at the N-terminus of alpha subunit. The
      enzyme was purified by affinity chromatography on Ni-NTA Superflow. About 7 mg
      purified alphabeta-LeuRS was obtained from 250 ml culture. The His6-tag at the N
      terminus did not affect the aminoacylation activity of the enzyme.

PMID- 15177297
TI  - Constitutive production of human leptin by fed-batch culture of recombinant rpoS-
      Escherichia coli.
AB  - High-level production of human leptin by fed-batch culture of recombinant
      Escherichia coli using constitutive promoter system was investigated. For the
      constitutive expression of the obese gene encoding human leptin, the strong
      constitutive HCE promoter cloned from the D-amino acid aminotransferase gene of
      Geobacillus toebii was used. To develop an optimal host-vector system, several
      different recombinant E. coli strains were compared for leptin production. In
      flask cultures, E. coli FMJ123, which is a rpoS mutant strain, showed the highest
      level of leptin production (41% of total proteins). By comparing the expression
      levels of leptin in several different rpoS- and rpoS+ strains, it could be
      concluded that rpoS mutation positively affected constitutive production of
      leptin. For the large-scale production of human leptin, fed-batch cultures of
      recombinant E. coli FMJ123 were carried out using three different feeding
      solutions--chemically defined, yeast extract-containing, and casamino acid
      containing feeding solutions. Among these, the use of casamino acid-containing
      feeding solution allowed production of leptin up to 2.1 g/L, which was 2.1- and
      1.8-fold higher than that obtained with chemically defined and yeast extract
      contained feeding solutions, respectively. These results suggest that the HCE
      promoter can be used for the efficient production of leptin, and most likely
      other recombinant proteins, in a constitutive manner.

PMID- 15177298
TI  - Emerging targets for the pharmacology of learning and memory.
AB  - Learning and memory are dynamic processes associated with modifications in
      morphology, biochemistry and physiology of the nervous system, that can be
      analysed at different levels of biological organization. Within this context,
      changes correlated with cognitive processes are identifiable at distinct cellular
      and molecular loci of the nervous system. Synaptic plasticity represents an
      experience-dependent alteration of neuronal properties that subserve learning and
      memory, and for which a neuronal network can be considered as a candidate for
      being part of an engram. Multiple molecular systems at various levels of the
      signal transduction cascade, such as those involving receptors, second messengers
      and gene expression, may be linked to synaptic remodelling during cognitive
      processes. After a brief overview of the various facets of memory and the higher
      levels of cerebral organization (with special attention to the hippocampus), this
      review is devoted to the presentation of some novel potential therapeutic targets
      within the signal transduction cascade that might be considered for rational
      pharmacological intervention to improve learning and memory in both diseased and
      healthy individuals.

PMID- 15177299
TI  - Phenolics-rich extracts from Silybum marianum and Prunella vulgaris reduce a high
      sucrose diet induced oxidative stress in hereditary hypertriglyceridemic rats.
AB  - The study tested the effects of phenolics-rich extracts from the plants Silybum
      marianum (silymarin) and Prunella vulgaris (PVE) on blood and liver antioxidant
      status and lipoprotein metabolism. Hereditary hypertriglyceridemic rats fed on
      standard diet (STD) or high-sucrose diet (HSD, 70cal% of sucrose) for two weeks
      were used. HSD doubled plasma and liver triacylglycerol (TAG) and increased
      plasma VLDL-TAG and VLDL-cholesterol compared to STD. Administration of silymarin
      or PVE as 1% dietary supplements in HSD did not influence lipid levels in plasma
      or liver, but both extracts caused decrease in plasma VLDL-cholesterol levels.
      HSD-induced oxidative stress was manifested in increased TBARS and conjugated
      dienes (CD) content, decreased GSH levels and glutathione peroxidase (GPX)
      activity in blood and liver. In blood the activity of superoxide dismutase (SOD)
      decreased, whereas in liver the activity of catalase increased after HSD. Feeding
      on HSD containing phenolics-rich extracts resulted in reduction of TBARS and CD
      content and in increase of blood GPX activity and elevated GSH content in liver.
      Besides, silymarin increased the activity of SOD and level of GSH in blood.
      Catalase activity in blood or liver was not influenced by the presence of plant
      extracts in the diet. These results indicate that silymarin and PVE improve
      antioxidant status in blood and liver and positively affect plasma lipoprotein
      profile in an experimental model of dietary induced hypertriglyceridemia.

PMID- 15177301
TI  - Effect of alpha-tocopherol and simvastatin on male fertility in
      hypercholesterolemic rats.
AB  - The effect of alpha-tocopherol, simvastatin and both on male fertility in
      hypercholesterolemic rats was studied. Induction of hypercholesterolemia was done
      by feeding rats on a diet containing 1% cholesterol for 30 days.
      Hypercholesterolemic rats were orally given alpha-tocopherol (3 mg kg(-1) BW) or
      simvastatin (1 mg kg(-1) BW) or both for 65 days. Fertility index, serum
      testosterone level, sex organs weight, semen analysis and histopathological
      examination of testes, seminal vesicles and prostate glands were the parameters
      used to evaluate the reproductive efficiency of rats. In hypercholesterolemic
      rats (control +ve), there was a marked decrease in fertility index, testicular
      weight, sperm cell count, and percentages of sperm motility and viability
      associated with a significant increase in sperm cell abnormalities. Oral
      administration of either alpha-tocopherol or simvastatin to hypercholesterolemic
      rats for 65 days significantly improved the fertility index, testicular weight
      and semen quality. Concomitant administration of alpha-tocopherol and simvastatin
      to hypercholesterolemic rats markedly increased fertility index and sperm
      motility and viability associated with a significant reduction of sperm cell
      abnormalities. Histopathological examination revealed that testes of
      hypercholesterolemic rats (control +ve) had degenerated, non-functioning and
      atrophied seminiferous tubules associated with arrest of spermatogenesis. Oral
      administration of alpha-tocopherol and simvastatin concomitantly to
      hypercholesterolemic rats resulted in active mature and full functioning
      seminiferous tubules. In conclusion, concomitant administration of alpha
      tocopherol and simvastatin to hypercholesterolemic male rats improved their
      reproductive efficiency and produced additional protection against reduced
      fertility induced by hypercholesterolemia.

PMID- 15177300
TI  - Studies on the glycemic and lipidemic effect of monopril and losartan in normal
      and diabetic rats.
AB  - The effects of the angiotensin-converting enzyme (ACE) inhibitor monopril and the
      angiotensin II receptor blocker losartan on serum glucose, protein levels and
      some serum lipid components were compared in normal and diabetic rats receiving
      oral antidiabetic drugs 'repaglinide or gliclazide'. The two antihypertensive
      agents, when administered concurrently with oral hypoglycemic agents 'repaglinide
      or gliclazide' in normal and diabetic rats exerted a significant hypoglycemic
      effect. Serum protein levels were mainly unaffected by the two antihypertensive
      drugs. Monopril and losartan exhibit a hypolipidemic effect in normal and
      diabetic rats when administered in combination with oral hypoglycemic agents
      'gliclazide or repaglinide'. Monopril or losartan when used alone exerted
      insignificant effect in high density lipoprotein (HDL) in normal rats, while in
      combination with gliclazide or repaglinide caused a significant increase in HDL
      in normal rats. Concomitantly, monopril or losartan, when administered alone or
      in combination with repaglinide or gliclazide in diabetic rats exerted a
      significant increase in serum HDL. On the other hand, all the investigated drugs
      showed a significant decrease in serum low density lipoprotein (LDL) in normal
      and diabetic rats.

PMID- 15177303
TI  - Is there an inhibitory effect of COX-2 inhibitors on bone healing?
AB  - The use of the new selective cyclooxygenase-2 (COX-2) inhibitors (such as
      celecoxib and rofecoxib) for the treatment of pain and inflammation caused by
      fractures, cementless total joint replacements, soft tissue healing to bone, and
      spinal fusion surgeries has been controversial due to the convincing data
      collected from nonspecific NSAIDs such as indomethacin and naproxen regarding
      their inhibitory effects on bone healing and the similar effects of COX-2
      specific NSAIDs in animal models. Is there a significant inhibitory effect of COX
      2 inhibitors on bone healing in humans? To answer this question, we reviewed
      existing scientific evidence (based mainly on a MedLine search) of the potential
      effects of COX-2 inhibitors on bone healing. The literature shows that COX-2
      inhibitors do have inhibitory effects on bone healing in animal models, but the
      effects of COX-2 inhibitors on similar processes in humans remain largely
      unknown.

PMID- 15177302
TI  - In vivo and in vitro anti-inflammatory activity of Mangifera indica L. extract
      (VIMANG).
AB  - A standard aqueous extract of Mangifera indica L., used in Cuba as an antioxidant
      under the brand name of VIMANG, was tested in vivo for its anti-inflammatory
      activity using commonly accepted assays. M. indica extract, administered
      topically (0.5-2 mg per ear), reduced ear edema induced by arachidonic acid (AA)
      and phorbol myristate acetate (PMA, ED50 = 1.1 mg per ear) in mice. In the PMA
      model, M. indica extract also reduced myeloperoxidase (MPO) activity. This
      extract p.o. administered also inhibited tumor necrosis factor alpha (TNFalpha)
      serum levels in both models of inflammation (AA, ED50 = 106.1 mg kg(-1) and PMA,
      ED50 = 58.2 mg kg(-1)). In vitro studies were performed using the macrophage cell
      line RAW264.7 stimulated with pro-inflammatory stimuli (LPS-IFNgamma or the
      calcium ionophore A23187) to determine PGE2 or LTB4 release, respectively. The
      extract inhibited the induction of PGE2 with IC50 = 64.1 microg ml(-1) and LTB4
      IC50 = 22.9 microg ml(-1). M. indica extract also inhibited human synovial
      secretory phospholipase (PL)A2 with IC 50 = 0.7 microg ml(-1). These results
      represent an important contribution to the elucidation of the mechanism involved
      in the anti-inflammatory and anti-nociceptive effects reported by the standard M.
      indica extract VIMANG.

PMID- 15177304
TI  - The synergistic effect of adenosine A2A receptors agonist, type IV
      phosphodiestease inhibitor and ATP-sensitive K channels activation on free
      radicals production and aggregation of human polymorphoneuclear leukocytes.
AB  - The adenosine A2A receptor agonist CGS21680 (50, 100 and 200 microg/ml), the
      phosphodiserease type IV (PDE IV) inhibitor Rolipram (50, 100 and 200 microg/ml)
      and, ATP-sensitive K+ channels activator Cromakalim (30 and 40 microg/ml), when
      added separately, inhibit oxygen free radicals production from isolated human
      polymorphoneuclear leukocytes (PMNLs), stimulated with phorbol myristate acetate
      (PMA), in a dose dependent manner. When both CGS21680 and Rolipram were combined,
      in vitro, the inhibitory effect on PMNLs free radicals production was
      synergistic. On the other hand, when both the ATP-sensitive K+ channels opener
      (KATP) Cromakalim and the type IV PDE inhibitor Rolipram were combined, produced
      negative synergism (the inhibitory effect of both drugs disappeared).
      Furthermore, CGS21680, Rolipram, Cromakalim and Forskolin produced no significant
      inhibitory effect on PMNLs aggregation when added separately. But when various
      combinations of the above drugs were used, produced significant inhibition of
      aggregation. Only CGS21680 exhibited a scavenging effect on free radicals
      production. From the above results, combination of adenosine A2A agonists and
      type IV PDE inhibitors could serve as potentially novel anti-inflammatory drugs.
      Furthermore, ATP-sensitive K+ channels activators should be considered for
      further investigation as anti-inflammatory drug.

PMID- 15177305
TI  - Protection against septic shock and suppression of tumor necrosis factor alpha
      and nitric oxide production on macrophages and microglia by a standard aqueous
      extract of Mangifera indica L. (VIMANG). Role of mangiferin isolated from the
      extract.
AB  - The present study illustrates the effects of a standard aqueous extract, used in
      Cuba under the brand name of VIMANG, from the stem bark of Mangifera indica L. on
      the production of tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) in
      in vivo and in vitro experiments. In vivo was determined by the action of the
      extract and its purified glucosylxanthone (mangiferin) on TNFalpha in a murine
      model of endotoxic shock using Balb/c mice pre-treated with lipopolysaccharide
      (LPS) 0.125 mg kg(-1), i.p. In vitro, M. indica extract and mangiferin were
      tested on TNFalpha and NO production in activated macrophages (RAW264.7 cell
      line) and microglia (N9 cell line) stimulated with LPS (10ng ml(-1)) and
      interferon gamma (IFNgamma, 2U ml(-1)). M. indica extract reduced dose
      dependently TNFalpha production in the serum (ED50 = 64.5 mg kg(-1)) and the
      TNFalpha mRNA expression in the lungs and livers of mice. Mangiferin also
      inhibited systemic TNFalpha at 20 mg kg(-1). In RAW264.7, the extract inhibited
      TNFalpha (IC50 = 94.1 microg ml(-1)) and NO (IC50 = 64.4 microg ml(-1)). In
      microglia the inhibitions of the extract were IC50 = 76.0 microg ml(-1)
      (TNFalpha) and 84.0 microg ml(-1) (NO). These findings suggest that the anti
      inflammatory response observed during treatment with M. indica extract must be
      related with inhibition of TNFalpha and NO production. Mangiferin, a main
      component in the extract, is involved in these effects. The TNFalpha and NO
      inhibitions by M. indica extract and mangiferin on endotoxic shock and microglia
      are reported here for the first time.

PMID- 15177306
TI  - Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer
      patients.
AB  - 5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid
      tumours, with a reported variability in the pharmacokinetic profile and inter
      patient differences in efficacy and toxicity. Since 5-FU is intracellularly
      metabolised to active cytotoxic fluoronucleotides, some authors suggested it
      would be useful to determine the plasma levels of its main metabolites 5-fluoro
      5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine
      (5-FdUrd), in order to better characterise population pharmacokinetics
      pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method
      to simultaneously determine plasma concentrations of 5-FU and the three main
      metabolites, and we analysed the plasma concentration-time curves of the first
      dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2)
      by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK
      analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the
      following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1),
      respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81
      lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the
      patient covariables which could influence the inter-patient variability in the
      area under the time-concentration curves, and we observed that age, sex, weight,
      body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd
      detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In
      eight subjects, we compared the PK data of the first and the fifth day of dose
      administration, and we found stable 5-FU values, but the 5-FUH2 disposition
      decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(
      1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day
      5. This fact, evident in almost every patient, could suggest a possible reduction
      in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of
      the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd
      and, in fact, in our patients these metabolites were detected only in few
      samples, but most of them at day 5. In conclusion, our study confirms the
      relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5
      FUH2, to better understand the metabolism and to improve the therapeutic
      efficacy.

PMID- 15177307
TI  - No influence of moderate hepatic impairment on the pharmacokinetics of
      lumiracoxib, an oral COX-2 selective inhibitor.
AB  - The aim of this study was to evaluate the influence of hepatic impairment on the
      pharmacokinetics (PK) of the novel cyclooxygenase-2 (COX-2) selective inhibitor
      lumiracoxib (Prexige), so that dose recommendations for clinical use can be
      provided. This was an open-label, single dose, case-controlled study in which
      eight subjects with liver cirrhosis classed as moderate hepatic impairment (Child
      Pugh score: 7-9) and eight demographically-matched healthy subjects received a
      single oral 400 mg dose of lumiracoxib. Routine safety assessments were made and
      blood samples were taken for determination of lumiracoxib concentrations for 96 h
      post dose. The ex vivo binding of lumiracoxib to plasma proteins was determined
      pre dose and at 2 and 12 h post dose. An analysis of variance was used to detect
      differences in PK parameters (AUC, Cmax and Tmax) between the treatment groups.
      There were no significant differences between subjects with moderate hepatic
      insufficiency and healthy subjects in the area under the lumiracoxib plasma
      concentration-time curves (AUC(0-infinity)): 29.2 +/- 6.7 microg h ml(-1) versus
      28.7 +/- 6.3 mircrog h ml(-1). The rate of absorption of lumiracoxib was not
      significantly altered by hepatic impairment based on Cmax and Tmax. The protein
      bound fraction of lumiracoxib exceeded 98% both in healthy control subjects and
      in those with moderate hepatic insufficiency. A single dose of 400 mg lumiracoxib
      was well tolerated. In conclusion, no dose adjustments appear to be required when
      lumiracoxib is administered to patients with either mild or moderate hepatic
      impairment.

PMID- 15177308
TI  - The effect of naringin, a bioflavonoid on ischemia-reperfusion induced renal
      injury in rats.
AB  - There is increasing evidence to suggest that toxic oxygen radicals play a role in
      the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study
      was designed to investigate the effects of naringin (Ng), a bioflavonoid in I/R
      induced renal failure in rats. The protective effect of naringin against the
      damage inflicted by reactive oxygen species (ROS) during renal I/R was
      investigated in Sprague-Dawley rats using histopathological and biochemical
      parameters. In one set of experiments animals were unilaterally nephrectomized,
      and subjected to 45 min of left renal pedicle occlusion and in another set both
      the renal pedicles were occluded for 45 min followed by 24h of reperfusion.
      Naringin (400 mg kg(-1), p.o.) was administered 60 min prior to ischemia. At the
      end of the reperfusion period, rats were sacrificed. Thiobarbituric acid reactive
      substances (TBARS), reduced glutathione (GSH) levels, catalase (CAT), and
      superoxide dismutase (SOD) activities were determined in renal tissue. Serum
      creatinine and blood urea nitrogen (BUN) concentrations were measured for the
      evaluation of renal function. Ischemic control animals demonstrated severe
      deterioration of renal function, renal morphology and a significant renal
      oxidative stress. Pretreatment of animals with naringin markedly attenuated renal
      dysfunction, morphological alterations, reduced elevated TBARS levels and
      restored the depleted renal antioxidant enzymes. The findings imply that ROS play
      a causal role in I/R induced renal injury and naringin exert renoprotective
      effects probably by the radical scavenging and antioxidant activities.

PMID- 15177309
TI  - Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian
      population.
AB  - The polymorphic cytochrome P450 isoenzymes (CYPs) 2C9, 2C19 and 2D6 metabolise
      many important drugs, as well as other xenobiotics. Their polymorphism gives rise
      to important interindividual and interethnic variability in the metabolism and
      disposition of several therapeutic agents and may cause differences in the
      clinical response to these drugs. In this study, we determined the genotype
      profile of a random Italian population in order to compare the CYP2C9, CYP2C19
      and CYP2D6 allele frequencies among Italians with previous findings in other
      Caucasian populations. Frequencies for the major CYP2C9, CYP2C19 and CYP2D6
      mutated alleles and genotypes have been evaluated in 360 unrelated healthy
      Italian volunteers (210 males and 150 females, aged 19-52 years). Genotyping has
      been carried out on peripheral leukocytes DNA by molecular biology techniques
      (PCR, RFLP, long-PCR). CYP2C9, CYP2C19 and CYP2D6 allele and genotype frequencies
      resulted in equilibrium with the Hardy-Weinberg equation. One hundred and
      fourteen subjects (31.7%) carried one and 23 subjects (6.4%) carried two CYP2C9
      mutated alleles. Sixty-eight (18.9%) volunteers were found to be heterozygous and
      six (1.7%) homozygous for the CYP2C19*2, while no CYP2C19*3 was detected in the
      evaluated population. Volunteers could be divided into four CYP2D6 genotypes
      groups: 192 subjects (53.3%) with no mutated alleles (homozygous extensive
      metabolisers, EM), 126 (35.0%) with one mutated allele (heterozygous EM), 12
      (3.4%) with two mutated alleles (poor metabolisers, PM) and 30 (8.3%) with
      extracopies of a functional gene (ultrarapid metabolisers, UM). Frequencies of
      both CYP2C9 and CYP2C19 allelic variants, as well as CYP2D6 detrimental alleles,
      in Italian subjects were similar to those of other Caucasian populations.
      Conversely, the prevalence of CYP2D6 gene duplication among Italians resulted
      very high, confirming the higher frequency of CYP2D6 UM in the Mediterranean area
      compared to Northern Europe.

PMID- 15177310
TI  - Echinomycin and a novel analogue induce apoptosis of HT-29 cells via the
      activation of MAP kinases pathway.
AB  - Echinomycin, in typical DNA minor groove binder, had comparable efficacy compared
      to 5-FU in the phase II trail of colon cancer treatment. To improve echinomycin's
      drawback (hydrophobicity, toxicity), we synthesized the YK-2000 series
      (echinomycin analogues). Among these, YK-2000 had the best in vitro cytotoxicity
      on six different human solid cancer cell lines. Echinomycin and YK-2000 were
      enabled to induce the apoptosis on the HT-29 colorectal cancer cell line. The
      hypothesis that apoptosis in the HT-29 cell was triggered by echinomycin and YK
      2000 were supported through DNA laddering, poly-(ADP-ribose) polymerase (PARP)
      cleavage, and flow cytometric analysis. In order to explore the signaling pathway
      of echinomycin and YK-2000, we examined the phosphorylation of extracellular
      signal-regulated kinase1/2 (ERK1/2), stress-activated protein kinase/c-Jun N
      terminal kinase (SAPK/JNK), and p38 MAP kinase. However, what the mechanism of
      cancer cell death would be induced by echinomycin and YK-2000 is unknown. Here,
      we present some evidence that one of the major apoptotic signaling pathways
      induced by echinomycin and YK-2000 is possibly the MAP kinases pathway in HT-29
      human colon cancer cells.

PMID- 15177312
TI  - Clinical presentation and physical examination.
AB  - The main points to assimilate concerning the presentation of peripheral nerve
      tumors are their subtle features, few symptoms, and even fewer signs. It is no
      surprise that most lesions become apparent only when a mass becomes palpable.
      Pain, paresthesia, and a positive Tinel's sign are sometimes the only features,
      with the paresthesia being variable and unreliable as a clinical entity. Loss of
      profound sensory function and motor function is generally a late feature. When
      patients present with progressive pain and significant sensory and any motor
      deficits, these signs suggest that a more sinister lesion is present. It cannot
      be overstressed that the stigmata of neurocutaneous disorders should be sought in
      all patients with suspected peripheral nerve tumors. Similarly, the presence of
      such stigmata in a patient presenting with vague paresthetic symptoms in a nerve
      distribution should make the clinician suspect and investigate for an underlying
      nerve tumor.

PMID- 15177311
TI  - An eclectic history of peripheral nerve surgery.
AB  - It is hard to decide where history stops and contemporary development of
      peripheral nerve surgery begins. This article provides an eclectic view of the
      history of peripheral nerve surgery. In trying to keep the story moving, the
      publications of many authors have been omitted. For this, we are sorry. We have
      also stopped short of reporting the contemporary history of molecular biology as
      applied to peripheral nerve regeneration. The future of peripheral nerve repairs
      lies in our understanding of the molecular cascades that stimulate axon growth
      and guide the axon to its proper destination. We hope that this review shows the
      reader that researchers who got us where we are traveled a road filled with
      erroneous dogma, bad advice,and misleading data. We believe that the lessons
      learned from those who brought us back to the right path are applicable to many
      disciplines.

PMID- 15177313
TI  - Diagnostic steps, imaging, and electrophysiology.
AB  - The patient with a peripheral nerve tumor can present with a variety of signs and
      symptoms, including pain, motor weakness, sensory deficit, a palpable mass, and
      even as an asymptomatic incidental finding. Although most tumors that arise from
      nerve are solitary tumors associated with a single nerve, they may also be
      associated with global diseases, such as neurofibromatosis type I (von
      Recklinghausen's), in which case, there maybe multiple masses involving several
      nerves. Most peripheral nerve tumors are histologically benign; however, they may
      experience malignant degeneration, especially in the setting of
      neurofibromatosis. Treatment in the form of gross total surgical removal is
      therefore indicated in most nerve tumors for histologic diagnosis as well as for
      relief of symptoms. The goals of the initial diagnostic steps, imaging and
      electrophysiology, are to determine baseline clinical neurologic function, define
      anatomic location and extent of the tumor, and record baseline electromyographic
      parameters. Once these elements are defined, the surgeon may proceed to the
      operating room with a level of confidence as to how to approach the lesion and
      remove it safely. Biopsy of peripheral nerve tumors is to be discouraged over
      gross total removal, and this can be avoided by proper preoperative diagnostic
      workup.

PMID- 15177314
TI  - The neurofibromatoses: hereditary predisposition to multiple peripheral nerve
      tumors.
AB  - Neurosurgeons must be aware of the neuro-fibromatoses because they frequently
      present with nervous system tumors. Such patients develop numerous peripheral
      nerve sheath tumors; fortunately, only a few of these tumors are symptomatic or
      malignant. The tumor burden in individual patients can be remarkable, however,
      producing significant morbidity and requiring extensive or repeated care by a
      skilled neurosurgeon. Because it is impossible to predict which of the deep
      neurofibromas will undergo malignant transformation, it behooves clinicians and
      patients to be aware of any change in symptoms or growth of tumors, because early
      resection of MPNST offers the only chance for cure. Neurosurgical professionals
      should be familiar with the diagnostic criteria of the neurofibromatoses, because
      the patient who presents with an initial neurofibroma or schwannoma immediately
      falls into a category in which those disorders must be ruled out. In this regard,
      a family history of nerve sheath tumors is revealing and should prompt referral
      for a clinical genetics evaluation. Cutaneous manifestations of NFI can confirm
      the diagnosis at initial presentation. Missing the initial presentation of a
      patient with NF2 can lead to marked morbidity, such as deafness,because
      surveillance for subsequent tumors was inadequate. Tumorigenesis in all
      neurofibromatoses involves loss of tumor suppressor genes. These disorders
      illustrate that the two-hit loss of tumor suppressor gene model, which applies
      best for NF2, is oversimplified. As with most cancers,a theory of multistep
      progressive acquisition of genetic changes that promote unregulated grow this
      emerging in schwannomatosis. In addition, the hyperpigmentation and learning
      disability of NF 1 highlight that loss of one copy of the gene is sufficient to
      cause nontumoral manifestations of the disorder. Genetic counseling and testing
      have an important role in the diagnosis of NFI and NF2 as well as in the
      management of all the neurofibromatoses.

PMID- 15177315
TI  - Pathologic classification of peripheral nerve tumors.
AB  - Peripheral nerve tumors show an interesting histologic variety despite being
      composed ofa limited array of cellular constituents. As we learn more about the
      interplay between the Schwann cells, perineurial cells, and ganglion cells that
      comprise these tumors, it is likely that we will better understand the biologic
      behavior of these important tumors. Key issues for the pathologist include
      distinguishing schwannomas from neurofibromas, ganglioneuromas from neurofibromas
      involving ganglia, and MPNSTs from cellular schwannomas or neurofibromas. The
      association of each of these tumors with genetic tumor disorders provides a
      unique window into discovering basic mechanisms of cell regulation and
      tumorigenesis that may ultimately shed light on the biology of a much wider array
      of human disease.

PMID- 15177316
TI  - Peripheral nerve tumors: surgical principles, approaches, and techniques.
AB  - The surgical treatment of peripheral nerve sheath tumors is dependent on the
      tumor's neoplastic nature and its anatomic location. Surgical principles for
      nerve sheath tumors focus on surgical decision making common to all peripheral
      nerve sheath tumor operations and then on that particular to a given tumor type.
      Surgical approaches for nerve sheath tumors vary according to the local anatomy.
      Exposure on an extremity is relatively straightforward, but as the location
      becomes more proximal, anatomy conspires to protect nerves, plexuses, and the
      spinal cord, making surgical exposure more difficult. As a consequence, selected
      surgical approaches to nerve sheath tumors in these more protected areas are
      specifically described.

PMID- 15177317
TI  - Operative outcomes of 546 Louisiana State University Health Sciences Center
      peripheral nerve tumors.
AB  - The surgical management of benign PNSTs and some other benign tumors can result
      in successful outcomes. Schwannomas and nonplexiform neurofibromas can be
      resected with minimal deficit by sparing all but the fascicles entering and
      exiting the tumor. These fascicles, if not functional by NAP testing, can be
      resected, and the tumor can be removed. Surgery to remove other benign lesions,
      such as intraneural ganglion cysts, hemangiomas,and ganglioneuromas, has become
      more timely. The desmoid tumor, although microscopically benign, is locally and
      regionally invasive, and chemotherapy and radiation therapy may need to be used
      as adjunctive therapy. Neurogenic sarcomas and other malignancies have high
      morbidity and mortality despite aggressive limb ablation or limb-sparing surgery
      with adjunctive therapy. Thus, surgery involving decompression as well as the
      most complete resection possible remains the essential initial step in the
      management of most malignancies.

PMID- 15177318
TI  - Complication avoidance.
AB  - Complications are relatively common in the evaluation and treatment of patients
      with peripheral nerve tumors. The complications are frequently avoidable.
      Physicians and surgeons managing patients with these lesions must possess
      sufficient knowledge about peripheral nerve tumors and their natural history as
      well as good diagnostic, decision-making, and technical skills. By avoiding often
      unnecessary complications, patients and surgeons can be rewarded with better
      outcomes.

PMID- 15177319
TI  - Malignant peripheral nerve sheath tumors.
AB  - The rarity of MPNSTs and the lack of any singular diagnostic radiologic or
      pathologic signature lead to several management challenges. These tumors are best
      managed as part ofa multidisciplinary team so as to optimize patient care and
      facilitate research. Suspicion of an MPNST based on clinical or radiologic
      alteration of a soft tissue mass in proximity to a peripheral nerve, especially
      in the context of NF I, should lead to referral to such a tertiary center. Early
      diagnosis followed by oncologic surgery to obtain tumor-free margins provides the
      best chance for long-term cure. Psychologic support and occupational
      rehabilitation are vital components of the overall care of these relatively young
      patients faced with often disabling surgery. Current adjuvant therapy with
      radiation and chemotherapy is suboptimal. There have been major inroads toward
      the molecular biologic understanding of MPNSTs,with several biologic targets that
      are of potential therapeutic interest. Proper evaluation of these novel and
      promising management strategies requires a concerted effort to refer these
      patients to the tertiary centers through which multi-institutional clinical
      trials can be undertaken.

PMID- 15177320
TI  - Paraspinal nerve sheath tumors.
AB  - Spinal tumors compose a vast heterogeneous group of neoplasms that are classified
      by origin into vertebral column, spinal canal, or paraspinal region tumors.
      Tumors with both intraspinal (intracanalicular) and paraspinal (extracanalicular)
      components that communicate via an intravertebral foramen are defined as
      "dumbbell tumors." This article focuses on the characteristics of a few types of
      paraspinal tumors, with special emphasis on the management of nerve sheath
      dumbbell tumors.

PMID- 15177321
TI  - Nonneoplastic peripheral nerve tumors.
AB  - Most of the nonneoplastic tumor-like lesions affecting the peripheral nervous
      system are rarely encountered. In many situations, a good history of the
      presenting symptoms can suggest a reactive or infectious neuroma. The physical
      examination can also suggest an inflammatory or hyperplastic lesion. In some
      cases, however, the correct diagnosis can only be made at surgery. Nonetheless,
      awareness of these lesions is important in limiting unnecessarily aggressive
      surgical procedures. Patients suspected of having nonneoplastic lesions are
      followed and treated surgically for symptomatic relief or when the diagnosis is
      unclear. In some situations, the surgical treatment of choice may be debated.
      Nevertheless, we adopt a conservative approach to these lesions and reserve more
      aggressive techniques for cases that do not respond to more conservative means.

PMID- 15177322
TI  - The management of neuropathic pain.
AB  - Although the definitive treatment for neuropathic pain remains elusive,
      scientific investigation continues to provide the field with better and better
      therapies. As our understanding of the neurophysiologic mechanisms of pain
      improves, pharmaceutic therapies have become more effective even as side effects
      are minimized. Surgical therapies have become more precise and less invasive.
      Advances in neurophysiology have given rise to new advances in the field of neuro
      modulation. As this therapy continues to emerge, ablative procedures recede as
      therapies offering minimal invasiveness, reversible mechanisms, and long-standing
      relief emerge to the forefront of treatment for neuropathic pain.

PMID- 15177323
TI  - Case studies for illustration and discussion: peripheral nerve tumors.
AB  - This article gives a presentation of a variety of surgical cases of peripheral
      nerve tumors for illustration and discussion. The first three cases include a
      schwannoma, a neurofibroma, and a desmoid tumor of the brachial plexus region.
      Case 4 is that of a patient with a common peroneal ganglion cyst, and case 5 is
      that of a patient with an angiolipoma of the forearm. Cases 6 through 8
      illustrate a plexiform neurofibroma, a malignant peripheral nerve sheath tumor,
      and a metastatic carcinoma to the brachial plexus region. In case 9, a patient
      with schwannomatosis was treated for multiple spinal schwannomas.

PMID- 15177326
TI  - IAEA-MEL's underground counting laboratory in Monaco--background characteristics
      of HPGe detectors with anti-cosmic shielding.
AB  - The background characteristics of large volume HPGe detectors installed in IAEA
      MEL's underground counting laboratory situated at a depth of 35 m water
      equivalent have been investigated. Both single gamma-ray spectra as well as gamma
      ray spectra gated by anti-cosmic shielding made of plastic scintillators are
      presented. The advantages of anti-cosmic shielding for HPGe detectors, especially
      in underground counting laboratories operating at shallow depths, are discussed.
      The authors present several examples of analysis of radionuclides in marine
      samples by single gamma-ray spectrometers with anti-cosmic shielding, an anti
      Compton spectrometer and a Ge-Ge telescope designed for the analysis of low
      energy gamma-emitters.

PMID- 15177327
TI  - The development of a 222Rn standard solution dispenser at NPL.
AB  - The design, operation and performance of a unit for dispensing standardised
      aqueous solutions of 222Rn is described. The unit consists of a sealed
      polyethylene capsule (containing a known weight of a 226Ra standard solution)
      immersed in water inside a cylindrical stainless-steel accumulation chamber. The
      chamber is fitted with valves at each end and has a central bellows so that the
      chamber can be compressed to dispense solution. The degree of compression, and
      thus the weight of solution dispensed, is controlled by a microprocessor
      controlled motor-drive mechanism. The solution is dispensed via a needle
      positioned beneath the lower valve.

PMID- 15177328
TI  - Fast methods for determination of antropogenic actinides and U/Th-series isotopes
      in aqueous samples.
AB  - Rapid and simple methods are applied at the PSI radioanalytical laboratory for
      determining anthropogenic actinides in waste and nuclear reactor waters (U, Pu,
      Am, Cm) as well as for analysis of naturally occurring alpha-emitters in
      continental river and ground water. Anion exchange chromatography followed by
      alpha-spectrometry as well as alpha/beta-LSC is applied for the reactor coolant
      waters. To avoid alpha-spectrum interference between 238Pu and 241Am at 5.5 MeV,
      the Pu-fraction is purified using anion exchange resin. Prior to the separation
      of the Pu-fraction, all actinides (U, Pu, Am, Cm) are adsorbed batch-wise under
      stirring onto Actinide Resin and subsequent decomposition of the reagent. The
      residue is then re-dissolved in a sulfate buffer solution for electrolytic
      deposition. In tabular water samples isotopes of Ra and Po are analyzed
      additionally via sorption onto manganese coated discs (Ra) and deposition on
      silver discs (Po). For counting times of 1 day and use of 0.1-1l sample aliquots,
      detection limits of a few mBql(-1) can be obtained easily.

PMID- 15177329
TI  - Locating a "hot spot" in the lungs when using an array of four HPGe detectors.
AB  - Considerable errors in the activity determination in lungs can be induced for the
      case of a "hot spot". Modern lung counter systems use several HPGe detectors, and
      the count rate ratios of the detectors can be used to locate the "hot spot" and
      apply correction algorithms. Some criteria for location determination of a point
      source in the lungs were investigated, and it is shown that an average error of
      up to about 10% can be achieved.

PMID- 15177330
TI  - Characterisation of selected cadmium--zinc--telluride detectors.
AB  - The performance of new detection technologies like the ambient temperature
      cadmium--zinc--telluride (CdZnTe) detectors is of interest for search and
      identification of radioactive material in a range of applications. Various types
      of CdZnTe detectors that are currently available on the market as well as some
      specially designed ones were tested and characterised. The examination included
      peak shape, energy-resolution, energy-range and also the usability in hand-held
      applications. Additionally, the effects of the use of a cooling system were
      evaluated.

PMID- 15177331
TI  - Extension of the efficiency calibration of germanium detectors using the GESPECOR
      software.
AB  - To avoid losses due to coincidence summing, the efficiency calibration of gamma
      spectrometers is often carried out by means of radionuclides emitting only one
      photon during a single decay. Calibration with this kind of radionuclides has,
      however the disadvantage that the energy range of the gamma rays (46 keV<E<1115
      keV) is limited. Coincidence-summing corrections can be calculated with the Monte
      Carlo program Germanium Spectrometry Correction for multi gamma radionuclides
      which emit photons with energies above this range. The efficiency curve as a
      function of energy can therefore be extended up to 2.7 MeV with uncertainties
      below 4%.

PMID- 15177332
TI  - Efficiency calibration of high volume samples using the GESPECOR software.
AB  - In this paper the Monte Carlo simulation program GESPECOR is applied for the
      computation of the efficiency of an HPGe gamma-spectrometry system used for the
      measurement of high volume samples. The detector characterization required for
      Monte Carlo simulation is achieved by a trial and error procedure using the
      efficiency values measured with point sources placed in several positions. After
      detector characterization, the efficiency values appropriate for the assessment
      of 220l waste drums are computed and compared with experimental values.

PMID- 15177333
TI  - Substrate characterization for underwater gamma spectrometry: tank measurement
      results utilizing efficiencies calculated via Monte-Carlo code.
AB  - In order to study the sediment contamination, underwater gamma-ray spectrometry
      measurements performed by the sub-marine detector Canberra HpGe with a relative
      efficiency of 80% were carried out in an equipped tank at the Ukrainian
      Hydrometeorological Institute of Kiev. Different substrates, certified sources
      and experiment geometrical set-up were arranged. Efficiencies were calculated by
      in situ object counting system (ISOCS) software. ISOCS performance tests using
      certified sources were carried out by comparing laboratory measurements, and
      measurement results for mineralogy and density performances are reported.

PMID- 15177334
TI  - Optimization of an active anti cosmic veto shielding.
AB  - The active veto shielding of a low-level gamma spectrometer has been optimized to
      reduce the background in the interval 20-2700 keV by a factor of nine. The signal
      to noise ratio was increased, due to the reduction of electromagnetic
      interference coming from the power line, by using an uninterruptible power supply
      and specially designed line filters. The overall performance of the veto
      shielding was improved by using time spectroscopy to find the optimum time
      duration for the coincidence window.

PMID- 15177335
TI  - Monte Carlo simulation of the response of a germanium detector for low-level
      spectrometry measurements using GEANT4.
AB  - In this paper, we will expose the work performed for the adaptation and
      refinement of the GEANT4 simulation toolkit (originally designed for Monte Carlo
      simulations in High-Energy Physics) in order to simulate Ge detectors in low
      level gamma spectrometry. Special emphasis will be given to show and validate our
      own algorithms implemented in GEANT4 code for variance reduction and data
      analysis, that have been used for a quicker and precise efficiency calibration at
      different source-detector configurations of one of the low-level germanium gamma
      systems available in our laboratory.

PMID- 15177336
TI  - Detection and quantification limits: basic concepts, international harmonization,
      and outstanding ("low-level") issues.
AB  - A brief review is given of concepts, basic definitions, and terminology for
      metrological detection and quantification capabilities, representing harmonized
      recommendations and norms of the International Union of Pure and Applied
      Chemistry (IUPAC) and the International Organization for Standardization (ISO),
      respectively. Treatment of the (low-level) blank and variance function are
      discussed in some detail, together with special problems arising with detection
      decisions and the reporting of low-level data. Key references to the
      international documents follow, as well as specialized references addressing very
      low-level counting data, skewed environmental blank distributions, and multiple
      and multivariate detection decisions.

PMID- 15177337
TI  - Currie detection limits in gamma-ray spectroscopy.
AB  - Currie Hypothesis testing is applied to gamma-ray spectral data, where an optimum
      part of the peak is used and the background is considered well known from nearby
      channels. With this, the risk of making Type I errors is about 100 times lower
      than commonly assumed. A programme, PeakMaker, produces random peaks with given
      characteristics on the screen and calculations are done to facilitate a full use
      of Poisson statistics in spectrum analyses. SHORT TECHNICAL NOTE SUMMARY: The
      Currie decision limit concept applied to spectral data is reinterpreted, which
      gives better consistency between the selected error risk and the observed error
      rates. A PeakMaker program is described and the few count problem is analyzed.

PMID- 15177338
TI  - Peak resolution and tailing in alpha-particle spectrometry for environmental
      samples.
AB  - Peak resolution in alpha-particle spectrometry is generally quoted as full-width
      at half maximum. However, the extent of tailing of alpha particle peaks into
      regions of lower energy is often a critical factor for accurate spectral
      analysis, particularly given the relatively low count rates observed for many
      environmental samples. In this paper we examine the influence of various factors
      on peak resolution and tailing for spectra collected using solid-state alpha
      detectors, in particular chamber gas pressure and source deposit thickness.

PMID- 15177339
TI  - Underground measurements of radioactivity.
AB  - The exceptional sensitivity of gamma-ray spectrometry in underground laboratories
      has increasing application because of the important science and technology that
      it allows to be studied. Early work focused on rare fundamental phenomena, e.g.
      double beta decay, but a growing number of underground measurements is being
      performed in fields such as environmental monitoring, surveillance of nuclear
      activities, benchmarking of other physical techniques and materials selection for
      equipment which require materials with extremely low levels of radioactivity.
      This report describes the state of the art in underground gamma-ray spectrometry.
      Backgrounds of HPGe-detectors at various underground laboratories are presented
      and compared. Improved techniques and detectors are described and needs of deep
      underground facilities for higher sensitivity measurements are discussed.

PMID- 15177340
TI  - Deep underground measurements of 60Co in steel exposed to the Hiroshima atomic
      bomb explosion.
AB  - When using gamma-ray spectrometry performed deep underground, it is possible to
      measure 60Co activities down to 0.1 mBq in steel samples of some 100 g without
      any pre-concentration. It is thus still possible to measure 60Co induced by
      neutrons from the atomic bomb explosion in Hiroshima in pieces of steel collected
      at distances up to about 1200 m slant range. The results of non-destructive
      measurements of eight steel samples are compared with the 1986 Dose Re-Evaluation
      (DS86) model calculations.

PMID- 15177341
TI  - Background components of Ge detectors in Ogoya underground laboratory.
AB  - Ogoya underground laboratory, (OUL; 270 m water equivalent), has 5 well, 4
      planar, and 1 coaxial-type ultra-low background Ge detectors with passive shield
      of old lead. An anticoincidence system with a plastic scintillator (PS) has been
      tested to reduce cosmic-ray-induced background. Energy spectra of PSs,
      coincidence counting rate, and angular distribution of cosmic rays were studied.
      Based on this study, we propose a new index of Ge surface area-normalized
      background counting rate (d(-1) cm(-2)) to compare shielding efficiency between
      different types of Ge detectors.

PMID- 15177342
TI  - Ogoya underground laboratory for the measurement of extremely low levels of
      environmental radioactivity: review of recent projects carried out at OUL.
AB  - Recent topical measurements performed in the Ogoya Underground Laboratory are
      briefly summarized. The paper deals mainly with the following topics:
      measurements of variations of airborne 222Rn, 210Pb, 210Po and 7Be with high
      temporal resolution; the depth profile of 137Cs in Pacific water collected in
      1957; cosmic-ray-induced 22Na in surface air, rain, river and lake waters; 152Eu
      in granite exposed to the Atomic Bomb in Hiroshima in 1945; and depleted uranium
      used in the Iraq War 2003.

PMID- 15177343
TI  - Low-level gamma spectrometry using beta coincidence and Compton suppression.
AB  - A low-level gamma-ray spectrometry system was developed using a Ge(Li) detector
      with 6% relative efficiency coupled to a 2pi beta plastic detector for
      coincidence selection and a massive NaI(Tl) detector for Compton suppression. The
      integral background count rate for (50-1500)keV was 0.5 s(-1)kg(-1) (Ge), using
      only beta coincidences. With Compton suppression, a value of 0.25 s(-1)kg(-1)
      (Ge) was obtained. Spectra with and without Compton suppression were studied for
      60Co, 137Cs and 152Eu point sources. Considerations are made concerning the
      Compton suppression advantages in different situations.

PMID- 15177344
TI  - Ar and Kr concentrations in nitrogen as a measure of the 39Ar and 85Kr activities
      in connection with the solar neutrino experiment BOREXINO.
AB  - Among other radionuclides, 39Ar and 85Kr are potential background sources in the
      solar neutrino detector BOREXINO. The expected low event rate requires that the
      nitrogen used in the experiment needs to have lower concentrations than 0.5
      microBq/m3 for 39Ar and 0.2 microBq/m3 for 85Kr, corresponding to volume
      concentrations in N2 of 0.4 x 10(-6)m3/m3 for Ar and 0.2 x 10(-12)m3/m3 for Kr.
      Applying gas mass spectrometry and special care in the sampling technique we
      succeeded in finding the required purity. In addition, we studied the possibility
      to purify nitrogen from Kr by the adsorption method.

PMID- 15177345
TI  - Spectrometric determination of low activities of gamma emitters in water samples.
AB  - Two variants of the ISO 10703:1997 procedure were developed: (i) the partial
      substitution of the reagents, thereby reducing the mass of the dry residue by a
      factor of 2; (ii) preparation of two gamma spectrometry sources by selectively
      precipitating the radioiodines onto one, and the rest of the radioactive cations
      onto the other. In variant (ii) the time required to prepare a 131I source from
      20 l of water is 2.5 days, and the detection limit is 0.9 mBq/l.

PMID- 15177346
TI  - Reference measurements of low levels of 60Co in steel.
AB  - Analysis of 60Co traces in the matrix steel has recently gained in importance.
      This paper deals with the low-level gamma-ray spectrometry measurements that were
      part of a recent German survey aiming at determining the present levels of
      artificial radionuclides in commercial steel. Specific 60Co activities in the
      order of 10(-5) Bq g(-1) were measured. To show equivalence in these
      measurements, a comparison exercise of European underground laboratories has been
      carried out, additionally.

PMID- 15177347
TI  - Highly sensitive measurements of radioactive noble gas nuclides in the BOREXINO
      solar neutrino experiment.
AB  - Low background miniaturized proportional counters as developed for the GALLEX
      solar neutrino experiment can be applied to the detection of radioactive noble
      gas nuclides at very low activities. We have developed an apparatus that allows
      the activity of trace amounts of isotopes of the four noble gases Ar, Kr, Xe and
      Rn to be measured. The technique includes contamination-free chromatographic
      purification of raw gas samples and subsequent low-level counting. Minimum
      detectable activities of 100 microBq and below have been attained. The developed
      techniques can be used to determine the 222Rn and 85Kr concentration in nitrogen
      for the solar neutrino experiment BOREXINO. By applying efficient techniques to
      concentrate noble gases from nitrogen, minimum detectable activity concentrations
      below 1 microBq/m3 of nitrogen (STP) have been reached for both nuclides.

PMID- 15177348
TI  - Collection efficiency of particulate and xenon sampling in the international
      monitoring system of the comprehensive Nuclear-Test-Ban Treaty.
AB  - Low-level monitoring of atmospheric radioactivity requires sampling with high
      collection efficiency for the aerosols and gases of interest. The radionuclide
      station network of the International Monitoring System designed to detect very
      low-levels of airborne radionuclides will consist of 80 particulate and 40 noble
      gas stations. This paper reports on studies performed to select suitable filter
      material and to characterise the sampling efficiency of air inlet configurations
      of high-volume particulate samplers. It also considers the collection
      characteristics of automatic xenon sampling systems.

PMID- 15177349
TI  - The measurement of radioactive noble gases by DWD in the frame of the Global
      Atmospheric Watch programme of WMO.
AB  - The Deutscher Wetterdienst (DWD, German Meteorological Service) is integrated
      into the Global Atmospheric Watch programme (GAW) of the World Meteorological
      Organization (WMO). According to this programme a variety of chemical compounds
      and radionuclides are measured at global stations. At the research platform
      "Schneefernerhaus" 7Be, 222Rn, and its decay products, 14C in CO2, tritium as
      HTO, 85Kr and 133Xe are continuously monitored by the DWD or are sampled and then
      measured at the central laboratory in Offenbach. The results are used as
      additional information for studying atmospheric mixing processes or on the other
      hand as information about the background level of radioactivity. As a main
      subject of this paper the integration and partly the optimization of sampling and
      measuring procedures for the detection of noble gases are described. In
      particular, the methods of quality assurance are discussed for Kr and Xe.

PMID- 15177350
TI  - Low level noble gas measurements in the field and laboratory in support of the
      Comprehensive Nuclear-Test-Ban Treaty.
AB  - Over 300 daily environmental radioxenon samples were analyzed using French
      developed SPALAX for automatic sample preparation including high-resolution gamma
      spectrometry. The 133Xe sensitivity was significantly better than 1 mBq/m3
      (specified criterion for Comprehensive Nuclear-Test-Ban Treaty verification).
      Radioxenon analysis was extended to include the X-ray region by improved detector
      window, sample cell design, efficiency calibration, line shape fitting and
      background analysis. The resulting analysis offers a 4-16 fold improvement in
      sensitivity for 133mXe and 131mXe, respectively.

PMID- 15177351
TI  - Development of radon calibration chamber at KRISS.
AB  - Radon calibration chamber has been constructed to test and calibrate radon and
      radon progeny detectors at various environmental conditions and to study the
      characteristic behavior of radon decay products. The size of main room in the
      chamber is 3.2 m x 3.3 m x 2.4 m (25.3 m3) and the total volume of the chamber is
      39.1 m3. The maximum concentration of radon in the chamber can be maintained up
      to 250 kBq m(-3) and temperature and humidity are controlled in the ranges of (10
      40) degrees C and (30-80)%, respectively. The equilibrium factor and unattached
      fraction of radon progeny are determined at the radon concentration of 2 kBq m(
      3).

PMID- 15177352
TI  - The influence of environmental parameters in electrostatic cell radon monitor
      response.
AB  - To better understand the influence of air parameters such as pressure, humidity
      and temperature on the counting efficiency of a radon monitor based on solid
      state silicon detectors and radon daughter electrostatic collection, a number of
      experimental and theoretical studies have been performed. This study has been
      carried out using a multiparameter acquisition system used to monitor radon,
      temperature, pressure and relative humidity. Results show that air humidity and
      temperature inside the cell influence radon daughter collection in a significant
      way. For the tested cell, a decrease of the 218Po counting efficiency vs.
      humidity and temperature increase was measured in the ranges from 10% to 90% and
      from 15 degrees C to 35 degrees C, respectively. These effects were also
      theoretically studied by using Monte-Carlo software, which takes into account
      electrostatic collection of radon daughters in the cell, by considering the
      recombination process as a function of climatic parameters. A satisfactory
      agreement was obtained between experimental measurements and theoretical
      calculations.

PMID- 15177354
TI  - Use of TEVA resin for the determination of U isotopes in water samples by Q-ICP
      MS.
AB  - In order to measure uranium isotopic mass ratio in natural water samples by Q-ICP
      MS, an application of TEVA resin (Eichrom) was studied to separate and
      concentrate U. After being evaporated to dryness, the sample residue was
      dissolved in 6 M HCl, then, TEVA extraction was carried out. U extracted on the
      resin could be removed with 20 ml of 1 M HCl (U fraction) when Fe content was
      lower than 2 mg. U recovery in U fraction showed a negative correlation with Fe
      content in the samples.

PMID- 15177353
TI  - Accelerator mass spectrometry measurement of 240Pu/239Pu isotope ratios in Novaya
      Zemlya and Kara Sea sediments.
AB  - Generally low levels of plutonium in environmental samples, often combined with
      limited sample sizes, necessitate reliable low-level techniques for determination
      of Pu isotopes. Accelerator mass spectrometry (AMS) has proved to be a powerful
      method for measuring low-level Pu activity concentrations and Pu isotope ratios.
      Based on procedural blanks, detection limits for AMS were below 1 fg Pu
      (equivalent to ca. 2 microBq 139Pu), which can compete with both TIMS, high
      sensitivity ICP-MS, and certainly alpha-spectrometry, while showing less
      interference, memory and matrix effects as compared to routine ICP-MS techniques.
      In addition to low detection limits, the technique offers the advantage of giving
      information on Pu isotope ratios. Measurements of sediments collected from
      dumping sites at Novaya Zemlya showed deviation from global fallout 240Pu/239Pu
      ratios.

PMID- 15177355
TI  - 2003: a centennial of spinthariscope and scintillation counting.
AB  - In 1903 W. Crookes demonstrated in England his "spinthariscope" for the visual
      observation of individual scintillations caused by alpha particles impinging upon
      a ZnS screen. In contrast to the analogue methods of radiation measurements in
      that time the spinthariscope was a single-particle counter, being the precursor
      of scintillation counters since. In the same period F. Giesel, J. Elster and H.
      Geitel in Germany also found that scintillations from ZnS represent single
      particle events. This paper summarises the historical events relevant to the
      advent of scintillation counting.

PMID- 15177356
TI  - Determination of ultra-low concentrations of Pb-210 in Antarctic glacier with
      cation exchange resins filter--results, problems and perspectives.
AB  - In this paper, we describe a new, reliable and simple method to determine 210Pb
      concentration in ice-core samples, based on "Radium 3M" filters (USA). The
      advantages are well-known chemical yield, simplified retention procedure and
      measurement by low-energy Ge gamma spectrometry. We compare the results with
      those obtained by MN 616 LSA-50 filters (Germany). The method permits us to
      determine activity concentrations down to 30 mBq/l. We proved the efficiency and
      applicability of the method in the study of ice cores drilled in Livingston
      Island's glacier in Antarctica.

PMID- 15177358
TI  - Distribution coefficients of polonium between 5% TOPO in toluene and aqueous
      hydrochloric and nitric acids.
AB  - The distribution coefficients (D) of polonium between 5% TOPO in toluene and
      aqueous hydrochloric and nitric acids have been studied. Results show that: (1) D
      values are ranged from 61.3 to 331 when the acidities vary from 0.10 to 10.0 M
      HCl, which means that Po can be well extracted by 5% TOPO in toluene in wide
      range of HCl acidities, (2) in the acidities of 0.010-10.0 M HNO3 the D values
      are much lower, there exists a maximum D value (2.46) at 1 M HNO3, and at the
      acidities of 6 M HNO3 and above only a negligible amount of Po (< or = 1.5%) can
      be extracted by 5% TOPO in toluene. The later fact provides an opportunity to
      separate Po from uranium effectively in the process of liquid--liquid extraction
      and column extraction chromatography of TOPO.

PMID- 15177357
TI  - Multisyringe flow injection analysis of stable and radioactive strontium in
      samples of environmental interest.
AB  - A multisyringe flow injection (MSFIA) method for the determination of stable and
      radioactive strontium, using a solid phase resin (Sr-Resin), has been developed.
      Strontium concentrations are determined by atomic emission spectroscopy and by a
      low background proportional counter. The method has been applied to different
      samples (water, milk and soil) of environmental interest. The LLD of the stable
      and radioactive Sr were 10 microg/l and 0.01 Bq, respectively. The standard
      deviation of the separation procedure is 2% (n=10).

PMID- 15177359
TI  - Aspects of sample preparation for the determination of actinoids in soil.
AB  - In the frame of the re-certification measurements of the IAEA-375 soil reference
      material the activity concentration of four actinoids (U, Th, Pu and Am) was
      determined. The method is based on microwave digestion or aqua regia leaching,
      separation by extraction chromatography and alpha-particle counting source
      preparation by co-precipitation or electro-deposition. This article describes
      some of the problems encountered during the validation of the sample preparation
      method and their solutions.

PMID- 15177360
TI  - Rapid determination of alpha emitters using Actinide resin.
AB  - The European Commission has recently published the recommended radiological
      protection criteria for the clearance of building and building rubble from the
      dismantling of nuclear installations. Radionuclide specific clearance levels for
      actinides are very low (between 0.1 and 1 Bq g(-1)). The prevalence of natural
      radionuclides in rubble materials makes the verification of these levels by
      direct alpha counting impossible. The capability of Actinide resin (Eichrom
      Industries, Inc.) for extracting plutonium and americium from rubble samples has
      been tested in this work. Besides a strong affinity for actinides in the tri,
      tetra and hexavalent oxidation states, this extraction chromatographic resin
      presents an easy recovery of absorbed radionuclides. The retention capability was
      evaluated on rubble samples spiked with certified radionuclide standards (239Pu
      and 241Am). Samples were leached with nitric acid, passed through a
      chromatographic column containing the resin and the elution fraction was measured
      by LSC. Actinide retention varies from 60% to 80%. Based on these results, a
      rapid method for the verification of clearance levels for actinides in rubble
      samples is proposed.

PMID- 15177361
TI  - A method for the determination of low-level organic-bound tritium activities in
      environmental samples.
AB  - The authors discuss some of the difficulties encountered when analyzing
      organically bound tritium (OBT) and describe a sensitive method for low-level OBT
      determination in biological samples. The methodology, which combines suitable
      sample treatment, a combustion apparatus for large-sized samples and low
      background liquid scintillation counting, provides exclusively carbon-bound
      tritium measurement. Two key points of this methodology are described and
      illustrated. The first one is the stage of removal of the exchangeable organic
      tritium. The efficiency of this stage, carried out by mixing powdered dry samples
      with tritium-free water, is evaluated. The second key point is the set of
      precautions taken at any stage of the treatment to avoid contamination of the
      samples by ambient atmospheric moisture. The detection limit of the method is
      about 0.5 Bq kg(-1) of dry material. Low-level applications of this methodology
      are given with estimation of the OBT/HTO ratios.

PMID- 15177363
TI  - Determination of parameters relevant to alpha spectrometry when employing source
      coating.
AB  - The recoil fragments from an alpha-emitting source may cause significant detector
      contamination. The simplest method to avoid the problem is to use a source
      coating. The influence of Mylar film coatings of different thickness on the
      resolution, efficiency and minimum detection level of an alpha spectrometry
      system was investigated. No significant deterioration of the system
      characteristics was observed when using thin films of about 0.25 mg/cm2.

PMID- 15177362
TI  - Sequential isotopic determination of plutonium, thorium, americium, strontium and
      uranium in environmental and bioassay samples.
AB  - A procedure has been developed to provide sequential analysis of 238Pu, 230Th,
      241Am, 238U, and 90Sr in environmental and bioassay samples. Tracers and/or
      carriers (242Pu, 243Am, 232U, and stable strontium) are added into the sample as
      chemical yield monitors, and then, plutonium, thorium, strontium, americium, and
      uranium are sequentially separated and purified by Dowex ion-exchange resin,
      EiChroM Sr-resin, EiChroM TRU-resin, and Chelate-100 resin, respectively. The
      radioactivities of 90Sr and the actinides are measured using the liquid
      scintillation counter and alpha-particle spectrometer, respectively. Acidified
      water, glass-fiber air filter, soil, synthetic urine and synthetic feces samples
      of US National Institute of Standard and Technology Radiochemical Intercomparison
      Program(NRIP) were analyzed to verify this method. All the analytical results of
      238Pu, 230Th, 90Sr, 241Am and 238U meet the traceability limit per ANSI N42.22,
      and when appropriate, evaluation of radiobioassay measurement bias and precision
      per ANSI N13.30.

PMID- 15177364
TI  - Long-term environmental monitoring and application of low-level 3H, 7Be, 137Cs
      and 210Pb activity concentrations in the non-biotic compartments of the Danube in
      Austria.
AB  - The aim, methods, and results of long-term low-level measurements of 3H, 7Be,
      137Cs and 210Pb in water and sediment of the Austrian part of the Danube are
      presented. The results are discussed focused on recent and obvious future
      applications in applied radioecology and environmental research. The long-term
      radiometric data supported by the low-level monitoring program act as basis for
      ecological modelling and environmental assessment.

PMID- 15177365
TI  - Low-level measurements of tritium in water.
AB  - Using a liquid scintillation counter, an experimental procedure for measuring low
      level activity concentrations of tritium in environmental water has been
      developed by our laboratory, using the electrolytic tritium enrichment.
      Additionally, some quality tests were applied in order to assure the goodness of
      the method. Well-known water samples collected in the Tagus River (West of Spain)
      and the Danube River (Bulgaria), both affected by nuclear plant releases, were
      analysed and results were compared to previous data. The analytical procedure was
      applied to drinking water samples from the public water supply of Seville and
      mineral waters from different springs in Spain in order to characterize its
      origin. Due to the very low levels of tritium in the analysed samples, some
      results were reported as lower than the minimum detectable activity concentration
      (MDA). However, the count rate of these measurements was over the background
      count rate of LS counter in all the cases. For that reason, an exhaustive
      discussion about the meaning of the MDA, using an experimental essay, was made in
      order to establish a rigorous criterion that leads to a reliable value in the
      case of low-level measurements.

PMID- 15177366
TI  - Source-term characterisation and solid speciation of plutonium at the
      Semipalatinsk NTS, Kazakhstan.
AB  - New data on the concentrations of key fission/activation products and
      transuranium nuclides in samples of soil and water from the Semipalatinsk Nuclear
      Test Site are presented and interpreted. Sampling was carried out at Ground Zero,
      Lake Balapan, the Tel'kem craters and reference locations within the test site
      boundary well removed from localised sources. Radionuclide ratios have been used
      to characterise the source term(s) at each of these sites. The geochemical
      partitioning of plutonium has also been examined and it is shown that the bulk of
      the plutonium contamination at most of the sites examined is in a highly
      refractory, non-labile form.

PMID- 15177368
TI  - Gross alpha determination in drinking water using a highly specific resin and
      LSC.
AB  - Some results of experiments concerning a new highly specific resin for the
      extraction of alpha-emitting nuclides from drinking water samples are presented.
      The product used during these experiments is a new extraction chromatographic
      resin which consists of a combination of several reagents and extractants
      supported on inert polymeric substrates, called "Resin" hereafter. It shows
      strong affinity for Actinides in the tri-, tetra- and hexavalent oxidation state,
      as well as for radium, even in presence of large amounts of calcium. Gross-alpha
      activities were determined using alpha-/beta-discrimination liquid scintillation
      counting (alpha-/beta-LSC) by direct measurement of the dried resin after
      extraction. Counting conditions were optimised accordingly. A method for the
      determination of alpha-emitting nuclides in drinking water was developed and
      tested using intercomparison and spiked drinking water samples.

PMID- 15177367
TI  - Gross alpha and beta activity analysis in water--a routine laboratory method
      using liquid scintillation analysis.
AB  - The generally accepted method for gross alpha and beta activity analysis of
      drinking water in Australia is based on ISO methods; ISO9696, water quality-
      measurement of gross alpha activity in non-saline water--thick source method, and
      ISO9697, water quality--measurement of gross beta activity in non-saline water. A
      liquid scintillation (LSA) based method that requires smaller sample quantities,
      less sample preparation time and operator intervention, and produces adequate
      minimum detection levels for local drinking water guidelines has been developed.
      A synthetic groundwater sample was analysed using the LSA method and compared
      with results from ISO method techniques used by two independent Australian
      laboratories. The results show that the LSA method exceeds performance of the ISO
      methods in measurement accuracy.

PMID- 15177369
TI  - Sequential extraction for radionuclide fractionation in soil samples: a
      comparative study.
AB  - Two sequential extraction procedures, Tessier's method (Anal. Chem. 51(7) (1979)
      844), and a current version known as Schultz's method (J. Environ. Radioact.
      40(2) (1998) 155), were compared. The two procedures were applied to a natural
      soil sample that presents high activity concentrations in natural radionuclides
      of the 238U series. Reproducibility studies of each method and a comparison
      between the two sets of results were performed for uranium, thorium, and radium.
      The results were different for each radionuclide. Analysis of the extracted
      fractions was carried out by alpha spectrometry.

PMID- 15177370
TI  - The use of instrumental neutron activation and multivariate statistic analyses in
      differentiation of Brazilian phosphate ores.
AB  - Phosphated rocks from three ores located in the Middle-West region of Brazil can
      be used as low-level radioactive reference material due to the fact that they
      contain significant concentrations of thorium and, in some cases, of uranium.
      This paper describes the procedure to characterise those samples using several
      analytical methods. Statistical analysis and correlations studies have shown
      several geochemical similarities and the results obtained suggest the possibility
      to produce a reference material composed of a mixture of two similar ores.

PMID- 15177371
TI  - Investigation of food contamination since the Chernobyl fallout in Austria.
AB  - In a large-scale investigation the decrease of the activity concentration of
      137Cs in foodstuffs after the widespread Chernobyl fallout was determined. At
      different times after the deposition in 1986 more than 1000 samples of various
      foodstuffs in Austria were taken and investigated with regard to their activity
      concentration. The investigation showed that in the first year after deposition,
      the activity concentration decreased to about 6-10% (milk, fruit), and 3-6%,
      respectively (grain, potatoes, vegetables) of the values in the fallout maximum.
      The calculated effective half-lives are significantly shorter than observed after
      nuclear weapon test series and result in a smaller long-term exposure than
      estimated before. The effective ingestion dose in the 50 years following of a one
      time nuclear fallout amounts to about 1.3 times of the first year ingestion dose.
      In 2002, the ingestion dose in Austria amounts to 2.24 microSv (adult), or 0.88
      microSv (5-year infant) respectively, which is less than 0.5% of the ingestion
      dose of the first year and amounts to 0.7% of the ingestion dose from natural
      radionuclides.

PMID- 15177372
TI  - A semi-empirical approach for determination of low-energy gamma-emmiters in
      sediment samples with coaxial Ge-detectors.
AB  - A simple method for the determination in sediment samples of low-energy gamma
      emitters with coaxial Ge detectors and using a cylindrical sample geometry is
      outlined. This method allows an easy estimation of self-absorption effects by
      knowing the apparent densities and the composition of the investigated samples.
      As calibration matrixes solid samples enriched in known amounts of natural
      radionuclides emitting low-energy gamma rays were used. In this way, the
      difficult homogenisation steps needed when liquid spikes are added to a solid
      blank for manufacturing the calibration sample are avoided. The method has been
      carefully checked and validated by applying it to sediment samples with known
      activities of some low-energy gamma-ray emitters. Additionally, these sediment
      measurements have allowed to evaluate the magnitude and importance of the self
      absorption corrections.

PMID- 15177373
TI  - On the integrated decay and ingrowth equations used in the measurement of
      radioactive decay families: the general solution.
AB  - In the measurement of radioactivity, a finite measurement time is employed to
      collect data. Usually, this time is small with respect to the half-life of the
      nuclide being measured and the 'usual' decay equations can be used to decay
      measured activities to a given reference time. In some applications, such as
      neutron activation, an integrated form of the decay equation needs to be employed
      as the measurement time is comparable to the half-life and using the non
      integrated form introduces a significant error. This correction is well known and
      is used widely. For radionuclide families, such as the natural decay series of
      uranium and thorium or simple parent--daughter systems, no such integrated form
      of the decay and ingrowth series appears to have been published in the open
      literature. This paper sets out the general solution for integrated decay and
      ingrowth of sequential decay and illustrates the validity of this theoretical
      solution by applying it to real examples.

PMID- 15177374
TI  - Results of IAEA intercomparisons in the frame of indirect methods for assessing
      intakes of radionuclides.
AB  - The IAEA safety activities to support the assessment of occupational exposure due
      to intake of radionuclides through a comprehensive set of Safety Guides, Safety
      Reports and other documents will soon be completed. The future IAEA activities in
      this field will focus more on training and international intercomparisons. In
      recent years extensive development in measurement techniques, phantoms and
      computational tools have occurred. Determination of the radionuclide activity in
      the body or excreta, the intake and the resulting internal dose can, therefore,
      be approached in many different ways, depending on the amount and quality of the
      data, the skill of the dosimetrist, computational tools available, the
      assumptions made and the methodology used. Thus, it is important for laboratories
      involved in internal dosimetry to undergo performance-testing procedures to
      demonstrate the correctness of the methods applied and also the consistency of
      their results with those obtained by other laboratories. Several intercomparison
      exercises were organized by the IAEA on the determination of radionuclides in
      human urine samples. These previous intercomparison exercises revealed
      significant differences in the approaches, methods and assumptions, and
      consequently in the results. This underlined the importance of this kind of
      intercomparison programmes as a key element of the harmonization process. The
      purpose of this paper is to present the current and future IAEA activities in
      support of assessment of occupational exposure due to intakes of radionuclides by
      organizing intercomparison runs focused on indirect methods for assessing intakes
      as well as the recommendations for setting up a Quality Management Systems for
      technical services in radiation safety.

PMID- 15177375
TI  - A preliminary intercomparison of gamma-ray spectrometry on building materials.
AB  - A preliminary intercomparison on gamma-ray spectrometry determination of natural
      radionuclides in building materials was carried out in 1999-2002. Samples
      measured were fly ash, sand and tuff. Laboratories used different experimental
      equipment and procedures. Corrections for blank, spectral interference, self
      absorption and coincidence summing effects were applied in most cases. The
      agreement between results was within 15-20%, most often within the reported
      uncertainties. Several general conclusions can be drawn regarding procedures
      correctness, uncertainty budget, secular equilibrium condition, and radionuclide
      representativeness in each natural series. Further studies are needed to draw
      more specific conclusions.

PMID- 15177376
TI  - Development of an organically bound tritium standard.
AB  - High-concentration factors between seawater and marine organisms have been
      observed for organically bound tritium (OBT). The absence of an available OBT
      standard impedes the validation of an analytical method for environmental
      samples. This paper describes the secondary standardisation of tritiated
      thymidine, which was chosen to act as an OBT standard, using liquid scintillation
      counting. Traceability was provided by using internal standards of tritiated
      water (HTO). The assumption that the counting efficiencies for tritiated
      thymidine and HTO were identical was tested with separate quench curves. The rate
      of self-decomposition for tritiated thymidine, which resulted in an activity
      concentration of tritiated thymidine lower than the total tritium activity
      concentration, was determined.

PMID- 15177377
TI  - Characterisation of reference materials for radioactivity with assigned values
      traceable to the SI units.
AB  - The Institute for Reference Materials and Measurements participates in an IAEA co
      ordinated project to upgrade Analytical Quality Control Services intercomparison
      materials to reference materials. The principal objective is to ensure that
      assigned property values are traceable to the International System of Units.
      General principles and practical mechanisms for achieving this traceability are
      described.

PMID- 15177378
TI  - Systematic and non-systematic effects of the uncertainty of the sample position
      in gamma-ray spectrometry.
AB  - When cylindrical samples placed coaxially with the detector are measured on a
      gamma-ray spectrometer, the position of the sample very often deviates from an
      ideal one with the axes of the sample and the detector less than perfectly
      aligned. If a calibrated source is used prior to the measurement and is presumed
      to have been positioned correctly, one might conclude that the misalignment of
      the measured sample should result in an uncertainty of the reported nuclide
      activity, since the efficiencies of the sample and the calibrated source are
      effectively different due to the difference in placement. The efficiency of a
      displaced cylindrical sample, however, is always lower than the one of a sample
      that is perfectly aligned. The net effect of misalignment can therefore be not
      only an increase in the uncertainty of the activity, but also a systematic error
      in its evaluation. Since the Guide to the Expression of Uncertainty in
      Measurement requires that all such systematic effects be corrected for, we have
      developed a method to assess the change in the efficiency resulting from
      misalignment and to introduce the required correction. The calculation of this
      correction only requires knowledge of basic sample and detector data. The
      uncertainty of the reported activity can then also be assessed and is influenced
      by the uncertainty of the efficiency evaluated around its new, corrected value.
      An appropriate expression for this uncertainty has been derived.

PMID- 15177379
TI  - Standardisation of low-activity actinide solutions by alpha-particle counting at
      a defined solid angle.
AB  - In the frame of an IAEA co-ordinated research project 232U, 236Pu and 229Th
      tracers were standardised by alpha-particle counting at a defined solid angle.
      The aim of this project was to assign property values that are traceable to the
      International System of Units (SI). This article depicts the standardisation of
      the tracers, elaborating on problems related to low activity and interference
      from daughter nuclides. The activity concentrations of 232U, 236Pu and 229Th were
      found to be, respectively (734+/-4), (142.0+/-0.9) and (528.2+/-2.6) Bq g(-1), at
      reference date (1 January 2003).

PMID- 15177380
TI  - Validation of methods for the determination of radium in waters and soil.
AB  - This article describes the advantages and disadvantages of several analytical
      methods used to prepare the alpha-particle source. As a result of this study, a
      new method combining commercial extraction and ion chromatography prior to a
      final co-precipitation step is proposed. This method has been applied and
      validated on several matrices (soil, waters) in the framework of international
      intercomparisons. The integration of this method in a global procedure to analyze
      actinoids and radium from a single solution (or digested soil) is also described.

PMID- 15177381
TI  - Proficiency tests for radionuclide laboratories supporting the network of IMS
      stations.
AB  - A tailored proficiency test programme in high-resolution gamma-spectrometric
      analysis has been established for the radionuclide laboratories designated to
      support the verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT). It
      entails certified reference samples that contain fission products relevant to the
      CTBT. The sample geometries and materials correspond to aerosol filter samples
      from the high-volume samplers of the radionuclide stations of the International
      Monitoring System (IMS) and the related calibration sources are matrix and
      geometry matched to the reference samples.

PMID- 15177382
TI  - Driving guidelines and neurological illness: a review.

PMID- 15177383
TI  - Alzheimer's disease pathogenesis and therapeutic interventions.
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous
      system associated with progressive cognitive and memory loss. Molecular hallmarks
      of the disease are characterized by extracellular deposition of the amyloid beta
      peptide (Abeta) in senile plaques, the appearance of intracellular
      neurofibrillary tangles (NFT), cholinergic deficit, extensive neuronal loss and
      synaptic changes in the cerebral cortex and hippocampus and other areas of brain
      essential for cognitive and memory functions. Abeta deposition causes neuronal
      death via a number of possible mechanisms including oxidative stress,
      excitotoxicity, energy depletion, inflammation and apoptosis. Despite their
      multifactorial etiopathogenesis, genetics plays a primary role in progression of
      disease. To date genetic studies have revealed four genes that may be linked to
      autosomal dominant or familial early onset AD (FAD). These four genes include:
      amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and
      apolipoprotein E (ApoE). Plaques are formed mostly from the deposition of Abeta,
      a peptide derived from APP. The main factors responsible for Abeta formation are
      mutation of APP or PS1 and PS2 genes or ApoE gene. All mutations associated with
      APP and PS proteins can lead to an increase in the production of Abeta peptides,
      specifically the more amyloidogenic form, Abeta42. In addition to genetic
      influences on amyloid plaque and intracellular tangle formation, environmental
      factors (e.g., cytokines, neurotoxins, etc.) may also play important role in the
      development and progression of AD. A direct understanding of the molecular
      mechanism of protein aggregation and its effects on neuronal cell death could
      open new therapeutic approaches. Some of the therapeutic approaches that have
      progressed to the clinical arena are the use of acetylcholinesterase inhibitors,
      nerve growth factors, nonsteroidal inflammatory drugs, estrogen and the compounds
      such as antioxidants, neuronal calcium channel blockers or antiapoptotic agents.
      Inhibition of secretase activity and blocking the formation of beta-amyloid
      oligomers and fibrils which may inhibit fibrilization and fibrilization-dependent
      neurotoxicity are the most promising therapeutic strategy against the
      accumulation of beta-amyloid fibrils associated with AD. Furthermore, development
      of immunotherapy could be an evolving promising therapeutic approach for the
      treatment of AD.

PMID- 15177384
TI  - Anaesthesia for endovascular treatment of cerebral aneurysms.
AB  - Endovascular treatment of cerebral aneuryms is now widely used and has important
      implications for the neuroanaesthetist. Significant issues include the decision
      to use general anaesthesia, factors associated with anaesthesia in the
      interventional radiology suite and treatment of complications. As endovascular
      treatment is now supported by evidence and established in practice,
      neuroanaesthetists should be involved in planning these procedures from a
      process, and individual patient, perspective.

PMID- 15177385
TI  - Driving and patients with brain tumours: a postal survey of neurosurgeons,
      neurologists and radiation oncologists.
AB  - This study was aimed at evaluating the consistency of driving advice given by
      treating clinicians to patients diagnosed with brain tumours. Secondary aims
      include assessing the awareness of current driving guidelines and whether or not
      there was a need for more specific guidelines in this group of patients. This was
      undertaken utilizing a scenario-based postal survey. The results show an overall
      poor consistency in the answers provided for each case scenario. 73.1%
      respondents were not aware of any current driving guidelines. Of those who were
      aware of driving guidelines, 67.7% wanted more specific guidelines to be
      developed. Possible explanations for this are a lack of awareness of the
      existence of any driving guidelines and a lack of objective criteria in the
      current driving guidelines. The authors recommend that the current driving
      guidelines be comprehensively distributed to clinicians who treat patients with
      brain tumours, as well as forming a multi-disciplinary working party to develop
      more specific and objective driving guidelines.

PMID- 15177386
TI  - Endovascular therapy versus surgical clipping for basilar artery bifurcation
      aneurysm: retrospective analysis of 117 cases.
AB  - OBJECTIVE: The purpose of this study was to retrospectively evaluate and compare
      the feasibility, indication and limitations of two treatment options, clipping
      and coil embolization, for basilar artery (BA) bifurcation aneurysms. MATERIALS
      AND METHODS: During the last 13 years, 117 patients with 117 BA bifurcation
      aneurysms were treated exclusively with direct surgery until February 1997, and
      with either direct surgery or coil embolization therapy since March 1997. Of
      them, 76 (65%) aneurysms were treated with direct clipping and 41 (35%) were
      treated with Guglielmi detachable coils (GDCs) embolization. The 76 surgically
      clipped aneurysms were analyzed on the basis of the pre-operative angiograms as
      to whether coil embolization would be feasible or not if each case had been
      attempted. The 41 embolized aneurysms, on the other hand, were analyzed as to
      whether clipping surgery would be feasible or not if it had been attempted.
      RESULTS: In the total 117 aneurysms, complete coil obliteration was judged to be
      possible and simple in 61 (52%) aneurysms, possible with complex techniques
      (difficult) in 29 (25%) and impossible in 27 (23%). Whereas, complete
      obliteration with direct clipping was judged to be simple in 66 (57%) aneurysms,
      difficult in 38 (32%) and impossible in the remaining 13 (11%). Linear
      correlation as to the technical difficulty was found in 61 (52%) aneurysms, but
      14 (12%) had marked discrepancy between the two methods. Of the 76 patients
      treated with clipping surgery, 17 (22%) were left with some post-operative
      neurological deficits, and in six out of the 17 aneurysms, embolization might
      have been simple. There were complications in two patients; one procedure-related
      and the other with late re-bleeding due to aneurysmal re-growth, in the
      embolization, group. CONCLUSIONS: Endovascular therapy is an effective
      alternative for treating BA bifurcation aneurysms, although a quarter of the
      cases cannot be obliterated completely. It is important to select a suitable
      treatment option in each case depending on the patient's condition and the
      angiographical features of each aneurysm as well as the characteristics of the
      two methods.

PMID- 15177387
TI  - Endovascular therapy versus surgical clipping for basilar artery bifurcation
      aneurysm.

PMID- 15177388
TI  - Current usage of three-dimensional computed tomography angiography for the
      diagnosis and treatment of ruptured cerebral aneurysms.
AB  - Our previous study suggested that 3D-CT angiography could replace digital
      subtraction (DS) angiography in most cases of ruptured cerebral aneurysms,
      especially in the anterior circulation. This study reviewed our further
      experience. One hundred and fifty patients with ruptured cerebral aneurysms were
      treated between November 1998 and March 2002. Only 3D-CT angiography was used for
      the preoperative work-up study in patients with anterior circulation aneurysms,
      unless the attending neurosurgeons agreed that DS angiography was required. Both
      3D-CT angiography and DS angiography were performed in patients with posterior
      circulation aneurysms, except for recent cases that were possibly treated with 3D
      CT angiography alone. One hundred sixteen (84%) of 138 patients with ruptured
      anterior circulation aneurysms underwent surgical treatment, but additional DS
      angiography was required in 22 cases (16%). Only two recent patients were treated
      surgically with 3D-CT angiography alone in 12 patients with posterior circulation
      aneurysms. Most patients with ruptured anterior circulation aneurysms could be
      treated successfully after 3D-CT angiography alone. However, additional DS
      angiography is still necessary in atypical cases. 3D-CT angiography may be
      limited to complementary use in patients with ruptured posterior circulation
      aneurysms.

PMID- 15177389
TI  - Neurological improvement after cranioplasty - analysis by transcranial doppler
      ultrasonography.
AB  - Cranioplasty can improve neurological status in patients with skull bone defects.
      The mechanism of postoperative improvement in neurologic status might be
      increased cerebral blood flow (CBF) velocity due to elimination of the effects of
      atmospheric pressure. Between May 2001 and June 2002, 13 patients (8 men and 5
      women; average age, 46 years; range, 21-65 years) were studied. Postoperative
      changes in neurological status and blood flow velocity were examined and compared
      using transcranial Doppler (TCD) sonography. The mean interval between
      craniectomy and cranioplasty was 122.3+/-100.4 days. The mean interval between
      cranioplasty and performance of TCD examination was 15.2+/-2.8 days. The results
      showed significant improvements after cranioplasty in GCS, arm muscle power, and
      Barthel Index. While the CBF velocities tended to increase after cranioplasty,
      only the increase in the non-lesion side middle cerebral artery (MCA) was
      statistically significant. The interval from decompressive craniectomy to
      cranioplasty and neurological status change before and after cranioplasty was
      significantly negatively correlated. We conclude that cranioplasty can improve
      neurological status, and it should be performed as earlier as edema has resolved.

PMID- 15177390
TI  - Intratumoral haemorrhage: a clinical study.
AB  - Although the incidence of spontaneous intracranial haemorrhage associated with
      meningioma is 1.3%, the incidence of intratumoral haemorrhage could not be
      determined. The authors report on 11 patients, six men and five women, with
      meningiomas that presented as spontaneous intratumoral haemorrhage, among 126
      meningioma cases which were evaluated radiologically and histopathologically. The
      average age of patients was 58.9 years (range 45-72 years). Two (1.5%) cases
      showed radiological, and nine cases (7.9%) showed microscopic bleeding. Most of
      these cases also showed microcysts (9.7%) and necrosis (6.3%). The location,
      histopathological types, sex, age, blood dyscrasia, hypertension do not influence
      the occurrence of intratumoral haemorrhages in meningiomas. We concluded that
      microcysts and necrosis are important in the occurrence of intratumoral
      haemorrhage in meningiomas.

PMID- 15177391
TI  - The executive clock drawing task (CLOX) is a poor screening test for executive
      dysfunction in Chinese elderly patients with subcortical ischemic vascular
      disease.
AB  - Executive dysfunction (ED) is a prominent feature of subcortical ischemic
      vascular disease. A screening test for ED is lacking among Chinese. The objective
      of the study is to investigate the validity and reliability of a Chinese version
      of the Executive clock drawing task (CLOX) in screening ED among Chinese elderly
      patients with small subcortical infarct (SSI). The Chinese version of CLOX
      correlated with MMSE, CDRS I/P, and WCST perseverative errors. However,
      multivariate regression analysis showed that only education (R(2) change=0.22, p
      < 0.001 ) and MMSE (R(2) change=0.35, p < 0.001), but none of the standard
      executive function tests, significantly accounted for the variance in the CLOX.
      Test-retest (r=0.84) and inter-rater reliability (r=0.84) were high for the CLOX.
      Conclusions. Although the CLOX is reliable, it is not valid in detecting ED in
      Chinese elderly patients with SSI.

PMID- 15177392
TI  - Treatment of traumatic carotid-cavernous fistula at the Udon Thani Center
      Hospital.
AB  - There are many options available in management of traumatic carotid-cavernous
      fistulae (CCF). The carotid occlusion or the carotid preservation techniques are
      two basic approaches available. This study evaluated the carotid occlusion
      technique performed at The Udon Thani Center Hospital. We retrospectively studied
      12 consecutive cases of traumatic CCF. The patients varied in terms of their
      ages, gender, side of lesion and symptoms. The occlusion was performed with
      muscle occlusion and trapping of the carotid artery. The diagnosis was made
      clinically and on CT brain. The Matas test was performed clinically with external
      compression of the contralateral carotid artery. No patient underwent cerebral
      angiography. From August 1997 to June 2002 the 12 patients were treated by muscle
      embolization only; muscle embolization with internal carotid ligation (Brooks
      technique); muscle embolization with trapping (Jaeger-Hamby procedure); or muscle
      embolization with trapping and external carotid ligation. The patients ranged
      from 15 to 62 years. Eleven were male. All had unilateral fistulae though only 3
      involved the left eye. Eleven patients were cured and there was only one major
      complication of a patient who developed a second and third nerve palsy. The
      carotid occlusion technique is less popular in view of the great advances with
      detachable balloons and success with carotid preservation techniques. Despite
      this, under extenuating circumstances such as the lack of angiography, poor socio
      economic status, or patients wanting to be treated close to home, this procedure
      is still an appropriate therapeutic option, as reflected by the success at our
      hospital. The more affluent patients had wider options and thus were sent to
      other centers for carotid preservation techniques like detachable balloon
      embolization.

PMID- 15177393
TI  - Dynamics of free radical processes in acute ischemic stroke: influence on
      neurological status and outcome.
AB  - The dynamics of free radical processes during the acute stage of ischemic stroke
      and their relationship with the clinical status of patients were studied. An
      enhanced extracellular generation of reactive oxygen species (ROS) by peripheral
      phagocytes was observed in severe stroke patients during the whole acute stage.
      This generation correlated positively with the size of infarct, the severity of
      neurological deficit and handicap and correlated negatively with the improvement
      of the neurological status of patients. An increase in the activity of two
      enzymes from the antioxidant defense mechanism, catalase and glutathione
      peroxidase, was registered during the whole acute phase of stroke, regardless of
      its severity. The concentration of lipid peroxidation products increased over
      time. Blood concentration of thiobarbituric acid-reactive material (TBARM)
      correlated positively with the size of infarct, the severity of neurological
      deficit and handicap. In conclusion, extracellular ROS generation by phagocytes
      and blood TBARM concentration could be used as indicators for stroke outcome.

PMID- 15177394
TI  - Focal brain edema and natriuretic peptides in patients with subarachnoid
      hemorrhage.
AB  - The present study was designed to assess the relationship between the presence of
      focal brain aedema and serum concentrations of atrial natriuretic peptide (ANP)
      or brain natriuretic peptide (BNP) in patients with subarachnoid haemorrhage
      (SAH). Serum levels of ANP and BNP were measured at six different time periods
      (Day 1, 2, 3, 4 to 7, 8 to 14, and 15 to 25) in 61 SAH-patients. Focal brain
      aedema, which was caused by an intracerebral haematoma associated with SAH or
      surgical complications, was found in eight SAH-patients by means of consecutive
      CT scans. The mean serum ANP and BNP levels in patients with focal brain aedema
      were significantly higher than those in patients without focal brain aedema
      between Days 4 and 14. These findings suggest that focal brain aedema may have
      some role in the pathogenesis of an excessive secretion of ANP and BNP during the
      subacute phase of SAH.

PMID- 15177395
TI  - Contrast enhancement of the spinal cord in a patient with cervical spondylotic
      myelopathy.
AB  - We wish to report a patient with cervical spondylotic myelopathy that
      demonstrated contranst enhancement on MRI which resolved following a
      decompressive procedure.

PMID- 15177396
TI  - Images in neuroscience.

PMID- 15177397
TI  - Effects of gamma-hydroxybutyrate on cerebrospinal fluid lactate and glucose
      levels after spinal cord trauma.
AB  - This study aims to evaluate the effects of gamma-hydroxybutyrate (GHB) after
      spinal cord trauma (SCT). Twenty rabbits were divided equally into four groups:
      group I was the sham-operated group, group II suffered from SCT but received no
      treatment, group III was given a dose of 400 mg/kg of GHB intravenously before
      SCT and group IV received the same dose after SCT. Cerebrospinal fluid (CSF)
      samples were obtained 30 min before SCT (T(0)), at 60 (T(1)) and 120 min (T(2))
      after SCT. There was a threefold increase in lactate levels from baseline value
      at T(2) in group II, while statistically significant elevation of the lactate
      levels were not observed in groups III and IV. Glucose levels at T(1) and T(2)
      were significantly lower in groups III and IV compared with the control group.
      The findings of this study demonstrate that GHB can control the increase of CSF
      lactate and glucose levels following SCT and that this metabolic effect may be
      associated with neuroprotective physiological changes.

PMID- 15177398
TI  - Solitary metastasis to the choroid plexus of the third ventricle mimicking a
      colloid cyst: a report of two cases.
AB  - Cerebral metastasis to the choroid plexus is rare and almost always occurs in the
      presence of multiple cerebral metastases. We present two cases of a solitary
      cerebral metastasis to the choroid plexus of the anterior third ventricle
      mimicking a colloid cyst. There appears to be an increased tendency for renal
      cell carcinomas to metastasis to the choroid plexus. Metastatic disease is an
      important differential diagnosis even for solitary lesions of the anterior third
      ventricle.

PMID- 15177399
TI  - Guillain-Barre syndrome during treatment with interferon alpha for hepatitis B.
AB  - We describe a patient who developed acute demyelinating polyneuropathy on the
      sixth week of interferon (IFN)alpha therapy for chronic hepatitis B (HBV)
      infection. A 23-year-old man with chronic HBV infection had acute onset of
      demyelinating polyneuropathy shortly after completing a standard 6-week course of
      therapy with IFNalpha 2a. Clinical findings, electrodiagnostic studies and
      elevated cerebrospinal fluid protein levels without cells supported the diagnosis
      of Guillain-Barre syndrome (GBS). Other potential causes of GBS were ruled out.
      It remains unknown whether IFNalpha or the HBV infection itself was the cause of
      GBS, but it is evident that IFNalpha could not have prevented the development of
      GBS in our patient. We suggest that coexistent HBV infection and IFNalpha therapy
      may play a role in triggering an autoimmune response to peripheral nerve myelin.

PMID- 15177400
TI  - Moyamoya disease with repeated intracranial haemorrhage in two consecutive
      pregnancies.
AB  - A 26-year-old woman presented with an intraventricular haemorrhage during the
      27th week of gestation in July 1996, and recovered without general or
      neurological complications after external ventricular drainage. The fetus was
      delivered spontaneously through the vagina at the 30th week of gestation, but
      eventually died. Cerebral angiography demonstrated typical appearances of
      moyamoya disease with occlusion of the supraclinoid portion of both internal
      carotid arteries and presence of abnormal collateral vessels. Five years later
      the second haemorrhage, an intracerebral haematoma in the right
      temporoparietooccipital area, occurred during the 28th week of pregnancy.
      Emergency craniotomy was performed and the intracerebral haematoma was removed
      totally. It is still unknown whether repeated pregnancy increases the risk of
      cerebrovascular accident in moyamoya disease. A long-term follow up study of
      several patients with haemorrhagic moyamoya disease is needed to clarify risk
      factors for rebleeding.

PMID- 15177401
TI  - Calcification and ossification of chronic encapsulated intracerebral haematoma:
      case report.
AB  - We report a case of calcified chronic encapsulated intracerebral haematoma (ICH)
      in a 29-year-old female who presented with progressive left sided weakness and
      intermittent seizures since childhood. The preoperative magnetic resonance (MR)
      imaging of the head initially suggested that a partially thrombosed aneurysm or
      vascular malformation was present. However, no vascular stain was found on the
      digital subtraction angiography (DSA) of both the carotid and vertebral arteries.
      The excised mass was histologically diagnosed as a chronic ICH. We traced the
      patient's medical history and found that at the age of one she sustained a head
      injury after a fall. So far, to our knowledge, no case of epilepsy secondary to a
      calcified chronic encapsulated ICH occurring 28 years after head injury has been
      reported. Calcified chronic encapsulated ICH concomitant with new bone formation
      within is even rarer. The possible pathogenesis of this case is discussed.

PMID- 15177402
TI  - A rare case of metastatic renal cell carcinoma resembling a nerve sheath tumor of
      the cauda equina.
AB  - We present a rare case of solitary metastasis to the cauda equina from the
      kidney. The patient was a 68-year-old man with a two-year history of low back
      pain. His past medical history revealed a renal cell carcinoma diagnosed seven
      years earlier. His lumbosacral MR imaging showed a well-demarcated, intradural
      extramedullary mass at the L3 level. He underwent an L2-4 laminectomy. The
      operative findings of the tumor quite resembled that of a nerve sheath tumor. It
      did not infiltrate into the subarachnoid space and involved only one spinal
      nerve. Pathology of the tumor was a metastasis of the renal cell carcinoma. Only
      10 cases with such a metastasis to the cauda equina have been reported in the
      English literature. We added the 11th and reviewed the literature with reference
      to tumor pathologies, clinical findings and route of metastasis to the cauda
      equina.

PMID- 15177403
TI  - Pituitary abscess associated with prolactinoma.
AB  - We present a 37-year-old female, who was admitted with a long standing history of
      menstrual abnormalities and galactorrhoea followed by progressive visual loss. X
      ray of the skull showed an enlarged sella with destruction of the floor. CT scan
      of the head revealed a giant pituitary adenoma with sellar and parasellar
      extension. At surgery, through a transsphenoidal approach, solid tissue and
      cystic areas containing pus from which Escherichia coli was cultured were
      encountered. She had an uneventful postoperative recovery. At 2 years follow up,
      she was doing well.

PMID- 15177404
TI  - Postoperative cerebellar herniation in a large intrapetrous aneurysmal bone cyst.
AB  - An 18-year old boy presented with a tumour involving a large part of the petrous
      bone. A radical resection of a petrous bone 'aneurysmal bone cyst' was achieved.
      A large defect in the dura adjoining the posterior surface of the petrous bone
      was made during surgery. Post-operative MR imaging showed complete tumour
      resection but herniation of cerebellum into the operative defect, a phenomenon
      probably assisting to seal the site of cerebrospinal fluid fistula.

PMID- 15177405
TI  - Writer's cramp in an Australian pedigree with DYT1 dystonia.
AB  - Oppenheim's or DYT1 dystonia is a primary dystonia typically presenting in a limb
      at an early age and usually becoming generalised within 5 years. Over the last
      decade research into this debilitating disorder has progressed considerably,
      enabling the identification of a genetic lesion (a 3bp deletion in the DYT1 gene)
      now widely accepted as the cause of a majority of cases. This case report
      presents the first molecularly diagnosed pedigree of an Australian family with
      DYT1 dystonia, which presented as writer's cramp in the 15-year-old proband and
      two of his cousins.

PMID- 15177406
TI  - Unusual presentation of petro-clival chondrosarcoma: short report.
AB  - Skull base chondrosarcoma is a rare neoplasm. Our patient presented with acute
      onset of diplopia along with symptoms of lower cranial nerve palsies in 1997. She
      showed complete resolution of symptoms following a short course of antibiotics
      and remained quiescent for three years. However, remission of symptoms in
      chondrosarcoma is unusual. An unusual case of a patient with petroclival low
      grade chondrosarcoma, who presented with relapse of symptoms after three years
      and was treated with surgery and radiotherapy, is presented.

PMID- 15177407
TI  - Obstructive hydrocephalus associated with arachnoid cyst in the elderly.
AB  - We present a case of a symptomatic frontal arachnoid cyst associated with
      hydrocephalus in an elderly patient. It is well known that symptomatic arachnoid
      cysts usually develop at an early age. This condition is rarely observed in the
      elderly. The authors hypothesized that compression of the brain and obstructive
      hydrocephalus caused the arachnoid cyst to become symptomatic.

PMID- 15177409
TI  - Acute interhemispheric subdural haematoma.

PMID- 15177408
TI  - Ossifying fibroma of the jugum sphenoidale.
AB  - We report a rare case of an eight year old boy with an ossifying fibroma of the
      jugum sphenoidale who presented with rapid onset bilateral blindness. This benign
      tumour was initially debulked and required re-operation with decompression of
      both optic nerves due to progressive visual deterioration. Post-operatively,
      there was good visual recovery in the left eye, but visual acuity in the right
      eye remained at <1/60. A 17 years follow period is described, in which there has
      been no clinical or radiological evidence of tumour recurrence.

PMID- 15177410
TI  - Giant cystic primary cerebral neuroblastoma in a child and solid primary cerebral
      neuroblastoma in an adult: two case reports.
AB  - Primary cerebral neuroblastoma is a rare entity in neurosurgical practice. They
      occur primarily in young children and are extremely rare in adults. Primary
      cerebral neuroblastoma is one of a group of highly malignant undifferentiated
      primitive neuroectodermal tumours arising from germinal matrix cells of the
      embryonic neural tube. They are difficult to diagnose preoperatively and
      pathologically. We present two cases of primary cerebral neuroblastoma.

PMID- 15177411
TI  - Primary plasma cell granuloma of petrous bone.
AB  - Plasma cell granulomas are rare intracranial lesions that can mimic a variety of
      intracranial tumours. As they are usually benign lesions, their identification
      assumes importance. We report a case of plasma cell granuloma in a 52-year-old
      man presenting with features of left sided V, VII and bilateral VIII nerve
      involvement who underwent subtotal excision of the lesion. The relevant
      literature is reviewed.

PMID- 15177412
TI  - Late recurrent bleeding after surgical treatment for pituitary apoplexy.
AB  - Pituitary apoplexy is an uncommon syndrome characterised by sudden onset of
      headache, meningeal signs, visual disturbances, ophthalmoplegia and confusion.
      Documented recurrent apoplexy or treated apoplexy is even rarer with only few
      reports in the literature. Between 1994 and 2001, 18 patients were treated for
      pituitary apoplexy at Bayindir Medical Centre through transsphenoidal route. In
      all, topical bromocriptine was applied after tumour resection as described by
      Ozgen. We hereby present the cases of two patients with recurrent apoplexy 3 and
      7 years after the initial surgical treatment for pituitary adenoma with apoplexy.
      The patients were treated non-surgically with success. Additional treatment in
      the form of radiosurgery was found necessary for the first patient. Surgical
      excision of the pituitary tumours with apoplexy reduces the risk of recurrent
      bleedings but eradication is not a rule. These patients need to be followed
      closely in the postoperative period for possible recurrence of bleeding.

PMID- 15177413
TI  - Intracranial optic nerve germinoma.
AB  - A 11-year-old boy presented with complaints of diminution of vision in the left
      eye for three months. On examination, the vision in this eye was reduced to only
      perception of light. Magnetic resonance imaging revealed a thickened left
      intracranial optic nerve. The lesion was explored by a pterional craniotomy. At
      surgery, the left optic nerve was diffusely thickened. The biopsy of a fleshy
      mass along the optic nerve showed that it was a germinoma on histopathology.
      Isolated optic nerve germinomas are extremely rare. Exclusive primary involvement
      of the intracranial portion of the optic nerve by a germinoma has not been
      reported in the literature. This rare case is discussed and the relevant
      literature has been reviewed.

PMID- 15177414
TI  - Linear deposition of immunoglobulins and complement components on the dura in
      normal pressure hydrocephalus complicating systemic lupus erythematosus.
AB  - We present a case of normal pressure hydrocephalus in a 70-year-old man with
      previously diagnosed systemic lupus erythematosus. Histological examination
      demonstrated the linear deposition of IgG, IgA, IgM, C(3) and C(1q) on the dura
      in the absence of inflammation or thrombosis that has previously been implicated
      in the aetiology of elevated pressure hydrocephalus in systemic lupus
      erythematosus. Our results suggest that the deposition of immunoglobulins and
      complement may play a pivotal role in an insidious manner in the pathogenesis of
      normal pressure hydrocephalus in systemic lupus erythematosus.

PMID- 15177415
TI  - Giant intracranial Rosai-Dorfman disease.
AB  - Rosai-Dorfman disease is a rare, non-neoplastic disease characterized by an
      unusual proliferation of histiocytic cells. It rarely manifests intracranially,
      and only 50 cases of intracranial lesions have been reported. We describe an
      unusual case of a huge, solid mass in the paranasal sinuses, orbits, cavernous
      sinuses, and suprasellar cisterns. A 29-year-old patient was admitted to our
      hospital with nasal obstruction and proptosis and visual loss in the right eye. A
      biopsy was done at another institution and the diagnosis was "pseudotumor of
      orbit". A right-sided cranio-orbitozygomatic craniotomy combined with a right
      sided lateral rhinotomy was used to excise the tumor with right orbital
      exenteration. The histopathological diagnosis was consistent with Rosai-Dorfman
      disease. The patient underwent postoperative chemotherapy. Involvement of the
      central nervous system in Rosai-Dorfman disease is rare, but the disease's
      ability to mimic other pathologies underlines its importance.

PMID- 15177416
TI  - Acute flank pain, an unusual first symptom of a spinal arteriovenous
      malformation.
AB  - This case report describes a 46-year-old man whose first symptom was an attack of
      acute flank pain, followed by the gradual onset neurological symptoms. We
      demonstrated a small nidus and serpentine signal-void area in the spinal cord by
      MRI and diagnosed a glomus type of spinal arteriovenous malformation (AVM). Flank
      pain is a rare initial finding in an adult with spinal AVM. In cases with acute
      flank pain, neurologists should consider spinal AVM as a differential diagnosis.

PMID- 15177417
TI  - Cardiac issues related to trastuzumab.

PMID- 15177418
TI  - Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment
      of metastatic breast cancer.
AB  - Trastuzumab (Herceptin) is a humanised monoclonal antibody that specifically
      targets HER2-positive breast cancer cells. Safety data collected from pivotal
      trials with trastuzumab indicate that this therapy is generally well tolerated.
      However trials of the combination of trastuzumab plus chemotherapy, and in
      particular chemotherapy with anthracyclines, have revealed an elevated incidence
      of cardiotoxicity in some patients, which was not apparent in preclinical or
      early clinical studies. Analyses of the available data suggest that in most cases
      the cardiotoxicity observed may reflect an exacerbation of anthracycline-induced
      cardiotoxicity. The biological mechanism of the cardiotoxicity has been
      investigated in several studies, and current data indicate that the
      heregulin/HER2-signalling pathway may have an important role. It is of note that
      the cardiotoxicity is generally reversible and can usually be managed with
      standard medical treatment. Improvement in cardiac function is seen both in
      patients who continue trastuzumab and in those in whom further therapy is
      withdrawn, indicating that with careful management anticancer therapy can be
      continued.

PMID- 15177419
TI  - Breast screening: the use of consensus opinion for all recalls.
AB  - The quality of a breast-screening programme is measured not only by it's cancer
      detection rates (sensitivity), but also by it's recall rates and positive
      predictive values (specificity). False positive screens, which lead to
      assessments with benign outcomes, can cause psychological and physical morbidity
      in previously well women. In 1999 the Wiltshire breast-screening programme
      adopted a novel recall strategy whereby all films marked for recall are subject
      to consensus opinion--even women "recalled" by both original readers may be
      returned to routine screening. Since 1999 our recall rates have fallen from above
      to below the national averages (prevalent 7.2% and incident 3.0% in 2001/02).
      Specificity has increased over the same period such that approximately one in
      seven women assessed will be diagnosed with cancer. The consensus meetings
      provide a forum for teaching and are very popular with our film readers, who all
      report reduced levels of stress.

PMID- 15177420
TI  - The prognostic influence of multifocality in breast cancer patients.
AB  - The aim of this study was to investigate whether multifocality (MF) is a factor
      that has significant effect on overall survival when controlling for known
      prognostic factors. A cohort of 929 breast cancer patients operated between 1985
      and 1990 was investigated. Of these, 158 (17%) patients had MF tumors and 771 had
      unifocal tumors. To investigate whether MF is an independent prognostic factor
      for overall survival in breast cancer, a Cox regression model was applied. Only
      tumor size, positive lymph nodes, histologic grade and receptor status had a
      significant effect on overall survival in the multivariate analysis. We found a
      positive correlation between tumor size and MF and between the number of positive
      lymph nodes and MF. In conclusion, MF had no significant effect on overall
      survival besides that which can be explained by other prognostic factors.

PMID- 15177421
TI  - Echogenicity of breast cancer: is it of prognostic value?
AB  - Echogenicity of colorectal metastases to the liver has been shown to correlate
      with prognosis. While there have been many studies looking at the echogenicity of
      breast cancer, there has been no study relating the issue of echogenicity to
      prognosis of breast cancer. In this study, we found that hyperechoic and mixed
      echogenicity breast cancers are rare compared to hypoechoic breast cancers. There
      was, however, no difference in the groups with respect to histological size,
      grade, axillary metastases, hormone receptor status and lymphovascular invasion.

PMID- 15177422
TI  - Sentinel node biopsy in the surgical management of breast cancer: experience in a
      general hospital with a dedicated surgical team.
AB  - The aims of this study were to analyse the feasibility and accuracy of the
      sentinel lymph node biopsy (SLNB) procedure as performed in a general hospital
      compared with the literature results; to report on the organizational aspects of
      planning surgical time with higher accuracy of pathological analysis; and to
      verify that there is a real advantage of SLNB in the surgical management of
      breast cancer. From October 1999 to September 2000, 371 consecutive patients with
      T1-2N0 breast lesions underwent SLNB. The immunoscintigraphic method of sentinel
      node identification was the main one used, the blue dye method being used only
      when the lymphoscintigraphic method was unsuccessful in identifying sentinel
      nodes. SLNB was done under either general or local anaesthesia, depending on how
      the surgical procedure was organized and clinically planned. SLNB was successful
      in 99% of these T1-2N0 breast cancer cases, and in 71% no metastases were found
      in the sentinel node. In 47% of cases with axillary metastasis only the sentinel
      node was involved. Nodal involvement was not present in any case of microinvasive
      or in situ carcinoma. In T1 cancers nodal involvement was present in 21%; in T2
      cases the corresponding rate reached 51%. The results obtained with the SLNB
      procedure at Bergamo Hospital are similar to the literature data. When a
      dedicated surgical team, the nuclear medicine department and the pathology
      department work together, a general hospital can provide breast cancer patients
      with appropriate surgical treatment.

PMID- 15177423
TI  - Fish-tail plasty: a safe technique to improve cosmesis at the lateral end of
      mastectomy scars.
AB  - BACKGROUND AND AIMS: Redundant skin at the lateral end of a mastectomy scar can
      be unsightly and uncomfortable, especially in elderly obese patients. The aim of
      this study is to evaluate a technique of mastectomy wound closure designed to
      maximise cosmesis at the lateral end. PATIENTS AND METHODS: Thirty lateral skin
      flap advancements were performed in 28 patients. The procedure was performed
      primarily in 27 cases. In three cases a delayed scar revision was performed.
      Following anterior advancement of the skin overlying the latissimus dorsi muscle,
      two areas of redundant skin were excised and the wound closed in the shape of Y
      plasty. RESULTS: The patients' mean age was 70.6 years (range 51-93) and the mean
      body mass index (BMI) 30.4 kg/m2 (range 21-35). The mean weight of the excised
      breast tissue was 1015 g (range 356-2003). The mean lengths of the two limbs of
      the Y-plasty were 5.3c m (range 3-10). The mean length of the base of the flap
      was 8.3 cm (range 4-14). One patient developed a small area of skin necrosis at
      the apex of the Y-plasty. Two further patients developed superficial wound
      infections. CONCLUSION: Fish-tail plasty is a safe and easy technique and may be
      recommended following mastectomy in obese patients to improve cosmesis and avoid
      discomfort caused by redundant skin.

PMID- 15177424
TI  - Oncological outcome after immediate breast reconstruction for invasive breast
      cancer: a long-term study.
AB  - Immediate breast reconstruction (IBR) was implemented in 1990. Patients operated
      on for invasive breast cancer were assessed for oncological outcome after a
      minimum of 5-year follow-up. The study had a form of a retrospective analysis of
      203 consecutive patients. The indications for IBR were always discussed in
      multidisciplinary case conferences. The pectoralis major fascia was left in
      place. The implant technique dominated. The break down by tumor stage was T1
      tumors in 122 cases, T2 in 72, and T3 tumors in nine. Preoperative chemotherapy
      was given to 21 patients for tumors > 4 cm. Thirteen patients, or 6.5%, developed
      a local recurrence and seven are still alive with their reconstructed breast
      after excisions, chemo- and radiation therapy. Most (11) of the 13 recurrences
      occurred within 24 months after IBR. The recurrence rate remained low with this
      surgery plus reconstruction approach and IBR is therefore considered a safe
      procedure when implemented by a multidisciplinary team. Most recurrences appear
      within 2 years after reconstruction.

PMID- 15177425
TI  - First line therapy with paclitaxel (Taxol) and pegylated liposomal doxorubicin
      (Caelyx) in patients with metastatic breast cancer: a multicentre phase II study.
AB  - The aim of this multicentric phase II study was to investigate the efficacy and
      toxicity of a combination of chemotherapy containing paclitaxel (Taxol) and a
      novel compound, a liposomal encapsulated doxorubicin (Caelyx), as first line
      therapy for patients with metastatic breast cancer. Thirty-four patients with
      advanced breast cancer were treated with a combination of paclitaxel 175 mg/m2
      and liposomal doxorubicin 30 mg/m2, every 3 weeks. The combination chemotherapy
      was effective in 73% of the patients (ITT) (95% CI 55-86%) (7 complete and 18
      partial responses). Grade 3/4 toxicities were documented in a small number of
      patients. Two toxic deaths (6%) were documented, one a hepatorenal failure and
      another a febrile neutropenia. One patient experienced pulmonary embolism but
      continued on treatment after appropriate therapy. The combination of paclitaxel
      and liposomal encapsulated doxorubicin induces a high and durable response rate
      with a moderate toxicity profile.

PMID- 15177426
TI  - Chemosensitization of breast carcinoma cells with the use of bcl-2 antisense
      oligodeoxynucleotide.
AB  - This study was designed to observe whether the rates of apoptosis induced in the
      breast cancer cell line MCF-7 by 5-fluorouracil (5-FU) could be enhanced by
      transfecting bcl-2 antisense oligonucleotide (ASODN). In our experiment, bcl-2
      ASODNs and control ODNs including untreated control, sense ODN and scrambled ODN,
      were transfected into MCF-7 cells. Changes in expression of the bcl-2 gene were
      examined by Western blot; cell growths were detected by MTT assay, and apoptosis
      rates were detected by flow cytometry (FCM). Expression of bcl-2 protein after
      transfection of bcl-2 ASODN was significantly lower than control ODNs. Moreover,
      incubation of MCF-7 with bcl-2 ASODN prior to 5-FU treatment caused remarkable
      loss of viable cells compared with all other control ODNs (P < 0.01). FCM showed
      the apoptosis rates for ASODN, untreated control, sense ODN and scrambled ODN
      (29.8 +/- 7.4)%, (8.0 +/- 2.3)%, (15.0 +/- 5.1)% and (16.5 +/- 7.1)%,
      respectively. Compared with control ODNs, ASODN achieved the strongest effect in
      terms of enhancing apoptosis (P < 0.01). These results suggest that combining bcl
      2 ASODN with 5-FU led to synergistic cytotoxicity.

PMID- 15177427
TI  - Imprint cytology of needle core-biopsy specimens of breast lesion: is it best of
      both worlds?
AB  - The concept and working of one-stop breast clinic has been evolving over the last
      10 years. With more frequent use of core biopsy by the dedicated breast units,
      one-stop results service cannot be provided. The purpose of this study was to
      examine the feasibility of the use of imprint cytology of the core-biopsy
      specimens of breast lesions in a one-stop setting, in order to spare patients
      pain and suffering of a needle test without anaesthetic while retaining the
      advantages of availability of greater pathological characteristics of tumours by
      core biopsy. Forty-one consecutive core-biopsy specimens from symptomatic
      patients who underwent free hand or ultrasound-guided core biopsies of the
      suspected breast lesion were rolled on a glass slide to obtain imprint cytology.
      The cytological reporting was done independent of histological reporting of core
      biopsy. Overall concordance between imprint cytology and histology was 90%. For
      imprint cytology overall sensitivity was 91% and specificity was 89%. The
      positive predictive value was 97% and negative predictive value was 73%. Imprint
      cytology was found to be a quick, reliable and effective way of diagnosing breast
      lesions in breast clinic.

PMID- 15177428
TI  - Bilateral extensive vascular calcification of the breast associated with
      coagulative necrosis: a calciphylaxis-like syndrome.
AB  - A case of asynchronous bilateral breast necrosis in a 40-year-old woman with
      untreated chronic hypercholesteraemia is described. Mastectomies were performed,
      and histological examination revealed bilateral breast calciphylaxis
      characterized by extensive vascular calcification with coagulative necrosis.
      Breast calciphylaxis is a rare disease clinically characterized by progressive
      tissular necrosis with secondary cutaneous ulceration and by vascular
      calcification and thrombosis. However, the nature of the vascular calcification
      has remained poorly understood up to now, owing to the absence of any precise
      mineralogical examination. In this case the mineral deposits were analysed for
      the first time: only hydroxyapatite was found. The etiology is discussed, and the
      high cholesterol rate of the patient is implicated.

PMID- 15177429
TI  - Screening-detected breast carcinoma in a patient with Cowden syndrome.
AB  - Cowden syndrome is a hereditary genetic disease whose incidence is still not
      precisely defined; it is due to a germline mutation in the PTEN gene. We reported
      a case of breast tumor caused by a PTEN gene mutation, which was detected within
      a National Screening Program; the diagnosis of Cowden syndrome was made on the
      basis of patient's particular clinical history. The identification of new genetic
      mutations has allowed clarification of some of the mechanisms that increase the
      risk of developing some types of tumors. Furthermore, new kind of mutations
      recently reported in the literature raise questions about their prognostic
      significance and how their carriers can be better screened, counseled and
      managed. These problematic issues will be encountered with increasing frequency
      in the near future, since many other more mutations are sure to be discovered.
      The PTEN gene mutation has been implicated in various human tumors, mainly in the
      breast and the thyroid gland. In the course of a screening program, the early
      identification of patients affected by a genetic mutation, which is rare,
      improves the definition of the prognosis and the therapeutic options.

PMID- 15177430
TI  - Granulocytic sarcoma of the breast antedating acute myelogenous leukemia.
AB  - We report a rare case of granulocytic sarcoma of the breast presenting as an
      isolated breast lump antedating bone marrow manifestation of acute myelogenous
      leukaemia.

PMID- 15177431
TI  - Benign phyllodes tumor associated with Maffucci's syndrome.
AB  - Reports of breast tumors together with Maffucci's syndrome are extremely rare in
      the literature. Maffucci's syndrome is an uncommon congenital disease
      characterized by the association of multiple enchondromas and different types of
      hemangiomas. To the best of our knowledge, this is the first well-documented case
      of a benign phyllodes tumor of the breast occurring in a patient with Maffucci's
      syndrome. The patient was an 18-year-old woman who had been diagnosed with
      Maffucci's syndrome at the age of 8 months when multiple enchondromas with
      subcutaneous hemangiomas of the toes were diagnosed. The tumor presented as a
      rapidly growing, painful mass of the right breast, which was removed by a wide
      resection with no apparent recurrence 10 months later. Our data, in addition to
      those on two other cases of fibroadenomas with this disease that have already
      been described in the literature, suggest that Maffucci's syndrome is probably a
      generalized mesodermal disorder that can also affect the connective tissue
      component of the breast.

PMID- 15177432
TI  - Pyoderma gangrenosum--an unusual differential diagnosis for acute infection.
AB  - Pyoderma gangrenosum rarely occurs in the breast and has only previously been
      reported in the literature in response to trauma. We describe a case occurring
      spontaneously in the breast that was initially mistaken for an infection.

PMID- 15177433
TI  - Hepatic resection in breast cancer metastases: should it be considered standard
      treatment?
AB  - A 34-year-old woman was diagnosed in October 1994 with a stage I breast cancer
      and treated with conservative surgery, locoregional radiotherapy and adjuvant
      chemotherapy. Nonetheless, 47 months after the initial diagnosis, an isolated
      liver metastasis was diagnosed in segments VII and VIII. A subsegmentectomy was
      performed, and chemotherapy with doxorubicin and paclitaxel was given for five
      cycles. High-dose chemotherapy with peripheral stem cell rescue was then
      administered and tamoxifen hormonal therapy was begun. Now, 54 months after the
      liver recurrence, the patient remains free of disease. Isolated liver metastases
      from breast cancer are rare and should be treated with surgical resection if
      possible, in the context of multimodality programs with hormonal and
      chemotherapy. According to the small series published in the literature, an
      improvement of 27-57 months in median survival rates can be expected when such
      treatment replaces standard therapies, although a selection bias cannot be
      excluded.

PMID- 15177434
TI  - Estimating recurrence probability for synchronous breast cancers.

PMID- 15177435
TI  - Granulomatous mastitis can mimic breast cancer on clinical, radiological or
      cytological examination: a cautionary tale.

PMID- 15177437
TI  - 3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel
      blockers.
AB  - For LVA T-type Ca2+ channel blockers, 3,4-dihydroquinazoline derivatives as new
      scaffolds were prepared and evaluated for the inhibitory activity against two
      members of the recombinant T-type Ca2+ channel family. Among them, 8a (KYS05001,
      IC50=0.9 microM) was nearly equipotent with mibefradil (IC50=0.84 microM) and
      inhibited LVA T-type Ca2+ channel with greater efficacy than HVA Ca2+ channel.

PMID- 15177438
TI  - 6-Arylamino-7-chloro-quinazoline-5,8-diones as novel cytotoxic and DNA
      topoisomerase inhibitory agents.
AB  - A series of 6-arylamino-7-chloro-quinazoline-5,8-diones were prepared and
      evaluated for their in vitro cytotoxicity in cultured human cancer cell lines
      A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer). The
      preliminary structure-activity relationship has been described for providing
      further development of potent antitumor agents. To further investigate the
      cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II
      activities have been assessed.

PMID- 15177440
TI  - Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR.
AB  - 4-Anilino-3-cyanoquinolines were reported to have irreversible binding to
      epidermal growth factor receptor kinase (EGFRK) by forming a covalent linkage to
      C773. Our initial docking studies gave results inconsistent with the in vitro
      data and showed two different binding modes. To perceive the exact mode of
      binding of these ligands, two models of the ligand-EGFR complexes were
      considered: (1) reversible binding mode in which the ligand had hydrogen bond
      interactions at the binding site and (2) irreversible binding mode wherein the
      ligand's Michael acceptor side chain has proximity to the sulfhydryl group of
      C773 of EGFR, thereby enabling a covalent interaction. The irreversible binding
      mode correlated better than reversible binding mode with respect to in vitro
      data. However, our results indicate that both modes are being adopted by the
      ligands and could be utilized to design more potent EGFRK inhibitors.

PMID- 15177439
TI  - Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare
      MMP-1.
AB  - The SAR of a series of sterically hindered sulfonamide hydroxamic acids with
      relatively large P1' groups is described. The compounds typically spare MMP-1
      while being potent inhibitors of MMP-13. The metabolically more stable compounds
      in the series contain either a monocyclic or bicyclic pyran ring adjacent to the
      hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical
      studies revealed that fibrosis in rats and MSS in humans is still produced.

PMID- 15177441
TI  - Thiourea inhibitors of herpes viruses. Part 2: N-Benzyl-N'-arylthiourea
      inhibitors of CMV.
AB  - A series of highly potent thiourea inhibitors of cytomegalovirus (CMV) with
      improved stability properties was prepared and evaluated. Compound 29 inhibited
      the virus in cultured HFF cells with IC50 of 0.2 nM.

PMID- 15177442
TI  - Lead identification of a potent benzopyranone selective estrogen receptor
      modulator.
AB  - Starting from a phenol screening hit (6), three series of benzopyranone selective
      estrogen receptor modulators (SERMs) have been designed, synthesized, and
      analyzed for both estrogen receptor alpha binding affinity and in vitro activity
      in two cell assays. The lead compound identified, SP500263 (13), was more potent
      than raloxifene and tamoxifen in a cell-based assay measuring inhibition of
      interleukin-6 release.

PMID- 15177443
TI  - Thienopyridine and benzofuran derivatives as potent anti-tumor agents possessing
      different structure-activity relationships.
AB  - (3-Amino-6-thiophen-2-yl-thieno[2,3-b]pyridin-2-yl)phenylmethanone (3) was
      discovered as a new type of cytotoxic agent selective against a tumorigenic cell
      line. The molecular structure of a previously reported compound, (4-hydroxy-3
      methyl-6-phenylbenzofuran-2-yl)phenylmethanone (2), had remarkably similar
      bioisosteric substructures to that of compound 3. Although the relationship
      between the molecular structure and biological activity of each derivative
      synthesized from these two hit compounds (2 and 3) were studied, unexpectedly no
      correlation was observed. However, after further synthetic study from 3, one of
      the most potent derivative (10k) having a different SAR profile from 2, was
      discovered.

PMID- 15177444
TI  - Nitroxide-labeled guanine as an ESR spin probe for structural study of DNA.
AB  - A guanine derivative with a covalently linked nitroxide spin label has been
      devised. The spin label was incorporated into oligodeoxynucleotides by post
      synthetic modification. The local environment of a variety of G-rich DNA is
      detectable by ESR using this spin probe.

PMID- 15177445
TI  - Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl
      acetic acid antagonists of the human CCR5 chemokine receptor.
AB  - Efforts toward the exploration of the title compounds as CCR5 antagonists are
      disclosed. The basis for such work stems from the fact that cellular
      proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4
      receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5
      antagonists displaying potent binding and antiviral properties in a HeLa cell
      based HIV-1 infectivity assay are discussed.

PMID- 15177446
TI  - Exploration of the P2-P3 SAR of aldehyde cathepsin K inhibitors.
AB  - The synthesis and biological activity of a series of aldehyde inhibitors of
      cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites
      with a series of carbamate derivatized norleucine aldehydes substituted at the P2
      and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130
      pM.

PMID- 15177447
TI  - 2-Ureidoquinoline: a useful molecular element for stabilizing single cytosine and
      thymine bulges.
AB  - We have demonstrated that aromatic heterocycles having hydrogen-bonding surfaces
      complementary to those of nucleotide bases are effective molecular elements for
      the binding to single nucleotide bulges and base mismatches. We here report that
      a new molecule, 2-ureidoquinoline having an alignment of hydrogen-bonding groups
      in the order of acceptor-donor-donor stabilizes single cytosine and thymine
      bulges in duplex DNAs. Furthermore, a dimeric form of 2-ureidoquinoline
      stabilizes cytosine-cytosine and cytosine-thymine mismatches.

PMID- 15177448
TI  - Exploring QSAR of melatonin receptor ligand benzofuran derivatives using E-state
      index.
AB  - Considering the recent challenge to the medicinal chemists for the development of
      selective melatonin receptor ligands, an attempt has been made to explore
      physicochemical requirements of benzofuran derivatives for binding with human MT1
      and MT2 receptor subtypes and also to explore selectivity requirements. In this
      study, E-states of different common atoms of the molecules (calculated according
      to Kier and Hall) and physicochemical parameters (partition coefficient and molar
      refractivity) were used as independent variables along with suitable dummy
      parameters. The best equation describing MT1 binding affinity [n = 34, Q2 =
      0.670, Ra2 = 0.790, R2 = 0.822, R = 0.907, s = 0.609, F = 25.8 (df 5, 28)]
      suggests that the binding affinity decreases as the value of n (number of CH2
      spacer beside R2) increases while it increases with rise in electrotopological
      state values of different atoms of the benzofuran ring. Again, presence of
      methoxy group at R1 and hydrogen, unsubstituted phenyl or fluoro-substituted
      phenyl group at R2 is conducive to the MT1 binding affinity. The binding affinity
      decreases if furyl substitution at R3 position is present. The best equation
      describing MT2 binding affinity [n = 34, Q2 = 0.602, Ra2 = 0.755, R2 = 0.792, R =
      0.890, s = 0.584, F = 213 (df 5, 28)] shows that the MT2 binding affinity depends
      on the similar factors as described for MT1 binding affinity; however, the
      contributions of the factors for the two affinities are different to some extent
      as evidenced from the regression coefficients. Among the selectivity relations,
      the best equation [n = 33, Q2 = 0.496 Ra2 = 0.681, R2 = 0.721, R = 0.849, s =
      0.458, F = 18.1(df 4, 28)] suggests that MT2 binding increases with increase in
      value of n, presence of methoxy group at R1, and E-state values of different
      atoms of the benzofuran ring, while it decreases in presence of furyl group at R3
      position.

PMID- 15177449
TI  - 2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones: functionally selective benzodiazepine
      binding site ligands on the GABAA receptor.
AB  - 2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine
      binding site ligands with functional selectivity for the alpha3 subtype over the
      alpha1 subtype. SAR studies to optimise this functional selectivity are
      described.

PMID- 15177450
TI  - Synthesis and anticancer activity of side chain analogs of the crambescidin
      alkaloids.
AB  - Twenty three side chain analogs of the crambescidin alkaloids were prepared from
      the corresponding pentacyclic zwitterionic core acid. In the crambescidin 800 and
      657 series, potency increased with increasing chain length. In addition,
      substantial variations in tumor selectivity with structure were seen.
      Crambescidin analogs having short, nonpolar side chains were identified for the
      first time as promising anticancer agents.

PMID- 15177451
TI  - Synthesis of S-alkyl L-homocysteine analogues of glutathione and their kinetic
      studies with gamma-glutamyl transpeptidase.
AB  - A series of S-alkyl L-homocysteine analogues of glutathione was synthesized with
      varied oxidation state of the sulfur and tested for inhibition of rat kidney
      gamma-glutamyl transpeptidase (GGT). The strong selectivity of the enzyme with
      respect to the sulfur oxidation state reveals important information for the
      development of powerful competitive inhibitors.

PMID- 15177452
TI  - Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors.
AB  - A new series of bis-statine based peptidomimetic inhibitors of human beta
      secretase (BACE 1) was developed by structure-based modification of the three
      regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C
      terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted
      in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general
      requirements for the optimal substrate-enzyme interaction are disclosed herein.

PMID- 15177453
TI  - Quantitative structure-polarization relationships (QSPR) study of BTEX tracers
      for the formation of antibody-BTEX-EDF complex.
AB  - The multiple linear regression (MLR) analysis and back propagation neural
      networks (NN) were performed to examine the quantitative structure-polarization
      relationships (QSPR) for the formation of antibody-BTEX-EDF complex. Five
      descriptors out of 18 ones were selected for both MLR and NN, respectively, and
      the selected descriptors in MLR were the same as those in NN. These descriptors
      were the number of atoms, which can form hydrogen bonds (HA), connolly surface
      area (Area), the highest occupied molecular orbital energy (HOMO), partial charge
      of C3 carbon atom (C3), and HOMO pi coefficient of C2 carbon atom (P2). The fact
      that the descriptors in MLR are identical to those in NN suggests that these
      descriptors have good linear relationships and play a significant role in the
      formation of antibody-tracer complex.

PMID- 15177454
TI  - Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
AB  - We screened a small library of known nucleic acid-binding ligands in order to
      identify novel inhibitors of recombinant human telomerase. Inhibitory compounds
      were classified into two groups: Group I inhibitors had a notably greater effect
      when added prior to telomerase assemblage and Group II inhibitors displayed
      comparable inhibition when added before or after telomerase assemblage. Hoechst
      33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with
      human telomerase RNA (hTR) leading us to propose that hTR is the molecular target
      for this and other Group I inhibitors. Our results suggest that hTR can be
      exploited as a small-molecule drug target and provide several new structural
      motifs for the further development of novel telomerase inhibitors.

PMID- 15177455
TI  - Synthesis and biological evaluation of phosphonic and thiophosphoric acid
      derivatives of lysophosphatidic acid.
AB  - Using an N-oleoyl ethanolamide scaffold, a series of phosphate polar head group
      analogues of LPA comprised of various alpha-substituted phosphonates and
      thiophosphates was prepared. In a broken cell GTP[gamma35S] binding assay,
      agonist activity was evaluated at the three LPA receptors of the endothelial
      differentiation gene (Edg) family. This study has resulted in the discovery of a
      nonhydrolyzable LPA1-selective agonist (11). Additionally, thiophosphate 19 bears
      an isosteric phosphate mimetic that confers agonism at the LPA1 receptor but not
      LPA2.

PMID- 15177456
TI  - Design and synthesis of oxadiazolidinediones as inhibitors of plasminogen
      activator inhibitor-1.
AB  - A novel series of PAI-1 inhibitors containing an oxadiazolidinedione moiety were
      identified by high through-put screening. Optimization of substituents by
      parallel synthesis and the iterative design toward understanding structure
      activity relationship to improve potency are described.

PMID- 15177457
TI  - Synthesis and biological activity of some known and putative duloxetine
      metabolites.
AB  - Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6
      hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-5-methoxy-, 5,6-dihydroxy-, and 4,6
      dihydroxyduloxetine were synthesized, and their phase II metabolite as
      glucuronide or sulfate conjugates were also synthesized. Their in vitro binding
      activities were compared to that of parent compound duloxetine.

PMID- 15177459
TI  - Design and synthesis of de novo cytotoxic alkaloids through mimicking taxoid
      skeleton.
AB  - Based on a common pharmacophore model and the hypothesis that the baccatin core
      of taxoids is a scaffold securing the proper orientation of the side chains, a
      bicyclic alkaloid scaffold was designed as a baccatin surrogate. Using this
      scaffold, two novel macrocyclic and open-chain 'taxoid-mimicking' compounds were
      synthesized. Two of these 'taxoid-mimics', 2 and 3, were found to possess
      cytotoxicity with micromolar level IC50 values against human breast cancer cell
      lines.

PMID- 15177458
TI  - Synthesis and anti-inflammatory effects of novel pimarane diterpenoid analogs.
AB  - Syntheses and excellent anti-inflammatory effects of a series of novel acanthoic
      acid analogs are reported. In particular, the mechanistic basis for their anti
      inflammatory effects is also described.

PMID- 15177460
TI  - The discovery of 3-(N-alkyl)aminopropylphosphonic acids as potent S1P receptor
      agonists.
AB  - 3-(N-Alkyl)aminopropylphosphonic acids are potent agonists of four of the five
      known sphingosine-1-phosphate (S1P) receptor subtypes.

PMID- 15177461
TI  - Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N
      benzyl)aminopropylphosphonic acid S1P receptor agonists.
AB  - Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor
      agonists that maintain affinity for S1P1, and have decreased affinity for S1P3
      are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents
      than do nonselective agonists.

PMID- 15177462
TI  - Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl
      compounds as PPARalpha selective activators.
AB  - Lipid accumulation in nonadipose tissues is increasingly linked to the
      development of type 2 diabetes in obese individuals. We report here the design,
      synthesis, and evaluation of a series of novel PPARalpha selective activators
      containing 1,3-dicarbonyl moieties. Structure-activity relationship studies led
      to the identification of PPARalpha selective activators (compounds 10, 14, 17,
      18, and 21) with stronger potency and efficacy to activate PPARalpha over
      PPARgamma and PPARdelta. Experiments in vivo showed that compounds 10, 14, and 17
      had blood glucose lowering effect in diabetic db/db mouse model after two weeks
      oral dosing. The data strongly support further testing of these lead compounds in
      other relevant disease animal models to evaluate their potential therapeutic
      benefits.

PMID- 15177463
TI  - Synthesis of a bioprobe for elucidation of target molecule of spongean anti
      malarial peroxides.
AB  - The reactants of an anti-malarial peroxide having a 6-carbomethoxymethyl-3
      methoxy-1,2-dioxane moiety treated with FeSO4 were analyzed. For mechanistic
      study of the anti-malarial peroxide, two biotinylated probes to elucidate the
      target molecules were designed and synthesized. The two synthesized probes showed
      potent anti-malarial activity, and one of them was proved to form an irreversible
      binding with protein in a model experiment.

PMID- 15177464
TI  - Synthesis of new 2'-beta-C-methyl related triciribine analogues as anti-HCV
      agents.
AB  - Ten new beta-D-ribofuranosyl and 2'-beta-C-methyl-beta-D-ribofuranosyl
      triciribine derivatives 4-13 with various N4 and 6-N substituents on the
      tricyclic ring were synthesized from the corresponding toyocamycin and new 2'
      beta-C-methyl toyocamycin derivatives. The inhibitory studies of these compounds
      in the HCV replicon assay reveal that some of them possess interesting anti-HCV
      properties with low cytotoxicity.

PMID- 15177465
TI  - 2-Alkyl-4-arylimidazoles: structurally novel sodium channel modulators.
AB  - A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities
      to the site-2 sodium (Na+) channel were determined. SAR studies led to highly
      potent Na+ channel blockers.

PMID- 15177466
TI  - BMS-201620: a selective beta 3 agonist.
AB  - A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were
      prepared and evaluated for their human beta3 adrenergic receptor agonist
      activity. SAR studies led to the identification of BMS-201620 (39), a potent
      beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety
      profile, BMS-201620 was chosen for clinical evaluation.

PMID- 15177467
TI  - Synthesis and evaluation of aminophosphinic acid derivatives as inhibitors of
      renal dipeptidase.
AB  - Renal dipeptidase (RDP) is an enzyme overexpressed in benign and malignant
      colorectal tumors. In an effort to identify potent inhibitors of this enzyme, a
      series of aminophosphinic acid derivatives were synthesized. Compounds 3a and 3c
      in which the phenyl ring was para substituted with F and Br and olefin with Z
      geometry, showed better inhibitory activity against RDP enzyme (IC50 = 5-6 nM).

PMID- 15177468
TI  - 2,3-Benzodiazepin-1,4-diones as peptidomimetic inhibitors of gamma-secretase.
AB  - 2,3-Benzodiazepin-1,4-diones were designed as peptidomimetics at the carboxy
      terminus of hydroxyamides. Inhibition of brain Abeta production was improved by
      one of the compounds containing constrained modification.

PMID- 15177469
TI  - Pseudodeflectusin, a novel isochroman derivative from Aspergillus pseudodeflectus
      a parasite of the sea weed, Sargassum fusiform, as a selective human cancer
      cytotoxin.
AB  - A new isochroman derivative named pseudodeflectusin was isolated from a culture
      broth of Aspergillus pseudodeflectus. The structure was determined by
      spectroscopic means as 9-hydroxy-7-methyl-2-(methylethylidine)-furano[3,2
      H]isochroman-3-one. This compound exhibited cytotoxicity for several human cancer
      cell lines from the stomach (NUGC-3), cervix (HeLa-S3), and peripheral blood (HL
      60), but did not affect those from the lung (A549) or colon (DLD-1). The LD50
      value of this compound for HL-60 cells was 39 microM.

PMID- 15177470
TI  - (4-Carboxamido)phenylalanine is a surrogate for tyrosine in opioid receptor
      peptide ligands.
AB  - (S)-4-(Carboxamido)phenylalanine (Cpa) is examined as a bioisosteric replacement
      for the terminal tyrosine (Tyr) residue in a variety of known peptide ligands for
      the mu, delta and kappa opioid receptors. The Cpa-containing peptides, assayed
      against cloned human opioid receptors, display comparable binding affinity (Ki),
      and agonist potency (EC50) to the parent ligands at the three receptors. Cpa
      analogs of delta selective peptides show an increase in delta selectivity
      relative to the mu receptor. Cpa is the first example of an amino acid that acts
      as a surrogate for Tyr in opioid peptide ligands, challenging the long-standing
      belief that a phenolic residue is required for high affinity binding.

PMID- 15177471
TI  - Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the
      thyroid hormone receptor beta.
AB  - A set of thyromimetics having improved selectivity for TR-beta1 were prepared by
      replacing the 3'-isopropyl group of 2 and 3 with substituents having increased
      steric bulk. From this limited SAR study, the most potent and selective compounds
      identified were derived from 2 and contained a 3'-phenyl moiety bearing small
      hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed
      with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl
      ethyl amide side chain. Movement of this amino acid side chain provides an
      expanded pocket for the bulky side chain while the ligand-receptor complex
      retains full agonist activity.

PMID- 15177472
TI  - Toxic effects of natural piperine and its derivatives on epimastigotes and
      amastigotes of Trypanosoma cruzi.
AB  - We describe herein an evaluation of trypanocidal effects of the natural alkaloid
      piperine and twelve synthetic derivatives against epimastigote and amastigote
      forms of the protozoan parasite Trypanosoma cruzi, the causative agent of the
      incurable human disease, Chagas' disease. The results obtained point to piperine
      as a suitable template for the development of new drugs with trypanocidal
      activity.

PMID- 15177473
TI  - Phosphonate inhibitors of antigen 85C, a crucial enzyme involved in the
      biosynthesis of the Mycobacterium tuberculosis cell wall.
AB  - The first phosphonate inhibitors of antigen 85C--a major protein component of the
      Mycobacterium tuberculosis cell wall possessing mycolyltransferase activity were
      prepared using structure-based design. These potential novel antituberculosis
      agents, consisting of a phosphonate moiety, hydrophobic alkyl chain and a simple
      trehalose-mimicking aromatic structure, were designed as tetrahedral transition
      state analogue inhibitors of antigen 85C, which catalyzes the key
      mycolyltransferase reaction involved in cell wall biosynthesis.

PMID- 15177475
TI  - Synthesis and immunological evaluation of an antitumor neoglycopeptide vaccine
      bearing a novel homoserine Tn antigen.
AB  - As part of our program on Tn-specific anti-tumor immunotherapy, our aim was to
      vary the nature of the aglyconic part of the tumor-associated Tn antigen (alpha-d
      GalNAc-Ser/Thr). This report describes the synthesis of Fmoc-hSer-(alpha-d
      GalNAc)-OH (4) in 19% overall yield from protected aspartic acid. The building
      block 4 was incorporated as trimeric clusters into a glycopeptide vaccine
      [MAG:Tn(hSer)3-PV], using solid-phase peptide synthesis. When injected in mice,
      the resulting MAG induces a strong antibody response, which recognizes native
      tumor-associated antigens (TAA) at the surface of human tumor cells. This
      approach may be extended to the use of other nonnatural TAA in order to improve
      half-life of synthetic anti-cancer vaccines.

PMID- 15177474
TI  - Synthesis and biological evaluation of benzimidazole-4,7-diones that inhibit
      vascular smooth muscle cell proliferation.
AB  - A series of 6-arylamino-5-chloro-benzimidazole-4,7-diones were synthesized and
      tested for their inhibitory activity on the rat aortic smooth muscle cell
      (RAoSMC) proliferation. Among them, 6-arylamino-5-chloro-2-methyl-benzimidazole
      4,7-diones exhibited potent antiproliferative activity. Benzimidazole-4,7-dione
      2c activated SAPK/JNK signaling pathway in the RAoSMCs.

PMID- 15177476
TI  - Synthesis, absolute stereochemistry and molecular design of the new antifungal
      and antibacterial antibiotic produced by Streptomyces sp.201.
AB  - The absolute stereochemistry of the new antifungal and antibacterial antibiotic
      produced by Streptomyces sp.201 has been established by achieving the total
      synthesis of the product. A series of analogues have also been synthesized by
      changing the side chain and their bioactivity assessed against different
      microbial strains. Among them, 1e (R = C8H17) was found to be the most potent
      with MIC of 8 microg/mL against Mycobacterium tuberculosis, 12 microg/mL against
      Escherichia coli and 16 microg/mL against Bacillus subtilis 6 microg/mL against
      Proteus vulgaris. This was followed by 1b (R = C5H11) with MIC of 10-20 microg/mL
      range and 1d (R = C7H15) with MIC of 14-24 g/mL, whereas 1a (R = C4H9) and 1f (R
      = C18H35) were found to be completely inactive. Besides, 1c (R = C6H13) showed
      certain extent of antibacterial activity in the range of 24-50 microg/mL.
      Mycobacterium tuberculosis was very sensitive to 1e (R = C8H17) with MIC of 8
      microg/mL. Antifungal activity of analogues 1d (R = C7H15) and 1e, (R = C8H17)
      against Fusarium oxysporum and Rhizoctonia solani were found promising with MFCs
      in the 15-18 microg/mL range.

PMID- 15177477
TI  - An aminomethylpyrimidine DPP-IV inhibitor with improved properties.
AB  - A recently identified DPP-IV inhibitor (1) was found to induce phospholipidosis
      and to inhibit CYP3A4. A small series of less lipophilic and less amphiphilic
      analogues was synthesized in an effort to overcome these issues. One compound
      from this series was equipotent to 1, did not induce phospholipidosis and showed
      a reduced CYP3A4 inhibition.

PMID- 15177478
TI  - Aminomethylpyridines as DPP-IV inhibitors.
AB  - In a novel series of DPP-IV inhibitors, a large increase of inhibitory activity
      was achieved by optimisation of aromatic substituents and conformational
      restriction.

PMID- 15177479
TI  - Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H
      pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I
      receptor kinase domain.
AB  - We have expanded our previously reported series of pyrazole-based inhibitors of
      the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6
      dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of
      this new series in both enzyme and cell based in vitro assays has revealed
      selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on
      the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our
      original pyrazole series, phenyl substituents tended to show greater selectivity
      against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also
      achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent
      examples of this new series, with the TbetaR-I receptor kinase domain.

PMID- 15177480
TI  - Novel and potent transforming growth factor beta type I receptor kinase domain
      inhibitor: 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)
      quinolines.
AB  - A novel series of 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol
      3-yl)-quinolines was synthesized and their TbetaR-1 inhibitory, p38 MAPK
      inhibitory, and TbetaR-1-dependent cellular activity were evaluated. Compound 5a
      was found to be a highly potent in the enzyme assay and TbetaR-1-dependent
      cellular assays. In addition, dimer (4g), with a urea linker, shows a similar
      enzyme and cellular activity despite a bulky substitution.

PMID- 15177481
TI  - Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl-pentylsulfones
      as CCR5 antagonists.
AB  - Cellular proliferation of HIV-1 requires the cooperative assistance of both the
      CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have
      resulted in the identification of N-alkyl piperidine sulfones as CCR5
      antagonists. These compounds display potent binding and show antiviral properties
      in HIV-1 spread cell-based assays.

PMID- 15177482
TI  - Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid
      arthritis.
AB  - A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5
      substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as
      p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four
      structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha
      with high efficacy in the LPS induced TNFalpha release model in the mouse, the
      adjuvant induced arthritis and the collagen induced arthritis in the rat with
      ED50s between 1.0 and 9.5 mg/kg p.o.

PMID- 15177483
TI  - SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with
      oral activity.
AB  - Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as
      p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral
      activity was found to depend upon substitution: 1,1-dimethylpropynylamine
      substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted
      benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with
      ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.

PMID- 15177484
TI  - [3H]-MRE 2029-F20, a selective antagonist radioligand for the human A2B adenosine
      receptors.
AB  - MRE 2029-F20 [N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7
      tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide] is a selective
      antagonist ligand of A2B adenosine receptors. For use as a radioligand, 1,3
      diallyl-xanthine, the precursor of [3H]-MRE 2029-F20, was synthesized, and
      tritiated on the allyl groups. [3H]-MRE 2029-F20 bound to human A2B receptors
      expressed in CHO cells showed a KD value of 1.65+/-0.10 nM and Bmax value of 36+/
      4 fmol/mg protein. [3H]-MRE2029-F20 represents a useful tool for the
      pharmacological characterization of human A2B adenosine receptor subtype.

PMID- 15177485
TI  - A mild, efficient and alpha-selective glycosidation by using potassium
      dodecatungstocobaltate trihydrate as catalyst.
AB  - Treatment of tri-O-acetyl-d-glucal 1 with several alcohols in the presence of
      catalytic amount of POM (K(5)CoW(12)O(40).3H(2)O) as a heterogeneous, reusable,
      efficient and environmentally benign catalyst under neutral conditions and
      ambient temperature gave the corresponding 2,3-unsaturated glycopyranosides in
      excellent yields, with good anomeric selectivity. This catalyst proved to be not
      efficient for phenols.

PMID- 15177486
TI  - Controversial effect of epoetin in cancer: grounds for a translational research
      exercise?

PMID- 15177487
TI  - Monoclonal antibodies in the treatment of colorectal cancer.
AB  - Monoclonal antibodies have been developed to target specific proteins involved in
      the development and progression of cancer. These reagents have the advantage of
      exquiste specificity, and as currently engineered, low toxicity. The impact
      monoclonal antibody therapy has recently been demonstrated in colorectal cancer,
      in which two pathways critical to carcinogenesis have been targeted. The targets
      are the epidermal growth factor receptor signaling pathway and angiogenesis.
      Antibodies directed to proteins in both pathways have shown significant activity
      especially in combination with chemotherapy, and studies in the adjuvant setting
      are in progress. We review the use of monoclonal antibodies in the treatment of
      colorectal cancer with particular attention to edrecolomab (Mab 17-1A),
      bevacizumab (Avastin), cetuximab (IMC-C225), ABX-EGF and EMD 72000. Additional
      compounds are in earlier stages of development, and the future of this approach
      in solid tumours is promising.

PMID- 15177488
TI  - Angiogenesis of gastrointestinal tumours and their metastases--a target for
      intervention?
AB  - Angiogenesis is an obligatory event for the growth of tumours beyond 2 mm in
      diameter, above which simple oxygen diffusion can no longer support the rapid
      proliferation of malignant cells. Angiogenesis is a fine balance between
      inhibitory and stimulatory factors, the knowledge of which offers novel targets
      for the treatment of gastrointestinal neoplasia. A literature search of Pubmed
      and Medline databases was undertaken, using the keywords colorectal cancer,
      pancreatic cancer, gastrointestinal cancer, angiogenesis and anti-angiogenesis
      therapy. It was found that angiogenesis in primary tumours is a sequential and
      highly complex cascade of molecular events resulting in the rapid exponential
      growth of the tumour. Hepatic metastases of primary tumours may be less reliant
      on traditional angiogenic pathways, by co-opting pre-existing hepatic
      vasculature. Research into angiogenesis has revealed many different sites that
      can be targeted by agents such as tyrosine kinase inhibitors. Many anti
      angiogenic agents are undergoing preclinical evaluation, with only a few entering
      phase I and phase III clinical trials. However, early results suggest that anti
      angiogenic therapy could be an important adjunct to conventional chemotherapy
      treatment of gastrointestinal neoplasia.

PMID- 15177489
TI  - An open multicentre comparative study of the efficacy, safety and tolerance of
      fluconazole and itraconazole in the treatment of cancer patients with
      oropharyngeal candidiasis.
AB  - Oropharyngeal candidiasis is a frequent infection in cancer patients who receive
      cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole
      and itraconazole were compared in non-neutropenic cancer patients with
      oropharyngeal candidiasis. Of 279 patients who were randomised between the two
      treatment groups, 252 patients were considered to be eligible (126 in each
      group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole
      (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was
      80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The
      safety and tolerance profile of both drugs were comparable. This study has shown
      that in patients with cancer and oropharyngeal candidiasis, fluconazole has a
      significantly better clinical and mycological cure rate compared with
      itraconazole.

PMID- 15177490
TI  - Bronchial-associated lymphoid tissue lymphoma: a clinical study of a rare
      disease.
AB  - Bronchial-associated lymphoid tissue (BALT) lymphoma is a distinct subgroup of
      low-grade B-cell extranodal non-Hodgkin's lymphoma, classified as marginal-zone
      lymphoma. This study was performed in order to assess the natural history of this
      rare entity. We evaluated retrospectively the clinical data of 22 patients with
      biopsy-proven BALT lymphoma at two tertiary-care institutions from 1996 to 2002.
      Immunophenotyping was done to confirm the abnormal populations of B-lymphoid
      cells in all cases, and clonality was determined by flow cytometry or molecular
      studies. There were 11 men and 11 women in the sample, median age 61 years (range
      21-80 years); nine were asymptomatic at diagnosis. All 13 symptomatic patients
      had non-specific pulmonary complaints. On computed tomographic examination of the
      chest, 11 patients had bilateral disease, 12 had lung nodules, and 10 had a mass
      or air-space consolidation. In all but one case the disease was localised to the
      lung at diagnosis and none had peripheral blood or bone marrow involvement. Out
      of 22 patients, 20 received treatment in various combinations, 12 had
      chemotherapy and/or rituximab, six had surgery, and two received radiation
      therapy as primary treatment. A complete response (CR) was achieved in nine
      patients and a partial response was obtained in 10 patients. Seven of 10 patients
      who had unilateral disease achieved a CR. The estimated progression-free survival
      was 53 months. All patients were alive during the median follow-up period of 36
      months (range 12-76 months). It appears that BALT lymphoma tends to be localised
      to lung at the time of diagnosis, responds well to local or systemic therapy, and
      has a favourable prognosis.

PMID- 15177491
TI  - A phase II study of ET-743/trabectedin ('Yondelis') for patients with advanced
      gastrointestinal stromal tumours.
AB  - Primary or secondary resistance to imatinib may occur in patients with
      gastrointestinal stromal tumours (GISTs) while these tumours have repeatedly been
      shown to be highly resistant to conventional doxorubicin- and ifosfamide
      containing regimens. The investigation of new drugs is therefore warranted in
      GIST. A phase II study was conducted between May 1999 and November 2000 in eight
      centres of the EORTC STBSG group to establish the efficacy and safety of ET743
      ('Yondelis') in GIST previously untreated with cytotoxic chemotherapy before the
      imatinib era. ET-743 was given was given at 1.5 mg/m(2) per course as a 24-h
      continuous intravenous infusion every 3 weeks. Twenty-eight patients were
      included, 16 males and 12 females. Median age was 54 years (range 25-73 years).
      Median performance status was 0 (range 0-1). 17 (63%), 4 (12%) and 7 (25%)
      patients, received 0-2, 3-5, and > or = 6 courses of ET-743, respectively. The
      best response was stable disease in 9 (33%) patients, and disease progression in
      18 patients (67%), with a median time to disease progression and overall survival
      of 51 days and 589 days, respectively. The treatment was well tolerated: there
      were grades 3-4 neutropenia, thrombocytopenia, and transaminase increases in 13
      (48%), 1 (4%) and 16 (59%) patients, respectively. There were no toxic deaths. ET
      743 at this dose and schedule is not an effective treatment for advanced GIST.

PMID- 15177492
TI  - RFS2000 (9-nitrocamptothecin) in advanced small cell lung cancer, a phase II
      study of the EORTC New Drug Development Group.
AB  - Camptothecins have shown efficacy in terms of response rate in patients with
      small cell lung cancer (SCLC). RFS2000 is a new camptothecin derivative, which
      has shown objective responses in various tumour types. The aim of this phase II
      study was to determine the objective response rate of RFS2000 in patients with
      sensitive and refractory SCLC. RFS2000 was given orally at 1.5 mg/m(2) per day
      for five consecutive days (five days on - two days off) on a continuous basis.
      Patients were evaluated weekly for toxicity and every six weeks for response.
      Thirty seven patients were included, 36 patients (14 with sensitive and 22 with
      refractory SCLC) were evaluable for toxicity, and 35 patients were evaluable for
      response. No objective responses were observed. Toxicity was acceptable, with
      myelosuppression, nausea/vomiting, and diarrhoea as the main toxicities. RFS2000
      therefore has an acceptable toxicity profile but is not active as a single agent
      in SCLC.

PMID- 15177493
TI  - Economic evaluation of treatments for cancer in childhood.
AB  - Treatment of cancer in childhood is an expensive undertaking for the health-care
      system and for the affected families. As there is a substantial burden of
      treatment-related morbidity, it is important to determine whether the effects of
      treatment are worth these monetary costs, especially from a societal perspective.
      Economic evaluation affords a comparison of the costs and consequences (effects)
      of relevant therapeutic alternatives. Preference-based measures of health-related
      quality of life are particularly useful for assessing the effects of treatment,
      for these tools integrate mortality and morbidity. These measures provide utility
      scores that can be used as weights on survival data to compute quality-adjusted
      life years (QALYs). Costs are incurred both within and outside of the health-care
      system. The former should include those in front-line patient care departments
      (e.g. nursing); the pro-rated share of the expenses of service departments (e.g.
      materials management) to those in the front line; and the fully allocated costs
      for capital invested in lands, building and equipment. The latter are costs borne
      by families that are both out-of-pocket (e.g. for over-the-counter drugs) as well
      as related to time spent in providing care, which may involve foregone income.
      Costs and consequences should be subject to discounting; a process for converting
      those items incurred in the future into contemporary equivalents. Economic
      evaluation provides estimates of incremental discounted costs per discounted QALY
      gained. By almost any interpretative standard this appears attractive with
      respect to cancer in childhood. Examples are provided with the encouragement that
      economic evaluation be undertaken in more clinical trials in paediatric oncology.

PMID- 15177494
TI  - Acute neurotoxicity in children with advanced stage B-non-Hodgkin's lymphoma and
      B-acute lymphoblastic leukaemia treated with the United Kingdom children cancer
      study group 9002/9003 protocols.
AB  - We reviewed the pattern of acute neurotoxicity in children with B-non-Hodgkin's
      lymphoma (B-NHL) and B-acute lymphoblastic leukaemia (ALL) treated with the
      UKCCSG 9002/9003 protocols. Among 175 patients, 21 (12%) developed acute
      neurotoxicity: 9002 protocol (n=11/112) and 9003 (n=10/63). There were 20 boys
      and the median age was 10 years. Patients with neurological symptoms due to other
      causes were excluded. Acute neurological symptoms developed following induction
      chemotherapy in 7 patients, or after a more intensive course of chemotherapy
      containing high-dose methotrexate (n=14). Nine patients required their
      chemotherapy to be altered because of the acute neurotoxicity. One patient died
      of cerebral haemorrhage but none of the remaining six deaths was attributed to
      acute neurotoxicity. We conclude that acute neurotoxicity is common in children
      treated with the 9002/9003 protocols and tends to be transient. Intrathecal and
      systemic chemotherapy including high-dose methotrexate is probably the most
      common predisposing factor. Modification of subsequent chemotherapy is not
      invariably necessary.

PMID- 15177495
TI  - Increasing incidence rates of childhood malignant diseases in Sweden during the
      period 1960-1998.
AB  - We analysed the trends in incidence rates of childhood cancer in Sweden. All
      cases of malignant diseases and benign brain tumours in children, 0-14 years old,
      reported to the Swedish Cancer Registry 1960 to 1998 were included, n=9298. Cases
      were classified according to the International Classification of Childhood
      Cancer. Average annual change in incidence rate was calculated to +1.01%, (95%
      confidence interval CI=0.80, 1.22). An increase in incidence rate per year was
      found for leukaemia, +0.85% (95% CI=0.42, 1.28), lymphomas +1.87% (95% CI=1.17,
      2.58), CNS (central nervous system) tumours +1.45% (95% CI=1.02, 1.88),
      sympathetic nervous system tumours +1.61% (95% CI=0.79, 2.44), hepatic tumours
      +2.62% (95% CI=2.02, 3.21), and germ cell and gonadal tumours +1.21% (95%
      CI=0.23, 2.19). Of the CNS tumours, significant changes were seen for low-grade
      glioma/astrocytoma +2.10% (95% CI=1.41, 2.80), benign brain tumours +3.77% (95%
      CI=2.47, 5.10), and PNET/medulloblastoma +1.96% (95% CI=0.48, 3.46). Changes in
      diagnostic criteria and better diagnostic tools may have contributed to these
      results.

PMID- 15177496
TI  - Up-to-date long-term survival of cancer patients: an evaluation of period
      analysis on Swedish Cancer Registry data.
AB  - The natural development of cancers as well as the measures to fight the disease
      are often long processes that require decades of follow up. Available information
      on long-term survival will thus often appear outdated and irrelevant. A few years
      ago, period-survival analysis was proposed as a means to obtain more up-to-date
      information on long-term cancer survival. This article assesses period and
      conventional cohort-based survival analyses on their ability to predict future
      survival. Based on historical data from the nationwide Swedish Cancer Registry 5
      , 10- and 15-year relative survival actually observed for patients diagnosed at
      one particular point in time are compared to the most recent period and cohort
      based survival estimates available at that point in time. The study shows that
      period analysis can, in most cases, be used to provide more up-to-date long-term
      estimates of cancer survival. Period analysis reduces the time lag of the
      survival estimates by some 5-10 years for all cancers combined and especially
      affects the survival estimates for small intestine carcinoids, meningioma and
      intracranial neurinoma of the brain, non-seminoma testicular cancer, chronic
      lymphocytic leukaemia and Hodgkin's lymphoma.

PMID- 15177497
TI  - Shift of syndecan-1 expression from epithelial to stromal cells during
      progression of solid tumours.
AB  - Syndecan-1 (SDC-1), a protein found on cells and in the extracellular matrix,
      participates in cell proliferation, cell migration and cell-matrix interactions.
      SDC-1 expression correlates with the maintenance of epithelial morphology and
      inhibition of invasiveness. In the present study, a second SDC-1 mRNA isoform was
      identified and the expression of both transcripts was investigated in various
      normal and malignant tissues. Both transcripts were coexpressed at equal levels
      in all tissues and organs analysed. Cancer-profiling array (CPA) analysis of 241
      non-enriched tumour and normal cDNAs revealed stronger upregulation of SDC-1 in
      tumour tissues as compared with oligonucleotide array-based expression analysis
      of SDC-1 in microdissected breast, prostate, lung, and colon carcinoma cells.
      With in situ hybridisation and immunohistochemistry it was demonstrated that this
      difference in SDC-1 expression originates from stromal cells present in tumour
      connective tissue. But only the cells in connective tissue surrounding breast,
      lung, colon and bladder carcinoma showed upregulation of SDC-1. These stromal
      cells were characterised as spindle cells with myofibroblastic differentiation
      and they may contribute to the dedifferentiation of tumour cells and the
      development of metastasis.

PMID- 15177498
TI  - Actin-dependent tumour cell adhesion after short-term exposure to the
      antimetastasis ruthenium complex NAMI-A.
AB  - Imidazolium trans-imidazoledimethylsulphoxidetrachlororuthenate (NAMI-A) was
      tested in vitro on the pro-adhesive properties, evaluated as resistance to
      trypsin treatment, which is a bona fide measure of adhesion strength, of KB and
      HeLa carcinoma cell lines and on human polymorphonuclear neutrophils (HPMN). NAMI
      A increased the pro-adhesive activity of KB cells at 0.001 mM concentration,
      after few minutes incubation and this effect was not influenced by the vehicle
      used for cell challenge, neither did it depend on NAMI-A concentration or on
      temperature. The same effect occurred on HeLa cells at 0.01 mM NAMI-A. This
      effect, detected at concentrations up to 100 times lower than those necessary to
      block cells at the G(2)-M premitotic phase of cell cycle, or to inhibit matrix
      metalloproteinase release or cell invasion, was not related to ruthenium uptake
      by tumour cells. HeLa cells and healthy HPMN, following short exposure to 0.1 mM
      NAMI-A, assumed a different shape, with the extrusion of filopodia (HeLa) and of
      large lamellopodia (HPMN), which increased their interactions with the substrate.
      This effect was attributed to stabilisation, altered turnover and sensitivity to
      cytochalasin D of actin filaments. Provided that adhesion is associated with cell
      motility and invasion, these data suggest that NAMI-A may exert antimetastatic
      properties at concentrations lower than those observed in the lungs at the end of
      a conventional intraperitoneal treatment in vivo.

PMID- 15177499
TI  - Suppression of hepatocellular carcinoma growth in mice by the alkaloid
      coccidiostat halofuginone.
AB  - Halofuginone, a widely used alkaloid coccidiostat, is a potent inhibitor of
      collagen alpha 1 (I) and matrix metalloproteinase 2 gene expression. Halofuginone
      also suppresses extracellular matrix deposition and fibroblast proliferation. It
      was recently shown to be effective in suppression of bladder carcinoma and
      glioma. This study sought to evaluate the effect of treatment with halofuginone
      on growth of hepatocellular carcinoma (HCC) in mice. Athymic Balb/c mice were
      injected subcutaneously with 10(7) human hepatoma cells (Hep3B), followed by
      treatment with halofuginone administered in the diet (750 microg/kg) starting on
      day 3, before tumour innoculation. The control group was received a normal diet.
      Mice were followed for survival, tumour volume and serum alpha-fetoprotein (alpha
      FP). The mechanism of the anti-tumour effect of halofuginone was determined in
      vitro by assessing tumour cell growth, and by measuring the serum concentrations
      of interferon-gamma (IFN gamma) and interleukin 2 (IL2). Halofuginone treatment
      induced almost complete tumour suppression in treated mice. Mortality rates were
      10% and 50%, in halofuginone-treated and control mice, respectively (P<0.001). No
      visible tumour was observed in treated mice, as compared with a 364 mm3 tumour in
      control mice. Serum alpha FP were 0.1 and 212 ng/ml in treated and control mice,
      respectively (P<0.005). Halofuginone significantly inhibited HCC proliferation in
      vitro. Maximal inhibition of 64% of tumour cell growth was observed at a
      concentration of 10(-8) M. The anti-tumour effect was mediated via a significant
      increase in IFN gamma and IL2 (90 vs. 35, and 210 vs. 34 pg/ml in treated and
      control groups, respectively, P<0.005). Treatment with halofuginone effectively
      suppressed the progression of HCC in mice. This effect may be associated with a
      direct anti-tumour effect, and/or enhancement of a systemic immune response.

PMID- 15177500
TI  - Prostate intraepithelial neoplasia in Noble rats, a potential intermediate
      endpoint for chemoprevention studies.
AB  - In most prostate chemoprevention studies conducted with animal models, the
      incidence and multiplicity of tumours have been used as endpoints for efficacy.
      However, the latency of tumours is usually over 1 year, making these studies
      costly and time consuming. The main purpose of this study was to assess the
      utility of prostate intraepithelial neoplasia (PIN), induced in Noble rats by
      continuous testosterone + oestradiol (T + E) administration, as a potential
      intermediate endpoint biomarker of efficacy in chemoprevention studies. Noble
      rats at the age of 12 weeks were treated for 36 weeks with T + E given
      subcutaneously via Silastic capsules. The incidence and multiplicity of PIN were
      assessed in various prostate glands by serial sections generated at three
      separate tissue levels. The efficacy of dehydroepiandrosterone (DHEA) and DHEA
      8354 (1000 and 2000 mg/kg diet), difluoromethylornithine (DFMO) (1000 and 2000
      mg/kg diet) and oltipraz (125 and 250 mg/kg diet) to inhibit PIN was assessed in
      two independent sets of experiments. T + E induced multiple PIN in the
      dorsolateral prostate (DLP) of 80-100% of the animals. DHEA and DHEA 8354 did not
      affect the incidence but decreased the multiplicity of PIN in the DLP, from 3.2
      +/- 1.0 in control group to 1.5 +/- 1.0 in the low-dose and to 1.6 +/- 0.6 in the
      high-dose group for DHEA (P<0.05 and P<0.02, respectively), and to 1.9 +/- 0.8 in
      the high-dose (P<0.05) DHEA 8354. Both agents did not affect PIN in anterior
      prostate, seminal vesicles or ventral prostate. In a second experiment, DFMO and
      oltipraz were found not effective in inhibiting PIN. In this study, we provide
      new evidence that PIN in Noble rats, induced by continuous T + E treatment, is a
      useful intermediate endpoint for determining the efficacy of DHEA and other
      potential chemopreventive agents. The hormonal pathogenesis, high multiplicity,
      short latency, preferential location in the DLP, similarity in morphology and
      biology to PIN of human prostate, and the sensitivity to agents that suppress
      prostate carcinogenesis, makes PIN in Noble rats a promising intermediate
      endpoint for chemoprevention studies.

PMID- 15177501
TI  - Tumour burden and interleukin-2 dose affect the interaction between low-dose
      total body irradiation and interleukin 2.
AB  - Low-dose total body irradiation (LTBI) has a synergistic immune-mediated
      antitumour effect when used in combination with interleukin 2 (IL-2) in a murine
      metastatic malignant melanoma model. To optimise the use of this combination
      treatment this study was performed to test the effect of tumour burden and dose
      of both LTBI and IL-2 on the therapeutic potential of this treatment strategy.
      Ten-week-old female C57BL/6 mice were inoculated intravenously (day 0) with 1
      million B16F1 malignant melanoma cells. Groups of mice received no treatment, a
      single fraction of LTBI alone, IL-2 treatment alone, or a combination of LTBI and
      IL-2. Two doses of LTBI and IL-2 were tested. LTBI was given on day +10 and IL-2
      treatment started on day +11. On day +18 the mice were killed. The lungs were
      removed and analysed for tumour burden. Lung sections were also tested for
      infiltrating leucocytes using immunohistochemical staining. In one experiment,
      mice were treated at day +7 with low-dose IL-2 with and without LTBI. LTBI (in
      the two tested doses) showed no independent therapeutic effects. An IL-2 dose of
      300,000 Cetus units (CU) that was effective and showed synergism with LTBI when
      mice were treated on day +7 failed to show a therapeutic effect when mice were
      treated on day +10, at which time the initial tumour burden had doubled. High
      dose IL-2 (600,000 CU), in contrast, led to a significant reduction in metastatic
      burden compared to the control group. Combining high-dose IL-2 with LTBI led to a
      further significant reduction in tumour burden. Moreover, this combination was
      associated with a less severe vascular leakage syndrome compared to IL-2 alone.
      IL-2 and combination treatment was associated with an increase in the number of
      tumour-infiltrating immune cells, but only the number of tumour-infiltrating
      natural killer cells reflected therapeutic efficacy. It was concluded that tumour
      burden at the time of treatment and IL-2 dose are two crucial factors affecting
      the synergism between LTBI and IL-2. The combination may not only be more
      effective than IL-2 alone but also less toxic.

PMID- 15177502
TI  - Transferrin receptor is a marker of malignant phenotype in human pancreatic
      cancer and in neuroendocrine carcinoma of the pancreas.
AB  - Transferrin receptor (TFRC) is a membrane-bound protein expressed in larger
      amounts in proliferating, e.g., malignant, cells than in quiescent cells. The
      specific expression of TFRC can represent a diagnostic tool or a therapeutic
      target in solid tumours expressing this antigen. Whether TFRC is expressed in
      human pancreatic tumours is unknown. The aim of this study was the investigation
      of the expression of TFRC and transferrin in human pancreatic cancer and in
      neuroendocrine tumours of the pancreas. Fifty one specimens of human pancreatic
      cancer and 14 samples of pancreatic neuroendocrine tumours were obtained after
      surgery. The expression of TFRC, transferrin and cytokeratin was studied by
      standard immunohistochemistry. Flow cytometry was used for the investigation of
      TFRC expression in nine cell lines of ductal pancreatic cancer in vitro. In
      contrast to normal tissue, 93% of pancreatic tumour cells showed positive (82%)
      or heterogeneous (11%) expression of TFRC. It was strongly expressed by malignant
      epithelial cells; normal stromal and endothelial cells were not stained by anti
      TFRC antibodies. Primary tumours and metastases showed a similar frequency of
      TFRC expression. Three neuroendocrine carcinomas showed positive expression of
      TFRC by malignant tumour cells. The expression of TFRC was negative in benign
      neuroendocrine tumours of the pancreas. The cell lines of pancreatic cancer were
      characterised by a low expression of TFRC in vitro. In contrast to normal
      pancreatic tissue and benign neuroendocrine tumours of the pancreas, pancreatic
      cancer and neuroendocrine carcinoma are therefore characterised frequently by
      high expression of TFRC. Hence, TFRC represents a marker of malignant
      transformation in the pancreas that could be applied as potential diagnostic and
      therapeutic target.

PMID- 15177503
TI  - Disturbed melanin synthesis and chronic oxidative stress in dysplastic naevi.
AB  - Dysplastic naevi (DN) are a known risk factor for malignant melanoma. Their
      occurrence is closely connected with the degree of skin pigmentation. People with
      a light complexion are more likely to develop DN than dark-skinned individuals.
      We examined the proposition that DN exhibit altered melanin formation, which may
      be involved in their malignant transformation. X-ray microanalysis was used to
      study the composition of melanosomes from DN and to compare the results with
      those obtained from melanomas, banal (dermal) naevi and normal cutaneous
      melanocytes. We analysed sulphur (an indicator of phaeomelanin) and two metals,
      iron and calcium, involved in oxidative stress. FACS analysis of dihydrorhodamine
      123-labelled cells was employed to quantify differences in the production of
      radical oxygen species in DN cells and normal skin melanocytes. A significantly
      higher sulphur content was found in melanosomes from DN cells and melanoma cells
      when compared with normal melanocytes and naevus cells from banal naevi. In
      addition, melanosomes of DN cells and melanoma cells contained higher amounts of
      iron and calcium. In the case of calcium, this was associated with a
      significantly elevated cytoplasmic concentration. FACS analysis showed that DN
      cells exhibited higher concentrations of radical oxygen species than normal skin
      melanocytes from the same individuals. We propose that increased
      phaeomelanogenesis in DN cells is connected with oxidative imbalance, which is
      reflected by increased intracellular concentrations of reactive oxygen species
      and raised calcium and iron concentrations. We show that the metabolic
      alterations in DN cells resemble those found in melanoma cells. Our findings
      provide support for the idea that DN cells are true precursor lesions of
      melanoma.

PMID- 15177504
TI  - Tumour seeding in peritoneal wound sites in relation to growth-factor expression
      in early granulation tissue.
AB  - The purpose of these experiments was to identify growth factors produced during
      the formation of a peritoneal wound in relation to tumour cell seeding and
      stimulated growth in granulation tissue. Gelfoam(c) gelatin sponge was implanted
      in the mesenteric fan of nude mice to initiate the granulation process. Human
      HT29 colon carcinoma cells were inoculated intraperitoneally at various times
      after sponge implantation and tumour growth in granulation tissue was determined.
      RNA isolated from granulation tissue was used for polymerase chain reaction
      analysis of the expression of specific growth factors and receptors [vascular
      endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and
      lysophosphatic acid (LPA)], and for microarray analysis of differentially
      expressed genes in early vs. late granulation tissue. Inflammatory cells
      infiltrated the sponge within 1 day, followed by fibroblasts and the formation of
      an extracellular matrix. Tumour cell inoculation at 8 h to 3 days after sponge
      implantation resulted in extensive tumour formation in all cases. Inoculation at
      10-28 days resulted in focal tumour growth in only 16-33% of the sponges. Low
      amounts of VEGF, TGF-beta(1-3), TGF-beta RIII and LPA receptors 1,2 were detected
      in early granulation tissue, with increased expression from day 10. Microarray
      analysis identified additional differentially expressed genes that may stimulate
      tumour take and growth in early granulation tissue.

PMID- 15177506
TI  - A comment on "Douglas House: a 'respice' for young people".

PMID- 15177505
TI  - Sodium butyrate induces apoptosis in human hepatoma cells by a
      mitochondria/caspase pathway, associated with degradation of beta-catenin, pRb
      and Bcl-XL.
AB  - Butyrate can promote programmed cell death in a number of tumour cells in vitro.
      This paper provides evidence that butyrate induces apoptosis in human hepatoma
      HuH-6 and HepG2 cells but is ineffective in Chang liver cells, an immortalised
      non-tumour cell line. In both HuH-6 and HepG2 cells, apoptosis appeared after a
      lag period of approximately 16 h and increased rapidly during the second day of
      treatment. In particular, the effect was stronger in HuH-6 cells, which were,
      therefore, chosen for ascertaining the mechanism of butyrate action. In HuH-6
      cells, beta-catenin seemed to exert an important protective role against
      apoptosis, since pretreatment with beta-catenin antisense ODN reduced the content
      of beta-catenin and anticipated the onset of apoptosis at 8 h of exposure to
      butyrate. Moreover, in HuH-6 cells, butyrate induced loss of mitochondrial
      membrane potential, release of cytochrome c from mitochondria, activation of
      caspase 9 and caspase 3, and degradation of poly(ADP-ribose) polymerase. In
      addition, during the second day of treatment, beta-catenin, pRb, and cyclins D
      and E were diminished and the phosphorylated form of pRb disappeared. Also, the
      content of the anti-apoptotic factor Bcl-XL fell markedly during this period,
      while that of the pro-apoptotic factor Bcl-Xs increased. These effects were
      accompanied by an increase in both Bcl-XL and Bcl-Xs mRNA transcripts, as
      ascertained by reverse transcriptase-polymerase chain reaction. Our results
      suggest that caspases have a crucial role in butyrate-induced apoptosis. This
      conclusion is supported by the observation that the inhibitors of caspases,
      benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone and benzyloxy carbonyl-Asp-Glu
      Val-Asp-fluoromethylketone, prevented apoptosis and the decrease in Bcl-XL, pRb,
      cyclins and beta-catenin. These effects were most probably responsible for the
      increased sensitivity of the cells to butyrate-induced apoptosis, which was
      observed on the second day of treatment.

PMID- 15177507
TI  - Unknown primary melanoma.

PMID- 15177509
TI  - Antiulcer effects of amylin: a review.
AB  - Amylin belongs to the calcitonin peptide family. Amylin is a peptide synthesized
      not only in the beta cells of pancreatic islets, but in small quantities also in
      other organs like in the intestinal and gastric mucosa, lungs and central nervous
      system. It is located in the same secretory granules as insulin. Amylin
      participates in the maintenance of glucose and calcium homeostasis. It also
      inhibits food intake and decreases body weight. Furthermore, amylin inhibits
      gastric acid secretion. It protects the gastric mucosa in ulcer models like
      stress, vagal stimulation, ethanol, acetic acid, reserpine and serotonine
      administration and pylorus ligation. This protective antiulcer is seen not only
      at pharmacological but also at near-physiological doses-0.5mkg/kg. Moreover
      amylin also exerts curative properties in the acetic acid and indomethacin ulcer
      models. Amylin decreases the aggressive factors like acid-pepsin secretion,
      increases mast cell stability and increases protective mechanisms like
      bicarbonate gastric secretion, dilates blood vessels, and it increases lymphatic
      mesenteric activity. Amylin seems to be a powerful protector of gastric mucosa in
      animals by increasing the stability of gastric mucosa. Further research remains,
      however, to be done.

PMID- 15177508
TI  - Imatinib in patients with metastatic gastrointestinal stromal tumours relapsing
      after hepatic transplantation.

PMID- 15177510
TI  - Reversible cholestasis induced by experimental partial obstruction of the bile
      duct; Biochemical, morphometric and hepatic transport kinetic studies.
AB  - The aim of this investigation was to reproduce in rats a partial stenosis of the
      common bile duct to analyze early liver functional and morphometric changes. The
      hepatic transport kinetics of sulfobromophthalein (organic anion) and rhodamine B
      (organic cation) was also investigated, and compartmental analysis of both
      compounds was performed. The humoral parameters of liver function indicated a
      cholestasis after 2 days of surgery, which reverted to reach normal values on the
      seventh day. Tumor necrosis factor alpha serum levels showed a tendency to
      increase on the second day of stenosis (7 out of 14 rats) while white blood cells
      increased on the second day of stenosis, and turned to normal levels on the
      seventh day. Histological studies showed increased volume of portal areas and
      ductular proliferation, which did no revert during the time of the study (up to 7
      days post-op). Conversely, a moderate fibrosis and leukocyte infiltrates in
      portal areas predominated on the second day of stenosis, but normalized on the
      seventh day. Bile flow was considerably diminished on the second day of partial
      obstruction as compared to controls. The mean recovery in bile of
      sulfobromophthalein after 1h of being injected was low on the second day of
      stenosis, but normalized on the seventh day. Conversely, that of rhodamine B was
      very low in all animals. Sulfobromophthalein kinetics showed that hepatic uptake
      and canalicular excretion were impaired during the second but normalized on the
      seventh day of stenosis. However, rhodamine B kinetics showed that this compound
      was poorly excreted in all groups although canalicular excretion increased on the
      second day. The results suggested a model of obstructive cholestasis induced by
      the experimental stenosis of the bile duct which was not only reversible but also
      implicates the role of hepatic inflammation.

PMID- 15177511
TI  - Recovery from immobilisation: responses of fast-twitch muscle fibres to
      spontaneous and intensive exercise in rat calf muscles.
AB  - Four weeks of immobilisation with two types of re-mobilisation programmes
      (intensive concentric treadmill exercising during 6 days, and free exercising,
      and immobilisation without any re-mobilisation period were studied to clarify
      possible exercise-induced calf muscle damage especially in fast-twitch fibres
      used in running compared to non-immobilised rats housing freely in their cages.
      As markers of muscle injury, conventional histology, beta-glucuronidase (beta-GU)
      activity and fetal myosin heavy chain expression (MHC-d) were assessed on Days 0,
      1, 3, 6 and 14 after the cast removal. Only minor focal hypercontraction,
      ruptures and necrosis of myofibrils, and weak inflammatory cell reactions were
      found in all samples examined, except in the controls. No MHC-d positive cells
      were found indicating absence of active regeneration after immobilisation or re
      mobilisation. Minor increase in beta-GU activity was observed in all three
      muscles studied, but statistically significant increase was observed only in the
      samples of the free exercising group on Day 14 after the cast removal. To
      conclude, intensive concentric treadmill exercise for 6 days did not cause
      significantly more muscle damage than did free exercising re-mobilisation.

PMID- 15177512
TI  - Hypoxia and hypercapnia affect contractile and histological properties of rat
      diaphragm and hind limb muscles.
AB  - The effects of hypoxia and hypercapnia on contractile and histological properties
      of the diaphragm and skeletal muscles of the hind limb were examined. Eight-week
      old male Sprague-Dawley rats ( [Formula: see text] ) were kept in hypobaric
      hypoxic ( [Formula: see text] ) or hypercapnic ( [Formula: see text] ) chambers
      for 6 weeks, and compared with the control rats (room air, [Formula: see text] ).
      Contractile properties were evaluated with twitch kinetics, force-frequency curve
      and fatigue tolerance. After the experiments on contractile activities, muscles
      were fixed for histological examination with ATPase staining. It was demonstrated
      that peak twitch tension of diaphragm decreased with no significant histological
      changes under hypoxic conditions while significant contractile and histological
      changes were observed under hypercapnic conditions. Skeletal muscles of the hind
      limbs were affected also under hypoxic and hypercapnic conditions but the
      profiles of the changes in contraction and histology were different from those of
      the diaphragm. These results suggest that hypoxia and hypercapnia affect
      differently on contractile and histological properties of respiratory and hind
      limb muscles. Furthermore, when we consider the conditions involved in chronic
      obstructive respiratory disease (COPD; both hypoxia and hypercapnia are deeply
      involved), our results indicate that COPD should be regarded as a systemic
      disorder rather than a respiratory disease.

PMID- 15177513
TI  - Normalization of periictal bihemispheric cerebral perfusion in temporal lobe
      epilepsy.
AB  - Under normal circumstances, cerebral blood flow (CBF), between the two
      hemispheres is coupled in a direct (i.e. positive slope), linear fashion.
      However, in temporal lobe epilepsy, the relationship between the two temporal
      cortices, during the interictal and postictal periods, is the inverse of normal
      (i.e. correlation is with negative slope and linear). Long-term combined temporal
      lobe thermal diffusion flowmetry (TDF) subdural regional cerebral blood flow and
      electroencephalographic (EEG) recording was performed to test the hypothesis
      that, during the 10min periictal period (i.e. 5min before and 5min following
      clinical seizure onset), the cerebral perfusion relationship between epileptic
      and nonepileptic cortex returns to normal (i.e. becomes direct, with positive
      slope, and linear). A consecutive series of 13 patients with complex partial
      epilepsy was studied. During continuous monitoring of clinical phenomenology in
      time sequence with subdural CBF/EEG, the 10min periictal period was characterized
      by a direct, linear correlation between epileptic and nonepileptic temporal
      cortical blood flow ( [Formula: see text], [Formula: see text], [Formula: see
      text], [Formula: see text] ). The fact that this pertubation in the CBF
      relationship between the bilateral temporal cortices begins prior to and
      continues for 5min following clinical and subdural EEG seizure onset raises the
      interesting possibility that normalization of periictal bilateral cerebral
      perfusion may be associated with temporal lobe epileptogenesis.

PMID- 15177514
TI  - Temporary augmentation of glycosaminoglycans content in the heart after left
      coronary artery ligation.
AB  - Introduction: Augmentation of glycosaminoglycans (GAG) in various tissues after
      injury is well known, however, there is no information about the metabolism of
      GAG during the heart remodeling after infarction. The study is focused on the
      changes of total GAG concentrations in the viable myocardium and scar after
      experimental left coronary artery occlusion. To shed some light on the possible
      mechanism of the changes, GAG were also evaluated in the skin. Methods: Male
      Wistar rats were subjected to left coronary artery ligation or to sham operation.
      After 3, 6 or 12 weeks of follow up the rats were sacrificed and the heart and
      skin were collected. The heart was cut into parts: right ventricle, septum,
      viable region of left ventricle and scar. The Farndale method was used for the
      estimation of GAG in the samples. Results: High level of GAG in the myocardial
      scar tissue was seen in the 3 weeks of follow up and reached maximum in the 6
      weeks and then decreased in week 12. Similar pattern of GAG changes was found in
      the contractile part of the heart. In both viable part of the left ventricle and
      septum the peak level of GAG was found in rats 6 weeks after the onset of
      infarction. Than the content of GAG decreased towards the control level. There
      was no alteration in the GAG content in the skin and a wall of the right
      ventricle. Conclusion: Temporary augmentation of GAG content is present not only
      in myocardium directly injured by ischaemia but also in the viable part of the
      heart subjected mainly to increased haemodynamic stresses. The local nature of
      mechanisms responsible for the GAG changes has been postulated.

PMID- 15177515
TI  - Hypercytolipidemia promotes diabetes (db/db) mutation-associated utero-ovarian
      involution: counter-regulatory influences of progesterone.
AB  - Background: The diabetes (db/db) mutation induces a hyperglycemic
      hyperinsulinemic endometabolic environment that promotes hypercytolipidemic,
      utero-ovarian involution in C57BL/KsJ mice, resulting in reproductive sterility
      and eventual organoatrophy. Objective: Evaluation of the effectiveness of
      progesterone therapy (P-HRx), initiated prior to the genetic expression of the
      overt diabetes-obesity syndrome (DOS), on moderating the severity of female
      reproductive tract involution promoted by db/db mutation expression was evaluated
      by analysis of cytoarchitectural, endocrine and tissue lipo-metabolic indices
      relative to oil (O)-vehicle-treated (HRx) control (+/?) and db/db groups.
      Experimental design: All HRx treatments were started at 4 weeks of age (pre-overt
      DOS stage) and continued through 16 weeks of age (chronic DOS expression) when
      tissue and cellular endometabolic parameters were evaluated. Results: The DOS
      induced a dramatic increase in phenotypic obesity, hyperglycemia and
      hyperinsulinemia in db/db groups, relative to +/?, throughout the experimental
      period. In contrast, utero-ovarian weights were dramatically reduced in db/db
      groups relative to +/? indices. Chronic P-HRx effectively reversed these DOS
      induced trends in db/db groups, maintaining moderated body and tissue weights, as
      well as re-establishing normal insulin indices, under a persistent hyperglycemic
      condition. In addition, P-HRx moderated the dramatic hypercytolipidemic condition
      which promotes utero-ovarian involution in db/db mice as evidenced by the
      reduction in observed tissue cytolipidemia. The concurrent normalization of
      tissue lipase and enhancement of glucose utilization indices by db/db utero
      ovarian compartments, under moderated insulin recognition parameters, indicated
      that P-HRx effectively suppressed the severity of both the structural and
      endometabolic consequences of the DOS in db/db groups, without restraining
      hyperglycemic conditions. Conclusion: These results indicate that the
      pathophysiological alterations induced by the db/db mutation may be modulated
      through low-dose steroidal therapy, the efficacy of which is suspected to occur
      by the augmentation of normal insulin-coupled, post-receptor directed glucose
      utilization via the stimulation of oxidative metabolic pathways capable of
      maintaining normal utero-ovarian structural continuity and metabolic homeostasis.

PMID- 15177517
TI  - Report on the 4th World Congress of Pathophysiology.

PMID- 15177516
TI  - Neck and shoulder pain related to computer use.
AB  - The neck and shoulder pain (NSP) symptoms are very common among intensive
      computer users. This paper reviews recent 20 years' research publications, which
      have focused on pathophysiology and other aspects of the neck and shoulder pain
      related to computer use (NSPRCU). The disorder is usually multidimensional,
      occupational, personal and social factors are among these evolved. Suggestions
      concerning the diagnostics, procedures of prevention, and treatment options have
      been discussed. As the details of pathophysiology of these disorders are not yet
      clear, further studies on NSPRCU are necessary.

PMID- 15177518
TI  - Angiotensin receptor blockade improves arterial distensibility and reduces
      exercise-induced pressor responses in obese hypertensive patients with the
      metabolic syndrome.
AB  - Patients with the metabolic syndrome have three or more of five cardiovascular
      risk factors and increased oxidative stress, arterial stiffness and pressor
      responses to exercise, which may contribute to their threefold greater risk for
      coronary heart disease. In addition to lowering basal blood pressure (BP),
      angiotensin receptor blockers (ARBs) may benefit metabolic syndrome patients by
      reducing oxidative stress, arterial stiffness, and pressor responses to exercise.
      Twelve patients, 7 women and 5 men, with the metabolic syndrome (aged 45 +/- 2
      years, BP 145 +/- 5/85 +/- 2 mm Hg, waist girth 110 +/- 3 cm, triglycerides 186
      +/- 23 mg/dL, HDL cholesterol 44 +/- 2 mg/dL, glucose 99 +/- 3 mg/dL) were
      studied off medications, while on modest sodium restriction ( approximately 100
      mmol/d). Patients were randomized to the ARB losartan or placebo for 3 weeks then
      crossed over to the complement for 3 weeks. Studies were performed at the end of
      each phase following an overnight fast. Serum lipids and biomarkers of oxidative
      stress (F2-isoprostanes, thiobarbituric acid reacting substances) were unchanged
      by losartan, whereas large artery elasticity at rest, measured with the HDI
      PulseWave, increased from 13.6 +/- 0.7 on placebo to 16.2 +/- 1.1 mL/mm Hg on
      losartan, P <.05. Losartan lowered systolic BP pre-exercise from 142 +/- 3 to 131
      +/- 3 mm Hg (P <.001) and systolic BP after 6 min of treadmill exercise from 192
      +/- 6 to 169 +/- 5 mm Hg (P <.001). Losartan lowered systolic BP (-23 +/- 3 v -11
      +/- 2 mm Hg, P <.05) and pulse pressure (-4 +/- 1 v -15 +/- 2 mm Hg, P <.05) more
      during exercise than rest. Losartan reduces the pressor response to exercise,
      perhaps by enhancing arterial compliance. In addition to lowering basal BP,
      angiotensin receptor blockade in patients with metabolic syndrome improves
      arterial compliance and reduces pressor reactivity to exercise.

PMID- 15177519
TI  - Prevalence of unrecognized abnormal glucose tolerance in patients attending a
      hospital hypertension clinic.
AB  - BACKGROUND: Diabetes mellitus (DM) and impaired glucose tolerance (IGT) are not
      uncommonly associated with hypertension. Fasting blood glucose level is still
      recognized as an indicator of DM. METHODS: We studied 99 consecutive patients who
      were not known to be diabetic patients and with no cardiac history, who were
      attending our Hypertension Clinic for investigation and management of
      uncontrolled blood pressure (BP). Oral glucose tolerance test (GTT) was carried
      out and area under the curve for the GTT (AUC-glucose) was calculated. All
      patients underwent 24-h ambulatory BP monitoring. RESULTS: The GTT was abnormal
      in 58 patients (58%), indicating IGT in 18, impaired fasting glucose in 16, and
      DM in 24. The fasting and 120-min glucose level and AUC-glucose in patients with
      DM on GTT was higher (P <.0001) than in those with IGT/IFG and in the latter was
      higher than those with normal GTT. Multiple regression analysis showed that
      abnormal GTT was independent of the following: level of clinic or ambulatory BP;
      presence or absence of nocturnal BP dip; cholesterol, sodium, and potassium
      levels; smoking history; alcohol intake; prior treatment for hypertension; and
      ethnicity. These results were also independent of antihypertensive medications
      taken. No significant difference was found in glucose level during GTT, AUC
      glucose, or age among the groups of patients receiving diuretics only, those
      receiving diuretics and beta-blockers, and those not receiving any of these
      agents. CONCLUSIONS: The prevalence of glucose abnormalities in hypertensive
      patients attending a hospital hypertension clinic is sufficiently high to warrant
      screening for DM and IGT, and fasting glucose levels are not accurate enough for
      this purpose. All patients attending such a clinic should undergo a GTT.

PMID- 15177520
TI  - Glucocorticoid sensitivity of circulating monocytes in essential hypertension.
AB  - BACKGROUND: Essential hypertension ranks among the strongest cardiovascular risk
      factors. Cytokine production by monocytes plays a key role in atherosclerosis
      development and acute coronary syndromes. We investigated whether stimulated
      monocyte cytokine release and its inhibition by glucocorticoids would differ
      between hypertensive and normotensive subjects. METHODS: Study participants were
      222 middle-aged male employees with industrial jobs. Following the criteria of
      the World Health Organization/International Society for Hypertension, 76 subjects
      were classified as being hypertensive (systolic blood pressure > or = 140 mm Hg
      or diastolic blood pressure > or = 90 mm Hg). In vitro monocyte tumor necrosis
      factor (TNF)-alpha release after lipopolysaccharide (LPS) stimulation was
      assessed with and without coincubation with incremental doses of dexamethasone.
      Monocyte glucocorticoid sensitivity was defined as the dexamethasone
      concentration inhibiting TNF-alpha release by 50%. RESULTS: Hypertensive subjects
      showed 11% higher LPS-stimulated TNF-alpha release than normotensive subjects
      (F(1,181)= 5.21, P =.024). In hypertensive subjects, monocyte glucocorticoid
      sensitivity was 21% lower than in normotensive subjects (F(1,178)= 4.94, P
      =.027), indicating that dexamethasone inhibited relatively less TNF-alpha release
      in hypertensive subjects. Results held significance when a set of classic
      cardiovascular risk factors was controlled for. CONCLUSION: The findings suggest
      that proinflammatory activity of circulating monocytes is higher in hypertensive
      than in normotensive men, providing one potential pathway to explain the
      increased atherosclerotic risk with essential hypertension.

PMID- 15177521
TI  - Initial angiotensin-converting enzyme inhibitor/calcium channel blocker
      combination therapy achieves superior blood pressure control compared with
      calcium channel blocker monotherapy in patients with stage 2 hypertension.
AB  - BACKGROUND: The Seventh Report of the Joint National Committee (JNC 7) on
      Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
      recommends initial combination therapy for patients whose blood pressure (BP) is
      >20/10 mm Hg above goal. This study evaluated the efficacy and safety of initial
      combination therapy versus that of monotherapy in patients with stage 2
      hypertension, who by definition meet the JNC 7 recommendation for initial
      combination antihypertensive therapy. METHODS: This multicenter, double-blind, 12
      week study randomized 364 patients with stage 2 hypertension to fixed-dose
      combination therapy with amlodipine besylate/benazepril HCl (5/20 mg/d titrated
      to 10/20 mg/d) or amlodipine besylate monotherapy (5 mg/d titrated to 10 mg/d).
      RESULTS: Significantly more patients randomized to combination therapy (74.2%)
      compared with those randomized to monotherapy (53.9%; P <.0001) achieved the
      primary end point (reductions in systolic BP > or =25 mm Hg, if baseline systolic
      BP was <180 mm Hg, or > or =32 mm Hg, if baseline systolic BP was > or =180 mm
      Hg). Significantly more patients randomized to combination therapy compared with
      monotherapy attained BP goals of <140/90 mm Hg (61.0% v 43.3%; P =.0007) and < or
      =130/85 mm Hg (35.7% v 19.1%; P =.0004). Among patients with baseline systolic BP
      > or =180 mm Hg, combination therapy resulted in significantly greater reductions
      in systolic BP compared with monotherapy (-42.3 v -30.4 mm Hg; P =.001). More
      than 90% of patients in each group were titrated to the higher dose. Both
      treatments were well tolerated. CONCLUSIONS: Combination therapy was well
      tolerated and resulted in significantly greater BP reductions and attainment of
      BP goals compared with monotherapy in patients with stage 2 hypertension. This
      evidence supports the recommendation of combination therapy as first-line
      treatment in stage 2 hypertension.

PMID- 15177522
TI  - Pravastatin has an additional depressor effect in patients undergoing long-term
      treatment with antihypertensive drugs.
AB  - BACKGROUND: Statins have been reported to have direct vascular effects
      independent of cholesterol reduction. To assess the antihypertensive effect of
      statins, a crossover study was designed to compare the depressor effect of
      pravastatin and probucol in hypertensive patients undergoing long-term treatment
      with antihypertensive drugs. METHODS: The subjects enrolled in this study were 52
      hypertensive patients (22 men and 30 women, mean age 62.8 +/- 9.3 years) who were
      treated with the same antihypertensive drugs for more than 1 year and had serum
      cholesterol levels of more than 5.69 mmol/L. In 26 subjects, pravastatin at a
      dose of 10 mg/d was given first for 6 months followed by treatment with probucol
      at a dose of 500 mg/d, and vice versa in the remaining 26 subjects. Serum lipids,
      apolipoproteins, glucose, and insulin were measured on the final day of the
      control period, and pravastatin and probucol treatments. The homeostatic model
      assessment insulin resistance index (HOMA-IR) was used to assess insulin
      resistance. RESULTS: The blood pressure decreased after pravastatin treatment
      (141.2 +/- 4.7/81.3 +/- 4.9 to 136.5 +/- 5.3/80.6 +/- 5.1 mm Hg, P <.001/.499),
      but did not decrease after probucol treatment (141.2 +/- 4.7/81.3 +/- 4.9 to
      141.4 +/- 4.9/80.8 +/- 4.9 mm Hg, P =.832/.634). Total cholesterol decreased
      significantly after pravastatin (6.69 +/- 0.69 to 5.23 +/- 0.77 mmol/L, P <.001)
      and probucol treatment (6.69 +/- 0.69 to 5.53 +/- 0.64 mmol/L, P <.001). The HOMA
      IR was decreased by probucol (1.92 +/- 0.78 to 1.57 +/- 0.59, P =.029), whereas
      pravastatin had no effect on HOMA-IR. CONCLUSIONS: It can be concluded that the
      depressor effect of pravastatin may have an additional benefit in the treatment
      of hypertensive patients with hyperlipidemia without any adverse effect on
      insulin sensitivity.

PMID- 15177523
TI  - The chest radiograph. A useful investigation in the evaluation of hypertensive
      patients.
AB  - BACKGROUND: The assessment of target organ damage is important in the evaluation
      of a hypertensive patient as it provides information on the severity of the
      hypertension and the cardiovascular risk assessment. The aim of our study was to
      determine the usefulness of the chest radiograph in the assessment of target
      organ damage in hypertensive patients. METHODS: Unselected patients attending an
      academic hypertension clinic were studied. The cardiothoracic ratio and the
      aortic knob width were measured and compared to other markers of target organ
      damage. The aortic width was measured in age- and sex-matched controls. RESULTS:
      Seventy-two hypertensive and 77 age- and sex-matched normotensives were
      evaluated. There was a highly significant difference the aortic knob width
      between the normotensive and hypertensive patients (3.28 cm v 3.69 cm, P <.0001).
      The aortic knob width was significantly correlated with age in normotensive and
      hypertensive patients, systolic and diastolic blood pressure (BP), and all
      markers of target organ damage except the electrocardiogram (ECG) voltage. The
      cardiothoracic ratio was also significantly correlated with age and other markers
      of target organ damage, but not clinic BP. Multiple regression analysis revealed
      that only the cardiothoracic ratio (r = 0.34, P <.02) and the ECG voltage (r =
      0.58, P <.00005) were independently correlated with left ventricular mass.
      CONCLUSIONS: The chest radiograph provides important predictive information of
      associated target organ damage in hypertensive patients.

PMID- 15177524
TI  - Linkage of serum creatinine and glomerular filtration rate to chromosome 2 in
      Utah pedigrees.
AB  - BACKGROUND: Serum creatinine and creatinine clearance are used as indicators of
      renal function and may indicate a propensity for development of end-stage renal
      disease. Identifying genes related to future decreases in renal function could be
      important in assessing risk and defining abnormal mechanisms amenable to
      preventive measures. Although creatinine clearance is a better measure of renal
      function than serum creatinine, proper and complete urine collections in large
      population studies are sometimes problematic. This can lead to a loss in power to
      detect linkage. Therefore, in this study we also investigated serum creatinine
      and estimated glomerular filtration rates (GFR), both of which are more reliably
      measured. METHODS: Linkage was tested in a genome scan using 49 large Utah
      pedigrees examined three times over 10 years to detect regions harboring genes
      related to reduced renal function. RESULTS: Heritability of serum creatinine
      ranged from 25% to 31% across three examinations, and heritability of GFR ranged
      from 37% to 42%. The highest log of the odds (LOD) score for serum creatinine was
      found on chromosome 2 at 145 cM on the Marshfield map (D2S1334). Consistent
      nonparametric linkage for serum creatinine was found for all three examinations
      (LOD = 3.15, 2.75, and 2.00, respectively). Estimates of GFR also showed linkage
      to this region. CONCLUSIONS: The consistency of linkage to chromosome 2 over
      longitudinally repeated measurements increases the likelihood that this region
      harbors a gene influencing phenotypic variation in serum creatinine and GFR.
      Identification of this gene could help to predict which individuals are most
      likely to progress to renal disease.

PMID- 15177525
TI  - Protection of cavernous tissue in male spontaneously hypertensive rats. Beyond
      blood pressure control.
AB  - Male erectile dysfunction is increased in prevalence in patients with
      hypertension. Previous experiments from our group demonstrated morphologic
      changes in erectile tissue from male spontaneously hypertensive rats (SHR). The
      aim of the present study was to determine whether blood pressure (BP) control is
      enough to preserve cavernous tissue from the deleterious effect of arterial
      hypertension. Eight-week-old male SHR and normotensive Wistar-Kyoto rats (WKY)
      were studied during 6 months: Group 1 (n = 10) SHR; group 2 (n = 10) SHR with 7.5
      mg/kg/d candesartan (C); group 3 (n = 10) SHR with 100 mg/kg/d atenolol (AT); and
      group 4 (n = 10) WKY. At the end of the experiment all the animals were killed
      for microscopic studies. Cavernous tissue was processed by hematoxylin-eosin,
      Masson's trichrome, monoclonal anti-alpha-smooth muscle actin, and anticollagen
      type III. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from
      cavernous arteries and the amounts of collagen type III were evaluated. At the
      end of the experiment, SHR with C and AT showed similar control in BP (group 2:
      131.3 +/- 5.5 mm Hg; group 3: 136.5 +/- 2.9 mm Hg) compared with untreated SHR
      (group 1: 199.6 +/- 5.1 mm Hg). However, animals with C presented significantly
      lower values (P <.01) of CSM layer in cavernous space and VSM in cavernous
      arteries (P <.01), and lower amounts of collagen type III (P <.01) compared to
      SHR with AT and untreated SHR. We conclude that C provides a significant
      protective role against structural changes in vessels as well as in cavernous
      spaces of the erectile tissue, caused by arterial hypertension in SHR, beyond BP
      control.

PMID- 15177526
TI  - Frequent nurse visits decrease white coat effect in stage III hypertension.
AB  - Arterial hypertension is a public health problem and patient adherence to
      treatment is challenging. This study tested whether frequent nurse visits provide
      additional benefits to antihypertensive treatment. Every 30 days, a pharmacist
      visited these patients to deliver antihypertensive drugs and perform a pill
      count. Nurses visited group A (48 patients) every 15 days and group B (52
      patients) every 90 days. Ambulatory blood pressure (BP) monitoring was performed
      15 and 180 days after randomization. At randomization, groups A and B had the
      same clinical systolic (191 +/- 5 v 186 +/- 3 mm Hg) and diastolic BP levels (122
      +/- 3 v 117 +/- 4 mm Hg), respectively. After 90 days, BP declined more in group
      A than in group B (35 +/- 5/19 +/- 3 v 27 +/- 5/9 +/- 3 mm Hg). At 180 days, the
      difference increased because the reduction persisted in group A but decreased in
      group B (36 +/- 6/21 +/- 4 v 17 +/- 4/10 +/- 2 mm Hg). The mean ambulatory BP
      monitoring values were similar in both groups at 15 and 180 days. However, the
      attenuation of the clinic-daytime BP difference was larger in group A than in
      group B (systolic, -13 +/- 4 v -3 +/- 4 mm Hg; diastolic -11 +/- 3 v -4 +/- 3 mm
      Hg). The patients with clinic-daytime differences decreased more in group A
      (systolic, 16 to 10; diastolic, 20 to 14) than in group B (systolic, 19 and 20;
      diastolic, 22 and 22). These data indicate that frequent nurse visits
      significantly attenuate the white coat effect (clinic daytime BP difference).

PMID- 15177527
TI  - Silent cerebral white matter lesions and cognitive function in middle-aged
      essential hypertensive patients.
AB  - BACKGROUND: An association between midlife blood pressure levels and late-life
      cognitive impairment has been reported. Hypertension is one of the most important
      factors related to the presence of cerebral white matter lesions, which is a
      prognostic factor for the development of cognitive impairment. Studies have shown
      a relationship between white matter lesions and cognitive decline in elderly
      hypertensive patients. The aim of the present study was to evaluate cognitive
      function in asymptomatic middle-aged hypertensive patients according to the
      presence or absence of white matter lesions. METHODS: Sixty never-treated
      essential hypertensive patients (38 men, 22 women), aged 50 to 60 years (mean
      age, 54.4 +/- 3.8 years), without clinical evidence of target organ damage, were
      studied. All patients underwent brain magnetic resonance imaging to establish the
      presence or absence of white matter lesions, using the Rotterdam criteria.
      Cognitive function was evaluated by a neuropsychologic test battery measuring
      attention, memory, intelligence, anxiety, and depression. RESULTS: Twenty-three
      hypertensive patients (38%) were found to have white matter lesions on brain
      resonance. These patients exhibited a significantly worse performance on digit
      span forward, a standardized measure of attention than hypertensives without
      white matter lesions (4.86 +/- 1.14 v 5.51 +/- 0.97; P =.027). Hypertensive
      patients with white matter lesions showed no differences on both visual and
      logical memory tests when compared with patients without lesions. CONCLUSIONS: We
      conclude that the presence of silent cerebral white matter lesions in middle-aged
      hypertensive patients is associated with a mild decline in basic attention.

PMID- 15177528
TI  - Pulse pressure is more susceptible to the white coat effect than is systolic
      blood pressure: observations from real-life ambulatory blood pressure monitoring.
AB  - BACKGROUND: Pulse pressure is a derivative of arterial stiffness. We have
      previously demonstrated ambulatory pulse pressure to be relatively independent
      from the blood pressure (BP) lowering during sleep, and thus of a neurogenic
      effect. On the other hand, white coat BP effects are thought to involve
      neurogenic activation. The aim of this work was to analyze white coat induced
      variability in pulse pressure. METHODS: Percent clinic-awake differences in
      systolic BP (SBP) and pulse pressure (white coat effects) were calculated for 688
      consecutive subjects (mean age 60 +/- 16 years, 58% female). Of the subjects, 23%
      had controlled hypertension, 45% uncontrolled hypertension, 8% normotension, and
      4% isolated office hypertension; all were referred to our unit for 24 h
      ambulatory BP monitoring. RESULTS: Pulse pressure highly correlated with SBP (r =
      0.82, P <.00001). We found a larger white coat effect on pulse pressure than on
      SBP (8.3% and 5.2%, respectively, P < or =.0001). This was true in all subgroups
      except in normotensive subjects. Specifically, the magnitude of the white coat
      effect on pulse pressure was greater than on SBP in subjects with treated
      hypertension, untreated hypertension, and isolated office hypertension, and in
      young hypertensive subjects, older subjects, and those with diabetes.
      CONCLUSIONS: Although pulse pressure is related to the mechanical properties of
      large arteries, it is also influenced by the white coat effect, a neurogenic
      process. Furthermore, in hypertensive but not in normotensive subjects, the white
      coat effect on pulse pressure is significantly more pronounced than on SBP.

PMID- 15177529
TI  - Effect of exercise training on central aortic pressure wave reflection in
      coronary artery disease.
AB  - BACKGROUND: Arterial stiffness is an important factor for cardiovascular
      performance and a predictor of cardiovascular risk. We investigated the effect of
      exercise training on arterial stiffness in coronary artery disease (CAD).
      METHODS: Arterial stiffness was assessed before and after 12 weeks of either
      exercise training or standard care in CAD patients. Arterial stiffness was
      evaluated by aortic augmentation index and time delay of the reflected wave
      (Deltat) using the SphygmoCor system. RESULTS: The augmentation index decreased
      (30% v 26%, P <.05) and Deltat increased (136 msec v 144 msec, P <.05) in
      patients with CAD after 12 weeks of exercise. CONCLUSION: These results suggest
      that endurance exercise training improves systemic arterial stiffness in
      individuals with CAD.

PMID- 15177530
TI  - Cardiac arrests, atrioventricular block, and pheochromocytoma.

PMID- 15177531
TI  - Aldosterone regulation for 18 years in a case of primary aldosteronism.

PMID- 15177532
TI  - Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of
      inflammatory bowel disease.
AB  - In the past decade, immunosuppressive drugs have come to play an integral role in
      the treatment of patients with inflammatory bowel disease. Cyclosporine,
      microemulsion cyclosporine, tacrolimus, and mycophenolate mofetil can be
      considered for the treatment of patients with refractory inflammatory Crohn's
      disease, fistulizing Crohn's disease, and severe ulcerative colitis. This article
      reviews the use of cyclosporine, tacrolimus, and mycophenolate mofetil in
      patients with inflammatory bowel disease, with emphasis on pharmacology, results
      in controlled clinical trials, and safety, and issues related to dosing and
      toxicity monitoring.

PMID- 15177533
TI  - Treatment of inflammatory bowel disease with corticosteroids.
AB  - Corticosteroids are a mainstay in the treatment of inflammatory bowel disease.
      Administered topically, orally, or intravenously corticosteroids rapidly and
      consistently improve moderate to severe active ulcerative colitis and Crohn's
      disease, although they are ineffective in the maintenance of remission in either
      illness. The beneficial effects of corticosteroid therapy are counterbalanced by
      their many side effects. A better understanding of the mechanism of steroid
      action and toxicity has led to the development of novel corticosteroids that
      offer the promise of continued efficacy with minimal toxicity. This article
      reviews the role of conventional and novel corticosteroids in the management of
      inflammatory bowel disease.

PMID- 15177534
TI  - General principles of medical therapy of inflammatory bowel disease.
AB  - Ulcerative colitis and Crohn's disease are chronic gastrointestinal diseases that
      affect patients in the prime of their lives. Because inflammatory bowel disease
      (IBD) patients generally live a normal lifespan, chronic medical therapy for IBD
      must be tolerable, simple to adhere to, and have as few side effects as possible.
      This article discusses the impact of IBD on quality of life and stresses the
      importance of appropriate and individualized medical therapy. To help clinicians
      determine the efficacy of particular IBD medications, this article offers a
      brief, practical interpretation of clinical, endoscopic, and quality-of-life end
      points used in clinical trials. Finally, it provides a summary of the current
      accepted medical therapies for ulcerative colitis adn Crohn's disease and
      recommendations for using these medications in clinical practice.

PMID- 15177535
TI  - Treatment of inflammatory bowel disease with azathioprine and 6-mercaptopurine.
AB  - 6-Mercaptopurine and azathioprine have become important therapeutic options for
      patients with inflammatory bowel disease (IBD). Although accumulating data in the
      literature have supported the use of these immunomodulators in the management of
      IBD, marked variation exists in the pattern of clinical practice regarding
      azathioprine or 6-mercaptopurine therapy in patients with IBD. This article
      provides a critical review of the data on the clinical efficacy and toxicities of
      6-mercaptopurine and azathioprine in the management of IBD. Emerging literature
      on the potential application of pharmacogenetic testing and metabolite monitoring
      are also discussed.

PMID- 15177536
TI  - Medical management of severe ulcerative colitis.
AB  - The medical management of patients with severe ulcerative colitis requires
      initial stabilization, careful and repeated evaluations to exclude confounding or
      coexisting diagnoses, and timely delivery of appropriate medications. Medical
      therapies for these patients are potent but may be toxic, and administration must
      be done by experienced medical professionals, with adequate access to appropriate
      laboratory, radiographic, endoscopic, and surgical facilities. Patients who fail
      to respond to high-dose intravenous corticosteroids in a timely basis should be
      evaluated for cyclosporin therapy, or proceed to surgery. The promise of newer,
      investigational therapies to induce and maintain remission must be borne out by
      large controlled trials.

PMID- 15177537
TI  - Novel biologics in inflammatory bowel disease.
AB  - Understanding of immunologic mechanisms involved in the initiation and
      perpetuation of chronic inflammation has led to new therapeutic opportunities in
      the inflammatory bowel diseases. The term "biologics" is used to distinguish new
      biotechnologic therapeutics from the conventional drugs used in the treatment of
      immune-mediated inflammatory disorders. This article reviews novel biologic
      therapies that are being investigated for the treatment of Crohn's disease and
      ulcerative colitis.

PMID- 15177538
TI  - Left-sided ulcerative colitis.
AB  - Left-sided ulcerative colitis is not a distinct entity, but a less extensive form
      of pancolitis. The epidemiologic and genetic characteristics are thought to be
      analogous. The rate of colorectal cancer, however, seems to be proportional to
      the extent of disease. Primary treatment for left-sided disease is topical 5
      aminosalicyclic acid (5ASA) agents. In patients who do not respond to topical
      therapy, oral 5ASA agents of differing delivery methods to the distal bowel can
      be used. There is much debate pertaining to the clinical superiority of the oral
      5ASA agents.

PMID- 15177539
TI  - Crohn's disease: future anti-tumor necrosis factor therapies beyond infliximab.
AB  - The dramatic benefit experienced by many Crohn's disease patients treated with
      the anti-tumor necrosis factor-alpha (TNF-alpha) antibody infliximab underscores
      the centrality of this cytokine in the pathogenesis of Crohn's disease and the
      potential use of the therapeutic strategy of blocking TNF-alpha in this disease.
      In the hopes of emulating and improving on the success of infliximab, numerous
      strategies are being devised and studied to inhibit the actions of TNF-alpha.
      This article focuses on those agents, other than infliximab, which target TNF
      alpha to treat inflammatory bowel disease as their central mechanism of action.

PMID- 15177540
TI  - Mesalamine derivatives in the treatment of Crohn's disease.
AB  - The role of the aminosalicylates for induction therapy of mild moderate
      ulcerative colitis and as maintenance treatment has been substantiated by a large
      series of controlled clinical trials and confirmatory meta-analyses. Both
      sulfasalazine and newer derivatives are effective in preventing relapses. It
      remains to be determined whether certain high-risk groups of patients may benefit
      from higher doses of mesalamine induction or maintenance therapy. Mesalamine
      derivatives are also of benefit in the treatment of Crohn's disease.
      Sulfasalazine is likely not effective in the maintenance of Crohn's disease,
      although other mesalamine formulations continue to show some prophylactic
      activity after mesalamine induced remissions and for patients with disease of the
      ileum who have undergone surgical resection.

PMID- 15177541
TI  - Management of refractory inflammatory bowel disease.
AB  - One of the most challenging aspects of the management of inflammatory bowel
      disease is the high frequency of incomplete or absent response to medical
      therapy. Although many patients may be truly refractory to medical therapy, a
      lack of response may indicate several possibilities, including incorrect
      diagnosis, progression of disease extent, intestinal complication,
      superinfection, underdosing of therapy, monotherapy instead of combination
      therapy, or medication intolerance. This article provides a practical general
      approach to refractory inflammatory bowel disease patients encountered in
      clinical practice.

PMID- 15177542
TI  - Treatment of inflammatory bowel disease with antibiotics.
AB  - Although antibiotics are clearly recognized as having a role in treating the
      infectious complications of inflammatory bowel diseases (IBD), their impact in
      the primary treatment of IBD has long been an area of speculation. Over the past
      decade there is increasing evidence that luminal gut bacteria play a role in the
      pathogenesis of IBD, particularly Crohn's disease. Compelling evidence that
      normal commensal bacteria induce chronic intestinal inflammation in susceptible
      rodents provides an excellent rationale for treatment of human IBD with
      antibiotics. This article summarizes published studies of antibiotics in IBD
      patients and reviews available data for the use of antibiotic therapy in Crohn's
      disease and ulcerative colitis.

PMID- 15177543
TI  - Medical management of postoperative recurrence in Crohn's disease.
AB  - More than half of Crohn's disease patients require surgery during the course of
      their disease. Although endoscopic recurrence does not necessarily imply that
      patients have symptom recurrence, the high need for repeated surgery indicates
      that lesions gradually developing after surgical remission lead to fibrostenosis
      or other complications. Despite multiple clinical trials a clear medical strategy
      to prevent disease recurrence has not been identified. Future well designed
      collaborative trials with specified end points are needed to optimize clinical
      practice in the prevention of postoperative Crohn's disease recurrence.

PMID- 15177544
TI  - Medical management of the pregnant patient with inflammatory bowel disease.
AB  - Gastroenterologists are not infrequently faced with questions regarding pregnancy
      when advising or treating their patients with inflammatory bowel disease (IBD).
      To advise patients effectively, the following factors must be considered: (1) the
      inheritance patterns of IBD for accurate counseling and family planning; (2) the
      effects of active IBD versus medications or surgery on fertility; (3) the effects
      of pregnancy on the course of IBD; (4) the effects and potential risks of active
      IBD versus those of diagnostic tests, medical treatments, and surgical treatments
      on the developing fetus; (5) approach to delivery; and (6) the risks of breast
      feeding while receiving treatment for IBD.

PMID- 15177545
TI  - Treatment of luminal and fistulizing Crohn's disease with infliximab.
AB  - Infliximab is a novel biologic agent developed from recombinant technology now
      used widely in the treatment of Crohn's disease. It is effective in inducing and
      maintaining response in patients with moderate to severe luminal and fistulizing
      disease refractory to conventional therapy. Infliximab has also been shown to
      have a steroid-sparing effect. Although safe and generally well tolerated, the
      drug carries side effects that clinicians need to be able to recognize and to
      manage properly. Studies are underway to determine the best strategies to avoid
      antibodies to infliximab and to refine use of the agent.

PMID- 15177546
TI  - Methotrexate in inflammatory bowel disease.
AB  - Over the past decade methotrexate has emerged as a new treatment for chronically
      active Crohn's disease. Although controlled trials to compare the relative
      efficacy and safety of azathioprine and methotrexate in therapy-resistant
      patients are desirable, these studies will be difficult, if not impossible, to
      conduct because of the relatively small differences in potency and tolerability
      between these agents. A more productive area for future investigations is to
      explore the use of these drugs in combination with infliximab and other biologic
      treatments.

PMID- 15177547
TI  - Treatment of fistulizing Crohn's disease.
AB  - The primary goals of the clinician in the treatment of fistulizing Crohn's
      disease (CD) include (1) defining the anatomy of the fistula, (2) draining any
      associated infectious material, (3) eradicating the fistulous tract through
      medical or surgical therapies, and (4) preventing recurrence of fistulas.
      Evaluation and therapeutic decisions require close collaboration between the
      gastroenterologist and surgeon. Appropriate evaluation should include
      identification of septic complications, delineation of the fistulous tract
      including the origin and terminus of the fistula, and determination of the extent
      of bowel involvement with active CD. Drainage of abscesses and control of septic
      complications through the placement of drains or setons is essential.
      Conservative therapy with avoidance of sphincter muscle-cutting procedures is the
      standard approach. The appropriate approach to asymptomatic patients is uncertain
      because there are little data to indicate if treatment alters the natural course
      of disease.

PMID- 15177548
TI  - Medical therapy of inflammatory bowel disease.

PMID- 15177549
TI  - Skeletal dysplasia and male infertility locus on mouse chromosome 9.
AB  - In mice and humans, growth insufficiency and male infertility are common
      disorders that are genetically and phenotypically complex. We describe a
      spontaneously arising mouse mutant, chagun, that is affected by both dwarfism and
      male infertility. Dwarfism disproportionately affects long bones and is
      characterized by a defect in the proliferative zone of chondrocytes in the growth
      plate. Gonads of mutant males are small, with apparent germ cell loss and no
      evidence of mature sperm. The locus responsible for chagun is recessive and maps
      to distal chromosome 9, in a region homologous to human chromosome 3. This
      location is consistent with chagun defining a novel locus. Identification of the
      mutant gene will uncover the basis for another type of skeletal dysplasia and
      male infertility.

PMID- 15177550
TI  - Genetic regulation of endotoxin-induced airway disease.
AB  - To identify novel genes regulating the biologic response to lipopolysaccharide
      (LPS), we used a combination of quantitative trait locus (QTL) analysis and
      microarray-based gene expression studies of C57BL/6J x DBA/2J(BXD) F2 and
      recombinant inbred (RI) mice. A QTL affecting pulmonary TNF-alpha production was
      identified on chromosome 2, and a region affecting both polymorphonuclear
      leukocyte recruitment and TNF-alpha levels was identified on chromosome 11.
      Microarray analyses of unchallenged and LPS-challenged BXD RI strains identified
      approximately 500 genes whose expression was significantly changed by inhalation
      of LPS. Of these genes, 28 reside within the chromosomal regions identified by
      the QTL analyses, implicating these genes as high priority candidates for
      functional studies. Additional high priority candidate genes were identified
      based on their differential expression in mice having high and low responses to
      LPS. Functional studies of these genes are expected to reveal important molecular
      mechanisms regulating the magnitude of biologic responses to LPS.

PMID- 15177551
TI  - Many amino acid substitution variants identified in DNA repair genes during human
      population screenings are predicted to impact protein function.
AB  - Over 520 different amino acid substitution variants have been previously
      identified in the systematic screening of 91 human DNA repair genes for sequence
      variation. Two algorithms were employed to predict the impact of these amino acid
      substitutions on protein activity. Sorting Intolerant from Tolerant (SIFT)
      classified 226 of 508 variants (44%) as "Intolerant." Polymorphism Phenotyping
      (PolyPhen) classed 165 of 489 amino acid substitutions (34%) as "Probably or
      possibly damaging." Another 9-15% of the variants were classed as "Potentially
      intolerant or damaging." The results from the two algorithms are highly
      associated, with concordance in predicted impact observed for approximately 62%
      of the variants. Twenty-one to thirty-one percent of the variant proteins are
      predicted to exhibit reduced activity by both algorithms. These variants occur at
      slightly lower individual allele frequency than do the variants classified as
      "Tolerant" or "Benign." Both algorithms correctly predicted the impact of 26
      functionally characterized amino acid substitutions in the APE1 protein on
      biochemical activity, with one exception. It is concluded that a substantial
      fraction of the missense variants observed in the general human population are
      functionally relevant. These variants are expected to be the molecular genetic
      and biochemical basis for the associations of reduced DNA repair capacity
      phenotypes with elevated cancer risk.

PMID- 15177552
TI  - Individual-specific variation of gene expression in peripheral blood leukocytes.
AB  - DNA microarray technology is used to determine gene expression profiles of
      various cell types, especially abnormal cells, such as cancer. By contrast,
      relatively little attention has been given to expression profiling of normal
      tissues. Here we describe studies of gene expression in peripheral blood
      leukocytes (PBL) from normal individuals sampled multiple times over periods
      ranging from several weeks up to 6 months. We demonstrate stable patterns of gene
      expression that differ between individuals. Among the genes whose expression
      varies by individual is a group of genes responsive to interferon stimulation.
      Certain individuals ( approximately 10-20% of those tested) showed higher
      baseline levels and lower inducibility of these genes in response to in vitro
      interferon stimulation. These studies demonstrate the feasibility of using DNA
      microarrays to measure the variations in gene expression of PBL from different
      individuals in response to environmental and genetic factors.

PMID- 15177553
TI  - T lymphocyte activation gene identification by coregulated expression on DNA
      microarrays.
AB  - High-capacity methods for assessing gene function have become increasingly
      important because of the increasing number of newly identified genes emerging
      from large-scale genome sequencing and cDNA cloning efforts. We investigated the
      use of DNA microarrays to identify uncharacterized genes specifically involved in
      human T cell activation. Activation of human peripheral blood T lymphocytes
      induced significant changes in hundreds of transcripts, but most of these were
      not unique to T cell activation. Variation of experimental parameters and
      analysis techniques allowed better enrichment for gene expression changes unique
      to T cell activation. Best results were achieved by identification of genes that
      were most highly coregulated with the T-cell-specific transcript interleukin 2
      (IL2) in a "compendium" of experiments involving both T cells and other cell
      types. Among the genes most highly coregulated with IL2 were many genes known to
      function during T cell activation, together with ESTs of unknown function. Four
      of these ESTs were extended to novel full-length clones encoding T-cell-regulated
      proteins with predicted functions in GTP metabolism, cell organization, and
      signal transduction.

PMID- 15177554
TI  - Gene expression profile of the mouse organ of Corti at the onset of hearing.
AB  - We describe the generation of an expressed sequence tag (EST) database of the
      mouse organ of Corti (OC). Over 20,000 independent clones were isolated,
      analyzed, and grouped into 8690 unique gene clusters. A large pool of novel genes
      unique to the OC was identified. Sequence alignments frequently revealed
      alternatively spliced forms of known genes potentially relevant in the OC
      function. We have also electronically mapped a subset of OC mouse ESTs to several
      syntenic regions associated with human autosomal and recessive deafness, which
      may prove useful for the identification of new positional candidates for these
      human diseases. The EST dataset is available as an interactive Web-based public
      database at. This resource provides both a view of the profile of gene expression
      in the OC at the onset of hearing and a tool to identify novel genes of
      importance in hearing.

PMID- 15177555
TI  - Identification of unique transcripts from a mouse full-length, subtracted inner
      ear cDNA library.
AB  - A small-scale full-length library construction approach was developed to
      facilitate production of a mouse full-length cDNA encyclopedia representing
      approximately 250 enriched, normalized, and/or subtracted cDNA libraries. One
      library produced using this approach was a subtracted adult mouse inner ear cDNA
      library (sIEa). The average size of the inserts was approximately 2.5 kb, with
      the majority ranging from 0.5 to 7.0 kb. From this library 22,574 sequence reads
      were obtained from 15,958 independent clones. Sequencing and chromosomal
      localization established 5240 clusters, with 1302 clusters being unique and 359
      representing new ESTs. Our sIEa library contributed 56.1% of the 7773
      nonredundant Unigene clusters associated with the four mouse inner ear libraries
      in the NCBI dbEST. Based on homologous chromosomal regions between human and
      mouse, we identified 1018 UniGene clusters associated with the deafness locus
      critical regions. Of these, 59 clusters were found only in our sIEa library and
      represented approximately 50% of the identified critical regions.

PMID- 15177557
TI  - A family of human Y chromosomes has dispersed throughout northern Eurasia despite
      a 1.8-Mb deletion in the azoospermia factor c region.
AB  - The human Y chromosome is replete with amplicons-very large, nearly identical
      repeats-which render it susceptible to interstitial deletions that often cause
      spermatogenic failure. Here we describe a recurrent, 1.8-Mb deletion that removes
      half of the azoospermia factor c (AZFc) region, including 12 members of eight
      testis-specific gene families. We show that this "b2/b3" deletion arose at least
      four times in human history-likely on inverted variants of the AZFc region that
      we find exist as common polymorphisms. We observed the b2/b3 deletion primarily
      in one family of closely related Y chromosomes-branch N in the Y-chromosome
      genealogy-in which all chromosomes carried the deletion. This branch is known to
      be widely distributed in northern Eurasia, accounts for the majority of Y
      chromosomes in some populations, and appears to be several thousand years old.
      The population-genetic success of the b2/b3 deletion is surprising, (i) because
      it removes half of AZFc and (ii) because the gr/gr deletion, which removes a
      similar set of testis-specific genes, predisposes to spermatogenic failure. Our
      present findings suggest either that the b2/b3 deletion has at most a modest
      effect on fitness or that, within branch N, its effect has been counterbalanced
      by another genetic, possibly Y-linked, factor.

PMID- 15177558
TI  - Detailed four-way comparative mapping and gene order analysis of the canine ctvm
      locus reveals evolutionary chromosome rearrangements.
AB  - Canine tricuspid valve malformation (CTVM) maps to canine chromosome 9 (CFA9), in
      a region syntenic with gene-dense human chromosome 17q. To define synteny blocks,
      we analyzed 148 markers on CFA9 using radiation hybrid mapping and established a
      four-way comparative map for human, mouse, rat, and dog. We identified a large
      number of rearrangements, allowing us to reconstruct the evolutionary history of
      individual synteny blocks and large chromosomal segments. A most parsimonious
      rearrangement scenario for all four species reveals that human chromosome 17q
      differs from CFA9 and the syntenic rodent chromosomes through two macroreversals
      of 9.2 and 23 Mb. Compared to a recovered ancestral gene order, CFA9 has
      undergone 11 reversals of <3 Mb and 2 reversals of >3 Mb. Interspecies reuse of
      breakpoints for micro- and macrorearrangements was observed. Gene order and
      content of the ctvm interval are best extrapolated from murine data, showing that
      multispecies genome rearrangement scenarios contribute to identifying gene
      content in canine mapping studies.

PMID- 15177559
TI  - Comparative analysis of a 229-kb medaka genomic region, containing the zic1 and
      zic4 genes, with Fugu, human, and mouse.
AB  - Medaka is one of the prominent model animals, which also include other fishes
      such as Fugu and zebrafish. Its genome is relatively compact but has not been
      well characterized. Here we have sequenced a 229-kb region of medaka, containing
      the Double anal fin (Da) locus, and compared its structure to those in Fugu,
      human, and mouse. This region, representing a gene-poor region, contains no major
      rearrangements and can be readily compared among different species. Comparison of
      G+C contents and repeats suggested that medaka and Fugu are highly related as
      expected and that medaka is more similar to mammals than Fugu is. Sequence
      comparisons of developmental genes zic1 and zic4, identified within this region,
      revealed that zic1, but not zic4, is highly conserved among vertebrates. The 5'
      coding region of zic4 is, however, extremely homologous among fishes with little
      synonymous substitutions, implying its distinct function in fish.

PMID- 15177560
TI  - Tissue-specific expression of a BAC transgene targeted to the Hprt locus in mouse
      embryonic stem cells.
AB  - The hypoxanthine phosphoribosyltransferase (Hprt) locus has been shown to have
      minimal influence on transgene expression when used as a surrogate site in the
      mouse genome. We have developed a method to transfer bacterial artificial
      chromosomes (BACs) as a single copy into the partially deleted Hprt locus of
      embryonic stem cells. BACs were modified by Cre/loxP recombination to contain the
      sequences necessary for homologous recombination into and complementation of the
      partially deleted Hprt locus. Modified BACs were shown to undergo homologous
      recombination into the genome intact, to be stably transmitted through the germ
      line of transgenic mice, and to be expressed in the proper tissue-specific
      manner. This technology will facilitate many studies in which correct
      interpretation of data depends on developmentally appropriate transgene
      expression in the absence of rearrangements or deletions of endogenous DNA.

PMID- 15177561
TI  - Identification and characterization of CPAMD8, a novel member of the complement
      3/alpha2-macroglobulin family with a C-terminal Kazal domain.
AB  - We have identified and characterized a novel member of the complement 3/alpha(2)
      macroglobulin (C3/alpha(2)M) family named CPAMD8 (complement 3 and pregnancy zone
      protein-like, alpha2-macroglobulin domain-containing 8). The gene maps to
      chromosome 19p13.2-p13.3 and spans approximately 130 kb. The gene partially
      overlaps with the protease-activated receptor-4 (PAR4) gene in the reverse
      orientation. The cDNA consists of 40 exons ( approximately 6 kb) and encodes a
      protein of 1885 amino acids. Similar to other proteins in this family, CPAMD8
      contains a signal sequence, an RXXR processing site, and a thioester motif. In
      addition, CPAMD8 has a Kazal-type serine proteinase inhibitor/follistatin-like
      domain at the C-terminus. The intact CPAMD8 protein generated by in vitro
      transcription and translation resolved as a single band of about 200 kDa on SDS
      PAGE. RT-PCR and immunoblot assays showed that CPAMD8 is expressed in a number of
      human tissues, most abundantly in the kidney, brain, and testis and at lower
      levels in heart, liver, and small intestine. CPAMD8 is also expressed in several
      types of cells in culture, in which it is proteolytically processed into two
      chains of about 70 and 130 kDa. The Kazal domain of CPAMD8 binds to heparin, and
      subcellular fractionation shows that CPAMD8 is membrane associated via ionic
      interaction. In response to immune stimulants, CPAMD8 expression is markedly up
      regulated in cells in culture. Thus, CPAMD8 may, like other members of the
      C3/alpha(2)M family, function in innate immunity but in a localized manner.

PMID- 15177562
TI  - C2360, a nuclear protein expressed in human proliferative cytotrophoblasts, is a
      representative member of a novel protein family with a conserved coiled coil
      helix-coiled coil-helix domain.
AB  - In this study, we describe the identification of nine novel genes isolated from a
      unique human first-trimester cDNA library generated from the placental bed. One
      of these clones, called C2360 and located on chromosome 10q22, was selected as it
      showed restricted expression in placental bed tissue as well as in JEG3
      choriocarcinoma cells with absent expression in adult tissues. We show that the
      expression is restricted to first-trimester proliferative trophoblasts of the
      proximal column and show that C2360 is a nuclear protein. No detectable
      transactivation potential was observed for different domains of the protein.
      Secondary structure prediction showed that C2360 is a representative member of a
      eukaryotic family of proteins with a low conservation at the amino acid level,
      but with strong conservation at the structural level, sharing the general domain
      (coiled coil 1)-(helix 1)-(coiled coil 2)-(helix 2), or CHCH domain. Each alpha
      helix within this domain contains two cysteine amino acids, and these
      intrahelical cysteines are separated by nine amino acids (C-X(9)-C motif). The
      fixed position within each helix indicated that both helices could form a hairpin
      structure stabilized by two interhelical disulfide bonds. Other proteins
      belonging to the family include estrogen-induced gene 2 and the ethanol-induced 6
      protein. The conserved motif was found in yeast, plant, Drosophila,
      Caenorhabditis elegans, mouse, and human proteins, indicating that the ancestor
      of this protein family is of eukaryotic origin. These results indicate that C2360
      is a representative member of a multifamily of proteins, sharing a protein domain
      that is conserved in eukaryotes.

PMID- 15177563
TI  - snf1lk encodes a protein kinase that may function in cell cycle regulation.
AB  - msk, myocardial SNF1-like kinase, was originally isolated in a screen for kinases
      expressed during early cardiogenesis in the mouse. msk maps to the proximal end
      of mouse chromosome 17 in a region that is syntenic with human chromosome
      21q22.3, where the gene for SNF1LK, a predicted protein that shares 80% identity
      at the amino acid level with Msk, is located. Accordingly, msk has been
      redesignated snf1lk. Interestingly, the region encompassing the SNF1LK locus has
      been implicated in congenital heart defects often observed in patients with Down
      syndrome. snf1lk is also expressed in skeletal muscle progenitor cells of the
      somite beginning at 9.5 dpc. These data suggest a more general role for snf1lk in
      the earliest stages of muscle growth and/or differentiation. Consistent with a
      role in cell cycling, we observe that Chinese hamster ovary cells that express a
      tetracycline-inducible SNF1LK kinase domain do not divide, but undergo additional
      rounds of replication to yield 8N and 16N cells. These data suggest a possible
      function for SNF1LK in G2/M regulation. We show data that indicate that SNF1LK
      does not share functional homology with other SNF1-related kinases, but
      represents a new subclass with novel molecular activities.

PMID- 15177556
TI  - Gene cataloging and expression profiling in human gastric cancer cells by
      expressed sequence tags.
AB  - To understand the molecular mechanism associated with gastric carcinogenesis, we
      identified genes expressed in gastric cancer cell lines and tissues. Of 97,609
      high-quality ESTs sequenced from 36 cDNA libraries, 92,545 were coalesced into
      10,418 human Unigene clusters (Build 151). The gene expression profile was
      produced by counting the cluster frequencies in each library. Although the
      profiles of highly expressed genes varied greatly from library to library, those
      genes related to cell structure formation, heat shock proteins, the glycolysis
      pathway, and the signaling pathway were highly represented in human gastric
      cancer cell lines and in primary tumors. Conversely, the genes encoding
      immunoglobulins, ribosomal proteins, and digestive proteins were down-regulated
      in gastric cancer cell lines and tissues compared to normal tissues. The
      transcription levels of some of these genes were confirmed by RT-PCR. We found
      that genes related to cell adhesion, apoptosis, and cytoskeleton formation were
      particularly up-regulated in the gastric cancer cell lines established from
      malignant ascites compared to those from primary tumors. This comprehensive
      molecular profiling of human gastric cancer should be useful for elucidating the
      genetic events associated with human gastric cancer.

PMID- 15177564
TI  - Expression pattern and raft association of NIPSNAP3 and NIPSNAP4, highly
      homologous proteins encoded by genes in close proximity to the ATP-binding
      cassette transporter A1.
AB  - The highly homologous genes NIPSNAP3 and NIPSNAP4, with 87% amino acid identity,
      are members of the NIPSNAP family with putative roles in vesicular trafficking.
      NIPSNAP3 mRNA and NIPSNAP4 mRNA and protein were detected in multiple tissues and
      cells at varying degrees. Interestingly, NIPSNAP3 is most highly expressed in
      skeletal muscle, where NIPSNAP4 has a low mRNA abundance. NIPSNAP4 was found
      associated with membranes and partly localized in rafts. The ubiquitous
      expression of the highly conserved NIPSNAPs and their association with membranes
      further support an important cellular function of these proteins probably linked
      to vesicular trafficking. The NIPSNAP3 and NIPSNAP4 genes are located in close
      proximity to the 3' end of the ATP-binding cassette transporter A1 (ABCA1), whose
      mutations cause familial high-density lipoprotein deficiency syndromes. The
      adjacent genomic location and the finding that ABCA1 is a regulator of vesicular
      trafficking may indicate a functional relation of these proteins, even though
      NIPSNAP4 does not interact directly with ABCA1 nor is its expression altered in
      cells with mutated ABCA1.

PMID- 15177565
TI  - Correlation between the clinical phenotype of MYH9-related disease and tissue
      distribution of class II nonmuscle myosin heavy chains.
AB  - Nonmuscle myosin heavy chain II-A is responsible for MYH9-related disease, which
      is characterized by macrothrombocytopenia, granulocyte inclusions, deafness,
      cataracts, and renal failure. Since another two highly conserved nonmuscle
      myosins, II-B and II-C, are known, an analysis of their tissue distribution is
      fundamental for the understanding of their biological roles. In mouse, we found
      that all forms are ubiquitously expressed. However, megakaryocytic and
      granulocytic lineages express only II-A, suggesting that congenital features,
      macrothrombocytopenia, and leukocyte inclusions correlate with its exclusive
      presence. In kidney, eye, and ear, where clinical manifestations have a late
      onset, as well as in other tissues apparently not affected in patients, II-A and
      at least one of the other two isoforms are expressed, suggesting that II-B and II
      C can partially compensate for each other. We hypothesize that cells expressing
      only II-A manifest the congenital defects, while tissues expressing additional
      myosin II isoforms show either late onset of abnormalities or no pathological
      sign.

PMID- 15177566
TI  - Molecular cloning and characterization of an endogenous antisense transcript of
      Nphs1.
AB  - Mutations of NPHS1, the gene encoding the kidney glomerular filtration barrier
      protein nephrin, cause congenital nephrotic syndrome of the Finnish type. Nephrin
      is a component of the interpodocyte-spanning slit diaphragm: it mediates outside
      in signaling and forms a nexus for homo- and heterotypic molecular interactions.
      When studying the nephrin-deficient mouse line generated by random insertional
      mutagenesis we unexpectedly discovered an endogenous antisense transcript
      originating from the nephrin-encoding locus. Further evidence of the antisense
      transcript (Nphs1as) was obtained by searching for Nphs1-like expressed sequence
      tags. Surprisingly, one clone showed exact complementarity in the antisense
      orientation. Nphs1as is expressed in the brain, thymus, and peripheral lymph
      nodes as well as in the embryonic stem cells. However, the mesenteric lymph nodes
      and the main sites of nephrin expression, the kidney and pancreas, were negative.
      Nphs1as is a continuous, polyadenylated mRNA that spans Nphs1 exons from 7 to 12
      in the reverse orientation. The relative amounts of sense and antisense mRNAs as
      well as nephrin protein were determined by semiquantitative RT-PCR and
      immunoblotting, respectively, in various mouse tissues. These results suggest
      that Nphs1as may be important for the regulation of the appropriate tissue- and
      cell-type-specific expression of nephrin.

PMID- 15177567
TI  - The human semaphorin 6B gene is down regulated by PPARs.
AB  - The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible
      transcription factors and belong to the nuclear hormone receptor superfamily.
      They form heterodimers with the retinoid X receptor and bind to specific
      peroxisome proliferator-response elements. The latter are direct repeat elements
      of two hexanucleotides with the consensus sequence TG(A/T)CCT separated by a
      single nucleotide spacer. Such a sequence, or a similar one, has been found in
      numerous PPAR-inducible genes. We developed an affinity method to isolate human
      genomic fragments containing binding sites for PPARs and to identify novel PPAR
      target genes. For this, an antibody raised against all PPAR subtypes was used.
      Immunoselected fragments were amplified and sequenced and one of them, ISF5148,
      was found to bind specifically to PPARs in gel mobility shift, supershift, and
      competition assays and to exhibit a down transregulation potentiality in
      transfection experiments under clofibrate (a PPARalpha agonist) treatment.
      ISF5148 was mapped by BLAST analysis 8.5 kb upstream of the human semaphorin 6B
      [(HSA)SEMA6B] gene. The latter encodes a member of the semaphorin family of axon
      guidance molecules. Expression of this gene in human glioblastoma T98G cells was
      strongly down regulated after treatment with clofibrate or Wy-14,643, two
      PPARalpha agonists. Our study establishes for the first time that PPAR activators
      diminish the expression of the human (HSA)SEMA6B gene. These data are relevant to
      the fact that PPARs are implicated in brain development, neuronal
      differentiation, and lipid metabolism in the central nervous system. In addition,
      cross talk between the peroxisome proliferator and retinoic acid pathways is
      suggested.

PMID- 15177568
TI  - Murine peptidoglycan recognition proteins PglyrpIalpha and PglyrpIbeta are
      encoded in the epidermal differentiation complex and are expressed in epidermal
      and hematopoietic tissues.
AB  - Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are pattern recognition
      molecules that are found in insects and mammals and are critical for innate
      immune responses. PGRPs bind peptidoglycan, a ubiquitous component of bacterial
      cell walls, and are involved in killing bacteria, degrading peptidoglycan, and
      initiating host defense reactions. Relatively little is known about the four
      mammalian PGRPs. In this article, we report the sequences of mouse PglyrpIalpha
      and PglyrpIbeta and provide details of their expression in wild-type mouse
      tissues. PglyrpIalpha and PglyrpIbeta are encoded within the epidermal
      differentiation complex on mouse chromosome 3F. Both genes are expressed in
      epidermal and hematopoietic tissues. PglyrpIbeta is expressed in each of 16
      tissues tested, while PglyrpIalpha expression is limited to fewer tissues,
      including the lung and spleen as well as several tissues of the digestive system.
      Both proteins are expressed in epithelial cells throughout the gut, and
      immunohistochemical staining shows expression in salivary glands, the squamous
      epithelium of the stomach, and the villi of the jejunum. Immunohistochemical
      staining further shows expression of both PglyrpIalpha and PglyrpIbeta in
      macrophages in the spleen. PglyrpIalpha is not expressed in resting RAW264.7
      macrophage-like cells, but is induced by stimulation with lipopolysaccharide.
      PglyrpIbeta is constitutively expressed in RAW264.7 cells and is unaffected by
      lipopolysaccharide or peptidoglycan stimulation. Computational and experimental
      data suggest that these proteins are secreted. This work provides a step toward
      understanding the roles of PglyrpIalpha and PglyrpIbeta in host defense and
      chronic inflammatory conditions induced by bacteria or their components.

PMID- 15177569
TI  - Are data from different gene expression microarray platforms comparable?
AB  - Many commercial and custom-made microarray formats are routinely used for large
      scale gene expression surveys. Here, we sought to determine the level of
      concordance between microarray platforms by analyzing breast cancer cell lines
      with in situ synthesized oligonucleotide arrays (Affymetrix HG-U95v2), commercial
      cDNA microarrays (Agilent Human 1 cDNA), and custom-made cDNA microarrays from a
      sequence-validated 13K cDNA library. Gene expression data from the commercial
      platforms showed good correlations across the experiments (r = 0.78-0.86),
      whereas the correlations between the custom-made and either of the two commercial
      platforms were lower (r = 0.62-0.76). Discrepant findings were due to clone
      errors on the custom-made microarrays, old annotations, or unknown causes. Even
      within platform, there can be several ways to analyze data that may influence the
      correlation between platforms. Our results indicate that combining data from
      different microarray platforms is not straightforward. Variability of the data
      represents a challenge for developing future diagnostic applications of
      microarrays.

PMID- 15177571
TI  - Deletion of multimerin-1 in alpha-synuclein-deficient mice.
AB  - A deletion of the murine Snca gene has been discovered in C57BL/6JOlaHsd, a
      population of the inbred strain C57BL/6J. We now characterize the exact nature of
      this deletion, Del(6)Snca1Slab. Detailed mapping and sequencing of the breakpoint
      revealed the absence of 365 kb, encompassing the Mmrn1 gene in addition to Snca.
      Despite the lack of alpha-synuclein and multimerin-1 C57BL/6JOlaHsd animals do
      not display obvious phenotypes. Sequence comparisons revealed that the
      chromosomal organization of Sncg and Mmrn2 is highly reminiscent of the region
      containing Snca and Mmrn1, suggesting a duplication event of a cluster of
      apparently unrelated genes during evolution.

PMID- 15177570
TI  - Evidence of systematic expressed sequence tag IMAGE clone cross-hybridization on
      cDNA microarrays.
AB  - We present evidence of a potentially serious source of error intrinsic to all
      spotted cDNA microarrays that use IMAGE clones of expressed sequence tags (ESTs).
      We found that a high proportion of these EST sequences contain 5'-end poly(dT)
      sequences that are remnants from the oligo(dT)-primed reverse transcription of
      polyadenylated mRNA templates used to generate EST cDNA for sequence clone
      libraries. Analysis of expression data from two single-dye cDNA microarray
      experiments showed that ESTs whose sequences contain repeats of consecutive 5'
      end dT residues appeared to be strongly coexpressed, while expression data of all
      other sequences exhibited no such pattern. Our analysis suggests that expression
      data from sequences containing 5' poly(dT) tracts are more likely to be due to
      systematic cross-hybridization of these poly(dT) tracts than to true mRNA
      coexpression. This indicates that existing data generated by cDNA microarrays
      containing IMAGE clone ESTs should be filtered to remove expression data
      containing significant 5' poly(dT) tracts.

PMID- 15177572
TI  - Moving with the times.

PMID- 15177573
TI  - Phacoemulsification in eyes with dense vitreous hemorrhage.

PMID- 15177575
TI  - Hazards of redundant corneal sutures: a safety message.

PMID- 15177576
TI  - Hazards of redundant corneal sutures: a safety message.

PMID- 15177577
TI  - Inhibition of lens epithelial cell migration by contact pressure.

PMID- 15177578
TI  - Effect of lidocaine on lens epithelial cells.

PMID- 15177579
TI  - Effect of contact lens use on corneal thickness measurements.

PMID- 15177580
TI  - Consultation section. Cataract surgical problem.

PMID- 15177588
TI  - Transscleral fixation of a dislocated IOL through sclerotomy.
AB  - We describe a technique for knotting a suture to the haptic of a dislocated
      intraocular lens (IOL) through a sclerotomy site without removing an IOL in 4
      patients. The suture was knotted to the haptic from outside the sclera. The
      remaining suture material was tied together and buried in the sclerotomy site. To
      prove that we could suture to the haptic safely, experiments were carried out
      using 4 scleral shells of donor eyes. No complications occurred, and good visual
      recovery was achieved. In this method, the haptic can be tied safely through the
      sclerotomy site and reduce the risk for knot-related complications. To our
      knowledge, this approach has not been reported.

PMID- 15177589
TI  - Inside-out delineation.
AB  - A technique of achieving precise hydrodelineation, in which fluid is injected
      from the inside of the nucleus to the outside, is described. The desired
      thickness of the nucleus-epinucleus bowl can be accomplished because the right
      angled cannula can direct the fluid in the desired plane. This technique is
      useful in eyes with posterior polar cataracts and in eyes with dense cataracts in
      which aggressive phacoparameters are necessary for their removal.

PMID- 15177590
TI  - Siepser slipknot for McCannel iris-suture fixation of subluxated intraocular
      lenses.
AB  - In 8 cases that presented with symptomatic posterior chamber IOL subluxation, a
      McCannel polypropylene (Prolene) suture was used with the Siepser slipknot
      technique to successfully refixate the IOLs to the iris. There were no
      intraoperative complications, and a round pupil was preserved in all cases.

PMID- 15177591
TI  - Intraocular telescopic lens evaluation in patients with age-related macular
      degeneration.
AB  - PURPOSE: To evaluate the improvement of distance and near visual acuity after
      removal of cataract and implantation of an 3.0x intraocular miniaturized
      telescope (IMT) in patients with stable atrophic type age-related macular
      degeneration (ARMD). SETTINGS: Instituto Oftalmologico de Alicante and a
      multicenter group. METHODS: In this prospective noncomparative multinational
      consecutive study, 40 eyes of 40 patients with dry-type ARMD were implanted with
      IMTs at multiple centers. Standard phacoemulsification procedure followed by
      enlargement of the incision to 10 mm and implantation in the capsular bag of an
      3.0x IMT was carried out in all the cases. Patients were followed for 12 months.
      Evaluation included the differences between preoperative and postoperative
      uncorrected and best corrected visual acuity for far and near, position of the
      IMT, intraocular pressure, and occurrence of any postoperative complications.
      RESULTS: Mean preoperative uncorrected distance visual acuity (UCDVA) in the
      operated eye was 0.9 logMAR (0.125 +/- 0.01, range 0.1 to 0.3 in decimal values);
      at 1 year postoperatively, mean UCDVA in the operated eye was 0.6 logMAR (0.25 +/
      0.14, range 0.1 to 0.5 in decimal values). Mean preoperative uncorrected near
      visual acuity (UCNVA) in the operated eye was 0.8 logMAR (0.16 +/- 0.13, range
      0.1 to 0.5 in decimal values); at 1 year postoperatively, mean UCNVA in the
      operated eye was 0.4 logMAR (0.4 +/- 0.26, range 0.1 to 1.0 in decimal values).
      The differences between pre- and postoperative distance and near visual acuities
      were statistically significant. Six cases were explanted, and 14 developed
      adverse effects, 7 of which were persistent. The corneal endothelium tolerated
      the procedure well. CONCLUSION: Implantation of IMT is feasible and plays an
      effective role in improving far and near visual acuity in patients with stable
      dry-type ARMD.

PMID- 15177592
TI  - Phakic refractive lens implantation in high myopic patients: one-year results.
AB  - PURPOSE: To evaluate the efficacy and safety of implantation of a new posterior
      chamber phakic refractive lens (PRL, Ciba Vision Surgical) in highly myopic eyes.
      SETTING: Department of Ophthalmology, Medical School, University of Crete,
      Vardinoyannion Eye Institute of Crete, Crete, Greece. METHODS: Thirty-four myopic
      eyes of 19 patients were treated for high myopia with implantation of a silicone
      PRL in the posterior chamber. Mean patient age was 29.0 years +/- 7.9 (SD) (range
      18 to 44 years). Manifest refraction in spherical equivalent (MR), uncorrected
      (UCVA) and best corrected (BCVA) visual acuity (decimal scale), intraocular
      pressure, higher-order aberrations (root-mean-square [RMS] wavefront error
      measured with a Shack-Hartmann wavefront sensor WASCA analyzer [Carl Zeiss,
      Meditec]), possible complications, and subjective symptoms were evaluated.
      RESULTS: Phakic refractive lenses were successfully implanted in all eyes. Mean
      follow-up was 17.17 +/- 3.76 months (range 12 to 24 months). There was a
      statistically significant reduction in the MR (from -14.70 D +/- 2.65 D [range 
      20.75 D to -10.50 D] to -0.61 D +/- 0.89 D [range -2.25 D to 1.00 D]) (P<.001).
      Twenty-seven (79%) and 15 eyes (44%) were within +/-1.00 D and +/-0.50 D of
      target refraction, respectively. Mean UCVA significantly improved (from counting
      fingers to 0.62 +/- 0.28 (range 0.08 to 1.20) (P<.001). Mean BCVA also improved
      from 0.70 +/- 0.24 (range 0.10 to 1.00) to 0.85 +/- 0.24 (range 0.10 to 1.20)
      (P<0.001). Overall, there was a mean increase in BCVA of 1.5 +/- 1.5 lines (range
      loss of 2 lines to gain of 5 lines). There was no statistically significant
      difference in higher-order aberrations after PRL implantation (pre-PRL RMS: 0.18
      microm +/- 0.08 microm [range 0.09 microm to 0.38 microm]; post-PRL RMS: 0.21
      microm +/- 0.08 microm; [range 0.05 microm to 0.38 microm]) (P =.12). CONCLUSION:
      The PRL showed encouraging results in treating high myopia. Additional patients
      and longer follow-up period are needed to detect the long-term efficacy and
      safety of this refractive lens.

PMID- 15177593
TI  - Light scattering and optical aberrations as objective parameters to predict
      visual deterioration in eyes with cataracts.
AB  - PURPOSE: To predict the visual deterioration of eyes with cortical (CC) or
      nuclear (NC) cataract from objective data on ocular higher-order aberration (HOA)
      and forward (FLS) and backward light scattering (BLS). SETTING: Osaka University
      Medical School, Osaka, Japan. METHODS: Twenty-two eyes with mild NC, 41 eyes with
      mild CC, and 11 normal eyes were examined. Higher-order aberrations were
      calculated with the Zernike polynomials up to the fourth order from the values
      obtained by wavefront analysis using the Hartmann-Shack aberrometer. Forward
      light scattering was calculated from the size of the aberrometer spot images for
      the central 4 mm, and backward light scattering (BLS) was calculated from the
      optical density of the Scheimpflug images. The relationship between the area
      under the log contrast sensitivity function (AULCSF) curve and HOAs, FLS, and BLS
      was examined. RESULTS: Area under the log contrast sensitivity function was
      moderately correlated with the HOAs, FLS, and BLS. Multiple linear regression
      analysis revealed that the AULCSF was predicted by the linear combination of
      these variables (R(2)=.484, P<.001). Area under the log contrast sensitivity was
      predicted by BLS and HOA (R(2)=.555) in the NC group and by FLS and HOAs
      (R(2)=.540) in the CC group. CONCLUSIONS: Loss of contrast sensitivity was
      predominantly due to BLS and HOA in eyes with NC and FLS and HOA in eyes with CC.
      Higher-order aberrations, FLS, and BLS, variables that are obtained objectively,
      can be used to predict quantitatively the visual deterioration in cataractous
      eyes.

PMID- 15177594
TI  - Laser in situ keratomileusis for myopia and the contrast sensitivity function.
AB  - PURPOSE: To characterize the clinical effects of laser in situ keratomileusis
      (LASIK) on the cornea and visual performance by the contrast sensitivity function
      (CSF). SETTING: Clinique d'Ophtalmologie IRIS, Laval, Quebec, Canada. METHODS:
      Thirty-four patients aged 18 to 50 years volunteered for this prospective study.
      All patients had bilateral LASIK to correct myopia between -1.00 and -6.75
      diopters (D) and refractive astigmatism less than 2.50 D. The mean spherical
      equivalent (SE) refractive error in the 68 eyes was -3.93 D +/- 1.67 (SD). A
      Hansatome microkeratome (Bausch & Lomb) and a Technolas 217C excimer laser
      (Bausch & Lomb) driven by the PlanoScan program were used. The monocular CSF for
      spatial frequencies of 3, 6, 12, and 18 cycles per degree (cpd) for both day and
      night vision simulations were made with a CSV-1000E system (Vector Vision) before
      and 1 month and up to 9 months after LASIK. All patients wore their best
      spectacle correction for the baseline CSF. RESULTS: The group (n = 68) averaged
      preoperative and postoperative CSFs did not differ at 1 month (analysis of
      variance [ANOVA], P>.05). In a subgroup of 11 eyes that had corneal microstriae,
      however, there was a significant reduction in the photopic and mesopic CSF at 6,
      12, and 18 cpd (ANOVA, P<.05) despite normal Snellen visual acuities. The CSF
      normalized in 6 to 9 months as the microstriae became less visible. CONCLUSIONS:
      Subtle central corneal microstriae after LASIK can reduce the baseline CSF at
      medium to high spatial frequencies even with 20/20 visual acuity. The CSF
      normalizes as the microstriae fade over time.

PMID- 15177595
TI  - Intraocular pressure rise after phacoemulsification surgery in glaucoma patients.
AB  - PURPOSE: To examine the changes in intraocular pressure (IOP) and the incidence
      of substantial rises in IOP in the early period after cataract surgery in eyes
      with open-angle glaucoma (OAG). SETTING: Hayashi Eye Hospital, Fukuoka, Japan.
      METHODS: The study included 32 eyes of 32 patients with OAG and 31 control eyes
      of 31 age-matched patients scheduled for phacoemulsification surgery. The IOP was
      measured preoperatively and 1, 2, 3, 5, 7, 14, and 28 days postoperatively. The
      incidence of a substantial rise in IOP postoperatively was evaluated, with the
      criterion being an IOP higher than 30 mm Hg. RESULTS: In the OAG group, the mean
      IOP increased 1, 2, and 3 days postsurgery and then decreased, whereas in the
      control group, it decreased from day 1 postsurgery. Although no significant
      differences were found between groups preoperatively, the mean IOP in the OAG
      group was significantly higher than in the control group postoperatively.
      Furthermore, the mean IOP decrease was also less in the OAG group than in the
      control group. A substantial increase in IOP occurred at day 1 postsurgery in 4
      eyes (12.5%) in the OAG group, whereas no eyes in the control group showed such
      an increase; this difference was significant (P =.0419). CONCLUSIONS: A
      substantial increase in IOP occurred in an approximately 13% of eyes with OAG 1
      day after phacoemulsification surgery. The IOP shortly after surgery was
      significantly greater in the eyes with OAG than in nonglaucomatous eyes.

PMID- 15177596
TI  - Long-term results of deep sclerectomy with collagen implant.
AB  - PURPOSE: To study prospectively the success rate and complications of deep
      sclerectomy with collagen implant (DSCI). SETTING: Glaucoma Unit, Department of
      Ophthalmology, Hopital Ophtalmique Jules Gonin, University of Lausanne, Lausanne,
      Switzerland. METHODS: This nonrandomized prospective trial comprised 105 eyes of
      105 patients with medically uncontrolled primary and secondary open-angle
      glaucoma. Visual acuity, intraocular pressure (IOP), and slitlamp examinations
      were performed before surgery and after surgery at 1 and 7 days, and 1, 3, 6, 9,
      12, 18, 24, 30, 36, 48, 54, 60, 66, 72, 78, 84, 90, and 96 months. Visual field
      examinations were repeated every 6 months. RESULTS: Mean follow-up period was 64
      months +/- 26.6 (SD). Mean preoperative IOP was 26.8 +/- 7.7 mm Hg, and mean
      postoperative IOP was 5.2 +/- 3.35 mm Hg at day 1 and 12 +/- 3 mm Hg at month 78.
      At 96 months, the qualified success rate (ie, patients who achieved IOP <21 mm Hg
      with and without medication) was 91%, and the complete success rate (ie, IOP <21
      mm Hg without medication) was 57%. At 96 months, 34% of patients had an IOP <21
      mm Hg with medication. Fifty-one patients (49%) achieved an IOP < or =15 mm Hg
      without medication. Neodymium:YAG goniopuncture was performed in 54 patients
      (51%); mean time of goniopuncture performance was 21 months, and mean IOP before
      goniopuncture was 20 mm Hg, dropping to 11 mm Hg after goniopuncture. No shallow
      or flat anterior chamber, endophthalmitis, or surgery-induced cataract was
      observed. However, 26 patients (25%) showed a progression of preexisting senile
      cataract (mean time 26 months; range 18 to 37 months). Injections of 5
      fluorouracil were administered to 25 patients (23%) who underwent DSCI to salvage
      encysted blebs. Mean number of medications per patient was reduced from 2.3 +/-
      0.7 to 0.5 +/- 0.7 (signed rank P<.0001). CONCLUSION: Deep sclerectomy with
      collagen implant appears to provide stable and reasonable control of IOP at long
      term follow-up with few immediate postoperative complications.

PMID- 15177597
TI  - Surgically induced corneal refractive change following glaucoma surgery:
      nonpenetrating trabecular surgeries versus trabeculectomy.
AB  - PURPOSE: To compare surgically induced corneal refractive change following
      trabeculectomy with the nonpenetrating trabecular filtering surgeries with and
      without implant. SETTING: Department of Ophthalmology, Ege University School of
      Medicine, Izmir, Turkey. METHODS: A consecutive series of 34 patients (34 eyes)
      with uncontrolled open-angle glaucoma had trabecular filtering surgery. Patients
      were assigned randomly to receive viscocanalostomy (12 patients), nonpenetrating
      deep sclerectomy (NPDS) with T-flux implant (10 patients), and trabeculectomy (12
      patients). Autokeratometry and computerized corneal videokeratoscopy with the
      Topcon KR-7000P autokeratorefractometer were performed preoperatively and 1 day
      and 1, 3, and 6 months postoperatively to analyze surgically induced keratometric
      and topographic astigmatism. RESULTS: Thirty patients (11 trabeculectomy, 11
      viscocanalostomy, and 8 NPDS with nonabsorbable implant) completed the study.
      Mean patient age was 61.7 years +/- 10.9 (SD) (range 37 to 81) and did not differ
      among groups. Postoperative intraocular pressure (IOP) levels and visual acuity
      (logMAR values) did not differ among groups compared with preoperative levels.
      Average induced astigmatism was lower in the NPDS group than the trabeculectomy
      group at postoperative month 3 and 6 based on autokeratometry values (P =.023
      and.042, respectively). Nonpenetrating surgeries resulted in less induced
      astigmatism in the early postoperative period and less against-the-rule shift
      over 6 months. CONCLUSION: Despite larger flap size and surgical area,
      nonpenetrating trabecular surgeries induced less astigmatism than trabeculectomy.

PMID- 15177598
TI  - Risk factors and retreatment results of intraoperative flap complications in
      LASIK.
AB  - PURPOSE: To evaluate the incidence, type, and risk factors of intraoperative
      complications leading to abandonment of laser in situ keratomileusis (LASIK), and
      to compare the safety and efficacy of retreated LASIK with uncomplicated primary
      LASIK. SETTING: Refractive surgery centers in Tokyo, Yokohama, Nagoya, Osaka, and
      Fukuoka, Japan. METHODS: A total of 3751 eyes of 2033 patients who were followed
      for 6 months after primary LASIK, of which 15 eyes were retreated after
      intraoperative flap complications, were reviewed. In most of the cases,
      retreatments were performed by recutting a new flap. RESULTS: Intraoperative flap
      complications occurred in 25 eyes, of which 15 eyes had retreatment at a later
      date. The overall incidence of complications was independent of the surgeons'
      experience, although incomplete flaps, in particular, occurred at a higher rate
      in the hands of inexperienced surgeons. No patient profile was detected as a risk
      factor for intraoperative flap complications. No flap-related complications
      occurred at retreatment. Refractive and visual outcomes were comparable to those
      in the uncomplicated cases within 6 months postoperatively. CONCLUSIONS:
      Retreatment after microkeratome flap complications by recutting the cornea is
      safe and effective.

PMID- 15177599
TI  - Persistent diplopia after retrobulbar anesthesia.
AB  - PURPOSE: To determine the causative factors of persistent diplopia after
      retrobulbar anesthesia. SETTING: Strabismus Section, Department of Ophthalmology,
      Seoul National University, Seoul, South Korea. METHODS: Prism and alternate cover
      tests in the diagnostic positions of gaze and ductions/versions were performed in
      28 patients with persistent diplopia 6 months after retrobulbar anesthesia. The
      Lancaster test, Bielshowsky head tilt test, double Maddox rod test, fundoscopic
      examination for torsion, forced duction test, force generation test, tensilon
      test, thyroid function test, and/or orbit computed tomography were performed when
      necessary. RESULTS: Most of the patients (26 patients, 93%) did not have diplopia
      before retrobulbar anesthesia. Of the 14 patients with extraocular muscles
      imbalance, 12 patients showed vertical rectus overaction (11 superior recti, 1
      inferior rectus) and 2 patients, mild vertical rectus underaction. Nine patients
      were presumed to have a sensory strabismus related to the preoperative poor
      vision, but this went unnoticed preoperatively. Three patients showed a small
      vertical deviation without any specific causative factors. CONCLUSIONS: Fifty
      percent of the cases of diplopia were associated with either direct trauma or
      anesthetic myotoxicity to the extraocular muscles, in which overactions were more
      common than underactions. Thirty-two percent of the patients were presumed to
      have sensory strabismus, which suggested the importance of preoperative
      examination for strabismus as well as providing an explanation about the risk of
      postoperative diplopia before surgery.

PMID- 15177600
TI  - Uveal and capsular biocompatibility of a single-piece, sharp-edged hydrophilic
      acrylic intraocular lens with collagen (Collamer): 1-year results.
AB  - PURPOSE: To analyze uveal and capsular biocompatibility 1 year following
      implantation of a sharp-edged, hydrophilic, collagen-containing posterior chamber
      intraocular lens (IOL). SETTING: Department of Ophthalmology, University of
      Vienna Medical School, Vienna, Austria. METHOD: In a prospective study, a
      Collamer CC4204BF IOL was implanted in 30 eyes of patients with senile cataract.
      A standardized surgical technique and postoperative regimen were applied. To
      assess uveal biocompatibility, cellular inflammation on the anterior IOL surface
      was evaluated with a specular microscope. Capsular biocompatibility was
      registered semiquantitatively with a biomicroscope, based on an assessment of
      fibrosis on the anterior and posterior capsules. Tyndall values were measured
      with the Kowa FC-1000 laser flare-cell meter. Decentration of the lens was also
      registered. RESULTS: One year after implantation, the values of flare and cell
      count in the anterior chamber were lower than preoperatively. Round and spindle
      shaped, epithelioid, and foreign-body giant cells were not found on the anterior
      surface of the IOL. The capsulorhexis rim was moderately fibrosed in 56.6% of
      cases. Fibrosis of the capsule over the optic was also moderate in 36.6%. The
      central portion of the posterior capsule was devoid of fibrosis in 43.3% and
      mildly fibrosed in 50%. Three lenses revealed outgrowth of lens epithelial cells
      to the anterior surface of the IOL. A neodymium:YAG capsulotomy had to be
      performed in 1 case. All lenses were well centered in the capsular bag 1 year
      after implantation. CONCLUSIONS: The absence of inflammatory cells on the
      anterior surface of the IOL indicates the high uveal biocompatibility of the
      lens. In terms of capsular biocompatibility, the results were satisfactory.

PMID- 15177601
TI  - Reading performance depending on the type of cataract and its predictability on
      the visual outcome.
AB  - PURPOSE: To investigate the influence of various types of cataract on reading
      performance in a standardized reading test setting. SETTING: Department of
      Ophthalmology, University of Vienna, Vienna, Austria. METHODS: The reading
      performance of 94 eyes with age-related cataract and normal macular function was
      evaluated with the Radner Reading Charts preoperatively and 4 weeks after
      cataract surgery. Distance visual acuity was tested with the ETDRS charts.
      Cataracts were graded using the Lens Opacities Classification System (LOCS) III,
      on which NO is nuclear opalescence and NC is nuclear color. RESULTS: Patients
      with pure nuclear cataracts (LOCS III: NO/NC 2.1-5) achieved a normally high MRS
      (99.84% +/- 7.65% of their postoperative MRS): preoperative MRS(1): 190.6 +/-
      30.74 words per minute (wpm); postoperative MRS(2): 191.21 +/- 29.36 wpm.
      Patients with mixed nuclear-cortical cataracts (LOCS III: NO/NC 2.1-5; C>2)
      preoperatively achieved 96.96% +/- 5.6% of their postoperative MRS (MRS(1):
      175.77 +/- 31.54 wpm; MRS(2): 181.34 +/- 30.56 wpm). In dense nuclear cataracts
      (LOCS III: NO/NC>5), the MRS was significantly reduced, achieving only 72.64 +/-
      19.19% of the postoperative MRS (MRS(1): 133.06 +/- 39.43 wpm; MRS(2): 185.76 +/-
      40.18 wpm). In posterior subcapsular cataracts, the preoperative MRS (134.1 +/-
      33.72 wpm) was significantly lower than postoperatively (191.14 +/- 27.08 wpm).
      CONCLUSIONS: In contrast to dense nuclear cataracts and posterior subcapsular
      cataracts, the preoperative reading speed of patients with pure nuclear or
      nuclear-cortical cataracts was normal at large print sizes. The preoperative
      evaluation of reading acuity and speed with standardized reading tests can
      therefore be used to estimate the postoperative reading performance in the latter
      2 types of cataract.

PMID- 15177602
TI  - Comparative estimation of anterior chamber depth by ultrasonography, Orbscan II,
      and IOLMaster.
AB  - PURPOSE: To assess the degree of agreement of anterior chamber depth (ACD)
      measurements by 2 optical devices (Orbscan II and IOLMaster) and compare them
      with contact ultrasound A-scan. SETTING: Department of Ophthalmology at Hull
      Royal Infirmary, England. methods: In this prospective study of 81 eyes of 41
      consecutive patients, ACD estimation was done by 3 methods-scanning slit
      topography (Orbscan II), partial coherence interferometry (IOLMaster), and
      contact ultrasound A-scan in that order. The same observer performed all
      measurements. Repeated measures Analysis of Variance (ANOVA) was used to analyze
      difference between ACD measurements by the 3 methods. Difference in measurements
      between methods was assessed using the paired t test. RESULTS: The mean ACD (+/
      SD) by the 3 methods was 3.32 mm (0.60), 3.33 mm (0.61), and 2.87 mm (0.55),
      respectively. There was a statistically significant difference between
      measurements recorded by the 3 methods (P<.01). Mean contact A-scan measurements
      were 0.40 mm and 0.43 mm lower than by Orbscan II and IOLMaster respectively
      (P<.01). CONCLUSION: Applanation ultrasound gives consistently lower measurements
      for ACD compared to Orbscan II and IOLMaster. Although a high degree of agreement
      between Orbscan II and IOLMaster was noted, further studies are needed to assess
      the interchangeability of measurements in clinical practice.

PMID- 15177603
TI  - Corneal pachymetry in normal and keratoconic eyes: Orbscan II versus ultrasound.
AB  - PURPOSE: To compare corneal thickness measurements using Orbscan II (OII) and
      ultrasonic (US) pachymetry in normal and in keratoconic eyes. SETTING: Eye
      Department, Heartlands and Solihull NHS Trust, Birmingham, United Kingdom.
      METHODS: Central corneal thickness (CCT) was measured by means of OII and US
      pachymetry in 1 eye of 72 normal subjects and 36 keratoconus patients. The apical
      corneal thickness (ACT) in keratoconus patients was also evaluated using each
      method. The mean of the difference, standard deviation (SD), and 95% limits of
      agreement (LoA = mean +/- 2 SD), with and without applying the default linear
      correction factor (LCF), were determined for each sample. The Student t test was
      used to identify significant differences between methods, and the correlation
      between methods was determined using the Pearson bivariate correlation. Bland
      Altman analysis was performed to confirm that the results of the 2 instruments
      were clinically comparable. RESULTS: In normal eyes, the mean difference (+/- 95%
      LoA) in CCT was 1.04 microm +/- 68.52 (SD) (P>.05; r = 0.71) when the LCF was
      used and 46.73 +/- 75.40 microm (P =.0001; r = 0.71) without the LCF. In
      keratoconus patients, the mean difference (+/- 95% LoA) in CCT between methods
      was 42.46 +/- 66.56 microm (P<.0001: r = 0.85) with the LCF, and 2.51 +/- 73.00
      microm (P>.05: r = 0.85) without the LCF. The mean difference (+/- 95% LoA) in
      ACT for this group was 49.24 +/- 60.88 microm (P<.0001: r = 0.89) with the LCF
      and 12.71 +/- 68.14 microm (P =.0077; r = 0.89) when the LCF was not used.
      CONCLUSIONS: This study suggests that OII and US pachymetry provide similar
      readings for CCT in normal subjects when an LCF is used. In keratoconus patients,
      OII provides a valid clinical tool for the noninvasive assessment of CCT when the
      LCF is not applied.

PMID- 15177604
TI  - Silicone oil content in ophthalmic viscosurgical devices.
AB  - PURPOSE: To examine the silicone oil content in 5 brands of ophthalmic
      viscoelastic devices (OVDs). SETTING: Department of Ophthalmology, Central
      Hospital of Vasteras, Vasteras, Sweden. METHODS: Phacoemulsification with
      intraocular lens (IOL) implantation was performed in 250 patients. Five brands of
      OVD were used, each one in 50 procedures. From each brand, 5 separate batches,
      each consisting of 10 syringes, were used. The 250 samples from identical batches
      were sent for spectrophotometric analysis, and 250 samples were used during
      surgery. RESULTS: The silicone oil content varied significantly between the OVD
      brands. CONCLUSIONS: Silicone oil is a common contaminant in many OVDs.
      Ophthalmic viscosurgical devices with relatively low silicone oil content are
      available.

PMID- 15177605
TI  - Laser in situ keratomileusis for hyperopia with the LADARVision 4000 with
      centration on the coaxially sighted corneal light reflex.
AB  - PURPOSE: To analyze the visual acuity, contrast sensitivity, and target
      deviations in patients who had laser in situ keratomileusis (LASIK) for primary
      hyperopia with the ablation centered on the coaxially sighted corneal light
      reflex. SETTING: University-based refractive surgery practice. METHODS:
      Retrospective review comprised 37 consecutive patients (61 eyes) who had LASIK
      for hyperopia with the LADARVision 4000 excimer laser (Alcon Laboratories).
      Preoperative and 3-month postoperative visual acuity and contrast sensitivity, as
      well as the target deviation, were assessed for each eye. The change in best
      spectacle-corrected visual acuity (BSCVA), best spectacle-corrected contrast
      sensitivity (BSCCS), and target deviation from the intended correction were
      analyzed. RESULTS: Postoperatively, the uncorrected visual acuity (UCVA) was
      20/20 or better in 44.4% of eyes. The mean deviation from target was +0.25
      diopter (D) +/- 0.82 (SD), with 65.6% of eyes within +/-0.50 D of target. None
      eye lost 2 or more lines of BSCVA. A loss of 3 or more patches of BSCCS were seen
      in 6.6% of the eyes and a loss of 4 or more patches, in 1.6%. CONCLUSION:
      Hyperopic LASIK with LADARVision 4000 with the ablation zone centered on the
      coaxially sighted corneal light reflex did not adversely affect BSCVA and BSCCS.

PMID- 15177606
TI  - Quality of vision following clinically successful penetrating keratoplasty.
AB  - PURPOSE: To evaluate visual function following clinically successful penetrating
      keratoplasty (PKP). SETTING: Department of Ophthalmology, Ege University, School
      of Medicine, Izmir, Turkey. METHODS: Patient group (PG) included 9 patients (12
      eyes) who had clinically successful PKP in our department. The control group (CG)
      included 12 people (18 eyes) who had no ocular disease other than refractive
      errors. Those with a visual acuity level less than 20/25 were not included in the
      study. Contrast sensitivity levels and light threshold values of the central
      retina were measured; scanning-slit corneal topography-pachymetry and
      aberrometric analysis were performed. RESULTS: There were no statistical
      difference in terms of age (32.55 years +/- 9.25 (SD) in PG, 36.75 +/- 5.85 years
      in CG; P =.53), cylinder power in plus form (2.60 +/- 1.25 diopter (D) in PG,
      2.79 D +/- 2.51 D in CG; P =.88), and spherical equivalent of refractive errors (
      3.66 +/- 3.57 D in PG, -5.52 +/- 3.37 D in CG; P =.29) between the PG and CG.
      Cambridge low-contrast grating scores were 96.5 +/- 41.1 in grafted eyes and 148
      +/- 27.7 in CG (P =.004). Central retinal light sensitivity was measured as 29.91
      +/- 2.39 db in PG and 33.08 +/- 1.56 db in CG (P =.001). In corneal topographic
      analysis, mean kappa intercept was 0.69 +/- 0.37 mm in PG and 0.55 +/- 0.24 mm in
      CG (P =.20). Lower-order Zernike root mean squares (RMS) were 7.30 +/- 3.89
      microm for PG and 8.58 +/- 3.46 microm for CG (P =.37). However, higher-order
      Zernike RMS were 2.15 +/- 0.78 in PG and 0.38 +/- 0.10 in CG, which is a
      statistically significant difference (P<.001). CONCLUSIONS: Even though the
      clinically successful PKP patients have correctable amount of spherocylindrical
      refractive errors with spectacle lenses, they still have reduced visual quality
      because of the significantly high amount of higher- order aberrations when
      compared with naturally occurring refractive errors.

PMID- 15177607
TI  - Subtle signs of zonular damage.
AB  - PURPOSE: To describe 5 subtle signs of zonular damage. SETTING: Cincinnati Eye
      Institute, Cincinnati, Ohio, USA. METHODS: Three patients with a history of
      ocular trauma and 1 patient with Marfan's syndrome are described. During the
      preoperative examination, subtle signs of zonular damage were detected. As a
      result of the early recognition, critical modifications in cataract surgery
      technique and technology were made. RESULTS: The signs of zonular damage
      identified in the patients were visibility of the lens equator during eccentric
      gaze, decentered nucleus in primary position, iridolenticular gap, changes in the
      contour of the lens periphery, and focal iridodonesis. CONCLUSION: Identification
      of subtle but important signs of zonular damage will better prepare the surgeon
      for a challenging surgical procedure.

PMID- 15177608
TI  - Quality assessment model of 3 different microkeratomes through confocal
      microscopy.
AB  - PURPOSE: To study the quality of the cut created by 3 microkeratomes from 2
      different generations using corneal confocal microscopy. SETTING: Department of
      Refractive Surgery, Instituto Oftalmologico de Alicante, Alicante, Spain.
      METHODS: Two different studies were conducted: Study 1 and Study 2. Study 1 was a
      prospective analysis using confocal microscopy examination data from 2 reference
      groups: Group A (control) with 20 nonoperated eyes of 20 healthy volunteers, and
      Group B with 50 eyes of 30 patients operated on with the Bausch & Lomb Automated
      Corneal Shaper (ACS) microkeratome. Study 2 was a prospective randomized double
      masked study in which 40 eyes of 20 patients underwent myopic laser in situ
      keratomileusis by 1 surgeon. The right and left eyes of each patient were
      randomly and alternatively assigned to Group C, flap made with the Hansatome
      microkeratome, or Group D, flap made with the Moria M2. Immediately after
      surgery, the microscopic appearance of the cut was subjectively evaluated by the
      surgeon. One month postoperatively, flap thickness, particle density, and the
      subclinical confocal wound healing opacity (WHO) index were evaluated with the
      corneal confocal microscope. RESULTS: Surgeon handling comfort was nearly the
      same with the Hansatome as with the M2 (P =.540). However, the apparent quality
      of the resulting flap was better with the M2 microkeratome (P =.041). The depth
      of the cuts made by the 3 microkeratomes were significantly different (P<.001),
      with the ACS flaps being thinner than the flaps made with the Hansatome or the
      M2. Particle density at the interface was significantly poorer in the eyes
      operated on with the ACS, but in these cases the WHO index was significantly
      greater (P<.001 in both cases). CONCLUSIONS: Confocal microscopy is a very useful
      tool to evaluate the quality of the cut made by different microkeratomes.
      Overall, the predictability in flap thickness and the apparent quality of the cut
      made by the Moria M2 microkeratome are better than those obtained with the
      Hansatome or the ACS. The thin flap made by the ACS microkeratome produced a
      significantly greater WHO index than the thicker flaps created with the other 2
      microkeratomes.

PMID- 15177609
TI  - Cataract progression and treatment following posterior lamellar keratoplasty.
AB  - PURPOSE: To describe the development and treatment of cataracts following
      posterior lamellar keratoplasty (PLK) in phakic eyes with Fuchs' endothelial
      dystrophy. SETTING: Price Vision Group, Indianapolis, Indiana, USA. METHODS: A
      retrospective chart review was performed on 47 PLK cases performed by a single
      surgeon between June 2001 and December 2002 in a tertiary care setting. Four of
      the eyes were phakic at the time of surgery. The PLK procedure consisted of
      dissecting a stromal pocket across the cornea and excising a central button. Then
      a posterior lamellar donor button, consisting of posterior stroma, Descemet's
      membrane, and endothelium, was transplanted without suture fixation. RESULTS: All
      4 phakic eyes that were treated with PLK developed a cataract within 1 year of
      transplant. The cataracts were removed with phacoemulsification through a clear
      corneal incision, and intraocular lenses (IOLs) were placed in all 4 eyes with no
      adverse effect on graft clarity. CONCLUSIONS: It is preferable to perform PLK in
      pseudophakic rather than phakic eyes because the manipulation involved in the
      procedure can induce cataract formation. Cataract surgery with placement of an
      IOL can be successfully performed following PLK.

PMID- 15177610
TI  - Surgically induced astigmatism after superotemporal and superonasal clear corneal
      incisions in phacoemulsification.
AB  - PURPOSE: To evaluate surgically induced corneal astigmatism after small
      superotemporal and superonasal clear corneal incision cataract surgery. SETTING:
      Department of Ophthalmology, School of Medicine, University of Afyon Kocatepe,
      Afyon, Turkey. METHODS: This prospective study comprised 56 eyes of 28 patients
      who had bilateral phacoemulsification and implantation of a foldable intraocular
      lens (IOL) through a corneal tunnel incision. A superotemporal incision was used
      in all right eyes, and a superonasal incision was used in all left eyes.
      Topography was performed preoperatively and at 1 week, 1, 3, and 6 months, and 1
      year. Surgically induced astigmatism (SIA) was calculated by vector analyses
      using the Holladay-Cravy-Koch method. The incision length was measured and was
      between 3.30 mm and 3.50 mm in all eyes. RESULTS: Although SIA did not differ
      significantly between the 2 incision groups (P>.05), decomposition of vectors
      showed that the horizontal component of SIA after superonasal incision was
      statistically significantly higher than superotemporal incision throughout the
      study (P<.05). Vertical components of SIA and the incision size after IOL
      implantation with the syringe/cartridge system between the 2 incision groups were
      not significantly different (P>.05). CONCLUSION: There was no statistically
      significant difference in SIA between superotemporal incisions in the right eyes
      and superonasal incisions in the left eyes 1 year after surgery for a surgeon who
      sits at the 12 o'clock. Superonasal clear corneal incisions can be used in left
      eyes and superotemporal clear corneal incisions in right eyes.

PMID- 15177611
TI  - Retrospective analysis of actual LASIK flap diameter compared with microkeratome
      ring size performed by different surgeons.
AB  - PURPOSE: To evaluate the difference in the diameter between microkeratome ring
      and actual laser in situ keratomileusis (LASIK) flap size by 4 different surgeons
      using 3 different microkeratomes in comparison to preoperative keratometry.
      SETTING: Gimbel Eye Centre, Calgary, Alberta, Canada. METHODS: A retrospective
      analysis of 6667 consecutive LASIK surgeries performed at the Gimbel Eye Centre
      between 1998 and 2002 was conducted. The study compared the difference in the
      actual LASIK flap diameter and microkeratome ring size for 3 Hansatome
      microkeratomes indicated by serial numbers 2230, 3048, and 3084 in comparison to
      the preoperative keratometry. The surgeries were performed by 4 surgeons from the
      Centre. RESULTS: A statistically significant correlation was found between the
      actual flap size and the microkeratome ring size. The deviation increased with
      corneal steepness (#2230: r = 0.45, P<.001; #3048: r = 0.28, P<.001; #3084: r =
      0.23, P<.001). The mean difference between actual flap size and the microkeratome
      ring size was 0.647 mm, 0.808 mm, and 0.916 mm for Hansatome microkeratome #2230,
      #3048, and #3084, respectively. The actual flap was larger than the microkeratome
      ring size in 92.8%, 93.8%, and 97.4% of eyes, respectively. The mean difference
      between microkeratome ring size and measured LASIK flap size was consistently
      significantly different (P<.0001) per surgeon for all microkeratomes.
      CONCLUSIONS: Estimation of the flap size is an important issue while selecting
      ring size and planning the treatment zone. In this study, the actual flap size
      was larger than the ring size for all surgeons and all 3 Hansatome
      microkeratomes. Higher preoperative keratometry values achieved larger flaps than
      those with lower keratometry values.

PMID- 15177612
TI  - Resulting refraction after same-day bilateral phacoemulsification.
AB  - PURPOSE: To study the refraction achieved after same-day bilateral cataract
      surgery, particularly with regard to anisometropia and the incidence of patient
      dissatisfaction caused by this complication. SETTING: Department of
      Ophthalmology, University Hospital of Linkoping, Sweden. METHODS: This was a
      retrospective study of 165 consecutive patients who had bilateral cataract
      surgery on the same day. Parameters examined were preoperative and postoperative
      visual acuity and refraction (spherical equivalent), preoperative keratometry and
      axial lengths, planned postoperative refraction, difference between planned and
      achieved refraction, anisometropia, and recorded evidence of patient
      dissatisfaction resulting from refraction or binocularity problems. RESULTS:
      Postoperative refraction was within +/-0.5 diopter (D) from target in 43%, +/-1 D
      from target in 71%, and +/-2 D from target in 95% of eyes. Anisometropia was < or
      =0.5 D in 48% of patients and < or =1 D in 82% of patients. Two patients (1.2%)
      had anisometropia >2 D. No patient returned with complaints caused by
      postoperative refraction. CONCLUSIONS: Although deviation from planned
      postoperative refraction occurred in several cases, no patient reported
      binocularity problems in the 1% of cases with significant anisometropia. Risk for
      deviation from planned refraction does not appear to be a contraindication to
      same-day bilateral phacoemulsification in patients without known risk factors.

PMID- 15177614
TI  - Increased aqueous flare intensity in eyes with liquefied after-cataract.
AB  - PURPOSE: To describe aqueous flare intensity in eyes with white liquefied after
      cataract. SETTING: Department of Ophthalmology, Toyama Medical and Pharmaceutical
      University, Toyama, Japan. METHODS: Seven patients with unilateral liquefied
      after-cataract and another 10 unaffected patients with an intraocular lens (IOL)
      were examined. The eyes were divided into 3 groups. The first group was composed
      of 7 eyes with liquefied after-cataract. The second group included the fellow
      eyes of the patients with unilateral liquefied after-cataract; 4 had an IOL, and
      3 had cataract. The third group included 10 additional eyes without liquefied
      after-cataract. All patients underwent cataract operations consisting of
      phacoemulsification/aspiration with continuous curvilinear capsulorhexis and
      acrylic IOL implantation in the capsular bag. Aqueous flare was measured using a
      laser flare-cell meter. RESULTS: The mean +/- SD of aqueous flare intensity was
      significantly higher in the first group (11.8 +/- 1.8 photon counts/msec) than in
      the second group (6.4 +/- 0.8 photon counts/msec) and in the third group (6.3 +/-
      0.7 photon counts/msec). CONCLUSION: It is possible that liquefaction of after
      cataract and disruption of the blood-aqueous barrier may be related.

PMID- 15177613
TI  - Simultaneous bilateral cataract surgery: a retrospective survey.
AB  - PURPOSE: To evaluate patient satisfaction and functional visual outcome, safety,
      and visual and refractive outcomes of simultaneous bilateral cataract surgery
      (SBCS). SETTING: North Karelia Central Hospital, Joensuu, Finland. METHODS: A
      retrospective external review of 200 patients drawn randomly from 637 patients
      who underwent SBCS at the North Karelia Central Hospital in 2001 was performed.
      Of the 200 eligible patients, 141 who returned a completed questionnaire on
      patient satisfaction and functional visual outcome of SBCS were enrolled.
      Postoperative refraction and best corrected visual acuity (BCVA) were available
      in 148 eyes of 74 patients. RESULTS: The surgery was carried out under topical
      anesthesia, and 98% were outpatient surgeries. No serious intraoperative or
      postoperative complications occurred. Of the 141 patients, 96% (95% confidence
      interval [CI]: 91-98) experienced SBCS as positive or quite positive, 89% (95%
      CI: 83-94) felt safe to go home after the surgery, and 91% (95% CI: 85-95) would
      recommend SBCS to their relatives or friends. The mean visual functioning index
      (VF-7 score) was 87.3 (median 95). Postoperative BCVA was 20/40 or better in 84%
      (95% CI: 77-89) and 20/25 or better in 66% (95% CI: 57-73) of the 148 eyes
      examined. The postoperative refraction was +/-0.75 diopter (D) of the target
      value in 78% (95% CI: 71-85) and +/-1.5 D in 95% (95% CI: 91-98), and the mean
      anisometropia was 0.26 D (SD 0.6 D, range 0-1.65). CONCLUSION: This study
      provides evidence that SBCS by experienced surgeons is likely to be a safe and
      efficient procedure and is positively received by patients.

PMID- 15177615
TI  - Single-piece AcrySof in the newborn rabbit eye.
AB  - PURPOSE: To evaluate the behavior of the single-piece AcrySof SA30AT intraocular
      lens (IOL) (Alcon) in the eyes of newborn rabbits and to compare the
      postoperative complications in aphakic and pseudophakic eyes. SETTING: St. Erik's
      Eye Hospital, Stockholm, Sweden. METHODS: Clear lens extraction was performed in
      both eyes of 20 3-week-old rabbits. In 1 randomly selected eye in each rabbit, a
      single-piece acrylic IOL was implanted. Preoperatively and 1 and 2 months
      postoperatively, axial length and corneal diameter were measured. Corneal
      thickness was measured at the endpoint. The rabbits were also examined
      clinically; the position of the IOL and signs of secondary glaucoma were noted.
      At 2 months, the 19 surviving animals were killed. In 10 rabbits, the wet mass of
      the after-cataract was measured, and the eyes of 9 rabbits were fixed in formalin
      for histologic evaluation. RESULTS: One animal died soon after surgery. Three
      rabbits developed secondary glaucoma in the aphakic eye. No rabbit developed
      glaucoma in the pseudophakic eye. In the 16 animals without secondary glaucoma,
      there were no significant differences in corneal diameter at 1 and 2 months or in
      corneal thickness at the endpoint; the axial length was significantly longer in
      aphakic eyes at 1 month, but not at 2 months. The aphakic eyes developed more
      posterior synechias and the pupil size at 1 and 2 months was significantly
      smaller in aphakic eyes than in pseudophakic eyes. Significantly more after
      cataract developed in aphakic eyes than pseudophakic eyes (eyes with secondary
      glaucoma included). No difference in inflammation was seen between eyes in the
      histologic evaluation. In 11 of 19 pseudophakic eyes, the anterior capsulorhexis
      was not completely on the optic. In these eyes, the optic moved partly forward
      into the anterior chamber. CONCLUSION: The single-piece AcrySof SA30AT IOL seems
      to induce less inflammation and probably inhibits secondary glaucoma. It does not
      retard eye growth as much as previously tested IOLs. However, it is important to
      keep the entire capsulorhexis margin on the optic, especially in these small
      eyes.

PMID- 15177616
TI  - Effect of intracameral injection of lidocaine and carbachol on the rabbit corneal
      endothelium.
AB  - PURPOSE: To determine the effect of intracameral injection of preservative-free
      lidocaine 1% and carbachol 0.01% on corneal endothelial cells of rabbits.
      SETTING: Department of Ophthalmology, National Taiwan University Hospital,
      Taipei, Taiwan. METHODS: Forty eyes of 20 New Zealand White rabbits were divided
      into 2 equal groups. In the first group, 1 eye was injected with 0.02 mL of
      preservative-free lidocaine 1% and the fellow eye was injected with 0.02 mL of
      normal saline as a control. In the second group, 1 eye was injected with 0.02 mL
      of carbachol 0.01% and the fellow eye was injected with 0.02 mL of normal saline.
      Specular microscopy was used to evaluate corneal endothelial cell loss and
      corneal thickness 1 week and 1 month postinjection. For morphologic studies,
      corneal buttons were excised and stained with alizarin red with trypan blue.
      Scanning electron microscopy (SEM) examination was performed. RESULTS: Specular
      microscopy revealed no significant endothelial cell loss and normal endothelial
      thickness with the intracameral injection of preservative-free lidocaine 1% and
      carbachol 0.01% compared with the control eye. Alizarin red with trypan blue
      stain and SEM examinations revealed smooth, distinct, and intact intercellular
      borders and normal viability of corneal endothelial cells in both groups.
      CONCLUSIONS: Intracameral injections of preservative-free lidocaine 1% and
      carbachol 0.01% do not produce morphologic and functional changes in the corneal
      endothelial cells of rabbits.

PMID- 15177617
TI  - Single-piece hydrophobic acrylic intraocular lens explanted within the capsular
      bag: case report with clinicopathological correlation.
AB  - A 74-year-old woman had uneventful phacoemulsification with implantation of a
      single-piece hydrophobic acrylic intraocular lens (IOL) (SA30AL) in her left eye.
      Two weeks after the surgery, the patient presented for ophthalmological
      consultation reporting pseudophakic dysphotopsia, which she had subjectively
      noted since surgery. Explantation/exchange of the IOL was performed 3 months
      after the surgery. The IOL was strongly attached to the capsule, which was
      fibrotic and contracted; explantation of the capsular bag complex in toto was
      done. To our knowledge, this is the first case of explantation of this IOL design
      with clinicopathological correlation.

PMID- 15177618
TI  - Retained IOL fragment and corneal decompensation after pseudophakic IOL exchange.
AB  - A 72-year-old man had exchange of a foldable silicone multifocal intraocular lens
      (IOL) by transection, removal, and monofocal IOL replacement. One month after the
      exchange, irreversible corneal edema developed and penetrating keratoplasty was
      performed. At the time of the corneal transplant, a small silicone fragment was
      discovered in and removed from the anterior chamber. Histologic evaluation of the
      patient's cornea demonstrated an absence of corneal endothelium, suggesting the
      fragment was the etiology of the corneal decompensation.

PMID- 15177620
TI  - Unusual presentation of angle-closure glaucoma treated by phacoemulsification.
AB  - We report the case of a 70-year-old woman with a history of acute primary angle
      closure glaucoma (PACG) in the left eye who, 2 hours after a fundus examination
      and mydriasis, experienced acutely elevated intraocular pressure (IOP) up to 40
      mm Hg in the presence of fully dilated pupil and a patent iridotomy. Gonioscopy
      revealed appositional angle closure in 3 quadrants. After medical control of the
      IOP, sutureless cataract surgery was performed, including clear corneal incision,
      phacoemulsification, and soft acrylic posterior chamber intraocular lens (IOL)
      implantation. Eighteen months after the operation, improvement of visual acuity,
      widening of anterior chamber angle, and deepening of anterior chamber depth were
      found. Intraocular pressures are now normal without medication, even after
      mydriasis. Modern cataract surgery is an effective treatment for selected
      patients with appositional angle closure and IOP elevation after acute PACG.

PMID- 15177619
TI  - Diffuse lamellar keratitis and corneal edema associated with viral
      keratoconjunctivitis 2 years after laser in situ keratomileusis.
AB  - A 47-year-old woman with a history of laser in situ keratomileusis (LASIK) 2
      years previously for myopia and astigmatism, presented with bilateral loss of
      vision due to diffuse lamellar keratitis (DLK) with corneal edema in the context
      of a pseudomembranous viral keratoconjunctivitis. After intense and early
      treatment with topical corticosteroids, the corneal edema and DLK resolved and
      corneal transparency was achieved with complete restoration of visual acuity.
      This case shows that DLK may occur associated with a viral pseudomembranous
      keratoconjunctivitis in patients who have had LASIK. Diffuse lamellar keratitis
      may present up to 2 years after lamellar surgery, which would indicate that the
      plane created by the microkeratome at the interface may remain unhealed for at
      least this period of time. Early diagnosis and treatment with topical
      corticosteroids can achieve complete resolution without visual loss.

PMID- 15177621
TI  - Histological observation of complete closure of anterior capsulotomy in 2 cases.
AB  - We report the histological finding of complete closure of the anterior
      capsulotomy window in 2 cases. The cases were successfully treated with surgery
      after neodymium:YAG laser anterior capsulotomy failed. Histology and
      immunohistochemistry were performed to determine the pathogenesis. Histology
      revealed the presence of elongated, fibroblast-like lens epithelial cells in
      association with extracellular matrix accumulation, which were positive for
      collagen types, fibronectin, and osteopontin. The cells were labeled with anti
      alpha-smooth muscle actin antibody. The finding indicates that phenotypic
      modulation in lens epithelial cell to contractile cell type and accumulation of
      matrix are involved in closure of the anterior capsulotomy window.

PMID- 15177622
TI  - Eccentric capsulorhexis and postoperative dysphotopsia following
      phacoemulsification.
AB  - We report a case of troublesome visual symptoms or dysphotopsia in a 68-year-old
      patient after right phacoemulsification and implantation of a 3-piece AcrySof(R)
      MA60BM acrylic intraocular lens (IOL) (Alcon) in the capsular bag. The patient
      described multiple horizontal streaks in dim lighting conditions with light
      sources in the right temporal visual field. The anterior capsulorhexis was
      eccentric, leaving the nasal optic edge and site of polypropylene haptic
      insertion uncovered by the semi-opaque anterior capsule and the probable source
      of the flare images. Miotic therapy was poorly tolerated and IOL exchange
      declined. The case illustrates the importance of creating a central capsulorhexis
      smaller than the IOL optic to reduce the risk photic phenomena and edge effect
      with square-edged IOLs.

PMID- 15177623
TI  - Complete bilateral vitreous detachment after LASIK retreatment.
AB  - We describe a case of a 47-year-old woman who underwent bilateral laser in situ
      keratomileusis (LASIK) for the correction of myopia and astigmatism. Two months
      later a residual refractive error was present in both eyes. LASIK retreatment was
      decided and performed the following day. Twenty-four hours after the procedure,
      the patient reported myodesopsia in both eyes. Funduscopic examination revealed a
      complete bilateral posterior vitreous detachment confirmed by kinetic ultrasound.
      Visual disturbance in both eyes continued to be present after 10 months of follow
      up. Sudden changes in intraocular pressure related to suction ring use might be
      the cause of posterior vitreous detachment in this patient.

PMID- 15177624
TI  - Enzymatic anterior capsulotomy in cataract surgery: an experimental rabbit study.

PMID- 15177625
TI  - A practical device to aid in immersion a-scan biometry.

PMID- 15177626
TI  - X-ray mapping technique: a preliminary study in discriminating gunshot residue
      particles from aggregates of environmental occupational origin.
AB  - The possibility of detection of lead-antimony-barium aggregates from non-firearm
      sources is confirmed according to the tests performed on brake pads, and firework
      and automobile workers. Moreover, information on particles taken from cartridge
      cases shows the relative feeble importance of the morphology in distinguishing
      gunshot residues (GSRs). Furthermore, also the presence in the spectrum of other
      elements (e.g., iron) is not so conclusive. In this panorama, the possibility of
      discriminating gunshot residue particles from other non-firearm lead-antimony
      barium aggregates is investigated: the proposed method is based on X-ray mapping
      technique--currently applied used in Reparto Carabinieri Investigazioni
      Scientifiche in Rome, the forensic service of Italian Carabinieri--according to
      which the spatial distribution of the emission energy of each element of the
      sample is pictured. Gunshot residues present the same lead-antimony-barium
      distribution (or at least the same antimony-barium distribution with lead
      nodules), as some other environmental occupational aggregates do not (different
      plaques of lead, antimony, and barium). So, X-ray mapping technique can offer a
      new fundamental evaluation parameter in analysis of gunshot residues with
      scanning electron microscopy/energy-dispersive (SEM/EDS) spectrometry, and new
      standards could be considered.

PMID- 15177627
TI  - On-site testing of illicit drugs: the use of the drug-testing device "Toxiquick".
AB  - Since 1998, driving under the influence of drugs such as amphetamine, MDMA, MDE,
      cannabis, cocaine, heroine and morphine is sanctioned due to Section 24a of the
      Road Traffic Regulations of Germany. Therefore, from December 2000 to June 2002
      altogether 751 roadside tests with the immunochemical test device Toxiquick were
      conducted on 302 drivers (273 male and 29 female) on oral fluid samples obtained
      during control actions in Franconia. The results of the tests are compared to the
      results obtained through quantification of corresponding blood samples by GC/MS.
      In general, in 75% the roadside test produced correct results and therefore gave
      helpful assistance to the police officers into the right direction regarding drug
      abuse. Except for cannabinoids, the number of false negative results was
      relatively small, whereas false positive results ranged between 32.2% for opiates
      and 10.7% for benzoylecgonine.

PMID- 15177629
TI  - False homozygosities at various loci revealed by discrepancies between commercial
      kits: implications for genetic databases.
AB  - Routine control of 2055 consecutive genotypes revealed discrepancies between the
      profiles established with the SGM plus and/or Profiler plus kits on one hand, and
      the profiles established with the Powerplex16 kit on the other hand. Furthermore,
      five discrepancies for vWA, three for D8S1179, two for FGA and three for D18S51
      loci were found. In 10 cases (loci vWA, FGA, D18S51, D8S1179), the SGM plus
      and/or Profiler plus profiles showed homozygosity and the Powerplex16 genotype
      revealed heterozygosities which were confirmed to be true, both by typing with
      individual primer pairs and DNA sequencing. In four cases (two discrepancies at
      locus FGA, one at D18S51 and an abnormal paternity pattern for D5S818), the
      Powerplex16 kit showed apparent homozygosity and the SGM plus and/or Profiler
      plus kits showed heterozygosity. Mutation analysis could be performed for some of
      these individuals and evidenced variants, presumably leading to an annealing
      failure of one primer; the identified mutations are reported. It is suggested
      that databases should include information about the kits used to determine the
      profiles while ensuring that the primer sequences are made available.

PMID- 15177630
TI  - Fatal intoxications in a Swedish forensic autopsy material during 1992-2002.
AB  - Compilations of substances detected in fatal intoxications are important in order
      to observe changes in intoxication patterns, to monitor effects of preventive
      work and to discover new trends in drug usage. The aim of the present study was
      to describe the current pattern of substances detected in fatal intoxications in
      Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry,
      Linkoping, Sweden, during 1992-2002, were analysed. All suicides, uncertain cases
      and accidents where the cause of death were fatal intoxications (ICD-9: E950,
      E980 and E859) were included and substances detected in more than 50 fatal
      intoxications (in femoral blood) were listed. For each substance, a cut off value
      was set, above which concentrations were considered toxic. Fatal intoxications
      were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic
      autopsies during the study period. Among the suicides, an average of 3.8
      substances were detected per case, the corresponding figure for uncertain cases
      and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the
      most frequently detected substance, detected in 43% (3039) of the fatal
      intoxications, of which 32% (960) had toxic concentrations, followed by
      propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74%
      (1370) had toxic concentrations. The number of cases where ethanol and
      propoxyphene were detected decreased during the study period. Moreover, other CNS
      active drugs such as antidepressants, analgesics and anxiolytics were also
      frequently detected. The drugs with high proportions of cases with toxic
      concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol,
      alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin
      reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in
      12% (833) and 10% (665), respectively. A significantly (P <0.001) higher
      proportion of cases where TCA were detected had toxic concentrations when
      compared with cases where SSRI were detected (64% versus 31%).

PMID- 15177631
TI  - Allele distribution of 15 PCR-based loci in the Rwanda Tutsi population by
      multiplex amplification and capillary electrophoresis.
AB  - A genetic study of 15 autosomal STRs is carried out (D2S1338, D3S1358, D5S818,
      D7S820, D8S1 79, D13S317, D16S359, D18S51, D19S433, D21S11, CSF1PO, FGA, TPOX,
      THO1, VWA) in a sample of unrelated Tutsis. The molecular phenotypes were
      determined by means of multiplex strategies (AmpFlSTR Identifiler PCR
      Amplification Kit, Applied Biosystems) followed by capillary electrophoresis.

PMID- 15177632
TI  - Y-chromosome STR haplotypes and alleles in the population sample of Old Believers
      residing in the Northeastern Poland.
AB  - Haplotype and allele frequencies for eight Y-STRs were determined in a population
      sample of Old Believers residing in the Northeastern Poland. A total of 127
      unrelated males produced 100 different haplotypes. The most common haplotype was
      shared by 3.97% of the sample, while 85 haplotypes were unique. The gene
      diversity was 0.99.

PMID- 15177633
TI  - Nineteen autosomal microsatellite data from Antioquia (Colombia).
AB  - Allele frequencies for 19 autosomal STRs (F13A01, FESFPS, F13B, LPL, D5S818,
      D7S820, THO1, TPOX, VWA31, CSF1P0, D16S539, D13S317, D3S1358, D8S1179, FGA, PENTA
      D, PENTA E, D21S11, D18S51) were estimated from a sample between 364 and 400
      unrelated individuals living in the northern department of Antioquia.

PMID- 15177634
TI  - Special issue: Festschrift dedicated to Christian Hodel.

PMID- 15177635
TI  - Safety evaluation of cosmetics in the EU. Reality and challenges for the
      toxicologist.
AB  - Council Directive 76/768/EEC, its seven amendments and 30 adaptations to
      technical progress form the basis of the cosmetic EU legislation today. There are
      actually four key principles for safety in the cosmetic legislation. (i) The full
      responsibility for the safety of cosmetics for human health is placed on the
      manufacturer, first importer in the EU or marketer. (ii) The safety evaluation of
      finished products is based on safety of individual ingredients, more specifically
      on their chemical structure, toxicological profile and their level of exposure.
      (iii) A compilation of information on each cosmetic product (dossier) must be
      kept readily available for inspection by the competent authorities of the Member
      State concerned. This information source, usually called a technical information
      file (TIF) or product information file/requirements (PIF(R)), contains, as the
      most important part, the safety assessment of the product undersigned by a
      competent safety assessor. (iv) The use of validated replacement alternative
      methods instead of animal testing forms the 4th key principle for safety of
      cosmetic products on the EU market. The 7th amendment imposes strict deadlines
      for the abolition of animal in vivo studies on cosmetic ingredients. These legal
      requirements induce a number of important challenges for the cosmetic industry
      and more specifically for the toxicologist involved as safety assessor.

PMID- 15177636
TI  - Good Evaluation Practice: a proposal of guidelines.
AB  - The intention of this proposal is to describe principles for Good Evaluation
      Practice (GEP) of toxicological and risk evaluations with the aim to improve the
      quality, reliability, and transparency of any evaluation in toxicology. The GEP
      has been outlined in the same way as the principles for Good Laboratory Practice
      (GLP) to facilitate its introduction and compliance. The main characteristic of
      GEP is transparency. The GEP procedure should include the following elements: (1)
      definition of terms; (2) description of evaluation organization; (3) description
      of the quality assurance of the programme; (4) description of the standard
      evaluation procedures; (5) performance of the evaluation; (6) reporting of the
      evaluation; (7) storage and retention of records and material; and (8) guidelines
      for the evaluation procedure. The authors' intent is to raise awareness,
      stimulate a debate about the proposal, expect and welcome feedback in order to
      refine it, and make it into an important tool for all toxicological evaluations
      in the future.

PMID- 15177637
TI  - Safety pharmacology: an essential interface of pharmacology and toxicology in the
      non-clinical assessment of new pharmaceuticals.
AB  - Safety pharmacology studies are defined as the studies that investigate the
      potential undesirable pharmacodynamic effects of a substance on physiological
      functions in relation to exposure. In consequence, these studies are an integral
      part of the non-clinical safety assessment of new pharmaceuticals, in association
      with toxicological studies. A retrospective shows the evolution of the discipline
      in these last years. Safety pharmacology studies are of special interest, and
      some drawbacks and pitfalls must be considered (i.e. invasive methods,
      difficulties related to GLP (good laboratory practices) requirements, choice of a
      strategy). In the future, some priority should be given to education, promotion
      of scientific activities, reinforcement of the links between pharmacologists and
      toxicologists and implementation of relevant guidelines.

PMID- 15177638
TI  - Carcinogenicity categorization of chemicals-new aspects to be considered in a
      European perspective.
AB  - Existing systems of classification of carcinogens are a matter of discussion,
      world-wide. There is agreement that it should be distinguished between genotoxic
      and non-genotoxic chemicals. The risk assessment approach used for non-genotoxic
      chemicals is similar among different regulatory bodies: insertion of an
      uncertainty (safety) factor permits the derivation of permissible exposure levels
      at which no relevant human cancer risks are anticipated. For genotoxic
      carcinogens, case studies of chemicals point to a whole array of possibilities.
      Positive data of chromosomal effects only, in the absence of mutagenicity, may
      support the characterization of a compound that produces carcinogenic effects
      only at high, toxic doses. Non-DNA-reactive genotoxins, such as topoisomerase
      inhibitors or inhibitors of the spindle apparatus are considered in this respect.
      In such cases, arguments are in favour of the existence of "practical"
      thresholds. Taking existing concepts together, it is proposed to basically
      distinguish between "perfect" and "practical" thresholds. There is a wide
      consensus that for non-DNA-reactive genotoxins such as aneugens (aneuploidy,
      chromosome loss, non-disjunction) thresholds should be defined. It is being
      discussed as to whether the identification of possible threshold effects should
      also include other mechanisms of genotoxicity, in addition to aneugenic effects.
      Specific mechanisms of clastogenicity have been repeatedly addressed as also
      having thresholds, such as topoisomerase II poisons or mechanisms based on
      reactive oxygen. Oxidative stress as an important mechanism is triggered by
      exposure to exogenous factors such as ultraviolet (UV) and ionizing radiation,
      anoxia and hyperoxia, and by chemicals producing reactive oxygen species. The
      idea is receiving increased support that reactive oxygen species (ROS)-mediated
      processes of carcinogenesis have practical thresholds. Since reactive oxygen
      species are genotoxic in principle, questions arise whether chemicals that
      increase ROS production will superimpose to an endogenously produced background
      level of DNA lesions, related to mechanisms that may result in non-linear dose
      effect relationships. The existence of "endogenous" DNA adducts has been
      generally accepted, and possible regulatory implications of the presence of
      endogenous carcinogens have been discussed. It is now becoming evident that a
      diversity of methods of carcinogenic risk extrapolation to low doses must be
      considered, dependent on the mode of action. Although there is an increasing
      international awareness of these developments, the system of classification of
      carcinogens of the European Union still remains static. This should be changed,
      as the philosophy of separation of a strictly sequential "hazard assessment" and
      "risk assessment" appears out-of-date.

PMID- 15177639
TI  - Risk assessment of peak exposure to genotoxic carcinogens: a pragmatic approach.
AB  - Short-term exposures to relatively high concentrations or doses are a regular
      cause of concern. Since carcinogenicity is often of great personal and social
      relevance the question arises whether short-term exposure (1-10 days) to a
      carcinogenic substance may contribute to tumour development and, if so, whether
      this contribution to the cancer risk can be quantified. The present object was to
      explore the possibility of a pragmatic estimation of the cancer risk of peak
      exposure to a genotoxic carcinogen relative to the cancer risk of the same
      cumulative dose of this carcinogen distributed over lifetime. A report published
      by the Health Council of The Netherlands served as point of departure. Published
      data strongly suggests that short-term or single exposure can indeed give rise to
      tumour formation in animal experiments. The application of a dose-rate correction
      factor (DRCF), defined as a factor by which the tumour incidence caused by a
      specific dose of a chemical carcinogen at low-dose rates is multiplied to derive
      the tumour incidence at high-dose rates, appears to be a feasible approach.
      Theoretical models calculated maximum values for the DRCF of up to seven for a
      young child acutely exposed to an initiator or first-stage carcinogen. A maximum
      value of 8.3 was calculated from animal experiments. A decision tree is presented
      which allows the pragmatic assessment of the carcinogenic risk following short
      term exposure to genotoxic carcinogens. It is recommended to validate this
      decision tree with model-substances.

PMID- 15177640
TI  - Dioxins, dioxin-like PCBs and non-dioxin-like PCBs in foodstuffs: occurrence and
      dietary intake in The Netherlands.
AB  - Data on occurrence of dioxins (polychlorinated dibenzo-p-dioxins [PCDDs] and
      dibenzofurans [PCDFs]), dioxin-like PCBs (polychlorinated non-ortho and mono
      ortho biphenyls) and non-dioxin-like PCBs (as represented by the so-called
      indicator-PCBs: congeners 28, 52, 101, 118, 138, 153 and 180) in food products
      consumed in The Netherlands that were collected in measurement programs carried
      out during 1998 and 1999, and combined with food consumption data to assess the
      dietary intake of these persistent food contaminants. The estimated median life
      long-averaged intake of the sum of dioxins and dioxin-like PCBs in the population
      is 1.2 pg WHO-TEQ (toxic equivalents) per kg body weight (bw) per day, while the
      estimated median life-long-averaged intake of indicator-PCBs is 5.6 ng per kg bw
      per day. The contribution of different food groups to the total intake of both
      dioxins + dioxin-like PCBs and non-dioxin-like PCBs is fairly uniformly
      distributed over the foods consumed: meat products (23% and 27%, respectively),
      dairy products (27% and 17%, respectively), fish (16% and 26%, respectively),
      eggs (4% and 5%, respectively), vegetable products (13% and 7%, respectively),
      and industrial oils and fats (17% and 18%, respectively). Compared with earlier
      intake estimations the present estimation shows a continued reduction in the
      intake of dioxins as well as PCBs. This reduction is related to the decrease in
      the concentration of these substances in the majority of foodstuffs.
      Nevertheless, a small part of the population still has a rather high life-long
      averaged intake: 8% of the population is exposed to intake levels above the
      tolerable weekly intake for dioxins and dioxin-like PCBs of 14 pg WHO-TEQ per kg
      bw per week, as recently derived by the Scientific Committee on Food of the
      European Commission. For the non-dioxin-like PCBs an internationally accepted
      maximum intake level is still lacking. However, to provide risk managers with a
      health-based guideline to prevent health effects of exposure to non-dioxin-like
      PCBs, the (international) derivation of a tolerable daily intake is recommended.
      Monitoring the dietary intake of PCBs is just as important as monitoring the
      intake of dioxins and dioxin-like PCBs, and attempts to decrease the exposure to
      both compound classes need continuous attention.

PMID- 15177641
TI  - Heavy metals (Ni, Cr, Cu) in the Karoon waterway river, Iran.
AB  - Environmental pollution is a world-wide problem, heavy metals belonging to the
      most important pollutants. The progress of industries has led to increased
      emission of pollutants into ecosystems. Karoon is the biggest and only navigable
      river in the South of Iran. Along the Karoon industrial units such as piping,
      steel, paint making, agriculture, paper mill, fish cultivation, abbottiors,
      electroplating industries drain their wastewater into the river. In this study,
      the concentrations of heavy metals (Ni, Cr, Cu) in the Karoon river have been
      determined. Samples were collected from 16 stations along the river, in winter
      and spring 1996. Heavy metal concentrations were measured by graphite furnace
      atomic absorption spectrometry. The minimal and maximal concentrations of these
      metals in winter were 69.3-110.7, 1.7-118.3, and 5.5-70.3 microg/l, for Ni, Cr,
      and Cu, respectively. The minimal and maximal concentrations of these metals in
      spring were 41.0-60.7, 0.7-19.8, and 0.5-28.7 microg/l, for Ni, Cr, and Cu,
      respectively. The results show that the pollution has increased along the river,
      down to the estuary at the Persian Gulf.

PMID- 15177642
TI  - Response of rat alveolar type II cells and human lung tumor cells towards
      oxidative stress induced by hydrogen peroxide and paraquat.
AB  - The expression of MDR1b coding mRNA is increased in alveolar type II cells from
      juvenile rat lung in culture. Hydrogen peroxide and paraquat-induced further
      upregulation supporting that oxidative stress mediated mechanisms are involved in
      the regulation of MDR1b in rat lung. The expression rates of mRNA for catalase,
      Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and Mn-superoxide dismutase (Mn-SOD)
      remains constant during culture and were not modulated by hydrogen peroxide or
      paraquat. Thus, antioxidative enzymes in primary A II cells from rat lung are not
      regulated by reactive oxygen species dependent mechanisms. Primary A II cells
      were substantially more sensitive towards paraquat-induced cytotoxicity and lipid
      peroxidation than the permanent human lung tumor cell lines H322 and H358. A 100
      microM hydrogen peroxide for 2h induces substantial DNA damage which is not
      paralleled by an increased rate of lipid peroxidation. The expression rate of
      mRNA coding for catalase and Mn-SOD was not changed and almost the same is true
      for the activity of catalase and Cu/Zn-SOD. Only 50 microM paraquat induced a
      significant decrease in catalase activity and an increase in Cu/Zn-SOD activity.

PMID- 15177643
TI  - The effect of curcumin on cadmium-induced oxidative damage and trace elements
      level in the liver of rats and mice.
AB  - The present study was designed to investigate in acute animal experiments the
      effects of oral curcumin pre-treatment (50 mg/kg body weight per day for 3 days)
      on liver oxidative damage and trace element changes caused by cadmium chloride
      administration (0.025 mmol/kg to rats and 0.03 mmol/kg to mice, s.c., 1h after
      the last curcumin treatment). In rats, the level of Cd-induced lipid peroxidation
      (320% of controls) was significantly lowered by curcumin pre-treatment (165% of
      controls), and was accompanied by significant increase of glutathione (GSH) level
      in both Cd-treated and Cd plus curcumin-treated group. In mice, the Cd-induced
      lipid peroxidation (125% of controls) was abolished by curcumin treatment.
      Concurrently, a depletion of GSH was found in the liver of both Cd-treated (67%
      of controls) and Cd plus curcumin-treated mice (54% of controls). Curcumin
      treatment did not change cadmium (Cd) distribution and did not cause systematic
      alterations in trace element status.

PMID- 15177644
TI  - Modulation of glucose uptake in glial and neuronal cell lines by selected
      neurological drugs.
AB  - Glucose is the main energy source of brain cells. The transport of glucose across
      the cell membrane is the first step of its utilization. Any modification in
      glucose uptake capacity may cause deleterious effects on neural cell functions.
      In the present study, 3-O-methyl-D-glucose (3-OMG) uptake and its modulation by
      selected neurological drugs (amitriptyline, selegiline, carbamazepine and
      phenytoin) were studied in differentiated (with retinoic acid and 12-O
      tetradecanoyl phorbol 13-acetate) and undifferentiated neuroblastoma SH-SY5Y and
      astrocytoma U-373 MG cell lines, using tracer methods. The expression of glucose
      transporters was studied by immunocytochemistry. SH-SY5Y and U-373 MG cells
      showed differences both in their glucose uptake properties and in the modulation
      of glucose uptake by the drugs, which might reflect different specialization of
      neuronal and glial cells in vivo. While selegiline and amitriptyline had a minor
      and variable effect on 3-OMG uptake in all cell cultures, the anticonvulsants
      carbamazepine and phenytoin increased 3-OMG uptake in U-373 MG cells, but
      decreased that in SH-SY5Y cells. Differentiated SH-SY5Y cells were more sensitive
      to the effects of the anticonvulsants than undifferentiated SH-SY5Y cells. The
      results suggest that, the cell lines are promising neural models for the
      evaluation of drug side effects due to disturbances in glucose uptake.

PMID- 15177645
TI  - Interaction of mercury(II) with the microtubule cytoskeleton in IMR-32
      neuroblastoma cells.
AB  - On the background of the neurotoxicity of mercury compounds, the interaction of
      mercury(II) with the cytoskeleton was investigated in vitro using IMR-32
      neuroblastoma cells. Conditions for culture of these cells on microscopic slides
      and procedures for immunofluorescence staining of the microtubule network were
      optimised. Both morphology and viability of IMR-32 cells were affected by
      mercury(II) at concentrations higher than 15 microM. Pronounced disintegration of
      the microtubule cytoskeleton was detected at 30 microM mercury(II). Compared to
      previous studies with fibroblasts, the no-observed-effect concentration was
      markedly lower, pointing to a particular sensitivity of nerve cells to mercury.
      This could be due to disturbed information transfer processes depending on an
      intact microtubule system.

PMID- 15177646
TI  - The thiol reactivity of the oxidation product of 3,5,7-trihydroxy-4H-chromen-4
      one containing flavonoids.
AB  - Flavonoids are assumed to have beneficial effects due to their antioxidant
      properties. The catechol moiety present in numerous flavonoids is oxidized during
      the antioxidative reaction yielding a quinone. Quinones are toxic due to their
      ability to react, e.g. with thiol groups. The 3,5,7-trihydroxy-4H-chromen-4-one
      group is another antioxidant pharmacophor in certain flavonoids. During the
      antioxidative reaction this group is also oxidized. The aim of the present study
      is to determine the thiol reactivity of this oxidized group. Galangin is a
      flavonoid that only contains the 3,5,7-trihydroxy-4H-chromen-4-one group as the
      antioxidant pharmacophor. Incubation of galangin with horseradish
      peroxidase/H(2)O(2) leads to an oxidation product which after addition of
      glutathione is instantaneously converted to an adduct. Based on these results it
      is expected that--similar to the catechol containing antioxidants--the 3,5,7
      trihydroxy-4H-chromen-4-one containing antioxidants shift the damage provoked by
      oxidative stress from lipid peroxidation to thiol arylation. This should be
      considered in application of these types of antioxidants.

PMID- 15177647
TI  - Genotoxicity of hormonal steroids.
AB  - Hormonal steroids have a widespread use in medicine and their side effects are
      continuously debated. The possible genotoxic activity of steroids has been the
      subject of many investigations. The natural estrogens estradiol, estrone and
      estriol are generally negative in the ICH core battery of tests, but several
      positive results have been obtained when using additional endpoints of
      genotoxicity. The genotoxic activity of the 4-hydroxy metabolites of estradiol
      and estrone is well established. The synthetic steroidal estrogens have a
      comparable profile of negative and positive test results. Cyproterone acetate and
      some of its analogues have a special position within the group of progestins.
      Their genotoxic potential has been established. Other progestins are generally
      negative in the routine tests. Anti-glucocorticoids, anti-progestins,
      corticosteroids, androgens, anabolics and anti-androgens appear to be devoid of
      genotoxic activities. The genotoxic potential of estradiol, estrone and
      cyproterone acetate with its analogues may play no role under normal
      physiological and therapeutic conditions. The metabolic conditions that are
      needed for the formation of DNA-reactive metabolites and oxygen radicals may not
      be present in humans. Epidemiological cancer data seem to support this view. The
      importance of thresholds in the dose-effect-relationship of genotoxicity data and
      their use in risk assessment is discussed.

PMID- 15177648
TI  - Comparative metabolic activation of benzidine and N-acetylbenzidine by
      prostaglandin H synthase.
AB  - Benzidine and N-acetylbenzidine are activated to genotoxic metabolite(s) within
      the urothelial target tissue, with phase-I and phase-II enzymes being relevant.
      In principle, both benzidine and N-acetylbenzidine are activated by prostaglandin
      H synthase (PHS) to reactive intermediates. However, the relative impacts of
      benzidine and N-acetylbenzidine in this process remain unclear. Two experimental
      in vitro systems were used in the present comparative investigation: ram seminal
      vesicle microsomes rich in PHS and porcine urinary bladder epithelial cells
      (PUBEC) as a model system mimicking the general metabolic situation within the
      human urothelium. Benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine were
      incubated with ram seminal vesicle microsomes and arachidonic acid and control
      incubations were performed with heat-inactivated microsomes. The metabolic
      disappearance of benzidine, N-acetylbenzidine or N,N'-diacetylbenzidine indicated
      a rapid turnover by PHS of benzidine and a slower turnover of N-acetylbenzidine.
      There was almost no PHS-associated metabolism of N,N'-diacetylbenzidine,
      suggesting that diacetylation of benzidine could represent a pathway of
      biological inactivation. Under similar conditions, incubations were performed
      with ram seminal vesicles and benzidine or N-acetylbenzidine upon addition of
      calf thymus DNA. After re-isolation of the DNA and 32P-postlabeling, with
      benzidine 2 distinct adducts were found of unknown nature, and with N
      acetylbenzidine a single adduct appeared with co-migrated with the N'-(3'
      monophosphodeoxyguanosin-8-yl)-N-acetylbenzidine. PUBEC cells were also incubated
      with benzidine or N-acetylbenzidine. No DNA adduct was found with benzidine, but
      a total of five adducts was produced from N-acetylbenzidine. The major adduct
      again co-migrated with N'-(3'-monophosphodeoxyguanosin-8-yl)-N-acetylbenzidine.
      When benzidine was incubated with PUBEC cells N-acetylbenzidine and, with some
      delay, N,N'-diacetylbenzidine were formed. Application of Lineweaver-Burk plots
      for the formation of N-acetylbenzidine from benzidine revealed a K(m) of 56.4
      microM and a Vmax of 7.05 nmol/h per 10(6) PUBEC cells. The investigations
      generally support a key role of N-acetylbenzidine at the target site of the
      urothelium.

PMID- 15177649
TI  - The modulating effects of quercetin and rutin on the mitomycin C induced DNA
      damage.
AB  - The present study was carried out to investigate the modulating effects of the
      two flavonoids quercetin and rutin on the mutagenic anticancer drug mitomycin C
      by single cell gel electrophoresis (Comet assay) in human lymphocytes.
      Lymphocytes were incubated with different concentrations of quercetin and rutin,
      with or without mitomycin C, and DNA damage was evaluated. Concentrations of
      0.03, 0.15, 0.3, 0.6, 1.5 and 3mM quercetin significantly reduced the DNA strand
      breakage induced by mitomycin C (P<0.001) but the highest concentration of 6mM
      quercetin did not show a protective effect. The frequency of damaged cells
      induced by mitomycin C was not changed at 0.02 mM, and also at the highest
      concentrations of 1.64 and 3.28 mM rutin. However, at concentrations of 0.08,
      0.16, 0.33 and 0.82 mM rutin cells were protected from DNA damage. Thus, in human
      lymphocytes quercetin and rutin displayed protective effects on DNA damage
      induced by mitomycin C, in a concentration-dependent manner.

PMID- 15177652
TI  - The inhibition of the high sensitive peripheral nerve soluble esterases by
      mipafox. A new mathematical processing for the kinetics of inhibition of
      esterases by organophosphorus compounds.
AB  - In the study of organophosphorus (OP) sensitive enzymes, careful discrimination
      of specific components within a complex multienzymatic mixture is needed.
      However, standard kinetic analysis gives inconsistent results (i.e., apparently
      different kinetic constants at different inhibitor concentration) with complex
      multienzymatic mixtures. A strategy is now presented to obtain consistent kinetic
      parameters. In the peripheral nerve, soluble carboxylesterases measured with the
      substrate phenylvalerate (PV) are found with extremely high sensitivity to some
      inhibitors. Tissue preparations were preincubated with mipafox at nanomolar
      concentrations (up to 100 nM) for different inhibition times (up to 180 min).
      Inhibition data were analyzed with model equations of one or two sensitive
      (exponential) components, with or without resistant components. The most complex
      model was %act=A1e-k1It+A2e-k2It+AR (step 1). From the curve with the highest
      mipafox concentration (100 nM), the amplitude for the resistant component was
      determined as AR=15.1% (step 2). The model equation with a fixed AR value was
      again applied (step 3) to deduce the second-order inhibition rate constants
      (k1=2.6 x 10(6) M-1 min-1 and k2=0.28 x 10(6) M-1 min-1), being conserved
      consistently throughout all mipafox concentrations. Finally, using fixed values
      of AR, k1, and k2, the amplitudes for the two exponential (sensitive) components
      (A1 and A2) were re-estimated (A1=50.2% and A2=34.2%). The operational process
      was internally validated by the close similarity with values obtained by directly
      fitting with a three-dimensional model equation (activity versus time and
      inhibitor concentration) to the same inhibition data. Carboxylesterase fractions
      separated by preparative chromatography showed kinetic properties consistent with
      the kinetically discriminated components. As practical conclusion, for routine
      analysis of esterases in toxicological studies, a simplified procedure using the
      inhibition with mipafox at 30 nM, 1 microM, and 1 mM for 30 min is suggested to
      discriminate the main esterase components in soluble fraction preparations.

PMID- 15177650
TI  - Genotoxicity of the isoflavones genistein, daidzein and equol in V79 cells.
AB  - Hormonally active chemicals in the human diet, such as man-made estrogenic
      chemicals or plant-derived compounds (phytoestrogens), have become a matter of
      public concern. A significant part of human exposure to phytoestrogens is
      attributable to soy isoflavones. Besides their estrogenic properties, soy
      isoflavones also exert genotoxic actions. In this paper, the micronucleus (MN)
      assay in V79 cells was used to study chromosomal genotoxicity. Genistein caused a
      clear dose-related induction of MN within the range of 5-25 microM; MN rates were
      declining at higher genistein concentrations. This was probably due to
      cytotoxicity of genistein since reduced neutral red uptake and MTT formation with
      an IC(50) of about 75 microM occurred. Daidzein induced a comparatively shallow
      increase in the number of MN between 25 and 100 microM. In contrast, the daidzein
      metabolite equol caused an increase in the number of MN up to 25 microM with no
      further increase at higher concentrations. Additional staining with anti
      kinetochore (CREST) antibodies served to determine if the micronuclei contain
      whole chromosomes or acentric fragments. Genistein induced mostly CREST(-)
      micronuclei, i.e. MN with chromosomal fragments, thus indicative of a clastogenic
      mode of action. MN induced by high concentrations of daidzein were partly
      CREST(+) and CREST(-), whilst equol induced mostly CREST(+) micronuclei
      indicative of an aneugenic action. These results point to a differential
      genotoxicity of phytoestrogens.

PMID- 15177651
TI  - Bovine chromaffin cell cultures as model to study organophosporus neurotoxicity.
AB  - Based on the high level of phenyl valerate esterase activities, and in particular
      of neuropathy target esterase (NTE) found in bovine adrenal medulla, chromaffin
      cells culture have been proposed as an alternative model for the study of
      organophosphorus neurotoxicity. Organophosphorus-induced polyneuropathy is a
      syndrome related to the inhibition and further modification by organophosphorus
      compounds of NTE (a protein that displays phenyl valerate esterase activity
      resistant to mipafox and sensitive to paraoxon). Total phenyl valerate esterase
      activities found in homogenate, particulate and soluble fractions of bovine
      adrenal medulla were 5200+/-35, 5000+/-280 and 1700+/-260 mU/g tissue,
      respectively. Cultured chromaffin cells displayed a total hydrolysing activity of
      41+/-5 mU/10(6) cells. Homogenates of bovine adrenal medulla displayed only about
      6% of activity sensitive to paraoxon. Most of the phenyl valerate esterase
      activity inhibited by mipafox (a neuropathy inducing compound) was found in
      particulate fraction. Cultured chromaffin cells displayed kinetics of inhibition
      by mipafox similar to the kinetics displayed by homogenates of bovine adrenal
      medulla. We conclude that NTE could be assayed in this system by only using one
      inhibitor (mipafox) instead of two (paraoxon and mipafox). Also, the proposal is
      supported of using chromaffin cells as in vitro model for the study of the role
      of NTE and related esterases in organophosphorus-induced polyneuropathy.

PMID- 15177653
TI  - Neurobehavioral effects of experimental exposures to low levels of styrene.
AB  - Two experimental studies were conducted with the intention to simulate exposure
      characteristics of work places with styrene exposure and to investigate the risk
      for neurobehavioral impairments. In experiment I 16 volunteers (8 in the morning,
      8 in the afternoon) were exposed to 0.5 and 20 ppm styrene on a constant level
      for 3h. In experiment II 24 volunteers (12 in the morning, 12 in the afternoon)
      were exposed for 4h to 0.5 and 20 ppm styrene on a constant level as well as to a
      changing exposure between 0.5 and 40 ppm with a TWA of 14 ppm. Simple reaction,
      choice reaction, attention, acute symptoms, and ratings for well-being were
      measured. Exposure related performance effects could not be detected. However, 6h
      time change resulted in delayed choice reactions in the morning hours. Analysing
      acute symptoms and the state of well-being the impact of styrene did not reach
      adverse extents of impaired well-being.

PMID- 15177654
TI  - Colour vision and occupational toluene exposure: results of repeated
      examinations.
AB  - Potential effects of human occupational exposures to toluene on colour vision
      were investigated in a follow-up study over 4 years with three repeated
      examinations. Colour vision was measured with the Lanthony desaturated colour
      vision test D-15d, and the colour confusion index (CCI) was calculated. The mean
      current exposures were 26+/-21 ppm for printers (high toluene level) and 3+/-4
      ppm for end-processors (low toluene level). The mean exposure durations were 23+/
      6 years for "long-time exposed" and 7+/-2 years for "short-time exposed"
      subjects. Repeated analyses (n=162) and multiple regressions (maximum available
      n=267) did not reveal significant effects of toluene with respect to intensity or
      duration of current or long-term exposure. Age and occupational qualification
      were significantly associated with CCI in both kinds of analysis, whereas alcohol
      consumption (carbohydrate-deficient transferrin, CDT) and smoking habits
      (cigarettes per day) were not. It is concluded that current industrial exposure
      limits of toluene provide sufficient protection against possible disturbance of
      colour vision.

PMID- 15177655
TI  - Carcinogenicity of azo colorants: influence of solubility and bioavailability.
AB  - In the past, azo colorants based on benzidine, 3,3'-dichlorobenzidine, 3,3'
      dimethylbenzidine (o-tolidine), and 3,3'-dimethoxybenzidine (o-dianisidine) have
      been synthesized in large amounts and numbers. Studies in exposed workers have
      demonstrated that the azoreduction of benzidine-based dyes occurs in man. The
      metabolic conversion of benzidine-, 3,3'-dimethylbenzidine- and 3,3'
      dimethoxybenzidine-based dyes to their (carcinogenic) amine precursors in vivo is
      a general phenomenon that must be considered for each member of this class of
      chemicals. Several epidemiological studies have demonstrated that the use of the
      benzidine-based dyes has caused bladder cancer in humans. However, in contrast to
      water-soluble dyes, the question of biological azoreduction of (practically
      insoluble) pigments has been a matter of discussion. As a majority of azo
      pigments are based on 3,3'-dichlorobenzidine, much of the available experimental
      data are focused on this group. Long-term animal carcinogenicity studies
      performed with pigments based on 3,3'-dichlorobenzidine did not show a
      carcinogenic effect. The absence of a genotoxic effect has been supported by
      mutagenicity studies with the 3,3'-dichlorobenzidine-based Pigment Yellow 12.
      Studies in which azo pigments based on 3,3'-dichlorobenzidine had been orally
      administered to rats, hamsters, rabbits and monkeys could generally not detect
      significant amounts of 3,3'-dichlorobenzidine in the urine. It, therefore,
      appears well established that the aromatic amine components from azo pigments
      based on 3,3'-dichlorobenzidine are practically not bioavailable. Hence, it is
      very unlikely that occupational exposure to insoluble azo pigments would be
      associated with a substantial risk of (bladder) cancer in man. According to
      current EU regulations, azo dyes based on benzidine, 3,3'-dimethoxybenzidine and
      3,3'-dimethylbenzidine have been classified as carcinogens of category 2 as
      "substances which should be regarded as if they are carcinogenic to man". This is
      not the case for 3,3'-dichlorobenzidine-based azo pigments.

PMID- 15177656
TI  - Assessing the genotoxicity of industrial cutting fluids under conditions of use.
AB  - Emulsions of water-soluble cutting fluids (wsCF) and non-water-soluble cutting
      fluids are used in large quantities for machining processes in the metal
      processing industry. From toxicological and epidemiological studies health risks
      resulting from handling of cutting fluids are well-known. Recently, the new
      technology of "minimist lubricant supply" (MLS) has been introduced which uses
      only minimal amounts of cutting fluids, in order to reduce the costs for use and
      disposal. This involves higher temperatures to which the fluids are subjected.
      Water-soluble cutting fluids supplemented with formaldehyde donors as biocides
      may lead to mutagenic potential. Current data show that attention should be given
      to generation of other genotoxic aldehydes from cutting fluids under condition of
      use, referring to both conventional and "minimist lubricant supply" technologies.

PMID- 15177657
TI  - Future applications of phosphotriesterases in the prophylaxis and treatment of
      organophosporus insecticide and nerve agent poisonings.
AB  - Organophosphorus compounds (OPs) are being used as insecticides and warfare
      agents. OP insecticides represent an important problem of public health, causing
      around 200,000 deaths annually. The World Health Organization has pointed to the
      necessity to introduce new medical practices that improve the results of
      classical treatments. Many studies have shown that the administration of
      phosphotriesterases (enzymes that detoxify OPs through hydrolysis) is a promising
      treatment of persons poisoned with OPs. Such an enzyme-based treatment might
      introduce important improvements in the treatment of patients having ingested
      large amounts of OPs. Phosphotriesterases might also be suitable for prophylactic
      treatment of persons at risk to be severely exposed. The new experimental
      treatments do not exhibit the intrinsic neurotoxicity of the classical
      prophylaxis based on carbamates and antimuscarinic drugs. Experimental data
      suggest that might be time to initiate clinical trials in order to study the
      efficacy of phosphotriesterases in the therapy and prophylaxis of OP
      intoxication.

PMID- 15177658
TI  - Carbohydrate-deficient transferrin (CDT) as a biomarker in persons suspected of
      alcohol abuse.
AB  - The coherence of carbohydrate-deficient transferrin (CDT) as a biomarker of
      alcohol abuse was investigated with 15 conventional laboratory parameters, with
      the self-reported medical history and with clinical findings, all previously
      reported to be associated with chronic alcohol intake. In total, 100 male persons
      who were at least suspected of abusing alcohol were assessed. Medical history,
      clinical picture and physical examination were taken, and laboratory parameters
      regarding blood count, liver enzymes, serum lipids, iron balance, Ig A and uric
      acid were determined. These data were correlated with the CDT values, the daily
      ethanol intakes reported, and several findings from medical history and clinical
      examination. The mean CDT level (mean+/-S.D.) of the entire group was 29.4+/-19.7
      U/l. Eighty-one patients admitted a daily ethanol intake of 60 g or more. The
      ratio AST/ALT (de Ritis ratio) appeared as the best conventional parameter
      correlated with both CDT and ethanol intake. Mean corpuscular volume (MCV), serum
      iron, AST and red blood cell count also correlated significantly with CDT. CDT,
      AST and ferritin correlated significantly with the reported daily ethanol intake.
      It is concluded that CDT provides a reliable estimate of long-term alcohol
      intake.

PMID- 15177659
TI  - Detection of clinical interactions between methadone and anti-retroviral
      compounds using an enantioselective capillary electrophoresis for methadone
      analysis.
AB  - A capillary electrophoresis method was developed to detect interactions between
      methadone and anti-retroviral compounds. Eight subjects, who underwent methadone
      maintenance treatment in the Province of Alicante (Spain), consented to
      participate in the present study. Of those, one subject was followed up for 123
      days to detect drug-drug interactions. The enantiomers of methadone and those of
      its main metabolite were conveniently resolved within 4 min using a chiral
      electrophoresis buffer mixture which consisted of phosphate buffer, pH 5, plus
      0.2% highly sulphated-(beta)-cyclodextrin. The effective mobility of the analytes
      was in the 0.061-0.140 cm(2)/(kV s) range at pH 5. The R-methadone plasma
      concentration range for seven patients was 91-318 ng/mL, it decreased from 186 to
      46 ng/mL in a patient followed-up on commencement of the anti-retroviral therapy,
      returning to the previous higher levels after progressive dose increases. We
      conclude that monitoring R-methadone plasma levels can be a useful tool for the
      dose adjustment of methadone.

PMID- 15177660
TI  - 1,3-Propane sultone, an extremely potent experimental carcinogen: what should be
      expected in humans?
AB  - 1,3-Propane sultone is directly alkylating, genotoxic and carcinogenic. In rats,
      it induces local and systemic tumours at multiple target sites. Preponderant
      systemic tumours occur at the central nervous system, especially gliomas. Other
      localisations include the mammary gland, the intestine, the haematopoietic system
      and the kidneys. In the German chemical industry, 1,3-propane sultone had been
      manufactured and used in limited amounts in the 1950s and 1960s, and for a very
      few purposes until the 1970s. The number of persons in contact with the compound
      is unknown but was limited. The medical history of some cases could be traced. As
      cerebral gliomas are the main systemic tumours induced by 1,3-propane sultone
      experimentally, the occurrence of a glioblastoma among previously exposed persons
      appears conspicuous. Three intestinal malignancies were recorded among the cases
      observed. Also noteworthy is one case of a duodenal carcinoma, normally a rare
      human malignancy. Two haematopoietic/lymphatic malignancies of different nature
      have been observed, and there was one case of a renal cell carcinoma. These
      malignancies observed within a group of persons exposed to 1,3-propane sultone
      appear surprisingly consistent with the expectations from the available animal
      studies. The present case studies point to long latency times (up to 30-40 years
      or more) after limited periods of past exposure.

PMID- 15177661
TI  - Challenges to environmental toxicology and epidemiology: where do we stand and
      which way do we go?
AB  - Modern toxicology investigates a wide array of both old and new health hazards.
      Priority setting is needed to select agents for research from the plethora of
      exposure circumstances. The changing societies and a growing fraction of the aged
      have to be taken into consideration. A precise exposure assessment is of
      importance for risk estimation and regulation. Toxicology contributes to the
      exploration of pathomechanisms to specify the exposure metrics for risk
      estimation. Combined effects of co-existing agents are not yet sufficiently
      understood. Animal experiments allow a separate administration of agents which
      can not be disentangled by epidemiological means, but their value is limited for
      low exposure levels in many of today's settings. As an experimental science,
      toxicology has to keep pace with the rapidly growing knowledge about the language
      of the genome and the changing paradigms in cancer development. During the
      pioneer era of assembling a working draft of the human genome, toxicogenomics has
      been developed. Gene and pathway complexity have to be considered when
      investigating gene-environment interactions. For a best conduct of studies,
      modern toxicology needs a close liaison with many other disciplines like
      epidemiology and bioinformatics.

PMID- 15177662
TI  - A tetranucleotide repeat polymorphism in the CYP19 gene and breast cancer
      susceptibility in a Greek population exposed and not exposed to pesticides.
AB  - Epidemiological studies have suggested that hormones, genetic factors, and
      environmental agents are significant risk factors in breast carcinogenesis. Some
      pesticides have the ability to act as xenoestrogens in vivo. The CYP19 gene
      encodes the aromatase enzyme which is involved in the estrogens biosynthetic
      pathways. We have assessed the frequency alleles of a (TTTA)(n) repeat of CYP19
      gene in breast cancer patients which were either exposed or not exposed to
      specific pesticides. No differences were observed in the distribution of the
      alleles between the two groups showing that the polymorphism does not have a
      significant functional role on the aromatase activity. When compared to healthy
      control Greek women group, only the (TTTA)(10) repeat variant presented a non
      significant increased risk in breast cancer susceptibility [odds ratio (OR):
      2.46, P>0.05 ]. Lack of strong association suggests that the polymorphic TTTA
      short tandem repeat of CYP19 gene may have not a functional effect on the
      enzyme's activity and thus its role in the development of breast cancer remains
      unclear.

PMID- 15177663
TI  - Association of cytochrome P450 2E1 polymorphisms and head and neck squamous cell
      cancer.
AB  - The development of head and neck squamous cell cancer (HNSCC) is known to be
      strongly associated with tobacco use. One of the main enzymes for bioactivation
      of tobacco-related substances is the cytochrome 450 (CYP)2E1, of which different
      genetic variants are described. Analyzing a correlation between certain neoplasia
      and alteration of the CYP2E1 gene, most studies focus on the polymorphisms 
      1053C>T and 7632T>A, but recently another polymorphism, named -71G>T, with
      enhanced transcriptional activity, has been identified. In the current case
      control study we investigate the putative association of the mentioned CYP2E1
      polymorphisms on the risk of HNSCC. Comparing 312 German individuals with HNSCC
      to 299 controls we found a significantly enhanced risk for the development of
      that neoplasia in smoking carriers of -71G>T heterozygosity, while in -1053C>T
      and 7632T>A polymorphisms a corresponding correlation was absent. Since a
      coincidence of an aberrant p53 gene and CYP2E1 mutations has been described, we
      choose a subgroup of 140 patients with HNSCC for analyzing an association of
      mutations in these two genes. However, no such association could be found in
      either of the mentioned polymorphisms. Further studies have to focus on the 
      71G>T polymorphism and its possible linkage to cancers, in which smoking is a
      known risk-factor, as well as its functional relevance concerning the
      bioactivation of tobacco-related substances.

PMID- 15177664
TI  - Polymorphic metabolic susceptibility genes and longevity: a study in
      octogonarians.
AB  - In order to investigate possible associations of genetic variants in genes of
      xenobiotic metabolism with longevity, we compared allele frequencies and genotype
      distributions of polymorphic genes between 205 octogenarians and a non-cancer
      reference group of 294 persons aged less than 80 years. We analyzed common
      sequence variations in the cytochrome P-450 genes CYP1A1 T461N, 3801 T > C and
      CYP1B1 V432L, and in the glutathione S-transferase genes GSTM1 (deletion), GSTT1
      (deletion), and GSTP1 (I105V). In octogenarians, the CYP1B1 432L allele was less
      prevalent than in the reference group (allele frequency 0.49 versus 0.60; odds
      ratio, OR, 0.63, 95% confidence limits (CI) 0.40-1.00). Octogenarians turned out
      to have marginally significant more GSTM1 negatives (frequency 0.56 versus 0.48;
      OR 1.41, 95% CI 0.97-2.05), but less GSTT1 deficient genotypes (frequency 0.14
      versus 0.21; OR 0.64; 95% CI 0.38-1.06). In octogenarians without cancer, GSTT1
      negative carriers were less prevalent than in the aged with cancer (frequency
      0.12 versus 0.27; OR 2.81; 95% CI 1.00-7.38). Polymorphic metabolic
      susceptibility genes could become relevant for processes of aging when toxic
      defense mechanisms decline.

PMID- 15177665
TI  - A pilot study on the application of statistical classification procedures to
      molecular epidemiological data.
AB  - The development of new statistical methods for use in molecular epidemiology
      comprises the building and application of appropriate classification rules. The
      aim of this study was to assess various classification methods that can
      potentially handle genetic interactions. A data set comprising genotypes at 25
      single nucleotide polymorphic (SNP) loci from 518 breast cancer cases and 586 age
      matched population-based controls from the GENICA study was used to built a
      classification rule with the discrimination methods SVM (support vector machine),
      CART (classification and regression tree), Bagging, Random Forest, LogitBoost and
      k nearest neighbours (kNN). A blind pilot analysis of the genotypic data set was
      a first approach to obtain an impression of the statistical structure of the
      data. Furthermore, this analysis was performed to explore classification methods
      that may be applied to molecular-epidemiological evaluation. The results showed
      that all blindly applied classification methods had a slightly smaller
      misclassification rate than a random classification. The findings, nevertheless,
      suggest that SNP data might be useful for the classification of individuals into
      categories of high or low risk of diseases.

PMID- 15177666
TI  - VHL mutations in renal cell cancer: does occupational exposure to
      trichloroethylene make a difference?
AB  - Occupational exposures have long been suspected to play a role in the incidence
      of renal cell carcinoma (RCC). Especially, the carcinogenicity of the industrial
      solvent trichloroethylene (TCE) has been controversially debated, both with
      respect to the epidemiological and the molecular studies. In order to further
      elucidate this issue, it appeared important to compare suitable RCC patient
      groups, i.e., TCE-exposed versus non-TCE-exposed patients. We evaluated RCC from
      a previous German study that had described differences in RCC risks between TCE
      exposed (n=17) and non-exposed patients (n=21). We compared age at diagnosis and
      histopathologic parameters of tumors as well as somatic mutation characteristics
      in the kidney cancer causing VHL tumor suppressor gene. RCC did not differ with
      respect to histopathological characteristics in both patient groups. We noticed a
      younger age at diagnosis in TCE-exposed patients compared to non-exposed patients
      (P=0.01). Moreover, the non-TCE-exposed patients did not share the somatic VHL
      mutation characteristics of TCE-exposed patients such as the previously
      identified hot spot mutation 454 C > T P81S or multiple mutations. These data
      support the notion of a putative genotoxic effect of TCE leading to VHL gene
      damage and subsequent occurrence of RCC in highly exposed subjects.

PMID- 15177667
TI  - Polymorphisms of cytochrome P450 1A1, glutathione S-transferases M1 and T1 in a
      Turkish population.
AB  - Intra-ethnic as well as inter-ethnic differences are known to exist in the
      frequencies of cytochrome P450 (CYP) 1A1, glutathione S-transferase (GST) M1, and
      GSTT1 gene polymorphisms with which associations have been shown for several
      cancers. In this study, CYP1A1 m2, GSTM1, and GSTT1 gene polymorphisms were
      determined among 133 healthy individuals of a Turkish population. On the basis of
      polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP)
      methodology, the frequency of CYP1A1 m2 mutation was determined. The multiplex
      PCR protocol was used to determine the frequency of the deleted genotypes of both
      GSTM1 and GSTT1 genes. The frequencies of Ile/Ile (wild type), Ile/Val
      (heterozygous variant), and Val/Val (homozygous variant) CYP1A1 m2 genotypes were
      90.2%, 9.8%, and 0%, respectively. The frequencies of the deleted GSTM1 (null)
      and GSTT1 (null) genotypes were 51.9% and 17.3%, respectively. These results show
      that the frequencies of the CYP1A1 m2, GSTM1, and GSTT1 gene polymorphisms in a
      Turkish population are similar to Caucasian populations.

PMID- 15177668
TI  - The development of large intestine during the fetal period.
AB  - OBJECTIVE: The aim of this study is to determine the colon types, developmental
      change of the colon morphology during the fetal period. METHODS: The study was
      realised on 131 human fetuses (male 69, female 62) ages between 10 and 40 weeks,
      which have no external pathology and anomalies. The colon types were evaluated in
      two parts. As the first part, the colon part between the ileal orifice and
      sigmoid colon was typed. The sigmoid colon was typed as the second part. The
      macroscopic diameters of parts of the colon and the thicknesses of wall layers of
      ascending and descending colons were measured under the light microscope.
      RESULTS: For the proximal part of the colon, there were seven types of colon, and
      there were five types for the sigmoid colon. For the first part, transverse type
      colon was a rare type during the fetal period (3%). The oblique type colon was
      observed mostly in the first and second trimester during the fetal period. Adult
      type colon was the most common type in the third trimester and full-term groups.
      The pendulous type colon was observed mostly in the third trimester. The
      development of the haustra and tenia coli in the first trimester was quite slow,
      but later the development increased more and more, and during the full-term
      period, the haustra and tenia coli could be seen clearly. CONCLUSION: The
      percentage distribution of the colon types between the trimesters was
      significant. It was observed that the maturation of haustra and tenia coli
      started from the ascending colon and progressed towards the sigmoid colon. The
      thickness of the tunica mucosa layer both in the ascending and in descending
      colon part increased considerably in the middle of the second trimester.

PMID- 15177669
TI  - Fetal adaptation to stress. Part I: acceleration of fetal maturation and earlier
      birth triggered by placental insufficiency in humans.
AB  - This review is an attempt to provide an integrative view for the biological
      changes triggered by fetal stress through a multidisciplinary approach.
      Acceleration of brain and lung maturation in certain risk pregnancies was first
      described clinically and confirmed by biochemical, electrophysiological and
      experimental data. Moreover, new experimental findings suggest that a fetal clock
      centrally mediated by fetal nutritional status could determine timing of
      parturition. However, some skepticism persisted about the usefulness of this body
      of knowledge for obstetrical management in developed countries. The interest
      concerning this adaptation to intrauterine stress was later renewed from various
      sources, as developed in Part II.

PMID- 15177670
TI  - Cell proliferation correlates with the postconceptual and not with the postnatal
      age in the hippocampal dentate gyrus, temporal neocortex and cerebellar cortex of
      preterm infants.
AB  - BACKGROUND: In previous studies, lower IQ scores and educational difficulties of
      preterm children were correlated with the reduced size of several brain areas,
      including the cerebellum and the hippocampus. The most plausible reason for
      reduction would be the reduced cell formation following premature birth. However,
      no data are available about the rate of postnatal cell proliferation in the
      different brain areas of preterms. METHODS: Cytoarchitectonics and cell
      proliferation were examined in the cerebellum, hippocampal formation and temporal
      neocortex of preterm infants who lived for several weeks or months. Cell
      proliferation was detected with Ki-67 immunostaining and proliferating cells were
      identified with vimentin as glial and with CD31 and periodic acid-Schiff (PAS)
      reaction as endothelial elements. RESULTS: The rate of cell formation and the
      width of the cytoarchitectonic layers of the cerebellum of preterm infants
      corresponded to that of the age-matched controls. In the hippocampal dentate
      gyrus, the rate of cell formation and the density of proliferating cells were
      slightly higher in the preterm infants than in the full-term age-matched
      controls. Endothelial cell proliferation and the surface area of the capillaries
      were larger in the dentate gyrus of preterms than in age-matched controls.
      CONCLUSION: Rate of cell proliferation that correlates with the postconceptual
      age is not reduced in preterms, therefore the reduced size of the cerebellum and
      hippocampal formation is unlikely to be the result of decreased cell formation.

PMID- 15177672
TI  - Acoustic study of swallowing behaviour in premature infants during tube-bottle
      feeding and bottle feeding period.
AB  - The premature infant has limited ability to integrate the swallowing-breathing
      cycle during feeding. The aim of this study was to assess the pattern of
      swallowing between the period of tube-bottle (TBF) and bottle (BF) feeding by
      means of cervical auscultation in premature infants. Twenty-three premature
      infants were enrolled (mean gestational age 34.7 +/- 1.7 weeks). Audiosignal
      recordings were made during TBF and BF with a small microphone set in front of
      the cricoid cartilage. The following parameters were calculated for 2 min and
      reported at 1 min: the percentage of time involved in swallowing (ST), the
      numbers of swallows (SN) and swallowing bursts (SB) and swallowing groups (SG).
      Individual histograms were established to show the individual pattern of
      swallowing behaviour and the distribution of groups, bursts and swallows over 2
      min. Mean (STm), (SNm), (SBm), (SGm) values were calculated (+/- S.D.).
      Statistical analysis was used to compare the means and to establish correlations
      between parameters and curves. (STm), (SNm) and (SBm) increased significantly
      during BF compared with TBF for all premature infants and during follow-up. The
      histograms showed that in BF the groups were high in bursts. These findings and
      the histograms for each infant will allow determination of transition to bottle
      feeding without risk corresponding to the stage of maturation of swallowing
      function.

PMID- 15177671
TI  - Skin reflectance changes in preterm infants with patent ductus arteriosus.
AB  - INTRODUCTION: Patent ductus arteriosus (PDA) is a common complication in preterm
      infants. While two-dimensional echocardiography is the method of choice for
      diagnosing a PDA, clinical signs are known to be of limited value. STUDY DESIGN:
      Haemodynamically significant PDA (hs-PDA) was defined as a ductal left-to-right
      shunt with elevated left atrial/aortic root ratio ( > 1.6:1), a ductal diameter >
      2 mm, retrograde diastolic flow exceeding 30% of the anterograde flow and
      anterograde peak diastolic flow velocity in left pulmonary artery > 50 cm/s. A hs
      PDA may affect the cerebral circulation and skin color is known to be related to
      local perfusion. In this study, we tested the value of a caudal-to-cephalic skin
      reflectance differential in detecting preterm infants with hs-PDA. The study was
      blinded and prospective. SUBJECTS: Fifteen infants with a hs-PDA (M: 8, F: 7;
      gestational age: 28.0 +/- 2.0 weeks, birth weight: 880 +/- 130 g) and 15 gender-
      and gestational age-matched infants without a haemodynamically significant PDA
      (M: 8, F: 7; gestational age: 28.2 +/- 2.3 weeks, birth weight: 885 +/- 135 g)
      participated to the study. OUTCOME MEASURE: Skin reflectance measurements were
      performed using a reflectance spectrophotometer (CM-2600d/2500d, Minolta, Osaka,
      Japan). Sole ("postductal" site) to forehead ("preductal" site) skin reflectance
      ratio (caudal-to-cephalic ratio). RESULTS: hs-PDA infants showed significantly
      lower forehead light reflectance values on for the whole visible spectrum (p < or
      = 0.043) with the exception of 580-590 nm (p = 0.058), whereas no statistically
      significant differences were observed for the sole skin reflectance between the
      two groups in the examined visible spectrum. Consequently, hs-PDA infants showed
      a significantly higher caudal to cephalic ratio in the 410-430 nm (p < or =
      0.042), 460-530 nm (p < or = 0.027) and 590-700 nm (p < or = 0.011) wavelength
      ranges. CONCLUSIONS: These findings may provide a previously unrecognised
      clinical marker for haemodynamically significant PDA in preterm infants, thus
      predicting those preterm infants who may require intervention for PDA.

PMID- 15177673
TI  - Nitric oxide metabolites and adrenomedullin in human breast milk.
AB  - We found high concentrations of nitrite/nitrate (166-1460 micromol/l) in 43 milk
      samples obtained from 32 women during postpartum days 1-8, which indicates
      enhanced mammary nitric oxide (NO) secretion. We detected adrenomedullin (AM)
      (2.7-20.7 pmol/l) only in 9 of the 43 samples using highly specific
      immunoradiometric assay. It is uncertain whether the entire adrenomedullin is
      actively secreted in human milk.

PMID- 15177675
TI  - Gene expression profiling of mouse postnatal cerebellar development using cDNA
      microarrays.
AB  - The cerebellum serves as a model system for developmental studies of the
      mammalian nervous system. Classical analysis of individual genes is insufficient
      to address the complex regulatory circuits underlying the developmental process.
      In this study, the postnatal cerebellar development of mice aged 2, 4, 8, 12, 16,
      21 and 42 days old was studied using a microarray spotted with 5494 cDNA clones
      collected from the cerebellum and the cerebrum of C57BL/6J mice. We were able to
      cluster the expression patterns into four groups and each was highly correlated
      with gene function. Housekeeping genes are in a cluster in which the expression
      pattern peaks at the neonatal stage, while genes related to brain function peak
      at the adult stage. The other two clusters, characterized by transiently
      upregulated or downregulated expression during days 8-16, contain genes with
      different functions, most notably related to cell differentiation and cell cycle
      progression. Based on this categorization and on motif scanning, we were able to
      assign hypothetical functions to functionally undetermined genes. The result
      indicates that expression profiling is an efficient method for generation of new
      hypotheses for the developmental study of the cerebellum. When combined with
      other studies such as pharmacology etc., data generated in this study may have
      application in the elucidation of genetic networks underlying developmental
      disorder.

PMID- 15177676
TI  - Detection of apoptosis during planarian regeneration by the expression of
      apoptosis-related genes and TUNEL assay.
AB  - Apoptosis is a tightly organized cell death process that plays a crucial role in
      metazoan development, but it has not yet been revealed whether apoptotic events
      are involved in the process of regeneration. Here, we tried to detect apoptotic
      cells during planarian regeneration using the TdT-mediated dUTP nick-end labeling
      (TUNEL) assay as well as the expression of apoptosis-related genes. Three novel
      cDNAs were isolated from a planarian cDNA library and shown to be closely related
      to other metazoan caspases at the amino acid sequence level. One of these cDNAs,
      Caspase-like gene 3 (DjClg3), was expressed primarily in apoptotic cells by
      double detections with the TUNEL assay. Whole mount in situ studies indicated
      that DjClg3 was expressed in the cells of the mesenchymal space and also around
      the pharynx of the intact body. Its expression in the regenerating head piece was
      seen in the blastema and less significantly in the brain, while in the
      regenerating tail piece, DjClg3 expression was detected uniformly throughout the
      entire region. In parallel experiments, we performed in situ TUNEL assays to
      localize the regions where cell death occurred during regeneration and comparable
      results to the DjClg3 expression patterns were obtained. This is the first report
      to show that planarians have apoptosis-related genes and the results suggest that
      the apoptotic mechanism probably takes place to a large extent in normal intact
      worms as well as during their regeneration. We hypothesize that the presence of
      apoptosis in planarians may have a role in controlling cell numbers, eliminating
      unnecessary tissues or cells and remodeling the old tissues of regenerating body
      parts.

PMID- 15177677
TI  - Mitogenomic analyses provide new insights into cetacean origin and evolution.
AB  - The evolution of the order Cetacea (whales, dolphins, porpoises) has, for a long
      time, attracted the attention of evolutionary biologists. Here we examine
      cetacean phylogenetic relationships on the basis of analyses of complete
      mitochondrial genomes that represent all extant cetacean families. The results
      suggest that the ancestors of recent cetaceans had an explosive evolutionary
      radiation 30-35 million years before present. During this period, extant
      cetaceans divided into the two primary groups, Mysticeti (baleen whales) and
      Odontoceti (toothed whales). Soon after this basal split, the Odontoceti diverged
      into the four extant lineages, sperm whales, beaked whales, Indian river dolphins
      and delphinoids (iniid river dolphins, narwhals/belugas, porpoises and true
      dolphins). The current data set has allowed test of two recent morphological
      hypotheses on cetacean origin. One of these hypotheses posits that Artiodactyla
      and Cetacea originated from the extinct group Mesonychia, and the other that
      Mesonychia/Cetacea constitutes a sister group to Artiodactyla. The current
      results are inconsistent with both these hypotheses. The findings suggest that
      the claimed morphological similarities between Mesonychia and Cetacea are the
      result of evolutionary convergence rather than common ancestry.

PMID- 15177679
TI  - LUCA, or just a conserved Archaeon?: comments on Xue et al.
AB  - In their recent paper, Xue et al. used an unusual technique of rooting the
      universal phylogenetic tree, which resulted in positioning of the last universal
      common ancestor within Archaea. The present paper brings some criticisms on the
      methods and results achieved.

PMID- 15177678
TI  - The in vivo form of the murine class VI POU protein Emb is larger than that
      encoded by previously described transcripts.
AB  - The class VI POU domain family member known as Emb in the mouse (rat Brn5 or
      human mPOU/TCFbeta1) is present in vivo as a protein migrating at about 80 kDa on
      western blots, considerably larger than that predicted (about 42 kDa) from
      previously cloned coding sequences. By RT-PCR and 5' RACE strategies a full
      length Emb sequence, Emb FL, is now identified. Shorter sequences encoding the 
      COOH terminal, and an -NH(2) terminal isoform, EmbN, were also isolated.
      Comparisons of Emb coding sequences between species, including the full-length
      zebra fish, POU(c), are presented, together with a compilation of the multiple
      transcripts produced by alternative splicing and the presence of different
      transcriptional start and stop sites, from the Emb gene.

PMID- 15177680
TI  - The evolution of the adenine nucleotide translocase family.
AB  - Homologous genes are grouped into families whose evolution may be different in
      the various organisms. For the variety of the processes and the well-known
      mechanism of gene gain and gene loss, which takes place in genome evolution, we
      deal in comparative analyses with a "one-to-many" or a "many-to-many"
      relationship between homologous genes going from invertebrates to vertebrates. In
      this scenario, it is important to understand how gene function has been preserved
      and in addition the innovations originated in a given lineage or species. The
      phylogenetic relations between gene family members and their molecular clock
      behavior may be very helpful to elucidate their functional fates in various
      organisms. This in turn can direct laboratory experiments and practical
      applications. In order to track the evolutionary history of the ANT gene family,
      we have collected and analyzed 46 sequences from fungi to mammals. Phylogenetic
      analyses have been performed on nucleotide and amino acidic sequences which have
      produced basically the same results. We observe the presence of multiple isoforms
      both in lower and higher eukaryotic species, thus a "many-to-many" correspondence
      between genes. The molecular phylogeny of ANT genes, reported in the present
      study, allows to date the time of divergence of ANT isoforms in various lineages.
      Furthermore, the logo analysis has been carried out to characterize the
      conservation features of ANT proteins particularly in their three similar domains
      originated by duplication.

PMID- 15177682
TI  - Comparative genomics: the evolutionary history of the Bcl-2 family.
AB  - The Bcl-2 family is a huge family composed of various members, occurring in all
      animals, which are key regulators of apoptosis, the cell death program critical
      for cell survival and development, tissue homeostasis, and protection against
      pathogens. The members of the Bcl-2 family can be divided into pro-apoptotic and
      anti-apoptotic proteins. A delicate balance between these members exists in each
      cell and the regulations of these two groups of proteins determines whether the
      cell survives or undergoes apoptosis. Bcl-2 family proteins are characterized by
      distinct domains. All members possess at least one of the four motifs known as
      Bcl-2 homology domains (BH1 to BH4). Most pro-survival members which can inhibit
      apoptosis facing a wide variety of cytotoxic insults, contain at least BH1 and
      BH2 domains; those most similar to Bcl-2 have all four BH domains. All the pro
      apoptosis family members possess BH3 domain which is the central domain. For the
      first time, a global phylogenetic analysis of all Bcl-2 family members is
      presented here. We have analyzed the genes known so far that have a different
      composition of the functional domains BH1, BH2, BH3 and BH4. The analyses were
      performed both on complete sequences (124 sites analyzed) and on single domains.
      We present the results obtained using both approaches. We have also analyzed the
      amino acid profile and the degree of conservation of the BH3 domains of pro- and
      anti-apoptotic proteins. The results of our phylogenetic analyses show that a
      clear-cut clustering into pro- and anti-apoptotic products, reproducible with
      different evolutionary methods, could also be obtained by analyzing restricted
      areas such as the BH1 and BH2 domains. It is noteworthy that even when the
      analysis is performed only on the BH3 domain, we have two clear-cut clusters. The
      evolutionary analysis of gene family members is a valuable tool to predict their
      functions and guide experimental assays to validate predictions. Once the
      functions of all the components are known, it will be possible to study the
      process in a holistic way.

PMID- 15177681
TI  - Mitogenomic analyses of deep gnathostome divergences: a fish is a fish.
AB  - It is commonly accepted that among recent fishes the lungfishes are the closest
      relatives of the tetrapods. According to this hypothesis, the tetrapods,
      lungfishes and coelacanths constitute a group of specialized fishes
      (Sarcopterygii) to the exclusion of other bony fishes. Here, we describe basal
      relationships among gnathostome (jawed) vertebrates as reconstructed by analysis
      of complete mitochondrial DNA sequences. The study includes all major extant
      groups of both tetrapods and fishes and uses agnathan (jawless) vertebrates as an
      outgroup to root the trees. The analyses split extant gnathostomes into two
      monophyletic groups: tetrapods and fishes (including cartilaginous fishes).
      Cladistia (bichirs, ropefish) is in a basal position on the piscine branch. Thus,
      contrary to the traditional view, the mitogenomic results suggest that among
      living gnathostomes a tetrapod is a tetrapod and a fish, a fish. Similarly,
      analyses of 18S and 28S rRNA genes (both nuclear) do not support the commonly
      accepted tree.

PMID- 15177683
TI  - Adaptive evolution and functional divergence of pepsin gene family.
AB  - In vertebrates, a large proportion of genes is organized in gene families.
      Paralogous gene groups generated by gene duplication are related by homology,
      high degree of sequence identity and similar structural architecture of their
      products. Aspartic proteinases form a widely distributed protein superfamily
      including cathepsins, pepsins, renin and napsin. In the present study, the
      nucleotide sequences coding for various pepsins in 30 vertebrate species have
      been used to derive a gene phylogeny. Gene duplication and losses have been
      inferred from a reconciled tree, reconstructed by combining information from gene
      tree and species tree. Our findings based on the results of the relative rate
      ratio test and maximum likelihood analysis suggest that each round of gene
      duplication is characterized by adaptive evolution, although instances of
      evolution under positive selection have been found also long after divergence of
      gene families. The results of functional divergence analysis provided statistical
      evidence for shifted evolutionary rate after gene duplication.

PMID- 15177684
TI  - The evolutionary origin of long-crowing chicken: its evolutionary relationship
      with fighting cocks disclosed by the mtDNA sequence analysis.
AB  - Chickens with exceptionally long crow are often favored all over the world, and
      connoisseur breeders have bred certain types of chicken exclusively for this
      trait. In Japan, three chicken varieties have been specifically bred to develop
      an exceptionally long crow of over 15 s. Although these three long-crowing
      chickens, Naganakidori, are honored as heritage varieties of Japan, the
      domestication process and genealogical origin of long-crowing chickens remain
      unclear. The purpose of this study is to clarify these issues using nucleotide
      sequences of the mitochondrial DNA D-loop region. Blood samples from a total of
      nine long-crowing chickens and 74 chickens from 11 Japanese native varieties were
      collected. DNA sequence data of two Junglefowl species were also collected from
      the International DNA database (DDBJ /EMBL/GenBank) for use as the outgroup. A
      phylogenetic tree was then constructed revealing that all three Naganakidori
      varieties were monophyletic and originated from a fighting cock, a Shamo, for
      cockfighting. These results suggest that these three long-crowing chickens share
      a common origin in spite of their conspicuously different characters, and that
      human cultures favoring long-crowing chickens might have been preceded by a
      tradition of cockfighting. Moreover, these long-crowing varieties first separated
      from the fighting cocks of Okinawa, which is geographically closer to Southern
      China and Indochina than Mainland Japan (Honshu/Kyushu). This implies that
      Japanese long-crowing chickens were first brought to Mainland Japan as fighting
      cocks from the surrounding regions of Southern China or Indochina and through
      Okinawa.

PMID- 15177685
TI  - Isolation of the LFY/FLO homologue in Orchis italica and evolutionary analysis in
      some European orchids.
AB  - It has been suggested that the evolutionary analysis of floral development genes
      could explain the divergences between the rates of morphological and molecular
      evolution. The LEAFY (LFY) gene of Arabidopsis thaliana is one of the central
      regulatory genes in the control of flower development. We have identified the
      homologue of this gene (OrcLFY) in Orchis italica using 5'/3'RACE and primer
      walking, and compared the coding sequences of several orchid species. We analyzed
      nonsynonymous and synonymous substitution rates between the OrcLFY coding regions
      of 14 species, and performed a McDonald-Kreitman test on Orchis morio and Orchis
      laxiflora populations, showing that purifying selection is acting on this gene in
      these orchids. We have performed a phylogenetic analysis showing that OrcLFY is a
      new useful marker to reconstruct molecular phylogenies at low taxonomic levels.

PMID- 15177686
TI  - Altered replication timing of the HIRA/Tuple1 locus in the DiGeorge and
      Velocardiofacial syndromes.
AB  - DiGeorge and Velocardiofacial syndromes (DGS/VCFS) are endowed by a similar
      complex phenotype including cardiovascular, craniofacial, and thymic
      malformations, and are associated with heterozygous deletions of 22q11
      chromosomal band. The Typically Deleted Region in the 22q11.21 subband (here
      called TDR22) is very gene-dense, and the extent of the deletion has been defined
      precisely in several studies. However, to date there is no evidence for a
      mechanism of haploinsufficiency that can fully explain the DGS/VCFS phenotype. In
      this study, we show that the candidate gene HIRA/Tuple1 mapping on the non
      deleted TDR22, in DGS/VCFS subjects presents a delayed replication timing.
      Moreover, we observed an increase in the cell ratio showing the HIRA/Tuple1 locus
      localised toward the nuclear periphery. It is known that replication timing and
      nuclear location are generally correlated to the transcription activity of the
      relative DNA region. We propose that the alteration in the replication/nuclear
      location pattern of the non-deleted TDR22 indicates an altered gene regulation
      hence an altered transcritpion in DGS/VCFS.

PMID- 15177687
TI  - Quantifying intrachromosomal GC heterogeneity in prokaryotic genomes.
AB  - The sequencing of prokaryotic genomes covering a wide taxonomic range has sparked
      renewed interest in intrachromosomal compositional (GC) heterogeneity, largely in
      view of lateral transfers. We present here a brief overview of some methods for
      visualizing and quantifying GC variation in prokaryotes. We used these methods to
      examine heterogeneity levels in sequenced prokaryotes, for a range of scales or
      stringencies. Some species are consistently homogeneous, whereas others are
      markedly heterogeneous in comparison, in particular Aeropyrum pernix, Xylella
      fastidiosa, Mycoplasma genitalium, Enterococcus faecalis, Bacillus subtilis,
      Pyrobaculum aerophilum, Vibrio vulnificus chromosome I, Deinococcus radiodurans
      chromosome II and Halobacterium. As we discuss here, the wide range of
      heterogeneities calls for reexamination of an accepted belief, namely that the
      endogenous DNA of bacteria and archaea should typically exhibit low
      intrachromosomal GC contrasts. Supplementary results for all species analyzed are
      available at our website: http://bioinfo2.ugr.es/prok.

PMID- 15177688
TI  - Representing GC variation along eukaryotic chromosomes.
AB  - Genome sequencing now permits direct visual representation, at any scale, of GC
      heterogeneity along the chromosomes of several higher eukaryotes. Plots can be
      easily obtained from the chromosomal sequences, yet sequence releases of
      mammalian or plant chromosomes still tend to use small scales or window sizes
      that obscure important large-scale compositional features. To faithfully reveal,
      at one glance, the compositional variation at a given scale, we have devised a
      simple scheme that combines line plots with color-coded shading of the regions
      underneath the plots. The scheme can be applied to different eukaryotic genomes
      to facilitate their comparison, as illustrated here for a sample of chromosomes
      chosen from seven selected species. As a complement to a previously published
      compact view of isochores in the human genome sequence, we include here an
      analogous map for the recently sequenced mouse genome, and discuss the
      contribution of repetitive DNA to the GC variation along the plots. Supplementary
      information, including a database of color-coded GC profiles for all recently
      sequenced eukaryotes and the program draw_chromosomes_gc.pl used to obtain them,
      are available at.

PMID- 15177689
TI  - Cytosine methylation and CpG, TpG (CpA) and TpA frequencies.
AB  - An analysis of dinucleotide frequencies was carried out on DNAs from insects and
      mammals, as well as on large DNA sequences from the genomes of Drosophila
      melanogaster, Anopheles gambiae, puffer fish (Takifugu rubripes), zebra fish
      (Danio rerio) and human. These organisms were chosen because Drosophila and
      Anopheles DNAs have an extremely low level of methylation, human DNA a high level
      and fish DNA a two-fold higher level compared to human. The results indicate
      that: (i) CpG deficiency and the corresponding TpG (CpA) excess show no
      correlation with the level of DNA methylation; indeed, genomes endowed with
      strikingly different levels of DNA methylation (such as those of Drosophila and
      human) exhibited similar TpG (CpA) levels; (ii) the correlation between GC levels
      of large (50 kb) DNA sequences and TpA or CpG shortage levels do not appear to be
      due to CpG methylation followed by deamination; (iii) CpG dinucleotides are more
      frequent in fishes than in mammals; interestingly, the monotreme Ornitorhinchus
      anatinus shows an intermediate CpG frequency. The implications of these results
      are discussed.

PMID- 15177690
TI  - Short-range compositional correlation in the yeast genome depends on
      transcriptional orientation.
AB  - This article reports an analysis of composition of about 5000 intergenic regions
      and neighboring ORFs in the nuclear genome of Saccharomyces cerevisiae, and their
      correlation. Intergenic regions flanked by divergently transcribed ORFs are GC
      richer (36%) than those separating convergent ORFs (29%). This difference in GC
      content cannot be fully attributed to its location upstream or downstream the
      ORFs, since no such strong compositional bias is found within 3' and 5' segments
      of intergenic regions between ORFs transcribed in the same direction. We have
      also found that the GC content of intergenic regions is positively correlated to
      that of its flanking ORFs in tandem and divergent orientations, but not in
      convergent orientations, and that the correlation coefficient between the GC
      content of nearby ORFs is higher for divergent pairs. Our observations are
      discussed in the light of recent work stressing the relationships between base
      composition, chromatin structure and meiotic recombination.

PMID- 15177691
TI  - Contingent, non-neutral evolution in a multicellular parasite: natural selection
      and gene conversion in the Echinococcus granulosus antigen B gene family.
AB  - Recent studies have demonstrated that the Echinococcus granulosus antigen B (AgB)
      interferes with the intermediate hosts' immune response and is encoded by a
      multigene family. The number of members within the family is still uncertain, but
      there are several evidences of a large genetic variability. The E. granulosus AgB
      genomic sequences available in nucleotide databases can be grouped into four
      clades, corresponding to genes EgAgB1, EgAgB2, EgAgB3 and EgAgB4. In the present
      study, we use PCR amplifications followed by cloning and sequencing to evaluate
      the genetic variability for AgB isoforms. Two pairs of primers were independently
      used for PCR amplification. Both PCR reactions from each of three isolated
      protoscolex (larvae) were cloned in a plasmid vector and the plasmid inserts of
      30 colonies from each cloning experiment were sequenced. Using phylogenetic
      tools, the 113 EgAgB clones are classified as follows: 25 are related to EgAgB1,
      24 to EgAgB2, 9 to EgAgB3 and 39 to EgAgB4. The remaining 16 clones form a
      separate cluster, which we name EgAgB5, more closely related to EgAgB3 than to
      any of the other genes. Within each gene group, a number of variant sequences
      occur, which differ from one another by one or few nucleotides. One EgAgB3 clone
      has a premature stop codon (pseudogene) and an EgAgB2 clone lacks the region
      corresponding to the intron. The overall variation cannot be explained by
      differences among the asexual protoscoleces, or by experimental artifacts. Using
      Echinococcuss AgB genes from other species/strains as outgroups, neutrality is
      rejected for EgAgB2, and balancing selection is detected for EgAgB5, which also
      seems to be involved in gene conversion. We suggest that EgAgB1-EgAgB5 represent
      a family of contingency genes, that is, genes that are variably expressed, so
      that some but not others are expressed in each individual parasite. Contingency
      genes are common in parasitic protozoa and other microparasites, but the EgAgB
      family is the first set identified in a multicellular parasite.

PMID- 15177692
TI  - Anticodon and wobble evolution.
AB  - The location of the root of life within the Archaea domain close to Methanopyrus
      kandleri and Aeropyrum pernix on the basis of tRNA sequence clustering has
      allowed the tracing of evolutionary change in anticodon usages and the wobble
      rules governing them among different living lineages. Analysis suggests that the
      primitive Archaea employed simple modes of wobble of anticodon-codon pairing that
      enable the reading of standard one-amino acid and two-amino acid odon boxes with
      the uniform use of GNN and UNN anticodons, or the uniform use of GNN, UNN and CNN
      anticodons, together with the use of a modified C to read the AUA codon of
      isoleucine. Later on, evolution of tRNA sequences and posttranscriptional
      modifications brought about in the Bacteria and Eukarya the more complex
      anticodon usages as described by the Crick Rules of wobble, often with different
      codon boxes being read with dissimilar anticodon combinations. Still later, the
      use of a single anticodon to read all four codons in a codon box appeared, both
      in free living organisms and in organelles. The striking simplicity of the
      uniform anticodon combinations used by the Archaea to read all standard one- and
      two-amino acid codon boxes provides strong confirmation for an archaeal root of
      life.

PMID- 15177693
TI  - Body temperature and evolutionary genomics of vertebrates: a lesson from the
      genomes of Takifugu rubripes and Tetraodon nigroviridis.
AB  - In this paper, we provide evidence for the body temperature effect on the
      formation of GC-rich isochores, by analysing genomic sequences from two puffer
      fishes living at different temperatures. The higher body temperature of Tetraodon
      nigroviridis compared to Takifugu rubripes (DeltaT approximately 15 degrees C)
      appears to be the cause of a higher compositional heterogeneity of the former due
      to the formation of GC-rich regions. Such an effect does not only concern large
      DNA segments but also coding sequences.

PMID- 15177694
TI  - Comparative genomics of Anopheles gambiae and Drosophila melanogaster.
AB  - A sequence analysis of the genomes of Anopheles gambiae and Drosophila
      melanogaster reveals that Anopheles DNA is more heterogeneous and GC-richer than
      Drosophila DNA. The gene concentration across the Anopheles genome is
      characterized by low levels in the GC-poor part of the genome and a 3-fold
      increase in the GC-richest part; this gene density gradient is approximately half
      that of Drosophila. GC levels of introns and flanking sequences are correlated
      with GC(3) values (GC levels of third codon positions) of the corresponding genes
      with slopes much lower than unity; in other words, most introns and intergenic
      sequences are less GC-rich than the corresponding GC(3) values. These findings,
      which describe a compositional shift within Diptera, is of interest because of
      their parallels in the well studied major shift in vertebrates.

PMID- 15177695
TI  - Incorrectly predicted genes in rice?
AB  - Between one third and one half of the proposed rice genes appear to have no
      homologs in other species, including Arabidopsis. Compositional considerations,
      and a comparison of curated rice sequences with ex novo predictions, suggest that
      many or most of the putative genes without homologs may be false positive
      predictions, i.e., sequences that are never translated into functional proteins
      in vivo.

PMID- 15177698
TI  - Urinary catecholamine levels in daily life are elevated in women at familial risk
      of breast cancer.
AB  - Recent experimental research has shown that women facing the chronic stress of
      being at familial risk of breast cancer have greater neuroendocrine reactivity
      responses to stressful laboratory tasks. Whether this enhanced stress response
      also occurs outside the laboratory under daily life conditions is unknown. In the
      present study, urinary epinephrine and norepinephrine excretion rates at work
      (e.g. 11:00 AM-3:00 PM), home (e.g. 6:00 PM-10:00 PM) and during sleep (e.g.
      10:00 PM-6:00 AM) were compared between 73 employed women with family histories
      of breast cancer in first degree relatives (FH+; age=36.8+/-8.7) and 81 without
      such family histories (FH-; age=38.1+/-9.4). Differences in sympathetic adrenal
      medullary responses to an ordinary life stressor (work) were assessed in
      naturalistic settings. Repeated measures MANCOVA with family history group as a
      fixed factor, body mass index as a covariate and daily microenvironment (work,
      home and sleep) as a repeating factor were conducted to evaluate whether
      catecholamine excretion rates differed between FH+ and FH- groups. The results
      revealed that women with family histories of breast cancer had a higher rate of
      epinephrine excretion while at work (p<0.005). In addition, women in the FH+
      group were also more reactive to the stress of work, showing a greater percentage
      of increase in both epinephrine and norepinephrine from sleep to work (p<0.05).
      The results also indicated that the chronic stress effects associated with a
      family history of breast cancer were moderated by BMI, such that their impact was
      more pronounced and apparent when women were not obese. These findings support
      the idea that the heightened neuroendocrine reactivity to experimental stressors
      in women at familial risk of breast cancer also occurs when women encounter
      stressors in ordinary life (work stress). Additional research to explore the
      health consequences of increased reactivity in women at familial risk of breast
      cancer, and perhaps in individuals at familial risk of other life-threatening
      disease, would appear warranted.

PMID- 15177697
TI  - Pulsatile luteinizing hormone disruption in depression.
AB  - Two independent groups recently published data comparing pulsatile luteinizing
      hormone (LH) release between depressed and control women. Despite similar
      populations and LH sampling frequency, they reached different conclusions: Meller
      et al. [Am. J. Psych. 154 (1997) 1454] found disruption of normal LH pulsatility
      in depressed women, whereas Young et al. [Arch. Gen. Psych. 57 (2000) 1157] did
      not. To resolve this discrepancy, the current study applies a single, well
      established statistical method, spectral analysis, to the two data sets and
      concludes that both depressed populations display significantly altered LH
      pulsatile release.

PMID- 15177699
TI  - The effect of growth hormone substitution on cognitive performance in adult
      patients with hypopituitarism.
AB  - OBJECTIVE: Adult hypopituitary patients with growth hormone deficiency, though on
      adequate adrenal, thyroid or sex hormone replacement therapy, complain of
      attention and memory disabilities. During the past years several studies have
      evidenced that growth hormone (GH) may exert distinctive effects on the central
      nervous system and induce beneficial effects on psychological capabilities. The
      aim of our study was to determine whether a long-term replacement therapy of
      recombinant human growth hormone (rhGH) affects cognitive performance in adults
      with GH deficiency. DESIGN: A double-blind, randomized placebo controlled trial
      over 6 months, followed by an open period of 6 months of rhGH treatment.
      MEASUREMENTS: The assessment of cognitive performance comprised attention, verbal
      memory and non-verbal intelligence and was examined at baseline (0), at 3, 6, 9,
      and 12 months. In addition, emotional well-being and energy were assessed using
      the Nottingham Health Profile self rating questionnaire. PATIENTS: Eighteen
      hypopituitary patients, mean age 41.6 (range 21-63) years with adult onset GH
      deficiency were evaluated. Patients were on adequate and stable adrenal, thyroid,
      gonadal and desmopressin replacement therapy where necessary, but not substituted
      for GH deficiency. RESULTS: After 3 and 6 months of rhGH treatment in the closed
      label phase a significant improvement of attentional performance was observed
      compared to baseline in the rhGH group but not in the placebo group. After 6
      months scores of attention were significantly different between rhGH and placebo
      treatment for the digit cancellation test and marginally different for the trail
      making test. In contrast, long-term verbal memory and non-verbal intelligence did
      not improve compared to baseline during therapy and short-term memory improved
      both in the GH and the placebo group after 3 and 6 months. This was considered as
      a placebo or practice effect. In the open-label phase a further improvement of
      attention was found in the GH group and subsequent treatment with rhGH for 3 and
      6 months in the placebo group also significantly improved attentional performance
      supporting the results of the rhGH group in the first 6 months of the double
      blind phase. CONCLUSION: RhGH treatment appears to have a beneficial effect on
      attentional performance in adult hypopituitary patients with GH deficiency when
      treated for at least 3 months. Our study does not support a role for GH in
      influencing verbal memory or non-verbal intelligence.

PMID- 15177700
TI  - Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH,
      cortisol and prolactin during sleep in healthy volunteers.
AB  - Ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue (GHS)
      receptor and some GHSs exert different effects on sleep electroencephalogram
      (EEG) and sleep-related hormone secretion in humans. Similar to GH-releasing
      hormone (GHRH) ghrelin promotes slow-wave sleep in humans, whereas GH-releasing
      peptide-6 (GHRP-6) enhances stage 2 nonrapid-eye movement sleep (NREMS). As GHRP
      6, hexarelin is a synthetic GHS. Hexarelin is superior to GHRH and GHRP-6 in
      stimulating GH release. The influence of hexarelin on sleep-endocrine activity
      and the immune system is unknown. We investigated simultaneously the sleep EEG
      and nocturnal profiles of GH, ACTH, cortisol, prolactin, leptin, tumor necrosis
      factor (TNF)-alpha, and soluble TNF-alpha receptors in seven young normal
      volunteers after repetitive administration of 4 x 50 microg hexarelin or placebo
      at 22.00, 23.00, 24.00 and 01.00 h. Following hexarelin, stage 4 sleep during the
      first half of the night, and EEG delta power during the total night decreased
      significantly. Significant increases of the concentrations of GH and prolactin
      during the total night, and of ACTH and of cortisol during the first half of the
      night were found. Leptin levels, TNF-alpha and soluble TNF receptors remained
      unchanged. We hypothesize that sleep is impaired after hexarelin since the
      GHRH/corticotropin-releasing hormone (CRH) ratio is changed in favour of CRH.
      There are no hints for an interaction of hexarelin and the immune system.

PMID- 15177701
TI  - Circulating levels of glucocorticoid hormones in WHHL and NZW rabbits: circadian
      cycle and response to repeated social encounter.
AB  - Social environment influences the progression of atherosclerosis in an important
      experimental model of disease, the Watanabe Heritable Hyperlipidemic rabbit
      (WHHL). Although the hypothalamic-pituitary-adrenocortical (HPA) system is likely
      to play an important role in the behavioral modulation of disease, relatively
      little is known about the glucocorticoid responses in these animals, or in other
      strains of rabbits. The purpose of the present study was to: (1) evaluate the
      rabbit glucocorticoid circadian rhythm, (2) compare plasma cortisol and
      corticosterone responses to social stress, and (3) examine strain differences
      (i.e., WHHL vs. New Zealand White (NZW)) in rabbit glucocorticoid responses to
      assess whether WHHLs have an aberrant HPA system. It was found that male rabbits
      secrete both corticosterone and cortisol in a circadian rhythm that peaks in the
      afternoon and reaches a nadir at 0600 h, i.e., approximately 12 h out-of-phase
      with the human glucocorticoid rhythm. Both glucocorticoids responded similarly to
      social stress induced by repeated daily 4 h pairings with another male rabbit;
      after 10 days of pairings, glucorticoid values were significantly correlated with
      the amount of defensive agonistic behavior exhibited. Finally, there were no
      significant strain differences in glucocorticoid circadian rhythms, baselines, or
      responses to social stress. These data suggest that glucocorticoid responses
      (i.e., circadian rhythms, responses to social stress) in the WHHL are similar to
      glucocorticoid responses in standard laboratory white rabbits.

PMID- 15177702
TI  - Biosocial factors, sexual orientation and neurocognitive functioning.
AB  - It has been proposed that sexual orientation related differences in cognitive
      performance are either due to the actions of prenatal factors early in
      development or the influence of gender role learning. This study examined the
      performance of 240 healthy, right-handed heterosexual and homosexual males and
      females (N = 60 per group) on a battery of cognitive tasks comprising mental
      rotation, judgement of line orientation (JLO), verbal fluency, perceptual speed
      and object location memory. Measures were also taken of the psychological gender,
      birth order, sibling sex composition and the 2nd to 4th finger length ratios of
      the right and left hands. A series of stepwise regression analyses revealed that
      sex and sexual orientation were the strongest predictors of cognitive
      performance, with IQ also contributing considerable variance. Psychological
      gender (M/F scores) added a small, but significant, amount of variance to mental
      rotation and perceptual speed scores in addition to these main factors, but
      prenatal hormone related indices, such as 2nd to 4th finger ratios, birth order
      and sibling sex composition added no independent predictive power. These findings
      are discussed in relation to biosocial influences on cognitive differences
      between heterosexuals and homosexuals.

PMID- 15177704
TI  - Thyroid function, depressed mood, and cognitive performance in older individuals:
      the Maastricht Aging Study.
AB  - The hypothesis was tested that thyroid function, as indicated by serum thyroid
      stimulating hormone (TSH) level, is associated with cognitive performance in a
      healthy aging population. In a random sample of 120 participants recruited from
      the Maastricht Aging Study (MAAS), aged between 49 and 71 years, we assessed TSH
      level, mood state (Symptom Check List, subscale depression), and three domains of
      cognitive function: verbal memory, general sensorimotor speed, and complex
      flexibility. After correction for age, sex, and educational level, a negative
      association between TSH and memory function was apparent: higher levels of TSH
      predicted lower levels of memory performance. Exclusion of individuals with TSH
      levels suspect for thyroid disorder (n=2) or who were on thyroid replacement
      (n=3) attenuated this association. Furthermore, additional control for mood
      status reduced the association below the significance level. No interaction
      between age and TSH on cognition was found, which indicated that the TSH-memory
      association was independent of age group level. We conclude that the association
      between TSH level and memory performance was small and dependent on mood status
      and the presence of (possible) thyroid disease in this relatively healthy
      population based sample. Prospective studies are needed to address the role of
      thyroid function in age-related cognitive decline.

PMID- 15177703
TI  - High levels of estrogen enhance associative memory formation in ovariectomized
      females.
AB  - The ovarian hormone estrogen is presumed to modulate processes of learning and
      memory in adulthood. In this study, we examined the effects of short-term
      estrogen replacement on associative memory formation. Adult ovariectomized female
      rats received two injections of estradiol (10, 20 or 40 microg) 24 h apart and
      were trained 4 h following each injection on the hippocampal-dependent task of
      trace eyeblink conditioning. Only the highest dose of estrogen, which produced
      plasma estradiol levels >250 pg/ml, enhanced conditioned responding. One day
      after the last injection, estrogen treated rats continued to exhibit elevated
      levels of conditioning and extinguished responding when the conditioned stimulus
      was no longer presented. Exposure to estrogen did not alter pain sensitivity or
      activity levels, but did greatly increase uterine weight. These results provide
      additional support to the view that that ovarian steroids are beneficial to the
      performance of certain forms of learning and memory tasks, albeit at
      supraphysiological doses. They are discussed with reference to hormone
      replacement and its effects on cognitive processes.

PMID- 15177705
TI  - Behavioral and physiological characterization of male mice under chronic
      psychosocial stress.
AB  - Social stress is a major factor in the etiology of several psychopathologies,
      with individuals greatly differing in vulnerability. The development of
      appropriate animal models of social stress is, thus, a major challenge of modern
      bio-medical research. Adult male mice were subjected to a new model of chronic
      psychosocial stress in which resident/intruder dyads live chronically in sensory
      contact and physically interact on a daily basis. Four behavioral categories were
      identified: Resident Dominants (RD), Resident Subordinates (RS), Intruder
      Dominants (InD), Intruder Subordinates (InS). Here we investigated: behavior
      during aggressive interactions; gross physiological components of mice
      metabolism; organ physiology; response to dexamethasone suppression test (DST).
      RD and InD mice showed persistently high levels of aggression. All four
      categories of mice showed robust lack of suppression of corticosterone level when
      challenged with the DST. Although food intake was not altered under chronic
      stress, body weight decreased in RD and InD mice while increased in InS and, even
      more so, in RS mice, suggesting an alteration of their metabolic functions. In
      conclusion, social status and territory ownership were factors determining
      individual vulnerability to stress exposure. Our model could, thus, be regarded
      as a valid model to investigate the biological basis of the individual
      differences in the response to stressful events.

PMID- 15177706
TI  - Prenatal exposure to testosterone and functional cerebral lateralization: a study
      in same-sex and opposite-sex twin girls.
AB  - In animals it has been shown that exposure to sex hormones is influenced by
      intrauterine position. Thus fetuses located between two male fetuses are exposed
      to higher levels of testosterone (T) than fetuses situated between two female
      fetuses or one female and one male fetus. In a group of opposite-sex (OS) twin
      girls and same-sex (SS) twin girls a potential effect of prenatal exposure to
      testosterone (T) on functional cerebral lateralization was investigated. We
      hypothesized that prenatal exposure to T would result in a more masculine, i.e. a
      more lateralized pattern of cerebral lateralization in OS twin girls than in SS
      twin girls. An auditory-verbal dichotic listening task (DLT) was used as an
      indirect method to study hemispheric specialization. Firstly, we established a
      sex difference on the DLT. Compared with SS girls, OS twin boys showed a more
      lateralized pattern of processing verbal stimuli. Secondly, as predicted OS girls
      had a more masculine pattern of cerebral lateralization, than SS girls. These
      findings support the notion of an influence of prenatal T on early brain
      organization in girls.

PMID- 15177707
TI  - Relationship between mood and TSH response to TRH stimulation in bipolar
      affective disorder.
AB  - Moderate to severe depression and mania are associated with a reduced thyroid
      stimulating hormone (TSH) response to TSH releasing hormone (TRH). Continued
      reduction of this response after clinical recovery seems indicative of early
      relapse. The aim of the present study was to test the relationship between mild
      changes in mood and the TSH response to TRH stimulation in patients with bipolar
      affective disorder. Nineteen outpatients with bipolar affective disorder were
      followed prospectively for three years. Every third month, mood symptoms were
      rated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Bech
      Rafaelsen Mania Scale (BRMS). A TRH test was performed in connection with each
      rating session (IV injection of 200 microg TRH), and serum TSH was measured at 0,
      20, and 60 min. The maximum TSH response (D-max TSH) and the temporal change in D
      max TSH between succeeding rating sessions (DD-max TSH) were determined.
      Psychometric rating and TRH data were obtained for a total of 198 examinations.
      The temporal change in mood symptom rating score was negatively correlated with
      the temporal change in D-max TSH, thus suggesting that increasing severity of
      mood symptoms was related to a reduced TSH response to TRH stimulation. The
      temporal change in TSH response to TRH stimulation correlated with the actual
      score on an overall index of symptom severity. In conclusion, milder fluctuations
      in mood in bipolar affective disorder seem to correlate with the TSH response to
      TRH stimulation: Increasing severity of mood symptoms seems to be associated with
      reduced TSH response.

PMID- 15177708
TI  - The effect of dawn simulation on the cortisol response to awakening in healthy
      participants.
AB  - Bright light exposure after awakening has been shown to elevate cortisol levels
      in healthy participants. The present study examined the effect of dawn simulation
      (a treatment for seasonal affective disorder) on the cortisol response to
      awakening and mood. Twelve healthy participants were supplied with a dawn
      simulator (The Natural Alarm Clock, Outside In, Cambridge Ltd), a bedside light
      that increases in intensity prior to awakening to approximately 250 lux over 30
      mins when an audible alarm sounds. A counterbalanced study was performed on 4
      consecutive normal weekdays, two of which were control days (no dawn simulation)
      and two experimental (dawn simulation). Saliva samples were taken immediately on
      awakening then at 15, 30 and 45 minutes post awakening on all 4 study-days. Total
      cortisol production during the first 45 mins after awakening was found to be
      significantly higher in the experimental condition than in the control condition.
      Participants also reported greater arousal in the experimental condition and
      there was a trend for an association between increased arousal and increased
      cortisol secretory activity under dawn simulation. This study provides supportive
      evidence for the role of light and the suprachiasmatic nucleus in the awakening
      cortisol response.

PMID- 15177709
TI  - Hormonal changes when falling in love.
AB  - To fall in love is the first step in pair formation in humans and is a complex
      process which only recently has become the object of neuroscientific
      investigation. The little information available in this field prompted us to
      measure the levels of some pituitary, adrenal and gonadal hormones in a group of
      24 subjects of both sexes who had recently (within the previous six months)
      fallen in love, and to compare them with those of 24 subjects who were single or
      were part of a long-lasting relationship. The following hormones were evaluated
      by means of standard techniques: FSH, LH, estradiol, progesterone,
      dehydroepiandrosterone sulphate (DHEAS), cortisol, testosterone and
      androstenedione. The results showed that estradiol, progesterone, DHEAS and
      androstenedione levels did not differ between the groups and were within the
      normal ranges. Cortisol levels were significantly higher amongst those subjects
      who had recently fallen in love, as compared with those who had not. FSH and
      testosterone levels were lower in men in love, while women of the same group
      presented higher testosterone levels. All hormonal differences were eliminated
      when the subjects were re-tested from 12 to 24 months later. The increased
      cortisol and low FSH levels are suggestive of the "stressful" and arousing
      conditions associated with the initiation of a social contact. The changes of
      testosterone concentrations, which varied in opposite directions in the two
      sexes, may reflect changes in behavioural and/or temperamental traits which have
      yet to be clarified. In conclusion, the findings of the present study would
      indicate that to fall in love provokes transient hormonal changes some of which
      seem to be specific to each sex.

PMID- 15177710
TI  - Testosterone shifts the balance between sensitivity for punishment and reward in
      healthy young women.
AB  - Animal research has demonstrated reductions in punishment sensitivity and
      enhanced reward dependency after testosterone administration. In humans, elevated
      levels of testosterone have been associated with violent and antisocial behavior.
      Interestingly, extreme forms of violent and antisocial behavior can be observed
      in the psychopath. Moreover, it has been argued that reduced punishment
      sensitivity and heightened reward dependency are crucially involved in the
      etiology and maintenance of psychopathy. A task that has been proven to be
      capable of simulating punishment-reward contingencies is the IOWA gambling task.
      Decisions to choose from decks of cards become motivated by punishment and reward
      schedules inherent in the task. Importantly, clinical and subclinical psychopaths
      demonstrate a risky, disadvantageous pattern of decision-making in the task,
      indicating motivational imbalance (insensitivity for punishment and enhanced
      reward dependency). Here, in a double-blind placebo-controlled crossover design
      (n = 12), whether a single administration of testosterone would shift the
      motivational balance between the sensitivity for punishment and reward towards
      this tendency to choose disadvantageously was investigated. As hypothesized,
      subjects showed a more disadvantageous pattern of decision-making after
      testosterone compared to placebo administration. These findings not only provide
      the first direct evidence for the effects of testosterone on punishment-reward
      contingencies in humans, but they also give further insights into the
      hypothetical link between testosterone and psychopathy.

PMID- 15177711
TI  - Decreased TNF-alpha and NK activity in obsessive-compulsive disorder.
AB  - BACKGROUND: Accumulating evidence points towards the involvement of autoimmune
      mechanisms in the pathophysiology of some subgroups of obsessive-compulsive
      disorder (OCD). This study was carried out to investigate whether obsessive
      compulsive disorder is associated with altered activity of the immune system, and
      whether these changes are related to particular clinical characteristics.
      METHODS: Ex vivo production of TNF-alpha, IL-4, IL-6, IL-10, and IFN-gamma in
      whole blood cultures, and NK-cell activity and peripheral blood NK cell-,
      monocytes-, T-cell-, and B-cell- percentages were measured in 50 medication-free
      outpatients with OCD and 25 controls. RESULTS: In OCD patients, we found a
      significant decrease in production of TNF-alpha (p < 0.0001) and NK-activity (p =
      0.002) in comparison with controls. No significant differences were observed in
      the other immune variables. Patients with first-degree relatives with OCD had
      significant lower NK-activity than patients who had no relatives with OCD (p =
      0.02), and patients with a childhood onset of OCD had significantly lower number
      of NK-cells than patients with a late onset (p= 0.003). CONCLUSIONS: Changes in
      TNF-alpha and NK activity suggest a potential role of altered immune function in
      the pathophysiology of obsessive-compulsive disorder.

PMID- 15177712
TI  - Salivary cortisol and short and long-term memory for emotional faces in healthy
      young women.
AB  - Elevated levels of the stress hormone cortisol are associated with increased
      episodic memory for emotional events. Elevated levels of cortisol are also seen
      in anxiety and depression disorders. Because it is well documented how both
      depression and anxiety are related to valence-specific biases in attention and
      memory, the present study sought to establish relations between basal cortisol
      levels and episodic memory for neutral, positive and negative stimuli. Thirty
      nine healthy young women performed an immediate recall and long-term (20 min)
      version of a task measuring spatial memory for neutral, happy and fearful faces.
      The sample as a whole showed a valence-specific better performance for happy
      faces than for neutral faces in the immediate recall condition, and a better
      performance for all emotional faces in the long-term condition. Salivary cortisol
      measures were found to be related to better memory for emotional faces in the
      long-term condition. This relation to cortisol was not valence-specific and is
      similar to effects predicted by a model on long-term consolidation and the
      influence of cortisol in this process.

PMID- 15177713
TI  - Chronic social stress differentially regulates neuroendocrine responses in laying
      hens: II. Genetic basis of adrenal responses under three different social
      conditions.
AB  - Chicken lines were divergently selected for both high (HGPS) or low (LGPS) group
      productivity and survivability resulting from cannibalism and flightiness in
      colony cages. Each line has unique characteristics in physical indexes, domestic
      behavior, and physiological responsiveness to stress. The differences between the
      selected lines could be reflected in differing regulation of the neuroendocrine
      system such as the hypothalamic-pituitary-adrenal axis. Change of the adrenal
      function is a key initial event in response to stress in animals, which differs
      for this trait. Comparisons between the selected lines showed that adrenal
      function was stable in HGPS hens but not in LGPS hens in response to chronic
      social stress. Social stress-induced adrenal hypertrophy and its positive
      correlation with plasma corticosterone concentrations were found in the LGPS hens
      but not in the HGPS hens. The data demonstrated that chickens selected for
      variations in productivity and survivability variously altered the adrenal system
      in response to social stressors. The results suggest that these chicken lines
      could be valuable animal models for biomedical investigation of the effect of
      genetic-environmental interactions on the neuroendocrine function in controlling
      stress responses.

PMID- 15177714
TI  - A survey of Blastocystis infection in anuran and urodele amphibians.
AB  - Blastocystis infection in amphibians was surveyed in three species of anuran and
      one species of urodele amphibians captured at two distinct locations in Japan.
      All three species of frogs were highly infected with Blastocystis, while 69
      individual urodele newts, Cynopus pyrrhogaster, were negative for infection.
      Eleven Blastocystis isolates (47.8%) were recovered from 23 Rana nigromaculata
      leopard frogs. Twenty-three (92%) of 25 Rana catesbeiana bullfrogs and all (100%)
      of 24 Bufo japonicus japonicus toads were positive for Blastocystis. Two distinct
      populations of the toad and bullfrog showed a high prevalence (100 or 84.6%) of
      Blastocystis infection, while in two populations of the leopard frog only one
      population was positive for Blastocystis (84.6%). Three Blastocystis isolates
      from different species of the frogs were established. Since none of the three
      isolates could survive at 37 degrees C, a temperature tolerance assay was
      performed to assess the optimal growth temperature and to determine the range of
      non-lethal temperatures. During the exponential growth phase of 3- or 4-day
      cultures at 25 degrees C, three isolates were exposed to 4, 28, 31, or 34 degrees
      C for 3 days and then returned to 25 degrees C to monitor the cell growth. Based
      on the optimal growth temperatures and different ranges of temperature tolerance
      among the three new isolates from frogs and two known species, Blastocystis
      hominis and Blastocystis lapemi, it was established that the three isolates
      recovered from different species of frogs had different physiological features
      from B. hominis and B. lapemi.

PMID- 15177715
TI  - Prevalence and age-related variation of Cryptosporidium species and genotypes in
      dairy calves.
AB  - Fifteen dairy farms in seven states on the east coast of the US were each visited
      on two consecutive years to determinate the prevalence of Cryptosporidium species
      in pre-weaned (5 days to 2 months) and post-weaned calves (3-11 months),
      respectively. After each of 971 fecal specimens collected directly from each calf
      was sieved and subjected to density gradient centrifugation to remove debris and
      concentrate oocysts, specimens were examined by immunofluorescence microscopy,
      and polymerase chain reaction (PCR). For all PCR-positive specimens the 18S rRNA
      gene of Cryptosporidium was sequenced. Cryptosporidium was identified from all
      farms. Types of housing appeared to have no influence with regard to prevalence
      of infection. Of 971 calves, 345 were infected with Cryptosporidium (35.5%), but
      more pre-weaned calves (253 of 503; 50.3%) than post-weaned calves (92 of 468;
      19.7%) were found to be infected. A total of 278 PCR-positive specimens
      characterized by gene sequencing revealed Cryptosporidium parvum, Cryptosporidium
      andersoni, and two unnamed Cryptosporidium genotypes Bovine B (AY120911) and deer
      like genotype (AY120910). The prevalence of these Cryptosporidium species and
      genotypes appeared to be age related between pre- and post-weaned calves. C.
      parvum, the only zoonotic species/genotype, constituted 85% of the
      Cryptosporidium infections in pre-weaned calves but only 1% of the
      Cryptosporidium infections in post-weaned calves. These findings clearly
      demonstrate that earlier reports on the presence and prevalence of C. parvum in
      post-weaned cattle that were based solely on oocyst morphology must be reassessed
      using molecular methods to validate species and genotype. This finding also
      indicates that persons handling or otherwise exposed to calves under 2 months of
      age are at greater risk of zoonotic infection from Cryptosporidium than the risk
      of infection from exposure to older calves.

PMID- 15177716
TI  - Confirmation of occurrence of Babesia canis vogeli in domestic dogs in South
      Africa.
AB  - The prevalence of Babesia infections in domestic dogs in South Africa was studied
      using reverse line blot hybridization and 18S sequence analysis. Babesia canis
      vogeli was confirmed for the first time in domestic dogs in South Africa. Out of
      a total of 297 blood samples collected from domestic dogs in Bloemfontein, East
      London, Johannesburg, Durban and from the Onderstepoort Veterinary Academic
      Hospital, 31 were positive for Babesia canis rossi, whereas B. c. vogeli was
      detected in 13 dogs. None of the dogs carried both parasites. The detection of B.
      c. vogeli has implications with regard to prevalence and varied clinical
      manifestation of canine babesiosis in South Africa.

PMID- 15177717
TI  - Babesia divergens (Phylum Apicomplexa) in vitro growth in the presence of calf
      serum.
AB  - Resistance to severe babesiosis in young calves has frequently been ascribed to
      an unknown serum factor(s) which inhibits growth of Babesia bovis in vitro. Our
      experiments show that young calf sera are as suitable as adult bovine sera for
      the in vitro culture of Babesia divergens, indicating that in this species at
      least inverse age resistance is due to alternative mechanisms. The suitability of
      commercial foetal calf sera for B. divergens cultures seems highly variable.

PMID- 15177718
TI  - An enzyme-linked immunosorbent assay for antibodies to Hepatozoon canis.
AB  - Canine hepatozoonosis is a tick-borne protozoal disease caused in the Old World
      and South America by Hepatozoon canis. An enzyme-linked immunosorbent assay
      (ELISA) using purified H. canis gamont antigen was applied for the detection of
      antibodies reactive with H. canis. Evaluation of the ELISA with sera from
      naturally infected parasitemic dogs indicated that it was sensitive (86%),
      specific (97%), and comparable to the indirect fluorescent antibody test (IFAT)
      for the detection of H. canis antibodies. A variable degree of serologic cross
      reactivity was found between sera from H. americanum-infected dogs and the H.
      canis antigen. Dogs experimentally infected with H. canis seroconverted 1-4 weeks
      post-infection (PI). Antibody levels peaked at 7-9 weeks PI and gradually
      declined thereafter remaining above the cut-off value until the conclusion of the
      study 7 months PI. The ELISA will be valuable for serological evaluation of dogs
      suspected of exposure to H. canis and for epidemiological studies.

PMID- 15177719
TI  - A geographic information systems model for mapping risk of fasciolosis in cattle
      and buffaloes in Cambodia.
AB  - A geographic information systems (GIS) model for mapping the risk of fasciolosis
      in cattle and buffaloes was developed for the Kingdom of Cambodia using
      determinants of inundation, proximity to rivers, land use, slope, elevation, and
      the density of cattle and buffaloes. Determinants were subjectively weighted
      according to their perceived relative importance before combining them to produce
      a risk-map of fasciolosis. The model estimates that 28% of Cambodia is
      potentially at risk of fasciolosis with areas of high and moderate risk
      concentrated in southern and central Cambodia. The estimates of risk reflect the
      actual prevalence of fasciolosis in most districts surveyed, suggesting that the
      epidemiological determinants and weightings used to produce the model were
      appropriate. These results will be progressively refined as more detailed field
      surveys are completed to fully validate the model.

PMID- 15177720
TI  - Evaluation of the anthelmintic activity of Khaya senegalensis extract against
      gastrointestinal nematodes of sheep: in vitro and in vivo studies.
AB  - The anthelmintic effect of Khaya senegalensis is described. In vitro and in vivo
      studies were conducted to determine possible direct anthelmintic effects of
      ethanolic and aqueous extracts of K. senegalensis towards different ovine
      gastrointestinal nematode. A larval development assay was used to investigate in
      vitro, the effect of aqueous and ethanolic extracts towards larvae of strongyles.
      The LC50 values of the effects of both the aqueous and ethanolic extracts were
      calculated. Another study was conducted in vivo to evaluate the therapeutic
      efficacy of the extracts administered orally at a dose rate of 125, 250 and 500
      mg/kg of sheep harbouring naturally acquired infection of gastrointestinal
      nematodes. The presence of K. senegalensis extracts in the cultures decreased the
      viability of larvae. The LC50 of the aqueous extract (0.69 mg/ml) is not
      significantly different (P >0.05, t-test) from the ethanolic extract (0.51
      mg/ml). The activity of the extract is concentration dependent in vivo. Sheep
      drenched with 500 mg/kg K. senegalensis ethanolic extract had a mean faecal egg
      count (FEC) reduction of 88.82%. The extract of K. senegalensis could find
      application in anthelmintic therapy in veterinary practice.

PMID- 15177721
TI  - Parasitic health of olive baboons in Bwindi Impenetrable National Park, Uganda.
AB  - This study examined the endoparasite load of a group of olive baboons (Papio
      cynocephalus anubis) that share their habitat with a population of mountain
      gorillas (Gorilla gorilla berengei) in Bwindi Impenetrable National Park, Uganda.
      During a 2-week period in June 2002, shared habitat was substantiated by noting
      the ranging patterns of both species and recording observations and trail remains
      with a global positioning system (GPS). Parasite load was determined by
      collecting fecal samples preserved in 10% formalin and analyzed by sedimentation
      techniques and immunofluorescent antibodies (IFA). Bwindi baboons were infected
      with Cryptosporidium, Giardia, Eimeria, Ascaris spp., Strongyloides spp.,
      Trichuris spp., Hymenolepis spp., and Ternidens diminuta. Of these, the Bwindi
      mountain gorillas had previously been found to carry Cryptosporidium, Giardia,
      Strongyloides spp., and Trichuris spp., but not Eimeria, Ascaris, Hymenolepis, or
      T. diminuta. This study is the first to record Giardia in olive baboons and
      demonstrates that at least three parasite species in Bwindi baboons have yet to
      be found in Bwindi gorillas. Early monitoring is essential to the health and well
      being of both of these sympatric primate species, especially as they continue to
      interact more often and over a larger area.

PMID- 15177722
TI  - Two-dimensional DNAPL migration affected by groundwater flow in unconfined
      aquifer.
AB  - The dense non-aqueous phase liquid (DNAPL) migration process was experimentally
      investigated in a laboratory-scale tank (150 cm width, 82.5 cm height, and 15 cm
      depth) to assess a site characterization on DNAPL contamination below a
      groundwater table. The heterogeneous ground of the tank model consisted of
      Toyoura sand (hydraulic conductivity, k = 1.5 x 10(-2) cm/s for void ratio, e =
      0.62) and silica #7 sand (k = 2.3 x 10(-3) cm/s for e = 0.72). A series of
      experiments was carried out with or without lateral groundwater flow.
      Hydrofluoroether was used as a representative DNAPL. The main results obtained in
      this study are as follows: (1) the DNAPL plume does not invade into the less
      permeable soil layer with higher displacement pressure head; (2) the DNAPL plume
      migrates faster with lateral groundwater flow than without it; (3) lateral
      groundwater flow does not affect lateral DNAPL migration; rather, it promotes
      downward migration; and (4) pore DNAPL pressure without groundwater flow is
      higher than that with it. The above experimental results were compared with
      numerical analysis. The fundamental behaviors of DNAPL source migration observed
      experimentally are expected to be useful for assessing the characteristics of two
      dimensional DNAPL migration in an aquifer.

PMID- 15177723
TI  - A review of NAPL source zone remediation efficiency and the mass flux approach.
AB  - A number of previous studies are reviewed to examine the actual reduction of NAPL
      from source zones and the effectiveness of the specific technique of remediation
      used at sites under study. It has been shown that complete removal of the NAPL in
      free phase or residual is not possible due to the complex entrapment architecture
      of NAPLs at field sites. Consequently, the assessment of remediation efficiency
      should not be solely based on the reduction of entrapped NAPL mass from source
      zone. Instead, it should be based on the reduction of risk achieved through the
      lowering of the concentration of the dissolved constituents emanating from the
      entrapped NAPL during source zone clean-up. The prediction of the concentration
      in the plume requires a knowledge of the dissolution of NAPLs in the source zone.
      Attention is directed to the need for the understanding the mass transfer from
      entrapped NAPLs in the source zone before and after remediation. In this paper,
      the current knowledge of mass transfer processes from the non-aqueous phase to
      the aqueous phase is summarised and the use of mass flux measurements (monitoring
      the concentration of contaminants in aqueous phase due to source zone NAPL
      groundwater mass transfer) is introduced as a potential tool to assess the
      efficiency of technologies used in source zone remediation. Preliminary results
      of numerical simulations reveal that factors such as source zone morphology as
      determined by the heterogeneity of the formation control the post-remediation
      dissolution behaviour, than the local mass transfer. Thus, accurate site
      characterization is essential for predicting NAPL dissolution and mass flux
      relationships as well as for assigning site-specific remediation target values.

PMID- 15177724
TI  - Studies of channel sediments contaminated with organics and heavy metals.
AB  - The paper discusses the geo-environmental studies carried out to revitalise a
      silted up channel in Guanabara Bay. A dredging operation has been planned to
      remove about 1.5 million cubic meters of contaminated sediment. Investigations
      were performed to characterise the sediment in terms of its physical and chemical
      properties and to evaluate the presence of heavy metals and organic compounds,
      particularly polycyclic aromatic hydrocarbons PAH. Finally, dredging and disposal
      schemes are briefly outlined based on measured contamination levels.

PMID- 15177725
TI  - Recovery of dodecane, octane and toluene spills in sandpacks using ethanol.
AB  - This paper is an extension of the work of Grubb et al. on the recovery of lighter
      than-water non aqueous phase liquids (LNAPLs) from sandpacks. Dodecane, toluene
      and octane (500 mL each) were used to simulate fresh and weathered petroleum
      spills. The ethanol flooding experiments evaluated the feasibility of recovering
      the LNAPLs from unconfined uniform sandpacks in a quasi two-dimensional
      apparatus. A combined pure ethanol and 50/50 (vol.%) ethanol-water blend flooding
      strategy successfully mobilized and recovered the simulated large-volume LNAPL
      spills (10x greater than previous studies). At flow rates < 7 m per day, the
      toluene and octane recoveries were approximately 84.9 and 88.1%, respectively,
      which are considered impressive as no optimization was even attempted.

PMID- 15177726
TI  - Bench- and field-scale evaluation of chromium and cadmium extraction by
      electrokinetics.
AB  - The results of bench-scale laboratory tests and in situ, pilot-scale
      demonstration of electrokinetic extraction of chromium and cadmium from
      contaminated soil are presented. The laboratory tests were conducted using 10 cm
      long samples under current density of 5A/m(2) for 1200 h. Tests were conducted
      with and without citric acid amendment at the cathode. The results showed that
      citric acid improved extraction, especially in the sections near the cathode.
      However, processing was not enough to result in complete cleanup. The field demo
      was conducted at the Naval Air Weapon Station (NAWS), Point Mugu, California.
      Three cathodes were centered between six anodes. The anode-cathode spacing was
      4.45 m (15 ft). Constant voltage of 60 V ( approximately 13 V/m) was applied for
      20 days and then was reduced to 45 V (10 V/m) for 6 months. Citric acid was used
      to maintain the cathode pH at 4. After 6 months of treatment, 78% of the soil
      volume has been cleared of chromium or treated to below natural background
      levels. The results also indicated that 70% of the soil between the electrodes
      had been cleared of cadmium contamination. A comparison between the bench-scale
      and field demo showed that the field process was more effective than the lab
      tests. This indicated that small sample size will induce a negative effect on the
      efficiency of the process due to an increased impact of the boundaries on the
      overall process.

PMID- 15177727
TI  - Evaluation of bioventing on a gasoline-ethanol contaminated undisturbed residual
      soil.
AB  - Remediation methods for environmental contamination problems based on physical or
      chemical processes frequently present low efficiency and/or high costs. On the
      other hand, biological treatment is being proved to be an accessible alternative
      for soil and water remediation. Bioventing is commonly used for petroleum
      hydrocarbon (PHC) spills. This process provides better subsurface oxygenation,
      thus stimulating degradation by indigenous microorganisms. In Brazil, gasoline
      and ethanol are routinely mixed; some authors suggest that despite gasoline high
      degradability, its degradation in the aquifer is hindered by the presence of much
      rapidly degrading ethanol. The present study evaluates a bioventing treatment of
      a gasoline-ethanol contaminated undisturbed residual soil from Rio de Janeiro.
      Contamination and treatment effects were monitored by conventional microbiology
      methods, chemical analysis, and ground penetrating radar (GPR) measurements.
      Results of culturable bacterial population counts show the effect of
      contamination and bioventing on the microbiota of gasoline and gasoline-ethanol
      containing soils; however, GPR responses to these variations are not conclusive
      and still need to be assessed.

PMID- 15177728
TI  - Bioleaching of heavy metals from a low-grade mining ore using Aspergillus niger.
AB  - The main concern of this study is to develop a feasible and economical technique
      to microbially recover metals from oxide low-grade ores. Owing to the significant
      quantities of metals that are embodied in low-grade ores and mining residues,
      these are potential viable sources of metals. In addition, they potentially
      endanger the environment, as the metals they contain may be released to the
      environment in hazardous form. Hence, mining industries are seeking an efficient,
      economic technique to handle these ores. Pyrometallurgical and hydrometallurgical
      techniques are either very expensive, energy intensive or have a negative impact
      on the environment. For these reasons, biohydrometallurgical techniques are
      coming into perspective. In this study, by employing Aspergillus niger, the
      feasibility of recovery of metals from a mining residue is shown. A. niger
      exhibits good potential in generating a variety of organic acids effective for
      metal solubilization. Organic acid effectiveness was enhanced when sulfuric acid
      was added to the medium. Different agricultural wastes such as potato peels were
      tested. In addition, different auxiliary processes were evaluated in order to
      either elevate the efficiency or reduce costs. Finally, maximum solubilization of
      68%, 46% and 34% were achieved for copper, zinc and nickel, respectively. Also
      iron co-dissolution was minimized as only 7% removal occurred.

PMID- 15177729
TI  - Field vapor extraction test and long-term monitoring at a PCE contaminated site.
AB  - The results of a field investigation, vapor extraction tests, and long-term
      monitoring at a PCE-contaminated site in Saga, Japan, are reported. The field
      investigation indicated that PCE likely was trapped in a surface clayey sand
      layer (vadose zone), and soil vapor extraction (SVE) was adopted as the
      remediation approach. The field test results the effectiveness of SVE in removing
      volatile organic compounds (VOCs) from contaminated sites. For the case where the
      radius of influence for an extraction well was 15-20 m, the blower capacity had
      no obvious effect on the radius of influence possibly due to the short circuiting
      of air from the ground surface. However, the maximum negative pressure
      (difference between vapor pressure and ambient pressure) in the extraction well
      was approximately proportional to blower capacity for the range of blower
      capacities tested. The long-term monitoring results indicate that PCE
      concentration varied seasonably, and temperature and rainfall are two of the
      influencing factors.

PMID- 15177730
TI  - Anaerobic biodegradation of an organic by-products leachate by interaction with
      different mine tailings.
AB  - Deinking by-products from paper recycling have been used as cover materials on
      acid-producing tailings. Due to residual cellulose, anaerobic degradation leads
      to the production of an organic-rich leachate, which may percolate through the
      tailings. This study aims at describing the influence of the tailings'
      characteristics on the attenuation of organic matter in leachate and at
      discussing the degradation mechanisms. To this end, leachate was mixed with
      different types of tailings, including three unoxidized tailings with varying
      acid generation potentials and one tailing in three states of oxidation.
      Regularly, selected biochemical parameters were analyzed to access the evolution
      of organic components. The results show that when leachate from deinking by
      products was placed in contact with tailings, phase and acid-base balance
      reactions took place in the beginning. Subsequently, oxidation-reduction
      reactions dominated the chemistry of the system. The type, the constituents, and
      the state of oxidation of the mine tailings condition the mechanisms of
      biodegradation of organic components. Methanogenesis was predominant in the
      control sample (pure organic leachate) but was absent in all leachate-tailings
      mixtures. No biodegradation was observed in the liquid phase for oxidized
      tailings and the organic concentration remained constant for unoxidized tailings,
      independently of the acid-generation potential. The biodegradation efficiency was
      optimal when the leachate was in contact with a mixture of oxidized and
      unoxidized tailings due to sulfate-reduction.

PMID- 15177731
TI  - Laboratory tests for reactive barrier design.
AB  - Owing to limitations of pump-and-treat, several technologies are being
      investigated for groundwater treatment. One of the most promising is the
      treatment of contaminants through the use of reactive barriers installed in situ,
      especially in the case of aquifers contaminated with chlorinated solvents. This
      work presents results of batch and column tests with metallic iron and some
      chlorinated solvents (1,2-DCA, 1,1,2-TCA and TCE). Such tests provided means to
      evaluate the degradation rates of these compounds and their byproducts. It is
      concluded that the reductive dechlorination with metallic iron can have different
      results, depending on the type of contaminant. Some contaminants may not present
      any degradation, or they have a half-life time so high that the use of the
      reactive barrier technology may not be practical. Furthermore, the formation of
      chlorinated byproducts, eventually more toxic than the original contaminant and
      that are not degradable using this same technology, emphasises that the treatment
      of aquifers should be sequential.

PMID- 15177732
TI  - A new procedure for treatment of oily slurry using geotextile filters.
AB  - A new procedure to mitigate the environmental impacts and reduce the cost of
      disposal of oil slurry is present in this paper. Waste from the petroleum
      industry has a high environmental impact. Systems for oil-water separation have
      been used to mitigate the contamination potential of these types of effluents. At
      the outlet of these systems, the oil is skimmed-off the surface, while the slurry
      is removed from the base. Due to the high concentration of contaminants, the
      disposal of this slurry is an environmentally hazardous practice. Usually this
      type of waste is disposed of in tanks or landfills after removal from the
      industrial plant. Basically, the proposed procedure utilizes drying beds with
      geotextile filters to both reduce the water content in the slurry and obtain a
      less contaminated effluent. Laboratory tests were carried out to simulate the
      drying system. Four types of filters were analyzed: two non-woven geotextiles,
      one woven geotextile, and a sand filter.

PMID- 15177733
TI  - Soil vapor extraction of chlorinated solvents at an industrial site in Brazil.
AB  - This study presents the design, monitoring and remediation strategy for a soil
      vapor extraction (SVE) system installed at an industrial site contaminated with a
      mixture of organic compounds, in particular 1,2 dichloroethane, carbon
      tetrachloride and chloroform. The unsaturated zone at the site is very deep and
      presents near ideal conditions for SVE, with the contaminated portion of the
      porous media characterized by alluvial deposits of a well graded sand followed by
      a capillary barrier at 28m of depth, which limited DNAPL downward migration. The
      soil cleanup time and the optimal removal rates of mass, considering different
      values of vacuum/discharge applied in the SVE system, have been estimated through
      the use of numerical sensitivity analysis. Results of the pilot-scale testing
      activities allowed for the calibration of flow and contaminated mass transport
      models and the determination, in a preliminary phase, of the infiltrated mass of
      different compounds.

PMID- 15177734
TI  - Natural attenuation of chlorinated organics in a shallow sand aquifer.
AB  - This work presents the second phase of a groundwater remediation program for the
      migration control of a 1,2-dichloroethane (1,2-DCA) contaminated plume which
      includes natural attenuation at a distance downgradient from the source area. The
      conceived system for the plume migration control, implemented just after a major
      accidental release of 1,2-DCA in the soil, included a 300 m long physical barrier
      (cement-bentonite diaphragm wall) and 12 extraction wells. Results of field
      investigations have provided evidence that 1,2-DCA was naturally biodegrading
      into vinyl chloride as well as ethene under the natural anaerobic-reducing
      conditions at the site. In that case, source control measures were implemented to
      accelerate the overall remediation process. Although the results are favorable,
      the natural degradation of the 1,2-DCA does not guarantee acceptable levels of
      concentrations. Therefore, a pilot test to evaluate the enhancement of these
      processes is being carried out through the use of a biosparging system. This test
      is being implemented near the source to achieve sequential aerobic-anaerobic
      treatment zones.

PMID- 15177735
TI  - Computational modelling of final covers for uranium mill tailings impoundments.
AB  - To properly design a final cover for uranium mill tailings impoundments the
      designer must attempt to find an effective geotechnical solution which addresses
      the radiological and non-radiological potential impact and prevents geochemical
      processes from occurring within the tailings. This paper presents a computer
      based method for evaluating the performance of engineered final covers for the
      remediation of uranium mill tailings impoundments. Three hypothetical final
      covers were taken from scientific literature to investigate the proposed method:
      (i) a compacted clay liner (CCL); (ii) a composite liner (CL) and (iii) a
      capillary barrier (CB). The processes investigated: (i) the saturated hydraulic
      flux; (ii) the unsaturated hydraulic flux (exclusively for the capillary barrier)
      and (iii) the radon exhalation to the atmosphere. The computer programs utilised
      for the analyses are: (i) Hydrologic Evaluation of Landfill Performance (HELP);
      (ii) SEEP/W and (iii) RADON. The site considered for the development of the
      research presented herein was the uranium mill tailings impoundment located at
      the Brazilian city of Pocos de Caldas, in the Minas Gerais State.

PMID- 15177736
TI  - Embedding expert knowledge in a decision model: evaluating natural attenuation at
      TCE sites.
AB  - This paper describes a generalized methodology that enables the translation of
      expert knowledge about any complex process involved in a remedial decision into
      easy-to-use decision tools. The methodology is applied to evaluate reductive
      dechlorination as a remedial possibility at sites contaminated with
      trichloroethene (TCE), building on an existing protocol/scoring system put forth
      by the US Air Force and the US EPA. An alternate scoring system is proposed,
      which has two major advantages, namely that it: (i) attributes relative weights
      to findings based on expert beliefs; and (ii) systematically includes negative
      weights for negative findings. The ability of the proposed scoring system to
      assess the bioattenuation potential of TCE is demonstrated using data from
      extensively studied sites.

PMID- 15177737
TI  - Oil spills debris clean up by thermal desorption.
AB  - Oil spills represent a significant environmental issue in Brazil. This paper
      presents the latest results of a comprehensive experimental programme aimed at
      understanding how the presence of spilled oil affects the properties of sands and
      at studying alternatives to remediate the affected shores. Results indicate that
      oil causes a slight increase in grain size and uniformity, and oiled debris
      presents a smaller void ratio but a larger unit weight. It was also observed that
      effective strength parameters for both the natural and oiled debris were the same
      although the undrained strength of a natural sand is much higher than that of the
      contaminated sand. At ambient temperature, oiled debris emits methane and
      ammonia, and these emissions tend to increase with rising temperatures. On the
      other hand, the oil and grease content from oiled debris decreases with rising
      temperature and prolonged exposure. Finally, in situ thermal desorption seems to
      be a promising method for cleaning debris from oil spills. It is simple, fast and
      avoids all the difficulties associated with digging up the soil for disposal or
      cleanup.

PMID- 15177738
TI  - Effect of NAPL entrapment conditions on air sparging remediation efficiency.
AB  - The effect of soil heterogeneity and the entrapment condition of NAPL source on
      the mass removal efficiency of air sparging coupled with soil vapour extraction
      (AS/SVE) was investigated using an intermediate scale two-dimensional laboratory
      soil tank. Four different NAPL entrapments were created by varying the height of
      the water table in heterogeneous soil models. Different mass removal efficiencies
      were achieved for different NAPL entrapment conditions, which were governed by
      soil heterogeneity and water table height before and during AS/SVE operation.
      Remobilization and redistribution of toluene and water improved the mass removal.
      Overall results suggested that it was difficult to achieve the complete
      remediation of NAPL source due to complex entrapment in heterogeneous soil
      system. In order to assess the potential contamination in the post-remediation
      stage, gas and dissolved concentrations of toluene were measured after the AS/SVE
      operation. The results showed that gas concentration close to remaining NAPL
      source zone increased rapidly and reached to steady state values, which were much
      smaller than the vapour pressure, whereas the aqueous phase concentrations
      increased continuously toward the solubility limit.

PMID- 15177739
TI  - Proceedings of the Fourth International Congress on Environmental Geotechnics.
      August 2002. Rio de Janeiro, Brazil.

PMID- 15177740
TI  - Planning for protective action decision making: evacuate or shelter-in-place.
AB  - Protecting the public from an airborne hazardous chemical release requires that
      appropriate protective actions be selected quickly. When deciding whether to
      recommend evacuation or shelter-in-place, decision makers must weigh the
      interaction of numerous factors that characterize the release, the meteorological
      conditions, and the populations that may be affected. This article examines the
      components of the protective action decision process and describes steps that
      should be taken in a planning context to prepare for efficient decision making
      during an emergency. Methods of organizing information to facilitate decision
      making are identified, and a model useful for detailed analysis of specific
      emergency scenarios is described.

PMID- 15177741
TI  - Measurement and numerical analysis of flammability limits of halogenated
      hydrocarbons.
AB  - Flammability limits measurement was made for a number of halogenated compounds by
      the ASHRAE method. Most of compounds measured are the ones for which discrepancy
      was noted between the literature values and predicted values of flammability
      limits. As a result, it has been found that most of the newly obtained values of
      flammability limits are not in accordance with the literature values. Numerical
      analysis was carried out for a set of flammability limits data including the
      newly obtained ones using a modified analytical method based on F-number scheme.
      In this method, fitting procedure was done directly to flammability limits
      themselves instead of fitting to F-number. After the fitting process, the average
      relative deviation between the observed and calculated values is 9.3% for the
      lower limits and 14.6% for the upper limits.

PMID- 15177742
TI  - Waste green sands as reactive media for groundwater contaminated with
      trichloroethylene (TCE).
AB  - Waste green sands are byproducts of the gray iron foundry industry that consist
      of sand, binding agents, organic carbon, and residual iron particles. Because of
      their potential sorptive and reactive properties, tests were conducted to
      determine the feasibility of using waste green sands as a low cost reactive
      medium for groundwater treatment. Batch and column tests were conducted to
      determine the reactivity, sorptive characteristics, and transport parameters for
      trichloroethylene (TCE) solutions in contact with green sands. Normalized rate
      constants for TCE degradation in the presence of iron particles extracted from
      green sands were found to be comparable to those for Peerless iron, a common
      medium used to treat groundwater. Rate constants and partition coefficients
      obtained from the batch tests were found to be comparable to those from the
      column tests. Analytical modeling shows that reactive barriers containing green
      sand potentially can be used to treat contaminated groundwater containing TCE at
      typical concentrations observed in the field.

PMID- 15177743
TI  - Removal of sulfide, sulfate and sulfite ions by electro coagulation.
AB  - The removal of various species of sulfur from beamhouse of tannery wastewater and
      also from synthetic samples was studied by electro-flotation technique.
      Consumable anodes of iron and aluminum and insoluble anode of titanium were
      tested as anodes. It was found that iron and aluminum anodes were effective for
      the removal of suspended solids, sulfide, sulfite and sulfate. Progress of
      simultaneous coagulation of suspended solids during electro-flotation was
      measured using particle size analysis. Coagulation was found to be essential for
      effective flotation of suspended solids. Metal ions generated in situ by
      electrolytic oxidation of anode were found to react with dissolved sulfide ions.
      Metal sulfides thus formed as colloidal suspension were coagulated and floated
      simultaneously by hydrogen bubbles generated from cathode. Simultaneous
      occurrence of precipitation, coagulation and flotation was observed during
      electro-flotation. X-ray diffraction studies were conducted to identify the
      nature of sulfide phase formed during electrolytic precipitation. The effect of
      pH, current density and initial concentration of pollutants was studied and the
      results are discussed. The removal of sulfite and sulfate ions is explained by
      zeta-potential measurements.

PMID- 15177744
TI  - Environmental behavior of cement-based stabilized foundry sludge products
      incorporating additives.
AB  - A series of experiments were conducted to stabilize the inorganic and organic
      pollutants in a foundry sludge from a cast iron activity using Portland cement as
      binder and three different types of additives, organophilic bentonite, lime and
      coal fly ash. Ecotoxicological and chemical behavior of stabilized mixes of
      foundry sludge were analyzed to assess the feasibility to immobilize both types
      of contaminants, all determined on the basis of compliance leaching tests. The
      incorporation of lime reduces the ecotoxicity of stabilized mixes and enhances
      stabilization of organic pollutants obtaining better results when a 50% of cement
      is replaced by lime. However, the alkalinity of lime increases slightly the
      leached zinc up to concentrations above the limit set under neutral conditions by
      the European regulations. The addition of organophilic bentonite and coal fly ash
      can immobilize the phenolic compounds but are inefficient to reduce the
      ecotoxicity and mobility of zinc of final products.

PMID- 15177745
TI  - Effect of pyrolysis on solvent extractability of toxic metals from chromated
      copper arsenate (CCA)-treated wood.
AB  - Solvent extraction was conducted to investigate the behavior of toxic metals in
      chromated copper arsenate (CCA)-treated wood and its pyrolysis residue. Four
      kinds of solvents, along with sulfuric and phosphoric acid as mineral agents, and
      citric and oxalic acid as complexing agents, were used. The CCA elements from the
      wood treated without pyrolysis were easily extracted. However, only a small
      amount of CCA elements were extracted from the pyrolyzed residue, even under very
      low pH conditions. The toxic elements in the pyrolyzed wood showed high
      stabilization against the solvent extraction. Pyrolysis strongly immobilized the
      toxic elements in the residue. Therefore, pyrolysis is not suitable as a
      pretreatment.

PMID- 15177746
TI  - Characterization of steel mill electric-arc furnace dust.
AB  - In order to make a complete characterization of electric-arc furnace (EAF) dust,
      as hazardous industrial waste, and to solve its permanent disposal and/or
      recovery, bearing in mind both the volumes formed in the Croatian steel industry
      and experiences of developed industrial countries, a study of its properties was
      undertaken. For this purpose, samples of EAF dust, taken from the regular
      production process in the Zeljezara Sisak Steel Mill between December 2000 and
      December 2001, were subjected to a series of tests. The chemical composition of
      EAF dust samples was investigated by means of a several different analytical
      methods. The results from the chemical analysis show that the approximate order
      of abundance of major elements in EAF dusts is as follows: Fe, Zn, Mn, Ca, Mg,
      Si, Pb, S, Cr, Cu, Al, C, Ni, Cd, As and Hg. Granular-metric composition of
      single samples was determined by applying sieve separation. Scanning electron
      micro-structural examination of EAF dust microstructure was performed and results
      indicated that all twelve EAF dusts were composed of solid spherical agglomerates
      with Fe, Zn, Pb, O, Si and Ca as the principal element. The investigation of
      grain morphology and the mineralogical composition of EAF dust were taken by
      combination of high resolution Auger electron spectroscopy (HR AES), X-ray
      photoelectron spectroscopy (XPS) and X-ray powder diffraction analysis. The
      analysis of XPS-spectra determined the presence of zinc in the form of ZnO phase
      and the presence of lead in the form of PbO phase, i.e. PbSO3/PbSO4 forms. The
      results of the X-ray diffraction phase analysis show that the basis of the
      examined EAF dust samples is made of a mixture of metal oxides, silicates and
      sulphates. The metal concentration, anions, pH value and conductivity in water
      eluates was determined in order to define the influence of EAF dust on the
      environment.

PMID- 15177747
TI  - Chromium removal from aqueous solution by the ferrite process.
AB  - This research summarises the results of the study on the removal of chromium by
      applying the ferrite process to the solutions obtained from two different Cr(VI)
      reduction processes utilising sodium sulphite and ferrous sulphate as reducing
      agents. For both solutions containing trivalent chromium ions, the optimum
      treatment conditions were determined. The generated sludges were characterised by
      XRD analysis and physical tests. In addition, to explore the dissolution
      properties of the sludges obtained, they were contacted with the solutions of
      sulphuric, citric, tartaric, oxalic and ascorbic acids and EDTA. Also, the sludge
      samples were subjected to standard toxicity characterisation leaching procedure
      (TCLP) test of USEPA in order to determine the pollution potential. An efficient
      Cr(III) removal (about 100%) in the solution from the Cr(VI) reduction process
      utilising sodium sulphite as reducing agent was achieved when the solution was
      treated at pH 9 and 50 degrees C for 60 min in the presence of Fe2+/Cr3+ weight
      ratio of 16. For the other Cr(III) solution prepared from Cr(VI) reduction by
      ferrous sulphate, a Fe2+/Cr3+ weight ratio of 17.9 at the same conditions was
      found to produce complete removal of Cr(III). It was determined that the spynel
      chromium-iron compounds obtained in the process were in the form of chromite
      (Cr2FeO4). Dissolution experiments and TCLP tests show that the concentrations of
      the chromium dissolved from both sludges were below the limit given as 5 mg l(-1)
      by USEPA. The results showed that Cr(III) removal through ferrite process
      provides the advantages that the sludges generated are non-voluminous, easily
      separable and environmentally stable.

PMID- 15177748
TI  - Metal behavior during vitrification of incinerator ash in a coke bed furnace.
AB  - In this study, municipal waste incinerator ash was vitrified in a coke bed
      furnace system and the behavior of metals was investigated. Coke and lime were
      added to provide heat which facilitated vitrification. Ash contributed more than
      90% of metal (except for Ca) input-mass. Metal species with low boiling points
      accounted for the major fraction of their input-mass adsorbed by air pollution
      control devices (APCDs) fly ash. Among the remaining metals, those species with
      light specific weights in this furnace tended to be encapsulated in slag, while
      heavier species were mainly discharged by ingot. Meanwhile, the leachability of
      hazardous metals in slag was significantly reduced. The distribution index (DI)
      was defined and used as an index for distribution of heavy metals in the system.
      A high DI assures safe slag reuse and implies feasibility of recovering hazardous
      heavy metals such as Cr, Cu, Fe, Pb and Zn. The vitrification in a coke bed
      furnace proved to be a useful technology for the final disposal of MSW
      incinerator ash. The heavy metals are separated into the slag, ingot and fly ash,
      allowing safe reuse of the slag and possible recovery of the metals contained in
      the ingot and ash fractions.

PMID- 15177749
TI  - Comparison of several advanced oxidation processes for the decolorization of
      Reactive Red 120 azo dye in aqueous solution.
AB  - In this study UV/TiO2, electro-Fenton (EF), wet-air oxidation (WAO), and
      UV/electro-Fenton (UV/EF) advanced oxidation processes (AOPs) have been applied
      to degrade Reactive Red 120 (RR120) dye in aqueous solution. The most efficient
      method on decolorization and mineralization of RR120 was observed to be WAO
      process. Photocatalytic degradation of RR120 by UV/TiO2 have been studied at
      different pH values. At pH 3 photocatalytic degradation kinetics of RR120
      successfully fitted to Langmuir-Hinshelwood (L-H) kinetics model. The values of
      second order degradation rate (k") constant and adsorption constant (K) were
      determined as 4.525 mg L(-1) min(-1) and 0.387 L mg(-1), respectively.
      Decolorization efficiency observed in the order of WAO > UV/TiO2 = UV/EF > EF
      while WAO > UV/TiO2 > UV/EF > EF order was observed in TOC removal
      (mineralization). For all AOPs, it was found that degradation products in
      reaction mixture can be disposed safely to environment after 90 min treatment.

PMID- 15177750
TI  - Environmental behaviour of stabilised foundry sludge.
AB  - Environmental characterisation of foundry sludge (FS) and the
      stabilised/solidified (S/S) derived products has been performed according to the
      leaching behaviour. Portland cement and lime have been used as binders and
      foundry sand fines, activated carbon and black carbon have been used as additives
      in the S/S processes. The results of the characterisation show that the behaviour
      of the waste in acid media is mainly influenced by the inorganic components of
      the waste, while the organic matter only has an influence in the redox potential
      of the leachates. Due to the complexity of the waste, a computer modelling of
      equilibrium (MINTEQ) has been used in order to compare the experimental
      extractability with the simulated curves of the metallic species. The zinc
      content in the leachate is close related to the theoretical curves in the waste
      and all S/S products, while the rest of the metals do not show a coherent
      behaviour with the hydroxides evolution. The results of compliance testing allow
      to obtain the best S/S formulations using activated and black carbon as sorbents.
      The comparison between different leaching procedures leads to equivalent results
      depending only on the pH.

PMID- 15177751
TI  - Recycling of Ni(II)-citrate complexes using precipitation in alkaline solutions.
AB  - When the excess of Ni(II) ions as compared to citrate concentration is used both
      Ni(II) ions and citrate can be precipitated in alkaline solutions. The ratio
      between Ni(II) and citrate in the precipitate and completeness of citrate
      precipitation depends on the ratio between the Ni(II) and citrate concentrations
      in the initial solution and its pH. The data of chemical analysis, potentiometric
      titration, FT-IR as well as visible spectrophotometric investigations suggest
      that Ni(II) in the insoluble compound is bound with three -COO- groups and -OH
      group of the citrate. The insoluble compound also contains SO4(2-) and
      hydroxides. The treatment of this precipitate with H2SO4 enables to recover a
      soluble Ni(II)-citrate complex, which can be reused in practice, and to remove
      the excess of Ni(II) in the form of insoluble Ni(OH)2.

PMID- 15177752
TI  - Catalytic combustion of volatile organic compounds.
AB  - Despite the success of adsorption and thermal incineration of (C)VOC emissions,
      there is still a need for research on techniques which are both economically more
      favorable and actually destroy the pollutants rather than merely remove them for
      recycling elsewhere in the biosphere. The catalytic destruction of (C)VOC to CO2,
      H2O and HCl/Cl2 appears very promising in this context and is the subject of the
      present paper. The experiments mainly investigate the catalytic combustion of
      eight target compounds, all of which are commonly encountered in (C)VOC emissions
      and/or act as precursors for the formation of PCDD/F. Available literature on the
      different catalysts active in the oxidation of (C)VOC is reviewed and the
      transition metal oxide complex V2O5-WO3/TiO2 appears most suitable for the
      current application. Different reactor geometries (e.g. fixed pellet beds,
      honeycombs, etc.) are also described. In this research a novel catalyst type is
      introduced, consisting of a V2O5-WO3/TiO2 coated metal fiber fleece. The
      conversion of (C)VOC by thermo-catalytic reactions is governed by both reaction
      kinetics and reaction equilibrium. Full conversion of all investigated VOC to
      CO2, Cl2, HCl and H2O is thermodynamically feasible within the range of
      experimental conditions used in this work (260-340 degrees C, feed concentrations
      30-60 ppm). A first-order rate equation is proposed for the (C)VOC oxidation
      reactions. The apparent rate constant is a combination of reaction kinetics and
      mass transfer effects. The oxidation efficiencies were measured with various
      (C)VOC in the temperature range of 260-340 degrees C. Literature data for
      oxidation reactions in fixed beds and honeycomb reactors are included in the
      assessment. Mass transfer resistances are calculated and are generally negligible
      for fleece reactors and fixed pellet beds, but can be of importance for honeycomb
      monoliths. The experimental investigations demonstrate: (i) that the conversion
      of the hydrocarbons is independent of the oxygen concentration, corresponding to
      a zero-order dependency of the reaction rate; (ii) that the conversion of the
      hydrocarbons is a first-order reaction in the (C)VOC; (iii) that the oxidation of
      the (C)VOC proceeds to a higher extent with increasing temperature, with multiple
      chlorine substitution enhancing the reactivity; (iv) that the reaction rate
      constant follows an Arrhenius dependency. The reaction rate constant kr (s(-1))
      and the activation energy E (kJ/mol) are determined from the experimental
      results. The activation energy is related to the characteristics of the (C)VOC
      under scrutiny and correlated in terms of the molecular weight. The kr-values are
      system-dependent and hence limited in design application to the specific VOC
      catalyst combination being studied. To achieve system-independency, kr-values are
      transformed into an alternative kinetic constant K (m3/(m2u)) expressed per unit
      of catalyst surface and thus independent of the amount of catalyst present in the
      reactor. Largely different experimental data can be fitted in terms of this
      approach. Results are thereafter used to define the Arrhenius pre-exponential
      factor A*, itself expressed in terms of the activation entropy. Destruction
      efficiencies for any given reactor set-up can be predicted from E- and A*
      correlations. The excellent comparison of predicted and measured destruction
      efficiencies for a group of chlorinated aromatics stresses the validity of the
      design approach. Since laboratory-scale experiments using PCDD/F are impossible,
      pilot and full-scale tests of PCDD/F oxidation undertaken in Flemish MSWIs and
      obtained from literature are reported. From the data it is clear that: (i)
      destruction efficiencies are normally excellent; (ii) the efficiencies increase
      with increasing operating temperature; (iii) the higher degree of chlorination
      does not markedly affect the destruction efficiency. Finally, all experimental
      findings are used in design recommendations for the catalytic oxidation of (C)VOC
      and PCDD/F. Predicted values of the a)VOC and PCDD/F. Predicted values of the
      acceptable space velocity correspond with the cited industrial values, thus
      stressing the validity of the design strategy and equations developed in the
      present paper.

PMID- 15177753
TI  - Kinetics and mechanism of removal of methylene blue by adsorption onto perlite.
AB  - The kinetics and mechanism of methylene blue adsorption on perlite have been
      studied. The effects of various experimental parameters, such as initial dye
      concentration, temperature and pH on the adsorption rate were investigated.
      Adsorption measurements show that the process is very fast and physical in
      nature. The extent of the dye removal increased with increase in the initial
      concentration of the dye and the initial pH and temperature of solution.
      Adsorption data were modelled using the first and second-order kinetic equations,
      mass transfer and intra-particle diffusion models. It was shown that the second
      order kinetic equation could best describe the sorption kinetics. The diffusion
      coefficient, D, was found to increase when the initial dye concentration, pH and
      temperature were raised. Thermodynamic activation parameters, such as DeltaG*,
      DeltaS* and DeltaH*, were calculated.

PMID- 15177754
TI  - Optimization of photocatalytic oxidation of 2,2',3,3'-tetrachlorobiphenyl.
AB  - Polychlorinated biphenyls (PCBs) are wide spread environmental pollutants. This
      research focused the optimum physico-chemical conditions under which
      photocatalytic oxidation (PCO) can be used to degrade 2,2',3,3'
      tetrachlorobiphenyl (tetra-CB). Among the optimal physico-chemical conditions
      studied were UV intensity, hydrogen peroxide (H2O2) and titanium dioxide (TiO2)
      concentrations, initial pH, and possible reaction intermediates were also
      determined. The results indicate that the optimal physico-chemical conditions
      necessary for the degradation of tetra-CB by PCO were UV intensity at 3.16
      mW/cm2, 30 mM of H2O2 and 100 mg/l of TiO2. In contrast to the results of PCO
      studies on other organic compounds, the optimum pH for PCO degradation of tetra
      CB was 5.5. The removal efficiency was also higher under acidic conditions than
      alkaline conditions. Although degradation intermediates such as 1,3-bis(1,1
      dimethylethyl)benzene, 2,4-bis(1,1-dimethylethyl)phenol, and 3,5-di-tert-butyl-4
      hydroxybenzaldehyde were identified at an early stage in the reaction process,
      they were not completely degraded even after 7h of PCO reaction.

PMID- 15177755
TI  - Tuning the diffusion dialysis performance by surface cross-linking of PPO anion
      exchange membranes--simultaneous recovery of sulfuric acid and nickel from
      electrolysis spent liquor of relatively low acid concentration.
AB  - The results of the development of the industrial diffusion dialysis technology
      and the unit based on it for sulfate acid recovery from nickel electrolysis waste
      have been considered. Unlike most acid recovery systems, this system has a
      relatively low acid concentration and the main aim is to recover both nickel and
      acid sulfate by recycling the waste and the recovered acid to the respective
      steps of electrolysis process. So the waste volume control seems to be the most
      important thing. To satisfy with this new request, the membrane is surface-cross
      linked with aqueous ammonium to decrease waste volume expansion caused by the
      water osmosis. The results showed that the best membrane for such operation is
      the one that cross-linked at least 8 h with a volumetric expansion factor
      (volumetric ratio of waste to feed) less than 1.1. Pilot diffusional runs were
      conducted with this membrane at various feed flow rate and flow ratio of
      stripping water and feed. After comprehensively considering all factors, the
      range of feed flow and the flow ratio has been recommended to be 1.2-1.8 l/h and
      1.05-1.1, respectively. Under these conditions, nickel leakage can be controlled
      within 4% and the acid recover ratio can attain as high as 66-72%. The recovered
      acid can be recycled to the back-extraction step by mixing it with high
      concentration acid and the waste recycled to the initial leaching stage by
      adjusting the acid concentration to recover valuable metal nickel and the
      residual acid. Therefore, the new technology discards nothing and shows many
      advantages whether in environmental aspect or economical aspect and thus should
      be deserved attention.

PMID- 15177756
TI  - Treatment of orange II azo-dye by electrocoagulation (EC) technique in a
      continuous flow cell using sacrificial iron electrodes.
AB  - This paper describes the EC treatment of orange II dye solution in a flow cell
      using sodium chloride as an internal electrolyte. In this technique dye solutions
      were passed through a flow-through EC apparatus consisting of a flow-through
      cell, the electrode assembly, the feed pump and the DC power supply unit. The
      cell contained five parallel iron electrodes, which form four parallel cells.
      Experiments were run at 25 degrees C under various electrolyte concentrations,
      dye concentrations, current density, flow rate of the solution, and pH at dc
      current range of 2-5A. Various number of recycles of the treated dye solution
      were also performed at the same dc current range. Optimum conditions to get high
      removal efficiency were experimentally determined. It was found that 98.5% of the
      dye was removed from the solution under the optimum conditions. The residue from
      a blank run (pH = 7.3) and a dye added run (pH = 8.5) were collected by vacuum
      filtration and analyzed by XRD after drying in a vacuum desiccator. The XRD data
      indicated the presence of mainly maghemite (gamma-Fe2O3) and magnetite (Fe3O4) in
      the residue. However, there is not much difference between the X-ray
      diffractograms of the blank sample and the dye-containing residue to warrant any
      conclusions therefrom with regard to the interactions between the oxides and the
      dye molecules.

PMID- 15177757
TI  - The hydration properties of pastes containing municipal solid waste incinerator
      fly ash slag.
AB  - This study investigated the hydration properties of Type I, Type III and Type V
      cements, mixed with municipal solid waste incinerator fly ash, to produce slag
      blended cement pastes. The setting time of slag-blended cement pastes that
      contained 40% slag showed significantly retardation the setting time compared to
      those with a 10% or even a 20% slag replacement. The compressive strength of slag
      blended cement paste samples containing 10 and 20% of slag, varied from 95 to
      110% that developed by the plain cement pastes at later stages. An increased
      blend ratio, due to the filling of pores by C-S-H formed during pozzolanic
      reaction tended to become more pronounced with time. This resulting densification
      and enhanced later strength was caused by the shifting of the gel pores. It was
      found that the degree of hydration was slow in early stages, but it increased
      with increasing curing time. The results indicated that it is feasible to use
      MSWI fly ash slag to replace up to 20% of the material with three types of
      ordinary Portland cement.

PMID- 15177758
TI  - Removal of sulfur dioxide from a continuously operated binary fluidized bed
      reactor using inert solids and hydrated lime.
AB  - Sulfur dioxide pollutant was treated in the laboratory with hydrated lime
      particles having a mean diameter of 9.1 microm in a continuously operating binary
      fluidized bed reactor also containing inert sand particles with sizes varying
      from 500 to 590 microm. The influence of temperature (500, 600, 700 and 800
      degrees C) on the reaction medium, of the superficial velocity of the gas (0.8,
      1.0 and 1.2 m/s), and of the Ca/S molar ratio (1, 2 and 3) on the SO2 removal
      efficiency were investigated for an inflow gas concentration of 1000 ppm and an
      initially static bed height of 10.0 cm. The pollutant removal efficiency proved
      to depend on the temperature and the velocity of the gaseous flow and was
      strongly influenced by the Ca/S molar ratio. The maximum efficiency of 97.7% was
      achieved at a temperature of 700 degrees C, a Ca/S ratio of 3 and a velocity of
      0.8 m/s. The lime particles' mean residence time was determined by an indirect
      method, which consisted of integrating the gas concentration curves normalized
      with respect to time. Based on a calculation of the critical transition
      velocities, it was concluded that the reactor operated in a bubbling regime under
      each condition investigated here.

PMID- 15177759
TI  - Biosorption of Hg2+, Cd2+, and Zn2+ by Ca-alginate and immobilized wood-rotting
      fungus Funalia trogii.
AB  - Funalia trogii biomass was immobilized in Ca-alginate gel beads. The live and
      heat inactivated immobilized forms were used for the biosorption of Hg2+, Cd2+
      and Zn2+ ions by using plain Ca-alginate gel beads as a control system. The
      effect of pH was investigated and the maximum adsorption of metal ions on the Ca
      alginate and both live and inactivated immobilized fungal preparations were
      observed at pH 6.0. The temperature change between 15 and 45 degrees C did not
      affect the biosorption capacity. The biosorption of Hg2+, Cd2+ and Zn2+ ions on
      the Ca-alginate beads and on both immobilized forms was studied in aqueous
      solutions in the concentration range of 30-600 mg/L. The metal biosorption
      capacities of the heat inactivated immobilized F. trogii for Hg2+, Cd2+ and Zn2+
      were 403.2, 191.6, and 54.0 mg/g, respectively, while Hg2+, Cd2+ and Zn2+
      biosorption capacities of the immobilized live form were 333.0, 164.8 and 42.1
      mg/g, respectively. The same affinity order on a molar basis was observed for
      single or multi-metal ions (Hg2+ > Cd2+ > Zn2+). The Langmuir and the Freundlich
      type models were found to exhibit good fit to the experimental data. The
      experimental data were analyzed using the first-order (Langergren equations) and
      the second order (Ritchie equations). The experimental biosorption capacity with
      time is found to be best fit the second-order equations. The alginate-fungus
      system could be regenerated by washing with a solution of hydrochloride acid (10
      mM). The percent desorption achieved was as high as 97. The biosorbents were
      reused in five biosorption-desorption cycles without significant loss of their
      initial biosorption capacity.

PMID- 15177760
TI  - Performance of BTX degraders under substrate versatility conditions.
AB  - A microbial consortium acclimatized with benzene, toluene or xylene (BTX) was
      employed to study the degradation pattern of these compounds individually under
      aerobic conditions. Batch and continuous experiments were conducted to evaluate
      the adaptability of the enriched cultures under substrate versatility conditions.
      The bio-kinetic parameters obtained under substrate versatility conditions were
      compared with those of a single substrate condition. Similar degradation patterns
      were observed for all the substrates with inhibition occurring at higher
      concentration (approximately 150 mg/L for benzene and xylene, and approximately
      200 mg/L for toluene). Toluene degradation was highest, followed by benzene and
      xylene in the aqueous phase. Adaptation to a more toxic compound like benzene and
      xylene improved the utilization of toluene. On the other hand, microbes grown on
      a less toxic compound (toluene) grew at a lower rate in the presence of more
      toxic compounds. Suitable kinetic parameters such as micro(max) (maximum specific
      growth rate per hour), Ks (half saturation constant, mg/L), and KI (threshold
      substrate inhibition constant, mg/L) were determined using Haldane and Levenspiel
      substrate inhibition models. The Haldane equation seems to be an adequate
      expression for the system. The degradation behavior of pollutants in the gas
      phase was also evaluated using a toluene acclimatized biotrickling filter
      operated in continuous mode. The biotrickling filter acclimatized with toluene
      could degrade benzene and xylene with a lower elimination capacity. But, the
      system could recover its original efficiency quite fast even after a prolonged
      shock loading. The degradation was better for toluene, followed by benzene and
      xylene.

PMID- 15177761
TI  - Solubilization of pyrene by anionic-nonionic mixed surfactants.
AB  - Surfactant-enhanced remediation (SER) is an effective approach for the removal of
      sorbed hydrophobic organic compounds from contaminated soils. The solubilization
      of pyrene by four anionic-nonionic mixed surfactants, sodium dodecyl sulfate
      (SDS) with Triton X-405 (TX405), Brij35, Brij58, and Triton X-100 (TX100), has
      been studied from measurements of the molar solubilization ratio (MSR), the
      micelle-water partition coefficient (Kmc), and the critical micelle concentration
      (CMC). The MSRs of pyrene in mixed surfactants are found to be larger than those
      predicted according to an ideal mixing rule. The mixing effect of anionic and
      nonionic surfactants on MSR for pyrene follows the order of SDS-TX405 > SDS
      Brij35 > SDS-Brij58 > SDS-TX100 and increases with an increase in the hydrophile
      lipophile balance (HLB) value of nonionic surfactant in mixed systems. In
      addition, the mixture of anionic and nonionic surfactants cause the Kmc value for
      pyrene to be greater than the ideal value in SDS-TX405 mixed system, but to be
      smaller than the ideal value in SDS-Brij35, SDS-Brij58, and SDS-TX100 mixed
      systems. Meanwhile, in the four mixed systems, the experimental CMCs are lower
      than the ideal CMCs at almost all mixed surfactant solution compositions. The
      mixing effect of anionic and nonionic surfactants on MSR for pyrene can be
      attributed to the conjunct or the net result of the negative deviation of the
      CMCs from ideal mixture and the increasing or decreasing Kmc.

PMID- 15177762
TI  - Adsorption of lead and cadmium ions in aqueous solutions onto modified lignin
      from alkali glycerol delignication.
AB  - Adsorptions of toxic metal ions (Pb(II) and Cd(II)) onto modified lignin from
      beech and poplar woods by alkali glycerol delignification are presented in this
      paper. The material exhibits good adsorption capacity and the adsorption data
      follow the Langmuir model. The maximum adsorption capacities are 8.2-9.0 and 6.7
      7.5 mg/g of the modified lignin for Pb(II) and Cd(II), respectively. The maximum
      adsorption percentage is 95.8 for Pb(II) for 4 h at 330 K and is 95.0 for Cd(II)
      for 10 h at 290 K. The adsorption of both the metal ions increased with
      increasing temperature indicating endothermic nature of the adsorption process.
      The maximum adsorption percentages of Pb(II) and Cd(II) ions decrease with time
      till 48 and 42 h and then again increase slightly with time. The adsorption of
      both heavy metal ions increases with pH. The adsorption of Pb(II) ions reached a
      maximum at a 5.0 value of pH.

PMID- 15177763
TI  - Diagnostic criteria for multiple sclerosis: an historical review.
AB  - Starting with Charcot, diagnostic criteria for multiple sclerosis (MS) have
      evolved to reflect advances in our understanding of the disease and the
      development of new diagnostic techniques, and from purely clinical considerations
      to increasing dependency upon imaging of the central nervous system. The MS
      diagnostic process was revolutionized by the 1981 introduction of magnetic
      resonance imaging (MRI), but the increasing reliance upon this technique has led
      to a surge in erroneous diagnoses, mostly because of the failure to distinguish
      between MS and disseminated encephalomyelitis (DEM), as well as mounting
      disregard for the data obtained from the traditional history and physical
      examination. The most recent scheme of McDonald et al. incorporated quantitative
      MRI criteria of dubious origin and reliability, but failed to provide
      qualitative, illustrative ones that would help differentiate between MS and DEM.
      The choice will have to be made by the neurological community between basing the
      diagnosis of MS on the MRI alone, or to use it as one aspect of a comprehensive
      clinical diagnostic algorithm. There will never be a substitute for the
      experienced and astute clinician's 'feel' for the patient.

PMID- 15177765
TI  - The multiple sclerosis trait: a disease waiting to happen?
AB  - There is increasing evidence that the etiology of MS is heterogeneous. MS is
      often described as a "disease waiting to happen". The pathogenesis of the
      critical transition to clinical disease according to diagnostic criteria is
      largely unknown. The role of environment and chance must also be considered.
      Implications for counselling "at risk" individuals, based on family history, are
      discussed.

PMID- 15177764
TI  - The nature of multiple sclerosis.
AB  - Multiple sclerosis (MS) has recently been classified according to its clinical
      course. Despite relapses and remissions, its course is invariably progressive,
      and the observed progression from the remitting-relapsing to the secondary
      progressive form represents the accumulation of permanent damage to the nervous
      system. Discussions of the nomenclatural position of Schilder's, Marburg's, and
      Balo's diseases, ignore the fact that the unique, pathognomonic, sharp-edged
      plaque of MS, is also the pathologic end-result in the three variants. Devic's
      disease or neuromyelitis optica (NMO) is quite different and with some
      exceptions, is a particular form of disseminated encephalomyelitis (DEM). There
      is no evidence that the 'oriental form of MS' is anything but NMO. The suggestion
      that MS and DEM are variants of the same condition is contradicted by the fact
      that the pathological characteristics of the two are quite different. While it is
      probable that the two share aspects of pathogenesis, the patients differ because
      of their genetic endowment. This was dramatically demonstrated in a group of
      Japanese patients who died after anti-rabies vaccination and were found to have
      the typical sharp-edged lesions of MS. The genetic determinant was also crucial
      in the marmoset in which EAE uniquely resulted in a chronic relapsing-remitting
      (RR) disease characterized by the classic sharp-edged lesions of MS. The question
      'ADEM: distinct disease or part of the MS spectrum?' can be answered with a
      resounding no. A new classification is proposed separating the different forms of
      MS from the various types of DEM.

PMID- 15177766
TI  - Multiple sclerosis in western Finland: evidence for a founder effect.
AB  - We have previously demonstrated that there is a high-risk focus for multiple
      sclerosis (MS) in the southern Ostrobothnian region of western Finland
      (population 376121 in 1993). Of the two southern Ostrobothnian health-care
      districts, Vaasa and Seinajoki, the incidence and prevalence of MS were
      especially high in the latter. In recent genetic studies, we identified
      haplotypes of the myelin basic protein (MBP) gene in a group of MS patients
      originating from southern Ostrobothnia, suggesting a founder effect. This finding
      led us to explore the population history of the southern Ostrobothnia and
      correlate it with MS epidemiology. Southern Ostrobothnia can be divided into
      three distinct regions with respect to its historical settlement: Vaasa,
      Seinajoki-south, and Seinajoki-north. Vaasa, the coastal region was settled by
      Swedes, who immigrated during the 13th century. In Vaasa, the prevalence of
      clinically definite MS (CDMS) in 1993 was 107/10(5) (95% CI 90-124). Seinajoki
      south was populated from the 13th century onwards from southwestern Finland, a
      region which has been recognised as a high-risk focus of MS. In Seinajoki-south,
      the prevalence of CDMS in 1993 was 219/10(5) (95% CI 190-247). Seinajoki-north
      was inhabited rather late starting in the 16th century from eastern Finland. In
      Seinajoki-north the prevalence of CDMS in 1993 was 136/10(5) (95% CI 108-164).
      The historical settlement pattern of the southern Ostrobothnia indicates that its
      population is quite heterogeneous. Seinajoki-south has a very high prevalence of
      MS, significantly higher than its two neighbouring regions. The distinctive
      settlement history of Seinajoki-south, the historical link with the other
      southwestern high-risk foci and molecular genetic evidence, suggest that a
      founder effect plays an important role in the high-risk of MS in western Finland.

PMID- 15177767
TI  - Diagnostic and therapeutic dilemmas.
AB  - Close blood relatives of MS patients have MRI changes suggestive of MS despite
      the absence of any symptoms. They have also been seen when an MRI is obtained for
      various reasons in unrelated persons. This raises questions regarding their
      clinical significance, if any, since typical MS plaques have been found at
      autopsy in eloquent parts of the nervous system in completely asymptomatic
      individuals. Do these people have MS and should immunomodulatory treatment be
      considered? Because they are not ill according to various dictionary definitions,
      no to both. A higher rate of MS in close blood relatives would be expected due to
      the known genetic susceptibility, but suggestive MRI changes are quite uncommon,
      even in unaffected twins. Finally, a review of the four published studies of MS
      lesions unexpectedly found at autopsy in neurologically asymptomatic persons
      revealed a prevalence of the disease of 0.1%, the same as the estimated
      prevalence of clinical MS in the United States.

PMID- 15177768
TI  - Sudden onset aphasic hemiplegia: an unusual manifestation of disseminated
      encephalomyelitis.
AB  - The association of the sudden onset of aphasia with hemiplegia, hemisenosry
      defect, and facial palsy, with MRI evidence of white matter lesions, requires
      differentiation between multiple sclerosis (MS) and acute disseminated
      encephalomyelitis (ADEM). We have observed eight patients with such a syndrome,
      all of whom were originally diagnosed as multiple sclerosis, but who, on closer
      examination, turned out to be instances of disseminated encephalomyelitis. The
      patterns of demyelination seen in T2-weighted MRI are quite different in both
      conditions. In two of our patients, MRI reverted to normal after the treatment;
      in others, the images remained unchanged. A review of the reported cases of
      multiple sclerosis presenting with the acute onset of aphasia, reveals that the
      majority of them are, in reality, instances of acute disseminated
      encephalomyelitis with a much better prognosis. Most of these cases are
      monophasic and immunomodulatory treatment is inappropriate.

PMID- 15177769
TI  - Non-MS recurrent demyelinating diseases.
AB  - The introduction of MRI has shown that the acute, recurrent (R), and multiphasic
      (M) forms of disseminated encephalomyelitis (DEM) are more common than suspected
      in adults, and that their MR images are sufficiently characteristic in most
      instances to make differentiation from multiple sclerosis (MS) possible. In
      addition, a number of clinical features of DEM are rarely seen in MS: fever,
      malaise, nausea, vomiting, positional vertigo, convulsions, aphasia, meningism,
      bilateral optic neuritis, and CSF leukocytosis and elevated protein. CSF
      oligoclonal bands are usually absent. It is remarkable that confusion between R-
      and MDEM and MS persists despite the numerous published reports on recurrent DEM
      dating back 70 years, many illustrating the characteristic MRIs. There are many
      case reports of DEM erroneously diagnosed as MS, Schilder's, Marburg's, Devic's,
      and Balo's disease, and, in particular brain tumors. It is probable that acute
      DEM is occasionally mistaken for a clinically isolated symptom of MS. Possible
      mechanisms for recurrence include localization at the site of a previous injury
      to the nervous system, or by the phenomenon of molecular mimicry. The importance
      of differentiating R- and MDEM from MS is greater today due to the recommendation
      that immunodulatory treatment be initiated in patients with a clinically isolated
      syndrome, or when the occurrence of a second clinical episode establishes the
      diagnosis of MS.

PMID- 15177770
TI  - Axonal damage in multiple sclerosis: a complex issue in a complex disease.
AB  - Multiple sclerosis is no longer considered to simply be an autoimmune
      demyelinating disease. Axonal destruction is another central pathological feature
      and a contributor to the accumulating disability of disease progression. The
      mechanism underlying axonal pathology has not been fully clarified but does not
      appear to be a simple one. The relationship between axonal damage and other
      components of the pathological features such as demyelination, inflammation and
      remyelination are under intense investigation. Experimental data suggest that
      therapeutic interventions such as the induction of rapid remyelination may lead
      to the protection of axons. In addition to immunomodulation, future strategies
      for neuroprotection may be of great importance.

PMID- 15177771
TI  - The initiation of the autoimmune response in multiple sclerosis.
AB  - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the
      central nervous system (CNS). Most evidence supports the autoimmune pathogenesis
      of the disease. According to this hypothesis, the activation of autoreactive T
      cells is a central event in the development of autoimmune response in MS. We
      examined molecular events involved in the initiation of autoimmune response in
      MS. Recent studies in our laboratory have reported an unexpectedly high degree of
      T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon
      that might play a role in the initiation of autoimmune response in MS. This paper
      provides insights into the physiologic and pathologic role of autoreactive T
      cells, and characterizes structurally and functionally the specific targets for
      new therapies of MS.

PMID- 15177772
TI  - Microarray gene expression profiling of chronic active and inactive lesions in
      multiple sclerosis.
AB  - Multiple sclerosis, a primary autoimmune disease of the central nervous system
      has been characterized by the presence of the demyelinating lesions (plaques) in
      the CNS. To further understand the gene transcription status of the two most
      common lesions, chronic active and chronic inactive, we have performed a cDNA
      microarray analysis of these two lesion type. Comparative analysis of
      differential gene expression of chronic active and inactive lesions have
      confirmed the existence of a significant difference in the transcriptional
      profiles of these two lesion types in both marginal and central areas. Different
      sets of genes were highlighted, including genes of inflammatory characteristics,
      apoptosis related and stress-induced, indicating their potential role in MS
      pathogenesis.

PMID- 15177773
TI  - Level of sFas/APO 1 in serum and cerebrospinal fluid in multiple sclerosis.
AB  - The aim of the study was to measure sFas/APO 1 serum and cerebrospinal fluid
      (CSF) levels in patients with relapsing-remitting multiple sclerosis (MS) during
      relapses, as an index of inhibition of apoptosis of activated lymphocytes in
      eight patients with clinically definite multiple sclerosis, and 12 healthy
      controls. The level of serum and CSF sFas/APO 1 was determined by commercially
      available enzyme-linked immunosorbent assay (ELISA) kits. No significant
      differences were detected in the sFas/APO 1 serum level between patients and
      controls, but the levels in CSF was lower in the former. Our results suggest the
      possibility of Fas mediated apoptosis as a contributing factor in the
      pathogenesis of multiple sclerosis.

PMID- 15177774
TI  - Cerebral demyelination in Wegener's granulomatosis.
AB  - A 38-year-old woman with a history of a granulomatous lesion of the nose,
      developed blurred vision, ataxic gait, and spastic tetraparesis. The presence of
      demyelination on the brain MRI led to the diagnosis of cerebral demyelination
      associated with Wegener's granulomatosis. Pulse cyclophosphamide administration
      resulted in some clinical of improvement of her condition. Demyelinating lesions
      seen in Wegener's have been ascribed to multiple sclerosis, but in this case,
      they are much more reminiscent of disseminated encephalomyelitis (DEM). The
      immunological challenge of the underlying disease, may, in the genetically
      susceptible person, presumably trigger the appearance of MS lesions. Wegener's
      granulomatosis must be considered in the differential diagnosis of MS.

PMID- 15177775
TI  - An adult case of Leigh disease.
AB  - Leigh's disease is a mitochondrial disease of infancy and early childhood, and is
      rare in adults. Following a febrile illness, a 21-year-old woman developed ataxic
      paraparesis and was originally diagnosed as multiple sclerosis. Her illness
      progressed to somnolence and quadriparesis. The unusual MR images, the discovery
      of elevated blood lactate and pyruvate levels, the results of muscle biopsy and
      the lack of response to corticosteroid treatment, led to the correct diagnosis of
      Leigh disease. Initiation of a ketogenic diet resulted in a rapid partial
      response. She recovered sufficiently to be able to walk after 6 months.

PMID- 15177776
TI  - Differential prevention of experimental autoimmune encephalomyelitis with antigen
      specific DNA vaccination.
AB  - We compared the potential therapeutic effect of vaccination with DNA constructs
      encoding two encephalitogenic proteins, PLP and MOG, on the outcome of subsequent
      sensitization of EAE induced in SJL/J and C57/B6 mice. Early sensitization for
      EAE (4 weeks after DNA vaccination) caused recipient animals to develop enhanced
      disease with DNA-encoding PLP but not with DNA-encoding MOG. Late sensitization
      (more than 10 weeks) resulted in an amelioration of EAE in animals vaccinated
      with both PLP and MOG DNA constructs. These results, confirming the DNA-mediated
      ameliorating effect on EAE, also indicate significant differences in the kinetics
      of development of EAE tolerance in response to vaccination with different DNA
      encoding myelin antigens. Since PLP and MOG require different MHC presentation
      and induce different EAE models, the results point to potential differences in
      immune system requirements for efficient DNA-induced amelioration of the
      autoimmune response.

PMID- 15177777
TI  - The pathogenesis and basis for treatment in multiple sclerosis.
AB  - The central concept underlying ideas on the pathogenesis of multiple sclerosis is
      that inflammatory events cause acute injury of axons and myelin. The phases of
      symptom onset, recovery, persistence and progression in multiple sclerosis can be
      summarized as functional impairment with intact structure due to direct effects
      of inflammatory mediators, demyelination and axonal injury with recovery through
      plasticity and remyelination, and chronic axonal loss due to failure of enduring
      remyelination from loss of trophic support for axons normally provided by cells
      of the oligodendrocyte lineage.

PMID- 15177778
TI  - Bio-markers of disease activity and response to therapy in multiple sclerosis.

PMID- 15177779
TI  - IFN-beta1a and IFN-beta1b have different patterns of influence on cytokines.
AB  - Multiple sclerosis is characterized by elevated levels of proinflammatory
      cytokines produced by Th1 cells and decreased levels of anti-inflammatory
      cytokines produced by Th2 cells. IFN-beta treatment shifts the immune response
      from the Th1 to Th2 pattern, thus enhancing the production of anti-inflammatory
      Th2 cytokines such as IL-4, IL-10, and decreasing the production of
      proinflammatory Th1 cytokines such as IFN-gamma. To determine which IFN-beta has
      the stronger immunomodulatory effect we compared the levels of IL-4, IL-10, and
      IFN-gamma of 12 relapsing-remiting MS patients treated with IFN-beta1b
      (Betaferon) with those of 10 patients treated with IFN-beta1a (Avonex). There
      were no statistically significant differences in duration of disease, number of
      relapses before and during treatment, and in EDSS after 2 years of treatment.
      After 1 year of treatment the concentration of IFN-gamma was significantly lower
      in the Betaferon group, and concentrations of IL-4 and IL-10 were significantly
      higher in the Avonex group. It appears that IFN-beta1b has a downregulatory
      effect on both Th1 and Th2 cytokines, while IFN-beta1a causes a shift of the
      cytokine profile toward the Th2 phenotype. These two IFN have different
      influences on the pattern of cytokines in MS: IFN-beta1a enhances the production
      of anti-inflammatory cytokines IL-4 and IL-10 and IFN-beta1b decreases the
      production of the proinflammatory cytokine IFN-gamma.

PMID- 15177780
TI  - CD95/Fas expression on peripheral blood T lymphocytes in patients with multiple
      sclerosis: effect of high-dose methylprednisolone therapy.
AB  - Recent data indicate that the apoptotic process, mediated by the CD95/Fas cell
      surface receptor, is impaired in activated lymphocytes of patients with relapsing
      remitting multiple sclerosis. Using flow cytometric-immunophenotyping, we
      analyzed the expression of CD95/Fas on peripheral blood CD4+ and CD8+ T
      lymphocytes (PBL) in 10 MS patients in relapse, and the effect of pulse
      corticosteroid therapy on the apoptosis of autoreactive lymphocytes. The
      proportions of CD8+ and CD8+CD95+ T lymphocytes were significantly higher in MS
      patients in relapse before than after pulse corticosteroid therapy. Conversely,
      the proportions of CD4+ and CD4+CD95+ T cells were significantly lower before
      than after therapy, but not significantly different from healthy persons. The
      different expression of CD95/Fas on peripheral blood CD8+ T lymphocytes in
      relapsing RRMS and in healthy controls suggests a possible involvement of
      apoptosis in the pathogenesis of MS. Our results also show that pulse
      corticosteroid therapy influences the CD95/Fas expression on CD8+ and CD4+ T
      lymphocytes in patients with RRMS.

PMID- 15177781
TI  - Non-specific immunosuppressants in the treatment of multiple sclerosis.
AB  - Immunosuppressants have been proposed as disease-modifying treatments in multiple
      sclerosis (MS) for almost 40 years, but only one, mitoxantrone, has recently been
      approved, whereas beta-interferons and glatiramer acetate have been licensed
      since the mid-90s. Recent therapeutic trials of potent immunosuppressive agents
      such as Campath-1H, mitoxantrone and cyclophosphamide of MS patients with high
      relapse rates, rapid accumulation of disability and high degree of MRI activity,
      have resulted in strong suppression of clinical and MRI inflammatory activity,
      provided that profound and prolonged lymphopenia was achieved. Clinical
      experience during the past decades has amply demonstrated that some patients with
      MS respond to immunosuppressants. The odds ratios of relapsing-remitting MS
      patients to remain relapse-free after a 2-year period of treatment are similar
      for Betaseron, Avonex, Rebif, Copaxone, intravenous immunoglobulins or
      azathioprine compared to placebo. The risk of cancer induction is not significant
      for up to 10 years of daily usage of azathioprine. Currently available non
      specific immunosuppressants are able to control inflammation and reduce relapses
      in MS, but cannot prevent neurodegeneration and the progression of irreversible
      disability; specific tools need to be developed for that purpose.

PMID- 15177782
TI  - Campath-1H treatment of multiple sclerosis: lessons from the bedside for the
      bench.

PMID- 15177783
TI  - Reparative mechanisms in the cerebellar cortex.
AB  - In the adult brain, different neuronal populations display different degrees of
      plasticity. Here, we describe the highly different plastic properties of inferior
      olivary neurones and Purkinje cells. Olivary neurones show a basal expression of
      growth-associated proteins, such as GAP-43 and Krox24/EGR-1, and remarkable
      remodelling capabilities of their terminal arbour. They also regenerate their
      transected neurites into growth-permissive territories and may reinnervate the
      lost target. Sprouting and regrowing olivary axons are able to follow specific
      positional information cues to establish new connections according to the
      original projection map. In addition, they set a strong cell body reaction to
      injury, which in specific olivary subsets is regulated by inhibitory target
      derived cues. In contrast, Purkinje cells do not have a constitutive level of
      growth-associated genes, and show little cell body reaction, no axonal
      regeneration after axotomy, and weak sprouting capabilities. Block of myelin
      derived signals allows terminal arbour remodelling, but not regeneration, while
      selective over-expression of GAP-43 induces axonal sprouting along the axonal
      surface and at the level of the lesion. We suggest that the high constitutive
      intrinsic plasticity of the inferior olive neurones allows their terminal arbour
      to sustain the activity-dependent ongoing competition with the parallel fibres in
      order to maintain the post-synaptic territory, and possibly underlies mechanisms
      of learning and memory. Such a plasticity is used also as a reparative mechanism
      following axotomy. In contrast, in Purkinje cells, poor intrinsic regenerative
      capabilities and myelin-derived signals stabilise the mature connectivity and
      prevent axonal regeneration after lesion.

PMID- 15177784
TI  - Regulation of neuromodulator receptor efficacy--implications for whole-neuron and
      synaptic plasticity.
AB  - Membrane receptors for neuromodulators (NM) are highly regulated in their
      distribution and efficacy-a phenomenon which influences the individual cell's
      response to central signals of NM release. Even though NM receptor regulation is
      implicated in the pharmacological action of many drugs, and is also known to be
      influenced by various environmental factors, its functional consequences and
      modes of action are not well understood. In this paper we summarize relevant
      experimental evidence on NM receptor regulation (specifically dopamine D1 and D2
      receptors) in order to explore its significance for neural and synaptic
      plasticity. We identify the relevant components of NM receptor regulation
      (receptor phosphorylation, receptor trafficking and sensitization of second
      messenger pathways) gained from studies on cultured cells. Key principles in the
      regulation and control of short-term plasticity (sensitization) are identified,
      and a model is presented which employs direct and indirect feedback regulation of
      receptor efficacy. We also discuss long-term plasticity which involves shifts in
      receptor sensitivity and loss of responsivity to NM signals. Finally, we discuss
      the implications of NM receptor regulation for models of brain plasticity and
      memorization. We emphasize that a realistic model of brain plasticity will have
      to go beyond Hebbian models of long-term potentiation and depression. Plasticity
      in the distribution and efficacy of NM receptors may provide another important
      source of functional plasticity with implications for learning and memory.

PMID- 15177785
TI  - Novel tracing paradigms--genetically engineered herpesviruses as tools for
      mapping functional circuits within the CNS: present status and future prospects.
AB  - The mammalian CNS is composed of an extremely complex meshwork of highly ordered
      interconnections among billions of neurons. To understand the diverse functions
      of this neuronal network we need to differentiate between functionally related
      and nonrelated elements. A powerful labeling method for defining intricate neural
      circuits is based on the utilization of neurotropic herpesviruses, including
      pseudorabies virus and herpes simplex virus type 1. The recent development of
      genetically engineered tracing viruses can open the way toward the conception of
      novel tract-tracing paradigms. These new-generation tracing viruses may
      facilitate the clarification of problems, which were inaccessible to earlier
      approaches. This article first presents a concise review of the general aspects
      of neuroanatomical tracing protocols. Subsequently, it discusses the molecular
      biology of alpha-herpesviruses, and the genetic manipulation and gene expression
      techniques that are utilized for the construction of virus-based tracers.
      Finally, it describes the current utilization of genetically modified
      herpesviruses for circuit analysis, and the future directions in their potential
      applications.

PMID- 15177786
TI  - Organisation and evocation of the semantic knowledge: a non-abstractive approach.
AB  - The majority of the models which attempt to explain category-specific deficits
      are based on the assumption that the conceptual knowledge is represented in a
      permanent way in memory (abstractive view). showed that a non-abstractive view
      would be more suitable to account for some of these cases. The present study aims
      to assess the hypotheses on the meaning evocation process as formulated by these
      authors, using a property verification task conducted on healthy subjects. The
      data were in agreement with these hypotheses and would be more hardly accounted
      in the frame of the abstractive view.

PMID- 15177787
TI  - Crossed apraxia of speech: a case report.
AB  - The present study reports on the first case of crossed apraxia of speech (CAS) in
      a 69-year-old right-handed female (SE). The possibility of occurrence of apraxia
      of speech (AOS) following right hemisphere lesion is discussed in the context of
      known occurrences of ideomotor apraxias and acquired neurogenic stuttering in
      several cases with right hemisphere lesion. A current hypothesis on AOS-the dual
      route speech encoding (DRSE) hypothesis-and predictions based on DRSE were
      utilized to explore the nature of CAS in SE. One prediction based on the DRSE
      hypothesis is that there should be no difference in the frequency of occurrence
      of apraxic errors on words and non-words. This prediction was tested using a
      repetition task. The experimental stimuli included a list of minimal pairs that
      signaled voice-voiceless contrasts in words and non-words. Minimal-pair stimuli
      were presented orally, one at a time. SE's responses were recorded using audio
      and videotapes. Results indicate that SE's responses were characterized by
      numerous voicing errors. Most importantly, production of real word minimal pairs
      was superior to that of non-word minimal pairs. Implications of these results for
      the DRSE hypothesis are discussed with regard to currently developing
      perspectives on AOS.

PMID- 15177788
TI  - A "voice inversion effect?".
AB  - Voice is the carrier of speech but is also an "auditory face" rich in information
      on the speaker's identity and affective state. Three experiments explored the
      possibility of a "voice inversion effect," by analogy to the classical "face
      inversion effect," which could support the hypothesis of a voice-specific module.
      Experiment 1 consisted of a gender identification task on two syllables
      pronounced by 90 speakers (boys, girls, men, and women). Experiment 2 consisted
      of a speaker discrimination task on pairs of syllables (8 men and 8 women).
      Experiment 3 consisted of an instrument discrimination task on pairs of melodies
      (8 string and 8 wind instruments). In all three experiments, stimuli were
      presented in 4 conditions: (1) no inversion; (2) temporal inversion (e.g.,
      backwards speech); (3) frequency inversion centered around 4000 Hz; and (4)
      around 2500 Hz. Results indicated a significant decrease in performance caused by
      sound inversion, with a much stronger effect for frequency than for temporal
      inversion. Interestingly, although frequency inversion markedly affected timbre
      for both voices and instruments, subjects' performance was still above chance.
      However, performance at instrument discrimination was much higher than for
      voices, preventing comparison of inversion effects for voices vs. non-vocal
      stimuli. Additional experiments will be necessary to conclude on the existence of
      a possible "voice inversion effect."

PMID- 15177789
TI  - Genes and memory: the neuroanatomical correlates of emotional memory in
      monozygotic twin discordant for schizophrenia.
AB  - BACKGROUND: Brain morphology and physiological measures in schizophrenia have
      yielded inconsistent results. This may be due in part to difficulties in
      ascertaining precisely to what degree each measure deviates from its genetically
      and environmentally determined potential level. We attempted to surmount this
      problem in a paradigm involving monozygotic twin pair discordant for
      schizophrenia. In this paradigm, the difference score and reaction time between
      the unaffected member and affected member of a twin pair should represent the
      degree of pathologic involvement irrespective of actual level. METHOD: We
      investigated, using fMRI, the neural substrate underlying encoding and retrieval
      of aversive and neutral IAPS pictures. RESULTS: An ANOVA on reaction time (RT)
      between schizophrenia patient (J) and normal sister (D) significant difference,
      (F = 5.2, p < or = .02) for J had less RT than D. Conversely, the ANOVA for the
      correct pictures retrieved was insignificant (F = 1.8, p < or = .2). When the
      brain activity associated with the encoding and retrieval of the aversive
      pictures was subtracted (J-D and D-J) from that associated with the neutral ones,
      significant loci of activation were found. During encoding: for J-D the right
      fusiform gyrus was significantly activated (p < .0001) and for D-J the
      orbitofrontal cortex was significantly activated (p < .05). During retrieval: for
      J-D the right anterior cingulate (p < .0001) was activated and the dorsolateral
      prefrontal cortex (p < .002). For D-J only the cerebellum showed activation (p <
      .0001). CONCLUSION: Results indicated subtle attenuations in some aspects of
      memory, thus providing another evidence for cognitive markers of a genetic
      component in schizophrenia. New approaches in neuropsychiatry-based on genetic
      methodologies should further define the cerebral physiology responsible for
      schizophrenia.

PMID- 15177790
TI  - The role of context in remembering familar persons: insights from semantic
      dementia.
AB  - Semantic dementia (SD) is a progressive condition characterized by an insidious
      and gradual breakdown in semantic knowledge. Patients suffering from this
      condition gradually lose their knowledge of objects and their attributes,
      concepts, famous persons, and public events. In contrast, these patients maintain
      a striking preservation of autobiographical memory. The aim of the present study
      was to examine in a patient suffering from SD the role of context in the ability
      to recall knowledge of familiar persons. In an experiment, patient J.M. was asked
      to name and identify familiar persons that appeared on family photographs from
      recent and remote periods of her life. In the first experimental condition, the
      pictures represented personally familiar persons present in a specific spatial
      and temporal context. In a second experimental condition, the pictures showed
      personally familiar persons who were presented without any specific episodic
      context. Results indicate that the patient was able to name and identify familiar
      persons irrespective of the context of presentation (with/without context) and of
      the time period (recent/remote). No temporal gradient was found using family
      photographs. Finally, in contrast with familiar persons, J.M. presented a severe
      anomia for celebrities. Results are discussed in light of recent research in the
      field.

PMID- 15177791
TI  - The handedness of Leonardo da Vinci: a tale of the complexities of
      lateralisation.
AB  - The handedness of Leonardo da Vinci is controversial. Although there is little
      doubt that many of his well-attributed drawings were drawn with the left hand,
      the hatch marks of the shading going downwards from left to right, it is not
      clear that he was a natural left-hander, there being some suggestion that he may
      have become left-handed as the result of an injury to his right hand in early
      adulthood. Leonardo's lateralisation may be illuminated by an obscure passage in
      his notebooks in which he describes crouching down to look into a dark cave,
      putting his left hand on his knee, and shading his eyes with his right hand. We
      carried out a questionnaire survey, using 33 written and photographic items, to
      find whether this behaviour was typical of right handers or left handers. In fact
      the 'Leonardo task' showed almost no direct association with handedness, meaning
      that it contributes little to the immediate problem of elucidating Leonardo's
      handedness. However, the lateralisation of the task did relate to other aspects
      of behavioural laterality in surprisingly complex ways. This suggests that
      individual differences in handedness, and behavioural laterality in general, have
      a structural complexity which is not fully encompassed by simple measures of
      direction or degree of handedness.

PMID- 15177792
TI  - The eyes have it!: an fMRI investigation.
AB  - For the past several years it has been thought that cues, such as eye direction,
      can trigger reflexive shifts in attention because of their biological relevance
      and their specialized neural architecture. However, very recently, reported that
      other stimuli, such as arrows, trigger reflexive shifts in attention in a manner
      that is behaviourally identical to those triggered by eyes. Nevertheless these
      authors speculated that reflexive orienting to gaze direction may be subserved by
      a neural system-the superior temporal sulcus (STS)-that is specialized for
      processing eyes. The present study presents fMRI data that provide direct and
      compelling empirical support to this proposal. Subjects were presented with
      fixation stimuli that, based on instruction, could be perceived as eyes or as
      another type of directional cue. Both produced equivalent shifts in reflexive
      attention, replicating Ristic et al. However, the neural systems subserving the
      two forms of orienting were not equivalent-with the STS being engaged
      exceptionally when the fixation stimulus was perceived as eyes.

PMID- 15177793
TI  - Pantomime and imitation of limb gestures in relation to the severity of
      Alzheimer's disease.
AB  - The present study was designed to investigate the relationship between
      performance of limb gestures and the severity of Alzheimer's disease (A.D.).
      Apraxia tends to occur at later stages of A.D., and the severity of apraxia has
      been shown to vary with the severity of A.D. dementia. Participants were 19 mild
      (including 9 with no cognitive impairment and 10 with mild impairment) and 18
      moderate A.D. patients as well as 25 controls and they were asked to pantomime
      (P) or imitate (both concurrent (CI) and delayed (DI)), eight transitive gestures
      to assess praxis performance. Results indicated that the moderate patients
      performed less accurately than mild and non-impaired patients, and that across
      all groups, the imitation conditions were performed less accurately than
      pantomime, relative to controls. Correlational analyses revealed that MMSE scores
      were correlated with all three performance conditions suggesting that impaired
      praxis performance may relate to more global impairment. Finally, a frequency
      analysis was conducted to examine whether A.D. patients showed patterns of
      apraxia as described in Roy's model (1996). Results indicated that A.D. patients
      showed greatest impairment on pattern 7 (deficits in P, DI, and CI), reflecting
      late-stage gesture production, with a greater frequency of moderate patients
      exhibiting each apraxic pattern.

PMID- 15177794
TI  - Does handedness influence the strength of phantom limb illusions in the virtual
      reality box?
AB  - Subjects had to judge the size of a tactile stimulus held in the unseen hand,
      while a visible phantom hand representing that unseen hand held a tactile
      stimulus of same or different size. No asymmetries in interference effects were
      found that could be related to hand or handedness. The method lends itself to
      quantification of virtual reality box illusions and can be used to evaluate the
      role of experience and sources of variability in the strength of the illusion
      across subjects.

PMID- 15177795
TI  - Emotion-based learning on a simplified card game: the Iowa and Bangor Gambling
      Tasks.
AB  - The Iowa Gambling Task (IGT) has been widely used in the assessment of
      neurological patients with frontal lesions. Emphasis has been placed on the
      complexity of the task (i.e., four decks of varying contingency pattern) with the
      suggestion that the participant must use emotion-based learning to deal with a
      complex decision-making process. The present study used a single deck card game
      (the Bangor Gambling Task, BGT), matched in many respects with the Iowa Gambling
      Task, in which the contingencies varied over time (gradually becoming worse for
      the participant) rather than across deck (as in the IGT). Forty participants
      performed both tasks. Performance on the tasks showed many similarities, with
      participants showing a comparable pattern of incremental learning on both tasks,
      reaching an analogous final level of performance. More importantly, there was a
      high correlation (r(2) = .93) in performance between the two tasks, the most
      salient feature of which was that virtually every participant who fell below
      categorisation of impaired IGT performance, also did very poorly on the BGT.
      These findings bear on the question of whether arguments about the 'complexity'
      of the Iowa Gambling Task necessarily explain why it appears to require emotion
      based learning. The Bangor Gambling Task might also be a useful tool for clinical
      neuropsychologists, in the assessment of patients with executive dysfunction
      given that the task is easier and quicker to administer than the Iowa Gambling
      Task, but appears to share the same performance features.

PMID- 15177797
TI  - Time estimation: the effect of cortically mediated attention.
AB  - Do people tend to underestimate time when their attention is engaged? Studies
      supporting this idea have routinely confounded attentional manipulations with
      changes in other factors, such as response complexity and memory load. The aim of
      the present study was to obtain the first direct evidence that attentional
      engagement mediated by cortical brain mechanisms affects time estimation.
      Participants were asked to perform a visual search task that either should not
      demand attention (simple feature search) or should demand cortical attentional
      engagement (conjunction search). Observers searched through 2, 4, 8, 16, 24, 32,
      or 40 items, for blocks of 40 or 60 trials. At the conclusion of each block
      participants were required to provide a written estimate of block duration. This
      time estimate was prospective in nature because subjects knew in advance that
      they would be asked to produce the estimate. Results showed that an attentionally
      demanding conjunction search task produced a large underestimation of time. And
      as the engagement of attention increased so did the underestimation of time.
      These findings provide strong support for an attentional model of prospective
      time estimation that is subserved by cortical brain mechanisms.

PMID- 15177796
TI  - Preference and performance measures of handedness.
AB  - Handedness cannot be predicted using a single performance measure, and preference
      measures of handedness are unreliable because of their subjectivity. This report
      was designed to examine the relationship between hand performance and hand
      preference using six different measures: the Waterloo Handedness Questionnaire (a
      measure of hand preference), the Wathand Box (a performance-based indicator of
      hand preference), two pegboard tasks, finger tapping, and grip strength and to
      determine the most accurate performance-based predictor of hand preference as
      measured by the Waterloo Handedness Questionnaire. Multiple linear regression
      analysis showed that together, the Wathand Box score and the lateralized place
      phase of the grooved pegboard task were the most accurate predictors of hand
      preference.

PMID- 15177798
TI  - Active versus passive proprioceptive straight-ahead pointing in normal subjects.
AB  - Eighty blindfolded healthy female subjects participated in an active and a
      passive straight-ahead pointing task to study the estimation of the subjective
      sagittal middle in the presence or absence of an active haptic exploration.
      Subjects were to point straight-ahead with their left or right index finger
      starting from different right- or left-sided locations, while performing either
      an active movement or with the hand being passively moved by the examiner.
      Results showed: (i) a significant effect of the hand used only on the active
      straight-ahead pointing task performance; (ii) a significant effect of the
      starting position both on the active and passive pointing performance; (iii) a
      significant correlation between the two protocols only in terms of spatial bias
      (algebraic error) but not in terms of precision (absolute errors). These results
      are discussed with regards to normal and neuropsychological studies of the
      egocentric frame of reference.

PMID- 15177799
TI  - Theoretical and methodological implications of language experience and vocabulary
      skill: priming of strongly and weakly associated words.
AB  - The effect of second language experience and vocabulary ability was investigated
      in a semantic priming experiment with weakly related English word pairs (e.g.,
      city-grass). Participants made lexical decisions to targets preceded by unrelated
      or weakly related primes or to nonword targets preceded by words. Reliable
      priming was found for monolingual participants; participants who had acquired a
      second language showed either marginal or nonreliable effects. A similar pattern
      of results was found with the analysis of vocabulary ability. Only participants
      with the greater vocabulary ability showed a priming effect. Although previous
      research has shown that participants with a broad range of linguistic backgrounds
      demonstrate the typical semantic priming effect (e.g., green-grass) with strongly
      associated word pairs, weaker relationships seem to require an extensive
      contextual history for retrieval.

PMID- 15177800
TI  - Priming of non-speech vocalizations in male adults: the influence of the
      speaker's gender.
AB  - Previous research reported a priming effect for voices. However, the type of
      information primed is still largely unknown. In this study, we examined the
      influence of speaker's gender and emotional category of the stimulus on priming
      of non-speech vocalizations in 10 male participants, who performed a gender
      identification task. We found a significant priming effect, which was greater for
      female than male vocalizations. In contrast, the emotional category of the
      stimuli did not appear to modulate the magnitude of priming. These data suggest
      that different aspects of the information conveyed in non-speech vocalizations
      may contribute differently to behavioral priming, possibly influenced by task
      relevance.

PMID- 15177801
TI  - Right hemisphere involvement in the attentional blink: evidence from a split
      brain patient.
AB  - When two masked targets are presented in a rapid sequence, correct identification
      of the first hinders identification of the second. This attentional blink (AB) is
      thought to be the result of capacity limitations in visual information
      processing. Neuropsychological and neuroimaging evidence implicated the right
      hemisphere as the source of this processing limitation. We investigated this idea
      by testing a split-brain patient (JW) in a modified AB task. The targets were
      presented in the same visual field (VF), and thereby to the same hemisphere, or
      in different VFs. We observed evidence of an AB both when the targets were
      presented to the same hemisphere and when the targets were presented to different
      hemispheres. However, the AB was more severe when the second target was presented
      to the RH. Our results are consistent with the notion that the right hemisphere
      plays a critical, but not unique, role in limited-capacity visual processing.

PMID- 15177802
TI  - Seeing the light: Adapting luminance reveals low-level visual processes in the
      attentional blink.
AB  - It is widely assumed that high-level visual processes subserve the attentional
      blink (AB). Recent evidence from studies of visual masking during the AB that
      were designed to directly test the contributions of high-level masking effects,
      however, have failed to provide empirical support for this position. The
      implication is that low-level visual processes are crucial to the AB. We tested
      this idea by manipulating adapting luminance in a standard AB paradigm.
      Consistent with the involvement of low-level neural mechanisms, the AB effect
      interacted with adapting luminance such that an AB was revealed only under
      photopic (light adapted) viewing conditions.

PMID- 15177803
TI  - Can semantic information be transferred between hemispheres in the split-brain?
AB  - Data from experiments with split-brain patients, who have had their left and
      right hemispheres disconnected, suggests a remarkable specialization of function
      within each hemisphere. At the same time, these patients conduct their daily
      lives with great proficiency. This ability suggests that some information
      integral to coordinated function between the hemispheres is available in the
      absence of the corpus callosum. Is information about the semantics of words one
      type of information that is shared? An experiment by suggests that it may be.
      Lambert reported that living/nonliving word categorization was delayed when
      disconnected hemispheres processed words belonging to the same category. Although
      other interpretations are plausible, Lambert described this effect as having a
      semantic source. We attempted to replicate the original effect with two
      additional split-brain patients, J.W. and V.P., and to extend the original design
      to clarify the source of the putative semantic effect. Our results indicate that
      any semantic interaction between the split hemispheres is not reliable. As such
      our study adds to the growing literature indicating that subcortical transfer of
      semantic information is more illusory than real.

PMID- 15177804
TI  - Does each hemisphere monitor the ongoing process in the contralateral one?
AB  - The present study was conducted to examine hemispheric division of labor in the
      initial processing and error monitoring in tasks for which hemispheric
      specialization exists. We used lexical decision as a left hemisphere task and
      bargraph judgment as a right hemisphere task, and manipulated cognitive load.
      Participants had to respond to one of two stimuli presented to both visual fields
      and were instructed to correct their errors. To achieve enough correctable
      errors, participants were encouraged to respond quickly by using a bonus system.
      The results showed the classical asymmetry for initial responses in both tasks
      and reversed asymmetry for corrections in the bargraph task at both load
      conditions, and in the lexical decision task at the high load condition. The
      results suggest that each hemisphere monitors the ongoing process in the
      contralateral one and that the dissociation of initial process and its monitoring
      grows with load of task.

PMID- 15177805
TI  - Spatial coupling affects both homologous and non-homologous limbs.
AB  - The present study examined the interaction between limb movements in space. The
      amount of interaction was measured by how much moving one limb affected the
      movement of another limb. Participants were 24 right-handed university students
      (19 female, mean age=19 years). The task was to draw lines with the right hand
      while moving another limb in lines or circles of different sizes. Significant
      coupling effects were found between both homologous and non-homologous limbs.
      Movement of the right hand was most strongly affected by the left hand, less by
      the right foot, and least by the left foot, consistent with the functional
      cerebral distance model. This effect of limb was observed only in the major
      dimension along which movement was not restrained. Both the limb and dimension
      effects were reduced when the trajectory of motion decreased in size.

PMID- 15177806
TI  - Multisensory executive functioning.
AB  - To better understand the prefrontal circuitry that putatively supports executive
      functions, such as those involved in switching tasks, we asked whether a current
      task set is open equally to receiving information from any sensory modality or if
      it is to some degree modality-specific. Subjects were presented with a sequence
      of digits to be classified as either odd/even or greater/less than five. The
      digits were either auditory or visual, with the modality varying randomly.
      Results demonstrated a reaction time (RT) cost associated with switching between
      tasks and also an unexpected cost of switching between modalities. When both
      modality and task switched, the two costs were greater than either of the costs
      alone, but significantly less than predicted simply by summing the two costs
      together (i.e., they were underadditive). These data indicate that the frontal
      mechanisms that allow for a switch in task are only partially modality-specific.
      Current theories of executive function must be adapted to account for this
      finding. We also suggest that the present paradigm is amenable to future research
      aimed at determining precisely how modalities are linked within a task set.

PMID- 15177807
TI  - Stimulation through simulation? Motor imagery and functional reorganization in
      hemiplegic stroke patients.
AB  - A key factor influencing reorganization of function in damaged neural networks of
      the adult brain is stimulation. How to stimulate motor areas of patients with
      paralyses is a formidable challenge. One possibility is to use internal movement
      simulations, or motor imagery, as an alternative to conventional therapeutic
      interventions that require voluntary limb movements. Before this alternative can
      be entertained, two preliminary issues must be resolved. First, do internal
      movement simulations involve the same neural circuits as comparable overt
      actions? Second, are motor-impaired populations capable of imagining movements
      they can no longer perform? Here, I show that under specific conditions, answers
      to these questions are affirmative. Further, I discuss preliminary evidence that
      internally simulating movements may induce functional reorganization of the
      contralesional hand representation of a chronic, densely hemiplegic, cerebral
      vascular accident (CVA) patient.

PMID- 15177808
TI  - Length effect in reading and lexical decision: evidence from skilled readers and
      a developmental dyslexic participant.
AB  - A number of experimental data have shown that naming latency increases with
      length for pseudo-words but not for frequent real words. Different
      interpretations have been proposed by current models of reading to account for
      such a length effect. The aim of the present study was to assess the impact of
      lexicality on length effect in both the reading and lexical decision tasks. For
      this purpose, skilled readers were asked to either name or make a lexical
      decision on words and pseudo-words differing in length from one to three
      syllables. Skilled readers' results show that length effect is modulated by
      lexicality in the reading task but no length effect was found in the lexical
      decision task. The tasks were further proposed to a well-compensated dyslexic
      participant who exhibited a visual attentional disorder in the absence of any
      associated phonological problems. A length effect on RTs was found for both words
      and pseudo-words in lexical decision but naming latencies were affected by length
      for the pseudo-words only. The present results largely conform to the predictions
      of the ACV98 model of reading. They are not compatible with the PDP models of
      reading and can only be partially accounted for by dual route models.

PMID- 15177809
TI  - Hemispheric, attentional, and processing speed factors in the treatment of
      developmental dyslexia.
AB  - Aim of the study is to analyze the contributions of hemispheric, attentional, and
      processing speed factors to the effects of neuropsychological treatment of
      developmental dyslexia. Four groups of dyslexic children (M-type dyslexia) were
      treated over a period of four months. A first group (n = 9) underwent Bakker's
      Hemisphere-Specific Stimulation, with presentation of words in the right and left
      visual field. A second group (n = 7) received the same stimuli randomly in either
      visual hemifield. A third group (n = 8) received the same words presented
      centrally at fixation point. A fourth group (n = 6) received central stimuli with
      fixed presentation time (1500 ms). The children were tested before and after
      treatment on reading and spelling measures. All groups improved significantly
      after treatment on all variables. However, the group that was treated with
      centrally presented stimuli improved more than the other groups in spelling
      measures. A possible explanation is that rapid, simultaneous presentation to both
      hemispheres enhances interhemispheric exchange, which could produce an advantage
      in tasks requiring a high degree of integration between left and right
      hemispheric functions, such as spelling. The absence of significant differences
      in reading improvement may point to the role of memory functions or strategic
      factors characterizing all the treatment programs, possibly overweighing the
      effect of the other factors.

PMID- 15177810
TI  - The effects of skill demands and object position on the distribution of preferred
      hand reaches.
AB  - Performance-based measures of hand preference have been developed as an objective
      method of examining handedness. Previous research using this method showed that
      both skill demands and the position of the object in working space affect
      preferential hand reaching. Specifically, preferred hand reaches predominated in
      left hemispace, in spite of the biomechanical inefficiency involved in reaching
      across the body midline. This was mediated by the skill demands, with a higher
      frequency of preferred hand reaches for tasks requiring more skill. To further
      examine this issue, we increased the task skill demands. Twenty-two right-handed
      adults reached for five tools located in an array of five positions in front of
      them. Participants were required to pick up the tool, pick up and demonstrate how
      to use it, or pick up and actually use the tool on the materials provided. The
      results showed that the frequency of right hand reaches was greatest for the tool
      use condition. This effect was mediated by the position of the object in
      hemispace, with more right hand reaches occurring for the Use task in left
      hemispace than the other tasks, in support of our previous work.

PMID- 15177811
TI  - Efficiency of orientation channels in the striate cortex for distributed
      categorization process.

PMID- 15177812
TI  - ERP study of pre-attentive auditory processing in treatment-refractory
      schizophrenia.
AB  - Event-related potential (ERP) studies have demonstrated impaired auditory sensory
      processing in patients with schizophrenia, as reflected in abnormal mismatch
      negativity (MMN). We sought to extend this finding by evaluating MMN in 13
      treatment-refractory patients with schizophrenia, and 14 age- and gender-matched
      healthy controls. Subjects responded to infrequent visual stimulation while
      ignoring binaurally presented auditory tones. The amplitude and topographical
      pattern of the MMN were analyzed. The control group presented the expected
      reduction in the amplitude of the MMN from frontal to central and parietal
      locations. In comparison, the MMN amplitude was not reduced in the treatment
      refractory patients, and was largest at the central-posterior electrode location.
      In addition, patients displayed larger negativities at left frontal, and left-
      and right-temporal electrode locations than the control subjects. These findings
      are consistent with pre-attentive abnormalities in treatment-refractory patients
      with schizophrenia.

PMID- 15177813
TI  - Hemispheric asymmetry for linguistic prosody: a study of stress perception in
      Croatian.
AB  - The aim of the study was to test for possible functional cerebral asymmetry in
      processing one segment of linguistic prosody, namely word stress, in Croatian.
      The test material consisted of eight tokens of the word pas under a falling
      accent, varying only in vowel duration between 119 and 185 ms, attached to the
      end of a frame sentence. The sentence could, depending on the duration of the
      vowel, mean 'This is a beautiful dog' or 'This is a beautiful belt/waist.' Each
      sentence was presented eight times in three dichotic listening conditions
      (binaural, left ear only, right ear only), in random order. Fourty healthy female
      right-handers participated in a forced-choice lexical task. For each presented
      sentence they had to decide whether it referred to the animal (short vowel in the
      key word) or to the belt/waist (long vowel in the key word). Their oral responses
      were analyzed in terms of response time and categoricity. No consistent
      significant differences were found among listening conditions. The responses
      possibly reflect the nonlateralized activity of subcortical regions or a
      simultaneous activity of both hemispheres relying on different cues.

PMID- 15177814
TI  - Neuropsychology and linguistic aphasiology: evidence in favor of case studies.
AB  - Two aphasic patients speaking Brazilian Portuguese and presenting the
      characteristics of Broca's aphasics were analyzed in relation to their capacities
      to express null subjects in two different grammatical persons: 1st and 3rd
      persons. The analysis consisted of looking at the means obtained from the two
      aphasic patients and their individual results concerning the production of null
      subjects in each grammatical person on focus. The individual pattern shown by
      each patient indicated the relevancy of analyzing individually the performance of
      neuropsychological patients. In this way the hypothesis which claims that in
      Brazilian Portuguese the null subject has two different natures could be
      verified.

PMID- 15177815
TI  - The effect of hemispatial neglect on the perception of centre.
AB  - Highly variable bisection performance in neglect patients has been attributed to
      an increased 'zone of indifference'. The indifference zone indicates the
      discrepancy between two line lengths which are judged as equal in length.
      Following this argumentation, the central area of a line should be expanded in
      neglect patients. The present two experiments investigated for the first time the
      expansion of the central area using a modified version of the Landmark Task. The
      location of a central or asymmetrical bisection mark on a horizontal line had to
      be judged (centre/left/right). In both experiments neglect patients, unlike
      healthy and patient controls, showed clear deficits in judging the location of
      the mark correctly and tended to judge asymmetrical marks of up to 4 cm as
      centrally positioned. The results are in agreement with and provide the first
      clear evidence of an enlarged perceptual zone of indifference in patients with
      hemispatial visual neglect.

PMID- 15177816
TI  - Predictive influence of phonological processing, morphological/syntactic skill,
      and naming speed on spelling performance.
AB  - This paper focuses on the predictive influence of phonological awareness,
      morphological/syntactic skill, and naming speed on spelling. The retrospective
      study correlated spelling performance in a group of 199 French-speaking children
      at the end of grade 2 with earlier capacities for phonemic manipulation,
      morphological/syntactic correction, and naming speed, assessed at the end of
      grade 1. The results are consistent with an integrative model that challenges the
      unitary phonological disorder hypothesis and confirmed that in French, as in
      other languages, naming speed is an independent predictor of reading performance.

PMID- 15177817
TI  - A diffusion model account of normal and impaired readers.
AB  - Acquired aphasics and dyslexics with even very profound word reading impairments
      have been shown to perform relatively well on the lexical decision task, but
      direct contrasts with unimpaired participant's data is often complicated by
      extremely long reaction times for patient data. The dissociation between lexical
      decision and word naming performance shown by these patients is of theoretical
      importance, and here we present an analysis of processing underlying the lexical
      decision task. We are able to determine what aspects of performance are affected
      by acquired aphasics in the lexical decision task. We fit lexical decision data
      from aphasic patients and from normal readers with a sequential sampling model
      (the diffusion model) that simultaneously considers reaction time and accuracy.
      This model provides a powerful means of assessing processes involved in impaired
      and unimpaired lexical decision. Our results suggest that lexical decision may
      tap impairments at both a linguistic and a nonlinguistic level. These impairments
      combine to make patients produce the exaggerated lexical decision reaction times
      typical of neurolinguistic patients: we demonstrate that patients have
      compromised decision and nondecision processes but that the quality of the
      information upon which they base their decisions is not much different from that
      of unimpaired participants.

PMID- 15177818
TI  - Feigned depression and feigned sleepiness: a voice acoustical analysis.
AB  - We sought to profile the voice acoustical correlates of simulated, or feigned
      depression by neurologically and psychiatrically healthy control subjects. We
      also sought to identify the voice acoustical correlates of feigned sleepiness for
      these same subjects. Twenty-two participants were asked to speak freely about a
      cartoon, to count from 1 to 10, and to sustain an "a" sound for approximately 5s.
      These exercises were completed three times (within the same testing session) with
      three differing sets of instructions to the participants. These three conditions
      were presented in pseudo-random order to control for any order effects, and all
      subjects were naive to the intended purpose of this study. For all three
      conditions, mean speaking rates and pitch ranges were calculated. A series of
      paired t tests showed significant differences in the speaking rates (counting
      numbers and free-speech exercises) between the 'normal' and feigned sleepy
      conditions, and between the normal and feigned depression conditions, but not
      between the 'sleepy' and 'depressed' conditions. The results for pitch range, for
      all speech exercises, were not different between the normal and either the
      feigned depression or feigned sleepiness conditions. These results indicate that
      persons feigning depression and sleepiness demonstrate some level of conscious
      control of their speech rate, but they did not convincingly alter their pitch
      ranges while feigning depression or sleepiness.

PMID- 15177819
TI  - Conflicting strategies and hemispheric suppression in a lexical decision task.
AB  - The research tests the prediction of the inhibitory-interaction hypothesis that
      experience with a task accentuates the functional imbalance between the
      hemispheres. Right-handed males who were experienced readers were presented a
      letter string to the centre visual field for lexical decision. The string was or
      was not accompanied by a blinking light to the left or right visual field. It was
      predicted that asymmetry would be greatest for strings that spelled words, less
      for strings that were orthographically correct (pseudowords) and least for
      strings that were orthographically incorrect (nonwords) because efficient adult
      readers have more experience with letter strings that do than do not spell a
      word, and have more experience with orthographically correct than incorrect
      letter strings. The analysis of response times supported the prediction.
      Moreover, in the nonword and in early trials of the pseudoword conditions,
      response times were faster when one or other hemisphere was distracted than when
      both were engaged suggesting the hemispheres use strategies that conflict when
      suppression has not been accentuated by practice. As well, as the trials
      progressed in the pseudoword condition, asymmetry reversed before increasing
      suggesting that the hemispheres reduce conflict by competing for and then
      strengthening suppression.

PMID- 15177820
TI  - Memory effects in syntactic ERP tasks.
AB  - The study presented here investigated the role of memory in normal sentence
      processing by looking at ERP effects to normal sentences and sentences containing
      grammatical violations. Sentences where the critical word was in the middle of
      the sentence were compared to sentences where the critical word always occurred
      in sentence-final position. Grammaticality judgments were required at the end of
      the sentence. While the violations in both conditions result in the expected
      increase in the P600 component (reflecting the fact that the syntactic violation
      is being processed), the sentences with the sentence-medial critical word also
      result in a late frontal negativity effect. It is hypothesized that this effect
      is due to greater memory requirements that are needed to keep the violation in
      mind until a response can be made at the end of the sentence. The maintenance of
      the decision that a sentence is ungrammatical must be kept in memory longer for
      sentence-medial violations as opposed to when the violation occurs at the end of
      the sentence (immediately preceding the moment at which the judgment can be
      made).

PMID- 15177821
TI  - Semantic memory and verbal working memory correlates of N400 to subordinate
      homographs.
AB  - N400 is an event-related brain potential that indexes operations in semantic
      memory conceptual space, whether elicited by language or some other
      representation (e.g., drawings). Language models typically propose three stages:
      lexical access or orthographic- and phonological-level analysis; lexical
      selection or word-level meaning and associate activation; and lexical
      integration, sentence- and discourse-level operations. The exact stage that N400
      reflects is unknown, although opinion favors lexical integration over lexical
      selection. Surprisingly, little research has assessed relationships between
      neuropsychological measures of semantic memory fund of information or verbal
      working memory capacity and N400. Subjects performed a homograph disambiguation
      comprehension task with minimal working memory load. Short sentences read: The
      noun was adjective/verb. The nouns were either homographs or unambiguous. The
      adjective/verb was disambiguating for the homograph, and congruent or incongruent
      for the unambiguous noun. The primary noun of interest was the subordinate
      homograph. Comprehension of the subordinate meaning should correlate with
      semantic memory stores, reflecting greater knowledge. If N400 primarily reflects
      lexical access operations, it should also correlate with measures of semantic
      knowledge. If N400 reflects lexical integration, it should correlate with
      measures of working memory capacity. Comprehension errors were associated with
      semantic memory stores, but not working memory capacity. N400 was related to
      working memory capacity, but not semantic knowledge, suggesting that N400
      primarily reflects late-stage working memory operations. N400 to subordinate
      disambiguating words was larger with greater working memory capacity, and thus
      may index the absolute capacity of working memory rather than difficulty in
      contextual integration.

PMID- 15177822
TI  - Gestural imitation and limb apraxia in corticobasal degeneration.
AB  - Limb apraxia is a common symptom of corticobasal degeneration (CBD). While
      previous research has shown that individuals with CBD have difficulty imitating
      transitive (tool-use actions) and intransitive non-representational gestures
      (nonsense actions), intransitive representational gestures (actions without a
      tool) have not been examined. In the current study, eight individuals with CBD
      and eight age-matched healthy adults performed transitive, intransitive
      representational and intransitive non-representational gestures to imitation. The
      results indicated that compared to controls, individuals with CBD were
      significantly less accurate in the imitation of transitive and intransitive non
      representational gestures but showed no deficits for the imitation of
      intransitive representational gestures. This advantage for intransitive
      representational gestures was thought to be due to fewer demands being placed on
      the analysis of visual-gestural information or the translation of this
      information into movement when imitating these gestures. These findings speak to
      the importance of context and the representation of gestures in memory in gesture
      performance.

PMID- 15177823
TI  - Unilateral forced nostril breathing affects dichotic listening for emotional
      tones.
AB  - Unilateral forced nostril breathing (UFNB) through the left nostril is associated
      with enhanced spatial abilities, whereas UFNB through the right nostril is
      associated with enhanced verbal abilities. However, the effects of UFNB on
      standard tasks of laterality (e.g., dichotic listening) are unknown. This study
      employed dichotic listening for word targets, which typically exhibits a right
      ear advantage (REA), and dichotic listening for emotional targets, which
      typically exhibits a left ear advantage (LEA). Participants were asked to breathe
      either through their dominant nostril (congruent UFNB) or to breathe through
      their non-dominant nostril (incongruent UFNB) for the entire testing session.
      There was a significant three-way interaction between the type of dichotic
      listening task, nostril dominance, and nostril assignment, with the expected REA
      for word targets and the expected LEA for emotional targets-with one exception.
      Right nostril dominant participants assigned to the congruent condition exhibited
      an LEA for emotional targets (p < .05). The other three groups exhibited the
      expected LEA/right hemisphere advantage for the detection of emotional targets
      and all groups exhibited the expected REA/left hemisphere advantage for detection
      of word targets. As such, possible bias induced by tactile stimulation of the
      contralateral face cannot account for these results. Thus, our data are
      consistent with a selective enhancement of right hemispheric lateralized
      functions by right nostril UFNB.

PMID- 15177824
TI  - Sparing of written production of proper nouns and dates in aphasia.
AB  - Aphasia is a total or partial loss of the ability to produce or understand
      language, usually caused by brain disease or injury. In this case study, the
      aphasic patient (BMW) has a profound impairment of oral production and a very
      moderate impairment in comprehension. Several years of informal observation lead
      to the current study that contrasts written naming of common nouns to written
      naming of proper nouns and dates. BMW named professional ice hockey players, team
      logos, and provided birthdays of players with near perfect accuracy and normal
      rates of production. In contrast, his performance on naming common nouns was only
      50% accurate and appeared very laborious. The results of this study thus show a
      clear preservation of date and proper noun production in contrast to common
      nouns.

PMID- 15177825
TI  - Impaired performance of children exposed in utero to cocaine on a novel test of
      visuospatial working memory.
AB  - The present study examines the potentially harmful effects of prenatal cocaine
      exposure on later visuospatial memory functions. A novel neuropsychological
      measure of immediate- and short-term memory for visuospatial information was
      administered to 40 children, who were identified as cocaine-exposed, and 11 age
      and socioeconomic status matched controls (all children were 8-9 years old). The
      Groton Maze Learning Test is a computer-based hidden maze learning test that
      consists of a 'timed chase test' (a simple measure of visuomotor speed), 5
      learning trials on a hidden maze, followed by a delayed recall trial after an 8
      min delay. The specific test parameters are chosen based on the age cohort of the
      subjects. The cocaine-exposed group performed significantly slower on the 'timed
      chase test,' the last 3 learning trials, and the delayed recall trial (p < or =
      .05 for all comparisons). Although there was a modest trend for the cocaine
      exposed group to make more errors throughout the learning trials, there were no
      significant group differences. These results suggest that children who were
      exposed in utero to cocaine exhibit slowed visuomotor speed, a possible
      impairment in procedural learning, and diminished efficiency in accessing and
      using the internal spatial map that subjects create to master the maze.

PMID- 15177826
TI  - Women's menarche stories from a multicultural sample.
AB  - This paper reports on the findings of a focus group study that examines how women
      have experienced menarche at the personal level and in relation to the larger
      cultural, religious, and societal environment. Fifty-three women from 34
      different countries were recruited in 13 focus groups. On the one hand, at the
      personal level, menarche stories shared in this study revealed salient themes
      concerning feelings experienced at the time of menarche, the importance of
      mother's reactions to their daughter's first menstruation, difficulties around
      understanding the meanings attached to menarche by others, managing menstrual
      products, as well as making sense of formal education related to menstruation,
      and the age of menarche. On the other hand, the discussions concerning how women
      experienced menarche in relation to the larger cultural, religious, and societal
      environment revealed secrecy to be a defining feature of many stories. Cultural
      expectations of learning, and following the rules and regulations surrounding
      menstruation led to different reactions in women at the time of their menarche.
      Very few women mentioned a ritual or celebration at the time of their menarche.
      Findings are discussed in terms of similarities and differences in menarche
      stories of women from different cultural backgrounds. Limitations of the study
      are mentioned and suggestions for future research are provided.

PMID- 15177827
TI  - Health service utilization for perceived postpartum morbidity among poor women
      living in Karachi.
AB  - To explore traditional beliefs and practices, to assess puerperal morbidity, and
      to understand care-seeking behaviors, a qualitative and quantitative study was
      conducted in low socio-economic settlements of Karachi, Pakistan. Five focus
      group discussions and 15 in-depth interviews were conducted in July and August
      2000. 525 Muslim women, who were 6-8 weeks post-partum, were then interviewed at
      home. Maternal care was relatively good-more than three-quarters of recent
      mothers sought antenatal care and more than half (267/525) delivered in a
      hospital or maternity home. Counseling to attend post-partum clinics among
      facility deliveries was 16% (43/267), of which only 26% (11/43) attended.
      Practices during the delivery and puerperium, such as massaging the vaginal walls
      with mustard oil during labor to facilitate delivery and inserting vaginal or
      rectal herbal pessaries to facilitate 'shrinkage of the uterus' and/or
      'strengthening of the backbone', were pervasive. The core symptoms that are
      clinically significant during the puerperium are heavy vaginal bleeding and high
      fever, since they are potentially fatal symptoms if appropriate and timely care
      is not sought. About half of the study women (53.3%) reported at least one
      illness symptom, high fever (21.1%), heavy vaginal bleeding (13.9%), and foul
      smelling vaginal discharge (9.6%). Women did not know the underlying biologic
      cause of their perceived post-partum morbidity; weakness was frequently
      mentioned. Women sought care initially from close relatives or traditional
      healers and if they continued to suffer from their morbidity they finally
      approached a trained health care (allopathic) provider. The high prevalence of
      perceived post-partum morbidity illustrates the demand for post-partum community
      based health care programs. We suggest promoting maternal health education that
      encourages women to seek appropriate and timely care by accessing public or
      private health services.

PMID- 15177828
TI  - Gender inequality, family planning, and maternal and child care in a rural
      Chinese county.
AB  - This study examines the determinants of prenatal and obstetric care utilization
      within the context of recent social and economic changes in contemporary rural
      China. The aim of this study is to test the general hypothesis that gender
      inequality (women's status and son preference) and the state's family planning
      policy have a significant influence on maternal and childcare utilization. Both
      qualitative and quantitative data from a field survey in 1994 in rural Yunnan
      were used in the study. The findings lend support to this hypothesis. For
      example, the extent to which the husband shares housework and childcare, as an
      important marker of rural Chinese women's position within the family, is
      positively associated with the likelihood that a woman receives prenatal
      examinations, stops heavy physical work before birth, and gives birth under
      aseptic conditions. Also, a woman's exposure to the larger world beyond the
      village increases her chances of giving birth with the assistance of a doctor or
      health worker. Son preference is an impeding factor for maternal and child health
      care utilization. Already having a son in the family reduces the chances that the
      mother will stop heavy physical work before birth for a subsequent pregnancy.
      Female infants with older sisters are the least likely to receive immunizations.
      Women with "outside the plan" pregnancies are less likely than those with
      "approved" pregnancies to receive prenatal examinations, to stop strenuous work
      before birth, and to deliver under aseptic conditions. Thus, the study provides
      further evidence that the family planning policy has a negative impact on women
      and their families, whose fertility and son preferences conflict with the birth
      control policy.

PMID- 15177829
TI  - Eating, drinking and being depressed: the social, cultural and psychological
      context of alcohol consumption and nutrition in a Brazilian community.
AB  - Much has been written about the socioeconomic distribution of nutritional status,
      both in more economically developed, and in developing nations. In general,
      persons of lower socioeconomic status suffer adverse consequences of poor
      nutritional status, although these consequences can vary depending on the level
      of development, i.e. in more developed countries the problem tends to be one of
      over-nutrition and obesity, while in developing countries the problem tends to be
      one of under-nutrition and nutritional deficiencies. In this paper, we explore
      the socioeconomic distribution of dietary intake in a Brazilian city, in an area
      that in some ways is neither prototypically developed or underdeveloped. The
      analysis presented here was stimulated by the surprising observation of no
      socioeconomic differences in total caloric intake in the context of extreme
      differences in income distribution. Further examination showed that socioeconomic
      differences in total caloric intake appeared after controlling for alcohol
      intake. A complete analysis of the data suggests that lower income leads to lower
      cultural consonance, which in turn leads to higher depression, higher alcohol
      intake, and higher total caloric intake. In this model, alcohol ingestion can be
      seen as both a psychological and nutritional adaptive strategy to economic,
      social and cultural marginality in a highly stratified society.

PMID- 15177830
TI  - Chronic diseases and depression: the modifying role of psychosocial resources.
AB  - Psychosocial coping resources have been found to protect against depressive
      symptoms in people with and without chronic diseases. It has not been
      established, however, whether these resources have the same effects across
      patients with different diseases. Therefore, the aim of the study was to estimate
      the direct and buffer effects of psychosocial resources on depression, and to
      examine whether these effects are different for various chronic diseases. Data
      were obtained from the Longitudinal Aging Study Amsterdam. In all, 2288 community
      dwelling respondents (age 55-85) were included and followed for a maximum of 6
      years. Depressive symptoms (using the Center for Epidemiologic Studies-Depression
      scale), the presence of seven frequently occurring chronic diseases, social
      support and personal coping resources, physical functioning and sociodemographic
      variables were assessed by structured interviews. Generalized estimating equation
      models were estimated for each disease, social support and personal coping
      resources. All resources, except social network size, showed a direct effect on
      depressive symptoms regardless of the presence of chronic diseases. Having a
      partner, high self-esteem, mastery, self-efficacy and feeling less lonely
      additionally buffered the negative effect of some, but not all, specific chronic
      diseases. Unexpectedly, in patients with cardiac disease, none of the
      psychosocial resources exerted a buffer effect on depressive symptoms. For
      instrumental and emotional support only direct (unfavorable) effects and no
      buffer effects could be observed. In conclusion, our study provides evidence that
      buffer effects of psychosocial resources are different across various chronic
      diseases. This suggests that interventions to enhance specific resources may
      ameliorate depressive symptoms in specific chronic patients groups.

PMID- 15177831
TI  - 'White liquor hits black livers': meanings of excessive liquor consumption in
      South Africa in the second half of the twentieth century.
AB  - Four years into South Africa's first democracy, the African National Congress
      Youth League, with the help of the liquor industry's Social Aspects of Alcohol
      Committee drafted a policy to prevent substance abuse in black communities. They
      declared that alcohol was 'often not used in a socially acceptable way'.
      Concerned not so much with post-apartheid policy as with making sense of what
      socially acceptable alcohol usage might mean, this article explores narratives of
      alcohol use and abuse in South Africa in the second half of the twentieth
      century. It demonstrates that while multiple understandings of excess in alcohol
      consumption were articulated, those notions tied to particular constructions of
      racial difference prevailed. Ideas pairing drinking habits with race were given
      effect by state institutions. By tying drinking habits to 'race' and by locating
      'race' in a social hierarchy, state institutions determined access to liquor and
      welfare services. By naturalising Africans as heavy drinkers, the state justified
      its sale of liquor to African men while denying the need for rehabilitation in
      the event of alcoholic dependence. By placing 'coloured' closer to 'white' in its
      racial order, the apartheid state found cause to extend limited rehabilitation
      services to those designated 'coloured'. By tying liquor revenues to apartheid
      administration, the ruling regime exonerated its policy of excluding blacks from
      the retail liquor trade even after lifting prohibition in 1962. This policy
      encouraged rampant illicit liquor dealing, created a social environment in which
      alcoholic excess, particularly after 1976, reached new proportions and generated
      new and dangerous meanings of socially acceptable drinking. Against the grain of
      these dominant discourses of racially designated meanings of drinking, African
      people forged a more complex set of practices and meanings not rendered any
      clearer by the ANC Youth League's discourse of acceptable and unacceptable usage.

PMID- 15177832
TI  - Sociocultural aspects of tuberculosis: a literature review and a case study of
      immigrant tuberculosis.
AB  - The resurgence of tuberculosis in recent years has obliged us to reconsider the
      existing explanations of the disease. Whereas biomedical literature tends to
      explain tuberculosis in terms of biological factors (e.g., bacterial infection),
      social scientists have examined various cultural, environmental, and politico
      economic factors. In this paper, sociocultural approaches to tuberculosis are
      reviewed according to their emphasis on cultural, environmental, and politico
      economic factors. Then how the public health establishment considers biological,
      cultural, environmental and politico-economic factors will be examined through a
      case study of immigrant tuberculosis. While public health facilities emphasize
      biological factors in the control of immigrant tuberculosis, an ethnographic
      study of tuberculosis among Chinese immigrants in New York City provides detailed
      contexts that illustrate the cultural, environmental, and politico-economic
      forces shaping tuberculosis and supports an emerging theorization of tuberculosis
      that encompasses a heterogeneous collection of factors. Finally, a number of
      implications for public health interventions will be discussed.

PMID- 15177833
TI  - A social disease/a social response: lessons in tuberculosis from early 20th
      century Chile.
AB  - During the 1930s, Chile reported the world's highest mortality rate due to
      tuberculosis. In this pre-antibiotic era, the attention of the biomedical
      community frequently turned to the underlying social inequalities and
      deficiencies that created conditions of heightened risk for Chile's rapidly
      expanding working class. With the recognition that crowded housing, chronic
      malnutrition and substandard working conditions fostered an environment in which
      the disease developed and spread with virulent rapidity, physicians frequently
      became vocal advocates for widespread and significant social reform. However, by
      the time of the introduction of efficacious pharmaceutical agents in the 1940s
      and with the overall rapid development of biomedicine in the mid-20th century,
      the larger medical discourse became more rigidly defined and characterized by the
      promotion of the new antibiotics and treatments. These factors increased the
      depth of the self-defined medical territory but substantially reduced its
      breadth. Accompanying this shift was an increasing focus on individual behaviors
      that were seen as deficient and were both socially censored and used as
      explanations for increased susceptibility. In the midst of the current worldwide
      epidemic of tuberculosis, this disease and its epidemiological pattern heightens
      our awareness of the significance and consequences of global inequalities. It
      also draws our attention to the importance of intervention within the social
      conditions from which these patterns emerge.

PMID- 15177834
TI  - Physician commitment in end of life care--perspectives from New Zealand and the
      Netherlands.
AB  - A social constructionist approach is taken to analyse the accounts of experiences
      of doctors who have provided end of life care, comprising five Dutch doctors and
      six New Zealand doctors who had not provided physician-assisted death, and five
      Dutch doctors who had. A core theme of 'commitment' to the patient crossed all
      interviews and when a request for assisted death was received this theme altered
      and evolved differently between the groups. All respondents reacted by exploring
      reasons for the request and offering palliative care. When the request persisted,
      those who had provided euthanasia entered into a 'contractual commitment',
      constructing another "vulnerable" self in the negotiations that invited the
      sympathy of the hearer. This evolved to 'sacrificial commitment' when the
      physician provided euthanasia despite negative personal psychological effects.
      Constructing a self who is willing to sacrifice personal comfort to relieve the
      suffering of another is useful in silencing criticism of actions. The two groups
      who had not provided euthanasia, intensified their efforts to find an alternative
      to assisted death in a 'pledged commitment' to the patient, constructing
      themselves as deeply committed to the patient in an intimate struggle to meet
      his/her need. While New Zealand doctors denied that euthanasia had ever been an
      option, some Dutch doctors evolved their commitment to 'potential sacrificial
      commitment', constructing an open-minded and accepting self, willing to consider
      euthanasia despite fears of negative personal consequences. The construction of
      alternative 'selves' in accounts is useful in inviting sympathy and silencing
      potential criticism of actions that may be construed negatively (because the
      patient was assisted to die, or because assistance to die was refused).

PMID- 15177835
TI  - RCT of a theory-based intervention promoting healthy eating and physical activity
      amongst out-patients older than 65 years.
AB  - A randomised controlled trial was used to evaluate a theory-based health
      promotion intervention. The intervention, a healthy living booklet, was designed
      to promote healthy eating and physical activity amongst people aged over 65 years
      attending hospital out-patient clinics. The booklet employed persuasive arguments
      targeting the most proximal cognitive antecedents of behaviour specified by the
      theory of planned behaviour, as well as goal setting prompts. Participants (N =
      252, average age=82) were randomly allocated to a control (patient satisfaction
      questionnaire) or intervention (healthy living booklet) group. Cognitions and
      behaviour were measured pre-intervention and at a two week follow up. The
      intervention group made significantly higher gains in perceived behavioural
      control, intention and behaviour for both target behaviours, suggesting that the
      intervention was successful. Sixty three of those invited to set goals to eat
      more healthily (e.g., "to eat five portions of fruit and vegetables a day") did
      so, and 67% of those who set such goals reported 100% success in acting on them.
      By contrast, only 34% of intervention participants set an activity goal (e.g., "a
      five minute walk everyday"), and only 51% reported 100% success in enacting these
      goals. Results suggest that the observed behavioural effects of the healthy
      eating booklet could be attributed to goal setting as well as changes in
      perceived behavioural control and intention.

PMID- 15177836
TI  - The impact of stigma on maternal attitudes toward placement of children with
      disabilities in residential care facilities.
AB  - This study examines willingness to consider placement of children with
      disabilities in residential care facilities among 81 mothers of children with
      disabilities. Perceived stigma is added to the Andersen and Newman model of
      health service utilization in order to evaluate its impact on placement attitudes
      controlling for predisposing, enabling and need characteristics and health
      beliefs. Findings of regression analyses suggest that older, single mothers of
      more severely disabled children are more likely than other mothers to consider
      residential placement and that adequate finances and residential stability may
      reduce this willingness. When these variables are controlled, the expectation
      that people with disabilities will be stigmatized by others in the community
      increases willingness to consider placement and does so by increasing the degree
      of caregiver burden experienced. Results also suggest, however, that among
      mothers of young children, specific aspects of perceived stigma have direct
      affects on willingness to consider placement even when perceived burden is
      controlled.

PMID- 15177837
TI  - Physical, mental and social factors associated with frequent attendance in Danish
      general practice. A population-based cross-sectional study.
AB  - Knowledge of which factors are prompting patients to seek primary care is
      important to the ongoing effort to improve management in general, and management
      of frequent attenders (FAs) in particular. We conducted a cross-sectional
      population-based study with the aim at examining associations between physical,
      mental and social factors and frequent attendance in general practice. We
      collected questionnaire and registry data in the County of Aarhus (630,000
      inhabitants), Denmark. Half of the county general practices (132 practices, 220
      GPs) were selected randomly. FAs were defined as the top 10% attenders over the
      past 12 months. A questionnaire including SF-36 and questions about physical and
      mental health and social conditions was sent to age and gender stratified samples
      of FAs and non-FAs from these practices. Impairments (SF-36) associated with
      frequent attendance were physical in 54-71% (prevalence difference (PD): 16-33%,
      adjusted prevalence ratio (adj. PR): 1.1-1.7), mental in 58-70% (PD: 17-25%, adj.
      PR:1.1-1.4) and social in 40-59% (PD: 13-28%, adj. PR:0.9-1.5). Among FAs, 46-88%
      had used three or more different drugs (PD: 26-39%, adj. PR:1.5-2.3) and 27-41%
      had been referred one or more times to outpatient specialists (PD: 4-19%, adj.
      PR:1.2-2.5). Although our data cannot determine the direction of causality, they
      clearly demonstrate that FAs carry a large burden of physical, mental and social
      impairments which underpins the complexity and heterogeneity of the problems
      which they present. The results make clear that biopsychosocial management is a
      core issue in FA management in general practice.

PMID- 15177838
TI  - Los Anos de la Crisis: an examination of change in differential infant mortality
      risk within Mexico.
AB  - The main aim of the present analysis is to test the possibility that the period
      of economic hardship characterizing Mexico over the decade 1986-1996 has
      negatively influenced infant health outcomes. Data on births from two
      installments of the Encuesta Nacional de la Dinamica Demografica, a nationally
      representative demographic survey, are used to determine whether a reduction in
      mortality differentials has paralleled the overall drop in the national infant
      mortality rate. The findings indicate that the decrease observed in the overall
      infant mortality rate has been matched by decreases in several disparities at the
      same time that it has been marred by increases in others. The data support the
      possibility that where you live has become an increasingly salient factor in
      determining the odds of infant mortality. High parity, low education and
      unemployment status have also become more salient factors in predicting post
      neonatal infant mortality risk in the more recent period as compared to the
      earlier period. As Mexico's infant mortality rate begins to stabilize in the near
      future, this research highlights the need to re-focus our research efforts on the
      causes and consequences of differential mortality trends.

PMID- 15177839
TI  - A comparison of traditional healers' medicinal plant knowledge in the Bolivian
      Andes and Amazon.
AB  - Medicinal plant knowledge of two groups of traditional healers was thoroughly
      studied during a 2-year ethnobotanical survey in the Bolivian Andes (Quechua
      farmers from Apillapampa) and Amazon rainforest (Yuracare-Trinitario slash-and
      burn cultivators from Isiboro-Secure National Park), respectively. Both areas
      represent ecologically and culturally diverse zones, differing in floristic
      diversity, physical accessibility to health care and degree of modernization, the
      latter evidenced by presence or intensity in use of modern services such as
      electricity, water distribution, and materials for house construction. It is
      generally believed that indigenous people have an impressive knowledge of useful
      plant species and that this knowledge reflects the plant wealth of their living
      environment. However, the present study shows that healers' knowledge of
      collected medicinal plants (expressed as percentage of plants known by name and
      use by the majority of healers) is higher in the Andean area characterised by a
      long history of anthropogenic activity, than in the biodiversity-rich rainforest
      (protected since 1965). Therefore, medicinal plant knowledge does not seem to
      depend on the level of plant diversity, degree of modernization or absence of
      Western health care infrastructure. Indeed, although Andean healers live in a
      floristically poorer environment, have adopted more modern services and have
      easier access to primary health care facilities, they are more knowledgeable
      about medicinal plants than rainforest healers who live isolated in an
      environment with considerable floristic/ecological variation and lack of Western
      health care. It is hypothesised that social factors underlying traditional
      medical practices (background of extensive family in traditional medicine) play
      an important role in transmission--and hence survival of knowledge on medicinal
      plants.

PMID- 15177840
TI  - Dhandha, dharma and disease: traditional sex work and HIV/AIDS in rural India.
AB  - This paper discusses the results of two ethnographic studies with female sex
      workers in rural areas of Karnataka and Rajasthan, India. In particular, we focus
      on women whose socio-economic status, and religious and occupational practices,
      are part of sex work systems that have historical precedents such that they can
      be termed "traditional" sex workers. The approach taken in the ethnographic work
      was informed by current critical approaches in medical anthropology and public
      health. The paper argues that in the context of an expanding HIV/AIDS epidemic in
      rural areas of India, understanding the historical and structural factors that
      operate to perpetuate female sex work as a culturally "sanctioned" occupation is
      critical if interventions intended to reduce the risk of HIV transmission are to
      succeed. We conclude that interventions designed to empower women collectively in
      these communities that are consistent with cultural traditions are needed to lead
      to healthier sexual behaviours and reduced risk of HIV/AIDS infection.

PMID- 15177841
TI  - 'It might happen or it might not': how patients with multiple sclerosis explain
      their perception of prognostic risk.
AB  - This qualitative study aimed to examine risk perception and seriousness of
      wheelchair dependence in patients with multiple sclerosis. Perceived absolute
      risk and perceived seriousness were assessed for 2-year, 10-year and lifetime
      prognosis of wheelchair dependence using visual analogue scales (VAS). In semi
      structured interviews, patients (n = 85) were asked to elucidate these VAS
      scores. Explaining perceived absolute risk, patients mentioned disease-related
      factors as well as psychological factors. Uncertainty about future disease
      progression was a predominant factor for all patients, even those with low and
      high perceptions of risk. Wheelchair dependence was perceived as a serious
      outcome primarily because of its possible implications, such as loss of
      independence. When perceptions of 2-year, 10-year and the lifetime prospect of
      wheelchair dependence were compared, it was found that patients discriminated in
      their perception of absolute risk, but less in that of seriousness. Comparison of
      quantitative and qualitative assessments indicated good construct validity for
      perception of the absolute risk and seriousness of wheelchair dependence.

PMID- 15177842
TI  - The post-war public health effects of civil conflict.
AB  - Civilian suffering from civil war extends well beyond the period of active
      warfare. We examine longer-term effects in a cross-national analysis of World
      Health Organization data on death and disability broken down by age, gender, and
      type of disease or condition. We find substantial long-term effects, even after
      controlling for several other factors. We estimate that the additional burden of
      death and disability incurred in 1999 alone, from the indirect and lingering
      effects of civil wars in the years 1991-1997, was nearly double the number
      incurred directly and immediately from all wars in 1999. This impact works its
      way through specific diseases and conditions, and disproportionately affects
      women and children.

PMID- 15177843
TI  - Antibiotic-resistant infections in the critically ill adult.
AB  - Intensive care units (ICUs) frequently are the epicenter of nosocomial infections
      with antibiotic-resistant bacteria. Optimization of antibiotic therapy for
      seriously ill patients with bacterial infections appears to have a strong
      influence on outcome. Laboratories can aid in provision of appropriate antibiotic
      therapy by providing clinicians with "antibiograms" to aid empiric antibiotic
      choice and by providing minimal inhibitory concentrations of key antibiotics so
      that antibiotic dosing is optimized to key pharmacodynamic targets. Laboratories
      also play a crucial role in the prevention of antibiotic resistance in the ICU.
      Molecular epidemiologic evidence of an oligoclonal outbreak of infections orients
      prevention measures toward investigation of common environmental sources of
      infection and prevention of patient-to-patient transmission. In contrast,
      evidence of polyclonality shifts prevention of antibiotic resistance to
      antibiotic management strategies.

PMID- 15177844
TI  - Antibiotic resistance in the institutionalized elderly.
AB  - Geriatric patients frequently are cared for in long term care facilities (LTCFs),
      which are now a major component of our health care delivery system. Nearly half
      of the 2.2 million people who turned 65 years old in 1990 will enter an LTCF at
      least once before they die. Infections are one of the principal causes of
      morbidity and mortality in LTCFs. Because LTCFs are a less costly alternative to
      hospitalization, clinicians are treating many serious infections in the nursing
      home. As a result of antibiotic use, LTCFs will increasingly be recognized as
      sources of organisms resistant to multiple antibiotics. b-Lactams are a valuable
      class of potent antimicrobials with broad-spectrum activity against Gram-negative
      and Gram-positive organisms. The safety and efficacy of this class of antibiotics
      make them easy choices for empiric treatment of infections in the elderly.
      Unfortunately, excessive use of these antibiotics has created serious threats to
      our therapeutic armamentarium: the emergence of methicillin-resistant
      Staphylococcus aureus and of Gram-negative pathogens resistant to third
      generation cephalosporins such as cefotaxime, ceftazidime, and ceftriaxone. Of
      these third-generation cephalosporins, resistance to ceftazidime is most
      frequently recognized. The major mechanism responsible for ceftazidime resistance
      in Gram-negative bacteria is the production of b-lactamases. This article
      summarizes the diversity of b-lactamases, highlights the important enzymes that
      confer ceftazidime resistance in LTCFs, and details some methods used to identify
      and characterize these enzymes. A clear challenge is to apply these techniques to
      epidemiologic and molecular studies conducted in LTCFs.

PMID- 15177845
TI  - Antibiotic-resistant gram-negative bacteria in hospitalized children.
AB  - Antibiotic-resistant Gram-negative bacilli are a prominent and growing problem
      among hospitalized children. Epidemics caused by these organisms have been
      implicated in many outbreaks in children's hospitals, primarily in neonatal
      intensive care units. These epidemics are characterized by efficient patient-to
      patient transmission of the outbreak clone via the hands of caregivers and
      through exposure of contaminated inanimate sources. The epidemiology of these
      resistant organisms in pediatric hospitals during endemic periods is more
      complex. The isolates cultured from hospitalized individuals in the absence of an
      outbreak usually are unique to each individual and are derived from the patient's
      endogenous flora or other disparate sources. As in adults, chronic care
      facilities for children represent significant reservoirs of antibiotic-resistant
      bacilli that are circulated back into the acute care hospital environment when
      the child becomes ill.

PMID- 15177846
TI  - Vancomycin resistance in Staphylococcus aureus.
AB  - Vancomycin resistance in enterococci, predominantly Enterococcus faecium,
      developed in the latter half of the 1980s, and the long anticipated development
      of vancomycin resistance in Staphylococcus aureus has now occurred. A number of
      vancomycin-intermediate strains have been described, and these strains have
      abnormal, thickened cell walls in the presence of vancomycin. Two mechanisms of
      resistance have been described in the strains: affinity trapping of vancomycin
      molecules by cell wall monomers and clogging of the outer layers of peptidoglycan
      by bound vancomycin molecules, and change in the structure or metabolism of
      teichoic acids. Of more serious concern has been the description in 2002 of two
      patients with vancomycin-resistant S aureus infections. In one instance, the
      patient had skin lesions coinfected with vancomycin resistant, vanA genotype, E
      faecalis, and the vanA resistance genes could have been transferred to the S
      aureus strain. Expression of resistance was high in one S aureus strain and low
      in the other, making detection more challenging in the latter instance. These
      developments are of great concern, and every effort should be made to prevent
      further development and spread of vancomycin resistance in staphylococci.

PMID- 15177847
TI  - Community-acquired methicillin-resistant Staphylococcus aureus infections.
AB  - Staphylococcus aureus causes a variety of minor diseases but also is responsible
      for staphylococcal pneumonia and sepsis, both of which can be fatal. It is
      thought to be responsible for many of the pneumonia deaths associated with the
      influenza pandemics of the 20th century. The introduction of penicillin in the
      1940s greatly improved the prognosis for patients with severe staphylococcal
      infections. However, after a few years of clinical use, most staphylococcal
      strains were able to hydrolyze penicillin by producing b-lactamases, making
      penicillin a useless antibiotic to treat staphylococcal infections caused by b
      lactamase-producing S aureus. Methicillin, a semisynthetic penicillin introduced
      in 1959, was specifically designed to be resistant to b-lactamase degradation,
      but resistance developed soon after its introduction into clinical practice.
      Methicillin-resistant S aureus (MRSA) was first reported in the United Kingdom in
      1961, followed by reports from other European countries, Japan, and Australia.
      The first reported case of MRSA in the United States was in 1968. Currently, MRSA
      is an important pathogen in nosocomial infections and is a problem in hospitals
      worldwide, and it is increasingly recovered from nursing home residents with
      established risk factors. More recently, community acquired MRSA infections have
      been documented among healthy individuals with no recognizable risk factors, and
      it seems clear that community-acquired MRSA (CA-MRSA) strains are
      epidemiologically and clonally unrelated to hospital-acquired strains. This
      review focuses on the epidemiology, clinical significance, and virulence markers
      of CA-MRSA infections.

PMID- 15177848
TI  - Mechanisms of resistance among respiratory tract pathogens.
AB  - Antimicrobial resistance among respiratory tract pathogens represents a
      significant health care threat. Identifying the antimicrobial agents that remain
      effective in the presence of resistance, and knowing why, requires a thorough
      understanding of the mechanisms of action of the various agents as well as the
      mechanisms of resistance demonstrated among respiratory tract pathogens. The
      primary goal of antimicrobial therapy is to eradicate the pathogen, via killing
      or inhibiting bacteria, from the site of infection; the defenses of the body are
      required for killing any remaining bacteria. Targeting a cellular process or
      function specific to bacteria and not to the host limits the toxicity to
      patients. Currently, there are four general cellular targets to which
      antimicrobials are targeted: cell wall formation and maintenance, protein
      synthesis, DNA replication, and folic acid metabolism. Resistance mechanisms
      among respiratory tract pathogens have been demonstrated for all four targets. In
      general, the mechanisms of resistance used by these pathogens fall into one of
      three categories: enzymatic inactivation of the antimicrobial, prevention of
      intracellular accumulation, and modification of the target site to which agents
      bind to exert an antimicrobial effect. Resistance to some agents can be overcome
      by modifying the dosage regimens (e.g., using high-dose therapy) or inhibiting
      the resistance mechanism (e.g., b-lactamase inhibitors), whereas other mechanisms
      of resistance can only be overcome by using an agent from a different class.
      Understanding the mechanisms of action of the various agents and the mechanisms
      of resistance used by respiratory tract pathogens can help clinicians identify
      the agents that will increase the likelihood of achieving optimal outcomes.

PMID- 15177849
TI  - Macrolide resistance in Streptococci and Haemophilus influenzae.
AB  - Antimicrobial resistance is a growing problem among pathogens from respiratory
      tract infections. b-Lactam resistance rates are escalating among Streptococcus
      pneumoniae and Haemophilus influenzae. Macrolides are increasingly used for the
      treatment of respiratory tract infections, but their utility is compromised by
      intrinsic and acquired resistance. This article analyses macrolide-resistance
      mechanisms and their worldwide distributions in S pneumoniae, S pyogenes, and H
      influenzae.

PMID- 15177850
TI  - Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of
      respiratory tract infections.
AB  - The pharmacologic field that studies antimicrobial pharmacokinetics and
      pharmacodynamics (PK/PD) has had a major impact on the choice and dosing regimens
      used for many antibiotics especially those used in the treatment of respiratory
      tract infections. PK/PD parameters are particularly important in light of
      increasing antimicrobial resistance. Drug pharmacokinetic features, such as serum
      concentrations over time and area under the concentration-time curve, when
      integrated with minimum inhibitory concentration (MIC) values of antibiotics
      against pathogens, can predict the probability of bacterial eradication and
      clinical success. These pharmacokinetic and pharmacodynamic relationships also
      are important in preventing the selection and spread of resistant strains and
      have led to the description of the mutation prevention concentration, which is
      the lowest concentration of antimicrobial that prevents selection of resistant
      bacteria from high bacterial inocula. b-lactams are time-dependent agents without
      significant post-antibiotic effects, resulting in bacterial eradication when
      unbound serum concentrations exceed MICs of these agents against infecting
      pathogens for >40% to 50% of the dosing interval. Macrolides, azaolides, and
      lincosamides are time-dependent agents with prolonged post-antibiotic effects,
      and fluoroquinolones are concentration-dependent agents, resulting in both cases
      in bacterial eradication when unbound serum area-under-the-curve to MIC ratios
      exceed 25 to 30. These observations have led to changes in recommended
      antimicrobial dosing against respiratory pathogens and are used to assess the
      role of current agents, develop new formulations, and assess potency of new
      antimicrobials.

PMID- 15177851
TI  - Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella
      catarrhalis to 17 oral antimicrobial agents based on pharmacodynamic parameters:
      1998-2001 U S Surveillance Study.
AB  - Pharmacokinetic/pharmacodynamic parameters were used to interpret susceptibility
      data for the oral agents tested in a clinically meaningful way. Among S
      pneumoniae isolates, >99% were susceptible to respiratory fluoroquinolones, 91.6%
      to amoxicillin, 92.1% to amoxicillin/clavulanic acid (95.2% at the extended
      release formulation breakpoint), 90.6% to clindamycin, 80.4% to doxycycline,
      71.0% to azithromycin, 72.3% to clarithromycin, 71.8% to cefprozil and cefdinir,
      72.6% to cefuroxime axetil, 66.3% to cexime, 63.7% to
      trimethoprim/sulfamethoxazole, and 19.7% to cefaclor. Among H influenzae
      isolates, 28.6% were b-lactamase positive, but virtually all were susceptible to
      amoxicillin/clavulanic acid (98.3%, with 99.8% at the extended-release
      formulation breakpoint), cexime (100%), and uoroquinolones (99.8%), whereas 93.5%
      were susceptible to cefdinir, 82.8% to cefuroxime axetil, 78.1% to
      trimethoprim/sulfamethoxazole, 70.2% to amoxicillin, 25.1% to doxycycline, 23.2%
      to cefprozil, and 5% to cefaclor, azithromycin and clarithromycin. Most isolates
      of M catarrhalis were resistant to amoxicillin, cefaclor, cefprozil, and
      trimethoprim/sulfamethoxazole. Thus significant b-lactam and macrolide/azalide
      resistance in Streptococcus pneumoniae and b-lactamase production and
      trimethoprim/sulfamethoxazole resistance in untypeable Haemophilus influenzae are
      still present. The results of this study should therefore be applied to clinical
      practice based on the clinical presentation of the patient, the probability of
      the patient's having a bacterial rather than a viral infection, the natural
      history of the disease, the potential of pathogens to be susceptible to various
      oral antimicrobial agents, the potential for cross-resistance between agents with
      S pneumoniae, and the potential for pathogens to develop further resistance.
      Antibiotics should be used judiciously to maintain remaining activity and chosen
      carefully based on activity determined by pharmacokinetic/pharmacodynamic-based
      breakpoints to avoid these bacteria developing further resistance, particularly
      to fluoroquinolones.

PMID- 15177852
TI  - Evolution of amoxicillin/clavulanate in the treatment of adults with acute
      bacterial rhinosinusitis and community-acquired pneumonia in response to
      antimicrobial-resistance patterns.
AB  - Current treatment guidelines for community-acquired respiratory tract infections
      no longer depend solely on the characteristics of the patient and the clinical
      syndrome, but on those of the offending pathogen, including presence and level of
      antimicrobial resistance. The most common respiratory tract pathogens known to
      cause acute bacterial rhinosinusitis (ABRS) and community-acquired pneumonia
      (CAP) include Streptococcus pneumoniae and Haemophilus influenzae. The prevalence
      of antimicrobial resistance, especially b-lactum and macrolide resistance, among
      S pneumoniae and H influenzae has increased dramatically during the past 2
      decades, diminishing the activity of many older antimicrobials against resistant
      organisms. A pharmacokinetically enhanced formulation of amoxicillin/clavulanate
      has been developed to fulfill the need for an oral b-lactam antimicrobial that
      achieves a greater time that the serum drug concentration exceeds the minimum
      inhibitory concentration (T > MIC) of antimicrobials against pathogens than
      conventional formulations to improve activity against S pneumoniae with reduced
      susceptibility to penicillin. The b-lactamase inhibitor clavulanate allows for
      coverage of b-lactamase-producing pathogens, such as H influenzae and M
      catarrhalis. This article reviews the rationale for, and evolution of, oral
      amoxicillin clavulanate for ABRS and CAP

PMID- 15177855
TI  - A qualitative study of women's perspectives of antenatal care in a rural area of
      Zimbabwe.
AB  - OBJECTIVE: To describe the perspectives and experiences of women in their use of
      antenatal care and in their reasoning on specific antenatal care routines.
      DESIGN: Two qualitative methods including focus group discussions and individual
      interviews were combined. SETTING: : a rural district in Zimbabwe where a
      randomised control trial had been undertaken to introduce a new antenatal care
      package. PARTICIPANTS: Forty-four women and twenty-four men participated in the
      study. FINDINGS: Women were observed to take actions contrary to those assumed
      professionally acceptable in antenatal care generally and in some specific
      changed routines. Visits were to be reduced and weighing was to be omitted, but
      women, especially younger women, said they preferred more than the stipulated
      five goal oriented visits. One reason for this was the importance of being
      assured that the fetus was growing well. They considered that visits spaced too
      widely would make it difficult for service providers to help, should
      complications develop. On the other hand, older women (above 35 years old), a
      group professionally considered to be at high risk, were not so concerned with
      the visits. All the women said they wanted to be weighed at all the visits. The
      antenatal care visits are simply known as 'going for scale'. The health care
      providers complied by weighing the women without recording. Cultural beliefs had
      great influence, especially on the time a pregnancy is acknowledged and reported.
      It is believed that pregnant women and the pregnancy are vulnerable to witchcraft
      during the early period of pregnancy. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE:
      We concluded that, whether in its traditional or new form, antenatal care ignores
      the experiences and views of women and the way they make sense of pregnancy and
      the care of pregnancy. The importance of understanding the perspectives of
      different stakeholders as the key to effective change is underlined.

PMID- 15177856
TI  - Women's behaviour, beliefs and information sources about physical exercise in
      pregnancy.
AB  - OBJECTIVE: To examine the potential effect of low-risk pregnancy on women's
      recreational activity patterns and to explore pregnant women's beliefs and
      information sources regarding physical exercise participation. DESIGN:
      Preliminary, prospective survey SETTING: Participants' homes in the East
      Midlands, UK. PARTICIPANTS: Fifty-seven nulliparous, pregnant women.
      MEASUREMENTS: Levels of maternal physical activity participation were assessed by
      semi-structured interview at 16, 25, 34 and 38 weeks gestation. The modified
      Baecke questionnaire provided a measure of women's habitual sport and leisure
      activities in the 12 months prior to pregnancy. A 10-item scale assessed maternal
      beliefs regarding the importance of physical activity in pregnancy. The fetal
      health locus of control scale measured the extent to which women believed their
      own behaviour, the behaviour of others and/or chance would influence fetal
      health. Open-ended questions assessed women's information sources. FINDINGS:
      Fourteen of the 36 (39%) women who reported participating in some form of weekly
      exercise before pregnancy did not report pursuing any similar activities during
      pregnancy. Rest and relaxation were perceived as being significantly more
      important during pregnancy than was regular exercise or the maintenance of an
      active lifestyle. Fifty-five respondents (96%) indicated that they had received
      advice about physical activity at least once during pregnancy. At 16 weeks
      gestation, women obtained most of their information from books and magazines.
      Between 25 and 38 weeks gestation, most advice came from family and friends.
      Participants who reported receiving this advice were significantly older, more
      educated and of a higher activity level pre-pregnancy. KEY CONCLUSIONS: Levels of
      maternal exercise may decline during pregnancy both as a result of the physical
      changes of pregnancy and from a combination of social and psychological factors.
      Present health education may be failing to correct inaccurate perceptions of the
      risks associated with physical exercise in pregnancy. IMPLICATIONS FOR PRACTICE:
      Improving the quantity and quality of information related to physical exercise
      has the potential to correct inaccurate perceptions and confer several benefits
      on maternal and fetal health. Effective intervention strategies should focus not
      only on the pregnant woman but also extend to her family, friends and exercise
      provider.

PMID- 15177857
TI  - Two-tailed tests and a statistical significance at 0.05: what do they mean?

PMID- 15177858
TI  - The range of coping strategies women use to manage pain and anxiety prior to and
      during first experience of labour.
AB  - OBJECTIVES: To investigate whether nulliparous women, during pregnancy, can
      identify their own pre-existing coping strategies for managing pain and anxiety
      and whether the range of coping strategies used in Labour by women who do not
      attend antenatal classes can be described. DESIGN: Qualitative semi-structured
      interviews. SETTING: Two large maternity units in a city in the North of England.
      PARTICIPANTS: Twenty-three nulliparous women were interviewed during their third
      trimester of pregnancy (prior to any antenatal class attendance) regarding
      strategies used to cope with previous experiences of pain and anxiety. A separate
      sample of 20 women, who had not attended any form of antenatal education, were
      interviewed within 72h of their first experience of labour regarding the coping
      strategies used to manage pain and anxiety during labour. FINDINGS: Template
      Analysis was used to code data from transcribed interviews. The findings indicate
      that as women approach their first experience of labour they can identify coping
      strategies that they have employed to manage pain and anxiety in their past.
      Equally women who have not attended antenatal classes use a wide range of
      strategies in labour. The range of identified coping strategies is described and
      comprises thoughts and behaviours with positive and negative consequences. KEY
      CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: It is possible to help nulliparous
      women to identify, in pregnancy, a range of strategies that they have previously
      employed to manage pain and anxiety. This range reflects the coping strategies
      that women may potentially use in labour to manage pain and anxiety. Women may
      benefit from assistance in pregnancy to develop strategies for labour that are
      based on knowledge of their own coping repertoire, which includes enhancing
      positive strategies and finding alternatives to negative strategies.

PMID- 15177859
TI  - A prospective randomised trial on the effect of position in the passive second
      stage of labour on birth outcome in nulliparous women using epidural analgesia.
AB  - OBJECTIVE: To determine whether the rate of instrumental birth in nulliparous
      women using epidural analgesia is affected by maternal position in the passive
      second stage of labour. DESIGN: A pragmatic prospective randomised trial.
      SETTING: Consultant maternity unit in the Midlands. PARTICIPANTS: One hundred and
      seven nulliparous women using epidural analgesia and reaching the second stage of
      labour with no contraindications to spontaneous birth. INTERVENTIONS: The lateral
      versus the supported sitting position during the passive second stage of labour.
      MEASUREMENTS: Mode of birth, incidence of episiotomy, and perineal suturing.
      FINDINGS: Recruitment was lower than anticipated (107 vs. 220 planned). Lateral
      position was associated with lower rates of instrumental birth rate (lateral
      group 33%; sitting group 52%; p=0.05, RR 0.64, CI for RR: 0.40-1.01; Number
      needed-to-treat (NNT)=5), of episiotomy (45% vs. 64%; p=0.05, RR 0.66, CI for RR:
      0.44-1.00, NNT=5), and of perineal suturing (78% vs. 86%; p=0.243, RR 0.75, CI
      for RR 0.47-1.17). The odds ratio for instrumental birth in the sitting group was
      2.2 (CI 1.00-4.6). Logistic regression of potential confounder variables was
      undertaken, due to a large variation in maternal weight between the randomised
      groups. Of the nine possible confounders tested, only position of the baby's head
      at full dilation affected the risk of instrumental birth significantly (p=0.4, OR
      2.7 where the fetal head was in the lateral or posterior position). Maternal
      weight did not appear to have any effect. The odds ratio for instrumental
      delivery for women randomised to the sitting position was slightly higher within
      the logistic regression model (adjusted OR 2.3). KEY CONCLUSIONS: Women
      randomised to the lateral position had a better chance of a spontaneous vaginal
      birth than those randomised to the supported sitting position. Position of the
      babies head at full dilation had an additional effect on mode of birth. These
      effects are not conclusively generalizable. RECOMMENDATIONS FOR PRACTICE: The
      lateral position is likely to be at best beneficial, and at the worst no less
      harmful than the sitting position for most women and their babies who meet the
      criteria set for this study. Conclusive evidence for or against the technique
      should be established using larger trials.

PMID- 15177860
TI  - Risk ratios and odds ratios--what are they?

PMID- 15177861
TI  - Young single women's experiences of pregnancy, adjustment, decision-making and
      ongoing identity construction.
AB  - OBJECTIVE: To explore young pregnant women's experiences of embodiment, ongoing
      identity construction, decision-making processes and the way in which these are
      influenced by contemporary discourse, information sources and interaction with
      health professionals and others. DESIGN: An exploratory descriptive pilot study.
      Data were collected via diaries kept during pregnancy, two face-to-face, open
      ended interviews, one in the second trimester of pregnancy and one six to eight
      weeks after the birth of the baby, and a brief telephone interview conducted six
      months post birth. SETTING: A major metropolitan hospital for women in Melbourne,
      Victoria, Australia, and the community. PARTICIPANTS: Five English speaking
      participants, aged between 17 and 23 years. FINDINGS: All the young women
      accepted, even welcomed, the physical changes of pregnancy. Acceptance of
      pregnancy and an evolving positive sense of identity was assisted by support from
      families, particularly mothers, access to sympathetic and expert health
      professionals, exposure to a range of opinions through classes, books and the
      media, general acceptance from society at large, support from friends, and
      choices and opportunities in relation to ongoing education and employment.

PMID- 15177862
TI  - Pregnant women's preferences and knowledge of term breech management, in an
      Australian setting.
AB  - OBJECTIVE: To assess women's familiarity with breech presentation and external
      cephalic version (ECV), and to identify women's preferences and attitudes
      regarding breech management. DESIGN: Cross-sectional survey. SETTING: King George
      V (KGV) Memorial Hospital for Mothers and Babies, Sydney, Australia, a major
      metropolitan teaching hospital. POPULATION: 174 pregnant women (20-38 weeks
      gestation) attending KGV for antenatal care in 2001. METHODS: Data were obtained
      from a self-administered questionnaire that was distributed through the antenatal
      clinics. MAIN OUTCOME MEASURES: Women's familiarity of breech presentation and
      ECV, women's attitude towards ECV, decision to attempt ECV, and with whom
      participants would like to make a decision regarding ECV. FINDINGS: Of the 174
      respondents, 85% could correctly identify breech presentation, and 66% had heard
      of ECV. For 87% this information was from books, and family/friends, and not
      their midwife/doctor. Equal numbers of women responded that they would or would
      not choose ECV (39%), and the remaining 22% were uncertain. Factors influencing
      their decision included concerns about the safety for the baby, ECV not
      guaranteeing vaginal birth despite successful version, and ECV not being
      effective enough. Seventy-two per cent wanted to make the decision to attempt ECV
      together with their doctor. CONCLUSION: Although the majority of the women had a
      preference for vaginal birth, their knowledge of ECV appeared insufficient to
      enable them to make informed decisions about attempting ECV. These findings
      suggest that care-providers should offer women information on ECV, in a shared
      decision-making environment.

PMID- 15177863
TI  - The value of a pilot study in breast-feeding research.
AB  - OBJECTIVE: To test the integrity of a protocol for a randomised controlled trial
      (RCT) to examine the effectiveness of skin-to-skin care compared to routine care
      on the initiation and duration of breast feeding and to provide data to be used
      in the power calculation for a proposed trial. DESIGN: Randomised pilot study.
      SETTING: Warrington Hospital, Cheshire, UK. PARTICIPANTS: Women at 36 weeks'
      gestation with healthy singleton pregnancies, who intended to breast feed, who
      had 'booked' for care at Warrington Hospital and had given informed consent to
      participate. Twenty-eight women were randomised in the pilot study. METHOD: Women
      were randomly allocated to receive either routine or skin-to-skin care following
      birth. The first breast feed was assessed using the Breast-feeding Assessment
      Tool (BAT). Mothers were followed up at discharge from hospital and again at four
      months to provide details of duration of breast feeding. FINDINGS: 66 women were
      approached to participate in the trial and 44 consented (67% consent rate).
      Twenty-eight women were randomised in the study and 26 breast feeds were observed
      (93%). The pilot study identified procedural changes that were required in the
      design of the main study, provided an estimate of recruitment rates and confirmed
      the previously calculated sample size. CONCLUSION: The pilot study demonstrated
      that a large RCT of skin-to-skin versus routine care was feasible. This is an
      example of how a pilot study has the ability to identify unforeseen challenges in
      the conduct of the trial as well as allowing necessary changes to be made to the
      design that will increase the quality of the subsequent research.

PMID- 15177865
TI  - Trefoil factor family (TFF) peptides: regulators of mucosal regeneration and
      repair, and more.

PMID- 15177864
TI  - Supplementing breast-fed babies in the UK to protect their mothers from tiredness
      or distress.
AB  - OBJECTIVE: To explore mothers' and healthcare professionals' beliefs,
      expectations and experiences in relation to supplementation of breast feeding in
      the postnatal ward and newborn-baby unit. DESIGN AND METHOD: A qualitative study
      using an ethnographic approach which involved participant observation and
      interviews. Analysis of the observation data informed who would be approached for
      interview and interviews also guided further observation work. Categories and
      themes were generated from the field notes and interviews. SETTING: A maternity
      unit in the South of England using six methods of supplementary feeding.
      PARTICIPANTS: 30 mothers, 17 midwives, four neonatal nurses, three
      paediatricians, three senior house officers and 3 healthcare assistants were
      interviewed in the postnatal ward and newborn-baby unit over a period of nine
      months in 2002. FINDINGS: A major theme was the healthcare professionals' desire
      to protect the mothers from tiredness or distress, although this at times
      conflicted with their role in promoting breast feeding. The categories
      'protecting the mother from guilt', 'making it easy to give up' and 'protecting
      the mother from distress' were linked to this theme. Sometimes midwives suggested
      supplementation because they perceived mothers to be tired, sometimes mothers
      themselves made the request. Thus the researcher constructs of 'midwife led' and
      'mother led' supplementation emerged. KEY CONCLUSIONS/IMPLICATIONS FOR PRACTICE:
      Healthcare professionals need to be aware that they may not be helping mothers in
      the longer-term when supplementation is used as a quick 'solution' to a mother's
      tiredness or distress. However, other strategies such as providing emotional
      support or role modelling 'settling' skills are time consuming and have resource
      implications for the maternity services.

PMID- 15177866
TI  - Development of a two-site ELISA assay for the dimeric form of human TFF1.
AB  - TFF1 is one of three human trefoil proteins expressed principally in the
      gastrointestinal tract in normal tissues. TFF1 protects the gastric mucosa
      against damage as a result of its ability to facilitate reconstitution of damaged
      gastric mucosa and its involvement in the secretion and structure of gastric
      mucus. The most biologically active molecular form in cell culture and animal
      models tested is a dimer formed by a disulfide bond between two cysteine residues
      close to the C terminus of the protein. We have therefore developed an assay for
      this form of TFF1 which should facilitate its measurement in biological samples.

PMID- 15177867
TI  - Urinary pS2/TFF1 levels in the management of hormonodependent breast carcinomas.
AB  - pS2/TFF1 overexpression in breast carcinomas correlates with response to
      hormonotherapy. We evaluated the clinical relevance of urinary pS2/TFF1 in breast
      cancer patients. In healthy controls (100 cases), it represents an individual and
      relatively stable parameter. Although 24 out 83 pre-operative breast cancer
      patients showed elevated levels, both the sensitivity and specificity of the test
      were too low for breast cancer screening. However, neoadjuvant hormonotherapy
      decreased pS2/TFF1 levels in nine out of 20 patients. Furthermore, among 22
      patients receiving long-term adjuvant hormonotherapy, four exhibited elevated
      levels, two of them at the time of relapse. Thus, urinary pS2/TFF1 quantification
      might be suitable as an in vivo diagnosis for tumor hormonodependency, and
      disease follow-up during hormonotherapy.

PMID- 15177868
TI  - TFF1 is membrane-associated in breast carcinoma cell line MCF-7.
AB  - Trefoil factor family (TFF) domain peptides, products of mucin-secreting
      epithelial cells, are thought to influence mucosal integrity. Molecular studies
      revealed that mammalian TFFs lack transmembrane domains. Using
      immunocytochemistry and FACS analysis we demonstrated the association of TFF1
      with the cell membrane in MCF-7 (a breast adenocarcinoma cell line), and tested
      the hypothesis that glycosylphosphatidylinositol (GPI) linkage is the mechanism
      for this association. Cleavage of GPI anchorage using phospholipase C did not
      affect TFF1 binding to the cell membrane. Our results demonstrate for the first
      time that TFF1 is associated with the cell membrane of MCF-7 cells and is not
      linked via a GPI anchor.

PMID- 15177869
TI  - Profiling trefoil factor family (TFF) expression in the mouse: identification of
      an antisense TFF1-related transcript in the kidney and liver.
AB  - The expression of the trefoil factor family (TFF) genes (TFF1, TFF2, and TFF3)
      was systematically analyzed in 18 different organs from male or female mice using
      RT-PCR analysis. The expression patterns showed some gender-specific differences,
      e.g., TFF3 transcripts in the urinary bladder and liver. Furthermore, the murine
      expression profile differed from that in human, e.g., in the respiratory tract
      and uterine cervix. As a hallmark, an aberrant TFF1-related transcript was
      detected specifically in the kidney and liver of several mouse strains. Molecular
      characterization of this rare 1.8kb long transcript from the kidney clearly
      revealed that its 3' region originated from the antisense strand of the TFF1
      locus containing particularly large parts of the antisense strands of introns 1
      and 2. Homology searches using various databases revealed that this antisense
      TFF1-related transcript is subject of intense alternative splicing and no protein
      product encoded by this antisense TFF1-related transcript could be identified.
      Although the function of this transcript is not known currently, we can speculate
      that this antisense TFF1-related transcript might have a gene silencing effect
      particularly on TFF1 expression in the murine kidney and liver.

PMID- 15177870
TI  - Expression of trefoil factor family 1, 2, and 3 peptide is augmented in
      hepatolithiasis.
AB  - Trefoil factor family (TFF) 1, 2, and 3 is a mucin-associated protein involved in
      the maintenance of mucosal barrier and restitution of lining epithelial cells. In
      this study, the expression of TFF1, 2, and 3 and MUC mucins were examined
      immunohistochemically in hepatolithiasis and control livers. The expression of
      TFF1, 2, and 3 were augmented markedly in biliary mucosa in hepatolithiasis in
      coordinate with gel-forming mucin. TFF3 was detected in hepatic bile samples of
      hepatolithiasis. Augmented expression and secretion of TFF in biliary mucosa in
      hepatolithiasis may play a role in lithogenesis together with gel-forming mucin
      in addition to mucosal defense and repair.

PMID- 15177871
TI  - TFF3 expression at the esophagogastric junction is increased in gastro-esophageal
      reflux disease (GERD).
AB  - At the gastric cardia, the molecular mechanisms of inflammation and metaplasia
      are incompletely understood. Thus, the aim of this study was to determine the
      expression of TFF1, TFF2 and TFF3 at this site and correlate these data with
      Helicobacter pylori infection or gastro-esophageal reflux disease (GERD). In 27
      patients without intestinal metaplasia at the cardia, endoscopic biopsies were
      obtained for histology and RT-PCR. TFF1 and TFF2 were expressed in all cardia
      samples. TFF3 expression was significantly more frequent at the cardia (n =
      15/24) than in the corpus (n = 2/26). TFF3 expression at the cardia was mainly
      observed in GERD patients, and there was a clear tendency towards higher
      interleukin-8 (IL-8) transcription levels; whereas TFF3 expression was not
      correlated with the H. pylori status or to tumor necrosis factor-alpha (TNF
      alpha) expression. The expression of TFF3 at the cardia may represent an
      adaptation to GERD and precede the development of Barrett's esophagus.

PMID- 15177872
TI  - Expression of trefoil peptides in the subtypes of intestinal metaplasia.
AB  - We studied the expression of trefoil peptides in the different types of
      intestinal metaplasia of the stomach. Endoscopic biopsy was performed in 132
      patients with dyspepsia. Intestinal metaplasia subtype was classified according
      to the pattern of alcian blue/PAS staining and high iron diamine staining.
      Expression of trefoil peptides was measured by immunohistochemistry. TFF1 and
      TFF3 were mainly expressed in goblet cells and TFF2 in columnar cells in all the
      types of intestinal metaplasia. There was a gradual decrease of TFF1 and TFF3,
      and increase of TFF2, during the progression of intestinal metaplasia from type I
      to type III via the type II intermediate.

PMID- 15177873
TI  - Bacterial expression and purification of biologically active human TFF3.
AB  - A glutathione S-transferase (GST) fusion protein expression system for the
      production and purification of recombinant human trefoil factor family-domain
      peptide 3 (hTFF3) was established. The hTFF3 gene, prepared by PCR, was cloned
      into a pBluescript KS(+) plasmid, and inserted into a pGEX-4T-1 GST fusion
      vector. The GST-hTFF3 fusion protein was expressed in Escherichia coli, and hTFF3
      was purified with Glutathione Sepharose 4B affinity chromatography, yielding
      about 3-4 mg of pure hTFF3 in one liter of culture broth. The biological activity
      of purified hTFF3 was tested in two previously reported rat gastric ulcer models.
      Oral administration of recombinant hTFF3 has a dose dependent protective effect
      against ethanol-induced or pylorus ligation-induced gastric mucosa injury in rat,
      which indicates that our recombinant hTFF3 is biologically active.

PMID- 15177874
TI  - Synergistic effects of systemic trefoil factor family 1 (TFF1) peptide and
      epidermal growth factor in a rat model of colitis.
AB  - Novel therapies for the treatment of colitis are required. We therefore examined
      the potential value of the trefoil factor family 1 (TFF1) peptide and epidermal
      growth factor (EGF) alone and in combination. Effects of TFF1- Cys58 +/- EGF on
      an in vitro HT29 cell wounding model of restitution showed synergistic activity
      when used in combination. In addition, animals had colitis induced by adding 4%
      dextran sulphate sodium (DSS) to the drinking water for 7 days and they also
      received twice daily subcutaneous injections of test peptides. Treatment with
      TFF1-Cys58 alone (100 microg/kg) reduced histological colitis score by 22%, but
      the TFF1-Ser58 variant was ineffective. In a second study, TFF1-Cys58 reduced
      histological colitis score by 15%, EGF (600 microg/kg) by 26%, and an additive
      response (42% reduction) was demonstrated when used together (P < 0.01 versus
      either peptide given alone). Similar results were found using tissue
      myeloperoxidase (MPO) activity as a marker of inflammation. Where clinical
      risk/benefit seems justified, these initial studies suggest that combination
      therapy of systemic EGF and TFF peptides may prove useful for treatment of
      colitis in patients with disease extending beyond the reach of topical (enema)
      therapy.

PMID- 15177875
TI  - TFF-2 inhibits iNOS/NO in monocytes, and nitrated protein in healing colon after
      colitis.
AB  - Endogenous trefoil (TFF) peptides have reparative and anti-inflammatory actions
      in colitis because luminal application in vivo potently reduces inflammatory
      indices and accelerates healing. Since chronic production of NO via inducible
      nitric oxide synthase activity (iNOS) leads to tissue damage and inflammation, we
      tested whether TFF2 could inhibit NO production in a monocyte cell line in
      response to bacterial endotoxin, and in vivo by measuring inflammatory indices
      and nitrated protein expression in rat colon after colitis induction. We showed
      that TFF2 can inhibit iNOS and NO in monocytes and inflammatory compartment size
      in vivo, and conclude that trefoils can regulate monocyte NO-mediated
      inflammation in colitis.

PMID- 15177876
TI  - TFF peptides in the human false vocal folds of the larynx.
AB  - TFF peptides (formerly P domain peptides, trefoil factors) are typical secretory
      products of mucin-producing cells and are thought to influence the rheological
      properties of mucous gels. We investigated the localization of these peptides in
      the human false vocal folds of the larynx, also known as the ventricular folds or
      vestibular folds. An analysis of TFF peptide mRNA by RT-PCR and TFF protein by
      Western blot detected TFF1 and TFF3, but not TFF2. Immunohistochemistry revealed
      TFF1 to be associated with the secretory product of goblet cells and mucous parts
      of subepithelial seromucous glands. TFF3 occurred in columnar epithelial cells of
      the mucosa and in serous cells and excretory duct cells of seromucous glands.
      These peptides may play a role in the rheological function of mucus secreted onto
      the true vocal folds and are thus important constituents of vocal production.

PMID- 15177877
TI  - Distribution of TFF peptides in corneal disease and pterygium.
AB  - The central cornea of 10 cadavers and 33 patients suffering from keratoconus,
      herpetic keratitis, Fuchs' dystrophy and pterygium were analysed focusing on the
      expression of TFF peptides by means of reverse transcription polymerase chain
      reaction and immunohistochemistry. TFF1 and TFF3 transcripts were detected in
      healthy corneae as well as in pterygia. Only TFF3 mRNA was transcribed in
      keratoconus, Fuchs' dystrophy and herpetic keratitis. Immunohistochemistry
      revealed absence of all three TFF peptides in healthy corneae but production of
      TFF3 in each of the diseased corneae. In pterygia both TFF1 and TFF3 synthesis
      was detectable in goblet cells. The absence of TFF peptide production in the
      healthy cornea indicates that TFF3 secretion is induced in different corneal
      diseases by yet unknown stimuli. Here TFF3 synthesis can be interpreted as a
      protection mechanism, because all corneal diseases analysed are characterized by
      progressive tissue destruction. TFF1 and TFF3 production by goblet cells in
      pterygia is comparable to the healthy conjunctiva suggesting that TFF peptides do
      not play a significant role in the pathogenesis of pterygia.

PMID- 15177878
TI  - Trefoil factor family (TFF) expression in the mouse brain and pituitary: changes
      in the developing cerebellum.
AB  - Trefoil factor family (TFF) peptides, besides their prominent expression in
      mucous epithelia, are also synthesized in the central nervous system. Previously
      TFF1 expression was observed in mouse brain astrocytes, while oxytocinergic
      neurons of the hypothalamo-pituitary axis are recognized sites of TFF3 synthesis.
      Here, the expression of TFF1, TFF2, and TFF3 was systematically studied using
      reverse transcription-polymerase chain reaction (RT-PCR) analysis of dissected
      adult mouse brain regions including the pituitary. Additionally, the
      developmental profile of TFF expression in murine cerebral cortex and cerebellum
      was monitored. Overall, the expression patterns of the three TFF genes differed.
      The TFF1 and TFF2 profiles shared some similarities, whereas the TFF3 expression
      pattern was completely different. TFF1 was nearly uniformly, but weakly expressed
      in all brain regions tested. The TFF1 and TFF2 expression patterns differed
      characteristically in the pituitary where abundant TFF2 transcription was
      detected in the anterior and not the posterior lobe and the expression level in
      males was higher than in females. In contrast, TFF3 expression was limited to the
      hippocampus, the temporal cortex, and the cerebellum, the latter being
      surprisingly the major site of expression. Here, TFF3 mRNA appeared to be
      restricted mainly to neurons and not glial cells. Cerebellar TFF3 expression is
      clearly developmentally regulated (maximum at P15), indicating a role for TFF3
      during postnatal cerebellar development.

PMID- 15177879
TI  - TFF3 induced Fos protein expression in the magnocellular oxytocin neurons of the
      hypothalamus.
AB  - TFF3 is synthesized in magnocellular oxytocin neurons of the supraoptic (SON) and
      paraventricular nuclei (PVN) of the rat and human hypothalamus. Here we
      investigated whether intracerebroventricular (i.c.v.) injection of TFF3
      stimulates oxytocin release into the blood and activates Fos protein
      immunoreactivity in oxytocin neurons of the SON and PVN in rats. The results show
      that plasma oxytocin concentrations were not altered after i.c.v. injection of
      TFF3 or vehicle. Fos protein expression was significantly increased in both the
      SON and PVN after TFF3 injections and double labeling studies showed that the Fos
      signal was predominantly in oxytocin neurons.

PMID- 15177880
TI  - Characterization of a CCAAT-enhancer element of trefoil factor family 2 (TFF2)
      promoter in MCF-7 cells.
AB  - Trefoil factors family 2 (TFF2), also known as spasmolytic polypeptide, is
      primarily expressed in the mucus neck cells of gastrointestinal tracts. It has
      been proposed that TFF2 plays an important physiological role in protection,
      repair, and healing of gastrointestinal mucosa. To investigate the cis-acting
      regulatory element that control TFF2 tissue-specific expression, we studied the
      basal TFF2 promoter activity through transient transfection in several human
      cancer cell lines. Expression of TFF2 was found to be significantly greater in
      human breast cancer MCF-7 cells compared to other cancer cells. Results from TFF2
      promoter luciferase reporter constructs revealed that the basal level of TFF2
      promoter activity was overall more than two-fold higher in MCF-7 cells compared
      to that of other cell lines examined. Using EMSA assays and site-directed
      mutagenesis, we identified a cell line-specific transcriptional regulation
      element located in the TFF2 promoter 5'-flank sequence at -32/-27, and which
      contains a CCAAT/enhance binding proteins (C/EBPs) consensus-binding site.
      Mutation of this consensus site reduced the basal promoter activity by more than
      50% in MCF-7 cells but had no effect in human gastric cancer cells. In
      conclusion, we have identified a CCAAT sequence as a cell line-specific cis
      acting regulatory element that may contribute to the high level expression of
      TFF2 in MCF-7 cells. These results also suggest the possibility that TFF2 could
      play a role in mammary gland tumorigenesis.

PMID- 15177881
TI  - Transcriptional control of TFF3 (intestinal trefoil factor) via promoter binding
      sites for the nuclear factor kappaB and C/EBPbeta.
AB  - The acute phase response is strictly connected with modulation of gene
      expression. Transcriptional control of many genes is mediated by binding of
      diverse transcription factors to cis-acting DNA motifs in the respective promoter
      sequence. We now describe such regulatory elements for the TFF3 gene coding for a
      peptide involved in response to gut irritation. TNF-alpha stimulation, which
      induces NF-kappaB activation, evoked up to 10-fold reduction of TFF3 expression
      in the colon tumour cell line HT-29. Several consensus binding sites for members
      of the NF-kappaB transcription factor subunits are located in the 5'-flanking
      region of TFF3. Mutating these sites was aimed at discovering which one is
      responsible for NF-kappaB binding and thus regulation of TFF3 expression.

PMID- 15177882
TI  - TFF2 (trefoil family factor2) inhibits apoptosis in breast and colorectal cancer
      cell lines.
AB  - We have recently demonstrated that human TFF2 inhibits apoptosis in the non-TFF2
      expressing breast adenocarcinoma cell line MCF-7. In this study we examined the
      impact of TFF2 and an anti-TFF2 antibody (hSP3) on the survival of other human
      adenocarcinoma cell lines; TFF2-positive (LS174T and SW480) and TFF2-negative
      (MCF-7 and T47D). Addition of TFF2 protected the (TFF2-) lines but had no effect
      on those constitutively expressing TFF2. Blocking with hSP3 significantly
      increased apoptosis in the (TFF2+) cell lines with minimal effect on the (TFF2-)
      cells. Our results show that the cytoprotective effect of TFF2 seen in MCF-7
      cells is not cell line-specific and can be abrogated by inhibition of its
      expression.

PMID- 15177883
TI  - Expression and motogenic activity of TFF2 in human breast cancer cells.
AB  - The expression of TFF2 in breast cancer cells and the effect of recombinant TFF2
      on breast cancer cell migration were assessed. TFF2 expression was detected by
      PCR in estrogen receptor-negative and at lower levels in estrogen receptor
      positive breast cancer cells. TFF2 expression was detected in nine out of 10
      primary breast tumors but its expression was not related to that of the estrogen
      receptor. Focal expression was observed in normal and tumor cells by
      immunohistochemistry. TFF2 stimulated the migration of estrogen-responsive MCF-7
      and non-responsive MDA-MB231 cells. We conclude that TFF2 is expressed in normal
      and malignant breast epithelial cells and that it stimulates the migration of
      breast cancer cells.

PMID- 15177885
TI  - Trefoil factor family (TFF) peptides and cancer progression.
AB  - TFF peptides are involved in mucosal maintenance and repair through motogenic and
      antiapoptotic activities. These peptides are overexpressed during inflammatory
      processes and cancer progression. They also function as scatter factors,
      proinvasive and angiogenic agents. Such a divergence is related to the
      pathophysiological state of tissues submitted to persistent aggressive situations
      during digestive processes in the normal gastrointestinal tract, inflammatory and
      neoplastic diseases. In agreement with this model, TFF peptides are connected
      with multiple oncogenic pathways. As a consequence, the TFF signaling pathways
      may serve as potential targets in the control of chronic inflammation and
      progression of human solid tumors.

PMID- 15177884
TI  - Molecular mechanisms involved in TFF3 peptide-mediated modulation of the E
      cadherin/catenin cell adhesion complex.
AB  - TFF3 is a member of the TFF-domain peptide family which is constitutively
      expressed in mucous epithelial tissues where it acts as a motogenic factor and
      plays an important role during epithelial restitution after wounding and during
      inflammation. In contrast to these beneficial functions, TFFs were also reported
      to be involved in cell scattering and tumor invasion. These changes in epithelial
      cell morphology and motility are associated with a modulation of cell contacts.
      In this respect, we here investigated the E-cadherin/catenin cell adhesion
      complex in FLAG-hTFF3-transfected HT29/B6 and MDCK cells. In hTFF3-transfected
      cells the amount of E-cadherin is reduced with a concomitant reduction of alpha-
      and beta-catenin levels. On one hand, E-cadherin expression is lowered at the
      transcriptional level as shown by multiplex RT-PCR analysis. This decrease does
      not depend on differences in the promoter methylation status as shown by
      methylation-specific PCR. On the other hand, pulse-chase experiments showed a
      reduction in the E-cadherin half-life in hTFF3-transfected cells reflecting
      increased E-cadherin degradation. In summary, hTFF3 induces transcriptional and
      posttranslational processes resulting in a modulation of E-cadherin-mediated cell
      cell contacts that may play an important role in the paradoxical benefical and
      pathogenic function of TFF peptides.

PMID- 15177886
TI  - The transmembrane domain of hepatitis C virus E1 glycoprotein induces cell death.
AB  - The E1 protein of hepatitis C virus (HCV) shows the ability to induce cell lysis
      by the alteration of membrane permeability when expressed in Escherichia coli
      cells. This function seems to be an intrinsic property of a C-terminal
      hydrophobic region of E1 as permeability changes and cell lysis can be blocked by
      mutagenesis of specific amino acids in this domain. To establish whether the
      expression of E1 protein and its C-terminal domain was able to induce cell death
      also in eukaryotic cell, we cloned HCV sequences expressing the full-length E1
      (E383), the C-terminal domain (SVP) and a mutant lacking the C-terminal region
      (E340) in the pRC/CMV expression vector. HepG2 cell line was co-transfected with
      empty vector or HCV expression plasmids and a reporter vector that expressed beta
      galactosidase (beta-gal) to visualize co-transfected blue cells. At 60 h after
      transfection, the loss of blue cells, considered as a measure of cell death, was
      31.5 and 64.3% for the E1 and SVP clones. On the contrary, the number of blue
      cells after transfection with E340 plasmid was similar to that observed with the
      control vector. The analysis by the terminal deoxynucleotidyltransferase-mediated
      dUTP nick end-labeling (TUNEL) assay revealed an increased number of apoptotic
      cells at 48 h after transfection with E1 and SVP clones. Furthermore, cells
      transfected with SVP revealed a typical internucleosomal DNA fragmentation and
      the activation of caspase-3-like proteases as the specific inhibitor Ac-DEVD-CHO
      peptide partially blocked SVP apoptosis. These data indicate that the
      intracellular expression of HCV E1 protein and its C-terminal domain induces an
      apoptotic response in human hepatoma cell line.

PMID- 15177887
TI  - Tissue specificity of enhancer and promoter activities of a HERV-K(HML-2) LTR.
AB  - Transient expression of a luciferase reporter gene was used to evaluate tissue
      specific promoter and enhancer activities of a solitary extraviral long terminal
      repeat (LTR) of the human endogenous retrovirus K (HERV-K) in several human and
      CHO cell lines. The promoter activity of the LTR varied from virtually not
      detectable (GS and Jurkat cells) to as high as that of the SV40 early promoter
      (Tera-1 human testicular embryonal carcinoma cells). The negative regulatory
      element (NRE) of the LTR retained its activity in all cell lines where the LTR
      could act as a promoter, and was also capable of binding host cell nuclear
      proteins. The enhancer activity of the LTR towards the SV40 early promoter was
      detected only in Tera-1 cells and was not observed in a closely related human
      testicular embryonal carcinoma cell line of different origin, NT2/D1. A
      comparison of proteins bound to central part of the LTR in nuclear extracts from
      Tera-1 and NT2/D1 by electrophoretic mobility shift assay revealed striking
      differences that could be determined by different LTR enhancer activities in
      these cells. Tissue specificity of the SV40 early promoter activity was also
      revealed.

PMID- 15177888
TI  - Plasmid-based generation of recombinant coxsackievirus B3 particles carrying
      capsid gene replacement replicons.
AB  - Recombinant infectious coxsackievirus B3 (CVB3) particles were generated by
      packaging of modified viral genomes in which the capsid coding P1-region was
      replaced by an EGFP-luciferase reporter gene. Efficient packaging of the
      recombinant genome was achieved by a novel method based on cotransfection of a
      plasmid encoding the subgenomic viral replicon together with two alternative
      helper plasmids carrying expression cassettes of the CVB3 capsid proteins, and a
      T7 RNA polymerase expression plasmid. Transcription of a reporter gene and
      expression of capsid proteins were achieved in a single step, eliminating the
      need of a helper virus. Recombinant viral stocks were used to infect human
      embryonal cardiomyocytes (hCMC) and other cell types, and luciferase activity was
      measured at different timepoints after infection. Neither progeny virus nor
      wildtype CVB3 was produced upon infection of target cells, facilitating analyses
      of infected cells without viral spread. The presence of an IRES sequence upstream
      of the P1 open reading frame in the helper plasmids was indispensable for the
      generation of recombinant particles, as no packaging was observed using helper
      plasmids without this feature. Luciferase data obtained by transfection of
      reporter plasmids with and without upstream 5'-NTR sequences suggests that the
      CVB3 IRES facilitates translation in T7 RNA polymerase-dependent gene
      transcription, both in presence and absence of viral replication.

PMID- 15177889
TI  - Molecular characterization of a virulent canine coronavirus BGF strain.
AB  - Molecular characterisation of a canine coronavirus (CCoV) isolate (BGF),
      associated with an outbreak of diarrhoea in puppies, showed 92.7% identity with
      attenuated Insavc-1 strain. Canine coronavirus BGF revealed a full length non
      structural protein 3b (nsp 3b), associated with virulence in other coronaviruses,
      and a highly divergent region at the amino terminal domain of the membrane
      protein that may be implicated in avoiding the host immune reaction. This new
      canine coronavirus strain could help to identify virulence factors in
      coronavirus.

PMID- 15177890
TI  - Characterization of the porcine reproductive and respiratory syndrome virus
      glycoprotein 5 (GP5) in stably expressing cells.
AB  - Porcine reproductive and respiratory syndrome virus (PRRSV) induces apoptosis in
      cultured cells and in infected tissues of pig, and the GP5 protein was reported
      to be responsible. To study the role of apoptosis during PRRSV infection, we
      established a subline of HeLa cells stably expressing the PRRSV GP5 protein under
      an inducible promoter to prevent cell death that may result from GP5 expression.
      The expression of GP5 was confirmed upon induction by immunofluorescence, Western
      blot, and immunoprecipitation. No reduction in cell numbers was observed in the
      GP5-expressing cells, and neither DNA fragmentation nor strand-breaks were
      detected in these cells. To examine if bystander cells underwent apoptosis, Marc
      145 or HeLa cells were co-cultivated with GP5-expressing cells, and the apoptotic
      characteristics were examined in the bystanders. Neither DNA laddering, strand
      breaks, nor reduction in cell numbers was observed in the co-cultivated cells.
      Gene expression profiles were examined for both GP5-expressing cells and
      bystanders by apoptosis-specific macroarrays and gene chip-based microarrays, but
      no genes related to apoptosis were specifically regulated. Our data suggest that
      the previously reported GP5-induced apoptosis may be an atypical observation. The
      GP5-expressing cells were immunoreactive with sera from pigs infected with the
      North American and European types of PRRSV, which implicates a potential
      usefulness of these cells as a diagnostic reagent for PRRSV.

PMID- 15177891
TI  - Individual expression of poliovirus 2Apro and 3Cpro induces activation of caspase
      3 and PARP cleavage in HeLa cells.
AB  - The expression of individual viral genes enables the study of their effects on
      cellular functions. Our group previously generated stable HeLa cell lines that
      efficiently express poliovirus proteases 2A (clone 2A7d) and 3C (clone 3C7) under
      the control of tetracycline [Virology 266 (2000a) 352; J. Virol. 74 (2000b)
      2383]. Upon induction of these proteases, the cells undergo drastic morphological
      alterations and eventually die. The present paper characterizes, in detail, the
      cellular and molecular events that lead to cell death in these lines. Several
      signs of apoptosis were observed in both 2A7d- and 3C7-induced cells, such as
      nuclear fragmentation, DNA breakdown (as determined by TUNEL), and
      phosphatidylserine translocation. Protease 2A induces the cleavage of poly-ADP
      ribose-polymerase (PARP). This is blocked by the caspase-3 inhibitor DEVD in both
      2A7d-On and 3C7-On cells suggesting that this enzyme might account for PARP
      cleavage in both cell lines. The results indicate that both poliovirus proteases
      induce apoptosis by mechanisms involving caspase activation, although the
      kinetics of apoptosis differs.

PMID- 15177892
TI  - Novel approaches to augment adeno-associated virus type-2 endocytosis and
      transduction.
AB  - Recombinant adeno-associated virus (rAAV) receptor binding, endocytosis, nuclear
      trafficking and second strand gene conversion have been described as potential
      rate-limiting steps in rAAV type-2 (rAAV-2) transduction. Several strategies have
      been developed to enhance rAAV-2 intracellular trafficking and gene conversion in
      an attempt to increase the efficiency of this virus as a gene therapy vector. To
      this end, the current study has investigated novel methods for augmenting rAAV
      transduction by enhancing endocytosis of rAAV-2. A selective trypsinization assay
      demonstrated that the abundance of internalized rAAV ssDNA was increased only in
      cells treated with both pyrrolidinedithiocarbonate (PDTC) and a genotoxic agent.
      Treating cells with each of these agents alone had no effect on rAAV endocytosis
      in comparison to controls. To investigate the mechanisms of this synergistic
      effect on rAAV transduction, the involvement of Rac1 protein was evaluated.
      Inhibition of the Rac1 pathway by expression of a dominant negative mutant of
      Rac1 (N17Rac1) decreased rAAV transduction. In contrast, expression of a dominant
      active form of Rac1 (V12Rac1) alone mimicked the up-regulated response seen in
      the presence of PDTC and genotoxic agents. These studies provide potential
      insights into the importance of the Rac1 pathway to enhance uptake of rAAV-2.

PMID- 15177893
TI  - Nuclear factor kappa B (NFkappaB) dependent modulation of Epstein-Barr virus
      latent membrane protein 1 (LMP1) in epidermal growth factor receptor (EGFR)
      promoter activity.
AB  - The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) oncoprotein may
      cause multiple cellular changes, including the induction of epidermal growth
      factor receptor (EGFR) expression and the activation of the nuclear factor kappa
      B (NFkappaB) transcription factor. LMP1 increases the levels of both EGFR protein
      and mRNA but does not stabilize EGFR mRNA. Thus the effects of LMP1 are likely to
      be mediated by direct activation of the EGFR promoter. In this study, induction
      of LMP1 increased the EGFR in both protein and promoter levels in a dose
      dependent manner using tetracycline-regulated LMP1 expression in nasopharyngeal
      carcinoma (NPC) cell line. Mutational analysis of the LMP1 protein indicated that
      the C-terminal activation region-1 (CTAR1) domain was mainly involved in the EGFR
      promoter induction, while CTAR2 was necessary but not sufficient to induce EGFR
      promoter. Inhibition of LMP1 mediated NFkappaB activation by constitutive
      repressive inhibitory kappa B alpha (IkappaBalpha) marginally decreased EGFR
      promoter activity using transiently transfected IkappaBalpha dominant negative
      mutant. Promoter mutagenesis analysis demonstrated that two putative NFkappaB
      binding sites of EGFR promoter were very necessary for the transcriptional
      activity of EGFR induced by LMP1, the proximal NFkappaB binding site was more
      important than the distal NFkappaB binding site. Taken together, Epstein-Barr
      virus latent membrane protein 1 modulated the EGFR promoter activity in a
      NFkappaB dependent manner.

PMID- 15177895
TI  - PCR-screening of human esophageal and bronchial cancers reveals absence of
      adenoviral DNA sequences.
AB  - A number of human esophageal (3) and bronchial (10) cancers have been
      characterized clinically and by their histopathology. These tumors have been
      investigated for the persistence of human adenoviral DNA sequences. The
      polymerase chain reaction (PCR) and Southern transfer hybridization (SBH)
      techniques have been applied. All analyses have consistently yielded negative
      results. These findings are discussed in the light of comparisons to the Ad12
      hamster tumor system in which tumor cell or transformed cell revertants can lose
      the integrated Ad12 DNA sequences, but retain the oncogenic phenotype, when
      reinjected into hamsters. Ad12-transformed cells and Ad12-induced tumor cells
      have previously been shown to exhibit altered cellular methylation and
      transcription patterns. In one of the revertants, which has lost all Ad12 DNA
      sequences, changes in cellular DNA methylation patterns are also maintained.
      Since in the hamster tumor system the loss of Ad12 DNA sequences is still
      compatible with the oncogenic phenotype, the possibility exists that human
      tumors, though themselves devoid of viral DNA sequences, could have had cells as
      precursors which originally carried integrated adenoviral DNA sequences.

PMID- 15177894
TI  - RNA-dependent RNA polymerase gene analysis of worldwide Newcastle disease virus
      isolates representing different virulence types and their phylogenetic
      relationship with other members of the paramyxoviridae.
AB  - Nucleotide sequence was determined for the RNA-dependent RNA polymerase (L) gene
      of 16 Newcastle disease virus (NDV) isolates from diverse geographic and
      chronological origins. The observed consensus amino acid sequence conformed to
      the six domains previously identified among paramyxovirus L proteins, and the
      putative 749QGDNQ753 active site was strictly conserved among all isolates.
      Analysis of predicted amino acid sequences allowed us to identify a sequencing
      error in the previously reported L genes for NDV. The correct sequences reported
      herein provided a more accurate alignment with predicted l-amino acid sequences
      of other paramyxoviruses. Comparison of L gene coding sequences among isolates
      revealed that synonymous substitutions dominated non-synonymous substitutions, as
      observed previously with other NDV genes. However, the overall substitution rate
      was lower than other genes examined making the L gene the most conserved of the
      NDV genome. Phylogenetic analysis of L genes among NDV isolates was consistent
      with previous results that suggested the existence of two major lineages. One
      group contained strains isolated in North America prior to 1970 and included
      virulent and vaccine strains, while the second group included virulent viruses
      isolated worldwide. A comparison of the NDV L coding sequences to other
      Paramyxoviridae illustrated the unique clustering of the avian-specific
      paramyxoviruses, further justifying the newly created Avulavirus genus.

PMID- 15177896
TI  - Phylogenetic analysis of the E2 gene of classical swine fever viruses from Lao
      PDR.
AB  - The E2 genes of 21 classical swine fever viruses (CSFV) were genetically
      characterized and compared with reference CSF viruses. The viruses originated
      from CSF outbreaks that occurred in the Lao People's Democratic Republic (Lao
      PDR) during 1997 though to 1999. All viruses characterized belonged to genogroup
      2 and were members of subgroups 2.1 and 2.2. Results demonstrated a geographic
      delineation between subgroups 2.1 that was only found in the North-Central
      region, and subgroup 2.2 that was mostly found in the South-Central regions of
      Lao PDR. Although it was not possible to determine the origin of these viruses,
      it is probable that they may have been introduced to Lao PDR following cross
      border trade. Alternatively, they have evolved independently of other viruses in
      the region.

PMID- 15177897
TI  - Akabane virus in Israel: a new virus lineage.
AB  - This report describes the first molecular characterization of Akabane virus
      (AKAV) in Israel. The virus was recognized by real-time RT-PCR in extracts from
      Culicoides imicola insects trapped at the Volcani Center located in the center of
      Israel. This is also the first report on the use of real-time RT-PCR to identify
      the virus. The quantitative capability of this technique was applied, and it was
      calculated that the insect extract contains 1.5 x 10(5) copies of the genome
      segment S. Following amplification of the small (S) genome segment, its
      nucleotide sequence was determined to have 93.4% identity or greater with the S
      segment of other AKAV isolates. The deduced amino acid (aa) sequence of the
      combined nucleocapsid and the non-structural protein showed more than 96.6%
      identity. Phylogentic trees constructed using the combined deduced nucleocapsid
      and the non-structural protein aa sequences showed that the Israeli isolate forms
      a fourth cluster of AKAV, indicating a separate virus lineage. Attempts to
      isolate the virus by inoculation to Vero cells and by intracerebral inoculation
      to mice were unsuccessful.

PMID- 15177898
TI  - MALDI-TOFMS compared with other polyphasic taxonomy approaches for the
      identification and classification of Bacillus pumilus spores.
AB  - To verify the efficacy of matrix-assisted laser desorption/ionization time-of
      flight mass spectrometry (MALDI-TOFMS) protein profiling for identifying and
      differentiating bacterial species, several strains of Bacillus pumilus were
      examined in a thorough taxonomic study incorporating a polyphasic approach.
      Sixteen isolates of putative B. pumilus isolated from spacecraft assembly
      facilities, the Mars Odyssey spacecraft, and the International Space Station,
      were characterized for their biochemical and molecular profiles using the Biolog
      system, DNA techniques, and MALDI-TOFMS protein profiling. MALDI-TOFMS protein
      profiling was more accurate than Biolog metabolic profiling, more discriminating
      than 16S rDNA sequence analysis, and complemented the results of gyrB sequence
      analysis and DNA-DNA hybridization for the identification of the B. pumilus
      spores. This is the first report whereby MALDI-TOFMS generated protein profiles
      from a set of microbes is compared directly with DNA-DNA hybridization yielding a
      positive correlation. Unique, cluster-specific biomarker peaks have been
      identified in the spores of the B. pumilus examined in this study. MALDI-TOFMS
      protein profiling is a rapid and simple analysis and has been demonstrated as a
      useful taxonomic tool for differentiating spores of the genus Bacillus. For
      practical purposes, it would be ideal (and necessary) to have a publicly
      available, standardized MALDI profile database, to facilitate the use of the
      technique as a diagnostic method to differentiate bacterial species.

PMID- 15177899
TI  - Immunological method for direct assessment of the functionality of a denitrifying
      strain of Pseudomonas fluorescens in soil.
AB  - This work describes an immunological method for detection and quantification in
      complex environments of the dissimilative nitrate reductase (NRA) responsible for
      the reduction of nitrate to nitrite, which plays an important role in ecosystem
      functioning. The alpha-catalytic subunit of the enzyme was purified from the
      denitrifying strain Pseudomonas fluorescens YT101 and used for the production of
      polyclonal antibodies. These antibodies were used to detect and quantify the NRA
      by a chemifluorescence technique on Western blots after separation of total
      proteins from pure cultures and soil samples. The specificity, detection
      threshold and reproducibility of the proposed method were evaluated. A soil
      experiment showed that our method can be applied to complex environmental
      samples.

PMID- 15177900
TI  - Ruthenium red staining for ultrastructural visualization of a glycoprotein layer
      surrounding the spore of Bacillus anthracis and Bacillus subtilis.
AB  - Ruthenium red is a polycationic stain used to visualize acid polysaccharides on
      the outer surface of cells. Ruthenium red staining followed by electron
      microscopic analysis was used to demonstrate the presence of an external
      glycoprotein layer surrounding the spore of both Bacillus anthracis and Bacillus
      subtilis. This layer is less apparent with traditional staining methods used for
      electron microscopy. Renografin gradients were used to purify B. subtilis spores.
      These purified spores displayed greatly enhanced staining with ruthenium red,
      indicating nonspecific binding of renografin, which has a major carbohydrate
      constituent, methylglucamine. For B. anthracis, staining with ruthenium red was
      sufficiently intense that it was not significantly enhanced by renografin
      purification. In addition to demonstrating a previously undiscovered layer
      surrounding the spores of B. subtilis, the results help explain a long-standing
      controversy as to ultrastructural differences among these genetically closely
      related organisms. Ruthenium red staining provides an important addition to the
      identification of surface glycoproteins in studies to define similarities and
      differences in the exosporium layers of Bacillus species.

PMID- 15177901
TI  - Glycine betaine as a cryoprotectant for prokaryotes.
AB  - Osmoprotectants are low molecular weight, hydrophilic, nontoxic molecules that
      assist a cell under osmotic stress to stabilize its concentration of internal
      solutes. These properties are similar to compounds used as cryoprotectants for
      the preservation of prokaryotic cells during freezing. This study tested the
      ability of a common compatible solute, glycine betaine (GB), to act as a
      cryoprotectant. In a series of freeze-drying studies using a variety of
      prokaryotes, GB performed as well, or better than, two commonly used
      cryoprotectants, sucrose/bovine serum albumin (S/BSA) and trehalose/dextran
      (T/D). GB did especially well maintaining cell viability after long-term storage
      (simulated equivalent of 20 years) for microorganisms like Neisseria gonorrhoeae
      and Streptococcus pneumoniae. GB was tested for its ability to preserve members
      of the genus Acidothiobacillus, a difficult genus to preserve. For two strains of
      Acidithiobacillus ferrooxidans that were preserved using liquid drying, GB
      performed as well as S/BSA. Results were more mixed for two strains of
      Acidithiobacillus thiooxidans; one strain could be preserved with S/BSA but not
      GB, the other strain gave low recoveries with both cryoprotectants. GB also
      proved to be a useful cryoprotectant for liquid nitrogen preservation yielding
      equivalent results to the cryopreservative, glycerol for halophilic archaea, and
      neutrophilic Fe-oxidizing bacteria. These results indicate that GB is a simple
      and useful cryoprotectant that works for a wide range of prokaryotic organisms
      under different cryopreservation regimens.

PMID- 15177902
TI  - Towards an international standard for PCR-based detection of foodborne
      thermotolerant campylobacters: interaction of enrichment media and pre-PCR
      treatment on carcass rinse samples.
AB  - As part of a large EU project for standardisation of polymerase chain reaction
      (PCR), a systematic evaluation of the interaction of enrichment media, type of
      DNA polymerase and pre-PCR sample treatment for a PCR detecting thermotolerant
      campylobacters was carried out. The growth-supporting capacity and PCR
      compatibility of enrichment in Preston, Mueller-Hinton and Bolton broth (blood
      containing and blood-free) were evaluated. The effect of resin-based DNA
      extraction and DNA extraction by boiling on the final PCR assay was investigated.
      The time-course studies indicated that a 20-h sample enrichment in blood
      containing Bolton broth, followed by a simple resin-based extraction of DNA and a
      PCR amplification using Tth polymerase, resulted in strong and clear PCR
      amplicons for target (287 bp) and internal amplification control (IAC, 124 bp).
      The enrichment PCR-based method, tested on 68 presumably naturally contaminated
      poultry-rinse samples, showed a diagnostic sensitivity of 97.5% (39 PCR
      positive/40 total positive samples) and a diagnostic specificity of 100% (28 PCR
      negative/28 total negative samples; P=0.32) when compared to a standard
      bacteriological method (ISO 10272).

PMID- 15177903
TI  - Method for assessment of functional affinity of antibodies for live bacteria.
AB  - A rapid and convenient method for assessment of functional affinity of antibodies
      against live bacteria is described. When a combination of immunomagnetic
      separation (IMS) with bioluminescent or fluorescent genetic labelling of the
      cells was employed, the method showed good correlation with plate count. However,
      the use of reporter bacteria allowed results to be obtained within 1 h compared
      with days using conventional methods. Due to its lower detection limit, the
      bioluminescent assay performed better than the fluorescent assay. Antibody
      affinities for Escherichia coli O157:H7 and Salmonella enteritidis were examined
      at different environmental conditions such as pH 3-7, temperature 4-25 degrees C,
      and sodium chloride concentrations 0-5% and compared with sensitivities of ELISA.

PMID- 15177905
TI  - A protocol for quantifying the birth, death and emigration rates of produce
      associated bacteria, illustrated by its application to Salmonella enterica
      serovar Typhimurium on cultivated mushrooms.
AB  - Colony counts, counts of immunostained cells, fluorescent assays for cell
      viability and titration of a superinfecting bacteriophage were incorporated into
      a protocol for studying the growth kinetics of produce-associated bacteria in
      vivo. A set of equations was assembled for measuring the true rates of birth,
      death and emigration of the bacteria within the frame of a "transit growth"
      model, thus allowing the independent measurement of the carrying capacity of the
      substrate and of the overall productivity of the system. Implementation of the
      protocol on two species of cultivated mushrooms inoculated with Salmonella
      enterica serovar Typhimurium showed that large bacterial populations developed on
      Agaricus bisporus A15 but emigration was not detected, whereas resident
      populations on Agrocybe aegerita FAR142 amounted to 79.7%, 65.1% and 80.7% of the
      cultivable, dead and total bacterial cells produced, owing to emigration.

PMID- 15177904
TI  - Detection of griseofulvin in a marine strain of Penicillium waksmanii by ion trap
      mass spectrometry.
AB  - A marine strain of Penicillium waksmanii Zaleski was isolated from a sample of
      seawater from shellfish-farming area in the Loire estuary (France). The in vitro
      marine culture showed an important antifungal activity. Bioassay-guided
      fractionation was used to purify the crude extract. Dereplication by electrospray
      ion trap/mass spectrometry (ESI-IT/MS) afforded the identification of the
      antifungal compound, after a semi-purification consisting of two stages. A
      comparison of the ionic composition between the active and the non-active
      fractions allowed the detection of a monocharged ion at m/z 353 containing a
      chlorine atom, which could be attributed to the antifungal griseofulvin
      [C17H17ClO6+H]+. Multi-stage fragmentation (MSn) confirmed the identity of the
      m/z 353 ion of the antifungal fraction as griseofulvin. It is the first
      description of griseofulvin production by a strain of P. waksmanii and the first
      chemical study of a strain of this species isolated from marine temperate cold
      water.

PMID- 15177906
TI  - Evaluation of methods for the identification of Salmonella enterica serotype
      Typhimurium DT104 from poultry environmental samples.
AB  - An increase in the prevalence of Salmonella enterica serotype Typhimurium DT104
      has been reported worldwide. This study examined the prevalence of this
      microorganism in poultry environmental samples from commercial layer flocks and
      pullet environments as well as the sensitivity and specificity of a PCR-based
      method, and multiple antibiotic resistance profile of Salmonella serogroup B
      isolates in relation to the serotype and phagetype reference method for the
      identification of Salmonella Typhimurium DT104. A total of 435 Salmonella
      isolates were obtained from poultry house environmental samples tested during a
      20-month period representing a prevalence of 5.5%. Of these, 313 (72%) isolates
      were identified as Salmonella serogroup B isolates. These isolates were tested by
      a PCR-based assay, and for resistance to five antibiotics: ampicillin,
      chloramphenicol, streptomycin, sulfonamides, and tetracycline (ACSSuT) for the
      rapid identification of Salmonella Typhimurium DT104. Upon comparing the
      antibiotic resistance and PCR results with serotype and phage type data, the
      sensitivity and specificity for the identification of Salmonella Typhimurium
      DT104 of both methods were found to be 100%, and 99.6%, respectively. Both
      methods can be completed within 24 h after obtaining an isolate, while serotyping
      and phagetyping required more than 5 days to complete.

PMID- 15177907
TI  - Methods evaluating vanadium tolerance in bacteria isolated from crude oil
      contaminated land.
AB  - Investigations into bacterial responses to vanadium are rare, and in this study
      were initiated by isolating cultures from crude oil contaminated soil from Russia
      and Saudi Arabia. Addition of vanadyl sulphate and vanadium pentoxide created
      acid conditions in the media whilst sodium metavanadate and sodium orthovanadate
      produced neutral and alkaline effects, respectively. Buffers were introduced for
      wider comparison of the sample set treatments and to distinguish between the
      effects of pH and compound toxicity. This study has resulted in the creation of
      protocols for the pH stabilisation of media containing vanadium compounds and
      revealed that, although vanadium salts demonstrated some toxic effects, as
      revealed by MIC and bioluminescence decay tests, the effects were mainly due to
      pH rather than inherent toxicity of the metal. Capacity for sorption of vanadium
      to biomass was also investigated.

PMID- 15177908
TI  - Isolation and characterization of the mitochondrion-like organelle from
      Blastocystis hominis.
AB  - Blastocystis hominis in an unusual protozoan parasite of the human intestinal
      tract. Previous studies have described the presence of mitochondrial-like
      structures despite the anaerobic nature of the organism. In this study, we
      describe a simple and rapid technique to isolate and characterize mitochondrion
      like organelles (MLO) from B. hominis. The parasite was disrupted using glass
      beads and the MLO were collected and purified using a sucrose gradient. Negative
      staining and transmission electron microscopy of the isolated organelles showed
      mitochondrial-like structures. B. hominis cells were stained with rhodamine 123
      and MitoLight to show the presence of transmembrane potential of the MLO. DAPI
      staining of the cells suggested the presence of DNA in the MLO. Though brief
      reports have been made in literature, this study is the first to describe a
      technique for the isolation of the MLO from this organism. Using this technique
      of isolation, major metabolic functions of the organelle, their associated
      macromolecules and intra-mitochondrial location can be extensively studied. The
      role of MLO in this anaerobic protozoan can be widely investigated using this
      protocol.

PMID- 15177909
TI  - Simultaneous identification of rifampin-resistant Mycobacterium tuberculosis and
      nontuberculous mycobacteria by polymerase chain reaction-single strand
      conformation polymorphism and sequence analysis of the RNA polymerase gene
      (rpoB).
AB  - Interspecies variations and mutations associated with rifampin resistance in rpoB
      of Mycobacterium allow for the simultaneous identification of rifampin-resistant
      Mycobacterium tuberculosis and nontuberculous mycobacteria by PCR-SSCP analysis
      and PCR- sequencing. One hundred and ten strains of rifampin-susceptible M.
      tuberculosis, 14 strains of rifampin-resistant M. tuberculosis, and four strains
      of the M. avium complex were easily identified by PCR-SSCP. Of another seven
      strains, which showed unique SSCP patterns, three were identified as rifampin
      resistant M. tuberculosis and four as M. terrae complex by subsequent sequence
      analysis of their rpoB DNAs (306 bp). These results were concordant with those
      obtained by susceptibility testing, biochemical identification, and 16S rDNA
      sequencing.

PMID- 15177910
TI  - 13CO2 pulse labelling of plants in tandem with stable isotope probing:
      methodological considerations for examining microbial function in the
      rhizosphere.
AB  - Recently developed 13CO2 pulse labelling and stable isotope probing (SIP) methods
      offer the potential to track 13C-labelled plant photosynthate into phylogenetic
      groups of microbial taxa in the rhizosphere, permitting an examination of the
      link between soil microbial diversity and carbon flow in situ. We tested the
      feasibility of this approach to detect functional differences in microbial
      communities utilising recently fixed plant photosynthate in moisture perturbed
      grassland turfs. Specifically, we addressed two questions: (1) How does moisture
      perturbation (three treatments; continual wetting, drying, and drying followed by
      rewetting) affect the assimilation of 13C-labelled exudates carbon into the soil
      microbial community?; (2) Can 13C deposited in soil from pulse-labelled plants be
      used to identify microbes utilising plant exudates using SIP methodologies? Net
      CO2 fluxes showed that prior to 13CO2 pulse labelling, all treatments were
      photosynthetically active, but differences were observed in night time
      respiration, indicating moisture treatments had impacted on net CO2 efflux.
      Measurements of pulse-derived 13C incorporated into soil RNA over 2 months showed
      that there was only evidence of 13C enrichment in the continuously wetted
      treatments. However, isotopic values represented only a 0.1-0.2 13C at.% increase
      over natural abundance levels and were found to be insufficient for the
      application of RNA-SIP. These findings reveal that in this experimental system,
      the microbial uptake of labelled carbon from plant exudates is low, and further
      optimisation of methodologies may be required for application of SIP to natural
      plant-soil systems where 13C tracer dilution is a consideration.

PMID- 15177911
TI  - Rapid detection of quinolone-resistant Salmonella by real time SNP genotyping.
AB  - A total of 63 isolates were screened for the gyrA mutation (87Asp-Tyr) in
      Salmonella enterica serovars using real time PCR. All of the isolates were
      successfully identified as resistant or susceptible, consistent with the MIC
      result of the agar dilution method and gyrA sequencing.

PMID- 15177912
TI  - Isolation of high quality RNA from Streptomyces.
AB  - Several molecular techniques require high quality RNA, completely free of DNA.
      Standard methods to isolate total RNA from Streptomyces spp. are based on the
      application of a 'Modified Kirby Mix' [Practical Streptomyces Genetics. The John
      Innes Foundation, Norwich, pp. 613]. Here we present an alternative procedure
      using Triton X-100 and EDTA for the isolation of total RNA from Streptomyces.

PMID- 15177913
TI  - Improved method for the isolation of RNA from (standing liquid cultures of)
      Streptomycetes.
AB  - Streptomycetes are complex soil bacteria capable of producing aerial reproductive
      mycelium and secondary metabolites. We observed novel phenomena such as an
      extended life cycle including flotation and anaerobiosis using standing liquid
      cultures. This paper describes an improved method for isolating good quality RNA
      from standing liquid cultures of S. coelicolor via excellent cell lysis.

PMID- 15177914
TI  - BioPD: a web-based information center for bioactive peptides.
AB  - Bioactive peptide database (BioPD) is a web-based knowledge base that contains
      more than 1100 protein sequences from human, mouse and rat, which are putative or
      are known to be bioactive peptides. In addition to peptide sequences and the
      annotation, the database also contains gene sequences with annotation, protein
      interaction and disease data related to the peptides. Each entry has as many
      references as possible to support the information represented. BioPD consists of
      six parts: PROTEIN, GENE, DISEASE, LINKS, INTERACTION, and REFERENCE. The
      database is searchable through keyword, gene and protein name, receptor name,
      etc. The links to PDB, InterPro, Pfam, OMIM, etc. are provided in each entry.
      Thus BioPD is formed as an information center for the bioactive peptide and
      serves as a gateway for exploration of bioactive peptides. The database can be
      accessed at http://biopd.bjmu.edu.cn.

PMID- 15177915
TI  - Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac
      hypertrophy.
AB  - Angiotensin II (Ang II) has a significant role in regulating cardiac homeostasis
      through humoral, autocrine and paracrine pathways, via binding to the plasma
      membrane AT1 receptor. Recent literature has provided evidence for intracrine
      growth effects of Ang II in some cell lines, which does not involve interaction
      with the plasma membrane receptor. We hypothesized that such intracrine
      mechanisms are operative in the heart and likely participate in the cardiac
      hypertrophy induced by Ang II. Adenoviral and plasmid vectors were constructed to
      express Ang II peptide intracellularly. Neonatal rat ventricular myocytes (NRVMs)
      infected with the adenoviral vector showed significant hypertrophic growth as
      determined by cell size, protein synthesis and enhanced cytoskeletal arrangement.
      Adult mice injected with the plasmid vector developed significant cardiac
      hypertrophy after 48 h, without an increase in blood pressure or plasma Ang II
      levels. This was accompanied by increased transcription of transforming growth
      factor-beta (TGF-beta) and insulin-like growth factor-1 (IGF-1) genes. Losartan
      did not block the growth effects, excluding the involvement of extracellular Ang
      II and the plasma membrane AT1 receptor. These data demonstrate a previously
      unknown growth mechanism of Ang II in the heart, which should be considered when
      designing therapeutic strategies to block Ang II actions.

PMID- 15177916
TI  - Effects of des-aspartate-angiotensin I on the actions of angiotensin III in the
      renal and mesenteric vasculature of normo- and hypertensive rats.
AB  - An earlier study showed that des-aspartate-angiotensin I (DAA-I) attenuated the
      pressor action of angiotensin III in aortic rings of the spontaneously
      hypertensive rat (SHR) but not the normotensive Wistar Kyoto (WKY) rat. The
      present study investigated similar properties of DAA-I in isolated perfused
      kidneys and mesenteric beds of WKY and SHR. In the renal vasculature, angiotensin
      III induced a dose-dependent pressor response, which was more marked in the SHR
      than WKY in terms of significant greater magnitude of response and lower
      threshold. DAA-I attenuated the pressor action of angiotensin III in both the WKY
      and SHR. The attenuation in SHR was much more marked, occurring at doses as low
      as 10(-15) M DAA-I, while effective attenuation was only seen with 10(-9) M in
      WKY. The effects of DAA-I was not inhibited by PD123319 and indomethacin,
      indicating that its action was not mediated by angiotensin AT2 receptors and
      prostaglandins. However, the direct pressor action of angiotensin III in the SHR
      but not the WKY was attenuated by indomethacin suggesting that this notable
      difference could be due to known decreased response of renal vasculature to
      vasodilator prostaglandins in the SHR. Pressor responses to angiotensin III in
      the mesenteric vascular bed was also dose dependent, but smaller in magnitude
      compared to the renal response. The responses in the SHR, though generally
      smaller, were not significantly different from those of the WKY. This trend is in
      line with the similar observations with angiotensin III and II by other
      investigators. In terms of the effect of DAA-I, indomethacin and PD123319 on
      angiotensin III action, similar patterns to those of the renal vasculature were
      observed. This reaffirms that in the perfused kidney and mesenteric bed, where
      the majority of the vessels are contractile, femtomolar concentrations of DAA-I
      attenuates the pressor action of angiotensin III. The attenuation is not
      indomethacin sensitive and does not involve the angiotensin AT2 receptor. The
      findings suggest that DAA-I possesses protective vascular actions and is involved
      in the pathophysiology of hypertension.

PMID- 15177917
TI  - Ghrelin stimulates gastric emptying but is without effect on acid secretion and
      gastric endocrine cells.
AB  - Ghrelin, a recently discovered peptide hormone, is produced by endocrine cells in
      the stomach, the so-called A-like cells. Ghrelin binds to the growth hormone (GH)
      secretagogue receptor and releases GH. It is claimed to be orexigenic and to
      control gastric acid secretion and gastric motility. In this study, we examined
      the effects of ghrelin, des-Gln14-ghrelin, des-octanoyl ghrelin, ghrelin-18, -10
      and -5 (and motilin) on gastric emptying in mice and on gastric acid secretion in
      chronic fistula rats and pylorus-ligated rats. We also examined whether ghrelin
      affected the activity of the predominant gastric endocrine cell populations, G
      cells, ECL cells and D cells. Ghrelin and des-Gln14-ghrelin stimulated gastric
      emptying in a dose-dependent manner while des-octanoyl ghrelin and motilin were
      without effect. The C-terminally truncated ghrelin fragments were effective but
      much less potent than ghrelin itself. Ghrelin, des-Gln14-ghrelin and des-octanoyl
      ghrelin neither stimulated nor inhibited gastric acid secretion, and ghrelin,
      finally, did not affect secretion from either G cells, ECL cells or D cells.

PMID- 15177918
TI  - Isolation and characterisation of an unexpected class of insulinotropic peptides
      in the skin of the frog Agalychnis litodryas.
AB  - Skin secretions of the frog Agalychnis litodryas were evaluated for the isolation
      and characterisation of novel insulinotropic peptides. Crude secretions obtained
      from young adult frogs by mild electrical stimulation of the dorsal skin surface
      were purified by reverse-phase high-performance liquid chromatography (HPLC)
      yielding 70 fractions. In acute 20-min incubations with glucose responsive BRIN
      BD11 cells, fractions 39-42 (band 1) and fractions 44-46 (band 2) significantly
      stimulated insulin release by 2-3.5-fold compared with 5.6 mM glucose alone.
      Pooled fractions in band 1 and band 2 were rechromatographed to reveal 20
      homogenous peptide peaks, which elicited significant 1.5-4-fold increases in
      insulin release. Mass spectrometry analyses indicated molecular masses of between
      1649.2 and 4988.9 Da. The two peptides with the greatest insulin-releasing
      activity were directly subjected to N-terminal amino acid sequence analysis. The
      sequence of the 3020 Da peptide, called frog skin insulinotropic peptide or FSIP,
      was determined as AVWKDFLKNIGKAAGKAVLNSVTDMVNE, which has 79% homology with the C
      terminal of the 75 amino acid dermaseptin BIV precursor. A partial N-terminal
      sequence was determined for the 2546.2 Da peptide as MLADVFEKIMGD... These data
      indicate that the skin secretions of A. litodryas frogs contain biologically
      active peptides which merit further evaluation as a new class of insulin
      secretagogues.

PMID- 15177919
TI  - Exogenous and endogenous ghrelin in gastroprotection against stress-induced
      gastric damage.
AB  - Ghrelin, identified in the gastric mucosa has been involved in control of food
      intake and growth hormone (GH) release but little is known about its influence on
      gastric secretion and mucosal integrity. The effects of ghrelin on gastric
      secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or
      3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous
      ghrelin (5, 10, 20, 40 and 80 microg/kg i.p.) increased gastric acid secretion
      and attenuated gastric lesions induced by ethanol and WRS and this was
      accompanied by the significant rise in plasma ghrelin level, gastric mucosal
      blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was
      abolished by vagotomy and attenuated by suppression of COX, deactivation of
      afferent nerves with neurotoxic dose of capsaicin or CGRP(8-37) and by inhibition
      of NOS with L-NNA but not influenced by medullectomy and administration of 6
      hydroxydopamine. We conclude that ghrelin exerts a potent protective action on
      the stomach of rats exposed to ethanol and WRS, and these effects depend upon
      vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG
      systems.

PMID- 15177920
TI  - Involvement of opioid receptors in the oxytocin-induced antinociception in the
      central nervous system of rats.
AB  - Recent studies showed that oxytocin and opioid peptides play important roles in
      pain modulation at different levels in the central nervous system. The present
      study was performed to explore whether opioid system is involved in the oxytocin
      induced antinociception in the brain of rats. The results showed that: (1)
      intracerebroventricular injection of oxytocin induced dose-dependent increases in
      hindpaw withdrawal latencies (HWL) to noxious thermal and mechanical stimulation
      in rats. (2) The antinociceptive effect of oxytocin was attenuated dose
      dependently by intracerebroventricular injection of naloxone, indicating an
      involvement of opioid system in the oxytocin-induced antinociception. (3) It is
      interesting that the antinociceptive effect of oxytocin was attenuated by
      subsequent intracerebroventricular injection of the mu-opioid antagonist beta
      funaltrexamine (beta-FNA) and the kappa-opioid antagonist nor-binaltorphimine
      (nor-BNI), but not the delta-opioid antagonist naltrindole. The results indicate
      that oxytocin plays an antinociceptive role in the brain of rats; mu- and kappa
      opioid receptors, not delta-receptors, are involved in the oxytocin-induced
      antinociception in the central nervous system of rats.

PMID- 15177922
TI  - The effects of reduced oxygen tension on swine granulosa cell.
AB  - Follicular growth is characterized by an augmented vascularization, possibly
      driven by a fall in the oxygen supply. The present study was undertaken to
      investigate the effects of hypoxia on swine granulosa cells. At first, we
      quantified oxygen partial pressure (pO2) in follicular fluid from different size
      follicles; the granulosa cells collected from large follicles (>5 mm) were
      subjected for 18 h to normoxia (19% O2), partial (5% O2) or total hypoxia (1%
      O2). The effects of these conditions were tested on the main parameters of
      granulosa cell function, steroidogenesis and cell proliferation, and on vascular
      endothelial growth factor (VEGF), nitric oxide (NO) and superoxide anion (O2-)
      production. Oxygen tension in follicular fluid was negatively related to
      follicular size, pointing out a gradual reduction during follicular growth.
      Severe hypoxic conditions determined a reduction of both 17beta estradiol and
      progesterone production, while partial hypoxia did not seem to affect them.
      Hypoxia increased VEGF as well as O2- production in swine granulosa cells without
      impairing cell growth; in addition, it decreased NO output. We may conclude that
      physiological hypoxia could play a pivotal role in the follicular angiogenic
      process stimulating VEGF synthesis by granulosa cells. ROS are possibly involved
      in hypoxic signalling.

PMID- 15177921
TI  - Influence of intravenously administered leptin on nitric oxide production, renal
      hemodynamics and renal function in the rat.
AB  - We investigated the effect of leptin on systemic nitric oxide (NO) production,
      arterial pressure, renal hemodynamics and renal excretory function in the rat.
      Leptin (1 mg/kg) was injected intravenously and mean arterial pressure (MAP),
      heart rate (HR), renal blood flow (RBF) and renal cortical blood flow (RCBF),
      were measured for 210 min after injection. Urine was collected for seven
      consecutive 30-min periods and blood samples were withdrawn at 15, 45, 75, 105,
      135, 165 and 195 min after leptin administration. Leptin had no effect on MAP,
      HR, RBF, RCBF and creatinine clearance, but increased urine output by 37.8% (0-30
      min), 32.4% (31-60 min) and 27.0% (61-90 min), as well as urinary sodium
      excretion by 175.8% (0-30 min), 136.4% (31-60 min) and 124.2% (61-90 min). In
      contrast, leptin had no effect on potassium and phosphate excretion. Plasma
      concentration of NO metabolites, nitrites + nitrates (NOx), increased following
      leptin injection at 15, 45, 75 and 105 min by 27.7%, 178.1%, 156.4% and 58.7%,
      respectively. Leptin increased urinary NOx excretion by 241.6% (0-30 min), 552.6%
      (31-60 min), 430.7% (61-90 min) and 88.9% (91-120 min). This was accompanied by
      increase in plasma and urinary cyclic GMP. These data indicate that leptin
      stimulates systemic NO production but has no effect on arterial pressure and
      renal hemodynamics.

PMID- 15177923
TI  - Alterations of adrenomedullin and its receptor system components in calcified
      vascular smooth muscle cells.
AB  - Vascular calcification is a common finding in many cardiovascular diseases.
      Paracrine/autocrine changes in calcified vessels, and the secreted factors
      participate in and play an important role in the progress of calcification.
      Adrenomedullin (ADM) is a potent vasodilator peptide secreted by vascular smooth
      muscle cells (VSMCs) and vascular endothelial cells. Recently, receptor activity
      modifying proteins (RAMPs) have been shown to transport calcitonin receptor-like
      receptor (CRLR) to the cell surface to present either as CGRP receptor or ADM
      receptor. In this work, we explored the production of ADM, alterations and
      significance of ADM mRNA and its receptor system components--CRLR and RAMPs mRNA
      in calcified VSMCs. Our results showed that calcium content, 45Ca2+ uptake and
      alkaline phosphatases (ALPs) activity in calcified VSMCs were increased,
      respectively, compared with control VSMCs. Content of ADM in medium was increased
      by 99% (p < 0.01). Furthermore, it was found that the levels of ADM, CRLR, RAMP2
      and RAMP3 mRNA in calcified cells were elevated, respectively, compared with that
      of control. The elevated levels of CRLR, RAMP2 and RAMP3 mRNA were significant
      correlation with ADM mRNA (r = 0.83, 0.92 and 0.93, respectively, all p's < 0.01)
      in calcified VSMCs. The results show that calcified VSMCs generate an increased
      amount of ADM, up-regulate gene expressions of ADM and its receptor system
      components--CRLR, RAMP2 and RAMP3, suggesting an important role of ADM and its
      receptor system in the regulation of vascular calcification.

PMID- 15177924
TI  - Interaction of ovokinin(2-7) with vascular bradykinin 2 receptors.
AB  - Intravenous administration of ovokinin(2-7), a cleavage peptide derived from
      ovalbumin, dose-dependently (0.1-5 mg/kg) lowered the mean arterial pressure
      (MAP) that was not accompanied by a significant change in the heart rate (HR) of
      urethane-anesthetized rats. The hypotensive effects of ovokinin(2-7) were five
      orders of magnitude lower compared to that of bradykinin and were largely
      prevented by pretreatment with the bradykinin B2 receptor antagonist HOE140 (81.6
      +/- 18.4%) and moderately affected by the B1 receptor antagonist [des-Arg10]
      HOE140 (26.3 +/- 15.5%). Intracellular Ca2+ levels, as measured by Fur 2-AM, were
      significantly elevated in cultured aorta smooth muscle cells by ovokinin(2-7).
      The increases were abolished by HOE140 and unaffected by [des-Arg10]-HOE140. The
      elevation of intracellular Ca2+ by ovokinin(2-7) was dependent on Ca2+ entry from
      extracellular space as it was reduced in a Ca2+ -free solution. Pretreatment of
      the cells with the phospholipase C inhibitor U73122 (2 microM) eliminated the
      Ca2+ increase by the peptide. PA phosphohydrolase and phospholipase A2 inhibitors
      significantly reduced the responses as well. Our results show that ovokinin(2-7)
      modulates cardiovascular activity by interacting with B2 bradykinin receptors.

PMID- 15177925
TI  - Dendroaspis natriuretic peptide system and its paracrine function in rat colon.
AB  - Dendroaspis natriuretic peptide (DNP), a 38-amino-acid peptide, was isolated from
      the venom of Green Mamba. It has structural and functional similarities to other
      members of the natriuretic peptide family. The purpose of this study was to
      determine whether DNP system is present in the rat colon and to define its
      biological functions. The serial dilution curve of extracts of colonic tissues
      was parallel to the standard curve of DNP and a major peak of molecular profile
      by HPLC was synthetic DNP. The concentration of DNP was 0.5 +/- 0.04 ng/g of
      colonic tissues. DNP as well as atrial natriuretic peptide and C-type natriuretic
      peptide caused dose-dependent increases in cGMP production in the purified
      membrane of colonic tissues. Three types of natriuretic peptide receptor mRNAs
      were detected using semi-quantitative RT-PCR. Functionally, synthetic DNP
      inhibited the spontaneous contraction of rat colonic circular muscle in a
      concentration-dependent manner. The potency appeared to be at least 10 times
      greater than that of CNP. Furthermore, DNP inhibited carbachol-induced muscle
      contraction, suggesting that it also can modulate the nerve regulation of colonic
      motility. This study demonstrates the presence of DNP system in rat colon and its
      function as a local regulator of colonic motility.

PMID- 15177926
TI  - Anorexigenic effects of pituitary adenylate cyclase-activating polypeptide and
      vasoactive intestinal peptide in the chick brain are mediated by corticotrophin
      releasing factor.
AB  - Intracerebroventricular (ICV) injection of pituitary adenylate cyclase-activating
      polypeptide-38 (PACAP) or vasoactive intestinal peptide (VIP) inhibits feeding in
      chicks. However, the underlying anorexigenic mechanism(s) has not yet been
      investigated. The present study investigated whether these peptides influence the
      activity of corticotrophin-releasing factor (CRF) neural pathways in the brain of
      chicks. Firstly, we found that ICV injections of PACAP and VIP increased plasma
      corticosterone concentrations. The corticosterone-releasing effect of PACAP was
      completely attenuated by co-injection of astressin, a CRF receptor antagonist,
      but this effect was only partial for VIP. These results demonstrated that CRF
      neurons mediate the actions of PACAP and, to a lesser extent, VIP, and suggest
      that the signaling mechanisms differ between the two peptides. This difference
      may arise from the two peptides interacting with different receptors because the
      corticosterone-releasing effect of PACAP, but not VIP, was completely attenuated
      by co-injection of PACAP (6-38), a PACAP receptor antagonist. Finally, we
      examined the effect of ICV co-injection of astressin on the anorexigenic effects
      of PACAP and VIP and found that the effects of both peptides were attenuated by
      astressin. Overall, the present study suggests that the anorexigenic effects of
      PACAP and VIP are mediated by the activation of CRF neurons.

PMID- 15177927
TI  - NPY and NPY Y1 receptor effects on noradrenaline overflow from the rat brain in
      vitro.
AB  - Neurotransmitters and neuropeptides play important roles in the regulation of
      various neuroendocrine functions particularly feeding. The aim of this study was
      to investigate whether a functional interaction occurs among neuropeptide Y (NPY)
      at NPY Y1 receptors and noradrenaline overflow, as this may contribute to the
      regulation of appetite. The release of endogenous noradrenaline and its
      metabolite 3,4-dihydroxyphenylglycol (DHPG) were examined from hypothalamic and
      medullary prisms using the technique of in vitro superfusion and high performance
      liquid chromatography (HPLC) with coulometric detection. Noradrenaline and DHPG
      overflow was investigated at rest, in response to NPY (0.1 microM) and in
      response to the NPY Y1 receptor agonist, [Leu31,Pro34]NPY (0.1 microM). Perfusion
      with NPY and [Leu31,Pro34]NPY significantly reduced noradrenaline overflow from
      the hypothalamus and medulla. Perfusion with NPY and [Leu31,Pro34]NPY was without
      significant effect on hypothalamic DHPG overflow, while medullary DHPG overflow
      was significantly reduced by NPY and [Leu31,Pro34]NPY. Results from this study
      provide evidence of NPY Y1 receptor-mediated inhibition of noradrenaline release
      in the hypothalamus and medulla, further illustrating a complex interaction
      between neurotransmitters and neuropeptides within the rat brain.

PMID- 15177928
TI  - Activation of MAP kinase by MC4-R through PI3 kinase.
AB  - The melanocortin 4 receptor (MC4-R) is a Galpha s-coupled receptor known to
      increase cAMP production following agonist stimulation. We demonstrate that the
      mitogen-activated protein kinases p42 (ERK2) and p44 (ERK1) are also activated by
      MC4-R following treatment with the MC4-R agonist NDP-alpha-MSH in stably
      transfected CHO-K1 cells. This time- and dose-dependent response is abolished by
      the MC4-R antagonist SHU-9119. p42/p44 MAPK activation is blocked by the
      phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 but not
      by the protein kinase A (PKA) inhibitor Rp-cAMPS, indicating that that signal
      activating the p42/p44 MAPK pathway is conveyed through inositol triphosphate.

PMID- 15177929
TI  - Roles of oxytocin in spatial learning and memory in the nucleus basalis of
      Meynert in rats.
AB  - The present study was performed to explore the role of oxytocin (OT) in spatial
      learning and memory in the nucleus basalis of Meynert (NBM) of rats. The latency,
      distance and swimming path to find the platform were tested by Morris water maze
      and recorded by a video camera connected to a computer. Intra-NBM injections of 2
      or 10 nmol of OT, but not 0.2 nmol of OT, induced significant increase on the
      latency of spatial learning. Rats receiving intra-NBM administrations of 2 or 10
      nmol of OT showed a more random search pattern. There were no significant changes
      in the swimming speed in Morris water maze test after the injection of OT.
      Furthermore, the impaired effect of OT on the latency of spatial learning was
      blocked by intra-NBM injection of the selective OT antagonist Atosiban,
      indicating that the effect of OT was mediated by OT receptor in the NBM of rats.
      Moreover, there were no influences of OT or Atosiban on the retention performance
      in rats. The results suggest that OT plays an inhibitory role in spatial learning
      in the NBM; the effect is mediated by OT receptor.

PMID- 15177930
TI  - Is there a link between salt-intake and atrial natriuretic peptide system during
      hypertension induced by nitric oxide blockade?
AB  - Long-term nitric oxide (NO) blockade is known to induce a severe and progressive
      hypertension. The influence of the salt-intake on atrial natriuretic peptide
      (ANP) system in this hypertension model is unknown. The aim of this study was to
      evaluate ANP plasma levels, content and mRNA in atria of male Wistar rats
      chronically treated with oral Nomega-nitro-L-arginine methyl ester (L-NAME) after
      4 weeks of high-salt diet. The high-salt diet induced an increase (P < 0.05) in
      ANP plasma levels in normotensive rats and no significant changes in hypertensive
      animals. We observed a significant increase in the ANP content in the left and
      right atria of hypertensive rats (P < 0.001) when compared to normotensive ones.
      However, no significant changes were observed during high-salt diet in
      normotensive and hypertensive animals. Northern blot analysis revealed that ANP
      gene expression is higher in the right and left atria of hypertensive rats when
      compared to normotensive rats. However, we found no significant changes in ANP
      mRNA of rats treated with high-salt diet in normotensive and hypertensive rats
      when compared to low-salt diet. The present observations indicate no interaction
      between salt-intake and activation of the ANP system during chronic nitric oxide
      synthase (NOS) inhibition.

PMID- 15177931
TI  - Prosomatostatin is proteolytically processed at the amino terminal segment by
      subtilase SKI-1.
AB  - Processing of prohormones to generate active products typically occurs at basic
      residues via cleavage by proprotein convertases. A less common type of cleavage
      is mediated at hydrophobic (L, V, F, N) or small amino acid (A, T, S) residues.
      Efforts to identify the proteinases responsible for processing precursors at
      their hydrophobic amino acids has led to the recent cloning of a new type-1
      membrane-bound subtilase called SKI-1. The NH2-terminal region of
      prosomatostatin, previously shown to contain a sorting signal for the regulated
      secretory pathways, is processed to generate PSST[1-10]. The exact cleavage
      mechanism is unknown, but has been assumed to involve monobasic processing at
      Lys13 followed by carboxypeptidase trimming. We found that K13A mutation did not
      block PSST[1-10] production. Since the prosomatostatin sequence R8-Q9-F10-L11 ?
      qualifies as a potential SKI-1 substrate, using a vaccinia virus expression
      system along with HPLC and radioimmunoassays, we observed that overexpression of
      recombinant SKI-1 in COS-1 and HEK-293 cells significantly increased the
      production of PSST[1-10]. Additionally, in CHO cells lacking SKI-1, there was a
      significant reduction in PSST[1-10] production which could be increased upon SKI
      1 stimulation. Mutagenesis studies showed that efficient processing of PSST to
      PSST[1-10] required the RXRXXL motif. However, this NH2-terminal cleavage was not
      a prerequisite for the formation of SST-14 and SST-28.

PMID- 15177932
TI  - Agonist-dependent internalization of the angiotensin II type one receptor (AT1):
      role of C-terminus phosphorylation in recruitment of beta-arrestins.
AB  - Beta-arrestins play a role in AT1 endocytosis by binding the cytoplasmic, C
      terminus region T332-S338, the major site of angiotensin II (Ang II)-induced
      phosphorylation. However, the processes responsible for recruiting beta-arrestin
      to the activated receptor are poorly defined. In this study, we used CHO-K1 and
      HEK 293 cells expressing wild-type or mutant AT1 to investigate two
      possibilities: activated AT1 induces global relocation of beta-arrestins to the
      plasma membrane or the phosphorylated C-terminus acts as bait to attract beta
      arrestins. Results obtained using high osmolarity and dominant-negative beta
      arrestin confirmed that internalization of AT1 in both CHO-K1 and HEK 293 cells
      is predominately via clathrin-mediated endocytosis involving beta-arrestin, and
      substitution of T332, S335, T336 and S338 with alanine to preclude
      phosphorylation markedly attenuated AT1 internalization. Confocal microscopy
      revealed that wild-type AT1 induced a time-dependent translocation of GFP-tagged
      beta-arrestins 1 and 2 to the cell surface. In contrast, the TSTS/A mutant did
      not traffic beta-arrestin 1 at all, and only trafficked beta-arrestin 2 weakly.
      Results of rescue-type experiments were consistent with the idea that both beta
      arrestins are able to interact with the non-phosphorylated receptor, albeit with
      much lower affinity and beta-arrestin 1 less so than beta-arrestin 2. In
      conclusion, this study shows that the high affinity binding of beta-arrestins to
      the phosphorylated C-terminus is the predominant mechanism of agonist-induced
      beta-arrestin recruitment to the cell surface and AT1 receptor.

PMID- 15177933
TI  - Reduction of infarct size by orally administered des-aspartate-angiotensin I in
      the ischemic reperfused rat heart.
AB  - Occlusion of the left main coronary artery for 45 min caused sizable infarct
      scarring of the left ventricular wall in the rat heart at 14 days post
      reperfusion. Daily oral administration of des-aspartate-angiotensin I (DAA-I) for
      14 days attenuated the area of the infarct scar and transmurality. The
      attenuation was dose-dependent and biphasic; maximum effective dose was 1524
      nmol/kg, and doses higher than this were progressively inactive. The exact
      mechanism of the biphasic attenuation is not known, and receptor down-regulation
      by internalization, which has been implicated in a similar biphasic nature for
      the anticardiac hypertrophic action of DAA-I, could be a likely cause.
      Indomethacin (101 micromol/kg, i.p.), administered sequentially after the daily
      oral dose of DAA-I (1524 nmol/kg), completely inhibited the attenuation at 14
      days post-reperfusion, indicating that prostaglandins may be involved in
      transducing the attenuation. The present findings support earlier indications
      that DAA-I exerts protective actions in cardiovascular pathologies in which
      angiotensin II is implicated. It is suggested that DAA-I exerts the
      cardioprotective action by acting on the same indomethacin-sensitive angiotensin
      AT1 receptor. Although similar array of protective actions are also seen with
      another endogenous angiotensin, angiotensin-(1-7), the present findings
      demonstrate for the first time the ability of an endogenous angiotensin to reduce
      the infarct size of an ischemic-reperfusion injured rat heart.

PMID- 15177934
TI  - Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect
      of Neurotensin on DNA synthesis in PC3 cells.
AB  - The mechanism by which neurotensin (NT) promotes the growth of prostate cancer
      epithelial cells is not yet defined. Here, androgen-independent PC3 cells, which
      express high levels of the type 1 NT-receptor (NTR1), are used to examine the
      involvement of epidermal growth factor receptor (EGFR), mitogen-activated protein
      kinases (ERK, SAPK/JNK and p38), PI3 kinase and PKC in the mitogenic effect of
      NT. NT dose dependently (0.1-30 nM) enhanced phosphorylation of EGFR, ERK and
      Akt, reaching maximal levels within 3 min as measured by Western blotting. These
      effects were associated with an accumulation of EGF-like substance(s) in the
      medium (assayed by EGFR binding) and a 2-fold increase in DNA synthesis (assayed
      by [3H]thymidine incorporation). The DNA synthesis enhancement by NT was non
      additive with that of EGF. The NT-induced stimulation of EGFR/ERK/Akt
      phosphorylation and DNA synthesis was inhibited by EGFR-tyrosine kinase
      inhibitors (AG1478, PD153035), metallo-endopeptidase inhibitor phosphoramidon and
      by heparin, but not by neutralizing anti-EGF antibody. Thus, transactivation of
      EGFR by NT involved heparin-binding EGF (HB-EGF or amphiregulin) rather than EGF.
      The effects of NT on EGFR/ERK/Akt activation and DNA synthesis were attenuated by
      PLC-inhibitor (U73122), PKC-inhibitors (bisindolylmaleimide, staurosporine,
      rottlerin), MEK inhibitor (U0126) and PI3 kinase inhibitors (wortmannin, LY
      294002). We conclude that NT stimulated mitogenesis in PC3 cells by a PKC
      dependent ligand-mediated transactivation of EGFR, which led to stimulation of
      the Raf-MEK-ERK pathway in a PI3 kinase-dependent manner.

PMID- 15177935
TI  - Angiotensin II and angiotensin-(1-7) inhibit the inner cortex Na+ -ATPase
      activity through AT2 receptor.
AB  - In the present paper, the modulation of the basolateral membrane (BLM) Na+ 
      ATPase activity of inner cortex from pig kidney by angiotensin II (Ang II) and
      angiotensin-(1-7) (Ang-(1-7)) was evaluated. Ang II and Ang-(1-7) inhibit the Na+
      -ATPase activity in a dose-dependent manner (from 10(-11) to 10(-5) M), with
      maximal effect obtained at 10(-7) M for both peptides. Pharmacological evidences
      demonstrate that the inhibitory effects of Ang II and Ang-(1-7) are mediated by
      AT2 receptor: The effect of both polypeptides is completely reversed by 10(-8) M
      PD 123319, a selective AT2 receptor antagonist, but is not affected by either
      (10(-12) - 10(-5) M) losartan or (10(-10)-10(-7) M) A779, selective antagonists
      for AT1 and AT(1-7) receptors, respectively. The following results suggest that a
      PTX-insensitive, cholera toxin (CTX)-sensitive G protein/adenosine 3',5'-cyclic
      monophosphate (cAMP)/PKA pathway is involved in this process: (1) the inhibitory
      effect of both peptides is completely reversed by 10(-9) M guanosine 5'-O-(2
      thiodiphosphate) (GDPbetaS; an inhibitor of the G protein activity), and mimicked
      by 10(-10) M guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS; an activator of the
      G protein activity); (2) the effects of both peptides are mimicked by CTX but are
      not affected by PTX; (3) Western blot analysis reveals the presence of the Gs
      protein in the isolated basolateral membrane fraction; (4) (10(-10)-10(-6) M)
      cAMP has a similar and non-additive effect to Ang II and Ang-(1-7); (5) PKA
      inhibitory peptide abolishes the effects of Ang II and Ang-(1-7); and (6) both
      angiotensins stimulate PKA activity.

PMID- 15177936
TI  - Naming progastrin-derived peptides.
AB  - The antral hormone gastrin continues to be in focus, because its hormonal and
      growth promoting effects are essential both for the function of the normal
      stomach and for the pathogenesis of major dyspeptic and neoplastic diseases.
      Deduction of the progastrin structure has improved the insight in the cellular
      synthesis of gastrin, but has also revealed that the biosynthetic machinery is
      complex, and, accordingly, that progastrin is processed to a multitude of more or
      less bioactive fragments. The naming of these fragments has, however, become
      inconsistent and confusing. Therefore, we propose a systematic nomenclature for
      progastrin-derived peptides of which there are three classes: (I) The gastrins
      with the evolutionary preserved tetrapeptide amide (Trp-Met-Asp-PheNH2) at the C
      terminus, which ensures high-affinity binding to the gastrin (CCK-B) receptor.
      Among the gastrins, gastrin-34 and gastrin-17 constitute the primary forms. (II)
      Processing intermediates, which are early products of progastrin that contain the
      structure of the primary gastrins within their sequence, but still cannot bind
      the gastrin receptor due to insufficient processing at their C-terminus. (III)
      Flanking fragments from the N- and C-termini of progastrin that do not contain
      any primary gastrin in their sequence, but nevertheless may undergo
      posttranslational processing. Each fragment can be specified with suffixes
      corresponding to the derived sequence in progastrin.

PMID- 15177937
TI  - Gut regulatory peptides bombesin and neurotensin reduce hepatic oxidative stress
      and histological alterations in bile duct ligated rats.
AB  - Gut regulatory peptides bombesin (BBS) and neurotensin (NT) exert a wide spectrum
      of biological actions on gastrointestinal tissues and we have previously shown
      that they improve intestinal barrier function and oxidative stress in
      experimentally jaundiced rats. In the present study, we explored their potential
      action on liver histology and oxidative status in bile duct ligated rats. Seventy
      male Wistar rats were randomly divided into five groups: controls, sham operated,
      bile duct ligated (BDL), BDL + BBS (10 microg/kg, s.c. x3), BDL + NT (300
      microg/kg, i.p.). At the end of the experiment, on day 10, serum total bilirubin
      and alanine aminotransferase (ALT) levels were determined and endotoxin was
      measured in portal and aortic blood. Liver tissue samples were examined
      histologically for evaluation of the ratio of portal tracts presenting changes of
      obstructive cholangiopathy and neutrophils' number in portal tracts. In addition,
      hepatic oxidative status was estimated on liver homogenates by measurements of
      lipid peroxidation (malondialdehyde), protein oxidation (protein carbonyl groups)
      and thiol redox state [reduced glutathione (GSH), oxidized glutathione (GSSG),
      total non-protein mixed disulfides (NPSSR) and protein thiols (PSH)].
      Administration of BBS or NT significantly reduced portal and aortic endotoxaemia
      observed in obstructive jaundice. Both agents significantly ameliorated liver
      injury, as demonstrated by improvement of obstructive cholangiopathy and
      reduction of ALT. This effect was accompanied by prevention of lipid
      peroxidation, protein oxidation and decrease of the oxidized forms GSSG and
      NPSSR. Moreover, neutrophil accumulation in portal tracts was significantly
      decreased. In conclusion, this study shows that gut regulatory peptides BBS and
      NT reduce cholestatic liver injury, exerting protective effects on portal tract
      architecture, neutrophil infiltration and hepatic oxidative stress in bile duct
      ligated rats.

PMID- 15177938
TI  - Gastrin stimulates receptor-mediated proliferation of human esophageal
      adenocarcinoma cells.
AB  - The prevalence of esophageal adenocarcinoma in the setting of Barrett's
      metaplasia continues to increase in Western nations at a rate greater than any
      other cancer. The trophic properties of gastrin have been documented in gastric,
      pancreatic and colon cancer cell lines, suggesting a potential role for this
      regulatory peptide in the growth of these malignancies. The aims of these studies
      were to identify and characterize the presence of functional cholecystokinin type
      2 (gastrin) receptors on the membranes of human esophageal adenocarcinoma cells.
      Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the
      presence of cholecystokinin type-2 receptor transcripts in human esophageal
      adenocarcinoma cell lines. Competitive binding assays revealed specific binding
      of gastrin in SEG-1 cells (IC50 of 2.4 x 10(-8) M). This finding was confirmed by
      laser scanning confocal microscopy through internalization of rhodamine green
      labeled gastrin heptapeptide in SEG-1 cells. Gastrin caused a dose-dependent
      increase in proliferation of SEG-1 cells when compared to controls. This effect
      was abolished by co-incubation with L365,260, a CCK-2-specific receptor
      antagonist. Gastrin-induced phosphorylation of the p44 and p42 mitogen-activated
      protein kinases was demonstrated by Western blot analysis. In conclusion, the
      studied human esophageal adenocarcinoma cell lines possess cholecystokinin type-2
      (gastrin) receptors. Receptors bind gastrin, resulting in increased proliferation
      in SEG-1 cells.

PMID- 15177939
TI  - Central NPY receptor-mediated alteration of heart rate dynamics in mice during
      expression of fear conditioned to an auditory cue.
AB  - Neuropeptide Y (NPY) is involved in the regulation of emotionality including fear
      and anxiety, which modulate autonomic control of cardiovascular function. We
      therefore investigated the central effects of porcine NPY, selective Y1, Y2 and
      Y5 receptor agonists and a Y1 receptor antagonist on heart rate (HR) and HR
      variability in freely moving mice using auditory fear conditioning.
      Intracerebroventricular (i.c.v.) injections were applied 15 min before the tone
      dependent memory test. NPY dose-dependently induced bradycardia associated with
      decreased HR variability, and blunted the stress-induced tachycardic response.
      The selective Y1 receptor antagonist BIBO 3304 blocked the NPY- and Y1-receptor
      agonist-induced suppression of conditioned tachycardia without affecting basal
      HR. The tachycardia elicited by both conditioned and unconditioned stressor was
      effectively attenuated by the Y1 receptor agonist. These results suggest a
      specific contribution of Y1, but not Y2 and Y5 receptors, to modulation of
      emotional responses most likely unrelated to impairment or modulation of memory.
      The NPY-induced bradycardia is attributed to not yet characterized NPY receptor
      subtypes other than Y1, Y2 and Y5, or a complex receptor interaction. In
      conclusion, NPY mediates central inhibition of sympathetic outflow, potentially
      coupled with attenuation of parasympathetic tone, i.e., mechanisms that may be
      associated with the reported anxiolytic action.

PMID- 15177940
TI  - Secretion of inflammatory mediators by isolated rat Kupffer cells: the effect of
      octreotide.
AB  - AIMS: We studied the production of inflammatory mediators by rat KC and the
      possible in vitro effect of the somatostatin analogue octreotide. METHODS:
      Primary KC cultures were incubated with LPS added alone or with different
      concentrations of octreotide. The production of TNFalpha, IL-6, IL-10, IL-12 and
      IL-13 was assessed in culture supernatants by ELISA and that of nitric oxide (NO)
      by a modification of the Griess reaction. RESULTS: Isolated KC produced a basal
      amount of TNFalpha, IL-6, IL-12, IL-13, and NO but not IL-10. LPS-stimulated KC
      secreted significantly increased amounts of TNFalpha (P < 0.001), IL-6 (P <
      0.01), IL-10 (P < 0.001), IL-12 (P < 0.01), and NO (P < 0.001) whereas IL-13
      production remained constant. Octreotide reduced IL-12 (P < 0.05) and increased
      IL-13 (P < 0.05) production by unstimulated KC. Furthermore, octreotide
      suppressed TNFalpha production (P < 0.05), without modifying TNFalpha mRNA
      expression and decreased iNOS expression and NO (P approximately 0.05) production
      by LPS-activated KC. These effects were reversed with Wortmannin pre-treatment
      suggesting that octreotide may act via interference with phosphatidylinositol 3
      kinase pathways. CONCLUSIONS: These data demonstrate that KC is a source of
      multiple inflammatory mediators, indicating a critical role in liver inflammatory
      disorders. Octreotide modulates inflammatory mediator production by isolated KC,
      suggesting that it might have immunoregulatory and anti-inflammatory effects in
      liver diseases.

PMID- 15177941
TI  - Eight-residue Abeta peptides inhibit the aggregation and enzymatic activity of
      Abeta42.
AB  - Insoluble Abeta1-42 is the main component of the amyloid plaque. We have
      previously demonstrated that exposure to low pH can confer the molten globule
      state on soluble Abeta1-42 in vitro [Biochem. J. 361 (2000) 547] and unfolding
      experiments with guadinine hydrochloride (GdnHCl) have now confirmed this
      observation. The molten globule state of the protein has many biological
      properties and understanding the mechanisms of its formation is an important step
      in devising a therapeutic strategy for Alzheimer's disease (AD). We therefore
      investigated the ability of a series of synthetic eight-residue peptides derived
      from Abeta1-42 to inhibit the acid-induced aggregation of Abeta1-42 and
      identified the potent peptides to be Abeta15-22, Abeta16-23 and Abeta17-24. A1
      antichymotrypsin, a member of the serine proteinase inhibitor (serpin) family is
      another major component of the amyloid plaque. In the present study, we
      investigated the proteolytic activity of Abeta1-42 against casein at different
      pHs. Chemical modification of amino acid residues in Abeta1-42 indicated that
      serine and histidine residues, but not aspartic acid, are necessary for enzymatic
      activity, suggesting that it is a serine proteinase. Amino acid substitution
      studies indicate that glutamic acids at positions 11 and 22 participate
      indirectly in proteolysis and we surmise that amino acid residues 29-42 are
      required to stabilize the conformer. A study of metal ions suggested that Cu2+
      affected the enzymatic activity, but Zn2+ and Fe2+ did not. Interestingly,
      Abeta14-21 and Abeta15-22 were the only peptides that inhibited the proteolytic
      activity of Abeta42. Therefore, Abeta15-22 may control both aggregation of Abeta1
      42 at acidic pH and its proteolytic activity at neutral pH. Consequently, we
      suggest that it may be of use in the therapy of Alzheimer's disease.

PMID- 15177942
TI  - Binding of the new morphiceptin analogs to human MCF-7 breast cancer cells and
      their effect on growth.
AB  - In the present study, we reported on the synthesis of two new mu-opioid peptide
      analogs, [D-1-Nal3]morphiceptin and [D-1-Nal4]-morphiceptin [1-Nal=3-(1-naphthyl)
      alanine] which expressed receptor binding affinities at least at the level of the
      primary opioid ligands. The new analogs also labeled mu-opioid receptors on the
      cells of human breast cancer MCF-7 cell line with affinity much higher than that
      of endomorphins and morphiceptin, the well-known mu-selective opioid peptides.
      However, none of the tested peptides significantly decreased cell proliferation
      of MCF-7 cells.

PMID- 15177944
TI  - Aldosterone modulates neural vasomotor response in hypertension: role of
      calcitonin gene-related peptide.
AB  - OBJECTIVE: We analyse the effect of aldosterone on vasomotor response induced by
      electrical field stimulation (EFS) in mesenteric arteries from Wistar Kyoto (WKY)
      and spontaneously hypertensive rats (SHR). RESULTS: Aldosterone (0.001-1 microM)
      reduced vasoconstrictor response to EFS in a dose- and time-dependent manner only
      in SHR. Thus, the rest of experiments were performed only in SHR. Aldosterone did
      not affect either noradrenaline response or release. Effect of aldosterone (1
      microM) on EFS response was not affected by NG-nitro-arginine-methyl esther (100
      microM), and was abolished by capsaicin (0.5 microM) and the calcitonin gene
      related peptide antagonist (CGRP 8-37, 0.5 microM). Calcitonin gene-related
      peptide (0.1 nM-0.1 microM) induced a concentration-dependent relaxation, which
      was enhanced by aldosterone (1 microM). Incubation with either spironolactone (1
      microM), glibenclamide (10 microM), RU 486 10 microM, ODQ (10 microM) or
      cycloheximide (10 microM) significantly reduced the enhancement of CGRP
      relaxation produced by aldosterone, while remained unmodified by SQ 22,536.
      CONCLUSIONS: Aldosterone decreases the vasoconstrictor response to EFS in
      mesenteric arteries from SHR but not from WKY. This effect is mediated by an
      increased response to the sensory neurotransmitter CGRP, substantially, through
      glucocorticoid receptors activation. Furthermore, this effect is mediated by an
      increase of cGMP synthesis and ATP-dependent potassium channel activation.

PMID- 15177943
TI  - PPARalpha agonists stimulate progastrin production in human colorectal carcinoma
      cells.
AB  - The three subtypes of peroxisome proliferator activated-receptors (PPARalpha,
      delta and gamma) control the storage and metabolism of fatty acids. Treatment of
      rats with the PPARalpha ligand ciprofibrate increases serum gastrin
      concentrations, and several lines of evidence suggest that non-amidated gastrins
      act as growth factors for the colonic mucosa. The aim of the present study was to
      investigate the expression of PPARs and the effect of PPAR ligands on gastrin
      production and cell proliferation in human colorectal carcinoma (CRC) cell lines.
      mRNAs for all three PPAR subtypes were detected by PCR in all CRC cell lines
      tested. The concentrations of progastrin, but not of glycine-extended or amidated
      gastrin, measured by radioimmunoassay in LIM 1899 conditioned media and cell
      extracts were significantly increased by treatment with the PPARalpha ligand
      clofibrate. Similar increases in progastrin were seen following treatment with
      the PPARalpha ligands ciprofibrate and fenofibrate, but not with bezafibrate,
      gemfibrozil or Wy 14643. The PPARgamma agonist rosiglitazone had no significant
      effect on progastrin production. The PPARalpha ligand clofibrate also stimulated
      proliferation of the LIM 1899 cell line. We conclude that some PPARalpha ligands
      increase progastrin production by the human CRC cell line LIM 1899, and that
      clofibrate increases proliferation of LIM 1899 cells. These studies have revealed
      a relationship between PPARs and gastrin, two regulatory molecules implicated in
      the pathogenesis of CRC.

PMID- 15177945
TI  - Effects of high-fat feeding and fasting on ghrelin expression in the mouse
      stomach.
AB  - Ghrelin is a peptide identified as an endogenous ligand for the growth hormone
      secretagogue receptor. Studies have shown that ghrelin stimulates growth hormone,
      promotes food intake and decreases energy expenditure. Furthermore, feeding
      status seems to influence plasma ghrelin levels, as these are increased during
      fasting, whereas feeding and oral glucose intake reduce plasma ghrelin. This
      study examined whether standardized obesity and fasting affect cellular
      expression of ghrelin. Specimens from the gastrointestinal tract of fed or 18-h
      fasted, low-fat or high-fat fed (10 weeks on diet) C57BL/6J mice were studied by
      immunocytochemistry (ICC) for ghrelin and in situ hybridization (ISH) for ghrelin
      mRNA. Ghrelin was expressed in especially the corpus but also the antrum of the
      stomach of all groups studied. Cells positive for ghrelin and ghrelin mRNA in the
      stomach were reduced in high-fat fed mice. In contrast, ghrelin expression was
      not affected by fasting. The reduction in ghrelin expression in the high-fat fed
      mice was associated with a reduction in plasma levels of ghrelin, whereas after
      fasting, when expression rate was not altered, there was an increase in plasma
      ghrelin. In conclusion, ghrelin is highly expressed in the corpus and antrum of
      the stomach of C57BL/6J mice. This expression is reduced in obesity, whereas
      fasting has no effect.

PMID- 15177946
TI  - Chromogranin A as a determinant of midgut carcinoid tumour volume.
AB  - Neuroendocrine (NE) tumours are characterized by their capacity to synthesize,
      store and release hormonal products. These substances are stored in
      neurosecretory vesicles together with chromogranin A (CgA). The concentration of
      plasma CgA in patients with NE tumours is thought to reflect the degree of NE
      differentiation, total tumour burden and effect of medical treatment. The aim of
      this study was to analyse the correlation between tumour weight and plasma CgA
      levels as well as the influence of treatment with a long-acting somatostatin
      analogue (octreotide) using nude mice with xenografted human ileal carcinoid
      tumours. There was a correlation between tumour weight and plasma CgA levels in
      all animals (p < 0.00001). In octreotide-treated mice, plasma CgA levels were
      significantly reduced versus untreated animals (p = 0.037). In conclusion, this
      study demonstrates that plasma CgA levels are closely correlated to tumour
      burden, and that plasma CgA is well suited for monitoring the clinical course and
      outcome of treatment in patients with NE tumours.

PMID- 15177947
TI  - Kinetic characters and resistance to inhibition of crude and purified brain
      acetylcholinesterase of three freshwater fishes by organophosphates.
AB  - Acetylcholinesterase (AChE) was purified from the brain of three fresh-water
      fishes, topmouth gudgeon (Pseudorasbora parva), goldfish (Carassius auratus
      auratus) and rainbow trout (Oncorrhychus mykiss, formerly named Salmo gairdneri)
      by PEG2000/phosphate-salt two phases extraction, DEAE-Sephadex A-50 and Sephadex
      G-200 chromatography. Kinetic characters and resistance to inhibition of crude
      and purified enzymes by organophosphates were then studied. Although the crude
      enzyme from the trout displayed a different specific activity, kinetic curve,
      Vmax, and sensitivity to inhibition by oxidized malathion and triazopos compared
      with the two cyprinoids (i.e. topmouth gudgeon and goldfish), the purified
      enzymes of all the three species showed no significant difference in all aspects.
      The result suggested a negligible intrinsic difference of brain AChEs among the
      tested species.

PMID- 15177948
TI  - Baltic salmon (Salmo salar) yolk-sac fry mortality is associated with
      disturbances in the function of hypoxia-inducible transcription factor (HIF
      1alpha) and consecutive gene expression.
AB  - Baltic salmon (Salmo salar) suffer from abnormally high yolk-sac fry mortality
      designated as M74-syndrome. In 1990s, 25-80% of salmon females, which ascended
      rivers to spawn, produced yolk-sac fry suffering from the syndrome. Symptoms of
      M74-affected fry include neurological disturbances, impaired vascular development
      and abnormal haemorrhages. The latter symptoms are observed in mammalian embryos
      if the function of hypoxia inducible transcription factor (HIF-1alpha), its
      dimerization partner aryl hydrocarbon nuclear translocator (ARNT) or target gene
      vascular endothelial growth factor (VEGF) is disturbed. To study the possible
      involvement of HIF-1alpha and its target gene VEGF in the development of the
      syndrome, we collected healthy and M74-affected wild Baltic salmon yolk-sac fry
      and analyzed HIF-1alpha mRNA and protein expression, HIF-1alpha DNA-binding,
      target gene VEGF protein expression, and blood vessel density in both groups at
      different stages of yolk-sac fry development. In addition, since Baltic salmon
      females contain organochlorine contaminants, which have been suggested to be the
      cause of M74 syndrome via the aryl hydrocarbon receptor (AhR)-dependent gene
      expression pathway, we studied AhR protein expression, AhR DNA-binding and target
      gene CYP1A protein expression. Since the parents of both healthy and M74-affected
      wild fry will have experienced the organochlorine load from the Baltic Sea,
      hatchery-reared fry were included in the studies as an additional control. The
      results show that the vascular defects observed in fry suffering from M74 are
      associated with reduced DNA-binding activity of HIF-1alpha and subsequent
      downregulation of its target gene vascular endothelial growth factor (VEGF). In
      addition, also AhR function is decreased in diseased fry making it unlikely that
      symptoms of M74-affected fry would be caused by an upregulation of xenobiotically
      induced AhR-dependent gene expression pathway.

PMID- 15177949
TI  - Cadmium tolerance, cysteine and thiol peptide levels in wild type and chromium
      tolerant strains of Scenedesmus acutus (Chlorophyceae).
AB  - Two strains of the unicellular green alga Scenedesmus acutus with different
      sensitivity to hexavalent chromium were compared for their tolerance of cadmium,
      by means of growth and recovery tests, and determination of cysteine, reduced
      glutathione and phytochelatin content, after short-term exposure to various
      cadmium concentrations (from 1.125 to 27 microM). Growth experiments showed that,
      after 7-day treatments with cadmium, the chromium-tolerant strain reached a
      significantly higher cell density and, after 24-h exposure to Cd, was able to
      resume growth significantly better than the wild type. Constitutive level of
      cysteine was higher in the chromium-tolerant strain, while glutathione levels
      were similar in the two strains. The higher content of cysteine and the
      maintenance of both reduced glutathione and phytochelatin high levels in the
      presence of cadmium, support the higher cadmium co-tolerance of the chromium
      tolerant strain in comparison with the wild type one.

PMID- 15177950
TI  - Humoral immune factors modulated by copper and chitosan in healthy or parasitised
      carp (Cyprinus carpio L.) by Ptychobothrium sp. (Cestoda).
AB  - As an environmental protection point of view, the potential toxicity of chitosan
      on aquatic animal health, alone or associated with copper must be investigated.
      Fish possess defence mechanisms to counteract the impact of toxics. The non
      cellular and non-specific immune defences (total immunoglobulin, ceruloplasmin,
      lysozyme and potential killing activity of phagocytic cells) can be modulated by
      the potential environmental pollutants but also by natural stimulants such as
      bacteria, viruses or parasites. In this study, we investigate the potential
      toxicity of copper (0.1 and 0.25 mg/L) or chitosan (75 and 150 mg/L) and the
      combination copper and chitosan (0.1 and 75 mg/L, respectively) on two groups of
      carp: healthy or parasitised by Ptychobothrium sp. Fish exposed to water-soluble
      chitosan for 96 h had significantly high levels of natural antibodies in plasma.
      Moreover, activities of lysozyme and ceruloplasmin were also increased in plasma
      after the same treatment. The exposition of fish to copper have shown apparently
      contradictory effects on the immune parameters measured but, significant increase
      of this bacteriolytic activity was observed, particularly in head kidney after 4
      days of treatment of fish with copper. The two products may induce separately an
      acute, short and local inflammatory acute phase response by stimulating some
      components of the innate immune response of healthy fish. The mixture seems to
      reduce the impact of the each product due to the physical and chemical properties
      of chitosan to complex with copper. The responses of humoral immune factors of
      treated carp was modulated by the presence of the parasite, as shown by the high
      elevation of lysozyme activity observed in parasitised carps after exposition to
      copper and by increases in natural antibodies levels observed in parasitised carp
      treated with the copper-chitosan mixture. This could indicate an additive effect
      on the stress response mediated by parasite. It occurred a greater stress
      response in the parasitised group than healthy group exposed to the same
      treatment evoking an additive effect. So, it is important to specify the health
      status of organisms to understand responses of immunological markers in fish.

PMID- 15177951
TI  - Accumulation and depuration of cyanobacterial paralytic shellfish toxins by the
      freshwater mussel Anodonta cygnea.
AB  - The increasing frequency by which the production of paralytic shellfish toxins
      (PST) by freshwater bloom-forming cyanobacteria is being noticed world-wide
      raises the possibility of PST bioaccumulation by freshwater mussels. This study
      evaluates PST accumulation and depuration by the freshwater mussel Anodonta
      cygnea exposed over a 14-day period to high densities (mean = 1.4 x 10(9) cells1(
      1), S.D. = 0.29 x 10(9) cellsl(-1)) of the toxic cyanobacterium Aphanizomenon
      issatschenkoi (corresponding to a mean toxin concentration of 25.5 nmol PSTl(-1),
      S.D. = 9.9 nmol PSTl(-1)). Mussels were subsequently detoxified either by
      starvation or by feeding on the non-toxic green-algae Ankistodesmus falcatus.
      Filter feeding activity and toxin uptake by the mussels were followed by cell
      counting and toxin analysis in water samples taken before and after each daily
      water renewal. The accumulation and depuration of PST as well as the anatomical
      distribution of toxins were monitored throughout the experiment by HPLC analysis
      of mussel extracts. Mussels fed the toxic cyanobacterium removed on average 65.3%
      of cells and 40.36% of total PST daily provided. Daily rates of cell clearance (%
      of initial) were negatively correlated with the amounts of PST daily provided
      (but not with the amount of cells). This suggests a negative effect of toxins on
      the feeding behaviour of mussels. Small amounts of toxins could be detected in
      the mussels after the second day of exposure, reaching a maximum of 26 microg
      PST100 g(-1) by day 7. The viscera contained the greatest proportion of toxins
      (78%) at the start of the toxification. However, increasing amounts of PST were
      found in the remaining tissues (gills, mantle and foot) over time. Toxins
      detected in the mussel extracts were the same provided in the dietary A.
      issatschenkoi. Nevertheless, mussels showed a higher proportion of saxitoxin and
      decarbomoylsaxitoxin and a lower proportion of gonyautoxin-5 than the fed
      cyanobacterium. Similar depuration efficiencies were observed among starved
      individuals (6.9% day(-1)) and those fed with A. falcatus (8.2% day(-1))
      indicating that both treatments had comparable effects on toxin metabolism.
      Mussels showed a typical S shaped depuration kinetics curve consisting of a first
      short period of slow toxin decay followed by a rapid loss and a subsequent slower
      release of toxins. Trace to undetectable levels of PST were found in mussels
      after the 14-day depurating period. Although freshwater mussels are not widely
      consumed by humans, their capacity to accumulate PST points to the risk of PST
      propagation through the food chain of freshwater ecosystems via filter-feeding
      mussels.

PMID- 15177952
TI  - Predictability of the mixture toxicity of 12 similarly acting congeneric
      inhibitors of photosystem II in marine periphyton and epipsammon communities.
AB  - Testing of single chemicals with single species is common ecotoxicological
      practice in contrast to contaminated environments where highly diverse biological
      communities are exposed to highly diverse mixtures of chemical compounds. We,
      therefore, investigated whether mixture toxicity approaches that have been used
      successfully for single species, might also be applied on a community level of
      biological complexity. Twelve inhibitors of photosystem II, selected by QSAR and
      chemometrical approaches as the structurally most similar from a congeneric group
      of phenylurea herbicides, were tested singly and as mixtures on two types of
      marine microalgal communities, periphyton and epipsammon. Inhibition of
      photosynthesis was measured in short-term tests using incorporation of
      radiolabelled carbon (14C) to estimate photosynthetic rates. Two basic concepts,
      concentration addition (CA) and independent action (IA), were used to predict the
      toxicities of the mixtures. Congeneric and similar-acting substances such as the
      phenylureas are expected to comply with CA rather than IA. The aim of the present
      study was to evaluate whether these concepts can be used to predict mixture
      toxicity also to periphyton and epipsammon photosynthesis, i.e. at the level of
      natural communities. We found that deviations between observed and predicted
      mixture toxicity were relatively small but that CA predictions were the more
      accurate ones. The predictions proved to be robust, when based on single
      substance information even from different seasons, years, and sites. We conclude
      that the concept of CA for predicting mixture toxicity applies also at the
      community level of algal testing; at least when a physiological short-term effect
      indicator is used that matches the mechanism of action of the substances.

PMID- 15177953
TI  - The effects of environmental pollutants on complex fish behaviour: integrating
      behavioural and physiological indicators of toxicity.
AB  - Environmental pollutants such as metals, pesticides, and other organics pose
      serious risks to many aquatic organisms. Accordingly, a great deal of previous
      research has characterized physiological mechanisms of toxicity in animals
      exposed to contaminants. In contrast, effects of contaminants on fish behaviour
      are less frequently studied. Because behaviour links physiological function with
      ecological processes, behavioural indicators of toxicity appear ideal for
      assessing the effects of aquatic pollutants on fish populations. Here we consider
      the many toxicants that disrupt complex fish behaviours, such as predator
      avoidance, reproductive, and social behaviours. Toxicant exposure often
      completely eliminates the performance of behaviours that are essential to fitness
      and survival in natural ecosystems, frequently after exposures of lesser
      magnitude than those causing significant mortality. Unfortunately, the
      behavioural toxicity of many xenobiotics is still unknown, warranting their
      future study. Physiological effects of toxicants in the literature include
      disruption of sensory, hormonal, neurological, and metabolic systems, which are
      likely to have profound implications for many fish behaviours. However, little
      toxicological research has sought to integrate the behavioural effects of
      toxicants with physiological processes. Those studies that take this
      multidisciplinary approach add important insight into possible mechanisms of
      behavioural alteration. The most commonly observed links with behavioural
      disruption include cholinesterase (ChE) inhibition, altered brain
      neurotransmitter levels, sensory deprivation, and impaired gonadal or thyroid
      hormone levels. Even less frequently studied are the implications of interrelated
      changes in behaviour and physiology caused by aquatic pollutants for fish
      populations. We conclude that future integrative, multidisciplinary research is
      clearly needed to increase the significance and usefulness of behavioural
      indicators for aquatic toxicology, and aim to highlight specific areas for
      consideration.

PMID- 15177954
TI  - Is pseudophakic retinal detachment a thing of the past in the phacoemulsification
      era?

PMID- 15177955
TI  - Efficacy and safety of adjunctive mitomycin C during Ahmed Glaucoma Valve
      implantation: a prospective randomized clinical trial.
AB  - PURPOSE: To evaluate the efficacy and safety of intraoperative mitomycin C (MMC)
      in eyes undergoing Ahmed Glaucoma Valve implantation. DESIGN: Randomized
      controlled clinical trial. PARTICIPANTS: Sixty patients with refractory glaucoma.
      INTERVENTION: Sixty eyes of 60 patients with refractory glaucoma were randomized
      to receive intraoperative MMC (0.5 mg/ml for 5 minutes) (n = 34) or balanced salt
      solution (n = 26) during Ahmed Glaucoma Valve implantation. MAIN OUTCOME
      MEASURES: Surgical success was defined according to 2 different criteria: (1)
      postoperative intraocular pressure (IOP) between 6 and 21 mmHg, with or without
      antiglaucoma medications, and (2) IOP reduction of at least 30% relative to
      preoperative values. Eyes requiring additional glaucoma surgery, developing
      phthisis, or showing loss of light perception were classified as failures.
      Success rates in both groups were compared using Kaplan-Meier survival curves and
      the log rank test. Other outcome measures were mean IOP, number of glaucoma
      medications, and complications. RESULTS: After a mean follow-up of 12.3 months,
      Kaplan-Meier survival analysis showed a probability of success of 59% at 18
      months for the MMC group and 61% for the control group when the first criterion
      for success was used (IOP between 6 and 21 mmHg). When an IOP reduction of at
      least 30% was used as the criterion to define success, the Kaplan-Meier survival
      analysis demonstrated a probability of success at 18 months of 62% for the MMC
      group and 67% for the control group. There were no significant differences in
      survival rates between the 2 groups with either criterion (P = 0.75 and P = 0.37,
      respectively). After 15 days postoperatively, the mean IOP did not significantly
      differ for both MMC and control eyes. Mean numbers of postoperative antiglaucoma
      medications were similar in MMC-treated eyes and controls. There was no
      significant difference between the incidences of postoperative complications in
      both groups. CONCLUSION: Mitomycin C did not increase the short- or intermediate
      term success rates of Ahmed Glaucoma Valve implantation.

PMID- 15177956
TI  - The Proview phosphene tonometer fails to measure ocular pressure accurately in
      clinical practice.
AB  - PURPOSE: To evaluate the Proview Eye Pressure Monitor as a medical instrument and
      as a technique for enabling a patient to obtain an accurate measure of his or her
      intraocular pressure (IOP). DESIGN: An experimental laboratory evaluation and an
      independent prospective clinical study to test the reproducibility and accuracy
      of the Proview technique relative to Goldmann applanation tonometry.
      PARTICIPANTS: For the laboratory study, we analyzed 3 tonometers, each packaged
      as a Proview Eye Pressure Monitor by Bausch & Lomb. In the independent
      prospective experimental study, 137 subjects participated, consisting of healthy
      volunteers and glaucoma patients. METHODS: For laboratory testing, we held each
      tonometer with a micrometer to assure controlled positioning and pressed its
      sensing tip against a force meter that produced a calibrated, digital force
      reading. For clinical testing, we taught subjects (n = 137) to use the Proview
      technique in accordance with the manufacturer's instructions. Each subject
      obtained 5 measurements with each of the 5 different Proview devices. A clinician
      measured the IOP using Goldmann applanation tonometry. MAIN OUTCOME MEASURES: We
      measured the absolute value, linearity, and repeatability of the force meter
      readings on the tonometers during the instrument laboratory evaluation. The
      accuracy was evaluated by comparing the Proview measurements to the Goldmann
      applanation measurements. Reproducibility of clinical Proview measurements was
      also measured. All measurements were in mmHg during the clinical evaluation.
      RESULTS: Laboratory: There was a linear relationship between the pressures read
      by the Proview tonometers and known forces. The Proview tonometers read the
      maximum pressure applied. Clinical: The Proview technique is simple to use
      because it was comfortable and reproducible, with an average variance of the
      measurements by the same patient of 3.4 mmHg(2). Other variables besides IOP seem
      to affect the Proview pressure measurements, as seen in the large scatter in our
      data, measured by our correlation coefficient of r = 0.41. The sensitivity of the
      Proview technique to detect patients with high IOP (which we defined as a
      Goldmann pressure of >/=22 mmHg) is low; the Proview pressure identified only 18%
      (4/22) of these patients. CONCLUSIONS: The Proview instrument and technique were
      reproducible. However, the Proview tonometer seems not to be reliable as an
      indicator of IOP. The sensitivity for detecting high IOP was low in this cohort,
      and the agreement with Goldmann applanation was poor for some individuals. This
      brings into question the underlying assumption that a force proportional to the
      IOP generates phosphenes.

PMID- 15177957
TI  - Artisan toric lens implantation for correction of postkeratoplasty astigmatism.
AB  - PURPOSE: To determine the efficacy of Artisan toric iris-fixated lens
      implantation after penetrating keratoplasty to correct high ametropia and
      astigmatism. DESIGN: Prospective, noncomparative case series. PARTICIPANTS:
      Artisan toric lens implantation was performed in 16 eyes of 16 patients who were
      contact lens intolerant or were unable to wear glasses because of anisometropia,
      high astigmatism, or both. INTERVENTION: Sixteen eyes of 16 patients received
      Artisan toric lenses for postkeratoplasty astigmatism, anisometropia, or both.
      MAIN OUTCOME MEASURES: Manifest refraction, uncorrected and spectacle-corrected
      visual acuity, and corneal topography were performed before surgery and 1, 3, 6,
      12, and 18 months after surgery. Efficacy, percent reduction of refractive
      astigmatism, topographical astigmatism, anisometropia of defocus, and the
      astigmatism correction index were determined. A patient satisfaction
      questionnaire and specular microscopy results were assessed. RESULTS: The mean +/
      standard deviation of the preoperative refractive cylinder was -6.66+/-1.93
      diopters (D; range, -4.0 to -10.0 D), which was reduced to -2.08+/-1.33 D, 
      2.14+/-1.76 D, -1.98+/-1.65 D, -1.84+/-0.77 D, and -1.42+/-0.78 D at 1 month, 3
      months, 6 months, 12 months, and the final follow-up examination (8.4+/-4.9
      months), respectively. Spherical equivalent was reduced from -4.90+/-5.50 D
      before surgery to -0.96+/-0.86 D at the final follow-up. The uncorrected and best
      corrected visual acuities were >/=20/40 in 42% and 100% of eyes, respectively.
      There was no loss of best-corrected visual acuity and a gain of at least 2 lines
      in 50% of eyes. The percent reduction in refractive astigmatism, topographical
      astigmatism, and anisometropia of defocus were 78.0+/-11.5%, 20.3+/-34.9%, and
      77.0+/-12.0%, respectively. The astigmatism correction index was 102.8+/-18.6%.
      Satisfaction increased from 3.2 to 8.3 after implantation. The endothelial cell
      loss was 7.6+/-18.9% at 3 months and 16.6+/-20.4% at the last follow-up. In 1
      patient, a reversible graft rejection occurred. CONCLUSIONS: Artisan toric lens
      implantation after penetrating keratoplasty was effective for reduction of
      refractive astigmatism and ametropia. All patients were suitable for spectacle
      correction after implantation. A longer follow-up and a larger number of patients
      are needed to assess the safety and the effect of the lens on the corneal graft
      endothelium.

PMID- 15177958
TI  - Unilateral photorefractive keratectomy for myopic anisometropia improves contrast
      sensitivity.
AB  - OBJECTIVE: To evaluate visual performance after unilateral photorefractive
      keratectomy (PRK) performed for >/=2.75-diopter (D) myopic anisometropia. DESIGN:
      Prospective observational case series. PARTICIPANTS: Eleven patients exhibiting
      >/=2.75-D myopic anisometropia appropriate for PRK. METHODS: Photorefractive
      keratectomy was performed on 11 eyes of 11 patients for myopic anisometropia
      ranging from -2.75 to -9.00 D. Best spectacle-corrected visual acuity (VA),
      contrast sensitivity (CS), and pattern visual evoked potentials (pVEPs) were
      measured preoperatively and at 3 and 6 months. MAIN OUTCOME MEASURES: Best
      spectacle-corrected VA; pVEPs; and CS, measured as the area under the CS curve.
      RESULTS: Best spectacle-corrected VA increased nonsignificantly 6 months after
      PRK. A tendency towards decreased latency time of pVEPs for both eyes was
      observed after PRK. A significant increase in CS occurred after PRK in the
      operated eye at 6 months, but a tendency toward decreased CS appeared in the
      unoperated eye at 3 months. Preoperative CS levels, however, were reached at 6
      months. CONCLUSIONS: The adult central visual system is sensitive to visual
      deprivation caused by anisometropia. Imbalance between eyes may improve visual
      performance in the more emmetropic eye. Anisometropia appears to reduce visual
      performance in the more myopic eye, but this can probably be reversed by
      refractive correction.

PMID- 15177959
TI  - Pellucid marginal corneal degeneration.
AB  - OBJECTIVE: To report the clinical features and outcome of patients with pellucid
      marginal corneal degeneration (PMCD). DESIGN: Retrospective noncomparative case
      series. METHODS: Retrospective chart review of 116 eyes of 58 patients with PMCD
      seen between 1990 and 2002 at the Cornea Service at L.V. Prasad Eye Institute,
      Hyderabad, India. The diagnosis of PMCD was based on the presence of corneal
      thinning with ectasia of the normal cornea above or below the area of thinning
      with no evidence of scarring, vascularization, or lipid deposition and typical
      topographic features whenever topography was performed. A detailed history
      including the age of presentation, onset of symptoms, systemic diseases, atopy,
      and relevant family history was reviewed. The visual acuity (VA) at presentation;
      the location, extent, and degree of thinning; presence of concurrent keratoconus
      and keratoglobus; and complications, if any, were noted. The mode of visual
      rehabilitation; surgical procedure, if any; and the final VA achieved were
      analyzed. MAIN OUTCOME MEASURES: Clinical features, associations, complications,
      and outcome of treatment. RESULTS: There were 45 males (77.6%) and 13 females
      (22.4%). All cases were bilateral. In one eye, no clinical features of PMCD were
      seen, but the diagnosis was made based on topographic features of typical PMCD.
      The age of the patients ranged from 8 to 66 years, with a mean of 34.0+/-14.8.
      One patient (1.7%) had associated vernal keratoconjunctivitis (VKC), 1 (1.7%) had
      Marfan's syndrome, and 1 (1.7%) had ocular hypertension. The degree of
      astigmatism was <5.0 diopters (D) in 19 eyes (19.2%), 5 to 10 D in 36 (36.4%), 10
      to 15 D in 23 (23.2%), 15 to 20 D in 15 (15.2%), and >20 D in 6 (6.1%). Typical
      inferior PMCD was seen in 99 eyes (85.3%), and superior PMCD was seen in 17
      (14.7%). The thinning was commonly seen between the 5-o'clock and 7-o'clock
      positions. In 12 eyes (10.3%), PMCD was associated with keratoconus, and in 15
      eyes (12.9%), keratoglobus was associated. Seven eyes (6.0%) had hydrops. Visual
      acuity improved in 52 eyes (55.3%) with correction, in 40 eyes (42.6%) it
      remained the same as that of the initial presentation, and in 2 eyes (2.1%) it
      worsened relative to the initial presentation. Forty-one eyes (35.3%) received
      spectacles, and 31 eyes (26.7%) were fitted with rigid gas-permeable contact
      lenses. Five eyes (4.3%) underwent surgery. Lamellar keratoplasty was performed
      in 3 eyes, and a crescentic lamellar graft was done in 2 eyes. Visual acuity
      improved in 4 eyes after surgery with a follow-up of 2 to 37 months. The final
      astigmatism in the operated eyes at the last follow-up ranged from 4 to 11 D.
      CONCLUSIONS: Pellucid marginal corneal degeneration was seen predominantly in
      males in this series, and was not strongly associated with VKC. Keratoconus was
      seen in approximately 10% of the eyes, and keratoglobus in approximately 13%.
      Superior PMCD was seen in approximately 15% of the eyes. In our study, patients
      presented with severe astigmatism, and hydrops was a common complication. The
      majority of patients were treated with spectacles or contact lens. Surgery for
      PMCD-lamellar keratoplasty and crescentic lamellar keratoplasty, if indicated
      usually results in significant residual astigmatism.

PMID- 15177960
TI  - Polymorphic corneal amyloidosis: a disorder due to a novel mutation in the
      transforming growth factor beta-induced (BIGH3) gene.
AB  - PURPOSE: To characterize the clinicopathologic phenotype as well as the molecular
      genetic basis of an autosomal dominant form of corneal amyloidosis. DESIGN:
      Clinicopathologic and molecular genetic study of a family with a form of corneal
      amyloidosis. PARTICIPANTS: Forty-nine individuals from one family were studied.
      METHODS: The medical records of affected family members were reviewed, and
      corneal tissue from those who had undergone penetrating keratoplasty (PK) was
      examined. Several family members were examined clinically, and corneas were
      photographed. Deoxyribonucleic acid from blood or buccal swabs was extracted from
      each consenting family member to determine the status of their transforming
      growth factor beta-induced (TGFBI) gene. The coding region of the TGFBI gene was
      analyzed for mutations in the proband's DNA, and compared with the nucleotide
      sequences of normal individuals. This was performed by amplifying and sequencing
      all exons of the TGFBI gene. In all other family members, only exons 4, 8, 11,
      and 12 of the gene were amplified, sequenced, and analyzed for mutations. MAIN
      OUTCOME MEASURES: Clinicopathologic manifestations in relation to mutational
      status of the TGFBI gene. RESULTS: Slit-lamp biomicroscopy revealed bilateral
      multiple polymorphic, polygonal, refractile, chipped ice-appearing gray and white
      opacities. There were also occasional deep filamentous lines that did not form a
      distinct lattice pattern. Corneal tissue of affected individuals who underwent PK
      contained widespread deposits of amyloid within the corneal stroma, particularly
      in the deep central stroma. Twelve members of the family were found to have a
      heterozygous single mutation in the TGFBI gene leading to a predicted amino acid
      substitution of aspartic acid for alanine (A546D). Nine of these individuals had
      ophthalmologist-documented corneal disease. The remaining 3, who were 11, 14, and
      15 years old, were asymptomatic. In addition, 4 inconsequential polymorphisms
      with the nucleotide changes 387 G/A (R129R), 981 G/A (V327V), 1416 T/C (L472L),
      and 1620 C/T (F540F) were found. CONCLUSION: A distinct, progressive form of
      corneal amyloidosis with an autosomal dominant mode of inheritance is
      characterized clinically by the presence of refractile polymorphic corneal
      opacities. We have designated this entity, which is caused by an A546D mutation
      in the TGFBI gene, polymorphic corneal amyloidosis.

PMID- 15177961
TI  - Autologous serum application in the treatment of neurotrophic keratopathy.
AB  - OBJECTIVE: To evaluate the effect of autologous serum application for epithelial
      disorders in neurotrophic keratopathy (NK). DESIGN: Retrospective, noncomparative
      case series. PARTICIPANTS: Fourteen eyes of 11 patients with NK seen at Tokyo
      Dental College, Ichikawa General Hospital, Department of Ophthalmology, were
      studied. INTERVENTION: Twenty percent topical autologous serum eye drops were
      applied 5 to 10 times daily until resolution of the NK. Patients underwent
      routine ophthalmic examinations, including slit-lamp examination, corneal
      fluorescein dye testing, Cochet-Bonnet corneal sensitivity (Luneau, France), and
      best-corrected visual acuity (BCVA) measurements before and at the end of the
      treatment. Moreover, serum samples from 10 healthy volunteers were studied for
      the levels of substance P (SP), insulinlike growth factor (IGF-1), and nerve
      growth factor (NGF) by using radioimmunoassay and enzyme-linked immunosorbent
      assay techniques. Tear samples from 3 healthy subjects also were analyzed for NGF
      and IGF-1 levels by the same techniques. MAIN OUTCOME MEASURES: The changes in
      corneal disease state, corneal sensitivity, and BCVA with treatment were
      evaluated. The levels of neural healing factors like SP, IGF-1, and NGF in serum
      as well as NGF and IGF-1 in tears of healthy subjects also were examined.
      RESULTS: The epithelial disorders healed completely in all eyes within 6 to 32
      days (mean, 17.1+/-8.0 days), with a decrease in corneal scarring. The mean
      pretreatment corneal sensitivity was 11.8+/-11.6 mm, which increased to 30.0+/
      22.9 mm after treatment at the last follow-up. Five eyes attained normal corneal
      sensitivity with treatment. The BCVA improved by >2 Landolt lines in 78.6% of the
      eyes. The mean concentrations of SP in diluted and undiluted serum were 31.4+/
      8.4 pg/ml and 157.0+/-42.1 pg/ml, respectively. The mean respective
      concentrations of IGF-1 in diluted and undiluted serum were 31.4+/-14.8 ng/ml and
      157.0+/-73.9 ng/ml. The mean concentrations for NGF were 93.6+/-63.5 pg/ml and
      468.3+/-317.4 pg/ml in serum samples with and without dilution, respectively. The
      mean concentration of NGF in tears was found to be 54 pg/ml. Insulinlike growth
      factor 1 was not detected in tears in this study. CONCLUSIONS: Autologous serum
      harbors neurotrophic factors. Autologous serum treatment may provide neural
      healers to the compromised ocular surface and seems promising for the restoration
      of the ocular surface epithelial integrity in patients with NK.

PMID- 15177962
TI  - The Los Angeles Latino Eye Study: design, methods, and baseline data.
AB  - OBJECTIVE: To describe the study design, operational strategies, procedures, and
      baseline characteristics of the Los Angeles Latino Eye Study (LALES), a
      population-based assessment of the prevalence of visual impairment, ocular
      disease, and visual functioning in Latinos. DESIGN: Population-based, cross
      sectional study. PARTICIPANTS: Six thousand three hundred fifty-seven Latinos 40
      years and older from 6 census tracts in Los Angeles, California. METHODS: A
      detailed interview and eye examination were performed on each eligible
      participant. The interview included an assessment of demographic, behavioral, and
      ocular risk factors and health-related and vision-related quality of life. The
      eye examination included a measurement of visual acuity, intraocular pressure,
      and visual fields; fundus and optic disc photography; a detailed anterior and
      posterior segment examination; and measurement of blood pressure, glycosylated
      hemoglobin levels, and blood glucose levels. MAIN OUTCOME MEASURES: Prevalence of
      visual impairment, blindness, cataract, glaucoma, diabetic retinopathy, and age
      related macular degeneration constitute the study's primary outcome variables.
      Secondary outcomes include odds ratios for risk factors associated with eye
      disease, health-related quality of life, and vision-related quality of life.
      Response rates and baseline characteristics are presented. RESULTS: Of the 7789
      individuals eligible for LALES, 6357 (82%) had a clinical examination; an
      additional 524 completed only an in-home interview. The majority of participants
      were female (58%), the average (+/- standard deviation) age was 54.9 (+/-10.8)
      years, and 80.0% were of Mexican origin and 0.4% self-identified as American
      Indian or Alaskan Native. The age distribution of LALES participants was similar
      to that of Latinos of Mexican origin in the rest of the United States.
      CONCLUSION: The LALES has recruited Latinos 40 and older for an ophthalmic
      epidemiologic study. The LALES cohort will provide information about the
      prevalence and risk factors of ocular disease in the largest and fastest growing
      minority in the United States.

PMID- 15177963
TI  - Prevalence and risk indicators of visual impairment and blindness in Latinos: the
      Los Angeles Latino Eye Study.
AB  - OBJECTIVE: To determine the age- and gender-specific prevalence and risk
      indicators of visual impairment and blindness in urban Latinos 40 years and
      older. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Six thousand
      three hundred fifty-seven Latinos 40 years and older from 6 census tracts in Los
      Angeles, California. METHODS: Of the 6357 study participants, 6122 underwent a
      complete ophthalmologic examination at the clinical center, including measurement
      of best-corrected distance visual acuity (VA) using a standard Early Treatment
      Diabetic Retinopathy Study protocol. Age- and gender-specific prevalence of
      visual impairment and blindness were contrasted using Mantel-Haenszel procedures.
      Sociodemographic and clinical risk indicators of visual impairment were explored
      using stepwise logistic regression. MAIN OUTCOME MEASURES: Prevalence and odds
      ratios for risk indicators of visual impairment and blindness. RESULTS: The
      overall prevalence for visual impairment (best-corrected VA of <==20/40 in the
      better eye) was 3.0% (n = 182) (range, 0.9% [40-49 years]-27.8% [>/=80 years]).
      The overall prevalence for blindness (best-corrected VA of <==20/200 in the
      better eye) was 0.4% (n = 26) (range, 0.2% [40-49 years]-4.2% [>/=80 years]).
      Visual impairment increased with age (P<0.0001) and was greater in women (P =
      0.02). Independent risk indicators (odds ratio [95% confidence interval]) for
      visual impairment were age 70-79 years (2.8 [1.3-5.8]) or >/=80 years (8.7 [3.9
      19.6]), history of ocular disease (3.2 [2.1-4.8]), being unemployed (3.3 [1.7
      6.3]), diabetes (2.2 [1.5-3.2]), and being separated/divorced (1.8 [1.0-3.1]) or
      widowed (2.8 [1.8-4.4]). Participants with >/=12 years of education (0.5 [0.3
      0.8]) were less likely to be visually impaired. CONCLUSIONS: Rates of visual
      impairment and blindness in Latinos are high, especially in older individuals.
      Better education and employment are likely to decrease the burden of visual
      impairment in Latinos.

PMID- 15177964
TI  - The impact of visual impairment on self-reported visual functioning in Latinos:
      The Los Angeles Latino Eye Study.
AB  - OBJECTIVE: To assess the association between presenting binocular visual acuity
      (VA) and self-reported visual function as measured by the 25-item National Eye
      Institute Visual Function Questionnaire (NEI-VFQ-25). DESIGN: A population-based,
      prevalence study of eye disease in Latinos 40 years and older residing in La
      Puente, California (Los Angeles Latino Eye Study [LALES]). PARTICIPANTS: Six
      thousand three hundred fifty-seven Latinos 40 years and older from 6 census
      tracts in La Puente. METHODS: All participants completed a standardized
      interview, including the NEI-VFQ-25 to measure visual functioning, and a detailed
      eye examination. Two definitions of visual impairment were used: (1) presenting
      binocular distance VA of 20/40 or worse and (2) presenting binocular distance VA
      worse than 20/40. Analysis of variance was used to determine any systematic
      differences in mean NEI-VFQ-25 scores by visual impairment. Regression analyses
      were completed (1) to determine the association of age, gender, number of
      systemic comorbidities, depression, and VA with self-reported visual function and
      (2) to estimate a visual impairment-related difference for each subscale based on
      differences in VA. MAIN OUTCOME MEASURES: The NEI-VFQ-25 scores in persons with
      visual impairment. RESULTS: Of the 5287 LALES participants with complete NEI-VFQ
      25 data, 6.3% (including 20/40) and 4.2% (excluding 20/40) were visually
      impaired. In the visually impaired participants, the NEI-VFQ-25 subscale scores
      ranged from 46.2 (General Health) to 93.8 (Color Vision). In the regression
      model, only VA, depression, and number of comorbidities were significantly
      associated with all subscale scores (R(2) ranged from 0.09 for Ocular Pain to
      0.33 for the composite score). For 9 of 11 subscales, a 5-point change was
      equivalent to a 1- or 2-line difference in VA. Relationships were similar
      regardless of the definition of visual impairment. CONCLUSION: In this population
      based study of Latinos, the NEI-VFQ-25 was sensitive to differences in VA. A 5
      point difference on the NEI-VFQ-25 seems to be a minimal criterion for a visual
      impairment-related difference. Self-reported visual function is essentially
      unchanged if the definition of visual impairment includes or excludes a VA of
      20/40.

PMID- 15177965
TI  - Prevalence of refractive error in Bangladeshi adults: results of the National
      Blindness and Low Vision Survey of Bangladesh.
AB  - PURPOSE: To determine the prevalence of refractive errors and to investigate
      factors associated with refractive error in adults 30 years of age and older in
      Bangladesh. DESIGN: Cross-sectional study. PARTICIPANTS: A nationally
      representative sample of 12 782 adults 30 years of age and older. METHODS: The
      sample of subjects was selected based on multistage, cluster random sampling with
      probability-proportional-to-size procedures. The examination protocol consisted
      of an interview that included measures of literacy, education, occupation, and
      refractive correction. Visual acuity testing (logarithm of the minimum angle of
      resolution [logMAR]), automated refraction, and optic disc examination were
      performed for all subjects. Subjects with <6/12 (0.3 logMAR) acuity in either eye
      were graded additionally for cataract and underwent a dilated fundal examination.
      Subjects for whom no refractive error was recorded (312 subjects; 2.7%) or who
      had undergone cataract surgery (123 subjects; 1.1%) were excluded from the
      analysis. MAIN OUTCOME MEASURES: Refractive error and socioeconomic variables
      (literacy, education, occupation). RESULTS: Eleven thousand six hundred twenty
      four subjects were examined (90.9% response rate; mean age+/-standard deviation,
      44+/-12.6 years). Five thousand four hundred eighty-nine subjects (49.1%) were
      men and 5700 subjects (50.9%) were women. Mean spherical equivalent was -0.19
      diopters (D; +/-1.50 D). Six thousand four hundred twelve subjects (57.3%) were
      emmetropic, 2469 (22.1%) were myopic (<-0.5 D), and 2308 (20.6%) were
      hypermetropic (>+0.5 D). Two hundred six subjects (1.8%) were highly myopic (<-5
      D). Myopia was more common in men (26.3%) than in women (21.0%), whereas
      hyperopia was more common in women (27.4%) than in men (15.8%). Overall, myopia
      increased with age (17.5% of those aged 30-39 years were myopic, compared with
      65.5% of those age 70 years and older). A subanalysis of subjects without
      cataract showed increasing hyperopia with age and an association between myopia
      and higher education. Myopia was more common among the employed than in
      unemployed subjects. Astigmatism (>0.5 D), present in 3625 subjects (32.4%), was
      more common among women, illiterate subjects, and unschooled subjects. Against
      the-rule astigmatism was more common (58.7%) than oblique astigmatism (29.3%),
      which was more common than with-the-rule (WTR) astigmatism (12.1%). Against-the
      rule astigmatism and oblique astigmatism increased with age, unlike WTR
      astigmatism. Of 830 (7.5%) subjects, women were more commonly anisometropic (>1.0
      D). Anisometropia increased with age. CONCLUSIONS: Refractive error data are
      described for a country and region that previously have lacked population-based
      data. Prevalence and factors associated with refractive error are presented, with
      a detailed comparison with other population-based surveys regionally and
      internationally.

PMID- 15177966
TI  - Causes of blindness, low vision, and questionnaire-assessed poor visual function
      in Singaporean Chinese adults: The Tanjong Pagar Survey.
AB  - OBJECTIVE: To determine the prevalence rates and causes of low vision, blindness,
      and patient-assessed deficient visual function among Singaporean Chinese adults.
      DESIGN: Population-based cross-sectional survey. PARTICIPANTS: Singaporean
      Chinese adults 40 to 79 years old (n = 1152). METHODS: From an initial sampling
      frame of 40- to 79-year-old Chinese in the Tanjong Pagar district in Singapore,
      2000 subjects were selected using a disproportionate, stratified, clustered,
      random-sampling method. Of 1717 eligible subjects, 1232 were examined
      (participation rate = 71.8%), and 80 adults who did not have visual acuity (VA)
      data were excluded from the analysis. MAIN OUTCOME MEASURES: Bilateral low vision
      was defined as best-corrected VA (BCVA) worse than 6/18 and 3/60 or better, and
      bilateral blindness as BCVA worse than 3/60 in the better eye or constriction of
      the visual field to within 10 degrees of fixation, in accordance with the World
      Health Organization criteria. Patient-assessed visual function was measured using
      a modified VF-14 questionnaire. RESULTS: The age- and gender-adjusted prevalence
      rates were 1.1% (95% confidence interval [CI], 0.6-1.8) for bilateral low vision
      and 0.5% (95% CI, 0.2-1.1) for bilateral blindness, and the mean visual function
      score was 98.6. The rates of bilateral low vision and blindness increased with
      age, whereas visual function scores decreased with age, even after adjusting for
      gender and education. Cataract accounted for 58.8% of bilateral low vision, 20.0%
      of bilateral blindness, and 52.0% of poor visual function (score<90). Glaucoma
      contributed to 60.0% of bilateral blindness. CONCLUSION: The age- and gender
      adjusted rates of low vision and blindness were 1.1% and 0.5%, respectively.
      Glaucoma is a leading cause of blindness in Singaporean Chinese adults, in
      addition to well-recognized causes in the rest of Asia such as cataract.

PMID- 15177967
TI  - Is medication use associated with the incidence of early age-related maculopathy?
      Pooled findings from 3 continents.
AB  - OBJECTIVE: To investigate whether there is an association between the use of
      medication and the incidence of early age-related maculopathy (ARM). DESIGN:
      Pooled data from 3 prospective, population-based cohort studies. PARTICIPANTS:
      Subjects without early and late ARM at baseline who participated in the follow-up
      of the Beaver Dam Eye Study (n = 3012), the Rotterdam Study (n = 3434), and the
      Blue Mountains Eye Study (n = 2203). METHODS: Stereoscopic color fundus
      photographs of all participants were graded according to a standardized protocol.
      At baseline, current use of prescription and over-the-counter medication was
      assessed by interview, and the drug name was confirmed at the research centers.
      Procedures and definitions were similar at both baseline and follow-up across the
      3 study sites. MAIN OUTCOME MEASURES: Incidence of early ARM, defined as the
      presence at follow-up of either soft distinct drusen with pigmentary changes or
      soft indistinct or reticular drusen. RESULTS: In the pooled cohort, 53.3% of
      participants used at least one of the medications selected for this study. Within
      a mean period of 5.6 years, a total of 683 subjects developed early ARM. Users of
      antihypertensive medication in general, and beta-blockers in particular, had a
      borderline statistically significant increased risk of early ARM (odds ratio [OR]
      for beta-blockers, 1.3; 95% confidence interval [CI], 1.0-1.6) when adjusted for
      systolic (or diastolic) blood pressure and other confounders. A protective effect
      of borderline significance was found among women using hormone replacement
      therapy (OR, 0.6; 95% CI, 0.4-1.0) and in persons using tricyclic antidepressants
      (OR, 0.4; 95% CI, 0.2-1.0). In contrast with beta-blockers, the direction and
      magnitude of the association with hormone replacement therapy and tricyclic
      antidepressants were inconsistent among the 3 study populations. CONCLUSIONS:
      Pooled data from 3 population-based studies showed no strong associations between
      medication use and the incidence of early ARM. Of borderline significance were a
      slightly increased risk among users of beta-blockers and a reduced risk among
      users of hormone replacement therapy and users of tricyclic antidepressants.
      Although beta-blocker use could be a proxy for systemic hypertension, these
      findings warrant further investigations, preferably including information on the
      dosage and duration of drug exposure.

PMID- 15177968
TI  - Five-year incidence of age-related maculopathy: the Visual Impairment Project.
AB  - PURPOSE: To describe the 5-year incidence of age-related maculopathy (ARM) and
      the progression of the early stages of ARM lesions in Melbourne, Australia.
      DESIGN: Population-based cohort study. PARTICIPANTS: A total of 3271 participants
      aged 40 years and older from Melbourne, Victoria, Australia. MAIN OUTCOME
      MEASURES: The 5-year incidence and progression of ARM lesions. METHODS:
      Participants were recruited through a cluster random sampling from 9 urban
      clusters. Baseline examinations were conducted from 1992 through 1994, and the
      follow-up data were collected from 1997 through 1999. Presence of ARM lesions was
      graded from color stereo fundus photographs according to the International
      Classification and Grading System. RESULTS: The overall cumulative 5-year
      incidence of age-related macular degeneration (AMD) was 0.49% (95% confidence
      interval [CI], 0.2-0.8) and that of early ARM was 17.3% (95% CI, 8.7-26.0). The
      incidence of all ARM lesions increased with age (all P<0.001). The 5-year
      incidence of AMD was 0%, 0.69%, 1.7%, and 6.3% and that of early ARM was 13%,
      22.7%, 29.8%, and 20% for participants aged 60 years and younger, aged 60 to 69
      years, aged 70 to 79 years, and aged 80 years and older at baseline,
      respectively. People with soft indistinct drusen with pigmentary abnormalities
      had a 9.5 times (95% CI, 1.9-45.6) higher risk of developing AMD compared with
      people with soft drusen or pigmentary abnormalities. After adjusting for age,
      people with unilateral early ARM at baseline were 3 times (95% CI, 0.98-8.0) as
      likely to have early ARM in their second eye when compared with people with no
      ARM in both eyes. CONCLUSIONS: These data suggest that 1 in 3 persons aged 70
      years or older will have ARM lesions over a 5-year period and that the disease
      will progress to a more severe form after the age of 80 years. The presence of
      soft indistinct drusen with pigmentary abnormalities significantly increased the
      risk for development of AMD.

PMID- 15177969
TI  - Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye
      Study: methodology, correlation between eyes, and effect of refractive errors.
AB  - OBJECTIVE: Narrowed retinal arterioles may independently predict cardiovascular
      disease. We describe a computer-assisted method to measure retinal vessel
      diameters from digitized fundus photographs in a large population, and examine
      the correlation of retinal vessel diameters between eyes and whether refractive
      errors affect these measurements. DESIGN AND POPULATION: Population-based, cross
      sectional study in Beaver Dam, Wisconsin (n = 4926; age, 43-84 years). METHODS:
      Retinal photographs were digitized, and all arterioles and venules located in an
      area 0.5 to 1 disc diameter from the optic disc were measured with the aid of
      computer software. MAIN OUTCOME MEASURES: Summary of retinal arteriolar and
      venular diameters, and the ratio of their diameters (arteriole:venule ratio
      [AVR]). RESULTS: Correlation between right and left eyes was substantial for
      retinal arteriolar diameters (Pearson correlation coefficient, rho = 0.71) and
      venular diameters (rho = 0.74), and moderate for the AVR (rho = 0.49). The
      inverse association of higher blood pressure and smaller retinal arteriolar
      diameters was similar using data from either one eye or two eyes; arteriolar
      diameters decreased by 4.1 microm (right eyes), 4.0 microm (left eyes), and 4.0
      microm (mean of both eyes) with each 10-mmHg increase in mean arterial blood
      pressure. A myopic refraction was associated with smaller retinal vessel
      diameters; arteriolar diameters decreased by 2.8 microm and venular diameters by
      3.3 microm with each -1.0-diopter shift towards myopia. However, the pattern and
      strength of the association of blood pressure and retinal vessel diameters were
      not altered by variations in refractive errors. CONCLUSIONS: There is good
      correlation of retinal vessel diameters between eyes. A myopic refraction is
      associated with smaller retinal vessel diameters. The association of retinal
      arteriolar diameters and blood pressure seems similar using data from either one
      eye or two eyes, and is minimally affected by refraction. These data suggest that
      measurement of retinal vessel diameters from one eye without regard to its
      refractive status may provide adequate information indicative of a person's
      retinal vessel caliber if information from two eyes and refraction is
      unavailable.

PMID- 15177970
TI  - Aqueous and vitreous penetration of linezolid (Zyvox) after oral administration.
AB  - OBJECTIVE: To investigate the penetration of linezolid, a synthetic oxazolidinone
      antibiotic, into the aqueous and vitreous humor after oral administration.
      DESIGN: Noncomparative interventional, prospective case series study, randomized
      into group 1 (dose, one 600-mg tablet) or group 2 (2 doses of 600 mg given 12
      hours apart). PARTICIPANTS: Patients undergoing pars plana vitrectomy between
      March 2001 and August 2002 at the University of Illinois at Chicago Eye Center
      who had not had prior vitrectomy surgery. METHODS: Aqueous, vitreous, and plasma
      samples were obtained and analyzed from 29 patients after oral administration of
      1 dose (group 1A, 13 patients [13 eyes] sampled less than 2 hours after
      administration; group 1B, 9 patients [9 eyes] sampled more than 2 hours after
      administration) or 2 doses 12 hours apart (group 2, 7 patients [7 eyes]) before
      surgery. MAIN OUTCOME MEASURES: Aqueous, vitreous, and plasma concentrations of
      linezolid (micrograms per milliliter). RESULTS: Group 1A achieved mean aqueous,
      vitreous, and plasma levels of 0.77+/-0.6 microg/mL, 0.3+/-0.3 microg/mL, and
      5.0+/-3.3 microg/mL, respectively. Group 1B achieved mean aqueous, vitreous, and
      plasma levels of 3.8+/-1.2 microg/mL, 2.3+/-1.4 microg/mL, and 7.6+/-2.7
      microg/mL, respectively. Group 2 achieved mean aqueous, vitreous, and plasma
      levels of 6.6+/-2.7 microg/mL, 5.7+/-2.7 microg/mL, and 10.3+/-4.1 microg/mL,
      respectively. CONCLUSIONS: Mean inhibitory aqueous and vitreous minimum
      inhibitory concentrations for 90% of isolates (MIC(90)) were achieved against all
      gram-positive bacteria, including vancomycin-resistant enterococcus, methicillin
      resistant Staphylococcus aureus, and streptococcal species after 2 doses given 12
      hours apart. Mean MIC(90) were achieved for many gram-positive pathogens after
      only one dose in many patients after approximately 4 hours.

PMID- 15177971
TI  - Retinal vein occlusions in patients taking warfarin.
AB  - OBJECTIVE: To describe development of retinal vein occlusion (RVO) in patients
      anticoagulated with warfarin. DESIGN: Retrospective, observational case series.
      PARTICIPANTS: Thirteen patients drawn from a private retina practice. METHODS:
      Review of clinical records, laboratory results, color fundus photographs, and
      fluorescein angiograms. MAIN OUTCOME MEASURES: Primary measures were
      international normalized ratio (INR), visual acuity, and concurrent systemic
      disease. RESULTS: The female-to-male ratio was 7 to 6. Age range was 44 to 86
      years, with a median age of 73 years. Two patients had systemic lupus
      erythematosus, 7 had hypertension, and 2 had primary open-angle glaucoma. Two had
      laboratory abnormalities: 1 with a combination of lupus anticoagulant and
      anticardiolipin antibodies and 1 with a combination of hyperhomocystinemia and
      low antithrombin III. Three patients were taking acetylsalicylic acid in addition
      to warfarin at the time of the RVO. The INRs at the time of RVO were 0.9 to 3.8,
      with 9 of 13 <==2.0. CONCLUSIONS: Anticoagulation with warfarin does not preclude
      RVO in predisposed patients, nor does combination therapy with warfarin and
      acetylsalicylic acid. Attention to keeping the INR >2.0 may be helpful.

PMID- 15177972
TI  - Subretinal recombinant tissue plasminogen activator injection and pneumatic
      displacement of thick submacular hemorrhage in Age-Related macular degeneration.
AB  - OBJECTIVE: To evaluate the anatomic and visual outcomes after a surgical
      procedure for displacement of thick submacular hemorrhage in patients with age
      related macular degeneration. DESIGN: Retrospective, noncomparative,
      interventional case series. PARTICIPANTS: Twenty-nine consecutive eyes of 28
      patients with thick submacular hemorrhage secondary to age-related macular
      degeneration. INTERVENTION: The procedure consisted of a pars plana vitrectomy
      with subretinal recombinant tissue plasminogen activator injection (125
      micrograms/ml) through a translocation microcannula, followed by fluid-air
      exchange and postoperative prone positioning [correction]. MAIN OUTCOME MEASURES:
      Intraoperative and postoperative surgical complications, preoperative and
      postoperative best-corrected visual acuities, postoperative fluorescein
      angiography results, and additional postoperative treatments. RESULTS: Total
      subfoveal blood displacement was achieved in 25 eyes, with subtotal displacement
      in the others. Based on fluorescein angiography results, 8 eyes were eligible for
      additional postoperative treatments. At 3 months, 17 eyes had gained more than 2
      lines of visual acuity, whereas 3 had lost more than 2 lines. The difference
      between preoperative and 3-month postoperative visual acuity was statistically
      significant (P = 0.0167). Complications consisted of 2 cases of vitreous
      hemorrhage that cleared within 4 weeks. CONCLUSIONS: This surgical technique
      seems useful in displacing thick submacular hemorrhage secondary to age-related
      macular degeneration, allowing postoperative fluorescein angiography testing and,
      potentially, subsequent treatments. No significant complication from the
      procedure was identified. However, further controlled studies will be required to
      assess its efficacy in the management of this difficult clinical problem.

PMID- 15177974
TI  - Fibrovascular ingrowth at sclerotomy sites in vitrectomized diabetic eyes with
      recurrent vitreous hemorrhage: ultrasound biomicroscopy findings.
AB  - PURPOSE: To evaluate the frequency of fibrovascular ingrowth (FVIG) at sclerotomy
      sites in vitrectomized eyes of diabetic patients with postoperative vitreous
      hemorrhage referred for ultrasound biomicroscopy (UBM). DESIGN: Retrospective
      observational case series. PARTICIPANTS: Twenty-six eyes of 23 diabetic patients
      with recurrent, nonclearing postoperative vitreous hemorrhage subsequent to pars
      plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). METHODS:
      Ultrasound biomicroscopy evaluation of all sclerotomy sites in patients referred
      for postoperative nonclearing or recurrent vitreous hemorrhage after PPV for PDR.
      Correlation with intraoperative findings was obtained in eyes undergoing revision
      of the vitrectomy. Eight eyes underwent repeat UBM after revision of the
      vitrectomy, and changes at previous sclerotomy sites were evaluated. MAIN OUTCOME
      MEASURES: Ultrasound biomicroscopy images at each sclerotomy site were classified
      into 3 categories: none (grade 0), minor (grade 1), and major (grade 2). The UBM
      characteristics of each category were defined by the examiner. Logistic
      regression analysis was performed to identify prognostic factors associated with
      development of FVIG in the study patients. RESULTS: Grade 1 or 2 FVIG was
      detected in 85% of cases, and grade 2 FVIG was identified in >/=1 sclerotomy site
      in 58% of cases. Grade 1 or 2 FVIG was detected in 56% of microvitrector sites,
      41% of infusion sites, and 61% of light port sites. Ten patients underwent repeat
      vitrectomy because of recurrent nonclearing vitreous hemorrhage and UBM images
      showing FVIG. Inspection of the sclerotomy site confirmed the UBM findings in
      every case. Eight of these patients underwent follow-up UBM evaluation subsequent
      to the repeat vitrectomy. In 6 of the 8 patients, follow-up UBM showed no
      residual FVIG. CONCLUSIONS: Ultrasound biomicroscopy showed FVIG in a high
      proportion of eyes that experienced recurrent nonclearing vitreous hemorrhage
      after PPV for PDR. Ultrasound biomicroscopy is capable of detecting and
      characterizing FVIG at sclerotomy sites and may aid in reoperative planning.

PMID- 15177973
TI  - Limited macular translocation: a clinicopathologic case report.
AB  - OBJECTIVE: To illustrate the histopathologic findings in a patient who underwent
      limited macular translocation. DESIGN: Observational case report. METHODS: The
      patient underwent limited macular translocation for subfoveal choroidal
      neovascularization resulting from age-related macular degeneration. Thirty-one
      months after surgery, the patient had died and both eyes were obtained at
      autopsy. Serial sections through both maculas were obtained. Immunohistochemistry
      of the foveas with C10C10 and hCAR/LUMIf antibodies for rods and cones,
      respectively, was performed. MAIN OUTCOME MEASURES: Histopathologic changes in
      the operated eye as compared with the fellow eye. RESULTS: There was no
      morphologic difference in the subfoveal retinal pigment epithelium, Bruch's
      membrane, or choriocapillaris, but there was a decreased cone density in the
      translocated fovea as compared with the fellow eye. CONCLUSIONS: In this patient,
      the fovea was translocated without causing apparent change in the underlying
      retinal pigment epithelium, Bruch's membrane, or choriocapillaris. Although there
      may be some photoreceptor loss, the excellent visual recovery suggests that the
      retinal pigment epithelium underlying the translocated fovea is functionally
      adequate.

PMID- 15177975
TI  - The application of chromatic dark-adapted kinetic perimetry to retinal diseases.
AB  - PURPOSE: To demonstrate the value of a 2-color perimetric procedure for
      determining cone and rod system contributions to the dark-adapted kinetic visual
      field (VF). DESIGN: Prospective evaluation of perimetric testing procedure.
      PARTICIPANTS: Five patients with retinal diseases and 6 visually normal
      individuals. METHODS: Long- and short-wavelength stimuli were presented under
      dark-adapted conditions in a Goldmann perimeter. Visual fields were measured for
      the II and V test target sizes with a long-wavelength filter (cut-on at 600 nm)
      and a short-wavelength filter (cutoff at 510 nm). Light intensities through these
      filters were matched scotopically for the rod system by producing equal
      peripheral boundaries on 6 visually normal individuals. To validate the
      application of this procedure, we tested a patient with congenital achromatopsia
      and another patient with congenital stationary night blindness (CSNB). We then
      tested 2 patients with retinitis pigmentosa (RP) and 1 patient with Usher's
      syndrome to determine the cone and rod contributions to their VF isopters. MAIN
      OUTCOME MEASURES: Isopters for long- and short-wavelength test stimuli, and the
      appearance of the test stimuli, whether reported as chromatic or achromatic.
      RESULTS: The patient with congenital achromatopsia showed superimposed isopters
      for the 2 stimuli, which were reported as achromatic, demonstrating that the
      peripheral field boundaries were rod mediated. The patient with CSNB showed an
      isopter in response to the long-wavelength stimulus that was considerably larger
      than that in response to the short-wavelength stimulus, both stimuli reported as
      chromatic, showing that the cone system determined peripheral thresholds for both
      stimuli. In 2 patients with RP, we observed a mixed pattern of cone or rod system
      detection of the chromatic stimuli. The peripheral isopters were rod mediated,
      whereas the cone system determined the central field isopters. In an Usher's
      syndrome patient, cones mediated both the peripheral and the central field
      isopters. CONCLUSIONS: A 2-color dark-adapted Goldmann perimetric procedure was
      able to determine whether the VF isopters were rod or cone mediated in 5 patients
      with various forms of retinal disease.

PMID- 15177977
TI  - Long-term follow-up results of observation or radiation for conjunctival
      malignant lymphoma.
AB  - PURPOSE: To elucidate the long-term prognosis of biopsy-proven malignant lymphoma
      of conjunctival origin after a treatment option of observation or radiation.
      DESIGN: Prospective noncomparative interventional case series. PARTICIPANTS:
      Thirteen patients with extranodal marginal zone B-cell lymphoma of mucosa
      associated lymphoid tissue (MALT) of conjunctival origin. METHODS: In the 11-year
      period from 1992 to 2002, 13 consecutive patients (7 female and 6 male) with ages
      ranging from 32 to 68 years (mean, 57) who showed malignant lymphoma of
      conjunctival origin were enrolled in the study. Histopathological and
      immunohistochemical studies of biopsy specimens of the conjunctival lesions
      proved extranodal marginal zone B-cell lymphoma of MALT in all patients. At the
      initial visit, magnetic resonance imaging (MRI) showed no orbital tumors, and
      gallium scintigraphy demonstrated no systemic involvement. The patients chose
      observation or radiation after the biopsy. MAIN OUTCOME MEASURES: Clinical
      disappearance of the conjunctival lymphoma lesions. RESULTS: Five patients chose
      30-Gy radiation to the remaining conjunctival lesions after the biopsy, whereas
      the other 8 patients were simply observed without administration of any
      medication. During the follow-up, ranging from 1 to 11 years (mean, 5.4), 7 of
      these 8 patients without radiation showed spontaneous regression of the
      conjunctival lesions 1 to 5 years after the biopsy. Yearly MRI of the orbit and
      gallium scintigraphy disclosed no lesions in any of the patients. CONCLUSIONS: A
      large fraction of patients with MALT lymphoma of conjunctival origin had
      spontaneous regression after the biopsy. Follow-up without radiation is an option
      for patients with MALT lymphoma of conjunctival origin after the pathologic
      diagnosis by biopsy.

PMID- 15177976
TI  - Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of
      birth cohort analysis.
AB  - PURPOSE: To assess change in incidence of retinoblastoma in Northern Europe and
      to compare commonly used methods for calculating its incidence against birth
      cohort analysis. DESIGN: Retrospective cohort study. PARTICIPANTS: Individual and
      pooled data of 291 Swedish and 174 Finnish children diagnosed with retinoblastoma
      between 1958 and 1998. MAIN OUTCOME MEASURES: Incidence per 1 million children
      younger than 5 years of age (37 812 035 person- years at risk) and per 100 000
      live births (7 152 265 live-born children at risk). METHODS: Data were from
      Swedish and Finnish Cancer Registries and corresponding national referral centers
      for retinoblastoma. Incidence was calculated both by standard analysis per
      children younger than 5 years of age and per live births, and by birth cohort
      analysis. Curves were smoothed with robust, locally weighted regression. Linear
      regression was used to fit pooled data. RESULTS: The number of new retinoblastoma
      cases per year ranged from 0 to 13 (1-13 per birth cohort) in Sweden and from 0
      to 10 in Finland (1-9 per birth cohort). The mean incidence was 11.8 (95%
      confidence interval [CI], 10.5-13.1) and 11.2 (95% CI, 9.4-13.0) per 1 million
      children younger than 5 years of age in Sweden and Finland, respectively, and 6.7
      (95% CI, 5.9-7.5) and 6.2 (95% CI, 5.3-7.2) per 100 000 live births,
      respectively. Analysis based on year of diagnosis suggested moderate increase in
      incidence since 1990, but by birth cohort analysis, incidence rates were stable
      for both countries. The pooled incidence by birth cohort was 6.0 (95% CI, 5.4
      6.6) per 100 000 live births, corresponding to 1 in 16 642 (95% CI, 15 105-18
      528) live births. CONCLUSIONS: The data suggest that the incidence of
      retinoblastoma is stable in Northern Europe. Analysis based on birth cohort is
      recommended for future epidemiologic studies, because it minimizes the effect of
      variable age at diagnosis of this developmental cancer and results in less
      variable incidence rates than standard analysis based on year of diagnosis.

PMID- 15177978
TI  - A 3-dimensional ultrasound C-scan imaging technique for optic nerve measurements.
AB  - PURPOSE: To evaluate the use of 3-dimensional ultrasound C-scan imaging for optic
      nerve diameter measurements. DESIGN: Prospective observational case series.
      PARTICIPANTS: Thirty-eight normal eyes of 32 healthy adults. METHODS: Coronal C
      scans of 38 normal optic nerves were imaged 3 mm behind the globe. MAIN OUTCOME
      MEASURES: Optic nerve sheath diameter (ONSD) and optic nerve diameter (OND).
      RESULTS: Mean ONSD was 4.8 mm (range: 3.9-5.9; SD 0.6), whereas mean optic OND
      was 1.9 mm (range: 1.8-2.1; SD 0.1). Mean ONSDs were 4.9 mm (male), 4.5 mm
      (female), 5.0 mm (subjects younger than 50 years), and 4.6 mm (subjects 50 and
      older). CONCLUSION: Coronal C-scans generated from 3-dimensional ultrasound can
      be used to measure the optic nerve diameters in adult eyes.

PMID- 15177979
TI  - Orbital varices, cranial defects, and encephaloceles: an unrecognized
      association.
AB  - PURPOSE: To highlight an apparently unreported association between orbital
      varices and malformations of the cranial skeleton with or without abnormalities
      of the underlying cerebral parenchyma. DESIGN: Retrospective, noncomparative
      review of case notes and radiologic imaging. PARTICIPANTS: Three hundred ten
      patients attending the Orbital Clinic at Moorfields Eye Hospital, London, with a
      diagnosis of low-pressure, low-flow orbital venous anomalies. METHODS: All
      available orbital imaging for patients with orbital venous anomalies was
      examined. For those with defects of the cranial base, the radiologic
      characteristics were noted and the clinical details were reviewed. MAIN OUTCOME
      MEASURES: The presence and type of orbital roof or medial wall defects and
      associated nasal or other cranial anomalies. RESULTS: Imaging was adequate for
      review in 222 of 310 patients (72%), and anomalies of the neighboring cranium or
      cerebral structure were found in 10 of 222 patients (4.5%). In the group with
      cranial anomalies, the proportion of men (7/10; 70%) did not significantly differ
      from that in the group with varices but without cranial anomalies (93/212; 44%; P
      = 0.19, Fisher exact test). Orbital varices were associated with 3 types of
      cranial anomaly: major midline encephaloceles (type I anomaly; 4 cases), large
      superomedial defects of the orbital wall (type II; 3 cases), or defects of the
      greater wing of the sphenoid (type III; 3 cases). CONCLUSIONS: Clinicians should
      be aware of the possibility of significant cranio-orbital or cranionasal
      anomalies in patients with orbital venous anomalies; these anomalies can vary
      from minor defects in the cranial base to large encephalomeningoceles. This rare
      association should not be overlooked when orbital varices become markedly
      inflamed, because intranasal encephaloceles are a known predisposition to
      recurrent meningitis.

PMID- 15177980
TI  - Isotretinoin-associated intracranial hypertension.
AB  - PURPOSE: To evaluate the association between intracranial hypertension (IH) and
      isotretinoin use. DESIGN: Observational case series. METHODS: In this
      retrospective study, approximately 1950 case reports of adverse ocular side
      effects related to isotretinoin were received from spontaneous reporting systems.
      Reports were evaluated as to the occurrence of IH with isotretinoin use. A survey
      was mailed to all members of the North American Neuro-ophthalmology Society
      soliciting their opinions on whether isotretinoin caused IH. RESULTS: One hundred
      seventy-nine reports of IH were associated with isotretinoin use. The mean time
      from drug exposure to IH diagnosis was 2.3 months. There were 6 cases of positive
      rechallenge; 5 new cases are reported here, along with 1 previously published
      report. Of neuro-ophthalmologists surveyed (62% response rate), 6% believed an
      association between IH and isotretinoin use was certain; 32%, probable; 52%,
      possible; and 10%, unlikely. Twelve respondents (4%) had personally seen one or
      more cases of positive rechallenge with isotretinoin causing IH. CONCLUSIONS:
      Based on the number and pattern of rapid IH onsets after isotretinoin exposure
      and the 6 cases of positive rechallenge, along with the probable similarity in
      metabolic pathways of this agent and vitamin A (a known cause of IH), it seems
      certain that there is a direct correlation between IH and isotretinoin use.

PMID- 15177981
TI  - Hypopyon uveitis and relapsing polychondritis: a report of 2 patients and review
      of autoimmune hypopyon uveitis.
AB  - OBJECTIVE: To report hypopyon uveitis as an ophthalmic finding associated with
      relapsing polychondritis. DESIGN: Interventional case reports. PARTICIPANTS: Two
      patients with hypopyon uveitis as a manifestation of relapsing polychondritis.
      METHODS: Complete ocular and systemic examinations as well as chart reviews were
      performed for 2 patients with hypopyon uveitis as a manifestation of relapsing
      polychondritis at presentation. MAIN OUTCOME MEASUREMENTS: Clinical observation
      and response to treatment in 2 patients with hypopyon uveitis secondary to
      relapsing polychondritis. RESULTS: A 70-year-old white male had unilateral
      hypopyon uveitis accompanied by a migratory polyarthralgia at presentation.
      Fifteen months later, he sought treatment for chondritis of the right auricle and
      was diagnosed with relapsing polychondritis. A 42-year-old white female with
      known relapsing polychondritis had bilateral hypopyon uveitis at presentation
      during a systemic relapse. Both patients had resolution of the hypopyon with
      topical and systemic steroids. CONCLUSIONS: Relapsing polychondritis should be
      considered in the differential diagnosis of sterile hypopyon uveitis. Steroids
      and systemic immunosuppression can be used to treat the uveitis.

PMID- 15177982
TI  - Strabismus surgery for adults: a report by the American Academy of Ophthalmology.
AB  - OBJECTIVE: To describe the effectiveness and safety of surgical treatment of
      adult patients with strabismus, and to review the reported functional benefits
      and complications of strabismus surgery for adults. METHODS: A literature search
      was conducted in September 2001. It was repeated and updated in April 2003, with
      retrieval of relevant citations. Panel members reviewed the articles and rated
      them according to their relevance to the topic and methodology. RESULTS: The
      literature search identified 49 reports that describe the surgical treatment of
      strabismus in adult patients and meet predetermined review criteria. Of these
      reports, 2 were of randomized controlled trials, and 1 addressed the primary
      objective of this review. In this randomized study of adults with strabismus,
      direct comparison of surgical correction with botulinum toxin A chemodenervation
      indicated that surgical treatment was superior to botulinum toxin A in realigning
      the eyes (76.9% vs. 29.4%, P = 0.027). Several large case series of adults with
      strabismus (level III evidence) with successful surgical realignment rates of 68%
      to 85% have been reported. Functional benefits of surgical treatment are reported
      in many patients. These include elimination of diplopia, development of binocular
      fusion, expansion of binocular visual fields, and improvement of head position.
      Surgical complications, including new, postoperative diplopia (1%-14%) or scleral
      perforation (0.8%-1.8%), occur in a minority of patients. Unplanned reoperations
      (subsequent strabismus procedures that were not anticipated as part of a staged
      treatment) were needed in up to 21% of patients in large case series of comitant
      strabismus, and in up to 50% of patients with thyroid ophthalmopathy.
      CONCLUSIONS: Despite the paucity of level I evidence from randomized controlled
      trials, the existing literature suggests that surgical treatment of adults with
      strabismus is safe and effective in improving ocular alignment. In many cases it
      improves visual function, based largely on level III evidence. Risks include
      unplanned reoperation, postoperative diplopia, and scleral perforation.
      Additional level I studies of surgical treatment of adult patients would help to
      document the effectiveness and substantiate the safety of this treatment.

PMID- 15177983
TI  - Clear lens extraction for myopia.

PMID- 15177984
TI  - LASIK and PRK malpractice predictors.

PMID- 15177986
TI  - LASIK and PRK malpractice predictors.

PMID- 15177988
TI  - Lasik and PRK malpractice predictors.

PMID- 15177989
TI  - Forensic psychiatric evaluation of perpetrators of crimes committed during the
      war in Croatia (1991-1995).

PMID- 15177990
TI  - Claims of crime-related amnesia in forensic patients.

PMID- 15177991
TI  - Psychological support for the concept of psycholegal competencies.

PMID- 15177992
TI  - PCL-R psychopathy and its relation to DSM-IV Axis I and II disorders in a sample
      of male forensic psychiatric patients in The Netherlands.

PMID- 15177993
TI  - Assessing the verity of children's allegations of abuse: a psychiatric overview.

PMID- 15177994
TI  - Accuracy of eyewitness memory for persons encountered during exposure to highly
      intense stress.

PMID- 15177995
TI  - Diagnostic validity and psychiatric expert testimony.

PMID- 15177996
TI  - Testing doctors' ability to assess patients' competence.

PMID- 15177997
TI  - Prevention of tissue injury in an ascending mouse model of chronic pyelonephritis
      -role of free radical scavengers.
AB  - The role of free radical scavengers in preventing the tissue injury using a non
      obstructive, ascending mouse model for chronic pyelonephritis was assessed. The
      parameters taken into consideration are Luminol Dependent Chemiluminescence
      (LDCL), histopathology and some biochemical investigations. We have observed that
      both catalase and Dimethyl-Sulfoxide (DMSO, free radical scavengers) were able to
      prevent the free radical mediated tissue injury and ultimate renal scarring,
      irrespective of the bacterial strain studied.

PMID- 15177998
TI  - B cell and macrophage response in chicks after oral administration of Salmonella
      typhimurium strains.
AB  - Despite the fact that, in a number of countries, vaccination programmes are
      extensively used to control Salmonella infection in poultry, information on the
      immune mechanisms, especially the cellular response, is still needed. The aim of
      the study was to characterise the B cell and macrophage response in caecum (IgA+,
      IgM+, IgG+ cells, macrophages), bursa of Fabricius (IgM+ cells, macrophages), and
      spleen (IgM+ cells) of chicks after oral administration of a non-attenuated
      Salmonella (S.) typhimurium wild-type strain (infection) or an attenuated
      commercial live S. typhimurium vaccine strain (immunisation) to day-old chicks as
      compared to non-treated control birds using immunohistochemistry and image
      analysis. In caecum, higher counts of IgM-secreting cells were detected in
      infected animals compared with the controls from day 5 until day 12 of age. In
      contrast, in treated groups, IgA-secreting cells were found in higher numbers
      only between day 8 and 12 of age. Infected birds showed a higher number of IgA+
      cells in spleen and bursa of Fabricius compared to the controls. In the bursa of
      Fabricius of immunised and infected birds, a depletion of strongly stained IgM+
      cells and macrophages was established between day 5 and 9 indicating a possibly
      special and independent role of this organ during the immunological reaction
      against Salmonella organisms. The results suggest that IgM- and IgA-secreting
      cells are of importance in the caecal immune response of chickens against
      Salmonella strains. Immunised chickens always showed a weaker immune reaction
      compared to infected animals. Present findings regarding the B cell reaction
      within avian caeca prove a participation of both humoral and cellular immunity in
      defence against Salmonella strains. Immunohistochemical examination of the
      cellular response (B cells and macrophages) in relevant organs of chickens may be
      an important tool to evaluate the immunogenic characteristics of potential
      Salmonella live vaccine candidates.

PMID- 15177999
TI  - Staphylococcus aureus: study of genomic similarity of strains isolated in
      veterinary pathology using amplified fragment length polymorphism (AFLP).
AB  - Staphylococcus aureus is a widespread pathogen causing infections in different
      animal species. The extensive use of antibiotics, particularly methicillin,
      causes the rise of antibiotic-resistant strains (MRSA). In order to verify the
      epidemiology and genetic relatedness among MRSA and sensible strains (MSSA), an
      accurate fingerprinting technique, the amplified fragment length polymorphism
      (AFLP), was carried out. The isolates were cultured, subdivided on MRSA and MSSA
      and submitted for the genomic DNA extraction that was utilized for AFLP. The data
      were analysed for genetic similarity using the Dice coefficient. The results of
      genomic analysis among MRSA and MSSA and within them revealed that the major
      component of variation was due to variation within strains (82.12%), while
      variance among strains was lower (17.88%). The low level of genomic similarity
      found among S. aureus strains implies high level of genetic diversity. Different
      similarity was found as well in all strains independently of the source.

PMID- 15178000
TI  - Cell-mediated immune responses to a killed Salmonella enteritidis vaccine:
      lymphocyte proliferation, T-cell changes and interleukin-6 (IL-6), IL-1, IL-2,
      and IFN-gamma production.
AB  - Two experimental approaches were used to investigate the immunological responses
      of chickens to a commercial killed Salmonella enteritidis (SE) vaccine. In the
      first, the effects of host age on antigen-specific proliferative responses and
      cytokine production were examined. Compared with non-vaccinated controls, 4-wk
      old vaccinated chickens showed higher proliferation to SE LPS and flagella. The
      lymphoproliferation responses to these antigens of 8-mo-old vaccinated chickens
      were not different compared to the non-vaccinated controls. Increased production
      of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) by antigen-stimulated
      splenocytes following vaccination were, in general, more often observed in 4-wk
      old compared with 8-mo-old chickens, whereas serum levels of these cytokines were
      consistently higher in the vaccinated birds compared with controls regardless of
      age. The second set of experiments were designed to determine the effects of SE
      vaccination on mitogen- or antigen-induced splenocyte proliferation and serum
      nitric oxide (NO) and cytokine levels. Splenocytes from vaccinated chickens
      stimulated with SE flagella showed significantly increased numbers of
      TCRgammadelta+ cells at 7 days post-vaccination compared with non-vaccinated
      birds. In contrast, no differences were noted with CD4+, CD8+, or TCRalphabeta+
      cells at any time points examined. Higher levels of NO production were observed
      following stimulation with SE flagella at 4, 7, 11, and 14 days after SE
      vaccination while serum levels of IFN-gamma, IL-1, IL-6, and IL-8 were elevated
      only at day 7 post-vaccination. In conclusion, younger chickens mounted a more
      robust antigen-specific immune response to the SE vaccine compared with older
      birds and vaccination induced not only T-cell-mediated responses but also host
      innate and pro-inflammatory responses.

PMID- 15178001
TI  - Isolation and characterisation of an Indian strain of Mycoplasma mycoides subsp.
      mycoides type LC from a case of caprine arthritis.
AB  - Isolation and characterisation of an Indian strain of Mycoplasma mycoides subsp.
      mycoides LC from a case of caprine arthritis is reported in the study. The
      isolate was identified based on biochemical, digitonin sensitivity and growth
      inhibition tests. The virulence of the organism was studied by pathogenicity test
      in mice and goat. The antigenic and genomic profile of the isolate was compared
      with that of the standard strain (Y-Goat). Using different sets of primers,
      polymerase chain reaction was employed for rapid detection of the strain.

PMID- 15178002
TI  - Three D structures of chitosan.
AB  - Crystal structures of two polymorphs of chitosan, tendon (hydrated) and annealed
      (anhydrous) polymorphs, have been reported. In both crystals, chitosan molecule
      takes up similar conformation (Type I form) to each other, an extended two-fold
      helix stabilized by intramolecular O3-O5 hydrogen bond, which is also similar to
      the conformation of chitin or cellulose. Three chitosan conformations other than
      Type I form have been found in the crystals of chitosan-acid salts. In the salts
      with acetic and some other acids, called Type II salts, chitosan molecule takes
      up a relaxed two-fold helix composed of asymmetric unit of tetrasaccharide. This
      conformation seems to be unstable because no strong intramolecular hydrogen bond
      like Type I form. Type II crystal changes to the annealed polymorph of chitosan
      by a spontaneous water-removing action of the acid. Chitosan molecule in its
      hydrogen iodide salt prepared at low temperature takes a 4/1 helix with
      asymmetric unit of disaccharide. The fourth chitosan conformation was found to be
      a 5/3 helix in chitosan salts with medical organic acids having phenyl group such
      as salicylic or gentisic acids. Similar conformation of chitosan molecule in the
      aspirin (acetylsalicylic acid) salt was suggested by a solid-sate NMR
      measurement.

PMID- 15178003
TI  - Mechanical properties of UV irradiated rat tail tendon (RTT) collagen.
AB  - The mechanical properties of RTT collagen tendon before and after UV irradiation
      have been investigated by mechanical testing (Instron). Air-dried tendon were
      submitted to treatment with UV irradiation (wavelength 254 nm) for different time
      intervals. The changes in such mechanical properties as breaking strength and
      percentage elongation have been investigated. The results have shown, that the
      mechanical properties of the tendon were greatly affected by time of UV
      irradiation. Ultimate tensile strength and ultimate percentage elongation
      decreased after UV irradiation of the tendon. Increasing UV irradiation leads to
      a decrease in Young's modulus of the tendon.

PMID- 15178004
TI  - 4-Chlorobutanol induces unusual reversible and irreversible thermal unfolding of
      ribonuclease A: thermodynamic, kinetic, and conformational characterization.
AB  - The thermal denaturation of ribonuclease A has been studied by differential
      scanning calorimetry in the presence of 4-chlorobutan-1-ol. The thermal
      transitions were observed to be reversible at pH 5.5 in the presence of low
      concentration (up to 50 mM) of the alcohol, irreversible in the intermediate (50
      mM < c < mM) and again reversible in the presence of 250 mM and higher
      concentrations of 4-chlorobutan-1-ol. In the presence of 50 mM 4-chlorobutan-1
      ol, ribonuclease A is present in two conformational states unfolding at different
      temperatures. The reversible thermal transitions have been fitted to a two-state
      native-to-denatured mechanism. Irreversible thermal transitions have been
      analyzed according to two-state irreversible native-to-denatured kinetic model.
      Using the irreversible model, rate constant as a function of temperature and
      energy of activation of the irreversible process have been calculated. Circular
      dichroism and fluorescence spectroscopic results corroborate the DSC observations
      and indicate a protein conformation with poorly defined tertiary structure and
      high content of secondary structure in the presence of 50 mM 4-chlorobutan-1-ol
      at a temperature corresponding to the second transition. Similar results have
      been observed at pH 3.9.

PMID- 15178005
TI  - Influence of the ionic strength on the heat-induced aggregation of the globular
      protein beta-lactoglobulin at pH 7.
AB  - The influence of the ionic strength on the structure of beta-lactoglobulin
      aggregates formed after heating at pH 7 has been studied using static and dynamic
      light scattering. The native protein depletion has been monitored using size
      exclusion chromatography. Above a critical association concentration (CAC) well
      defined clusters are formed containing about 100 monomers. The CAC increases with
      decreasing ionic strength. The so-called primary aggregates associate to form
      self similar semi-flexible aggregates with a large scale structure that is only
      weakly dependent on the ionic strength. The local density of the aggregates
      increases with increasing ionic strength. At a critical gel concentration, Cg,
      the size of the aggregates diverges. Cg decreases from 100 g/l without added salt
      to 1 g/l at 0.4M NaCl. For C > Cg the system gels except at high ionic strength
      close to Cg where the gels collapse under gravity and a precipitate is formed.

PMID- 15178006
TI  - Interfacial tension of aqueous biopolymer mixtures close to the critical point.
AB  - Proteins and polysaccharides, being the main constructional materials in many
      biological structures, have a limited compatibility in aqueous media. At
      sufficiently high concentrations, they form water-in-water emulsions. Interfacial
      tension is an important parameter in such systems since it is a controlling
      factor in the morphology development during processing. In this work a rheo
      optical methodology, based on the analysis of small angle light scattering (SALS)
      patterns during fibril break-up, is used to study the interfacial tension of
      water-sodium caseinate-sodium alginate systems located close to and relatively
      far from the binodal. The interfacial tension close to the critical point was
      approximately 10(-8) N/m, and it increased considerably, to a value of up to 5.2
      x 10(-6) N/m farther from the critical point. For the scaling of the interfacial
      tension with the density difference between the phases, a scaling exponent of 3.1
      +/- 0.3 was found, in agreement with the critical mean-field scaling exponent of
      3.

PMID- 15178007
TI  - Antitumor activity of levan polysaccharides from selected microorganisms.
AB  - Levans were isolated from the cultures of Gluconoacetobacter xylinus (G-levan; Mw
      = 40,000), Microbacterium laevaniformans (M; Mw = 710,000), Rahnella aquatilis
      (R; Mw = 380,000), and Zymomonas mobilis (Z; Mw = 570,000). The levans were
      composed mainly of fructose residues when analyzed by TLC and HPLC, and their
      main backbones were beta-(2,6)-linkages with beta-(2,1)-branches by GC-MS and
      NMR. In the in vitro antitumor activity test of the levans against eight
      different tumor cell lines, relatively stronger activity was observed from the
      SNU-1 and HepG2. The M- (52.54-62.05%) and R-levan (52.15-58.58%) showed the
      significantly high activity against SNU-1, while M-levan showed the highest
      (49.93-61.82%) activity against HepG2. During the in vivo analysis of inhibitory
      activity of the levans against Sarcoma-180 growth, M-, R- and Z-levans showed
      strong antitumor activity (average 66%) but G-levan (42%) had significantly lower
      activity.

PMID- 15178008
TI  - Non-equilibrium processes of interchain association induced by Cs+ ions in kappa
      carrageenan aqueous solutions.
AB  - We present preliminary results of the investigation of interchain association
      processes induced by Cs+ ions in kappa-carrageenan aqueous solution. The
      solutions contained variable amounts of NaI and CsI, under the condition that the
      total concentration of 1:1 electrolyte was 0.1M. The associative processes were
      observed by static light scattering under isothermal conditions (at T = 25
      degrees C), after cooling molecularly dispersed solutions obtained at high
      temperature (80 degrees C). It was found that, under all the investigated
      conditions of polymer concentration (from 0.2 to 2 g l(-1)) and ionic
      composition, the onset of time-dependent association fails to lead to an
      equilibrium, but proceeds up to physical gelation of the associating system.
      Depending on the experimental variables, however, the gelation threshold may take
      up to several days to be achieved.

PMID- 15178009
TI  - Gelatin-alpha olefin sulfonate interactions studied by dynamic light scattering.
AB  - Dynamic light scattering (DLS) measurements were performed to study the binding
      of anionic surfactant alpha olefin sulfonate (AOS) to gelatin chains at various
      NaCl concentrations at 30 degrees C in aqueous sodium phosphate buffer (pH = 6.8)
      solutions. The surfactant concentration was varied from 0 to 80 mM and the NaCl
      concentrations chosen were 0.025, 0.05, and 0.1 M. AOS exhibited electrostatic
      binding to the positively charged sites of the polypeptide chain resulting in
      considerable reduction in its hydrodynamic radius up to critical micellar
      concentration (cmc = 8 mM for no salt, 0.01 and 0.025 M, and 5 mM for 0.05 M and
      2 mM for 0.1 M solutions). The correlation function revealed the presence of two
      types of structures above cmc; namely the micelles of AOS and gelatin-AOS micelle
      complexes. The micellar radii (Rm), the effective gelatin-surfactant complex
      radii (Rc), have been determined as a function of salt concentration. No critical
      aggregation concentration (cac) was observed. The inter-gelatin-surfactant
      complex (kD1) and inter-micellar interactions (kD2), were determined by fitting
      the concentration dependence of Rm and Rc to a virial expansion in reduced
      concentration (c - cmc), which are compared. While kD1 showed strong ionic
      strength dependence, kD2 remained invariant of the same. The protein to
      surfactant binding ratio was found to be smaller than normal. Results have been
      discussed within the framework of the necklace-bead model of polymer-surfactant
      interactions.

PMID- 15178010
TI  - Structural plasticity associated with the beta-propeller architecture.
AB  - The beta-propeller architecture observed in protein tertiary structure and
      classified into the five different types according to number of 'blades' (or beta
      sheets) and a sixth type classified according to the secondary structure
      composition of the blades (the beta beta alpha beta-molecular unit) is
      characterized by variations (or plasticity) in the structure. These correspond to
      the number of beta-strands associated with the blade, the number of amino acid
      residues associated with equivalent beta-strands in the different blades and the
      presence of alpha-helices and twisted beta-strands. We have generated a beta
      sheet associated beta-strand pattern that may be important for protein structure
      prediction and modeling. Analysis of the beta-propellers extracted primarily from
      the SCOP database revealed there are 179 beta-propellers. The examination of the
      secondary structure corresponding to the beta-propeller using PDBsum that was
      useful to define the beta-sheet associated beta-strand pattern, combined with
      visualization on graphics display revealed structural plasticity associated with
      the beta-propeller architecture. Particularly, the type 6- and 7-bladed beta
      propellers known to be associated with sequence and functional diversity are more
      common and associated with relatively more structural variations compared to the
      other beta-propeller types.

PMID- 15178011
TI  - Anti-herpes simplex virus activity of sulfated galactans from the red seaweeds
      Gymnogongrus griffithsiae and Cryptonemia crenulata.
AB  - This study presents the chemical composition and antiviral activity against
      herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) of sulfated galactan crude
      extracts and main fractions obtained from two red seaweeds collected in Brazil,
      Gymnogongrus griffithsiae and Cryptonemia crenulata. Most of the eighteen tested
      products, including homogeneous kappa/iota/nu carrageenan and DL-galactan hybrid,
      exhibited antiherpetic activity with inhibitory concentration 50% (IC50) values
      in the range 0.5-5.6 microg/ml, as determined in a virus plaque reduction assay
      in Vero cells. The galactans lacked cytotoxic effects and showed a broad spectrum
      of antiviral activity against HSV-1 and HSV-2. No direct virus inactivation was
      observed after virion treatment with the galactans. The mode of action of these
      compounds could be mainly ascribed to an inhibitory effect on virus adsorption.
      Most importantly, a significant protection against a murine vaginal infection
      with HSV-2 was afforded by topical treatment with the sulfated galactans.

PMID- 15178012
TI  - Interaction between alginates and manganese cations: identification of preferred
      cation binding sites.
AB  - Algal and bacterial alginates have been studied by means of 13C NMR spectroscopy
      in presence of paramagnetic manganese ions in order to reveal the nature of their
      interaction with bivalent cations. It is found that the mannuronate blocks bind
      manganese cations externally near their carboxylate groups, while guluronate
      blocks show the capability to integrate Mn2+ into pocket-like structures formed
      by adjacent guluronate residues. In alternating mannuronate-guluronate blocks,
      manganese ions preferentially locate in a concave structure formed by guluronate
      mannuronate pairs. Partial acetylation of the alginate generally reduces its
      capability to interact with bivalent cations, however, the selectivity of the
      binding geometry is conserved. The results may serve as a hint for the better
      understanding of the alginate gelation in presence of calcium ions.

PMID- 15178013
TI  - Dynamic light scattering studies of irradiated kappa carrageenan.
AB  - Investigation of the dynamic behavior of irradiated kappa carrageenan (in KCl) as
      a function of irradiation dose and temperature was done by dynamic light
      scattering (DLS). The intensity correlation function (ICF) shifted towards
      shorter relaxation times with increasing radiation dose as a result of
      radiolysis. The characteristic decay time distribution function, G(gamma),
      indicates the presence of fast and slow mode peaks respectively at around 0.1-10
      ms and 100-1000 ms. A peak broadening of the fast mode peak in G(gamma) appeared
      with decreasing temperature, indicating that coil-to-helical conformational
      transition took place. The conformation transition temperature (CTT) decreased
      with increasing radiation dose. No transition was observed for kappa-carrageenan
      irradiated at 200 kGy. A new faster relaxation mode appeared at around 0.1-1 ms
      at temperatures below the CTT. This peak is found in kappa-carrageenan irradiated
      at doses exclusively between 75 and 175 kGy. The peak height of this mode is
      largest at 100 kGy which corresponds to the optimum biologic activity of kappa
      carrageenan reported previously.

PMID- 15178014
TI  - Wet spinning of silk polymer. I. Effect of coagulation conditions on the
      morphological feature of filament.
AB  - Regenerated silk fibroin (SF) filaments were prepared by the wet spinning
      technique. The effect of coagulation conditions, such as coagulant type and
      coagulation temperature, was investigated on the morphological feature of SF
      filaments and a theoretical approach was also performed to understand the
      coagulation phenomena. SEM observation revealed that as the R group size of
      alcoholic coagulant (ROH) increased, the cross-sectional shape deviated more from
      a circular form. This is attributed to the fact that as the R group size
      increased, the mass transfer rate difference increased, but the coagulation rate
      decreased due to a reduced diffusion rate. Most non-alcoholic coagulants
      exhibited this circular cross-sectional shape, except dioxane, which showed a
      clover shape. As the coagulation bath temperature increased, the cross-section
      deviated less from a circular form, with the reduction of fiber diameter. When
      methanol/water mixture was used as a coagulant, an ellipse or a dog-bone shape
      was obtained with higher water content in methanol, which was attributed to the
      decrease of coagulation rate. Although methanol exhibited a positive value of
      mass transfer rate difference, a circular shape of cross-section was obtained due
      to the density difference of the coagulated and uncoagulated parts in the
      coagulating SF filament.

PMID- 15178015
TI  - Wet spinning of silk polymer. II. Effect of drawing on the structural
      characteristics and properties of filament.
AB  - Regenerated silk fibroin (SF) filaments were prepared by the wet spinning
      technique. The rheological behavior of the SF dope solution prepared with formic
      acid was examined and the drawing effect on the structural characteristics and
      mechanical properties of SF filament was comparatively studied with those of
      natural silk fiber. SF dope exhibited shear thinning, but, as the dope
      concentration increased, the effect of shear thinning decreased, an indication
      that a higher concentration of dope solution will result in good spinnability.
      Wet-spun SF filaments exhibited a uniform and circular cross-sectional shape and
      dense morphology under SEM observation. X-ray diffraction (XRD) results revealed
      that the crystallinity of wet-spun regenerated filaments was hardly affected by
      the draw ratio, whereas the crystalline and amorphous orientation of regenerated
      SF filament showed different features depending on the drawing. The crystalline
      orientation of regenerated filaments increased with an increase of draw ratio and
      was lower than that of natural silk fiber. On the contrary, the amorphous
      orientation was constant throughout 1X-5X draw ratios, after an abrupt increase
      at 1X, and was higher than that of natural silk fiber. These differences in the
      orientation behaviors are attributed to the different spinning mechanisms
      involved. The tensile property was strongly dependent on the draw ratio. The
      breaking strength and elongation of the regenerated filament at 5X draw ratio
      were 2.2 g/day and 17%, respectively.

PMID- 15178016
TI  - Calorimetric studies of the action of chitosan-N-2-hydroxypropyl trimethyl
      ammonium chloride on the growth of microorganisms.
AB  - The water-soluble quaternary ammonium salt of chitosan was synthesized by
      reaction of chitosan with glycidyl trimethylammonium chloride. It was
      characterized by Fourier transform infrared and carbon-13 magnetic resonance
      spectra. Its microbiostatic effects against Staphylococcus aureus, Escherichia
      coli and Candid albicans were explored by microcalorimetry. The antimicrobial
      activity of the quaternized chitosan was stronger in alkaline condition than that
      in weak acidic condition.

PMID- 15178017
TI  - Study of the interpolyelectrolyte reaction between chitosan and alginate:
      influence of alginate composition and chitosan molecular weight.
AB  - The interpolyelectrolyte reaction between chitosan (CHI) and alginate (ALG) was
      followed by conductimetry and potentiometry. Five chitosan samples, all with
      almost the same degree of N-acetylation (DA approximately 0.20) and molecular
      weights ranging from 5 x 10(3) to 2.5 x 10(5) Da were used. The polyelectrolyte
      complex was formed using alginate samples with three different M/G values (0.44,
      1.31 and 1.96). The composition of the complex, Z (Z = [CHI]/[ALG]) resulted 0.70
      +/- 0.02, independently of the molecular weight of chitosan and the composition
      of the alginate used. The degree of complexation was 0.51 with no dependence on
      the alginate composition.

PMID- 15178018
TI  - The role of the salt concentration, proton, and phosphate binding on the thermal
      stability of wild and cloned DNA-binding protein Sso7d from Sulfolobus
      solfataricus.
AB  - The acidic pH (1.5-7.0) and ionic strength (0.005-0.2M) dependence of
      thermodynamic functions of protein Sso7d from Sulfolobus solfataricus, cloned (c
      Sso7d) and N-heptapeptide deleted [c-des(1-7)Sso7d] in glycine, and phosphate
      buffers was studied by means of adiabatic scanning calorimetry. The difference of
      proton binding was estimated from deltaHcal(pH), Td(pH), and (deltaTd/deltapH).
      It was found that a single group non-co-operative ionization with apparent pKa =
      3.25 for both cloned and deleted proteins govern the thermal unfolding of two
      different (protonated and unprotonated) forms. deltaH degrees is found to be pH
      independent and the changes in stability (deltaG degrees ) originate from changes
      in entropy terms. The apparent pKa measured at high salt concentrations decreases
      with 0.5 pH units from glycine to phosphate and the free energy of transfer at
      high ionic strength is 0.7 kcal/mol. The ionic strength dependence for the pH
      dependent D-states is very different at pH 6.0 and 1.5. This is consistent with
      the property of denatured state to be more compacted or "closed" (Dc) at neutral
      or weak acidic pH and more random or "open" (Do) at acidic pH. From the Bjerrum's
      relation was found the number of screened charges important for the unfolding
      process. The main conclusions are: (1) the thermal stability of Sso7d has
      prominently entropic nature; (2) a single non-co-operative ionization controls
      the conformations in the D-state; and (3) pH-dependent conformational equilibrium
      could be functionally important in Sso7d-DNA recognition.

PMID- 15178019
TI  - Relative potency of PAHs and heterocycles as aryl hydrocarbon receptor agonists
      in fish.
AB  - The relative potency of polycyclic aromatic compounds as aryl hydrocarbon
      receptor (AhR) agonists in fish was determined using data on CYP1A induction or
      AhR binding for 74 polycyclic aromatic hydrocarbons (PAHs) and heterocycles in
      teleost, avian, or mammalian systems from 18 published papers. Each PAH was
      assigned a fish potency factor relative to the potency of 2,3,7,8
      tetrachlorodibenzo-p-dioxin as an AhR agonist. Two and three ring unsubstituted
      PAHs were generally inactive in fish, avian, and mammalian systems.
      Benzo[k]fluoranthene and indeno[1,2,3-cd]pyrene were consistently the most potent
      PAHs, with fish potency factors of 0.001-0.002. Common structural features
      associated with higher potency PAHs included 4-6 rings containing fluoranthene or
      phenanthrene structures with an exposed bay region. These results show that PAHs
      can have similar potency as many dioxin-like PCBs, and AhR mediated toxicity
      should be considered in assessing the risks of PAHs in fish.

PMID- 15178020
TI  - Functional analysis of xenobiotic response elements (XREs) in CYP 1A of the
      European Flounder (Platichthys flesus).
AB  - The induction of hepatic cytochrome P450 1A (CYP 1A) is an important step in the
      response to contaminants such as polycyclic aromatic hydrocarbons (PAHs), and has
      been used as a biomarker of exposure in fish. Several consensus response elements
      have been identified, including eight potential xenobiotic response elements
      (XREs) in the promoter region of the European flounder cytochrome P450 1A gene.
      However not all of these sequences are necessarily active. To help elucidate the
      molecular regulation of this important gene, site directed mutagenesis and dual
      luciferase reporter gene assays were employed to characterize the consensus
      transcription factor binding sites of the CYP 1A 5' flanking region. Mutation of
      response elements situated -1103, -859, -709 and -172 bases upstream of the
      transcription start site reduced the induction to 2.75, 1.51, 3.25 and 3.05 fold,
      respectively, compared with the full-length promoter (4.0-fold induction) on
      exposure to the PAH 3-methylcholanthrene (3MC) (1.0 microM). These results
      indicate that four out of eight different XREs are functional in the control of
      CYP 1A in the flounder. The activity of these response elements adds to the
      evidence for considerable diversity in vertebrate CYP 1A regulation.

PMID- 15178021
TI  - Identification of constitutive androstane receptor cDNA in northern fur seal
      (Callorhinus ursinus).
AB  - Constitutive androstane receptor (CAR) plays a key role in the transcriptional
      regulation of CYP2B, 2C and 3A genes in response to phenobarbital, ortho-chlorine
      substituted polychlorinated biphenyls (PCBs) and sex steroids in rodents and
      human. However, studies addressing CAR are limited to certain laboratory animals
      and cell lines, and there is little information on the presence of CAR and its
      physiological and contaminant-related functions in wildlife. While aquatic
      mammals including seal species are at the top of food chain and highly
      contaminated by xenochemicals such as PCBs, induction of CYP2/3 subfamilies by
      such chemical exposure and their regulatory mechanisms have not yet been
      established in these animals. To investigate mechanisms of CAR-CYPs signaling
      pathways in aquatic mammals, we initially attempted to isolate CAR cDNA in the
      liver of northern fur seals (Callorhinus ursinus) from off-Sanriku, Japan. The
      full-length CAR cDNA had an open reading frame of 1047 bp that encodes a protein
      containing 348 amino acids. Comparison of the amino acid sequence of CAR from the
      fur seal with those from other mammalian species showed high identities with CARs
      from human (83%), monkey (82%), rat (76%) and mouse (73%), revealing a
      conservation of CAR among the mammalian species. Phylogenetic analysis
      demonstrated that the fur seal CAR was classified into CAR clade and not into
      PXR/BXR or VDR clade, suggesting the CARs would be conserved among divergent
      mammals including aquatic species. With our concomitant paper, where CAR cDNA
      isolation from the liver of Baikal seal is reported (Iwata et al., in
      preparation), to our knowledge, this is the first study on the identification of
      CAR cDNA from wildlife species.

PMID- 15178022
TI  - Identification of aryl hydrocarbon receptor 2 in aquatic birds; cDNA cloning of
      AHR1 and AHR2 and characteristics of their amino acid sequences.
AB  - The toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its related
      planar halogenated aromatic hydrocarbons (PHAHs) are mediated by the aryl
      hydrocarbon receptor (AHR). To investigate the potential sensitivity to PHAHs and
      the evolutional diversity of AHR in aquatic birds, AHR cDNAs were initially
      cloned and sequenced from the livers of a black-footed albatross (Diomedea
      nigripes) and a common cormorant (Phalacrocorax carbo). In this study, we report
      the identification of two distinct AHR paralog genes in these species. The two
      full-length AHR cDNAs from albatross were highly divergent (33% overall amino
      acid identity, and 60% identity in the N-terminal half). Phylogenetic analysis
      showed that one of them belongs to the AHR1 clade and the other one to the AHR2
      clade, which has been identified only from fishes, but not yet from mammals and
      birds. Albatross AHR1 encoded a 861-residue protein with a predicted molecular
      mass of 96.7 kDa, and in the case of albatross AHR2, 925 amino acids and 100.7
      kDa. From cormorant liver, the full-length AHR1 cDNA and the partial AHR2 cDNA
      were cloned. This result strongly suggests that bird species also possess two
      distinct AHR genes (AHR1 and AHR2). To our knowledge, this is the first report on
      the presence of an AHR2-like isoform in bird species as well as in fish.

PMID- 15178023
TI  - Cloning and analysis of the CYP1A promoter from the atlantic killifish (Fundulus
      heteroclitus).
AB  - Enzymes in the cytochrome P450 gene family 1 (CYP1) catalyze the metabolic
      activation of numerous hydrocarbon carcinogens and various natural compounds.
      CYP1 family members have been identified in several vertebrates, including fish,
      amphibians, birds, and mammals, and are inducible by aromatic hydrocarbons acting
      through the aryl hydrocarbon receptor (AHR). Together with its heterodimeric
      partner ARNT, the ligand-bound AHR binds conserved xenobiotic response elements
      (XREs) near the promoter of CYP1A and other genes. However, some populations of
      the Atlantic killifish Fundulus heteroclitus inhabiting highly contaminated sites
      are refractory to CYP1A induction by aromatic hydrocarbons. To better understand
      the mechanisms underlying this phenomenon, we are characterizing the AHR-CYP1A
      signaling pathway in this species. We report here the characterization of a
      genomic clone containing the 5(') end of the wild-type F. heteroclitus CYP1A
      gene. The 5(') coding sequence matches that of the F. heteroclitus CYP1A cDNA
      reported earlier [Comp. Biochem. Physiol. 121C (1998) 231]. Consistent with its
      inducibility by AHR agonists, the CYP1A gene contains three consensus XREs
      (5(')CACGC3(')) within 1.6 kb of the putative transcriptional start site. When
      oligonucleotides containing each of these sites were analyzed in an
      electrophoretic mobility shift assay, one of these showed a strong, TCDD
      inducible mobility shift in the presence of in vitro expressed mouse AHR protein.
      These sequence data and initial functional characterization provide a valuable
      tool for the study of genetic variations in CYP1A expression and activity in
      sensitive and resistant populations. These studies may ultimately shed light on
      the importance of P4501A activity in xenobiotic toxicity.

PMID- 15178024
TI  - Cloning of cytochrome P450 1A (CYP1A) genes from the hermaphrodite fish Rivulus
      marmoratus and the Japanese medaka Oryzias latipes.
AB  - To use two small fish Rivulus marmoratus (Cyprinodontiformes, Rivulidae) and the
      Japanese medaka Oryzias latipes (Belloniformes) as testing models in molecular
      ecotoxicology, we have cloned the cytochrome P450 1A (CYP1A) gene after screening
      of both genomic DNA libraries, and sequenced 11,863 and 7,243 bp including all
      the exons and introns with promoter regions, respectively. The Rivulus and the
      medaka CYP1A gene consisted of seven exons (including non-coding exons) with high
      homology to mammals. In the promoter region, Rivulus CYP1A gene has seven
      xenobiotic response elements (XREs) and two metal response elements (MREs), while
      the Japanese medaka CYP1A gene has six XREs and four MREs. Interestingly, medaka
      CYP1A gene has a number of MREs at the promoter, which may affect its response on
      metal exposure. We describe here the gene structure of both fish CYP1A genes.

PMID- 15178025
TI  - Agonistic effect of imidazole and triazole fungicides on in vitro oocyte
      maturation in rainbow trout (Oncorhynchus mykiss).
AB  - The purpose of the present study was to assess the in vitro effect of some
      imidazole (prochloraz, imazalil) and triazole (epoxiconazole) agricultural
      fungicides on gonadotropin-induced oocyte maturation in rainbow trout. Results
      show that prochloraz, epoxiconazole and imazalil strongly potentiated the
      induction of oocyte maturation by gonadotropin in a dose-dependent manner.
      Furthermore, 10(-5) M prochloraz and epoxiconazole alone induced oocyte
      maturation. The mRNA biosynthesis inhibitor, actinomycin d, completely inhibited
      oocyte maturation induced by fungicides, suggesting that the gonadotropin-like
      effect of these chemicals is at least dependent on de novo gene expression.

PMID- 15178026
TI  - Oestrogenic markers and reduced population fertile egg production in a sand goby
      partial life-cycle test.
AB  - Understanding the ecological significance of oestrogenic biomarker responses,
      seen in field surveys of some UK estuarine fish, requires a suitable model to
      link biochemical and reproductive effects. The sand goby (Pomatoschistus minutus)
      is a common inshore fish that has been successfully bred in laboratory aquaria.
      Juvenile sand goby were continuously exposed to 17beta-oestradiol (E2) during
      gonadal maturation, and their subsequent reproductive success investigated.
      Exposure endpoints included hepatic vitellogenin (VTG) mRNA expression and
      maturation (male nuptial colouration, sperm duct gland- and gonado-somatic
      indices (SDGSI, GSI)). Reproductive endpoints included spawning behaviour, brood
      size, fertility and population-level fertile egg production. Measured E2 exposure
      concentrations were <5 (controls), 17, 71 and 530 ngl(-1). Male maturation
      decreased with increasing E2 concentration. VTG mRNA expression increased with E2
      concentration, but not with duration of exposure. Reproductive endpoints showed
      progressive impairment with increasing E2 concentration. For most endpoints, the
      lowest observed effect concentration (LOEC) was 71 ngl(-1), and EC50s were in the
      range 87-165 ngl(-1). Pre-breeding male colouration, VTG expression and SDGSI
      were good predictors of subsequent population-level fertile egg production, but
      GSI was not. The sensitivity of oestrogenic markers in sand goby are comparable
      to those used in other species, and feral fish populations exhibiting such
      oestrogenic responses at molecular and organ levels are likely to have reduced
      fertile egg production.

PMID- 15178027
TI  - Linkages between cellular biomarker responses and reproductive success in oysters
      -Crassostrea virginica.
AB  - The purpose of these studies was to evaluate if there were relationships between
      lysosomal destabilization or glutathione concentrations and gamete viability of
      oysters, Crassostrea virginica. Oysters were collected from field sites during
      the peak spawning period (May-June) during 2001 and 2002. Lysosomal
      destabilization rates and glutathione concentrations of hepatopancreas tissues
      (e.g. digestive gland) were determined. Eggs and sperm from the same adults were
      also used to conduct embryo development assays with reference seawater collected
      from a clean site, site water, and also a range of Cd concentrations (the Cd
      exposures were used to determine if there were differences in susceptibility to
      pollutants). Baseline embryo development success (e.g. percent normal development
      when the assays were conducted with reference seawater or site water) was related
      to lysosomal destabilization, but not glutathione status. However, the
      susceptibility of embryos to metal toxicity was related to glutathione status,
      i.e., sensitivity to Cd exposures increased with decreasing glutathione levels.
      These studies support the hypotheses that there are linkages between embryo
      development success and susceptibility to pollutant stress and cellular biomarker
      responses. These kinds of effects on reproductive success could lead to subtle
      but significant long-term effects on recruitment and viability of oyster
      populations.

PMID- 15178028
TI  - Chronic toxicity of tributyltin on development and reproduction of the
      hermaphroditic snail Physa fontinalis: Influence of population density.
AB  - Tributyltin (TBT) is toxic to aquatic organisms and occurs widely in sediments
      and surface waters of American and European rivers and lakes. This study
      investigated TBT effects on development and population growth rate (r) of the
      common, hermaphroditic European freshwater snail Physa fontinalis. Egg ropes of
      similar age (1-3 days old) were exposed to a control (solvent only) and nominal
      concentrations of 0.01, 1.0 and 10 microg TBT l(-1) in triplicate. Hatching and
      mortality were recorded during 0-40 days of exposure. At day 40, 18 juveniles
      were randomly selected from each concentration (i.e., six from each test vessel)
      and individually exposed to the same concentration of TBT in 50 ml beakers. A
      cohort of 20 juveniles was allowed to continue developing in the original test
      vessels, so that individual and grouped results could be compared. Mortality and
      reproduction were recorded at 48-h intervals throughout the study period (110
      days). Abnormal embryonic development was observed at 1 and 10 microg TBT l(-1).
      Although 50% of eggs hatched at 10 microg TBT l(-1), all these hatchlings failed
      to survive. Survivorship of hatchlings was significantly reduced by TBT at 1
      microgl(-1). In general, there was a delay in egg production in isolated snails
      when compared with the grouped snails. Survival, fecundity and population growth
      rate (r) were reduced in both individual and grouped P. fontinalis at 1.0 microg
      TBT l(-1). Only a decline in r was observed in snails exposed individually to
      0.01 microg TBT l(-1).

PMID- 15178029
TI  - Teratogenesis in Fundulus heteroclitus embryos exposed to a creosote-contaminated
      sediment extract and CYP1A inhibitors.
AB  - The goal of these experiments was to explore the relationship between cytochrome
      P4501A (CYP1A) induction and the teratogenicity of sediments from the Atlantic
      Wood Industries Superfund site (Elizabeth River, VA) in Fundulus heteroclitus
      embryos. In these experiments we used embryos spawned from reference site adults
      to assess CYP1A activity and teratogenicity induced by aqueous Elizabeth River
      sediment extracts (ERSE). Embryo exposures to ERSE induced CYP1A activity and
      caused deformities, including pericardial edema, heart elongation and tail
      shortening. Co-exposures with various CYP1A inhibitors significantly decreased
      CYP1A activity and increased the teratogenicity of the sediment extract.
      Potential mechanisms for this increased toxicity are discussed herein.

PMID- 15178030
TI  - Endocrine disruption in a marine amphipod? Field observations of intersexuality
      and de-masculinisation.
AB  - Intersexuality has been found in both males and females of the marine/estuarine
      amphipod, Echinogammarus marinus, at polluted and reference sites in East
      Scotland. Polluted sites had significantly more intersex specimens than reference
      sites, however the cause of intersexuality is unclear. Discriminant analysis of
      morphometric data showed that normal male specimens from the most polluted site
      resembled pooled intersex males, suggesting that subtle endocrine disruption (ED)
      maybe occurring in these otherwise apparently normal males. The main
      discriminating character was gnathopod size, recognised to be under androgenic
      gland control. The association of distinctive morphometry with intersexuality may
      provide a new approach to biomarkers of ED in crustaceans. The opportunities for
      other novel biomarkers, for example biochemical or behavioural markers, may also
      be explored through study of intersex animals.

PMID- 15178031
TI  - Combined effects of ethanol and cinnamaldehyde in the Japanese medaka embryo
      larval assay (MELA).
AB  - The Japanese medaka (Oryzias latipes) was used in the medaka embryo-larval assay
      (MELA) to determine possible adverse developmental effects of ethanol and the
      spice component, cinnamaldehyde (CAD). Fish may be exposed to waterborne ethanol
      and a variety of natural products from non-point sources or leaks during ethanol
      use as a fuel and from point source processing plant effluents. Consumption of
      ethanol during human pregnancy is known to cause fetal alcohol syndrome (FAS), a
      collection of birth defects including craniofacial abnormalities thought to be
      caused by the generation of free radicals during ethanol metabolism by both
      alcohol and aldehyde dehydrogenase(s). Fish are also susceptible to FAS
      (Dasmahapatra et al., meeting abstract). The activity of aldehyde dehydrogenase
      is inhibited by CAD [Biochem. J. 282 (1992) 353-360; Biochem. Pharmacol. 45
      (1993) 1621-1630], and CAD is known to cause developmental abnormalities in the
      rat [Food Chem. Toxicol. 27 (1989) 781-786]. Therefore, the combined effects of
      treatment with both ethanol and CAD would be expected to produce additive or
      greater than additive effects in the MELA assay. Medaka were exposed to ethanol
      at 100 mM, CAD at 10, 1.0, 0.67 or 0.50 mM, to ethanol and CAD combined, or were
      non-treated controls. Ethanol at 100 mM was without effect. CAD alone at 10 mM
      and 1.0 mM was lethal by 1 dpf. Embryos exposed to 100 mM ethanol and 0.67 mM CAD
      exhibited cardiovascular and pigmentation defects and delayed hatching. Embryos
      exposed to 0.50 mM CAD alone had less severe cardiovascular problems as compared
      to the combined ethanol and CAD treatment. Taken together the results indicate
      that the combined effects of ethanol and CAD are greater than the individual
      effects and indicate the need to monitor effluents in fish nursery areas to
      protect natural fish populations. Supported by PHS/NIH ES07929.

PMID- 15178032
TI  - Identification of the multidrug resistance-associated protein (mrp) related gene
      in red mullet (Mullus barbatus).
AB  - Multixenobiotic resistance mechanism (MXR) in aquatic organisms is mediated by
      the activity of the P-glycoprotein (Pgp) transporter that binds and actively
      effluxes different chemicals out of cell. In addition to the Pgp, several other,
      non-Pgp transport proteins have been recently identified in different human and
      animal tissues. Given their characteristics and tissue distribution we
      hypothesized that members of the so-called multidrug resistance-associated
      protein (MRP) family may be expressed in aquatic organisms. This study attempted
      to identify MRP related genes in different tissues of several marine and
      freshwater bivalves (Mytilus galloprovincialis, Dreissena polymorpha, Anodonta
      cygnea) and fish species (Mullus barbatus, Cyprinus carpio, Salmo trutta).
      Following an alignment of known MRP1 and MRP2 human sequences, as well as the
      GenBank available mrp2 sequences from different animals, we determined highly
      conserved regions and used them to design three pairs of consensus primers. Total
      RNA was isolated, reverse transcribed to cDNA and the obtained cDNAs were PCR
      amplified with the corresponding primers. The amplified PCR products were
      sequenced and their homology compared with Pgp and MRP protein sequences from
      different species. The expression of MRP related mRNA was clearly identified only
      in liver tissue isolated from red mullet, with homologies at the protein level
      ranging from 75% to 76%. Described results clearly pointed at the possibility
      that at least in the red mullet MXR as a general defense mechanism may be
      mediated by the activities of at least two different types of transport proteins.

PMID- 15178033
TI  - Inhibition of P-glycoprotein transport: a mechanism for endocrine disruption in
      the channel catfish?
AB  - P-glycoprotein (pgp), an efflux transporter localized in a variety of tissues
      including the intestinal mucosa, renal tubules and bile canaliculi, is known to
      participate in the disposition of a variety of chemicals, including steroid
      hormones. This study examined the relationship of pgp to the movement into the
      bile of the hormone estradiol (E2), and the potential for transport interactions
      between the environmental pollutant nonylphenol ethoxylate (NPE) and E2. Biliary
      cannulated in situ-prepared isolated perfused livers were used to assess pgp
      transport function. E2, in competitive transport preparations with Rhodamine 123
      (Rho123), a pgp substrate, demonstrated significant decreases in Rho123 transport
      into bile, as did the prototypic inhibitor and substrate verapamil. [3H]E2 (0.28
      nM) transport into bile was significantly reduced with either 20 M NPE or
      verapamil. These results suggest that E2 is a substrate and/or modulator for the
      catfish biliary pgp transporter, and that NPE potentially influences biliary
      transport and excretion of E2.

PMID- 15178034
TI  - Cell responses to xenobiotics: comparison of MCF7 multi-drug- and mussel blood
      cell multi-xenobiotic-defense mechanisms.
AB  - Multi-drug resistance (MDR) in MCF7 breast cancer cells and multi-xenobiotic
      resistance (MXR) in mussel (Mytilus edulis) blood cells (MBC) are well known
      mechanisms that contribute to the decrease in intracellular concentrations of
      many unrelated but cytotoxic compounds. In the present work, we have carried out
      comparative investigations of the MDR/MXR protective mechanisms using a rapid
      colorimetric assay for cell viability and calcein accumulation for MDR/MXR
      activities. These studies were performed using cultured MCF7 and MBC before and
      after in vitro exposure to xenobiotics. Our results indicate that a 5-day
      exposure to doxorubicin or vincristine decreased calcein accumulation in MBC
      which is consistent with an induction of multi-xenobiotic resistance. The
      increase in calcein accumulation provoked by 1-h treatment with 50 microM
      verapamil was much lower in MBC when compared to the P-glycoprotein
      overexpressing MCF7 cell line. We conclude that such microplate assays could be
      used in primary cultures of MBC to estimate the effects of various chemicals on
      MXR activity.

PMID- 15178035
TI  - Fatal attraction: synthetic musk fragrances compromise multixenobiotic defense
      systems in mussels.
AB  - We studied interactions of nitromusk compounds musk ketone and musk xylene and
      polycyclic musks Galaxolide trade mark (HHCB), Celestolide trade mark (ADBI),
      Tetralide trade mark (AHTN), and Traseolide trade mark (AITI) with
      multixenobiotic resistance (mxr) transporters in gill tissue of the marine mussel
      Mytilus californianus (Conrad, 1837). A competitive substrate transport test with
      rhodamine B was used to assay modulation of transport activity by musks. All
      tested musks inhibited the transport activity in the low microm range as
      indicated by increased accumulation of rhodamine B in the tissue. Compared to
      known substrates of mxr transporters, the effective concentration range was
      similar to quinidine and about 100 times higher than verapamil. Musk ketone and
      musk xylene also inhibited efflux of rhodamine B from gill tissue which was
      loaded with the dye and subsequently incubated with these compounds. Synthetic
      musk compounds are persistent environmental pollutants in aquatic environments
      with a high potential to bioaccumulate. As potent inhibitors of mxr transporters
      they may also play a role as chemosensitizers that enable toxic mxr substrates to
      accumulate in cells of aquatic organisms.

PMID- 15178036
TI  - Environmental prognostics: is the current use of biomarkers appropriate for
      environmental risk evaluation?
AB  - Environmental Prognostics is proposed as an integrated explanatory framework for
      adverse changes in whole systems, from cells to animals to ecosystems. The aim is
      to develop such frameworks for the evaluation of "health of the environment" and
      prediction of consequences resulting from future environmental events based on
      integrating the reactions of biomarkers for cellular and physiological processes,
      through conceptual, statistical and computational modelling. These are urgently
      needed to synthesise complex information on environmental chemistry and injurious
      effects of pollutants into predicted harmful impact on health of sentinel
      animals.

PMID- 15178037
TI  - Ecosystem management bioindicators: the ECOMAN project--a multi-biomarker
      approach to ecosystem management.
AB  - The ECOMAN project was initiated from an awareness of the complexity of the
      functioning of coastal marine systems and the clear need for more pragmatic
      environmental assessment techniques linking environmental degradation with its
      causes. The aim of the project is to develop a suite of easy to use, cost
      effective and environmentally valid biological responses (biomarkers) to assess
      the general health of coastal systems, including estuaries. To achieve this aim,
      various sublethal endpoints are being measured and evaluated from a range of
      common coastal organisms showing different feeding types (filter feeding, grazing
      and predation) and habitat requirements (estuary and rocky shore) and at
      different levels of biological response (cellular, physiological and
      behavioural). This holistic integrated approach is essential to identify the full
      impact of chemical contamination on organisms, and enables the sensitivity of
      organisms to be ranked and key sentinel species for specific habitats to be
      identified.

PMID- 15178038
TI  - Exploratory data analysis of the Mediterranean component of the BEEP programme.
AB  - Work Package 3 (WP3) uses the data generated by ecotoxicologists from 11
      laboratories who sample twice per year at four sites (France, Italy, Spain and
      Greece) to conduct the Mediterranean portion of the BEEP programme (Biological
      Effects of Environmental Pollution in marine coastal ecosystems). The WP3 data
      have been compiled into files using a data base structure (one record=one
      measurement) that eases statistical analysis and importation of new data. Here we
      present our first attempt of exploratory analysis based on a subset of data from
      the campaigns in May and September of 2001 and 2002. For most biomarkers, data
      plot revealed a strong station*campaign interaction, confirmed by two-way ANOVAs.
      This could be "true" variability with biomarkers responding to contaminant inputs
      that have changed among the four sampling times. Alternatively it could betray
      analytical problems and inadequate sampling designs or a lack of stability in the
      biomarkers themselves whereby they change in random ways unrelated to
      environmental factors.

PMID- 15178039
TI  - Sub-lethal effects of metal exposure: physiological and behavioural responses of
      the estuarine bivalve Macoma balthica.
AB  - Variation in glycogen concentration, condition index (CI) and filtration activity
      were measured in the bivalve Macoma balthica buried in sediment and
      experimentally exposed to cadmium (Cd). The stress due to elevated but sub-lethal
      concentrations (300 ppb Cd) affected the overall fitness of the organism as all
      parameters monitored responded significantly. Lower concentrations tested (10, 30
      and 100 ppb) only induced a significant decrease in filtration activity, which
      may play a protective role, enabling the organism to slow down its metabolic
      activity and preserving the integrity of its reserves (reflected by stable CI and
      glycogen levels). Hence, the various endpoints selected show different
      thresholds. Our results also demonstrate that under high exposure, small
      individuals loose proportionally more glycogen per unit of weight than larger
      ones, thus confirming the higher sensitivity of small individuals to metal
      contamination. Furthermore, exposure to intermediate concentration (30 ppb) seems
      to be beneficial to the small individuals as indicated by their high CI values
      compared to the control. These results showed thus that non-sigmoidal
      concentration-response relationship and sizes of individuals should be considered
      in monitoring programmes and risk assessment.

PMID- 15178040
TI  - Apparent lack of CYP1A response to high PCB body burdens in fish from a
      chronically contaminated PCB site.
AB  - Chronic exposure to organic contaminants such as polychlorinated biphenyls (PCBs)
      can lead to the development of resistance to these chemicals, a condition
      associated with reduced response of CYP1A1, a pollutant-inducible biomarker. We
      measured CYP1A activity (ethoxyresorufin o-deethylase, EROD) and PCB
      concentrations in feral fish from the Town Branch/Mud River system (Logan County,
      KY), a stream historically contaminated with PCBs and partially remediated. As a
      first step in evaluating the possible development of resistant populations in
      this system, we measured CYP1A expression and PCB body burdens in resident fish
      from sites we previously characterized as containing biologically significant
      levels of CYP1A inducing compounds. Mean PCB concentrations in edible flesh
      ranged from 75.2 to 16.7 microg/g in fish collected from Town Branch remediated
      sites and were relatively low (1.23 microg/g) in Town Branch reference site fish.
      However, hepatic CYP1A activity was similar among individuals of most species
      collected from reference and contaminated/remediated sites. The absence of
      elevated CYP1A levels in resident fish species despite the presence of
      significant PCB body burdens may indicate these fish have developed reduced
      sensitivity to CYP1A induction, a condition associated with acquired resistance
      to toxicants.

PMID- 15178041
TI  - Detecting a field gradient of PAH exposure in decapod crustacea using a novel
      urinary biomarker.
AB  - Norwegian coastal waters are subject to PAH contamination from electrochemical
      industries such as aluminium smelters. Evidence of PAH exposure has been
      established in fish and bivalves. The present study tests the applicability of a
      novel crustacean PAH exposure biomarker to a PAH contamination gradient in the
      field (Karmsund Strait, SW Norway). Fluorescence analysis of urine samples
      collected from crabs at each site revealed 1-OH pyrene "equivalent" levels
      (indicative of pyrogenic PAH contamination) decreased with increasing distance
      from a point source of pyrogenic PAH (a large aluminium works). The assay was
      shown to be suitable for the detection of PAH exposure in wild crustacean
      populations, for discriminating between contaminated and clean sites and is also
      sufficiently sensitive to detect gradients of PAH contamination. The method
      provides a rapid, inexpensive and non-destructive measure of biologically
      available PAH in crustaceans.

PMID- 15178042
TI  - Histological and morphological alterations induced by copper exposure in
      Laeonereis acuta (Polychaeta, Nereididae).
AB  - Laeonereis acuta (Polychaeta, Nereididae) was collected in an unpolluted (UP) and
      an polluted (P) site at the Patos Lagoon estuary (Southern Brazil) and maintained
      under control conditions (UPC and PC, respectively) or exposed to waterborne
      copper (UPCu and PCu; 500 microg Cu/l), for 48 h. Four groups (aaUPC, aaPC,
      aaUPCu, and aaPCu) were also pre-exposed for 48 h to ascorbic acid (aa; 0.1 mM)
      before copper exposure. Histological and morphological alterations, as well as
      oxygen consumption changes were evaluated. Independently of the sampling site and
      the pre-exposure to the ascorbic acid, morphological abnormalities were evident
      in more than 80% of worms exposed to copper. Conspicuous histological changes
      (coeloma obliteration, cuticle separation from the epidermis, and absence of
      dorsal vessel) were also observed. In addition, PCu worms showed loss of the
      digestive epithelium and coiling behavior. Similar oxygen consumption values were
      observed in control and copper exposed worms.

PMID- 15178043
TI  - Assessment of toxicological status of a SW Mediterranean segment population of
      striped dolphin (Stenella coeruleoalba) using skin biopsy.
AB  - Various studies have revealed high concentrations of contaminants such as
      organochlorines (OCs) and heavy metals in Mediterranean cetaceans. A geographical
      trend of contamination (PCBs and DDTs) has been found for striped dolphin
      (Stenella coeruleoalba). In this study we used a non-lethal approach (skin
      biopsy) to investigate bioaccumulation of OCs, including polychlorobiphenyls
      (PCBs), DDTs, polychlorodibenzo-p-dioxins (PCDDs), polychlorodibenzofurans
      (PCDFs), trace elements (Hg, Cd, Pb) and CYP1A activity (BPMO) in nine striped
      dolphins sampled in the Aeolian area (Sicily - Italy) in summer 2002. The
      arithmetic mean value of BPMO activity in this group was 43.46 AUF/g tissue/h.
      This value is approximately 3 times and 5 times lower, respectively, than the
      value found in the Ionian and in the Ligurian groups. Skin biopsies of striped
      dolphins emerged as a suitable material for assessing the toxicological status of
      the various Mediterranean groups.

PMID- 15178045
TI  - Evaluation of fixed wavelength fluorescence and synchronous fluorescence
      spectrophotometry as a biomonitoring tool of environmental contamination.
AB  - A field study was carried out to investigate whether polyaromatic hydrocarbon
      (PAH) contamination in shore crabs (Carcinus maenas) could be measured using
      fluorescence spectrometry. Crabs were collected as part of an integrated study to
      assess PAH contamination in Southampton Water, UK. Urine was collected from crabs
      via a non-destructive technique and analysed using fixed wavelength fluorescence
      (FF) and synchronous fluorescence spectrophotometry (SFS) in order to determine
      the presence of PAH metabolites, indicative of PAH exposure. By scanning at
      wavelength pairs specific to a variety of PAH groups the fluorescence of
      metabolites was analysed and attributed to the following PAH groups;
      naphthalenes, pyrenes and benzo[a]pyrene (BAP). Naphthalene-type, pyrene-type and
      BAP-type metabolites were detected using FF and SFS techniques and two distinct
      parameters were measured; Peak Intensity and Peak Area. Results showed that crabs
      obtained near a petroleum refinery, a point source of PAH discharge, exhibited
      significantly higher PAH metabolites for all PAH groups, than at sites sampled
      along the estuary (ANOVA, p<0.05). This study highlights the effectiveness of
      using FF and SFS as a rapid and cost-effective biomonitoring tool for detecting
      PAH contamination.

PMID- 15178044
TI  - Biomarker responses to pollution in two invertebrate species: Scrobicularia plana
      and Nereis diversicolor from the Cadiz bay (SW Spain).
AB  - The clam Scrobicularia plana and the polychaete worm Nereis diversicolor were
      collected in several sites from a littoral enclosure in SW Spain. The aim of our
      study was to relate various biomarker responses in these species to a pollution
      gradient caused by untreated domestic discharges and to verify the adequacy of
      the selected species as sentinels in this habitat. The biomarkers selected were
      the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPX) and DT
      diaphorase (DT-D). In addition, the activities of cytochrome P450-dependent
      ethoxyresorufin O-deethylase (EROD) activity, the phase II detoxifying enzyme
      glutathione S-transferase (GST) and the neurotoxicity marker acetylcholinesterase
      (AChE) were measured. Metallothionein levels were selected as biomarkers of heavy
      metals exposure in both species. The results suggest a different response in the
      water filtering organism (clam) and the sediment eater (polychaete), probably as
      a consequent of different pollution exposure and that samples from the "Cano
      Sancti-Petri" were exposed to biologically active compounds that altered some of
      their biochemical responses. AChE was the most sensitive biomarker in both
      species and N. diversicolor proved to be a more robust sentinel in this
      ecosystem.

PMID- 15178046
TI  - Spatial and temporal variation of biomarkers in mussels (Mytilus
      galloprovincialis) from the Lagoon of Venice, Italy.
AB  - A multiple biomarker approach was adopted in a seasonal study carried out in the
      Lagoon of Venice, with the double aim of evaluating the natural and anthropic
      stresses influencing the biological responses of mussel (Mytilus
      galloprovincialis) and of assessing the effects due to spatial rather than
      temporal variations. Biochemical (aldehyde dehydrogenase and catalase
      activities), cellular (neutral red retention time) and physiological (survival in
      air and condition index) biomarkers were determined in mussels collected in four
      differently impacted lagoon areas. Multivariate analysis showed that samples were
      distributed mainly according to temperature and four seasonal groups were
      identified. The combination of spatial and temporal information enabled us to
      distinguish physiological variations due to natural causes from those due to
      anthropic stress, and to identify the sampling period when several biomarkers are
      less influenced by both natural and endogenous factors.

PMID- 15178047
TI  - Antioxidant efficiency and detoxification enzymes in spotted dogfish Scyliorhinus
      canicula.
AB  - Although elasmobranchs are widely distributed species, commonly found on sandy,
      gravely or muddy bottoms, several biological aspects of their metabolism still
      remain poorly investigated. In this work the efficiency of antioxidant system and
      detoxification enzymes were investigated in the coastal spotted dogfish
      Scyliorhinus canicula and in the red mullet Mullus barbatus for comparison with a
      teleost species. Organisms were sampled during a bottom trawl survey and analyzed
      for the biotransformation activity (EROD), levels of metallothioneins, catalase,
      glutathione S-transferases and total oxyradical scavenging capacity (TOSC) toward
      peroxyl radicals and hydroxyl radicals. EROD activity in the elasmobranchs was
      more than one order of magnitude lower than in the red mullets, while similar
      levels of metallothioneins were measured in these species. S. canicula showed
      significantly lower antioxidant enzymes and a more reduced efficiency in
      neutralizing *OH; on the other hand the scavenging capability toward ROO* was
      comparable in S. canicula and M. barbatus.

PMID- 15178048
TI  - Biomarker responses in Macoma nasuta (Bivalvia) exposed to sediments from
      northern San Francisco Bay.
AB  - Our study investigates biomarker responses and survival of Macoma nasuta exposed
      to sediments collected from six locations in northern San Francisco Bay.
      Biomarkers analyzed were stress proteins (hsp70) in gill, mantle and digestive
      gland, lysosomal membrane damage and histopathologic lesions. Sediments and clam
      tissues were analyzed for a comprehensive suite of heavy metals and trace organic
      pollutants. Sediment grain size and organic carbon content were determined. Clams
      accumulated metals, polyaromatic hydrocarbons (PAHs) and organochlorine
      pesticides (aldrin and p,p(')-DDT and its metabolites p,p(')-DDD and p,p(')-DDE).
      Pearson and Spearman correlation analysis revealed that mortality, hsp70 in gill
      and histopathologic lesion scores in gonads, and lysosomal membrane damage were
      significantly correlated with tissue concentrations of DDT and/or its
      metabolites. Tissue concentrations of metals, in particular nickel, chromium, and
      copper, were associated with macrophage aggregates in digestive gland and germ
      cell necrosis. Cadmium was linked to mortality and lysosomal membrane damage.

PMID- 15178049
TI  - Evaluation of toxicity in tributaries of the Mersey estuary using the isopod
      Asellus aquaticus (L.).
AB  - Increasing numbers of industrial, agricultural and natural chemicals are present
      in sewage effluent and are known to elicit toxic effects in laboratory exposures,
      but little is known of their combined sub-lethal effect in the field. In this
      study, a combination of esterase activity and ventilation rate assays was
      performed to determine the neurological and physiological function of the
      freshwater crustacean Asellus aquaticus (L.) at sites above and below a sewage
      treatment works (STW). Cholinesterase and carboxylesterase activities were
      significantly inhibited (n=8, P<0.05) and ventilation rates increased (n=8,
      P=0.0001) in A. aquaticus at STW sites compared to those from reference sites,
      indicating a decrease in neurological and physiological function. The ecological
      relevance of these findings for the population dynamics of the organisms in the
      field is discussed.

PMID- 15178050
TI  - Vitamin E co-treatment reduces Aroclor 1254-induced impairment of reproductive
      neuroendocrine function in Atlantic croaker.
AB  - We have shown previously that exposure of Atlantic croaker to a PCB mixture
      (Aroclor 1254) results in impaired reproductive neuroendocrine function. In
      addition, we have identified hypothalamic tryptophan hydroxylase (TPH), the rate
      limiting enzyme in serotonin (5-hydroxytryptamine) synthesis, as a target of PCB
      neuroendocrine toxicity. In order to further elucidate the mechanisms of PCB
      neurotoxicity, the present study investigated whether PCB-induced decrease in
      hypothalamic TPH activity resulted from degradation of the enzyme protein. Fish
      were exposed to Aroclor 1254 in the diet (0.1 mg/100 g body weight (BW)/day) for
      30 days. The PCB exposure elicited a significant decrease in hypothalamic TPH
      protein content, which could be at least partially responsible for the reduced
      TPH activity. To test whether a similar PCB exposure could cause oxidative damage
      in croaker hypothalamic tissues, we examined the formation of malondialdehyde
      (MDA) protein adducts as a marker of lipid peroxidation (LPO). The same dose of
      PCB increased the MDA-protein adduct formation in the hypothalamus. In a separate
      experiment, the role of vitamin E, an antioxidant, to prevent or decrease the
      effect of PCB on hypothalamic TPH activity and gonadal growth was examined. The
      vitamin E co-treatments (1 and 10 mg/100 g BW/day) with PCB significantly reduced
      the effects of PCB on TPH activity and gonadal growth. These results suggest
      possible involvement of oxidative processes in PCB neurotoxicity.

PMID- 15178051
TI  - An aromatase inhibitor and tamoxifen decrease plasma levels of o,p'-DDT and its
      metabolites in Nile tilapia (Oreochromis niloticus).
AB  - The objective of this study was to determine if tamoxifen or an aromatase
      inhibitor (4-hydroxyandrostenedione; 4-OHA) affected plasma concentrations of
      o,p' -DDT and its metabolites, o,p'-DDD and o,p'-DDE, in mature tilapia. Male and
      female tilapia were injected 6 times intraperitoneally with o,p'-DDT (40 mg/kg)
      alone or in combination with 4-OHA (2 mg/kg) over a 12 day period. An additional
      group of male fish was injected with tamoxifen (5 mg/kg) plus o,p'-DDT. At the
      end of the treatment period, plasma samples were extracted and analyzed by
      GC/ECD. Females injected only with o,p'-DDT had significantly higher levels of
      o,p'-DDT compared with males. Interestingly, females and males treated
      concomitantly with o,p'-DDT and 4-OHA or tamoxifen had significantly lower
      concentrations of plasma o,p'-DDT (about 50%) compared with fish treated with
      only o,p'-DDT. These initial results suggest that an interaction between
      endocrine-active compounds occurs in vivo in tilapia and may involve alterations
      in metabolism of o,p'-DDT.

PMID- 15178052
TI  - Increased toxicity of benzo(a)pyrene-7,8-dihydrodiol in the presence of
      polychlorobiphenylols.
AB  - Benzo(a)pyrene (BaP) and polychlorinated biphenyls (PCBs) often co-exist in
      contaminated environments. Polychlorobiphenylols (OH-PCBs), formed by CYP
      dependent monooxygenation of PCBs, are potent inhibitors of the glucuronidation
      of hydroxylated BaP metabolites. We hypothesized that OH-PCBs could drive the
      biotransformation of (-)BaP-7,8-dihydrodiol (BaP-7, 8-D) away from detoxication
      and towards formation of the reactive metabolite. A mixture of five OH-PCBs with
      4-6 Cl atoms was infused into isolated, perfused, biliary intact livers (n=3
      fish) removed from 3-methylcholanthrene-induced channel catfish. Controls (n=3)
      were infused with vehicle. Subsequently, [3H]-BaP-7, 8-D was infused into each
      liver and bile was collected for 1 h. The livers were taken for analysis of
      metabolites and DNA adducts. Induction status was confirmed by EROD assay. Bile
      was analyzed for metabolites. It was found that preinfusion of the mixture of OH
      PCBs reduced the extent of glucuronidation of BaP-7, 8-D and increased the
      formation of DNA adducts 5-fold over controls. GSH conjugates, tetrols and triols
      were increased in the OH-PCB-infused fish, providing further support for our
      hypothesis that if the glucuronidation were inhibited, CYP-dependent activation
      would increase. These studies suggest a mechanism for synergy of toxicity of PAH
      and PCBs.

PMID- 15178053
TI  - Effects of organochlorine compounds on cytochrome P450 aromatase activity in an
      immortal sea turtle cell line.
AB  - Many classes of environmental contaminants affect the reproductive function of
      animals through interactions with the endocrine system. The primary components
      affected by endocrine active compounds (EACs) are the steroid receptors and the
      enzymes responsible for steroidogenesis. This study sought to develop an in vitro
      model for assessing EAC effects in sea turtles by examining their ability to
      alter cytochrome P450 aromatase (CYP19) activity. Aromatase is the enzyme
      responsible for the conversion of testosterone to estradiol. This enzyme is
      critical in the sexual differentiation of reptiles which demonstrate temperature
      dependent sex determination. An immortal testis cell line GST-TS from a green sea
      turtle was grown in culture at 30 degrees C in RPMI 1640 media. The cells were
      exposed to three known aromatase inducers; dexamethasone (Dex), 8Br-cyclic AMP,
      or human chronic gonadotropin (HCG) and one aromatase inhibitor 4-androstenol
      dione (4-OHA). In addition, the GST-TS cells were exposed to 0.1-30 microM
      atrazine and 3-100 microM 4,4'-DDE. The inducing compounds that have been shown
      to increase aromatase activity in other systems failed to induce aromatase
      activity in the GST-TS cells, yet exposure to the inhibiting compound, 4-OHA, did
      result in a significant reduction. Atrazine (0.1, 1.0 and 10 microM)
      significantly induced aromatase activity following a 24 h exposure, and 4,4'-DDE
      inhibited the activity but only at cytotoxic concentrations (100 microM). Based
      on these results, this in vitro model can be useful in examining the endocrine
      effects of EACs in sea turtles.

PMID- 15178054
TI  - Flow cytometry and pigment analyses as tools to investigate the toxicity of
      herbicides to natural phytoplankton communities.
AB  - Characterisation of natural phytoplanktonic communities is currently being
      advanced through flow cytometry and high resolution pigment analyses. To date,
      toxicological methods to assess impacts of herbicides on natural phytoplankton
      populations are lacking. Here, we report the novel use of these techniques in
      combination to study changes in phytoplankton populations exposed to 2-methylthio
      4-tertiary-butylamino-6-cyclopropylamino-s-triazine (Irgarol 1051), a herbicide
      used in antifouling paints. Flow cytometry results revealed that following a 72-h
      exposure to approximately 100 ngL(-1), eukaryote abundance was less than half
      that in the controls. High performance liquid chromatographic analyses of
      pigments demonstrated that 19'-hexanoyloxyfucoxanthin was selectively lost
      relative to the control. This carotenoid is specific to the prymnesiophytes which
      are key constituents of phytoplanktonic communities within temperate marine
      waters. Values of EC(50) (72 h) as low as 70 ngL(-1) were calculated from the
      selective reduction in this compound. Concentrations substantially exceeding this
      level have been reported in UK and other European coastal waters.

PMID- 15178055
TI  - Metal donation and apo-metalloenzyme activation by stable isotopically labeled
      metallothionein.
AB  - Coupled HPLC-ICP-MS has been used to quantitatively study the effects of GSSG and
      GSH on the ability of metallothionein (MTII) to donate essential and non
      essential metals to apo-carbonic anhydrase. Stable isotopically labeled
      (67)Zn(3)Cd(4) MTII was used to enable Zn donated from MTII to be differentiated
      from extraneous sources of Zn. Transfer of both (67)Zn and Cd from MTII to apo
      carbonic anhydrase was noted in the absence of either GSSG or GSH. GSSG increased
      the initial transfer of both Zn and Cd. Thereafter, a gradual increase in the
      (67)Zn content at the expense of Cd was noted over 24-h indicating continued
      interaction and exchange between MTII and the enzyme commensurate with the
      relative preferences shown by the proteins for these two metals. Although GSH
      also increased transfer of (67)Zn from MT it reduced the simultaneous transfer of
      Cd to the enzyme thereby conferring protection against Cd induced activation.

PMID- 15178056
TI  - Effect of cadmium, copper and mercury on antioxidant enzyme activities and lipid
      peroxidation in the gills of the hydrothermal vent mussel Bathymodiolus azoricus.
AB  - Metals are known to influence lipid peroxidation and oxidative status of marine
      organisms. Hydrothermal vent mussels Bathymodiolus azoricus live in deep-sea
      environments with anomalous conditions, including high metal concentrations.
      Although B. azoricus are aerobic organisms they possess abundant methano and
      thioautotrophic symbiotic bacteria in the gills. The enzymatic defences
      (superoxide dismutase (SOD), catalase (CAT), total glutathione peroxidase (Total
      GPx) and selenium-dependent glutathione peroxidase (Se-GPx)) and lipid
      peroxidation were determined in the gills of B. azoricus exposed to Cd (0.9
      microM), Cu (0.4 microM) and Hg (0.1 microM) with different times of exposure.
      The experiments were performed in pressurized containers at 9+/-1 degrees C and
      85 bars. Results show that vent mussels possess antioxidant enzymatic protection
      in the gills. Cd and Cu had an inhibitory effect in the enzymatic defence system,
      contrarily to Hg. These enzymatic systems are not completely understood in the B.
      azoricus, since reactive oxygen species might be produced through other processes
      than natural redox cycling, due to hydrogen sulphide and oxygen content present.
      Also the symbiotic bacteria may play an important contribution in the antioxidant
      protection of the gills.

PMID- 15178057
TI  - B[a]P-DNA binding in early life-stages of Atlantic tomcod: population differences
      and chromium modulation.
AB  - Atlantic tomcod (Microgadus tomcod) from the Hudson River (HR) are resistant at
      the molecular and organismic levels to the effects of exposure to dioxin-like
      aromatic hydrocarbon (AH) compounds, but much less so to benzo[a]pyrene (B[a]P).
      The aims of this study were to determine in early life-stages of tomcod exposed
      to B[a]P: (1) if DNA binding levels differed between fish from the HR and
      Miramichi River (MR), and (2) if co-exposure to chromium could modulate this
      genotoxic effect. After exposure to [(3)H]B[a]P alone, DNA-bound radioactivity
      was 5-10-fold higher in embryos and larvae of MR than HR descent. Co-exposure to
      chromium modulated DNA binding levels in offspring of both populations. In MR
      embryos, co-exposure to chromium inhibited B[a]P uptake. These results
      demonstrated resistance to the genotoxic effects of B[a]P in early life stages of
      HR tomcod at an ecologically important endpoint and suggest the ability of
      chromium to modulate AH-induced genotoxicity.

PMID- 15178058
TI  - Regulation of Tilapia metallothionein gene expression by heavy metal ions.
AB  - Tilapia is a common fish species inhabiting inland waters and estuarine regions
      in Hong Kong and Southeast Asia, and useful for bio-monitoring of metal
      pollution. Metallothionein (MT) gene expression in fish tissues has been useful
      to sub-lethal risk assessment as biomarker of exposure to metal ions in fishes
      inhabiting metal contaminated area. To investigate metal inductions of Tilapia MT
      gene expression in vivo, Tilapias were injected with different concentrations of
      heavy metals and tissues were then removed for quantitative PCR assay using mimic
      PCR methods. All of the metal ions tested (Cu(2+), Cd(2+), Hg(2+), Ni(2+), Pb(2+)
      and Zn(2+)) were able to induce hepatic MT mRNA levels. Renal MT mRNA levels of
      Cd(2+) and Zn(2+) treated fish was not induced with significant fold induction,
      however MT mRNA levels in gills were sensitive to the administrations of these
      metal ions. These data indicated that Tilapia MT mRNA levels in gills and liver
      are sensitive biomarker of exposure to various metal ions.

PMID- 15178059
TI  - Bioavailability of heavy metals bound to sediments affected by a mining spill
      using Solea senegalensis and Scrobicularia plana.
AB  - After the Aznalcollar mining spill (April, 1998) different ecosystems along the
      Guadiamar river and the Guadalquivir estuary were impacted by high concentrations
      of metals. The concentration of metals Zn, Cd, Pb, Cu and As has been detected as
      a good tracer of the pathway of the toxic spill. Different individuals of the
      fish Solea senegalensis and the clam Scrobicularia plana were exposed to
      contaminated sediments after the accidental spill in the south-west Spain. The
      induction of metallothioneins in fish and the bioaccumulation of metals in clams
      were determined in different tissues to determine the biological adverse effect
      associated with the heavy metals from the spill. A relationship between the
      enrichment of metals in the tissues and the induction of metallothioneins was
      determined for those assays performed using contaminated sediments. The
      bioaccumulation of metals indicates that the risk associated with the spill
      should be continuously evaluated to establish the sublethal effects related to
      the accident.

PMID- 15178060
TI  - Cholinesterase activities in the Antarctic scallop Adamussium colbecki: tissue
      expression and effect of ZnCl2 exposure.
AB  - Biochemical characterization of cholinesterase activity (ChE) was carried out on
      the Antarctic scallop Adamussium colbecki collected in winter 2000 from Campo
      Icaro (Ross Sea, Antarctica) in order to increase its suitability as a sentinel
      organism for monitoring the Antarctic environment. The digestive gland, gills and
      adductor muscle were investigated for substrate specificity and inhibitors
      sensitivity using acetylthiocholine iodide (ASCh) and butyrylthiocholine iodide
      (BSCh) as substrates and tetra (monoisopropyl)pyrophosphor-tetramide (Iso-OMPA),
      1,5-bis(4-allyldimethylammoniumphenyl)-penthan-3-one dibromide (BW284c51) and the
      insecticide chlorpyrifos as inhibitors. Effect of in vivo exposure to ZnCl(2) was
      also investigated. All the tissues expressed ChE activity (gill > adductor muscle
      > digestive gland) and low substrates specificity throughout the hydrolysis of
      both ASCh and BSCh substrates. Partial (25-29%) and total inhibition (100%) of
      ChE activity in gills was demonstrated following in vitro incubation with Iso
      OMPA and BW284c51 (3 mM), respectively. Concentration-dependent inhibition was
      also evident with chlorpyrifos in the range 10(-4)-10(-10) M (IC(50) 10(-6))
      while in vivo exposure to ZnCl(2) did not seem to affect ChE activity in the
      scallop. The potential use of ChE in the A. colbecki as biomarker for monitoring
      water contamination in the marine Antarctic environment is discussed.

PMID- 15178061
TI  - Kinetics of vitellogenin protein and mRNA induction and depuration in fish
      following laboratory and environmental exposure to oestrogens.
AB  - Plaice, flounder and sand goby were exposed to ethynylestradiol (EE2) for 21 days
      and then followed for up to 31 days after removal of the oestrogen. Plasma
      vitellogenin (VTG) and hepatic VTG mRNA were determined in groups of fish sampled
      during the induction and post-exposure phases. VTG mRNA increased slightly
      earlier than plasma protein, but both reached maxima by 21 days. In contrast, VTG
      mRNA decayed much more rapidly than protein after EE2 exposure was terminated
      (typical values t(1/2) mRNA 3 days, protein 15-30 days). Vitellogenin and VTG
      mRNA thus measure different temporal events and this is illustrated by field data
      of male flounder in which both parameters have been determined. Few fish show co
      ordinate increased VTG mRNA and vitellogenin but rather more fish have increased
      vitellogenin. Low level increases of VTG mRNA (5 X) is observed in some fish
      without increased vitellogenin and this may represent polymorphic differences
      between individual fish.

PMID- 15178062
TI  - Evaluation of ecotoxicological effects of endocrine disrupters during a four-year
      survey of the Mediterranean population of swordfish (Xiphias gladius).
AB  - In this project we investigated the ecotoxicological effects of endocrine
      disrupters in a four-year survey of the Mediterranean population of swordfish
      (Xiphias gladius). In the Mediterranean environment, top predators, such as
      swordfish, accumulate high concentrations of polyhalogenated aromatic
      hydrocarbons (PHAHs) and toxic metals, potentially incurring high toxicological
      risk. The effects of organochlorines and trace elements (Hg, Cd and Pb) in 192
      swordfish specimens, caught in the Strait of Messina, Sicily, Italy, were
      investigated using vitellogenin (Vtg), zona radiata proteins (Zrp) and CYP1A
      (BPMO, EROD) activities. Vtg and Zrp were found to be dramatically induced in
      some adult male specimens, suggesting that this species is highly exposed to
      estrogens in the Mediterranean Sea. A role of organochlorines in this induction
      phenomenon is suggested by the statistically significant correlations between Zrp
      in plasma and PCB concentrations in muscle (p<0.032) and Vtg in plasma and PCB
      concentrations in liver (p<0.034) of male specimens. Levels of trace elements in
      liver were in the following ranges: Hg 1-22, Cd 1-28 and Pb 0-1.6 ppm d.w. These
      data indicate potential reproductive alterations in large pelagic fish and
      suggest the need for continuous monitoring to avoid reductions in the population
      of this fish species of high commercial and ecological interest.

PMID- 15178063
TI  - Assessment of hormonal activity of UV filters in tadpoles of frog Xenopus laevis
      at environmental concentrations.
AB  - Residues of UV filters used as ultraviolet absorbers in sunscreens, cosmetics and
      in light protection have been found in surface water and fish. Recently some of
      them were shown bearing estrogenic activity, however, very little is known about
      possible adverse effects to aquatic life. Here we investigate whether two UV
      filters, 4-methylbenzylidene camphor (4-MBC) and 3-benzylidene camphor (3-BC),
      interfere with the thyroid and sex hormone system during frog metamorphosis.
      Xenopus laevis tadpoles were exposed to 1, 5 and 50 microg/L of 4-MBC and 3-BC,
      respectively, for 35 days (NF stage 52-66). The rate of metamorphosis was not
      affected, and no obvious differences in body and tail length compared to controls
      were observed. Neither 4-MBC, nor 3-BC led to effects on the sex ratio or gross
      gonad morphology of X. laevis at stage 66. Our results indicate that these UV
      filters do not negatively affect the thyroid system and sex ratio of frogs at
      environmental concentrations.

PMID- 15178064
TI  - Biochemical and histological responses in mussel (Mytilus edulis) exposed to
      North Sea oil and to a mixture of North Sea oil and alkylphenols.
AB  - Several environmental chemicals are suspected to be responsible for adverse
      health effects on the reproductive system in various organisms. During this work,
      environmentally relevant concentrations of North Sea oil were used alone or in
      combination with alkylphenols and additional PAH to study the effect on
      vitellogenin-like protein expression and gonadal development in mussels. North
      Sea oil (0.5 ppm) induced the expression of phospho-proteins in both sexes
      indicating that some compounds are oestrogen-mimics. This induction was not seen
      in samples dosed with the mixture but signs of toxic effects were observed in the
      gonads. Indeed, numerous degenerating ovarian follicles in females and foci,
      similar to vertebrate melanomacrophage centres, were observed in testes.

PMID- 15178065
TI  - Effects of 17beta-estradiol exposure in the mussel Mytilus galloprovincialis.
AB  - Mussels Mytilus galloprovincialis were exposed to different concentrations of
      estradiol (20, 200, and 2000 ng/l) in a semi-static regime (1-day dosing
      intervals) for up to 7 days in an attempt to see how mussels dealt with exogenous
      estrogenic compounds. Sex hormone levels were determined in whole tissue. Free
      estradiol was only significantly elevated at the highest exposure dose (up to 10
      fold). Most of the estradiol was in the tissues as fatty acid esters (> 78%),
      which sharply increased in a dose-dependent manner (from 4 ng/g in controls to
      258 ng/g at the high exposure group). In contrast, neither free nor esterified
      testosterone levels showed significant differences between control and exposure
      groups. The results suggest the existence of mechanisms that allow mussels to
      maintain their hormonal status, and the important role that fatty acid
      esterification may play within those mechanisms. Synthesis and conjugation rates
      of estradiol were further investigated by measuring the activity of P450
      aromatase, and palmitoyl-CoA:estradiol acyltransferase, in digestive gland
      microsomal fractions. Overall, the study contributes to the better knowledge of
      molluscan endocrinology, and defines new mechanisms of regulation of free steroid
      levels in mussels.

PMID- 15178066
TI  - Estradiol and estriol suppress CYP1A expression in rainbow trout primary
      hepatocytes.
AB  - Hepatic levels of the pollutant inducible enzyme, CYP1A, are strongly suppressed
      in spawning female fish, a phenomenon attributed to high plasma levels of the
      female sex steroid hormone, estradiol. To evaluate the contribution of estrogen
      metabolites to estradiol-mediated CYP1A regulation, we treated primary
      hepatocytes isolated from juvenile rainbow trout (Oncorhynchus mykiss) with
      vehicle, 17beta-estradiol, or the estrogen metabolite, estriol, alone and in
      combination with each other and with the potent CYP1A inducer, benzo[a]pyrene
      (B[a]P). We found dose-dependent suppression of B[a]P-induced CYP1A activity by
      both steroids relative to controls. At 10(-7) M doses, estradiol and estriol
      suppressed B[a]P-induced CYP1A activity by 3- and 2-fold, respectively. Although
      not statistically significant, mean basal CYP1A activity levels were 15- and 13
      fold lower in estradiol and estriol treated hepatocytes, respectively, relative
      to vehicle treated controls. Combining doses of estradiol and estriol failed to
      produce synergistic suppression of either basal or B[a]P-induced CYP1A activity
      relative to treatment with either steroid alone. The observed suppression is well
      below the often strong suppression observed in spawning female fish. We conclude
      that factors in addition to estradiol and estriol are likely involved in
      producing sexual dimorphism in CYP1A expression observed in spawning fish.

PMID- 15178067
TI  - Analysis of medaka cytochrome P450 3A homotropic and heterotropic cooperativity.
AB  - We have previously demonstrated that medaka CYP3A is associated with metabolism
      of several endobiotics including steroids and bile acids. In this study, we
      demonstrate that medaka CYP3A catalysis exhibits unusual kinetic behaviors
      consistent with allosteric interaction which cannot be described by hyperbolic
      kinetic models. Using 7-benzyloxy-4-(trifluoromethyl)-coumarin (BFC) and
      nonylphenol as CYP3A substrates, we describe both homotropic and heterotropic
      cooperative interactions. Given the role of CYP3A in maintaining the homeostatic
      balance for numerous endobiotics, enzymatic activation/inhibition by endocrine
      disruptors (EDCs) represents a putative (non-genomic) mechanism for endocrine
      disruption.

PMID- 15178068
TI  - Glucuronidation in the polar bear (Ursus maritimus).
AB  - Polar bears bioaccumulate lipophilic pollutants, including polychlorinated
      biphenyls (PCBs), into their bodies from their exclusive diet of marine
      organisms. Hydroxylated PCB metabolites (OH-PCBs) have been found in plasma,
      presumably due to CYP-dependent biotransformation of PCBs in liver. Little is
      known about the phase 2 metabolism of hydroxylated xenobiotics in polar bears.
      The objective of this study was to examine UDP-glucuronosyltransferase (UGT)
      activity with OH-PCBs and a hydroxylated polycyclic aromatic hydrocarbon, 3
      hydroxy-benzo(a)pyrene (3-OH-BaP), in polar bear liver. Samples of frozen polar
      bear liver were used to prepare microsomes. UGT activity with 3-OH-BaP in Brij
      treated microsomes, measured by a fluorescence assay, was readily measurable with
      protein concentrations in assay tubes of up to 10 g/ml, but dropped off very
      sharply at higher protein concentrations. The apparent Km for 3-OH-BaP was 1.71
      +/- 0.04 microM, and Vmax 1.26 +/- 0.16 nmol/min/mg protein (mean +/- SD, n=3).
      UGT activities with a model tetrachloro-OH-PCB (4'-OH-CB72) and a model
      hexachloro-OH-PCB (4'-OH-CB159) were assayed with [14-C]-UDPGA and separation of
      the [14-C]-glucuronide by ion-pair extraction and thin-layer chromatography. [14
      C]-glucuronide conjugates were readily formed by polar bear liver microsomes in
      the absence of added substrate, apparently from contaminants present in liver.
      This phenomenon was not observed using hepatic microsomes from laboratory-held
      catfish. Glucuronidation efficiency was much higher with 4'-OH-CB72 (Km 7.3
      microM; Vmax 1.55 nmol/min/mg) than 4'-OH-CB159 (Km 16.1 microM; Vmax 0.46
      nmol/min/mg). The identities of the aglycones present in polar bear liver are not
      known, but could include OH-PCBs or hydroxylated metabolites of other persistent
      organic pollutants. This study demonstrates that UGT with high activity for 3-OH
      BaP and other substrates is present in polar bear liver.

PMID- 15178070
TI  - GSTA is a major glutathione S-transferase gene responsible for 4-hydroxynonenal
      conjugation in largemouth bass liver.
AB  - We have previously shown that largemouth bass (Micropterus salmoides) has a
      remarkable ability to conjugate 4-hydroxy-2-nonenal (4HNE), a mutagenic and
      cytotoxic alpha,beta-unsaturated aldehyde produced during the peroxidation of
      lipids. In addition, we have isolated a glutathione S-transferase cDNA (bass
      GSTA) that encodes a recombinant protein which is highly active in 4HNE
      conjugation and structurally similar to plaice (Pleuronectes platessa) GSTA. In
      the present study, HPLC-GST subunit analysis revealed the presence of at least
      two major GST isoforms in bass liver, with one peak constituting 80% of the total
      bass liver GST protein. Liquid chromatography mass spectrometry (LC-MS) and
      electrospray ionization analysis of the major bass GST subunit yielded a
      molecular weight of 26,396 kDa. Endo-proteinase Lys-C digestion and Edman
      degradation protein sequencing of this GST peak demonstrated that this protein
      was encoded by bass GSTA. Analysis of genomic DNA fragments isolated by nested
      PCR indicated the presence of a GST gene cluster in bass liver that contained
      GSTA, and was similar to a GST gene cluster characterized by Leaver et al., in
      plaice. Collectively, our data indicates the presence of a major GST in bass
      liver involved in the protection against oxidative stress. This GST is part of a
      gene cluster that may be conserved in certain freshwater and marine fish.

PMID- 15178069
TI  - Esterification of vertebrate-like steroids in the eastern oyster (Crassostrea
      virginica).
AB  - The esterification of two model vertebrate steroid hormones - estradiol (E2) and
      dehidroepiandrosterone (DHEA) - was studied in the oyster Crassostrea virginica.
      The activity of acyl-CoA:steroid acyltransferase was characterized in microsomal
      fractions isolated from oyster digestive glands. The apparent Km and Vmax values
      changed with the fatty acid acyl-CoA used (C20:4, C18:2, C18:1, C16:1, C18:0 or
      C16:0), and were in the range of 9-17 microM, and 35-74 pmol/min/mg protein for
      E2, and in the range of 45-120 microM, and 30-182 pmol/min/mg protein for DHEA.
      Kinetic parameters were also assessed in gonadal tissue. The enzyme saturated at
      similar concentrations, although conjugation rates were lower than in digestive
      gland. Preliminary data shows that tributyltin (TBT) in the low microM range (1
      50) strongly inhibits E2 and DHEA esterification, the esterification of E2 being
      more sensitive to inhibition than that of DHEA. Overall, results indicate that
      apolar conjugation occurs in oysters, in both digestive gland and gonads, at a
      very similar rate to mammals, suggesting that this is a well conserved
      conjugation pathway during evolution. Esterification, together with other
      mechanisms, can modulate endogenous steroid levels in C. virginica, and might be
      a target for endocrine disrupters, such as TBT.

PMID- 15178071
TI  - Microsomal estrogen metabolism in channel catfish.
AB  - Our goal was to study the involvement of cytochrome P450 genes in estrogen
      metabolism and the extent to which the potentially carcinogenic 4
      hydroxyestradiol metabolite is formed by channel catfish (Ictalurus punctatus;
      CC). Estradiol metabolism and ethoxyresorufin-O-deethylase (EROD) activity were
      assessed in several tissues from fish collected from three variably contaminated
      sites in the Mississippi River Delta, from laboratory control fish, and from fish
      exposed to 20 mg/kg benzo(a)pyrene (BaP) i.p. for 4 days. Liver EROD activity was
      induced by BaP, but Delta fish EROD activities were not statistically higher than
      activities in control fish. Gill microsomal EROD activity was also induced by
      BaP, but activities were 8- to 77-fold lower than those from liver. The
      predominant estrogen metabolites formed by CC liver, gill and gonad microsomes
      were 2-hydroxyestradiol and estrone as detected by GC/MS. Liver and gill 2
      hydroxyestradiol formation was induced in BaP-dosed fish. The trends in
      hydroxyestradiol formation in field collected fish were more variable. In all
      fish liver microsomes there was more 2- compared to 4-hydroxyestradiol formed.
      However, BaP-treatment increased the 4:2 hydroxyestradiol ratio from 0.04 in
      control fish to 0.2 in BaP-exposed fish, suggesting that BaP induces the
      formation of the potentially genotoxic estrogen metabolite. No detectable 4
      hydroxyestradiol was produced by gill and gonad microsomes. These results will
      ultimately help in determining which fish P450 genes are susceptible to
      environmental contamination and may be involved in estrogen genotoxicity.

PMID- 15178072
TI  - Searching for novel CYP members using cDNA library from a minke whale liver.
AB  - The contaminant-induced cytochrome P450 (CYP) members in minke whale
      (Balaenoptera acutorostrata) can be potential biomarkers of the contaminant
      exposure and toxic effects. In this study, we constructed a cDNA library from the
      liver of minke whale from the North Pacific, and further screened a total of 6930
      clones randomly selected in the library for the isolation of cDNA clones encoding
      novel members of CYP superfamily. The screening revealed the isolation of six
      novel CYP cDNA clones that are classified into CYP1A, CYP2C, CYP2E, CYP3A, CYP4,
      and CYP4A subfamilies. The BLAST homology search using the partial cDNA fragments
      of four CYP subfamilies (CYP1A, CYP2C, CYP2E and CYP4A) demonstrated that the
      minke whale CYPs were most closely related to pig CYPs (81-91%). Identification
      of multiple CYP genes in marine mammal species such as minke whale will provide
      new insights into the metabolic or toxicological functions of individual CYP
      members.

PMID- 15178073
TI  - Unique monooxygenation pattern indicates novel flavin-containing monooxygenase in
      liver of rainbow trout.
AB  - Vertebrate flavin-containing monooxygenases (FMOs) have only been isolated from
      mammalian organisms. However, many FMO substrates include pesticides which may
      adversely affect fish and other aquatic organisms residing in adjacent waterways
      to treated fields. Although FMO activities have been identified in fish, the
      exact isoform profile is uncertain. Utilizing prochiral methyl tolyl sulfides
      (MTS) and isoform-selective antibodies, an attempt was made to identify specific
      FMO isoforms which may be involved in sulfoxidation reactions which have been
      shown to bioactivate thioether pesticides, such as aldicarb. Rainbow trout
      hepatic microsomes treated with detergent to eliminate cytochrome P450
      contributions catalyzed the formation of the sulfoxide of MTS in 75% S
      enantiomeric excess. These catalytic results contrast activities of the five
      other FMO isoforms including FMO1 (> 98% R) and FMO3 (50% R). Benzydamine N
      oxidation was also observed as were methimazole, thiourea, and aldicarb
      sulfoxidation reactions. Antibodies to FMO1 recognized a single protein of 60 kDa
      in trout liver microsomes, while anti-FMO3 antibodies only slightly reacted with
      a 55-kDa microsomal protein. These results indicate a novel isoform profile in
      rainbow trout liver implicating either a mixture of competing FMO isoforms or a
      FMO1-like isoform displaying unique catalytic activity.

PMID- 15178074
TI  - Characterization of cholinesterase activity from different tissues of Nile
      tilapia (Oreochromis niloticus).
AB  - Cholinesterases (ChE) from brain, muscle and liver in Nile tilapia (Oreochromis
      niloticus) were characterized using three substrates: acetylthiocholine iodide,
      propionylthiocholine iodide, and butyrylthiocholine iodide. Eserine was used as a
      total ChE inhibitor; BW284c51 and iso-OMPA were used as selective inhibitors for
      acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), respectively. The
      results indicate that AChE is the enzyme present in brain, whereas in both liver
      and muscle, the presence of atypical ChEs are suggested. These findings indicate
      that characterization of ChE is necessary prior to use in monitoring programs.

PMID- 15178075
TI  - Induction of cytochrome P4501A and biliary PAH metabolites in European eel
      Anguilla anguilla: Seasonal, dose- and time-response variability in field and
      laboratory conditions.
AB  - Induction of cytochrome P4501A in fish is a well-known indicator of exposure to
      polycyclic aromatic hydrocarbons (PAHs) and determination of PAH metabolites in
      bile by fixed wavelength fluorescence (FF) or synchronous fluorescence
      spectroscopy (SFS), has become an useful method in monitoring programs. In this
      work the relationship between cytochrome P4501A (EROD activity) and levels of
      biliary PAH metabolites was measured in the European eel Anguilla anguilla, in
      both field and laboratory conditions: organisms were sampled on a seasonal basis
      from the Orbetello lagoon (Tuscany) to characterize the natural variability of
      these biological parameters, while in laboratory eels were intraperitoneally
      injected with benzo[a]pyrene to investigate temporal and dose-dependent induction
      patterns. Results showed that induction of cytochrome P450 and accumulation of
      PAHs metabolites in bile are not necessarily correlated either in field, or in
      laboratory investigations; different seasonal changes were measured in natural
      conditions and slight variations in dose and time response patterns were also
      obtained in laboratory exposures.

PMID- 15178076
TI  - The DNA de-methylating agent 5-azacytidine does not restore CYP1A induction in
      PCB resistant Newark Bay killifish (Fundulus heteroclitus).
AB  - Newark Bay (NB) killifish (Fundulus heteroclitus) have been chronically exposed
      to environmental contaminants that activate the aryl hydrocarbon receptor (AHR)
      and are tolerant to toxic effects and CYP1A induction provoked by AHR ligands.
      Resistance to CYP1A induction could be due to an epigenetic mechanism such as DNA
      methylation. We measured in-ovo CYP1A catalytic activity (ethoxyresorufin-O
      deethylase, EROD) in NB and reference site killifish embryos aqueously exposed to
      various concentrations of the de-methylating agent 5-azacytidine, 5-AC (5, 50 and
      500 micro(micro)M) with or without 0.2 micro(micro)g/l of the CYP1A inducer
      3,3',4,4',5 pentachlorobiphenyl (IUPAC PCB126). Neither PCB126 alone, nor PCB126
      plus 5-AC, induced EROD above levels in vehicle treated Newark Bay fish. In
      reference site fish, the same PCB126 dose provoked a 7.4-fold EROD induction
      relative to controls. We conclude that Newark Bay killifish are resistant to
      CYP1A induction by co-planar PCBs during early embryological development and our
      data suggests that DNA methylation does not play a critical role in resistance to
      CYP1A induction in this model.

PMID- 15178077
TI  - Inhibitory effects of divalent metal ions on liver microsomal 7-ethoxyresorufin O
      deethylase (EROD) activity of leaping mullet.
AB  - The purpose of the present study was to elucidate in vitro effects of Hg(2+),
      Zn(2+), Ni(2+) and Cd(2+) on cytochrome P4501A1 (CYP1A1) dependent EROD
      activities in leaping mullet liver microsomes. Fish captured from the most
      polluted part of Izmir Bay, had highly elevated EROD activities, and induced
      CYP1A1 protein levels as determined by Western blotting. Although all of the
      metal ions caused inhibition of the initial velocity of the reaction, Hg(2+) and
      Cd(2+) exhibited much higher inhibitory effect at lower concentrations and they
      were evidently more potent inhibitors than others. The inhibitor concentration
      giving 50% inhibition (IC(50) values) of Zn(2+), Ni(2+), Cd(2+) and Hg(2+) of
      initial EROD activity were 107, 16, 1.3 and 0.15 micromolar, respectively.
      Glutathione (GSH) at 0.5 mM final concentration, completely reversed Ni(2+) and
      Cd(2+) inhibition of EROD activity indicating the protective action of GSH.

PMID- 15178078
TI  - Induction of phenol-type sulfotransferase and glucuronosyltransferase in channel
      catfish and mummichog.
AB  - Conjugation of phenolic xenobiotics and metabolites through sulfation and
      glucuronidation is an important biotransformation pathway. Sulfotransferases
      (SULT) are generally considered non-inducible, while some UDP
      glucuronosyltransferase (UGT) isoenzymes are co-induced with cytochrome P450-1A
      by Ah-receptor ligands. To test these assumptions for two fish species, we
      measured sulfation and glucuronidation of 9-hydroxybenzo[a]pyrene in 3
      methylcholanthrene (3-MC) treated channel catfish (Ictalurus punctatus) and in
      mummichog (Fundulus heteroclitus) from the creosote contaminated Atlantic Wood
      site in the Elizabeth River, VA. The results show a significant induction of both
      UGT and SULT activity in 3-MC treated catfish, linked to the expected induction
      of EROD activity. In mummichog, significant induction of UGT was measured at the
      contaminated site over the reference site (King's Creek, VA), as well as
      extremely low SULT activities at both sites. Western blots, using a polyclonal
      antibody for catfish phenol-type SULT, confirmed the absence of phenol-type SULT
      in mummichog. Residual, though slightly inducible, SULT activity may be
      attributed to other SULT isoforms.

PMID- 15178079
TI  - A cDNA microarray technique applied for analysis of global gene expression
      profiles in tributyltin-exposed ascidians.
AB  - To analyze global gene expressions, we constructed a cDNA microarray from a basal
      chordate, the ascidian Ciona intestinalis. Ciona is a cosmopolitan species and a
      genomic analysis of Ciona revealed that ascidians had approximately 15,500
      protein-coding genes. Our "Ciona intestinalis cDNA chip version 1 (Ci cDNA chip
      ver. 1)" has arrayed 13,400 unique Ciona cDNAs. To establish a detection system
      for gene expression profiles in wild ascidians using a cDNA microarray, we
      analyzed gene expressions in the whole body of Ciona adults after exposure to 100
      nM tributyltin (TBT) for 24 h. In our preliminary array data using Ci cDNA chip
      ver. 1, we found more than 200 genes that showed strong differential expressions.
      These genes encoded proteins that were concerned with stress response,
      detoxification, oxidoreduction reaction, biosynthesis, and catabolism. This, the
      first large cDNA microarray of this animal, should facilitate analyses of global
      gene expressions following exposure to TBT.

PMID- 15178080
TI  - Induction of zona radiata and vitellogenin genes in estradiol and nonylphenol
      exposed male sheepshead minnows (Cyprinodon variegatus).
AB  - Several genes normally induced by estradiol (E(2)) in female fish, those for
      vitellogenins (VTGs) and zona radiata proteins (ZRPs), are also inducible in
      males exposed to estrogenic chemicals. Male sheepshead minnows (SHM) were exposed
      to both E(2) and para-nonylphenol (NP), at several doses and times to determine a
      dose-response. Quantitative real time PCR was used to measure mRNA for VTG1,
      VTG2, ZRP2 and ZRP3. Both E(2) and NP elicited a dose-response increase in all of
      the mRNAs tested. Exposure to both chemicals resulted in VTG2 expression at about
      a 10-fold lower level than VTG1, and ZRP2 expression at a lower level than ZRP3.

PMID- 15178081
TI  - Isolation of differentially expressed genes from contaminant exposed European
      flounder by suppressive, subtractive hybridisation.
AB  - Commercially farmed European flounder (Platichthys flesus) were treated with
      benzo[a]pyrene or cadmium under controlled laboratory conditions. In addition,
      animals were collected from the polluted Tyne and relatively clean Alde estuaries
      in the UK. Potential differentially expressed genes were isolated from liver
      tissue by means of suppressive, subtractive hybridisation. A total of 284
      different mRNAs were identified as having the potential for being differentially
      expressed, of which 84 could be tentatively identified by homology with database
      sequences. These clones will form part of a flounder cDNA array for validation
      and future applications, with full identification being pursued for those
      expressed sequence tags for which differential expression can be confirmed by
      array technology.

PMID- 15178082
TI  - Identification of transcriptional effects of ethynyl oestradiol in male plaice
      (Pleuronectes platessa) by suppression subtractive hybridisation and a nylon
      macroarray.
AB  - Suppression subtractive hybridisation (SSH) was used to generate cDNA libraries
      representing genes differentially expressed in response to ethynyl oestradiol
      (EE2) exposure in liver from male plaice (Pleuronectes platessa) previously
      analysed for vitellogenin (VTG) induction. Characterisation of the cDNA clones
      identified many as VTG (2 genes) and zona radiata proteins (ZRP) (3 genes), but
      40 encoded other proteins, with more than half cryptic. Further analysis
      identified 85 non-redundant clones suitable for array on nylon membrane.
      Radiolabelled cDNAs were prepared from hepatic mRNA from EE2 treated plaice (0
      and 21 days) and hybridised with the arrayed clones. Analysis of the data showed
      that 11/17 novel, 21/22 VTG, 13/14 ZRP, 2/2 liver aspartic proteinase (LAP) and
      8/10 other mRNAs were up-regulated by EE2 exposure.

PMID- 15178083
TI  - Use of suppressive subtractive hybridization and cDNA arrays to discover patterns
      of altered gene expression in the liver of dihydrotestosterone and 11
      ketotestosterone exposed adult male largemouth bass (Micropterus salmoides).
AB  - In this study male largemouth bass (LMB) were exposed to the naturally occurring
      androgens, dihydrotestosterone (DHT) or 11-ketotestosterone (11-KT) in order to
      identify genes that are differentially regulated by these steroid hormones. Using
      subtractive hybridization on livers of fish treated with DHT against vehicle
      control, many novel LMB genes were cloned. These genes were added to our gene
      library and arrayed. Six genes were up-regulated and five were down-regulated by
      both androgens. But, each androgen also regulated specific genes. One gene that
      was identified as a potential androgen marker was spermidine-spermine-N(1)
      acetyltransferase that was up-regulated by both androgens. Determining which
      genes are responsive to natural androgens will help to identify biochemical
      pathways that are impacted.

PMID- 15178084
TI  - A comparison of pollutant biomarker responses with transcriptional responses in
      European flounders (Platicthys flesus) subjected to estuarine pollution.
AB  - European flounders from two UK estuaries with different contaminant profiles were
      sampled and analysed for impacts of PAHs, heavy metals and estrogenic compounds
      by currently adopted measurement procedures used in statutory monitoring
      programs. These showed that fish from the polluted Tyne estuary had responded to
      all three classes of pollutants with elevations in hepatic EROD, MT and plasma
      VTG and that there was considerable interanimal variation in the magnitude of the
      response. Analysis of PAH metabolites in bile showed recent uptake of low
      molecular weight PAHs. The pollutant response was also apparent when hepatic
      levels of cytochrome P450 1A (CYP1A), metallothionein (MT) and vitellogenin (VTG)
      mRNAs were quantified by real time PCR. Whilst there did not appear to be a
      direct correlation between levels of gene transcripts and their protein products
      on an individual basis, these results demonstrate that measurements of mRNA
      levels of specific genes, or their protein products both demonstrate induction in
      polluted environments and are thus valid measures in biomonitoring studies.
      Procedurally, the use of the single generic technology of Q-PCR was much simpler
      and is worth pursuing in future studies.

PMID- 15178085
TI  - Oxidative stress in two populations of killifish (Fundulus heteroclitus) with
      differing contaminant exposure histories.
AB  - A population of killifish (Fundulus heteroclitus) inhabiting a creosote-polluted
      inlet of the Elizabeth River demonstrates tolerance to the acute toxic effects
      exerted by contaminated sediments on reference site killifish. Previous data have
      suggested that upregulated antioxidant defenses contribute to short-term
      tolerance in killifish exposed to Elizabeth River sediments. This study
      investigated population differences in antioxidant defenses from wild caught
      Elizabeth River and reference population killifish in different seasons, and
      after being held in the laboratory. Parameters measured in the killifish were
      total glutathione concentrations (GSH(T)), activities of glutathione reductase
      (GR), glutathione peroxidase (GPx), and lipid peroxidation (LPO), all in adult
      hepatic tissues. The Elizabeth River population exhibited greater GSH(T), higher
      GPx activities, and increased LPO as compared to the reference population. Sex
      specific population differences were also observed in GSH(T) and GPx. Both
      populations displayed decreased GSH(T) and increased GR from early to late
      summer, as well as after being held in the laboratory. This study indicates that
      there are many factors that may contribute to differences in levels of
      antioxidant defenses in addition to exposure to contaminants, including
      reproductive status and environmental conditions.

PMID- 15178086
TI  - Diet restriction induced autophagy: a lysosomal protective system against
      oxidative- and pollutant-stress and cell injury.
AB  - Nutrient deprivation or dietary restriction (DR) confers protection against
      ageing and stress in many animals and induced lysosomal autophagy is part of this
      mechanism. The effects of dietary restriction on the toxicity of copper and the
      polycyclic aromatic hydrocarbon phenanthrene have been investigated in the common
      marine mussel Mytilus edulis. The findings show that DR-induced autophagy
      facilitates the recovery of the digestive gland (i.e., molluscan liver analogue)
      from cell injury caused by both copper and phenanthrene. It is inferred that DR
      induced autophagy and lysosomal proteolysis results in improved cellular
      "housekeeping" through the more efficient removal of oxidatively and pollutant
      damaged proteins (e.g., protein carbonyls, protein adducts, etc.) and that this
      contributes to stress resistance.

PMID- 15178087
TI  - Time-course evaluation of ROS-mediated toxicity in mussels, Mytilus
      galloprovincialis, during a field translocation experiment.
AB  - Harbours can be considered as model environments for developing and validating
      field monitoring procedures and to investigate mechanistic relationships between
      different biological responses. In this study several biomarkers were
      investigated in marine mussels caged for 4 weeks (June-July 2001) into an
      industrialized harbour of NW Italy. Organisms were collected at different time
      intervals to better characterize the sensitivity, temporal variations and
      interactions of analysed responses. Besides single antioxidants the total
      oxyradical scavenging capacity (TOSC) assay was used to analyse the capability of
      the whole antioxidant system to neutralize specific forms of radicals: these data
      were further integrated by measurement of DNA integrity, oxidized bases and the
      impairment of lysosomal membrane stability in haemocytes. Results showed a
      biphasic trend for single antioxidants and TOSC, with an increase during the
      first 2 weeks of exposure to the polluted site followed by a progressive decrease
      up to a severe depletion in the final part of the experiment.

PMID- 15178088
TI  - Total oxyradical scavenging capacity of the deep-sea amphipod Eurythenes gryllus.
AB  - Environmental concern for the deep-sea ecosystem is increasing as contaminants,
      originating from anthropogenic activities, have been detected in deep-sea biota.
      However, little is known on the xenobiotics metabolising capability of deep-sea
      fauna. In this study, the deep-sea amphipod Eurythenes gryllus was selected as
      sentinel species to measure the total oxyradical scavenging capacity (TOSC).
      Individuals of E. gryllus were sampled at 2000 m depth in the Arctic Ocean. The
      TOSC assay was measured on the cytosolic fraction and the soluble fraction (3
      kDa) of the digestive gland and on the cell-free haemolymph toward peroxyl,
      hydroxyl and peroxynitrite radicals according to the method of Winston et al.
      [Free Radical Biology and Medicine 24 (3) (1998) 480] and Regoli and Winston
      [Toxicology and Applied Pharmacology 156 (1999) 96]. These results provide the
      first baseline data set for total antioxidant capacity in a deep-sea amphipod.

PMID- 15178089
TI  - Molecular cloning of superoxide dismutase (Cu/Zn-SOD) from aquatic molluscs.
AB  - The potential of the first line of the active oxygen-scavenging system, partial
      cDNA encoding Cu/Zn superoxide dismutase (SOD) was isolated in three aquatic
      mollusc species: Ruditapes decussatus (marine clam), Dreissena polymorpha
      (continental water mussel) and Bathymodiolus azoricus (hydrothermal vent mussel).
      These SOD cDNA fragments were amplified by PCR with degenerate oligonucleotide
      primers derived from the amino acid sequence conserved in the Cu/Zn-SOD from
      several other organisms. A partial cDNA of CuZn-SOD was obtained for R.
      decussates (510 bp), D. polymorpha (510 bp) and B. azoricus (195 bp). The deduced
      amino acid sequence showed high similarity among the three mollusc species (57
      63%) and among other species (50-65%). The residues involved in coordinating
      copper (His-47, 49, 64, 121) and zinc (His-64, 72, 81 and Asp-84) were well
      conserved among the three Cu/Zn-SOD sequences.

PMID- 15178090
TI  - Oxidative stress in Laeonereis acuta (Polychaeta, Nereididae): environmental and
      seasonal effects.
AB  - Laeonereis acuta was seasonally collected in an industrially polluted site (P)
      and in an unpolluted site (UP) at the Patos Lagoon estuary (southern Brazil).
      Glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT)
      activity (U/mg protein) was determined in five groups of worms from each site.
      Metallothionein (MT - mol GSH/g ww) and lipid peroxides content (LPO - nmoles of
      cumene hydroperoxide/g ww) were also measured. Annual mean values for CAT
      (UP=3.7+/-0.3; P=5.7+/-0.6), GST (UP=0.034+/-0.003; P=0.045+/-0.004) and MT
      (UP=0.15+/-0.02; P=0.23+/-0.03) were higher (p<0.05) in worms from the P site. In
      autumn, CAT activity was higher (p<0.05) in worms from the P site (7.6 +/- 1.3)
      than in those from the UP site (3.6 +/- 0.4). In summer, MT concentration was
      higher in worms from the P site (0.37 +/- 0.03) than in those from the UP site
      (0.19 +/- 0.01). No significant difference (p>0.05) in the LPO content was
      observed in worms from the different sites or collected in different seasons.
      These results indicate that worms from the polluted site showed higher
      antioxidant responses than those from the unpolluted site, sufficient to prevent
      oxidative damage in terms of LPO.

PMID- 15178091
TI  - An in vitro procedure for evaluation of early stage oxidative stress in an
      established fish cell line applied to investigation of PHAH and pesticide
      toxicity.
AB  - Oxidative stress by increased production of reactive oxygen species such as
      superoxide has been implicated in the toxicity of PCB's and non-target toxicity
      of many pesticides. We report the development of a microplate-based method for
      determination of early stage oxidative stress using an established cell line
      (EPC) from a skin tumour of carp Cyprinus carpio L. and 2',7'
      dichlorodihydrofluorescein diacetate (H(2)-DCFDA) as a fluorescent probe for
      detection of reactive oxygen species (ROS) formation. Sublethal concentrations of
      the herbicide Paraquat, an established redox cycling agent and a crude PCB
      mixture, Arochlor 1254 elicited a linear increase in ROS formation over 2 h
      exposure which was some 45- and 10-fold higher, respectively, than attributable
      to basal respiration, confirming the suitability and response of the test system.
      Whilst in vivo studies in mammals have implicated early stage oxidative stress in
      the toxicity of pesticides, we did not observe an increase in ROS production
      after exposure of EPC cells to sublethal concentrations of Carbaryl, 2,4-DDT,
      Lindane or Malathion implying that this is not the causative mechanism of acute
      toxicity in this fish cell line. The apparent involvement of oxidative stress in
      their mammalian toxicity may therefore be an indirect effect or dependent upon
      compound metabolism.

PMID- 15178092
TI  - Variations of antioxidant efficiency and presence of endosymbiotic diatoms in the
      Antarctic porifera Haliclona dancoi.
AB  - The role of endosymbiotic diatoms as pro-oxidant stressors in porifera has been
      investigated in the Antarctic sponge Haliclona dancoi in which the presence of
      diatoms is influenced by marked seasonal variations during the austral summer.
      Both chlorophaeopigments and frustules were absent in sponge tissues sampled in
      early November at the beginning of the summer and increased from the mid of
      December with slightly shifted temporal trends. The efficiency of antioxidant
      defenses in the sponge showed a marked response to symbionts with clearly
      enhanced values corresponding to the peak of diatoms.

PMID- 15178093
TI  - CYP1A- and CYP3A-immunopositive protein levels in digestive gland of the mussel
      Mytilus galloprovincialis from the Mediterranean Sea.
AB  - CYP1A-immunopositive protein can be elevated in response to planar PAHs and PCBs
      in Mytilus sp. digestive gland whilst CYP3A-immunopositive protein has been
      associated with testosterone 6beta-hydroxylation in fish. Levels of CYP1A- and
      CYP3A-immunopositive protein were determined in Mytilus galloprovincialis
      digestive gland microsomes collected from 12 sites in the Mediterranean Sea
      during May and September 2001. CYP1A-immunopositive protein was significantly
      highest at contaminated sites whilst CYP3A-immunopositive protein was
      significantly lowest. A weak negative correlation (r2 = 0.21) was seen between
      CYP1A- and CYP3A-immunopositive protein. Little evidence of differences at the
      different sampling times was observed. These results confirm previous work
      indicating elevation of CYP1A-immunopositive protein in Mytilus sp. digestive
      gland at contaminated sites. Further study is required to characterise CYP3A-like
      expression in Mytilus and to elucidate the consequences of possible CYP3A-like
      down-regulation at contaminated sites.

PMID- 15178094
TI  - Development of two novel CYP-antibodies and their use in a PCB exposure
      experiment with Mytilus edulis.
AB  - In an attempt to learn more about the cytochrome P450 (CYP) system of mussels, we
      used protein databases and alignment software to extract highly conserved CYP
      sequences. From these alignments synthetic peptides were produced and used for
      rabbit immunisation, which yielded polyclonal antibodies against the CYP families
      2 and 4. The antibodies were evaluated with Western Blot and ELISA assays, using
      digestive gland microsomal samples from the mussel Mytilus edulis. Western Blots
      revealed immunoreactions for both antibodies. The anti-CYP2 sequence rendered one
      major immunopositive protein of approximately 49 kDa size, and weak signals for
      proteins of approximately 41 and 56 kDa size. The anti-CYP4 sequence rendered two
      major bands of approximately 56 and 59 kDa size, and also a weak immunoreaction
      with a protein of approximately 43 kDa size. ELISA rendered only weak signals
      even with a 1:50 dilution of IgG-purified serum. A 10-day exposure to Aroclor
      1254 did not appear to affect any of the immunopositive proteins, while total
      PCBs in soft bodies increased from 14-40 ng/g DW in controls to 373-638 ng/g DW
      in exposed mussels.

PMID- 15178095
TI  - Application of real-time PCR for quantitative determination of hepatic
      vitellogenin transcript levels in the striped sea bream, Lithognathus mormyrus.
AB  - The striped sea bream (Lithognathus mormyrus) has been recently introduced as a
      bioindicator fish species in Mediterranean coastal habitats. The purpose of this
      study was to apply a real-time PCR assay for the determination of absolute levels
      of hepatic VTG transcript in this fish, identifying minimal and maximal levels
      and establishing the relationship between VTG RNA levels and ovarian development.
      A partial VTG cDNA was cloned from hepatic RNA of a striped sea bream female.
      Specific primers were designed based on its sequence and used for PCR and also
      for in vitro synthesis of partial VTG RNA standard. Hepatic VTG transcript levels
      were quantified by real-time PCR, using serially diluted VTG RNA standards for
      construction of a calibration curve and equation. VTG RNA levels were normalized
      to total RNA or 18S ribosomal RNA (determined by real-time PCR). VTG RNA was
      hardly detected in the liver of males, or females with small oocytes (diameter <
      100 microm). A linear correlation was found between these two parameters at
      larger oocyte diameter (> 150 microm). VTG level reached a maximum of 204
      fmol/pmol 18S RNA or 49 fmol/microg RNA. The results demonstrate the wide dynamic
      range of the established real-time PCR assay.

PMID- 15178096
TI  - Cloning of a chub metallothionein cDNA and development of competitive RT-PCR of
      chub metallothionein mRNA as a potential biomarker of heavy metal exposure.
AB  - Metallothionein has been assayed in a range of aquatic animal tissues as an
      indicator of metal exposure. We sequenced chub (Leuciscus cephalus)
      metallothionein cDNA which showed over 90% homology to common carp, goldfish and
      stone loach and 77% homology to rainbow trout sequences for metallothionein. We
      then used the extended primer method to develop an accurate quantitative
      competitive RT-PCR assay for metallothionein mRNA. RT-PCR was used to measure
      metallothionein mRNA in feral chub from a range of field sites, with different
      levels of heavy metal pollution, in the West Midlands, UK. Measurements were
      complemented by analysis of liver and gill metallothionein protein by capillary
      electrophoresis. There was no significant difference in the metallothionein
      protein levels between fish of different rivers and there was no evidence of
      elevation of mRNA at the sites of highest metal exposure. The level of metal
      exposure (e.g. zinc, nickel and cadmium each ranging between 15 and 28 microg/l )
      at the pH (7.5-8.5) of these rivers appears insufficient to elevate hepatic or
      gill metallothionein in chub. A lack of elevation of hepatic metallothionein mRNA
      in chub exposed to zinc, copper and manganese for 24 h and 10 days in the
      laboratory also suggests a non-responsiveness of this species.

PMID- 15178097
TI  - Simulating a heavy metal spill under estuarine conditions: effects on the clam
      Scrobicularia plana.
AB  - We describe the effect of heavy metals Zn, Cd, Pb and Cu on the induction of
      methallothioneins on the clam Scrobicularia plana along a salinity gradient
      simulated under laboratory conditions. The clams were exposed to constant heavy
      metal concentrations in a dynamic estuary simulator during a 15-day assay to
      investigate possible induction of metal-binding proteins in them. The
      concentration of heavy metals in water was analysed. Clams were analysed for
      methallothionein concentrations. The speciation of Zn, Cd, Pb and Cu along the
      salinity gradient was modelled. Zn showed the highest concentrations and its
      prevalent species was the free ion. Intersite differences have been observed in
      methallothionein concentration and related to the salinity gradient. It seems
      that synthesis of methallothioneins is the result of physiological forces acting
      in concert with the changes in the chemical speciation of metals, owing to the
      trace metals uptake is controlled by means of an interaction of physiology and
      physicochemistry.

PMID- 15178098
TI  - Effects of beta-naphthoflavone on hepatic biotransformation and glutathione
      biosynthesis in largemouth bass (Micropterus salmoides).
AB  - We are investigating the effects of in vivo exposure of prototypical enzyme
      inducing agents on hepatic biotransformation enzyme expression in largemouth bass
      (Micropterus salmoides), a predatory game fish found throughout the United States
      and Canada. The current study targeted those genes involved in biotransformation
      and oxidative stress that may be regulated by Ah-receptor-dependent pathways.
      Exposure of bass to beta-naphthoflavone (beta-NF, 66 mg/kg, i.p.) elicited a 7-9
      fold increase in hepatic microsomal cytochrome P4501A-dependent ethoxyresorufin O
      deethylase (EROD) activities, but did not affect cytosolic GST catalytic
      activities toward 1-chloro-2,4-dinitrobenzene (CDNB) or 5-androstene-3,17-dione
      (ADI). Glutathione S-transferase A (GST-A) mRNA expression exhibited a transient,
      but non-significant increase following exposure to beta-NF, and generally tracked
      the minimal changes observed in GST-CDNB activities. Expression of the mRNA
      encoding glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting
      enzyme in glutathione (GSH) biosynthesis, was increased 1.7-fold by beta-NF.
      Changes in GCLC mRNA expression were paralleled by increases in intracellular
      GSH. In summary, largemouth bass hepatic CYP1A-dependent and GSH biosynthetic
      pathways, and to a lesser extent GST, are responsive to exposure to beta-NF.

PMID- 15178099
TI  - Cloning and sequence analysis of the self-fertilizing fish Rivulus marmoratus
      immediate early gene c-fos.
AB  - We have cloned the proto-oncogene c-fos from a self-fertilizing fish Rivulus
      marmoratus (Cyprinodontiformes, Rivulidae) after screening of R. marmoratus
      lambdaGEM-11 genomic DNA library, and sequenced over 12 kb including all exons,
      introns and the promoter region. The R. marmoratus c-fos gene consisted of one
      noncoding exon and four exons with high similarity to those of fugu and mammals.
      We sequenced approximately 7 kb of the R. marmoratus c-fos gene promoter region
      to gain a better understanding of the molecular anatomy of the immediate response
      of this gene upon cellular damage. In the promoter region, R. marmoratus c-fos
      gene has seven xenobiotic response elements (XREs) and eight metal response
      elements (MREs) as well as two estradiol (E2), 4 NFkappaB, 2 CarG, 2 prolactin
      (PRL) motifs and one pit1 site, while the 3'-UTR of this gene contains the
      estrogen response element (ERE). The seven XRE and eight MRE motifs raise the
      possibility of its regulation by exposure to environmental pollutants. In this
      paper, we discuss the gene structure of R. marmoratus c-fos gene and compare its
      promoter region with those of other organisms' c-fos genes. We propose its
      potential use in ecotoxicology.

PMID- 15178100
TI  - Genomic cloning and expression of vitellogenin gene from the self-fertilizing
      fish Rivulus marmoratus (Cyprinodontiformes, Rivulidae).
AB  - We cloned the vitellogenin gene from the self-fertilizing fish Rivulus
      marmoratus, and sequenced 12,326 bp. The number of exons of R. marmoratus and
      rainbow trout vitellogenin genes were different, and also the splicing junctions
      are different throughout most of the exons and introns but the amino acid
      similarity of R. marmoratus vitellogenin gene to other species was rather high.
      In promoter region of R. marmoratus vitellogenin gene, there were several E2
      binding sites and the estrogen response element (ERE). We discuss here the gene
      structure and expression of R. marmoratus vitellogenin gene.

PMID- 15178101
TI  - Detection of DNA damage in mussels and sea urchins exposed to crude oil using
      comet assay.
AB  - The single-cell microgel electrophoresis assay or the comet assay was used to
      evaluate DNA damage of dispersed crude oil on sea urchins (Strongylocentrotus
      droebachiensis) and mussels (Mytilus edulis L.). Sea urchins were exposed to 0.06
      and 0.25 mg/L dispersed crude oil in a continuous flow system, while the mussels
      were exposed to 0.015, 0.06 and 0.25 mg/L dispersed crude oil. Sea urchin
      coelomocytes and mussel haemocytes were sampled after 4 and 5 weeks exposure,
      respectively. In the sea urchin coelomocytes, there was a significant
      concentration-related increase in the percentage of DNA in comet tail. In mussel
      haemocytes, there was a significantly higher percentage of DNA in comet tail for
      all treatments compared to the control. The responses were concentration-related
      up to 0.06 mg/L oil. The two highest exposure concentrations of mussels were not
      significantly different from each other. These results indicate that the comet
      assay can be used for biomonitoring of DNA damage in marine invertebrates
      following oil contamination.

PMID- 15178102
TI  - Assessing DNA damage in cnidarians using the Comet assay.
AB  - The assessment of DNA damage by the Comet assay has been described as a useful
      non-specific general biomarker of stress in many marine organisms. In field
      situations it has successfully been employed to distinguish between reference and
      polluted sites and in the laboratory it has been widely used as a mechanistic
      tool to determine pollutant effects and mechanisms of DNA damage. To date a wide
      range of marine vertebrates and invertebrates have been used, however, the
      usefulness of this assay as a biomarker in cnidarians has not yet been assessed.
      The aims of this study were to optimize the Comet assay for cnidarian cells and
      to assess its utility for detecting genotoxic damage in these cells. Cells were
      isolated from the North American pacific coast temperate sea anemone Anthopleura
      elegantissima using a non-enzymatic dissociation procedure and viability was
      determined to be in excess of 90%. Cells were incubated either with (1 h acute
      exposures) hydrogen peroxide (H(2)O(2)), ethylmethanesulphonate (EMS) or
      benzo(a)pyrene (B[a]P). In comparison to other marine species, anemone cells
      exhibited high control or background levels of DNA strand breaks. Despite this,
      however, we observed dose responses for each of the study chemicals with no
      reduction in cell viability. This study demonstrates that anemone cells respond
      to known DNA damaging agents, including B[a]P which requires metabolism to exert
      its genotoxic effect, and that the Comet assay may prove to be a useful biomarker
      of stress in cnidarian species.

PMID- 15178103
TI  - Exposure of grass shrimp to sediments receiving highway runoff: Effects on
      reproduction and DNA.
AB  - A grass shrimp bioassay was carried out on sediments from three estuarine
      stations which were different distances from a highway storm drain. Total
      polycyclic aromatic hydrocarbon (PAH) concentrations were 29, 1.5 and 0.1
      microg/g sediment at stations A (next to drain), B (100 m from drain) and C (500
      m from drain), respectively. Lower embryo production and embryo hatching rates
      and a higher level of DNA strand breaks (comet assay) were observed in grass
      shrimp exposed to stations A and B sediments. There appeared to be an association
      between reproduction abnormalities and increased DNA strand breaks as a result of
      grass shrimp exposure to estuarine sediments receiving highway runoff.

PMID- 15178104
TI  - Mycobacteria, but not mercury, induces metallothionein (MT) protein in striped
      bass, Morone saxitilis, phagocytes, while both stimuli induce MT in channel
      catfish, Ictalurus punctatus, phagocytes.
AB  - Recent advances in molecular immunology indicate that the expression of inducible
      pro-inflammatory proteins is increased in vertebrates in response to both
      infectious disease agents and various xenobiotics. For example, iNOS, COX-2, and
      CYP1A are induced by both inflammation and AhR ligands. Moreover, the expression
      of these proteins in response to stimuli varies among individuals within
      populations. Little is known of the differences among fish in the inducibility of
      proinflammatory proteins in response to both infectious agents and xenobiotics.
      Through random screening of a striped bass, Morone saxitilis, peritoneal
      macrophage cDNA library, a full length metallothionein (MT) gene was cloned and
      sequenced. MT is a low-molecular weight (6-8 kDa), cysteine-rich metal binding
      protein. Metals are required by pathogenic bacteria for growth, and by the host
      defense system by serving as a catalyst for the generation of reactive oxygen
      intermediates (ROIs) by phagocytes. A recombinant striped bass MT (rMT) was
      expressed and purified, then used to generate a specific mAb (MT-16). MT protein
      expression was followed in freshly isolated striped bass and channel catfish,
      Ictalurus punctatus, phagocytes after in vitro exposure to the naturally
      occurring intracellular pathogen Mycobacteria fortuitum or to 0.1 and 1 microM
      mercury (Hg), as HgCl(2). MT expression was increased by 24 h in both channel
      catfish and striped bass phagocytes as a result of exposure to M. fortuitum
      cells. On the other hand, MT was induced by Hg in channel catfish cells, but not
      those of striped bass. These results indicate that metal homeostasis in
      phagocytes is different between catfish and striped bass. In addition, these data
      suggest that care should be taken to distinguish between inflammation-induced vs.
      metal-induced MT when using MT expression as a biomarker of metal exposure.

PMID- 15178105
TI  - Oxidative damage to DNA: an immunohistochemical approach for detection of 7,8
      dihydro-8-oxodeoxyguanosine in marine organisms.
AB  - The modified nucleoside 7,8-dihydro-8-oxodeoxyguanosine (8-oxo-dG) is an index of
      oxidative DNA damage. An immunohistochemical approach based on the use of
      monoclonal antibody 1F7 against 8-oxo-dG was investigated in marine organisms
      with immunoperoxidase and immunofluorescent detection. Relative staining
      intensity as a measure of the 8-oxo-dG level was microscopically assessed. After
      laboratory exposures to benzo[a]pyrene (B[a]P), higher levels of oxidative DNA
      damage were clearly detected in all treated animals compared to controls. While
      this method eliminates DNA extraction reducing the processing of biological
      samples, absolute values are not provided. Further, the method requires only
      small amounts of tissue and potentially discriminates susceptibility to oxidative
      damage in different cell types. These results suggest that the assay should have
      practical applications in marine ecotoxicology.

PMID- 15178106
TI  - Suppressive effects of benzo[a]pyrene upon fish immune function: evolutionarily
      conserved cellular mechanisms of immunotoxicity.
AB  - Knowledge gained through the use of alternative animal models has significantly
      enhanced our understanding of life at all levels of biological organization. The
      discipline of toxicology is under considerable pressure to develop such models
      due to increasing public concern regarding the experimental use of mammals.
      Studies in this laboratory have focused on the utility of a small laboratory fish
      model, the Japanese medaka (Oryzias latipes), to investigate immunotoxicological
      effects of benzo[a]pyrene (BaP). BaP is a ubiquitous environmental contaminant
      and known mammalian immunotoxicant. This laboratory has demonstrated that in vivo
      exposure of medaka to BaP (2-200 microg/g BW) significantly depresses both innate
      and humoral immunity. Further studies have indicated that BaP activates its own
      biotransformation pathway within medaka immune cells following both in vivo and
      in vitro exposure. In addition, reduction of BaP metabolism with alpha
      naphthoflavone results in the reversal of BaP-induced suppression of antibody
      production in vitro. Inhibition of CYPlA-mediated metabolism within medaka immune
      cells also alleviates the immunotoxicity induced by benzo[a]pyrene-7,8
      dihydrodiol, but not benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). This
      suggests that BPDE may be an ultimate immunotoxicant. Results from this study in
      medaka are in agreement with previously conducted rodent studies that indicated a
      role for immunotoxic BaP metabolites in BaP-induced suppression of humoral
      immunity.

PMID- 15178107
TI  - Interactive effects of UV, benzo[alpha] pyrene, and cadmium on DNA damage and
      repair in embryos of the grass shrimp Paleomonetes pugio.
AB  - We examined the link between DNA strand breaks and hatching rates in grass
      shrimp, (Paleomonetes pugio), embryos exposed to 0.2 microM benzo[alpha] pyrene
      (BP), 5 microM cadmium (Cd) and 330 kJ/m(2) UV light, either alone or together.
      After exposure, embryos were transferred to clean seawater with or without 5
      microM Cd. Hatching rates and DNA strand breaks (Comet Assay) were determined.
      DNA lesions caused by exposure to BP, UV light, or BP/cadmium were rapidly
      repaired and were not associated with any effects on hatching. Exposure to Cd
      after exposure to BP or UV did not affect embryological development or DNA
      repair. Exposure to BP/UV resulted in a high level of DNA lesions which were
      slowly repaired. Exposure to cadmium following BP/UV exposure inhibited hatching
      and DNA repair. Adducts formed during exposure to BP/UV exposure may be difficult
      to excise or may saturate the nucleotide excision repair system.

PMID- 15178108
TI  - Measuring lysosomal stability as an effective tool for marine coastal
      environmental monitoring.
AB  - The use of lysosomal stability in the mussel, Mytilus galloprovincialis, as a
      potential biomarker of environmental contamination has been evaluated along the
      Portuguese coast. To this end, the neutral red retention (NRR) time was measured
      in mussel haemocytes gathered from nine different locations reflecting different
      degrees of anthropogenic contamination. Mussels collected in the vicinity of
      industrial and urban areas showed the lowest lysosomal stability. Additionally,
      no significant seasonal variability (winter-spring/summer) for NRR time was
      observed. In order to further support the usefulness of this method as an
      integrated tool for monitoring marine coastal environments, we compared the
      levels of xenobiotics in mussel tissues with the obtained NRR values. The results
      highlighted a consistent pattern, with the lowest lysosomal stability intimately
      correlated with the higher contaminant concentrations. In summary, this
      integrated approach further demonstrated that the NRR assay can provide useful
      and objective indications of the real health status of organisms subjected to
      different stress agents, being a valid option for environmental monitoring.

PMID- 15178109
TI  - c-Reactive protein levels as a biomarker of inflammation and stress in the
      Atlantic sharpnose shark (Rhizoprionodon terraenovae) from three southeastern USA
      estuaries.
AB  - Circulating c-reactive protein (CRP) levels can be used as a bioindicator of the
      acute phase inflammatory response and as a possible biomarker of inflammation and
      neurogenic stress in vertebrates. Currently, there are no data describing the
      ranges of CRP levels in sharks living in different habitats, especially habitats
      of differing degrees of pollution. Developing antibodies against CRP is a first
      and critical step towards developing sensitive methods for quantifying CRP, and
      thus inflammatory and stress responses in sharks. Sharpnose shark, Rhizoprionodon
      terraenovae, serum C-reactive protein was purified sequentially over AH-sepharose
      4B-PC and sepharose CL-4B columns and used to immunize balb/c mice for generating
      stocks of polyclonal anti-sera. Serum samples from 131 sharpnose sharks were
      collected from three different geographical regions along the coast of SC and GA,
      USA between June and November 2002. Total CRP concentrations were quantified by
      ELISA and found to be highest in the sharpnose shark population collected in the
      summer from Charleston, SC, compared to Beaufort, SC and Brunswick, GA. Seasonal
      comparisons indicated a higher CRP concentration in the summer of the Charleston,
      SC population compared to the fall. These data suggest that sharks living in the
      Charleston, SC harbor estuary may be exposed to a suite of pathogens or other
      stressors that are different than those found in the Beaufort, SC and Brunswick,
      GA estuaries. These data support the use of CRP as a bioindicator of health
      status in elasmobranchs.

PMID- 15178111
TI  - The viviparous blenny (Zoarces viviparus) as a bioindicator of contaminant
      exposure: application of biomarkers of apoptosis and DNA damage.
AB  - The viviparous blenny (Zoarces viviparus), also known as eelpout, is considered a
      suitable biomonitor for use in European estuarine and coastal waters. We have
      previously shown that Z. viviparus from the industrialised Tyne estuary (UK)
      display certain histopathologies (e.g., ovotestis and hepatic nuclear and
      cellular pleomorphism), which are associated with contaminant exposure [Mar.
      Environ. Res. 55 (2003) 137]. Furthermore, the prevalence of these pathologies
      was higher than in fish collected from a less contaminated reference site (the
      Alde estuary, UK). Here, tissue samples were collected from Z. viviparus from the
      Tyne and Alde estuaries (in the spring and autumn) and analysed for DNA adducts
      using the (32)P-postlabelling assay and for histopathology. Z. viviparus caught
      from the Tyne during the spring (56.4+/-18.5 adducts per 10(8) nucleotides) and
      autumn (63.1+/-7.5 adducts per 10(8) nucleotides) exhibited patterns of DNA
      adducts which indicated exposure to a complex mixture of genotoxins. In contrast,
      levels of DNA adducts in Z. viviparus from Alde estuary were significantly lower
      during both sampling periods. Histopathological changes to the gonads included
      intersex (ovotestis) and germ cell apoptosis (detected via the TUNEL assay) in
      male fish captured from the Tyne estuary. Further studies on the use of germ cell
      apoptotic rate at different estuarine sites are required if it is to be used as a
      reproductive biomarker of contaminant exposure in male fish.

PMID- 15178110
TI  - Measurement of DNA single-strand breaks in gill and hemolymph cells of mussels,
      Mytilus sp., collected on the French Atlantic Coast.
AB  - DNA single-strand breaks were measured by the comet assay in both gill and
      hemolymph cells of mussels collected in 3 sampling areas of the French coast
      (Pointe du Castelli, Pen Bron and Saint-Nazaire Harbour). Whole mussel tissue
      samples were also collected for the chemical determination of PAH, PCB and heavy
      metal concentrations. In mussel, a higher level of DNA strand breaks was measured
      in gill than in hemolymph cells (p < 0.01). Despite a factor of contamination
      from 2 to 3 between sites, no difference in the extent of mussel DNA strand
      breaks was shown between sampling locations (p > 0.05), questioning the
      sensitivity of the assays used in biomonitoring studies.

PMID- 15178112
TI  - DNA strand breakage in mussels (Mytilus edulis L.) deployed in intertidal and
      subtidal zone in Reykjavik harbour.
AB  - DNA single-strand breaks were analysed in the blue mussel (Mytilus edulis L.)
      deployed in intertidal and subtidal zones in the PAH contaminated Reykjavik
      harbour and at a reference site, Hvalfjorethur, Iceland. DNA strand breaks were
      analysed by Comet assay in isolated gill and haemocyte cells from six mussels
      from each site and depth. Increased DNA damage in both gill cells and haemocytes
      were observed in mussels deployed in Reykjavik harbour compared to the reference
      site. Intertidal mussels from Reykjavik harbour had higher DNA damage in
      haemocytes compared to subtidal mussels. The Comet assay seems to be useful for
      measuring genotoxic exposure in mussels from the field, and that DNA damage might
      be higher in the intertidal zone either due to higher exposure to contaminants or
      because of physiological and biochemical responses to variations in oxygen
      availability.

PMID- 15178113
TI  - Temperature-dependent physiological response of Carcinus maenas exposed to
      copper.
AB  - The effect of temperature on the heart rate (fH) of Carcinus maenas exposed to a
      sublethal nominal concentration (0.5 mg l(-1)) of copper is reported. Adult,
      intermoult males (4 cm carapace width) were collected from Stavanger Fjord
      (Norway) in August (seawater TEMPERATURE=17 degrees C) and maintained in the
      laboratory (fed ad libitum) at 5, 15 and 25 degrees C for 7 days. Following this
      holding period, crabs were exposed to waterborne copper at the same temperature.
      After 3 days of exposure, individual fH was measured using the non-invasive
      Computer Aided Physiological MONitoring system (CAPMON) method. Copper-exposed
      individuals demonstrated significantly increased fH compared with controls at 5
      and 25 degrees C (P<0.01). It is inferred that physiological function in C.
      maenas may be more vulnerable to copper contamination at seasonal temperature
      extremes (5 and 25 degrees C) than at the 'standard' test temperature (15 degrees
      C). Additionally, cardiac arrest observed at 5 degrees C is interpreted as a
      physiological response to limit copper uptake while the erratic fH in the 25
      degrees C group reflected enhanced copper toxicity.

PMID- 15178114
TI  - Effects of hypoxia on gene and protein expression in the blue crab, Callinectes
      sapidus.
AB  - Increases in hypoxic conditions are one of the major factors responsible for
      declines in estuarine habitat quality, yet to date there are no indicators for
      recognizing populations of estuarine organisms that are suffering from chronic
      hypoxic stress. Here we test the hypothesis that alterations in gene and protein
      expression of antioxidant enzymes and other stress-specific proteins can be used
      as molecular indicators of hypoxic stress. Blue crabs, Callinectes sapidus, were
      exposed to 2-3 ppm DO for 5 days. Gene expression was measured using macroarrays
      constructed from cDNA of 10 partial gene transcripts cloned from blue crab
      hepatopancreas. Significant (p< or =0.05) down-regulation of gene expression was
      found for MnSOD, hemocyanin, ribosomal S15 and L23. Subtractive hybridization
      using RNA from control and hypoxic hepatopancreas tissues also indicated down
      regulation of hemocyanin transcription. In contrast, Western blotting showed a
      significant (p< or =0.05) increase of hemocyanin protein in the hepatopancreas
      and cross-linking of MnSOD proteins in hypoxia-exposed crabs. Thus, hypoxia
      responsive cDNA arrays and Westerns may be useful diagnostic tools for monitoring
      effects of hypoxia in estuarine crustacea.

PMID- 15178115
TI  - Effects of copper and decreased salinity on survival rate and development of
      Tridacna gigas larvae.
AB  - Giant clams (Family: Tridacnidae) are endangered species distributed in the Indo
      Pacific region. In this study, survival rate and development of Tridacna gigas
      larvae were studied for three days in ambient water (32 psu), copper (2.5 microg
      Cu(2+) L(-1)), reduced salinities (25 and 20 psu) and the combination of copper
      and 25 psu salinity. No significant differences were found in larval development
      between treatments. The survival rates decreased considerably with reduced
      salinities although the combination of copper and reduced salinity gave
      synergistic effects. As a consequence, this could limit population growth of
      giant clams in coastal areas and could also explain the absence of larval
      settlement on reefs close to harbours or river mouths. More research is needed to
      understand the basic requirements and stress tolerance in giant clam larvae for
      reef restoration and other management actions to be successful.

PMID- 15178116
TI  - Stress-induced apoptosis in sea urchin embryogenesis.
AB  - We find that early sea urchin embryos have the capability to induce programmed
      cell death, or apoptosis, in response to chemical and physical stress.
      Strongylocentrotus purpuratus embryos (fertilized, 4 cell, 16 cell, 64 cell, and
      early blastula) were exposed to known cytotoxins, in order to determine when
      apoptosis occurs naturally and in response to stress. Using cell permeability as
      an indicator of early stage apoptosis, caspase activation as a mid-stage
      indicator, and DNA fragmentation as a late stage indicator, we find that during
      the cleavage stage of embryogenesis apoptosis is almost completely absent.
      However, a statistically significant (p<0.001) rise in apoptosis in stressed
      embryos is evident around 24 h after fertilization, during the early blastula
      stage and shortly after hatching. Before this stage, exposed embryos show no
      statistically significant increases in apoptosis in comparison to the controls.
      This pattern of apoptosis in development is similar to that seen in lower
      vertebrate models in which stress-induced apoptosis occurs only around the mid
      blastula transition. We conclude that apoptosis may be used to rid embryos of
      aberrant or damaged cells in early development, but this response is stage
      dependant. Repair, rather than apoptosis, may be utilized during earlier stages,
      or alternatively, embryos exposed to such stressors may continue development with
      damaged cells and perhaps damaged DNA. Our continued studies will focus on these
      alternative hypotheses.

PMID- 15178117
TI  - The influence of salinity on the heat-shock protein response of Potamocorbula
      amurensis (Bivalvia).
AB  - For biomarkers to be useful in assessing anthropogenic impacts in field studies
      involving aquatic organisms, they should not be affected by naturally occurring
      changes in environmental parameters such as salinity. This is especially
      important in estuarine environments and for relatively unspecific biomarkers like
      heat-shock proteins (hsps, stress proteins). In this study, the heat-shock
      protein response was measured in the euryhaline clam, Potamocorbula amurensis,
      after exposure to a range of salinities reflecting normal and extreme
      environmental conditions in Northern San Francisco Bay, California. The ability
      to raise cellular hsp70 levels in response to heat-shock was significantly
      impaired in P. amurensis collected from a low (0.5 ppt) salinity field site, and
      after 14 day exposure to low salinity in the laboratory.

PMID- 15178118
TI  - Molecular and cellular biomarker responses to pesticide exposure in juvenile
      chinook salmon (Oncorhynchus tshawytscha).
AB  - We determined the effects of two pesticides, chlorpyrifos and esfenvalerate in
      juvenile Chinook salmon. Four to five month old salmon were exposed to a range of
      pesticide concentrations, and tissue samples of surviving fish were analyzed for
      stress protein expression, cytokine transcription, and acetylcholinesterase
      (AChE) activity. At the highest concentrations, both pesticides led to complete
      mortality, whereas medium and low concentrations resulted in high survival rates.
      Significant differences in stress protein expression, cytokine transcription and
      AChE activity were found between control and surviving chlorpyrifos-exposed fish.
      Elevated stress protein expression was the only detectable response to
      esfenvalerate.

PMID- 15178119
TI  - A carbon and nitrogen flux model of mussel digestive gland epithelial cells and
      their simulated response to pollutants.
AB  - The mussel digestive gland epithelial cells provide a key interface between the
      organism and pollutants such as aromatic hydrocarbons. The simulation of their
      uptake and export mechanisms as well as an internal protein degradation pathway,
      and any subsequent disruption to any of them, has been undertaken. A
      computational model is described, which simulates the flow of carbon and nitrogen
      through a mussel's digestive cell. The model uses a compartmentalised view of the
      cell with inviolate 'pipelines' connecting each of the volume-variable
      partitions. Only the major physiological pathways relevant to the flow of either
      carbon or nitrogen or volume are modelled. Simulated response to hydrocarbon
      exposure is examined.

PMID- 15178120
TI  - Metal uptake in zebrafish embryo-larvae exposed to metal-contaminated sediments.
AB  - Heavy metal contamination in coastal and estuarine regions of inner Tolo Harbour,
      as well as some river and nullah areas, is one of the major water-pollution
      issues in Hong Kong. Zebrafish (Danio rerio) embryo-larvae was used to study
      metal uptake from coastal sediments collected from Fo Tan River (industrial area,
      Sha Tin), Tai Po River (residential area, Tai Po) and Wu Kai Sa (rural area, Tolo
      Harbour). Exposure experiments (7-days) were carried out using different
      concentrations (0.1%, 0.5%, 1% and 0% as control) of sediments that were added to
      aquaria containing fertilized zebrafish eggs until they hatched to become larvae.
      Uptake of heavy metals (Cd, Cu, Pb and Zn) was determined in whole embryo-larvae
      following exposure. Significant levels of Cd, Cu, Pb and Zn were detected in the
      embryo-larvae exposed to sediments from Tai Po River. However, significant levels
      of only Cd and Cu were found in embryo-larvae exposed to sediments from Fo Tan
      River.

PMID- 15178121
TI  - Toxicokinetics of heavy metals from a mining spill using Carcinus maenas.
AB  - The knowledge of the reproduction and growth background related to the shore crab
      Carcinus maenas promotes the use of this crab as a model crustacean to asses the
      potential for endocrine disruption in crustaceans. In addition, an enzyme linked
      inmunosorbent assay (ELISA), sensitive to the shore crab vitellogenin in serial
      hemolymph samples allows determination of the extent of disruption of the process
      of vitellogenesis in female crabs and its likely impact on reproductive output.
      Intermoult females Carcinus maenas were exposed to concentrations of Cd: 3
      microgl(-1), Cu: 15 microgl(-1) and Zn: 700 microgl(-1) determined at the
      Guadalquivir estuary after the Aznalcollar mining spill, during 21 days. Crab
      hemolymph samples, were taken every seven days, and analyzed through an ELISA for
      Carcinus maenas vitellogenin. Vitellogenin concentration along the time was
      fitted to a first order kinetic approach. Results showed a good correlation among
      experimental values and estimated ones. Metal exposure resulted in an increase in
      vitellogenin concentration in hemolymph, especially for cadmium.

PMID- 15178122
TI  - Total content and chemical speciation of arsenic in the polychaete Sabella
      spallanzanii.
AB  - An unusual feature has been observed in polychaetes regarding their capacity to
      accumulate high levels of relatively toxic forms of arsenic in specific tissues.
      Basal levels of arsenic and distribution of its compounds were investigated in
      tissues of the Mediterranean polychaete Sabella spallanzanii. Particularly high
      concentrations were measured in the branchial crown (1036+/-136 microg/g d.w.)
      and chemical speciation revealed that the predominant form was the relatively
      toxic dimethylarsinate (DMA). These data suggest a potential role of As as anti
      predatory strategy in polychaetes.

PMID- 15178123
TI  - Chemical speciation of arsenic in different marine organisms: Importance in
      monitoring studies.
AB  - Arsenic is a widely distributed element in the marine environment. Inorganic and
      organic compounds have extremely different toxicological effects, and their
      characterization is thus of great utility when monitoring and assessing the
      impact of arsenic pollution. In this study both the levels of total arsenic and
      its chemical speciation were analyzed in several marine organisms collected from
      Cienfuegos Bay (Cuba) following an episode of acute As-contamination. Fish from
      the more impacted site were characterized by elevated concentrations of arsenic
      (up to 500 microg/g d.w.) and inorganic species represented the predominant forms
      in muscle tissues of these organisms.

PMID- 15178124
TI  - Achieving environmentally relevant organochlorine pesticide concentrations in
      eggs through maternal exposure in Alligator mississippiensis.
AB  - Alligator mississippiensis eggs from organochlorine pesticide (OCP) contaminated
      sites in Florida exhibit high rates of embryonic mortality compared to reference
      sites (P < 0.05). The objective of the present study was to use captive adult
      alligators to test the hypotheses that maternal exposure to OCPs results in
      increased OCP concentrations in eggs, and that increased exposure is associated
      with increased embryonic mortality. A total of 24 adult alligators (8 males and
      16 females) were housed in eight pens. Eight females in four pens were dosed with
      a mixture of p,p'-DDE, toxaphene, dieldrin, and chlordane at a rate of 0.2+/-0.01
      mg/kg/day for 274+/-8 days. Treated females produced eggs containing higher OCP
      concentrations (12,814+/-813 ng/g yolk) than controls (38+/-4 ng/g yolk). Eggs of
      treated females exhibited decreased viability (13+/-22%) as compared to controls
      (45+/-20%). Results indicated that 0.6% of administered OCPs were maternally
      transferred to the eggs of American alligators, and that maternal exposure is
      associated with decreased egg/embryo viability in this species.

PMID- 15178126
TI  - A qualitative study of therapeutic effect from a user's perspective.
AB  - This study investigated the experiences of adults who have completed a course of
      therapy for stammering. The objective was to inform clinicians about the effect
      of therapy by listening to the client's own account of the experience after they
      had been discharged from therapy. The study involved individuals discussing their
      experiences and their views on the effect of therapy in an in-depth, semi
      structured interview. The individual transcripts were subjected to analyses and
      several major themes emerged. A number of the themes had implications for
      clinical practice and these were considered in detail. The value of having a
      dialogue with clients about the effect of therapy after it has formally come to
      an end is discussed in relation to monitoring of therapeutic effectiveness.
      EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe ways of
      evaluating the effect of therapy; (2) summarize qualitative methodology involving
      interviewing techniques; (3) utilize the client experience of therapy in
      monitoring therapeutic effectiveness.

PMID- 15178127
TI  - Linguistic stress, within-word position, and grammatical class in relation to
      early childhood stuttering.
AB  - The purpose of the present study was to investigate whether the link that has
      been established between stuttering and linguistic stress in adolescents and
      adults (the so-called stress effect) can also be observed in childhood
      stuttering. To account for confounding variables, both within-word position and
      grammatical class were measured, because these factors covary with linguistic
      stress. Speech samples of 22 preschool children (mean time of 9 months since
      onset of stuttering) were analyzed. The relative stress of each syllable was
      rated and syllables were categorized into long and short stressed, unstressed,
      and intermediately stressed syllables. Results showed that 97.8% of stuttering
      events occurred on first syllables of words and 76.5% on the first sound of
      syllables, that means a clear word-initial effect. Stuttering frequency on first
      syllables of function words was 16.9% and significantly higher than the frequency
      of stuttered first syllables of content words (11.5%). In function words short
      stressed syllables and intermediately stressed syllables were stuttered more
      often than unstressed syllables. The analysis for individual disfluency types
      revealed that, for function words, stuttering on short stressed syllables was
      associated with prolongations and syllable repetitions. However, in
      intermediately stressed syllables stuttering coincided most often with one
      syllable word repetitions. This differentiation of the stress effect may suggest
      different causal mechanisms underlying these disfluency types. EDUCATIONAL
      OBJECTIVES: The reader will learn about and be able to: (1) describe how within
      word position, grammatical class, and linguistic stress effect stuttering
      frequency in preschool children who stutter; (2) explain how the occurrence of
      individual disfluency types depends on linguistic stress; (3) discuss how
      patterns of adults and preschool children who stutter differ in regard to these
      aspects.

PMID- 15178128
TI  - Stuttering, emotions, and heart rate during anticipatory anxiety: a critical
      review.
AB  - Persons who stutter often report their stuttering is influenced by emotional
      reactions, yet the nature of such relation is still unclear. Psychophysiological
      studies of stuttering have failed to find any major association between
      stuttering and the activity of the sympathetic nervous system. A review of
      published studies of heart rate in relation to stressful speech situations
      indicate that adults who stutter tend to show a paradoxical reduction of heart
      rate compared with nonstuttering persons. Reduction of heart rate has also been
      observed in humans and mammals during anticipation of an unpleasant stimulus, and
      is proposed to be an indication of anticipatory anxiety resulting in a "freezing
      response" with parasympathetic inhibition of the heart rate. It is suggested that
      speech-related anticipatory anxiety in persons who stutter is likely to be a
      secondary, conditioned reaction based on previous experiences of stuttering.
      EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe how the
      autonomic nervous system is modulated by emotional responses; (2) explain how
      anticipatory fear often results in inhibition of heart rate due to
      parasympathetic activation; (3) discuss why emotional reactions in persons who
      stutter may be secondary to negative experiences of speech problems.

PMID- 15178129
TI  - The relationship between anxiety and stuttering: a multidimensional approach.
AB  - The relationship between anxiety and stuttering is equivocal from both clinical
      and empirical perspectives. This study examined the relationship within the
      framework of the multidimensional interaction model of anxiety that includes an
      approach to general anxiety in specific situations [J. Pers. Soc. Psychol. 60
      (1991) 919]. Ninety-four males aged 18-43, half disfluent speakers and half
      fluent speakers completed two questionnaires: The Trait Anxiety Inventory [C.D.
      Spielberger, R.L. Gorsuch, R.E. Lushene, Manual for the State-Trait Anxiety
      Inventory (Self Evaluation Questionnaire), Consulting Psychologists Press, Palo
      Alto, CA, 1970] and the Speech Situation Checklist [G.J. Brutten, Neurolinguistic
      Approaches to Stuttering, Mouton, The Hague; G.J. Brutten, Stuttering: A Second
      Symposium, Harper and Row, New York, 1973; G.J. Brutten, P. Janssen, Proceedings
      18th Congress of the International Association of Logopedics and Phoniatrists,
      Washington, DC, 1975; M. Vanryckeghem, Proceedings of the XXIVth Congress of the
      International Association of Logopedists and Phoniatrists, Nijmegen University
      Press, Nijmegen, 1981]. In addition, after performing speech and non-speech
      tasks, participants evaluated their level of anxiety on a subjective scale,
      labeled Task-Related Anxiety--TRA. The stuttering group also evaluated the level
      of severity of their stuttering. Findings indicate that trait anxiety is higher
      among people who stutter compared to fluent speakers, thus indicating that
      anxiety is a personality trait of people who stutter. State anxiety in social
      communication is higher among severe stutterers as compared to mild stutterers
      and fluent speakers. Thus, state anxiety is related to stuttering severity. The
      results are discussed in the frame of the multidimensional model of anxiety.
      EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe the
      multidimensional anxiety model; (2) extend the model to the relations between
      stuttering and anxiety; (3) describe stuttering severity in relation to the
      levels of anxiety within the model.

PMID- 15178130
TI  - Predicting stuttering from phonetic complexity in German.
AB  - This study investigated how phonetic complexity affects stuttering rate in German
      and how this changes developmentally. Phonetic difficulty was assessed using
      Jakielski's index [Motor Organization in the Acquisition of Consonant Clusters,
      Dissertation/Ph.D. Thesis, University of Texas Austin, 1998] of phonetic
      complexity (IPC) in which words are scored on eight different characteristics.
      Stuttering rate was not related to IPC score for German function words, as
      previously shown for Spanish and English. Significant correlations between
      stuttering rate and IPC score were found for content words for children over the
      age of six and adults. It was also found that German content words have a higher
      mean IPC sum compared to their English counterparts. There was a bigger
      difference in IPC score between fluent and stuttered words in German than in
      English. Factor 5 (word shape) influenced stuttering rates in both German age
      groups. This has also been found for Spanish but does not apply to English.
      EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe a method to
      measure phonetic complexity and how this affects stuttering rates for words of
      different grammatical classes; (2) explain why this method is suitable for
      different languages and age groups; (3) detect which phonetic characteristics
      have most impact on different age groups in English and German; (4) assess
      possible theoretical reasons for these findings.

PMID- 15178131
TI  - Mitochondrial oxidative stress can lead to nuclear hypermutability.
AB  - Reactive oxygen species (ROS) are generated in mitochondria and are thought to be
      important in aging, carcinogenesis, and the development of other pathologies. We
      now provide direct experimental evidence linking mitochondrial ROS generation to
      the induction of nuclear DNA damage and subsequent mutagenesis of a chromosomal
      gene. Specifically, we demonstrate that the mev-1 mutant of Caenorhabditis
      elegans has elevated levels of oxidative damage in its chromosomal DNA. This
      mutant was shown previously to overproduce ROS in its mitochondria. We also show
      that mutation frequencies were higher in the mev-1 mutant under hypoxia than in
      the wild type strain. By extension, these data imply that mitochondrially derived
      ROS mutate other genes, including tumor suppressor genes and oncogenes. We
      propose that this three-step process (mitochondrial ROS --> nuclear DNA damage -
      > mutation) contributes to aging and age-associated diseases.

PMID- 15178132
TI  - Tolerance of aged Fischer 344 rats against chlordecone-amplified carbon
      tetrachloride toxicity.
AB  - We have investigated the effects of chlordecone 1(CD)+CCl4 combination in adult
      (3 months), middle aged (14 months), and old aged (24 months) male Fischer 344
      (F344) rats. After a non-toxic dietary regimen of CD (10 ppm) or normal powdered
      diet for 15 days, rats received a single non-toxic dose of CCl4 (100 microl/kg,
      i.p., 1:4 in corn oil) or corn oil (500 microl/kg, i.p.) alone on day 16. Liver
      injury was assessed by plasma ALT, AST, and histopathology during a time course
      of 0-96 h. Liver tissue repair was measured by [3H-CH3]-thymidine (3H-T)
      incorporation into hepatic nuclear DNA and proliferating cell nuclear antigen
      (PCNA) immunohistochemistry. Hepatomicrosomal CYP2E1 protein, enzyme activity,
      and covalent binding of 14CCl4-derived radiolabel were measured in normal and CD
      fed rats. Exposure to CCl4 alone caused modest liver injury only in 14- and 24
      month-old rats but neither progression of injury nor mortality. The CD+CCl4
      combination led to 100% mortality in 3-month-old rats by 72 h, whereas none of
      the 14- and 24-month-old rats died. Both 3- and 14-month-old rats exposed to
      CD+Cl4 had identical liver injury up to 36 h indicating that bioactivation
      mediated CCl4 injury was the same in the two age groups. Thereafter, liver injury
      escalated only in 3-month-old while it declined in 14-month-old rats. In 24-month
      old rats initial liver injury at 6 h was similar to the 3- and 14-month-old rats
      and thereafter did not develop to the level of the other two age groups,
      recovering from injury by 96 h as in the 14-month-old rats. Neither
      hepatomicrosomal CYP2E1 protein nor the associated p-nitrophenol hydroxylase
      activity or covalent binding of 14CCl4-derived radiolabel to liver tissue
      differed between the age groups or diet regimens 2 h after the administration of
      14CCl4. Compensatory liver tissue repair (3H-T, PCNA) was prompt and robust soon
      after CCl4 liver injury in the 14- and 24-month-old rats. In stark contrast, in
      the 3-month-old rats it failed allowing unabated progression of liver injury.
      These findings suggest that stimulation of early onset and robust liver tissue
      repair rescue the 14- and 24-month-old F344 rats from the lethal effect of the
      CD+CCl4 combination.

PMID- 15178133
TI  - Mathematical modeling confirms the length-dependency of telomere shortening.
AB  - Telomeres, the ends of chromosomes, shorten with each cell division in human
      somatic cells, because of the end-replication problem, C-strand processing and
      oxidative damage. On the other hand, the reverse transcriptase telomerase can add
      back telomeric repeats at the telomere ends. It has been suggested that once
      telomeres have reached a critical length, cells cease proliferation, also known
      as senescence. Evidence is accumulating that telomere shortening and subsequent
      senescence might play a crucial role in life-threatening diseases. So far,
      mathematical models described telomere shortening as an autonomous process, where
      the loss per cell division does not depend on the telomere length itself. In this
      study, published measurements of telomere distributions in human fibroblasts and
      human endothelial cells were used to show that telomeres shorten in a length
      dependent fashion. Thereafter, a mathematical model of telomere attrition was
      composed, in which a shortening factor and an autonomous loss were incorporated.
      It was assumed that the percentage of senescence was related to the percentage of
      telomeres below a critical length. The model was compared with published data of
      telomere length and senescence of human endothelial cells using the maximum
      likelihood method. This enabled the estimation of physiologically important
      parameters and confirmed the length-dependency of telomere shortening.

PMID- 15178134
TI  - Loss of N-cadherin and alpha-catenin in the proximal tubules of aging male
      Fischer 344 rats.
AB  - Aging is associated with a loss of renal reserve, and increased sensitivity to
      either xenobiotic or physiologic insult. Given the critical role of the
      cadherin/catenin complex in establishing and maintaining the integrity and
      polarity of tubular epithelial cells, it was hypothesized that aging was
      associated with alterations in renal cadherin/catenin complexes. Histological
      assessment of aged (24 months) kidneys harvested from male Fischer 344 rats
      demonstrates mild degeneration of proximal tubules, multifocal chronic
      lymphocytic infiltration, moderate development of protein casts inside tubules,
      and tubular dilatation or degeneration. Western blot analysis revealed that N
      cadherin protein expression is not constant over 24 months. N-cadherin expression
      increased from 4 to 9 months, with peak levels at 9 and 13 months. A decrease in
      expression was seen at 19 months and an almost complete loss of expression was
      seen at 24 months. In contrast, the expression of E- and Ksp-cadherin was
      constant over 24 months. A loss of alpha-catenin at was seen at 19 and 24 months
      in the absence of changes in beta-, gamma-, and p120-catenin. This pattern of N
      cadherin expression (increase followed by decrease) was confirmed by real-time
      PCR analysis, which demonstrated a similar pattern as the Western blot,
      suggesting that the loss of N-cadherin protein was due to decreased gene
      expression. The loss of N-cadherin was specific for the kidney, as no changes in
      N-cadherin expression in the liver, brain, or testes were seen during aging. The
      conclusion that loss of N-cadherin expression is a critical component of the
      renal dysfunction associated with aging is supported by the finding that caloric
      restriction attenuates the loss of N-cadherin, as well as the finding that a
      significant loss of N-cadherin is seen in the kidneys of ZDF x SHHF rats, a
      genetic model of end-stage renal disease. Cadherin and catenin expression was
      further analyzed by immunofluorescence. A significant loss of staining of both N
      cadherin and alpha-catenin was seen in the proximal tubules of rats at 24 months.
      Interestingly, this corresponded with delocalization of the alpha-1 subunit of
      the Na+K+-ATPase, i.e. aberrant staining on cell-cell borders and some indication
      of apical staining in proximal tubules. Taken together, these data suggest that
      aging is associated with decreased expression of N-cadherin and alpha-catenin and
      is associated with a loss of cell polarity.

PMID- 15178135
TI  - The effects of complex I function and oxidative damage on lifespan and anesthetic
      sensitivity in Caenorhabditis elegans.
AB  - A mutation in a subunit of complex I of the mitochondrial electron transport
      chain (gas-1) causes Caenorhabditis elegans to be hypersensitive to volatile
      anesthetics and oxygen as well as shortening lifespan. We hypothesized that
      changes in mitochondrial respiration or reactive oxygen species production cause
      these changes. Therefore, we compared gas-1 to other mitochondrial mutants to
      identify the relative importance of these two aspects of mitochondrial function
      in determining longevity. Lifespans of gas-1 and mev-1 were decreased compared
      with N2, while that of clk-1 was increased. Rates of oxidative phosphorylation
      were decreased in all three mutants, but the ROS damage was decreased only in clk
      1. Suppressors of gas-1 increased rates of oxidative phosphorylation, decreased
      oxidative damage to mitochondrial proteins and increased lifespan. Two strains
      containing combinations of mutations predicted to have very decreased complex I
      function, had unexpectedly long lifespans. We conclude that mitochondrial changes
      in lifespan appear to be mediated primarily by changes in oxidative damage rather
      than by changes in rates of oxidative phosphorylation. In contrast, the effects
      of mitochondrial changes on anesthetic sensitivity appear to be mediated by both
      altered respiration and oxidative damage.

PMID- 15178136
TI  - The ethics of public health decision making.

PMID- 15178137
TI  - The exercise of public health powers in an era of human rights: the particular
      problems of tuberculosis.
AB  - Public health legislation provides powers of removal to hospital and detention in
      circumstances where a patient with active, infectious tuberculosis (TB) is
      unwilling to comply with the recommended treatment programme. However, these
      public health powers were drafted at a time of very different scientific
      understandings of the epidemiology of disease, and at a time of a very different
      appreciation of the balance between State paternalism and individual rights. The
      re-emergence of TB as a serious threat to public health in Britain, and the
      increasing incidence of multi-drug-resistant TB raises concerns about public
      health approaches to non-compliant patients. The Human Rights Act (1998)
      introduces into English domestic law, protections against interference with
      individual rights by public authorities. The Human Rights Act not only provides a
      new basis of challenge of the exercise of powers by a public body, but has also
      had implications for the development of traditional means of challenge such as
      judicial review and litigation for damages. The consequence is that NHS
      authorities and local authorities are now more vulnerable to challenge in the
      exercise of public health powers. Health bodies should explore all possible
      alternatives to detention of a patient suffering from TB. It is to be hoped that
      the heralded reform to public health legislation is undertaken as a priority.

PMID- 15178138
TI  - Compulsory detention of recalcitrant tuberculosis patients in the context of a
      new tuberculosis control programme in Israel.
AB  - OBJECTIVE: To analyse the use of compulsory detention in the context of a new
      national tuberculosis (TB) control programme launched in 1997. METHODS: A
      retrospective review was made of the use of compulsory detention in the
      management of infectious TB before and after the initiation of a new TB control
      programme, using data from the central TB registry in the Ministry of Health and
      the charts of each patient. RESULTS: Between 1994 and 2001, 13 recalcitrant
      patients out of 3056 (0.43%) cases of pulmonary TB were brought to trial. Eleven
      patients were detained. All were either hospitalized under a court order and,
      when failing to comply with the order, hospitalized in prison, or referred
      directly to a prison hospital. Twelve of 13 (92%) patients were new immigrants.
      After the new programme was launched, proportionately fewer patients were brought
      to trial [6/943 (0.64%) in 1994-1996 compared with 7/2113 (0.33%) in 1997-2001].
      CONCLUSION: The reduction in the number of individuals detained could be viewed
      as an improvement in TB control due to the new TB control programme. It remains
      to be shown whether these individuals, most of whom had drug-resistant strains of
      TB, posed a sufficient threat to public health to justify detention.

PMID- 15178139
TI  - Local research ethics committees of the Mexican Institute of Social Security:
      results of a national survey.
AB  - OBJECTIVE: To identify the structure, composition and work of the local research
      ethics committees (LRECs) of the Mexican Institute of Social Security (IMSS) in
      Mexico. DESIGN: A descriptive cross-sectional study was performed that included
      all LRECs of the IMSS. METHODS: A total of 335 questionnaires coded in advance
      were posted to each LREC secretary. The requested information was from January to
      December 2001. RESULTS: The response rate was 100%. Two hundred and thirty-eight
      (71%) LRECs were reported as 'active' during the evaluation period. Although
      almost all LRECs were composed of diverse professionals, physicians dominated the
      LRECs' membership. The rejection rate for research projects was lower than 1 per
      1000, and less than half of the LRECs held meetings to issue a report of
      projects' evaluation. CONCLUSIONS: LRECs need to foster good ethical research;
      implementation of an audit system to examine their work might help improve LRECs'
      performance and accountability.

PMID- 15178140
TI  - Does the association between ill health and unemployment differ between young
      people and adults? Results from a 14-year follow-up study with a focus on
      psychological health and smoking.
AB  - OBJECTIVES: Research has given a comprehensive picture of the negative health
      consequences of unemployment without offering sufficient comparison between
      different age groups. The aim of this study was to analyse whether the
      associations between ill health, particularly poor psychological health and
      smoking, and unemployment differ between young and adult men and women. STUDY
      DESIGN: A 14-year follow-up study of graduates of compulsory school in an
      industrial town in northern Sweden was undertaken. The subjects were analysed at
      ages 16, 21 and 30 years. Complete data on the cohort were collected for 1044
      individuals with the aid of a comprehensive questionnaire. The response rate was
      96.4%. METHODS: The main health measurements used in this study were poor
      psychological health and smoking, analysed by multivariate logistic regression.
      RESULTS: After controlling for several background variables, associations between
      long-term unemployment and poor psychological health were found in young men and
      women, and adult men. Long-term unemployment was only associated with smoking in
      young people. CONCLUSIONS: The association between long-term unemployment and
      psychological health, as well as smoking, seemed to be stronger in young people
      than adults.

PMID- 15178141
TI  - Relationship between economic development and suicide mortality: a global cross
      sectional analysis in an epidemiological transition perspective.
AB  - AIM: The aim of this study was to analyse the relationship between suicide rates
      and economic development within the theoretical framework of epidemiological
      transition. RESULT: A weak positive correlation was found between suicide rates
      and GNP per capita in both sexes for all ages. DISCUSSION: According to previous
      studies, there is a clear decline in deaths due to unintentional injuries with
      improved economic conditions. This example of a man-made disease that declines
      during the fourth stage is in agreement with the theory of epidemiological
      transition. However, our results found the opposite pattern for deaths due to
      intentional self-inflicted injury. CONCLUSION: Mortality rates due to
      unintentional and intentional self-inflicted injury show deviating patterns from
      an epidemiological transition perspective.

PMID- 15178142
TI  - Relationship between illness-associated absence in day-care children and weather
      parameters.
AB  - This 5-year study demonstrated a statistically significant correlation between
      morbidity among children attending day-care centres and various weather
      parameters. The study was undertaken in south-central Sweden, where sharp
      seasonal contrasts in climatic and weather conditions occur. Illness-associated
      absence (IAA) decreased significantly when the weather was bright, sunny and
      warm, determined using average monthly weather parameters analysed over 60
      months. This may be because good weather encourages outdoor activities which, in
      turn, reduce the risk of spreading respiratory tract infections as outdoor play
      areas are larger, body contact is less frequent, and any bacteria and viruses
      present will be readily dispersed. In multiple regression analysis, outdoor
      temperature was the most prominent parameter linked with IAA. This may reflect
      the behaviour of the staff with regard to various weather conditions. It is
      therefore to be recommended that children attending day-care centres should be
      allowed and encouraged to play outdoors when conditions allow.

PMID- 15178143
TI  - Monitoring organ donor rates: a predictive model based on routinely available
      data in France applied to the year 2002.
AB  - Temporal trends in organ donor harvesting rates are subject to variability. It is
      important to detect variations as early as possible using current data. We
      developed a predictive model for monitoring harvesting activity using the number
      of donors harvested monthly between 1996 and 2001. A Poisson model was used to
      predict the number of donors harvested each month along with their confidence
      intervals. This model also updates, on a monthly basis, the predicted number of
      donors for the current year. During 2002, the number of donors observed each
      month followed the predicted monthly variations, but a significant increase was
      observed in March and May. These models can be used by transplantation agencies
      for monitoring purposes and for the evaluation of organ donation programmes.

PMID- 15178144
TI  - Re-organizing services for the management of upper gastrointestinal cancers:
      patterns of care and problems with change.
AB  - The 'Calman-Hine' report (1995) recommended that cancer surgery should be limited
      to specialist high-volume units. National guidance from the National Health
      Service (NHS) Executive in 2001 stated that specialist oesophagogastric cancer
      centres should 'aim to draw patients from catchment areas with a population of 1
      2 million.' For pancreatic cancers, the catchment areas should be between 2 and 4
      million, reflecting the relatively lower incidence of disease. For the West
      Midlands region, these recommendations would suggest that four or five centres
      might be required to provide specialist surgical management for oesophagogastric
      cancer, and one or two centres for pancreatic disease. We used Hospital Episode
      Statistics to analyse trends in management patterns for these tumours within the
      West Midlands during the period 1992-2000. Over 20 different units were involved
      in the management of oesophagogastric and pancreatic disease, and we were unable
      to discern any clear and consistent move towards the centralisation of the upper
      gastrointestinal work in high-volume units since the publication of the Calman
      Hine report in 1995. Although the drive for centralisation might be anticipated
      to increase following the publication of the NHS Executive's guidance, there is a
      substantial way to go before the provision of surgical services for upper
      gastrointestinal cancers is limited to a small number of high-volume specialist
      units.

PMID- 15178145
TI  - Health of children looked after by the local authorities.
AB  - Objectives. To assess the healthcare needs of looked-after children in East
      Surrey. Methods. Epidemiological, comparative and corporate approaches were used
      to study the healthcare needs of looked-after children. Information was obtained
      from published and unpublished sources, case note review, cross-referencing with
      records from specialist services, and interviews with stakeholders. Results. Of
      the 136 children whose case notes were reviewed, only 64% had undergone statutory
      medical examinations. Several physical health problems were identified, emotional
      and behavioural problems were present in 34% of children, 25% of school-aged
      children had a statement of special educational need, and 36% had ever used child
      and adolescent mental health services. Immunization coverage was lower than that
      of children who were not in care. Several unmet needs and gaps in service
      provision were identified. Conclusions. Children in care have a higher degree of
      physical and mental health needs than their not-in-care counterparts. The local
      service for children in care needs to be improved to meet these health needs and
      lead to better health and health-related outcomes for the children.

PMID- 15178146
TI  - Missed opportunities for tetanus vaccination in pregnant women, and factors
      associated with seropositivity.
AB  - The aim of this study was to identify the seroprevalance rate of tetanus and to
      determine missed opportunities for tetanus vaccination. Two hundred and twenty
      seven female volunteers who were hospitalized following delivery participated in
      the study. Blood samples were analyzed using enzyme-linked immunoassay to measure
      tetanus antibody levels. In addition, a questionnaire was used to investigate the
      factors associated with vaccination status. Sixty-five percent of the study
      participants had safe protective levels of antibodies. Factors associated with
      antibody level were age, level of education and number of doses. Only 25.7% of
      women who received antenatal care (ANC) had received tetanus vaccinations. Women
      who received ANC from primary healthcare facilities were more likely to have been
      vaccinated than those who received ANC from hospitals or private practice (P <
      0.05). Factors associated with both tetanus vaccination and immunizations in
      pregnant women should be further investigated by qualitative and quantitative
      studies. Knowledge, attitude and practice surveys of mothers and healthcare
      providers on provision of the tetanus vaccine to pregnant women need to be
      undertaken urgently.

PMID- 15178147
TI  - Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity
      in mice lacking the 5-HT-3A receptor.
AB  - The serotonin-3 (5-HT-3A) receptor has been localized in limbic and brainstem
      structures that regulate anxiety-related behavior and hypothalamic-pituitary
      adrenal (HPA) activity, but its role in regulating anxiety-related behaviors is
      equivocal, and evidence for its role in regulating HPA activity is limited.
      Therefore, we used 5-HT-3A receptor knockout (KO) mice to further study these
      issues. Behavior in the elevated plus maze, open field, light-dark box and after
      Pavlovian fear conditioning was examined in addition to HPA activity under basal
      and acute stress conditions. Compared to age-matched adult male wild-type (WT)
      controls, adult male KO mice exhibited increased distance traveled in the open
      arms of the elevated plus maze, consistent with decreased measures of anxiety.
      There were no differences between the two genotypes in exploratory behavior in
      the open field or light-dark test. KO mice displayed enhanced fear conditioning
      indexed by fear-induced freezing behavior. KO mice displayed lower
      adrenocorticotropin (ACTH) responses to restraint or lipopolysaccharide (LPS). In
      addition, lower vasopressin mRNA in the paraventricular nucleus of the
      hypothalamus (PVN) and higher corticotropin-releasing hormone (CRH) mRNA in the
      central amygdala were observed in KO compared to WT mice. Therefore, deletion of
      the 5-HT-3A receptor revealed an important role for this receptor in regulating
      HPA responses to acute stress and a potential interaction between the 5-HT-3A
      receptor and CRH in the amygdala. Together, these data suggest that the 5-HT-3A
      receptor does not have a unitary role in the regulation of anxiety- and fear
      related behaviors but has a potentially substantial role in the regulation of HPA
      activity.

PMID- 15178148
TI  - Increased glucocorticoid response to a novel stress in rats that have been
      restrained.
AB  - Rats exposed to repeated restraint stress (3 h of restraint on each of 3 days)
      lose weight during stress and do not return to the weight of nonstressed controls
      once stress ends. Others have reported that chronic stress raises the daily nadir
      of corticosterone release and increases the adrenal response to subsequent
      stress; therefore, we examined glucocorticoid release in rats that had been
      exposed to repeated restraint. Repeated restraint had no effect on the diurnal
      pattern of corticosterone or insulin release, measured 12 days after restraint
      had ended, indicating that the reduced weight of the rats is not associated with
      an elevated corticosterone-insulin ratio. In contrast, rats that had been exposed
      to repeated restraint, 12 days previously, showed a blunted corticosterone
      release during a second restraint stress, a normal response to the novel
      physiological stress of 2-deoxy glucose (2-DG) injection, but an exaggerated
      corticosterone response to the novel mild stress (MS) of either placement in a
      unfamiliar environment or an intraperitoneal injection of saline. Mice exposed to
      repeated restraint showed a similar hyperresponsiveness to novel MS, suggesting
      that repeated restraint lowers the threshold for stress-induced activation of the
      adrenal gland. MS caused a small, but significant, degree of hypophagia in rats
      that had been exposed to repeated restraint stress. Therefore, multiple aspects
      of the stress response may be exaggerated in these animals and contribute to the
      chronic reduction in body weight.

PMID- 15178149
TI  - Reduced thirst in old, thermally dehydrated rats.
AB  - Water intake and blood parameters of young (7-month) and old (23-month) male
      Brown Norway rats were assessed following a period of thermal dehydration. Rats
      of both ages were randomly assigned to one of three groups: (1) Unheated-blood
      sample, (2) Heated-blood sample, and (3) Heated-water intake. The colonic
      temperature of heated rats was raised at the rate of 0.05 degrees C/min for 1 h
      using an infrared heat lamp. Water intake was then measured over the following 2
      h. The heating protocol resulted in a similar level of dehydration in both young
      and old rats; however, plasma osmolality and sodium concentration increased to a
      significant extent only in the young rats. Old rats drank significantly less
      water at all time points during the 2 h following the heat stress. While neither
      group replaced the water lost as a result of the thermal dehydration, the young
      rats did rehydrate to a greater extent. These results suggest that the diminished
      level of rehydration in aged rats, following a thermal dehydration, is due to an
      attenuated rise in plasma osmolality.

PMID- 15178150
TI  - Daily locomotor activity and melatonin rhythms in Senegal sole (Solea
      senegalensis).
AB  - The daily locomotor and melatonin rhythms of the Senegal sole, a benthonic
      species of increasing interest in aquaculture, are still unknown, despite the
      fact that such knowledge is of prime importance for optimising its production.
      The aim of the present research was therefore to investigate the daily rhythms of
      locomotor activity and melatonin in the Senegal sole. For this purpose, the
      individual locomotor activity rhythms of fish were registered using a photocell.
      Plasma and ocular melatonin rhythms were studied in animals reared in circular
      tanks placed in earth under an LD 12:12 light regime and 16-18 degrees C
      temperature range (spring equinox). Blood and eye samples were taken every 3 h
      during a complete 24-h cycle. The impact of a light pulse in the middle of the
      dark period (MD) on plasma melatonin was also studied. Locomotor activity was
      mainly nocturnal, with 84.3% of the total activity occurring during darkness. The
      levels of plasma melatonin were higher at night (55 pg/ml) than during the day (2
      pg/ml), while ocular melatonin levels appeared to be arrhythmic. Both weight and
      melatonin content were found to be significantly higher in the left eye in
      relation to the right eye. A light pulse in MD provoked a significant decrease in
      plasma melatonin levels. In summary, photoperiod is a key factor in synchronizing
      locomotor activity and melatonin rhythms in the Senegal sole, whose nocturnal
      habits should be taken into account for their rearing by aquaculture.

PMID- 15178151
TI  - Alpha-lactalbumin combined with a regular diet increases plasma Trp-LNAA ratio.
AB  - Brain serotonin influences food intake and mood. It is synthesised from
      tryptophan (Trp) of which uptake in the brain is dependent on plasma ratio of
      tryptophan to the sum of other large neutral amino acids (Trp-LNAA). A
      carbohydrate-rich diet increases this ratio, whereas a protein-rich diet
      decreases it. Yet, if the protein source is alpha-lactalbumin the ratio
      increases. It is, however, unknown whether this also happens in the context of a
      regular diet (15% protein). We studied the effect of an alpha-lactalbumin
      supplement combined with regular diet on plasma Trp-LNAA ratio, serum prolactin
      (marker of serotonin synthesis), food intake, appetite, macronutrient preference
      and mood. Eighteen healthy males participated in a double-blind, randomised,
      placebo-controlled, crossover study. One hour after breakfast they received a
      drink containing alpha-lactalbumin and carbohydrates (AS) or carbohydrates (PS)
      only. Plasma Trp-LNAA ratio, serum prolactin, food intake, appetite,
      macronutrient preference and mood were assessed before and 90 min after
      consumption of the supplement. Changes of plasma Trp-LNAA ratio differed (P<.001)
      between both supplements, increasing by 16% after AS and decreasing by 17% after
      PS. Decrease of serum prolactin was slightly smaller after AS than after PS
      (P=.083). Appetite, food intake, macronutrient preference or mood did not differ
      between supplements. We conclude that an alpha-lactalbumin-enriched supplement
      combined with a regular diet increases plasma Trp-LNAA ratio and may influence
      serum prolactin, but we could not demonstrate effects on appetite, food intake,
      macronutrient preference and mood.

PMID- 15178152
TI  - Nonevoked facial pain in rats following infraorbital nerve injury: a parametric
      analysis.
AB  - Unilateral chronic constriction injury to the infraorbital nerve (IoN-CCI)
      induces an increase in face-grooming behavior that is not part of normal body
      grooming (i.e., "isolated face grooming"). Despite the validity of isolated face
      grooming as a measure of spontaneous neuropathic pain, variation between rats in
      postoperative face grooming has limited its usefulness. We examined whether
      performing bilateral rather than unilateral IoN surgery could induce a more
      stable face-grooming behavior. It was found that bilaterally ligated rats
      performed a significantly greater amount of isolated face grooming (approximately
      four- to fivefold) when compared with unilaterally ligated rats. However, this
      effect was accompanied by an equivalent increase in between-subjects variation.
      No significant difference in face grooming during body grooming was found between
      bilaterally and unilaterally ligated rats. Rats were observed in two different
      sizes of observation cages; also, in addition to the amount of time spent on face
      grooming, the number and average duration of the face-grooming episodes were
      recorded. The effects of IoN surgery are caused by increases in the number of
      episodes. The effects of cage size were mostly related to differences in episode
      duration; that is, rats performed longer face-grooming episodes in the small
      compared to the large observation cage. The present data confirm previous reports
      that isolated face grooming is a more sensitive measure than the total amount of
      face grooming. Bilateral IoN surgery does not seem to offer a more stable outcome
      measure; increases in isolated face grooming were, however, more clearly observed
      in the small cage.

PMID- 15178153
TI  - Dietary n-3 fatty acids selectively attenuate LPS-induced behavioral depression
      in mice.
AB  - Systemic administration of bacterial lipopolysaccharide (LPS) induces a series of
      physiological and pathological alterations as well as behavioral depression in
      experimental animals. These alterations induced by LPS administration are known
      to be mediated by endogenous cytokines and arachidonate metabolites, which may be
      modulated by dietary n-3 fatty acids. Mice were fed a diet supplemented with n-3
      or n-6 fatty acids for 4 weeks prior to LPS administration. Food-motivated
      behavior after intraperitoneal administration of LPS as compared with that before
      LPS administration was significantly depressed in the mice fed with the n-6 fatty
      acid-rich diet (47% to 85% reduction; P<.05) but not significantly in the mice
      fed with the n-3 fatty-acid-rich diet. Depression of social exploration by
      intraperitoneal LPS administration in the n-3 fatty-acid-rich diet group (39%
      reduction vs. vehicle group) was significantly less in the n-6 fatty-acid-rich
      diet group (76% reduction vs. vehicle group; P<.05). The behavioral depressions
      induced by intracerebroventricular LPS injection were not significantly different
      between the two dietary groups (P=.60). The elevation of serum corticosterone and
      the hypoglycemic response following intraperitoneal LPS administration were not
      significantly different between the two dietary groups (P=.57 and P=.43,
      respectively). We demonstrate that dietary n-3 fatty acids attenuate behavioral
      depression in mice peripherally administered with LPS without affecting the
      increase in serum corticosterone and the decrease in serum glucose concentration.

PMID- 15178155
TI  - Absence seizures during pregnancy in WAG/Rij rats.
AB  - Spontaneously occurring spike-wave discharges (SWDs) and serum concentrations of
      ovarian steroid hormones were investigated before, during and after pregnancy in
      WAG/Rij rats, a rat strain with genetically determined absence seizures. Eight
      groups of rats were included in the assays of progesterone and estradiol: rats at
      diestrus, at various days of pregnancy and at lactating days. The number of SWDs
      in cortical EEG of WAG/Rij rats was decreased from the 3rd up to the 18th day of
      pregnancy and subsequently increased to control level. Thereafter, a new decrease
      was found 2-3 days after parturition. Serum concentration of progesterone was
      threefold increased at the 3rd day of pregnancy, remained elevated until the 18th
      day of pregnancy and returned to control values before delivery. Over measured
      days, estradiol was significantly elevated only at the 18th day of pregnancy.
      Results demonstrate that physiological conditions induced by the state of
      pregnancy lead to suppression of occurrence of SWDs. Changes in plasma
      progesterone concentration correspond to the changes in number of SWDs: an
      increased level of progesterone during pregnancy is accompanied by a decreased
      number of SWDs, while a decrease in circulating progesterone before parturition
      is paralleled by an increase of SWDs. Of interest, the relationship between SWDs
      and concentration of progesterone found during pregnancy is diametrically
      opposite to results obtained in acute administration studies of progesterone in
      nonpregnant animals.

PMID- 15178154
TI  - CCK-8 and PGE1: central effects on circadian body temperature and activity
      rhythms in rats.
AB  - Cholecystokinin-octapeptide (CCK-8) has been shown to possess an acute
      thermogenic and hyperthermic action when given intracerebroventricularly in
      slightly restrained rats. To substantiate the febrile nature of that hyperthermia
      freely moving animals should be used and together with body core temperature, at
      least one behavioral parameter, such as general activity, should also be
      recorded. In the present studies, Wistar rats (N=34) exposed to thermoneutral (26
      28 degrees C) or cold (4 degrees C) ambient temperature and to a 12:12-h
      light/darkness schedule were infused intracerebroventricularly with CCK-8 or
      prostaglandin E1 (PGE1) for several days using ALZET minipump and changes in body
      core temperature and general activity were recorded by biotelemetry (Minimitter).
      In rats exposed to a thermoneutral ambient temperature, low doses of CCK-8
      induced slight but significant rises of day minima of circadian body temperature
      rhythm (CBTR) and with a high dose (1 microg/h) of the peptide--infused either at
      thermoneutrality or during cold exposure--an increase of acrometron could also be
      recorded. All of these changes were observed only during the first 2-4 days of 7
      day-long infusions. Intracerebroventricular infusion of PGE1 administered at
      thermoneutrality in a dose of 1 microg/h for 7 days induced a marked rise in body
      core temperature with a disappearance of CBTR in some rats for 2-3 days or with
      rises of day minima/acrometron in others. General activity--running parallel with
      CBTR in periods without infusions--tended to be decreased when core temperature
      rose during the first couple of days of intracerebroventricular infusion of
      higher doses of CCK-8 or of PGE1. The decreased general activity--one component
      of sickness behavior--together with an increased body core temperature found in
      the present study, supports the view that they are components of a genuine fever
      induced by the central effect of the two mediators used.

PMID- 15178156
TI  - Recognition of competitors by male golden hamsters.
AB  - Golden hamsters, like many animals, form dominant/subordinate relationships after
      aggressive encounters. We examined whether behavioral responses by males that won
      or lost fights would differ toward familiar and unfamiliar male stimulus animals.
      In Experiment 1, male winners or losers of fights explored an arena containing a
      confined stimulus animal that was either familiar or novel and had either won or
      lost a fight. Compared to dominant males, losers spent less time in proximity to
      stimulus males and investigated them less. Losers also displayed higher levels of
      stretch-attend postures (indicative of risk assessment) than winners, and they
      showed more escape and locomotion in response to familiar winners than to
      unfamiliar winners, indicating recognition of the male that they had lost to. In
      Experiment 2, losers scent marked less to the odors of a familiar winner than to
      those of an unfamiliar winner. Thus, male hamsters appear to use familiarity with
      a former opponent's odors to adaptively regulate their responses to variations in
      social threat.

PMID- 15178158
TI  - Diet salinity and vasopressin as reproduction modulators in the desert-dwelling
      golden spiny mouse (Acomys russatus).
AB  - The time for reproduction in mammals largely depends on the availability of water
      and food in their habitat. Therefore, in regions where rains are limited to
      definite seasons of the year, mammals presumably will restrict their breeding
      correspondingly. But while mammals living in predictable ecosystems would benefit
      by timing their season to an ultimate predictable cue, such as photoperiod, in
      unpredictable ecosystems (e.g., deserts) they will need to use a more proximate
      signal. We suggest a mechanism by which water shortage (low water content in
      plants) could act as a proximate cue for ending the reproductive season. The
      golden spiny mouse (Acomys russatus), a diurnal rodent living in extreme deserts,
      may face an increased dietary salt content as the summer progresses and the
      vegetation becomes dry. Under laboratory conditions, increased diet salinity lead
      to reproductive hiatus in females, notable in imperforated vagina, and a
      significant decrease in the ovaries, uteri, and body masses. In females treated
      with vasopressin (VP), a hormone expressed during water stress, the uteri and
      body masses have decreased significantly, and the ovaries exhibited an increased
      number of atretic follicles. VP has also led to a significant decrease in
      relative medullary thickness (RMT) of the kidney. It is thus suggested that VP
      could act as a modulator linking the reproductive system with water economy in
      desert rodents, possibly through its act on the energetic pathways.

PMID- 15178157
TI  - Response to urinary volatiles and chemosensory function decline with age in a
      prosimian primate.
AB  - The age-related decline in olfaction is well documented in humans. However, no
      data are available to date on changes in olfactory sensitivity with age in
      nonhuman primates. In the male gray mouse lemur (Microcebus murinus), a prosimian
      primate, the sense of smell is of high relevance for the modulation of both
      behavioral and physiological functions. We first assessed the effect of aging on
      physiological responses to urinary cues by measuring reproductive function in
      adult and aged males exposed to urine odor of preoestrous females. We then
      evaluated the effect of aging on chemosensory function using a discrimination
      test in freely behaving animals. Our results indicate that whereas adult animals
      show a clear increase in testosterone levels when exposed to female urine odor,
      this effect is lacking in aged animals. In addition, chemosensory function shows
      a progressive decline with age. Using both physiological responses to urinary
      volatiles and spontaneous behavior, this study provides the first data set on the
      effect of aging on chemosensory responsiveness in a nonhuman primate.

PMID- 15178159
TI  - Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs
      prepulse inhibition of acoustic startle.
AB  - There is growing evidence that 1,25-dihydroxyvitamin D3 is involved in normal
      brain development. The aim of this study was to examine the impact of prenatal
      and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle
      in adult rats. We compared six groups of rats: control rats with normal vitamin D
      throughout life and normal litter size (Litter); control rats with normal vitamin
      D but with a reduced litter size of two (Control); offspring from reduced litters
      of vitamin D deplete mothers who were repleted at birth (Birth), repleted at
      weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or
      control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of
      age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks
      of age for acoustic startle responses and for PPI. There were no significant
      group differences at 5 weeks of age on the acoustic startle response or on PPI.
      At 10 weeks of age, rats in the Life group only had impaired PPI despite having
      normal acoustic startle responses. We conclude that combined prenatal and chronic
      postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI.

PMID- 15178160
TI  - Presleep relaxed 7-8 Hz EEG from left frontal region: marker of localised
      neuropsychological performance?
AB  - Others have shown that frontally dominant EEG activity of around 7-8 Hz is linked
      to ongoing cognitive performance. Interestingly, we have found that this EEG
      activity is particularly evident during the relatively artefact-free period
      following "lights out" at bedtime when people report "thinking" when lying
      relaxed in their own beds prior to the appearance of EEG-determined sleepiness.
      Here, we explore the extent to which this localised activity is indicative of
      'trait' performance on left frontal neuropsychological tasks, as well as with
      less localised, more general tasks. Twelve right-handed young adults (mean age:
      21.3 years) and 12 right-handed older adults (mean age: 67.2 years) underwent (i)
      morning, laboratory-based, waking EEGs comprising (eyes closed) contrived
      thinking tasks, and (ii) a home-based wake EEG at bedtime. EEGs divided the
      cortex into the four comparable quadrants: Fp1-F3; Fp2-F4; O1-P3; and O2-P4. From
      a wide frequency band of 3-10 Hz analysed in 1-Hz bins, only 7-8 Hz was
      associated with the neuropsychological performance (nonverbal planning, verbal
      fluency) for both younger and older participants. This was most evident during
      relaxed waking after 'lights out,' and from the left frontal EEG. Such
      associations were not apparent for the other EEG channels or for the nonspecific
      tasks. Laboratory-based daytime, frontal EEG recordings are problematic because
      of eye movement artefact and when participants are not fully relaxed. In
      contrast, the nighttime data are almost artefact-free and from fully relaxed
      participants. This particular EEG is useful for assessing cortically localised
      behaviour and indicates that a more traditional approach of using large
      bandwidths (e.g., the whole of "alpha" or "theta" ranges) may mask subfrequencies
      of functional importance.

PMID- 15178161
TI  - Role of unsaponifiable fraction on the preference for beef tallow in C57Black/6
      mice.
AB  - We examined the contribution of unsaponifiable fraction, a model for minor
      substances in food fat, on the preference for beef tallow in C57Black/6NCrj mice.
      First, we tested the difference in preference among three kinds of beef tallow in
      mice by a two-bottle choice test. The beef tallow samples were preferred in the
      order 'premium' food-use, food-use, and chemical grades. The amount of
      unsaponifiable fraction was the highest in the premium and the lowest in the
      chemical-grade beef tallow sample. Fatty acid and triacylglycerol profiles,
      however, were similar in the three samples. Subsequently, we examined the effects
      and role of unsaponifiable fraction in the preference for triacylglycerol.
      Unsaponifiable fraction prepared from premium beef tallow sample alone did not
      affect the preference in mice, but a preference was observed when triolein and
      unsaponifiable fraction coexisted. These results indicated that the
      unsaponifiable fraction in beef tallow contributed to the preference in mice. In
      addition, it was suggested that the unsaponifiable fraction acted as an enhancer
      in the preference for triacylglycerol in C57Black/6NCrj mice.

PMID- 15178162
TI  - Androgen receptor blockade in the MPOA or VMN: effects on male sociosexual
      behaviors.
AB  - Previously, our laboratory has shown that androgen receptors in the medial
      preoptic area (MPOA) and ventromedial nucleus (VMN) are necessary for copulation
      in male rats. The present study examined whether these receptors are required for
      other sociosexual behaviors. In Experiment 1, different regions of the VMN were
      implanted with the antiandrogen hydroxyflutamide (OHF). We found that implants
      located in anterodorsal portions of the VMN were more effective at inhibiting the
      restoration of copulation than implants in the posteroventral VMN. In Experiment
      2, a second set of male rats was pretested for copulation and other sociosexual
      behaviors and was castrated. Experimental animals then received Silastic capsules
      filled with testosterone (T) plus intracranial (IC) implants filled with OHF to
      selectively block androgen receptors in either the MPOA or VMN. We found that
      androgen receptor blockade in the MPOA inhibited the restoration of copulation
      but had no effect on other sociosexual behaviors. OHF directed at the VMN
      inhibited the restoration of copulation and 50-kHz vocalizations but had no
      effect on scent marking. Two tests were used to assay sexual motivation: partner
      preference and conditioned place preference (CPP). Both methods revealed
      impairments in sexual motivation in the VMN group but not in animals receiving
      OHF in the MPOA. Taken together, these data suggest that androgen receptors in
      the MPOA are essential for copulatory performance, while androgen receptors in
      the VMN are important for copulation, sexual motivation, and androgen-dependent
      vocalizations.

PMID- 15178163
TI  - Effect of viewing a humorous vs. nonhumorous film on bronchial responsiveness in
      patients with bronchial asthma.
AB  - The effect of viewing a humorous film on bronchial responsiveness to methacholine
      [methacholine study: 20 healthy participants and 20 patients with house dust mite
      (HDM)-allergic bronchial asthma (BA)] or to epigallocatechin gallate (EGCg; EGCg
      study: 15 normal participants and 15 EGCg-allergic BA patients) was studied. At
      baseline, bronchial challenge test to methacholine (20 normal participants and 20
      HDM-allergic BA patients) or EGCg (15 normal participants and 15 EGCg-allergic BA
      patients) were performed. After 2 weeks, patients and healthy participants were
      randomly assigned to watch a humorous or a nonhumorous film. Two weeks later, the
      alternate film was watched. Immediately after viewing, bronchial challenge test
      to methacholine or ECGg to each study group were performed. Viewing a humorous
      film significantly reduced bronchial responsiveness to methacholine or EGCg,
      while viewing a nonhumorous film failed to do so in BA patients without affecting
      bronchial responsiveness to methacholine or EGCg in healthy participants. These
      findings indicate that viewing a humorous film may be useful in the treatment and
      study of BA.

PMID- 15178164
TI  - Exploration and risk assessment: a comparative study of male house mice (Mus
      musculus musculus) and two laboratory strains.
AB  - The ability to gather information and assess risks in novel environments is
      crucial for survival and fitness in the wild. Our aim was to characterise
      behavioural strategies of exploration and risk assessment in novel environments
      and to investigate in what respects wild house mice differ from domesticated
      mice. A total of 39 adult male mice from three genetic backgrounds (Wild, BALB/c,
      and C57BL/6) were tested in three behavioural tests, the concentric square field
      (CSF), a modified open field (OF), and a conventional elevated plus maze (EPM).
      In addition to spatial measures, behavioural measures of exploration and risk
      assessment were registered. The parameters were categorised according to their
      relevance to activity, exploration, approach-avoidance, and use of open
      areas/shelter. Wild mice had lower activity and a higher avoidance of open areas
      than the laboratory strains. No differences were found in exploratory motivation.
      The BALB/c mice avoided risk areas and showed high risk assessment (SAP), whereas
      C57BL/6 mice were more explorative and risk taking and showed little risk
      assessment. Wild mice seemed to have a different behavioural strategy of risk
      assessment in being more cautious before entering a potentially dangerous zone
      but explored all zones after assessed as nonrisky. A principal component analysis
      (PCA) of the animals' behaviour in the CSF arena supported these findings by
      clearly separating the three strains on the basis of their behavioural
      performances. It is concluded that there are obvious differences in behavioural
      strategies related to risk assessment and risk taking among wild mice versus
      domesticated house mice and also among laboratory strains. The relationship
      between the animal's risk concern and adaptability is discussed and should be a
      matter of importance considering animal welfare as well as the experimental aim
      and protocol.

PMID- 15178165
TI  - Ethanol-conditioned flavor preferences compared with sugar- and fat-conditioned
      preferences in rats.
AB  - Rats can learn to prefer flavors paired with ethanol and various nutrients. The
      present study examined the relative strengths of flavor preferences conditioned
      by 5% ethanol and isocaloric solutions of 7.18% sucrose, 7.18% fructose, or 3.26%
      corn oil. In three experiments, nondeprived rats were trained with different
      flavored solutions (conditioned stimuli, CS) paired with intragastric (IG)
      infusions: a CS+E flavor paired with ethanol infusion, a second CS+ paired with a
      nutrient infusion, and a CS- paired with water infusion. In two-bottle tests,
      rats strongly preferred a sucrose-paired CS+S over the CS- and over the CS+E. The
      preference for the CS+E over CS- was weaker. These effects occurred when the rats
      drank substantially more CS+S than CS+E in training and when training intakes
      were matched. Similar results were obtained when the nutrient infusion was
      fructose or corn oil, except that preferences for the CS+F or CS+O over the CS+E
      were less pronounced than with CS+S. Consistent with the IG results, rats trained
      to drink flavored sucrose and ethanol solutions preferred the CS+S to CS+E in a
      flavored water test. These results confirm prior reports of ethanol-conditioned
      preferences but show that ethanol is less effective than other nutrients at
      isocaloric concentrations. The marked individual differences in ethanol
      conditioned preferences may be related to the impact of the sugar or fat
      infusions on the reward evaluation of the ethanol-paired flavor.

PMID- 15178166
TI  - Convergent and divergent effects of neck proprioceptive and visual motion
      stimulation on visual space processing in neglect.
AB  - Visual motion stimulation as well as neck muscle vibration are known to
      effectively modulate the subjective body orientation in spatial neglect. However,
      so far only motion stimulation has been demonstrated to substantially influence
      size and space distortion in neglect patients. The present study aimed to compare
      the two stimulation methods with respect to their potentially differential impact
      on subjective body orientation and on space and size distortion, in five neglect
      patients showing perceptual distortions. We found comparable beneficial effects
      during left motion stimulation and left neck vibration for the subjective
      straight ahead. Additionally, left motion stimulation significantly ameliorated
      the leftward overextension in size matching, line bisection and distance
      estimation in all five patients. In contrast, during neck vibration only two
      patients showed an improvement for line bisection and size estimation and none
      did so for distance estimation. Since these two patients differed from the others
      as they had either no visual field defects or a major visual field sparing, we
      suggest--based on recent anatomical and neuropsychological findings--that neck
      vibration only tends to improve pure neglect-related visuo-perceptual distortions
      whereas motion stimulation can additionally improve perceptual distortions in
      neglect associated with hemianopia.

PMID- 15178167
TI  - My left brain and me: a dissociation in the perception of self and others.
AB  - We investigated hemispheric asymmetries in face processing using a task in which
      participants judged the likeness of chimeric faces to their own face and to the
      face of a close friend based on their memory for those faces. When asked to
      choose which of two mirror-symmetric images (one made from the left half and one
      from the right half of a photograph of their face) looked more like themselves as
      remembered, participants showed a significant bias for the composite
      corresponding to the half face that lies in their right visual field when they
      look at themselves in the mirror. They showed the opposite bias when asked to
      make the same choice for images of a close friend, that is, they showed a
      significant bias for the composite corresponding to the half face that lies in
      their left visual field when they look at their friend. This result shows that in
      the case of these highly familiar faces--self and friend--the perceptual
      asymmetry is preserved in the memory representation. Assuming that people
      remember their own face as a mirror-image, the data also suggest a dissociation
      in face processing such that the left brain is dominant for the recognition of
      self and the right brain is dominant for the recognition of others.

PMID- 15178168
TI  - Processing biases towards the preferred hand: valid and invalid cueing of left-
      versus right-hand movements.
AB  - A Posner-like paradigm was employed to investigate the effects of valid and
      invalid cueing of each hand on reaction time, movement time and peak velocity in
      an aiming task. Given claims of left hemisphere superiority in movement selection
      and inhibition (and the privileged within-hemisphere access of the right hand to
      such systems), it was hypothesised that invalidly cueing the left hand (i.e.
      right-hand movement precued, left-handed movement required by a go signal) would
      result in increased reaction time relative to invalid right-hand cueing. The
      hypothesis was not confirmed as reaction times of both hands were slowed
      equivalently by invalid cueing. Nevertheless, it was found that the movement
      duration of the left hand was increased substantially by invalid cueing, while
      the right hand was unaffected on this measure, suggesting a possible intentional
      rather than attentional difference between the two hands. These results are
      discussed in terms of a possible asymmetry of intentional processes related to
      hand movement and the right-hand advantage in movement duration.

PMID- 15178169
TI  - Cortical Activations during judgments about the self and an other person.
AB  - Self-related thought and other person related thought have received a great deal
      of study in recent years, but have seldom been examined in the same experiment.
      This study used functional magnetic resonance imaging (fMRI) to compare the
      neural correlates of judgments of ones own preferences with judgments of another
      person's preferences. Each participant viewed food names and made one of three
      decisions: self (whether he or she liked the food); other (whether a specific
      friend liked the food), or letter (whether there were more than two vowels in the
      food name). Self and other decisions both activated bilateral medial areas of the
      frontal and parietal lobes and the bilateral insula in comparison to the letter
      task. Self activated superior medial parietal areas in comparison to other,
      whereas other led to greater activation in inferior medial parietal and left
      lateral frontal areas than self. These results indicate that the neural networks
      underlying self processing and other person processing may share common neural
      substrates, particularly regions associated with representation of the body and
      mental states.

PMID- 15178170
TI  - Topographical memory impairments after unilateral lesions of the anterior
      thalamus and contralateral inferotemporal cortex.
AB  - Monkeys with crossed unilateral excitotoxic lesions of the anterior thalamus and
      unilateral inferotemporal cortex ablation were severely impaired at learning two
      tasks which required the integration of information about the appearance of
      objects and their positions in space. The lesioned monkeys were also impaired at
      learning a spatial task and a task which required the integration of information
      about the appearance of objects and the background on which the objects were
      situated. Monkeys with only one of the unilateral lesions were not impaired and
      previous work has shown that monkeys with bilateral lesions of the anterior
      thalamus were not impaired on these tasks. These results indicate that the whole
      of the inferotemporal cortex-anterior thalamic circuit, which passes via the
      hippocampus, fornix, mamillary bodies and mamillothalamic tract, is essential for
      the topographical analysis of information about specific objects in different
      positions in space. Together with previous work, the results show that a
      unilateral lesion may affect cognition in the presence of other brain damage when
      an equivalent bilateral lesion alone does not. The tasks required the slow
      acquisition of information into long term memory and therefore assessed semantic
      knowledge although other research has shown impairment on topographical
      processing within working or episodic memory following lesions of the hippocampal
      diencephalic circuit. It is argued that the hippocampal-diencephalic circuit does
      not have a role in a specific form of memory such as episodic memory but rather
      is involved in topographical analysis of the environment in perception and across
      all types of declarative memory.

PMID- 15178171
TI  - The impact of lexical-semantic impairment and of executive dysfunction on the
      word reading performance of patients with probable Alzheimer dementia.
AB  - The influence of lexical-semantic impairment and of executive dysfunction on word
      naming performance was investigated in a group of patients with probable
      Alzheimer dementia (AD). The patients, who varied in the severity of the illness,
      were tested in a word naming task where they had to read aloud Italian three
      syllable words with a dominant or subordinate stress pattern. These types of
      words have been shown to interact with frequency in normal adults [J. Exp.
      Psychol.: Hum. Percept. Perform. 18 (4) (1992) 987], so that the effect of the
      subordinate stress pattern (slower reading times) is only apparent for low
      frequency words. The frequency and stress effects on accuracy increased across
      dementia severity levels. Regression analyses showed that the impairment in
      reading low frequency words with subordinate stress depended largely on the level
      of lexical-semantic impairment, measured by a test of semantic memory and
      comprehension. Implications for the current reading models are discussed.

PMID- 15178172
TI  - Residual oculomotor and exploratory deficits in patients with recovered
      hemineglect.
AB  - Several studies on hemineglect have reported that patients recover remarkably
      well when assessed with neuropsychological screening tests, however, they show
      deficits on novel or complex tasks. We investigated whether such deficits can be
      revealed with eye movement analysis, applying two basic oculomotor tasks as well
      as two exploratory tasks. Eye movements were recorded in eight hemineglect
      patients at least eleven months after right-hemisphere brain damage had occurred.
      Sixteen healthy volunteers participated in the control group. Regarding the basic
      oculomotor tasks, only the overlap task revealed residual deficits in patients,
      suggesting that a directional deficit in disengaging attention persisted during
      recovery. Further residual deficits were evident in the exploratory tasks. When
      everyday scenes were explored, patients showed a bias in early orienting towards
      the ipsilateral hemispace. In a search task, they demonstrated the same orienting
      bias as well as a non-directional deficit concerning search times. Moreover,
      patients preferentially fixated in the contralateral hemispace, but did not
      benefit from this asymmetry in terms of search times, i.e. they did not detect
      contralateral targets faster than ipsilateral ones. This suggests a dissociation
      between oculomotor processes and attentional ones. In conclusion, we have
      identified behavioural aspects that seem to recover slower than others. A
      disengagement deficit and biases in early orienting have been the most pronounced
      residual oculomotor deficits.

PMID- 15178173
TI  - Verbal fluency performance in dementia of the Alzheimer's type: a meta-analysis.
AB  - A meta-analysis of 153 studies with 15,990 participants was conducted to compare
      the magnitude of deficits upon tests of phonemic and semantic fluency for
      patients with dementia of the Alzheimer's type (DAT) relative to healthy
      controls. As has been found for patients with focal temporal cortical lesions
      (but not for patients with focal frontal cortical lesions), DAT patients were
      significantly more impaired on tests of semantic relative to phonemic fluency
      (r=0.73 and 0.57, respectively). Thus, since phonemic and semantic fluency are
      considered to impose comparable demands upon executive control processes such as
      effortful retrieval, but the latter is relatively more dependent upon the
      integrity of semantic memory, these results suggest that the semantic memory
      deficit in DAT reflects a degradation of the semantic store. Also supporting this
      conclusion, confrontation naming, a measure of semantic memory that imposes only
      minimal demands upon effortful retrieval, was significantly more impaired than
      phonemic fluency (r=0.60 versus 0.55, respectively). However, since semantic
      fluency was also significantly more impaired than confrontation naming (r=0.73
      versus 0.61), deficits in semantic memory and effortful retrieval may be
      additive. Semantic, but not phonemic fluency, was significantly more impaired
      than measures of verbal intelligence and psychomotor speed. Thus, the semantic
      memory deficit in DAT qualifies as a differential deficit, but executive
      dysfunction as indexed by phonemic fluency does not constitute an additional
      isolated feature of the disorder. Dementia severity was not significantly related
      to the relative magnitude of deficits upon phonemic and semantic fluency.

PMID- 15178174
TI  - Recovery of oculo-motor bias in neglect patients after prism adaptation.
AB  - Patients with "neglect dyslexia" usually make errors in reading the left part of
      words and non-words. It has been shown that "neglect dyslexia" can improve
      following a short period of adaptation to wedge prisms [Neuropsychologia 40
      (2002) 718], however the mechanisms underlying this amelioration are still
      unknown. The present study evaluated the effect of prism adaptation (PA) on
      ocular scanning behaviour of neglect dyslexia patients by investigating: (a) the
      first saccade landing position during reading a letter string and (b) the
      distribution of fixation time as a function of the side of oculo-motor
      exploration of words and non-words. This in order to assess whether possible
      changes (in reading performance) after the adaptation might be attributed to a
      resetting of the oculo-motor system. Eye movements' performances were recorded
      before and after a single prismatic exposure on right brain-damaged patients with
      left hemispatial neglect and "neglect dyslexia". The results obtained in
      Experimental neglect patients before and after PA were then compared to that of
      control neglect patients, who were wearing goggles with neutral lenses. Moreover,
      in order to provide normative data on ocular scanning behaviour during letter
      string reading, neurologically healthy subjects were also studied. Following a
      single session of prism adaptation, the results showed, in the Experimental
      neglect patients, an improvement of neglect dyslexia, an increased left-sided
      exploration of the letter string and an increased amplitude of the first left
      sided saccade. In contrast, in the Control neglect patients, neglect dyslexia as
      well as the oculo-motor system behaviour, remained the same after the use of
      goggles with neutral lenses. These findings demonstrate that the beneficial
      effect induced by a single prismatic adaptation may be conceived as a complex
      interaction between sensory stimulation and a resetting of oculo-motor system.

PMID- 15178176
TI  - Neural correlates of implicit object identification.
AB  - The present study sought to assess neural correlates of implicit identification
      of objects by means of fMRI, using tasks that require matching of the physical
      properties of objects. Behavioural data suggests that there is automatic access
      to object identity when observers attend to a physical property of the form of an
      object (e.g. the object's orientation) and no evidence for semantic processing
      when subjects attend to colour. We evaluated whether, in addition to neural areas
      associated with decisions to specific perceptual properties, areas associated
      with access to semantic information were activated when tasks demanded processing
      of the global configuration of pictures. We used two perceptual matching tasks
      based on the global orientation or on the colour of line drawings. Our results
      confirmed behavioural data. Activations in the inferior occipital cortex,
      fusiform and inferior temporal gyri in both tasks (orientation and colour)
      account for perceptual and structural processing involved in each task. In
      contrast, activations in the posterior and medial parts of the fusiform gyrus,
      shown to be involved in explicit semantic judgements, were more pronounced in the
      orientation-matching task, suggesting that semantic information from the pictures
      is processed in an implicit way even when not required by the task. Thus, this
      study suggests that cortical regions usually involved in explicit semantic
      processing are also activated when implicit processing of objects occurs.

PMID- 15178175
TI  - Preserved verb generation in patients with cerebellar atrophy.
AB  - A role of the right cerebellar hemisphere has been suggested in linguistic
      functions. Nevertheless, studies of verb generation in cerebellar patients
      provide inconsistent results. The aim of the present study was to examine verb
      generation in a larger group of cerebellar patients with well-defined lesions.
      Ten subjects with degenerative cerebellar disorders and ten healthy matched
      controls participated. Subjects had to generate verbs to the blocked presentation
      of photographs of objects (i.e. four blocks of sixteen objects). As control
      condition, the objects had to be named. Furthermore, dysarthria was quantified by
      means of a sentence production and syllable repetition task. Volumetric analysis
      of individual 3D-MR scans was performed to quantify cerebellar atrophy.
      Cerebellar patients were slower in the sentence production and syllable
      repetition tasks, and cerebellar volume was decreased compared to controls.
      Despite cerebellar atrophy and dysarthria, the answers produced did not differ
      between patients and controls. In addition, both groups revealed the same amount
      of decrease in verbal reaction time over blocks (i.e. learning). The results
      suggest that the role of the cerebellum in verb generation is less pronounced
      than previously suggested.

PMID- 15178177
TI  - Divided attention and mental effort after severe traumatic brain injury.
AB  - The aim of this study was to assess dual-task performance in TBI patients, under
      different experimental conditions, with or without explicit emphasis on one of
      two tasks. Results were compared with measurement of the subjective mental effort
      required to perform each task. Forty-three severe TBI patients at the subacute or
      chronic phase performed two tasks under single- and dual-task conditions: (a)
      random generation; (b) visual go-no go reaction time task. Three dual-task
      conditions were given, requiring either to consider both tasks as equally
      important or to focus preferentially on one of them. Patients were compared to
      matched controls. Subjective mental effort was rated on a visual analogic scale.
      TBI patients showed a disproportionate increase in reaction time in the go-no go
      task under the dual-task condition. However, they were just as able as controls
      to adapt performance to the specific instructions about the task to be
      emphasised. Patients reported significantly higher subjective mental effort, but
      the variation of mental effort according to task condition was similar to that of
      controls. These results suggest that the divided attention deficit of TBI
      patients is related to a reduction in available processing resources rather than
      an impairment of strategic processes responsible for attentional allocation and
      switching. The higher level of subjective mental effort may explain why TBI
      patients frequently complain of mental fatigue, although this subjective
      complaint seems to be relatively independent of cognitive impairment.

PMID- 15178178
TI  - The neural areas that control the retrieval and selection of semantics.
AB  - Semantic retrieval consistently activates left inferior frontal regions, yet
      lesions to these areas do not typically result in semantic deficits. This
      discrepancy has led to the hypothesis that left prefrontal areas are primarily
      involved in executive processes while semantic information is retrieved from
      temporal cortices. We investigated semantic executive processing by changing,
      over trials, the semantic association to a stimulus. Using fMRI and PET, we
      demonstrate that changes in semantic association increased activation in temporal
      as well as frontal areas. The similar effects in temporal and frontal areas
      suggest that semantic executive processes are not confined to the left inferior
      frontal cortex but might be distributed throughout the semantic system.

PMID- 15178179
TI  - Behavioral and neural correlates of perceived and imagined musical timbre.
AB  - The generality of findings implicating secondary auditory areas in auditory
      imagery was tested by using a timbre imagery task with fMRI. Another aim was to
      test whether activity in supplementary motor area (SMA) seen in prior studies
      might have been related to subvocalization. Participants with moderate musical
      background were scanned while making similarity judgments about the timbre of
      heard or imagined musical instrument sounds. The critical control condition was a
      visual imagery task. The pattern of judgments in perceived and imagined
      conditions was similar, suggesting that perception and imagery access similar
      cognitive representations of timbre. As expected, judgments of heard timbres,
      relative to the visual imagery control, activated primary and secondary auditory
      areas with some right-sided asymmetry. Timbre imagery also activated secondary
      auditory areas relative to the visual imagery control, although less strongly, in
      accord with previous data. Significant overlap was observed in these regions
      between perceptual and imagery conditions. Because the visual control task
      resulted in deactivation of auditory areas relative to a silent baseline, we
      interpret the timbre imagery effect as a reversal of that deactivation. Despite
      the lack of an obvious subvocalization component to timbre imagery, some activity
      in SMA was observed, suggesting that SMA may have a more general role in imagery
      beyond any motor component.

PMID- 15178180
TI  - Cluster approximations for epidemic processes: a systematic description of
      correlations beyond the pair level.
AB  - The spread of a virus is an example of a dynamic process occurring on a discrete
      spatial arrangement. While the mean-field approximation reasonably reproduces the
      spreading behaviour for topologies where the number of connections per node is
      either high or strongly fluctuating and for those that show small-world features,
      it is inaccurate for lattice structured populations. Various improvements upon
      the ordinary pair approximation based on a number of assumptions concerning the
      higher-order correlations have been proposed. To find approaches that allow for a
      derivation of their dynamics remains a great challenge. By representing the
      population with its connectivity patterns as a homogeneous network, we propose a
      systematic methodology for the description of the epidemic dynamics that takes
      into account spatial correlations up to a desired range. The equations that the
      dynamical correlations are subject to are derived in a straightforward way, and
      they are solved very efficiently due to their binary character. The method embeds
      very naturally spatial patterns such as the presence of loops characterizing the
      square lattice or the tree-like structure ubiquitous in random networks,
      providing an improved description of the steady state as well as the invasion
      dynamics.

PMID- 15178181
TI  - Evolutionary computer programming of protein folding and structure predictions.
AB  - In order to understand the mechanism of protein folding and to assist the
      rational de-novo design of fast-folding, non-aggregating and stable artificial
      enzymes it is very helpful to be able to simulate protein folding reactions and
      to predict the structures of proteins and other biomacromolecules. Here, we use a
      method of computer programming called "evolutionary computer programming" in
      which a program evolves depending on the evolutionary pressure exerted on the
      program. In the case of the presented application of this method on a computer
      program for folding simulations, the evolutionary pressure exerted was towards
      faster finding deep minima in the energy landscape of protein folding. Already
      after 20 evolution steps, the evolved program was able to find deep minima in the
      energy landscape more than 10 times faster than the original program prior to the
      evolution process.

PMID- 15178182
TI  - Can extinction rates be estimated without fossils?
AB  - There is considerable interest in the possibility of using molecular phylogenies
      to estimate extinction rates. The present study aims at assessing the statistical
      performance of the birth-death model fitting approach to estimate speciation and
      extinction rates by comparison to the approach considering fossil data. A
      simulation-based approach was used. The diversification of a large number of
      lineages was simulated under a wide range of speciation and extinction rate
      values. The estimators obtained with fossils performed better than those without
      fossils. In the absence of fossils (e.g. with a molecular phylogeny), the
      speciation rate was correctly estimated in a wide range of situations; the bias
      of the corresponding estimator was close to zero for the largest trees. However,
      this estimator was substantially biased when the simulated extinction rate was
      high. On the other hand the estimator of extinction rate was biased in a wide
      range of situations. Surprisingly, this bias was lesser with medium-sized trees.
      Some recommendations for interpreting results from a diversification analysis are
      given.

PMID- 15178183
TI  - Predation, competition, and nutrient recycling: a stoichiometric approach with
      multiple nutrients.
AB  - A model for two competing prey species and one predator is formulated in which
      three essential nutrients can limit growth of all populations. Prey take up
      dissolved nutrients and predators ingest prey, assimilating a portion of ingested
      nutrients and recycling or respiring the balance. For all species, the nutrient
      contents of individuals vary and growth is coupled to increasing content of the
      limiting nutrient. This model was parameterized to describe a flagellate preying
      on two bacterial species, with carbon (C), nitrogen (N), and phosphorus (P) as
      nutrients. Parameters were chosen so that the two prey species would stably
      coexist without predators under some nutrient supply conditions. Using numerical
      simulations, the long-term outcomes of competition and predation were explored
      for a gradient of N:P supply ratios, varying C supply, and varying preference of
      the predator for the two prey. Coexistence and competitive exclusion both
      occurred under some conditions of nutrient supply and predator preference. As in
      simpler models of competition and predation these outcomes were largely governed
      by apparent competition mediated by the predator, and resource competition for
      nutrients whose effective supply was partly governed by nutrient recycling also
      mediated by the predator. For relatively small regions of parameter space, more
      complex outcomes with multiple attractors or three-species limit cycles occurred.
      The multiple constraints posed by multiple nutrients held the amplitudes of these
      cycles in check, limiting the influence of complex dynamics on competitive
      outcomes for the parameter ranges explored.

PMID- 15178184
TI  - Necessary conditions for a minimal model of receptor to show adaptive response
      over a wide range of levels of stimulus.
AB  - Sensory systems respond to temporal changes in the stimulus and adapt to the new
      level when it persists, this pattern of response being maintained in a wide range
      of levels of stimulus. Here we use a simple model of adaptation developed by
      Segel et al. (J. Theor. Biol. 120 (1986) 151-179) and extended by Hauri and Ross
      (Biophys. J. 68 (1995) 708-722) to study the conditions in which it shows wide
      range of response. The model consists of a receptor that switches between a
      variable number of states, either by mass action law or by covalent modification.
      Using a global optimization procedure, we have optimized the adaptive response of
      the alternatives of the model with different number of states. We find that it is
      impossible to obtain a wide range of response if the receptor switches between
      states following mass-action laws, irrespective of the number of states. Instead,
      a wide range (of five orders of magnitude of ligand concentration) can be
      obtained if the receptor switches between several states by irreversible covalent
      modification, in agreement with previous models. Therefore, in this model,
      expenditure of energy to maintain a large number of covalent modification cycles
      operating outside equilibrium is necessary to achieve a wide range of response.
      The optimal values of the parameters present similar patterns to those reported
      for specific receptors, but there is no quantitative agreement. For instance,
      ligand affinity varies several orders of magnitude between the different states
      of the receptor, what is unlikely to be fulfilled by real systems. To see if the
      minimal model can show adaptive response and range with quantitatively plausible
      parameter values a sub-optimal receptor was studied, finding that adaptive
      response of high intensity can still be obtained in at least three orders of
      magnitude.

PMID- 15178185
TI  - Maximum geometrical hindrance to diffusion in brain extracellular space
      surrounding uniformly spaced convex cells.
AB  - Brain extracellular space (ECS) constitutes a porous medium in which diffusion is
      subject to hindrance, described by tortuosity, lambda = (D/D*)1/2, where D is the
      free diffusion coefficient and D* is the effective diffusion coefficient in
      brain. Experiments show that lambda is typically 1.6 in normal brain tissue
      although variations occur in specialized brain regions. In contrast, different
      theoretical models of cellular assemblies give ambiguous results: they either
      predict lambda-values similar to experimental data or indicate values of about
      1.2. Here we constructed three different ECS geometries involving tens of
      thousands of cells and performed Monte Carlo simulation of 3-D diffusion. We
      conclude that the geometrical hindrance in the ECS surrounding uniformly spaced
      convex cells is independent of the cell shape and only depends on the volume
      fraction alpha (the ratio of the ECS volume to the whole tissue volume). This
      dependence can be described by the relation lambda = ((3-alpha)/2)1/2, indicating
      that the geometrical hindrance in such ECS cannot account for lambda > 1.225.
      Reasons for the discrepancy between the theoretical and experimental tortuosity
      values are discussed.

PMID- 15178186
TI  - Periodic stimulus and the single cardiac cell-getting more out of 1D maps.
AB  - The response of an isolated cardiac cell to a periodic stimulus has traditionally
      been studied in terms of the duration of the action potential (APD) immediately
      following each stimulus. The APD approach offers explanations of several
      experimental observations, including the stability of the so-called 1:1 response
      which is thought to be relevant to the problem of spiral wave breakup and the
      onset of fibrillation. A discussion of some theoretical problems with the APD
      approach is given in order to motivate the derivation of a new type of map. This
      new one-dimensional map, which gives successive values of the prestimulus
      transmembrane potential instead of successive values of APD, relies on the
      presence of a one-dimensional slow manifold in the underlying dynamics. This slow
      manifold map extends the understanding offered by the APD approach to include an
      explanation of Wenckebach rhythms. In addition, the bifurcation structure of the
      map provides a unified description of the parameter dependence that agrees fairly
      well with experimental observation.

PMID- 15178187
TI  - A modeling framework describing the enzyme regulation of membrane lipids
      underlying gradient perception in Dictyostelium cells.
AB  - Gradient perception describes the process by which information about the
      chemoattractant concentration field surrounding a cell is transformed into an
      internal signal which is responsible for directed cell motion. Recently, many
      important biochemical details in immobilized and mobile Dictyostelium cells have
      been uncovered regarding the roles of enzymes regulating phosphoinositide lipids
      on the cell membrane which are responsible for gradient perception. We report on
      a modeling framework that describes the relationship between the membrane
      concentration of the primary 3'phosphoinositide lipids and the enzymes which
      regulate them. The model takes the form of partial differential equations
      describing the membrane concentration of these lipids. Working within this
      framework, we describe mechanisms which can be responsible for spatial
      amplification of these lipids and which do not employ lipid-enzyme feedback. An
      analysis of a basic module underlying this process is also performed.

PMID- 15178188
TI  - Tamoxifen treatment failure in cancer and the nonlinear dynamics of TGFbeta.
AB  - The process of cancer invasion involves a complex interplay between cell-cell and
      cell-medium adhesion, proteolytic enzyme secretion, cell birth and death
      processes, random and directed motility, and immune response, as well as many
      other factors. The growth factor TGF beta is known to have a complex effect on
      this process. It inhibits mitosis and promotes apoptosis in a concentration
      dependent manner in vitro, and it is for this reason that its secretion is
      thought to be helpful in inhibiting tumour growth. However, recent in vitro and
      in vivo results have shown a significant effect of this growth factor in
      promoting the sensitivity of malignantly transformed cells to gradients of
      extracellular matrix proteins--an effect which tends to increase invasiveness.
      The drug tamoxifen has been demonstrated to be therapeutically effective in the
      treatment of patients with breast cancer; however, it is known also that many
      patients become resistant to the effect of this drug after a few years, and the
      reasons for this remain controversial. In this work we take our established model
      of cancer invasion (J. Theor. Biol. 216(1) (2002) 85), and extend it to include
      the effect of TGF beta. In so doing we demonstrate that a tamoxifen-stimulated
      upregulation of the secretion of TGF beta may give rise to a tumour which has a
      smaller number of cells but which has a greater invasiveness, greater metastatic
      potential, and a tumour histology which is known to correlate with a poorer
      prognosis. These data suggest that tamoxifen-stimulated secretion of TGF beta
      might explain treatment failure in some patients.

PMID- 15178189
TI  - pH effects on the binding of oxygen to non-vertebrate monomeric hemoglobins. A
      linked function model.
AB  - Monomeric invertabrate hemoglobins with high oxygen affinity usually contain a
      tyrosine in the distal region of the heme. This feature has stimulated
      investigations revealing that one of the properties resulting from the presence
      of the distal tyrosines is a decreased off rate on the binding of oxygen, thus
      developing the high affinity. Despite that fact that the pK value of the tyrosine
      group differs significantly from the groups it replaces little attention has been
      paid to the pH dependence of the binding of oxygen to the high affinity
      hemoglobins. Such a pH dependence has been reported on two of the monomeric
      hemoglobins with relatively low oxygen affinity and one monomeric hemoglobin of
      intermediate affinity. The pH data of these hemoglobins has been analysed with a
      linked function model involving the hydrogen ion. pK values required for the low
      affinity hemoglobins vary from 4.5 to 7.5. When applied to the high-affinity
      hemoglobins, the linked function model provides reasonable values for the binding
      parameters. These pK values vary from 3.0 to 9.0.

PMID- 15178190
TI  - The basic reproductive number of Ebola and the effects of public health measures:
      the cases of Congo and Uganda.
AB  - Despite improved control measures, Ebola remains a serious public health risk in
      African regions where recurrent outbreaks have been observed since the initial
      epidemic in 1976. Using epidemic modeling and data from two well-documented Ebola
      outbreaks (Congo 1995 and Uganda 2000), we estimate the number of secondary cases
      generated by an index case in the absence of control interventions R0. Our
      estimate of R0 is 1.83 (SD 0.06) for Congo (1995) and 1.34 (SD 0.03) for Uganda
      (2000). We model the course of the outbreaks via an SEIR (susceptible-exposed
      infectious-removed) epidemic model that includes a smooth transition in the
      transmission rate after control interventions are put in place. We perform an
      uncertainty analysis of the basic reproductive number R0 to quantify its
      sensitivity to other disease-related parameters. We also analyse the sensitivity
      of the final epidemic size to the time interventions begin and provide a
      distribution for the final epidemic size. The control measures implemented during
      these two outbreaks (including education and contact tracing followed by
      quarantine) reduce the final epidemic size by a factor of 2 relative the final
      size with a 2-week delay in their implementation.

PMID- 15178191
TI  - Analysis of compartmental models of ligand-induced endocytosis.
AB  - Kinetic models have played a pivotal role in the study of ligand-induced
      endocytosis. However, an analysis that suggests a systematic way to validate such
      models is lacking. The current work analyses the base model of ligand-induced
      endocytosis for three widely used experimental protocols. In protocol I cells
      initially devoid of ligand are incubated in ligand solution, whereas protocols II
      and III are desorption experiments in which an initial pool of surface or
      internalized ligand-receptor complexes, respectively, are released into an
      elution medium that is initially devoid of ligand. A short-time analysis of
      protocol I using successive substitutions yielded a corrected pre-factor for the
      In/Sur plot introduced by Wiley and Cunningham (Cell 25 (1981) 433). In contrast,
      neglecting the variation in receptor numbers yielded an approximation of protocol
      I that is valid for long times (e.g. tens of minutes). Similarly, the low cell
      concentration limits of protocols II and III are derived by neglecting the
      concentration of free ligand. The simplicity of these approximations provides a
      simple and reliable method for estimating the parameters governing ligand
      kinetics, while their definitive nature implies that they can be used to verify
      the validity of the base model. This analysis also provides insight on the fast
      endocytosis and recycling limit of protocol III.

PMID- 15178192
TI  - Hypotheses for the functions of intercellular bridges in male germ cell
      development and its cellular mechanisms.
AB  - In oogamous reproduction of multicellular organisms, a striking phenomenon is the
      prevailing synchronous development of male germ cells connected by wide
      intercellular bridges (IBs, 0.1-2 microm), which is well conserved in both animal
      and plant species ranging from algae to human. In the literature, IBs are
      believed either to allow genetically segregated haploid spermatids to share
      diploid gene products after meiosis, or to mediate rapid transfer of some vital
      signals or nutrients. Although intercellular sharing of gene transcripts has
      experimental evidences, these hypotheses are still not satisfactory. To explore
      the unknown roles of IB, we assume that developing male germ cells may be
      especially sensitive to stochastic gene expression to become heterogeneous. To
      achieve best gamete quality, such heterogeneity must be eliminated so that
      relatively uniform gametes with normal functions can be produced. Development
      within a common syncytium may be the only way for this purpose. The process may
      require not only the intercellular exchange of a few molecular signals but also
      the mixing of protoplasm between the connected cells so that they have similar
      levels/states of mRNAs, proteins and organelles, which can be achieved only
      through wide IBs. This hypothesis can explain some quite intriguing aspects of
      male gametogenesis and provide unique predictions that can be tested
      experimentally.

PMID- 15178193
TI  - Monte Carlo sampling can be used to determine the size and shape of the steady
      state flux space.
AB  - Constraint-based modeling results in a convex polytope that defines a solution
      space containing all possible steady-state flux distributions. The properties of
      this polytope have been studied extensively using linear programming to find the
      optimal flux distribution under various optimality conditions and convex analysis
      to define its extreme pathways (edges) and elementary modes. The work presented
      herein further studies the steady-state flux space by defining its hyper-volume.
      In low dimensions (i.e. for small sample networks), exact volume calculation
      algorithms were used. However, due to the #P-hard nature of the vertex
      enumeration and volume calculation problem in high dimensions, random Monte Carlo
      sampling was used to characterize the relative size of the solution space of the
      human red blood cell metabolic network. Distributions of the steady-state flux
      levels for each reaction in the metabolic network were generated to show the
      range of flux values for each reaction in the polytope. These results give
      insight into the shape of the high-dimensional solution space. The value of
      measuring uptake and secretion rates in shrinking the steady-state flux solution
      space is illustrated through singular value decomposition of the randomly sampled
      points. The V(max) of various reactions in the network are varied to determine
      the sensitivity of the solution space to the maximum capacity constraints. The
      methods developed in this study are suitable for testing the implication of
      additional constraints on a metabolic network system and can be used to explore
      the effects of single nucleotide polymorphisms (SNPs) on network capabilities.

PMID- 15178194
TI  - Simulated complex dynamics of glycolysis in the protozoan parasite Trypanosoma
      brucei.
AB  - Glycolysis in Trypanosoma brucei was modeled using a reaction transport simulator
      and tested for possible complex dynamics. The glycolytic model is multi
      compartmentalized and accounts for the exchange of metabolites between the
      glycosomes, cytosol, mitochondrion and the host medium. The model is used to
      examine the effects of a range of culture medium concentrations of oxygen on the
      glycolysis of T. brucei. Our results are in good agreement with steady-state
      experiments. We also find that under aerobic conditions, increasing the activity
      of glycerol-3-phosphate dehydrogenase induces complex dynamics in the system. We
      report the presence of three distinct types of these dynamics. Varying the oxygen
      concentration in the medium can induce the transition between these dynamics.

PMID- 15178195
TI  - Proteomic analyser with applications to diagnostics and vaccines.
AB  - This paper describes a method for proteomic analysis with applications to
      diagnostics and vaccines. A panel of N (> or = 1) reagents called X(j), with j =
      1 to N, is used. The binding strength of each of the X(j) reagents to each other
      is measured, for example by an ELISA assay, giving an N x N matrix K. The matrix
      K is used to define another set of N reagents called Y(j), with j = 1 to N, each
      of which is a linear combination of the X(j) reagents and each of which is
      tailored to be complementary to one of the X(j) reagents. Each of the N pairs of
      reagents X(j) and Y(j) defines an axis in an N-dimensional shape space. The
      definition of these axes facilitates proteomic analysis of diverse biological
      samples, for example, mixtures of proteins such as serum samples or T cell
      extracts. A method for defining and measuring similarity between pairs of
      biological samples and between sets of biological samples in the context of the
      set of N reagent pairs is described. This leads to methods for using the N
      reagent pairs in the diagnosis of diseases and in the formulation of preventive
      and therapeutic vaccines. The relationship of this work to previous research on
      shape space is discussed.

PMID- 15178196
TI  - Free energy transduction in a chemical motor model.
AB  - Motor enzymes catalyse chemical reactions, like the hydrolysis of ATP, and in the
      process they also perform work. Recent studies indicate that motor enzymes
      perform work with specific biochemical steps in their catalysed reactions,
      challenging the classical view that work can only be performed within a
      biochemical state. To address these studies an alternative class of models, often
      referred to as chemical motor models, has emerged in which motors perform work
      with biochemical transitions. In this paper, I develop a novel, self-consistent
      framework for chemical motor models, which accommodates multiple pathways for
      free energy transfer, predicts rich behaviors from the simplest multi-motor
      systems, and provides important new insights into muscle and motor function.

PMID- 15178197
TI  - Tumor classification using phylogenetic methods on expression data.
AB  - Tumor classification is a well-studied problem in the field of bioinformatics.
      Developments in the field of DNA chip design have now made it possible to measure
      the expression levels of thousands of genes in sample tissue from healthy cell
      lines or tumors. A number of studies have examined the problems of tumor
      classification: class discovery, the problem of defining a number of classes of
      tumors using the data from a DNA chip, and class prediction, the problem of
      accurately classifying an unknown tumor, given expression data from the unknown
      tumor and from a learning set. The current work has applied phylogenetic methods
      to both problems. To solve the class discovery problem, we impose a metric on a
      set of tumors as a function of their gene expression levels, and impose a tree
      structure on this metric, using standard tree fitting methods borrowed from the
      field of phylogenetics. Phylogenetic methods provide a simple way of imposing a
      clear hierarchical relationship on the data, with branch lengths in the
      classification tree representing the degree of separation witnessed. We tested
      our method for class discovery on two data sets: a data set of 87 tissues,
      comprised mostly of small, round, blue-cell tumors (SRBCTs), and a data set of 22
      breast tumors. We fit the 87 samples of the first set to a classification tree,
      which neatly separated into four major clusters corresponding exactly to the four
      groups of tumors, namely neuroblastomas, rhabdomyosarcomas, Burkitt's lymphomas,
      and the Ewing's family of tumors. The classification tree built using the breast
      cancer data separated tumors with BRCA1 mutations from those with BRCA2
      mutations, with sporadic tumors separated from both groups and from each other.
      We also demonstrate the flexibility of the class discovery method with regard to
      standard resampling methodology such as jackknifing and noise perturbation. To
      solve the class prediction problem, we built a classification tree on the
      learning set, and then sought the optimal placement of each test sample within
      the classification tree. We tested this method on the SRBCT data set, and
      classified each tumor successfully.

PMID- 15178198
TI  - The truthful signalling hypothesis: an explicit general equilibrium model.
AB  - In mating competition, the truthful signalling hypothesis (TSH), sometimes known
      as the handicap principle, asserts that higher-quality males signal while lower
      quality males do not (or else emit smaller signals). Also, the signals are
      "believed", that is, females mate preferentially with higher-signalling males.
      Our analysis employs specific functional forms to generate analytic solutions and
      numerical simulations that illuminate the conditions needed to validate the TSH.
      Analytic innovations include: (1) A Mating Success Function indicates how female
      mating choices respond to higher and lower signalling levels. (2) A congestion
      function rules out corner solutions in which females would mate exclusively with
      higher-quality males. (3) A Malthusian condition determines equilibrium
      population size as related to per-capita resource availability. Equilibria
      validating the TSH are achieved over a wide range of parameters, though not
      universally. For TSH equilibria it is not strictly necessary that the high
      quality males have an advantage in terms of lower per-unit signalling costs, but
      a cost difference in favor of the low-quality males cannot be too great if a TSH
      equilibrium is to persist. And although the literature has paid less attention to
      these points, TSH equilibria may also fail if: the quality disparity among males
      is too great, or the proportion of high-quality males in the population is too
      large, or if the congestion effect is too weak. Signalling being unprofitable in
      aggregate, it can take off from a no-signalling equilibrium only if the trait
      used for signalling is not initially a handicap, but instead is functionally
      useful at low levels. Selection for this trait sets in motion a bandwagon,
      whereby the initially useful indicator is pushed by male-male competition into
      the domain where it does indeed become a handicap.

PMID- 15178199
TI  - Complex bursting in pancreatic islets: a potential glycolytic mechanism.
AB  - The electrical activity of insulin-secreting pancreatic islets of Langerhans is
      characterized by bursts of action potentials. Most often this bursting is
      periodic, but in some cases it is modulated by an underlying slower rhythm. We
      suggest that the modulatory rhythm for this complex bursting pattern is due to
      oscillations in glycolysis, while the bursting itself is generated by some other
      slow process. To demonstrate this hypothesis, we couple a minimal model of
      glycolytic oscillations to a minimal model for activity-dependent bursting in
      islets. We show that the combined model can reproduce several complex bursting
      patterns from mouse islets published in the literature, and we illustrate how
      these complex oscillations are produced through the use of a fast/slow analysis.

PMID- 15178200
TI  - From dissimilarities among species to dissimilarities among communities: a double
      principal coordinate analysis.
AB  - This paper presents a new ordination method to compare several communities
      containing species that differ according to their taxonomic, morphological or
      biological features. The objective is first to find dissimilarities among
      communities from the knowledge about differences among their species, and second
      to describe these dissimilarities with regard to the feature diversity within
      communities. In 1986, Rao initiated a general framework for analysing the extent
      of the diversity. He defined a diversity coefficient called quadratic entropy and
      a dissimilarity coefficient and proposed a decomposition of this diversity
      coefficient in a way similar to ANOVA. Furthermore, Gower and Legendre (1986)
      built a weighted principal coordinate analysis. Using the previous context, we
      propose a new method called the double principal coordinate analysis (DPCoA) to
      analyse the relation between two kinds of data. The first contains differences
      among species (dissimilarity matrix); the second the species distribution among
      communities (abundance or presence/absence matrix). A multidimensional space
      assembling the species points and the community points is built. The species
      points define the original differences between species and the community points
      define the deduced differences between communities. Furthermore, this
      multidimensional space is linked with the diversity decomposition into between
      community and within-community diversities. One looks for axes that provide a
      graphical ordination of the communities and project the species onto them. An
      illustration is proposed comparing bird communities which live in different areas
      under mediterranean bioclimates. Compared to some existing methods, the double
      principal coordinate analysis can provide a typology of communities taking
      account of an abundance matrix and can include dissimilarities among species.
      Finally, we show that such an approach generalizes some of these methods and
      allows us to develop new analyses.

PMID- 15178201
TI  - Infection, reinfection, and vaccination under suboptimal immune protection:
      epidemiological perspectives.
AB  - The SIR (susceptible-infectious-resistant) and SIS (susceptible-infectious
      susceptible) frameworks for infectious disease have been extensively studied and
      successfully applied. They implicitly assume the upper and lower limits of the
      range of possibilities for host immune response. However, the majority of
      infections do not fall into either of these extreme categories. We combine two
      general avenues that straddle this range: temporary immune protection (immunity
      wanes over time since infection), and partial immune protection (immunity is not
      fully protective but reduces the risk of reinfection). We present a systematic
      analysis of the dynamics and equilibrium properties of these models in comparison
      to SIR and SIS, and analyse the outcome of vaccination programmes. We describe
      how the waning of immunity shortens inter-epidemic periods, and poses major
      difficulties to disease eradication. We identify a "reinfection threshold" in
      transmission when partial immunity is included. Below the reinfection threshold
      primary infection dominates, levels of infection are low, and vaccination is
      highly effective (approximately an SIR model). Above the reinfection threshold
      reinfection dominates, levels of infection are high, and vaccination fails to
      protect (approximately an SIS situation). This association between high
      prevalence of infection and vaccine failure emphasizes the problems of
      controlling recurrent infections in high-burden regions. However, vaccines that
      induce a better protection than natural infection have the potential to increase
      the reinfection threshold, and therefore constitute interventions with a
      surprisingly high capacity to reduce infection where reduction is most needed.

PMID- 15178202
TI  - Identify catalytic triads of serine hydrolases by support vector machines.
AB  - The core of an enzyme molecule is its active site from the viewpoints of both
      academic research and industrial application. To reveal the structural and
      functional mechanism of an enzyme, one needs to know its active site; to conduct
      structure-based drug design by regulating the function of an enzyme, one needs to
      know the active site and its microenvironment as well. Given the atomic
      coordinates of an enzyme molecule, how can we predict its active site? To tackle
      such a problem, a distance group approach was proposed and the support vector
      machine algorithm applied to predict the catalytic triad of serine hydrolase
      family. The success rate by jackknife test for the 139 serine hydrolases was 85%,
      implying that the method is quite promising and may become a useful tool in
      structural bioinformatics.

PMID- 15178203
TI  - Polyp oriented modelling of coral growth.
AB  - The morphogenesis of colonial stony corals is the result of the collective
      behaviour of many coral polyps depositing coral skeleton on top of the old
      skeleton on which they live. Yet, models of coral growth often consider the
      polyps as a single continuous surface. In the present work, the polyps are
      modelled individually. Each polyp takes up resources, deposits skeleton, buds off
      new polyps and dies. In this polyp oriented model, spontaneous branching occurs.
      We argue that branching is caused by a so called "polyp fanning effect" by which
      polyps on a convex surface have a competitive advantage relative to polyps on a
      flat or concave surface. The fanning effect generates a more potent branching
      mechanism than the Laplacian growth mechanism that we have studied previously. We
      discuss the application of the polyp oriented model to the study of
      environmentally driven morphological plasticity in stony corals. In a few
      examples we show how the properties of the individual polyps influence the whole
      colony morphology. In our model, the spacing of polyps influences the thickness
      of coral branches and the overall compactness of the colony. Density variations
      in the coral skeleton may also be important for the whole colony morphology,
      which we address by studying two variants of the model. Finally, we discuss the
      importance of small scale resource translocation in the coral colony and its
      effects on the morphology of the colony.

PMID- 15178204
TI  - Can statins treat the strokes they fail to prevent?

PMID- 15178205
TI  - Differentiating between peripheral and central causes of vertigo.

PMID- 15178206
TI  - Effect of pretreatment with statins on the severity of acute ischemic
      cerebrovascular events.
AB  - OBJECTIVE: Treatment with statins reduces the risk of ischemic stroke among
      patients at increased risk for vascular disease. Recent experimental data suggest
      neuroprotective properties of statins in acute cerebral ischemia. We investigated
      whether a premedication with statins is associated with a better outcome in
      patients with acute ischemic cerebrovascular events. METHODS: Within a cross
      sectional study, nested in a cohort we identified 1691 patients with a recent
      ischemic stroke or transient ischemic attack. Clinical severity of the vascular
      event was evaluated by the modified Rankin Scale (mRS) after 1 week. By means of
      multivariate logistic regression modeling, we determined the influence of prior
      statin use on stroke severity with adjustment for potential confounding factors.
      RESULTS: Severe stroke, defined as a modified Rankin Scale of 5 or 6 (n=231;
      14%), was less frequent in patients receiving statin treatment before the event
      (6% vs. 14%, OR=0.37; 95% CI 0.19 to 0.74; p=0.004). This association remained
      significant after adjustment for confounding factors. We found a significant
      interaction between the presence of diabetes and the effect of pretreatment with
      statins on stroke outcome. Of the patients with diabetes, none of those on statin
      treatment but 16% of those without a statin had a bad outcome. After exclusion of
      the group of diabetic patients with prior statin medication, the protective
      effect was reduced and not statistically significant anymore. CONCLUSIONS:
      Pretreatment with statins seems to be associated with reduced clinical severity
      in patients with acute ischemic cerebrovascular events, particularly in patients
      with diabetes.

PMID- 15178207
TI  - Free radical scavenger, edaravone, in stroke with internal carotid artery
      occlusion.
AB  - BACKGROUND: Edaravone has potent free radical quenching and antioxidant actions.
      The agent has been recently in commercial use for acute ischemic stroke patients.
      In this study, we investigated the therapeutic effect of edaravone on severe
      carotid-territorial stroke. METHODS: Stroke patients with internal carotid artery
      occlusion and baseline NIH Stroke Scale Score > or =15 were treated for 14 days
      with drip intravenous infusion of edaravone (n=30) and were compared with a
      historical control cohort of similar patients (n=31). Glycerol was also
      administered to all patients in both groups. RESULTS: Infarct volume (P<0.02) and
      midline shift (P<0.02) on CT performed on day 2 of the patients treated with
      edaravone were smaller than those without edaravone. For patients with edaravone,
      infarct volume (P<0.0001) and midline shift (P<0.0001) on days 5-7 were greater
      than those on day 2. Hemorrhagic transformation of infarcts on day 2 was less
      severe in patients with than without edaravone (P<0.03). Within 14 days after the
      onset of stroke, 6 patients with edaravone (20%) and 14 without edaravone (45%)
      died directly of stroke (P<0.03). Among all patients, only two treated with
      edaravone were independent without any assistance 8 weeks after the onset.
      CONCLUSIONS: Edaravone was associated with delayed evolution of infarcts and
      edema in patients with severe carotid-territorial stroke and decreased mortality
      during the acute stage. The agent, however, failed to prevent evolution of
      infarcts and edema on later days, and did not significantly improve functional
      outcome among the surviving patients.

PMID- 15178208
TI  - CSF levels of neurofilament is a valuable predictor of long-term outcome after
      cardiac arrest.
AB  - AIMS: Prognostication of brain damage after cardiac arrest mainly relies on
      clinical observations. Recently, it has been shown that biochemical markers of
      brain damage measured in serum aid in this process. In the present study, we
      wanted to test the usefulness of CSF determinations of a neuronal protein, the
      neurofilament protein (NFL). METHODS AND RESULTS: Lumbar punctures were performed
      during week 2 or 3 in 22 patients surviving cardiac arrests. CSF NFL
      concentrations were analysed using an ELISA. Levels were increased in cardiac
      arrest patients. Patients with poor outcome according to the Glasgow outcome
      scale (GOS), low performance at a mini mental state examination (MMSE) and
      dependent according to Katz at 1 year follow up had the highest NFL levels. The
      NFL levels correlated well with anoxia time and coma depth. High positive and
      negative predictive values, particularly for poor outcome according to GOS were
      observed. CONCLUSIONS: Levels of CSF NFL give a reliable measure of the brain
      damage following cardiac arrest and the levels are highly predictive of poor
      outcome. This observation urges the development of sensitive serum assays of this
      marker to be used in the clinical setting.

PMID- 15178209
TI  - Stroke in women of reproductive age: comparison between stroke related and
      unrelated to pregnancy.
AB  - Pregnancy may increase the risk of stroke. However, few studies have compared
      strokes in women of reproductive age that occur in pregnancy or the puerperium
      (pregnancy-related stroke, PRS) with those unrelated to pregnancy. This study
      assesses risk factors and etiologies of stroke in these women based on
      relationship to pregnancy. From 1984 to 2002, all female patients 15 through 40
      years of age with a first-ever stroke at National Taiwan University Hospital were
      included in this study. PRS was defined as patients who had stroke occurrence
      during pregnancy or within 6 weeks postpartum. Stroke was categorized as cerebral
      infarction (CI), cerebral hemorrhage (CH), or subarachnoid hemorrhage (SAH) and
      divided into subtype according to etiology. Risk factors and etiologies were
      compared for patients with PRS and stroke unrelated to pregnancy. We identified
      49 patients with PRS, and 353 patients with stroke unrelated to pregnancy. There
      was no statistically significant difference in distribution of CI subtypes.
      Cerebral venous thrombosis (CVT) was more common in PRS than stroke unrelated to
      pregnancy (39% vs. 7%, P<0.001), and 73% of these cases occurred postpartum.
      Preeclampsia-eclampsia was an important cause of peripartum CH (37%), but not CI
      (4%). Among PRS cases, postpartum cerebral venous thrombosis and preeclampsia
      eclampsia were the major causes of CI and CH, respectively.

PMID- 15178210
TI  - A novel mutation in KCNQ2 gene causes benign familial neonatal convulsions in a
      Chinese family.
AB  - Benign familial neonatal convulsions (BFNC) are a rare autosomal dominant
      inherited epilepsy syndrome. Two voltage-gated potassium channel genes, KCNQ2 on
      chromosome 20q13.3 and KCNQ3 on chromosome 8q24, have been identified as the
      genes responsible for benign familial neonatal convulsions. By linkage analysis
      and mutation analysis of KCNQ2 gene, we found a novel frameshift mutation of
      KCNQ2 gene, 1931delG, in a large Chinese family with benign familial neonatal
      convulsions. This mutation is located in the C-terminus of KCNQ2, in codon 644
      predicting the replacement of the last 201 amino acids with a stretch of 257
      amino acids showing a completely different sequence. An unusual clinical feature
      of this family is that the seizures of every patient did not remit until 12 to 18
      months. This is the first report of KCNQ2 gene mutation in China.

PMID- 15178211
TI  - Autosomal dominant childhood onset slowly progressive leukodystrophy--a Japanese
      family with spastic paraparesis, ataxia, mental deterioration, and skeletal
      abnormality.
AB  - Autosomal dominant leukodystrophy is an extremely rare disease. Here we report on
      a dominantly inherited disease in a Japanese family with slowly progressive
      clinical course. Their symptoms and signs started in early childhood and very
      slowly progressed. In most patients spastic gait was the initial symptom.
      Neurological manifestations were characterized by pyramidal signs, ataxia, and
      mental deterioration. In addition to these neurological signs, the skeletal
      anomalies such as scoliosis and congenital hip dislocation were also present. MR
      images showed no abnormality in the early stage, but T2-weighted images revealed
      high intensity areas in the cerebral and cerebellar white matter, and the dentate
      nucleus in the advanced stage. Proton MR spectroscopy showed decrease of N
      acetylaspartate/creatine ratio and increase of choline/creatine ratio in the
      advanced stage. Proton MR spectroscopy revealed normal N-acetylaspartate/creatine
      ratio and increase of choline/creatine ratio in the early stage. We suggested
      that these patients had abnormality in the white matter when MRI was still
      normal. We considered that intracranial demyelination was gradually progressed as
      the symptoms got aggravated.

PMID- 15178212
TI  - Effects of citalopram on the excitability of the human motor cortex: a paired
      magnetic stimulation study.
AB  - Several recent reports suggest the possibility of monitoring pharmacological
      effects on brain excitability through transcranial magnetic stimulation (TMS).
      Different drugs have been studied using paired magnetic stimulation in normal
      subjects and patients. In particular, it has been suggested that antidepressant
      drugs may have an appreciable effect on motor excitability. The aim of the
      present study was to investigate motor area excitability in normal subjects after
      oral administration of a single dose of citalopram, a selective serotonin
      reuptake inhibitor (SSRI) antidepressant. Motor cortex excitability was studied
      by single and paired transcranial magnetic stimulation before and 2.5 and 36
      (t1/2=36 h) h after oral administration of 30 mg of citalopram. Cortical
      excitability was measured using different transcranial magnetic stimulation
      parameters: motor threshold (MT), motor-evoked potential (MEP) amplitude and
      latency, motor recruitment, duration of cortical silent period (CSP),
      intracortical inhibition and intracortical facilitation. Spinal excitability and
      peripheral nerve conduction were measured by F response and M wave. Temporary but
      significant increases in motor threshold, motor-evoked potentials, silent period
      and intracortical inhibition were observed 2.5 h after drug administration,
      without any significant changes in motor-evoked potential amplitude and latency
      and spinal excitability parameters. Our findings suggest that a single oral dose
      of citalopram can induce significant but transitory suppression of motor cortex
      excitability in normal subjects.

PMID- 15178213
TI  - Repetitive nerve stimulation for the evaluation of peripheral nerve
      hyperexcitability.
AB  - OBJECTIVE: To examine the utility of repetitive nerve stimulation (RNS) in the
      evaluation of peripheral nerve hyperexcitability (PNH). BACKGROUND: PNH describes
      a group of disorders characterized by muscle cramps, twitching and stiffness.
      When severe, PNH may be characterized by the presence of continuous muscle fiber
      activity on routine needle electromyography (EMG). In milder forms of the
      disease, nerve hyperexcitability may be evidenced by the presence of after
      discharges or cramp potentials following RNS. METHODS: Fifty-four patients were
      prospectively recruited and classified into one of three groups-PNH, other
      neuromuscular disease and controls. We recorded and quantified the after
      discharges and cramp potentials following RNS at 1, 5, 10 and 30 Hz. RESULTS: The
      proportion of nerves with after-discharges and/or cramp potentials was
      significantly greater in the PNH group than the control group at both 5 Hz
      (p=0.03) and 10 Hz (p=0.01), as well as in the neuromuscular disease group
      compared to controls at 5 Hz (p=0.02). There was also a significant concordance
      between complaints of muscle cramps and fasciculations and the finding of after
      discharges and/or cramp potentials at both 5 Hz (p=0.005) and 10 Hz (p=0.004). At
      a stimulation frequency of 10 Hz, the sensitivity of RNS for the diagnosis of PNH
      (primary or secondary) was 79% and the specificity was 88%. CONCLUSION: Our
      findings suggest that RNS at or below a stimulation frequency of 10 Hz (when
      positive) is a useful test for the diagnosis of PNH, whether it is primary or
      secondary.

PMID- 15178214
TI  - Electrophysiological correlates of associative visual agnosia lesioned in the
      ventral pathway.
AB  - Visual agnosia has been well studied by anatomical, neuropsychological and
      neuroimaging studies. However, functional changes in the brain have been rarely
      assessed by electrophysiological methods. We carried out electrophysiological
      examinations on a 23-year-old man with associative visual agnosia, prosopagnosia
      and cerebral achromatopsia to evaluate the higher brain dysfunctions of visual
      recognition. Electrophysiological methods consisted of achromatic, chromatic and
      category-specific visual evoked potentials (CS-VEPs), and event-related
      potentials (ERPs) with color and motion discrimination tasks. Brain magnetic
      resonance imaging revealed large white matter lesions in the bilateral temporo
      occipital lobes involving the lingual and fusiform gyri (V4) and inferior
      longitudinal fasciculi due to multiple sclerosis. Examinations including CS-VEPs
      demonstrated dysfunctions of face and object perception while sparing semantic
      word perception after primary visual cortex (V1) in the ventral pathway. ERPs
      showed abnormal color perception in the ventral pathway with normal motion
      perception in the dorsal pathway. These electrophysiological findings were
      consistent with lesions in the ventral pathway that were detected by clinical and
      neuroimaging findings. Therefore, CS-VEPs and ERPs with color and motion
      discrimination tasks are useful methods for assessing the functional changes of
      visual recognition such as visual agnosia.

PMID- 15178215
TI  - Influence of 17-beta-estradiol on cerebrovascular impedance during menstrual
      cycle in women.
AB  - Numerous experimental studies showed that estrogen alters diameters of cerebral
      arteries by modifying production of vasoactive substances. In this study, we
      address a question whether increased concentration of 17-beta-estradiol (E2)
      during a typical menstrual cycle of young, healthy women influences
      cerebrovascular impedance, as measured with Doppler pulsatility index (PI) in the
      common (CCA), internal (ICA), and external (ECA) carotid arteries using duplex
      Doppler sonography. PI was determined and correlated with plasma E2 concentration
      in 14 women (ages 23-25) throughout their menstrual cycle. The concentration of
      E2 increased in the follicular phase of the cycle and reached a peak of 140-300
      pg/ml on days 13 and 14, whereas concentration of progesterone remained low (<1
      ng/ml). Along with an increase in E2 concentration, the ICA PI decreased from its
      initial level on average by 11% on day 13 and by 7% on day 14 (r=-0.41, P<0.05).
      In contrast, the value of the ECA PI showed an increasing trend during the peak
      of E2 concentration. There were no significant changes in the CCA PI as well as
      in the systolic blood pressure, heart rate, hematocrit, and hemoglobin
      concentration during the menstrual cycle. Cerebral vascular impedance in young
      women is modulated by concentration of E2 throughout the menstrual cycle. The
      decrease in the ICA PI during the late follicular phase seems to be attributed to
      a decrease in cerebrovascular resistance.

PMID- 15178216
TI  - Analysis of the unmyelinated primary sensory neurone projection through the
      dorsal columns of the rat spinal cord using transganglionic transport of the
      plant lectin Bandeiraea simplicifolia I-isolectin B4.
AB  - We have examined the projection of unmyelinated primary sensory neurones through
      the dorsal columns of the rat spinal cord using transganglionic transport of the
      plant lectin Bandeiraea simplicifolia I-isolectin B4. A small volume of the
      lectin was injected into the sciatic nerve of anaesthetised rats to label the
      central terminals of nociceptive primary sensory neurones. Following a survival
      period of 7 days, transverse and longitudinal sections of the superficial dorsal
      horn, dorsolateral funiculus and the dorsal columns from spinal segments L4
      through to T13 were screened for lectin transport using light and electron
      microscopy. Longitudinal sections of the thoraco-lumbar region of spinal cord
      were also examined for lectin binding. Light and electron microscopy revealed
      transganglionically transported and bound lectin in the superficial dorsal horn
      and dorsolateral funiculus of the L3 and L4 segments of spinal cord. However, no
      lectin transport or binding was observed within the dorsal columns at any level
      of spinal cord examined. From these results, we suggest that the unmyelinated
      neurones within the dorsal columns do not express the binding site for BSI-B4
      and, as such, may be responsible for visceral rather than cutaneous sensation. In
      line with the theories regarding a postsynaptic dorsal column pathway, these
      results suggest that nociceptors that bind BSI-B4 are not involved in a direct
      ascending projection through the dorsal columns.

PMID- 15178217
TI  - Primary diffuse leptomeningeal sarcoma with rhabdomyoblastic differentiation. A
      case report and immunohistochemical study.
AB  - Primary meningeal neoplasias are rare, and their diffuse growth within the
      subarachnoid space may simulate inflammatory processes or metastatic neoplastic
      dissemination. We report here the case of a boy with an 18-day history of fever
      and progressive neurological deterioration. While in the hospital, the patient
      showed neurological deterioration and did not respond to antituberculosis
      treatment. His cerebrospinal fluid (CSF) cytology disclosed an elevated white
      blood cell count accompanied by a mildly elevated protein level and a slightly
      decreased glucose level. The child died, and pathology revealed that his
      meningeal process was a sarcoma. The immunophenotype of the neoplastic cells
      showed expression of a sarcomeric actin marker, characterizing rhabdomyoblastic
      differentiation of the cells that occupied the subarachnoid space and invaded
      superficially the encephalon. Rhabdomyoblastic differentiation in leptomeningeal
      diffuse primary sarcoma (LDPS) is an aspect rarely observed in this malignant
      meningeal neoplasia, with few reported cases. The present case is the first
      reported in the Portuguese literature and the fifth reported in the English
      literature.

PMID- 15178218
TI  - A case of reversible postpartum cytotoxic edema in preeclampsia.
AB  - We report on a 32-year-old woman who developed reversible cortical blindness and
      right-sided weakness after cesarean section at 36 weeks of gestation, due to
      preeclampsia. An initial brain MRI demonstrated high signal intensity lesions in
      the bilateral occipito-parietal and left frontal lobes on T2-weighted and
      diffusion-weighted imaging. All of the lesions showed low signal intensity on
      apparent diffusion coefficient (ADC) map, which were compatible with cytotoxic
      edema, and MR angiography (MRA) showed diffuse vasospasm of the intracranial
      vessels. A follow-up brain MRI showed that most of the lesions disappeared and
      the vasospasm also resolved. This case suggests that the cytotoxic edema in
      preeclampsia may evolve differently from the pattern in cerebral infarction and
      explains the relatively benign course of the neurological signs in preeclampsia.

PMID- 15178219
TI  - Ischemic pituitary apoplexy associated with the lupus anticoagulant.
AB  - PURPOSE: To report a case of ischemic pituitary apoplexy secondary to a
      hypercoagulable state following elective orthopedic surgery. DESIGN:
      Observational case report. METHODS: A 48-year-old Caucasian man underwent an
      uneventful, left-sided total hip replacement and corrective osteotomy of the
      proximal femur. Two days post-operative, he developed a frontal headache and
      blurred vision in both eyes. RESULTS: Ophthalmic examination revealed right VIth
      cranial nerve palsy. Imaging studies indicated pituitary apoplexy with a large
      hypodense pituitary lesion with widening of the sella turcica. Laboratory
      findings included positive lupus anticoagulant, a normal prothrombin time (PT),
      and an elevated activated partial thromboplastin time (aPTT). Five days after the
      initial symptoms, a transsphenoidal pituitary resection was performed. At a 6
      months follow-up, the VIth nerve paresis was completely resolved. CONCLUSIONS:
      This case describes ischemic pituitary apoplexy associated with a pre-operatively
      elevated aPTT and positive lupus anticoagulant. This is the first report, to our
      knowledge, of atypical apoplexy concurrent with antiphospholipid (aPL) antibodies
      following an uneventful surgery. The results we obtained on this patient suggest
      that an associated hypercoaguable state may increase the risk of thrombosis
      following elective orthopedic surgery.

PMID- 15178220
TI  - Coexistence of tuberous sclerosis and Friedreich ataxia.
AB  - Tuberous sclerosis (TS) is caused by point mutations in the TSC1 or TSC2 genes on
      chromosomes 9q33-34 or 16p13, respectively. Clinical manifestations can be quite
      variable but are primarily limited to cutaneous, neurologic, and cardiovascular
      abnormalities. Phenotypes range from neurologically devastated to those with
      silent lesions. A 34-year-old patient with genetically documented TSC1 developed
      progressive ataxia over a decade, without TS lesions to correlate with this
      finding. After evaluation of common causes including long-term antiepileptic
      regimens, DNA testing for hereditary ataxias was performed and revealed the
      presence of an additional mutation on chromosome 9. The patient was homozygous
      for the Friedreich ataxia (FA) mutation, with 500 and 700 GAA repeats in the FRDA
      gene on chromosome 9q13. There is no established relationship between these two
      disorders and the occurrence of two mutations on the same chromosome is probably
      coincidental but emphasizes the importance of searching for additional genetic
      causes when the phenotype does not fit with an established genetic diagnosis.

PMID- 15178221
TI  - HTLV-1-associated myelopathy/tropical spastic paraparesis accompanied with
      psoriasis.
AB  - Two adult females developed HTLV-1-associated myelopathy/tropical spastic
      paraparesis (HAM/TSP) and psoriasis. Both showed chronic progressive paraparesis
      and sharply demarcated erythematous scaling plaques on their extremities and
      trunk. One patient had polymyositis while in the other anti-thyroid antibodies,
      antinuclear antibodies and SS-A antibody, all autoantibodies, were positive. Both
      patients were treated by intramuscular injections of interferon-alpha for 2 to 4
      weeks, resulting in amelioration of paraparesis. After the therapy psoriasis and
      polymyositis markedly improved in one patient without any additional therapy,
      while in the other simultaneous use of topical corticosteroids was effective.
      This is the first report to describe occurrences of psoriasis in HAM/TSP
      patients. Although there are several reports indicating interferon-alpha induces
      or exacerbates psoriasis, our experience suggests that psoriasis associated with
      HAM/TSP can be successfully managed even during interferon-alpha therapy.

PMID- 15178222
TI  - IgA monoclonal gammopathy of undetermined significance with peripheral
      neuropathy.
AB  - Monoclonal gammopathy of undetermined significance (MGUS) and peripheral
      neuropathy may be causally linked. In most cases, the M-protein is of IgG or IgM
      type. Peripheral neuropathy associated with IgA MGUS is uncommon, and there are
      limited reports. Here, we report a case of a 55-year-old male who was diagnosed
      to have symmetrical sensorimotor peripheral neuropathy associated with IgA MGUS
      with deposits of IgA-monoclonal protein in the myelin sheath.

PMID- 15178223
TI  - Antibodies to dorsal root ganglia and olfactory cells in a patient with chronic
      sensory neuropathy and anosmia.
AB  - We report the case of a 51-year-old woman with anosmia and chronic sensory ataxic
      neuropathy. Olfactory tests suggested neurosensory anosmia. Immunocytochemical
      analysis showed serum antibodies against dorsal root ganglion (DRG) cells and
      olfactory neurons, in the absence of other known causes of anosmia and sensory
      neuropathy. Clinical and laboratory data suggested a slow autoimmune process
      affecting dorsal root ganglion and olfactory cells.

PMID- 15178224
TI  - Early vestibular dysfunction in Machado-Joseph disease detected by caloric test.
AB  - The selective vulnerability of distinct neuronal structures is a major feature of
      Machado-Joseph disease (MJD), also known as spinocerebellar ataxia 3 (SCA3).
      Vestibular dysfunction is known to be a symptom of MJD, but little is known about
      precisely when the vestibular system becomes impaired. Using a caloric test, we
      evaluated vestibular function in 2 MJD patients. One developed the initial
      symptom 1 year before evaluation, and the other 3 years before evaluation.
      Neither demonstrated a bilateral response in electronystagmography using ice-cold
      water irrigation, indicating severe vestibular disturbance. These results suggest
      that vestibular dysfunction is a symptom that develops very early in MJD and may
      contribute to unsteady gait as the initial symptom. The vestibular system thus
      appears to be one of the structures most vulnerable to MJD.

PMID- 15178225
TI  - Large-artery stroke in a young patient with Crohn's disease. Role of vitamin B6
      deficiency-induced hyperhomocysteinemia.
AB  - An increased incidence of ischemic stroke has been reported in patients with
      Crohn's disease. Cerebral infarcts are usually considered as a complication of
      the hypercoagulable state associated with this inflammatory bowel disease (IBD).
      The association between Crohn's disease, hyperhomocysteinemia and large-artery
      stroke of the young has rarely been reported. A 39-year-old woman, with prior
      medical history of Crohn's disease and hypertension, presented with an ischemic
      stroke of the left internal carotid artery (ICA) territory. Etiological workup
      disclosed bilateral high-grade ICA stenosis and atheroma of the subclavian and
      vertebral arteries. Exhaustive search for prothrombotic factors showed
      inflammation, with an increased level of fibrinogen and factor IX, and a marked
      hyperhomocysteinemia. Both vitamin B1 and vitamin B6 plasmatic levels were
      decreased. Heterozygous C677T methylene-tetrahydrofolate reductase gene mutation
      was present. This observation highlights the combined proatherogenic effect of
      vitamin B deficiency-induced hyperhomocysteinemia and inflammation leading to
      large-artery stroke of the young in the setting of Crohn's disease. Our case
      report stresses the importance of vitamin deficiency screening in patients with
      IBD in terms of stroke prevention.

PMID- 15178226
TI  - A case of isolated nodulus infarction presenting as a vestibular neuritis.
AB  - We reported a patient with cerebellar infarction who presented with purely
      isolated vertigo, ipsilesional spontaneous nystagmus, and contralesional axial
      lateropulsion without usual symptoms or signs of cerebellar dysfunction. An MRI
      of the brain showed a small left cerebellar infarct selectively involving the
      nodulus. A pure vestibular syndrome in our patient may be explained by
      ipsilateral involvement of nodulo-vestibular inhibitory projection to vestibular
      nucleus. Clinicians should be aware of the possibility of a nodulus infarction in
      patient with acute vestibular syndrome, even if the pattern of nystagmus and
      lateropulsion is typical of a vestibular neuritis.

PMID- 15178227
TI  - T2-hypointensity in the cortex.

PMID- 15178229
TI  - Clinical gait and balance scales for Parkinson's disease.

PMID- 15178231
TI  - Safety beliefs and safe behavior among midwestern college students.
AB  - PROBLEM: This study investigated the impact of safety beliefs on safe behavior
      and the effect of age, gender, class standing, and geographic region on these
      beliefs and behaviors. It also compares the level of safety beliefs and safe
      behavior of Midwestern college students in 1993 to those in 2002. METHOD: A total
      of 1,059 undergraduate students at four Midwestern universities completed the 33
      item questionnaire developed by Crowe (J. Saf. Res. 26 (1995) 187) during the
      spring semester of 2002. RESULTS: Significant main effects for gender and age on
      safety beliefs and safe behavior were found as well as a significant interaction
      between gender and age for both outcome variables. The regression model with the
      independent variables of personal responsibility and gender yielded a multiple R
      of.58, which explained 34% of the variance of the self-reported safe behavior.
      Midwestern college students in 2002 were found less safety-conscious in terms of
      self-reported safety beliefs and safe behavior than those in 1993. DISCUSSION:
      The findings indicate that safety education of adolescents and young adults in
      the United States has not been effective, at least for the last decade, or
      today's social and school environment is less conducive to the students' safe
      behavior and beliefs than a decade ago. IMPACT ON INDUSTRY: Proactive
      multidisciplinary approaches to enhance safe behavior and beliefs of young adults
      should be made based on critical evaluation of current approaches.

PMID- 15178232
TI  - An evaluation of scaffold safety at construction sites.
AB  - PROBLEM: This study evaluated common scaffold safety practices in construction.
      METHOD: A 150-point checklist was used to evaluate supported scaffold safety
      practices at 113 scaffolds in nine areas of the eastern United States. RESULTS:
      Thirty-six scaffolds (31.9%) were either in danger of collapse or missing
      planking, guardrails, or adequate access. There was a strong statistical
      correlation between structural flaws and fall protection hazards, and between
      proper scaffold safety practice and (a) competent persons with scaffold safety
      training, (b) use of separate scaffold erection contractors, and (c) scaffolds
      that were not simple frame types. A slightly weaker correlation was found with
      union status of the scaffold erector, and no correlation was found with
      geography, site size, number of scaffold users, and trade working on the
      scaffold. DISCUSSION: Recommendations are made for safer scaffold practice,
      including a simple four-factor scaffold inspection method. IMPACT ON INDUSTRY:
      Implementation of the four-factor method could result in a cost-effective way to
      identify unsafe scaffolds.

PMID- 15178233
TI  - Farm fatalities to youth 1995-2000: A comparison by age groups.
AB  - PROBLEM: Although a myriad of research illustrates the safety issues related to
      farm fatalities in youth populations, very little empirical evidence exists that
      includes work and non-work related farm fatalities to all youths under 20 years
      of age at the national level. METHODS: This research will use death certificate
      data for the six years from 1995 to 2000 that were collected by NIOSH from all 50
      state vital statistics registries. Demographic data from the 1998 CAIS were used
      in rate calculations. In addition to providing annual fatality rates and
      descriptions of the general causes of death, this research will examine the
      variation between age groups. RESULTS: Analysis of 695 total farm-related youth
      fatalities shows an average annual fatality rate of 9.3 fatalities per 100,000
      youths. Males account for 80% of these fatalities. The most prevalent causes of
      death are: machinery (25%), motor vehicle (17%), drowning (16%), suicide (8%) and
      homicide (6%). Of all youth fatalities occurring while at work, 45% are to youths
      less than 16 years of age. This same age group accounts for 71% of all non-work
      related fatalities. SUMMARY: This research will provide farm families and
      researchers more detailed information on farm hazards that contribute to the
      deaths of youths. As these youths may encounter hazards while working or playing
      in their daily environment, identification and elimination of these hazards will
      increase overall safety on the farm. This research also indicates the need to
      include youths under 16 years of age in future comprehensive farm safety
      research.

PMID- 15178234
TI  - CSHM: Web-based safety and health monitoring system for construction management.
AB  - INTRODUCTION: This paper describes a web-based system for monitoring and
      assessing construction safety and health performance, entitled the Construction
      Safety and Health Monitoring (CSHM) system. METHOD: The design and development of
      CSHM is an integration of internet and database systems, with the intent to
      create a total automated safety and health management tool. A list of safety and
      health performance parameters was devised for the management of safety and health
      in construction. A conceptual framework of the four key components of CSHM is
      presented: (a) Web-based Interface (templates); (b) Knowledge Base; (c) Output
      Data; and (d) Benchmark Group. RESULTS: The combined effect of these components
      results in a system that enables speedy performance assessment of safety and
      health activities on construction sites. With the CSHM's built-in functions,
      important management decisions can theoretically be made and corrective actions
      can be taken before potential hazards turn into fatal or injurious occupational
      accidents. IMPACT ON INDUSTRY: As such, the CSHM system will accelerate the
      monitoring and assessing of performance safety and health management tasks.

PMID- 15178235
TI  - Road safety is no accident.

PMID- 15178236
TI  - The role of enforcement programs in increasing seat belt use.
AB  - Seat belt laws by themselves led to increased belt use in the United States and
      Canada, but initial effects were limited. Canadian provincial officials launched
      highly publicized enforcement campaigns in the early 1980s that resulted in
      substantially increased belt use. Canadian-style enforcement programs
      subsequently were adopted in the United States, and the use of such programs has
      grown in recent years. Lessons from these efforts include the importance of
      police leadership, focused publicity about enforcement, and sustained rather than
      single-shot efforts. What is needed in the United States to achieve a national
      belt use rate of 90% or greater is widespread, methodical, and sustained
      application of enforcement programs augmented by creative publicity. Enhanced
      penalties-in particular drivers license points-likely will be needed to reach
      hard-core nonusers.

PMID- 15178237
TI  - Documenting the sustainability of a mature Click It or Ticket program: the North
      Carolina experience.
AB  - North Carolina was the first United States jurisdiction to implement a statewide
      program (called Click It or Ticket) coupling concentrated enforcement with
      massive publicity to increase seat belt use. After a successful pilot program in
      three very different North Carolina communities, the statewide program was
      launched in October 1993, and has been most active and productive as well as
      imitated by many other states over the past decade. This paper explores the
      combination of ingredients that have been employed and sustained over that period
      of time. These include: (a) a basic coalition of critical public-private agencies
      (central to the planning, execution, and publicity of the many Click It or Ticket
      programs); (b) critical top-down commitments (starting with the governor); (c)
      pervasive and innovative media events/press releases/ PSAs/ web site information;
      (d) vigorous and well-publicized law enforcement; (e) feedback on results with
      solid, updated data; (f) related statewide and local programs/activities; and
      last but not least (g) continuous funding.

PMID- 15178239
TI  - Taking the Click It or Ticket model nationwide.
AB  - Click It or Ticket is an occupant protection Selective Traffic Enforcement
      Program (sTEP) combining intensive paid and earned publicity with enforcement
      during a brief two to four week period. North Carolina demonstrated substantial
      increases in safety belt use associated with their implementation of the first
      statewide Click It or Ticket program in 1993. In 2000, Click It or Ticket was
      implemented in South Carolina. In 2001, Click It or Ticket was implemented across
      all eight states of the southeast. In 2002, ten states in various parts of the
      country implemented Click It or Ticket; four states implemented parts of the full
      Click It or Ticket program; and four states were used as comparisons. Belt use
      increases were greatest in the full implementation states. Click It or Ticket was
      implemented nationally in 2003. This paper presents a historical perspective on
      the implementation and evaluation of Click It or Ticket programs.

PMID- 15178238
TI  - Effectiveness of primary enforcement safety belt laws and enhanced enforcement of
      safety belt laws: a summary of the Guide to Community Preventive Services
      systematic reviews.
AB  - BACKGROUND: The use of safety belts is the single most effective means of
      reducing fatal and nonfatal injuries in motor-vehicle crashes. This paper
      summarizes the systematic reviews of two interventions to increase safety belt
      use: primary enforcement safety belt laws and enhanced enforcement of safety belt
      laws. The reviews were previously published in the American Journal of Preventive
      Medicine. METHODS: We conducted the systematic reviews using the methodology
      developed for the Guide to Community Preventive Services. RESULTS: These reviews
      provide strong evidence that primary laws are more effective than secondary laws
      in increasing safety belt use and decreasing fatalities and that enhanced
      enforcement is effective in increasing safety belt use. Increases in belt use are
      generally highest in states with low baseline rates of belt use. DISCUSSION:
      Primary safety belt laws and enhanced enforcement programs tend to result in
      greater increases in usage rates for target groups with lower baseline rates.
      Concerns regarding public opposition to these interventions may impede their
      implementation in some jurisdictions. However, surveys indicate that a
      substantial majority of the public supports implementation of both primary laws
      and enhanced enforcement programs. CONCLUSION: Based on the strong evidence for
      effectiveness of primary safety belt laws and enhanced enforcement programs, the
      Task Force on Community Preventive Services recommended that all states enact
      primary safety belt laws and that communities implement enhanced enforcement
      programs.

PMID- 15178240
TI  - The effect of earned and paid media strategies in high visibility enforcement
      campaigns.
AB  - The primary objective of this paper is to describe the impact of national seat
      belt enforcement mobilizations in terms of changes in public awareness,
      perceptions, and opinions as they relate to Operation ABC (Always Buckle Up). In
      order to monitor changes in public awareness and perceptions, a number of
      national telephone surveys were conducted. Survey results indicated that the
      following characteristics were associated with lower self-reported seat belt use
      rates: (a) males; (b) 18-34 age group; (c) persons with lower income; (d) persons
      with lower education; (e) persons living in rural areas; (f) residents of the
      Northeast, Midwest, and Great Lakes; (g) residents of states with secondary
      enforcement laws; and (h) persons less likely to read a newspaper and more likely
      to listen to the radio. Telephone surveys also suggested that the following
      groups are more likely to fail to properly secure a child under 12: (a) persons
      who say they have problems securing a child in seat belt; (b) farm belt
      residents; (c) Hispanic and Latinos; (d) persons who indicate that they always
      wear a seat belt but indicate they have not in the past month; (e) persons with
      older vehicles; (f) lower income respondents; (g) residents of the Deep South;
      (h) internet non-users; and (i) urban men. These findings provide support for
      some basic guidelines and suggestions for conducting seat belt enforcement
      activities.

PMID- 15178241
TI  - Ninety five percent: an evaluation of law, policy, and programs to promote seat
      belt use in Washington state.
AB  - Seat belt use in Washington state was 83% in 2001. In 2002, a series of law,
      policy, and program initiatives coalesced to produce a dramatic increase in seat
      belt use. Washington enacted a primary enforcement seat belt, the Chief of the
      Washington State Patrol made safety belt enforcement one of the core missions of
      that agency, and Washington participated in the national Memorial Day Click It or
      Ticket program during May 2002 and continued the program into 2003. Evaluation of
      these initiatives was accomplished through observation surveys of seat belt use,
      analysis of seat belt violation data, and analysis of data on traffic deaths of
      motor vehicle occupants. The major findings were that there was a two- to three
      fold increase in enforcement of the seat belt law, belt use rates increased to
      93% in 2002 and again to 95% in 2003, and motor-vehicle occupant fatalities
      decreased by 13%. IMPACT ON PRACTICE AND POLICY: The primary seat belt law and
      Click It or Ticket program activities were critical factors in increasing belt
      use in Washington state. Media and enforcement programs targeting seat belt use
      can be very effective in raising the belt use rate, but a long-term commitment to
      continuation of these program activities is essential. Other states implementing
      new primary seat belt laws should consider delivering a Click It or Ticket
      campaign prior to the effective date of the primary law and continuing these
      activities during subsequent months and years.

PMID- 15178242
TI  - Occupant restraint use in Canada.
AB  - Legislation regarding seat belt use in Canada is a provincial/territorial
      responsibility. Each of the 13 jurisdictions has enacted legislation and set the
      penalties regarding non-use of seat belts and appropriate child restraint
      systems. The federal government regulates occupant restraint systems and child
      restraints. In addition, Transport Canada (TC) gathers annual survey data on the
      use of seat belts and child restraints on Canadian roads and provides research
      support. National coordination toward the Canadian Road Safety Vision 2010 goal
      of a 40% reduction in fatalities and serious injuries related to non-belt/child
      restraint use and a 95% restraint usage rate is provided by the Canadian Council
      of Motor Transport Administrators' (CCMTA) National Occupant Restraint Program
      (NORP). The paper examines the history of legislation, provincial/territorial
      penalties, NORP, and TC involvement in promoting the use of occupant restraints.

PMID- 15178243
TI  - A research agenda for increasing safety belt use in the United States.
AB  - On November 13-14, 2003, a symposium on high-visibility safety belt use
      enforcement in Raleigh, NC: (a) celebrated the 10th anniversary of North
      Carolina's Click It or Ticket program; (b) documented current knowledge regarding
      safety belt use; (c) proposed strategies to increase use further; and (d)
      discussed research to support these strategies.

PMID- 15178244
TI  - Recent estimates of safety belt use.
AB  - The National Occupant Protection Use Survey (NOPUS) has shown that safety belt
      use in the United States has increased steadily over the past decade. Increases
      have been consistent since 2000, when the National Highway Traffic Safety
      Administration, in partnership with the Air Bag & Seat Belt Safety Campaign,
      increased its encouragement of states to implement highly visible enforcement
      programs. In 2003, significant increases were found in the South; in secondary
      law states; in all types of vehicles; during both weekdays and weekends; and
      during both rush-hours and non-rush-hours. In spite of these increases, use
      remains significantly lower in secondary law states; pickup trucks; the
      Northeast; and the Midwest. The differences between primary and secondary law
      states and between pickups and other passenger vehicles have been consistent from
      year to year. A controlled intersection study, which is part of the NOPUS, has
      shown that safety belt use has increased for both sexes, for nearly all age
      groups, and for all races for which data are available. Finally, the NOPUS
      suggests that children are 3-4 times as likely to be unrestrained when riding
      with an unbuckled driver as when driving with a buckled driver.

PMID- 15178245
TI  - Structural modes of stabilization of permissive phosphorylation sites in protein
      kinases: distinct strategies in Ser/Thr and Tyr kinases.
AB  - Protein kinases phosphorylate several cellular proteins providing control
      mechanisms for various signalling processes. Their activity is impeded in a
      number of ways and restored by alteration in their structural properties leading
      to a catalytically active state. Most protein kinases are subjected to positive
      and negative regulation by phosphorylation of Ser/Thr/Tyr residues at specific
      sites within and outside the catalytic core. The current review describes the
      analysis on 3D structures of protein kinases that revealed features distinct to
      active states of Ser/Thr and Tyr kinases. The nature and extent of interactions
      among well-conserved residues surrounding the permissive phosphorylation sites
      differ among the two classes of enzymes. The network of interactions of highly
      conserved Arg preceding the catalytic base that mediates stabilization of the
      activation segment exemplifies such diverse interactions in the two groups of
      kinases. The N-terminal and the C-terminal lobes of various groups of protein
      kinases further show variations in their extent of coupling as suggested from the
      extent of interactions between key functional residues in activation segment and
      the N-terminal alphaC-helix. We observe higher similarity in the conformations of
      ATP bound to active forms of protein kinases compared to ATP conformations in the
      inactive forms of kinases. The extent of structural variations accompanying
      phosphorylation of protein kinases is widely varied. The comparison of their
      crystal structures and the distinct features observed are hoped to aid in the
      understanding of mechanisms underlying the control of the catalytic activity of
      distinct subgroups of protein kinases.

PMID- 15178246
TI  - Molecular interactions between a plant virus movement protein and RNA: force
      spectroscopy investigation.
AB  - RNA-protein interactions are fundamental for different aspects of molecular
      biology such as gene expression, assembly of biomolecular complexes or
      macromolecular transport. The 3a movement protein (MP) of a plant virus, Cucumber
      mosaic virus (CMV), forms ribonucleoprotein (RNP) complexes with viral RNA,
      capable of trafficking from cell-to-cell throughout the infected plant only in
      the presence of the CMV capsid protein (CP). However, deletion of the C-terminal
      33 amino acid residues of the CMV MP (in the mutant designated 3aDeltaC33 MP)
      resulted in CP-independent cell-to-cell movement. The biological differences in
      the behaviour of CMV wild type (wt) 3a MP and 3aDeltaC33 MP could have been a
      consequence of differences in the RNA-binding properties of the two MPs detected
      previously using biochemical assays on ensembles of molecules. To investigate the
      physical mechanisms of MP-RNA interactions at a single molecule level, we applied
      atomic force microscopy to measure for the first time unbinding forces between
      these individual binding partners. Minimal unbinding forces determined for
      individual interaction of the CMV RNA molecule with the CMV wt or truncated MPs
      were estimated to be approximately 45 pN and approximately 90 pN, respectively,
      suggesting that the distinct differences in the strength of MP-RNA interactions
      for the wt MP and truncated MP are attributable to the molecular binding
      mechanism. We also demonstrated that molecules of both CMV 3a MP and 3aDeltaC33
      MP were capable of self-interaction with minimal unbinding forces of
      approximately 50 pN and approximately 70 pN, respectively, providing a physical
      basis for the cooperative mechanism of the RNA binding. The significance of
      intermolecular force measurements for understanding the structural and functional
      aspects of viral RNP formation and trafficking is discussed.

PMID- 15178247
TI  - Characteristic patterns of N Oct-3 binding to a set of neuronal promoters.
AB  - N Oct-3, a neurospecific POU protein, homodimerizes in a non-cooperative fashion
      on the neuronal aromatic l-amino acid decarboxylase gene promoter and generates
      heterodimers with HNF-3beta. Several other neuronal gene promoters, the
      corticotropin releasing hormone and the aldolase C gene promoters also contain
      overlapping binding sites for N Oct-3 and HNF-3beta. We have demonstrated that N
      Oct-3 presents a non-cooperative homodimerization on these two additional targets
      and can also give rise to heterodimers with HNF-3beta. Surprisingly, despite the
      high degree of conservation of the respective POU subunits, the ubiquitous POU
      protein Oct-1 can only form monomers even in the presence of either N Oct-3 or
      HNF-3beta on these DNA targets. Our data indicate that this difference is
      correlated with the specific ability of a portion of the N Oct-3 linker to fold
      as an alpha-helix, a property shared by class III POU proteins. These results
      suggest that this novel binding pattern permits the heterodimerization of N Oct-3
      and HNF-3beta on the neuronal promoters, which could be a key issue in the
      development of the nervous system and possibly tumors of neural origin.

PMID- 15178248
TI  - A biophysical characterisation of factors controlling dimerisation and
      selectivity in the NF-kappaB and NFAT families.
AB  - The Rel/NF-kappaB family of eukaryotic transcription factors bind DNA with high
      specificity and affinity as homo- or heterodimers to mediate a diverse range of
      biological processes. By comparison, the nuclear factor of activated T-cells
      (NFAT) family has been recognised as Rel homologues due to structural
      similarities between the DNA-binding domains, yet they bind DNA as lower-affinity
      monomers. The structural and functional overlap between the NF-kappaB and NFAT
      families suggests that they may be evolutionarily divergent from a common,
      monomeric ancestor but have evolved different mechanisms to achieve high-affinity
      binding to their target DNA sequences. In order to understand the origin of these
      mechanistic differences, we constructed two chimeric proteins, based on molecular
      modelling, comprising the DNA-binding domain of NFAT and the dimerisation domain
      of NF-kappaB p50, differing only in the position of the splice site. Biophysical
      characterisation of the wild-type and chimeric proteins revealed that one of the
      chimeras bound DNA as a high-affinity, NF-kappaB-like cooperative dimer, whilst
      the other bound as a lower-affinity, NFAT-like monomer, demonstrating the
      importance of the interdomain linker in controlling the intrinsic ability of
      NFATc to form dimers. In addition, we have studied the rate of exchange of
      monomers between preformed NF-kappaB dimers and have determined, for the first
      time, the intrinsic homodimerisation constant for NF-kappaB p50. These data
      support a model in which NF-kappaB proteins bind DNA both in vitro and in vivo as
      high-affinity preformed homo- or heterodimers, which in an unbound form can still
      exchange monomer units on a physiologically relevant timescale in vivo.

PMID- 15178249
TI  - Dual role of boxB RNA motif in the mechanisms of termination/antitermination at
      the lambda tR1 terminator revealed in vivo.
AB  - Rho-dependent transcription termination at the phage lambda tR1 terminator is
      governed primarily by the upstream rut element that encodes two RNA regions rutA
      and rutB. The two regions are separated by the boxB RNA motif, which is believed
      to be dispensable for Rho activity but serves as a binding site for lambda N
      protein in the antitermination process. By using a minimal in vivo termination
      system, we show that the intervening boxB RNA motif has a double function in the
      mechanisms of termination/antitermination at lambdatR1. As a folded hairpin
      structure, it acts as a clamp that holds rutA and rutB side by side for optimal
      interactions with Rho leading to efficient termination. Conversely, the binding
      of N protein to boxB induces antitermination at lambdatR1 by preventing access of
      Rho to the rut sequences. This dual role was clearly shown in vivo by studying
      the effects of multiple mutations within the boxB hairpin stem on transcription
      termination and by substituting the N/boxB couple with the unrelated coat protein
      of phage MS2 and its stem-loop RNA binding site.

PMID- 15178250
TI  - Monomer and dimer of Chandipura virus unphosphorylated P-protein binds leader RNA
      differently: implications for viral RNA synthesis.
AB  - Interaction of the leader RNA with the unphosphorylated P-protein has been
      proposed to play a key role in the transcription-replication transition of
      Chandipura virus, a model rhabdovirus. Electrophoretic mobility shift assay with
      the leader RNA and the unphosphorylated P-protein demonstrated existence of two
      distinct complexes in vitro. Measurements of stoichiometry indicate the protein
      monomer/RNA ratio to be 1:1 and 2:1 for faster and slower migrating bands,
      respectively. We have also observed a concentration-dependent oligomerization of
      the unphosphorylated P-protein, in sub-micromolar to low micromolar range.
      Sedimentation velocity, dynamic light scattering and large zone gel filtration
      experiments suggest a monomer-dimer-tetramer model of association. RNA binding
      experiments suggest that the two complexes assembled from one molecule of the
      leader RNA binding to either a protein monomer or a dimer. A truncated RNA
      consisting of a 3' region of the leader transcript exclusively formed the 1:1
      complex, whereas a RNA consisting of only the 5' region forms the 2:1 complex
      exclusively. RNA binding experiments at different protein concentrations suggest
      that binding of the RNA comprising the 3' region weakens significantly at higher
      P(0) concentrations, whereas in contrast the binding of the RNA comprising the 5'
      region becomes modestly tighter. Implications of two different types of leader
      RNA-P-protein complexes in viral RNA synthesis are discussed.

PMID- 15178251
TI  - X-ray analysis of Mycobacterium smegmatis Dps and a comparative study involving
      other Dps and Dps-like molecules.
AB  - The structure of the DNA binding protein from starved cells from Mycobacterium
      smegmatis has been determined in three crystal forms and has been compared with
      those of similar proteins from other sources. The dodecameric molecule can be
      described as a distorted icosahedron. The interfaces among subunits are such that
      the dodecameric molecule appears to have been made up of stable trimers. The
      situation is similar in the proteins from Escherichia coli and Agrobacterium
      tumefaciens, which are closer to the M.smegmatis protein in sequence and
      structure than those from other sources, which appear to form a dimer first.
      Trimerisation is aided in the three proteins by the additional N-terminal
      stretches that they possess. The M.smegmatis protein has an additional C-terminal
      stretch compared to other related proteins. The stretch, known to be involved in
      DNA binding, is situated on the surface of the molecule. A comparison of the
      available structures permits a delineation of the rigid and flexible regions in
      the molecule. The subunit interfaces around the molecular dyads, where the
      ferroxidation centres are located, are relatively rigid. Regions in the vicinity
      of the acidic holes centred around molecular 3-fold axes, are relatively
      flexible. So are the DNA binding regions. The crystal structures of the protein
      from M.smegmatis confirm that DNA molecules can occupy spaces within the crystal
      without disturbing the arrangement of the protein molecules. However, contrary to
      earlier suggestions, the spaces do not need to be between layers of protein
      molecules. The cubic form provides an arrangement in which grooves, which could
      hold DNA molecules, criss-cross the crystal.

PMID- 15178252
TI  - Compensatory energetic mechanisms mediating the assembly of signaling complexes
      between interleukin-2 and its alpha, beta, and gamma(c) receptors.
AB  - Interleukin-2 is a key immuno-regulatory cytokine whose actions are mediated by
      three different cell surface receptors: the alpha, beta and the "common gamma"
      (gamma(c)) chains. We have undertaken a complete thermodynamic characterization
      of the stepwise assembly cycle for multiple possible combinations of the receptor
      ligand, and receptor-receptor interactions that are necessary for formation of
      the high-affinity IL-2/alphabetagamma(c) signaling complex. We find an
      entropically favorable high affinity interaction between IL-2 and its alpha
      receptor, a moderately entropically favorable low affinity interaction between IL
      2 and its beta receptor, and no interaction between IL-2 and the shared receptor,
      gamma(c). Formation of the stable intermediate trimolecular complexes of IL-2
      with alpha and beta receptors, as well as IL-2 with beta and gamma(c) receptors
      proceeds through enthalpy-entropy compensation mechanisms. Surprisingly, we see a
      moderate affinity interaction between the unliganded receptor alpha and beta
      chains, suggesting that a preformed alphabeta complex may serve as the initial
      interaction complex for IL-2. Reconstitution of the IL-2/Ralphabetagamma(c) high
      affinity quaternary signaling complex shows it to be assembled through
      cooperative energetics to form a 1:1:1:1 assembly. Collectively, the favorable
      entropy of the bimolecular interactions appears to be offset by the loss in rigid
      body entropy of the receptor components in the higher-order complexes, but
      overcome by the formation of increasingly enthalpically favorable composite
      interfaces. This enthalpic mechanism utilized by gamma(c) contrasts with the
      favorable entropic mechanism utilized by gp130 for degenerate cytokine
      interaction. In conclusion, we find that several energetically redundant pathways
      exist for formation of IL-2 receptor signaling complexes, suggesting a more
      complex equilibrium on the cell surface than has been previously appreciated.

PMID- 15178253
TI  - The roles of Glu186 and Glu380 in the catalytic reaction of soybean beta-amylase.
AB  - It has previously been suggested that the glutamic acid residues Glu186 and
      Glu380 of soybean beta-amylase play critical roles as a general acid and a
      general base catalyst, respectively. In order to confirm the roles of Glu186 and
      Glu380, each residue was mutated to a glutamine residue and the crystal
      structures of the substrate (E186Q/maltopentaose) and product (E380Q/maltose)
      complexes were determined at resolutions of 1.6 Angstrom and 1.9 Angstrom,
      respectively. Both mutant enzymes exhibited 16,000- and 37,000-fold decreased
      activity relative to that of the wild-type enzyme. The crystal structure of the
      E186Q/maltopentaose complex revealed an unambiguous five-glucose unit at subsites
      -2 to +3. Two maltose molecules bind on subsites -2 to -1 and +2 to +3 in the
      E380Q/maltose complex, whereas they bind in tandem to -2 to -1 and +1 to +2 in
      the wild-type/maltose complex. The conformation of the glucose residue at subsite
      -1 was identified as a stable (4)C(1) alpha-anomer in the E380Q/maltose complex,
      whereas a distorted ring conformation was observed in the wild-type/maltose
      complex. The side-chain movement of Gln380 to the position of a putative
      attacking water molecule seen in the wild-type enzyme caused the inactivation of
      the E380Q mutant and an altered binding pattern of maltose molecules. These
      results confirm the critical roles played by Glu186 in the donation of a proton
      to the glycosidic oxygen of the substrate, and by Glu380 in the activation of an
      attacking water molecule. The observed difference between the backbones of
      E186Q/maltopentaose and E380Q/maltose in terms of Thr342 suggests that the side
      chain of Thr342 may stabilize the deprotonated form of Glu186 after the cleavage
      of the glycosidic bond.

PMID- 15178254
TI  - Three-dimensional structures of idiotypically related Fabs with intermediate and
      high affinity for fluorescein.
AB  - Multi-disciplinary studies of fluorescein-protein conjugates have led to the
      generation of a family of antibodies with common idiotypes and affinities for
      fluorescein ranging over five orders of magnitude. The high affinity 4-4-20
      prototype traps the ligand in a highly complementary binding slot, which is lined
      by multiple aromatic side-chains. An antibody (9-40) of intermediate affinity
      belongs to the same idiotypic family as 4-4-20 and shares substantial amino acid
      identities within the VL and VH domains. To establish the structural basis for
      the affinity differences, we solved the crystal structure of the 9-40 Fab
      fluorescein complex at a resolution of 2.3A. Similar to 4-4-20, 9-40 binds
      fluorescein in a tight aromatic slot with its xanthenonyl ring system
      accommodated by end-on insertion. However, the combined effects of the amino acid
      substitutions have resulted in reorganization of the binding site, with the HCDR3
      loops showing the greatest differences in conformations. Access to the binding
      site of 9-40 is substantially more open, leaving the fluorescein's
      phenylcarboxylate moiety partially exposed to solvent. In addition to the usage
      of a different D (diversity) mini-gene encoding the HCDR3 loop, the decrease in
      fluorescein affinity in the 9-40 antibody family appears to be correlated with
      the substitution of histidine (9-40) for arginine (4-4-20) in position 34 of the
      antibody light chains.

PMID- 15178255
TI  - Structural similarities of micelle-bound peptide YY (PYY) and neuropeptide Y
      (NPY) are related to their affinity profiles at the Y receptors.
AB  - Here, we investigate the structure of porcine peptide YY (pPYY) both when
      unligated in solution at pH 4.2 and when bound to dodecylphosphocholine (DPC)
      micelles at pH 5.5. pPYY in solution displays the PP-fold, with the N-terminal
      segment being back-folded onto the C-terminal alpha-helix, which extends from
      residue 17 to 31. In contrast to the solution structure of Keire et al. published
      in the year 2000 the C-terminal helix does not display a kink around residue 23
      25. The root mean square deviation (RMSD) for backbone atoms of the NMR ensemble
      of conformers to the mean structure is 0.99(+/-0.35) Angstrom for residues 14-31.
      The back-fold is supported by values of 0.60+/-0.1 for the (15)N(1)H-NOE and by
      generalized order parameters S(2) of 0.74+/-0.1 for residues 5-31 which indicate
      that the peptide is folded in that segment. We have additionally used DPC
      micelles as a membrane model and determined the structure of pPYY when bound to
      it. Therein, an alpha-helix occurs in the segment comprising residues 17-31 and
      the N terminus freely diffuses in solution. The hydrophobic side of the
      amphipathic helix forms the micelle-binding interface and hydrophobic side-chains
      extend into the micelle interior. A significant stabilization of helical
      conformation occurs in the C-terminal pentapeptide, which is important for
      receptor binding. The latter is supported by positive values of the heteronuclear
      NOE in that segment (0.52+/-0.1 compared to 0.08+/-0.4 for the unligated form)
      and by values of S(2) of 0.6+/-0.2 (versus 0.38+/-0.2 for the unligated form).
      The structures of micelle-bound pPYY and pNPY are much more similar than those of
      pPYY and bPP with pairwise RMSDs of 1.23(+/-0.21)A or 3.21(+/-0.39) Angstrom,
      respectively. In contrast to the conformational similarities in the DPC-bound
      state their structures in solution are very different. In fact pPYY is more
      similar to bPP, which with its strong preference for the Y(4) receptor displays a
      completely different binding profile. Considering the high degree of sequence
      homology of pNPY and pPYY (>80%) and the fact, that their binding affinities at
      all receptor subtypes are high and, more importantly, rather similar, it is much
      more likely that PYY and NPY are recognized by the Y receptors from the membrane
      bound state. As a consequence of the latter the PP-fold is not important for
      recognition of PYY or NPY at the Y receptors. To our knowledge this work provides
      for the first time strong arguments derived from structural data that support a
      membrane-bound receptor recognition pathway.

PMID- 15178256
TI  - NMR and MD studies on the interaction between ligand peptides and alpha
      bungarotoxin.
AB  - The interaction between alpha-bungarotoxin and linear synthetic peptides,
      mimotope of the nicotinic acetylcholine receptor binding site, has been
      characterised extensively by several methods and a wealth of functional, kinetic
      and structural data are available. Hence, this system represents a suitable model
      to explore in detail the dynamics of a peptide-protein interaction. Here, the
      solution structure of a new complex of the protein toxin with a tridecapeptide
      ligand exhibiting high affinity has been determined by NMR. As observed for three
      other previously reported mimotope-alpha-bungarotoxin complexes, also in this
      case correlations between biological activity and kinetic data are not fully
      consistent with a static discussion of structural data. Molecular dynamics
      simulations of the four mimotope-toxin complexes indicate that a relevant
      contribution to the complex stability is given by the extent of the residual
      flexibility that the protein maintains upon peptide binding. This feature,
      limiting the entropy loss caused by protein folding and binding, ought to be
      generally considered in a rational design of specific protein ligands.

PMID- 15178257
TI  - DafA cycles between the DnaK chaperone system and translational machinery.
AB  - DafA is encoded by the dnaK operon of Thermus thermophilus and mediates the
      formation of a highly stable complex between the chaperone DnaK and its co
      chaperone DnaJ under normal growth conditions. DafA(Tth) contains 87 amino acid
      residues and is the only member of the DnaK(Tth) chaperone system for which no
      corresponding protein has yet been identified in other organisms and whose
      particular function has remained elusive. Here, we show directly that the
      DnaK(Tth)-DnaJ(Tth)-DafA(Tth) complex cannot represent the active chaperone
      species since DafA(Tth) inhibits renaturation of firefly luciferase by
      suppressing substrate association. Since DafA(Tth) must be released before the
      substrate proteins can bind we hypothesized that free DafA(Tth) might have
      regulatory functions connected to the heat shock response. Here, we present
      evidence that supports this hypothesis. We identified the 70S ribosome as binding
      target of free DafA(Tth). Our results show that the association of DafA(Tth) and
      70S ribosomes does not require the participation of DnaK(Tth) or DnaJ(Tth). On
      the contrary, the assembly of DnaK(Tth)-DnaJ(Tth)-DafA(Tth) and ribosome
      DafA(Tth) complexes seems to be competitive. These findings strongly suggest the
      involvement of DafA(Tth) in regulatory processes occurring at a translational
      level, which could represent a new mechanism of heat shock response as an
      adaptation to elevated temperature.

PMID- 15178258
TI  - Short-range, long-range and transition state interactions in the denatured state
      of ACBP from residual dipolar couplings.
AB  - Residual dipolar couplings in the denatured state of bovine acyl-coenzyme A
      binding protein (ACBP) oriented in strained polyacrylamide gels have been shown
      to be a sensitive, sequence-specific probe for residual secondary structure.
      Results supporting this were obtained by comparing residual dipolar couplings
      under different denaturing conditions. The data were analyzed using the program
      molecular fragment replacement (MFR), which demonstrated alpha-helix propensity
      in four isolated stretches along the protein backbone, and these coincide with
      the location of native helices. This is in full agreement with earlier findings
      based on secondary chemical shift values. Furthermore, N-H residual dipolar
      couplings provided direct evidence for the existence of native-like hydrophobic
      interactions in the acid-denatured state of ACBP at pH 2.3. It was shown that
      replacement of the hydrophobic side-chain of residue Ile27 with alanine in helix
      A2 leads to large decreases of residual dipolar couplings in residues that form
      helix A4 in the native state. It is suggested that the Ile to Ala mutation
      changes the probability for the formation of long-range interactions, which are
      present in the acid-denatured state of the wild-type protein. These long-range
      interactions are similar to those proposed to form in the transition state of
      folding of ACBP. Therefore, the application of residual dipolar couplings in
      combination with a comparative mutation study has demonstrated the presence of
      precursors to the folding transition state under acid-unfolding conditions.

PMID- 15178259
TI  - Use of oxide minerals to abate fluoride from water.
AB  - The removal of fluoride from aqueous solutions has been investigated using
      various oxide ores such as refractory grade bauxite, feed bauxite, manganese ore,
      and hydrated oxides of manganese ores (WAD). The refractory grade bauxite showed
      promising results. The studies were carried out as functions of contact time, pH,
      concentration of adsorbents, concentration of adsorbate, and temperature. The
      adsorption was rapid during the initial 5 min but equilibrium was attained within
      120 min. The adsorption followed first-order kinetics. The present system
      followed the Langmuir adsorption isotherm model. Various thermodynamic parameters
      such as free energy, enthalpy, entropy, and equilibrium constants were
      calculated. The isosteric heat calculations showed that the adsorption process
      followed a heterogeneous model.

PMID- 15178260
TI  - Binding of ionic surfactants to purified humic acid.
AB  - The binding of organic contaminants to dissolved humic acids reduces the free
      concentration of the contaminants in the environment and also may cause changes
      to the solution properties of humic acids. Surfactants are a special class of
      contaminants that are introduced into the environment either through wastewater
      or by site-specific contamination. The amphiphilic nature of both surfactants and
      humic acids can easily lead to their mutual attraction and consequently affect
      the solution behavior of the humics. Binding of an anionic surfactant (sodium
      dodecyl sulfate, SDS) and two cationic surfactants (dodecyl- and cetylpyridinium
      chloride, DPC and CPC) to purified Aldrich humic acid (PAHA) is studied at pH
      values of 5, 7, and 10 in solutions with a 0.025 M ionic strength (I). Monomer
      concentrations of the surfactants are measured with a surfactant-selective
      electrode. At I = 0.025 M, no significant binding is observed between the anionic
      surfactant (SDS) and PAHA, whereas the two cationic surfactants (DPC, CPC) bind
      strongly to PAHA over the pH range investigated. The binding is due both to
      electrostatic and hydrophobic attraction. The initial affinity increases with
      increasing pH (i.e., negative charge of PAHA) and tail length of the surfactant.
      Binding reaches a pseudo-plateau value (2-5 mmol/g) when the charge associated
      with PAHA is neutralized by that of the bound surfactant molecules. The pseudo
      plateau values for DPC and CPC are very similar and depend on the solution pH.
      The cationic surfactant-PAHA complexes precipitate when the charge neutralization
      point is reached. This occurs at approximately 10% of the critical micelle
      concentration or CMC. This type of phase separation commonly occurs during
      surfactant binding to oppositely charged polyelectrolytes. For CPC, the
      precipitation is complete, but in the case of DPC, a noticeable fraction of PAHA
      remains in solution. At very low CPC concentrations (less than 0.1% of the CMC),
      CPC binding to PAHA is cooperative. The investigated range of concentrations for
      DPC was too limited to reach a similar conclusion. The results of this study
      demonstrate that the fate of humic acids will be strongly affected by the
      presence of low cationic surfactant concentrations in aqueous environmental
      systems.

PMID- 15178261
TI  - Temperature effect on xanthate sorption by chalcopyrite.
AB  - Xanthate ions sorption on copper ore (chalcopyrite) is studied as a function of
      temperature (273-293 K) in the pH range (8-11). The sorption of xanthate ions at
      all the pH values is observed to increase with the increase in temperature. The
      changes in pH, dissolution studies of the ore, SO2(4)- concentration
      determinations, and FTIR studies were employed to probe the mechanism of the
      process of adsorption. The results are found to fit successfully to the linear
      form of the Freundlich equation. The isosteric heats of adsorption (DeltaHi) are
      also calculated and show that the adsorption of xanthate on copper ore under the
      given experimental condition is endothermic in nature. The values of DeltaHi
      found are in conformity with the ion exchange sorption of xanthate by the
      chalcopyrite.

PMID- 15178262
TI  - Multicomponent adsorption on activated carbons under supercritical conditions.
AB  - Adsorption of binary mixtures onto activated carbon Norit R1 for the system
      nitrogen-methane-carbon dioxide was investigated over the pressure range up to 15
      MPa. A new model is proposed to describe the experimental data. It is based on
      the assumption that an activated carbon can be characterized by the distribution
      function of elements of adsorption volume (EAV) over the solid-fluid potential.
      This function may be evaluated from pure component isotherms using the equality
      of the chemical potentials in the adsorbed phase and in the bulk phase for each
      EAV. In the case of mixture adsorption a simple combining rule is proposed, which
      allows determining the adsorbed phase density and its composition in the EAV at
      given pressure and compositions of the bulk phase. The adsorbed concentration of
      each adsorbate is the integral of its density over the set of EAV. The comparison
      with experimental data on binary mixtures has shown that the approach works
      reasonably well. In the case of high-pressure binary mixture adsorption, when
      only total amount adsorbed was measured, the proposed model allows reliably
      determining partial amounts of the adsorbed components.

PMID- 15178263
TI  - Hybrid aniline/silica xerogel cation adsorption and thermodynamics of
      interaction.
AB  - Aniline groups chemically immobilized on silica through the sol-gel process were
      employed to extract divalent nickel and manganese from aqueous solutions at room
      temperature. The maximum adsorption capacity of the xerogel was studied from
      adsorption isotherms using a batch technique. The isotherms obtained were
      adjusted following the Langmuir equation. The xerogel adsorbent appears to have
      better affinity for nickel than manganese. From calorimetric titration,
      thermodynamic data on cation/nitrogen basic atom interaction in the solid/liquid
      interface were determined. The enthalpic values, -0.46 +/- 0.02 and -.029 +/-
      0.02 kJ mol(-1) for nickel and manganese, respectively, are in agreement with the
      low availability of the basic nitrogen atom on the aniline group and also the
      possible steric hindrance of the phenyl group bonded to nitrogen. However,
      thermodynamics indicated the existence of favorable conditions for such cation
      nitrogen interactions.

PMID- 15178265
TI  - Adsorption behavior of Hg(II), Pb(II), and Cd(II) from aqueous solution on
      Duolite C-433: a synthetic resin.
AB  - The adsorption behavior of Hg(II), Pb(II), and Cd(II) on Duolite C-433 synthetic
      resin has been determined at different temperatures by batch process. The various
      thermodynamic parameters, such as equilibrium constant K0, free energy DeltaG0,
      entropy DeltaS0, and enthalpy DeltaH0, have been calculated in order to predict
      the nature of sorption.

PMID- 15178264
TI  - New insights into the fundamental nature of lignocellulosic fiber surface charge.
AB  - The surface and total charge density of industrially manufactured hardwood and
      softwood grade kraft lignocellulosic fibers can mainly be attributed to
      carboxylic acid functionalities as determined from topochemical adsorption of a
      cationic polymer (methyl glycol chitosan) and the use of conductometric
      titration. These charge density measurement methods have led to a powerful and
      accurate photometric method for the quantitative analysis of surface charge. The
      method is based on directly monitoring the iodide ion, the counterion of the
      chitosan polymer, which is released upon electroneutralization between a chitosan
      cationic site and an anionic site at the fiber surface, thereby directly
      providing the concentration of surface charge. The stoichiometry for the chitosan
      adsorption onto the fiber surfaces is unity despite pulp types and adsorption
      quantity of cationic polymer. Given the high charge density of the chitosan
      molecule and the determined physical charge density limitations for its
      distribution onto the surface of pulps, a new and heretofore unused concept
      referred to as the subsurface was posited to adequately describe the surface
      charge determination after the adsorption of cationic polymer on the fibers. More
      specifically, within the subsurface of the suspended fibers in solution,
      carboxylates (COO-) were neutralized by the cationic sites of chitosan. The COO-
      sites in the subsurface can electrically attract positive sites of the cationic
      polymer, resulting in the complete release of counterions. To account for the
      charge density measurements, the charge measurement of the fibers includes not
      only nominal topochemical surface charges but also charges below this surface
      (subsurface).

PMID- 15178266
TI  - Structure of adsorbed n-dodecyl-beta-D-maltoside layers on hematite.
AB  - The composition, structure, and thickness of n-dodecyl-beta-D-maltoside self
      assembled layers on hematite have been evaluated using infrared external
      reflection spectroscopy and spectral simulation techniques. From the qualitative
      and quantitative analysis of the reflection spectra of the same sample recorded
      at different specific angles of incidence and two polarizations, the orientation
      of the sugar ring and hydrocarbon chain were obtained. Both of these molecular
      groups are positioned parallel to hematite surface, the adsorbed molecules being
      at low (2.2-nm-thick layer) as well as higher (11-nm) coverages. The maltoside is
      adsorbed through interaction of sugar ring OH groups with hematite surface
      hydroxyl groups. The adsorption of maltoside is not very strong and desorption
      takes place easily from acidic and low-basic solutions but with more difficulty
      from strong-basic solution.

PMID- 15178267
TI  - Prediction of multicomponent liquid adsorption using excess quantities. II.
      Calculations for the liquid/solid interface.
AB  - The utilization of excess quantities as the basis for a thermodynamic approach
      can simplify the prediction of multicomponent liquid adsorption from binary data.
      A new method for predicting liquid adsorption on solids is suggested, which is
      different from the existing equations with respect to the theoretical background
      and formulation. The applicability of the new model is tested with three ternary
      adsorption systems. The predicted surface excesses are discussed and compared
      with experimental ones and with those of other prediction models in the
      literature. The accordance between measured and predicted ternary data is
      convincing.

PMID- 15178268
TI  - Prediction of multicomponent liquid adsorption using excess quantities. III.
      Calculations for the liquid/air interface.
AB  - The utilization of excess quantities as the basis of a thermodynamic approach can
      simplify the prediction of multicomponent data from binary ones. Whereas in Part
      II the excess formalism was applied to the prediction of liquid phase adsorption
      on solids, in this paper, the liquid/air interface is investigated. In order to
      show the generality of the suggested approach, thermodynamic equations are
      developed in analogy to Part II. Surface tensions are predicted by different
      excess models and compared with experimental data. From predicted surface
      tensions, ternary adsorption isotherms on the liquid/air interface are
      calculated.

PMID- 15178269
TI  - Silica adsorbent prepared from spent diatomaceous earth and its application to
      removal of dye from aqueous solution.
AB  - The objective of this work is to study the activation regeneration of spent
      diatomaceous earth (SDE) for the preparation of silica adsorbents using thermal
      regeneration and acid/alkaline activation methods. Under the experimental
      conditions investigated, it was found that the alkaline activation method carried
      out by sodium hydroxide under controlled conditions is significantly superior to
      other heat and activation methods. The porosities of solids thus obtained are
      over 0.2, indicating that they are basically mesoporous. The optimal porous
      material thus prepared was used as a mineral adsorbent for methylene blue at 25
      degrees C. The adsorption equilibrium revealed that the silica adsorbent can take
      up over 50 mg/g at relatively low concentrations in aqueous medium from the
      fittings of Langmuir and Freundlich isotherms with high correlations. On the
      other hand, the adsorption kinetic of methylene blue under various adsorbent
      dosages can be well described with a pseudo-second-order reaction model.

PMID- 15178270
TI  - Solubilization of p-nitrophenol in aggregates formed by hydrophobically modified
      polyelectrolytes.
AB  - The solubilization of p-nitrophenol into the hydrophobic microdomains provided by
      polyelectrolytes carrying alkyl side chains of different length has been
      investigated in aqueous solutions of pH 5.0 and 8.0. Under these pH conditions p
      nitrophenol is predominantly present in its neutral and ionic forms,
      respectively. Potassium salts of poly(maleic acid-co-1-olefins), PA-nK2 with n =
      12, 14, 16, 18, were synthesized, and the pseudo-phase model was used to
      determine the distribution coefficient KS, and the standard free energy of
      transfer Deltamut0 of p-nitrophenol between water and polymer aggregates. The
      results indicate that at both pH's the solubilization of p-nitrophenol increases
      with increasing size of the side alkyl chain; i.e., the values of KS follow the
      order PA-18K2 > PA-16K2 > PA-14K2 > PA-12K2. The free energies, Deltamut0, were
      plotted as a function of the number of carbon atoms in the side alkyl chain and a
      linear relation was found. From these plots contributions of -0.324 and -0.676 kJ
      mol(-1) per methylene group were determined at pH 5.0 and 8.0, respectively. The
      effect of aggregate size on the solubility of phenol is attributed to the
      hydrophobic contribution per CH2 group to the free energy of transfer. The
      hydrophobic nature of the CH2 group is suggested to derive largely from the
      enthalpic contribution.

PMID- 15178271
TI  - Thermodynamics of micellization of tapered statistical copolymers of ethylene
      oxide and propylene oxide in water.
AB  - Two tapered statistical copolymers were prepared by the oxyanionic polymerization
      of ethylene oxide and propylene oxide and characterized by gel permeation
      chromatography and 13C NMR spectroscopy. We denote the copolymers t-E/P38 and t
      E/P30, where E = oxyethylene, OCH2CH2, and P = oxypropylene, OCH2CH(CH3), and the
      number denotes the mole percentage P. In each case the copolymer chain length was
      ca. 100 oxyalkylene units. The association of the copolymers to form micelles in
      aqueous solution was checked by dynamic light scattering. The critical micelle
      temperatures (cmt) of the copolymers at several concentrations were determined by
      static light scattering and dye solubilization, and values of the apparent
      standard enthalpy of micellization (DeltamicHapp0) were obtained. For both
      copolymers, a low value of DeltamicHapp0 was found when the copolymer
      concentration exceeded ca. 150 g dm(-3).

PMID- 15178272
TI  - A simple geometrical model for emulsifier free polymer colloid formation.
AB  - In this paper we propose a simple model for the formation of monodisperse polymer
      colloids, which provides a convenient set of synthetic parameters for given bead
      diameters. We provide experimental data in support of this model.

PMID- 15178273
TI  - Water-swellable polyelectrolyte microgels polymerized in an inverse microemulsion
      using a nonionic surfactant.
AB  - A series of poly(dimethylacrylamide-co-2-acrylamido-2-methyl-1-propanesulfonic
      acid) microgels slightly crosslinked by methylene-bis-acrylamide (MBA) were
      polymerized in a novel inverse microemulsion polymerization (IMEP) system. To
      determine a suitable composition of the IMEP system, the phase diagram of a
      pseudoternary system was made. The pseudoternary polymerization system consisted
      of n-hexane, a nonionic surfactant (polyoxyethylene oleyl ether, C18En), and an
      aqueous monomer solution. Polymerization was performed in a single-phase reversed
      micelle solution. The reversed micelles were about 50 nm in diameter, as
      determined by FF-TEM. The viscometric characteristics of the polymers extracted
      from the IMEP system were studied in 3 mM sodium chloride aqueous solution. The
      intrinsic viscosity values for the noncrosslinked and crosslinked (0.1 mol% MBA
      was incorporated) samples were 25 and 7.4 dl/g, respectively. The overlap
      concentration (c*) of crosslinked polymer microgel occurred at c[eta] = 1 in the
      solvent. When the volume fraction (phi) of the microgel was 0.7, the value of the
      apparent yield stress of the microgel solution was observed. These results show
      that the microgel has a significant thickening effect above c* due to friction
      between the microgel particles. It is assumed that the microgels polymerized in a
      confined space retain the shape or size of the nanosized reactor with a diameter
      on the order of 50 nm.

PMID- 15178274
TI  - Mesoscopic analysis of conformational and entropic contributions to nonspecific
      adsorption of HP copolymer chains using dynamic Monte Carlo simulations.
AB  - Dynamic Monte Carlo simulations of short linear HP-type copolymers exhibiting
      proteinlike characteristics are used to investigate both chain dynamics and
      changes in chain conformational entropy and their contributions to the energetics
      of adsorption onto a solid-liquid interface. The dMC results show that the
      conformations and energies of adsorbed chains are highly degenerate. The ensemble
      averaged energy of the adsorbed state is dependent on temperature, chain
      sequence, native-state stability, and sorbent surface geometry and
      hydrophobicity. Mesoscopic thermodynamic analyses reveal that, although increased
      chain conformational entropy contributes to the driving force for adsorption in
      certain cases, many conditions exist where the change in conformational entropy
      is either negligible or unfavorable due to constraints imposed by the need to
      form a large and specific number of favorable intra- and intermolecular contacts
      and by the impenetrable nature of the sorbent surface. Step-number-averaged
      energy trajectories, based on sampling of a large number of energy trajectories
      and thus conformational states at each step number, suggest that the search for a
      global energy minimum is gradual, so that adsorption is first reversible but
      becomes apparently irreversible with longer exposure to the sorbent. These
      results appear to be connected to the conformational adaptability of the chain
      both on the surface and in solution, and an adsorption model taking chain
      conformational dynamics into account is proposed.

PMID- 15178275
TI  - Preparation of DNA-loaded polysulfone microspheres by liquid-liquid phase
      separation and its functional utilization.
AB  - DNA-loaded polysulfone (PSf) microspheres were fabricated by means of a liquid
      liquid phase separation technique. The porous microspheres were then used to
      remove DNA-binding intercalating materials--ethidium bromide, acridine orange,
      and endocrine disruptors. The DNA-loaded PSf microspheres are stable in water.
      The stability of the DNA-loaded microspheres and/or the release rate of DNA from
      the microspheres can be controlled by manipulating the microsphere structure.
      Increasing the polymer concentration, which causes lower porosity and smaller
      pores on the outer surface of the microspheres, led to increased stability of the
      microspheres and decreased release rate of DNA. Additionally, the drying
      temperature also affected the stability of the microspheres. The DNA-loaded PSf
      microspheres could effectively accumulate harmful DNA-intercalating pollutants
      and endocrine disruptors, such as ethidium bromide, acridine orange, biphenyl,
      dibenzofuran, and dibenzo-p-dioxin. The amount of pollutants removed by the
      microspheres is dependent on the amount of incorporated DNA and on the
      microsphere structure. The DNA-loaded microspheres have the potential to be used
      in environmental applications.

PMID- 15178276
TI  - Expulsion of bovine serum albumin from the air/water interface by a sparingly
      soluble lecithin lipid.
AB  - Dynamic surface tensiometry, ellipsometry, and infrared reflection-absorption
      spectroscopy (IRRAS) were used to study the dynamic adsorption and surface
      tensions of dilauroylphosphatidylcholine (DLPC) in the presence of bovine serum
      albumin (BSA). Results show that the equilibrium adsorbed layers consist mostly
      of DLPC, which can produce dynamic surface tensions (1 mN/m) as low as the more
      successful lung surfactant replacement formulations. When the aqueous surface
      expands and contracts sinusoidally, BSA can coadsorb and lead to slightly higher
      dynamic surface tensions than when DLPC is alone. Similar results were obtained
      with BSA and sodium myristate [McClellan and Franses, Colloids Surf. B 30 (2003)
      1]. Expulsion of the BSA in the layer by DLPC can take from 5 to 15 min,
      depending on relative concentrations and history of solute addition. This is
      shown by tensiometry measurements on mixtures, and also by injecting aqueous DLPC
      underneath adsorbed BSA layers and probing the surface layer with ellipsometry
      and IRRAS. Albumin layers from buffer solutions aged up to 30 h can be expelled
      by DLPC. In pure water, there is an initial enhancement in protein adsorption
      after the DLPC is injected. This can be explained by the hypothesis that DLPC
      molecules bind with BSA molecules to form a hydrophobic lipoprotein complex,
      which is more hydrophobic than the protein itself. Since DLPC produces lower
      surface energy than BSA and--being slightly soluble--adsorbs to the surface by a
      molecular mechanism, it fulfills the thermodynamic and dynamic requirements for
      expelling the BSA from the surface. The results have implications for minimizing
      lung surfactant inhibition by serum proteins, as it occurs in the cases of adult
      or acute respiratory distress syndrome.

PMID- 15178277
TI  - Plasma protein adsorption and thrombus formation on surface functionalized
      polypyrrole with and without electrical stimulation.
AB  - A surface modification technique was developed in which heparin was covalently
      immobilized onto electrically conductive polypyrrole (PPY) film through
      poly(ethylene glycol) methacrylate (PEGMA) graft copolymerization and subsequent
      cyanuric chloride activation. In vitro plasma protein adsorption and thrombus
      formation experiments were carried out on the various films. The PEGMA-graft
      copolymerized PPY surfaces with immobilized heparin have good bioactivity
      indicated by low level of protein adsorption, high ratio of albumin to fibrinogen
      adsorption, and low thrombus formation, making them potentially good candidates
      for biomedical applications. Since the PPY film retained significant electrical
      conductivity after surface modification, the effect of electrical stimulation on
      protein adsorption and thrombus formation was also evaluated. The covalently
      immobilized heparin on the PPY film was able to retain its bioactivity after 4
      days of immersion in PBS. The film after long-term immersion in PBS also retained
      sufficient electrical conductivity for electrical stimulation still to be
      effective for reducing protein adsorption.

PMID- 15178278
TI  - Rapid synthesis of Au, Ag, and bimetallic Au core-Ag shell nanoparticles using
      Neem (Azadirachta indica) leaf broth.
AB  - We report on the use of Neem (Azadirachta indica) leaf broth in the extracellular
      synthesis of pure metallic silver and gold nanoparticles and bimetallic Au/Ag
      nanoparticles. On treatment of aqueous solutions of silver nitrate and
      chloroauric acid with Neem leaf extract, the rapid formation of stable silver and
      gold nanoparticles at high concentrations is observed to occur. The silver and
      gold nanoparticles are polydisperse, with a large percentage of gold particles
      exhibiting an interesting flat, platelike morphology. Competitive reduction of
      Au3+ and Ag+ ions present simultaneously in solution during exposure to Neem leaf
      extract leads to the synthesis of bimetallic Au core-Ag shell nanoparticles in
      solution. Transmission electron microscopy revealed that the silver nanoparticles
      are adsorbed onto the gold nanoparticles, forming a core-shell structure. The
      rates of reduction of the metal ions by Neem leaf extract are much faster than
      those observed by us in our earlier studies using microorganisms such as fungi,
      highlighting the possibility that nanoparticle biological synthesis methodologies
      will achieve rates of synthesis comparable to those of chemical methods.

PMID- 15178280
TI  - Preparation of Y2O3 nanoparticulate thin films using an emulsion liquid membrane
      system.
AB  - Y2O3 nanoparticulate thin films have been prepared using an emulsion liquid
      membrane (water-in-oil-in-water (W/O/W) emulsion) system, consisting of Span 83
      (sorbitan sesquioleate) as a surfactant and VA-10 (2-methyl-2-ethylheptanoic
      acid) as an extractant (cation carrier). Yttrium ions were extracted from the
      external water phase and stripped into the internal water phase to make precursor
      oxalate nanoparticles. Y2O3 nanoparticulate thin film was prepared by casting the
      W/O emulsion, separated from the external phase and containing the Y oxalate
      nanoparticles, on a Si substrate, followed by calcination in air. Well-arranged
      thin-layer nanoparticulate film, consisting of Y2O3 nanoparticles smaller than 20
      nm, was obtained via spin coating of the W/O emulsion. A multilayer
      nanoparticulate thin film was also fabricated via a simple procedure of repeated
      coating and subsequent calcination.

PMID- 15178279
TI  - Synthesis of CdSe nanoparticles in the presence of aminodextran as stabilizing
      and capping agent.
AB  - Water-dispersible Amdex-CdSe nanoparticle complexes with sufficient luminescence
      intensity were prepared at room temperature by rapidly mixing aqueous solutions
      of either sodium selenide or selenourea with those of cadmium chloride in the
      presence of amino-derivatized polysaccharides (Amdex) as stabilizing agent. It
      was shown that the size of CdSe crystallites decreased with increasing content of
      the polymer in the precipitation process. When present in a sufficient amount,
      Amdex was found to be an effective stabilizing and capping agent, producing CdSe
      nanocrystals of weak-to-medium luminescence intensity (maximum room temperature
      quantum yields of 15-16%). Furthermore, Amdex has proven to be an effective
      protective agent against photochemical degradation.

PMID- 15178281
TI  - Electrostatic free energy of interacting ionizable double layers.
AB  - The electrostatic contribution to the interaction free energy of charge
      regulating materials, similar as well as dissimilar, contains electric work as
      well as chemical work and can be obtained from an integration over the diffuse
      part of the double layer together with a summation of the surface contribution to
      the free energy over the two surfaces. Examples for the surface contribution are
      given for acid, base, zwitterionic, and amphoteric (1-pK and 2-pK) materials for
      a diffuse double layer and for the Stern-Gouy-Chapman model, with and without ion
      adsorption. For charge-regulating materials, the electrostatic contribution to
      the interaction free energy at contact (adhesion force of curved surfaces, or
      particles) is always finite and can be obtained from a simple calculation.

PMID- 15178282
TI  - Surface charge properties of Fe2O3 in aqueous and alcoholic mixed solvents.
AB  - Iron oxide (Fe2O3) was identified and characterized by surface area, X-ray
      diffractometry, and FTIR analyses. Surface charge densities, point of zero charge
      (PZC), and surface ionization constants were determined from the potentiometric
      titration data in various aqueous and aqueous organic mixed solvents in the
      temperature range 293-313 K. The surface charge densities were observed to
      decrease with the increase in temperature and concentration of metal ions in both
      the aqueous and aqueous organic mixed solvents. The absolute values of the
      surface charge density were found to change in the order aqueous >
      aqueous/methanol > aqueous/ethanol. Further, the PZC of the iron oxide was
      observed to shift to the higher pH values in the order ethanol > methanol >
      aqueous solution, which indicated a decrease in the acidity of the surface -OH
      groups. The pKa1 and pKa2 values of iron oxide were also determined and then used
      for determination of the surface potential (psi0) of the solid in aqueous and
      aqueous organic mixed solvents. The surface potential-surface charge curves
      generally supplemented the results derived from psi0-pH curves.

PMID- 15178283
TI  - Surface modification of pyrophyllite with amino silane coupling agent for the
      removal of 4-nitrophenol from aqueous solutions.
AB  - The surface of naturally hydrophobic mineral pyrophyllite was modified to
      hydrophilic by treatment with prehydrolyzed N-(2-aminoethyl)-3
      aminopropyltrimethoxysilane (APEO) coupling agent to prepare a novel and
      effective adsorbent for the removal of 4-nitrophenol (4-NP) from aqueous
      solutions. XRD, FTIR, and SEM analyses were used to characterize the surface
      modification. It was found that after the grafting procedure, heat treatment at
      110 degrees C results in condensation reaction between the OH groups of the APEO
      molecule and the hydroxyl groups and/or oxygen atoms on the pyrophyllite surface
      and the adsorption of 4-NP by APEO-modified pyrophyllite involves interactions
      between dissociated 4-NP molecules and protonated amine groups of APEO molecules
      attached to the mineral surface. Adsorption equilibrium data for 4-NP adsorption
      on APEO-treated and untreated pyrophyllite were most satisfactorily fitted using
      the Freundlich adsorption isotherm and adsorption capacity was found to be 0.268
      mg/g for modified pyrophyllite whereas it was only 0.105 mg/g for untreated
      pyrophyllite.

PMID- 15178284
TI  - The foam analogy: from phases to elasticity.
AB  - By mapping the interactions of colloidal particles onto the problem of minimizing
      areas, the physics of foams can be used to understand the phase diagrams of both
      charged and fuzzy colloids. We extend this analogy to study the elastic
      properties of such colloidal crystals and consider the face-centered cubic, body
      centered cubic and A15 lattices. We discuss two types of soft interparticle
      potentials corresponding to charged and fuzzy colloids, respectively, and we
      analyze the dependence of the elastic constants on density as well as on the
      parameters of the potential. We show that the bulk moduli of the three lattices
      are generally quite similar, and that the shear moduli of the two non-close
      packed lattices are considerably smaller than in the face-centered cubic lattice.
      We find that in charged colloids, the elastic constants are the largest at a
      finite screening length, and we discuss a shear instability of the A15 lattice.

PMID- 15178285
TI  - Double layer interaction between two plates with polyelectrolyte brushes.
AB  - When polyelectrolyte chains are grafted to colloidal particles, the electric
      field between particles is affected by the charges of the chains. In some
      previous theoretical attempts, the charge density of the polyelectrolyte chains
      per unit length was considered constant, and its effect was accounted for by
      introducing an additional constant charge density into the unidimensional Poisson
      Boltzmann equation, which was evaluated assuming that it is uniformly distributed
      in the polyelectrolyte volume of the brush. In this paper, a more detailed model
      is employed for the calculation of the electrical potential between two plates on
      which polyelectrolyte brushes are present. In this model, the polyelectrolyte
      chain is viewed as a rigid cylinder, on the surface of which charges are
      generated through the dissociation of ionizable sites and adsorption of the
      cations of the electrolyte. To each of the chains an atmosphere is attached which
      for simplicity is assumed cylindrical. In the brush region, the electrical
      potential is described by a two-dimensional Poisson-Boltzmann equation, while in
      the region free of polyelectrolyte chains by a unidimensional Poisson-Boltzmann
      equation. Such a model is physically suitable when the charges of the chains are
      sufficiently large for the repulsion they generate to ensure that the chains are
      fully extended. Such cases are quite frequent, because relatively low charges
      lead to an almost complete extension of the chains. In this paper, both the plate
      surface and the surface of the cylinders are considered charged. The effects of
      electrolyte concentration, pH, brush thickness and chain coverage density on the
      repulsion between plates are examined.

PMID- 15178286
TI  - On the rate of relativistic surface chemical reactions.
AB  - On the basis of special relativity and the classical theory of chemical reaction
      rates it is shown how the surface chemical reaction rates vary as v --> c, where
      v is the velocity of the object under study and c is the velocity of light.

PMID- 15178287
TI  - Interfacial aggregate growth process of Fe(II) and Fe(III) complexes with
      pyridylazophenol in solvent extraction system.
AB  - The complexation mechanism and aggregate formation of bis[2-(5-bromo-2
      pyridylazo)-5-diethylaminophenolate] iron(II) and iron(III) complexes at the
      heptane-water interface were studied spectrophotometrically by the high-speed
      stirring method and the centrifugal liquid membrane method. Furthermore, the
      reduction process of the Fe(III) complex with ascorbic acid at the interface was
      spectrophotometrically observed. The chemical compositions of the interfacial
      aggregate of complexes have been proved by the X-ray photoelectron spectroscopy.
      The aggregation of the complex at the interface was observed as a red-shifted,
      very strong and narrower absorption band with respect to the absorption band of
      the monomer complex. The aggregate of Fe(III) complex showed more shifted
      spectrum than that of Fe(II) complex, which proposed the larger aggregation
      number of Fe(III) aggregate (n = 8) than that of Fe(II) aggregate (n = 3). The
      obtained rate constants of interfacial aggregation were smaller than rate
      constants of interfacial monomer complexation, because the formation of aggregate
      required the assembly of the monomers.

PMID- 15178288
TI  - Ion exchange studies on natural and modified zeolites and the concept of exchange
      site accessibility.
AB  - In the present study natural and Na-rich form of clinoptilolite are examined, in
      respect to ion exchange of Pb2+, Cu2+, Cr3+, and Fe3+. Equilibrium and kinetic
      studies performed, under the same normality (0.01 N). Equilibrium studies
      demonstrate that Na+ enrichment of clinoptilolite is beneficial in respect to
      metal uptake for all metals, except Cr3+, which is shown to have the same
      equilibrium behavior in both materials. Kinetic study shows that diffusion
      coefficients are in the range of 0.16 to 9 x 10(-9) cm2/s, and are not always
      improved in Na-rich form of clinoptilolite. The effect of temperature on
      diffusion coefficients is also examined, and Arrhenius activation energy is
      determined to be in the range of 3.02 to 13.9 kcal/mol, for all metals and
      materials, except Cu2+, which have extremely low activation energy in the natural
      sample, equal to 0.04 kcal/mol.

PMID- 15178289
TI  - Surface analysis of plasma-patterned biofunctional hybrid titanate-aminosilane
      xerogel films.
AB  - The functionalization and patterning of biomedical materials with enhanced
      surface activity is a main objective for the development of high-specificity
      biosensors. The surfaces of sol-gel condensed aminopropyltriethoxysilane
      tetraisopropyl orthotitanate hybrid materials have been studied in order to
      describe the mechanisms that allow the fixation of amino groups. X-ray
      photoelectron spectra obtained from these surfaces are compared with those coming
      from the surfaces of plasma-etched coatings. The results show that aminopropyl
      radicals remain on the surface after room-temperature condensation and that they
      are drastically removed after partial etching of the coating in an Ar plasma.
      This confirms that the functionalization is effectively a surface feature and
      suggests that amino groups may remain at the surface covalently bonded to the
      original amorphous Si-O- structure. Further evidence of the surface
      functionalization efficiency is illustrated with contact angle and zeta-potential
      measurements. It is complementarily proved by confocal microscopy that masked
      regions conserve their molecular activity and are not affected by the etching
      process. These facts suggest that these materials could play an active role when
      incorporated into biosensor devices.

PMID- 15178290
TI  - Montmorillonite intercalated with polyaminoamide-epichlorohydrin: preparation,
      characterization, and sorption behavior.
AB  - Organophilic and cationic montmorillonite is desirable for pitch control in the
      pulp and paper industry. In this paper, polyaminoamide-epichlorohydrin (PAE)
      modified montmorillonite was prepared via either solution intercalation or melt
      intercalation of polyaminoamide into montmorillonite, followed by the reaction
      with epichlorohydrin. The modified montmorillonite samples were characterized by
      FTIR spectroscopy, X-ray diffraction, and thermal gravimetric analysis. The
      amount of PAE intercalated and the surface charge densities of cationic-modified
      montmorillonite were determined. It was found that melt intercalation appeared to
      be more effective in the inclusion of PAE than solution intercalation. However,
      both solution- and melt-intercalated samples with various surface charge
      densities exhibited strong affinity toward dispersed colloidal rosin acid.

PMID- 15178291
TI  - Influence of oxygen plasma treatment on hydrogen chloride removal of activated
      carbon fibers.
AB  - The oxygen plasma treatment of activated carbon fibers (ACFs) was carried out to
      introduce oxygen-containing groups onto carbon surfaces. Surface properties of
      the ACFs were determined by X-ray photoelectron spectroscopy (XPS) and scanning
      electron microscopy (SEM). N2/77 K adsorption isotherms were investigated by BET
      and D-R plot methods to characterize specific surface area, pore volume, and pore
      size distribution. The efficiency of hydrochloride removal was confirmed by two
      kinds of methods; one is detecting tubes (range: 1-40 ppm), and the other is a
      gas chromatography technique. As experimental results, the hydrochloride removal
      efficiency of the ACFs was increased with the number of plasma treatment times up
      to around 300%, resulting from newly formed oxygen-containing functional groups
      (especially phenolic and carboxylic) on carbon surfaces, in the decreased
      specific surface areas or pore volumes. These results indicate that the plasma
      treatment leads to the increase of hydrochloride removal due to the improvement
      of surface functional groups containing oxygen on the carbon surfaces.

PMID- 15178292
TI  - Photochromic inorganic-organic multilayer films based on polyoxometalates and
      poly(ethylenimine).
AB  - Novel photochromic inorganic-organic multilayers composed of polyoxometalates and
      poly(ethylenimine) have been prepared by the layer-by-layer (LbL) self-assembly
      method. The growth process, composition, surface topography, and photochromic
      properties of the multilayer films were investigated by UV-visible and Fourier
      transform infrared spectroscopy, atomic force microscopy, electrospin resonance
      (ESR), and X-ray photoelectron spectroscopy (XPS). Irradiated with ultraviolet
      light, the transparent films changed from colorless to blue. Moreover, the blue
      films showed good reversibility of photochromism and could recover the colorless
      state gradually in air, where oxygen plays an important role in the bleaching
      process. On account of the ESR and XPS results, parts of W6+ in multilayers were
      reduced to W5+, which exhibited a characteristic blue; a possible photochromic
      mechanism can be speculated. This work provides basic guideline for the assembly
      of multilayers with photochromic properties.

PMID- 15178293
TI  - Electrostatic potentials and fields in the vicinity of engineered nanostructures.
AB  - We have developed a method for calculating the electrostatic potentials and
      fields in the vicinity of geometrically complex engineered nanostructures
      composed of varying materials in electrolytes of arbitrary pH and ionic strength.
      The method involves direct summation of charged Debye-Huckel spheres composing
      the nanostructural surfaces and, by including charge redistribution on the
      surface of conducting materials held at constant potential, is applicable to
      mixed boundary conditions. The method is validated by comparison to analytical
      solutions for an infinite plane (Gouy-Chapman), an infinite cylinder (Bessel
      functions), and an infinite plane which contains a hole and which is held at
      constant potential. Excellent agreement between the potentials obtained by our
      numerical method and the closed form solutions is found for these conditions. The
      method is applied to the calculation of the electric field enhancement in the
      vicinity of a nanomembrane whose pore wall is held at constant charge and whose
      membrane surfaces are held at constant potential. The electric field is found to
      be enhanced by the charge buildup in the rim of the hole of the nanomembrane; the
      buildup results from the potential being held constant in the conducting region.
      Ion concentrations are also calculated. Positive ion rejection is found to be
      enhanced by this charge buildup in the region of the rim when a constant positive
      potential is applied.

PMID- 15178294
TI  - Effect of pH on adsolubilization of single and binary organic solutes into a
      cationic hydrocarbon surfactant adsorbed layer on silica.
AB  - The adsolubilization behaviors of 2-naphthol, biphenyl, and their binary solutes
      in the hexadecyltrimethyl ammonium bromide (HTAB) adsorbed layer formed on silica
      have been studied with solution pH. Two feed concentrations of HTAB are employed:
      1.5 and 3.0 mmol dm(-3). At the feed concentration of 1.5 mmol dm(-3) HTAB, most
      of HTAB are adsorbed on the silica as a monolayer, while a bilayer formation
      occurs at the feed concentration of 3.0 mmol dm(-3). It is found that the
      adsolubilized amounts of respective single solutes increase with increasing
      solution pH except acidic region for biphenyl under a constant feed concentration
      of 2-naphthol (0.4 mmol dm(-3)) and biphenyl (0.047 mmol dm(-3)). The
      adsolubilization of binary solutes depends on the feed concentration of HTAB; at
      the low HTAB feed concentration, competitive adsolubilization between 2-naphthol
      and biphenyl occurs above pH 4.5, while at the high HTAB feed concentration the
      adsolubilization of biphenyl is enhanced by the incorporation of 2-naphthol over
      a whole pH region. These behaviors in the adsolubilization are discussed from the
      surfactant structure of HTAB adsorbed as well as the admicellar partitioning
      coefficients.

PMID- 15178295
TI  - Interactions of quaternary ammonium salt-type gemini surfactants with sodium
      poly(styrene sulfonate).
AB  - The interactions of cationic gemini surfactants, 1,2
      bis(alkyldimethylammonio)ethane dibromide (m-2-m: m is hydrocarbon chain length,
      m = 10 and 12), and an anionic polymer, sodium poly(styrene sulfonate) (PSS),
      have been characterized by several techniques such as tensiometry, fluorescence
      spectroscopy, and dynamic light scattering. The surface tension of gemini
      surfactant/PSS mixed systems decreases with surfactant concentration, reaching
      break points, which are taken as critical aggregation concentrations (cac). The
      surface tension at the cac of mixtures is higher than that of single surfactants,
      and it is found that at concentrations above the cac, the surfactant molecules
      are associated with the polymer in the bulk. The 12-2-12/PSS mixed system shows
      higher surface activity than both 10-2-10/PSS and the monomeric surfactant of
      dodecyltrimethylammonium bromide/PSS systems. Fluorescence measurements of these
      mixed systems suggest the formation of a complex with a highly hydrophobic
      environment in the bulk of the solution. Additionally, dynamic light scattering
      measurements show that the hydrodynamic diameter of the 12-2-12/PSS mixed system
      is smaller than that of PSS only at low concentration, indicating interactions
      between surfactant and polymer. These result from the electrostatic attraction
      between ammonium and sulfate headgroups as well as the hydrophobic interaction
      between their hydrocarbon chains.

PMID- 15178296
TI  - Characterization of micelles of polyoxyethylene nonylphenol (Igepal) and its
      complexation with 3,7-diamino-2,8-dimethyl- 5-phenylphenazinium chloride.
AB  - This paper explores the association of a nonionic surfactant, Igepal
      (polyoxyethylene nonylphenol), in aqueous media by means of absorption and
      fluorescence spectroscopy. The critical micellar concentration (CMC) of the
      aggregate formed in the aqueous medium has been determined, using three different
      methods: UV-visible spectroscopy, fluorescence spectroscopy, and Stokes shift.
      The correlation of CMC with hydrophile-lipophile balance (HLB) indicates that the
      CMC decreases with decreased HLB. The obtained CMC values from different methods
      are close to each other and have allowed the determination of DeltaG values
      associated with the micellization. The association constant of the dye molecule
      Safranine T (ST) with the nonionic micelle of Igepal, aggregation number of the
      surfactant monomer, and location of the fluorophore in the micellar environment
      have been determined. The vertical ionization potential of Igepal, electron
      affinity of the dye, and degree of charge transfer from the micellar aggregate to
      the dye molecule have been determined by AM1 calculation. The experimental charge
      transfer transition energies are well correlated with the determined ionization
      potential values (ID) of Igepal. The degree of charge transfer (ground state
      complexes) has been found to be low. The polarity of the micelle solubilization
      sites has been estimated from the solvatochromic shift, Kosowar Z value, and
      ET30, and ETN values.

PMID- 15178297
TI  - Multilayer vesicles and vesicle clusters formed by the fullerene-based surfactant
      C60(CH3)5K.
AB  - The self-assembly behavior of a fullerene-based surfactant, C60(CH3)5K, in water
      was studied using a combination of static and dynamic light scattering, as well
      as transmission electron microscopy, and compared to that of the compound
      C60(C6H5)5K. Both fullerene surfactant systems spontaneously assemble into large
      vesicles consisting of closed spherical shells formed by bilayers, with critical
      aggregation concentrations (CAC) lower than 10(-6) g ml(-1). At low
      concentrations, the aggregate sizes of C60(CH3)5K (radius R approximately 26.8
      nm) and C60(C6H5)5K (R approximately 17.0 nm) were found to be substantially
      different from each other, showing that the change of the substituents
      surrounding the polar cyclopentadienide head group makes it possible to control
      the size of the resulting aggregates. Furthermore, the C60(CH3)5K vesicles were
      found to exist in two qualitatively different types of aggregation with a
      critical reaggregation concentration (CRC) located at 3.30 x 10(-6) g ml(-1).
      Above the CRC, larger aggregates were observed (R approximately 37.6 nm), showing
      a more complex form of supramolecular aggregation, e.g., in terms of multi
      bilayer vesicles and/or of clusters of bilayer vesicles.

PMID- 15178298
TI  - Dependence of lipoprotein-lipase-catalyzed triacylglycerol hydrolysis on droplet
      size of synthetic monodisperse emulsions measured with static light scattering.
AB  - Well-defined triolein emulsions of low polydispersity were prepared by shearing a
      crude emulsion in a modified Couette cell, resulting in radii in the range of 300
      to 900 nm. These emulsions were used as synthetic substrates for lipoprotein
      lipase, a key enzyme for the hydrolysis of serum triacylglycerols. The change in
      radius with time was studied with on-line static light scattering at 37 degrees
      C. An optimum radius of about 750 nm was found for this reaction.

PMID- 15178299
TI  - Preparation and dilute solution properties of model gemini nonionic surfactants.
AB  - Dimeric poly(ethylene oxide) surfactants (or nonionic gemini surfactants) with
      the structure (Cn-2H2n-3CHCH2O(CH2CH2O)mH)2(CH2)6 (or GemnEm), where n is the
      alkyl length and m is the average number of ethylene oxides per head group, were
      synthesized. Surfactants were synthesized with alkyl chain lengths n = 12, 14,
      and 20 and m = 5, 10, 15, 20, and 30. Water solubilities and cloud temperatures
      at 1 wt% were determined by measuring turbidity as a function of temperature.
      Cloud temperatures increase with m and decrease with n, as observed for
      conventional surfactants. For large m the cloud temperatures were all above 100
      degrees C. Surfactants with small m (i.e., n = 12, 14, m = 5 and n = 20, m = 10)
      were insoluble at room temperature, forming two-phase mixtures. Critical micelle
      concentrations (CMCs) were measured using a pyrene fluorescence method and are
      all in the range of 10(-7) to 10(-6) M, with the lowest values from the
      surfactants with large n and small m. CMCs of mixtures with both anionic and
      nonionic conventional (monomeric) surfactants were well described by an ideal
      mixing model.

PMID- 15178300
TI  - Materials based on solid-stabilized emulsions.
AB  - Solid-stabilized emulsions are obtained by shearing a mixture of oil, water, and
      solid colloidal particles. In this article, we present a large variety of
      materials, resulting from a limited coalescence process. Direct (o/w), inverse
      (w/o), and multiple (w/o/w) emulsions that are surfactant-free and monodisperse
      were produced in a very wide droplet size range, from micrometers to centimeters.
      These materials exhibit original properties compared with surfactant-stabilized
      emulsions: outstanding stability with respect to coalescence and unusual
      rheological behavior. For such systems, the elastic storage modulus G' is not
      controlled by interfacial tension but by the interfacial elasticity resulting
      from the strong adhesion between the solid particles adsorbed at the oil-water
      interface. Due to the wide accessible droplet size range, concentrated emulsions
      can be extremely fluid while emulsions with low droplet volume fraction can
      behave as solids.

PMID- 15178301
TI  - Electrophoretic mobility of a highly charged colloidal particle in a solution of
      general electrolytes.
AB  - For a highly charged particle in an electrolyte solution, counterions are
      condensed very near the particle surface. The electrochemical potential of
      counterions accumulated near the particle surface is thus not affected by the
      applied electric field, so that the condensed counterions do not contribute to
      the particle electrophoretic mobility. In the present paper we derive an
      expression for the electrophoretic mobility mu(infinity) of a highly charged
      spherical particle of radius a and zeta potential zeta in the limit of very high
      zeta in a solution of general electrolytes with large ka (where k is the Debye
      Huckel parameter) on the basis of our previous theory for the case of symmetrical
      electrolytes (H. Ohshima, J. Colloid Interface Sci. 263 (2003) 337). It is shown
      that zeta can formally be expressed as the sum of two components: the co-ion
      component, zetaco-ion, and the counterion component, zetacounterion (where zeta =
      zetaco-ion + zetacounterion) and that the limiting electrophoretic mobility
      mu(infinity) is given by mu(infinity) = epsilonr epsilon0 zetaco
      ion(infinity)/eta + 0(1/ka), where zetaco-ion(infinity) is the high zeta-limiting
      form of zetaco-ion, epsilonr and eta are, respectively, the relative permittivity
      and viscosity of the solution, and epsilon0 is the permittivity of a vacuum. That
      is, the particle behaves as if its zeta potential were zetaco-ion(infinity),
      independent of zeta. For the case of a positively charged particle in an aqueous
      electrolyte solution at 25 degrees C, the value of zetaco-ion(infinity) is 35.6
      mV for 1-1 electrolytes, 46.0 mV for 2-1 electrolytes, and 12.2 mV for 1-2
      electrolytes. It is also found that the magnitude of mu(infinity) increases as
      the valence of co-ions increases, whereas the magnitude of mu(infinity) decreases
      as the valence of counterions increases.

PMID- 15178302
TI  - An analysis of induced pressure fields in electroosmotic flows through
      microchannels.
AB  - Induced pressure gradients are found to cause band-broadening effects which are
      important to the performance of microfluidic devices, such as capillary
      electrophoresis and capillary chromatography. An improved understanding of the
      underlying mechanisms causing an induced pressure gradient in electroosmotic
      flows is presented. The analysis shows that the induced pressure distribution is
      the key to understanding the experimentally observed phenomena of leakage flows.
      A novel way of determining the static pressures at the inlet and outlet of
      microchannels is also presented that takes account of the pressure losses due to
      flow contraction and expansion. These commonly neglected pressure losses at the
      channel entrance and outlet are shown to be important in accurately describing
      the flow. The important parameters that define the effect of induced pressure on
      the flows are discussed, which may facilitate the design of improved microfluidic
      devices. The present model clearly identifies the mechanism behind the
      experimentally observed leakage flows, which is further confirmed by numerical
      simulations. Not only can the leakage flow occur from the electric-field-free
      side channel to the main channel, but also the fluid in the main channel can be
      attracted into the side channel by the induced pressure gradient.

PMID- 15178303
TI  - Frequency-dependent laminar electroosmotic flow in a closed-end rectangular
      microchannel.
AB  - This article presents an analysis of the frequency- and time-dependent
      electroosmotic flow in a closed-end rectangular microchannel. An exact solution
      to the modified Navier-Stokes equation governing the ac electroosmotic flow field
      is obtained by using the Green's function formulation in combination with a
      complex variable approach. An analytical expression for the induced backpressure
      gradient is derived. With the Debye-Huckel approximation, the electrical double
      layer potential distribution in the channel is obtained by analytically solving
      the linearized two-dimensional Poisson-Boltzmann equation. Since the counterparts
      of the flow rate and the electrical current are shown to be linearly proportional
      to the applied electric field and the pressure gradient, Onsager's principle of
      reciprocity is demonstrated for transient and ac electroosmotic flows. The time
      evolution of the electroosmotic flow and the effect of a frequency-dependent ac
      electric field on the oscillating electroosmotic flow in a closed-end rectangular
      microchannel are examined. Specifically, the induced pressure gradient is
      analyzed under effects of the channel dimension and the frequency of electric
      field. In addition, based on the Stokes second problem, the solution of the slip
      velocity approximation is presented for comparison with the results obtained from
      the analytical scheme developed in this study.

PMID- 15178304
TI  - Synthesis, antiprotozoal and cytotoxic activities of new N-(3,4-dimethyl-5
      isoxazolyl)-1,2-naphthoquinone-4-amino derivatives.
AB  - Three derivatives of N-(3,4-dimethyl-5-isoxazolyl)-1,2-naphthoquinone-4-amino
      (1), a compound which exhibits significant activity against Trypanosoma cruzi and
      Plasmodium falciparum but with cytotoxicity toward murine L-6 cells, were
      synthesized with the aim of ameliorating its cytotoxicity. The in vitro
      antiprotozoal and cytotoxic activities of the synthesized compounds were
      evaluated against T. cruzi, Trypanosoma brucei rhodesiense, P. falciparum and
      murine L-6 cells. The hydroxymethyl (2) and the oxime (3) derivatives were active
      against T. cruzi, with IC50 values in a range comparable to those of 1 (IC50:
      0.65 microg/ml) and benznidazole (IC50: 0.56 microg/ml) while the
      carboxymethyloxime (4) was inactive. Compounds 2 and 3 were cytotoxic toward L-6
      cells, with IC50 values identical to that of 1 (IC50: 0.50 microg/ml). The
      results did not support the suggestion that 2 and 3 may be used as prodrugs of 1.

PMID- 15178305
TI  - Kinetics of hydrolysis of 4-methoxy-2-[2-hydroxy-3(4-phenyl-1-piperazinyl)]propyl
      2,3-dihydro-6-methyl-1,3-dioxo-1H-pyrrolo[3,4-c]pyridine in aqueous solutions.
AB  - The kinetics of hydrolysis of 4-methoxy-2-[2-hydroxy-3(4-phenyl-1
      piperazinyl)]propyl-2,3-dihydro-6-methyl-1,3-dioxo-1H-pyrrolo[3,4-c]pyridine (I)
      in aqueous solutions at 333, 343, 353 and 363 K over the pH range 0.4-4.8 was
      investigated. The decomposition was observed with the HPLC method (LiChrosorb)
      100 RP-18 column 250 x 4.0 mm ID, dp = 5 microm; mobile phase: acetonitrile--0.01
      M phosphate buffer (H3PO4 + KH2PO4; pH 3) (50:50, v/v-phase A) or (30:70, v/v
      phase B). The pH-rate profile indicated specific acid- and base-catalyzed
      reactions as well as spontaneous water-catalyzed decomposition of both
      dissociated and undissociated molecules of I. Various buffer substances exhibited
      general acid and base catalysis of the degradation. The ionic strength effect,
      the pKa value (4.2), the pHmin value (2.0) and thermodynamic parameters of the
      reaction (energy and enthalpy of activation and the frequency coefficient for the
      specific rate constants) were determined.

PMID- 15178306
TI  - Synthesis and in vitro antifungal activity of 4-substituted phenylguanidinium
      salts.
AB  - A series of 4-substituted phenylguanidinium derivatives was synthesized and its
      antimicrobial activity was evaluated in vitro against eight potentially
      pathogenic strains of fungi.

PMID- 15178308
TI  - New derivatives of pyrrolo[3,4-d]pyridazinone and their anticancer effects.
AB  - Eighteen new derivatives of pyrrolo[3,4-d]pyridazinone modified at the pyrrole
      and pyridazine rings were synthesized and 12 of them were evaluated in vitro
      through anticancer screenings. The structures of new compounds were confirmed by
      elemental analysis and spectral data (IR, 1H NMR). None of the eight compounds
      assayed blocked the cell cycle regulating CDK1/cyclin B kinase, whereas two of
      the six compounds tested were active in anticancer screening at the cell
      experiments at a concentration of > or = 10(-5) M/l.

PMID- 15178307
TI  - Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3
      (pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones.
AB  - 3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a
      l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2
      methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The
      synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for
      their antileukemic activity against L-1210 (murine leukemia), K-562 (human
      chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in
      some cases good activity.

PMID- 15178309
TI  - New 6-nitroquinolones: synthesis and antimicrobial activities.
AB  - Pursuing our searches on quinolonecarboxylic acids we used a simple three-step
      one pot procedure to synthesize novel 1,7-disubstituted-6-nitroquinolones. The
      new derivatives were tested against Mycobacterium tuberculosis and Mycobacterium
      avium complex (MAC) as well as against both gram-positive and gram-negative
      bacteria. In vitro assays showed some derivatives were endowed with good
      inhibiting activities against tested mycobacteria. Some derivatives were also
      found more potent than ciprofloxacin and ofloxacin (used as reference drugs)
      against gram-positive bacteria.

PMID- 15178310
TI  - The use of molecular electrostatic potentials as hydrogen-bonding-donor
      parameters for QSAR studies.
AB  - Hydrogen bonding is an important interaction, which controls solubility,
      partitioning and transport of drugs and is an important force in drug-receptor
      interactions. Unfortunately it is difficult to quantify, and so inclusion of
      hydrogen bonding descriptors into quantitative structure-activity relationships
      (QSARs) is often restricted to indicator variables. The prime objective of this
      work was to devise readily accessible hydrogen bonding descriptors by means of
      theoretical chemistry to use in QSAR studies. Because of the dominantly
      electrostatic nature of this bond, molecular-electrostatic potential was
      considered and the highest electrostatic potential on the solvent accessible
      surface (ESP+) was used as the hydrogen-bonding-donor ability of the molecule.
      The ability of this descriptor to predict the measured hydrogen bonding parameter
      of sigmalphaH2 was compared with that of the empirically derived atomic charges.
      The efficiency of ESP+ in a QSAR was also examined. The results suggested that
      ESP+ was superior to the atomic charge descriptor and that the use of this
      parameter as the hydrogen bonding parameter in QSAR studies was successful.

PMID- 15178311
TI  - Flow-injection determination of isoniazid using sodium dichloroisocyanurate- and
      trichloroisocyanuric acid-luminol chemiluminescence systems.
AB  - A chemiluminescent (CL) method for the determination of isoniazid is described.
      The method is based on the CL generated during the oxidation of luminol by sodium
      dichloroisocyanurate (SDCC) and trichloroisocyanuric acid (TCCA) in alkaline
      medium. It was found that isoniazid greatly enhances this CL intensity when
      present in the luminol solution. Based on this observation, a new flow-injection
      CL method for the determination of isoniazid has been proposed in this paper. The
      detection limits were 2 and 3 ng ml(-1) isoniazid for the SDCC-luminol and TCCA
      luminol CL systems, respectively. The relative CL intensity was linear with the
      isoniazid concentration in the range of 4-100 and 100-200 ng ml(-1) for the SDCC
      luminol CL system, and 6-200 and 200-1000 ng ml(-1) for the TCCA-luminol CL
      system. The results obtained for the assay of pharmaceutical preparations
      compared well with those obtained by the official methods and demonstrated good
      accuracy and precision.

PMID- 15178312
TI  - Spectrophotometric determination of some beta-blockers in dosage forms based on
      complex formation with Cu(II) and Co(II).
AB  - Four sensitive and accurate spectrophotometric methods have been developed for
      the assay of Acebutolol Hydrochloride (ACH), Atenolol (ATE) and Propranolol
      Hydrochloride (PRH), which are based on the complexation of drugs with copper(II)
      (Cu(II)) and cobalt(II) (Co(II)). The coloured products are measured at 613, 694,
      548 and 614 nm for ACH-Co(II), ATE-Cu(II), PRH-Cu(II) and PRH-Co(II) method,
      respectively. The optimization of various experimental conditions is described.
      Conformity with Beer's Law was evident over a concentration range in the of 2 x
      10(-5) - 1 x 10(-2) mol/L. The molar absorptivity, detection and quantification
      limits are calculated. The results obtained showed good recoveries of 100.2 +/-
      1.1, 100.3 +/- 1.2, 100.75 +/- 1.0 and 99.55 +/- 1.1 % with relative standard
      deviations of 0.410, 0.490, 0.161 and 0.140 % for ACH-Co(II), ATE-Cu(II), PRH
      Cu(II) and PRH-Co(II) method, respectively. They were applied to the analysis of
      tablet forms of the drugs and the results were statistically compared with those
      obtained by official and literature methods using t- and F-tests. There were no
      significant difference among the mean values and precisions of the methods at 95%
      confidence level.

PMID- 15178314
TI  - Modeling drug solubility in water-cosolvent mixtures using an artificial neural
      network.
AB  - Application of the artificial neural network (ANN) to calculate the solubility of
      drugs in water-cosolvent mixtures was shown using 35 experimental data sets. The
      networks employed were feedforward backpropagation errors with one hidden layer.
      The topology of neural network was optimized and the optimum topology achieved
      was a 6-5-1 architecture. All data points in each set were used to train the ANN
      and the solubilities were back-calculated employing the trained networks. The
      differences between calculated solubilities and experimental values was used as
      an accuracy criterion and defined as mean percentage deviation (MPD). The overall
      MPD (OMPD) and its S.D. obtained for 35 data sets was 0.90 +/- 0.65%. To assess
      the prediction capability of the method, five data points in each set were used
      as training set and the solubility at other solvent compositions were predicted
      using trained ANNs whereby the OMPD (+/-S.D.) for this analysis was 9.04 +/-
      3.84%. All 496 data points from 35 data sets were used to train a general ANN
      model, then the solubilities were back-calculated using the trained network and
      MPD (+/-S.D.) was 24.76 +/- 14.76%. To test the prediction capability of the
      general ANN model, all data points with odd set numbers from 35 data sets were
      employed to train the ANN model, the solubility for the even data set numbers
      were predicted and the OMPD (+/-S.D.) was 55.97 +/- 57.88%. To provide a general
      ANN model for a given cosolvent, the experimental data points from each binary
      solvent were used to train ANN and back-calculated solubilities were used to
      calculate MPD values. The OMPD (+/-S.D.) for five cosolvent systems studied was
      2.02 +/- 1.05%. A similar numerical analysis was used to calculate the solubility
      of structurally related drugs in a given binary solvent and the OMPD (+/-S.D.)
      was 4.70 +/- 2.02%. ANN model also trained using solubility data from a given
      drug in different cosolvent mixtures and the OMPD (+/-S.D.) obtained was 3.36 +/-
      1.66%. The results for different numerical analyses using ANN were compared with
      those obtained from the most accurate multiple linear regression model, namely
      the combined nearly ideal binary solvent/Redlich-Kister equation, and the ANN
      model showed excellent superiority to the regression model.

PMID- 15178313
TI  - Spectrophotometric determination of penicillamine and carbocisteine based on
      formation of metal complexes.
AB  - A simple spectrophotometric method was developed for the determination of
      penicillamine and carbocisteine. The method depends on complexation of
      penicillamine with Ni, Co and Pb ions in acetate buffer pH of 6.3, 6.5 and 5.3,
      respectively, and carbocisteine with Cu and Ni ions in borate buffer pH of 6.7; 1
      70 microg/ml of these drugs could be determined by measuring the absorbance of
      each complex at its specific lambdamax. The results obtained are in good
      agreement with those obtained using the official methods. The proposed method was
      successfully applied for the determination of these compounds in their dosage
      forms. Also, the molar ratio and stability constant of the metal complexes were
      calculated and a proposal of the reaction pathway was postulated.

PMID- 15178315
TI  - Structural commonalities among integral membrane enzymes.
AB  - The X-ray crystal structures of five distinct enzymes (prostaglandin H(2)
      synthase, squalene cyclase, fatty acid amide hydrolase, microsomal cytochrome
      P450, and estrone sulfatase) challenge contemporary descriptions of integral
      membrane proteins. This structurally divergent group represents an important
      component of the integral membrane proteome that lies at the bilayer's aqueous
      interface. We summarize here what is collectively understood about the membrane
      insertion of these proteins, what roles they may play in lipid biology, and their
      relationship to soluble structural homologs.

PMID- 15178316
TI  - Calmodulin bridging of IQ motifs in myosin-V.
AB  - Ca(2+)-saturated calmodulin binds to double-length IQ lever-arm sequences from
      murine myosin-V, forming a 1:1 "bridging" complex with very high affinity,
      (K9d)<10 pM for double motifs, IQ34, IQ45 and IQ56). Such a 1:1 complex involves
      interaction of one calmodulin (CaM) molecule with two adjacent IQ-motifs,
      providing a molecular mechanism for the observed Ca(2+)-dependent CaM
      dissociation from the IQ-region. Structural considerations suggest that formation
      of the 1:1 complex requires a severe distortion of the lever-arm, potentially
      regulating functional motility. This would be consistent with a recent report of
      diverse, irregular shapes of the lever arm of myosin-V induced by the presence of
      Ca(2+).

PMID- 15178317
TI  - Protein phosphatase 1, but not protein phosphatase 2A, dephosphorylates DNA
      damaging stress-induced phospho-serine 15 of p53.
AB  - Okadaic acid (OA) is a protein phosphatase (PP) inhibitor and induces
      hyperphosphorylation of p53. We investigated whether the inhibition of PP1 by OA
      promotes the phosphorylation of the serine 15 of p53. In vitro dephosphorylation
      assay showed that PP1 dephosphorylated ultraviolet C (UVC)-induced phospho-ser15
      of p53, and that OA treatment inhibited it. One of the PP1 regulators, growth
      arrest and DNA damage 34 (GADD34), disturbed PP1 binding with p53, interfered
      with the dephosphorylation of p53 and increased the amount of phospho-p53 after
      UVC-treatment. This report provides the first evidence that PP1, but not PP2A,
      dephosphorylates phospho-serine 15 of p53.

PMID- 15178318
TI  - A carotenoid-binding protein (CBP) plays a crucial role in cocoon pigmentation of
      silkworm (Bombyx mori) larvae.
AB  - We examined the role of carotenoid-binding protein (CBP) in yellow cocoon
      pigmentation. First, using yellow or white cocoon races, we investigated the
      linkage between the yellow pigmentation and CBP expression. CBP was expressed
      only in the silk gland of the yellow cocoon races, which utilize carotenoids for
      cocoon pigmentation. Furthermore, CBP expression in the silk glands of day 1-7
      fifth instar larvae matched the period of carotenoid uptake into the silk gland.
      Finally, we gave double-stranded CBP RNA to Bombyx mori (B. mori) larvae to
      induce RNA interference. The significantly reduced expression of CBP in the silk
      gland of fifth instar larva was confirmed on day 4 and a decrease in yellow
      pigmentation was observed in the cocoon. We showed that CBP plays a key role in
      the yellow cocoon pigmentation caused by carotenoids.

PMID- 15178319
TI  - A protein carboxylate coordinated oxo-centered tri-nuclear iron complex with
      possible implications for ferritin mineralization.
AB  - The crystal structure of an oxo-centered tri-nuclear iron complex formed on a
      protein surface is presented. The cluster forms when crystals of the class Ib
      ribonucleotide reductase R2 protein from Corynebacterium ammoniagenes are
      subjected to iron soaking. The tri-iron-oxo complex is coordinated by protein
      derived carboxylate ligands arranged in a motif similar to the one found on the
      inner surface of ferritins and may mimic an early stage in the mineralization of
      iron in ferritins. In addition, the structure adds to the very limited data on
      protein-mineral interfaces.

PMID- 15178320
TI  - Expression and biochemical analysis of the entire HIV-2 gp41 ectodomain:
      determinants of stability map to N- and C-terminal sequences outside the 6-helix
      bundle core.
AB  - The folding of HIV gp41 into a 6-helix bundle drives virus-cell membrane fusion.
      To examine the structural relationship between the 6-helix bundle core domain and
      other regions of gp41, we expressed in Escherichia coli, the entire ectodomain of
      HIV-2(ST) gp41 as a soluble, trimeric maltose-binding protein (MBP)/gp41 chimera.
      Limiting proteolysis indicated that the Cys-591-Cys-597 disulfide-bonded region
      is outside a core domain comprising two peptides, Thr-529-Trp-589 and Val-604-Ser
      666. A biochemical examination of MBP/gp41 chimeras encompassing these core
      peptides indicated that the N-terminal polar segment, 521-528, and C-terminal
      membrane-proximal segment, 658-666, cooperate in stabilizing the ectodomain. A
      functional interaction between sequences outside the gp41 core may contribute
      energy to membrane fusion.

PMID- 15178321
TI  - Oxidation of thioredoxin reductase in HeLa cells stimulated with tumor necrosis
      factor-alpha.
AB  - Stimulation of cells with tumor necrosis factor-alpha (TNF-alpha) results in the
      increase in generation of H(2)O(2) in mitochondria that leads to apoptosis. The
      effect of H(2)O(2) produced by TNF-alpha on the redox status of selenocysteine
      (SeCys) residue essential for mitochondrial thioredoxin reductase (TrxR2) was
      investigated in HeLa cells. TNF-alpha caused accumulation of oxidized TrxR2 with
      a thioselenide bond. The conditional induction of SeCys-deficient TrxR2 resulted
      in the increased production of H(2)O(2) and apoptosis. These results suggest that
      the SeCys residue of TrxR2 plays a critical role in cell survival by serving as
      an electron donor for Trx-II and subsequent peroxiredoxin-III, which is a primary
      line of defense against H(2)O(2) in mitochondria.

PMID- 15178322
TI  - Molecular cloning and characterization of a glucosyltransferase catalyzing
      glucosylation of curcumin in cultured Catharanthus roseus cells.
AB  - Catharanthus roseus cell suspension cultures are capable of converting
      exogenously supplied curcumin to various glucosides. The glucosylation efficiency
      is enhanced by addition of methyl jasmonate (MJ) to the cultures prior to
      curcumin administration. Two cDNAs encoding UDP-glucosyltransferases (CaUGT1 and
      CaUGT2) were isolated from a cDNA library of cultured C. roseus cells, using a
      PCR method directed at the conserved UDP-binding domain of plant
      glycosyltransferases. The sequence identity between their deduced amino acid
      sequences was 27%. The expression of both genes was up-regulated by addition of
      MJ to the cell cultures although the mRNA level of CaUGT1 was much lower than
      that of CaUGT2. The corresponding cDNAs were expressed in Escherichia coli as
      fusion proteins with maltose-binding protein. The recombinant CaUGT1 exhibited no
      glucosylation activity with either curcumin or curcumin monoglucoside as
      substrate, whereas the recombinant CaUGT2 catalyzed the formation of curcumin
      monoglucoside from curcumin and also conversion of curcumin monoglucoside to
      curcumin diglucoside. The use of the recombinant CaUGT2 may provide a useful new
      route for the production of curcumin glucosides.

PMID- 15178323
TI  - Inhibition of motility and invasiveness of renal cell carcinoma induced by short
      interfering RNA transfection of beta 1,4GalNAc transferase.
AB  - Human renal cell carcinoma (RCC) has been characterized by remarkable changes in
      ganglioside composition. TOS1 cells, typical of metastatic RCC, are characterized
      by predominance of GM2 as monosialoganglioside, and beta 1,4GalNAc disialyl-Lc(4)
      (RM2 antigen) as disialoganglioside [J. Biol. Chem. 276 (2001) 16695]. In order
      to observe the functional role of gangliosides in RCC malignancy, TOS1 cells were
      transfected with short interfering RNA (siRNA) based on open reading frame
      sequence of beta 1,4GalNAc transferase (beta 1,4GalNAc-T), and its disordered
      sequence of siRNA (dsiRNA) as control. In siRNA transfectant, beta 1,4GalNAc-T
      mRNA level and GM2 expression were greatly reduced, whereby GM3 expression
      appeared. In contrast, RM2 antigen level was unchanged, even though it has the
      same beta 1,4GalNAc epitope at the terminus. dsiRNA transfectant showed no change
      of beta 1,4GalNAc-T mRNA and did not express GM3. Concomitant with reduction of
      GM2 and appearance of GM3, siRNA transfectant showed greatly reduced motility and
      invasiveness, although growth rate was unaltered. Both transfectants with siRNA
      and dsiRNA expressed the same level of tetraspanin CD9. Since CD9/GM3 complex is
      known to reduce integrin-dependent motility and invasiveness [Biochemistry 40
      (2001) 6414], it is plausible that motility and invasiveness of siRNA
      transfectant of TOS1 cells may be reduced by enhanced formation of such complex.

PMID- 15178324
TI  - Exocytic pathway-independent plasma membrane targeting of heterotrimeric G
      proteins.
AB  - Heterotrimeric G proteins are lipid-modified, peripheral membrane proteins that
      function at the inner surface of the plasma membrane (PM) to relay signals from
      cell-surface receptors to downstream effectors. Cellular trafficking pathways
      that direct nascent G proteins to the PM are poorly defined. In this report, we
      test the proposal that G proteins utilize the classical exocytic pathway for PM
      targeting. PM localization of the G protein heterotrimers alpha s beta 1 gamma 2
      and alpha q beta 1 gamma 2 occurred independently of treatment of cells with
      Brefeldin A, which disrupts the Golgi, or expression of Sar1 mutants, which
      prevent the formation of endoplasmic reticulum to Golgi transport vesicles.
      Moreover, the palmitoylation of alpha q was unaffected by Brefeldin A treatment,
      even though the palmitoylation of SNAP25 was blocked by Brefeldin A. Non
      palmitoylated mutants of alpha s and alpha q failed to stably bind to beta gamma
      and displayed a dispersed cytoplasmic localization when co-expressed with beta
      gamma. These findings support a refined model of the PM trafficking pathway of G
      proteins, involving assembly of the heterotrimer at the endoplasmic reticulum and
      transport to the PM independently of the Golgi.

PMID- 15178325
TI  - The large subunit determines catalytic specificity of barley sucrose:fructan 6
      fructosyltransferase and fescue sucrose:sucrose 1-fructosyltransferase.
AB  - Plant fructosyltransferases are highly homologous in primary sequence and
      typically consist of two subunits but catalyze widely different reactions. Using
      functional expression in the yeast Pichia pastoris, we show that the substrate
      specificity of festuca sucrose:sucrose 1--beta-D-fructosyltransferase (1-SST) and
      barley sucrose:fructan 6--beta-D-fructosyltransferase (6-SFT) is entirely
      determined by the large subunit. Chimeric enzymes with the large subunit of
      festuca 1-SST (LSuB) and the small subunit of barley 6-SFT have the same
      catalytic specificity as the native festuca 1-SST and vice versa. If the LSuB is
      expressed alone, it does not yield a functionally active enzyme, indicating that
      the small subunit is nevertheless essential.

PMID- 15178326
TI  - Overexpression of wild-type and mutant mucolipin proteins in mammalian cells:
      effects on the late endocytic compartment organization.
AB  - Mucolipin-1 is a 65-kDa membrane protein encoded by the MCOLN1 gene, which is
      mutated in patients with mucolipidosis type IV (MLIV), a rare neurodegenerative
      lysosomal storage disorder. We studied the subcellular localization of wild-type
      and three different mutant forms (T232P, F408del and F465L) of mucolipin by
      expressing Myc-tagged proteins in HeLa cells. The overexpressed wild-type
      mucolipin colocalizes to late endocytic structures and induces an aberrant
      distribution of these compartments. F408del and F465L MLIV mutant proteins show a
      distribution similar to the wild-type protein, whereas T232P is retained in the
      endoplasmic reticulum. Among the mutants, only F408del induces a redistribution
      of the late endocytic compartment. These findings suggest that the overexpression
      of the mucolipin cation channel influences the dynamic equilibrium of late
      endocytic compartments.

PMID- 15178327
TI  - Chromatin from two classes of platyhelminthes display both protist H1 and higher
      eukaryote core histones.
AB  - Histones from the parasitic platyhelminthes, Echinococcus granulosus and Fasciola
      hepatica, were systematically characterized. Core histones H2A, H2B, H3 and H4,
      which were identified on the basis of amino acid sequencing and mass spectrometry
      data, showed conserved electrophoretic patterns. Histones H1, identified on the
      basis of physicochemical properties, amino acid composition and amino acid
      sequencing, showed divergence, both in their number and electrophoretic
      mobilities, between the two species and among other organisms. According to these
      data, core histones but not H1 histones, would be stabilized during evolution at
      the level of platyhelminthes.

PMID- 15178328
TI  - Rac1 and PAK1 are upstream of IKK-epsilon and TBK-1 in the viral activation of
      interferon regulatory factor-3.
AB  - The anti-viral type I interferon (IFN) response is initiated by the immediate
      induction of IFN beta, which is mainly controlled by the IFN-regulatory factor-3
      (IRF-3). The signaling pathways mediating viral IRF-3 activation are only poorly
      defined. We show that the Rho GTPase Rac1 is activated upon virus infection and
      controls IRF-3 phosphorylation and activity. Inhibition of Rac1 leads to reduced
      IFN beta promoter activity and to enhanced virus production. As a downstream
      mediator of Rac signaling towards IRF-3, we have identified the kinase p21
      activated kinase (PAK1). Furthermore, both Rac1 and PAK1 regulate the recently
      described IRF-3 activators, I kappa B kinase- and TANK-binding kinase-1,
      establishing a first canonical virus-induced IRF-3 activating pathway.

PMID- 15178329
TI  - Functionally and structurally relevant residues of enzymes: are they segregated
      or overlapping?
AB  - There is a delicate balance between stability and flexibility needed for enzyme
      function. To avoid undesirable alteration of the functional properties during the
      evolutionary optimization of the structural stability under certain
      circumstances, and vice versa, to avoid unwanted changes of stability during the
      optimization of the functional properties of proteins, common sense would suggest
      that parts of the protein structure responsible for stability and parts
      responsible for function developed and evolved separately. This study shows that
      nature did not follow this anthropomorphic logic: the set of residues involved in
      function and those involved in structural stabilization of enzymes are rather
      overlapping than segregated.

PMID- 15178330
TI  - Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1
      in breast cancer cells.
AB  - Recent studies have shown that p21-activated kinase 1 (Pak1) phosphorylates
      estrogen receptor-alpha (ER alpha) at Ser 305 and also promotes its
      transactivation function. Here, we sought to investigate whether substitution of
      serine 305 in ER with glutamic acid (ER alpha-S305E), which mimics the
      phosphorylation state, would influence the status of ER-target genes. To explore
      this possibility, we generated clones overexpressing ER alpha-S305E in ER
      negative MDA-MB-231 cells and analyzed the status of ER-regulated genes using a
      gene array. Results indicated that the expression of ER alpha-S305E is sufficient
      to upregulate the expression of a few but not all ER-regulated genes, i.e.,
      cyclin D1 and zinc finger protein 147 (estrogen-responsive finger protein), while
      there was no significant change in the expression of remaining genes on the
      array. In addition, we found an increased expression as well as nuclear
      accumulation of cyclin D1 protein in MDA-MB-231 cells expressing ER alpha-S305E
      as compared to the level of cyclin D1 in MDA-MB-231 cells expressing WT-ER alpha
      or pcDNA. Furthermore, ER alpha-S305E, but not mutation of ER alpha-S305 to
      alanine, enhanced the cyclin D1 promoter activity. These findings suggest that ER
      alpha activation at S305 is sufficient to upregulate the expression of cyclin D1,
      an ER-regulated gene that is implicated in the progression of breast cancer.
      Phosphorylation of ER alpha by Pak1 or its upstream regulators could upregulate
      the expression of a subset of ER-target genes in a ligand-independent manner and
      hence, might contribute toward the development of hormone independence in breast
      cancer cells.

PMID- 15178331
TI  - Suppression of the caspase cleavage of beta-amyloid precursor protein by its
      cytoplasmic phosphorylation.
AB  - beta-Amyloid precursor protein (APP) is a type I transmembrane protein. Its
      cleavages by beta- and gamma-secretases yield beta-amyloid, which is the main
      constituent of senile plaques in Alzheimer's disease (AD). In apoptotic cells and
      AD brains, APP is alternatively cleaved by caspases in the cytoplasmic region
      after the Asp664 residue (with respect to the numbering conversion for the APP695
      isoform). Caspase-cleaved fragments of APP are cytotoxic and have been implicated
      in AD pathogenesis; however, the mechanisms regulating the cleavage have not been
      studied. APP is constitutively phosphorylated at Thr668 in brain. In the present
      study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to
      cytoplasmic cleavage by caspase-3 and caspase-8. This suggests that APP
      phosphorylation suppresses the generation of caspase-cleaved fragments of APP in
      the brain and that perturbation of this phosphorylation may be involved in APP
      mediated neurotoxicity.

PMID- 15178332
TI  - Direct fluorometric measurement of hepatitis C virus helicase activity.
AB  - The non-structural protein 3 (NS3) of hepatitis C virus (HCV) is a highly
      promising target for anti-HCV therapy because of its multiple enzymatic
      activities, such as RNA-stimulated nucleoside triphosphatase, RNA helicase and
      serine protease. The helicase domain of NS3 as well as domain 2 of the helicase
      were expressed in a baculovirus system to obtain in high yield active proteins
      for prospective studies of complexes of the helicase with its inhibitors. A novel
      direct fluorometric test of helicase activity with a quenched DNA substrate, 3'
      labeled with a Cy3 dye and 5' labeled with a Black Hole Quencher, was developed
      and optimal reaction conditions established. This test based on fluorescence
      resonance energy transfer is simple and fast. It allows for direct measurements
      of enzyme activity, circumventing laborious and complicated radioactive
      techniques that are poorly reproducible. The results obtained encourage us to
      propose this new fluorescent assay as a method enabling high throughput screening
      of anti-helicase compounds.

PMID- 15178333
TI  - Regulatory mechanisms controlling biogenesis of ubiquitin and the proteasome.
AB  - Analysis of several Saccharomyces cerevisiae ump mutants with defects in
      ubiquitin (Ub)-mediated proteolysis yielded insights into the regulation of the
      polyubiquitin gene UBI4 and of proteasome genes. High-molecular weight Ub-protein
      conjugates accumulated in ump mutants with impaired proteasome function with a
      concomitant decrease in the amount of free Ub. In these mutants, transcriptional
      induction of UBI4 was depending in part on the transcription factor Rpn4.
      Deletion of UBI4 partially suppressed the growth defects of ump1 mutants,
      indicating that accumulation of polyubiquitylated proteins is deleterious to cell
      growth. Transcription of proteasome subunit genes was induced in ump mutants
      affecting the proteasome, as well as under conditions that mediate DNA damage or
      the formation of abnormal proteins. This induction required the transcriptional
      activator Rpn4. Elevated Rpn4 levels in proteasome-deficient mutants or as a
      response to abnormal proteins were due to increased metabolic stability. Up
      regulation of proteasome genes in response to DNA damage, in contrast, is shown
      to operate via induction of RPN4 transcription.

PMID- 15178334
TI  - NMR solution structure and position of transportan in neutral phospholipid
      bicelles.
AB  - Transportan is a chimeric cell-penetrating peptide constructed from the peptides
      galanin and mastoparan, which has the ability to internalize living cells
      carrying a hydrophilic load. In this study, we have determined the NMR solution
      structure and investigated the position of transportan in neutral bicelles. The
      structure revealed a well-defined alpha-helix in the C-terminal mastoparan part
      of the peptide and a weaker tendency to form an alpha-helix in the N-terminal
      domain. The position of the peptide in relation to the membrane, as studied by
      adding paramagnetic probes, shows that the peptide lies parallel to, and in the
      head-group region of the membrane surface. This result is supported by amide
      proton secondary chemical shifts.

PMID- 15178335
TI  - Kinetic study of the H103A mutant yeast transketolase.
AB  - Data from site-directed mutagenesis and X-ray crystallography show that His103 of
      holotransketolase (holoTK) does not come into contact with thiamin diphosphate
      (ThDP) but stabilizes the transketolase (TK) reaction intermediate, alpha,beta
      dihydroxyethyl-thiamin diphosphate, by forming a hydrogen bond with the oxygen of
      its beta-hydroxyethyl group [Eur. J. Biochem. 233 (1995) 750; Proc. Natl. Acad.
      Sci. USA 99 (2002) 591]. We studied the influence of His103 mutation on ThDP
      binding and enzymatic activity. It was found that mutation does not affect the
      affinity of the coenzyme to apotransketolase (apoTK) in the presence of Ca(2+) (a
      cation found in the native holoenzyme) but changes all the kinetic parameters of
      the ThDP-apoTK interaction in the presence of Mg(2+) (a cation commonly used in
      ThDP-dependent enzymes studies). It was concluded that the structures of TK
      active centers formed in the presence of Mg(2+) and Ca(2+) are not identical.
      Mutation of His103 led to a significant acceleration of the one-substrate
      reaction but a slow down of the two-substrate reaction so that the rates of both
      types of catalysis became equal. Our results provide evidence for the
      intermediate-stabilizing function of His103.

PMID- 15178336
TI  - Poorer NF-kappa B signaling by microfilariae in macrophages from BALB/c mice
      affects their ability to produce cytotoxic levels of nitric oxide to kill
      microfilariae.
AB  - Upon activation with microfilariae (mf), macrophages from C57Bl/6 mice showed
      higher nuclear factor-kappa B (NF-kappa B) but lower activating protein 1 DNA
      binding activity as compared to BALB/c macrophages. The C57Bl/6 macrophages
      produced cytotoxic levels of nitric oxide (NO) to kill Setaria cervi mf as
      compared to BALB/c macrophages. Inhibition of the NF-kappa B signal by
      pyrrolidine dithiocarbamate (PDTC) blocked NO production and microfilaricidal
      activity of C57Bl/6 macrophages and inclusion of the exogenous NO generator (SNP)
      in the PDTC treated C57Bl/6 macrophage cultures induced mf cytotoxicity. These
      results underscore that the NF-kappa B signal (induced in response to mf) is
      important for the NO-mediated microfilaricidal activity of macrophages.

PMID- 15178337
TI  - Replicative senescence enhances apoptosis induced by pemphigus autoimmune
      antibodies in human keratinocytes.
AB  - We have recently shown that skin lesions of the autoimmune disease pemphigus
      vulgaris are associated with Fas-mediated apoptosis. Here, we describe the
      induction of the Fas-dependent apoptosis pathway in cultured keratinocytes by
      pemphigus vulgaris autoantibodies (PV-IgG), as seen from a variety of cellular,
      morphological and biochemical parameters. All apoptotic characters appear
      stronger and faster in aged cultures than in young, showing increased
      susceptibility of senescent keratinocytes to PV-IgG-mediated apoptotic death and
      culture lesions. Together with immunosenescence, this phenomenon may explain the
      late onset of pemphigus disease.

PMID- 15178338
TI  - Isolation and characterization of anti-HIV peptides from Dorstenia contrajerva
      and Treculia obovoidea.
AB  - Using a high throughput screen based on the interaction of the HIV-1 gp41
      ectodomain with the virucidal protein cyanovirin-N (CV-N), we isolated two new
      peptides which inhibited the binding of CV-N to gp41 and which subsequently
      showed anti-HIV activity in a whole cell assay. A 5-kDa (contrajervin) and 10 kDa
      (treculavirin) peptide were isolated from Dorstenia contrajerva and Treculia
      obovoidea, respectively. Treculavirin was composed of two subunits, each
      containing 50 amino acid residues, which are covalently linked by at least one
      disulfide bond between the subunits. Both peptides were shown to bind to gp41 and
      gp120 and to inhibit the cytopathic effects of HIV-1(RF) infection in a human T
      lymphoblastoid cell line (CEM-SS).

PMID- 15178339
TI  - Inhibition of the gamma interferon response by a Sendai virus C protein mutant
      with no STAT1-binding ability.
AB  - Sendai virus C protein interacts with the signal transducer and activator of
      transcription (STAT) 1. This interaction is believed to be essential for the
      Sendai virus inhibition of the interferon (IFN) response. We here analyzed
      C(F170S) (a C protein mutant with the F170S mutation) with no STAT1-binding
      ability. C(F170S) lacked the ability to inhibit the IFN-alpha response, but
      retained the ability to inhibit the IFN-gamma response. IFN-gamma stimulation
      caused STAT1 phosphorylation, formation of the gamma-activated factor capable of
      binding to a gamma-activated sequence DNA probe, and STAT1 nuclear translocation,
      even in the presence of C(F170S). These results suggest that C protein has the
      STAT1-binding-independent anti-IFN-gamma mechanism, which targets processes after
      the STAT1 nuclear translocation event.

PMID- 15178340
TI  - BOF: a novel family of bacterial OB-fold proteins.
AB  - Using top-of-the-line fold recognition methods, we assigned an
      oligonucleotide/oligosaccharide-binding (OB)-fold structure to a family of
      previously uncharacterized hypothetical proteins from several bacterial genomes.
      This novel family of bacterial OB-fold (BOF) proteins present in a number of
      pathogenic strains encompasses sequences of unknown function from DUF388 (in Pfam
      database) and COG3111. The BOF proteins can be linked evolutionarily to other
      members of the OB-fold nucleic acid-binding superfamily (anticodon-binding and
      single strand DNA-binding domains), although they probably lack nucleic acid
      binding properties as implied by the analysis of the potential binding site. The
      presence of conserved N-terminal predicted signal peptide indicates that BOF
      family members localize in the periplasm where they may function to bind
      proteins, small molecules, or other typical OB-fold ligands. As hypothesized for
      the distantly related OB-fold containing bacterial enterotoxins, the loss of
      nucleotide-binding function and the rapid evolution of the BOF ligand-binding
      site may be associated with the presence of BOF proteins in mobile genetic
      elements and their potential role in bacterial pathogenicity.

PMID- 15178341
TI  - Arabidopsis homologues of the autophagy protein Atg8 are a novel family of
      microtubule binding proteins.
AB  - Autophagy is the non-selective transport of proteins and superfluous organelles
      destined for degradation to the vacuole in fungae, or the lysosome in animal
      cells. Some of the genes encoding components of the autophagy pathway are
      conserved in plants, and here we show that Arabidopsis homologues of yeast Atg8
      (Apg8/Aut7) and Atg4 (Apg4/Aut2) partially complement the yeast deletion strains.
      The yeast double mutant, a deletion strain with respect to both Atg8 and Atg4,
      could not be complemented by Arabidopsis Atg8, indicating that Arabidopsis Atg8
      requires Atg4 for its function. Moreover, Arabidopsis Atg8 and Arabidopsis Atg4
      interact directly in a two-hybrid assay. Interestingly, Atg8 shows significant
      homology with the microtubule binding light chain 3 of MAP1A and B, and here we
      show that Arabidopsis Atg8 binds microtubules. Our results demonstrate that a
      principle component of the autophagic pathway in plants is similar to that in
      yeast and we suggest that microtubule binding plays a role in this process.

PMID- 15178342
TI  - Kinetic evidence related to substrate-assisted catalysis of family 18 chitinases.
AB  - The hydrolytic reaction of family 18 chitinase has been considered to occur via
      substrate assisted catalysis. To kinetically investigate the enzyme reaction
      mechanism, we synthesized compounds designed to reduce the polarization of the
      carbonyl in N-acetyl group, GlcNAc-GlcN(TFA)-UMB (2) and GlcNAc-GlcN(TAc)-UMB
      (3). Kinetic parameters in the hydrolysis of these compounds by chitinase A from
      Serratia marcescens (ChiA) were compared with those from the hydrolysis of
      (GlcNAc)2-UMB (1). The kcat of 2 was 3.4% of 1, but the Km of 2 was 10-fold that
      of 1. In contrast, the kcat of 3 was only 0.3% of that of 1, and the two
      reactions had an identical Km. The drastic decreases in kcat were probably due to
      the weak nucleophilic activity of the C2-N-trifluoroacetamide and N-thioacetamide
      groups at reducing ends of compounds 2 and 3, respectively. These results
      indicate that the anchimeric assistance of the C2 N-acetamide group at GlcNAc
      plays a key role in the hydrolytic reactions catalyzed by family 18 chitinases.

PMID- 15178344
TI  - Insights into the specificity of RNA cleavage by the Escherichia coli MazF toxin.
AB  - The mazEF (chpA) toxin-antitoxin system of Escherichia coli is involved in the
      cell response to nutritional and antibiotic stresses as well as in bacterial
      programmed cell death. Valuable information on the MazF toxin was derived from
      the determination of the crystal structure of the MazE/MazF complex and from in
      vivo data, suggesting that MazF promoted ribosome-dependent cleavage of messenger
      RNA. However, it was concluded from recent in vitro analyses using a MazF-(His6)
      fusion protein that MazF was an endoribonuclease that cleaved messenger RNA
      specifically at 5'-ACA-3' sites situated in single-stranded regions. In contrast,
      our work reported here shows that native MazF protein cleaves RNA at the 5' side
      of residue A in 5'-NAC-3' sequences (where N is preferentially U or A). MazF
      dependent cleavage occurred at target sequences situated either in single- or
      double-stranded RNA regions. These activities were neutralized by a His6-MazE
      antitoxin. Although essentially consistent with previous in vivo reports on the
      substrate specificity of MazF, our results strongly suggest that the
      endoribonuclease activity of MazF may be modulated by additional factors to
      cleave messenger and other cellular RNAs.

PMID- 15178343
TI  - Hypoxia-dependent regulation of PHD1: cloning and characterization of the human
      PHD1/EGLN2 gene promoter.
AB  - The recent identification of hypoxia-inducible-factor (HIF) prolyl hydroxylases
      (PHD1, 2, and 3), which modify HIF-1 alpha in an oxygen-dependent manner,
      provided an important link between oxygen availability and hypoxia-induced gene
      expression. However, little is known about the regulation of the PHDs. To
      investigate the transcriptional regulation of PHD1, we cloned the PHD1 gene
      promoter. Here, we report that the expression of PHD1 is reduced under hypoxic
      conditions. Furthermore, we identified binding sites for aryl hydrocarbon nuclear
      translocator (ARNT/HIF-1 beta) within the PHD1 promoter, and showed that ARNT is
      associated in vivo with the PHD1 promoter following hypoxia, which implies a role
      for ARNT in the hypoxia-dependent regulation of PHD1. Taken together, our
      findings suggest a hypoxia-induced regulatory loop of PHD1 expression, mediated
      by ARNT.

PMID- 15178345
TI  - RACK1 inhibits the serum- and anchorage-independent growth of v-Src transformed
      cells.
AB  - Cancer cells are capable of serum- and anchorage-independent growth, and focus
      formation on monolayers of normal cells. Previously, we showed that RACK1
      inhibits c-Src kinase activity and NIH3T3 cell growth. Here, we show that RACK1
      partially inhibits v-Src kinase activity, and the serum- and anchorage
      independent growth of v-Src transformed cells, but has no effect on focus
      formation. RACK1-overexpressing v-Src cells show disassembly of podosomes, which
      are actin-rich structures that are distinctive to fully transformed cells.
      Together, our results demonstrate that RACK1 overexpression in v-Src cells
      partially reverses the transformed phenotype of the cells. Our results identify
      an endogenous inhibitor of the oncogenic Src tyrosine kinase and of cell
      transformation.

PMID- 15178346
TI  - Progesterone receptor gene inactivation and CpG island hypermethylation in human
      leukemia cancer cells.
AB  - Previous studies showed that progesterone receptor (PR), one of the hormone
      receptor superfamily, was only connected with the sex-correlated cancers such as
      breast cancer, endometrial cancer, prostate cancer, etc. This article deals with
      the PR gene in leukemia. We investigated the methylation status and the
      expression of the two different PR isoforms, PRA and PRB, in three leukemia
      cancer cell lines using methylation-specific polymerase chain reaction (MSP-PCR)
      and reverse transcription-PCR. The correlation of PR methylation and expression
      together with DNA methyltransferase (DNMT1) was further studied. We found that
      DNMT1 is required to maintain CpG methylation and aberrant gene silencing of PR
      gene in human leukemia cancer cells. The activity of 5-aza-2'-deoxycytidine in
      demethylation and gene reactivation may be through depleting cellular DNMT1
      levels. In addition, extensive methylation of PRA and PRB was also observed in
      leukemia samples. Our results suggest that PR CpG island aberrant
      hypermethylation could be one molecular and genetic alteration in leukemia.

PMID- 15178347
TI  - Is an intermediate state populated on the folding pathway of ubiquitin?
AB  - In the last couple of years, there has been increasing debate as to the presence
      and role of intermediate states on the folding pathways of several small
      proteins, including the 76-residue protein ubiquitin. Here, we present detailed
      kinetic studies to establish whether an intermediate state is ever populated
      during the folding of this protein. We show that the differences observed in
      previous studies are attributable to the transient aggregation of the protein
      during folding. Using a highly soluble construct of ubiquitin, which does not
      aggregate during folding, we establish the conditions in which an intermediate
      state is sufficiently stable to be observed by kinetic measurements.

PMID- 15178348
TI  - Voltage-gated sodium channel expressed in cultured human smooth muscle cells:
      involvement of SCN9A.
AB  - Voltage-gated Na(+) channel (I(Na)) is expressed under culture conditions in
      human smooth muscle cells (hSMCs) such as coronary myocytes. The aim of this
      study is to clarify the physiological, pharmacological and molecular
      characteristics of I(Na) expressed in cultured hSMCs obtained from bronchus, main
      pulmonary and coronary artery. I(Na), was recorded in these hSMCs and inhibited
      by tetrodotoxin (TTX) with an IC(50) value of approximately 10 nM. Reverse
      transcriptase/polymerase chain reaction (RT-PCR) analysis of mRNA showed the
      prominent expression of transcripts for SCN9A, which was consistent with the
      results of real-time quantitative RT-PCR. These results provide novel evidence
      that TTX-sensitive Na(+) channel expressed in cultured hSMCs is mainly composed
      of Na(v)1.7.

PMID- 15178349
TI  - Characterization of radioligand binding to a transmembrane receptor reconstituted
      into Lipobeads.
AB  - Lipobeads are hydrogel beads surrounded by a lipid bilayer membrane and have been
      developed to act as a cell analogue. The FLAG-tagged M(2) muscarinic receptor was
      incorporated onto the surface of the Lipobead by incubating pre-Lipobeads with
      proteoliposomes containing the receptor. Receptors reconstituted onto the surface
      of the Lipobeads were functional in that they bound the antagonists
      quinuclidinylbenzilate and scopolamine with characteristic muscarinic affinities.
      This demonstrates the feasibility of using Lipobeads to study the binding
      properties of the M(2) muscarinic receptor and offers a promising approach to the
      study of transmembrane protein biology in general.

PMID- 15178350
TI  - Cytotoxic and pro-apoptotic activities of cynaropicrin, a sesquiterpene lactone,
      on the viability of leukocyte cancer cell lines.
AB  - Cynaropicrin, a sesquiterpene lactone from Saussurea lappa, has been reported to
      possess immunomodulatory effects on cytokine release, nitric oxide production and
      immunosuppressive effects. In this study, we have examined cytotoxic effect of
      cynaropicrin against several types of cell lines such as macrophages,
      eosinophils, fibroblasts and lymphocytes. Cynaropicrin potently inhibited the
      proliferation of leukocyte cancer cell lines, such as U937, Eol-1 and Jurkat T
      cells, but some other cells such as Chang liver cells and human fibroblast cell
      lines were not strongly suppressed by cynaropicrin treatment. The cytotoxic
      effect of cynaropicrin was due to inducing apoptosis and cell cycle arrest at
      G1/S phase, according to flow-cytometric, DNA fragmentation and morphological
      analyses using U937 cells. Evidence that combination treatment with l-cysteine
      and N-acetyl-l-cysteine, reactive oxygen species scavengers, or rottlerin (1-[6
      [(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2, 2-dimethyl-2H
      1-benzopyran-8-yl]-3-phenyl-2-propen-1-one), a specific protein kinase (PK)
      Cdelta inhibitor, abolished cynaropicrin-mediated cytotoxicity and morphological
      change, and that cynaropicrin-induced proteolytic cleavage of PKCdelta suggests
      that reactive oxygen species and PKCdelta may play an important role in mediating
      pro-apoptotic activity by cynaropicrin. Taken together, these results indicate
      that cynaropicrin may be a potential anticancer agent against some leukocyte
      cancer cells such as lymphoma or leukemia, through pro-apoptotic activity.

PMID- 15178351
TI  - Amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA
      synthesis in breast cancer MCF-7 cells than is the parent drug.
AB  - A novel amidine analogue of chlorambucil-N-(2-(4-(4-bis(2
      chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2
      furancarboxamide hydrochloride (AB(1)) and the parent drug were compared for
      their effects on collagen and DNA biosynthesis in breast cancer MCF-7 cells.
      IC(50) values for chlorambucil and AB(1) for collagen biosynthesis were found to
      be about 33 and 13 microM, respectively. The greater potency of AB(1) to suppress
      collagen synthesis was found to be accompanied by a stronger compared with
      chlorambucil inhibition of prolidase activity and expression. The phenomenon was
      related to inhibition of beta(1)-integrin and IGF-I receptor-mediated signaling
      caused by this compound. The expression of beta(1)-integrin receptor, as well as
      Src, son of sevenless protein (SOS) and phosphorylated mitogen activated protein
      (MAP) kinases (MAPK), extracellular-signal-regulated kinase 1 (ERK(1)) and kinase
      2 (ERK(2)) but not focal adhesion kinase pp125(FAK) (FAK), Shc, and Grb-2 was
      significantly decreased in cells incubated for 24 h with 10 microM AB(1) compared
      to the control, whereas in the same conditions chlorambucil did not evoke any
      changes in expression of all these signaling proteins, as shown by Western
      immunoblot analysis. Furthermore, AB(1) induced a stronger down-regulation of the
      expression of IGF-I receptor and evoked a higher antiproliferative effect. During
      12 and 24 h of incubation AB(1) decreased DNA biosynthesis by about 33 % and 51 %
      of the control, whereas chlorambucil decreased it by about 19 % and 35 %,
      respectively. These data suggest that the amidine analogue of chlorambucil is a
      stronger inhibitor of protein and DNA synthesis in MCF-7 cells than is the parent
      drug.

PMID- 15178352
TI  - Antitumor effects of amlodipine, a Ca2+ channel blocker, on human epidermoid
      carcinoma A431 cells in vitro and in vivo.
AB  - Amlodipine, a dihydropyridine Ca(2+) channel blocker, is reported to inhibit
      proliferation of human epidermoid carcinoma A431 cells, and specifically
      attenuates Ca(2+) responses evoked by thapsigargin, an inhibitor of endoplasmic
      reticulum Ca(2+)-ATPases. In this study, we further examined the possible
      mechanism of the antiproliferative action of amlodipine and its antitumor effect
      on A431 xenografts in nude mice. Amlodipine reduced BrdU incorporation into
      nucleic acids in serum-starved A431 cells, and the reduction was diminished by
      uridine 5'-triphosphate (UTP), a phospholipase C (PLC)-linked agonist.
      Fluorometric measurement of intracellular free Ca(2+) concentration revealed that
      amlodipine blunted the UTP-induced Ca(2+) release from the internal Ca(2+) stores
      and consequently Ca(2+) influx through Ca(2+)-permeable channels on the plasma
      membrane. Although amlodipine alone caused Ca(2+) release from thapsigargin
      sensitive Ca(2+) stores, such an effect was not reproduced by other
      dihydropyridine Ca(2+) channel blockers, including nicardipine and nimodipine,
      despite their antiproliferative effects in the cells. Daily intraperitoneal
      administration of amlodipine (10 mg/kg) for 20 days into mice bearing A431
      xenografts retarded tumor growth and prolonged the survival of mice. Our results
      suggest a potential antitumor action for amlodipine in vitro and in vivo, which
      may be in part mediated by inhibiting Ca(2+) influx evoked by the passive
      depletion of internal Ca(2+) stores and by PLC-linked agonist stimulation.

PMID- 15178353
TI  - Differential agonistic and antagonistic effects of the urotensin-II ligand SB
      710411 at rodent and primate UT receptors.
AB  - SB-710411 (Cpa-c[d-Cys-Pal-d-Trp-Lys-Val-Cys]-Cpa-amide) inhibited
      [(125)I]urotensin-II rat and monkey UT receptor binding (pK(i)s 7.50+/-0.07 and
      6.82+/-0.06). However, whereas SB-710411 antagonized urotensin-II-induced
      inositol phosphate formation at the rat UT receptor (pK(b) 6.54+/-0.05), this
      ligand functioned as an agonist at the monkey UT receptor (pEC(50) 6.56+/-0.35,
      E(max) 5.27+/-0.65-fold over basal). Indeed, in contrast to the rat UT receptor
      (and rat isolated arteries), SB-710411 exhibited intrinsic activity in monkey
      arteries acting as an efficacious vasoconstrictor (pEC(50)s 5.03+/-0.18 to 5.71+/
      0.21, E(max)s 101+/-4 to 218+/-58% KCl). These data demonstrate that caution must
      be taken when extrapolating the pharmacology of a specific ligand(s) between the
      rodent and primate UT receptors.

PMID- 15178354
TI  - Interaction of inducible nitric oxide synthase and cyclooxygenase-2 inhibitors in
      formalin-induced nociception in mice.
AB  - Studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2
      inhibitor were conducted to assess their synergistic antinociceptive effect and
      possible therapeutic advantage. The antinociceptive interaction of rofecoxib, a
      selective cyclooxygenase-2 inhibitor, with aminoguanidine hydrochloride, a
      selective iNOS inhibitor, was examined in the formalin-induced paw-licking model
      in mice. Analysis of variance (ANOVA) and the isobolographic method were used to
      identify the nature of the antinociceptive interaction. Different doses of
      rofecoxib (1, 3, 10 and 30 mg/kg) and aminoguanidine hydrochloride (10, 30, 100
      and 300 mg/kg) alone were administered orally to adult male albino mice (20-30
      g). Only high doses of rofecoxib (10 and 30 mg/kg) and aminoguanidine
      hydrochloride (100 and 300 mg/kg) showed a statistically significant
      antinociceptive effect. Combination of a subthreshold dose of rofecoxib (1 mg/kg)
      with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg)
      resulted in potentiated antinociception (P<0.05). Combined therapy with a
      subthreshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing
      doses of rofecoxib (1, 3, 10 and 30 mg/kg) also resulted in significant
      antinociception (P<0.05). These results suggest that rofecoxib and aminoguanidine
      hydrochloride act synergistically in their antinociceptive action in mice. A
      possible mechanism of interaction is that nitric oxide (NO) stimulates the
      activity of cyclooxygenase-2 by combining with its heme component. Furthermore,
      the present results suggest that combination therapy with rofecoxib and
      aminoguanidine hydrochloride may provide an alternative for the clinical control
      of pain.

PMID- 15178355
TI  - Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and
      dihydroheroin analgesia and their differentiation from morphine.
AB  - The present study examined the pharmacology of dihydromorphine, 6
      acetyldihydromorphine and dihydroheroin (3,6-diacetyldihydromorphine). Like
      morphine, dihydromorphine and its acetylated derivatives all were highly
      selective mu-opioids in receptor binding assays. All the compounds were potent mu
      selective analgesics, as shown by their sensitivity towards the mu-selective
      opioid receptor antagonists naloxonazine and beta-funaltrexamine. However, the
      actions of dihydromorphine and its analogs were readily distinguished from those
      of morphine, differences that were surprising in view of the very limited
      structural differences among them that consisted of only the reduction of the 7,8
      double bond. Like heroin and morphine-6beta-glucuronide, the analgesic actions of
      dihydromorphine and its two acetylated derivatives were antagonized by 3-O
      methylnaltrexone at a dose that was inactive against morphine analgesia.
      Antisense mapping also distinguished between morphine and the dihydromorphine
      compounds. Antisense oligodeoxynucleotides targeting exon 2 of the cloned MOR-1
      gene decreased dihydromorphine analgesia and that of its acetylated derivatives,
      but not morphine analgesia. Conversely, the exon 1 antisense that effectively
      lowered morphine analgesia was inactive against dihydromorphine and its analogs.
      Finally, dihydromorphine and its analogs retained their analgesic activity in a
      mouse model of morphine tolerance, consistent with incomplete cross-tolerance.
      Together, these findings imply that the mu-opioid receptor mechanisms mediating
      the analgesic actions of dihydromorphine and its acetylated analogs are distinct
      from morphine and more similar to those of heroin and morphine-6beta-glucuronide.

PMID- 15178356
TI  - No evidence for G-protein-coupled epsilon receptor in the brain of triple opioid
      receptor knockout mouse.
AB  - Pharmacological approaches have defined the epsilon receptor as a beta-endorphin
      preferring opioid receptor, described in rat vas deferens and in brain of several
      species. Only three opioid receptors-mu, delta and kappa-have been cloned and the
      existence of this additional subtype as a distinct protein remains controversial.
      Recently, the mouse brain epsilon receptor was detected in a G protein activation
      assay, as mediating residual beta-endorphin activity following pharmacological
      blockade of mu, delta and kappa receptors. To clarify whether this site is
      independent from mu, delta and kappa receptors, we performed beta-endorphin
      induced [(35)S]GTPgammaS binding using mice lacking these three receptors (triple
      knockout mice). We tested both pons-medulla and whole brain preparations. beta
      Endorphin strongly stimulated [(35)S]GTPgammaS binding in wild-type membranes but
      had no detectable effect in membranes from triple knockout mice. We conclude that
      the brain epsilon site involves mu, delta and/or kappa receptors, possibly
      coupled to nonclassical G proteins.

PMID- 15178357
TI  - Effects of mGlu1 and mGlu5 metabotropic glutamate antagonists to reverse morphine
      tolerance in mice.
AB  - Intracerebroventricular (i.c.v.) injection of phospholipase C inhibitors and
      structurally dissimilar PKC inhibitors were shown to completely reverse morphine
      antinociceptive tolerance in mice. Since Group I metabotropic glutamate receptors
      (mGlu(1) and mGlu(5)) activate phospholipase C through Galpha(q) Galpha(11)
      proteins, we hypothesized that morphine tolerance could occur through an increase
      in mGlu(1) and mGlu(5) receptor stimulation. Seventy-two hours after implantation
      of placebo or 75 mg morphine pellets, mice were tested in the 56 degrees C warm
      water tail-withdrawal test following i.c.v. injection of vehicle or test drug.
      The mGlu(1) receptor antagonist CPCCOEt (7-(Hydroxyimino)cyclopropa[b]chromen-1a
      carboxylate ethyl ester) partly but significantly reversed morphine tolerance.
      The mGlu(5) receptor antagonist MPEP (2-Methyl-6-(phenylethynyl)pyridine
      hydrochloride) also partly reversed the antinociceptive tolerance. Co
      administering CPCCOEt with MPEP completely reversed the tolerance. Furthermore,
      the mixed mGlu(1)/mGlu(5) antagonist AIDA ((RS)-1-Aminoindan-1,5-dicarboxylic
      acid) also completely reversed the tolerance. Thus, greater mGlu(1) and mGlu(5)
      receptor stimulation during morphine tolerance may lead to persistent activation
      of the phosphatidylinositol cascade.

PMID- 15178358
TI  - Apomorphine increases vesicular monoamine transporter-2 function: implications
      for neurodegeneration.
AB  - Apomorphine is a nonselective dopamine D1/D2 receptor agonist used in Europe to
      treat symptoms resulting from the dopaminergic degeneration associated with
      Parkinson's disease. In addition, neuroprotective effects of this agent in rodent
      models have been reported. Recent studies indicate that treatments that alter
      vesicular monoamine transporter-2 (VMAT-2) function may be protective in models
      of dopaminergic degeneration. Hence, the purpose of the present study was to
      examine the effect of apomorphine on VMAT-2 function. Results revealed that
      apomorphine rapidly and reversibly increased vesicular dopamine uptake, as
      determined in purified striatal vesicles obtained from treated rats. This
      increase occurred in both postnatal day 40 and postnatal day 90 rats, and was
      associated with a redistribution of VMAT-2 protein within nerve terminals. This
      effect of apomorphine on vesicular dopamine uptake was blocked by pretreating
      with eticlopride, a dopamine D2 receptor antagonist. The implications of these
      findings relevant to the treatment of neurodegeneration are discussed.

PMID- 15178359
TI  - PKC and PKA inhibitors reverse tolerance to morphine-induced hypothermia and
      supraspinal analgesia in mice.
AB  - Morphine antinociceptive tolerance in the tail-flick test is completely reversed
      by inhibitors of protein kinase C (PKC) or cAMP-dependent protein kinase (PKA).
      The effects of these inhibitors on tolerance to supraspinally mediated
      antinociception, such as the hot-plate test was unknown, as well as their effects
      in tests of mechanical nociception. The PKC inhibitors bisinolylmaleimide I ((2
      [1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) and Go
      7874 [2[1[(3-Dimethylaminopropyl)-5-methozyindol-3-yl]-3-(1H-indol-3-yl)
      hydrochloride] completely reversed the tolerance to morphine in both the hot
      plate and tail-pinch tests. Similarly, the PKA inhibitor KT-5720 (8R, 9S, 11S)-(
      )-9-hydroxy-9-hexoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H
      2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one also reversed tolerance in
      both tests. The role of PKC and PKA in mediating tolerance to morphine-induced
      hypothermia was also investigated. Bisinolylmaleimide I, Go-7874 and KT-5720 only
      partly reversed the 32-fold level of tolerance induced by the morphine pellets.
      However, co-administration of bisinolylmaleimide I with KT-5720 or Go-7874 with
      KT-5720 completely reversed the tolerance. This demonstrates that tolerance in a
      non-behavioral system involves the actions of PKC and PKA.

PMID- 15178360
TI  - Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self
      administration.
AB  - 18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self
      administration in animal models of addiction. Previously, we proposed that these
      effects are mediated by the ability of 18-methoxycoronaridine to inhibit
      nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more
      potent 18-methoxycoronaridine analogs, we have tested a series of 18
      methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293
      cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate
      NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range
      of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50)
      values similar to 18-methoxycoronaridine, and all of these were ineffective at
      NMDA receptors. The congeners also retained their ability to reduce morphine and
      methamphetamine self-administration. These data are consistent with the
      importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate
      drug seeking. These compounds may constitute a new class of synthetic agents that
      act via the nicotinic alpha3beta4 mechanism to combat addiction.

PMID- 15178361
TI  - Metabotropic glutamate receptor 5 and dorsal raphe serotonin release in
      inflammatory pain in rat.
AB  - In this study, we evaluated the effects of 2-methyl-6-(phenylethynyl)-pyridine
      (MPEP), a selective antagonist of metabotropic glutamate subtype 5 receptors
      (mGlu(5)), delivered through different paths on dorsal raphe serotonin (5-HT) and
      on thermoceptive responses in rats with inflammatory pain. Intraplantar formalin
      and carrageenan increased 5-HT (137+/-11% and 212+/-6% of pre-injection baseline,
      respectively) and reduced nociceptive threshold (23+/-7% and 19+/-3% of pre
      injection baseline, respectively). MPEP (2 mg/kg i.p.) further enhanced formalin
      and carrageenan-induced 5-HT increases (180+/-11% and 260+/-12% of pre-injection
      baseline, respectively) and reduced thermal hyperalgesia (71+/-8% and 80+/-10% of
      pre-injection baseline, respectively). MPEP (1 mM) through microdialytic probe
      into the dorsal raphe did not change formalin- or carrageenan-induced 5-HT
      increases (147+/-10% and 189+/-10% of pre-injection baseline, respectively) and
      thermal hyperalgesia (35+/-8% and 25+/-9% of pre-injection baseline,
      respectively). Finally, MPEP (30 nmol/rat) into the hind paw reduced the formalin
      and carrageenan-induced 5-HT increase (108+/-3% and 126+/-7% of pre-injection
      baseline, respectively) and thermal hyperalgesia (77+/-6% and 117+/-7% of pre
      injection baseline, respectively). Dorsal raphe serotonergic neurons activity
      increased following a peripherally induced inflammatory injury. In these
      conditions, peripheral but not dorsal raphe mGlu(5) receptors blockade prevented
      over activation of dorsal raphe serotonergic neurons and reversed thermal
      hyperalgesia.

PMID- 15178362
TI  - Effects of selective endothelin ET(A) receptor antagonists on endothelin-1
      induced potentiation of cancer pain.
AB  - In some diseases in which endothelin-1 production increases, e.g. prostate
      cancer, endothelin-1 is considered to be involved in the generation of pain. In
      the present study, we investigated the effects of a selective endothelin ET(A)
      receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4
      yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on the nociception
      potentiated by endothelin-1 in a cancer inoculation-induced pain model in mice,
      induced by inoculation of the androgen-independent human prostate cancer cell
      line PPC-1 into the hind paws of severe combined immunodeficiency (SCID) mice. No
      pain responses were observed in the sham-operated mice, whereas monophasic pain
      responses were observed in the PPC-1-inoculated mice. Endothelin-1 (1 to 10
      pmol/paw) but not sarafotoxin S6c potentiated the pain response in prostate
      cancer-inoculated mice. Both YM598 and atrasentan (0.3 to 3 mg/kg, p.o.)
      significantly inhibited the endothelin-1 (10 pmol/paw)-induced potentiation of
      nociception in a dose-dependent manner. These results suggest that selective
      endothelin ET(A) receptor antagonists might relieve pain in patients with various
      diseases in which endothelin-1 production is increased, e.g. prostate cancer.

PMID- 15178363
TI  - Effects of anticholinergic drugs selective for muscarinic receptor subtypes on
      prepulse inhibition in mice.
AB  - The effects of anticholinergic drugs selective for muscarinic receptor subtypes
      on prepulse inhibition of acoustic startle response were determined in mice. The
      prepulse inhibition is associated with sensorimotor information processing in the
      brain. The anticholinergic agent scopolamine (0.3 mg/kg, s.c.) significantly
      attenuated prepulse inhibition, while the drug (1-10 mg/kg, s.c.) had no effects
      on startle amplitude as an indicator of startle response. The muscarinic M(1)
      receptor antagonist pirenzepine (0.1-10 microg/mouse, i.c.v.) and the muscarinic
      M(2) receptor antagonist AF-DX116 (11-[[2-[(diethylamino)methyl]-1
      piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) (0.1
      10 microg/mouse, i.c.v.) had no effects on prepulse inhibition or startle
      amplitude. The muscarinic M(3) receptor antagonist 4-DAMP (1,1-dimethyl-4
      diphenylacetoxy-piperidinium iodide) (30 microg/mouse, i.c.v.) and the muscarinic
      M(4) receptor antagonist tropicamide (0.1 microg/mouse, i.c.v.) significantly
      attenuated prepulse inhibition, while tropicamide (0.01 microg/mouse, i.c.v.) but
      not 4-DAMP (10 and 30 microg/mouse, i.c.v.) produced a significant increase in
      startle amplitude. These results suggest that the blockade of muscarinic M(3) and
      M(4) receptors leads to the disruption of prepulse inhibition.

PMID- 15178364
TI  - Suppression by baclofen of the stimulation of alcohol intake induced by morphine
      and WIN 55,212-2 in alcohol-preferring rats.
AB  - Administration of morphine and cannabinoids stimulates alcohol intake in rats.
      The present study investigated whether the promoting effect of morphine and of
      the cannabinoid receptor agonist, WIN 55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3
      (4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1
      naphthalenylmethanone], on alcohol intake was prevented by the gamma-aminobutyric
      (GABA)(B) receptor agonist, baclofen. Sardinian alcohol-preferring (sP) rats were
      given alcohol (10%, v/v) and water under the standard homecage two-bottle-free
      choice regimen with unlimited access for 24 h/day. Baclofen (0, 0.5 and 1 mg/kg;
      i.p.) was administered acutely 30 min before lights off. Morphine (0 and 1 mg/kg,
      s.c.) or WIN 55,212-2 (0 and 2 mg/kg, i.p.) was administered acutely 10 min after
      baclofen. Alcohol intake was recorded 60 min after lights off. As predicted, both
      morphine and WIN 55,212-2 produced a specific and marked increase in alcohol
      intake. Pretreatment with baclofen, which failed to alter alcohol intake when
      given alone, dose-dependently suppressed morphine- and WIN 55,212-2-induced
      promotion of alcohol drinking. These results suggest the involvement of the
      GABA(B) receptor in the neural circuitry mediating the stimulating effect of
      morphine and cannabinoids on alcohol consumption in sP rats.

PMID- 15178365
TI  - Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a
      rat model of depression.
AB  - Due to the interest in the antidepressant potential of nonpeptide corticotropin
      releasing factor (CRF)(1) receptor antagonists, the present investigation
      examined the antidepressant-like effects of the CRF(1) receptor antagonist CP
      154,526 on the exaggerated swim test immobility in the Flinders Sensitive Line
      (FSL) rat, a genetic animal model of depression. Chronic treatment with CP
      154,526 (10 mg/kg; 2x day) for 14 days increased swimming in the Flinders
      Sensitive Line rats. Citalopram (5 and 10 mg/kg; 2x day) and desipramine (5
      mg/kg; 1x day) also significantly increased swimming in the Flinders Sensitive
      Line rats, as expected. However, neither CP-154,526 nor citalopram (10 mg/kg)
      altered swimming times in the control Flinders Resistant Line (FRL) rats.
      Citalopram (10 mg/kg) and CP-154,526 also increased the abnormally low level of
      social interaction behavior in the Flinders Sensitive Line rats. These findings
      indicate that citalopram and CP154,526, a CRF(1) receptor antagonist, have both
      antidepressant and anxiolytic effects that can be detected in an experimental
      model of depression only and not in "normal" control animals.

PMID- 15178366
TI  - Beneficial effects of 5-aminoisoquinolinone, a novel, potent, water-soluble,
      inhibitor of poly (ADP-ribose) polymerase, in a rat model of splanchnic artery
      occlusion and reperfusion.
AB  - Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks
      in DNA, plays an important role in the tissue injury associated with ischemia
      reperfusion and inflammation. Splanchnic artery occlusion and reperfusion causes
      an enhanced formation of reactive oxygen species which contribute to the
      pathophysiology of shock. The aim of the present study was to investigate the
      effects of 5-aminoisoquinolinone (5-AIQ), a potent water-soluble inhibitor of
      poly(ADP-ribose) polymerase (PARP), in the pathogenesis of splanchnic artery
      occlusion shock. Splanchnic artery occlusion shock was induced in rats by
      clamping both the superior mesenteric artery and the celiac artery for 45 min,
      followed thereafter by release of the clamp (reperfusion). At 60 min after
      reperfusion, all animals were sacrificed for histological examination and
      biochemical studies. Treatment of rats with 5-AIQ (3 mg/kg i.v.), attenuated the
      fall of mean arterial blood pressure caused by splanchnic artery occlusion shock.
      5-AIQ also attenuated the ileum injury as well as the increase in the tissue
      levels of myeloperoxidase and malondialdehyde caused by splanchnic artery
      occlusion shock in the ileum. The immunohistochemical examination also
      demonstrated a marked increase in the immunoreactivity to PAR, nitrotyrosine, and
      intercellular adhesion molecule (ICAM-1) in the necrotic ileum from splanchnic
      artery occlusion-shocked rats. 5-AIQ treatment significantly reduced the increase
      of positive staining for PAR, nitrotyrosine and ICAM-I. In conclusion, these
      results show that 5-AIQ, a new water-soluble potent inhibitor of poly(ADP-ribose)
      polymerase, exerts multiple protective effects in splanchnic artery
      occlusion/reperfusion shock.

PMID- 15178367
TI  - Evidence for superoxide anion generation in aortas of cholesterol-fed rabbits
      treated with L-arginine.
AB  - The inducible form of nitric oxide synthase (iNOS) is present in advanced
      atherosclerotic lesions. The aim of the present paper was to compare the
      functionality of iNOS in rabbits fed a 0.3% cholesterol-diet for 24 weeks
      (Baseline), and 36 weeks, with l-arginine (l-Arg) or vehicle supplementation
      (Saline) for the last 12 weeks. N-iminoethyl-l-lysine (l-NIL; 10 microM), a
      selective inhibitor of iNOS, potentiated the contractions to phenylephrine in
      aortas from Baseline, Saline and l-Arg rabbits confirming the presence of a
      functional iNOS. In l-Arg rabbits, the contractions induced by l-NIL were less
      pronounced than those noted in Baseline and Saline rabbits; superoxide dismutase
      (150 U/ml) significantly increased the phenylephrine-induced contractions only in
      the l-Arg rabbits. In the presence of NADPH, aortas from l-Arg rabbits produced
      more superoxide anions than aortas from saline rabbits as evidenced by the
      lucigenin-enhanced chemiluminescence technique. In conclusion, our results show
      functional and biochemical evidence for an increased superoxide anion production
      in atherosclerotic aortas from hypercholesterolemic rabbits treated with l-Arg
      for 12 weeks. These data may thus help to explain the lack of beneficial effects
      of l-Arg on atherosclerosis progression in long-term experimental
      hypercholesterolemia as well as in severely atherosclerotic humans.

PMID- 15178368
TI  - Differential inhibition by TAK-044 of the inotropic effects of endothelin-1 and
      endothelin-3.
AB  - The influence of a nonselective antagonist of endothelin receptors, TAK-044
      (cyclo-[d-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-l-alanyl-l-alpha
      aspartyl-d-2-(2-thienyl)glycyl-l-leucyl-d-tryptophyl] disodium), on the positive
      inotropic effect of endothelin-1 and endothelin-3 was investigated in isolated
      rabbit myocardium. While TAK-044 produced a concentration-dependent rightward
      shift of the concentration-response curve for endothelin-1 and endothelin-3, the
      effect of endothelin-3 was hundred times more sensitive to TAK-044 than that of
      endothelin-1. The combination of FR139317 ([2-(R)-[2(R)-[2(S)-[[1-(hexahydro-1H
      azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3-[3-(1-methyl-1H
      indolyl)]propionyl] amino-3-(2-pyridyl)propionic acid]) and BQ-788 (N-cis-2,6
      dimethylpiperidinocarbonyl-l-gamma-methylleucyl-d-1-methoxycarbonyltryptophanyl-d
      norleucine) mimicked the inhibitory action of TAK-044 on the positive inotropic
      effect of endothelin-3 but enhanced the effect of endothelin-1. In a receptor
      binding assay, TAK-044 was four times more potent in antagonizing the specific
      binding of endothelin-1 than that of endothelin-3. Endothelin-1 may activate
      receptor subtypes that trigger both positive and negative inotropic effects, the
      latter being more susceptible to the antagonistic action of TAK-044, which may
      explain in part the differential antagonistic action of TAK-044 on the inotropic
      effect of endothelin-1 and endothelin-3.

PMID- 15178369
TI  - Ouabain increases myofibrillar Ca2+ sensitivity but does not influence the Ca2+
      release in human skinned fibres.
AB  - The present study investigated the impact of the Na(+) pump inhibitor ouabain (g
      strophanthin) on Ca(2+) sensitivity and Ca(2+) release in human right auricular
      trabeculae (coronary bypass) and in skinned muscle fibres from left ventricular
      myocardium (cardiac transplantation, dilated cardiomyopathy). A time-dependent
      increase in force of contraction was observed in right auricular trabeculae in
      response to ouabain (100 nM) before the intracellular Ca(2+) transient (fura-2)
      increased (n=6). In triton X-skinned fibres (no sarcoplasmic reticulum) of human
      failing myocardium, ouabain (1-100 nM) concentration-dependently increased
      tension at a free extracellular Ca(2+) concentration of 1 microM and the Hill
      coefficient of the Ca(2+)-dependent tension development. Ouabain (1-100 nM) did
      not directly induce a Ca(2+) release out of the sarcoplasmic reticulum, nor did
      it alter the caffeine (10 mM) induced sarcoplasmic reticulum Ca(2+) release in
      saponin-skinned fibre preparations in which the sarcoplasmic reticulum had been
      Ca(2+)-loaded. In conclusion, ouabain increases myofibrillar Ca(2+) sensitivity
      possibly due to an increase in the cooperativity of the thick and thin
      myofilaments. This mechanism may additionally contribute to the positive
      inotropic effect of ouabain.

PMID- 15178370
TI  - Analysis of the mechanisms underlying the vasorelaxant action of kaurenoic acid
      in the isolated rat aorta.
AB  - The present work describes the mechanisms involved in the vasorelaxant effect of
      the diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid). Kaurenoic acid (10, 50
      and 100 microM) concentration-dependently inhibited phenylephrine and KCl-induced
      contraction in either endothelium-intact or -denuded rat aortic rings. Kaurenoic
      acid also reduced CaCl(2)-induced contraction in Ca(2+)-free solution containing
      KCl (30 mM). The diterpene did not interfere with Ca(2+) release from
      intracellular stores mediated by either phenylephrine (1 microM) or caffeine (30
      mM). Kaurenoic acid (1-450 microM) concentration dependently relaxed
      phenylephrine-pre-contracted rings with intact (72.27+/-3.79%) or denuded
      endothelium (73.28+/-5.91%). The diterpene also relaxed KCl-pre-contracted rings
      with intact (80.44+/-3.68%) or denuded endothelium (78.12+/-1.26%). Pre
      incubation of denuded aortic rings with N(G)-nitro-l-arginine methyl ester (l
      NAME, 100 microM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM)
      and 7-nitroindazole (100 microM) reduced kaurenoic acid-induced relaxation
      (percentage of relaxation: 49.12+/-3.26%, 53.10+/-6.72% and 51.74+/-4.76%,
      respectively). Indomethacin (10 microM) did not affect kaurenoic acid-induced
      relaxation. In endothelium-intact rings, 7-nitroindazole and N(pi)-nitro-l
      arginine (l-NNA, 100 microM) displaced the curves for the diterpene to the right.
      Tetraethylammonium (5 mM), 4-amynopiridine (1 mM) and charybdotoxin (0.1 microM)
      caused a rightward displacement of the concentration-response curve for kaurenoic
      acid. Conversely, neither apamin (1 microM) nor glibenclamide (3 microM) affected
      kaurenoic acid-induced relaxation. Collectively, our results provide functional
      evidence that the effects elicited by kaurenoic acid involve extracellular Ca(2+)
      influx blocked. Its effects are also partly mediated by the activation of NO-cGMP
      pathway and the opening of K(+) channels sensitive to charybdotoxin and 4
      amynopiridine. Additionally, the activation of the endothelial and neuronal NO
      synthase isoforms are required for the relaxant effect induced by kaurenoic acid.

PMID- 15178371
TI  - In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905)
      for urinary bladder over salivary gland in rats.
AB  - Solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4
      tetrahydroisoquinoline-2-carboxylate monosuccinate] is a new muscarinic receptor
      antagonist developed for the treatment of overactive bladder. The aim of the
      present study was to evaluate the in vitro and in vivo bladder selectivity
      profile of solifenacin over salivary gland in the same animal species, and to
      compare the results with those obtained for tolterodine, oxybutynin, darifenacin
      and atropine. Solifenacin and the other antimuscarinic drugs inhibited carbachol
      induced increases in intracellular Ca(2+) levels in bladder smooth muscle cells
      and salivary gland cells isolated from rats in a concentration-dependent manner.
      The inhibitory effect of solifenacin for bladder smooth muscle cells (pK(i)=8.12)
      was 3.6-fold more potent than that for salivary gland cells (pK(i)=7.57). In
      contrast, the inhibitory effects of the other antimuscarinic drugs for bladder
      smooth muscle cells were 1.7- to 2.2-fold more potent than those for salivary
      gland cells. In anesthetized rats, solifenacin dose-dependently inhibited
      carbachol-induced intravesical pressure elevation and salivary secretion, and
      exhibited functional selectivity (3.7- to 6.5-fold) for urinary bladder over
      salivary gland. Tolterodine was also 2.2- to 2.4-fold more selective in
      inhibition of bladder response. In contrast, oxybutynin, darifenacin and atropine
      did not show functional selectivity for urinary bladder. These results indicate
      that solifenacin exerts greater selectivity for urinary bladder over salivary
      gland than tolterodine, oxybutynin, darifenacin and atropine, and may
      consequently provide symptomatic benefit in the treatment of overactive bladder
      with less dry mouth than currently used antimuscarinic drugs.

PMID- 15178372
TI  - Cough reflex in allergic dogs.
AB  - This study investigated the effects of antigen challenge on the cough reflex in
      dogs that were neonatally sensitized to ragweed. Tidal volume (V(T)), respiratory
      rate (f), pulmonary resistance (R(L)), dynamic lung compliance (C(Dyn)) and the
      number and amplitude (increase in mean peak expiratory pressure) of coughs
      induced by mechanical stimulation of the intrathoracic trachea were measured in
      propofol-anesthetized dogs. Aerosolized ragweed challenge had no effect to induce
      spontaneous cough but increased f and R(L) and reduced V(T) and C(Dyn).
      Mechanical stimulation of the intrathoracic trachea at this time produced 19+/-5
      coughs with an average increase in cough amplitude of 11+/-1 cm H(2)O which
      differed significantly from the number (9+/-2 coughs) and amplitude (30+/-5.5 cm
      H(2)O) of mechanically induced coughs after treatment with aerosolized saline.
      Both the number and amplitude of mechanically induced coughs returned to baseline
      values by 24-48 h after the ragweed challenge. Similar results were obtained
      after challenge with aerosolized histamine (0.3-1% histamine) that did not induce
      spontaneous coughs but increased f, reduced V(T) and decreased C(Dyn) and
      increased the number but reduced the amplitude of the mechanically induced
      coughs. In conclusion, both antigen and histamine bronchoprovocation changed the
      characteristics of the mechanically induced cough in dogs to a response of
      increased cough number but reduced mean expiratory cough amplitude.

PMID- 15178373
TI  - Influence of 5-HT1 receptor agonists on feline stomach relaxation.
AB  - Sumatriptan is known for its stomach relaxing properties in both humans and cats,
      but the receptor involved has not been characterized. In a barostat study the
      intragastric volume was monitored in sedated cats at constant pressure. The
      maximum intragastric volume increase after subcutaneous or intravenous
      administration of saline or agonists was registered [mean (n=4-5)]. Sumatriptan
      (0.01-1 mg kg(-1)) induced a dose-dependent intragastric volume increase vs.
      saline (4-15 vs. 5 ml, respectively) that was sometimes accompanied by retching
      after 8-10 min. Pre-treatment with nitric oxide-synthase inhibitors and different
      5-HT(1) receptor antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2
      pyridinyl-cyclohexanecarboxamide(WAY-100635), 2-methyl-4-(5-methyl
      [1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic-acid[4-methoxy-3-(4-methyl-piperazin
      1-yl)-phenyl]amide(GR-127935), N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan
      amide(5-HTP-DP) and 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine
      HCl(NAN-190) did not affect the sumatriptan-induced effect. Alniditan (5
      HT(1A/1D) receptor agonist) and flesinoxan (5-HT(1A) receptor agonist) did not
      induce significant intragastric volume changes. The 5-HT(1F) receptor agonists 5
      hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole(BRL-54443) and (R)-(+)-N-(3
      dimethylamino-1,2,3,4-tetrahydro-9H-carbazol-6-yl)-4-fluorobenzamide(LY-344864;
      0.003-3 mg kg(-1)) however induced a dose-dependent intragastric volume increase
      (6-36 and 5-26 ml, respectively), no retching was seen. Our results suggest that
      stimulation of 5-HT(1F) receptors induces feline stomach relaxation. Whether the
      sumatriptan-induced gastric relaxation in cats is due to interaction with 5
      HT(1F) receptors could not be proven absolutely in view of the lack of selective
      5-HT(1F) receptor antagonists.

PMID- 15178375
TI  - Effects of intravenous infusion of highly purified vitamin B2 on
      lipopolysaccharide-induced shock and bacterial infection in mice.
AB  - We investigated the effect of an i.v. infusion of highly purified vitamin B(2)
      (riboflavin 5'-sodium phosphate: purity >97%) on lipopolysaccharide-induced shock
      and bacterial infection in mice. Six hours after lipopolysaccharide injection or
      1 h after bacterial infection, vitamin B(2) or human activated protein C (APC)
      was administered by 6-h i.v. infusion. Vitamin B(2) at 10 mg/kg/6 h and up to 80
      mg/kg/6 h significantly improved lipopolysaccharide-induced endotoxin shock. APC
      was also effective at low doses, but was deleterious at higher doses. Moreover,
      vitamin B(2) at 80 mg/kg/6 h significantly reduced the lethality of Escherichia
      coli and Staphylococcus aureus infection, whereas APC at up to 600 units/kg/6 h
      was ineffective. The i.v. infusion of vitamin B(2) reduced the elevations of
      proinflammatory cytokines and nitric oxide induced by lipopolysaccharide. These
      results suggest that i.v. infusion of vitamin B(2) represents a promising
      strategy for the treatment of sepsis and septic shock.

PMID- 15178374
TI  - Marrubenol interacts with the phenylalkylamine binding site of the L-type calcium
      channel.
AB  - Marrubenol inhibits contraction of rat arteries by blocking L-type calcium
      (Ca(2+)) channels in smooth muscle cells, but its interaction with binding sites
      for calcium antagonists had never been investigated. Competition binding studies
      indicated that marrubenol was a weak inhibitor of 1,4-dihydropyridine binding in
      membranes isolated from rat intestinal smooth muscle but completely displaced
      specifically bound (-)-[(3)H]desmethoxyverapamil ([(3)H]D888) with an apparent
      K(i) value of 16 microM (95% confidence interval: 6.5-39.5 microM). As marrubenol
      inhibited the contraction evoked by KCl depolarization of intestinal smooth
      muscle half-maximally at a concentration of approximately 12 microM, interaction
      with the phenylalkylamine binding site seems to account for the inhibition of L
      type Ca(2+) channels by marrubenol.

PMID- 15178377
TI  - How surprising is a simple pattern? Quantifying "Eureka!".
AB  - Simple patterns are compelling. When all the observed facts fit into a simple
      theory or "story," we are intuitively convinced that the pattern must be real
      rather than random. But how surprising is a simple pattern, really? That is,
      given a pattern of featural data, such as the properties of a set of objects, how
      unlikely would the pattern be if they were actually generated at random? In
      conventional statistics dealing with patterns of numbers, this type of question
      would be answered by reference to a null distribution such as the t distribution.
      This paper gives the analogous answer in the realm of concept learning, that is,
      the formation of generalizations from patterns of featural data. Using a formal
      but psychologically valid definition of complexity, I derive and exhibit the
      distribution of subjective complexity under the hypothesis of no pattern. This
      leads directly to a number of applications, including a statistical test
      indicating whether an observed pattern is sufficiently simple that it is not
      likely to have been an accident: literally, the "significance of simplicity."

PMID- 15178376
TI  - Young infants' reasoning about hidden objects: evidence from violation-of
      expectation tasks with test trials only.
AB  - The present research examined alternative accounts of prior violation-of
      expectation (VOE) reports that young infants can represent and reason about
      hidden objects. According to these accounts, young infants' apparent success in
      these VOE tasks reflects only novelty and familiarity preferences induced by the
      habituation or familiarization trials in the tasks. In two experiments, 4-month
      old infants were tested in VOE tasks with test trials only. The infants still
      gave evidence that they could represent and reason about hidden objects: they
      were surprised, as indicated by greater attention, when a wide object became
      fully hidden behind a narrow occluder (Experiment 1) or inside a narrow container
      (Experiment 2). These and control results demonstrate that young infants can
      succeed at VOE tasks involving hidden objects even when given no habituation or
      familiarization trials. The present research thus provides additional support for
      the conclusion that young infants possess expectations about hidden objects.
      Methodological issues concerning the use of habituation or familiarization trials
      in VOE tasks are also discussed.

PMID- 15178378
TI  - Towards an auditory account of speech rhythm: application of a model of the
      auditory 'primal sketch' to two multi-language corpora.
AB  - The world's languages display important differences in their rhythmic
      organization; most particularly, different languages seem to privilege different
      phonological units (mora, syllable, or stress foot) as their basic rhythmic unit.
      There is now considerable evidence that such differences have important
      consequences for crucial aspects of language acquisition and processing. Several
      questions remain, however, as to what exactly characterizes the rhythmic
      differences, how they are manifested at an auditory/acoustic level and how
      listeners, whether adult native speakers or young infants, process rhythmic
      information. In this paper it is proposed that the crucial determinant of
      rhythmic organization is the variability in the auditory prominence of phonetic
      events. In order to test this auditory prominence hypothesis, an auditory model
      is run on two multi-language data-sets, the first consisting of matched pairs of
      English and French sentences, and the second consisting of French, Italian,
      English and Dutch sentences. The model is based on a theory of the auditory
      primal sketch, and generates a primitive representation of an acoustic signal
      (the rhythmogram) which yields a crude segmentation of the speech signal and
      assigns prominence values to the obtained sequence of events. Its performance is
      compared with that of several recently proposed phonetic measures of vocalic and
      consonantal variability.

PMID- 15178379
TI  - Nine-month-olds extract structural principles required for natural language.
AB  - Infants' ability to rapidly extract properties of language-like systems during
      brief laboratory exposures has been taken as evidence about the innate linguistic
      state of humans. However, previous studies have focused on structural properties
      that are not central to descriptions of natural language. In the current study,
      infants were exposed to 3- and 5-syllable words from one of the two artificial
      languages that employed the same stress assignment constraints found in natural
      languages. Infants were able to generalize beyond the stress patterns encountered
      during familiarization to new patterns reflecting the same constraints. The
      results suggest that infants are able to rapidly extract the types of structural
      information required for human language.

PMID- 15178380
TI  - The effects of late acquisition of L2 and the consequences of immigration on L1
      for semantic and morpho-syntactic language aspects.
AB  - It has been hypothesized that some aspects of a second language (L2) might be
      learned easier than others if a language is learned late. On the other hand, non
      use might result in a loss of language skills in one's native, i.e. one's first
      language (L1) (language attrition). To study which, if any, aspects of language
      are affected by either late acquisition or non-use, long-term German immigrants
      to the US and English native speakers who are long-term immigrants to Germany as
      well as two additional control groups of native German speakers were tested with
      an auditory semantic and morpho-syntactic priming paradigm. German adjectives
      correctly or incorrectly inflected for gender and semantically associated or not
      associated with the target noun served as primes. Participants made a lexical
      decision on the target word. All groups of native German speakers gained from
      semantically and morpho-syntactically congruent primes. Evidence for language
      attrition was neither found for semantic nor morpho-syntactic priming effects in
      the German immigrants. In contrast, English native speakers did not gain from a
      morpho-syntactic congruent prime, whereas semantic priming effects were similar
      as for the remaining groups. The present data suggest that the full acquisition
      of at least some syntactic functions may be restricted to limited periods in life
      while semantic and morpho-syntactic functions seem to be relatively inured to
      loss due to non-use.

PMID- 15178381
TI  - Differential involvement of left prefrontal cortex in inductive and deductive
      reasoning.
AB  - While inductive and deductive reasoning are considered distinct logical and
      psychological processes, little is known about their respective neural basis. To
      address this issue we scanned 16 subjects with fMRI, using an event-related
      design, while they engaged in inductive and deductive reasoning tasks. Both types
      of reasoning were characterized by activation of left lateral prefrontal and
      bilateral dorsal frontal, parietal, and occipital cortices. Neural responses
      unique to each type of reasoning determined from the Reasoning Type (deduction
      and induction) by Task (reasoning and baseline) interaction indicated greater
      involvement of left inferior frontal gyrus (BA 44) in deduction than induction,
      while left dorsolateral (BA 8/9) prefrontal gyrus showed greater activity during
      induction than deduction. This pattern suggests a dissociation within prefrontal
      cortex for deductive and inductive reasoning.

PMID- 15178382
TI  - Synthesis of N-sugar-substituted phthalimides and their derivatives from sugar
      azides and phthalic anhydride.
AB  - N-Sugar-substituted phthalimides and tetrachlorophthalimide derivatives can be
      prepared in good yields under essentially neutral conditions. Mixing a sugar
      azide, NaI, Me3SiCl, phthalic or substituted phthalic anhydride and
      tetrabutylammonium iodide as catalyst in acetonitrile at rt or 60 degrees C,
      afforded 12 imides in 83-95% yields.

PMID- 15178383
TI  - Metal-ion interactions with sugars. The crystal structure and FTIR study of an
      SrCl2-fructose complex.
AB  - The single-crystal structure of SrCl2 x 2C6H12O6 x 3H2O was determined with Mr =
      572.88, a = 16.252, b = 7.941(2), c = 10.751(3) angstroms, beta = 127.652(4)
      degrees, V = 1098.5(6) angstroms3, C2, Z = 2, mu = 0.71073 angstroms and R =
      0.0296 for 1998 observed reflections. The fructose moiety of the complex exists
      as a beta-d-pyranose. The strontium atom is surrounded by eight oxygen atoms,
      which are arranged in symmetry-related pairs that are derived from four sugar and
      two water molecules. Three nonvicinal hydroxyl groups of fructose are involved in
      strontium binding. All the hydroxyl groups and water molecules are involved in
      forming an extensive hydrogen-bond network. The Sr-fructose complex is
      isostructural with the Ca-fructose complex, and the crystal structures and FTIR
      spectra of the two complexes are compared in this article. The O-H, C-O, and C-O
      H vibrations are shifted, and the relative intensities changed in the complexes
      IR spectra, which indicate sugar metalation. By studying the metal-binding
      properties of fructose, it is hoped that such would aid in the understanding of
      the structural chemistry of metal ions interacting with saccharides, as an actual
      biological system, and thereby aid in the interpretation of some particular
      biological processes.

PMID- 15178384
TI  - Inclusion complexes of V-amylose with undecanoic acid and dodecanol at atomic
      resolution: X-ray structures with cycloamylose containing 26 D-glucoses
      (cyclohexaicosaose) as host.
AB  - Crystal structures are reported of cycloamylose containing 26 D-glucose residues
      (CA26, cyclohexaicosaose, C156H260O130) in complexes with undecanoic acid (CA26 x
      2C10H21COOH x 34.95 H2O, orthorhombic P2(1)2(1)2(1), one CA26 and two bound
      undecanoic acids F1 and F2 in the asymmetric unit, resolution 0.95 angstroms) and
      with dodecanol ((CA26)(0.5) x C12H25OH x 32.0H2O, monoclinic C2, half a CA26
      binding one dodecanol, A, in the asymmetric unit, resolution 1.0 angstroms). The
      macrocycle of CA26 is folded like the figure '8' into two 10 D-glucoses long left
      handed V-amylose helices forming approximately 5A wide V-channels that are
      occupied by undecanoic acid (F1, F2) or dodecanol (A) as guest molecules. The
      functional head groups of the guests near the O(6) ends of the V-channels are
      hydrogen bonded with d-glucose O(6)n-H; the aliphatic termini beyond C(9)
      protrude from the O(2), O(3) ends. Parts of the aliphatic chains enclosed in the
      V-channels are all-trans except for one torsion angle each (approximately 130
      degrees ) in undecanoic acid molecules F1 and F2. There are several (guest)C
      H...O hydrogen bonds to O(4) and O(6) of CA26 in both complexes, and H...H van
      der Waals interactions with d-glucose C(3)-H and C(5)-H dominate. C(5)-H
      determine the position of the aliphatic chains of undecanoic acid F1 and of
      dodecanol A in contrast to F2 where both C(3)-H and C(5)-H contribute equally,
      probably because the V-channel is narrower than in F1 and in dodecanol. Complexes
      of polymeric V-amylose with fatty acids and alcohols studied by X-ray fiber
      diffraction could not provide the here described high resolution.

PMID- 15178385
TI  - Proton-acceptor properties and capability for mutarotation of some glucosylamines
      in methanol.
AB  - N-(m-Nitrophenyl)-beta-D-glucopyranosylamine (Gln), N-(N-methylphenyl)-beta-D
      glucopyranosylamine (Glm), N-beta-D-glucopyranosylpyrazole (Glp), and N-beta-D
      glucopyranosylimidazole (Gli) have been synthesized. Their basicity constants,
      pKb, determined in methanol were, respectively, 14.99, 14.36, 15.04, and 9.74.
      The derivatives of secondary amines (Glm, Glp, and Gli) did not mutarotate in
      methanol in the presence of 3,5-dinitrobenzoic acid and hydrochloric acid. The
      heats of formation and entropies were calculated by the AM1 and PM3 methods for
      the glucosylamines and their cations under consideration of two plausible
      protonation centers. Thermodynamic parameters for the proton transfer in the
      reaction: glucosylamine + CH3OH2+ = glucosylamineH+ + CH3OH were determined and
      the protonation center in the glucosylamine molecule was identified. The
      mechanism of mutarotation of the glucosylamines is discussed and the conclusion
      made that formation of an acyclic immonium cation is not a satisfactory condition
      for the reaction to proceed.

PMID- 15178386
TI  - Solution and solid-state structure of N-acetamido-3,4,6-tri-O-acetyl-2-azido-2
      deoxy-alpha-D-galactopyranosylamine.
AB  - High resolution 1H NMR and 13C NMR spectroscopic and single crystal X-ray
      structural analyses of N-acetamido-3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D
      galactopyranosylamine (1), a minor product of azidonitration reaction of 3,4,6
      tri-O-acetyl galactal, are reported. The solution phase studies of 1 reflect that
      the compound exists in 4C1 conformation with cis-orientation of the substituents
      at C-1 and C-2. The solid-state structure of 1 reveals that a molecule of water
      is entrapped in the solid state of 1 and this water molecule serves to mediate N
      H...O and C-H...O interactions.

PMID- 15178387
TI  - Synthesis, (1-->3)-beta-D-glucanase-binding ability, and phytoalexin-elicitor
      activity of a mixture of 3,4-epoxybutyl (1-->3)-beta-D-oligoglucosides.
AB  - We describe a approach for the synthesis of a mixture of 3,4-epoxybutyl (1-->3)
      beta-D-oligoglucosides. The particular (1-->3)-beta-D-glucan isolated from the
      cell walls of Saccharomyces cerevisiae was recovered from the aqueous medium as
      water-insoluble particles by the spray drying (GS) method, and it was
      characterized by FTIR spectroscopy. The acid-solubilized (1-->3)-beta-D
      oligoglucosides were prepared by partial acid hydrolysis of glucan particles,
      which were qualitatively analyzed by fluorophore-assisted carbohydrate
      electrophoresis (FACE). The peracetylated 3-butenyl (1-->3)-beta-D
      oligoglucosides were synthesized by treating peracetylated (1-->3)-beta-D
      oligoglucosides with the 3-butenyl alcohols and a Lewis acid (SnCl4) catalyst.
      Epoxidation of the peracetylated 3-butenyl oligoglucosides took place with m
      chloroperoxybenzoic acid (m-CPBA). NaOMe in dry methanol was used for the
      deacetylation of the blocked derivatives, to give the 3,4-epoxybutyl (1-->3)-beta
      D-oligoglucoside mixture in an overall yield of 21%. The sample was analyzed by
      positive-ion electrospray ionization mass spectrometry (ESIMS). In a 3,4
      epoxybutyl (1-->3)-beta-D-oligoglucoside-binding (1-->3)-beta-D-glucanase assay,
      we found that the (1-->3)-beta-D-glucanase was obviously inactivated by the 3,4
      epoxybutyl (1-->3)-beta-D-oligoglucosides. At the same time, we found the 3,4
      epoxybutyl (1-->3)-beta-D-oligoglucoside mixture was more active as compared to
      the underivatized oligoglucoside mixture in eliciting phytoalexin accumulation in
      tobacco cotyledon tissue. Furthermore, it could be kept for a longer time than a
      (1-->3)-beta-D-oligoglucoside mixture, which indicated it is much more stable
      than (1-->3)-beta-D-oligoglucosides.

PMID- 15178389
TI  - Structural elucidation of the extracellular and cell-wall teichoic acids of
      Staphylococcus epidermidis RP62A, a reference biofilm-positive strain.
AB  - The ability to adhere to artificial surfaces and form biofilms is considered as a
      virulence factor of Staphylococcus epidermidis, one of the major causes of
      nocosomial infections, especially those related to implanted medical devices.
      Cell-wall teichoic acid is known to play an important role in biofilm formation
      of staphylococci. The structure of the cell wall and extracellular teichoic acids
      of S. epidermidis RP62A, a reference biofilm-positive strain, was studied by NMR
      spectroscopy and capillary electrophoresis-mass spectrometry. Their structures
      were found to be a (1-->3)-linked poly(glycerol phosphate), substituted at the 2
      position of glycerol residues with alpha-Glc, alpha-GlcNAc, D-Ala and alpha
      Glc6Ala. D-Alanyl acylation of a sugar hydroxyl group seems to be a novel
      structural feature of teichoic acids from staphylococci.

PMID- 15178388
TI  - A nearly idealized 6'-O-methylated iota-carrageenan from the Australian red alga
      Claviclonium ovatum (Acrotylaceae, Gigartinales).
AB  - The polysaccharides extracted from Claviclonium ovatum were studied by a
      combination of compositional assays, reductive partial hydrolysis, linkage
      analysis, Fourier Transform infrared (FTIR) spectroscopy, and 13C, 1H, and 13C/1H
      heteronuclear multiple quantum correlation (HMQC) two-dimensional nuclear
      magnetic resonance (NMR) spectroscopy. The chemical and spectroscopic data showed
      that the alkali-modified C. ovatum polysaccharides are composed of a nearly
      idealized repeating unit of 6'-O-methylcarrabiose 2,4'-disulfate (the repeating
      unit of 6'-O-methylated iota-carrageenan), although some minor components were
      also present. The C. ovatum galactans are the most highly methylated carrageenans
      reported.

PMID- 15178390
TI  - Preparation and structure elucidation of alginate oligosaccharides degraded by
      alginate lyase from Vibro sp. 510.
AB  - Alginate that was purified from the fermentation solution of marine bacteria
      Vibro sp. 510 under specific reaction conditions was hydrolyzed by alginate
      lyase. Seven oligosaccharides, including di-, tri- and tetrasaccharides, were
      isolated through low-pressure, gel-permeation chromatography (LP-GPC) and
      semipreparative strong-anion exchange (SAX) fast-protein liquid chromatography
      (FPLC). The oligosaccharide structures were elucidated based on ESIMS and 2D NMR
      spectral analysis. The hydrolytic specificity of this alginate lyase to alginate
      is discussed.

PMID- 15178391
TI  - The structure of the glucuronoxylomannan produced by culinary-medicinal yellow
      brain mushroom (Tremella mesenterica Ritz.:Fr., Heterobasidiomycetes) grown as
      one cell biomass in submerged culture.
AB  - The yellow brain mushroom Tremella mesenterica possesses a wide spectrum of
      medicinal properties, including immunostimulating, protecting against radiation,
      antidiabetic, anti-inflammatory, hypocholesterolemic, hepatoprotective, and
      antiallergic effects. A unique feature of T. mesenterica is that most of the
      above mentioned medicinal properties depend on glucuronoxylomannan (GXM)
      contained in fruiting bodies or produced in pure culture conditions. We developed
      a new strain of T. mesenterica CBS 101939, which grows in submerged culture and
      offers superior yields of one-cell biomass rich in exocellular
      heteropolysaccharide GXM. The structure of the GXM was analyzed by NMR
      spectroscopy and chemical methods. The polysaccharide has a defined repeating
      unit structure, which is O-acetylated at several points: [structure: see text].
      These results differ from previously published structure of Tremella
      extracellular polysaccharides, where mannan backbone was believed to be randomly
      glycosylated with xylan chains of different length.

PMID- 15178392
TI  - Structural and immunochemical relationship between the O-antigenic
      polysaccharides from the enteroaggregative Escherichia coli strain 396/C-1 and
      Escherichia coli O126.
AB  - The structure of the O-antigen polysaccharide (PS) from the enteroaggregative
      Escherichia coli strain 396/C-1 has been determined. Sugar and methylation
      analyses together with 1H and 13C NMR spectroscopy were the main methods used.
      Inter-residue correlations were determined by 1H,1H-NOESY, 1H,13C-heteronuclear
      multiple-bond correlation and dipole-dipole cross-correlated relaxation
      experiments. The PS is composed of pentasaccharide repeating units with the
      following structure: [structure: see text]. Analysis of NMR data reveals that on
      average the PS consists of approximately 13 repeating units and indicates that
      the biological repeating unit contains an N-acetylglucosamine residue at its
      reducing end. This structure is different to that reported for the O-antigen
      polysaccharide from E. coli O126. Monospecific anti-E. coli O126 rabbit serum
      from The International Escherichia and Klebsiella Centre did not distinguish
      between the E. coli strain 396/C-1 and the E. coli O126 reference strain, neither
      in slide agglutination nor in an indirect enzyme immunoassay. Subsequent
      successful serotyping of the E. coli strain 396/C-1 showed it to be E. coli
      O126:K+:H27.

PMID- 15178393
TI  - Unexpected reductions of glycosyl spacer-armed phthalimides.
AB  - An unusual reductive ring-opening reaction in the title compounds, of the
      phthalimide group with sodium hydride in anhydrous DMF is observed for the first
      time and the presumed mechanism is described in detail. An unexpected
      hydrogenation of the phthalimide group was also observed.

PMID- 15178394
TI  - Synthesis of a hexasaccharide fragment of group E streptococci polysaccharide and
      the tetrasaccharide repeating unit of E. coli O7:K98:H6.
AB  - Syntheses of a hexasaccharide, the dimer of the repeating unit of the group E
      streptococci polysaccharide, and a tetrasaccharide, the repeating unit of the E.
      coli O7:K98:H6, were achieved by constructing alternate alpha-L-(1-->2)- and
      alpha-L-(1-->3)-linked L-rhamnopyranose backbones and substituting with beta
      linked D-glucopyranose side chains for the former, and a D-glucopyranosyluronate
      branch for the latter, respectively, at O-2 of the L-rhamnose ring.

PMID- 15178395
TI  - Synthesis of chacotriose analogues.
AB  - We report here the synthesis of three chacotriose analogues, namely beta-L
      fucopyranosyl-(1-->2)-[beta-L-fucopyranosyl-(1-->4)]-D-glucopyranose, beta-L
      fucopyranosyl-(1-->2)-[beta-L-fucopyranosyl-(1-->4)]-d-galactopyranose, and alpha
      L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->4)]-alpha-D
      galactopyranose.

PMID- 15178396
TI  - Enzymatic synthesis of two salicin analogues by reaction of salicyl alcohol with
      Bacillus macerans cyclomaltodextrin glucanyltransferase and Leuconostoc
      mesenteroides B-742CB dextransucrase.
AB  - Beta-Salicin is a naturally occurring glycoside found in the bark of poplar and
      willow trees. Ancient man used it as an analgesic and antipyretic. It has a D
      glucopyranose unit attached by a beta-linkage to the phenolic hydroxyl of salicyl
      alcohol. Two new salicin analogues have been enzymatically synthesized by
      transglycosylation reactions: (a) by the reaction of Bacillus macerans
      cyclomaltodextrin glucanyltransferase with cyclomaltohexaose and salicyl alcohol,
      followed by reactions with alpha amylase and glucoamylase to give D-glucopyranose
      attached by an alpha-linkage to the phenolic hydroxyl of salicyl alcohol as the
      major product, alpha-salicin; and (b) by the reaction of Leuconostoc
      mesenteroides B-742CB dextransucrase with sucrose and salicyl alcohol, followed
      by reactions with dextranase and glucoamylase to give alpha-d-glucopyranose
      attached to the primary alcohol hydroxyl of salicyl alcohol as the major product,
      alpha-isosalicin.

PMID- 15178397
TI  - Chemical synthesis of UDP-4-O-methyl-GlcNAc, a potential chain terminator of
      chitin synthesis.
AB  - Chitin synthase converts uridine diphosphoryl-N-acetylglucosamine (UDP-GlcNAc) to
      chitin (poly-beta-(1-->4)-GlcNAc). During polymerization, elongation occurs at
      the 4-OH (nonreducing) terminus of the growing chitin chain. Blockage of the 4-OH
      via incorporation of UDP-N-acetyl-4-O-methylglucosamine (UDP-4-OMe-GlcNAc, 3) can
      potentially terminate chitin polymerization, and represents a novel strategy for
      chitin synthase inhibition. The chemical synthesis of 3 and preliminary
      evaluation of its possible incorporation by chitin synthase are reported herein.

PMID- 15178398
TI  - New class of quaternary ammonium salts, derivatives of methyl D-glucopyranosides.
AB  - Reactions of two aromatic and two aliphatic amines with methyl 6-O-p
      toluenesulfonyl-alpha-D-glucopyranoside or methyl 6-O-p-toluenesulfonyl-beta-D
      glucopyranoside were performed on a micro-scale. The synthesis and preparative
      isolation methods have been developed for quaternary N-(methyl 2,3,4-tri-O-acetyl
      6-deoxy-alpha- and -beta-D-glucopyranoside-6-yl)ammonium salts derived from three
      amines: trimethylamine, 2-methylpyridine, and pyridine. The reaction products
      were examined with 1H, 13C NMR spectroscopy. N-(Methyl 2,3,4-tri-O-acetyl-6-deoxy
      beta-d-glucopyranoside-6-yl)trimethylammonium tosylate was additionally analyzed
      with X-ray crystallography.

PMID- 15178399
TI  - Synthesis of 2-[(2-pyridyl)amino]ethyl beta-D-lactosaminide and evaluation of its
      acceptor ability for sialyltransferase: a comparison with 4-methylumbelliferyl
      and dansyl beta-D-lactosaminide.
AB  - We reported the synthesis of beta-D-lactosaminide with a 2-aminopyridyl group
      that is linked to a glycosyl tether at the reducing end. This fluorescent
      disaccharide acts as an acceptor for both alpha-(2-->6)- and alpha-(2-->3)
      sialyltransferases. In addition, the acceptor ability of this disaccharide was
      evaluated and compared with that of beta-D-lactosaminide having a dansyl or a 4
      methylumbelliferyl group.

PMID- 15178400
TI  - Crystal structure of 1L-1,2:4,5-di-O-isopropylidene-allo-inositol: a comparison
      of its conformation in solid and solution states.
AB  - The X-ray crystal structure of 1l-1,2:4,5-di-O-isopropylidene-allo-inositol, is
      described. The inositol ring deviate slightly from the ideal chair conformation
      to a flattened chair. A comparison of its conformation in solution with that in
      solid was made by the use of 1H NMR. This conformational analysis revealed that
      the title compound adopts similar conformations in solid state and in solution in
      low polar solvents like benzene and CHCl3 while in high polar solvents such as
      Me2SO, the solid state conformation is not retained.

PMID- 15178401
TI  - Structure of the O-polysaccharide of Providencia stuartii O49.
AB  - The O-specific polysaccharide chain (O-antigen) of the lipopolysaccharide (LPS)
      of Providencia stuartii O49 was studied using sugar and methylation analyses
      along with 1H and 13C NMR spectroscopy, including two-dimensional COSY, TOCSY,
      ROESY, H-detected 1H, 13C HSQC and HMBC experiments. The polysaccharide was found
      to have the trisaccharide repeating unit with the following structure: -->6)-beta
      D-Galp(1-->3)-beta-D-GalpNAc(1-->4)-alpha-D-Galp(1-->

PMID- 15178402
TI  - Novel approaches to the syntheses of N-substituted S-glycosyl-sulfenamides.
AB  - Bis(tetra-O-acetyl-beta-D-glucopyranosyl)disulfide reacts, under silver ion
      activation, with primary and secondary aliphatic as well as aromatic amines to
      furnish the title compounds in moderate to good yields. The same derivatives
      could also be obtained from (tetra-O-acetyl)-beta-D-glucopyranosyl
      methanethiolsulfonate 1 by nucleophilic substitution with amines. It was shown
      that the polarization of the S-S-bond in 1 is enhanced by Ag+ so as to allow
      reaction with sterically hindered amines as well.

PMID- 15178403
TI  - Facile route for the synthesis of the iminosugar nucleoside (3R,4R)-1-(pyren-1
      yl)-4-(hydroxymethyl)pyrrolidin-3-ol.
AB  - N-(Pyren-1-yl)-(3R,4S)-4-[(1S,2R)-1,2,3-trihydroxypropyl]pyrrolidin-3-ol (4) was
      obtained in 36% yield from 3-deoxy-3-C-formyl-1,2:5,6-di-O-isopropylidene-alpha-D
      allofuranose (3) by combined hydrolysis and aminoalkylation reactions with 1
      aminopyrene in a one-pot reaction. Cleavage reactions of the exocyclic triol
      chain in 4 with NaIO4 and NaBH4 resulted in iminosugars 7 and 8, which are
      analogues of the furanose forms of 2-deoxy-D-allose and of 2-deoxy-d-ribose, the
      latter analogue N-(pyren-1-yl)-(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (8) being
      formed in 83% yield.

PMID- 15178404
TI  - Synthesis of 2,5-anhydro-(beta-d-glucopyranosyluronate)- and (alpha-l
      idopyranosyluronate)-d-mannitol hexa-O-sulfonate hepta sodium salt.
AB  - Glycosidation of 2,5-anhydro-1,6-di-O-benzoyl-D-mannitol with methyl(2,3,4-tri-O
      acetyl-alpha-d-glucopyranosyl-1-O-trichloroacetimidate)uronate in the presence of
      trimethylsilyl triflate afforded the corresponding 3-O-beta-glycoside, which
      after deprotection was converted into its hexa-O-sulfate with DMF x SO3 to give
      after treatment with sodium acetate and subsequent saponification of the methyl
      ester with sodium hydroxide the hepta sodium salt of 2,5-anhydro-3-O-(beta-d
      glucopyranosyl uronate)-D-mannitol hexa-O-sulfate. Glycosidation of the same
      acceptor with the alpha-thiophenylglycoside of methyl 2,4-di-O-acetyl-3-O-benzyl
      L-idopyranosyl uronate in the presence of NIS/TfOH afforded the corresponding 3-O
      alpha-glycoside in very low yield, therefore the alpha-thiophenylglycoside of 2-O
      acetyl-2,4-O-benzylidene-3-O-benzyl-L-idopyranose was used as donor. The terminal
      hydroxymethyl group of the obtained disaccharide was subsequently oxidised with
      NaOCl/TEMPO and the obtained iduronic acid derivative was converted into the
      hepta sodium salt of 2,5-anhydro-3-O-(-alpha-L-idopyranosyluronate)-D-mannitol
      hexa-O-sulfonate with DMF x SO3 and subsequent treatment with sodium acetate.

PMID- 15178405
TI  - Enhancement of metal bioremediation by use of microbial surfactants.
AB  - Metal pollution all around the globe, especially in the mining and plating areas
      of the world, has been found to have grave consequences. An excellent option for
      enhanced metal contaminated site bioremediation is the use of microbial products
      viz. microbial surfactants and extracellular polymers which would increase the
      efficiency of metal reducing/sequestering organisms for field bioremediation.
      Important here is the advantage of such compounds at metal and organic compound
      co-contaminated site since microorganisms have long been found to produce surface
      active compounds when grown on hydrocarbons. Other options capable of proving
      efficient enhancers include exploiting the chemotactic potential and biofilm
      forming ability of the relevant microorganisms. Chemotaxis towards environmental
      pollutants has excellent potential to enhance the biodegradation of many
      contaminants and biofilm offers them a better survival niche even in the presence
      of high levels of toxic compounds.

PMID- 15178406
TI  - RIP5 is a RIP-homologous inducer of cell death.
AB  - Members of the RIP serine/threonine kinase family are involved in activation of
      NF-kappaB, JNK, and p38, and induction of apoptosis. Here we report the
      identification of a novel RIP-homologous protein designated as RIP5. The C
      terminus of RIP5 contains a kinase domain, which is mostly homologous with the
      kinase domain of RIP. RIP5 also contains a large unconserved N-terminal domain.
      Overexpression of RIP5 induces cell death with characteristic apoptotic
      morphology. Overexpression of RIP5 also induces DNA fragmentation and this is
      blocked by the caspase inhibitor crmA. However, RIP5-induced apoptotic morphology
      is not blocked by crmA. These findings suggest that RIP5 may induce both caspase
      dependent apoptosis and caspase-independent cell death.

PMID- 15178407
TI  - Beta-adrenergic stimulation induces interleukin-18 expression via beta2-AR, PI3K,
      Akt, IKK, and NF-kappaB.
AB  - We investigated whether beta-adrenergic receptor (beta-AR) stimulation induces
      the expression of interleukin (IL)-18, a proinflammatory cytokine, in myocardium
      and in cardiac-derived endothelial cells (CDEC) via activation of nuclear factor
      (NF)-kappaB. Our results indicate that isoproterenol (ISO) activates NF-kappaB
      DNA binding activity, and induces myocardial and systemic elaboration of IL-18
      via beta2-AR signaling. Furthermore, in CDEC, ISO increased basal and inducible
      promoter activities, increased IL-18 gene transcription and mRNA stability, and
      induced IL-18 expression via beta2-AR agonism. Signaling required GiPI3K, PI3K,
      Akt, IKK, and NF-kappaB. In conclusion, our results indicate for the first time
      that isoproterenol induces myocardial and systemic elaboration of IL-18 via a
      beta2-AR and NF-kappaB-dependent mechanism. Similar events may occur in heart
      failure, a disease state characterized by sustained beta-AR activation.

PMID- 15178408
TI  - Structural and conformational changes concomitant with the E1-E2 transition in
      H(+)K(+)-ATPase: a comparative protein modeling study.
AB  - Comparative modeling studies on conserved regions of the gastric H(+)K(+)-ATPase
      reveal that the E1-E2 conformational transition induces significant tertiary
      structural changes while conserving the secondary structure. The residues 516-530
      of the cytoplasmic domain and TM10 within the transmembrane (TM) regions undergo
      maximum tertiary structural changes. The luminal regions exhibit comparatively
      lesser tertiary structural deviations. Residues 249-304 show maximum secondary
      structural deviation in the conformational transition. The Cys-815 and Cys-323
      residues involved in inhibitor binding are found to have smaller buried side
      chain areas in the E1 conformation compared to E2. Retention of activity
      correlates well with the buried side chain area when selected amino acid residues
      in TM6 are mutated using modeling techniques with bulkier amino acid residues.
      Conformational specificity for ion binding is corroborated with the fraction of
      side chains exposed to polar atoms of the residues E345, D826, V340, A341, V343,
      and E822.

PMID- 15178409
TI  - Paracrine effect of TGF-beta1 on downregulation of gap junctional intercellular
      communication between human dermal fibroblasts.
AB  - Disruption of gap junctional intercellular communication (GJIC) is associated
      with tumor progression during multistage carcinogenesis. A coordinated
      interaction of epithelial tumor cells with the stromal environment via growth
      factors is a prerequisite for tumor invasion. Here, the involvement of growth
      factors in downregulation of homologous GJIC of dermal fibroblasts, used as model
      for stromal cells, was examined. Tumor cell derived transforming growth factor
      beta1 (TGF-beta1), having oncogenic activities at late stages of carcinogenesis,
      was identified as being responsible for downregulation of GJIC via an increase in
      the level of reactive oxygen species in stromal fibroblasts. Lowering the level
      of reactive oxygen species by antioxidants, such as the cell-permeable N-acetyl-L
      cysteine, prevented TGF-beta1-mediated downregulation of intercellular
      communication between confluent fibroblasts.

PMID- 15178410
TI  - The receptor and transporter for internalization of Clostridium botulinum type C
      progenitor toxin into HT-29 cells.
AB  - Orally ingested botulinum toxin enters the circulatory system and eventually
      reaches the peripheral nerves, where it elicits a response of neurological
      dysfunction. In this study, we report the important findings concerning the
      mechanism of Clostridium botulinum type C progenitor toxin (C16S) endocytic
      mechanism. C16S toxin bound to high molecular weight proteins on the surface of
      human colon carcinoma HT-29 cells and was internalized, but not if the cells were
      pretreated with neuraminidase. Benzyl-GalNAc which inhibited O-glycosylation of
      glycoproteins also interfered in the toxin's ability to bind the cell surface. On
      the other hand, the toxin was internalized in spite of pretreatment of the cells
      with PPMP, an inhibitor of ganglioside synthesis. These results suggest that the
      glycoproteins, like mucin, fulfill the important roles of receptor and
      transporter of C16S toxin.

PMID- 15178411
TI  - Controlled transcriptional regulation in eukaryotes by a novel transcription
      factor derived from Escherichia coli purine repressor.
AB  - Unlike the DNA-binding domains (DBD) of most eukaryotic transcription factors,
      Escherichia coli LacI family transcription factors are unable to bind to specific
      target DNA sequences without a cofactor-binding domain. In the present study, we
      reconstructed a novel DBD designated as PurHG, which binds constitutively to a
      16bp purine repressor operator, by fusion of the purine repressor (PurR) DBD
      (residues 1-57) and the GAL4 dimerization domain (DD, residues 42-148). Binding
      of PurHG to DNA requires the dimerization and a hinge helix of PurR DBD. When the
      PurHG was expressed as a fusion protein in a form of a transcription activator
      (PurAD) or an artificial nuclear receptor (PurAPR or PurAER) responding to
      ligand, such as RU486 or beta-estradiol, it could regulate the expression of the
      reporter genes in NIH3T3 cells. The prerequisite region of the GAL4 DD for DNA
      binding was amino acid residues from 42 to 98 in the form of PurAD, while the
      amino acid residues from 42 to 75 were sufficient for ligand-dependent regulation
      in the form of PurAPR. These results suggest that the dimerization function of
      the progesterone ligand-binding domain could be substituted for region 76-98 of
      the GAL4 DD. In summary, the fusion of the PurR DBD and the GAL4 DD generates
      fully active DNA-binding protein, PurHG, in vitro and in vivo, and these results
      provide the direct evidence of structural predictions that the proximate
      positioning of PurR hinge helical regions is critical for DNA-binding.

PMID- 15178413
TI  - Functional and physical interactions of Faf1p, a Saccharomyces cerevisiae
      nucleolar protein.
AB  - We report the discovery and characterisation of a novel nucleolar protein of
      Saccharomyces cerevisiae. We identified this protein encoded by ORF YIL019w,
      designated in SGD base as Faf1p, in a two hybrid interaction screen using the
      known nucleolar protein Krr1 as bait. The presented data indicate that depletion
      of the Faf1 protein has an impact on the 40S ribosomal subunit biogenesis
      resulting from a decrease in the production of 18S rRNA. The primary defect is
      apparently due to inefficient processing of 35S rRNA at the A(0), A(1), and A(2)
      cleavage sites.

PMID- 15178412
TI  - Cytoglobin expression is upregulated in all tissues upon hypoxia: an in vitro and
      in vivo study by quantitative real-time PCR.
AB  - The vertebrate globin family has been extended with two members: neuroglobin and
      cytoglobin. We here investigate the changes of expression levels upon hypoxia of
      cytoglobin in parallel with neuroglobin, in vivo and in vitro, by using real-time
      quantitative PCR. Our data prove that cytoglobin is upregulated upon hypoxia in
      all tissues. The mechanism of induction of cytoglobin is regulated by the hypoxia
      inducible factor 1, a posttranscriptionally regulated transcription factor
      controlling several hypoxia-inducible genes. The latter is argumented by: (1)
      cytoglobin is significantly upregulated upon hypoxia and this is dependent on the
      tissue and severity of hypoxia; (2) the regulation of cytoglobin expression in
      HIF-1 (+/-) knockout mice is affected; (3) the variations of the expression
      regulation are in the same manner as seen in the expression of our control gene
      VEGF, that is proven to be regulated by the HIF-1-pathway; and (4) cytoglobin
      promoter region contains HRE sites.

PMID- 15178414
TI  - The role of long-chain fatty-acid-CoA ligase 3 in vitamin D3 and androgen control
      of prostate cancer LNCaP cell growth.
AB  - The antiproliferative effect of 1alpha,25(OH)(2)D(3) on human prostate cancer
      cells is well known, but the mechanism is still not fully understood, especially
      its androgen-dependent action. Based on cDNA microarray results, we found that
      long-chain fatty-acid-CoA ligase 3 (FACL3/ACS3) might play an important role in
      vitamin D(3) and androgen regulation of LNCaP cell growth. The expression of
      FACL3/ACS3 was found to be significantly upregulated by 1alpha,25(OH)(2)D(3) and
      the regulation was shown to be time-dependent, with the maximal regulation over
      3.5-fold at 96h. FACL3/ACS3 was a dominant isoform of FACL/ACS expressed in LNCaP
      cells as indicated by measuring the relative expression of each isoform.
      1alpha,25(OH)(2)D(3) had no significant effect on the expression of FACL1(FACL2),
      FACL4 and FACL6 except for its downregulation of FACL5 at 24 and 48h by around
      twofold. The upregulation of FACL3/ACS3 expression by 1alpha,25(OH)(2)D(3) was
      accompanied with increased activity of FACL/ACS as demonstrated by enzyme
      activity assay using a (14)C-labeled substrate preferential for FACL3/ACS3. The
      growth inhibitory effect of 1alpha,25(OH)(2)D(3) on LNCaP cells was significantly
      attenuated by FACL3/ACS3 activity inhibitor. Androgen withdrawal (DCC-serum), in
      the presence of antiandrogen Casodex or in AR-negative prostate cancer cells (PC3
      and DU145), vitamin D(3) failed to regulate FACL3/ACS3 expression. The
      upregulation of FACL3/ACS3 expression by vitamin D(3) was recovered by the
      addition of DHT in DCC-serum medium. Western blot analysis showed that the
      expression of androgen receptor (AR) protein was consistent with vitamin D(3)
      regulation of FACL3/ACS3 expression. Taken together, the data suggest that the
      upregulation of FACL3/ACS3 expression by vitamin D(3) is through an androgen/AR
      mediated pathway and might be one of the contributions of the vitamin D(3)
      antiproliferative effect in prostate cancer LNCaP cells.

PMID- 15178415
TI  - Extracellular proton sensing of the rat gustatory cyclic nucleotide-gated
      channel.
AB  - Elevations of the intracellular levels of cyclic nucleotides appear to cause the
      cation influx through gustatory cyclic nucleotide-gated (CNGgust) channels
      expressed in taste cells. Although changes in the oral pH may directly regulate
      the activity of the CNGgust channel, the mechanism of pH-dependent control of the
      channel is not understood. In the present study, we combined the whole-cell patch
      clamp recording and the site-directed mutagenesis to investigate the effect of
      extracellular pH on the ion permeation through CNGgust channels expressed in
      HEK293 cells. Extracellular acidification strongly inhibited ion permeation
      through open CNGgust channels. Mutation of Glu(289) remarkably attenuated the pH
      dependence of the channel, suggesting that Glu(289) in the pore-forming region is
      a major proton acceptor site. However, the mutant E289A-CNGgust channel possesses
      the other residual protonation/deprotonation site. The channel activity, tightly
      regulated by pH(o) and [cNMP](i), suggests the involvement of its pH(o)-dependent
      ion permeation in taste signal transduction events.

PMID- 15178416
TI  - Cellular localization of Type I restriction-modification enzymes is family
      dependent.
AB  - Cellular localization of Type I restriction-modification enzymes EcoKI, EcoAI,
      and EcoR124I-the most frequently studied representatives of IA, IB, and IC
      families-was analyzed by immunoblotting of subcellular fractions isolated from
      Escherichia coli strains harboring the corresponding hsd genes. EcoR124I shows
      characteristics similar to those of EcoKI. The complex enzymes are associated
      with the cytoplasmic membrane via DNA interaction as documented by the release of
      the Hsd subunits from the membrane into the soluble fraction following benzonase
      treatment. HsdR subunits of the membrane-bound enzymes EcoKI and EcoR124I are
      accessible, though to a different extent, at the external surface of cytoplasmic
      membrane as shown by trypsinization of intact spheroplasts. EcoAI strongly
      differs from EcoKI and EcoR124I, since neither benzonase nor trypsin affects its
      association with the cytoplasmic membrane. Possible reasons for such a different
      organization are discussed in relation of the control of the restriction
      modification activities in vivo.

PMID- 15178417
TI  - A novel laccase with fair thermostability from the edible wild mushroom
      (Albatrella dispansus).
AB  - A laccase with a novel N-terminal sequence was purified from fresh fruiting
      bodies of the edible wild mushroom Albatrella dispansus using a procedure that
      entailed ion exchange chromatography on DEAE-cellulose, affinity chromatography
      on Affi-gel blue gel and Con A-Sepharose, and gel filtration by fast protein
      liquid chromatography on Superdex 75. In contrast to most of the previously
      reported laccases from mushroom mycelia, the laccase was unadsorbed on DEAE
      cellulose. Although it was also unadsorbed on Affi-gel blue gel, it was adsorbed
      on Con A-Sepharose, indicating that it is a glycoprotein. It exhibited a
      molecular mass of 62kDa in gel filtration and SDS-PAGE. The activity of the
      laccase increased with temperature from 20 to 70 degrees C, and notably remained
      high at 80 degrees C. The pH optimum for the enzyme was around 4. Enzyme activity
      was indiscernible at pH 8 and pH 9. The laccase did not exert any inhibitory
      activity toward HIV-1 reverse transcriptase at a concentration of 1mg/ml, unlike
      some previously reported mushroom proteins.

PMID- 15178418
TI  - Cloning and expression of human UDP-glucuronosyltransferase 1A4 in Bac-to-Bac
      system.
AB  - UDP-glucuronosyltransferases (UGTs) catalyze the transfer of glucuronic acid from
      uridine diphosphate-glucuronic acid (UDP-GA) to compounds with amine, hydroxyl,
      and carboxylic acid moieties. N-glucuronidation is an important pathway for
      elimination of many tertiary amine therapeutic agents used in humans. UGT1A4 has
      been reported to be specific for glucuronidating primary, secondary, and tertiary
      amines, forming N-glucuronides. To further investigate the drugs metabolized by
      UGT1A4, the Bac-to-Bac expression system was used to express the recombinant
      UGT1A4 with His-tag on the C-terminal. The His-tagged recombinant UGT1A4
      expressed in Spodoptera frugiperda (Sf9) cells were detected using anti-His
      antibody and the molecular weight of the recombinant protein was approximately
      55kDa. The enzyme activity towards imipramine in cell homogenate protein was
      found to be 83.14+/-15pmol/min/mg protein (n=3) with 0.5mM imipramine by HPLC,
      but was not detectable in blank Sf9 cells. It paved the way for the further
      studies for drug glucuronidation by UGT1A4. The purification of the UGT1A4 can be
      done by Ni-resin. This is helpful to do research on the structure of the UFT1A4.

PMID- 15178419
TI  - Actin monomer enhances supervillin-modulated androgen receptor transactivation.
AB  - Actin-binding protein, supervillin, has been identified as an androgen receptor
      (AR) coregulator. Although actin has been suggested to participate in
      transcription regulation, the mechanism is not clear. Here we demonstrate signals
      involved in the cytoskeleton dynamic can modulate the coregulator function of
      supervillin. Three actin isoforms cooperate with supervillin in additive manner
      to further enhance AR transactivation. Latrunculin B toxin, an actin chelator,
      reduces the availability of monomer actin and attenuates supervillin function.
      Rac, the small G-protein kinase, is well studied in reorganization of
      cytoskeleton. The overexpression of constitutive-active Rac triggers the membrane
      ruffling site and reduces the coregulator activity of supervillin. Together, the
      availability of actin monomer affects supervillin-modulated AR transactivation.

PMID- 15178420
TI  - Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.
AB  - Overexpression of human APOA5 in mice results in dramatically decreased plasma
      triglyceride levels. In this study we explored the mechanism underlying this
      hypotriglyceridemic effect. Initially we found that triglyceride turnover was
      faster in hAPOA5 transgenic mice compared to controls, and this strongly
      correlated with increased LPL activity in postheparin plasma. Furthermore, we
      show that in vitro recombinant apoAV interacts physically with lipoprotein lipase
      and significantly increased its activity. We show that both apoB and apoCIII are
      decreased in hAPOA5 transgenic mice indicating a decrease in VLDL number. To
      further investigate the mechanism of hAPOA5 in a hyperlipidemic background, we
      inter-crossed hAPOA5 and hAPOC3 transgenic mice. We found a marked decrease in
      VLDL triglyceride and cholesterol, as well as apolipoprotein B and CIII levels.
      These data indicated that apoAV induces a decrease in VLDL size by activating
      lipolysis and an increase of VLDL clearance. In a postprandial state, the normal
      triglyceride response found in wild-type mice was significantly reduced in hAPOA5
      transgenics. In addition, we demonstrated that in response to this fat load in
      hAPOA5xhAPOC3 mice, apoAV, but not apoCIII, was redistributed from primarily HDL
      to VLDL. This shift of apoAV in VLDL appears to limit the increase of
      triglyceride by activating the lipoprotein lipase.

PMID- 15178421
TI  - KN-62, a selective inhibitor of Ca(2+)/calmodulin-dependent protein kinase II,
      inhibits the lysozyme pre-mRNA splicing in myelomonocytic HD11 cells.
AB  - The lysozyme primary transcript has been shown to be slowly spliced, particularly
      in LPS-activated myelomonocytic HD11 cells. In this study, Northern blot analysis
      shows that the splicing of lysozyme pre-mRNA in LPS-activated cells is
      significantly delayed by treatment with KN-62, a selective inhibitor of the
      Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), but not with Go 6976 and
      herbimycin A, inhibitors of Ca(2+)-dependent PKC and PTK, respectively. In vitro
      kinase assay using autocamtide 2 as specific substrate for CaMKII demonstrates
      that KN-62, when added to the extract from HD11 cells, inhibits selectively
      CaMKII activity. Treatment of HD11 cells with cycloheximide, a potent inhibitor
      of protein synthesis, results in a transient increase in lysozyme pre-mRNA
      levels, whilst the mature mRNA levels are not increased. Moreover, neither
      cycloheximide nor KN-62 has any effect on the glyceraldehyde-3-phosphate
      dehydrogenase pre-mRNA splicing. Together, our results indicate that
      phosphorylation by CaMKII, and probably new protein synthesis may be required for
      the lysozyme pre-mRNA processing.

PMID- 15178422
TI  - Post-transcriptional regulation of the cystic fibrosis gene in cardiac
      development and hypertrophy.
AB  - Eukaryotic gene expression, reflected in the amount of steady-state mRNA, is
      regulated at the post-transcriptional level. The 5'-untranslated regions (5'
      UTRs) of some transcripts contain cis-acting elements, including upstream open
      reading frames (uORFs), that have been identified as being fundamental in
      modulating translation efficiency and mRNA stability. Previously, we demonstrated
      that uORFs present in the 5'-UTR of cystic fibrosis transmembrane conductance
      regular (CFTR) transcripts expressed in the heart were able to modulate
      translation efficiency of the main CFTR ORF. Here, we show that the same 5'-UTR
      elements are associated with the differential stability of the 5'-UTR compared to
      the main coding region of CFTR transcripts. Furthermore, these post
      transcriptional mechanisms are important factors governing regulated CFTR
      expression in the heart, in response to developmental and pathophysiological
      stimuli.

PMID- 15178423
TI  - Exercise regulates Akt and glycogen synthase kinase-3 activities in human
      skeletal muscle.
AB  - Activation of Akt and deactivation of GSK3 are critical signals regulating a
      number of cellular processes in multiple systems. Whether physical exercise
      alters Akt and GSK3 activity in human skeletal muscle is controversial. beta
      Catenin, a GSK3 substrate and important Wnt signaling protein that alters gene
      transcription, has not been investigated in human skeletal muscle. In the present
      study, eight healthy human subjects performed 30min of cycling exercise at 75% of
      maximum workload (submaximal) followed by 6 bouts of 60s at 125% maximum workload
      (maximal). Biopsies of vastus lateralis muscle were taken at rest (basal), and
      within 15s following cessation of the submaximal and maximal exercise bouts.
      Exercise at both submaximal and maximal intensities significantly increased Akt
      activity (40% and 110%, respectively). Increases in Akt activity were accompanied
      by increases in Akt Thr(308) and Ser(473) phosphorylation, decreased GSK3alpha
      activity ( approximately 30% at both intensities), and increased phosphorylation
      of GSK3alpha Ser(21). Exercise at both intensities also decreased beta-catenin
      Ser(33/37)Thr(41) phosphorylation (50-60% at both intensities). These results
      demonstrate that Akt, GSK3, and beta-catenin signaling are regulated by exercise
      in human skeletal muscle, and as such identify them as possible molecular
      mediators of exercise's effect on metabolic and transcriptional processes in
      skeletal muscle.

PMID- 15178424
TI  - pDNA bioparticles: comparative heterogeneity, surface, binding, and activity
      analyses.
AB  - New applications for nucleic acid-bound micro/nanoparticles are emerging in drug
      delivery, biocatalysis, diagnostics, and toxicology. Bioactivity of viral or
      liposomal based technologies is limited by heterogeneity, partitioning,
      aggregation, and protein binding in physiological fluids, underlying
      immunotoxicity, and poor in vitro and cell-culture corollaries. Here we have
      systematically investigated novel pDNA bioparticles formed through complexation
      to model non-viral/non-lipid materials, peptides, aminoglycans, and small
      molecules (polybrene, chitosan, butirosin, protamine, Lys10, RGDS, bupivacaine,
      and chlorpromazine). On the basis of characterization by heterogeneity, kinetics,
      partitioning in physiological fluid and serum protein-binding, surface, size and
      electrophoretic behavior, transfection, and immunotoxicity, notably protamine,
      and chitosan DNA particles gave a long lifetime (12-18h), low protein-binding
      (<10microg/ml), good transfection activity (10(2)-10(4)RLU/mg cell protein), and
      low immunotoxicity. Our results support further evaluation of these materials as
      potential alternatives to viral or liposomal approaches, in combination with pDNA
      as binding, expression or therapeutic agents.

PMID- 15178425
TI  - Insights from modelling the 3D structure of the extracellular domain of alpha7
      nicotinic acetylcholine receptor.
AB  - Based on the crystal structure of acetylcholine-binding protein, the three
      dimensional structures of the extracellular domain, or the ligand-binding
      domains, of the monomer, homodimer, and homopentamer of the alpha7 nicotinic
      acetylcholine receptor were derived. The interface between two subunits, where
      the ligand-binding site is located, was investigated. Furthermore, an explicit
      definition of the ligand-binding pocket was illustrated that might provide useful
      clues for conducting various mutagenesis studies for finding drugs against
      schizophrenia and Alzheimer's disease.

PMID- 15178426
TI  - Characterisation of a novel homodimeric N-acetyl-beta-D-glucosaminidase from
      Streptococcus gordonii.
AB  - An N-acetyl-beta-D-glucosaminidase (GcnA) from Streptococcus gordonii FSS2 was
      cloned and sequenced. GcnA had a deduced molecular mass of 72,120 Da. The
      molecular weight after gel-filtration chromatography was 140,000 Da and by SDS
      PAGE was 70,000 Da, indicating that the native protein was a homodimer. The
      deduced amino acid sequence had significant homology to a glycosyl hydrolase from
      Streptococcus pneumoniae and the conserved catalytic domain of the Family 20
      glycosyl hydrolases. GcnA catalysed the hydrolysis of the synthetic substrates, 4
      methylumbelliferyl (4MU)-N-acetyl-beta-D-glucosaminide, 4MU-N-acetyl-beta-D
      galactosaminide, 4-MU-beta-D-N,N'-diacetylchitobioside, and 4-MU-beta-D-N,N',N''
      chitotrioside as well as the respective chito-oligosaccharides. GcnA was
      optimally active at pH 6.6 and 42 degrees C. The Km for 4-MU-beta-D-N,N',N''
      chitotrioside, 45 microM, was the lowest for all the substrates tested. Hg2+,
      Cu2+, Fe2+, and Zn2+ completely inhibited while Co2+, Mn2+, and Ni2+ partially
      inhibited activity. S. gordonii FSS2 and a GcnA negative mutant grew equally well
      on chito-oligosaccharides as substrates. The S. gordonii sequencing projects
      indicate two further N-acetyl-beta-D-glucosaminidase activities.

PMID- 15178427
TI  - Identification of a structural site on acetylcholinesterase that promotes neurite
      outgrowth and binds laminin-1 and collagen IV.
AB  - The cell adhesion and neurite outgrowth-promoting function of
      acetylcholinesterase has been localised to the area of the peripheral anionic
      site. In order to precisely determine the site involved, we used synthetic
      peptides representing sequences of the peripheral anionic site and its surrounds,
      and investigated their binding to a panel of monoclonal antibodies that inhibit
      cell adhesion/neurite outgrowth and/or to recognise the peripheral anionic site.
      Binding to laminin-1 and collagen IV was also investigated. A relationship
      between recognition of the sequence 37-50, representing a surface loop adjacent
      to the peripheral anionic site, and the degree of inhibition of cell adhesion was
      observed; both laminin-1 and collagen IV also bound this loop with high affinity.
      Neurite outgrowth on coverslips coated with this peptide was similar to those
      coated with acetylcholinesterase itself. Adhesion-inhibiting antibodies also
      recognised the omega loop 69-96, as did laminin-1 and collagen IV. Laminin also
      bound the sequences 55-66 and 340-353, recognised by the antibodies to varying
      degrees, but collagen did not. All these peptides were able to promote neurite
      outgrowth to some degree. No binding to the amyloid-binding omega loop 275-304 by
      the ligands was observed, nor did the antibodies recognise this consistently. No
      relationship was observed between the degree of inhibition of
      acetylcholinesterase and inhibition of neurite outgrowth by the antibodies from
      which we conclude that the neurite outgrowth function is non-cholinergic. In
      conclusion, we have identified a specific conformational structure on
      acetylcholinesterase, comprising adjacent surface loops between residues 37-50
      and 69-96, with additional involvement of the sequences 55-66 and 340-353, that
      mediates cell adhesion and neurite outgrowth.

PMID- 15178428
TI  - Dibasic amino acid residues at the carboxy-terminal end of kinase homology domain
      participate in the plasma membrane localization and function of
      phosphatidylinositol 5-kinase gamma.
AB  - Type I phosphatidylinositol 4-phosphate (PI(4)P) 5-kinases (PIP5Ks) catalyze the
      synthesis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)), an essential
      lipid molecule involved in various cellular processes such as regulation of actin
      cytoskeleton and membrane traffic. The protein localizes to the plasma membrane
      where its activity has been shown to be regulated by small GTPase ARFs and/or
      phosphatidic acid. Deletion analysis of amino- or carboxy-terminal sequences of
      PIP5Kgamma fused with EGFP demonstrated that the presence of central kinase
      homology domain (KHD), a 380 amino acid-long region highly conserved among PIP5K
      family, was necessary and sufficient for the plasma membrane localization of
      PIP5Kgamma. Particularly, the dibasic Arg-Lys sequence located at the carboxy
      terminal end of KHD was shown to be crucial for the plasma membrane targeting of
      PIP5Kgamma, since the deletion or charge-reversal mutation of this dibasic
      sequence resulted in the mislocalization of the protein to the cytoplasm.
      Mislocalized mutants also failed to complement the temperature-sensitive growth
      of Saccharomyces cerevisiae mss4-1 mutant defective in PIP5K function. The
      presence of dibasic residues at the C-terminal end of KHD was conserved among
      mammalian as well as invertebrate PIP5K family members, but not in the type II
      PIPKs that are not targeted to the plasma membrane, suggesting that the conserved
      dibasic motif provides a mechanism essential for the proper localization and
      cellular function of PIP5Ks.

PMID- 15178429
TI  - NIRF induces G1 arrest and associates with Cdk2.
AB  - NIRF is a RING finger protein with a ubiquitin-like domain, a PHD finger, a
      YDG/SRA domain, and a RING finger domain. Previous study showed that NIRF is a
      nuclear protein expressed in association with cell proliferation. In this study,
      we further characterized NIRF functions in cell cycle regulation. Flow cytometric
      analysis showed that overexpression of NIRF induced an increase in G1 phase
      cells. Immunoprecipitation and immunoblotting experiments showed that NIRF bound
      to the inactive Cdk2-cyclin E complex. There existed phosphorylated NIRF in
      cells, and dephosphorylated NIRF interacted with Cdk2. NIRF was phosphorylated by
      Cdk2 in vitro. These results suggest that NIRF may participate in the G1/S
      transition regulation.

PMID- 15178430
TI  - A landscape for the dynamics of an immune response.
AB  - Dynamic shaping of the antibody repertoire is essential for effective immunity.
      We describe here a novel approach for clarifying how the antibody repertoire is
      shaped over time for development of a specific immune response. We obtained over
      500 immunoglobulin G1 clones harboring VH186.2 from the spleen, bone marrow, and
      microdissected individual germinal centers of (4-hydroxy-3-nitrophenyl) acetyl
      immunized C57BL/6 mice at various time points postimmunization. Statistical
      analyses provided an index for defining clonal diversity and cluster analyses
      gave us a three-dimensional landscape with which clone distance was visualized
      with the expression level of antibodies. This landscape approach facilitated our
      understanding of the dynamics shaping the actual antibody repertoire, in which
      pre-existing naturally occurring population persisted and provided a significant
      impact upon the repertoire. To the established model for describing production of
      the antibody-forming cells, we were able to append an indispensable issue in
      considering the maturation of humoral immune response.

PMID- 15178431
TI  - The human taste receptor hTAS2R14 responds to a variety of different bitter
      compounds.
AB  - The recent advances in the functional expression of TAS2Rs in heterologous
      systems resulted in the identification of bitter tastants that specifically
      activate receptors of this family. All bitter taste receptors reported to date
      exhibit a pronounced selectivity for single substances or structurally related
      bitter compounds. In the present study we demonstrate the expression of the
      hTAS2R14 gene by RT-PCR analyses and in situ hybridisation in human circumvallate
      papillae. By functional expression in HEK-293T cells we show that hTAS2R14
      displays a, so far, unique broad tuning towards a variety of structurally diverse
      bitter compounds, including the potent neurotoxins, (-)-alpha-thujone, the
      pharmacologically active component of absinthe, and picrotoxinin, a poisonous
      substance of fishberries. The observed activation of heterologously expressed
      hTAS2R14 by low concentrations of (-)-alpha-thujone and picrotoxinin suggests
      that the receptor is sufficiently sensitive to caution us against the ingestion
      of toxic amounts of these substances.

PMID- 15178432
TI  - Modifying the substrate specificity of penicillin G acylase to cephalosporin
      acylase by mutating active-site residues.
AB  - The penicillin G acylase (PGA) and cephalosporin acylase (CA) families, which are
      members of the N-terminal (Ntn) hydrolases, are valuable for the production of
      backbone chemicals like 6-aminopenicillanic acid and 7-aminocephalosporanic acid
      (7-ACA), which can be used to synthesize semi-synthetic penicillins and
      cephalosporins, respectively. Regardless of the low sequence similarity between
      PGA and CA, the structural homologies at their active-sites are very high.
      However, despite this structural conservation, they catalyze very different
      substrates. PGA reacts with the hydrophobic aromatic side-chain (the phenylacetyl
      moiety) of penicillin G (PG), whereas CA targets the hydrophilic linear side
      chain (the glutaryl moiety) of glutaryl-7-ACA (GL-7-ACA). These different
      substrate specificities are likely to be due to differences in the side-chains of
      the active-site residues. In this study, mutagenesis of active-site residues
      binding the side-chain moiety of PG changed the substrate specificity of PGA to
      that of CA. This mutant PGA may constitute an alternative source of engineered
      enzymes for the industrial production of 7-ACA.

PMID- 15178433
TI  - Binding site analysis of full-length alpha1a adrenergic receptor using homology
      modeling and molecular docking.
AB  - The recent availability of crystal structure of bovine rhodopsin offers new
      opportunities in order to approach the construction of G protein coupled
      receptors. This study focuses the attention on the modeling of full-length
      alpha(1a) adrenergic receptor (alpha(1a)-AR) due to its biological role and
      significant implications in pharmacological treatment of benign prostate
      hyperplasia. This work could be considered made up by two main steps: (a) the
      construction of full structure of alpha(1a)-AR, through homology modeling
      methods; (b) the automated docking of an endogenous agonist, norepinephrine, and
      of an antagonist, WB-4101, using BioDock program. The obtained results highlight
      the key residues involved in binding sites of both agonists and antagonists,
      confirming the mutagenesis data and giving new suggestions for the rational
      design of selective ligands.

PMID- 15178434
TI  - Endothelial Chlamydia pneumoniae infection promotes oxidation of LDL.
AB  - The bacterium Chlamydia pneumoniae chronically infects atheromatous lesions and
      is linked to atherosclerosis by modifying inflammation, proliferation, and the
      lipid metabolism of blood monocytes. As continuous LDL modification in the
      vascular intima is crucial for atherogenesis we investigated the impact of
      endothelial infection on LDL oxidation. HUVEC were infected with a vascular C.
      pneumoniae strain. Supernatants of infected cells but not cell lysates increased
      lipid peroxidation products (6.44 vs 6.14 nmol/ml, p<0.05) as determined by
      thiobarbituric acid reacting substances assay. Moreover, supernatants rendered
      human LDL more susceptible to oxidation as shown in a copper-ion catalysed LDL
      oxidation assay by a 16% reduction of LDL resistance against pro-oxidative
      stimuli (p<0.05). Chlamydial infection of vascular endothelial cells releases
      acellular components that convert LDL to its proatherogenic form and reduce its
      resistance against oxidation. Foci of chronic endothelial chlamydial infection
      may thus continuously contribute to the dysregulated lipid metabolism that
      promotes atherogenesis.

PMID- 15178436
TI  - Adipogenic differentiation by adipose-derived stem cells harvested from GFP
      transgenic mice-including relationship of sex differences.
AB  - We have previously demonstrated that adipose-derived stromal cells (ASCs) as well
      as bone marrow-derived stromal cells (BSCs) differentiate into a variety of cell
      lineages both in vitro and in vivo. Both types are considered to include
      mesenchymal stem cells. Taking advantage of homogeneously marked cells from green
      fluorescent protein (GFP) transgenic mice, we have also previously reported the
      plasticity of BSCs and ASCs. In this study, we focused on adipogenic
      differentiation in vitro by ASCs harvested from GFP transgenic mice. Moreover,
      preadipocytes and mature adipocytes were harvested at the same time, and the
      cells were cultured to compare them with ASCs. Inguinal fat pads from GFP
      transgenic mice were used for the isolation of ASCs, preadipocytes, and mature
      adipocytes. After expansion to three passages of ASCs, the cells were incubated
      in an adipogenic medium for two weeks. Adipogenic differentiation of ASCs was
      assessed by Oil Red O staining and the expression of the adipocyte specific
      peroxisome proliferative activated receptor gamma2 (PPAR-gamma2) gene. These ASCs
      stained positively, and expression of PPAR-gamma2 was detected. Moreover, we also
      tried to characterize the influence of sex differences on the adipogenic
      differentiation of ASCs harvested from both male and female mice. This was
      assessed by the expression levels of the PPAR-gamma2 gene using real-time PCR.
      The results showed that the expression levels of ASCs harvested from female mice
      were a maximum of 2.89 times greater than those harvested from male mice. This
      suggests that the adipogenic differentiation of ASCs is closely related to sex
      differences.

PMID- 15178435
TI  - Accumulation of 8-nitroguanine in human gastric epithelium induced by
      Helicobacter pylori infection.
AB  - Helicobacter pylori infection causes chronic inflammation, which can lead to
      gastric carcinoma. A double immunofluorescence labeling study demonstrated that
      the level of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)
      apparent in gastric gland epithelium was significantly higher in gastritis
      patients with H. pylori infection than in those without infection. A significant
      accumulation of proliferating cell nuclear antigen, a prognostic factor for
      gastric cancer, was observed in gastric gland epithelial cells in patients with
      H. pylori infection as compared to those without infection, and its accumulation
      was closely correlated with the formation of 8-nitroguanine and 8-oxodG. These
      results suggest that nitrosative and oxidative DNA damage in gastric epithelial
      cells and their proliferation by H. pylori infection may lead to gastric
      carcinoma. 8-Nitroguanine could be not only a promising biomarker for
      inflammation but also a useful indicator of the risk of gastric cancer
      development in response to chronic H. pylori infection.

PMID- 15178437
TI  - Central and peripheral interactions between the agouti-related protein and
      leptin.
AB  - The agouti-related protein (AgRP) is a powerful appetite modulator expressed in
      the hypothalamus and the adrenal gland and regulated by leptin. Here we report
      the robust expression of AgRP in epididymal fat and its upregulation in this
      tissue by feeding rather than by fasting. This was observed in both the obesity
      susceptible C57BL/6J and the obesity-resistant CAST/Ei mouse strains.
      Surprisingly, AgRP expression was higher in the hypothalamus and the adrenal
      gland in the leaner and obesity-resistant CAST/Ei strain. In vitro leptin
      treatment upregulated endogenous AgRP in mouse hypothalamus and adrenal cells,
      after an acute 6-h exposure, but it downregulated AgRP after a long-term 60-h
      exposure. AgRP, on the other hand, upregulated its own endogenous expression in
      the hypothalamus and the adrenal cells and also upregulated endogenous leptin in
      the adrenal cells. These results reveal a novel feedback loop and reciprocal
      transcriptional regulation between AgRP and leptin centrally and peripherally.

PMID- 15178438
TI  - Immunolocalization of TASK-3 (KCNK9) to a subset of cortical neurons in the rat
      CNS.
AB  - Tandem pore domain (2P) K channels constitute the most diverse family of K
      channels and are responsible for background (leak or baseline) K currents. Of the
      15 human 2P K channels, TASK-1, TASK-2, and TASK-3 are uniquely sensitive to
      physiologic pH changes as well as being inhibited by local anesthetics and
      activated by volatile anesthetics. In this study polyclonal antibodies selective
      for TASK-3 have been used to localize its expression in the rat central nervous
      system (CNS). TASK-3 immunostaining was found in rat cortex, hypothalamus, and
      hippocampus. Double immunofluorescent studies identified a discrete population of
      TASK-3 expressing neurons scattered throughout cortex. Using immunogold electron
      microscopy TASK-3 was identified at the cell surface associated with synapses and
      within the intracellular synthetic compartments. These results provide a more
      finely detailed picture of TASK-3 expression and indicate a role for TASK-3 in
      modulating cerebral synaptic transmission and responses to CNS active drugs.

PMID- 15178439
TI  - Role of auxiliary beta1-, beta2-, and beta3-subunits and their interaction with
      Na(v)1.8 voltage-gated sodium channel.
AB  - The nociceptive C-fibers of the dorsal root ganglion express several sodium
      channel isoforms that associate with one or more regulatory beta-subunits (beta1
      beta4). To determine the effects of individual and combinations of the beta
      subunit isoforms, we co-expressed Nav1.8 in combination with these beta-subunits
      in Xenopus oocytes. Whole-cell inward sodium currents were recorded using the two
      microelectrode voltage clamp method. Our studies revealed that the co-expression
      beta1 alone or in combination with other beta-subunits enhanced current
      amplitudes, accelerated current decay kinetics, and negatively shifted the steady
      state curves. In contrast, beta2 alone and in combination with beta1 altered
      steady-state inactivation of Nav1.8 to more depolarized potentials. Co-expression
      of beta3 shifted steady-state inactivation to more depolarized potentials;
      however, combined beta1beta3 expression caused no shift in channel availability.
      The results in this study suggest that the functional behavior of Nav1.8 will
      vary depending on the type of beta-subunit that expressed under normal and
      disease states.

PMID- 15178440
TI  - eIF4E binding protein 1 and H-Ras are novel substrates for the protein kinase
      activity of class-I phosphoinositide 3-kinase.
AB  - Class-I phosphoinositide 3-kinases (PI 3-kinases) are dual specificity enzymes
      that possess both lipid and protein kinase activity. While the best characterized
      property of this protein kinase is as an autokinase activity, there have also
      been reports it can phosphorylate exogenous substrates including peptides, IRS-1
      and PDE-3B. The identification of two novel potential protein substrates of PI 3
      kinase is described here. By employing in vitro kinase assays using recombinant
      proteins as the substrates, it is shown that the translational regulator 4EBP1
      becomes phosphorylated by the p110alpha and p110gamma isoforms of class-I PI 3
      kinases. The lipid kinase activity of both these isoforms is increased by
      allosteric binding of H-Ras or betagamma subunits of heterotrimeric G proteins,
      but we find this is not the case for the protein kinase activity. Surprisingly
      though, a site on H-Ras is phosphorylated by p110alpha and p110gamma. This raises
      the possibility that these proteins could serve as physiological substrates for
      the protein kinase activity of PI 3-kinase and suggests this activity operates in
      a physiological context by phosphorylating substrates other than the PI 3-kinase
      itself. This may be particularly important in regulating the interaction of Ras
      with PI 3-kinase.

PMID- 15178441
TI  - Sp1-decoy oligodeoxynucleotide inhibits high glucose-induced mesangial cell
      proliferation.
AB  - Mesangial expansion caused by cell proliferation and glomerular extracellular
      matrix accumulation is one of the earliest renal abnormalities observed at the
      onset of hyperglycemia in diabetes mellitus. Transcription factor Sp1 is
      implicated in the transcriptional regulation of a wide range of genes
      participating in cell proliferation, and is assumed to play an essential role in
      mesangial expansion. We have generated a phosphorothioated double-stranded Sp1
      decoy oligodeoxynucleotide that effectively blocks Sp1 binding to the promoter
      region for transcriptional regulation of transforming growth factor-beta1 and
      plasminogen activator inhibitor-1. The Sp1-decoy oligodeoxynucleotide suppressed
      transcription of these cytokines and proliferation of primary rat mesangial cells
      in response to high glucose. These results suggest that the Sp1-decoy
      oligodeoxynucleotide could be a powerful tool in preventing the pathogenesis of
      renal hypertrophy.

PMID- 15178442
TI  - The reaction of bisphenol A 3,4-quinone with DNA.
AB  - The 3,4-quinone of the estrogen-active compound bisphenol A (BPA), characterized
      by a single crystal X-ray structure determination, has been shown by (1)H NMR
      spectroscopy to react with herring testes DNA, and with deoxyguanosine (dG), in
      aqueous buffer at pH 7, to form a BPA 3,4-quinone-guanine-N7 adduct (BPAQ-N7
      Gua). Presumably this adduct resulted from decomposition (by loss of deoxyribose)
      of an initially formed, but unstable, BPAQ-N7-dG adduct. Chemical synthesis if
      BPAQ-N7-Gua, in up to 60% yield, was achieved by the reaction of BPAQ and dG in
      aqueous acetic acid. Characterization of this product, by NMR spectroscopy and
      high resolution mass spectrometry, allowed the monitoring (by (1)H NMR
      spectroscopy) of the reaction of BPAQ with DNA and with dG. The relevance of this
      adduct formation to the potential mutagenicity and carcinogenicity of BPA will
      depend upon confirmation of the necessary metabolic oxidative transformation of
      BPA in vivo.

PMID- 15178443
TI  - Overexpression of LI-cadherin in gastric cancer is associated with lymph node
      metastasis.
AB  - Gastric cancer remains the second leading cause of cancer deaths worldwide.
      Patients usually present late with local invasion or metastatic diseases. The
      present study investigated the expression level of liver-intestine cadherin (LI
      cadherin) by RT-PCR and its correlation with clinicopathological data in 71 pairs
      of tumor and non-cancerous gastric mucosa. Protein expression level of LI
      cadherin was determined by Western blotting and immunohistochemistry. The mRNA of
      LI-cadherin was highly expressed in tumor as compared to non-cancerous mucosa.
      Lymph node metastasis was significantly associated with the expression of LI
      cadherin (p=0.038). On multivariate analysis, T staging and LI-cadherin
      expression were found to be independent factors associated with lymph node
      metastasis.

PMID- 15178444
TI  - Magnetically labeled insulin-secreting cells.
AB  - Iron oxide nanoparticles have been shown to magnetically label cells in order to
      visualize them in vivo via MR imaging. This technology has yet to be implemented
      in insulin secreting cells, thus it is not known whether the presence of these
      nanoparticles in the cytoplasm of the cells affects insulin secretion. This study
      investigates the effectiveness and consequence of labeling mouse insulinoma
      betaTC3 and betaTC-tet cells with monocrystalline iron oxide nanoparticles
      (MION). Our data show that MION can be internalized in both betaTC3 and betaTC
      tet cells following a 24h exposure to 0.02mg/ml MION solution. The metabolic and
      secretory activities of both MION-labeled cell lines were statistically
      indistinguishable from sham treatment. Furthermore, cell viability and apoptosis
      remained constant throughout the cell's exposure to MION. Finally, MR images
      demonstrated significant contrast between labeled and sham-treated cells. Thus,
      labeling murine insulinoma cell lines with magnetic iron oxide nanoparticles does
      not hinder their insulin secretion, while it provides MR imaging contrast.

PMID- 15178445
TI  - Effective neutrophil chemotaxis is strongly influenced by mean IL-8
      concentration.
AB  - Neutrophils need to correctly interpret gradients of chemotactic factors (CFs)
      such as interleukin 8 (IL-8) to migrate to the site of infection and perform
      immune functions. Because diffusion-based chemotaxis assays used in previous
      studies suffer from temporally changing gradients, it is difficult to distinguish
      the influence of CF gradient steepness from mean CF concentration on chemotaxis.
      To better understand the roles of mean CF concentration and CF gradient
      steepness, we developed a microfluidic device that can maintain stable IL-8
      gradients. We report that the random motility of neutrophils is a biphasic
      function of IL-8 concentration and its magnitude plays a decisive role in
      effective chemotaxis, a quantitative measure of migration. We show that the
      concentrations for the optimum chemotaxis in linear IL-8 gradients and for the
      maximum random motility in uniform IL-8 coincide. In contrast, we find that the
      steepness of IL-8 gradients has no significant effect on effective chemotaxis.

PMID- 15178446
TI  - Potent receptor-mediated cytotoxicity of granulocyte colony-stimulating factor
      Pseudomonas exotoxin, a fusion protein against myeloid leukemia cells.
AB  - A chimeric toxin in which the cell-surface binding domain of Pseudomonas exotoxin
      A was replaced with mature human granulocyte colony-stimulating factor (G-CSF)
      was produced in Escherichia coli, purified and tested for its biological activity
      on the human G-CSF-responsive myeloid leukemia cell line, UT7/GR. This fusion
      protein, termed G-CSF-PE40, showed potent cytotoxicity in the cell line in a dose
      dependent manner. G-CSF-PE40 displaced binding of biotinylated G-CSF to its
      receptor, and the cytotoxicity of G-CSF-PE40 was neutralized by an excess of wild
      type G-CSF, indicating the receptor-mediated effects of this chimeric toxin. When
      G-CSF-PE40 was injected into normal mice, they showed transient neutropenia but
      no significant changes in the numbers of red blood cells or platelets.
      Furthermore, G-CSF-PE40 prolonged the survival of mice transplanted with
      syngeneic myeloid leukemia cells. These observations suggest that G-CSF-PE40 may
      be useful in targeted therapy of myeloid leukemia cells expressing G-CSF
      receptors.

PMID- 15178447
TI  - Phosphorylation of ICBP90 by protein kinase A enhances topoisomerase IIalpha
      expression.
AB  - Inverted CCAAT box binding protein of 90kDa (ICBP90) is a nuclear protein
      involved in the topoisomerase IIalpha (TopoIIalpha) gene expression. It belongs
      to a family of E3 ligases of the RING finger type and its expression is
      deregulated in cancer cells. Previous studies have shown that high expression of
      ICBP90 may impair the control of G1/S transition of the cell cycle in various
      cancer cell lines. Since PKA signaling pathway is involved in G1/S transition of
      the cell cycle, the aim of the present study was to investigate whether cAMP
      signaling pathways involve phosphorylation of ICBP90. Here, we show that
      phosphorylation of ICBP90 through the cAMP signaling pathway accelerates exit of
      forskolin-treated cells from the G1 phase and increases binding of ICBP90 to the
      ICB2 element of the TopoIIalpha gene promoter with a subsequent increase of
      TopoIIalpha expression. We identify S298 of ICBP90 as target for PKA. We propose
      that cAMP signaling pathway enhances TopoIIalpha expression through ICBP90
      phosphorylation, which may be one of the major events involved in the G1/S
      transition.

PMID- 15178448
TI  - Poly(ADP-ribose) polymerase-1 inhibits ATM kinase activity in DNA damage
      response.
AB  - DNA double-strand breaks (DSB) mobilize DNA-repair machinery and cell cycle
      checkpoint by activating the ataxia-telangiectasia (A-T) mutated (ATM). Here we
      show that ATM kinase activity is inhibited by poly(ADP-ribose) polymerase-1 (PARP
      1) in vitro. It was shown by biochemical fractionation procedure that PARP-1 as
      well as ATM increases at chromatin level after induction of DSB with
      neocarzinostatin (NCS). Phosphorylation of histone H2AX on serine 139 and p53 on
      serine 15 in Parp-1 knockout (Parp-1(-/-)) mouse embryonic fibroblasts (MEF) was
      significantly induced by NCS treatment compared with MEF derived from wild-type
      (Parp-1(+/+)) mouse. NCS-induced phosphorylation of histone H2AX on serine 139 in
      Parp-1(-/-) embryonic stem cell (ES) clones was also higher than that in Parp
      1(+/+) ES clone. Furthermore, in vitro, PARP-1 inhibited phosphorylation of p53
      on serine 15 and (32)P-incorporation into p53 by ATM in a DNA-dependent manner.
      These results suggest that PARP-1 negatively regulates ATM kinase activity in
      response to DSB.

PMID- 15178449
TI  - Neuregulin induces proliferation of neural progenitor cells via PLC/PKC pathway.
AB  - Nestin-expressing neural progenitor cells (NPCs) have been isolated from
      hippocampus of brains and propagated with epidermal growth factor and basic
      fibroblast growth factor (bFGF). However, the underlying signaling mechanisms
      regulating NPC proliferation remain elusive. Here we showed that neuregulinbeta1
      (NRG), like bFGF, effectively promoted the proliferation of hippocampus-derived
      NPCs and maintained the progenitor states of NPCs. Activation of protein kinase C
      (PKC), a downstream effector of phospholipase C (PLC), with 12-O
      tetradecanoylphorbol-13-acetate (TPA) mimicked the NRG-induced proliferation of
      NPCs. The synergic effect of TPA plus NRG on neurosphere growth further prompted
      us to find that NRG induced NPC propagation through PLC/PKC signaling pathway.
      ErbB4, an important functional receptor of NRG, had an interaction with PLCgamma1
      protein. In addition, inactivation of PLC pathway led to severe proliferative
      suppression of NPCs. Our study suggests that activation of PLC/PKC pathway plays
      an essential role in the NRG-induced proliferation of hippocampus-derived NPCs.

PMID- 15178450
TI  - Conditional transformation of mouse pancreatic epithelial cells: an in vitro
      model for analysis of genetic events in pancreatocarcinogenesis.
AB  - Pancreatic ductal adenocarcinomas arise through the accumulation of certain
      genetic alterations including ras, p16, p53, and DPC4. We found that activation
      of ras and inactivation of p53 could cooperatively induce in vitro tumorigenicity
      in conditionally immortalized pancreatic epithelial (IMPE) cells. IMPE cells were
      established from transgenic mice bearing a temperature-sensitive mutant SV40
      Large T (LT) antigen. IMPE cells grew continuously under permissive conditions
      (33 degrees C with interferon-gamma), but rapidly suffered growth arrest under
      non-permissive conditions (39 degrees C without interferon-gamma). The cells
      showed strong expression of E-cadherin and beta-catenin as epithelial markers,
      and cytokeratin 19, a specific ductal cell marker. Cell proliferation under
      permissive conditions was associated with down-regulation of p21 expression
      through inactivation of p53 after overexpression of LT antigen. Intriguingly, the
      shift from the permissive to non-permissive culture conditions caused G2/M arrest
      of IMPE cells. Although the cells did not form colonies when cultured in soft
      agar without activation of ras, cells with ras activation via an adenovirus
      vector formed colonies under permissive conditions. These findings suggest that
      activation of ras and inactivation of p53 can cooperatively induce anchorage
      independent growth of IMPE cells. This cell line might be useful for studying the
      processes involved in pancreatocarcinogenesis.

PMID- 15178451
TI  - Expression of a truncated secreted form of the mGluR3 subtype of metabotropic
      glutamate receptor.
AB  - In this study, 10 truncated constructs encompassing all or part of the
      extracellular ligand binding domain of the mGluR3 subtype of metabotropic
      glutamate receptor were generated, expressed in human embryonic kidney cells, and
      tested for secretion and binding of the high affinity agonist [(3)H]DCG-IV. The
      effect of inserting epitope tags into the N or C termini on cell secretion and
      radioligand binding was also examined. Secretion into the cell culture media was
      observed for 8 of the 10 truncated receptors and all secreted forms displayed
      high affinity agonist binding. The highest level of binding was observed in the C
      terminal polyhistidine-tagged receptor truncated at serine 507. Reduction and
      enzymatic deglycosylation of the serine 507 truncated receptor using
      endoglycosidase H and PNGase F showed that the secreted receptor was a disulfide
      linked dimer containing complex oligosaccharides. Pharmacological
      characterization demonstrated that the truncated receptor showed the same rank
      order of potency of agonist binding, a relatively small 2-fold decrease in
      agonist affinity, and a larger 10-fold decrease in affinity for the antagonist
      LY341495 compared to the full-length membrane-bound receptor. These results
      define the essential requirements for ligand binding to the extracellular domain
      of mGluR3 and highlight parameters important for the optimization of receptor
      expression in mammalian cells.

PMID- 15178452
TI  - RhoA and Rac1 signals in fMLP-induced NF-kappaB activation in human blood
      monocytes.
AB  - GTPase RhoA is required for fMet-Leu-Phe (fMLP)-stimulated NF-kappaB activation
      in human peripheral blood monocytes. Here we have investigated different members
      of the Rho family of GTPases Rac1, Cdc42, and RhoA in regulating the
      transcription factor nuclear factor-kappaB (NF-kappaB) in human peripheral blood
      monocytes. Stimulation of monocytes with fMLP rapidly activated Rac1, Cdc42, and
      RhoA and cotransfection of the monocytic THP1 cells with dominant negative forms
      of Rho GTPases, we found that Rac1 and RhoA, but not Cdc42, involved fMLP
      stimulated kappaB reporter gene expression. These results indicate that fMLP
      stimulates three members of the Rho family of GTPases Rac1, Cdc42, and RhoA
      activity in monocytes, and that Rac1 and RhoA, but not Cdc42, is required for
      fMLP-induced NF-kappaB activation. Furthermore, our data also suggest that RhoA
      is mediated by signals independent of Rac1 in NF-kappaB activation in human
      peripheral blood monocytes stimulated with bacterial products.

PMID- 15178453
TI  - Binding site of Escherichia coli RNA polymerase to an RNA promoter.
AB  - The DNA-dependent RNA polymerase (RNAP) from Escherichia coli has previously been
      reported to specifically initiate transcription from viroid-derived RNA promoters
      in vitro. In order to gain insight into the molecular mechanism of RNA promoter
      recognition by this RNAP, we have used nucleic acid intercalators and RNA:protein
      footprinting experiments to study the interaction between the polymerase and an
      RNA promoter at the initiation site. Our data revealed that the polymerase binds
      an external single-stranded loop, rather than a double-stranded region as is the
      case for DNA templates. Despite this divergence in promoter binding, the model
      RNA template was bound by both the beta and beta' subunits of the RNAP, as is
      observed with DNA templates. Most importantly, this work proposes large single
      stranded RNA hairpin loops have the potential to be promoters for DNA-dependent
      RNAP.

PMID- 15178454
TI  - Rho-kinase is involved in mouse blastocyst cavity formation.
AB  - During mammalian embryonic development, the formation and subsequent expansion of
      a fluid-filled cavity, the blastocoel, is crucial for successful implantation.
      Our present experiments were aimed at exploring the contribution of Rho-kinase, a
      downstream effector of the small GTP-binding protein RhoA, to mouse blastocoel
      formation. RT-PCR analysis showed that Rho-kinase mRNA is present throughout
      mouse preimplantation development. When 2-cell embryos were cultured in the
      presence of a specific inhibitor of Rho-kinase, Y-27632, they developed to the
      morula stage but failed to develop to the blastocyst stage. Y-27632 inhibited the
      formation of the blastocoel cavity from the morula stage, and this inhibitory
      effect was reversible when embryos were returned to medium without Y-27632.
      Moreover, Y-27632 reduced the rate of re-expansion of blastocysts collapsed by
      cytochalasin D upon transfer to the control medium. These results suggest that
      Rho-kinase is likely involved in blastocyst formation.

PMID- 15178455
TI  - Direct interaction of Smac with NADE promotes TRAIL-induced apoptosis.
AB  - Second mitochondria-derived activator of caspase (Smac) has been implicated in
      the activation of apoptosis in response to cell stress. We screened for
      Smac/DIABLO-binding protein for further understanding of Smac-mediated apoptosis.
      We identified NADE, previously known as p75NTR-associated cell death executor, as
      a Smac-binding protein. Smac-NADE interaction was mapped to the N-terminal region
      of Samc and the C-terminal region of NADE. Co-expression of NADE and Smac
      promotes TRAIL-induced apoptosis in MCF-7 cells. Interestingly, the co-presence
      of Smac and NADE inhibits XIAP-mediated Smac ubiquitination. In conclusion, our
      results provide the first evidence that the interaction between Smac and NADE
      regulates apoptosis through the inhibition of Smac ubiquitination.

PMID- 15178456
TI  - Role of N-glycan trimming in the folding and secretion of the pestivirus protein
      E(rns).
AB  - N-glycosylation inhibitors have antiviral effect against bovine viral diarrhea
      virus. This effect is associated with inhibition of the productive folding
      pathway of E1 and E2 envelope glycoproteins. E(rns) is the third pestivirus
      envelope protein, essential for virus infectivity. The protein is heavily
      glycosylated, its N-linked glycans counting for half of the apparent molecular
      weight. In this report we address the importance of N-glycan trimming in the
      biosynthesis, folding, and intracellular trafficking of E(rns). We show that
      E(rns) folding is not assisted by calnexin and calreticulin; however, the protein
      strongly interacts with BiP. Consistently, the N-glycan trimming is not a
      prerequisite for either the acquirement of the E(rns) native conformation, as it
      retains the RNase enzymatic activity in the presence of alpha-glucosidase
      inhibitors, or for dimerization. However, E(rns) secretion into the medium is
      severely impaired suggesting a role for N-glycosylation in the transport of the
      glycoprotein through the secretory pathway.

PMID- 15178457
TI  - Different ways to regulate the PPARalpha stability.
AB  - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand
      activated transcription factor. PPARalpha regulates lipid and glucose metabolism
      and controls the inflammatory response. Recently, we have shown that PPARalpha is
      a short-lived protein degraded by the ubiquitin-proteasome system. In this study,
      we have analysed the effects of interaction with RXRalpha, CBP, and N-CoR and
      also the implication of phosphorylation on ubiquitination and stability of
      PPARalpha. Our results show that interaction of PPARalpha with RXRalpha or CBP
      leads to an increase in the turnover of the protein. In contrast, interaction
      with the corepressor N-CoR, which inhibits its transcriptional activity, leads to
      a stabilization of the protein. Interestingly, treatment of cells with an
      inhibitor of Ser/Thr phosphatases known to lead to hyperphosphorylation of
      PPARalpha induces its transcriptional activity which is accompanied by a
      stabilization of the protein. These data indicate that heterodimerization,
      recruitment of cofactors, and post-translational modifications can modulate the
      stability of PPARalpha.

PMID- 15178458
TI  - Cell-free protein synthesis using cell extract of Pseudomonas fluorescens and
      CspA promoter.
AB  - We have modified the cell-free coupled transcription/translation system of
      bacteria. The cell-free extract of Pseudomonas fluorescens was used for
      translation instead of Escherichia coli. In addition, transcription of the target
      gene was regulated by CspA promoter with endogenous RNA polymerase instead of by
      T7 promoter with exogenous T7 RNA polymerase. We could increase the yields of
      soluble proteins using different combinations of the S30 extract and the promoter
      and different temperatures for protein synthesis. Increasing the variety of
      synthesis systems allows production of large quantities of soluble proteins. In
      order to carry out efficient cell-free protein synthesis, versatile pCop-plasmids
      carrying CspA promoter were constructed and these plasmids were applicable to
      expression of recombinant proteins in E. coli cells.

PMID- 15178459
TI  - Identification of monohydroxy progesterones produced by CYP106A2 using
      comparative HPLC and electrospray ionisation collision-induced dissociation mass
      spectrometry.
AB  - Two previously uncharacterised products, produced by recombinant CYP106A2 of
      Bacillus megaterium ATCC 13368 using progesterone as substrate, were identified.
      For this purpose a combination of comparative HPLC and electrospray ionisation
      collision induced dissociation mass spectrometry (ESI CID MS) was established and
      applied for rapid identification of the steroids, which were identified as
      11alpha-hydroxyprogesterone and 9alpha-hydroxyprogesterone. The pharmaceutical
      relevance of these steroids is discussed. Furthermore, the hydroxylation activity
      was quantified for all monohydroxylation products (15beta-hydroxyprogesterone,
      6beta-hydroxyprogesterone, 11alpha-hydroxyprogesterone, and 9alpha
      hydroxyprogesterone). The V(max) values for 15beta-hydroxyprogesterone, 6beta
      hydroxyprogesterone, 11alpha-hydroxyprogesterone, and 9alpha-hydroxyprogesterone
      were determined as 337.3+/-43.7, 22.3+/-0.9, 17.5+/-0.9, and 6.5+/-0.3nmol
      product/min/nmol CYP106A2, respectively.

PMID- 15178460
TI  - Pak regulates calpain-dependent degradation of E3b1.
AB  - E3b1, a binding partner of Eps8, plays a critical role in receptor tyrosine
      kinase (RTK)-mediated Rac activation by facilitating the interaction of Eps8 with
      Sos-1 and the consequent activation of the Rac-specific guanine nucleotide
      exchange factor activity of Sos-1. Here we present evidence that E3b1 levels are
      regulated by the Ca(2+)-activated protease calpain, and also by Pak, a downstream
      target of Rac signaling. Serum starvation of Rat2 or COS7 cells resulted in rapid
      loss of E3b1 that was reversed by calpain inhibitors. Loss was also prevented by
      expressing the constitutively active Pak1 mutant, Pak1(H83,86L). Activation of
      endogenous Pak by platelet-derived growth factor or the constitutively active
      Rac1 mutant, Rac1(G12V), also inhibited degradation. In contrast, inhibition of
      endogenous Pak activity by expressing the Pak auto-inhibitory domain caused
      degradation of over-expressed E3b1 even in the presence of serum. Taken together,
      these findings indicate that E3b1 is down-regulated by calpain activation and
      stabilized by Pak activation. They also suggest that RTK-mediated Rac activation
      can be modulated by changes in the level of E3b1 in response to signals that
      affect the activity of calpain or Pak.

PMID- 15178461
TI  - Breast cancer cell line MDA-MB 231 exerts a potent and direct anti-apoptotic
      effect on mature osteoclasts.
AB  - Cancer cells metastasized to bone stimulate osteoclastogenesis resulting in bone
      destruction. However, the influence of tumor cells on fully differentiated
      osteoclasts is much less known. We postulated that breast cancer cells directly
      stimulate the survival of mature osteoclasts. We thus tested the effect of
      conditioned media (CM) prepared from MDA-MB-231 cells on the activity and
      apoptosis of osteoclasts isolated from 10-day-old rabbit long bones. First, we
      demonstrated that CM increased the bone resorbing activity in our cell model of
      rabbit mature osteoclasts. Using a highly purified osteoclast cell population, we
      found that MDA-MB-231 CM dramatically inhibited osteoclast apoptosis. In the
      presence of 20% CM, apoptosis was decreased by approximately 60%. LY294002, a PI3
      kinase inhibitor, strongly prevented the CM anti-apoptotic effect. Neutralizing
      experiments with human antibody revealed that macrophage-colony stimulating
      factor originating from MDA-MB 231 cells was possibly involved in the CM anti
      apoptotic effect. These results suggest that breast cancer cells, in addition to
      stimulating osteoclastogenesis, potently inhibit mature osteoclast apoptosis, a
      mechanism which may greatly contribute to their osteolytic potential.

PMID- 15178462
TI  - Infiltrating leukocytes confound the detection of E-cadherin promoter methylation
      in tumors.
AB  - Promoter hypermethylation is known to result in transcriptional downregulation of
      many genes including the CDH1 gene. In this study we set out to determine CDH1
      promoter methylation in breast tumors with decreased or absent E-cadherin protein
      expression and without CDH1 gene mutations by methylation-specific PCR (MSP).
      Interestingly, some tumor samples with normal E-cadherin expression yielded a
      methylation-specific PCR product. We hypothesized that other cells than tumor
      cells contribute to these products. Since in normal breast tissue no CDH1
      promoter methylation is detected, infiltrating leukocytes, often present in
      tumors, might account for these methylation-specific fragments. Indeed, a
      methylation-specific fragment is found in all twelve leukocyte samples tested.
      Furthermore, activated T-cells also yielded a methylation-specific fragment.
      Sequencing of these fragments reveals two distinct methylation profiles.
      Leukocytes have only partial methylation of some CpGs, while the tumor-associated
      methylation profile shows complete methylation of most CpGs. Therefore, to assess
      whether CDH1 methylation is tumor associated, sequencing of MSP products is a
      prerequisite. Here we show that out of six lobular tumors lacking E-cadherin
      protein expression, three have tumor-associated CDH1 promoter methylation while
      in three other tumors no methylation is detected.

PMID- 15178463
TI  - Driving and riding avoidance following motor vehicle crashes in a non-clinical
      sample: psychometric properties of a new measure.
AB  - Three studies were conducted to assess the reliability and validity of a measure
      that we developed using a non-clinical sample of university undergraduates, the
      Driving and Riding Avoidance Scale (DRAS). Study 1 indicated that the scale was
      internally consistent (alpha=0.92) and that a four-factor model (general
      avoidance, avoidance of traffic and busy roads, avoidance of weather or darkness,
      and riding avoidance) provided the best fit to the data in a sample of 386 crash
      survivors. This study also revealed that survivors who received medical treatment
      for their crash-related injuries reported significantly greater avoidance than
      people who were uninjured or injured and not medically treated. Study 2 revealed
      that the DRAS possessed acceptable test-retest reliability (r=0.83) over a 4-week
      interval in a sample of 67 crash survivors. Using a sample of 118 survivors,
      study 3 examined the instrument's convergent and divergent validity through
      correlations with the Accident Fear Questionnaire (AFQ), the Mobility Inventory
      (MI), the Fear Survey Schedule-II (FSS-II), and the Fear Questionnaire (FQ). The
      strongest relationships were observed between the DRAS and the AFQ and with a
      driving subscale created from the MI items. The DRAS exhibited significantly
      weaker relationships with the FQ subscales that assessed other kinds of phobic
      avoidance.

PMID- 15178464
TI  - Interpretive cues and ambiguity in generalized anxiety disorder.
AB  - The current study investigated whether generalized anxiety disorder (GAD)
      individuals rely on antecedent information to interpret ambiguity and whether
      reliance on such preceding cues persists in the absence of potential threat.
      Twenty-six GAD and 23 nonanxious control college students performed a lexical
      decision task, using homographs (i.e. words with multiple meanings) as ambiguous
      primes. In half the trials, a homograph prime that possessed both threat-related,
      as well as neutral meanings was followed by a target word related to one of these
      two meanings. In addition, each ambiguous prime was immediately preceded by a
      series of four antecedent words that were either: (a) associated with the
      threatening meaning of the prime; (b) associated with the neutral meaning of the
      prime; or (c) unrelated to either meaning of the homograph, as well as the
      target. Homographs for which both meanings were neutral in valence comprised the
      other half of the trials. Effect size statistics suggest that GAD participants
      utilized the antecedent words to interpret the homograph primes with threat
      related meanings, unlike their nonanxious counterparts (p<0.06). When both
      meanings of the homograph prime were neutral in valence, the GAD group appeared
      deficient in the use of preceding information to interpret the ambiguous prime.

PMID- 15178465
TI  - Symmetry, ordering and arranging compulsive behaviour.
AB  - Compulsive ordering and arranging, and a preoccupation with symmetry are features
      of obsessive-compulsive disorder (OCD) that have not been examined
      experimentally. Three connected studies were conducted to examine this
      phenomenon: a self-report measure of this behaviour was developed and validated,
      participants were asked to engage in tasks designed to assess preferences for
      order, and to assess the interference of disorderly surroundings in the
      completion of a stressful activity. The self-report measure has sound
      psychometric properties and validity. Participants with a strong preference for
      order were made more anxious by having to complete a difficult task in a
      disorganized environment. Participants without this preference did not show this
      effect. The results are discussed in terms of the phenomenology of compulsive
      ordering and arranging, and its relationships with both OCD and normal human
      behaviour. It is suggested that compulsive ordering and a drive for symmetry are
      extreme manifestations of the common preference for order and symmetry.

PMID- 15178466
TI  - The effects of self-focused attention, performance demand, and dispositional
      sexual self-consciousness on sexual arousal of sexually functional and
      dysfunctional men.
AB  - Sexually functional (N=26) and sexually dysfunctional heterosexual men with
      psychogenic erectile disorder (N=23) viewed two sexually explicit videos.
      Performance demand was manipulated through verbal instruction that a substantial
      genital response was to be expected from the videos. Self-focused attention was
      manipulated by introducing a camera pointed at the participant. Dispositional
      self-consciousness was assessed by questionnaire. Performance demand was found to
      independently inhibit the genital response. No main effect of self-focus was
      found. Self-focus inhibited genital response in men scoring high on general and
      sexual self-consciousness traits, whereas it enhanced penile tumescence in low
      self-conscious men. Inhibition effects were found in both volunteers and
      patients. No interaction effects of performance demand and self-focus were found.
      Subjective sexual arousal in sexually functional men was highest in the self
      focus condition. In sexually dysfunctional men, subjective sexual response proved
      dependent on locus of attention as well as presentation order.

PMID- 15178467
TI  - Trait anxiety, trait depression, worry, and memory.
AB  - A study is reported which investigated the proposal that high trait anxiety is
      associated with a memory bias for worry themes. Forty-five participants were
      categorised as being high or low trait anxious on the basis of scores on the
      (Spielberger et al., 1983) (Manual for the State-Trait Anxiety Inventory (Form Y)
      (1983)). The participants were requested to rate a number of worry and non-worry
      statements for how much they generally thought about the issues represented by
      them. Analysis of the ratings given by the participants showed that low trait
      anxiety individuals thought about the non-worry items significantly more than
      worry items. The high trait anxiety participants, however, showed little or no
      difference in the amount of time spent thinking about worry and non-worry themes.
      In a subsequent free recall task of the statements it was observed that the low
      trait anxiety group recalled significantly more non-worry than worry items,
      whereas there was no such difference for the high trait group. It was also found
      that the degree of memory bias was related to both positive affectivity and trait
      anxiety. The implications of such findings are discussed.

PMID- 15178468
TI  - Preattentive bias for snake words in snake phobia?
AB  - Stroop interference and skin conductance responses (SCRs) for words related to
      snakes, spiders, flowers, and mushrooms were studied in a group of women (n=40)
      with snake phobia who were randomised to a stress or no-stress condition. The 21
      low-stress snake phobics showed Stroop interference for unmasked (but not for
      masked) snake words, compared with 21 age- and sex-matched controls. Stroop
      interference was not significantly different between high-stress and low-stress
      snake phobics. No support for stronger SCRs for masked snake words was found in
      snake phobics in a lexical decision task with masked presentations of the same
      words. The lack of a masked Stroop interference in snake phobics suggests a
      possible difference in cognitive-emotional mechanisms underlying specific phobia
      vs. other anxiety disorders that deserves further investigation.

PMID- 15178469
TI  - Cell surface oxygen consumption by mitochondrial gene knockout cells.
AB  - Mitochondrial gene knockout (rho(0)) cells that depend on glycolysis for their
      energy requirements show an increased ability to reduce cell-impermeable
      tetrazolium dyes by electron transport across the plasma membrane. In this
      report, we show for the first time, that oxygen functions as a terminal electron
      acceptor for trans-plasma membrane electron transport (tPMET) in HL60rho(0)
      cells, and that this cell surface oxygen consumption is associated with oxygen
      dependent cell growth in the absence of mitochondrial electron transport
      function. Non-mitochondrial oxygen consumption by HL60rho(0) cells was
      extensively inhibited by extracellular NADH and NADPH, but not by NAD(+),
      localizing this process at the cell surface. Mitochondrial electron transport
      inhibitors and the uncoupler, FCCP, did not affect oxygen consumption by
      HL60rho(0) cells. Inhibitors of glucose uptake and glycolysis, the ubiquinone
      redox cycle inhibitors, capsaicin and resiniferatoxin, the flavin centre
      inhibitor, diphenyleneiodonium, and the NQO1 inhibitor, dicoumarol, all inhibited
      oxygen consumption by HL60rho(0) cells. Similarities in inhibition profiles
      between non-mitochondrial oxygen consumption and reduction of the cell
      impermeable tetrazolium dye, WST-1, suggest that both systems may share a common
      tPMET pathway. This is supported by the finding that terminal electron acceptors
      from both pathways compete for electrons from intracellular NADH.

PMID- 15178470
TI  - Thermoinactivation analysis of vacuolar H(+)-pyrophosphatase.
AB  - Vacuolar H(+)-translocating pyrophosphatase (H(+)-PPase; EC 3.6.1.1) catalyzes
      both the hydrolysis of PP(i) and the electrogenic translocation of proton from
      the cytosol to the lumen of the vacuole. Vacuolar H(+)-PPase, purified from
      etiolated hypocotyls of mung bean (Vigna radiata L.), is a homodimer with a
      molecular mass of 145 kDa. To investigate the relationship between structure and
      function of this H(+)-translocating enzyme, thermoinactivation analysis was
      employed. Thermoinactivation studies suggested that vacuolar H(+)-PPase consists
      of two distinct states upon heat treatment and exhibited different transition
      temperatures in the presence and absence of ligands (substrate and inhibitors).
      Substrate protection of H(+)-PPase stabilizes enzyme structure by increasing
      activation energy from 54.9 to 70.2 kJ/mol. We believe that the conformation of
      this enzyme was altered in the presence of substrate to protect against the
      thermoinactivation. In contrast, the modification of H(+)-PPase by inhibitor
      (fluorescein 5'-isothiocyanate; FITC) augmented the inactivation by heat
      treatment. The native, substrate-bound, and FITC-labeled vacuolar H(+)-PPases
      possess probably distinct conformation and show different modes of susceptibility
      to thermoinactivation. Our results also indicate that the structure of one
      subunit of this homodimer exerts long distance effect on the other, suggesting a
      specific subunit-subunit interaction in vacuolar H(+)-PPase. A working model was
      proposed to interpret the relationship of the structure and function of vacuolar
      H(+)-PPase.

PMID- 15178471
TI  - Rotenone-sensitive mitochondrial potential in Phytomonas serpens: electrophoretic
      Ca(2+) accumulation.
AB  - Phytomonas sp. are flagellated trypanosomatid plant parasites that cause diseases
      of economic importance in plantations of coffee, oil palm, cassava and coconuts.
      Here we investigated Ca(2+) uptake by the vanadate-insensitive compartments using
      permeabilized Phytomonas serpens promastigotes. This uptake occurs at a rate of
      1.13+/-0.23 nmol Ca(2+) mg x protein(-1) min(-1). It is completely abolished by
      the H(+) ionophore FCCP and by valinomycin and nigericin. It is also inhibited by
      2 microM ruthenium red, which, at this low concentration, is known to inhibit the
      mitochondrial calcium uniport. Furthermore, salicylhydroxamic acid (SHAM) and
      propylgallate, specific inhibitors of the alternative oxidase in plant and
      parasite mitochondria, are also effective as inhibitors of the Ca(2+) transport.
      These compounds abolish the membrane potential that is monitored with safranine
      O. Rotenone, an inhibitor of NADH-CoQ oxidoreductase, can also dissipate 100% of
      the membrane potential. It is suggested that the mitochondria of P. serpens can
      be energized via oxidation of NADH in a pathway involving the NADH-CoQ
      oxidoreductase and the alternative oxidase to regenerate the ubiquinone. The
      electrochemical H(+) gradient can be used to promote Ca(2+) uptake by the
      mitochondria.

PMID- 15178472
TI  - Energy transfer and trapping in the Photosystem I complex of Synechococcus PCC
      7942 and in its supercomplex with IsiA.
AB  - The cyanobacterium Synechococcus PCC 7942 grown under iron starvation assembles a
      supercomplex consisting of a trimeric Photosystem I (PSI) complex encircled by a
      ring of 18 CP43' or IsiA complexes. It has previously been shown that PSI of
      Synechococcus PCC 7942 contains less special long-wavelength ('red') chlorophylls
      than PSI of most other cyanobacteria. Here we present a comparative analysis by
      time-resolved absorption difference and fluorescence spectroscopy of the
      processes of energy transfer and trapping in trimeric PSI and PSI-IsiA
      supercomplexes from Synechococcus PCC 7942. All experiments were performed with
      the primary electron donor of PSI (P700) in the oxidized state. Our data suggest
      that in the PSI complex the excitation energy is equilibrated with a lifetime of
      0.6 ps among the so-called bulk chlorophylls, is distributed in 3-4 ps between
      the bulk and red chlorophylls, and is trapped in the reaction center in 19 ps.
      This trapping time is shorter than that observed for other cyanobacteria, which
      we attribute to the lower content of red chlorophylls in PSI of this organism. In
      the PSI-IsiA supercomplexes, the distribution of excited states is blue-shifted
      compared to that in PSI, leading to a lengthening of the equilibration processes.
      We attributed a phase of about 1 ps to initial energy equilibration steps among
      the IsiA and PSI core bulk chlorophylls, a 5-7 ps phase to equilibration between
      bulk and red chlorophylls within the PSI core, and a 38 ps phase to trapping in
      the reaction center. The data suggest that the excitation energy is equilibrated
      among the IsiA and PSI core antenna chlorophylls before trapping occurs. Data
      analysis based on a simple kinetic model revealed an intrinsic rate constant for
      energy transfer from IsiA to PSI in the range of 2+/-1 ps. Based on this value we
      suggest the presence of one or more linker chlorophylls between the IsiA and PSI
      core complexes. These results confirm that IsiA acts as an effective light
      harvesting antenna for PSI.

PMID- 15178473
TI  - Apparent redundancy of electron transfer pathways via bc(1) complexes and
      terminal oxidases in the extremophilic chemolithoautotrophic Acidithiobacillus
      ferrooxidans.
AB  - Acidithiobacillus ferrooxidans is an acidophilic chemolithoautotrophic bacterium
      that can grow in the presence of either the weak reductant Fe(2+), or reducing
      sulfur compounds that provide more energy for growth than Fe(2+). We have
      previously shown that the uphill electron transfer pathway between Fe(2+) and
      NAD(+) involved a bc(1) complex that functions only in the reverse direction [J.
      Bacteriol. 182, (2000) 3602]. In the present work, we demonstrate both the
      existence of a bc(1) complex functioning in the forward direction, expressed when
      the cells are grown on sulfur, and the presence of two terminal oxidases, a bd
      and a ba(3) type oxidase expressed more in sulfur than in iron-grown cells,
      besides the cytochrome aa(3) that was found to be expressed only in iron-grown
      cells. Sulfur-grown cells exhibit a branching point for electron flow at the
      level of the quinol pool leading on the one hand to a bd type oxidase, and on the
      other hand to a bc(1)-->ba(3) pathway. We have also demonstrated the presence in
      the genome of transcriptionally active genes potentially encoding the subunits of
      a bo(3) type oxidase. A scheme for the electron transfer chains has been
      established that shows the existence of multiple respiratory routes to a single
      electron acceptor O(2). Possible reasons for these apparently redundant pathways
      are discussed.

PMID- 15178474
TI  - Characterization of the bonding interactions of Q(B) upon photoreduction via A
      branch or B-branch electron transfer in mutant reaction centers from Rhodobacter
      sphaeroides.
AB  - In Rhodobacter sphaeroides reaction centers (RCs) containing the mutation Ala
      M260 to Trp (AM260W), transmembrane electron transfer along the full-length of
      the A-branch of cofactors is prevented by the loss of the Q(A) ubiquinone, but it
      is possible to generate the radical pair P(+)H(A)(-) by A-branch electron
      transfer or the radical pair P(+)Q(B)(-) by B-branch electron transfer. In the
      present study, FTIR spectroscopy was used to provide direct evidence for the
      complete absence of the Q(A) ubiquinone in mutant RCs with the AM260W mutation.
      Light-induced FTIR difference spectroscopy of isolated RCs was also used to probe
      the neutral Q(B) and the semiquinone Q(B)(-) states in two B-branch active
      mutants, a double AM260W-LM214H mutant, denoted WH, and a quadruple mutant,
      denoted WAAH, in which the AM260W, LM214H, and EL212A-DL213A mutations were
      combined. The data were compared to those obtained with wild-type (Wt) RCs and
      the double EL212A-DL213A (denoted AA) mutant which exhibit the usual A-branch
      electron transfer to Q(B). The Q(B)(-)/Q(B) spectrum of the WH mutant is very
      close to that of Wt RCs indicating similar bonding interactions of Q(B) and Q(B)(
      ) with the protein in both RCs. The Q(B)(-)/Q(B) spectra of the AA and WAAH
      mutants are also closely related to one another, but are very different to that
      of the Wt complex. Isotope-edited IR fingerprint spectra were obtained for the AA
      and WAAH mutants reconstituted with site-specific (13)C-labeled ubiquinone.
      Whilst perturbations of the interactions of the semiquinone Q(B)(-) with the
      protein are observed in the AA and WAAH mutants, the FTIR data show that the
      bonding interaction of neutral Q(B) in these two mutants are essentially the same
      as those for Wt RCs. Therefore, it is concluded that Q(B) occupies the same
      binding position proximal to the non-heme iron prior to reduction by either A
      branch or B-branch electron transfer.

PMID- 15178476
TI  - Arsenite oxidation by the heterotroph Hydrogenophaga sp. str. NT-14: the arsenite
      oxidase and its physiological electron acceptor.
AB  - Heterotrophic arsenite oxidation by Hydrogenophaga sp. str. NT-14 is coupled to
      the reduction of oxygen and appears to yield energy for growth. Purification and
      partial characterization of the arsenite oxidase revealed that it (1). contains
      two heterologous subunits, AroA (86 kDa) and AroB (16 kDa), (2). has a native
      molecular mass of 306 kDa suggesting an alpha(3)beta(3) configuration, and (3).
      contains molybdenum and iron as cofactors. Although the Hydrogenophaga sp. str.
      NT-14 arsenite oxidase shares similarities to the arsenite oxidases purified from
      NT-26 and Alcaligenes faecalis, it differs with respect to activity and overall
      conformation. A c-551-type cytochrome was purified from Hydrogenophaga sp. str.
      NT-14 and appears to be the physiological electron acceptor for the arsenite
      oxidase. The cytochrome can also accept electrons from the purified NT-26
      arsenite oxidase. A hypothetical electron transport chain for heterotrophic
      arsenite oxidation is proposed.

PMID- 15178475
TI  - Yessotoxin, a shellfish biotoxin, is a potent inducer of the permeability
      transition in isolated mitochondria and intact cells.
AB  - The diarrhetic poisoning by bivalve molluscs, diarrhetic shellfish poisoning, is
      due to consumption of mussels containing biotoxins produced by some
      Dinoflagellate species. Toxic effects of yessotoxin (YTX) include morphological
      alterations of mitochondria from heart and liver but the biochemical basis for
      these alterations is completely unknown. This paper demonstrates that YTX is a
      very powerful compound that opens the permeability transition pore (PTP) of the
      inner mitochondrial membrane of rat liver mitochondria at nanomolar
      concentrations. The effect requires the presence of a permissive level of
      calcium, by itself incapable of opening the pore. The direct effect of YTX on PTP
      is further confirmed by the inhibition exerted by cyclosporin A (CsA) that is
      known as a powerful inhibitor of PTP opening. Moreover, YTX induces membrane
      depolarization as shown by the quenching of tetramethylrhodamine methyl ester
      (TMRM), also prevented by the addition of CsA. YTX caused PTP opening in Morris
      Hepatoma 1C1 cells, as shown by the occurrence of CsA-sensitive depolarization
      within minutes of the addition of submicromolar concentrations of the toxin.
      These results provide a biochemical basis for the mitochondrial alterations
      observed in the course of intoxication with YTX, offering the first clue into the
      pathogenesis of diseases caused by YTX, and providing a novel tool to study the
      PTP in situ.

PMID- 15178477
TI  - Inhibition studies on Rhodospirillum rubrum H(+)-pyrophosphatase expressed in
      Escherichia coli.
AB  - The membrane-bound proton-pumping inorganic pyrophosphatase from Rhodospirillum
      rubrum was heterologously expressed in Escherichia coli C43(DE3) cells and was
      inhibited by 4-bromophenacyl bromide (BPB), N,N'-dicyclohexylcarbodiimid (DCCD),
      diethyl pyrocarbonate (DEPC) and fluorescein 5'-isothiocyanate (FITC). In each
      case, the enzyme activity was rather well protected against inhibitory action by
      the substrate Mg(2)PPi. Site-directed mutagenesis was employed in attempts to
      identify target residues for these inhibitors. D217 and K469 appear to be the
      prime targets for DCCD and FITC, respectively, and may thus be involved in
      substrate binding. No major effect on enzyme activities was seen when any one of
      the four histidine residues present in the enzyme were substituted. Nevertheless,
      a mutant with all of the four charged histidine residues replaced retained only
      less than 10% of the hydrolysis and proton-pumping activities. Substitution of
      D217 with A or H yielded an enzyme with at least an order of magnitude lower
      hydrolysis activity. In contrast with the wild-type, these variants showed higher
      hydrolysis rates at lower concentrations of Mg(2+), possibly reflecting a change
      in substrate preference from Mg(2)PPi to MgPPi. BPB is a H(+)-pyrophosphatase
      inhibitor that apparently has not been used previously as an inhibitor of these
      enzymes.

PMID- 15178478
TI  - Cyclic electron flow under saturating excitation of dark-adapted Arabidopsis
      leaves.
AB  - The rate of cyclic electron flow measured in dark-adapted leaves under aerobic
      conditions submitted to a saturating illumination has been performed by the
      analysis of the transmembrane potential changes induced by a light to dark
      transfer. Using a new highly sensitive spectrophotometric technique, a rate of
      the cyclic flow of approximately 130 s(-1) has been measured in the presence or
      absence of 3-(3,4-dichloro-phenyl)-1,1-dimethylurea (DCMU). This value is
      approximately 1.5 times larger than that previously reported [Proc. Natl. Acad.
      Sci. U. S. A. 99 (2001) 10209]. We have characterized in the presence or absence
      of DCMU charge recombination process (t(1/2) approximately 60 micros) that
      involves P(700)(+) and very likely the reduced form of the iron sulfur acceptor
      F(X). This led to conclude that, under saturating illumination, the PSI centers
      involved in the cyclic pathway have most of the iron sulfur acceptors F(A) and
      F(B) reduced. In the proposed mechanism, electrons are transferred from a
      ferredoxin bound to a site localized on the stromal side of the cytochrome b(6)f
      complex to the Q(i) site. Two possible models of the organization of the membrane
      complexes are discussed, in which the cyclic and linear electron transfer chains
      are isolated one from the other.

PMID- 15178479
TI  - Stark effect measurements on monomers and trimers of reconstituted light
      harvesting complex II of plants.
AB  - The electric-field induced absorption changes (Stark effect) of reconstituted
      light-harvesting complex II (LHCII) in different oligomerisation states-monomers
      and trimers-with different xanthophyll content have been probed at 77 K. The
      Stark spectra of the reconstituted control samples, containing the xanthophylls
      lutein and neoxanthin, are very similar to previously reported spectra of native
      LHCII. Reconstituted LHCII, containing lutein but no neoxanthin, shows a similar
      electrooptical response in the Chl a region, but the Stark signal of Chl b around
      650 nm amounts to at most approximately 25% of that of the control samples. We
      conclude that neoxanthin strongly modifies the electronic states of the nearby
      Chl b molecules causing a large electrooptical response at 650 nm stemming from
      one or more Chls b in the control samples. Ambiguities about the assignment of
      several bands in the Soret region [Biochim. Biophys. Acta 1605 (2003) 83] are
      resolved and the striking difference in electric field response between the two
      lutein molecules is confirmed. The Stark effect in the carotenoid spectral region
      in both control and neoxanthin-deficient samples is almost identical, showing
      that the neoxanthin Stark signal is small and much less intense than the lutein
      Stark signal.

PMID- 15178481
TI  - Photoaccumulation of two ascorbyl free radicals per photosystem I at 200 K.
AB  - Illumination of photosystem I (PSI) from the cyanobacterium Synechocystis sp. PCC
      6803 at 200 K in the presence of ascorbate leads to the formation of two ascorbyl
      radicals per PSI, which are formed by P700(+) reduction by ascorbate. During
      photoaccumulation, one half of the ascorbyl radicals is formed with a halftime of
      1 min and the other half with a halftime of 7 min. Pulsed electron paramagnetic
      resonance (EPR) experiments with protonated/deuterated PSI show that a PSI
      proton/deuteron is strongly coupled to the ascorbyl radical. Our data indicate
      that reactive ascorbate molecules bind to PSI at two specific locations, which
      might be symmetrically located with respect to the pseudo-C(2) axis of symmetry
      of the heterodimeric core of PSI. Reduction of P700(+) by ascorbate leads to
      multiple turnover of PSI photochemistry, resulting in partial photoaccumulation
      of the doubly reduced species (F(A)(-), F(B)(-)). A modified form of F(B)(-)-in
      accordance with Chamorovsky and Cammack [Biochim. Biophys. Acta 679 (1982) 146
      155], but not of F(A)(-), is observed by EPR after illumination at 200 K, which
      indicates that reduction of F(B) at 200 K is followed by some relaxation process,
      in line with this cluster being the most exposed to the solvent.

PMID- 15178480
TI  - Quantum molecular dynamics simulation of proton transfer in cytochrome c oxidase.
AB  - Proton transfer/translocation is studied in cytochrome c oxidase (CcO) by a
      combination of quantum mechanics (QM) for the transferring protons and classical
      molecular dynamics (MD) for the protein and solvent. The possibility of a
      glutamate, Glu286 in the Rhodobacter sphaeroides numbering scheme, acting as a
      rely point for proton translocation is investigated. The MD finds a hydrogen
      bonded cycle of two waters and the carboxylate oxygens of Glu286. The possibility
      of protonating Glu286 to form neutral GluH is studied and we find that, as
      experimentally inferred, this glutamate can spend most of its time as GluH. Since
      translocation relies on the presence of water chains within CcO channels, MD is
      used to assess their formation. Glu286 and Mg(2+) can be connected by continuous
      hydrogen-bonded chains that are robust, though transient, and the protein appears
      spongy above (toward the outer membrane) the Mg(2+). In contrast, the D-channel
      spanning Asp132, close to the inner membrane surface, to Glu286, forms water
      chains that are much sparser and do not continuously connect these residues.
      Rather, there are chains spanning Glu286 to the vicinity of Asn140, and other
      more robust and ramified water structures that connect Asp132 with waters close
      to Asn140.

PMID- 15178482
TI  - Involvement of lysine-193 of the conserved "K-T-G-G" motif in the catalysis of
      maize starch synthase IIa.
AB  - It has been suggested that the lysine residue in the conserved K-T-G-G motif
      could be the substrate ADP-glucose binding site of Escherichia coli glycogen
      synthase (GS). Since the K-X-G-G motif is highly conserved between E. coli GS and
      all the maize starch synthase (SS) isozymes, it has become widely accepted that
      the lysine in the conserved K-T-G-G motif may also function as the ADPGlc binding
      site of maize SS. We have used chemical modification and site-directed
      mutagenesis to study the function of lysine residues in SS. Pyridoxal-5'
      phosphate inactivated maize SSIIa activity in a time and concentration dependent
      manner. ADPGlc completely protected SSIIa from inactivation by pyridoxal-5'
      phosphate, indicating that lysine residue(s) could be important for ADPGlc
      binding and enzyme catalysis. In contrast to E. coli GS, mutation of conserved
      lysine193 (K-T-G-G) in maize SS did not alter the ADPGlc binding while
      significantly changing the enzyme activity toward different primers. Our results
      suggest that lysine-193 (K-T-G-G) is not directly involved in ADPGlc binding,
      instead mutation in the conserved lysine position affected the primer preference.

PMID- 15178483
TI  - Expression of calpastatin isoforms in muscle and functionality of multiple
      calpastatin promoters.
AB  - Calpastatin is the specific endogenous inhibitor of calpain proteinase that is
      encoded by a single gene. Transient transfection assays in both a non-fusing
      skeletal muscle and non-muscle cell-line demonstrated that the putative porcine
      calpastatin promoter regions 5' to exons 1xa, 1xb, and 1u were functional. Both
      real-time quantitative and semi-quantitative RT-PCR on porcine skeletal muscle
      total RNA indicated that steady-state expression of Type I and III mRNAs
      containing exons 1xa and 1u, respectively, was at equivalent levels whilst the
      expression of Type II mRNA containing exon 1xb was significantly less (p<0.001).
      Immunoprobing of Western blotted muscle extracts with an antibody raised against
      a peptide sequence encoded by exon 1xa indicated that Type I protein was
      expressed and that there was significantly more Type I protein in cardiac than
      skeletal muscle (p<0.001). The results suggest that the expression of the single
      calpastatin gene was differentially controlled at several levels.

PMID- 15178484
TI  - Acetaminophen stimulates the peroxidative metabolism of anthracyclines.
AB  - Acetaminophen, a common analgesic and antipyretic drug, is frequently
      administered to individuals undergoing anthracycline chemotherapy. Here, the
      effect of acetaminophen on the metabolism of daunorubicin and doxorubicin by
      isolated enzymes lactoperoxidase and myeloperoxidase, and by myeloperoxidase
      containing human leukemia HL-60 cells was investigated using spectrophotometric
      and EPR techniques. We report that at pharmacological concentrations
      acetaminophen strongly stimulates oxidation of the anthracyclines by
      lactoperoxidase and myeloperoxidase systems, which results in irreversibly
      altered (colorless) products. The initial rate and efficacy of daunorubicin
      oxidation depends on pH. While at pH approximately 7 the oxidation is rapid and
      extensive, almost no oxidation occurs at pH approximately 5. In the absence of
      daunorubicin, oxidation of acetaminophen by lactoperoxidase/hydrogen peroxide is
      only weakly dependent on pH, however, at pH 7.4 it strongly depends on
      [daunorubicin]. Ascorbate and reduced glutathione strongly inhibited oxidation of
      anthracyclines by lactoperoxidase and HL-60 systems. Using EPR, a daunorubicin
      derived radical was detected in a daunorubicin/acetaminophen/peroxidase/hydrogen
      peroxide system as a narrow single line (0.175 mT) with g = 2.0047. When
      daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected
      (g = 2.0043, line width approximately 0.5 mT). Similar results were obtained with
      doxorubicin. We suggest that the stimulation by acetaminophen is primarily due to
      its preferential oxidation by peroxidases to the corresponding phenoxyl radical,
      which subsequently reacts with daunorubicin (doxorubicin). Because biological
      properties of oxidatively transformed anthracyclines will certainly be different
      from those of their parent compounds, the possible acetaminophen-enhanced
      degradation of the anthracyclines in vivo is likely to interfere with anticancer
      and/or cardiotoxic activities of these agents.

PMID- 15178485
TI  - A novel ribotoxin with ribonuclease activity that specifically cleaves a single
      phosphodiester bond in rat 28S ribosomal RNA and inactivates ribosome.
AB  - A unique ribonuclease named Biota orientalis ribonuclease (Biota orientalis
      RNase) is purified to homogeneity from mature seeds of oriental arborvitae (Biota
      orientalis). The molecular mass of Biota orientalis RNase is about 13 kDa. When
      the concentration of Mg(2+) is 25 mM in the incubation buffer, the ribonuclease
      specifically cleaves the phosphodiester bond between C4453 and A4454 in region K
      (a region in domain VII) of 28S RNA in rat ribosome, resulting in inactivation of
      ribosome. Thus, it is a ribotoxin similar to alpha-sarcin. The region around
      C4453-A4454 in rat 28S rRNA is named "Biota orientalis RNase region." Rat
      ribosome treated by Biota orientalis RNase produces a small RNA fragment (S
      fragment) that contains 333 nucleotides from the 3'-terminus of rat 28S rRNA. The
      distance between the cleavage-sites of alpha-sarcin (G4325) and Biota orientalis
      RNase (C4453) is 128 nucleotides. Under restricted conditions (25 mM Mg(2+)), the
      substrate specificity of Biota orientalis RNase is extremely high: it acts only
      on the "Biota orientalis RNase region" of the largest RNA in ribosomes from
      certain eukaryotes. The ribosome specifically damaged by Biota orientalis RNase
      is unable to EF-1alpha-dependently bind aminoacyl-tRNA, whereas the formation of
      the EF-2/GDP/ribosome complex is not affected. It is proposed that Biota
      orientalis RNase inactivates ribosome at least partially by interfering with the
      EF-1alpha-dependent binding of aminoacyl-tRNA to ribosome. Biota orientalis RNase
      might be a useful tool in studying the structure/function of ribosome.

PMID- 15178486
TI  - Intermolecular interactions in the AhpC/AhpD antioxidant defense system of
      Mycobacterium tuberculosis.
AB  - The AhpC/AhpD system of Mycobacterium tuberculosis provides important antioxidant
      protection, particularly when the KatG catalase-peroxidase activity is depressed,
      as it is in many isoniazid resistant strains. In the absence of lipoamide or
      bovine dihydrolipoamide dehydrogenase (DHLDH), components of the normal catalytic
      system, covalent dimers, tetramers, and hexamers are formed when a mixture of
      AhpC and AhpD is exposed to peroxide. Each of the oligomers contains equimolar
      amounts of AhpC and AhpD. This oligomerization is reversible because the
      oligomers can be fully reduced to the monomeric species by dithiothreitol. Using
      mutagenesis, we confirm here that Cys61 and Cys174 of AhpC as well as Cys133 and
      Cys130 of AhpD are critical for activity in the fully reconstituted system
      consisting of AhpC, AhpD, lipoamide, DHLDH, and NADH. A key step in the reduction
      of oxidized AhpC by reduced AhpD is formation of a disulfide cross-link between
      Cys61 of AhpC and Cys133 of AhpD. This cross-link can be reduced by
      intramolecular reaction with either Cys174 of AhpC or Cys130 of AhpD. Cys176 can
      also, to some extent, substitute for Cys174, providing a measure of redundancy
      that helps to maintain the efficiency of this antioxidant protective system.

PMID- 15178487
TI  - Molecular cloning and characterization of a cytochrome P450 taxoid 2alpha
      hydroxylase involved in Taxol biosynthesis.
AB  - The Taxol biosynthetic pathway, arising from the primary isoprenoid precursors
      isopentenyl diphosphate and dimethylallyl diphosphate in yew (Taxus), consists of
      approximately twenty steps, at least nine of which are thought to be cytochrome
      P450-mediated oxygenations. Several oxygenases involved in the early
      hydroxylation steps of the pathway have been identified and the corresponding
      genes have been cloned; however, defining the enzymes and their genes responsible
      for oxygenations in the central portion of the pathway is more difficult because
      neither the exact sequence of reactions nor the relevant intermediates are known.
      A surrogate substrate, (+)-taxusin (taxa-4(20),11(12)-dien
      5alpha,9alpha,10beta,13alpha-tetraol tetraacetate), that was previously employed
      in the isolation of a taxoid 7beta-hydroxylase, was used here to functionally
      screen a family of cytochrome P450 oxygenases originating from a Taxus cell EST
      library. This in vivo screen in yeast led to the identification of a 1488bp cDNA
      clone (encoding a 495 residue protein) that was capable of producing 2alpha
      hydroxytaxusin from taxusin with a K(m) value of 10.5 +/- 2.7 microM and k(cat)
      of about 0.05 s(-1) for the surrogate substrate. This structurally typical
      cytochrome P450 resembles most closely the previously isolated taxoid 7beta
      hydroxylase, which also uses taxusin as a substrate, and both 2alpha- and 7beta
      hydroxylases are capable of the reciprocal conversion of their respective pentaol
      tetraacetate products to the common hexaol tetraacetate. This C2-hydroxylase
      would appear to mediate the mid-pathway functionalization of the C2-position of
      the taxane core that ultimately bears a benzoyl group as an important Taxol
      pharmacophore. Overexpression of this cytochrome P450 taxoid 2alpha-hydroxylase
      in Taxus cells may improve Taxol yields and could prove useful in the production
      of other 2alpha-hydroxy taxoids as starting materials for subsequent acylation at
      this position.

PMID- 15178488
TI  - Biochemical and molecular biological analysis of different responses to 2,3,7,8
      tetrachlorodibenzo-p-dioxin in chick embryo heart and liver.
AB  - We studied the mechanism of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD) in the chick embryo, which is an organism highly sensitive to TCDD. TCDD
      was injected into egg yolks prior to embryogenesis, and eggs were incubated for
      12 or 18 days. In TCDD-exposed embryos, we observed increased heart wet weight
      and change in the color of the liver, with abnormal fatty vesicle formation. To
      determine whether these effects were mediated by the aryl hydrocarbon receptor
      (AhR), we examined expression levels of AhR, CYP1A4, and CYP1A5. AhR was
      expressed continuously in the heart and liver during embryogenesis, whereas
      induction of CYP1A4 and CYP1A5 by TCDD was detected only in the liver. In situ
      hybridization study of tissue sections revealed induction of CYP1A4 in the
      abnormal liver tissue in which color change was not observed. To determine
      whether these different responses to TCDD depended on the cell type, primary
      cultures of chick hepatocytes and cardiac myocytes were established and 7
      ethoxyresorufin-O-deethylase (EROD) activity was measured. Induction of EROD
      activity following exposure to TCDD was detected in hepatocytes but not in
      cardiac myocytes. Although the heart is a principal target organ for TCDD
      toxicity and AhR is expressed throughout embryogenesis, induction of CYP1A was
      not observed in the chick heart. Thus, we conclude that defects in the heart
      induced by exposure to TCDD occur via a different pathway than that occurring in
      the liver.

PMID- 15178489
TI  - Eukaryotic initiation factor 2-associated glycoprotein, p67, shows differential
      effects on the activity of certain kinases during serum-starved conditions.
AB  - Phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 is the
      major regulatory step in the initiation of protein synthesis in mammals. P67, a
      cellular glycoprotein, protects phosphorylation of eIF2alpha from kinases. P67
      has five conserved amino acid residues at the D251, D262, H331, E364, and E459
      positions. To determine the roles of these conserved amino acid residues in
      eIF2alpha phosphorylation during serum-starved conditions, we constitutively
      expressed D251A, D262A, H331A, E364A, and E459A mutants in rat tumor hepatoma
      cells. We find that the point mutants D251A, H331A, and E364A lower the levels of
      eIF2alpha phosphorylation. These low levels of phosphorylation decrease when
      serum-starved cells are grown in medium containing serum. To understand the
      mechanism of action of the p67 mutants in eIF2alpha phosphorylation during serum
      starvation, we performed detailed biochemical analyses with the D251A mutant. We
      find that neither the O-GlcNAc modification on the D251A mutant nor the binding
      of D251A mutant with eIF2gamma has significant effects on eIF2alpha
      phosphorylation during serum-starved conditions. However, the D251A mutant
      inhibits p67's activity to suppress the activity of ERK1/2. Our data suggest that
      both p67 and the D251A mutant bind to ERK1, thus strengthening the idea that p67
      regulates the activity of ERK1. During serum-starvation conditions, both PKR and
      PERK are phosphorylated and the D251A mutant shows increased stability of PERK as
      well as a slight decrease in its activity. Altogether, our data provide evidence
      to suggest that p67 modulates the expression and activity of certain eIF2alpha
      specific kinases.

PMID- 15178490
TI  - Filamentous actin binding ability of cortactin isoforms is responsible for their
      cell-cell junctional localization in epithelial cells.
AB  - Cortactin is an F-actin binding protein that contributes to cytoskeleton
      remodelling. We identified five isoforms of mouse cortactin that differ in the
      number of tandem 37-amino acid repeats, named cortactin repeats. The
      transcription of minor isoforms with 4.5, 3.5 or 2.5 cortactin repeats was low in
      most adult tissues whereas an isoform with 4.5 cortactin repeats was highly
      transcribed in the adult brain. In accordance with the brain-specific
      upregulation of a minor isoform, a brain-specific novel 72-kDa cortactin protein
      was identified. Major isoforms with 6.5 or 5.5 cortactin repeats bound F-actin
      more robustly than minor isoforms in vitro. All isoforms were concentrated at
      cell-cell junction sites in epithelial cells. Deletion mutants lacking whole
      cortactin repeats did not bind F-actin and were not concentrated at cell-cell
      junction sites. Thus, the F-actin binding ability is mostly correlated with the
      number of cortactin repeats and is required for the cell-cell junctional
      localization.

PMID- 15178491
TI  - The monoclonal antibody mAB 1A binds to the excitation--contraction coupling
      domain in the II-III loop of the skeletal muscle calcium channel alpha(1S)
      subunit.
AB  - Interactions of the II-III loop of the voltage-gated Ca(2+) channel alpha(1S)
      subunit with the Ca(2+) release channel (RyR1) are essential for skeletal-type
      excitation-contraction (EC) coupling. Here, we characterized the binding site of
      the monoclonal alpha(1S) antibody mAB 1A and used it to probe the structure of
      the II-III loop in chimeras with different EC coupling properties. Phage-display
      epitope mapping of mAB 1A revealed a minimal consensus binding sequence X-P-X-X-D
      X-P. Immunofluorescence labeling of (1S), alpha(1C), alpha(1D), and of II-III
      loop chimeras expressed in dysgenic myotubes established that mAB 1A reacted
      specifically with amino acids 737-744 in the II-III loop of alpha(1S), which is
      within the domain (D734-L764) critical for bidirectional coupling with RyR1.
      Comparing mAB 1A immunoreactivity with known structural and functional properties
      of II-III loop chimeras in which the non-conserved skeletal residues were
      systematically mutated to their cardiac counterparts indicated a correlation of
      mAB 1A immunoreactivity and skeletal-type EC coupling.

PMID- 15178492
TI  - Partial identification of carbohydrate-binding sites of a
      Galalpha1,3Galbeta1,4GlcNAc-specific lectin from the mushroom Marasmius oreades
      by site-directed mutagenesis.
AB  - The Galalpha1,3Galbeta1,4GlcNAc-specific lectin from the mushroom Marasmius
      oreades (MOA) contains a ricin B chain-like (QXW)(3) domain at its N-terminus
      that is composed of three identical subdomains (alpha, beta, and gamma) and a C
      terminal domain of unknown function. Here, we investigate the structure-function
      relationship of MOA to define the number and location of its carbohydrate-binding
      sites. Based on the sequence alignment of MOA to the ricin B-chain lactose
      binding sites, we systematically constructed mutants by site-directed
      mutagenesis. We have used precipitation and hemagglutination assay for the
      primary analyses, and surface plasmon resonance for the kinetic analysis. Among
      amino acid residues at the putative carbohydrate-binding sites, Gln(46) in the
      alpha subdomain and Trp(138) in the gamma subdomain have been identified to be
      important amino acid residues directly or indirectly involved in carbohydrate
      recognition. By surface plasmon resonance, Q46A and W138A were 2.4- and 4.3-fold
      less active than that of the wild-type MOA (K(a) = 2 x 10(7)), respectively. A
      double-site mutant (Q46A/W138A) had activity similar to W138A. The C-terminal
      deletion mutant MOADeltaC showed hemagglutination and precipitation activity,
      although its binding constant was 12.5-fold less active (K(a) = 1.6 x 10(6)) than
      that of the wild-type MOA. A C-terminal deletion mutant with mutations at both
      Gln(46) and Trp(138) (MOADeltaC-Q46A/W138A) was 12,500-fold less active (K(a) =
      1.6 x 10(3)) than that of the wild-type MOA. On the basis of this observation, we
      conclude that both alpha and gamma subdomains are most probably involved in
      carbohydrate binding, but the beta subdomain appears to be inactive.

PMID- 15178493
TI  - Carnosine disaggregates glycated alpha-crystallin: an in vitro study.
AB  - Protein glycation, which promotes aggregation, involves the unwanted reaction of
      carbohydrate oxidation products with proteins. Glycation of lens alpha-crystallin
      occurs in vivo and may contribute to cataractogenesis. Anti-glycation compounds
      such as carnosine may be preventive, but interestingly carnosine reverses lens
      opacity in human trials. The mechanism for this observation may involve
      carnosine's ability to disaggregate glycated protein. We investigated this
      hypothesis using glycated alpha-crystallin as our in vitro model. Methylglyoxal
      induced glycation of alpha-crystallin caused aggregation as evidenced by
      increased 90 degrees light scattering. After addition of carnosine, light
      scattering returned to baseline levels suggesting that the size of the glycation
      induced aggregates decreased. Additionally, carnosine decreased tryptophan
      fluorescence polarization of glycated alpha-crystallin, suggesting that carnosine
      increased peptide chain mobility, which may contribute to the controlled
      unfolding of glycated protein. Comparatively, guanidine-HCl and urea had no
      effect. Our data support the hypothesis that carnosine disaggregates glycated
      alpha-crystallin.

PMID- 15178494
TI  - A non-active site mutation in human hypoxanthine guanine
      phosphoribosyltransferase expands substrate specificity.
AB  - Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) lacks the ability to
      phosphoribosylate xanthine, a property exhibited by HGPRTs from many parasitic
      protozoa. Using random mutagenesis we have obtained a mutant, F36L, of human
      HGPRT that phosphoribosylates xanthine. Examination of the structure indicates
      that F36 does not make direct contact with the purine, but long-range modulation
      via loop IV, a segment contacting purine at C2 position, could influence
      substrate specificity. Expanded substrate specificity to include xanthine
      probably arises from increased flexibility of loop IV as a consequence of
      mutation at F36. Mutation of the corresponding residue, L44 in Plasmodium
      falciparum HGPRT, also results in alteration of K(m) and k(cat) for xanthine,
      substantiating its role in affecting purine base affinity. Our studies show that
      mutation of this residue in the core of the protein also affects the stability of
      both enzymes.

PMID- 15178495
TI  - Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost
      effectiveness analysis.
AB  - PURPOSE: Clopidogrel is more effective than aspirin in preventing recurrent
      vascular events, but concerns about its cost-effectiveness have limited its use.
      We evaluated the cost-effectiveness of clopidogrel and aspirin as secondary
      prevention in patients with a prior myocardial infarction, a prior stroke, or
      peripheral arterial disease. METHODS: We constructed Markov models assuming a
      societal perspective, and based analyses on the lifetime treatment of a 63-year
      old patient facing event probabilities derived from the Clopidogrel versus
      Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial as the base case.
      Outcome measures included costs, life expectancy in quality-adjusted life-years
      (QALYs), incremental cost-effectiveness ratios, and events averted. RESULTS: In
      patients with peripheral arterial disease, clopidogrel increased life expectancy
      by 0.55 QALYs at an incremental cost-effectiveness ratio of $25,100 per QALY, as
      compared with aspirin. In poststroke patients, clopidogrel increased life
      expectancy by 0.17 QALYs at a cost of $31,200 per QALY. Aspirin was both less
      expensive and more effective than clopidogrel in post-myocardial infarction
      patients. In probabilistic sensitivity analyses, our evaluation for patients with
      peripheral vascular disease was robust. Evaluations of stroke and myocardial
      infarction patients were sensitive predominantly to the cost and efficacy of
      clopidogrel, with aspirin therapy more effective and less expensive in 153 of
      1000 simulations (15.3%) in poststroke patients and clopidogrel more effective in
      119 of 1000 simulations (11.9%) in the myocardial infarction sample. CONCLUSION:
      Clopidogrel provides a substantial increase in quality-adjusted life expectancy
      at a cost that is within traditional societal limits for patients with either
      peripheral arterial disease or a recent stroke. Current evidence does not support
      increased efficacy with clopidogrel relative to aspirin in patients following
      myocardial infarction.

PMID- 15178496
TI  - Neurological examination findings to predict limitations in mobility and falls in
      older persons without a history of neurological disease.
AB  - PURPOSE: To estimate the prevalence of neurological signs and their association
      with limitations in mobility and falls in a sample of older persons without known
      neurological disease. METHODS: A neurologist examined 818 participants from the
      InCHIANTI study who were aged > or =65 years and who did not have cognitive
      impairment, treatment with neuroleptics, and a history of neurological disease.
      Mobility was assessed as walking speed and self-reported ability to walk at least
      1 km without difficulty. Participants were asked to report falls that had
      occurred in the previous 12 months. RESULTS: Less than 20% (160/818) of
      participants had no neurological signs. Neurological signs were more prevalent in
      older participants and those with impaired mobility. When all neurological signs
      were included in sex-and age-adjusted multivariate models, 10 were mutually
      independent correlates of poor mobility. After adjusting for age and sex, the
      number of neurological signs was associated with progressively slower walking
      speed (P <0.001), a higher probability of reported inability to walk 1 km (P
      <0.001), and a history of falls (P <0.05). CONCLUSION: Neurological signs are
      independent correlates of limitations in mobility and falls in older persons who
      have no clear history of neurological disease.

PMID- 15178497
TI  - Cost-effectiveness of testing for hypercoagulability and effects on treatment
      strategies in patients with deep vein thrombosis.
AB  - PURPOSE: Among patients with deep vein thrombosis, hypercoagulable conditions
      impart a substantial risk of recurrent thrombosis. We sought to determine the
      cost-effectiveness of testing for these disorders, as well as which tests should
      be selected and how results should be used. METHODS: Using a Markov state
      transition model, strategies of testing or not testing for a hypercoagulable
      state followed by anticoagulation for 6 to 36 months were compared in a
      hypothetical cohort of patients with apparently idiopathic deep vein thrombosis
      who were followed for life. Strategies were compared based on lifetime costs,
      quality-adjusted life-years (QALYs), and marginal cost-effectiveness. RESULTS: In
      the base case, testing followed by 24 months of anticoagulation in patients with
      a hypercoagulable condition was more cost-effective ($54,820; 23.76 QALYs) than
      usual care, which comprised 6 months of anticoagulation without testing ($55,260;
      23.72 QALYs). All hypercoagulable conditions tested were common enough and
      associated with a sufficient risk of recurrence to justify inclusion in a test
      panel. Twenty-four months of initial anticoagulation was preferred
      (<$50,000/QALY) for most conditions, whereas lifetime anticoagulation was
      preferred for patients with antiphospholipid antibody syndrome ($2928/QALY) or
      homozygous factor V Leiden mutation ($3804/QALY). Models using newer evidence on
      recurrence suggested 18 to 36 months of anticoagulation without testing as the
      preferred approach. CONCLUSION: Testing for hypercoagulable disorders in patients
      with idiopathic deep vein thrombosis followed by 2 years of anticoagulation in
      affected patients is cost-effective. A simpler approach of treating all patients
      with prolonged anticoagulation without testing is justified if data confirm the
      persistent risk of recurrent thrombosis.

PMID- 15178498
TI  - Natural history of hepatitis B e antigen to antibody seroconversion in patients
      with normal serum aminotransferase levels.
AB  - BACKGROUND: Natural history studies of hepatitis B virus infection have shown
      relapse of hepatitis in 5% to 15% of patients and progression to cirrhosis in 2%
      to 6% annually. Follow-up of patients beginning at the early phase of infection
      might provide data with less referral bias than in previous studies. METHODS:
      Test of liver biochemistry, assessment of virological markers, and ultrasound
      examinations were performed at regular intervals during the course of hepatitis B
      e antigen (HBeAg) to antibody (anti-HBe) seroconversion in 240 HBeAg carriers
      with normal alanine aminotransferase levels at baseline. Factors predictive of
      cirrhosis were identified by multivariate analysis. RESULTS: We enrolled 130 men
      and 110 women. The mean (+/- SD) age at entry was 27.6 +/- 6.2 years. During the
      HBeAg-positive phase, 29% of patients had alanine aminotransferase levels > or
      =200 U/L, 3% had bilirubin levels > or =2.0 mg/dL, and 5% had two or more
      episodes of alanine aminotransferase levels > or =200 U/L. The mean age at anti
      HBe seroconversion was 31.3 +/- 7.0 years, with remission of hepatitis in all
      patients. However, hepatitis recurred in 36 patients (15%), with an annual rate
      of 2.2%. Thirteen patients (5%) progressed to cirrhosis. The annual incidence of
      cirrhosis was 0.5%, and the cumulative probability of cirrhosis after 17 years
      was 12.6%. Age at anti-HBe seroconversion and relapse of hepatitis were
      independent risk factors for cirrhosis. CONCLUSION: The clinical severity of
      chronic hepatitis B was milder in this cohort than in previous studies. Delayed
      HBeAg seroconversion and relapse of hepatitis were associated with increased risk
      of cirrhosis.

PMID- 15178499
TI  - Utilization of nonsteroidal anti-inflammatory drugs and antisecretory agents: a
      managed care claims analysis.
AB  - PURPOSE: To describe patients initiating nonsteroidal anti-inflammatory drug
      (NSAID) therapy with regard to gastrointestinal and cardiac risks and patterns of
      antisecretory agent use, and to explore the relation between therapy type and
      subsequent outcomes. METHODS: We studied patients aged 18 years or older who had
      continuous coverage from 1998 to 2001 and who had initiated treatment with
      cyclooxygenase-2 (COX-2) selective inhibitors or nonselective NSAIDs. Patients
      were categorized with respect to gastrointestinal and cardiac risk profiles.
      Proton pump inhibitor use within 15 days of initiating NSAID therapy was
      considered prophylactic. Logistic regression analysis was used to evaluate
      associations between treatment and hospitalization events, cardiac events, and
      health care costs. RESULTS: We identified 106,564 eligible NSAID initiators:
      65.2% used COX-2 inhibitors and 34.8% used traditional NSAIDs. Users of COX-2
      inhibitors were more likely to be at higher risk of gastrointestinal bleeding and
      cardiac events than were NSAID users. Proton pump inhibitor prophylaxis was most
      common among users of COX-2 inhibitors, but was only 11% in patients at high risk
      of gastrointestinal bleeding. There were no differences among treatment groups in
      terms of gastrointestinal or cardiac events. Initiation of COX-2 inhibitor
      therapy was associated with greater total health care costs. CONCLUSION: Although
      we found that COX-2 inhibitors were used more frequently than were traditional
      NSAIDs in certain groups of patients with varying cardiac or gastrointestinal
      risk, we did not find that their use resulted in reductions in clinical events,
      cotherapy with proton pump inhibitors, or costs, suggesting that a better
      understanding of the relation between NSAID treatment strategies and outcomes in
      patients with differing risk characteristics is needed.

PMID- 15178500
TI  - Fire ant attacks on patients in nursing homes: an increasing problem.
AB  - We review the medical reports of fire ant attacks on residents of nursing homes
      in the context of the medical entomology of these insects, and present
      recommendations to prevent and manage future attacks. Two reports were recent
      cases, while a computer-assisted search yielded four other similar cases of
      attacks by foraging fire ants in the last 10 years. One patient experienced an
      anaphylactic reaction and 4 patients died within 1 week of the attack. Ants were
      usually noted in health care facilities days before the attacks. The presence of
      fire ants around immobile, often cognitively impaired, patients seems to be the
      primary risk factor for massive fire ant attacks. Health care providers and
      administrators in fire ant endemic areas must be aware that the presence of fire
      ants in hospitals and nursing homes represents a hazard. Fire ant infestation can
      lead to sting attacks on patients, causing respiratory tract obstruction,
      worsening of pre-existing medical conditions, or frank anaphylaxis. All the
      attacks reported here have resulted in legal action involving physicians and
      health care facilities.

PMID- 15178501
TI  - Radiological evidence of nonalcoholic fatty liver disease in familial combined
      hyperlipidemia.

PMID- 15178502
TI  - Aspirin or clopidogrel for secondary prevention of cardiovascular events: is
      there a winner?

PMID- 15178503
TI  - Neurologic signs and mobility limitations: a neglected link in the elderly.

PMID- 15178504
TI  - Does anti-TNF therapy reduce new-onset heart failure in rheumatoid arthritis?

PMID- 15178505
TI  - Does hospital-based influenza vaccination result in unintended revaccination?

PMID- 15178506
TI  - Capecitabine-induced abnormalities in thyroid function tests.

PMID- 15178507
TI  - The decision to get vaccinated against influenza.

PMID- 15178508
TI  - Postmortem sperm retrieval: an ethical dilemma.

PMID- 15178509
TI  - The future of accreditation of medical education.

PMID- 15178511
TI  - Emerging therapeutic strategies for the management of dyslipidemia in patients
      with the metabolic syndrome.
AB  - The benefits of lipid-lowering therapy in significantly reducing cardiovascular
      events has been established in many at-risk populations. However, patients with
      the metabolic syndrome (MS) pose a challenge for clinical management. A high
      degree of residual risk exists in patients with the MS or diabetes mellitus, and
      this is of growing importance because of the increasing prevalence of obesity and
      its associated comorbidities in the world. As the MS has emerged as a major risk
      factor for both cardiovascular disease and diabetes, targeting treatment to
      achieve aggressive goals becomes paramount. This article reviews emerging
      therapeutic strategies for the management of dyslipidemia in patients with the
      MS.

PMID- 15178512
TI  - Dietary factors in the prevention of diabetes mellitus and coronary artery
      disease associated with the metabolic syndrome.
AB  - Coronary artery disease (CAD) and diabetes mellitus are 2 of the most common
      causes of morbidity and mortality in the United States. Diabetes has been
      recognized for decades as a major risk factor for the development of CAD.
      However, a growing consensus has emerged over the last several years that
      diabetes and CAD share a number of common precursors, which are metabolically
      linked and which often occur together in the same individual. This cluster of
      metabolic disturbances has been coined the metabolic syndrome by the Third Adult
      Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP).
      Other terms have been used to describe this constellation of risk factors,
      including syndrome X, the deadly quartet, and the insulin resistance syndrome.

PMID- 15178513
TI  - Effects of lipid-altering treatment in diabetes mellitus and the metabolic
      syndrome.
AB  - The metabolic syndrome (MS) poses an increased risk for the development of
      diabetes mellitus and cardiovascular events. The syndrome typically includes
      dyslipidemia, characterized by elevated plasma triglycerides and low high-density
      lipoprotein cholesterol concentrations. Retrospective analyses of coronary artery
      disease outcomes trials in patient subpopulations with diabetes or the MS
      indicate that lipid-altering therapies provide benefits for patients with the MS
      at least as much as observed in patients without diabetes or the MS. Analyses of
      the effects of lipid-altering therapy on the lipid profile in patients with the
      MS also indicate that beneficial lipid changes are similar in patients with the
      MS compared with those in patients without the MS. The benefits of statin
      treatment in patients with the MS have become increasingly clear, and it is
      likely that further improvements in treatment may be achieved with newer statins
      or a combination of lipid-altering drugs. Prospective data from clinical trials
      examining the preventive effects of lipid-altering therapy in MS patients are
      needed to better define potential benefits and optimal treatment in this
      population.

PMID- 15178514
TI  - Strategies in ongoing clinical trials to reduce cardiovascular disease in
      patients with diabetes mellitus and insulin resistance.
AB  - Diabetes mellitus and impaired glucose tolerance (IGT) are common disorders, and
      their prevalence is predicted to increase over the next several decades. The
      major serious complication of these disorders is large vessel atherosclerosis
      leading to myocardial infarction and stroke. Aggressive control of hypertension
      and dyslipidemia can significantly reduce risk for cardiovascular events, but a
      large amount of residual cardiovascular disease remains. A major remaining
      question is the potential role of aggressive glucose control for reducing
      macrovascular event rates in patients with diabetes. An ongoing trial addresses
      this issue, and a large number of other concurrent trials address several novel
      therapeutic strategies to reduce further the cardiovascular complications of
      diabetes or IGT. Many of these strategies test approaches that may directly
      target the vessel wall. Therapeutic modalities currently being evaluated include
      thiazolidinediones, angiotensin-converting enzyme inhibitors, and angiotensin II
      receptor blockers. Most of these trials will report their findings in the next 5
      years. It is likely that the results of ongoing trials will significantly improve
      our approach to managing cardiovascular risk in patients with diabetes and IGT.

PMID- 15178515
TI  - Role of surrogate markers in assessing patients with diabetes mellitus and the
      metabolic syndrome and in evaluating lipid-lowering therapy.
AB  - Diabetes mellitus and the metabolic syndrome (MS) are reaching epidemic
      proportions in the United States, and cardiovascular disease continues to be the
      leading cause of death among patients with diabetes. A range of noninvasive
      screening tools may help reduce the morbidity and mortality of patients with
      diabetes because of early detection of subclinical cardiovascular disease and
      active monitoring of the effectiveness of therapy. Surrogate markers of
      subclinical disease include conventional and contrast-enhanced ultrasound imaging
      of carotid artery intima-media thickness (c-IMT), 2-dimensional echocardiography,
      coronary artery calcium imaging, cardiac magnetic resonance imaging, ankle
      brachial indices, and brachial artery reactivity testing. Because these
      noninvasive imaging tools are relatively comfortable and entail relatively low
      risk to the patient, they are ideal for initial screening and for the repeated
      imaging that is required for monitoring the effectiveness of therapy. Moreover,
      when used in large numbers of patients with diabetes, prediabetes, and the MS,
      these imaging tools may be useful in developing and validating thresholds for the
      use of lipid-lowering therapy as well as clear therapeutic goals for this
      population. In addition, contrast-enhanced c-IMT scans now produce real-time
      images of the vasa vasorum and neovascularization of atherosclerotic plaque,
      potentially causing a paradigm shift in our view of the genesis of
      atherosclerosis and affecting treatment options for all populations. Thus,
      surrogate markers may not only help improve individual patient outcomes, they
      also may help direct scarce medical resources to maximize medical benefits,
      improve overall medical care, and minimize costs and untoward side effects.

PMID- 15178517
TI  - Vocal-manual trade-offs in hemispheric sharing of human performance control.
AB  - Experiment 1 established the linear ordering of performance and rated difficulty
      of three finger-sequencing tasks. Experiment 2 embedded these tasks within a dual
      task paradigm employing vocalization of words and nonwords as concurrent
      activities. Concurrent vocal activity interfered with right-more than with left
      handed performance, and this lateralized interference effect increased
      monotonically with increased sequence difficulty. Results are discussed in terms
      of hemispheric sharing of dual task performance control.

PMID- 15178516
TI  - Regulatory issues in the approval of new drugs for diabetes mellitus,
      dyslipidemia, and the metabolic syndrome.

PMID- 15178518
TI  - Dynamic visual acuity: a possible factor in catching performance.
AB  - Forty subjects took part in a one-handed catching ask in which the period for
      which the mechanically projected tennis ball was illuminated in flight was varied
      systematically. Additionally, they were tested for (a) static visual acuity and
      (b) dynamic visual acuity, in which angular velocity was varied. As expected,
      both viewing period in the catching task and angular velocity in the acuity task
      were significant variables in performance. Correlation and principal-components
      analyses confirmed the findings of a previous experiment in that the correlated
      static visual acuity tasks were unrelated to both dynamic visual acuity (even
      when angular velocity was only 75 degrees /sec) and catching performance.
      Further, dynamic acuity and catching were related under the majority of the
      combinations, and most frequently at the highest angular velocity, a fact which
      suggested that the dynamic element in both tasks is the common factor.

PMID- 15178519
TI  - Reliability and motor memory.
AB  - The generalizability framework was employed to estimate variance components and
      reliability of performance in a positioning task. The subjects (n =70) performed
      16 trials at each of three target lengths of 25 cm, 45 cm, and 65 cm. The data
      were analyzed using a subjects x targets x trials repeated measures ANOVA. Two
      reliability coefficients were estimated. The first (R) provided an estimate of
      performance reliability generalized over targets and trials. The second (R')
      treated targets as a source of true-score variance and hence was generalized over
      trials alone. Both reliability coefficients were higher for algebraic error than
      for absolute error, and R1 provided higher reliability estimates than R for both
      dependent variables. Increasing the number of positioning trials from 2 to 16 at
      each target length did not appreciably alter either reliability coefficient. The
      overall low reliability of R appears to compound the dependent variables and
      statistical power problems associated with short-term motor-memory studies.

PMID- 15178520
TI  - Intrinsic feedback, interpolation, and the closed-loop theory.
AB  - The amount of experience of a target location, or its surrounding locations, was
      manipulated to test Adams' (1971) prediction that the perceptual trace (stored
      perception of the correct response) is based on repeated sensations of the
      correct response. Sixteen learning trials, each followed by knowledge of results,
      on a linear-positioning task were permitted for all subjects. Each learning trial
      required movement to an adjustable physical stop. In learning condition without
      target experience, movements never terminated in a zone within which the target
      was interpolated. Other groups experienced movements terminating at the target
      point. The strength of the perceptual trace was inferred from the ability to move
      to the target during 20 test trials with the stop removed and without knowledge
      of the results. Slow movements could be made to a novel location equally as well
      as to a repeatedly practiced location.

PMID- 15178521
TI  - Repetition effects: a methodological issue in motor short-term memory.
AB  - A source of possible error in the design of many motor short-term memory studies-
      the effect of repeated testing of the same criterion positions- was evaluated
      together with a secondary factor, motivation. Using an arm-positioning task,
      three groups of five subjects, representing different motivational levels, were
      tested repeatedly on the same three test positions. Constant and variable error
      measures indicated significant effects of the repetition factor. Subjects became
      more accurate with repeated testing of the same positions as reflected by a
      positive shift in constant error in the direction of the criterion. There was an
      initial decrease and subjects' motivational level. The apparent assumption in
      prior studies, that presentations of intervening test items obviates a repetition
      effect, was clearly refuted. Thus, in many motor short-term memory studies,
      treatment effects have been inextricably mixed with the effects of repetition.

PMID- 15178522
TI  - Evidence for recognition and recall schemata.
AB  - Two experiments manipulated elements postulated to be crucial for the formation
      of recognition and recall schemata for discrete motor skills. Experiment 1 tested
      predictions for the formation of a schema to recognize novel and practiced
      positioning movements. Sensations of practiced locations, followed by knowledge
      of results, enabled accurate judgment of movement extent. The specification of
      distances before active practice movements did not help recognition performance.
      To test recall schema, Experiment 2 allowed practice with active movements over
      specified distances, or unspecified passive movements. The allowance of response
      specifications during practice provided clear superiority of recall-dependent
      performance. This aspect of recall memory should enable the construction of
      movements with extents and velocities different from those practiced.

PMID- 15178523
TI  - The effects of success and failure on the patterning of neuromuscular energy.
AB  - Weinberg and Hunt (1976) demonstrated that high- and low-anxious subjects
      differed in their patterning of neuromuscular energy in performance under failure
      feedback. The present study extends these findings to conditions that involve
      success feedback. The Sport Competition Anxiety Test and State-Trait Anxiety
      Inventory were administered to distinguish A-State and A-Trait subjects, while
      EMG indicated qualitative aspects of throwing. High-and low-trait anxiety
      subjects received either success, failure, or no feedback. High-anxious subjects
      performed best under success feedback, and low-anxious subjects performed best
      after failure feedback. High-anxious subjects used more EMG energy before,
      during, and after the throw in all conditions, and success feedback was
      beneficial for high-anxious subjects. The results are discussed in terms of the
      inter-relationships between efficiency of neuromuscular energy, motor
      performance, and state anxiety.

PMID- 15178524
TI  - The effect of rest following massed practice of continuous and discrete motor
      tasks.
AB  - Theories of the rest-related phenomena of reminiscence and warm-up decrement
      regard them as independent, being due to different factors. In this study it was
      found that rest following massed practice of a continuous task increased
      performance (reminiscence) and rest following massed practice of a discrete task
      lowered performance (warm-up decrement). The near-zero correlation found between
      the phenomena indicates that they are indeed independent and task-specific.
      Implications of the findings for the prediction of the effect of rest, and the
      fact that much motor learning and performance is task-specific, is discussed.

PMID- 15178525
TI  - Recognition and recall in slow movements: separate memory states?
AB  - If slow positioning movements are governed only by a recognition process (e.g.,
      Schmidt, 1975) then subject's performance should be independent of the mode or
      response (active versus passive). Two groups learned a criterion movement under
      either active or passive conditions following which KR was withdrawn. Although no
      differences were apparent on acquisition trials, active-group performance
      deteriorated dramatically during KR withdrawal while passive-group performance
      remained stable. These results suggest that recall and recognition are
      potentially separable in slow movements on the basis of the information available
      to the performer.

PMID- 15178526
TI  - Precueing response factors in choice reaction time: a word of caution.
AB  - This note discusses the assumption researchers make when movement attributes are
      precued in a choice reaction time (RT) paradigm-i.e., that the precue only
      reduces the number of response alternatives, so that changes in RT reflect the
      programming time for the unprecued attributes. However, it is argued that since
      the precue reduces the number of stimulus alternatives, changes in RT reflect
      changes in both stimulus processing and response programming. Therefore, the
      interpretation made by Klapp (1977), using the precue paradigm, that response
      selection and response timing are not independent sequential stages in the
      programming sequence, is not necessarily correct.

PMID- 15178527
TI  - The problem may be more difficult to solve than it appears: a reply to zelaznik.
AB  - Zelznik (1978) and I agree that his comment applies only to Experiment 1 of my
      series of three experiments, and I note that the weight of my argument was based
      on the other two experiments. Although agreeing with his analysis of the problem
      in Experiment 1, I note that the recommended solution may introduce a new problem
      in the course of eliminating the old one. It is fortunate that my conclusion can
      rest on converging operations and is not tied to the particular paradigm in
      question.

PMID- 15178528
TI  - Initiation of bilateral responses in a kinesthetic reaction time task.
AB  - Two experiments are presented in which different mechanisms controlling each limb
      in a bilateral arm response to a unilateral kinesthetic stimulus are postulated
      to occur. In Experiment 1, the limb serving as the stimulus are postulated to
      occur. In Experiment 1, the limb serving as the stimulus limb was described as
      operating with relative invariance by using a tightly coupled input-output
      reflexive pathway, whereas the nonstimulus limb appeared to be controlled by
      higher-order processing thought to be more susceptible to influences such as
      hemispheric specialization and stimulus expectancy. The differential control
      model was further tested in Experiment 2 by retaining the interhemispheric
      pathway of the unilateral kinesthetic stimulus but experimentally uncoupling the
      reflex mechanism from the stimulus side. Analyses of bilateral EMG premotor
      latencies under these conditions revealed that each response side can be
      controlled at separate levels-i.e., by a reflexive type mechanism or by higher
      order processing when one of the response limbs is also the stimulus limb, both
      sides reflect behavior that is best described by an information processing type
      of voluntary control.

PMID- 15178529
TI  - Anticipatory control of postural and task muscles during rapid arm flexion.
AB  - A multicomponent pattern of premovement (anticipatory) activity in both task and
      postural muscles was examined for a unilateral rapid arm flexion movement
      (Belen'kii, Gurflnkel, & Pal'tsev, 1967) performed under simple visual reaction
      time conditions. Subjects performed 30 right- and 30 left-side responses on each
      of four consecutive days. The anticipatory postural muscle activity may be
      considered a valid component of voluntary unilateral arm flexion. Invariances and
      variability in the spatial and temporal characteristics of the neuromuscular
      pattern are described in relationship to behavioral and motor control models of
      response organization. It is suggested that some temporal patterning among
      response components may not be preprogrammed centrally.

PMID- 15178530
TI  - Bilateral transfer as a function of mental imagery.
AB  - Three experiments are reported which investigate the role of mental imagery in
      the bilateral transfer from right to Ie ft hand of rotary pursuit skill. In
      Experiment 1 both mental imagery and physical rehearsal showed significant
      positive transfer relative to a control condition. However, work decrement may
      have accumulated and transferred in the physical rehearsal group thereby
      depressing this group's left-hand performance. Experiment 2 was conducted under
      conditions designed to allow work decrement to dissipate prior to transfer to the
      contralateral limb. The data still showed no difference between physical
      rehearsal and mental imagery. One interpretation of these data is that work
      decrement was present under both the physical rehearsal and mental imagery
      manipulations in Experiment 1. The data from Experiment 3 confirmed this
      interpretation as well as replicated the positive transfer effects found for
      mental imagery in Experiments 1 and 2. The data are discussed in terms of central
      versus peripheral explanatory mechanisms.

PMID- 15178531
TI  - Short-term rhythms in the performance of a simple motor task.
AB  - Following the discovery of short-term rhythmicities In physiological processes, a
      study was conducted to investigate existence of similar rhythms in motor
      behavior. Two groups of eight subjects each were tested every 10 or 20 min
      respectively in the performance of a linear positioning task with augmented
      auditory and proprioceptive feedback, for 10 consecutive hr. Each testing sample
      consisted of five trials with knowledge of results (KR), followed by five trials
      without knowledge of results (NKR). Between tests subjects drank constant amounts
      of fluids and urine flow was measured. Movement accuracy in the NKR condition
      varied rhythmically with periodicities centered at 100 min/ cycle. No comparable
      rhythms were found in the KR trials or in movement time. Urine flow also varied
      rhythmically with similar dominant periodicities, but these rhythms were
      unrelated to rhythms in error. The findings are interpreted to indicate rhythmic
      modulations in the efficiency of short-term storage and information processing
      from movement execution. Significance of these results to current views of motor
      control is discussed.

PMID- 15178532
TI  - The effects of memory strategy instruction in the short-term motor memory of the
      mentally retarded.
AB  - The present study investigated the effectiveness of teaching mnemonic strategies
      aimed at overcoming difficulties of mentally retarded students in retaining the
      motor short-term memory information of a preselected movement. The memory
      strategy employed was a combination of the "feel" of the movement and the spatial
      location of the hand relative to the body. The design of the study was a 2 x 2
      (Instructional Treatment x Retention Condition) factorial. The instructional
      treatment factor included teaching the subjects a memory strategy versus no
      memory-strategy instruction. The retention condition factor included immediate
      recall and a 15-sec retention interval. There were five trials per subject. The
      data were interpreted as supporting the effectiveness of the memory-strategy
      instruction.

PMID- 15178533
TI  - Tests of the duomemory notion for movement information.
AB  - The validity of the duomemory notion (i.e. the concept of two separate memory
      systems, one for recently presented events and another for learned acts) for
      motor behavior was tested in an experiment which sought to determine the extent
      to which interference differentially influenced the recall of a movement when it
      is initially experienced and after it is repeatedly practiced. Using a
      traditional linear-positioning task, subjects moved to five defined target
      locations on each trial and after a retention interval attempted to recall the
      targets in reverse order. One location was repeated on each of 10 trials while
      the others were always different. Control subjects were presented and recalled
      only the repeated criterion location on each trial. The results indicated (a) a
      constant superiority of criterion recall accuracy for the control condition
      throughout the 10 trials and (b) and absence of improvement over practice by the
      experimental group in the recall of the criterion location relative to that of
      nonrepeated targets. The findings were interpreted as a lack of support for the
      duomemory notion, and the exploration of an alternative framework (Craik &
      Lockhart, 1972) for the investigation of memory for movement information was
      suggested.

PMID- 15178534
TI  - Target-size influences on reaction time with movement time controlled.
AB  - The variable that affect motor programming time may be studied by changing the
      nature of the response and measuring the subsequent changes in reaction time
      (RT). One notion of motor programming suggests that aiming responses with reduced
      target size and/or increased target amplitude require more "complex" motor
      programs that require longer RTs. In a series of five experiments which movement
      time (MT) was experimentally varied target size neither influences RT when the
      movement amplitude was 2 or 30 cm nor when the target sizes differed by as much
      as a factor of 16:1. Increasing the movement amplitude from 15 to 30 cm also had
      no influence on RT. Movement time, however, did affect RT, with 200-msec
      movements having longer RTs than 120-msec movements. Target size and movement
      amplitude did not appear to be factors that influence programming time or program
      complexity.

PMID- 15178535
TI  - The activity-set hypothesis for warm-up decrement in a movement balance task.
AB  - This study investigated the activity-set hypothesis in reducing warm-up
      decrement. With regard to the hypothesis, it is predicted that warm-up decrement,
      which is a temporary loss of skill performance following rest, could be reduced
      if an appropriate reinstating activity were engaged in just prior to the
      resumption of practice. Seventy-five subjects were given twenty 20-sec tests on
      the stabilo-meter (criterion task), and then either (a) rested, (b) rested and
      then performed on interpolated "activity-set" task, or (c) rested and then
      performed an interpolated "activation" task. All subjects, after receiving one of
      the three conditions were then retested on the stabilometer for an additional six
      trials. An analysis of planned comparisons showed that the activity-set
      interpolated task was effective in reducing warm-up decrement and that activation
      was not a factor.

PMID- 15178536
TI  - The sex difference in rotary pursuit performance: aptitude or inhibition?
AB  - This study examined the hypothesis that male dominance in the acquisition and
      performance of rotary pursuit skill reflects a lower male proclivity for the
      generation and accumulation of reactive inhibition rather than some innately
      superior ability to profit from practice. On this hypothesis, the magnitude of
      male dominance should decline as the length of the intertrial interval increases.
      The experimental sample consisted of 120 Caucasian subjects (60 of each sex) who
      were given sixty 30-sec trials on rotary pursuit with intertrial intervals
      ranging from 0 to 40 sec. The principal finding was that the magnitude of the sex
      difference depended significantly upon the length of the intertrial interval, as
      hypothesized. When the interval was 10 sec or longer, performance levels of the
      sexes were essentially equal. The sex variance was reduced to insignificance even
      on the first trial when allowance was made for the inhibitory effect of practice.
      Thus, male dominance in rotary pursuit skill appears to be a procedural effect
      mediated by and inhibitory mechanism rather than a consequence of differential
      endowments of learning ability.

PMID- 15178537
TI  - The relative weightings of visual and nonvisual coding in a simple motor learning
      task.
AB  - A linear positioning task was used to examine the effects of visual and nonvisual
      inputs on motor learning. The experiment had three factors with two levels of
      each namely: sensory modality (visual-nonvisual), transfer at recall (changed
      unchanged), size of movement (25.4 cm, 50.8 com). Three dependent variable were
      used: absolute error (AE), constant error (CE), and variable error (VE). The
      results suggest that visual dominance causes disruption of recall in the visual,
      changed conditions. No disruption of recall was found for the nonvisual condition
      other than in terms of CE with respect to movement sizes. The results are taken
      to follow Posner et al.'s (1976) theory of visual dominance, but some account of
      the spatial qualities of visual and kinesthetic information is needed.

PMID- 15178538
TI  - Lateralized hand gesture during speech.
AB  - A group of individuals conversing in natural dyads and a group of lecturers were
      observed for lateral hand movement patterns during speech. Right-handed
      individuals in both groups displayed a significant right hand bias for gesture
      movements but no lateral bias for self-touching movements. The study provides
      external validity for previous laboratory studies of lateralized hand gesture.
      The results were interpreted as evidence of a central processor for both spoken
      and gestural communication.

PMID- 15178539
TI  - Oxidant activity in skeletal muscle fibers is influenced by temperature, CO2
      level, and muscle-derived nitric oxide.
AB  - Free radicals are produced continuously by skeletal muscle fibers. Extracellular
      release of reactive oxygen species (ROS) and nitric oxide (NO) derivatives has
      been demonstrated, but little is known about intracellular oxidant regulation. We
      used a fluorescent oxidant probe, 2',7'-dichlorofluorescin (DCFH), to assess net
      oxidant activity in passive muscle fiber bundles isolated from mouse diaphragm
      and studied in vitro. We tested the following three hypotheses. 1) Net oxidant
      activity is decreased by muscle cooling. 2) CO(2) exposure depresses
      intracellular oxidant activity. 3) Muscle-derived ROS and NO both contribute to
      overall oxidant activity. Our results indicate that DCFH oxidation was diminished
      by cooling muscle fibers from 37 degrees C to 23 degrees C (P < 0.001). The rate
      of DCFH oxidation correlated positively with CO(2) exposure (0-10%; P < 0.05) and
      negatively with concurrent changes in pH (7.0-8.5; P < 0.05). Separate exposures
      to anti-ROS enzymes (superoxide dismutase, 1 kU/ml; catalase, 1 kU/ml), a
      glutathione peroxidase mimetic (ebselen, 30 microM), NO synthase inhibitors
      (N(omega)-nitro-l-arginine methyl ester, 1 mM; N(omega)-monomethyl-l-arginine, 1
      mM), or an NO scavenger (hemoglobin, 1 microM) each inhibited DCFH oxidation (P <
      0.05). Oxidation was increased by hydrogen peroxide, 100 microM, an NO donor (NOC
      22, 400 microM), or the substrate for NO synthase (l-arginine, 5 mM). We conclude
      that net oxidant activity in resting muscle fibers is 1) decreased at
      subphysiological temperatures, 2) increased by CO(2) exposure, and 3) influenced
      by muscle-derived ROS and NO derivatives to similar degrees.

PMID- 15178540
TI  - Intergenerational consequences of fetal programming by in utero exposure to
      glucocorticoids in rats.
AB  - Epidemiological studies linking low birth weight and subsequent cardiometabolic
      disease have given rise to the hypothesis that events in fetal life permanently
      program subsequent cardiovascular risk. The effects of fetal programming may not
      be limited to the first-generation offspring. We have explored intergenerational
      effects in the dexamethasone-programmed rat, a model in which fetal exposure to
      excess glucocorticoid results in low birth weight with subsequent adult
      hyperinsulinemia and hyperglycemia underpinned by increased activity of the key
      hepatic gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found
      that the male offspring of female rats that had been exposed prenatally to
      dexamethasone, but were not manipulated in their own pregnancy, also had reduced
      birth weight (5.66 +/- 0.06 vs. 6.12 +/- 0.06 g, P < 0.001), glucose intolerance,
      and elevated hepatic PEPCK activity (5.7 +/- 0.6 vs. 3.3 +/- 0.2 nmol.min(-1).mg
      protein(-1), P < 0.001). These effects resolved in a third generation. Similar
      intergenerational programming was observed in offspring of male rats exposed
      prenatally to dexamethasone mated with control females. The persistence of such
      programming effects through several generations, transmitted by either maternal
      or paternal lines, indicates the potential importance of epigenetic factors in
      the intergenerational inheritance of the "programming phenotype" and provides a
      basis for the inherited association between low birth weight and cardiovascular
      risk factors.

PMID- 15178541
TI  - Adrenomedullin in the rostral ventrolateral medulla increases arterial pressure
      and heart rate: roles of glutamate and nitric oxide.
AB  - This study was done to investigate the effects of microinjections of
      adrenomedullin (ADM), a vasoactive neuropeptide, in the rostral ventrolateral
      medulla (RVLM) on mean arterial pressure (MAP) and heart rate (HR) in urethane
      anesthetized rats, and to assess the potential roles of glutamate and nitric
      oxide (NO) in these effects. Unilateral injections of ADM (0.01 or 0.1 pmol) into
      the RVLM significantly increased MAP and HR in a dose-dependent manner, whereas
      ADM at 0.001 pmol was ineffective. Microinjections of ADM (0.01 pmol) outside the
      RVLM had no effects on MAP or HR. Coinjections of a putative ADM receptor
      antagonist, ADM(22-52) (0.01 pmol), abolished the increases in MAP and HR evoked
      by ADM (0.01 pmol). The vasopressor effects of ADM (0.01 pmol) in the RVLM were
      abolished by coinjections of either dizocilpine hydrogen maleate (a selective
      NMDA glutamate receptor antagonist, 500 pmol) or 6-cyano-7-nitroquinoxaline-2,3
      dione (a selective non-NMDA glutamate receptor antagonist, 50 pmol). The ADM
      induced vasopressor effects were also abolished by coadministration of either 7
      nitroindazole sodium salt (a selective neuronal NO synthase inhibitor, 0.05 pmol)
      or methylene blue (a soluble guanylyl cyclase inhibitor, 100 pmol). These results
      suggest that ADM in the RVLM stimulates increases in MAP and HR through ADM
      receptor-mediated mechanisms. These effects are mediated by glutamate via both
      NMDA and non-NMDA receptors. NO, derived from neuronal NO synthase, also
      contributes to the ADM-induced vasopressor effects via a soluble guanylyl cyclase
      associated signaling pathway.

PMID- 15178543
TI  - Absence of the cholecystokinin-A receptor deteriorates homeostasis of body
      temperature in response to changes in ambient temperature.
AB  - The circadian rhythm of the body core temperature (T(c)) and the effects of
      changes in ambient temperatures on the homeostasis of T(c) in Otsuka Long Evans
      Tokushima Fatty (OLETF) rats, which are naturally occurring cholecystokinin (CCK)
      A receptor (CCK-AR) gene knockout (-/-) rats, were examined. In addition, the
      peripheral responses to warming or cooling of the preoptic and anterior
      hypothalamic region (PO/AH) were determined. The circadian rhythm of T(c) in
      OLETF rats was similar to that in Long-Evans Tokushima (LETO) rats; this rhythm
      was characterized by a higher T(c) during the dark period and a lower T(c) during
      the light period. When the ambient temperature was changed within the limits of 0
      degrees C to 30 degrees C, the changes in T(c) of LETO rats were associated with
      the changes in ambient temperature, whereas those in OLETF rats were dissociated
      from the temperature changes. The OLETF rats showed a large hysteresis. The
      peripheral responses to warming or cooling of PO/AH, including shivering of the
      neck muscle and changes in skin temperature of the tail and footpad, were similar
      in OLETF and LETO rats. To confirm the role of CCK-AR in the regulation of body
      temperature, the values of T(c) in the CCK-AR(-/-) mice were compared with those
      in CCK-B receptor (CCK-BR) (-/-), CCK-AR(-/-)BR(-/-), and wild-type mice. In the
      mice, the circadian rhythms of T(c) were the same, regardless of the genotype.
      Mice without CCK-AR showed larger hysteresis than mice with CCK-AR. From these
      results, we conclude that the lack of CCK-AR causes homeostasis of T(c) in rats
      and mice to deteriorate.

PMID- 15178542
TI  - Influence of gestational age and fetal iron status on IRP activity and iron
      transporter protein expression in third-trimester human placenta.
AB  - Placental iron transport during the last trimester of pregnancy determines the
      iron endowment of the neonate. Iron transport is a function of the major iron
      transport proteins: transferrin receptor-1 (TfR-1) and ferroportin-1 (FPN-1). The
      mRNAs for TfR-1 and, potentially, FPN-1 are posttranscriptionally regulated by
      iron regulatory protein (IRP)-1 and IRP-2. We assessed the effect of gestational
      age and fetal iron status on IRP-1- and IRP-2-binding activity and on the
      localization and protein expression of TfR-1 and FPN-1 protein at 24-40 wk of
      gestation in 21 placentas obtained from iron-sufficient nonanemic mothers.
      Gestational age had no effect on cord serum ferritin concentration, IRP-2 RNA
      binding activity, transporter protein location, and TfR-1 or FPN-1 protein
      expression. IRP-1 activity remained constant until full term, when it decreased
      (P = 0.01). Placental ferritin (r = 0.76, P < 0.001) and FPN-1 (r = 0.44, P <
      0.05) expression increased with gestational age. Fetal iron status, as indexed by
      cord serum ferritin concentration, was inversely related to placental IRP-1 (r = 
      0.66, P < 0.001) and IRP-2 (r = -0.42, P = 0.05) activities. Placental ferritin
      protein expression correlated better with IRP-1 (r = -0.45, P = 0.04) than with
      IRP-2 (r = -0.35, P = 0.10) activity. Placental TfR-1 and FPN-1 protein
      expression was independent of fetal or placental iron status and IRP activities.
      Iron status had no effect on transport protein localization. We conclude that,
      toward the end of the third trimester of iron-sufficient human pregnancy, the
      placenta accumulates ferritin and potentially increases placental-fetal iron
      delivery through increased FPN-1 expression. IRP-1 may have a more dominant role
      than IRP-2 activity in regulating ferritin expression.

PMID- 15178544
TI  - Effect of fasting on the VO2-fh relationship in king penguins, Aptenodytes
      patagonicus.
AB  - King penguins (Aptenodytes patagonicus) may fast for up to 30 days during their
      breeding period. As such extended fasting may affect the relationship between the
      rate of O(2) consumption (Vo(2)) and heart rate (f(H)), five male king penguins
      were exercised at various speeds on repeated occasions during a fasting period of
      24-31 days. In addition, Vo(2) and f(H) were measured in the same animals during
      rest in cold air and water (4 degrees C). Vo(2) and f(H) at rest and Vo(2) during
      exercise decreased with fasting. There was a significant relation between Vo(2)
      and f(H) (r(2) = 0.56) that was improved by including speed, body mass (M(b)),
      number of days fasting (t), and a cross term between f(H) and t (r(2) = 0.92). It
      was concluded that there was a significant change in the Vo(2)-f(H) relationship
      with fasting during exercise. As t is measurable in the field and was shown to be
      significant and, therefore, a practical covariate, a regression equation for use
      when birds are ashore was obtained by removing speed and M(b). When this equation
      was used, predicted Vo(2) was in good agreement with the observed data, with an
      overall error of 3.0%. There was no change in the Vo(2)-f(H) relationship in
      penguins at rest in water.

PMID- 15178545
TI  - Role of vasa vasorum in transendothelial solute transport in the coronary vessel
      wall: a study with cryostatic micro-CT.
AB  - Using cryostatic microscopic computed tomography (micro-CT), we sought to
      determine the role of coronary vasa vasorum (VV) in transendothelial solute
      transport in arteries with normal and increased permeability due to high plasma
      cholesterol levels. In 6-mo-old pigs on a normal (n=23) and 2% high cholesterol
      (HC) diet (n=8), 2-cm segments of the proximal left anterior descending coronary
      arteries were removed in vivo after a selective injection of X-ray contrast
      solution. Harvesting of the specimens occurred at 0, 15, 25, 35, or 45 s after
      completion of the contrast injection. Specimens were snap frozen and scanned in
      our cryostatic micro-CT. The spatial distribution of contrast in the coronary
      artery wall was quantified using the CT images. Right coronary arteries were
      infused with Microfil to determine VV density (VV/mm2) and the cumulative lumen
      surface area (mm2/mm3). Transendothelial diffusion of contrast into the coronary
      vessel wall is a dynamic process starting at both the subintima and the
      adventitia. The subintimal opacification moves as a wave toward the adventitia,
      whereas the adventitial wave resolves. The coronary vessel wall in animals on a
      HC diet shows higher opacification than in normal coronary arteries without an
      increase of VV total luminal surface area. The loss of endothelial integrity in
      hypercholesterolemia significantly alters VV solute washin to, and washout from,
      the coronary artery wall.

PMID- 15178546
TI  - Pulse-synchronous sympathetic burst power as a new index of sympathoexcitation in
      patients with heart failure.
AB  - The upper limit of incidence of muscle sympathetic neural bursts can lead to
      underestimation of sympathetic activity in patients with severe heart failure.
      This study aimed to evaluate the pulse-synchronous burst power of muscle
      sympathetic nerve activity (MSNA) as a more specific indicator that could
      discriminate sympathetic activity in patients with heart failure. In 54 patients
      with heart failure, the pulse-synchronous burst power at the mean heart rate was
      quantified by spectral analysis of MSNA. Thirteen patients received a central
      sympatholytic agent (guanfacine) for 5 days to validate the feasibility of this
      new index. Both burst incidence and plasma norepinephrine level showed no
      significant difference between patients in New York Heart Association functional
      class III (94 +/- 6 per 100 heartbeats and 477 +/- 219 pg/ml, respectively) and
      class II (79 +/- 14 per 100 heartbeats and 424 +/- 268 pg/ml, respectively). In
      contrast, the burst power was useful for discriminating patients in class III
      from those in class II (61 +/- 8% vs. 39 +/- 10%; P < 0.05). Inhibition of
      sympathetic nerve activity by guanfacine was more sensitively reflected by the
      change of burst power (-36 +/- 25%) than by that of burst incidence (-12 +/- 14%;
      P < 0.001). The sympathetic burst power reflects both burst frequency and
      amplitude independently of the absolute values and provides a sensitive new index
      for interindividual comparisons of sympathetic activity in patients with heart
      failure.

PMID- 15178548
TI  - Biventricular hypertrophy in dogs with chronic AV block: effects of cyclosporin A
      on morphology and electrophysiology.
AB  - Chronic atrioventricular (AV) block (CAVB) and biventricular hypertrophy in dogs
      increase susceptibility to drug-induced polymorphic ventricular tachycardia
      (PVT). In various rodent models, cyclosporin A (CsA) prevented hypertrophy. A
      similar effect in the CAVB model would allow us to determine whether hypertrophy
      represents an epiphenomenon, the cause of electrophysiological changes, and/or
      the anatomic substrate for PVTs. Upon AV node ablation, 6 dogs were studied
      acutely (AAVB), 25 dogs were kept for 6 (6W) and 12 wk (12W), receiving no
      treatment [CTL-CAVB-6W (n=6) and CTL-CAVB-12W (n=7)] or a daily oral dose of 10
      20 mg/kg CsA directly (n=6, CsA-CAVB-6W) or 6 wk after radio-frequency ablation
      (n=6, CsA-CAVB-12W). For the final study, dogs were anesthetized, and 60 needles
      were inserted into both ventricles and connected to a multiplexer mapping system.
      Local effective refractory periods (ERPs) were determined at 56 +/- 22 randomly
      selected sites (extrastimulus technique, basic cycle length=800 ms). Arrhythmias
      within 30 min after application of almokalant (0.34 micromol/kg iv) were
      registered. The hearts were then excised to obtain the heart weight-body weight
      index (HBWI). Compared with AAVB, CTL-CAVB-6W and CTL-CAVB-12W showed increased
      HBWI and ERP associated with PVT inducibility in none of six AAVB dogs, four of
      six CTL-CAVB-6W dogs, and one of seven CTL-CAVB-12W dogs. Compared with CTL-CAVB
      6W and CTL-CAVB-12W, CsA-CAVB-6W and CsA-CAVB-12W partially prevented hypertrophy
      or led to a regression of hypertrophy without reducing ERP prolongation. Despite
      ERP prolongation, PVTs were no longer inducible with CsA treatment. Thus
      prolongation of refractoriness seems to provide the trigger, but hypertrophy
      provides the essential substrate for the induction of PVTs in this model.

PMID- 15178547
TI  - Increased abdominal-to-peripheral fat distribution contributes to altered
      autonomic-circulatory control with human aging.
AB  - Autonomic nervous system (ANS) control of the circulation is altered with aging
      in adult humans. Similar changes are observed in obesity, particularly abdominal
      obesity. To determine whether age-associated differences in ANS-circulatory
      function can be partially explained by increased body fatness, we examined ANS
      function and three expressions of adiposity (total body fat, abdominal body fat,
      and abdominal-to-peripheral body fat distribution; dual-energy X-ray
      absorptiometry) in 43 healthy men: 27 young (25 +/- 1 yr) and 16 older (65 +/-
      1). ANS functions assessed included 1) autonomic support of arterial blood
      pressure (BP; radial artery catheter), i.e., the reduction in BP during versus
      before acute ganglionic blockade (GB; intravenous trimethaphan); 2) baroreflex
      buffering, i.e., the increase in systolic BP with continuous incremental and
      bolus infusions of phenylephrine during versus before GB; 3) cardiovagal
      baroreflex sensitivity (Oxford technique); and 4) heart rate variability (time-
      and frequency-domain analyses). Covarying for abdominal-to-peripheral fat
      distribution reduced or abolished age-related differences in ANS support of BP,
      cardiovagal baroreflex sensitivity, and heart rate variability but did not affect
      age-related differences in baroreflex buffering. Covarying for abdominal and
      total fat had small selective or no effects on age-associated differences in
      autonomic-circulatory control. Abdominal-to-peripheral fat distribution explains
      a significant portion of the variance in a number of autonomic-circulatory
      functions attributable to aging. Therefore, the development of this fat pattern
      may contribute to several changes in ANS-cardiovascular function observed with
      aging. These results may help explain how changes in body fat distribution with
      advancing age are linked to impairments in circulatory control.

PMID- 15178549
TI  - IGFBP-3 activates TGF-beta receptors and directly inhibits growth in human
      intestinal smooth muscle cells.
AB  - We have shown that human intestinal smooth muscle cells produce IGF-I and IGF
      binding protein-3 (IGFBP-3). Endogenous IGF-I acts in autocrine fashion to
      stimulate growth of these cells. IGFBP-3 inhibits the binding of IGF-I to its
      receptor and thereby inhibits IGF-I-stimulated growth. In several carcinoma cell
      lines and some normal cells, IGFBP-3 regulates growth independently of IGF-I. Two
      mechanisms for this effect have been identified: IGFBP-3 can directly activate
      transforming growth factor-beta (TGF-beta) receptors or it can undergo direct
      nuclear translocation. The aim of the present study was to determine whether
      IGFBP-3 acts independently of IGF-I and to characterize the mechanisms mediating
      this effect in human intestinal smooth muscle cells. The direct effects of IGFBP
      3 were determined in the presence of an IGF-I receptor antagonist to eliminate
      its IGF-I-dependent effects. Affinity labeling of TGF-beta receptors (TGF-betaRI,
      TGF-betaRII, and TGF-betaRV) with 125I-labeled TGF-beta1 showed that IGFBP-3
      displaced binding to TGF-betaRII and TGF-betaRV in a concentration-dependent
      fashion. IGFBP-3 stimulated TGF-betaRII-dependent serine phosphorylation
      (activation) of both TGF-betaRI and of its primary substrate, Smad2(Ser465/467).
      IGFBP-3 also caused IGF-I-independent inhibition of basal [3H]thymidine
      incorporation. The effects of IGFBP-3 on Smad2 phosphorylation and on smooth
      muscle cell proliferation were independent of TGF-beta1 and were abolished by
      transfection of Smad2 siRNA. Immunoneutralization of IGFBP-3 increased basal
      [3H]thymidine incorporation, implying that endogenous IGFBP-3 inhibits
      proliferation. We conclude that endogenous IGFBP-3 directly inhibits
      proliferation of human intestinal smooth muscle cells by activation of TGF-betaRI
      and Smad2, an effect that is independent of its effect on IGF-I-stimulated
      growth.

PMID- 15178550
TI  - Global gene expression profiles reveal an increase in mRNA levels of collagens,
      MMPs, and TIMPs in late radiation enteritis.
AB  - Radiation enteritis, a common complication of radiation therapy for abdominal and
      pelvic cancers, is characterized by severe transmural fibrosis associated with
      mesenchymal cell activation, tissue disorganization, and deposition of fibrillar
      collagen. To investigate the mechanisms involved in this pathological
      accumulation of extracellular matrix, we studied gene expression of matrix
      components along with that of genes involved in matrix remodeling, matrix
      metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs).
      Hybrid selection on high-density cDNA array, real-time RT-PCR, gelatin zymography
      and immunohistochemistry were used to characterize the mRNA expression profile,
      activity, and tissue location of extracellular matrix-related genes in radiation
      enteritis compared with healthy ileum. cDNA array analysis revealed a strong
      induction of genes coding for collagens I, III, IV, VI, and VIII, SPARC, and
      tenascin-C, extracellular-matrix degrading enzymes (MMP-1, -2, -3, -14, -18+19),
      and metalloproteinase inhibitors (TIMP-1, -2, plasminogen activator inhibitor-1)
      in radiation enteritis. This increase was correlated with the degree of
      infiltration of the mucosa by inflammatory cells, and the presence of
      differentiated mesenchymal cells in the submucosa and muscularis propria. Despite
      the fact that expression of collagens, MMPs, and TIMPs simultaneously increase,
      quantification of net collagen deposition shows an overall accumulation of
      collagen. Our results indicate that late radiation enteritis tissues are
      subjected to active process of fibrogenesis as well as fibrolysis, with a balance
      toward fibrogenesis. This demonstrates that established fibrotic tissue is not
      scarred fixed tissue but is subjected to a dynamic remodeling process.

PMID- 15178551
TI  - Regional differences in L-type Ca2+ channel expression in feline lower esophageal
      sphincter.
AB  - In humans and cats, muscle from the lower esophageal sphincter (LES) circular
      region exhibits greater spontaneous tone than LES sling muscle, whereas the sling
      muscle is much more responsive to cholinergic stimulation. Despite physiological
      and pharmacological evidence for the presence of L-type Ca2+ channel current
      (ICa,L) activity in LES circular muscle, the identity of this channel has not
      been demonstrated biochemically or electrophysiologically fingerprinted.
      Furthermore, there is no information on the channel's presence and role in the
      sling region of the LES. We hypothesized that regional differences in the
      expression of ICa,L between LES circular and sling muscles, if present, could
      contribute to the functional asymmetry observed within the LES. ICa,L expression
      was compared between circular and sling regions of the LES by Western blot
      analysis. The patch-clamp technique was used to study ICa,L. Muscle strip studies
      assessed ICa,L contribution to contractile activity. We found both protein
      expression of ICa,L and ICa,L density to be greater in LES circular muscle than
      sling muscle. ICa,L voltage- and time-dependent activation and inactivation
      curves were similar in cells from both regions. ICa,L blockade with nifedipine
      inhibited spontaneous tone and ACh-induced contractions only in circular muscle
      but was able to abolish depolarization (KCl)-induced contractions in both sling
      and circular muscles. In contrast, La3+ inhibited tone and ACh-induced
      contractions in muscles from both regions. Therefore, regional myogenic
      differences in ICa,L expression within the LES circular and sling muscle exist
      and provide one explanation for the differential contribution of sling and
      circular muscle to LES contractility.

PMID- 15178552
TI  - Neuronal activity and CRF receptor gene transcription in the brains of rats with
      colitis.
AB  - We aimed to characterize neuronal and corticotropin-releasing factor (CRF)
      pathways at the acute phase of a model of colitis in rats. Male rats received an
      intracolonic injection of either vehicle (controls) or trinitrobenzenesulfonic
      acid (TNBS) and were killed 1, 2, 3, 4, 6, 12, or 24 h later. Coronal frozen
      sections of the brain were cut and mRNAs encoding the rat c-fos, CRF1 receptor,
      and CRF2alpha,beta receptors were assayed by in situ hybridization
      histochemistry. Localization of these transcripts within CRF-immunoreactive (CRF
      ir) neurons of the paraventricular nucleus (PVN) of the hypothalamus was also
      determined. Intracolonic TNBS induced c-fos mRNA expression in brain nuclei
      involved in the autonomic, behavioral, and neuroendocrine response to a stimulus
      (PVN, amygdala, locus coeruleus, parabrachial nucleus, nucleus of the solitary
      tract) and in circumventricular organs (lamina terminalis, subfornical organ,
      area postrema). CRF pathways, particularly in the PVN, were activated in this
      model as represented by a robust signal of c-fos and CRF1 receptor transcripts in
      the PVN and numerous CRF-ir neurons expressed c-fos or CRF1 receptor transcripts
      in the PVN of TNBS-treated animals. No expression of CRF2 receptor transcripts
      was observed in the PVN, either in basal conditions or after TNBS. These
      neuroanatomical data argue for an involvement of CRF pathways, through CRF1
      receptor, within the PVN in TNBS-induced colitis.

PMID- 15178553
TI  - Complex regulation of the lactase-phlorizin hydrolase promoter by GATA-4.
AB  - Lactase-phlorizin hydrolase (LPH), a marker of intestinal differentiation, is
      expressed in absorptive enterocytes on small intestinal villi in a tightly
      regulated pattern along the proximal-distal axis. The LPH promoter contains
      binding sites that mediate activation by members of the GATA-4, -5, and -6
      subfamily, but little is known about their individual contribution to LPH
      regulation in vivo. Here, we show that GATA-4 is the principal GATA factor from
      adult mouse intestinal epithelial cells that binds to the mouse LPH promoter, and
      its expression is highly correlated with that of LPH mRNA in jejunum and ileum.
      GATA-4 cooperates with hepatocyte nuclear factor (HNF)-1alpha to synergistically
      activate the LPH promoter by a mechanism identical to that previously
      characterized for GATA-5/HNF-1alpha, requiring physical association between GATA
      4 and HNF-1alpha and intact HNF-1 binding sites on the LPH promoter. GATA-4 also
      activates the LPH promoter independently of HNF-1alpha, in contrast to GATA-5,
      which is unable to activate the LPH promoter in the absence of HNF-1alpha. GATA-4
      specific activation requires intact GATA binding sites on the LPH promoter and
      was mapped by domain-swapping experiments to the zinc finger and basic regions.
      However, the difference in the capacity between GATA-4 and GATA-5 to activate the
      LPH promoter was not due to a difference in affinity for binding to GATA binding
      sites on the LPH promoter. These data indicate that GATA-4 is a key regulator of
      LPH gene expression that may function through an evolutionarily conserved
      mechanism involving cooperativity with an HNF-1alpha and/or a GATA-specific
      pathway independent of HNF-1alpha.

PMID- 15178554
TI  - Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and
      inflammation.
AB  - Late in the 18th century, William Hewson recognized that the formation of a clot
      is characteristic of many febrile, inflammatory diseases (Owen C. A History of
      Blood Coagulation. Rochester, Minnesota: Mayo Foundation; 2001). Since that time,
      there has been steady progress in our understanding of coagulation and
      inflammation, but it is only in the past few decades that the molecular
      mechanisms linking these 2 biologic systems have started to be delineated. Most
      of these can be traced to the vasculature, where the systems most intimately
      interact. Thrombomodulin (TM), a cell surface-expressed glycoprotein,
      predominantly synthesized by vascular endothelial cells, is a critical cofactor
      for thrombin-mediated activation of protein C (PC), an event further amplified by
      the endothelial cell protein C receptor (EPCR). Activated PC (APC), in turn, is
      best known for its natural anticoagulant properties. Recent evidence has revealed
      that TM, APC, and EPCR have activities that impact not only on coagulation but
      also on inflammation, fibrinolysis, and cell proliferation. This review
      highlights recent insights into the diverse functions of this complex
      multimolecular system and how its components are integrated to maintain
      homeostasis under hypercoagulable and/or proinflammatory stress conditions.
      Overall, the described advances underscore the usefulness of elucidating the
      relevant molecular pathways that link both systems for the development of novel
      therapeutic and diagnostic targets for a wide range of inflammatory diseases.

PMID- 15178555
TI  - Vasodilator-stimulated phosphoprotein regulates proliferation and growth
      inhibition by nitric oxide in vascular smooth muscle cells.
AB  - OBJECTIVE: Vasodilator-stimulated phosphoprotein (VASP) was identified as a
      substrate for cGMP-dependent protein kinase (PKG) and cAMP-dependent protein
      kinase (PKA). It is preferentially phosphorylated at serine239 by PKG, whereas
      serine157 is a preferred phosphorylation site for PKA. In addition, serine157 is
      phosphorylated by PKC in response to serum. We have investigated the effects of
      VASP and VASP phosphorylation at serine157 and serine239 on smooth muscle cell
      (SMC) proliferation and nitric oxide (NO)-mediated growth inhibition. METHODS AND
      RESULTS: Aortic SMCs derived from VASP-deficient mice were transduced with
      retroviral vectors encoding either wild-type VASP or VASP mutants (S157A-VASP and
      S239A-VASP), in which serine157 and serine239, respectively, were replaced by a
      nonphosphorylatable amino acid, alanine. Expression of wt-VASP and S239A-VASP
      significantly increased proliferation, whereas expression of S157A-VASP was
      inhibitory. Expression of S239A-VASP rendered SMCs less sensitive to growth
      inhibition by the NO donor, S-nitroso-n-acetylpenicillamine, when compared with
      cells expressing wt-VASP. Similar effects were observed in cultured rat SMCs in
      which wt-VASP, S157A-VASP, and S239A-VASP were expressed. CONCLUSIONS: Our data
      suggest that VASP phosphorylation at serine157 is required for the growth
      stimulatory effect of VASP in SMCs, whereas VASP phosphorylation at serine239 is
      involved in the growth inhibitory effects of NO on SMCs.

PMID- 15178556
TI  - Attenuation of graft arterial disease by manipulation of the LIGHT pathway.
AB  - OBJECTIVE: The tumor necrosis factor (TNF) superfamily member LIGHT, which binds
      herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR), plays
      important roles in regulating the immune response. To clarify the mechanism
      underlying graft arterial disease (GAD), we investigated the role of the LIGHT
      pathway in the progression of GAD. METHODS AND RESULTS: Hearts from Bm12 mice
      were transplanted into C57BL/6 (B/6) mice (class II mismatch). Recipients were
      injected intraperitoneally with HVEMIg (100 microg per treatment) every 7 days
      for 8 weeks. Treatment with HVEMIg significantly attenuated GAD (luminal
      occlusion=16.5+/-7.7% versus control allograft=62.6+/-12.1%, P<0.05), and
      significantly decreased intragraft IL-4, IL-6, and interferon-gamma (IFN-gamma)
      mRNA expression compared with controls. LTbetaR was expressed in smooth muscle
      cells (SMCs) with or without cytokine stimulation, whereas HVEM was detected in
      SMCs stimulated by IFN-gamma. Coculture of SMCs with T cells after
      transplantation induced SMC proliferation, and addition of HVEMIg resulted in
      inhibition of SMC proliferation. CONCLUSIONS: These results indicate that the
      LIGHT pathway plays important roles in the regulation not only of T-cell
      activation but also of SMC proliferation. Blockade of the LIGHT pathway is a
      promising avenue for the prevention of GAD.

PMID- 15178557
TI  - Statins upregulate PCSK9, the gene encoding the proprotein convertase neural
      apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia.
AB  - OBJECTIVE: Neural apoptosis-regulated convertase (NARC)-1 is the newest member of
      the proprotein convertase family implicated in the cleavage of a variety of
      protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the
      third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2
      other known genes implicated in ADH encode the low-density lipoprotein receptor
      and apolipoprotein B. As an approach toward the elucidation of the physiological
      role(s) of NARC-1, we studied its transcriptional regulation. METHODS AND
      RESULTS: Using quantitative RT-PCR, we assessed NARC-1 regulation under
      conditions known to regulate genes involved in cholesterol metabolism in HepG2
      cells and in human primary hepatocytes. We found that NARC-1 expression was
      strongly induced by statins in a dose-dependent manner and that this induction
      was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by
      cholesterol depletion but insensitive to liver X receptor activation. Human,
      mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol
      regulation: a sterol regulatory element (SRE) and an Sp1 site. CONCLUSIONS: PCSK9
      regulation is typical of that of the genes implicated in lipoprotein metabolism.
      In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.

PMID- 15178558
TI  - Lysosomal cysteine proteases in atherosclerosis.
AB  - Atherosclerosis is an inflammatory disease characterized by extensive remodeling
      of the extracellular matrix architecture of the arterial wall. Although matrix
      metalloproteinases and serine proteases participate in these pathologic events,
      recent data from atherosclerotic patients and animals suggest the participation
      of lysosomal cysteine proteases in atherogenesis. Atherosclerotic lesions in
      humans overexpress the elastolytic and collagenolytic cathepsins S, K, and L but
      show relatively reduced expression of cystatin C, their endogenous inhibitor,
      suggesting a shift in the balance between cysteine proteases and their inhibitor
      that favors remodeling of the vascular wall. Extracts of human atheromatous
      tissue show greater elastolytic activity in vitro than do those from healthy
      donors. The cysteinyl protease inhibitor E64d limits this increased elastolysis,
      indicating involvement of cysteine proteases in elastin degradation during
      atherogenesis. Furthermore, inflammatory cytokines augment expression and
      secretion of active cysteine proteases from cultured monocyte-derived
      macrophages, vascular smooth muscle cells, and endothelial cells and increase
      degradation of extracellular elastin and collagen. Cathepsin S-deficient cells or
      those treated with E64d show significantly impaired elastolytic or collagenolytic
      activity. Additionally, recent in vivo studies of atherosclerosis-prone, LDL
      receptor-null mice lacking cathepsin S show participation of this enzyme in the
      initial infiltration of leukocytes, medial elastic lamina degradation,
      endothelial cell invasion, and neovascularization, illustrating an important role
      for cysteine proteases in arterial remodeling and atherogenesis.

PMID- 15178559
TI  - Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular
      smooth muscle cell function.
AB  - OBJECTIVE: With age, rat arterial walls thicken and vascular smooth muscle cells
      (VSMCs) exhibit enhanced migration and proliferation. Monocyte chemotactic
      protein-1 (MCP-1) affects these VSMC properties in vitro. Because arterial
      angiotensin II, which induces MCP-1 expression, increases with age, we
      hypothesized that aortic MCP-1 and its receptor CCR2 are also upregulated and
      affect VSMC properties. METHODS AND RESULTS: Both MCP-1 and CCR2 mRNAs and
      proteins increased in old (30-month) versus young (8-month) F344xBN rat aortas in
      vivo. Cellular MCP-1 and CCR2 staining colocalized with that of alpha-smooth
      muscle actin in the thickened aortas of old rats and were expressed by early
      passage VSMCs isolated from old aortas, which, relative to young VSMCs, exhibited
      increased invasion, and the age difference was abolished by vCCI, an inhibitor of
      CCR2 signaling. MCP-1 treatment of young VSMCs induced migration and increased
      their ability to invade a synthetic basement membrane. The MCP-1-dependent VSMC
      invasiveness was blocked by vCCI. After MCP-1 treatment, migration and invasion
      capacities of VSMCs from young aortas no longer differed from those of VSMCs
      isolated from older rats. CONCLUSIONS: Arterial wall and VSMC MCP-1/CCR2 increase
      with aging. MCP-1 enhances VSMC migration and invasion, and thus, MCP-1/CCR2
      signaling may play a role in age-associated arterial remodeling.

PMID- 15178561
TI  - Endothelial overexpression of Fas ligand decreases atherosclerosis in
      apolipoprotein E-deficient mice.
AB  - OBJECTIVE: Fas ligand (FasL) can induce apoptosis in cells bearing the Fas
      receptor. The role of FasL in the vasculature with regard to atherosclerosis is
      controversial. This study examined the function of endothelial FasL during
      atherosclerosis. METHODS AND RESULTS: Transgenic (Tg) mice that specifically
      overexpress different levels of FasL on vascular endothelial cells were crossed
      into the apolipoprotein E-knockout background (ApoE-KO) to generate ApoE-KO/FasL
      Tg mice. Although plasma cholesterol and triglyceride levels were not different
      between ApoE-KO/FasL-Tg mice and ApoE-KO mice after 12 weeks of a high-fat diet,
      overexpression of the FasL transgene significantly reduced atherosclerotic lesion
      area in aortae by 49%. The reduction of atherosclerotic lesion area was more
      pronounced in thoracic and abdominal aortae than in the aortic arch, and a 34%
      reduction in lesion area was observed in aortic root sections from the ApoE
      KO/FasL-Tg group compared with the ApoE-KO group. Immunostaining revealed
      significant decreases in both macrophage and CD8 T-cell accumulation in lesions
      of ApoE-KO/FasL-Tg mice. ApoE-KO/FasL-Tg mice that express lower levels of
      endothelial FasL also displayed reduced lesion size, but this reduction was
      statistically significant at the aortic arch only. CONCLUSIONS: Overexpression of
      endothelial FasL is antiinflammatory and inhibits atherosclerosis under
      hypercholesterolemic conditions.

PMID- 15178560
TI  - Cholesterol-lowering independent regression and stabilization of atherosclerotic
      lesions by pravastatin and by antimonocyte chemoattractant protein-1 therapy in
      nonhuman primates.
AB  - OBJECTIVE: Anti-atherosclerotic effects of statins might be mediated partly by
      pleiotropic cholesterol-lowering independent mechanisms. We used nonhuman
      primates and examined whether treatment with pravastatin or antimonocyte
      chemoattractant protein-1 (MCP-1) therapy can induce regression and stabilization
      of established atherosclerotic lesions through cholesterol-lowering independent
      mechanisms. METHODS AND RESULTS: Advanced atherosclerosis was induced in the
      abdominal aorta and the common iliac artery of cynomolgus monkeys by undergoing
      balloon injury and giving atherogenic diet for 6 months. At 6 months, the diet
      was changed to normal chow, and the animals were allocated to 4 treatment groups:
      control vehicle group and other groups treated with pravastatin (1 or 10 mg/kg)
      or with mutant MCP-1 gene transfection for additional 6 months. Each compound was
      treated instead of the atherogenic diet, and cholesterol contents in pravastatin
      treated groups were adjusted to equalize plasma cholesterol level among groups.
      Pravastatin reduced neointimal formation in the aorta, but not in the common
      iliac artery. Pravastatin reduced intimal macrophage area and other markers of
      plaque destabilization in the common iliac artery. Equivalent inhibitory effects
      were observed in animals that received mutant MCP-1 gene transfection. No serious
      side effects were noted by 2 therapeutic modalities. CONCLUSIONS: This study
      demonstrated cholesterol-lowering independent regression and stabilization of
      established atherosclerotic lesions by pravastatin and by anti-MCP-1 therapy in
      nonhuman primates. An anti-inflammatory mechanism may be involved in the
      beneficial effects of pravastatin.

PMID- 15178562
TI  - Leukocyte-derived interleukin 10 is required for protection against
      atherosclerosis in low-density lipoprotein receptor knockout mice.
AB  - BACKGROUND: Atherosclerosis is an immunoinflammatory disease. Here we examined
      the role of leukocyte-derived interleukin 10 (IL-10) on advanced atherosclerosis
      development in low-density lipoprotein receptor knockout (LDLr-/-) mice. METHODS
      AND RESULTS: Bone marrow cells harvested from C57BL/6 IL-10-/- and IL-10+/+ mice
      were transplanted into irradiated male LDLr-/- mice. Four weeks after
      transplantation, mice were fed a high-fat cholate-free diet for 14 weeks. Despite
      no differences in weights, serum total, and HDL-cholesterol levels between the 2
      groups, IL-10 deficiency in leukocytes induced a >2-fold increase in lesion
      development in the thoracic aorta compared with controls. We also found a
      significant 35% increase in aortic root lesion area of IL-10-/- mice compared
      with IL-10+/+ mice. Furthermore, IL-10 deficiency led to a marked increase in
      lymphocyte and macrophage accumulation associated with a significant reduction in
      collagen accumulation. Finally, transfer of IL-10-/- splenocytes to LDLr-/- mice
      resulted in a 3-fold increase in lesion size in the aortic sinus compared with
      mice transplanted with IL-10+/+ splenocytes. CONCLUSIONS: IL-10 expressed by
      leukocytes prevents exaggerated advanced atherosclerosis development and plays a
      critical role in modulation of cellular and collagen plaque composition, at least
      in part, through a modulation of the systemic immune response.

PMID- 15178563
TI  - Lysophosphatidylcholine enhances cytokine production of endothelial cells via
      induction of L-type amino acid transporter 1 and cell surface antigen 4F2.
AB  - OBJECTIVE: A diverse range of lipid oxidation products detected in oxidized low
      density lipoprotein (oxLDL) and atherosclerotic lesions are capable of eliciting
      biological responses in vascular cells. We performed DNA microarray experiments
      to explore novel responses of human umbilical vein endothelial cells (HUVECs) to
      oxLDL and its components. METHODS AND RESULTS: cDNA microarray analysis showed
      that oxLDL, lysophosphatidylcholine (LysoPC), 4-hydroxy-2-nonenal, and oxysterols
      altered gene expression specifically, but some genes were commonly induced in
      HUVECs. Solute carrier family 3 member 2 and family 7 member 5, encoding the
      heavy chain of the cell surface antigen 4F2 (4F2hc) and the L-type amino acid
      transporter 1 (LAT1), respectively, were induced by oxLDL and many oxidation
      products. LAT1 requires 4F2hc to form a heterodimeric functional complex to
      transport neutral amino acids into the cell. LysoPC increased membrane protein
      levels of LAT1 confirmed by Western blot analysis and also uptake of L
      [(14)C]leucine, which was inhibited by a competitive inhibitor for LAT1. The
      release of interleukin 6 (IL-6) and IL-8 was increased in LysoPC-treated cells
      and was attenuated by the LAT1 inhibitor. CONCLUSIONS: These findings suggest
      that an increase in uptake of neutral amino acids induced by LysoPC results in
      enhancement of inflammatory responses of endothelial cells.

PMID- 15178564
TI  - Heat shock protein 90 transfection reduces ischemia-reperfusion-induced
      myocardial dysfunction via reciprocal endothelial NO synthase serine 1177
      phosphorylation and threonine 495 dephosphorylation.
AB  - OBJECTIVES: The interaction of the heat shock protein 90 (Hsp90) with the
      endothelial NO synthase (eNOS) has been shown to account for a sustained
      production of NO in vitro. Here, we examined whether overexpression of Hsp90 in a
      pig model of cardiac infarct could preserve the myocardium from the deleterious
      effects of ischemia-reperfusion. METHODS AND RESULTS: Percutaneous liposome-based
      gene transfer was performed by retroinfusion of the anterior interventricular
      vein before left anterior descending occlusion and reperfusion. We found that
      recombinant Hsp90 expression in the ischemic region of the heart led to a 33%
      reduction in infarct size and prevented the increase in postischemic left
      ventricular end diastolic pressure observed in mock-transfected animals. Regional
      myocardial function, assessed by subendocardial segment shortening in the infarct
      region, was increased in Hsp90-transfected animals at baseline and after pacing.
      All these effects were completely abrogated by administration of the NOS
      inhibitor N(G)-nitro-L-arginine methyl ester. We further documented in vivo and
      in cultured endothelial cells that the cardioprotective effects of Hsp90 were
      associated to its capacity to act as an adaptor for both the kinase Akt and the
      phosphatase calcineurin, thereby promoting eNOS serine 1177 phosphorylation and
      threonine 495 dephosphorylation, respectively. CONCLUSIONS: Hsp90 is a promising
      target to enhance NO formation in vivo, which may efficiently reduce myocardial
      reperfusion injury.

PMID- 15178565
TI  - EGF-Like domain of tenascin-C is proapoptotic for cultured smooth muscle cells.
AB  - OBJECTIVE: Based on our previous observations on the expression of Tenascin-C (Tn
      C) in human atherosclerotic plaques and its colocalization with macrophages, we
      explored whether Tn-C undergoes fragmentation and the potential pathobiological
      significance of this fragmentation. METHODS AND RESULTS: Using cultured human
      smooth muscle cells (SMCs), we found that Tn-C upregulates expression of matrix
      metalloproteinases (MMPs). Western blot analysis revealed that Tn-C substrate is
      fragmented and most of the cleavage products have fibronectin-like and epidermal
      growth factor-like (EGF-like) domains of Tn-C. One fragment that contains an EGF
      like domain was found in some human atherosclerotic plaques. Cell culture studies
      revealed that the recombinant EGF-like domain inhibits growth, induces apoptosis
      of SMCs in a dose-dependent, time-dependent, and caspase-dependent manner, and
      activates caspase-3 before SMC detachment. Conversely, the caspase inhibitor z
      YVAD.cmk, serum, and protease inhibitors blocked cell apoptosis conferred by the
      EGF-like domain. In addition, these inhibitors blocked EGF-like domain-induced
      caspase-3 activation. In contrast to this EGF-like domain, intact Tn-C, its
      fibronectin-like, and its fibrinogen-like domains were inactive. CONCLUSIONS:
      Together with our previous observations, our data suggest that Tn-C upregulates
      MMP expression that cleaves Tn-C into fragments containing the EGF-like domain.
      This domain has proapoptotic activity for SMCs.

PMID- 15178566
TI  - Subphysiologic apolipoprotein E (ApoE) plasma levels inhibit neointimal formation
      after arterial injury in ApoE-deficient mice.
AB  - OBJECTIVE: Apolipoprotein E (apoE) reduces mouse atherosclerosis progression
      independent of plasma cholesterol level effects. A mouse artery injury model was
      used to examine whether apoE exhibits beneficial lipid-independent effects on
      neointimal formation. METHODS AND RESULTS: ApoE-deficient (apoE-/-), wild-type
      (WT), and transgenic apoE-/- mice (secreting apoE at different levels from
      adrenal glands) underwent femoral artery injury. Mice with low expression of
      plasma apoE (0.1% of WT) had cholesterol levels approximately half those of apoE
      /- littermates (but still approximately 6x >WT). Mice with higher expression (HE;
      2% to 3% of WT) of plasma apoE had cholesterol levels approximately twice those
      of WT. Injured WT mouse (versus apoE-/-) arteries had a smaller mean intima-to
      media (I/M) ratio (0.87 versus 1.96; P<0.05). HE mice tended to have lower mean
      I/M ratios (1.3; P>0.05 versus apoE-/- mice). Multiple regression analysis
      indicated that apoE levels were significantly associated with reduced I/M ratios,
      but plasma cholesterol levels were not, before or after adjusting for apoE. In
      addition, foam cell content of the neointima and media of injured arteries, a
      negative prognostic indicator in postangioplasty human lesions, was inversely
      related to plasma apoE levels. CONCLUSIONS: Similar to its effects on
      atherosclerosis progression, in a mouse model of restenosis, a subphysiological
      level of apoE was associated with beneficial effects on lesion size/composition.

PMID- 15178567
TI  - A novel efflux-recapture process underlies the mechanism of high-density
      lipoprotein cholesteryl ester-selective uptake mediated by the low-density
      lipoprotein receptor-related protein.
AB  - OBJECTIVE: To determine the mechanism of low-density lipoprotein (LDL) receptor
      related protein (LRP)-mediated selective uptake of high-density lipoprotein (HDL)
      derived cholesteryl esters (CE). METHODS AND RESULTS: Apolipoprotein E (apoE) and
      heparin sulfate proteoglycans are required for LRP-mediated selective uptake in
      adipocytes. Furthermore, 2-deoxyglucose and NaN(3) abolish this process,
      indicating that cellular energy is required. LRP-mediated selective uptake is
      also abolished by monensin or when clathrin-mediated internalization is inhibited
      (using hypotonic, K(+)-free medium or hyperosmolar sucrose), clearly implicating
      receptor endocytosis. The receptor-associated protein (RAP), an inhibitor of
      ligand binding to LRP, reduced the transport of CE into an intracellular
      compartment but not into the plasma membrane. Remarkably, the CE that is
      ultimately transported by LRP first enters the plasma membrane then undergoes
      apoE-mediated CE efflux before being recaptured and internalized by LRP.
      CONCLUSIONS: According to this "efflux-recapture" model, LRP contributes to
      selective uptake because it recovers CE that would normally be lost by efflux
      mediated by apoE. In adipocytes, the LDL receptor-related protein contributes to
      selective uptake when it recaptures and internalizes HDL-derived cholesteryl
      esters that are otherwise lost by apoE-mediated efflux. This novel "efflux
      recapture" process explains some conflicting observations of selective uptake and
      underscores the bi-directional nature of efflux.

PMID- 15178568
TI  - IL-8 plasma concentrations and the risk of future coronary artery disease in
      apparently healthy men and women: the EPIC-Norfolk prospective population study.
AB  - OBJECTIVE: To study the role of IL-8 in predicting future coronary artery disease
      (CAD) in apparently healthy men and women. METHODS AND RESULTS: A nested case
      control study was performed in the prospective EPIC-Norfolk population study. We
      measured baseline IL-8 concentrations among 785 apparently healthy individuals in
      whom fatal or nonfatal CAD developed during follow-up and 1570 matched controls.
      Baseline IL-8 concentrations were higher in cases than in matched controls (3.5
      pg/mL versus 3.1 pg/mL, P=0.001). The risk of future CAD increased with
      increasing quartiles of IL-8 (P linearity <0.0001). Among individuals in the
      highest IL-8 quartile, the unadjusted odds ratio for future CAD was 1.72 (95% CI,
      1.34 to 2.21; P<0.0001). The odds ratio for future CAD was still significant
      after adjustment for traditional risk factors (OR, 1.58; 95%CI, 1.19 to 2.09;
      P=0.002) and after additional adjustment for C-reactive protein and white cell
      count (OR, 1.77; 95% CI, 1.21 to 2.60; P=0.001). CONCLUSIONS: We conclude that
      among apparently healthy men and women, elevated levels of IL-8 are associated
      with an increased risk of future CAD. These prospective data support a role for
      IL-8 in the development of CAD events.

PMID- 15178569
TI  - Incidence of obesity-associated cardiovascular disease is related to inflammation
      sensitive plasma proteins: a population-based cohort study.
AB  - BACKGROUND: Although obesity is associated with increased inflammation, it is
      unclear whether this accounts for the increased cardiovascular risk in obesity.
      This population-based study explored whether inflammation-sensitive plasma
      proteins (ISPs) modify the cardiovascular risk in overweight or obese men.
      METHODS AND RESULTS: The ISPs (fibrinogen, orosomucoid, alpha1-antitrypsin,
      haptoglobin, ceruloplasmin) were measured in 6075 healthy men, aged 28 to 61
      years. The incidences of cardiovascular events (myocardial infarction, stroke,
      cardiovascular deaths), cardiac events (fatal or nonfatal myocardial infarction),
      and stroke were followed-up over 18+/-4 years. High ISPs were associated with an
      increased cardiovascular risk in all categories of body mass index (BMI). The age
      adjusted relative risks for cardiovascular events in obese men (BMI >30) were 2.1
      (95% CI, 1.4 to 3.4), 2.4 (CI, 1.5 to 3.7), 3.7 (CI, 2.3 to 6.0), and 4.5 (CI,
      3.0 to 6.6), respectively, for those with 0, 1, 2, and > or =3 ISPs in the top
      quartile (trend P=0.002) (reference: BMI <25 and no elevated ISP). This trend
      persisted after adjustments for several potential confounders (P=0.02). Incidence
      of cardiac events showed similar relations with the number of elevated ISPs in
      obese men. CONCLUSIONS: The cardiovascular risk varies widely between obese or
      overweight men with high and low ISPs. Relationships with ISPs contribute to, but
      cannot fully explain, the increased cardiovascular risk in obese men.

PMID- 15178570
TI  - Fifty (or more) ways to leave your platelets (in a thrombus).

PMID- 15178571
TI  - Proatherogenic role for NK cells revealed.

PMID- 15178572
TI  - Of mice, men, and hormones.

PMID- 15178573
TI  - TGF-beta in atherosclerosis.

PMID- 15178574
TI  - Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma.
AB  - Therapy of lymphoblastic lymphoma (LL) has evolved with use of chemotherapy
      regimens modeled after those for acute lymphocytic leukemia (ALL). We treated 33
      patients with LL with the intensive chemotherapy regimens hyper-CVAD
      (fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone) or
      modified hyper-CVAD used for ALL at our institution. Induction consolidation was
      administered with 8 or 9 alternating cycles of chemotherapy over 5 to 6 months
      with intrathecal chemotherapy prophylaxis, followed by maintenance therapy.
      Consolidative radiation therapy was given to patients with mediastinal disease at
      presentation. No consolidation with autologous or allogeneic stem cell
      transplantation was performed. At diagnosis, 80% were T-cell immunophenotype, 70%
      were stages III to IV, 70% had mediastinal involvement, and 9% had central
      nervous system (CNS) disease. Of the patients, 30 (91%) achieved complete
      remission, and 3 (9%) achieved partial response. Within a median of 13 months, 10
      patients (30%) relapsed or progressed. Estimates for 3-year progression-free and
      overall survival for the 33 patients were 66% and 70%, respectively. Estimates
      for the patients with known T-cell immunophenotype were 62% and 67%,
      respectively. No parameters (eg, age, stage, serum lactate dehydrogenase [LDH],
      beta(2) microglobulin) appeared to influence outcome except for CNS disease at
      presentation. Modification of the hyper-CVAD regimen with anthracycline
      intensification did not improve outcome. Other modifications of the program could
      include incorporation of monoclonal antibodies and/or nucleoside analogs,
      particularly for slow responders or those with residual mediastinal disease.

PMID- 15178575
TI  - Activated protein C variants with normal cytoprotective but reduced anticoagulant
      activity.
AB  - Recombinant activated protein C (APC), a well-defined anticoagulant enzyme,
      reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent
      anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor,
      failed to do so, implying the physiologic relevance of APC's less well-defined
      anti-inflammatory and antiapoptotic activities. Recombinant APC therapy conveys
      an increased risk of serious bleeding complications due to APC anticoagulant
      activity. To generate recombinant APC variants with reduced risk of bleeding due
      to reduced anticoagulant activity, we dissected APC's anticoagulant activity from
      its cytoprotective activity by site-directed mutagenesis. Using staurosporine
      induced endothelial cell apoptosis assays, we show here that Ala mutations
      (RR229/230AA and KKK191_ 193AAA) in 2 APC surface loops that severely reduce
      anticoagulant activity result in 2 APC variants that retain normal antiapoptotic
      activity that requires protease activated receptor-1 and endothelial cell protein
      C receptor. Thus, it is possible to reduce anticoagulant activity while
      preserving antiapoptotic activity of recombinant APC variants. We suggest that
      therapeutic use of such APC variants may reduce serious bleeding risks while
      providing the beneficial effects of APC acting directly on cells.

PMID- 15178576
TI  - Creation of a mouse expressing defective human factor IX.
AB  - The majority of cases of human hemophilia B are the result of missense mutations
      in the coagulation factor IX gene and defective circulating factor IX is
      detectable in most patients. The available mouse factor IX knockout models of
      hemophilia B (FIXKO mouse) reproduce the bleeding phenotype of human hemophilia
      B, but because the models produce no factor IX they fail to reproduce the
      dominant human phenotype. We have created a human factor IX mouse model of
      hemophilia B (R333Q-hFIX mouse) by homologous recombination in embryonic stem
      cells. The mouse expresses no mouse factor IX, but instead expresses a missense
      mutant human factor IX from the mouse FIX promoter. Mutant human factor IX mRNA
      transcript and circulating human factor IX are detectable throughout development,
      but factor IX activity is less than 1% and the mouse exhibits the hemophilic
      phenotype. When R333Q-hFIX mice were challenged by intramuscular injection of
      adeno-associated virus expressing human factor IX, factor IX expression without
      the development of antibodies was observed. In contrast, given the same
      treatment, FIXKO mice consistently develop antibodies. Our R333Q-hFIX mice strain
      will complement the FIXKO mice for studying factor IX circulating kinetics and
      gene therapy.

PMID- 15178577
TI  - Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non
      MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer
      cell receptors.
AB  - We have recently shown that interleukin-2 (IL-2)-activated CD8(+)CD44(hi) cells
      from normal mice express both adaptive and innate immune system receptors and
      specifically kill syngeneic tumor cells, particularly those that express NKG2D
      ligands. Here we show that CD8+ T cells from antigen-expressing H-Y T-cell
      receptor (TCR) transgenic mice also exhibit characteristics of both T cells and
      natural killer (NK) cells. Interaction with cognate self-antigen was required for
      the optimal expansion of these cells in peripheral lymphoid tissues. Although
      these cells possess a higher activation threshold relative to naive T cells, they
      can be activated by cytokine alone in vitro. They also undergo bystander
      proliferation in response to a bacterial infection in vivo. Interestingly, upon
      activation, the cells express the NKG2D receptor as well as the DNAX activation
      protein 12 (DAP12) adaptor protein. We provide evidence that NKG2D can act
      additively with the TCR in the killing of target cells, and it can also function
      as a directly activating receptor in non-major histocompatibility complex (MHC)
      restricted killing of target cells. These properties of CD8+ T cells from H-Y TCR
      transgenic mice are remarkably similar to CD8(+)CD44(hi) cells that are found in
      normal mice. The H-Y TCR transgenic mice provide a well-defined system for
      characterizing the developmental biology and function of these cells.

PMID- 15178578
TI  - FcgammaRIII discriminates between 2 subsets of Vgamma9Vdelta2 effector cells with
      different responses and activation pathways.
AB  - Upon recognition of nonpeptidic phosphoantigens, human Vdelta2 T lymphocytes
      enter a lineage differentiation pattern that determines the generation of memory
      cells with a range of effector functions. Here, we show that within the effector
      memory Vdelta2 population, 2 distinct and complementary subsets with regard to
      phenotype, mode of activation, and type of responses can be identified: Vdelta2
      T(EMh) cells, which express high levels of chemokine receptors, but low levels of
      perforin and of natural killer receptors (NKRs) and which produce large amounts
      of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in
      response to T-cell receptor (TCR)-specific stimulation by phosphoantigens; and
      Vdelta2T(EMRA) cells, which constitutively express several NKRs, high amounts of
      perforin, but low levels of chemokine receptors and of IFN-gamma. These NK-like
      cells are refractory to phosphoantigen but respond to activation via FcgammaRIII
      (CD16) and are highly active against tumoral target cells. Thus, circulating
      Vdelta2T lymphocytes comprise 2 functionally diverse subsets of effector memory
      cells that may be discriminated on the basis of CD16 expression.

PMID- 15178579
TI  - Functional characterization of highly purified human hematopoietic repopulating
      cells isolated according to aldehyde dehydrogenase activity.
AB  - Human hematopoietic stem cells (HSCs) are commonly purified by the expression of
      cell surface markers such as CD34. Because cell phenotype can be altered by cell
      cycle progression or ex vivo culture, purification on the basis of conserved stem
      cell function may represent a more reliable way to isolate various stem cell
      populations. We have purified primitive HSCs from human umbilical cord blood
      (UCB) by lineage depletion (Lin(-)) followed by selection of cells with high
      aldehyde dehydrogenase (ALDH) activity. ALDH(hi)Lin(-) cells contained 22.6% +/-
      3.0% of the Lin(-) population and highly coexpressed primitive HSC phenotypes
      (CD34(+) CD38(-) and CD34(+)CD133(+)). In vitro hematopoietic progenitor function
      was enriched in the ALDH(hi)Lin(-) population, compared with ALDH(lo)Lin(-)
      cells. Multilineage human hematopoietic repopulation was observed exclusively
      after transplantation of ALDH(hi)Lin(-) cells. Direct comparison of repopulation
      with use of the nonobese diabetic/severe combined immunodeficient (NOD/SCID) and
      NOD/SCID beta2 microglobulin (beta2M) null models demonstrated that 10-fold
      greater numbers of ALDH(hi)-Lin(-) cells were needed to engraft the NOD/SCID
      mouse as compared with the more permissive NOD/SCID beta2M null mouse, suggesting
      that the ALDH(hi)Lin(-) population contained committed progenitors as well as
      primitive repopulating cells. Cell fractionation according to lineage depletion
      and ALDH activity provides a viable and prospective purification of HSCs on the
      basis of cell function rather than cell surface phenotype.

PMID- 15178580
TI  - A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface
      expressed nonfunctional receptors.
AB  - Complete interleukin-12/interleukin-23 receptor beta1 (IL-12Rbeta1) deficiency is
      the most frequent known genetic etiology of the syndrome of Mendelian
      susceptibility to mycobacterial disease. The patients described to date lack IL
      12Rbeta1 at the surface of their natural killer (NK) and T cells due to IL12RB1
      mutations, which either interrupt the open reading frame or disrupt protein
      folding. We describe a patient with a large in-frame deletion of 12165
      nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the
      surface expression of nonfunctional IL-12Rbeta1. These 6 exons encode the
      proximal NH2-terminal half of the extracellular domain downstream from the
      cytokine-binding domain. Five of 6 monoclonal anti-IL-12Rbeta1 antibodies tested
      recognized the internally truncated chain on the cell surface. However, IL-12 and
      IL-23 did not bind normally to the patient's IL-12Rbeta1-containing respective
      heterodimeric receptors. As a result, signal transducer and activator of
      transcription-4 (STAT4) was not phosphorylated and interferon-gamma (IFN-gamma)
      production was not induced in the patient's cells upon stimulation with even high
      doses of IL-12 or IL-23. The functional defect was completely rescued by
      retrovirus-mediated IL-12Rbeta1 gene transfer. Thus, the detection of IL-12Rbeta1
      on the cell surface does not exclude the possibility of complete IL-12Rbeta1
      deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the
      largest IL12RB1 mutation detected is associated with the cell surface expression
      of nonfunctional IL-12Rbeta1, defining a novel genetic form of IL-12Rbeta1
      deficiency.

PMID- 15178581
TI  - Identifying and characterizing a novel activating mutation of the FLT3 tyrosine
      kinase in AML.
AB  - The FLT3 receptor is activated by juxtamembrane insertion mutations and by
      activation loop point mutations in patients with acute myeloid leukemia (AML). In
      a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons
      were sequenced in samples from 53 patients with AML, 9 patients with acute
      lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three
      patients had novel point mutations at residue N841 that resulted in a change to
      isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I
      cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation,
      receptor phosphorylation, and constitutive activation of signal transducer and
      activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK),
      suggesting that the N841I mutation confers constitutive activity to the receptor.
      An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC(50)
      10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced
      tyrosine phosphorylation of the mutant receptor and inhibited STAT5
      phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841
      is the key residue in a hydrogen-bonding network that likely stabilizes the
      activation loop. These results suggest that mutations at N841 represent a
      significant new activating mutation in patients with AML and that patients with
      such mutations may respond to small-molecule FLT3 inhibitors such as PKC412.

PMID- 15178582
TI  - Inhibition of iron transport across human intestinal epithelial cells by
      hepcidin.
AB  - We investigated the effects of the iron regulatory peptide hepcidin on iron
      transport by the human intestinal epithelial Caco-2 cell line. Caco-2 cells were
      exposed to hepcidin for 24 hours prior to the measurement of both iron transport
      and transporter protein and mRNA expression. Incubation with hepcidin
      significantly decreased apical iron uptake by Caco-2 cells. This was accompanied
      by a decrease in both the protein and the mRNA expression of the iron-response
      element containing variant of the divalent metal transporter (DMT1[+IRE]). In
      contrast, iron efflux and iron-regulated gene1 (IREG1) expression were unaffected
      by hepcidin. Hepcidin interacts directly with a model intestinal epithelium. The
      primary effect of this regulatory peptide is to modulate the apical membrane
      uptake machinery, thereby controlling the amount of iron absorbed from the diet.

PMID- 15178583
TI  - Heparin-activated antithrombin interacts with the autolysis loop of target
      coagulation proteases.
AB  - A unique pentasaccharide fragment of heparin can enhance the reactivity of
      antithrombin with coagulation proteases factors IXa and Xa by 300- to 600-fold
      through a conformational activation of the serpin, without having a significant
      effect on the reactivity of antithrombin with thrombin. In this study, it was
      hypothesized that differences in the structure of the autolysis loop of
      coagulation proteases (residues 143-154 in chymotrypsin numbering) may be
      responsible for their differential reactivity with the native and heparin
      activated antithrombin. To test this hypothesis, the autolysis loops of both
      thrombin and the anticoagulant serine protease-activated protein C were replaced
      with the corresponding loop of factor Xa. Inhibition studies revealed that in
      contrast to the approximately 1.5-fold difference in the reactivity of thrombin
      with antithrombin in the absence and presence of pentasaccharide, the difference
      in reactivity was increased to approximately 37-fold for the mutant thrombin. In
      the case of the activated protein C mutant, similar to factor Xa, pentasaccharide
      accelerated the reaction 375-fold. These results suggest that structural
      differences in the autolysis loop of coagulation proteases play a key role in
      their differential reactivity with the native and heparin-activated conformations
      of antithrombin.

PMID- 15178584
TI  - Rescue of lethal c-KitW/W mice by erythropoietin.
AB  - Homozygous natural white-spotted (W) mutations in the gene encoding the receptor
      tyrosine kinase c-Kit are associated with hypoplastic bone marrow, severe
      macrocytic anemia, and lethality during early postnatal life. c-Kit(W/W) mice can
      be rescued by wild-type hematopoietic stem cells (HSCs), but it is not known
      whether the lethality of c-Kit(W/W) mice is the result of HSC failure or defects
      specific for erythropoiesis. Here we show that transgenic expression of
      erythropoietin (EPO) can overcome the lethality caused by the c-Kit(W/W)
      mutation. In W mutant mice rescued by EPO, termed WEPO, erythrocyte colony
      forming units (CFU-Es) are rescued to normal frequencies. Hence, Epo receptor
      signals can partially bypass the strict requirement for c-Kit signaling in
      erythropoiesis in the absence of c-Kit in vivo. Using a series of W and rescue
      mouse strains, we define here the erythropoietic threshold permitting survival in
      vivo. The lethality of c-Kit(W/W) mice has precluded analysis of this crucial
      receptor-ligand pair in adult stem/progenitor cells. Our strategy to generate
      viable c-Kit(W/W) mice will be useful to analyze the role of this important
      receptor tyrosine kinase in adult life in vivo.

PMID- 15178585
TI  - Systematic review of the relative efficacy of non-steroidal anti-inflammatory
      drugs and opioids in the treatment of acute renal colic.
AB  - OBJECTIVE: To examine the relative benefits and disadvantages of non-steroidal
      anti-inflammatory drugs (NSAIDs) and opioids for the management of acute renal
      colic. DATA SOURCES: Cochrane Renal Group's specialised register, Cochrane
      central register of controlled trials, Medline, Embase, and reference lists of
      retrieved articles. REVIEW METHODS: Randomised controlled trials comparing any
      opioid with any NSAID in acute renal colic if they reported any of the following
      outcomes: patient rated pain, time to pain relief, need for rescue analgesia,
      rate of recurrence of pain, and adverse events. RESULTS: 20 trials totalling 1613
      participants were identified. Both NSAIDs and opioids led to clinically important
      reductions in patient reported pain scores. Pooled analysis of six trials showed
      a greater reduction in pain scores for patients treated with NSAIDs than with
      opioids. Patients treated with NSAIDs were significantly less likely to require
      rescue analgesia (relative risk 0.75, 95% confidence interval 0.61 to 0.93). Most
      trials showed a higher incidence of adverse events in patients treated with
      opioids. Compared with patients treated with opioids, those treated with NSAIDs
      had significantly less vomiting (0.35, 0.23 to 0.53). Pethidine was associated
      with a higher rate of vomiting. CONCLUSIONS: Patients receiving NSAIDs achieve
      greater reductions in pain scores and are less likely to require further
      analgesia in the short term than those receiving opioids. Opioids, particularly
      pethidine, are associated with a higher rate of vomiting.

PMID- 15178586
TI  - Direct vascular delivery of primitive hematopoietic cells to bone marrow improves
      localization but not engraftment.

PMID- 15178587
TI  - Fighting obesity.

PMID- 15178588
TI  - Financial incentives for doctors.

PMID- 15178589
TI  - Scars and keloids.

PMID- 15178590
TI  - Sentinel lymph node biopsy.

PMID- 15178591
TI  - The first wave of NHS foundation trusts.

PMID- 15178592
TI  - Italian doctors face criminal allegations over bribes.

PMID- 15178593
TI  - German prosecutors probe again into bribes by drug companies.

PMID- 15178594
TI  - New law forces Italian couple with genetic disease to implant all their IVF
      embryos.

PMID- 15178595
TI  - HIV positive witness learns of his status in courtroom.

PMID- 15178596
TI  - Commons committee slates inaction on obesity.

PMID- 15178597
TI  - Secret smoking documents finally to go on the web.

PMID- 15178600
TI  - New guidelines aim to improve management of COPD.

PMID- 15178601
TI  - Dutch reporting of euthanasia cases falls--despite legal reporting requirements.

PMID- 15178602
TI  - Mental illness should be recognised as a disability.

PMID- 15178604
TI  - Appeal court upholds Oregon's assisted suicide law.

PMID- 15178608
TI  - FDA warns of risks from breast implants.

PMID- 15178610
TI  - US accreditor moves to tackle industry's influence on medical education.

PMID- 15178611
TI  - Hospitals in India woo foreign patients.

PMID- 15178613
TI  - Slipped capital femoral epiphyses associated with the withdrawal of a
      gonadotrophin releasing hormone.

PMID- 15178612
TI  - Effectiveness of antibiotics in preventing meningococcal disease after a case:
      systematic review.
AB  - OBJECTIVE: To summarise the evidence for the role of antibiotics in preventing
      further cases of meningococcal disease through chemoprophylaxis given to the
      index patient, household contacts, and children in day care settings after a
      single case. DESIGN: Systematic review. METHODS: Studies were identified by
      searching Embase (1983-2003), Medline (1965-2003), and CAB Health (1973-2003) and
      by contacting the World Health Organization and the European meningococcal
      disease surveillance network and examining references of identified papers. The
      review included all studies with at least 10 cases in which outcomes were
      compared between treated and untreated groups. MAIN OUTCOME MEASURE: Subsequent
      cases of meningococcal disease 1-30 days after onset of disease in the index
      patient. RESULTS: Four observational studies and one small trial met the
      inclusion criteria. Meta-analysis of studies on chemoprophylaxis given to
      household contacts showed a significant reduction in risk (risk ratio 0.11, 95%
      confidence interval 0.02 to 0.58). The number needed to treat to prevent a case
      was estimated as 218 (121 to 1135). Primary outcome data were not available in
      studies of chemoprophylaxis given to the index patient: when prophylaxis had not
      been given, rate of carriage after discharge from hospital was estimated as 3% (0
      to 6), probably an underestimate of the true rate. No studies of chemoprophylaxis
      in day care settings were identified that met the inclusion criteria. CONCLUSION:
      There have been no high quality experimental trials looking at control policies
      for meningococcal disease. The best available evidence is from retrospective
      studies. The risk of meningococcal disease in household contacts of a patient can
      be reduced by an estimated 89% if they take antibiotics known to eradicate
      meningococcal carriage. Chemoprophylaxis should be recommended for the index
      patient and all household contacts.

PMID- 15178614
TI  - Female dyspareunia.

PMID- 15178615
TI  - Management of venous leg ulcers.

PMID- 15178617
TI  - Toxicity after intermittent inhalation of nitrous oxide for analgesia.

PMID- 15178618
TI  - ABC of burns. Introduction.

PMID- 15178619
TI  - Trafficking and health.

PMID- 15178620
TI  - Administering, analysing, and reporting your questionnaire.

PMID- 15178621
TI  - Campaign to revitalise academic medicine: crisis in UK academia affects academic
      medicine too.

PMID- 15178622
TI  - Campaign to revitalise academic medicine: Isolation hinders academic medicine.

PMID- 15178623
TI  - Campaign to revitalise academic medicine: funding needs to be on the discussion
      table.

PMID- 15178624
TI  - Campaign to revitalise academic medicine: a road map needs to be drawn for the
      21st century.

PMID- 15178625
TI  - Campaign to revitalise academic medicine: direction of academic medicine is
      worrying.

PMID- 15178626
TI  - Campaign to revitalise academic medicine: focus on health care is needed.

PMID- 15178627
TI  - Campaign to revitalise academic medicine: academic medicine needs teeth.

PMID- 15178628
TI  - Campaign to revitalise academic medicine: some thoughts for academic revisionists
      to consider.

PMID- 15178629
TI  - Roll Back Malaria: a failing global health challenge: options for malaria control
      need to be weighed.

PMID- 15178630
TI  - Roll Back Malaria: a failing global health challenge: developing a market for bed
      nets and insecticides is problematic.

PMID- 15178631
TI  - Management of diastolic heart failure in older adults: diagnosing diastolic
      dysfunction is complex.

PMID- 15178632
TI  - Management of diastolic heart failure in older adults: B-type natriuretic peptide
      was not mentioned.

PMID- 15178633
TI  - Effect of public smoking ban in Helena, Montana: When results look too good to be
      true, they probably are.

PMID- 15178634
TI  - Effect of public smoking ban in Helena, Montana: can law really make a
      difference?

PMID- 15178635
TI  - Eating more vegetables might explain reduced asthma symptoms.

PMID- 15178638
TI  - Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live
      neonatal rat cardiac myocytes reveals distinct functions of compartmentalized
      phosphodiesterases.
AB  - Cardiac myocytes have provided a key paradigm for the concept of the
      compartmentalized cAMP generation sensed by AKAP-anchored PKA. Phosphodiesterases
      (PDEs) provide the sole route for degrading cAMP in cells and are thus poised to
      regulate intracellular cAMP gradients. PDE3 and PDE4 represent the major cAMP
      degrading activities in rat ventriculocytes. By performing real-time imaging of
      cAMP in situ, we establish the hierarchy of these PDEs in controlling cAMP levels
      in basal conditions and on stimulation with a beta-adrenergic receptor agonist.
      PDE4, rather than PDE3, appears to be responsible for modulating the amplitude
      and duration of the cAMP response to beta-agonists. PDE3 and PDE4 localize to
      distinct compartments and this may underpin their different functional roles. Our
      findings indicate the importance of distinctly localized PDE isoenzymes in
      determining compartmentalized cAMP signaling.

PMID- 15178637
TI  - Atorvastatin restores endothelial function in normocholesterolemic smokers
      independent of changes in low-density lipoprotein.
AB  - Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA
      reductase inhibitors (statins) may favorably affect endothelial function via
      nonlipid mechanisms. We tested the hypothesis that statins would improve
      endothelial function independent of changes in lipids in cigarette smokers.
      Twenty normocholesterolemic cigarette smokers and 20 matched healthy control
      subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks,
      washed out for 4 weeks, and then crossed-over to the other treatment. Baseline
      low-density lipoprotein (LDL) levels were similar in smokers and healthy
      subjects, 103+/-22 versus 95+/-27 mg/dL, respectively (P=NS) and were reduced
      similarly in smokers and control subjects by atorvastatin, to 55+/-30 and 58+/-20
      mg/dL, respectively (P=NS). Vascular ultrasonography was used to determine
      brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin
      mediated, endothelium-independent vasodilation. To elucidate potential molecular
      mechanisms that may account for changes in endothelial function, skin biopsy
      specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine.
      Endothelium-dependent vasodilation was less in smokers than nonsmoking control
      subjects during placebo treatment, 8.0+/-0.6% versus 12.1+/-1.1%, (P=0.003).
      Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5+/
      1.3% (P=0.017 versus placebo) but did not change endothelium-dependent
      vasodilation in control subjects (to 11.0+/-0.8%, P=NS). Endothelium-independent
      vasodilation did not differ between groups during placebo treatment and was not
      significantly affected by atorvastatin. Multivariate analysis did not demonstrate
      any association between baseline lipid levels or the change in lipid levels and
      endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin
      microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared
      with controls but unaffected by atorvastatin treatment. Atorvastatin restores
      endothelium-dependent vasodilation in normocholesterolemic cigarette smokers
      independent of changes in lipids. These results are consistent with a lipid
      independent vascular benefit of statins but could not be explained by changes in
      eNOS message and tissue oxidative stress. These findings implicate a potential
      role for statin therapy to restore endothelial function and thereby investigate
      vascular disease in cigarette smokers.

PMID- 15178639
TI  - Origins of serum semicarbazide-sensitive amine oxidase.
AB  - Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of
      deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide.
      This activity has been associated with vascular adhesion protein-1 (VAP-1) and is
      found in the serum, endothelium, adipose, and smooth muscle of mammals.
      Circulating SSAO activity is increased in congestive heart failure, diabetes, and
      inflammatory liver diseases. To investigate the origin of circulating SSAO
      activity, two transgenic mouse models were created with full-length human VAP-1
      (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP
      1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions
      a circulating form of hVAP-1 was found at high levels in the serum of mice with
      endothelium-specific expression and at low levels in the serum of mice with
      adipose specific expression. The level of circulating hVAP-1 in the transgenic
      mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO
      activity was absent from VAP-1 knockout mice and endothelial cell-specific
      expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout
      mice. Together, these experiments show that in the mouse VAP-1 is the only source
      of serum SSAO, that under physiological conditions vascular endothelial cells can
      be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can
      originate from both endothelial cells and adipocytes during experimental
      diabetes. An increased endothelial cell capacity for lymphocyte binding and
      altered expression of redox-sensitive proteins was also associated with the
      mTIEhVAP-1 transgene.

PMID- 15178640
TI  - Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent
      pathway.
AB  - Although it has been established that myocyte enhancer factor 2 (MEF2) plays
      pivotal roles in the development of the cardiovascular system as well as skeletal
      muscle cells, little is known of its role in vascular inflammatory diseases such
      as atherosclerosis and restenosis after angioplasty. To investigate the role of
      MEF2 in vascular inflammation and that of p38 in the activation of MEF2, we
      infected cultured rat vascular smooth muscle cells (VSMCs) with an adenovirus
      construct expressing a dominant-negative mutant of MEF2A (MEF2ASA) or mitogen
      activated protein kinase kinase 6 (MEK6AA), and examined their effects on the
      expression of monocyte chemoattractant protein-1 (MCP-1), which is known to play
      important roles in vascular inflammation. We also examined the role of MEF2 in
      vivo using a rat model of transluminal wire-induced injury of the femoral artery.
      Angiotensin II (Ang II)-induced expression of MCP-1 mRNA was significantly
      inhibited by infection with adenoviruses encoding MEF2ASA (AdMEF2ASA) or MEK6AA.
      Ang II-induced increase of MCP-1 promoter activity was also significantly
      suppressed by overexpression of MEF2ASA or MEK6AA. Ang II stimulated the
      transactivating function of MEF2A and this activation was inhibited by
      overexpression of MEK6AA. Infection with AdMEF2ASA suppressed MCP-1 expression in
      the femoral artery after the transluminal mechanical injury. AdMEF2ASA infection
      also inhibited macrophages infiltration and neointimal formation in the wire
      injured femoral arteries. These results suggested that MEF2 activation via the
      p38-dependent pathway mediates vascular inflammation via stimulation of MCP-1
      expression in VSMCs and macrophages infiltration.

PMID- 15178641
TI  - Uncontrolled expression of vascular endothelial growth factor and its receptors
      leads to insufficient skin angiogenesis in patients with systemic sclerosis.
AB  - Systemic sclerosis (SSc) skin lesions are characterized by disturbed vessel
      morphology with enlarged capillaries and an overall reduction in capillary
      density, suggesting a deregulated, insufficient angiogenic response. It has been
      postulated that this phenomenon is due to reduced expression of the potent
      angiogenic factor vascular endothelial growth factor (VEGF). In contrast to this
      hypothesis, we demonstrate that the expression of both VEGF and its receptors
      VEGFR-1 and VEGFR-2 is dramatically upregulated in skin specimens of SSc patients
      throughout different disease stages. Interestingly, upregulation of VEGF was not
      mediated by hypoxia-inducible transcription factor-1 (HIF-1) as indicated by only
      a weak expression of the oxygen-sensitive alpha-subunit of HIF-1 in the skin of
      SSc patients. This was unexpected on measuring low Po2 values in the SSc skin by
      using a polarographic oxygen microelectrode system. Considering our observation
      that PDGF and IL-1beta costimulated VEGF expression, we propose that chronic and
      uncontrolled VEGF upregulation that is mediated by an orchestrated expression of
      cytokines rather than VEGF downregulation is the cause of the disturbed vessel
      morphology in the skin of SSc patients. Consequently, for therapeutic approaches
      aiming to improve tissue perfusion in these patients, a controlled expression and
      timely termination of VEGF signaling appears to be crucial for success of
      proangiogenic therapies.

PMID- 15178642
TI  - LNP 906, the first high-affinity photoaffinity ligand selective for I1
      imidazoline receptors.
AB  - 1 The hypotensive effect of imidazoline-like drugs, such as clonidine, was
      attributed both to alpha2-adrenergic receptors and nonadrenergic imidazoline
      receptors, which are divided into I1, I2 and I3 subtypes. 2 We have recently
      synthesized a derivative of (2-(2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline
      (LNP 911), the first high-affinity and selective ligand for I1 receptors (I1R),
      with a photoactivable function (LNP 906). 3 This work aims to test whether this
      derivative retained the binding properties of LNP 911 and bound irreversibly to
      I1R. 4 Binding studies showed that LNP 906 exhibited nanomolar affinity for I1R
      and was selective for I1R over I2 receptors and alpha2-adrenergic receptors
      (alpha2Ars). 5 Upon exposure to u.v. light, LNP 906 irreversibly blocked the
      binding of [125I]-paraiodoclonidine (PIC) to I1R, time- and dose-dependently, on
      PC12 cell membranes and interacted with I1R in a reversible and competitive
      manner in the absence of light. Pharmacological studies showed that this blockade
      was prevented by the concomitant presence of rilmenidine (a well-known I1
      agonist), but not by rauwolscine (an alpha2 antagonist). 6 Finally, LNP 906
      clearly antagonized the decrease in forskolin-stimulated cAMP level induced by
      rilmenidine, but not by melatonin. 7 These results indicate that LNP 906 is the
      first high-affinity and selective photoaffinity ligand for I1R and that it
      behaves as an I1R antagonist.

PMID- 15178643
TI  - Effects of dehydroepiandrosterone and flutamide on hippocampal CA1 spine synapse
      density in male and female rats: implications for the role of androgens in
      maintenance of hippocampal structure.
AB  - The effects of androgens and the androgen antagonist, flutamide, on the density
      of dendritic spine synapses in the CA1 subfield of the hippocampus were studied
      in gonadectomized male and female rats. Treatment of orchidectomized male rats
      with dehydroepiandrosterone (DHEA; 2 d, 1 mg/d sc) increased the density of CA1
      spine synapses observed 2 d later, by 106%, without significantly affecting
      ventral prostate weight. The hippocampal response to DHEA was unaffected by
      blockade of intracerebral estrogen biosynthesis using the aromatase inhibitor,
      letrozole. By contrast, flutamide alone (2 d; 5 mg/d, sc) increased CA1 spine
      synapse density by 66%, whereas in combination the effects of flutamide and DHEA
      were additive rather than inhibitory. Additive effects on CA1 synapse density
      were also observed in males using combinations of flutamide with 5alpha
      dihydrotestosterone (2 d, 500 microg/d, sc). At the same doses, flutamide had no
      effect on prostate weight and completely blocked the effects on the prostate of
      treatment with 5alpha-dihydrotestosterone. Treatment of ovariectomized females
      with DHEA increased CA1 spine synapse density to a level similar to that observed
      in the male. As in males, flutamide in females increased CA1 spine synapse
      formation and further augmented the response to DHEA. These results demonstrate
      that flutamide and DHEA have positive effects on hippocampal CA1 spine synapse
      density in both sexes. They also suggest that conventional measures of androgen
      agonist or antagonist activity, exemplified by ventral prostate growth, may not
      be indicative of effects on hippocampal CA1 synaptogenesis.

PMID- 15178644
TI  - Gonadal hormones and frontocortical expression of vascular endothelial growth
      factor in male stroke-prone, spontaneously hypertensive rats, a model for
      attention-deficit/hyperactivity disorder.
AB  - Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral
      disorder associated, in part, with male preponderance and reduced regional
      cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance
      and reduced rCBF in AD/HD are unclear. The present study profiles the expression
      of angiogenic and hormonal factors likely to underlie these symptoms using a
      recently characterized AD/HD animal model, juvenile male stroke-prone
      spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth
      factor (VEGF) signaling cascade and gonadal steroids are key regulators of
      angiogenesis and gender-based behavior, respectively, we profiled their patterns
      of expression in the frontal cortex of SHRSP to elucidate their roles in the
      genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF
      receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt
      (pAkt), estrogen receptor-alpha, aromatase, and capillary density in sham
      operated SHRSP were remarkably down-regulated, whereas androgen receptor levels
      were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats.
      Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted
      these effects. Dihydrotestosterone, but not testosterone, reversed the
      beneficiary effects of castration. Estrogen receptor-beta levels remained
      unchanged in all groups examined. We postulate that changes in androgen
      metabolism that tend to up-regulate local dihydrotestosterone concentration and
      diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may
      lower levels and/or activity of VEGF and its signaling cascade and, subsequently,
      reduce rCBF. These findings could, in part, help explain the pathogenesis of
      reduced rCBF and male preponderance in AD/HD.

PMID- 15178645
TI  - Expression of pituitary tumor transforming gene (PTTG) and its binding protein in
      human astrocytes and astrocytoma cells: function and regulation of PTTG in U87
      astrocytoma cells.
AB  - Human securin, pituitary tumor transforming gene (PTTG), is a protooncogene. Here
      we report expressions of PTTG and its interacting protein, PTTG-binding factor in
      human astrocytic cells. PTTG expression was higher in malignant cells than in
      primary astrocytes, whereas PTTG-binding factor was not. Using a
      xenotransplantable, glioma cell line (U87), we observed that knocking down PTTG
      mRNA by RNA silencing inhibited serum-induced proliferation by approximately 50%.
      Furthermore, in U87 cells PTTG expression was up-regulated by promalignant
      ligands epithelial growth factor (EGF) and TGFalpha, both at the protein and mRNA
      levels. PTTG induction by EGF receptor (EGFR) ligands could be blocked by the
      specific EGFR inhibitor, AG1478. Hepatocyte growth factor (HGF) also induced PTTG
      but to a lesser extent than EGF. Although EGF stimulates HGF secretion in U87
      cells, the effect of EGF on PTTG mRNA expression is independent of HGF as
      neutralizing antibody against HGF failed to abolish EGF-induced up-regulation of
      PTTG mRNA. PTTG mRNA was unchanged by incubating U87 cells with the promalignant
      growth factor TGFbeta, apoptosis inducing TNFalpha and ligands for nuclear
      receptors, such as retinoic acid and retinoid X receptors and peroxisome
      proliferator-activated receptor-gamma, known for their growth-inhibitory and
      apoptosis-inducing effects on gliomas. In addition, 17beta-estradiol and Ca2+,
      known to activate PTTG expression, did not change PTTG mRNA levels in U87 cells.
      In summary, we show higher PTTG expression in astrocytoma than normal astrocytes
      and secondly, PTTG is involved in glioma cell growth. Finally, regulation of its
      expression has glioma-specific features and is selectively regulated by
      promalignant cytokines including EGFR ligands and HGF.

PMID- 15178646
TI  - Pyruvate prevents restraint-induced immunosuppression via alterations in
      glucocorticoid responses.
AB  - Stress-evoked immunosuppression may reflect increased demands on cellular energy
      signaled via elevated glucocorticoid concentrations. We hypothesized that
      treatment with pyruvate, an alternative energy source, would ameliorate restraint
      induced elevation of glucocorticoids and that this reduction in glucocorticoid
      exposure will prevent stress-induced immunosuppression. We provided exogenous
      pyruvate to mice exposed to repeated restraint and then assessed splenocyte
      counts and splenocyte proliferation in response to the mitogen, concanavalin A as
      well as IgM production in response to keyhole limpet hemocyanin. Immune function
      was suppressed in mice undergoing repeated restraint but not in mice exposed to
      repeated restraint followed by pyruvate treatment. All mice exposed to restraint,
      regardless of pyruvate supplementation, displayed equivalent occurrences of
      repeated elevations in corticosterone concentrations; however, the cumulative
      exposure to corticosterone after one episode of restraint was reduced in those
      mice treated with pyruvate after restraint. Finally, we tested the
      immunoprotective ability of pyruvate supplementation in the presence of
      chronically elevated corticosterone. Mice implanted with restraint-like
      concentrations of corticosterone after adrenalectomy decreased splenocyte counts,
      compared with either unmanipulated mice or mice that were implanted with a
      cholesterol pellet after adrenalectomy, regardless of pyruvate supplementation.
      These data suggest that pyruvate does not possess immunoprotective properties in
      the presence of chronically elevated corticosterone. Pyruvate supplementation
      preserves immune function during exposure to repeated restraint stressors;
      altered dynamics of corticosterone concentrations after pyruvate administration
      may mediate this immunoprotection. Pyruvate prevents restraint-induced
      immunosuppression via alterations in the glucocorticoid response to restraint.

PMID- 15178647
TI  - The developmental regulation of peroxisome proliferator-activated receptor-gamma
      coactivator-1alpha expression in the liver is partially dissociated from the
      control of gluconeogenesis and lipid catabolism.
AB  - The developmental regulation of peroxisome proliferator-activated receptor-gamma
      coactivator-1alpha (PGC-1alpha) gene expression was studied in mice and compared
      with that of marker genes of liver energy metabolism. The PGC-1alpha gene was
      highly expressed in fetal liver compared with that in adults and remained high in
      neonatal liver. The regulation of PGC-1alpha gene expression during the fetal and
      early neonatal periods was dissociated from that of gluconeogenic genes, i.e. the
      phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase)
      genes. Only under the effects of starvation was PGC-1alpha gene expression
      induced in parallel to phosphoenolpyruvate carboxykinase and G6Pase mRNAs during
      the perinatal period. Furthermore, the PGC-1alpha gene was not regulated as part
      of the developmental program of gene expression associated with the maturation of
      hepatic gluconeogenesis, as revealed by the impaired PEPCK and G6Pase gene
      expression but unaltered PGC-1alpha mRNA levels in CCAAT/enhancer-binding protein
      alpha-null fetus and neonates. Regulation of the PGC-1alpha gene and that of
      mitochondrial 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase, acyl-coenzyme A
      oxidase, and long-chain acyl-coenzyme dehydrogenase, marker genes of lipid
      catabolism, were dissociated in fetuses and neonates. The expression of lipid
      catabolism genes was down-regulated in fasted neonates, whereas PGC-1alpha was
      oppositely regulated. The independent regulation of PGC-1alpha and lipid
      catabolism genes was also found in peroxisome proliferator-activated receptor
      alpha-null neonates, in which PGC-1alpha mRNA levels were unaffected whereas gene
      expression for 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase and acyl-coenzyme
      A oxidase was impaired. Thus, regulation of the PGC-1alpha gene is partially
      dissociated from the patterns of regulation of hepatic genes encoding enzymes
      involved in gluconeogenesis and lipid catabolism during fetal ontogeny and in
      response to the initiation of lactation.

PMID- 15178648
TI  - Dual hormonal regulation of endocrine tissue mass and vasculature by
      adrenocorticotropin in the adrenal cortex.
AB  - The mass of healthy adult tissues is stable and their vasculature is quiescent,
      but this equilibrium is disrupted under certain physiological or pathological
      situations. There is an emerging concept indicating that these trophic changes
      may be initiated by modifications of the vasculature. In the current study, we
      documented over a period of 14 d the serial alterations occurring in both
      endocrine and endothelial compartments during adrenal atrophy induced by ACTH
      suppression in mice. After dexamethasone perfusion, a rapid fall of plasmatic
      ACTH and corticosterone concentrations was observed within the first 24 h. During
      the first 4 d of treatment, adrenal weight and adrenal cortex cellularity
      decreased rapidly. This was correlated with an inhibition of cell proliferation
      and a massive induction of endocrine cell apoptosis. Between d 4 and d 14, a
      slower but sustained decay of adrenal cortex size and cellularity was observed.
      This second phase was associated with progressive loss of vascular endothelial
      growth factor protein expression in the endocrine cells and regression of the
      vascular network. These data support the concept that ACTH controls adrenal
      cortex trophicity through a dual mechanism involving its antiapoptotic effect on
      endocrine cells and its indirect vascular endothelial growth factor-mediated
      action on endothelial cells.

PMID- 15178649
TI  - Seasonal morphological changes in the neuro-glial interaction between
      gonadotropin-releasing hormone nerve terminals and glial endfeet in Japanese
      quail.
AB  - In a previous study we showed that photoperiodically generated T3 in the
      hypothalamus is critical for the photoperiodic response of gonads in Japanese
      quail. The expression of thyroid hormone receptors in the median eminence (ME)
      suggested that photoperiodically generated T3 acts on the ME. Because thyroid
      hormone is known to play a critical role in the development and plasticity of the
      central nervous system, in the present study we have examined ultrastructure of
      the ME in Japanese quail kept in short-day and long-day environments.
      Immunoelectron microscopy revealed that GnRH nerve terminals are in close
      proximity to the basal lamina under long-day conditions, and conventional
      transmission electron microscopy demonstrated the encasement of the terminals by
      the endfeet of glia under short-day conditions. These morphological changes may
      regulate photoperiodic GnRH secretion.

PMID- 15178650
TI  - Aromatase-deficient (ArKO) mice have reduced blood pressure and baroreflex
      sensitivity.
AB  - Aromatase-deficient (ArKO) mice are deficient in estrogens due to deletion of the
      aromatase gene. We hypothesized that there may be changes in the cardiovascular
      system of ArKO mice because of evidence linking estrogens with improved
      cardiovascular outcomes and the induction of the glucocorticoid-metabolizing
      enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), gene in the
      kidney, which is important for the regulation of blood pressure (BP). BP and
      baroreflex sensitivity (BRS) in female conscious ArKO mice were compared with
      those in age- and weight-matched wild-type (WT) mice. Power spectral analysis was
      used to determine cardiovascular variability and BRS. Although systolic BP was
      similar in the two groups, diastolic and mean BPs were lower in the ArKO mice (
      6.3 +/- 1.9 and -4.6 +/- 2.1 mm Hg, respectively). Heart rate (HR) was greater in
      the ArKO mice (+36 +/- 6 beats/min). The mean BP in WT mice was 105 mm Hg, and
      the HR was 481 beats/min. In the autonomic frequency range, BP variability was
      74% greater, and HR variability was only 26% that in WT mice. The BRS of ArKO
      mice was 46% of the value observed in WT mice. 11betaHSD2 levels were unaltered
      in ArKO mice, except in the kidney, where they were only 10% of WT levels.
      Estradiol administration to ArKO mice restored renal 11betaHSD2 to WT levels. The
      results show that ArKO mice have lower diastolic BP, but increased BP
      variability, perhaps due to an impaired BRS. Thus, aromatase activity is critical
      for normal autonomic control of the heart and, hence, for reducing the
      deleterious effects of high BP variability.

PMID- 15178651
TI  - Identification of CYP2B6 sequence variants by use of multiplex PCR with allele
      specific genotyping.
AB  - BACKGROUND: Cytochrome P450 2B6 (CYP2B6) has a role in the metabolism of many
      clinically important substances, but the variation within the CYP2B6 gene has not
      been fully characterized. The aim of the present study was to develop a reliable
      and robust assay for determining genotypic variants. METHODS: We used a two-stage
      procedure. An initial multiplex PCR reaction amplified the relevant gene
      fragments in exonic and regulatory regions to ensure isolation of CYP2B6 from its
      similar pseudogene (CYP2B7). This product was then genotyped by allele-specific
      PCR. RESULTS: The assay detected the following published single-nucleotide
      polymorphisms: C64T (Arg22Cys), C78T, G216C, G516T (Gln172His), C777A
      (Ser259Arg), A785G (Lys262Arg), and C1459T (Arg487Cys), as well as additional
      loci found within the single-nucleotide polymorphism (SNP) databases: A1190G,
      C1268A, C1330T, A1382G, A1402T, and an A/T SNP in intron 2 (A12917T). This
      approach detected all common, previously reported alleles and identified a new
      allele (CYP2B6*4C) present in 2.2% of a Caucasian population. Genotypic
      frequencies obtained were consistent with previously published results.
      CONCLUSIONS: This method is simple, reliable, rapid, and amenable to automation
      and could facilitate the large-scale genotypic analysis of CYP2B6.

PMID- 15178652
TI  - Three-dimensional microarray compared with PCR-single-strand conformation
      polymorphism analysis/DNA sequencing for mutation analysis of K-ras codons 12 and
      13.
AB  - BACKGROUND: We developed a rapid, precise, and accurate microarray-based method
      that uses a three-dimensional platform for detection of mutations. METHODS: We
      used the PamChip microarray to detect mutations in codons 12 and 13 of K-ras in
      15 cell lines and 81 gastric or colorectal cancer tissues. Fluorescein
      isothiocyanate-labeled PCR products were analyzed with the microarray. We
      confirmed the microarray results with PCR-single-strand conformation polymorphism
      (SSCP) analysis and DNA sequencing. RESULTS: We could correctly identify wild
      type, heterozygous, and homozygous mutant genotypes with the PamChip microarray
      in <3.5 h. The array data were consistent with those of PCR-SSCP analysis and DNA
      sequencing. All 15 cell lines and 80 of 81 clinical cancer specimens (98.8%; 95%
      confidence interval, 96.4-100%) were genotyped accurately with the microarray, a
      rate better than that of direct DNA sequencing (38.9%) or SSCP (93.8%). Only one
      clinical specimen was misdiagnosed as homozygous for the wild-type allele.
      Densitometric analysis of SSCP bands indicated that the content of the mutant
      allele in the specimen was approximately 16%. The PamChip microarray could detect
      mutant alleles representing more than 25% of the SSCP band proportions.
      Therefore, the limit for detection of mutant alleles by the PamChip microarray
      was estimated to be 16-25% of the total DNA. CONCLUSIONS: The PamChip microarray
      is a novel three-dimensional microarray system and can be used to analyze K-ras
      mutations quickly and accurately. The mutation detection rate was nearly 100% and
      was similar to that of PCR-SSCP together with sequencing analysis, but the
      microarray analysis was faster and easier.

PMID- 15178653
TI  - Serial analysis of plasma proteomic signatures in pediatric patients with severe
      acute respiratory syndrome and correlation with viral load.

PMID- 15178654
TI  - Validation of safety procedures for the cryopreservation of semen contaminated
      with hepatitis C virus in assisted reproductive technology.
AB  - BACKGROUND: In France, assisted reproductive technologies involving a hepatitis C
      virus (HCV)-infected man requires the cryopreservation of potentially infected
      semen (in order to establish the presence of HCV), hence the need for a safe and
      secure storage system. We evaluated the safety of high-security straws for the
      conservation of semen containing HCV RNA under routine conditions. METHODS:
      Ionomeric resin (IR) straws were filled with seminal plasma spiked with different
      concentrations of HCV RNA and sealed using a thermo-solder. After a 4% sodium
      hypochlorite treatment and/or cryopreservation for 7 days in liquid nitrogen, the
      outside ends of each straw were rinsed with RNAse-free water. RESULTS: No HCV RNA
      could be detected in any of the water samples. Additional samples included the
      rinsing water from straws sealed by thermo-solder and from the heating wire used
      to cut the end of straws containing HCV-positive semen. The latter samples were
      found positive for both HCV RNA and the protamine-2 gene expressed by
      spermatozoa. CONCLUSIONS: These results demonstrate the safety of IR straws, the
      filling system and the thermo-solder for cryopreservation of semen containing HCV
      in liquid nitrogen. Decontamination of the straw after sealing and the use of
      disposable scissors to open the straws are strongly recommended.

PMID- 15178655
TI  - Establishment of a capillary-cumulus model to study the selection of sperm for
      fertilization by the cumulus oophorus.
AB  - BACKGROUND: Spermatozoa have to traverse the cumulus oophorus before
      fertilization in vivo. Evidence suggests that the cumulus oophorus plays an
      important role in the fertilization process. We describe the establishment of a
      capillary-cumulus oophorus model with which to study the action of cumulus mass
      on the function of human spermatozoa. METHODS: Human cumulus oophorus was
      aspirated into a glass capillary. Spermatozoa were allowed to pass through the
      cumulus mass in the capillary from one end of the capillary. The spermatozoa that
      had traversed the mass were collected at the other end of the capillary and
      underwent sperm function analyses. RESULTS: Compared with those spermatozoa
      cultured in medium alone, spermatozoa exposed to the cumulus mass were more
      likely to have normal morphology, be capacitated and acrosome reacted, with a
      distinct motility pattern and better zona-binding capacity. CONCLUSION: A novel
      in vitro model for spermatozoa penetration through the cumulus oophorus was
      established. The model can be applied to investigate the effect of the cumulus
      oophorus on sperm functions.

PMID- 15178656
TI  - Bleeding patterns after vaginal misoprostol for treatment of early pregnancy
      failure.
AB  - BACKGROUND: Dilatation and curettage (D&C) has been the usual treatment for early
      pregnancy failure (EPF). Medical management with misoprostol may be an effective
      alternative. Bleeding patterns during and after medical management of EPF are
      unknown. METHODS: A prospective cohort study was conducted at University-based
      clinics and physician offices. Eighty women <11 weeks estimated gestational age
      with a diagnosis of missed abortion or fetal demise were enrolled. Treatment
      consisted of either 800 micro g of moistened (2 ml of saline) or dry vaginal
      misoprostol. Self-reported bleeding and sanitary product usage were recorded in a
      daily 2 week diary. Haemoglobin was assessed at enrollment and 2 weeks later.
      RESULTS: After misoprostol treatment, patients reported bleeding or spotting
      every day for the 14 days observed. Self-assessed heavy bleeding days were few
      (median 3) and usually occurred immediately after treatment. Sanitary pad use was
      highly variable (mean 30.5, range 2-125 pads over the 2 week period) and not
      related to changes in haemoglobin. The mean decrease in haemoglobin was 0.5 g/dl
      (SD 1.2). Complete expulsion without D&C occurred in 85% of subjects.
      CONCLUSIONS: Bleeding for at least 2 weeks after vaginal misoprostol for EPF is
      common. Heavy bleeding is usually limited to a few days after treatment.
      Clinically important changes in haemoglobin are rare.

PMID- 15178657
TI  - Proliferation of ovarian theca-interstitial cells is modulated by antioxidants
      and oxidative stress.
AB  - BACKGROUND: Maintenance of ovarian homeostasis requires precise regulation of
      proliferation of thecal- interstitial (T-I) cells. Recent evidence indicates that
      oxidative stress and antioxidants modulate proliferation of various tissues under
      both physiological and pathological conditions. This study evaluated the effects
      of oxidative stress and antioxidants on T-I proliferation. METHODS: Rat T-I cells
      were cultured in serum-free medium and proliferation was assessed by
      determination of DNA synthesis using the thymidine incorporation assay, by 3-[4,5
      dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and by direct
      counting of steroidogenically active cells and steroidogenically inactive cells.
      RESULTS: Antioxidants and reactive oxygen scavengers induced a dose-dependent
      decrease of T-I proliferation. Vitamin E succinate was inhibitory at 10-100 micro
      mol/l, ebselen was inhibitory at 0.3-30 micro mol/l, and superoxide dismutase was
      inhibitory at 300-1000 IU/ml. In contrast, oxidative stress resulted in a
      biphasic effect. Modest oxidative stress induced by 1 mmol/l hypoxanthine and
      xanthine oxidase (3-30 micro U/ml) stimulated proliferation of T-I cells, while
      greater oxidative stress induced by xanthine oxidase (1 mU/ml) profoundly
      inhibited proliferation. Direct cell counting demonstrated comparable effects on
      steroidogenically active and inactive cells. CONCLUSIONS: Reactive oxygen species
      may play a role in the regulation of growth of ovarian mesenchyme. Under
      pathological conditions, such as those encountered in polycystic ovary syndrome,
      excessive oxidative stress and depletion of antioxidants may contribute to
      ovarian mesenchymal hyperplasia.

PMID- 15178658
TI  - Cervical dilatation has a positive impact on the outcome of IVF in randomly
      assigned cases having two previous difficult embryo transfers.
AB  - BACKGROUND: The difficulty of embryo transfer has been reported to affect success
      rates in some centres, but not in others. Cervical dilatation has been proposed
      as a means to overcome difficult embryo transfer, but consistent criteria for
      patient selection are lacking. In a prospective randomized study, we examined the
      influence of cervical dilatation 1-3 months before embryo transfer on the outcome
      of IVF in cases having difficult embryo transfer in two previously failed IVF
      cycles. METHODS: Two alternative methods of embryo transfer preparation were
      evaluated in 283 randomly assigned women having difficult embryo transfers in two
      previously failed IVF attempts. Randomization was made using a computer-generated
      random number table. Cervical dilatation before starting any IVF treatment was
      used in 145 cases, and no dilatation was performed in 138 cases. RESULTS: The
      cervical dilatation group yielded a significantly higher pregnancy rate than the
      non-dilated group (40% versus 24%; P < 0.01). Likewise, the implantation rate
      (24.1% versus 14.9%; P < 0.01) and the live birth rate (34.48% versus 19.56%; P <
      0.01) were significantly higher in the dilatation group than in the non-dilated
      group. CONCLUSIONS: In patients with prior difficult embryo transfer, cervical
      dilatation 1-3 months before embryo transfer lead to an improved pregnancy rate.

PMID- 15178659
TI  - Adhesion-related readmissions following gynaecological laparoscopy or laparotomy
      in Scotland: an epidemiological study of 24 046 patients.
AB  - BACKGROUND: Gynaecological laparotomies are associated with considerable adhesion
      related burdens; however, few data are available concerning laparoscopic surgery.
      This study evaluated the epidemiology of adhesion-related readmissions following
      open and laparoscopic procedures. METHODS: Records from 24,046 patients
      undergoing gynaecological surgery in Scottish National Health Service hospitals
      during 1996 were assessed retrospectively. Cohorts comprised 15,197 patients
      undergoing laparoscopic surgery and 8849 patients undergoing laparotomies.
      Adhesion-related readmission episodes (directly and possibly related) were
      assessed over 4 years following initial surgery and were expressed as percentages
      of the number of initial procedures. RESULTS: Directly adhesion-related
      readmissions 1 year after initial laparoscopic surgery were: in the high-risk
      group (adhesiolysis and cyst drainage) 1.3%; medium-risk (therapeutic and
      diagnostic procedures not categorized as high- or low-risk) 1.5%; and low-risk
      (Fallopian tube sterilizations) 0.2%. Readmissions for laparotomy following
      surgery on the Fallopian tubes were 0.9%, ovaries 2.1%, uterus 0.6% and vagina
      0%. Readmissions occurred at reduced rates in the second, third and fourth years
      after surgery. Exclusion of patients who underwent surgery within the previous 5
      years resulted in reduced readmission rates following laparotomy and high-risk
      laparoscopy. CONCLUSIONS: With the exception of laparoscopic sterilizations, open
      and laparoscopic gynaecological surgery are associated with comparable risks of
      adhesion-related readmissions.

PMID- 15178660
TI  - Can the Internet widen participation in reproductive medicine education for
      professionals?
AB  - BACKGROUND: Traditional campus-based models of education are unsuitable to many,
      particularly if in full-time employment supporting families, whereas the Internet
      now permits new models of education. Following an iterative process of
      development and evaluation in 2001, the University of Bristol launched a masters
      programme covering reproduction and development delivered principally over the
      Internet. METHODS: Students attend short biannual residential workshops and the
      rest of the course is delivered online. In 2003, the 20 active students were
      invited to complete a structured online questionnaire. RESULTS: The 18 students
      completing the questionnaire identified distance learning as the key factor in
      their course selection. Most students felt that residential workshops aided
      subsequent electronic communication. Discussion of ideas is an essential
      component of postgraduate courses and web-based discussion forums appeared to
      provide an acceptable medium for this. The use of web-based audio lectures and
      computer-assisted assessments was well received. Also these systems may reduce
      disadvantages overseas students encounter when completing assessments in their
      non-native language. CONCLUSIONS: The overall positive response from students
      (and their tutors) to using the Internet for multiprofessional reproductive
      medicine education is encouraging and has wider potential in the future.

PMID- 15178661
TI  - Association of the T45G polymorphism in exon 2 of the adiponectin gene with
      polycystic ovary syndrome: role of Delta4-androstenedione.
AB  - BACKGROUND: Insulin resistance is a prominent feature of polycystic ovary
      syndrome (PCOS), independent of obesity. It is possible that insulin resistance
      in PCOS is genetically determined. Adiponectin is a protein that modulates
      insulin action and is regarded as a possible link between adiposity and insulin
      resistance. The objective of this study was to examine the role of the
      adiponectin gene T45G polymorphism, located in exon 2, in PCOS, since this
      polymorphism has been shown to be associated with obesity and insulin resistance.
      SUBJECTS AND METHODS: Two hundred and thirty-two women were studied, and were
      classified as follows: 132 women with PCOS [62 with body mass index (BMI) > 25
      kg/m2 and 70 with BMI < 25 kg/m2] and 100 ovulating women without
      hyperandrogenemia (controls: 19 with BMI > 25 kg/m2 and 81 with BMI < 25 kg/m2).
      From all subjects a whole-blood sample was taken and was used for isolation of
      peripheral blood leukocytes. The adiponectin T45G polymorphism, located in exon
      2, was genotyped by amplification of genomic DNA. In all subjects, serum
      gonadotropin, androgen, 17-OH-progesterone, fasting glucose, insulin and
      adiponectin levels were measured between the third and sixth day of the menstrual
      cycle. RESULTS: A statistically significant difference was observed in the
      frequency of GG and TG genotypes between women with PCOS (40/132; 30.3%) and
      controls (19/100; 19.0%). In a subgroup of PCOS women with high Delta4
      androstenedione levels (Delta4A > 3.11 ng/ml), a statistically significant
      difference between the frequencies of the genotypes was also noticed compared
      with the control group, in contrast to the subgroup with relatively low Delta4
      androstenedione levels (Delta4A < 3.11 ng/ml). No significant associations were
      found between this adiponectin polymorphism and BMI, testosterone level,
      adiponectin levels and glucose-to-insulin ratio. CONCLUSIONS: Our study suggests
      that adiponectin polymorphisms are not causatively involved in the metabolic
      disturbances of PCOS, but that an interaction between adiponectin and steroid
      synthesis or action might exist.

PMID- 15178662
TI  - Increase in peripheral blood mononuclear cell (PBMC)- and CD56+ cell-mediated
      killing of endometrial stromal cells by mycobacteria; a possible role in
      endometriosis immunotherapy?
AB  - BACKGROUND: Immunological therapies have shown promising results in the treatment
      of endometriosis. Mycobacteria are one of the most common immune therapies used
      in other diseases. We have assessed the effects of mycobacteria in altering the
      ability of peripheral blood mononuclear cells (PBMCs) and natural killer (NK)
      cells to kill endometrial stromal cells using an in vitro model. This may have
      implications in the immunotherapy of endometriosis. METHODS: Primary cultures of
      endometrial stromal cells were grown from female patients and PBMCs were
      extracted from healthy female volunteers. Effector cells (PBMCs or NK cells) were
      exposed to varying concentrations of mycobacteria before their ability to kill
      cultured endometrial cells was tested using a 51Cr-release assay. RESULTS:
      Treatment of effector cells with the Connaught Substrain Bacillus of Calmette and
      Guerin (BCG) led to increased killing of target cells by PBMCs and NK cells. The
      optimal concentration for treatment of effector cells with Connaught BCG was
      approximately 0.1 multiplicities of infection (m.o.i.). There was a trend towards
      increased killing after treatment with Pasteur BCG. CD56+ (NK) cells treated with
      BCG at 0.1 m.o.i. showed increased killing of target cells compared with
      untreated effector cells. CONCLUSIONS: Endometrial stromal cells are susceptible
      to killer cells activated by mycobacteria. This in vitro work suggests a possible
      role for mycobacteria in the immunotherapy of endometriosis.

PMID- 15178663
TI  - Ovulation induction using laparoscopic ovarian drilling in women with polycystic
      ovarian syndrome: predictors of success.
AB  - BACKGROUND: Although laparoscopic ovarian drilling (LOD) has been widely used to
      induce ovulation in women with polycystic ovarian syndrome (PCOS), predicting the
      clinical response to this treatment remains to be elucidated further. This study
      was carried out to identify factors that may help to predict the outcome of LOD.
      METHODS: This retrospective study included 200 patients with anovulatory
      infertility due to PCOS who underwent LOD between 1990 and 2002. The influence of
      the various patients' pre-operative characteristics on the ovulation and
      pregnancy rates after LOD was evaluated. In addition, women were divided into two
      or three categories according to the severity of each of the various clinical and
      biochemical parameters of PCOS. The success rates were compared between the
      categories of each factor using contingency table analyses. Multiple logistic
      regression analysis was used to identify independent predictors of success of
      LOD. RESULTS: Women with body mass index (BMI) > or = 35 kg/m2, serum
      testosterone concentration > or = 4.5 nmol/l, free androgen index (FAI) > or = 15
      and/or with duration of infertility > 3 years seem to be poor responders to LOD.
      In LOD responders, serum LH levels > 10 IU/l appeared to be associated with
      higher pregnancy rates. CONCLUSION: Marked obesity, marked hyperandrogenism
      and/or long duration of infertility in women with PCOS seem to predict resistance
      to LOD. High LH levels in LOD responders appear to predict higher probability of
      pregnancy.

PMID- 15178664
TI  - Age and homocysteine plasma levels are risk factors for thrombotic complications
      after ovarian stimulation.
AB  - BACKGROUND: The magnitude of thrombotic risk during ovarian stimulation cycles is
      not known. We calculated the magnitude of thrombotic risk in a cohort of women
      starting a new cycle of ovarian stimulation and investigated the role of
      inherited and acquired thrombophilia for these events. METHODS: This is an
      observational study involving outpatients of a clinical research centre.
      Consecutive women undergoing ovarian stimulation (n = 305) were enrolled. Blood
      samples for studying inherited and acquired thrombophilia were obtained > or = 2
      months after the last cycle of treatment. Odds ratios (OR) and confidence
      intervals (CI) were determined for markers significantly associated with
      thrombotic events. Blood samples were analysed for inherited and acquired causes
      of thrombophilia (antithrombin, protein C, protein S, antiphospholipid
      antibodies, the Factor V Leiden and FIIA20210 mutations, the TT677 MTHFR
      genotype, and homocysteine plasma levels). RESULTS: Thrombotic events were
      observed in 4/747 cycles of ovarian stimulation, with a prevalence of 0.5%,
      corresponding to 1.6 per 100 000 cycles/woman. Age > or = 39 years and
      homocysteine plasma levels above the 97.5 percentile were significantly
      associated with thrombotic events during IVF [OR 15.2 (95% CI 2.0-115.0) and 14.4
      (1.5-141.3) respectively]. CONCLUSIONS: Age > or = 39 years and mild
      hyperhomocysteinaemia are strongly associated with the occurrence of thrombotic
      events during IVF.

PMID- 15178665
TI  - Metformin reduces pregnancy complications without affecting androgen levels in
      pregnant polycystic ovary syndrome women: results of a randomized study.
AB  - BACKGROUND: Investigation of a possible effect of metformin on androgen levels in
      pregnant women with polycystic ovary syndrome (PCOS). METHODS: A prospective,
      randomized, double-blind, placebo-controlled pilot study was conducted. Forty
      pregnant women with PCOS received diet and lifestyle counselling and were
      randomized to either metformin 850 mg twice daily or placebo. Primary outcome
      measures were changes in serum levels of dehydroepiandrosterone sulphate,
      androstenedione, testosterone, sex hormone-binding globulin, and free
      testosterone index. Secondary outcome measures were pregnancy complications and
      outcome. Two-tailed t-tests and chi2-tests were used. RESULTS: Maternal androgen
      levels were unaffected by metformin treatment in pregnant women with PCOS. While
      none of the 18 women in the metformin group experienced a severe pregnancy or
      post-partum complication, seven of the 22 (32%) women experienced severe
      complications in the placebo group (P = 0.01). CONCLUSIONS: Metformin treatment
      did not reduce maternal androgen levels in pregnant women with PCOS. In the
      metformin-treated group we observed a reduction of severe, pregnancy and post
      partum complications. Metformin treatment of pregnant PCOS women may reduce
      complications during pregnancy and in the post-partum period.

PMID- 15178666
TI  - Do world conferences live up to their promise?

PMID- 15178667
TI  - Recreational injuries among older Americans, 2001.
AB  - OBJECTIVE: To describe the epidemiology of non-fatal recreational injuries among
      older adults treated in United States emergency departments including national
      estimates of the number of injuries, types of recreational activities, and
      diagnoses. METHODS: Injury data were provided by the National Electronic Injury
      Surveillance System-All Injury Program (NEISS-AIP), a nationally representative
      subsample of 66 out of 100 NEISS hospitals. Potential cases were identified using
      the NEISS-AIP definition of a sport and recreation injury. The authors then
      reviewed the two line narrative to identify injuries related to participation in
      a sport or recreational activity among men and women more than 64 years old.
      RESULTS: In 2001, an estimated 62 164 (95% confidence interval 35 570 to 88 758)
      persons >/=65 years old were treated in emergency departments for injuries
      sustained while participating in sport or recreational activities. The overall
      injury rate was 177.3/100 000 population with higher rates for men (242.5/100
      000) than for women (151.3/100 000). Exercising caused 30% of injuries among
      women and bicycling caused 17% of injuries among men. Twenty seven percent of all
      treated injuries were fractures and women (34%) were more likely than men (21%)
      to suffer fractures. CONCLUSIONS: Recreational activities were a frequent cause
      of injuries among older adults. Fractures were common. Many of these injuries are
      potentially preventable. As more persons engage in recreational activities,
      applying known injury prevention strategies will help to reduce the incidence of
      these injuries.

PMID- 15178668
TI  - Injuries from paintball game related activities in the United States, 1997-2001.
AB  - OBJECTIVE: To quantify and characterize injuries resulting from paintball game
      related activities among persons >/=7 years in the United States. SETTING:
      Hospitals included in the National Electronic Injury Surveillance System (NEISS);
      these are composed of a stratified probability sample of all hospitals in the
      United States with emergency departments. METHODS: Using NEISS, non-fatal injury
      data for paintball game related injury cases from 1997-2001 were obtained from
      emergency department records. Participation estimates used to calculate injury
      rates were obtained from a yearly survey funded by the National Sporting Goods
      Association. RESULTS: An estimated 11 998 persons >/=7 years with paintball game
      related injuries were treated in emergency departments from 1997-2001, with an
      annual average rate of 4.5 per 10 000 participants (95% confidence interval 3.3
      to 5.7). The paintball game related injury rate was highest for 18-24 year olds
      (4.9 per 10 000 participants) and most injuries (94.0%) occurred among males.
      Almost 60% of all injured persons >/=7 years were treated for paintball pellet
      wounds of which most were to the eye. While 76.9% of injured persons ages 7-17
      years were treated for paintball pellet wounds, almost 40% of those >/=18 years
      were treated for injuries resulting from overexertion or a fall. Lower extremity
      injuries were also common (23.0%), mostly from overexertion. Most injured persons
      (95.5%) were treated and released. CONCLUSIONS: As paintball games become more
      popular, efforts are needed to increase training, enforce rules, and educate
      participants about how to stay safe, such as wearing protective eye gear, when
      engaged in paintball games at home, in a public area, or in a sports field.

PMID- 15178669
TI  - A population based investigation of head injuries and symptoms of concussion of
      children and adolescents in schools.
AB  - OBJECTIVE: To examine the incidence of head injury and symptoms of concussion
      among children at school and to determine the relationship of age, gender, and
      cause to incidence rates. DESIGN: Incident reports involving head injury for
      schools in the Province of Ontario, Canada during the year 2000 were evaluated.
      PARTICIPANTS: The population base for the schools represented was 1 372 979
      children aged 6 to 16. SETTING: 95% of schools in the province of Ontario, Canada
      participated in the injury reporting system. MAIN OUTCOME MEASURES: A head injury
      was defined as any injury to the head that came to the attention of a school
      official. Head injuries accompanied by symptoms of concussion became a secondary
      outcome measure. RESULTS: There were 11 068 unduplicated head injury reports for
      the year 2000 of which 1861 qualified as producing signs or symptoms of
      concussion. Young children were more likely to have a head injury than older
      children, but slightly less likely to experience concussive symptoms. The primary
      cause of injury to young children was falls. Older children were more likely to
      receive head injuries and symptoms of concussion from sports activities.
      CONCLUSIONS: Overall rate of injury (3.98 per 100 children) was consistent with
      previous studies using prospective injury reporting systems. Probability of a
      head injury with symptoms of concussion among schoolchildren was only 1.9% for
      boys and <1% for girls during the course of their school years. There is ample
      justification for prevention efforts in schools.

PMID- 15178670
TI  - Newspaper framing of fatal motor vehicle crashes in four Midwestern cities in the
      United States, 1999-2000.
AB  - OBJECTIVE: To examine the public health messages conveyed by newspaper coverage
      of fatal motor vehicle crashes and determine the extent to which press coverage
      accurately reflects real risks and crash trends. METHODS: Crash details were
      extracted from two years of newspaper coverage of fatal crashes in four
      Midwestern cities in the United States. Details and causal factors identified by
      reporters were compared to data from the National Highway Traffic Safety
      Administration's Fatality Analysis Reporting System (FARS) using odds ratios and
      two tailed z tests. RESULTS: Papers covered 278 fatal crashes over the two year
      period, in contrast to 846 fatal crashes documented in FARS. Papers assigned
      blame in 90% of crashes covered, under-reported restraint use and driver's risk
      of death, failed to reflect the protective value of restraints, and
      misrepresented the roles played by alcohol and teen drivers. CONCLUSION:
      Newspaper coverage did not accurately reflect real risk. Papers presented fatal
      crashes as dramas with a victim/villain storyline; in keeping with this narrative
      strategy, papers were most likely to cover stories where a driver survived to
      take the blame. By highlighting crashes that diverge from the norm, focusing on
      the assignment of blame to a single party, and failing to convey the message that
      preventive practices like seatbelt use increase odds for survival, newspapers
      removed crashes from a public health context and positioned them as individual
      issues. Public health practitioners can work with media outlets in their areas to
      draw attention to misrepresentations and change the way these stories are framed.

PMID- 15178671
TI  - Pedestrian crashes: higher injury severity and mortality rate for light truck
      vehicles compared with passenger vehicles.
AB  - INTRODUCTION: During the last two decades changes in vehicle design and increase
      in the number of the light truck vehicles (LTVs) and vans have led to changes in
      pedestrian injury profile. Due to the dynamic nature of the pedestrian crashes
      biomechanical aspects of collisions can be better evaluated in field studies.
      DESIGN AND SETTING: s: The Pedestrian Crash Data Study, conducted from 1994 to
      1998, provided a solid database upon which details and mechanism of pedestrian
      crashes can be investigated. RESULTS: From 552 recorded cases in this database,
      542 patients had complete injury related information, making a meaningful study
      of pedestrian crash characteristics possible. Pedestrians struck by LTVs had a
      higher risk (29%) of severe injuries (abbreviated injury scale >/=4) compared
      with passenger vehicles (18%) (p = 0.02). After adjustment for pedestrian age and
      impact speed, LTVs were associated with 3.0 times higher risk of severe injuries
      (95% confidence interval (CI) 1.26 to 7.29, p = 0.013). Mortality rate for
      pedestrians struck by LTVs (25%) was two times higher than that for passenger
      vehicles (12%) (p<0.001). Risk of death for LTV crashes after adjustment for
      pedestrian age and impact speed was 3.4 times higher than that for passenger
      vehicles (95% CI 1.45 to 7.81, p = 0.005). CONCLUSION: Vehicle type strongly
      influences risk of severe injury and death to pedestrian. This may be due in part
      to the front end design of the vehicle. Hence vehicle front end design,
      especially for LTVs, should be considered in future motor vehicle safety
      standards.

PMID- 15178672
TI  - Parental perceptions regarding mandatory mouthguard use in competitive youth
      soccer.
AB  - OBJECTIVE: To understand factors that influence parental perceptions regarding
      mandatory mouthguard use in competitive youth soccer. SETTING AND SUBJECTS: A web
      based survey of parents whose 8-14 year old children participated in outdoor
      competitive youth soccer during the fall of 2002. Questions focused on: previous
      injury, education provided, dentist/physician recommendations, and parental
      perceptions of mouthguard use. MAIN OUTCOME MEASURE: The outcome variable was
      parental agreement with the statement "mouthguards should be mandatory for
      competitive youth soccer". Logistic regression and chi(2) were performed using
      STATA 8.0. RESULTS: Altogether 120 parents participated. The children had a mean
      (SD) age of 11.8 (1.5) years and 48% were female; 14% wore mouthguards and 11%
      suffered orofacial injuries. Nineteen percent of parents reported receiving
      educational material from the youth soccer organization. Although 92% of parents
      believed that mouthguards were effective in reducing orofacial injuries, only one
      half agreed that mouthguards should be mandatory. Thirty percent of respondents
      reported that their dentist/physician recommended mouthguards for competitive
      youth soccer. Logistic regression showed that dentist/physician recommendation
      and parental female gender were independently associated with parental agreement
      for mandatory mouthguard use (odds ratio 2.9, 95% confidence interval (CI) 1.2 to
      7.3; odds ratio 3.0, 95% CI 1.1 to 6.5). CONCLUSIONS: Few athletes wear
      mouthguards during competitive youth soccer. Health care professionals in this
      study did not capitalize on the apparent influence they have on parental beliefs
      regarding mouthguard use. Efforts are needed by both health professionals and
      soccer organizations to educate parents about orofacial injuries and mouthguard
      use in competitive youth soccer.

PMID- 15178673
TI  - Unsupervised firearm handling by California adolescents.
AB  - OBJECTIVE: Relatively little is known about the behavior of adolescents around
      firearms. The present investigation was undertaken to estimate the proportion of
      community-residing adolescents who report that they have ever handled a gun
      without adult knowledge or supervision. METHODS: A random digit dial interview
      was conducted with 5801 California adolescents as part of the California Health
      Interview Survey. Respondents were asked whether they have ever held a gun and
      whether they have ever done so without adult knowledge or supervision. Study
      design and population weights were applied to these data. In addition,
      adolescents' reports about the most recent unsupervised handling incident were
      coded to ascertain what they were doing with the gun as well as with whom and
      where the incident occurred. RESULTS: One third (33%) of California adolescents
      report that they have handled a firearm; 5% report that they have done so without
      adult knowledge or supervision. Half (49%) of all unsupervised handling involved
      shooting and only 11% occurred in the respondent's home. Several demographic
      variables (being male, African American, living in a rural area) and risk
      behaviors (smoking, drinking, being the victim of a gun related threat), as well
      as having a gun in the home and parents not knowing the adolescent's whereabouts
      in the afternoon were each associated with unsupervised gun handling.
      CONCLUSIONS: Unsupervised gun handling is associated with other health risk
      behaviors. Unsupervised gun handling typically involves shooting the gun and
      usually occurs with friends, away from the home.

PMID- 15178674
TI  - Are medical societies developing a standard for gun injury prevention?
AB  - CONTEXT: Following heightened gun violence in the 1990s, many medical societies
      in the United States adopted policies on the topic. OBJECTIVE: Identify points of
      firearm violence policy agreement among large medical organizations. DESIGN:
      Fourteen national medical societies-clinical focus, demonstrated interest in gun
      injury prevention, >2000 members-were selected for policy review in 2002.
      Policies were categorized on areas covered and items within these. Consensus
      areas were addressed by >/=7/14 societies. Consensus items were included by
      >/=7/14 societies, shared items by 5-6. RESULTS: There were five consensus areas:
      access prevention, gun commerce, research, public education, and clinical
      counseling. There were four consensus items: restricting gun access by enforcing
      existing laws, restricting access to all guns at the point of sale, restricting
      access to handguns at the point of sale, and creating a national database on gun
      injury and death. Shared items promote violence prevention, clinical education on
      risks of guns in the home, treating guns as consumer products, restricting gun
      access to children, bans on automatic weapons, and promoting trigger locks.
      CONCLUSIONS: Large medical societies in the United States agree on key approaches
      for reducing gun injury mortality and morbidity. Future research will be needed
      to track the evolution of this emerging standard for physician action, which now
      includes the consensus areas and items. It promises to be, in effect, a medical
      standard of care for gun injury prevention. The United States experience may be
      useful to others working on gun injury prevention.

PMID- 15178675
TI  - Comparative performance of playground surfacing materials including conditions of
      extreme non-compliance.
AB  - OBJECTIVE: A recent case series study found that only 4.7% of 402 playgrounds in
      which arm fractures occurred in Victorian schools complied with the recommended
      20 cm depth of tanbark. Tanbark depths at fall sites varied between 0-27 cm and
      the mean was 11.1 (5.0) cm. The purposes of the present study were to (1) measure
      impact attenuation properties of shallow and compacted depths of tanbark; (2)
      validate laboratory measurements with in situ data; (3) compare impact
      attenuation properties of compacted tanbark with an Australian manufactured
      rubber based surface material; and (4) study the impact performance of rubber and
      tanbark hybrid surfacing. METHODS: A standard test headform was dropped on
      tanbark and rubber surfaces in a laboratory setting to measure peak impact
      deceleration and head injury criterion (HIC) values. Variations in surface depth
      ranged from 2 cm-20 cm (tanbark) and 2 cm-9 cm (rubber). Drop height ranged from
      0.5 m-2.5 m. RESULTS: Peak deceleration and HIC increased with increasing drop
      height and decreasing surface depth. Laboratory measurements at depths less than
      8 cm overestimated peak deceleration and HIC values compared with in situ
      playground measurements. Impact attenuation of a 9 cm thick bilaminate rubber
      material was comparable to that of an 18 cm depth of compacted tanbark. Rubber
      tanbark hybrid surfaces showed improved impact attenuation over individual
      surfaces. CONCLUSIONS: Compacted tanbark of depth less than 8 cm is ineffective
      in attenuating playground falls, resulting in excessive impact deceleration and
      HIC values. Shallow and compacted tanbark found in many Victorian school
      playgrounds poses a high risk for severe head injury. This calls for stricter
      enforcement of playground surface depth compliance.

PMID- 15178676
TI  - Community based prevention programs targeting all injuries for children.
AB  - OBJECTIVE: Community based models for injury prevention have become an accepted
      part of the overall injury control strategy. This systematic review of the
      scientific literature examines the evidence for their effectiveness in reducing
      all-cause injury in children 0-14 years of age. METHODS: A comprehensive search
      of the literature was performed using the following study selection criteria:
      community based intervention study; children under 14 years; outcome measure was
      injury rates; and either a community control or an historical control was used in
      the design. Quality assessment and data abstraction were guided by a standardized
      procedure and performed independently by two authors. Data synthesis was in
      tabular and text form with meta-analysis not being possible due to the
      discrepancy in methods and measures between the studies. RESULTS: Thorough
      electronic and library search techniques yielded only nine formally evaluated
      community based all-cause child injury prevention programs that have reported
      actual injury outcomes. Of these nine studies, seven provided high level evidence
      where contemporary control communities were used for comparison; the remaining
      two used a pre and post-design or time trend analysis where historical data from
      the community were used as the comparison. Only three of the seven studies with
      contemporary control communities found significant effect of the intervention;
      the two studies without controls noted significant reductions in injury rates
      after the intervention period. CONCLUSION: There is a paucity of research from
      which evidence regarding the effectiveness of community based childhood injury
      prevention programs can be obtained and hence a clear need to increase the effort
      on developing this evidence base.

PMID- 15178678
TI  - Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells.
AB  - S100 calcium-binding proteins such as S100B are elevated in primary malignant
      melanoma and are used as markers for this and numerous other cancers. Wild-type
      p53 protein levels are relatively low in these cancer cells (i.e. when compared
      with cells without S100B) but are elevated when RNA antisense to S100B is
      introduced. This result implicates S100B in the down-regulation of p53 and is
      consistent with the large decreases in p53 protein levels observed previously in
      transient co-transfections of p53 and S100B (Lin, J., Blake, M., Tang, C.,
      Zimmer, D., Rustandi, R. R., Weber, D. J., and Carrier, F. (2001) J. Biol. Chem.
      276, 35037-35041). Down-regulation of p53 in primary malignant melanoma cells is
      likely the result of a direct interaction with S100B, which was observed by co
      immunoprecipitation experiments. Furthermore, p53 binds regions of the S100B
      promoter, one of which matches the 20-nucleotide p53-binding consensus DNA
      sequence perfectly. Therefore, when p53 levels increase, it contributes to its
      own demise by up-regulating the transcription of S100B as part of a negative
      feedback loop. This is analogous to what is found for another protein that down
      regulates p53, namely hdm2 (human double mutant 2).

PMID- 15178677
TI  - Practical introduction to record linkage for injury research.
AB  - The frequency of early fatality and the transient nature of emergency medical
      care mean that a single database will rarely suffice for population based injury
      research. Linking records from multiple data sources is therefore a promising
      method for injury surveillance or trauma system evaluation. The purpose of this
      article is to review the historical development of record linkage, provide a
      basic mathematical foundation, discuss some practical issues, and consider some
      ethical concerns. Clerical or computer assisted deterministic record linkage
      methods may suffice for some applications, but probabilistic methods are
      particularly useful for larger studies. The probabilistic method attempts to
      simulate human reasoning by comparing each of several elements from the two
      records. The basic mathematical specifications are derived algebraically from
      fundamental concepts of probability, although the theory can be extended to
      include more advanced mathematics. Probabilistic, deterministic, and clerical
      techniques may be combined in different ways depending upon the goal of the
      record linkage project. If a population parameter is being estimated for a purely
      statistical study, a completely probabilistic approach may be most efficient; for
      other applications, where the purpose is to make inferences about specific
      individuals based upon their data contained in two or more files, the need for a
      high positive predictive value would favor a deterministic method or a
      probabilistic method with careful clerical review. Whatever techniques are used,
      researchers must realize that the combination of data sources entails additional
      ethical obligations beyond the use of each source alone.

PMID- 15178679
TI  - PINA is essential for growth and positively influences NIMA function in
      Aspergillus nidulans.
AB  - The phospho-Ser/Thr-directed prolyl-isomerase Pin1 was originally identified in
      vertebrate systems as a negative regulator of NIMA, a Ser/Thr protein kinase that
      regulates the G(2)/M transition in Aspergillus nidulans. Here we explore the
      physiological roles of the Pin1 orthologue, PINA, in A. nidulans and evaluate the
      relevance of the interaction of PINA with NIMA in this fungus. We find pinA to be
      an essential gene in A. nidulans. In addition, when PINA levels are reduced 50
      fold the cells grow at a reduced rate. Upon germination under conditions that
      repress PINA expression, the cells are delayed in the interphase activation of
      NIMX(cdc2), whereas they traverse the other phases of the cell cycle at a similar
      rate to controls. These results indicate that a marked reduction of PINA results
      in a lengthening of G(1). Additionally, PINA repression increases the rate at
      which the cells enter mitosis following release from a hydroxyurea arrest without
      altering the sensitivity of the fungus to agents that activate the replication or
      DNA damage checkpoints. In contrast to predictions based on Pin1, the physical
      interaction between PINA and NIMA is primarily dependent upon the prolylisomerase
      domain of PINA and the C-terminal 303 amino acids of NIMA. Finally, reduction of
      PINA levels exacerbates the nimA5 temperature-sensitive mutant, whereas
      overexpression of PINA decreases the severity of this mutation, results that are
      consistent with a positive genetic interaction between PINA and NIMA. Thus,
      although PINA is essential and positively regulates NIMA function, A. nidulans is
      most sensitive to a reduction in PINA concentration in G(1) rather than in
      G(2)/M.

PMID- 15178680
TI  - NMR structure of the alpha-hemoglobin stabilizing protein: insights into
      conformational heterogeneity and binding.
AB  - The structure of alpha-hemoglobin stabilizing protein (AHSP), a molecular
      chaperone for free alpha-hemoglobin, has been determined using NMR spectroscopy.
      The protein native state shows conformational heterogeneity attributable to the
      isomerization of the peptide bond preceding a conserved proline residue. The two
      equally populated cis and trans forms both adopt an elongated antiparallel three
      alpha-helix bundle fold but display major differences in the loop between the
      first two helices and at the C terminus of helix 3. Proline to alanine single
      point mutation of the residue Pro-30 prevents the cis/trans isomerization. The
      structure of the P30A mutant is similar to the structure of the trans form of
      AHSP in the loop 1 region. Both the wild-type AHSP and the P30A mutant bind to
      alpha-hemoglobin, and the wild-type conformational heterogeneity is quenched upon
      complex formation, suggesting that just one conformation is the active form.
      Changes in chemical shift observed upon complex formation identify a binding
      interface comprising the C terminus of helix 1, the loop 1, and the N terminus of
      helix 2, with the exposed residues Phe-47 and Tyr-51 being attractive targets for
      molecular recognition. The characteristics of this interface suggest that AHSP
      binds at the intradimer alpha1beta1 interface in tetrameric HbA.

PMID- 15178681
TI  - The T-cell lymphokine interleukin-26 targets epithelial cells through the
      interleukin-20 receptor 1 and interleukin-10 receptor 2 chains.
AB  - The cellular members of the interleukin-10 (IL-10) cytokine family share sequence
      homology with IL-10, whereas their sites of expression and their functions are
      divergent. One of these factors, AK155 or IL-26, was discovered because of its
      overexpression in human T lymphocytes after growth transformation by the simian
      rhadinovirus herpesvirus saimiri. In addition, the gene is transcribed in various
      types of primary and immortalized T-cells. Here we describe epithelial cells,
      namely colon carcinoma cells and keratinocytes, as targets of this T-cellular
      lymphokine. Purified recombinant IL-26 induced the rapid phosphorylation of the
      signal transducer and activator of transcription factors 1 and 3. As a result,
      secretion of IL-10 and IL-8, as well as cell surface expression of CD54 were
      enhanced. Moreover, we show that the IL-26 protein binds to heparin, is released
      from the cell surface, and can be functionally inhibited by heparin. The
      sensitivity to recombinant IL-26 of various cell lines strictly correlated with
      the expression of the long chain of the IL-20 receptor. Because blocking
      antibodies against either the short chain of the IL-10 receptor or the long chain
      of the IL-20 receptor inhibited IL-26-dependent signal transduction, and
      transient expression of these receptor chains induced IL-26 responsivity in non
      sensitive cells, we propose that the IL-20 receptor 1 and IL-10 receptor 2 chains
      participate in forming the IL-26 receptor. Targeting epithelial cells, the T-cell
      lymphokine IL-26 is likely to play a role in local mechanisms of mucosal and
      cutaneous immunity.

PMID- 15178682
TI  - Mice lacking catalase develop normally but show differential sensitivity to
      oxidant tissue injury.
AB  - Catalase plays a major role in cellular antioxidant defense by decomposing
      hydrogen peroxide, thereby preventing the generation of hydroxyl radical by the
      Fenton reaction. The degree of catalase deficiency in acatalasemic and
      hypocatalasemic mice varies from tissue to tissue. They therefore may not be
      suitable for studying the function of this enzyme in certain models of oxidant
      mediated tissue injury. We sought to generate a new line of catalase null mice by
      the gene targeting technique. The mouse catalase (Cat or Cas1) gene was disrupted
      by replacing parts of intron 4 and exon 5 with a neomycin resistance cassette.
      Homozygous Cat knockout mice, which are completely deficient in catalase
      expression, develop normally and show no gross abnormalities. Slices of liver and
      lung and lenses from the knockout mice exhibited a retarded rate in decomposing
      extracellular hydrogen peroxide compared with those of wild-type mice. However,
      mice deficient in catalase were not more vulnerable to hyperoxia-induced lung
      injury; nor did their lenses show any increased susceptibility to oxidative
      stress generated by photochemical reaction, suggesting that the antioxidant
      function of catalase in these two models of oxidant injury is negligible. Further
      studies showed that cortical injury from physical impact caused a significant
      decrease in NAD-linked electron transfer activities and energy coupling
      capacities in brain mitochondria of Cat knockout mice but not wild-type mice. The
      observed decrease in efficiency of mitochondrial respiration may be a direct
      result of an increase in mitochondrion-associated calcium, which is secondary to
      the increased oxidative stress. These studies suggest that the role of catalase
      in antioxidant defense is dependent on the type of tissue and the model of
      oxidant-mediated tissue injury.

PMID- 15178683
TI  - Targeted ablation of plasma membrane Ca2+-ATPase (PMCA) 1 and 4 indicates a major
      housekeeping function for PMCA1 and a critical role in hyperactivated sperm
      motility and male fertility for PMCA4.
AB  - The relative importance of plasma membrane Ca2+-ATPase (PMCA) 1 and PMCA4 was
      assessed in mice carrying null mutations in their genes (Atp2b1 and Atp2b4). Loss
      of both copies of the gene encoding PMCA1 caused embryolethality, whereas
      heterozygous mutants had no overt disease phenotype. Despite widespread and
      abundant expression of PMCA4, PMCA4 null (Pmca4-/-) mutants exhibited no
      embryolethality and appeared outwardly normal. Loss of PMCA4 impaired phasic
      contractions and caused apoptosis in portal vein smooth muscle in vitro; however,
      this phenotype was dependent on the mouse strain being employed. Pmca4-/- mice on
      a Black Swiss background did not exhibit the phenotype unless they also carried a
      null mutation in one copy of the Pmca1 gene. Pmca4-/- male mice were infertile
      but had normal spermatogenesis and mating behavior. Pmca4-/- sperm that had not
      undergone capacitation exhibited normal motility but could not achieve
      hyperactivated motility needed to traverse the female genital tract.
      Ultrastructure of the motility apparatus in Pmca4-/- sperm tails was normal, but
      an increased incidence of mitochondrial condensation indicated Ca2+ overload.
      Immunoblotting and immunohistochemistry showed that PMCA4 is the most abundant
      isoform in testis and sperm and that it is localized to the principle piece of
      the sperm tail, which is also the location of the major Ca2+ channel (CatSper)
      required for sperm motility. These results are consistent with an essential
      housekeeping or developmental function for PMCA1, but not PMCA4, and show that
      PMCA4 expression in the principle piece of the sperm tail is essential for
      hyperactivated motility and male fertility.

PMID- 15178684
TI  - Topoisomerase I-DNA complexes contribute to arsenic trioxide-induced apoptosis.
AB  - Topoisomerase I is an essential enzyme that relaxes DNA supercoiling by forming
      covalent DNA cleavage complexes, which are normally transient. Topoisomerase I
      DNA complexes can be trapped by anticancer drugs (camptothecins) as well as by
      endogenous and exogenous DNA lesions. We show here that arsenic trioxide (a
      potent inducer of apoptosis that induces the intracellular accumulation of
      reactive oxygen species and targets mitochondria) induces cellular topoisomerase
      I cleavage complexes. Bcl-2 overexpression and quenching of reactive oxygen
      species, which prevent arsenic trioxide-induced apoptosis, also prevent the
      formation of topoisomerase I-DNA complexes, whereas enhancement of reactive
      oxygen species accumulation promotes these complexes. The caspase inhibitor,
      benzyloxycarbonyl-VAD partially prevents arsenic trioxide-induced topoisomerase I
      DNA complexes and apoptosis, suggesting that activated caspases further maintain
      intracellular levels of reactive oxygen species that induce the formation of
      topoisomerase I-DNA complexes. Down-regulation of topoisomerase I expression
      decreases arsenic trioxide-induced apoptotic DNA fragmentation. Thus, we propose
      that arsenic trioxide induces topoisomerase I-DNA complexes that participate in
      chromatin fragmentation and programmed cell death during apoptosis.

PMID- 15178685
TI  - Structural evidence of a passive base-flipping mechanism for beta
      glucosyltransferase.
AB  - Beta-glucosyltransferase (BGT) is a DNA-modifying enzyme and a
      glycosyltransferase. This inverting enzyme transfers glucose from UDP-glucose to
      the 5-hydroxymethyl cytosine bases of T4 phage DNA. From previous structural
      analyses we showed that Asp-100 and Asn-70 were, respectively, the catalytic base
      and the key residue for specific DNA recognition (Lariviere, L., Gueguen
      Chaignon, V., and Morera, S. (2003) J. Mol. Biol. 330, 1077-1086). Here, we
      supply biochemical evidence supporting their essential roles in catalysis. We
      have also shown previously that BGT uses a base-flipping mechanism to access 5
      hydroxymethyl cytosine (Lariviere, L., and Morera, S. (2002) J. Mol. Biol. 324,
      483-490). Whether it is an active or a passive process remains unclear, as is the
      case for all DNA cleaving and modifying enzymes. Here, we report two crystal
      structures: (i) BGT in complex with a 13-mer DNA containing an A:G mismatch and
      (ii) BGT in a ternary complex with UDP and an oligonucleotide containing a single
      central G:C base pair. The binary structure reveals a specific complex with the
      flipped-out, mismatched adenine exposed to the active site. Unexpectedly, the
      other structure shows the non-productive binding of an intermediate flipped-out
      base. Our structural analysis provides clear evidence for a passive process.

PMID- 15178686
TI  - Coordinated activation of notch, Wnt, and transforming growth factor-beta
      signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch
      target gene Hey1 inhibits mineralization and Runx2 transcriptional activity.
AB  - To examine early events in osteoblast differentiation, we analyzed the expression
      of about 9,400 genes in the murine MC3T3 cell line, whose robust differentiation
      was documented cytochemically and molecularly. The cells were stimulated for 1
      and 3 days with the osteogenic stimulus containing bone morphogenic protein 2.
      Total RNA was extracted and analyzed by Affymetrix GeneChip oligonucleotide
      arrays. A regulated expression of 394 known genes and 295 expressed sequence tags
      was detected. The sensitivity and reliability of detection by microarrays was
      shown by confirming the expression pattern for 20 genes by radioactive
      quantitative reverse transcription-PCR. Functional classification of regulated
      genes was performed, defining the groups of regulated growth factors, receptors,
      and transcription factors. The most interesting finding was concomitant
      activation of transforming growth factor-beta, Wnt, and Notch signaling pathways,
      confirmed by strong up-regulation of their target genes by PCR. The transforming
      growth factor-beta pathway is activated by stimulated production of the growth
      factor itself, while the exact mechanism of Wnt and Notch activation remains
      elusive. We showed that bone morphogenic protein 2 stimulated expression of Hey1,
      a direct Notch target gene, in mouse MC3T3 and C2C12 cells, in human mesenchymal
      cells, and in mouse calvaria. Small interfering RNA-mediated inhibition of Hey1
      induction led to an increase in osteoblast matrix mineralization, suggesting that
      Hey1 is a negative regulator of osteoblast maturation. This negative regulation
      is apparently achieved via interaction with Runx2: Hey1 completely abrogated
      Runx2 transcriptional activity. These findings identify the Notch-Hey1 pathway as
      a negative regulator of osteoblast differentiation/maturation, which is a
      completely novel aspect of osteogenesis and could point to possible new targets
      for bone anabolic agents.

PMID- 15178687
TI  - Isohumulones, bitter acids derived from hops, activate both peroxisome
      proliferator-activated receptor alpha and gamma and reduce insulin resistance.
AB  - The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors
      that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects
      of fibrate drugs and the therapeutic benefits of the thiazolidinedione drugs are
      due to their activation of PPARalpha and -gamma, respectively. In this study,
      isohumulones, the bitter compounds derived from hops that are present in beer,
      were found to activate PPARalpha and -gamma in transient co-transfection studies.
      Among the three major isohumulone homologs, isohumulone and isocohumulone were
      found to activate PPARalpha and -gamma. Diabetic KK-Ay mice that were treated
      with isohumulones (isohumulone and isocohumulone) showed reduced plasma glucose,
      triglyceride, and free fatty acid levels (65.3, 62.6, and 73.1%, respectively,
      for isohumulone); similar reductions were found following treatment with the
      thiazolidinedione drug, pioglitazone. Isohumulone treatment did not result in
      significant body weight gain, although pioglitazone treatment did increase body
      weight (10.6% increase versus control group). C57BL/6N mice fed a high fat diet
      that were treated with isohumulones showed improved glucose tolerance and reduced
      insulin resistance. Furthermore, these animals showed increased liver fatty acid
      oxidation and a decrease in size and an increase in apoptosis of their
      hypertrophic adipocytes. A double-blind, placebo-controlled pilot study for
      studying the effect of isohumulones on diabetes suggested that isohumulones
      significantly decreased blood glucose and hemoglobin A1c levels after 8 weeks (by
      10.1 and 6.4%, respectively, versus week 0). These results suggest that
      isohumulones can improve insulin sensitivity in high fat diet-fed mice with
      insulin resistance and in patients with type 2 diabetes.

PMID- 15178688
TI  - Endoplasmic reticulum (ER) stress induced by a neurovirulent mouse retrovirus is
      associated with prolonged BiP binding and retention of a viral protein in the ER.
AB  - Some murine retroviruses cause a spongiform neurodegenerative disease exhibiting
      pathology resembling that observed in transmissible spongiform encephalopathies.
      The neurovirulence of these "spongiogenic retroviruses" is determined by the
      sequence of their respective envelope proteins, although the mechanisms of
      neurotoxicity are not understood. We have studied a highly neurovirulent virus
      called FrCasE that causes a rapidly progressive form of this disease. Recently,
      transcriptional markers of endoplasmic reticulum (ER) stress were detected during
      the early preclinical period in the brains of FrCasE-infected mice. In contrast,
      ER stress was not observed in mice infected with an avirulent virus, F43, which
      carries a different envelope gene, suggesting a role for ER stress in disease
      pathogenesis. Here we have examined in NIH 3T3 cells the cause of this cellular
      stress response. The envelope protein of F43 bound BiP, a major ER chaperone,
      transiently and was processed normally through the secretory pathway. In
      contrast, the envelope protein of FrCasE bound to BiP for a prolonged period, was
      retained in the ER, and was degraded by the proteasome. Furthermore, engagement
      of the FrCasE envelope protein by ER quality control pathways resulted in
      decreased steady-state levels of this protein, relative to that of F43, both in
      NIH 3T3 cells and in the brains of infected mice. Thus, the ER stress induced by
      FrCasE appears to be initiated by inefficient folding of its viral envelope
      protein, suggesting that the neurodegenerative disease caused by this virus
      represents a protein misfolding disorder.

PMID- 15178689
TI  - Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane
      inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury.
AB  - Reactive oxygen species (ROS) play a key role in promoting mitochondrial
      cytochrome c release and induction of apoptosis. ROS induce dissociation of
      cytochrome c from cardiolipin on the inner mitochondrial membrane (IMM), and
      cytochrome c may then be released via mitochondrial permeability transition (MPT)
      dependent or MPT-independent mechanisms. We have developed peptide antioxidants
      that target the IMM, and we used them to investigate the role of ROS and MPT in
      cell death caused by t-butylhydroperoxide (tBHP) and 3-nitropropionic acid (3NP).
      The structural motif of these peptides centers on alternating aromatic and basic
      amino acid residues, with dimethyltyrosine providing scavenging properties. These
      peptide antioxidants are cell-permeable and concentrate 1000-fold in the IMM.
      They potently reduced intracellular ROS and cell death caused by tBHP in neuronal
      N(2)A cells (EC(50) in nm range). They also decreased mitochondrial ROS
      production, inhibited MPT and swelling, and prevented cytochrome c release
      induced by Ca(2+) in isolated mitochondria. In addition, they inhibited 3NP
      induced MPT in isolated mitochondria and prevented mitochondrial depolarization
      in cells treated with 3NP. ROS and MPT have been implicated in myocardial
      stunning associated with reperfusion in ischemic hearts, and these peptide
      antioxidants potently improved contractile force in an ex vivo heart model. It is
      noteworthy that peptide analogs without dimethyltyrosine did not inhibit
      mitochondrial ROS generation or swelling and failed to prevent myocardial
      stunning. These results clearly demonstrate that overproduction of ROS underlies
      the cellular toxicity of tBHP and 3NP, and ROS mediate cytochrome c release via
      MPT. These IMM-targeted antioxidants may be very beneficial in the treatment of
      aging and diseases associated with oxidative stress.

PMID- 15178690
TI  - Amino acid substitutions in the C-terminal AAA+ module of Hsp104 prevent
      substrate recognition by disrupting oligomerization and cause high temperature
      inactivation.
AB  - Hsp104 is an important determinant of thermotolerance in yeast and is an unusual
      molecular chaperone that specializes in the remodeling of aggregated proteins.
      The structural requirements for Hsp104-substrate interactions remain unclear.
      Upon mild heat shock Hsp104 formed cytosolic foci in live cells that indicated co
      localization of the chaperone with aggregates of thermally denatured proteins. We
      generated random amino acid substitutions in the C-terminal 199 amino acid
      residues of a GFP-Hsp104 fusion protein, and we used a visual screen to identify
      mutants that remained diffusely distributed immediately after heat shock.
      Multiple amino acid substitutions were required for loss of heat-inducible
      redistribution, and this correlated with complete loss of nucleotide-dependent
      oligomerization. Based on the multiply substituted proteins, several single amino
      acid substitutions were generated by site-directed mutagenesis. The singly
      substituted proteins retained the ability to oligomerize and detect substrates.
      Intriguingly, some derivatives of Hsp104 functioned well in prion propagation and
      multiple stress tolerance but failed to protect yeast from extreme thermal
      stress. We demonstrate that these proteins co-aggregate in the presence of other
      thermolabile proteins during heat treatment both in vitro and in vivo suggesting
      a novel mechanism for uncoupling the function of Hsp104 in acute severe heat
      shock from its functions at moderate temperatures.

PMID- 15178691
TI  - Suppression of androgen receptor-mediated transactivation and cell growth by the
      glycogen synthase kinase 3 beta in prostate cells.
AB  - Androgens play important roles in the growth of normal prostate and prostate
      cancer via binding to the androgen receptor (AR). In addition to androgens, AR
      activity can also be modulated by selective growth factors and/or kinases. Here
      we report a new kinase signaling pathway by showing that AR transactivation was
      repressed by wild type glycogen synthase kinase 3beta (GSK3 beta) or
      constitutively active S9A-GSK3 beta in a dose-dependent manner. In contrast, the
      catalytically inactive kinase mutant GSK3 beta showed little effect on the AR
      transactivation. The suppression of AR transactivation by GSK3 beta was abolished
      by the GSK3 beta inhibitor lithium chloride. The in vitro kinase assay showed
      that GSK3 beta prefers to phosphorylate the amino terminus of AR that may lead to
      the suppression of activation function 1 activity located in the NH(2)-terminal
      region of AR. GSK3 beta interrupted the interaction between the NH(2) and COOH
      termini of AR, and overexpression of the constitutively active form of GSK3 beta,
      S9A-GSK3 beta, reduced the androgen-induced prostate cancer cell growth in stably
      transfected CWR22R cells. Together, our data demonstrated that GSK3 beta may
      function as a repressor to suppress AR-mediated transactivation and cell growth,
      which may provide a new strategy to modulate the AR-mediated prostate cancer
      growth.

PMID- 15178692
TI  - BmBKTx1, a novel Ca2+-activated K+ channel blocker purified from the Asian
      scorpion Buthus martensi Karsch.
AB  - BmBKTx1 is a novel short chain toxin purified from the venom of the Asian
      scorpion Buthus martensi Karsch. It is composed of 31 residues and is
      structurally related to SK toxins. However, when tested on the cloned rat SK2
      channel, it only partially inhibited rSK2 currents, even at a concentration of 1
      microm. To screen for other possible targets, BmBKTx1 was then tested on isolated
      metathoracic dorsal unpaired median neurons of Locusta migratoria, in which a
      wide variety of ion channels are expressed. The results suggested that BmBKTx1
      could specifically block voltage-gated Ca(2+)-activated K(+) currents (BK-type).
      This was confirmed by testing the BmBKTx1 effect on the alpha subunits of BK
      channels of the cockroach (pSlo), fruit fly (dSlo), and human (hSlo),
      heterologously expressed in HEK293 cells. The IC(50) for channel blocking by
      BmBKTx1 was 82 nm for pSlo and 194 nm for dSlo. Interestingly, BmBKTx1 hardly
      affected hSlo currents, even at concentrations as high as 10 microm, suggesting
      that the toxin might be insect specific. In contrast to most other scorpion BK
      blockers that also act on the Kv1.3 channel, BmBKTx1 did not affect this channel
      as well as other Kv channels. These results show that BmBKTx1 is a novel kind of
      blocker of BK-type Ca(2+)-activated K(+) channels. As the first reported toxin
      active on the Drosophila Slo channel dSlo, it will also greatly facilitate
      studying the physiological role of BK channels in this model organism.

PMID- 15178693
TI  - Mutagenesis of the ezrin-radixin-moesin binding domain of L-selectin tail affects
      shedding, microvillar positioning, and leukocyte tethering.
AB  - L-selectin is a cell adhesion molecule that mediates the initial capture
      (tethering) and subsequent rolling of leukocytes along ligands expressed on
      endothelial cells. We have previously identified ezrin and moesin as novel
      binding partners of the 17-amino acid L-selectin tail, but the biological role of
      this interaction is not known. Here we identify two basic amino acid residues
      within the L-selectin tail that are required for binding to ezrin-radixinmoesin
      (ERM) proteins: arginine 357 and lysine 362. L-selectin mutants defective for ERM
      binding show reduced localization to microvilli and decreased phorbol 12
      myristate 13-acetate-induced shedding of the L-selectin ectodomain. Cells
      expressing these L-selectin mutants have reduced tethering to the L-selectin
      ligand P-selectin glycoprotein ligand-1, but rolling velocity on P-selectin
      glycoprotein ligand-1 is not affected. These results suggest that ERM proteins
      are required for microvillar positioning of L-selectin and that this is important
      both for leukocyte tethering and L-selectin shedding.

PMID- 15178695
TI  - Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum
      dysfunction.
AB  - Endoplasmic reticulum (ER) stress-induced cell death plays an important role in
      cerebral ischemia. In the present study, we investigated whether edaravone (3
      methyl-1-phenyl-pyrazolin-5-one), a free radical scavenger, can protect against
      ER damage induced by cerebral ischemia. In a mouse model of hypoxia/ischemia,
      treatment with edaravone reduced edema-corrected infarction volume, attenuated
      hemispheric swelling, and improved neurological status. Moreover, edaravone
      suppressed ER stress-mediated apoptosis by inhibiting eukaryotic initiation
      factor alpha phosphorylation, C/EBP homologous protein (CHOP) induction, and
      caspase-12 activation. In mouse primary cultured glial cells, edaravone
      attenuated ER stress as evidenced by inhibition of the induction of glucose
      regulated protein 78 and CHOP and XBP-1 splicing under treatment with tunicamycin
      (Tm), which induces ER stress. Tm did not induce the production of reactive
      oxygen species in primary cultured glial cells. In addition, the free radical
      scavengers N-acetyl-l-cysteine and ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)
      one] did not affect ER stress response caused by Tm. These results demonstrated a
      novel action of edaravone that can protect against ER dysfunction in cerebral
      ischemia.

PMID- 15178694
TI  - SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5
      tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one], a new, reversible, and mixed
      inhibitor of monoamine oxidase-A and monoamine oxidase-B: biochemical and
      behavioral profile.
AB  - SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5
      tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one] is a new, nonselective, and
      reversible monoamine oxidase (MAO) inhibitor, belonging to a oxazoloquinolinone
      series. In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B
      with IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki values of 3.3 and
      4.2 nM, respectively. In ex vivo conditions, the oral administration of SL25.1131
      induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat
      brain with ED50 values of 0.67 and 0.52 mg/kg, respectively. In the rat brain,
      duodenum, and liver, the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg
      p.o.) was reversible, and the recovery of MAO-A and MAO-B activities was complete
      16 h after administration. SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of
      dopamine (DA), norepinephrine, and 5-hydroxytryptamine and decreased levels of
      their deaminated metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid,
      and 5-hydroxyindolacetic acid. In mice, SL25.1131 induced a dose-dependent
      potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced
      stereotypies with ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131
      was able to reestablish normal striatal dopaminergic tone and locomotor activity
      in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. In addition, when
      coadministered with L-DOPA, SL25.1131 increased the available DA in the striatum
      and the duration of L-DOPA-induced hyperactivity. The duration of the effect of L
      DOPA on circling behavior in 6-hydroxydopamine-lesioned rats was also increased.
      The neurochemical profile of SL25.1131 demonstrates that this compound is a
      mixed, potent, and reversible MAO-A/B inhibitor in vitro, in vivo, and ex vivo.
      SL25.1131 has therapeutic potential as a symptomatic treatment during the early
      phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early
      and late phases of the disease.

PMID- 15178696
TI  - Identification of amino acid residues involved in the inactivation of cytochrome
      P450 2B1 by two acetylenic compounds: the role of three residues in nonsubstrate
      recognition Sites.
AB  - The homologous rat cytochrome P450s 2B1 and 2B2 differ by 13 amino acids. A
      chimeric construct of P450 2B1/2B2 was used in conjunction with several site
      directed mutants to identify key residues involved in the inactivation of P450
      2B1 by two acetylenic compounds, 17alpha-ethynylestradiol (17EE) and tert-butyl 1
      methyl-2-propynyl ether (tBMP). 17EE is a mechanism-based inactivator of P450 2B1
      but not of P450 2B2. We show here that tBMP is also a mechanism-based inactivator
      of P450 2B1 and not P450 2B2. Minimal loss in 7-ethoxy-4
      (trifluoromethyl)coumarin (7-EFC) activity was observed when P450 2B1 G478A was
      incubated with either inactivator, suggesting that this residue plays a role in
      the inactivation. However, P450 2B2 A478G behaved like wild-type P450 2B2,
      indicating that this residue alone is not sufficient for inactivation. A chimeric
      construct of P450 2B1/2B2 that is essentially P450 2B1 with five residues of P450
      2B2 (including residue 478), was not inactivated by either tBMP or 17EE,
      suggesting that these five residues are important for inactivation. Sequential
      mutagenesis of the chimeric construct to quadruple (S407T-N417D-A419T-G478A) and
      triple (S407T-N417D-A419T) mutants of P450 2B1 did not result in inactivation by
      either inactivator. However, the triple mutant with mutations only in non
      substrate recognition site (SRS) regions still exhibits wild-type P450 2B1 7-EFC
      O-deethylation activity with a K(m) value of 25 microM and V(max) of 8
      nmol/min/nmol P450. These results demonstrate that substitution of three non-SRS
      residues in P450 2B1 leads to protection against inactivation of 2B enzymes by
      these two acetylenic compounds.

PMID- 15178697
TI  - Angiotensin II-induced relaxation of anococcygeus smooth muscle via
      desensitization of AT1 receptor, and activation of AT2 receptor associated with
      nitric-oxide synthase pathway.
AB  - We evaluated the role of receptor desensitization, activation of AT(2) receptors,
      and enzymatic degradation of angiotensin II (Ang II) by amino/neutral
      endopeptidases in rat anococcygeus smooth muscle (ASM) relaxation. Ang II (0.3 nM
      to 10 microM) produced contractions (E(max) = 21.50 +/- 5.73%) followed by
      passive relaxations (E(max) reduced to 9.08 +/- 2.55%). Contractions were
      inhibited (E(max) = 13.67 +/- 2.03%) by losartan (0.1 microM; AT(1) antagonist)
      but not by PD123,319 [S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5
      (diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid]
      (0.1 microM; AT(2) antagonist). Conversely, the passive relaxation was inhibited
      (E(max) = 18.00 +/- 3.45%) by PD123,319 but not by losartan. Ang II (0.3 microM
      to 100 microM) produced initial contractions (E(max) = 11.49 +/- 9.39%) followed
      by active relaxations [I(max) (maximum inhibition elicited by the agonist) =
      47.85 +/- 4.23%] on strips precontracted by bethanechol (100 microM). A second
      administration of Ang II on the background of bethanechol (1 h later) resulted in
      stronger relaxations (I(max) = 64.03 +/- 5.47%) without the initial contractions.
      N(G)-Nitro-l-arginine methyl ester [nitric-oxide synthase (NOS) inhibitor], ODQ
      (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; guanylate cyclase inhibitor),
      PD123,319, and tetrodotoxin (neurotoxin) inhibited the relaxations. The presence
      of AT(1) and AT(2) receptors was confirmed by Western blot. Experiments with
      amastatin (1 microM) and thiorphan (1 microM), aminopeptidase, and neutral
      endopeptidase inhibitors, respectively, excluded the involvement of enzymatic
      degradation in Ang II-induced relaxation of ASM. In conclusion, the rat ASM
      relaxation by Ang II is the result of active and passive relaxations. The passive
      relaxation depends on desensitization of excitatory AT(1) receptors, and the
      active relaxation is mediated by stimulation of AT(2) receptors and activation of
      the neuronal NOS/soluble guanylate cyclase pathway.

PMID- 15178698
TI  - Electrophysiological, pharmacological, and molecular evidence for alpha7
      nicotinic acetylcholine receptors in rat midbrain dopamine neurons.
AB  - Dopamine (DA) neurons located in the mammalian midbrain have been generally
      implicated in reward and drug reinforcement and more specifically in nicotine
      dependence. However, roles played by nicotinic acetylcholine receptors, including
      those composed of alpha7-subunits [alpha7-nicotinic acetylcholine receptors
      (nAChRs)], in modulation of DA signaling and in nicotine dependence are not
      clearly understood. Although midbrain slice recording has been used previously to
      identify functional alpha7-nAChRs, these preparations are not optimally designed
      for extremely rapid and reproducible drug application, and rapidly desensitized,
      alpha7-nAChR-mediated currents may have been underestimated or not detected.
      Here, we use patch-clamp, whole-cell current recordings from single neurons
      acutely dissociated from midbrain nuclei and having features of DA neurons to
      characterize acetylcholine-induced, inward currents that rapidly activate and
      desensitize, are mimicked by the alpha7-nAChR-selective agonist, choline, blocked
      by the alpha7-nAChR-selective antagonists, methyllycaconitine and alpha
      bungarotoxin, and are similar to those of heterologously expressed, human alpha7
      nAChRs. We also use reverse transcriptase-polymerase chain reaction, in situ
      hybridization, and immunocytochemical staining to demonstrate nAChR alpha7
      subunit gene expression as message and protein in the rat substantia nigra pars
      compacta and ventral tegmental area. Expression of alpha7 subunit message and of
      alpha7-nAChR-mediated responses is developmentally regulated, with both being
      absent in samples taken from rats at postnatal day 7, but later becoming present
      and increasing over the next 2 weeks. Collectively, this electrophysiological,
      pharmacological, and molecular evidence indicates that nAChR alpha7 subunits and
      functional alpha7-nAChRs are expressed somatodendritically by midbrain DA
      neurons, where they may play important physiological roles and contribute to
      nicotine reinforcement and dependence.

PMID- 15178700
TI  - Immobilization of rolling NK cells on platelet-borne P-selectin under flow by
      proinflammatory stimuli, interleukin-12, and leukotriene B4.
AB  - Recruitment of leukocytes from bloodstream to extrahematic sites is tightly
      regulated by a variety of adhesion molecules that are expressed on the leukocytes
      and the vessel walls. In this manuscript, we describe the interactions between
      natural killer (NK) cells and activated, autologous platelets under physiologic
      flow. We found that surface-adherent human platelets are capable of recruiting
      human NK cells from flow and that this recruitment is characterized by an initial
      tethering followed by a rolling phase. Both phases were dependent on the adhesion
      molecule P-selectin and its counter-ligand on the NK cells (P-selectin
      glycoprotein ligand 1). Activation of rolling NK cells with inflammatory
      mediators commonly found in atherosclerotic plaques (interleukin-12 and
      leukotriene B4) causes immediate cessation of the rolling process and conversion
      to stationary adhesion. Blocking antibodies to the adhesion molecules membrane
      activated complex-1 and leukocyte function antigen-1 inhibited this conversion.
      Our data suggest that platelets deposited at sites of vascular injury may provide
      an alternative substrate to endothelial cells for initial recruitment of NK cells
      to the vessel wall. This may result in extravasation of the NK cells if the
      appropriate chemotactic signal is applied. These data implicate the P-selectin
      and integrin family of adhesion molecules in the recruitment of NK cells to
      atherosclerotic sites.

PMID- 15178699
TI  - cAMP protects neutrophils against TNF-alpha-induced apoptosis by activation of
      cAMP-dependent protein kinase, independently of exchange protein directly
      activated by cAMP (Epac).
AB  - It is unclear by which receptor cyclic adenosine monophosphate (cAMP) acts to
      promote neutrophil survival. We found that 8-(4-chlorophenylthio)-2'-O-methyl
      cAMP, a specific activator of the recently discovered cAMP receptor, cAMP
      regulated guanosine 5'-triphosphate exchange protein directly activated by cAMP,
      failed to protect human neutrophils from cell death. In contrast, specific
      activators of cAMP-dependent protein kinase type I (cA-PKI) could protect against
      death receptor [tumor necrosis factor receptor 1 (TNFR-1), Fas]-mediated
      apoptosis as well as cycloheximide-accelerated "spontaneous" apoptosis. A novel
      "caged" cA-PK-activating analog, 8-bromo (8-Br)-acetoxymethyl-cAMP, was more than
      20-fold more potent than 8-Br-cAMP to protect neutrophils challenged with TNF
      alpha against apoptosis. This analog acted more rapidly than forskolin (which
      increases the endogenous cAMP production) and allowed us to demonstrate that cA
      PK must be activated during the first 10 min after TNF-alpha challenge to protect
      against apoptosis. The protective effect was mediated solely through cA-PK
      activation, as it was abolished by the cA-PKI-directed inhibitor Rp-8-Br-cAMPS
      and the general cA-PK inhibitor H-89. Neutrophils not stimulated by cAMP
      elevating agents showed increased apoptosis when exposed to the cA-PK inhibitors
      Rp-8-Br-cAMPS and H-89, suggesting that even moderate activation of cA-PK is
      sufficient to enhance neutrophil longevity and thereby contribute to neutrophil
      accumulation in chronic inflammation.

PMID- 15178701
TI  - Loss of lineage antigens is a common feature of apoptotic lymphocytes.
AB  - The analysis of apoptosis in cell populations involves the detection of their
      specific lineage antigen (LAg) expression. This experimental approach relies on
      their assumed constant expression, but it is unclear whether such expression is
      actually maintained during cell death. We examined whether the loss of LAgs is a
      common feature of apoptotic lymphocytes and whether some might completely lose
      their LAgs. The changes in the expression of CD3, CD5, CD8, CD4, CD28, CD56, and
      CD19 were monitored in highly purified lymphocyte populations obtained by
      negative selection in a fluorescence-activated cell sorter. These were cultured
      for 24 h with or without phytohemagglutinin or staurosporin. For each LAg
      positive subset studied, apoptosis was consistently more common among cells
      showing partial or total loss of LAg expression compared with cells maintaining
      their initial LAg levels. The kinetics of expression loss was rapid for CD8,
      CD56, and CD28, and more than 80% of initial expression was lost in the early
      stages of apoptosis but was slower for CD3, CD5, and CD4. For CD3 and CD5,
      expression was dependent on the apoptotic stimulus used. It is interesting that
      loss of antigen expression was independent of cell size. This phenomenon was also
      found in nonmanipulated, highly pure CD19 B lymphocytes of peripheral blood
      mononuclear cells from B chronic lymphocytic leukemia patients. Loss of LAg
      expression appeared to be a common feature of apoptotic lymphocytes under all the
      conditions assayed. The different kinetic patterns of LAg loss suggest apoptotic
      cells might actively regulate this process.

PMID- 15178702
TI  - Human epidermal Langerhans cells differ from monocyte-derived Langerhans cells in
      CD80 expression and in secretion of IL-12 after CD40 cross-linking.
AB  - Langerhans cells (LCs) represent an immature population of myeloid dendritic
      cells (DCs). As a result of their unique Birbeck granules (BGs), langerin
      expression, and heterogeneous maturation process, they differ from other immature
      DCs. Monocyte-derived LCs (MoLCs) mimic epidermal LCs. MoLCs with characteristic
      BGs are generated by culturing blood-derived monocytes with granulocyte
      macrophage-colony stimulating factor, interleukin (IL)-4, and transforming growth
      factor-beta1. Here, we compare maturation-induced antigen expression and cytokine
      release of LCs with MoLCs. To achieve comparable cell populations, LCs and MoLCs
      were isolated by CD1c cell sorting, resulting in high purity. In unstimulated
      cells, CD40 was expressed at equal levels. After stimulation with CD40 ligand
      (CD40L), LCs and MoLCs acquired CD83 and increased CD86. High CD80 expression was
      exclusively detected in CD1c-sorted MoLCs. Human leukocyte antigen-DR and CD54
      expression was found in all cell populations, however, at different intensities.
      CD40 triggering increased the potency of LCs and MoLCs to stimulate CD4+ T cell
      proliferation. Activated MoLCs released IL-12p70 and simultaneously, anti
      inflammatory IL-10. The application of the Toll-like receptor ligands
      peptidoglycan, flagellin, and in particular, lipopolysaccharide (LPS) increased
      the corelease of these cytokines. LCs secreted IL-10 at a comparable level with
      MoLCs but failed to produce high amounts of IL-12p70 after application of danger
      signals. These data indicate that MoLCs as well as LCs display no maturation
      arrest concerning CD83 and CD86 expression. In difference to MoLCs, LCs resisted
      activation by CD40L and LPS in terms of IL-12 production. This shows that natural
      and generated LCs share similar features but differ in relevant functions.

PMID- 15178703
TI  - Human neutrophils synthesize IL-8 in an IgE-mediated activation.
AB  - It has been demonstrated that neutrophils are responsible for the release of
      large amounts of the inflammatory chemokine interleukin-8 (IL-8), associated with
      inflammation. To further define the mechanisms implicated, we have analyzed the
      response of human neutrophils from allergic patients to specific antigens or
      challenge with anti-immunoglobulin (Ig)E antibodies. Neutrophils showed a dose-
      and time-dependent production of IL-8. The release of the cytokine was parallel
      to expression of IL-8 mRNA analyzed by the polymerase chain reaction. This
      expression was transient-it occurred after 3 h of anti-IgE treatment and was
      maintained for 18 h. Trifluoperazine, EGTA, reduced nicotinamide adenine
      dinucleotide phosphate-oxidase inhibitors, and reactive oxygen species (ROS)
      scavengers inhibited IL-8 production, indicating a critical dependence of calcium
      and oxidative stress. Moreover, an inhibitory effect of cyclosporin A, an
      immunosuppressor that inhibits calcineurin activity, on IL-8 release and IL-8
      mRNA expression was observed. This is the first evidence of the involvement of
      ROS and calcium/calcineurin in IgE-dependent IL-8 production. These findings open
      new perspectives into the functional role of neutrophils in IgE-associated
      diseases.

PMID- 15178704
TI  - IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells.
AB  - Interleukin (IL)-21 is a T cell-derived cytokine that regulates innate and
      adaptive immune responses. IL-21 receptor (IL-21R), which is expressed in natural
      killer (NK) and T cells, is structurally homologous to IL-2Rbeta and IL-15Ralpha.
      These receptors also share a common cytokine receptor gamma-chain with IL-4, IL
      7, and IL-9. Macrophage- or dendritic cell-derived interferon (IFN)-alpha/beta is
      a key cytokine in regulation of NK and T cell functions. We demonstrate here that
      in addition to activating IFN-gamma gene expression, IFN-alpha/beta and IL-12
      enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN
      alpha/beta enhanced T cell receptor stimulation-induced IL-21 and IFN-gamma gene
      expression in resting T cells. The promoter analysis of IL-21 gene revealed a
      putative IFN-gamma activation site element, which was found to bind signal
      transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4
      proteins in IFN-alpha/beta-stimulated NK or T cell extracts. In contrast to IL-21
      expression, IFN-alpha/beta down-regulated IL-21R mRNA expression in NK and T
      cells. IFN-alpha/beta-induced down-regulation of IL-21R expression resulted in
      reduced STAT3 phosphorylation and DNA binding after IL-21 stimulation. In
      conclusion, our results suggest a novel role for IFN-alpha/beta in the regulation
      of IL-21 response.

PMID- 15178705
TI  - Endogenous ligands of Toll-like receptors.
AB  - Extensive work has suggested that a number of endogenous molecules such as heat
      shock proteins (hsp) may be potent activators of the innate immune system capable
      of inducing proinflammatory cytokine production by the monocyte-macrophage system
      and the activation and maturation of dendritic cells. The cytokine-like effects
      of these endogenous molecules are mediated via the Toll-like receptor (TLR)
      signal-transduction pathways in a manner similar to lipopolysaccharide (LPS; via
      TLR4) and bacterial lipoproteins (via TLR2). However, recent evidence suggests
      that the reported cytokine effects of hsp may be a result of the contaminating
      LPS and LPS-associated molecules. The reasons for previous failure to recognize
      the contaminant(s) being responsible for the putative TLR ligands of hsp include
      failure to use highly purified hsp free of LPS contamination; failure to
      recognize the heat sensitivity of LPS; and failure to consider contaminant(s)
      other than LPS. Whether other reported putative endogenous ligands of TLR2 and
      TLR4 are a result of contamination of pathogen-associated molecular patterns is
      not clear. It is essential that efforts should be directed to conclusively
      determine whether the reported putative endogenous ligands of TLRs are a result
      of the endogenous molecules or of contaminant(s), before exploring further the
      implication and therapeutic potential of these putative TLR ligands.

PMID- 15178706
TI  - Unique phenotype of human uterine NK cells and their regulation by endogenous TGF
      beta.
AB  - Natural killer (NK) cells are a major population of lymphocytes in the human
      endometrium (EM), and NK cells can be a significant source of cytokines that
      alter local immune responses. The aim of this study was to determine the
      expression of NK cell receptors in situ and to test whether uterine NK (uNK)
      cells produce cytokines and how this activity may be regulated by transforming
      growth factor-beta (TGF-beta). We observed that human uNK cells were CD56+, CD3-,
      CD57-, CD9+, CD94+, killer inhibitory receptor+, and CD16+/- in situ by confocal
      microscopy. We examined cytokine production by uNK cells and uNK cell clones
      derived from human EM. Stimulation of uNK cells with interleukin (IL)-12 and IL
      15, both of which are expressed in the human EM, induced interferon-gamma (IFN
      gamma) and IL-10 production. IFN-gamma production by uNK cell clones was
      completely inhibited by TGF-beta1 in a dose-dependent manner with an inhibitory
      concentration 50% value of 20 pg/ml. IL-10 secretion by uNK cell clones was also
      inhibited by TGF-beta1 at similar concentrations. Furthermore, blocking
      endogenous TGF-beta in fresh human endometrial cell cultures increased the
      production of IFN-gamma by uNK cells. These data indicate that uNK cells have a
      unique phenotype that is distinct from blood NK cells. Further, data demonstrate
      that uNK cells can produce immunoregulatory cytokines and that inhibition of uNK
      cells by locally produced TGF-beta1 is a likely mechanism to regulate NK cell
      function in the human EM.

PMID- 15178707
TI  - Lysophosphatidylcholine up-regulates CXCR4 chemokine receptor expression in human
      CD4 T cells.
AB  - Oxidized low-density lipoprotein (OxLDL) is an inflammatory modulator in the
      atherosclerotic plaque. We examined the effect of lysophosphatidylcholine
      (lysoPC), a main phospholipid component of OxLDL, on inflammatory responses in
      human CD4 T cells. We found that lysoPC dose- and time-dependently increased
      expression of CXCR4, the chemokine receptor on CD4 T cells. This increase was
      inhibited by caffeic acid phenethyl ester or SN50, nuclear factor-kappaB
      inhibitors, and also by suppression of G2A expression, the specific receptor for
      lysoPC, using antisense oligonucleotide. lysoPC enhanced CD4 T cell chemotaxis in
      response to stromal cell-derived factor-1 (SDF-1), the exclusive ligand for
      CXCR4. lysoPC also enhanced SDF-1-stimulated production of inflammatory cytokines
      interleukin-2 and interferon-gamma by CD4 T cells activated by anti-CD3
      immunoglobulin G. In conclusion, this study demonstrates that lysoPC directly
      modulates inflammatory responses in human CD4 T cells. The data suggest that the
      presence of lysoPC and SDF-1 in atherosclerotic lesions may trigger inflammatory
      responses mediated by CD4 T cells, which may play an important role in
      progression of atherosclerosis.

PMID- 15178708
TI  - I-TAC/CXCL11 is a natural antagonist for CCR5.
AB  - The selective CXC chemokine receptor 3 (CXCR3) agonists, monokine induced by
      interferon-gamma (IFN- gamma)/CXC chemokine ligand 9 (CXCL9), IFN-inducible
      protein 10/CXCL10, and IFN-inducible T cell alpha chemoattractant (I-TAC)/CXCL11,
      attract CXCR3+ cells such as CD45RO+ T lymphocytes, B cells, and natural killer
      cells. Further, all three chemokines are potent, natural antagonists for
      chemokine receptor 3 (CCR3) and feature defensin-like, antimicrobial activities.
      In this study, we show that I-TAC, in addition to these effects, acts as an
      antagonist for CCR5. I-TAC inhibited the binding of macrophage-inflammatory
      protein-1alpha (MIP-1alpha)/CC chemokine ligand 3 (CCL3) to cells transfected
      with CCR5 and to monocytes. Furthermore, cell migration evoked by regulated on
      activation, normal T expressed and secreted (RANTES)/CCL5 and MIP-1beta/CCL4, the
      selective agonist of CCR5, was inhibited in transfected cells and monocytes,
      respectively. In two other functional assays, namely the release of free
      intracellular calcium and actin polymerization, I-TAC reduced CCR5 activities to
      minimal levels. Sequence and structure analyses indicate a potential role for
      K17, K49, and Q51 of I-TAC in CCR5 binding. Our results expand on the potential
      role of I-TAC as a negative modulator in leukocyte migration and activation, as I
      TAC would specifically counteract the responses mediated by many "classical,"
      inflammatory chemokines that act not only via CCR3 but via CCR5 as well.

PMID- 15178709
TI  - Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice.
AB  - Macrophages play an important role in organ development, tissue homeostasis, and
      remodeling. Thus, we monitored the presence of F4/80-positive macrophages in the
      pancreas of wild-type mice, and some developmental features of this complex
      tissue were compared throughout life in wild-type and macrophage-deficient
      Csf1op/Csf1op (op/op) mice. The combined use of immunohistochemistry,
      morphometry, and cell quantification allows us to evaluate insulin and glucagon
      cell mass, total and insulin cell proliferation, and apoptosis in fetuses
      (E18.5), weanings (postnatal day 21), nonpregnant adults, and adults in late
      pregnancy (18.5 days). F4/80-positive macrophages were found in pancreases
      recovered from Csf1op/Csf1+ (op/+) mice but were extremely scarce or absent in
      pancreas recovered from op/op ones at all studied time-points. The macrophage
      deficient op/op phenotype was clearly associated with a major insulin mass
      deficit in fetuses and adults, abnormal postnatal islet morphogenesis, and
      impaired pancreatic cell proliferation at weaning and late pregnancy. We also
      obtained indirect evidence of increased neogenesis in this model at time-points
      when pancreatic remodeling does occur. The demonstration of the colony
      stimulating factor 1-dependent macrophage involvement in life-time pancreas
      development/remodeling allows us to pinpoint the tissue-modeling and remodeling
      functions of this leukocyte lineage.

PMID- 15178710
TI  - Nitric oxide post-transcriptionally up-regulates LPS-induced IL-8 expression
      through p38 MAPK activation.
AB  - Nitric oxide (NO(.-)) contributes to vascular collapse in septic shock and
      regulates inflammation. Here, we demonstrate in lipopolysaccharide (LPS)
      stimulated human THP-1 cells and monocytes that NO(.-) regulates interleukin (IL)
      8 and tumor necrosis factor alpha (TNF-alpha) by distinct mechanisms. Dibutyryl
      cyclic guanosine 5'-monophosphate (cGMP) failed to simulate NO(.-)-induced
      increases in TNF-alpha or IL-8 production. In contrast, dibutyryl-cyclic
      adenosine monophosphate blocked NO(.-)-induced production of TNF-alpha (P=0.009)
      but not IL-8. NO(.-) increased IL-8 (5.7-fold at 4 h; P=0.04) and TNF-alpha mRNA
      levels (2.2-fold at 4 h; P=0.037). However, nuclear run-on assays demonstrated
      that IL-8 transcription was slightly decreased by NO(.-) (P=0.08), and TNF-alpha
      was increased (P=0.012). Likewise, NO(.-) had no effect on IL-8 promoter activity
      (P=0.84) as measured by reporter gene assay. In THP-1 cells and human primary
      monocytes treated with actinomycin D, NO(.-) had no effect on TNF-alpha mRNA
      stability (P>0.3 for both cell types) but significantly stabilized IL-8 mRNA
      (P=0.001 for both cell types). Because of its role in mRNA stabilization, the p38
      mitogen-activated protein kinase (MAPK) pathway was examined and found to be
      activated by NO(.-) in LPS-treated THP-1 cells and human monocytes. Further,
      SB202190, a p38 MAPK inhibitor, was shown to block NO(.-)-induced stabilization
      of IL-8 mRNA (P<0.02 for both cell types). Thus, NO(.-) regulates IL-8 but not
      TNF-alpha post-transcriptionally. IL-8 mRNA stabilization by NO(.-) is
      independent of cGMP and at least partially dependent on p38 MAPK activation.

PMID- 15178711
TI  - Why take the vascular and interventional radiology maintenance of certification
      examination or maintain a subspecialty certificate in vascular and interventional
      radiology?

PMID- 15178712
TI  - Quality improvement guidelines for uterine artery embolization for symptomatic
      leiomyomata.

PMID- 15178713
TI  - Use of concomitant glycoprotein IIb/IIIa inhibitors with catheter-directed
      peripheral arterial thrombolysis.

PMID- 15178714
TI  - Antibiotic prophylaxis in interventional radiology.
AB  - Despite several decades of advances in both minimally invasive techniques and
      antibiotic therapy, infection remains one of the more common complications of
      invasive procedures. Interventional radiology (IR) has traditionally been
      believed to be associated with lower infection rates than surgery. However, new
      interventional techniques, as well as more aggressive therapeutic interventions,
      have presented new challenges in relation to pharmacological management of
      postprocedural infection and pain. The risk of infection associated with IR
      procedures can never be completely eliminated, and the reasons for this are
      manifold, including more virulent organisms, ongoing and newly emerging
      antibiotic resistance, increased numbers of immunocompromised patients, and the
      adoption into everyday interventional practice of more aggressive interventional
      techniques such as chemoembolization, uterine fibroid embolization, and complex
      biliary intervention. Despite the widespread use of prophylactic antibiotics in
      IR, and the widely held belief that they are beneficial and are the standard of
      care, randomized controlled clinical trials have never validated the use of
      antibiotics in this setting. As such, an argument could be made not to use
      antibiotics at all for prophylaxis in IR. The purpose of this article is to
      discuss some of the issues relating to the use of prophylactic antibiotics, and
      what choice of antibiotics physicians make when they decide to use prophylaxis
      for IR procedures.

PMID- 15178715
TI  - Reteplase with or without abciximab for peripheral arterial occlusions: efficacy
      and adverse events.
AB  - PURPOSE: To retrospectively evaluate reteplase in thrombolysis of peripheral
      arterial occlusion (PAO). MATERIALS AND METHODS: Forty limbs in 36 patients were
      treated with reteplase (0.5 U/h) with or without abciximab (bolus and 12-hour
      infusion). Twenty-four occlusions were in bypass grafts and 16 were in native
      arteries. Nineteen patients were treated with reteplase alone and 21 patients
      were treated with reteplase and abciximab. Chart review provided data from
      procedures and follow-up at 30 days and 6 months. Multivariable, analysis of
      variance, and Student t test comparisons of results and complications were
      performed. RESULTS: Reteplase infusions averaged 31 hours in duration (range, 12
      72 hours). The technical success rate was 80%. The clinical success rates were:
      immediate, 80%; 30-day, 65%; and 6-month, 45%. Major bleeding complications
      occurred in 20% of cases and intracranial hemorrhage occurred in 2.5%. The 6
      month amputation-free survival rate was 78%. Major, minor, and lack of
      complications were statistically associated with mean decreases in fibrinogen
      levels from baseline of 72%, 46%, and 15%, respectively (P =.000013).
      Complications were not associated with length of infusion or use of abciximab (P
      =.77). Patients with grafts accounted for 89% of the major complications (eight
      of nine; P =.009) and had worse clinical success immediately (71%), at 30 days
      (50%), and at 6 months (21%; P =.002, P =.003, P =.00001). CONCLUSIONS: There was
      significant fibrinogen depletion with use of reteplase for PAO. The percent
      decrease in fibrinogen level correlates with lack of complications and incidence
      of minor and major complications. Abciximab use did not increase the complication
      rate. Thrombolysis of grafts is associated with increased incidence of
      complications and worse outcomes compared with thrombolysis of native arteries.

PMID- 15178716
TI  - Pharmacomechanical thrombolysis and early stent placement for iliofemoral deep
      vein thrombosis.
AB  - PURPOSE: To evaluate an approach to the treatment of iliofemoral deep vein
      thrombosis (DVT) that included pharmacomechanical catheter-directed thrombolysis
      with reteplase and the Helix mechanical thrombectomy device, followed by early
      stent placement. MATERIALS AND METHODS: During 3-year period, 23 symptomatic
      limbs in 18 patients with iliofemoral DVT were treated with reteplase catheter
      directed thrombolysis. After an initial infusion of 8 to 16 hours, any residual
      acute thrombus over a long segment (> 10 cm) was treated by maceration with use
      of the Helix thrombectomy device. Residual short-segment (< 10 cm) iliac vein
      thrombus and/or stenosis were treated with stent placement. Technical success,
      clinical success, complications, thrombolytic infusion time, total thrombolytic
      agent dose, fibrinogen level changes, and late limb status were retrospectively
      analyzed. RESULTS: Technical success was achieved in 23 of 23 limbs (100%).
      Clinical success was achieved in 22 of 23 limbs (96%). Complete or partial
      thrombolysis was observed in 19 of 23 limbs (83%). Major bleeding was observed in
      one patient (6%) and necessitated blood transfusion. Mean per-limb thrombolytic
      infusion time and total dose were 19.6 hours +/- 8.1 and 13.8 U +/- 5.3
      reteplase, respectively. Mean serum fibrinogen nadir and percentage drop in serum
      fibrinogen were 282 mg/dL +/- 167 and 47% +/- 24%, respectively. Late (mean, 19.8
      +/- 11.6 months) modified Venous Disability Scores were 0 (none) for six limbs, 1
      (mild) for 10 limbs, 2 (moderate) for two limbs, and 3 (severe) for no limbs.
      CONCLUSION: In a preliminary experience, pharmacomechanical catheter-directed
      iliofemoral DVT thrombolysis with early stent placement was safe and effective.

PMID- 15178717
TI  - Dose-ranging trial with a recombinant urokinase (urokinase alfa) for occluded
      central venous catheters in oncology patients.
AB  - PURPOSE: Recombinant urokinase (r-UK) is a high-molecular-weight urokinase
      produced in transfected, non-human, mammalian cells. A Phase II, randomized,
      double-blind, parallel, placebo-controlled, dose-ranging study was performed to
      compare the safety and efficacy of one or two instillations of three intraluminal
      concentrations of r-UK (5,000; 15,000; and 25,000 IU/mL) with a placebo for
      reestablishment of total function to occluded central venous access devices
      (CVADs). MATERIALS AND METHODS: One-hundred eight patients with CVAD withdrawal
      or total occlusion were enrolled and randomized to treatment; 104 patients
      received at least one instillation of study drug and 101 patients completed
      treatment. All but one patient had cancer. RESULTS: All three concentrations of r
      UK were significantly superior to placebo in restoring total CVAD function
      (patency of all occluded lumens) after one or two instillations of study
      medication (25,000 IU/mL r-UK, 68% vs. placebo, 28% [P =.007]; 15,000 IU/mL r-UK,
      69% vs. placebo, 24% [P =.004]; 5,000 IU/mL r-UK, 70% vs. placebo, 28% [P
      =.003]). Comparisons of the three r-UK concentrations indicated no difference
      after one or two instillations with regards to patency restoration. Treatment
      emergent hemorrhagic events occurring within 72 hours after study drug exposure
      were experienced by four patients (17%) in the 25,000 IU/mL r-UK group, two
      patients (7%) in the 15,000 IU/mL r-UK group, no patients in the 5,000 IU/mL r-UK
      group, and no patients in the placebo group. CONCLUSIONS: Efficacy and safety
      results of this study support further evaluation of a 5,000 IU/mL concentration
      of r-UK for treatment of occluded CVADs in adult and pediatric patients from 1
      year of age.

PMID- 15178718
TI  - Relationship between chest port catheter tip position and port malfunction after
      interventional radiologic placement.
AB  - PURPOSE: The relationship between catheter tip position of implanted subcutaneous
      chest ports and subsequent port malfunction was investigated. Tip movement from
      initial supine position to subsequent erect position was also evaluated.
      MATERIALS AND METHODS: Patients who underwent imaging-guided internal jugular
      chest port placement between July 2001 and May 2003 were identified with use of a
      quality-assurance database. Sixty-two patients were included in the study (22 men
      and 40 women), with a mean age of 58 years (range, 27-81 years). Catheter tip
      location on the intraprocedural chest radiograph was determined with use of two
      methods. First, the distance from the right tracheobronchial angle (TBA) was
      recorded (TBA distance). Second, tip location was classified into six anatomic
      regions: 1, internal jugular veins; 2, brachiocephalic veins; 3, superior vena
      cava (SVC; n = 11); 4, SVC/right atrial junction (n = 22); 5, upper half of right
      atrium (n = 25); and 6, lower half of right atrium (n = 4). For the duration of
      follow-up, catheter tip location was documented, as were all episodes of catheter
      malfunction. RESULTS: Patients with catheter tips initially placed in position 3
      had a higher risk of port malfunction (four of 11; 36%) than patients with
      catheter tips located in position 5 (two of 25; 8%). This difference narrowly
      fell short of statistical significance (P =.057). When comparing intraprocedural
      chest radiographs to the first erect chest radiographs, significant upward tip
      movement was noted. The tips migrated cephalad an average of 20 mm (P =.003) and
      1.0 position units (P =.001). DISCUSSION: Catheter tips placed in the SVC tended
      to have a greater risk of port malfunction compared with those positioned in the
      right atrium. Chest ports migrated cephalad between the supine and erect
      positions.

PMID- 15178719
TI  - Correlation of intragraft blood flow with characteristics of stenoses found
      during diagnostic fistulography.
AB  - PURPOSE: To determine if intragraft blood flow measurements correlate with the
      anatomical characteristics of stenoses found during diagnostic fistulography.
      MATERIALS AND METHODS: This investigation was a retrospective review of 40
      patients with decreased intragraft blood flow (<600 mL/min) in patent
      polytetrafluoroethylene hemodialysis grafts who underwent diagnostic
      fistulography and angioplasty. Intragraft blood flow was measured with the
      ultrasonic dilution technique. The fistulogram images were reviewed and the
      anatomic characteristics of all stenoses were measured and recorded. These
      characteristics were correlated with the intragraft blood flow values. RESULTS:
      The mean intragraft blood flow was 476 mL/min (range, 270-600 mL/min).
      Fistulography revealed a total of 71 stenoses and all 40 patients had at least
      one lesion with > 50% stenosis. There was no correlation between the intragraft
      blood flow and the location, length, or number of stenoses. There was a moderate
      inverse correlation between the intragraft blood flow and the degree of stenosis
      (P =.08). Fifty-nine stenoses were treated with angioplasty. The mean
      postangioplasty blood flow was 796 mL/min (range, 470-1565 mL/min). The mean
      change in blood flow after angioplasty was 311 mL/min (range, 15-1154 mL/min)
      There was no association between the change in blood flow after angioplasty and
      the number, length, or degree of residual stenosis. CONCLUSION: Intragraft blood
      flow < 600 mL/min is an excellent predictor of the presence of at least one
      significant (>/=50%) stenosis. There was an inverse correlation between
      intragraft blood flow and the degree of stenosis. There was no association
      between the intragraft blood flow and the location, length, or number of
      stenosis.

PMID- 15178720
TI  - Percutaneous sclerotherapy of lymphangiomas with acetic acid.
AB  - PURPOSE: To evaluate the efficacy of percutaneous image-guided sclerotherapy of
      lymphangiomas with use of acetic acid. MATERIALS AND METHODS: Twelve patients
      with lymphangiomas were treated with acetic acid as the sclerosant. There were
      eight male patients and four female patients, ranging in age from 1 to 29 years
      (mean, 11 years). The lymphangiomas were located at the neck (n = 5), upper
      extremity (n = 3), axilla (n = 1), cervicomediastinum (n = 1), anterior chest
      wall (n = 1), and retroperitoneum (n = 1). Two patients had recurrent
      lymphangiomas after surgery and two patients had undergone failed sclerotherapy
      with another sclerosant. The acetic acid used as the sclerosant was 40%-50% in
      concentration, and the amounts used ranged from 2 mL to 70 mL (mean, 11.3 mL),
      which was equivalent to 4.6%-50% (mean, 30.6%) of the aspirated lymphatics. All
      procedures were performed under ultrasonographic and fluoroscopic guidance. The
      sclerosant was removed after sclerotherapy. All patients except one underwent one
      treatment session. RESULTS: Complete resolution of the lymphangioma was achieved
      in eight patients (66.7%), good resolution (>50% reduction) was achieved in three
      (25.0%), and poor resolution (<50% reduction) was seen in one (8.3%).
      Complications encountered included pneumonitis adjacent to the lymphangioma (n =
      1), pain (n = 2), hematuria (n = 1), and tingling sensation in the forearm (n =
      1). CONCLUSION: Percutaneous sclerotherapy of the lymphangiomas with use of
      acetic acid is an effective method without serious complications.

PMID- 15178721
TI  - Stent-based controlled release of intravascular angiostatin to limit plaque
      progression and in-stent restenosis.
AB  - PURPOSE: To evaluate the importance of angiogenesis in plaque progression after
      stent placement, this study examines stent-based controlled delivery of the
      antiangiogenic agent, angiostatin, in a rabbit model. MATERIALS AND METHODS:
      Controlled release biodegradable microspheres delivering angiostatin or polymer
      only microspheres (polylactic-co-glycolic-acid-polyethylene glycol; PLGA/PEG)
      were loaded in channeled stents, anchored, and deployed in the aorta of adult New
      Zealand white rabbits (n = 6 animals per group, three each per time point). The
      stented aortas were harvested at 7 days and 28 days and evaluated for
      neovascularization, local inflammation, vascular smooth muscle cell
      proliferation, and in-stent plaque progression. RESULTS: At 7 days,
      neovascularization was significantly decreased in the angiostatin groups (1.6 +/-
      1.6 neovessels per mm(2) plaque) versus the control group (15.4 +/- 2.6
      neovessels per mm(2) plaque; P =.00081), as were local inflammation where
      angiostatin-treated groups demonstrated significantly lower macrophage
      recruitment per cross section (34.9 +/- 4.9 cells per cross section) relative to
      the control group (55.2 +/- 3.84 cells per cross section; P =.0037). And a
      significant decrease in the overall vascular smooth muscle cell proliferation
      (143.8 +/- 26.3 Ki-67 positive cells per mm(2)) relative to the control group
      (263.2 +/- 16.6 Ki-67 positive cells per mm(2); P =.00074). At both 7 and 28
      days, in-stent plaque progression in the angiostatin groups was successfully
      limited relative to the control group by 54% (0.255 +/- 0.019% of cross section;
      P =.00016) and 19% (1.981 +/- 0.080; P =.0033) respectively and resulted in
      reduction of in-stent restenosis relative to the control group. CONCLUSION:
      Angiostatin-eluting stents may limit neovascularity after arterial implantation,
      offer insight into in-stent restenosis, and allow future refinement of bioactive
      stent designs and clinical strategies, particularly in light of evidence that
      intimal smooth muscle cells may in part be marrow-derived.

PMID- 15178722
TI  - Fallopian tube occlusion with use of a small intestine submucosa device:
      evaluation in a rabbit model.
AB  - PURPOSE: The present study evaluates the short- and midterm efficacy of a small
      intestinal submucosa (SIS) device for fallopian tube occlusion in rabbits.
      MATERIALS AND METHODS: In a pilot study, several SIS device designs were tested
      for positional stability (absence of migration). The design selected for further
      testing consisted of a center of spongy SIS surrounded by an SIS sheet and held
      together by a 0.006-inch wire helix with two barbs. It was delivered on the tip
      of a short coaxial 3-F/5-F catheter set. Using this design, bilateral
      transuterine fallopian tube occlusion was performed in eight New Zealand White
      rabbits. Follow-up consisted of plain radiography at 2 weeks and
      hysterosalpingography at 6 weeks (n = 4 animals; eight tubes), 12 weeks (n = 2
      animals; four tubes), or 24 weeks (n = 2 animals; four tubes). Thereafter, the
      animals were killed and the fallopian tubes were harvested for histologic
      evaluation. RESULTS: A single device was placed successfully in each fallopian
      tube. Fifteen of 16 devices (94%) remained in place throughout follow-up. One
      device migrated into the vagina at 2-week follow-up. Hysterosalpingography of the
      15 tubes with occluders in place showed occlusion in seven of seven (100%) at 6
      weeks, three of four (75%) at 12 weeks, and two of four (50%) at 24 weeks.
      Histologic evaluation revealed luminal occlusion by reorganized SIS containing
      macrophages, fibrocytes, and scant foreign-body giant cells. Only a mild
      inflammatory reaction was observed around the tube. In the animals with
      recanalization at 12 and 24 weeks, new channels were found alongside the original
      still-occluded fallopian tube lumen. CONCLUSIONS: The original lumen of the
      fallopian tube was effectively occluded by the SIS occluder, which was remodeled
      within the fallopian tubes of rabbits. Partial peripheral recanalization was
      observed over time.

PMID- 15178723
TI  - CT and MR imaging of nitinol stents with radiopaque distal markers.
AB  - PURPOSE: To evaluate imaging characteristics and artifacts of a nitinol stent
      with distal tantalum markers with computed tomography (CT) angiography and
      magnetic resonance (MR) angiography. MATERIALS AND METHODS: A vascular phantom
      was built to simulate in-stent restenosis. A nitinol stent with tantalum markers
      (Luminexx stent) was evaluated with CT angiography in different orientations
      relative to the z-axis and with MR angiography in different positions relative to
      both B0 and the readout gradient. Stenosis measurements were compared with
      conventional digital subtraction angiography for both modalities. In-stent signal
      intensity obtained with different flip angles was assessed in two nitinol stents
      with distal markers (Luminexx stent and SMART stent) and one without markers
      (Memotherm-FLEXX stent). RESULTS: Stenosis detection was not possible with CT
      angiography when the stent was perpendicular to the z-axis because of streak-like
      artifacts induced by tantalum markers. Stenosis evaluation with multiplanar
      reformation was accurate when the stent was in parallel and oblique orientations
      relative to the table axis. With MR angiography, metallic artifacts were mostly
      related to the stent orientation with B0, whereas orientation of the readout
      gradient had little influence. The mean error (overestimation) for stenosis
      measurements varied between 0.1% and 7.4% for CT imaging in parallel and oblique
      positions and 3.6% and 9.5% for MR imaging. Higher flip angles did not improve
      signal intensity inside the three stents tested. CONCLUSION: CT and MR
      angiography can be used for evaluating the patency of stents with distal markers
      that are parallel or oblique relative to the table axis (iliac, carotid, or
      femoral stents). MR angiography is preferred if the stent is perpendicular to the
      table axis (renal stent).

PMID- 15178724
TI  - Arteriovenous fistula after endovenous laser treatment of the short saphenous
      vein.
AB  - Reports of major complications from endovenous laser treatment of saphenous veins
      with use of perivenous tumescent anesthesia are very rare. The author reports a
      major complication of endovenous laser treatment, the creation of an
      arteriovenous (AV) fistula. The fistula was created between the short saphenous
      vein (SSV) and the superficial sural artery in the popliteal fossa during
      endovenous laser treatment of the SSV. The proximity of the superficial sural
      artery and the SSV in the popliteal fossa increases the risk of fistula
      formation. Color-flow Doppler ultrasonography can demonstrate potentially
      dangerous anatomic relationships between the vein segment intended for treatment
      and adjacent arteries. Recognition of these relationships should increase the
      operator's ability to minimize the risk of AV fistula formation.

PMID- 15178725
TI  - Atrial septal perforation from TIPS stent migration.
AB  - Transjugular intrahepatic portosystemic shunts (TIPS) are safe and effective for
      the treatment of portal hypertension. Cardiac complications are unusual. This
      study reports a case of TIPS stent migration to the right atrium causing
      perforation of the atrial septum in a patient with end-stage liver disease. The
      shunt was removed transvenously but attempts at transvenous occlusion of the
      septal perforation were unsuccessful. The patient went on to undergo combined
      open-heart surgery with septum repair and liver transplantation. The case
      highlights a rare complication of TIPS and methods for treatment including
      transvenous removal, transvenous repair, and combined cardiotomy-liver
      transplantation surgery.

PMID- 15178726
TI  - Interventional radiologic treatment for hepatic arterial occlusion after repeated
      hepatic arterial infusion chemotherapy via implanted port-catheter system.
AB  - The present study evaluated the feasibility of interventional radiologic
      treatments for hepatic arterial occlusion after hepatic arterial infusion
      chemotherapy (HAIC) via an implanted port-catheter system. Treatment for hepatic
      arterial occlusion was attempted in seven patients with unresectable liver
      cancer. In six, the obstructed hepatic artery was recanalized. In three patients,
      the recanalized hepatic artery again became obstructed. However, by performing
      additional interventional radiologic procedures, secondary patency of the hepatic
      artery was successfully obtained in two patients. In conclusion, when hepatic
      arterial occlusion occurs, HAIC can be resumed in the attempt to recanalize the
      hepatic artery.

PMID- 15178727
TI  - Turn-back technique with use of a shaped microcatheter for superselective
      catheterization of arteries originating at acute angles.
AB  - The authors have developed a novel "turn-back" technique with use of a shaped
      microcatheter for superselective catheterization of arteries originating at acute
      angles. Herein this technique is described in clinical use for superselective
      catheterization of several arteries including the middle hepatic artery, right
      gastric artery, right inferior phrenic artery, and tracheal artery in six
      patients after failed catheterization by conventional techniques as a result of
      difficult geometry of the arteries. Superselective catheterization and
      intervention were successfully performed without complication in all cases. This
      turn-back technique is useful for superselective catheterization of arteries
      originating at acute angles.

PMID- 15178728
TI  - Difficult retrieval of a recovery IVC filter.

PMID- 15178729
TI  - Hepatopulmonary syndrome successfully treated with transjugular intrahepatic
      portosystemic shunt: a three-year follow-up.

PMID- 15178730
TI  - Artery of the cervical enlargement originating from the inferior thyroid artery:
      an angiographic observation.

PMID- 15178731
TI  - Comment: therapy switching in patients receiving long-acting opioids.

PMID- 15178733
TI  - Cholesterol: point-of-care testing.
AB  - OBJECTIVE: To review the literature regarding point-of-care (POC) cholesterol
      monitors and describe their role in pharmacy practice. DATA SOURCES: Primary
      articles were identified by a MEDLINE search (1966-May 2003); references cited in
      these articles provided additional resources. STUDY SELECTION AND DATA
      EXTRACTION: All of the articles identified from this search were reviewed, and
      all information deemed relevant was included. DATA SYNTHESIS: Hyperlipidemia is a
      well-established risk factor for coronary artery disease, which is the leading
      cause of death in the US. The use of POC cholesterol monitors may help to improve
      the identification and management of this disease. Pharmacists may use many of
      these devices in their practice and are also in an ideal position to provide
      patient education on selection and use of these monitors and interpretation of
      the results. CONCLUSIONS: The availability of POC cholesterol monitors has
      increased in recent years. Based on currently available data, these monitors are
      best suited for screening purposes and to assist in the management of
      hyperlipidemia. There is not enough evidence to support the notion that POC
      cholesterol monitors can replace laboratory or office monitoring. Their
      application in the diagnosis of hyperlipidemia is also currently limited.

PMID- 15178734
TI  - Preliminary experience with formoterol for the treatment of stuttering.

PMID- 15178735
TI  - Using a computerized drug prescription screening system to trace drug
      interactions in an outpatient setting.
AB  - BACKGROUND: Drug-drug interactions are one of the main causes of adverse effects.
      These events have been studied most often in hospital settings; however,
      investigations on prescribing based on community practice have shown a high
      prevalence rate of potential drug interactions. OBJECTIVE: To develop a
      computerized system able to trace drug interactions quickly through the
      identification of clinicians issuing potentially unsafe prescriptions. METHODS:
      We retrospectively evaluated hazardous concomitant prescriptions of
      hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and azole
      antifungals, which were invoiced through 9 months of 2001 within an outpatient
      setting. The study was conducted in Badajoz, a southern Spanish province, and was
      divided in three 3-month periods according to the release of 2 warning notes on
      this drug combination by the Spanish Drug Agency. Prescriptions written during
      this period were optically scanned each month, and the resulting information,
      including data from patients, physicians, and drugs involved, was converted to a
      database and searched for potentially unsafe coprescriptions. RESULTS: A total of
      8342711 prescriptions were invoiced in the period of study, 174 of which were for
      a statin-azole combination. The number of these prescriptions remained fairly
      constant during periods I and II (63 and 71, respectively), decreasing to 40 in
      period III. Some clinicians (12.6%) repeatedly prescribed a hazardous drug
      combination at some point in this study, whereas 18 of 171 patients who received
      the hazardous coprescription at any time did so repeatedly within a given period.
      The impact of drug alerts was remarkably deeper in urban rather than rural care
      centers. CONCLUSIONS: The computerized drug prescription handling system
      described here is able to readily identify physicians and patients who
      issue/consume hazardous drug combinations, thus allowing both the possibility of
      individually informing the healthcare professionals involved and early detection
      of adverse effects.

PMID- 15178737
TI  - Lyme disease--US, 2001-2002.

PMID- 15178736
TI  - Amantadine in the akinetic-rigid variant of Huntington's disease.
AB  - OBJECTIVE: To report the effects of amantadine on an akinetic-rigid variant of
      Huntington's disease (HD). CASE SUMMARY: We describe a 36-year-old woman with HD
      who was treated with intravenous amantadine for 5 days. The woman was evaluated
      with the Unified Huntington's Disease Rating Scale before and after treatment.
      Parkinsonism, bradykinesia, and dystonia improved significantly. DISCUSSION:
      Amantadine is a noncompetitive N-methyl d-aspartate receptor antagonist. It is
      mainly used in the treatment of Parkinson's disease, as it increases dopamine
      levels in the brain. This effect is said to ameliorate akinesia. Although the
      effect of amantadine on choreatic dystonia in HD has been reported in several
      studies, to the best of our knowledge, this is the first report of the
      ameliorative effects of amantadine on the rigid form of HD. Our patient showed
      improvements of gait, parkinsonism, and dystonia. Fine-motor tasks and eye
      movement did not change significantly. CONCLUSIONS: We suggest that amantadine
      treatment might be of value to patients with the akinetic-rigid variant of HD.

PMID- 15178740
TI  - Effects of continuous vasopressin infusion in patients with septic shock.
AB  - BACKGROUND: Small studies have reported that vasopressin improves hemodynamic
      instability in patients with septic shock. OBJECTIVE: To determine whether
      vasopressin infusion increases blood pressure, decreases catecholamine
      vasopressor use, and improves renal function in a large patient population with
      septic shock when used in a clinical setting. METHODS: A retrospective chart
      audit was conducted of critically ill patients who received vasopressin infusion
      for septic shock from January 2000 through September 2002. Demographic,
      hemodynamic, laboratory, vasopressor, and adverse event data were collected.
      Statistical methods included ANOVA with Tukey's test for post hoc analysis.
      RESULTS: A total of 102 of 353 patients met study criteria. The mean +/- SD
      vasopressin dosage regimen was 0.11 +/- 0.17 units/min for 53.8 +/- 71.5 hours.
      Compared with baseline, vasopressin infusion improved mean arterial pressure
      (MAP) by 15% within one hour (p < 0.05), reduced heart rate by 9% within 4 hours
      (p < 0.05), and reduced hourly dopamine dosage by 25% within 8 hours (p < 0.05).
      These effects persisted through 96 hours. Other hemodynamic variables and
      catecholamine vasopressor usage parameters were not statistically different from
      baseline. Urine output, serum creatinine, and serum sodium concentrations were
      not statistically changed from baseline. Adverse events possibly associated with
      vasopressin infusion included ischemic digits/extremities, myocardial infarction,
      and hyponatremia. CONCLUSIONS: Vasopressin infusion was effective in increasing
      MAP and reducing heart rate while decreasing the dopamine dosage in patients with
      septic shock. Comparative studies with catecholamine vasopressors are needed to
      define the optimal role of vasopressin in septic shock therapy. In the meantime,
      vasopressin infusion at <or=0.03 units/min should be considered only if response
      to 1 or 2 catecholamine vasopressors is inadequate or as a method to reduce the
      dose of these therapies.

PMID- 15178741
TI  - How do site-specific DNA-binding proteins find their targets?
AB  - Essentially all the biological functions of DNA depend on site-specific DNA
      binding proteins finding their targets, and therefore 'searching' through
      megabases of non-target DNA. In this article, we review current understanding of
      how this sequence searching is done. We review how simple diffusion through
      solution may be unable to account for the rapid rates of association observed in
      experiments on some model systems, primarily the Lac repressor. We then present a
      simplified version of the 'facilitated diffusion' model of Berg, Winter and von
      Hippel, showing how non-specific DNA-protein interactions may account for
      accelerated targeting, by permitting the protein to sample many binding sites per
      DNA encounter. We discuss the 1-dimensional 'sliding' motion of protein along non
      specific DNA, often proposed to be the mechanism of this multiple site sampling,
      and we discuss the role of short-range diffusive 'hopping' motions. We then
      derive the optimal range of sliding for a few physical situations, including
      simple models of chromosomes in vivo, showing that a sliding range of
      approximately 100 bp before dissociation optimizes targeting in vivo. Going
      beyond first-order binding kinetics, we discuss how processivity, the interaction
      of a protein with two or more targets on the same DNA, can reveal the extent of
      sliding and we review recent experiments studying processivity using the
      restriction enzyme EcoRV. Finally, we discuss how single molecule techniques
      might be used to study the dynamics of DNA site-specific targeting of proteins.

PMID- 15178742
TI  - Accelerated mammary gland development during pregnancy and delayed
      postlactational involution in vitamin D3 receptor null mice.
AB  - The vitamin D receptor (VDR) is present in mammary gland, and VDR ablation is
      associated with accelerated glandular development during puberty. VDR is a
      nuclear receptor whose ligand, 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] is
      generated after metabolic activation of vitamin D by specific vitamin D
      hydroxylases. In these studies, we demonstrate that both the VDR and the vitamin
      D 1-alpha hydroxylase (CYP27B1), which produces 1,25-(OH)(2)D are present in
      mammary gland and dynamically regulated during pregnancy, lactation, and
      involution. Furthermore, we show that mice lacking VDR exhibit accelerated
      lobuloalveolar development and premature casein expression during pregnancy and
      delayed postlactational involution compared with mice with functional VDR. The
      delay in mammary gland regression after weaning of VDR knockout mice is
      associated with impaired apoptosis as demonstrated by reductions in terminal
      deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining,
      caspase-3 activation and Bax induction. Under the conditions used in this study,
      VDR ablation was not associated with hypocalcemia, suggesting that altered
      mammary gland development in the absence of the VDR is not related to
      disturbances in calcium homeostasis. Furthermore, in the setting of
      normocalcemia, VDR ablation does not affect milk protein or calcium content.
      These studies suggest that the VDR contributes to mammary cell turnover during
      the reproductive cycle, and its effects may be mediated via both endocrine and
      autocrine signaling pathways. Unlike many mammary regulatory factors that exert
      transient, stage-specific effects, VDR signaling impacts on mammary gland biology
      during all phases of the reproductive cycle.

PMID- 15178743
TI  - Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor.
AB  - Among nuclear receptors, the androgen receptor (AR) is unique in that its ligand
      binding domain (LBD) interacts with the FXXLF motif in the N-terminal domain,
      resembling coactivator LXXLL motifs. We compared AR- and estrogen receptor alpha
      LBD interactions of the wild-type AR FXXLF motif and coactivator transcriptional
      intermediary factor 2 LXXLL motifs and variants of these motifs. Random
      mutagenesis revealed a key role for the F residues in FXXLF motifs in high
      affinity and selective AR LBD interaction. The FXXLF motif in full-length AR and
      transcriptional intermediary factor 2 LXXLL motifs competed for an overlapping
      binding site. A computer model of the AR LBD/AR FXXLF complex showed that the
      bulky F residues are buried in a deep coactivator-binding groove. The
      corresponding groove in estrogen receptor alpha LBD is considerably shallower,
      explaining lack of binding of any of the FXXLF motifs tested. FXXLF and LXXLL
      motif interaction depended on different charged amino acid residues in the AR LBD
      present at opposite ends of the coactivator groove. In conclusion, our data
      demonstrate the importance of a deep hydrophobic groove and alternative usage of
      charged amino acids in specifying peptide binding to the AR LBD.

PMID- 15178744
TI  - The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor
      for lactoferrin in osteoblastic cells.
AB  - Lactoferrin induces osteoblast proliferation and survival in vitro and is
      anabolic to bone in vivo. The molecular mechanisms by which lactoferrin exerts
      these biological actions are not known, but lactoferrin is known to bind to two
      members of the low-density lipoprotein receptor family, low- density lipoprotein
      receptor-related proteins 1 (LRP1) and 2 (LRP2). We have examined the role(s) of
      these receptors in the actions of lactoferrin on osteoblasts. We show that
      lactoferrin binds to cultured osteoblastic cells, and that LRP1 and LRP2 are
      expressed in several osteoblastic cell types. In primary rat osteoblastic cells,
      the LRP1/2 inhibitor receptor associated protein blocks endocytosis of
      lactoferrin and abrogates lactoferrin-induced p42/44 MAPK signaling and
      mitogenesis. Lactoferrin-induced mitogenesis is also inhibited by an antibody to
      LRP1. Lactoferrin also induces receptor associated protein-sensitive activation
      of p42/44 MAPK signaling and proliferation in osteoblastic human SaOS-2 cells,
      which express LRP1 but not LRP2. The mitogenic response of LRP1-null fibroblastic
      cells to lactoferrin is substantially reduced compared with that of cells
      expressing wild-type LRP1. The endocytic and signaling functions of LRP1 are
      independent of each other, because lactoferrin can activate mitogenic signaling
      in conditions in which endocytosis is inhibited. Taken together, these results 1)
      suggest that mitogenic signaling through LRP1 to p42/44 MAPKs contributes to the
      anabolic skeletal actions of lactoferrin; 2) demonstrate growth-promoting actions
      of a third LRP family member in osteoblasts; and 3) provide further evidence that
      LRP1 functions as a signaling receptor in addition to its recognized role in
      ligand endocytosis.

PMID- 15178745
TI  - The mitogenic and antiapoptotic actions of ghrelin in 3T3-L1 adipocytes.
AB  - Ghrelin, a stomach-derived hormone, induces adiposity when administered to
      rodents. Because ghrelin receptor is abundantly expressed in adipose tissue, we
      investigated the role of ghrelin in adipocyte biology. We observed ghrelin
      receptor expression in 3T3-L1 preadipocytes and adipocytes. Treatment of
      preadipocytes with ghrelin induced cellular proliferation and differentiation to
      mature adipocytes, as well as basal and insulin-stimulated glucose transport, but
      it inhibited adipocyte apoptosis induced by serum deprivation. Exposure of 3T3-L1
      cells to ghrelin caused a rapid activation of MAPKs, especially ERK1/2. Chemical
      inhibition of MAPK blocked the mitogenic and antiapoptotic effects of ghrelin.
      Ghrelin also stimulated the insulin receptor substrate-associated
      phosphatidylinositol 3-kinase/Akt pathway in 3T3-L1 preadipocytes and adipocytes,
      whereas inhibition of this pathway blocked the effects of ghrelin on cell
      proliferation, antiapoptosis and glucose uptake. These findings suggest that the
      direct effects of ghrelin on proliferation, differentiation, and apoptosis in
      adipocytes may play a role in regulating fat cell number. These effects may be
      mediated via activation of the MAPK and phosphatidylinositol 3-kinase/Akt
      pathways.

PMID- 15178746
TI  - Hormonal defect in maspin heterozygous mice reveals a role of progesterone in
      pubertal ductal development.
AB  - Progesterone and PR are mainly thought to affect tertiary ductal side branching
      and alveologenesis in late stage of mammary gland development. Here, we present
      evidence that they also play a role in early ductal development. This conclusion
      derived from our analysis of maspin heterozygous (Mp+/-) mice that showed
      defective ductal development at puberty. The defect was due to a reduced systemic
      level of progesterone. We show that treatment of Mp+/- mice with progesterone
      rescued the defect of ductal development. When both wild-type and Mp+/- mice were
      ovariectomized at 4 wk of age, treatment with progesterone alone can stimulate
      their ductal growth. In addition, treatment of wild-type mice with the
      progesterone inhibitor RU486 slowed ductal development in a dose-dependent
      manner. To confirm that progesterone receptor (PR) was required for progesterone
      action in ductal development at pubertal stage, we treated ovariectomized PR
      deficient (PRKO) and wild-type mice with progesterone and examined ductal
      development at 7 wk of age. Whereas wild-type mammary glands displayed abundant
      ductal growth after progesterone treatment, there was a significant retardation
      of ductal growth in PRKO mice. Furthermore, we observed reduced ductal
      development in intact PRKO mice at 7 wk of age compared with that of wild-type
      mice. However, the defect was rescued at late stage of mammary development in
      PRKO mice. These data demonstrate that progesterone signaling, which is mediated
      by PR, plays an important role in early ductal development. In PRKO mice, a
      compensatory mechanism occurs that rescues the ductal defect at a late stage of
      mammary development.

PMID- 15178747
TI  - Identification of genes regulated by leukemia-inhibitory factor in the mouse
      uterus at the time of implantation.
AB  - The endometrium is prepared for implantation by the actions of estradiol (E2) and
      progesterone (P4). In mice the luminal epithelium (LE) only becomes fully
      receptive to the attaching blastocyst in response to the nidatory estrogen surge
      on d 4 of pregnancy. The cytokine leukemia-inhibitory factor (LIF) is rapidly
      induced by nidatory estrogen and has been shown to be the primary mediator of its
      action. Implantation fails in the absence of LIF, and injection of LIF on d 4 of
      pregnancy can substitute for the nidatory estrogen. In this study, we sought to
      identify genes regulated by LIF in the uterine epithelium. We used
      oligonucleotide microarrays to compare the transcript profiles of paired uterine
      horns from LIF-deficient MF1 mice after intraluminal injection of LIF or PBS on d
      4 of pseudopregnancy. IGF-binding protein 3 was identified as a gene up-regulated
      by LIF; this was confirmed by RT-PCR. In situ hybridization showed that the
      primary site of IGF-binding protein 3 expression is the luminal epithelium (LE),
      the known site of LIF action in the uterus. We identified two other genes:
      amphiregulin and immune response gene-1, the expression of which were also up
      regulated by LIF. Immune response gene 1 has recently been shown to be essential
      for implantation. Expression of all three of these genes in the LE is known to be
      regulated by P4. The expression of osteoblast-specific factor 2 and leukocyte
      12/15 lipoxygenase, which are also expressed in LE under the control of P4, were
      not increased by LIF. This suggests that one of the actions of LIF on LE may be
      to enhance the expression of a subset of P4-regulated genes.

PMID- 15178749
TI  - Postnatal refinement of peripheral olfactory projections.
AB  - Axonal projections from the olfactory epithelium to the olfactory bulb are
      organized into glomeruli according to the expressed odorant receptor. Using gene
      targeted mice, we show that glomerular maturation proceeds along different time
      courses for two similar receptors and requires sensory input during distinct
      sensitive periods. During early development, some glomeruli are innervated by
      axons of neurons that do not express the same receptor. These heterogeneous
      glomeruli normally disappear with age, but they persist in adults deprived of
      sensory input by unilateral and permanent naris closure. Persistence may be due,
      in part, to prolonged survival of olfactory sensory neurons.

PMID- 15178748
TI  - Paramutation: the chromatin connection.

PMID- 15178750
TI  - Control of light emission by 3D photonic crystals.
AB  - Three-dimensional (3D) photonic crystals containing artificial point defects have
      been fabricated to emit light at optical communications wavelengths. They were
      constructed by stacking 0.7-micrometer-period gallium arsenide striped layers,
      resulting in a 3D "woodpile" photonic crystal. Indium-gallium arsenide-phosphide
      quantum-well layers emitting at a wavelength of 1.55 micrometers were
      incorporated in the center of the crystal. Samples having up to nine stacked
      layers were constructed, and artificial point-defect cavities of different sizes
      were formed in the light-emitting layer. Light emission was suppressed in the
      photonic crystal regions, whereas cavity modes were successfully observed at the
      point defects and were size dependent.

PMID- 15178751
TI  - The bacterial condensin MukBEF compacts DNA into a repetitive, stable structure.
AB  - Condensins are conserved proteins containing SMC (structural maintenance of
      chromosomes) moieties that organize and compact chromosomes in an unknown
      mechanism essential for faithful chromosome partitioning. We show that MukBEF,
      the condensin in Escherichia coli, cooperatively compacts a single DNA molecule
      into a filament with an ordered, repetitive structure in an adenosine
      triphosphate (ATP) binding-dependent manner. When stretched to a tension of
      approximately 17 piconewtons, the filament extended in a series of repetitive
      transitions in a broad distribution centered on 45 nanometers. A filament so
      extended and held at a lower force recondensed in steps of 35 nanometers or its
      multiples; this cycle was repeatable even in the absence of ATP and free MukBEF.
      Remarkably, the pattern of transitions displayed by a given filament during the
      initial extension was identical in every subsequent extension. Hence, after being
      deformed micrometers in length, each filament returned to its original compact
      structure without the addition of energy. Incubation with topoisomerase I
      increased the rate of recondensation and allowed the structure to extend and
      reform almost reversibly, indicating that supercoiled DNA is trapped in the
      condensed structure. We suggest a new model for how MukBEF organizes the
      bacterial chromosome in vivo.

PMID- 15178752
TI  - Small bilaterian fossils from 40 to 55 million years before the cambrian.
AB  - Ten phosphatized specimens of a small (<180 micrometers) animal displaying clear
      bilaterian features have been recovered from the Doushantuo Formation, China,
      dating from 40 to 55 million years before the Cambrian. Seen in sections, this
      animal (Vernanimalcula guizhouena gen. et sp. nov.) had paired coeloms extending
      the length of the gut; paired external pits that could be sense organs;
      bilateral, anterior-posterior organization; a ventrally directed anterior mouth
      with thick walled pharynx; and a triploblastic structure. The structural
      complexity is that of an adult rather than a larval form. These fossils provide
      the first evidence confirming the phylogenetic inference that Bilateria arose
      well before the Cambrian.

PMID- 15178753
TI  - Random sequencing of an induced Taxus cell cDNA library for identification of
      clones involved in Taxol biosynthesis.
AB  - Biosynthesis of the anticancer drug Taxol involves 19 enzymatic steps from the
      universal diterpenoid progenitor geranylgeranyl diphosphate derived by the
      plastidial methylerythritol phosphate pathway for isoprenoid precursor supply. To
      gain further insight about Taxol biosynthesis relevant to the improved production
      of this drug and to draw inferences about the organization, regulation, and
      origins of this complex natural product pathway, random sequencing of a cDNA
      library derived from Taxus cuspidata cells (induced for taxoid biosynthesis with
      methyl jasmonate) was undertaken. This effort revealed surprisingly high
      abundances for transcripts of several of the 12 defined genes of Taxol
      biosynthesis, yielded cDNAs encoding two previously uncharacterized cytochrome
      P450 taxoid hydroxylases, and provided candidate genes for all but one of the
      remaining seven steps of this extended sequence of reactions.

PMID- 15178754
TI  - T cell receptor-ligand interactions: a conformational preequilibrium or an
      induced fit.
AB  - Kinetic parameters of T cell receptor (TCR) interactions with its ligand have
      been proposed to control T cell activation. Analysis of kinetic data obtained has
      so far produced conflicting insights; here, we offer a consideration of this
      problem. As a model system, association and dissociation of a soluble TCR (sT1)
      and its specific ligand, an azidobenzoic acid derivative of the peptide SYIPSAEK
      (ABA)I (residues 252-260 from Plasmodium berghei circumsporozoite protein), bound
      to class I MHC H-2K(d)-encoded molecule (MHCp) were studied by surface plasmon
      resonance. The association time courses exhibited biphasic patterns. The fast and
      dominant phase was assigned to ligand association with the major fraction of TCR
      molecules, whereas the slow component was attributed to the presence of traces of
      TCR dimers. The association rate constant derived for the fast phase, assuming a
      reversible, single-step reaction mechanism, was relatively slow and markedly
      temperature-dependent, decreasing from 7.0 x 10(3) at 25 degrees C to 1.8 x 10(2)
      M(-1).s(-1) at 4 degrees C. Hence, it is suggested that these observed slow rate
      constants are the result of unresolved elementary steps of the process. Indeed,
      our analysis of the kinetic data shows that the time courses of TCR-MHCp
      interaction fit well to two different, yet closely related mechanisms, where an
      induced fit or a preequilibrium of two unbound TCR conformers are operational.
      These mechanisms may provide a rationale for the reported conformational
      flexibility of the TCR and its unusual ligand recognition properties, which
      combine high specificity with considerable crossreactivity.

PMID- 15178755
TI  - Rapid and sequential movement of individual chromosomal loci to specific
      subcellular locations during bacterial DNA replication.
AB  - The chromosomal origin and terminus of replication are precisely localized in
      bacterial cells. We examined the cellular position of 112 individual loci that
      are dispersed over the circular Caulobacter crescentus chromosome and found that
      in living cells each locus has a specific subcellular address and that these loci
      are arrayed in linear order along the long axis of the cell. Time-lapse
      microscopy of the location of the chromosomal origin and 10 selected loci in the
      origin-proximal half of the chromosome showed that during DNA replication, as the
      replisome sequentially copies each locus, the newly replicated DNA segments are
      moved in chronological order to their final subcellular destination in the
      nascent half of the predivisional cell. Thus, the remarkable organization of the
      chromosome is being established while DNA replication is still in progress. The
      fact that the movement of these 10 loci is, like that of the origin, directed and
      rapid, and occurs at a similar rate, suggests that the same molecular machinery
      serves to partition and place many, if not most, chromosomal loci at defined
      subcellular sites.

PMID- 15178756
TI  - The topoisomerase IV ParC subunit colocalizes with the Caulobacter replisome and
      is required for polar localization of replication origins.
AB  - The process of bacterial DNA replication generates chromosomal topological
      constraints that are further confounded by simultaneous transcription.
      Topoisomerases play a key role in ensuring orderly replication and partition of
      DNA in the face of a continuously changing DNA tertiary structure. In addition to
      topological constraints, the cellular position of the replication origin is
      strictly controlled during the cell cycle. In Caulobacter crescentus, the origin
      of DNA replication is located at the cell pole. Upon initiation of DNA
      replication, one copy of the duplicated origin sequence rapidly appears at the
      opposite cell pole. To determine whether the maintenance of DNA topology
      contributes to the dynamic positioning of a specific DNA region within the cell,
      we examined origin localization in cells that express temperature-sensitive forms
      of either the ParC or ParE subunit of topoisomerase (Topo) IV. We found that in
      the absence of active Topo IV, replication initiation can occur but a significant
      percent of replication origins are either no longer moved to or maintained at the
      cell poles. During the replication process, the ParC subunit colocalizes with the
      replisome, whereas the ParE subunit is dispersed throughout the cell. However, an
      active ParE subunit is required for ParC localization to the replisome as it
      moves from the cell pole to the division plane during chromosome replication. We
      propose that the maintenance of DNA topology throughout the cell cycle
      contributes to the dynamic positioning of the origin sequence within the cell.

PMID- 15178757
TI  - A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
AB  - 220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K
      ATPase, and inositol trisphosphate (InsP(3)) receptor at transverse
      tubule/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function
      mutation of ankyrin-B identified in an extended kindred causes a dominantly
      inherited cardiac arrhythmia, initially described as type 4 long QT syndrome.
      Here we report the identification of eight unrelated probands harboring ankyrin-B
      loss-of-function mutations, including four previously undescribed mutations,
      whose clinical features distinguish the cardiac phenotype associated with loss of
      ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B
      mutations display varying degrees of cardiac dysfunction including bradycardia,
      sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic
      polymorphic ventricular tachycardia, and risk of sudden death. However, a
      prolonged rate-corrected QT interval was not a consistent feature, indicating
      that ankyrin-B dysfunction represents a clinical entity distinct from classic
      long QT syndromes. The mutations are localized in the ankyrin-B regulatory
      domain, which distinguishes function of ankyrin-B from ankyrin-G in
      cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal
      Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K
      ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes. This study, considered
      together with the first description of ankyrin-B mutation associated with cardiac
      dysfunction, supports a previously undescribed paradigm for human disease due to
      abnormal coordination of multiple functionally related ion channels and
      transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP(3)
      receptor.

PMID- 15178758
TI  - Visualization of ribosome-recycling factor on the Escherichia coli 70S ribosome:
      functional implications.
AB  - After the termination step of protein synthesis, a deacylated tRNA and mRNA
      remain associated with the ribosome. The ribosome-recycling factor (RRF),
      together with elongation factor G (EF-G), disassembles this posttermination
      complex into mRNA, tRNA, and the ribosome. We have obtained a three-dimensional
      cryo-electron microscopic map of a complex of the Escherichia coli 70S ribosome
      and RRF. We find that RRF interacts mainly with the segments of the large
      ribosomal subunit's (50S) rRNA helices that are involved in the formation of two
      central intersubunit bridges, B2a and B3. The binding of RRF induces considerable
      conformational changes in some of the functional domains of the ribosome. As
      compared to its binding position derived previously by hydroxyl radical probing
      study, we find that RRF binds further inside the intersubunit space of the
      ribosome such that the tip of its domain I is shifted (by approximately 13 A)
      toward protein L5 within the central protuberance of the 50S subunit, and domain
      II is oriented more toward the small ribosomal subunit (30S). Overlapping binding
      sites of RRF, EF-G, and the P-site tRNA suggest that the binding of EF-G would
      trigger the removal of deacylated tRNA from the P site by moving RRF toward the
      ribosomal E site, and subsequent removal of mRNA may be induced by a shift in the
      position of 16S rRNA helix 44, which harbors part of the mRNA.

PMID- 15178759
TI  - Identification of the xenosensors regulating human 5-aminolevulinate synthase.
AB  - Heme is an essential component of numerous hemoproteins with functions including
      oxygen transport, energy metabolism, and drug biotransformation. In
      nonerythropoietic cells, 5-aminolevulinate synthase (ALAS1) is the rate-limiting
      enzyme in heme biosynthesis. Upon exposure to drugs that induce cytochromes P450
      and other drug-metabolizing enzymes, ALAS1 is transcriptionally up-regulated,
      increasing the rate of heme biosynthesis to provide heme for cytochrome P450
      hemoproteins. We used a combined in silico-in vitro approach to identify
      sequences in the ALAS1 gene that mediate direct transcriptional response to
      xenobiotic challenge. We have characterized two enhancer elements, located 20 and
      16 kb upstream of the transcriptional start site. Both elements respond to
      prototypic inducer drugs and interact with the human pregnane X receptor NR1I2
      and the human constitutive androstane receptor NR1I3. Our results suggest that
      the fundamental mechanism of drug induction is the same for cytochromes P450 and
      ALAS1. Transcriptional activation of the ALAS1 gene is the first step in the
      coordinated up-regulation of apoprotein and heme synthesis in response to
      exogenous and endogenous signals controlling heme levels. Understanding the
      direct effects of drugs on heme synthesis is of clinical interest, particularly
      in patients with hepatic porphyrias.

PMID- 15178760
TI  - Kinetic isotope effects in Ras-catalyzed GTP hydrolysis: evidence for a loose
      transition state.
AB  - A remote labeling method has been developed to determine (18)O kinetic isotope
      effects (KIEs) in Ras-catalyzed GTP hydrolysis. Substrate mixtures consist of
      (13)C-depleted GTP and [(18)O,(13)C]GTP that contains (18)O at phosphoryl
      positions of mechanistic interest and (13)C at all carbon positions of the
      guanosine moiety. Isotope ratios of the nonvolatile substrates and products are
      measured by using a chemical reaction interface/isotope ratio mass spectrometer.
      The isotope effects are 1.0012 (0.0026) in the gamma nonbridge oxygens, 1.0194
      (0.0025) in the leaving group oxygens (the beta-gamma oxygen and the two beta
      nonbridge oxygens), and 1.0105 (0.0016) in the two beta nonbridge oxygens. The
      KIE in the beta-gamma bridge oxygen was computed to be 1.0116 or 1.0088 by two
      different methods. The significant KIE in the leaving group reveals that
      chemistry is largely rate-limiting whereas the KIEs in the gamma nonbridge
      oxygens and the leaving group indicate a loose transition state that approaches a
      metaphosphate. The KIE in the two beta nonbridge oxygens is roughly equal to that
      in the beta-gamma bridge oxygen. This indicates that, in the transition state,
      Ras shifts one-half of the negative charge that arises from P(gamma)-O(beta
      gamma) fission from the beta-gamma bridge oxygen to the two beta nonbridge
      oxygens. The KIE effects, interpreted in light of structural and spectroscopic
      data, suggest that Ras promotes a loose transition state by stabilizing negative
      charge in the beta-gamma bridge and beta nonbridge oxygens of GTP.

PMID- 15178761
TI  - Selective pressures on the olfactory receptor repertoire since the human
      chimpanzee divergence.
AB  - The availability of the sequence of the chimpanzee genome provides an opportunity
      to examine human genes and their chimpanzee orthologs and to analyze selective
      pressures that have been shaping the olfactory receptor repertoire since the
      human-chimpanzee divergence. We determined the ratio of nonsynonymous to
      synonymous changes for each of 186 orthologous pairs and then examined how the
      distribution of these ratios compares with the distribution expected under
      neutral drift. Consistent with the diminishing importance of olfaction for these
      species, we find no evidence for positive selection and we find evidence of weak
      purifying selection affecting over half of the repertoire.

PMID- 15178762
TI  - Manipulation of light signal transduction as a means of modifying fruit
      nutritional quality in tomato.
AB  - Fruit constitutes a major component of human diets, providing fiber, vitamins,
      and phytonutrients. Carotenoids are a major class of compounds found in many
      fruits, providing nutritional benefits as precursors to essential vitamins and as
      antioxidants. Although recent gene isolation efforts and metabolic engineering
      have primarily targeted genes involved in carotenoid biosynthesis, factors that
      regulate flux through the carotenoid pathway remain largely unknown.
      Characterization of the tomato high-pigment mutations (hp1 and hp2) suggests the
      manipulation of light signal transduction machinery may be an effective approach
      toward practical manipulation of plant carotenoids. We demonstrate here that hp1
      alleles represent mutations in a tomato UV-DAMAGED DNA-BINDING PROTEIN 1 (DDB1)
      homolog. We further demonstrate that two tomato light signal transduction genes,
      LeHY5 and LeCOP1LIKE, are positive and negative regulators of fruit pigmentation,
      respectively. Down-regulated LeHY5 plants exhibit defects in light responses,
      including inhibited seedling photomorphogenesis, loss of thylakoid organization,
      and reduced carotenoid accumulation. In contrast, repression of LeCOP1LIKE
      expression results in plants with exaggerated photomorphogenesis, dark green
      leaves, and elevated fruit carotenoid levels. These results suggest genes
      encoding components of light signal transduction machinery also influence fruit
      pigmentation and represent genetic tools for manipulation of fruit quality and
      nutritional value.

PMID- 15178763
TI  - Structure of vaccinia complement protein in complex with heparin and potential
      implications for complement regulation.
AB  - Vaccinia virus complement control protein (VCP), a homolog of the regulators of
      the complement activation family of proteins, inhibits complement activation
      through mechanisms similar to human fluid-phase complement regulators factor H
      and C4b-binding protein. VCP has a heparin-binding activity that assists vaccinia
      in host interactions. Interaction with cell-surface polyanions like heparin is
      centrally important in the functioning of fluid-phase complement regulators and
      is the basis of host-target discrimination by the alternative pathway. We report
      the structure of VCP in complex with a heparin decasaccharide, which reveals
      changes in VCP that might be pertinent to complement regulation. Properties that
      VCP shares with fluid-phase complement regulators suggest that such
      conformational changes may be of relevance in the functioning of other complement
      regulators. Additionally, comparison of VCP-heparin interactions with potentially
      similar interactions in factor H might enable understanding of the structural
      basis of familial hemolytic uremic syndrome, attributed to mutational disruption
      of heparin and C3b binding by factor H.

PMID- 15178764
TI  - Hypoxic inducible factor 1alpha, extracellular signal-regulated kinase, and p53
      are regulated by distinct threshold concentrations of nitric oxide.
AB  - NO produced in tumors can either positively or negatively regulate growth. To
      examine this dichotomy, effects of NO concentration and duration on the
      posttranslational regulation of several key proteins were examined in human
      breast MCF7 cells under aerobic conditions. We found that different concentration
      thresholds of NO appear to elicit a discrete set of signal transduction pathways.
      At low steady-state concentrations of NO (<50 nM), extracellular signal-regulated
      kinase (ERK) phosphorylation was induced via a guanylate cyclase-dependent
      mechanism. Hypoxic inducible factor 1alpha (HIF-1alpha) accumulation was
      associated with an intermediate amount of NO (>100 nM), whereas p53 serine 15
      phosphorylation occurred at considerably higher levels (>300 nM). ERK
      phosphorylation was transient during NO exposure. HIF-1alpha stabilization
      paralleled the presence of NO, whereas p53 serine 15 phosphorylation was detected
      during, and persisted after, NO exposure. The dose-dependent effects of synthetic
      NO donors were mimicked by activated macrophages cocultured with MCF7 cells at
      varying ratios. ERK and HIF-1alpha activation was similar in breast cancer cell
      lines either mutant (MB231) or null (MB157) in p53. The stabilization of HIF
      1alpha by NO was not observed with increased MCF7 cell density, demonstrating the
      interrelationship between NO and O(2) consumption. The findings show that
      concentration and duration of NO exposure are critical determinants in the
      regulation of tumor-related proteins.

PMID- 15178765
TI  - Suppression of p160ROCK bypasses cell cycle arrest after Aurora-A/STK15
      depletion.
AB  - Alterations in the expression and activity of the centrosomal kinase, Aurora
      A/serine/threonine kinase 15 (STK15), affect genomic stability, disrupt the
      fidelity of centrosome duplication, and induce cellular transformation. Here, we
      provide evidence that p160ROCK, a Rho-associate serine/threonine kinase,
      associates with Aurora-A in a protein complex with other STK15-associated
      factors. Suppression of Aurora-A by small interfering RNA in HeLa cells blocks
      the ability of centrosomes to organize normal mitotic spindles, induces G(2)/M
      cell cycle arrest, and promotes accumulation of tetraploid cells. In many cases,
      one outcome of such abnormalities is apoptosis. Introduction of a second genetic
      lesion, suppression of p160ROCK by RNA interference, can rescue abnormal mitotic
      spindle formation, release the G(2)/M cell cycle arrest, and alleviate apoptosis,
      leading to a greater accumulation of aneuploid cells. These results suggest that
      Aurora-A and p160ROCK act in a common genetic pathway that promotes and monitors
      progression through G(2)/M.

PMID- 15178766
TI  - Age-structured red blood cell susceptibility and the dynamics of malaria
      infections.
AB  - Malaria parasites and immune responses in an infected human interact on a dynamic
      landscape, in which a population of replicating parasites depletes a population
      of replenishing red blood cells (RBCs). These underlying dynamics receive
      relatively little attention, but they offer unique insights into the processes
      that control most malaria infections. Here, we focus on the observation that
      three of the four malaria-parasite species that infect humans are restricted to
      particular age classes of RBC. We explicitly incorporate this observation in
      models of infection dynamics to distinguish common from species-specific
      pressures on host immune responses, and we find that age structuring has profound
      effects on the course of infection. For all four species conditions exist under
      which the parasites may persist at low densities, or may clear, even in the
      absence of an immune response. Catastrophic anemia can occur even with the two
      species that attack only the youngest RBCs, although only a small fraction of
      cells are parasitized at any point. Furthermore, with these two, compensatory
      erythropoetic responses in the host accelerate parasite population growth. A
      "basic reproduction rate" characterizes these differences in outcomes.

PMID- 15178768
TI  - The obesity epidemic.

PMID- 15178770
TI  - Planetary origins. Youngest extrasolar planet reported.

PMID- 15178769
TI  - Publishing. U.S. trade policy creates confusion over co-authorship.

PMID- 15178771
TI  - Gene therapy. Side effects sideline hemophilia trial.

PMID- 15178772
TI  - Paleontology. Controversial fossil could shed light on early animals' blueprint.

PMID- 15178767
TI  - Spatiotemporal retinoid-X receptor activation detected in live vertebrate
      embryos.
AB  - Most studies on the nuclear retinoid-X receptor (RXR) have focused on its role as
      a heterodimeric partner but less about its own activation pattern during
      development and the distribution of potential endogenous ligands. The aim of this
      study is to visualize the distribution of activated RXRalpha in live transgenic
      Xenopus laevis embryos across a wide range of developmental stages. We adopted a
      nuclear receptor-Gal4 fusion/upstream activation sequence-based reporter system
      for our assay. Strong activation of the RXRalpha ligand-binding domain was
      observed in a segment of the spinal cord just posterior to the hindbrain. This
      activation is first detected in neurula stage embryos and persists up to swimming
      tadpole stages, after which activation strongly declines. Addition of exogenous
      ligands, such as 9-cis retinoic acid or all-trans retinoic acid, expands the
      activation of RXR throughout the spinal cord but not in the brain, whereas the
      RXR-specific ligand LG268 expanded the Gal4-RXR activation into the brain and
      olfactory epithelia. Treatment with the RAR-specific ligand 4-(E-2-(5,6,7,8
      tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid or thyroid
      hormone had no effect on Gal4-RXR activation, whereas these compounds
      significantly increased their corresponding Gal4/receptor fusion proteins under
      similar conditions. Embryos expressing a Gal4-RXR fusion protein with a deletion
      in the ligand-dependent activation domain (AF2) show no reporter gene activation.
      The results shown in this paper reveal a specific activation pattern for Gal4
      RXRalpha specifically in the developing spinal cord and suggest the existence of
      RXR ligand "hot-spots" in this region.

PMID- 15178773
TI  - Genomics. TIGR escapes Venter's plan for consolidation.

PMID- 15178774
TI  - Plant genomics. Syngenta donates 48,000 mutant Arabidopsis plants.

PMID- 15178775
TI  - Intellectual property. NIH weighs demand to force sharing of AIDS drug patents.

PMID- 15178776
TI  - Development spending. Economists rate greenhouse gas curbs a poor investment.

PMID- 15178777
TI  - HIV/AIDS in China. Poised for takeoff?

PMID- 15178778
TI  - HIV/AIDS in China. A new treatment campaign, but with limited weapons.

PMID- 15178779
TI  - HIV/AIDS in China. Changing course to break the HIV-heroin connection.

PMID- 15178780
TI  - HIV/AIDS in China. Vaccine development with a distinctly Chinese flavor.

PMID- 15178781
TI  - HIV/AIDS in China. An unsafe practice turned blood donors into victims.

PMID- 15178782
TI  - HIV/AIDS in China. A scoop of international proportions.

PMID- 15178783
TI  - A plea for DNA banking.

PMID- 15178784
TI  - Setting priorities for genomic research.

PMID- 15178785
TI  - Questions about disclosure.

PMID- 15178786
TI  - Sociology. What if we give a census and no one comes?

PMID- 15178787
TI  - Neuroscience. Crossing the midline.

PMID- 15178788
TI  - Physics. Ion entanglement in quantum information processing.

PMID- 15178789
TI  - Materials science. Designer nanotubes by molecular self-assembly.

PMID- 15178790
TI  - Cancer. A bull's eye for targeted lung cancer therapy.

PMID- 15178791
TI  - Plant sciences. Yoda would be proud: valves for land plants.

PMID- 15178792
TI  - Challenges of modeling ocean basin ecosystems.
AB  - With increasing pressure for a more ecological approach to marine fisheries and
      environmental management, there is a growing need to understand and predict
      changes in marine ecosystems. Biogeochemical and physical oceanographic models
      are well developed, but extending these further up the food web to include
      zooplankton and fish is a major challenge. The difficulty arises because
      organisms at higher trophic levels are longer lived, with important variability
      in abundance and distribution at basin and decadal scales. Those organisms at
      higher trophic levels also have complex life histories compared to microbes,
      further complicating their coupling to lower trophic levels and the physical
      system. We discuss a strategy that builds on recent advances in modeling and
      observations and suggest a way forward that includes approaches to coupling
      across trophic levels and the inclusion of uncertainty.

PMID- 15178794
TI  - Toward Heisenberg-limited spectroscopy with multiparticle entangled states.
AB  - The precision in spectroscopy of any quantum system is fundamentally limited by
      the Heisenberg uncertainty relation for energy and time. For N systems, this
      limit requires that they be in a quantum-mechanically entangled state. We
      describe a scalable method of spectroscopy that can potentially take full
      advantage of entanglement to reach the Heisenberg limit and has the practical
      advantage that the spectroscopic information is transferred to states with
      optimal protection against readout noise. We demonstrate our method
      experimentally with three beryllium ions. The spectroscopic sensitivity attained
      is 1.45(2) times as high as that of a perfect experiment with three non-entangled
      particles.

PMID- 15178793
TI  - Odorant receptors on axon termini in the brain.

PMID- 15178795
TI  - Control and measurement of three-qubit entangled states.
AB  - We report the deterministic creation of maximally entangled three-qubit states
      specifically the Greenberger-Horne-Zeilinger (GHZ) state and the W state-with a
      trapped-ion quantum computer. We read out one of the qubits selectively and show
      how GHZ and W states are affected by this local measurement. Additionally, we
      demonstrate conditional operations controlled by the results from reading out one
      qubit. Tripartite entanglement is deterministically transformed into bipartite
      entanglement by local operations only. These operations are the measurement of
      one qubit of a GHZ state in a rotated basis and, conditioned on this measurement
      result, the application of single-qubit rotations.

PMID- 15178796
TI  - Self-assembled hexa-peri-hexabenzocoronene graphitic nanotube.
AB  - An amphiphilic hexa-peri-hexabenzocoronene self-assembles to form a pi
      electronic, discrete nanotubular object. The object is characterized by an aspect
      ratio greater than 1000 and has a uniform, 14-nanometer-wide, open-ended hollow
      space, which is an order of magnitude larger than those of carbon nanotubes. The
      wall is 3 nanometers thick and consists of helical arrays of the pi-stacked
      graphene molecule, whose exterior and interior surfaces are covered by
      hydrophilic triethylene glycol chains. The graphitic nanotube is redox active,
      and a single piece of the nanotube across 180-nanometer-gap electrodes shows,
      upon oxidation, an electrical resistance of 2.5 megohms at 285 kelvin
      [corrected]. This family of molecularly engineered graphite with a one
      dimensional tubular shape and a chemically accessible surface constitutes an
      important step toward molecular electronics.

PMID- 15178797
TI  - Atmospheric new particle formation enhanced by organic acids.
AB  - Atmospheric aerosols often contain a substantial fraction of organic matter, but
      the role of organic compounds in new nanometer-sized particle formation is highly
      uncertain. Laboratory experiments show that nucleation of sulfuric acid is
      considerably enhanced in the presence of aromatic acids. Theoretical calculations
      identify the formation of an unusually stable aromatic acid-sulfuric acid
      complex, which likely leads to a reduced nucleation barrier. The results imply
      that the interaction between organic and sulfuric acids promotes efficient
      formation of organic and sulfate aerosols in the polluted atmosphere because of
      emissions from burning of fossil fuels, which strongly affect human health and
      global climate.

PMID- 15178798
TI  - The acquisition of exogenous algal symbionts by an octocoral after bleaching.
AB  - Episodes of coral bleaching (loss of the symbiotic dinoflagellates) and coral
      mortality have occurred with increasing frequency over the past two decades.
      Although some corals recover from bleaching events, the source of the
      repopulating symbionts is unknown. Here we show that after bleaching, the adult
      octocoral Briareum sp. acquire dinoflagellate symbionts (Symbiodinium sp.) from
      the environment. Uptake of exogenous symbionts provides a mechanism for response
      to changes in the environment and resilience in the symbiosis.

PMID- 15178799
TI  - Flexibility in algal endosymbioses shapes growth in reef corals.
AB  - The relation between corals and their algal endosymbionts has been a key to the
      success of scleractinian (stony) corals as modern reef-builders, but little is
      known about early stages in the establishment of the symbiosis. Here, we show
      that initial uptake of zooxanthellae by juvenile corals during natural infection
      is nonspecific (a potentially adaptive trait); the association is flexible and
      characterized by a change in (dominant) zooxanthella strains over time; and
      growth rates of experimentally infected coral holobionts are partly contingent on
      the zooxanthella strain harbored, with clade C-infected juveniles growing two to
      three times as fast as those infected with clade D.

PMID- 15178800
TI  - Stomatal development and pattern controlled by a MAPKK kinase.
AB  - Stomata are epidermal structures that modulate gas exchange between a plant and
      its environment. During development, stomata are specified and positioned
      nonrandomly by the integration of asymmetric cell divisions and intercellular
      signaling. The Arabidopsis mitogen-activated protein kinase kinase kinase gene,
      YODA, acts as part of a molecular switch controlling cell identities in the
      epidermis. Null mutations in YODA lead to excess stomata, whereas constitutive
      activation of YODA eliminated stomata. Transcriptome analysis of seedlings with
      altered YODA activity was used to identify potential stomatal regulatory genes. A
      putative transcription factor from this set was shown to regulate the
      developmental behavior of stomatal precursors.

PMID- 15178801
TI  - Roles of the two Drosophila CRYPTOCHROME structural domains in circadian
      photoreception.
AB  - CRYPTOCHROME (CRY) is the primary circadian photoreceptor in Drosophila. We show
      that CRY binding to TIMELESS (TIM) is light-dependent in flies and irreversibly
      commits TIM to proteasomal degradation. In contrast, CRY degradation is dependent
      on continuous light exposure, indicating that the CRY-TIM interaction is
      transient. A novel cry mutation (cry(m)) reveals that CRY's photolyase homology
      domain is sufficient for light detection and phototransduction, whereas the
      carboxyl-terminal domain regulates CRY stability, CRY-TIM interaction, and
      circadian photosensitivity. This contrasts with the function of Arabidopsis CRY
      domains and demonstrates that insect and plant cryptochromes use different
      mechanisms.

PMID- 15178802
TI  - Crystal structure of the long-chain fatty acid transporter FadL.
AB  - The mechanisms by which hydrophobic molecules, such as long-chain fatty acids,
      enter cells are poorly understood. In Gram-negative bacteria, the
      lipopolysaccharide layer in the outer membrane is an efficient barrier for fatty
      acids and aromatic hydrocarbons destined for biodegradation. We report crystal
      structures of the long-chain fatty acid transporter FadL from Escherichia coli at
      2.6 and 2.8 angstrom resolution. FadL forms a 14-stranded beta barrel that is
      occluded by a central hatch domain. The structures suggest that hydrophobic
      compounds bind to multiple sites in FadL and use a transport mechanism that
      involves spontaneous conformational changes in the hatch.

PMID- 15178803
TI  - A microdomain for protein secretion in Gram-positive bacteria.
AB  - Gram-positive bacteria face unique challenges in generating biologically active
      conformations for their exported proteins because they lack a dedicated
      compartment for folding secreted polypeptides. We have discovered that protein
      secretion by way of the general secretory (Sec) pathway in the important human
      pathogen Streptococcus pyogenes proceeds through a single microdomain. Unlike
      other mechanisms for asymmetry involving the Sec pathway, proteins destined for
      secretion are targeted to a single locus distal to either cell pole that has
      specialized to contain the Sec translocons. This subcellular organization may
      represent a paradigm for secretion common to other Gram-positive pathogens with
      profound implications for pathogenesis.

PMID- 15178806
TI  - Application of quantitative structure-toxicity relationships for the comparison
      of the cytotoxicity of 14 p-benzoquinone congeners in primary cultured rat
      hepatocytes versus PC12 cells.
AB  - Quinones are believed to induce their toxicity by two main mechanisms: oxygen
      activation by redox cycling and alkylation of essential macromolecules. The
      physicochemical parameters that underlie this activity have not been elucidated,
      although redox potential is believed to play a significant role. In this study,
      we have evaluated the cytotoxicity, formation of reactive oxygen species (ROS),
      and the glutathione (GSH) depleting ability of 14 p-benzoquinone congeners in
      primary rat hepatocyte and PC12 cell cultures. All experiments were performed
      under identical conditions (37 degrees C, 5% CO2/air) in 96-well plates. The most
      cytotoxic quinone was found to be tetrachloro-p-benzoquinone (chloranil), and the
      least toxic was duroquinone or 2,6-di-tert-butyl-p-benzoquinone. The cytotoxic
      order varied between the cell types, and in particular, the di-substituted
      methoxy or methyl p-benzoquinones were particularly more cytotoxic towards PC12
      cells. We have derived one- and two-parameter quantitative structure-toxicity
      relationships (QSTRs) which revealed that the most cytotoxic quinones had the
      highest electron affinity and the smallest volume. Cytotoxicity did not correlate
      with the lipophilicity of the quinone. Furthermore, we found that p-benzoquinone
      cytotoxicity correlated well with hepatocyte ROS formation and GSH depletion,
      whereas in PC12 cells, cytotoxicity did not correlate with ROS formation and
      somewhat correlated with GSH depletion. Hepatocytes had far greater hydrogen
      peroxide detoxifying capacity than PC12 cells, but PC12 cells contained more
      GSH/mg protein. Thus, p-benzoquinone-induced ROS formation was greater towards
      PC12 cells than with hepatocytes. To our knowledge, this is the first QSTR
      derived for p-benzoquinone cytotoxicity in these cell types and could form the
      basis for distinguishing certain cell-specific cytotoxic mechanisms.

PMID- 15178804
TI  - A process for controlling intracellular bacterial infections induced by membrane
      injury.
AB  - Strategies for inhibiting phagolysosome fusion are essential for the
      intracellular survival and replication of many pathogens. We found that the
      lysosomal synaptotagmin Syt VII is required for a mechanism that promotes
      phagolysosomal fusion and limits the intracellular growth of pathogenic bacteria.
      Syt VII was required for a form of Ca2+-dependent phagolysosome fusion that is
      analogous to Ca2+-regulated exocytosis of lysosomes, which can be triggered by
      membrane injury. Bacterial type III secretion systems, which permeabilize
      membranes and cause Ca2+ influx in mammalian cells, promote lysosomal exocytosis
      and inhibit intracellular survival in Syt VII +/+ but not -/- cells. Thus, the
      lysosomal repair response can also protect cells against pathogens that trigger
      membrane permeabilization.

PMID- 15178807
TI  - The tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) provokes a
      prolonged morphologic response and ERK activation in Tsc2-null renal tumor cells.
AB  - Loss of tumor suppressor function dramatically alters the cellular response to
      chemicals. The phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate
      (TPA), stimulates cell proliferation through rapid activation of protein kinase C
      (PKC), followed by gradual degradation of the kinase. TPA also activates the
      GTPase Rap1 in some cell types. The tumor suppressor protein Tsc2 has a proposed
      GTPase activating protein (GAP) function for Rap1, providing a common mechanistic
      target for Tsc2 and TPA. We compared the cellular response of Tsc2-null (ERC-18)
      and Tsc2-competent (NRK-52E) renal epithelial cells to TPA treatment. Treatment
      of ERC-18 cells with 100 ng/ml TPA for 24 h resulted in loss of cell-cell
      contact, retraction of the cell periphery and rounding. These changes were
      reversed 1 h after treatment in NRK-52E cells and were apparent 24 h after
      treatment of ERC-18 cells. Expression of Tsc2 in ERC-18 cells abrogated the
      prolonged morphologic response. TPA treatment rapidly increased phosphorylation
      of ERK, a reported downstream effector of both PKC and Rap1, in ERC-18 cells, but
      induced weak Rap1 activation. TPA-induced ERK phosphorylation was prolonged in
      ERC-18 cells compared to NRK-52E cells and expression of Tsc2 in ERC-18 cells did
      not inhibit prolonged ERK activation. The selective PKC inhibitor,
      bisindolylmaleimide VIII, however, inhibited TPA-induced changes in morphology
      and ERK activation. These results imply that TPA-induced changes in morphology
      and ERK activation are mediated primarily through PKC and not Rap1 in renal
      epithelial cells. These data also imply that Tsc2 expression modulates TPA
      induced changes in renal epithelial cell morphology via an ERK-independent
      mechanism.

PMID- 15178808
TI  - Use of the tail moment of the lymphocytes to evaluate DNA damage in human
      biomonitoring studies.
AB  - The Comet assay has gained increasing popularity for use in human biomonitoring
      or epidemiologic studies; however, one of the shortcomings of the Comet assay is
      a lack of agreement on a single appropriate Comet parameter that is capable of
      adequately describing observed DNA damages. Among the tail parameters of Comet
      features, the most frequently used are the tail moments (both the Olive tail
      moment and the extent tail moment), the tail DNA, and the tail length. Some
      studies comparing Comet parameters have been found in cell toxicity research, but
      there are few comparative studies that use human biomonitoring or epidemiologic
      data. In this study, we evaluate those four tail parameters in both high and low
      DNA damaged cells with the use of epidemiologic data. To do this, a new graphical
      approach, the so-called quantile dispersion graphs (QDGs) are used. In a
      comparison of an exposed group and a control group, either the tail moment or
      tail DNA is preferable to the tail length. With respect to providing smaller
      variability in quantiles for the amount of DNA damage, however, the tail moment
      is the preferred parameter for both groups. Moreover, the tail moment provides
      the most stable estimates for DNA damage because it has a larger degree of
      uniformity in quantile dispersions. To study high degrees of damage from toxic
      exposure using B cells or G cells, however, the tail DNA showed more significant
      discrepancies than the other parameters, in terms of both the mean differences
      and the graphical differences between the two groups. In view of this result, it
      is suggested that both the tail moment and the tail DNA be presented as tail
      parameters in human biomonitoring studies.

PMID- 15178810
TI  - Vascular endothelial growth factor as a target for anticancer therapy.
AB  - The development of a vascular supply is a critical factor in the growth and
      metastatic spread of malignant tumors. Of the multitude of growth factors that
      regulate physiological and pathological angiogenesis, vascular endothelial growth
      factor (VEGF) is believed to be the most important. There is evidence that
      overexpression of VEGF is correlated with an adverse prognosis, at least in some
      tumors. Tumor-expressed VEGF is particularly attractive as a target for
      anticancer therapy because its angiogenesis-promoting activity is at the level of
      the endothelial cell and, compared with agents that directly target tumor cells,
      tumor penetration is less critical for VEGF inhibitors. Moreover, recent work has
      shown that inhibiting tumor angiogenesis increases the effectiveness of
      coadministered chemotherapy and radiotherapy. This suggests that drugs that
      target VEGF or its receptors can be combined with traditional treatment
      modalities to ensure maximum effectiveness. A variety of agents aimed at blocking
      VEGF or its receptor-signaling system are currently being developed for the
      treatment of cancer. Of these, bevacizumab, a humanized monoclonal antibody
      directed at VEGF, is the most advanced in clinical development and has shown
      promising results in clinical trials.

PMID- 15178811
TI  - Targeted therapy of colorectal cancer: clinical experience with bevacizumab.
AB  - Advanced colorectal cancer remains an urgent health concern, despite improvements
      in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy
      with minimal side effects. Angiogenesis (the formation of new blood vessels) is
      essential for tumor growth and metastasis and may be an ideal target in the
      search for new antineoplastic agents. Vascular endothelial growth factor is one
      of the best characterized of the proangiogenic growth factors that regulate
      angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab
      (Avastin; Genentech Inc.; South San Francisco, CA), a humanized murine monoclonal
      antibody directed at vascular endothelial growth factor, is being evaluated in
      the treatment of various types of cancer. It has shown promising efficacy in
      phase II clinical trials in patients with metastatic colorectal cancer. Addition
      of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus
      leucovorin) resulted in a higher objective response rate (40% versus 17%), longer
      time to disease progression (9.0 versus 5.2 months), and longer median survival
      time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal
      safety concerns, but were manageable. Further phase II/III studies of
      bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without
      irinotecan and/or oxaliplatin, in colorectal cancer, are under way.

PMID- 15178812
TI  - Non-small cell lung cancer and antiangiogenic therapy: what can be expected of
      bevacizumab?
AB  - There is an urgent need for new therapies to treat non-small cell lung cancer
      (NSCLC), as progress with current chemotherapy regimens has been limited. The
      roles of vascular endothelial growth factor (VEGF) in promoting tumor
      angiogenesis, maintaining existing vasculature, and contributing to resistance to
      traditional therapies, together with its negative prognostic significance in
      NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin; Genentech
      Inc., South San Francisco, CA), a monoclonal antibody directed against VEGF, has
      shown promise in treating a number of different cancers. In a recent phase II
      trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to
      standard carboplatin/paclitaxel chemotherapy produced a significantly longer time
      to progression (32.1 versus 18.4 weeks) and greater response rate (31% versus 19%
      [not significant]) than chemotherapy alone. In the subset of patients with
      nonsquamous histologies, response rates and survival were further enhanced, with
      a mean survival time of 17.9 months versus 12.3 months with chemotherapy alone.
      Bevacizumab was generally well tolerated and did not appear to increase the
      incidences or severities of the nausea/vomiting, neuropathy, and renal toxicity
      that are typically associated with carboplatin/paclitaxel chemotherapy. Adverse
      events in phase I and II studies included hypertension, thrombosis, proteinuria
      (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related
      bleeding episodes (hemoptysis/hematemesis) appear to be the main safety concern
      in patients with NSCLC, with squamous cell histology as a possible risk factor.
      Further work is needed to identify the best way to use bevacizumab in NSCLC,
      including use in combination with other biologic agents and in the adjuvant
      setting.

PMID- 15178813
TI  - Expanding the clinical development of bevacizumab.
AB  - Bevacizumab (Avastin; Genentech, Inc.; South San Francisco, CA) is a recombinant,
      humanized monoclonal antibody to vascular endothelial growth factor, a key
      regulator of tumor angiogenesis. Bevacizumab demonstrated potent antitumor
      activity in preclinical models and has also shown biologic activity and clinical
      benefit in clinical studies. Notably, a randomized, placebo-controlled phase II
      trial in renal cell carcinoma demonstrated a significantly longer time to tumor
      progression with bevacizumab monotherapy. Furthermore, in a phase III trial for
      untreated advanced colorectal cancer, the addition of bevacizumab to chemotherapy
      led to significantly longer overall survival and progression-free survival times
      than chemotherapy alone. The clinical development of bevacizumab has been
      expanded to include confirmatory phase III trials and exploratory phase II trials
      in a variety of solid tumors and hematologic malignancies. Treatment regimens
      being examined include bevacizumab alone and in combination with conventional
      chemotherapy, radiation, immune therapy, and biologically targeted agents.

PMID- 15178814
TI  - Maximizing the potential of bevacizumab in cancer treatment.
AB  - Promising results have been obtained with bevacizumab (Avestin; Genentech, Inc.;
      South San Francisco, CA) in clinical trials in patients with a range of solid
      tumors; however, to maximize the potential of this agent, further research is
      needed to clarify a number of important issues. These include the optimization of
      bevacizumab dosage and schedule of administration, the potential value of this
      agent in combination with other treatment modalities like chemotherapy and
      radiation, the management of toxicities, and the selection of patients most
      likely to benefit from treatment. Intriguing results from two recent phase III
      trials highlight the need for a better understanding of the best ways to
      incorporate bevacizumab into clinical practice. Ultimately, maximizing the
      potential value of this agent may require a more thorough understanding of
      bevacizumab's mechanism of action and the pathways mediating resistance.

PMID- 15178818
TI  - Very long-term outcome after stroke in Auckland, New Zealand.
AB  - BACKGROUND AND PURPOSE: Limited information exists on the long-term outcome from
      stroke. We aimed to determine survival and health status at 21-year follow-up of
      patients who participated in a population-based stroke incidence study undertaken
      in Auckland, New Zealand. METHODS: During 12 months beginning March 1, 1981, half
      of all residents of Auckland with acute first-ever or recurrent stroke (n=680)
      were assessed and followed up prospectively during the next 2 decades. In 2002,
      their vital status and health-related quality of life (HRQoL) using the 36-item
      short-form questionnaire (SF-36) were determined by telephone interviews. Kaplan
      Meier survival probabilities for the stroke cohort were compared with life table
      estimates for the New Zealand population. The SF-36 profile of 21-year stroke
      survivors was compared with a standardized New Zealand population. RESULTS:
      Overall, 626 of the original cohort had died and 4 were lost to follow-up,
      leaving 50 (7%) individuals (57% male; mean age 70 years) available in 2002, of
      whom 12% were residents of an institutional care facility and 19% required help
      with everyday activities. The stroke cohort had nearly twice the mortality rate
      of the New Zealand population, but the SF-36 profile of very long-term stroke
      survivors was broadly similar to the general population. CONCLUSIONS: Because
      stroke is generally a disease of older people and has a high case fatality, it is
      not surprising that <1 in 10 people survive 2 decades after onset. However, of
      those who do, their HRQoL profile suggests that they meld relatively successfully
      within the general population, despite ongoing disability and a higher mortality
      risk.

PMID- 15178815
TI  - Bevacizumab in the treatment of breast cancer: rationale and current data.
AB  - Vascular endothelial growth factor (VEGF) has emerged as a key target for the
      treatment of cancer. As the ligand to the VEGF receptor, it plays a central role
      in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in
      patients with breast cancer and other tumors. Preclinical studies have shown that
      the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc.,
      South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of
      solid tumors, either alone or in combination with chemotherapy. As a single agent
      or added to vinorelbine, bevacizumab has produced encouraging results in phase II
      clinical trials in patients with refractory metastatic breast cancer. When added
      to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater
      response rate, but did not prolong progression-free survival. This may reflect
      the late disease stage and poor prognostic factors in the patient population. A
      large, ongoing, phase III, cooperative group trial is evaluating the effect of
      bevacizumab in combination with paclitaxel as first-line therapy for metastatic
      disease. The adverse effect profile of bevacizumab differs from that of cytotoxic
      chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.

PMID- 15178819
TI  - Predictors of hyperacute clinical worsening in ischemic stroke patients receiving
      thrombolytic therapy.
AB  - BACKGROUND AND PURPOSE: Although long-term outcome determinants in acute ischemic
      stroke (AIS) patients have been defined, less is known about those predicting
      hyperacute worsening after thrombolytic therapy (TT). We investigated predictors
      of short-term clinical worsening (National Institutes of Health Stroke Scale
      [NIHSS] change > or =4 within 24 hours of admission). METHODS: We studied 201 AIS
      patients who received TT within 6 hours of symptom onset. We determined baseline
      demographics, comorbidities, NIHSS at baseline and at 24 hours after TT, head
      computed tomography scan before and within 24 hours after TT, and angiographic
      recanalization in patients treated with intra-arterial (IA) thrombolysis.
      Significance of relationships was evaluated by t test or Wilcoxon signed rank sum
      test. Logistic regression model (LRM) was fitted to determine independence of
      significant variables. RESULTS: Of 201 patients, 13% worsened, 39% improved, and
      48% remained unchanged 24 hours after TT. Most patients (72%) received IA
      thrombolysis. Patients who deteriorated, compared with those who improved, were
      more likely to have complicating intracranial hemorrhage (ICH; P<0.001), absent
      recanalization (P=0.026), and higher blood glucose (BG; P=0.049). Hyperglycemia
      (>150 mg/dL) was greater in patients who worsened even in presence of
      recanalization (P=0.004, odds ratio [OR] 6.47). LRM showed that adjusted OR for
      increased risk of bad outcome and mortality for an increase of BG by 50 mg/dL is
      1.56 and 1.38, respectively. CONCLUSIONS: Hyperglycemia and ICH are independent
      predictors of hyperacute worsening in AIS patients receiving TT. Although
      recanalization is the purpose of IA thrombolysis, its impact on clinical
      improvement may not be apparent without strict BG control.

PMID- 15178820
TI  - Prospective study of plasma carotenoids and tocopherols in relation to risk of
      ischemic stroke.
AB  - BACKGROUND AND PURPOSE: Intake of fruits and vegetables has been related to lower
      risk of ischemic stroke, but nutrients responsible for this apparent benefit
      remain ill-defined. Tocopherols (vitamin E) have also been proposed to be
      protective. METHODS: We conducted a prospective, nested case-control analysis
      among male physicians without diagnosed cardiovascular disease followed-up for up
      to 13 years in the Physicians' Health Study. Samples from 297 physicians with
      ischemic stroke were analyzed with paired controls, matched for age and smoking,
      for 5 major carotenoids (alpha- and beta-carotene, beta-cryptoxanthin, lutein,
      and lycopene), retinol, and alpha- and gamma-tocopherol. RESULTS: Baseline plasma
      levels of alpha-carotene and beta-carotene and lycopene tended to be inversely
      related to risk of ischemic stroke with an apparent threshold effect. As compared
      with men whose plasma levels were in the lowest quintile, the multivariate
      adjusted odds ratios (ORs) of ischemic stroke among men with levels in the second
      through fifth quintiles were 0.59 (95% CI, 0.36 to 0.98) for alpha-carotene, 0.62
      (95% CI, 0.38 to 1.01) for beta-carotene, and 0.61 (95% CI, 0.37 to 1.00) for
      lycopene. A tendency toward an inverse association was found for beta
      cryptoxanthin, but the result was not statistically significant. No association
      was found for lutein, retinol, and tocopherols. CONCLUSIONS: Our data suggest
      that higher plasma levels of carotenoids, as markers of fruit and vegetable
      intake, are inversely related to risk of ischemic stroke and provide support for
      recommendations to consume fruits and vegetables regularly.

PMID- 15178821
TI  - Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis
      and improves neurological function in rats.
AB  - BACKGROUND AND PURPOSE: Erythropoietin (EPO) promotes proliferation and
      differentiation of erythroid progenitors and the survival of maturing erythroid
      cells. Here, we investigated the role of EPO in brain repair after stroke.
      METHODS: Rats were treated with recombinant human EPO (rhEPO) at 24 hours after
      the onset of embolic stroke. An array of behavior tests was performed. Rats were
      euthanized 28 days after stroke for measurements of infarct volume, angiogenesis,
      and neurogenesis. In vitro, neurospheres derived from the subventricular zone
      (SVZ) of the rat and cerebral endothelial cells derived from the mouse were
      treated with rhEPO. Capillary-like tube formation and neuronal differentiation
      were measured. RESULTS: Treatment with rhEPO significantly improved functional
      recovery, along with increases in density of cerebral microvessels at the stroke
      boundary and numbers of BrdU, doublecortin, and nestin immunoreactive cells in
      the SVZ. rhEPO treatment significantly increased brain levels of vascular
      endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). In
      vitro, rhEPO enhanced capillary tube formation of cerebral endothelial cells,
      which was inhibited by a specific VEGF receptor 2 antagonist (SU1498). Incubation
      of neurospheres derived from stroke SVZ with anti-EPO neutralizing antibody
      inhibited neurogenesis, whereas incubation of stroke-derived neurospheres with
      rhEPO enhanced neurogenesis. CONCLUSIONS: Our data suggest that EPO-increased
      VEGF and BDNF may be involved in angiogenesis and neurogenesis, which could
      contribute to functional recovery.

PMID- 15178822
TI  - Cerebral venous flow velocity predicts poor outcome in subarachnoid hemorrhage.
AB  - BACKGROUND AND PURPOSE: Predictors of clinical outcome in aneurysmal subarachnoid
      hemorrhage (SAH) vary in reliability. Measurement of cerebral venous hemodynamics
      by transcranial color-coded duplexsonography (TCCS) has become of increasing
      interest lately, and correlation with intracranial pressure (ICP) seems to be
      high. The aim of the presented study was to assess changes of cerebral venous
      hemodynamics in SAH and evaluate its relationship with clinical outcome. METHODS:
      We performed sequential TCCS of venous peak flow velocities (vp-FVs) in the
      transversal sinus in 28 consecutive patients with aneurysmal SAH (Hunt and Hess
      scale 1 to 5). Measurement was initiated at onset of arterial vasospasm up to 5
      days after SAH. All patients had a continuous ICP monitoring. Clinical outcome
      was evaluated with the modified ranking scale (MRS) 30 days after SAH. Patients
      were divided according to outcome: group I good recovery (MRS 0-III) and group II
      poor outcome (death or MRS IV-V). Maximum vp-FV, time-averaged vp-FV (mv-FV), and
      ICP were compared between groups. RESULTS: Vp-FV and mv-FV as well as ICP of
      group II exceeded values of group I (P<0.001 for all 3 parameters). Vp-FV showed
      a positive correlation with ICP (r=0.63; P<0.001). A vp-FV exceeding 35.4 cm/s
      (sensitivity 100%; specificity 90.9%), an mv-FV exceeding 27.3 cm/s (sensitivity
      94.1%; specificity 81.8%), and an ICP exceeding 24 mm Hg (sensitivity 87.5%;
      specificity 81.8%) predicted poor outcome (receiver operating characteristic
      analysis). CONCLUSIONS: Increased ICP values correlate with increased venous flow
      velocities. In SAH, increased ICP and increased venous flow velocities are
      associated with poor outcome. Flow velocity of the transversal sinus is a highly
      sensitive, reliable, and early predictor of outcome in SAH.

PMID- 15178823
TI  - A2 alelle of GpIIIa gene is a risk factor for stroke caused by large-vessel
      disease in males.
AB  - BACKGROUND AND PURPOSE: Glycoprotein IIIa (GpIIIa) is a platelet membrane
      receptor for fibrinogen and von Willebrand factor. It plays a key role in
      platelet aggregation. Previous studies in stroke patients, without analysis based
      on specific subtypes of stroke cause, have not shown any link between GpIIIa
      A1/A2 polymorphism and stroke risk. We studied the significance of the GpIIIa
      gene A1/A2 polymorphism in stroke patients with different stroke causes. METHODS:
      We genotyped 92 patients with stroke caused by large-vessel disease (LVD stroke)
      and 184 matched controls; 103 patients with stroke caused by small-vessel disease
      (SVD stroke) and 206 controls; and 182 patients with cardioembolic stroke (CE
      stroke) and 182 controls (TOAST criteria). The GpIIIa A1/A2 polymorphism was
      analyzed by polymerase chain reaction followed by restriction enzyme digestion
      and electrophoresis. RESULTS: The genotype distribution of the GpIIIa gene in
      patients with LVD stroke (A1/A1, 63%; A1/A2, 34.8%; A2/A2, 2.2%) differed
      significantly from their controls (A1A1, 79.3%; A1/A2, 20.1%; A2/A2, 0.6%). The
      distribution of the GpIIIa A1/A2 polymorphism in patients with SVD stroke and CE
      stroke was similar to that of their controls. In contrast to females with LVD
      stroke, we found that males with LVD stroke presented with an overrepresentation
      of at least 1 A2 allele of the GpIIIa gene when compared with their controls
      (39.7% versus 23.0%; P=0.003). Conditional logistic regression analysis showed
      that possession of at least 1 A2 allele of the GpIIIa gene was an independent
      risk factor for LVD stroke in males (OR, 2.51; 95% CI, 1.21 to 5.20).
      CONCLUSIONS: A2 allele of the GpIIIa gene is an independent risk factor for LVD
      stroke in males.

PMID- 15178824
TI  - White matter hyperintensity on cranial magnetic resonance imaging: a predictor of
      stroke.
AB  - BACKGROUND AND PURPOSE: We have previously reported that several "silent"
      infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke.
      Several recent reports have shown that high white matter grade (WMG) and
      increasing WMG over time were risk factors for stroke. We tested the hypothesis
      that high WMG > or =2 was a predictor of risk for stroke, independent of other
      risk factors. METHODS: We examined the extent of white matter hyperintensity on
      cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The
      degree of white matter hyperintensity was graded from least severe (grade=0) to
      most severe (grade=9). Participants were followed-up for an average of 7 years
      for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital
      records reviewed by an adjudication committee expert in stroke diagnosis. During
      this period, 278 strokes occurred. Results The relative risk of stroke increased
      significantly as the WMG increased. The risk of stroke was 2.8% per year for
      participants with high WMG (grades > or =5), compared with only 0.6% for
      participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is
      independent of traditional stroke risk factors and persists when controlling for
      MRI infarcts, another subclinical imaging marker of cerebrovascular disease.
      Assessment of white matter disease may be valuable in assessing future risk of
      stroke.

PMID- 15178825
TI  - SLOW-MAG.

PMID- 15178826
TI  - Perihematomal edema in primary intracerebral hemorrhage is plasma derived.
AB  - BACKGROUND AND PURPOSE: The mechanisms of perihematomal injury in primary
      intracerebral hemorrhage (ICH) are incompletely understood. An MRI study was
      designed to elucidate the nature of edema and blood flow changes after ICH.
      METHODS: Perihematomal blood flow and edema were studied prospectively with
      perfusion-weighted MRI (PWI) and diffusion-weighted MRI in 21 ICH patients. MRI
      and computed tomography (CT) images were coregistered to ensure perfusion and
      diffusion changes were outside of the hematoma. Edema volumes were measured on T2
      weighted images. Apparent diffusion coefficient (ADC) values of the edematous
      regions were calculated. RESULTS: Mean patient age was 64.2 years (45 to 89), and
      median National Institutes of Health stroke scale score was 12 (3 to 24). Median
      time to MRI was 21 hours (4.5 to 110). Average hematoma volume on CT was 26.1 (4
      to 84) mL. PWI demonstrated perihematomal relative mean transit time (rMTT) was
      significantly correlated with hematoma volume (r=0.60; P=0.004) but not edema
      volume. Perihematomal oligemia (rMTT >2 s) was present in patients with hematoma
      volumes of >15 mL (average rMTT 4.6+/-2.0 s). Perihematomal edema was present in
      all patients. ADC values within this region (1178+/-213x10(-6) mm2/s) were
      increased 29% relative to contralateral homologous regions. Increases in
      perihematomal ADC predicted edema volume (r=0.54; P=0.012) and this was confirmed
      with multivariate analysis. CONCLUSIONS: Acute perihematomal oligemia occurs in
      acute ICH but is not associated with MRI markers of ischemia and is unrelated to
      edema formation. Increased rates of water diffusion in the perihematomal region
      independently predict edema volume, suggesting the latter is plasma derived.

PMID- 15178827
TI  - Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic
      mice.
AB  - BACKGROUND AND PURPOSE: Hyperhomocysteinemia is an emerging risk factor for
      stroke, but little is known about effects of hyperhomocysteinemia on cerebral
      vascular function. We tested the hypothesis that chronic hyperhomocysteinemia in
      mice causes endothelial dysfunction in cerebral arterioles through a mechanism
      that involves superoxide. METHODS: Mice heterozygous for a targeted disruption of
      the cystathionine beta-synthase gene (Cbs+/-) and their wild type littermates
      (Cbs+/+) were fed either a control diet or a high-methionine diet for 10 to 12
      months. RESULTS: Plasma total homocysteine was elevated with the high-methionine
      diet compared with the control diet for both Cbs+/+ (7.9+/-1.0 versus 5.0+/-0.5
      micromol/L; P<0.05) and Cbs+/- (20.5+/-3.1 versus 8.2+/-0.9 micromol/L; P<0.001)
      mice. Dilatation of cerebral arterioles ( approximately 30 microm baseline
      diameter) was measured in vivo in response to the endothelium-dependent dilator
      acetylcholine or the endothelium-independent dilator nitroprusside.
      Vasodilatation to acetylcholine was impaired with the high-methionine diet
      compared with the control diet for both Cbs+/+ and Cbs+/- mice (P<0.01).
      Dilatation of arterioles to acetylcholine was restored toward normal by the
      superoxide scavenger tiron (P<0.05). Vasodilatation to nitroprusside was not
      influenced by Cbs genotype or diet. Dihydroethidium (DHE) staining for vascular
      superoxide was elevated in Cbs+/- mice fed the high-methionine diet and was
      inhibited by apocynin or Nomega-nitro-l-arginine methyl ester, implicating
      NAD(P)H oxidase and nitric oxide synthase as potential sources of superoxide.
      CONCLUSIONS: Superoxide is a key mediator of endothelial dysfunction in the
      cerebral circulation during diet-induced hyperhomocysteinemia.

PMID- 15178828
TI  - Age at natural menopause and stroke mortality: cohort study with 3561 stroke
      deaths during 37-year follow-up.
AB  - BACKGROUND AND PURPOSE: Young age at natural menopause has been related to
      increased cardiovascular mortality, but few studies have examined the
      relationship with stroke risk specifically. METHODS: In a cohort of 19,731
      Norwegian women, we analyzed the relationship between age at natural menopause
      and stroke mortality. A total of 3561 women died of stroke during the 37-year
      follow-up from 1961 through 1997. Smoking prevalence was low in the underlying
      population, and use of hormone replacement therapy was very rare. RESULTS: No
      significant linear relationship was found between age at menopause and stroke
      mortality. A 3-year increase in age at menopause was associated with a 1.0%
      estimated increase in stroke mortality (95% CI, -1.5, 3.6). No relationships were
      found for ischemic strokes (271 deaths) or hemorrhagic strokes (389 deaths) when
      considering the stroke deaths with sufficient information on death certificates.
      The estimate of the association between age at natural menopause and stroke
      mortality was hardly influenced by mortality in women with very early (aged <40
      years) or late (aged >55 years) menopause, or by a number of possible confounding
      variables. CONCLUSIONS: Age at natural menopause is essentially unrelated to
      stroke mortality.

PMID- 15178829
TI  - D-JNKI1, a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against
      cell death in severe cerebral ischemia.
AB  - BACKGROUND AND PURPOSE: In 2 models of severe ischemic injury, we have evaluated
      the neuroprotective action of D-JNKI1, a cell-penetrating and protease-resistant
      peptide selectively inhibiting the c-Jun-N-terminal kinase (JNK). METHODS:
      Hippocampal slices from newborn rats were subjected to oxygen (5%) and glucose (1
      mmol/L) deprivation for 30 minutes. Cell death was evaluated with propidium
      iodide, and the evoked potential responses were recorded in the CA1 region after
      stimulation in CA3. Male ICR-CD1 mice were subjected to permanent endoluminal
      "suture" middle cerebral artery occlusion (MCAo). The lesion size was determined
      after 24 hours by triphenyl-tetrazolium chloride staining, and neurological
      scores and rotarod treadmill performance were used to evaluate the neurological
      outcome. RESULTS: In vitro, D-JNKI administration 6 hours after oxygen glucose
      deprivation reduced cell death at 24 hours from 21%+/-8% (n=10) to 5%+/-3% (n=7,
      P<0.01). This protective effect was still seen at 48 hours, paralleled by an
      improved amplitude of the evoked potential response. In vivo in the mouse, D
      JNKI1 administration 3 hours after ischemia significantly reduced the infarct
      volume from 162+/-27 mm(3) (n=14) to 85+/-27 mm(3) (n=9, P<0.001). The functional
      outcome was also improved. CONCLUSIONS: JNK inhibition prevents cell death
      induced by oxygen and glucose deprivation in hippocampal slice cultures in vitro
      and by permanent suture MCAo in vivo. D-JNKI1 is a powerful neuroprotectant in
      models of both mild and severe cerebral ischemia, with an extended therapeutic
      window. Further investigations are needed to identify the relevant JNK target(s)
      mediating ischemic neuronal death.

PMID- 15178830
TI  - Pediatric Stroke Belt: geographic variation in stroke mortality in US children.
AB  - BACKGROUND AND PURPOSE: Numerous studies have demonstrated higher stroke
      mortality rates in adults residing in the Southeastern United States (the "Stroke
      Belt"). If the Stroke Belt is solely caused by regional differences in
      atherosclerotic stroke risk factors, it should not apply to children. METHODS:
      For the years 1979 to 1998, we determined rates of death from stroke in children
      <20 years of age based on death certificates, and compared age-adjusted stroke
      mortality rates in 11 Stroke Belt states versus other US states. For comparison,
      the same methods were applied to adults. RESULTS: Children in Stroke Belt states
      have an increased risk of death from stroke compared with children in other
      states (relative risk [RR], 1.21; 95% CI, 1.12 to 1.29). The greater risk in
      Stroke Belt states was apparent for ischemic and hemorrhagic stroke, for all age
      groups and both sexes, and persisted after adjustment for ethnicity. The
      geographic disparity in children was similar in magnitude to that in adults.
      CONCLUSIONS: Similar to adults, children in Stroke Belt states have a higher risk
      of death from stroke than children in other US states. Stroke risk factors that
      are applicable to both children and adults should be considered in attempts to
      explain this geographic variation.

PMID- 15178831
TI  - Cs2Mo15S19: a novel ternary reduced molybdenum sulfide containing Mo6 and Mo9
      clusters.
AB  - The crystal structure of dicaesium pentadecamolybdenum nonadecasulfide,
      Cs(2)Mo(15)S(19), consists of a mixture of Mo(6)S(8)S(6) and Mo(9)S(11)S(6)
      cluster units in a 1:1 ratio. Both units are interconnected via inter-unit Mo-S
      bonds. The Cs(+) cations occupy large voids between the different cluster units.
      The Cs and two inner S atoms lie on sites with 3 symmetry (Wyckoff site 12c) and
      the Mo and S atoms of the median plane of the Mo(9)S(11)S(6) cluster unit on
      sites with 2 symmetry (Wyckoff site 18e).

PMID- 15178832
TI  - Catena-poly[[silver(I)-mu-hexane-1,6-diamine-kappa2N:N'] cinnamate dihydrate].
AB  - The title compound, [[Ag(C(6)H(16)N(2))](C(9)H(7)O(2)).2H(2)O](n), has been
      synthesized and characterized by elemental analysis and single-crystal X-ray
      diffraction. The Ag atom is coordinated in a linear configuration by two N atoms
      from two hexane-1,6-diamine ligands, giving a zigzag polymeric chain with an [-Ag
      N-C-C-C-C-C-C-N-](n) backbone running parallel to the c axis. In the crystal
      packing, adjacent chains interact with the anions via the lattice water
      molecules, thus forming layers parallel to the bc plane.

PMID- 15178833
TI  - Dibarium zirconium tetraoxalate trihydrate.
AB  - A new mixed barium zirconium oxalate, triaquatetra-mu-oxalato
      dibarium(II)zirconium(IV), Ba(2)Zr(C(2)O(4))(4).3H(2)O or
      [Ba(2)Zr(C(2)O(4))(4)(H(2)O)(3)](n), has been synthesized. The complex is built
      from eightfold-coordinated Zr atoms and eleven- and sixfold-coordinated Ba atoms,
      linked by oxalate groups. The Zr atom, the two Ba atoms and one water O atom lie
      on crystallographic twofold axes, so that each coordination polyhedron has
      imposed C2 symmetry. Packing in the crystal is also assumed through hydrogen
      bonds.

PMID- 15178834
TI  - Poly[diaquacobalt(II)-di-mu4-benzene-1,2,4-tricarboxylato-bis[1,10
      phenanthrolinecobalt(II)]].
AB  - In the polymeric title compound, [Co(3)(btc)(2)(phen)(2)(H(2)O)(2)](n) [btc is
      the benzene-1,2,4-tricarboxylate trianion (C(9)H(3)O(6)) and phen is 1,10
      phenanthroline (C(12)H(8)N(2))], there are two different Co centres, Co1 and Co2.
      The Co1 centre has a deformed trigonal-bipyramidal geometry, while the Co2 centre
      lies on an inversion centre and has distorted octahedral geometry. Moreover, the
      1,2-dicarboxylate groups of one btc ligand bridge the two adjacent Co2 centres,
      and each Co2 centre is coordinated by four carboxylate O atoms from four
      different btc ligands, forming a novel kind of intersecting double-chain
      structure, with a Co.Co separation of 7.755 A, along the a axis. On the other
      hand, the two Co1 centres are bridged by two btc ligands and chelated by phen
      molecules, respectively, producing a binuclear unit with a Co.Co separation of
      8.406 A, and these binuclear units are linked by btc bridges and Co2 centres to
      extend hybrid chains of Co1 and Co2 along the [101] direction. Furthermore, each
      btc ligand acts as a pentadentate bridge, linking the Co2 double-chain structures
      and the hybrid chains of Co1 and Co2 to yield a two-dimensional network, and this
      leads to the formation of very different kinds of voids.

PMID- 15178835
TI  - Cis-dinitrito(1,4,8,11-tetraazacyclotetradecane-kappa4N)chromium(III) nitrite.
AB  - In the title compound, [Cr(ONO)(2)(cyclam)]NO(2) (cyclam is 1,4,8,11
      tetraazacyclotetradecane, C(10)H(24)N(2)), the complex cation is located on a
      twofold symmetry axis. The central Cr atom has a distorted octahedral
      coordination, involving two Cr-O bonds, with the monodentate nitrite O atoms
      adopting a cis configuration, and four Cr-N bonds. The mean Cr-N and Cr-O
      distances are 2.0895 (14) and 1.9698 (14) A.

PMID- 15178836
TI  - Pentaethylenehexaminemanganese(II) pentaborate.
AB  - The title compound, (pentaethylenehexamine-kappa(6)N)manganese(II) 4,4',6,6'
      tetrahydroxy-2,2'-spirobi(cyclotriboroxane)(1-),
      [Mn(C(10)H(28)N(6))][B(5)O(6)(OH)(4)](2), was synthesized under mild solvothermal
      conditions. The B(5)O(6)(OH)(4)(-) units are connected to one another via
      hydrogen bonds, forming a three-dimensional framework with large channels along
      the a and c axes, in which the templating [Mn(C(10)H(28)N(6))](2+) cations are
      located. The Mn(II) complex cation has a twofold axis and the coordination
      geometry of the MnN(6) group is that of a distorted trigonal prism.

PMID- 15178837
TI  - Di-mu-pivalamidato-kappa4N:O;O:N-bis[(2,2'-bipyridine-kappa2N,N')(sulfato
      kappaO)platinum(III)] tetrahydrate in a head-to-tail isomerism.
AB  - The title compound,
      [Pt(2)(III)(C(5)H(10)NO)(2)(SO(4))(2)(C(10)H(8)N(2))(2)].4H(2)O, is the first
      reported example of a complex in which an amidate-bridged Pt(bpy) dimer is
      stabilized in the oxidation level of Pt(III) (bpy is 2,2'-bipyridine). The
      asymmetric unit consists of one half of the formula unit with a twofold axis
      passing through the center of the dimer. The intradimer Pt(III)-Pt(III) bond
      distance [2.5664 (6) A] is comparable to those reported for alpha-pyridonate
      bridged cis-diammineplatinum(III) dimers [2.5401 (5)-2.5468 (8) A; Hollis &
      Lippard (1983). Inorg. Chem. 22, 2605-2614], in spite of the close contact
      between the bpy planes within the dimeric unit. The axial Pt-O(sulfate) distance
      is 2.144 (7) A.

PMID- 15178838
TI  - Tetrakis(pyridinium-2-thiolato)zinc(II) dinitrate.
AB  - The crystal structure of the title compound, [Zn(C(5)H(5)NS)(4)](NO(3))(2),
      consists of a [Zn(C(5)H(5)NS)(4)](2+) (C(5)H(5)NS is pyridinium-2-thiolate)
      cation and two nitrate anions. The central Zn(II) atom lies at a site with
      imposed -4 symmetry and is surrounded by four S atoms [Zn-S = 2.3371 (5) A] from
      four symmetrical pyridinium-2-thiolate ligands in a distorted tetrahedral
      geometry. There are N-H.O hydrogen-bonding interactions between the pyridinium-2
      thiolate ligands and nitrate O atoms. In addition, pi-pi interactions via
      aromatic N-containing ligands are discussed.

PMID- 15178839
TI  - Catena-poly[[bis(1H-benzotriazole-kappaN3)cobalt(II)]-di-mu-tricyanomethanido
      kappa2N:N'] and catena-poly[[bis(3,5-dimethyl-1H-pyrazole-kappaN2)manganese(II)]
      di-mu-tricyanomethanido-kappa2N:N'].
AB  - Two new one-dimensional coordination polymers, viz. the title compounds,
      [Co[C(CN)(3)](2)(C(6)H(5)N(3))(2)](n), (I), and
      [Mn[C(CN)(3)](2)(C(5)H(8)N(2))(2)](n), (II), have been synthesized and
      characterized by X-ray diffraction. Both complexes consist of linear chains with
      double 1,5-tricyanomethanide bridges between neighbouring divalent metal ions.
      The Co and Mn atoms are located on centres of inversion. In (I), the coordination
      environment of the Co(II) atom is that of an elongated octahedron. The Co(II)
      atom is coordinated in the equatorial plane by four nitrile N atoms of four
      bridging tricyanomethanide ions, with Co-N distances of 2.106 (2) and 2.110 (2)
      A, and in the apical positions by two N atoms from the benzotriazole ligands,
      with a Co-N distance of 2.149 (2) A. The [Co[C(CN)(3)](2)(C(6)H(5)N(3))(2)] units
      form infinite chains extending along the a axis. These chains are crosslinked via
      a hydrogen bond between the uncoordinated nitrile N atom of a tricyanomethanide
      anion and the H atom on the uncoordinated N atom of a benzotriazole ligand from
      an adjacent chain, thus forming a three-dimensional network structure. In (II),
      the Mn(II) atom also adopts a slightly distorted octahedral geometry, with four
      nitrile N atoms of tricyanomethanide ligands [Mn-N = 2.226 (2) and 2.227 (2) A]
      in equatorial positions and two N atoms of the monodentate 3,5-dimethylpyrazole
      ligands [Mn-N = 2.231 (2) A] in the axial sites. In (II), one-dimensional
      polymeric chains extending along the b axis are formed, with tricyanomethanide
      anions acting as bidentate bridging ligands. A hydrogen bond between the
      uncoordinated nitrile N atom of the tricyanomethanide ligand and the H atom on
      the uncoordinated N atom of a 3,5-dimethylpyrazole group from a neighbouring
      chain links the molecule into a two-dimensional layered structure.

PMID- 15178840
TI  - trans-[1,3-Bis(2,4-dimethylphenyl)imidazolidin-2
      ylidene]dichloro(triphenylphosphine-kappaP)palladium(II).
AB  - The title complex, [PdCl(2)(C(19)H(22)N(2))(C(18)H(15)P)], shows slightly
      distorted square-planar coordination of the palladium(II) metal center. The Pd-C
      bond distance between the N-heterocyclic ligand and the metal atom is 2.008 (3)
      A. The dihedral angle between the two dimethylphenyl ring planes is 33.17 (13)
      degrees.

PMID- 15178841
TI  - (4,4,12,12-Tetramethyl-5,8,11-triazapenta-2,14-dione 2-oxime 14-oximato
      kappa(5)N)copper(II) perchlorate: a copper(II) compound with a pentadentate
      triamine-oxime-oximate ligand.
AB  - The title compound, [Cu(C(16)H(34)N(5)O(2))]ClO(4), has discrete square-pyramidal
      (triamine-oxime-oximato)copper(II) cations and perchlorate anions. The cations
      have very approximate mirror symmetry, with the oxime [Cu-N = 2.066 (2) A],
      oximate [Cu-N = 2.087 (2) A] and amine N atoms [Cu-N = 2.138 (2) and 2.095 (2) A]
      in the tetrahedrally twisted basal plane, and the 'central' amine N atom
      coordinated axially [Cu-N = 2.183 (2) A]. The oxime and oximate groups are linked
      by an O-H.O hydrogen bond, forming a pseudo-cyclic pentadentate ligand, with an
      O.O distance of 2.395 (3) A.

PMID- 15178842
TI  - Tris[bis[hydrotris(1-pyrazolyl)borato-kappa3N2,N2',N2"]iron(III)]
      hexaisothiocyanatoiron(III).
AB  - The title compound, [Fe(C(9)H(10)BN(6))(2)](3)[Fe(NCS)(6)] or
      [Fe(III)(Tp)(2)](3)[Fe(III)(NCS)(6)] [Tp is hydrotris(1-pyrazolyl)borate],
      crystallizes in space group R-3; the asymmetric unit comprises one-half of an
      [Fe(Tp)(2)](+) cation, with its Fe atom on a crystallographic inversion centre,
      and one-sixth of an [Fe(NCS)(6)](3-) anion, on a site of -3 symmetry. The anions
      and cations are stacked into a three-dimensional supramolecular aggregate via two
      distinct types of weak C-H.pi interactions.

PMID- 15178843
TI  - A novel thiocyanate-bridged one-dimensional chain complex: [Cu(NCS)2(Hambi)]
      (Hambi is 2-aminomethyl-1H-benzimidazole).
AB  - Using 2-aminomethyl-1H-benzimidazole as the ligand, a new thiocyanate-bridged
      copper(II) complex, namely bis(2-aminomethyl-1H-benzimidazole
      kappa(2)N(2),N(3))dithiocyanatocopper(II),[Cu(NCS)(2)(C(8)H(9)N(3))], has been
      synthesized and structurally characterized. The Cu atom is five-coordinated and
      exhibits a distorted square-pyramidal geometry. The thiocyanate ions (NCS(-)) act
      as either bridging or terminal ligands. The bridging NCS(-) ligands connect
      neighboring Cu atoms, constructing chains, while the terminal NCS(-) ligands form
      hydrogen bonds with amine H atoms, leading to a complicated network.

PMID- 15178844
TI  - Polymeric (mu2-nitrato-kappa2O:O')(mu2-nitrato-kappa2O:O)(mu4-pyridinium-4
      thiolato-kappa4S:S:S:S)disilver(I).
AB  - The title compound, [Ag(2)(NO(3))(2)(C(5)H(5)NS)](n), was obtained from the
      reaction of silver nitrate with bis(4-pyridyl) disufide (4-PDS) in a mixture of
      ethanol and water, which suggests that the disulfide bond of 4-PDS can be cleaved
      under mild conditions. The structure of the title compound is a two-dimensional
      infinite array in which the asymmetric unit contains two Ag atoms, a pyridinium-4
      thiolate molecule and two nitrate groups. Each pyridinium-4-thiolate molecule
      acts as a mu(4) bridge, linking four Ag atoms, with Ag-S bond distances of 2.4870
      (19), 2.5791 (19), 2.5992 (19) and 2.848 (2) A. The Ag.Ag distances lie in the
      range 2.889 (2)-3.049 (1) A.

PMID- 15178845
TI  - cis-Diphenylbis(1,3,5-triaza-7-phosphaadamantane-kappaP)platinum(II).
AB  - The structure of the title compound, [Pt(C(6)H(5))(2)(C(6)H(12)N(3)P)(2)] or
      [Pt(Ph)(2)(PTA)(2)] (where Ph is phenyl and PTA is 1,3,5-triaza-7
      phosphaadamantane), is discussed. Selected geometric parameters are: Pt-P =
      2.2888 (16) and 2.2944 (17) A, Pt-C = 2.052 (5) and 2.064 (6) A, C-Pt-C = 84.6
      (2) degrees and P-Pt-P = 99.28 (6) degrees. The effective cone angle for the PTA
      ligands was calculated as 113 degrees.

PMID- 15178846
TI  - A one-dimensional double-chain coordination polymer: [Mn(C12H13NO6S)(C10H8N2)]n.
AB  - In the title compound, poly[[(2,2'-bipyridine-kappa(2)N,N')manganese(II)]
      micro(3)-N-tosyl-L-glutamato-kappa(4)O,O':O":O"'], [Mn(tsgluo)(bipy)](n), where
      tsgluo is N-tosyl-L-glutamate (C(12)H(13)NO(6)S) and bipy is 2,2'-bipyridine
      (C(10)H(8)N(2)), the Mn atoms are octahedrally coordinated by two N atoms of one
      bipy ligand and by four O atoms of three tsgluo(2-) anions. The gamma-carboxyl
      group coordinates to the Mn(II) atom in a chelating mode, while the alpha
      carboxyl group coordinates in a bidentate-bridging mode. The complex displays a
      one-dimensional double-chain structure.

PMID- 15178847
TI  - (1R,2R)-(-)-Bis[mu4-1-[[1,1-dimethyl-2-(trimethylsilyl)amidino]amino]-2-([1,1
      dimethyl-2-[1,1-dimethyl-2
      (trimethylsilyl)amidino]amidino]amino)cyclohexane]tetralithium(I).
AB  - The title compound, [Li(4)(C(21)H(46)N(8)Si(2))(2)], has been prepared and its
      structure determined. The whole molecule can be regarded as a molecular cage made
      up of the central eight-membered ring and six contiguous rings of three types. As
      the first example of a bridged amidinate-dicyanamide framework, this noteworthy
      structure and its electronic features are presented.

PMID- 15178848
TI  - Di-mu-aqua-bis[(N-salicylidene-beta-alaninato-kappa3O,N,O')copper(II)] urea
      disolvate.
AB  - Crystals of the title compound, [Cu(2)(C(10)H(9)NO(3))(2)(H(2)O)(2)].2CH(4)N(2)O,
      consist of two (N-salicylidene-beta-alaninato-kappa(3)O,N,O')copper(II)
      coordination units bridged by two water moieties to form a dimer residing on a
      crystallographic inversion center, along with two uncoordinated urea molecules.
      The Cu(II) atom has square-pyramidal coordination, with three donor atoms of the
      tridentate Schiff base and an O atom of the bridging aqua ligand in the basal
      plane. The axial position is occupied by the second bridging water ligand at a
      distance of 2.5941 (18) A. Hydrogen bonds between molecules of urea and the
      neighboring dimer units lead to the formation of a two-dimensional grid of
      molecules parallel to [101]. The superposition of the normals of the pyramidal
      base planes in the direction [100] indicates possible pi-pi interactions between
      the neighboring units.

PMID- 15178849
TI  - catena-Poly[[silver(I)-mu3-2,2'-[o-phenylenebis(methylenethio)]dianiline
      kappa4N:S,S':N'] nitrate chloroform solvate].
AB  - In the title complex, [[Ag(C(20)H(20)N(2)S(2))](NO(3)).CHCl(3)](n), the
      coordination about the Ag atom is a slightly distorted tetrahedron, involving the
      two S atoms of the ligand and two N-atom donors from two amine groups of two
      adjacent complexes related by centrosymmetry, so building up a chain running all
      along the crystal structure.

PMID- 15178850
TI  - Poly[[diaquatris(mu6-benzene-1,2,4,5-tetracarboxylato)tris(mu2-4,4'
      bipyridine)hexacopper(II)] dihydrate].
AB  - The hydrothermal reaction of an aqueous solution of Cu(CH(3)COO)(2).H(2)O,
      1,2,4,5-benzenetetracarboxylic acid and 4,4'-bipyridine gave rise to the
      interesting title three-dimensional polymer [[Cu(6)(btec)(3)(4,4'
      bpy)(3)(H(2)O)(2)].2H(2)O](n) (btec is 1,2,4,5-benzenetetracarboxylate,
      C(10)H(2)O(8)(4-), and 4,4'-bpy is 4,4'-bipyridine, C(10)H(8)N(2)), in which each
      btec ligand links six copper(II) cations into a lamellar
      [Cu(6)(btec)(3)(H(2)O)(2)](n) subpolymer framework. There are two distinct
      diamine units and two distinct carboxylate units, with one of each lying across
      an inversion centre.

PMID- 15178851
TI  - Bis(mu-1,10-phenanthrolin-2-olato-kappa3N,N':O)dicopper(I)(Cu-Cu) monohydrate.
AB  - The crystal structure of the title compound, [Cu(2)(C(12)H(7)N(2)O)(2)].H(2)O,
      shows that this dinuclear complex has shorter Cu-N, Cu-O and Cu-Cu distances
      within the coordination sphere than similar reported complexes. The complex
      molecule is located on a centre of symmetry and the water molecule is on a
      twofold axis of the space group C2/c. The discrete complex molecules are extended
      into a two-dimensional supramolecular array via pi-pi stacking interactions,
      intermolecular Cu.Cu interactions and C-H.O hydrogen bonds.

PMID- 15178852
TI  - Poly[[[aquamanganese(II)]-mu2-4,4'-bipyridine-mu3-succinato] 4,4'-bipyridine
      hemisolvate].
AB  - The polymeric title complex,
      [[Mn(C(4)H(4)O(4))(C(10)H(8)N(2))(H(2)O)].0.5C(10)H(8)N(2)](n), possesses a three
      dimensional open-framework structure, with the solvate 4,4'-bipyridine (bipy)
      molecules, which lie around centers of inversion, clathrated in the channels of
      the framework. The Mn(II) center is surrounded by three succinate (succ) ligands,
      one water molecule and two bipy ligands, and displays a slightly distorted
      octahedral coordination environment, with cis angles ranging from 84.14 (12) to
      96.56 (11) degrees. Each succ dianion coordinates to three Mn(II) atoms, thus
      acting as a bridging tridentate ligand; in turn, the Mn(II) atoms are bridged by
      three succ ligands, thus forming a two-dimensional Mn-succ sheet pillared by the
      bridging bipy ligands. Two hydrogen-bonding interactions, involving the water
      molecules and the carboxy O atoms of the succ ligands, are present in the crystal
      structure.

PMID- 15178853
TI  - catena-Poly[[aqua(2,2'-bipyridine-kappa2N,N')manganese(II)]-mu-terephthalato
      kappa3O,O':O"].
AB  - The title complex, [Mn(C(8)H(4)O(4))(C(10)H(8)N(2))(H(2)O)](n), takes the form of
      a zigzag chain, with the terephthalate dianion (tp) acting as a tridentate
      ligand. The Mn(II) center is surrounded by two tp ligands, one water molecule and
      one 2,2'-bipyridine (bipy) ligand and exhibits a severely distorted octahedral
      coordination environment, with cis angles ranging from 57.31 (8) to 123.97 (11)
      degrees. The complete solid-state structure can be described as a three
      dimensional supramolecular framework stabilized by hydrogen-bonding interactions
      involving the coordinated water molecule and the carboxy O atoms of the tp
      ligands, and by pi-pi stacking interactions involving the bipy rings and the
      benzene ring of the tp ligand.

PMID- 15178854
TI  - Three novel non-centrosymmetric compounds of glycine: glycine lithium sulfate,
      glycine nickel dichloride dihydrate and glycine zinc sulfate trihydrate.
AB  - The crystal structures of three compounds of glycine and inorganic materials are
      presented and discussed. The orthorhombic structure of
      glycinesulfatodilithium(I), [Li(2)(SO(4))(C(2)H(5)NO(2))](n), consists of
      corrugated sheets of [LiO(4)] and [SO(4)] tetrahedra. The glycine molecules are
      located between these sheets. The main features of the monoclinic structure of
      diaquadichloroglycinenickel(II), [NiCl(2)(C(2)H(5)NO(2))(H(2)O)(2)](n), are
      helical chains of [NiO(4)Cl(2)] octahedra connected by glycine molecules. The
      orthorhombic structure of triaquaglycinesulfatozinc(II),
      [Zn(SO(4))(C(2)H(5)NO(2))(H(2)O)(3)](n), is made up of [O(3)SOZnO(5)] clusters.
      These clusters are linked by glycine molecules into zigzag chains. All three
      compounds are examples of non-centrosymmetric glycine compounds.

PMID- 15178855
TI  - Poly[iron(II)-di-mu-imidazole-4,5-dicarboxylato-kappa3N3,O4:O5].
AB  - In the title compound, [Fe(C(5)H(3)N(2)O(4))(2)](n), each Fe atom lies on a
      centre of symmetry, in an octahedral coordination environment consisting of two
      chelate rings [Fe-N = 2.154 (3) A and Fe-O = 2.180 (3) A] and two carboxylate O
      atoms [Fe-O = 2.111 (2) A] from imidazole-4,5-dicarboxylate ligands. Extensive
      hydrogen-bonding interactions exist between layers constructed of Fe(4) squares,
      forming tunnels along the a axis with large voids.

PMID- 15178856
TI  - 4,4,6,6-Tetrachloro-2,2-(propylenedioxydi-o-phenylenediimino)
      2lambda5,4lambda5,6lambda5-cyclotriphosphazene.
AB  - The title compound, C(15)H(16)Cl(4)N(5)O(2)P(3), is a cyclophosphazenic lariat
      (PNP-pivot) ether with a spiro-cyclic 12-membered macrocyclic ligand containing
      two ether O and two N atoms; the phosphazene ring is nearly planar. In the
      macrocyclic ring, there is a four-center (trifurcate) N-H.O/N-H.N hydrogen bond.
      The relative inner-hole size of the macrocycle is estimated as approximately 0.95
      A.

PMID- 15178857
TI  - [2-(Anilinomethyl)phenyl]diphenylphosphine and [2-[(N
      methylanilino)methyl]phenyl]diphenylphosphine.
AB  - The title compounds, Ph(2)PCH(2)N(H)Ph or C(25)H(22)NP and Ph(2)PCH(2)N(CH(3))Ph
      or C(26)H(24)NP, respectively, are isomorphous, with calculated theoretical
      Tolman angles of 174 and 182 degrees.

PMID- 15178858
TI  - 1-(2-Deoxy-beta-D-erythro-pentofuranosyl)-4-nitro-1H-indazole.
AB  - In the title compound, C(12)H(13)N(3)O(5), the conformation of the glycosylic
      bond is anti [torsion angle = -105.3 (2) degrees ]. The 2'-deoxyribofuranose
      moiety adopts an S-type sugar pucker and the orientation of the exocyclic C-C
      bond is -sc (trans).

PMID- 15178859
TI  - 1,2,5-Substituted derivatives of 2-phenylpyrrolidine.
AB  - The structures of the potential anti-human-immunodeficiency virus type 1 (HIV-1)
      non-nucleoside reverse transcriptase inhibitors (NNRTI) 1-tert-butoxycarbonyl-2
      phenylpyrrolidine-2-carboxylic acid, C(16)H(21)NO(4), (I), and 2-ammoniomethyl-1
      benzyl-5-oxo-2-phenylpyrrolidine chloride, C(18)H(21)N(2)O(+).Cl(-), (II), have
      been investigated by X-ray diffraction. The investigations confirm a butterfly
      like conformation for both compounds. In (I), the pyrrolidine ring has a marked
      half-chair conformation, while it has a weakly pronounced envelope conformation
      in (II). Intermolecular hydrogen bonds, viz. O-H.O in (I), and N-H.O and N-H.Cl
      in (II), build infinite chains in both structures. Rotational disorder of the
      three methyl groups is observed in (I).

PMID- 15178860
TI  - Ammonium 4-methoxycinnamate.
AB  - In the title compound, NH(4)(+).C(10)H(9)O(3)(-), bimolecular layers of the
      anions are formed between layers of the cations. There are N-H.O hydrogen bonds
      between the ammonium ion and the carboxylate groups of the anions. In the crystal
      structure, the C=C moiety of the cinnamate ion makes an angle of 117.1 (2)
      degrees with that of the nearest neighbour, indicating that a pedal rotation is
      required before beta-type [2+2]-photodimerization can take place, which is the
      predominant mode of the photochemistry of this compound.

PMID- 15178861
TI  - The supramolecular structure of 6-hydroxy-1,3-benzoxathiol-2-one (tioxolone).
AB  - The planar molecules of 6-hydroxy-1,3-benzoxathiol-2-one, C(7)H(4)O(3)S, are
      linked by extensive O-H.O and C-H.O hydrogen bonding and are further stablilized
      by face-to-face pi-pi interactions.

PMID- 15178862
TI  - Bergenin monohydrate from the rhizomae of Astilbe chinensis.
AB  - The title compound, 4-methoxy-2-[(1S,2R,3S,4S,5R)-3,4,5,6-tetrahydro-3,4,5
      trihydroxy-6-(hydroxymethyl)-2H-pyran-2-yl]-alpha-resorcylic acid delta-lactone
      monohydrate, C(14)H(16)O(9).H(2)O, is a C-glucoside of 4-O-methylgallic acid
      which has antiasthmatic, antitussive, anti-inflammatory, antifungal, anti-HIV and
      antihepatotoxic activity. The molecule is composed of three six-membered rings:
      an aromatic ring, a glucopyranose ring and an annellated delta-lactone ring. The
      glucopyranose ring exhibits only small deviations from an ideal chair
      conformation. The annellated delta-lactone ring possesses the expected half-chair
      conformation. There is one intra- and six intermolecular hydrogen bonds which
      form an extensive hydrogen-bonding network within the crystal.

PMID- 15178863
TI  - Diospyrin.
AB  - The structure of the title natural product, 1',5-dihydroxy-3',7-dimethyl-2,2'
      binaphthalene-1,4,5',8'-tetrone, C(22)H(14)O(6), confirms the atomic connectivity
      postulated on the basis of spectroscopic data. The geometric parameters are
      normal and the angle between the planes of the two ring systems is 59.74 (2)
      degrees. The crystal packing is influenced by O-H.O hydrogen bonds, and possible
      short C-H.O and pi-pi stacking interactions.

PMID- 15178864
TI  - Monoalkylated 4'-aryl-substituted terpyridines.
AB  - 1-Methyl-2-[4-phenyl-6-(pyridinium-2-yl)pyridin-2-yl]pyridinium diperchlorate,
      C(22)H(19)N(3)(2+).2ClO(4)(-), (I), and 2-[4-(methoxyphenyl)-2,2'-bipyridin-6-yl]
      1-methylpyridinium iodide, C(23)H(20)N(3)O(+).I(-), (II), both crystallize in the
      monoclinic space group P2(1)/c. In contrast with the monocharged molecule of
      (II), the doubly charged molecule of (I) contains an additional protonated
      pyridine ring. One of the two perchlorate counter-anions of (I) interacts with
      the cation of (I) via an N-H.O hydrogen bond. In (II), two molecules related by a
      centre of symmetry are connected by weak pi-pi interactions, forming dimers in
      the crystal structure.

PMID- 15178865
TI  - 2'-(4-Fluorophenyl)-[1,2,3]triazolo[4',5':16,17]androst-5-en-3beta-ol methanol
      hemisolvate.
AB  - The asymmetric unit of the title compound, C(25)H(30)FN(3)O.0.5CH(3)OH, contains
      four symmetry-independent steroid and two methanol molecules. The conformations
      of the independent steroid molecules are very similar. Intermolecular O-H.O
      hydrogen bonds create two independent chains, each of which links two of the
      independent steroid molecules plus one methanol molecule via a co-operative O-H.O
      H.O-H pattern. Intermolecular C-H.O and C-H.F interactions are also observed.

PMID- 15178866
TI  - (-)-Parasantonic acid and its enol lactone, (+)-parasantonide: observation of the
      rare acid-to-acid catemeric hydrogen-bonding mode in a gamma,epsilon
      diketocarboxylic acid.
AB  - The title diketo acid, (-)-alpha,3a,7-trimethyl-5,8-dioxo-1,4
      ethanoperhydropentalene-1-acetic acid, C(15)H(20)O(4), is shown to aggregate in
      the solid state as acid-to-acid hydrogen-bonded catemers, whose chains follow
      2(1) screw axes from each carboxyl H atom to the C=O group of a neighboring
      carboxyl group [O.O = 2.672 (4) A and O.H-O = 173 degrees ]. Two parallel
      counterdirectional screw-related single-strand hydrogen-bonded chains pass
      through the cell in the a direction. Two intermolecular C=O.H-C close contacts
      are present in this compound. Both this diketo acid and its enol lactone, (+)
      parasantonide [systematic name: (-)-alpha,3a,7-trimethyl-5-oxo-1,4
      ethenoperhydropentalene-1,8-carbolactone], C(15)H(18)O(3), have an R
      configuration at the methylated chiral center adjacent to the carboxyl group,
      unlike the precursor from which they are derived, viz. (-)-santonic acid.

PMID- 15178867
TI  - (3aS,7aS)-1-[2-Oxo-1,3-bis[(S)-1-phenylethyl]perhydro-1,3,2lambda5
      benzodiazaphosphol-2-yl]-1-phenylmethanol: a mixture of diastereoisomers in a
      disordered crystal.
AB  - In the title compound, C(29)H(35)N(2)O(2)P, the stereogenic C center alpha to the
      P atom, formed during the Pudovik condensation reaction between a deprotonated
      chiral diazaphosphole and benzaldehyde, has disordered substituents, giving a
      mixture of Calpha-R and Calpha-S diastereoisomers. Moreover, this compound
      crystallizes with two independent molecules in the asymmetric unit. The observed
      configuration at the Calpha atom is 0.741 (6)-S mixed with 0.259 (6)-R,
      indicating diastereoisomeric enrichment during crystallization. Data from
      solution and solid-state studies consistently point to an epimerization process
      at the Calpha atom.

PMID- 15178868
TI  - p-Nitrophenyl isocyanide.
AB  - Achiral p-nitrophenyl isocyanide, C(7)H(4)N(2)O(2), crystallizes in the
      orthorhombic chiral space group P2(1)2(1)2(1). Attractive intermolecular
      interactions between the nitro O atoms and both aromatic H and nitro N atoms of
      neighbouring molecules are observed. The O.N interaction is surprisingly strong
      [N.O = 2.869 (2) A] compared with other aromatic nitro compounds.

PMID- 15178869
TI  - p-Decylphenyl isocyanide and p-decylbenzonitrile: isomorphous isonitrile/nitrile
      isomers.
AB  - p-Decylphenyl isocyanide, p-C(10)H(21)-C(6)H(4)-NC or C(17)H(25)N, and p
      decylbenzonitrile, p-C(10)H(21)-C(6)H(4)-CN or C(17)H(25)N, are isomorphous. The
      molecules lie in mirror planes, with the C(6) rings perpendicular to the mirror.
      The packing of both molecules includes an aliphatic region, with close to ideal
      packing of the C(10)H(21) chains, and an aromatic region, with phenyl ring-CN
      interactions. In addition, the CN ends of the molecules are also involved in a
      CN.NC dipolar interaction.

PMID- 15178870
TI  - Molecular conformation and supramolecular aggregation in four 2,3,4,5-tetrahydro
      3,4-diphenylbenzothiazepines.
AB  - In (2RS,4RS)-1-acetyl-2,3,4,5-tetrahydro-2,4-diphenyl-1,5-benzothiazepine,
      C(23)H(21)NOS, (I), and (2RS,4RS)-1-chloroacetyl-2,3,4,5-tetrahydro-2,4-diphenyl
      1,5-benzothiazepine,C(23)H(20)ClNOS, (II), the seven-membered rings have boat
      conformations, whereas in (2RS,4RS)-1-benzoyl-2,3,4,5-tetrahydro-2,4-diphenyl-1,5
      benzothiazepine, C(28)H(23)NOS, (III), this ring has a conformation intermediate
      between the boat and twist-boat forms. The molecules of (I) are linked into
      isolated R(2)(2)(16) dimers by two C-H.O hydrogen bonds [H.O = 2.41 and 2.47 A,
      C.O = 3.268 (3) and 3.336 (3) A, and C-H.O = 150 and 152 degrees ]. In (II), the
      molecules are again linked by two C-H.O hydrogen bonds [H.O = 2.42 and 2.48 A,
      C.O = 3.295 (3) and 3.364 (2) A, and C-H.O = 153 and 154 degrees ], forming
      chains of alternating R(2)(2)(18) and R(2)(2)(22) rings. Two C-H.O hydrogen bonds
      [H.O = 2.49 and 2.53 A, C.O = 3.347 (2) and 3.295 (2) A, and C-H.O = 150 and 138
      degrees ] link the molecules of (III) into sheets containing alternating
      R(2)(2)(22) and R(6)(4)(30) rings. Re-examination of the published structure of
      (2RS,4RS)-2,3,4,5-tetrahydro-2,4-diphenyl-1,5-benzothiazepine shows that the
      molecules are linked by three C-H.pi(arene) hydrogen bonds into a three
      dimensional framework.

PMID- 15178871
TI  - Exo Diels-Alder adducts between ortho- and para-N-acetoxyphenylmaleimides and
      furan.
AB  - In exo-2-(3,5-dioxo-10-oxa-4-azatricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)phenyl
      acetate, C(16)H(13)NO(5), the plane of the acetoxy group lies almost
      perpendicular to that of the phenyl ring [dihedral angle = 89.8 (1) degrees ], in
      contrast with the smaller deviations found in the para isomer exo-4-(3,5-dioxo-10
      oxa-4-azatricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)phenyl acetate, C(16)H(13)NO(5),
      these being 63.6 (1) and 37.0 (1) degrees for the two crystallographically
      independent molecules. Irrespective of the position of the acetoxy group, both
      compounds pack through soft C-H.X (X is O or phenyl) interactions, forming
      interlinked centrosymmetric tetramers in the bc plane.

PMID- 15178872
TI  - N-[(1E)-Amino[3-methyl-5-(4-methylphenyl)-4,5-dihydro-1H-pyrazol-1-yl]methylene]
      1H-imidazole-1-carboxamide.
AB  - In the title compound, C(16)H(18)N(6)O, an N-carbonylimidazole derivative of
      pyrazoline-1-carboximidamide, the pi-electron density of the N atom in the 1
      position on the pyrazoline ring is delocalized through the amidine moiety and the
      adjacent carbonyl group. The imidazole ring, though coplanar with the rest of the
      molecule, is deconjugated. The pyrazoline ring adopts a flat-envelope
      conformation, having the substituted phenyl ring oriented perpendicular to the
      mean plane of the heterocycle. Both of the two potential hydrogen-bond donors are
      involved in intramolecular hydrogen-bonding interactions.

PMID- 15178873
TI  - Two types of monoethyl alpha-anilinobenzylphosphonates: a zwitterion and a
      molecular compound.
AB  - The crystal structures of the potential antitumour agents monoethyl (alpha
      anilinobenzyl)phosphonate, C(15)H(18)NO(3)P, (I), and its 4-azobenzene
      substituted derivative monoethyl [alpha-[4
      (phenyldiazenyl)anilino]benzyl]phosphonate, C(21)H(22)N(3)O(3)P, (II), are
      described. A zwitterionic form of (I) and a neutral molecular form of (II) are
      observed, which is fully in accordance with previously reported spectroscopic
      studies. In both structures, hydrogen bonding induces the formation of zigzag
      head-to-head double layers parallel to the crystallographic b axis.

PMID- 15178874
TI  - Three hexahydropyridopyrimidine-spiro-cyclohexanetriones: supramolecular
      structures generated by O-H...O, N-H...O, C-H...O and C-H...pi hydrogen bonds,
      and pi-pi stacking interactions.
AB  - 4',4'-Dimethyl-2-methylsulfanyl-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-6
      spiro-1'-cyclohexane-2',4,6'-trione, C(15)H(19)N(3)O(3)S, (I), has a markedly
      polarized molecular-electronic structure, and the molecules are linked into a
      three-dimensional framework by a combination of N-H.O, C-H.O and C-H.pi hydrogen
      bonds. 8-Hydroxymethyl-4',4'-dimethyl-2-methylsulfanyl-3,4,5,6,7,8
      hexahydropyrido[2,3-d]pyrimidine-6-spiro-1'-cyclohexane-2',4,6'-trione,
      C(16)H(21)N(3)O(4)S, (II), where the hydroxymethyl substituent is disordered over
      two sets of sites, has a much less polarized structure than (I); the molecules
      are linked by a combination of O-H.O and N-H.O hydrogen bonds into chains
      containing alternating R(2)(2)(8) and R(2)(2)(16) rings, and these chains are
      linked into sheets by a combination of a pi-pi stacking interaction and a C-H.O
      hydrogen bond. 8-Ethoxymethyl-2-methoxy-4',4'-dimethyl-3,4,5,6,7,8
      hexahydropyrido[2,3-d]pyrimidine-6-spiro-1'-cyclohexane-2',4,6'-trione,
      C(18)H(25)N(3)O(5), (III), has an unpolarized electronic structure, and a
      combination of N-H.O, C-H.O and C-H.pi hydrogen bonds links the molecules into
      sheets.

PMID- 15178875
TI  - Hydrogen-bonding adducts of benzenepolycarboxylic acids with N,N
      dimethylformamide: benzene-1,4-dicarboxylic acid N,N-dimethylformamide disolvate,
      benzene-1,2,4,5-tetracarboxylic acid N,N-dimethylformamide tetrasolvate and
      benzene-1,2,3-tricarboxylic acid N,N-dimethylformamide disolvate monohydrate.
AB  - The N,N-dimethylformamide (DMF) solvates of terephthalic acid, H(2)TA.2DMF
      (C(8)H(6)O(6).2C(3)H(7)NO), pyromellitic acid, H(4)PMA.4DMF
      (C(10)H(6)O(8).4C(3)H(7)NO), and hemimellitic acid, H(3)HMA.2DMF.H(2)O
      (C(9)H(6)O(6).2C(3)H(7)NO.H(2)O), are reported. The DMF solvate of terephthalic
      acid is centrosymmetric, containing one complete formula unit in the asymmetric
      unit. Both carboxylic acid groups hydrogen bond to a DMF molecule via an
      R(2)(2)(7) O-H.O/C-H.O motif. Discrete H(2)TA.2DMF units are observed. The DMF
      solvate of pyromellitic acid is centrosymmetric and the asymmetric unit contains
      half a formula unit. One of the unique carboxylic acid groups forms an R(2)(2)(7)
      motif with a DMF molecule, while the other forms a linear O-H.O hydrogen bond to
      the second unique DMF molecule. Discrete H(4)PMA.4DMF units are observed. The DMF
      solvate of hemimellitic acid is non-centrosymmetric and includes a molecule of
      water per formula unit. Both DMF molecules form an R(2)(2)(7) motif with the two
      outer carboxylic acid groups of HMA. A one-dimensional ladder structure is formed
      via hydrogen bonding between the central carboxylic acid group and the water
      molecules. The carboxylic acid R(2)(2)(8) head-to-tail motif is not observed in
      any of these examples. The inclusion of DMF thereby has the effect of limiting
      the dimensionality of the structures.

PMID- 15178876
TI  - (+/-)-3-Ethyl-2-methyl-4-oxocyclohexanecarboxylic acid: catemeric hydrogen
      bonding in a cyclic delta-keto acid.
AB  - In the title compound, C(10)H(16)O(3), the two molecules of the asymmetric unit
      form acid-to-ketone hydrogen-bonded chains. The two species differ only very
      slightly and are related by a pseudo-center, so that the apparent translational
      relationship among the units of the hydrogen-bonded chain is actually a pseudo
      translation, with the molecules alternating in type. Two counterdirectional pairs
      of chains proceed through each cell [O.O = 2.743 (2) and 2.683 (2) A, and O-H.O =
      171 (3) and 157 (3) degrees ]. Three intermolecular C-H.O close contacts were
      found, involving all three O atoms of one of the molecules.

PMID- 15178877
TI  - Non-merohedrally twinned crystals of N,N'-bis(3-methylphenyl)-N,N'-diphenyl-1,1'
      biphenyl-4,4'-diamine: an excellent triphenylamine-based hole transporter.
AB  - N,N'-Bis(3-methylphenyl)-N,N'-diphenyl-1,1'-biphenyl-4,4'-diamine (TPD),
      C(38)H(32)N(2), crystallizes in the monoclinic space group P2(1) with a pseudo
      orthogonal lattice, rather than the previously reported orthorhombic space group
      P2(1)2(1)2(1) [Kennedy, Smith, Tackley, David, Shankland, Brown & Teat (2002). J.
      Mater. Chem. 12, 168-172]. The asymmetric unit consists of two independent
      molecules, A and B, which are arranged along the [100] direction to form vertical
      layers of alternately stacked A and B molecules. Molecule A shows a great deal of
      rotational movement in the four terminal aryl rings, resulting in two disordered
      tolyl groups split over two sites, while molecule B exhibits an almost cis
      configuration of the two terminal tolyl groups with respect to these ring planes.

PMID- 15178878
TI  - 3-Methoxy-5-(4-methylphenyldiazenyl)salicylaldehyde and 3-methoxy-5-(2
      methylphenyldiazenyl)salicylaldehyde.
AB  - The two title molecules, both C(15)H(14)N(2)O(3), are roughly planar and display
      a trans conformation with respect to the -N=N- double bond, as found for other
      diazene derivatives. In both compounds, there are intramolecular O-H.O hydrogen
      bonds and the crystal packing is governed by weak intermolecular C-H.O hydrogen
      bonds and pi-pi stacking.

PMID- 15178879
TI  - 3-Hydroxy-6-[(4-hydroxyphenylamino)methylene]cyclohexa-2,4-dienone and 2-hydroxy
      6-[(4-hydroxyphenylamino)methylene]cyclohexa-2,4-dienone.
AB  - The title compounds, both C(13)H(11)NO(3), exist as the keto-amine tautomers, and
      the formal hydroxyl H atoms, which display strong intramolecular hydrogen bonds,
      are located on the N atoms. This is a verification of the preference for the keto
      amine tautomeric form in the solid state. The 2-hydroxy isomer has two
      independent molecules, with the molecules linked by intramolecular N-H.O and O
      H.O and intermolecular O-H.O hydrogen bonds into three-dimensional networks.

PMID- 15178880
TI  - Overlooking impacted canines.

PMID- 15178881
TI  - Clinical uses of diode lasers in orthodontics.

PMID- 15178882
TI  - The Butterfly System.

PMID- 15178883
TI  - The Wave Spring.

PMID- 15178884
TI  - Comparative study of manual and computerized cephalometric analyses.

PMID- 15178885
TI  - Micro-implant anchorage for forced eruption of impacted canines.

PMID- 15178886
TI  - The regulatory role of dendritic cells in the immune response.
AB  - Dendritic cells (DCs) are key regulators of immune reactions. They control early
      innate responses, regulate long-lasting adaptive immunity and contribute to the
      maintenance of self-tolerance. DCs continuously monitor the environment through a
      multifaceted innate antigen receptor repertoire and, in response to
      perturbations, start a complex genetic reprogramming that leads to a complete
      activation of innate and, then, adaptive immune responses. This review discusses
      how DCs become efficient activators of NK and, subsequently, T cells following a
      microbial encounter.

PMID- 15178887
TI  - T lymphocyte-mediated immune responses to chemical haptens and metal ions:
      implications for allergic and autoimmune disease.
AB  - Chemical haptens and metal ions interact with proteins and thereby become
      recognizable by T and B lymphocytes. They induce the production of
      proinflammatory cytokines and chemokines by various cell types due to triggering
      of innate immune responses. This is an important prerequisite for the activation
      of the adaptive immune system and the development of diseases like allergic
      contact dermatitis and adverse drug and autoimmune reactions. Our increasing
      knowledge about the molecular basis of hapten and metal ion recognition by T
      cells and about the pathomechanisms of contact hypersensitivity and chemical
      induced autoimmune reactions allows concomitant progress in the development of
      modern strategies for immunotherapy and will hopefully enable more specific
      intervention in hapten- and metal ion-induced human diseases in the future.

PMID- 15178888
TI  - Quantitative analysis of mast cells in benign and malignant breast lesions.
      Immunohistochemical study on formalin-fixed, paraffin-embedded tissues.
AB  - BACKGROUND: It has been reported that the number of mast cells was significantly
      greater in malignant breast carcinomas than in benign breast lesions. This was
      due to tryptase-containing mast cells while tryptase, chymase-containing mast
      cells had no effect. However, analysis of mast cells in breast carcinomas and
      benign breast lesions based on their histological findings remains to be
      elucidated. METHODS: Using immunohistochemical methods morphological examinations
      of mast cells were undertaken in benign and malignant breast tissues from 51
      patients (30 benign, 21 malignant), which were formalin-fixed and paraffin
      embedded. In the study with malignant breast tissues, samples of malignant
      tissues and adjacent healthy tissues were obtained from a single patient, and the
      number of mast cells was compared. RESULTS: Among benign breast tissues, the
      number of mast cells in intracanalicular fibroadenoma was significantly lower
      than that in pericanalicular fibroadenoma as well as that in mastopathy. The
      number of mast cells was significantly greater in malignant lesions than that in
      benign lesions. The number of mast cells in scirrhous carcinoma and that in solid
      tubular carcinoma were significantly increased compared with that in adjacent
      healthy tissues. In addition, the number of mast cells in scirrhous carcinoma was
      highest among breast carcinomas, and significantly greater than that in
      papillotubular carcinoma. CONCLUSION: We were the first to find the significant
      lower number of mast cells in intracanalicular breast fibroadenoma when compared
      with that in pericanalicular fibroadenoma as well as that in mastopathy.
      Moreover, the number of mast cells in scirrhous carcinoma was significantly
      greater than that in papillotubular carcinoma.

PMID- 15178889
TI  - Association of IL4 gene polymorphisms with asthma in North Indians.
AB  - BACKGROUND: Asthma is a complex airway disorder, and a number of genetic loci
      have been found to be associated with asthma. The 5q31-33 region is one of the
      most important loci linked to asthma and atopic disorders. However, association
      studies with candidate genes in this region, such as IL4, were inconclusive, as
      both positive and negative results were obtained in several populations studied.
      The aim of our case-control study was to determine the association between IL4
      and asthma in North Indians. PATIENTS AND METHODS: Polymorphisms in the promoter
      and a dinucleotide repeat in the 2nd intron in IL4 were genotyped by sequencing
      and GeneScan analysis, respectively, in ethnically matched, unrelated patients (n
      = 171) and controls (n = 128), following the guidelines of the American Thoracic
      Society. RESULTS: The proximal promoter region of the IL4 gene was found to be
      invariant. Previously reported polymorphisms, -590 C/T and +33 C/T, were found to
      be absent in our population. The chi2 test using only large expected cell counts
      (more than 5% of the sample size) showed a significant association between allele
      size and disease status (chi2 = 38.08, d.f. = 6, p < 0.05). In addition, a
      significant difference was observed for the allele and genotype frequencies (p <
      0.0005 and p = 0.0009, respectively) in the patient and the control groups using
      the Fisher-Freeman-Halton test. CONCLUSION: Our studies indicate that the
      promoter of the IL4 gene is invariant in our population. The case-control studies
      on the CA repeat polymorphism in the 2nd intron of the IL4 gene have shown
      interesting results and indicate the need for further family-based studies.

PMID- 15178890
TI  - Enhancement of interleukin-4 production in activated CD4+ T cells by diphthalate
      plasticizers via increased NF-AT binding activity.
AB  - BACKGROUND: Diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), two
      commonly used plasticizers in flexible polyvinylchloride formulations, have
      potentially adverse effects on human health. However, the influence of these
      diphthalates on allergic responses remains unclear. In this study we examined the
      effects of DEHP and DINP on IL-4 production in CD4+ T cells and the level of IgE
      in sera, critical hallmarks associated with allergic diseases. METHODS: Mouse T
      cells were exposed to two diphthalates in vitro and in vivo. The levels of IL-4
      and IgE were determined by ELISA, and the degree of NF-AT activation was
      determined by IL-4 gene promoter assay and electrophoretic mobility shift assay.
      RESULTS AND DISCUSSION: Both DEHP and DINP significantly enhanced IL-4 production
      in activated CD4+ T cells in a concentration-dependent manner. Treatment with
      DEHP or DINP in vivo resulted in a significant increase of IL-4 production in
      CD4+ T cells and of IgE levels in sera. Furthermore, DEHP and DINP enhanced the
      activation of IL-4 gene promoter in EL4 T cells and the enhancing effect mapped
      to a region in the IL-4 promoter containing binding sites for a transcription
      factor, NF-AT. The activation of T cells resulted in markedly enhanced binding
      activities to the NF-AT site, which significantly increased upon addition of DEHP
      or DINP, indicating that NF-AT was involved in the enhancing effect of DEHP and
      DINP on IL-4 production. These findings suggest that both DEHP and DINP enhance
      allergic responses by enhancement of IL-4 production in CD4+ T cells via
      stimulation of NF-AT-binding activity.

PMID- 15178891
TI  - Expression of costimulatory molecules in peripheral blood mononuclear cells of
      atopic asthmatic children during virus-induced asthma exacerbations.
AB  - BACKGROUND: Respiratory viruses are the most frequent triggers of acute asthma
      exacerbations. Herein we investigate costimulatory molecule expression on
      peripheral blood mononuclear cells (PBMC) during such exacerbations. METHODS:
      Eleven children with atopic asthma were followed prospectively and respiratory
      symptoms were recorded on diary cards. A blood sample and nasopharyngeal wash
      (NPW) were obtained at baseline and subsequently during an exacerbation. PBMC
      were immunophenotyped using flow cytometry. NPW samples were examined for the
      presence of respiratory viruses by RT-PCR. RESULTS: A virus was detected in 73%
      of exacerbations and none at baseline. A drop of NK cells and a marginal increase
      of monocytes were the only changes of cell count during the exacerbation. A
      significant downregulation of B7-2 on NK cells and of B7-1 on monocytes was also
      observed during exacerbations. CONCLUSIONS: The above observations are in
      contrast to in vitro findings showing an upregulation of costimulatory molecules
      after exposure of blood cells to viruses or allergens. It is possible that
      activated immune cells leave the blood stream to migrate to the inflammation site
      during acute asthma exacerbations.

PMID- 15178892
TI  - Altered levels of the soluble IL-1, IL-4 and TNF receptors, as well as the IL-1
      receptor antagonist, in intermittent allergic rhinitis.
AB  - BACKGROUND: The effects of cytokines are modulated by soluble cytokine receptors
      (SCR) and receptor antagonists. Therefore, allergic disease may depend on altered
      proportions between cytokines, their SCR and receptor antagonists, rather than
      absolute changes in cytokine levels. Little is known about SCR in intermittent
      allergic rhinitis (IAR). OBJECTIVE: To examine the concentrations of SCR, i.e.
      sIL-1R2, sIL-4R, sIL-6R and sTNFR1, as well as the interleukin-1 receptor
      antagonist (IL-1Ra) in nasal fluids from allergen-challenged patients with IAR
      and healthy controls. METHODS: 30 patients with birch- or grass-pollen-induced
      IAR and 30 healthy controls were studied. In the patients nasal fluids were
      obtained before as well as 1 and 6 h after allergen provocation. RESULTS: Both
      symptom scores and rhinoscopic signs of rhinitis increased in the patients after
      allergen challenge. Comparisons between patients and controls showed that sIL-4R
      was lower in patients before and 1 and 6 h after provocation. IL-1Ra was lower
      before and 1 h after provocation. In addition, lower concentrations of sTNFR1
      were found in patients after 1 h, while sIL-1R2 concentrations were higher after
      1 h. Comparisons of patients before and after challenge showed that IL-1Ra and
      sTNFR1 decreased after 1 h, while sIL-1R2 increased. No significant differences
      were found compared to 6 h. sIL-6R did not significantly differ between the study
      groups. CONCLUSIONS: After allergen challenge, significant changes in the nasal
      fluid levels of IL-1Ra, sIL-1R2 and sTNFR1 were found. By contrast, sIL-4R
      remained at lower levels than in controls both before and after challenge. Since
      sIL-4R modulates IgE synthesis, this may play a role in the pathogenesis of IAR.

PMID- 15178893
TI  - Acetaldehyde induces histamine release from human airway mast cells to cause
      bronchoconstriction.
AB  - BACKGROUND: Approximately half of the Japanese asthmatics experience exacerbation
      of asthma after alcohol consumption. We previously reported that this phenomenon
      is probably caused by histamine release from mast cells by acetaldehyde
      stimulation. However, no reports have described the effects of acetaldehyde on
      human airway mast cells. The purpose of the present study was to demonstrate
      acetaldehyde-induced histamine release from human airway mast cells with
      subsequent airway smooth muscle contraction and to investigate the ensuing
      mechanisms. METHODS: Human tissue samples were prepared from the lungs resected
      from patients with lung cancer. The effect of acetaldehyde on airway muscle tone
      and the concentration of chemical mediators released in the organ bath were
      measured before and after acetaldehyde stimulation. Mast cells were prepared from
      lung parenchyma by the immunomagnetic method and then stimulated with
      acetaldehyde to determine the chemical mediators released. RESULTS: Acetaldehyde
      (>3 x 10(-4) M) increased airway muscle tone, which was associated with a
      significant increase in the release of histamine, but not thromboxane B2 or
      cysteinyl-leukotrienes. A histamine (H1 receptor) antagonist completely inhibited
      acetaldehyde-induced bronchial smooth muscle contraction. Acetaldehyde also
      induced a significant histamine release from human lung mast cells and
      degranulation of mast cells. CONCLUSIONS: The present results strongly suggest
      that acetaldehyde stimulates human airway mast cells to release histamine, which
      may be involved in bronchial smooth muscle contraction following alcohol
      consumption.

PMID- 15178894
TI  - Impaired interferon-gamma production in a subset population of severe atopic
      dermatitis.
AB  - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease
      characterized by pruritic chronic eczema. The immunopathogenesis of this
      condition is still not well understood. We assessed the transcription and
      production of IFN-gamma, the Th1 cytokine, and the Th2 cytokine IL-5 in
      peripheral blood mononuclear cells (PBMCs) from patients with severe AD. METHODS:
      The subjects included 17 severe (serum IgE: 5,000-92,000 U/ml, median: 20,000
      U/ml), 4 mild AD (IgE: 2-520 U/ml) and 8 nonatopic controls (IgE: <100 U/ml). The
      severe AD patients were classified into two groups according to the response to
      standard treatment with topical glucocorticoids. Individuals were classified as
      poorly responsive (AD-P) if the clinical score decreased less than one third
      after 2 weeks of hospital treatment and as responsive (AD-R) if the score
      decreased more than one third. PBMCs isolated from the subjects were stimulated
      with PHA and PMA. RESULTS: The expression of IFN-gamma in PBMCs in the AD-P group
      was much lower than that observed in the other groups at both mRNA and protein
      levels. There were no significant differences in the levels of IL-5 both in mRNA
      and protein levels between the groups. There were no significant differences in
      STAT4 DNA-binding activity following PHA/IL-2/IL-12 stimulation between AD-P and
      controls. CONCLUSIONS: These results suggest that the decreased INF-gamma
      production may account for the abnormal immunopathogenesis of severe, intractable
      AD.

PMID- 15178895
TI  - A possible role of TARC in antigen-specific Th2-dominant responses in patients
      with Paragonimiasis westermani.
AB  - BACKGROUND: Paragonimiasis westermani (Pw), a common parasitic zoonosis in Asia,
      is typically associated with eosinophilia. Th2 cytokines seem to have an
      important role in the clinical manifestations of this disease. Thymus and
      activation-regulated chemokine (TARC) is a potential key regulator of Th2
      mediated inflammation. The purpose of the present study was to evaluate the
      antigen-specific Th2-dominant responses in patients with Pw. METHODS: The
      concentrations of cytokines and chemokines in supernatants of peripheral blood
      mononuclear cell (PBMC) cultures with or without antigen stimulation were
      measured by enzyme-linked immunosorbent assay (ELISA). TARC levels in serum from
      Pw patients were also evaluated by ELISA. The number of Th2 cells expressing the
      CC-chemokine receptor 4 (CCR4) in the peripheral blood was evaluated by flow
      cytometry. RESULTS: Antigen-stimulation induced production of IL-5 and IL-13, but
      not IFN-gamma from PBMC cultures in patients with Pw. Pw patients had elevated
      serum TARC levels and a higher proportion of CCR4-expressing cells among CD4+ T
      cells in the peripheral blood. There were also higher levels of TARC, but not IP
      10, in supernatants of antigen-stimulated PBMC culture compared to unstimulated
      PBMC culture in patients with Pw. CONCLUSION: Our findings clarify antigen
      specific Th2-dominant responses in patients with Pw and suggest a possible role
      for TARC in Th2-dominant responses.

PMID- 15178896
TI  - Chronic granulomatous disease: a clinical survey of 41 patients from the Iranian
      primary immunodeficiency registry.
AB  - BACKGROUND: Chronic granulomatous disease (CGD) represents a group of inherited
      disorders of the phagocytic system, involving recurrent infections at different
      sites, especially the respiratory system. The present study was accomplished in
      order to determine the clinical spectrum of Iranian patients with CGD. METHODS:
      Forty-one patients (29 males and 12 females) with CGD, who had already been
      referred to two immunodeficiency referral centers in Iran, were reviewed during a
      22-year period (1980-2002). RESULTS: These patients belonged to 34 families, and
      56% of them were consanguineous. The median age at the time of study was 12 years
      (3 months to 22 years). The median age at onset of symptoms was 4 months (1 month
      to 12 years), and the median diagnostic age was 5.5 years (2 months to 20 years),
      with a diagnostic delay of 3 years on average. The most common presenting
      complaint in our CGD patients was lymphadenopathy (seen in 11 patients, 26.8%).
      The most common manifestations of CGD (in descending order) were lymphadenopathy
      (75.6%), pulmonary infections (65.9%) and skin involvement (63.4%) during their
      illness, followed by gastrointestinal (56.1%), skeletal (29.3%), upper
      respiratory tract (26.8%) and central nervous system (2.4%) involvement.
      CONCLUSIONS: Early diagnosis of the disease is crucial. In view of the
      possibility of timely treatment, i.e. prophylactic treatment of infection, CGD
      should be excluded in any patient with unexplained infections or granulomas.

PMID- 15178897
TI  - Successful treatment of severe anaphylactic shock with vasopressin. Two case
      reports.
AB  - Severe anaphylactic shock is a life-threatening situation that needs immediate
      treatment of progressive hemodynamic failure. We report two cases of severe
      anaphylactic shock treated with arginine-vasopressin (AVP): In a 42-year-old male
      patient anaphylactic shock was caused by the sting of a hornet. At the scene, he
      was found unconscious, cyanotic, with a heart rate of 130/min without measurable
      blood pressure. The patient was intubated and ventilated with 100% oxygen,
      intravenous epinephrine (1 mg over 2 min) had no effect on blood pressure. After
      injection of 10 IU vasopressin, followed by infusion of 40 IU vasopressin,
      hemodynamics could be stabilized at once. In the second case, a 47-year-old male
      patient was stung by a wasp. At the scene he was unconscious, blood pressure was
      not measurable, heart rate was 140/min. The patient was treated with 40 IU
      vasopressin followed by rapid infusion of 500 ml NaCl 0.9%. After injection of
      vasopressin, blood pressure raised to 80/50 mm Hg and heart rate decreased to
      90/min. Both patients needed ventilator therapy for several days and recovered
      fully.

PMID- 15178898
TI  - Hormone therapy after endometrial cancer.
AB  - Endometrial carcinoma is listed among the absolute contra-indications to hormone
      therapy. After all the existing opinions so far, hormone therapy after FIGO stage
      I or II endometrial cancer is still thought of as a possibility, and up to now
      the continuous combined oestrogen/progestogen replacement therapy would be
      recommended. However, until today, only observational studies have been put
      forward. Although no study has established an increased rate of recurrences or
      mortality, alternatives such as phytopreparations, tibolone, or, in, particular,
      psychotherapeutic drugs such as venlafaxine should be considered for the relief
      of climacteric complaints. Progestogen-only therapy also comes particularly into
      question. Indeed, the wider discussion about the gestagen effects regarding the
      risks of breast cancer is to be considered. Generally, after hysterectomy, at
      least for patients with cardiovascular risk factors, the preference today is to
      use low-dose oestrogen therapy (patches, gels) instead of continuous combined
      oestrogen/progestogen replacement therapy, and this also is now recommended for
      patients after endometrial cancer. This is to be noted because of the risk
      factors for endometrial carcinomas, such as hypertension, obesity, polycystic
      ovary syndrome, diabetes mellitus, etc. However, each form of hormone therapy
      should only be exceptionally recommended, and the patients must be informed about
      the risks that exist and the use of alternatives.

PMID- 15178899
TI  - Genetic amniocentesis complications: is the incidence overrated?
AB  - AIMS: To estimate the complication rate of 2nd-trimester amniocentesis and to
      determine the associated risk factors. METHODS: A retrospective chart review of
      genetic amniocenteses performed at a single tertiary care institution, from 1996
      to 1998, was done. The variables studied included gestational age, indication for
      amniocentesis, number and site of needle punctures, and amniotic fluid color.
      Complications included fetal loss, rupture of membranes, and bleeding. RESULTS:
      Out of the 1,347 procedures analyzed, the most common indications were advanced
      maternal age (72.3%) and abnormal triple screen (20.3%). Transplacental genetic
      amniocenteses totaled 234 (17.4%). Clear fluid was observed in 98.2% of the
      patients. Twenty-two complications (1.6%) were observed: fetal loss (0.22%),
      bleeding (0.59%), and rupture of membranes (0.82%). An abnormal karyotype was
      detected in 34 (2.5%) fetuses. In separate univariate logistic regression
      analyses, complications were significantly associated with gestational age [odds
      ratio OR = 1.19; 95% confidence interval CI = (1.08, 1.32); p = 0.001], number of
      punctures [OR = 8.2; 95% CI = (1.76, 37.97); p = 0.007], and ultrasound anomalies
      [OR = 5.82; 95% CI = (1.65, 20.58); p = 0.006]. Gestational age and number of
      punctures remained significant in multivariate logistic regression analysis.
      CONCLUSIONS: Genetic amniocentesis performed at a tertiary care institution is
      rather safe, and the fetal loss rate of 0.22% is significantly lower (p < 0.001)
      than the previously published incidence of 1/200. The risk of complications is
      significantly and independently associated with advanced gestational age and
      number of punctures.

PMID- 15178900
TI  - Dynamism of NF-kappaB and AP-1 activation in the signal transduction of ischaemic
      myocardial preconditioning.
AB  - Nuclear factor (NF)-kappaB and activation protein (AP)-1 transcription factors
      play an important role in the signal transduction of delayed ischaemic
      preconditioning (PC) leading to myocardial cytoprotection. Because the exact
      mechanism of the activation of these factors is still not clear, we aimed to
      monitor the time fluctuation of NF-kappaB and AP-1 induction in an in vivo animal
      model. Furthermore, we measured the induction rate of these factors using
      repeated cycles of PC. Following median thoracotomy, anaesthetized animals (24
      New Zealand White rabbits) were subjected to ischaemic PC by occlusion of the
      left anterior descending coronary artery for 5 min. After 10 and 30 min, and 1,
      2, 3 and 4 h of reperfusion, tissue samples were taken from the ischaemic
      myocardium, and the DNA binding activity of the transcription factors was
      measured with electrophoretic mobility shift assay. A further 12 animals were
      subjected to 2 x, 3 x or 4 x 5-min ischaemic PC, and after a 30-min or 1-hour
      reperfusion period, we investigated the possible modulation of NF-kappaB and AP-1
      induction. Our results show significant, biphasically increased NF-kappaB
      activity with peak levels at 30 min and 3 h of reperfusion in preconditioned
      myocardium. AP-1 increased monophasically, with the peak level at 1 h of
      reperfusion. Repeated PC stimuli enhanced the activity of both transcription
      factors analyzed, but there was no significant correlation between the number of
      cycles and the rate of activation. Our results show that the activation of NF
      kappaB and AP-1 have a specific time curve, and the induction of these factors is
      only slightly influenced by the number of PC cycles.

PMID- 15178901
TI  - Beneficial effects of recombinant platelet-activating factor acetylhydrolase and
      BN 52021 on bacterial translocation in cerulein-induced pancreatitis.
AB  - BACKGROUND: Bacterial translocation (BT) has been suggested to be responsible for
      the high incidence of infections occurring after acute pancreatitis (AP). The aim
      of this study was to investigate the effects of the platelet-activating factor
      (PAF) inactivator, recombinant PAF-acetylhydrolase (rPAF-AH), and the PAF
      receptor antagonist, BN 52021, in AP. METHODS: Forty-eight male Wistar rats were
      divided into 4 groups: the sham group received saline intraperitoneally every
      hour for 6 h; the control group received cerulein 50 g/kg i.p. every hour for 6
      h; the rPAF-AH group received AP plus rPAF-AH (5 mg/kg i.v. bolus), and the
      BN52021 group received AP plus BN 52021 (5 mg/kg i.v. bolus). The animals were
      sacrificed 12 h after the first cerulein injection. RESULTS: Supramaximal
      cerulein stimulation induced an increase in serum pancreatic enzymes, interleukin
      (IL)-6, pancreatic edema, and produced histologic evidence of AP. Compared with
      the control group, the addition of PAF receptor antagonists had a significant
      effect on serum pancreatic enzymes, pancreatic edema, and the histologic score of
      the pancreatitis. AP caused significant increases in BT in mesenteric lymph nodes
      (MLNs), pancreas, liver, spleen and blood. Compared with the control group, both
      rPAF-AH and BN 52021 decreased BT in the pancreas and blood. In addition, rPAF-AH
      decreased BT in the MLNs. We also found that PAF receptor antagonists suppressed
      the elevation in IL-6 levels. CONCLUSION: PAF antagonists attenuated the severity
      of experimental AP and reduced pancreatitis-induced BT to distant sites.

PMID- 15178902
TI  - Local and remote ischemia-reperfusion injury is mitigated in mice overexpressing
      human C1 inhibitor.
AB  - Activation of the classical complement pathway is crucially involved in
      complement-mediated endothelial cell damage in ischemia-reperfusion injury. C1
      inhibitor is the only known physiological inhibitor of classical complement
      pathway activation. Transgenic mice overexpressing human C1 inhibitor were used
      in a surgical lower torso and a liver ischemia-reperfusion model. Organ-specific
      endothelial disruption was determined by 125I-tagged albumin extravasation. In
      the lower torso ischemia-reperfusion model, transgenic mice overexpressing the C1
      inhibitor were protected in the muscle and the lungs from endothelial cell
      damage. In the liver ischemia-reperfusion model, endothelial cell integrity was
      preserved in transgenic animals in the liver, the gut and the lungs. Our data
      indicate that inhibiting complement activation by a transgenic approach is
      effective in protection against ischemia-reperfusion injury.

PMID- 15178903
TI  - In vivo and in vitro cellular ingrowth into a new generation of artificial
      ligaments.
AB  - Artificial ligaments are a useful tool in ligament reconstruction. Although the
      new generation of artificial ligaments shows encouraging clinical results, in
      contrast to earlier generations studies on the biological properties are lacking.
      Biopsies were taken from a ligament advancement reinforcement system (LARS) 6
      months after implantation and investigated by histochemistry. An in vitro study
      seeding human fibroblasts or osteoblast-like cells (up to 10(6) cells for 21
      days) on ligament pieces (5 x 5 mm) was conducted and analyzed by histochemistry.
      The biopsies showed complete cellular and connective tissue ingrowth in the LARS
      ligament. In vitro fibroblasts and osteoblast-like cells encapsulated the fibers
      by building a cellular net around them. To our knowledge, these findings
      demonstrate for the first time the cellular ingrowth into the LARS ligament. This
      mechanism might explain the strength and the inert behavior of the ligament
      without the synovialitis shown in clinical studies.

PMID- 15178904
TI  - Morphological alterations in small intestine of rats with myenteric plexus
      denervation.
AB  - We aimed to investigate the effect of myenteric denervation by benzalkonium
      chloride (BAC) on small intestine morphology in the rat, and whether segmental
      myenteric denervation alters morphology elsewhere in the small intestine. Forty
      male Sprague-Dawley rats were equally divided into 4 groups: control (0.9% NaCl);
      denervation (0.062% BAC); chemical inflammation (5% acetic acid), and
      intraluminal stasis produced by partial obstruction. 28 days after operation
      tissue samples were taken from the treated segment, 10 cm distal to the treated
      segment, and 20 cm proximal to the treated segment. Morphological changes and the
      number of ganglion cells were examined under the light microscope. BAC
      application reduced the number of myenteric neurons by 85% in the treated
      segment. Denervation increased villus height and crypt depth in the treated and
      proximal segments. But changes in muscle thickness were seen throughout the
      intestine. As a result, although myenteric plexus denervation caused mucosa
      morphology in the treated and proximal segments, it caused smooth muscle changes
      throughout the small intestine.

PMID- 15178905
TI  - Effects of hyperosmolar agents--lactulose, lactitol, sodium phosphate and
      polyethylene glycol--on cecal coliform bacteria during traditional bowel
      cleansing: an experimental study in rats.
AB  - Mechanical bowel cleansing is considered to be necessary prior to colorectal
      surgery, some radiological or endoscopic procedures, and for fecal disimpaction.
      Traditional bowel cleansing (TBC) with cathartics and enemas is a method of
      mechanical bowel cleansing for patients who have restrictive factors for whole
      bowel irrigation (WBI), such as excessive fecal impaction, cardiac, hepatic or
      renal disorders. In this experimental study, TBC with hyperosmolar agents was
      evaluated in terms of their effects on colonic flora and bacterial translocation
      (BT). Sprague-Dawley rats were divided into 6 groups. The animals, except
      controls, were not fed for 72 h but received tap water ad libitum. During this
      period, lactulose, lactitol, sodium phosphate (NaP), polyethylene glycol 3350
      (PEG3350) and physiological saline gavages were administered to the rats in
      groups 1-5, respectively, once a day. All animals except controls (group 6)
      received enemas with 15 ml of warm saline twice a day. The cecum, mesenteric
      lymph nodes (MLNs) and portal vein blood were sampled for microbiological and
      histopathological analysis. The highest level of coliform bacterial overgrowth
      and BT to MLNs were observed in the lactulose group, although the others, except
      the saline and control groups, also caused some degree of BT. Portal vein
      cultures were negative for all groups. Histopathological damage was not
      associated with cecal bacterial count and BT. As a result of this study, PEG3350
      seems to be safer and more effective than lactulose, lactitol and NaP during TBC.

PMID- 15178906
TI  - Does botulinum type-A toxin affect motor activity after proctocolectomy and ileal
      pouch-anal anastomosis? An experimental study in dogs.
AB  - AIM OF THE STUDY: The use of anticholinergic drugs has provided a useful
      therapeutic approach to reduce stool frequency in patients with proctocolectomy
      and ileal pouch-anal anastomosis (IPAA). Botulinum type-A (BTA) toxin has been
      shown to specifically block acetylcholine release in the intestinal wall.
      Therefore this study investigated the effect of BTA on small intestinal and J
      pouch motility after IPAA. MATERIAL AND METHODS: Proctocolectomy and IPAA were
      performed in 4 dogs. The motility of the small intestine and the ileal pouch was
      recorded by serosal electrodes and strain gauge transducers. The intestinal
      transit time was determined radiologically and pouch compliance was determined
      manometrically. Multiple measurements were performed before and after endoscopic
      injection of BTA into the pouch wall. RESULTS: This treatment did not
      significantly influence stool frequency, intestinal transit time or pouch
      compliance. Intrinsic pouch motility was characterized by irregular contractions,
      the amplitudes and frequencies of which remained unchanged after BTA
      administration. With the exception of lower contraction amplitudes directly
      proximal to the pouch, there were no significant differences in the
      characteristics of the migrating myoelectric complex or in the fed pattern of the
      small intestine and ileal pouch. CONCLUSIONS: BTA does not significantly affect
      ileal pouch motility. The beneficial effects of anticholinergic drugs therefore
      seem to be due to their multifactorial mode of action and not to the inhibition
      of cholinergic neurons in the pouch.

PMID- 15178907
TI  - Effects of intra-aortic balloon occlusion on intestinal perfusion, oxygen
      metabolism and gastric mucosal PCO2 during experimental hemorrhagic shock.
AB  - BACKGROUND: Aortic occlusion has been suggested for the initial treatment of
      severe uncontrolled hemorrhagic shock. Our objective is to determine the impact
      of aortic occlusion, during hemorrhagic shock, on splanchnic mucosal perfusion
      and to correlate these findings with other systemic and regional markers of
      splanchnic ischemia. METHODS: Fourteen dogs (17 +/- 1.7 kg) anesthetized with
      pentobarbital were bled to a mean arterial pressure (MAP) of 40 mm Hg. After 30
      min, the animals were randomly assigned to controls (no aortic occlusion, n = 7)
      and transfemoral aortic occlusion (TAO) at T9 level (n = 7). Superior mesenteric
      artery blood flow (SMABF, ultrasonic flow probe), gastric mucosal PCO2 (gastric
      tonometry) and splanchnic oxygen extraction ratio (O2ERsplanc) were evaluated for
      120 min. RESULTS: Hemorrhage caused a marked reduction in SMABF and increases in
      PCO2-gap and O2ERsplanc in both groups. TAO significantly improved MAP and
      further increased the PCO2-gap and O2ERsplanc, with a decreased SMABF. After
      reperfusion, SMABF, MAP and O2ERsplanc returned to pre-occlusion values, although
      the PCO2-gap remained higher in the TAO group. CONCLUSION: Aortic occlusion
      promotes blood pressure restoration with an additional insult to mucosal
      perfusion, which could be adequately predicted by global and/or splanchnic oxygen
      derived variables during ischemia, but not during the early reperfusion period.

PMID- 15178908
TI  - Devascularization surgical model of acute liver failure in minipigs.
AB  - AIM: The study was designed to develop a readily reproducible model of acute
      liver failure (ALF) in the minipig, to gain an 8-hour therapeutic window to
      mimic, as closely as possible, acute liver failure in man. METHOD: We used
      reversible devascularization model of ALF in the minipig involving hepatic artery
      ligation and establish an end-to-side portocaval anastomosis. Standard laboratory
      monitoring was complemented with intracranial pressure (ICP) measurement.
      MATERIAL: Twenty minipigs (weight 25-30 kg) were used for the experiment. The
      animals were divided into 3 groups: I: 10 animals in an experimental group with
      ALF; II: 5 animals in an experimental group with ALF and ICP measurement, and
      III: 5 animals in a control group without ALF. RESULTS: Laboratory testing has
      shown the significant changes in levels of AST (33.44 +/- 39.96 vs. 1.56 +/- 0.50
      mmol/l), lactate (2.97 +/- 1.16 vs. 1.18 +/- 0.61 mmol/l), and ammonia (264.3 +/-
      93.05 vs. 42.5 +/- 12.98 mmol/l) between ALF groups and controls (p < 001) 6 h
      after the operative procedure, and significant changes in hypoglycemia and
      intracranial pressure were found 4 h after the operative procedure. The
      difference in Quick values (67.4 +/- 17.03 vs. 75.2 +/- 2.68) was not
      significant. We assume that the therapeutic window starts 4 h after the beginning
      of the experiment. CONCLUSION: Our devascularization model of ALF is simple and
      readily reproducible. The therapeutic window occurring shortly after surgery and
      persisting for a mean 9 h is suitable to evaluate bioartificial liver devices.

PMID- 15178909
TI  - What is SkinChip? From silicon image sensor technology to SkinChip.

PMID- 15178910
TI  - Exercise-induced purpura.
AB  - Exercise-induced purpura (EIP) occurs on the lower legs after unusual or major
      muscular activity, as in marathon runners or as after long walks, especially in
      the mountains in hot weather. In leisure walkers, patients are otherwise healthy
      females. There is no relation with chronic venous disorder. Erythematous,
      urticarial or purpuric plaques arise on the lower leg, usually sparing the skin
      compressed by socks. Symptoms include itch, pain and a burning sensation.
      Histopathology demonstrates leukocytoclastic vasculitis. The lesions fade after
      some days, with frequent relapses at further muscular exercises and may be
      prevented in some cases by compression, intake of venoactive drugs and local
      application of steroids. EIP is not uncommon, even if very few descriptions have
      yet been published. It appears to be consecutive to venous stasis induced by an
      acute failure of the muscle pump of the calf and thermoregulation decompensation,
      after a prolonged and unusual exercise, such as running or walking in hot
      weather.

PMID- 15178911
TI  - T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab
      (Raptiva): mechanisms of action.
AB  - Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous
      manifestations. New evidence on the central role of the immune system in the
      pathogenesis of psoriasis increasingly provides insight into pathogenic steps
      that can be modulated to provide disease control. Numerous biological therapies
      are in various stages of clinical development, with expectation of providing
      enhanced safety and efficacy over currently available psoriasis therapies.
      Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted
      T-cell modulator that inhibits multiple steps in the immune cascade that result
      in the production and maintenance of psoriatic plaques, including initial T-cell
      activation and T-cell trafficking into sites of inflammation, including psoriatic
      skin, with subsequent reactivation in these sites. This article reviews the
      pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II
      and III efalizumab trials in patients with moderate to severe chronic plaque
      psoriasis.

PMID- 15178912
TI  - Influence of age on the lips and perioral skin.
AB  - BACKGROUND: There are few objective descriptions of the age-related changes
      taking place on the lips and perioral skin. This zone, however, has great
      importance in relational functions. OBJECTIVES: To describe quantitatively the
      age-related changes in dimension of the lips and the appearance of the perioral
      wrinkles, to revisit, thanks to a new method, the pattern of the lip furrows, to
      compare the hydration states of the upper and lower lips. METHODS: On 100 women,
      we clinically scored wrinkles, dryness of the lips and the general photoageing of
      the facial skin. We used a Corneometer for measuring dryness of the lips and
      SkinChip for recording lip surface patterns. RESULTS: The upper lip is more
      hydrated than the lower one, and there is no correlation between lip capacitance
      and the clinical score of lip dryness. The surface pattern can be classified into
      3 main groups with no relation to age. Wrinkle number and visibility are linearly
      related to age, becoming visible during the fifth decade. The intercommissural
      distance increases with age, whereas lip height decreases. CONCLUSIONS: Both lips
      are different in terms of dryness. Inversely to their surface pattern, their
      dimensions are markedly changed with age. The time of apparition of vertical
      wrinkles suggests a possible influence of hormones.

PMID- 15178913
TI  - Laron syndrome (primary growth hormone insensitivity): a unique model to explore
      the effect of insulin-like growth factor 1 deficiency on human hair.
AB  - BACKGROUND: Classical Laron syndrome is a recessive disease of primary insulin
      like growth factor 1 (IGF-1) deficiency and primary growth hormone insensitivity.
      Affected children have, among other defects, sparse hair growth and frontal
      recessions. The hair is thin and easy to pluck. Young adults have various degrees
      of alopecia, more pronounced in males. OBJECTIVE: The aim of the present study
      was to investigate the effect of primary IGF-1 deficiency on hair structure. The
      study sample included 11 patients with Laron syndrome--5 children (2 untreated)
      and 6 adults (5 untreated). Hairs were examined by light and electron microscopy.
      RESULTS: The most significant structured defect, pili torti et canaliculi, was
      found in 2 young, untreated patients. Grooving, tapered hair and trichorrhexis
      nodosa were found in the remainder. IGF-1-treated patients had either none or
      significantly fewer pathological changes compared to the untreated patients.
      CONCLUSION: This is the first documentation of the role of primary IGF-1
      deficiency on hair structure in human beings.

PMID- 15178914
TI  - Type IV hypersensitivity from rubber chemicals: a 15-year experience in Taiwan.
AB  - BACKGROUND: Allergic contact dermatitis from rubber chemicals is frequent but has
      not been reported form Asia. OBJECTIVE: To study the pattern of type IV allergy
      to rubber chemicals in a Chinese-based population. METHODS: A retrospective study
      was conducted by reviewing the patch test results of 2,235 (604 men, 1,631 women)
      patients from January 1986 to December 2000. RESULTS: Ninety-nine patients (4.4%)
      had one or more positive reactions, 42 (6.9%) men and 57 (3.5%) women. The
      incidence did not increase throughout the study period. Among thiuram, mercapto,
      carba and black-rubber mix, thiuram is the most potent sensitizer, mostly for the
      hand and mercapto mix for the foot. Thiuram allergy is considered occupation
      related, while mercapto allergy, mostly from rubber slippers, is not typically
      related to an occupation. A negative correlation between thiuram and carba was
      found despite the frequent association between these two mixes. A high risk of
      rubber sensitization was noted in construction, health service, transportation,
      agriculture and hairdressing workers. A high frequency of concomitant sensitivity
      to cobalt was found. CONCLUSION: This is the first statistically analyzed study
      of rubber chemical allergy in Asia, which supports major trends concerning rubber
      chemical allergy from European studies. However, wearing rubber slippers in
      Taiwan contributes to the high percentage of foot dermatitis. Carba should still
      be retained in the European standard series because of the coexistence of thiuram
      and carba in rubber products. The concomitant sensitization to cobalt in rubber
      allergic patients needs further evaluations.

PMID- 15178915
TI  - A comparative study on the effects of naltrexone and loratadine on uremic
      pruritus.
AB  - BACKGROUND: Two recent studies have provided opposite results on the efficacy of
      naltrexone on uremic pruritus. We have performed a third study. OBJECTIVE: To
      compare the efficacy and tolerance of naltrexone and loratadine in uremic
      pruritus. PATIENTS/METHODS: Among 296 hemodialyzed patients, 65 suffered from
      uremic pruritus. Fifty-two patients participated in the study. The patients were
      treated for 2 weeks with naltrexone (50 mg/day; 26 patients) or loratadine (10
      mg/day; 26 patients), after a washout of 48 h. Pruritus intensity was scored by a
      visual analogue scale (VAS). Adverse events were carefully searched for. The two
      groups were statistically equivalent. RESULTS: There was no significant
      difference in the mean VAS scores after treatment, but naltrexone allowed a
      dramatic decrease in VAS scores (Delta >3/10) in 7 patients. Adverse events
      (mainly nausea and sleep disturbances) were observed in 10/26 patients.
      CONCLUSIONS: Naltrexone is effective only in a subset of patients. Adverse events
      are very frequent. The differences of efficacy and tolerance between patients
      might be due to metabolism. Naltrexone might be considered as a second-line
      treatment.

PMID- 15178916
TI  - Subcutaneous granuloma pyogenicum in patients with antiphospholipid antibodies.
AB  - We describe 2 cases of subcutaneous granuloma pyogenicum occurring in patients
      with antiphospholipid antibodies. The 2 patients had asymptomatic nodules with
      histopathological findings of a typical subcutaneous granuloma pyogenicum. In
      addition, case 1 was diagnosed as primary antiphospholipid syndrome with livedo
      reticularis, superficial thrombophlebitis, thrombocytopenia, cerebral and
      pulmonary infarcts and renal involvement. Case 2 had no clinical manifestations
      of vascular occlusive diseases, although anticardiolipin antibody levels were
      highly positive. To our knowledge, these are the first reported cases of
      subcutaneous granuloma pyogenicum associated with antiphospholipid antibodies.
      Antiphospholipid-antibody-mediated thrombosis or immunological mechanisms may be
      involved in subcutaneous granuloma pyogenicum in our cases.

PMID- 15178917
TI  - Annular lichen planus: study of the cellular mechanisms of annularity.
AB  - Annular lichen planus is a rare, unique subtype of lichen planus. We report a 34
      year-old Japanese male who had multiple, dark red to purple, annular macules with
      slightly raised borders. Histopathological examination of a skin biopsy specimen
      from the peripheral region of the macule showed the typical features of lichen
      planus. Immunohistochemical stainings revealed that a number of CD1a-positive, S
      100-protein-positive Langerhans cells were present at the border zone of the
      annular lesion and most of the infiltrating cells were CD4-positive, CD8-negative
      lymphocytes. Conversely, inside the annular lesion, the number of Langerhans
      cells was decreased, and an equal number of CD4-positive cells and CD8-positive
      cells was present in the sparse infiltration. These results suggest that
      activation of Langerhans cells initiated a lichenoid tissue reaction but a
      subsequent depletion of Langerhans cells suppressed the lymphocyte infiltration.
      These sequential events might be involved in the formation of the unique annular
      structure in this condition.

PMID- 15178918
TI  - A case of propylthiouracil-induced pyoderma gangrenosum associated with
      antineutrophil cytoplasmic antibody.
AB  - A 27-year-old woman who had been receiving propylthiouracil for 2 years for
      Graves' disease presented with painful ulceration on the lower limbs which had
      first appeared 2 weeks previously. Well-circumscribed hemorrhagic ulcerations
      with ragged borders were noted on both legs. Skin biopsy demonstrated a florid
      neutrophilic infiltrate and evidence of leukocytoclasis around small blood
      vessels in the papillary dermis compatible with the diagnosis of pyoderma
      gangrenosum. A highly positive perinuclear pattern of antineutrophil cytoplasmic
      antibody with specificities for IgM myeloperoxidase was observed. The authors
      think that propylthiouracil is associated with the occurrence of pyoderma
      gangrenosum in this patient.

PMID- 15178919
TI  - Secondary lymphoedema of the lower leg as an unusual side-effect of a liquid
      silicone injection in the hips and buttocks.
AB  - We report an unusual case of secondary lymphoedema of the lower extremities as a
      result of injections of liquid silicone. A 30-year-old transsexual had received
      large-volume injections of silicone in the hips and buttocks for cosmetic
      purposes in order to obtain a female body form. Painful silicone granulomas
      developed in both the treated areas and areas outside the original injection
      location, and a progressive lymphoedema of feet and legs developed during a
      period of 5 years.

PMID- 15178920
TI  - Blue rubber bleb nevus syndrome associated with consumption coagulopathy:
      treatment with interferon.
AB  - The blue rubber bleb nevus syndrome (BRBNS) is a rare vascular malformation
      syndrome with cutaneous and visceral lesions frequently associated with serious,
      even fatal bleeding. No systemic therapy is currently available. We report here a
      case with disseminated skin and gastrointestinal venous malformations and
      findings of disseminated intravascular coagulation that was treated with
      interferon beta. The disseminated intravascular coagulation manifestations were
      cleared with the treatment. The regression of the coagulopathy in our patient led
      us to think that the use of interferon beta in BRBNS might be beneficial.

PMID- 15178921
TI  - Lethal perianal Buschke-Lowenstein tumor in a female patient with AIDS.

PMID- 15178922
TI  - Multiple dermatofibromas in a patient with atopic dermatitis.

PMID- 15178923
TI  - ACE-inhibitor-induced drug eruption resembling lymphocytic infiltration (of
      Jessner-Kanof) and Lupus erythematosus tumidus.

PMID- 15178924
TI  - An outbreak of eruptive pseudoangiomatosis-like lesions due to mosquito bites:
      erythema punctatum Higuchi.

PMID- 15178925
TI  - Oral isotretinoin for severe acne in beta-thalassemia major.

PMID- 15178926
TI  - Flare of cutaneous lupus erythematosus induced by bupropion (Zyban).

PMID- 15178927
TI  - Gianotti-Crosti syndrome associated with endogenous reactivation of Epstein-Barr
      virus.

PMID- 15178928
TI  - Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate
      atopic dermatitis.
AB  - BACKGROUND: Pimecrolimus cream 1% is a non-steroid, selective inflammatory
      cytokine inhibitor indicated for atopic dermatitis (AD). OBJECTIVE: To compare
      the safety and efficacy of pimecrolimus cream 1%-based treatment versus
      conventional therapy in adults with moderate AD. METHODS: Patients were
      randomized to receive pimecrolimus cream 1% (n = 62) or vehicle (n = 68) at the
      first signs/symptoms of AD, for 24 weeks as required. A moderately potent topical
      corticosteroid (prednicarbate 0.25% cream) was allowed in both groups to treat
      flares. RESULTS: Corticosteroids were required on fewer days in the pimecrolimus
      group, compared with the vehicle group (9.7 vs. 37.8%, p < 0.001). Furthermore,
      59.7% of pimecrolimus-treated patients experienced no flares during the study
      period, compared with 22.1% of vehicle-treated patients (p < 0.001). Pimecrolimus
      cream 1% was well tolerated throughout the study. CONCLUSION: For adults with
      moderate AD, pimecrolimus cream 1% is well tolerated, reduces the incidence of
      flares, reduces/eliminates corticosteroid use, improves long-term disease control
      and enhances the patients' quality of life.

PMID- 15178929
TI  - Multiple organ system failure in critically ill cirrhotic patients. A comparison
      of two multiple organ dysfunction/failure scoring systems.
AB  - OBJECTIVES: The prognosis for critically ill cirrhotic patients depends on the
      extent of hepatic and extrahepatic organ dysfunction/failure. We hypothesize that
      a graded multiple organ dysfunction score, sequential organ failure assessment
      (SOFA), would provide more descriptive and discriminative power for predicting
      the hospital mortality for critically ill cirrhotic patients than the classical
      organ system failure (OSF) score, which defines organ failure as an all-or-none
      phenomenon. METHODS: 160 patients diagnosed with liver cirrhosis were admitted to
      the medical intensive care unit (ICU) from January 2002 to June 2003. Information
      considered necessary for calculating the Child-Pugh, OSF and SOFA scores on ICU
      admission was collected prospectively. RESULTS: Hepatitis B infection was the
      most common cause of liver cirrhosis. A significantly progressive increase in
      mortality rate was associated with OSF and SOFA scores (p < 0.001). Close
      correlation between OSF and SOFA scores (p < 0.001) suggested that both systems
      evaluated the same event. In patients with similar organ dysfunction, the number
      of failed organ system(s) was significantly higher among non-survivors. However,
      no correlation existed between the SOFA scores and mortality rate in patients
      with the same OSF number. Meanwhile, both OSF and SOFA scores displayed excellent
      discriminative power (areas under receiver-operating characteristic (AUROC) were
      0.906 and 0.892, respectively), while Child-Pugh scores clearly performed more
      poorly (AUROC 0.712). Both OSF and SOFA demonstrate a good fit using the Hosmer
      and Lemeshow goodness-of-fit test. CONCLUSIONS: Both OSF and SOFA scores are
      excellent tools for predicting prognosis for cirrhotic patients admitted to ICU.
      Both of them are superior to Child-Pugh score. Hospital mortality for critically
      ill cirrhotic patients occurs owing to severe failure of a relatively few organs,
      rather than because of an accumulation of mild dysfunction in many organ systems.
      Graded organ dysfunction scales provide no further benefit for predicting
      hospital mortality for critically ill cirrhotic patients.

PMID- 15178930
TI  - Natural history of frontotemporal dementia: comparison with Alzheimer's disease.
AB  - INTRODUCTION: Frontotemporal dementia (FTD) is a more common cause of dementia
      than previously recognised. Few data are available regarding the natural course
      of FTD in terms of survival, nursing home admission and causes of death. METHODS:
      An observational study of all consecutive patients referred to the memory centre
      of Lille, France, between 1995 and 1999, and examined at least twice in this
      centre, with a diagnosis of FTD (frontal or behavioural variant) or of
      Alzheimer's disease (AD) was performed. Kaplan-Meyer analysis allowing for
      delayed entry was used to compare the survival functions in FTD and AD. RESULTS:
      552 patients were included, of whom 49 (8.9%) were lost to follow-up at 3 years.
      FTD patients were younger (mean age at onset 59 years), had more often a family
      history of psychiatric disorders (20%), had a longer delay between first symptoms
      and first visit (5.9 years) and a higher Mini-Mental State Examination (MMSE)
      score at first visit (24.5) than patients with AD (19.9). The mean annual MMSE
      score decline was 0.9 point in FTD vs. 2.0 points in AD (p < 0.0004). Fewer
      patients with FTD than with AD entered an institution (RR: 0.20, 95% CI 0.05
      0.81). After adjustment for sex, age at first visit, level of education and MMSE
      score at first visit, survival rates in FTD and AD did not differ significantly.
      Patients with FTD often had a sudden death, the cause of which could not be
      found. The earlier the first visit after onset, the longer the survival rate,
      whatever the diagnosis (RR: 0.76, 95% CI 0.67-0.86, p < 0.0001 per year of
      earlier first visit). CONCLUSION: This large study showed that the mean duration
      of FTD was 2 years longer than that of AD, but the risk of death after adjustment
      for age and sex was similar in FTD and in AD. Sudden and unexplained causes of
      death were frequent and need further study. Early management increases the life
      span of demented patients.

PMID- 15178931
TI  - The tau gene locus and frontotemporal dementia.
AB  - Frontotemporal lobar degeneration (FTLD) has become an increasingly recognised
      form of dementia. It has been demonstrated that a proportion of cases of FTLD
      result from mutations in the tau gene on chromosome 17. A pathological hallmark
      in the brains from patients with tau mutations is an accumulation of insoluble
      tau within neurons and glia that is considered neurotoxic. However, there are
      reports of families with FTLD linked to the tau locus on chromosome 17 in which
      no mutations have been found, and these families lack any accumulation of
      insoluble tau. Recently, two new tau mutations have been described that also
      appear to cause disease in the absence of any tau accumulation. The role of the
      tau locus and tau accumulation in contributing to the neurodegenerative process
      in chromosome-17-linked families without mutations and in families with tau
      mutations without insoluble tau is discussed.

PMID- 15178932
TI  - Phenotypic variation in frontotemporal dementia and parkinsonism linked to
      chromosome 17.
AB  - Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP
      17) caused by mutations in the tau gene shows a wide range in age at onset,
      several distinct clinical presentations, and a spectrum of tau pathology.
      Although the clinical and pathological phenotype often correlate with the
      location of the mutation, there also exists considerable interfamilial and
      intrafamilial phenotypical variation. Not all families with FTDP-17 do have
      mutations and deposition of hyperphosphorylated tau in the brain, but show
      ubiquitin-positive, tau-negative inclusions. Future research should focus on the
      role of other genetic and environmental factors in this form of FTDP-17, whereas
      the responsible gene defect(s) has still to be identified for hereditary FTD
      without tau mutations.

PMID- 15178933
TI  - Epidemiology of frontotemporal lobar degeneration.
AB  - A few epidemiologic studies have dealt with the prevalence of frontotemporal
      lobar degeneration (FTLD), including Pick's disease. The aim of this study was to
      review the epidemiologic studies of FTLD in western countries and to compare them
      with those in Japan. A community-based study of early-onset dementia in London
      revealed that 12% of cases with frontotemporal dementia (FTD) fulfilled the Lund
      Manchester criteria in contrast to 34% of cases with Alzheimer's disease (AD) in
      a sample of 185 cases. The Cambridge Group has recently examined the prevalence
      of early-onset dementia in a community-based study. Of 108 cases, 15.7% had FTLD
      and 25% had AD. FTLD included 13 FTD cases, and 2 each with semantic dementia
      (SD) and nonfluent progressive aphasia (PA). Almost one third of cases with FTLD
      (29%) had a positive family history. Of our consecutive 330 outpatients with
      dementia (hospital setting without age limitation), 42 (12.7%) had FTLD and 215
      (65.1%) had AD. In our series of patients, 22 FTD, 15 SD and 5 PA cases were
      identified. There was no family history in all subtypes of FTLD. Epidemiologic
      studies, both community-based and hospital-based, demonstrate that FTLD is a more
      common cause of early-onset dementia than previously recognized. Regarding the
      subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less
      common, SD may be more common and PA is equally common. The reason for this
      discrepancy is supposed to be mainly based on the role of heredity.

PMID- 15178934
TI  - Patterns of referring of patients with frontotemporal lobar degeneration to
      psychiatric in- and out-patient services. Results from a prospective multicentre
      study.
AB  - Dementia with frontotemporal lobar degeneration (FTLD) is clinically
      characterized by the occurrence of various psychiatric symptoms. In a recent
      study, the hospital-based prevalence of FTLD and the circumstances of the
      patients' admission to German psychiatric state hospitals were estimated. On the
      basis of further continuous assessment, this original FTLD group (n = 33) has
      been enlarged to 58 patients. The authors here present demographic and clinical
      data, and reasons for admission to geriatric psychiatry hospitals in comparison
      with 17 patients, who primarily attended the Memory Disorders Clinic of the
      University of Regensburg. The results implicate that both institutions see
      patients with different clinical syndromes: (1) patients were primarily referred
      to the Memory Disorders Clinic presenting memory and/or speech difficulties as
      the leading symptoms; (2) major reasons for hospitalisation of patients with FTLD
      in geriatric psychiatry hospitals were behavioural disturbances; (3) late-onset
      FTLD (>65 years) was more common than previously assumed in both institutions,
      and (4) increasing age at admission increased the likelihood to obtain a limited
      diagnostic approach of brain imaging (only cranial computer tomography) to
      evaluate the cause of dementia.

PMID- 15178935
TI  - Frontotemporal dementia linked to chromosome 3.
AB  - A large pedigree with autosomal dominant frontotemporal dementia has been
      identified. Positional cloning has linked the disease gene to the pericentromeric
      region of chromosome 3. Clinical, neuropsychological, imaging, pathological and
      molecular genetic data are presented. The genetic mutation responsible for the
      disease has not been identified.

PMID- 15178936
TI  - Recognition of emotion in the frontal and temporal variants of frontotemporal
      dementia.
AB  - Recent studies have suggested that the frontal and temporal variants of
      frontotemporal dementia (fvFTD and tvFTD) are both associated with impairments in
      emotional processing. However, the degree and type of emotional processing
      deficits in the two syndromes have not been previously compared. We used the
      Florida Affect Battery to examine recognition of facial expressions of emotion in
      fvFTD and tvFTD patients who have no evidence of visual perceptual difficulties
      for faces. In general, both groups were impaired at recognizing emotions compared
      with age-matched controls. In tvFTD, this deficit was limited to emotions with a
      negative valence (sadness, anger, fear), while fvFTD patients showed impairment
      for positive valence (happiness) as well. These results suggest that damage to
      frontal lobe regions in FTD may lead to more profound impairment in recognition
      of emotion than when damage is more limited to the temporal lobe.

PMID- 15178937
TI  - Relationship between frontotemporal dementia and corticobasal
      degeneration/progressive supranuclear palsy.
AB  - Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were
      described as separate entities, but prior to that an extrapyramidal variety of
      Pick's disease was recognized. Subsequently a pathological overlap between these
      conditions and clinical overlap between frontotemporal dementia, primary
      progressive aphasia, corticobasal degeneration syndrome and more recently PSP was
      recognized. Initially only the movement disorder had been emphasized, but now the
      behavioral and language symptoms are considered common. The syndromes of
      frontotemporal dementia/Pick's disease can be produced by underlying CBD, PSP or
      Pick pathology as well as with neural inclusions of the motor neuron disease
      type. The concept of this overlap has been confirmed genetically finding a
      similar spectrum of pathology with different tau mutations and even with tau
      negative pathology, which could be a deficiency of normal tau. The overlap of CBD
      with PSP and both with PPA and FTD allows to consider these relatively rare
      conditions as part of a more commonly occurring degenerative disease than
      previously recognized.

PMID- 15178938
TI  - Familial presenile dementia with bitemporal atrophy.
AB  - This study describes the clinical, neuropsychological, neuroimaging and genetic
      characteristics in two generations of a Swedish family affected by presenile
      dementia. The pedigree includes 5 cases (mother and 4 of 5 children) of
      progressive dementia with onset between 54 and 62 years. The clinical picture is
      characterized by insidious onset and progressive decline in episodic memory
      without spatial impairment or dyspraxia, followed by changes in personality and
      behaviour, with signs of disinhibition, irritability, impulsivity and loss of
      social awareness. Three siblings, examined after 10 years of duration, showed
      moderate language deficits but preserved spatial function and praxis. CT and MRI
      showed progressive bilateral temporal atrophy and moderate frontal white matter
      changes. Regional cerebral blood flow measurements showed hypoperfusion in
      temporal areas bilaterally. Quantitative EEG was normal within 5 years after
      symptom onset and thereafter showed a moderate increase in relative theta power.
      Sequencing of the tau gene (chromosome 17) revealed the previously described
      R406W mutation in exon 13 as a likely cause of the disease. This mutation was
      identified in all affected cases. The clinical picture of this family shows
      striking similarities not only to frontotemporal dementia but also to Alzheimer's
      disease.

PMID- 15178939
TI  - Pick's disease pathology of a missense mutation of S305N of frontotemporal
      dementia and parkinsonism linked to chromosome 17: another phenotype of S305N.
AB  - We report the second phenotype of frontotemporal dementia and parkinsonism linked
      to chromosome 17 with S305N similar to Pick's disease pathology in two brothers.
      The brain of the older brother showed macroscopic atrophy compatible with Pick's
      disease, and subsequent tau gene analysis revealed heterozygous S305N mutation in
      exon 10 of the tau gene. Round-shaped neuronal inclusions similar to Pick's
      bodies were positive for phosphorylated serine 262 as well as other anti-tau
      antisera, which is different from immunoexpression of Pick's bodies.
      Ultrastructurally, these neuronal inclusions consisted of straight, randomly
      orientated fibrils measuring approximately 10-20 nm in width and 60-600 nm in
      length. This ultrastructural profile is similar to that of the first case of
      S305N. S305N reported here can cause another phenotype closely resembling Pick's
      disease.

PMID- 15178940
TI  - The tau R406W mutation causes progressive presenile dementia with bitemporal
      atrophy.
AB  - Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are two frequent
      causes of dementia that share both clinical and neuropathological features.
      Common to both disorders are the neurofibrillary tangles consisting of
      aggregations of hyperphosphorylated tau protein. Recently, a number of different
      pathogenic mutations in the tau gene have been identified in families with FTD
      and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a
      Swedish family with presenile degenerative dementia with bitemporal atrophy was
      screened for mutations in the tau gene. As a result, the R406W mutation in exon
      13 was identified in all affected cases. This mutation has previously been
      reported in two different FTDP-17 families of Dutch and Midwestern American
      origin. Common features to these two kindreds and our family are the late age at
      onset and long duration of the disease. Our pedigree as well as the American one
      show early memory impairment and pronounced temporal lobar atrophy similar to AD,
      while the Dutch cases show more FTD features. This further illustrates the large
      clinical variability among cases with tau mutations and stresses the importance
      of genetic classification in addition to the traditional clinical classification
      of neurodegenerative disorders.

PMID- 15178941
TI  - Initial complaints in frontotemporal lobar degeneration.
AB  - AIMS: Frontotemporal lobar degeneration (FTLD) is probably underrecognized. The
      goal of this study was to investigate initial complaints of both patients and
      their caregivers at first specialist referral. Also, we tried to assess whether
      misrecognition of symptoms contributed to diagnostic delay. METHODS: The case
      notes of all patients diagnosed with FTLD at the VU University Medical Center,
      Alzheimer Center of Amsterdam, The Netherlands, since 1998 were retrospectively
      reviewed. Only patients of whom detailed information of first specialist referral
      was available were included. The diagnosis of FTLD was based on the clinical
      diagnostic criteria of Neary and Snowden, supported by ancillary investigations.
      RESULTS: Forty-six patients with FTLD were included. Twenty-one patients had
      frontotemporal dementia (FTD), 17 semantic dementia (SD) and 8 progressive
      nonfluent aphasia (PA). The majority of the FTD patients presented without
      complaints or with somatic complaints and nearly a quarter of them expressed
      memory complaints. The presenting complaints of most of their caregivers differed
      from the patients' complaints and often consisted of cognitive complaints. In SD
      and PA, language problems but also forgetfulness were presented. Misrecognition
      of the initial symptoms in some cases seemed to have contributed to diagnostic
      delay. CONCLUSION: Presenting complaints in FTLD can be misleading. In our
      cohort, memory complaints occurred relatively often. A multidisciplinary
      approach, including a structured behavioral interview, is important to recognize
      symptoms of FTLD.

PMID- 15178942
TI  - Longitudinal patterns of regional change on volumetric MRI in frontotemporal
      lobar degeneration.
AB  - The aim of this study was to assess the longitudinal patterns of regional change
      in the different syndromic variants of frontotemporal lobar degeneration (FTLD).
      Ten patients with semantic dementia, 7 with progressive non-fluent aphasia and 29
      with frontotemporal dementia had two serial volumetric MR scans. Fluid
      registration was used to match serial scans from each individual. Voxel-level
      analysis of change across subject groups was performed using statistical
      parametric mapping. The analysis showed patterns of increased rates of volume
      loss (atrophy) in frontal, temporal and parietal regions in the whole FTLD group
      compared with controls. The different FTLD syndromes displayed different patterns
      of change. This technique gives an insight into disease evolution over time in
      these disorders and may be useful as a method of tracking change in clinical
      trials.

PMID- 15178943
TI  - Clinicopathological staging of frontotemporal dementia severity: correlation with
      regional atrophy.
AB  - The pattern and degree of brain atrophy in frontotemporal dementia (FTD) has the
      potential for use as an aid in the diagnosis of this disorder and its
      differentiation from other neurodegenerative diseases. However, before this can
      occur, the sequence and progression of atrophy needs to be fully elucidated.
      Recently, we have described a four-point scheme for staging the severity of
      degeneration in FTD, which correlates with both duration of disease and severity
      of dementia [Broe M., et al.: Neurology 2003;60:1005-1011]. When volumetric
      analysis is performed in post-mortem-confirmed cases of FTD, atrophy of all lobes
      is present by stage 2 and then progresses with successive stages. Within each
      lobe, there is variation in the degree of atrophy between different functionally
      discreet brain regions with some regions showing marked atrophy and others
      showing little. Much of the frontal lobe, the amygdala and hippocampus are
      severely atrophic by stage 2, suggesting that they are some of the earliest areas
      affected in FTD.

PMID- 15178944
TI  - MRI with diffusion tensor imaging post-mortem at 3.0 T in a patient with
      frontotemporal dementia.
AB  - The formalin-fixed brain of a patient with clinically diagnosed frontotemporal
      dementia (FTD) was examined post-mortem using magnetic resonance imaging (MRI)
      with diffusion tensor imaging (DTI) at 3.0 T. Frontotemporal atrophy as well as
      bilateral frontal white matter abnormalities were seen. The white matter changes
      were slightly more extensive on DTI than on conventional MRI. Correlation with
      histopathology of the corresponding regions revealed typical frontal lobe
      degeneration of non-Alzheimer type, with mild frontotemporal degeneration in the
      outer cortical layers and a moderate frontal white matter gliosis with
      demyelination. Post-mortem MRI/DTI with histopathologic correlation will enhance
      our understanding of the basis of white matter changes observed in dementia
      patients and may improve the in vivo MRI/DTI diagnostic assessment in FTD.

PMID- 15178945
TI  - Confrontation naming and morphometric analyses of structural MRI in
      frontotemporal dementia.
AB  - We studied the neural basis for confrontation naming difficulty in 29 patients
      with frontotemporal dementia (FTD) by correlating naming with voxel-based
      morphometric analyses of gray matter volume in structural MRI. We found that
      naming is significantly impaired in FTD, including patients with semantic
      dementia (SD), progressive nonfluent aphasia (PNFA), and nonaphasic patients (NON
      APH) with a disorder of social and executive functioning. Significant cortical
      atrophy was found in the left anterior temporal cortex in all three FTD subgroups
      relative to healthy seniors. We also found significant cortical atrophy in unique
      anatomic distributions in each FTD subgroup. This included: lateral, ventral, and
      parahippocampal regions of the left temporal lobe in SD; inferior, orbital,
      dorsolateral, and premotor regions of the left frontal lobe in PNFA, and
      bilateral frontal regions in NON-APH. Direct correlations between confrontation
      naming and gray matter volume revealed distinct patterns in each FTD subgroup. SD
      patients showed a significant correlation in the left lateral temporal cortex,
      PNFA patients in several left frontal regions, and NON-APH patients in the right
      dorsolateral prefrontal cortex. These findings suggest that confrontation naming
      is supported by a large-scale neural network, and that naming is compromised in
      FTD due to interruption of the network in several different ways.

PMID- 15178946
TI  - Lateralization on neuroimaging does not differentiate frontotemporal lobar
      degeneration from Alzheimer's disease.
AB  - Lateralization on neuroimaging was compared in cases of frontotemporal lobar
      degeneration (FTLD; n = 10) and cases of definite Alzheimer's disease (AD; n =
      17). All of the cases were pathologically confirmed and semi-quantitative and
      statistical parametric mapping methods were employed. Seven of the 10 FTLD cases
      had lateralization on at least one neuroimaging modality: single photon emission
      computerized tomography (SPECT), MRI, or CT. All 6/6 FTLD cases with SPECT showed
      lateralization. MRI results generally agreed with SPECT findings. Three of 4 FTLD
      cases had lateralized atrophy on CT. For the AD cases, 10/17 SPECTs, 2/7 MRIs,
      and 1/9 CTs showed lateralized findings. Of the neuroimaging modalities utilized,
      SPECT was the most sensitive in detecting lateralization.

PMID- 15178947
TI  - Right and left medial orbitofrontal volumes show an opposite relationship to
      agreeableness in FTD.
AB  - Recent investigations of the neuroanatomy of complex social behaviors suggest
      that the underlying brain circuits involve multiple cortical and subcortical
      structures. The neuroanatomic origins of agreeableness have not yet been clearly
      elucidated. However, frontotemporal dementia (FTD) patients can evidence dramatic
      alterations in agreeableness arising from frontal and temporal lobe damage. Based
      on previous research, we hypothesized that agreeableness would be negatively
      correlated with left medial orbitofrontal cortex size and positively correlated
      with right amygdala volume. First-degree relatives of 27 FTD patients (diagnosed
      according to the Lund-Manchester criteria) were asked to fill out the NEO-Five
      Factor Inventory to assess the patients' current level of agreeableness, a
      construct comprised of the facets trust, straightforwardness, altruism,
      compliance, modesty, and tender-mindedness. These patients underwent T(1)
      weighted MRI imaging, and gray matter volumes for right and left orbitofrontal
      lobes and amygdalas were derived via segmentation and region of interest tracing,
      normalizing for total intracranial volume. Regression analysis revealed that 38%
      of the variance in the NEO agreeableness score was predicted by a model in which
      right orbitofrontal volume (beta = 0.731) was positively correlated with
      agreeableness, and left orbitofrontal lobe volume (beta = -0.638) was negatively
      correlated with agreeableness (p < 0.01). Contrary to our hypothesis, amygdala
      volume did not significantly predict agreeableness. This finding partly
      replicates a previous study that used a different measure of social functioning,
      the Interpersonal Adjective Scale, to delineate a left frontal-right amygdala
      circuit for agreeableness. These data support the hypothesis that regulation of
      agreeableness arises from a balanced, mutually inhibitory circuit involving both
      hemispheres.

PMID- 15178948
TI  - Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic
      cases.
AB  - Ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions are
      characteristically found in the extramotor cortex in patients with motor neuron
      disease (MND) and dementia (MND-dementia) and in a subset of patients with
      frontotemporal dementia (FTD) without motor symptoms (FTD-MND type). Recently, ub
      ir neuronal intranuclear inclusions have been described in a small number of
      patients with familial FTD-MND type. To better define the sensitivity and
      specificity of this pathological change, we examined postmortem tissue from 14
      patients with FTD-MND type (8 familial, 6 sporadic), 10 cases of MND-dementia (5
      familial, 5 sporadic) and 19 cases of MND with no history of cognitive
      dysfunction (2 familial, 17 sporadic). Numerous intranuclear inclusions were
      found in multiple anatomic sites in 6/8 cases of familial FTD-MND. Rare
      intranuclear inclusions were present in the hippocampal dentate granule cells in
      1 case of familial MND-dementia. No sporadic cases had intranuclear inclusions.
      These findings suggest that intranuclear inclusions are specific for familial FTD
      and may identify a subset of families with a common genetic basis. Although
      intranuclear inclusions are most characteristic of families with pure FTD, they
      may also be found in some pedigrees with both FTD and MND, further supporting the
      hypothesis that FTD-MND type and MND-dementia represent a clinicopathological
      spectrum of disease.

PMID- 15178949
TI  - Characterization of amyotrophic lateral sclerosis and frontotemporal dementia.
AB  - Amyotrophic lateral sclerosis (ALS) produces progressive weakness, muscular
      wasting, and spasticity leading to death from respiratory failure at a median of
      3 years after onset. ALS and frontotemporal dementia (FTD) overlap in both
      familial and sporadic cases of ALS. When both occur in families, the affected
      members may have only ALS, only FTD, or both. This suggests a relationship in the
      cause of these disorders. We investigated the frequency of ALS in FTD patients
      and of FTD in ALS patients and found the overlap to be more common than had
      previously been reported. We report the features of cognitive impairment and
      pattern of motor involvement in these ALS-FTD patients, and the degree of overlap
      in both populations.

PMID- 15178950
TI  - Hippocampal sclerosis and ubiquitin-positive inclusions in dementia lacking
      distinctive histopathology.
AB  - The aim of this study was to determine the frequency of ubiquitin-positive
      inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their
      relationship to other pathologic features, such as hippocampal sclerosis (HpScl),
      as well as genetic factors. Routine and immunohistochemical studies were carried
      out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while
      HpScl was demonstrated in 76%. There was no significant correlation among
      pathologic features or between pathologic features and genetic factors. The high
      prevalence of UPI demonstrated in this study implies that DLDH is similar to
      motor neuron disease inclusion dementia. The high prevalence of HpScl may be the
      cause of some of the clinical features observed in patients with frontotemporal
      lobar degeneration.

PMID- 15178951
TI  - Negative neurofilament light and tau immunostaining in frontotemporal dementia.
AB  - We investigated the immunohistochemical stainability of phosphorylated tau and
      the light (NFL), intermediate (NFM), and heavy (NFH) neurofilament proteins in
      postmortem brain tissue from 8 patients with frontotemporal dementia (FTD), for
      comparison with 6 patients with Alzheimer's disease (AD), and 6 normal controls.
      In the FTD group, the neuropathological diagnosis was pure frontal-lobe
      degeneration of non-Alzheimer type (FLD) in 6 cases and in the remaining 2 cases
      mixed FLD-AD and frontal AD, respectively. The staining for tau was negative in 5
      of the FLD cases and faintly positive in 1, but positive in all AD cases. The
      antibodies against NFM and NFH stained positive in FLD, AD, and controls, whereas
      the staining for NFL was negative in all FLD cases and positive in 1 AD case and
      in the controls. These findings regarding NFL and tau staining may be useful in
      the differential diagnosis of FLD and AD.

PMID- 15178952
TI  - Total and phosphorylated tau proteins: evaluation as core biomarker candidates in
      frontotemporal dementia.
AB  - An ever increasing number of patients with neurodegenerative disorders calls for
      the evaluation of potential diagnostic markers that allow an early diagnosis and
      an early initiation of specific therapy. Clinical diagnosis of Alzheimer's
      disease (AD), the most common neurodegenerative disorder, reaches 80-90% accuracy
      upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical
      or preclinical stages is far less accurate, as is the differential diagnosis
      between AD and other primary dementias, such as frontotemporal dementia (FTD).
      Microtubule-associated tau protein is abnormally phosphorylated in AD and
      aggregates as paired helical filaments in neurofibrillary tangles. Recently,
      immunoassays have been developed detecting tau phosphorylated at specific
      epitopes in cerebrospinal fluid (CSF). Four years of clinical research
      consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased
      in AD compared to healthy controls and may differentiate AD from its most
      relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau(231))
      shows excellent differentiation between AD and FTD, whereas serine 181 (p
      tau(181)) enhances accurate differentiation between AD and dementia with Lewy
      bodies. Moreover, p-tau(231) levels decline with disease progression, correlating
      with cognitive performance at baseline. Total tau (t-tau) is regarded as a
      general marker of neurodegeneration for evaluation in future population-based
      studies. p-tau(231) and p-tau(181) yield excellent discrimination between AD and
      non-AD dementias including FTD, exceeding the differential diagnostic and
      prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker
      candidate for future evaluation in large national and international multicenter
      networks.

PMID- 15178953
TI  - Frontotemporal dementia: a randomised, controlled trial with trazodone.
AB  - Behavioural troubles due to frontotemporal dementia (FTD) are difficult to treat.
      The serotonergic system is associated with frontal lobes, the degeneration of
      which contributes to FTD. Trazodone increases the extracellular 5-HT levels in
      the frontal cortex. In a randomised, double-blind, placebo-controlled cross-over
      study, we investigated the effect of trazodone. There was a significant decrease
      in the Neuropsychiatry Inventory (NPI) total score with trazodone (p = 0.028) in
      the 26 evaluable patients. A decrease of more than 50% in the NPI score was
      observed in 10 patients with trazodone. This improvement was mainly based on the
      improvement of 4 items of the scale (irritability, agitation, depressive symptoms
      and eating disorders). The Mini-Mental State Examination was not modified and
      trazodone was well tolerated. Results of this first placebo-controlled trial
      suggest that trazodone is an effective treatment for the behavioural symptoms of
      FTD.

PMID- 15178955
TI  - Establishing the association for frontotemporal dementia.

PMID- 15178956
TI  - Prenatal screening and the reduction of birth defects in populations.
AB  - OBJECTIVES: Birth defects occur in populations in 3-5% of births. This paper
      assesses whether population-wide screening programmes for pregnant women would be
      likely to result in major decreases in the prevalence of birth defects. METHOD:
      Relevant literature on this question is reviewed and synthesized. RESULTS: Given
      certain assumptions, a decrease from 3-5 to 2-4% in the prevalence of defects at
      birth may be possible. The resources required to put in place an appropriately
      delivered programme to achieve this are substantial. CONCLUSIONS: As well as the
      potential benefit of a decrease, there are opportunity costs, and potential
      serious harms. Unless undertaken in a carefully planned and monitored way, a
      population-based birth defects reduction programme is likely to bring harm and
      anxiety rather than benefit.

PMID- 15178954
TI  - Isolated executive impairment and associated frontal neuropathology.
AB  - Cognitive impairment in the absence of dementia is common in elderly individuals
      and is most often studied in the context of an isolated impairment in memory. In
      the current study, we report the neuropsychological and neuropathological
      features of a nondemented elderly individual with isolated impairment on a test
      of executive function (i.e., Trail Making Test) and preserved memory, language,
      and visuospatial function. Postmortem studies indicated that cortical
      neurofibrillary tangles (NFT) varied considerably, and some regions contained
      large numbers of neuritic senile plaques. Semiquantitative immunohistochemistry
      showed higher NFT and amyloid-beta (Abeta) loads in the frontal cortex relative
      to the temporal, entorhinal, occipital, and parietal cortices. A survey of the
      entire cingulate gyrus showed a wide dispersion of Abeta42 with the highest
      concentration in the perigenual part of the anterior cingulate cortex; Abeta
      appeared to be linked with neuron loss and did not overlap with the heaviest
      neuritic degeneration. The current case may represent a nonmemory presentation of
      mild cognitive impairment (executive mild cognitive impairment) that is
      associated with frontal and anterior cingulate pathology and may be an early
      stage of the frontal variant of Alzheimer disease.

PMID- 15178957
TI  - Down syndrome and parity.
AB  - OBJECTIVE: To investigate the effect of parity on Down syndrome (DS). METHODS:
      The study was conducted on data from Northeast Italy (NEI) (1981-1996) and Sicily
      (ISMAC) (1991-1996) Congenital Malformation Registries. In these areas, all DS
      births are recorded and confirmed by chromosomal analysis; the NEI Registry also
      registers pregnancy terminations (TOPs) after prenatal diagnosis of DS. In order
      to estimate the effect of parity independently of the mother's age and to reduce
      the truncation effect, different age classes and three classes of parity (1, 2-4,
      >4) were defined. RESULTS: The study sample consisted of 1,088 consecutive
      newborns and 169 consecutive fetuses affected by DS. In both NEI and ISMAC
      samples, we found a significantly increased risk of having a DS child for
      multiparas > or =35 years of age. In the NEI sample, the inclusion of TOP data
      did not seem to modify this finding. In the ISMAC sample, a significantly reduced
      risk for primiparas was found at all ages. CONCLUSIONS: Our data confirm a higher
      risk of having a DS child in women with parity >4. As this effect is evident only
      in women > or =35 years age, its practical impact is null because these women are
      usually offered prenatal diagnosis in any case. However, the mechanisms involved,
      if this association is true, are very intriguing and the observation should
      stimulate scientific studies allowing a better knowledge of the nondisjunction
      mechanism.

PMID- 15178958
TI  - Analysis of the population structure in Oman.
AB  - Knowledge of a population structure can be a unique aid in planning genetic
      services. In order to facilitate the development of genetic services in the
      Sultanate of Oman, a tribal data base has been developed. The historic records of
      the beginning of the 19th century were used as the basis and were updated with
      contemporary information. The tribal data base includes tribal names, locations,
      and the main 185 major tribes and their subsections. Tribal data can be used for
      health care planning and the development of disease-specific genetic registers if
      the hospital records also include the tribal name. They may also provide a useful
      aid in genetic screening and disease prevention programmes, as when specific
      mutations are found in rare diseases, it is likely that these will be found to be
      exclusive to specific tribes, and laboratory testing will be greatly simplified.
      It is likely that similar data bases could be developed elsewhere in the Middle
      East and in the immigrant communities in Western Europe.

PMID- 15178959
TI  - Screening for alpha-thalassemia-1 heterozygotes in expecting couples by the
      combination of a simple erythrocyte osmotic fragility test and a PCR-based
      method.
AB  - OBJECTIVE: To develop a simple method for the prospective identification of
      couples at risk of homozygous alpha-thalassemia-1 (Hb Bart's hydrops fetalis) in
      pregnancy. METHODS: Antenatal care (ANC) women and their husbands were analyzed
      using a simple erythrocyte osmotic fragility (EOF) test and a PCR-based method
      for the detection of the mutation leading to alpha-thalassemia-1 of the Southeast
      Asian type (SEA). RESULTS: Heterozygosity for the alpha-thalassemia-1 (SEA)
      deletion was found to correlate with an EOF value <60%. For a prospective
      screening, ANC women and their husbands are analyzed with the EOF test and only
      those having a value <60% were further checked by PCR. Of 2,769 cases analyzed
      during a 6-month period, 24 couples in which both partners are heterozygotes
      could be identified for genetic counseling and prenatal diagnosis. The
      application of the EOF test decreased the workload for PCR by approximately 80%.
      CONCLUSION: Prospective screening for alpha-thalassemia-1 (SEA) heterozygotes in
      northern Thailand is becoming easier to realize by the combination of EOF test
      and PCR.

PMID- 15178960
TI  - Genetic, epidemiologic and social features of colour blindness.
AB  - Red-green colour blindness is an inherited defect which shows interesting
      epidemiologic and social features. Its mean frequency within the indigenous
      population of Calabria (Southern Italy) was found to be 5.25%, one of the highest
      in continental Italy, showing a decreasing trend from the province of Cosenza
      (Northern Calabria, 6.23%), to the province of Catanzaro (Central Calabria,
      4.65%) and the province of Reggio Calabria (Southern Calabria, 3.43%). A similar
      trend has not been previously recognized, according to the recent literature,
      because no other region has been fully screened. The mean frequency (7.40%) of
      red-green colour blindness in the Albanian ethnic minority in Calabria is
      significantly different from that of the indigenous population, and this minority
      does not have the protanomalous phenotype. Screening showed that 96% of the
      colour-blind students attending middle school and 65% of the colour-blind
      university students are not aware of their anomalous vision status. Thus,
      screening during the school years would greatly help affected students to choose
      their future professional orientation.

PMID- 15178962
TI  - Commissioning clinical genetic services in the UK.

PMID- 15178961
TI  - Study of 290 cases of polyhydramnios and congenital malformations in a series of
      225,669 consecutive births.
AB  - OBJECTIVES: To provide data on polyhydramnios associated with congenital
      anomalies in 225,669 consecutive pregnancies. MATERIAL AND METHODS: The
      information in this study came from births of known outcome recorded in our
      registry of congenital malformations. Routine ultrasonographic examination was
      performed. Polyhydramnios was diagnosed ultrasonographically. A case-control
      study allowed the examination of genetic and environmental causal factors of
      polyhydramnios associated with congenital malformations. RESULTS: The prevalence
      of this association was 1.28/1,000 (290 cases). Polyhydramnios associated with
      congenital malformations was diagnosed prenatally in 44.5% of the cases, 10.3% of
      the infants were stillborn. Forty-one percent of the cases had more than one
      malformation, 14.5% had a chromosomal aberration, and 20.0% had multiple
      malformations that do not constitute a syndrome. The more frequent malformations
      associated with polyhydramnios were cardiac, digestive, central nervous system,
      musculoskeletal, and urinary. There was increased parental consanguinity. The
      incidence of polyhydramnios and congenital anomalies among first-degree relatives
      was 4.1% and first-degree relatives had more malformations than controls (6.2 vs.
      3.2%, p < 0.05). Threatened abortions and diabetes mellitus were significantly
      more frequent among mothers of children with congenital malformations associated
      with polyhydramnios than among controls. CONCLUSIONS: Our study demonstrated that
      careful fetal examination has to be performed when polyhydramnios is diagnosed as
      congenital malformations are often associated with polyhydramnios. We recommend
      the use of fetal chromosome analysis and careful ultrasonographic examination in
      every pregnancy complicated by polyhydramnios.

PMID- 15178963
TI  - Development and use of a national haemoglobinopathy register in Oman.

PMID- 15178964
TI  - Screening for female fragile X premutation and full mutation carriers. A
      commentary on the work of Wildhagen et Al.

PMID- 15178965
TI  - Epidemiology of Usher syndrome in Valencia and Spain.
AB  - OBJECTIVE: To obtain epidemiological data on the prevalence of the different
      types of Usher syndrome (US) in Spain, since these data were missing; to estimate
      the proportion of sporadic cases among simplex families, and calculate the
      prevalence of the Usher syndrome in a homogeneous population from Eastern Spain
      (3,875,234 inhabitants) that is representative of the Spanish population.
      METHODS: Otological, ophthalmological and genetic studies were performed in 89 US
      patients from 46 families and subjected to statistical and segregation analysis.
      RESULTS: 41.6% of them suffered US type I, 46.1% type II, and in 12.3% the
      classification remains unclear. The estimated prevalence for the Province of
      Valencia was 4.2/100,000. There was a notable excess of male-only affected
      multiplex sibships in our sample that could be attributable to an X-linked
      inheritance. CONCLUSIONS: The number of families with USI type was similar to
      that of families with USII type. The estimated prevalence for the Province of
      Valencia is in agreement with other reports in which the estimate for the
      prevalence of US ranges from 1.8 to 6.2/100,000.

PMID- 15178966
TI  - Hereditary nonpolyposis colorectal cancer: an approach to the selection of
      candidates to genetic testing based on clinical and molecular characteristics.
AB  - OBJECTIVE: Identification of clinical and molecular characteristics associated
      with constitutional MLH1 and MSH2 mutations and definition of a stepwise strategy
      for the selection of colorectal cancer (CRC) patients amenable to MLH1 and MSH2
      genetic testing. METHODS: 90 unrelated CRC patients were initially selected on
      the basis of either familial or early onset occurrence of CRC. They were screened
      for the presence of constitutional MLH1 and MSH2 mutations and for microsatellite
      instability (MSI). RESULTS: 16 pathogenetic mutations (9 MLH1 and 7 MSH2) were
      identified in 41% of Amsterdam hereditary nonpolyposis colorectal cancer (HNPCC)
      families, 5% of suspected HNPCC families, and 14% of sporadic early-onset CRC
      patients. The presence of the mutations correlated with MSI, with early age of
      onset and proximal location of the tumor, and with the presence of some
      extracolonic tumors of the HNPCC spectrum and/or multiple tumors in the family.
      CONCLUSIONS: Evaluation of clinical and molecular characteristics is useful for
      the identification of candidates to MLH1 and MSH2 mutational analysis and allows
      the application of a rational approach to genetic testing.

PMID- 15178967
TI  - Assessment of family cancer history collection and utilization in patient care.
AB  - OBJECTIVES: This study was conducted to determine whether patients and
      accompanying persons visiting the Gynecologic Oncology Clinic were aware if a
      family cancer history was recorded and utilized in their medical care; whether
      they were aware of the importance of a family cancer history, and whether they
      would like to learn more about familial cancer. METHODS: Sixteen- and 17-item
      self-report questionnaires were administered to patients and their accompanying
      persons, respectively, who were visiting the Gynecologic Oncology Clinic. All
      responses were anonymous. RESULTS: Two hundred forty-four patient questionnaires
      and 114 accompanying person questionnaires were completed. Seventy-eight percent
      of the patients and 70% of the accompanying persons replied that a physician had
      inquired about their family history of cancer. Only 40% of those patients and 70%
      of those accompanying persons (31 and 49% of total patients and accompanying
      persons, respectively) replied that the inquiry was by their family physician.
      Sixty-seven percent of these patients and 63% of these accompanying persons
      reported that a written record was made of the family history. Thirty-one percent
      of the patients and 28% of accompanying persons knew that their family cancer
      history information had been used to aid in their medical care. Eighty-eight
      percent of the patients and 83% of the accompanying persons reported the
      occurrence of at least one relative with cancer; however, only 44% of the
      patients and 35% of the accompanying persons replied that a health care provider
      had ever provided teaching about the importance of a family cancer history.
      Seventy-five percent of the patients and 73% of the accompanying persons
      indicated that they would like to learn more about hereditary cancer and cancer
      genetics. CONCLUSIONS: This study demonstrates that patients desire information
      about cancer genetics and hereditary cancer. Therefore, health care providers
      should provide better education and information to their patients as well as
      improve their family history-taking skills.

PMID- 15178968
TI  - The molecular spectrum of beta-thalassemia and abnormal hemoglobins in the
      allochthonous and autochthonous dutch population.
AB  - The prevalence at birth of hemoglobin defects in the autochthonous North-European
      population is low. However, the long immigration and colonial history of the
      Netherlands has resulted in a group of about 1-2 million 'autochthonous'
      inhabitants, with Asian, South-European or African ancestors, in whom a moderate
      birth prevalence of globin gene mutations can be expected. Furthermore, at least
      10% of the Dutch population consists of recent immigrants from different
      countries with high birth prevalence of hemoglobinopathies. Because of the
      endogamous partner choice, which is prevalent in this population, the risk for
      homozygous progeny remains elevated. At least 100,000 carriers of
      hemoglobinopathies of recent allochthonous origin are present in the Netherlands,
      and the number of homozygous children is rising. Prevention by prenatal diagnosis
      requires a suitable protocol and knowledge about the molecular defects present in
      the country. Therefore we have analyzed a large number of patients and carriers,
      both at the hematological and at the DNA level. Our survey revealed 47 different
      beta-thalassemia determinants, characterized on 223 independent chromosomes from
      individuals of different ethnic origins. As expected, the most prevalent
      mutations were largely represented. The cd39 (C-->T) mutation was found in 70% of
      the immigrants from Morocco, Sardinia and other Central-West-Mediterranean
      regions while the IVS-I-110 (G-->A) was prevalent in the East-Mediterranean
      populations. The IVS-I-5 (G-->C) mutation was found in 45% of the patients of
      Indonesian origin. We also registered 308 independent chromosomes with common
      structural defects (HbS, HbC, HbE, Hb Lepore, Hb Constant Spring and HbD Punjab)
      and 33 chromosomes with 19 different, less frequent, rare or very rare mutants.
      Seven structural mutants were described for the first time and published
      separately. Furthermore, 139 independent chromosomes with deletional and
      nondeletional alpha-thalassemia defects were characterized.

PMID- 15178969
TI  - The Hungarian periconceptional service as a model for community genetics.
AB  - OBJECTIVES: This review describes the methods and results of the Hungarian
      periconceptional service consisting of counselling, examinations and medical
      interventions. (The term periconceptional is used instead of preconceptional
      because the early postconceptional period is also involved to this service.)
      METHODS: The service was based on three steps: check-up examination of
      reproductive health (i.e., preconceptional screenings), a 3-month preparation for
      conception, dispensed and/or supervised by qualified nurses, and a better
      protection in early pregnancy for the most sensitive early development of the
      embryo for voluntary and eligible couples. RESULTS: Experiences from the
      coordinating centre of the Hungarian periconceptional service are summarized
      between February 1, 1984, and January 31, 1999, thus 15 years. Participants with
      positive family histories, case histories and subjects with genito-urinary
      infections had a more effective flow towards secondary care. Infertile couples
      were diagnosed and treated sooner. The periconceptional service is effective for
      the introduction of periconceptional folic acid-containing multivitamin
      supplementation and for the reduction of smoking and alcohol consumption in
      females in the preconceptional period. The rate of major congenital abnormalities
      (20.6 per 1,000) was significantly lower than expected. CONCLUSIONS: The
      periconceptional service is feasible and has many benefits. Thus, proper
      preparation for conception is the earliest and probably the most important effort
      to prevent genetic diseases.

PMID- 15178970
TI  - Introduction. The National Dialogue on Genetics.

PMID- 15178971
TI  - Consumer perspectives on genetic testing, research and services for
      ethnoculturally diverse populations.
AB  - A panel of individuals from diverse ethnocultural backgrounds and representing a
      variety of genetic disorders presented their consumer perspectives on genetic
      programs, testing and services. Their remarks emphasized how misunderstanding and
      miscommunication between health care professionals and many of the populations
      for whom they provide services can lead to unfilled genetic service needs.
      Panelists recommended that health care professionals become more aware and
      knowledgeable about the diversity of customs, beliefs and cultures of those
      receiving their services. Only by building a foundation of trust and mutual
      respect will genetic testing, research and services become more accessible to
      individuals from diverse populations, their families and their communities.

PMID- 15178972
TI  - Genetic services in the new era: Native American perspectives.
AB  - American Indians have arrived at a critical point in their more than 500-year
      history with the United States Government. With the advent of the new bio
      revolution, a number of tribes have voiced vehement opposition to genetic
      patenting, creation of cell lines, transgenic experimentation and cloning. While
      many are opposed to the Human Genome Diversity Project, Human Genome Project and
      diversity research currently being conducted by the Indian Health Service, a few
      embrace the beneficial aspects of biomedical/biogenetic research. Moreover, an
      increasing number of Indians see the need for and are seeking genetic counseling
      and other services. This paper briefly describes some of the issues associated
      with developing and implementing effective genetic services within Native
      American communities. Problems of access, perception of services, previous
      experience with genetics and cultural and other barriers are discussed.
      Recommendations also are rendered to assist health professionals in the
      development of services.

PMID- 15178973
TI  - Genetic services to the latino population in the United States.
AB  - In 1998 Latinos (Hispanics) in the United States number 30 million persons and
      account for 11.3% of the total population, while it is predicted that by the year
      2020 they will become the largest minority. This article describes the
      demographics and health profile of the Latino population in the United States. A
      brief account is given of common cultural traditions and health beliefs that
      modulate the interaction of this population with the health delivery system in
      general, and that of genetic services in particular. Further, some problems in
      the access to, and utilization of genetic services are outlined, and the
      experience of a project designed to overcome those problems in New York City is
      described.

PMID- 15178974
TI  - Strengthening genetic services in primary care for Asian Americans and Pacific
      Islanders.
AB  - The Association of Asian Pacific Community Health Organizations (AAPCHO) is a
      national membership organization of community health centers (CHCs) that serve
      medically underserved Asian Americans and Pacific Islanders (AAPIs) with limited
      English-speaking proficiency and low income. OBJECTIVES: In 1995, AAPCHO was
      funded for a 3-year national genetics training project to improve genetics
      training among primary care providers at CHCs and strengthen linkages with
      tertiary genetic centers (TGCs). Three model linkages between CHCs and TGCs were
      documented on the coordination of genetic services for medically underserved
      AAPIs. METHODS: Guidelines were developed for three CHCs to document their
      genetic programs and linkages with TGCs. In addition, one clinic conducted a mail
      survey to assess understanding of prenatal genetic counseling sessions by
      patients that visited the clinic during the past 2 years. RESULTS: Model linkages
      between CHCs and TGCs to improve cultural and linguistic accessibility for
      patients include formal coordination between the CHCs and TGCs for the delivery
      of genetic services and the provision of varying levels of genetic services at
      the CHC. From the patient survey, there was a 59% response rate among 70 surveys
      mailed to former patients. The survey results showed that while a majority of
      patients understood and recalled key genetic concepts, one-fifth of patients
      experienced difficulty understanding their genetic counseling sessions.
      CONCLUSION: Based on model linkages between CHCs and TGCs and the patient
      satisfaction survey results, the following strategies are recommended to improve
      accessibility of genetic services for medically underserved AAPIs: (1) genetics
      education should be developed for all levels of health center staff; (2)
      counseling should be culturally sensitive and focus on key issues that must be
      conveyed for appropriate informed consent; (3) genetics education should employ
      the use of translated audiovisual aids and brochures to improve understanding;
      (4) genetic services should be coordinated between CHCs and TGCs to provide
      culturally and linguistically competent care for medically underserved AAPIs, and
      (5) financial mechanisms should be available to support genetic testing of
      patients and their families with little or no coverage for genetic services.

PMID- 15178975
TI  - Genetic education to diverse communities employing a community empowerment model.
AB  - Lack of equity in access to health care, in general, and genetic services in
      particular, places communities of color at a distinct disadvantage when
      considering the rapidly evolving genetic technology. Much of this disparity is
      owed to lack of trust and credibility in the genetic care system as well as
      multiple ethnocultural barriers to services. This paper presents a 3-year
      community outreach demonstration project in genetic education. The project
      employed the premise that the empowerment of the target communities to take
      active part in their genetic education, with attention to a wide array of the
      community's health care needs, is the most efficacious manner in which to provide
      genetic education to underserved communities.

PMID- 15178976
TI  - Improving access to and utilization of genetic services in Arizona's Hispanic
      population.
AB  - This abstract presents a model project aimed to train community lay health
      workers about genetics, increase cultural competency of genetic services
      providers, and provide local access to genetic services in primarily Hispanic
      communities in the state of Arizona. Health Start, a community-based prenatal
      outreach program, served as the basis for providing genetic education and
      services. A genetics training curriculum was developed and training of community
      lay health workers was provided. Cultural and Spanish language training was
      provided for all genetic services providers. Pediatric genetics outreach clinics
      were established in eight communities. Community-based lay health workers eagerly
      incorporate genetic information into their public health knowledge base, but this
      may not lead to acceptance of these personnel by local health care providers as
      sources of referrals for specialized health services such as genetics. Cultural
      competence training of genetic service providers is enthusiastically accepted and
      utilized in the provision of locally accessible genetics clinics.

PMID- 15178978
TI  - WHO Human Genetics Programme: a brief overview.

PMID- 15178977
TI  - Genetic testing: can it predict the lived experience of individuals and families?
      A personal testimony.
AB  - An individual's and family's experience with a genetic disease is too complex and
      diverse to be totally predicted using genetic testing. Stigmatization and
      discrimination of gene carriers can occur if society chooses to utilize genetic
      technology to eliminate 'disease and disability' without accepting human
      variation and devoting any possible efforts for ameliorating the life of
      individuals faced with disabilities. In this paper I use Friedreich's ataxia (FA)
      to illustrate some ways in which a disease experience can differ from what is
      expected from textbook descriptions of a given condition. I describe the expected
      medical characteristics with FA and some of my own personal experience with the
      disease as well as that of my family.

PMID- 15178979
TI  - Study of 224 cases of oligohydramnios and congenital malformations in a series of
      225,669 consecutive births.
AB  - OBJECTIVES: To provide data on oligohydramnios associated with congenital
      anomalies in 225,669 consecutive pregnancies. MATERIAL AND METHODS: The
      malformations in this study came from births of known outcome recorded in our
      registry of congenital malformations. Routine ultrasonographic examination was
      performed. Diagnosis of oligohydramnios was made ultrasonographically. For each
      case, a control was chosen. RESULTS: The prevalence of this association was 0.99
      per thousand (224 cases). A case-control study allowed the examination of genetic
      and environmental factors for the origin of oligohydramnios associated with
      congenital malformations. Diagnosis of oligohydramnios associated with congenital
      malformations was made prenatally in 32.6% of the cases; 12.0% of the infants
      were stillborn. Fifty-nine percent of the cases had more than one malformation,
      13.8% had a chromosomal aberration, and 27.6% had multiple malformations that do
      not constitute a syndrome. The more frequent malformations associated with
      oligohydramnios were urinary, musculoskeletal, digestive and cardiac. There was
      increased parental consanguinity. The frequency of oligohydramnios and congenital
      anomalies among first-degree relatives was 4.5% and first-degree relatives had
      more malformations than controls (8.0 vs. 3.1%, p < 0.05). Threatened abortions
      and diabetes mellitus were significantly more frequent among mothers of the
      children with congenital malformations associated with oligohydramnios than among
      the controls. CONCLUSIONS: Our study demonstrated that careful fetal examination
      has to be performed when oligohydramnios is diagnosed as congenital malformations
      are often associated with oligohydramnios. We recommend the use of fetal
      chromosome analysis and careful ultrasonographic examination in every pregnancy
      complicated by oligohydramnios.

PMID- 15178980
TI  - A cytogenetic register of down syndrome in Lebanon.
AB  - OBJECTIVES: To provide data on the cytogenetics and epidemiology of Down syndrome
      in our community. METHODS: All cases of Down syndrome diagnosed cytogenetically
      were entered over a period of 5 years together with data regarding age at
      referral, parental ages and parity. RESULTS: A total of 280 cases were entered.
      In postnatal cases, the mean maternal age was 32.19 years and 41.5% of mothers
      were over 35 years. Only 47.3% of Down syndrome children were diagnosed at less
      than 1 month of age. The male to female sex ratio of 1.66 is significantly more
      elevated than that reported in larger registers. CONCLUSIONS: Because of problems
      inherent to Lebanon, this register does not have a high level of ascertainment,
      however it appears that the emphasis in a potential prevention programme should
      be placed on education, information and family planning.

PMID- 15178981
TI  - The history of community genetics: the contribution of the haemoglobin disorders.
AB  - The emerging possibilities of applying new diagnostic technologies for genetic
      diagnosis and screening point to the need for a discipline of community genetics.
      Genetic population screening for haemoglobin disorders (thalassaemias and sickle
      cell disorders) has been practised on a large scale for over 20 years, and basic
      concepts and methods of community genetics have been developed within this
      framework, under the auspices of the WHO. Genetic population screening is a
      public health activity. It involves many disciplines, and planning depends on
      reliable and regularly updated information. Basic methods for describing genetic
      epidemiology in terms of service needs, and for regular service audit have been
      developed, and IT-based approaches for making simple, accurate and diagnosis
      specific information accessible to the public and health professionals are being
      explored.

PMID- 15178982
TI  - The impact of consanguinity worldwide.
AB  - Consanguineous marriages have been practiced for hundreds of years in many parts
      of the world. The rate of congenital malformations among the offspring is 2.5
      times higher than that among the offspring of unrelated parents, mainly due to
      the expression of autosomal-recessive disorders, and hospitalization for these
      reasons causes a major financial burden. An increase in sterility and in the
      rates of abortion, stillbirths, perinatal losses and neonatal deaths has been
      reported by some authors but not by others. It is generally accepted that the
      advantages of consanguinity outweigh the disadvantages; however, strategies for
      reducing the burden require a unique approach as discussed in this article.

PMID- 15178983
TI  - Role of primary care providers in the delivery of genetics services.
AB  - Fruits of the Human Genome Project are already transforming health care. Primary
      care providers, regardless of specialty, will need to integrate new genetics
      knowledge into routine practice in order to fulfill their role in genetics
      services delivery. Unfortunately, few are prepared for this revolution, and
      current educational efforts are inadequate. To effect the changes that are
      needed, we must teach genetics as an integrative discipline at all stages of
      professional education and emphasize the value of this knowledge to practice.

PMID- 15178984
TI  - Uptake and impact of carrier testing for cystic fibrosis. A review and a
      theoretical framework about the role of knowledge, health beliefs and coping.
AB  - The first aim of the paper is to review research into the uptake of carrier
      testing for cystic fibrosis and into the impact of carrier testing on self
      esteem, risk perception and reproductive decisions. The second aim is to connect
      the most important findings to psychological theories and concepts. Thirdly, we
      infer practical suggestions for genetic counselling. The uptake of genetic
      testing for CF could be explained by at least three (complementary) interrelated
      psychological concepts: the (lack of) genetic information, the individual's
      health beliefs and the concept of coping with a health threat. Cognitive and/or
      emotional coping mechanisms played also an important role in preserving self
      esteem after a positive carrier test and in the subjective evaluation of the
      residual risk after a negative test result. Suggestions are given regarding
      genetic counselling in general and regarding free informed decision making.

PMID- 15178985
TI  - Explorative study of costs, effects and savings of screening for female fragile X
      premutation and full mutation carriers in the general population.
AB  - OBJECTIVE: Evaluation of the costs, effects and savings of three strategies for
      female fragile X premutation and full mutation carrier screening in the general
      population. METHODS: We calculated the costs, effects and savings by using a
      general model for prenatal, preconceptional, and school carrier screening.
      Assumptions were based on literature data, expert opinions, prices and tariffs.
      RESULTS: Prenatal screening will detect most carriers and will lead to the
      highest number of avoided fragile X syndrome patients. The costs per detected
      carrier are quite similar for all screening programmes (around USD 45,000). All
      screening strategies have a favourable cost-savings balance (USD 14 million for
      prenatal screening, USD 9 million for preconceptional screening and USD 2 million
      for school screening). CONCLUSIONS: From an economic point of view, there is no
      obstacle to fragile X screening. The decision to screen or not can (and should)
      therefore concentrate on discussion of medical, social, psychological and ethical
      considerations.

PMID- 15178986
TI  - A Commentary on the NIH Consensus Development Statement 'Genetic Testing for
      Cystic Fibrosis'.
AB  - A NIH Consensus Development Statement recommends implementation of a cystic
      fibrosis carrier screening in the general pregnant and pre-pregnant population.
      This suggestion is discussed in the light of missing or insufficient data about
      the reasons for high uptake rates in pilot projects, psychological and social
      risks, and optimal educational and counselling settings. It is concluded that the
      recommendation is not defendable and, at best, premature.

PMID- 15178987
TI  - Analysis of 16,922 patients with acute ischemic stroke and transient ischemic
      attack in Japan. A hospital-based prospective registration study.
AB  - OBJECTIVE: The purpose of the present study was to clarify the present status of
      stroke medicine in Japan using a hospital-based, prospective registration study
      of 156 hospitals from all over Japan. METHODS: Consecutive patients with acute
      ischemic stroke and transient ischemic attack (TIA) who presented to hospital
      within 7 days of onset from May 1999 to April 2000 were enrolled in this study. A
      common protocol was applied in every participating hospital. RESULTS: A total of
      16,922 patients (TIA, 6.4%) with a mean age of 70.6 +/- 11.5 years (median 71
      years, range 18-107 years) were enrolled in the study. Lacunar stroke was the
      most frequent stroke subtype (38.8%), followed by atherothrombotic (33.3%),
      cardioembolic (21.8%) and other stroke (6.1%). NIH stroke scale score on
      admission was 8.0 +/- 7.9 (median 5; 25th to 75th percentile, 2-11). 36.8%
      arrived at hospital within 3 h of symptom onset, and 49.5% within 6 h. The
      ambulance was used for 70.2% of patients arriving within 3 h after onset, but in
      only 29.9% of patients visiting the hospital later than 3 h after onset (p <
      0.0001). 60.8% displayed good outcome (modified Rankin Scale score of 0-2 at
      discharge), while 32.3% displayed poor outcome (score 3-5), and mortality rate
      was 6.9%. CONCLUSIONS: More than half of the acute stroke patients arrived at
      hospital later than 6 h after onset. Establishment of ideal emergency systems is
      needed for better management of stroke and for improvement of patient outcome, in
      particular, in the future after approval of intravenous recombinant tissue
      plasminogen activator for acute ischemic stroke by the Japanese government.

PMID- 15178988
TI  - Carotid artery stenting:the need for randomised trials.
AB  - Endovascular treatment for carotid artery stenosis avoids some of the
      complications of carotid endarterectomy, but has not been widely accepted.
      Concerns about the risks and benefits of endovascular treatment led to the
      Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). There was
      no difference in major outcome events between endovascular treatment and carotid
      endarterectomy, but the rate of procedural stroke or death was higher than
      desirable. There was no difference either in the rate of stroke during follow-up,
      but the confidence intervals were very wide and severe ipsilateral carotid
      stenosis was more frequent 1 year after endovascular treatment than after carotid
      surgery. Two other randomised trials of carotid stenting were stopped early after
      poor outcomes in stented patients. These early trials used techniques which have
      now been superseded, but the results emphasise the need to improve the safety of
      endovascular treatment. Recent advances designed to improve safety include new
      designs of stents and delivery systems, and devices designed to protect the brain
      from embolisation during stenting. However, there is little convincing evidence
      that these new devices reduce the rate of stroke. Moreover, a systematic review
      of the existing randomised trial data concluded that there the current evidence
      does not support a shift away from recommending carotid endarterectomy as the
      standard treatment for carotid stenosis. There is therefore a clear need for
      further randomised trials of carotid stenting. Three of the ongoing trials, EVA
      3S, SPACE and ICSS (CAVATAS-2), have prospectively agreed to combine individual
      patient data after completion of follow-up. This meta-analysis will provide
      results similar to a mega-trial and should also allow informative subgroup
      analyses. The co-operation between the trials in agreeing to perform this meta
      analysis is a major advance in trial design. The result should determine whether
      carotid stenting truly rivals carotid endarterectomy as the treatment of choice
      for carotid stenosis.

PMID- 15178989
TI  - The Stent-Supported Percutaneous Angioplasty of the Carotid Artery vs.
      Endarterectomy Trial.
AB  - The Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus
      Endarterectomy (SPACE) Trial is investigating if both treatment modalities are
      equivalent in the treatment of severe symptomatic carotid stenoses. Patients with
      symptomatic (transient ischaemic attack or minor stroke) stenosis (above 50%
      following the North American Symptomatic Endarterectomy Trial criteria) eligible
      for both methods can be recruited into this trial. The primary endpoint is the
      incidence of an ipsilateral stroke or death between randomisation and day 30
      after treatment. Surgeons as well as the interventionalists have to demonstrate
      their expertise prior to participation in the trial. Funding is mostly by public
      institutions (Federal Ministry of Education and Research and German Research
      Foundation). An external monitoring is applied. Thirty-two centres are currently
      taking part in the SPACE Trial that has been running in Germany, Austria and
      Switzerland for 3 years, and they have been able to recruit a total of around 670
      patients. The definitive results of this study cannot be expected before 3-5
      years.

PMID- 15178990
TI  - International carotid stenting study: protocol for a randomised clinical trial
      comparing carotid stenting with endarterectomy in symptomatic carotid artery
      stenosis.
AB  - BACKGROUND: Carotid stenting avoids general anaesthesia, cranial nerve injury and
      the discomforts of surgical treatment of carotid stenosis. A systematic review of
      the randomised trials showed no overall difference in the major risks of
      endovascular treatment for carotid stenosis compared with surgery, but the
      confidence intervals were wide and both methods carried a significant risk of
      stroke. The use of protection devices appears to improve the safety of
      endovascular treatment, but there are little randomised data available about long
      term outcomes. We have therefore set up an international, multicentre,
      randomised, controlled, open, prospective clinical trial, namely the
      International Carotid Stenting Study (ICSS), also known as CAVATAS-2. The
      objectives of the ICSS are to compare the risks, benefits and cost-effectiveness
      of a treatment policy of referral for carotid stenting compared with referral for
      carotid endarterectomy. METHODS: Centres are required to have a team with audited
      expertise in carotid endarterectomy and stenting procedures, including at least
      one neurologist or stroke physician, a surgeon and an interventionalist.
      Attendance at a carotid stenting training course is required. Centres with more
      limited experience can join the trial as probationary centres, but stenting must
      then be proctored by an experienced interventionalist. Symptomatic patients are
      included over the age of 40 years with atherosclerotic carotid stenosis, suitable
      for both stenting and surgery, and are randomised in equal proportions between
      carotid endarterectomy and stenting. Stents and other devices are chosen for use
      at the discretion of the interventionalists but must be approved by the devices
      committee. The protocol recommends that a cerebral protection system should be
      used whenever the operator thinks one can be safely deployed. The combination of
      aspirin and clopidogrel is recommended to cover stenting procedures. Standard or
      eversion endarterectomy is allowed using local or general anaesthesia, shunts or
      patches. All patients will receive best medical care. Patients will be followed
      up by neurologists at 30 days after treatment, 6 months after randomisation and
      then annually up to 5 years after randomisation. The primary outcome measure is
      the difference in the long-term rate of fatal or disabling stroke in any
      territory between patients randomised to stenting or surgery. Secondary outcome
      measures include any stroke, myocardial infarction or death within 30 days of
      treatment, treatment- related cranial nerve palsy or haematoma. Restenosis (>70%)
      on ultrasound follow-up, economic measures and quality of life will also be
      analysed. The sample size is estimated at 1,500 patients, which will provide 95%
      confidence intervals of +/- 3.0 percentage points for the outcome measure of 30
      day disabling stroke and death rate and +/- 3.3 percentage points for the outcome
      measure of death or stroke during follow-up. The trial office monitors outcome
      events at individual centres and a rate of events above a given threshold
      triggers a blinded assessment of the events, submitted to the chairman of the
      data-monitoring committee. CONCLUSIONS: The ICSS protocol incorporates a number
      of novel features to ensure patient safety, including the concept of probationary
      centres, proctoring of inexperienced investigators and monitoring of individual
      centre results on an ongoing basis. The protocol is also designed to mirror
      routine clinical practice as far as possible, so that the results will be widely
      applicable and relevant to determining the place of carotid stenting in clinical
      practice in the future.

PMID- 15178991
TI  - Simultaneous cardiogenic embolism in bilateral internal carotid arteries -
      carotid ultrasonography, MRI and autopsy findings.

PMID- 15178992
TI  - Use of CT perfusion to differentiate between brain tumour and cerebral
      infarction.

PMID- 15178993
TI  - Major stroke in thrombotic-thrombocytopenic purpura (Moschcowitz syndrome).

PMID- 15178994
TI  - Changes in vessel stenosis due to internal carotid artery dissection during
      anticoagulant treatment.

PMID- 15178995
TI  - Transient blurred vision as the only manifestation of basilar stenosis.

PMID- 15178996
TI  - Comments on 'computed tomographic parameters predicting fatal outcome in large
      middle cerebral artery infarction'.

PMID- 15178998
TI  - Minimal residual disease in hematological malignancies.

PMID- 15178999
TI  - Minimal residual disease studies by flow cytometry in acute leukemia.
AB  - Minimal residual disease (MRD) assays are increasingly important in the clinical
      management of patients with acute leukemia. Among the methods available for
      monitoring MRD, flow cytometry holds great promise for clinical application
      because of its simplicity and wide availability. Several studies have
      demonstrated strong correlations between MRD levels by flow cytometry during
      clinical remission and treatment outcome, lending support to the reliability of
      this approach. Flow-cytometric detection of MRD is based on the identification of
      immunophenotypic combinations expressed on leukemic cells but not on normal
      hematopoietic cells. Its sensitivity depends on the specificity of the
      immunophenotypes used to track leukemic cells and on the number of cells
      available for study. Immunophenotypes that allow detection of 1 leukemic cell in
      10,000 normal cells can be identified in at least 90% of patients with acute
      lymphoblastic leukemia; immunophenotypes that allow detection of 1 leukemic cell
      in 1,000-10,000 normal cells can be identified in at least 85% of patients with
      acute myeloid leukemia. Identification of new markers of leukemia by gene array
      technology should lead to the design of simple and reliable antibody panels for
      universal monitoring of MRD. Here we review the relative advantages and
      disadvantages of flow cytometry for MRD studies, as well as results obtained in
      correlative studies with treatment outcome.

PMID- 15179000
TI  - Strategies and clinical implications of chimerism diagnostics after allogeneic
      hematopoietic stem cell transplantation.
AB  - Analysis of donor chimerism has become a routine method for the documentation of
      engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). In
      recent years several groups have also focused on the application of this
      technique for the detection of relapsing disease after allogeneic HSCT. This
      review addresses technical issues (sensitivity, specificity) and discusses the
      advantages and limitations of methods currently used for chimerism analysis and
      their usefulness for the detection of MRD. In addition, the potential impact of
      novel procedures, e.g. subset chimerism or real-time PCR-based procedures, is
      discussed.

PMID- 15179001
TI  - The multiparametric scanning system for evaluation of minimal residual disease in
      hematological malignancies.
AB  - Combined simultaneous analysis of morphology, immunophenotyping and fluorescence
      in situ hybridization on the same cell offers advantages that may help to
      disclose the relevance of minimal residual disease (MRD) detection. Morphological
      analysis of small populations of cells related either to malignancy or recipient
      associated markers may improve the accuracy of chimerism and MRD testing and
      delineate their clinical significance.

PMID- 15179002
TI  - Standardization of preanalytical factors for minimal residual disease analysis in
      chronic myelogenous leukemia.
AB  - Optimal sample quality is a prerequisite to generate valid data in the detection
      of minimal residual disease (MRD) in leukemias. Thus, the risk of obtaining
      'false'-negative results is increased when both quality and quantity of RNA are
      suboptimal. Factors which affect the sensitivity and consequently the validity of
      MRD results are reviewed. RNA degradation in unstabilized peripheral blood (PB)
      samples does not play a major role in samples being processed on the day of blood
      collection. However, the simulation of sample shipping at room temperature with a
      delay of sample processing of up to 3 days causes a dramatic loss of intact RNA.
      RNA degradation can be prevented by the use of a bedside RNA stabilization
      system. Additionally, the stabilizing procedure is capable of keeping real-time
      quantitative polymerase chain reaction (RQ-PCR) results comparable whether the
      sample is processed immediately or with a delay of up to 3 days. Consistent
      quantitative data cannot be obtained with unstabilized blood samples.
      Furthermore, the optimum volume of PB required for MRD diagnostics in patients
      with BCR-ABL-positive chronic myelogenous leukemia in complete cytogenetic
      remission is revisited. Ten milliliters of PB is sufficient for processing on the
      day of blood collection whereas the use of only 5 ml PB may result in false
      negative results. Standardization of preanalytical and analytical factors is
      necessary to provide a comparability of RQ-PCR results from different
      laboratories within multicenter studies. The definition of 'undetectable BCR-ABL'
      in an individual patient should take these preanalytical parameters into
      consideration.

PMID- 15179003
TI  - Minimal residual disease in childhood acute lymphoblastic leukemia: current
      status and challenges.
AB  - The pace of disappearance of leukemic blasts in response to therapy has long been
      recognized as the most important prognostic factor in childhood acute
      lymphoblastic leukemia (ALL). Recent technological advancements enable detection
      of submicroscopic leukemic cells. The extent of reduction in the level of minimal
      residual disease (MRD) during the first phase of therapy can be exploited for
      improved risk classification of children with ALL. Current prospective studies
      test the hypothesis that tailoring treatment to the level of MRD will improve
      patients' outcome.

PMID- 15179004
TI  - Detection of minimal residual disease in acute myelogenous leukemia.
AB  - Acute myelogenous leukemia (AML) is considered to be in complete remission when
      fewer than 5% of the cells in bone marrow are blasts. Nevertheless, approximately
      two thirds of patients relapse due to persisting leukemic blasts. The persistence
      of these cells, below the threshold of morphological detection, is termed minimal
      residual disease (MRD) and various methods are used for its detection. These
      methods include classical cytogenetics, fluorescence in situ hybridization,
      qualitative and quantitative RT-PCR and multiparametric flow cytometry.
      Currently, less than half of the AML patients have a specific marker detectable
      by RT-PCR techniques. The major specific molecular markers are involvement of the
      MLL gene with up to 50 different partners and partial tandem duplications, the
      core binding factor leukemias with AML1/ETO and CBFbeta/MYH11 rearrangements,
      PML/RARalpha in acute promyelocytic leukemia, internal tandem duplications and
      mutations of FLT3 and some other rare translocations. In addition, several other
      genes show abnormal expression levels in AML, including the Wilms tumor gene, the
      PRAME gene and Ig/TCR rearrangements. Most of these genetic abnormalities can be
      detected by qualitative but more importantly by quantitative RT-PCR. The kinetics
      of disappearance of molecular markers in AML differs between the various types of
      leukemias, although at least a 2 log reduction of transcript after induction
      chemotherapy is necessary for long-term remission in all types. Conversely, the
      change of PCR from negativity to positivity is highly predictive of relapse.
      Whereas in acute lymphoblastic leukemia, multiparametric flow cytometry is an
      established method for MRD detection, this is less so in AML. The reason is the
      absence of well-characterized leukemia-specific antigens and the existence of
      phenotypic changes at relapse. On the other hand, this method is convenient due
      to its simplicity and universal applicability. In conclusion, several methods can
      be used for MRD detection in AML patients; each has its pros and cons. Several
      issues still remain to be settled including the choice of the best method and the
      timing for MRD monitoring and above all the practical clinical implications of
      MRD in the various types of AML.

PMID- 15179005
TI  - Pathogenesis, diagnosis and monitoring of residual disease in acute promyelocytic
      leukaemia.
AB  - The clinical course of acute promyelocytic leukaemia (APL) has changed over the
      last 25 years from one that was fatal for the majority of patients to
      representing one of the most curable subtypes of acute myeloid leukaemia. Besides
      improved supportive care this has mainly been achieved through the introduction
      of novel targeted therapies in the form of all-trans retinoic acid (ATRA) and
      arsenic trioxide that specifically address the underlying molecular lesion. APL
      is characterized by chromosomal rearrangements of 17q21 leading to the formation
      of fusion proteins involving retinoic acid receptor alpha (RARA). To date five
      different fusion partners of RARA have been identified, but the vast majority of
      cases are characterized by the presence of the t(15;17)(q22;q12-21), which
      involves the promyelocytic leukaemia (PML) gene. The identification of different
      breakpoint microclusters within RARA intron 2 suggests that sequence-associated
      or structural factors play a role in the formation of the t(15;17). In addition,
      the comparison of forward and reverse genomic junctions has revealed
      microhomologies, deletions and/or duplications of either gene consistent with the
      hypothesis that the t(15;17) occurs by non-homologous recombination of DNA after
      processing of the double strand breaks by a dysfunctional DNA damage repair
      mechanism. The detection of the PML-RARA fusion gene by reverse-transcription
      polymerase chain reaction (RT-PCR) is routinely used for diagnosis and monitoring
      of minimal residual disease (MRD). In PML-RARA-positive APL about 70% of patients
      are expected to be cured with a combination of ATRA and anthracycline-based
      chemotherapy. However, relapse remains a major problem. The identification of
      patients at high risk of relapse and the development of risk-adapted treatment
      schedules are therefore clearly the most challenging tasks in the treatment of
      APL. Recent studies have shown that pre-emptive chemotherapy at the time of
      molecular relapse improves survival compared to treatment at the point of
      haematological relapse. Quantitative RT-PCR technology is expected to further
      improve the predictive value of MRD monitoring and therefore to guide therapy in
      order to reduce the rate of relapses and to increase rates of cure in high-risk
      patients.

PMID- 15179006
TI  - FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia.
AB  - Length mutations within the FLT3 gene (FLT3-LM) can be found in 23% of acute
      myeloid leukaemia (AML) and thus are the most frequent mutations in AML. FLT3-LM
      are highly correlated with AML with normal karyotype and other cytogenetic
      aberrations of the prognostically intermediate group. This group is supposed to
      be a mixed group of AML with differences in the underlying pathogenesis. For more
      individualized treatment options it would be helpful to better characterize this
      large AML group not only by molecular mutations but also use these markers for
      the definition of minimal residual disease (MRD). However, so far the
      cytogenetically intermediate AML has been lacking suitable markers for PCR-based
      MRD detection like the fusion genes in the prognostically favourable subgroups.
      The suitability of the FLT3-LM as a target for PCR-based MRD was discussed
      controversially as it seemed to be a rather unstable marker. Thus, we aimed at
      the evaluation of FLT3-LM as a marker for residual disease in a large cohort of
      AML. Paired samples of 97 patients with AML at diagnosis and at relapse were
      analyzed. It could be shown that in only four cases a loss of the length mutation
      was detected. This is in the range of other well-characterized AML relapsing with
      a different geno- and/or phenotype. In contrast, a change in the ratio of the
      mutated allele in comparison to the wild-type allele was frequently observed. In
      detail, the FLT3-LM showed a tendency to accumulate during disease progression
      and was found more frequently at relapse than at diagnosis. In addition, 45
      patients were analyzed at different time points during and after therapy. Using
      conventional PCR it clearly could be shown that for most of the patients positive
      at presentation FLT3-LM is a reliable PCR marker for monitoring treatment
      response. Even an early detection of relapse was possible in some cases.

PMID- 15179007
TI  - WT1 as a universal marker for minimal residual disease detection and
      quantification in myeloid leukemias and in myelodysplastic syndrome.
AB  - Monitoring of acute leukemia patients during and after treatment for the presence
      of remaining leukemic cells (minimal residual disease, MRD) has been shown to
      give major insight into the effectiveness of treatment. However, so far the
      applicability of this strategy has been limited to those leukemia subsets
      characterized by genetic markers amenable to sensitive detection by PCR. Although
      PCR for immunoglobulin and T cell receptor gene rearrangement represents the gold
      standard for MRD detection in most cases of ALL without any fusion gene
      transcripts as molecular markers available, the situation in AML is more
      complicated because, at present, more than 50% of them lack any sort of clonality
      markers suitable for MRD monitoring. Thus, a number of studies have been
      performed in an attempt to identify cytogenetic and molecular abnormalities
      associated with leukemic transformation. In this paper we describe the
      effectiveness of the quantitative assessment of the Wilms tumor gene (WT1)
      transcript as a molecular marker for the detection of the leukemic clone useful
      for monitoring the presence of MRD in all the patients affected by acute and
      chronic leukemias as well as myelodysplastic syndromes.

PMID- 15179008
TI  - Molecular surveillance of chronic myeloid leukemia patients in the imatinib era -
      evaluation of response and resistance.
AB  - Residual disease in chronic myeloid leukemia patients may be assessed by various
      molecular methods. After imatinib treatment a significant proportion of patients
      achieve complete cytogenetic remission (CCR) and a sensitive method is necessary
      to monitor treatment response and to detect early signs of relapse. Reverse
      transcriptase polymerase chain reaction (RT-PCR) is by far the most sensitive
      approach to assess residual disease in this group of patients. Qualitative PCR
      methods give only limited information about the residual leukemic mass.
      Quantitative RT-PCR (Q-PCR) assays enable to monitor the kinetics of residual BCR
      ABL transcripts over time in patients with a good response to imatinib. Early Q
      PCR results on imatinib treatment can help to identify individuals who are likely
      to have a good response. In chronic phase patients after CCR, Q-PCR may identify
      patients who are likely to continue with their CCR or to relapse and may help to
      optimize treatment for this group of patients. The definition of molecular
      surrogate endpoints beyond CCR for studies which are currently planned demands
      standardization of the nomenclature and of technologies to measure these targets.

PMID- 15179009
TI  - Clinical implications of minimal residual disease monitoring for stem cell
      transplantation after reduced intensity and nonmyeloablative conditioning.
AB  - Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for
      a variety of hematological malignancies; however, relapse and treatment-related
      toxicities are major obstacles to cure. Nonmyeloablative and reduced-intensity
      conditioning regimens were designed not to eradicate the malignancy completely,
      but rather to be immunosuppressive enough to allow engraftment, and to serve as a
      platform for additional cellular immunotherapy. Minimal residual disease (MRD)
      typically persists after SCT, and is gradually eliminated with different kinetics
      typical of each disease. Significant progress has been achieved with technologies
      for MRD assessment. Quantitative PCR tests are very sensitive in detecting tumor
      associated transcripts, allowing serial monitoring. Threshold levels have been
      established for some malignancies, above which relapse is imminent. Persistent
      negative tests, a low level or a decreasing MRD level are consistent with
      continuous remission, whereas high-level MRD or increasing levels predict an
      incipient relapse. Patients at high risk of relapse are candidates for additional
      cellular or targeted therapy. Immunotherapy is more effective for MRD than at
      frank relapse. Timing and dosing of therapy are not yet well established and
      depend on aggressiveness of the disease, type of conditioning, level and kinetics
      of MRD.

PMID- 15179010
TI  - Molecular and clinical follow-up after treatment of multiple myeloma.
AB  - Multiple myeloma (MM) is a B cell malignancy characterized by accumulation of
      plasma cells (PCs) in the bone marrow. Traditional methods for the detection of
      minimal residual disease (MRD) measure the presence of monoclonal immunoglobulin
      protein secreted by the malignant PCs. However, changes in the level of MRD in MM
      may span 6 logs, and methods with a high sensitivity and dynamic range are
      necessary for quantitating MRD in MM. The two main technologies used in MRD
      detection are flow cytometry and patient-specific reverse transcription (RT) PCR.
      Patient-specific RT-PCR has high sensitivity and may be beneficial in monitoring
      patients receiving allogeneic transplantation. However, for the MRD evaluation of
      autotransplants, where few patients achieve molecular remission, flow cytometry
      monitoring seems to be sufficient.

PMID- 15179011
TI  - Significance of minimal residual disease in lymphoid malignancies.
AB  - Modern treatment protocols lead to complete remission (CR) in a considerable
      proportion of patients with lymphoproliferative disorders. However, many of these
      patients ultimately relapse, implying that achievement of a clinical CR is
      compatible with significant amounts of residual malignant cells. Cytogenetic,
      molecular and immunological techniques that are more sensitive than morphology
      are increasingly used to assess and quantify minimal residual disease (MRD).
      Immunological marker analysis allows the detection of aberrant or unusual
      immunophenotypes, PCR techniques target fusion regions of chromosome aberrations
      and clone-specific immunoglobulin and T-cell receptor gene rearrangements. The
      rationale underlying MRD studies is to improve measurement of treatment response,
      to provide independent prognostic information and to optimise therapeutic
      strategies. In acute lymphoblastic leukemia (ALL), the MRD based evaluation of
      initial response to front-line therapy emerged as a highly relevant diagnostic
      tool, particularly in childhood ALL, where MRD has been shown to be an
      independent prognostic factor allowing a precise risk group classification. In
      patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL)
      the prognostic significance of MRD is still a matter of debate, as the majority
      of patients remain MRD positive after conventional treatment. This phenomenon has
      changed with the implementation of new treatment modalities, such as application
      of monoclonal antibodies, where a significant proportion of patients with NHL
      converts to MRD negativity and experiences prolonged remission. Whether this
      molecular remission will translate into a superior overall survival is currently
      the goal of ongoing prospective studies.

PMID- 15179012
TI  - Auditory event-related potentials and psychological changes during sleep
      deprivation.
AB  - This study investigated the psychophysiological effects of sleep deprivation on
      auditory event-related potentials (AERPs) and their relationship with
      psychological parameters. Twenty-four subjects remained awake for 37 h under
      continuous surveillance. In the mornings and the evenings of 2 consecutive study
      days, AERPs were recorded and 4 self-rated scales (sleepiness, fatigue, anxiety,
      and mood) were quantified. The latencies of P300 and N200 were significantly
      prolonged (p < 0.001) and their amplitudes decreased (p < 0.05) as a consequence
      of sleep deprivation. However, the only significant change in N100 and P200 was
      an increase in the P200 amplitude (p < 0.05). The increase in the latencies of
      P300 and N200 were correlated with increased sleepiness (p < 0.05), and the
      increase in P200 amplitude was correlated with negative mood, anxiety, and
      fatigue (p < 0.05). Although the changes in P300 and N200 induced by sleep
      deprivation are due to sleepiness, which may slow cognitive processing and
      decrease the efficiency of mental processing, the increase in P200 may be related
      with increased anxiety, negative mood, and fatigue.

PMID- 15179013
TI  - Plasma concentrations of anxiolytic neurosteroids in men with normal anxiety
      scores: a correlation analysis.
AB  - Neurosteroids are physiological regulators of anxiety in experimental animals,
      but there are no data for humans about the modulatory effects of the hormones on
      normal aspects of this emotional parameter. Plasma concentrations of four
      neurosteroids, pregnenolone, progesterone (PROG), allopregnanolone and
      tetrahydrodeoxycorticosterone, suggested to be major anxiety regulators in
      experimental animals, were measured in a group of 58 physically and
      psychologically normal adult male subjects. In parallel, trait (genotypical) and
      state (phenotypical) anxiety scores were measured by the State-Trait Anxiety
      Inventory. The possible correlations between the hormonal secretions and the
      psychological parameters were statistically analyzed. The neurosteroid
      concentrations and the anxiety scores of the probands were within the ranges of
      normality according to data of the literature and our own. PROG concentrations
      correlated significantly with state anxiety scores. These data suggest that
      neurosteroids may physiologically modulate anxiety not only in experimental
      animals but also in humans.

PMID- 15179014
TI  - Lack of plasma norepinephrine cyclicity, increased estradiol during the
      follicular phase, and of progesterone and gonadotrophins at ovulation in women
      with premenstrual syndrome.
AB  - In healthy women, plasma norepinephrine (NE) has a cycle with the highest levels
      occurring at ovulation and early luteal phase. We examined plasma NE cyclicity in
      premenstrual syndrome (PMS) patients as compared to controls, its relation to
      estradiol (E(2)), progesterone (P), luteinizing hormone and follicle-stimulating
      hormone, and the correlation of these parameters with the PMS symptoms. Lack of
      NE cyclicity was observed in PMS patients. In controls, peak NE levels occurred
      at ovulation and early luteal phase. In PMS, serum E(2) was higher during the
      follicular phase, while P and gonadotrophins were higher especially at ovulation
      and the luteal phase. In the late luteal phase, E(2) levels were lower in PMS
      patients than in controls. A negative correlation was observed between the area
      under the curve for E(2) in the luteal phase and PMS somatic and mental scores.
      Plasma NE showed a negative correlation with abrupt mood swings, impatience,
      nervousness, tiredness, weakness, apathy, and headache. These data suggest that
      lack of NE cyclicity characterizes PMS, some symptoms being related to low E(2)
      levels during the late luteal phase and decreased noradrenergic activity at
      ovulation and the luteal phase.

PMID- 15179015
TI  - Association study of -1727 A/T, -50 C/T and (CAA)n repeat GSK-3beta gene
      polymorphisms with schizophrenia.
AB  - Glycogen synthase kinase-3 (GSK-3) is a downstream component of the Wnt pathway
      and recent studies have reported abnormal levels of GSK-3beta in schizophrenia.
      In a sample of 147 schizophrenic patients and 212 healthy individuals, we
      analyzed two common SNPs at position -1727 A/T and -50 C/T and a (CAA)(n) repeat
      polymorphism localized in intron 1 of the gene. The results showed that the
      allele, genotype and haplotype distributions for the three polymorphisms
      investigated do not differ between schizophrenic patients in general and control
      subjects. However, in the subtype of paranoid schizophrenic patients, we found
      that the (CAA)(3)/(CAA)(5) heterozygotes were more often represented. Although
      taken from a small sample, our results support the reports that GSK-3beta appears
      to be involved in a subtype of schizophrenic patients, but not in schizophrenia
      in general. In conclusion, we would speculate that this gene may be linked to
      some features of psychotic disorders rather than to schizophrenia itself.

PMID- 15179016
TI  - Perception of dreams and subjective sleep quality in patients with myasthenia
      gravis.
AB  - OBJECTIVES: Recent reports have led to the hypothesis of a central nervous system
      involvement in myasthenia gravis (MG). As the central cholinergic system also
      plays an important role in sleep/wake rhythms and in the regulation of REM sleep,
      sleep perception and dreaming may be altered in MG patients. PATIENTS AND
      METHODS: Seventeen consecutive patients with MG (mean age 49.5 +/- 13.6 years)
      and 14 healthy controls (mean age 50.5 +/- 16.0 years) were investigated by means
      of the Self-Rating Depression Scale, Self-Rating Anxiety Scale, Quality of Life
      Index, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale as well as a
      self-rating questionnaire for sleep and awakening quality and dreaming for 2
      weeks. RESULTS: Subjective sleep and awakening quality and sleep efficiency were
      reduced (p < 0.05), and the number of nocturnal awakenings (p = 0.02) as well as
      dream recall frequency (p = 0.02) were increased in patients with MG. Patients
      reported more often body-related and tactile sensations during dreaming (p =
      0.001) and dreamed less often visually (p = 0.04). Dream content, emotions, and
      dream sources did not differ between both groups. Whereas the number of
      awakenings was related to dream recall frequency in healthy controls, no such a
      relationship was found in the patient group. CONCLUSION: There is no clear
      evidence for the arousal-retrieval model of dream recall in patients with MG, but
      more for the continuity hypothesis of dreaming. Other factors such as the
      functional state of the brain, possibly related to a central cholinergic
      involvement in MG or its anticholinesterase treatment, may be important in
      explaining dream recall in this patient group.

PMID- 15179017
TI  - Serotonin-mediated cyclic AMP inhibitory pathway in platelets of patients
      affected by panic disorder.
AB  - Cyclic adenosine monophosphate (cAMP) pathway abnormalities have been suggested
      to be involved in anxiety disorders including panic (PD). The present study
      sought at investigating the downstream inhibitory adenylyl cyclase (AC) pathway
      activated by 5-HT in platelets obtained from 22 patients with a diagnosis of PD
      versus 22 healthy volunteers. In PD patients, a significant impairment of 5-HT
      potency to inhibit AC was observed. One month of treatment with paroxetine
      induced a significant increase of 5-HT potency in T1 patients close to the
      control values. [(35)S]GTPgammaS binding studies showed that in PD patients, a
      reduction of 5-HT receptor-G protein coupling occurred without any significant
      changes in G protein levels. These findings demonstrated that (1) a reduction of
      the inhibitory AC pathway activated by 5-HT occurred in platelets from PD
      patients; (2) the reduced 5-HT responsiveness in PD was related to an impairment
      of 5-HT receptor-G protein coupling, and (3) after 1 month of treatment with
      paroxetine, such a dysfunction significantly reversed together with a significant
      improvement of clinical symptoms.

PMID- 15179019
TI  - ADHD and sleep in homicidal men with antisocial personality disorder.
AB  - A history of attention deficit hyperactivity disorder (ADHD) is commonly found in
      subjects with antisocial personality disorder (ASP). Besides ASP, childhood ADHD
      also predicts drug abuse disorders and criminal activity in adulthood. Childhood
      ADHD and ASP appear to be the only psychiatric disorders reported to be
      associated with an increase in deep sleep. The aims of the present study were to
      retrospectively measure the childhood ADHD of habitually violent men with ASP and
      Cloninger type 2 alcoholism, and to characterize the possible relationship
      between childhood ADHD and sleep architecture in these men. The subjects of the
      study consisted of 14 homicidal offenders recruited from a forensic psychiatric
      examination. Ten age- and gender-matched healthy volunteers served as controls.
      Childhood ADHD symptoms were measured using the Wender-Utah Rating Scale (WURS).
      The main findings were that violent offenders with ASP had significantly higher
      mean WURS scores compared with controls, and both the absolute and percentage
      amount of stage 4 sleep as well as delta and theta powers in this sleep stage
      were positively correlated with the WURS scores. The present study supports the
      idea that childhood ADHD is associated with the abnormal sleep architecture in
      habitually violent men with ASP. These two disorders seem to share, at least
      partly, the same central nervous system deficit.

PMID- 15179018
TI  - Association study of adrenergic beta3 receptor (Trp64Arg) and G-protein beta3
      subunit gene (C825T) polymorphisms and weight change during clozapine treatment.
AB  - Weight gain, a common adverse effect of clozapine, may impair health and affect
      patient compliance during treatment with this agent. The aim of this study was to
      investigate the relationship between genetic variants of the adrenergic beta3
      receptor (ADRB3) and the G-protein beta3 subunit (GNB3) and clozapine-induced
      body weight change (BWC). Eighty-seven treatment-resistant schizophrenic patients
      were weighed before and after 4 months of clozapine treatment, with the subjects
      gaining an average of 2.6 kg in body weight. No statistically significant
      relationship was demonstrated for the investigated ADRB3 Trp64Arg and the GNB3
      C825T polymorphisms in terms of BWC post-treatment, suggesting these two
      polymorphisms do not play a significant role in clozapine-induced BWC. Further
      exploration of other genetic variants implicated in clozapine-induced BWC is
      important, however, in order to predict and reduce clozapine-associated weight
      gain.

PMID- 15179020
TI  - Effects of electroconvulsive therapy on frontal white matter in late-life
      depression: a diffusion tensor imaging study.
AB  - This study was conducted to elucidate the effects of electroconvulsive therapy
      (ECT) on frontal white matter in late-life depressed patients. Diffusion tensor
      imaging was performed on 8 late-life depressed patients and 12 healthy age
      matched controls. The patients were scanned before and after a course of ECT.
      Fractional anisotropy (FA) was determined in the frontal and temporal regions and
      the corpus callosum. A significant white matter FA reduction was found in
      widespread frontal and temporal brain regions in patients with depression before
      ECT treatment compared with controls. A significant increase in frontal white
      matter FA was seen following ECT treatment. A course of bilateral ECT ameliorated
      white matter integrity in frontal brain regions. This suggests a strong
      relationship with the antidepressant action of ECT.

PMID- 15179021
TI  - Decreased plasma antioxidants in schizophrenia.
AB  - An aberration in the level of antioxidants has been suggested in schizophrenia.
      Therefore, this study examined the difference in the antioxidant level between
      patients with schizophrenia and healthy controls, as well as the difference
      between the drug-naive schizophrenic patients with a first episode (FSPR) and the
      risperidone-treated chronic schizophrenia (RCSPR) patients. The plasma albumin,
      bilirubin and uric acid levels were determined in 47 FSPR and 55 chronic
      schizophrenia patients who met the DSM-IV criteria for schizophrenia, and in 68
      controls. The albumin and bilirubin levels were significantly lower in the
      schizophrenic patients compared to the controls, although there was no
      significant difference between the FSPR and RCSPR patients. The bilirubin level
      was significantly lower in the negative subgroup of the patient group. This study
      supports the hypothesis that an aberration in the antioxidant levels may be
      involved in schizophrenia. In addition, this study suggests that the antioxidant
      level may be associated with the clinical symptomatology as well as the treatment
      implications in schizophrenia, particularly the negative symptoms.

PMID- 15179022
TI  - A randomised study comparing escitalopram with venlafaxine XR in primary care
      patients with major depressive disorder.
AB  - This 8-week, randomised, double-blind study compared the efficacy and
      tolerability of escitalopram to that of venlafaxine XR in primary care patients
      with major depressive disorder. The efficacy of escitalopram (10- 20 mg; n = 148)
      was similar to venlafaxine XR (75- 150 mg; n = 145), based on mean change from
      baseline to week 8 in Montgomery and Asberg Depression Rating Scale total score.
      In ad hoc analyses, escitalopram-treated patients achieved sustained remission
      significantly faster than did venlafaxine-treated patients. More venlafaxine
      treated patients had nausea, constipation, and increased sweating (p < 0.05).
      When treatment was completed after 8 weeks, significantly more venlafaxine
      treated patients had discontinuation symptoms (p < 0.01). Thus escitalopram
      treatment was similar to venlafaxine treatment with respect to efficacy and was
      better tolerated by patients in primary care.

PMID- 15179023
TI  - Low-dose pramipexole in the management of restless legs syndrome. An open label
      trial.
AB  - Dopaminergic agents are considered the treatment of choice for restless legs
      syndrome (RLS); levodopa is the only substance licensed for this disorder in some
      European countries. However, in a substantial proportion of patients symptoms are
      not adequately controlled for a whole night due to the short half-life of
      levodopa or because symptom augmentation may develop. To further investigate the
      impact of pramipexole on the management of RLS we performed a short-term open
      label trial with pramipexole in 17 patients who were being insufficiently treated
      with levodopa or for whom pramipexole was primarily being considered because of
      the severity of the RLS symptoms. A single dose of 0.125-0.75 mg pramipexole
      (mean 0.3 +/- 0.2 mg) in the evening resulted in a significant improvement of
      subjective RLS symptoms as rated by the International RLS Study Group Severity
      Scale (IRLS scores: 29.8 +/- 4.7 baseline vs. 7.3 +/- 5.9 endpoint; p = 0.0001).
      Polysomnographic recordings showed a significant improvement of the periodic leg
      movements (PLM) index, PLM sleep arousal index, sleep-onset latency, total sleep
      time and sleep efficiency. All patients who had developed a worsening of RLS
      symptoms under levodopa recovered from daytime symptoms after their medication
      was switched to pramipexole. Since pramipexole was well tolerated, an ideal
      dosage to control RLS symptoms could be reached rapidly. Pramipexole has proven a
      suitable alternative in patients with moderate to severe RLS, particularly when
      their therapy has to be switched to a dopamine agonist.

PMID- 15179024
TI  - Pharmacodynamic effects of acamprosate on markers of cerebral function in alcohol
      dependent subjects administered as pretreatment and during alcohol abstinence.
AB  - Animal studies suggested that acamprosate modulates neuronal hyperexcitability of
      acute alcohol withdrawal, acting through the glutamatergic neurotransmission. In
      the present study, we further investigated whether treatment with acamprosate
      could attenuate the post-alcohol withdrawal hyperexcitability or hyperarousal in
      humans using brain magnetoencephalography mapping of spontaneous fields. A double
      blind, randomised, placebo-controlled study with a parallel group design
      comparing 2,000 mg/day of acamprosate versus placebo was conducted in alcohol
      dependent subjects meeting DSM-IV criteria for alcohol dependence. Treatments
      were initiated 8 days before alcohol withdrawal and prolonged during the 15
      following (abstinence) days. The study demonstrated that during alcohol
      withdrawal, acamprosate decreased the arousal level as reflected by alpha slow
      wave index (ASI) measurement. This effect was mostly evidenced in left
      parietotemporal regions and, to a lesser extent, in the contiguous anterior,
      posterior and right-sided regions. In the placebo group, on the contrary, ASI
      measures increased between day 2 (acute withdrawal) and day 14 (prolonged
      withdrawal). The present results suggest a sustained effect of acamprosate on the
      hyperexcitability state due to alcohol withdrawal in alcohol-dependent patients
      and that acamprosate may have a protective effect when administered 8 days before
      alcohol withdrawal.

PMID- 15179025
TI  - The Austrian multicentre study on smoking: subgroups of nicotine dependence and
      their craving.
AB  - BACKGROUND: The misconception of tobacco smoking as a 'bad habit' has been
      replaced by a diagnosis of addiction. Although help to quit is offered by
      nicotine replacement, antidepressants and psychotherapeutic support, there is no
      cure yet. One cause of impediment might be psychiatric comorbidity. Therefore, we
      searched for smoker subgroups, needing different treatments. AIM OF THE STUDY:
      The study aimed at subtyping smokers in an attempt to better understand the
      phenomenon of resistant smokers and provide more information that could
      potentially become useful to treatment centres assuming the subtypes correlate
      directly with outcomes of different smoking cessation treatments, tailor-made
      according to subtypes. METHODS: 330 out of 430 recruited smokers were classified
      as nicotine dependent (ICD-10) and tobacco dependent (DSM-IV) and remained in the
      study. They were investigated with different diagnostic assessments: Fagerstrom
      Test (FT), Lubeck Craving Risk Relapse Questionnaire and Lesch Typology
      Questionnaire (the last two being modified for smoking). RESULTS: Dependence
      severity degree is reflected by the FT. FT scores >/=5 indicated higher
      conspicuousness. Four clusters for nicotine craving were found: (1) 'depressed',
      (2) 'stimulated', (3) 'relaxed mood state' and (4) 'socially triggered tensed
      mood'. In contrast to alcoholism, 'stimulation' was one of the major craving
      conditions in smokers. The decision tree, consisting of the FT and the Lesch
      Typology Questionnaire, distinguishes four subgroups of nicotine-dependent
      persons. CONCLUSION: The subgroups reflect different reinforcement and
      psychosocial disturbances. They match treatment and can be applied as outcome
      predictors in controlled treatment and relapse prevention studies.

PMID- 15179026
TI  - Effects of the South American psychoactive beverage ayahuasca on regional brain
      electrical activity in humans: a functional neuroimaging study using low
      resolution electromagnetic tomography.
AB  - Ayahuasca, a South American psychotropic plant tea obtained from Banisteriopsis
      caapi and Psychotria viridis, combines monoamine oxidase-inhibiting beta
      carboline alkaloids with N,N-dimethyltryptamine (DMT), a psychedelic agent
      showing 5-HT(2A) agonist activity. In a clinical research setting, ayahuasca has
      demonstrated a combined stimulatory and psychedelic effect profile, as measured
      by subjective effect self-assessment instruments and dose-dependent changes in
      spontaneous brain electrical activity, which parallel the time course of
      subjective effects. In the present study, the spatial distribution of ayahuasca
      induced changes in brain electrical activity was investigated by means of low
      resolution electromagnetic tomography (LORETA). Electroencephalography recordings
      were obtained from 18 volunteers after the administration of a dose of
      encapsulated freeze-dried ayahuasca containing 0.85 mg DMT/kg body weight and
      placebo. The intracerebral power density distribution was computed with LORETA
      from spectrally analyzed data, and subjective effects were measured by means of
      the Hallucinogen Rating Scale (HRS). Statistically significant differences
      compared to placebo were observed for LORETA power 60 and 90 min after dosing,
      together with increases in all six scales of the HRS. Ayahuasca decreased power
      density in the alpha-2, delta, theta and beta-1 frequency bands. Power decreases
      in the delta, alpha-2 and beta-1 bands were found predominantly over the temporo
      parieto-occipital junction, whereas theta power was reduced in the temporomedial
      cortex and in frontomedial regions. The present results suggest the involvement
      of unimodal and heteromodal association cortex and limbic structures in the
      psychological effects elicited by ayahuasca.

PMID- 15179027
TI  - Hostility-aggressiveness, sensation seeking, and sex hormones in men: re
      exploring their relationship.
AB  - To evaluate the relationship between sex hormones and aggressiveness, hostility
      and sensation seeking we studied 30 healthy males. Using a standardised technique
      of radioimmunoassay, we obtained blood values of luteinizing hormone (LH),
      follicle-stimulating hormone (FSH), 17beta-estradiol (E(2)), total testosterone
      (TT), sex hormone-binding globulin (SHBG) and the free androgen index (FAI).
      Personality was evaluated by the Buss-Durkee Hostility Inventory and the
      Sensation-Seeking Scale, form V. The results showed a lack of significant
      correlations between the measures of aggressiveness-hostility and hormones.
      Nevertheless, Spearman and Pearson correlations between Sensation Seeking and
      testosterone were positive and significant after controlling for age.
      Considerably higher correlations were obtained after controlling for LH and SHBG.
      A group of subjects with high scores in a factor made up of Experience Seeking,
      Disinhibition and Boredom Susceptibility obtained significantly higher scores on
      TT and FAI. Subjects with high scores in a factor made up of Assault, Indirect
      Aggression and Verbal Aggression obtained significantly higher scores in SHBG and
      TT. These findings support Zuckerman's personality model for the sensation
      seeking trait.

PMID- 15179028
TI  - Hemodynamic effects of negative emotional pictures - a test-retest analysis.
AB  - We investigated subjective and hemodynamic responses towards disgust-inducing,
      fear-inducing, and neutral pictures in a functional magnetic resonance imaging
      study. Within an interval of 1 week, 24 male subjects underwent the same block
      design twice in order to analyze possible response changes to the repeated
      picture presentation. The results showed that disgust-inducing and fear-inducing
      scenes provoked a similar activation pattern in comparison to neutral scenes.
      This included the thalamus, primary and secondary visual fields, the amygdala,
      the hippocampus, and various regions of the prefrontal cortex. During the retest,
      the affective ratings hardly changed. In contrast, most of the previously
      observed brain activations disappeared, with the exception of the temporo
      occipital activation. An additional analysis, which compared the emotion-related
      activation patterns during the two presentations, showed that the responses to
      the fear-inducing pictures were more stable than the responses to the disgust
      inducing ones.

PMID- 15179029
TI  - Syndecans-2 and -4; close cousins, but not identical twins.
AB  - The vertebrate syndecans, which make up a four-member family of small type I
      transmembrane heparan sulfate proteoglycans, constitute evolutionarily conserved
      family proteins. In particular, sequences in the transmembrane and cytoplasmic
      domains are a unifying feature within the family. However, the extracellular
      domain sequences are molecule-specific, implying that different syndecans have
      evolved to carry out similar, but non-identical, functions. While all four
      syndecans have been implicated in regulation of the cytoskeleton, their roles are
      clearly complex. Recent developments indicate that the closely related syndecan-2
      and -4 have separable functions, though both bind a number of ligands through
      their heparan sulfate chains. The specification of these activities is probably
      core protein related, but is it due to a distinct expression pattern or molecule
      specific regulatory mechanisms? Although there is not yet enough data to provide
      unambiguous answers, here we shall review the known functions and regulatory
      mechanisms of syndecan-2 and -4.

PMID- 15179030
TI  - Mitogenic signal transduction by integrin- and growth factor receptor-mediated
      pathways.
AB  - Engagement of cells with the extracellular matrix (ECM) proteins is crucial for
      various biological processes, including cell adhesion, spreading, proliferation,
      differentiation, migration, apoptosis, and gene induction, contributing to
      maintenance of tissue integrity, embryogenesis, wound healing, and the metastasis
      of tumor cells (Hynes, 2002b; Juliano, 2002). The engagement involves cell
      adhesion mediated by integrins, a large family of cell adhesion receptors that
      are transmembrane glycoproteins which bind to ECM or to counter-receptors on
      neighbor cells. In this review, the molecular basis of signaling mediated by
      integrins and their collaboration with growth factor receptors will be discussed,
      based on recent observations. Although other cell adhesion receptors including
      cadherins, selectins, syndecans, and the immunoglobulin superfamily of cell
      adhesion molecules (IgCAMs) can play important roles or be involved in these
      processes, we suggest readers refer to recent outstanding reviews on them
      (Barclay, 2003; Brummendorf and Lemmon 2001; Panicker et al. 2003).

PMID- 15179031
TI  - Contributions of the alpha6 integrins to breast carcinoma survival and
      progression.
AB  - This review summarizes recent findings that support a key role for the alpha6
      integrins (alpha6beta1 and alpha6beta4) in the progression of breast carcinoma.
      The hypothesis that emerges from the existing data is that both of these
      integrins have the ability to sustain the survival of breast carcinoma cells,
      especially in stress conditions such as those that exist in the tumor
      microenvironment. The mechanisms by which these integrins promote survival appear
      to involve their ability to regulate the expression of vascular endothelial
      growth factor (VEGF), either at the level of transcription or translation. VEGF
      produced by breast carcinoma cells in response to alpha6 integrin regulation can
      function in an autocrine manner to promote survival signaling.

PMID- 15179032
TI  - The effects of thalidomide on the stimulation of NF-kappaB activity and TNF-alpha
      production by lipopolysaccharide in a human colonic epithelial cell line.
AB  - The immunomodulatory and anti-inflammatory effects of thalidomide are associated
      with inhibition of TNF-alpha levels. However, the mechanism by which thalidomide
      reduces TNF-alpha production remains elusive. NF-kappaB is known to play a
      central role in regulating inflammatory responses in patients with inflammatory
      bowel disease (IBD). We tested whether thalidomide acts through inhibiting NF
      kappaB activity. HT-29 cells were stimulated with LPS (1 microg/ml) alone, or
      after pretreatment with thalidomide (100 microg/ml), and NF-kappaB activity was
      determined by gel mobility shift assays. RT-PCR was used to measure expression of
      the proinflammatory cytokine genes TNF-alpha, IL-1beta and IL-8. The level of TNF
      alpha mRNA was also analyzed by real-time quantitative RT-PCR, and TNF-alpha
      protein was measured by ELISA. Thalidomide pretreatment did not affect NF-kappaB
      activity in HT-29 cells stimulated with LPS but production of TNF-alpha was
      depressed. Thalidomide was found to accelerate the degradation of TNF-alpha mRNA,
      but had little effect on IL-1beta or IL-8. These observations suggest that the
      immunomodulatory effect of thalidomide in colonic epithelial cells is associated
      with inhibition of TNF-alpha. However, it does not act by inhibiting NF-kappaB
      but rather by inducing degradation of TNF-alpha mRNA.

PMID- 15179033
TI  - Mechanism of transcriptional repression by TEL/RUNX1 fusion protein.
AB  - Human chromosomal translocation t(12;21)(p12;q22) is one of the most frequent
      rearrangement in human leukemia, and produces the TEL/RUNX1 fusion protein. The
      TEL/RUNX1 fusion protein creates a transcriptional repressor that interferes in
      dominant fashion with RUNX1-dependent transactivation. Here, we demonstrate that
      the repressor activity of TEL/ RUNX1 differs from that of TEL, even though both
      TEL and TEL/RUNX1 interact with the nuclear hormone co-repressor (N-CoR) and
      histone deacetylase (mSin3A) in vivo. Co-immunoprecipitation experiments
      demonstrated that TEL/RUNX1 forms homodimers in vivo, and heterodimerizes with
      the TEL when the two proteins are expressed together. These interactions require
      the HLH (helix-loop-helix) region of TEL. Immunoprecipitation and
      immunofluorescence analysis showed that p300 interacts with TEL/RUNX1 and is
      sequestered in the cytoplasm by it. These results suggest that the p300-TEL/RUNX1
      complex and heterodimerization of TEL/RUNX1 with TEL may be responsible for the
      ability of TEL/RUNX1 to inhibit RUNX1-mediated transactivation. It appears that
      loss of TEL function activates a pathway that cooperates with TEL/RUNX1 and
      sequesters coactivator(s) into nonfunctional complex in the cytoplasm thus
      inhibiting transcription of target genes.

PMID- 15179034
TI  - Interaction of tomato mosaic virus movement protein with tobacco RIO kinase.
AB  - Tomato mosaic virus (ToMV) has a regulatory gene encoding a movement protein (MP)
      that is involved in the cell-to-cell movement of viral RNA through plasmodesmata.
      To identify the host cell factors interacting with ToMV MP, we used a recombinant
      MP probe to isolate cDNA clones from a phage expression library of Nicotiana
      tabacum by a far-Western screening method. One of the cDNA clones encoded an MP
      interacting protein, MIP-T7, homologous to the yeast novel protein kinase, Rio1p.
      We isolated a full-length cDNA by RT-PCR. The putative gene product was
      designated NtRIO, and shared 33 and 73% amino acid identity with yeast and
      Arabidopsis RIO kinases, respectively. In vitro analyses using recombinant
      proteins showed that NtRIO also interacted with a different MP derived from
      Cucumber mosaic virus. NtRIO had autophosphorylation activity and phosphorylated
      ToMV MP. Addition of recombinant tobacco casein kinase 2 resulted in a marked
      increase in the phosphorylation of NtRIO. The interaction between NtRIO and ToMV
      MP was inhibited by phosphorylation of NtRIO.

PMID- 15179035
TI  - Identification of genes induced in wound-treated wild rice (Oryza minuta).
AB  - A subtracted library was constructed from wound-treated wild rice (Oryza minuta)
      by suppression subtractive hybridization (SSH) in combination with mirror
      orientation selection (MOS). To distinguish between differentially expressed
      transcripts and false positive clones, DNA chips containing 960 random clones
      were applied as a form of reverse Northern screening. Based on the signal
      intensities and expression ratios obtained from experiments performed in
      triplicate, 371 clones were selected. ESTs produced from the subtracted library
      showed 63.2% redundancy, and 72% of all clones could be matched to the GenBank
      nonredundant database. Functional categorization placed the identified enriched
      genes in categories of subcellular localization, metabolism, cell rescue and
      defense, and transcription. These EST-related resistance mechanisms could be used
      in investigations into the defense mechanisms of wild species, and to provide new
      routes to improving the germplasm of cultivated rice.

PMID- 15179036
TI  - Cloning of genes differentially expressed during the initial stage of fruit
      development in melon (Cucumis melo cv. Reticulatus).
AB  - We have cloned genes involved in the initial stage of fruit development in the
      melon by suppression subtractive hybridization. A cDNA library of unfertilized
      ovules was subtracted from that of fruit 9 days after pollination (DAP); 10 of
      the 40 selected cDNA clones were identified by reverse Northern analysis as genes
      differentially expressed in fruit at 9 DAP. Seven of the ten genes were
      homologous to genes of known function; two were related to genes with unknown
      functions, and one was novel. With the exception of cucumisin, none of the cDNAs
      had been previously identified in melon. According to Northern analyses, six of
      the genes were expressed at high levels early in fruit development. Expression of
      cucumisin, Cmf-25, Cmf-30, and Cmf-124 was highest at 9 DAP, implying that these
      genes are involved in the initial stage of fruit development. Cmf-30, a seed
      nucellus-specific gene, was also expressed early in seed development. The other
      genes were expressed at a moderate level throughout fruit development, with the
      highest expression occurring in fruit at 9 and 18 DAP. In conclusion, nine new
      genes involved in early fruit development in melon were cloned, and their
      temporal and spatial expression patterns indicate that they are preferentially
      expressed during the active growing stage of fruit.

PMID- 15179037
TI  - Carbofuran induces apoptosis of rat cortical neurons and down-regulates surface
      alpha7 subunit of acetylcholine receptors.
AB  - Carbofuran (CF), an anticholinesterase carbamate, is one of the most widely used
      N-methylcarbamate esters in insect and nematode control. Despite its serious
      adverse health effects on wildlife and humans, cellular and molecular studies of
      the damage of CF to CNS neurons are very limited. We have examined the cytotoxic
      effects of CF on cultured rat cortical cells, and the expression of the alpha7
      subunit of the nicotinic acetylcholine receptor (alpha7 nAChR) in hippocampal
      neurons. CF was cytotoxic with an IC50 approximately 730 and approximately 640
      microm when assessed by the lactate dehydrogenase (LDH) assay and propidium
      iodide (PI) staining, respectively, 3 days after treatment. CF induced DNA
      fragmentation and exposure of phosphatidyl serine (PS) on the cell surface.
      Surface labeling of the alpha7 nAChR with Alexa Fluor 488-conjugated alpha
      bungarotoxin (alphaBgt) revealed a significant decrease in the density of the
      subunits in treated (500 microm CF) hippocampal neurons. Our data indicate that
      CF induces neuronal death by apoptosis and down-regulates nAChRs.

PMID- 15179038
TI  - Role of occludin, a tight junction protein, in blastocoel formation, and in the
      paracellular permeability and differentiation of trophectoderm in preimplantation
      mouse embryos.
AB  - Tight junctions (TJ) are critical for blastocoel formation in mammalian embryos.
      The present study aimed to examine the role of tight junctions in the
      differentiation of the trophectoderm (TE), and in the pluripotency of
      blastomeres, as well as in the formation and integrity of the blastocoel. We
      examined the effect of occludin antibody on blastocoel formation, blastocyst
      permeability, and expression of H19 and Oct-4, markers of TE differentiation and
      blastomere pluripotency, respectively. Eight-cell mouse embryos and morulae were
      cultured in the presence or absence of occludin antibody for 31 h. Occludin
      antibody inhibited blastocoel formation and increased permeability of the TE of
      nascent and expanding blastocysts to FITC-dextran (4 kDa), a permeability tracer.
      At the same time Oct-4 expression increased while expression of H19 became barely
      detectable. These observations indicate that occludin is involved in establishing
      the blastocoel, as well as in maintaining its impermeability, and that the
      development of tight junction is critical for TE formation in mouse embryos.

PMID- 15179039
TI  - Molecular characterization of NbCHMP1 encoding a homolog of human CHMP1 in
      Nicotiana benthamiana.
AB  - In humans, CHMP1 encodes a protein of dual function that plays a role in both
      modification of chromatin structure and endosomal vesicle trafficking. Recently,
      it was found that sal1, a CHMP1 homolog in maize, is important for the
      development of the aleurone cell layers in maize endosperm. In this study, we
      investigated the structure and function of a Nicotiana benthamiana CHMP1 homolog
      designated NbCHMP1. NbCHMP1 encodes a small protein with a bipartite nuclear
      localization signal at its N-terminus, and good homology with the corresponding
      genes from diverse plants and animals. NbCHMP1 mRNA was present at comparable
      levels in stems, roots, flowers, and leaves. A GFP fusion of the full length
      NbCHMP1 protein was localized to the cytosol in distinct structures, while a GFP
      fusion of its N-terminal 80 aa was targeted to the nucleus, suggesting dual
      targeting of NbCHMP1 in plants. Overexpression of NbCHMP1 in yeast did not affect
      its growth and the expressed protein was present in the cytosol in particulate
      form. Virus-induced gene silencing of NbCHMP1 resulted in subtle alterations of
      leaf morphology and color, without significantly affecting plant viability or
      development. Thus the CHMP1 homolog apparently does not play an essential role in
      the development of the vegetative tissues of N. benthamiana, in contrast to the
      essential role of sail in formation of the aleurone cell layers during maize
      endosperm development.

PMID- 15179040
TI  - Purification and cDNA cloning of a cecropin-like peptide from the great wax moth,
      Galleria mellonella.
AB  - A cecropin-like antimicrobial peptide, Gm cecropin, was purified from hemolymph
      of larvae of the wax moth, Galleria mellonella, immunized against E. coli, and
      its antibacterial activity was examined in a radial diffusion assay. The
      molecular mass of Gm cecropin was 4,160.69 Da by matrix-assisted laser desorption
      ionization-time-of-flight mass spectrometry analysis. The full-length cDNA of the
      Gm cecropin precursor was cloned by a combination of RT-PCR, based on the N
      terminal sequence obtained by Edman degradation, and 5'-RACE-PCR. Analysis of the
      cDNA showed that cecropin is synthesized as a prepropeptide, with a putative 22
      residue signal peptide, a 4-residue propeptide and a 39-residue mature peptide
      with a calculated mass of 4,344.18 Da the difference between the calculated and
      measured masses suggests that Gm cecropin is a 37-residue peptide generated by
      removal of the C-terminal residue and amidation.

PMID- 15179041
TI  - Molecular characterization of membrane type and ganglioside-specific sialidase
      (Neu3) expressed in E. coli.
AB  - Endogenous expression of human membrane type ganglioside sialidase (Neu3) was
      examined in various cell lines including NB-1, U87MG, SK-MEL-2, SK-N-MC, HepG2,
      Hep3B, Jurkat, HL-60, K562, ECV304, Hela and MCF-7. Expression was detected in
      the neuroblastoma cell lines NB-1 and SK-N-MC, and also in erythroleukemia K562
      cells, but not in any other cells. We isolated a Neu3 cDNA from K562 cells and
      expressed a His-tagged derivative in a bacterial expression system. The purified
      recombinant product of approximately 48 kDa had sialidase activity toward 4
      methyl-umbelliferyl-alpha-D-N-acetylneuraminic acid (4MU-NeuAc). The optimal pH
      of the purified Neu3 protein for GD3 ganglioside was 4.5. The enzyme also
      efficiently hydrolyzed GD3, GD1a, GD1b and GM3 whereas sialyllactose, 4MU-NeuAc,
      GM1 and GM2 were poor substrates, and it had no activity against sialylated
      glycoproteins such as fetuin, transferrin and orosomucoid. We conclude that the
      sialidase activity of Neu3 is specific for gangliosides.

PMID- 15179042
TI  - Cloning and expression of the glucose-1-phosphate thymidylyltransferase gene
      (gerD) from Streptomyces sp. GERI-155.
AB  - GERI-155 is a macrolide antibiotic containing two deoxyhexose molecules, that has
      antimicrobial activity against Gram-positive bacteria. The deoxysugar
      biosynthetic gene cluster of GERI-155 was cloned from Streptomyces sp., GERI-155.
      One of the orfs, gerD, appeared to encode glucose-1-phosphate
      thymidylyltransferase (dTDP-glucose synthase), which converts dTTP and glucose-1
      phosphate to dTDP-D-glucose and pyrophosphate. GerD was expressed in E. coli in
      vector pHJ2 and the expressed protein was purified to apparent homogeneity by
      ammonium sulfate precipitation and DEAE-Sepharose CL-6B and DEAE-Trisacryl column
      chromatography. The specific activity of the enzyme increased 16-fold with a
      recovery of 10%. It migrated as a single band on SDS-PAGE with a molecular mass
      of 30 kDa. The purified protein had glucose-1-phosphate thymidylyltransferase
      activity, catalyzing a reversible bimolecular group transfer reaction. In the
      forward reaction the highest activity was obtained with the combination of dTTP
      and alpha-D-glucose-1-phosphate, and only 5.5% of that activity was obtained with
      UTP in place of dTTP. In the opposite direction the purified protein was highly
      specific for dTDP-D-glucose and pyrophosphate.

PMID- 15179043
TI  - The transmembrane domain of AtToc64 and its C-terminal lysine-rich flanking
      region are targeting signals to the chloroplast outer envelope membrane
      [correction].
AB  - The targeting mechanism of chloroplast outer envelope membrane proteins remains
      largely unknown. We investigated the targeting of AtToc64. In protoplasts, the
      transmembrane domain (TMD) and its C-terminal Iysine-rich flanking region (LFR)
      were both necessary and sufficient for targeting to the outer envelope membrane.
      The lysine residues of the flanking region were critical; without the LFR, the
      TMD was targeted to the ER or the plasma membrane. In addition, the types of
      amino acid residues of the TMD, but not the amino acid sequence per se, is a
      signal for targeting to the chloroplast envelope membrane. TMDs containing
      phenylalanines were not targeted to the chloroplast in vivo. Based on these
      results, we propose that the chloroplast targeting signal of AtToc64 comprises
      two different components: 1) the LFR, which is a signal for evading SRP-mediated
      co-translational translocation and 2) the hydrophobic amino acid side chains of
      the TMD, whose size functions as a signal for a cytosolic factor that mediates
      transport to the chloroplast.

PMID- 15179044
TI  - Differential regulation of ciliary neurotrophic factor and its receptor in the
      rat hippocampus in response to kainic acid-induced excitotoxicity.
AB  - We analyzed the changes in expression of ciliary neurotrophic factor (CNTF) and
      its receptor, ligand-binding subunit a (CNTFRa), in the hippocampus following
      intraperitoneal administration of a convulsant dose of kainic acid (KA).
      Immunohistochemistry and immunoblotting showed that CNTF levels rose dramatically
      between day 1 and day 10, and that the CNTF was located in reactive astrocytes.
      In contrast, upregulation of CNTFRalpha mRNA, occurred in neurons as well as
      astrocytes. A rapid, and short-lived (3 h-2 d) increase in CNTFRalpha was also
      observed in the more resistant granule cells and CA2 pyramidal neurons. The
      increase in astrocytes was detected by day 1 and was sustained for more than 5 d.
      These results show that CNTF and CNTFRalpha are differentially regulated in
      hippocampal neurons and reactive astrocytes following KA injection, indicating
      that these proteins may be involved in the regulation of astrocyte and neuronal
      degenerative responses.

PMID- 15179045
TI  - A stable gene transfer system for hematopoietic progenitor cells from human bone
      marrow using pseudotyped retroviral vectors.
AB  - Recombinant DNA technology has permitted tremendous progression in delivering
      genes into cells; however, further advances in gene replacement techniques are
      needed prior to application to hematological diseases. One of the greatest
      obstacles to gene therapy in human hematopoietic stem cells is the lack of a
      defined protocol in humans and low transduction efficiency. Currently, murine
      leukemia virus (MuLV) is the most popular choice as a gene transfer vehicle but
      it cannot infect non-dividing cells. In our study, vesicular stomatitis G protein
      pseudotyped MuLV and HIV-1 were produced by a split gene transfection method.
      Mononuclear cells were separated from healthy human bone marrow and pre
      stimulated with cytokines to form myeloid cell lineages. The cells were infected
      at different MOls with highly concentrated virus and infection rates were
      analyzed by flow cytometry and progenitor cell assays. eGFP expression was much
      higher when using HIV-1 system than when using MuLV. Progenitor cell assays
      agreed with the results obtained by FACS, but the difference was less great. We
      conclude that the lentiviral system is more suitable for gene transfer to
      hematopoietic progenitor cells probably because it stably infects both dividing
      and non-dividing cells. In addition, fibronectin was shown to improve the rate of
      infection with HIV-1.

PMID- 15179046
TI  - Changes in parvalbumin immunoreactivity in the parietofrontal cortex after
      transient forebrain ischemia in the Mongolian gerbil.
AB  - We investigated the changes in parvalbumin (PV)-immunoreactive (IR) neurons in
      the parietofrontal cortex after transient forebrain ischemia. In the sham
      operated group, PV-IR neurons were present in all layers of the parietofrontal
      cortex except layer I. Shortly after ischemia the number of PV-IR neurons in
      layer II/III first increased, and then declined dramatically 12 h after ischemic
      insult, followed by a second increase after 2 days. At this time the PV
      immunoreactivity was very weak and only present in the peripheral neuronal
      cytoplasm. The reversible increase in the number of PV-IR neurons and in the
      level of their immunoreactivity could result from a transient ischemia-induced
      increase in intracellular calcium. This pattern of expression was particularly
      pronounced in layer II/III of the parietofrontal cortex, suggesting that these
      neurons are especially?susceptible to ischemic insult.

PMID- 15179047
TI  - Establishment of a human embryonic germ cell line and comparison with mouse and
      human embryonic stem cells.
AB  - Human embryonic stem (ES) cells and embryonic germ (EG) cells are pluripotent and
      are invaluable material for in vitro studies of human embryogenesis and cell
      therapy. So far, only two groups have reported the establishment of human EG cell
      lines, whereas at least five human ES cell lines have been established. To see if
      human EG cell lines can be reproducibly established, we isolated primordial germ
      cells (PGCs) from gonadal ridges and mesenteries (9 weeks post-fertilization) and
      cultured them on mouse STO cells. As with mouse ES colonies, the PGC-derived
      cells have given rise to multilayered colonies without any differentiation over a
      year of continuous culture. They are karyotypically normal and express high
      levels of alkaline phosphatase, Oct-4, and several cell-surface markers.
      Histological and immunocytochemical analysis of embryoid bodies (EBs) formed from
      floating cultures of the PGC-derived cell colonies revealed ectodermal,
      endodermal, and mesodermal tissues. When the EBs were cultured in the presence of
      insulin, transferrin, sodium selenite, and fibronectin for 1 week, markers of
      primitive neuroectoderm were expressed in cells within the EBs as well as in
      cells growing out from the EBs. These observations indicate that our PGC-derived
      cells satisfy the criteria for pluripotent stem cells and hence may be EG cells.

PMID- 15179048
TI  - Involvement of two NF-kappaB binding sites in PMA-induced expression of the human
      leukotactin-1/CCL15 gene in U937 monocytoid cells.
AB  - Leukotactin-1 (Lkn-1)/CCL15, is a recently cloned chemotactic chemokine that
      appears to play important roles in the inflammatory process by recruiting immune
      cells to inflammatory sites. Expression of the Lkn-1/CCL15 gene is inducible in
      monocytes but its transcriptional regulation has not been studied. To identify
      Lkn-1/CCL15 regulatory sequences in monocytic cells, U937 cells were transiently
      transfected with the luciferase reporter gene linked to various deletions of the
      Lkn-1/CCL15 promoter region. The region -269 to -43 bp from the transcription
      start site proved to be important for induction by PMA. This region contained two
      potential NF-kappaB sites: one between -191 and -182 bp, and the other between 
      60 and -51 bp. Mutation of either element reduced PMA-induced expression and
      electrophoretic mobility shift assays revealed that NF-kappaB recognized both
      potential NF-kappaB sites. In addition, PMA-induction of Lkn-1/CCL15 in
      transiently transfected U937 cells was blocked by proteasome inhibitor 1. These
      observations demonstrate that the two NF-kappaB binding sites are essential for
      PMA-induced Lkn-1/CCL15 expression in human monocytes.

PMID- 15179049
TI  - The complete mitochondrial genome of the rockfish Sebastes schlegeli
      (Scorpaeniformes, Scorpaenidae).
AB  - We isolated rockfish Sebastes schlegeli mitochondrial DNA by long-polymerase
      chain reaction (Long-PCR) with conserved primers, and sequenced it by primer
      walking using flanking sequences as sequencing primers. S. schlegeli
      mitochondrial DNA consists of 16,526 bp and its structural organization is
      conserved in comparison with other fish. Using mitochondrial control region
      sequences, we compared related species from the genus Sebastes (Scorpaeniformes,
      Scorpaenidae), showing the similarity of S. schlegeli isolated from Korean and
      Japanese waters. In this paper, we report the basic characteristics of the S.
      schlegeli mitochondrial genome including structural organization, base
      composition of rRNAs and the tRNAs and protein-encoding genes, and
      characteristics of mitochondrial tRNAs. These findings are applicable to
      aquaculture and to molecular phylogenetics in the genus Sebastes.

PMID- 15179050
TI  - Bee venom acupoint stimulation increases Fos expression in catecholaminergic
      neurons in the rat brain.
AB  - Fos immunocytochemistry was combined with tyrosine hydroxylase (TH) or dopamine
      beta-hydroxylase (DBH) immunolabeling to examine brainstem catecholaminergic
      neuronal activation resulting from bee venom (BV) stimulation of the Zusanli
      acupoint (ST36) in Sprague-Dawley rats. BV injection into the Zusanli acupoint
      caused increased Fos expression in catecholaminergic neurons located in the
      hypothalamic arcuate nucleus (Arc), the dorsal raphe (DR), the A5 cell group (A5)
      and the locus coeruleus (LC). BV acupoint stimulation significantly increased Fos
      TH double-labeled neurons in the Arc, LC and DR. Fos-DBH positive neurons were
      also increased by BV acupoint stimulation in the LC and A5. In contrast BV
      stimulation of a non-acupoint only increased Fos expression and Fos-TH double
      labeled neurons in the Arc. These data indicate that BV acupoint stimulation
      activates brainstem catecholaminergic neurons and that this activation underlies
      BV acupoint-induced antinociception.

PMID- 15179051
TI  - A TMV-Cg mutant with a truncated coat protein induces cell death resembling the
      hypersensitive response in Arabidopsis.
AB  - Tobacco mosaic virus (TMV)-Cg is able to propagate and multiply systemically to
      high levels in Arabidopsis thaliana ecotype Col-0. In this study, we obtained a
      Cg mutant, Cgk1, which expresses a coat protein with a truncated carboxyl
      terminus. Interestingly, Cgk1 induced necrosis that resembled the hypersensitive
      response and caused more pronounced disease symptoms than wild type Cg in
      Arabidopsis Col-0 plants. A reactive oxidative burst occurred prior to this
      necrosis. We found that expression of the pathogenesis-related gene PR-1 was
      induced by Cgk1 infection, and also by infection with wild type Cg, but only in
      npr1-2 mutant plants, not in NahG transgenic plants. These results suggested that
      PR-1 expression is dependent on the salicylic acid signaling pathway, but is
      independent of NPR1.

PMID- 15179052
TI  - Iron enhances NGF-induced neurite outgrowth in PC12 cells.
AB  - Rat pheochromocytoma 12 (PC12) cells undergo neuronal differentiation in response
      to nerve growth factor (NGF). NGF-induced differentiation involves a number of
      protein kinases, including extracellular signal-regulated kinase (ERK). We
      studied the effect of iron on neuronal differentiation, using as model the
      neurite outgrowth of PC12 cells triggered by NGF when the cells are plated on
      collagen-coated dishes in medium containing 1% serum. The addition of iron
      enhanced NGF-mediated cell adhesion, spreading and neurite outgrowth. The
      differentiation-promoting effect of iron seems to depend on intracellular iron,
      since nitrilotriacetic acid (an efficient iron-uptake mediator) enhanced the
      response to iron. In agreement with this, intracellular, but not extracellular,
      iron enhanced NGF-induced neurite outgrowth in pre-spread PC12 cells, and this
      was correlated with increased ERK activity. Taken together, these data suggest
      that intracellular iron promotes NGF-stimulated differentiation of PC12 cells by
      increasing ERK activity.

PMID- 15179053
TI  - Inactivation of mitochondrial electron transport by photosensitization of a
      pheophorbide a derivative.
AB  - We examined the damage to mitochondrial electron transport caused by
      photosensitization of a pheophorbide a derivative, DH-I-180-3, shown recently to
      induce necrosis of lung carcinoma cells with low dark toxicity. Confocal
      microscopy showed that DH-I-180-3 co-localized with dihydrorhodamine-123
      suggesting that it mainly accumulates in mitochondria. The photosensitizer alone
      in the dark did not affect mitochondrial electron transport. Illumination of
      isolated mitochondria in the presence of DH-I-180-3 resulted in inhibition of
      both NADH- and succinate-dependent respiration. Measurement of the activity of
      each component of the electron transport chain revealed that Complex I and III
      were very susceptible to the treatment whereas Complex IV was resistant. We
      conclude that the photosensitizer is localized in mitochondria and, upon
      illumination, produces reactive oxygen species that inactivate Complexes I and
      III.

PMID- 15179055
TI  - SCOPExplorer: a tool for browsing and analyzing structural classification of
      proteins (SCOP) data.
AB  - We have developed a tool, named "SCOPExplorer", for browsing and analyzing SCOP
      information. SCOPExplorer 1) contains a tree-style viewer to display an overview
      of protein structure data, 2) is able to employ a variety of options to analyze
      SCOP data statistically, and 3) provides a function to link protein domains to
      protein data bank (PDB) resources. SCOPExplorer uses an XML-based structural
      document format, named "SCOPML", derived from the SCOP data. To evaluate
      SCOPExplorer, proteins containing more than 20 domains were analyzed. The Skp1
      Skp2 protein complex and the Fab fragment of IgG2 contain the largest numbers of
      domains in the current eukaryotic SCOP database. These proteins are known to
      either bind to various proteins or generate diversity. This suggests that the
      more domains a protein has, the more interactions or more variability it will be
      capable of. (SCOPExplorer is available for download at
      http://scopexplorer.ulsan.ac.kr).

PMID- 15179054
TI  - Intracellular delivery of p53 fused to the basic domain of HIV-1 Tat.
AB  - p53 is a potent tumor suppressor inactivated in many cancers. In this study, the
      membrane permeability of the HIV-1 Tat basic domain was exploited to introduce
      functional p53 into cancer cells. We expressed and purified a p53 fusion protein
      with the HIV-1 Tat basic domain at its N terminus (Tat-p53), and examined its
      transduction profile and biological activity in cancer cells. Tat-p53 was
      efficiently delivered to both the cytoplasm and nucleus of cells, and was
      transcriptionally active, as judged by the level of p21/WAF1 protein and of p21
      promoter activity. Transduction of cells with Tat-p53 resulted in apoptotic cell
      death in both p53 positive and negative human tumor cell lines. These results
      suggest that Tat-p53 could be useful in cancer therapy.

PMID- 15179056
TI  - Molecular phylogenetic status of the Korean goral and Japanese serow based on
      partial sequences of the mitochondrial cytochrome b gene.
AB  - To investigate the molecular phylogenetic status of the Korean goral, Nemorhaedus
      caudatus raddeanus, and Japanese serow, Capricornis crispus, we determined
      partial sequences of the mitochondrial cytochrome b gene of twelve Korean gorals
      and sixteen Japanese serows, and compared them with those of the major lineages
      of Rupicaprini species including two other Nemorhaedus species and two other
      Capricornis species. The Korean gorals examined possessed two haplotypes with
      only one nucleotide difference between them, while the Japanese serows showed
      slightly higher sequence diversity with five haplotypes. Genetic distances and
      molecular phylogenetic trees indicated that there is considerable genetic
      divergence between the Korean goral and N. caudatus (the Chinese goral) [Groves
      and Shields (1996)], but virtually none between Korean and Russian gorals. The
      Korean and Russian gorals may therefore be distinct from the Chinese goral. The
      data highlight the importance of conservation of the goral populations of these
      regions, and the need to reconsider the taxonomic status of Korean and Russian
      gorals. Our study also clearly demonstrated sufficient genetic distance between
      serows and gorals to justify their assignment to separate genera. Of the three
      species of Capricornis, the Formosan serow, C. swinhoei is more closely related
      to C. sumatraensis than to the Japanese serow, suggesting that the Formosan serow
      is a distinct species. Preliminary data on intraspecific genetic variation in the
      Japanese serow are also presented.

PMID- 15179057
TI  - Novel vector systems optimized for injecting in vitro-synthesized mRNA into
      zebrafish embryos.
AB  - Microinjection of nucleic acids or proteins is a useful way of studying embryonic
      development. In particular, injection of in vitro-transcribed capped RNA is
      commonly employed to achieve ectopic or increased expression of genes. Two vector
      systems, pCS2+ and pT7Ts, have been used for this purpose in zebrafish. However,
      they were initially optimized for Xenopus embryos not for zebrafish. Here we
      describe a vector, pcGlobin2, optimized for zebrafish, and its derivative,
      pcGlobin2-GST. This new vector system offers several advantages. First, pcGlobin
      2 contains three critical elements 15' and 3' zebrafish beta-globin UTRs, and a
      poly(A) tail] for generating stable mRNAs and greatly improving translation
      efficiency. Second, subcloning and preparation of template DNA is easier because
      of the larger number of restriction sites. Third, protein-binding assays can be
      performed directly on the injected embryos with pcGlobin2-GST. Lastly, this
      vector system can be transfected into animal cells without additional subcloning.

PMID- 15179058
TI  - A method of high frequency virus-induced gene silencing in chili pepper (Capsicum
      annuum L. cv. Bukang).
AB  - Using a tobacco rattle virus (TRV)-based virus-induced gene silencing (VIGS)
      system, expression of phytogene desaturase (PDS) and ribulose-1,5-bisphosphate
      carboxylase small-subuit (rbcS) genes was suppressed in Nicotiana benthamiana and
      pepper plants (Capsicum annuum L. cv. Bukang). The silenced phenotypes of pale
      yellow (rbcS), and photobleached leaves (PDS), were invariably obvious 2 weeks
      after inoculation with the TRV-based vector. In a parallel experiment, the same
      set of genes was silenced in N. benthamiana and yielded identical phenotypes to
      pepper 1 week after inoculation. Northern blot analyses showed that the
      endogenous levels of CarbcS and CaPDS transcripts were dramatically reduced in
      the silenced leaf tissues. These observations confirm that the silenced phenotype
      is closely correlated with the pattern of tissue expression. To our knowledge,
      this is the first high frequency VIGS method in pepper plants. It should provide
      a tool for large-scale gene silencing studies in pepper functional genomics.

PMID- 15179060
TI  - Increased intracranial pressure: idiopathic and otherwise.

PMID- 15179061
TI  - Chronic intracranial hypertension with unexplained cerebrospinal fluid
      pleocytosis.
AB  - In a retrospective review of all cases with a diagnosis of idiopathic
      intracranial hypertension in two academic departments of neurology over a nine
      year period, the authors identified six patients with a clinical course typical
      of idiopathic intracranial hypertension (IIH) except for the finding of
      cerebrospinal fluid pleocytosis. There were five women and one man with a mean
      age at presentation of 25.7 years (range, 25-32 yr). All were obese but had no
      other associated medical conditions or identifiable risk factors for IIH. In five
      patients, all or most cerebrospinal fluid cells were lymphocytes. Cerebrospinal
      fluid pleocytosis persisted for several months in all patients. Patients
      underwent a thorough laboratory and neuroimaging evaluation that did not reveal a
      primary cause. Medical treatment directed solely at lowering intracranial
      pressure was effective in five patients; one patient required lumboperitoneal
      shunting. Ophthalmic manifestations of increased intracranial pressure stabilized
      or remitted after treatment was withdrawn with a mean follow-up period of 33
      months (range, 14-55 mo). Some patients may present with idiopathic chronic
      meningitis and elevated intracranial pressure that responds to treatment used for
      IIH.

PMID- 15179062
TI  - Visual hallucinations during prolonged blindfolding in sighted subjects.
AB  - The authors report the occurrence of visual hallucinations of varying complexity
      in 13 normal subjects after sudden, complete, and prolonged visual deprivation.
      The subjects were all healthy individuals with no history of cognitive
      dysfunction, psychosis, or ocular pathology. They wore a specially designed
      blindfold for a period of five consecutive days (96 hours) and were asked to
      record their daily experiences using a hand-held microcassette recorder. Ten
      (77%) of the subjects reported visual hallucinations, which were both simple
      (bright spots of light) and complex (faces, landscapes, ornate objects). The
      onset of hallucinations was generally after the first day of blindfolding.
      Subjects were insightful as to their unreal nature. These results indicate that
      rapid and complete visual deprivation is sufficient to induce visual
      hallucinations in normal subjects.

PMID- 15179063
TI  - Bilateral horizontal gaze palsy in presumed paraneoplastic brainstem encephalitis
      associated with a benign ovarian teratoma.
AB  - A 28-year-old woman with a previous history of recurrent benign ovarian teratoma
      developed a bilateral horizontal gaze palsy, a right facial paresis, and
      bilateral trigeminal hypesthesia. Magnetic resonance imaging disclosed high
      signal in the rostral pons. Results of all other laboratory studies, including
      those for antineuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-Tr, anti-Ma1,
      anti-Ma2, and anti-CV2/CRMP5), were negative. Pelvic ultrasound revealed a
      residual mass in the left ovary, which was confirmed as teratoma on surgical
      pathological examination. Complete neurologic recovery occurred within two weeks
      of surgical removal of the teratoma and treatment with intravenous
      corticosteroids and immunoglobulin. This case demonstrates that a search for an
      occult neoplasm is extremely important in the diagnosis of presumed
      paraneoplastic encephalitis even if antineuronal antibodies are not found.

PMID- 15179064
TI  - Metastatic neuroblastoma presenting with binocular blindness from intracranial
      compression of the optic nerves.
AB  - A 2-year-old boy with blindness as an isolated symptom was found to have no light
      perception binocularly because of compression of both optic nerves by a
      neuroblastoma infiltrating the walls of the optic canals and medial sphenoid
      bone. Imaging disclosed a primary tumor near the kidney and multiple osseous
      metastases. Although neuroblastoma commonly causes blindness by metastasis to the
      orbit, it rarely causes bilateral blindness from intracranial compression of the
      optic nerves. This is the first report of bilateral blindness as the presenting
      feature.

PMID- 15179065
TI  - Visual manifestations of visible and buried optic disc drusen.
AB  - BACKGROUND: It has been reported that visible optic disc drusen are associated
      with decreased visual acuity and loss of peripheral visual field. Patients with
      buried optic disc drusen have not been as well characterized. METHODS: An
      observational, retrospective review was made of 92 eyes with funduscopic or
      ultrasonographic evidence of optic disc drusen. Demographics, presenting
      symptoms, visual acuity, refractive error, intraocular pressure, presence of an
      afferent pupillary defect, cup-to-disc ratio, appearance of the optic nerve, and
      visual field were recorded. RESULTS: Fifty-one (55%) of the eyes were
      symptomatic; among them, 63% had symptoms of visual acuity loss, and 49% had
      symptoms of visual field loss. Seventy-nine (86%) of the optic discs appeared
      abnormal on ophthalmoscopy, but only 42% of these had visible drusen. Forty-five
      (49%) of the eyes had a visual field defect, and 73% of these were nerve fiber
      bundle in type. Overall, 73% of optic discs with visible drusen had abnormal
      visual fields compared with only 36% of optic discs with buried drusen (P <
      0.05). CONCLUSIONS: Among 92 eyes with optic disc drusen, only slightly more than
      50% produced visual symptoms. Fewer than 50% of drusen were visible
      ophthalmoscopically. Buried optic disc drusen identified by ultrasound had a
      significantly lower frequency of associated visual field defects than did visible
      optic disc drusen.

PMID- 15179066
TI  - Galloping ophthalmoplegia and numb chin in Burkitt lymphoma.
AB  - A 57-year-old man developed complete bilateral ophthalmoplegia over a period of
      10 days, together with bilateral facial pain and numbness of the chin. He had no
      other clinical manifestations. Findings on brain magnetic resonance imaging and
      spinal fluid formula from the first lumbar puncture were normal, but
      cerebrospinal fluid flow cytometry disclosed a kappa restriction monoclonal B
      cell population, indicating malignant lymphoma. Computed tomography of the chest,
      abdomen, and pelvis then revealed multiple enlarged lymph nodes. Biopsy of an
      inguinal node showed findings consistent with Burkitt lymphoma. Within six weeks,
      intravenous and intrathecal chemotherapy resolved all neurologic findings except
      a partial right-side sixth nerve palsy and mild chin numbness. Eighteen months
      after disease onset, the patient remained in remission. Meningeal spread of
      Burkitt lymphoma is not commonly a presenting feature in immunocompetent adults.
      Chin numbness, a characteristic feature caused by infiltration of the mental
      nerve, should facilitate earlier recognition, which may be life saving.

PMID- 15179067
TI  - Concurrent sino-orbital aspergillosis and cerebral nocardiosis.
AB  - A 79-year-old man with myelodysplastic syndrome developed a right optic
      neuropathy with optic disc edema and intractable periocular pain, one month after
      undergoing removal of a gangrenous gallbladder. Although results of a temporal
      artery biopsy were negative, he was treated with prednisone for presumed temporal
      arteritis. Attempts at tapering the prednisone dose led to recurrence of
      periocular pain. On neuro-ophthalmologic evaluation six months after the
      prednisone treatment was begun, he had developed right fourth and sixth cranial
      nerve palsies, and magnetic resonance imaging demonstrated a right orbital apex
      mass. Trans-sphenoidal biopsy revealed Aspergillus fumigatus. During treatment of
      aspergillosis, the patient developed a left hemiparesis. Magnetic resonance
      imaging disclosed multiple ring-enhancing cerebral masses. Biopsy revealed
      Nocardia asteroides. The patient was successfully treated for both infections
      with recovery of neurologic function except for the right optic neuropathy.
      Although immunocompromised patients are known to be subject to multiple
      infections, this may be the first reported case of concurrent sino-orbital
      aspergillosis and cerebral nocardiosis.

PMID- 15179068
TI  - Idiopathic intracranial hypertension.
AB  - The syndrome of intracranial hypertension without structural brain or
      cerebrospinal fluid abnormalities and without identifiable cause, now most
      appropriately termed idiopathic intracranial hypertension, was described over a
      century ago. Although the pathogenesis of this condition remains unknown,
      diagnostic and therapeutic developments during the past two decades have
      substantially advanced patient management.

PMID- 15179069
TI  - Cerebrospinal fluid diversion procedures.
AB  - Cerebrospinal fluid (CSF) diversion procedures remain the principal method of
      treatment of hydrocephalus and an important option in treating idiopathic
      intracranial hypertension. Recent advances in CSF shunt hardware offer some
      promise in reducing the rate of complications. Third ventriculostomy has become
      an increasingly practiced alternative to conventional shunting in an ever
      widening patient population. Long-term follow-up studies have identified
      complications of lumboperitoneal shunt placement. Advances in surgical navigation
      suggest that ventriculoperitoneal shunting may be a viable alternative in
      patients with idiopathic intracranial hypertension.

PMID- 15179070
TI  - Cerebral venous thrombosis.
AB  - Cerebral venous thrombosis is an infrequent condition characterized by extreme
      variability in its clinical presentation and mode of onset. The combination of
      magnetic resonance imaging and magnetic resonance angiography is currently the
      best method for diagnosis. The proportion of cases of unknown etiology remains
      high. The prognosis, although better than previously thought, remains
      unpredictable. Treatment, which should be started as soon as the diagnosis is
      established, consists of reversing the underlying cause when known, control of
      seizures and intracranial hypertension, and the use of antithrombotics. Heparin
      should be the first-line antithrombotic agent. Recent studies have confirmed its
      safety even in patients with hemorrhagic parenchymal lesions. Local thrombolysis
      is indicated in the very rare cases that deteriorate despite adequate
      anticoagulation. Cerebrospinal fluid diversion or optic nerve fenestration is
      used for vision-threatening papilledema when intracranial pressure control is
      difficult.

PMID- 15179072
TI  - 41st annual meeting of the Japanese Neuro-Ophthalmology Society, Kyoto, Japan,
      December 12-13, 2003.

PMID- 15179071
TI  - Vasculopathies affecting the eye.
AB  - The retinal arteries and veins may be involved in isolation or as the result of a
      systemic vasculitis. This article emphasizes neurologic diseases in which the
      ocular vasculature is affected.

PMID- 15179073
TI  - 29th International Stroke Conference, San Diego, California, February 5-7, 2004.

PMID- 15179074
TI  - Increased intracranial pressure associated with ophthalmoplegia, ataxia, and
      areflexia.

PMID- 15179075
TI  - Cat scratch disease in two brothers.

PMID- 15179076
TI  - Contralateral amaurosis after retrobulbar anesthetic injection.

PMID- 15179077
TI  - Eye movement abnormalities in a case of X-linked dystonia-Parkinsonism (lubag).

PMID- 15179078
TI  - Laser visual field testing.

PMID- 15179080
TI  - Incorporation of implant overdentures into the predoctoral dental curriculum.

PMID- 15179081
TI  - Re: Perel ML. The speed limit. Implant Dent. 2004 Mar;13(1):1.

PMID- 15179086
TI  - Resistance to crown displacement on a hexagonal implant abutment.
AB  - The purpose of this study was to evaluate the resistance and retention of a
      hexagonal abutment to crown displacement with varying crown heights (10, 12, and
      14 mm) and axis of load. Implants were embedded in resin blocks at a 30 degree
      angle to the vertical. Crowns were made at heights of 10, 12, and 14 mm. Groups
      of 5 crowns for each of the 3 crown heights were loaded (200 N) both under the
      long axis and off axis. The marginal gaps were measured using standardized
      periapical radiographs before and after loading. The gaps were statistically
      compared using a 3-way analysis of variance with factors of load, crown height,
      and point of load. Crowns were loaded to 10 cycles or point of failure. The 10-mm
      crowns did not show any displacement. The 12-mm and 14-mm groups only showed
      displacement of the off axis-loaded crowns. The average marginal displacement was
      193.56 micro (standard deviation [SD] +/- 138.62 micro) at point of failure
      (320,717 cycles) and 400.18 micro (SD +/- 644.31) at point of failure (134,278
      cycles), respectively. A 1-piece implant with a standardized abutment design can
      provide sufficient resistance and retention form for crowns of varying dimension
      if loads are centered over the long axis of the crown.

PMID- 15179087
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.
      Orthdontic 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- 15179088
TI  - Labyrinthine concussion and positional vertigo after osteotome site preparation.
AB  - An incident of positional vertigo associated with osteotome technique for
      installation of multiple maxillary dental implants is reported. The symptoms
      resolved after 2 weeks with restricted physical activity and prohibition of
      lifting. There is a discussion of labyrinthine concussion and treatments.
      Suggestions for prevention are to use small sizes of osteotomes first and then
      progress to larger sizes and to avoid neck extension head position during
      osteotome use.

PMID- 15179089
TI  - Stereolithography in oral implantology: a comparison of surgical guides.
AB  - This article presents the use of stereolithography in oral implantology.
      Stereolithography is a new technology that can produce physical models by
      selectively solidifying an ultraviolet-sensitive liquid resin using a laser beam,
      reproducing the true maxillary and mandibular anatomic dimensions. With these
      models, it is possible to fabricate surgical guides that can place the implants
      in vivo in the same places and same directions as those in the planned computer
      simulation. A 70-year-old woman, in good health, with severe mandibular bone
      atrophy was rehabilitated with an over-denture supported by 2 Branemark implants.
      Two different surgical planning methods were considered: 1) the construction of a
      surgical guide evaluating clinical aspects, and 2) the surgical guide produced by
      stereolithographic study. The accuracy of surgical planning can reduce the
      problems related to bone density and dimensions. Furthermore, the
      stereolithographic study assured the clinicians of a superior location of
      fixtures in bone. Surgical planning based on stereolithographic technique is a
      safe procedure and has many advantages. This technologic advance has biologic and
      therapeutic benefits because it simplifies anatomic surgical management for
      improved implant placement.

PMID- 15179090
TI  - Risk factors and management of dehiscent wounds in implant dentistry.
AB  - Successful implant dentistry is based on adequate training, proper selection of
      patients, careful surgery, preplanned restorations, and postoperative and
      supportive care. Although implant therapy is highly successful and predictable,
      it is not without possible early and/or late complications. The aim of this
      article is to highlight the importance of a relatively neglected subject of
      dehiscent wounds in the dental implant literature. This article covers the
      definitions of wound healing and wound dehiscence and some of the common risk
      factors related to suture line opening as an immediate postoperative
      complication. These factors appear to be largely iatrogenic in nature and partly
      related to patient neglect. Hence, it deserves documentation to confirm a
      strategy for their avoidance and management. A management protocol is presented
      on how to deal with different types of dehiscence and causal factors.

PMID- 15179091
TI  - Trephine bone core sinus elevation graft.
AB  - The sinus cavity often limits the amount of available bone for the placement of
      implants in the posterior maxilla. The sinus lift operation and graft is a
      technique that can add grafted bone in excess of 10 to 16 mm through a lateral
      wall quadrilateral osteotomy. However, when moderate alveolar atrophy is present,
      an osteotome technique can provide an average bone height in crease of 3.5 mm.
      This article presents the trephine bone core sinus elevation graft, which is
      intended to increase bone height 4 to 8 mm. This procedure is especially
      indicated when adjacent teeth are present and there is only moderate atrophy of
      the alveolus.

PMID- 15179092
TI  - Extraction sockets and implantation of hydroxyapatites with membrane barriers: a
      histologic study.
AB  - The purpose of this pilot study was to investigate the effect on extraction
      socket healing when an absorbable hydroxyapatite (AH) and a nonabsorbable
      anorganic bovine bone mineral (ABB) covered with either an acellular dermal
      matrix allograft (ADMA) or expanded polytetrafluoroethylene (ePTFE) membrane
      barrier were left exposed to the oral cavity. Following tooth extraction, a total
      of 16 sockets in 15 patients with deficient buccal plates of > or =5 mm were
      randomly divided into 4 treatment groups: 1) AH covered with ADMA, 2) AH covered
      with an ePTFE membrane, 3) ABB covered with ADMA, and 4) ABB covered with an
      ePTFE membrane. Primary coverage was not attempted or obtained in any of the 16
      treated sockets. Six to 8 months postextraction at the time of implant placement,
      histologic cores of the treatment sites were obtained. These cores were
      processed, stained with Stevenel's blue/van Gieson's picro fuchsin, and
      histomorphometrically analyzed. Vital bone, connective tissue and marrow, and
      residual graft particles were reported as a percentage of the total core. The
      mean vital bone was 34.5% (AH with ADMA), 41.7% (ABB with ADMA), 27.6% (ePTFE and
      AH), and 17.8% (ePTFE and ABB). The average percentage of vital bone in the 8
      sockets covered with ADAMA was 38% compared with an average percentage vital bone
      of 22% in the 8 sockets covered with ePTFE membrane barriers. Because of the
      small number of specimens in the 4 groups, statistical analysis was not possible.
      However, in this pilot study, ADMA-covered sites resulted in more vital bone
      present 6 to 8 months postsocket treatment than obtained in the ePTFE-covered
      sites regardless of bone replacement materials used. Further research is
      warranted to see if these results show a similar difference in bone-to-implant
      contact after implant placement.

PMID- 15179093
TI  - Treatment of the contaminated implant surface using the Er,Cr:YSGG laser.
AB  - Treatment of the contaminated implant surface by mechanical and chemotherapeutic
      means has met with mixed success. Incomplete surface debridement or alteration of
      the implant surface could compromise attempts at grafting and reintegration of
      the implant body. Development of a laser system operating at 2780 nm and using an
      ablative hydrokinetic process offers the possibility for more efficient
      decontamination and debridement. The Er,Cr: YSGG laser is evaluated and compared
      with the most commonly used chemotherapeutic modality for treatment of the
      implant surface. A scanning electron microscope study is presented comparing YSGG
      ablation to citric acid treatment of the titanium plasma sprayed and HA-coated
      implant surface. We can conclude that laser ablation using the YSGG laser is
      highly efficient at removing potential contaminants on the roughened implant
      surface while demonstrating no effects on the titanium substrate.

PMID- 15179094
TI  - Growth and proliferation of human osteoblasts on different bone graft
      substitutes: an in vitro study.
AB  - The purpose of this study was to investigate the effect of different bone graft
      substitutes onto the growth and proliferation pattern of bone cells derived from
      human iliac cancellous bone. Five different bone graft materials were used to
      investigate the effect on the proliferation of osteoblasts in vitro: phytogene
      hydroxyapatite (Algipore), alpha-Tricalcium phosphate (Bio-Base), bovine
      hydroxyapatite (low temperature) (Bio-Oss), bovine hydroxyapatite (high
      temperature) (Osteograf), and bovine hydroxyapatite (high temperature) enhanced
      with p-15, synthetic peptide (PepGen p-15). The osteoblasts were derived from
      human iliac cancellous bone and seeded with the different bone substitutes. The
      cell proliferation and viability (WST-1), alkaline phosphatase as an early marker
      of osteoblast proliferation, was evaluated after 6 and 9 days. The cultures were
      examined for cell growth pattern and morphology by normal light and scanning
      electron microscopy. The human osteoblasts showed a different proliferation
      pattern according to the type of applied bone graft substitute. PepGen P-15
      showed the highest proliferation and differentiation rate followed by Osteograf,
      Algipore, and Bio-base. Bio-Oss showed the lowest. These results were confirmed
      by electron microscopy and light microscopy evaluation in which similar growth
      pattern were observed. Distinct bone graft materials have different impact onto
      the proliferation pattern of human osteoblasts in vitro.

PMID- 15179095
TI  - Demonstration of the osseoinductive effect of bone morphogenetic protein within
      endosseous dental implants.
AB  - The purpose of this case report was to demonstrate the host osseous response in
      the maxilla after placing bone morphogenetic protein (BMP) within a specially
      designed implant. Under normal circumstances, it is usually necessary to wait
      from 4 to 6 months, or even longer in some cases, for osseous integration. Our
      objective was to assess the ability of BMP, which was carried on an absorbable
      collagen sponge in horizontal portals of the subject im plant,to affect the
      formation of bone in a Macaca fascicularis monkey. A control implant was loaded
      internally with autogenous bone recovered from the preparation of the osteotomy.
      The results demonstrated that osseous peri-implant healing occurs using BMP in
      this format.

PMID- 15179096
TI  - Roughness and bonding strength of bioactive apatite layer on dental implants.
AB  - This study examined the roughness and bonding strength of the chemical-made
      apatite layer in comparison with the titanium surface and the plasma-sprayed
      apatite. Commercially pure titanium plates were heated and chemically treated to
      deposit crystalline apatite on their surface. The roughness of the titanium
      surface of the original samples and the apatite surface was analyzed by a
      roughness surface tester. A scratch test was used to compare the adhesion of the
      chemical apatite layer to the titanium with the adhesion of a plasma-sprayed
      layer. A dense bone-like apatite layer was formed on the surface of the titanium
      by a simple chemical method. The surface roughness test showed that the chemical
      apatite coating increased the roughness of the samples. The scratch test showed
      that the bonding strength of the chemical-made apatite coatings to the titanium
      substrate was higher than the plasma-sprayed apatite coatings. The apatite layer
      produced by chemical treatment did not show a lower roughness than the titanium
      substrate. This chemical apatite layer also bonded tighter to the titanium than
      the plasma-sprayed apatite. This chemically made apatite coating is expected to
      provide a long-term implant-bone fixation.

PMID- 15179097
TI  - Secondary prevention and cardiac rehabilitation: have we got the terms right?

PMID- 15179098
TI  - Serum uric acid and risk of death from cancer, cardiovascular disease or all
      causes in men.
AB  - OBJECTIVE: Although many epidemiological studies have suggested that increased
      serum uric acid levels are a risk factor for mortality, this relationship remains
      uncertain. This cohort study examined the effects of serum uric acid level on
      death from cancer, atherosclerotic cardiovascular disease (ASCVD) or all causes
      in men. METHOD: A 9-year, prospective cohort study was carried out with 22698
      Korean men, aged 30 to 77 years, who received health insurance from the National
      Health Insurance Corporation and who underwent biennial, secondary medical
      evaluations in 1992-1996. The main outcome measures were death from cancer, ASCVD
      or all causes, compared by quintiles of serum uric acid level. At baseline, the
      mean (SD) level of serum uric acid was 354.4 (98.1) micromol/l. RESULTS: During
      199746 person-years of follow-up, there were 387 cancer deaths, 323 ASCVD (99
      ischaemic heart disease, 192 stroke) deaths and 1625 all-cause deaths. In
      multivariate Cox proportional hazards models, having controlled for age, current
      smoking, diabetes, hypertension and hypercholesterolaemia, uric acid levels were
      not associated with mortality from cancer, ASCVD or all causes. However, for
      those with diabetes, uric acid levels were associated with mortality from all
      causes even after full adjustment of the covariates. When the interaction term
      was included in the multivariate model, there was significant interactive effect
      of uric acid with diabetes (RR=1.26, 95% confidence interval 1.02-1.55) on the
      risk of all cause of death, whereas the effects of uric acid itself did not
      attain significance. CONCLUSION: These findings indicate that uric acid level is
      not an independent risk factor for death from cancer, ASCVD or all causes.

PMID- 15179099
TI  - Relationship between physical fitness and lifestyle behaviour in healthy young
      men.
AB  - BACKGROUND: There is substantial knowledge about the inverse association of
      physical fitness and CVD risk factors and CVD mortality. However, physical
      fitness per se might be influenced by lifestyle conditions such as physical
      training, smoking and drinking habits. HYPOTHESIS: We evaluated the relationship
      between physical fitness, physical activity, endurance training, smoking and
      drinking habits and blood pressure, lipids and leukocytes as surrogate
      cardiovascular risk markers in a large-scale cross-sectional study of healthy
      young men. STUDY DESIGN AND METHODS: A total of 6748 healthy young men were
      selected during their primary flight medical examination for military flying
      duties. Physical fitness was assessed by achieved physical working capacity at a
      heart rate of 170 beats per min (PWC170) during cycle ergometry. Parameters such
      as physical activity, endurance sports, smoking of cigarettes and drinking of
      alcoholic beverages were assessed by means of standardized questionnaires.
      Systolic and diastolic blood pressures were measured manually. Fasting
      cholesterol and triglycerides as well as white blood counts were obtained.
      RESULTS: Physical activity itself was not related to significant differences in
      the tested variables, whereas good physical fitness showed a significant
      association with improved blood pressure and blood lipids (P<0.001) with no
      detectable threshold. This effect was independent of endurance training, smoking
      and drinking. Whereas drinking was associated with elevated systolic blood
      pressure, smoking was associated with markedly increased triglycerides as well as
      with elevated leukocytes. CONCLUSION: Physical fitness is associated with
      improved blood pressure and blood lipids. This effect is independent of
      participating mainly in endurance or nonendurance sports, of physical activity
      per se, and it does not depend on smoking and drinking habits. Smoking itself
      revealed relevant higher inflammation independent of fitness.

PMID- 15179100
TI  - Does a family history of coronary heart disease modify the relationship between
      physical activity and blood pressure in young adults?
AB  - BACKGROUND: The purpose of this study was to examine the relationships between
      physical activity, a family history (FH) of coronary heart disease (CHD), and
      blood pressure (BP) in young adults. We were specifically interested in
      determining whether the relationship between moderate-to-vigorous physical
      activity and BP was modified by a FH of CHD. METHODS: Subjects were 230 (103
      males, 127 females) university students. Family history was self-reported and
      habitual physical activity was assessed with a 3-day activity diary. Indicators
      of habitual physical activity included estimated daily energy expenditure (EE)
      and EE in moderate-to-vigorous physical activity (MVPA) [median metabolic
      equivalent (MET) > or =4.8] and inactivity (IA) (MET<2.8). Blood pressure was
      measured by an automated device according to standard procedures. RESULTS: A
      large proportion of the sample (63% of males and 68% of females) reported a FH of
      CHD. In general, correlations between physical activity and BP were low (r<0.30),
      but in the expected direction (i.e., positive for IA and negative for MVPA and
      EE). In males IA was significantly related to BP (r =0.25-0.29), but MVPA was not
      significantly related to BP (r= -0.01 to -0.16). In females diastolic BP was
      significantly related to IA (r= -0.21) and total EE (r= -0.18). Total EE was
      significantly correlated to DBP (r= -0.22) in males and to mean arterial pressure
      (r= -0.18) in females. No significant differences in BP were found between
      subjects with or without a FH of CHD. Slightly stronger correlations emerged
      between MVPA and BP for subjects with a negative FH of CHD compared to those with
      a positive FH of CHD. CONCLUSION: These data show a significant association
      between sedentary behavior and blood pressure in young adults. It is suggestive
      that the magnitude of the relationship between MVPA and BP may be modified by a
      FH of CHD. Thus, individuals with a FH of CHD may not be as responsive to
      increased levels of MVPA compared to those without a FH of CHD.

PMID- 15179101
TI  - Microalbuminuria, cardiovascular risk factors and cardiovascular morbidity in a
      British population: the EPIC-Norfolk population-based study.
AB  - BACKGROUND: Microalbuminuria is independently associated with increased
      cardiovascular risk and renal function deterioration in diabetes and
      hypertension, but the clinical relevance of raised albuminuria in the general
      population is less certain. We examined the prevalence of microalbuminuria and
      its relationship to cardiovascular risk factors and cardiovascular morbidity in
      the UK general population. METHODS: Cross-sectional population-based study of
      23,964 individuals, aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk
      Study. Smoking status, prevalent physician diagnosed diabetes, hypertension,
      cardiovascular disease and cancer were derived from a health and lifestyle
      questionnaire. Albumin-to-creatinine ratios were estimated from random spot urine
      specimens collected at the survey visit, and using these ratios participants were
      categorized into normoalbuminuria, microalbuminuria (2.5-25 mg/mmol), and
      macroalbuminuria. RESULTS: The prevalence of microalbuminuria and
      macroalbuminuria was 11.8% and 0.9% respectively in the total population and
      significantly higher in women (14.4%) compared with men (8.9%) (P<0.001).
      Independent determinants of microalbuminuria were age, sex, systolic blood
      pressure and current smoking. Microalbuminuria was independently associated with
      cardiovascular morbidity, after adjusting for known cardiovascular risk factors,
      with odds ratio (95% confidence interval) for prevalent cardiovascular disease of
      1.30 (1.12-1.51) in all men and women. CONCLUSION: Microalbuminuria was present
      in approximately 12% of this population. It was independently associated with
      cardiovascular risk factors and prevalent cardiovascular disease.
      Microalbuminuria may be a useful indicator of high absolute cardiovascular risk
      in the community but prospective data are needed to establish its independent
      predictive value for future events.

PMID- 15179102
TI  - Monocyte cytokine production, systemic inflammation and cardiovascular disease in
      very elderly men and women: the Framingham Heart Study.
AB  - In very elderly participants of the Framingham Heart Study (mean age 79 years,
      276 men and 462 women), interleukin-6 correlated with C-reactive protein (CRP)
      levels. Interleukin-6, tumour necrosis factor alpha and interleukin-1 production,
      and CRP were not associated with prevalent cardiovascular disease, and
      nonsteroidal anti-inflammatory drug use did not influence cytokine or CRP levels.
      Further studies are warranted to examine the prognostic implications of CRP and
      related cytokines for CVD in the elderly.

PMID- 15179103
TI  - High intensity aerobic interval exercise is superior to moderate intensity
      exercise for increasing aerobic capacity in patients with coronary artery
      disease.
AB  - BACKGROUND: Increased aerobic exercise capacity appears to reduce both all-cause
      mortality and cardiovascular disease mortality. Physical exercise to improve peak
      oxygen uptake (VO2peak) is thus strongly recommended, however evidence regarding
      the most efficient training intensity for patients with coronary artery disease
      (CAD) is still lacking. The purpose of this randomized study was therefore to
      assess the effects of high intensity aerobic interval exercise compared to
      moderate intensity exercise, representing the same total training load, for
      increasing VO2peak in stable CAD-patients. METHODS: Twenty-one stable CAD
      patients were randomized to supervised treadmill walking at either high intensity
      (80-90% of VO2peak) or moderate intensity (50-60% of VO2peak) three times a week
      for 10 weeks. RESULTS: After training VO2peak increased by 17.9% (P=0.012) in the
      high intensity group and 7.9% (P=0.038) in the moderate intensity group. The
      training-induced adaptation was significantly higher in the high intensity group
      (P=0.011). CONCLUSIONS: High intensity aerobic interval exercise is superior to
      moderate exercise for increasing VO2peak in stable CAD-patients. As VO2peak seems
      to reflect a continuum between health and cardiovascular disease and death, the
      present data may be useful in designing effective training programmes for
      improved health in the future.

PMID- 15179104
TI  - Impact of a correct breathing stereotype on pulmonary minute ventilation, blood
      gases and acid-base balance in post-myocardial infarction patients.
AB  - STUDY OBJECTIVE: The aim of the study was to evaluate the impact of a long-term
      (6-month) correct breathing stereotype on minute ventilation, capillary blood
      gases and acid-base balance in post-myocardial infarction patients. METHODS:
      Fifty-five men (age 57.2 +/- 12.5) were examined 2 months later after myocardial
      infarction. Spirometry and assessment of acid-base balance and capillary blood
      gases were performed at rest and repeated after 10 days and 6 months. Breathing
      correction was taught over 5 days. A session for the control and maintenance of
      the correct breathing skills was hosted once a month (during the 6-month period).
      RESULTS: Changes of minute ventilation, capillary blood gases and acid-base
      balance were revealed in 55% of patients 2 months later after myocardial
      infarction. Twenty patients (group I) were randomly selected for breathing
      correction while 10 patients made up the control group (group II). After
      breathing correction minute ventilation significantly decreased (18.5 +/- 5.5
      versus 9.8 +/- 2.5 l/min), oxygen ventilatory equivalent decreased (39.8 +/- 5.2
      versus 22.5 +/- 3.8), partial pressure of blood carbon dioxide increased (33.2 +/
      1.7 versus 44.2 +/- 2.5 mmHg), plasma bicarbonate concentration augmented (19.1
      +/- 2.2 versus 24.5 +/- 1.8 mmol/l), base excess normalized (-2.90 +/- 2.5 versus
      +1.3 +/- 2.1 mmol/l), and pH shifted to more alkaline value (7.36 +/- 0.01 versus
      7.43 +/- 0.02). CONCLUSIONS: A long-term correct breathing stereotype improved
      respiratory function and could be an additional measure in rehabilitation
      programmes for post-myocardial infarction patients.

PMID- 15179105
TI  - Heart rate variability decreased by coronary artery surgery has no prognostic
      value.
AB  - BACKGROUND: Decreased heart rate variability (HRV) may predict cardiac death
      after myocardial infarction (MI). Coronary artery bypass grafting (CABG) strongly
      decreases HRV, but improves survival. The aim of the study was to determine the
      prognostic value of HRV decreased by coronary surgery. DESIGN AND METHODS: Four
      year follow-up was performed in 175 consecutive patients with HRV decreased by
      CABG (51) or MI (124). Mortality and secondary events rate were analysed.
      Decreased HRV, defined by the standard deviation of mean RR interval (SDNN) < 100
      ms, was detected by a routine 24-h Holter electrocardiogram at admission to
      stationary rehabilitation 3 weeks to 3 months after acute MI or CABG. Two groups
      did not differ except by age; CABG patients were younger (56 versus 64 years,
      P<0.01), but this did not influence differences in survival (NS). RESULTS: HRV
      was lower among CABG patients than among MI patients (SDNN=66 +/- 20 ms versus 77
      +/- 14 ms; P<0.001), but cumulative survival and event-free survival were much
      better in the CABG group than in the MI group. During a 46 +/- 20 months follow
      up, there were 10% new events in the CABG and 43% in the MI group (P<0.001).
      Mortality was 8% in the CABG and 33% in the MI group (log-rank=3.6; P<0.001).
      Unlike in the MI group, HRV was not different between survivors and non-survivors
      in the CABG group. CONCLUSIONS: In contrast to the strong prognostic potential of
      HRV in patients with MI, decreased HRV has no prognostic significance in patients
      who have undergone CABG surgery.

PMID- 15179106
TI  - How general practitioners perceive and grade the cardiovascular risk of their
      patients.
AB  - BACKGROUND: Although risk assessment charts have been proposed to identify
      patients at high cardiovascular risk, in everyday practice general practitioners
      (GPs) often use their knowledge of the patients to estimate the risk
      subjectively. DESIGN: A cross-sectional study aimed to describe how GPs perceive,
      qualify and grade cardiovascular risk in everyday practice. METHODS: General
      practitioners had to identify in a random sample of 10% of their contacts the
      first 20 consecutive patients perceived as being at cardiovascular risk. For each
      patient essential data were collected on clinical history, physical examination
      and laboratory tests, for the qualification of risk. At the end of the process
      GPs subjectively estimated the overall patient's level of risk. General
      practitioners grading was compared with the risk estimate from a reference chart.
      RESULTS: Over a mean time of 25 days 3120 patients perceived as being at
      cardiovascular risk were enrolled. According to the inclusion scheme each GP had
      contact with more than 200 patients at cardiovascular risk every month. Thirty
      percent of these patients had atherosclerotic diseases. Up to 72% of patients
      without any history of atherosclerotic diseases but perceived to be at risk could
      be classified according to a reference chart as being at moderate to very high
      risk. Comparing GPs' grading of risk with a chart estimate there was agreement in
      42% of the cases. Major determinants of GPs' underestimation of risk were age,
      sex and smoking habits, while obesity and family history were independently
      associated with overestimation. CONCLUSIONS: On the basis of their perception GPs
      properly identify patients at cardiovascular risk in the majority of cases.
      General practitioners subjective grading of risk level only partially agreed with
      that given by a chart.

PMID- 15179107
TI  - No long-term psychological reaction to information about increased risk of
      coronary heart disease in general practice.
AB  - BACKGROUND: Randomised, controlled trials focusing on long-term psychological
      reactions to information about increased risk of coronary heart disease are
      scarce. DESIGN: A population-based randomised, controlled, 5-year follow-up trial
      was conducted in general practice. METHODS: In 1991, invitations were sent to
      2,000 middle-aged people registered in the general practices in the district of
      Ebeltoft, Denmark. A total of 1,507 (75.4%) agreed to participate and were
      randomised into a control group and two intervention groups: one included health
      screening, a written feedback and an optional follow-up visit with the general
      practitioner; the other included health screening, written feedback and a planned
      45-min follow-up visit with the general practitioner. The participants were
      informed at screening about their risk of developing coronary heart disease.
      Psychological distress was measured by the GHQ-12 before screening and at the 1
      and the 5-year follow-up. RESULTS: Before the screening (0 year), 1 and 5 years
      after there were no significant differences in the GHQ-12 score between the
      control group and the two intervention groups. Nor were there any differences
      related to information about increased risk of coronary heart disease between
      scores obtained at the 1 and the 5-year follow-up. CONCLUSION: Middle-aged
      persons had no long-term psychological reaction after information about increased
      risk of developing coronary heart disease following a health screening in general
      practice evaluated by the GHQ-12, 1 year and 5 years after the examinations.

PMID- 15179108
TI  - Fibrate treatment and prevalence risk of mild hyperhomocysteinaemia in clinical
      coronary heart disease patients.
AB  - BACKGROUND: Several prospective studies reported that fibrates might increase
      blood total homocysteine (tHcy). In this study we aimed to establish whether the
      reported fibrate treatment was associated with an increased risk of mild
      hyperhomocysteinaemia in patients with clinical coronary heart disease, and to
      establish whether confounding variables may influence this effect. DESIGN: A
      retrospective, case-control analysis. METHODS: A total of 410 patients, 301 males
      and 109 females, mean age 59.2 were examined in a Czech sample from the
      EUROASPIRE II survey. In addition to examinations and measurements, defined by
      the protocol, we estimated serum total homocysteine (tHcy), folate, B12 vitamin
      and methylenetetrahydrofolate reductase (MTHFR) genotypes. RESULTS: We found
      significantly higher tHcy concentrations in patients with reported treatment with
      fibrate (16.6 +.- 0.66 micromol/l) compared with no lipid-lowering treatment
      (13.5 +/- 0.64 micromol/l, P<0.001) or to statin (12.4 +/- 0.39 micromol/l,
      P<0.001). Concentrations of tHcy > or =15 mmol/l (i.e. mild
      hyperhomocysteinaemia) as a dependent variable were positively associated with
      age (OR 1.18, P<0.0003), serum vitamin B12 (OR 0.87, P<0.003), serum creatinine
      (OR 1.35, P<0.0001 and treatment with fibrates (OR 1.30, P<0.0001), using
      multiple regression. Using unifactorial or multifactorial analyses, association
      between fibrate and tHcy is independent from conventional confounders such as
      age, gender, smoking, folate or B12 concentration, serum creatinine and MTHFR
      genotypes, however interference of low folate or B12 and fibrate treatment
      resulted in concentrations of tHcy more than 20 micromol/l. CONCLUSIONS: Fibrate
      treatment was associated with a significant increase in prevalence of the risk of
      mild hyperhomocysteinaemia in coronary patients, independently from conventional
      confounders.

PMID- 15179109
TI  - The dose-response relation between serum homocysteine and cardiovascular disease:
      implications for treatment and screening.
AB  - BACKGROUND: With the recognition that serum homocysteine may cause cardiovascular
      disease there is clinical interest in homocysteine measurement to guide treatment
      with folic acid. It is uncertain whether treatment is best directed at those with
      high homocysteine or those at high risk irrespective of initial homocysteine.
      DESIGN AND METHODS: Dose-response plots of the associations between serum
      homocysteine and ischaemic heart disease and deep vein thrombosis were determined
      from retrospective (case-control) studies (a meta-analysis of 12 age-matched
      studies) prospective studies and studies of the C677T MTHFR polymorphism (a
      comparison of risk in three genotypes in a meta-analysis of 72 studies). The
      value of serum homocysteine as a screening test was assessed from distributions
      of serum homocysteine in men who did and did not die from ischaemic heart disease
      in a large prospective study. RESULTS: There were straight-line relationships
      between serum homocysteine and disease events in the three types of study; a
      given decrease in homocysteine would produce a similar proportional risk
      reduction from any pre-treatment level. There was substantial overlap between the
      distributions of serum homocysteine in men who did and did not die of ischaemic
      heart disease, indicating poor screening performance; there was no serum
      homocysteine cut-off that concentrated the majority of disease events into a
      small minority of the population. CONCLUSION: Interventions to lower serum
      homocysteine, if judged to be worthwhile, should not be limited to people with a
      high homocysteine but should be offered to everyone at high risk, regardless of
      pre-treatment homocysteine.

PMID- 15179111
TI  - Head shadow, squelch, and summation effects in bilateral users of the MED-EL
      COMBI 40/40+ cochlear implant.
AB  - OBJECTIVE: The aim of the study was to investigate the impact of bilateral
      cochlear implant use on speech perception in noise in bilateral users of the MED
      EL COMBI 40/40+ cochlear implants. DESIGN: Speech reception thresholds were
      measured in 21 subjects using the Oldenburg sentence test. Speech was always
      presented from the front. Noise was either presented from the front, from the
      left side, or from the right side. Each condition was measured for unilateral and
      bilateral implant use. RESULTS: For three subjects, the test was too difficult to
      be administered. The 18 subjects from whom a complete data set could be obtained
      showed a significant head shadow effect and summation effect for all test
      conditions, whereas the squelch effect was significant for noise from the left
      side only. Average effect sizes were significant for all effects and amounted to
      6.8 dB for the head shadow effect, 0.9 dB for the squelch effect, and 2.1 dB for
      the summation effect. Effect sizes were not correlated with duration of deafness.
      CONCLUSIONS: Bilateral cochlear implant users can at least qualitatively benefit
      from the effects that are known from normal-hearing subjects, that is, head
      shadow, summation, and squelch effect. Bilateral cochlear implantation also
      reduces the performance gap between cochlear implant users and normal-hearing
      subjects.

PMID- 15179112
TI  - Sound localization in bilateral users of MED-EL COMBI 40/40+ cochlear implants.
AB  - OBJECTIVE: The purpose of the study was to investigate sound localization with
      bilateral and unilateral cochlear implants. DESIGN: Sound localization tests were
      performed on 20 bilaterally implanted MED-EL COMBI 40/40+ users. All subjects
      were bilaterally implanted during adolescence or later. Sound localization was
      tested in the frontal horizontal plane by using 9 equally spaced loudspeakers and
      speech-shaped noise bursts at randomized levels. RESULTS: The group of subjects
      who were bilaterally deafened after 5 to 6 yr of age (18 subjects) showed a
      statistically significant improvement in sound localization when using both
      implants, compared with when using only one. The mean deviation between the
      presentation azimuth and the response azimuth was 16.6 degrees when using both
      implants, which was on average 37.1 degrees smaller than when using one implant
      only. When adjusted for the localization error that was constant across
      loudspeakers, the mean deviation was 15.9 degrees for bilateral implant use,
      representing an improvement of 30.1 degrees over unilateral implant use.
      Statistical analysis showed that in this group, performance measures were not
      correlated with subject details such as age at onset of deafness or duration of
      unilateral implant use. In contrast, subjects who were bilaterally deafened
      before 6 yr of age (2 subjects) did not show a benefit in sound localization from
      bilateral implants. CONCLUSIONS: Bilateral cochlear implants offer a substantial
      benefit in sound localization to late-deafened, late-implanted subjects. The very
      limited data from early-deafened subjects implanted at a later age could suggest
      that these subjects may not benefit in sound localization from bilateral cochlear
      implants. It is possible that early implantation for early deafened subjects
      might allow better acquisition of spatial hearing, thus leading to improved
      localization performance.

PMID- 15179113
TI  - Noise reduction results of an adaptive filtering technique for dual-microphone
      behind-the-ear hearing aids.
AB  - OBJECTIVE: The performance of an adaptive beam-former in a 2-microphone, behind
      the-ear hearing aid for speech understanding in noisy environments was evaluated.
      Physical and perceptual evaluations were carried out. This was the first large
      scale test of a wearable real-time implementation of this algorithm. The main
      perceptual research questions of this study were related to the influence on the
      noise reduction performance of (1) the spectro-temporal character of the jammer
      sound, (2) the jammer sound scene, (3) hearing impairment, and (4) the basic
      microphone configuration in the hearing aid. Four different speech materials were
      used for the perceptual evaluations. All tests were carried out in an acoustical
      environment comparable to living room reverberation. DESIGN: The adaptive
      beamformer was implemented in Audallion, a small, body-worn processor, linked to
      a Danasound 2-microphone behind-the-ear aid. The strategy was evaluated
      physically in different acoustical environments. Using speech reception threshold
      (SRT) measurements, the processing was evaluated perceptually and the different
      research questions addressed with three groups of subjects. Groups I, II, and III
      consisted of 10 normal-hearing, 5 hearing-impaired, and 7 normal-hearing persons,
      respectively. The tests were carried out in three spectro-temporally different
      jammer sounds (unmodulated and modulated speech weighted noise, multitalker
      babble) and in three different noise scenarios (single noise source at 90
      degrees, noise sources at 90 degrees and 270 degrees relative to speaker
      position, diffuse noise scene). Two microphone configurations were compared: a
      device equipped with two omnidirectional microphones and a device equipped with
      one hardware directional and one omnidirectional microphone. In each of these
      conditions, the adaptive beamformer and the directional and omnidirectional
      microphone configurations were tested. RESULTS: The improvement in signal-to
      noise ratio from the use of the adaptive beamformer did not depend on the spectro
      temporal character of the jammer sounds and the speech materials used, although
      the absolute levels of the SRTs varied appreciably for different speech-noise
      combinations. The performance of the adaptive noise reduction depended on the
      jammer sound scene. CONCLUSIONS: No difference in signal-to-noise ratio
      improvement was observed between hearing-impaired and normal-hearing listeners,
      although individual SRT levels may differ. On average, an SRT improvement of 7.7
      and 3.9 dB for a single noise source at 90 degrees and 5.9 and 3.4 dB for two
      noise sources at 90 degrees and 270 degrees was obtained for both normal-hearing
      and hearing-impaired listeners, using the adaptive beamformer and the directional
      microphone, respectively, relative to the omnidirectional microphone signal. In
      diffuse noise, only small improvements were obtained.

PMID- 15179114
TI  - Optimizing dynamic range in children using the nucleus cochlear implant.
AB  - OBJECTIVE: The aim of this study was to investigate the benefits of the
      preprocessing scheme "Adaptive Dynamic Range Optimization" (ADRO) in children
      using Nucleus cochlear implants. Previous research with adults indicates improved
      speech perception in quiet and improved sound quality in everyday listening
      environments with the ADRO scheme. DESIGN: Children were given 4 wk of take-home
      experience with ADRO, with a minimum of 2 wk in which ADRO was "locked-in." After
      1 wk of ADRO use and again after 4 wk of ADRO use, Bench-Kowal-Bamford (BKB)
      sentence perception in quiet at a low input level of 50 dB SPL (unweighted root
      mean square) and sentence perception in noise were compared with the child's
      everyday (Standard) program and the ADRO program. Children also rated the
      loudness of a variety of environmental sounds and indicated which program
      provided the best hearing in a variety of everyday listening situations. RESULTS:
      On average, BKB sentence perception in quiet at 50 dB SPL was significantly
      better with the ADRO program compared with the Standard program. The group mean
      improvement was 8.60%. Similarly, group mean scores for BKB sentences presented
      at 65 dB SPL in multitalker babble were significantly higher with the ADRO
      program (an improvement of 6.87%). The ADRO program was the preferred program in
      46% of the listening situations, whereas the Standard program was preferred in
      26% of situations. Everyday sounds were not unacceptably loud with ADRO.
      CONCLUSIONS: There was an ADRO benefit for this group of children in quiet and in
      noise. These findings suggest that young children would benefit from the ADRO
      programming option being locked in along with other processor settings in the
      SPrint processor once their MAP levels have stabilized. Some older children and
      teenagers may choose to use ADRO selectively for specific listening situations.

PMID- 15179115
TI  - Temporal fine-structure cues to speech and pure tone modulation in observers with
      sensorineural hearing loss.
AB  - OBJECTIVE: The purpose of this study was to examine the effect of sensorineural
      hearing loss on the ability to make use of fine temporal information and to
      evaluate the relation between this ability and the ability to recognize speech.
      DESIGN: Fourteen observers with normal hearing and 12 observers with
      sensorineural hearing loss were tested on open-set word recognition and on
      psychophysical tasks thought to reflect use of fine-structure cues: the detection
      of 2 Hz frequency modulation (FM) and the discrimination of the rate of amplitude
      modulation (AM) and quasifrequency modulation (QFM). RESULTS: The results showed
      relatively poor performance for observers with sensorineural hearing loss on both
      the speech recognition and psychoacoustical tasks. Of particular interest was the
      finding of significant correlations within the hearing-loss group between speech
      recognition performance and the psychoacoustical tasks based on frequency
      modulation, which are thought to reflect the quality of the coding of temporal
      fine structure. CONCLUSIONS: These results suggest that sensorineural hearing
      loss may be associated with a reduced ability to use fine temporal information
      that is coded by neural phase-locking to stimulus fine-structure and that this
      may contribute to poor speech recognition performance and to poor performance on
      psychoacoustical tasks that depend on temporal fine structure.

PMID- 15179116
TI  - Perception and production of mandarin tones in prelingually deaf children with
      cochlear implants.
AB  - OBJECTIVE: Mandarin is a lexical tone language in which four tones are crucial
      for determining lexical meanings. Acquisition of such a tone system may be
      challenging to prelingually deaf children with cochlear implants because, as
      recent studies have shown, cochlear implant devices are ineffective in encoding
      voice pitch information required for tone recognition. This study aimed to
      investigate Mandarin tone production and perception skills of children with
      cochlear implants. DESIGN: Thirty prelingually deaf children with cochlear
      implants, ages 6;0 (yr;mo) to 12;6, participated. These children received their
      implants at an average age of 5;8, with a range from 2;3 to 10;3. The average
      length of their cochlear implant experience was 3;7, with a range from 1;7 to
      6;5. Tasks of tone production and tone identification involved a pictorial
      protocol of 48 words containing the targeted tones in either monosyllabic or
      disyllabic forms. RESULTS: The average scores for tone production was 53.09% (SD
      = 15.42), and for tone identification was 72.88% (SD = 19.68; chance level =
      50%). Significant differences were found in the percentages across the production
      or identification of tone types or tone pairs. The children with exceptional
      performance in tone production tended to also perform well in tone
      identification. The children's performance levels in tone identification and
      production were also discussed in relation to the factors of age at implantation
      and length of cochlear implant experience. CONCLUSIONS: The present results
      suggest that the majority of prelingually deaf children with cochlear implants
      did not master Mandarin tone production. However, a small group of participants
      demonstrated nearly perfect skills of Mandarin tone production in addition to
      tone perception. Thus, it is necessary to consider factors other than the
      device's limitations to explain these high levels of performance in the
      perception and production of Mandarin lexical tones.

PMID- 15179117
TI  - Development of auditory sensitivity in children who stutter and fluent children.
AB  - OBJECTIVE: The purpose of this study was to establish whether there are any
      differential changes in auditory sensitivity over ages in a variety of peripheral
      and central auditory tasks between participants who stutter and participants who
      do not stutter. DESIGN: The auditory sensitivity of 37 participants who stutter
      and 44 participants who do not stutter, ages between 8 and 19 yr, assigned to
      three age categories, were obtained in five listening conditions: Pure tone
      threshold, simultaneous masking, backward masking, notched backward masking, and
      simple dichotic (simultaneous) masking. RESULTS: Across all listening conditions
      and both talker groups, thresholds decreased over age. The thresholds of
      participants who do not stutter decreased for simultaneous, backward, and notched
      backward masking conditions over the 8- to 19-year age range. Analysis of each
      condition only showed significant improvement over age groups for backward
      masking for the participants who stutter. CONCLUSIONS: These results indicate
      that auditory sensitivity for sounds in noise continues to develop through to
      teenage, and a different pattern of auditory development exists for the
      participants who stutter compared with participants who do not stutter.

PMID- 15179118
TI  - Pitch ranking with deeply inserted electrode arrays.
AB  - OBJECTIVE: Electrode pitch ranking was assessed as a function of cochlear region,
      electrode spacing, and stimulation rate in eight subjects implanted with the MED
      EL COMBI 40+ implant. The MED-EL COMBI 40+ electrode array allows deep insertion
      of the electrode up to the apex of the cochlea and provides a wide electrode
      spacing of 2.4 mm. DESIGN: The pitch of a reference electrode was compared with
      the pitch of two apical and two basal probe electrodes using a two-alternative
      forced-choice procedure. The reference electrodes were placed in the apical
      region, in the middle region, and in the basal region of the cochlea. Each
      condition was tested at pulse rates of 1515 pps, 500 pps, and 250 pps. RESULTS:
      Electrode pitch ranking did not depend on electrode spacing, the position of the
      reference electrode in the cochlea, or stimulation rate. CONCLUSIONS: These
      results indicate that a spacing of 2.4 mm seems sufficient to allow good
      electrode pitch ranking performance for the average user and that electrode pitch
      ranking is similar in the apical, middle, and basal region of the cochlea,
      irrespective of the stimulation rate. Most importantly, the results of this study
      indicate that residual neural structures in the apical region of the cochlea are
      sensitive to pitch changes provided by different places of electrical
      stimulation.

PMID- 15179119
TI  - Automatic auditory processing of english words as indexed by the mismatch
      negativity, using a multiple deviant paradigm.
AB  - OBJECTIVE: The aim of this study was to investigate mismatch negativity (MMN)
      responses to a variety of speech stimuli (/de:/, /ge:/, /deI/ "day", and /geI/
      "gay") in a multiple deviant paradigm. It was hypothesized that all speech
      stimulus contrasts in the multiple deviant paradigm, including the fine acoustic
      speech contrast [d/g], would elicit robust MMN responses and that consonant vowel
      (CV) real word deviants (e.g., "day" and "gay") would elicit larger MMN responses
      than CV nonword deviants (e.g., "de" and "ge") within and across experimental
      contrasts. DESIGN: Ten healthy, right-handed, native English-speaking adults
      (23.4 +/- 2.27 yr) with normal hearing were presented with 12 blocks of stimuli,
      using a multiple deviant oddball paradigm. Each of the four speech stimuli were
      presented as standards (p = 0.7) in three blocks, with the remaining stimuli
      acting as deviants (p = 0.1 each). Subjects were also presented with the same
      stimuli in a behavioral discrimination task. RESULTS: MMN responses to the fine
      acoustic speech contrast [d/g] (e.g., "de" versus "ge", "day" versus "gay") did
      not reach significance. However, a significant and larger MMN response was
      obtained at an earlier latency to the real word deviants among nonword standards
      with the same initial consonant (i.e., de-->day, ge-->gay) when compared with the
      responses to nonword deviants among word standards (day-->de, gay-->ge).
      CONCLUSIONS: The results showed that MMN responses could be elicited by speech
      stimuli with large, single acoustic deviances, within a multiple deviant paradigm
      design. This result has positive clinical implications for the testing of
      subjects who may only tolerate short testing sessions (e.g., pathological
      populations) in that responses to a wider range of speech stimuli may be recorded
      without necessarily having to increase session length. The results also
      demonstrated that MMN responses were elicited by large, single acoustic deviances
      but not fine acoustic deviances within the speech stimuli. The poor results for
      the fine acoustic deviances support previous studies that have used single
      contrast paradigms and found that when carefully controlled methodological
      designs and strict methods of analysis are applied, robust responses to fine
      grained CV syllable contrasts may be difficult to obtain. The enhanced MMN
      observed in response to the real word deviants among nonword standards may
      provide further evidence for the presence of long-term neural traces for words in
      the brain, however possible contextual effects limit the interpretation of these
      data. Further research is needed to investigate the ability of the MMN response
      to accurately reflect speech sounds with fine acoustic contrasts, as well as the
      ability of the MMN to reflect neural traces for words in the brain, before it can
      be reliably used as a clinical tool in the investigation of spoken word
      processing in pathological populations.

PMID- 15179121
TI  - Recurrent and refractory angina following revascularization procedures in
      patients with stable angina pectoris.

PMID- 15179122
TI  - Medical versus interventional management of stable angina.
AB  - Several randomized trials have been performed comparing medical management with
      surgery, medical management with angioplasty, and angioplasty with surgery for
      patients with stable angina. They were conducted in parallel with the progress of
      the revascularization techniques and as such, each of them reflects the
      prevailing practice of its time. Percutaneous revascularization and, to a lesser
      extent, coronary surgery have been, and it seems they will continue to be,
      rapidly evolving specialities. Medical management has also improved and future
      advances are likely to occur. One of the most remarkable advances in medical
      management is a new concept in metabolic approach in the treatment of angina
      pectoris. Despite the complexity of drawing conclusions from trials that compared
      approaches already outperformed in current practice, in this paper we review the
      relevant literature in an attempt to outline the comparative efficacy of the
      available treatment strategies.

PMID- 15179120
TI  - Determining the upper limits of stimulation for auditory steady-state response
      measurements.
AB  - OBJECTIVE: To determine the maximum stimulus levels at which a measured auditory
      steady-state response (ASSR) can be assumed to be a reliable measure of auditory
      thresholds. DESIGN: ASSR thresholds were measured at octave frequencies from 500
      to 4000 Hz in 10 subjects with profound hearing loss. These subjects provided no
      behavioral responses to sound at the limits of pure-tone audiometers and at the
      limits of the stimulus levels produced by the ASSR device. Subjects were divided
      into two groups of five, with repeated measures obtained within the same session
      in one group and repeated measures obtained in a separate session on a different
      day in the other group. RESULTS: ASSR thresholds were observed in all 10 subjects
      at each of four frequencies and in both trials. On average, these ASSR thresholds
      were observed at 100 dB HL (SD = 5 dB). Because these responses were at least 18
      to 22 dB below the limits of the equipment where all subjects had no behavioral
      responses, it is reasonable to conclude that the ASSRs were not generated by the
      auditory system. CONCLUSIONS: An artifact or distortion may be present in the
      recording of ASSRs at high levels. These data bring into question the view that
      there is a wider dynamic range for ASSR measurements compared with auditory brain
      stem response measurements, at least with current implementation.

PMID- 15179123
TI  - Recurrent angina after revascularization: an emerging problem for the clinician.
AB  - Recurrent angina after percutaneous or surgical coronary procedures may occur as
      a consequence of several potential causes, such as bypass graft failure,
      restenosis, or atherosclerotic disease progression. Repeat invasive procedures
      are frequently performed for patients with recurrent symptoms. Nevertheless, non
      invasive pharmacological treatment to decrease disease progression or reduce
      anginal symptoms are an integral part of the management of the patients. New
      metabolic modulators such as trimetazidine may constitute important therapeutic
      agents in the symptomatic control of patients with recurrent angina after
      invasive revascularization.

PMID- 15179124
TI  - Clinical benefits of trimetazidine in patients with recurrent angina.
AB  - In clinical practice there is a major problem with angina, which is resistant to
      medical therapy with hemodynamically acting agents. In that group of patients it
      is necessary to consider the indications for coronary angiography and
      percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass
      grafts (CABG). But some of these patients, especially those who had previous CABG
      or PTCA, coronary diabetic patients and elderly patients do not qualify for
      revascularization procedures. In patients with recurrent angina the beneficial
      effect of trimetazidine, a metabolic agent, that shifts cardiac energy metabolism
      from fatty acid oxidation to glucose oxidation was demonstrated. In the TRIMPOL
      II analysis of subgroup of post-revascularized patients with recurrent angina was
      demonstrated the improvement in exercise treadmill test parameters and clinical
      symptoms in a group treated with trimetazidine added to preexisting monotherapy
      with metoprolol in comparison with placebo plus metoprolol. The time to 1 mm ST
      segment depression was increased with trimetazidine by 80s and was significantly
      greater than that recorded in the placebo group (465+/-143.8s vs 385.1+/-144.6s,
      P<0.01). The time to onset of angina was significantly greater for the group
      treated with trimetazidine in comparison with placebo (508.1+/-132.4 vs 433.6+/
      164s, P=0.031). The total duration of exercise was significantly greater than
      that recorded for patients with placebo plus metoprolol (524.4+/-131.5 vs 466.9+/
      144.8, P=0.048). A similarly significant observation was made regarding workload
      (10.1+/-2.4 vs 9+/-2.4 METs, P=0.035). The maximum ST-segment depression at peak
      exercise was significantly smaller in the trimetazidine group than in placebo
      group (1.4+/-0.8 vs 1.8+/-0.7 mm, P<0.01). The mean number of angina attacks per
      week was 1.7+/-2.3 for patients in the trimetazidine treated group, as compared
      with 3.1+/-2.9 for patients receiving placebo (P<0.01). The rate-pressure product
      at peak of exercise remained unchanged. The results suggest the rationale for
      metabolic therapy in post-revascularized patients with recurrent angina. Because
      no influence on heart rhythm, blood pressure, blood glucose level and excellent
      tolerability, trimetazidine may be also especially recommended for elderly and
      coronary diabetic patients, especially those with impaired left ventricular
      function.

PMID- 15179125
TI  - Recurrent and resistant angina: is the metabolic approach an appropriate answer?
AB  - Chronic stable angina is the first manifestation of ischemic heart disease in one
      half of patients; in the United States, the annual incidence of angina in 213 of
      1000 of the population is over 30 years of age. The morbidity associated with
      ischemic heart disease is considerable: each years millions of patients have an
      MI, or are hospitalised for unstable angina. In recent years less attention has
      been paid to chronic ischemic syndrome; a possible explanation is that most
      patients with angina, refractory to medical treatment, are referred for
      myocardial revascularization in order to improve symptoms and to prevent death
      and myocardial infarction. Unfortunately available data do not support this
      common belief. The current evidence allows us to conclude that percutaneous
      transluminal coronary angioplasty (PTCA) in chronic coronary artery disease does
      not reduce the rate of subsequent MI or mortality and that PTCA results in
      superior symptomatic relief of angina and improved exercise tolerance compared
      with medical therapy, but the difference narrows with time. Several mechanisms
      may be considered to explain the persistence of angina/ischemia after a
      revascularization procedure, including incomplete revascularization, graft/PTCA
      failure, and disease progression in native coronary arteries. Microvascular
      dysfunction may play a prominent role in the unexpected prevalence of angina
      after the removal of obstructions in the major coronary branches. A better
      understanding of the metabolism derangements associated with ischemia and
      reperfusion allowed the development of new pharmacological approaches. In
      contrast to classic "hemodynamic" agents, metabolic agents have no hemodynamic,
      inotropic or chronotropic effect and interfere with cardiac energy metabolism.

PMID- 15179127
TI  - Transfusion of the injured patient: proceed with caution.
AB  - Transfusion of the injured patient with packed red blood cells (PRBCs) is a
      dynamic process requiring vigilance during the acute resuscitative and recovery
      phases postinjury. Although adverse events have been reported in 2% to 10% of
      injured patients, the advent of new detection techniques for viral pathogens has
      markedly decreased the risk of infectious transmission. However, transfusions are
      strongly associated with immunosuppression in the host, which may occur days
      after the initial injury and may lead to bacterial infections. Conversely, early
      transfusion of stored PRBCs, > 6 units in the first 12 h postinjury, contributes
      to an early state of hyperinflammation that is a strong, independent predictor of
      multiple organ failure (MOF) in those patients with intermediate injury severity
      scores. The roles of prestorage leukoreduction are also reviewed with respect to
      the promotion of both immunosuppression and hyperinflammation. We further
      summarize studies with hemoglobin substitutes, whose use may obviate many of the
      untoward events of transfusion and promise to lead to better outcomes for injured
      patients.

PMID- 15179129
TI  - Association of interleukin-10 promoter polymorphism with the incidence of
      multiple organ dysfunction following major trauma: results of a prospective pilot
      study.
AB  - A dysbalanced immune response is thought to account for a substantial part of the
      morbidity and mortality after severe trauma. The cytokine interleukin-10 (IL-10)
      suppresses the transcription of proinflammatory cytokines, mainly in macrophages
      and monocytes. The objectives of this prospective study in a level I trauma
      center in Germany were to examine the distribution of IL-10 promoter
      polymorphisms in a cohort of severely injured patients, to measure IL-10 cytokine
      levels and relate these to the genotype, and to identify associations of IL-10
      polymorphisms with the incidence of severe multiple organ dysfunction syndrome
      (MODS). The genotypes of polymorphisms -592 and -1082 were determined by
      polymerase chain reaction (PCR) and restriction cleavage with Rsa 1 or Mnl I,
      respectively. We analyzed 119 severely injured trauma patients [mean Injury
      Severity Score (ISS) 38.0 +/- 13.2]. The frequency of the -1082A allele was
      0.542, and that of the -592C allele was 0.807. IL-10 polymorphisms were not
      significantly associated with mean systemic IL-10 cytokine levels 6, 12, and 18 h
      after admission to the ICU. Carriers of the genotype -592AC had significantly
      higher overall MOD scores than non-AC carriers (P = 0.018; P(corr) = 0.036). The
      genotypes of the IL-10 SNP -1082 were not significantly associated with MOD
      scores. A multivariate Cox hazard regression analysis including important factors
      of the patients' anatomic and physiological trauma impact revealed only the shock
      index, the severity of the head injury, and the IL-10 -592 genotype AC as
      significant independent risk factors for the development of MODS. In this
      multivariate analysis, carriers of the genotype -592AC displayed a 3.3-fold
      increase in the relative risk of developing a MODS (P = 0.008, hazard ratio 3.29,
      95% CI 1.36-7.97). Our data suggest a possible link between the AC genotype of
      the -592 single nucleotide polymorphism and significantly higher mean MOD scores.
      The AC genotype was associated in multivariate analysis with a higher relative
      risk of MODS in multiply injured patients. Further investigations in larger
      cohorts need to focus on the potential diagnostic and therapeutic options of this
      SNP.

PMID- 15179128
TI  - Preload optimization using "starling curve" generation during shock
      resuscitation: can it be done?
AB  - Preload-directed resuscitation is the standard of care in U.S. trauma centers. As
      part of our standardized protocol for traumatic shock resuscitation, patients who
      do not respond to initial interventions of hemoglobin replacement and fluid
      volume loading have optimal preload determined using a standardized algorithm to
      generate a "Starling curve." We retrospectively analyzed data from 147
      consecutive resuscitation protocol patients during the 24 months ending August
      2002. Fifty (34%) of these patients required preload optimization, of which the
      optimization algorithm was completed in 36 (72%). The average age of those who
      required preload optimization was 44 +/- 3 years vs. 34 +/- 1 years for patients
      who did not. Execution of the algorithm caused PCWP to increase from 18 +/- 1
      mmHg to a maximum of 25 +/- 2 mmHg and CI to increase from 3.2 +/- 0.1 L/min m(
      2) to 4.5 +/- 0.4 L/min m(-2). Algorithm logic determined PCWP = 24 +/- 2 to be
      optimal preload at the maximum CI = 4.8 +/- 0.4, and as the volume loading
      threshold for the remaining time of the resuscitation process. Starling curve
      preload optimization was begun 6.5 +/- 0.8 h after start of the resuscitation
      protocol and required 36 +/- 5 min and 4 +/- 0.4 fluid boluses (1.6 +/- 0.2 L).
      Comparison of early response of those patients who required preload optimization
      and those who did not indicated hemodynamic compromise apparent in the 1st 4 h of
      standardized resuscitation. We conclude that preload optimization using
      sequential fluid bolus and PCWP-CI measurement to generate a Starling curve is
      feasible during ICU shock resuscitation, but that there is the disadvantage that
      increasing and maintaining high PCWP may contribute to problematic tissue edema.

PMID- 15179130
TI  - Cell adhesion molecules as a marker reflecting the reduction of endothelial
      activation induced by glucocorticoids.
AB  - In vitro, steroids down-regulate the expression of cell adhesion molecules (CAMs)
      in endothelial cells stimulated by lipopolysaccharide. Low-dose hydrocortisone is
      a new treatment of patients with septic shock, a state that is characterized by
      an endothelial injury. The aim of the present study was to investigate whether
      the plasma levels of soluble CAMs, reflecting in vivo endothelial activation,
      could be modulated in patients with septic shock treated by hydrocortisone. This
      was a prospective and observational study conducted in the intensive care unit at
      a university hospital. The subjects included 40 patients with septic shock
      (American College of Chest Physicians Consensus Conference/Society of Critical
      Care Medicine definition); 45 healthy blood donors served as controls. The
      patients receiving the standard care ("reference group") during the first 6
      months were compared with the patients receiving the hydrocortisone therapy
      ("hydrocortisone group") for the next 6 months. Measurements of sCAMs were
      performed on days 1 and 3 of the disease. On day 1, sE-selectin, sP-selectin,
      sVCAM-1, and sICAM-1 were significantly elevated in patients with septic shock
      compared with healthy donors. sE-selectin levels significantly decreased between
      days 1 and 3 in the "hydrocortisone group," whereas there was no significant
      change in the "reference group". Surprisingly, sICAM-1 levels significantly
      increased between days 1 and 3 only in patients treated by hydrocortisone. No
      significant changes were observed for sP-selectin and sVCAM-1 levels in the two
      groups. In patients with septic shock, glucocorticoids differently affected the
      pattern of evolution of sCAMs, with sE-selectin being decreased and sICAM-1 being
      increased. Expression of sP-selectin and sVCAM-1 was not affected.

PMID- 15179131
TI  - Leukocyte mitochondrial alterations after cardiac surgery involving
      cardiopulmonary bypass: clinical correlations.
AB  - Cardiac surgery with the use of cardiopulmonary bypass (CPB) is known to initiate
      systemic inflammatory responses that are associated with immune dysregulations,
      but the pathomechanisms underlying these changes remain elusive. Mitochondrial
      transmembrane potential (MTP) is an important determinant of leukocytic functions
      and viability, and may be altered as a part of the cellular responses to systemic
      inflammatory insults. Therefore, we examined MTP in three subsets of peripheral
      leukocytes in 18 patients receiving uncomplicated cardiac surgery involving CPB.
      The MTP of neutrophils and lymphocytes significantly increased, whereas that of
      monocytes significantly declined, after the surgery. The alterations in
      leukocytic MTP were transient, normalizing 3 days to 1 week after the surgery,
      and were accompanied by transient overproduction of intracellular oxidants,
      including nitric oxide and superoxide. Despite these perturbations, the viability
      status of leukocytes remained unaltered. Positive correlations were found between
      the changes of leukocyte MTP and various clinical parameters, implying that
      leukocyte mitochondrial alterations are parts of the systemic immune
      perturbations induced by the bypass surgery.

PMID- 15179132
TI  - Flow motion in the intestinal villi during hemorrhagic shock: a new method to
      characterize the microcirculatory changes.
AB  - Conventional parameters are often inadequate to describe the dynamic flow changes
      in microcirculation. We used a novel approach to characterize oscillatory flow
      conditions in a canine model of hemorrhagic shock. Microcirculation in the ileal
      mucosal villi was visualized using intravital microscopy with the orthogonal
      polarization spectral imaging technique. The distribution of red blood cell
      velocity (RBCV) was estimated from the relative time periods of observed RBCV,
      and the average RBCV (A-RBCV) and its SD were then computed from the first and
      second moments of the RBCV distribution, respectively. Hemorrhagic shock (for 60
      min) was followed by resuscitation with saline, hypertonic saline-Dextran
      solution (HSD, 7.2% NaCl-10% Dextran, 4 mL/kg), or HSD supplemented with the
      selective endothelin-A receptor antagonist ETR-p1/fl peptide (100 nmol/kg),
      respectively. The macrohemodynamic derangement (70% decrease in cardiac index and
      ileal blood flow) during shock was associated with the appearance of flow motion
      in the villi and an enhanced endothelin-1 release. The calculated A-RBCV was
      decreased by 40%. At resuscitation onset, continuous flow periods were
      transiently seen in 33%, 40%, and 50% of the experiments after saline, HSD, and
      HSD + ETR p1/fl treatment, respectively. HSD with or without endothelin-A
      antagonist treatment resulted in an increased relative duration of high-flow
      periods (by 20%) and a significant, 20% to 40% rise in A-RBCV. These results
      demonstrate that time-wise variability of RBCV should be used for the analysis of
      oscillatory flow conditions. The probabilistic estimation of A-RBCV provides a
      quantitative basis for comparison of the effectiveness of different resuscitation
      or vasoactive strategies.

PMID- 15179133
TI  - Development and characterization of a novel porcine model of neonatal sepsis.
AB  - Sepsis and its sequela remain a major source of morbidity and mortality in
      neonates despite advances in antimicrobials and aggressive supportive care. Many
      models of neonatal sepsis have been developed for investigating the
      pathophysiology of this disease and application of therapy, and a model with an
      infectious focus is closer to clinical reality. To establish an animal model that
      mimics the clinical characteristics of neonatal sepsis, the cecal
      devascularization and perforation procedure was implemented on 15 mixed-strain
      newborn piglets, which produced an infectious focus that acted as a continuous
      source of microorganisms to the peritoneal cavity. The mean survival time in
      animals with sepsis was 10.4 h (range 5.5-17.9 h), whereas all of the sham
      operated control animals survived more than 24 h. Animals with sepsis showed a
      gradual significant decrease in the mean systemic blood pressure (mSBP; 71 +/- 3
      mmHg in sepsis vs. 64 +/- 3 mmHg in control at 3 h, 38 +/- 7 mmHg in sepsis vs.
      59 +/- 4 mmHg in control at 6 h, mean +/- SEM). They also showed an increase of
      serum levels of endotoxin (5.6 x 10 +/- 4.5 x 10 pg/mL in sepsis vs. 6.0 x 10 +/-
      3.8 x 10 pg/mL in control at 6 h). Serum levels of TNF-alpha in the animals with
      sepsis became significantly higher than the control animals at 0 h (96 +/- 31
      pg/mL in sepsis vs. 12 +/- 1 pg/mL in control) and remained significantly higher
      than all through the experiment. Serum levels of IL-6 in animals with sepsis
      showed a gradual increase (484 +/- 231 pg/mL in sepsis in its peak at 6 h vs. 24
      +/- 5 pg/mL in control), however, there were no significant differences in serum
      IL-10 levels between the groups. Microorganisms detected in the blood of animals
      with sepsis were gram-negative enteric and anaerobic organisms. These results
      suggested that this model mimics the clinical state of neonatal sepsis and hence
      may have significant implications for the treatment of sepsis, including its use
      as a model in further investigations.

PMID- 15179134
TI  - Resuscitation from septic shock with capillary leakage: hydroxyethyl starch (130
      kd), but not Ringer's solution maintains plasma volume and systemic oxygenation.
AB  - There is evidence suggesting that early fluid resuscitation is beneficial in the
      treatment of septic shock. The question as to which solution should be used
      remains controversial. Using a porcine septic shock model, we tested the effects
      of a new synthetic colloid hydroxyethyl starch (HES 130 kD) and a crystalloid
      regimen with Ringer's solution (RS) on plasma volume (PV) maintenance as well as
      on systemic and regional hemodynamics. Fourteen anaesthetized mechanically
      ventilated pigs received 0.75 g kg body weight of feces into the abdominal cavity
      to induce sepsis. They were randomly allocated to receive 6% HES 130 kD (n = 5)
      or RS (n = 5) and were compared with nonseptic controls receiving 6% HES 130 kD
      (n = 4). The infusion rate was titrated to maintain a central venous pressure of
      12 mmHg. PV was determined by chromium-51-tagged erythrocytes and hematocrit.
      Albumin escape rate (AER) was calculated using iodine-125-labeled albumin.
      Arterio-intramucosal pCO2 gap, systemic hemodynamics, and oxygenation were
      obtained before and 6 h after induction of sepsis. AER increased in the HES
      (+38%) and RS groups (+38%) compared with control. PV was reduced in the RS group
      (-39%), but was maintained in the HES group (-1%). After 6 h of sepsis, HES 130
      kD-treated animals had a significantly higher cardiac output (166 +/- 28 mL min
      kg vs. 90 +/- 18 mL min kg, P < 0.05), and a significantly higher mixed-venous
      oxygen saturation (65% +/- 8% vs. 40% +/- 14%, P < 0.05) than RS animals. In this
      porcine septic shock model with concomitant capillary leakage syndrome,
      resuscitation with HES 130 kD but not RS could maintain PV and preserve systemic
      hemodynamics and oxygenation.

PMID- 15179135
TI  - High-density lipoproteins reduce the intestinal damage associated with
      ischemia/reperfusion and colitis.
AB  - High-density lipoproteins (HDLs) have been shown to reduce the organ injury and
      mortality in animal models of shock by reducing the expression of adhesion
      molecules and proinflammatory enzymes. However, there is limited evidence that
      HDL treatment reduces inflammation. As inflammation plays an important role in
      the development of colitis as well as ischemia/reperfusion (I/R) injury of the
      intestine, we have investigated the effects of HDL in animal models of associated
      with gut injury and inflammation (splanchnic artery occlusion [SAO] shock and
      dinitrobenzene sulfonic acid [DNBS]-induced colitis). We report here for the
      first time that the administration of reconstituted HDLs (recHDLs; 80 mg/kg i.v.
      bolus 30 min prior to ischemia in the SAO-shock model or 40 mg/kg i.v. every 24 h
      in the colitis model) exerts potent anti-inflammatory effects (e.g., reduced
      inflammatory cell infiltration and histological injury, and delayed the
      development of the clinical signs) in vivo. Furthermore, recHDL reduced the
      staining for nitrotyrosine and poly(ADP-ribose) (immunohistochemistry) and the
      expression of intercellular adhesion molecule-1 in the ileum of SAO-shocked rats
      and in the colon from DNBS-treated rats. Thus, recHDL reduces the inflammation
      caused by intestinal I/R and colitis. HDLs may represent a novel therapeutic
      approach for the therapy of inflammation of the gut.

PMID- 15179136
TI  - Calpain inhibitors improve myocardial dysfunction and inflammation induced by
      endotoxin in rats.
AB  - Excessive activation of calpains has been implicated in the pathophysiology of
      inflammation, trauma, and ischemia reperfusion injury. Here, we investigated the
      effects of calpain inhibition on myocardial dysfunction and inflammation induced
      by endotoxin in rats. Rats were treated i.v. with endotoxin (10 mg/kg) or
      endotoxin plus calpain inhibitors and were then prepared after 4 h for myocardial
      contractility assessment, detection of endothelium leukocyte interactions, and
      plasma TNF-alpha, nitrite/nitrate, and endocan levels. Compared with vehicle
      treated rats, hearts from endotoxin-treated rats had reduced systolic performance
      that was partially prevented by calpain inhibitors, i.e., acetyl-leucyl-leucyl
      arginal (leupeptin), carbobenzoxy-valyl-phenylalanial (calpain inhibitor III),
      and N-acetyl-leucinyl-leucinyl-norleucinal (ALLN). Leupeptin and calpain
      inhibitor III reduced plasma TNF-alpha levels in endotoxin-treated rats. ALLN
      reduced plasma TNF-alpha and nitrite/nitrate levels in endotoxin-treated rats.
      Endotoxin treatment increased mesenteric venule leukocyte rolling (10 +/- 3
      leukocytes/min vs. 44 +/- 10 leukocytes/min; P < 0.01) and adhesion (2 +/- 2
      leukocytes/min vs. 15 +/- 3 leukocytes/min; P < 0.01), which was reduced by
      calpain inhibitors. Attenuation of leukocyte endothelium interactions observed in
      calpain inhibitor-treated rats with sepsis was associated with increases in
      plasma anti-adhesion molecule endocan. In conclusion, calpain inhibitors improved
      endotoxin-induced cardiac dysfunction, which may be attributed to the modulation
      of endothelium leukocyte interactions in the inflamed vasculature.

PMID- 15179137
TI  - Depression of mitochondrial respiratory enzyme activity in rostral ventrolateral
      medulla during acute mevinphos intoxication in the rat.
AB  - We investigated possible changes in bioenergetics at the rostral ventrolateral
      medulla (RVLM), a medullary site where sympathetic vasomotor tone originates and
      where the organophosphate poison mevinphos (Mev) acts to elicit cardiovascular
      intoxication. In Sprague-Dawley rats maintained under propofol anesthesia,
      microinjection bilaterally of Mev (10 nmol) into the RVLM induced progressive
      hypotension that was accompanied by an early augmentation (80-100 min post-Mev;
      Phase I), followed by a decrease (>100 min post-Mev; Phase II) in the power
      density of the vasomotor components (0-0.8 Hz) in systemic arterial pressure
      (SAP) signals. Enzyme assay revealed that local application of Mev into the RVLM
      also significantly and progressively depressed the activity of NADH cytochrome c
      reductase (marker for Complexes I and III) and cytochrome c oxidase (marker for
      Complex IV) in the mitochondrial respiratory chain of the RVLM, but not the
      heart. On the other hand, the activity of succinate cytochrome c reductase
      (marker for Complexes II and III) remained unaltered. Both the cardiovascular
      consequences and depression of mitochondrial respiratory chain enzymes elicited
      by Mev were significantly antagonized on comicroinjection of atropine (3.5 or 7
      nmol) bilaterally into the RVLM. We conclude that Mev adversely effects
      cardiovascular control by acting as a cholinesterase inhibitor in the RVLM, whose
      neuronal activity is intimately related to the death process. The resulting
      accumulation of acetylcholine and prolonged activation of muscarinic receptors in
      the RVLM is manifested by a selective dysfunction of respiratory enzyme Complexes
      I and IV in the mitochondrial respiratory chain that underlies cardiovascular
      toxicity associated with organophosphate poisons such as Mev.

PMID- 15179138
TI  - Bacterial DNA and RNA induce rat cardiac myocyte contraction depression in vitro.
AB  - Sepsis and septic shock, the systemic immunologic and pathophysiologic response
      to overwhelming infection, are associated with perturbation of a variety of
      metabolic cell pathways and with multiple organ failure (MOF) including cardiac
      depression. This depression has been attributed to the effect of several
      circulating and locally produced proinflammatory mediators. Recent data suggest
      that bacterial nucleic acids can produce profound systemic inflammatory responses
      characterized by circulatory shock in intact animals. In this study, bacterial
      DNA and RNA derived from pathogenic clinical S. aureus and E. coli isolates are
      shown to induce early concentration-dependent depression of maximum extent and
      peak velocity of contraction of electrically paced neonatal rat ventricular
      myocytes in culture. Significant but more modest depression was generated by a
      nonpathogenic E. coli isolate. Pretreatment with a DNase or RNase abrogated this
      effect. Further, synthetic, double-stranded RNA (dsRNA) also induced
      concentration-dependent depression of myocyte contraction, with the effect also
      being prevented by pretreatment with RNase. These data suggest that bacterial DNA
      and RNA may contribute to myocardial depression during bacterial sepsis and
      septic shock.

PMID- 15179139
TI  - Effect of hyperbaric oxygen on endotoxin-induced lung injury in rats.
AB  - Oxygen therapy remains the main component of the ventilation strategy for
      treatment of patients with acute lung injury. Hyperbaric oxygen therapy (HBO(2))
      is the intermittent administration of 100% oxygen at pressure greater than sea
      level and has been applied widely to alleviate a variety of hypoxia-related
      tissue injuries. The purpose of this study was to evaluate the effect of
      hyperbaric oxygen on acute lung injury induced by intratracheal spraying of
      lipopolysaccharide (LPS) in rats. Male Sprague-Dawley rats underwent implantation
      of a carotid artery catheter under general anesthesia. Aerosolized LPS was
      delivered twice into the lungs via intratracheal puncture. Animals were either
      breathing room air (n = 27) or subjected to hyperbaric oxygen (HBO(2)) exposure
      (n = 27) 1 h after LPS spraying. Acute lung injury was evaluated 5 h and 24 h
      later. Compared with the control group, intratracheal spraying of LPS caused
      profound hypoxemia, greater wet/dry weight ratio (W/D) of the lung (5.67 +/- 0.22
      vs. 4.98 +/- 0.19), and higher protein concentration (1706 +/- 168 vs. 200 +/- 90
      mg/L) and LDH activity (129 +/- 30 vs. 46 +/- 15, mAbs/min) in bronchoalveolar
      lavage (BAL) fluid. Intratracheal spraying of LPS also caused significant WBC
      sequestration in the lung tissue. HBO2 treatment significantly reverted
      hypoxemia, reduced lung injury measures evaluated at 5 and 24 h, and enhanced 24
      h animal survival rate (chi = 5.08, P = 0.024). The malondialdehyde (MDA)
      concentrations in lung tissue and serum were both increased after LPS spraying.
      Neither single HBO(2) therapy nor five sequential daily treatments enhanced MDA
      production in lung tissue or serum. Our results suggested that hyperbaric oxygen
      might reduce acute lung injury caused by intratracheal spraying of LPS in rats.
      This treatment modality is not associated with enhancement of oxidative stress to
      the lung.

PMID- 15179140
TI  - Heme oxygenase-1 gene expression in pericentral hepatocytes through beta1
      adrenoceptor stimulation.
AB  - Induction of heme oxygenase (HO)-1 may confer hepatocellular protection, e.g., in
      reperfusion injury. Previous reports suggest that intracellular cAMP up-regulates
      HO-1. The aim of the present study was to assess the role of adrenoceptor
      agonists as a means to induce HO-1 and to assess molecular mechanisms of HO-1
      gene expression by adrenoceptor agonists. Induction of HO-1 in primary cultures
      of hepatocytes and in rat liver in vivo was assessed by Northern blot, Western
      blot, and immunohistochemistry. The beta-receptor agonists (+/-)isoproterenol and
      (-)isoproterenol induced HO-1 in primary cultures of hepatocytes but not the
      inactive enantiomer (+)isoproterenol. No induction of HO-1 was observed after
      alpha1, alpha2, beta2, or beta 3 agonists. beta1-Receptor agonists dobutamine and
      xamoterol induced HO-1 dose dependently, whereas the beta1-receptor antagonist
      metoprolol attenuated HO-1 induction by beta1-receptor agonists. Furthermore, 8
      Br-cAMP and forskolin induced HO-1. Inhibition of protein kinase A (PKA)
      abolished induction by dobutamine and 8 Br-cAMP. Parallel changes were observed
      for the transcription factor AP-1. In vivo infusion of dobutamine for 6 h induced
      HO-1 in rat livers. Immunohistochemical detection of HO-1 revealed a pericentral
      expression pattern of HO-1 in hepatocytes, i.e., the area at risk for
      ischemia/reperfusion injury. These results suggest induction of HO-1 by beta1
      adrenoceptor agonists via the PKA pathway in hepatocytes, reflecting a potential
      means for "pharmacological preconditioning."

PMID- 15179141
TI  - Weighing infants in the pediatric emergency department: the diaper can stay on!

PMID- 15179142
TI  - Use of emergency department chief complaint and diagnostic codes for identifying
      respiratory illness in a pediatric population.
AB  - OBJECTIVES: (1) To determine the value of emergency department chief complaint
      (CC) and International Classification of Disease diagnostic codes for identifying
      respiratory illness in a pediatric population and (2) to modify standard
      respiratory CC and diagnostic code sets to better identify respiratory illness in
      children. METHODS: We determined the sensitivity and specificity of CC and
      diagnostic codes by comparing code groups with a criterion standard. CC and
      diagnostic codes for 500 pediatric emergency department patients were
      retrospectively classified as respiratory or nonrespiratory. Respiratory
      diagnostic codes were further classified as upper or lower respiratory. The
      criterion standard was a blinded, reviewer-assigned illness category based on
      history, physical examination, test results, and treatment. We also modified our
      respiratory code sets to better identify respiratory illness in this population.
      RESULTS: Four hundred ninety-six charts met inclusion criteria. By the criterion
      standard, 87 (18%) patients had upper and 47 (10%) had lower respiratory illness.
      The specificity of CC and diagnostic codes groups was >0.97 [95% confidence
      interval (CI) 0.95-0.98]. The code group sensitivities were as follows: CC was
      0.47 (95% CI 0.38-0.55), upper respiratory diagnostic was 0.56 (95% CI 0.45
      0.67), lower respiratory diagnostic was 0.87 (95% CI 0.74-0.95), and combined CC
      and/or diagnostic was 0.72 (95% CI 0.63-0.79). Modifying the respiratory code
      sets to better identify respiratory illness increased sensitivity but decreased
      specificity. CONCLUSIONS: Diagnostic and CC codes have substantial value for
      emergency department syndromic surveillance. Adapting our respiratory code sets
      to a pediatric population forced a tradeoff between sensitivity and specificity.

PMID- 15179143
TI  - Community childhood injury surveillance: an emergency department-based model.
AB  - OBJECTIVE: To describe the use of an emergency department (ED)-based injury
      surveillance model to determine the incidence and mechanisms of nonfatal injuries
      among children living in Cabrini Green, a poor urban community. METHODS: Using ED
      records and census data, population-based injury rates were determined for a
      retrospective cohort of children, 0 to 14 years old, (N = 3908) with nonfatal
      injuries resulting in ED treatment between January 1994 and December 1998.
      RESULTS: There were 1950 nonfatal injuries during the 5-year study period (annual
      injury incidence of 998/10,000). Age-specific rates (per 10,000 per year) were
      899 among 0- to 4-year olds, 616 among 5- to 9-year olds, and 435 among 10- to 14
      year olds. Sixty-three percent were male. The most common injury mechanisms were
      falls (339/10,000 per year), being struck by/against an object (201/10,000 per
      year), and being cut/pierced by an object (87/10,000 per year). Falls from a
      building window (2/10,000 per year) were infrequent. The incidence of housefire
      related burns was 1.5/10,000 per year. Intentional injuries included alleged
      child abuse, 43/10,000 per year, and assaults, 30/10,000 per year. The assault
      rate among 10- to 14-year-old males was 100/10,000 per year. One hundred thirty
      four children were admitted to the hospital (average annual rate of 69/10,000).
      The most frequent admission diagnoses were falls (22/10,000) among 0- to 9-year
      olds and assaults (13/10,000) among 10- to 14-year olds. CONCLUSION: An ED-based
      injury surveillance system can provide an efficient and useful way to determine
      injury incidence in a defined urban community. The data suggest that rates of
      violence-related injuries were high, while rates of window falls and housefires
      were low. These data have allowed targeted injury prevention efforts in Cabrini
      Green, and future surveillance will allow the evaluation of injury prevention
      activities.

PMID- 15179144
TI  - Outcomes of children referred to an emergency department by an after-hours call
      center.
AB  - BACKGROUND AND OBJECTIVES: After-hours call centers are increasingly prevalent,
      yet there is little patient outcomes data. We sought to determine compliance with
      referral to an emergency department (ED) and describe outcomes and clinical
      characteristics of referred patients including triage classifications,
      therapeutic interventions, diagnostic testing, diagnoses, and hospitalization
      rates. DESIGN AND PARTICIPANTS: A retrospective cohort design. We studied
      hospital-based primary care patients who were referred to the ED of a tertiary
      care children's hospital by the call center, without physician consultation.
      RESULTS: Of the 8265 telephone calls to the call center, 1473 (18%) children were
      referred to the ED, and 931 (63%) were compliant. Compliant patients were
      significantly younger (P = 0.01) and were more likely to have been referred to
      the ED immediately (P = 0.01) compared with noncompliant patients. Among
      compliant patients, 48% were classified as nonurgent at ED triage; of these, half
      did not have a therapeutic intervention or diagnostic test or require
      hospitalization. Overall, therapeutic interventions were administered to 44%,
      diagnostic tests were performed for 45%, and 13% were hospitalized. Compared to
      children referred immediately to the ED, the proportion instructed to go to the
      ED within 4 hours of the telephone call received significantly lower ED triage
      classifications (93% vs. 77%, P < 0.00001) and hospitalizations (15% vs. 6%, P =
      0.001). CONCLUSIONS: In this study, we report the outcomes and clinical
      characteristics of children referred to the ED by an after-hours call center.
      Data such as these may be used by call centers in the assessment of management
      advice and referral practices.

PMID- 15179145
TI  - A comparison of the influence of hospital-trained, ad hoc, and telephone
      interpreters on perceived satisfaction of limited English-proficient parents
      presenting to a pediatric emergency department.
AB  - BACKGROUND: Latinos are the fastest growing minority group in the United States
      with a significant percentage of this population having limited English
      proficiency. OBJECTIVE: To determine whether mode of interpretation influences
      satisfaction of limited English-proficient parents presenting to a tertiary care
      pediatric emergency department. DESIGN: One hundred eighty parents of patients
      presenting to a pediatric emergency department were surveyed after receiving
      services from one of the following interpreters: hospital-trained, ad hoc, or
      telephone. An English-proficient comparison group of 60 parents of any ethnicity
      was also surveyed (total N = 240). RESULTS: Parents were significantly more
      satisfied (P < 0.001) with hospital-trained interpreters. While no significant
      difference was found in overall visit satisfaction, there were significant
      differences in several other outcome variables. When hospital-trained
      interpreters were used, parents were significantly more satisfied (P < 0.001)
      with their physicians and nurses. With regard to the ability to communicate with
      pediatric emergency department personnel, parents using hospital-trained
      interpreters averaged significantly higher scores (P < 0.001) than the telephone
      group. Quality-of-care scores were significantly higher (P < 0.001) for parents
      assigned to hospital-trained interpreters than for the other forms of
      interpretation. English-proficient parents scored highest in the following
      categories: ability to communicate, quality of care, and overall visit
      satisfaction. Parents using hospital-trained interpreters scored higher than
      English-proficient parents when questioned about physician and nursing
      satisfaction. CONCLUSION: Hospital-trained interpreters are a valuable and needed
      resource to facilitate communication with limited English-proficient patients and
      families. Other interpretation services are useful but have limitations.

PMID- 15179146
TI  - Yo-yo injuries.
AB  - OBJECTIVE: This study was undertaken to describe pediatric yo-yo injuries as
      published in the English-language medical literature and in a large national
      database of emergency department visits in the United States. METHODS: Two search
      strategies of public data were used. All available materials from January 1993
      through December 2002 including accident investigations, reported incidents,
      death certificates, and data from the National Electronic Injury Surveillance
      System involving yo-yos were requested from the United States Consumer Product
      Safety Commission. Data were also obtained from a search of the English-language
      medical literature accessing MEDLINE, a database of more than 11 million
      citations. RESULTS: Fourteen cases of injuries sustained during proper yo-yo use
      were identified. The injuries were sustained by children 5 to 14 years. Eleven
      (79%) of the subjects were boys. Most injuries involved minor blows to the face
      and scalp. None of these injuries were serious. CONCLUSIONS: When properly used,
      yo-yos appear to be relatively safe toys. Training in the proper use of a yo-yo
      to avoid being struck in the head, face, or eyes may be helpful for school-aged
      children. Employing a search strategy using data available from the Consumer
      Product Safety Commission including information provided by the National
      Electronic Injury Surveillance System and electronically accessing MEDLINE appear
      to yield useful information when questions about the safety of a consumer product
      arise.

PMID- 15179147
TI  - Value of rigid bronchoscopy in the management of critically ill children with
      acute lung collapse.
AB  - OBJECTIVE: To describe the potential uses of a rigid bronchoscopy in pediatric
      patients, as well as explaining the advantage of a rigid bronchoscopy versus a
      flexible bronchoscopy in pediatric patients with acute lung collapse. DESIGN:
      Case report. SETTING: Pediatric intensive care unit. PATIENT: A 16-month-old male
      infant with a 5-day history of cough, congestion, and "wheezing" that
      progressively worsened. INTERVENTIONS: A rigid bronchoscopy. MEASUREMENTS AND
      MAIN RESULTS: The evolution of the patient's acute lobar collapse to his final
      discharge is described. This includes the initial presentation, primary methods
      employed to improve the patient's condition, the use of a rigid bronchoscopy in
      removing a mucous plug, and the patient's results up to his final discharge.
      CONCLUSION: This report demonstrates the value of rigid bronchoscopy in pediatric
      patients with severe atelectasis and pneumonia. Although bronchoscopy may not be
      indicated as an initial procedure to remove respiratory tract secretions, it may
      provide a beneficial option in cases where less invasive methods prove
      ineffective in removing secretions and mucous plugs.

PMID- 15179148
TI  - Seizures secondary to a high-grade atrioventricular block as a presentation of
      acute myocarditis.

PMID- 15179149
TI  - Postobstructive pulmonary edema in children.
AB  - Children with either acute or chronic upper airway obstruction are at risk for
      postobstructive pulmonary edema. Appropriate diagnosis and management are
      important in leading to a good outcome for the patient. We describe 2 cases of
      postobstructive pulmonary edema caused by brief acute upper airway obstruction.
      In the first case, a child choked on a hot dog and in the second on a
      "jawbreaker." Both children developed symptoms of complete upper airway
      obstruction and were managed initially with the Heimlich maneuver and
      subsequently developed increased work of breathing associated with an oxygen
      requirement after relief of the obstruction. Both children were managed in the
      pediatric intensive care unit and were discharged after resolution of symptoms
      without sequelae.

PMID- 15179150
TI  - COX-2 inhibitors: a review.

PMID- 15179152
TI  - No sympathy for a boy with obtundation.

PMID- 15179153
TI  - ECGs in the ED.

PMID- 15179154
TI  - Fall on hand and arm: pain.

PMID- 15179155
TI  - Pediatric trauma: "a horse of a different color".

PMID- 15179156
TI  - Reduction in contamination of urine samples obtained by in-out catheterization by
      culturing the later urine stream.

PMID- 15179158
TI  - Asthma medication in Finnish olympic athletes: no signs of inhaled beta2-agonist
      overuse.
AB  - INTRODUCTION: Occurrence of asthma has been reported to be frequent in endurance
      athletes and especially high in winter sport athletes. Recently, the
      International Olympic Committee has restricted the use of inhaled beta2-agonists
      and requires documentation for their use. However, epidemiologic data comparing
      the use of antiasthmatic medication in different sport events are mostly missing.
      METHODS: A cross-sectional questionnaire survey was carried out in 2002. All the
      athletes (N = 494) financially supported by National Olympic Committee comprised
      the study group. Of them, 446 (90.3%) filled in a structured questionnaire
      concerning asthma and allergies, use of medication, characteristics of sport
      activities, and smoking habits. A representative sample of Finnish young adults
      (N = 1 504) served as controls. RESULTS: Physician-diagnosed asthma was more
      common in athletes as compared with controls (13.9% vs 8.4%). Use of any asthma
      medication was reported by 9.6% of the athletes and by 4.2% of the controls. No
      difference was observed in the frequency of asthma medication used by winter or
      summer sport athletes (10.0% vs 9.4%). Inhaled beta2-agonists were used by 7.4%
      and 3.0% of the athletes and controls, respectively. After adjusting for age,
      sex, and smoking, odds ratio with 95% confidence interval for use of any asthma
      medication was 0.69 (0.17-2.92) for motor skills demanding events, 1.87 (0.85
      4.11) for speed and power sports, 3.00 (1.68-5.37) for team sports, and 4.16
      (2.22-7.78) for endurance events as compared with controls. None of the athletes
      used antiasthmatic medication without physician diagnosis. CONCLUSIONS: The
      frequency of antiasthmatic medication is clearly lower than the occurrence of
      physician-diagnosed asthma in Finnish Olympic athletes. No evidence of overuse of
      inhaled beta2-agonists is found.

PMID- 15179159
TI  - Overuse of asthma medication in athletics?

PMID- 15179160
TI  - Core stability measures as risk factors for lower extremity injury in athletes.
AB  - INTRODUCTION/PURPOSE: Decreased lumbo-pelvic (or core) stability has been
      suggested to contribute to the etiology of lower extremity injuries, particularly
      in females. This prospective study compares core stability measures between
      genders and between athletes who reported an injury during their season versus
      those who did not. Finally, we looked for one or a combination of these strength
      measures that could be used to identify athletes at risk for lower extremity
      injury. METHODS: Before their season, 80 female (mean age = 19.1 +/- 1.37 yr,
      mean weight 65.1 +/- 10.0 kg) and 60 male (mean age = 19.0 +/- 0.90 yr, mean
      weight 78.8 +/- 13.3 kg) intercollegiate basketball and track athletes were
      studied. Hip abduction and external rotation strength, abdominal muscle function,
      and back extensor and quadratus lumborum endurance was tested for each athlete.
      RESULTS: Males produced greater hip abduction (males = 32.6 +/- 7.3%BW, females =
      29.2 +/- 6.1%BW), hip external rotation (males = 21.6 +/- 4.3%BW, females = 18.4
      +/- 4.1%BW), and quadratus lumborum measures (males = 84.3 +/- 32.5 s, females =
      58.9 +/- 26.0 s). Athletes who did not sustain an injury were significantly
      stronger in hip abduction (males = 31.6 +/- 7.1%BW, females = 28.6 +/- 5.5%BW)
      and external rotation (males = 20.6 +/- 4.2%BW, females = 17.9 +/- 4.4%BW).
      Logistic regression analysis revealed that hip external rotation strength was the
      only useful predictor of injury status (OR = 0.86, 95% CI = 0.77, 0.097).
      CONCLUSION: Core stability has an important role in injury prevention. Future
      study may reveal that differences in postural stability partially explain the
      gender bias among female athletes.

PMID- 15179161
TI  - Strain on the anterior cruciate ligament during closed kinetic chain exercises.
AB  - PURPOSE: The purpose of this investigation was to characterize the ACL strains
      produced during four commonly prescribed CKC exercises; the step-up, the step
      down, the lunge, and the one-legged sit to stand. We hypothesized that the ACL
      strains produced during the lunge and one-legged sit to stand exercises (the
      exercises that challenge the leg musculature to a greater extent and utilize
      greater hip flexion) would be less than those produced during the step-up and
      step-down exercises. METHODS: The strains in the anteromedial bundle of the ACL
      were measured while nine subjects, who had normal ligaments, performed the four
      exercises. Peak ACL strain values and the ACL strain patterns as a function of
      knee flexion angle were compared between exercises. RESULTS: No significant
      differences were found between the peak ACL strain values (mean +/- SEM) between
      exercises (step-up: 2.5 +/- 0.36; step-down: 2.6 +/- 0.34; lunge 1.9 +/- 0.50;
      one-legged sit to stand: 2.8 +/- 0.27). The mean ACL strain values as a function
      of knee flexion angle were not significantly different. On average, there was a
      significant increase in ACL strain as the knee was extended for each exercise.
      CONCLUSIONS: The ACL strain responses produced during these CKC exercises were
      equal and similar to those produced during other rehabilitation exercises (i.e.,
      squatting, active extension of the knee) previously tested.

PMID- 15179162
TI  - Applying a systems model of training to a patient with coronary artery disease.
AB  - PURPOSE: The aim of the present study was to apply a systems model of training
      for athletes to a patient with coronary artery disease (CAD) undergoing phase 3
      rehabilitation. METHODS: A patient with CAD underwent 14 wk of training during
      which exercise was quantified using intensity and duration. Real exercise
      tolerance was assessed twice a week during this period using a constant-load
      test. The model exercise tolerance was obtained by convolving the quantified
      training to real exercise tolerance. The model parameters were obtained by
      fitting the real exercise tolerance to model exercise tolerance by the least
      square method. These parameters were then used to calculate the time needed after
      a training impulse to reach maximal tolerance (tg) and then to return to the
      pretraining level of tolerance (ti). RESULTS: The results showed that: 1) the fit
      between real and model exercise tolerances was significant (r = 0.73, P < 0.05),
      and 2) tg and ti were predicted 17 and 120 d posttraining, respectively.
      CONCLUSIONS: The application of a systems model of training for athletes to a
      patient with CAD was successful. We were able to predict the maximal exercise
      tolerance and the duration of increased tolerance subsequent to the training
      period.

PMID- 15179163
TI  - Effect of training on beta1 beta2 beta3 adrenergic and M2 muscarinic receptors in
      rat heart.
AB  - OBJECTIVE: Physical training is known to alter several cardiovascular parameters.
      These adaptations are for a great part linked to an alteration of the myocardial
      responses to its autonomic nervous regulation. To further explain the
      parasympathetic and catecholamine effects, we hypothesized that endurance
      training could modify rat myocardial beta1, beta2, beta3 adrenoreceptors (AR) and
      M2 muscarinic cholinergic receptor (AchR) densities. METHODS: Two groups of
      adults female Wistar rats were studied: controls (C) (N = 7) and trained (T) (N =
      9). An 8-wk treadmill training protocol was performed, 5 d x wk and of 1 h x d.
      At the end of the training session, left ventricle and atria muscle were isolated
      and weighed. Then, quantification of beta1, beta2, beta3 AR and M2 AchR was
      performed using Western blot analysis. RESULTS: M2 AchR densities were not
      modified in left ventricle or in atria by training (respectively, 100 +/- 22%, C
      vs 101 +/- 14%, T and 100 +/- 23%, C vs 119 +/- 30%, T). Concerning the left
      ventricle beta AR isoforms, beta1AR density was decreased in T (80 +/- 10% T vs
      100 +/- 14% C, P = 0.01), beta2AR was unaltered (102 +/- 12%, T vs 100 +/- 17%,
      C), and beta3 AR density was increased in T (139 +/- 38% T vs 100 +/- 15% C; P <
      0.05). CONCLUSIONS: Our results show for the first time that in female rats an 8
      wk treadmill training protocol alters specifically the left ventricle beta AR
      isoforms densities but not the M2 AchR one. These results could explain some of
      the beneficial cardiovascular adaptations of the physically trained heart.

PMID- 15179164
TI  - Apolipoprotein C-III SstI genotypes modulate exercise-induced
      hypotriglyceridemia.
AB  - PURPOSE: To investigate whether the efficacy of exercise as an
      antitriglyceridemic treatment was dependent on the apolipoprotein (apo) C-III
      SstI gene polymorphism. METHODS: A subgroup of 100 Korean men, who were
      prescreened by genotypes (S1S1 = 40, S1S2 = 40, S2S2 = 20), participated in a 6-d
      moderate-exercise intervention using either a motor-driven treadmill or a cycle
      ergometer. Height and weight for body mass index and waist circumference were
      measured. Fasting total cholesterol, triglycerides (TG), high-density lipoprotein
      cholesterol, low-density lipoprotein cholesterol, glucose, and insulin were
      measured. Univariate analysis of variance and ANCOVA followed by Bonferroni post
      hoc tests were used to compare the preintervention values and the pre- to
      postexercise change (delta) scores in the measured variables across the
      genotypes, respectively. Multivariate linear regressions were carried out with
      age, smoking, waist circumference, body mass index, and genotype as independent
      variables and lipids, glucose, and insulin as dependent variables. RESULTS:
      Subjects with the S2S2 genotype had a significantly higher preintervention TG
      concentration than subjects with the S1S1 genotype (P = 0.022). Waist
      circumference and genotype were the only significant predictors for the
      preintervention TG (P < 0.001). With respect to the delta scores, the subjects
      with the S2S2 genotype had a greater reduction in TG than the subjects with the
      S1S1 genotype, adjusted for the preintervention difference (P = 0.047).
      CONCLUSION: This study suggests that the apo C-III SstI gene polymorphism might
      be useful for determining who is most susceptible to intervention by exercise in
      lowering fasting TG concentration.

PMID- 15179165
TI  - Influence of physical activity on serum IL-6 and IL-10 levels in healthy older
      men.
AB  - INTRODUCTION: Chronic inflammation is thought to play a role in disease
      development and functional decline during aging. The purpose of this research was
      to examine the influence of regular physical activity, independent of disease and
      disability, on the levels of pro- and anti-inflammatory cytokines in older (65-74
      yr) males. METHODS: Subjects were carefully screened for participation in this
      study based upon the SENIEUR protocol. In addition, subjects were selected based
      upon their weekly volume of aerobic exercise. Twelve extremely healthy "SENIEUR"
      males (six very active, six less active) completed this study. Serum
      concentrations of MIP-1alpha, IL-1ra, IL-1beta, IL-6, IL-10, and C-Reactive
      protein were measured by ELISA. RESULTS: The very active group demonstrated
      significantly lower levels of IL-6 (P = 0.016) and significantly higher levels of
      IL-10 (P = 0.016) compared with the less active group. CONCLUSIONS: The higher
      volume of regular physical activity was associated with decreased IL-6 levels and
      increased IL-10 levels in very healthy older males. Thus, exercise may play a
      vital role in controlling inflammatory markers during the aging process.

PMID- 15179166
TI  - Muscle glycogen depletion alters oxygen uptake kinetics during heavy exercise.
AB  - PURPOSE: To test the hypothesis that muscle fiber recruitment patterns influence
      the oxygen uptake (VO2) kinetic response, constant-load exercise was performed
      after glycogen depletion of specific fiber pools. METHODS: After validation of
      protocols for the selective depletion of Type I and II muscle fibers, 19 subjects
      performed square-wave exercise at 80% VT (moderate) and at 50% of the difference
      between VT and VO2max (heavy) without any prior depleting exercise (CON), after
      HIGH (10 x 1-min exercise bouts at 120% VO2max), and after LOW (3 h of exercise
      at 30% VO2max) exercise. RESULTS: Differences in VO2 kinetic parameters were only
      observed in heavy exercise AFTER HIGH: the VO2 primary component was higher (1.75
      +/- 0.12 L x min) compared with CON (1.65 +/- 0.11 L x min, P < 0.05), and the
      VO2 slow component was lower (0.18 +/- 0.03 L x min) compared with CON (0.24 +/-
      0.04 L x min, P < 0.05). CONCLUSIONS: The results indicate that the VO2 response
      to heavy constant-load exercise can be altered by depletion of glycogen in the
      Type II muscle fibers, lending support to the theory that muscle fiber
      recruitment influences both the VO2 primary and slow component amplitudes during
      heavy intensity exercise.

PMID- 15179167
TI  - Slow-twitch fiber glycogen depletion elevates moderate-exercise fast-twitch fiber
      activity and O2 uptake.
AB  - PURPOSE: We tested the hypotheses that previous glycogen depletion of slow-twitch
      (ST) fibers enhances recruitment of fast-twitch (FT) fibers, elevates energy
      requirement, and results in a slow component of VO2 during moderate-intensity
      dynamic exercise in humans. METHODS: Twelve healthy, male subjects cycled for 20
      min at approximately 50% VO2max with normal glycogen stores (CON) and with
      exercise-induced glycogen depleted ST fibers (CHO-DEP). Pulmonary VO2 was
      measured continuously and single fiber, muscle homogenate, and blood metabolites
      were determined repeatedly during each trial. RESULTS: ST fiber glycogen content
      decreased (P < 0.05) during CON (293 +/- 24 to 204 +/- 17 mmol x kg d.w.), but
      not during CHO-DEP (92 +/- 22 and 84 +/- 13 mmol x kg d.w.). FT fiber CP and
      glycogen levels were unaltered during CON, whereas FT fiber CP levels decreased
      (29 +/- 7%, P < 0.05) during CHO-DEP and glycogen content tended to decrease (32
      +/- 14%, P = 0.07). During CHO-DEP, VO2 was higher (P < 0.05) from 2 to 20 min
      than in CON (0-20 min:7 +/- 1%). Muscle lactate, pH and temperature, ventilation,
      and plasma epinephrine were not different between trials. From 3 to 20 min of CHO
      DEP, VO2 increased (P <0.05) by 5 +/- 1% from 1.95 +/- 0.05 to 2.06 +/- 0.08 L x
      min but was unchanged during CON. In this exercise period, muscle pH and blood
      lactate were unaltered in both trials. Exponential modeling revealed a slow
      component of VO2 equivalent to 0.12 +/- 0.04 L x min during CHO-DEP. CONCLUSION:
      This study demonstrates that previous glycogen depletion of ST fibers enhances FT
      fiber recruitment, elevates O2 cost, and causes a slow component of VO2 during
      dynamic exercise with no blood lactate accumulation or muscular acidosis. These
      findings suggest that FT fiber recruitment elevates energy requirement of dynamic
      exercise in humans and support an important role of active FT fibers in producing
      the slow component of VO2

PMID- 15179168
TI  - Effects of oral ATP supplementation on anaerobic power and muscular strength.
AB  - PURPOSE: We examined 14 d of oral adenosine 5'-triphosphate (ATP) supplementation
      on indices of anaerobic capacity and muscular strength. METHODS: Twenty-seven
      healthy males successfully completed the trial, after randomly receiving in a
      double-blind manner an oral dose of low dose (150 mg) or high dose (225 mg) ATP,
      or matched placebo. To improve absorption characteristics, the ATP was
      enterically coated. Total blood ATP (whole blood and plasma ATP) concentrations,
      two Wingate anaerobic power tests (30 s), and muscular strength (1RM and three
      sets of repetitions to fatigue at 70% of 1RM) were measured under three
      conditions: (i) baseline; (ii) acutely (7d later, no prior supplementation and 75
      min after ATP ingestion); and (iii) after 14 d of daily ingestion (post).
      RESULTS: Statistical analyses showed no significant between or within group
      treatment effects for whole blood ATP or plasma ATP concentrations for any
      treatment condition. We also did not observe any treatment effects for any
      Wingate testing parameter including peak PO, total work, average PO for 30 s, or
      post-Wingate lactate accumulation. Overall, we observed no significant between
      group treatment effects for any muscular strength parameter. We did observe
      several within group differences for the group ingesting the high ATP dosage
      including 1RM (6.6%; P < 0.04) and repetitions to fatigue during set 1 of
      posttesting (18.5%; P < 0.007) and total lifting volume at post (22%; P < 0.003).
      CONCLUSIONS: We conclude that enterically coated oral ATP supplementation may
      provide small ergogenic effects on muscular strength under some treatment
      conditions.

PMID- 15179169
TI  - Blood volume expansion and cardiorespiratory function: effects of training
      modality.
AB  - PURPOSE: To evaluate the effects of different modalities of aerobic (i.e.,
      interval (INT) and continuous (CONT)) training on cardiorespiratory function and
      the importance of training-induced blood volume (BV) expansion on aerobic power
      and LV function. We hypothesized that if modality-mediated differences in
      cardiorespiratory function exist after INT and CONT, they would be related
      directly to differences in training-induced hypervolemia. METHODS: We examined
      the effects of 12 wk of CONT and INT on BV, volume-regulatory hormones
      (angiotensin II, aldosterone, atrial natriuretic peptide), and cardiorespiratory
      function in 20 untrained males (mean age 30 +/- 4 (SD)). Participants were
      stratified (mass and VO2max) and randomly assigned to control, CONT, or INT.
      RESULTS: There were no significant changes in cardiorespiratory function or BV in
      the control group. Twelve weeks of continuous and interval training,
      respectively, resulted in significant changes in VO2max (23 +/- 18 vs 21 +/-
      10%), peak stroke volume (20 +/- 18 vs 11 +/- 18%), and BV (12 +/- 9 vs 10 +/-
      6%). Changes in VO2max were directly related to changes in BV (r = 0.47).
      Angiotensin II significantly increased after 1 wk of CONT and INT and thereafter
      returned to baseline values. There was no significant difference between the CONT
      and INT groups with regard to changes in vascular volumes, volume-regulatory
      hormones, and/or cardiorespiratory function. CONCLUSIONS: These data indicate
      that: 1) 12 wk of CONT and INT result in similar improvements in VO2max, and LV
      function and 2) training-induced hypervolemia accounts for approximately 47% of
      the changes in VO2max after CONT and INT.

PMID- 15179170
TI  - Immune status of physically active women during lactation.
AB  - PURPOSE: The purpose of this study was to provide baseline data on immune status
      of exercising and sedentary exclusively lactating women. Dietary intake and body
      composition were also investigated to determine whether they related to immune
      function. METHODS: Healthy, exclusively breastfeeding women with a body mass
      index between 20 and 30 kg x m were studied at 3 months postpartum. Participants
      in the exercise group (EG; N = 27) exercised aerobically at least 30 min x d, 3x
      wk, and women in the sedentary group (SG; N = 23) exercised once a week or less
      during the previous 6 wk. Immune status while at rest was determined by
      measuring: 1) a complete blood cell count and differential leukocyte count; 2)
      percentages and absolute counts of peripheral blood T cells (CD3+), cytotoxic T
      cells (CD3+CD8+), helper T cells (CD3+CD4+), B cells (CD19+), and natural killer
      cells (CD56+); 3) neutrophil bacterial killing and oxidative burst activity; and
      4) in vitro mitogenic responsiveness of lymphocytes. Cardiorespiratory fitness,
      body composition, and dietary intake were also measured. RESULTS: Participants in
      the EG had a significantly higher level of mean predicted cardiorespiratory
      fitness than women in the SG (39.5 +/- 1.1 vs 32.5 +/- 1.0 mL O2 x min x kg; P <
      0.05); however, there were no significant differences in body composition or
      dietary intake. There were no significant differences in any of the indicators of
      immune status between groups. In addition, there were no significant
      relationships between body composition or dietary intake and immune status.
      CONCLUSIONS: The results of this study suggest that women may exercise moderately
      during lactation and increase their fitness level without impairing their immune
      function.

PMID- 15179171
TI  - Effect of gender and defensive opponent on the biomechanics of sidestep cutting.
AB  - PURPOSE: Anterior cruciate ligament (ACL) injuries often occur in women during
      cutting maneuvers to evade a defensive player. Gender differences in knee
      kinematics have been observed, but it is not known to what extent these are
      linked to abnormal neuromuscular control elsewhere in the kinetic chain.
      Responses to defense players, which may be gender-dependent, have not been
      included in previous studies. This study determined the effects of gender and
      defense player on entire lower extremity biomechanics during sidestepping.
      METHODS: Eight male and eight female subjects performed sidestep cuts with and
      without a static defensive opponent while 3D motion and ground reaction force
      data were recorded. Peak values of eight selected motion and force variables
      were, as well as their between-trial variabilities, submitted to a two-way
      (defense x gender) ANOVA. A Bonferroni-corrected alpha level of 0.003 denoted
      statistical significance. RESULTS: Females had less hip and knee flexion, hip and
      knee internal rotation, and hip abduction. Females had higher knee valgus and
      foot pronation angles, and increased variability in knee valgus and internal
      rotation. Increased medial ground reaction forces and flexion and abduction in
      the hip and knee occurred with the defensive player for both genders.
      CONCLUSIONS: A simulated defense player causes increased lower limb movements and
      forces, and should be a useful addition to laboratory protocols for sidestepping.
      Gender differences in the joint kinematics suggest that increased knee valgus may
      contribute to ACL injury risk in women, and that the hip and ankle may play an
      important role in controlling knee valgus during sidestepping. Consideration of
      the entire lower extremity contributes to an understanding of injury mechanisms
      and may lead to better training programs for injury prevention.

PMID- 15179172
TI  - Knee biomechanics of the support leg in soccer kicks from three angles of
      approach.
AB  - PURPOSE: To examine knee joint kinematics, electromyographic (EMG) activity
      patterns and ground reaction forces (GRF) during an instep soccer kick from three
      different approaches relative to the ball. METHODS: Ten male soccer players
      performed maximum kicks from 0 rad (K0), 0.81 rad (K45), and 1.62 rad (K90) angle
      between the players' starting position and the position of the ball. GRF data and
      3-D kinematics and EMG activity of the vastus medialis (VM), vastus lateralis
      (VL), and biceps femoris (BF) muscles of the lower leg were recorded. RESULTS:
      colon; Compared with K0, K90, and K45 demonstrated higher medial and posterior
      GRF and lower anterior GRF. K90 and K45 also demonstrated higher external
      rotation displacement, maximum flexion, internal rotation, abduction, and
      adduction velocity of the tibia relative to the femur of the support leg compared
      with K0 (P < 0.01). The BF EMG before and immediately after ground contact was
      also higher in K90 and K45 compared with K0 (P < 0.01). CONCLUSION: Soccer kicks
      using a high angle of approach increase the medial and posterior GRF, which is
      indicative of an altered stance during the kick, resulting in an altered balance.
      Such kicks are accompanied by significant alterations in knee joint kinematics
      and an increased BF activation around ground contact. Soccer kicks from an angled
      approach may induce significant loads to knee joint structures of the support
      leg.

PMID- 15179173
TI  - Effect of swim suit design on passive drag.
AB  - INTRODUCTION: The drag (D) of seven (7) male swimmers wearing five (5) swimsuits
      was investigated. METHODS: The drag was measured during passive surface tows at
      speeds from 0.2 up to 2.2 m x s and during starts and push-offs. The swimsuits
      varied in body coverage from shoulder-to-ankle (SA), shoulder-to-knee (SK), waist
      to-ankle (WA) and waist-to-knee (WK) and briefs (CS). RESULTS: Differences in
      total drag among the suits were small, but significant. In terms of least drag at
      2.2 m x s, the swimsuits ranked: SK, SA, WA, WK and CS. The drag was decomposed
      into its pressure drag (DP), skin friction drag (DSF) and wave drag (DW)
      components using nonlinear regression and classical formulations for each drag
      component. The transition-to-turbulence Reynolds number and decreasing frontal
      area with speed were taken into account. The transition-to-turbulence Reynolds
      number location was found to be very close to the swimmers' "leading edge," i.e.
      the head. Flow was neither completely laminar, nor completely turbulent; but
      rather, it was transitional over most of the body. The DP contributed the most to
      drag at low speeds (<1.0 m x s) and DW the least at all speeds. DSF contributed
      the most at higher speeds for SA and SK suits, whereas DP and DW were reduced
      compared with the other suits. CONCLUSION: The decomposition of swimmer drag into
      DSF, DP and DW suggests that increasing DSF on the upper-body of a swimmer
      reduces DP and DW by tripping the boundary layer and attaching the flow to the
      body from the shoulder to the knees. It is possible that body suits that cover
      the torso and legs may reduce drag and improve performance of swimmers.

PMID- 15179175
TI  - Use of RPE-based training load in soccer.
AB  - PURPOSE: The ability to accurately control and monitor internal training load is
      an important aspect of effective coaching. The aim of this study was to apply in
      soccer the RPE-based method proposed by Foster et al. to quantify internal
      training load (session-RPE) and to assess its correlations with various methods
      used to determine internal training load based on the HR response to exercise.
      METHODS: Nineteen young soccer players (mean +/- SD: age 17.6 +/- 0.7 yr, weight
      70.2 +/- 4.7 kg, height 178.5 +/- 4.8 cm, body fat 7.5 +/- 2.2%, VO2max, 57.1 +/-
      4.0 mL x kg x min) were involved in the study. All subjects performed an
      incremental treadmill test before and after the training period during which
      lactate threshold (1.5 mmol x L above baseline) and OBLA (4.0 mmol x L) were
      determined. The training loads completed during the seven training weeks were
      determined multiplying the session RPE (CR10-scale) by session duration in
      minutes. These session-RPE values were correlated with training load measures
      obtained from three different HR-based methods suggested by Edwards, Banister,
      and Lucia, respectively. RESULTS: Individual internal loads of 479 training
      sessions were collected. All individual correlations between various HR-based
      training load and session-RPE were statistically significant (from r = 0.50 to r
      = 0.85, P < 0.01). CONCLUSION: The results of this study show that the session
      RPE can be considered a good indicator of global internal load of soccer
      training. This method does not require particular expensive equipment and can be
      very useful and practical for coaches and athletic trainer to monitor and control
      internal load, and to design periodization strategies.

PMID- 15179174
TI  - Carbohydrate supplementation and perceived exertion during prolonged running.
AB  - PURPOSE: The purpose of this study was to investigate the relationship between
      carbohydrate energy substrate and hormonal regulation on the perception of
      exertion during prolonged running. METHODS: Sixteen experienced marathoners ran
      on treadmills for 3 h at approximately 70% VO2max on two occasions while
      receiving 1 L x h carbohydrate (C) or placebo (P) beverages. Blood and vastus
      lateralis muscle biopsy samples were collected before and after exercise.
      RESULTS: The pattern of change in ratings of perceived exertion (RPE) over time
      was significantly different between C and P ingestion (P < 0.01) with attenuated
      RPE responses found in the latter part of the 3 h run. The pattern of change in
      the respiratory exchange ratio and carbohydrate oxidation rates were
      significantly greater (P < 0.01) in the C than P condition. Change in muscle
      glycogen content did not differ between C and P (P = 0.246). C relative to P
      ingestion was associated with higher plasma levels of glucose, insulin, and
      lactate and lower levels plasma cortisol. CONCLUSIONS: These data indicate that a
      lower RPE was associated with a higher carbohydrate oxidation, plasma glucose,
      and insulin levels, and lower plasma cortisol during prolonged running after C
      supplementation as compared with P feeding despite no differences in muscle
      glycogen content. These findings support a physiological link between RPE and
      carbohydrate substrate availability as well as selected hormonal regulation
      during prolonged running.

PMID- 15179176
TI  - In professional road cyclists, low pedaling cadences are less efficient.
AB  - PURPOSE: To determine the effects of changes in pedaling frequency on the gross
      efficiency (GE) and other physiological variables (oxygen uptake (VO2), HR,
      lactate, pH, ventilation, motor unit recruitment estimated by EMG) of
      professional cyclists while generating high power outputs (PO). METHODS:
      Following a counterbalanced, cross-over design, eight professional cyclists (age
      (mean +/- SD): 26 +/- 2 yr, VO2max: 74.0 +/- 5.7 mL x kg x min) performed three 6
      min bouts at a fixed PO (mean of 366 +/- 37 W) and at a cadence of 60, 80, and
      100 rpm. RESULTS: Values of GE averaged 22.4 +/- 1.7, 23.6 +/- 1.8 and 24.2 +/-
      2.0% at 60, 80, and 100 rpm, respectively. Mean GE at 100 rpm was significantly
      higher than at 60 rpm (P < 0.05). Similarly, mean values of VO2, HR, rates of
      perceived exertion (RPE), lactate and normalized root-mean square EMG (rms-EMG)
      in both vastus lateralis and gluteus maximum muscles decreased at increasing
      cadences. CONCLUSIONS: In professional road cyclists riding at high PO,
      GE/economy improves at increasing pedaling cadences.

PMID- 15179177
TI  - Effect of bicycle saddle designs on the pressure to the perineum of the
      bicyclist.
AB  - PURPOSE: Increasing awareness of an association between bicycling and male sexual
      dysfunction has led to the appearance of a variety of bicycle saddles that share
      the design objective of reducing pressure in the groin of the cyclist by removal
      of the narrow protruding nose of the saddle. This study compared three of these
      saddle designs to a traditional sport/road racing saddle with a narrow protruding
      nose in terms of pressure in the region of the perineum (groin) of the cyclist.
      METHODS: Saddle, pedal, and handlebar contact pressure were measured from 33
      bicycle police patrol officers pedaling a stationary bicycle at a controlled
      cadence and workload. Pressure was characterized over the saddle as a whole and
      over a region of the saddle assumed to represent pressure on the cyclist's
      perineum located anteriorly to the ischial tuberosities. RESULTS: The traditional
      sport/racing saddle was associated with more than two times the pressure in the
      perineal region than the saddles without a protruding nose (P < 0.01). There were
      no significant differences in perineal pressure among the nontraditional saddles.
      Measures of load on the pedals and handlebars indicated no differences between
      the traditional saddle and those without protruding noses. This finding is
      contradictory to those studies suggesting a shift toward greater weight
      distribution on the handlebars and pedals when using a saddle without a nose.
      CONCLUSIONS: The recommendation of a saddle without a narrow protruding nose
      appears to be justified to reduce pressure to the perineum of the bicyclist.

PMID- 15179178
TI  - Validity of a multi-sensor armband in estimating rest and exercise energy
      expenditure.
AB  - The SenseWear Armband (SWA; BodyMedia, Inc.), using multiple sensors, was
      designed to estimate energy expenditure (EE) in free-living individuals. PURPOSE:
      To examine the reliability and validity of the SWA during rest and exercise
      compared with indirect calorimetry (IC). METHODS: EE was assessed with SWA and IC
      in 13 males during two resting and one cycle ergometry (40 min at 60% VO2peak)
      sessions. In a second experiment, 20 adults walked on a treadmill for 30 min at
      three intensities (80.5 m x min, 0% grade; 107.3 m x min, 0% grade; 107.3 m x
      min, 5% grade) while IC and SWA measured EE. RESULTS: At rest, no significant
      differences were found between EE measurements from the SWA (1.3 +/- 0.1 kcal x
      min) and IC (1.3 +/- 0.1 kcal x min), and the two methods were highly correlated
      (r = 0.76; P < 0.004). The SWA EE estimation was reliable when comparing the two
      resting visits (r = 0.93; P < 0.001). For the ergometer protocol, no significant
      differences were found between the SWA and IC measurements of EE early, mid, or
      late in exercise or for the total bout, although the measurements were poorly
      correlated (r = 0.03-0.12). The SWA EE estimate of walking increased with
      treadmill speed but not with incline. The SWA significantly overestimated (13
      27%) the EE of walking with no grade (P < 0.02) and significantly underestimated
      (22%) EE on the 5% grade (P < 0.002). The SWA estimation of EE correlated
      moderately with IC (r = 0.47-0.69). CONCLUSION: The SWA provided valid and
      reliable estimates of EE at rest and generated similar mean estimates of EE as IC
      on the ergometer; however, individual error was large. The SWA overestimated the
      EE of flat walking and underestimated inclined walking EE.

PMID- 15179179
TI  - Effect of race and musculoskeletal development on the accuracy of air
      plethysmography.
AB  - PURPOSE: The purpose of this study was to determine the effect of race and
      musculoskeletal development on the accuracy of estimates of body fatness (%fat)
      via air displacement plethysmography (AP). METHODS: Estimates of %fat were made
      via AP, hydrostatic weighing (HW), dual-energy x-ray absorptiometry (DXA), and
      the criterion, a four-component model (4C) in 64 black (B) and white (W) men, who
      were either resistance trained (RT) or served as controls (C). RESULTS: Based on
      a three-way ANOVA, there were no statistically significant three-way or race x
      musculoskeletal development interactions. There was no main effect of race on the
      validity of estimating %fat by AP; the mean bias between %FatAP and %Fat4C was
      similar for B (3.6% body fat) and W (3.7%). In addition, the density of the fat
      free mass (Dffm) for B (1.098 +/- 0.002 g x mL) was not different than 1.10 g x
      mL. There was a significant effect of musculoskeletal development on the validity
      of the estimation of %fat from AP; the mean difference in %fat between %FatAP and
      %Fat4C was less in RT (1.5% body fat) than in C (5.3%), but a large SEE of 5.5%
      was observed for RT. A significant (P < 0.05) correlation was found between the
      mean bias between methods and body volume (-0.44) and mesomorphy (-0.55).
      CONCLUSIONS: Race does not affect the accuracy of estimating %fat by AP. Race
      specific equations estimating %fat via densitometry (e.g., AP, HW) such as the
      Schutte are not justified, because Dffm is not greater than 1.10 g x mL.
      Estimation of %fat via AP is more accurate in larger individuals with high
      musculoskeletal development as a group, but individual results are highly
      variable.

PMID- 15179180
TI  - Effects of acute modafinil ingestion on exercise time to exhaustion.
AB  - PURPOSE: The purpose of this study was to investigate the effect of acute
      ingestion of modafinil (M) on time to exhaustion during high-intensity exercise.
      Modafinil (M) is a psychostimulant developed to treat narcolepsy, with "arousal"
      properties attributed to an increased release of dopamine in the CNS. Because
      other stimulants with similar properties have ergogenic effects, it was
      hypothesized that acute treatment with M would enhance physical performance.
      METHODS: Fifteen healthy male subjects, with a maximal aerobic power (VO2max) of
      47 +/- SD 8 mL x kg x min, exercised on a cycle ergometer for 5 min at 50% VO2max
      and then at approximately 85% VO2max to exhaustion. They did this weekly for 3
      wk: a control trial (C) the first week, and then 3 h after ingesting either
      placebo (P) or M (4 mg x kg) during the remaining 2 wk. The P and M trials were
      conducted with a balanced order, double-blind design. RESULTS: : Mean +/- SD
      times to exhaustion at 85% VO2max (TE) were 14.3 +/- 2.8, 15.6 +/- 3.8 and 18.3
      +/- 3.5 min for the C, P, and M trials, respectively. TE for M was significantly
      longer than for the C and P trials. Oxygen uptake at exhaustion was slightly but
      significantly greater for M compared with P and C. HR increased with time and was
      further elevated by M. Subjective ratings of perceived exertion (RPE) were
      significantly lower for M compared with C and P but only after 10 min of exercise
      at 85% VO2max. CONCLUSION: Acute ingestion of modafinil prolonged exercise time
      to exhaustion at 85% VO2max and reduced RPE. The RPE results suggest that the
      dampening of the sensation of fatigue was likely a factor responsible for the
      enhanced performance.

PMID- 15179181
TI  - Inverse relationship between VO2max and economy in world-class cyclists.

PMID- 15179183
TI  - Physiological factors limiting exercise performance in CFS.

PMID- 15179184
TI  - Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M
      cell cycle arrest and apoptosis in human melanoma cells.
AB  - Curcumin (diferuloylmethane) inhibits tumour cell growth by inducing apoptosis in
      many tumour types, including melanoma, via complex and ill-defined pathways.
      Recent studies have shown that curcumin is both a nitric oxide scavenger and an
      inhibitor of inducible nitric oxide synthase (iNOS) expression, low levels of
      which correlate with antiapoptotic function and poor survival and which may be
      regulated by inhibition of nuclear factor-kappaB (NFkappaB) activation. To
      elucidate the mechanisms by which curcumin inhibits melanoma proliferation, we
      tested the in vitro effects of curcumin on specific cell cycle pathways and
      melanoma cell survival, including NFkappaB activation. Curcumin induced melanoma
      cell apoptosis and cell cycle arrest, which is associated with the downregulation
      of NFkappaB activation, iNOS and DNA-dependent protein kinase catalytic subunit
      expression, and upregulation of p53, p21(Cip1), p27(Kip1) and checkpoint kinase
      2. Curcumin also downregulated constitutive iNOS activity in melanoma cells. Our
      results demonstrate that curcumin arrested cell growth at the G(2)/M phase and
      induced apoptosis in human melanoma cells by inhibiting NFkappaB activation and
      thus depletion of endogenous nitric oxide. Therefore, curcumin should be
      considered further as a potential therapy for patients with melanoma.

PMID- 15179185
TI  - Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation
      and survival.
AB  - In the present study the deacetylase inhibitor trichostatin A (TSA) was used to
      elucidate the effect of protein acetylation on cell cycle progression and
      survival in seven human malignant melanoma cell lines. It was shown that TSA
      treatment led to a transient G(2)/M phase delay and accumulation of
      unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly
      induced protein expression of the cyclin-dependent kinase inhibitor
      p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not
      expressing p21(WAF1/CIP1) constitutively, whereas the levels of both wild-type
      and mutated p53 protein were reduced. The effect on p53 was not a direct result
      of inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) activation by
      TSA, as treatment of the cells with the mitogen-activated protein
      kinase/extracellular signal-regulated kinase kinase-1 (MEK1) inhibitor PD98059
      did not result in decreased p53 protein level. Furthermore, TSA treatment led to
      reduction in cyclin D1 whereas cyclin D3 accumulated, the latter due to increased
      protein stability. Similarly, cyclin A protein was reduced whereas cyclin E level
      was elevated. The effect on p27(Kip1), CDK4 and CDK2 was only marginal. In all
      the examined cell lines, TSA treatment resulted in a profound induction of
      apoptosis and cleavage of poly-(ADP-ribose)-polymerase (PARP) indicative of
      caspase activity. Similarly, TSA-mediated apoptosis was reversed by the caspase
      inhibitor z-vad-fmk. Altogether, these results suggest that p21(WAF1/CIP1) in
      melanomas is silenced by deacetylation, and furthermore that inhibition of
      deacetylation may have potential in anticancer therapy of melanoma patients.

PMID- 15179186
TI  - Antitumoral action of the neurokinin-1 receptor antagonist L-733 060 on human
      melanoma cell lines.
AB  - Melanoma represents 1% of all cancers and accounts for approximately 65% of skin
      cancer deaths. At present, effective treatment does not exist. Substance P (SP)
      is a neuropeptide expressed in invasive malignant melanomas. We studied the in
      vitro growth inhibitory capacity of the potent and long-acting neurokinin-1 (NK1)
      receptor antagonist L-733 060 at concentration ranges of 2.5-20 microM, 10-30
      microM and 20-50 microM in the melanoma cell lines COLO 858, MEL H0 and COLO 679,
      respectively. A Coulter counter was used to determine the number of viable cells,
      and the tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5-(3
      carboxymethoxyphenyl)2-(4-sulphophenyl)-2H-tetrazolium, inner salt (MTS)
      colorimetric method was used to evaluate cell proliferation. L-733 060 inhibited
      the growth of all three cell lines in a dose-dependent manner. The 50% inhibition
      concentration (IC(50)) was 8.7 microM at 48 h and 7.1 microM at 96 h for COLO
      858, 27.5 microM at 24 h and 18.9 microM at 48 h for MEL H0, and 33.8 microM at
      30 h and 31.5 microM at 72 h for COLO 679. These findings indicate that the NK1
      receptor antagonist L-733 060 acts as an antitumoral agent. This action, shown
      here for the first time, suggests that the NK1 receptor antagonist L-733 060
      could be a promising therapeutic drug in the treatment of the human melanoma.

PMID- 15179187
TI  - In vitro antitumour activity of resveratrol in human melanoma cells sensitive or
      resistant to temozolomide.
AB  - Resveratrol, a polyphenol present in many plant species, exhibits a wide range of
      biological and pharmacological activities both in vitro and in vivo. It has been
      shown to exert a potent chemopreventive effect in carcinogenesis models and to
      induce cell growth inhibition and apoptosis in human tumour cells, including
      melanoma cells. Malignant melanoma is considered to be a chemotherapy-refractory
      tumour, and the commonly used anticancer drugs do not seem to modify the
      prognosis of metastatic disease. To further evaluate the therapeutic potential of
      resveratrol in the treatment of melanoma, we selected three human melanoma cell
      lines with different levels of resistance to temozolomide (TMZ), an antitumour
      triazene compound. The cell lines were subjected to resveratrol treatment and
      analysed for cell growth inhibition, cell cycle perturbation and apoptosis
      induction. We found that resveratrol markedly impaired proliferation of both the
      TMZ-sensitive M14 and the TMZ-resistant SK-Mel-28 and PR-Mel cell lines. The
      latter cell line was two-fold more resistant to the drug than M14 and SK-Mel-28
      cells. The sensitivity of normal human keratinocytes to resveratrol was found to
      be significantly higher than that of M14 and SK-Mel-28 cells and similar to that
      of the PR-Mel cell line. This suggests a possible good in vivo therapeutic index
      for resveratrol. Our results also show that the growth-inhibitory effect of
      resveratrol on melanoma cells is mainly due to its ability to induce S-phase
      arrest and apoptosis. Taken together, our data indicate that resveratrol is an
      interesting candidate for the treatment of advanced melanoma.

PMID- 15179188
TI  - In vitro and in vivo effects of polyhaemoglobin-tyrosinase on murine B16F10
      melanoma.
AB  - Melanoma is an increasingly common fatal skin cancer. Many groups are carrying
      out research on potential treatments for melanoma. One of these approaches has
      shown that lowering tyrosine can inhibit the growth of melanoma in cell cultures
      and of B16BL6 melanoma in mice. However, humans cannot tolerate tyrosine
      restricted diets for lowering tyrosine because of nausea, vomiting and weight
      loss. We report here our preparation and characterization of a novel soluble
      polyhaemoglobin-tyrosinase complex. This preparation prevents native tyrosinase
      from having adverse effects and from rapid removal after injection. The
      preparation inhibited murine B16F10 melanoma cell growth in culture and delayed
      its growth in a mice model. Intravenous injection of the preparation lowers the
      systemic tyrosine level without causing adverse effects such as vomiting and
      weight loss in mice. It is therefore possible that this complex could be useful
      in the treatment of human melanoma.

PMID- 15179189
TI  - The RAS-BRAF kinase pathway is not involved in uveal melanoma.
AB  - An activating mutation has been recently observed in cutaneous melanoma in a
      downstream component of RAS-BRAF. The most common mutation, occurring in 80% of
      cutaneous melanoma samples, is a T-to-A transition resulting in a single amino
      acid substitution (V599E). Since cutaneous and uveal melanoma (UM) have a common
      origin, we aimed to establish whether activation of the BRAF proto-oncogene is
      also an important factor in the development of UM. Exons 11 through 18 of the
      BRAF gene were screened from 33 primary UMs and 11 UM cell lines. Genomic
      polymerase chain reaction products were evaluated using single-strand
      conformation polymorphism analysis, followed by sequencing of aberrant products.
      The most common mutation, T1796A in the kinase domain of BRAF, was not observed
      in any of the primary UM samples. This mutation was also absent in 10 of the 11
      UM cell lines. In one of the UM cell lines, OCM1, the T1796A mutation was
      present. We conclude that, in contrast to cutaneous melanoma, BRAF does not
      appear to be involved in the pathogenesis of UM.

PMID- 15179191
TI  - S100beta protein in peripheral blood may predict progressive disease during
      interleukin-2 based immunotherapy in patients with metastatic melanoma.
AB  - The aim of this study was to evaluate the biological variation in the serum level
      of S100beta protein in untreated patients with metastatic melanoma and to use
      this variation to subsequently evaluate serum levels as a method of monitoring
      objective response to interleukin-2 (IL2) based treatment. Such an approach has
      not, to our knowledge, been published previously. Consecutive blood samples were
      collected before, during and after treatment and in the follow-up period from 66
      patients treated with IL2-based immunotherapy. In 11 of these patients, a further
      three samples were drawn on each of 3 days prior to treatment to evaluate the
      variation in S100beta. This variation was later used to distinguish between
      increased, unchanged or decreased S100beta levels during treatment. We observed a
      significant association between changes in S100beta levels and clinical outcome
      after the first and second treatment cycles. All responding patients had a
      decline in S100beta levels or normal values during the first cycle. Changes in
      S100beta levels after the first cycle and the type of treatment were independent
      predictive factors for the clinical outcome in multivariate analysis. In
      conclusion, increasing S100beta values were independently associated with
      progressive disease, and our data suggest that significant changes in S100beta
      levels may be valuable for monitoring and predicting clinical outcome during IL2
      based immunotherapy and chemoimmunotherapy.

PMID- 15179190
TI  - Her2/neu is not a commonly expressed therapeutic target in melanoma -- a large
      cohort tissue microarray study.
AB  - Melanoma is among the most chemotherapy-resistant malignancies. Numerous new
      agents have been developed that target specific molecules on cancer cells,
      including the monoclonal antibody trastuzumab, which targets Her2/neu and has
      been very beneficial in the treatment of breast cancer. There are conflicting
      reports in the literature about Her2/neu expression in melanoma specimens, but
      all of the cohorts studied have been small. We therefore examined Her2/neu
      expression in a very large cohort of melanoma specimens in order to determine the
      value of exploring trastuzumab therapy for melanoma patients. Immunohistochemical
      staining was performed on two tissue microarrays, together containing 600 intact
      specimens. Expression was evaluated semi-quantitatively and correlated with
      tumour stage and other clinicopathological data. Of the 600 specimens in the
      cohort, 31 patients (5.2%) had positive Her2/neu expression. Among the primary
      cutaneous specimens (n=269), 7% had positive Her2/neu staining, while 3.6% of the
      recurrent or metastatic specimens (n=331) had positive Her2/neu staining
      (P=0.06). Among the primary lesions there was no significant correlation between
      Her2/neu expression, Clark level and ulceration; however, Her2/neu expression was
      associated with lesions with a Breslow depth of < 2 mm (P=0.05). Using this very
      large cohort of melanoma specimens, we found only a few cases with aberrant
      Her2/neu expression, many of them being primary cutaneous lesions rather than
      recurrent or metastatic lesions. Our findings suggest that drugs that
      specifically target Her2/neu are not likely to be useful for the treatment of
      metastatic melanoma or as adjuvant therapy for melanoma patients at high risk for
      recurrence.

PMID- 15179192
TI  - Phase I/II randomized trial of intrahepatic arterial infusion chemotherapy with
      cisplatin and chemoembolization with cisplatin and polyvinyl sponge in patients
      with ocular melanoma metastatic to the liver.
AB  - Ocular melanoma has a unique metastatic predilection for the liver and is
      refractory to most forms of therapy. The dual blood supply of the liver with
      differential perfusion of metastatic lesions and normal hepatocytes by the
      hepatic artery and portal vein, respectively, has led to the evaluation of
      intrahepatic chemotherapy and chemoembolization in this disease. Despite
      suggestion of efficacy in phase II trials, this therapy has not been
      systematically evaluated. We conducted a randomized phase I/II trial evaluating
      escalating doses of intrahepatic chemotherapy with cisplatin with or without
      polyvinyl sponge (PVS) in 19 patients with ocular melanoma and liver metastases.
      The cisplatin dose was initiated at 100 mg/m and was increased in 25% increments.
      Patients were randomized to receive cisplatin alone or cisplatin plus PVS. Seven
      patients were treated with intrahepatic cisplatin at 100 mg/m: four with PVS, and
      three without. The dose was escalated to 125 mg/m with or without PVS in the
      remaining 12 patients. The maximum tolerated dose for intra-hepatic cisplatin was
      determined to be 125 mg/m with or without PVS. The overall response rate was 16%.
      Dose-limiting toxicities included renal, hepatic and haematological effects. This
      therapy produces a modest response rate in patients with ocular melanoma and
      liver metastases.

PMID- 15179193
TI  - Concurrent adjuvant radiotherapy and interferon-alpha2b for resected high risk
      stage III melanoma -- a retrospective single centre study.
AB  - Interferon-alpha2b (IFNalpha2b) is the only form of systemic adjuvant therapy for
      stage III melanoma with documented survival benefit. Radiotherapy can also be
      utilized in the adjuvant setting in patients at high risk of nodal basin
      recurrence. As IFNalpha2b is associated with substantial toxicity, we sought to
      determine both the systemic and radiation-related toxicities in patients treated
      with combined adjuvant IFNalpha2b and regional adjuvant radiotherapy delivered in
      the setting of a single institution. Eighteen consecutive patients who commenced
      adjuvant IFNalpha2b between November 1997 and August 2002 were analysed
      retrospectively for toxicities associated with the combination of IFNalpha2b and
      adjuvant radiotherapy (40-50 Gy in 15-25 fractions) to nodal basins delivered
      during the maintenance phase of IFNalpha2b therapy (median dose during
      radiotherapy of 6.5 MU/m three times per week). Seven out of 18 patients who
      received concurrent radiotherapy and IFNalpha2b displayed grade 3 skin reactions.
      Severe radiation-induced toxicity was seen in three further patients, one who
      developed radiation pneumonitis, one who developed severe oral mucositis, and one
      who developed wound dehiscence that took 10 months to resolve. Non-radiation
      related toxicity to IFNalpha2b therapy was typical for this dose and schedule. We
      conclude that concurrent use of adjuvant radiotherapy and IFNalpha2b may enhance
      radiation-induced toxicity. However, overall we found concurrent radiation and
      IFNalpha2b could be safely delivered with appropriate clinical monitoring.

PMID- 15179194
TI  - Dermatoscopic and histopathological diagnosis of primary and metastatic melanoma:
      report of a workshop at the Third Research Meeting on Melanoma, Milan, Italy, May
      2003.
AB  - The clinical and histopathological session of the Third Research Meeting on
      Melanoma, Milan, Italy, held in May 2003, highlighted several key topics,
      including clinical, dermatoscopic and computer-aided diagnosis and the use of
      immunohistochemical, immunological and biochemical approaches to diagnosis and
      monitoring. This report is a brief summary of the main themes covered.

PMID- 15179195
TI  - Use of the vacuum-assisted closure device in enhancing closure of a massive skull
      defect.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to describe a novel technique for
      reconstructing the cranial vertex without the use of free tissue transfer. STUDY
      DESIGN: Case report, literature review, and discussion. METHODS: A 50-year-old
      woman presented from a remote Pacific Island community with a 12 x 14-cm,
      necrotic, grossly contaminated eccrine gland carcinoma of the cranial vertex that
      extended through the calvarium but did not invade the dura. Following tumor
      extirpation, the resulting bony defect was 10 x 12 cm in size, with a concomitant
      scalp defect of 14 x 16 cm. Free tissue transfer was impossible because of severe
      intimal peripheral vascular disease, posing a challenging reconstructive dilemma.
      After tumor resection, the bony edges were covered with local scalp flaps and the
      vacuum-assisted closure device was placed over the wound at a constant setting of
      -50 mm Hg. The vacuum-assisted closure device was changed three times per week
      for 3 weeks. RESULTS: A thick, 1-cm bed of granulation tissue developed over the
      dura, allowing temporary coverage by a split-thickness skin graft, and the scalp
      defect decreased in size by approximately 25%. The patient did not develop
      meningitis, headache, or localized infection as a result of placement of the
      vacuum-assisted closure device and tolerated the vacuum-assisted closure well.
      After a requisite period of healing, tissue expanders and calvarial
      reconstruction will be performed. CONCLUSION: Use of the vacuum-assisted closure
      device is a safe, reliable adjunct in the closure of large cranial defects with
      exposed dura and offers a novel reconstructive option for complex defects of the
      head and neck.

PMID- 15179196
TI  - A pilot study of quantitative aspiration in patients with symptoms of obstructive
      sleep apnea: comparison to a historic control group.
AB  - OBJECTIVE: It has been shown that many healthy people aspirate secretions at
      night. Patients with obstructive sleep apnea (OSA) have frequent episodes of
      gasping at night that may predispose them to aspiration. The purpose of this
      study was to determine whether patients with symptoms of OSA are predisposed to
      pharyngeal aspiration. STUDY DESIGN: A prospective study in which patients with
      symptoms of OSA were compared with a historic group of normal controls by using
      the same methodology. METHODS: The study was offered to patients with symptoms of
      OSA undergoing a sleep study. The radiotracer Technicium was infused through a
      plastic tube placed in the nasopharynx after the patient achieved stage II sleep.
      A chest radionuclide scan determined the amount of material aspirated. The
      Wilcoxon-rank sum test was used to compare the mean amount aspirated between the
      experimental and historic control groups. RESULTS: Fourteen patients successfully
      completed the study. One normal volunteer in our study aspirated a quantity
      similar to the historic normal control group. The amount of aspirated material in
      the study group ranged from 0.152 to 3.648 mL, with a mean of 1.24 mL +/- 0.905
      (SD). When compared with the historic normal control group, the patients with
      symptoms of OSA aspirated significantly more radio-tracer (P <.01). There was a
      lack of association between respiratory disturbance index and amount aspirated.
      CONCLUSIONS: The results suggest there is an apparent risk of increased
      pharyngeal aspiration in patients with symptoms of OSA.

PMID- 15179197
TI  - Management of cerebrospinal fluid rhinorrhea: the Medical College of Wisconsin
      experience.
AB  - INTRODUCTION: The management of cerebrospinal fluid (CSF) rhinorrhea has evolved
      in recent years. The purpose of this comprehensive retrospective study is to
      assess issues related to the management of skull base defects associated with CSF
      rhinorrhea involving the nose and paranasal sinuses. METHODS: A retrospective
      review of CSF leak management was conducted. This study included patients with
      CSF rhinorrhea managed by the Department of Otolaryngology, Medical College of
      Wisconsin, Milwaukee, WI, from 1992 to 2002. Data collected included site of
      leak, surgical approach, and any recurrence of leak. RESULTS: Fifty-seven CSF
      leaks occurred in 53 patients with CSF rhinorrhea originating from the nose or
      paranasal sinuses. Twenty-eight of the 53 had iatrogenic injuries resulting in
      CSF rhinorrhea, 16 had leaks from trauma, and 13 developed spontaneous CSF leaks.
      Ten patients responded to nonoperative management with bed rest with or without
      lumbar drain placement. Forty-three patients with 47 leaks underwent surgical
      repair of CSF rhinorrhea, of which 38 resolved after initial repair. Five of
      these patients developed recurrent CSF leaks at the repair site but resolved with
      subsequent surgery. Of these, two initially presented with spontaneous CSF leaks,
      one patient had a gunshot wound with massive skull base injury, and two recurred
      after repair of an iatrogenic injury. Factors associated with failure included
      lateral sphenoid leaks and elevated body mass index (BMI). DISCUSSION: Multiple
      approaches to the management of CSF rhinorrhea can be successful. An endoscopic
      repair results in resolution of CSF rhinorrhea in the majority of cases. Patients
      with spontaneous CSF rhinorrhea, elevated BMI, lateral sphenoid leaks, and
      extensive skull base defects are at increased risk for recurrence. Alternative
      management options may need to be considered in these cases.

PMID- 15179198
TI  - Impact of pneumococcal polysaccharide vaccine (Prevnar) on middle ear fluid in
      children undergoing tympanostomy tube insertion.
AB  - OBJECTIVES: The purpose of this study was to describe the bacteriology of middle
      ear effusions in children who have received the pneumococcal polysaccharide
      vaccine (Prevnar) compared with unvaccinated children. METHODS: A prospective
      review of medical records from July 2001 to July 2002 was conducted on children
      with middle ear effusion at time of tympanostomy tube insertion. Middle ear fluid
      was plated onto culture media immediately after acquisition, and antimicrobial
      resistance of cultured organisms along with serotyping of Streptococcus
      pneumoniae was examined. Vaccination status, demographics, and risk factors were
      determined from patients' medical records, parent interviews, or contact with
      their primary care physicians. RESULTS: After adjusting for age and number of
      previous infections, children vaccinated with Prevnar are two times less likely
      to have non-S. pneumoniae pathogenic bacteria isolated than children not
      vaccinated. Of those with growth, vaccinated children were almost three times
      more likely than nonvaccinated children to have the presence of H. influenzae.
      Vaccinated children with H. influenzae were 7.5 times less likely to have beta
      lactamase producing H. influenzae than nonvaccinated children with H. influenzae.
      CONCLUSION: Because the incidence of S. pneumoniae was low, no inference could be
      made whether Prevnar decreased otitis media with effusion or recurrent acute
      otitis caused by the S. pneumoniae serotypes covered by the vaccine. However,
      vaccinated children did appear to have the unexpected benefit of having a certain
      level of protection to growth of typical acute otitis media pathogens.

PMID- 15179199
TI  - Diagnosis and pathology of unilateral maxillary sinus opacification with or
      without evidence of contralateral disease.
AB  - OBJECTIVE: Determine the diagnostic criteria and etiology of complete unilateral
      maxillary sinus opacification. METHODS: A prospective analysis was performed on
      patients presenting to a tertiary care rhinology practice with complaints of
      chronic rhinosinusitis or acute exacerbation. Sixty-four consecutive patients
      were identified with unilateral maxillary sinus opacification on computed
      tomography (CT) scan after at least a 3-week medical therapy for rhinosinusitis.
      The study population comprised 30 men and 34 women with a mean age of 47.0 years.
      All patients completed a symptom score questionnaire, received nasal endoscopy,
      and CT imaging. Patient symptoms and endoscopic and radiographic findings were
      analyzed to determine patterns related to final diagnosis. RESULTS: All 64
      patients underwent functional endoscopic sinus surgery. Each surgical specimen
      was sent for pathologic confirmation of the diagnosis. Sixteen mucoceles, 12
      cases of nasal polyposis, 27 cases of acute or chronic sinusitis, 7 cases of
      inverting papilloma, and 2 cases of mycetoma were identified. Endoscopic and
      radiographic appearances were correlated with each disease process. CONCLUSION:
      Unilateral maxillary sinus opacification is a relatively common finding. Early
      identification of inverting papillomas and mucoceles may avoid delay in surgical
      intervention, whereas acute/chronic rhinosinusitis and nasal polyposis can
      initially be managed medically. Careful history, endoscopic examination, and
      radiographic studies can often determine the responsible disease process.

PMID- 15179200
TI  - Prolonged visual disturbance secondary to isolated sphenoid sinus disease.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to evaluate the efficacy of endoscopic
      sinus surgery in patients with isolated sphenoid sinus disease with visual
      disturbances of more than 72 hours' duration. STUDY DESIGN: Retrospective review.
      METHODS: A sequential series of patients with isolated sphenoid sinus disease
      with visual disturbances who underwent endoscopic surgery performed by the same
      surgeon between 1995 and 2002 were reviewed. Patients with malignant tumors were
      excluded from the study. Patients were evaluated preoperatively and
      postoperatively to record the effects of this approach on visual acuity and
      diplopia. RESULTS: The study population included six women and seven men with a
      mean age of 56.2 years (age range, 31-75 y). Eight eyes had vision loss
      attributable to compressive optic neuropathy (27%) and optic neuritis (27%);
      seven eyes with diplopia had abducens palsy (40%) and oculomotor nerve palsy
      (7%). Sphenoid sinus lesions included sinusitis (38%), mucocele (31%), and
      aspergillosis (31%). The mean interval between the onset of visual disturbances
      and surgery was 6.6 months (range, 3 d-3.5 y). Visual disturbances improved in
      60% of the patients (P <.01). There was better improvement in diplopia than in
      vision loss (P <.01). The results of endoscopic sinus surgery for patients with
      abducens palsy and aspergillosis were excellent (83% and 80%, respectively).
      Optic neuritis and visual disturbances lasting for more than 6 months were
      regarded as poor prognostic factors. CONCLUSION: The study supports the treatment
      of visual disturbances resulting from isolated sphenoid sinus disease by
      endoscopic sinus surgery. A timely operation may prevent permanent sequelae.

PMID- 15179201
TI  - Comprehensive algorithm for skull base dural lesion and cerebrospinal fluid
      fistula diagnosis.
AB  - OBJECTIVES/HYPOTHESIS: Skull base dural lesions and cerebrospinal fluid (CSF)
      fistulas are potentially vital conditions whose diagnosis can be challenging. The
      authors' aim was to compose a comprehensive algorithm that combines the most
      modern diagnostic tools in easily applicable patterns to indicate a possible
      dural lesion or CSF fistula. STUDY DESIGN: Prospective clinical study. METHODS:
      The authors collected the data of all patients with suspicion of CSF fistula or
      dural lesion, or both, between January 1999 and December 2002. Beta-trace
      protein, beta2-transferrin, and endoscopic and laboratory sodium fluorescein
      tests; high-resolution computed tomography; and magnetic resonance cisternography
      were used according to the symptoms and etiological factors. The results of the
      diagnostic tools that were used and intraoperative findings (in case of an
      operative treatment) were reviewed. RESULTS: From 1999 to 2002, 236 patients were
      evaluated because of suspicion of dural lesion or CSF fistula, mostly after head
      trauma. Pattern I of the algorithm was applied for head trauma in dural lesion or
      CSF leak assessment, pattern II for postoperative CSF leaks, pattern III for
      evaluation of spontaneous CSF rhinorrhea, and pattern IV for the assessment of
      recurrent pneumococcal meningitis related to dural lesions without CSF fistula.
      By applying the patterns of this algorithm, a dural lesion or CSF leak that was
      also confirmed intraoperatively was detected in 48 patients. CONCLUSION: The four
      patterns of the new diagnostic algorithm described in the present study enable
      physicians to reliably clarify suspicions of dural lesions and CSF fistulas and
      aim to help them choose the best possible management. Each pattern uses the
      optimal combination of CSF tests and radiological imaging to reach a synergistic
      effect for precisely detecting dural lesions or CSF fistulas. Accordingly, this
      improves surgical decision-making when necessary.

PMID- 15179202
TI  - Pseudoaneurysms of the superficial temporal artery: treatment options.
AB  - OBJECTIVES: Pseudoaneurysms of the superficial temporal artery present as slowly
      growing masses of the face or scalp. They may arise as a result of infection or
      autoimmune disease but most commonly are sequelae of blunt, penetrating, or
      surgical trauma. We describe their clinical presentation and differential
      diagnosis and compare several treatment options. STUDY DESIGN: Observational case
      series. METHODS: We retrospectively reviewed the presentations, diagnostic
      evaluations, and management in three young men who presented with pseudoaneurysms
      after trauma. A computerized review of the world's literature revealed a variety
      of methods for the control of head and neck pseudoaneurysms. RESULTS: Surgical
      resection, ligation without resection, intravascular sclerosis, and coil
      embolization have all been used to treat these lesions. We treated two lesions by
      coil embolization and one by surgical resection. Long-term control was achieved
      in each case. CONCLUSIONS: Surgical resection cures pseudoaneurysms in most
      cases. The frontal and zygomatic branches of the facial nerve are at risk during
      this procedure. Local sclerosis is effective but may cause distal tissue
      necrosis. Coil embolization is highly effective and leaves no facial scar but
      carries small risks of stroke, lower extremity ischemia, and groin
      pseudoaneurysm.

PMID- 15179203
TI  - Analysis of chromosomes 8 and 17 aneuploidies in laryngeal squamous cell
      carcinoma by fluorescence in situ hybridization.
AB  - OBJECTIVES/HYPOTHESIS: The objectives were to investigate chromosomes 8 and 17
      numerical aberrations by using fluorescence in situ hybridization in laryngeal
      squamous cell carcinoma and also to determine whether there is any association
      between chromosomes 8 and 17 aneuploidies and TNM classification and subgroups of
      laryngeal squamous cell carcinomas. STUDY DESIGN: Descriptive study. METHODS:
      Tumor and control samples were taken from 23 patients with LSCC by surgical
      operation. Fluorescence in situ hybridization analysis with chromosomes 8- and 17
      specific alpha-satellite DNA probes was performed on the interphase nuclei.
      RESULTS: The percentages for chromosomes 8 and 17 aneuploidies were 33% (SD =
      25.7%) (median value, 26.2%; range, 3.5%-81.8%) and 19.2% (SD = 15.8%) (median
      value, 9.8%; range, 3.6%-63.7%), respectively. There was a significant difference
      between stage 2 and stage 3 (P <.05) and between stage 2 and stage 4 for
      chromosome 8 aneuploidy (P <.05) but not for chromosome 17 aneuploidy (P >.05).
      There was also a significant difference for the T classification for chromosome 8
      aneuploidy (P <.05) but not for chromosome 17 (P >.05). CONCLUSION: Chromosome 8
      aneuploidy may be related to stage and T classification of laryngeal squamous
      cell carcinoma and its progression.

PMID- 15179204
TI  - Vibration with the canalith repositioning maneuver: a prospective randomized
      study to determine efficacy.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to determine whether the inclusion of
      vibration and additional treatment cycles has an effect on short- and long-term
      success rates in the treatment of benign paroxysmal positional vertigo with the
      canalith repositioning maneuver. STUDY DESIGN: Prospective randomized study of
      patients treated at a tertiary vestibular rehabilitation center. METHODS:
      Variables identified for statistical analysis included patient age, gender,
      vibration used, and canalith repositioning cycles. Analysis using Student t test,
      chi2 test, Kaplan-Meier curves with log rank test, and Cox proportional hazards
      regression was performed. RESULTS: One hundred two patients with benign
      paroxysmal positional vertigo treated over a 1-year period (August 2001-August
      2002) were randomly assigned to receive the canalith repositioning maneuver with
      or without vibration. Average duration of follow-up was 9.44 months. The single
      treatment success rate was 93.1%. To relieve symptoms, 29.4% of patients required
      more than one canalith repositioning cycle. The relapse rate was 30.5%. Thirty
      nine patients were assigned to the canalith repositioning group with vibration,
      and 63 to the canalith repositioning group without vibration. There was no
      statistical difference in age, gender, initial success rates, or relapse rates
      between the canalith repositioning groups with and without vibration. On average,
      patients required 1.38 canalith repositioning cycles for successful treatment.
      Vibration did not affect the number of canalith repositioning cycles required to
      convert the Dix-Hallpike test result to normal. The need for additional canalith
      repositioning cycles had no statistical effect on initial treatment success or
      relapse rates. CONCLUSION: Vibration provided no additional benefit in initial
      treatment success or in reducing long-term relapse rates when included in the
      canalith repositioning maneuver. Many patients with benign paroxysmal positional
      vertigo require more than one canalith repositioning cycle at the time of initial
      treatment to relieve symptoms, but this does not indicate a higher likelihood for
      recurrence. No variable predicted a higher rate of recurrence.

PMID- 15179205
TI  - Cerebrospinal fluid leak prevention after translabyrinthine removal of vestibular
      schwannoma.
AB  - OBJECTIVES/HYPOTHESIS: The purpose of the report was to present an update on the
      authors' results for prevention and management of cerebrospinal fluid (CSF) leak
      after translabyrinthine approach for vestibular schwannoma. STUDY DESIGN: :
      Retrospective case review. METHODS: The study was conducted at Gruppo Otologico
      (Piacenza, Italy), a tertiary referral center for neurotology and skull base
      surgery. In all, 710 patients underwent translabyrinthine approach for the
      removal of vestibular schwannoma at that institution between April 1987 and
      December 2002. The medical records were retrospectively reviewed to identify
      tumor size, the incidence of postoperative CSF leak, and its treatment. RESULTS:
      The overall rate of CSF leak was 1.4%. CONCLUSION: The use of proper surgical
      technique minimizes the risk of CSF leak. Study results show that the continued
      application of the authors' proposed preventive measures resulted in the
      maintenance of a low rate of CSF leak. Immediate management of CSF fistulae helps
      prevent meningitis.

PMID- 15179206
TI  - Association between birth control pills and voice quality.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to extend our knowledge of the effect of
      birth control pills on voice quality in women based on various acoustic measures.
      STUDY DESIGN: A longitudinal comparative study of 14 healthy young women over a
      36- to 45-day period. METHODS: Voices of seven women who used birth control pills
      and seven women who did not were recorded repeatedly approximately 20 times.
      Voice samples were analyzed acoustically, using an extended set of frequency
      perturbation parameters (jitter, relative average perturbation, pitch period
      perturbation quotient), amplitude perturbation parameters (shimmer, amplitude
      average perturbation quotient), and noise indices (noise-to-harmonics ratio,
      voice turbulence index). RESULTS: Voice quality and stability were found to be
      better among the women who used birth control pills. Lower values were found for
      all acoustic measures with the exception of voice turbulence index. Results also
      provided preliminary indication for vocal changes associated with the days
      preceding ovulation. CONCLUSION: In contrast to the traditional view of oral
      contraceptives as a risk factor for voice quality, and in keeping with the
      authors' previous work, the data in the present study showed that not only did
      oral contraceptives have no adverse effect on voice quality but, in effect, most
      acoustic measures showed improved voice quality among women who used the birth
      control pill. The differences in the noise indices between groups may also shed
      light on the nature of the effect of sex hormones on vocal fold activity. It was
      suggested that hormonal fluctuations may have more of an effect on vocal fold
      regulation of vibration than on glottal adduction.

PMID- 15179207
TI  - Epstein-Barr virus in head and neck cancer assessed by quantitative polymerase
      chain reaction.
AB  - OBJECTIVES/HYPOTHESIS: Epstein-Barr virus (EBV) has classically been associated
      with nasopharyngeal carcinoma and Burkitt's lymphoma. Recently, multiple studies
      have been published linking EBV with oral squamous cell carcinoma and, to a
      lesser extent, hypopharyngeal and laryngeal tumors. Using a sensitive method of
      detection, the authors sought to analyze the presence and quantity of EBV DNA in
      a large cohort of head and neck cancers. STUDY DESIGN: : Retrospective cohort
      study. METHODS: Three hundred head and neck cancer samples exclusive of
      nasopharyngeal carcinoma were examined for the presence of EBV using quantitative
      polymerase chain reaction. Eighty-four tumor samples from the larynx, 30 from the
      hypopharynx, 73 from the oropharynx, and 113 from the oral cavity were analyzed
      for EBV quantity, which was expressed as the number of viral copies per cell
      genome. Representative samples, which contained the highest EBV DNA levels, were
      examined using in situ hybridization. Results were correlated with tumor grade
      and site and tobacco and alcohol exposure. RESULTS: Three of 300 (1%) tumor
      samples were overtly positive for EBV DNA (defined as >0.1 copies of viral
      DNA/cell genome). Five of 300 (2%) tumor samples showed low levels (defined as
      >0.01 and <0.1 copies of viral DNA/cell genome), and 68 of 300 tumor samples
      (23%) showed trace levels (defined as < 0.01 copies of viral DNA/cell genome) of
      EBV DNA. No correlation was found between EBV positivity and tobacco exposure,
      alcohol exposure, or tumor grade. CONCLUSION: In the overwhelming majority of
      head and neck cancers in this North American cohort, EBV did not appear to
      contribute to growth of a dominant clonal population with integrated EBV genome
      and was unlikely to be a genetic etiological agent in tumor development. The low
      quantities of EBV detected in a minority of head and neck cancers may be related
      to the presence of EBV genome in rare lymphoid or epithelial cells adjacent to
      the primary head and neck cancer.

PMID- 15179208
TI  - Cathepsin gene expression profile in rat acute pneumococcal otitis media.
AB  - OBJECTIVES/HYPOTHESIS: Acute otitis media, often caused by infection with
      Streptococcus pneumoniae, is characterized by inflammation of the middle ear
      mucosa. A prominent feature of the host response to bacterial infection of the
      middle ear mucosa is an influx of inflammatory cells that contributes to the
      local pool of inflammatory mediators by releasing additional inflammatory
      chemicals, which in turn cause further tissue injury. The objective was to
      identify candidate effector and signaling molecules involved in acute otitis
      media pathogenesis caused by S pneumoniae infection. STUDY DESIGN: Male Sprague
      Dawley rats were randomly assigned to 1 of 5 groups, including 1 control group
      without treatment, 2 placebo groups (12 and 48 hours) and 2 infected groups (12
      and 48 hours). The rat middle ear was bilaterally inoculated with either 25
      microL of tryptic soy broth (TSB group) or 25 microL of TSB containing
      approximately 1.24 x 10(9) cfu/mL of S pneumonias type 6A (SP group). Rats were
      killed at 12 and 48 hours after inoculation and the middle ear mucosa was
      collected. Total RNA was extracted and pooled from each group for gene expression
      assays. METHODS: Gene expression profiles for rat middle ear mucosa at 12 and 48
      hours after S pneumoniae or placebo inoculation were constructed using microarray
      technology (Clontech Atlas Rat 1.2 Array, 1176 cDNAs). Genes of interest were
      further validated by real-time polymerize chain reaction. RESULTS: Middle ear
      mucosa expression of a gene cluster encoding the lysosomal cysteine proteases,
      cathepsins B (Ctsb), L (Ctsl), and K (Ctsk), was modified after S pneumoniae
      challenge. Specifically, at 12 hours, Ctsk and Ctsl messenger RNA that was
      abundantly expressed in the normal middle ear mucosa was decreased, whereas Ctsb
      transcript was induced. The changes in Ctsb and Ctsk gene expression were
      sustained at 48 hours. CONCLUSION: The constitutive expression of Ctsk and Ctsl
      messenger RNA in normal middle ear mucosa supports a function in the maintenance
      of middle ear mucosa homeostasis, and their downregulation as an early event in
      acute otitis media may reflect a disruption in that function. The induction of
      Ctsb messenger RNA in the infected middle ear mucosa suggests a role in early
      tissue injury; thus, Ctsb may represent a potential target for molecular
      diagnostics and/or rational intervention during the development of acute otitis
      media.

PMID- 15179209
TI  - A numerical simulation of intranasal air temperature during inspiration.
AB  - OBJECTIVES/HYPOTHESIS: In vivo measurements of the intranasal air temperature are
      feasible. The present study was designed to reproduce temperature distributions
      within the human nasal cavity by means of numerical simulation. STUDY DESIGN:
      Numerical simulation. METHODS: Based on computed tomography (CT), a steady-state
      computational fluid dynamics (CFD) simulation was performed displaying the
      temperature distribution throughout the human nasal cavity during inspiration.
      The results of the numerical simulation were compared with in vivo temperature
      measurements. RESULTS: The numerical simulation demonstrated that the major
      increase of the inspiratory air temperature can be found in the anterior nasal
      segment, especially within the nasal valve area, which is comparable to in vivo
      measurements. Intranasal areas of high temperature were characterized by
      turbulent airflow with vortices of low velocity. The results of numerical
      simulation showed an excellent comparability to the results of previous in vivo
      measurements in the entire nasal cavity. CONCLUSION: The anterior nasal segment
      is the most effective part of the nose in heating of the ambient air. The
      findings demonstrated the complexity of the relationship between airflow patterns
      and heating of inspired air. A numerical simulation of the temperature
      distribution using CFD is practicable.

PMID- 15179210
TI  - The effect of beta-blocker premedication on the surgical field during endoscopic
      sinus surgery.
AB  - OBJECTIVES/HYPOTHESIS: A number of previous studies have tried to assess the
      effects of hypotension on the surgical field during endoscopic sinus surgery.
      These studies have been limited by inadequate sample sizes, lack of a control
      group, and limited data collection. The aim of the present study was to determine
      whether the routine use of beta-blockers as a pre-medication could improve the
      operative field in endoscopic sinus surgery. STUDY DESIGN: A prospective,
      randomized, double-blinded, placebo-controlled trial. METHODS: Eighty patients
      undergoing endoscopic sinus surgery who fit the inclusion and exclusion criteria
      were randomly assigned to receive either a beta-blocker, Metoprolol (group 1), or
      a placebo tablet (group 2) 30 minutes before surgery. A standard anesthetic
      protocol was followed. At the commencement of surgery and at regular 15-minute
      intervals the surgical field, blood loss, heart rate, blood pressure, and
      isoflurane concentration were assessed. RESULTS: There was a significant
      difference in overall mean heart rate between the placebo and beta-blocker groups
      (P <.0001). In the entire group, surgical grade correlated with heart rate (r =
      0.36, P <.05) but not with mean arterial blood pressure. Mean surgical grade was
      similar between the placebo and beta-blocker groups, but early in the study a
      significantly better surgical field was recorded in the beta-blocker group (P
      <.001). Surgical grade was significantly better in those with a mean heart rate
      of less than 60 beats per minute (P <.02). CONCLUSION: Although "optimum"
      conditions were present in the patients receiving beta-blocker, the authors
      thought that the grading system was not discriminating enough to demonstrate a
      significant difference between the groups. The crucial finding in the study was
      the correlation between heart rate and surgical grade in the entire group. During
      endoscopic sinus surgery surgery, anesthetic manipulations should be directed at
      maintaining a low heart rate.

PMID- 15179211
TI  - Facial translocation approach in the management of central skull base and
      infratemporal tumors.
AB  - OBJECTIVES/HYPOTHESIS: The objectives were to systematize the indications of
      various types of facial translocation and to present a technical modification to
      avoid some sequelae of this approach. STUDY DESIGN: Retrospective analysis was
      made of patients treated with different types of facial translocation approach to
      resect nasopharyngeal, infratemporal, and sinonasal tumors. METHODS: Thirty-nine
      patients underwent facial translocation approaches for neoplasms originally
      involving the nasopharynx (27) infratemporal fossa (7), and nasal cavity (5). Of
      the 21 malignant tumors, 2 were stage T2, 5 were stage T3, and 14 were stage T4.
      From the entire series of patients, 10 received a unilateral medial
      translocation, 3 a bilateral medial translocation, 25 a standard facial
      translocation, and 1 an extended medial facial translocation. RESULTS: Fifteen
      patients (38%) developed some kind of complication, such as wound infection (nine
      cases) and osteomyelitis and cerebrospinal fluid leak (five cases each). Two
      patients died as a result of postoperative complications (5.2%). Overall 5-year
      survival for malignant tumors was 43%. Neither the histological appearance of the
      tumor nor the T stage influenced the survival of patients. Survival of patients
      with intracranial involvement was significantly decreased compared with patients
      with involvement of other areas (P =.0003). CONCLUSION: The facial translocation
      approach offers an excellent exposure in tumors with large degree of involvement
      of the nasopharynx, infratemporal fossa, nasal cavity, and maxillary sinus. More
      limited osteotomies are indicated in smaller tumors. The use of midfacial
      degloving minimizes the number of sequelae of these approaches.

PMID- 15179212
TI  - Upper airway and its surrounding structures in obese and nonobese patients with
      sleep-disordered breathing.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to understand the pathophysiological
      relationship between obesity and sleep-disordered breathing by using cephalometry
      with the Muller maneuver. STUDY DESIGN: A prospective study. METHODS: One hundred
      habitually snoring men were evaluated for sleep-disordered breathing at the Sleep
      Center of Chang Gung Memorial Hospital (Taipei, Taiwan). Each subject received
      overnight polysomnography and two lateral cephalograms at the end-expiration
      phase (L1) and the Muller maneuver (L2), respectively, to evaluate the facial
      skeleton and the upper airway and its surrounding structures (soft palate,
      tongue, epiglottis, and hyoid bone). After excluding 14 patients from the study
      because of jaw opening during cephalometry, 86 (39 nonobese and 47 obese)
      patients with sleep-disordered breathing were enrolled. RESULTS: Patients with
      varying degrees of obesity significantly differed in terms of the facial skeleton
      and the structure and function of the upper airway and its surrounding
      structures. The Muller maneuver caused dynamic changes in the hypopharyngeal
      airway and position of the tongue, and these dynamic changes were related to the
      pathogenesis of sleep-disordered breathing for the two groups (nonobese and obese
      patients). The regression model generated for the nonobese group revealed that
      the apnea hypopnea index was significantly related to the pharyngeal length (L2)
      and the soft palate thickness (L1). In contrast, the regression model generated
      for the obese group revealed that the apnea hypopnea index was significantly
      related to the soft palate (length [L1] and dynamic position change), the hyoid
      position (vertical [L1] and horizontal [L2]), the tongue (dynamic position
      change), and body mass index. CONCLUSION: Cephalometry with the Muller maneuver
      may provide further insight into the pathogenesis of sleep-disordered breathing
      for the two groups of patients (nonobese and obese patients).

PMID- 15179213
TI  - An alternative technique for nasal biopsy.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to investigate the effectiveness of co
      phenylcaine as a topical anesthetic agent for nasal mucosal biopsy. STUDY DESIGN:
      A prospective study. METHODS: Nasal mucosal biopsy specimens were taken from a
      site just anterior to the inferior turbinate following topical anesthesia with co
      phenylcaine. All volunteers graded pain according to standard visual analogue
      scale (0-10) (VAS) scoring, and all were followed up after 24 hours for any
      epistaxis. RESULTS: Ninety nasal biopsy specimens were removed from 41 patients
      in all. Eight-two percent did not report any discomfort following this procedure
      (VAS score, 0). Ten patients reported mild discomfort (VAS scores ranging
      between, 1 and 3) and only six reported pain (VAS scores ranging from 5 to 7).
      However, five of these patients agreed to further biopsy and documented no
      discomfort during the repeat procedure. Only one patient required immediate
      intervention for hemorrhage after the procedure. In cases in which bleeding
      occurred (seven patients) it was documented within the first 6 hours, was minimal
      in content, and was controlled with local pressure. No systemic side effects were
      experienced. CONCLUSION: Co-phenylcaine is a suitable topical anesthetic agent
      for nasal mucosal biopsy. Removal of nasal tissue from a site anterior to the
      inferior turbinate can be performed under direct vision and provides sufficient
      tissue for histological assessment.

PMID- 15179214
TI  - Different risk factors in basaloid and common squamous head and neck cancer.
AB  - OBJECTIVES/HYPOTHESIS: The prevalence of human papillomavirus (HPV), herpes
      simplex virus (HSV), cigarette smoking and alcohol abuse was compared between two
      histological subgroups of head and neck cancer. STUDY DESIGN: Retrospective
      review. METHODS: Paraffin-embedded, histologically confirmed surgical specimens
      from the oropharynx, hypopharynx and larynx, comprising 67 conventional squamous
      cell carcinomas (SCC) and 10 basaloid squamous cell carcinomas (BSCC), were
      analyzed for the presence of HPV and HSV DNA using polymerase chain reaction
      (PCR) techniques. The PCR products were verified by direct sequencing. Patient
      charts were reviewed for clinical data and risk factors. RESULTS: Given an
      overall HPV DNA detection rate of 32.5%, a basaloid morphology of the carcinomas
      correlated significantly with occurrence of HPV DNA (P =.0001). An association
      could also be demonstrated between basaloid appearance and evidence of HSV DNA
      (single and combined with HPV DNA; P =.014 and 0.0429, respectively), even if
      this result based on a low overall HSV DNA detection rate (6.5%). Demonstration
      of viral DNA in the BSCC specimens was not related to tobacco or alcohol
      consumption. In contrast, cigarette smoking proved as significant characteristic
      of SCC (P =.0087). Alcohol abuse occurred also predominately in patients with
      SCC, but without statistical significance. CONCLUSION: These results hint at
      differences in the etiology of two distinct histological entities of head and
      neck cancer. Further research in this field could complete these preliminary data
      and provide the background for specific preventive strategies.

PMID- 15179215
TI  - Extracorporeal lithotripsy for salivary calculi: a long-term clinical experience.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to assess in a large series of patients
      with a long-term clinical follow-up the validity of extracorporeal
      electromagnetic shock wave lithotripsy as a minimally invasive therapy for
      sialolithiasis. STUDY DESIGN: Consecutive patient series. METHODS: Three hundred
      twenty-two consecutive symptomatic outpatients with single or multiple calculi in
      the submandibular (234 patients) or parotid (88 patients) gland underwent a
      complete extracorporeal electromagnetic shock wave lithotripsy treatment.
      Treatment results were classified into three groups: successful result with
      complete ultrasonographic elimination of the stone after lithotripsy, successful
      result with residual ultrasonographic fragments that were less than 2 mm in
      diameter, and unsuccessful result with residual ultrasonographic fragments that
      were greater than 2 mm in diameter. Univariate and multivariate statistical
      analyses were performed. RESULTS: Complete elimination of the stone was achieved
      in 45% of patients. On ultrasonography, residual fragments (<2 mm in diameter)
      were detected in 27.3% of patients, and persisting fragments greater than 2 mm in
      diameter were assessed in 27.7% of patients. In 3.1% of patients, all with
      submandibular gland stones, sialoadenectomy was performed. Recurrence of calculi
      in the treated gland was observed during a median follow-up period of 57 months
      in four patients with complete ultrasonographic clearance of the stone occurring
      10 to 58 months after lithotripsy. Univariate analysis showed that a favorable
      treatment result was significantly associated with the younger age of the
      patients (< or = 46 y), parotid and intraductal localization of the stone,
      diameter of the stone (< or = 7 mm), and number of therapeutic sessions (< or =
      6). On multivariate analysis, the age of the patient, parotid site of the stone,
      stone diameter, number of therapeutic sessions, and number of shock waves were
      associated with favorable outcome. CONCLUSION: Extracorporeal electromagnetic
      shock wave lithotripsy is to be considered an efficient, minimally invasive
      treatment modality for salivary calculi.

PMID- 15179216
TI  - Intraepithelial nerve fibers project into the lumen of the larynx.
AB  - OBJECTIVES/HYPOTHESIS: Studies on the morphology and location of the sensory
      receptors in the laryngeal mucosa have resulted in insufficient and sometimes
      conflicting data. In the present study the authors analyzed the distribution and
      morphology of sensory nerve plexuses and terminal fibers in the laryngeal mucosa
      of the rat. STUDY DESIGN: Two groups of Male Wistar rats were used in this
      laboratory study; the larynx of the first group were used to analyse the
      sensitive innervation of its epithelium, whereas the larynx of the second group
      (controls) were tested for the specificity of the antibodies used. METHODS: The
      larynges of the animals were entirely removed after perfusion, and coronal or
      horizontal sections were immunoprocessed for further randomized analysis of the
      mucosa. Primary afferents were detected by immunoreaction to two widely
      recognized markers of sensory nerves, calcitonin gene-related peptide and
      substance P, and visualized using diaminobenzidine as a chromogen. RESULTS: The
      nerve plexuses were more densely distributed in the dorsal half of the vocal
      folds and in the laryngeal aspect of the epiglottis. Dense networks of fine
      fibers with many varicosities en passant, immunoreactive for both calcitonin gene
      related peptide and substance P, occurred in the lamina propria and along the
      epithelial thickness. Calcitonin gene-related peptide-immunoreactive and
      substance P-immunoreactive fibers extended across the epithelium and projected to
      the laryngeal lumen itself, reaching the space between the cilia. CONCLUSION: The
      projection of intraepithelial nerve fibers into the lumen of the larynx indicates
      that in the absence of mucus, nerve endings may be exposed and thus receive
      direct stimulation from airborne substances. Furthermore, it suggests that the
      laryngeal mucosa of the rat may constitute an experimental model for studying the
      direct activation or manipulation of primary afferents at the periphery and
      neurogenic inflammation.

PMID- 15179217
TI  - Functional significance of peripheral head-shaking nystagmus.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to determine the characteristics of
      horizontal head-shaking nystagmus of peripheral origin and its relationship to
      vestibular dysfunction. STUDY DESIGN: Retrospective case series. METHODS: Eighty
      three patients met the inclusion criteria of having peripheral and unilateral
      vestibular disease. Patients were tested with video nystagmography. Head-shaking
      nystagmus was performed in the horizontal plane during 30 cycles at a frequency
      of approximately 3 Hz. Head-shaking nystagmus was classified as monophasic or
      biphasic and, based on the pathological ear, as ipsilateral or contralateral
      related to nystagmus fast phases. The two-tailed t test, ANOVA, Mann-Whitney and
      chi2 tests, and lineal and polynomial regression tests were used for statistical
      analysis. RESULTS: Twenty-three patients showed a positive head-shaking
      nystagmus. All cases of head-shaking nystagmus observed were horizontal. There
      were four biphasic and 19 monophasic cases of head-shaking nystagmus. First
      phases of biphasic head-shaking nystagmus beat toward the normal ear. Eleven of
      the monophasic cases of head-shaking nystagmus were ipsilateral, and nine were
      contralateral. There was a statistically significant correlation between caloric
      weakness and head-shaking nystagmus. Ipsilateral head-shaking nystagmus
      corresponded to lower caloric asymmetries, and contralateral and biphasic head
      shaking nystagmus corresponded to greater caloric weakness (P <.001). As the
      caloric asymmetry increased, the maximal slow-phase eye velocity of head-shaking
      nystagmus was greater (P =.01) and its duration shortened (P =.008). Ipsilateral
      responses could be distinguished from contralateral responses based on their
      latency (P =.03), maximal slow-phase eye velocity (P <.05), and duration (P
      =.02). The frequency of head-shaking nystagmus was significantly higher among
      older patients. There was no correlation between head-shaking nystagmus and
      clinical patterns. CONCLUSION: Head-shaking nystagmus of peripheral vestibular
      origin is a response both qualitatively and quantitatively associated with the
      degree of the vestibular loss.

PMID- 15179218
TI  - Deafness due to A1555G mitochondrial mutation without use of aminoglycoside.
AB  - OBJECTIVES/HYPOTHESIS: The objective was to clarify the characteristics of
      deafness associated with the A1555G mutation within mitochondrial 12S ribosomal
      RNA gene in the absence of aminoglycoside exposure. STUDY DESIGN: Clinical and
      genetic studies in family members with the A1555G mitochondrial mutation were
      performed. METHODS: The subjects were 123 maternally related members of a large
      Japanese family with the A1555G mutation. All subjects had no previous history of
      exposure to aminoglycosides. Hearing disability and handicap, tinnitus, and
      medical histories were analyzed by interviews in all of the subjects, genetic
      testing was performed in 41 subjects, and pure-tone audiometry was conducted in
      26 subjects with hearing disability and handicap. RESULTS: The A1555G mutation
      was detected in a homoplasmic form (meaning that all the mitochondrial DNA
      carries the mutation) in all 41 subjects who were screened. The risk for
      developing postlingual hearing loss was likely to be much higher in the present
      subjects than in the general population. Both the severity and age at onset of
      the phenotype were similar in affected subjects within the same sibling group.
      Pure-tone averages were significantly worse in subjects who developed hearing
      loss before age 10 years than in those who developed hearing loss later.
      CONCLUSION: The present study demonstrated that the prevalence of deafness in
      individuals with the A1555G mitochondrial mutation was likely to be high even in
      the absence of aminoglycoside exposure and clearly showed the association of
      severe to profound hearing loss with the onset of hearing loss before age 10
      years.

PMID- 15179219
TI  - Objective outcome after functional endoscopic sinus surgery: prediction factors.
AB  - OBJECTIVES/HYPOTHESIS: After failure of medical treatment, chronic rhinosinusitis
      and nasal polyposis require surgical management. However, little is known about
      the predictive factors for objective outcome after sinus surgery. The aims of the
      study were to correlate preoperative, intraoperative, and postoperative clinical
      factors to healing outcome and to establish their respective predictive values.
      STUDY DESIGN: Prospective study. METHODS: Eighteen patients who had surgery for
      chronic rhinosinusitis and 18 who had surgery for nasal polyposis at the Ghent
      University Hospital (Ghent, Belgium) were followed for a 6-month period. In all,
      76 operated sides were independently considered. The healing quality was
      evaluated by endoscopy weekly and then monthly for a period of 6 months. A
      logistic regression analysis with healing quality at month 6 as outcome was
      performed on preoperative, intraoperative, and postoperative factors. RESULTS:
      Previous sinus surgery (P =.0006) and initial disease (P =.0430) were found to be
      highly predictive for the healing outcome at month 6, patients with nasal
      polyposis or previous surgery showing significantly worse objective outcome (P
      =.0034 and P <.0001, respectively). The preoperative computed tomography scan had
      no predictive value with respect to the extent of surgery (P =.0281).
      Postoperative parameters had less predictive value. CONCLUSION: Initial disease
      and its severity as reflected by the extent of surgery and surgical antecedents
      were the best predictors for the objective outcome at 6 months after sinus
      surgery. Whereas the first postoperative phase showed similar characteristics for
      all patients, the healing course differed between patients from month 1 to the
      end point.

PMID- 15179220
TI  - Mood improvement after surgery for obstructive sleep apnea.
AB  - OBJECTIVE: Patients with obstructive sleep apnea (OSA) may experience unfavorable
      psychologic symptoms such as depression and anxiety. The aim of this study was to
      confirm this hypothesis and to investigate whether the psychologic symptoms among
      OSA patients can be relieved by surgical intervention. STUDY DESIGN: Prospective,
      longitudinal intervention study. METHODS: The 5-Item Mental Health scale (MH-5)
      was used to evaluate the postoperative changes of mood after extended
      uvulopalatal flap (EUPF) surgery on 84 Taiwanese patients with OSA. The
      preoperative and postoperative MH-5 data obtained from these patients were
      compared with a Taiwanese population norm. RESULTS: Before surgery, the MH-5
      scores of the OSA patients were significantly worse than the Taiwanese population
      norm of 72.8 (P <.0001). Postoperatively, mean MH-5 scores significantly
      increased from 61.8 +/- 16.0 to 70.0 +/- 15.8 (P =.0006). The effect size of this
      score change was 0.51, indicating a moderate degree of mood improvement. However,
      this score was still inferior to that of the population norm (P =.0045). The mood
      improvement was not significantly associated with the changes in either sleep
      apnea events or the level of sleepiness. Neither the changes in respiratory
      disturbance index (P =.4382), maximum arterial oxygen saturation (P =.4866), nor
      the change in Epworth Sleepiness Scale scores (P =.4951) were predictive of the
      MH-5 score improvement (R = 0.07). CONCLUSIONS: This study demonstrated that
      patients with OSA had a higher level of anxiety, depression, and probable
      behavior or personality changes than the population norm. EUPF surgery could
      significantly improve the mood status among OSA patients; the effect of surgery
      was mild but clinically relevant. However, the extent of mood improvement
      experienced by OSA patients receiving operations may not simply be attributable
      to the changes in sleep apnea events or a reduced level of sleepiness.

PMID- 15179221
TI  - Incidence of unexpected malignancies in routine tonsillectomy specimens in
      children.
AB  - OBJECTIVES: Controversy continues to exist regarding the necessity to routinely
      send for histologic examination those specimens obtained after tonsillectomy with
      or without adenoidectomy in children. Otolaryngologists fear missing an
      unsuspected diagnosis, such as a tonsil malignancy. However, given the rare
      incidence of this event, the cost-effectiveness ratio of routine microscopic
      analysis is questionable. The purpose of this study was to assess the incidence
      of clinically relevant unexpected diagnosis among children who underwent
      tonsillectomy with or without adenoidectomy in our units and to review current
      available series on this topic. STUDY DESIGN: Retrospective study and review.
      METHODS: All patients aged less than 16 years who underwent routine tonsillectomy
      (with or without adenoidectomy) at San Gerardo Hospital, Monza, Italy from
      January 1994 to June 2002 were reviewed. Histologic examination is routinely
      performed in our units. Patients were excluded if the primary indication for
      surgery was to rule out a tonsil malignancy. RESULTS: One thousand one hundred
      twenty-three (1,123) patients were recruited. Two cases of non-Hodgkin's lymphoma
      were detected, corresponding to a rate of 0.18% (95% confidence interval [CI]
      0.07-0.56). Three previously published series were identified. The reported
      incidences of unexpected clinically relevant diagnoses varied between 0.0% and
      0.05%. CONCLUSIONS: The results of our study highlight that the incidence of
      unexpected clinically relevant diseases of the tonsil in pediatric patients is
      low, albeit not extremely rare. This finding could be used to perform a cost
      effectiveness analysis.

PMID- 15179222
TI  - Medialization laryngoplasty with strap muscle transposition for vocal fold
      atrophy with or without sulcus vocalis.
AB  - OBJECTIVE: Vocal fold atrophy with or without sulcus vocalis may result in a
      spindle-shaped glottal incompetence (SGI). Because of varying drawbacks with all
      existing materials (e.g., Silastic block, Teflon, fat, etc.) used for
      medialization or augmentation of the atrophic vocal folds, there is a need to
      supplant these materials with a more stable, autologous tissue to correct the
      SGI. STUDY DESIGN: Thirty-two patients with vocal fold atrophy underwent
      medialization laryngoplasty with strap muscle transposition. METHODS: Under local
      or general anesthesia, the thyroid lamina on the more affected side was
      vertically incised 5 mm off the midline. The inner perichondrium was carefully
      elevated from the overlying thyroid ala. Care was taken not to enter the
      laryngeal lumen. After dividing the thyrohyoid and cricothyroid membranes, the
      lamina was retracted laterally. To accommodate the muscle flap more easily, the
      caudal edge of the lamina was trimmed using a small burr. A bipedicled strap
      muscle flap was then transposed into the space between the lamina and the
      paraglottic soft tissue. The thyroid cartilages were carefully sutured back in
      place. All patients underwent pre- and postoperative voice evaluations including
      laryngostroboscopy, perceptual assessment, and acoustic and aerodynamic analyses.
      Patients who had been followed up for more than 3 months were enrolled in this
      study. RESULTS: A total of 27 of the 32 patients with complete pre- and
      postoperative voice function measurements were included in the analysis. Vocal
      improvement was demonstrated in 26 of these 27 (96%) patients. No dyspnea or
      other major complications were noted in any patients. CONCLUSION: The results
      indicate that medialization laryngoplasty with strap muscle transposition is a
      prosthesis-free, safe, and effective technique for correcting SGI caused by vocal
      fold atrophy.

PMID- 15179223
TI  - Difluoromethylornithine-induced reversible hearing loss across a wide frequency
      range.
AB  - OBJECTIVES: Alpha-difluoromethylornithine (DFMO) is an antineoplastic agent that
      causes reversible hearing loss (HL) by an unknown mechanism. Previous neonatal
      gerbil studies have identified a dosing regimen of 1 g/kg per day of DFMO given
      for 3 weeks that results in reversible HL on click-evoked auditory brainstem
      response (ABR). The objectives of this study are 1) to measure HL and recovery at
      several frequencies in neonatal gerbils after DFMO therapy at two different
      dosing regimens and 2) to identify any effects of DFMO on cochlear histology.
      STUDY DESIGN: Prospective, nonrandomized, experimental design with placebo
      controls. METHODS: ABR to tone pips at 2, 4, 8, 16, and 32 kHz were recorded on
      62 21-day-old Mongolian gerbils after daily subcutaneous injections of DFMO
      (group A at 1 g/kg, group B at 750 mg/kg) or saline from day 3 to day 20 after
      birth. Thirty-seven animals were retested after a 3-week drug-free recovery
      period. Twenty-seven animals were killed for analysis of cochlear histology.
      RESULTS: Animals that were administered DFMO demonstrated higher ABR thresholds
      across all five frequencies, with mean threshold differences of 21 to 29 dB in
      group A and 11 to 17 dB in group B as compared with controls. Higher thresholds
      were demonstrated at higher frequencies. Fewer side effects were noted at the
      lower dose. After a 3-week drug-free recovery period, auditory thresholds
      returned to pretreatment levels. No significant cochlear structural abnormalities
      were identified under light microscopy. CONCLUSION: An 18-day regimen of 750
      mg/kg per day of DFMO given subcutaneously in neonatal gerbils causes minimal
      side effects with broad-frequency HL that, after 3 weeks of recovery, is fully
      reversible.

PMID- 15179224
TI  - Nerve-muscle transplantation to the paraglottic space after resection of
      recurrent laryngeal nerve.
AB  - OBJECTIVE: To evaluate a new method of nerve-muscle transplantation (NMT) to the
      paraglottic space after resection of the recurrent laryngeal nerve (RLN) during
      surgery for thyroid cancer. DESIGN: Review of nine consecutive patients with RLN
      paralysis caused by the thyroid cancer before surgery. METHOD: After the usual
      extirpation of the thyroid cancer with concomitant removal of the RLN, the lower
      part of the sternohyoid muscle approximately 1 cm in width and 2 cm in length
      with the ansa cervicalis nerve connected was inserted into the paraglottic space
      by way of anterior retraction of the thyroid ala with the inferior horn cut off.
      When the muscle or the nerve was adhesive to the cancer, the nerve-muscle on the
      opposite side was used with transfer through the space under the thyrohyoid
      muscles and the superior horn of thyroid ala. RESULTS: The voice quality was good
      or fair after surgery. In most patients, the maximum phonation time was 10
      seconds or longer, and the mean flow rate was lower than 200 mL/s. The vocal
      functions were good immediately after surgery and maintained good values for 2
      years or more after surgery. Vocal fold atrophy was not found in any patient.
      CONCLUSION: When the RLN is resected during surgery for thyroid cancer end-to-end
      anastomosis of the nerve is impossible, NMT to the paraglottic space is a useful
      method for preserving good voice and preventing atrophy of the vocal fold.

PMID- 15179225
TI  - A new classification system for congenital laryngeal cysts.
AB  - OBJECTIVES: A new classification system for congenital laryngeal cysts based on
      the extent of the cyst and on the embryologic tissue of origin is proposed. STUDY
      DESIGN: Retrospective chart review. METHODS: The charts of 20 patients with
      either congenital or acquired laryngeal cysts that were treated surgically
      between 1987 and 2002 at the Hospital for Sick Children, Toronto were
      retrospectively reviewed. Clinical presentation, radiologic findings, surgical
      management, histopathology, and outcome were recorded. A new classification
      system is proposed to better appreciate the origin of these cysts and to guide in
      their successful surgical management. RESULTS: Fourteen of the supraglottic and
      subglottic simple mucous retention cysts posed no diagnostic or therapeutic
      challenge and were treated successfully by a single endoscopic excision or
      marsupialization. The remaining six patients with congenital cysts in the study
      were deemed more complex, and all required open surgical procedures for cure. On
      the basis of the analysis of the data of these patients, a new classification of
      congenital laryngeal cysts is proposed. Type I cysts are confined to the larynx,
      the cyst wall composed of endodermal elements only, and can be managed
      endoscopically. Type II cysts extend beyond the confines of the larynx and
      require an external approach. The Type II cysts are further subclassified
      histologically on the basis of the embryologic tissue of origin: IIa, composed of
      endoderm only and IIb, containing endodermal and mesodermal elements (epithelium
      and cartilage) in the wall of the cyst. CONCLUSIONS: A new classification system
      for congenital laryngeal cysts is proposed on the basis of the extent of the cyst
      and the embryologic tissue of origin. This classification can help guide the
      surgeon with initial management and help us better understand the origin of these
      cysts.

PMID- 15179226
TI  - A larynx holder: a device for training in microlaryngeal surgery.

PMID- 15179227
TI  - Scapular bone flap harvests of patients in a supine position.

PMID- 15179228
TI  - Modified translabyrinthine approach and hearing preservation.
AB  - OBJECTIVES/HYPOTHESIS: In 1991, the translabyrinthine approach was modified by
      sealing the vestibule with bone wax, which allowed preservation of the hearing
      function in one patient. The present study aimed specifically at evaluating the
      effectiveness of the modified translabyrinthine approach in preserving hearing
      function in a group of patients with vestibular schwannoma that involved the
      internal auditory canal. STUDY DESIGN: Prospective study. METHODS: The series
      consisted of 12 patients with vestibular schwannoma (average age, 49.7 y). The
      schwannoma was smaller than 2 cm in all patients who had surgery. The patients
      accepted for the study were required to have preserved hearing function. RESULTS:
      None of the patients has shown signs of persistence or tumoral relapse on
      postoperative magnetic resonance imaging. Immediately after surgery, the entire
      group had excellent facial functionality. Six patients had maintained their
      hearing function (four in Class 1 and two in Class 2 according to the Gardner
      Robertson scale) at the last follow-up after surgery. A patient during follow-up
      noted fluctuating hearing contemporarily with a tinnitus in the ear that had
      maintained its hearing, which was attributable to an endolymphatic hydrops. Three
      of the six patients with preserved hearing complained of persistent tinnitus.
      None of the patients had any of the complications or consequences of
      cerebellopontine surgery. CONCLUSION: In our patients, Class 1 or 2 hearing was
      preserved in 50% of the patients, with no persistence or tumoral relapse. The
      follow-up has obviously been short, but the first results are encouraging and
      deserve to be studied further in a more comprehensive survey.

PMID- 15179229
TI  - The appropriate diagnostic threshold for ventilator-associated pneumonia using
      quantitative cultures.
AB  - BACKGROUND: The use of quantitative cultures of the bronchoalveolar lavage (BAL)
      effluent to distinguish between posttraumatic inflammatory response and
      ventilator-associated pneumonia (VAP) is becoming more common. However, the
      diagnostic threshold of either 10 or 10 colonies/mL remains debatable. Because
      mortality from VAP is related to treatment delay, some have chosen a lower
      diagnostic threshold (>10 colonies/mL). This may result in unnecessary antibiotic
      use with its sequelae: increased resistant organisms, antibiotic-related
      complications, and increased costs. The purpose of this study is to determine the
      optimal diagnostic threshold for VAP diagnosis using quantitative cultures of the
      BAL effluent. METHODS: Data on patients with fiberoptic bronchoscopy with BAL are
      maintained in a prospectively collected database at our Level I trauma center.
      This database was reviewed for timing and frequency of BAL and the colony counts
      of each organism identified. Indication for bronchoscopy was clinical evidence of
      VAP. VAP was defined as >10 colonies/mL in the BAL effluent. A false-negative BAL
      was defined as any patient who had <10 colonies/mL and developed VAP with the
      same organism up to 7 days after the previous culture. RESULTS: Over a 46-month
      period, 526 patients underwent 1,372 fiberoptic bronchoscopy procedures with BAL.
      Of these, 72% were male patients, 91% followed blunt injury, and mean age and
      Injury Severity Score were 43 years and 30, respectively. Overall mortality was
      14%. There were 1,898 organisms identified (42% were gram-positive and 58% were
      gram-negative). VAP was diagnosed in 38% of BAL. Overall, there were 43 episodes
      in 38 patients defined as false-negative (3%). The false-negative rate was 9% in
      patients with 10 organisms. The most common false-negative organisms were
      Pseudomonas and Acinetobacter species. CONCLUSION: The VAP diagnostic threshold
      for quantitative BAL in trauma patients should be >10 colonies/mL. One may
      consider a threshold of >10 colonies/mL in severely injured patients with
      Pseudomonas or Acinetobacter species.

PMID- 15179230
TI  - Intubation alone does not mandate trauma surgeon presence on patient arrival to
      the emergency department.
AB  - BACKGROUND: Current American College of Surgeons Committee on Trauma criteria for
      major resuscitation include prehospital respiratory compromise or obstruction
      and/or intubation and mandate an attending trauma surgeon's presence on patient's
      arrival to the emergency department (ED). A substantial number of trauma patients
      arrive intubated, with no other physiologic compromise. We hypothesized that
      field or ED intubation in the absence of other major criteria does not require
      trauma surgeon presence on patient arrival. METHODS: Data were collected from our
      trauma registry on all injured patients intubated in the field or on arrival to
      the ED over a 30-month period ending in June 2003. Patients meeting other
      American College of Surgeons Committee on Trauma criteria (systolic blood
      pressure < 90 mm Hg; gunshot wound to the neck, chest, or abdomen; and unstable
      patient transfers) were excluded. RESULTS: During this period, 7,645 trauma
      patients were admitted to the ED; 834 were intubated, of whom 489 (59%) had no
      other criteria for major resuscitation. One was pronounced dead, 6 were admitted
      to the ward, 415 (85%) were admitted to the intensive care unit, and 67 (14%)
      were transferred directly to the operating room. Twenty-two (4%) required
      nonorthopedic or nonneurosurgical procedures, 11 (2%) of which were for
      hemorrhage control. Twelve of 16 stab wounds (75%) required emergent operation, 7
      (44%) of which were for hemorrhage control. In contrast, 8 (3%) of 244 motor
      vehicle crashes required emergent operation, 4 (2%) of which were for hemorrhage
      control. CONCLUSION: Intubated patients with central stab wounds represent a high
      risk group and should mandate trauma surgeon presence on patient arrival.
      Excluding stab wounds, field or ED intubation alone rarely requires emergent
      surgical decision-making. Therefore, field or ED intubation alone should not
      mandate trauma surgeon presence on patient arrival.

PMID- 15179231
TI  - Protocol-driven ventilator weaning reduces use of mechanical ventilation, rate of
      early reintubation, and ventilator-associated pneumonia.
AB  - BACKGROUND: Mechanical ventilation is the defining event of intensive care unit
      management. To reduce use, a literature-based protocol was introduced to
      facilitate weaning. The effect of protocol-driven ventilator weaning on
      ventilator use, ventilator-associated pneumonia (VAP), and intensive care unit
      (ICU) length of stay (LOS) is described in a survey of 2 years' activity in a
      multidisciplinary surgical ICU. METHODS: Data were gathered from April to
      September 2000 and from April to September 2002 before and after introduction of
      nurse/therapist-driven weaning. VAP was identified by chest radiography, clinical
      presentation, Gram's stains, and cultures from tracheal aspirates or
      bronchoalveolar lavage. Infection control practitioners diagnosed VAP. Failed
      extubation was defined as reintubation within 72 hours. RESULTS: Overall, there
      was a 2:1 ratio of male patients to female patients. The total number of patients
      and days of mechanical ventilation increased, but the use ratio (ventilator
      days/ICU days) fell from 0.47 to 0.33. Patients failing extubation fell from 43
      (in 2000) to 25 (in 2002). From these patients, 17 cases of VAP occurred in 2000
      and 5 in 2002. Mean age (40 years), Injury Severity Score (24), and ICU LOS (5.7
      7.4 days; p = not significant) were unchanged in injured patients. ICU discharge
      was frequently delayed because of the need for subsequent respiratory care.
      CONCLUSION: Protocol-driven weaning reduces use of mechanical ventilation and
      VAP. Injured and general surgical patients show reduction in complications, but
      shorter ICU LOS depends on resources elsewhere in the health care system.

PMID- 15179232
TI  - A prospective evaluation of ultrasonography for the diagnosis of penetrating
      torso injury.
AB  - BACKGROUND: Ultrasound (US) is commonly used for the diagnosis of hemoperitoneum
      after blunt abdominal trauma, but the value of US as an aid for identification of
      operative lesions after penetrating trauma is not well documented. The purpose of
      this investigation was to determine the accuracy of US for the evaluation of
      penetrating torso trauma and to assess the impact of this information on patient
      management. METHODS: We conducted a prospective cohort observational study of
      consecutive penetrating torso patients at a Level I trauma center. RESULTS:
      During the 6-month trial period, 177 victims of penetrating torso trauma were
      assessed by our trauma teams. Ninety-two patients had stab wounds, 84 patients
      had gunshot wounds, and 1 patient had a puncture wound. All 28 patients with
      positive US examination had an exploratory laparotomy or thoracotomy (one patient
      had more than one procedure), resulting in 26 therapeutic operations. There were
      149 negative US examinations, but in this group, 36 patients underwent laparotomy
      or thoracotomy, and 28 had therapeutic operations. The overall accuracy of the US
      examination was therefore 85%, the sensitivity was 48%, and the specificity was
      98%. There were only three patients who had their initial management altered by a
      positive US examination. CONCLUSION: The US examination lacks sensitivity to be
      used alone in determining operative intervention after gunshot or stab wounds.
      Rarely does US information contribute to the management of patients with
      penetrating abdominal injuries.

PMID- 15179233
TI  - Is pediatric trauma still a surgical disease? Patterns of emergent operative
      intervention in the injured child.
AB  - BACKGROUND: Nonoperative management of many pediatric injuries has generated
      debate as to whether surgeons must be routinely involved in the early assessment
      and management of pediatric trauma. This study examines the frequency of
      operative intervention among injured children and evaluates potential predictors
      of emergent intervention. METHODS: Pediatric (age < 18 years) patients were
      identified from the National Trauma Data Bank. Primary outcome measures were
      surgical intervention by specialty, time to intervention, and mortality.
      Prehospital factors were evaluated as predictors of emergent surgical
      intervention. RESULTS: Thirty percent of trauma admissions underwent operative
      intervention, with 57% of these requiring emergent surgery. Patients needing
      emergent general or neurosurgical intervention were at increased risk of death.
      Requiring one type of emergent surgical intervention was predictive of needing a
      second type of emergent procedure. Predictors of emergent general surgical
      intervention were penetrating mechanism, increasing age, and the presence of
      shock or coma. CONCLUSION: These data support the continued routine involvement
      of surgeons in the initial assessment and management of the injured child.

PMID- 15179234
TI  - Initial head computed tomographic scan characteristics have a linear relationship
      with initial intracranial pressure after trauma.
AB  - BACKGROUND: Despite current recommendations by the Brain Trauma Foundation
      regarding the placement of intracranial pressure (ICP) monitoring devices,
      advances in computed tomographic (CT) scan technology have led to the suggestion
      that increased ICP may be predicted by findings on admission head CT scan and
      that patients without such findings do not require such monitoring. A linear
      relationship exists between characteristics of admission head CT scan and initial
      ICP level, allowing for selective placement of ICP monitoring devices. METHODS:
      From 1997 to 2001, a retrospective review of patients admitted with a Glasgow
      Coma Scale (GCS) score < 8 and head CT scan who underwent ventriculostomy
      placement at our institution, was conducted. Patients undergoing craniotomy with
      evacuation of mass lesions before ventriculostomy placement were excluded. Age,
      sex, mechanism of injury, anoxia, osmotic treatment, presence of drugs/alcohol,
      initial mean arterial pressure, initial GCS score, and initial ICP were recorded.
      Initial head CT scans were reviewed independently by two neuroradiologists who
      were blinded to ICP measurements, neurosurgical treatment, patient outcome, and
      each other's interpretation. Initial CT scans were evaluated and scored on a 1
      (normal) to 3 (abnormal) scale with respect to ventricle size, basilar cistern
      size, sulci size, degree of transfalcine herniation, and gray/white matter
      differentiation. Initial ICP readings and CT scan findings were compared to
      determine whether a significant linear relationship existed between the above CT
      scan findings and ICPs. Logistic and univariate linear regression were used to
      compare averaged radiologist score versus dichotomized ICP at baseline. RESULTS:
      Initial head CT scan characteristics show a linear relationship to baseline ICPs.
      These findings are associative, but are not uniformly predictive. CONCLUSION:
      Therefore, the current Brain Trauma Foundation recommendation of ICP monitoring
      in those patients presenting with a GCS score < 8 with an abnormal CT scan or a
      normal CT scan with age > 40 years, systolic blood pressure < 90 mm Hg, or
      exhibiting posturing should be followed.

PMID- 15179235
TI  - Application of a zeolite hemostatic agent achieves 100% survival in a lethal
      model of complex groin injury in Swine.
AB  - BACKGROUND: Techniques for better hemorrhage control after injury could change
      outcome. We have previously shown that a zeolite mineral hemostatic agent (ZH)
      can control aggressive bleeding through adsorption of water, which is an
      exothermic process. Increasing the residual moisture content (RM) of ZH can
      theoretically decrease heat generation, but its effect on the hemostatic
      properties is unknown. We tested ZH with increasing RM against controls and other
      hemostatic agents in a swine model of battlefield injury. METHODS: A complex
      groin injury was created in 72 swine (37 +/- 0.8 kg). This included
      semitransection of the proximal thigh and complete division of the femoral artery
      and vein. After 3 minutes, the animals were randomized to 1 of 10 groups: group
      1, no dressing (ND); group 2, standard dressing (SD); group 3, SD + 3.5 oz ZH
      with 1% RM (1% ZH); group 4, SD + 3.5 oz ZH with 4% RM (4% ZH); group 5, SD + 2
      oz ZH with 1% RM (1% ZH 2oz); group 6, SD + 3.5 oz ZH with 8% RM (8% ZH); group
      7, SD + chitosan-based hemostat, HemCon (HC); group 8, SD + 3.5 oz nonzeolite
      mineral hemostat, Quick Relief (NZH); group 9, SD + bovine clotting factors-based
      hemostat, Fast Act (FA); and group 10, SD + 30 g of starch-based hemostat,
      TraumaDex (TDex). Resuscitation (500 mL of Hespan over 30 minutes) was started 15
      minutes after injury and hemodynamic monitoring was performed for 180 minutes.
      Primary endpoints were survival for 180 minutes and blood loss. In addition,
      maximum wound temperatures were recorded, and histologic damage to artery, vein,
      nerve, and muscle was documented. RESULTS: Use of 1% ZH decreased blood loss and
      reduced mortality to 0% (p < 0.05). Increasing the RM adversely affected efficacy
      without any significant decrease in wound temperatures. Minimal histologic tissue
      damage was seen with ZH independent of the percentage of RM. CONCLUSION: The use
      of zeolite hemostatic agent (1% residual moisture, 3.5 oz) can control hemorrhage
      and dramatically reduce mortality from a lethal groin wound.

PMID- 15179237
TI  - Therapeutic potential of exogenous ubiquitin during resuscitation from severe
      trauma.
AB  - BACKGROUND: Recent studies suggest that extracellular ubiquitin could have a
      physiologic role in immunodepression in sepsis and trauma. The therapeutic
      potential of exogenous ubiquitin after trauma has not been examined. To fill this
      gap, we designed a series of experiments in a clinically relevant trauma model.
      METHODS: Forty minutes after femur fractures and hemorrhage, swine received 1.3
      mg of ubiquitin per kilogram or bovine serum albumin intravenously followed by
      fluid resuscitation to maintain systemic hemodynamics. Leukocyte function and the
      immunomodulatory capacity of serum were assessed measuring endotoxin-evoked tumor
      necrosis factor-alpha (TNF alpha) production ex vivo. TNF alpha and ubiquitin
      were quantified with enzyme-linked immunosorbent assay. RESULTS: Intravenous
      ubiquitin had no significant hemodynamic effect in normal animals. After injury,
      ubiquitin significantly reduced fluid requirements by at least 60% (p < 0.05).
      The injury was associated with transient immunodepression, as reflected by
      reduced endotoxin-evoked TNF alpha production by 40% to 50%. With ubiquitin, this
      response remained depressed for 100 to 160 minutes (p < 0.05), but fully
      recovered to baseline with albumin. CONCLUSION: Ubiquitin is apparently safe and
      effective for reducing fluid requirements as a measure of diffuse capillary leak.
      This immunomodulatory property suggests a new therapeutic approach after injury
      in particular, and for infectious and noninfectious inflammation in general.

PMID- 15179236
TI  - Surgical treatment of liver injury with microwave tissue coagulation: an
      experimental study.
AB  - OBJECTIVE: The purpose of this study was to examine whether microwave tissue
      coagulation (MTC) therapy is capable of stopping bleeding from severe liver
      injury in pigs. METHODS: Ten pigs (38 +/- 4 kg) underwent a 30-mL/kg isovolemic
      exchange transfusion with 3% low-molecular-weight dextran to produce dilutional
      coagulopathy, and then a through-and-through laceration injury measuring
      approximately 8 cm in length was induced in the right hepatic lobe. Immediately
      after inflicting the injury, the animals were randomly divided into two groups:
      Group A (n = 5, MTC was repeated along the liver laceration at intervals of 2.0
      cm with manual compression) or Group B (n = 5, the injured lobe was manually
      compressed without MTC therapy for 1 minute). All animals received lactated
      Ringer's solution to maintain the mean arterial pressure at 75 mm Hg for 1 hour
      after the abdominal closure. The intraperitoneal blood loss, mean arterial
      pressure, volume of lactated Ringer's solution, and hematologic variables were
      compared between the groups. For further laboratory evaluation, three additional
      experimental animals were treated with the MTC therapy after inflicting the
      injury and then were allowed to survive for 14 days. RESULTS: Mean arterial
      pressure declined from a mean value of 88 +/- 10 mm Hg (range, 75-107 mm Hg) to
      62 +/- 3 mm Hg (range, 50-75 mm Hg) after the induction of liver injury. The
      total blood loss in Group A was 192 +/- 58 g (range, 120-250 g), which was lower
      (p < 0.01) than that of 448 +/- 138 g (range, 260-650 g) in Group B. The
      resuscitation fluid volume of Group A animals was 304 +/- 204 mL (range, 100-600
      mL), which was smaller (p < 0.01) than that of 1,320 +/- 654 mL (range, 900-2,250
      mL) in Group B. At 14 days, all three animals that were treated in the additional
      study were found to be in good health. Their necropsies showed no evidence of an
      intrahepatic abscess, hematoma, or biloma. CONCLUSION: MTC therapy was thus found
      to provide simple, rapid, and definitive hemorrhage control in cases of severe
      liver injury without the need for reoperation.

PMID- 15179238
TI  - Impact of shock and fluid resuscitation on the morphology and apoptosis of bone
      marrow: an experimental study.
AB  - BACKGROUND: We hypothesized that bone marrow failure after hemorrhagic shock
      might be secondary to impaired apoptosis regulation. Our objective was to assess
      the morphologic alterations and the rate of apoptosis in bone marrow after
      hemorrhagic shock and resuscitation. METHODS: Under pentobarbital anesthesia,
      Wistar rats (n = 70) underwent femoral vessel cannulation. The hemorrhagic shock
      model involved a controlled retrieval of blood, maintaining mean blood pressure
      at 40 +/- 5 mm Hg during 50 minutes. During the resuscitation period, lactated
      Ringer's (twice the blood volume retrieved, group LR) or NaCl 7.5% (4 mL/kg,
      group HS) was infused, followed by the previously retrieved blood. Bone marrow
      was collected through left femoral puncture. Morphology was assessed by Leishmann
      stained smears, and apoptosis was assessed through terminal deoxynucleotide
      transferase-mediated dUTP nick-end labeling assay. Analysis of variance and
      Tukey's test were applied for statistical treatment, considering p < 0.05 as
      significant. RESULTS: LR animals presented a statistically significant decrease
      in the lymphocytic series (LR, 24.2 +/- 4.2%; Sham, 55.1 +/- 6.6%), together with
      an increase in the percentage of granulocyte (LR, 51.4% +/- 2.3%; Sham, 31.5 +/-
      2.9%) and monocyte precursors (LR, 7.3 +/- 1.3%; Sham, 3.3 +/- 1.1%), detected 72
      hours after shock (p < 0.05). Both LR and HS groups presented a significant
      increase in apoptosis, when compared with the sham group (LR, 13.1 +/- 0.5%; HS,
      12.2 +/- 0.7%; Sham, 6.8 +/- 0.4%). The alterations detected in the bone marrow
      morphology of LR group were not observed in HS animals. CONCLUSION: There was an
      increase in bone marrow apoptosis after hemorrhagic shock. The type of
      resuscitation scheme used did influence bone marrow morphology.

PMID- 15179239
TI  - Is seat belt use associated with fewer days of lost work after motor vehicle
      collisions?
AB  - BACKGROUND: Seat belt use has consistently been shown to reduce motor vehicle
      collision (MVC)-related morbidity and mortality. The goal of this study is to
      determine whether seat belt use is associated with fewer lost workdays among
      occupants involved in MVCs. METHODS: The 1995 to 2000 National Automotive
      Sampling System (NASS) data files were used. The NASS is a national probability
      sample of passenger vehicles involved in police-reported tow-away MVCs.
      Occupants' lost workdays, which are routinely collected as part of an NASS
      investigation, were compared according to seat belt use. RESULTS: During 1995 to
      2000 in the United States, surviving occupants involved in MVCs lost a total of
      42.1 million workdays (approximately 7.0 million lost workdays per year; 2.4 lost
      workdays per person). The overall difference in lost workdays between the belted
      and unbelted occupants was 1.59 days (1.99 days vs. 3.58 days, respectively; p <
      0.001). After adjusting for potentially confounding factors, belted occupants had
      1.52 fewer lost workdays compared with unbelted occupants (p < 0.001). This
      translates to an estimated 7.3 million lost workdays and an associated $566
      million in lost wages and $1.25 billion in work-place costs attributable to lack
      of seat belt use in the United States during 1995 to 2000. CONCLUSION: Lost
      workdays attributable to MVCs in the United States have sizable financial
      implications. Furthermore, seat belt use significantly reduces lost time at work
      and is associated with a significant cost savings. The national impact of
      unbelted driving on work productivity is dramatic, and further efforts to promote
      appropriate seat belt use should continue as part of the national safety agenda.

PMID- 15179241
TI  - Computed tomographic scanning reduces cost and time of complete spine evaluation.
AB  - BACKGROUND: We hypothesize that data collected from computed tomographic (CT)
      scans obtained for workup of chest or abdominal injuries provide data that are
      sufficient to screen for spinal fractures and will decrease the cost and time of
      spine evaluation after trauma. METHODS: We reviewed plain radiographs from 55
      selected trauma patients who also underwent CT scanning of the chest, abdomen,
      and pelvis. We also timed the radiologic workup of 50 consecutive trauma patients
      to determine the time required to complete radiographic spine evaluation.
      RESULTS: Forty-seven patients had thoracolumbar fractures. Thirteen patients were
      found to have 33 thoracolumbar spine fractures identified by CT scan but not
      plain radiography. Fractures were found on initial trauma CT scans of the chest,
      abdomen, and pelvis obtained to evaluate for visceral injuries. No injuries seen
      on plain film were missed on CT scan. CONCLUSION: We recommend using the data
      acquired from CT scans to evaluate the spine, supplementing them with additional
      studies only when needed for further clarification.

PMID- 15179240
TI  - A focused educational intervention can promote the proper application of seat
      belts during pregnancy.
AB  - BACKGROUND: The failure to properly use automobile restraints during pregnancy is
      a significant contributor to both maternal and fetal injury and death.
      Misconceptions as to the effects of restraint use on the fetus and a lack of
      instruction as to proper restraint positioning contribute to this problem.
      METHODS: Focus groups were used to develop an intervention consisting of
      educational material for prenatal care clinic patients and staff pertaining to
      seat belt use during pregnancy. The intervention was administered over a 2-month
      period. Two groups of women, one preintervention and one postintervention, were
      surveyed to determine demographics, pregnancy status, and current restraint use
      characteristics. RESULTS: Preintervention and postintervention surveys were
      administered to 450 and 285 women, respectively. The proportion of women
      reporting correct placement of seat belts increased from 70.8% to 83.0% (p <
      0.001) after the intervention. Knowledge of seat belt effectiveness also
      increased significantly (p < 0.001) after the intervention. Only 25.2% of women
      in the preintervention group reported receiving information from clinic staff on
      restraint use compared with 76.8% of the postintervention group (p < 0.001).
      CONCLUSION: Lack of knowledge regarding restraint use during pregnancy
      contributes to a lack of consistent and proper use of restraints. Educational
      tools that improve both knowledge and behavior have the potential to increase
      automotive safety during pregnancy.

PMID- 15179242
TI  - A comparison of prehospital and hospital data in trauma patients.
AB  - OBJECTIVE: The use of prehospital data as an indicator for trauma team activation
      has been established. The relationship between field (Fd) and emergency
      department (ED) systolic blood pressure (SBP), Glasgow Coma Scale (GCS) score,
      and airway control as it relates to outcomes is unclear. We hypothesized that ED
      and Fd physiologic parameters are equally valid predictors of outcomes. In
      addition, we hypothesized that early field intubation will improve survival
      compared with later ED intubation. METHODS: Trauma registry data from two
      academic Level I centers from 1994 to 2001, excluding all transfers and burn
      patients, were analyzed using Wilcoxon signed-rank test and multivariate logistic
      regression with appropriate adjustments. RESULTS: There were 19,409 patients,
      16,277 blunt and 3,132 penetrating trauma. There were 3,571 Fd and 746 ED
      intubations. ED intubation was associated with increased risk of fatal outcome
      compared with nonintubated patient (adjusted odds ratio, 3.1; p < 0.0001) and
      field intubations (adjusted odds ratio, 3.0; p < 0.0001). ED-GCS score was not
      significantly different from Fd-GCS score, with 82% having the same GCS category.
      This was not the case for SBP, and only in 60% of the cases were ED-SBP and Fd
      SBP in the same category. In 31% of the patients, the ED-SBP increased, and in 9%
      of cases, the ED-SBP decreased compared with Fd-SBP. This was true for both blunt
      and penetrating trauma. Both Fd-SBP and ED-SBP were independent predicators of
      fatal outcome, and mortality rate significantly increased if ED-SBP category
      decreased compared with Fd-SBP. CONCLUSION: Early field intubation was associated
      with a decreased risk of fatal outcome compared with ED intubation. ED-GCS score
      was not significantly different from Fd-GCS score, and either one can be used to
      predict fatal outcome. However, ED-SBP was different from Fd-SBP in 40% of the
      patients, with the majority of cases having higher ED-SBP. Although ED-SBP was a
      better predictor of outcome, the best model is achieved when both ED and field
      SBP are used.

PMID- 15179243
TI  - A survey assessment of the level of preparedness for domestic terrorism and mass
      casualty incidents among Eastern Association for the Surgery of Trauma members.
AB  - OBJECTIVE: The goal of this survey was to establish a benchmark for trauma
      surgeons' level of operational understanding of the command structure for a pre
      hospital incident, a mass casualty incident (MCI), and weapons of mass
      destruction (WMD). The survey was distributed before the World Trade Center
      destruction on September 11, 2001. METHODS: The survey was developed by the
      authors and reviewed by a statistician for clarity and performance. The survey
      was sent to the membership of the 2000 Eastern Association for the Surgery of
      Trauma spring mailing, with two subsequent mailings and a final sampling at the
      Eastern Association for the Surgery of Trauma 2001 meeting. Of 723 surveys
      mailed, 243 were returned and statistically analyzed (significance indicated by p
      < 0.05). RESULTS: No statistical difference existed between level of designation
      of a trauma center (state or American College of Surgeons) and a facility's level
      of pre-paredness for MCIs or WMD. Physicians in communities with chemical plants,
      railways, and waterway traffic were statistically more likely to work at
      facilities with internal disaster plans addressing chemical and biological
      threats. Across all variables, physicians with military training were
      significantly better prepared for response to catastrophic events. With the
      exception of cyanide (50%), less than 30% of the membership was prepared to
      manage exposure to a nerve agent, less than 50% was prepared to manage illness
      from intentional biological exposure, and only 73% understood and were prepared
      to manage blast injury. Mobile medical response teams were present in 46% of the
      respondents' facilities, but only 30% of those teams deployed a trauma surgeon.
      Approximately 70% of the membership had been involved in an MCI, although only
      60% understood the command structure for a prehospital incident. Only 33% of the
      membership had training regarding hazardous materials. Of interest, 76% and 65%,
      respectively, felt that education about MCIs and WMD should be included in
      residency training. CONCLUSION: A facility's level of pre-paredness for MCIs or
      WMD was not related to level of designation as a trauma center, but may be
      positively influenced by local physicians with prior military background.
      Benchmark information from this survey will provide the architecture for the
      development and implementation of further training in these areas for trauma
      surgeons.

PMID- 15179244
TI  - The effect of age on functional outcome in mild traumatic brain injury: 6-month
      report of a prospective multicenter trial.
AB  - OBJECTIVE: Elderly patients (aged 60 years and older) have been demonstrated to
      have an increased mortality after isolated traumatic brain injury (TBI); however,
      the prognosis of those patients surviving their hospitalization is unknown. We
      hypothesized that surviving elderly patients would also have decreased functional
      outcome, and this study examined the functional outcome of patients with isolated
      TBI at discharge and at 6 months posthospitalization. METHODS: This was a
      multicenter prospective study of all patients with isolated moderate to severe
      TBI defined as Head Abbreviated Injury Scale score of 3 with an Abbreviated
      Injury Scale score in any other body area of 1. Patients surviving to discharge
      gave their consent and were enrolled. Data collected included demographics,
      Glasgow Coma Scale (GCS) score at admission, and neurosurgical interventions.
      Outcome data included discharge disposition and Glasgow Outcome Scale score and
      modified Functional Independence Measure (FIM) score at discharge and at 6
      months. RESULTS: Two hundred thirty-five patients were enrolled, with 44 (19%)
      aged greater than or equal to 65 years. Mechanisms of injury were falls (34%),
      assaults (28%), motor vehicle collisions (14%), pedestrian (11%), and other
      (12%). Falls were more common in the older patients and assaults in the younger
      group. The mean admitting GCS score was 12.8 (95% confidence interval [CI], 12.4
      13.3), with older patients having a higher mean GCS score, 14.1 (95% CI, 13.6
      14.6) versus 12.5 (95% CI, 12.0-13.1; p = 0.03). There were no differences in the
      percentage of patients admitted to the intensive care unit or requiring
      neurosurgical intervention between younger and older patients. Because there were
      few elderly patients with low GCS scores who survived to discharge, outcome
      measures focused on those patients with GCS scores of 13 to 15. A greater
      percentage of elderly were discharged to rehabilitation (28% vs. 16%, p =0.08).
      The mean discharge FIM score was 10.4 (95% CI, 9.8-11.0) for the elderly versus
      11.4 (95% CI, 11.1-11.7) for the young (p =0.001), with 68% elderly and 89% young
      discharged with total independent scores of 11 to 12. At 6 months, the difference
      narrowed, but the mean FIM score was still greater for the young group, 11.7 (95%
      CI, 11.6-11.9) versus 11.0 (95% CI, 10.6-11.4; p < 0.001). CONCLUSION: Functional
      outcome after isolated mild TBI as measured by the Glasgow Outcome Scale and
      modified FIM is generally good to excellent for both elderly and younger
      patients. Older patients required more inpatient rehabilitation and lagged behind
      their younger counterparts but continued to recover and improve after discharge.
      Although there were statistically significant differences in the FIM score at
      both discharge and 6 months, the clinical importance of these small differences
      in the mean FIM score to the patient's quality of life is less clear. Measurable
      improvement in functional status during the first 6 months after injury is
      observed in both groups. Aggressive management and care of older patients with
      TBI is warranted, and efforts should be made to decrease inpatient mortality.
      Continued follow-up is ongoing to determine whether these outcomes persist at 12
      months.

PMID- 15179246
TI  - Relationship of early hyperglycemia to mortality in trauma patients.
AB  - INTRODUCTION: Recent randomized prospective data suggest that early hyperglycemia
      is associated with excess mortality in critically ill patients, and tight glucose
      control leads to improved outcome. This concept has not been carefully examined
      in trauma patients, and the relationship of early hyperglycemia to mortality from
      sepsis in this population is unclear. The objective of this study was to
      determine the relationship different levels of early blood glucose elevation to
      outcome in a trauma ICU population. METHODS: The records of all patients admitted
      to the ICU over a 2-year period at a Level I trauma center were reviewed for age,
      injury severity scores (ISS), admission Glasgow Coma Scale (GCS) score, base
      deficit (BD), blood glucose, and mortality. Three possible cutoffs in defining
      hyperglycemia were examined (glucose > or =110 mg/dL, > or =150 mg/dL, > or =200
      mg/dL) in relation to infection and mortality. Early hyperglycemia was defined as
      elevated blood glucose on hospital days 1 or 2. Those with diabetes mellitus were
      excluded. RESULTS: From 1/00-12/01, 516 eligible patients were admitted to the
      ICU after injury. Early hyperglycemia occurred in 483 at the > or =110 mg/dL
      level, 311 at the > or =150 mg/dL level, and 90 patients at the > or =200 mg/dL
      level. Univariate logistic regression demonstrated a significant relationship
      between ISS and subsequent infection(p = 0.02) and a trend toward such a
      relationship in GCS score, glucose > or =150 mg/dL, and glucose > or =200 mg/dL
      (p = 0.06, 0.12, and 0.06). A similar analysis for the relationship of these
      variables to eventual mortality showed a significant correlation with all
      examined variables except glucose > or =110 mg/dL. Multiple logistic regression
      to control for the effect of age, ISS, GCS score, and BD found early glucose > or
      =200 mg/dL to be an independent predictor of both infection and mortality while
      no such relationship was found with > or = 110 mg/dL or > or =150 mg/dL.
      CONCLUSIONS: Early hyperglycemia as defined by glucose > or =200 mg/dL is
      associated with significantly higher infection and mortality rates in trauma
      patients independent of injury characteristics. This was not true at the cutoffs
      of > or =110 mg/dL or > or =150 mg/dL. These data support the need for a
      prospective analysis of tight glucose control, keeping serum glucose <200 mg/dL
      in critically ill trauma patients. However, aggressive maintenance of levels <110
      mg/dL as reported by others may not be necessary.

PMID- 15179245
TI  - Cerebral perfusion pressure elevation with oxygen-carrying pressor after
      traumatic brain injury and hypotension in Swine.
AB  - BACKGROUND: Previously, we had shown that elevation of cerebral perfusion
      pressure, using pressors, improved short-term outcomes after traumatic brain
      injury and hemorrhagic shock in swine. The current study evaluates outcomes after
      resuscitation with diaspirin cross-linked hemoglobin (DCLHb)--a hemoglobin-based
      oxygen carrier with pressor activity--in the same swine model of traumatic brain
      injury and hemorrhagic shock. METHODS: Anesthetized and ventilated swine received
      traumatic brain injury via cortical fluid percussion (6-8 atm) followed by 45%
      blood volume hemorrhage. One hour later, animals were randomized to either a
      control group (SAL) resuscitated with normal saline equal to three times shed
      blood volume or to one of two experimental groups resuscitated with DCLHb. The
      two experimental groups consisted of a low-dose group, resuscitated with 250 mL
      of DCLHb (Hb1), and a high-dose group, resuscitated with 500 mL of DCLHb (Hb2).
      Animals were observed for 210 minutes postresuscitation. Outcomes evaluated were
      cerebral oxygenation by measuring partial pressure and saturation of oxygen in
      cerebrovenous blood; cerebral function by evaluating the preservation and
      magnitude of cerebrovascular carbon dioxide reactivity; and brain structural
      damage by semiquantitatively assessing beta amyloid precursor protein positive
      axons. RESULTS: Postresuscitation, cerebral perfusion pressure was higher in the
      DCLHb groups (p < 0.05, Hb1 and Hb2 vs. SAL), and intracranial pressure was lower
      in the Hb2 group (p < 0.05 vs. SAL). Cerebrovenous oxygen level was similar in
      all groups (p > 0.05). At baseline, 5% carbon dioxide evoked a 16 +/- 1% increase
      in cerebrovenous oxygen saturation, indicating vasodilatation. At 210 minutes,
      this response was nearly absent in SAL (4 +/- 4%) (p < 0.05 vs. baseline) and Hb1
      (1 +/- 5%), but was partially preserved in Hb2 (9 +/- 5%). There was no
      intergroup difference in beta amyloid precursor protein positive axons. Five of
      20 SAL and 0 of 13 DCLHb animals developed brain death (flat
      electroencephalogram) (p = 0.05, SAL vs. DCLHb). Postresuscitation, DCLHb animals
      maintained higher mean pulmonary arterial pressure (28 +/- 1 mm Hg, SAL; 42 +/- 1
      mm Hg, Hb1; 45 +/- 1 mm Hg, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL) and lower
      cardiac output (3.9 +/- 1.6 L/min, SAL; 2.6 +/- 0.1 L/min, Hb1; 2.7 +/- 0.1
      L/min, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL). Three Hb2 animals died as a result
      of cardiac failure, and one SAL animal died as a result of irreversible shock.
      CONCLUSION: In this swine model of traumatic brain injury and hemorrhagic shock,
      resuscitation with DCLHb maintained a higher cerebral perfusion pressure. Low
      dose DCLHb (minimal increase in oxygen carriage) failed to significantly improve
      short-term outcome. With high-dose DCLHb (significant improvement in oxygen
      carriage), intracranial pressure was lower and cerebrovascular carbon dioxide
      reactivity was partially preserved; however, this was at the cost of poorer
      cardiac performance secondary to high afterload.

PMID- 15179247
TI  - Blunt splenic injuries: high nonoperative management rate can be achieved with
      selective embolization.
AB  - BACKGROUND: This retrospective review tests the hypothesis that including
      selective splenic arteriography and embolization in the algorithm of a previously
      existing nonoperative management (NOM) strategy will result in higher rates of
      successful NOM in patients with blunt splenic injury. METHODS: All patients with
      blunt splenic injuries documented by computed tomographic scan and/or operative
      findings over a 24-month period at a Level I trauma center were reviewed. A
      previously published series from this institution of 251 patients with splenic
      injury (Group 1) was then compared with the patients that constitute this current
      review (Group 2). Group 2 was then compared with patients described in a previous
      publication advocating nonselective arteriography in blunt splenic injuries.
      RESULTS: Thirteen patients with blunt splenic injury in Group 2 underwent 14
      splenic embolization procedures, with 12 (93%) being successfully treated without
      operation. Group 2 had a significantly higher NOM rate (82% vs. 65%, p < 0.01)
      than Group 1. These results are similar to the series published by Sclafani et
      al. (82.1% vs. 83.1%) in which every patient with splenic injury that was managed
      non-operatively underwent arteriography with or without embolization. CONCLUSION:
      A high rate of NOM can be achieved with observation and selective use of
      arteriography with or without embolization in the management of blunt splenic
      injuries.

PMID- 15179249
TI  - Acute traumatic spinal cord injury, 1993-2000A population-based assessment of
      methylprednisolone administration and hospitalization.
AB  - BACKGROUND: Administration of methylprednisolone sodium succinate (MPSS) after
      acute traumatic spinal cord injury (TSCI) is controversial. This study compared
      differences in acute care charge, hospital stay, and related variables as a
      function of MPSS receipt. METHODS: Determinants of MPSS administration were
      examined after acute TSCI for South Carolina patients during the period 1993 to
      2000 in a multivariate logistic regression model. RESULTS: Administration of MPSS
      was documented for 48.7% of 1,227 randomly selected patients with TSCI. Patients
      admitted via trauma centers and emergency departments were more likely to receive
      MPSS (trama center level 1 odds ratio [OR], 4.06; 95% CI confidence interval
      [CI], 2.11-7.83; emergency department OR, 1.64; 95% CI, 1.20-2.23). Hospital
      charge and length of stay were significantly higher for MPSS recipients.
      CONCLUSIONS: The study findings indicate MPSS use is associated with higher acute
      care charges and longer hospital stays. These findings suggest the need for
      outcome studies to assess the long-term benefits of MPSS administration.

PMID- 15179248
TI  - The utility of clinical and laboratory data for predicting intraabdominal injury
      among children.
AB  - BACKGROUND: The initial assessment of the child with blunt injury should lead
      ideally to a low rate of missed intraabdominal injury (IAI) while avoiding
      unnecessary imaging among children without IAI. The purpose of this study was to
      determine the utility of clinical and laboratory data for predicting the risk for
      IAI. METHODS: Among 351 children evaluated for possible blunt abdominal trauma,
      23 variables potentially associated with IAI were determined retrospectively.
      Logistic regression and recursive partitioning were used to identify variables
      and develop predictive models. RESULTS: Logistic regression identified four
      positive predictors (abdominal tenderness, abrasion, ecchymoses, and alanine
      aminotransferase) and two negative predictors (injury caused by a motor vehicle
      crash and hematocrit) for IAI. The recursive partitioning model predicted the
      absence of IAI with a sensitivity of 100% (95% CI confidence interval, 86-100%)
      and a specificity of 87% (95% CI confidence interval, 81-91%) using abdominal
      examination and aspartate aminotransferase as discriminating variables.
      CONCLUSIONS: Physical examination combined with selected laboratory studies can
      be used to predict the risk of IAI accurately among children who sustain blunt
      trauma. Application of these findings may be useful in reducing costs and
      improving the accuracy of diagnosing IAI among children.

PMID- 15179250
TI  - Glasgow Coma Scale score, mortality, and functional outcome in head-injured
      patients.
AB  - BACKGROUND: Preresuscitation Glasgow Coma Scale (P-GCS) score is frequently
      obtained in injured patients and incorporated into mortality prediction. Data on
      functional outcome in head injury is sparse. A large group of patients with head
      injuries was analyzed to assess relationships between P-GCS score, mortality, and
      functional outcome as measured by the Functional Independence Measure (FIM).
      METHODS: Records for patients with International Classification of Diseases,
      Ninth Revision diagnosis codes indicating head injury in a statewide trauma
      registry between 1994 and 2002 were selected. P-GCS score, mortality, and FIM
      score at hospital discharge were integrated and analyzed. RESULTS: Of 138,750
      patients, 22,924 patients were used for the mortality study and 7,150 patients
      for the FIM study. A good correlation exists between P-GCS score and FIM, as
      determined by rank correlation coefficients, whereas mortality falls steeply
      between a P-GCS score of 3 and a P-GCS score of 7 followed by a shallow fall.
      Although P-GCS score is related to mortality in head-injured patients, its
      relationship is nonlinear, which casts doubt on its use as a continuous measure
      or an equivalent set of categorical measures incorporated into outcome prediction
      models. The average FIM scores indicate substantial likelihood of good outcomes
      in survivors with low P-GCS scores, further complicating the use of the P-GCS
      score in the prediction of poor outcome at the time of initial patient
      evaluation. CONCLUSION: Although the P-GCS score is related to functional outcome
      as measured by the FIM score and mortality in head injury, current mortality
      prediction models may need to be modified to account for the nonlinear
      relationship between P-GCS score and mortality. The P-GCS score is not a good
      clinical tool for outcome prediction in individual head-injured patients, given
      the variability in mortality rates and functional outcomes at all scores.

PMID- 15179251
TI  - Factors associated with mortality in trauma: re-evaluation of the TRISS method
      using the National Trauma Data Bank.
AB  - BACKGROUND: TRISS remains a standard method for predicting survival and
      correcting for severity in outcome analysis. The National Trauma Data Bank (NTDB)
      is emerging as a major source of trauma data that will be used for both primary
      research and outcome benchmarking. We used NTDB data, to determine whether TRISS
      is still an accurate predictor of survival coefficients and to determine whether
      the ability of TRISS to predict survival could be improved by updating the
      coefficients or by building predictive models that include information on co
      morbidities. METHODS: To compare the utility of different methods of TRISS
      calculation we identified the records of 72,517 trauma patients (62,103 blunt
      trauma and 10,414 penetrating trauma) who had complete information for all of the
      covariates to be considered in the analysis. Multiple logistic regression was
      used to recalculate the TRISS coefficients in models using both the original
      TRISS covariates and in models which also included variables for co-morbidities
      that could potentially affect survival. Model discrimination was evaluated by
      calculating the area under the receiver operating characteristic curves (AUC),
      and model calibration was evaluated with the Hosmer-Lemeshow Goodness-of-Fit
      Statistic (H-L). RESULTS: For penetrating trauma the original TRISS equation had
      good discriminative ability (AUC=0.98), but was poorly calibrated (H-L=267.04).
      When logistic regression was used to generate revised coefficients,
      discrimination was unchanged, but calibration improved (H-L=38.66). The only co
      morbid factor significantly associated with survival after penetrating trauma was
      acute alcohol consumption, which was associated with increased survival (p <
      0.0001). However, its inclusion in a logistic model did not improve
      discrimination, but improved calibration somewhat (AUC =0.98; H-L=19.95). The
      original TRISS equation was a less accurate predictor of survival after blunt
      trauma (AUC = 0.84; H-L= 10,720.7). When logistic regression was used to generate
      revised coefficients for the original TRISS covariates, predictions after blunt
      trauma improved (AUC = 0.94; H-L=25.45). With blunt trauma, acute alcohol
      consumption and prior hypertension were associated with increased survival, and
      male gender, congestive failure, cirrhosis, and prior myocardial infarction were
      associated with decreased survival. However, inclusion of these covariates in a
      logistic model did not improve predictions of survival (AUC = 0.94; H-L= 34.83).
      CONCLUSIONS: In the NTDB the traditional TRISS had limited ability to predict
      survival after trauma. Accuracy of prediction was improved by recalculating the
      TRISS coefficients, but further improvements were not seen with models that
      included information about co-morbidities.

PMID- 15179252
TI  - Blind nasotracheal intubation for patients with penetrating neck trauma.
AB  - BACKGROUND: Early airway management is advocated for patients with penetrating
      neck trauma who have any signs of airway compromise. This study examined the
      clinical course of patients with penetrating neck trauma who received prehospital
      blind nasotracheal intubation, including successful intubation rates, and
      outcomes. METHODS: A retrospective review of patients admitted to the emergency
      department for penetrating neck trauma was conducted from January 1, 1993 to July
      1, 2001 at the Denver Health Medical Center. Patients were identified from the
      trauma registry, and data were collected using standardized inclusion and
      exclusion criteria. RESULTS: The study identified 240 patients with penetrating
      neck trauma. Overall mortality was 8.3%. Among the 240 patients, 89 (37%)
      required airway management, and 40 (17%) underwent prehospital management with
      blind nasotracheal intubation. The success rate for prehospital intubation using
      the blind nasotracheal method was 90%. The mean number of attempts was 1.16
      (range, 1-4), and the mortality in this group was 5%. CONCLUSION: The patients
      managed with blind nasotracheal intubation did not experience complications
      related to the choice of airway management. Despite prior warnings in the
      literature, the results of this study suggest that blind nasotracheal intubation
      may well be a valuable tool for the management of patients with penetrating neck
      trauma.

PMID- 15179253
TI  - Transacromial Knowles pin in the treatment of Neer type 2 distal clavicle
      fracturesA prospective evaluation of 32 cases.
AB  - BACKGROUND: The high rate of non-union makes surgical intervention necessary for
      a distal clavicle fracture. This report presents the outcome of a simple surgical
      method using a transacrominal Knowles pin for this unstable fracture. METHODS: In
      this study, 32 patients with Neer type 2 distal clavicle fractures were treated
      using a single transacromial Knowles pin without repair of the torn ligament. All
      32 patients were studied prospectively and followed up for a mean of 80 months
      (range, 12-132 months). The clinical outcome was evaluated with the UCLA score,
      and the fracture union was judged roentgenographically. RESULTS: All the patients
      showed excellent results with solid union. The mean union time was 6.8 weeks
      (range, 4-12 weeks). No major complication was noted, and only one asymptomatic
      acromioclavicular arthrosis developed. CONCLUSIONS: Single transacrominal Knowles
      pin fixation offers a simple and safe method for treating patients with displaced
      Neer type 2 distal clavicle fractures.

PMID- 15179254
TI  - Sixty-five clinical cases of free tissue transfer using long arteriovenous
      fistulas or vein grafts.
AB  - Traumatic limb injuries requiring free tissue transfer for coverage, often lack
      healthy recipient vessels adjacent to the defect. In these patients, vein grafts
      are required to bridge the gap of either the artery, vein or both. For the latter
      situation, a temporary arteriovenous fistula (AVF) can be created and allowed to
      mature and then divided and used as recipient artery and veins for the free flap.
      These cases are challenging and several variables including vein graft length,
      vein graft diameter, and arterial inflow affect the patency of the vessels and
      the final outcome of the reconstruction. Sixty-five defects were reconstructed
      with free tissue transfers using vein grafts of significant length (>20 cm for
      the arterial gap). The ipsilateral or contralateral great saphenous veins were
      used for vessel lengthening in all cases. Inflow arteries were either major
      arteries (superficial femoral, popliteal or brachial), or lesser arteries (sural,
      anterior or posterior tibial, thoracodorsal, or superior gluteal). The patients
      were divided into those that underwent AVF followed by free tissue transfer in
      two stages (n = 6), AVF followed by free tissue transfer in one stage (n = 28)
      and patients that underwent vein grafting for the arterial defect only with (n =
      6) or without (n = 25) a simultaneous bypass graft for lower limb
      revascularization. In the two-stage AVF group, the rate of occlusion of the graft
      after AVF creation was 50% (3/6); re-exploration rate was 33.3% (2/6); free flap
      failure rate was 33.3% (2/6); and limb salvage rate was 83.3% (5/6). In the one
      stage AVF group: re-exploration rate was 28.6% (8/28); free flap success rate was
      89.3% (25/28); and limb salvage rate was 92.9% (26/28). In the long vein graft
      group for arterial defects only: re-exploration rate was 25.8% (8/31); free flap
      success rate was 96.8% (30/31); and limb salvage rate was 87.1% (27/31). In
      patients where the graft was anastomosed to a major artery the re-exploration
      rate and free flap failure rate were 22.4% (11/49) and 8.2% (4/49). In patients
      where the graft was anastomosed to a lesser artery, the re-exploration rate and
      free flap failure rate were 43.4% (7/16) and 12.5% (2/16). The limb salvage rate
      was comparable in both groups (89.8%, 44/49, versus 87.5%, 14/16). In all groups,
      patients undergoing re-exploration were noted to have a an arterial gap of 31.78
      cm as compared with the patients that did not require re-exploration which had an
      arterial gap of 26.26 cm. Vein grafting for bridging vascular defects is a safe
      procedure when proper indications and techniques are followed. Although a longer
      graft length seemed to be associated with a higher re-exploration rate, there was
      no statistical significance. One-stage AVFs can be used with good results,
      however, two-stage AVFs are associated with a high graft occlusion rate, wound
      failure rate and limb amputation rate. In all cases, a large caliber graft such
      as the great saphenous vein provided a large (relatively low resistance) conduit
      for bridging the defect.

PMID- 15179255
TI  - Composite palmaris longus-venous flap for simultaneous reconstruction of extensor
      tendon and dorsal surface defects of the hand--long-term functional result.
AB  - Soft tissue loss in the dorsum of the hand resulting from trauma often involves
      the extensor mechanism due to its thin skin coverage. When such composite skin
      and extensor tendon defects occur, the wound could be reconstructed with an
      ipsilateral forearm venous flap with accompanying palmaris longus tendon.
      Eighteen dorsal finger defects in 12 patients underwent composite venous flap and
      tendon transfers in the acute stage. We used both Buck-Gram-cko and Tubiana's
      methods for objective functional assessments. With the former method, the average
      composite flexion, extension deficit, and total active motion were 207.2 degrees,
      39.0 degrees, and 164.7 degrees, respectively. The average score was 12.1 points,
      which qualified for a "good" result. With Tubiana's method, the average active
      flexion was 4.9, and the average extension defect was 2.3. The average score was
      7.2 point, which also qualified for a "good" result. Thus, a one-stage composite
      forearm venous flap could be used to reconstruct dorsal skin and tendon defects
      of the finger with a predictably good functional outcome.

PMID- 15179256
TI  - Rapid sequence intubation of trauma patients in Scotland.
AB  - BACKGROUND: Endotracheal intubation remains the gold standard for trauma airway
      management. Rapid sequence intubation (RSI) has traditionally been performed by
      anesthesiologists but increasingly, emergency physicians are also undertaking
      RSI. We aimed to compare success and complication rates for trauma intubations
      for the two specialties. METHODS: Two year, prospective multi-center descriptive
      study of trauma RSI in seven Scottish urban emergency departments. RESULTS: 439
      trauma patients were identified, including 233 RSIs. Patients intubated by
      emergency physicians had a higher median ISS (p < 0.001) and lower median RTS (p
      < 0.001) compared with anesthesiologists. For RSI, anesthesiologists had more
      grade I & II views at laryngoscopy (p = 0.051) and more successful first attempt
      intubations (p = 0.034) but there was no difference in the number of patients
      suffering complications (emergency physicians 10.0%, anesthesiologists 10.6%).
      CONCLUSION: There is no significant difference in complication rates for trauma
      RSI between emergency physicians and anesthesiologists in Scottish urban centers.
      A collaborative approach to the critical trauma airway is vital. Emergency
      physicians should consult with senior anesthesiologists before RSI when
      intubation is predicted to be difficult.

PMID- 15179257
TI  - Life-threatening hemorrhage during microvascular free tissue transfer in a non
      hemophiliac patient with acquired inhibitor to factor VIII.

PMID- 15179258
TI  - Survival after severe penetrating non-missile brainstem injury: case report.

PMID- 15179259
TI  - Transient adrenocortical insufficiency following traumatic bilateral adrenal
      hemorrhage.

PMID- 15179260
TI  - Management of penile fracture.
AB  - BACKGROUND: Penile fracture is not a frequent event. It consists of rupture of
      the tunica albuginea of the corpora cavernosa. Fracture occurs when the penis is
      erect, as the tunica is very thin and not flexible. METHODS: This prospective
      study was carried out over a period of 1 year and included 12 patients presenting
      with penile fracture. RESULTS: Diagnosis was made clinically, and there was no
      need to perform cavernosography in any case. The most common cause of fracture
      was trauma to the erect penis during intercourse. Mean age of patients was 29.5
      (+8.96) years, and mean time of presentation was 15.5 (+8.04) hours. Subcoronal
      circumferential degloving incision was done in all cases. Nine patients were
      operated on, and three patients refused surgery and were treated conservatively.
      Repair consisted of evacuation of hematoma and repair of the tunical defect with
      absorbable sutures. The mean operative time was 33.9 (+8.2) minutes. Preoperative
      and postoperative antibiotics were used, and all operated cases were discharged
      on the second postoperative day. All operated cases were able to achieve full
      erection with straight penis except one, in whom mild curvature and pain during
      erection was observed. CONCLUSION: Penis fracture is a true urologic emergency.
      It should be treated surgically as early as possible to ensure a better outcome.

PMID- 15179261
TI  - Cystoscopic removal of a large-caliber bullet from the left ureter: a case report
      of missile migration after a gunshot wound.

PMID- 15179262
TI  - Delayed presentation of small bowel injury after blunt abdominal trauma: case
      report.

PMID- 15179263
TI  - Successful pregnancy outcome after splenic artery embolization for blunt maternal
      trauma.

PMID- 15179264
TI  - Posttraumatic diaphragmatic eventration.

PMID- 15179265
TI  - Multiple border-zone infarcts after hemorrhagic shock in trauma victims: three
      case reports.

PMID- 15179266
TI  - New approaches to shock and trauma research: learning from multidisciplinary
      exchange.
AB  - BACKGROUND: Our understanding of the complex network of pathophysiology after
      multiple injury is limited. It is proposed to overcome the limitations of the
      traditional linear reductionism approach by merging the expertise of biology and
      medicine with other disciplines such as mathematics, physics and computer
      science. METHODS: We organized a two-days-workshop, where surgeons and surgical
      scientists explained the problem from the medical (pathophysiological)
      perspective to a well selected group of German applied mathematicians and
      computer scientists. Vice versa they presented and discussed their approaches to
      complex system analysis. RESULTS AND CONCLUSIONS: Physicians found it difficult
      to develop questions and concepts that go beyond the classic mechanistic
      thinking. Well formulated questions are the most important prerequisites for
      successful application of mathematical tools. The possibilities and borders of
      Artificial Neural Networks (ANN), Hidden Markow Models (HMM), Agent Based Models
      (ABM), differential equations for problem solving were discussed. There is no
      master model for all aspects of pathophysiology, however, application of the
      models to specific problems is mandatory. CONCLUSIONS: Future breakthroughs can
      only be expected if we overcome language problems between disciplines. This cross
      talk was considered by all participants as a most important step.

PMID- 15179267
TI  - Centers for Disease Control and Prevention injury research agenda: identification
      of acute care research topics of interest to the Centers for disease Control and
      Prevention--National Center for Injury Prevention and Control.
AB  - BACKGROUND: The purpose of this report is to identify the most important research
      questions pertaining to the acute care of the injured patient using a Web-based
      Delphi technique to achieve expert opinion consensus. METHODS: Experts in trauma
      care from the United States and Canada (n =39) generated structured research
      questions and then ranked these questions in order of importance, using a Web
      based survey for question generation, question ranking, and a Delphi technique of
      consensus. Guidelines for question construction and ranking specified that
      participants considered questions that fall within the interest and domain of the
      Centers for Disease Control (CDC)-National Center for Injury Prevention and
      Control (NCIPC). RESULTS: One hundred thirty-seven questions in 18 distinct
      categories of interest were initially generated. After two rounds of merging,
      collating, reassessing, and ranking by significance and importance, 25 research
      questions were deemed most important and significant in the care of the injured
      patient. Ten of these (40%) were considered to be appropriate issues for the CDC
      NCIPC to address and fund, dealing with injury prevention strategies, trauma
      systems design and funding, the epidemiology of injury, and global outcome
      determinants. These 25 questions were also reviewed with consideration given to
      the most likely source of federal funding of investigations. CONCLUSION: This
      report identifies the areas of trauma care in which research efforts might best
      be directed. Fully 40% of the key research questions could be considered to fall
      under the interest and auspices of the CDC-NCIPC. The remaining questions cover a
      broad range of topics and likely funding sources, emphasizing the need for a
      coordinated oversight of research funding in trauma care.

PMID- 15179268
TI  - Active bleeding from a lacerated appendicular artery in a blunt trauma patient.

PMID- 15179270
TI  - Vestibular schwannomas.

PMID- 15179271
TI  - [Vestibular schwannomas radiosurgery].

PMID- 15179272
TI  - [New developments in the management of vestibular schwannomas in the modern era
      of radiosurgery].

PMID- 15179273
TI  - [Homage to professor Robert Sedan].

PMID- 15179274
TI  - [Evolution of vestibular schwannoma surgery].

PMID- 15179275
TI  - [Microsurgery of vestibular schwannoma: persisting questions].

PMID- 15179276
TI  - [Functional outcomes after translabyrinthine approach for vestibular
      schwannomas].
AB  - PURPOSE: The aim of this paper is to present the functional outcomes after
      translabyrinthine approach (TLA) for vestibular schwannoma (VS). We analyzed data
      from 95 patients who had undergone surgery on between 1991 and 2001. METHODS:
      This retrospective study of clinical and radiological data concerned 95 patients
      operated on by TLA for a unilateral vestibular schwannoma, excluding NF2 patients
      and those who have been operated on after a gamma-knife treatment. Results were
      evaluated with at least 2 Years follow-up and compared with recent data in the
      literature. RESULTS: Complete tumor removal was achieved in 84% of cases. The
      facial nerve was normal at the end of the operative procedure in 85%. Facial
      nerve function was evaluated in 90 patients with two Years follow-up: 62% were
      grade I or II according to the House and Brackmann scale, 21% were grade III and
      16.5% grade IV to VI. CSF leakage was noted in 8.4% including rhinorrhea in 4.2%.
      No deaths occurred during this period. CONCLUSION: The results related here show
      that TLA is a safe and efficient procedure for the removal of large acoustic
      neuromas.

PMID- 15179278
TI  - [Radiology of radiosurgery].
AB  - Proper understanding of the fundamentals of radiosurgery and the main principles
      of radiobiology is a key point for the development and adaptation of therapeutic
      strategies and for the definition of indications. The prediction of local effects
      of radiosurgery requires taking into account both the target Volume and the
      marginal dose (energy,...) and not only the marginal dose which alone is poorly
      predictive of the outcome. Other additional factors such as topography, age,
      previous irradiations,... are likely to influence this risk relationship. The
      comparison of different dose regimens leads to proposing theoretical models for
      calculating radiobiological equivalences: the Biological Equivalent Dose (BED)
      Using these models one can think in terms of the practical consequences of dose
      fractionation. This allows, depending on the medical context, identifying the
      potential advantages of the radiosurgery or of a fractionated regimen. For small
      mid-sized vestibular schwannomas this approach indicates a clear advantage for a
      single-dose regimen. Retrospectively it has been possible to identify the dose
      Volume relationship to the risk of neuropathy for facial motor function, facial
      sensitivity, and hearing.

PMID- 15179277
TI  - Gamma knife radiosurgery of acoustic neurinomas. A historic perspective.

PMID- 15179279
TI  - [Radiosurgery: basic principles].
AB  - Radiosurgery is a way of treating in-brain lesions which uses convergence of very
      thin multiple ionisation beams in a unique focus point coinciding with the
      target. This enables obtaining a therapeutic effect without opening the skull,
      and thus avoiding eventual complications or contraindications of classical
      neurosurgery. In certain cases irradiation can be delivered with submillimetric
      precision. This particularly new approach is historically essentially based on
      the work of the Swedish neurosurgeon Lars Leksell in the 50s. Since that time new
      imaging techniques (e.g. digital imaging) have considerably widened indications.
      Three ionisation beam sources are generally used in this context: gamma rays
      emitted by radioactive cobalt 60 sources for the Gamma Knife, high energy LINAC X
      rays modified in comparison to their classical use in external radiation therapy,
      and, more rarely, protons produced in cyclotrons. Several teams world-wide are
      still perfecting and refining this developing technique.

PMID- 15179280
TI  - [Stereotactic mapping for radiosurgical treatment of vestibular schwannomas].
AB  - RATIONALE: As an exclusively image-guided surgery method, radiosurgery requires
      special attention in the choice of imaging modalities and acquisition parameters
      must be set with extreme care. METHODS: Quality control for resolution and
      accuracy of computed tomography (CT) scanners must be performed. Magnetic
      resonance imaging (MRI) distortions should be limited through magnetic field
      homogeneity adjustment (shimming) and acquisition parameters optimization. These
      inaccuracies should then be quantified through systematic combination of MRI and
      CT in the radiosurgery planning system. MRI pulse sequences selection criteria
      are defined by their ability to delineate tumor contrast enhancement and to image
      cranial nerves and vessels relative arrangement in the cistern and canal.
      Topography of the petrous structures, such as cochlea, vestibulum and facial
      nerve canal should be visible. Exact definition of real extension of the lesion
      at the end of the canal may require specific technical solutions. These technical
      requirements must be balanced depending on the lesion Volume staging (Koos), the
      treatment history (microsurgery), the clinical condition (hearing quality), the
      pathological context (NF2) or the age of the patient. RESULTS: T1-weighted
      Volumetric MRI pulse sequences (3D-T1) show a contrast enhanced signal that is
      useful for both the pons interface delineation in Koos III cases, and the canal
      ending in Ohata A and B. On the other hand, 3D-T1 introduce inaccuracies from
      magnetic susceptibility distortions and partial Volume effects. High resolution
      CISS T2-weighted Volumetric pulse sequences (3D-T2) give superior stereotaxic
      definition attributable to their better resolution (half a millimeter) minimizing
      partial Volume effects and to their lower magnetic susceptibility minimizing
      distortions. 3D-T2 allows direct nerve visualization. Moreover, this pulse
      sequence with contrast injection, show improved distinction between the pons and
      the nerves due to signal differences within the schwannomas. Fat saturation pulse
      sequences are of interest in post-microsurgery conditions. CONCLUSIONS: Radiology
      phase quality is critical and its complexity requires a high commitment to obtain
      satisfactory clinical results. Solelt the 3D-T1 MRI modality seems to us not to
      comply to minimum security criteria.

PMID- 15179281
TI  - [Imaging for stereotaxic treatment of vestibular schwannomas. Error factors and
      corrections].
AB  - BACKGROUND AND PURPOSE: Gamma Knife radiosurgery treatment of vestibular
      schwannomas requires high accuracy for the prescribed dose definition and
      delivery. The main factors contributing to the error are the anatomical
      distortions of imaging modalities used for treatment planning. Imaging
      limitations and error factors are reviewed and detailed. Multimodality rationale
      for the delineation of vestibular schwannomas and surrounding structures are
      assessed. Quality control strategies are discussed and a distortion correction
      technique using a radiological phantom is presented. METHODS: Computed tomography
      is considered as the reference for spatial accuracy after appropriate scanner
      quality control using the stereotaxic fiducials system. Magnetic resonance
      imaging pulse sequence distortions are measured with a phantom designed for 3D
      non-linear local distortion evidence. A distortion correction transformation is
      computed from the phantom images and applied to the patient images. Results are
      verified using the stereotaxic fiducials system. RESULTS: Fiducials registration
      errors show spatial accuracy improvement, approaching computed tomography
      quality, after distortion correction of magnetic resonance images. CONCLUSIONS:
      The multimodal imaging approach for the dose planning of vestibular schwannomas
      radiosurgery treatment is relevant. Quality control of spatial accuracy for
      imaging modalities is mandatory and realistic in clinical routine.

PMID- 15179282
TI  - [Dosimetric planning for radiosurgical treatment of vestibular schwannomas].
AB  - Dosimetry planning is certainly the most typical neurosurgical instant in the
      radiosurgical procedure for the treatment of vestibular schwannomas (VS). Indeed,
      it is a key-moment in which the therapeutical choices will have a major influence
      on the clinical results, in terms of efficacy and safety. The therapist has to
      inform the patient about the rationale of the treatment, its limitations, the
      expected results, and the specific risks. Deep knowledge of the radiosurgical
      technique, of the principles of dosimetry, and of the therapist's personal
      experience, allows an a posteriori analytical study of the influence of the
      dosimetry therapeutic choices on the patient's outcome. Correlation between the
      preoperative therapeutic choices and the postoperative clinico-radiological
      information is mandatory to optimize therapeutic strategies. These therapeutic
      choices should be the result of a reflection integrating the clinical status of
      the patient, an understanding of the specific pathology of VS, awareness of the
      other therapeutic choices, and knowledge of radiological and surgical anatomy.
      The way a certain number of parameters will be defined during the dosimetry
      planning will have a major influence on the clinical results. This explains wide
      variability of clinical results from one operator to another, for the same
      radiological and radiosurgical tools. This emphasizes the need for specific and
      long-term training, associated with continuous education and a good knowledge of
      the very active literature.

PMID- 15179283
TI  - [Functional outcomes of radiosurgical treatment of vestibular schwannomas: 1000
      successive cases and review of the literature].
AB  - RATIONALE: To evaluate the functional results of Gamma Knife surgery of
      vestibular schwannomas relying on a large and prospective series of consecutive
      cases. MATERIAL AND METHOD: The first 1000 patients with cerebello-pontine angle
      schwannomas were consecutively treated by Gamma Knife in Marseille Timone
      University Hospital between July 1992 and March 2001. Patients without NF2 and or
      clinico-radiological arguments in favor of a facial origin accounted for a
      population of 927 patients (414 males, for 513 females) including 843 treated in
      first intention. In this series the Koos classification was: stage I 77 patients,
      stage II 520 patients, stage III 287 patients and stage IV 42 patients. The
      average Volume was 12.7mm3. Haring was usefull (Gardner and Robertson) before
      radiosurgery in 47% of the patients (subnormal in 20.3%). RESULTS: Tumor control
      at last follow-up was 97%. Globally, a clinical trigeminal injury was observed in
      0.6% of the patients and a facial palsy in 1.3%. There was clearly a decrease of
      the incidence of neuropathies with time; no facial palsy being reported among the
      last 258 patients. The rate of functional hearing preservation (Gardner) for
      patients initially in class I was 77.8% (47.6% for class II) at 3 Years. This
      rate of functional preservation reached 95% among patients with tinnitus as a
      first symptom. CONCLUSION: Today, strong evidence surports the superiority of
      Gamma Knife surgery in term of functional perservation and equal efficacy
      compared with microsurgical removal. Consequently, radiosurgery must be preferred
      as a first intention choice for young patients with few symptoms presenting with
      a small to middle size vestibular schwannomas (Koos I-III).

PMID- 15179284
TI  - [Changing radiological results, pitfalls and criteria of failure].
AB  - RATIONALE: To evaluate the morphological changes occurring during the Years
      following radiosurgery in order to better define the cure-failure parameters.
      MATERIAL AND METHODS: Between July 1992 and January 2002 the otoneurosurgical
      group of the Timone Hospital in Marseille have operated 1000 vestibular
      schwannomas. The MR imaging performed before (at diagnosis) during and after
      radiosurgery (6 months, 1 year, 2 years, 3 years, 5 years, 7 years and 10 years)
      was carefully studied. Systematically six lenghts measurements were obtained for
      each lesion. RESULTS: Preoperatively 129 patients were had progressive tumors. At
      time of radiosurgery, median tumor Volume was 732mm3 (mean: 1346, range: 20
      14405). According to the Koos topographical classification, lesions were stage I
      in 80 patients, stage II in 538 patients, stage III in 322 patients and stage IV
      in 56 patients. A clear loss of the central enhancement was visible on the
      postoperative MR control at 6 months and/or 1 Year in 45.5% of patients. In 64%
      of these patients, this loss of the central contrast enhancement have
      disappeared. A significant increase of the tumor size was recorded in 15% of the
      patients. The median increase was 62% (mean: 78%, range: 30-350%). Progression
      led to salvage surgery (either resection or radiosurgery), in only 3% of the
      patients. CONCLUSION: The specificity of the morphological changes after
      radiosurgery, when ignored, can lead to misinterpretation and eventually to
      inappropriate decisions, dangerous for the patient. The analysis of our results
      had led us to consider continuous progression after 3 Years as mandatory to
      retain the diagnosis of failure.

PMID- 15179285
TI  - [In vivo evaluation of tumor response to radiosurgery: application to vestibular
      schwannomas].
AB  - Imaging follow-up of vestibular schwannomas (VS), such as CT or MR, does not
      allow assessing the response of the tumor tIssue to radiosurgery. Changes in
      contrast enhancement are frequently observed, with a loss of contrast enhancement
      within the treated VS. However, this typical aspect does not anticipate the long
      term success of radiosurgery for VS. New functional and metabolic image
      modalities could be useful to assess in vivo radiosurgery-induced tIssue changes.
      Such data already exist, using techniques such as MR spectroscopy, positron
      emission tomography (PET) and SPECT, but they concern almost exclusively the
      evaluation of primary SNC tumors and metastases of systemic cancers. There are,
      however, very sparse metabolic and functional data concerning the in vivo
      evaluation of the response of the tumor tIssue to radiosurgery. Moreover, such
      information is only anecdotal in VS. In other disorders, PET and MR spectroscopy
      data suggest interesting new directions for the assessment of radiosurgery follow
      up. Based on the predictive information provided by PET and MR spectroscopy in
      primary CNS tumors, it would be worthwhile to design a prospective study
      evaluating the role of these imaging modalities for in vivo assessment of
      radiosurgery-treated SV.

PMID- 15179286
TI  - Histopathological observations on vestibular schwannomas after Gamma Knife
      radiosurgery: the Marseille experience.
AB  - BACKGROUND AND PURPOSE: Radiosurgery has become a successful treatment modality
      in the management of vestibular schwannomas (VS) during the past four decades.
      Although the number of treated cases has been increasing continuously we know
      relatively little about the pathological effect of high dose irradiation on VS
      following radiosurgery. The purpose of this study was to analyze
      histopathological changes in VS after Leksell Gamma Knife (LGK) radiosurgery.
      METHODS: Out of a series of 1350 VS cases treated with LGK surgery 22 patients
      underwent craniotomy for tumor removal in 6-92 Months interval after
      radiosurgery. Surgical pathology material was available in 17 cases. Routine
      histological and immunohistochemical investigations were performed on the tIssue
      samples. Histopathological findings were compared with clinical and radiological
      follow-up data. RESULTS: Coagulation necrosis in the central part of the
      schwannomas surrounded with a transitional zone containing loosened tIssue
      structure of shrunken tumor cells covered with an outer capsule of vigorous
      neoplastic cells was the basic histopathological lesion. Granulation tIssue
      proliferation with inflammatory cell infiltration, different extent of
      hemorrhages and scar tIssue development was usually present. Endothelial
      destruction or wall damage of vascular channels was a common finding. Analyzing
      the follow-up data it turned out that 7 patients out of the 22 were operated on
      because of radiological progression only without clinical deterioration and 4 of
      them was removed during the latency period after radiosurgery. CONCLUSION:
      Results of the present histopathological study suggest that radiosurgery works
      with double effect on VS: it seems to destroy directly tumor cells (with necrosis
      or inducing apoptosis), and causes vascular damages as well. The loss of central
      contrast enhancement on CT and MR images following radiosurgery might be
      consequence of necrosis and vascular impairment. From clinical-pathological point
      of view we think that patients should not undergo craniotomy just because of
      radiological progression of the tumor without clinical deterioration, mainly in
      the latency period. This requires consultation and common decision-making between
      the radiosurgical and the microsurgical team.

PMID- 15179287
TI  - Injury of the lacrimal component of the nervus intermedius function after
      radiosurgery versus microsurgery.
AB  - RATIONALE: Due to the synergetic role of the facial nerve and the nervus
      intermedius in the mechanical protection of the eye, vestibular schwannomas (VS)
      and/or their treatment are dangerous for the visual function. Our goal was to
      evaluate and compare the impact of the tumor itself, and the microsurgery (MS) or
      radiosurgery (RS). MATERIAL AND METHOD: A functional questionnaire evaluating
      among other items the patient's complaints related to the eye was addressed to a
      series of 100 patients, 3 years after GKS of a previously unresected unilateral
      VS. Answers were compared with those of a group of 100 patients operated
      microsurgically. A Shirmer test was additionally performed before radiosurgery,
      and more than 2 years after radiosurgery in 46 patients. RESULTS: The risk of dry
      eye and burning eye was much higher in patients operated by MS compared to
      patients operated by GKS due to the high incidence of facial palsy in the former
      (57/99) and the its absence in the later (0/80). In the population operated
      microsurgically, the presence of a permanent facial palsy (57 patients among 99
      responding to the questionnaire) was, of course, associated with a high rate of
      complaints about burning eye (n=18) and crying eye (n=23). Among patients from
      the two arms with no facial palsy, a dry eye was reported by 8/64 after GKS and
      7/42 after MS (NS) and a burning eye by 9/64 after GKS and 9/42 after MS (NS).
      Thus patients with no clinical signs of impairement of the VII motor nerve
      accounted for 14% of the cases signs indicating injury of the intermedius nerve
      with the same probability whatever the kind of surgery. When no permanent facial
      palsy was observed a crocodile tear syndrome was more frequently observed after
      MS (4/42 versus 1/64, p=0.07). This suggests an early lesion of the VII motor and
      intermedius, and a subsequent abnormal regrowth. The only patient reporting a
      crocodile tear syndrome after GKS turned out to have presented transiently a
      discret deficit of orbicular muscle signaling transient partial facial nerve
      injury. In absence of facial palsy, a "crying eye" was reported more frequently
      after MS (16/42 versus 9/64, p=0.01), leading us to suspect frequent
      infraclinical VII nerve injury in patients with no obvious facial palsy operated
      by MS. Patients tested with Shirmer test, before and more than 2 Years after,
      were improved in 28.3%, stable in 56.5%, and worse in 15.2%. CONCLUSIONS: This
      study is the first demonstrating that radiosurgery can induce nervus intermedius
      injury in a small percentage of cases (14%). These patients had been treated 11
      years ago with what we can consider as "archeoGKS technology" compared to today's
      refinements. The impact of modern GKS on the nervus intermedius is currently
      under evaluation in our group. However, symptoms related to the eye either due to
      the injury of the nervus intermedius or of the VII motor or both are much more
      frequent after MS than after RS.

PMID- 15179288
TI  - [Hydrocephalus and vestibular schwannomas treated by Gamma Knife radiosurgery].
AB  - The occurrence of hydrocephalus in association with a vestibular schwannoma (VS)
      is a well-known phenomenon. It is usually supported, albeit never demonstrated,
      that radiosurgery increases the risk of hydrocephalus. The purpose of this study
      is to investigate this Issue in our own series of patients in order to provide
      more data. Between July 1992 and January 2002, among the 1000 VS that have been
      treated at the Timone hospital using a Gamma knife, 43 patients displayed a
      hydrocephalus, 32 of them before the treatment (group A) and 11 of them only
      after the treatment (group B). It is of note that in both groups, age at the time
      of treatment (median age of 70 in A & B) and Volume of tumor were comparable and
      significantly higher than for the whole treated population. Following
      radiosurgery, 75% of the patients from the group A did not require a shunt
      whereas all the patients from the group B did, including 3 who also had
      significant tumor progression requiring surgery. Occurrence of a de novo
      hydrocephalus was a rare event (1%) that required a shunt early after
      radiosurgery, at a mean interval of 14.8 Months (4-31). Results from this study
      suggest that radiosurgery does not significantly increase the risk of
      hydrocephalus during the natural history of a VS. We can postulate that Gamma
      Knife radiosurgery might provide a protective influence on hydrocephalus
      decompensation since the number of preexisting hydrocephalus that necessitated a
      shunt after the treatment was small. More investigations involving more patients
      will bring more arguments in the near future.

PMID- 15179289
TI  - [Preserving hearing function after Gamma Knife radiosurgery for unilateral
      vestibular schwannoma].
AB  - OBJECTIVE: The majority of the patients still lose hearing function in spite of
      the technical advances in microsurgery. We wanted to evaluate preservation of
      hearing function potential after Gamma Knife Surgery. MATERIAL AND METHOD: In
      Marseille, we performed 1000 Gamma-Knife procedures for vestibular schwannomas
      between July 1992 and January 2002. This population included 175 patients
      undergoing first intention surgery for a unilateral schwannoma with functional
      preoperative hearing (Gardner and Robertson 1 or 2) who were studied with a
      follow-up longer than 3 Years. Univariate and multivariate analysis was
      performed. RESULTS: Numerous parameters significantly influenced the probability
      of functional hearing preservation at 3 years. The overall rate of preservation
      was 60%. The main parameters of predictability were limited hearing loss (Gardner
      and Robertson stage 1 versus 2) before radiosurgery, presence of tinnitus as the
      initial symptom, young age and the small tumor size. Preservation of functional
      hearing at 3 years was 77.8% when the patient was initially in stage I, 80% when
      the patient's first symptom was tinnitus, and 95% when the patient had both. In
      these patients, the probability of functional preservation at 5 years was 84%.
      CONCLUSION: We report a large population of patients treated by radiosurgery with
      initial functional hearing. These results demonstrate that a large percentage of
      selected patients can preserve functional hearing after Gamma Knife Surgery,
      their chances of functional preservation being greater than after microsurgery or
      simple surveillance.

PMID- 15179290
TI  - [Improvement in postural orientation and stability after stereotactic gamma
      irradiation of acoustic neurinomas].
AB  - Non-surgical stereotactic gamma ionizing irradiation was developed in order to
      produce a lethal effect on unilateral acoustic neurinomas (vestibular
      schvannomas). We present a study of postural vestibular dependent performances in
      218 patients before and after curative irradiation. Subjects were asked to stand
      at ease on a static dynamometric foot-plate, gazing at a fixed point in front of
      them (EO condition) or to stand eyes closed (EC condition). Statokinesigrams were
      registered during two consecutive sessions of 51.2 sec, under EO and EC
      conditions. These sessions were first managed the days before (d-1), and after
      (d+1) irradiation; others were performed later (d+1 to 5 Years; n=37). Center of
      pressure (CofP) mediolateral (X) and sagittal (Y) positions were quantified every
      100 msec. Mean Xm session value (with SD) was taken as a personal parameter for
      left or right body inclination. Area S for 90% of the XY successive placements of
      the CofP observed during a session was taken as an index for 2D postural way.
      Before irradiation the overall average of the 218 personal Xm mean values
      demonstrated a statistically significant body inclination toward the affected
      side, however under EC condition only. The day after irradiation, a significant
      reduction of the overall mean value of body inclination was observed. Paired Xm
      statistics of confirmed this trend toward usual symmetry. The day after stereo
      irradiation, averaging areas S of ellipses indicated a shift of instability
      toward normality. For the two parameters, the pseudo-Romberg ratios (performance
      EC/performance EO) indicated that a special visual contribution to balance
      control is present in patients with a neurinoma tumor (here I and II grades). The
      relative importance of this visual support declined shortly after ionizing
      treatment. Because the radiation is neither noxious nor excitatory we think such
      a rapid recovery is due to some recovery of vestibular nerve afferent conduction,
      and a rapid neural reprogramming of the balance control. These attractive results
      call for deeper investigations of both vestibular and auditory functions.

PMID- 15179291
TI  - [Surgical management of vestibular schwannomas secondary to type 2
      neurofibromatosis].
AB  - To evaluate the results of Gamma Knife radiosurgery treating vestibular
      schwannomas (VS) secondary to type 2 neurofibromatosis (NF2) we reviewed our
      clinical experience. Among the VS that have been treated between July 1992 and
      January 2002, we could analyze retrospectively the data of 50 VS from 37
      patients. Fourteen patients had the mild phenotype while 23 were affected by the
      severe form. Before radiosurgery, one or two microsurgery attempts had been
      undertaken in 16 VS. Tumor Volume ranged from 120 to 14405 mm3 (mean: 3468 mm3)
      at the time of treatment; 12 tumors were Koos stade 4. Median clinical and
      radiological follow-up was 62 Months and ranged from 27 to 123 Months. The 5-Year
      and 10-Year actuarial survival rates without failure justifying tumor removal
      were 90 and 85% respectively. The 5-Year actuarial survival rate without hearing
      decreasing was 36% when selecting the cases of useful hearing (Gardner I & II) at
      the time of treatment. Severe phenotype (p=0.05) and dose (>12 Gy) delivered at
      the tumor margin (p=0.032) were correlated to hearing deterioration at
      univariated analysis. Permanent facial neuropathy occurred in 2%. Even though the
      level of tumor control and hearing preservation is not the same as for sporadic
      VS, these results show that Gamma Knife radiosurgery is a valuable alternative
      treatment for VS in NF2 patients. Future orientation of early proactive
      radiosurgical treatment of intracanalicular VS will probably improve these
      results.

PMID- 15179292
TI  - [Results and indications of gamma knife radiosurgery for large vestibular
      schwannomas].
AB  - Regular treatment of large vestibular schwannomas (VS) is surgical resection of
      the tumor with attempt of facial nerve preservation. In a very reduced number of
      tumors, microsurgery is not warranted mainly because of controlateral deafness or
      the risk of life-threatening open surgery. The purpose of this study was to
      analyze the results of Gamma Knife radiosurgery delivered for large VS. Between
      July 1992 and January 2002, we treated 50 patients harboring a large VS defined
      as a Koos grade IV tumor. Data and follow-up were available for 45 tumors
      involving 44 patients, including 12 neurofibromatosis type 2. Mean age at the
      time of treatment was 43,5 (range: 14-84), mean diameter of the tumor in the CPA
      was 18mm (range: 12-30) and the mean Volume was 4301 mm3 (range: 1340-11405).
      Gamma knife treatment was undertaken using on average 13.4 isocenters (range: 4
      48) and 10.2 Gy at the tumor margin (range: 8-14). Median follow-up was 45.5
      Months (from 24 to 108 Months). Tumor control was 69% (interval confidence: 52
      83%) and 3 patients had to be operated because of continuous tumor growth.
      Statistical analysis showed that tumor Volume was correlated to Gamma Knife
      failure in a uni-and multivariate model (p=0.027). No brain stem complication was
      observed. No facial nerve deterioration was found and hearing preservation could
      be obtained at a useful level in 12 out of 20 patients (60%). These results
      suggest that in a highly selected subgroup of patients with large VS,
      radiosurgery can be an interesting alternative to open surgery, particularly if
      hearing preservation is required. Information should be given to the patients
      that the risk of failure is greater than for small and medium sized VS.

PMID- 15179293
TI  - [Surgical removal of unilateral vestibular schwannomas after failed Gamma Knife
      radiosurgery].
AB  - One of the primary criticismes of vestibular schwannoma (VS) radiosurgery is that
      the risk of surgical morbidity is increased for patients whose tumor progresses
      after the procedures. We reviewed the French experience of operated patients
      after failed Gamma Knife radiosurgery. From July 1992 to January 2002, 25 out of
      the 1000 treated patients underwent another treatment procedure for a gamma knife
      failure. Excluding the NF2 patients, 21 patients have been operated and the
      present study shows the data collected for 20 of them. In order to analyze the
      difficulties observed during the surgery, a questionnaire was filled by the
      surgeons. The mean interval between radiosurgery and removal was 36 Months, from
      10 to 83 Months. The mean increase in Volume was 559% (37 to 3036%, median 160%).
      Evolution of the Koos grading was found from 8 grade II, 10 grade III et 2 grade
      IV to 10 grade III and 10 grade IV. Patients have been operated for radiological
      tumor growth in 7 cases and for clinico-radiological evolution in 13 cases. In 9
      cases, the surgeon considered that he had to face unusual difficulties mainly
      because of adhesion of the tumor to neurovascular structures. Tumor removal was
      total in 14 cases, near total in 4 cases and subtotal in 2 cases. One case of
      venous infarction was noticed at the second day following surgery responsible of
      hemiparesis and aphasia that gradually recovered. At last follow-up examination,
      facial nerve was normal (House and Brackmann grade I and II) in 10 cases while it
      was a grade III in 7 cases and grade IV and V in 3 cases. We recommend that the
      decision for surgical removal of growing vestibular schwannoma after Gamma Knife
      treatment should be done after a sufficiently long follow-up period. Our results
      show that the quality of removal and of facial nerve preservation might be
      impaired by radiosurgery in half of cases. However these results do not support a
      change in our policy of radiosurgical treatment of small to medium size
      vestibular schwannoma.

PMID- 15179294
TI  - [Radiosurgery of vestibular schwannomas after microsurgery and combined radio
      microsurgery].
AB  - Significant morbidity is expected after microsurgery for recurrent or growing
      residual vestibular schwannoma (VS). In order to avoid this procedure,
      radiosurgery appeared as an interesting alternative. The purpose of this study is
      to analyze the results of Gamma Knife radiosurgery in this indication. Between
      July 1992 and January 2002, 60 patients (including 12 NF2 patients) underwent
      radiosurgical treatment after one or more attempts of surgical resection
      (including 27 growing remnant VS and 19 recurrent VS) and could be followed with
      enough informations, out of 103 patients (10% of the VS population treated during
      the same period). Mean interval between surgical removal and radiosurgery was
      71.5 Months (1.8-127.8 Months). Technical difficulties during the procedure were
      observed in the 12 cases, mainly due to problems in identifying the target.
      Median follow-up was 51.6 Months. Four out of 58 patients (7%, confidence
      interval: 1.9-16.7) were diagnosed as failure. Statistical study failed to find
      significant parameters influencing failure. Facial and trigeminal nerves were not
      impaired while one case of severe bulbopontine radio-induced injury leading to a
      lower cranial nerve deficit was observed. These results show that, in spite of
      additional difficulties to treat these patients with radiosurgery, this treatment
      is efficient with acceptable morbidity and can avoid another microsurgical
      procedure. The strategy of planned combined micro-and radiosurgical treatment of
      large VS deserves additional investigations to be validated.

PMID- 15179295
TI  - [Cystic vestibular schwannomas].
AB  - RATIONALE: Patients with cystic vestibular schwannomas (VS) are a radiologically
      well-defined subgroup of patients who classically have poor outcome after
      microsurgical resection. Since Pendl's report of a high rate of failures, they
      are also considered as poor candidates for radiosurgery. MATERIAL AND METHOD:
      Among the 1000 consecutive patients who underwent Gamma Knife surgery in
      Marseilles, France between July 1992 and January 2002, we have collected and
      studied 54 patients with cystic VS at the time of treatment. RESULTS: The median
      follow-up of this group was 26 Months (mean: 33, range: 6-90). Failure (6.4%) led
      to microsurgical removal in 2 patients and a radiosurgery in 1 patient with a
      delay of 2 Years for 2 of them and 3 Years for the third. No facial palsy has
      been reported. Two patients developed transient hypesthesia. Among the 32
      patients with functional hearing at the time of treatment, 53% preserved their
      hearing function at 3 Years. CONCLUSIONS: We found an increased risk of failure
      in this group compared to patients with no cyst at time of radiosurgery (93.6%
      instead of 98%). But this is also a group were we observe most dramatic
      shrinkage. Prudent radiosurgical treatment of cystic vestibular schwannomas
      remains mandatory: strict follow-up is specially important.

PMID- 15179296
TI  - [Gamma Knife surgery for VII nerve schwannomas].
AB  - RATIONALE: Radical resection of VII nerve schwannomas classically implies a high
      risk of severe facial palsy. Due to the rarity of facial palsy after Gamma Knife
      surgery (GKS) of vestibular schwannomas the evaluation of GKS in this specific
      difficult group of patient appears rational. We have found no similar evaluation
      in the literature. METHOD: Among 1.000 schwannomas of the cerebello-pontine angle
      operated in Marseilles, France between July 1992 and March 2003, 9 have been
      diagnosed as originating from the VII. Criterias for this diagnosis are the
      involvement of the second or third portion of the VII nerve canal (7 patients)
      and/or peroperative observation during a previous microsurgery (2 patients). The
      rare facial palsy after vestibular schwannomas radiosurgery occurring usually
      before 18 Months have been considerated only the patients with more than 2 Years
      of follow-up (8 patients). RESULTS: Four of these patients had the experience of
      a previous spontaneous facial palsy one (3 patients) or several times (1
      patient). A normal motor facial function was observed only in 2 cases before GKS
      (House 2 in 6 patients, House 3 in one). The follow-up was 2-7 Years for the
      evaluable patients. None of these have developed or worsened facial palsy, two
      have improved their preoperative facial palsy. To date, all tumors have been
      evaluated. The specificity and heterogeneity of this group of patients led us to
      develop an original classification in 4 anatomical types presenting different
      clinical and surgical difficulties. CONCLUSION: This first study demonstrates
      that radiosurgery allows treating these patients while preserving a normal motor
      facial function. Because of this advantage, GKS must be considered as a first
      option for all small to middle sized facial nerve schwannomas.

PMID- 15179297
TI  - [Radiosurgery and brain radio-induced carcinogenesis: update].
AB  - The use of radiosurgery Gamma-knife for many benign tumors and diseases has
      increased significantly over the last two decades. The long-term potential
      carcinogenic risk has not been evaluated until recently. The definition of radio
      induced tumors was based on Cahan's criteria: it must occur in the previously
      irradiated field, with a sufficiently long interval from irradiation, it must be
      pathologically different from the primary tumor, not be present at time of
      irradiation and no genetic predisposition for second tumor. The brain is one of
      most sensitive tIssues and no minimal dose has been established. Even doses as
      low as 1 Gy have been associated with second tumor formation and relative risk
      between 1.57 and 8.75. This relative risk increases to 18.4 for an interval time
      between 20 and 25 Years. Many publications emphaze the risks after larger-field,
      fractionated radiotherapy with low non-cell-killing dose delivered to central
      nervous system. Furthermore, therapeutic radiation doses for benign tumors
      associated with a long life (parasellar tumors, meningioma) were implicated in
      carcinogenesis. Incidence of radiation-associated tumors is linked to different
      factors such as age and individual genetic susceptibility. At this time and to
      our knowledge, 3 radiation-associated gliomas and 5 malignant acoustic neurinomas
      have been reported in the literature. Moreover, these second tumors met some but
      not all Cahan criteria. We also report 2 cases from our radiosurgical experience
      and discuss these points. Long time follow-up is needed to observe the crude
      incidence of radiation-induced tumors at 5 to 30 Years. The relative risk is
      estimated less than 1 and must be announced to each patient before the
      radiosurgical procedure and counterbalanced wit the 1% annual risk of mortality
      from bleeding of untreated MAV or the 1% mortality rate of benign tumors after
      surgery alone.

PMID- 15179298
TI  - Fractionation of radiation treatment in acoustics. Rationale and evidence in
      comparison to radiosurgery.
AB  - Stereotactic fractionated radiotherapy has been proposed as a strategy to improve
      upon the results of single-fraction radiosurgery. The rationale for the strategy
      is that fractionation will allow complciations to be reduced while maintaining
      the same degree of long-term tumor control. This paper reviews the
      radiobiological arguements for fractionating radiation treatment of acoustic
      neuromas and examines claims for improvement in outcome.

PMID- 15179299
TI  - Acoustic neuroma radiosurgery. Origins, contemporary use and future expectations.
AB  - Patients who have an acoustic neuroma (vestibular schwannoma) can be managed with
      observation, open surgical resection, stereotactic radiosurgery, or fractionated
      radiotherapy. Increasing numbers of patients are choosing radiosurgery over
      resection for their tumor. In this report we discuss the history of stereotactic
      radiosurgery, and the evolution in technique that has led to current results with
      this approach. We discuss the indications for and expectations with the different
      treatments. The literature on radiosurgery and radiotherapy is reviewed. It is
      expected that clinical and basic studies will further improve results.

PMID- 15179300
TI  - [Early recurrence of Groenouw type I corneal dystrophy after phototherapeutic
      keratectomy. Molecular biology study suggests epithelial genesis].
AB  - PURPOSE: Granular corneal dystrophy Groenouw type 1 (GGI) is a rare autosomal
      dominant disease caused by allelic mutations of the BIGH3 gene. The specific
      phenotype is characterized by granular opacities (white, sharply demarcated spots
      resembling bread crumbs) in corneal stroma, which cause recurrent corneal
      erosions and blurred vision. Phototherapeutic keratectomy (PTK) is an effective
      procedure that improves visual acuity, but recurrences are unavoidable. Though
      GGI deposits are well described, their origin is not completely known. The
      production of mutated keratoepithelin protein (a product of the BIGH3 gene) is
      the first step necessary for deposits to appear. Molecular biology experiments
      were conducted to determine the role of corneal cell types in the genesis of
      early recurrent deposits of post-PTK GGI. METHODS: Tissue specimens from a
      patient undergoing penetrating keratoplasty for recurrence of GGI (12 months
      after PTK) and five normal corneas were examined by hybridization in situ and
      immunohistology to study the expression of BIGH3 and location of keratoepithelin.
      RESULTS: Only one healthy cornea expressed BIGH3 mainly in the epithelium and
      less in keratinocytes and endothelial cells. In the GGI corneas, BIGH3 was highly
      expressed in the modified, hyperplastic epithelium. The keratoepithelin was
      accumulated under the epithelium where deposits were formed. CONCLUSION: This
      observation confirms that corneal epithelium is the main producer of mutated
      keratoepithelin on the cellular scale and thus constitutes the principal source
      of dystrophic deposit formation during recurrence.

PMID- 15179301
TI  - [OCT3 exploration of anterior segment].
AB  - PURPOSE: Posterior pole imaging with OCT3 provides macular scans with a very high
      resolution. Use of OCT1 has already been described for anterior segment imaging.
      This work presents the advantages of OCT3 in anterior segment imaging compared to
      UBM (50 MHz) and 20-MHz ultrasound imaging with long focal distance (patent
      pending PCT/FR98/02788). MATERIAL: and methods: We used an OCT3 unit dedicated to
      the posterior pole. By defocusing the laser beam we obtained high-resolution
      scans of the cornea, angle, lens and IOLs. Fifty-seven eyes (35 patients) were
      imaged by OCT3 and high-resolution ultrasound in cases of corneal dystrophy,
      corneal transplant, LASIK, narrow angle, iris bowing, etc. RESULTS: In all cases
      OCT3 provided high-resolution information with a limit of penetration at the
      posterior part of the iris. This limitation was not observed with ultrasound
      imaging. Nevertheless, OCT3 is a useful tool for corneal imaging in cases of
      opacities limiting biomicroscope imaging. OCT3 corneal scans at high resolution
      make it possible to identify the corneal interface in lamellar transplants or
      LASIK. With a narrow angle, a dynamic test of angle closure can be done. With
      iris bowing, OCT3 can differentiate iris cysts and iris tumors. Anterior chamber
      IOLs can be imaged with their relationships to anterior segment structures.
      CONCLUSION: OCT3 provides non-contact anterior segment imaging with high
      resolution but with a limit of penetration given by posterior part of the iris.

PMID- 15179302
TI  - [Glaucoma and ultrasound biomicroscopy].
AB  - Ultrasound biomicroscopy (UBM) can provide high-resolution images in the living
      human eye; this resolution has been compared to microscopic resolution. This
      system is particularly useful in studying the anterior segment and analyzing the
      different types of glaucoma. Anatomical aspects, physiopathological processes and
      surgical results in glaucoma could be evaluated with UBM. This exploration is
      also important in determining differential diagnosis, risk factors, and
      prognostic elements. In addition, using UBM after filtering surgery helps detect
      early complications and understand poor surgical outcome.

PMID- 15179303
TI  - [Severe bilateral capsulorhexis contraction after cataract surgery in myotonic
      dystrophy: a case report].
AB  - INTRODUCTION: The Authors report the case of a 50-Year-old man with myotonic
      dystrophy, who developed severe bilateral capsulorhexis contracture after
      uneventful cataract surgery. OBSERVATION: Phacoemulsification was performed in
      both eyes with implantation of intraocular lenses. The patient came to complain
      of decreased vision in both eyes (4/10 Parinaud 4). Visual acuity initially
      improved after surgery to 8/10 P2 in each eye. After 7 months for the right eye
      and 3 Months for the left eye, the patient presented with dramatically reduced
      vision, caused by a severe capsulorhexis contracture. Anterior capsulotomies with
      the Nd:YAG laser were performed in both eyes to treat this complication. It was
      sufficient on the left eye but the right eye required a surgical anterior
      capsulectomy to remove the IOL and the bag and put in an Artisan lens.
      DISCUSSION: Capsulorhexis contracture results from fibrous metaplasia of lens
      epithelial cells from the anterior capsule. Myotonic dystrophy appears to
      predispose to the development of severe capsulorhexis contracture after
      phacoemulsification.

PMID- 15179304
TI  - [Late metastases of malignant choroidal melanoma after curietherapy: two case
      reports].
AB  - PURPOSE: The technical advancements now provide conservative treatment of
      choroidal melanoma. The course of the disease remains marked by the metastases
      that usually set in within 3 years. The aim of this paper is to report two
      unusual cases of hepatic metastases of choroidal melanoma that set in 11 and 18
      Years after curietherapy. METHODS: A 40-year-old woman and a 50-year-old man
      presented with T2 and T3 choroidal melanomas and were treated by cobalt plaque.
      The tumors decreased within the year and the patients were monitored every 3
      months for 5 years. RESULTS: Metastases set in, respectively, 11 and 18 years
      after treatment. DISCUSSION AND CONCLUSION: These two observations show that the
      metastases had already spread at the moment of diagnosis and that the cell
      doubling time of the melanoma was very long. These findings indicate the
      difficulties in monitoring patients with choroidal melanoma.

PMID- 15179305
TI  - [Vitrectomy for floaters].
AB  - PURPOSE: To clarify vitrectomy indications in the treatment of vitreous floaters.
      METHODS: This is a retrospective study of four patients, four eyes (age, 42-65
      years), who underwent vitrectomy for the treatment of vitreous floaters. Two
      patients had a total posterior vitreous detachment. All patients were required to
      think about the intervention for several months before consenting. RESULTS:
      Preoperative visual acuity ranged from 20/40 to 30/30 and after the operation it
      ranged from 20/40 to 10/10. Minimum follow-up was 1 year. Visual acuity did not
      decrease after treatment in any patients. All patients expressed satisfaction
      with their postoperative visual function. DISCUSSION-CONCLUSION: Visual acuity
      measures do not always accurately reflect patients' visual discomfort. Vitrectomy
      has been known for many years. It can be proposed as a last resort after thorough
      retina examination, after patients have received adequate information and they
      are psychologically ready for the procedure.

PMID- 15179306
TI  - [Buphthalmia secondary to congenital pigmented epithelial iris cyst].
AB  - We report the case of a 2-day-old child with buphthalmia caused by a congenital
      pigmented epithelial iris cyst. The use of ultrasound biomicroscopy (UBM) and
      high-resolution echography (20MHz) specified the diagnosis before general
      anesthesia for complete examination and treatment. Surgery can control
      intraocular pressure and the opening of the visual axis; there is, however,
      relative amblyopia. This case confirms the advantage of UBM in examining tumors
      of the anterior segment. The early diagnosis, facilitated by use of the UBM,
      provided quick and well-adapted treatment.

PMID- 15179307
TI  - [Persistent hyperplastic primary vitreous and Aicardi syndrome].
AB  - INTRODUCTION: Aicardi syndrome is characterized by infantile spasms, agenesis of
      the corpus callosum and chorioretinal lacunae. This disorder affects mostly
      females, with early embryonic lethality in males. Numerous general and ocular
      disorders may be associated with this affection. We present here a case of
      persistent hyperplastic primary vitreous (PHPV) in association with Aicardi
      syndrome in a 30-year-old woman. CASE REPORT: The authors report a case of a 30
      year-old woman with Aicardi syndrome associated with persistent hyperplastic
      primary vitreous. DISCUSSION: Aicardi syndrome is a polymalformative disease
      occurring at an early period of embryogenesis. It can affect many ocular
      structures. This syndrome is essentially described in female children, who rarely
      reach an adult age. The observation we report is particular because of the
      patient's age (30-years-old) and the association with a persistent hyperplastic
      primary vitreous, exceptional in this context. CONCLUSION: With a review of the
      literature, the Authors discuss the clinical neuroradiological and prognostic
      aspects of this polymalformative syndrome and different associated general and
      ocular abnormalities, emphasizing particularly those of persistent hyperplastic
      primary vitreous in this affection.

PMID- 15179308
TI  - [White-centered retinal hemorrhage revealing acute lymphoblastic leukemia].
AB  - Retinal involvement during leukemia is frequent (varying from 28% to 50%), can be
      the result of different mechanisms, and may reveal the disease. We describe two
      patients, 10 and 50 years old, who consulted for a sudden drop in visual acuity.
      Fundus examination showed bilateral retinal hemorrhage with a white center in
      both eyes associated with other hemorrhages in the posterior pole. Acute leukemia
      was found in both patients and chemotherapy was institgated. The younger patient
      died of general complications, the other is in remission phase. Retinal
      hemorrhage with a white center is a rare manifestation of acute leukemia and is
      exceptionally the first sign of the disease. Through these cases, we detail the
      physiopathology and clinical aspects. We stress the importance of ocular findings
      in leukemia in both diagnosis and therapy.

PMID- 15179310
TI  - [Theme topic: round table "ocular herpes"].

PMID- 15179309
TI  - [BIG-H3 protein: mutation of codon 124 and corneal amyloidosis].
AB  - In 1997, a group of hereditary corneal dystrophies was related to mutations in
      the TGFBI (BIGH3) gene. Within this group, some corneal dystrophies present
      particular biochemical features in that they are characterized by corneal amyloid
      deposition. Contrary to clinical and genetic knowledge, the biochemical
      characteristics of the encoded protein (Big-h3) and the mechanisms of its amyloid
      conversion remain unclear. We review the current knowledge on the Big-h3 protein
      and focus on the behavior of the codon 124 region. We discuss this protein's
      mechanisms of amyloid conversion from our results and previous reports as well as
      from other types of amyloidosis. These data provide a better understanding of the
      putative processes leading to the phenotypic variations linked with their
      respective codon 124 mutation.

PMID- 15179311
TI  - [Clinical and diagnostic developments in corneal herpes].
AB  - The indications for keratoplasty in treating herpes keratitis are currently
      declining because of recent progress in diagnosis and treatment. Clinically,
      corneal signs may be caused by HSV reactivation or a secondary anti-HSV immune
      response. Corneal opacification may be acute or the expression of sequela (meta
      herpetic keratitis). The virus can be detected on a corneal surface sample by
      direct examination or cell culture, the only way to detect an infective virus.
      The detection of local antibody production in the aqueous humor is an inexpensive
      method, indicating the local immune anti-HSV response. Detection of HSV DNA using
      PCR is more sensitive, but the presence of HSV DNA within corneal tIssue may be
      more delicate to interpret. It is now proven that HSV can be transmitted through
      a corneal graft from donor to recipient, but no diagnostic test currently detects
      potentially infective corneas in eyebanks.

PMID- 15179312
TI  - [Viral uveitis].
AB  - Viral eye diseases are common and associated with different well-known forms of
      uveitis. However, experimental models and clinical observations have led to an
      infectious, in particular a viral etiology in different autoimmune conditions.
      The use of molecular techniques is particularly informative, not only to
      characterize the previously well-known subgroup of presumed viral uveitis, but
      also to define the role of these agents or emerging viruses in atypical forms of
      autoimmune uveitis resistant to conventional therapy. PCR detection of viral DNA
      in patients with uveitis is a rapid, sensitive and accurate procedure. Therefore,
      aqueous humor could be analyzed when uveitis is unresponsive to anti-inflammatory
      molecules, in order to exclude a viral condition and dramatically modify the
      therapeutic management. Several new viral entities have recently been identified
      such as cytomegalovirus-associated chronic anterior uveitis and non-necrotizing
      herpetic retinopathies in immunocompetent hosts. Systemic antiviral drugs should
      be proposed rapidly in order to control viral replication before the use of
      corticosteroids. Maintenance therapy based on low-dose antivirals can reduce the
      rate of recurrence and should be considered.

PMID- 15179313
TI  - [Necrotic herpetic retinitis].
AB  - The diagnosis of necrotic herpetic retinitis is suggested on clinical grounds,
      prompting urgent appropriate intravenous and intravitreal treatment. PCR on
      ocular samples is most often successful in identifying the herpetic agent.
      Classic acute retinal necrosis syndrome caused by herpes simplex or zoster virus
      and the different clinical forms present in immunocompetent or immunodepressed
      patients are described. The differential diagnosis includes atypical presentation
      of retinal necrosis caused by toxoplasmosis, syphilis, or ocular lymphoma; the
      ocular samples are useful in establishing the etiological diagnosis. We describe
      the different therapeutic strategies in the acute phase and as secondary
      prophylactic treatment. The clinical outcome appears to be influenced by rapid,
      appropriate treatment, limiting the extension of the retinal necrosis.

PMID- 15179314
TI  - [The latest in herpes simplex keratitis therapy].
AB  - Herpetic keratitis is characterized by spontaneous recurrences and a risk of
      vision loss, the latter being more serious when relapses are frequent and severe.
      Two clinical forms are commonly distinguished: epithelial keratitis, usually
      quickly resolved with topical antivirals, and stromal keratitis, which has a
      slower progression, even when both steroids and antivirals are used. Great
      strides have been made during the last 20 Years in the therapy of herpes
      keratitis, which is now considered and treated as a chronic disease. Randomized
      controlled studies definitively showed the decrease in spontaneous herpetic
      ocular events in patients treated with long-term oral acyclovir. The
      effectiveness of preventive treatment has also been shown during high-risk
      periods, especially ocular surgery, in patients with a history of herpes
      keratitis. However, the optimal duration and dosage of antiviral prevention have
      yet to be defined. We can also hope that in the future novel antiviral strategies
      such as vaccination will reduce the place of herpes keratitis as an indication
      for corneal graft.

PMID- 15179316
TI  - [Daivobet: new therapeutic management for psoriasis. Introduction].

PMID- 15179317
TI  - [Daivobet: from concept to medication].

PMID- 15179318
TI  - [Factors for good compliance].

PMID- 15179319
TI  - [Clinical experience with Daivobet].

PMID- 15179321
TI  - Targeting Janus kinase 3 in the treatment of leukemia and inflammatory diseases.
AB  - Janus tyrosine kinases (JAKs) are cytoplasmic protein tyrosine kinases that play
      a crucial role in the initial steps of cytokine signaling. JAK3, a member of JAK
      kinase family of four (JAK1, JAK2, JAK3 and TYK2), is abundantly expressed in
      lymphoid cells. JAK3 has been found to initiate signaling of interleukin (IL)-2,
      IL-4, IL-7, IL-9, IL-13 and IL-15. Indispensable role of JAK3 in lymphocyte
      development and function has been revealed recently. Because of the involvement
      of JAK3 in T cell activation and proliferation, and the documented genetic
      evidence for the role of JAK3 in autoimmune or transplant -induced inflammatory
      disorders, the selective targeting of JAK3 in T cells may potentially be
      clinically beneficial in T cell-derived pathologic disorders. In this review we
      discuss inhibitors of JAK3 as a new class of immunomodulatory agents with
      immunosuppressive, anti-inflammatory, anti-allergic, and anti-leukemic
      properties. Preclinical data from multiple experimental model systems of
      autoimmune diabetes, allergy, solid organ transplantation, pancreatic islet
      transplantation and bone marrow transplantation are discussed in the context of
      the clinical need for new immunomodulatory agents with such properties.

PMID- 15179322
TI  - Functions of human complement inhibitor C4b-binding protein in relation to its
      structure.
AB  - Considering the destructive potential of the complement cascade, it is no
      surprise that there are several complement inhibitors present in blood and
      expressed on virtually all cells of the body to protect self tissue. C4b-binding
      protein (C4BP) is a potent soluble inhibitor of the classical and lectin pathways
      of complement. This large (500 kDa) plasma glycoprotein consists of seven
      identical 75 kDa alpha-chains and a unique 40 kDa beta-chain that are held
      together by disulphide bridges. Both types of subunit are almost exclusively
      composed of complement control protein (CCP) domains. In recent years, detailed
      studies of structure-function relationships have yielded new understanding of the
      interactions between C4BP and the activated complement factors C4b and C3b,
      heparin, and vitamin K-dependent anticoagulant protein S. This review describes
      the localization of binding sites for a number of C4BP ligands in relation to
      well-established and novel functions of C4BP such as complement inhibition,
      protection of apoptotic cells from complement, CD40-dependent stimulation of B
      cells, and the contribution of a number of human pathogens to pathogenesis.

PMID- 15179323
TI  - Anti-GBM glomerulonephritis: a T cell-mediated autoimmune disease?
AB  - Anti-glomerular basement membrane (GBM) glomerulonephritis, which was among the
      earliest recognized human autoimmune diseases, is characterized by the presence
      of anti-GBM antibody. It has been a prototypical example of autoantibody-mediated
      autoimmune disease. However, decades of research on this disease, based either on
      clinical observations or experimental models, have revealed that T cell-mediated
      cellular immunity may potentially be a more important mediator of
      glomerulonephritis. We have made several breakthroughs in understanding the T
      cell-mediated mechanism causing this disease in a rat model based on
      Goodpasture's antigen, non-collagen domain 1 of alpha3 chain of type IV collagen
      (Col4alpha3NC1). We demonstrated that anti-GBM glomerulonephritis was induced by
      either passive transfer of Col4 alpha3NC1-specific T cells or active immunization
      with the nephritogenic T cell epitope of Col4alpha3NC1. Immunization with the T
      cell epitope also triggered production of anti-GBM antibodies to diversified GBM
      antigens. Thus, a single nephritogenic T cell epitope alone is sufficient to
      induce the clinical spectrum of anti-GBM glomerulonephritis, including
      proteinuria, glomerular injury, and anti-GBM antibody. A possible T cell-mediated
      mechanism for causing human anti-GBM disease is proposed.

PMID- 15179324
TI  - Leucine-rich repeats in host-pathogen interactions.
AB  - Leucine-rich repeats (LRRs) are versatile binding motifs found in a variety of
      proteins and are involved in protein-protein interactions. The LRR domain is
      composed of repeats forming a characteristic solenoid horse-shoe structure, which
      provides a scaffold for numerous insertions involved in binding to pathogen
      associated molecular patterns and surface receptors. LRRs have been shown to be
      involved in the host defense systems of both plants (resistance genes) and
      mammals (Toll-like receptors and nucleotide-binding oligomerisation domain
      proteins), where they sense specific pathogen-associated molecules and activate
      the innate immune system. Paradoxically, LRRs have also been shown to be part of
      microbial virulence factors involved in the interaction with host cells and
      establishment of infection. The potential of LRRs to bind a vast array of
      structurally unrelated ligands and their well-documented involvement in microbial
      pathogenesis make them a potential target for vaccines and new drugs. The recent
      identification of LRRs in the obligate intracellular protozoan parasite
      Leishmania and their participation in the macrophage-parasite interaction have
      added new insight into the role of LRRs in the host cell invasion.

PMID- 15179325
TI  - Genetic and biochemical background of chronic granulomatous disease.
AB  - Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome
      caused by a profound defect in the oxygen metabolic burst machinery. Activity of
      NADPH oxidase is absent or profoundly diminished, as at least one of its
      components (gp91(phox), p22(phox), p47(phox) and p67(phox)) is lacking or non
      functional. This review explains the molecular basis of NADPH oxidase dysfunction
      by the effects of mutations in genes coding for particular oxidase components.
      Among the four types of CGD, the most common is X-linked CGD (approximately 65%),
      with defects in the CYBB gene encoding gp91(phox). A wide spectrum of mutations
      has been described in the CYBB gene with no predominant genotype. The second most
      common subtype of CGD caused by NCF1 mutation accounts for 30% of CGD patients
      and is inherited in an autosomal recessive manner, with predominance of a
      homozygotous deltaGT deletion in the genotype. The other two CGD subtypes having
      an autosomal recessive pattern together account for no more than 10% of CGD
      cases. A strategy for the molecular diagnostics in CGD patients is proposed and
      principles of genetic counseling are discussed here.

PMID- 15179326
TI  - Characterization and serological classification of a collection of Proteus
      penneri clinical strains.
AB  - INTRODUCTION: Bacteria of the genus Proteus, which are a common cause of urinary
      tract infections, are divided into four species: P. mirabilis, P. vulgaris, P.
      penneri, and P. hauseri, and three unnamed genomospecies, Proteus 4, 5, and 6
      (single-strain species P. myxofaciens was isolated from the gypsy moth).
      Establishing the serological classification of these species would aid in
      completing the classification scheme of the whole genus Proteus and in applying
      serological methods in diagnostic procedures and epidemiological investigations
      for these opportunistic pathogens. The aim of this research was a serological
      characterization and classification of 57 Proteus penneri clinical strains,
      isolated from patients from different countries all over the world, into Proteus
      O serogroups. MATERIAL/METHODS: Purified lipopolysaccharides (LPSs) extracted
      from 57 P. penneri strains were used as antigens in enzyme immunosorbent assay
      (EIA), SDS/PAGE, and Western blot techniques, and alkali treated LPSs in passive
      immunohemolysis test (PIH), inhibition of PIH, and absorption of rabbit
      polyclonal O-antisera. RESULTS: That result confirms the serological distinction
      of this species within the genus Proteus, and may have diagnostic significance.
      CONCLUSIONS: As a result of serological studies of LPSs extracted from the P.
      penneri strains, one new Proteus serogroup, represented by the P. penneri 97
      strain, was established. Three further strains were classified into the Proteus
      serogroup O8, which had not contained any P. penneri strains before. All the
      remaining strains were classified into 11 already existing Proteus O serogroups.
      It is important to emphasize that 72% of studied strains were classified into
      serogroups that contain P. penneri strains only.

PMID- 15179327
TI  - Effect on peripheral blood natural killer cytotoxic cell activity in rats after
      intraperitoneal implantation of double veloured polyester (Dacron) prosthesis.
AB  - INTRODUCTION: The aim of this study was to assess the changes affecting natural
      killer cytotoxic cell (NKCC) activity following intraperitoneal implantation of a
      double veloured polyester prosthesis in a rat model. MATERIAL/METHODS: Blood
      samples were taken by cardiac puncture 1 h before (base line) and 14, 28, 100 and
      180 days post-implantation. Peripheral blood mononuclear cells were separated
      from heparinized blood by density centrifugation. A standard, 4 h (51)Cr-release
      assay against YAC-1 target cells at effector to target ratios of 12:1; 25:1 and
      50:1 was performed and the number of total leukocytes, lymphocytes, granulocytes,
      monocytes, and large granular lymphocytes (LGLs), as well as serum corticosterone
      levels (radioimmunoassay method) were determined. RESULTS: Comparative analysis
      of the results obtained from animals with implants, baseline samples, and a
      control group (laparotomy only) revealed lower NKCC, LGL, leukocyte and
      lymphocyte counts and elevated plasma corticosterone levels in animals receiving
      the implant on the 14th day post-implantation. CONCLUSIONS: Our findings indicate
      that the polyester implant can transiently modulate immune system activities.
      Since NK cells are important in the control of viral infection and carcinogenesis
      in humans, it is possible that the stress generated by polyester prostheses can
      exacerbate the surgical stress and put patients at a higher risk for viral
      infection and/or metastases.

PMID- 15179329
TI  - Is revascularization and limb salvage always the treatment for critical limb
      ischemia?
AB  - Despite marked advances in the technical ability to perform lower extremity
      revascularization, the decision whether to perform primary amputation or attempt
      revascularization in high risk patients is a major part of modern vascular care.
      With an aging population and improved medical care that has increased life
      expectancy, more patients with severe systemic disease are presenting with
      critical limb ischemia (CLI). In addition, it is well recognized that CLI
      patients suffer diagnostic delays and poor risk factor modification, which in
      part contributes to limb loss and poor patient survival. Unlike other disease
      entities, CLI does not have a clear clinical pattern that provides consistent
      entry to medical care and uniform treatment algorithm. In this commentary we will
      discuss the issue from several viewpoints. The unique features of the antecedent
      natural history of CLI will be presented. Available data on functional outcomes
      on both therapies for CLI will be presented. Morbidity and mortality of both
      approaches will be covered, including the risk of multiple procedures, followed
      by an examination of specific problematic patient populations. Finally, we will
      close with some potential approaches to these problems and future studies that
      are needed to push forward our ability to appropriately make these difficult
      decisions for an increasingly aging population.

PMID- 15179330
TI  - Remote superficial femoral artery endarterectomy.
AB  - The advent of minimally invasive procedures such as percutaneous transluminal
      angioplasty with or without stent, laser-assisted balloon angioplasty, and
      atherectomy, whose results have proven disappointing in the treatment of long
      segment (> more than 15 cm) superficial femoral artery (SFA) occlusive disease,
      stimulated a reassessment of SFA endarterectomy. With the evolution of remote
      superficial femoral artery endarterectomy (RSFAE) a minimally invasive technique
      became available which could be performed through a single incision, allowed,
      debulking of the arterial plaque, and placement of an endovascular stent. We
      report results of RSFAE in an initial trial, results of RSFAE in concert with the
      aSpire Covered Stent which is a flexible ePTFE covered Nitinol stent with
      significant radial strength to withstand torsional stresses at the knee joint,
      and RSFAE and distal vein bypass for limb salvage.

PMID- 15179331
TI  - Treatment of superficial femoral artery occlusive disease.
AB  - The aim of this paper was to compile a literature summary of current treatment
      modalities for the treatment of superficial femoral arterial (SFA) disease. The
      English-language literature was searched for studies describing the treatment of
      SFA occlusive disease using surgical bypass (vein or prosthetic), percutaneous
      bypass (stent-grafts), bare stents, percutaneous transluminal angioplasty (PTA),
      and subintimal angioplasty (SA). Inclusion criteria for articles were
      presentation of primary patency rates, a minimum study population of 10, and
      baseline characteristics of the study population. Average primary and secondary
      patency rates for each treatment modality were obtained by weighting the results
      of each trial by the number of limbs treated. All identified papers were included
      in the summary, regardless of the study inclusion/exclusion criteria,
      comorbidities, or patient population. Since the study conditions and patient
      populations varied widely, this is not intended to be a meta-analysis or for use
      in directly comparing the efficacy of different treatment modalities; rather, it
      is to provide general information on their performance under the reported
      conditions. One hundred and twelve studies met the inclusion criteria for the 6
      treatment modalities identified. Compilation of the data revealed different
      patient populations for the different treatment modalities. For example, PTA was
      generally used to treat short, stenotic lesions, while endografts and SA were
      generally used for longer, total occlusions. For this reason, patency rates for
      the different treatment modalities cannot be directly compared.

PMID- 15179332
TI  - Dorsalis pedis, tarsal and plantar artery bypass.
AB  - Bypass to the dorsalis pedis, tarsal, or plantar artery is often required in
      efforts to salvage the ischemic lower extremity in diabetic patients. The
      objective of this review was to summarize the current indications, techniques,
      and outcomes associated with such distal revascularization procedures. A review
      of the literature and our own institutional experience with dorsalis pedis (n=1
      032), tarsal (n=21), and plantar (n=77) bypass was performed. Bypass to the
      dorsalis pedis, tarsal, or plantar artery is essential in efforts for limb
      salvage in the ischemic limb in the absence of a more proximal bypass target
      option. Inframalleolar bypass can be performed with an acceptable perioperative
      mortality rate (<1%). Limb salvage and patency rates achieved warrant the
      consideration of these distal bypass procedures as an alternative to limb
      amputation. Careful patient selection, detailed preoperative work-up and
      meticulous operative technique play a crucial role in the success of these
      arterial reconstructions.

PMID- 15179333
TI  - Cryopreserved saphenous vein allografts in infrainguinal arterial reconstruction.
AB  - Cryopreserved saphenous vein allografts (cryografts) have been used as conduit in
      infrainguinal revascularization when autogenous vein is inadequate or
      unavailable. Numerous reports on the subject exist, however most are hampered by
      small sample size or retrospective design. Despite poor patency rates, limb
      salvage in patients undergoing cryograft bypass is acceptable. In this article we
      review the literature of cryograft use in infrainguinal revascularization and
      define its role in the armamentarium of the modern vascular surgeon.

PMID- 15179334
TI  - Subintimal angioplasty in lower limb ischaemia.
AB  - Subintimal angioplasty has been suggested as a treatment option for occlusive
      disease and has become an established practice in some centres, reducing their
      operative workload considerably. Others have concerns about the safety and
      durability of the procedure. This review will focus on the evidence for the use
      of subintimal angioplasty in lower limb occlusive disease. A systematic review of
      the literature from a Medline search has been carried out. Despite a paucity of
      trial data, subintimal angioplasty is now an established technique for the
      treatment of lower limb occlusive disease. The results for femoro-popliteal
      disease are well documented, with excellent technical and clinical success rates
      and low complication rates. The results for iliac disease are less well
      documented and demand caution. For infra-popliteal disease with critical
      ischaemia, the technique is again safe with good short and long-term results in a
      group of patients in whom distal bypass surgery is often risky. Subintimal
      angioplasty has a definite learning curve and those wishing to take it up should
      visit an experienced centre first. To achieve widespread acceptance it is likely
      to require large scale randomised controlled trials.

PMID- 15179335
TI  - The value of subintimal angioplasty in the management of critical lower extremity
      ischemia: failure is not always associated with a rethreatened limb.
AB  - The technique of subintimal angioplasty was developed in Leicester, UK in 1987.
      Recently a growing number of centers in Europe and the United States have been
      gaining experience with this technique. Promising results have been reported and
      the application of the technique expanded to include the iliac and crural
      arteries. Despite this growing experience, the technique has not gained
      widespread acceptance. It has been speculated that this may be due in large part
      to a steep learning curve and/or skepticism regarding the procedure given the
      relatively low primary patency rates seen in most series. However, limb salvage
      rates from these same and other series have been considerably higher than the
      patency rates, and advocates of the technique have urged that the results of
      clinical series be viewed with these limb salvage rates primarily in mind.
      Although primary patency rates remain low for patients undergoing subintimal
      angioplasty limb salvage rates remain high. Given the many advantages of this
      technique, including reduced anesthesia requirements, a minimally invasive
      approach, and potential reductions in length of stay and cost subintimal
      angioplasty will continue to have a role in the treatment of lower extremity
      ischemia. When applied judiciously, bypass options are preserved. This does not
      mean that the availability of this technique should be used as justification to
      lower the threshold for the treatment of mild intermittent claudication. When a
      subintimal angioplasty fails, it frequently does so without the recurrence of
      symptoms, especially when a gangrenous lesion or ulcer has healed. Various
      approaches for the performance of subintimal angioplasty and clinical results
      will be discussed.

PMID- 15179336
TI  - Excimer laser assisted angioplasty for the treatment of critical limb ischemia.
AB  - Two decades after the clinical introduction of percutaneous transluminal
      angioplasty (PTA), controversy still exists about the role of PTA for the
      treatment of occlusive disease in the femoropopliteal and infragenicular
      arteries. For the patient with critical limb ischemia (CLI), where diffuse
      disease and long occlusions are the rule, the results with PTA have not been
      optimal. Surgical revascularization has long been considered the gold standard
      for this patient population, but this procedure is associated with significant
      morbidity and mortality and up to 37% of patients may be poor surgical
      candidates. With advances in laser catheter design and refinement of
      recanalization techniques, improved results have been seen with laser assisted
      angioplasty of complex peripheral arterial disease. There has been renewed
      interest in excimer laser angioplasty for the treatment of patients with long
      total occlusions and diffuse disease who otherwise would have limited options for
      treatment. Excimer laser assisted angioplasty has been shown to be a successful
      approach to the treatment of long occlusions in the superficial femoral artery.
      Data from the recently completed Laser Angioplasty for Critical Limb Ischemia
      Phase 2 Trial (LACI) suggest that this is a viable treatment strategy for
      patients with CLI who are otherwise not good candidates for bypass surgery.

PMID- 15179337
TI  - The role of beating heart coronary artery bypass grafting in the current era: a
      point of view.
AB  - Despite coronary artery revascularization on the beating heart was originally
      introduced in the 1960's, its further development was halted for several decades
      by advances in medical technology and by the development of the extracorporeal
      circulation. It is only in recent years that coronary artery bypass grafting on
      the beating heart has gained a secure role in the armamentarium of cardiac
      surgeons, mainly as a result of the popularization of new techniques of coronary
      exposure and stabilization. In later years, the expansion of interventional
      cardiology and the refinement of catheter-based techniques for treating coronary
      artery disease have corresponded to a substantial decline in the overall number
      of patients referred for surgery. Additionally, more and more patients have
      extensive disease and concomitant risk factors. These factors have made the
      future of coronary artery surgery uncertain. As these trends are likely to
      persist, and probably become more prominent in the future, it is essential for
      surgeons to embrace changes that may lead to improved surgical outcomes after
      coronary revascularization. In this article the authors review some of the
      aspects that have contributed to the popularization of off-pump coronary artery
      bypass and speculate on the importance of embracing innovative techniques in the
      field of coronary artery surgery.

PMID- 15179338
TI  - Minimally invasive direct coronary artery bypass grafting: a systematic review.
AB  - AIM: Recently minimally invasive direct coronary artery bypass grafting (MIDCAB)
      has become an interesting alternative to conventional coronary artery bypass
      grafting, especially in patients with a high-grade left anterior descending
      coronary artery (LAD) stenosis unsuitable for balloon angioplasty. Although
      MIDCAB offers several advantages such as the avoidance of sternotomy and
      cardiopulmonary bypass, concerns have been raised about the technical accuracy of
      the anastomoses that can be performed on a beating heart. Therefore, clinical and
      angiographic outcomes after MIDCAB are the subject of current controversy.
      METHODS: A literature search for all published outcome studies of MIDCAB grafting
      was performed for the period from January 1995 through April 2003. Sixteen
      articles were enrolled in this review. The data presented in the studies was
      analysed with regard to clinical outcome and angiographic results. RESULTS: Early
      mortality ranged from 0% to 4.9% and late mortality (>30 days after MIDCAB)
      ranged from 0.3% to 12.6%. Infarct rates (non-fatal myocardial infarction) ranged
      between 0% and 3.1%. Intra- and postoperative complications (wound infections,
      reoperation for management of bleeding, arrhythmias, stroke, etc.) occurred in
      1.6-40%. The conversion rate to sternotomy/cardiopulmonary bypass ranged between
      0% and 6.2%. Reinterventions due to graft failure were necessary in up to 8.9% of
      patients (surgical revision or percutaneous transluminal coronary angioplasty,
      PTCA). Short-term and mid-term angiographic outcomes are given in Table I.
      CONCLUSION: Clinical outcomes and immediate graft patency after MIDCAB are
      acceptable. However, long-term follow-up results and further randomized
      prospective clinical trials comparing this new technique with standard
      revascularization procedures are needed.

PMID- 15179340
TI  - Risk factors associated with perioperative myocardial damage in patients with
      severe aortic stenosis.
AB  - AIM: Few studies have been performed about the risk factors associated with
      perioperative myocardial damage in patients undergoing valve surgery for severe
      aortic stenosis. METHODS: To assess the prevalence of perioperative myocardial
      damage, we studied 103 consecutive patients with aortic stenosis. Perioperative
      myocardial damage (PMD) was diagnosed by both enzymatic data of peak creatine
      kinase iso-enzyme (CK-MB) and new appearance of electrocardiographic abnormality.
      PMD was noticed in 16 patients, and PMD was not noticed in 87 patients. A
      stepwise multiple logistic regression model was used to investigate predictors of
      PMD in several categorized parameters such as preoperative data, cardioplegic
      delivery method, and aortic clamping time. RESULTS: A multivariate analysis
      identified that cardioplegic delivery method, preoperative left ventricular (LV)
      wall thickness, and aortic clamping time were independent predictors of PMD. The
      incidence of PMD in the combined antegrade and continuous retrograde delivery
      method was significantly lower than that in antegrade delivery method (odds ratio
      0.11, CI 0.02-0.61, p=0.011). The peak CK-MB value of the combined antegrade and
      retrograde method was significantly lower than that of the antegrade method (48+/
      24 vs 71+/-50 IU/L; p=0.009). The peak lactate-dehydrogenase value of the
      combined method was significantly lower than that of the antegrade method (590+/
      249 vs 1058+/-656 IU/L; p<0.001). The combined method decreased the incidence of
      PMD in patients with increased total wall thickness. CONCLUSION: Cardioplegic
      delivery method, LV total wall thickness, and aortic clamping time were
      independent predictors for PMD. Combined antegrade and continuous retrograde
      delivery method may be an important factor to obtain adequate myocardial
      protection.

PMID- 15179339
TI  - Myocardial function in early hours after coronary artery bypass grafting in
      patients with left ventricular dysfunction: comparison of blood and crystalloid
      cardioplegia.
AB  - AIM: This study was done to evaluate a myocardial function in the early hours
      after coronary artery bypass grafting (CABG) in patients with left ventricular
      dysfunction and to compare blood and crystalloid cardioplegia. METHODS: One
      hundred consecutive patients with left ventricular ejection fraction <35%
      scheduled for CABG were randomly divided into 2 groups. In the 1st group we used
      cold blood cardioplegia, in the 2nd group cold crystalloid cardioplegia. We
      measured hemodynamic data in the early hours after operation, enzyme release and
      we collected relevant clinical data. RESULTS: The mortality rate in the
      crystalloid and blood cardioplegia group was 2% and 0%, respectively. We didn't
      find any significant difference in the incidence of perioperative myocardial
      infarction, arrhythmia and use of intraaortic balloon pumping between groups.
      Differences between groups were found in the enzymatic response. Average creatine
      kinase and MB isoenzyme of creatine kinase (CK-MB), was lower in the blood
      cardioplegia group lower during the whole examined period. We also found some
      significant differences in hemodynamic data in the postoperative period. In the
      crystalloid cardioplegia group there was a decrease in left ventricular stroke
      work index immediately after operation. The preoperative value was reached in
      about 2 hours after operation. On the other hand, we didn't find this decrease in
      the blood cardioplegia group. This difference between groups was statistically
      significant. Other hemodynamic data didn't show any significant difference.
      CONCLUSION: Blood cardioplegia shows earlier improvement of myocardial function
      after the operation. It could be beneficial in patients with severe left
      ventricular dysfunction.

PMID- 15179341
TI  - Airport and superficial femoral artery obstruction due to a wandering coronary
      stent: the possibility of airport detection of modern implant metals.
AB  - In the treatment of coronary artery disease, peripheral loss of a coronary stent
      is an unusual complication. We present the case of a patient who suggested that
      his right leg claudication was caused by a slipped coronary stent 2 years
      previously. The patient was convinced about this unusual finding based on an
      airport security check. Examination proved him to be right. However, the ability
      to detect an object using eddy currents is dependent on the object's permeability
      and its conductivity. Ferrous (iron) content is not the critical factor. Modern
      implant materials and processing techniques result in implants that are difficult
      to magnetize i.e. their permeability is very low. In addition their conductivity
      is very low. This enables modern implants to escape detection at airports. For
      this reason the event at the airport, as described by our patient, is considered
      coincidental.

PMID- 15179342
TI  - A prospective randomized study of diluted versus non-diluted cardioplegia
      (minicardioplegia) in primary coronary artery bypass surgery.
AB  - AIM: Sanguineous (blood) cardioplegia has been established as the prime option
      for myocardial protection but the choice of dilution (4:1 blood to crystalloid
      ratio) versus use of blood from the cardiopulmonary bypass alone
      (minicardioplegia) remains controversial. The purpose of this prospective
      randomized clinical trial was to compare the clinical outcome and enzymatic
      endpoints (troponin I, CK-MB isoenzyme release) in patients undergoing primary
      CABG surgery. METHODS: From June 1999 to October 2000, 59 patients were
      randomized preoperatively to undergo coronary artery bypass grafting surgery
      using cardiopulmonary bypass and either diluted (4:1 blood to crystalloid ratio;
      n=25) or undiluted sanguineous cardioplegia (minicardioplegia; n=4) at the
      Montreal Heart Institute. Clinical data and biochemical markers of ischemia were
      recorded. Tepid cardioplegia and moderate hypothermic cardiopulmonary bypass were
      used in 92% of patients. RESULTS: There were no significant differences in
      preoperative variables between the 2 groups. There were no statistically
      significant differences in low output syndrome, stroke rate, arrhythmia or
      hospital length of stay between both groups. There was no statistically
      significant difference between minicardioplegia and diluted groups in the release
      of troponin T 24 hours postoperatively (0.36+/-0.31 versus 0.23+/-0.22,
      respectively). There was a slightly higher release of troponin T in the
      minicardioplegia group 48 hours after surgery (0.38+/-0.35 versus 0.20+/-0.16)
      (p=0.03) and of CK-MB 24 hours postoperatively (22.9+/-18.6 versus 10.2+/-5.3)
      (p<0.01). CONCLUSION: Clinical outcomes are similar in patients undergoing
      primary CABG surgery with tepid cardioplegia and moderate hypothermic bypass with
      diluted or minicardioplegia. Minicardioplegia may be the optimal method of
      myocardial protection because of low cost, ease of use and lack of hemodilutive
      effect.

PMID- 15179343
TI  - Preoperative semi-selective left internal mammary artery angiography: easy, safe,
      necessary and worthy.
AB  - AIM: The left internal mammary artery is the graft of choice for coronary artery
      bypass surgery. The necessity for preoperative internal mammary artery
      angiography is still controversial. We designed a prospective left internal
      mammary angiography for evaluating the risk of stenosis in the left internal
      mammary and subclavian artery, and the risk and the necessity for pre-operative
      internal mammary artery angiography. METHODS: Eighty-six patients were included
      in a prospective study for semi-selective left internal mammary artery
      angiography during cardiac catheterization via the left radial or femoral
      approach. Stenosis of the left internal mammary and proximal left subclavian
      arteries was calculated with DCA; Chi2 analysis was used for analyzing the
      correlation between the risk factors and arterial stenosis. RESULTS: One patient
      (1.2%) showed left internal mammary artery stenosis and 5 (5.8%) showed proximal
      left subclavian artery stenosis. No complications were found in all cases. The
      only significant factor affecting left subclavian or internal mammary artery
      stenosis was the female sex. All patients tolerated the procedure well.
      CONCLUSION: Semi-selective left internal mammary artery angiography is a safe and
      easy procedure that should be performed routinely for patients with CAD prior to
      coronary artery bypass surgery.

PMID- 15179344
TI  - Extra-anatomic coronary artery bypass graftings in patients with porcelain aorta.
AB  - AIM: Severely atherosclerotic (porcelain) ascending aorta is associated with
      increased morbidity and mortality during coronary artery bypass grafting (CABG)
      due to the increased risk of perioperative atheroembolism. Three maneuvers during
      CABG can cause atheromatous embolism from the diseased ascending aorta: 1)
      cannulation of the ascending aorta; 2) cross- clamping; 3) partial clamping for
      the construction of the proximal anastomosis. METHODS: In our hospital, extra
      anatomic CABG was performed in 8 patients with heavily calcified ascending aorta:
      6 patients were men and 2 women. Operations were performed on the beating heart
      in 5 patients, 2 patients operated on beating heart and another patient on
      fibrillating heart with supportive cardiopulmonary bypass (CPB). Arterial
      cannulation was done through the right femoral artery on these patients. Apart
      from internal mammary artery (IMA) grafts, proximal anastomotic sites were the
      right axillary, right subclavian and innominate arteries. RESULTS: One patient
      who preoperatively had dialysis dependent chronic renal failure, died as a result
      of dialysis complication on the 5th day. The postoperative course was uneventful
      in the other patients and no patient experienced either any cerebrovascular or
      visceral organ injury as a result of atheroemboli. CONCLUSION: We think that
      extra-anatomic CABG procedures are safe and reliable in patients with severely
      atherosclerotic (porcelain) ascending aorta to minimize the prevalence of
      perioperative stroke and systemic embolization.

PMID- 15179345
TI  - Preoperative shift from glibenclamide to insulin is cardioprotective in diabetic
      patients undergoing coronary artery bypass surgery.
AB  - AIM: The cardioprotective effects afforded by volatile anesthetics, i.e.
      isoflurane, during heart surgery may be due to preconditioning of the myocardium
      through the activation of KATP channels. The aims of this study were to establish
      whether glibenclamide prevents the isoflurane-induced cardioprotection in
      diabetic patients undergoing coronary surgery (CABG) and whether this
      cardioprotective effect can be restored by preoperative shift from glibenclamide
      to insulin therapy. METHODS: We enrolled 60 patients undergoing CABG. Twenty
      consecutive non-diabetic patients were randomized to receive conventional
      anesthesia (CA) or conventional anesthesia plus isoflurane (ISO) (added to the
      inspired oxygen before starting cardiopulmonary bypass); 40 consecutive diabetic
      patients in chronic treatment with oral glibenclamide were randomized to
      conventional anesthesia (G-CA), conventional anesthesia plus isoflurane (G-ISO),
      conventional anesthesia after shifting to insulin (I-CA) or conventional
      anesthesia plus isoflurane after shifting to insulin (I-ISO). Serum levels of
      cardiac troponin I (CTnI) and CK-MB, as markers of ischemic injury, were obtained
      1, 24, 48 and 96 hours, postoperatively. RESULTS: Postoperative peak levels of
      CTnI and CK-MB were lower in ISO than in CA (0.5+/-0.3 vs 2.8+/-2.2 ng/ml, p<0.05
      and 61+/-27 vs 79+/-28 U/L, p<0.05, respectively), as well as in I-CA and I-ISO
      than G-CA and G-ISO groups (0.5+/-0.7 and 0.7+/-0.9 vs 3.5+/-3 and 2.7+/-2.5
      ng/ml, p<0.05; 47+/-7 and 41+/-5 vs 85+/-28 and 50+/-23 U/L, p<0.05,
      respectively). No significant differences were detected in postoperative
      hemodynamic variables or in-hospital outcome. CONCLUSION: This prospective
      randomized study shows a cardioprotective effect of preoperative administration
      of isoflurane during CABG. Such an effect is prevented by glibenclamide, but can
      be restored in diabetic patients by preoperative shift from glibenclamide to
      insulin.

PMID- 15179346
TI  - A variation of the radial artery and its clinical implications for coronary
      artery bypass grafting.
AB  - Since the radial artery is increasingly harvested as a bypass graft, surgeons are
      confronted with its anatomical variations. We report on a radial artery running
      laterally around the distal part of the radius, while a superficial palmar branch
      is running straight down. The radial artery can be dissected distally to get
      enough length for the bypass graft, but attention has to be paid to the
      superficial branch of the radial nerve running nearby to prevent postoperative
      paresthesias and numbness. The superficial palmar branch of the radial artery can
      be ligated. Allen's test in such a case is not valid because it is always
      negative.

PMID- 15179347
TI  - Cardiac echinococcosis in a 3-year-old child.
AB  - A 3-year-old girl was admitted with the diagnosis of left ventricular hydatid
      cyst. She also had pulmonary, hepatic and splenic cysts. The diagnosis of the
      left ventricular cyst was made by means of computerized tomography and confirmed
      using cardiac magnetic resonance imaging and transthoracic echocardiography. The
      patient was submitted to cystectomy on beating heart with a straightforward
      postoperative period.

PMID- 15179348
TI  - In vivo transluminal microvascular endothelial cell seeding on balloon injured
      rabbit arteries.
AB  - AIM: Seeding venous endothelial cells (EC) onto damaged vascular surfaces
      attenuates the development of intimal hyperplasia. Unlike venous EC, fat derived
      microvascular endothelial cells (MVEC) do not require a culture step to increase
      the yield. The authors investigated whether fat derived MVEC are suitable to
      reduce intimal hyperplasia after PTA. METHODS: Five rabbits were subjected to
      percutaneous transluminal angioplasty (PTA) of both iliac arteries. One side was
      seeded transluminally with autologous perirenal fat derived MVEC, using a double
      balloon catheter. The contralateral side was sham seeded, and served as a
      control. Follow-up was 4 weeks. Another rabbit was used for a feasibility
      experiment. This rabbit was subjected to a 1-sided seeding procedure and was
      sacrificed after 1 week. In a 7th rabbit, a 1-sided PTA was transformed, and
      autologous labelled cells were injected in the distal aorta instead of seeded,
      follow-up was 1 week. Histological investigation was per-formed. RESULTS: The
      MVEC seeded artery of the pilot experiment was patent. All sham seeded arteries
      (5) except for 1 were patent. The patent ones showed moderate intimal
      hyperplasia. MVEC seeding (5) resulted in occlusion twice. In the patent MVEC
      seeded arteries intimal hyperplasia was present in more extended form than in the
      sham seeded arteries. Both the patent MVEC- and sham-seeded arteries were covered
      with an EC layer. Injected labelled MVEC were not found again on the de
      endothelialized artery. CONCLUSION: In this study seeding of fat derived MVEC on
      damaged native arteries results in an increased development of intimal
      hyperplasia and a decreased patency. One of the reasons may be the presence of
      non-EC in the seeded cell population.

PMID- 15179349
TI  - Venous blood flow through vein grafts before harvesting minimizes endothelial
      cell desquamation immediately after implantation.
AB  - AIM: The aim of this paper was to examine effectiveness of maintaining venous
      blood flow through dissected, but not harvested, grafts on prostaglandin I2
      production and endothelial cell regeneration after implantation. METHODS: Using
      10 dogs, 8-cm-long bilateral jugular veins were dissected; 1 was harvested, and
      immersed in heparinized blood for 60 or 120 min. The other was left in situ with
      retained blood flow until harvest after 60 or 120 min. Two 1-cm-long specimens
      were obtained from these 4 graft types and subjected to PGI2 assay or silver
      nitrate staining for measurement of endothelial cell coverage area. The remaining
      6-cm portions of the 120-min grafts were autogenously implanted into the
      abdominal aorta, retrieved after 7 days and assayed and measured. RESULTS:
      Comparisons between groups suggested beneficial effects of preserving venous
      blood flow until implantation on endothelial coverage and PGI2 production
      (p<0.05). CONCLUSION: Venous blood flow through dissected vein grafts effectively
      helps preserve PGI2 production.

PMID- 15179350
TI  - Ser128Arg gene polymorphism for E-selectin and severity of atherosclerotic
      arterial disease.
AB  - AIM: Genetic factors appear to be important in the pathogenesis of cardiovascular
      and cerebrovascular disease. Adhesion molecules like the members of the selectin
      family participate in the interaction between leukocytes and the endothelium.
      They are also involved in the pathogenesis of the atherosclerotic process. In E
      selectin, exchange from serine to arginine (position 128, S128R) is correlated
      with early atherosclerosis. The aim of this study was to assess E-selectin
      Ser128Arg polymorphism in subjects with clinical and instrumental evidence of
      atherosclerosis and to analyze the correlations with clinical severity. METHODS:
      A total of 144 subjects (100 men and 44 women, mean age 72 years, range 48-78)
      with atherosclerotic disease in different vascular sites documented by
      angiography were studied; 138 volunteers were recruited as a control group. Whole
      blood was collected; DNA was extracted with a commercial kit and amplified with 2
      primers. The PCR was performed by standard procedure. To assess the disease
      severity all patients were classified by an arbitrary clinical and angiographic
      score scale. RESULTS: The genotype distribution between patients and controls was
      different, although statistical significance was not achieved (p=0.06). In
      patients a significant difference in Arg allele frequency was observed between
      mild and severe atherosclerotic disease (OR 2.28; 95% CI 1.15-4.52; p=0.017).
      Four ho-mozygous cases for S128R were found in patients, none in controls. All
      these 4 patients had the highest severity score, that means a more severe
      atherosclerotic disease. CONCLUSION: Our study suggests that the E-selectin
      polymorphism may be associated with severity of atherosclerotic disease, but does
      not allow us to conclude that it is actually a risk factor for atherosclerosis.

PMID- 15179351
TI  - Aortoplasty with a bovine venous xenograft for pseudoaneurysm after heart
      transplantation.
AB  - The case was a 54-year-old man after orthotopic heart transplantation with
      infected pseudoaneurysm of the ascending aorta. The operation was performed with
      hypothermic circulatory arrest. Pseudoaneurysm was excised and aortoplasty was
      performed with a bovine venous xenograft patch. Six months after the operation,
      and 2 years after transplantation, the patient is doing well.

PMID- 15179352
TI  - Ruptured pancreaticoduodenal artery aneurysm. A case report and review of the
      literature.
AB  - Pancreaticoduodenal artery aneurysms (PDAA) are very rare (2% of the visceral
      aneurysms) but characterized by a high mortality rate if ruptured. Here a case of
      ruptured PDAA with an atypical clinical presentation that simulated an acute
      hepatobiliar syndrome is reported. A 60-year-old female presented with epigastric
      pain, nausea, gastric vomiting, elevated levels of hepatic enzymes, normal
      hemoglobin and cholelithiasis on echography. With persistent pain and
      progressively decreasing hemoglobin, an urgent contrast computed tomography was
      performed and revealed a large retroperitoneal hematoma that appeared to come
      from a branch of the superior mesenteric artery (SMA). A selective SMA
      angiography showed a small aneurysm of the antero-superior pancreaticoduodenal
      artery with signs of hemorrhage. The patient underwent surgical ligature of the
      PDAA, after superselective transcatheter arterial embolization appeared
      technically impossible. The postoperative period was characterized by a
      progressive normalization of the hepatic values and hemoglobin and a post
      operative angiogram confirmed the total exclusion of the PDAA and the integrity
      of the posterior pancreaticoduodenal arch. The pre-operative diagnosis of PDAA is
      usually very difficult. Symptoms can be vague or misleading, as in our case.
      Angiography is the most accurate diagnostic tool to locate a ruptured PDAA.
      Moreover, it can be immediately used for urgent endovascular treatment. Post
      operative angiography is essential to confirm the total exclusion of the PDAA and
      demonstrate visceral circulation.

PMID- 15179353
TI  - Surgical closure of coronary arteriovenous fistulas draining into the pulmonary
      artery using off-pump coronary artery bypass technique.

PMID- 15179354
TI  - Early vascular graft infection due to Yersinia enterocolitica after repair of an
      abdominal aortic aneurysm.

PMID- 15179355
TI  - Congenital cystic adenomatoid malformation of the lung in an adult presenting as
      unilobar expanding compressive cyst.

PMID- 15179356
TI  - Solitary fibrous tumor of the pleura. A single institution's experience.

PMID- 15179357
TI  - False aneurysm of the radial artery with sharp injury of the brachial artery,
      median and ulnar nerves. An unusual presentation.

PMID- 15179358
TI  - Re-expansion pulmonary syndrome: a serious complication of pleural drainage.

PMID- 15179359
TI  - Cancer mortality surveillance--United States, 1990-2000.
AB  - PROBLEM/CONDITION: Cancer is the second leading cause of death in the United
      States and is expected to become the leading cause of death within the next
      decade. Considerable variation exists in cancer mortality between the sexes and
      among different racial/ethnic populations and geographic locations. The
      description of mortality data by state, sex, and race/ethnicity is essential for
      cancer-control researchers to target areas of need and develop programs that
      reduce the burden of cancer. REPORTING PERIOD COVERED: 1990-2000. DESCRIPTION OF
      SYSTEM: Mortality data from CDC were used to calculate death rates and trends,
      categorized by state, sex, and race/ethnicity. Trend analyses for 1990-2000 are
      presented for all cancer sites combined and for the four leading cancers causing
      death (lung/bronchus, colorectal, prostate, and breast) categorized by state,
      sex, and race/ethnicity. Death rates per 100,000 population for the 10 primary
      cancer sites with the highest age-adjusted rates are also presented for each
      state and the District of Columbia by sex. For males, the 10 primary sites
      include lung/bronchus, prostate, colon/rectum, pancreas, leukemia, non-Hodgkin
      lymphoma, liver/intrahepatic bile duct, esophagus, stomach, and urinary bladder.
      For females, the 10 primary sites include lung/bronchus, breast, colon/rectum,
      pancreas, ovary, non-Hodgkin lymphoma, leukemia, brain/other nervous system,
      uterine corpus, and myeloma. RESULTS: For 1990-2000, cancer mortality decreased
      among the majority of racial/ethnic populations and geographic locations in the
      United States. Statistically significant decreases in mortality among all races
      combined occurred with lung and bronchus cancer among men (--1.7%/year);
      colorectal cancer among men and women (--2.0%/year and--1.7%/year, respectively);
      prostate cancer (--2.6%/year); and female breast cancer (--2.3%/year). For 1990
      2000, cancer mortality remained stable among American Indian/Alaska Native
      populations. Statistically significant increases in lung and bronchus cancer
      mortality occurred among women of all racial/ethnic backgrounds, except among
      Asian/Pacific Islanders. INTERPRETATION: Although cancer remains the second
      leading cause of death in the United States, the overall declining trend in
      cancer mortality demonstrates considerable progress in cancer prevention, early
      detection, and treatment. PUBLIC HEALTH ACTION: More effective tobacco-cessation
      programs are necessary to reduce lung and bronchus cancer mortality among women
      and sustain the decrease in lung and bronchus cancer mortality among men.
      Additional programs that deter smoking initiation among adolescents are essential
      to ensure future decreases in lung and bronchus cancer mortality. Continued
      research in primary prevention, screening methods, and therapeutics is needed to
      further reduce disparities and improve quality of life and survival among all
      populations.

PMID- 15179360
TI  - Responding to detection of aerosolized Bacillus anthracis by autonomous detection
      systems in the workplace.
AB  - Autonomous detection systems (ADSs) are under development to detect agents of
      biologic and chemical terror in the environment. These systems will eventually be
      able to detect biologic and chemical hazards reliably and provide approximate
      real-time alerts that an agent is present. One type of ADS that tests
      specifically for Bacillus anthracis is being deployed in hundreds of postal
      distribution centers across the United States. Identification of aerosolized B.
      anthracis spores in an air sample can facilitate prompt on-site decontamination
      of workers and subsequent administration of postexposure prophylaxis to prevent
      inhalational anthrax. Every employer who deploys an ADS should develop detailed
      plans for responding to a positive signal. Responding to ADS detection of B.
      anthracis involves coordinating responses with community partners and should
      include drills and exercises with these partners. This report provides guidelines
      in the following six areas: 1) response and consequence management planning,
      including the minimum components of a facility response plan; 2) immediate
      response and evacuation; 3) decontamination of potentially exposed workers to
      remove spores from clothing and skin and prevent introduction of B. anthracis
      into the worker's home and conveyances; 4) laboratory confirmation of an ADS
      signal; 5) steps for evaluating potentially contaminated environments; and 6)
      postexposure prophylaxis and follow-up.

PMID- 15179361
TI  - Potential benefits of the new Leapfrog standards: effect of process and outcomes
      measures.
AB  - OBJECTIVE: The Leapfrog Group standards for evidence-based hospital referral
      underwent significant revision in 2003. In addition to other changes, risk
      adjusted mortality and process of care measures now augment or replace volume
      standards for some procedures. The objective of this study was to estimate the
      potential benefits of these newly expanded standards. METHODS: Leapfrog's 2003
      standards were based on minimum volume standards alone for 2 operations
      (esophagectomy, pancreatectomy), volume standards and a process measure
      (perioperative beta blockade) for 1 operation (abdominal aortic aneurysm repair),
      and volume standards coupled with risk-adjusted mortality rates for 2 operations
      (coronary artery bypass grafting [CABG] and percutaneous coronary intervention
      [PCI]). We used data from the 2000 Nationwide Inpatient Sample to determine
      eligible surgical populations, volume-outcome associations, and risk-adjusted
      hospital mortality rates for the 5 operations. A recent meta-analysis was used to
      estimate the effectiveness of perioperative beta-blocker use. RESULTS:
      Approximately 23,790 patients died in 2000 in the United States undergoing 1 of
      the 5 procedures. We estimate that full implementation of the Leapfrog standards
      would have averted 7818 of these deaths: CABG (4089), PCI (3016), elective
      abdominal aortic aneurysm repair (356), esophageal resection (180), and
      pancreatic resection (177). For CABG and PCI, standards based on risk-adjusted
      mortality rates would save at least 5 times more lives than those based on volume
      criteria alone. CONCLUSIONS: Widespread implementation of the 2003 Leapfrog
      standards for evidence-based referral could avert a large number of surgical
      deaths. For some procedures, standards comprised of process of care or direct
      outcome measures would be more effective than those based on volume alone.

PMID- 15179362
TI  - Invited commentary: Measurement of quality in surgery: that's our job.

PMID- 15179363
TI  - Bioinformatics tools to understand human diseases.

PMID- 15179364
TI  - Estimation of physiologic ability and surgical stress (E-PASS) for a surgical
      audit in elective digestive surgery.
AB  - BACKGROUND: This study was undertaken to establish an equation to estimate
      mortality with the use of the prediction scoring system designated as the
      Estimation of Physiologic Ability and Surgical Stress (E-PASS), and to evaluate
      the system's usefulness in defining quality of care by comparing it with the
      Physiologic and Operative Severity Score for the enUmeration for Mortality and
      morbidity (POSSUM) and Portsmouth-possum (P-POSSUM) scoring systems previously
      generated for surgical audit. METHODS: Patients (n=5212; group A) who underwent
      elective gastrointestinal surgery were analyzed to establish equations for
      estimated 30-day and in-hospital mortality rates. The usefulness of E-PASS was
      evaluated in another series of 1934 patients (group B) who underwent elective
      digestive surgery in 6 national hospitals. The ratio of observed to estimated
      mortality rates (OE ratio) of each hospital was defined as a measure of quality.
      RESULTS: In group A, 30-day and in-hospital mortality rates increased as the
      Comprehensive Risk Score (CRS) increased, providing equations for estimated
      mortality rates. There was an excellent correlation between the estimated and
      observed mortality rates in individual diseases: R=0.958, N=6, P=.0027 for in
      hospital mortality; R=0.937, N=6, P=.0059 for 30-day mortality. In all patients
      of group B, the E-PASS system estimated the 30-day mortality rates by 0.63-fold
      (linear analysis), whereas the POSSUM score was 11.0-fold (exponential analysis).
      The E-PASS system estimated the in-hospital mortality rates by 1.2-fold (linear
      analysis), whereas the P-POSSUM score was 4.5-fold (linear analysis). The OE
      ratios for 30-day mortality among the 6 hospitals defined by E-PASS correlated
      well with those defined by POSSUM: R=0.996, N=6, P<.0001. Similarly, the OE
      ratios for in-hospital mortality defined by E-PASS were also highly correlated
      with those defined by P-POSSUM:(R=0.929, N=6, P=.0075. CONCLUSIONS: The E-PASS
      scoring system may be useful in defining surgical quality and may be more
      accurate than existing systems in evaluating elective digestive surgery.

PMID- 15179365
TI  - Surgical strategy for hepatocellular carcinoma originating in the caudate lobe.
AB  - BACKGROUND: The prognosis of hepatocellular carcinoma originating in or mainly
      involving the caudate lobe (caudate HCC) is generally poor. We reviewed the
      clinicopathologic findings of patients who underwent liver resection of caudate
      HCC and correlated the outcome with the surgical strategy. METHODS: Records of
      402 patients who underwent liver resection for HCC were reviewed. The patients
      were divided into 2 groups. One group consisted of 15 patients who underwent
      liver resection for caudate HCC. The other group included 387 patients with HCC
      in a site other than the caudate lobe. RESULTS: Anatomic resection of Couinaud
      segment I or IX (a partial caudate lobectomy), conforming to portal anatomy, was
      performed in 13 patients with caudate HCC, and segmentectomies of segments I and
      IX (a total caudate lobectomy) were performed in 2 patients with caudate HCC. The
      incidence of postoperative complications was similar in the caudate HCC group and
      HCC in other sites group, with no operative deaths in the caudate HCC group.
      Tumor-free survival and cumulative survival were similar in the 2 groups.
      However, among patients with caudate HCC, tumor-free and cumulative survival were
      lower in patients with than without microscopic portal venous involvement
      (P<.01). CONCLUSIONS: Partial caudate lobectomy (anatomic resection of segment I
      or IX) along the portal system is an appropriate procedure for caudate HCC,
      especially in patients with impaired liver function or a small HCC. Patients with
      caudate HCC who have microscopic portal venous involvement may require adjuvant
      therapy as early recurrence is likely.

PMID- 15179366
TI  - Prognostic significance of Bcl-xL in human hepatocellular carcinoma.
AB  - BACKGROUND: Proliferation and apoptosis of liver cancer cells are closely related
      phenomena. We investigated the correlation between overexpression of Bcl-xL, an
      anti-apoptosis-related protein of the Bcl-2 family, and the clinical course of
      hepatocellular carcinoma (HCC). METHODS: Specimens from 7 HCC patients were used
      for Western blotting and immunoelectron microscopy tests. Samples from 33 HCC
      patients who had undergone hepatectomies were used for immunohistochemical
      staining. The degrees of expression of Bcl-xL and Ki-67, as an index of HCC
      mitosis severity, were each classified into 2 groups. RESULTS: With the use of
      Western blot analysis, enhanced immunoreactivity of Bcl-xL was found in cancerous
      specimens. Bcl-xL overexpression was found in cancer specimens in 21 of 33
      patients (63.6%). The overall survival (P=.019) and disease-free survival
      (P=.030) rates of the group overexpressing Bcl-xL were definitely poorer. The Ki
      67 higher labeling index LI > 10) group had a poorer survival rate (P=.016).
      There were significant correlations between Bcl-xL and overall survival and
      disease-free survival. Multivariate analyses revealed that Bcl-xL, tumor size,
      histologic portal invasion, and histologic metastatic foci were independent
      prognostic factors for overall survival and disease-free survival. CONCLUSIONS:
      These results showed Bcl-xL in HCC specimens, suggesting that Bcl-xL was a
      significant prognostic factor for disease progression in human HCC.

PMID- 15179367
TI  - Management and outcome of patients with combined bile duct and hepatic arterial
      injuries after laparoscopic cholecystectomy.
AB  - BACKGROUND: Recent collective reviews have described the management and outcome
      of bile duct injuries during laparoscopic cholecystectomy. However, few have
      reported on the clinical significance of concomitant right hepatic arterial
      injuries. This study was conducted to examine the correlation of combined bile
      duct and vascular injuries and to evaluate the impact of these injuries on
      patient morbidity. METHODS: From January 1990 to February 2002, a total of 54
      patients with bile duct injuries during laparoscopic cholecystectomy were
      surgically treated in our institution. In 46 patients a Roux-en-Y
      hepaticojejunostomy was performed. Eleven patients had a concomitant vascular
      injury. Arterial reconstruction was performed in addition to Roux-en-Y
      hepaticojejunostomy in 2 patients. Eight patients underwent other surgical
      procedures and were not included in the statistical analysis. To evaluate the
      impact of vascular injuries, univariate and multivariate analysis was performed.
      RESULTS: The rate of postoperative biliary complications was 21.7% for all
      patients. Univariate and multivariate analysis identified 2 risk factors for the
      development of biliary complications after reconstructive surgery: (1) combined
      bile duct and hepatic arterial injuries (6 of 11 patients [54.5%] vs 4 of 35
      patients [11.4%]; P=.006) and (2) surgical repair in active peritonitis (8 of 13
      patients [61.5%] vs 2 of 33 [6.1%]; P <.001). In the other, late referred
      patients with concomitant right hepatic arterial injury, the distal part of the
      artery was not exposable. After a median follow-up time of 44.6 months (range, 2
      to 143.5 months) a successful outcome was achieved in 42 of 46 patients (91.3%),
      which included the patients who required additional endoscopic or surgical
      treatment after primary reconstruction. CONCLUSIONS: The outcome of bile duct
      reconstruction is worse in patients with concomitant arterial injuries. We
      therefore recommend the assessment of patients with major bile duct injuries for
      additional vascular injuries. Further studies are needed to evaluate the
      importance of hepatic arterial revascularization in early recognized injuries to
      the long-term outcome of bile duct reconstructions.

PMID- 15179368
TI  - TNF alpha-induced hepatocyte apoptosis is associated with alterations of the cell
      cycle and decreased stem loop binding protein.
AB  - BACKGROUND: Inhibition of nuclear factor kappa B (NF kappa B) during liver
      regeneration induces hepatocyte apoptosis associated with normal DNA synthesis
      but decreased mitosis, suggesting that inhibition of NF kappa B impairs
      progression from S-phase through the G(2)/M phase of the cell cycle. Our aim was
      to determine if inhibition of NF kappa B alters cell cycle characteristics in
      hepatocytes treated with tumor necrosis factor alpha (TNF alpha). METHODS:
      Primary hepatocytes from BALB/c mice were infected with adenoviruses expressing
      luciferase (control; AdLuc) or the I kappa B super-repressor (AdI kappa B) and
      treated with or without TNF alpha (30 ng/ml). Flow cytometry was performed (0 to
      40 hours) to determine apoptosis and cell cycle progression. Reverse
      transcriptase-polymerase chain reaction and immunoblots assessed changes in cell
      cycle mediators and antiapoptotic factors. RESULTS: Primary hepatocytes treated
      with AdI kappa B and TNF alpha demonstrated significantly more S-phase cells (14%
      +/- 3% vs 6% +/- 2%, P<.05) at 14 hours compared with controls. Inhibition of NF
      kappa B with or without TNFalpha was associated with decreased expression of stem
      loop bind protein, a marker of cell cycle progression through S-phase. The NF
      kappa B-induced antiapoptotic proteins, iNOS and TRAF2, had decreased message at
      9 and 12 hours, respectively, in TNF alpha- and AdI kappa B-treated cells.
      CONCLUSION: Inhibition of NF kappa B in TNF alpha-treated primary mouse
      hepatocytes is associated with increased S-phase cell cycle retention and
      decreased stem loop bind protein.

PMID- 15179369
TI  - A simplified technique for the en bloc procurement of abdominal organs that is
      suitable for pancreas and small-bowel transplantation.
AB  - BACKGROUND: Graft shortage makes multiorgan procurement mandatory. We describe
      the results of a simplified method for the en bloc procurement of multiple
      organs, which permits isolated transplantation of all abdominal grafts, including
      the pancreas and the small bowel, to different recipients. METHODS: Three hundred
      forty-three multiorgan procurements were done with a simplified en bloc
      technique. RESULTS: None of the 1374 grafts that were procured sustained injuries
      that potentially precluded transplantation. Seventy-two grafts that were procured
      from 18 donors (5%) who were diagnosed with a neoplasm were discarded. Overall,
      339 grafts that were procured from 325 donors were discarded because of specific
      contraindications, and 963 grafts (74%) were transplanted. Ninety-seven pancreata
      were transplanted. In 3 instances the pancreas and the small bowel were procured
      simultaneously and transplanted to different recipients. A total of 287 liver
      grafts were also transplanted at 13 different institutions. In 42 instances, the
      liver was not allocated to our center. Forty liver teams (95%) from 11 different
      institutions agreed to procure their grafts according to the simplified en bloc
      technique. Our team performed 18 procurements, and a surgeon from the liver
      transplantation team, who was assisted by one of the members of our team,
      performed 22 procurements. In all, 576 kidneys were transplanted, either alone or
      simultaneously, with other abdominal grafts at 15 different institutions.
      CONCLUSIONS: This procurement method has high yields, allows pancreas and small
      bowel procurement, and can be learned readily.

PMID- 15179370
TI  - Protection against ischemia/reperfusion injury by the cavitary two-layer method
      in canine small intestinal transplantation with reduction of reactive oxygen
      species.
AB  - BACKGROUND: Ischemia and reperfusion (I/R) injury is a major determinant of early
      graft dysfunction and long-term graft survival in small intestinal
      transplantation. The cavitary two-layer method (TLM) has been reported to be
      superior to the University of Wisconsin cold storage method (UWM) in long-term
      preservation of canine small intestine. This study was designed to evaluate the
      protective effect of the cavitary TLM against I/R injury in canine small
      intestinal transplantation. METHODS: Intestinal grafts harvested from beagles
      were allotransplanted after 24-hour preservation by UWM (group 1) or the cavitary
      TLM (group 2). The graft in the controls (group 3) was immediately
      allotransplanted without preservation. I/R injury was assessed by functional
      success rates, biochemical assay, graft adenosine triphosphate (ATP) and lipid
      peroxidation (LPO) concentrations, and histopathologic examination including
      TUNEL staining for apoptosis. RESULTS: In group 1, ATP recovery was delayed after
      reperfusion, and most recipients died with hemorrhage of the grafts and lungs. In
      group 2, graft ATP concentrations recovered rapidly, and I/R injury was prevented
      with reduced LPO production, resulting in good outcome. CONCLUSIONS: The cavitary
      TLM protected intestinal grafts against I/R injury evidenced by maintenance of
      graft ATP levels and reduction of LPO production compared with UWM in canine
      small intestinal transplantation.

PMID- 15179371
TI  - Enterocyte metabolism during early adaptation after extensive intestinal
      resection in a rat model.
AB  - OBJECTIVE: A better knowledge of intestinal adaptation after resection is
      required to improve the nutritional support that is given to patients. The aim of
      this study was to understand the metabolic changes underlying early adaptation
      after massive intestinal resection. METHODS: Rats were assigned to either 80%
      intestinal resection or transection. All animals received the same intragastric
      nutrition. On day 8, plasma glutamine turnover was measured. Substrate use was
      determined on isolated enterocytes that were incubated in the presence of D-[U
      (14)C] glucose (2 mmol/L), L-[U-(14)C] glutamine (2 mmol/L), L-[U-(14)C] arginine
      (1 mmol/L), or L-[1-(14)C] ornithine (1 mmol/L). RESULTS: Plasma glutamine
      turnover was similar in both groups. The rate of enterocyte glutamine use was
      significantly increased in the resection group, although the maximal glutaminase
      activity was unchanged. Glutathione generation was enhanced 3-fold in remnant
      intestine as compared with transected intestine (P <.05). L-ornithine
      decarboxylation was increased markedly in resected animals (P <.05), without any
      detectable change of maximal ornithine decarboxylase activity. CONCLUSION: The
      early phase of intestinal adaptation after resection induces changes in
      enterocyte glutamine and ornithine metabolism that may be related, in part, to
      increased de novo polyamine synthesis. This observation suggests that a
      supplementation of artificial nutrition by nutrients that lead to the generation
      of trophic agents may be of potential interest.

PMID- 15179372
TI  - Surgical injury induces the mobilization of endothelial progenitor cells.
AB  - BACKGROUND: Endothelial progenitor cells (EPCs) are derived from the bone marrow
      and incorporate into the foci of tumor neovascularization to increase tumor
      growth. We hypothesized that surgery induces the mobilization of EPCs. METHODS:
      C57BL/6 mice were assigned randomly to standardized laparotomy or anesthesia-only
      treatment groups (n=102 mice). Animals were killed at 6, 24, 48, and 72 hours.
      Bone marrow EPCs were detected by blood flow cytometric dual staining for stem
      cell antigen-1/cKit. Circulating EPCs were characterized in blood by vascular
      endothelial growth factor receptor 2(+)/macrophage activating complement-1(-)
      staining. EPCs were detected in splenic homogenates by dual staining for lectin
      and acetylated low-density lipoprotein uptake. Plasma vascular endothelial growth
      factor was determined by enzyme-linked immunosorbent assay. RESULTS: Surgery
      induced increases in bone marrow and splenic EPC levels (0.2% +/- 0.01% vs 2.9%
      +/- 0.3%) at 24 hours and in circulating EPC levels (2.5% +/- 0.01% vs 35.2% +/-
      6%) at 48 hours compared with control subjects (P <.001). Surgical injury also
      caused an increase in vascular endothelial growth factor release (81 +/- 8 vs 14
      +/- 2 pg; P>.02). CONCLUSIONS: EPCs were mobilized by surgical injury, which may
      have implications for residual and metastatic tumor growth during the
      perioperative period.

PMID- 15179373
TI  - Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic
      shock.
AB  - BACKGROUND: Three different protocols tested the hypothesis that hind limb muscle
      tissue O(2) saturation (StO(2)), measured noninvasively with near-infrared
      spectroscopy (NIRS), is as reliable as invasive systemic oxygenation indices to
      guide fluid resuscitation. METHODS: In series 1, swine (n=30) were hemorrhaged,
      then received either no fluid, a fixed volume of colloid (15 mL/kg), or shed
      blood plus lactated Ringer's (LR) titrated to MAP >60 mm Hg. In series 2, swine
      (n=16) received a penetrating femur injury, a 47% to 55% hemorrhage to determine
      a median lethal dose (LD(50)) then shed blood plus LR titrated to MAP >60 mm Hg.
      In series 3, swine (n=5) received the femur injury plus LD(50) hemorrhage, and
      were resuscitated with LR titrated to StO(2) >50%. RESULTS: In series 1, StO(2)
      tracked mixed venous O(2) saturation (SvO(2)), but discriminated between 3
      survivor groups better than SvO(2), arterial lactate, or arterial base excess. In
      series 2, StO(2) tracked SvO(2) but discriminated between 2 survivor groups
      better than SvO(2), arterial lactate, or arterial base excess. In series 3,
      animals survived to extubation when resuscitated to an StO(2) target.
      CONCLUSIONS: Noninvasive muscle StO(2) determined by NIRS was more reliable than
      invasive oxygenation variables as an index of shock. Because muscle StO(2) can be
      easily monitored in emergency situations, it may represent an improved method to
      gauge the severity of shock or the adequacy of fluid resuscitation after trauma.

PMID- 15179375
TI  - Management of complicated umbilical hernias in patients with end-stage liver
      disease and refractory ascites.

PMID- 15179374
TI  - Short-term enteral glutamine does not enhance protein accretion in burned
      children: a stable isotope study.
AB  - OBJECTIVE: Glutamine is a nonessential amino acid that, in recent years, has been
      found to play important roles in several metabolic and immunologic processes. It
      has been theorized that, in a stressed state, it may become "conditionally
      essential" because the patient's ability to manufacture glutamine may not be
      adequate to meet their needs under this condition. We chose to evaluate the
      ability of 48 hours of enteral glutamine to enhance immediate nitrogen accretion
      in stressed pediatric burn patients. METHODS: Nine children with serious burns
      who were tolerating tube feedings were enrolled in a human studies committee
      approved protocol in which they received 48 hours of enteral feedings with
      glutamine replacing 20% of essential and nonessential amino acids and 48 hours of
      isonitrogenous, isocaloric standard enteral feedings. This interval was chosen to
      help ensure that the study periods were comparable from a metabolic perspective.
      At the end of each period, protein kinetics were determined by a primed constant
      infusion of L-[1-(13)C] leucine tracer. The order of the studies was randomized.
      Seven children completed both phases of the study. Results were compared by
      paired t test and are presented as mean +/- standard error of the mean. RESULTS:
      During the glutamine feeding period, the leucine flux and leucine oxidation rate
      were significantly lower than those in the conventional feeding period. This
      reflects a reduction in total leucine intake from 80 +/- 11 to 62 +/- 10
      micromol/kg per hour. However, there was no significant difference in the net
      balance of leucine accretion into proteins between these 2 dietary periods, which
      indicated that enriched glutamine feeding for 48 hours did not result in an
      immediate whole body protein gain in this group of pediatric patients. In
      addition, plasma glutamine concentration showed a moderate increase after 48
      hours of supplementation but did not reach significance. CONCLUSION: Rapid
      protein accretion does not occur with short-term enteral glutamine
      supplementation. Several days of glutamine supplementation may be required to
      restore plasma glutamine levels and stimulate protein synthesis.

PMID- 15179376
TI  - Comprehensive genetic and endoscopic evaluation may be necessary to distinguish
      sporadic versus familial adenomatous polyposis-associated abdominal desmoid
      tumors.
AB  - BACKGROUND: There are limited data regarding how many patients with desmoid
      tumors actually represent cases with underlying familial adenomatous polyposis.
      METHODS: A proband presenting with desmoid tumors and several of the family
      members underwent a detailed family history, genetic (adenomatous polyposis coli
      [APC] gene sequencing), and upper and lower endoscopic evaluation. RESULTS: The
      proband's initial diagnosis was of a sporadic desmoid tumor. Colonoscopy was
      entirely normal. However, on subsequent esophagogastroduodenoscopy, several
      gastric polyps were found. The proband's mother subsequently underwent
      colonoscopy and was found to have multiple colon adenomas. On genetic analysis, a
      deletion of "T" was identified at codon 2645 of the APC gene in the proband. The
      proband's mother had a normal APC protein truncation test result. However, on
      full gene sequencing, the mother was found to harbor the same APC gene mutation.
      CONCLUSION: A detailed family history and endoscopic and genetic evaluations for
      patients with desmoid tumors are vital because they may be the sentinel
      presentation of familial adenomatous polyposis. If confirmed in larger studies,
      APC full gene sequencing and upper and lower gastrointestinal tract evaluation
      may need to be part of standard evaluation of patients with abdominal desmoid
      tumors.

PMID- 15179377
TI  - Management of a pancreatic duct injury with an endoscopically placed stent.

PMID- 15179379
TI  - Fournier's gangrene complicating blunt thoracic trauma.

PMID- 15179380
TI  - The Ginzburg you never heard of.

PMID- 15179381
TI  - Re: Cancer cells in mesenteric vein and peripheral vessels by measuring
      telomerase activity in patients with colorectal cancer.

PMID- 15179389
TI  - Concerted effort needed to clarify complex issues for general public.

PMID- 15179390
TI  - Outcomes in a 2-phase randomized clinical trial of early Class II treatment.
AB  - In a 2-phased, parallel, randomized trial of early (preadolescent) versus later
      (adolescent) treatment for children with severe (>7 mm overjet) Class II
      malocclusions who initially were developmentally at least a year before their
      peak pubertal growth, favorable growth changes were observed in about 75% of
      those receiving early treatment with either a headgear or a functional appliance.
      After a second phase of fixed appliance treatment for both the previously treated
      children and the untreated controls, however, early treatment had little effect
      on the subsequent treatment outcomes measured as skeletal change, alignment, and
      occlusion of the teeth, or length and complexity of treatment. The differences
      created between the treated children and untreated control group by phase 1
      treatment before adolescence disappeared when both groups received comprehensive
      fixed appliance treatment during adolescence. This suggests that 2-phase
      treatment started before adolescence in the mixed dentition might be no more
      clinically effective than 1-phase treatment started during adolescence in the
      early permanent dentition. Early treatment also appears to be less efficient, in
      that it produced no reduction in the average time a child is in fixed appliances
      during a second stage of treatment, and it did not decrease the proportion of
      complex treatments involving extractions or orthognathic surgery.

PMID- 15179391
TI  - Autotransplantation of premolars to premolar sites. A long-term follow-up study
      of 40 consecutive patients.
AB  - This article describes the long-term outcome of 40 consecutive patients having
      transplanted premolars. The objective of this ongoing study is to investigate
      survival rate, pulp survival rate, periodontal condition, and root development of
      autotransplanted premolars in orthodontic patients. This report covers 17 years;
      32 orthodontic patients had 40 premolars transplanted into contralateral or
      opposing jaw quadrants where a premolar was missing. The teeth were examined
      systematically with clinical and radiographic measures at 1, 2, 6, 12, and 60
      months or more after autotransplantation. The observation time varied from 2
      years 5 months to 22 years 3 months, with a mean of 10 years 4 months. Bonded.018
      in edgewise appliances were used, subjecting 87.5% of the transplanted teeth to
      normal orthodontic forces. One tooth was removed because of root fracture during
      the observation period, and 2 more had complications possibly related to the
      transplantation. The remaining 37 teeth and their supporting structures were all
      healthy at the last examination--a 92.5% success rate. Transplants with closed
      apices received endodontic therapy, but, in those with open or half-open apices,
      a 66% pulp survival rate was observed. No teeth in the sample had signs of
      replacement resorption or developed periodontal attachment loss. Inflammatory
      resorption in 2 teeth was arrested after endodontic treatment. Root formation,
      when not complete, continued on transplanted teeth, giving normal root form and
      adequate root length for normal function. It is concluded that
      autotransplantation of premolars combined with orthodontic treatment should be
      the first treatment alternative in cases of missing premolars, when a suitable
      donor tooth is available.

PMID- 15179392
TI  - Growth and development: hereditary and mechanical modulations.
AB  - Growth and development is the net result of environmental modulation of genetic
      inheritance. Mesenchymal cells differentiate into chondrogenic, osteogenic, and
      fibrogenic cells: the first 2 are chiefly responsible for endochondral
      ossification, and the last 2 for sutural growth. Cells are influenced by genes
      and environmental cues to migrate, proliferate, differentiate, and synthesize
      extracellular matrix in specific directions and magnitudes, ultimately resulting
      in macroscopic shapes such as the nose and the chin. Mechanical forces, the most
      studied environmental cues, readily modulate bone and cartilage growth. Recent
      experimental evidence demonstrates that cyclic forces evoke greater anabolic
      responses of not only craniofacial sutures, but also cranial base cartilage.
      Mechanical forces are transmitted as tissue-borne and cell-borne mechanical
      strain that in turn regulates gene expression, cell proliferation,
      differentiation, maturation, and matrix synthesis, the totality of which is
      growth and development. Thus, hereditary and mechanical modulations of growth and
      development share a common pathway via genes. Combined approaches using genetics,
      bioengineering, and quantitative biology are expected to bring new insight into
      growth and development, and might lead to innovative therapies for craniofacial
      skeletal dysplasia including malocclusion, dentofacial deformities, and
      craniofacial anomalies such as cleft palate and craniosynostosis, as well as
      disorders associated with the temporomandibular joint.

PMID- 15179393
TI  - Patients' perceptions of recovery after exposure of impacted teeth with a closed
      eruption technique.
AB  - This prospective study evaluated patients' perceptions of recovery after surgical
      exposure of impacted teeth treated with a closed-eruption surgical-orthodontic
      technique. Twenty-nine patients (16 female, 13 male; mean age, 16 +/- 2.8 years)
      were given a health-related quality of life questionnaire to be completed each
      postoperative day (POD) for 7 days. The questionnaire was designed to assess the
      patient's perception of recovery: pain, oral function, general activity, and
      other parameters. The impact of possible predictor variables, such as age, sex,
      length of surgical procedure, tooth location, height of impaction, and need for
      bone removal were assessed. Severe pain (27.6%, 13.8%, 3.4%) and consumption of
      analgesics (76%, 41%, 17%) declined gradually over the first 3 PODs. Improvement
      in oral function and other symptoms was evident by PODs 3 and 4. Absence from
      school outweighed interference in daily activity by 3 days (POD 6 vs POD 3).
      Buccolingual tooth location was the most significant predictor variable, with
      results showing a delayed recovery for patients with buccally impacted teeth. The
      most striking difference was reported with regard to swelling (P <.0001),
      followed by mouth opening (P =.008) and speech (P =.05). When the surgical
      procedure lasted 30 minutes or longer, there was prolonged recovery from pain (P
      =.01). This study provides information to patients and clinicians on
      postoperative recovery after surgical exposure of impacted teeth by the closed
      eruption surgical-orthodontic technique.

PMID- 15179394
TI  - Dentoskeletal effects induced by rapid molar distalization with the first class
      appliance.
AB  - The purpose of this study was to evaluate the treatment effects of the first
      class appliance (FCA; Leone, Firenze, Italy), a new intraoral device for
      unilateral or bilateral rapid molar distalizaton. A retrospective study was
      conducted to compare the predistalization and postdistalization cephalograms of
      17 patients (10 male, 7 female) with Class II malocclusions treated with the FCA.
      Mean age at the start of treatment was 13 years 4 months. The FCA produced rapid
      molar distalization, and the bilateral Class II molar relationship was corrected
      in 2.4 months, on average. Maxillary molar distalization contributed to 70% of
      the space created anterior to the first molars; 30% of the space was due to
      reciprocal anchorage loss of the maxillary second premolars. The maxillary first
      molars showed a significant distalization of 4.0 mm, associated with a
      significant distal axial incline of 4.6 degrees and a significant extrusion of
      1.2 mm. As for anchorage loss, the second premolars exhibited a significant
      mesial movement of 1.7 mm, associated with a significant mesial axial incline of
      2.2 degrees and a nonsignificant extrusion of 1.0 mm. In the anterior region, a
      significant mesial movement of the maxillary incisor of 1.3 mm was associated
      with a significant incisor proclination (2.6 degrees ) and a significant increase
      in overjet (1.2 mm). No significant changes in either sagittal or vertical
      skeletal relationships were observed. The results suggest that the FCA is an
      efficient and reliable device for distalizing the maxillary permanent first
      molars.

PMID- 15179395
TI  - Biomechanical evaluation of mandibular midline distraction osteogenesis by using
      the finite element method.
AB  - The aim of this study was to evaluate the biomechanical effects of mandibular
      midline distraction osteogenesis on the mandibular complex by using a 3
      dimensional finite element model, whose construction was based on computer
      tomography scans of the mandible of a 22-year-old man. The computer tomography
      pictures were transferred and converted to the finite element model by means of a
      procedure developed for this study. The final mesh consisted of 1314 solid
      elements with 3076 nodes. The distraction was performed on the middle
      intersection point of the vertical and horizontal planes on the mandibular
      symphysis. The mechanical response in terms of displacement and von Mises
      stresses was determined by widening the mandible up to 5 mm on both sides. The
      results indicate that the mandible was separated almost in a parallel manner
      (4.45-5.0 mm separation from the mandibular incisors to the lower border of the
      mandibular symphysis and 4.09-4.92 mm from the mandibular canines to the
      symphyseal border at the canine region), superoanteriorly. Anteroposterior
      evaluation demonstrated that the greatest widening was achieved at the symphyseal
      region, and the widening effect gradually decreased from anterior to posterior.
      Viewed occlusally, the width of the mandibular bone at the symphyseal region
      increased remarkably, whereas the ramal and gonial regions of the mandible and
      the condyle had shown minimal displacement. Mandibular bone was displaced forward
      and slightly downward. The highest stress levels were observed bilaterally below
      the condylar areas. High stress levels were also observed in the ramal region of
      the mandible.

PMID- 15179396
TI  - A quantitative approach for measuring crowding in the dental arch: Fourier
      descriptors.
AB  - Dental crowding is defined as a discrepancy between tooth size and jaw size that
      results in a misalignment of the tooth row. Proposed reasons for crowding include
      excessively large teeth, small jaws, and a combination of both. Nevertheless, the
      parameters that would allow the prediction of crowding have not been identified.
      This study compared the shape of crowded and uncrowded dental arches, matched for
      size and sex. The application of elliptical Fourier functions (EFFs) provided an
      accurate numeric description of the dental arch form. Dental casts from the Nihon
      University School of Dentistry at Matsudo, Chiba, Japan, were studied. Group I,
      the control group, consisted of 118 dental cast pairs (49 female, 69 male, aged
      20.40 +/- 1.68 years [mean +/- SD]) with little or no crowding. Group II, which
      exhibited crowding, consisted of 78 dental cast pairs (64 female, 14 male, aged
      19.67 +/- 4.95 years). From photographs, a set of 24 homologous points describing
      the tooth row was identified. These points were then fitted with EFFs. Each
      maxillary and mandibular outline was subsequently standardized for size by
      scaling the bounded area to a constant 10,000 mm(2). These "shape only" data were
      used to assess differences between arches in the 2 groups. By multivariate
      analysis of variance, statistically significant shape differences between groups
      I and II were obtained for both arches. Patients with crowding exhibited more
      variability than did the controls. This variability was illustrated with
      canonical axes derived from discriminant function analysis.

PMID- 15179397
TI  - Influence on binding of third-order torque to second-order angulation.
AB  - Using an earlier model, which described the critical contact angle for binding
      from second-order angulation alone, a more generalized model is derived that
      combines the effects of angulation and torque. From this vantage point, the onset
      of binding is evaluated for 3 scenarios: second-order angulation alone, third
      order torque only, and a combination of second-order angulation and third-order
      torque. These scenarios are detailed by plotting the critical contact angle for
      binding against the torque angle as a function of 10 wire dimensions (16 x 16, 16
      x 22, 17 x 17, 17 x 22, 17 x 25, 18 x 18, 18 x 22, 18 x 25, 19 x 25, and 21 x 25
      mil), 4 bracket widths (70, 100, 130, and 160 mil), and 4 bracket slots (18,
      20.5, 22, and 24.5 mil). From these plots, we learn that each wire base dimension
      (eg, an 18-mil base as found in 18 x 18-mil, 18 x 22-mil and 18 x 25-mil
      archwires) has a common maximum critical contact angle for binding. Moreover,
      each wire-slot combination has a common maximum torque angle, which is
      independent of bracket width. Finally, we learn that archwire-bracket
      combinations that use a metric 0.5-mm slot might have some advantages with regard
      to torquing--given the current philosophy that light, continuous forces are more
      favorable.

PMID- 15179398
TI  - Enamel loss associated with orthodontic adhesive removal on teeth with white spot
      lesions: an in vitro study.
AB  - Teeth with white spot lesions (WSL) might be more prone to enamel loss during
      bracket debonding. This in vitro study compared enamel loss from teeth with (n =
      14) and without (n = 14) WSL after polishing with low-speed finishing burs or
      disks (Sof-Lex, 3M ESPE, St Paul, Minn). Debonded surfaces were analyzed with a
      contact stylus profilometer, and digitized data were compared with baseline
      readings by using AnSur NT software (Regents, University of Minnesota,
      Minneapolis, Minn). Specimen surfaces were also examined with a scanning electron
      microscope. Two-way analysis of variance was performed to analyze the data. In
      teeth without WSL, the volume losses were 0.16 mm(3) for the bur group and 0.10
      mm(3) for the disk group; the mean maximum depths were 47.7 microm for the bur
      group and 54.3 microm for the disk group. In teeth with WSL, the volume losses
      were 0.06 and 0.17 mm(3), and the mean maximum depths were 35.1 and 48.7 microm
      for the bur and disk groups, respectively. There were no significant differences
      in enamel loss between the 2 groups of teeth without WSL (P =.12). However, in
      teeth with WSL, the burs removed less enamel than the disks (P = 0.006). Scanning
      electron microscope examination showed that any damage on the enamel surface was
      usually located in the cervical third of the teeth. On most specimens, even
      though tooth surfaces appeared resin-free to the naked eye, there were remnants
      of it. The differences between groups were so small that they might be clinically
      insignificant.

PMID- 15179400
TI  - Graduate orthodontic programs: who is admitted?

PMID- 15179399
TI  - Orthodontic care in an insured population in Washington: demographic factors.
AB  - Few studies have used insurance claims data to investigate demographic factors
      related to orthodontic care. This study sought to describe age and sex
      distributions in a large, insured population in Washington. Additionally, the
      demand for orthodontic care was evaluated with respect to county population, and
      the impact of the availability of orthodontists was investigated. All orthodontic
      claims in 2001 were retrieved from the Washington Dental Service database, along
      with associated provider and patient information. A total of 102,984 claims were
      included in this study. A large percentage of subjects (86%) were less than 20
      years old, with most patients in their early teens. Overall, about 64% of all
      orthodontic patients were female. The demand for orthodontic treatment was the
      highest in the counties with the largest populations. Although there was
      considerable variation in the data, the number of orthodontic claims submitted by
      general dentists tended to decline as the availability of orthodontists
      increased.

PMID- 15179401
TI  - Why does the file get too large when I paste a picture in PowerPoint?

PMID- 15179402
TI  - Litigation, legislation, and ethics. Record keeping to avoid or defend lawsuits:
      a defense attorney's perspective.

PMID- 15179403
TI  - Postmarketing surveillance for drug safety: surely we can do better.

PMID- 15179404
TI  - "Irinogenetics" and UGT1A: from genotypes to haplotypes.

PMID- 15179405
TI  - UGT1A1 haplotypes associated with reduced glucuronidation and increased serum
      bilirubin in irinotecan-administered Japanese patients with cancer.
AB  - PURPOSE: A comprehensive haplotype analysis of UGT1A1 in the Japanese population
      was conducted, and the effects of these haplotypes were investigated with respect
      to UGT1A1-related phenotypic parameters in patients with cancer who received
      irinotecan. METHODS: The UGT1A1 gene, including the enhancer, the promoter, and
      all 5 exons and their flanking regions, was sequenced from 195 Japanese subjects.
      The gene was divided into 2 blocks, and the haplotypes of each block were
      assigned. The association of these haplotypes with area under the concentration
      time curve (AUC) ratios (7-ethyl-10-hydroxycamptothecin glucuronide [SN-38G]/7
      ethyl-10-hydroxycamptothecin [SN-38]) and pretreatment levels of serum total
      bilirubin was investigated in 85 cancer patients who received irinotecan.
      RESULTS: Four haplotype groups (*1, *60, *28, and *6) were assigned in block 1,
      and 2 haplotype groups (*IA and *IB) were in block 2. The majority of the *IB
      haplotypes in block 2 were linked to either the *1 or the *60 haplotype but not
      to *28 in block 1. Highly significant associations were obtained between the *28
      haplotypes and both a reduced AUC ratio (P =.0014, Jonckheere-Terpstra [JT] test)
      and an increased total bilirubin level (P =.0007, JT test). Increased total
      bilirubin levels in the *60 (P =.0048, JT test) and *IB groups (P =.0224, JT
      test) were also observed. The reduction in the AUC ratio by the *6 group was
      moderate (P =.0372, JT test) but was remarkable in combination with *60 (*6/*60)
      or *28 (*6/*28) as compared with the *1 group (*1/*1) (P =.049 and P =.0071,
      respectively; nonparametric Dunnett test). CONCLUSION: This study identified
      several UGT1A1 haplotypes significantly associated with the reduced AUC ratio
      (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and
      suggested that the novel haplotype *IB might be functionally important. These
      findings will be useful for further pharmacogenetic studies on adverse reactions
      to irinotecan.

PMID- 15179406
TI  - CYP3A5 genotype has a dose-dependent effect on ABT-773 plasma levels.
AB  - BACKGROUND: The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically
      expressed as a result of genetic variants that do not encode functional protein.
      Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux
      pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for
      pharmacokinetics is controversial. OBJECTIVE: Our objective was to determine
      whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein)
      influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate
      for both CYP3A and P-glycoprotein. METHODS: Healthy volunteers given 3 different
      oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1
      polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at
      least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area
      under the plasma concentration-time curves (AUCs) from 0 to 6 hours (AUC(t)) and
      maximum postdose plasma concentration (C(max)) after a single dose and on day 5
      of a twice-daily regimen were calculated and correlated with genotypes. RESULTS:
      ABT-773 AUC(t) and C(max) were, on average, higher in CYP3A5-negative subjects
      given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical
      doses (n = 8). The relationship for AUC(t) was statistically significant both
      after a single dose (geometric mean and 95% confidence interval [CI], 5.0
      microg.h/mL [3.9-6.4 microg.h/mL] versus 2.8 microg.h/mL [1.8-4.3 microg.h/mL]; P
      =.03) and on the fifth day of twice-daily dosing (12.4 microg.h/mL [8.7-17.6
      microg.h/mL] versus 7.4 microg.h/mL [5.5-9.8 microg.h/mL], P =.04). The
      relationship for C(max) was statistically significant after a single dose (1220
      microg/mL [867-1167 microg/mL] versus 727 microg/mL [506-1044 microg/mL], P =.04)
      and showed a trend in the same direction on the fifth day of twice-daily dosing
      (2566 microg/mL [1813-3631 microg/mL] versus 1621 microg/mL [1122-2343
      microg/mL], P =.07). In contrast, AUC(t) and C(max) were not significantly
      different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or
      300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes.
      CONCLUSIONS: These results suggest that CYP3A5 genotype may be an important
      determinant of in vivo drug disposition and that this effect may be dose
      dependent.

PMID- 15179407
TI  - CYP3A5 genotype and midazolam clearance in Australian patients receiving
      chemotherapy.
AB  - OBJECTIVES: Cytochrome P450 (CYP) 3A enzymes are key metabolizing enzymes for
      many chemotherapeutic agents, and detection of functionally significant CYP3A
      genetic variants may be useful in predicting interpatient variation of drug
      clearance. We have examined the significance of CYP3A5*3 single-nucleotide
      polymorphism to overall CYP3A activity in vivo in a predominantly Caucasian
      Australian cancer population. METHODS: Screening for wild-type CYP3A5*1 and
      CYP3A5*3 single nucleotide polymorphism by use of Taqman MGB probe allelic
      discrimination was performed in 67 patients with cancer (58 Caucasian patients).
      CYP3A activity was documented via clearance of either oral or intravenous
      midazolam in 64 patients. RESULTS: All patients had at least 1 CYP3A5*3 allele,
      and 9 (13%) patients were heterozygous for CYP3A5*3 and CYP3A5*1. Within the
      subset of Caucasian patients, 6 of 58 (10%) were CYP3A5*1/*3 heterozygotes. Mean
      midazolam clearance was 1.7 times higher in CYP3A5*1/*3 subjects than in
      CYP3A5*3/*3 subjects (95% confidence interval, 1.15-2.51; P =.01, 2-way ANOVA).
      CONCLUSION: Overall CYP3A activity is related to CYP3A5 genotype. CYP3A5
      genotyping may be helpful in predicting the drug-metabolizing capability of
      individual cancer patients who are predominantly Caucasian in origin.

PMID- 15179408
TI  - Alpha 1A-adrenergic receptor polymorphism and vascular response.
AB  - OBJECTIVE: The alpha(1A)-adrenergic receptor is highly expressed in human
      vasculature including resistance arteries and veins, and its stimulation is
      primarily responsible for adrenergically mediated smooth muscle contraction.
      Variability in sensitivity to phenylephrine, an alpha(1A) adrenergic agonist, has
      a large genetic component. We examined the hypothesis that a common polymorphism
      of alpha(1A)-adrenergic receptor (Arg347Cys) affects in vivo response. METHODS:
      We measured vascular sensitivity to phenylephrine using the dorsal hand vein
      linear variable differential transformer technique and determined alpha(1A)
      adrenergic receptor genotype in 74 healthy, nonsmoking adults (28 Arg/Arg, 30
      Arg/Cys, and 16 Cys/Cys). RESULTS: Sensitivity to phenylephrine, expressed as the
      dose of phenylephrine resulting in 50% venoconstriction (Phe(50)), was not
      significantly different in subjects with the 3 alpha(1A) adrenergic receptor
      genotypes: Phe(50) geometric mean (95% confidence interval) was 513 ng/min (287
      918 ng/min) for Arg/Arg, 431 ng/min (274-680 ng/min) for Arg/Cys, and 471 ng/min
      (197-1124 ng/min) for Cys/Cys (P =.90). CONCLUSION: We conclude that the
      Arg347Cys receptor polymorphism does not alter agonist-mediated venoconstriction
      in vivo.

PMID- 15179409
TI  - Effect of St John's wort dose and preparations on the pharmacokinetics of
      digoxin.
AB  - BACKGROUND AND OBJECTIVE: St John's wort preparations vary in composition, main
      constituents, formulation, and daily dose administered. The aim of the study was
      to evaluate the possible pharmacokinetic interaction of marketed St John's wort
      formulations and doses with digoxin. METHODS: A randomized, placebo-controlled,
      parallel-group study was performed in 96 healthy volunteers in 3 study parts. A 7
      day loading phase with digoxin was followed by 14 days of comedication with
      placebo or one of 10 St John's wort products varying in dose and formulation. The
      pharmacokinetics of digoxin was determined before comedication and on day 14 of
      comedication. RESULTS: Comedication comprised traditionally used Hypericum
      products; 2 g powder without hyperforin, tea, juice, oil extract, and placebo had
      no significant interaction with digoxin nor did hyperforin-free extract (Ze 117)
      or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g).
      However, comedication with the high-dose hyperforin-rich extract LI 160 resulted
      in a reduction of digoxin area under the curve from time 0 to 24 hours (AUC(0
      24)) of -24.8% (95% confidence interval [CI], -28.3 to -21.3), a reduction in
      digoxin maximal plasma concentration (C(max)) of -37% (95% CI, -42 to -32), and a
      reduction in digoxin plasma concentration at 24 hours after previous dosing
      (C(trough)) of -19% (95% CI, -27 to -11). Comedication with 4 g Hypericum powder
      with comparable hyperforin content resulted in a reduction in digoxin AUC(0-24)
      of -26.6% (95% CI, -37.3 to -15.9), a reduction in digoxin C(max) of -38% (95%
      CI, -48 to -18), and a reduction in digoxin C(trough) of -19% (95% CI, -27 to 
      10). Two grams of Hypericum powder with half the hyperforin content resulted in a
      less prominent reduction in AUC(0-24) of -17.7% (95% CI, -21.6 to -13.7), C(max)
      (-21%; 95% CI, -40 to -2), and C(trough) (-13%; 95% CI, -21 to -5). CONCLUSIONS:
      The interaction of St John's wort and digoxin varies within St John's wort
      preparations and doses and seems to be correlated with the dose, particularly of
      hyperforin.

PMID- 15179410
TI  - Assessment of drug-drug interaction potential of enfuvirtide in human
      immunodeficiency virus type 1-infected patients.
AB  - INTRODUCTION: Enfuvirtide is the first drug to block human immunodeficiency virus
      type 1 (HIV-1) glycoprotein 41-mediated viral fusion to host cells. This study
      investigated whether enfuvirtide can influence the activities of cytochrome P450
      (CYP) enzymes in HIV-1-infected patients. METHODS: An open-label, 1-sequence
      crossover study was conducted in 12 HIV-1-infected adults, by use of a 5-drug
      cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN,
      debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1,
      CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N
      acetyltransferase activity. Patients received a single dose of the cocktail alone
      on day -15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg
      subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index
      parameters were estimated and analyzed by ANOVA with factors subject and day (-15
      and 6). RESULTS: The phenotypic index parameters, with and without enfuvirtide,
      for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least
      squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N
      acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The
      phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76
      versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and
      CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not
      substantially different. CONCLUSIONS: Enfuvirtide had no clinically important
      effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N
      acetyltransferase and had little effect on the metabolism of drugs mediated by
      CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide
      and concomitantly administered drugs metabolized by the CYP enzymes tested in
      this study is low.

PMID- 15179411
TI  - 6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect.
AB  - OBJECTIVE: Our objective was to assess the contribution of 6',7'
      dihydroxybergamottin (DHB) to the inhibitory effect of grapefruit juice toward
      intestinal cytochrome P450 (CYP) 3A4. METHODS: An aqueous extract was prepared
      from grapefruit juice by centrifugation, filtration, and repeated washing of the
      particulate with water. The concentrations of various furanocoumarins in this
      grapefruit juice "serum" and in whole grapefruit juice were measured by HPLC and
      their identities confirmed by liquid chromatography-tandem mass spectrometry.
      Five healthy volunteers were given a single tablet of felodipine (10 mg) with
      whole grapefruit juice, orange juice-containing serum, or plain orange juice
      (control). The pharmacokinetic outcomes of felodipine were evaluated by
      noncompartmental methods. The effects of serum and purified DHB (at the same
      concentrations as those measured in the orange juice-containing serum used in the
      clinical study) were compared, in vitro, with regard to (1) the reversible and
      mechanism-based inhibition of the catalytic activity of complementary
      deoxyribonucleic acid-expressed CYP3A4 and (2) the time-dependent loss of
      immunoreactive CYP3A4 protein in modified Caco-2 cells. RESULTS: The
      concentration of DHB in serum was comparable to that measured in whole grapefruit
      juice (38 micromol/L versus 43 micromol/L), and the concentrations of other known
      furanocoumarins were well below the lowest published concentration required to
      inhibit catalytic activity by 50%. Relative to plain orange juice, orange juice
      containing serum significantly increased the median felodipine area under the
      plasma concentration-time curve by 1.9-fold (P =.04) and increased the maximum
      concentration by 1.7-fold (P =.01). In vitro, serum and purified DHB had similar
      inhibitory effects toward CYP3A4 activity with respect to both reversible
      inhibition (95% confidence interval, 85% +/- 5.7% and 75% +/- 4.5%, respectively)
      and mechanism-based inhibition after a 15-minute preincubation (95% confidence
      interval, 79% +/- 6.8% and 78% +/- 5.7%, respectively). In Caco-2 cells the time
      averaged extents of CYP3A4 protein loss caused by serum and purified DHB were
      identical (43%). CONCLUSION: The interaction between grapefruit juice serum and
      felodipine can be attributed largely to DHB. This establishes DHB as an important
      contributor to the grapefruit juice effect.

PMID- 15179412
TI  - Peripheral neuropathy in patients treated with leflunomide.
AB  - OBJECTIVE: Our objective was to describe the clinical features, time course, and
      outcome of new-onset peripheral neuropathy occurring in patients treated with
      leflunomide. METHODS: Case reports of peripheral neuropathy submitted to the US
      Food and Drug Administration in association with leflunomide use were reviewed.
      Data on patient demographics, underlying medical conditions and medications,
      details of leflunomide therapy, and treatment and outcome of the neuropathy event
      were abstracted. Time to neuropathy onset and time to improvement or recovery
      were analyzed by survival analysis. RESULTS: Of 80 reported patients, 61% were
      women. The patients' mean age was 62 years. Symptoms of peripheral neuropathy
      began after a mean of 6 months of leflunomide use (range, 3 days to 3 years).
      Electrodiagnostic testing in 37 patients was consistent with a distal axonal,
      sensory, or sensorimotor polyneuropathy in most patients. Patients who stopped
      leflunomide use within 30 days of neuropathy symptom onset were more likely to
      have improvement or recovery than those who continued taking leflunomide for a
      longer period (P <.001). CONCLUSION: Leflunomide use is associated with
      peripheral neuropathy in some patients. This neuropathy is usually axonal in
      nature, affecting multiple sensory or motor nerves of distal extremities.
      Patients who stopped leflunomide use within 30 days of symptom onset were more
      likely to have improvement of symptoms or complete recovery than were patients
      who continued to use the drug for longer periods of time.

PMID- 15179413
TI  - Pharmacokinetic studies in hepatic impairment: is the Maddrey function a relevant
      marker?

PMID- 15179414
TI  - Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status.

PMID- 15179415
TI  - From the editor.

PMID- 15179416
TI  - Hyperbaric oxygenation and wound healing.
AB  - The purpose of this article is to review literature related to hyperbaric
      oxygenation and wound healing. The article discusses the role of oxygen in wound
      healing, as well as the effects of hyperbaric oxygenation to promote wound
      healing, and focuses on the use of hyperbaric oxygenation to treat foot wounds in
      patients with diabetes. A review of salient literature to support the use of
      hyperbaric oxygenation as a viable adjunct to healing foot wounds in patients
      with diabetes is provided. In addition, this article discusses appropriate
      patient selection for treatment with hyperbaric oxygenation. A discussion of the
      hyperbaric treatment, including preparation of the patient, contraindications,
      adverse effects, and treatment protocols, is provided. This article was designed
      to provide WOC nurses with information to provide appropriate referrals to
      technology that promises to increase the healing potential of foot wounds in
      patients with diabetes and subsequently reduce amputations in this population.

PMID- 15179417
TI  - Update on statins.

PMID- 15179418
TI  - Meta-analysis research.
AB  - Beginning with Florence Nightingale, nurses have attempted to base their practice
      on the best evidence. Research findings often form part of the evidence for
      practice. The proliferation of studies and the frequent contradictory findings
      between studies make it difficult to determine the scientific basis for practice.
      Increasingly, nurses are finding meta-analysis research reports on important
      practice topics. This article provides an overview of key features of meta
      analyses to enable nurses to determine whether meta-analyses findings are valid
      and useful for their practice.

PMID- 15179419
TI  - Hypertension management in patients with vascular disease.
AB  - Hypertension (HTN), the leading cause of morbidity and mortality worldwide, is a
      modifiable risk factor for atherosclerosis. However, all too often, HTN is not
      well controlled in patients with vascular disease. Studies have demonstrated that
      patients whose blood pressure is controlled achieve at least a 50% reduction in
      cardiovascular events compared with similar patients whose blood pressure is not
      controlled. The Seventh Report of the Joint National Committee on Prevention,
      Detection, Evaluation, and Treatment of High Blood Pressure recently prepared and
      distributed new guidelines for the management of HTN. This article will highlight
      the new recommendations for HTN management and how they can be applied to the
      patient with vascular disease.

PMID- 15179420
TI  - Chemoembolization of hepatoma.

PMID- 15179422
TI  - Old before their time.

PMID- 15179423
TI  - Spicy treatment for cystic fibrosis.

PMID- 15179424
TI  - Helping rats kick coke.

PMID- 15179425
TI  - Victims of animal rights movement unite.

PMID- 15179427
TI  - HHS proposes revised regulations on misconduct in research.

PMID- 15179429
TI  - Pig surgery: can reduction be a protocol violation?

PMID- 15179433
TI  - A word from USDA.

PMID- 15179434
TI  - Intraoperative deaths in rats undergoing experimental ocular surgery.

PMID- 15179436
TI  - Developing and maintaining a surgical research program: surgical suite design.
AB  - When building or renovating a laboratory animal facility, one must consider the
      requirements of the surgery program. The authors outline the critical
      considerations for designing a large-animal surgical suite.

PMID- 15179437
TI  - Equipping the operating room for USDA-covered species.

PMID- 15179438
TI  - Maintaining the surgical research facility: the role of the surgical technician.
AB  - Building a well-equipped surgical facility is only half the battle. By ensuring
      that these facilities and their equipment are kept clean and well maintained, and
      that clear and thorough documentation is kept, research staff can protect both
      the quality of their work and the well-being of their animal patients.

PMID- 15179439
TI  - Ventral approach to the lumbar spine of the Sprague-Dawley rat.
AB  - Lumbar intervertebral disc repair is an important tissue-engineering research
      area. In creating an in vivo rat model to evaluate repair techniques, the authors
      developed a surgical transperitoneal approach that permits the easy exposure of
      four lumbar vertebral bodies with no surgery-related peri- or postoperative
      complications.

PMID- 15179440
TI  - Prevention of heterotopic ossification after spinal cord injury with COX-2
      selective inhibitor (rofecoxib).
AB  - STUDY DESIGN: A randomized, prospective, double-blind, placebo-controlled
      clinical trial. OBJECTIVES: To determine the effect of COX-2-selective inhibitor
      on the prevention of heterotopic ossification (HO) after spinal cord injury
      (SCI). SETTING: County and University Teaching Hospital, Miami, FL, USA. METHODS:
      A total of 76 patients were enrolled in the study. Among them, 39 patients
      received placebo, and 37 received COX-2-selective inhibitor rofecoxib 25 mg daily
      for a period of 4 weeks. Prevention was started 3 weeks after spinal cord injury
      (SCI). In both groups of patients there was similar age as well as the level of
      SCI and ASIA impairment scale. Two methods were used to diagnose early HO,
      clinical symptoms and bone scintigraphy. Radiography was used for diagnosis of
      late stages of HO development. RESULTS: A significantly lower incidence of HO was
      found in the rofecoxib group (13.4%) than in the placebo group (33.3%: P<0.05).
      In patients receiving rofecoxib, there was a 2.5 times lower relative risk of
      developing HO than in the placebo group (95% CI, 2.3-6). There were no patients
      who discontinued the study due to adverse effects of medication. CONCLUSION: Our
      data suggest that COX-2-selective inhibitor rofecoxib is an effective medication
      in prevention of HO after SCI.

PMID- 15179441
TI  - The Neuropsychopharmacology and Toxicology of 3,4-methylenedioxy-N-ethyl
      amphetamine (MDEA).
AB  - This paper reviews the pharmacology and toxicology of 3,4-methylenedioxy-N
      ethylamphetamine (MDEA, "eve"). MDEA is a ring-substituted amphetamine (RSA) like
      MDMA, its well known N-methyl analog. Both have become very popular substances of
      abuse in the techno- and house-music scene. They can evoke psychomotor
      stimulation, mild alterations of perception, sensations of closeness and a
      positive emotional state as well as sympathomimetic physical effects. At present,
      the name "ecstasy" is no longer used only for MDMA, but for the whole group of
      RSAs (MDA, MDMA, MDEA and MBDB) as they are chemically and pharmacologically
      nearly identical; moreover, many ecstasy pills contain mixtures of the RSAs.
      Hence, for a selective review on MDEA, it is crucial to strictly differentiate
      between: 1) street and chemical names, and 2) studies with or without chemically
      defined substances. In order to present MDEA-specific information, the
      pharmacodynamics and kinetics are described on the basis of MDEA challenge
      studies in animals and humans. In the toxicology section, we present a collection
      of case reports on fatalities where MDEA was toxicologically confirmed. On the
      question of serotonergic neurotoxicity and possible long-term consequences,
      however, MDEA-specific information is available from animal studies only. The
      neurotoxic potential of MDEA in humans is difficult to estimate, as ecstasy users
      do not consume pure substances. For future research, challenge studies in animals
      using dosing regimens adapted to human consumption patterns are needed. Such
      challenge studies should directly compare individual RSAs. They will represent
      the most viable and fruitful approach to the resolution of the highly
      controversial issues of serotonergic neurotoxicity and its functional
      consequences.

PMID- 15179442
TI  - Antinociceptive properties of fadolmidine (MPV-2426), a novel alpha2-adrenoceptor
      agonist.
AB  - Fadolmidine (MPV-2426) is a novel alpha2 -adrenoceptor (alpha2) -AR) agonist
      developed for spinal analgesia. It is highly selective for alpha2 -ARs, but it
      lacks subtype selectivity. Due to its pharmacokinetic properties, it only poorly
      penetrates blood-brain barrier or spreads from the site of injection within the
      central nervous system. By intrathecal (i.t.) administration to laboratory
      animals, fadolmidine produces dose-dependent antinociception in healthy controls
      and in models of inflammatory, postoperative and neuropathic pain. Fadolmidine
      has been effective against various submodalities of pain such as heat pain,
      mechanical pain, and visceral pain. In general, the antinociceptive potency of
      fadolmidine, i.t., was equal to that of dexmedetomidine. At antinociceptive i.t.
      doses fadolmidine did not suppress motoneurons or responses to innocuous
      stimulation. It produced no hemodynamic depression and considerably less sedation
      than dexmedetomidine. By peripheral administration fadolmidine had no or only a
      weak antinociceptive action, except following nerve injury, particularly that of
      the postganglionic sympathetic nerve fibers. Together these experimental animal
      studies indicate that i.t. administration of fadolmidine provides a segmentally
      restricted treatment of somatic and visceral pain, with only minor cardiovascular
      and sedative side effects. Additionally, peripheral administration of fadolmidine
      might provide a selective treatment for some hypersensitivity states that involve
      dysfunction of the sympathetic nervous system.

PMID- 15179443
TI  - The cellular biochemistry of cholesterol and statins: insights into the
      pathophysiology and therapy of Alzheimer's disease.
AB  - The causes of late onset Alzheimer disease (AD) are poorly understood. Although
      beta-amyloid (Abeta) is thought to play a critical role in the pathophysiology of
      AD, no genetic evidence directly ties Abeta to late onset AD. This suggests that
      the accumulation of Abeta and neurodegeneration associated with AD might result
      from an abnormality that indirectly affects Abeta production or accumulation.
      Increasing evidence suggests that abnormalities in the metabolism of cholesterol
      and related molecules, such as cholseterol esters and 24(S) hydroxycholesterol
      might contribute to the pathophysiology of late onset AD by increasing production
      of Abeta. 24(S) Hydroxycholesterol is a member of a family of oxidized
      cholesterol catabolites, termed oxysterols, which function to regulate export of
      cholesterol from the cell and transcription of genes related to cholesterol
      metabolism. Cholesterol esters are cholesterol derivatives used for cholesterol
      storage. Levels of 24(S) hydroxycholesterol increase with AD. Polymorphisms in
      several different genes important for cholesterol physiology are associated with
      an increased load or level of Abeta in AD. These genes include apolipoprotein E,
      cholesterol 24 hydroxylase (Cyp46), acyl-CoA:cholesterol acetyltransferase
      (ACAT), and the cholesterol transporter ABCA1. Other studies show that levels of
      cholesterol, or its precursors, are elevated in subjects early in the course of
      AD. Finally, studies of the processing of amyloid precursor protein show that
      cholesterol and its catabolites modulate amyloid precursor protein processing and
      Abeta production. These lines of evidence raise the possibility that genetic
      abnormalities in cholesterol metabolism might contribute to the pathophysiology
      of AD.

PMID- 15179444
TI  - TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator
      with antidepressant, neuroprotective and long-lasting cognitive effects.
AB  - The development of selective ligands targeting neuronal nicotinic acetylcholine
      receptors to alleviate symptoms associated with neurodegenerative diseases
      presents the advantage of affecting multiple deficits that are the hallmarks of
      these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist
      with high selectivity for neuronal nicotinic receptors. Microdialysis studies
      indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC
      1734, by either acute or repeated administration, exhibits memory enhancing
      properties in rats and mice and is neuroprotective following excitotoxic insult
      in fetal rat brain in cultures and against alterations of synaptic transmission
      induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal
      doses, TC-1734 produced additive cognitive effects when used in combination with
      tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not
      develop following repeated administration of TC-1734. Its pharmacokinetic (PK)
      profile (half-life of 2 h) contrasts with the long lasting improvement in working
      memory (18 h) demonstrating that cognitive improvement extends beyond the
      lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor
      activity profile provides additional mechanistic basis for its suggested
      potential as a clinical candidate. TC-1734 was very well tolerated in acute and
      chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials
      demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral
      administration at doses ranging from 2 to 320 mg. The bioavailability,
      pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an
      example of a safe, potent and efficacious neuronal nicotinic modulator that holds
      promise for the management of the hallmark symptomatologies observed in dementia.

PMID- 15179446
TI  - Ramatroban (BAY u 3405): a novel dual antagonist of TXA2 receptor and CRTh2, a
      newly identified prostaglandin D2 receptor.
AB  - It is known that thromboxane A2 (TXA2) contributes to various diseases such as
      bronchial asthma, ischemic heart disease, cerebrovascular disorders and allergic
      rhinitis. A number of TXA2 synthase inhibitors and TXA2 receptor (TP receptor)
      antagonists have been developed to treat these diseases. Ramatroban (BAY u 3405)
      was developed as a potent TP receptor antagonist with excellent efficacy against
      allergic rhinitis in many animal models and patients. Recent studies also
      revealed that ramatroban can block the newly identified PGD2 receptor,
      chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2). PGD2
      induces migration and degranulation of eosinophils through CRTh2 and contributes
      to late-phase inflammation and cell damage. Accordingly, it was considered that
      ramatroban suppresses the late-phase inflammation via TP receptor and CRTh2
      blockade. In terms of the efficacy on vascular systems, it was revealed that
      ramatroban can suppress the expression of monocyte chemoattractant protein-1 (MCP
      1) and adhesion molecules in endothelial cells and prevent exacerbation of
      inflammation by blocking these responses. According to our recent studies in
      hypercholesterolemic rabbits ramatroban prevents macrophage infiltration through
      MCP-1 downregulation and neointimal formation after balloon injury and attenuates
      vascular response to acetylcholine. Therefore, ramatroban may be beneficial in
      the treatment of atherosclerosis.

PMID- 15179445
TI  - ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine
      receptor agonist for the potential treatment of cognitive disorders.
AB  - ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is
      a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing
      properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT
      089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor
      subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the
      alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro
      electrophysiological and cation flux assays, ABT-089 displays differential
      activity including agonism, partial agonism and antagonism depending upon the NNR
      subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at
      evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore,
      ABT-089 is neuroprotective against excitotoxic glutamate insults, with even
      greater potency seen after chronic treatment. Similarly, ABT-089 is effective in
      models of cognitive functioning, including enhancement of baseline functioning as
      well as improvement of impaired cognitive functioning seen following septal
      lesioning and natural aging. In neuroprotective assays the compound is most
      potent by chronic administration. In stark contrast to the positive effects in
      the cognitive models, ABT-089 shows little propensity to induce adverse effects
      such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side
      effects. Together these data suggest that ABT-089 is a NNR modulator with the
      potential for treating cognitive disorders with markedly limited adverse
      cardiovascular and gastrointestinal side effects.

PMID- 15179447
TI  - Pharmacological effects of xanthones as cardiovascular protective agents.
AB  - Many epidemiological studies indicate that consumption of dietary polyphenolic
      compounds is beneficial in the prevention of cardiovascular diseases. Xanthones
      are a class of polyphenolic compounds that commonly occur in plants and have been
      shown to have extensive biological and pharmacological activities. Recently, the
      pharmacological properties of xanthones in the cardiovascular system have
      attracted great interest. Xanthones and xanthone derivatives have been shown to
      have beneficial effects on some cardiovascular diseases, including ischemic heart
      disease, atherosclerosis, hypertension and thrombosis. The protective effects of
      xanthones in the cardiovascular system may be due to their antioxidant,
      antiinflammatory, platelet aggregation inhibitory, antithrombotic and/or
      vasorelaxant activities. In particular, the antagonism of endogenous nitric oxide
      synthase inhibitors by xanthones may represent the basis for improved endothelial
      function and for reduction of events associated with atherosclerosis.

PMID- 15179448
TI  - Bimatoprost: a novel antiglaucoma agent.
AB  - The aim of glaucoma therapy is to preserve vision by reducing intraocular
      pressure (IOP). Following recent National Eye Institute sponsored studies, it is
      becoming increasingly apparent that every mmHg of extra IOP lowering counts.
      Bimatoprost is the newest and most effective addition to the physician's
      armamentarium of ocular hypotensive drugs. Direct clinical comparisons have
      demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor
      agonist prodrugs, latanoprost and travoprost, as well as a beta-adrenoceptor
      antagonist, timolol, alone or in fixed combination with the carbonic anhydrase
      inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost
      therapy may be successfully treated with bimatoprost. Such evidence provides
      support, at the clinical level, for the contention that bimatoprost is
      pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a
      structural analog of PGF2alpha-ethanolamide (prostamide F2alpha), which is formed
      from the endocannabinoid anandamide by a biosynthetic pathway involving
      cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that
      bimatoprost may be regarded as a prostamide mimetic. The target receptor for
      bimatoprost and the prostamides appears unique and unrelated to PG- and
      endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism
      studies in non-human primates demonstrate that bimatoprost is not a prodrug, it
      remains essentially intact. Its profound ocular hypotensive effects may,
      therefore, be attributed to its prostamide-mimetic properties.

PMID- 15179449
TI  - Low-molecular-weight heparins in thrombosis and cancer: emerging links.
AB  - Heparin as well as low-molecular-weight heparins (LMWHs) have polypharmacological
      actions at various levels. Earlier studies focused on the plasma anti-Xa and anti
      IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters
      for heparin and LMWHs might explain the diverse clinical impacts of this class of
      agents in thrombosis and beyond: the release of the vascular tissue factor
      pathway inhibitor (TFPI), inhibition of key matrix-degrading enzymes, and other
      mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation
      in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer
      patients reportedly have 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 its low
      molecular weight fractions interfere with various processes involved in tumor
      growth and metastasis. Clinical trials have suggested a clinically relevant and
      improved efficacy of LMWHs, as compared to UFH, on the survival of cancer
      patients with deep vein thrombosis. Our laboratory has demonstrated a significant
      role for LMWHs and for LMWH-releasable TFPI on the regulation of angiogenesis,
      tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix
      degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs
      or non-anticoagulant LMWH derivatives was shown to be reversed by anti-TFPI.
      Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH-releasable
      TFPI and the inhibitory effects on matrix-degrading enzymes beside the
      anticoagulant efficacy have provided an expanded clinical utility for LMWHs in
      angiogenesis-associated disorders, including human tumor growth and metastasis.

PMID- 15179450
TI  - Treatment of portal hypertension with NCX-1000, a liver-specific NO donor. A
      review of its current status.
AB  - Portal hypertension, a life threatening complication of liver cirrhosis, results
      from increased intrahepatic resistance and increased portal blood inflow through
      a hyperdynamic splanchnic system. The increased intrahepatic vascular tone is the
      result of an enhanced activity of endogenous vasoconstrictors and a deficiency of
      nitric oxide (NO) release by sinusoidal endothelial cells. These
      pathophysiological events provide the rational basis for using NO-based therapies
      for the treatment of portal hypertension. Clinical studies have demonstrated that
      nitrate therapy results in a significant reduction of portal pressure as assessed
      by hepatic venous portal gradient but causes vasodilation in both systemic
      arterial and venous vascular beds, aggravating the progression of the
      vasodilatory syndrome of cirrhotic patients. For this reason, the ideal drug for
      the treatment of portal hypertension should act by decreasing intrahepatic
      vascular resistance, without worsening the splanchnic/systemic vasodilatation.
      NCX-1000 is the prototype of a family of NO-releasing derivatives of
      ursodeoxycholic acid (UDCA). These compounds are releasing selectively, from
      parenchymal and non-parenchymal hepatic cells, biologically active NO into the
      liver microcirculation with no detectable effect on systemic circulation.
      Preclinical studies have shown that long- and short-term administration of NCX
      1000 to rodents with chronic liver injury protects against the development of
      portal hypertension and reduces the intrahepatic hyperreactivity to alpha1
      adrenoceptor agonists. The finding of increased liver nitrite/nitrate content in
      NCX-1000-treated animals together with an increase in cGMP levels in their liver
      homogenates suggests that this nitro-compound behaves as a liver-selective NO
      donor. In contrast to conventional NO-donors such as isosorbide mono- and di
      nitrate, which are also used for primary and secondary prevention of
      gastrointestinal bleeding, NCX-1000 has no effect on mean arterial pressure in
      either normal or cirrhotic animals indicating the absence of adverse systemic
      effect. In summary, these data suggest that NCX-1000 may provide a novel therapy
      for the treatment of patients with portal hypertension.

PMID- 15179451
TI  - hOR17-4 as a potential therapeutic target.
AB  - More than a decade ago, the unexpected finding of olfactory receptor expression
      in human testicular tissue led to speculation about a potential role of these
      chemoreceptors in various aspects of mature sperm behavior, especially sperm
      chemotaxis. Recently, first evidence in favor of this hypothesis was provided by
      the identification of hOR17-4, a testicular olfactory receptor that mediates
      human sperm chemotaxis in various bioassays. A detailed characterization of the
      receptor's molecular receptive range as well as the first description of a potent
      receptor antagonist could provide the basis for future applications in fertility
      treatment with important consequences in procreation and/or contraception.

PMID- 15179452
TI  - Mechanism-based therapies for pain.
AB  - Pain is a universal human experience. Usually pain is a normal homeostatic
      mechanism to force an organism to avoid or reduce injury. As such, the body has
      many pain messengers, receptors and neural pathways to sense that information.
      Sensing a stimulus that leads to, or has the potential to cause, tissue injury is
      termed "nociception." In clinical disease states, pain may be the result of
      tissue damage or aberrant signal processing. In either case, we may want to
      interrupt or reduce nociception to produce clinical analgesia. We will discuss
      the mechanisms of pain sensation, sites and actions of analgesic therapies
      presently used, and potential avenues for the development of novel pharmaceutical
      agents to interrupt the sensation and signaling of pain and thus provide pain
      relief or analgesia. Two other terms are used commonly in the pain literature,
      hyperalgesia and allodynia. Hyperalgesia is an increase in the magnitude of pain
      induced by a stimulus that is normally painful. Allodynia is when a usually
      nonpainful stimulus, like light touch, becomes painful. The review is divided
      into two parts: Nociceptors and Pain pathways to the brain. The first part
      discusses nociception at the peripheral nerve ending, while the second discusses
      the neurotransmission of pain signals to the spinal cord and up to the brain.

PMID- 15179453
TI  - The potential of bacterial fatty acid biosynthetic enzymes as a source of novel
      antibacterial agents.
AB  - Bacteria can produce new progeny in only 20 minutes (500,000 times faster than
      humans), enabling them to rapidly mutate and evolve ingenious methods to outwit
      just about all of the currently available antibiotics. These mechanisms can then
      disseminate rapidly through bacterial populations via transmissible pieces of DNA
      such as transposons, integrons and plasmids. This leads to resistance mechanisms
      becoming geographically dispersed and has resulted in the overall decrease in the
      susceptibility of microorganisms to antibiotics that used to be highly
      efficacious. There is an obvious need for new antibiotics that kill bacteria via
      novel mechanisms not previously exploited by existing agents; this will provide
      new generations of antibiotics unlikely to be compromised by preexisting
      resistance mechanisms. The fatty acid biosynthetic pathway is an essential
      metabolic process in bacteria and presents several novel targets for antibiotic
      development.

PMID- 15179454
TI  - The roles of centrosome in cancer development.
AB  - The accumulation of a series of genetic alterations involving the activation of
      proto-oncogenes and inactivation of tumor suppressor genes has long been regarded
      as a major driving force in carcinogenesis. Therefore, cancer is currently
      considered a genetic disease induced by DNA damage. However, the molecular
      etiology remains enigmatic. In recent years, the centrosome, together with the
      embedded centrioles and connecting filaments (or microtubules), has come to be
      regarded as the "brain" of a cell, being a key in maintaining genetic stability
      and in coordinating other cellular activities. Abnormalities in the centrosome
      and/or microtubules may result in unequal chromosome segregation leading to
      genetic alterations. Therefore, cancer is appropriately interpreted primarily as
      a "brain illness" of a cell rather than a genetic disease. We provide a brief
      overview of the latest advances in the understanding of the roles of the
      centrosome in cancer development, and then we discuss the mechanisms causing
      centrosome abnormalities and the implications for future research.

PMID- 15179455
TI  - Molecule of the month. Ciclesonide.

PMID- 15179456
TI  - Multidisciplinary approach to breast cancer management.
AB  - The 21st Annual Miami Breast Cancer Conference took place in Miami Beach,
      Florida, United States, February 25-28, 2004. This meeting aimed to provide
      practicing surgical and medical oncologists with a multidisciplinary approach to
      the practice of breast cancer management with incorporation of molecular biologic
      translation from laboratory to bedside. The expanding knowledge in molecular
      biology has given rise to the potential for the use of gene expression profiles,
      molecular fingerprinting and biomarkers for clinical decision making. The theme
      of this year's meeting was stated to be, "What can you learn that you can use
      Monday morning and what can you look forward to on Friday?" It is the focus on
      the most recent practical advances that attracted more than 450 international
      participants to this 3-day meeting. More than half of all presentations explored
      recent advances in early breast cancer biology, predictive and prognostic
      markers, prevention and early diagnosis. This report will collate various
      presentations to attempt to present a coherent picture of the advances in this
      area.

PMID- 15179457
TI  - Successes in drug discovery and design.
AB  - The Society for Medicines Research (SMR) held a one-day meeting on case histories
      in drug discovery on December 4, 2003, at the National Heart and Lung Institute
      in London. These meetings have been organized by the SMR biannually for many
      years, and this latest meeting proved extremely popular, attracting a capacity
      audience of more than 130 registrants. The purpose of these meetings is
      educational; they allow those interested in drug discovery to hear key learnings
      from recent successful drug discovery programs. There was no overall linking
      theme between the talks, other than each success story has led to the
      introduction of a new and improved product of therapeutic use. The drug discovery
      stories covered in the meeting were extremely varied and, put together, they
      emphasized that each successful story is unique and special. This meeting is also
      special for the SMR because it presents the "SMR Award for Drug Discovery" in
      recognition of outstanding achievement and contribution in the area. It should be
      remembered that drug discovery is an extremely risky business and an extremely
      costly and complicated process in which the success rate is, at best, low.

PMID- 15179458
TI  - The history of bacterial meningitis treatment.
AB  - Few diseases have been affected more by the advent of antimicrobial therapy than
      bacterial meningitis. From its recognition in 1805 to the early 20th century,
      bacterial meningitis was deadly. The 1940s brought the advent of effective drug
      therapy. Bacterial meningitis remains common today with growing drug resistance
      to the disease organisms complicating antibiotic therapy.

PMID- 15179459
TI  - Addition reactions of ROPHy/SOPHy oxime ethers: asymmetric synthesis of nitrogen
      containing compounds.
AB  - Oxime ethers prepared from (R)- or (S)-O-(1-phenylbutyl)hydroxylamine (ROPHy or
      SOPHy) are versatile intermediates for the asymmetric synthesis of a range of
      nitrogen containing compounds including simple amines, 1,2-aminoalcohols, alpha-
      and beta-amino acids, heterocyclic building blocks of natural products,
      piperidine alkaloids, lactams, 5- to 8-membered ring nitrogen heterocycles, imino
      sugars, and chiral ferrocene based receptors.

PMID- 15179460
TI  - A modular, self-assembled, separated ion pair binding system.
AB  - Assembly of a silver(I) complex of a simple pyridyl ligand containing a urea
      derivative is templated by nitrate; analogous complexes of Ag(2)SO(4) and
      AgCF(3)SO(3) exhibit radically different geometries.

PMID- 15179461
TI  - Linear distortion of octahedral metal centres by multiple hydrogen bonds in
      modular ML(4) systems.
AB  - A series of compounds of the type [M(1)(4)(H(2)O)(2)]SO(4)[middle dot]2H(2)O
      containing a simple urea-based pyridyl ligand have been synthesised and
      characterised by X-ray crystallography. The enclathrated water exists within
      discrete linearly stacked cavities and causes significant distortions in the M
      OH(2) bonds due to the presence of a strongly hydrogen bonded water square.

PMID- 15179462
TI  - ITQ-15: the first ultralarge pore zeolite with a bi-directional pore system
      formed by intersecting 14- and 12-ring channels, and its catalytic implications.
AB  - The pore topology of ITQ-15 zeolite consists of an ultra-large 14-ring channel
      that is intersected perpendicularly by a 12-ring pore; acid sites have been
      introduced in its framework and this unique structure shows advantages over
      unidirectional ultralarge pore zeolites for diffusing and reacting large
      molecules.

PMID- 15179463
TI  - Water and tris(5-acetyl-3-thienyl)methane (TATM) assemble into a one-dimensional
      channel compound.
AB  - Tris(5-acetyl-3-thienyl)methane (TATM), a well known hydrophobic host compound,
      assembles with water molecules into a material with one-dimensional channels that
      also contain water.

PMID- 15179464
TI  - Electrostatic and short-range interactions compete in directing the structure of
      p-tert-butylcalix[4]arene inclusion compounds of fluorinated benzenes.
AB  - p-tert-Butylcalix[4]arene guest-host compounds with fluorinated benzenes show
      several structural motifs, thus indicating that the guest-host structure can be
      tuned to produce either a form with included guests or a form where the host self
      includes with the guests outside the cavity.

PMID- 15179465
TI  - Zn(II)-induced conformational control of amphiphilic cavitands in langmuir
      monolayers.
AB  - The reversible switching from the C(4v)-symmetric vase to the C(2v)-symmetric
      kite conformation of an amphiphilic resorcin[4]arene cavitand was induced by
      Zn(II) ion coordination. Langmuir monolayers were obtained of both conformers
      with the area per molecule increasing dramatically from 120 A(2) for the vase to
      270 A(2) for the kite form. (1)H NMR spectroscopy in chloroform solution supports
      the formation of a stoichiometric kite-cavitand[radical dot](Zn(II))(2) complex,
      with the metal ions coordinating to pairs of neighbouring quinoxaline N-atoms.

PMID- 15179466
TI  - A nucleic acid base derivative tethered to a ruthenium carbene complex: hydrogen
      bonded dimers in both the solid state and solution?
AB  - A ruthenium carbene bearing a uracil (Ur) substituent has been prepared and has a
      dimeric structure in the solid state-the dimer being held together by hydrogen
      bonds between two uracil groups on neighbouring molecules: evidence for the
      persistence of this interaction in solution has been obtained.

PMID- 15179467
TI  - A high-throughput NMR-based ee-assay using chemical shift imaging.
AB  - The throughput of a previously described NMR-based -assay has been increased by a
      factor of at least 4 as a consequence of adapting the system to chemical shift
      imaging; by using a 19-capillary system the enantiomeric purity of 5600 samples
      can be measured per day.

PMID- 15179468
TI  - Metal bis[trifluoromethyl)sulfonyl]amide complexes: highly efficient Friedel
      Crafts acylation catalysts.
AB  - A range of metal bis[(trifluoromethyl)sulfonyl]amide complexes, including many
      unreported ones, have been synthesised, most of which have been found to be
      excellent Friedel-Crafts acylation catalysts in the absence of solvent; these
      reactions have also been carried out in ionic liquids, which allow the catalysts
      to be recycled and reused.

PMID- 15179469
TI  - Synthesis and characterization of the hexagonal prismatic cage [THF[subset or is
      implied by][PhB(CN)(3)](6)[Cp*Rh](6)](6+).
AB  - Condensation of [Cp*Rh(CH(3)NO(2))(n)](2+) and the tricyanoborate [PhB(CN)(3)](-)
      affords the hexagonal bipyramidal cage [[PhB(CN)(3)](6)[Cp*Rh](6)](6+),
      demonstrating that tetrahedral tricyanide building blocks can lead to novel cage
      structures.

PMID- 15179470
TI  - The single-step synthesis of a DNA tetrahedron.
AB  - A tetrahedral nanostructure whose edges are DNA double helices self-assembles
      spontaneously when four appropriately designed oligonucleotides are annealed
      together in solution; the ease of synthesis, rigidity, and adaptability of this
      construct make it a promising candidate as a cage for other large molecules and
      as a building block for more complicated nanostructures.

PMID- 15179471
TI  - Optical properties of mesoporous II-VI semiconductor compound films.
AB  - Direct liquid crystal templating from non-ionic polyoxyethylene surfactants has
      been utilised to produce well-defined birefringent films of nanostructured
      cadmium telluride films which displayed good optical properties as evidenced by
      UV/VIS reflectance spectroscopy.

PMID- 15179473
TI  - Phase selectively soluble dendrimer-bound osmium complex: a highly effective and
      easily recyclable catalyst for olefin dihydroxylation.
AB  - A new switched biphasic catalysis system for highly effective olefin
      dihydroxylation has been described, in which the dendritic osmium catalyst
      preferred to dissolve in the non-polar organic layer and could be easily
      separated from the polar diol products through phase separation induced by
      addition of water at the end of the reaction.

PMID- 15179472
TI  - Synthesis, characterization and optical properties of ordered macroporous
      organosilicas.
AB  - Ordered macroporous organosilica materials with uniform pore size in the range of
      0.2-1.35 [micro sign]m have been fabricated by using self-assembled colloidal
      crystals as templates, and characterized with SEM, TGA, FTIR, MAS NMR, and
      optical reflectance spectrometry.

PMID- 15179474
TI  - Transition of oscillatory mechanism for methanol electro-oxidation on nano
      structured nickel hydroxide film (NNHF) electrode.
AB  - Instead of CO(ad) formation and removal as on Pt electrodes, coupling of charge
      transfer with diffusion and convection mass transfer accounts for the oscillation
      found in the methanol electro-oxidation on the NNHF electrode.

PMID- 15179475
TI  - Allylation and highly diastereoselective syn or anti crotylation of N
      toluenesulfonylimines using potassium allyl- and crotyltrifluoroborates.
AB  - Air and moisture stable potassium allyl- and crotyltrifluoroborates undergo
      addition to N-sulfonyl and N-sulfinyl aldimines in the presence of Lewis acids,
      to provide the corresponding homoallylic amines in high yields and excellent
      diastereoselectivity.

PMID- 15179476
TI  - Tetrathiafulvalene based phosphino-oxazolines: a new family of redox active
      chiral ligands.
AB  - Reaction of the lithium salt of EDT-TTF-2-(4-methyl)oxazoline with chloro
      diphenylphosphine afforded the novel redox active chiral chelating ligands, EDT
      TTF-phosphino-oxazolines, for which a palladium (II) dichloride complex was
      synthesized and structurally characterized.

PMID- 15179478
TI  - Potassium hexacyanoferrate(II)--a new cyanating agent for the palladium-catalyzed
      cyanation of aryl halides.
AB  - A new advantageous cyanating agent, potassium hexacyanoferrate(II), is described
      for the palladium-catalyzed cyanation of aryl halides. All cyanide ions on the
      iron(II) center can be transferred to the aryl halide using palladium(II) acetate
      and dppf as the catalyst. Under optimized reaction conditions good yields of
      benzonitriles and unprecedented catalyst productivities are observed.

PMID- 15179477
TI  - Bis(phenanthroline)-ethylenediamine conjugate displays excimer fluorescence upon
      binding with DNA.
AB  - 1,2-Bis(1,10-phenanthrolin-2-yl)ethylenediamine (1) displays a unique long-life
      time excimer fluorescence at 528 nm by binding with calf thymus DNA, while its
      monomer fluorescence at 400 nm shows a decrease upon binding with DNA.

PMID- 15179479
TI  - Thermal and light induced polymorphism in iron(II) spin crossover compounds.
AB  - The spin crossover complexes [Fe[H(2)B(pz)(2)](2)L]([H(2)B(pz)(2)](-)=
      dihydrobis(pyrazolyl)borate, L = 2,2[prime or minute]-bipyridine (1), bipy and
      1,10-phenanthroline, phen (2)) undergo both thermal and light induced spin
      crossover, but the structure of the low spin and light induced high spin states
      for are different from that of the thermally induced high spin state and from
      those of.

PMID- 15179480
TI  - A novel asymmetric route to succinimides and derived compounds: synthesis of the
      lignan lactone (+)-hinokinin.
AB  - A novel approach to chiral succinimides and derived compounds has been developed
      that involves chiral lithium amide desymmetrisation of an N-ortho-tert
      butylphenyl succinimide to generate a putative atropisomeric intermediate
      enolate, alkylation of which enables access to the lignan lactone (+)-hinokinin.

PMID- 15179481
TI  - Effective cation-assisted chirality induction using a dibenzo-diaza-30-crown-10
      with bis(zinc(II) porphyrin) units.
AB  - The first rationalized crown ether-bis(porphyrin) conjugate with a large ring
      based conformation flexibility 1 has been synthesized; the achiral-to-chiral
      transformation upon complexation with chiral diamines is assisted by K(+)
      accommodated in the crowned moiety, and it is possible to determine the chirality
      of carboxylates as potassium salts.

PMID- 15179482
TI  - Iron-catalysed propylene epoxidation by nitrous oxide: dramatic shift of allylic
      oxidation to epoxidation by the modification with alkali metal salts.
AB  - A dramatic shift of allylic oxidation to epoxidation has been observed during the
      oxidation of propylene by N(2)O when the FeO(x)/SBA-15 catalyst is modified with
      alkali metal salts, and the roles of alkali metal salts are to suppress the
      reactivity of lattice oxygen and to induce an iron coordination structure
      effective for epoxidation with N(2)O.

PMID- 15179483
TI  - C-H activation of a 2,2[prime or minute]-bipyridine ligand within
      (mono)pentamethylcyclopentadienyl lutetium complexes.
AB  - We report the activation of a 2,2'-bipyridine ligand within a class of
      (mono)cyclopentadienyl lanthanide complexes when reacted with carbon monoxide.

PMID- 15179484
TI  - Palladium catalyzed amination of vinyl chlorides: a new entry to imines, enamines
      and 2-amino-1,3-butadienes.
AB  - Vinyl chlorides are employed for the first time in palladium catalyzed cross
      coupling reactions with amines to furnish imines and enamines. The new
      methodology has been applied to the synthesis of 2-amino-1,3-butadienes, that
      could not be achieved from the corresponding bromides.

PMID- 15179485
TI  - Plasmachemical surface functionalised beads: versatile tailored supports for
      polymer assisted organic synthesis.
AB  - Plasmachemical surface modification of porous polystyrene beads with allylamine
      or diaminopropane provides reactive amine functionality exclusively at accessible
      surface sites, allowing faster reactions than classically prepared materials.

PMID- 15179486
TI  - Fe-Ce-ZSM-5 a new catalyst of outstanding properties in the selective catalytic
      reduction of NO with NH(3).
AB  - A Fe-Ce-ZSM-5 catalyst elaborated from a new synthesis route exhibits very high
      NO conversion (75-100%) in the selective catalytic reduction of NO by NH(3) in a
      wide temperature window (523-823 K), even in the presence of H(2)O and SO(2).

PMID- 15179487
TI  - Preparation of helical gold nanowires on surfactant tubules.
AB  - Electroless gold nanoplating of various forms of surfactant tubules yielded mono
      , double- and multi-helical gold nanowires and their yarns in solution.

PMID- 15179488
TI  - Unexpected effect of Ru-substitution in lightly doped manganites.
AB  - In this communication we report the unexpected effect of ruthenium doping in
      sodium lightly doped manganites. This effect seems to be in contrast with the
      usual model applied to describe the effect of this magnetic ion into the
      manganite structure. We propose a possible compensation mechanism which seems
      also able to describe other peculiar features encountered in these materials.

PMID- 15179489
TI  - Computational screening of combinatorial catalyst libraries.
AB  - A catalyst design methodology, utilizing combinatorial synthesis in parallel with
      chemometric analysis, is presented, which considers the 3D steric and
      electrostatic properties of substituents about a constant core structure.

PMID- 15179490
TI  - Kinetics of chalcone oxidation by peroxide anion catalysed by poly-l-leucine.
AB  - An insight into the kinetics, mechanism and optimum reaction conditions of the
      Julia-Colonna epoxidation has been gained using a soluble polyleucine catalyst.

PMID- 15179491
TI  - Asymmetric Michael addition reactions of 2-silyloxyfurans catalyzed by
      binaphthyldiimine-Ni(II) complexes.
AB  - N,N'-Bis(2-quinolylmethylene)-1,1'-binaphthyl-2,2'-diamine-Ni(II) complex and
      analogous complexes were found to be efficient chiral Lewis acid catalysts for
      the asymmetric Michael addition reactions between 2-silyloxyfurans and 3-alkenoyl
      2-oxazolidinones, for which asymmetric inductions of up to 97% ee were obtained.

PMID- 15179492
TI  - Growth of aligned carbon nanofibres over large areas using colloidal catalysts at
      low temperatures.
AB  - Highly purified cobalt colloids have been employed as a catalyst to grow aligned
      carbon nanofibres at temperatures as low as 300 degree C by dc plasma enhanced
      chemical vapour deposition over large areas.

PMID- 15179493
TI  - Supertetrahedral decametallic Ni(II) clusters directed by micro(6)-tris
      alkoxides.
AB  - We report the syntheses, structures and magnetic properties of two decametallic
      Ni(II) clusters with unprecedented supertetrahedral cores, stabilised by the
      (hitherto unobserved) micro(6)-coordination modes of the tris-alkoxides
      [MeC(CH(2)O)(3)](3-) and [C(6)H(9)O(3)](3-).

PMID- 15179494
TI  - A novel isopolytungstate functionalized by ruthenium:
      [HW(9)O(33)Ru(II)(2)(dmso)(6)](7-).
AB  - The ruthenium-supported isopolyanion [HW(9)O(33)Ru(II)(2)(dmso)(6)](7-) (1) is
      composed of a nonatungstate wheel stabilized by two Ru(dmso)(3) groups,
      representing the first structurally characterized Ru-coordinated polyoxotungstate
      and a novel class of isopolyanions supporting photochromic moieties.

PMID- 15179495
TI  - Rearrangement of pyrrolines derived from the Birch reduction of electron
      deficient pyrroles: radical ring-expansion to substituted tetrahydropyridines.
AB  - Access to the synthetically important tetrahydropyridine motif has been achieved
      by radical rearrangement of pyrrolines obtained from the Birch reduction of
      electron-deficient pyrroles.

PMID- 15179497
TI  - Selective production of hydrogen from partial oxidation of methanol over silver
      catalysts at low temperatures.
AB  - Hydrogen can be effectively and selectively produced from the partial oxidation
      of methanol over Ag/CeO(2)-ZnO catalyst at low temperatures (T(r) < 200 degree
      C).

PMID- 15179498
TI  - Rotor-like ZnO by epitaxial growth under hydrothermal conditions.
AB  - Rotor-like ZnO was grown from a mixture of rod-like ZnO powder and a saturated
      Zn(OH)(4)(2-) solution under moderate hydrothermal conditions at 100 degree C, in
      which the precursor rod-like ZnO crystal plane acts as a matrix core, and the
      branched nanorods showed fast epitaxial growth on the six directions around the
      prism core.

PMID- 15179496
TI  - Multi-nuclear platinum complexes encapsulated in cucurbit[n]uril as an approach
      to reduce toxicity in cancer treatment.
AB  - The dinuclear platinum complex trans-[[Pt(NH(3))(2)Cl](2)micro-dpzm](2+)(di-Pt)
      binds inside cucurbit[7]uril with slow exchange kinetics which does not
      significantly affect the cytotoxicity of the dinuclear complex but reactivity at
      the platinum centre is reduced.

PMID- 15179499
TI  - Stepwise growth of polypalladium chains in 1,4-diphenyl-1,3-butadiene sandwich
      complexes.
AB  - A series of 1,4-diphenyl-1,3-butadiene multinuclear palladium sandwich complexes
      are synthesized by stepwise growth of palladium chains within a sandwich
      framework.

PMID- 15179500
TI  - p-type macroporous silicon having three-dimensional structure.
AB  - Macroporous silicon with three-dimensional structure was fabricated using organic
      based electrolyte, dimethylformamide (DMF), in the p-type silicon. The obtained
      three-dimensional macroporous structures grew wholly along the <100> orientation
      of the p-type silicon wafer.

PMID- 15179501
TI  - Cross-metathesis between ethane and toluene catalyzed by [([triple bond, length
      as m-(SiO)(2)TaH]: the first example of a cross-metathesis reaction between an
      alkane and an aromatic.
AB  - The silica-supported tantalum hydride [([triple bond, length as m
      dash]SiO)(2)TaH] catalyzes at moderate temperature (150-250 degree C) the cross
      metathesis reaction between toluene and ethane, to form mainly ethylbenzene and
      xylenes.

PMID- 15179502
TI  - Analysis of the conversion of indigo into indigo carmine dye using SERRS.
AB  - In a novel application SERRS has been used, by employing a silver sol, to monitor
      and analyse the conversion of indigo into the indigo carmine dye.

PMID- 15179503
TI  - Fluorescence properties of 2-aminopurine in human telomeric DNA.
AB  - The substitution of 2-aminopurine (Ap) for A7 in the human telomeric sequence
      d[AGGG(TTAGGG)(3)] resulted in a significant increase in the fluorescence
      intensity of Ap for the conformational change from duplex to quadruplex.

PMID- 15179504
TI  - Direct syntheses of functionalized mesostructured silica by using an inexpensive
      silica source.
AB  - The co-condensation of water soluble sodium silicate and different
      organotrialkoxysilanes in the presence of non-ionic triblock copolymers under
      acidic conditions provides a very convenient, general and economic one step
      synthesis methodology for the preparation of organically functionalised
      mesostructured silica.

PMID- 15179505
TI  - [Chemical peels in aesthetic dermatology].
AB  - Chemical peels are classified as very superficial (exfoliation), superficial
      (epidermal), medium (papillary dermal) and deep (reticular dermal). A successful
      peel depends upon a number of variables, such as choice of the peeling agent, its
      concentration, and the pressure and frequency of the applications; all must be
      adjusted to the patient's skin condition. Through standardization of the peeling
      agents, the level of injury can be determined pre-operatively and complications
      minimized. Trichloroacetic acid (TCA) is the most popular peeling agent used in
      different concentrations. It has the broadest spectrum of indications due to its
      versatility in combination with other peeling agents. Indications for superficial
      peels include skin resurfacing, wrinkles, actinically damaged skin, actinic
      keratoses and benign pigmented lesions. Superficial peels have the advantage that
      they can be used on most regions of the body. The use of different chemical
      peels, their varying effects and their potential complications are reviewed.
      There are at present more than 45 chemical peels with different combinations of
      agents available on the European market.

PMID- 15179507
TI  - The efficacy of therapy with albendazole in mice with parasitic meningitis caused
      by Angiostrongylus cantonensis.
AB  - Matrix metalloproteinase 9 (MMP-9) is involved in the pathogenesis of parasitic
      meningitis caused by the nematode Angiostrongylus cantonensis. The present study
      evaluated the efficacy of albendazole therapy in BALB/c mice infected with the
      third stage larvae of this nematode. Albendazole showed a pronounced larvicidal
      activity. Eosinophil numbers significantly increased in infected mice but
      decreased upon administration of albendazole. Densitometric scanning indicated
      that albendazole reduced gelatinolytic activity detected by gelatin-substrate
      zymography. In the cerebrospinal fluid, albendazole reduced the lytic area
      intensity of the 94 kDa MMP-9 band by 46.5% within 7 days, and by 51.5% by day
      14. Examination of brain tissue revealed a similar pattern of decrease (48.6% by
      day 7, and 53.9% by day 14). Albendazole may thus be an effective compound for
      the treatment of angiostrongyliasis through its larvicidal activity and
      facilitation of an improved inflammatory response via the reduction of MMP-9
      activity.

PMID- 15179508
TI  - Targeting a DBL3gamma domain of the Plasmodium falciparum erythrocyte membrane
      protein 1 to the surface of Saccharomyces cerevisiae.
AB  - The availability of the full genomes of the malarial parasite Plasmodium
      falciparum and its two hosts, man and Anopheles gambiae, has dramatically
      increased the demand for protein display systems to study host/parasite
      interactions at the molecular level. Here, we explored the potential of a
      Saccharomyces cerevisiae expression and display system that allows proteins of
      interest to be targeted to the yeast surface. As proof of this principle, we used
      a P. falciparum erythrocyte membrane protein 1 DBL3gamma domain which mediates
      the binding of P. falciparum-infected erythrocytes to chondroitin-4-sulfate, a
      host receptor involved in parasite sequestration in the placenta. Our data
      revealed localization of the DBL3gamma domain to the yeast surface, demonstrating
      the value of the yeast system as a tool for displaying P. falciparum protein
      fragments. However, binding of the respective yeast strains to chondroitin-4
      sulfate could not be demonstrated.

PMID- 15179509
TI  - Tourniquet syndrome--accident or abuse?
AB  - The tourniquet syndrome describes severe strangulations of appendages by hair,
      cotton or similar material mainly observed in young infants. The painful
      swellings of digits or external genitals are surgical emergencies because the
      strangulation can cause ischaemia and tissue necrosis. More than 100 cases of the
      tourniquet syndrome have been reported in most of which the aetiology was
      unclear. We have treated five patients with a tourniquet syndrome. Four of them
      presented with strangulations of one or more toes by hair or threads and one girl
      was diagnosed with a clitoral tourniquet syndrome. In each case the strangulating
      material could be removed in time avoiding permanent damage. The lack of any
      reasonable explanation and the meticulous wrapping made a non-accidental course
      very likely. Due to the lack of convincing explanations in our cases as well as
      in most of those described in the literature, we suggest that the tourniquet
      syndrome is often the result of child abuse, an aetiology overlooked for decades.
      CONCLUSION: the tourniquet syndrome in childhood should be included in the list
      of possible forms of child abuse and should be considered as a differential
      diagnosis until another aetiology can be convincingly proven.

PMID- 15179510
TI  - Periventricular leucomalacia: a review.
AB  - Periventricular leucomalacia is a condition that causes lifelong disability and
      considerable economic burden. It occurs in premature infants of less than 32
      weeks gestation due to their unique anatomical features. The white matter of
      these infants is poorly vascularised and contains oligodendrocyte progenitors
      (pre-oligodendrocytes), which are sensitive to the effects of ischaemia and
      infection. Only recently have newer imaging techniques identified both a diffuse
      and focal component of white matter damage. The most immature infants with
      diffuse injury develop white matter atrophy and ventriculomegaly; others with
      focal injury have cyst formation, resorption and gliosis. Since the original
      description by Virchow in 1867, much progress has been made in establishing the
      underlying cause of this condition. It is an ischaemia reperfusion injury of the
      white matter, free radicals being the final pathway to pre-oligodendrocyte
      destruction and impaired myelination. Contributory factors include hypotension,
      hypocarbia and infection. CONCLUSION: new imaging and EEG techniques are likely
      to improve our ability to predict disability in this vulnerable group of infants.
      Research is needed into blocking the pathway to pre-oligodendrocyte destruction
      and the safe use of free radical scavengers.

PMID- 15179511
TI  - Comparative analysis of the Kekkon molecules, related members of the LIG
      superfamily.
AB  - Leucine-rich repeats (LRRs) and immunoglobulin (Ig) domains represent two of the
      most abundant sequence elements in metazoan proteomes. Despite this prevalence,
      comparatively few molecules containing both LRR and Ig (LIG) modules exist, and
      fewer still have been functionally defined. One LIG whose function has been
      investigated is the Drosophila protein Kekkon1 (Kek1). In vivo studies have
      demonstrated a role for Kek1 in Epidermal Growth Factor Receptor (EGFR) signaling
      and have suggested a role in neuronal pathfinding. Kek1 is the founding member of
      the Kek family, a group of six Drosophila transmembrane proteins that contain
      seven LRRs and a single Ig in their extracellular domains. While this arrangement
      of domains predicts a possible role as cell adhesion molecules (CAMs), to date
      little is known about the function or evolutionary relationship of these
      additional Kek molecules. Here we report that orthologs of Kek1, Kek2, Kek5, and
      Kek6 exist in the mosquito, Anopheles gambiae, and the honeybee, Apis mellifera,
      indicating that this family has been conserved for ~300 million years of
      evolutionary time. Comparative sequence analyses reveal remarkable identity among
      these orthologs, primarily in their extracellular regions. In contrast, the
      intracellular regions are more divergent, exhibiting only small pockets of
      conservation. In addition, we provide support for the general notion that these
      molecules may share common functions as CAMs, by demonstrating that Kek family
      members can form homotypic and heterotypic complexes.

PMID- 15179512
TI  - Primary metabolism in N2-fixing Alnus incana-Frankia symbiotic root nodules
      studied with 15N and 31P nuclear magnetic resonance spectroscopy.
AB  - The primary nitrogen metabolism of the N2-fixing root nodule symbiosis Alnus
      incana (L.)- Frankia was investigated by 31P and 15N nuclear magnetic resonance
      (NMR) spectroscopy. Perfusion of root nodules in a pulse-chase approach with 15N-
      or 14N-labeled NH4+ revealed the presence of the amino acids alanine (Ala), gamma
      amino butyric acid, glutamine (Gln), glutamic acid (Glu), citrulline (Cit) and
      arginine (Arg). Labeling kinetics of the Gln amide-N and alpha-amino acids
      suggested that the glutamine synthetase (GS; EC 6.3.1.2)-glutamate synthase
      (GOGAT; EC 1.4.1.13) pathway was active. Inhibition of the GS-catalyzed reaction
      by methionine sulphoximine abolished incorporation of 15N. Cit was labeled in all
      three N positions but most rapidly in the omega position, consistent with
      carbamoyl phosphate as the precursor to which Gln could be the amino donor
      catalyzed by carbamoyl phosphate synthase (CPS; EC 6.3.5.5). Ala biosynthesis
      occurred consistent with a flux of N in the sequence Gln-Glu-Ala. 31P NMR
      spectroscopy in vivo and of extracts revealed several metabolites and was used in
      connection with the 15N pulse-chase experiment to assess general metabolic
      status. Stable concentrations of ATP and UDP-glucose during extended perfusions
      showed that the overall root nodule metabolism appeared undisturbed throughout
      the experiments. The metabolic pathways suggested by the NMR results were
      confirmed by high activities of the enzymes GS, NADH-GOGAT and ornithine
      carbamoyltransferase (OCT; EC 2.1.3.3). We conclude that the primary pathway of
      NH4+ assimilation in A. incana root nodules occurs through the GS-GOGAT pathway.
      Biosynthesis of Cit through GS-CPS-OCT is important and is a link between the
      first amino acid Gln and this final transport and storage form of nitrogen.

PMID- 15179513
TI  - Regulation of vacuolar invertase by abscisic acid or glucose in leaves and roots
      from maize plantlets.
AB  - Recent studies have demonstrated in leaves of maize (Zea mays L.) plants
      submitted to a moderate water stress an early enhancement of vacuolar invertase
      activity that paralleled the expression of the vacuolar invertase Ivr2 gene and
      the accumulation of hexoses. In this paper, the direct role of abscisic acid
      (ABA) was checked by providing this hormone to the root medium of hydroponically
      grown maize plantlets. ABA supplied to 10-day-old seedlings appeared to enhance
      the vacuolar invertase activity within 1 h in roots and 2 h in leaves, the
      maximum being reached at 4 and 8 h, respectively. The Ivr2 gene expression varied
      accordingly, except that the maximum values were earlier. During the first 8 h of
      activity enhancement, hexose and sucrose concentrations were not significantly
      affected by ABA. The changes in activity were correlated to leaf and root ABA
      concentrations and they were concentration dependent in roots and leaves. In
      contrast, the addition of 1% glucose or polyethylene glycol, at the same osmotic
      potential, was ineffective on invertase activity, but glucose supply enhanced
      Ivr2 transcript levels, after 18 h, in a concentration-dependent manner in the
      leaf, whereas they were repressed at higher concentrations in intact roots. The
      latter result appeared specific to intact roots since similar treatments
      performed using excised leaf or root pieces confirmed a previous report on the
      enhancement of Ivr2 and Ivr1 transcript levels by glucose in roots [J. Xu et al.
      (1996) Plant Cell 8:1209-1220]. Therefore, ABA appears to be a strong inducer of
      Ivr2-invertase expression in roots and leaves.

PMID- 15179514
TI  - The MsPRP2 promoter enables strong heterologous gene expression in a root
      specific manner and is enhanced by overexpression of Alfin 1.
AB  - Promoter specificity and efficiency of utilization are essential for endogenous
      and transgene expression. Selective root expression remains to be defined in
      terms of both promoter elements and transcription factors that provide high
      levels of ubiquitous expression. We characterized expression from the MsPRP2
      promoter with the green fluorescent protein (GFP) reporter transgene in alfalfa
      (Medicago sativa) and found that a promoter fragment (+1 to -652 bp) retained the
      root and callus specificity of the endogenous MsPRP2 gene and hence this promoter
      fragment contains elements necessary for root-specific expression. The strong
      ubiquitous expression obtained from this promoter was comparable to that of the
      CaMV 35S promoter in roots and was enhanced by transgenic overexpression of Alfin
      1, a root- and callus-specific transcription factor in alfalfa. No transgenic
      expression was obtained in leaves with this promoter in the presence or absence
      of Alfin 1. The increased expression of GFP in alfalfa containing the Alfin 1
      transgene confirms the function of Alfin 1 binding sites in the MsPRP2 promoter
      fragment and also indicates that Alfin 1 concentrations are limiting for maximal
      expression in calli and roots. These findings characterize the MsPRP2 promoter as
      a novel root- and callus-specific promoter of plant origin that can be used as an
      effective tool for strong root-directed gene expression. In addition, we have
      demonstrated that the signal sequence of MsPRP2 can be used for efficient
      secretion of transgene products from callus and roots.

PMID- 15179516
TI  - Two cases of left-sided gastroschisis: review of the literature.
AB  - In gastroschisis, the opening is almost always to the right of the umbilicus,
      although eight cases of left-sided gastroschisis have been reported in the
      literature. We encountered two additional cases of left-sided gastroschisis. One
      was treated successfully, but the another child died. We report the present two
      these two cases and a review of the literature.

PMID- 15179515
TI  - In vivo assessment of subretinally implanted microphotodiode arrays in cats by
      optical coherence tomography and fluorescein angiography.
AB  - BACKGROUND: Following multiple promising investigations into restoration of
      vision in degenerative retinal disease by implantation of a sub- or epiretinal
      prosthesis, the step to clinical use in humans is impending. In this study we
      intended to establish optical coherence tomography (OCT) and fluorescein
      angiography (FA) first in research animals for noninvasive assessment of the
      condition of the posterior pole of eyes after intraocular implant surgery.
      METHODS: Three adult cats that had undergone subretinal implant surgery were
      evaluated by OCT and FA between 1 and 470 days postoperatively. Eight adult cats
      served as control. In addition histology was performed. RESULTS: In all three
      cats OCT demonstrated stable positioning of the implants in the subretinal space
      during the complete examination period. Transient retinal edema was found in the
      early postoperative period but decreased during follow-up. The retina over the
      implants was well attached at all times in cats 1 and 2; however, in cat 3
      localized retinal detachment was demonstrated. FA showed intact retinal
      vasculature over the subretinal implant in high detail without interference from
      choroidal background fluorescence. CONCLUSIONS: OCT and FA have been fruitfully
      applied to cats to assess the morphological and circulatory conditions of the
      neuroretina and of its interface with the subretinal implant. The techniques may
      therefore provide a tool for objective, noninvasive in vivo evaluation of eyes
      that have undergone subretinal implant surgery, both in research animals and in
      humans.

PMID- 15179517
TI  - Changes in gastric myoelectrical activity in hypertrophic pyloric stenosis and
      after surgical correction.
AB  - The changes of gastric myoelectrical activity were investigated in 20 infants by
      cutaneous electrogastrography (EGG) before and after the surgical correction of
      infantile hypertrophic pyloric stenosis (IHPS). The dominance of 2-4 cycles per
      minute (CPM) "slow waves" is typical of the healthy gastric function. The shift
      of the dominant frequencies towards the slower frequency (0-2 CPM) is defined as
      bradygastria, whereas a shift towards the more frequent waves (4-10 CPM) is
      called tachygastria. Unlike with healthy infants, the electrogastrogram showed
      pathologic patterns in 85% (18 out of 20) of IHPS patients. In all except two of
      these infants with pathologic electrical patterns, the frequency of the waves
      significantly shifted towards tachygastria. The effect of feeding on the gastric
      myoelectrical activity could only be studied in limited (9/20) cases because of
      recurring vomiting during the preoperative period. In IHPS infants, a significant
      increase in the bradygastria group was observed in the postprandial period
      compared with healthy infants. Three to 5 days after surgical repair
      (pyloromyotomy) and the reintroduction of feeding in gradually increasing
      amounts, the gastric myoelectrical activity showed physiologic patterns again,
      showing that the pyloric function was back to normal. Cutaneous EGG is a useful,
      noninvasive method to obtain indirect information about the motor function of the
      stomach and might be further applicable to pediatric gastric motility disorders.

PMID- 15179518
TI  - Childhood head injury: causes, outcome, and outcome predictors. A Nigerian
      perspective.
AB  - Head injury is the most common cause of death following trauma among children in
      most developed and underdeveloped countries. Management of the head-injured child
      remained conservative in the hands of the general and orthopedic surgeons until
      October 2000 in our center. To determine outcome and outcome-predictors in
      children managed nonoperatively for head injury in Ilorin, Nigeria, a 10-year
      retrospective study of children managed for head injury was done. Outcome was
      measured by Glasgow outcome scoring. Clinical variables including age, gender,
      and postresuscitation Glasgow coma score were tested against Glasgow outcome
      score by linear regression analysis. During the study period (1989-1999), 267
      children (173 males and 94 females) aged 16 years and below with head injuries
      were admitted. Their injuries were due mostly to road traffic accidents (64.1%)
      and falls (30.7%). Other injuries were domestic, sport-related, or due to
      assaults or the fall of collapsed walls, water-pots, and coconut shells on
      victims' heads. Head injuries were isolated in 60% of patients but associated
      with skeletal, facial, and spinal injuries in 58, 18, and seven cases,
      respectively. They were mild in 100 (37.5%), moderate in 73 (27.3%), but severe
      in 94 (35.2%) cases. Outcome was good in 207 (77.5%) but fatal in 38 (14.2%)
      children. Only age (p=0.0206) and coma score (p=0.0000), but not gender (p=
      0.3043), could predict outcome. Outcome was good in more than 75% of cases of
      head-injured children managed nonoperatively. It varied with the patient's age
      and postresuscitation Glasgow coma score.

PMID- 15179519
TI  - Unexpected mortality in pediatric patients with postoperative Hirschsprung's
      disease.
AB  - Hirschsprung's disease is characterized by lower intestinal obstruction. In this
      retrospective study, we investigated the postoperative complications and the
      causes of death in pediatric patients with Hirschsprung's disease. Between
      January 1981 and June 1998, 147 patients with Hirschsprung's disease underwent
      surgical intervention (129 with both colostomy and Soave's pull-through
      procedures) at Mackay Hospital. Of 147 total patients, 83.67% had aganglionosis
      in the rectosigmoid, 5.44% had colon involvement, and 4.08% had total colon
      aganglionosis, documented pathologically after a Soave's pull-through procedure.
      Any post-pull-through patient who showed symptoms of fever, leukocytosis,
      diarrhea, and clinical sepsis was diagnosed with Hirschsprung's enterocolitis.
      Four patients died within 4.5 months of surgery, and one patient died more than 4
      years after surgery; these five patients were positive for Thomsen (T-) antigen.
      One patient died soon after rectal irrigation was performed in preparation for
      the surgery. All five of these patients had sepsis clinically, and anaerobic
      sepsis was attributed as the main cause of their deaths. Of interest in these
      cases is the presence of T-antigen, a potentially useful marker for anaerobic
      bacterial infection that may not be well known to most pediatricians. We
      recommend (1) determining the presence of T-antigen in patients with recurrent
      Hirschsprung's enterocolitis, (2) administering empirical antibiotics with anti
      anaerobic activity as soon as possible, and (3) irrigating the colon in those
      patients who develop sepsis after a pull-through procedure.

PMID- 15179520
TI  - Left-sided gastroschisis and pseudoexstrophy: a rare combination of anomalies.
AB  - Pseudoexstrophy is a rare variant of the exstrophy/epispadias complex, comprised
      of the musculoskeletal defects of classic exstrophy but with an intact bladder
      and urethra. We present a case of a neonate with left-sided gastroschisis and
      pseudoexstrophy, the first reported combination of these two anomalies. The
      anomalies in this case were unusual but highlight the importance of careful
      clinical evaluation before and during surgery so as to carefully define the
      anatomy of the abnormalities, which will assist in planning surgery and further
      postoperative management. Identifying and reporting these unusual cases is
      essential to further expand our understanding of these conditions and their
      potential associations.

PMID- 15179521
TI  - The mitochondrial plasmid of the true slime mold Physarum polycephalum bypasses
      uniparental inheritance by promoting mitochondrial fusion.
AB  - Mitochondrial DNA (mtDNA) is inherited maternally in most eukaryotes. Linear
      mitochondrial plasmids in higher plants and fungi are also transmitted from the
      maternal parent to the progeny. However, mF, which is a mitochondrial linear
      plasmid of Physarum polycephalum, evades uniparental mitochondrial inheritance.
      We examined 36 myxamoebal strains of Physarum and isolated three novel mF+
      strains (JE8, TU111, NG111) that harbored free mF plasmids. These strains were
      mated with the mF- strain KM88. Of the three mF- x mF+ crosses, only KM88 x JE8
      displayed complete uniparental inheritance. However, in KM88 x TU111 and KM88 x
      NG111, the mtDNA of KM88 and mF of TU111 and NG111 were inherited by the
      plasmodia and showed recombination. For example, although the mtDNA of TU111 was
      eliminated, the mF of TU111 persisted and became inserted into the mtDNA of KM88,
      such that recombinant mtDNA represented 80% of the total mtDNA. The parental
      mitochondria fused to yield giant mitochondria with two or more mitochondrial
      nucleoids. The mF appears to exchange mitochondria from the recipient (paternal)
      to the donor (maternal) by promoting mitochondrial fusion.

PMID- 15179522
TI  - [Nucleoside induced hepatopathy in HIV patients. Diagnostic value of liver biopsy
      assessment].
AB  - Hepatic steatosis together with lactic acidosis is a life threatening side effect
      in HIV infected patients receiving highly active antiretroviral therapy (HAART).
      We describe 5 patients developing hepatic drug toxicity during longterm treatment
      with nucleoside reverse transcriptase inhibitors. The main clinical symptoms
      included abdominal pain, fever, and neurological disorders. Serum lactate levels
      were elevated leading to severe metabolic acidosis in 3 cases. Liver biopsies
      revealed extensive macro- and microvesicular steatosis. Mitochondrial alterations
      were detected by electronmicroscopy. Microvesicular steatosis was seen in one
      case with elevated liver enzymes, but normal serum lactate levels, and was most
      extensive in a patient with a severe lactic acidotic coma. We conclude that
      detection of microvesicular steatosis and mitochondrial alterations in liver
      biopsies may help to identify the development of a nucleoside induced hepatopathy
      before the onset of severe lactic acidosis.

PMID- 15179524
TI  - [Congenital disorders of the colonic innervation. A diagnostic guide].
AB  - Hirschsprung's disease (HD, aganglionosis) is the most important form of
      congenital disturbance of intestinal innervation, requiring surgical
      intervention. Furthermore, hypoganglionosis of the transitional zone forms the
      most significant factor in morbidity. Pre-operative definition of the length of
      neuronally disturbed segment is still a diagnostic challenge for both clinical
      physician and pathologist. Enzyme histochemical studies form the method of
      choice, but certain limitations in their use must be observed. Other
      dysganglionoses, particularly the so-called "Intestinal Neuronal Dysplasia" (IND)
      cannot-because of an excessive overlapping with age-correlated normal values
      unequivocally be defined as an entity on its own. The only exception to this, is
      the ganglionic neuromatosis, which arises as part of a genetic illness.

PMID- 15179523
TI  - [Regression of the Philadelphia chromosome (bcr/abl)-positive myelo- and
      megakaryopoiesis after Imatinib (STI571) therapy in chronic myelogenous leukemia
      (CML)].
AB  - In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic
      and cytogenetic response is associated with conspicuous changes of bone marrow
      morphology. However, it is not known to which extent these alterations are
      accompanied by a loss of the bcr/abl translocation. To study regression of the
      leukemic cell population we recruited 14 patients lacking pretreatment. Therapy
      resulted in a reduction of CD61(+) megakaryopoiesis. Dwarf megakaryocytes
      characteristic for this disorder were replaced by large, normally appearing cells
      of this lineage. Morphometric analysis confirmed the significant decrease in the
      number of micromegakaryocytes and yielded planimetric parameters in keeping with
      normalization. Moreover, a fluorescence in-situ hybridization study in five
      patients of this cohort revealed that before therapy 70% of all myeloid cells
      exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the
      micromegakaryocytes displayed positive signals. Following treatment these
      bcr/abl(+) cell populations decreased significantly while the emerging large
      megakaryocytes lacked a proper labeling. Because cytogenetic response and
      reduction of atypical micromegakaryocytes are linked, this feature may be useful
      to monitor therapeutic efficacy.

PMID- 15179525
TI  - [Classification of etiologic agents in fungal sinusitis by immunohistochemistry,
      histology and culture].
AB  - In the invasive forms of fungal sinusitis rapid identification of etiologic agent
      is of vital importance because of the different reaction of the fungi to various
      antifungal agents. In the non-invasive forms it is of interest for epidemiologic
      reasons and because of the potential transition to invasive and generalized
      mycoses in case of additional immunodeficiency. A diagnosis of fungal genus in
      histologic slides is desirable since up to 70% of the fungal cultures remain
      without result.In the present study 77 cases of fungal sinusitis were examined
      with the comercially available antibodies Anti-Aspergillus and Anti-Rhizomucor.
      The results of the histological examination and fungal cultures were added. The
      immunohistochemical examination permitted in 64 cases a classification as
      Aspergillus/Penicillium. Two cases caused by Zygomyzetes alone or in combination
      could be confirmed immunohistochemically. Four fungus balls showed no significant
      immunoreaction with both antibodies. If these where caused by other Hyphomycetes
      p.e. Pseudallescheria or if it where Aspergillus fungus balls that did not react
      because of extreme regressive change can not be decided.

PMID- 15179526
TI  - The generation of high biomass from chlororespiring bacteria using a continuous
      fed-batch bioreactor.
AB  - A continuous fed-batch reactor system was developed to rapidly obtain dense
      chlororespiring cultures of Anaeromyxobacter dehalogenans strain 2CP-C. A syringe
      pump continuously delivered concentrated 2,6-dichlorophenol (50-150 mM) to an
      anaerobic reactor vessel at a rate that sustained linear growth but prevented the
      substrate toxicity of chlorophenol. Dechlorination was not significantly
      inhibited by end product phenol up to 8 mM. A cell density of 76.8 mg protein l(
      1) was obtained in 24 h. Specific growth rates averaged 0.033 h(-1)at 50%
      substrate limitation, which was in agreement with the maximum specific growth
      rate of 0.068 h(-1). This reactor system provides an efficient, cost-effective,
      and convenient method to rapidly obtain dense dechlorinating biomass and is
      promising to accelerate investigations of enzymes involved in chlororespiration.

PMID- 15179528
TI  - Lactate production in an integrated process configuration: reducing cell
      adsorption by shielding of adsorbent.
AB  - The problem of binding of microbial cells to an adsorbent matrix during in situ
      recovery of bioproducts from a fermentation broth has been addressed by shielding
      the adsorbent with a thin layer of a non-ionic polymer. Extractive bioconversion
      of lactic acid by integrating ion-exchange adsorption with the fermentation stage
      was studied. The effect of coating of the ion-exchanger with agarose on product
      recovery and cell adsorption was evaluated. Extractive fermentation with both
      uncoated and coated resin resulted in an increase in reactor productivity as
      compared to the normal fermentation. The free cell density in the system with
      agarose-coated beads was similar to that in control fermentation, but was
      significantly lower in the system with the uncoated ion-exchanger. Electron
      microscopic scanning of the bead surface after passage of the fermentation broth
      showed cells attached to the native adsorbent but not to the coated one.

PMID- 15179529
TI  - Engineered biosynthesis of 16-membered macrolides that require methoxymalonyl-ACP
      precursors in Streptomyces fradiae.
AB  - Development of host microorganisms for heterologous expression of polyketide
      synthases (PKS) that possess the intrinsic capacity to overproduce polyketides
      with a broad spectrum of precursors supports the current demand for new tools to
      create novel chemical structures by combinatorial engineering of modular and
      other classes of PKS. Streptomyces fradiae is an ideal host for development of
      generic polyketide-overproducing strains because it contains three of the most
      common precursors--malonyl-CoA, methylmalonyl-CoA and ethylmalonyl-CoA--used by
      modular PKS, and is a host that is amenable to genetic manipulation. We have
      expanded the utility of an overproducing S. fradiae strain for engineered
      biosynthesis of polyketides by engineering a biosynthetic pathway for
      methoxymalonyl-ACP, a fourth precursor used by many 16-membered macrolide PKS.
      This was achieved by introducing a set of five genes, fkbG-K from Streptomyces
      hygroscopicus, putatively encoding the methoxymalonyl-ACP biosynthetic pathway,
      into the S. fradiae chromosome. Heterologous expression of the midecamycin PKS
      genes in this strain resulted in 1 g/l production of a midecamycin analog. These
      results confirm the ability to engineer unusual precursor pathways to support
      high levels of polyketide production, and validate the use of S. fradiae for
      overproduction of 16-membered macrolides derived from heterologous PKS that
      require a broad range of precursors.

PMID- 15179530
TI  - Metal release in metallothioneins induced by nitric oxide: X-ray absorption
      spectroscopy study.
AB  - Metallothioneins (MTs) are low molecular weight proteins that include metal ions
      in thiolate clusters. The capability of metallothioneins to bind different metals
      has suggested their use as biosensors for different elements. We study here the
      interaction of nitric oxide with rat liver MTs by using in situ X-ray absorption
      spectroscopy techniques. We univocally show that the presence of NO induces the
      release of Zn atoms from the MT structure to the solution. Zn ions transform in
      the presence of NO from a tetrahedral four-fold coordinated environment in the MT
      into a regular octahedral six-fold coordinated state, with interatomic distances
      compatible with those of Zn solvated in water.

PMID- 15179531
TI  - Cerebellar white matter involvement in Salla disease.

PMID- 15179532
TI  - Virtopsy post-mortem multi-slice computed tomography (MSCT) and magnetic
      resonance imaging (MRI) demonstrating descending tonsillar herniation: comparison
      to clinical studies.
AB  - Descending cerebellar tonsillar herniation is a serious and common complication
      of intracranial mass lesions. We documented three cases of fatal blunt head
      injury using post-mortem multi-slice computed tomography (MSCT) and magnetic
      resonance imaging (MRI). The results showed massive bone and soft-tissue injuries
      of the head and signs of high intracranial pressure with herniation of the
      cerebellar tonsils. The diagnosis of tonsillar herniation by post-mortem
      radiological examination was performed prior to autopsy. This paper describes the
      detailed retrospective evaluation of the position of the cerebellar tonsils in
      post-mortem imaging in comparison to clinical studies.

PMID- 15179533
TI  - Study of traffic pollution by metals in Seville (Spain) by physical and chemical
      speciation methods.
AB  - Eighty-three samples of atmospheric particles were collected at a representative
      traffic site in the Mediterranean city of Seville during a period of one year.
      Urban particles were collected on quartz filters with a high-volume sampler
      coupled with a cascade impactor which separates particles into six size ranges:
      >10, 10-4.9, 4.9-2.7, 2.7-1.3, 1.3-0.6, and <0.6 microm. The total metal content,
      its distribution by size (physical speciation), and the concentrations of
      different chemical forms (chemical speciation) in particles less than 0.6 microm
      were determined. The chemical speciation scheme furnished four fractions: soluble
      and exchangeable metals; carbonates, oxides, and reducible metals; oxidisable and
      sulfidic metals bound to organic matter; and residual metals. The samples were
      analysed by ICP-OES for Pb, Ni, Cd, S, Fe, Zn, Cu, Ba, Mn, and V. Gaseous
      pollutants, traffic intensities, and primary meteorological data provided by the
      atmospheric and traffic networks were statistically related to the analytical
      data. Analytical and statistical results from physical and chemical speciation
      singled out Ba as a valid tracer of vehicular traffic, instead of Pb, in cities
      with high traffic density. Another important relationship was found between Pb
      and Cu. Physical speciation of lead showed that the major risk for health was
      from fine particles less than 2.7 microm, because particles between 2.7 and 0.6
      microm were the size fractions of the total suspended particles with the major
      mass abundance of lead (mainly particles between 2.7 and 1.3 microm) and because
      particles less than 0.6 microm were the fraction of airborne particles most
      abundant in the urban air. Chemical speciation results showed that special
      attention must be taken with Ni and Cd concentrations, because of their high
      potential bioavailability, mainly a result of the high solubility of the chemical
      forms of Ni in the finest particles.

PMID- 15179534
TI  - Silica-nanoparticle-based interface for the enhanced immobilization and sequence
      specific detection of DNA.
AB  - A biocompatible and uniform interface based on silica nanoparticles derivatized
      with amino groups has been constructed for the effective immobilization and
      sensitive sequence-specific detection of calf thymus DNA. Atomic force microscopy
      (AFM) and scanning electron microscopy (SEM) results showed that a monolayer of
      silica nanoparticles can be formed on a gold electrode under our experimental
      conditions using cysteine self-assembly monolayer as binder medium.
      Electrochemical impedance spectroscopy and X-ray photoelectron spectroscopy (XPS)
      verified the successful immobilization of DNA on silica-nanoparticle-modified
      gold electrodes. Quantitative results demonstrated that enhanced immobilization
      of single-strand DNA (ss-DNA) up to 1.6 x 10(-8) mol cm(-2) could be achieved
      owing to the larger surface area and the special properties of silica
      nanoparticles. In addition, hybridization experiments demonstrated that the
      immobilized ss-DNA on silica nanoparticles could specifically interact with
      complementary DNA in solutions.

PMID- 15179535
TI  - Preconcentration of copper, cadmium, and lead with a
      thiacalix[4]arenetetrasulfonate-loaded Sephadex A-25 anion-exchanger for graphite
      furnace atomic-absorption spectrometry.
AB  - A rapid column-adsorption method has been developed for concentrating traces of
      copper, cadmium, and lead in water prior to their determinations by graphite
      furnace atomic-absorption spectrometry. The adsorbent used was prepared by
      loading a strongly basic anion-exchanger QAE-Sephadex A-25 (50 mg) with
      thiacalix[4]arenetetrasulfonate (20 micromol). Two-hundredfold preconcentration
      of the analyte elements was achieved by passing 100 mL of sample solution (pH
      8.0) through a column packed with the adsorbent (6 mm i.d. x 7 mm high) at a flow
      rate of 10 mL min(-1) and by the subsequent elution with 500 microL of aqueous
      nitric acid solution (1 mol L(-1)). The practical applicability of the proposed
      method was evaluated by analyzing certified reference seawater samples.

PMID- 15179536
TI  - Standardless PIXE analysis of thick biomineral structures.
AB  - The particle-induced X-ray emission (PIXE) of thick biomineral targets provides
      pertinent surface analysis, but if good reference materials are missing then
      complementary approaches are required to handle the matrix effects. This is
      illustrated by our results from qualitative and semiquantitative analysis of
      biomaterials and calcified tissues in which PIXE usually detected up to 20
      elements with Z > 14 per sample, many at trace levels. Relative concentrations
      allow the classification of dental composites according to the mean Z and by
      multivariate statistics. In femur bones from streptozotocin-induced diabetic
      rats, trace element changes showed high individual variability but correlated to
      each other, and multivariate statistics improved discrimination of abnormal
      pathology. Changes on the in vitro demineralization of dental enamel suggested
      that a dissolution of Ca compounds in the outermost layer results in the
      uncovering of deeper layers containing higher trace element levels. Thus, in
      spite of significant limitations, standardless PIXE analysis of thick biomineral
      samples together with proper additional procedures can provide relevant
      information in biomedical research.

PMID- 15179537
TI  - Ion-beam analysis of CuInSe2 solar cells deposited on polyimide foil.
AB  - CuInSe(2) (CIS) solar cells deposited on polyimide foil by the Solarion company
      in a web-coater-based process using sputter and evaporation techniques were
      investigated in the ion beam laboratory LIPSION of the University of Leipzig by
      means of Rutherford backscattering spectrometry (RBS) and particle-induced X-ray
      emission (PIXE) using high-energy broad ion beams and microbeams. From these
      measurements the composition of the absorber and the lateral homogeneity and film
      thicknesses of the individual layers could be determined on the basis of some
      reasonable assumptions. For the first time, quantitative depth profiling of the
      individual elements was performed by microPIXE measurements on a beveled section
      prepared by ion-beam etching of a CIS solar cell. Within the CIS absorber layer
      no significant concentration-depth gradients were found for Cu, In, and Se, in
      contrast with results from secondary neutral mass spectrometry (SNMS) depth
      profiling, which was applied to the same samples for comparison. Furthermore,
      both PIXE and SNMS showed the presence of a remarkable amount of Cd from the CdS
      buffer layer in the underlying absorber.

PMID- 15179538
TI  - Academia: in the ivory tower, surrounded by ivy-covered walls.

PMID- 15179539
TI  - Superheated water extraction, steam distillation and Soxhlet extraction of
      essential oils of Origanum onites.
AB  - Superheated water extraction (SWE) at various temperatures (100, 125, 150 and 175
      degrees C), steam distillation, and Soxhlet extraction were compared in the
      extraction of essential oils from two samples of the plant Origanum onites, one
      cultivated, the other wild. C18 solid-phase extraction was used to elute the
      essential oils from the SWE aqueous extract. The compositions of the extracted
      essential oils obtained from all three methods were then characterized by
      comprehensive GCxGC/time-of-flight mass spectrometry (TOF/MS). The highest
      essential oil yields were obtained by using SWE at 150 degrees C with a flow rate
      of 2 mL min(-1) and a pressure of 60 bar for 30 min: these were 3.76 and 4.11%
      for wild and cultivated O. onites samples, respectively, expressed as a
      percentage of 100 g of dry (leaf) matter. The yields obtained using SWE at 150
      degrees C were slightly higher than those from conventional methods. Steam
      distillation was performed for 3 h, and Soxhlet extraction was completed in 12 h.
      The major compounds found were borneol, terpinen-4-ol and carvacrol.

PMID- 15179540
TI  - Effects of pharmacological doses of 2-deoxyglucose on plasma catecholamines and
      glucose levels in patients with schizophrenia.
AB  - RATIONALE: Several lines of evidence suggest that the pathophysiology of
      schizophrenia may be associated with altered noradrenergic and glucoregulatory
      function. OBJECTIVE: The aim of this study was to investigate these alterations
      during a perturbed homeostatic state. METHODS: Fifteen patients with
      schizophrenia and 13 healthy individuals were given a glucose deprivation
      challenge through administration of pharmacological doses of 2-deoxyglucose (2DG;
      40 mg/kg), and their plasma was assayed over the next 60 min for concentrations
      of norepinephrine (NE), the intraneuronal NE metabolite dihydroxyphenylglycol
      (DHPG), epinephrine and glucose. RESULTS: 2DG induced significant increases in
      plasma NE, epinephrine and glucose levels in both groups with significantly
      greater NE and glucose increments in patients than in controls. For DHPG, 2DG
      produced increases in patients and decreases in the control subjects. NE
      responses correlated positively and significantly with the DHPG and glucose
      responses in schizophrenics, but not in controls. CONCLUSIONS: These findings
      suggest that patients with schizophrenia have exaggerated NE and glucose
      responses to an acute metabolic perturbation.

PMID- 15179541
TI  - Chronic low dose risperidone and clozapine alleviate positive but not negative
      symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia.
AB  - RATIONALE: The rat neonatal ventral hippocampal (VH) ibotenic lesion model has
      been proposed as a developmental model of schizophrenia, based on evidence that
      it encompasses aspects of the disorder including psychomotor agitation
      (hyperactivity), deficits in prepulse inhibition (PPI), and deficits in social
      interaction (SI), measures presumed to reflect positive symptoms, sensory gating
      deficits and negative symptoms, respectively. However, validation of the model as
      a predictive pharmacological screening tool has been minimal. OBJECTIVE:
      Determine the effects of a chronic 3-week low dose treatment of clozapine or
      risperidone on locomotor hyperactivity, PPI and SI in lesioned and control rats.
      RESULTS: Both clozapine, 2.5 mg/kg per day IP and risperidone, 0.1 mg/kg per day
      IP, reversed lesion-induced locomotor hyperactivity; however, the compounds also
      decreased locomotor activity in the non-lesioned controls. Clozapine 2.5 mg/kg
      per day and risperidone 0.1 mg/kg per day significantly attenuated lesion-induced
      PPI deficits. Neither compound induced a significant attenuation of lesion
      induced SI deficits. In order to see if SI deficits required a higher dose of an
      antipsychotic, the dose of clozapine was increased to 4 mg/kg per day; however
      this dose induced such marked decreases in the activity and startle responses in
      the control rats, i.e. up to 74% decrease, that the effects on the lesioned rats
      could not be adequately interpreted. CONCLUSIONS: These data add further support
      to the neonatal VH lesion model as a predictive pharmacological screening assay
      for identifying compounds effective in the treatment of positive symptoms of
      schizophrenia. However, the usefulness of the model in detecting compounds
      effective in treating negative symptoms of schizophrenia is still in question.

PMID- 15179542
TI  - Evaluation of the mood and physical symptoms scale (MPSS) to assess cigarette
      withdrawal.
AB  - RATIONALE: The mood and physical symptoms scale (MPSS) was developed in the early
      1980s to assess cigarette withdrawal symptoms, and variants of it have been used
      for 20 years. To date, no paper has been published on the properties of the
      scale. OBJECTIVES: To evaluate psychometric properties of MPSS and the
      interrelationship between the key tobacco withdrawal symptoms. METHODS: The core
      elements of the MPSS involve 5-point ratings of depressed mood, irritability,
      restlessness, difficulty concentrating and hunger and 6-point ratings of strength
      of urges to smoke and time spent with these urges. The data set chosen for
      analysis was well suited to the task in that it involved a relatively large
      sample, abstinence was defined as "not a puff" for 24 h biochemically verified,
      participants were not using any medication that would have reduced withdrawal
      discomfort (e.show $132#g. nicotine patch), the abstinence rate was very high
      resulting in minimal bias due to attrition, and ratings were provided on three
      occasions prior to abstinence. The study involved 111 smokers setting a target
      quit date of whom 106 attempted abstinence and 96 achieved it. RESULTS: The MPSS
      items were stable prior to abstinence and sensitive to abstinence. Post
      abstinence increases in mood and physical symptoms demonstrated a high level of
      internal coherence. Ratings of urges to smoke correlated highly with changes in
      mood and other symptoms. Ratings of hunger correlated less well with the scale as
      a whole and may involve some distinct processes. CONCLUSIONS: The MPSS meets the
      key requirements of a cigarette withdrawal scale. Although urge to smoke/craving
      was not included in the list of DSM-IV withdrawal symptoms, it should be regarded
      as forming part of the withdrawal syndrome.

PMID- 15179543
TI  - Prediction of changes in memory performance by plasma homovanillic acid levels in
      clozapine-treated patients with schizophrenia.
AB  - RATIONALE: Cognitive dysfunction in schizophrenia has been demonstrated to be
      dependent, in part, on dopaminergic activity. Clozapine has been found to improve
      some domains of cognition, including verbal memory, in patients with
      schizophrenia. OBJECTIVES: This study tested the hypothesis that plasma
      homovanillic acid (pHVA) levels, a peripheral measure of central dopaminergic
      activity, would predict the change in memory performance in patients with
      schizophrenia treated with clozapine. METHODS: Twenty-seven male patients with
      schizophrenia received clozapine treatment for 6 weeks. Verbal list learning
      (VLL)-Delayed Recall (VLL-DR), a test of secondary verbal memory, was
      administered before and after clozapine treatment. Blood samples to measure pHVA
      levels were collected at baseline. RESULTS: Baseline pHVA levels were negatively
      correlated with change in performance on VLL-DR; the lower baseline pHVA level
      was associated with greater improvement in performance on VLL-DR during treatment
      with clozapine. Baseline pHVA levels in subjects who showed improvement in verbal
      memory during clozapine treatment ( n=13) were significantly lower than those in
      subjects whose memory performance did not improve ( n=14). CONCLUSIONS: The
      results of this study indicate that baseline pHVA levels predict the ability of
      clozapine to improve memory performance in patients with schizophrenia.

PMID- 15179544
TI  - Four days of citalopram increase suppression of cortisol secretion by
      prednisolone in healthy volunteers.
AB  - RATIONALE: Chronic antidepressant treatment increases glucocorticoid-mediated
      negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, and thus
      reduces HPA axis activity, in depressed patients and healthy controls. In
      contrast, acute antidepressant treatment induces an activation of basal HPA axis
      activity. OBJECTIVES: We examined the effects of 4 days of treatment with the
      selective serotonin reuptake inhibitor, citalopram, on basal salivary cortisol
      and on suppression of salivary cortisol by prednisolone. METHODS: We used a
      single-blind, placebo-controlled, repeated-measure design. Salivary cortisol was
      measured from 0900 to 1700 hours. In the first phase of the study, basal salivary
      cortisol secretion was measured on 2 study days, before and after 4 days of
      treatment with citalopram (orally, 20 mg/day). In the second phase, salivary
      cortisol secretion after suppression by prednisolone (5 mg, given at 2200 hours
      the night before) was measured on 2 study days, again before and after 4 days of
      treatment with citalopram (orally, 20 mg/day). Eight volunteers participated to
      the study. RESULTS: Citalopram increased basal salivary cortisol in the morning
      (0900-1100 hours) by approximately 47% (P=0.003). Moreover, citalopram increased
      suppression by prednisolone in the morning (0900-1100 hours): suppression was
      approximately 22% before citalopram and 45% after citalopram (P=0.05).
      CONCLUSIONS: Citalopram increases glucocorticoid-mediated negative feedback on
      the HPA axis after as little as 4 days of treatment. This effect could be due to
      an increased function of the corticosteroid receptors. Our findings further
      support the notion that one of the mechanisms by which antidepressants exert
      their therapeutic effects is by normalizing HPA axis hyperactivity in depressed
      patients.

PMID- 15179545
TI  - GHB ameliorates naloxone-induced conditioned place aversion and physical aspects
      of morphine withdrawal in mice.
AB  - RATIONALE: Gamma-hydroxybutyric acid (GHB) is a naturally occurring substance in
      the brain, the administration of which has proved useful in the treatment of the
      opiate withdrawal symptoms in humans. OBJECTIVES: The aim of the present work was
      to validate this beneficial effect on the physical and motivational aspects of
      morphine withdrawal in mice. METHODS: In a first experiment, animals rendered
      morphine-dependent were conditioned to develop a place aversion (CPA) to the
      compartment paired with naloxone administration in a two-chamber apparatus. The
      conditioning phase consisted of three pairings of either naloxone (0.250 mg/kg)
      or vehicle in one compartment, both with similar time allotments during the
      preconditioning test. During the testing phase, mice were again allowed to
      explore the entire apparatus. GHB (6, 12.5, 25, and 50 mg/kg) was administered
      during either the acquisition or expression phase of this conditioning. In a
      second experiment, the capacity of GHB to ameliorate the intensity of physical
      signs of morphine withdrawal was evaluated. RESULTS: GHB blocked CPA in both
      phases: administered during acquisition (from 12.5 mg/kg and higher) as well as
      in the expression phase (from 6 mg/kg, except for 25 mg/kg). It also decreased
      the intensity of physical signs of morphine withdrawal to near control levels
      measured by the modified Gellert-Holtzman scale (25 mg/kg and higher). Decreases
      in jumping, body shakes, and paw tremor were also observed. CONCLUSIONS: Our
      results support the idea that GHB ameliorates both aspects of morphine
      withdrawal, physical as well as motivational signs.

PMID- 15179547
TI  - The effect of allo-injury in an in vitro model of allograft microvasculature.
AB  - Endothelial cells are critical to the integrity of allograft vasculature and can
      be damaged by alloreactive T cells or soluble mediators of alloreactivity. The
      biochemical effects of T cell-mediated damage to the endothelial cells have been
      studied, but not the structural and morphological effects of allo-injury on
      endothelial cells in the allograft. We utilized an assay that reproduces
      microvasculature in vitro to study the effect of alloreactivity on endothelial
      cells. In this assay, endothelial cells are induced into capillary-like networks
      that simulate microvascular capillaries. We studied the effect of allogeneic T
      cells and of soluble mediators from both mixed lymphocyte cultures (MLCs) and
      rejected heart allograft tissue on the in vitro capillaries. We found that both
      allogeneic T cells and soluble mediators inhibit the formation of the in vitro
      endothelial capillaries, suggesting that they cause a mild-to-moderate
      dysfunction of the endothelial cells. The inhibitory effect of the soluble
      mediators seems to be mediated, at least partly, by IFN-gamma, since this effect
      was prevented by antibody to IFN-gamma. Furthermore, pre-incubation of the in
      vitro capillaries with IFN-gamma appeared to magnify the effect of allogeneic T
      cells, as shown by a complete breakdown of well-formed in vitro capillary
      networks. Our experiments suggest that the in vitro capillary-tube model reflects
      structural injury to allograft vasculature by alloreactive T cells and their
      soluble mediators.

PMID- 15179546
TI  - Inhibition of the morphine-induced rewarding effect by direct activation of
      spinal protein kinase C in mice.
AB  - RATIONALE: We previously demonstrated that the morphine-induced rewarding effect
      was attenuated under a neuropathic pain-like state following partial sciatic
      nerve ligation in rodents. Furthermore, the up-regulation of protein kinase C
      (PKC) activity in the spinal cord is considered to be the key factor for
      induction of hyperalgesia following sciatic nerve ligation. However, little
      direct evidence is available for the involvement of activated PKC in the spinal
      cord in reduction of rewarding effects induced by morphine under chronic pain
      like state. OBJECTIVE: The present study was to investigate whether direct
      activation of spinal PKC by intrathecal (IT) administration of a specific PKC
      activator, phorbol 12,13-dibutyrate (PDBu) could produce hyperalgesia and
      suppress the place preference induced by morphine in mice. METHOD: The morphine
      induced rewarding effect was investigated using the conditioned place preference
      method. Conditioning sessions (three for morphine, three for saline) were started
      24 h after IT injection of PDBu or saline and conducted once daily for 6 days. On
      the day after the final conditioning session, a post-conditioning test was
      performed. RESULTS: IT-administered PDBu produced a long-lasting thermal
      hyperalgesia. Under these conditions, the place preference induced by morphine
      was abolished by a single IT pretreatment with PDBu. The effect was reversed by
      concomitant IT treatment with the specific PKC inhibitor Ro-32-0432. In contrast,
      IT-administered PDBu failed to affect the hyperlocomotion and supraspinal
      antinociception induced by morphine. CONCLUSION: The present findings suggest
      that activated PKC in the spinal cord with chronic pain-like hyperalgesia may
      play a substantial role in the suppression of the morphine-induced rewarding
      effect in mice with chronic pain-like hyperalgesia.

PMID- 15179548
TI  - [A synopsis of medication for degenerative osteoarthritis].
AB  - Drug treatment options should be used before starting operative procedures for
      degenerative osteoarthritis. The directed use of drugs helps to convert activate
      arthritis to the asymptomatic phase. This article summarizes guidelines and gives
      an overview of the effects and problems.

PMID- 15179549
TI  - QTL controlling root and shoot traits of maize seedlings under cold stress.
AB  - The improvement of early vigour is crucial for the adaptation of maize (Zea mays
      L.) to the climatic conditions of central Europe and the northern Mediterranean,
      where early sowing is an important strategy for avoiding the effect of summer
      drought. The objectives of this study were to identify quantitative trait loci
      (QTL) controlling cold-related traits and to investigate the relationships among
      them. A set of 168 F2:4 families of the Lo964 x Lo1016 cross was grown in a sand
      vermiculite substrate at 15/13 degrees C (day/night) until the one-leaf stage.
      Twenty QTL were identified for the four shoot and two seed traits examined.
      Analysis of root weight and digital measurements of the length and diameter of
      primary and seminal roots led to the identification of 40 QTL. The operating
      efficiency of photosystem II (PhiPSII) was related to seedling dry weight at both
      the phenotypic and genetic level (r = 0.46, two matching loci, respectively) but
      was not related to root traits. Cluster analysis and QTL association revealed
      that the different root traits were largely independently inherited and that root
      lengths and diameters were mostly negatively correlated. The major QTL for root
      traits detected in an earlier study in hydroponics were confirmed in this study.
      The length of the primary lateral roots was negatively associated with the
      germination index (r = -0.38, two matching loci). Therefore, we found a large
      number of independently inherited loci suitable for the improvement of early
      seedling growth through better seed vigour and/or a higher rate of
      photosynthesis.

PMID- 15179550
TI  - Prognostic factors in renal cell carcinoma.

PMID- 15179552
TI  - The cellular and molecular basis of natural antitumor immunity in renal cell
      carcinoma patients.

PMID- 15179551
TI  - Prediction of site-specific metastases in surgically treated nonmetastatic renal
      cell cancer. Changes of follow-up protocol.

PMID- 15179554
TI  - Target-specific therapy requires target-specific populations in the treatment of
      renal cell carcinoma.

PMID- 15179553
TI  - Therapeutic approaches in metastatic renal cell carcinoma: local immunotherapy.
AB  - Since 1990, aerosol interleukin (IL)-2 has been used to treat pulmonary
      metastatic renal cell carcinoma (pmRCC). Inhalation therapy deposits a drug into
      the airways to achieve a high, local, clinical effect while avoiding serious
      systemic side effects. We report three studies to describe safety and efficacy of
      aerosol IL-2 in patients with pmRCC. In a multicenter study, 24 patients received
      exclusive inhalation (study I) of natural IL-2 (three dose levels, 48 weeks) and
      response and toxicity were evaluated. The survival of high-risk patients (study
      II) with mainly inhaled IL-2 (n=94) was compared with that of patients receiving
      systemic IL-2 (n=103). In ten patients we analyzed in detail lung function and
      markers of airway inflammation before and during inhalational IL-2 therapy (study
      III). Study I: The response of exclusive inhalation was 33.3% at 3 months and
      16.7% at 6 months. Treatment was well tolerated, cough being the most frequent
      adverse event. Study II: The probabilities of survival at 5 years were 21% for
      the inhalational group and 0% for the systemic group. Study III: Inhaled IL-2
      induced a moderate decline of forced expiratory volume (FEV), while exhaled
      nitric oxide (NO) and sputum eosinophils rose accompanied by moderate cough and
      dyspnea. In conclusion, inhalational IL-2 combines good efficacy and improves
      tolerability. This is especially important for patients who are not able to
      benefit from systemic IL-2 therapy. Whether the local eosinophilic response
      additionally supports the antitumor effect remains a challenging question.

PMID- 15179555
TI  - [Evaluation of costs incurred for patients with multiple trauma particularly from
      the perspective of the hospital].
AB  - The aim of this study was to evaluate the costs involved in treating severely
      injured patients at the clinic differentiated by several characteristics (injury,
      age), sectors (emergency room, surgery, intensive and normal care), and kinds of
      costs (fixed costs, variable costs) and to determine influencing factors
      regarding costs based on the register of the DGU (Deutsche Gesellschaft fur
      Unfallchirurgie). All patients were taken into account who had an injury severity
      score (ISS) of at least 16. On this basis costs of 3702 patients were analyzed.
      They were compared by using analysis of variance for different groups of patients
      classified according to kind of injury, severity of injury, and age. Moreover,
      multiple regression was performed to control the common influence of demographic
      factors and the type of injury on costs. The average ISS of the analyzed patients
      was 30.6 (+/-11.6) points. The average costs of the clinic were 32,166 (+/
      25,404) EUR per patient. More than half of the costs was incurred by intensive
      care and about one-fourth by surgery. On average 30.6% were variable costs and
      69.4% were fixed costs. The analysis of variance revealed that costs increased
      with advancing age and severity of injury (ISS). Multiple regression confirmed
      these interrelations indicating that extremities are very cost intensive. Due to
      the high portion of fixed costs, the overall costs strongly depend on the
      capacity utilization and less on hospital stay. That is why it may be necessary
      in the future to create centers for trauma care to maintain economic efficiency
      for treatment of these patients. Besides large differences of costs within
      closely defined groups of patients, hospitals carry a high economic risk so that
      a more complex reimbursement system should be discussed than implemented by the
      German DRGs.

PMID- 15179556
TI  - ["Shrinkage of cruciate ligaments"--a biomechanical study. Shrinkage of elongated
      cruciate ligaments using an application of radiofrequency energy].
AB  - The aim of this study was to evaluate structural properties of native and
      elongated bovine anterior cruciate ligaments after the application of bipolar
      radiofrequency. Using a material testing machine typical load-elongation curves
      were used to determine the initial strength of untreated (group 1, n = 20) and
      elongated cruciate ligaments (group 2, n = 20) after treatment with bipolar
      radiofrequency (ArthroCare). After the application of a cyclic loading protocol
      (1000 x 400 N) elongation, yield load, maximal load, and stiffness were
      determined. Native ligaments served as a control group (group 3, n = 20). In both
      groups 4 mm reduction in length was caused by the application of radiofrequency.
      Elongation was significantly higher; yield load, maximal load, and stiffness of
      cruciate ligaments treated with radiofrequency (groups 1 and 2) were
      significantly reduced after the application of a cyclic loading protocol in
      comparison to the control group (p < 0.05). Group 2 ligaments showed the lowest
      values. The application of radiofrequency weakens the biomechanical properties of
      native and elongated cruciate ligaments significantly. When radiofrequency energy
      is used to shrink elongated cruciate ligaments, a nonaggressive rehabilitation
      protocol should be applied.

PMID- 15179558
TI  - Use of leaves to inspect ectoparasites in wild chimpanzees: a third cultural
      variant?
AB  - We report 26 cases of using leaves as tools with which wild chimpanzees (Pan
      troglodytes schweinfurthii) in the Sonso community, Budongo Forest, Uganda,
      appeared to inspect objects removed during grooming. Careful removal of potential
      ectoparasites and delicate lip or manual placement on leaves followed by intense
      visual examination characterised this behaviour. It appears to be done to judge
      whether either ingestion or discarding is most appropriate, the former occurring
      in most cases. This behaviour may represent a third variant of ectoparasite
      handling, different from those described at Tai and Gombe, yet sharing features
      with the latter. These two East African techniques may thus have evolved from
      leaf grooming.

PMID- 15179557
TI  - Behavioral and cardiophysiological responses of common marmosets (Callithrix
      jacchus) to confrontations with opposite-sexed strangers.
AB  - Common marmosets exhibit under captive conditions socially monogamous
      propensities. During confrontation with opposite-sexed stranger, in the presence
      of the pairmate, common marmosets often respond aggressively. However, in the
      absence of their mates, males actively solicit contact and even sexual
      interactions with strange females whereas mated females are indifferent to
      strange males. In the present study behavioral and cardiophysiological responses
      of pairmates of six established pairs of common marmosets were recorded during
      confrontation with an opposite-sexed stranger (1) in the presence or (2) in the
      absence of the familiar pairmate. Systolic and diastolic blood pressure, heart
      rate as well as locomotor activity were recorded telemetrically through
      peritoneally implanted transmitters. Behavioral responses were videotaped and in
      addition, urine samples from the female individuals were analyzed for their
      estrogen concentrations to monitor their ovarian cycles. The cardiophysiological
      values did not differ significantly between the two confrontation conditions.
      However, compared to baseline, heart rate values of both sexes and in males also
      blood pressure values, were significantly higher during confrontations. Hence,
      confrontations with an opposite-sexed conspecific clearly affect
      cardiophysiological parameters. Between confrontees affiliative behaviors could
      not been recorded but aggressive and sexual behaviors occurred.

PMID- 15179559
TI  - Down-regulation of Bcl-2 in the fetal brain of the Gaucher disease mouse model: a
      possible role in the neuronal loss.
AB  - Gaucher disease is a lysosomal storage disorder resulting from an inborn
      deficiency of glucocerebrosidase. To investigate the genes responsible for the
      neuronal symptoms of Gaucher disease, gene expression profiles were analyzed in
      brains of the Gaucher disease mouse model using a cDNA microarray, and it was
      found that the bcl-2 gene is down-regulated. Immunoblotting and apoptosis assay
      were performed to study the relationship between the decreased expression of Bcl
      2 and neuronal death on the brains of Gaucher mice fetuses at embryonic day 17.5
      (E17.5) and E19.5. Decreased expression of Bcl-2 was observed in the brain stem
      and cerebellum but not in cortex by immunoblotting. In situ labeling of DNA
      fragmentation using terminal transferase-mediated dUTP nick-end-labeling (TUNEL)
      assay confirmed that apoptosis occurred in the brain stem and cerebellum. More
      apoptotic cells were detected in the brains of Gaucher mice fetuses at E19.5 than
      at E17.5. These results suggest that the accumulation of either glucocerebroside
      or glucosylsphingosine, as a result of glucocerebrosidase deficiency, affects
      gene expression and could be responsible for neuronal cell death.

PMID- 15179560
TI  - Association between genetic variation in the gene for death-associated protein-3
      (DAP3) and adult asthma.
AB  - Lung epithelium plays a central role in modulation of the lung inflammatory
      response, and lung repair and airway epithelial cells are targets in asthma and
      viral infection. Activated T lymphocytes release cytokines such as interferon
      gamma (IFN-gamma) that induce apoptosis, or programmed cell death, of damaged
      epithelial cells. Death-associated protein-3 (DAP3) is involved in mediating IFN
      gamma-induced cell death. To assess the possible involvement of genetic variants
      of DAP3 with asthma, we searched for single-nucleotide polymorphisms (SNPs) in
      the gene and conducted a case-control study with 1,341 subjects. We found a
      strong association between bronchial asthma (BA) in adults (P=0.0051, odds
      ratio=1.87, 95% CI=1.20-2.92), whereas no association was found with childhood
      asthma. The tendency was more prominent in patients with higher serum total
      immunoglobulin E (IgE) (>250 IU/ml) (P=0.00061, odds ratio=2.40, 95% CI=1.44
      4.00). DAP3 was expressed in normal bronchial epithelial cells, and the
      expression was induced by IFN-gamma. These results indicated that specific
      variants of the DAP3 gene might be associated with the mechanisms responsible for
      adult BA and contribute to airway inflammation and remodeling.

PMID- 15179561
TI  - Efficacy of stabilization splints for the management of patients with masticatory
      muscle pain: a qualitative systematic review.
AB  - This study aimed at providing an answer to two clinical questions related to
      patients with masticatory muscle pain: 1) Does the use of a full-coverage hard
      acrylic occlusal appliance (stabilization splint) lead to a significant decrease
      of symptoms? and 2) Is the treatment success achieved with a stabilization splint
      more pronounced than the success attained with other forms of treatment
      (including placebo treatment) or no treatment? A systematic search was carried
      out in different electronic databases, supplemented by handsearch in four
      selected dental journals and by examination of the bibliographies of the
      retrieved articles. Thirteen publications, representing nine controlled clinical
      studies, could be identified. Reporting quality of most studies as assessed with
      the Jadad score ranged from 1 to 5. Based on the currently best available
      evidence it appears that most patients with masticatory muscle pain are helped by
      the incorporation of a stabilization splint. Nevertheless, evidence is equivocal
      if improvement of pain symptoms after incorporation of the intraoral appliance is
      caused by a specific effect of the appliance. A stabilization splint does not
      appear to yield a better clinical outcome than a soft splint, a non-occluding
      palatal splint, physical therapy, or body acupuncture. The scarcity of current
      external evidence emphasizes the need for more and better clinical research.

PMID- 15179562
TI  - Decreased taste sensitivity in cancer patients under chemotherapy.
AB  - GOALS OF WORK: The aim of the study was to measure taste thresholds among cancer
      patients under chemotherapy compared to controls. PATIENTS AND METHODS: The study
      was performed with 110 cancer patients and 170 healthy subjects of similar age
      distribution were included in the study. The electrogustometric detection
      threshold was evaluated as the lowest current intensity perceived by the subject
      in three tongue sites independently with a constant current generator. MAIN
      RESULTS: Taste thresholds for all cancer patients demonstrated significantly
      higher values compared to controls. CONCLUSIONS: Cancer patients treated by
      chemotherapy demonstrated a temporary taste sensitivity deficit. Associated with
      the illness due to the treatment, this deficit explains the patients complaining
      of "abnormal or bad tastes", which results in food aversion and has a negative
      impact on nutritional status and quality of life. In order to prevent the risk of
      anorexia and the enhanced morbidity related to this deficit, treatment should
      include relevant information to the subject for anticipating objective taste
      modifications and a psychological follow-up during the actual change of taste
      quality perceptions in everyday life.

PMID- 15179563
TI  - Quality of life of survivors of testicular germ cell cancer: a review of the
      literature.
AB  - GOALS OF WORK: Testicular cancer (TC) affects young men in the prime of life. The
      excellent prognosis and an increasing incidence have led to a growing number of
      testicular cancer survivors (TCSs). The aim of this review was to summarize and
      discuss research findings on the quality of life (QOL) of TCSs in terms of
      physical, psychological, and social well-being. PATIENTS AND METHODS: Literature
      databases were used to identify studies published between 1980 and 2003. A
      quality assessment using methodological and treatment-related criteria was
      performed to distinguish stronger- from poorer-quality studies. MAIN RESULTS:
      Twenty-three studies met the inclusion criteria. Quality assessment showed that
      seven studies were qualitatively stronger. The majority of TCSs in both stronger
      and poorer quality studies reported a good QOL. Prospective and retrospective
      studies showed that QOL after completion of treatment increased and negative
      consequences of TC on life decreased compared to the situation directly after
      diagnosis. The stronger-quality studies reported mainly on physical and
      psychological well-being but did not examine social well-being and the impact of
      treatment-related characteristics comprehensively. CONCLUSIONS: Both stronger-
      and poorer-quality studies indicate that the majority of TCSs experience a good
      QOL, but the shortcomings on both the methodological and content level prevent us
      from drawing such a conclusion. Additional research with strong designs is needed
      to gain clearer insight into the QOL of TCSs as a group and of individuals at
      risk for physical, psychological, and social problems.

PMID- 15179564
TI  - Prognostic factors of posterior urethral valves and the role of antenatal
      detection.
AB  - The aim of the study was to investigate the significance of different prognostic
      factors and long-term renal outcome in boys with posterior urethral valves (PUVs)
      detected either antenatally or during infancy. A total of 46 cases of PUVs, 23
      antenatal and 23 postnatal, were followed prospectively from 1983 to 2003. The
      mean follow-up time was 12.5 years. The impact of vesicoureteral reflux (VUR),
      urinary tract infections (UTIs), urinary continence, and renal parenchymal damage
      on patient outcome was evaluated. Long-term renal outcome was defined as
      favorable if renal function was either normal or moderately impaired (glomerular
      filtration rate > or = 60 ml/min per 1.73 m(2)) and poor if the patient had
      either chronic renal failure or end-stage renal disease. The outcome was poor in
      14 (30%) of the 46 boys and was associated with a significantly higher nadir
      serum creatinine concentration (mean 157 micromol/l) during the 1st year of life
      ( P<0.001), with bilateral VUR ( P<0.05) and breakthrough UTIs ( P<0.05). In our
      patients, age at achieving urinary continence, and the presence of renal
      parenchymal damage did not have a statistically significant association with long
      term renal outcome. The long-term outcome among boys with antenatally detected
      PUVs did not differ from that among those cases detected postnatally after
      developing symptoms ( P=0.25).

PMID- 15179565
TI  - Rare causes of acute hyperkalemia in the 1st week of life. Three case reports.
AB  - We describe three neonates with hyperkalemia and renal salt wasting during the
      1st week of life. Endocrinological evaluation led to the diagnosis of selective
      hypoaldosteronism (HA) in two neonates and secondary pseudohypoaldosteronism
      (PHA) in one. The infant with PHA developed a urinary tract infection, and
      radiological investigation demonstrated a small dysplastic left kidney with
      vesicoureteral reflux. The electrolyte and hormonal disturbances in this infant
      persisted throughout the first months of life. The two infants with selective HA
      improved rapidly after administration of fludrocortisone orally and the
      electrolytes and renin values returned to normal. Secondary PHA and selective HA
      should be considered in the differential diagnosis in salt-losing neonates during
      the first days of life. Renal ultrasonography, urine culture, and assays of
      aldosterone and plasma renin activity should be performed in any infant
      presenting with hyperkalemia and salt wasting after the exclusion of congenital
      adrenal hyperplasia.

PMID- 15179568
TI  - Snakebite-induced acute renal failure. A case report and review of the
      literature.
AB  - Snakebite is not an uncommon cause of acute renal failure (ARF) in developing
      countries. We report a12-year-old boy who presented with oliguric ARF following
      snakebite. He had pallor, icterus, generalized edema, hypertension, and was
      oliguric. Investigations revealed severe azotemia, microangiopathic hemolytic
      anemia, thrombocytopenia, prolonged coagulation parameters, and raised fibrin
      degradation products, suggesting disseminated intravascular coagulation as the
      cause of ARF. The patient improved with antisnake venom, dialysis, and other
      supportive treatment.

PMID- 15179569
TI  - ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder
      dysfunction.
AB  - The objective of this study was to investigate whether DNA polymorphisms of the
      renin-angiotensin system (RAS) genes were associated with renal scar formation in
      pediatric patients with bladder dysfunction (BD). Although these children are
      born healthy, due to persistence of immature voiding habits and evolution of BD,
      some develop progressive renal damage. It has been suggested that the DD genotype
      of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal
      prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and
      the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were
      identified by polymerase chain reaction amplification in 42 children with BD
      (aged 5-14 years) and 198 healthy adult controls. Twelve children had urgency
      syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16
      patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan.
      In children with renal lesions there was significant over-representation of the
      DD genotype compared with either controls or patients without renal damage (
      P<0.05). On multivariate analysis, the DD genotype was the only factor that had a
      significant impact on renal scar formation, introducing a 2.51-fold risk (odds
      ratio 2.51, 95% confidence interval 1.04-6.04, P=0.04). The A1166C gene
      polymorphism was not significantly associated with the development of parenchymal
      damage in children with BD. Our findings introduce ACE I/D gene polymorphism as
      an independent risk factor for parenchymal destruction in pediatric patients with
      BD.

PMID- 15179572
TI  - Congenital sodium diarrhea in a neonate presenting as acute renal failure.
AB  - Congenital sodium diarrhea is a rare cause of secretory diarrhea due to a defect
      in the sodium/proton exchanger that results in decreased sodium absorption and
      increased excretion in stools. We report a pre-term baby boy with a birth weight
      of 1.4 kg who was referred because of rapidly rising serum urea and creatinine.
      The initially reported high urine output was later found to be severe watery
      diarrhea with severe oliguria and acute renal failure. Associated findings were
      normal anion gap metabolic acidosis with hyponatremia that required > 50 mmol/kg
      of sodium per day for correction and about 300 ml/kg per day of replacement fluid
      to correct fluid and electrolyte abnormalities. The patient continues to do well
      5 months after diagnosis.

PMID- 15179570
TI  - Lipid peroxidation and antioxidant enzymes in children with chronic renal
      failure.
AB  - Increased lipid peroxidation (LP) has been observed in dialysis patients and in
      predialysis adults with advanced chronic renal failure (CRF). The aim of this
      study was to investigate whether predialysis CRF children have increased LP in
      plasma and red blood cells (RBC) and to evaluate the activity of the antioxidant
      enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase
      (GSH-Px)] in RBC. Concentrations of selenium (Se), copper (Cu), and zinc (Zn)
      cofactors of these enzymes-were determined both in erythrocytes and in plasma. LP
      was monitored by plasma and erythrocyte malonyldialdehyde (MDA) and by plasma
      organic hydroperoxide (OHP) concentrations. Forty-six predialysis children, aged
      5-18 years, divided into two groups according to their serum creatinine levels
      [group I ( n=14, mean serum creatinine 421.61+/-141.08 micromol/l), group II (
      n=32, mean serum creatinine 174.94+/-45.50 micromol/l)] and 27 age-matched
      healthy subjects were enrolled in the study. Significantly higher concentrations
      of plasma and erythrocyte MDA and plasma OHP, significantly lower activities of
      GSH-Px and CAT, and significantly lower concentrations of erythrocyte Se, Cu, and
      Zn and plasma Se and Cu were found in both groups of renal patients compared with
      controls. The SOD activity was reduced in both groups of CRF children. In group I
      the activity of SOD and GSH-Px was significantly lower than in group II. In
      summary, there is increased LP in plasma and RBC in children with predialysis
      CRF, even those patients with moderate renal insufficiency. The activity of the
      enzymatic antioxidant defense system is reduced in the RBC of predialysis
      patients. The antioxidant capacity is related to the severity of renal failure.

PMID- 15179571
TI  - Hypopnea in pediatric patients with obesity hypertension.
AB  - Obesity is associated with the development of hypertension but it is still not
      clear why hypertension is not observed in all obese patients. Obesity is a risk
      factor for the development of obstructive sleep apnea syndrome (OSAS) in
      children. OSAS has been linked to the development of hypertension in adults and
      children. The purpose of this study was to test the hypothesis that OSAS is one
      of the reasons that some obese children are hypertensive and some are not. The
      overnight polysomnography records of 90 patients (aged 4.2-18.8 years) were
      reviewed. BMI(score) [body mass index (BMI)/95th percentile BMI for age, sex, and
      race] was used to express the degree of obesity. The severity of systolic
      hypertension and diastolic hypertension were expressed as SBP(score) (systolic
      BP/the 95th percentile systolic BP for age, sex, and height) and DBP(score)
      (diastolic BP/the 95th percentile diastolic BP for age, sex, and height),
      respectively. OSAS was defined as more than one episodes of apnea per hour (AI)
      or an O(2) saturation associated with obstructive apnea of less than 90%. There
      were 56 obese patients; 42 were hypertensive and 40 patients were diagnosed with
      OSAS. The incidence of hypertension (68% vs. 30%) and obesity (75% vs. 52%) was
      higher in OSAS patients than those without OSAS. Compared with the non-obese
      patients, obese patients had a higher incidence of hypertension or OSAS, a higher
      BMI(score), SBP(score), DBP(score), AI, hypopnea index (HI), and apnea-hypopnea
      index (AHI). In obese patients, both SBP(score) and DBP(score) correlated
      positively with BMI(score), arousal index, and HI. DBP(score) also correlated
      positively with AHI. Multiple regression analysis showed that HI and BMI(score)
      were significant independent predictors of SBP(score) or DBP(score). Obese and
      hypertensive patients had a higher HI, AHI, and incidence of OSAS (64% vs. 29%)
      than the obese and normotensive patients. In conclusion, HI had a significant
      correlation with the degree of hypertension in obese patients, which could not be
      attributed to the degree of obesity. These findings are consistent with the
      hypothesis that OSAS is one of the reasons why some obese children are
      hypertensive and some are not.

PMID- 15179574
TI  - Linearized kinetic model of Listeria monocytogenes biofilm growth.
AB  - In this study the dynamics of biofilm formation on aluminum has been
      investigated. The process of cell growth has been observed using fluorescence
      microscopy. It has been confirmed that the process of biofilm formation can be
      represented as a sum of two separate processes: cell adhesion and colony
      proliferation. The derived set of equations describes kinetics of surface
      population growth and characteristic times for adsorption and combined growth
      processes, including characteristic time for the nutrient supply depletion. All
      equations contain variables based on the fundamental characteristics of bacterial
      population and can be easily determined from the experimental data or estimated
      theoretically. The developed theoretical model allows obtaining realistic values
      for population growth time and characteristic time for nutrient limitation
      occurrence during the biofilm development. Resulting equations qualitatively
      describe the biofilm formation process, and allow predicting microbial kinetics
      in the batch reactor system and determining critical values of the process
      parameters.

PMID- 15179573
TI  - Rasburicase prevents tumor lysis syndrome despite extreme hyperleukocytosis.
AB  - Hyperleukocytosis [white blood cell count (WBC) >100 x 10(9)/l] occurs in 5%-22%
      of pediatric patients with acute leukemia. Rasburicase (recombinant urate
      oxidase) is very effective for the prophylaxis and treatment of hyperuricemia,
      but its efficacy in marked hyperleukocytosis (WBC >200 x 10(9)/l) is not well
      known. We describe three children with marked hyperleukocytosis (WBC of 508, 320,
      and 242 x 10(9)/l) at initiation of induction chemotherapy. All three received
      rasburicase. Minimal metabolic disturbance occurred in all patients. We conclude
      that WBC reduction strategies may not be required solely for the risk of tumor
      lysis syndrome in patients with very high WBC (>200 x 10(9)/l) who are treated
      with rasburicase.

PMID- 15179576
TI  - On the relationships between leaf-litter lignin and net primary productivity in
      tropical rain forests.
AB  - We investigated if tropical rainforest trees produced more-lignified leaves in
      less productive environments using forests on Mount Kinabalu, Borneo. Our
      investigation was based on two earlier suggestions that slower litter
      decomposition occurs under less productive forests and that trees under resource
      limitation invest a large amount of carbon as lignin as a defense substance to
      minimize the loss from herbivores. When nine forests at different altitudes (700
      3100 m) and soil conditions (derived from sedimentary or ultrabasic rocks) but
      with the same gentle relief position were compared, the concentrations of leaf
      litter lignin were positively correlated with litterfall rates and leaf-litter
      nitrogen concentrations. These patterns would be reinforced in intact leaves if
      the effects of resorption at the time of leaf shedding were taken into account,
      because greater magnitude of resorption of mobile elements but not of lignin
      would occur in less productive environments (i.e. dilution of lignin in intact
      leaves). These results did not support earlier suggestions to explain the
      variation of leaf-litter lignin. Instead, we suggest that lower lignin contents
      are adaptive to recycle minerals without retarding decomposition in less
      productive environments.

PMID- 15179575
TI  - Allocation to defense or growth in dipterocarp forest seedlings in Borneo.
AB  - We quantified the allocation of net production to plant secondary metabolites
      (especially condensed tannins and lignins) to evaluate the investment into
      defense mechanisms of three tropical forest canopy species in Borneo vis-a-vis
      the resource availability hypothesis. In particular, we focused on Borneo
      ironwood (Eusideroxylon zwageri, Lauraceae), which seemed to employ an extreme
      defensive strategy. The wood of this species is extremely durable and has a high
      specific gravity with a very slow growth rate. The allocation to defense by
      Borneo ironwood was compared to two emergent species of Dipterocarpaceae, the
      dominant family in this forest community. We conducted shade-house experiments on
      seedlings under four controlled conditions (two light levels x two nutrient
      levels) and showed that the growth rate of E. zwageri was much lower than those
      of the other two species, and it allocated more of its net production to leaves
      and roots than to stems. The concentrations of condensed tannins and lignins were
      very high in the leaves and stems of this species, at about 20 and 30%,
      respectively. In total, E. zwageri allocated a maximum of about 35% of its net
      production to defensive substances (i.e., condensed tannins + lignins). In
      contrast, the two dipterocarp species allocated about 20-25% of their net
      production to defensive substances. The condensed tannins in E. zwageri help to
      prolong the lifespan of the leaves, and the lignins in the stems enhance the
      durability of the wood. Thus, although E. zwageri grows very slowly, the
      allocation to defensive substances seems to be an advantageous strategy for
      survival under dark conditions.

PMID- 15179577
TI  - Fine root branch orders respond differentially to carbon source-sink
      manipulations in a longleaf pine forest.
AB  - Fine roots are a key component of carbon (C) flow and nitrogen (N) cycling in
      forest ecosystems. However, the complexity and heterogeneity of the fine root
      branching system have hampered the assessment and prediction of C and N dynamics
      at ecosystem scales. We examined how root morphology, biomass, and chemistry
      differed with root branch orders (1-5 with root tips classified as first order
      roots) and how different root orders responded to increased C sink strength (via
      N fertilization) and reduced carbon source strength (via canopy scorching) in a
      longleaf pine (Pinus palustris L.) ecosystem. With increasing root order, the
      diameter and length of individual roots increased, whereas the specific root
      length decreased. Total root biomass on an areal basis was similar among the
      first four orders but increased for the fifth order roots. Consequently, total
      root length and total root surface area decreased systematically with increasing
      root order. Fine root N and lignin concentrations decreased, while total non
      structural carbohydrate (TNC) and cellulose concentrations increased with
      increasing root order. N addition and canopy disturbance did not alter root
      morphology, but they did influence root chemistry. N fertilization increased fine
      root N concentration and content per unit area in all five orders, while canopy
      scorching decreased root N concentration. Moreover, TNC concentration and content
      in fifth order roots were also reduced by canopy scorching. Our results indicate
      that the small, fragile, and more easily overlooked first and second order roots
      may be disproportionately important in ecosystem scale C and N fluxes due to
      their large proportions of fine root biomass, high N concentrations, relatively
      short lifespans, and potentially high decomposition rates.

PMID- 15179578
TI  - Carbon and nitrogen stoichiometry and nitrogen cycling rates in streams.
AB  - Stoichiometric analyses can be used to investigate the linkages between N and C
      cycles and how these linkages influence biogeochemistry at many scales, from
      components of individual ecosystems up to the biosphere. N-specific NH4+ uptake
      rates were measured in eight streams using short-term 15N tracer additions, and C
      to N ratios (C:N) were determined from living and non-living organic matter
      collected from ten streams. These data were also compared to previously published
      data compiled from studies of lakes, ponds, wetlands, forests, and tundra. There
      was a significant negative relationship between C:N and N-specific uptake rate;
      C:N could account for 41% of the variance in N-specific uptake rate across all
      streams, and the relationship held in five of eight streams. Most of the
      variation in N-specific uptake rate was contributed by detrital and primary
      producer compartments with large values of C:N and small values for N-specific
      uptake rate. In streams, particulate materials are not as likely to move
      downstream as dissolved N, so if N is cycling in a particulate compartment, N
      retention is likely to be greater. Together, these data suggest that N retention
      may depend in part on C:N of living and non-living organic matter in streams.
      Factors that alter C:N of stream ecosystem compartments, such as removal of
      riparian vegetation or N fertilization, may influence the amount of retention
      attributed to these ecosystem compartments by causing shifts in stoichiometry.
      Our analysis suggests that C:N of ecosystem compartments can be used to link N
      cycling models across streams.

PMID- 15179579
TI  - Reduction of solar UV-B mediates changes in the Sphagnum capitulum
      microenvironment and the peatland microfungal community.
AB  - The influence of near-ambient and reduced solar UV-B radiation on a peatland
      microfungal community was assessed by exposing experimental plots to UV-selective
      filtration. Replicate plots were covered with special plastic films to effect
      treatments of near-ambient and attenuated solar UV-B. The microfungal community
      from the top 1 cm of Sphagnum capitulum in a Tierra del Fuego peatland was
      censused throughout three growing seasons, between 1999 and 2002. Sphagnum
      capitula under near-ambient UV-B were more compressed and held more water than
      capitula under reduced UV-B. This water had a greater conductivity and was more
      acidic under near-ambient UV-B, as would be expected with increased leaching from
      the Sphagnum leaves. Nine regularly occurring hyphal fungi from the peatland were
      identified, at least to genus. Over three field seasons, no treatment effect on
      total fungal colony abundance was recorded, but individual species abundance was
      increased (Mortierella alpina), decreased (Penicillium frequentans), or was
      unaffected (P. thomii, Aureobasidium) by near-ambient UV-B. Species richness was
      also slightly lower under near-ambient UV-B. These treatment differences were
      smaller than seasonal or inter-annual fluctuations in abundance and species
      richness. In a growth chamber experiment, lamp UV-B treatments indicated that
      realistic fluxes of UV-B can inhibit fungal growth in some species. In addition
      to this direct UV-B effect, we suggest that changes in the peatland fungal
      community under near-ambient solar UV-B may also result from increased nutrient
      and moisture availability in the Sphagnum capitulum. The subtle nature of the
      responses of peatland fungi to solar UV-B suggests that most fungal species we
      encountered are well adapted to current solar UV-B fluxes in Tierra del Fuego.

PMID- 15179580
TI  - Friend or foe? A behavioral and stable isotopic investigation of an ant-plant
      symbiosis.
AB  - In ant-plant symbioses, the behavior of ant inhabitants affects the nature of the
      interaction, ranging from mutualism to parasitism. Mutualistic species confer a
      benefit to the plant, while parasites reap the benefits of the interaction
      without reciprocating, potentially resulting in a negative impact on the host
      plant. Using the ant-plant symbiosis between Cordia alliodora and its ant
      inhabitants as a model system, I examine the costs and benefits of habitation by
      the four most common ant inhabitants at La Selva Biological Station, Costa Rica.
      Costs are measured by counting coccoids associated with each ant species.
      Benefits include patrolling behavior, effectiveness at locating resources, and
      recruitment response. I also compare the diets of the four ant species using
      stable isotope analysis of nitrogen (N) and carbon (C). Ants varied in their
      rates of association with coccoids, performance of beneficial behaviors, and
      diet. These differences in cost, benefit, and diet among the ant species suggest
      differences in the nature of the symbiotic relationship between C. alliodora and
      its ants. Two of the ant species behave in a mutualistic manner, while the other
      two ant species appear to be parasites of the mutualism. I determined that the
      mutualistic ants feed at a higher trophic level than the parasitic ants.
      Behavioral and dietary evidence indicate the protective role of the mutualists,
      and suggest that the parasitic ants do not protect the plant by consuming
      herbivores.

PMID- 15179581
TI  - Weather variation and trophic interaction strength: sorting the signal from the
      noise.
AB  - Weather can have important consequences for the structure and function of
      ecological communities by substantially altering the nature and strength of
      species interactions. We examined the role of intra- and inter-annual weather
      variability on species interactions in a seasonal old-field community consisting
      of spider predators, grasshopper herbivores, and grass and herb plants. We
      experimentally varied the number of trophic levels for 2 consecutive years and
      tested for inter-annual variation in trophic abundances. Grasshopper emergence
      varied between years to the extent that the second growing season was 20% shorter
      than the first one. However, the damage grasshoppers inflicted on plants was
      greater in the second, shorter growing season. This inter-annual variation in
      plant abundance could be explained using the foraging-predation risk trade-off
      displayed by grasshoppers combined with their survival trajectory. Decreased
      grasshopper survival not only reduced the damage inflicted on plants, it weakened
      the strength of indirect effects of spiders on grass and herb plants. The most
      influential abiotic factor affecting grasshopper survival was precipitation. We
      found a negative association between grasshopper survival and the total yearly
      precipitation. A finer scale analysis, however, showed that different
      precipitation modalities, namely, number of rainy days and average precipitation
      per day, had opposing effects on grasshopper survival, which were inconsistent
      between years. Furthermore, our results suggest that small changes in these
      factors should result in changes of up to several orders of magnitude in the
      mortality rate of grasshoppers. We thus conclude that in this system the foraging
      predation risk trade-off displayed by grasshoppers combined with their survival
      trajectory and relevant weather variability should be incorporated in analytical
      theory, whose goal is to predict community dynamics.

PMID- 15179583
TI  - Influence of recruit condition on food competition and predation risk in a coral
      reef fish.
AB  - Settlement rate is considered to be a major determinant of the population
      structure of coral reef fishes. In this study, the effects of larval
      physiological condition on survival, predation risk and competitive ability are
      assessed for a small damselfish, Pomacentrus moluccensis. New settlers were
      collected and fed for 5 days to produce high and low condition (measured as
      lipid) treatment fish. In a field experiment, pairs (one high and one low
      condition fish) were transplanted to corals. Persistence over 2 weeks was much
      higher (100% vs. 25%) in high condition fish. In mixed groups in the laboratory,
      high condition fish were both aggressively dominant and consumed more of a
      limiting prey source than low condition fish. In addition, low condition fish
      were shown to be at much higher risk of predation. All of the low condition fish
      but only 33% of high condition fish in mixed groups were consumed by fish
      predators, and in a separate experiment, 73% of feeding strikes by predators were
      directed at low condition fish. Quality of new settlers can have an important
      influence on subsequent juvenile survival. The mechanisms for this effect are
      likely to include a combination of effects of condition on food competition and
      predation risk.

PMID- 15179582
TI  - Energy gradients and the geographic distribution of local ant diversity.
AB  - Geographical diversity gradients, even among local communities, can ultimately
      arise from geographical differences in speciation and extinction rates. We
      evaluated three models--energy-speciation, energy-abundance, and area--that
      predict how geographic trends in net diversification rates generate trends in
      diversity. We sampled 96 litter ant communities from four provinces: Australia,
      Madagascar, North America, and South America. The energy-speciation hypothesis
      best predicted ant species richness by accurately predicting the slope of the
      temperature diversity curve, and accounting for most of the variation in
      diversity. The communities showed a strong latitudinal gradient in species
      richness as well as inter-province differences in diversity. The former vanished
      in the temperature-diversity residuals, suggesting that the latitudinal gradient
      arises primarily from higher diversification rates in the tropics. However, inter
      province differences in diversity persisted in those residuals--South American
      communities remained more diverse than those in North America and Australia even
      after the effects of temperature were removed.

PMID- 15179584
TI  - Evaluating predation pressure on green treefrog larvae across a habitat gradient.
AB  - The effect of a predator on the abundance of a prey species depends upon the
      predator's abundance and its ability to capture that prey. The objectives of this
      research were to evaluate the community structure of predators of green treefrog
      (Hyla cinerea) tadpoles across habitat types and evaluate the effectiveness of
      individual predators on H. cinerea tadpoles. Correspondence and cluster analyses
      of predator frequencies across 23 aquatic habitats indicated that the majority of
      variance in predator communities was due to a division between permanent and
      temporary habitats. Experimental work demonstrated that survival of the smallest
      H. cinerea tadpoles was significantly lower than survival of medium and large
      tadpoles with the most effective predators, indicating that H. cinerea tadpoles
      attain a refuge from predation at larger body sizes. We combined the
      effectiveness of predators in experiments with the abundance of each predator
      species from the predator community survey to demonstrate that predation pressure
      on H. cinerea tadpoles is higher in temporary ponds. This pattern may explain in
      part why this species generally breeds successfully only in permanent habitats.
      It also confirms that discussions about an increasing gradient of predation
      pressure from temporary to permanent aquatic habitats should be restricted to
      individual prey species for which such a gradient has been demonstrated.

PMID- 15179585
TI  - Clinal variation in body and cell size in a widely distributed vertebrate
      ectotherm.
AB  - Bergmann's rule states that, among conspecific populations, individuals are
      larger in cooler than in warmer environments as a consequence of selection
      related to heat conservation. Many of the most comprehensive assessments of
      Bergmann's rule to date have examined clinal patterns in body size among species
      assemblages. Our study is a more direct test of Bergmann's rule because we
      examine the pattern within a single, widely distributed species. We examined
      geographic variation in body and cell size in the spotted turtle ( Clemmys
      guttata). Our analysis of 818 turtles collected from the entire range (45-28
      degrees N), indicated that body size increased with latitude; however, the
      relationship was driven by a population of large turtles at the northern extreme
      of the species' range. When the northern population was removed from the
      analyses, Bergmann's rule was not supported, and the smallest turtles occurred
      near the central part of the species' distribution. Recent literature has
      suggested that latitudinal clines in body size may simply be a physiological
      byproduct of the effects of temperature on cell division, resulting in larger
      cells, and hence larger organisms, from cooler temperatures. Measurements of the
      diameter of skin cells did not support the hypothesis that cell size increases
      with latitude and decreases with temperature in the spotted turtle, nor was there
      a significant relationship between body size and cell size. Our study suggests
      that neither Bergmann's rule nor cell size variation sufficiently explain the
      body size cline observed in the spotted turtle. We hypothesize that patterns in
      body size are related to variation in female size at maturity and reproductive
      cycles.

PMID- 15179586
TI  - Intraguild predation and successful invasion by introduced ladybird beetles.
AB  - Introductions of two ladybird beetle (Coleoptera: Coccinellidae) species,
      Coccinella septempunctata and Harmonia axyridis, into North America for aphid
      biocontrol have been followed by declines in native species. We examined
      intraguild predation (IGP) between larvae of these two exotic species and larvae
      of the two most abundant native coccinellids in eastern Washington State, C.
      transversoguttata and Hippodamia convergens. In pairings between the two native
      species in laboratory microcosms containing pea ( Pisum sativum) plants, neither
      native had a clear advantage over the other in IGP. When the natives were paired
      with either Harmonia axyridis or C. septempunctata, the natives were more
      frequently the victims than perpetrators of IGP. In contrast, in pairings between
      the exotic species, neither had an IGP advantage, although overall rates of IGP
      between these two species were very high. Adding alternative prey (aphids) to
      microcosms did not alter the frequency and patterns of relative IGP among the
      coccinellid species. In observations of encounters between larvae, the introduced
      H. axyridis frequently survived multiple encounters with the native C.
      transversoguttata, whereas the native rarely survived a single encounter with H.
      axyridis. Our results suggest that larvae of the native species face increased
      IGP following invasion by C. septempunctata and H. axyridis, which may be
      contributing to the speed with which these exotic ladybird beetles displace the
      natives following invasion.

PMID- 15179587
TI  - Local modification of benthic flow environments by suspension-feeding stream
      insects.
AB  - Larval black flies often exhibit spatially aggregated distributions, and
      individuals within patches can potentially reduce the supply of suspended food
      particles to downstream neighbors by modifying local flow characteristics. We
      used hot-film anemometry to quantify the magnitude and spatial extent of flow
      modifications downstream from feeding Simulium vittatum larvae in a laboratory
      flume, and to determine whether temporal patterns of flow variation are related
      to movements of the larval feeding appendages. Mean velocity 1 mm downstream from
      feeding larvae was reduced by 75%, and the percent reduction in velocity
      diminished asymptotically with downstream distance. Reduced velocities were
      evident as much as 60 mm downstream from, and 3 mm to either side of, larvae.
      Turbulence intensity (i.e., the SD of the velocity time series) was generally
      higher in this region relative to control flow conditions. Three results
      demonstrate the major contribution of the larval feeding appendages (i.e., labral
      fans) to such flow modification. First, there was a minimal reduction in mean
      velocity 5 mm downstream from non-feeding larvae (i.e., with closed labral fans),
      whereas mean velocity at the same location was reduced markedly when larvae were
      feeding. Second, the power spectrum of the velocity time series exhibited
      greatest power at frequencies that corresponded to the frequency of labral fan
      motions. Third, fan flick times accounted for most of the variance in the
      velocity power spectrum. The large local flow modifications that we documented
      have potentially important consequences for the feeding performance and growth of
      individuals located within larval aggregations, and are likely to influence
      behavioral interactions and spacing patterns.

PMID- 15179588
TI  - Morphological analysis of transportation pathways of microspheres after their
      introduction into the uterine horn cavity in cyclic pigs.
AB  - Countercurrent transfer is thought to be one of the most important mechanisms
      involved in the transfer of substances between the uterus and oviduct. The
      present study was aimed at recognizing other putative transportation pathways
      from the uterine cavity through the oviduct onto the surface of and into internal
      ovarian structures. Microspheres (latex beads, 0.8 microm in diameter) were
      introduced into the uterine horn cavity of pigs, for 30 min, at various days of
      the estrous cycle. The transportation pathways of the beads were then analyzed by
      light and electron microscopy. The transport of microspheres through the oviduct
      canal into ovarian tissues took place on each day of the estrous cycle. The
      largest numbers of microspheres passed through the tunica albuginea to the
      corpora lutea. Some of microspheres also reached the surface of the uterine
      ligament through the oviduct canal, where they attained the lumen of blood and
      lymphatic vessels, mainly of the vascular subovarian (VSP) and paraovarian
      lymphatic plexus (PLP), via the lymphatic stomata pathway. Transport of
      microspheres also took place simultaneously through the uterine and oviduct walls
      and from particular organs through blood and lymphatic vessels. Although the
      present results do not exclude the participation of countercurrent transfer
      between venous, lymphatic, and arterial vessels, they provide morphological
      evidence for the presence of direct transportation pathways of substances,
      released into the uterine lumen, into ovarian tissues through the oviduct canal.

PMID- 15179589
TI  - [News in rheumatology].

PMID- 15179590
TI  - [Longterm outcome of TNF blockade in adult-onset Still's disease].
AB  - BACKGROUND AND OBJECTIVE: Adult-onset Stills disease (AOSD) is a rare entity. The
      course of the disease can be mild or severe, acute or chronic. The intention of
      this survey was to evaluate the longterm efficacy of TNF blockade in patients
      with severe and active AOSD. PATIENTS AND METHODS: Eight patients with the
      diagnosis of AOSD, according to the diagnostic criteria developed by Yamaguchi in
      1992, and pretreatment with either high dosage steroid or more intensive
      immunosuppressive therapy were treated with infliximab in a dosage of 3 - 5 mg/kg
      at time pointsduring week 0, 2 and 6. Later on, the treatment regimen was adapted
      to the individual needs of the patients. The follow-up period was between one and
      five years. RESULTS: Seven patients responded to treatment with infliximab.
      Symptoms like fever, arthralgia, hepato-splenomegaly and serological parameters
      instantly improved. Five of these patients remained in remission over years after
      discontinuation of therapy. One of the responding patients needed permanent
      intensive treatment with TNF-blockers to control his severe chronic arthritis.
      Three patients experienced infusion reactions. One responding patient was
      therefore switched to etanercept and kept on this therapy. The one patient, who
      had not responded to infliximab also had no benefit from consecutive treatment
      with etanercept or adalimumab. CONCLUSION: Anti-TNF therapy can have a lasting
      beneficial effect on the course of AOSD. Five of eight patients remained in
      remission even after termination of therapy.

PMID- 15179591
TI  - [Trypanosomiasis in a woman from Cameroon mimicking systemic lupus
      erythematosus].
AB  - HISTORY: A 27-year-old woman from Cameroon was admitted because of arthralgia,
      myalgia and severe thrombocytopenia (20,000/ micro l). She had been suffering
      from weakness, recurrent febrile episodes, generalized lymphadenopathy and
      pancytopenia for 2 years. Having a typical autoantibody constellation and
      fulfilling four (pleurisy, autoimmune-hemolytic anemia, antinuclear antibodies
      (ANA), anti-Sm antibodies) of the American College of Rheumatology (ACR)
      classification criteria, systemic lupus erythematosus (SLE) had been diagnosed at
      another hospital. Treatment with corticosteroids and azathioprine did not improve
      her condition. INVESTIGATIONS: Abnormal laboratory findings were pancytopenia,
      elevated markers of inflammation and extreme hypergammaglobulinemia (70 %) with
      polyclonal IgM (73 g/l). Antinuclear antibodies (ANA), anti-Sm-, anti-Scl 70-,
      anti-U1-RNP-, anti-histo-, anti-leukocyte- and IgM anticardiolipin antibodies
      were detected. A bone marrow biopsy showed polyclonal B-cell and plasma cell
      infiltrates. Examination of peripheral blood smears disclosed trypanosoma brucei
      infection. DIAGNOSIS, TREATMENT AND COURSE: After the diagnosis of stage 2 West
      African trypanosomiasis (sleeping sickness) specific treatment was initiated
      leading to subsequent remission of the disease. CONCLUSION: This case report
      underlines the importance of a thorough differential diagnosis in cases of
      suspected autoimmune disease. Induction of autoantibodies during infectious
      diseases may be misleading. The use of the ACR criteria for SLE must be
      restricted to the classification of proven connective tissue diseases.

PMID- 15179592
TI  - [Diagnosis and therapy of rheumatoid arthritis].
AB  - In the past years, the substantially increased number of potent drugs for the
      therapy of rheumatoid arthritis has made the goal of an early, highly effective
      therapy more feasible. In addition, combination therapy trials including
      biologics revealed that joint protection and downregulation of inflammation can
      be achieved also in stages of active articular destruction, and the detection of
      novel markers such as antibodies against cyclic citrullinated peptides supports
      an earlier diagnosis of the disease. The price for these advances, however, are
      more complex, demanding and expensive therapeutic regimens that need to be
      handled carefully by the rheumatologist, especially with regard to a new field of
      side effects inherent with the use of TNF inhibiting agents. Finally, the current
      therapeutic standard includes also the ongoing clinical and scientific exchange
      with the orthopedic surgeon to optimize the long-term treatment for the
      individual patient.

PMID- 15179593
TI  - [Primary systemic vasculitides: diagnostic pathways].

PMID- 15179594
TI  - [Spondyloarthritides--new aspects of classification, diagnosis and therapy].

PMID- 15179595
TI  - [Which abortion prevention should be chosen in the case of antiphospholipid
      syndrome?].

PMID- 15179596
TI  - [Fibromyalgia--is it a disease?--pro].

PMID- 15179597
TI  - [Fibromyalgia--is it a disease?--contra].

PMID- 15179598
TI  - [Hereditary hemorrhagic telangiectasia].

PMID- 15179600
TI  - Opportunities for microbiologists in an emerging industry.

PMID- 15179599
TI  - Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees
      and linkage to chromosome 12q13.
AB  - Avascular necrosis of the femoral head (ANFH) is a debilitating disease that
      commonly leads to destruction of the hip joint in adults. The etiology of ANFH is
      unknown, but previous studies have indicated that heritable thrombophilia
      (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to
      lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH. We
      recently identified two families with ANFH showing autosomal dominant
      inheritance. By applying linkage analysis to a four-generation pedigree, we
      excluded linkage between the family and three genes related to thrombophilia and
      hypofibrinolysis: protein C, protein S, and plasminogen activator inhibitor.
      Furthermore, by a genomewide scan, a significant two-point LOD score of 3.45
      (recombination fraction [theta] = 0) was obtained between the family with ANFH
      and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a
      second family with ANFH and replicated the linkage to D12S368 (pedigree I: LOD
      score 2.47, theta = 0.05; pedigree II: LOD score 2.81, theta = 0.10). When an age
      dependent-penetrance model was applied, the combined multipoint LOD score was
      6.43 between D12S1663 and D12S85. Thus, we mapped the candidate gene for
      autosomal dominant ANFH to a 15-cM region between D12S1663 and D12S1632 on
      chromosome 12q13.

PMID- 15179601
TI  - IS200: an old and still bacterial transposon.
AB  - IS200 is a mobile element found in a variety of eubacterial genera, such as
      Salmonella, Escherichia, Shigella, Vibrio, Enterococcus, Clostridium,
      Helicobacter, and Actinobacillus. In addition, IS200-like elements are found in
      archaea. IS200 elements are very small (707-711 bp) and contain a single gene.
      Cladograms constructed with IS200 DNA sequences suggest that IS200 has not spread
      among eubacteria by horizontal transfer; thus it may be an ancestral component of
      the bacterial genome. Self-restraint may have favored this evolutionary
      endurance; in fact, unlike typical mobile elements, IS200 transposes rarely.
      Tight repression of transposase synthesis is achieved by a combination of
      mechanisms: inefficient transcription, protection from impinging transcription by
      a transcriptional terminator, and repression of translation by a stem-loop mRNA
      structure. A consequence of IS200 self-restraint is that the number and
      distribution of IS200 elements remain fairly constant in natural populations of
      bacteria. This stability makes IS200 a suitable molecular marker for
      epidemiological and ecological studies, especially when the number of IS200
      copies is high. In Salmonella enterica, IS200 fingerprinting is extensively used
      for strain discrimination.

PMID- 15179602
TI  - Competition for polymers among heterotrophic bacteria, isolated from particles of
      the Equatorial Atlantic.
AB  - Three heterotrophic bacterial strains, isolated from organic particles of the
      upper water column of the Equatorial Atlantic, taken during a cruise on the R/V
      METEOR (1997), were investigated concerning their physiological and phylogenetic
      properties using classic microbiological and modern molecular-biological methods.
      All isolates are gram-negative rods able to use polymers such as cellulose,
      chitin or starch as sole carbon source. The phylogeny of these isolates was
      investigated by fluorescence in situ hybridization (FISH) and 16S rDNA
      sequencing. The three isolated strains belong to the Cytophaga/Flavobacteria,
      gamma-Proteobacteria (Marinobacter sp.), and alpha-Proteobacteria (Sulfitobacter
      pontiacus). In order to study succession during growth on polymers naturally
      occurring in marine habitats, FISH was used as a new approach to detect cells
      from different phylogenetic clusters in the course of a single growth experiment.
      Mixed cultures consisting of the isolated strains in equal amounts were incubated
      with cellulose, chitin or starch. Isolate 4301-10/2, a member of the gamma
      Proteobacteria, dominated in mixed cultures growing on cellulose, chitin, or
      starch after only 10 days, with 55, 60, and 95%, respectively, of cells
      hybridizing with 4,6-diamidino-2-phenylindole (DAPI).

PMID- 15179603
TI  - Distribution of phototrophic populations and primary production in a microbial
      mat from the Ebro Delta, Spain.
AB  - Microbial mats arising in the sand flats of the Ebro Delta (Tarragona, Spain)
      were investigated during the summer season, when the community was highly
      developed. These mats are composed of three pigmented layers of phototrophic
      organisms, an upper brown layer mainly composed of Lyngbya aestuarii and diatoms,
      an intermediate green layer of the cyanobacterium Microcoleus chthonoplastes, and
      an underlying pink layer of a so-far unidentified purple sulfur bacterium. In the
      photic zone, oxygenic phototrophs constitute about 58% of total photosynthetic
      biomass, measured as biovolume, and anoxygenic phototrophs represent 42%. Diatoms
      constitute 11.8% of the oxygenic biomass, M. chthonoplastes 61.2%, and L.
      aestuarii and coccoid cyanobacteria 20.6 and 6.4%, respectively. In this
      laminated community, organic matter has an autochthonous origin, and
      photosynthesis is the most important source of organic carbon. Oxygen production
      reaches up to 27.2 mmol O(2) m(-2) h(-1), measured at 1000 microE m(-2) s(-1)
      light intensity, whereas oxidation of sulfide in the light has been calculated to
      be 18.6 mmol S m(-2) h(-1). This amount represents 26% of the total
      photosynthetic production in terms of photoassimilated carbon, demonstrating the
      important role of anoxygenic phototrophs as primary producers in the pink layer
      of Ebro Delta microbial mats.

PMID- 15179604
TI  - Nucleotide sequence and expression of the ncr nickel and cobalt resistance in
      Hafnia alvei 5-5.
AB  - The structural genes for the nickel and cobalt resistance of the conjugative
      plasmid pEJH 501 of Hafnia alvei 5-5, contained on a SalI-EcoRI fragment of 4.8
      kb, were cloned and sequenced. The DNA sequence included five genes in the
      following order: ncrA, ncrB, ncrC, ncrY, and ncrX. The predicted amino acid
      sequences of ncrA were homologous to the amino acid sequences of nreB of
      Achromobacter xylosoxidans 31A. Expression of ncr with the T7 RNA polymerase
      promoter system allowed Escherichia coli BL21 (DE3) to overexpress NcrA, NcrB,
      and NcrC but not NcrY, and NcrX. The apparent molecular masses of NcrA, NcrB, and
      NcrC were 30, 33, and 17 kDa, respectively. Primer-extension analysis showed that
      ncr mRNA started at nucleotide position 23 upstream from ncrA. The promoter
      region of the ncr operon possessed a strong, putative -35 element of sigma(32)
      type promoter sequence, and transcriptional 'lacZ fusion studies indicated that
      the -35 element influenced sigma(32)-specific transcription.

PMID- 15179605
TI  - Cell aggregation: a mechanism of pathogenic Leptospira to survive in fresh water.
AB  - Transmission of leptospirosis is facilitated by the survival of pathogenic
      leptospires in moist environments outside their mammalian host. In the present
      study, the survival mechanisms of Leptospira interrogans serovar Canicola in
      aqueous conditions and lack of nutrients were investigated. In distilled water,
      leptospires were able to remain motile for 110 days (pH 7.2). However, when
      incubated in a semi-solid medium composed of distilled water and 0.5% purified
      agarose (pH 7.2), they survived 347 days. In this viscous environment, aggregates
      of live spirochetes were observed. Neither antibiotics (e.g. tetracycline and
      ampicillin) nor nutrients inhibited leptospiral aggregation. Immunoblot analysis
      suggested that cells incubated in water down-regulate the expression of LipL31,
      an inner-membrane protein, but retain expression of other membrane proteins.
      These studies provide insights into the mechanisms by which pathogenic Leptospira
      survives for prolonged periods of time in natural aqueous environments, a key
      stage in the leptospiral lifecycle.

PMID- 15179606
TI  - Signature sequences in diverse proteins provide evidence for the late divergence
      of the Order Aquificales.
AB  - The Aquificales species are presently believed to be the earliest branching
      lineage within Bacteria. However, the branching order of this group in different
      phylogenetic trees is highly variable and not resolved. In the present work, the
      phylogenetic placement of Aquificales was examined by means of a cladistic
      approach based on the shared presence or absence of definite signature sequences
      (consisting of conserved inserts or deletions) in many highly conserved and
      important proteins, e.g. RNA polymerase beta (RpoB), RNA polymerase beta (RpoC),
      alanyl-tRNA synthetase (AlaRS), CTP synthase, inorganic pyrophosphatase (PPase),
      Hsp70 and Hsp60. For this purpose, fragments of the above genes that contained
      the signature regions were cloned from different Aquificales species
      (Calderobacterium hydrogenophilum, Hydrogenobacter marinus, and Thermocrinis
      ruber) and the sequence data were compared with those available from all other
      species. The presence in Aquificales species of distinctive inserts in Hsp70 and
      Hsp60 that are not found in any Firmicutes, Actinobacteria, or Thermotoga
      Clostridium species excluded them from these groups of Bacteria. The shared
      presence of prominent indels in the RpoB (>100 amino acids), RpoC (>100 amino
      acids) and AlaRS (4 amino acids) proteins, which are only found in the various
      Aquificales species, the Chlamydiae, the CFBG (Cytophaga-Flavobacteria
      Bacteroides-green sulfur bacteria) group, and Proteobacteria, strongly suggests
      their placement within these groups of Bacteria. A specific relationship between
      Proteobacteria and Aquificales is suggested by the presence in inorganic
      pyrophosphatase of a 2-amino-acid insert that is uniquely found in these phyla.
      However, the Aquificales species lacked a number of other protein signatures
      (e.g. indels in CTP synthase and Hsp70) that are characteristic of
      Proteobacteria, indicating that they constitute a distinct phylum related to
      Proteobacteria. These results provide strong and consistent evidence that the
      Aquificales diverged after the branching of Firmicutes, Actinobacteria,
      Thermotoga, Deinococcus-Thermus, green nonsulfur bacteria, Cyanobacteria,
      Spirochetes, Chlamydiae, and CFBG group, but before the emergence of the
      Proteobacteria.

PMID- 15179607
TI  - Laboratory diagnosis of brucellosis in a rural endemic area in northeastern
      Spain.
AB  - Sera obtained from 62 patients from four mountain counties in Catalonia
      (Northeastern Spain), in whom brucellosis had been diagnosed on the basis of
      clinical evidence and/or personal history, were analyzed using the rose Bengal
      test, standard serum agglutination test (SAT), Coombs' test, ELISA, and
      complement fixation. The diagnosis was further confirmed through blood cultures.
      Clinical evidence, epidemiology, and the results from serologic tests were used
      to assign patients to one of two groups: group 1 (n = 38) patients had primary
      infections, whereas group 2 (n = 24) patients had been previously exposed to the
      microorganism, i.e. re-infection of group 2 individuals occurred after long
      periods of time during which no active infection by Brucella had been detected.
      Receiving-operating charts (ROC) were used to determine the diagnostic value of
      the different tests and to establish discriminant values. Blood culture was a
      valuable diagnostic tool in group 1 (0.92 sensitivity) but was inappropriate in
      group 2 (0.08). The combination of positive rose Bengal test and agglutination
      >/=1/160 was valid for diagnosis in group 1. In group 2, agglutination <1/160
      (including negative agglutination) did not rule out brucellosis. The combination
      of positive rose Bengal test and Coombs' test >/=1/320 was the best diagnostic
      criterion (0.8 specificity; 1 sensitivity). ELISA (for IgG, IgM, or both) did not
      improve diagnostic accuracy.

PMID- 15179608
TI  - Clostridium difficile pilot study: effects of probiotic supplementation on the
      incidence of C. difficile diarrhoea.
AB  - Colonic infection with Clostridium difficile, leading to pseudomembranous
      colitis, is a common complication of antibiotic therapy, especially in elderly
      patients. It has been suggested that non-pathogenic probiotic bacteria might
      prevent the development and recurrence of C. difficile infection. This double
      blind, placebo-controlled study examines the role of probiotic administration in
      the prevention of C. difficile-associated diarrhoea (CDAD) in elderly patients
      receiving antibiotic therapy. Consecutive patients (150) receiving antibiotic
      therapy were randomised to receive either a probiotic containing both
      Lactobacillus and Bifidobacterium or placebo for 20 days. Upon admission to
      hospital, bowel habit was recorded and a faecal sample taken. Trial probiotic or
      placebo was taken within 72 h of prescription of antibiotics, and a second stool
      sample was taken in the event of development of diarrhoea during hospitalisation
      or after discharge. Of the randomised patients, 138 completed the study, 69 with
      probiotics in conjunction with antibiotics and 69 with antibiotics alone. On the
      basis of development of diarrhoea, the incidence of samples positive for C.
      difficile-associated toxins was 2.9% in the probiotic group compared with 7.25%
      in the placebo-control group. When samples from all patients were tested (rather
      than just those developing diarrhoea) 46% of probiotic patients were toxin
      positive compared with 78% of the placebo group.

PMID- 15179609
TI  - Simultaneous PCR detection of ica cluster and methicillin and mupirocin
      resistance genes in catheter-isolated Staphylococcus.
AB  - Recent data show that more than 50% of catheter-associated bloodstream infections
      are caused by staphylococci. Staphylococcal infections produced by intercellular
      adhesion cluster (ica) carriers can be even more problematic due to the presence
      of methicillin and mupirocin resistance genes. In the present study, a multiplex
      PCR protocol that allows the simultaneous identification of staphylococci and
      detection of both the ica and methicillin and/or mupirocin resistance genes was
      developed. Furthermore, the method allows differential detection of the ica locus
      from Staphylococcus aureus and Staphylococcus epidermidis.

PMID- 15179610
TI  - In memory of Federico Uruburu (1934-2003).

PMID- 15179611
TI  - Happy microbes in hostile niches. A symposium on extremophiles.

PMID- 15179620
TI  - Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic
      therapy.
AB  - Angiogenesis is required for multistage carcinogenesis. The inducible enzyme
      cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor
      growth. COX-2 expression occurs in a wide range of preneoplastic and malignant
      conditions; and the enzyme has been localized to the neoplastic cells,
      endothelial cells, immune cells, and stromal fibroblasts within tumors. The
      proangiogenic effects of COX-2 are mediated primarily by three products of
      arachidonic metabolism: thromboxane A(2) (TXA(2)), prostaglandin E(2) (PGE(2)),
      and prostaglandin I(2) (PGI(2)). Downstream proangiogenic actions of these
      eicosanoid products include: (1) production of vascular endothelial growth
      factor; (2) promotion of vascular sprouting, migration, and tube formation; (3)
      enhanced endothelial cell survival via Bcl-2 expression and Akt signaling; (4)
      induction of matrix metalloproteinases; (5) activation of epidermal growth factor
      receptor-mediated angiogenesis; and (6) suppression of interleukin-12 production.
      Selective inhibition of COX-2 activity has been shown to suppress angiogenesis in
      vitro and in vivo. Because these agents are safe and well tolerated, selective
      COX-2 inhibitors could have clinical utility as antiangiogenic agents for cancer
      prevention, as well as for intervention in established disease alone or in
      combination with chemotherapy, radiation, and biological therapies.

PMID- 15179621
TI  - The role of COX-2 inhibition in breast cancer treatment and prevention.
AB  - Several studies have suggested that cyclooxygenase-2 (COX-2) expression is
      associated with parameters of aggressive breast cancer, including large tumor
      size, positive axillary lymph node metastases, and HER2-positive tumor status.
      Studies of mammary tumors in mice and rats have indicated that moderate to high
      COX-2 expression is related to the genesis of mammary tumors that are sensitive
      to treatment with nonspecific and specific COX-2 inhibitors. Moreover, these
      studies also suggest that mammary tumors are associated with high prostaglandin
      levels and induction of aromatase, a cytochrome P450 enzyme that catalyses
      estrogen production. Mechanistically, lack of apoptosis and increased
      angiogenesis and invasiveness have been implicated as mechanisms of tumor growth
      in COX-2-dependent mammary tumors. Based on these observations, clinical trials
      are evaluating adjunctive therapy with a selective COX-2 inhibitor, celecoxib, in
      combination with several regimens used in the metastatic and adjuvant or
      neoadjuvant settings of breast cancer. In addition, proof-of-principle trials are
      being conducted to ascertain the effects of celecoxib on known markers of
      proliferation, angiogenesis, and apoptosis. Finally, based on the apparent
      synergy between celecoxib and the aromatase inhibitor exemestane, the National
      Cancer Institute of Canada Clinical Trials Group is launching a phase III trial
      comparing exemestane with or without celecoxib against placebo in postmenopausal
      women with elevated risk of breast cancer. Results of these trials will help to
      define the role of celecoxib in the management and prevention of breast cancer.
      Epidemiologic evidence suggests the incidence of breast, colon, and lung cancers
      is inversely related to the use of aspirin and nonsteroidal anti-inflammatory
      drugs, which are nonspecific inhibitors of COX. COX-1 and COX-2 are enzymes that
      generate prostaglandins and thromboxanes from free arachidonic acid. Genetic
      approaches pursued in animal models and biochemical evidence obtained from human
      tumor cell lines have strongly implicated COX-2, an inducible enzyme, in many
      preinvasive and invasive human tumors. In this article we will first review data
      that point to COX-2 as an important indicator in the genesis of breast cancer and
      discuss planned and ongoing clinical trials evaluating specific COX-2 inhibitors
      in the treatment and prevention of breast cancer.

PMID- 15179622
TI  - COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs in genitourinary
      cancer.
AB  - Selective cyclooxygenase (COX)-2-inhibiting and other nonsteroidal anti
      inflammatory drugs (NSAIDs) show promise for preventing and treating bladder and
      prostate cancers. In contrast to the strong NSAID epidemiology in colorectal
      cancer, the epidemiologic data on NSAIDs and genitourinary (GU) cancers are
      limited and mixed. However, a substantial body of preclinical in vitro and in
      vivo animal model data shows consistent NSAID activity in treating, and in some
      cases preventing, GU cancers and begins to address the mechanisms behind this
      activity (eg, involving Akt and ERK2 in the prostate). Many preclinical and
      clinical NSAID studies currently under way are helping to resolve the best type
      (selective or nonselective COX inhibitors or non-COX inhibitors), dose and
      duration of NSAID treatment for prevention in the GU setting. Future studies
      likely will focus on clarifying the NSAID mechanisms behind and developing NSAID
      combinations for both treating and preventing GU cancers.

PMID- 15179623
TI  - COX-2 inhibition and lung cancer.
AB  - Cyclooxygenase-2 (COX-2) overexpression is seen in many malignancies including
      lung cancer. In non-small cell lung cancer (NSCLC), COX-2 is overexpressed in
      most adenocarcinomas and squamous cell carcinomas. Elevated tumor COX-2
      prostaglandin E(2) (PGE(2)) levels have been implicated in angiogenesis, tumor
      invasion, resistance to apoptosis, and suppression of antitumor immunity.
      Preclinical animal model studies show tumor reduction when animals are treated
      with either nonspecific or specific inhibitors of COX-2. These studies suggest
      nonsteroidal anti-inflammatory drugs may act on multiple tumor-progression
      targets via both COX-2-dependent and-independent pathways. Consistent with these
      findings, epidemiologic evidence has shown a decreased incidence of lung cancer
      in patients who use nonsteroidal anti-inflammatory drugs. Based on these
      observations, celecoxib, a selective COX-2 inhibitor, has been evaluated in
      combination with chemotherapy for the management of metastatic NSCLC in patients
      who have failed prior chemotherapy. Several clinical trials are ongoing that
      evaluate celecoxib in combination with chemoradiation for unresectable, locally
      advanced NSCLC. Another trial evaluating celecoxib in a preoperative combination
      with paclitaxel and carboplatin has generated overall clinical response rates at
      least comparable to those reported in the Bimodality Lung Oncology Team trial.
      Ongoing clinical trials are also evaluating the combination of celecoxib with
      chemotherapy and/or radiation or celecoxib in combination with epidermal growth
      factor receptor inhibitors of NSCLC. This article reviews preclinical information
      on COX-2 inhibitors in lung cancer and presents updated data from several ongoing
      clinical trials that are evaluating celecoxib in NSCLC.

PMID- 15179627
TI  - Acute coronary syndromes: initial evaluation and risk stratification.
AB  - Chest pain, the second most frequent presenting complaint in the emergency
      department (ED), often poses a challenge to the physicians dealing with these
      patients owing to the wide spectrum of presentation of acute coronary syndromes
      (ACS). A majority of the patients presenting with chest pain are usually admitted
      to the hospital for further evaluation and management. Despite the availability
      of modern-day tools for diagnosis of acute myocardial infarction (AMI), about 5%
      of patients with AMI are missed in the ED with subsequent associated morbidity
      and mortality and legal consequences. Several centers have adapted critical
      pathways derived from American College of Cardiology/American Heart Association
      (ACC/AHA) guidelines for the management of patients presenting with ACS. We now
      have some evidence suggesting adherence to the critical pathways derived from
      ACC/AHA guidelines will optimize the quality of patient care and probably result
      in better patient outcomes. This article reviews initial evaluation and the
      importance of risk stratification of the patients presenting with chest pain
      using the currently available clinical and diagnostic tools. Critical pathways
      derived from the ACC/AHA guidelines for various presentations of ACS are also
      reviewed.

PMID- 15179628
TI  - Development of the chest pain center: rationale, implementation, efficacy, and
      cost-effectiveness.

PMID- 15179629
TI  - Markers of cardiac ischemia, injury, and inflammation.

PMID- 15179630
TI  - Diagnostic strategies for the evaluation of the patient presenting with chest
      pain.

PMID- 15179631
TI  - Early exercise testing in the management of low risk patients in chest pain
      centers.

PMID- 15179632
TI  - Approach to the patient with chest pain and nonobstructive coronary artery
      disease.
AB  - Patients with chest pain and nonobstructive coronary artery disease (NOCAD)
      utilize a significant part of our health care resources. Their diagnosis and
      treatment can often be difficult and time consuming. A simple classification
      system and stepwise diagnostic approach may help to reduce unnecessary testing.
      Also, utilization of a chest pain clinic may be beneficial for these patients.

PMID- 15179633
TI  - Heart failure management in the emergency department observation unit.
AB  - The United States is currently in the midst of a heart failure epidemic. This has
      a tremendous impact on morbidity, mortality, and associated costs to our health
      care system. With demographic trends expected to double the at-risk cohort over
      the next 30 years, there is a serious need to develop more efficacious strategies
      addressing early diagnosis, treatment options, and outcomes in patients stricken
      with heart failure. This article reviews the newest diagnostics, therapeutics,
      and strategies for the management of heart failure and suggests appropriate
      implementation of these approaches in the emergency department observation unit.

PMID- 15179637
TI  - Recovery of ambulation after traumatic brain injury.
AB  - OBJECTIVES: To identify variables that are predictive of independent ambulation
      after traumatic brain injury (TBI) and to define the time course of recovery.
      DESIGN: Retrospective review of consecutive admissions of patients with severe
      TBI over a 32-month period. SETTING: Brain injury unit in an acute, inpatient
      rehabilitation hospital. PARTICIPANTS: Of 264 patients screened, 116 met criteria
      that included the ability to participate in motor and functional evaluation on
      admission to acute rehabilitation, and the absence of other neurologic disorders
      or fractures that affect one's ability to ambulate. INTERVENTION: Inpatient
      rehabilitation on a specialized TBI unit by an interdisciplinary team.Main
      outcome measures Recovery of independent ambulation and time to recover
      independent ambulation. RESULTS: Of eligible patients, 73.3% achieved independent
      ambulation by latest follow-up (up to 5.1 mo). Patients who achieved independent
      ambulation were significantly younger (P<.05), had better gait scores on
      admission (P<.05), and tended to be less severely injured-based on duration of
      posttraumatic amnesia (PTA; P=.058)-than those who did not ambulate
      independently. There were no differences in recovery based on neuropathologic
      profile. Mean time to independent ambulation +/- standard deviation was 5.7+/-4.3
      weeks; of those achieving independent ambulation, 82.4% did so by 2 months and
      94.1% by 3 months. If not independent by 3 months postinjury, patients had a
      13.9% chance of recovery. Multivariate regression analysis generated prediction
      models for time to independent ambulation, using admission FIM instrument scores
      and age (38% of variance); initial gait score, loss of consciousness, and age
      (40% of variance); or initial gait score and PTA (58% of variance), when
      restricted to just those patients with diffuse axonal injury. CONCLUSIONS: Most
      patients with severe TBI achieved independent ambulation; the vast majority did
      so within 3 months postinjury. Functional measures, injury severity measures, and
      age can help guide prognosis and expectations for time to recover.

PMID- 15179638
TI  - Water-based exercise for cardiovascular fitness in people with chronic stroke: a
      randomized controlled trial.
AB  - OBJECTIVE: To evaluate the effect of an 8-week, water-based exercise program
      (experimental group) with that of an upper-extremity function program (control
      group) to increase cardiovascular fitness within a community setting for people
      with stroke. DESIGN: Single-blind randomized controlled trial. SETTING: Public
      community center. PARTICIPANTS: A volunteer sample of 12 community-dwelling
      people with stroke with mild to moderate residual motor deficits. INTERVENTION:
      Study subjects participated in group exercise programs for 1 hour, 3 times a week
      for 8 weeks. The experimental group exercised in chest-deep water at targeted
      heart rates. The control group performed arm and hand exercises while sitting.
      Main outcome measures The primary outcome measure was cardiovascular fitness
      (V(O2)max). Secondary measures were maximal workload, muscle strength, gait
      speed, and the Berg Balance Scale score. RESULTS: The experimental group attained
      significant improvements over the control group in cardiovascular fitness,
      maximal workload, gait speed, and paretic lower-extremity muscle strength. The
      relatively short program (8 wk) of water-based exercise resulted in a 22%
      improvement in cardiovascular fitness in a small group of people with stroke who
      had relatively high function. CONCLUSIONS: A water-based exercise program
      undertaken as a group program may be an effective way to promote fitness in
      people with stroke.

PMID- 15179639
TI  - Biomechanic characteristics of patients with spastic and dystonic hypertonia in
      cerebral palsy.
AB  - OBJECTIVE: To determine what biomechanic characteristics of knee joint motion and
      walking show potential to quantitatively differentiate spasticity and dystonia in
      cerebral palsy (CP). DESIGN: Descriptive measurement study. SETTING: University
      hospital. PARTICIPANTS: Seventeen pediatric and adult patients with CP.
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured the resistance
      of the knee joint at different velocities and positions, maximum muscle
      activation during external motion, amplitude of knee tendon reflexes, maximum
      isometric flexion and extension torques, velocity of walking, and knee kinematics
      during the gait cycle. Patients were classified into 2 groups (dystonia or
      spasticity) if at least 2 of 3 physicians agreed that a prominent component of
      dystonia was present. RESULTS: Patients with dystonia had a greater degree of co
      contraction and an increased resistance to external motion at slow velocities.
      The tendon reflexes were almost normal in patients with dystonia, whereas they
      were increased in patients with spasticity. Muscle strength was more impaired in
      patients with dystonia, probably as a result of greater muscle co-contraction.
      They also walked slower, with smaller knee ranges of motion, during the stance
      phase of walking. CONCLUSIONS: The measurement of resistance and of muscle
      activation during passive motion and tendon reflexes shows potential to
      differentiate dystonia from spasticity in CP patients with a mixed form of
      hypertonia. More studies are needed to confirm these results.

PMID- 15179640
TI  - A functional electric stimulation-assisted exercise therapy system for hemiplegic
      hand function.
AB  - OBJECTIVE: To test a functional electric stimulation (FES)-assisted exercise
      therapy system for improvement of motor function of the hemiplegic upper
      extremity. DESIGN: A before-after trial, with 2-month follow-up. SETTING: A
      university research laboratory. PARTICIPANTS: A convenience sample of 6 subjects
      (3 men, 3 women). Main inclusion criteria were that stroke had occurred more than
      1 year before the study (mean time poststroke, 5.6+/-4.4y) and had resulted in
      hemiplegia, and that FES produced adequate hand opening. INTERVENTION: A
      prototype workstation with instrumented objects was used by subjects to perform a
      set of tasks with their affected hand during 1-hour sessions for 12 consecutive
      workdays. A FES stimulator was used to assist hand opening. Main outcome measures
      Kinematic data, provided by the workstation sensors, and 3 clinical tests.
      RESULTS: Kinematic data indicated statistically significant improvement in
      subjects' performance (pre-/posttreatment effect size [pre/post ES] of the mean
      performance scores=5.46; mean pretreatment/follow-up ES [pre/FU ES]=3.44). Two of
      3 clinical tests showed improvement in hand function (mean pre/post ES=.51; mean
      pre/FU ES=.61). CONCLUSIONS: Improvement in hemiplegic hand function because of
      FES-assisted therapy was documented in a small group of people with hemiplegia
      whose motor impairment would exclude them from participation in constraint
      induced movement therapy. However, the long-term clinical relevance of such
      improvement needs further study.

PMID- 15179641
TI  - Recovery of standing balance in postacute stroke patients: a rehabilitation
      cohort study.
AB  - OBJECTIVE: To identify and interrelate static and dynamic characteristics of the
      restoration of quiet standing balance in a representative sample of stroke
      survivors in the Netherlands during their inpatient rehabilitation. DESIGN:
      Exploratory study using an inception cohort with findings related to reference
      values from healthy elderly persons. SETTING: Rehabilitation center.
      PARTICIPANTS: Thirty-seven inpatients (mean age, 61.6y; mean time poststroke,
      10.0wk) with a first hemispheric intracerebral infarction or hematoma who were
      admitted to retrain standing balance and walking. INTERVENTION: Individualized
      therapy. MAIN OUTCOME MEASURES: Center of pressure fluctuations were registered
      under each foot and in the sagittal and frontal planes separately by using a dual
      plate force platform. The first balance measurements took place as soon as
      patients were able to stand unassisted for at least 30 seconds as well as 2, 4,
      8, and, 12 weeks later. Quiet standing was assessed under 4 conditions: with and
      without a visual midline reference, with the eyes closed, and while performing a
      concurrent arithmetic task. RESULTS: The stroke patients showed excessive
      postural sway and instability, particularly in the frontal plane, compared with
      reference values. Frontal plane balance was, however, also most responsive to the
      effects of balance training and recovery (P<.001). The degree of visual
      dependency for frontal plane balance control showed a significant reduction in
      time (P<.02). Weight-bearing asymmetry, which was most pronounced in patients
      with disturbed sensibility or ankle clonus, diminished considerably during the
      first 4 weeks of the follow-up period (P<.02). Yet, a substantial degree of
      weight-bearing asymmetry persisted during the 8 weeks thereafter, and it
      continued to be aggravated by attentional distraction (P<.001). During the same
      period, static asymmetry (ie, the degree of pes equinovarus loading at the
      paretic side) and dynamic asymmetry (ie, the extent to which compensatory ankle
      moments are applied at the nonparetic side) did not show normalization at all,
      although motor selectivity of the paretic leg improved by 1 stage on the 6-stage
      Brunnstrom scale (P<.001) and the independency level of balance and walking
      skills improved by 2 points on the 6-point Functional Ambulation Categories
      (P<.001). CONCLUSIONS: Balance recovery in postacute stroke inpatients is
      characterized by a reduction in postural sway and instability as well as by a
      reduction in visual dependency, particularly with regard to frontal plane
      balance. These restoration characteristics may be important factors underlying
      the relearning of independent standing and walking abilities. The clear lack of
      normalization for measures reflecting static and dynamic aspects of postural
      asymmetry suggests that the functional improvements in balance and gait must be
      more related to other mechanisms than to the restoration of support functions and
      equilibrium reactions of the paretic leg.

PMID- 15179642
TI  - Intrasession reliability of center of pressure measures of postural steadiness in
      healthy elderly people.
AB  - OBJECTIVES: To estimate the immediate test-retest reliability of a single measure
      of several center of pressure (COP) variables, to report the number of trials to
      be averaged to obtain a reliable measurement of postural steadiness, and to
      determine the minimal metrically detectable change (MMDC). DESIGN: Cross
      sectional study. SETTING: University biomechanics laboratory. PARTICIPANTS: Seven
      community-living, healthy elderly people over the age of 60 years (range, 62
      73y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The COP was estimated
      from 2 force platforms and the following measures were calculated: (1) root mean
      square (RMS), (2) COP range, (3) COP mean velocity, (4) mean power frequency
      (MPF), (5) median power frequency (MedPF), and (6) sway area. Intraclass
      correlation coefficients (ICCs) were determined by using 9 successive quiet
      standing trials. RESULTS: The ICCs obtained for 1 measure of 120 seconds were.58
      and.58 for the RMS,.83 and.94 for the COP mean velocity,.52 and.62 for the COP
      range,.44 and.30 for the MPF, and.34 and.47 for the MedPF in anteroposterior (AP)
      and mediolateral (ML) directions, respectively. The ICC of the COP sway area
      obtained for 1 measure was.41. Only 2 trials had to be averaged to obtain an ICC
      over.90 for the COP mean velocity associated with an MMDC of +/-1.2mm/s (AP) and
      +/-0.6mm/s (ML). CONCLUSIONS: Mean velocity was the most reliable COP measure and
      using 2 repetitions allowed for reliable measurement of postural steadiness. For
      the other COP variables, 3 trials of 120 seconds were needed to obtain an ICC
      over.80.

PMID- 15179643
TI  - The effect of combined use of botulinum toxin type A and functional electric
      stimulation in the treatment of spastic drop foot after stroke: a preliminary
      investigation.
AB  - OBJECTIVE: To investigate the effect of combined botulinum toxin type A (BTX) and
      functional electric stimulation (FES) treatment on spastic drop foot in stroke.
      DESIGN: Nonblinded randomized controlled trial. SETTING: Hospitals. PARTICIPANTS:
      Consecutive sample of 21 ambulant adults within 1 year after stroke with a
      spastic drop foot, of whom 18 completed the study. INTERVENTIONS: The treatment
      group received BTX injections (Dysport) on 1 occasion into the medial and lateral
      heads of the gastrocnemius (200U each) and tibialis posterior (400U each) muscles
      and FES, used on a daily basis for 16 weeks to assist walking. Both groups
      continued with physiotherapy at the same rate. MAIN OUTCOME MEASURES: Walking
      speed, Physiological Cost Index, Modified Ashworth Scale, Rivermead Motor
      Assessment, and Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS:
      Walking speed increased over 12 weeks in both control (P=.020) and treatment
      groups (nonstimulated, P=.004; stimulated, P=.042). The baseline corrected
      (analysis of covariance) increase in mean walking speed at 12 weeks, relative to
      controls, was.04m/s (95% confidence interval [CI],.003-.090) without stimulation,
      and.09m/s (95% CI,.031-.150) with stimulation. CONCLUSIONS: Combined treatment
      effectively improved walking and function. A larger study is needed to quantify
      the treatment effect and to investigate its impact on quality of life.

PMID- 15179644
TI  - H-reflex and physiologic measures of ejaculation in men with spinal cord injury.
AB  - OBJECTIVE: To investigate the various physiologic parameters characterizing and
      predicting ejaculation. DESIGN: Single case-control study. SETTING: A referred
      care center and university setting. PARTICIPANTS: Two men with spinal cord injury
      (SCI) and 2 control subjects. INTERVENTION: Subjects were asked to self-stimulate
      with a Ferticare vibrator to induce ejaculation over 5 to 8 independent sessions.
      MAIN OUTCOME MEASURES: Penile tumescence, blood pressure, heart rate,
      electromyographic activity of the bulbocavernosus muscles, abdominal muscles,
      soleus H-reflex, and occurrence of ejaculation. RESULTS: Changes on all measures
      were observed, with penile tumescence being more stable in control subjects.
      Blood pressure increased in both groups, whereas tachycardia was observed in
      controls and bradycardia in subjects with SCI. H-reflex dropped slightly in
      controls but increased in subjects with SCI. Muscular patterns differed on
      ejaculatory success or failure. CONCLUSIONS: Physiologic changes on all measures
      can be observed in men with SCI as a function of ejaculation. Changes include
      hypertension and bradycardia, characteristic of hyperreflexia, and tachycardia in
      controls. The neural mechanisms underlying these patterns are discussed. H-reflex
      showed increased spinal cord excitability in subjects with SCI after ejaculation,
      which suggests spasticity. The results support investigation of the H-reflex to
      predict ejaculatory success or failure in men with SCI, along with specific
      analysis of muscular patterns.

PMID- 15179645
TI  - Antispastic effect of penile vibration in men with spinal cord lesion.
AB  - OBJECTIVE: To evaluate the possible antispastic effect of penile vibratory
      stimulation (PVS) in men with spinal cord lesion (SCL). DESIGN: Unblinded, before
      after trial. SETTING: Ambulatory care. PARTICIPANTS: Nine men with SCLs from C2
      to T8 were randomly allocated into 2 groups. INTERVENTION: Twenty-four hours of
      electromyographic recordings from the quadriceps and tibialis anterior muscles
      were taken, followed by PVS or no treatment and another 24 hours of
      electromyographic recordings. The presence of electromyographic activity of an
      amplitude 4 times the baseline, with a duration of more than 5 seconds, was taken
      to signify a spasm. The number of spasms per hour was calculated before and after
      PVS and no treatment. Spasticity was evaluated by the Modified Ashworth Scale
      (MAS). MAIN OUTCOME MEASURE: Reduction in spasticity and spasms. RESULTS: The
      electromyographic data showed a significant reduction in the frequency of leg
      spasms up to 3 hours (P<.05). Significantly decreased spasticity, as evaluated by
      MAS, was found immediately after vibration (P<.01). CONCLUSIONS: PVS may be
      useful as an antispastic therapy.

PMID- 15179646
TI  - Effects of spinal cord injury level on the activity of shoulder muscles during
      wheelchair propulsion: an electromyographic study.
AB  - OBJECTIVE: To determine the influence of spinal cord injury (SCI) level on
      shoulder muscle function during wheelchair propulsion. DESIGN: Fine-wire
      electromyographic activity of 11 muscles was recorded during wheelchair
      propulsion. SETTING: Biomechanics research laboratory. PARTICIPANTS: Convenience
      sample of 69 men, in 4 groups by SCI level (low paraplegia, n=17; high
      paraplegia, n=19; C7-8 tetraplegia, n=16; C6 tetraplegia, n=17). INTERVENTIONS:
      Not applicable. MAIN OUTCOME MEASURES: Timing of muscle activity onset,
      cessation, and duration, and time of peak intensity for each functional group
      were compared with 1-way analysis of variance. Median electromyographic intensity
      was also compared. RESULTS: Two functional synergies were observed: push
      (anterior deltoid, pectoralis major, supraspinatus, infraspinatus, serratus
      anterior, biceps) and recovery (middle and posterior deltoid, supraspinatus,
      subscapularis, middle trapezius, triceps). Push phase activity began in late
      recovery and ceased in early to late push. Recovery phase muscles functioned from
      late push to late recovery. Recruitment patterns for the groups with paraplegia
      were remarkably similar. For subjects with tetraplegia, pectoralis major activity
      was significantly prolonged compared with subjects with paraplegia (P<.05).
      Subscapularis activity shifted from a recovery pattern in subjects with
      paraplegia to a push pattern in persons with tetraplegia. CONCLUSIONS: Level of
      SCI significantly affected the shoulder muscle recruitment patterns during
      wheelchair propulsion. Differences in rotator cuff and pectoralis major function
      require specific considerations in rehabilitation program design.

PMID- 15179647
TI  - Manual wheelchair pushrim dynamics in people with multiple sclerosis.
AB  - OBJECTIVES: To define differences in pushrim dynamics during manual wheelchair
      propulsion by users with multiple sclerosis (MS) relative to 2 control groups of
      subjects with spinal cord injury (SCI) and no disability (ND) and to investigate
      changes in propulsion biomechanics at different speeds and with fatigue. DESIGN:
      Case-control. SETTING: Biomechanics laboratory. PARTICIPANTS: A convenience
      sample of 42 people, 8 women and 6 men per group. INTERVENTIONS: Not applicable.
      MAIN OUTCOME MEASURES: The propulsion pattern, mean maximum speed, percentage of
      time in push and recovery phases, push angle, push frequency, mean maximum
      resultant pushrim force, mean work and push cycle, and hand-to-pushrim coupling
      and decoupling effects. RESULTS: The MS groups tended to use an arcing propulsion
      pattern more than did the control groups (Pmax=.003). The MS group pushed at a
      lower mean maximum velocity (v) when allowed to choose the speed of propulsion
      (v(MS),.67+/-.20m/s; v(SCI), 1.10+/-0.23m/s; P=.001), when asked to push at 1m/s
      (v(MS),.91+/-.26m/s; v(SCI), 1.12+/-0.11m/s; v(ND), 1.05+/-0.13m/s; P=.010), and
      were unable to maintain a self-selected speed during a 5-minute trial
      (Deltav(MS),.15+/-.02m/s; Deltav(ND),.03+/-.06m/s; P<.001). The MS group spent a
      higher proportion of time in the push phase of propulsion (Pmax=.001). In
      general, the MS group had smaller push angles, but push frequencies similar to
      the controls. Statistically adjusted MS group pushrim forces and work per push
      measures varied depending on context, but in all trials the MS group displayed a
      braking effect when grasping and releasing the pushrim. The MS group had declines
      in most measures when pushing at a self-selected speed for 5 minutes. In all
      trials, the MS group was more likely to display asymmetry between right and left
      sides in biomechanic parameters. CONCLUSIONS: Manual wheelchair users with MS
      have difficulty grasping and releasing the pushrim and maintaining speed during a
      fatigue trial. This likely leads to a slow self-selected speed of propulsion that
      may not be functional. Clinicians should remember these results when prescribing
      manual wheelchairs for people with MS.

PMID- 15179648
TI  - Community integration and satisfaction with functioning after intensive cognitive
      rehabilitation for traumatic brain injury.
AB  - OBJECTIVE: To evaluate the effectiveness of an intensive cognitive rehabilitation
      program (ICRP) compared with standard neurorehabilitation (SRP) for persons with
      traumatic brain injury (TBI). DESIGN: Nonrandomized controlled intervention
      trial. SETTING: Community-based, postacute outpatient brain injury rehabilitation
      program. PARTICIPANTS: Fifty-six persons with TBI. INTERVENTIONS: Participants in
      ICRP (n=27) received an intensive, highly structured program of integrated
      cognitive and psychosocial interventions based on principles of holistic
      neuropsychologic rehabilitation. Participants in SRP (n=29) received
      comprehensive neurorehabilitation consisting primarily of physical therapy,
      occupational therapy, speech therapy, and neuropsychologic treatment. Duration of
      treatment was approximately 4 months for both interventions. MAIN OUTCOME
      MEASURES: Community Integration Questionnaire (CIQ); and Quality of Community
      Integration Questionnaire assessing satisfaction with community functioning and
      satisfaction with cognitive functioning. Neuropsychologic functioning was
      evaluated for the ICRP participants. RESULTS: Both groups showed significant
      improvement on the CIQ, with the ICRP group exhibiting a significant treatment
      effect compared with the SRP group. Analysis of clinically significant
      improvement indicated that ICRP participants were over twice as likely to show
      clinical benefit on the CIQ (odds ratio=2.41; 95% confidence interval, 0.8-7.2).
      ICRP participants showed significant improvement in overall neuropsychologic
      functioning; participants with clinically significant improvement on the CIQ also
      showed greater improvement of neuropsychologic functioning. Satisfaction with
      community functioning was not related to community integration after treatment.
      Satisfaction with cognitive functioning made a significant contribution to
      posttreatment community integration; this finding may reflect the mediating
      effects of perceived self-efficacy on functional outcome. CONCLUSIONS: Intensive,
      holistic, cognitive rehabilitation is an effective form of rehabilitation,
      particularly for persons with TBI who have previously been unable to resume
      community functioning. Perceived self-efficacy may have significant impact on
      functional outcomes after TBI rehabilitation. Measures of social participation
      and subjective well-being appear to represent distinct and separable
      rehabilitation outcomes after TBI.

PMID- 15179649
TI  - Changes in sagittal ground reaction forces after intra-articular hyaluronate
      injections for knee osteoarthritis.
AB  - OBJECTIVES: To examine the gait patterns and the sagittal ground reaction forces
      (GRFs) in persons with knee osteoarthritis (OA) after intra-articular injection
      of hyaluronate and to investigate the duration of its treatment effectiveness.
      DESIGN: Case-comparison study. SETTING: Gait laboratory in a tertiary care
      center. PARTICIPANTS: Fifteen subjects (30 knees) with symptomatic knee OA (stage
      I or II, according to the Ahlback grading system), and 15 age-, mass-, and gender
      matched non-OA control subjects (30 knees). INTERVENTION: After initial gait
      analysis, the group with knee OA received 5 weekly intra-articular injections of
      hyaluronate to bilateral knees. Gait analysis was performed again for the group
      with knee OA after the completion of hyaluronate injections. MAIN OUTCOME
      MEASURES: Forceplate sagittal GRFs and gait parameters of velocity, cadence, step
      length, and stride time. RESULTS: The distinctive 2-peak force vector GRF was
      lost in persons with knee OA. The first peak rise time was significantly delayed
      (P<.05). The group with knee OA also revealed slower walking velocity and
      cadence, as well as longer stride time, than the control group (P<.05). The
      distinctive 2-peak force vector GRF diagram could be recovered in patients with
      knee OA after the completion of hyaluronate injections. CONCLUSIONS: Gait
      patterns and GRFs improved significantly after intra-articular knee injection of
      hyaluronate in persons with Ahlback stages I and II knee OA. The clinical
      treatment effect was immediate and may last for 6 months or more.

PMID- 15179650
TI  - Electric muscle stimulation of the quadriceps in the treatment of patellofemoral
      pain.
AB  - OBJECTIVE: To compare a commercially available electric muscle stimulation
      regimen with a novel form of stimulation for the rehabilitation of the quadriceps
      muscle, in patients with patellofemoral pain syndrome. DESIGN: Double-blinded
      randomized trial with a parallel control group and stratified randomization.
      SETTING: Home-based rehabilitation program assessed in research center.
      PARTICIPANTS: Eighty patients (47 women, 33 men) with patellofemoral pain
      syndrome. INTERVENTIONS: One group (EMPI) received 1 uniform constant frequency
      component of 35Hz. The other (EXPER) group received an experimental form of
      stimulation that contained 5 simultaneously delivered frequency components of
      125, 83, 50, 2.5, and 2Hz. Stimulation was applied to the quadriceps muscles of
      the affected leg for 1 hour daily for 6 weeks, a total of 42 treatments. MAIN
      OUTCOME MEASURES: Lower-limb isometric and isokinetic torque, quadriceps fatigue,
      knee flexion, patellar pain, a step test, quadriceps cross-sectional area, and
      Kujala patellofemoral score for pain before and after treatment. RESULTS: Seventy
      four patients (43 women, 31 men) completed the trial. Patients in both groups
      showed significant improvements in all outcomes (P<.05). No significant
      differences existed between the 2 stimulators in any outcome (P>.05) except for
      quadriceps cross-sectional area (P=.023). CONCLUSIONS: One form of stimulation
      was just as efficacious as the other in improving subjective and objective
      measures.

PMID- 15179651
TI  - Effect of ultrasound on acute inflammation of transected medial collateral
      ligaments.
AB  - OBJECTIVE: To evaluate the effect of therapeutic ultrasound on the acute
      inflammation of soft-tissue injuries by measuring the levels of prostaglandin
      E(2) (PGE(2)) and leukotriene B(4) (LTB(4)). DESIGN: Randomized, case-control
      study. SETTING: Laboratory animal facility. ANIMALS: Thirty 3-month-old male
      Sprague-Dawley rats. INTERVENTION: Rats with medial collateral ligament
      transection were given 5 minutes of pulsed ultrasound therapy (1:4) daily, with
      different durations (1, 5, 10d) and intensities (0, 0.5, 1.5, 2.3W/cm(2)). MAIN
      OUTCOME MEASURES: Levels of PGE(2) and LTB(4). RESULTS: The levels of PGE(2) and
      LTB(4) were higher in all intensity subgroups that received 2.3W/cm(2) intensity
      on postinjury day 2. On postinjury day 11, LTB(4) was significantly decreased,
      but PGE(2) was significantly increased. CONCLUSIONS: Pulsed ultrasound therapy
      may stimulate inflammation of acute ligament injury.

PMID- 15179652
TI  - Measuring activity limitations in climbing stairs: development of a hierarchical
      scale for patients with lower-extremity disorders living at home.
AB  - OBJECTIVE: To develop a hierarchical scale that measures activity limitations in
      climbing stairs in patients with lower-extremity disorders living at home.
      DESIGN: Cross-sectional study with Mokken scale analysis of 15 dichotomous items.
      SETTING: Outpatient clinics of secondary and tertiary care centers. PARTICIPANTS:
      Patients (N=759; mean age +/- standard deviation, 59.8+/-15.0y; 48% men) living
      at home, with different lower-extremity disorders: stroke, poliomyelitis,
      osteoarthritis, amputation, complex regional pain syndrome type I, and diabetic
      foot problems. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: (1) Fit of
      the monotone homogeneity model, indicating whether items can be used for
      measuring patients; (2) fit of the double monotonicity model, indicating
      invariant (hierarchical) item ordering; (3) intratest reliability, indicating
      repeatability of the sum score; and (4) differential item functioning, addressing
      the validity of comparisons between subgroups of patients. RESULTS: There was (1)
      good fit of the monotone homogeneity model (coefficient H=.50) for all items for
      all patients, and for subgroups defined by age, gender, and diagnosis; (2) good
      fit of the double monotonicity model (coefficient H(T)=.58); (3) good intratest
      reliability (coefficient rho=.90); and (4) no differential item functioning with
      respect to age and gender, but differential item functioning for 4 items in
      amputees compared with nonamputees. CONCLUSIONS: A hierarchical scale, with
      excellent scaling characteristics, has been developed for measuring activity
      limitations in climbing stairs in patients with lower-extremity disorders who
      live at home. However, measurements should be interpreted with caution when
      comparisons are made between patients with and without amputation.

PMID- 15179653
TI  - Obstacle avoidance during human walking: effects of biomechanical constraints on
      performance.
AB  - OBJECTIVE: To determine whether fixation of the ankle joint, the knee joint, or
      both increasingly affects the performance of a newly learned task, that is,
      stepping over an obstacle. DESIGN: Randomized trial. SETTING: Research laboratory
      of a university hospital in Switzerland. PARTICIPANTS: Eighteen healthy, young
      volunteers. INTERVENTION: Subjects walked on a treadmill and, with reduced
      vision, stepped with the right leg over a randomly approaching obstacle. They
      adapted to the task during the 2 runs. In the third run, fixating orthoses of the
      ankle-foot (AFO), knee (KO), or both (KAFO) were attached to the left leg. MAIN
      OUTCOME MEASURE: The "performance" consisted of leg muscle activity, joint
      movements, swing phase duration, and the clearance between the foot and the
      obstacle. The changes within runs (adaptation) and between runs (eg, transfer)
      were evaluated. RESULTS: The attached orthoses caused a reduced transfer of
      performance in the KAFO and KO between runs 2 and 3. No differences in the rate
      of adaptation were observed among the 3 groups during the third run. CONCLUSIONS:
      A movement restriction of the supporting leg worsened the performance of the
      contralateral leg in a locomotor task. Performance was more affected by knee
      joint fixation than by ankle-joint fixation alone and, consequently, the need for
      relearning is greater.

PMID- 15179654
TI  - Ultrasound imaging distinguishes between normal and weak muscle.
AB  - OBJECTIVE: To determine whether real-time ultrasound imaging can provide
      quantitative data that distinguish pathologic from healthy muscle and that
      correlate with strength measures. DESIGN: Nonrandomized matched-pair, repeated
      measures design. SETTING: Ultrasound imaging laboratory, rehabilitation medicine
      department, government research hospital. PARTICIPANTS: Nine patients with stable
      active or inactive myositis, stratified into 3 groups based on their 10-point
      manual muscle test (MMT) scores, and 9 age- and gender-matched controls.
      INTERVENTIONS: Maximal isometric contraction of the rectus femoris muscle in 2
      knee-flexion positions (60 degrees, 90 degrees ) during simultaneous ultrasound
      imaging and muscle force dynamometry. MAIN OUTCOME MEASURES: Changes of the
      rectus femoris muscle in horizontal (X) and vertical (Y) diameters between
      relaxed and contracted states, and muscle force measurements. RESULTS: The X
      diameters decreased and the Y diameters increased during isometric contraction in
      all participants. For each group, average changes in cross-sectional diameters
      were consistently higher in controls than in patients. Patients with MMT less
      than 8 differed significantly from controls in both X and Y dimensions. A
      moderately strong correlation was found between muscle force and the Y diameter
      during contraction at 60 degrees (r =.78) and 90 degrees (r =.67) knee-flexion
      angles. CONCLUSIONS: Ultrasonography provided a quantitative measure of change
      between relaxed and contracted state of muscle, which correlated with muscle
      force. Ultrasound identified significant differences in cross-sectional diameters
      between the myopathic and normal muscles sampled and may be useful for measuring
      muscle response to drug and exercise therapy.

PMID- 15179655
TI  - Rhomboid muscle electromyography activity during 3 different manual muscle tests.
AB  - OBJECTIVE: To determine which of 3 previously published rhomboid manual muscle
      tests (MMTs) elicits the maximal rhomboid electromyographic activity in an
      asymptomatic population. DESIGN: Criterion standard. SETTING: Motion analysis
      laboratory at tertiary care medical center. PARTICIPANTS: Eleven male volunteers
      (age range, 24-40y) without shoulder or neck pain. INTERVENTIONS: Not applicable.
      MAIN OUTCOME MEASURES: Peak 1-second normalized electromyographic activity in the
      rhomboid muscle during 8 different MMT positions, including 3 different rhomboid
      MMT positions (Kendall, Kendall-Alternative, Hislop-Montgomery). RESULTS: The
      Kendall MMT (78% maximal voluntary contraction [MVC]) produced higher rhomboid
      electromyographic activity than the Kendall-Alternative (71% MVC) or the Hislop
      Montgomery MMT (52% MVC), but the differences were not statistically significant.
      The posterior deltoid MMT generated the greatest rhomboid electromyographic
      activity of all MMTs, and 4% to 30% greater rhomboid electromyographic activity
      than the 3 rhomboid MMTs (P=.0001; posterior deltoid > Hislop-Montgomery).
      Electromyographic profiles of the Kendall and Kendall-Alternative MMTs were
      similar, whereas the Hislop-Montgomery MMT produced less upper trapezius activity
      (P=.0001 vs Kendall and Kendall-Alternative) and more latissimus dorsi activity
      (P=.0001 vs Kendall-Alternative). The standard MMT positions for the middle
      trapezius, levator scapula, posterior deltoid, and latissimus dorsi produced the
      maximal electromyographic activity for their respective target muscles.
      CONCLUSIONS: The posterior deltoid MMT position should be used to produce maximal
      rhomboid electromyographic activity for normalization purposes during
      kinesiologic studies. The Kendall and Kendall-Alternative rhomboid MMT are likely
      to be clinically indistinct. It is unlikely that clinicians can use standard MMT
      positions to distinguish rhomboid strength from synergists, such as the levator
      scapula and middle trapezius muscle, for diagnostic purposes.

PMID- 15179656
TI  - Short-term repeatability of body sway during quiet standing in people with
      hemiparesis and in frail older adults.
AB  - OBJECTIVE: To investigate short-term repeatability of a posturographic quiet
      standing test protocol in people with hemiparesis and in frail older adults.
      DESIGN: Test-retest design, using 5 different quiet standing task conditions in
      which size and compliance of the support surface, visual influence, and cognitive
      demands were manipulated. Retest was performed after 15 minutes. SETTING:
      Rehabilitation units and day care center. PARTICIPANTS: Twenty-three people with
      stroke (mean age, 74.4y) and 16 frail older adults (mean age, 82.1y).
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Repeatability of trunk
      acceleration root mean square by within-subject standard deviation, coefficient
      of variation, and intraclass correlation coefficients (ICCs). RESULTS: The
      ICC(1,2) ranged from.13 to.75 for people with hemiparesis and from.73 to.92 for
      frail older adults when tested with their eyes open. The least demanding task
      condition gave the best repeatability. Standing with eyes closed resulted in very
      low ICC(1,2) in people with hemiparesis (.16) and in frail older adults (-.18).
      Interpretation of the results was similar for the other 2 reliability measures.
      CONCLUSIONS: A mean of 2 repeated measures gave adequate repeatability for frail
      older adults but not for people with stroke when they were tested with their eyes
      open. This study showed the importance of establishing short-term repeatability
      relative to each clinical population in which such tests are used.

PMID- 15179657
TI  - The ultrasonographic and electrodiagnostic findings of ulnar neuropathy at the
      elbow.
AB  - OBJECTIVE: To evaluate and compare the morphologic changes of the ulnar nerve at
      the elbow, using ultrasonography, between patients with cubital tunnel syndrome
      and retrocondylar compression syndrome determined with electrodiagnosis. DESIGN:
      Prospective study using electrodiagnosis and ultrasonography. SETTING: An
      outpatient rehabilitation clinic in a tertiary university hospital in South
      Korea. PARTICIPANTS: Thirteen patients (8 men, 5 women; mean age, 48.2y).
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: In the electrodiagnostic
      study, we used the inching technique to localize the ulnar nerve lesion at the
      elbow. In the ultrasonography study, we measured the length of the swollen ulnar
      nerve and the ratio of the nerve diameter between the proximal end of the medial
      epicondyle to the elbow joint level and the tip of medial epicondyle to the elbow
      joint level. RESULTS: The mean length of the swollen ulnar nerve segment in
      retrocondylar compression syndrome (2.58+/-0.58cm) was significantly longer than
      that of cubital tunnel syndrome (1.64+/-0.31cm). The mean ratio of the nerve
      diameter between the proximal end of medial epicondyle and the elbow joint level
      was significantly larger in retrocondylar compression syndrome (1.52+/-0.25) than
      that of cubital tunnel syndrome (1.06+/-0.06). CONCLUSIONS: Ultrasonography
      detected the morphologic changes and the extent of the ulnar nerve lesion at the
      elbow, and it can become a screening and follow-up imaging modality in patients
      with ulnar neuropathy at the elbow.

PMID- 15179658
TI  - Contraindications for superficial heat and therapeutic ultrasound: do sources
      agree?
AB  - OBJECTIVES: To determine the amount of agreement among general rehabilitation
      sources for both superficial heating and therapeutic ultrasound
      contraindications. DATA SOURCES: English-language textbook and peer-reviewed
      journal sources, from January 1992 to July 2002. Searches of computerized
      databases (HealthSTAR, CINAHL, MEDLINE, Embase) as well as Library of Congress
      Online Catalogs, Books in Print, and AcqWeb's Directory of Publishers and
      Venders. DATA SELECTION: Sources were excluded if they (1) were published before
      1992, (2) failed to address general rehabilitation audiences, or (3) were
      identified as a researcher's related publication with similar information on the
      topic. DATA EXTRACTION: Type and number of contraindications, type of audience,
      year of publication, number of references, rationales, and alternative treatment
      strategies. DATA SYNTHESIS: Eighteen superficial heat and 20 ultrasound sources
      identified anywhere from 5 to 22 and 9 to 36 contraindications/precautions,
      respectively. Agreement among sources was generally high but ranged from 11% to
      95%, with lower agreement noted for pregnancy, metal implants, edema, skin
      integrity, and cognitive/communicative concerns. Seventy-two percent of
      superficial heat sources and 25% of ultrasound sources failed to reference at
      least 1 contraindication claim. CONCLUSIONS: Agreement among contraindication
      sources was generally good for both superficial heat and therapeutic ultrasound.
      Sources varied with regard to the number of contraindications, references, and
      rationales cited. Greater reliance on objective data and standardized
      classification systems may serve to develop more uniform guidelines for
      superficial heat and therapeutic ultrasound.

PMID- 15179659
TI  - Long-term relief of posttraumatic headache by sphenopalatine ganglion pulsed
      radiofrequency lesioning: a case report.
AB  - Posttraumatic headache is a common and disabling pain syndrome in patients who
      sustain a head injury. Unfortunately, conventional treatments may fail or cause
      intolerable side effects. Because chronic headache may be mediated by central and
      peripheral neural processes, these structures may be therapeutic targets. One
      target, the sphenopalatine ganglion (SPG), is implicated in several headache
      disorders and has been lesioned for headache relief. Because of the risks of
      neurolytic procedures, nonablative procedures that provide pain relief would be
      useful. We present a case wherein a man in his late twenties with posttraumatic
      headache obtained more than 17 months of relief with SPG pulsed-mode
      radiofrequency lesioning. SPG pulsed-mode radiofrequency is a nonablative, neural
      lesioning method that may be useful in the treatment of posttraumatic headache.

PMID- 15179660
TI  - Eye patching biases spatial attention after thalamic hemorrhage in a patient
      without spatial neglect: a case report.
AB  - Monocular patching has been advocated as a treatment for spatial neglect. Eye
      patching, however, is also reported to increase spatial bias. Thus, patching
      brain injury patients for ocular conditions may also impair their attention. To
      learn if an eye patch may induce asymmetric attention in a patient without
      spatial neglect, we tested a woman with diplopia after a left thalamic
      intraventricular hemorrhage. She had no spatial neglect on bedside attention
      tasks. Using a laser pointer, she bisected a blank space at near (279 mm) and far
      (914 mm) distances under 3 conditions: unpatched and wearing a right or left eye
      patch. Unpatched, she showed no bias. She erred further leftward with right
      patching at both distances. Right eye patching appeared to induce neglect of
      right space when the patient performed this task. With left patching, leftward
      error tended to increase in near space only. Clinicians prescribing eye patches
      to patients with brain injury even for purely ocular indications, should evaluate
      them for spatial neglect once the patch is in place.

PMID- 15179661
TI  - An instance of an atypical intraspinal cyst presenting as S1 radiculopathy: a
      case report and brief review of pathophysiology.
AB  - Intraspinal cysts are rare, but typically they originate from a degenerate
      zygapophyseal joint. These cysts have been commonly referred to as juxtafacet
      cysts and occur concomitantly with lumbar and occasionally lower-limb radicular
      pain. Documented cases have shown pseudoarthroses developing from nonhealing pars
      defects. Histologic analyses have found synovial tissue within these
      fibrocartilaginous accumulations. We present a case of S1 radiculopathy indicated
      by an intraspinal pseudocyst arising as a complication of a chronic spondylolytic
      defect. A brief review of the related pathophysiology is also included.

PMID- 15179663
TI  - Effects of vision and arm position on amplitude of arm postural tremor in
      patients with multiple sclerosis.
AB  - OBJECTIVES: To quantify the effects of vision and arm position on arm postural
      tremor, comparisons were made between flexed and extended arm positions performed
      with the eyes open and closed. DESIGN: Case-control study. SETTING: National
      multiple sclerosis (MS) center in Belgium. PARTICIPANTS: Sixteen patients (32
      arms) with MS who had intention tremor and 16 healthy controls (32 arms).
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The amplitude of postural
      tremor was assessed by a magnetic position sensor attached to the index finger.
      RESULTS: The amplitude of postural tremor was not influenced by changes in visual
      condition or different arm positions. Both healthy controls and MS patients made
      more directional changes in the flexed, compared with the extended arm position.
      CONCLUSIONS: The amplitude of the arm postural tremor in MS is independent of
      vision and arm position. Selecting 1 arm position is sufficient to assess
      postural tremor amplitude.

PMID- 15179664
TI  - Myths and facts about post traumatic stress disorder.

PMID- 15179662
TI  - Computerized biofeedback knee goniometer: acceptance and effect on exercise
      behavior in post-total knee arthroplasty rehabilitation.
AB  - OBJECTIVE: To assess device accuracy, patient acceptance, and effect of a
      computerized biofeedback knee goniometer (CBG), on patients' compliance with
      active range of motion (AROM) exercises after total knee arthroplasty (TKA).
      DESIGN: Two-stage study: measurement validation on asymptomatic controls and an
      unblinded, multiple crossover trial. SETTING: Inpatient rehabilitation.
      PARTICIPANTS: Asymptomatic controls (n=14) and post-TKA inpatients (n=11).
      INTERVENTIONS: For measurement validation, CBG-angle measurements were compared
      with manual, clinician-obtained angles. To assess motivational effect, the CBG
      was worn after TKA; on alternating days, it either monitored AROM silently (no
      feedback) or provided audiovisual feedback about reaching preset range of motion
      (ROM) goals and prompted the patients to exercise when idle. MAIN OUTCOME
      MEASURES: To assess accuracy, the device's readings were compared with manual
      measurements. Patient satisfaction was determined by a self-report questionnaire;
      exercise compliance was assessed by calculating activity rate and stratified
      interactivity intervals. RESULTS: CBG readings reproduced clinician measurements
      reliably between 0 degrees and 100 degrees (eta(2)=98.5%). Auditory feedback was
      more helpful than visual feedback for motivating exercise. During feedback-on
      days, the mean total activity rate +/- standard deviation was 15.1+/-10.9
      activity counts per hour, and the interactivity interval was 6.7+/-5.7 minutes.
      The activity rate was higher on feedback-off days-22.5+/-11.1 counts/hour (P=.11)
      and the mean interactivity interval was 3.6+/-2.7 minutes (P=.07). CONCLUSIONS:
      The CBG provided reliable, unbiased estimates of clinician measurements of joint
      angle within the range of 0 degrees to 100 degrees. The CBG was accepted well by
      most patients. Surprisingly, slightly more ROM activity was noted during feedback
      off days than feedback-on days.

PMID- 15179665
TI  - Historical review: Autointoxication and focal infection theories of dementia
      praecox.
AB  - The popularity of theories of autointoxication and focal infection in general
      medicine and dentistry in the late nineteenth and early twentieth centuries led
      Emil Kraepelin and others to speculate that dementia praecox was caused by a
      poisoning of the brain from toxins produced in other parts of the body, notably
      the sex glands, the intestines and the mouth. Emil Kraepelin's commitment to the
      autointoxication theory is ignored in the literature on the history of psychiatry
      due to the focus of historians and clinicians on the major contributions of
      Kraepelin's methods of clinical psychopathology. Besides heredity,
      autointoxication and focal infection were the other most dominant theories of the
      organic aetiology of dementia praecox in the first three decades of its existence
      as a nosological entity in psychiatry. Rational treatments for dementia praecox
      that followed logically from these aetio-logical theories were colonic
      irrigations and major abdominal surgeries such as appendicostomies, colectomies
      and the removal of presumably infected ovaries, testes and other organs
      associated with reproduction. Autointoxication and focal infection theories
      disappeared from psychiatry by the mid-1930s.

PMID- 15179666
TI  - Atypical antipsychotics and diabetes mellitus.
AB  - Recently, increasing attention has been drawn to the potential diabetogenic
      effect of novel antipsychotics. Until now, large prospective studies examining
      the relationship between atypical antipsychotics and impaired glucose metabolism
      have been lacking. However, the case reports and retrospective studies that we
      review here suggest an increased risk of developing diabetes mellitus (DM) in
      patients treated with atypical antipsychotics compared to schizophrenic patients
      treated with conventional antipsychotics or those without treatment. Although
      most atypical antipsychotic agents might have a diabetogenic potential, the risk
      of developing DM might be higher in patients treated with either clozapine or
      olanzapine than with risperidone, whereas data on quetiapine and ziprasidone is
      presently limited and needs further attention. Possible mechanisms include the
      induction of peripheral insulin resistance and the direct influence on pancreatic
      beta-cell function by 5-HT1A/2A/2C receptor antagonism, by inhibitory effects via
      alpha 2-adrenergic receptors or by toxic effects. On the other hand, atypical
      antipsychotics might not be an independent risk factor for the development of DM,
      but hasten the onset of DM in patients bearing other risk factors. It is
      suggested that schizophrenic patients should be monitored for the occurrence of
      glucose metabolism abnormalities before starting atypical antipsychotics, and at
      a 3-month interval at least during therapy.

PMID- 15179667
TI  - Rationale for diagnosing human prion disease.
AB  - Human prion diseases (PrD) like Creutzfeldt-Jakob disease (CJD) include sporadic,
      acquired and familial neurodegenerative disorders. The central events in the
      neuropathological process of PrDs are severe neuronal loss, spongiform change and
      accumulation of abnormal prion protein (PrPSc). The latter is a conformational
      variant of the host-encoded cellular PrP (PrPC), a copper-binding protein. The
      physiological role of PrPC is debated. Definitive diagnosis of PrD is based on
      post mortem demonstration of PrPSc by immunohistochemistry or Western blot.
      Mutations in the PrP gene (PRNP), the polymorphic site at codon 129, and the
      molecular characteristic of protease resistant PrP influence the phenotype.
      Clinical symptoms, cranial MRI scan, EEG and investigation of 14-3-3 protein in
      cerebrospinal fluid (CSF) suggest a diagnosis of probable CJD. Variant CJD,
      related to bovine spongiform encephalopathy, shows a different clinical course,
      symmetrical high intensity MRI signal in the pulvinar, presence of PrPSc in
      tonsil biopsy tissue, and a lower sensitivity of CSF 14-3-3 protein compared to
      sporadic CJD. Future possibilities in diagnosis of PrDs include either the
      demonstration of PrPSc in body fluids or disease associated changes in laboratory
      variables or gene expression.

PMID- 15179668
TI  - Polyunsaturated fatty acid levels in red cell membranes of unmedicated
      schizophrenic patients.
AB  - There are several reports of reduced levels of polyunsaturated fatty acids
      (PUFA), particularly arachidonic acid (AA) and docosahexaenoic acid (DHA), in
      membrane phospholipid from various tissues including red blood cells (RBC) taken
      from schizophrenic patients. However, reports have not been entirely consistent
      and most studies have been confounded by the potential effects of environmental
      factors including antipsychotic medication and diet. We measured PUFA levels in
      RBC from two separate groups of unmedicated patients and control subjects from
      India and Malaysia, populations which have substantial differences in diet. We
      found no significant difference in levels of AA between patients and control
      subjects in either population. Levels of adrenic acid were significantly reduced,
      and levels of DHA significantly increased in both clinical populations. However,
      diet-related differences in DHA between the populations from India and Malaysia
      were much greater than differences between schizophrenic patients and controls.
      It is concluded that reduced RBC membrane levels of AA and DHA are not
      pathognomic of schizophrenia but that variations in cell membrane fatty acid
      levels are an epiphenomenon which may reflect underlying abnormalities of
      phospholipid and fatty acid metabolism and their interaction with environmental
      factors including medication and diet.

PMID- 15179669
TI  - Antipsychotic drugs influence transport of the beta-adrenergic antagonist [3H]
      dihydroalprenolol into neuronal and blood cells.
AB  - The amine hypothesis suggests that the cause of schizophrenic or depressive
      psychosis is dysfunction of noradrenergic or serotonergic neurotransmission. We
      investigated pharmacological properties of [3H]-dihydroalprenolol (DHA) transport
      into C6, IMR32, native lymphocytes, B-lymphoblastoids and MOLT-3 cells. DHA
      transport was inhibited by a heterogeneous group of structurally related
      compounds exhibiting an amine group and various aromatic ring structures. It was
      verified on cells of neuronal/glial and blood cell origin but in detail on B
      lymphoblastoids. The latter once showed strongest inhibition of DHA transport
      using tricyclic antidepressants (amitriptyline: IC50 = 2.86 microM, imipramine:
      IC50 = 3.33 microM) and haloperidol (IC50 = 3.98 microM) as a neuroleptic.
      Antipsychotics like clozapine (IC50 = 11 microM), olanzapine (IC50 = 15 microM),
      spiperone (IC50 = 66 microM) and EMD 49980 (ICso >> 100 microM) were less
      effective. In contrast to cells of blood origin, a stimulation of DHA transport
      by antipsychotics was not detectable using neuronal cells. As antipsychotics
      showed a distinct inhibition and, concerning cells of blood origin, a stimulation
      of transport after pre-incubation, further investigations seem to be of interest
      in respect to its involvement in the cellular uptake of drugs and therefore its
      impact on the quality of therapy of psychiatric patients.

PMID- 15179670
TI  - Validating Kraepelin's two types of depressive mixed states: "depression with
      flight of ideas" and "excited depression".
AB  - Despite a venerable classic tradition going back to at least Kraepelin,
      depressive mixed states (DMX) are not represented in official diagnostic manuals
      in psychiatry. We have operationalised this condition as a major depressive
      episode (MDE) with three or more intra-episode hypomanic signs and symptoms
      (DMX3). Of 320 consecutive bipolar II outpatients, presenting for MDE treatment
      and interviewed using the Structured Clinical Interview for DSM-IV, modified to
      permit the systematic evaluation of hypomanic features during the index MDE, 200
      met our criteria for DMX3 (62.5%). When compared with the remaining non-DMX
      bipolar II, they had significantly earlier age at onset, higher percentage of
      females, atypical features and bipolar family history. Multivariate logistic
      regression ofintra-MDE hypomanic signs and symptoms found evidence supporting an
      "excited depression" subtype (defined by the core feature of psychomotor
      agitation, and further characterised by talkativeness, irritable mood and
      distractability) and a "depression with flight of ideas" subtype (defined by the
      core feature of racing/crowded thoughts, and further characterised by risky
      pleasurable impulses including, among others, those with intense sexual arousal).
      We thereby documented the existence of two distinct DMX subtypes which testify to
      the clinical acumen of Kraepelin (and his pupil Weygandt) who in 1899 described
      these two subforms of depressive mixed states in more severely ill hospitalised
      patients.

PMID- 15179671
TI  - Serotonin syndrome associated with fluoxetine and olanzapine.
AB  - This case report describes a patient with treatment-resistant depression treated
      with fluoxetine and olanzapine who developed serotonin syndrome.

PMID- 15179672
TI  - Let the facts prevail.

PMID- 15179673
TI  - [Histamine and diseases of central nervous system].

PMID- 15179674
TI  - [Reversing effect of histamine on neuron death induced by N-methyl-D-aspartate].
AB  - OBJECTIVE: To determine the effect of histamine on N-methyl-D-aspartate (NMDA)
      induced neuron death and to elucidate its mechanism. METHODS: The primary
      cortical cell culture was adopted. Neuron morphology and MTT assay were used to
      evaluate the drugs effects. RESULT: Histamine at doses of 10(-4) 10(-6) 10(-7)
      10(-8) mol/L reversed the neuron death induced by NMDA (50 micromol/L) for 3 h.
      The protection of histamine peaked at doses of 10(-4) mol/L and 10(-7)mol/L. The
      effect of histamine of 10(-7) mol/L was reversed only by cimetidine an
      H(2)receptor antagonist. However, the effect of histamine of 10(-4) mol/L was
      reversed only by pyrilamine but not cimetidine. CONCLUSION: Histamine could
      reduce neuron death induced by NMDA; its protection at a low dose might be
      mediated by H(2)receptor, and at a high dose by H(1)receptor.

PMID- 15179675
TI  - [Changes of brain mast cells after transient global ischemia in rats].
AB  - OBJECTIVE: To investigate changes of brain mast cells after transient global
      ischemia in rats. METHODS: Transient global ischemia damage was induced by four
      vessel occlusion. After 1 h to 14 days of ischemia, rats were perfused
      intracardially by 4% paraformaldehyde. The brains were dissected to serial
      sections using freeze microtome, and then stained with toluidine blue. Brain mast
      cell was observed under microscope. RESULT: Most brain mast cells were located in
      thalamus. The number of mast cells in thalamus markedly decreased during
      reperfusion after transient global ischemia. However, the degranulation rate of
      thalamus mast cells showed reverse change after ischemia. CONCLUSION: Brain mast
      cells markedly degranulate after transient global ischemia, which may be involved
      in the pathological process after ischemia.

PMID- 15179676
TI  - [Effect of alahistidine on brain histamine content and seizure development].
AB  - OBJECTIVE: To investigate the effect of alahistidine on brain histamine content
      and seizure development. METHODS: The kindling seizure was induced by ip
      injection with subconvulsant dose of pentylenetetrazole every 48 h. Monoamines
      and their metabolites were measured using a HPLC system and fluorometric assay.
      RESULT: Chronic low histamine feeding markedly decreased histamine content in
      cortex and hypothalamus, and promoted seizure development induced by
      pentylenetetrazole. However, alahistidine feed reversed the decreased histamine
      content and slowed seizure development caused by low histamine feed. Both low
      histamine and alahistidine feed had no effect on norepinephrine, dopamine and its
      metabolites. CONCLUSION: Alahistidine may affect histaminergic system and seizure
      development.

PMID- 15179678
TI  - [Influence of chronic epilepsy on spatial memory retrieval in rats].
AB  - OBJECTIVE: To investigate the influence of chronic epilepsy on spatial memory
      retrieval in rats, and to evaluate the effects of TAK-147, an
      acetylcholinesterase inhibitor, and histidine, the precursor of histamine, on the
      amnesia induced by epilepsy. METHODS: After successfully trained in the 8-arm (4
      arm baited) radial maze, the rats were ip injected with a subconvulsive dose of
      pentylenetetrazole (PTZ) every 48 h until fully kindled. Memory retrieval was
      tested at the same maze. RESULT: Impairment of memory retrieval was in a steady
      state 1 to 18 days after fully kindled, the ability of memory retrieval returned
      to the control level 31 days after fully kindled. TAK-147 showed an ameliorating
      effect on memory impairment induced by epilepsy, including reference and working
      memory in a dose-dependent manner. Histidine only ameliorated reference but not
      working memory. CONCLUSION: PTZ-kindled seizure impair spatial memory retrieval,
      which it might be due to a decrease of brain acetylcholine and histamine induced
      by epilepsy.

PMID- 15179677
TI  - [Mechanisms of the effect of brain histamine on chronic epilepsy induced by
      pentylenetetrazole].
AB  - OBJECTIVE: To investigate the mechanisms of histamine on chronic epilepsy induced
      by pentylenetetrazole (PTZ). METHODS: To induce chemical kindling, a
      subconvulsive dose (35mg/kg) of PTZ was ip injected every 48 h in rats. Behavior
      changes were observed for 30 min after every injection of PTZ. RESULT: Ip
      injection of histidine or icv injection of clobenpropit inhibited the development
      of kindling induced by PTZ, presenting prolonged latency for myoclonic jerks and
      clonic generalized seizures and depressed seizure stages in a dose-dependent
      manner. H(3)receptor agonist, immepip, and histidine decarboxylase, alpha
      fluoromethylhistidine reversed the ameliorating effect of clobenpropit on seizure
      development in a dose-dependent manner. CONCLUSION: Brain histamine plays an
      important role in protection against myoclonic jerks and clonic generalized
      clonic seizures and its action may be via H(3)receptor.

PMID- 15179679
TI  - [Effects between the first-and second-generation histamine H1-antagonists on
      seizure development of pentylenetetrazole-induced kindling in rats].
AB  - OBJECTIVE: To investigate the effects and the mechanisms of the first-generation
      histamine H(1)-antagonist diphenhydramine and the second-generation histamine
      H(1)-  antagonist fexofenadine on seizure development of pentylenetetrazole (PTZ)
      induced kindling in rats. METHODS: The first-or second-generation histamine H(1)
      antagonists and/or histidine were ip injected in rats every 48 h, followed by a
      subconvulsive dose of PTZ (35 mg/kg). Then the behavioral changes were observed
      for 30 min after every injection of PTZ. The histamine content of brain was
      measured spectrofluorometrically. RESULT: Compared with the control group,
      diphenhydramine (5 mg/kg) significantly augmented the severity of seizure
      development of PTZ-induced kindling, whereas fexofenadine (5 mg/kg) had no marked
      influence. The effects of diphenhydramine were antagonized by histidine, the
      precursor of histamine. CONCLUSION: Seizure development of PTZ-induced kindling
      is promoted by the first-but not the second  generation histamine H(1)
      antagonists via the blockade of brain histamine H(1)-receptor.

PMID- 15179680
TI  - [Effects of pentylenetetrazol at subconvulsant and convulsant dose on NMDA
      receptor subunits in rats].
AB  - OBJECTIVE: To investigate the expression of N-methyl-D-asparate (NMDA) receptor
      subunit proteins after administration of different doses of pentylenetetrazol
      (PTZ). METHODS: After ip injection of a subconvulsant (35 mg/kg) and convulsant
      (50 mg/kg) dose of PTZ, the rats were decapitated at different time points. The
      levels of cortical NR1  NR2A and NR2B subunit proteins were detected by
      immunoblotting. RESULT: 35 mg/kg PTZ and 50 mg/kg PTZ elicited different
      behavioral changes (P<0.001). The NR2A subunit in the cortex significantly
      increased 1 h after PTZ injection (P<0.05). For the 50 mg/kg group, both the NR2A
      and NR2B subunits proteins increased at 1 h in the cortex and then decreased; the
      protein levels returned to normal after 48 h. However, NR1 subunit had no
      changes. CONCLUSION: The NR2 subunit is involved in PTZ-induced seizure.

PMID- 15179681
TI  - [Insulin resistance in epileptic patients during treatment of valproic acid].
AB  - OBJECTIVE: To investigate the possible role of valproic acid therapy in the
      development of the weight gain and hyperinsulinemia of epileptic patients.
      METHODS: The weight and fasting insulin levels were measured in 43 epileptic
      patients treated with valproic acid (VPA) alone and 39 patients with
      carbamazepine (CBZ) alone for at last 2 years. The body mass index (BMI) and
      homeostasis model assessment (HOMA) index were studied in the two groups. RESULT:
      BMI was higher in the VPA-treated group (23.47+/-1.45) than that in the CBZ
      treated group (22.27+/-2.10, P<0.05). Fasting insulin level and HOMA index in the
      VPA group were also higher [(6.64+/-0.79)mU/L and 1.33+/-0.21] than those in the
      CBZ group [(5.52+/- 0.52)mU/L, P<0.01; 1.15+/-0.12, P<0.01]. While BMI in the VPA
      group showed no significant correlation with plasma concentration and dose of
      valproate. CONCLUSION: VPA therapy is associated with significantly greater
      weight gain and hyperinsulinemia, suggesting development of insulin resistance.

PMID- 15179682
TI  - [Protective effect of minocycline on oxygen/glucose deprivation and NMDA-induced
      neurotoxicity in rat primary neurons and hippocampal slices].
AB  - OBJECTIVE: To develop oxygen/glucose deprivation (OGD)-and NMDA-induced
      neurotoxicity models in rat primary neurons and hippocampal slices, and to
      determine the protective effect of minocycline. METHODS: The injuries of primary
      neurons were induced by OGD or NMDA (50micromol/L). Morphological changes of
      neurons were observed, and neuron viability was evaluated by MTT assay. The
      changes of light transmittance (LT) were induced by OGD or NMDA in rat
      hippocampal slices. The effects of minocycline and MK-801, an NMDA receptor
      antagonist, were observed in the models of OGD-or NMDA-induced injuries. RESULT:
      Minocycline concentration dependently inhibited OGD  induced decrease of neuron
      viability and ameliorated neuron morphological changes at 1 and 10 micromol/L. It
      also inhibited NMDA insult at 10 and 100 micromol/L. MK-801 inhibited both
      injuries at 1 micromol/L. However, minocycline at 1 or 10 micromol/L did not
      inhibit the augment of LT in hippocampal slices induced by OGD or NMDA, while MK
      801 inhibited both OGD-and NMDA-induced LT augments. CONCLUSION: Minocycline
      protects neurons from OGD insult, which may inhibit NMDA receptor-mediated
      neurotoxicity through an indirect pathway, but has no effect on OGD-or NMDA
      induced immediate injury in hippocampal slices.

PMID- 15179683
TI  - [Investigation on release model of insoluble drug in hydroxypropyl methycellulose
      matrix tablets].
AB  - OBJECTIVE: To investigate the release model of insoluble drug carbamazepine (CBM)
      based on HPMC matrix tablets. METHODS: CBM release profile from matrices and HPMC
      erosion rate were determined. RESULT: The mathematical model by matrix erosion
      rate and drug release from HPMC K15M were established for the fractional HPMC and
      CBM released as M(P(t))/M(P(infinity))=-[0.8095ln((t))+1.2775]Meq((-0.0622t
      0.305)) and M(d(t))/M(d(infinity))=-[0.1891t-0.1294]Meq(-0.9326). In comparison
      with the data of HPMC K4M matrix erosion and CBM release from HPMC K4M matrices,
      theoretical value agreed well with experimental data. CONCLUSION: The two
      mathematical models can be satisfactorily applied to insoluble drug release,
      which is governed by matrix erosion.

PMID- 15179684
TI  - [Gene transfer by novel non-viral vector polyethylenimine].
AB  - OBJECTIVE: To investigate the influencing factors of polyethylenimine (PEI) in
      gene transfer in vitro. METHODS: Cytotoxic effects of PEI on in vitro cultured
      NIH 3T3 cells were quantified by MTT assay. The interaction between PEI and DNA
      at different charge ratios was analyzed by agarose gel electrophoresis
      retardation assay. The expression of gene transfer was monitored in Cos-7 cells
      using pEGFP and pSV beta plasmids as the reporter gene systems. Influences of
      chloroquine, albumin, serum, salt ion strength, and Mg(2+) ion and other factors
      on PEI/DNA transfer efficiency were evaluated. RESULT: The survival rate of
      NIH3T3 cells at 6 mg/L of PEI was 64.2% and at 7 mg/L of PEI was 54.4%. Gel
      electrophoresis retardation assays showed that PEI completely retarded DNA
      migration at 3.0 PEI nitrogen per DNA phosphate. Chloroquine enhanced the
      transfection efficiency of PEI. Albumin and serum in the culture medium decreased
      the transfection efficiency. HBS(HEPES buffered solution) or 150 mmol/L NaCl as
      the dilution solution of PEI/DNA was superior over 278 mmol/L glucose solution in
      the transfection efficiency. Mg(2+) in the dilution solution decreased the
      transfer efficiency of PEI/DNA. CONCLUSION: PEI is efficient gene transfer agent
      of eukaryotes in vitro, and can be possibly used in vivo.

PMID- 15179685
TI  - [DNA repair of CHL cells and HeLa cells after DNA damage induced by different
      oxidative agents].
AB  - OBJECTIVE: To investigate DNA repair in CHL cells and HeLa cells after DNA damage
      induced by different oxidative agents. METHODS: CHL cells and HeLa cells were
      exposed to various damaging agents, CHL cells: H(2)O(2) for 25 min, K(2)Cr(2)O(7)
      for 105 min, doxorubicin (Dox) for 75 min HeLa cells: H(2)O(2) for 25 min,
      K(2)Cr(2)O(7) for 105 min; then cells were continuously cultured for 0-3 h after
      washing. Alkaline single cell gel electrophoresis (ASCGE) assay was used to
      detect DNA strand breaks. RESULT: (1) DNA strand breaks were induced in CHL cells
      after exposure to H(2)O(2) K(2)Cr(2)O(7) or Dox, which were repaired evidently
      after continuous culture for 1 h(P<0.01). The damages induced by H(2)O(2) or
      K(2)Cr(2)O(7) were repaired completely after culture for 2-3 h. However, the
      demage induced by Dox was repaired incompletely. (2) DNA strand breaks were
      induced also in HeLa cells after exposure to H(2)O(2) or K(2)Cr(2)O(7), which
      were repaired evidently after continuous culture for 0.5 h(P<0.01),and completely
      after culture for 1 h. (3) The regression coefficient related to the rate of
      comet cells and repair time was statistically different (P<0.05) between CHL
      cells and HeLa cells. CONCLUSION: DNA damage induced by Dox is repaired more
      difficult than that induced by H(2)O(2) or K(2)Cr(2)O(7). The repair initiates
      immediately after DNA damage in both of cells, but more rapidly in HeLa cells
      than in CHL cells.

PMID- 15179686
TI  - [Enhancing effect of isoflavonoid genistein on radiosensitivity of DU145 prostate
      cancer cells].
AB  - OBJECTIVE: To study the enhancing effect of isoflavonoid genistein in irradiation
      (IR) on prostate DU145 cancer cells. METHODS: Prostate cancer cell line DU145 was
      used in this experiment. Clonogenic assay was applied to compare the survival
      fractions of DU145 cells after treatments with genistein alone and/or graded IR.
      DNA electrophoresis and TUNEL method were applied to detect cell apoptosis. Cell
      cycle was observed using flow cytometry and related protein expressions by
      immunoblotting. RESULT: Clonogenic assay demonstrated that genistein, even at low
      to medium concentrations, enhanced the radiosensitivity of DU145 cells. After
      treatments with IR and/or genistein for 24 h, apoptosis was mainly seen with
      genistein at high concentration and was minimally dependent on IR. Apoptosis also
      occurred after treatments for 72 h with lower concentrations of genistein,
      especially when combined with IR. While IR or genistein led to a G2/M cell cycle
      arrest, combination of them could further increase DU145 cells at G2/M phase.
      This G2/M arrest was largely maintained at 72 h, and accompanied by increasing
      apoptosis and hyperdiploid cell populations. Cell-cycle related protein analysis
      disclosed biphasic changes in cyclin B1, less markedly increased cdc-2 and stably
      elevated p21(cip1) levels with increasing genistein concentrations. CONCLUSION:
      Genistein could enhance the radiosensitivity of DU145 prostate cancer cells. The
      mechanisms might be involved in the increased apoptosis, prolonged cell cycle
      arrest and impaired damage repair induced by the combined treatment.

PMID- 15179687
TI  - [Expression of matrix metalloproteinase-2 and-9 in kidney of diabetic rats].
AB  - OBJECTIVE: To investigate the expression of matrix metalloproteinase-2 (MMP-2),
      matrix metalloproteinase-9(MMP-9), transforming growth factor beta(1)(TGF
      beta(1)) and IV-collagen (C-IV) in kidneys of diabetic rats. METHODS: Rat
      diabetic model was induced by streptozotocin (70 mg/kg), and kidneys were
      examined pathologically and the expressions of MMP-  2, MMP-9, TGF-beta(1) and C
      IV were studied by immunohistochemistry. The results were analyzed by imaging
      quantitative analysis technique. RESULT: Immunoreactive MMP-2 and MMP-9 were
      mainly expressed in the mesangial cells, endothelial cells, parietal layer of
      Bowman's capsule and tubular cells. The expression of MMP-2 was significantly
      weaker in the glomeluri of diabetic rats than that of the control animals
      (P<0.05), while the expression of TGF-beta(1) and C-IV in the glomeluri of
      diabetic rats was significantly stronger than that of the controls (P%lt;0.05).
      The expression of MMP-9 didn't show significant different in glomeluri of the two
      groups (P>0.05). CONCLUSION: Expression of MMP-2 in glomeluri is decreased in
      diabetic rats, which may be related to the increased TGF-beta(1) and in turns
      promote the accumulation of C-IV.

PMID- 15179688
TI  - [Magnetic resonance behavior of lipiodol--an experimental study].
AB  - OBJECTIVE: To describe the characteristics of magnetic resonance (MR) signals
      generated by lipiodol and to assess the influence on MR imaging of hepatoma
      nodule. METHODS: Pure lipiodol and lipiodol emulsions mixed with 76% urografin in
      different ratio were imaged by both CT and MR; quantitative T(1) and T(2)
      measurements of lipiodol were performed. Fourty-one SD rats with transplanted
      walker-256 sarcoma in liver were randomly divided into six groups: 0.4-0.6 ml
      lipiodol emulsion was infused via hepatic artery in experimental groups by means
      of laparotomy under celiac anesthesia. The changes in MRI signal of hepatoma
      nodule were observed. RESULT: In vitro, iodized oil demonstrated high signal on
      T(1)-weighted images when performed at 37 degree, but all could be suppressed by
      the fat saturation sequence, and showed very low signal on T(2)-weighted images.
      The characteristic of MR signal with ultra fluid lipiodol was different from that
      of iodized oil (P<0.01), showing short T(1) and long T(2) signal; the high signal
      on T(1)-weighted images was only partially suppressed by the fat saturation
      sequence. With descending ratio of lipiodol in emulsion, the signal behavior was
      gradually similar to urografin (r -0.958, P<0.01). When rats were transarterially
      infused with emulsion, the intensity of the signal on MRI was nearly the same as
      that in the control rats, but when lipiodol was injected out of the hepatic
      artery and accumulated in lymphadenopathy, it demonstrated a signal similar to
      fat; the high intensity signal was maintained on T(1)-weighted images and T(2)
      weighted images. CONCLUSION: There are little changes in MR signal intensity when
      the lipiodol is accumulated in the tumor nodules. MR behavior of lipiodol is
      determined by its deposit area.

PMID- 15179689
TI  - [Effect of homocysteine on NF-kappaB activity in cultured rat vascular smooth
      muscle cells].
AB  - OBJECTIVE: To investigate the effect of homocysteine (Hcy) on nuclear factor
      kappaB (NF-kappaB) activity in cultured rat vascular smooth muscle cells (VSMCs).
      METHODS: Rat VSMCs were stimulated with 0.25 mmol/L Hcy. Cells were collected and
      nuclear protein was extracted at 30 min, 1 h and 2 h following stimulation. NF
      kappaB activity was examined by electrophoretic mobility shift assay (EMSA).
      RESULT: Baseline NF-kappaB nuclear binding in VSMCs increased more than 1.76-fold
      at 30 min (P<0.01), 1.91-fold at 1h (P<0.01) and 1.84-fold at 2 h (P<0.01)
      following stimulation of Hcy. CONCLUSION: Hcy can enhance transient mobilization
      of N-kappaB in VSMCs, which suggests that some regulating effect of Hcy on VSMCs
      might be exerted through NF-kappaB activation pathway.

PMID- 15179690
TI  - [Effect of finasteride on intraoperative bleeding and irrigating fluid absorption
      during transurethral resection of prostate: a quantitative study].
AB  - OBJECTIVE: To evaluate the effect of pretreatment with finasteride in decreasing
      intraoperative bleeding and irrigating fluid absorption during transurethral
      resection of prostate (TURP). METHODS: Eighty patients with benign prostate
      hypertrophy undergoing TURP were divided into two groups: 40 patients were
      pretreated with finasteride for 7 to 14 days before TURP and 40 patients without
      pretreatment. Absorption of irrigating fluid was quantified by analyzing the
      serum concentration of gentamycin. Intraoperative blood loss was calculated based
      on hemoglobin concentrations before and after operation. RESULT: The whole blood
      loss, hemoglobin concentration of irrigating fluid used, blood loss per minute,
      blood loss per gram tissue resected, whole irrigation absorption, irrigation
      absorption per minute and per gram tissue resected in patients pretreated with
      finasteride were significantly less than those in patients without pretreatment
      (P<0.05). The blood transfusion volume, the incidence of hypotension and
      hyponatremia in patients pretreated with finasteride were significantly less than
      those in patients without pretreatment (P<0.05). CONCLUSION: Pretreatment with
      finasteride is of value in reducing intraoperative bleeding, irrigation
      absorption and perioperative complication during TURP.

PMID- 15179691
TI  - [Left renal vein transposition in treatment of the left renal vein nutcracker
      syndrome].
AB  - OBJECTIVE: To improve the operative procedure of the left renal vein nutcracker
      syndrome. METHODS: Two patients underwent transposition of the left renal vein in
      the treatment of the left renal vein nutcracker syndrome. RESULT: Renal ischemia,
      due to clamping of the renal artery, lasted 14 minutes and 13 minutes,
      respectively. The gross hematuria disappeared 1 day and 4 days respectively after
      surgery, and microhematuria ceased spontaneously 5 days and 7 days respectively
      after surgery. Transposition of the left renal vein effectively relieved the
      symptoms related to the left renal vein nutcracker syndrome. The patients had no
      recurrence of symptoms following up during 3 months. CONCLUSION: Transposition of
      the left renal vein is a safe and effective surgical approach in the treatment of
      the left renal vein nutcracker syndrome.

PMID- 15179692
TI  - [Study on registration method of functional SPECT brain imaging with CT anatomic
      brain imaging].

PMID- 15179693
TI  - [CT evaluation of lymphoma in the abdominal lymph nodes].

PMID- 15179694
TI  - [Proliferation of neural stem cell and therapy of neuronal degenerative
      diseases].

PMID- 15179695
TI  - The FDA, politics, and plan B.

PMID- 15179696
TI  - The changing face and implications of childhood obesity.

PMID- 15179697
TI  - The changing face and implications of childhood obesity.

PMID- 15179698
TI  - Estrogen plus progestin and colorectal cancer in postmenopausal women.

PMID- 15179699
TI  - Estrogen plus progestin and colorectal cancer in postmenopausal women.

PMID- 15179700
TI  - Impaired mitochondrial activity and insulin-resistant offspring of patients with
      type 2 diabetes.

PMID- 15179701
TI  - Impaired mitochondrial activity and insulin-resistant offspring of patients with
      type 2 diabetes.

PMID- 15179702
TI  - Impaired mitochondrial activity and insulin-resistant offspring of patients with
      type 2 diabetes.

PMID- 15179703
TI  - Return to El Calaboz. Interview by James E Mattson.

PMID- 15179704
TI  - Tool for developing clinical leadership.

PMID- 15179705
TI  - Becoming a transformational leader through reflection.

PMID- 15179706
TI  - Improving communication through practical reflection.

PMID- 15179707
TI  - Worth a thousand words.

PMID- 15179708
TI  - Elephant in the living room.

PMID- 15179709
TI  - Nurse-led train-the-trainer program breaks new ground in HIV/AIDS care.

PMID- 15179710
TI  - Honor Society of Nursing partners with EPA to reduce environmental risks for
      aging.

PMID- 15179711
TI  - Indiana passes balancing act in long-term care; Honor Society of Nursing lends
      support to public awareness program.

PMID- 15179712
TI  - Quantum dynamics of gas-phase SN2 reactions.
AB  - Understanding the state-resolved dynamics of elementary chemical reactions
      involving polyatomic molecules, such as the well-known reaction mechanism of
      nucleophilic bimolecular substitution (SN2), is one of the principal goals in
      chemistry. In this Review, the progress in the quantum mechanical treatment of
      SN2 reactions in the gas phase is reviewed. The potential energy profile of this
      class of reactions is characterized by two relatively deep wells, which
      correspond to pre- and post-reaction chargedipole complexes. As a consequence,
      the complex-forming reaction is dominated by Feshbach resonances. Calculations in
      the energetic continuum constitute a major challenge because the high density of
      resonance states imposes considerable requirements on the convergence and the
      energetic resolution of the scattering data. However, the effort is rewarding
      because new insights into the details of multimode quantum dynamics of elementary
      chemical reactions can be obtained.

PMID- 15179713
TI  - Electronic structure and chemical reactivity of carbon nanotubes: a chemist's
      view.
AB  - A qualitative description of the electronic structure of single-wall carbon
      nanotubes from a chemical perspective is presented using real-space orbital
      representations and traditional concepts of aromaticity, orbital symmetry and
      frontier orbitals. This unusual view of carbon nanotubes allows us to merge the
      solid-state physics description of band structures with the molecular orbitals
      framework of reaction mechanisms used in organic chemistry and to predict
      intriguing chemical selectivity based on electronic structure.

PMID- 15179714
TI  - Molecular beams and model catalysis: activity and selectivity of specific
      reaction centers on supported nanoparticles.
AB  - Reaction kinetics on nanometer-scale particles are different from those on
      extended surfaces of bulk materials. This fact has been utilized for a long time
      to empirically maximize the performance of heterogeneous catalysts, but the
      understanding of the underlying effects is poor at the microscopic level. Modern
      molecular beam-based methods, however, allow us to derive very detailed kinetic
      information on catalytically active surfaces. In combination with structurally
      highly controlled model catalysts, microscopic insights into the activity and
      selectivity of specific reaction centers on catalyst nanoparticles can be
      obtained. This combined approach is illustrated through simple model reactions.

PMID- 15179715
TI  - Comparison of properties of Aib-rich peptides in crystal and solution: a
      molecular dynamics study.
AB  - In order to study the differences of the structural properties of Aib-rich
      peptides in solution and in the crystalline state, molecular dynamics (MD)
      simulations of the Aib-containing peptide II (pBrBz-(Aib)5-Leu-(Aib)2-OMe) were
      performed in the crystalline state, starting from two different conformers
      obtained experimentally by X-ray diffraction. The structural properties as
      derived from X-ray crystallography (e.g., torsional angles and hydrogen bonds)
      are well-reproduced in both constant-volume and constant-pressure simulations,
      although the force-field parameters used result in a too-high density of the
      crystals. Through comparison with the results from previous MD and nuclear
      magnetic resonance (NMR) studies of the very similar peptide I (Z-(Aib)s-Leu
      (Aib)2-OMe) in dimethylsulfoxide (DMSO) solution, it is found that, in the
      crystal simulation, the conformational distribution of peptide II is much
      narrower than that in the solution simulation of peptide. I. This leads to a
      significant difference in 3 [symbol: see text] (HN, HC alpha) coupling constant
      values, in agreement with experimental data, whereas the NOE intensities or
      proton-proton distance bounds appear insensitive to the difference in
      conformational distribution. For small peptides the differences between their
      conformational distribution in the crystalline form and in solution may be much
      larger than for proteins, a fact which should be kept in mind when interpreting
      molecular properties in the solution state by using X-ray crystallographic data.

PMID- 15179716
TI  - Probing the basicity of regular and defect sites of alkaline earth metal oxide
      surfaces by BF3 adsorption: a theoretical analysis.
AB  - The basicity of regular and low-coordinate (LC) sites (steps, edges and corners)
      at the surface of alkaline earths with NaCl structure (MgO, CaO, SrO, and BaO)
      has been investigated by using BF3 as a probe molecule. B-O and B-F distances; O
      B-F bond angles; B-F asymmetric stretching frequencies; O, B and F 1s core-level
      binding energies; and the interaction energy of adsorbed BF3 were determined by
      means of DFT calculations on cluster models. These adsorption properties were
      compared with those of complexes of BF3 with molecules with various basicities
      (water, ammonia, phosphine, etc.). We show that many properties of adsorbed BF3,
      and in particular the experimentally accessible shifts in vibrational frequency,
      in B and F 1s core levels, and in BF3 desorption temperature, exhibit a linear
      correlation with the surface basicity as measured by the vertical ionization
      potential of the oxide anions. On the other hand, shifts of the O 1s core level
      binding energy do not provide a simple way to detect surface basicity. On a given
      oxide surface, the differing basicities of various sites result in measurable
      differences in adsorption properties. This suggests the potential use of BF3 as a
      probe molecule for titrating LC sites on the surface of ionic oxides.

PMID- 15179717
TI  - Effects of ion-carrier substituents on the potentiometric-response
      characteristics in anion-selective membrane electrodes based on iron porphyrins.
AB  - The potentiometric response characteristics with respect to salicylate anion of
      several membrane electrodes based on iron(III) tetraphenylporphyrin chloride
      (FeTPPCl) and derivatives with electrophilic and nucleophilic substituents,
      incorporated into plasticized polyvinylchloride (PVC) membranes were
      investigated. Complexes tetraphenyl porphyrin iron(III) chloride (FeTPPCl; A),
      tetrakis (4-methoxyphenyl) porphyrin iron(III) chloride (Fe(TOCH3PP)Cl; B),
      tetrakis (2,6-dichlorophenyl) porphyrin iron(III) chloride (Fe(TDClPP)Cl; C),
      tetrakis (4-nitrophenyl) porphyrin iron(III) chloride (Fe(TNO2PP)Cl; D), and
      tetrakis (pentafluorophenyl) porphyrin iron(III) chloride (Fe(TPFPP)Cl; E) were
      used as anion carriers in the membrane electrodes. The sensitivity, working
      range, detection limit, response mechanism, and selectivity of the membrane
      sensor toward interference shows a considerable dependence on the type of carrier
      substituent and the pH value of the sample solution. Potentiometric
      investigations in solutions of various pH show that the carrier complex
      containing fluoro substituents (E), which have very strong electron-accepting
      properties and a high ability to form hydrogen bonds, is capable of serving as a
      positively charged ionophore. Some other ionophores are capable of serving as
      both charged and neutral carriers under different conditions. The electrodes
      prepared in this work show super-Nernstian slopes with respect to salicylate
      concentration, which tend to a Nernstian response (slope near to -59 mV decade-1)
      upon an increase of the pH of the test solution. The results of UV/Vis absorption
      spectroscopy are used for interpretation of the formation of an oxene complex
      between salicylate and iron porphyrins.

PMID- 15179718
TI  - Kinetics and mechanism of the C6H5 + CH3CHO reaction: experimental measurement
      and theoretical prediction of the reactivity toward four molecular sites.
AB  - The kinetics and mechanism of the reaction of C6H5 with CH3CHO have been
      investigated experimentally and theoretically. The total rate constant for the
      reaction has been measured by means of the cavity ring-down spectrometry (CRDS)
      in the temperature range 299-501 K at pressures covering 20-75 Torr. The overall
      bimolecular rate constant can be represented by the expression k = (2.8 +/- 0.2)
      x 10(11) exp[-(700 +/- 30)/T] cm3 mol-1 s-1, which is slightly faster than for
      the analogous C6H5 + CH2O reaction determined with the same method in the same
      temperature range. The reaction mechanism for the C6H5 + CH3CHO reaction was also
      explored with quantum-chemical calculations at various hybrid density functional
      theories (DFTs) and using ab initio high-level composite methods. The theories
      predict that the reaction may occur by two hydrogen-abstraction and two addition
      channels with the aldehydic hydrogen-abstraction reaction being dominant. The
      rate constant calculated by the transition state theory for the aldehydic
      hydrogen-abstraction reaction is in good agreement with the experimental result
      after a very small adjustment of the predicted reaction barrier (+0.3 kcal mol
      1). Contributions from other product channels are negligible under our
      experimental conditions. For combustion applications, we have calculated the rate
      constants for key product channels in the temperature range of 298-2500 K under
      atmospheric-pressure conditions; they can be represented by the following
      expressions in units of cm 3mol-1 s-1: k1,cho = 8.8 x 10(3)T2.6 exp(-90/T),
      k2,ch3 = 6.0 x 10(1)T3.3 exp(-950/T), k3a(C6H5COCH3 + H) = 4.2 x 10(5)T0.6 exp(
      410/T) and k3b(C6H5CHO + CH3) = 6.6 x 10(9)T-0.5 exp(-310/T).

PMID- 15179719
TI  - Abrasively immobilised multiwalled carbon nanotube agglomerates: a novel
      electrode material approach for the analytical sensing of pH.
AB  - We demonstrate for the first time that agglomerates of multiwalled carbon
      nanotubes (MWCNTs) can be formed in which the binder in the agglomerate is itself
      a redox-active molecular solid. Two separate agglomerates were formed by
      dissolving 9,10-phenanthraquinone (PAQ) or 1,2-napthaquinone (NQ) in acetone
      together with MWCNTs and adding an excess of aqueous solution to cause
      precipitation of agglomerates, approximately 10 microns in dimension, which
      consist of bundles of nanotubes running into and throughout the amorphous
      molecular solid that binds the agglomerate together. The nature of this
      structure, when immobilised on a substrate electrode and in contact with aqueous
      electrolyte solutions, gives rise to many three-phase boundaries,
      electrolyte|agglomerate|conductor, which is advantageous to the solid-state
      analytical electrochemistry of such a material as it imparts a larger
      electroactive surface area than other modified carbon electrodes. The two
      agglomerates each gave a voltammetrically measurable response to changes in pH;
      when abrasively immobilised on a basal plane pyrolitic graphite electrode a plot
      of peak potential against pH produced a linear response for both MWCNT-PAQ and
      MWCNT-NQ agglomerates over the pH range pH 1-12 and over the temperature range 20
      70 degrees C.

PMID- 15179720
TI  - Photophysical aspects of single-molecule detection by two-photon excitation with
      consideration of sequential pulsed illumination.
AB  - An important goal in single molecule fluorescence correlation spectroscopy is the
      theoretical simulation of the fluorescence signal stemming from individual
      molecules and its autocorrelation function. The simulation approaches developed
      up to now are based exclusively on continuous-wave (cw) illumination and
      consequently on cw-excitation. However, this approximation is no longer valid in
      the case of two-photon excitation, for which pulsed illumination is usually
      employed. We present a novel theoretical model for the simulation of the
      fluorescence signal of single molecules and its autocorrelation function with
      consideration of the time dependence of the excitation flux and thus of all
      illumination-dependent photoprocesses: two-photon excitation, induced emission
      and photobleaching. Further important characteristics of our approach are the
      consideration of the dependence of the photobleaching rate on illumination and
      the low intersystem-crossing rates of the studied coumarins. Moreover, using our
      approach, we can predict quantitatively the effect of the laser pulse width on
      the fluorescence signal of a molecule, that is, the contributions of the
      photobleaching and saturation effects, and thus we can calculate the optimal
      laser pulse width. The theoretical autocorrelation functions were fitted to the
      experimental data, and we could ascertain a good agreement between the resulting
      and the expected parameters. The most important parameter is the photobleaching
      constant sigma, the cross section of the transition Sn<--S1, which characterises
      the photostability of the molecules independent of the experimental conditions.
      Its value is 1.7 x 10(-23) cm2 for coumarin 153 and 5 x 10(-23) cm2 for coumarin
      314.

PMID- 15179721
TI  - Dissolution of crystallites: surface energetic control and size effects.
AB  - Traditional understanding of dissolution assumes that the reaction is spontaneous
      and continues until equilibrium is reached. This paper presents theoretical and
      experimental data to support a dissolution mechanism that involves the existence
      of critical conditions for dissolution, in which the reaction is accompanied by
      the formation of pits and the subsequent displacement of pit steps. The
      accompanying increase in surface roughness leads to changes in surface energy
      with losses of crystal mass that are positive rather than negative and the
      existence of critical dissolution conditions. Critical pits and dissolution steps
      are verified experimentally and a relationship between the size and rate of
      displacement of steps is also demonstrated, in which the rate decreases with size
      and approaches zero at a critical size, r*. These microscopic step dynamics are
      consistent with the observed size-effects in bulk dissolution, which cannot be
      explained using traditional dissolution theories. The observed size effects
      include self-inhibition, in which the dissolution rate decreases with extent of
      reaction, dissolution suppression, and periodic resumption. These interesting
      dissolution phenomena are only readily displayed when the sizes of dissolving
      crystallites fall in the same range as the critical size (i.e., within 50r*). It
      is interesting to note that natural biominerals and many nanoparticles fall into
      this category, so that their suspensions can be dynamically stabilized without
      dissolution in undersaturated supporting media. The current research implies that
      dissolution kinetics cannot be understood well without appealing to fundamental
      physical concepts about the energetic control of dissolution steps on a molecular
      level. A new dissolution model for crystallites is introduced systemically.

PMID- 15179722
TI  - Reactive ion surface scattering as an Eley-Rideal process: a molecular dynamics
      study into the abstraction reaction mechanism by low energy Cs+ from Pt(111).
AB  - We have employed a classical molecular dynamics simulation for the direct pick-up
      reaction of adsorbates by very low energy (1-60 eV) ions scattered at a surface.
      The system investigated is the reactive ion scattering (RIS) of Cs+ with an
      adsorbate on a Pt(111) surface. The ion-dipole attraction between the projectile
      and the physisorbed adsorbate drives the abstraction reaction, in which the ion
      projectile at first collides with the surface to release a substantial amount of
      its kinetic energy, and subsequently pulls the adsorbate along in the outgoing
      trajectory. Desorption induced by the ion-dipole attraction is a precursor to the
      formation of the Cs(+)-adsorbate product. This Eley-Rideal-type mechanism must
      accommodate the inertia of the adsorbate. Consequently, a successful abstraction
      works well only for low mass adsorbates and slow outgoing Cs+ ions. The efficient
      energy transfer to the Pt(111) surface makes Cs+ a better candidate for RIS than
      lighter projectile ions. Optimal conditions for the efficient RIS abstraction
      mechanism are found for physisorbed adsorbates with a mass below 32 amu, and for
      10 eV Cs+ ions at a 45 degrees incidence.

PMID- 15179723
TI  - Ultrafast proton-coupled electron-transfer dynamics in pyrene-modified pyrimidine
      nucleosides: model studies towards an understanding of reductive electron
      transport in DNA.
AB  - 5-(Pyren-1-yl)-2'-deoxyuridine (PydU) and 5-(Pyren-1-yl)-2'-deoxycytidine (PydC)
      were used as model nucleosides for DNA-mediated reductive electron transport (ET)
      in steady-state fluorescence and femtosecond time-resolved transient absorption
      spectroscopy studies. Excitation of the pyrene moiety in PydU and PydC leads to
      an intramolecular electron transfer that yields the pyrenyl radical cation and
      the corresponding pyrimidine radical anion (dU.- and dC.-. By comparing the
      excited state dynamics of PydC and PydU, we derived information about the energy
      difference between the two pyrimidine radical anion states. To determine the
      influence of protonation on the rates of photoinduced intramolecular ET, the
      spectroscopic investigations were performed in acetonitrile, MeCN, and in water
      at different pH values. The results show a significant difference in the basicity
      of the generated pyrimidine radical anions and imply an involvement of proton
      transfer during electron hopping in DNA. Our studies revealed that the radical
      anion dC.- is being protonated even in basic aqueous solution on a picosecond
      time scale (or faster). These results suggest that protonation of dC.- may also
      occur in DNA. In contrast, efficient ET in PydU could only be observed at low pH
      values (< 5). In conclusion, we propose--based on the free energy differences and
      the different basicities--that only dT.- but not dC.- can participate as an
      intermediate charge carrier for excess electron migration in DNA.

PMID- 15179724
TI  - Spontaneous organization of individual silver nanoparticles into one
      dimensionally ordered nanostructures.

PMID- 15179725
TI  - A novel and efficient system of a visible-light-responsive organic
      photoelectrocatalyst working in a water phase.

PMID- 15179726
TI  - Gold-colloid-modified AgCl photocatalyst for water oxidation to O2.

PMID- 15179727
TI  - An anhydrous proton conductor based on lactam-lactim tautomerism of uracil.

PMID- 15179728
TI  - DNA-based formation of a supported, three-dimensional lipid vesicle matrix probed
      by QCM-D and SPR.

PMID- 15179729
TI  - Oxide surfaces that catalyse an acid-base reaction with surface lattice oxygen
      exchange: evidence of nucleophilicity of oxide surfaces.

PMID- 15179730
TI  - Structural distortion of pyridazine in the 1(n, pi) excited state: evidence for
      local excitation.

PMID- 15179731
TI  - Probing the vibrations of shared, OH+O-bound protons in the gas phase.

PMID- 15179732
TI  - Sensitized emission in Ln(3+)-doped TiO2 semiconductor nanoparticles.

PMID- 15179734
TI  - Large-area fabrication of a nanostructure-induced hydrophobic surface from a
      hydrophilic polymer.

PMID- 15179733
TI  - Parallel beta-sheet assemblies at interfaces.

PMID- 15179735
TI  - Reducing medical errors. IT helps secure the patient safety net.

PMID- 15179736
TI  - Reality EMRs. Coming soon to an organization near you--electronic record keeping.

PMID- 15179737
TI  - Filing for dollars. Claims clearinghouses are moving downmarket with upmarket
      products.

PMID- 15179738
TI  - Combatting crisis. When did you last revamp your disaster recovery strategy?

PMID- 15179739
TI  - Maximizing IT in smaller hospitals. Benefits of combined clinical information and
      cost accounting systems exceed those of either one alone.

PMID- 15179740
TI  - IT stitches up surgery data. The surgical suite can put automation to good use.

PMID- 15179741
TI  - Automation optimizes nursing workflow. An organization follows its pledge to lead
      with process, enable with technology.

PMID- 15179742
TI  - Content management. Could your organization use some help in tackling JCAHO
      compliance?

PMID- 15179743
TI  - Physical and psychological partner aggression across a decade: a growth curve
      analysis.
AB  - The course of physical and psychological partner aggression was investigated over
      a decade in 203 wives from Suffolk County, New York. Wives reported on their own
      and on their partners' aggression at one month before marriage and 6, 18, 30, and
      120 months after marriage. This follow-up is the longest period over which
      partner aggression has been examined. Prevalence rates of wife's report of wife-
      and husband-perpetrated physical aggression were 48% and 35% at premarriage, and
      13% and 10% ten years later. Using HLM, husband- and wife-perpetrated physical
      aggression were found to decrease on average approximately one act of aggression
      per month, regardless of severity and even when controlling for changes in
      marital satisfaction. There was no significant pattern of change in psychological
      aggression. These findings are consistent with cross-sectional analyses, and
      suggest that physical partner aggression decreases in community samples of
      couples.

PMID- 15179744
TI  - Male partner violence against women in stepfamilies: an analysis of risk and
      explanations in the Canadian milieu.
AB  - Using a representative sample of 2,703 Canadian women living in either a
      stepfamily or a biological family, this investigation assesses the extent of
      women's elevated risk for violence in stepfamilies relative to biological
      families as well as explanations for this relationship. Canadian women living in
      stepfamilies are shown to be twice as likely as their counterparts in biological
      families to experience violence. Differences between the two groups are greatest
      on some of the most severe forms of violence, suggesting that women in
      stepfamilies are at particular risk for severe violence. Institutional
      incompleteness (number of children; depression; alcohol consumption), duration of
      relationship, evolutionary psychology (sexual possessiveness; sexual jealousy;
      female employment; education compatibility) and selection factors (previous
      marriage/common-law union; previous partner violence; marital status) are applied
      and tested. Results show partial support for each explanation and that no
      explanation alone accounts for the disproportionate risk of violence in
      stepfamilies. Rather, a combination of elements from all explanations is required
      to account for the higher odds of violence against women in stepfamilies.

PMID- 15179745
TI  - Rural and urban women's perceptions of barriers to health, mental health, and
      criminal justice services: implications for victim services.
AB  - The purpose of this study was to examine rural and urban women's perceptions of
      barriers to health and mental health services as well as barriers to criminal
      justice system services. Eight focus groups were conducted, two in a selected
      urban county (n = 30 women) and two in each of three selected rural counties (n =
      98 women). Results were classified into a barrier framework developed in the
      health service utilization literature which suggests there are four main
      dimensions of barriers: affordability, availability, accessibility, and
      acceptability. Results indicate that: (1) women face many barriers to service use
      including affordability, availability, accessibility, and acceptability barriers;
      (2) it takes an inordinate level of effort to obtain all kinds of services;
      however, women with victimization histories may face additional barriers over and
      above women without victimization histories; (3) barriers to health and mental
      health service utilization overlap with barriers to utilizing the criminal
      justice system; and (4) there are many similarities in barriers to service use
      among rural and urban women; however, there are some important differences
      suggesting barriers are contextual. Future research is needed to further clarify
      barriers to service use for women with victimization histories in general, and
      specifically for rural and urban women. In addition, future research is needed to
      better understand how women cope with victimization in the context of the
      specific barriers they face in their communities.

PMID- 15179746
TI  - The role of alcohol use in intimate partner violence and non-intimate partner
      violence.
AB  - Alcohol use is a risk factor for violent victimization in general, and intimate
      partner violence in particular. However, there has been limited empirical
      attention on whether alcohol use is more often associated with IPV or non-IPV
      offenses. Further, few studies on the association between alcohol use and
      victimization have assessed for incident-specific alcohol use, or examined both
      victim and perpetrator alcohol use. We used data from the National Violence
      Against Women Survey to determine if incident-specific alcohol use is more
      prevalent in IPV or non-IPV physical assaults, and to determine if the
      association varied by gender. Results indicated that among women, perpetrator
      alcohol use was twice as likely in IPV incidents than in non-IPV incidents, but
      among men, perpetrator alcohol use was four times less likely in IPV incidents
      than in non-IPV incidents. Our results highlight the important role of gender in
      understanding the association between alcohol use and victimization risk.

PMID- 15179747
TI  - Methods of filicide: stepparents and genetic parents kill differently.
AB  - Stepparents commit filicide at higher rates than do genetic parents. According to
      M. Daly and M. I. Wilson (1994), motivational differences generate differences in
      the methods by which stepparents and genetic parents kill a child. Using Canadian
      and British national-level databases, Daly and Wilson (1994) found that
      stepfathers were more likely than genetic fathers to commit filicide by beating
      and bludgeoning, arguably revealing stepparental feelings of bitterness and
      resentment not present to the same degree in genetic fathers. Genetic fathers, in
      contrast, were more likely than stepfathers to commit filicide by shooting or
      asphyxiation, methods which often produce a relatively quick and painless death.
      We sought to replicate and extend these findings using a United States national
      level database of over 400,000 homicides. Results replicate those of Daly and
      Wilson (1994) for genetic fathers and stepfathers. In addition, we identified
      similar differences in the methods by which stepmothers and genetic mothers
      committed filicide. Discussion addresses stepparental psychology in light of the
      current research, limitations of the current study, and future directions for
      research on this topic.

PMID- 15179748
TI  - Space city revisited: patterns of legal outcomes in Houston homicide.
AB  - This study re-examines, and updates, that of Lundsgaarde (1977), who found that
      among homicide offenders in Houston, Texas, in 1969, less than 50% of those who
      killed intimates or other family members were ever prosecuted for their lethal
      acts. The general pattern that emerges from our analysis of a random sample of
      428 homicide cases during 1985 to 1994 indicates that killers of intimate
      partners or relatives are somewhat more likely to be prosecuted as offenders who
      were friends or strangers to their victims. Also during this 1985 to 1994 time
      period, the relative percent of defendants who were sentenced to a prison term of
      20 years of less was smallest for those who killed intimate partners or other
      family members compared to those convicted of killing friends/acquaintances or
      strangers. As for sex-specific legal dispositions in cases of lethal violence
      against intimates or other relatives, we found that sanctions against women were
      considerably less severe than those against male offenders, in both time periods.

PMID- 15179749
TI  - Experience of maltreatment as a child and acceptance of violence in adult
      intimate relationships: mediating effects of distortions in cognitive schemas.
AB  - Links exist between being subjected to maltreatment as a child and tendencies to
      accept violence as normative in adult relationships. Constructivist Self
      Development Theory suggests that such relationships may be affected by "cognitive
      disruptions" in "self" and "other" schemas. Mediating effects of distorted
      cognitive schemas on the association between history of child maltreatment and
      the acceptance of violence in intimate interpersonal relationships were
      investigated among 433 men and women. Outcomes indicated that individuals who
      reported childhood maltreatment were more likely to display distortions in their
      cognitive schemas and those individuals with disrupted schemas were more likely
      to accept relationship violence. Least-square multiple regression analyses
      revealed that distorted beliefs fully mediated the relationship between reporting
      childhood maltreatment and acceptance of violence, for both men and women.
      Subsidiary analyses suggested that this full mediation was replicated for schemas
      involving the self but not for schemas about others.

PMID- 15179750
TI  - Experimental avoidance as a mediator of the effects of adolescent sexual
      victimization on negative adult outcomes.
AB  - The study examined experiential avoidance as a mediator between sexual
      victimization and negative adult outcomes. Baron and Kenny's (1986) regression
      analyses were performed on a sample of 304 undergraduate women to assess direct
      and indirect effects of sexual victimization on depressive, psychological
      distress, and alcohol abuse symptoms. Experiential avoidance accounted for
      statistically significant, but modest effects of victimization on depressive and
      distress symptoms. Child sexual abuse was not directly associated with
      experiential avoidance or negative outcomes, but increased vulnerability for
      adolescent sexual victimization. Adolescent sexual victimization contributed to
      increased experiential avoidance, which was associated with greater negative
      outcomes. These results uniquely contribute to the existing literature linking
      experiential avoidance to psychological problems.

PMID- 15179751
TI  - [Overview of the history of thyroid surgery].
AB  - Thyroid gland surgery passed through history from the suggestions for
      prohibition, during middle of XIX century due to unacceptable mortality even for
      medieval condition, to highest vel of surgical laser, as W. Halsted sad. First
      thyroidectomy was done by Albucasis (El Zahrawi) in 925 a.d. and after him by
      Roger from Salerno. While Pierre-Joseph Dusalt in 1791 has done first operation
      on thyroid gland than can fulfill todays criteria, Teodor Billroth gave
      scientific grounds of thyroid surgery. Genius attitude and surgical talent of
      Theodor Kocher raised thyroid surgery o scientific level, brought surgical skills
      on the top of surgical art pyramid, and brought him personally to the Nobel Prize
      in 1909. Every important contribution to development of thyroid surgery gave its
      giants: Johann von Mikulic, William Halsted, Charles Mayo, George W. Crile and
      Rank Lahey. Thomas P. Dunhill, F.A. Coller, A.M. Boydena and many others did
      important contribution, too. Development of thyroid srugery was constant to
      nowadays, with tendention for multidisciplinary approach in specialized centres.
      Thyroid surgery in Serbia followed this world trends, in spite of treat problems
      in the area during history.

PMID- 15179752
TI  - [Rational diagnosis and surgical treatment of solitary thyroid nodules].
AB  - Few subjects in endocrine surgery have generated as much controversy as the
      management of thyroid nodule. The controversial issues include evaluation of
      laboratory findings and imaging diagnostic procedures in the patient with
      solitary thyroid nodule. The major issue in relation to controversies is choice
      of optimal diagnostic workup.

PMID- 15179753
TI  - [Cytologic evaluation of solitary thyroid nodules].
AB  - Fine-needle aspiration is a low-cost diagnostic tool with principal value in
      determining which patients with thyroid nodules should undergo surgery. Team work
      and close cooperation among endocrinologists, surgeons, and pathologists are
      essential for success. Cytologic criteria for diagnosis of the most frequent
      conditions (benign cystic lesions), Hashimoto thyroiditis and malignancies found
      in thyroid aspirates have been provided. The unsolved problem of the so-called
      "follicular" or oxyphilic lesion or neoplasia will be investigated by
      immunocytochemistry.

PMID- 15179754
TI  - [Occurrence of carcinoma in solitary thyroid nodules].
AB  - Find of malignancies in solitary thyroid gland nodes represent an entity in
      itself in thyroid surgery and endocrinology because of frequency in occurrence
      and differential diagnosis of thyroid diseases. Similarities in clinical
      characteristics and differences in the histological structure and development of
      the disease, request quick and adequate application of all available diagnostic
      procedures in evaluation of disease. After all clinic methods of examination,
      surgery includes necessary range of extraction of tissue at benign changes while
      at malignant changes radical intervention on the gland is suggested and if it is
      necessary on the surrounding structures of the neck. "Biopsio ex tempore" still
      represents vital method in histological diagnosis and help in making decision
      about radically of operative procedure. Because of that, surgery represents at
      last diagnostic and therapy procedure. Data analysis shows the presence of
      carcinoma in solitary thyroid gland nodes in 15% of all cases.

PMID- 15179755
TI  - [Current opinion on the etiology of differentiated thyroid carcinoma].
AB  - It is apparent that in the last decade carcinoma of the thyroid is becoming
      increasingly prevalent. The multistage complex theory of thyroid carcinogenesis
      is based on observations made on cohort patients studies and during animal
      experiments over a period of last fifty years. The process of thyroid oncogenesis
      is conceived to be a series of events induced by genetic and environmental
      factors which alter follicular cells division and growth control. These factors
      can be considered as initiators (chemical agents and ionising radiation) and
      promoters (some goitrogenes and drugs). The first class of factors induce
      incipient tumorigenesis while the second augments TSH secretion and radically
      increases tumour growth. Normally silent, intracellular proto-oncogenes (of which
      Ret/PTC series are the most conceived ones) can become activated by chromosomal
      translocations, deletions or mutations and can transform normal follicular cell
      into a condition of uncontrolled division and growth. The most significant known
      cause of thyroid carcinomas in men is exposure to external or internal ionising
      radiation. Beside that, long-term iodine deficiency, effects of certain chemical
      carcinogens, drugs and goitrogenes must be considered as significant risk
      factors. Possible role of sodium/iodide symporter is becoming an objective of the
      most recent investigations.

PMID- 15179756
TI  - [Classification, staging, prognostic factors and risk factors in thyroid
      carcinoma].
AB  - Thyroid carcinomas arise from follicular cells (papillary, follicular, Hurthle,
      anaplastic), parafollicular cells (medullary) and stroma (lymphoma, sarcoma).
      Gradation and prognostic factors are different for every one of histological
      type. Most patients with papillary and follicular thyroid cancer have an
      excellent prognosis. At the other extreme is anaplastic thyroid cancer whose
      usual mean survival can be measured in months. Exposure to external radiation and
      living in endemic goiter area increase the frequency of thyroid cancer. Medullary
      thyroid carcinoma is often familial and may occur in associations with the
      multiple endocrine neoplasia syndromes.

PMID- 15179757
TI  - [Pathohistologic and immunohistochemical characteristics of thyroid carcinoma].
AB  - Numerous pathohistologic criteria, difficulties and pitfalls in the process of
      diagnosing of thyroid carcinoma are discussed. Benign hyperplastic papillae may
      be present in colloidal cystic goiter and hyperplastic goiter. These structures
      are lined by cells with normochromatic nuclei and do not disturb the thyroid
      tissue architecture. Papillae in papillary thyroid carcinoma have cells with
      ground-glass, hypochromatic nuclei. Follicles inspissated in capsula of
      follicular or even colloidal adenoma may be evaluated as capsular invasion-
      diagnostic feature of follicular carcinoma. Undifferentiated thyroid carcinoma is
      sometimes similar to fibrosarcoma and reveal cellular pleomorphism, anaplasia and
      numerous foci of necrosis. Medullary thyroid carcinoma with scanty stromal
      amyloid, its papillary variant and carcinoid-like histologic type consist of oval
      cells with eosinophilic cytoplasm and dark nuclei.

PMID- 15179758
TI  - Differential expression of galectin-3 in papillary projections of malignant and
      non-malignant hyperplastic thyroid lesions.
AB  - Galectin-3 is a a beta-galactoside binding protein recently proposed to be a
      promising presurgical molecular marker for distinguishing benign from malignant
      thyroid neoplasms. We analyzed galectin-3 expression immunohistochemically in
      papillary areas of hyperplastic lesions of benign thyroid tissue in comparison
      with malignant papillary projections of papillary thyroid carcinoma (PTC). A
      monoclonal antibody to galectin-3 and ABC immunohistochemical technique were used
      to evaluate galectin-3 expression in 26 cases of benign papillary hyperplasia (8
      cases of hyperplastic adenoma, 8 cases of hyperplastic colloid goiter, 10 cases
      of Graves disease) in comparison with 25 cases of PTC. Immunohistochemical
      results showed no reactivity for galectin-3 in papillary areas of benign
      hyperplastic lesions. Strong cytoplasmic galectin-3 immunoreactivity was found in
      all 25 cases of PTC. These results show that galectin-3 expression is a feature
      of malignant papillary projections but not of benign papillary hyperplasia. Thus,
      the immunohistochemical evaluation of galectin-3 might contribute to differential
      diagnosis between malignant and benign thyroid lesions with papillary
      projections.

PMID- 15179759
TI  - [Specifics of preoperative care, intraoperative monitoring and postoperative
      evaluation of patients with thyroid carcinoma].
AB  - The aim of the study was to show the standards of preoperative management,
      intraoperative monitoring and postoperative evaluation of patients with thyroid
      gland carcinoma. It was point out the importance of the preoperative diagnosis of
      the tumor, and the concurrent diseases. The special attention was paid to
      difficult airway recognition and resolving this situation. Both, anesthetist's
      and surgeon's point of view of perioperative and postoperative complications were
      discussed with special interest on early surgical complications and the need for
      urgent anesthetic treatment. Criteria for minimal and desirable monitoring of
      vital functions were suggested in order to prevent, recognize and cure
      complications. Our conclusions were based on recent references from the world
      literature and on our own experience in Center for endocrine surgery KCS,
      Belgrade.

PMID- 15179761
TI  - [Papillary carcinoma of the thyroid in intrathoracic goiter].
AB  - Intrathoracic goiter (more than 80% of tissue in the thoracic cavity) represents
      very rare clinical entity (less than 1% of total number of thyroid gland surgical
      procedures). Cancer incidence in these goiter is 0-5%. The aim of this article is
      to present a case report of intrathoracic thyroid papillary carcinoma with
      multiple compressive syndrome and review of compressive intrathoracic syndrome of
      thyroid etiology. In our patient we have found: tracheal and oesophageal
      deviation and compression, superior vena cava syndrome, downhill varices,
      chylothorax, pericardial effusion, compress of the left a. subclavia, unilateral
      lesion of recurrent and phrenic nerve, and brachial plexopathy. This was a unique
      case with multiple compressive syndrome between 3000 patients surgically treated
      for all kinds of thyroid diseases. Intrathoracic goiter can cause all the known
      symptoms and syndromes of intrathoracic compression with possibility of rapid
      deterioration and fatal end.

PMID- 15179760
TI  - [Papillary carcinoma of the thyroid gland].
AB  - Papillary thyroid cancer is after ovarian cancer the most frequent malignant
      disease of the endocrine system and because of this fact, early detection and
      appropriate surgical treatment is essential. Radical surgical treatment lower the
      risk of the disease relapse and postoperative adjuvant therapy with radioiodine
      is possible as well as postoperative follow up with thyreoglobulin measurement.
      If the total thyroidectomy is performed in highly specialized institution the
      risk of postoperative complications is acceptable and therefore is the treatment
      of choice for papillary thyroid cancer. Only the patients with occult papillary
      thyroid cancer can be treated with hemithyroidectomy. In our series of 410
      patients the majority of the patients (85.12%) were in the early phase of the
      disease and the degree of successfully performed radical surgery for papillary
      thyroid cancer was very high (tumor reduction was performed in only 1.46% of
      cases).

PMID- 15179762
TI  - [Papillary microcarcinoma of the thyroid and secondary hyperparathyroidism in a
      patient on hemodialysis].
AB  - Association between non-medullary thyroid carcinoma and secondary
      hyperparathyroidism have been rarely reported in patients with renal failure. A
      few cases of micropapillary thyroid carcinoma have been reported in patients
      before and after renal transplantation. We present a case of incidental detection
      of thyroid carcinoma at the time of parathyroidectomy in patient on dialysis
      after cadaver renal transplantation.

PMID- 15179763
TI  - [Principles of lymph node surgery in differentiated thyroid carcinoma].
AB  - Surgery is the initial therapy in differentiated thyroid carcinoma (DTC). The
      surgery is performed on organ of tumor origin and regional lymphatic basins. The
      aim of surgery in DTC is to eradicate all tumor foci, cure the most number of
      patients, reduce recurrence and mortality rate, and provide good quality of life.
      There is no doubt between oncologists that the surgery for thyroid carcinoma has
      no alternative. The extent of surgery is matter of actual controversies. It
      should be performed by well trained surgeons. Dissection of central and biopsy of
      supraclavicular and lower third of jugulo-carotid chain of neck lymph nodes is
      the integral part of surgery in DTC, together with total thyroidectomy. If lymph
      node metastases are found in jugulo-carotid chain, modified radical neck
      dissection, unilateral or bilateral is indicated. Dissection of mediastinal lymph
      nodes should be performed too in cases of involvement. The extent of primary
      surgery should be dictated by stage of disease and prognostic factors. The
      quality of surgery and incidence of complications depends prognostic factors, as
      well as on surgeon's skill and experience. That is why the surgeon is factor of
      prognosis in treatment of patients with DTC.

PMID- 15179764
TI  - [Identification of sentinel lymph nodes in thyroid carcinoma].
AB  - Sentinel lymph node (SLN) was defined as the first lymph node that the tumor
      would drain to, within that tumors regional lymphatic basin. In 1998, Kelemen and
      coworkers have published the first results on SLN lymphonodectomy in thyroid
      carcinomas. Different methods have been used in a goal of lymphatic mapping
      (application of vital blue dye and/or radiocolloid). In a period from 2001 to
      2003 we have performed SLN biopsy in 64 patients with thyroid tumors. There were
      12 cases of thyroid carcinoma. SLN identification rate was 73.44%. We found no
      false positive or negative results on definitive histopathology. The impact of
      lymph node metastases in differentiated thyroid carcinoma is still controversial.
      The management of cervical lymph nodes varies from berry picking to modified
      radical neck dissection. There is a significant disproportion in percentage of
      pre and intraoperatively enlarged lymph nodes (27-45%) and histologically
      confirmed lymph node metastases (80-90%) in papillary thyroid carcinoma. In the
      current literature the average rate of SLN identification is 91% (66-100%) and
      when identified, the SLN accurately predicts the disease status of the neck in
      most patients (80-100%). The SLN biopsy for thyroid carcinoma is good and
      feasible technique for estimating the cervical lymph node status.

PMID- 15179765
TI  - [Follicular carcinoma of the thyroid gland].
AB  - Follicular thyroid cancer is the second most common thyroid malignancy. This
      tumor has a predisposition for hematogenous dissemination an extra thyroid
      spread. Accurate cytological diagnosis of follicular thyroid cancer is not
      possible and this fact highlights the necessity for surgical treatment of any
      suspicious thyroid nodule. Aggressiveness of this tumor is greater than in the
      case of papillary thyroid cancer and it is the reason for radical surgical
      treatment of follicular thyroid cancer. Total thyroidectomy facilitates later
      adjuvant therapy with thyroid hormones and radioiodine. This procedure improves
      the outcome and the risk of relapse. Results of our study clearly demonstrate
      that diagnosis of follicular thyroid cancer in us is established in the early
      phase of the disease (78.57%), but the significant number of the patients
      (21.43%) is still in the advanced phase of the disease.

PMID- 15179766
TI  - [Medullary carcinoma of the thyroid gland (sporadic, familial)].
AB  - Medullary thyroid cancer (MTC) is uncommon thyroid tumor with specific
      characteristics which undoubtedly divide this tumor from other thyroid
      malignancies. Patients with sporadic or hereditary form of MTC differ in clinical
      presentation, recurrence of the disease and outcome. The aim of study was to
      establish surgical characteristics of MTC as well as clinical factors that
      influence surgical treatment. The study group consisted of 68 patients with MTC
      managed at the Center for Endocrine Surgery between 1987 and 1999. Retrospective
      analysis included clinical form of the disease, general data, histological and
      other tumor characteristics. Mean age of the patients were 47.3 years
      (female/male ratio: 1.5:1). Mean size of tumor was 80.5 cm3, 72.1% patients had
      tumor greater than 4 cm. in diameter or extrathyroid spread. The majority of
      patients were in II and III stadium of the disease. Primary operation (at least
      total thyroidectomy) was performed in 57 (84%) patients. 2(3%) had
      postoperatively temporally nerve palsy and 7(10.29%) temporally
      hypoparathyroidism. The overall survival was 46.8 +/- 9.9% after 9 years and 63.6
      +/- 7.2% at 5 years. Postoperative calcitonin value is significant predictor of
      survival/Spearman's coefficient (R = 0.7048)/, worse prognosis is in correlation
      with high postoperative calcitonin values. The treatment of choice is at least
      total thyroidectomy and central lymph nodes resection if enlarged lymph nodes are
      found. Precise operative technique lowers the risk of postoperative
      complications. Complex approach to the patient with MTC includes all available
      methods in pre and postoperative evaluation as well as surgeon's knowledge and
      skill.

PMID- 15179767
TI  - Medullary thyroid carcinoma. Genetic screening and prophylactic thyroidectomies.
AB  - Medullary thyroid cancer is a rare, neuroendocrine, tumor. It arises from
      parafollicular or C-cells with the ability to produce and secrete different
      bioactive substances like calcitonin (TC) and CEA (1-5) TC is ideal tumor marker
      in early diagnosis, in patents' follow up and in evaluation of their treatment.
      TC determinations after ca/pentagastrine stimulation test give us even more
      accurate results and the procedure is used for biochemical family screening. MTC
      occurs as a sporadic tumor or in hereditary settings MEN 2A, MEN 2B and FMCT.
      Germ/line point mutations in RET proto/onkogene are responsible for tumor arise
      and inheritance of settings. Genetic screening provides information of these RET
      mutations in family members even before pathologic changes occur. These
      individuals with MEN 2A, 2B and FMCT characteristic RET mutations are almost
      certain to acquire MTC (95% penetrance) in their lives and are candidates for
      preventive total thyroidectomy (TT), with or without central neck dissection
      (CND). Surgery is still the treatment of choice for MTC and only C-cell
      hyperplasia and early stage of MTC can be cured. Prophylactic thyroid surgery
      eliminates the possibility of MTC but doesn't influence appearance of other
      diseases (PHEO, HPTH) of MEN 2 syndromes.

PMID- 15179768
TI  - [Medullary carcinoma of the thyroid gland: effect of postoperative transcutaneous
      radiotherapy on local control and results of treatment].
AB  - In the period of Octo. 01, 1987. up to Dec. 31, 1998. retrospective-prospective,
      non-randomized study was conducted at IORS, which included 36 patients diagnosed
      with thyroid gland medullar cancer. Our study had the following aims: evaluation
      of treatment results following probability of total survival, survival without
      signs of disease and disease-free interval until local recurrence of the disease
      and influence of parameters of transcutaneous radiotherapy (intensity of total
      tumor dose and length of disease-free interval from date of performed operation
      to beginning of radiotherapy). After finished treatment, median of the patient
      follow-up was 37.75 months (3.5 up to 141 months); probability of total five-year
      survival was 62.61% and of 10 year survival was 23.48%. Probability of 5-year
      survival, without signs of disease was 37.13%, and of 10-year survival 18.56%. As
      to radiotherapy parameters intensity of total therapy dose was statistically
      insignificant, while time interval to beginning of transcutaneous radiotherapy,
      shorter than 2 months, was statistically significant in relation to prognosis of
      disease outcome.

PMID- 15179769
TI  - [Anaplastic carcinoma of the thyroid gland].
AB  - The aim of the present paper was to study some characteristics and possibility of
      surgery of anaplastic thyroid cancer. During five years period in Center for
      endocrine surgery, we found anaplastic thyroid cancer in 65 patient (44 female
      and 21 male), median age 63 years (from 37 to 88 years). Surgical treatment was
      peerformed in one half (32) anaplastic thyroid cancer patients, at majority of
      them operative biopsy or tumor reduction only. Radical surgery was performed in
      about 10% patients. Possibility of surgery in anaplastic thyroid cancer are very
      limited. In one third patients there were long standing goiter or thyroid nodule
      or histological verified dedifferentiation of papillary thyroid cancer. This
      patient should be operated formerly, before anaplastic transformation.

PMID- 15179770
TI  - [Characteristics of thyroid carcinoma in Grave's disease Hashimoto's thyroiditis
      and nodular goiter].
AB  - The biology of thyroid cancer represents a spectrum of behavior ranging from well
      differentiated lesions with an excellent prognosis to anaplastic carcinoma, which
      is almost fatal. For this reason, it is important that clinicians have methods at
      their disposal to asses the characteristics of patient's thyroid malignancy. In
      this work we discuss the behavior of differentiated thyroid cancer in associated
      diseases of thyroid as: Graves' disease, chronic lymphocytic thyroiditis-
      Hashimoto and nodular goiter. This is retrospectively reviewing of 50 patients
      treated for differentiated thyroid carcinoma at Department of surgery, Clinical
      Centre of Montenegro in Podgorica from 1998 until 2003. We evaluated occurrence,
      as well as the role of this diseases in patients with thyroid cancer. We found a
      more favorable course of thyroid cancer in the presence of chronic lymphocytic
      thyroiditis and nodular goiter, a contrary Graves' disease. In associated
      diseases of thyroid, a significantly greater proportion of patients with thyroid
      cancer, have modular goiter.

PMID- 15179771
TI  - [Lymphoma and other rare malignant tumors of the thyroid].
AB  - Primary thyroid lymphomas are rare. Surgery is seldom indicated. The aim of the
      study is to find out the main characteristics of primary thyroid lymphomas in our
      patients, indications for surgery and the possibility of treatment. frequency and
      characteristics of rare thyroid tumors. METHOD: Retrospective study of 1044
      patient operated for malignant thyroid tumor. RESULTS: From 1995 to may 2003. We
      operated upon 15 patients with primary thyroid lymphomas. 2 men and 13 women mean
      age of 50.12 years (from 22 to 74 years), also one patient of age 69 with insular
      thyroid cancer. Reason for surgery was thyroid tumor in all, compressive
      disturbances in 9, among them 4 with asphyxia. Radical total thyroidectomy was
      performed in 4 (26.7%), whole in others some residual tumor tissue was could not
      be removed in spite of thyroidectomy in 3, hemithyroidectomy in 2, tumor
      debulking in 5 and only open biopsy was performed in one patient. There was no
      operative mortality. no postoperative hypocalcaemia and no recurrent nerve palsy.
      Histological type of tumor was Non-Hodgkin lymphoma in 13 patients, Hodgkin
      disease in 2 female patients of age 22 and 24. Hashimoto thyroiditis was present
      in 3 patients. After surgery, 13 patients were treated with chemotherapy, one
      patient died one month after the operation and one patient refused chemotherapy.
      Follow-up data are available for 9 patients and the mean follow-up period was 20
      months (1-48 months). Three patients died after a month, 2 and 3 years after
      surgery. Six patients are without local relapse. In one patient who refused
      chemotherapy, a year after thyroid surgery, resection of large intestine was
      performed because of lymphoma of the colon. CONCLUSION: Malignant thyroid
      lymphomas are rare. They present with rapidly growing thyroid tumor, compression
      and asphyxia. Surgery is only temporarily effective and it is necessary to start
      with chemo-radiotherapy as soon as possible. Rare forms of thyroid cancer have to
      be histologically recognised in order to choose the best way of treatment.

PMID- 15179772
TI  - [Surgical treatment of recurrent thyroid carcinoma].
AB  - Recurrent thyroid tumors are much less frequent but more aggressive than primary
      tumors. The aim is to find out their characteristics, aggressiveness and the
      possibility of radical surgical excision as well as the frequency of
      complications. METHOD AND MATERIAL: Retrospective study on 69 patients operated
      for recurrent thyroid tumors. RESULTS: Recurrent tumors were found in 42 patients
      with papillary, 11 with follicular (8 with Hurthle), 9 with medullary and 7 with
      anaplastic thyroid tumors. Relapse in thyroid bed on dominant side had 41
      patients (59.4%), relapse on the opposite side we found in 19 patients (27.5%)
      and relapse in lymph nodes outside of thyroid bed in 37 patients (53.6%). In
      33/69 patients, the first procedure was incomplete (reduction in 5, partial
      resection in 19, hemithyroidectomy in 9). The second procedure was incomplete in
      14, near total thyroidectomy in 2, total thyroidectomy in 33 and dissection of
      lymph nodes in 33, among them in 20 with the operation in thyroid bed. Pre
      operative recurrent nerve palsy had 2 patients and transitional recurrent nerve
      palsy occurred after second procedure in 2 patients. Among 33 patients after
      thyroidectomy for recurrent tumor, postoperative hypoparathyroidism occurred in 8
      (24.2%), of whom in 2 permanent (6%). In the group of 54 patients with recurrent
      differentiated thyroid cancer, radioiodine therapy after first operation had
      received only 7 patients (13%). CONCLUSION: The main causes of thyroid cancer
      relapse are incomplete first procedure and aggressiveness of cancer. It is not
      always possible to excise the complete recurrent tumor. After surgery for
      papillary cancer, radioiodine therapy is seldom used.

PMID- 15179774
TI  - [Early diagnosis, therapy, follow-up and survival in patients with thyroid
      malignancies].
AB  - The Aim of the paper was to give a review of an early diagnosis, therapy, follow
      up and survival rate of patients with thyroid malignancy (TM). The paper
      presented the algorithm of early diagnosis: clinical, scintigraphic and
      ultrasonographic examination together with fine needle biopsy, cytologic analysis
      of the smear and biopsy ex tempore of the clear and suspected thyroid node to
      malignancy. Therapy of all TM forms was mainly surgical: postsurgical treatment
      was dependent on the type of malignancy: radioiodine 131-I, radiologic treatment,
      chemotherapy and radioimmunotherapy, (the latest one being in the phase of a
      clinical research). Follow-up was in accordance with the protocol and it was
      necessary because it contributes to the survival rate. In the presentation of
      survival rate for differentiated and medullar carcinomas we gave our results and
      literature data, while for the other malignancies only data from literature were
      presented. CONCLUSION: Only an early diagnosis of the nodular goiter together
      with an up-to-date treatment can cure TM patients in a high percentage and
      prevent development of a terminal stage of the disease which is extremely severe
      in all forms of this malignancy.

PMID- 15179773
TI  - [Early complications in surgical treatment of thyroid diseases: analysis of 2100
      patients].
AB  - Thyroid gland surgery today is not saddled with high incidence of main
      complications. Miscellaneous surgical institutions with different surgical
      approach, operative technique and radicality have published reports with great
      discrepancy in incidence of complications, analyzing them with different methods
      of diagnosis and result evaluation. In the same way it is well known that higher
      latitude of operative procedure gave better control of thyroid diseases, but it
      can be accompanied with more complications. All of that motivate us to analyze
      complications of operative treatment in our patients under well known criteria,
      with hypothesis that higher radicality of operative procedure do not increase
      incidence of complications, and that this incidence is in correlations with
      results published in world literature. Aim of this nonrandomized study was to
      analyze results of operative treatment for huge number of consecutively operated
      patients in our teaching hospital, to analyze and compare results according to
      group of diseases and operative procedures, and to compare final results with
      results published in the world literature. Complications of operative treatment
      were analyzed retrospectively for period 1988-1997 (Group I) and prospectively in
      period 1998-2002 (Group II). Operations were performed by 20 surgeons and 20
      young surgeons during their education. We have analyzed only complications during
      first 30 days after operation. In Group I there was 1425 patients with 1451
      operations (192 thyroid malignancies, 247 hyperthyreosis, 98 reoperations, 13%
      thyroidectomies and 14.8% lobectomies), with complication rate of 14.3%. Most
      common complication was recurrent laryngeal nerve injury in 9.3% patients or 6.3%
      according to number of exposed nerves (nerve at risk), then postoperative
      hypocalcemia with rate of 4.7% (persistent in 1.3%). In Group II in 675 patients
      there was 687 operations (96 thyroid malignancies, 111 hyperthyreosis, 35
      reoperations, 36.6% thyreoidectomies and 25% lobectomies), with complication rate
      of 10.7%. Most common postoperative complication was hypocalcemia with 5% rate
      (persistent in 0.7%), then recurrent laryngeal nerve injury in 4.4% patients or
      2.9% according to number of exposed nerves. Incidence of recurrent laryngeal
      nerve injury in Group II is less frequent than in Group I, highly statistically
      significant (p < 0.01), while for other complications there is no statistically
      significant difference. Totally for both groups there was 0.7% tracheotomies,
      postoperative bleeding in 1.1% of patients, wound hemathoma in 0.5%. wound
      infections in 0.9%, pneumonia in 0.5%, mortality 0.5% and most common cause of
      death (8/11) was problem with respiration, Airway obstruction. In Group II
      complications were less frequent in total thyroidectomies in relation to
      lobectomy with contra lateral subtotal lobectomy. In both groups and totally
      incidence of complications was higher in reoperations, in patients with more
      extensive operative procedure, in malignant diseases and hyperthyreosis. In
      thyroid gland surgery more extensive operative treatment with improved operative
      technique (micro dissection, recurrent laryngeal nerve visualization and
      parathyroid gland preservation), in our teaching hospital, do not have influence
      on incidence of postoperative complications, even recurrent laryngeal nerve
      injury was significantly less frequent. This results are in correlation with
      published results of similar hospitals around the world.

PMID- 15179775
TI  - [Radiotherapy in malignant tumors of the thyroid gland].
AB  - The primary treatment of thyroid gland malignoma is surgery. Success of
      radiotherapy depends of extent of the previous surgery treatment. The types of
      radiotherapy are: curative (prophylactic and postoperative) and palliative. Tumor
      dose and radiotherapy tehnique depend on histologica type, extent of the previous
      surgery treatment, curative or paliative intent and general condition of patient,
      and they are from 40 Gy to 65 Gy by conventional fractionation. The basis of
      radiotherapy treatment planning and choice of radiotherapy treatment technique in
      survey of the region of interest by imaging procedure. On the basis of those data
      we determine therapeutic volume and structure of risk (spinal cord, lung) and
      protection of the risky structures is planned.

PMID- 15179776
TI  - DengueNet in India.

PMID- 15179777
TI  - Assessment of risk to human health associated with outbreaks of highly pathogenic
      H5N1 avian influenza in poultry--situation as at 14 May 2004.

PMID- 15179778
TI  - [Effects of angustmycin on callus occurrence and proliferation of Panax
      notogingseng in vitro].
AB  - In order to explore quick, efficient inducement and proliferation of Panax
      notogingseng callus, the stem sections were taken as explants in the following 5
      groups of medium: 1. MS + 2,4-D 2 mg/L (CK), 2. MS + 2,4-D 2 mg/L + N6-BA 2 mg/L,
      3. MS + 2,4-D 2 mg/L + KT 2 mg/L, 4. MS + 2,4-D 2 mg/L + ZT 2 mg/L, 5. MS + 2,4-D
      2 mg/L + LFS 2 mg/L. The results showed: 1. LFS (Lingfasu, a new kind of CTK) was
      able to promote the callus formation earlier 1-2 week than CK and to raise the
      rate of induced callus as high as 81%, higher 30% than that on other 4 mediums;
      2. On medium 5, the fresh weight of callus increased 360.2% after being cultured
      40 d, on other 4 mediums increased only 13.4%-21.8%. At the same time, 1 g callus
      cultured 40 d could obtain dry material 81.5 mg on medium 5, but on other 4
      mediums only 21.5-25.9 mg; 3. The callus cultured on medium 5. continual
      generation to generation could live as long as more than 3 years, on other 4
      mediums the callus hardened and aged quickly.

PMID- 15179779
TI  - [The resource conservation and breeding of wild Hydropotes inermis in China].
AB  - There have been four larger populations of wild water deer (Hydropotes inermis)
      in China, but all the populations lie in the endangered status. Most of
      populations are very small, and their distrbution ranges have already been broken
      up into many isolated patches. Furthermore, their habitats have been
      deteriorating. So it is very necessary to enhance the protection of habitat in
      the first place. Some endangered and small populations of wild water deer can be
      saved by inflows of domestic health deer. It is a valid way between conservation
      and utilization.

PMID- 15179780
TI  - [Determination of adulteration musk by GC-MS, SPME and HS2000].
AB  - Musk is one of the rare traditional Chinese medicinal materials and is usually
      sophisticated with different adulterants. Some new adulterants have been detected
      by GC-MS, SPME and HS2000.

PMID- 15179781
TI  - [Distinguishing Chinese medicinal herbs by chemical oscillating fingerprints].
AB  - OBJECTIVE: A new method is found in distinguishing Chinese medicinal herbs.
      METHODS: Chemical oscillating technology was used to study discrimination of
      Chinese medicinal herbs. RESULTS: Chemical oscillating fingerprints of over 30
      kinds of Chinese medicinal herbs were obtained. CONCLUSION: Chemical oscillating
      fingerprints can be used to distinguish Chinese medicinal herbs.

PMID- 15179782
TI  - [Analysis of chemical constituents of volatile oil in Armeniaca mume Sieb from
      different habitats by gas chromatography-mass spectrometry].
AB  - OBJECTIVE: To analyse chemical constituents of volatile oil in Armeniaca mume
      Sieb. METHODS: After stream distillation, the volatile oil was extracted with
      ether and concentrated. Then it was analysed by gas chromatography/mass
      spectrometry. RESULT: More than 70 different compounds were separated and
      identified from the volatile oil in A. mume. The identified constituents from
      each kind of A. mume represent about 90% of the total volatile oil. CONCLUSION:
      The main compounds of the volatile oil in A. mume were hexadecanoic acid,
      linoleic acid, benzoic acid, furfural, benzaldehyde, benzenemethanol, etc.

PMID- 15179784
TI  - [Phenolic acid from culture broth of fungus Cephalosporium sp. AL031].
AB  - Three phenolic acids were isolated from the culture broth of the fungus
      Cephalosporium sp. AL031 whose metabolites have been proven to possess antifungal
      and antibacterial activities. Their structures were elucidated as 2,4-dihydroxy
      3,6-dimethyl-benzoic acid (1),3,6-dihydroxy-2,4-dimethylbenzoic acid(2) and 4
      hydroxy-phenylacetic acid(3) by IR, EIMS, 1HNMR, 13CNMR, DEPT, HMQC and HMBC.

PMID- 15179783
TI  - [Determination of GA, GB and GC in total lactone of ginkgo (TLG) raw material].
AB  - OBJECTIVE: To determine the different lactone content of 10 batches of TLG raw
      material. METHODS: RP-HPLC-ELSD were used to determine ginkgolide A, B, C(GA, GB,
      GC). RESULTS: Content of GA, GB and GC were different but TLG very high (all >
      90%). CONCLUSION: The quality of TLG could be affected by habitat, season and the
      preparation method.

PMID- 15179785
TI  - [Study on therapeutic window of opportunity for Panax notoginseng saponins
      following focal cerebral ischemia/reperfusion injury in rats].
AB  - OBJECTIVE: To study the therapeutic window of opportunity for Panax notoginseng
      saponins (Pns) following focal cerebral ischemia/reperfusion injury in rats.
      METHODS: Focal cerebral ischemia (2 h)/reperfusion (24 h) model in male rats was
      induced by transient occlusion and middle cerebral artery (MCA) for 2 h and
      reperfusion for 24 h. Drugs were administered at 3 h, 4 h, 5 h and 6 h after the
      onset of ischemia respectively and neurological deficit score, infarct size and
      brain edema were examined. RESULTS: The administration of Pns at 3-4 h after
      onset of ischemia significantly reduced neurological deficit score, infarct size
      and brain edema. When administrating Pns at 5 h after onset of ischemia, the
      neuroprotection decreased. When administrating Pns at 6 h after onset of
      ischemia, there are not significant protective effects. CONCLUSION: The
      therapeutic window of opportunity for Pns following focal cerebral
      ischemia/reperfusion injury in rats is not more than 5 h after the onset of
      ischemia.

PMID- 15179786
TI  - [Therapeutic effect and its mechanism of "huo xue bu qi fang" on fetal rats with
      intrauterine growth retardation].
AB  - OBJECTIVE: To probe into therapeutic effect and its mechanism of "Huo Xue Bu Qi
      Fang" (HXBQF) on fetal rats with intrauterine growth retardation (IUGR). METHOD:
      The model of pregnant rat with IUGR was established by passive smoking method.
      Forty pregnant rats with IUGR were randomly divided into intervention group (with
      high-, middle- and low-dose Chinese traditional medicine) and non-intervention
      group. In addition, 10 normal pregnant rats were taken into control group.
      Intervention group was adminstered with 16.2, 5.4 and 1.62 g/kg HXBQF
      respectively. Non-intervention group and control group were administered with 10
      ml/kg saline. Fetal rats were taken out, and blood and urine samples were
      collected from pregnant rats on day 21 of the pregnancy. The weight, nose-hip
      length and poundera index of these fetal rats were measured. Serum NO, plasma ET
      1 and urine 8-epi-PGF2 alpha level from pregnant rats were determined by nitro
      reductase method, radioimmunoassay (RIA) and enzyme immunoassay (EIA)
      respectively. RESULT: Compared with fetal rats from non-intervention group, fetal
      weight, distance between nose-hip, poundera index serum NO level and NO/ET-1 were
      increased, plasma ET-1 level and urine 8-epi-PGF2 alpha level were decreased in
      those from intervention group (P < 0.01). CONCLUSION: There is an enhancement of
      lipid peroxidation and NO/ET-1 ratio imbalance in pregnant rats with IUGR. HXBQF
      has good therapeutic effect on IUGR since it can inhibit lipid oxidation and
      regulate NO/ET-1 balance.

PMID- 15179787
TI  - [Pharmacological study of Limax extract on inhibiting H14 cell].
AB  - OBJECTIVE: To study the inhibitive effect of Limax extract on H14 and inducement
      effect of apoptosis and differentiation of H14 cells in vitro. METHODS: MTT
      method, DNA gel electrophoresis, cell stain and microscope observation. RESULTS:
      After H14 cell line was induced by Limax extract, the growth of H14 cell was
      inhibited in vitro and the morpha of the cells changed. CONCLUSION: Limax extract
      had inhibitive effect on H14 cell, partially by apoptosis, and partially by
      differentiation.

PMID- 15179788
TI  - [Study on extraction and isolation of active constituents from Sorbaria
      sorbifolia and antitumor effect of the constituents in vivo].
AB  - OBJECTIVE: To study the constituents from Sorbaria sorbifolia and their antitumor
      activities. METHODS: The constituents were isolated with silia gel column
      chromatography and identified by physicochemical properties and spectroscopic
      analysis. Thirty six mice were inoculated with sarcocarcinoma 180 according to
      the standard method, Sorbaria sorbifolia ethyl acetate etract was administrated
      for 10 days, tumor and body weight, the activities of NK cell and the contents of
      TNF-alpha, IL-2 in serum were detected. RESULTS: Three compounds were isolated
      from the ethyl acetate extract and identified as 5,2',4'-trihydroxy-6,7,5'
      trimethoxyflavone(I), succinic acid(II) and p-hydroxybenzoic acid(III). The tumor
      of the test groups were lighter than that of control group(P < 0.05). There was
      no remarkable difference between the control and test groups in body weight (P >
      0.05). The activity of NK cell and the contents of TNF-alpha, IL-2 in serum were
      higher than that of control group (P < 0.05). CONCLUSION: Compounds I and II were
      isolated from Sorbaria sorbifolia ethyl acetate extract for the first time. The
      ethyl acetate extract could improve immune function and strengthen antitumor
      effect in sarcocarcinoma 180.

PMID- 15179789
TI  - [Study on antitumor and synergy effect of "bushen huayu jiedu formula" on mice
      hepatocarcinoma H22].
AB  - OBJECTIVE: To explore antitumor and synergy effect of "Bushen Huayu Jiedu
      Formula" (BSHYJDF) on hepatocarcinoma H22. METHODS: Transplanted hepatocarcinoma
      H22 mice were used, the inhibitory rates of H22 were observed respectively to
      BSHYJDF and BSHYJDF combined with cisplatin (DDP). RESULTS: BSHYJDF could
      significantly inhibit hepatocarcinoma H22 in transplanted mice (P < 0.05).
      CONCLUSION: BSHYJDF had inhibitive effect and synergy with chemotherapy to a
      certain extent in transplanted hepatocarcinoma mice.

PMID- 15179790
TI  - [Study on antitumor activities of ginkgolic acids from Ginkgo sarcotestas in
      vitro].
AB  - OBJECTIVE: To study the influence of ginkgolic acids on human tumor cells and
      normal cells. METHODS: Ginkgolic acids (total concentration 90%) was prepared
      from ginkgo sarcotestas. The inhibitive effect of ginkgolic acids on human tumor
      cells and normal cells lines was examined by MTT assay. RESULTS: When the
      concentration was 5.0 micrograms/ml, ginkgolic acids obviously inhibited the
      growth of tumor cells and didn't influence the normal cells. Inhibitive rate of
      ginkgolic acids on LTEP-a-2 was 59.1%. High-concentration ginkgolic acids had
      inhibitive effect on the growth of tumor cells and normal cells. CONCLUSION:
      Ginkgolic acids had a obvious inhibitive effect on tumor cells in vitro. When the
      concentration was under 5.0 micrograms/ml, ginkgolic acids didn't influence the
      growth of normal cells.

PMID- 15179791
TI  - [Herbalogical textual study on "guanzhong"].
AB  - Herbalogical textual study indicated "Guanzhong" recorded in Bencaojing at Han
      Dynasty had pteridophyte characters. In the period of Wei and Jin Dynasties, the
      name of "Guanzhong" was really belonged to spermatophyte. Since Southern and
      Northern Dynasties, fern has been the main source of "Guanzhong" in which
      Woowardia japonica was used longer than others.

PMID- 15179792
TI  - [Clinical observation of "dan shao tang" in treating mesangial proliferative
      glomerulonephritis of deficiency of yin with damp-heat symptom].
AB  - OBJECTIVE: To explore the effect of "Dan Shao Tang" (DST) on mesangial
      proliferative glomerulonephritis (MsPGN) of deficiency of Yin with damp-heat
      symptom. METHODS: 90 patients with MsPGN of deficiency of Yin with damp-heat
      symptom were randomly divided into two groups. 54 patients in treatment group
      were treated with DST and western medicine, and 36 patients in control group were
      treated only with western medicine. We observed the effect and indexes change
      including renal function, proteinuria, hematuria, lipid before and after
      treatment. RESULTS: After three months treatment, the general effective rate in
      treatment group was 75.93%, which was markedly higher than that in control group
      (47.22%, P < 0.01). Treatment group is obviously better than control group on
      decreasing proteinuria and hematuria, improving renal function, ameliorating
      lipid metabolism (P < 0.05). CONCLUSION: DST is effective on MsPGN of deficiency
      of Yin with damp-heat symptom.

PMID- 15179793
TI  - [The clinical observation of puerarin injection on unstable angina pectoris].
AB  - OBJECTIVE: To observe the clinical curative effect of Puerarin Injection on
      unstable angina pectoris. METHOD: 59 patients with unstable angina pectoris (UAP)
      were divided into treatment group and control group. Control group was treated
      with routine method. Besides routine treatment, treatment group was administrated
      Puerarin Injection 0.4 g plus 5% glucose by vein injection. Course of treatment
      was 14 days. RESULT: The effectual rate and total effective rate of treatment
      group were 53.1% and 93.8%, respectively. Those of control group were 37% and
      74.1%, respectively. There were statistical difference between above-mentioned
      groups (P < 0.01). CONCLUSION: Puerarin Injection has obvious curative effect on
      UAP and no obvious vice effect.

PMID- 15179794
TI  - [Asymptomatic cerebral infarction and depression--the concept of vascular
      depression].
AB  - At 1997, Alexopoulos and Krishnan coined the term "vascular depression" to
      describe depression associated with cerebrovascular disease. Vascular depression
      included both post-stroke depression, depression occurring after a stroke, and
      MRI-defined vascular depression in which cerebral infarction is detected by
      magnetic resonance imaging findings. Post-stroke depression is well known as
      showing cerebral infarction on imaging modalities as well as clinical symptoms
      such as localized neurological symptoms related to infarcts. MRI-defined vascular
      depression demonstrates cerebral infarction on imaging modalities, but there are
      no clinical symptoms such as localized neurological symptoms or stroke. MRI
      defined vascular depression is equivalent to the term "depression with silent
      cerebral infarction", a condition we studied in the past decade. When the
      accumulation of infarct lesions induces obstruction in the neuron network related
      to mood and will exceeds a certain threshold, the patient becomes predisposed to
      vascular depression. Neurological factors are more prominent than genetic factors
      or psychosocial stressors in patients with vascular depression due to an
      accumulation of infarct lesions. Anti-cholinergic drugs and anti-dopaminergic
      drugs easily induce adverse central nervous system reactions in patients with
      vascular depression demonstrating prominent neurological factors. Research on
      vascular depression has contributed to clarifying the onset mechanism of
      endogenous depression.

PMID- 15179795
TI  - [Naikan therapy for prolonged depression: psychological changes and long-term
      efficacy of intensive Naikan therapy].
AB  - OBJECTIVE: Many studies have shown that a considerable number of patients with
      prolonged depression are refractory to drug therapy or supportive psychotherapy.
      A few studies have shown the short-term effectiveness of intensive Naikan therapy
      for prolonged depression, but the long-term effects have not been reported. For
      other psychotherapies also, few studies have demonstrated their long-term
      effectiveness for prolonged depression. The purpose of the present study was to
      assess the long-term efficacy of intensive Naikan therapy for patients with
      prolonged depression and to investigate the factors contributing to its efficacy.
      METHOD: At Tottori University Hospital, 23 inpatients with prolonged depression
      were treated with intensive Naikan therapy. The age, sex, age at onset, number of
      depressive episodes, duration of the present episode, diagnosis and family
      history were investigated. The Tokyo University Egogram (TEG), Yatabe-Guiltora
      personality inventory (YG test) and Rosenzweig picture-frustration (PF) study
      were conducted before and after intensive Naikan therapy to investigate
      psychological changes. The long-term efficacy (average: 24.5 +/- 10.6 months) of
      intensive Naikan therapy for prolonged depression was assessed with Global
      Assessment of Functioning scale (GAF). "Improvement" was defined as a post
      therapy GAF score of 61 or higher. The Hamilton Depression Rating Scale (HAM-D)
      was applied to confirm the GAF results. Whether the patient achieved awareness of
      other's viewpoint, awareness of egocentricity, feeling of love, breaking out from
      self and sense of fulfillment after intensive Naikan therapy was investigated.
      RESULTS: Fifteen patients (65.2%) showed improvement in GAF and HAM-D (improved
      group) and eight patients showed no improvement (non-improved group). The average
      GAF score changed from 46.1 (before Naikan therapy) to 81.8 (at outcome
      assessment) in the improved group and from 45.3 to 52.8 in the non-improved
      group. The improved group had significantly shorter average duration of the
      present depressive episode and significantly less depressive episodes compared to
      the non-improved group. Only the improved group showed significantly lower scores
      on the critical parent (CP) scale of TEG, cyclic tendency (C) on the YG test and
      extraggression (E-A) in PF study. In the improved group, significantly more
      patients achieved deep insight (Naikan); and significantly more patients achieved
      awareness of other's viewpoint, awareness of egocentricity, feeling of love,
      breaking out from self and sense of fulfillment after intensive Naikan therapy.
      CONCLUSIONS: Our results suggested that intensive Naikan therapy for prolonged
      depression was equally as effective as Morita therapy, interpersonal therapy or
      group psychotherapy, and the effects of intensive Naikan therapy continued for a
      long term. Attainment of deep Naikan brought psychological changes in patients
      showing improvement, motivating them to continue Naikan therapy in daily life. We
      consider that this is the key factor that maintains the long-term efficacy of
      intensive Naikan therapy.

PMID- 15179796
TI  - [Alterations of symptoms with borderline personality disorder after fronto
      temporal traumatic brain injury. A case study].
AB  - We report a case of borderline personality disorder in which severe self
      mutilation, sense of futility and tendency to manipulate others disappeared after
      fronto (orbital cortex and dorso-lateral surface) temporal traumatic brain
      injury. The patient, a right-handed 34 year-old woman began having severe
      depressive moods, irritability, and performed recurrent self-mutilation by wrist
      cutting after her marriage at age 20. She was diagnosed as having borderline
      personality disorder. At the age of 30, she attempted to kill herself by leaping
      from a building, and sustained a frontotemporal traumatic brain injury. After 5
      years of follow-up, she recovered from Wernicke's-like aphasia, but could not
      understand anything complex. She also showed disturbances of writing,
      calculating, attention, working memory, recent and remote memories, motivation,
      and sense of self. The results of tests of higher brain function were as follows:
      Wisconsin card sorting test (Keio version), C = 1, D = 2, P = 23; FAB (Frontal
      Assessment Battery) = 7/18; Trail making test B = impossible. Brain MRI
      demonstrated left frontal lobe (orbital cortex and dorso-lateral surface)
      contusions, severe atrophy in the left temporal cortex including the hippocampus
      and amygdala, and diffuse axonal injury in the left frontal white matter.
      Although her recurrent self-mutilation had disappeared after brain injury, a
      certain type of anxiety, which occasionally induced irritability, unstable moods
      and devaluation of others, occurred without any trigger once or twice a month.
      This anxiety continued two or three days and faded away within a week. Because of
      its frequency and duration, this anxiety can be considered to originate not from
      the traumatic brain injury, but from her intrinsic nature, and seems to be
      parallel to annihilation anxiety (Reich A, Klein M) and abandonment anxiety (DSM
      IV). Because she showed this anxiety after a severe higher brain dysfunction
      including disturbances of language, attention, working memory, recent and remote
      memories, motivation, and sense of self, we considered this anxiety to be an
      unarticulated form of annihilation anxiety and abandonment anxiety.

PMID- 15179797
TI  - [Expectation and the current status of young psychiatrists in Japan].

PMID- 15179798
TI  - [Expectation on the training of young psychiatrists in Japan].

PMID- 15179799
TI  - [Expectation on young psychiatrists overseas: from the experience with the EPA
      (World Psychiatric Association)].

PMID- 15179800
TI  - [Development and expectation on the organization of young psychiatrists in
      Japan].

PMID- 15179801
TI  - [Education and training at small psychiatric hospitals].

PMID- 15179802
TI  - [Education and training at large psychiatric hospitals].

PMID- 15179803
TI  - [Expectation on hospitals specializing in psychiatry by university hospital
      psychiatry departments].

PMID- 15179804
TI  - [Training and education of young psychiatrists at hospitals specializing in
      psychiatry--expectation of the committee on postgraduate training of a medical
      association on private psychiatric hospitals].

PMID- 15179805
TI  - [Language in psychiatric treatment].

PMID- 15179806
TI  - [Therapeutic interviews and psychiatry].

PMID- 15179807
TI  - [Significance of expressed emotion (EE) in psychotherapy].

PMID- 15179808
TI  - [Characteristics and clinical application of "Naikan" therapy].

PMID- 15179810
TI  - Need advice from NATN?.

PMID- 15179809
TI  - [Nerve-protective action of lithium].

PMID- 15179811
TI  - Mind your busyness.

PMID- 15179812
TI  - Career and pay progression.

PMID- 15179813
TI  - The nurse anaesthetist.
AB  - With the ongoing debate on New Ways of Working in the National Health Service,
      the role of nurses and other perioperative practitioners in anaesthetics is
      becoming an increasingly prominent issue. The opening up of new anaesthetic roles
      to nurses and their non-medical colleagues raises questions as to their own
      acceptance of these new roles and their acceptance by their medical colleagues.
      In this article, the author addresses the question as to whether perioperative
      practitioners are ready for the nurse anaesthetist, and whether the UK as a whole
      is ready for this initiative.

PMID- 15179815
TI  - The National Blood Service. Supporting better blood transfusion.
AB  - The National Blood Service (NBS) is an integral part of the National Health
      Service that provides blood, blood components, blood products and tissues from
      fifteen blood centres to England and North Wales. Each year, the NBS collects
      tests, processes, stores and issues approximately 2.3 million blood donations.
      The service also undertakes research into blood safety, provides clinical advice
      to hospital staff and supports hospital transfusion practitioners. Rebecca
      Gerrard describes some of the initiatives to improve blood transfusion practices,
      including monitoring of the serious hazards of transfusion, bench marking schemes
      and the roles of blood transfusion liaison (BTL) nurses.

PMID- 15179814
TI  - Nurse practitioners in theatre. An investigation.
AB  - A small qualitative study was conducted to identify in-depth views of three nurse
      practitioners who work in one unit--two are part-time 'F' grades and one is a
      full-time 'H' grade. Data was collected by three semi-structured interviews based
      on three themes highlighted in the literature. By introducing nurse
      practitioners, the continuity and quality of patient care will be enhanced, and
      flexible working will be facilitated from a reduction in doctor's hours.

PMID- 15179816
TI  - Management of a CJD case. Part 2. The patient with CJD in the operating theatre.
AB  - Along with details as to how CJD-associated instrumentation should now be
      handled, following a recent updating of DoH advice, this article contains
      comprehensive guidelines which can be followed in the event of a procedure
      involving a CJD patient. All the practicalities associated with managing a CJD
      case are dealt with step by step, from collection of the patient from the ward,
      through terminal cleaning of the theatre, to discharge of the patient from
      Recovery.

PMID- 15179817
TI  - Management of bedwetting in children.
AB  - Bedwetting (nocturnal enuresis) is common among school-aged children, with around
      one in six 5-year-olds, and at least one in fifty 7-year-old boys and one in a
      hundred 7-year-old girls, wetting the bed more than once a week. Moreover, in
      some children, the problem can persist, with around 0.8% of girls and 1.6% of
      boys aged 15-16 years wetting at least once every 3 months. The condition can
      affect the child's self-esteem, and may lead to teasing or bullying, reduced
      social interactions and behavioural problems. The frequent changing and washing
      of bedding and night-clothes can place an additional workload and financial
      burden on the family. Parents may become intolerant of the situation, and this
      may even lead to physical punishment of the child. Here we review the primary
      care management of children with bedwetting.

PMID- 15179818
TI  - Gout in primary care.
AB  - Gout affects around 1% of people in the UK, most aged over 45 years. The
      condition, which is five times more common in men than women, usually presents as
      a painful inflammatory monoarthritis, which can be diagnosed clinically and
      successfully treated with a high dose of an NSAID. Problems arise when the
      features are atypical or when high doses of an NSAID are inappropriate. Also;
      there is no robust evidence to guide when to start prophylactic therapy or what
      advice to give on lifestyle changes. Here we review current practice and offer
      advice on managing patients with this increasingly common condition,
      concentrating on approaches to be taken by the non-specialist.

PMID- 15179819
TI  - [Protein hormones, receptors, and other proteins in mechanisms of hormonal
      regulation].
AB  - The amino acid sequence of porcine beta-lipotropin was the first protein primary
      structure studied in Russia. This peptide as well as ACTH is liberated after
      proteolysis of proopiomelanocortin (POMC). alpha-MSH and beta-MSH
      (melanocortins), which are the fragments of ACTH and beta-lipotropin
      respectively, are the mediators of leptin action on appetite and lipid
      metabolism. The structure and molecular aspects of hormone signaling of the
      membrane receptors of leptin and melanocortins were analysed in the connection to
      the regulation of food consumption, growth, and puberty. Some aspects of insulin
      receptor and IGF-I receptor as well as intracellular receptors of lipid hormones
      (steroid and thyroid hormones) were also discussed. The postulate: "All organs,
      tissues, and cells of humans and animals are endocrine" is formulated on the
      basis of the accumulated data.

PMID- 15179820
TI  - [The liver and the nervous system].
AB  - This review considers the liver adrenergic and cholinergic innervation in
      connection with its trophic function. The attempt was made to analyse mechanisms
      of nervous regulation of liver metabolism and to estimate the role of co
      transmitters in metabolic functions of the peptidergic fibers. Liver and portal
      vein afferent sensors for amino acids, glucose, insulin, glucagon, leptin and
      osmosensors were described. These sensors detect the liver metabolic signals and
      transmit them by vagal hepatic afferents to the network of hypothalamic and
      cortical structures.

PMID- 15179821
TI  - [G-protein coupled peptide receptors and their ligands in human genome].
AB  - The G-protein coupled peptide receptors as well as their ligands, endogenous
      peptides, are involved in regulation of many important physiological processes in
      the organism and therefore represent attractive targets for pharmaceutical
      investigation and drug design. With the completion of the human draft genome
      sequencing, it has become possible to take a comprehensive picture of all genes
      encoding both peptide receptors and peptides themselves. In the present study a
      first attempt has been made to carry out a comprehensive analysis of G-protein
      coupled peptide receptors and their respective endogenous peptide ligands in the
      human genome. We searched the genome sequence by means of sequential application
      of standard bioinformatical methods (such as homology search, hierarchical
      cluster analysis, building of hmm-profiles etc.) with the goal of identifying all
      the components of peptide ligand/receptor system in the human genome. As a result
      of this search it was concluded that the probable number of functional peptide
      receptors in the human genome is 218, and the probable peptide precursors' number
      is 126 amino acid sequences. These two groups include, respectively, 12 novel G
      protein coupled peptide receptors and 10 novel peptide precursors, discovered in
      the present study. The probable biological functions of newly discovered
      candidates were determined based on the sequence similarity to the earlier known
      proteins. Classification of all peptide GPCRs and their ligands based on the
      ligand specificity was performed for all probable G-protein coupled peptide
      receptors. The issue of ligand-receptor specificity in the human genome is also
      discussed.

PMID- 15179823
TI  - [Effect of hyperbaric oxygenation on glutamine metabolism in damaged and intact
      lobes of the operated liver].
AB  - Employment of hyperbaric oxygenation (HBO, 3 bar, 50 min, 1 session per day)
      during the first three days after resection of liver (15-20% of mass) normalized
      glutamine metabolism impairments caused by operational trauma.

PMID- 15179822
TI  - [Remote effects of Aroclor 1254 on the rat liver microsomal monooxygenase
      activity in acute pancreatitis].
AB  - Constitutive activities of the liver cytochromes P450 1A1, 1A2, 2C6 and 2B1 were
      lower in rats with the acute experimental pancreatitis during ten days of this
      disease. In rats pretreated with a single dose of Arochlor 1254 on the second day
      of pancreatitis activities of these enzymes remained elevated to the tenth day.
      Thus, acute pancreatitis caused long-term suppression of microsomal monooxygenase
      system, whereas induction by Arochlor 1254 increased cytochromes P450 activity in
      both control animals and in rats with pancreatitis.

PMID- 15179824
TI  - [Cysteine proteinases and their inhibitors in the development of mouse HA-1
      hepatoma and antineoplastic therapy].
AB  - Development of murine HA-1 hepatoma was accompanied by increased activity of
      cathepsin B (in ascitic cells), cathepsin D (in ascitic fluid) and increased
      activity of procathepsin B. There were some changes of cysteine proteinases in
      liver and spleen, not involved directly into tumor growth. The most prominent
      changes included the decreased level of cysteine proteinase inhibitors cystatin C
      and stefin A in ascitic cells (and to a lesser degree in liver tissue). During
      tumor development serum cystatin C concentration decreased by 3-times compared to
      intact mice. Treatment by antitumor drug Ukraine increased life span of mice with
      HA-1 hepatoma (transplanted intravenously), decreased the increment of tumor
      weight. In ascite such treatment caused a decrease of number of tumor cells and
      an increase of number of macrophages. Ukraie (administered once or 5-times in a
      dose of 0.5 mg per mice) increased cystatin C level, revealing protective
      mechanism of action.

PMID- 15179825
TI  - [Phosphatidylcholine as the basis for artificial pulmonary surfactants:
      comparison of surface active properties].
AB  - The Wilhelmy balance was used for in vitro testing of surface active properties
      of natural phosphatidylcholines (PCs) as possible basis for surfactant
      replacement therapy. Saturated PC, dipalmitoylphosphatidylcholine (DPPC) and
      phospholipon (PL) had similar parameters of surface activity: minimal values of
      equilibrium surface tension (EST) and the longest surface spreading time (SST).
      Unsaturated egg and soybean PCs also shared similar values of surface activity
      parameters (EST and SST). Correlation between fatty acid saturation of PCs and
      EST or SST allows to consider both these parameters as informative ones for
      surface tension evaluation in the search of components for artificial surfactant.
      Since parameters of DPPC and PL surface activity are equivalent in their
      performance, they may be potentially employed for testing instead of DPPC as a
      possible base for artificial surfactant.

PMID- 15179826
TI  - [Activity of the messenger systems in the altitude chamber hypoxia].
AB  - The activity of phosphoinositide and adenylate cyclase systems of second
      messengers in rat brain were investigated under altitude chamber treatment (6000
      m x 24 hours). Selective suppression of each messenger system was achieved by
      pretreatment of rats with either lithium chloride or propranolol for 8 days.
      Consequences of this treatment and/or hypoxia were evaluated by orientation
      behavior and physical exercise test. Administration of LiCl caused reduction of
      phosphoinositide level; hypoxia (6000 m) caused further impairments in the second
      messenger content. The synergism between phosphoinositide and adenylatcyclase
      systems was demonstrated.

PMID- 15179827
TI  - [Changes in phospholipids of the brain grey and white matter during in vitro
      autolysis in rats subjected to acute hypobaric hypoxic hypoxia].
AB  - The development of autolysis in grey brain matter of albino rats was accompanied
      by desintegration of aminophospholipids with parallel increase of
      glycerophosphates (GLP) and phosphatidic acids (PA) on early stages of incubation
      and lysophospholipids (LPL) on later stages. Acute hypobaric hypoxic hypoxia
      decreased the level of phosphatidylethanolamines (PE) with simultaneous
      accumulation of PA. Previous hypoxia altered the character of autolytic
      reorganizations of phospholipids. Oscillatory reciprocal reorganizations in the
      system PE > PS (phosphatidylserine) were observed at early stage (1 h) and at
      late stages of autolysis (24 h). At the same time increased transformation of
      phosphatidylcholines (PC) into sphingomyelins (SM) with simultaneous accumulation
      GLP was registered. During autolysis of brain white matter of control rats
      opposite oscillatory reorganizations of PE, PC, SM, PA with reduction of PE and
      simultaneous increase of LPL and PA level after 1 hour of incubation were
      observed. Reciprocal reactions of biotransformation in system PS > PE were
      revealed at 4th hour. Previous hypobaric hypoxic hypoxia reduced the level of
      total phospholipids as well as PS at simultaneous increase of LPL. Acute
      hypobaric hypoxic hypoxia increased autolytic transformations in system PC > SM
      and induced hydrolysis of PE, PC into LPL at late stages of autolysis.

PMID- 15179828
TI  - [Hemostasis and trophoblast-specific beta 1-glycoprotein in spontaneous
      abortion].
AB  - The relationship between the increase in maternal serum concentration of
      pregnancy-specific beta 1-glycoprotein (SP1) and levels of components of
      hemostasis system was investigated. The concentrations of SP1 were measured in
      the blood sera of 234 pregnant women with recurrent spontaneous abortions, in 115
      somatically healthy pregnant women and 75 donors. A direct correlation between
      serum SP1 and levels of components of hemostasis system was shown. Results
      suggest that disturbances in hemostasis system influence synthesis of some
      placental proteins, including SP1.

PMID- 15179829
TI  - [Levels of unified metabolites and thyroid hormones in blood and oral fluid of
      children with minimal brain dysfunction].
AB  - Minimal brain dysfunctions in children with various perinatal complications are
      accompanied by metabolic imbalance manifested by decreased total protein content,
      the tendency to reduced triglycerides, increased cholesterol concentrations in
      the oral fluid, the trend to hypoproteinaemia, hypoglycaemia,
      hypotriglyceridaemia. The most significant changes in the redox systems alpha
      ketoglutarate-glutamate, oxaloacetate-malate, pyruvate-lactate, dioxyacetone
      phosphate-alpha-glycerophosphate in biological fluids were revealed in cases of
      antenatal alcoholisation. A certain correlation was found between anemia in
      pregnant women and hypothyroidal background in children. In addition, a high
      level of free and total thyroxine, that of total triiodthyronine were found in
      the oral fluid. Hypophysis--thyroid dysregulation in children with minimal brain
      dysfunction associated with gestosis in their mothers during pregnancy, was
      manifested by decreased content of total and free T4 and T3 in blood serum and
      increased level of the thyroid-stimulating hormone.

PMID- 15179830
TI  - [Effective method of DNA purification from contaminated matters and optimization
      of amplification].
AB  - A new modification of DNA purification has been developed. It includes: 1)
      standard treatment of biological material with proteinase K followed by phenol
      chlorophorm extraction; 2) subsequent sample purification using micro-columns
      packed with Dowex-50 and Sephadex G-50. Oligonucleotide primers often used for
      DNA typing in man by means of polymerase chain reaction have also been modified.
      These are VNTR (variable number of tandem repeats) loci of apoB and D17S5. The
      increase of stability and specificity of amplification of VNTR loci of apoB and
      D17S5 was achieved by increase of primer length and amplification cycle. The
      sensitivity of this mode of amplification is 2-4 ng DNA-template. Employment of
      the nested amplification for apoB locus increased sensitivity of this method up
      to a few copies of DNA.

PMID- 15179831
TI  - [Accelerated hydrophobic chromatography of plant extracts: a promising tool for
      study of biologically active polyphenols].
AB  - A simple and efficient technique for fast isolation and purification of a total
      polyphenol fraction from dry herbal plant extract ("Phytoprost" preparation) has
      been developed. The method is based on sequential cascade of 1.0-5.0 kDa
      ultrafiltration and the following subsequent column chromatography of resultant
      oligo/polymeric compounds on Phenyl-Sepharose 4B-CL. This novel procedure allows
      to obtain a highly purified (not more than 0.5-0.6% of aromatic and heterocyclic
      impurities) fraction of plant polyphenols in amounts required for
      pharmacological/biochemical screening (0.85 +/- 0.06 A280/g dry extract) within 8
      9 hours.

PMID- 15179832
TI  - Intracystic hemorrhage with spontaneous rupture of liver cyst complicated by
      infection: a case report.
AB  - A 78-year-old man who was being followed-up for a liver cyst was admitted to
      Asakayama General Hospital because of the sudden onset of severe right
      hypochondralgia and fever, with a preceding dull pain in the right upper quadrant
      of the abdomen of four 'days' duration. Computed tomography revealed remarkable
      enlargement of the liver cyst. We diagnosed intracystic hemorrhage and
      spontaneous rupture of the liver cyst. As we diagnosed bacterial infection in the
      ruptured cyst, transhepatic cystic drainage was performed. After improving the
      clinical status of the patient, we injected ethanol into the cyst, inducing a
      significant decrease in its size. There has been a few previous reports of
      intracystic hemorrhage and spontaneous rupture of a liver cyst complicated by
      infection. Transhepatic cyst drainage combined with antibiotic therapy and
      intracystic ethanol injection may be a useful and minimally invasive method for
      liver cysts with these complications, especially in compromised patients.

PMID- 15179833
TI  - Intrahepatic cystadenocarcinoma with pleural dissemination: a case report.
AB  - A 40-year-old Japanese woman, who previously had undergone choledocho-jejunostomy
      in childhood for a congenital choledocal cyst, presented with right-sided chest
      pain. Computed tomography and ultrasonography demonstrated a right pleural
      effusion and a 10-cm unilocular hepatic cystic lesion with no solid component.
      These findings suggested a non-neoplastic cyst or cystadenoma. However,
      intracystic fluid aspirated had high concentrations of carbohydrate antigen 19-9
      and carcinoembryonic antigen. Cytology of the pleural effusion demonstrated
      malignant cells. During exploratory laparo- and thoracotomy, a hepatic
      cystadenocarcinoma with invasion of the diaphragm and pleural dissemination was
      discovered. This case demonstrates that malignancy should be ruled out when a
      patient with an intrahepatic unilocular cystic lesion presents with atypical
      symptoms and findings, such as chest pain, pleural effusion, and high serum
      concentration of tumor markers. We believe that intrahepatic cystic lesions
      should be approached aggressively, including the use of exploratory
      laparotomy/laparoscopy to be certain that cancer is not present.

PMID- 15179834
TI  - Limy bile: a case of obstructive jaundice and review of 26 cases.
AB  - BACKGROUND: A number of reports on limy bile have been published but obstructive
      jaundice due to limy bile is quite rare. We report a case of obstructive jaundice
      due to limy bile and review 26 cases of limy bile diagnosed in our institution.
      CASE OUTLINE: A 39-year-old woman was admitted to our hospital with epigastric
      pain and jaundice. Abdominal ultrasonography and computed tomography revealed
      limy bile in the common bile duct and a gallbladder stone with biliary
      obstruction. Percutaneous transhepatic biliary drainage was performed. The limy
      bile drained out through the catheter over a few weeks. Cholecystectomy and
      choledochotomy with choledocholithotomy were subsequently performed. DISCUSSION:
      The strategy for managing patients with limy bile is individualized based on
      symptoms, the clinical conditions, and the location of the limy bile, and any
      associated biliary stones or lesions causing cystic duct obstruction.

PMID- 15179835
TI  - Comparison of the Nuss procedure for pectus excavatum by age and uncommon
      complications.
AB  - BACKGROUND: We summarized our experience of the Nuss procedure for pectus
      excavatum with comparison by age and uncommon complications. METHODS: Twenty
      three patients underwent the Nuss procedure. Their age ranged from 3 to 19 years
      old. The outcome was compared between two groups divided by age: teenagers (> or
      = 13 yrs old, n = 5, Group 1) and younger patients (n = 18, Group 2). RESULTS:
      Cosmetic results were significantly better, and the operating time and
      postoperative hospital stay in Group 2 were significantly shorter than in Group
      1. Complications were more frequently seen in Group 1 than in Group 2. In all
      three younger patients whose bars were removed after 2 years, the ribs holding
      the bar were deformed. Uncommon complications occurred in two cases. In one case,
      pneumothorax occurred due to laceration by a fragment of wire after 12 months,
      and the fragment fell into the thoracic cavity. In another case, pneumothorax
      occurred due to injury by the port of a thin thoracoscope. CONCLUSION: The
      teenaged patients had more complications and poorer cosmetic results. Therefore,
      this operation should be performed before the teenage years. In younger patients
      with rapid growth, the bar should be removed less than 2 years to prevent
      restriction of costal growth.

PMID- 15179836
TI  - Postoperative adjuvant use of carmofur for early breast cancer.
AB  - OBJECTIVE: The efficacy of oral fluoropyrimidine carmofur was evaluated for
      adjuvant use for breast cancer. METHODS: 150 patients with breast cancer of T0N1,
      T1, N1, T2N0, and T2N1 were randomized to 100 for carmofur and 50 for carboquone.
      Both drugs were administered continuously for 28 days cyclically for 5 years with
      a cessation period of 28 days for carmofur and 56 days for carboquone. RESULTS:
      Overall survival excluding non-breast cancer death was 90% for the carmofur group
      and 88% for the carboquone group, adjusted by Cox's regression analysis.
      Difference in drug never affected survival. Leukocyte count was decreased in the
      carboquone group, but no change in serum transaminase was found in either group.
      Ten patients, 5 for carmofur and 5 for carboquone, suffered from second
      malignancy, more than expected in the normal population, but difference in the
      cumulative rate of each group was not significant. CONCLUSION: Adjuvant use of
      carmofur as well as carboquone is beneficial for early breast cancer.

PMID- 15179837
TI  - Detection of choroidal neovascularization by subtraction indocyanine green
      angiography.
AB  - BACKGROUND: Indocyanine green (ICG) angiography is considered to be an effective
      clinical tool to detect choroidal neovascularization (CNV) in age-related macular
      degeneration. However, CNV detection by angiography becomes difficult when a
      thick hemorrhagic lesion exists. METHODS: CNV was analyzed in 20 eyes (20
      patients) showing age-related macular degeneration and accompanying subretinal
      hemorrhage using the subtraction method of ICG angiography. RESULTS: Subtraction
      ICG angiography revealed hyperfluorescent areas determined as dye leakage from
      CNV in all 20 cases. In 6 of the 20 cases, ill-defined fluorescence-increasing
      areas were observed which expanded during continuing angiography. On the other
      hand, the remaining 7 cases showed well-defined fluorescence-increasing areas
      which did not expand over time. CONCLUSIONS: The subtraction method is an
      effective clinical tool to detect CNV concomitant with subretinal hemorrhage.
      Moreover, this method provides information to elucidate an increasing pattern of
      fluorescence surrounding CNV.

PMID- 15179838
TI  - Clinical management. Where medicine meets management. Faith healers.
AB  - An inner London mental health trust wanted to improve services for Muslim
      patients. Staff at the trust attended workshops on the religion and a cross
      cultural nurse was appointed. Inpatient service users are feeling increasingly
      able to discuss their beliefs.

PMID- 15179839
TI  - Community engagement. Heads you win.
AB  - Football clubs are short of cash and communities are short of sites for new
      facilities. Health initiatives can use football stadiums, bringing in rent for
      the clubs. A primary care trust is setting up a healthcare centre offering a wide
      range of services at one stadium.

PMID- 15179840
TI  - Mental health. Inside out.

PMID- 15179841
TI  - HSJ people. Different strokes.

PMID- 15179842
TI  - Nonlinear tensile properties of bovine articular cartilage and their variation
      with age and depth.
AB  - Tensile stiffness of articular cartilage is much greater than its compressive
      stiffness and plays an essential role even in compressive properties by
      increasing transient fluid pressures during physiological loading. Recent studies
      of nonlinear properties of articular cartilage in compression revealed several
      physiologically pertinent nonlinear behaviors, all of which required that
      cartilage tensile stiffness increase significantly with stretch. We therefore
      performed sequences of uniaxial tension tests on fresh bovine articular cartilage
      slices using a protocol that allowed several hours to attain equilibrium and
      measured longitudinal and transverse tissue strain. By testing bovine cartilage
      from different ages (6 months to 6 years) we found that equilibrium and transient
      tensile modulus increased significantly with maturation and age, from 0 to 15 MPa
      at equilibrium and from 10 to 28 MPa transiently. Our results indicate that
      cartilage stiffens with age in a manner similar to other highly hydrated
      connective tissues, possibly due to age-dependent content of enzymatic and
      nonenzymatic collagen cross links. The long relaxation period used in our tests
      (5-10 hours) was necessary in order to attain equilibrium and avoid a very
      significant overestimation of equilibrium modulus that occurs when much shorter
      times are used (15-30 minutes). We also found that equilibrium and transient
      tensile modulus increased nonlinearly when cartilage is stretched from 0 to 10%
      strain without any previous tare load. Although our results estimate a nonlinear
      increase in tensile stiffness with stretch that is an order of magnitude lower
      than that required to predict nonlinear properties in compression, they are in
      agreement with previous results from other uniaxial tension tests of collagenous
      materials. We therefore speculate that biaxial tensile moduli may be much higher
      and thereby more compatible with observed nonlinear compressive properties.

PMID- 15179843
TI  - Determination of Poisson's ratio of articular cartilage by indentation using
      different-sized indenters.
AB  - Articular cartilage is often characterized as an isotropic elastic material with
      no interstitial fluid flow during instantaneous and equilibrium conditions, and
      indentation testing commonly used to deduce material properties of Young's
      modulus and Poisson's ratio. Since only one elastic parameter can be deduced from
      a single indentation test, some other test method is often used to allow separate
      measurement of both parameters. In this study, a new method is introduced by
      which the two material parameters can be obtained using indentation tests alone,
      without requiring a secondary different type of test. This feature makes the
      method more suitable for testing small samples in situ. The method takes
      advantages of the finite layer effect. By indenting the sample twice with
      different-sized indenters, a nonlinear equation with the Poisson's ratio as the
      only unknown can be formed and Poisson's ratio obtained by solving the nonlinear
      equation. The method was validated by comparing the predicted Poisson's ratio for
      urethane rubber with the manufacturer's supplied value, and comparing the
      predicted Young's modulus for urethane rubber and an elastic foam material with
      modulii measured by unconfined compression. Anisotropic and nonhomogeneous finite
      element (FE) models of the indentation were developed to aid in data
      interpretation. Applying the method to bovine patellar cartilage, the tissue
      Young's modulus was found to be 1.79 +/- 0.59 MPa in instantaneous response and
      0.45 +/- 0.26 MPa in equilibrium, and the Poisson's ratio 0.503 +/- 0.028 and
      0.463 +/- 0.073 in instantaneous and equilibrium, respectively. The equilibrium
      Poisson's ratio obtained in our work was substantially higher than those derived
      from biphasic indentation theory and those optically measured in an unconfined
      compression test. The finite element model results and examination of
      viscoelastic-biphasic models suggest this could be due to viscoelastic,
      inhomogeneity, and anisotropy effects.

PMID- 15179844
TI  - Effect of plant interaction on wind-induced crop motion.
AB  - Plant motion due to wind affects plant growth, a phenomenon called
      thigmomorphogenesis. Despite intensive studies of the turbulence over plant
      canopies, the study of plant motion induced by wind has often been limited to
      individual trees or cereal plants. Few models of global canopy motions are
      available. Moreover the numerical analysis of models that are based on individual
      stems becomes time consuming when dealing with crops. A model of motion within
      the canopies is proposed here using a wave propagation equation within a
      homogenized continuous medium, and a forcing function representing turbulent
      gusts advected over the canopy. This model is derived from a discrete model of a
      set of plant shoots represented as individual oscillators, including elastic
      contacts between shoots. Such contacts induce nonlinearities into the wave
      equation. A new experimental method to measure stem dynamical properties and
      elastic collision properties is presented with an illustration on alfalfa stems.
      Results obtained modeling plant motions in an alfalfa crop are presented.

PMID- 15179845
TI  - Microstructural mechanics of collagen gels in confined compression:
      poroelasticity, viscoelasticity, and collapse.
AB  - BACKGROUND: Collagen gels are important as platforms for in vitro study of cell
      behavior and as prototypical bioartificial tissues, but their mechanical
      behavior, particularly on the microscopic scale, is still poorly understood.
      METHOD OF APPROACH: Collagen gels were studied in step (10% strain in 0.05 s) and
      ramp (0.1%/s strain rate for 100 s) confined compression. Real-time birefringence
      mapping gave the local collagen concentration and orientation along with piston
      stress. Variations in the retardation allowed material-point tracking and
      qualitative determination of the strain distribution. RESULTS: Ramp tests showed
      classical poroelastic behavior: compression near the piston and relaxation to a
      uniform state. Step tests, however, showed an irreversibly collapsed region near
      the piston. CONCLUSIONS: Our results suggest that interstitial flow and fibril
      bending at crosslinks are the dominant mechanical processes during compression,
      and that fibril bending is reversible before collapse.

PMID- 15179846
TI  - Measurement and simulation of water and methanol transport in algal cells.
AB  - BACKGROUND: Experimental data and a complementary biophysical model are presented
      to describe the dynamic response of a unicellular microalga to osmotic processes
      encountered during cryopreservation. METHOD OF APPROACH: Chlorococcum texanum (C.
      texanum) were mounted on a cryoperfusion microscope stage and exposed
      sequentially to various solutions of sucrose and methanol. Transient volumetric
      excursions were determined by capturing images of cells in real time and
      utilizing image analysis software to calculate cell volumes. A biophysical model
      was applied to the data via inverse analysis in order to determine the plasma
      membrane permeability to water and to methanol. The data were also used to
      determine the elastic modulus of the cell wall and its effect on cell volume. A
      three-parameter (hydraulic conductivity (Lp), solute permeability; (omega), and
      reflection coefficient, (sigma)) membrane transport model was fit to data
      obtained during methanol perfusion to obtain constitutive property values. These
      results were compared with the property values obtained for a two coefficient (Lp
      and omega) model. RESULTS: The three-parameter model gave a value for sigma not
      consistent with practical physical interpretation. Thus, the two-coefficient
      model is the preferred approach for describing simultaneous water and methanol
      transport. The rate of both water and methanol transport were strongly dependent
      on temperature over the measured temperature range (25 degrees C to -5 degrees C)
      and cells were appreciably more permeable to methanol than to water at all
      measured temperatures. CONCLUSION: These results may explain in part why methanol
      is an effective cryoprotective agent for microalgae.

PMID- 15179847
TI  - Computational Fluid Dynamics (CFD) study of the 4th generation prototype of a
      continuous flow Ventricular Assist Device (VAD).
AB  - The continuous flow ventricular assist device (VAD) is a miniature centrifugal
      pump, fully suspended by magnetic bearings, which is being developed for
      implantation in humans. The CF4 model is the first actual prototype of the final
      design product. The overall performances of blood flow in CF4 have been simulated
      using computational fluid dynamics (CFD) software: CFX, which is commercially
      available from ANSYS Inc. The flow regions modeled in CF4 include the inlet
      elbow, the five-blade impeller, the clearance gap below the impeller, and the
      exit volute. According to different needs from patients, a wide range of flow
      rates and revolutions per minute (RPM) have been studied. The flow rate-pressure
      curves are given. The streamlines in the flow field are drawn to detect
      stagnation points and vortices that could lead to thrombosis. The stress is
      calculated in the fluid field to estimate potential hemolysis. The stress is
      elevated to the decreased size of the blood flow paths through the smaller pump,
      but is still within the safe range. The thermal study on the pump, the blood and
      the surrounding tissue shows the temperature rise due to magnetoelectric heat
      sources and thermal dissipation is insignificant. CFD simulation proved valuable
      to demonstrate and to improve the performance of fluid flow in the design of a
      small size pump.

PMID- 15179848
TI  - Particle-hemodynamics simulations and design options for surgical reconstruction
      of diseased carotid artery bifurcations.
AB  - Based on the hypothesis that aggravating hemodynamic factors play a key role in
      the onset of arterial diseases, the methodology of "virtual prototyping" of
      branching blood vessels was applied to diseased external carotid artery (ECA)
      segments. The goals were to understand the underlying particle-hemodynamics and
      to provide various geometric design options for improved surgical reconstruction
      based on the minimization of critical hemodynamic wall parameters (HWPs). First,
      a representative carotid artery bifurcation (CAB) and then CABs with stenosed
      ECAs, i.e., a distally occluded ECA and an ECA stump, were analyzed based on
      transient three-dimensional blood flow solutions, employing a user-enhanced
      commercial finite volume code. Specifically, the HWPs, i.e., oscillatory shear
      index, wall shear stress angle gradient, near-wall residence time of monocytes,
      and near-wall helicity angle difference were evaluated to compare the merits of
      each design option, including a reconstructed near-optimal junction which
      generates the lowest HWP-values. The results provide physical insight to the
      biofluid dynamics of branching blood vessels and guide vascular surgeons as well
      as stent manufacturers towards interventions leading to high sustained patency
      rates.

PMID- 15179849
TI  - Thermodynamic nonequilibrium phase change behavior and thermal properties of
      biological solutions for cryobiology applications.
AB  - Understanding the phase change behavior of biomaterials during freezing/thawing
      including their thermal properties at low temperatures is essential to design and
      improve cryobiology applications such as cryopreservation and cryosurgery.
      However, knowledge of phase change behavior and thermal properties of various
      biomaterials is still incomplete, especially at cryogenic temperatures (< or = 
      40 degrees C). Moreover, in these applications, chemicals are often added to
      improve their outcome, which can result in significant variation in the phase
      change behavior and thermal properties from those of the original biomaterials.
      These chemical additives include cryoprotective agents (CPAs), antifreeze protein
      (AFP), or cryosurgical adjuvants like sodium chloride (NaCl). In the present
      study, phase change behavior and thermal properties of saline solutions--either
      water-NaCl or phosphate buffered saline (PBS)--with various chemical additives
      were investigated. The chemical additives studied are glycerol and raffinose as
      CPAs, an AFP (Type III, molecular weight = 6500), and NaCl as a cryosurgical
      adjuvant. The phase change behavior was investigated using a differential
      scanning calorimeter (DSC) and a cryomicroscope. The specific and latent heat of
      these solutions were also measured with the DSC. The saline solutions have two
      distinct phase changes--water/ice and eutectic phase changes. During freezing,
      eutectic solidification of both water-NaCl and PBS are significantly supercooled
      below their thermodynamic equilibrium eutectic temperatures. However, their
      melting temperatures are close to thermodynamic equilibrium during thawing. These
      eutectic phase changes disappear when even a small amount (0.1 M glycerol) of CPA
      was added, but they are still observed after the addition of an AFP. The specific
      heats of these solutions are close to that of ice at very low temperatures (< or
      = -100 degrees C) regardless of the additives, but they increase between -100
      degrees C and -30 degrees C with the addition of CPAs. The amount of latent heat,
      which is evaluated with sample weight, generally decreases with the addition of
      the additives, but can be normalized to approximately 300 J/g based on the weight
      of water which participates in the phase change. This illustrates that thermal
      properties, especially latent heat, of a biomaterial should be evaluated based on
      the understanding of its phase change behavior. The results of the present study
      are discussed in the context of the implications for cryobiology applications.

PMID- 15179850
TI  - Effect of forced convection on the skin thermal expression of breast cancer.
AB  - A bioheat-transfer-based numerical model was utilized to study the energy balance
      in healthy and malignant breasts subjected to forced convection in a wind tunnel.
      Steady-state temperature distributions on the skin surface of the breasts were
      obtained by numerically solving the conjugate heat transfer problem. Parametric
      studies on the influences of the airflow on the skin thermal expression of tumors
      were performed. It was found that the presence of tumor may not be clearly shown
      due to the irregularities of the skin temperature distribution induced by the
      airflow field. Nevertheless, image subtraction techniques could be employed to
      eliminate the effects of the flow field and thermal noise and significantly
      improve the thermal signature of the tumor on the skin surface. Inclusion of the
      possible skin vascular response to cold stress caused by the airflow further
      enhances the signal, especially for deeply embedded tumors that otherwise may not
      be detectable.

PMID- 15179851
TI  - Manipulabilities of the index finger and thumb in three tip-pinch postures.
AB  - Tip-pinch, in which the tips of the index finger and thumb pick up and hold a
      very fine object, plays an important role in the function of the hand. The
      objective of this study was to investigate how human subjects affect
      manipulabilities of the tips of the index finger and thumb within the
      flexion/extension plane of the finger in three different tip-pinch postures. The
      index finger and thumb of twenty male subjects, were modeled as linkages, based
      on measurement results obtained using two three-dimensional position measurement
      devices. The manipulabilities of the index finger and thumb were investigated in
      three tip-pinch postures, using three criteria indicating the form and posture of
      the manipulability ellipse of the linkage model. There were no significant
      differences (p > 0.05, ANOVA) in each criterion of each digit across the
      subjects, except for two criteria of the thumb. The manipulabilities of the index
      finger and thumb were separately similar across all subjects in tip-pinch
      postures. It was found that the manipulability for the cooperation of the index
      finger and thumb of all the subjects in tip-pinch depended on the posture of the
      index finger, but not on the posture of the thumb. In two-dimensional tip-pinch,
      it was possible that the index finger worked actively while the thumb worked
      passively to support the manipulation of the index finger.

PMID- 15179852
TI  - Effect of fluid boundary conditions on joint contact mechanics and applications
      to the modeling of osteoarthritic joints.
AB  - The long-term goal of our research is to understand the mechanism of
      osteoarthritis (OA) initiation and progress through experimental and theoretical
      approaches. In previous theoretical models, joint contact mechanics was
      implemented without consideration of the fluid boundary conditions and with
      constant permeability. The primary purpose of this study was to investigate the
      effect of fluid boundary conditions at the articular surfaces on the contact
      mechanics, in terms of load sharing and fluid flow properties using variable
      permeability. The tested conditions included totally sealed surfaces, open
      surfaces, and open surfaces with variable permeability. While the sealed surface
      model failed to predict relaxation times and load sharing properly, the class of
      open surface models (open surfaces with constant permeability, and surfaces with
      variable permeability) gave good agreement with experiments, in terms of
      relaxation time and load sharing between the solid and the fluid phase. In
      particular, the variable permeability model was judged to be the most realistic
      of the three models, from a biological and physical point of view. This model was
      then used to simulate joint contact in the early and late stages of OA. In the
      early stages of OA, the model predicted a decrease in peak contact pressure and
      an increase in contact area, while in the late stages of OA, peak pressures were
      increased and contact areas were decreased compared to normal. These findings
      agree well with experimental observations.

PMID- 15179853
TI  - A proposed injury threshold for mild traumatic brain injury.
AB  - Traumatic brain injuries constitute a significant portion of injury resulting
      from automotive collisions, motorcycle crashes, and sports collisions. Brain
      injuries not only represent a serious trauma for those involved but also place an
      enormous burden on society, often exacting a heavy economical, social, and
      emotional price. Development of intervention strategies to prevent or minimize
      these injuries requires a complete understanding of injury mechanisms, response
      and tolerance level. In this study, an attempt is made to delineate actual injury
      causation and establish a meaningful injury criterion through the use of the
      actual field accident data. Twenty-four head-to-head field collisions that
      occurred in professional football games were duplicated using a validated finite
      element human head model. The injury predictors and injury levels were analyzed
      based on resulting brain tissue responses and were correlated with the site and
      occurrence of mild traumatic brain injury (MTBI). Predictions indicated that the
      shear stress around the brainstem region could be an injury predictor for
      concussion. Statistical analyses were performed to establish the new brain injury
      tolerance level.

PMID- 15179854
TI  - Changes in foot loading following plantar fasciotomy: a computer modeling study.
AB  - Forward dynamic simulations of a toe-rise task were developed to explore the
      outcomes of plantar fasciotomy, a surgery commonly performed to relieve heel
      pain. The specific objectives of this study were to develop such a simulation,
      validate its predictions, and simulate rising on toes using a model from which
      the plantar fascia had been removed. Root-mean squared differences between the
      intact model and measurements of healthy subjects were found to be 0.009 body
      weights (BW) and 0.055 BW for the horizontal and vertical ground reaction forces
      and 7.1 mm, 11.3 mm, and 0.48 deg for the horizontal, vertical and rotational
      positions of the pelvis. Simulated plantar fasciotomy increased passive arch
      torques by 7.4%, increased metatarsal head contact forces by 18%, and resulted in
      greater toe flexor activity. These simulations may explain the mechanisms behind
      plantar fasciotomy complications when patients perform activities that require
      loading of the plantarflexors and the longitudinal arch.

PMID- 15179855
TI  - The structure and mechanical properties of the mitral valve leaflet-strut chordae
      transition zone.
AB  - Biaxial testing, histological measurements and theoretical continuum mechanics
      modeling were employed to investigate the structure and mechanical properties of
      the mitral valve leaflet-strut chordae transition zone (LCT). The results showed
      that geometry changes and collagen fiber angle distribution contribute to
      variations in mechanical properties in the LCT zone. A simple three-coefficient
      exponential constitutive law was able to simulate the variation in stress-stretch
      behavior in the LCT zone by spatially varying a single coefficient and
      incorporating collagen fiber angle and degree of alignment. This quantitative
      information can greatly improve the predictions from biomechanical valve models
      by incorporating regional variations of structure and properties in the mitral
      leaflet-chordae tendineae system. These data provide the foundation for a
      computational model for studying stress distributions before and following
      chordal rupture, which may indicate the underlying reasons for the development of
      valve insufficiency in patients.

PMID- 15179856
TI  - Strain-rate sensitive mechanical properties of tendon fascicles from mice with
      genetically engineered alterations in collagen and decorin.
AB  - Tendons have complex mechanical behaviors that are nonlinear and time dependent.
      It is widely held that these behaviors are provided by the tissue composition and
      structure. It is generally thought that type I collagen provides the primary
      elastic strength to tendon while proteoglycans, such as decorin, play a role in
      failure and viscoelastic properties. This study sought to quantify such structure
      function relationships by comparing tendon mechanical properties between normal
      mice and mice genetically engineered for altered type I collagen content and
      absence of decorin. Uniaxial tensile ramp to failure experiments were performed
      on tail tendon fascicles at two strain rates, 0.5%/s and 50%/s. Mutations in type
      I collagen led to reduced failure load and stiffness with no changes in failure
      stress, modulus or strain rate sensitivity. Fascicles without decorin had similar
      elastic properties to normal fascicles, but reduced strain rate sensitivity.
      Fascicles from immature mice, with increased decorin content compared to adult
      fascicles, had inferior elastic properties but higher strain rate sensitivity.
      These results showed that tendon viscoelasticity is affected by decorin content
      but not by collagen alterations. This study provides quantitative evidence for
      structure-function relationships in tendon, including the role of proteoglycan in
      viscoelasticity.

PMID- 15179857
TI  - Mechanical thresholds for initiation and persistence of pain following nerve root
      injury: mechanical and chemical contributions at injury.
AB  - There is much evidence supporting the hypothesis that magnitude of nerve root
      mechanical injury affects the nature of the physiological responses which can
      contribute to pain in lumbar radiculopathy. Specifically, injury magnitude has
      been shown to modulate behavioral hypersensitivity responses in animal models of
      radiculopathy. However, no study has determined the mechanical deformation
      thresholds for initiation and maintenance of the behavioral sensitivity in these
      models. Therefore, it was the purpose of this study to quantify the effects of
      mechanical and chemical contributions at injury on behavioral outcomes and to
      determine mechanical thresholds for pain onset and persistence. Male Holtzman
      rats received either a silk or chromic gut ligation of the L5 nerve roots, a sham
      exposure of the nerve roots, or a chromic exposure in which no mechanical
      deformation was applied but chromic gut material was placed on the roots. Using
      image analysis, nerve root radial strains were estimated at the time of injury.
      Behavioral hypersensitivity was assessed by measuring mechanical allodynia
      continuously throughout the study. Chromic gut ligations produced allodynia
      responses for nerve root strains at two-thirds of the magnitudes of those strains
      which produced the corresponding behaviors for silk ligation. Thresholds for
      nerve root compression producing the onset (8.4%) and persistence of pain (17.4%
      22.2%) were determined for silk ligation in this lumbar radiculopathy model. Such
      mechanical thresholds for behavioral sensitivity in a painful radiculopathy model
      begin to provide biomechanical data which may have utility in broader
      experimental and computational models for relating injury biomechanics and
      physiologic responses of pain.

PMID- 15179858
TI  - Comparison of a multi-layer structural model for arterial walls with a fung-type
      model, and issues of material stability.
AB  - The goals of this paper are (i) to re-examine the constitutive law for the
      description of the (passive) highly nonlinear and anisotropic response of healthy
      elastic arteries introduced recently by the authors, (ii) to show how the
      mechanical response of a carotid artery under inflation and extension predicted
      by the structural model compares with that for a three-dimensional form of Fung
      type strain-energy function, (iii) to provide a new set of material parameters
      that can be used in a finite element program, and (iv) to show that the model has
      certain mathematical features that are important from the point of view of
      material and numerical stability.

PMID- 15179859
TI  - On the effects of residual stress in microindentation tests of soft tissue
      structures.
AB  - Microindentation methods are commonly used to determine material properties of
      soft tissues at the cell or even sub-cellular level. In determining properties
      from force-displacement (FD) data, it is often assumed that the tissue is
      initially a stress-free, homogeneous, linear elastic half-space. Residual stress,
      however, can strongly influence such results. In this paper, we present a new
      microindentation method for determining both elastic properties and residual
      stress in soft tissues that, to a first approximation, can be regarded as a pre
      stressed layer embedded in or adhered to an underlying relatively soft, elastic
      foundation. The effects of residual stress are shown using two linear elastic
      models that approximate specific biological structures. The first model is an
      axially loaded beam on a relatively soft, elastic foundation (i.e., stress-fiber
      embedded in cytoplasm), while the second is a radially loaded plate on a
      foundation (e.g., cell membrane or epithelium). To illustrate our method, we use
      a nonlinear finite element (FE) model and experimental FD and surface contour
      data to find elastic properties and residual stress in the early embryonic chick
      heart, which, in the region near the indenter tip, is approximated as an
      isotropic circular plate under tension on a foundation. It is shown that the
      deformation of the surface in a microindentation test can be used along with FD
      data to estimate material properties, as well as residual stress, in soft tissue
      structures that can be regarded as a plate under tension on an elastic
      foundation. This method may not be as useful, however, for structures that behave
      as a beam on a foundation.

PMID- 15179860
TI  - Bi-directional mechanical properties of the axillary pouch of the glenohumeral
      capsule: implications for modeling and surgical repair.
AB  - The objective of this study was to determine the mechanical properties of the
      axillary pouch of the inferior glenohumeral ligament in the directions
      perpendicular (transverse) and parallel (longitudinal) to the longitudinal axis
      of the anterior band of the inferior glenohumeral ligament. A punch was used to
      excise one transverse and one longitudinal tissue sample from the axillary pouch
      of each cadaveric shoulder (n = 10). Each tissue sample was preconditioned and
      then a load-to-failure test was performed. All tissue samples exhibited the
      typical nonlinear behavior reported for ligaments and tendons. Significant
      differences (p < 0.05) were detected between the transverse and longitudinal
      tissue samples for ultimate stress (0.8 +/- 0.4 MPa and 2.0 +/- 1.0 MPa,
      respectively) and tangent modulus (5.4 +/- 2.9 MPa and 14.8 +/- 13.1 MPa,
      respectively). No significant differences (p > 0.05) were observed between the
      ultimate strain (transverse: 23.5 +/- 11.5%, longitudinal: 33.3 +/- 23.6%) and
      strain energy density (transverse: 10.8 +/- 8.5 MPa, longitudinal: 21.1 +/- 15.4
      MPa) of the transverse and longitudinal tissue samples. The ultimate stress
      determined for the longitudinal axillary pouch tissue samples was comparable to a
      previous study that reported it to be 5.5 +/- 2.0 MPa. The ratio of the
      longitudinal to transverse moduli (3.3 +/- 2.8) is considerably less than that of
      the medial collateral ligament of the knee (30) and interosseous ligament of the
      forearm (385), suggesting that the axillary pouch functions to stabilize the
      joint in more than just one direction. Future models of the glenohumeral joint
      and surgical repair procedures should consider the properties of the axillary
      pouch in its transverse and longitudinal directions to fully describe the
      behavior of the inferior glenohumeral ligament.

PMID- 15179861
TI  - Nonlinear viscoelastic material property estimation of lower extremity residual
      limb tissues.
AB  - Axisymmetric nonlinear finite-element analysis was used to simulate force
      relaxation and creep data obtained during in vivo indentation of the residual
      limb soft tissues of six individuals with trans-tibial amputation [1]. The finite
      element models facilitated estimation of an appropriate set of nonlinear
      viscoelastic material coefficients of extended James-Green-Simpson material
      formulation for bulk soft tissue at discrete, clinically relevant test locations.
      The results indicate that over 90% of the experimental data can be simulated
      using the two-term viscoelastic Prony series extension of James-Green-Simpson
      material formulation. This phenomenological material formulation could not,
      however, predict the creep response from relaxation experiments, nor the
      relaxation response from creep experiments [2-5]. The estimated material
      coefficients varied with test location and subject indicating that these
      coefficients cannot be readily extrapolated to other sites or individuals.

PMID- 15179862
TI  - In vivo measurement of the dynamic 3-D kinematics of the ovine stifle joint.
AB  - The ovine stifle joint is a promising animal model for investigation of joint
      mechanobiology. A method for in vivo measurement of dynamic 3-D kinematics of the
      ovine stifle joint is described (accuracy: 0.36 +/- 0.39 mm). Inter-subject
      variability in kinematics is greater than both intra-subject and inter-session
      variability. For future studies in which joint kinematics are measured prior to
      and following controlled orthopaedic interventions, pooling of data should be
      avoided and each subject should act as its own control.

PMID- 15179863
TI  - Electrical impedance tomography of cell viability in tissue with application to
      cryosurgery.
AB  - Tissue damage that is associated with the loss of cell membrane integrity should
      alter the bulk electrical properties of the tissue. This study shows that
      electrical impedance tomography (EIT) should be able to detect and image necrotic
      tissue inside the body due to the permeabilization of the membrane to ions.
      Cryosurgery, a minimally invasive surgical procedure that uses freezing to
      destroy undesirable tissue, was used to investigate the hypothesis. Experimental
      results with liver tissue demonstrate that cell damage during freezing results in
      substantial changes in tissue electrical properties. Two-dimensional EIT
      simulations of liver cryosurgery, which employ the experimental data, demonstrate
      the feasibility of this application.

PMID- 15179864
TI  - Measurements of mouse pulmonary artery biomechanics.
AB  - BACKGROUND: Robust techniques for characterizing the biomechanical properties of
      mouse pulmonary arteries will permit exciting gene-level hypotheses regarding
      pulmonary vascular disease to be tested in genetically engineered animals. In
      this paper, we present the first measurements of the biomechanical properties of
      mouse pulmonary arteries. METHOD OF APPROACH: In an isolated vessel perfusion
      system, transmural pressure, internal diameter and wall thickness were measured
      during inflation and deflation of mouse pulmonary arteries over low (5-40 mmHg)
      and high (10-120 mmHg) pressure ranges representing physiological pressures in
      the pulmonary and systemic circulations, respectively. RESULTS: During inflation,
      circumferential stress versus strain showed the nonlinear "J"-shape typical of
      arteries. Hudetz's incremental elastic modulus ranged from 27 +/- 13 kPa (n = 7)
      during low-pressure inflation to 2,700 +/- 1,700 kPa (n = 9) during high-pressure
      inflation. The low and high-pressure testing protocols yielded quantitatively
      indistinguishable stress-strain and modulus-strain results. Histology performed
      to assess the state of the tissue after mechanical testing showed intact medial
      and adventitial architecture with some loss of endothelium, suggesting that
      smooth muscle cell contractile strength could also be measured with these
      techniques. CONCLUSIONS: The measurement techniques described demonstrate the
      feasibility of quantifying mouse pulmonary artery biomechanical properties.
      Stress-strain behavior and incremental modulus values are presented for normal,
      healthy arteries over a wide pressure range. These techniques will be useful for
      investigations into biomechanical abnormalities in pulmonary vascular disease.

PMID- 15179865
TI  - Feasibility of using orthogonal fluoroscopic images to measure in vivo joint
      kinematics.
AB  - Accurately determining in vivo knee kinematics is still a challenge in biomedical
      engineering. This paper presents an imaging technique using two orthogonal images
      to measure 6 degree-of-freedom (DOF) knee kinematics during weight-bearing
      flexion. Using this technique, orthogonal images of the knee were captured using
      a 3-D fluoroscope at different flexion angles during weight-bearing flexion. The
      two orthogonal images uniquely characterized the knee position at the specific
      flexion angle. A virtual fluoroscope was then created in solid modeling software
      and was used to reproduce the relative positions of the orthogonal images and X
      ray sources of the 3-D fluoroscope during the actual imaging procedure. Two
      virtual cameras in the software were used to represent the X-ray sources. The 3-D
      computer model of the knee was then introduced into the virtual fluoroscope and
      was projected onto the orthogonal images by the two virtual cameras. By matching
      the projections of the knee model to the orthogonal images of the knee obtained
      during weight-bearing flexion, the knee kinematics in 6 DOF were determined.
      Using regularly shaped objects with known positions and orientations, this
      technique was shown to have an accuracy of 0.1 mm and 0.1 deg in determining the
      positions and orientations of the objects, respectively.

PMID- 15179866
TI  - [Complication of polyacrylamide hydrogel injection for facial plasty].
AB  - OBJECTIVE: To investigate the causes of complications of polyacrylamide hydrogel
      injection for facial plasty and reliable treatments. METHODS: Eight patients were
      included in the study. Some of them were examined by MRI. All the patients
      received surgical treatments. RESULTS: The injected polyacrylamide hydrogel was
      found in the superficial layer of the superficial temporal fasica, the loose
      connective tissue below the deep temporal fascia, the subcutaneous tissue or the
      orbicularis muscle. Polyacrylamide hydrogel injected into the superficial layer
      of the superficial temporal fascia could spread to the face along the SMAS.
      Polyacrylamide hydrogel injected into the loose connective tissue below the deep
      temporal fascia could spread down to the cheek. The patients' symptoms were
      relieved with the operation. Satisfactory results were obtained. CONCLUSION:
      Polyacrylamide hydrogel injection does not adapt to facial plasty. The
      reliability of polyacrylamide hydrogel injection for facial plasty is in doubt.

PMID- 15179867
TI  - [Clinically analyzing the possible side-effects after injecting hydrophilic
      polyacrylamide gel as a soft-tissue filler].
AB  - OBJECTIVE: To evaluate the possible side-effects after injecting hydrophilic
      polyacrylamide gel for augmentation of the soft-tissue. METHODS: Fifteen patients
      with some side-effects after injecting the hydrophilic polyacrylamide gel had
      been undergoing for the treatment in our unit from 2000 to 2001. Their symptoms
      were analyzed and the specimen of the tissue was also removed for pathologic
      examination. RESULTS: The major complaints of the patients after injecting
      hydrophilic polyacrylamide gel were feeling pain(60.00%), uncomfortable (13.33%),
      no cosmetic improvement results (33.33%), secondary deformity (20.00%), long
      lasting swelling (6.67%), and nodules (80.00%). The pathologic examination was
      showing the capsule formation (53.33%), macrophagocyte infiltration (60.00%) and
      granuloma producing (20.00%). CONCLUSION: Clinical application of the hydrophilic
      polyacrylamide gel may result in some serious side-effects. It should be cautious
      to the physicians who may apply the product for clinic use.

PMID- 15179868
TI  - [Analysis and treatment of complications induced by polyacrylamide hydrogel
      injection].
AB  - OBJECTIVE: To explore the reasons for the complications of polyacrylamide
      hydrogel injection. METHODS: 39 patients were included in this study, who had
      complications after polyacrylamide hydrogel injection in the breasts, nose,
      temproal area or depressed locus. The clinical manifestations of the
      complications were analyzed. RESULTS: Postoperative infection occurred in 5
      cases, induration in 23, pain in 25, ulceration of the puncture points in 9,
      displacement in 6, galactostasis in 1, skin necrosis in 1, breast deformation in
      3, bilateral asymmetry in 4, aseptic inflammation in 10, and skin-acne-like
      changes on the face in 4. CONCLUSION: Some complications were caused mainly by
      incorrect manipulation and others were relative to the injected material. The
      applications of polyacrylamide hydrogel as a clinical implant material need
      further investigations. Polyacrylamide hydrogel injection should be cautiously
      used.

PMID- 15179869
TI  - [Applications of ultrasound in the treatment of the complications of breast
      augmentation with polyacrylamide hydrogel injection].
AB  - OBJECTIVE: To search for a simple and non-invasive method to assist the treatment
      of the complications of breast augmentation with polyacrylamide hydrogel
      injection. METHODS: High-frequency ultrasound was used to examine the breast and
      observe the distributions of the injected polyacrylamide hydrogel. The operation
      procedure was predetermined according to the ultrasound information. The
      ultrasound results were compared with what was seen during the operation.
      RESULTS: 40 patients (80 breasts) were examined. The ultrasound results were
      coincident with the outcomes of surgery. The results of postoperative follow-up
      were coincident with the predicted. CONCLUSION: Ultrasound is an accurate method
      for examining the augmented breast with polyacrylamide hydrogel injection. It is
      helpful in predetermining the operation procedure, predicting postoperative
      results.

PMID- 15179870
TI  - [Repair of whole auricular defects with implant-plasty and prosthesis].
AB  - OBJECTIVE: To repair the whole auricular defects with implant-plasty and
      prosthesis technique. The indications, complications and implant sites of this
      method were discussed. METHODS: In reconstruction of the whole auricular defect,
      the self-developed pure titanium implants, specialized for plastic surgery, were
      used for intra-osseous fixation for retaining the artificial ear. 10 cases were
      treated with this method. RESULTS: Follow-up of three years demonstrated that
      this implant system, with stable function, could generate osseointegration and be
      used as an abutment of intra-osseous fixation to retain the auricular prosthesis
      for a long time. CONCLUSION: The operation is simple and convenient with little
      trauma and short-term of treatment. The artificial ear has lifelike appearance,
      proper color and satisfactory effects. This technique has wide indications and is
      worth popularization.

PMID- 15179871
TI  - [Treatment of helical keloid with retroauricular skin expansion].
AB  - OBJECTIVE: To introduce a new technique for the treatment of helical keloid.
      METHODS: The procedure consisted of two steps. In the first step, a kidney-shaped
      expander of 50 ml was placed subcutaneously in the retroauricular area. Routine
      inflation with normal saline followed. In the second step, about two months
      afterwards, the expander was taken out and the helical keloid was excised. The
      expanded flap was advanced to cover the wound. RESULTS: The operation has been
      performed on 12 patients of 16 sites of helical keloid since 2000. Postoperative
      follow-up from 3 months to 2 years revealed satisfactory results. The
      reconstructed ear maintained a good contour. CONCLUSION: The technique creates a
      retroauricular flap rich in blood supply, which can be used to close the defect
      left by helical keloid excision. It provides a good treatment for the helical
      keloid replaced with normal skin from the mastoid region.

PMID- 15179872
TI  - [Staging and management of extracranial arteriovenous malformations].
AB  - OBJECTIVE: Congenital arteriovenous malformations(AVM) are considered to be the
      most difficult and challenging problems in the treatment of hemangiomas and
      vascular lesions. This study focused on the natural history, the clinical
      classification, the choice and effectiveness of various treatments. METHODS: This
      retrospective review included 83 patients with extracranial arteriovenous
      malformations, who were referred to our department over the past 6 years. The
      anatomic patterns, clinical staging, respective treatments, influential factors
      of endovascular treatment, causes of recurrence were analyzed. RESULTS: According
      to clinical manifestations, arteriovenous malformations were categorized as three
      clinical stages: the quiescence, the expansion and the decompensation stages.
      Most AVMS in the quiescence stage only require endovascular treatment while those
      in the decompensation stage require surgical resection. Angiography was performed
      not only for diagnosis of AVM but also as an initial therapeutic step in the form
      of embolization, which might be the only means to some AVM without surgical
      possibility or necessity. CONCLUSION: The new concept of staging and management
      is expected to be helpful for diagnosis and treatments of AVM.

PMID- 15179873
TI  - [Expression of apoptosis and Bcl-2, Bax in hemangioma and vascular
      malformations].
AB  - OBJECTIVE: To study the expression of apoptosis and their regulatory genes, Bcl
      2, Bax in hemangioma and vascular malformations. METHODS: The specimens were
      taken from 68 cases of strawberry hemangioma or vascular malformations and 11
      cases of normal skin. The expression of Bcl-2, Bax and Ki-67 in endothelial cells
      were investigated by immunohistochemical S-P method. The apoptosis index (AI) in
      endothelial cells was investigated by TUNEL method. RESULTS: Ki-67 was positive
      in all the proliferating strawberry hemangioma, negative in the other groups. The
      expression of Bax was significantly higher in strawberry hemangioma than in
      vascular malformations and normal skin (P < 0.01). Bcl-2 was negative in all
      groups. The AI in endothelial cells of strawberry hemangioma was significantly
      higher than that of vascular malformations and normal skin. There were no
      statistically significant differences between the proliferating and involution
      strawberry hemangioma. There were no statistically significant differences
      between various types of vascular malformations and normal skin. With the
      increasing of the expression of Bax in strawberry hemangioma, the AI increased.
      CONCLUSION: These findings clearly demonstrate a much higher apoptotic activity
      in strawberry hemangioma than in vascular malformations and normal skin and
      suggest that apoptosis might be a cause of spontaneous involution of strawberry
      hemangioma and might not be a cause of the pathogenesis of vascular malformation.
      Bcl-2, Bax might play an important regulatory role in apoptosis in endothelial
      cells of strawberry hemangioma.

PMID- 15179874
TI  - [A clinical pathological study on cavernous venous malformation of the body
      surface].
AB  - OBJECTIVE: To investigate the clinical pathology of cavernous venous
      malformations of the body surface. METHODS: Tissue samples of cavernous venous
      malformations from 42 cases were stained with hematoxylin and eosin to observe
      the pathologic structure. The clinical manifestations and case history were
      summarized accordingly. RESULTS: There was no distribution difference of the
      malformation in sex and body sides, but with obvious difference in anatomic
      sites. The malformation occurred most frequently at the head and neck, more
      frequently at extremities and least frequently at the trunk. According to
      pathologic structure, cavernous venous malformations of the body surface can be
      divided into three types: the cellular, the canaliform and the mixed. CONCLUSION:
      The cause of distribution difference in anatomic sites remains unclear. Internal
      hemorrhage and infection may account for the increased growth and ache of the
      lesion. The different pathologic structure of the malformation may cause
      different clinical manifestations.

PMID- 15179875
TI  - [Finger reconstruction with extended free second toe flap transfer].
AB  - OBJECTIVE: To investigate an ideal method for finger reconstruction with extended
      the second toe flap transfer. METHODS: The second toe free flap was created,
      combined with an pedicled skin flap from the fibular side of the great toe inlaid
      in the ventral side of the second toe, a double-wing flap and the distal part of
      the metatarsal bone. The composite free flap was transferred by vascular
      anastomosis for finger reconstruction. RESULTS: The reconstructed finger
      exhibited nice looking and better function. The procedure had little influence to
      the appearance and function of the donor foot. CONCLUSION: This method is
      effective in ameliorating the appearance and function of the reconstructed finger
      with the second toe transfer.

PMID- 15179876
TI  - [Clinical applications of the buried-guided-suture method in the treatment of
      facial depression].
AB  - OBJECTIVE: To develop a method for the treatment of facial depression without
      incision scar. METHODS: In repairing the facial depression, the ruptured
      subdermal adipocellular tissue was approximated and reunite with the buried
      guided-suture method through an intraoral or a concealed skin incision. RESULTS:
      17 patients with facial depressions from trauma were treated. Postoperative
      follow-up of 10 patients for one year showed satisfactory results without
      recurrence. CONCLUSION: The buried-guided-suture method for repair of facial
      depression from trauma is simple, reliable and worth recommendation.

PMID- 15179877
TI  - [The possibility of midface skeleton protraction: an experimental study in dogs].
AB  - OBJECTIVE: To probe the feasibility of a new technique of sutural distraction
      osteogenesis for midface hypoplasia repair. METHODS: A protraction system was
      developed, which consisted of three parts: a rigid external framework, a bone
      hook, and the elastic band. Four 12-week mongreal dogs were randomly assigned
      into two groups: the control (n = 1) and the experimental groups (n = 3). Four
      pairs of titanium bone markers were fixed on either side of the bone sutures of
      all animals. The experimental group was fitted with a distraction device, through
      which a forward elastic force was exerted for 1 month. Clinical observations and
      X-ray examinations were performed at the beginning and the end of distraction.
      New bone specimens were examined histologically. RESULTS: All the animals in the
      experimental group showed progressively forward movement of the maxilla and
      manifested class II occlusion at the end of the experiment. The distance increase
      between each pair of bone markers showed that premaxilla advancement was more
      than that of the maxilla. The next was zygoma. There was no obvious difference
      between the control and the experimental group in terms of the basilar-maxillary
      angle and counterclockwise rotation. Theer was active osteogenesis in the
      sutures, especially in premaxilla-maxillary sutures. The number of osteoblasts
      and fibroblasts increased dramatically and new bone formation was found at the
      edge of the suture. CONCLUSION: This technique can create effective advancement
      of the maxilla. The direct force can avoid counterclockwise rotation of the
      maxilla during distraction.

PMID- 15179878
TI  - [Analysis of the complications following correction of mandibular angle
      prominence].
AB  - OBJECTIVE: To investigate the causes and the prophylactic measures for the
      complications following correction of mandibular angle prominence. METHODS: From
      1996 to 2001, a total of 203 patients with mandibular angle prominence underwent
      mandibular angle osteotomy. RESULTS: Of them, 9 patients had postoperative
      complications, which included bleeding, hematoma, infection, mental nerve injury,
      labia scar, asymmetry, and steep mandibular angle. CONCLUSION: The correction of
      mandibular angle prominence should be designed and performed precisely. Care must
      be taken to avoid severe complications like condyle fracture.

PMID- 15179879
TI  - [Repair of severe blepharoptosis with a frontalis muscle complex suspension
      technique].
AB  - OBJECTIVE: To search an ideal method for treatment of severe blepharoptosis.
      METHODS: Fifty-four eyes of 47 patients with severe blepharoptosis were
      undergoing for the treatment with a frontalis muscle complex flap, included in
      the frontalis muscle, orbicularis oculi muscle and SMAS membranes, to suspend the
      dropped eyelids. RESULTS: The 54 eyes with severe blepharoptosis were
      successfully treated with the frontalis muscle complex suspension technique.
      Although the lagophthalmos in different degrees was shown in 3 months after the
      operation, it usually disappeared 6 months after the operation. The results were
      shown good appearance without recurrence. CONCLUSION: The above mentioned
      technique may be a good and effective method for treatment of the severe
      blepharoptosis, compared with the traditional technique.

PMID- 15179880
TI  - [An experiment study on repair of peripheral nerve defects by GDNF gene modified
      Schwann cells].
AB  - OBJECTIVE: To investigate an effective treatment of peripheral nerve injuries by
      means of gene transference. METHODS: 48 adult Wister rats were divided evenly
      into 3 groups. A 10 mm sciatic nerve gap was created and bridged with a silicone
      chamber. The silicone chamber was filled with glial cell-line derived
      neurotrophic factor(GDNF) gene modified Schwann cells(SCs) (group 1), the normal
      SCs(group 2) and nothing(the control). At 4, 8, 12, and 16 weeks after the
      operation, the general and histological observations, the electromyographic and
      immunohistochemical examinations were performed to the regenerated nerves.
      RESULTS: The GDNF-SCs group was significantly better than the SCs and the control
      groups in nerve conduction velocity, the number and density of reinnervation, the
      area of regenerated nerve and the thickness of myelin sheath of the regenerated
      nerves. CONCLUSION: GDNF gene modified SCs secrete higher levels of neurotrophic
      factors for a prolonged time, which are more effective in peripheral nerve repair
      than the normal SCs.

PMID- 15179881
TI  - [The therapy with rhVEGF gene for ischemic TRAM flap in rats].
AB  - OBJECTIVE: To establish a stable ischemic TRAM flap model in rats and observe the
      effects of rhVEGF gene on the ischemic flap. METHODS: Materials were
      administrated via subcutaneous injection 5 days before the TRAM flap procedure.
      32 animals were divided into four groups. The first group was treated with
      PcDNA3.1 VEGF; the second group with PcDNA3.1 as the negative control; the third
      group with normal saline as the frank control, and the fourth group with VEGF as
      the positive control. The material was given while the procedures were performed.
      The serum levels of VEGF before and after the operation were measured with ELISA
      kit. The flap was harvested for immunohistological evidence of VEGF protein
      expression. The viable area of the flap was calculated with AutoCAD software. The
      microvessel density(MVD) of the subcutaneous tissue of the flap was counted.
      RESULTS: The average viable area of the TRAM flap in model animals was (3.61 +/-
      1.06) cm2 [(16.04 +/- 4.71)%]. Comparing the mean viable area of the flap in the
      PcDNA3.1 VEGF group[(7.98 +/- 2.64) cm2] with that in the normal saline group
      [(4.13 +/- 1.77) cm2], the difference was significant(P < 0.05). There was no
      significant difference between the PcDNA3.1 VEGF group and the VEGF group[(7.31
      +/- 1.22)cm2] in terms of mean viable flap area. The difference of mean MVD
      values between the PcDNA3.1 VEGF group and the negative control group was
      significant(P < 0.05), but was not significant between the gene treatment group
      and the positive control group. The serum level of VEGF did not increase
      significantly up to 9 days after the administration of PcDNA3.1 VEGF(P > 0.05).
      Immunohistochemical staining documented the increased deposition of VEGF protein
      in the plasma of endothelial cells of the flap that was injected with PcDNA3.1
      VEGF. CONCLUSION: The unilateral inferior-pedicled TRAM flap as an ischemic flap
      model is stable and suitable for statistic treatment. Subcutaneous injection of
      rhVEGF gene can express biologically active VEGF at the site, increase MVD and
      the viable area of the TRAM flap.

PMID- 15179883
TI  - Pay-for-performance programs pressure and please physicians.

PMID- 15179882
TI  - [A study on the inhibiting effects of transforming growth factor-beta R II
      antibody on fibroblasts].
AB  - OBJECTIVE: To investigate the inhibiting action of transforming growth factor
      beta type R II receptor(TGF-beta R II) antibody to fibroblasts. METHODS: Four
      groups of cultured skin fibroblasts were treated with different dosages of TGF
      beta R II antibody. Examinations were performed with HYP, MTT, microscope, and
      flow cytometry techniques. RESULTS: TGF-beta R II antibody resulted in
      significant inhibition of fibroblasts(P < 0.01). CONCLUSION: TGF-beta R II
      antibody has inhibiting effects on the proliferation of skin fibroblasts and with
      a dose-dependent manner.

PMID- 15179884
TI  - Improving clinical quality and sharing the profits with your physicians.

PMID- 15179885
TI  - The ethical aspects of gain sharing with physicians.
AB  - Gain sharing arrangements involving physicians can be a model combination of
      ethical business practices and maximizing profits. Or, gain sharing can be as
      unethical as fee-splitting was at the turn of the century, and as corrupt as any
      conflict of interest. The devil is--or is not--in the details.

PMID- 15179886
TI  - World Bank physician practices alternative medicine with international flavor.

PMID- 15179887
TI  - Dealing with angry patients.
AB  - Understanding what angers patients, how to listen to their concerns and what
      steps to take to find a resolution sound like relatively easy tasks. But, in
      reality, they can be one of the toughest challenges physician executives face.

PMID- 15179888
TI  - The virtual patient encounter--units of service in the electronic age.
AB  - A patient, preoperative evaluation center can reduce delays and cancellations,
      but it's critical to measure staff workload and determine the best ways to
      coordinate care. See how one clinic in Ohio is succeeding with this effort.

PMID- 15179889
TI  - Reducing litigation costs through better patient communication.
AB  - The most common cause of malpractice suits is failed communication with the
      patients and their families. Explore ways that better communication could lead to
      fewer malpractice claims and allow health care organizations to reduce litigation
      costs.

PMID- 15179891
TI  - Preparation is key to successful job interviews.

PMID- 15179890
TI  - The DRG dilemma.
AB  - Government agencies and insurance companies are increasingly utilizing diagnosis
      related group databases to evaluate physician and hospital practices. However,
      the average practicing physician and physician executive has little or no
      knowledge of his own or his institution's profile.

PMID- 15179892
TI  - 7 critical steps to implementing clinical guidelines.

PMID- 15179893
TI  - To assume is human.

PMID- 15179894
TI  - The hospital/physician divide: understanding the drivers of their relationships.

PMID- 15179895
TI  - 6 steps to negotiating hospital stipends.

PMID- 15179896
TI  - Characteristics of the sophisticated job candidate.

PMID- 15179897
TI  - American health care, Internet style.

PMID- 15179898
TI  - The ADA of tomorrow: a five point plan.

PMID- 15179899
TI  - A Minnesota dental laboratory of 100 years ago.

PMID- 15179900
TI  - An ongoing diligence: the MDA president's interview 2004.

PMID- 15179901
TI  - The first impression: your chance to establish rapport.

PMID- 15179903
TI  - No present like the time.

PMID- 15179902
TI  - What's a dentist to do?

PMID- 15179904
TI  - Socioeconomic status and health: a micro-level analysis of exposure and
      vulnerability to daily stressors.
AB  - This study examines the interconnections among education--as a proxy for
      socioeconomic status--stress, and physical and mental healthy by specifying
      differential exposure and vulnerability models using data from The National Study
      of Daily Experiences (N = 1,031). These daily diary data allowed assessment of
      the social distribution of a qualitatively different type of stressor than has
      previously been examined in sociological stress research--daily stressors, or
      hassles. Moreover, these data allowed a less biased assessment of stress exposure
      and a more micro-level examination of the connections between stress and healthy
      by socioeconomic status. Consistent with the broad literature describing
      socioeconomic inequalities in physical and mental health, the results of this
      study indicated that, on any given day, better-educated adults reported fewer
      physical symptoms and less psychological distress. Although better educated
      individuals reported more daily stressors, stressors reported by those with less
      education were more severe. Finally, neither exposure nor vulnerability explained
      socioeconomic differentials in daily health, but the results clearly indicate
      that the stressor-health association cannot be considered independent of
      socioeconomic status.

PMID- 15179905
TI  - Chronic stressors and daily hassles: unique and interactive relationships with
      psychological distress.
AB  - Using daily telephone interviews of a U.S. national sample of adults, aged 25-74
      (N = 1,031), the present analyses draw from theories of the stress process and
      recent research to examine how chronic role-related stressors and daily hassles
      affect psychological distress. Four separate hypotheses are examined. The first
      explores the association between chronic stressors and daily hassles. The second
      tests whether daily hassles function as an intervening variable between chronic
      stressors and psychological distress. The third tests whether a chronic stressor
      moderates the relationship between daily hassles and psychological distress. The
      fourth hypothesis tests for cross-domain effects of chronic stressors and daily
      hassles. Findings indicate that chronic stressors and daily hassles are distinct
      types of stressors with unique contributions to psychological distress. The study
      provides support for chronic home stressors functioning as a moderating factor on
      the relationship between daily hassles and psychological distress both within and
      across domains.

PMID- 15179906
TI  - Personal resources and depression in the transition to adulthood: ethnic
      comparisons.
AB  - Based on a representative sample of 1,803 South Florida young adults, we examine
      the extent to which personal attributes mediate or moderate the ethnicity
      depression relationship and condition the effects of social stress on depression.
      Our sample contains nearly equal proportions of African American, Cuban American,
      "other" Hispanic, and non-Hispanic white respondents. Findings suggest that there
      are ethnic variations in four of the five personal resources considered.
      Additionally, when accounting for ethnic differences in response tendencies and
      in the confounding of personal resources with depression, there is strong
      evidence for both direct and stress-buffering effects of personal resources.
      Although naive comparisons of within group findings imply a number of ethnic
      variations in those effects, few statistically significant differences are
      observed. It is suggested that ethnic similarities outweigh differences, at least
      with respect to the mental health significance of the personal resources
      considered. Overall, the results highlight some of the complexities inherent in
      making multi-ethnic comparisons.

PMID- 15179907
TI  - Public attitudes toward the use of psychiatric medications for children.
AB  - Psychiatric medication use for children has increased dramatically over the past
      three decades. Despite substantial media attention to the issue, little is known
      about how the lay public feels about the use of psychiatric medications for
      children. Drawing on theories of medicalization, we describe and analyze
      Americans' attitudes towards the use of psychiatric medications generally and
      Prozac specifically for children described as having three types of behavioral
      problems. Using data from the 1998 General Social Survey's Pressing Issues in
      Health and Medical Care Module, we find that more Americans (57%) are willing to
      use psychiatric medications for children who have expressed suicidal statements
      than for "oppositional" behaviors (34.2%) or for hyperactivity (29.5%). Across
      the board, respondents are less willing to give Prozac than the general class of
      psychiatric medications. While socio-demographics do little to identify Americans
      with differing positions, the strongest and most consistent correlates of
      willingness to give psychiatric medications to children are trust in personal
      physicians, general attitudes towards psychiatric medications, and the
      respondent's expressed willingness to take psychiatric medications herself or
      himself.

PMID- 15179908
TI  - Fear of people with mental illnesses: the role of personal and impersonal contact
      and exposure to threat or harm.
AB  - Vignette and laboratory experiments suggest that negative reactions to people
      with mental illness are a direct consequence of their symptomatic behavior, but
      because of their poor external validity, these studies cannot tell us whether
      widespread negative public reactions to people with mental illness actually
      result from observation of symptomatic behavior. Focusing on perceived danger, we
      use a large national survey to test the "behavior hypothesis" in the general
      population. We reason that, if this hypothesis is correct, contact with people
      with mental illnesses should be associated with more perceived danger, and
      exposure to threat or harm should mediate this association. On the contrary,
      respondents with more personal and impersonal contact perceive people with mental
      illness to be less dangerous. Exposure to threat is more common among people with
      more contact, but this exposure explains very little of the variance in perceived
      danger. These findings do not support the conclusion that public fear of people
      with mental illness is due to the observation of violent behavior.

PMID- 15179910
TI  - Linking race and well-being within a biopsychosocial framework: variation in
      subjective sleep quality in two racially diverse older adult samples.
AB  - Differential life experiences associated with race may critically affect the
      balance between physical and psychological well-being. This study investigated an
      age-related and disease-related symptom, restless sleep, among older African
      American and white members of two sociodemographically matched cohorts, community
      dwelling older adults and older adults with chronic renal failure undergoing
      maintenance dialysis therapy. Sleep behaviors reflect age-dependent and disease
      dependent homeostatic and circadian state regulation but are also socioculturally
      patterned. As hypothesized, restless sleep was significantly more characteristic
      of the older adults in the chronic disease cohort. With non-renal health
      conditions, depressed mood, perceived health, medication use, and
      sociodemographic variables controlled, however, African Americans were
      significantly less likely than whites in the chronic disease cohort to report
      restless sleep. African American and white patients differed in their expression
      of public and private religiousness, which in turn were associated, respectively,
      with depressed mood and restless sleep complaint. In addition, we suggest that
      differences for African American and white patients in the environmental exposure
      of chronic dialysis therapy, including African Americans' greater social
      integration within the dialysis treatment setting, contributed to their being
      less at risk than their white peers for subjective perception of sleep decay, a
      marker of overall well-being.

PMID- 15179911
TI  - Ahead of the pack: custom trays facing buyer scrutiny.

PMID- 15179909
TI  - Marital status, marital transitions, and health: a gendered life course
      perspective.
AB  - We work from a life course perspective to assess the impact of marital status and
      marital transitions on subsequent changes in the self-assessed physical health of
      men and women. Our results suggest three central conclusions regarding the
      association of marital status and marital transitions with self-assessed health.
      First, marital status differences in health appear to reflect the strains of
      marital dissolution more than they reflect any benefits of marriage. Second, the
      strains of marital dissolution undermine the self-assessed health of men but not
      women. Finally, life course stage is as important as gender in moderating the
      effects of marital status and marital transitions on health.

PMID- 15179912
TI  - Price survey. Endoscope prices, popularity rise.

PMID- 15179913
TI  - Saving laboratory records: what, how, how long?

PMID- 15179914
TI  - WNV: where in the world did that come from?

PMID- 15179915
TI  - NCCLS simplifies the order of draw: a brief history.

PMID- 15179916
TI  - Building the lab workforce of the future.

PMID- 15179917
TI  - Tomorrow's lab: the stuff of dreams.

PMID- 15179918
TI  - Rob Bush of Orchard focuses on LIS trends. Interview by Dottie Dunham.

PMID- 15179919
TI  - Addressing management issues.

PMID- 15179920
TI  - If you have liability insurance--stop reading now.

PMID- 15179921
TI  - The real economic value of Medicaid--it's more than you think!

PMID- 15179922
TI  - What nurses need to know about the National Standards for Culturally and
      Linguistically Appropriate Services (CLAS) in health care.

PMID- 15179923
TI  - A study of South Carolina nurses attitudes of addiction within the profession.

PMID- 15179924
TI  - Collection and preparation of blood products.
AB  - Blood-component therapy has become an integral part of veterinary practice.
      Although access to veterinary blood banks has increased, practitioners may prefer
      to create their own blood-donor program to provide for their blood-product needs
      or to respond to an emergent need. Before embarking on such an endeavor, it is
      important to understand the techniques and requirements for such a program. This
      article will discuss issues in donor selection and management, supplies and
      techniques of blood-component acquisition, and supplies and techniques of blood
      component preparation.

PMID- 15179925
TI  - Blood-component therapy: selection, administration and monitoring.
AB  - Transfusion of blood products is a frequent necessity in small animal practice.
      Transfusion medicine has become more sophisticated with increased access to blood
      components, knowledge of blood types, and cross-matching requirements. Although
      potentially life saving, this procedure does carry some risk. In addition to
      selecting the appropriate blood product, several steps need to be completed to
      prepare the product for administration and the patient for receiving a
      transfusion.

PMID- 15179926
TI  - Infection and blood transfusion: a guide to donor screening.
AB  - In recent years, blood-component therapy has become more accessible in veterinary
      practice. As with human medicine, care must be taken to minimize the risk of
      disease transmission from donor to recipient. Determining the appropriate
      diseases to screen for is complicated by regional variations in disease
      incidence, the existence of chronic carrier states for some diseases, the
      difficulty in screening-test selection, and testing cost. The feline diseases
      considered include retroviral infections, feline coronaviruses, ehrlichiosis
      (Ehrlichia canis-like), anaplasmosis (Anaplasma phagocytophilum),
      neorickettsiosis (Neorickettsia risticii), hemoplasmosis (Mycoplasma hemofelis
      and M. hemominutum, previously feline hemobartonellosis), and cytauxzoonosis
      (Cytauxzoon felis). The canine diseases considered in this paper include
      babesiosis (Babesia canis and B. gibsonii,) ehrlichiosis (E. canis and E.
      ewingii), anaplasmosis (A. phagocytophilum), neorickettsiosis (N. risticii var.
      atypicalis), leishmaniasis (Leishmania donovani complex), brucellosis (Brucella
      canis), hemoplasmosis (M. hemocanis, previously canine hemobartonellosis), and
      bartonellosis (Bartonella vinsonii).

PMID- 15179927
TI  - Blood transfusion in the perioperative period.
AB  - In the perioperative period, blood transfusions are most commonly administered to
      address acute blood loss resulting from trauma, neoplasia, or surgery. In this
      setting, transfusions may be life saving, allowing time for clotting or surgical
      hemostasis. In recent years, however, there is a growing awareness that the
      administration of blood products may not be a benign treatment. In addition to
      the more commonly cited complications such as transfusion reactions, disease
      transmission, and electrolyte disturbances, blood transfusions have also been
      linked to poor surgical outcomes, increased risk of infection, cancer recurrence,
      and acute lung injury. The recognition of these problems has lead to more
      conservative transfusion strategies, and questioning of what constitutes an
      appropriate transfusion trigger. In this section, we will discuss the
      pathophysiology of acute blood loss, the benefits and risks of transfusions in
      surgical patients, management of perioperative blood transfusions, and
      alternative strategies to minimize the need for blood products.

PMID- 15179928
TI  - Transfusion medicine in veterinary emergency and critical care medicine.
AB  - Transfusion medicine is a vital part of veterinary emergency and critical care
      medicine. The goals of this article are to review blood banking and the
      transfusion principles surrounding care of the critically ill or injured small
      animal, to highlight the differences in emergency/critical care transfusions
      compared with standard transfusion medicine, and to discuss traumatic blood loss
      and sepsis as unique entities in emergency and critical medicine.

PMID- 15179929
TI  - Transfusion medicine in exotic pets.
AB  - The decision to transfuse a patient should always be based on the packed cell
      volume and clinical status of the patient. This article discusses indications for
      transfusion and blood substitutes in exotic animal patients. The administration
      of blood products requires careful donor selection, knowledge of blood groups,
      cross-matching, and use of anticoagulants. Collection sites, volume, and
      administration techniques are given for different species of animals including
      birds, rabbits, and ferrets. Blood-transfusion therapy is not without risk. The
      frequency with which transfusion reactions occur in exotic pets is unknown. The
      most common transfusion reactions seen in small animals, along with suggested
      treatment, are discussed. The availability of blood products is limited in exotic
      pet medicine; therefore, the use of blood substitutes (Oxyglobin) has the
      advantage of long storage potential, no need for cross-matching, and no potential
      for disease transmission. General principles of blood substitutes and
      administration techniques will be discussed.

PMID- 15179930
TI  - The process of informed consent.

PMID- 15179931
TI  - Where in the world is the vision for nursing?

PMID- 15179932
TI  - Cleaners, disinfectants and sterilants.

PMID- 15179933
TI  - An American healthcare primer.

PMID- 15179935
TI  - The evolutionary origin of the mammalian isocortex: towards an integrated
      developmental and functional approach.
AB  - The isocortex is a distinctive feature of mammalian brains, which has no clear
      counterpart in the cerebral hemispheres of other amniotes. This paper speculates
      on the evolutionary processes giving rise to the isocortex. As a first step, we
      intend to identify what structure may be ancestral to the isocortex in the
      reptilian brain. Then, it is necessary to account for the transformations
      (developmental, connectional, and functional) of this ancestral structure, which
      resulted in the origin of the isocortex. One long-held perspective argues that
      part of the isocortex derives from the ventral pallium of reptiles, whereas
      another view proposes that the isocortex originated mostly from the dorsal
      pallium. We consider that, at this point, evidence tends to favor correspondence
      of the isocortex with the dorsal cortex of reptiles. In any case, the isocortex
      may have originated partly as a consequence of an overall "dorsalizing" effect
      (that is, an expansion of the territories expressing dorsal-specific genes)
      during pallial development. Furthermore, expansion of the dorsal pallium may have
      been driven by selective pressures favoring the development of associative
      networks between the dorsal cortex, the olfactory cortex, and the hippocampus,
      which participated in spatial or episodic memory in the early mammals. In this
      context, sensory projections that in reptiles end in the ventral pallium, are
      observed to terminate in the isocortex (dorsal pallium) of mammals, perhaps owing
      to their participation in these associative networks.

PMID- 15179936
TI  - The Newell Test for a theory of cognition.
AB  - Newell (1980; 1990) proposed that cognitive theories be developed in an effort to
      satisfy multiple criteria and to avoid theoretical myopia. He provided two
      overlapping lists of 13 criteria that the human cognitive architecture would have
      to satisfy in order to be functional. We have distilled these into 12 criteria:
      flexible behavior, real-time performance, adaptive behavior, vast knowledge base,
      dynamic behavior, knowledge integration, natural language, learning, development,
      evolution, and brain realization. There would be greater theoretical progress if
      we evaluated theories by a broad set of criteria such as these and attended to
      the weaknesses such evaluations revealed. To illustrate how theories can be
      evaluated we apply these criteria to both classical connectionism (McClelland &
      Rumelhart 1986; Rumelhart & McClelland 1986b) and the ACT-R theory (Anderson &
      Lebiere 1998). The strengths of classical connectionism on this test derive from
      its intense effort in addressing empirical phenomena in such domains as language
      and cognitive development. Its weaknesses derive from its failure to acknowledge
      a symbolic level to thought. In contrast, ACT-R includes both symbolic and sub
      symbolic components. The strengths of the ACT-R theory derive from its tight
      integration of the symbolic component with the sub-symbolic component. Its
      weaknesses largely derive from its failure, as yet, to adequately engage in
      intensive analyses of issues related to certain criteria on Newell's list.

PMID- 15179937
TI  - [Treatment for hypertension in patients with renal diseases].

PMID- 15179938
TI  - [Cerebrovascular disease: Impact of INDANA meta-analysis and PROGRESS trial].

PMID- 15179939
TI  - The role of the angiopoietins in tumour angiogenesis.
AB  - Angiogenesis--the growth of new blood vessels from existing ones--is a
      prerequisite for the growth of solid tumours beyond a diameter of approximately 2
      mm. In recent years, the angiopoietins have emerged as important regulators of
      angiogenesis. They mediate a delicate balance between vascular quiescence,
      regression and new growth, but their mechanism of action is not fully understood.
      This work attempts to provide a mathematical description of the role of the
      angiopoietins in angiogenesis. The model is formulated within the framework of
      reinforced random walks, which allows easy transition between the continuum
      (macroscopic) and discrete (microscopic) forms. Model predictions are in
      qualitative agreement with experimental observations, and may have implications
      for antiangiogenic cancer therapies.

PMID- 15179940
TI  - Clinical criteria for trigeminal neuralgia.

PMID- 15179941
TI  - In re Guardianship of Schiavo.

PMID- 15179942
TI  - CMS issues phase II Stark regulations. Rule applies to home health services
      interim final rule published in March 26, 2004 Federal Register.

PMID- 15179943
TI  - In the cradle of heredity; French physicians and l'heredite naturelle in the
      early 19th century.
AB  - This paper argues that our modern concept of biological heredity was first
      clearly introduced in a theoretical and practical setting by the generation of
      French physicians that were active between 1810 and 1830. It describes how from a
      traditional focus on hereditary transmission of disease, influential French
      medical men like Esquirol, Fodere, Piorry, Levy, moved towards considering
      heredity a central concept for the conception of the human bodily frame, and its
      set of physical and moral dispositions. The notion of heredity as a natural
      force, with a wide ranging capabilities of transmitting differentially both
      fundamental and accidental characters was generalized by that generation of
      physicians with the help of contemporary naturalists and physiologists. By 1830
      the term heredite was widespread, and it shared the explanatory and semantic
      qualities of traditional medical concepts like constitution and temperament. An
      analysis is given of the main developments that led to the conception of
      biological (including human) bodies as consisting of a layered, hierarchical
      organization of characters, differentially affected by the law of conservation
      (Heredity) and change (Inneity, Variation). The mid-century work of the French
      physician Prosper Lucas, Traite Philosophique et Physiologique de L' Heredite
      Naturelle, is shown to be the culmination of the efforts of several generations
      of French physicians towards having a feasible, complexly structured notion of
      how heredity works.

PMID- 15179944
TI  - A pulmonary snowstorm.

PMID- 15179945
TI  - In re Guardianship of Schiavo.

PMID- 15179946
TI  - In re Guardianship of Schiavo.

PMID- 15179947
TI  - Sublingual glyceryl trinitrate as prehospital treatment for hypertension in
      Irukandji syndrome.

PMID- 15179948
TI  - In re Guardianship of Schiavo.

PMID- 15179949
TI  - Survival gap widens in UK.

PMID- 15179950
TI  - A new era in informatics.

PMID- 15179952
TI  - Better one or two?

PMID- 15179951
TI  - The nurse of parasites: gender concepts in Patrick Manson's parasitological
      research.
AB  - Patrick Manson (1844-1922), the so-called father of tropical medicine, played a
      pivotal role in making that discipline into a specialty. During his early career
      in China he discovered that the mosquito was the intermediate host of the
      filarial parasite and he somewhat peculiarly called the mosquito the "nurse" of
      the filarial worm. The discovery contributed greatly to the intellectual
      foundation of modern parasitology. In this paper I situate Manson's nomenclature
      in the context of nineteenth-century biological research on reproductive mech
      anisms and argue that Manson's concept of the "nurse" was derived from nineteenth
      century theories of sexual division of labor in nature's economy. The way he
      framed the relation between the mosquito and the parasite, moreover, can be
      understood in the terms of the domestic arrangement of the colonial European
      household. Manson's research demonstrates the significant exchange between
      medical concerns over European women's procreative role in the tropics and
      biological studies of parasitic reproduction.

PMID- 15179953
TI  - Canadian drugs: panacea or problem?

PMID- 15179954
TI  - Situating gender and professional identity in American child study, 1880-1910.
AB  - The boundaries of psychological expertise in modern America were often imagined
      in gendered terms. Studies of child development served as one area where dominant
      notions of masculinity and femininity collided at a historical moment in which
      women were increasingly present inthe traditionally male worlds of science and
      higher education. Attributes that many female authors regarded as necessary
      qualifications for understanding child development (such as patience, sympathy,
      and maternal care) were routinely dismissed by male writers as contrary to an
      authentic scientific disposition. Thus, disputes over the meaning of child
      development (and the methods of studying it) indicate some of the ways that
      women's labor was both acknowledged and demoted during the formative years of
      American social science.

PMID- 15179955
TI  - Conquering chronic diseases: disease management programs help patients with
      chronic illnesses while saving money.

PMID- 15179956
TI  - Footnote: orchestrating the podocyte and the immune system in FSGS.

PMID- 15179957
TI  - The hiring of James Mark Baldwin and James Gibson Hume at the University of
      Toronto in 1889.
AB  - In 1889, George Paxton Young, the University of Toronto's philosophy professor,
      passed away suddenly while in the midst of a public debate over the merits of
      hiring Canadians in preference to American and British applicants for faculty
      positions. As a result, the process of replacing Young turned into a continuation
      of that argument, becoming quite vociferous and involving the popular press and
      the Ontario government This article examines the intellectual, political, and
      personal dynamics at work in the battle over Young's replacement and its eventual
      resolution. The outcome would have an impact on both the Canadian intellectual
      scene and the development of experimental psychology in North America.

PMID- 15179958
TI  - The role of nonautomatic processes in activity regulation: from Lipps to
      Galperin.
AB  - The authors present the historical analysis of one of the central questions in
      psychology: how and why the nonautomatic, psychological level of regulation (in
      contrast to automatic physiological processes) emerges both in evolution and in
      everyday context of activity. They discuss several approaches (by Lipps, Groos,
      Stern, James, Dewey, Claparede, Pavlov, and Leontiev) that culminated in the
      system of ideas developed by Galperin, one of the key figures in the cultural 
      historical activity theory. The authors analyze the relation of Galperin's ideas
      to Vygotsky's theoretical framework and then focus on Galperin's account of the
      origin and functions of mental activity. Galperin's contribution is highly
      relevant for understanding the role of psychological regulation and for
      contemporary research on cognition, consciousness, and conscious awareness.

PMID- 15179959
TI  - Change, consolidation, and competition in health care markets.
AB  - The health care industry is being transformed. Large firms are merging and
      acquiring other firms. Alliances and contractual relations between players in
      this market are shifting rapidly. Within the next few years, many markets are
      predicted to be dominated by a few large firms. Antitrust enforcement authorities
      like the Department of Justice and the Federal Trade Commission, as well as
      courts and legislators at both the federal and state levels, are struggling with
      the implications of these changes for the nature and consequences of competition
      in health care markets. In this paper we summarize the nature of the changes in
      the structure of the health care industry. We focus on the markets for health
      insurance, hospital services, and physician services. We then discuss the
      potential implications of the restructuring of the health care industry for
      competition, efficiency, and public policy. As will become apparent, this area
      offers a number of intriguing questions for inquisitive researchers.

PMID- 15179960
TI  - Watson's behaviorism: a comparison of the two editions (1925 and 1930).
AB  - J.B. Watson's Behaviorism, a complete presentation of the mature psychological
      points of view of its author, had 2 editions, in 1925 and 1930, which presented
      significant differences in their texts. Although Watson maximized such
      variations, to the point of considering the 2nd edition as nearly a brand-new
      book, both suppressions and additions reveal his feelings when presenting his
      ideas to a general audience. Such variations are here presented through an in
      depth analysis.

PMID- 15179961
TI  - Localized nodular hypertrophy mimicking rhabdomyoma in the fetal heart: prenatal
      sonographic and pathology findings.
AB  - Multiple intracardiac masses (ICM) are considered to be diagnostic of rhabdomyoma
      often associated with tuberous sclerosis. We describe a fetus with multiple ICM
      detected by fetal sonography at 18.7 wk gestation. The appearance and number were
      consistent with leading diagnosis of rhabdomyoma. Due to complications of
      pregnancy and extreme prematurity, the fetus did not survive. Autopsy showed the
      cardiac masses to be localized nodular hypertrophy (LNH) of the myocardium. No
      features of rhabdomyoma or tuberous sclerosis were present. In a review of the
      literature, similar lesions were reported in a child and two adults, perhaps as
      localized variants of hypertrophic cardiomyopathy. Our case does not, however,
      show the histopathologic features of hypertrophic cardiomyopathy. Isolated
      developmental abnormalities, such as in this case, can have a mass effect
      mimicking cardiac tumors. At the time of autopsy, the largest mass in the
      anterior wall of the right ventricle extended to and obstructed the right
      ventricular outflow tract.

PMID- 15179962
TI  - Healthy bodies and thick wallets: the dual relation between health and economic
      status.
AB  - The first section of this paper documents the size of the association between
      health and one prominent economic status measure--household wealth. The next
      section deals with how health influences economic status by sketching out reasons
      why health may alter household savings (and eventually wealth) and then providing
      estimates of the empirical magnitude of these effects. The third section shifts
      attention to the other pathway--the links between economic status and health--and
      summarizes major controversies and evidence surrounding these issues.

PMID- 15179963
TI  - Heterotopic pancreatic tissue presenting as a solid and cystic lung lesion: a
      very unusual bronchopulmonary foregut malformation.
AB  - We describe the history and lung pathology of a premature female infant, who
      presented with respiratory distress immediately after birth. A thoracic
      computerized tomography scan showed abnormalities suggestive of congenital cystic
      adenomatoid malformation of the left lung. In addition, echocardiography revealed
      a tetralogy of Fallot. A left thoracotomy was performed and the lower lobe of the
      left lung was removed. Despite intensive supportive therapy, pulmonary
      hypoperfusion resulted in severe hypoxemia and death. Gross and microscopic
      analysis of the resected lobe revealed a partly cystic and solid lesion with
      multiple bronchus-derived cysts and an exuberant multifocal proliferation of
      glandular tissue, resembling bronchial glands, mixed with heterotopic cartilage
      surrounding ducts. Immunohistochemical analysis showed the presence of
      chromogranin A-reactive islet-like structures amidst exocrine tissue showing
      trypsin and chymotrypsin immunoreactivity, establishing the diagnosis of
      pulmonary pancreatic heterotopy. In the remaining pulmonary parenchyma, there
      were secondary changes consistent with partial obstruction and lymphangiectasis
      which was attributed to the presence of the cardiac malformation. To our
      knowledge, this is only the fourth reported case of heterotopic pancreatic tissue
      in the lung, and the first case where this bronchopulmonary foregut anomaly is
      not associated with a enteric duplication.

PMID- 15179964
TI  - Health and schooling investments in Africa.
AB  - This paper first outlines an organizing framework for considering how health and
      schooling affect labor productivity and growth, and how household and community
      factors can in turn affect the demand for these human capital investments. Both
      cross-country growth models and various aspects of microeconomic studies of
      individual productivity as related to education and health are discussed. The
      conclusion offers some tentative leads for policy in this area based on existing
      research, and an agenda for future research.

PMID- 15179965
TI  - Medicare reform: fundamental problems, incremental steps.
AB  - This paper presents an overview of the Medicare reform debate. I begin by
      reviewing some of the features of Medicare and then turn to a discussion of
      reforms, both on the benefits side and on the financing side of the program. The
      reform proposals raise difficult policy and political issues, and could have
      important implications for the federal budget, the efficiency of the health
      sector, and the well-being of the elderly and disabled.

PMID- 15179966
TI  - Amitriptyline for inpatients and SSRIs for outpatients with depression?
      Systematic review and meta-regression analysis.
AB  - BACKGROUND: Although the selective serotonin reuptake inhibitors (SSRIs) are
      widely used as first-line agents in depression, amitriptyline, a reference
      tricyclic (TCA) agent, has the edge in terms of efficacy over control
      antidepressants (ADs), but it is not clear whether this advantage can be
      attributed to a more favourable profile in inpatients, but not in outpatients,
      with depression. The aim of this study was to investigate the contribution of
      study setting on outcome in clinical trials comparing amitriptyline with any
      other AD. METHODS: A systematic review and meta-regression analysis of
      amitryptiline randomised clinical trials was carried out. The electronic search
      yielded 181 randomised clinical trials, 47% enrolling inpatients and 53%
      outpatients with depression. RESULTS: Both on a dichotomous and continuous out
      come, amitriptyline was more effective than control agents in in-patients [Peto
      odds ratio (OR): 1.22, 95%, Confidence Interval (CI): 1.04, 1.42; Standardised
      Mean Difference (SMD): 0.28, 95 %,Cl: 0.08, 0.46], but not in outpatients (Peto
      OR: 1.01, 95%, CI: 0.88,1.17; SMD: 0.10,95% CI: -0.02,0.23). Among inpatients
      amitriptyline was significantly more effective than TCA and nonsignificantly more
      effective than the SSRIs. Among outpatients no statistically significant
      differences emerged between amitriptyline and TCA and between amitriptyline and
      the SSRIs. Amitriptylinewas less well tolerated than control agents in
      outpatients (Peto OR: 0.90, 95%, CI: 0.81, 0.99), but not in inpatients (Peto
      OR:1.09, 95% CI: 0.95, 1.25). CONCLUSIONS: These data suggest that a reasonable
      approach could be the first-line prescription of newer agents in the routine
      outpatient care of depressive subjects, and the use of amitriptyline in
      inpatients with severe depression.

PMID- 15179968
TI  - Walking the tightrope on Medicare reform.

PMID- 15179967
TI  - Hypothalamic-pituitary-adrenal system regulation in recently detoxified
      alcoholics is not altered by one week of treatment with acamprosate.
AB  - BACKGROUND: Acamprosate decreases relapse rates in alcohol-dependent patients by
      approximately 10-20% within the first year after detoxification. Psychological
      stress is a major risk fac-tor for relapse and is associated with activation of
      the hypothalamic-pituitary-adrenocortical (HPA) system. In recently detoxified
      alcoholics, the HPA system is dysregulated with non-suppression of cortisol after
      dexamethasone administration. We therefore investigated whether acamprosate
      normalizes HPA hyperactivity in alcoholics within the first 3 weeks of
      abstinence, employing a combined dexamethasone/corticotropin-releasing hormone
      (Dex-CRH)-test. METHODS: Thirty alcohol-dependent patients were tested one week
      after withdrawal signs had disappeared. In 15 patients, acamprosate, 1332-1998
      mg/day, was administered orally and a second Dex-CRH test was performed 1 week
      later. In the other 15 patients, acamprosate treatment was offered only after the
      second test. RESULTS: CRH-stimulated cortisol secretion was significantly
      increased in both the acamprosate group and the group receiving no anti-relapse
      medication compared to a control group of 15 healthy subjects. Acamprosate
      treatment had no effect on basal or CRH-stimulated ACTH or cortisol secretion.
      CONCLUSIONS: We conclude that 1 week of acamprosate treatment does not attenuate
      the HPA dysregulation ob-served during early abstinence.

PMID- 15179969
TI  - Spontaneous remission of SSRI-induced orgasm delay.
AB  - BACKGROUND: Orgasm delay is a common side effect of SSRIs,causing negative
      influence on patients' compliance and quality of life. A possible strategy for
      the management of SSRI-induced orgasm delay is waiting for tolerance to develop.
      The authors studied the natural course of SSRI-induced orgasm delay over a period
      of 6 months. METHODS: One hundred eight patients having been started on SSRIs
      were included in an open, naturalistic study. Sexual dysfunction was assessed at
      monthly intervals using a structured interview. RESULTS: Twenty-six patients
      developed clinically relevant SSRI-induced orgasm delay. Eight patients (30.8%)
      reported complete remission of sexual dysfunction, while four patients (15.4%)
      noted a marked improvement. Four patients (15.4%) continued to describe severe
      orgasm delay at the end of the observation period. High severity of orgasm delay
      significantly correlated with lack of remission. CONCLUSIONS: A significant
      proportion of patients, especially those with mild to moderate orgasm delay,
      develop tolerance within 6 months.

PMID- 15179970
TI  - Medicare reform: the larger picture.

PMID- 15179971
TI  - Health care for the aging baby boom: lessons from abroad.

PMID- 15179973
TI  - Making the transition to prepaid Medicare.

PMID- 15179972
TI  - Olanzapine- and clozapine-induced stuttering. A case series.
AB  - Drug-induced stuttering has been described in association with several drugs, in
      particular antidepressants and low-potency neuroleptics. Here we describe a case
      series of stuttering induced by the atypical neuroleptics olanzapine and
      clozapine. Patients receiving neuroleptic treatment were carefully screened for
      stuttering as a possible side effect. We have studied all patients in the
      outpatient department (800 per year) as well as most inpatients (1300 per year)
      within 3 years. Seven cases of drug-induced stuttering were observed. Six
      patients suffered from stuttering in association with olanzapine treatment, and
      one received clozapine. Stuttering arose on average 2-21 days after initiation of
      treatment and ceased 2-5 days after discontinuation. Most patients suffered from
      additional diseases, such as brain pathology due to cortical atrophy or celiac
      disease, or received concomitant medication (i.e. intrathecal morphine pump). Our
      case series suggests that the atypical neuroleptic olanzapine can induce
      stuttering in the absence of a history of stuttering without accompanying
      akathisia or general decline of function. It appears that preexisting brain
      pathology or concomitant anti-depressant medication might predispose some
      patients to this side effect.

PMID- 15179974
TI  - Data watch: research data in health economics.

PMID- 15179975
TI  - Policy watch: U.S. disability policy in a changing environment.

PMID- 15179977
TI  - Policy watch: the Federal Employees Health Benefits Plan.

PMID- 15179978
TI  - Pharmaceuticals in U.S. health care: determinants of quantity and price.

PMID- 15179979
TI  - Pharmaceuticals and the developing world.

PMID- 15179976
TI  - [Neural control of the respiratory nasal mucosa].
AB  - Respiratory nasal mucosa fulfils the function of pretreating the inspired air.
      The periodic nasal cycle and pathologic functional disturbances of the endonasal
      tissue influence the nasal passages. The secretion of the seromucous glands and
      extravasation from the blood vessels are essential for mucocilliary transport.
      These physiological mechanisms are partially controlled by neural regulation.
      Besides classic neurotransmitter neuropeptides such as VIP, CGRP, SP and NPY,
      nitric oxide also shares this role. A network of sensory, sympathetic and
      parasympathetic nerve fibres protects the respiratory mucous membranes from
      external and internal irritation. In addition, blood vessels and glands are
      influenced by endothelial and humoral factors. For the different types of
      rhinitis, sensory neuropeptides and inflammatory mediators take part in the
      pathomechanisms and can lead to a so called neurogenic inflammation of the nasal
      mucosa.

PMID- 15179980
TI  - Health care costs: on the rise again.

PMID- 15179981
TI  - [Established medical specialists on the way "out"?].

PMID- 15179982
TI  - [Legal aspects of advanced medical education].

PMID- 15179983
TI  - JLO Travelling Fellowship 1st report 2003. Vancouver Head and Neck Surgery
      Fellowship 1st March-31st August 2003.

PMID- 15179984
TI  - [Immunotherapy for advanced renal cell carcinoma].
AB  - Significant advances have been achieved in the surgical treatment of localized
      renal cell carcinoma over recent years. However, despite significant research
      efforts, the prognosis is still dismal in the majority of patients with advanced
      disease. Treatment with IFN-ac leads to moderately increased survival. In
      addition, survival can be prolonged by tu-mor nephrectomy in patients with
      synchronous metastases. Combined treatment with IFN-a, IL-2 and 5-FU has
      demonstrated a survival benefit in a single randomized controlled trial. High
      dose IL-2 causes long-term regression in a small fraction of patients. All of
      these treatments, however, frequently cause significant morbidity and therefore
      the potential benefit has to be weighed carefully against toxicity in each
      individual patient. Although, in general, the results of immunotherapeutic
      approaches have been dis-appointing, studies using allogeneic stem cells,
      allogeneic mononuclear cells and vaccines clearly demonstrate, that tumor control
      can be achieved by means of immunological intervention. Future research will
      hopefully lead to the development of strategies helpful for a greater proportion
      of patients with this disease.

PMID- 15179985
TI  - [Arthroscopy of the hip].
AB  - Arthroscopy of the hip has become a well-established procedure for minimally
      invasive therapy of hip disorders. The surgical technique is demanding. A
      fracture table for distraction of the joint is required, as well as an exact
      positioning technique is most important. Because of eh great distance between
      skin and joint only restrictive intrarticular maneuvers are possible.
      Arthroscopically the hip can be divided into a central and peripheral
      compartment. For arthroscopy of the central compartment distraction of the joint
      is necessary. This part comprises the loaded surface of the femoral head and the
      lunate cartilage. The peripheral compartment consists of the unloaded cartilage
      of the femoral head and the femoral neck until the capsular insertion. This
      compartment can be visualized without traction. Good results can be achieved in
      the therapy of labral lesions, loose bodies, moderate osteoarthritis, synovial
      diseases and pathology of the teres ligament. Performing hip arthroscopy in an
      adequate technique and under consideration of contraindications, complications
      are rare.

PMID- 15179986
TI  - Practice what we preach.

PMID- 15179987
TI  - Mentorship in physical therapy practice.

PMID- 15179996
TI  - Making the most of your infection control professional.

PMID- 15179997
TI  - Putting cardiac surgery patients on the "fast track".

PMID- 15179998
TI  - Neurologic assessment for pronator drift.

PMID- 15179999
TI  - Delivering multiple medications via backpriming.

PMID- 15180000
TI  - Cardiac stress tests: which one, why, and when?

PMID- 15180001
TI  - Managing diabetes with "Agent Oral".

PMID- 15180002
TI  - Unlock the mysteries of insulin therapy.

PMID- 15180003
TI  - Mr. Sam's visitor.

PMID- 15180004
TI  - RN education: a matter of degrees.
AB  - Until recently, no research had been done to explore the effect of nurse
      education on patient care. In a study published in JAMA in September 2003,
      nursing researcher Linda H. Aiken, RN, PhD, led a study to determine the
      association between the educational levels of hospital RNs and the mortality of
      surgical patients. The study examined 168 adult acute care hospitals in
      Pennsylvania reporting a total of 232,342 surgical discharges to the Pennsylvania
      Health Care Cost Containment Council in 1999. The researchers also surveyed a
      random sample of 50% of hospital nurses who live in Pennsylvania and were
      registered with the Pennsylvania Board of Nursing. In all, 10,184 nurses (52% of
      nurses surveyed) responded. According to the survey results, the average age of
      respondents was between 40 and 41 years, and between 30% and 31% of respondents
      had earned a BSN or a higher degree. Hospital nurses who participated in the
      study had 14.2 years' nursing experience with a mean patient load of 5.7 per day.
      The researchers examined how the education of hospital nurses affected the death
      rates of surgical patients within 30 days of admission and death rates within 30
      days of admission among patients who experienced complications. The study also
      took into consideration whether a board-certified surgeon performed the surgery.
      The types of surgeries examined included general surgery, orthopedic, and
      vascular procedures. The study found that years of nursing experience don't
      predict a patient's outcome and that patients cared for in hospitals with a
      higher proportion of nurses holding a BSN degree or higher have a better chance
      of postsurgical survival. Specifically, the study stated that "a 10% increase in
      the proportion of nurses holding a bachelor's degree [in hospitals] was
      associated with a 5% decrease in both the likelihood of patients dying within 30
      days of admission and the odds of failure to rescue." Failure to rescue was
      defined as "deaths in patients with serious complications." The researchers
      recognized two limitations to their study: the low (52%) response rate of the
      nurses surveyed, the examination of hospitals from only one state. The
      researchers concluded that although these preliminary findings raise concern over
      nurse education as it relates to patient outcomes, further study of nurses and
      hospitals nationwide would be required to make these results irrefutable.

PMID- 15180005
TI  - Choosing the right fluid to counter hypovolemic shock.

PMID- 15180006
TI  - JCAHO says: watch your p's and q's.

PMID- 15180007
TI  - Chronic obstructive pulmonary disease (COPD).

PMID- 15180008
TI  - Taking the weight off with bariatric surgery.

PMID- 15180009
TI  - OSHA cracks down on sharps-safety violators.

PMID- 15180011
TI  - Myths and facts...about polycystic kidney disease.

PMID- 15180010
TI  - How transthoracic echocardiography detects cardiac tamponade.

PMID- 15180012
TI  - Anaphylaxis.

PMID- 15180013
TI  - J. Marion Sims: a defense of the father of gynecology.

PMID- 15180014
TI  - Personal digital assistant use in Florida obstetrics and gynecology residency
      programs.
AB  - OBJECTIVES: Improvements in electronic technologies have resulted in affordable,
      smaller computers that operate at faster speeds. The personal digital assistant
      (PDA) is a tool that has the potential to enhance residency education by allowing
      residents immediate access to an abundance of information. This article assesses
      the current use of this tool at obstetrics and gynecology residency programs in
      the state of Florida. METHODS: The authors conducted a statewide survey
      addressing the general question: is the PDA useful in an obstetrics and
      gynecology residency training program? Specifically, the authors asked residents
      how much time was perceived to be saved weekly with the use of this tool, and in
      what aspect of their training use of this tool was most helpful. RESULTS: At the
      survey's close, five of seven programs had returned the survey for evaluation.
      These five institutions included both university- and community-based residency
      programs. Forty percent of obstetrics and gynecology residents at these programs
      responded to this questionnaire. Resident responses to the survey revealed that
      most of the perceived benefit was in maintaining procedural statistics logs,
      pharmacology reference manuals, and personal clinical protocols. Most responses
      revealed that only minimal time savings (<2 h/wk) were gained with using this
      tool. However, many residents felt they were not using this tool to its maximum
      potential. Nearly 90% of those who responded felt that the PDA should be
      available at residency programs and anticipated using it after completing
      residency. CONCLUSIONS: This study posed the question of PDA usefulness at
      obstetric and gynecology residency programs in the state of Florida. Although not
      all programs provided their residents with a PDA, 95% of the respondents revealed
      that they owned one of these tools. Experience at the authors' institution
      revealed high expectations for the potential uses of a PDA. Although many
      residents were not using this tool to its full potential, a PDA tutorial session
      could educate residents on the many applications available for PDAs, including
      applications to maintain on-call schedules and sign-out lists, statistics and
      procedure logs for credentialing and board certification, electronic billing, and
      electronic prescriptions.

PMID- 15180015
TI  - Comparison of pediatric airway foreign bodies over fifty years.
AB  - Prevention and early recognition remain critical factors in the treatment of
      foreign body inhalation in children. Accidental inhalation of both organic and
      nonorganic foreign body material continues to be a cause of childhood morbidity
      and mortality. The University of North Carolina Department of Otolaryngology has
      collected foreign bodies acquired from the airways of young children since its
      inception in 1954. The authors reviewed 26 foreign bodies removed
      bronchoscopically from the airways of children during the years 1955 to 1960, and
      compared these to 27 foreign bodies collected from 1999 to 2003. Findings showed
      remarkable similarities in the types of foreign bodies aspirated. Organic foreign
      bodies were most commonly found. Differences existed in the type of organic
      foreign body aspirated, with popcorn being retrieved in 15% of cases during the
      later time period. Also, an increase in bronchoscopically removed small toy parts
      was found in the later group.

PMID- 15180016
TI  - Florida health care providers' knowledge of folic acid for the prevention of
      neural tube defects.
AB  - OBJECTIVES: The purpose of this study was to determine the impact of an
      educational program on the knowledge and practice behavior of health care
      providers regarding folic acid use for the prevention of neural tube defects.
      METHODS: A survey was mailed to selected Florida health care providers to
      determine baseline knowledge and practice behavior. After a statewide educational
      program, another mail survey was sent to the same groups of providers to
      determine the effect of the campaign. RESULTS: Comparison between the two surveys
      showed a significant increase in knowledge and in the percentage of health care
      providers who recommended the periconceptional use of folic acid for the
      prevention of neural tube defects. Providers graduating in 1992 or later were
      more likely than those graduating before 1992 to have the appropriate knowledge
      about folic acid use but were less likely to recommend it to their patients.
      CONCLUSIONS: Significant gains were made in increasing knowledge and changing
      practice behavior among selected Florida health care providers. Regardless of the
      magnitude of these gains, our data show that some health care providers who have
      regular contact with women of childbearing age still do not know the recommended
      doses of folic acid or do not recommend its use. This points toward the need for
      continued education as well as efforts to modify provider behavior.

PMID- 15180017
TI  - Is eclampsia preventable? A case control review of consecutive cases from an
      urban underserved region.
AB  - OBJECTIVES: The purpose of this study was to determine whether eclampsia is
      potentially preventable. METHODS: This was a retrospective case control study
      comparing 25 cases of eclampsia, 33 cases of preeclampsia and 50 pregnant
      controls. Eclampsia cases were classified as follows: group A was potentially
      preventable by patient education if there were preeclamptic symptoms before
      presenting to the hospital; group B was potentially preventable by health care
      provider if patient presented to health care with evidence of preeclampsia and
      was not appropriately treated; group C was not preventable if eclampsia developed
      without symptoms or preeclampsia. Statistical analysis was done as applicable.
      RESULTS: The mean gestational age at seizure was 34 weeks; 50% of seizures
      occurred outside a hospital and 44% had multiple seizures. Twenty were
      antepartum, three intrapartum, and two postpartum. Fourteen (56%) cases were
      classified as group A, 4 (16%) as group B and 7 (28%) as group C. Compared to
      controls, African-Americans, nulliparity, premature delivery, and increased
      neonatal morbidity were significantly associated with eclampsia. Compared with
      preeclamptics, eclamptic subjects had more symptomatology and more adverse
      maternal complications. CONCLUSIONS: In this underserved population, a
      significant percentage of eclampsia cases are potentially preventable by patient
      education or health care response. In a smaller percentage, eclampsia may develop
      without any symptomatology or preeclampsia.

PMID- 15180018
TI  - Correlates of breastfeeding initiation in southeast Arkansas.
AB  - OBJECTIVES: Southeast Arkansas is a primarily rural, low-income area with low
      breastfeeding rates. Given the demonstrated positive impacts of breastfeeding on
      a variety of health indicators, it is important to understand and counteract this
      situation. METHODS: We reviewed the medical records of 1,260 women who delivered
      infants at the only major hospital in southeastern Arkansas between February 1997
      and January 1998 to determine the rate of breastfeeding initiation and to assess
      associated factors. RESULTS: Only 18% of mothers initiated breastfeeding. Black
      mothers, unmarried mothers, and those with less than high school education were
      least likely to breastfeed. Participation in childbirth education classes was
      positively associated with breastfeeding, but participation in the Supplemental
      Food Program for Women, Infants, and Children, health care provider, and hospital
      variables were not predictive in multivariate models. CONCLUSIONS: Breastfeeding
      promotion programs are clearly needed in this region, and health care providers
      and the Supplemental Food Program for Women, Infants, and Children can play
      significant roles.

PMID- 15180019
TI  - Sedation during mechanical ventilation in infants and children: dexmedetomidine
      versus midazolam.
AB  - BACKGROUND: We sought to compare the efficacy of midazolam versus dexmedetomidine
      for sedation during mechanical ventilation in infants and children. METHODS: We
      performed a prospective, randomized trial in a pediatric intensive care unit in a
      tertiary care center. Infants and children requiring mechanical ventilation
      underwent a continuous infusion of either midazolam (starting dose of 0.1
      mg/kg/h) or dexmedetomidine (starting dose of either 0.25 or 0.5 microg/kg/h)
      with intermittent morphine, as needed. The efficacy of sedation was assessed
      using the Ramsay sedation scale, pediatric intensive care unit sedation score,
      and the tracheal suctioning score as well as bispectral monitoring. RESULTS:
      There were 10 patients in each group. Sedation as assessed by the clinical
      sedation scores and the bispectral index was equivalent in the 3 groups. There
      were 36 morphine boluses administered to the midazolam group versus 29 and 20
      morphine boluses administered respectively to the 0.25 and 0.5 microg/kg/h
      dexmedetomidine groups (P = 0.02 for midazolam versus 0.5 microg/kg/h
      dexmedetomidine). Total morphine use (mg/kg/24 h) was 0.74 +/- 0.5, 0.55 +/-
      0.38, and 0.28 +/- 0.12 in the midazolam and the two dexmedetomidine groups
      respectively (P = not significant for midazolam versus 0.25 dexmedetomidine, P =
      0.01 for midazolam versus 0.5 dexmedetomidine). In the two dexmedetomidine
      groups, 5 of 6 patients who at some point had a Ramsay score of 1 were less than
      12 months of age while only 1 was more than 12 months of age (P < 0.05).
      CONCLUSIONS: At a dose of 0.25 microg/kg/h, dexmedetomidine was approximately
      equivalent to midazolam at 0.22 mg/kg/h. At 0.5 microg/kg/h, dexmedetomidine
      provided more effective sedation as demonstrated by the need for fewer bolus
      doses of morphine, a decrease in the 24-hour requirements for supplemental
      morphine, as well as a decrease in the total number of assessment points with a
      Ramsay score of 1 (inadequate sedation) and the number of patients who had a
      Ramsay score of 1.

PMID- 15180020
TI  - Dynamic weight-bearing cervical magnetic resonance imaging: technical review and
      preliminary results.
AB  - BACKGROUND: Conventional magnetic resonance imaging (MRI) of complex cervical
      spine disorders may underestimate the magnitude of structural disease because
      imaging is performed in a nondynamic non-weight-bearing manner. Myelography
      provides additional information but requires an invasive procedure. METHODS: This
      was a prospective review of the first 20 upright weight-bearing cervical MRI
      procedures with patients in the flexed, neutral, and extended positions conducted
      in an open-configuration MRI unit. RESULTS: This technique clearly illustrated
      the changes in spinal cord compression, angulation, and spinal column alignment
      that occur during physiologic movements with corresponding changes in midsagittal
      spinal canal diameter (P < 0.05). Image quality was excellent or good in 90% of
      the cases. CONCLUSIONS: Dynamic weight-bearing MRI provides an innovative method
      for imaging complex cervical spine disorders. This technique is noninvasive and
      has adequate image quality that may make it a good alternative to cervical
      myelography.

PMID- 15180021
TI  - Ureteral injury due to penetrating trauma.
AB  - OBJECTIVES: We sought to evaluate the diagnosis and management of penetrating
      ureteral injuries at our trauma center. METHODS: We retrospectively reviewed the
      cases of 12 patients with ureteral injuries secondary to penetrating ureteral
      trauma. RESULTS: From January 1995 to December 2000, a total of 12 patients were
      diagnosed and treated for penetrating ureteral injuries. The diagnosis was made
      acutely in nine patients, and a delayed diagnosis was made in three patients.
      Hematuria was present in the nine patients diagnosed acutely, and these patients
      had either preoperative or intraoperative imaging. All patients underwent
      exploratory laparotomy, and ureteral injuries were missed in the three patients
      without radiologic imaging or hematuria. Repair of the ureteral injuries was
      highly successful, and patients diagnosed acutely had decreased morbidity.
      CONCLUSIONS: Traumatic ureteral injuries from penetrating trauma are uncommon,
      and a high index of suspicion is necessary to diagnose ureteral injuries when
      hematuria is not present and imaging is nondiagnostic.

PMID- 15180022
TI  - Declining susceptibility to neomycin and polymyxin B of pathogens recovered in
      otitis externa clinical trials.
AB  - BACKGROUND: Otitis externa is usually treated empirically with topical
      neomycin/polymyxin B/hydrocortisone. The predominant pathogens associated with
      this infection are Pseudomonas aeruginosa and Staphylococcus aureus. METHODS: Two
      multicenter clinical trials (one in adults and adolescents, and one in children),
      conducted between 1995 and 1996, compared neomycin/polymyxin B/hydrocortisone
      with ofloxacin for the treatment of otitis externa; two similar trials were
      conducted between 1999 and 2000. Assessments included the minimum inhibitory
      concentrations (MICs) of each antimicrobial drug for the major pathogens,
      bacterial eradication, and clinical efficacy. RESULTS: The MICs of all bacterial
      isolates (including P. aeruginosa) for neomycin and polymyxin B increased
      markedly in the 1999 to 2000 studies compared with the 1995 to 1996 studies. In
      the later studies, mean MICs for all major pathogens tested had increased above
      the breakpoint for polymyxin B (> or = 4 microg/ml). In contrast, MICs of all
      isolates for ofloxacin remained similar between the two study periods and were
      within the susceptible range for this drug. CONCLUSIONS: Although the bacterial
      eradication rates for both treatments in each study were equivalent, the clinical
      cure rate for neomycin/polymyxin B/hydrocortisone was lower (87%) than for
      ofloxacin (93%). Therefore, the organisms most often causing otitis externa
      appear to be developing resistance to neomycin and polymyxin B but not to
      ofloxacin.

PMID- 15180023
TI  - Older sarcoidosis patients: experience of a medical center in Turkey.
AB  - OBJECTIVES: Although sarcoidosis is classically defined to be a disease of young
      adults, it might also be seen at older ages. There are very few clinical studies
      which focus on the features of patients diagnosed at older ages. In this study,
      we tried to determine the frequency of patients diagnosed at or above 50 years of
      age and to compare the clinical and demographic features of these subjects with
      other sarcoidosis patients. METHODS: We evaluated the general clinical features
      of sarcoidosis patients more than 50 years of age who were diagnosed at our
      center within a 36-year period. We also compared the clinical features of older
      sarcoidosis patients with the features of other patients. RESULTS: Of 579
      sarcoidosis patients being followed up at our center, 102 (17.7%) were older than
      50 years of age at the time of initial diagnosis. The female to male ratio in
      this group was higher than the ratio in other sarcoidosis patients (3.43 versus
      1.85, P = 0.015). When the features of older patients were compared with other
      sarcoidosis patients, extrapulmonary involvement was observed to be more common
      in this group (P < 0.001). By contrast, arthritis or arthralgia (P < 0.001),
      clinical presentation in the form of Lofgren syndrome (P < 0.001), erythema
      nodosum (P < 0.001), and uveitis (P = 0.006) were less frequent. CONCLUSIONS:
      Although generally presenting as a disease of the young, in many subjects
      sarcoidosis is diagnosed at older ages, and this study indicates that the
      clinical features of sarcoidosis in older subjects differ from those found among
      younger patients.

PMID- 15180024
TI  - Income, income inequality, and cardiovascular disease mortality: relations among
      county populations of the United States, 1985 to 1994.
AB  - OBJECTIVES: Despite the major contribution of cardiovascular disease (CVD) to
      total mortality, and reports demonstrating strong relations between income and
      CVD, the joint relations of population-level income and income inequality with
      CVD mortality are not well described. This study was undertaken to describe
      relations among population-level income, income equality, and mortality due to
      cardiovascular disease, coronary heart disease, and stroke. METHODS: County
      income distributions were determined from 1990 census data, and CVD mortality
      rates were obtained from the Compressed Mortality File. Relations among income,
      income inequality, and CVD mortality were examined in stratified and Poisson
      regression analyses. RESULTS: County income was inversely related and income
      inequality was directly related to CVD, coronary heart disease, and stroke
      mortality. Relations were strongest for stroke. Relations of stroke mortality
      with income inequality were strongest in low-income populations. CONCLUSIONS: The
      CVD mortality experiences of county populations are related to both income and
      income distribution in a complex, disease-dependent manner. The authors' findings
      are especially relevant to the Southeast, a region of high income inequality, low
      income, and high stroke mortality.

PMID- 15180025
TI  - Nonsurgical treatment to regain hip abduction motion in Perthes disease: a
      retrospective review.
AB  - The purpose of this study was to document the ability of a nonsurgical program to
      improve restricted passive hip abduction in children with Perthes disease.
      Containment as a form of treatment was recommended if passive hip abduction of 30
      degrees or more could be achieved. Medical records and radiographs were
      retrospectively reviewed for 74 children. Age at admission and onset, side,
      length of stay, and measurement of passive hip abduction at admission/discharge
      were recorded. The average increase in abduction with the hip extended was 13
      degrees. Forty-two children achieved 30 degrees or more of abduction with the hip
      extended. Average length of stay was 13 days. Management of restricted abduction
      in an inpatient setting can allow consideration of containment in 61% of children
      previously not thought to have the required motion.

PMID- 15180026
TI  - Profound hypothyroidism--a clinical review with eight recent cases: is it right
      before our eyes?

PMID- 15180027
TI  - J. Marion Sims, the father of gynecology: hero or villain?
AB  - J. Marion Sims (1813-1884) has been called the "Father of Gynecology" for his
      revolutionary approach to treating the diseases of women. He rose from humble
      origins to become a successful surgeon, teacher, and writer. His innovations
      included the first successful treatment for vesicovaginal fistula, the first
      gallbladder surgery, and the introduction of antiseptic principles in all areas
      of surgical treatment. The "Sims position" and "Sims speculum" are eponymic
      tributes to his accomplishments. In recent years Sims has, however, become a
      focus of controversy because of his experimental surgeries on slave women. His
      powerful personality and messianic attitude led him to minimize moral problems,
      and to bristle against opposition. Ethical principles of autonomy and beneficence
      are important criteria for evaluating Sims' research. An exploration of the
      nature of Sims' work and the atmosphere in which he practiced will illuminate the
      critical ethical questions surrounding Sims' use of slave women as experimental
      subjects.

PMID- 15180029
TI  - Tuberous sclerosis complex in a young woman diagnosed incidentally on the basis
      of pregnancy ultrasonography.
AB  - Tuberous sclerosis complex (TSC) is more prevalent than previously believed and
      most cases result from new mutations and, hence, do not have affected relatives.
      Many patients who meet the new diagnostic criteria have unrecognized skin lesions
      and/or occult lesions in internal organs. As early diagnosis and appropriate
      intervention can reduce morbidity and mortality from the neurologic. renal, and
      pulmonary complications of TSC, physicians should be alert for the dermatological
      signs of the condition and for the incidental finding of TSC lesions during
      diagnostic testing. Patients with TSC may be asymptomatic and of normal
      intelligence. We report a case of TSC diagnosed by the incidental finding of
      renal lesions in a young woman during pregnancy ultrasonic examination.

PMID- 15180028
TI  - Osteoprotegerin-receptor activator of nuclear factor-kappaB ligand ratio: a new
      approach to osteoporosis treatment?
AB  - Osteoporosis, the most commonly occurring bone disease, is characterized by
      enhanced bone fragility and increased risk of fracture. Bone remodeling is the
      process in which bone is broken down by osteoclasts and then built back again by
      osteoblasts. In healthy adult bone, these two processes are balanced and a
      constant level of bone mass is maintained. Some of the proteins involved in the
      interaction between osteoblasts and osteoclasts have recently been identified.
      Receptor activator of nuclear factor-kappaB (RANK) ligand is produced by
      osteoblasts and exerts its effects through binding to its receptor (RANK) on
      osteoclast precursor cells. Binding results in activation of osteoclasts.
      Osteoblasts also produce osteoprotegerin (OPG), a potent inhibitor of osteoclast
      formation and a decoy receptor for RANK. The relative ratio of OPG and RANK
      ligand in the bone marrow microenvironment may determine the number of active
      osteoclasts, bone resorption rate, and bone mass. OPG is currently under
      investigation for osteoporosis treatment.

PMID- 15180030
TI  - A newborn with cardiac failure secondary to a large vein of Galen malformation.
AB  - We report the case of a term newborn with vein of Galen aneurysm. No antenatal
      diagnosis was done. The infant was admitted secondary to cardiac failure, with
      cardiomegaly and pulmonary hypertension. Physical examination was remarkable for
      acrocyanosis, microcephaly, cranial bruit, bilateral neck swelling, coarse breath
      sounds, and a hyperdynamic precordium with continuous murmur. Head ultrasound
      demonstrated a large, midline venous structure. Computed tomographic scan
      confirmed vein of Galen malformation.

PMID- 15180031
TI  - Reversal of delayed union of anterior cervical fusion treated with pulsed
      electromagnetic field stimulation: case report.
AB  - We present a case report of anterior cervical fusion non-union that was
      successfully treated with pulsed electromagnetic field (PEMF) stimulation. In
      this case, a C6-C7 nonunion was identified clinically and radiographically 1 year
      after surgery. Imaging revealed nonunion with partial resorption of the bone
      graft compared with imaging studies performed 8 months earlier. The patient wore
      a PEMF stimulation device for 3 h/d for 10 months. After 3 months of treatment,
      the patient's symptoms were resolved. X-rays obtained after 15 weeks of
      stimulation showed improvement in bone fusion, and x-rays obtained at 31 weeks
      after stimulation showed even bone density around the C7 screws. The patient
      remained symptom-free 13 months after the termination of PEMF stimulation at last
      assessment. PEMF stimulation demonstrated its clinical potential in healing
      established nonunion of anterior cervical spine fusion. Its use is noninvasive
      and can be considered an alternative to surgical intervention in selected
      patients.

PMID- 15180032
TI  - Female genital schistosomiasis: case report and review of the literature.
AB  - A 37-year-old woman, originally from South Africa, presented for a gynecologic
      examination. Speculum examination revealed a friable cervical lesion. Both the
      cervical smear and biopsy contained intact, viable schistosome eggs consistent
      with those of Schistosoma haematobium. Appropriate treatment was initiated
      promptly, avoiding significant morbidity. The diagnosis of female genital
      schistosomiasis must be considered when the patient has a history of travel to or
      residence in endemic areas.

PMID- 15180033
TI  - Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes
      (MELAS): a mitochondrial disorder presents as fibromyalgia.
AB  - This case report describes a patient who presented with symptoms and signs of
      longstanding fibromyalgia. Routine laboratory tests revealed an elevated anion
      gap. Evaluation of the elevated anion gap demonstrated elevated lactate and
      pyruvate levels and a lactate-to-pyruvate ratio greater than 20:1. A muscle
      biopsy was performed, exhibiting red ragged fibers, pathognomonic for a
      mitochondrial disorder. The patient was diagnosed with mitochondrial
      encephalomyopathy with lactic acidosis and strokelike episodes (MELAS). This is
      the first report describing fibromyalgia as the initial presentation of MELAS.
      This article outlines the diagnostic process that can assist the physician in
      distinguishing mitochondrial disorders from other muscular diseases, particularly
      fibromyalgia.

PMID- 15180034
TI  - Scar endometriosis developing after an umbilical hernia repair with mesh.
AB  - A 44-year-old female was initially evaluated for a 3-cm umbilical hernia, which
      developed after a laparoscopic myomectomy performed seven years prior. The
      umbilical hernia was repaired using a synthetic mesh. Eight months after the
      umbilical hernia repair, the patient returned with chronic pain in a 3-cm raised
      mass originating from the umbilical hernia repair incision. The mass and mesh
      were surgically removed. The umbilical fascial defect was repaired with a primary
      fascia-to-fascia closure and the umbilicus was reconstructed from adjacent skin.
      The mass was found histologically to be endometriosis and fascial scarring with a
      foreign body reaction to synthetic mesh. Umbilical endometriosis developed either
      from peritoneal endometrial seeding from a laparoscopic myomectomy or from
      metaplasia of multipotential cells, which developed into endometriosis due to
      inflammatory stimulation by the synthetic mesh. Synthetic mesh probably should be
      avoided in the surgical repair of a laparoscopically caused umbilical hernia in a
      premenopausal female especially if there is a history of pelvic endometriosis.

PMID- 15180036
TI  - Pura vida.

PMID- 15180035
TI  - Reviewers and authors must attend to details.

PMID- 15180037
TI  - Study raises questions about diesel emissions.

PMID- 15180038
TI  - UN sets treatment standard for ballast water.

PMID- 15180039
TI  - New beach warning system needed.

PMID- 15180040
TI  - POPs levels linked to climate fluctuations.

PMID- 15180041
TI  - Capturing mercury with ultraviolet light.

PMID- 15180042
TI  - Extracting hydrogen and electricity from renewable resources.

PMID- 15180043
TI  - Public mis-notification of coastal water quality: a probabilistic evaluation of
      posting errors at Huntington Beach, California.
AB  - Whenever measurements of fecal pollution in coastal bathing waters reach levels
      that might pose a significant health risk, warning signs are posted on public
      beaches in California. Analysis of historical shoreline monitoring data from
      Huntington Beach, southern California, reveals that protocols used to decide
      whether to post a sign are prone to error. Errors in public notification
      (referred to here as posting errors) originate from the variable character of
      pollutant concentrations in the ocean, the relatively infrequent sampling
      schedule adopted by most monitoring programs (daily to weekly), and the intrinsic
      error associated with binary advisories in which the public is either warned or
      not. In this paper, we derive a probabilistic framework for estimating posting
      error rates, which at Huntington Beach range from 0 to 41%, and show that
      relatively high sample-to-sample correlations (>0.4) are required to
      significantly reduce binary advisory posting errors. Public mis-notification of
      coastal water quality can be reduced by utilizing probabilistic approaches for
      predicting current coastal water quality, and adopting analog, instead of binary,
      warning systems.

PMID- 15180044
TI  - Establishing remediation levels in response to a radiological dispersal event (or
      "dirty bomb").
AB  - The detonation of a radiological dispersal device (RDD) could produce significant
      social and economic damage, the extent of which would depend largely on how
      quickly and effectively cleanup levels were established and on public acceptance
      of those levels. This paper shows that current radiological cleanup laws and
      regulations, models for converting dose or risk goals to cleanup concentrations,
      and existing site-specific criteria were not designed specifically for RDD
      cleanups but, absent changes, would apply by default. The goals and approaches of
      these legal and methodological structures often conflict; using them in response
      to terrorism could undermine public confidence, cause delays, and produce
      unnecessary costs or unacceptable cleanups. RDD cleanups would involve immediate
      priorities not envisioned in the existing radiological cleanup framework, such as
      balancing radiation risks with the health, economic, and other societal impacts
      associated with access to the infrastructure necessary to sustain society (e.g.,
      hospitals, bridges, utilities). To minimize the achievement of terrorism goals,
      the elements of an RDD cleanup response--including updating existing
      legal/regulatory structures to clarify federal authority, goals, and methods for
      developing RDD cleanup criteria--must be in place soon; given the complexity of
      the issues and the potential societal impact, this effort should be expedited.

PMID- 15180045
TI  - Generation and characterization of four dilutions of diesel engine exhaust for a
      subchronic inhalation study.
AB  - Exposure atmospheres for a rodent inhalation toxicology study were generated from
      the exhaust of a 2000 Cummins ISB 5.9L diesel engine coupled to a dynamometer and
      operated on a slightly modified heavy-duty Federal Test Procedure cycle.
      Exposures were conducted to one clean air control and four diesel exhaust levels
      maintained at four different dilution rates (300:1, 100:1, 30:1, 10:1) that
      yielded particulate mass concentrations of 30, 100, 300, and 1000 microg/m3.
      Exposures at the four dilutions were characterized for particle mass, particle
      size distribution (reported elsewhere), detailed chemical speciation of gaseous,
      semivolatile, and particle-phase inorganic and organic compounds. Target analytes
      included metals, inorganic ions and gases, organic and elemental carbon, alkanes,
      alkenes, aromatic and aliphatic acids, aromatic hydrocarbons, polycyclic aromatic
      hydrocarbons (PAH), oxygenated PAH, nitrogenated PAH, isoprenoids, carbonyls,
      methoxyphenols, sugar derivatives, and sterols. The majority of the mass of
      material in the exposure atmospheres was gaseous nitrogen oxides and carbon
      monoxide, with lesser amounts of volatile organics and particle mass (PM)
      composed of carbon (approximately 90% of PM) and ions (approximately 10% of PM).
      Measured particle organic species accounted for about 10% of total organic
      particle mass and were mostly alkanes and aliphatic acids. Several of the
      components in the exposure atmosphere scaled in concentration with dilution but
      did not scale precisely with the dilution rate because of background from the
      rodents and scrubbed dilution air, interaction of animal derived emissions with
      diesel exhaust components, and day-to-day variability in the output of the
      engine. Rodent-derived ammonia reacted with exhaust to form secondary inorganic
      particles (at different rates dependent on dilution), and rodent respiration
      accounted for volatile organics (especially carbonyls and acids) in the same
      range as the diesel exhaust at the lowest exhaust exposure concentrations. Day-to
      day variability in the engine output was implicated partially for differences of
      several components, including some of the particle bound organics. Though these
      observations have likely occurred in nearly all inhalation exposure atmospheres
      that contain complex mixtures of material, the speciations conducted here
      illustrate many of them for the first time.

PMID- 15180046
TI  - Further studies on the latitudinal and temporal trends of persistent organic
      pollutants in Norwegian and U.K. background air.
AB  - Data are presented for PBDEs, PCBs, and selected organochlorine compounds,
      measured at background locations by passive air samplers (semipermeable membrane
      devices, SPMDs) along a latitudinal transect from the south of the U.K. to the
      north of Norway during 2000-2002. This work is part of an ongoing air sampling
      campaign in which PCB data were previously obtained in 1994-1996 and 1998-2000.
      Comparisons of the masses of chemicals sequestered by the SPMDs during these
      different time intervals are used to investigate spatial and temporal trends. The
      study yielded examples of compounds that increase, decrease, or remain uniform
      with latitude, suggestive of differences in the relative importance of deposition
      versus atmospheric reaction in controlling their long-range atmospheric transport
      potential. The main constituents of the penta-BDE product were detected at
      amounts equivalent to 2.0 (range 1.1-2.5) and 1.1 (0.8-1.6) pg m(-3) for the U.K.
      and Norway background sites, respectively. Fractionation of PBDEs was observed,
      because the amounts of lighter BDEs decreased with latitude, while the heavier
      molecular weight congeners were quite uniformly distributed. In contrast, the
      sequestered amounts of the lighter PCBs were uniformly distributed with latitude,
      with heavier PCBs decreasing. Sequestered amounts of hexachlorobenzene increased
      with latitude. Preliminary PCB atmospheric clearance rates were derived using the
      1994-1996, 1998-2000, and 2000-2002 data. They averaged ca. 3.5 years for all
      congeners/locations. No systematic differences in congeners or locations were
      noted, supporting the hypothesis that the underlying trends in European
      background air are still controlled by primary, rather than secondary, sources.

PMID- 15180047
TI  - Emission of di-2-ethylhexyl phthalate from PVC flooring into air and uptake in
      dust: emission and sorption experiments in FLEC and CLIMPAQ.
AB  - The emission of di-2-ethylhexyl phthalate (DEHP) from a PVC flooring was studied
      for up to 472 days in both the FLEC (Field and Laboratory Emission Cell) and the
      CLIMPAQ (Chamberfor Laboratory Investigations of Materials, Pollution, and Air
      Quality). The loading of the CLIMPAQs was varied but was constant in the FLECs.
      The sorption properties of FLEC and CLIMPAQ were investigated using different
      methods. In addition, the uptake of DEHP by office floor dust on the PVC flooring
      was studied in CLIMPAQ experiments. The concentration versus time curves in both
      FLECs and CLIMPAQs increased slowly over about 150 days and reached a quasi
      static equilibrium at 1 microg m(-3). The main conclusions were that (i) the
      emission rate of DEHP was limited by gas-phase mass transport and (ii) the dust
      layer increased the emission rate by increasing the external concentration
      gradient above the surface of the PVC. These conclusions were based on the facts
      that the specific emission rate was inversely proportional to the loading and
      that the dust had sorbed about four times as much DEHP over a 68-day period as
      emitted in the gas-phase experiments. About one-half of the emitted DEHP was
      deposited on the internal surfaces of both the FLEC and the CLIMPAQ.

PMID- 15180048
TI  - How do climate fluctuations affect persistent organic pollutant distribution in
      North America? Evidence from a decade of air monitoring.
AB  - Interannual variations of persistent organic pollutant (POP) air concentrations
      from the Great Lakes region and the Arctic during the 1990s are strongly
      associated with atmospheric low-frequency fluctuations, notably the North
      Atlantic Oscillation (NAO), the El Nino-Southern Oscillation (ENSO), and the
      Pacific North American (PNA) pattern. This suggests interactions between climate
      variation and the global distribution of POPs. Atmospheric concentrations of
      hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), and several lighter
      polychlorinated biphenyls (PCBs) measured around the Great Lakes basin increased
      during the positive phases of NAO and ENSO in the spring. This implies that
      anomalous high air temperatures associated with NAO and ENSO enhance
      volatilization of POPs from reservoirs on the Earth's surface accumulated in the
      past. These compounds are then available for transport from source regions to
      more pristine regions such as the Arctic under favorable flow patterns associated
      with global climate variations.

PMID- 15180049
TI  - Emission rates of particulate matter and elemental and organic carbon from in-use
      diesel engines.
AB  - Elemental carbon (EC), organic carbon (OC), and particulate matter (PM) emission
      rates are reported for a number of heavy heavy-duty diesel trucks (HHDDTs) and
      back-up generators (BUGs) operating under real-world conditions. Emission rates
      were determined using a unique mobile emissions laboratory (MEL) equipped with a
      total capture full-scale dilution tunnel connected directly to the diesel engine
      via a snorkel. This paper shows that PM, EC, and OC emission rates are strongly
      dependent on the mode of vehicle operation; highway, arterial, congested, and
      idling conditions were simulated by following the speed trace from the California
      Air Resources Board HHDDT cycle. Emission rates for BUGs are reported as a
      function of engine load at constant speed using the ISO 8178B Cycle D2. The EC,
      OC, and PM emission rates were determined to be highly variable for the HHDDTs.
      It was determined that the per mile emission rate of OC from a HHDDT in congested
      traffic is 8.1 times higher than that of an HHDDT in cruise or highway speed
      conditions and 1.9 times higher for EC. EC/OC ratios for BUGs (which generally
      operate at steady states) and HHDDTs show marked differences, indicating that the
      transient nature of engine operation dictates the EC/OC ratio. Overall, this
      research shows that the EC/OC ratio varies widely for diesel engines in trucks
      and BUGs and depends strongly on the operating cycle. The findings reported here
      have significant implications in the application of chemical mass balance
      modeling, diesel risk assessment, and control strategies such as the Diesel Risk
      Reduction Program.

PMID- 15180050
TI  - Effect of engine load on diesel soot particles.
AB  - This study concentrates on characterization of nonvolatile fraction of diesel
      particles. These particles have an impact on earth's radiation balance as well as
      on health effects of vehicle emissions. In addition to composition and size
      distribution of particles, an important factor affecting their health effects and
      properties and lifetimes in the atmosphere is their morphology. The effect of
      engine parameters on soot particle size distributions and also on particle
      morphology has been studied. It was found that the shape of the size distribution
      and also the structure of diesel particles depend on engine load. The number
      distributions were found to obey log-normal assumption. The width of the
      distribution increased with increasing engine load. The geometric standard
      deviations of measured distributions varied from 1.7 to 2.1. Simultaneously, the
      fractal dimension of particles decreased with increasing engine load. The values
      for mass fractal dimensions based on sealing of particle mass and mobility size
      were between 2.6 and 2.8. Both electron microscopy and measurements of
      aerodynamic size versus mobility size suggest that the morphology of particles in
      different size regimes vary, with the large particles being less compact than the
      small ones.

PMID- 15180051
TI  - Phase and size distribution of polycyclic aromatic hydrocarbons in diesel and
      gasoline vehicle emissions.
AB  - Emission measurements were obtained for a variety of military vehicles at Hill
      Air Force Base (Ogden, UT) in November 2000 as part of a Strategic Environmental
      Research and Development Program. Aircraft ground support equipment vehicles
      using gasoline, diesel, and JP8 fuels were tested using chassis dynamometers
      under predetermined load. The exhaust from the tested vehicle was passed to a
      dilution tunnel where it was diluted 30-40 times and collected using Micro
      Orifice Uniform Deposit Impactor (MOUDI) fitted with aluminum substrates, an XAD
      coated annular denuder, and a filter followed by a solid adsorbent. All MOUDI
      substrates were analyzed for mass and for organic and elemental (EC) carbon by
      the thermal/optical reflectance method and for polycyclic aromatic hydrocarbons
      (PAHs) by GC/MS. Black carbon was measured with a photoacoustic instrument. The
      denuder and filter/solid adsorbent samples were analyzed for semivolatile PAH.
      Overall, there is more mass and higher EC contribution when the vehicle is run
      under higher load in comparison with the low load. However, older vehicles
      generally show more mass and EC emissions than newer vehicles, and there is a
      shift toward smaller particle sizes for the low load, which is most pronounced
      for newer vehicles. The particle-associated semivolatile PAHs and nonvolatile
      four-through six-ring PAHs are present predominantly on the submicron particles
      collected on MOUDI stages 0.1-0.18, 0.18-0.32, and 0.32-0.56 microm. For the low
      load runs, the distribution of PAHs seems to be shifted toward smaller size
      particles. The gas-particle phase distribution of semivolatile PAHs depends also
      on the engine loading. For idle, not only are the more volatile two- and three
      ring PAHs, from naphthalene to dimethylphenanthrenes, retained on the denuder
      portion, but also less volatile four-ring PAHs, such as fluoranthene and pyrene,
      are retained by the denuder at the 80-90% range, which implies that they are
      present predominantly in the gas phase. In contrast, for engines under high
      loads, a much larger portion of three- and four-ring PAHs are partitioned to the
      particle phase.

PMID- 15180052
TI  - Atmospheric concentrations and deposition of polychorinated biphenyls to the
      Hudson River Estuary.
AB  - The first estimates of atmospheric deposition fluxes of polychlorinated biphenyls
      (PCBs) to the Hudson River Estuary are presented. Concentrations of PCBs were
      measured in air, aerosol, and precipitation at nine sites representing a variety
      of land-use regimes at regular intervals from October 1997 through May 2001.
      Highest concentrations in the gas phase were observed at urban sites such as
      Camden and Jersey City (sigmaPCB concentrations averaged 3250 and 1260 pg m(-3),
      respectively). In great portions of the state encompassing forested, coastal, and
      suburban environments, gas-phase sigmaPCB concentrations were essentially the
      same (averaging 150-220 pg m(-3)). This spatial trend suggests that atmospheric
      PCBs arise from highly localized, urban sources which influence atmospheric
      concentrations and deposition fluxes over a distance of a few tens of kilometers.
      Atmospheric sigmaPCB deposition fluxes (gas absorption + dry particle deposition
      + wet deposition) ranged from 7.3 to 340 microg m(-2) yr(-1) and increased with
      proximity to urban areas. While the magnitude of the fluxes increased with
      urbanization,the relative proportions of wet, dry, and gaseous deposition
      remained largely constant. Because the Hudson River Estuary is adjacent to urban
      areas such as Jersey City, it is subject to higher depositional fluxes of PCBs.
      These depositional fluxes are at least 2-10 times those estimated for the
      Chesapeake Bay and Lake Michigan. Inputs of PCBs to the Hudson River Estuary from
      the upper Hudson River and from wastewater treatment plants are 8-18 times
      atmospheric inputs, and volatilization of PCBs from the estuary exceeds
      atmospheric deposition of low molecular weight PCBs.

PMID- 15180053
TI  - Sources and dechlorination of polychlorinated biphenyl congeners in the sediments
      of Fox River, Wisconsin.
AB  - Polychlorinated biphenyl (PCB) congeners were analyzed in eight deep, dated
      sediment cores collected from the immediate upstream and downstream of DePere dam
      in Fox River, Wisconsin. The average time span of the cores is about 100 yr,
      except for one core (FR-9) which is influenced by mixing or covers a short time
      period (2 yr). The total PCB concentrations have a range of 0.2-6.8 ppm for the
      upstream and 0.3-17.6 ppm for the downstream cores. The PCB data obtained from
      the sampling were analyzed as upstream and downstream data, using a factor
      analysis (FA) model with nonnegative constraints to identify PCB sources and
      congener patterns. The factor loadings obtained from the FA model were
      interpreted in terms of the presence of possible environmental degradation
      mechanisms. In addition, a recently developed model, which is used to identify
      and quantify possible pathways of anaerobic dechlorination of PCBs in the
      sediments, was validated on the basis of in situ data from the literature, and
      then applied to the congener patterns obtained from the FA model. The major PCB
      source to the Fox River sediments is identified as Aroclor 1242, for both the
      upstream and the downstream sediments. Loss of di- and trichlorobiphenyls (e.g.,
      2-4, 25-2) from the sediments suggests desorption from the sediments. On the
      other hand, observation of elevated amounts of certain congeners such as 24-3 and
      25-3 indicates the presence of anaerobic dechlorination activity. The anaerobic
      dechlorination model demonstrates significant similarities between the Aroclor
      1242 profile altered according to dechlorination processes Q (upstream) and H'
      (downstream) and the dominant congener patterns obtained from the FA model.

PMID- 15180054
TI  - Vehicle traffic as a source of particulate polycyclic aromatic hydrocarbon
      exposure in the Mexico City metropolitan area.
AB  - Surface properties of aerosols in the Mexico City metropolitan area have been
      measured in a variety of exposure scenarios related to vehicle emissions in 2002,
      using continuous, real-time instruments. The objective of these experiments is to
      describe ambient and occupational particulate polycyclic aromatic hydrocarbon
      (PAH) concentrations associated with vehicular traffic and facilities using
      diesel vehicles. Median total particulate PAH concentrations along Mexico City's
      roadways range from 60 to 910 ng m(-3), averaged over a minimum of 1 h. These
      levels are approximately 5 times higher than concentrations measured in the
      United States and among the highest measured ambient values reported in the
      literature. The ratio of particulate PAH concentration to aerosol active surface
      area is much higher along roadways and in other areas of fresh vehicle emissions,
      compared to ratios measured at sites influenced more by aged emissions or
      noncombustion sources. For particles freshly emitted by vehicles, PAH and
      elemental carbon (EC) concentrations are correlated because they both originate
      during the combustion process. Comparison of PAH versus EC and active surface
      area concentrations at different locations suggests that surface PAH
      concentrations may diminish with particle aging. These results indicate that
      exposure to vehicle-related PAH emissions on Mexico City's roadways may present
      an important public health risk.

PMID- 15180055
TI  - Evaluating differences between measured personal exposures to volatile organic
      compounds and concentrations in outdoor and indoor air.
AB  - Accurate estimation of human exposures to volatile organic compounds (VOCs) is a
      key element of strategies designed to protect public health from the adverse
      effects of hazardous air pollutants. The focus here is on examining the
      capability of three different exposure metrics (outdoor community concentrations,
      indoor residential concentrations, and a simple time-weighted model) to estimate
      observed personal exposures to 14 VOCs. The analysis is based on 2-day average
      concentrations of individual VOCs measured concurrently in outdoor (O) air in
      three urban neighborhoods, indoor (I) air in participant's residences, and
      personal (P) air near the breathing zone of 71 healthy, nonsmoking adults. A
      median of four matched P-I-O samples was collected for each study participant in
      Minneapolis/St. Paul over three seasons (spring, summer, and fall) in 1999 using
      charcoal-based passive air samplers (3M model 3500 organic vapor monitors).
      Results show a clear pattern for the 14 VOCs, with P > I > O concentrations.
      Intra-individual variability typically spanned at least an order of magnitude,
      and inter-individual variability spanned 2 or more orders of magnitude for each
      of the 14 VOCs. Although both O and I concentrations generally underestimated
      personal exposures, I concentrations provided a substantially better estimate of
      measured P concentrations. Mean squared error (MSE) as well as correlation
      measures were used to assess estimator performance at the subject-specific level,
      and hierarchical, mixed effects models were used to estimate the bias and
      variance components of MSE by tertile of personal exposure. Bias and variance
      both tended to increase in the upper third of the P exposure distribution for O
      versus P and I versus P. A simple time-weighted model incorporating measured
      concentrations in both outdoor community air and indoor residential air provided
      no improvement over I concentration alone for the estimation of P exposure.

PMID- 15180056
TI  - Occurrence and bioavailability of polybrominated diphenyl ethers and
      hexabromocyclododecane in sediment and fish from the Cinca River, a tributary of
      the Ebro River (Spain).
AB  - Fish and sediments from four places along the Spanish River Cinca were analyzed
      for polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD). The
      samples were collected up- and downstream from Monzon, a heavily industrialized
      town draining to the river. PBDEs and HBCD were found in sediments at levels
      ranging from 2 to 42 ng/g dry weight and from not detected (nd) to 514 ng/g dry
      weight, respectively. Twenty-three fish samples (Barbus graellsi) collected at
      the same places were also analyzed, showing levels from nd to 446 ng/g wet weight
      for PBDEs and from nd to 1172 ng/g wet weight for HBCD. The lowest values for
      both sediment and fish samples were found upstream of the industry. Of 40
      congeners (from mono- to deca-BDEs) included in the analytical work, 8 PBDE
      congeners were detected in river sediments, whereas 17 different PBDEs were found
      in fish samples. Large fish-to-sediment ratios for these brominated compounds
      indicate that they are highly bioavailable, with the exception of deca-BDE which
      was only detected in sediment samples. Concentrations of PBDEs and HBCD were
      slightly higher in muscle tissues than in liver samples obtained from the same
      specimen of fish. Moreover, PBDE and HBCD concentrations are correlated with fish
      length indicating the bioaccumulation of these contaminants.

PMID- 15180057
TI  - Application of multicriteria decision making methods to air quality in the
      microenvironments of residential houses in Brisbane, Australia.
AB  - This paper reports the first application of the multicriteria decision making
      methods, PROMETHEE and GAIA, to indoor and outdoor air quality data. Fourteen
      residential houses in a suburb of Brisbane, Australia were investigated for 21
      air quality-influencing criteria, which included the characteristics of the
      houses as well as the concentrations of volatile organic compounds, fungi,
      bacteria, submicrometer, and supermicrometer particles in their indoor and
      outdoor air samples. Ranking information necessary to select one house in
      preference to all others and to assess the parameters influencing the
      differentiation of the houses was found with the aid of PROMETHEE and GAIA. There
      was no correlation between the rank order of each house and the health complaints
      of its occupants. Patterns in GAIA plots show that indoor air quality in these
      houses is strongly dependent on the characteristics of the houses (construction
      material, distance of the house from a major road, and the presence of an in
      built garage). Marked similarities were observed in the patterns obtained when
      GAIA and factor analysis were applied to the data. This underscores the potential
      of PROMETHEE and GAIA to provide information that can assist source apportionment
      and elucidation of effective remedial measures for indoor air pollution.

PMID- 15180058
TI  - Evidence for dynamic air-water coupling and cycling of persistent organic
      pollutants over the open Atlantic Ocean.
AB  - Ship-board air samples collected between The Netherlands and South Africa in
      January-February 2001 were analyzed for PCBs and selected organochlorine
      compounds. Broad latitudinal trends in compound concentrations were influenced by
      proximity to source areas, land, and air mass origin. Lowest concentrations were
      observed in the remote south Atlantic (1-32 degrees S), where sigma7PCB
      concentrations were approximately 10 pg m(-3). Here, a diurnal cycle was noted
      for some PCB congeners, with the daytime concentrations higher than the nighttime
      concentrations, typically by a factor of 1.5-2.5. The data are consistent with a
      close coupling of air-open ocean concentrations, which has important implications
      for future rates of POP removal from the global "recyclable pool". The
      observations are discussed in the context of the potential controlling variables.
      Interactions between the phytoplankton and the dissolved phase are implicated in
      controlling the observations made here and a hypothesis to explain the cycling
      trends is presented. However, the precise mechanisms remain unclear; further
      studies are urgently required to elucidate them.

PMID- 15180059
TI  - Locating sources of surf zone pollution: a mass budget analysis of fecal
      indicator bacteria at Huntington Beach, California.
AB  - The surf zone is the unique environment where ocean meets land and a place of
      critical ecological, economic, and recreational importance. In the United States,
      this natural resource is increasingly off-limits to the public due to elevated
      concentrations of fecal indicator bacteria and other contaminants, the sources of
      which are often unknown. In this paper, we describe an approach for calculating
      mass budgets of pollutants in the surf zone from shoreline monitoring data. The
      analysis reveals that fecal indicator bacteria pollution in the surf zone at
      several contiguous beaches in Orange County, California, originates from well
      defined locations along the shore, including the tidal outlets of the Santa Ana
      River and Talbert Marsh. Fecal pollution flows into the ocean from the Santa Ana
      River and Talbert Marsh outlets during ebb tides and from there is transported
      parallel to the shoreline by wave-driven surf zone currents and/or offshore tidal
      currents, frequently contaminating >5 km of the surf zone. The methodology
      developed here for locating and quantifying sources of surf zone pollution should
      be applicable to a wide array of contaminants and coastal settings.

PMID- 15180060
TI  - Scaling and management of fecal indicator bacteria in runoff from a coastal urban
      watershed in southern California.
AB  - This paper describes a series of field studies aimed at identifying the spatial
      distribution and flow forcing of fecal indicator bacteria in dry and wet weather
      runoff from the Talbert watershed, a highly urbanized coastal watershed in
      southern California. Runoff from this watershed drains through tidal channels to
      a popular public beach, Huntington State Beach, which has experienced chronic
      surf zone water quality problems over the past several years. During dry weather,
      concentrations of fecal indicator bacteria are highest in inland urban runoff,
      intermediate in tidal channels harboring variable mixtures of urban runoff and
      ocean water, and lowest in ocean water at the base of the watershed. This inland
      to-coastal gradient is consistent with the hypothesis that urban runoff from the
      watershed contributes to coastal pollution. On a year round basis, the vast
      majority (>99%) of fecal indicator bacteria loading occurs during storm events
      when runoff diversions, the management approach of choice, are not operating.
      During storms, the load of fecal indicator bacteria in runoff follows a power law
      of the form L approximately Qn, where L is the loading rate (in units of fecal
      indicator bacteria per time), Q is the volumetric flow rate (in units of volume
      per time), and the exponent n ranges from 1 to 1.5. This power law and the
      observed range of exponent values are consistent with the predictions of a
      mathematical model that assumes fecal indicator bacteria in storm runoff
      originate from the erosion of contaminated sediments in drainage channels or
      storm sewers. The theoretical analysis, which is based on a conventional model
      for the shear-induced erosion of particles from land and channel-bed surfaces,
      predicts that the magnitude of the exponent n reflects the geometry of the
      stormwater conveyance system from which the pollution derives. This raises the
      possibility that the scaling properties of pollutants in stormwater runoff (i.e.,
      the value of n) may harbor information about the origin of nonpoint source
      pollution.

PMID- 15180061
TI  - Urinary PAH metabolites as biomarkers of exposure in aquatic environments.
AB  - While immunoassays have been extensively applied to evaluate environmental
      contamination, to date they have rarely been used for the analysis of biological
      fluids outside of human medicine. These media are important because pollutants
      such as polycyclic aromatic hydrocarbons (PAHs) and their metabolites become
      concentrated in tissues, body fluids, and excreta, thereby offering a measure of
      exposure to biologically available contaminants. Such analyses also provide a
      nondestructive tool for monitoring exposure. Crabs (Carcinus maenas) were exposed
      to phenanthrene and pyrene (separately) at concentrations ranging from 0 to 200
      microg L(-1). After 48 h, urine samples were taken and analyzed by immunoassay
      and UV-fluorescence spectrophotometry. Urinary levels (calibrated against
      hydroxylated metabolites) proved to be dose dependent for both compounds, and
      good agreementwas demonstrated between the immunoassay and the fluorescence
      techniques. The cross reactivity of the immunochemical technique (ELISA) for
      pyrene and hydroxy-metabolites was lower than for phenanthrene. HPLC analyses
      demonstrated that urine from the crabs exposed to pyrene contained mainly
      conjugate PAH metabolites whose concentrations (the sum of the four main pyrene
      metabolites/conjugates) showed very good agreement with the ELISA (r2 > 0.94) and
      fluorescence (r2 > 0.91) data. Environmental samples were also analyzed by ELISA
      and UV-fluorescence, and both techniques detected PAH (mainly petrogenic)
      contamination in the urine samples from a polluted harbor. These data demonstrate
      the potential of urine analyses by ELISA and UV-fluorescence to measure exposure
      of crabs to PAH.

PMID- 15180062
TI  - Factors affecting linear alkylbenzene sulfonates removal in subsurface flow
      constructed wetlands.
AB  - The behavior of linear alkylbenzene sulfonate (LAS) and sulfophenyl carboxylate
      (SPC) biointermediates in a pilot subsurface flow constructed wetland (SFCW) is
      reported for the first time. The effects of wetland configuration and operation
      on their treatment efficiency were investigated. The pilot SFCW constituted by
      eight beds of 55 m2 with different aspect ratios (1 x 1; 1.5 x 1; 2 x 1; 2.5 x
      1), two water depths (i.e., 0.47 and 0.27 cm) at 5 cm below surface and two
      medium sizes (i.e., D60 = 10 mm and 3.5 mm) planted with Phragmites sp. That SFCW
      pilottreats urban wastewater (i.e., 200 inhabitants) and was operated at four
      hydraulic loading rates (HLRs) (20, 27, 36, and 45 mm d(-1)). Influent and
      effluent sampling was carried out from May 2001 to January 2002 with a weekly
      pattern. Main results were as follows: (i) water depth has a major influence on
      the performance of SFCW for the LAS removal, and HLR shows significant effect on
      SPC evolution; (ii) water temperature has a significant effect on the LAS
      evolution; (iii) biodegradation of LAS and SPC can occur under sulfate-reducing
      environment and mixed conditions (i.e., sulfate-reducing and denitrification),
      but aerobic respiration cannot be excluded; and (iv) C13 LAS homologues were
      generally removed in higher extent than the shorter alkyl chain counterparts. In
      the most appropriate conditions, LAS and SPC can be biodegraded up to 71% and
      11%, respectively, in the pilot SFCW evaluated.

PMID- 15180063
TI  - Effect of dissolved organic carbon on the photoproduction of dissolved gaseous
      mercury in lakes: potential impacts of forestry.
AB  - The production of dissolved gaseous mercury (DGM) in freshwater lakes is induced
      by solar radiation and is also thought to be linked to processes mediated by
      dissolved organic carbon (DOC). Studies investigating these processes using
      comparisons between lakes are often confounded by differences in DOC content and
      structure. In this study, we investigated the link between DOC concentrations and
      DGM production by using tangential ultrafiltration to manipulate DOC
      concentrations in water samples taken from a given lake. In this way, a range of
      samples with different DOC concentrations was produced without substantial
      changes to DOC structure or dissolved ions. This was repeated for four lakes in
      central Quebec: two with highly logged drainage basins and two with minimally
      logged drainage basins. On two separate days for each lake, water samples
      (filtered to remove >99% of microorganisms) with varying DOC concentrations were
      incubated in clear and dark Teflon bottles on the lake surface. DGM
      concentrations were measured at 3.5-h intervals over the course of 10.5 h. Levels
      of DGM concentrations increased with increasing cumulative irradiation for all
      lakes until approximately 4000 kJ m(-2) (400-750 nm, photosynthetically active
      radiation (PAR)), when DGM concentrations reached a plateau (between 20 and 200
      pg L(-1)). When we assumed that DGM production was limited by the amount of
      photoreducible mercury, reversible first-order reaction kinetics fitted the
      observed data well (r2 ranging between 0.59 and 0.98, p < 0.05 with the exception
      of N70 100% DOC, 0% DOC, and K2 0% DOC with p = 0.06, 0.10, and 0.11,
      respectively). The DGM plateaus were independent of DOC concentrations but
      differed between lakes. In contrast, photoproduction efficiency (DGMprod) (i.e.,
      the amount of DGM produced per unit radiation (fg L(-1) (kJ/m2)(-1)) below 4000
      kJ m(-2) PAR) was linearly proportional to DOC concentration for both logged
      lakes (r2 = 0.97, p < 0.01) and nonlogged lakes (r2 = 0.52, p = 0.018) studied.
      Furthermore, logged lakes had a lower DGMprod per unit DOC (p < 0.01) than the
      nonlogged lakes. In these four lakes, the rate of DGM production per unit PAR was
      dependent on the concentration of DOC. The DGM plateau was independent of DOC
      concentration; however, there was a significant difference in DGM plateaus
      between lakes presumably due to different DOC structures and dissolved ions. This
      research demonstrates an important mechanism by which logging may exacerbate
      mercury levels in biota.

PMID- 15180064
TI  - Modeling expected solute concentration in randomly heterogeneous flow systems
      with multicomponent reactions.
AB  - Many environmental problems require assessment of extensive reaction systems
      within natural subsurface flow systems exhibiting large physical and
      biogeochemical heterogeneity. We present an approach to couple stochastic
      advective-reactive modeling of physical solute transport (LaSAR) with the
      geochemical model PHREEQC for modeling solute concentrations in systems with
      variable flow velocity and multicomponent reactions. PHREEQC allows for general
      and flexible quantification of a multitude of linear and nonlinear geochemical
      processes, while LaSAR efficiently handles field-scale solute spreading in
      stochastic heterogeneous flow fields. The combined LaSAR-PHREEQC approach
      requires very modest computational efforts, thereby allowing a large number of
      reactive transport problems to be readily assessed and facilitating handling of
      quantifiable uncertainty in environmental model applications. Computational
      efficiency and explicit handling of field-scale dispersion without introduction
      of excessive fluid mixing that may impair model results are general advantages of
      the LaSAR compared with alternative solute transport modeling approaches. The
      LaSAR-PHREEQC approach is restricted to steady or unidirectional flow fields, and
      our specific application examples are limited to homogeneous reaction systems
      without local or transverse dispersion-diffusion, although these are not general
      methodological limitations. As a comprehensive application example, we simulate
      the spreading of acid mine drainage in a groundwater focusing on Zn2+ and
      including relevant, major-component geochemistry. Model results show that Zn2+
      may be substantially attenuated by both sorption and precipitation, with flow
      heterogeneity greatly affecting expected solute concentrations downstream of the
      mine waste deposit in both cases.

PMID- 15180065
TI  - Accurate quantification of aromaticity and nonprotonated aromatic carbon fraction
      in natural organic matter by 13C solid-state nuclear magnetic resonance.
AB  - An improved approach for accurately determining the aromatic carbon fraction (fa)
      and nonprotonated aromatic carbon fraction (faN) in natural organic matter by
      solid-state 13C NMR is described. Quantitative peak areas are obtained from
      direct polarization 13C nuclear magnetic resonance (NMR) under high-speed magic
      angle spinning (MAS). The problem of overlap between aromatic and alkyl carbon
      resonances around 90-120 ppm in 13C NMR spectra is solved by a 13C chemical shift
      anisotropy (CSA) filter technique. After correction for residual spinning
      sidebands, an accurate value of the aromaticity fa is obtained. To obtain a
      quantitative faN fraction, dipolar dephasing was adapted for high-speed MAS 13C
      NMR; the separation of the signals of nonprotonated alkyl and aromatic carbons
      was achieved by CSA filtering plus dipolar dephasing. The method is demonstrated
      on a peat humic acid, yielding fa = 45 +/- 2% and faN = (0.64 +/- 0.07) x 45%.

PMID- 15180066
TI  - Standards development of global warming gas species: methane, nitrous oxide,
      trichlorofluoromethane, and dichlorodifluoromethane.
AB  - Environmental scientists from federal agencies, such as the National Oceanic and
      Atmospheric Administration (NOAA), and academia have long suspected that
      increasing anthropogenic inputs of various trace gases into the atmosphere can
      cause changes in the earth's climate and protective ozone layer. Nitrous oxide
      and methane, cited in the Kyoto Protocol, as well astrichlorofluoromethane (CFC
      11) and dichlorodifluoromethane (CFC-12), cited in the Montreal Protocol, are all
      greenhouse gases and are implicated in the destruction of the stratospheric ozone
      layer. The lack of national standards prompted research to determine the
      feasibility of preparing accurate and stable standards containing these four
      compounds. Development of these standards would support the measurement of these
      species by those in the atmospheric research community not having their own
      source of standards. A suite of eight primary gas standards containing methane,
      nitrous oxide, CFC-11, and CFC-12 in a balance of air were prepared
      gravimetrically to bracket the ambient atmospheric concentrations. The combined
      uncertainties (uc) were calculated from error propagation analysis that included
      the weighing data from the gravimetric preparation and other sources of error
      such as the purity analysis of the compounds and air matrix. The expanded
      uncertainties (U) for the gravimetric standards were < 0.5% as calculated from
      the equation U = kuc, where the coverage factor k is equal to 2 for a 95%
      confidence interval. Analyses of the suite of standards by gas chromatography
      with flame-ionization and electron capture detection resulted in average absolute
      residuals of < 0.25% from regression models. The NIST suite of eight gravimetric
      standards was used to determine the concentrations in two standardsfrom NOAA.
      Those analyses resulted in bias across the two laboratories of < or = 2.1%.

PMID- 15180067
TI  - Experimental and numerical test of the micrometeorological mass difference
      technique for the measurement of trace gas emissions from small plots.
AB  - Micrometeorological methods for measuring fluxes of gases between the land
      surface and the atmosphere are non-invasive: in fact, they do not interfere with
      natural processes of gas exchange. The Micrometeorological Mass Difference (MMD)
      approach can be used for many environmental monitoring purposes, such as to
      measure methane and carbon dioxide emission from landfills, methane production by
      grazing animals, trace gas emission from waste products and from agricultural
      soils, photosynthesis, and transpiration of plant canopies. The purpose of this
      study is to adapt the MMD technique, originally developed in Australia, to
      monitor CO2 and trace gases exchange rate at the plot level. Comparison of
      different treatments in replicated experiments requires plots of few rather than
      tens of meters. The tests reported here were performed on a square area (4 m x 4
      m) in the meteorological field of the experimental farm of CNR-ISAFOM located in
      Vitulazio, province of Caserta, Italy (40 degrees 07' N, 14 degrees 50' E, 25 m
      above sea level) and consisted of the release of pure CO2 at different rates
      (1.7, 1.3, 0.6 L min(-1)) from a single source on the ground in the center of the
      experimental area and the consequent measurement of the environmental variables
      (wind speed and direction, CO2 concentration) at different times at four heights
      (up to 1.2 m) in order to compute the mass balance according to MMD technique.
      Measured flow rates well accounted for the mass of CO2 released. A flow
      underestimation occurred when wind speed dropped below 1.5 m s(-1), in accord
      with the previous findings obtained in Australia: this happened because
      anemometers can stall at low speeds, and their measurements are unreliable and
      because of significant loss of mass from the top of the apparatus. The
      experimental results were compared with outputs of Computational Fluid Dynamic
      (CFD) simulations. The commercial CFD package Fluent was used to evaluate
      performances and sources of errors. According to the experimental and numerical
      results, the MMD apparatus in our present configuration is suitable to be used
      for the monitoring of trace gas emissions of experimental plots. Advantages and
      limits of the present approach are discussed.

PMID- 15180068
TI  - Characterizing uptake kinetics of PAHs from the air using polyethylene-based
      passive air samplers of multiple surface area-to-volume ratios.
AB  - Polyethylene passive sampling devices (PSDs) were deployed to investigate how
      passive samplers of multiple surface area-to-volume ratios could be used to
      characterize uptake kinetics for polyaromatic hydrocarbons (PAHs). Theoretically,
      uptake profiles for different thickness PSDs of the same surface area should show
      the following: where uptake is linear, the amount of compound accumulated in the
      different PSDs will be the same and where equilibrium is approached, the amount
      accumulated by the different PSDs will be proportional to sampler thickness.
      Polyethylene sheets of the same surface area and approximately 100 and 200 microm
      thickness were collected after 30, 60, and 90 days of exposure along with samples
      from a codeployed high volume sampler. Twelve priority pollutant PAHs could be
      routinely quantified in replicate PSDs. Overall, reproducibility between
      replicate PSDs was satisfactory, with normalized differences rarely exceeding
      25%. The smallest analytes quantified, fluorene, phenanthrene, and anthracene,
      were shown to approach equilibrium during the deployment period, whereas uptake
      for fluoranthene and pyrene moved into the curvilinear stage. For most of the
      larger molecular weight PAHs such as indeno[1,2,3-cd]pyrene, uptake could be
      described using a linear uptake model. Preliminary sampling rates for the
      compounds which remained in the linear stage of uptake ranged between 0.5 and 1.5
      m3 d(-1) dm(-2). Sampler to air partition coefficients were estimated for PAHs
      which approached equilibrium and predicted for some of the other compounds.
      Results suggest that a single deployment of PSDs with multiple surface area-to
      volume ratios can be sufficient to determine whether uptake was linear or
      approaching equilibrium for a range of PAHs.

PMID- 15180069
TI  - Characterization of diesel particles: effects of fuel reformulation, exhaust
      aftertreatment, and engine operation on particle carbon composition and
      volatility.
AB  - Diesel exhaust particles are the major constituent of urban carbonaceous aerosol
      being linked to a large range of adverse environmental and health effects. In
      this work, the effects of fuel reformulation, oxidation catalyst, engine type,
      and engine operation parameters on diesel particle emission characteristics were
      investigated. Particle emissions from an indirect injection (IDI) and a direct
      injection (DI) engine car operating under steady-state conditions with a
      reformulated low-sulfur, low-aromatic fuel and a standard-grade fuel were
      analyzed. Organic (OC) and elemental (EC) carbon fractions of the particles were
      quantified by a thermal-optical transmission analysis method and particle size
      distributions measured with a scanning mobility particle sizer (SMPS). The
      particle volatility characteristics were studied with a configuration that
      consisted of a thermal desorption unit and an SMPS. In addition, the volatility
      of size-selected particles was determined with a tandem differential mobility
      analyzer technique. The reformulated fuel was found to produce 10-40% less
      particulate carbon mass compared to the standard fuel. On the basis of the carbon
      analysis, the organic carbon contributed 27-61% to the carbon mass of the IDI
      engine particle emissions, depending on the fuel and engine operation parameters.
      The fuel reformulation reduced the particulate organic carbon emissions by 10
      55%. In the particles of the DI engine, the organic carbon contributed 14-26% to
      the total carbon emissions, the advanced engine technology, and the oxidation
      catalyst, thus reducing the OC/EC ratio of particles considerably. A relatively
      good consistency between the particulate organic fraction quantified with the
      thermal optical method and the volatile fraction measured with the thermal
      desorption unit and SMPS was found.

PMID- 15180070
TI  - Nitrate reduction by zerovalent iron: effects of formate, oxalate, citrate,
      chloride, sulfate, borate, and phosphate.
AB  - Recent studies have shown that zerovalent iron (Fe0) may potentially be used as a
      chemical medium in permeable reactive barriers (PRBs) for groundwater nitrate
      remediation; however, the effects of commonly found organic and inorganic ligands
      in soil and sediments on nitrate reduction by Fe0 have not been well understood.
      A 25.0 mL nitrate solution of 20.0 mg of N L(-1) (1.43 mM nitrate) was reacted
      with 1.00 g of Peerless Fe0 at 200 rpm on a rotational shaker at 23 degrees C for
      up to 120 h in the presence of each of the organic acids (3.0 mM formic, 1.5 mM
      oxalic, and 1.0 mM citric acids) and inorganic acids (3.0 mM HCl, 1.5 mM H2SO4,
      3.0 mM H3BO3, and 1.5 mM H3PO4). These acids provided an initial dissociable H+
      concentration of 3.0 mM available for nitrate reduction reactions under
      conditions of final pH < 9.3. Nitrate reduction rates (pseudo-first-order)
      increased in the order: H3PO4 < citric acid < H3BO3 < oxalic acid < H2SO4 <
      formic acid < HCl, ranging from 0.00278 to 0.0913 h(-1), corresponding to surface
      area normalized rates ranging from 0.126 to 4.15 h(-1) m(-2) mL. Correlation
      analysis showed a negative linear relationship between the nitrate reduction
      rates for the ligands and the conditional stability constants for the soluble
      complexes of the ligands with Fe2+ (R2 = 0.701) or Fe3+ (R2 = 0.918) ions. This
      sequence of reactivity corresponds also to surface adsorption and complexation of
      the three organic ligands to iron oxides, which increase in the order formate <
      oxalate < citrate. The results are also consistent with the sequence of strength
      of surface complexation of the inorganic ligands to iron oxides, which increases
      in the order: chloride < sulfate < borate < phosphate. The blockage of reactive
      sites on the surface of Fe0 and its corrosion products by specific adsorption of
      the inner-sphere complex forming ligands (oxalate, citrate, sulfate, borate, and
      phosphate) may be responsible for the decreased nitrate reduction by Fe0 relative
      to the chloride system.

PMID- 15180071
TI  - Novel aqueous foams for suppressing VOC emission.
AB  - Reducing volatile organic compound (VOC) emissions from crude oil/gasoline
      distribution and storage facilities is important in controlling environmental
      pollution and enhancing workplace safety. Stable aqueous foam formulations are
      developed to provide a mass transfer barrier to the emission of VOCs during
      loading of gasoline. Experiments are carried out in a bench-scale foam cell using
      liquid hexane as oil. The foam columns of 32 cm in height were able to suppress
      the plateau concentration of hexane vapors in the effluent by 87% under
      experimental conditions tested. Vapor suppression increased with foam height but
      was almost insensitive to liquid viscosity. These experiments are then upscaled
      from bench-scale to a vessel having an exposed surface area of roughly 2 orders
      of magnitude higher. Gasoline is used as oil in the upscaled experiments, and the
      concentrations of volatile hydrocarbons in the effluent are measured during oil
      loading. A 40-cm-thick foam column is found to reduce the emissions by 96% for
      foams prepared with deionized water and by 93.8% for foams prepared with 3.5 wt %
      NaCl brine for 10 h of oil loading.

PMID- 15180072
TI  - Highly efficient liquid-phase photooxidation of an azo dye methyl orange over
      novel nanostructured porous titanate-based fiber of self-supported radially
      aligned H2Ti8O17 x 1.5H2O nanorods.
AB  - Novel nanostructured porous fibers of self-supported, radially aligned H2Ti8O17 x
      1.5H2O nanorods were prepared from layered H2Ti4O9 x 1.2H2O tetratitanate fibers
      by novel solvothermal reaction in glycerine at 150-250 degrees C. The H2Ti8O17 x
      1.5H2O fibers with diameters of 0.5-1.5 microm and lengths of 10-20 microm
      consist of multi-scale nanopores and nanostructures. They also are of high
      crystallinity, large surface area of 127 m2 g(-1), and stable phase up to 350
      degrees C. Photocatalytic activity of the H2Ti8O17 x 1.5H2O fibers was evaluated
      in aqueous photooxidation of an azo dye methyl orange in the presence of UV
      irradiation and 02, using P-25 as the standard sample. Both the photocatalytic
      activity and the dispersity-agglomeration property of H2Ti8O17 x 1.5H2O fibers
      are pH-controllable. Highly photooxidative activity, superior to that of P-25,
      occurs at pH 6.0-11.0 due to certain distinguishable material characteristics and
      to large amounts of adsorbed reactants of surface active OH* free radicals,
      surface hydroxyl OH, O2*-, O*OH, and methyl orange. The agglomeration of H2Ti8O17
      x 1.5H2O fibers becomes more serious from pH 2.0 to pH 5.0 and from pH 6.0 to pH
      11.0. Well-dispersed H2Ti8O17 x 1.5H2O fibers occur at pH 6.0. Both the total
      photodegradation of waste chemicals and the entire sedimentation of H2Ti8O17 x
      1.5H2O fibers can be timed to end simultaneously at suitable pH value. The
      photocatalyst-free reaction solution is then easily removed, and the fresh
      wastewater is added again. Standard unit operation processes of chemical
      engineering are used to design a continuous, low-cost, large-scale, liquid-phase
      photocatalysis technique based on the H2Ti8O17 x 1.5H2O fibers.

PMID- 15180073
TI  - Identifying children with dental care needs: evaluation of a targeted school
      based dental screening program.
AB  - OBJECTIVES: It has been suggested that changes in the distribution of dental
      caries mean that targeting high-risk groups can maximize the cost effectiveness
      of dental health programs. This study aimed to assess the effectiveness of a
      targeted school-based dental screening program in terms of the proportion of
      children with dental care needs it identified. METHODS: The target population was
      all children in junior and senior kindergarten and grades 2, 4, 6, and 8 who
      attended schools in four Ontario communities. The study was conducted in a random
      sample of 38 schools stratified according to caries risk. Universal screening was
      implemented in these schools. The parents of all children identified as having
      dental care needs were sent a short questionnaire to document the
      sociodemographic and family characteristics of these children. Children with
      needs were divided into two groups: those who would and who would not have been
      identified had the targeted program been implemented. The characteristics of the
      two groups were compared. RESULTS: Overall, 21.0 percent of the target population
      were identified as needing dental care, with 7.4 percent needing urgent care. The
      targeted program would have identified 43.5 percent of those with dental care
      needs and 58.0 percent of those with urgent needs. There were substantial
      differences across the four communities in the proportions identified by the
      targeted program. Identification rates were lowest when the difference in
      prevalence of need between the high- and low-risk groups was small and where the
      low-risk group was large in relation to the high-risk group. The targeted program
      was more effective at identifying children from disadvantaged backgrounds. Of
      those with needs who lived in households receiving government income support,
      59.0 percent of those with needs and 80.1 percent of those with urgent needs
      would be identified. CONCLUSIONS: The targeted program was most effective at
      identifying children with dental care needs from disadvantaged backgrounds.
      However, any improvements in cost effectiveness achieved by targeting must be
      balanced against inequities in access to public health care resources.

PMID- 15180074
TI  - Validation of a Hebrew version of the Oral Health Impact Profile 14.
AB  - OBJECTIVE: This study determined the validity of a Hebrew version of the Oral
      Health Impact Profile in a cross-sectional study of a general dental practice in
      Israel. METHODS: The original English version of a short-form oral health impact
      profile (OHIP-14) was translated into Hebrew using the back-translation
      technique. Participants were interviewed and examined clinically by a calibrated
      dentist. Information on the subjects' sociodemographic background and oral health
      conditions was collected. RESULTS: A total of 142 persons were interviewed and
      clinically examined. The Cronbach's alpha and the standardized item alpha for
      OHIP-14 were both 0.88. Cronbach's alpha of the translated OHIP-14 subscales
      ranged from 0.48 to 0.76. Construct validity of the translated Hebrew version was
      supported by the finding that the total OHIP score correlated with the number of
      decayed teeth, missing teeth, need for prosthodontic treatment, and pattern of
      dental attendance. Participants with oral pain were more likely to report impact
      on one of the OHIP subscales and to have more impacts than participants who were
      pain free. CONCLUSIONS: The Hebrew version of OHIP-14 presented acceptable
      validity and reliability. Further research is needed to assess the value of this
      measure in Israel.

PMID- 15180075
TI  - The effects of the Women, Infants, and Children's Supplemental Food Program on
      dentally related Medicaid expenditures.
AB  - OBJECTIVE: This study estimates the effects of the Special Supplemental Nutrition
      Program for Women, Infants, and Children (WIC) on dentally related Medicaid
      expenditures for young children. METHODS: We used a five-year cohort study design
      to compare dentally related Medicaid expenditures for children enrolled in WIC
      versus those not enrolled for each year of life up to age 5 years. There were
      49,795 children born in North Carolina in 1992 who met the inclusion criteria for
      the study. Their birth records were linked to Medicaid enrollment and claims
      files, WIC master files, and the Area Resource File. Our analysis strategy
      included a logit and OLS two-part model with CPI dollar adjustments. RESULTS:
      Children who participated in WIC at ages 1 and 2 years had significantly less
      dentally related expenditures than those who did not participate. WIC
      participation at age 3 years did not have a significant effect. Fewer WIC
      children received dental care under general anesthesia than non-WIC children.
      CONCLUSIONS: The WIC program has the potential for decreasing dentally related
      costs to the Medicaid program, while increasing use of dental services.

PMID- 15180076
TI  - Financing of dental services in Turkey: opinions and expectations of dentists,
      residents, and patients.
AB  - OBJECTIVES: This study investigates the attitudes of dentists, residents, and
      patients on the financing of dental services in Turkey. METHODS: In this
      descriptive study, randomly selected groups of 860 dentists, 641 patients, and
      866 residents from 9 provinces of Turkey were interviewed. Their agreement on
      various statements on financing issues of dental services were recorded and
      analyzed. RESULTS: Eighty-two percent of the dentists, 83.8 percent of the
      patients, and 76.4 percent of the residents agreed that "governments should
      finance all dental services." The majority of the dentists (83.6%), patients
      (74.7%), and residents (84.4%) stated that patients should pay a copayment for
      their dental treatment. CONCLUSION: Survey results indicate that the current
      financing system of dental services in Turkey is not satisfactory either for the
      providers or for the users.

PMID- 15180077
TI  - Use of clinical services compared with patients' perceptions of and satisfaction
      with oral health status.
AB  - OBJECTIVES: To examine the relationship between rates of clinical service use and
      self-reported perception of and satisfaction with oral health status. METHODS:
      Dental services provision rates were calculated using health maintenance
      organization electronic data for members 55 years of age and older with at least
      four years of eligibility between 1990 and 2000. A mail survey yielded 986
      responses (response rate = 65.7%). Poisson regression was used to examine the
      relationship between service utilization rates and self-reported perception of
      and satisfaction with oral health status, controlling for age, education, sex,
      and marital status. RESULTS: Perceptions of oral health status and levels of
      satisfaction with oral health status generally were closely associated. Greater
      dissatisfaction with oral health status and perception of poorer oral health
      status were associated with higher usage of nonpreventive dental services. Less
      satisfaction with oral health status was associated with higher restorative
      services usage and lower preventive services usage and slightly associated with
      periodontal service usage. Perception of a less favorable oral health status was
      strongly associated with higher restorative and periodontal services usage, but
      had only a weak association with preventive services usage. CONCLUSIONS: Dental
      plan members' service use is associated with their perception of their oral
      health status and their level of satisfaction with it. Future work should seek to
      clarify whether opinions on oral health status and satisfaction are a result of
      clinical experiences over time or whether the behavior and the values associated
      with seeking and obtaining care instead shape opinions on status and
      satisfaction.

PMID- 15180078
TI  - Change in caries prevalence after implementation of a fluoride varnish program.
AB  - OBJECTIVE: In 1996 the caries prevalence of schoolchildren living in Neukolln, a
      district of Berlin, Germany, was higher than the mean of total Berlin. Hence, a
      special preventive program including the application of fluoride varnish was
      initiated. All 49 primary schools of the district joined the project. The aim of
      the present study was to evaluate in a cross-sectional study whether the
      preventive program resulted in a reduced caries prevalence. METHODS: The complete
      program included oral health education as well as the application of a highly
      concentrated fluoride varnish (Duraphat). All children whose parents' consent was
      given could receive fluoride varnish twice a year. All children were examined
      once a year by four calibrated dentists. The baseline examination was conducted
      in 1995-96, the final examination in 1999-2000 (1995-96: n = 7,748; 1996-97: n
      =15,673; 1997-98: n = 19,362; 1998-99: n = 19,822; 1999-2000: n = 17,984).
      RESULTS: A total of 80,589 dental records were used for data analysis. A decline
      of DMFT-values was observed in all age groups and school years. The major
      improvement was found in school year 1999-2000, when the program had been
      established for four years. CONCLUSION: The described program may be an effective
      public health measure for 6- to 12-year-old children with high caries prevalence.

PMID- 15180079
TI  - Caries prevalence in a rural Chilean community after cessation of a powdered milk
      fluoridation program.
AB  - OBJECTIVE: The milk fluoridation scheme established in Codegua, Chile, between
      1994 and 1999 demonstrated the effectiveness of powdered milk as a community
      based vehicle for fluoride to prevent dental caries. The present study aimed to
      compare caries prevalence in both the Codeguan control and test communities,
      three years after ending fluoride distribution through the powdered milk
      fluoridation scheme, to assess whether the benefits of such milk fluoridation
      were still present in the test community. METHODS: Children 3-6 years old living
      in Codegua (test community) and La Punta (control community) were examined for
      dental caries at their educational facilities by three trained and calibrated
      examiners using natural light, dental mirrors, and sickle probes. Differences in
      caries prevalence (dmfs) by year of the study were tested for statistically
      significant differences using the Mann-Whitney U test. RESULTS: Findings from
      Codegua (1999-2002) indicate that the dental caries experience increased in all
      age groups following the termination of powdered milk fluoridation. These
      differences reached levels of statistical significance in the 3-, 4-, and 5- year
      old group (P < .03). Comparing results from Codegua and La Punta (2002), no
      statistically significant differences were found. CONCLUSIONS: Termination of the
      powdered milk fluoridation scheme resulted in a deterioration of the dental
      health of children. After three years, dental caries prevalence was higher than
      that reached at the end of the scheme and equivalent to that of the control
      community without fluoride exposure. These results emphasize the need to
      establish and maintain an alternative mechanism of community-based fluoridation
      of proven effectiveness for the prevention of dental caries in communities where
      water fluoridation is not available.

PMID- 15180080
TI  - A comparison of the costs and patient acceptability of professionally applied
      topical fluoride foam and varnish.
AB  - OBJECTIVES: In Canada and the United States, professionally applied topical
      fluorides (PATF) are usually applied as a gel or foam. However, fluoride varnish
      has also been found to be effective for caries prevention and may be a preferred
      method because less time is required and fluoride exposure can be better
      controlled. The goal of this study was to compare the costs and patient
      acceptability of two methods of PATF (foam and varnish). METHODS: The study
      population was a convenience sample of high-risk children from the York Region
      and the city of Hamilton, Ontario, Canada, who had been identified as requiring
      fluoride therapy (n = 256). Children received from dental hygienists either
      fluoride foam applied in trays or fluoride varnish painted on tooth surfaces. An
      observer recorded the time to perform each procedure, adverse outcomes, and the
      satisfaction of children with treatment. RESULTS: The varnish technique took
      significantly less time compared to foam (5.81 vs 7.86 minutes; P < .0001).
      Significant differences between procedure times were found in all age groups, but
      the largest difference was for children aged 3-6 years (5.22 vs 8.61 minutes; P <
      .0001). Signs of gagging were observed in a lower proportion of participants who
      received varnish (3.8% vs 15.1%; P < .01), and this difference was largest for
      children aged 3-6 years (2.6% vs 29.7%; P < .01). The cost per varnish
      application, for children aged 3-6 years, was substantially less after labor
      costs were considered (dollar 3.43 vs dollar 4.43, CDN). CONCLUSIONS: Varnish
      applications were found to take less time and resulted in fewer signs of
      discomfort. These results support the use of fluoride varnish in caries
      prevention programs, especially for younger children.

PMID- 15180081
TI  - Oral health in the pediatric practice setting: a survey of Washington State
      pediatricians.
AB  - BACKGROUND: Pediatric health care providers may be the only source of preventive
      oral health education for families of young children who lack access to
      professional dental care. OBJECTIVE: We surveyed Washington State pediatricians
      in order to characterize their oral health-related educational needs and
      anticipatory guidance practices. METHODS: A 38-question survey was mailed to all
      606 general pediatricians in Washington State. Topics included anticipatory
      practices and confidence in oral health-related activities. RESULTS: Of 483
      eligible participants, 271 returned completed surveys (response rate: 57%). A
      median of 30 percent of the well-child visit was devoted to providing
      anticipatory guidance. A majority (83.7%) of respondents reported providing
      anticipatory guidance on oral health. CONCLUSION: Washington State pediatricians
      are already involved in providing oral health anticipatory guidance. Certain
      factors are identified that should be addressed to allow pediatricians to promote
      oral health more effectively.

PMID- 15180082
TI  - Acceptability of powered toothbrushes for elderly individuals.
AB  - OBJECTIVES: This study evaluated the usefulness of powered toothbrushes in
      elderly individuals for removing supragingival plaque and improving gingival
      health and comparing this to the use of regular manual toothbrushes. METHODS:
      Fourteen persons aged 68-85 years having moderate gingivitis were included in the
      study. A crossover clinical trial consisting of two phases of three months'
      duration each was carried out. All the participants were given an oral
      prophylaxis, following which they were instructed to use the manual toothbrush
      for three months. Again, for the same subjects, an oral prophylaxis was given and
      they were asked to use the powered toothbrush for the next three months. Plaque
      Index and Gingival Index scores were recorded one, two, and three months after
      the use of each toothbrush. Oral hygiene instruction was reinforced only at
      baseline. RESULTS: The powered toothbrush was more effective than a regular
      manual toothbrush in removing plaque and controlling gingivitis. CONCLUSION: The
      powered toothbrush may prove to be a good alternative to the manual toothbrush
      for this segment of the population, as it does not require any special dexterity
      to use.

PMID- 15180084
TI  - Expertise and experience.

PMID- 15180083
TI  - Oral health care knowledge and practices of a group of deaf adolescents in Lagos,
      Nigeria.
AB  - OBJECTIVE: This study sought to determine the oral health care knowledge and
      practices of a group of deaf adolescents in Lagos. METHODS: The study involved 50
      students of Wesley School 1 for the Deaf, Lagos (26 males and 24 females, aged 10
      19 years, mean 13.3 +/- 2.8). Information about previous dental care, oral
      hygiene, and snacking habits were obtained through a questionnaire and sign
      language by the teachers. RESULTS: Only 12 percent of pupils had received dental
      care. Eight percent and 72 percent, respectively, gave correct answers to causes
      of tooth decay and bleeding gums. Ninety-four percent brushed their teeth once
      daily, with no significant sex difference (P > .05). Reported dental problems
      include bleeding gums (36%), tooth discoloration, and tooth decay. The majority
      of pupils (60%) preferred biscuits and soft drinks as snacks. More than 90
      percent were willing to have a dental check-up. CONCLUSIONS: The oral health
      knowledge and practices of this group of children will improve through a
      controlled school-based oral health education program.

PMID- 15180085
TI  - Exploring the third dimension in root resorption.
AB  - OBJECTIVE: To review and investigate the validity of various 2D quantitative
      measurement techniques, and to explore the third dimension of root resorption.
      DESIGN: A review of the literature involving various quantitative evaluation of
      root resorption. RESULTS: Quantitative evaluation of resorption using radiographs
      has proven to be highly inaccurate because of magnification errors and their
      inability to be readily repeated and reproduced. Studies using histology sections
      of samples have proven to be laborious and technique sensitive. Inherent parallax
      errors and loss of material in data transfer have denied the true understanding
      of this 3D event. CONCLUSION: With the evolution in computing technology and
      digital imaging, the vision of evaluating the extent of root resorption in 3D has
      materialized. It was demonstrated that 3D volumetric quantitative evaluation of
      root resorption craters was feasible and its accuracy and repeatability was high.

PMID- 15180086
TI  - Meta analysis of the treatment-related factors of external apical root
      resorption.
AB  - OBJECTIVE: To elucidate possible treatment-related etiological factors--such as,
      duration of treatment and apical displacement--for external root resorption.
      DESIGN: Meta-analysis of the available English-language literature. INCLUSION &
      EXCLUSION CRITERIA: Papers with a sample size > 10, fixed appliances, pre- and
      post-operative radiographs, and apical displacement recorded were included.
      History of trauma, prior root resorption and endodontic treatment were excluded.
      Appropriateness of these selections was tested with a 'funnel plot' analysis.
      OUTCOME MEASURE: Correlations between root resorption, apical displacement, and
      treatment duration. RESULTS: Mean apical root resorption was strongly correlated
      with total apical displacement (r = 0.822) and treatment duration (r = 0.852).
      CONCLUSION: The treatment-related causes of root resorption appear to be the
      total distance the apex had moved and the time it took.

PMID- 15180087
TI  - Root resorption and its association with alterations in physical properties,
      mineral contents and resorption craters in human premolars following application
      of light and heavy controlled orthodontic forces.
AB  - OBJECTIVES: To study the effect of different orthodontic force levels on
      cementum, investigating from the point of view of its physical properties,
      alterations in the mineral components, type and location of the resorption
      craters and the exploration in 3D of space. DESIGN: In vivo human premolars
      subjected to heavy and light forces were employed for this study. After a period
      of movement they were analyzed for hardness and elasticity. Also, the mineral
      composition measuring Ca, P and F of the cementum root surface was investigated.
      A new method for volumetric analysis of resorption craters was developed.
      RESULTS: There were no significant differences for hardness and elastic modulus
      between the light and heavy force groups and no significant effects for different
      tooth positions. Significant inter-individual variation in the Ca, P and F
      concentrations was noted. Force-related data showed that mean volume of the
      resorption crater in light-force group was 3.49-fold greater than the control
      group, and the heavy-force group 11.59-fold more than control group. The heavy
      force group had 3.31-fold greater total resorption volume then light force group.
      Buccal cervical and lingual apical regions demonstrated significantly more
      resorption craters than the other regions. The 2D measurements were strongly
      correlated to 3D measurements. CONCLUSION: The application of light and heavy
      forces did not show any statistically significant differences in hardness and
      elastic modulus when compared with untreated teeth. The inconsistent increase or
      decrease of Ca, P and F contents between control and experimental teeth at sites
      of compression and tension were difficult to explain. There was more resorption
      by volume in the heavy force group as compared with the light group and controls.
      Our data also suggested that the high-pressure zones might be more susceptible to
      resorption after 28 days of force application.

PMID- 15180088
TI  - Mechanical stress generated by orthodontic forces on apical root cementum: a
      finite element model.
AB  - OBJECTIVES: 1) To determine the mechanical stress generated at the root apex
      during different types of tooth movement using a finite element model of an
      ideal, human maxillary central incisor. 2) To determine the relationship of
      thickness of cementum and the magnitude of mechanical stress at the root apex.
      DESIGN: Computer simulation. SETTING AND SAMPLE POPULATION: Not applicable,
      computer simulation. EXPERIMENTAL VARIABLES: Tooth and investing tissue layers
      (enamel, dentin, cementum, pulp, periodontal ligament, and alveolar bone).
      OUTCOME MEASURE: Von Mises and maximum principal stresses. RESULTS: Increasing
      the apical thickness of cementum increases the amount of mechanical stress.
      CONCLUSION: A finite element model incorporating all layers of a human maxillary
      central incisor has been developed. This model was used to determine the location
      and magnitude of mechanical stress generated for all regions of the tooth, PDL,
      and enclosed alveolar bone, when orthodontic forces are applied to the tooth.
      Mechanical stresses were found to increase at the root apex with increasing
      thickness of apical cementum.

PMID- 15180089
TI  - Characteristics of patients with severe root resorption.
AB  - OBJECTIVES: The purpose of this study was to compare a group of patients in whom
      all four maxillary incisors were resorbed at least 20% with a matched group.
      MATERIALS AND METHODS: Retrospective, case-control. Root resorption was measured
      on pre- and post-treatment periapical radiographs collected from 868 patients
      treated in private practices in southern California. Diagnostic and treatment
      factors were recorded, and vertical and horizontal apical movement calculated
      from cephalometric films. Root shape was assessed with a six-object non
      parametric rating system. From this patient population, 25 patients were found
      who had >20% root resorption on all four maxillary incisors. A case control group
      without severe root resorption matched by sex, treating office, age at start,
      ethnicity, and duration of treatment was created with two controls for each
      severe case. RESULTS: There were no statistically significant differences found
      for extractions, use of Class II and finishing elastics, transverse treatments,
      overjet, overbite, vertical, tooth length, habits, and root shape. Higher
      estimated risk was found for abnormal root shape for both maxillary incisors, and
      tongue thrust. Horizontal apical displacement was not significantly different (p
      = 0.07) but severely resorbed incisors were retracted an average of one
      millimeter further. CONCLUSIONS: Twenty-five of 868 patients were found to have
      over 20% of all four of their maxillary incisors resorbed. This is <3% of the
      total patients. Matching this group by sex, ethnicity, office, treatment time,
      and age greatly reduced the number of factors that would differentiate these
      patients from 50 who did not get severe root resorption. We conclude that
      horizontal root displacement, tongue thrust, and abnormal root shape may have
      higher estimated risk but interoffice variability and treatment time cannot be
      underestimated.

PMID- 15180090
TI  - Incidence and severity of root resorption in orthodontically moved premolars in
      dogs.
AB  - OBJECTIVES: To study treatment-related factors for external root resorption
      during orthodontic tooth movement. DESIGN: An experimental animal study. SETTING
      AND SAMPLE POPULATION: Department of Orthodontics and Oral Biology, University
      Medical Centre Nijmegen, The Netherlands. Twenty-four young adult beagle dogs.
      EXPERIMENTAL VARIABLE: Mandibular premolars were bodily moved with continuous or
      intermittent controlled orthodontic forces of 10, 25, 50, 100, or 200 cN
      according to standardized protocols. At different points in time histomorphometry
      was performed to determine the severity of root resorption. OUTCOME MEASURE:
      Prevalence of root resorptions, defined as microscopically visible resorption
      lacunae in the dentin. Severity of resorption was defined by the length, relative
      length, depth, and surface area of each resorption area. RESULTS: The incidence
      of root resorption increased with the duration of force application. After 14-17
      weeks of force application root resorption was found at 94% of the root surfaces
      at pressure sides. The effect of force magnitude on the severity of root
      resorption was not statistically significant. The severity of root resorption was
      highly related to the force regimen. Continuous forces caused significantly more
      severe root resorption than intermittent forces. A strong correlation (0.60 < r <
      0.68) was found between the amount of tooth movement and the severity of root
      resorption. CONCLUSIONS: Root resorption increases with the duration of force
      application. The more teeth are displaced, the more root resorption will occur.
      Intermittent forces cause less severe root resorption than continuous forces, and
      force magnitude is probably not decisive for root resorption.

PMID- 15180091
TI  - Nitric oxide synthase expression is increased by occlusal force in rat
      periodontal ligament.
AB  - OBJECTIVES: The goal of this study was to investigate the role of nitric oxide
      synthase (NOS) in occlusal force-induced signal transduction in rat periodontal
      ligament (PDL). DESIGN: Rats were fitted with a bite plate and a metal cap to the
      maxillary and mandibular incisors, respectively, to eliminate the occlusal forces
      on rat molars. One group was sacrificed at 7 days (exclusion group), while the
      remaining rats had their appliances removed to reestablish molar occlusal contact
      (reload group) and were sacrificed 7 days thereafter. Another group of rats
      (normal group) were left completely untreated. Frozen cross sections of the upper
      first molars were stained with NADPH-diaphorase to quantify NOS activity. The
      distal sides of the disto-palatal roots of the upper first molars were examined,
      and the number and the area of stained cells in the PDL were measured. RESULTS:
      In the normal group, NOS expression was detected in blood vessels, monocyte
      macrophages, fibroblastic cells and osteoclastic cells. NOS expression was lower
      in the exclusion group when compared with the normal group or the reload group (p
      < 0.05), and the exclusion group exhibited occluded blood vessels and a narrowing
      of PDL. In contrast, in the reload group the PDL and blood vessel structure had
      recovered and NOS expression was increased to the level of the controls.
      CONCLUSION: Occlusal force resulted in increased NOS expression. NO may mediate
      changes in PDL structure in response to occlusal force.

PMID- 15180093
TI  - Human cloning and embryo research: the 2003 John J. Conley Lecture on medical
      ethics.
AB  - The author, a member of the U.S. President's Council on Bioethics, discusses
      ethical issues raised by human cloning, whether for purposes of bringing babies
      to birth or for research purposes. He first argues that every cloned human embryo
      is a new, distinct, and enduring organism, belonging to the species Homo sapiens,
      and directing its own development toward maturity. He then distinguishes between
      two types of capacities belonging to individual organisms belonging to this
      species, an immediately exerciseable capacity and a basic natural capacity that
      develops over time. He argues that it is the second type of capacity that is the
      ground for full moral respect, and that this capacity (and its concomitant degree
      of respect) belongs to cloned human embryos no less than to adult human beings.
      He then considers and rejects counter-arguments to his position, including the
      suggestion that the capacity of embryos is equivalent to the capacity of somatic
      cells, that full human rights are afforded only to human organisms with
      functioning brains, that the possibility of twinning diminishes the moral status
      of embryos, that the fact that people do not typically mourn the loss of early
      embryos implies that they have a diminished moral status, that the fact that
      early spontaneous abortions occur frequently diminishes the moral status of
      embryos, and that his arguments depend upon a concept of ensoulment. He concludes
      that if the moral status of cloned human embryos is equivalent to that of adults,
      then public policy should be based upon this assumption.

PMID- 15180092
TI  - The natural history and prognosis of rheumatoid arthritis: association of
      radiographic outcome with process variables, joint motion and immune proteins.
AB  - OBJECTIVE: The purposes of the present study were: 1) to investigate how the long
      term course of outcome and inflammatory variables could be described in
      individual patients and suitably summarized in groups of patients; 2) to
      investigate the associations between outcome and inflammatory variables on the
      basis of the defined summary measures; and 3) to investigate new prognostic
      aspects of RA by means of frozen sera and DNA specimens. PATIENTS AND METHODS:
      During the period 1966-78, 685 Danish Caucasian patients with RA, classified
      according to the 1958 American Rheumatism Association (ARA) criteria, were
      admitted to the Department of Rheumatology of Aarhus University Hospital. For
      scientific purposes all patients went through the same examination programme,
      including biochemical variables, clinical evaluation of 68 diarthrodial joints,
      and radiographic evaluation of 46 diarthrodial joints. Since 1987, data from
      these patients have been organized in a database. The data are arranged according
      to onset of disease. This thesis is based on about 600,000 data-points from 257
      patients. RESULTS: The thesis is based on six studies. The first study shows that
      early symptomatic improvement of RA during gold treatment was stable over several
      years, but when evaluated radiographically, the condition continued to
      deteriorate. In the second study, six main types of radiographic progression were
      identified: (a) a rare type with no radiographic progression at all (<1%); (b) a
      type with a slow or moderate onset, but an increasing progression rate
      (exponential growth type) (9%); (c) a linear type (30%); (d) a type with a
      moderate to fast onset, and a stable progression rate (the square root type)
      (11%); (e) a type with a fast onset, but a later decreasing progression rate (the
      first order kinetics type) (30%) and (f) a type characterized by slow onset, then
      acceleration and later deceleration (the sigmoid type) (20%). The fact that there
      was a systematic progression was used to define a system of radiographic events,
      which could be used as outcome measures in prediction models of the long-term
      course of RA. The third study shows that low serum levels of the complement
      activating serum lectin, mannan (mannose) binding protein (lectin) (MBP = MBL),
      are associated with a higher erythrocyte sedimentation rate (ESR) (p=0.006),
      joint swelling score (JS score) (p=0.019), limitation of joint motion score (LM
      score) (p=0.027), and annual increase in radiographic destruction score (R score)
      (p=0.053). The fourth study demonstrated a highly significant association between
      summary measures of inflammatory variables and radiographic outcome, as defined
      in the second study, indicating that the degree of inflammation is important for
      the development of destructive joint damage in RA. The fifth study showed that
      MBL-insufficient patients (two defective structural MBL alleles, or one defective
      allele combined with a low-expression variant of the normal allele) had a
      relative risk of a severe radiographic event of 3.1 compared with the MBL
      competent group (p<0.0001). The sixth study showed that the relative risk (RR) of
      early interleukin (IL)-1alpha auto-antibodies (aAb) positive patients developing
      serious radiographic joint destruction was significantly lower than for IL-1alpha
      aAb-negative patients, RR=0.29 (p=0.04). In rheumatoid factor (RF) positive
      patients RR was only 0.18 (p=0.02). Patients who seroconverted >2 years after the
      onset of RA showed the most aggressive development of joint erosion, with RR of
      serious radiographic joint destruction of 2.56 (p=0.048). Other factors
      investigated in subgroups of the patients were HLA-DR4, chemokine receptor 5 (CCR
      5) genotypes. IL-6 aAb, vascular endothelial growth factor (VEGF) aAb, and
      interferon (IFN)-gamma aAb. About 80% of the patients were HLA-DR4 positive,
      indicating the importance of HLA-DR4 as a predisposing factor for RA. There was
      no association between IL-6 aAb and radiographic outcome, or CCR5 genotypes and
      radiographic outcome. VEGF aAb and IFN-gamma aAb were quantitatively unimportant.
      CONCLUSION: In spite of a general improvement in single measures of inflammatory
      variables, and a general deterioration in radiographic outcome of RA, there is a
      highly significant association between summary measures of inflammatory variables
      and radiographic outcome. The progression of radiographic damage in RA follows
      mathematical patterns. A new method of evaluating the long-term radiographic
      outcome by means of Kaplan-Meier plots is demonstrated. It is shown that MBL and
      IL-1alpha aAb are predictors of the prognosis of RA and may play important roles
      in the pathogenesis of RA.

PMID- 15180094
TI  - Intersex(es) and informed consent: how physicians' rhetoric constrains choice.
AB  - When a child is born with ambiguous genitalia it is declared a psychosocial
      emergency, and the policy first proposed by John Money (Johns Hopkins University)
      and adapted by the American Academy of Pediatrics (and more broadly accepted in
      Canada, the U.K., and Europe) requires determination of underlying condition(s),
      selection of gender, surgical intervention, and a commitment by all parties to
      accept the "real sex" of the patient, all no later than 18-24 months, preferably
      earlier. Ethicists have recently questioned this protocol on several grounds:
      lack of medical necessity, violation of informed consent, uncertainty of
      standards of success, among others. This suggests that the faults in the protocol
      can be addressed and improved. Through a rhetorical approach informed by
      Perelman/Olbrechts-Tyteca, the disciplinary pathologization and reconstruction of
      the body are explored as incidents of constraining rhetoric that enact their
      persuasion upon the body of intersexed children. This essay shows that the
      presumptions, judgments, values, and presuppositions brought by the physician to
      the identification, diagnosis, and curative procedures create a network of
      constraints that exclude alternative possibilities. The result is a situation
      wherein parents, physicians, and intersexed patients have "no choice" but to
      accept the medical treatment guidelines.

PMID- 15180095
TI  - Medical ethics and double effect: the case of terminal sedation.
AB  - The use of terminal sedation to control the intense discomfort of dying patients
      appears both to be an established practice in palliative care and to run counter
      to the moral and legal norm that forbids health care professionals from
      intentionally killing patients. This raises the worry that the requirements of
      established palliative care are incompatible with moral and legal opposition to
      euthanasia. This paper explains how the doctrine of double effect can be relied
      on to distinguish terminal sedation from euthanasia. The doctrine of double
      effect is rooted in Catholic moral casuistry, but its application in law and
      morality need not depend on the particular framework in which it was developed.
      The paper further explains how the moral weight of the distinction between
      intended harms and merely foreseen harms in the doctrine of double effect can be
      justified by appeal to a limitation on the human capacity to pursue good.

PMID- 15180096
TI  - The double life of double effect.
AB  - The U.S. Supreme Court's majority opinion in Vacco v. Quill assumes that the
      principle of double effect explains the permissibility of hastening death in the
      context of ordinary palliative care and in extraordinary cases in which
      painkilling drugs have failed to relieve especially intractable suffering and
      terminal sedation has been adopted as a last resort. The traditional doctrine of
      double effect, understood as providing a prohibition on instrumental harming as
      opposed to incidental harming or harming as a side effect, must be distinguished
      from other ways in which the claim that a result is not intended might be offered
      as part of a justification for it. Although double effect might appropriately be
      invoked as a constraint on ordinary palliative care, it is not clear that it can
      be coherently extended to justify such practices as terminal sedation. A better
      approach would reconsider double effect's traditional prohibition on hastening
      death as a means to relieve suffering in the context of acute palliative care.

PMID- 15180097
TI  - Why aren't we more ahead? The risk of variant Creutzfeldt-Jakob disease from
      eating bovine spongiform encephalopathy-infected foods: still undetermined.

PMID- 15180098
TI  - Trends in violent deaths among young people 10-24 years old, in Switzerland, 1969
      1997.
AB  - PURPOSE: To assess violent death rates and trends between 1969 and 1997 among
      young people aged 10-24 years old in Switzerland. METHODS: Total causes of death,
      all external causes of injuries, traffic injuries, suicides and overdoses were
      retrieved from the databank of the Swiss Federal Statistical Office (SFSO), using
      the eighth and tenth revisions of the International Classification of Diseases
      (ICD). Mortality rates per 100,000 individuals were computed by gender and by age
      (10-14, 15-19, 20-24) using census records as denominators. RESULTS: In 1995
      1997, violent deaths represented the primary cause of fatalities among young
      people. Rates of violent death were much higher among males than among females,
      with a ratio of 3.5:1 in 1995-1997 and also became increasingly elevated from the
      age range of 10-14 to 20-24 years (1.9:1-4.4:1). In 1995-1997, violent deaths
      accounted for 66% (n = 1221) of all fatalities among young people. Among violent
      deaths, 36% were due to traffic injuries, 13% to other types of injuries, 32% to
      suicide, 15% to overdoses, 3% to homicides and 1% to undetermined intent. Between
      1969 and 1997, rates of traffic injuries decreased in both genders and in the
      three age groups considered, while rates of suicide remained stable and rates of
      overdoses stabilised during the nineties after a sharp increase during the
      eighties. CONCLUSION: Although violent deaths in Switzerland have become
      significantly less frequent over the last 30 years, they still represent the
      single greatest cause of fatalities among young people and, as such, constitute a
      major public health challenge.

PMID- 15180099
TI  - The role of age in cardiovascular risk factor clustering in non-diabetic
      population free of coronary heart disease.
AB  - The objectives were to analyse whether cardiovascular risk factors appear
      simultaneously in the population and to determine whether it depends on age. The
      participants belong to a random sample of individuals 25-74 years of age,
      representative of the non-diabetic population free of coronary heart disease of
      the province of Gerona, Spain, studied during 1994-1996. Exploratory factor
      analysis was used to assess clustering of cardiovascular risk factors and
      confirmatory factor analysis to compare clustering among age groups (25-54 and 55
      74). RESULTS: In the 25-54 age group, we observed in both sexes the Central
      Metabolic Syndrome factor, which included glucose, lipids, and waist-to-hip
      ratio, and Metabolic Hypertension factor, which included systolic and diastolic
      blood pressures, waist-to-hip ratio, low-density lipoproteins, glycaemia, and
      triglycerides. In the 55-74 age group we observed in both sexes the Central
      Metabolic Syndrome factor, with the same composition as in younger subjects, and
      Isolated Hypertension factor, composed only of systolic and diastolic blood
      pressures. In both sexes, the chi2 value for the model of the combined age groups
      was higher than the sum of chi2 values of the best models for each age group
      separately (p < 0.01), which indicates that both sexes presented factor
      structures that differed by age group. CONCLUSIONS: The Central Metabolic
      Syndrome factor was common to all four sex and age groups studied. In younger
      subjects blood pressure was related to lipids, obesity, and glycaemia, suggesting
      the existence of a Metabolic Hypertension factor, while systolic and diastolic
      blood pressures were found to be the only significant variables in the
      hypertension factor after 54 years.

PMID- 15180100
TI  - Flavonol and flavone intake and the risk of intermittent claudication in male
      smokers.
AB  - The objective of this study was to investigate the association between flavonol
      and flavone intake and the risk of intermittent claudication in male smokers. The
      study population consisted of participants of the Finnish alpha-Tocopherol, beta
      Carotene Cancer Prevention (ATBC) Study, who were free of intermittent
      claudication at study entry. These 25,041 male smokers were 50-69 years old at
      baseline. Participants completed a validated dietary questionnaire at baseline.
      The occurrence of intermittent claudication was assessed by annual administration
      of the Rose questionnaire. During the median follow-up of 4.1 years, 2412 new
      cases of intermittent claudication were observed. Dietary intake of flavonols and
      flavones was inversely associated with the risk of intermittent claudication when
      adjusted for cardiovascular risk factors (relative risk, RR in the highest vs.
      lowest quintile of intake 0.86, 95% confidence interval, CI: 0.75-0.98, p for
      trend 0.007). However, after further adjustment for intakes of vitamins C and E
      and total carotenoids, the association was attenuated (RR: 0.93, 95% CI: 0.81
      1.08, p for trend 0.12). The risk of intermittent claudication was lower among
      men in the highest quintile of vegetable consumption (RR: 0.78, 95% CI: 0.69
      0.89, p for trend 0.0001) and among wine drinkers (RR: 0.63, 95% CI: 0.41-0.98).
      Adjustment for flavonol and flavone intake only marginally changed these
      associations. In conclusion, flavonol and flavone intake was not independently
      associated with the risk of intermittent claudication.

PMID- 15180102
TI  - The epidemiology of hand injuries in The Netherlands and Denmark.
AB  - Little is known about the magnitude of hand injuries at national levels. This
      paper quantifies and characterises the incidence of hand injuries that require
      acute medical attention at Emergency Departments in The Netherlands and Denmark.
      Except for the incidence rate and the referral after treatment, the overall
      picture of hand injuries is similar for both countries: hand injuries show a peak
      for teenagers, result mainly from home and leisure accidents, are mainly caused
      by objects and falls, the majority affect fingers and result mainly in
      superficial injuries, open wounds and fractures, a small proportion of the
      victims is admitted into hospital. We conclude that hand injuries are a real
      burden to society and are worthwhile to be prevented with special attention for
      home and leisure accidents and occupational accidents. Data recording on the
      backgrounds of accidents and their long term consequences should be improved.

PMID- 15180101
TI  - Participation behavior of bladder cancer survivors in a medical follow-up survey
      on quality of life in France.
AB  - The objectives were to ascertain the sociodemographic background of bladder
      cancer survivors acting on their participation behavior to a medical follow-up
      survey. This population-based quality of life (QOL) survey was realized by mail
      with 201 survivors (M:F = 171:30, median age = 74 years, range 33-99) randomly
      selected from the 1731 patients diagnosed between 1990 and 1994 in two regions of
      France. Response rate was 47.3%. Female and younger survivors were more receptive
      to the survey than were males and older survivors. Furthermore, survivors who had
      experienced a cystectomy were more responsive than those who did not. Similarly,
      the length of time since a major treatment was significant, with a shorter
      interval associated with a better response. The missing item rate in the QOL
      questionnaire was 13.8%. Other variables were not significantly associated with
      acceptance of the survey. Missing items among the responders were found more
      often in the sub-scale of social/familial well-being (15.6%). The older and male
      subjects left more questions blank. The reason for this low response rate can be
      categorized to the following three points: (1) Physically and psychologically not
      motivated to answer, (2) sensitive and private content of the question, and (3)
      methodological problem. Clearer concepts of the research would have helped the
      participants understand the objectives and better relate to the survey.
      Subsequently, these three issues should be given more attention in organizing
      questionnaire survey for improved participation rates in future studies.

PMID- 15180103
TI  - Determinants of allogeneic transfusion among patients who had an autologous blood
      procedure, France.
AB  - Autologous transfusion techniques have been proposed to decrease viral
      contamination related to allogeneic transfusion. Epidemiological studies looking
      at the actual effect of such policy are scarce. The aim of this study was to
      assess factors associated to the transfusion of additional allogeneic units among
      autologous blood recipients in France. We used a subgroup of data of RECEPT, a
      representative study of transfusion in French hospitals, and described blood
      recipients and components during the first 24 hours following a transfusion in
      175 teaching and non teaching hospitals. We analysed data regarding patients
      included in the original study, who received autologous blood transfusion (376
      patients). Almost one fifth of patients transfused with autologous blood was
      exposed to additional allogeneic transfusion. Patients undergoing cardiovascular
      surgery and who were transfused with blood salvage received allogeneic
      transfusion more frequently than patients undergoing orthopaedic surgery. Further
      implication of epidemiologists in studies of transfusion or other health
      technologies could help better formulate policies purported at decreasing risks.

PMID- 15180104
TI  - Do users of dietary supplements differ from nonusers in their food consumption?
AB  - The objective of the study was to analyse macronutrient and food intakes of
      regular users (310 men, 495 women) and nonusers (1136 men, 1269 women) of vitamin
      and mineral supplements, aged 18-79 years. These, were participants of the German
      Nutrition Survey, which was part of the German National Health Interview and
      Examination Survey 1998. Information on dietary behaviour including
      supplementation habits was assessed using a validated computerised dietary
      history method (DISHES 98). There were no major differences in macronutrient
      intakes between regular users and nonusers. After adjustment for age, energy
      intake, smoking, sport activity, socio-economic status and East/West German
      residence, regular supplement use was associated with a higher consumption of
      drinking water. Among men, a higher consumption of vegetable fat, poultry and
      fruit/vegetable juice, and among women, a higher consumption of fish, milk
      products, fruits and tea was also associated with regular supplement use. An
      inverse association was observed between regular supplement use and the
      consumption of coffee among women. Significant differences in food consumption
      between regular users and nonusers were observed, indicating a tendency for a
      healthier food choice among regular users.

PMID- 15180105
TI  - Prevalence and factors associated with the consumption of betel-nut among
      military conscripts in Taiwan.
AB  - OBJECTIVE: This study evaluates the prevalence of betel-nut chewing among
      military personnel stationed on Taiwan's offshore islands. Furthermore, this
      study examines variables to identify which may predict a greater predilection
      toward betel-nut chewing among the conscript population studied. METHODS: A cross
      sectional mass screening was conducted of compulsory military service personnel
      stationed on Taiwan's offshore islands between August 1 and December 31, 2001. A
      total of 7574 military employees were included in this survey. Information
      regarding betel-nut chewing habits were ascertained using a standard structured
      questionnaire, which including the level and duration of betel-nut chewing as
      well as respondents' knowledge, attitude and practices with regard to consumption
      of this product. RESULTS: Conscripts were found to be less likely to chew betel
      nut regularly while performing military service. There are 1535 (20.3%) of
      respondents reporting to habitually chew betel-nut prior to active duty shrank to
      1048 (13.8%) after going on active-duty. The most reasons to chew betel-nut among
      the recruits after military services are curiosity (33.3%) and as a stimulant
      (29.8%). About 46% of military employees who currently chew betel-nut report an
      interest to quit in the future. The risk factors for betel-nut chewing include
      individual factors (e.g., age, education, knowledge, and attitude toward betel
      nut chewing), lifestyle habits (e.g., cigarette smoking), and familial factors
      (e.g., consumption of betel-nut by parents). More interesting, the recruits had
      the habit of cigarette smoking associated with increase risk for betel-nut
      chewing (OR: 7.18; 95% CI: 5.66-9.20). CONCLUSIONS: Although the military has
      made considerable progress in reducing betel-nut chewing on military campuses,
      the prevalence of betel-nut chewing is still relatively high and, in 2001,
      affected about one quarter of all military personnel stationed on the
      abovementioned offshore islands. In future efforts to lower betel-nut consumption
      among high risk groups, targeting the group of conscripted military personnel
      described in this study should be considered.

PMID- 15180106
TI  - The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the
      elderly: a comparison of meta-analyses.
AB  - A 23-valent polysaccharide pneumococcal vaccine (PPV) has been available in the
      UK for more than 20 years and is currently recommended for use in high-risk
      groups (HRG) of 2+ years of age. The degree of protection afforded by the PPV
      remains a critical issue, although a number of randomised clinical trials and
      case-control studies (CCS) have been published. The aim of this work is to review
      the estimates on the efficacy of PPV against pneumococcal pneumonia and invasive
      pneumococcal disease (IPD) in the elderly and to perform a meta-analysis in order
      to obtain a pooled estimate of the level of protection in high and low risk
      individuals. These two groups of individuals are at the centre of the current
      debate on whether or not to extend the vaccination programme to all elderly
      individuals 65+. Only randomised and quasi-randomised studies are included in the
      analysis and results are compared with previous meta-analyses. The effect of the
      inclusion of observational studies is investigated in the sensitivity analysis.
      When taken with the results of other meta-analyses and observational studies, it
      appears that PPV offers protection against IPD in the general elderly population
      (VE = 65%; 95% CI: -49-92%) whereas it has a moderate effect in the high-risk
      elderly (VE = 20%; 95% CI: -188-78%). The vaccine has little or no effect against
      pneumonia (VE = 16% in the general elderly and -20% in HRG).

PMID- 15180108
TI  - Could measuring of perceived risk among general practitioners have helped
      anticipate the French BSE crisis?
AB  - In October of 2000, a second BSE crisis caught French public authorities
      unprepared and caused a collapse in beef consumption as well as considerable
      political turmoil. Data collected between May and July, 2000, among a group of
      general practitioners (GPs), while national consumption of beef was back to pre
      BSE levels, paradoxically showed high latent risk perception, suggesting a new
      crisis was possible or likely.

PMID- 15180109
TI  - Nocardial infections in Japan from 1992 to 2001, including the first report of
      infection by Nocardia transvalensis.
AB  - In the period from 1992 to 2001, 303 cases of nocardioses were diagnosed in
      Japan, with the corresponding etiological agents isolated and characterized.
      Taxonomic analyses of these 303 strains showed that most nocardial infections
      were caused by members of the Nocardia asteroides group (72.3%). Speciation
      showed that 72 strains were N. asteroides, 31 strains were N. cyriacigeorgica, 2
      strains were N. beijingensis, 81 strains were N. farcinica, and 33 strains were
      N. nova. Sixty-six strains of N. brasiliensis were the next most prevalent
      species of the total Nocardia isolates, followed by 14 strains of N.
      otitidiscaviarum. Infections by N. transvalensis (3 strains) and N.
      pseudobrasiliensis (1 strain) were also confirmed. The infections due to N.
      transvalensis, N. cyriacigeorgica, and N. beijingensis were the first reported in
      Japan. The most common factor that predisposed individuals to nocardial infection
      in Japan was therapy by immunosuppressive agents (22.4%), including SLE therapy
      (3.6%), followed by cancer (6.6%), diabetes (3.6%) and AIDS (2.0%). Nocardial
      infections occurred more commonly in the elderly, with most of the patients
      between the ages of 61 and 80 years of age. No significant difference regarding
      infectivity levels between the sexes was observed.

PMID- 15180107
TI  - The 23-valent pneumococcal polysaccharide vaccine. Part II. A cost-effectiveness
      analysis for invasive disease in the elderly in England and Wales.
AB  - The 23-valent pneumococcal polysaccharide vaccine (PPV) has been available for a
      number of years and is recommended for high-risk categories. Relatively
      immunocompetent elderly people are not included in this group, although their
      probability of getting invasive pneumococcal infection is high. The objective of
      this study was to assess whether vaccinating all elderly people over 65 years of
      age was a cost-effective policy for England and Wales. The analysis was performed
      comparing the cost and health effects produced by vaccination, to what would have
      been occurred if vaccination were not introduced. A decision analysis model was
      used in order to predict health outcomes under different vaccination scenarios.
      Unit costs were applied to the outcome and the cost per life-year gained was
      calculated. Sensitivity analysis was performed to allow for uncertain parameters
      to vary. The current UK recommendation does not appear to be the most cost
      effective strategy due to the low level of efficacy of the vaccine in high-risk
      groups (HRG) and their shorter life expectancy. Routine vaccination of all
      elderly appears to be more cost-effective. These results are, nevertheless, very
      much dependent on the uncertainties around vaccine efficacy estimates, which
      appear to be still present, especially in HRG, and on the number of
      hospitalisations and deaths attributable to invasive pneumococcal disease (IPD).

PMID- 15180110
TI  - Newly diagnosed HIV-1 infections in pregnancy: evidences from a cohort study in
      south-eastern Italy.
AB  - The authors report and discuss the characteristics of 22 women who discovered
      their HIV seropositivity while pregnant. Most of the women had never been tested
      for HIV and this occurred not only for 'not at risk' women but also for sexual
      partners of HIV-infected men. Several infections were diagnosed late in pregnancy
      when most women were already immunodeficient. An implementation of HIV prenatal
      testing as an early standard clinical practice, should be promoted in all women,
      regardless of the presence of risk factors.

PMID- 15180111
TI  - Stereotactic radiosurgery.

PMID- 15180112
TI  - Strategic planning--building the foundation to formulate strategies.

PMID- 15180114
TI  - The next level of distributed learning: the introduction of the personal digital
      assistant.
AB  - Handheld technology has grown in both popularity and capabilities. Studies
      continue to be done on their impact in numerous fields. At The Ohio State
      University Medical Center, a handheld program was started in 2001, initially
      involving third- and fourth-year medical students and residents. The presence of
      these digital devices presented the opportunity to examine their use in taking
      traditional materials and delivering them in a personal digital assistant
      friendly format. The objective was to offer these materials within an "anytime
      anywhere" set-up, thereby positively affecting the learning experience while also
      laying the foundation for other such uses.

PMID- 15180113
TI  - Design and technology: good business partners.

PMID- 15180115
TI  - Evaluating technology for acquisition.
AB  - Cancer care consumes approximately 8% to 9% of all healthcare spending. The use
      of technology plays a key role in cancer, with both diagnostic and treatment
      implications, and technology is a large driver of healthcare spending.
      Understanding the role of technology and its integration in care may contribute
      to appropriate selection and utilization of technology, better decision making as
      to priorities in acquisition, and clinical cost efficiency.

PMID- 15180116
TI  - Comparison of effects of exercise programme, pulsed ultrasound and transverse
      friction in the treatment of chronic patellar tendinopathy.
AB  - OBJECTIVE: To compare the effectiveness of an exercise programme, pulsed
      ultrasound and transverse friction in the treatment of chronic patellar
      tendinopathy. DESIGN: Randomized controlled trial. SETTING: Rheumatology and
      Rehabilitation Centre. SUBJECTS: This study was carried out with 30 patients who
      had chronic patellar tendinopathy. They were randomized into three groups.
      INTERVENTIONS: Group A (n = 10) was treated with exercise programme. Pulsed
      ultrasound was given to group B (n = 10). Group C (n = 10) received transverse
      friction. All patients received three treatments per week for four weeks.
      OUTCOMES: Patients' pain was evaluated at the end of the four-week course of
      treatment (week 4), one month (week 8) and three months (week 16) after the end
      of treatment. RESULTS: The exercise programme was statistically significantly
      better than the other two treatments at the end of treatment (chi2 = 12.21, p <
      0.01), one month (chi2 = 23.2, p < 0.001) and three months (chi2 = 23.2, p <
      0.001) after the end of the treatment. CONCLUSION: Although the results suggested
      that the exercise programme was more effective treatment than ultrasound and
      transverse friction at the end of the treatment as well as at the follow-ups,
      future controlled studies are needed to establish the relative and absolute
      effectiveness of each of the three treatment interventions.

PMID- 15180117
TI  - The effect of preoperative physiotherapy and education on the outcome of total
      hip replacement: a prospective randomized controlled trial.
AB  - OBJECTIVE: To investigate the effects of preoperative physical therapy for
      patients undergoing total hip replacement. DESIGN: Prospective randomized
      controlled study. SETTING: Department of Orthopaedics and Traumatology in a
      university hospital. SUBJECTS: Sixty patients with osteoarthritis of the hip
      scheduled to receive total hip replacement were randomly assigned into two
      groups. INTERVENTIONS: Subjects in the study group received preoperative
      physiotherapy designed to strengthen the muscles of the upper and lower limbs and
      to improve range of motion of the hip, beginning from eight weeks before the
      operation. These patients also received an educational programme about living
      with a prosthesis. The control group received no preoperative physiotherapy or
      educational programme. MAIN OUTCOME MEASURES: Patients were evaluated at baseline
      (study group only, eight weeks prior to operation), before surgery, at discharge,
      three months and two years postoperatively using Harris Hip Score, visual
      analogue scale and range at hip abduction. RESULTS: Although patients in the
      study group performed transfer activities earlier than the control group, there
      were no significant differences between the groups at discharge with regard to
      the improvement in Harris Hip Score (p < 0.48) and hip adduction (p < 0.97) and
      visual analogue scale at rest (p < 0.54) and activity (p < 0.89). At the latest
      follow-up (two years postoperatively) both groups had improved in Harris Hip
      Score, but rate of improvement between the groups was similar (p < 0.05).
      CONCLUSIONS: We conclude that the routine use of preoperative physiotherapy and
      education programme is not useful in total hip replacement surgery.

PMID- 15180118
TI  - Percutaneous neuromuscular electrical stimulation (P-NMES) for treating shoulder
      pain in chronic hemiplegia. Effects on shoulder pain and quality of life.
AB  - OBJECTIVE: To evaluate the effect of percutaneous neuromuscular electrical
      stimulation (P-NMES) of the shoulder muscles on shoulder pain intensity and
      health-related quality of life in chronic hemiplegia. DESIGN: Prospective, open
      label design. SETTING: The outpatient services of a large teaching rehabilitation
      hospital in The Netherlands. SUBJECTS: Fifteen stroke survivors with chronic (>
      six months) hemiplegia and a therapy-resistant painful shoulder with subluxation.
      All patients suffered from clinically relevant shoulder pain, as assessed by a
      score of at least 4 out of 10 on a numerical rating scale. Shoulder subluxation
      was indicated by at least 1/2 fingerbreadth of glenohumeral separation on
      palpation. INTERVENTION: Six hours of P-NMES per day for a total of six weeks.
      MAIN OUTCOME MEASURES: Shoulder pain (Brief Pain Inventory), shoulder subluxation
      (clinical and radiographic), shoulder pain-free external rotation (hand-held
      goniometer), motor impairment (Fugl-Meyer Motor test) and quality of life (SF-36)
      were assessed before treatment, after six weeks of intramuscular stimulation, at
      three months and six months follow-up. RESULTS: A significant reduction in pain
      was found on the Brief Pain Inventory. Pain reduction was still present at six
      months follow-up. All domains, in particular bodily pain, of the SF-36 showed
      improvement in the short term. After six months of follow-up, bodily pain was
      still strongly and significantly reduced, whereas social functioning and role
      physical demonstrated a nonsignificant improvement of more than 10% compared with
      baseline. CONCLUSION: This pilot suggests that P-NMES potentially reduces
      shoulder pain in chronic hemiplegia. To establish the clinical value of P-NMES in
      treating hemiplegic shoulder pain a randomized controlled trial is needed.

PMID- 15180119
TI  - Comparison of two ultrasonographic localization techniques for the treatment of
      lateral epicondylitis with extracorporeal shock wave therapy: a randomized study.
AB  - OBJECTIVE: To describe and compare two ultrasonographic localization techniques
      for the treatment of lateral epicondylitis with extracorporeal shock wave therapy
      (ESWT). DESIGN: Forty-one subjects selected through clinical examination were
      randomly assigned to two groups of treatment. INTERVENTIONS: Each subject
      received a three-session ultrasound-guided ESWT (performed weekly). Lateral
      tangential focusing was used in group A, whereas back tangential focusing was
      used for group B. MAIN OUTCOME MEASURES: Total Elbow Scoring System (TESS) and a
      visual analogue scale (VAS) were used to evaluate each subject before the
      treatment and at six months follow-up. RESULTS: TESS and VAS pretreatment scores
      were homogeneous between the groups (p > 0.05). In both groups there was a
      significant (p < 0.05) increase in the TESS score and a decrease in the VAS score
      but there was no resolution of the pain. TESS and VAS follow-up scores were
      homogeneous between the two groups (p > 0.05). CONCLUSIONS: There was no
      difference between the two techniques of using ESWT.

PMID- 15180120
TI  - Effectiveness of provision of outdoor mobility services and devices in The
      Netherlands.
AB  - OBJECTIVE: To answer the following questions: What are the problems encountered
      by people with outdoor mobility disabilities? What solutions are being offered to
      them in The Netherlands? How effective are these solutions? How responsive is the
      IPPA instrument (Individually Prioritized Problem Assessment)? DESIGN: Analysing
      the results of a follow-up study using the IPPA instrument. SETTING: The Dutch
      Service for the Disabled Act (SDA, in Dutch: WVG) provision system. This act is
      responsible for the provision of mobility aids and home adaptations. SUBJECTS:
      Fifty-nine people with outdoor mobility disabilities. INTERVENTIONS: The
      provision of outdoor mobility service and devices. MAIN OUTCOME MEASURES:
      Effectiveness of provisions as measured using IPPA (i.e., the degree to which
      activities have become less difficult to perform), effect size of IPPA with this
      intervention. RESULTS: Problems identified by clients are very diverse and
      specific but can be classified fairly well on the basis of the International
      Classification of Functioning, Disability and Health (ICF); in the main, the
      solutions they are provided with are very similar and generic. Effectiveness is
      excellent at a group level, but insufficient for some at an individual level. The
      IPPA instrument is highly responsive in this setting. Most mobility problems
      respondents identified, although very individual and specific, were related to
      shopping, social visits or leisure activities. These specific sets of problems
      were solved using 'standard', generic solutions. CONCLUSIONS: The Dutch provision
      system should be more 'demand oriented' and less 'supply oriented'. IPPA turns
      out to be a useful, structured and individual-oriented method to evaluate service
      delivery.

PMID- 15180121
TI  - Preventing falls and stump injuries in lower limb amputees during inpatient
      rehabilitation: completion of the audit cycle.
AB  - OBJECTIVES: To study the factors contributing to falls among recent lower limb
      amputees, and to reduce the number of falls during inpatient rehabilitation and
      resulting injuries. DESIGN: Retrospective, followed by prospective, cohort study,
      then a follow-up study conducted after interventions. SETTING: Twenty-bedded
      inpatient rehabilitation unit for amputees. SUBJECTS: Lower limb amputees.
      INTERVENTIONS: Patient education, environmental modifications and application of
      a bivalve plaster of Paris stump protector to patients who were aged 70 or over,
      or cognitively impaired. MAIN OUTCOME MEASURES: Numbers of falls and other
      accidents, and resulting injuries. RESULTS: In phase 1 of the study, a
      retrospective audit of incident forms that had been completed on lower limb
      amputees who had an accident during their inpatient rehabilitation, between 1
      April 1996 and 31 Ocotber 1998, was carried out. This showed that approximately a
      third of admissions (32%) were complicated by an accident. Most accidents were
      falls. In phase 2, a prospective study of 113 patients admitted to the unit was
      undertaken. Patients who fell were significantly older than those who did not. In
      phase 3, 62 consecutive patients were studied. There were 37 accidents in total,
      of which 35 were falls. Compared with the phase 2 study, there was no reduction
      in the proportion of patients who had a fall or other accident in phase 3, but
      significantly fewer falls resulted in any injury (p = 0.05). CONCLUSIONS:
      Although the interventions employed did not reduce the proportion of patients who
      had falls or other accidents, significantly fewer falls resulted in injuries.

PMID- 15180122
TI  - Psychometric properties of the sensory scale of the Fugl-Meyer Assessment in
      stroke patients.
AB  - OBJECTIVE: To examine the psychometric properties of the sensory scale of the
      Fugl-Meyer Assessment (FMA-S) in stroke patients with a broad range of
      neurological and functional impairment at times from 14 to 180 days after stroke.
      SUBJECTS: A total of 176 first stroke patients consecutively admitted to a
      university-based medical centre. DESIGN: This prospective, longitudinal
      investigation was based on data collected at 14, 30, 90 and 180 days after
      stroke. MAIN OUTCOME MEASURES: Reliability (inter-rater reliability and internal
      consistency), validity (convergent and predictive validity) and responsiveness of
      the FMA-S were examined. RESULTS: The inter-rater agreement of the total score of
      the FMA-S was excellent, with an intraclass correlation coefficient of 0.93. The
      Cronbach's alphas of the FMA-S at four time points after stroke ranged from 0.94
      to 0.98, indicating excellent internal consistency. However, the FMA-S showed a
      significant ceiling effect (more than 44.4% of the subjects achieving the highest
      score), poor to moderate inter-rater reliability for light touch items (weighted
      kappa ranging from 0.30 to 0.55), low to moderate validity (Spearman's rho
      ranging from 0.29 to 0.53), and low to moderate responsiveness (standardized
      response mean ranging from 0.27 to 0.67) at different post-stroke stages of
      recovery. CONCLUSIONS: The psychometric properties of the FMA-S in measuring
      sensory function do not support its clinical use in stroke patients. Further
      studies on methods to improve the psychometric properties of the FMA-S are
      needed.

PMID- 15180123
TI  - Rehabilitation outcomes after brain injury: disability measures or goal
      achievement?
AB  - BACKGROUND: The outcome of rehabilitation interventions following brain injury is
      commonly rated by disability scales. Goal-setting and achievement are important
      in inpatient rehabilitation, but seldom assessed as outcomes. OBJECTIVE: To
      compare the information acquired from using disability ratings and goal
      attainment/variances as outcome measures in brain injury rehabilitation. SETTING:
      An inpatient regional neurological rehabilitation unit. SUBJECTS: One hundred and
      seventy-seven patients admitted after single incident brain injury over a three
      year period. MAIN MEASURES: (1) Disability outcomes by the Barthel Index and the
      Functional Independence Measure, (2) goal achievement and variance distribution,
      and (3) the influence of diagnosis and demographics on these measures. RESULTS:
      Patients improved significantly on all disability scales employed (p < 0.0001),
      with the baseline admission scores being inversely correlated with changes in
      dependency by discharge (rho approximately -0.4). The median attainment rate of
      long-term goals was 75% per patient. Nonachievement was most frequently due to
      cognitive problems (38%), followed by behavioural difficulties and physical
      limitations (18% each). Goal achievement correlated poorly with disability
      outcome at discharge (rho < 0.3). Patients who accomplished all their goals
      tended to be less disabled at admission. Diagnostic groups and demographic
      factors had little influence on either disability or goal achievement outcomes.
      CONCLUSIONS: The use of a simple goal achievement and variance coding scheme has
      been relatively straightforward to incorporate into the daily practice of the
      unit. It provides useful information on rehabilitation process and outcome after
      brain injury that is complementary to the utilization of disability measures.

PMID- 15180124
TI  - Correlation between upper limb functional ability and structural hand impairment
      in an early rheumatoid population.
AB  - OBJECTIVE: To explore the relationship in individuals with early rheumatoid
      arthritis (RA) between self-report upper limb function, therapist-assessed upper
      limb function and therapist-assessed measures of structural impairment (handgrip,
      active hand motion and metacarpophalangeal (MCP) joint ulnar deviation). DESIGN:
      Thirty-six patients with early RA were recruited across seven outpatient
      occupational therapy departments. OUTCOME MEASURES: Upper limb functional
      activity and ability was measured using the Disability of the Arm, Shoulder and
      Hand (DASH) questionnaire and the Grip Ability Test (GAT). Upper limb impairment
      was assessed by bilateral power handgrip using the MIE Digital Grip Analyser,
      goniometry measures of bilateral metacarpophalangeal (MCP) joint ulnar deviation
      and bilateral active motion of the wrist. RESULTS: Strong correlations (> 0.7)
      were seen between the self-report DASH questionnaire and the therapist-rated GAT
      assessment. Bilateral power handgrips were also strongly correlated with both
      functional assessments. Dominant ulnar deviation at the MCP joints demonstrated a
      weak correlation (0.3-0.4) with both self-report and therapist-rated functional
      ability and a weak to moderate. (0.1-0.5) correlation on the nondominant side.
      CONCLUSION: In this early RA population handgrip strength is an accurate
      indicator of upper limb ability. Ulnar deviation at the MCP joints shows only a
      weak to moderate association with upper limb functional activity and ability.
      Although the DASH and the GAT were strongly correlated, the DASH was a more
      discriminating measure than the GAT in assessing upper limb ability in this
      sample population.

PMID- 15180125
TI  - Measurement properties of the Frenchay Activities Index among individuals with a
      lower limb amputation.
AB  - OBJECTIVE: To assess the reliability and validity of the original and a modified
      version of the Frenchay Activities Index (FAI) among individuals with a lower
      limb amputation. DESIGN: Two week test-retest design. SETTING: South Western
      Ontario Amputee Program, London, Ontario, Canada. SUBJECTS: Consecutive sample of
      84 individuals, primarily men (78.6%), mean age 56.5 years with a unilateral
      transtibial (71.4%) or transfemoral amputation related to traumatic (59.5%) or
      vascular causes. INTERVENTIONS: All subjects completed a questionnaire containing
      the FAI and other scales, the 2-minute walk and timed up and go tests during a
      regularly scheduled clinic visit. Fifty-five subjects completed a second FAI
      which was mailed to them two weeks later. Twenty-nine others completed the second
      FAI upon return for testing related to another project. MAIN MEASURES: FAI,
      Activity-specific Balance Confidence Scale, Prosthetic Evaluation Questionnaire
      Mobility Scale, 2-minute walk, timed up and go and walking device aid use.
      RESULTS: Relative reliability for the FAI (intraclass correlation coefficient
      (ICC) = 0.79) and FAI-18 (ICC = 0.78) was acceptable, however bias between
      measurements was detected. Hypothesized relationships (p < 0.001) between both
      FAI versions and the Activity-specific Balance Confidence Scale, Prosthetic
      Evaluation Questionnaire-Mobility Scale, 2-minute walk and timed up and go test
      were observed. Significant group differences were observed for amputation cause,
      mobility device use, age and years as an amputee. Neither version distinguished
      between amputee level or gender groups. CONCLUSIONS: The original and modified
      FAI are valid and reliable tools for unilateral amputees. Reliability is adequate
      to detect group but not individual level differences. Additional FAI-18 items did
      not substantially improve the ability to detect between-amputation-group
      differences.

PMID- 15180126
TI  - Characteristics of psychosexual functioning in adults with cerebral palsy.
AB  - OBJECTIVE: To investigate the characteristics of psychosexual functioning in
      adults with cerebral palsy, as compared with able-bodied control subjects,
      matched by gender and marital status, and to identify the factors affecting
      psychosexual functioning. DESIGN: Interview and survey using the Derogatis Sexual
      Functioning Inventory (DSFI). SETTING: Inpatient and outpatient units in a
      rehabilitation hospital and welfare facilities. SUBJECTS: Sixty-two adults with
      cerebral palsy and 142 age-matched able-bodied controls participated in this
      study. The participants were grouped into four subgroups according to gender and
      marital status. MAIN MEASURES: General characteristics of the subjects, 10 domain
      scores of the DSFI and Sexual Functioning Index (SFI) as a global score were
      assessed. The scores for each cerebral palsy group according to gender and
      marital status were compared with those of their corresponding able-bodied
      control group. RESULTS: Unmarried men with cerebral palsy demonstrated lower SFI
      and weakness in sexual information, experience, drive, attitude, psychological
      symptoms, affect and satisfaction, compared with unmarried able-bodied men (p <
      0.05). In contrast to unmarried men, unmarried women did not reveal any
      significant differences in all but body image domain score (p < 0.05) between the
      groups. Married adults with cerebral palsy showed higher levels of psychological
      distress in both men and women and lower sexual satisfaction in women (p < 0.05).
      Nonambulatory people with cerebral palsy had significantly a lower sexual
      information, experience and satisfaction, and a lower SFI than ambulatory (p <
      0.05). Barthel Index was significantly related to body image (p < 0.05).
      Psychosexual functioning was not significantly different according to cerebral
      palsy type. CONCLUSION: This study revealed the characteristics on psychosexual
      functioning in adults with cerebral palsy, depending on gender and marital
      status. The results suggested that nonambulatory unmarried men with cerebral
      palsy were at high risk in terms of psychosexual dysfunction.

PMID- 15180127
TI  - Psychological well-being of spouses of stroke patients during the first year
      after stroke.
AB  - OBJECTIVE: To investigate whether spouses' psychological well-being changed
      between the first weeks after their partner's stroke and four months and one year
      later, and to study the relationship between spouses' psychological well-being
      and objective characteristics of the stroke patients. DESIGN: Prospective,
      longitudinal study. SETTING: Hospital care and follow-ups. SUBJECTS: Sixty-seven
      consecutively enrolled spouses to first-ever stroke patients < 75 years. MAIN
      MEASURES: The Psychological General Well-Being (PGWB) Index. Clinical examination
      of the stroke patients. The Barthel Index. RESULTS: The spouses' psychological
      well-being was significantly lower in the first weeks after their partner's
      stroke as compared with norms. At four months, it had increased significantly.
      Between four months and one year, individual changes were observed in both
      positive and negative directions; thus, the mean level of the group remained
      constant. The spouses' psychological well-being in the first weeks was
      significantly related to the patients' sensorimotor impairments, while it was
      related at four months to cognitive impairment and the patients' abilities in
      self-care. At one year, psychological well-being was related to remaining
      sensorimotor and cognitive impairments. A significant relationship was also seen
      between the spouses' and the stroke patients' emotional health. CONCLUSIONS: The
      spouses' psychological well-being increased after the first chaotic weeks. The
      presence of visible impairments initially seemed to affect spouses' emotional
      health, while cognitive and emotional impairments became more evident in everyday
      life. In the long term, however, the spouses' individual life situations and
      coping abilities seem to be of relatively increasing importance for their
      continued well-being.

PMID- 15180128
TI  - Predicting spasticity after stroke in those surviving to 12 months.
AB  - OBJECTIVE: To measure muscle tone in a cohort of patients 12 months after stroke
      and develop a preliminary model, using data recorded routinely after stroke, to
      predict who will develop spasticity. DESIGN: A cohort study. SETTING: Initially
      hospitalized but subsequently community-dwelling stroke survivors in Liverpool,
      United Kingdom. SUBJECTS: One hundred and six consecutively presenting stroke
      patients surviving to 12 months. MAIN OUTCOME MEASURES: Spasticity measured at a
      range of joints using the Tone Assessment Scale. RESULTS: The Tone Assessment
      Scale revealed spasticity in 38 (36%) patients and more severe spasticity in 21
      (20%) of the 106 patients. Logistic regression analysis revealed that lower day 7
      Barthel Index score and early arm or leg weakness were significant predictors of
      abnormal muscle tone; and lower day 7 Barthel Index score, left-sided weakness
      and ever smoked to be significant predictors of more severe muscle tone.
      CONCLUSIONS: Using the models, it may be possible to predict whether or not
      spasticity will develop in patients 12 months after stroke. The utility of the
      models is aided by their use of predictor variables that are routinely collected
      as part of stroke care in hospital and which are easy to measure. The models need
      testing prospectively in a new cohort of patients in order to test their
      validity, reliability and utility and to determine if other data could improve
      their efficiency.

PMID- 15180129
TI  - Pulmonary rehabilitation programmes in the UK: a national representative survey.
AB  - BACKGROUND: Respiratory disease is a common cause of disability in middle and
      late life. Pulmonary rehabilitation programmes improve exercise capacity and
      quality of life in patients with chronic lung diseases. However, currently, in
      the UK the availability of pulmonary rehabilitation programmes and their
      characteristics are unknown. METHODS: We surveyed pulmonary rehabilitation
      programmes in terms of number, size, duration, content of educational and
      exercise programme, and staffing. We mailed a 17-item questionnaire previously
      used in Canadian study to 190 physiotherapy departments within acute hospitals in
      UK. RESULTS: One hundred and seventy-one (90%) responses were received. Sixty
      eight centres (40%) run a pulmonary rehabilitation programme (99% outpatient).
      Mean age of subjects was > or = 70 in only seven centres (10%), though most cited
      no upper age limit. Ninety-nine per cent of centres incorporated exercise
      training. Programmes recruited a median group size of 10 patients (range 4-17) at
      a given time with a median duration of eight weeks (range 5-24) weeks. Most (71%)
      run twice per week with a duration of 2 hours (63%). Only half offered smoking
      cessation support, and a minority gave advice on coping with disease, travel and
      sexual matters. CONCLUSION: Around 40% of surveyed hospitals run a pulmonary
      rehabilitation programme and most of the programmes are similar in their format,
      content and staffing. Despite the high prevalence of chronic obstructive
      pulmonary disease (COPD)-related disability in old age most programmes chiefly
      included younger subjects. This may reflect lack of referral. Greater awareness
      and expansion of availability of programmes is indicated.

PMID- 15180131
TI  - Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's
      disease.
AB  - Levodopa and the dopamine agonists are effective symptomatic treatments for
      Parkinson's disease, and all patients receive at least one of these agents during
      their illness. Long-term use of levodopa is commonly associated with motor
      complications such as dyskinesia, and both the dosing frequency and total daily
      dose of levodopa determine the rate of onset and severity. Dopamine agonists have
      gained popularity as first-line monotherapy in Parkinson's disease, as they
      effectively reverse motor deficits and reduce the risk of motor complications.
      Long-acting dopamine agonists providing continuous, rather than pulsatile,
      dopaminergic stimulation appear able to avoid dyskinesia induction. Current
      treatments act predominantly on D2 receptors, but drugs acting on both the D1 and
      D2 receptor families may produce an additive motor response, although this
      remains to be proven in patients with Parkinson's disease. Most currently used
      dopamine agonists are selective for D2-like receptors, with only pergolide and
      apomorphine potentially interacting with D1 receptor populations.

PMID- 15180130
TI  - Physical fitness in persons with hemiparetic stroke: its structure and
      longitudinal changes during an inpatient rehabilitation programme.
AB  - OBJECTIVE: To test the hypothesis that the structure of fitness in patients with
      hemiparetic stroke can be categorized into impairment/disability,
      cardiopulmonary, muscular and metabolic domains, and to study longitudinal
      changes in their fitness during an inpatient rehabilitation programme. DESIGN:
      Structure analysis of multiple fitness parameters with principal component
      analysis (PCA), and a before and after trial. SETTING: Tertiary rehabilitation
      centre in Japan. PATIENTS: One hundred and seven consecutive inpatients with
      hemiparetic stroke. INTERVENTION: A conventional stroke rehabilitation programme
      consisting of 80 minutes of physical therapy and occupational therapy sessions
      five days a week, and daily rehabilitation nursing for a median duration of 105.5
      days. MAIN OUTCOME MEASURES: Principal component scores extracted from
      measurement of paresis/daily living (the Stroke Impairment Assessment Set (SIAS)
      and the Functional Independence Measure (FIM)); muscular (grip strength (GS),
      knee extensor torque, and cross-sectional areas of thigh muscles); metabolic
      (body mass index (BMI) and fat accumulation on CT); cardiopulmonary (heart rate
      oxygen coefficient (HR-O2-Coeff) obtained with a graded bridging activity and a
      12-minute propulsion distance). RESULTS: PCA categorized the original 15
      variables into four factors corresponding to paresis/activities of daily living,
      muscular, metabolic and cardiopulmonary domains, and explained 78.1% of the total
      variance at admission and 69.6% at discharge. Except the metabolic domain, PCA
      scores for the other three domains improved significantly at discharge (paired t
      test, p < 0.05). CONCLUSION: The hypothetical structure of fitness was confirmed,
      and the PCA scores were useful in following longitudinal changes of fitness
      during inpatient rehabilitation.

PMID- 15180132
TI  - The pharmacokinetics of pergolide in Parkinson's disease.
AB  - Three decades of research have led to a fuller understanding of the
      pharmacokinetics of pergolide. Pergolide is rapidly absorbed following oral
      dosing, reaching peak plasma concentrations within 2-3 h. It is about 90% protein
      bound yet has negligible drug interactions. Pergolide undergoes extensive first
      pass metabolism and is completely eliminated within 4-5 days. The
      metabolism/elimination profile varies between patients but is consistent within
      the individual, highlighting the importance of careful titration to an effective
      dose. Pergolide has a long half-life of about 21 h; this has interesting
      implications, as it should produce a more physiological or continuous stimulation
      of dopamine receptors, avoiding or delaying the induction of dyskinesia.

PMID- 15180133
TI  - Comparing dopamine agonists in Parkinson's disease.
AB  - Dopamine agonists are effective in the management of both advanced and early
      stage Parkinson's disease. Unfortunately, randomized head-to-head comparative
      studies between the many different dopamine agonists now available are sparse.
      Indirect comparisons of dopamine agonists show that ergot derivatives, such as
      pergolide and cabergoline, are as effective as non-ergot derivatives, such as
      ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in
      patients in early or advanced stages of the condition. As far as safety and
      tolerability are concerned, no significant differences between dopamine agonists
      are found. However, some specific adverse events, such as somnolence and sleep
      attacks, seem less frequent in monotherapy studies with pergolide than in those
      with the non-ergot dopamine agonists; however, because of the lack of direct
      comparison studies this cannot be proved conclusively. Randomized, controlled
      comparative studies between dopamine agonists are necessary to verify any
      possible differences in their effectiveness and tolerability in the treatment of
      Parkinson's disease.

PMID- 15180134
TI  - Appropriate dosing of pergolide in monotherapy and adjunctive therapy in
      Parkinson's disease.
AB  - Pergolide is one of the most well-tested and widely used dopamine agonists for
      the treatment of Parkinson's disease; however, there is worrying evidence that
      sub-therapeutic dosing of pergolide is widespread in clinical practice. Clinical
      studies in Caucasians suggest that a pergolide dose of 3 mg/day provides the
      optimal efficacy to tolerability ratio and that, in Japanese patients, a dose in
      excess of 2.25 mg/day may be ideal. Whether pergolide is used early in patients
      with de-novo Parkinson's disease or as adjunctive therapy later in the disease,
      in order to optimize its clinical efficacy, it is recommended that practitioners
      aim to achieve at least these doses, or higher ones, if the drug is well
      tolerated.

PMID- 15180135
TI  - Rationale for dopamine agonist use as monotherapy in Parkinson's disease.
AB  - Dopamine agonists are increasingly being used in the initial treatment of
      patients with de-novo Parkinson's disease because they provide symptom relief and
      a low risk of the dyskinesia frequently associated with levodopa. Evidence is
      also mounting in preclinical models that dopamine agonists protect dopaminergic
      neurons from the toxic effects of oxidative stress and the by-products of
      dopamine and L-dopa metabolism. Ergot derivatives, such as pergolide, induce
      minor side-effects and provide significant and sustained improvements in motor
      function in patients with early Parkinson's disease. Dopamine agonists also
      appear to reduce the loss of functional dopamine transporters when used early in
      the disease course, and these factors combine to build a case for the use of
      dopamine agonists in early-stage Parkinson's disease.

PMID- 15180136
TI  - The charter on medical professionalism: an important issue that concerns us all.

PMID- 15180137
TI  - Enhancing vision care integration: 1. Development of practice algorithms.
AB  - BACKGROUND: Appropriate access to the best quality of vision care is enhanced
      when patients receive eye care services from the right professional, at the right
      time, and in the right place. This paper, the first in a two-part series,
      describes the development of an integrated framework for vision care delivery.
      Specifically, two patient-centred vision care algorithms for the
      multidisciplinary management of diabetic retinopathy and the red eye are
      outlined, and the process that resulted in their development is described.
      METHODS: The method used relies on a description of a multidisciplinary
      collaboration that occurred among ophthalmologists, optometrists, general
      practitioners and representatives of the Nova Scotia Department of Health with
      the aim of developing an integrated patient-focused multidisciplinary framework
      for vision care delivery. RESULTS: The process of collaborative negotiation among
      the four groups resulted in the development of multidisciplinary algorithms for
      the screening of patients with diabetes mellitus and the treatment of those
      presenting with a red eye. INTERPRETATION: Professional scope of practice has
      always been a contentious issue among health care professions. However, where
      parties agree to work within an atmosphere of respect and to accept guidance in
      areas of disagreement from a third party respected by all, compromise is
      possible. The result was the development of two vision care algorithms and
      ongoing efforts on the development of other algorithms.

PMID- 15180138
TI  - Enhancing vision care integration: 2. Implementation of practice algorithms.
AB  - BACKGROUND: Appropriate access to the best quality of vision care is enhanced
      when patients receive eye care services from the right professional, at the right
      time, and in the right place. In the preceding article the authors describe the
      development of two patient-centred vision care algorithms for the
      multidisciplinary management of diabetic retinopathy and red eye. Subsequently, a
      questionnaire survey was done to determine ophthalmologist, optometrist and
      general practitioner (GP) familiarity with and acceptance of the vision care
      algorithms. METHODS: The survey was conducted in the summer of 2001 among all
      ophthalmologists, optometrists and GPs registered with their respective
      professional body in Nova Scotia to assess their knowledge and acceptance of the
      diabetes mellitus and red eye algorithms. They were also asked to indicate their
      preferred method(s) of education and dissemination regarding these and future
      algorithms. RESULTS: Of the 740 practising GPs in Nova Scotia, 188 completed the
      questionnaire, for a response rate of 25.4%. The corresponding figures for
      optometrists and ophthalmologists were 73.6% (53/72) and 43.5% (20/46)
      respectively. Most of all three types of clinicians practise in Halifax County.
      More than 80% of the optometrists and ophthalmologists were aware of the
      algorithms, but less than 50% of the GPs were aware of them. A large majority of
      respondents in all three groups (77% to 98%) indicated that they were comfortable
      using the diabetes and red eye algorithms as presented. INTERPRETATION:
      Ophthalmologists, optometrists and GPs indicated an understanding of and
      willingness to use the diabetes and red eye algorithms. However, they were not
      unanimous regarding the choice of implementation method. Therefore, six different
      strategies for implementing the vision care algorithms are currently being used
      and are described in the paper.

PMID- 15180139
TI  - Intraocular pressure spike after YAG iridotomy in patients with pigment
      dispersion.
AB  - BACKGROUND: The role of laser peripheral iridotomy to break a suspected reverse
      pupil block in the long-term control of pigment dispersion is promising, but the
      usefulness of this procedure has not been completely established. The author
      examined whether patients with pigment dispersion are at higher risk for an
      intraocular pressure (IOP) spike after laser peripheral iridotomy due to possible
      compromise of trabecular meshwork function, compared with patients undergoing
      prophylactic peripheral iridotomy for an occludable angle. METHODS: Data were
      collected prospectively on the first eye of 87 patients with occludable angles
      and 13 patients with pigment dispersion treated with peripheral laser iridotomy
      between November 1995 and October 1996 at the glaucoma service of a university
      affiliated hospital in Toronto. All patients received one drop of 0.5%
      apraclonidine before the procedure. IOP was measured before and 1 and 24 hours
      after the procedure. RESULTS: There was no difference between the two groups in
      the distribution of right vs. left eyes, sex, race, the mean total energy
      required to produce a patent iridotomy, the mean number of medications used or
      the mean IOP before the procedure. The patients with pigment dispersion were
      significantly younger than those with occludable angles (mean age [and standard
      deviation (SD)] 40.5 [9.45] years vs. 66.4 [10.78] years) (p < 0.001). There was
      no difference between the two groups in mean IOP at 1 hour or at 24 hours. Twenty
      nine patients (33%) in the occludable angle group and seven (54%) in the pigment
      dispersion group had an IOP spike greater than 2 mm Hg after the procedure (p =
      0.001). Among these patients, the mean IOP (36.4 [SD 10.83] mm Hg vs. 30.3 [SD
      7.04] mm Hg, p = 0.05) and the mean rise in IOP (14.0 [SD 10.63] mm Hg vs. 8.7
      [SD 4.73] mm Hg, p = 0.04) were significantly higher in those with pigment
      dispersion than in those with occludable angles. Among the patients who used
      antiglaucoma medications before the procedure or had a prelaser IOP level greater
      than 22 mm Hg, those with pigment dispersion were more likely than those with
      occludable angles to have an IOP spike at 1 hour (p < or = 0.005).
      INTERPRETATION: Patients with pigment dispersion undergoing iridotomy to break a
      reverse pupil block should be carefully assessed after the procedure, as
      significant pressure spikes requiring treatment may occur.

PMID- 15180140
TI  - The use of RADAAR (ratio of rim area to disc area asymmetry) in detecting
      glaucoma and its severity.
AB  - BACKGROUND: In a previous study it was shown that the asymmetry of rim area and
      disc area of fellow eyes expressed as a ratio (rim area to disc area asymmetry
      ratio [RADAAR]) was associated with the diagnosis of glaucoma in patients with
      highly asymmetric disease. Furthermore, this ratio was able to distinguish these
      patients from groups of glaucoma suspects and subjects without glaucoma. The
      purpose of this study was to investigate whether the RADAAR correlates with the
      diagnosis and severity of glaucoma in a large glaucomatous population. METHODS:
      We reviewed the records of 140 randomly selected patients with open-angle, normal
      tension or pseudoexfoliative glaucoma evaluated at the glaucoma service of a
      tertiary care centre in Philadelphia between January 1996 and April 2000.
      Heidelberg Retina Tomograph (HRT) disc area, rim area, cup-to-disc area ratio,
      pattern-standard deviation and mean deviation as well as maximum intraocular
      pressure (IOP) were recorded. Disc staging and visual fields determined severity
      of glaucoma, and fellow eyes were classified as "better" or "worse." RESULTS: The
      RADAAR was significantly correlated with IOP (r = 0.23, p < 0.03), mean deviation
      (r = -0.22, p < 0.02), cup-to-disc area ratio (r = 0.19, p < 0.03) and disc stage
      of glaucomatous optic nerve damage (r = 0.17, p < 0.05) in "worse" eyes. RADAAR
      groups were also correlated with fellow-eye differences in mean deviation (p <
      0.05) and cup-to-disc area ratio (p < 0.02). INTERPRETATION: The RADAAR, a new
      HRT-derived measure of asymmetry in fellow eyes, is associated with the diagnosis
      of glaucoma and its severity.

PMID- 15180141
TI  - Pseudophakic cystoid macular edema: ketorolac alone vs. ketorolac plus
      prednisolone.
AB  - BACKGROUND: Pseudophakic cystoid macular edema (CME) following
      phacoemulsification is the most common complication after cataract surgery.
      Treatment focuses on the reduction of inflammation with topical use of both
      steroids and NSAIDS. The latter have been shown to be of benefit in chronic CME,
      but topical NSAID and steroid treatment has only recently been shown to be of
      benefit in acute CME. We evaluated the use of topically administered NSAIDS and
      steroids in the management of both acute and chronic pseudophakic CME. METHODS:
      This was a prospective double-masked randomized controlled trial. Patients with
      clinical CME occurring at least 6 weeks following cataract extraction were
      referred for consideration of enrolment. Patients were excluded if they had
      Snellen vision better than 20/40, no CME on clinical examination, no CME on
      angiography, recent use of steroids, preexisting macular disease or diabetic
      maculopathy on angiography. Ten patients were randomly assigned to receive either
      0.5% ketorolac tromethamine plus placebo (four patients) or 0.5% ketorolac
      tromethamine plus 1% prednisolone acetate (six patients); all 10 completed the
      study. Patients were assessed at baseline and at 30, 60 and 90 days. Fluorescein
      angiography was performed at baseline and at 90 days. The primary outcome
      measures were improvement in Early Treatment Diabetic Retinopathy Study Snellen
      equivalent vision and resolution of cysts on clinical examination. RESULTS: No
      statistically significant differences were found between the two groups in either
      of the outcome measures at any visit. Subgroup analysis of the patients with
      chronic CME also showed no significant difference between the two groups.
      INTERPRETATION: We found no statistically significant difference in outcome
      between patients who received ketorolac and those who received ketorolac plus
      prednisolone for acute or chronic CME. The value of topical steroid therapy for
      chronic CME remains unproven.

PMID- 15180142
TI  - Internal limiting membrane: ultrastructural relationships, with clinical
      implications for macular hole healing.
AB  - BACKGROUND: Recent data on macular hole formation have changed our understanding
      of the mechanisms involved. However, the mechanisms of macular hole closure,
      despite the introduction of internal limiting membrane (ILM) removal, are not
      fully understood. We reviewed the charts of patients who underwent surgery for
      macular hole with and without intentional removal of ILM and reviewed the basic
      science literature on the components and relationships of the ILM-glial cell
      interface to help interpret our surgical data. METHODS: We reviewed the records
      of 205 eyes with a clinical diagnosis of macular hole at a university centre in
      Montreal between 1998 and 2002. Of these, 117 eyes of 108 patients were included.
      Vitrectomy with intentional ILM removal was done under indocyanine green (ICG)
      staining. Macular hole stage and rates of hole closure, failure and reopening
      were recorded, comparing the eyes with intentional ILM peeling versus no ILM
      peeling. Anatomic success was defined as a flat/closed configuration. A basic
      science literature review was done through the PubMed search engine with the key
      words "internal limiting membrane," "internal limiting lamina," "macular hole,"
      "retinal glial cells" and "retinal Muller cells." RESULTS: Eighty-four eyes had
      ICG-guided ILM removal (26 stage 2 macular holes, 45 stage 3 holes and 13 stage 4
      holes), and 33 eyes had no ILM removal (10 stage 2 holes and 23 stage 3 holes).
      Of the 117 eyes 110 (94.0%) were successfully closed. Four (3.6%) of the closed
      holes reopened (none had ILM peeling), and 7 (6.0%) of the 117 eyes had primary
      failure. Ten of the 11 eyes that had primary failure or hole reopening were
      reoperated, and 8 were successfully closed after the second procedure. One
      patient refused reoperation. Including second procedures, the final anatomic
      closure rate was 97.4% (114/117). INTERPRETATION: Intentional ILM peeling is not
      mandatory for all macular holes to close but does play a role in preventing
      reopening. Removal of ILM increases the rate of flat/closed hole configuration on
      reoperation without the need for biologic adjuvants. Review of the basic science
      evidence helped clarify the possible role of ILM removal.

PMID- 15180143
TI  - Visual prognosis in patients with traumatic choroidal rupture.
AB  - BACKGROUND: There is a paucity of work in the literature examining the long-term
      visual prognosis of patients with choroidal ruptures. We performed a study to get
      a better assessment of long-term visual recovery in these patients as well as to
      identify prognostic indicators. METHODS: We reviewed the charts of 32 patients
      who experienced traumatic choroidal rupture following blunt ocular trauma. All
      charts contained International Classification of Diseases code 363.63 (choroidal
      rupture). For inclusion in the study, the chart had to contain detailed drawings
      or photographic evidence that could confirm the presence and location (foveal,
      juxtafoveal or extrafoveal) of the choroidal rupture. In addition, demographic
      data and visual acuity on follow-up examinations had to be present. The mechanism
      and location of the injury, initial and final visual acuity, associated ocular
      findings and length of follow-up were recorded. RESULTS: Of the 32 eyes 31 had
      indirect choroidal ruptures and I had a direct rupture. The mean final visual
      acuity values in the foveal, juxtafoveal and extrafoveal subgroups were 20/68,
      20/35 and 20/60 respectively after a mean duration of follow-up of 4.5, 3.5 and
      4.4 years respectively. There was no statistically significant difference in mean
      final visual acuity or mean length of follow-up between the three groups. The
      eight patients with multiple choroidal ruptures had a mean final vision of 20/31
      after a mean follow-up period of 3.8 years. The 24 patients with a single
      choroidal rupture achieved a mean final vision of 20/47 over a mean duration of
      follow-up of 4.1 years. There was no difference in final vision or in length of
      follow-up between the two groups. The six patients under 15 years of age attained
      a mean final vision of 20/34 over a mean follow-up period of 4.5 years, whereas
      the adult group achieved a mean final vision of 20/44 over a mean follow-up
      period of 3.8 years. Again, there was no difference in final vision or in length
      of follow-up between the two groups. INTERPRETATION: Traumatic choroidal rupture
      involving the fovea has been thought to have a poor visual prognosis. Our
      findings show that eyes with foveal choroidal ruptures may regain good central
      vision over longer follow-up. Furthermore, multiple choroidal ruptures do not
      necessarily predict a poor visual outcome. Children with choroidal ruptures
      attained good final visual outcomes.

PMID- 15180144
TI  - Strabismus after regional anesthesia for cataract surgery.
AB  - BACKGROUND: An adult strabismus clinic in a regional eye centre provided an
      opportunity to estimate the risk of postoperative diplopia from regional
      anesthesia after cataract surgery and to describe the management of these
      patients. METHODS: Retrospective cohort analysis. All cases were referred over a
      22-month period (November 1997 to September 1999) for investigation of
      postoperative diplopia after cataract surgery. The surgical and anesthetic
      records were reviewed to determine the number and location of injections, and the
      volume and type of regional anesthesia. The evolution and management of patients'
      diplopia was studied prospectively. RESULTS: Twenty-one patients (12 women and 9
      men aged 63 to 88 [median 76] years) were ascertained with postoperative
      diplopia. In 11 cases the right eye was affected, and in 10 cases, the left eye.
      Vertical diplopia occurred most commonly from inferior rectus restriction (16
      cases). Three cases resolved without treatment, which indicated that the diplopia
      was transient. Four patients declined treatment, five required prism in
      eyeglasses only, and nine required strabismus surgery. One patient required
      surgery and prism in eyeglasses. Two patients required more than one strabismus
      operation to relieve the diplopia. For the period of data collection, we estimate
      the risk of nontransient postoperative diplopia from regional anesthesia as 2.6
      cases per 1000 cataract procedures (95% confidence interval 1.9-4.7).
      INTERPRETATION: Patients should be forewarned of the risk of diplopia after
      cataract surgery with regional anesthesia. The treatment of the diplopia may
      require prism in eyeglasses or strabismus surgery or both.

PMID- 15180145
TI  - Phenotypic variations in patients with a 1630 A>T point mutation in the PAX6
      gene.
AB  - BACKGROUND: The extreme clinical case-to-case variability of aniridia, even
      within families, can cause difficulties in making the correct diagnosis,
      prognosis and treatment plan. We describe seven patients from two families
      demonstrating variable expression of this syndrome, all with the same single
      point mutation within the PAX6 gene. METHODS: Case presentations. The authors
      review the clinical ophthalmic findings of the aniridia-keratopathy syndrome from
      two families, one involving four generations, the other with two generations.
      Polymerase chain reaction amplification of all 14 exons of the PAX6 gene was
      performed for five patients. RESULTS: The iris findings varied from classic total
      absence to nearly normal iris appearance. Corneal changes were minimal in the
      younger patients but vision-impairing in the older. None of the patients had
      glaucoma. The five patients who underwent DNA analysis shared the same PAX6 point
      mutation defect (1630A>T). INTERPRETATION: Bilateral corneal changes progressing
      from mild opacification at the limbus to vascularized central keratopathy,
      especially in the presence of nystagmus, are highly suggestive of a PAX6
      mutation. Such patients may theoretically benefit from early limbal stem cell
      replacement therapy.

PMID- 15180146
TI  - An intraocular cilium of uncertain origin.

PMID- 15180147
TI  - Atypical presentation of traumatic globe rupture.

PMID- 15180148
TI  - Management of ophthalmomyiasis externa: case report.

PMID- 15180149
TI  - Central retinal artery occlusion as the initial ophthalmic presentation of
      Susac's syndrome.

PMID- 15180150
TI  - Effect of aeration on gliotoxin production by Aspergillus fumigatus in its
      culture filtrate.
AB  - Gliotoxin, one of the mycotoxins produced by Aspergillus fumigatus, has various,
      potent bioactivities. However, it has not been considered to be a toxic (or
      virulence) factor because of its slow production. The aim of the present study
      was to investigate the effects of aeration on the cytotoxicity of A. fumigatus
      culture filtrate, and to determine the optimal condition for the rapid production
      of gliotoxin from this fungus. Fungal culture filtrates were made in three
      different containers under various conditions of aeration and O2 concentration.
      These filtrates were compared in terms of their cytotoxicity on murine
      macrophages and analyzed by gas chromatography. The culture filtrate showed high
      cytotoxicity when it was made under highly aerated conditions, but it was
      significantly less cytotoxic when prepared under non-aerated conditions. The
      cytotoxic activity became evident within 15 h of culture at 20% O2, when the
      fungus had already started producing gliotoxin. The culture filtrates also
      contained some other as yet unidentified substances that might also to some
      extent contribute to the cytotoxicity. In light of these results, the authors
      propose that a highly aerated condition is responsible for the rapid production
      of gliotoxin, and that gliotoxin might play an important role in the respiratory
      infection by A. fumigatus, with other toxic substances acting additively or
      synergistically.

PMID- 15180152
TI  - First isolation of Cryptococcus magnus from a cat.
AB  - A 6-month-old male Japanese domestic cat with otitis externa due to Aspergillus
      fumigatus was treated with antifungal agents for 25 days and appeared to be
      cured. Many yeast colonies however developed from the ear canal samples on
      Sabouraud's dextrose agar at 27 degrees C for 5 days, instead of A. fumigatus.
      This yeast colony was cream-colored and slim in texture with smooth and highly
      glossy surface after 5-day incubation on Sabouraud's dextrose agar at 27 degrees
      C. The isolate was identified as Cryptococcus magnus by mycological analysis and
      28S ribosomal analysis.

PMID- 15180151
TI  - Prevalence and exoenzyme secretion by Candida albicans isolates from oral and
      vaginal mucosas of HIV-infected women.
AB  - A cross-sectional study was performed to evaluate the prevalence and the
      aetiology of forms of mucosal fungal infections of HIV-negative and HIV-positive
      women. Candida albicans was the predominate specie isolated from both groups of
      patients, with remarkable proportion of isolation from symptomatic women. All 239
      C. albicans isolates, regardless of their source, showed activity of proteinase
      and phospholipase. It was verified that isolates with particularly higher levels
      of exoenzymes production were significantly more common in HIV-positive patients.
      However, isolates obtained from the HIV-positive patients in use of HAART, with
      protease inhibitor, presented lower levels of these exoenzymes, similar to the
      levels observed in the isolates from HIV-negative patients.

PMID- 15180153
TI  - Isolation of dermatophytes and other keratinophilic fungi from the vicinity of
      salt pan soils of Mumbai, India.
AB  - Soil samples from twenty salt pans and their vicinity around Mumbai and Thane
      were screened for the occurrence of keratinophilic fungi and related
      dermatophytes. Ten species classified in six genera were recovered using horse
      hair as bait. The isolated species were reported in the following order of
      dominance: Chrysosporium indicum (12.0%), Microsporum gypseum complex (7.2%), C.
      tropicum (5.6%), C. state of Ctenomyces serratus (4.0%), Trichophyton terrestre
      (3.2%), Malbranchea aurantiaca (2.4%), C. fluviale (1.6%), Uncinocarpus reesii
      (1.6%), Malbranchea sp. (0.8%), and T. mentagrophytes (0.8%).

PMID- 15180154
TI  - Pulmonary aspergillosis outbreak in Rhea americana in southern Brazil.
AB  - Commercial raising of rheas is currently in expansion in the south of Brazil, and
      many diseases previously restricted to other avian species are currently emerging
      on rhea farms, especially as a result of careless management of these animals.
      The objective of the present article is to report a pulmonary aspergillosis
      outbreak that occurred in great rhea (Rhea americana) in the south of Brazil.
      About 50 birds aged 30 to 60 days died suddenly and one of them was submitted to
      autopsy which revealed the presence of white caseous nodules 0.5 mm in diameter
      occupying 95% of the lung area. One lung was sent to the Federal University of
      Santa Maria for histopathological and mycological analyses. Histopathological
      analysis revealed multifocal areas with necrosis and inflammatory infiltrates and
      the presence of fungal hyphae, giant cells and fibrous tissue proliferation at
      the periphery. Aspergillus fumigatus was recovered as pure culture from all
      culture media. This appears to be the first report of aspergillosis among great
      rhea in Brazil and the second in the world.

PMID- 15180155
TI  - Dermatomycoses caused by Nattrassia mangiferae in Sao Paulo, Brazil.
AB  - Nattrassia mangiferae formerly known as Hendersonula toruloidea, is a phaeoid
      coelomycete described by Nattrass in 1933. We report five cases of N. mangiferae
      infections in Sao Paulo, Brazil. This fungus was isolated from interdigital
      lesions on the feet in one patient, toenails in three cases and fingernails in
      the other one. The infections were initially considered to be caused by a
      dermatophyte. Although there are only a few cases described in the medical
      literature, the five cases reported suggest that N. mangiferae should be taken
      into consideration in the differential diagnosis of tinea pedis infections.

PMID- 15180156
TI  - Lignocellulolytic enzyme production by aquatic hyphomycetes species isolated from
      the Nile's delta region.
AB  - Twenty-six species of aquatic hyphomycetes were isolated from woody sources
      (unidentified wood segments, leaf skeletons and neck of leaves and bark) in the
      North River Nile (Delta region). Alatospora acuminata, Anguillospora crassa,
      Flagellaspora penicillioides, Lunulospra curvula, Tetracladium marchalianum and
      Triscelophorus monosporus were the most common species. Temperature was the
      highest physico-chemical parameter affecting the aquatic hyphomycetes occurrence.
      Twelve species of hyphomycetes, isolated from woody substrates, were screened for
      their ability to produce extracellular lignocellulolytic enzymes on solid media.
      The enzymes tested included: endoglucanase, endoxylanase, beta-glucosidase,
      laccase, peroxidase, polyphenoloxidase, tyrosinase and beta-xylosidase. Three
      species, A. acuminata, F. penicillioides, T. monosporus, were positive for all
      tested enzymes. Also, A. longissima was positive for all enzymes except lignin
      peroxidase. The ability to produce cellulase was 100% for all species while only,
      four species were positive for lignin-peroxidase. The ability of the species to
      produce other lignocellulotic enzyme ranged from 50% to 83%. Freshwater
      hyphomycetes have been shown to produce a rich array of enzymes able to degrade
      the polysaccharides of plant debris.

PMID- 15180157
TI  - Onychomycosis caused by Fusarium solani and Fusarium oxysporum in Sao Paulo,
      Brazil.
AB  - Fusarium species are common soil saprophytes and plant pathogens that have been
      frequently reported as etiologic agents of opportunistic infections in humans. We
      report eight cases of onychomycosis caused by Fusarium solani (4) and Fusarium
      oxysporum (4) in Sao Paulo, Brazil. These species were isolated from toenails in
      all cases. The infections were initially considered to be caused by
      dermatophytes. The clinical appearance of the affected toenails was leukonychia
      or distal subungual hyperkeratosis with yellowish brown coloration. The eight
      cases reported here suggest that Fusarium spp. should be taken into consideration
      in the differential diagnosis of tinea unguium.

PMID- 15180158
TI  - Histopathology of Sclerotinia sclerotiorum attack on flower parts of Helianthus
      annuus heads in tolerant and susceptible varieties.
AB  - Sunflower head rot is a major disease caused by Sclerotinia sclerotiorum.
      Sunflower varieties which are tolerant to the fungus have been developed. The
      changes occurring in flower parts at different times after inoculation with
      pathogen ascospores were studied for two sunflower varieties (tolerant HA 302 and
      susceptible HA 89). In variety HA 302 there was cell collapse, changes in cell
      wall composition, and an increase in phenolic compounds in the tissues of corolla
      and style, which prevented the pathogen from advancing. This response was weaker
      in susceptible variety HA 89, and occurred only in the style, so did not stop the
      pathogen from developing and reaching the ovary. Phenolic compounds were found in
      HA 302 corolla and style tissues only when the pathogen was present, constituted
      an induced response that prevented further development of the fungus. Principal
      component analysis (PCA) showed that at the beginning of the infection there was
      no difference in behavior between the two varieties. The difference arose during
      the final observation times, when in variety HA 89, the pathogen colonized ovary,
      style and base of filaments and produced noticeable colonization of the corolla.

PMID- 15180159
TI  - Frequency and diversity of fungi colonizing tissues of upland cotton.
AB  - A study of the mycoflora of upland cotton in Alabama was conducted throughout the
      2000 and 2001 growing seasons. Plants were sampled at seedling, first bloom, full
      bloom, and maturity stages of development. Thirty-seven genera representing 58
      species of fungi were isolated, including 9 species of Fusarium. Fusarium
      oxysporum, F. solani, and F. equiseti were the most common members of this genus
      occurring at all four sampling stages in both years. Eight species accounted for
      67% of the total fungi isolated during the two-year study. Alternaria alternata
      was the most common fungus encountered, accounting for 19 and 10% of the total
      fungi isolated in 2000 and 2001, respectively. Twenty species of fungi are
      reported for the first time colonizing upland cotton tissues.

PMID- 15180160
TI  - Intraspecific diversity within Diaporthe helianthi: evidence from rDNA intergenic
      spacer (IGS) sequence analysis.
AB  - Diaporthe helianthi is the causal agent of sunflower stem canker, a serious
      pathogen of sunflower in Europe but recorded sporadically in Italy. The genetic
      diversity of D. helianthi isolates from different geographic origins (Argentina,
      France, Italy, Yugoslavia, Romania) was investigated using IGS sequences. A 400
      bp fragment of the portion of the IGS region flanking the 5' end of the 18S gene
      was amplified from each isolate. The aligned nucleotide sequences showed
      intraspecific sequence homology from 99-100% among French/Yugoslavian isolates to
      95-100% among Italian isolates. French/Yugoslavian isolates shared 90-92%
      sequence homology with Italian isolates. The phylogenetic tree obtained from the
      aligned data revealed three separate groups. Group 1 included all isolates from
      France and former Yugoslavia and one isolate from Argentina; Group 2 included all
      Italian isolates and one isolate from Argentina. The most distantly related
      isolate was that from Romania (Group 3). The average genetic distances among
      isolates within Group 1 and within Group 2 were 0.22 and 3.29 respectively. The
      analysis showed that all isolates originating from countries where severe
      outbreaks of the disease are reported annually (France and former Yugoslavia)
      form a well defined taxon characterized by relatively low variability. This group
      is distinct from the group formed by isolates originating from Italy, whose
      variability is relatively much higher. Results obtained revealed a marked
      differentiation among pathogen isolates, and members of Group 1 seem not yet to
      have spread into Italian sunflower-growing areas.

PMID- 15180161
TI  - Foliar blight of Roselle and its effect on yield in tropical forest region of
      southwestern Nigeria.
AB  - The etiology of foliar blight of roselle and its effect on yield in the tropical
      forest of southwestern Nigeria was investigated. More than 40% of leaves of
      roselle plants in fields under continuous cultivation (endemic plots) were
      blighted by Phyllosticta hibiscini. However, no infection was found on roselle
      plants in fields never previously planted with roselle. Over 20% leaf yield loss
      and over 34% edible leaf loss were due to leaf blight. The mean marketable and
      biological yield loss of calyces in 1999 and 2000 were 35% and 38% respectively,
      while seed yield loss was 30% and 32%.

PMID- 15180162
TI  - Expression of pectinase activity among Aspergillus flavus isolates from
      southwestern and southeastern United States.
AB  - Aspergillus flavus is a widely distributed filamentous fungus that contaminates
      crops with the potent carcinogen aflatoxin. This species can be divided into S
      and L strains on the basis of sclerotial morphology. During crop infection, A.
      flavus can secrete a large array of hydrolytic enzymes. These include pectinase,
      which aids fungal spread through plant tissues. A survey of pectinase expression
      by soil isolates derived from different regions of the United States revealed
      geographic polymorphisms. Strain L isolates from Arizona produced moderate to
      high levels of a specific pectinase P2c, while S strain isolates produced
      variable amounts of P2c. In contrast, L strain isolates from southeastern U.S.
      yielded variable P2c production, while S strain isolates consistently expressed
      high P2c levels. These results were corroborated by pectinase surveys of
      additional collections of A. flavus from soil and cottonseed. Expression patterns
      for P2c and pectinmethylesterase were evaluated for a select number of isolates
      using an isoelectric focusing technique. Clear zone reactions from the pectinase
      plate assay corresponded to the presence of P2c, while red ring reactions
      corresponded to the lack of P2c. Commercial cottonseed infected by S strain
      isolates frequently contained aflatoxin, even when infected by S strain isolates
      that did not produce pectinase P2c. Thus, although P2c-lacking isolates have
      reduced invasiveness, these isolates still have sufficient pathogenicity to cause
      aflatoxin contamination.

PMID- 15180164
TI  - Penitrem and thomitrem formation by Penicillium crustosum.
AB  - The levels of penitrems A, B, C, D, E, F, roquefortine C and thomitrem A and E
      recovered from extracts of 36 Norwegian, 2 American and one each of Japanese,
      German, South African, Danish and Fijian isolates of Penicillum crustosum Thom
      were quantitatively determined using high performance liquid chromatography-mass
      spectrometry (HPLC-MS). Forty-two of the 44 isolates of penitrem-producing
      isolates grown on rice, afforded levels of thomitrem A and E comparable to that
      of penitrem A. Thomitrems A and E were also found, but at lower levels, when
      cultures were grown on barley. No thomitrems were found when the isolates were
      grown on liquid media. The effects of time and temperature on mycotoxin formation
      were studied on rice over a 4 week period at 10, 15 and 25 degrees C,
      respectively. No mycotoxins could be detected after 1 week at 10 degrees C, but
      after 2 weeks at 10 degrees C levels were similar to those produced at 15 and 25
      degrees C. Higher levels of thomitrems A and E were detected when media were
      maintained at lower pH. The possibility that thomitrems A and E might be derived
      by acid promoted conversion of penitrems A and E was explored in stability trials
      performed at pH 2, 3, 4, 5 and 7 in the presence and absence of media. Thomitrems
      were formed at pH 2, 3 and 4 but not at pH 5 and 7.

PMID- 15180163
TI  - Inhibition of serine palmitoyltransferase by myriocin, a natural mycotoxin,
      causes induction of c-myc in mouse liver.
AB  - Myriocin, a fungal metabolite isolated from Myriococcum albomyces, Isaria
      sinclairi, and Mycelia sterilia, is a potent inhibitor of serine
      palmitoyltransferase (SPT), a key enzyme in de novo synthesis of sphingolipids.
      To evaluate the biological effects of myriocin in vivo, we investigated the
      levels of free sphingoid bases and expression of selected genes regulating cell
      growth in mouse liver. Male Balb/c mice, weighing 22 g were injected
      intraperitoneally with myriocin at 0, 0.1, 0.3, and 1.0 mg kg(-1) body weight
      daily for 5 days. Animals were euthanized 24 hours after the last treatment.
      Levels of plasma alanine aminotransferase and aspartate aminotransferase were not
      significantly altered by the treatment. A dose-dependent decrease in free
      sphinganine but not sphingosine was detected by high performance liquid
      chromatography in both liver and kidney. The decrease of free sphinganine
      paralleled the decrease in SPT activity. Reverse transcriptase polymerase chain
      reaction analysis on liver mRNA revealed an increase in expression of c-myc, but
      no changes in tumor necrosis factor alpha, transforming growth factor beta, and
      hepatocyte growth factor. Results showed that myriocin blocked de novo synthesis
      of sphingolipids in vivo by SPT inhibition and induced c-myc expression in liver.

PMID- 15180165
TI  - Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial
      occlusive disease (PAOD)--a review based on randomized, controlled studies.
AB  - OBJECTIVE: The present review gives an overview and evaluation of clinical
      studies proving the efficacy of EGb 761 in patients with PAOD. METHODS: Relevant
      original papers and reports on this topic were identified by means of a
      literature search. Only randomized, double-blind, placebo-controlled clinical
      trials in patients with the indication peripheral arterial occlusive disease in
      stage II according to Fontaine were included (only treatment with the oral form
      of EGb 761). For the selected studies the ratio theta of the walking distance
      between EGb 761 and placebo was calculated and a test for relevant superiority of
      EGb 761 was performed (according to the guidelines of the Deutsche Gesellschaft
      fur Angiologie (German Society of Angiology) [Heidrich et al. 1996]).
      Furthermore, a pooled estimation of the ratio was carried out. RESULTS: Nine
      studies complied with the criteria. The methodological quality and design of the
      trials were heterogeneous. In the majority of the studies, there was an advantage
      of EGb 761 in the increase of pain-free walking distance compared to placebo. For
      7 studies, the advantage was found to be statistically significant. Testing the
      relevant superiority showed a significant result in 6 of the selected studies.
      The pooled estimator of the ratio amounts to theta = 1.23 (95% CI: 1.16, 1.31)
      and demonstrates the efficacy of EGb 761 over placebo as well. CONCLUSIONS: This
      review confirms the efficacy of Ginkgo biloba special extract EGb 761. It
      demonstrates not only the statistical significance of the difference with respect
      to placebo but also the clinical relevance for the treatment of patients with
      PAOD.

PMID- 15180166
TI  - Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype.
AB  - The metabolism of acetaminophen (paracetamol) is thought to be altered in
      patients with Gilbert's syndrome (GS), a chronic unconjugated hyperbilirubinemia.
      The underlying cause of GS is a polymorphism in the promotor region of the
      uridine diphosphate glucuronosyltransferase isoform 1A1 gene (UGT1A1*28), its
      encoded enzyme being responsible for the glucuronidation of bilirubin and
      presumably acetaminophen. Decreased enzyme activity results in elevated bilirubin
      levels and may activate various metabolic pathways leading to higher amounts of
      potentially hepatotoxic acetaminophen metabolites. Patients with GS might be more
      susceptible to unexpected side effects while taking acetaminophen and other drugs
      which are substrates of UGT1A1. The possibility of a correlation between
      glucuronidation capacity with respect to acetaminophen, UGT1A1 promotor
      polymorphism and the bilirubin serum level were investigated in 23 healthy male
      volunteers selected for UGT1A1 genotype (6 wildtypes, 9 mutants and 8
      heterozygotes). One gram acetaminophen was administered p.o. and urine was
      collected over 2 4-hour periods. Unchanged acetaminophen and its glucuronide
      metabolite were determined using HPLC. The metabolic ratios unchanged
      acetaminophen/acetaminophen glucuronide in UGT1A1-wildtypes, heterozygotes and
      mutants showed no statistically significant differences. An association between
      metabolic ratio and serum bilirubin level could not be detected in any of the
      urine collection periods. These data confirm that there is no correlation between
      the capacity to glucuronidate acetaminophen, the UGT1A1 genotype and the
      bilirubin serum level. Acetaminophen is likely to be substrate of a UGT isoform
      other than the UGT1A1.

PMID- 15180167
TI  - CYP1A1 alleles in women with focal nodular hyperplasia of the liver (FNH).
AB  - OBJECTIVE: Disorders of steroid hormone metabolism might be related to the
      etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor,
      especially prevalent in women. The cytochrome P450 1A1 (CYP1A1) enzyme is
      implicated in the bioactivation of multiple precarcinogens as well as in the
      metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with
      altered catalytic activity in the hydroxylation of sex hormones and this may
      account for interindividual variability in exposure to hormone-mediated cell
      proliferation signals and reactive steroid metabolites. In the study at hand, we
      aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4
      alleles and FNH. METHOD: Genotyping of 26 affected female patients of Caucasian
      origin was carried out using PCR/RFLP. RESULTS: Allele frequencies for the CYP1A1
      variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and
      0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95%
      CI 0.23-2.44), 0.72 (95% CI 0.10-5.34) and 1.96 (95% CI 0.59-6.50), respectively.
      There were no significant differences between these values and corresponding
      allele frequencies obtained in a large German sample of unaffected Caucasian
      women. CONCLUSION: The present data do not suggest a relevant association between
      CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female
      Caucasians.

PMID- 15180168
TI  - Changes in hemorheological and biochemical parameters following short-term and
      long-term smoking cessation induced by nicotine replacement therapy (NRT).
AB  - OBJECTIVES: Cigarette smoking causes cardiovascular (CV) disease, but the
      relative roles of nicotine and other components of tobacco smoke remain unclear.
      We investigated the effect of stopping smoking by using nicotine replacement
      therapy (NRT) on hemorheology parameters, on the cotinine and thiocyanate plasma
      concentrations and the exhaled carbon monoxide (CO). DESIGN: Open, parallel-group
      trial (intervention group and control smokers). SUBJECTS: 197 males, aged 25-45
      years, smoking > 20 cigarettes per day (cpd). INTERVENTIONS: 164 subjects were
      instructed to stop smoking and received NRT for 12 weeks and 33 acted as
      controls. After 12 weeks, NRT was discontinued and all subjects were followed-up
      at 26 weeks. Beginning with week 4, the treated subjects were divided into
      abstainers (self-reported, verified by exhaled CO < 10 ppm) and nonabstainers,
      not able to stay abstinent since baseline. The group of the nonabstainers was
      stratified in 2 subgroups, the reducers (smoked < 50% of baseline number of cpd)
      and relapsers (smoked 50-100% of baseline cpd). MAIN OUTCOME MEASURES: Plasma
      viscosity, erythrocyte deformability, fibrinogen, transcutaneous partial oxygen
      tension (tcpO2), hematocrit, white blood cells, cotinine and thiocyanate plasma
      concentrations and exhaled CO, all assessed at 4, 8, 12 and 26 weeks. RESULTS:
      After 6 months, plasma fibrinogen (228.2 vs. 275.4 mg/dl at baseline, p < 0.001),
      tcpO2 (50.4 vs. 34.9 mm mercury at baseline, p < 0.0001) were significantly
      improved in abstainers, but changes in plasma viscosity and erythrocyte
      deformability were inconclusive. Cotinine and thiocyanate (abstainers: 6.2 ng/ml
      at week 26 vs. 10.4 ng/ml at baseline, p < 0.0001) and expired CO (abstainers:
      30.4 vs. 4.2 ppm, control vs. week 26, p < 0.0001) accurately followed the
      changes in smoking and/or NRT use in all of the groups. Other CV risk factors
      such as hematocrit and white blood cell count decreased to a greater extent in
      abstainers than in reducers and relapsers. Not only abstainers but also reducers
      did benefit of the temporarily stop smoking. CONCLUSIONS: Smoking cessation
      improved CV parameters despite the measured cotinine and thiocyanate plasma
      levels, and use of nicotine medications did not negate these improvements. A
      smoking cessation for a short time and smoking of reduced cpd also improved these
      parameters temporarily.

PMID- 15180169
TI  - Predicting the glomerular filtration rate from serum creatinine, serum cystatin C
      and the Cockcroft and Gault formula with regard to drug dosage adjustment.
AB  - OBJECTIVES: To compare the accuracy of the classification of the degree of
      decrease in glomerular filtration rate (GFR), measured exactly (as inulin
      clearance) on the basis of serum concentrations of creatinine (Scr), cystatin C
      (Scyst) and creatinine clearance predicted according to Cockcroft and Gault (CG),
      and to establish whether any of the above methods is more accurate than the other
      2. SUBJECTS: The study was conducted in 126 patients (52 men, 74 women) aged 18
      to 64 years with various chronic renal diseases (predominantly various forms of
      glomerulonephritis and tubulointerstitial nephritis). The study subjects were
      divided into 3 subgroups according to GFR levels. Subgroup A (n = 41) included
      individuals with GFR >50 ml/min/1.73 m2, subgroup B (n = 56) was made up by
      individuals with GFR of 20-50 ml/min/1.73 m2, while subgroup C (n = 29) comprised
      individuals with GFR <20 ml/min/1.73 m2. METHODS: GFR was determined on the basis
      of renal inulin clearance (Cin) under conditions of stable plasma levels and
      water loading. Each individual had his/her Scr, Scyst values measured and CG was
      calculated. Results were evaluated using discrimination analysis. RESULTS: Mean
      values and SD of the monitored markers in the subgroups were as follows. Subgroup
      A: Scr 102.4 (38.3) micromol/l, Scyst 1.46 (0.42) mg/l, CG 80.0 (19.2)
      ml/min/1.73 m2. Subgroup B: Scr 161.2 (45.6) micromol/l, Scyst 2.01 (0.55) mg/l,
      CG 46.1 (16.7) ml/min/1.73 m2. Subgroup C: Scr 314.9 (58.3) micromol/l, Scyst
      3.41 (0.96) mg/l, CG 24.8 (7.6) ml/min/1.73 m2. The percent of correct
      classifications and the respective confidence intervals (95%) for the methods
      used were as follows. Subgroup A: Scr 79.3 (64.6, 94.0), Scyst 75.9 (60.3, 91.5),
      CG 86.2 (73.6, 98.8). Subgroup B: Scr 51.8 (35.5, 68.1), Scyst 57.1 (41.5, 72.7),
      CG 64.3 (48.6, 80.0). Subgroup C: Scr 90.2 (81.0, 99.2), Scyst 80.5 (68.1, 92.9),
      CG 87.8 (77.8, 97.8). The percent of correct classifications established on the
      basis of Scr, Scyst and CG in subgroup B is significantly lower than that of
      correct classifications in subgroups A and C (p < 0.05-0.001). The percent of
      correct classifications using Scr, Scyst and CG, estimated separately for each
      subgroup (A, B, C) does not differ significantly. CONCLUSIONS: The findings
      support the assumption that estimation of the decrease in GFR using Scr, Scyst
      and CG is, as regards their utilization in everyday practice, suitable for
      individuals with severely decreased GFR (<20 ml/min/1.73 m2) and for individuals
      with a decrease in GFR to levels >50 ml/min/173 m2. Estimation of the decrease in
      GFR using the above subgroups did not demonstrate significant differences among
      Scr, Scyst and CG. Using the above markers, estimation of the decrease in GFR is
      the least reliable with GFR values in the range of 20-50 ml/min/1.73 m2.

PMID- 15180170
TI  - Safety of AT-1015, a novel 5-HT2A antagonist, in combination with high-dose
      aspirin: an open-label study.
AB  - OBJECTIVE: To assess the safety of AT-1015 in combination with high-dose aspirin
      (300 mg daily). Study subjects were 17 healthy male volunteers. METHODS: This was
      an open-label, single-center study. Subjects received aspirin 300 mg once daily,
      alone on days 1-4, and together with AT-1015 40 mg twice daily on days 5-11. A
      follow-up assessment was performed on day 18. The primary outcome measure was
      bleeding time; secondary outcome measures were vital signs, adverse events,
      physical examinations, 12-lead electrocardiograms (ECG) and laboratory safety
      tests. RESULTS: There was a significant increase in bleeding time between
      screening and the end of the aspirin-only period (mean bleeding time 4.8 vs 7.6
      min, p = 0.01), but there were no further significant increases during the
      combination treatment period. The most common adverse events were dry mouth,
      epistaxis, gingival bleeding and abdominal pain. All treatment-related adverse
      events were mild in severity and no major bleeding episodes occurred. There were
      no clinically significant changes in vital signs, physical examinations, 12-lead
      ECGs or laboratory safety tests. CONCLUSIONS: AT-1015 was safe and well-tolerated
      in healthy male volunteers when taken in combination with high-dose aspirin, and
      did not significantly prolong bleeding time compared with aspirin alone.

PMID- 15180171
TI  - Drug changes at the interface between primary and secondary care.
AB  - OBJECTIVE: To analyze the frequency and factors associated with drug change in a
      sample of patients referred to hospital by their general practitioner. METHODS:
      This observational study is based on a chart review of 100 consecutively
      recruited patients with a chronic disease who were referred to the general
      internal medicine wards in each of 3 district general hospitals in Germany (total
      300 patients). The frequency of drug cancellation, replacement, dosage
      alteration, change in manufacturer and of commencing treatment with a new drug
      were recorded. RESULTS: Half of the drugs used in chronic treatment (644/1,330)
      and prescribed by general practitioners were continued during hospitalization.
      The fraction canceled was 36%. In the rest of the drugs in this group, there were
      some minor changes carried out by the hospital. On the day of the drug survey, a
      total of 1,572 drugs were being taken by the patients and 724 of these drugs were
      newly prescribed by hospital. Only 13 patients experienced no change to their
      drug regimen during their stay in hospital. In more than 60% of patients
      (184/300), there were 3 or more changes made in their drug regimen. The rate of
      drug cancellation for antihypertensive and cardiac drugs in patients referred to
      hospital for cardiovascular and non-cardiovascular problems did not differ.
      CONCLUSION: During hospitalization, nearly every patient is confronted with some
      form of drug change. Of major concern is the high rate of drug change affecting
      drugs being taken for diseases other than that associated with the
      hospitalization. Hospital drug policy should encourage clinicians to continue
      drug regimens in newly admitted patients whenever medically appropriate and
      caution clinicians against making unnecessary changes to drug regimens prescribed
      by general practitioners.

PMID- 15180172
TI  - Alternative versus conventional treatment strategy in uncomplicated acute otitis
      media in children: a prospective, open, controlled parallel-group comparison.
AB  - OBJECTIVES: Evidence from clinical trials questions the benefit-risk ratio of
      first-line antibiotic treatment for uncomplicated acute otitis media in
      childhood. Alternative treatment strategies are very popular but have not been
      the subject of larger controlled clinical trials. This trial compares an
      alternative with a conventional treatment strategy for acute otitis media.
      METHODS AND PATIENTS: 390 children aged 1-10 years presenting with uncomplicated
      acute otitis media participated in a prospective, open, non-randomized,
      controlled, parallel-group study. According to self-assignment of investigators,
      children were treated either conventionally (free combinations of decongestant
      nose drops, mucolytics, analgesics and antibiotics) or alternatively with
      Otovowen (fixed combination of plant-based tinctures and homeopathic potencies),
      supplemented by conventional medications when considered necessary. RESULTS:
      Alternatively treated patients (n = 192) had significantly less severe otoscopic
      findings and clinical symptom ratings at baseline than children treated in
      conventional centers (n = 193). Patients cared for by conventional therapists
      took more antibiotics (80.5% vs. 14.4%; chi2-test, p < 0.001) and analgesics
      (66.8% vs. 53.2%; chi2-test, p = 0.007). Times to recovery were 5.3 +/- 2.4 and
      5.1 +/- 2.2 days for alternative and conventional treatment, respectively. Odds
      ratios (OR) with a lower limit of 1-sided 97.5% confidence interval (CI) were
      0.98 (0.76), 0.95 (0.73) and 0.88 (0.69) for results adjusted to baseline
      otoscopy, pain and symptom score, respectively (Cox-Mantel test). Absence from
      school or preschool nursery was 1.7 days in both groups; ORs (CI) were 1.00
      (0.76), 0.96 (0.73) and 1.04 (0.80). Noninferiority of alternative treatment (CI
      limit of OR above 0.696) was not proven for pain resolution (-5.2 vs. -5.8 score
      points); OR (CI) were 0.87 (0.68), 1.15 (0.87) and 0.74 (0.58). Alternative
      treatment was judged both by doctors (Mann-Whitney estimator with 2-sided 95% CI
      0.41 (0.35-0.47)) and parents (0.42 (0.36-0.48)), to be significantly better
      tolerated than conventional treatment. CONCLUSIONS: In primary care management of
      uncomplicated acute otitis media in childhood, an alternative treatment strategy
      based on the natural medicine, Otovowen may substantially reduce the use of
      antibiotics without disadvantage to the clinical outcome.

PMID- 15180173
TI  - Therapeutic drug monitoring of trazodone: are there pharmacokinetic interactions
      involving citalopram and fluoxetine?
AB  - OBJECTIVE: Therapeutic drug monitoring (TDM) of the new generation
      antidepressants is subject of controversial discussion. Nonetheless, TDM may
      safeguard against drug-drug interactions, can be used to control compliance and
      is valuable in the investigation of overdose. METHOD: The aim of this prospective
      study was to investigate serum levels of trazodone when prescribed as monotherapy
      or when used in combination with the selective serotonin reuptake inhibitors
      citalopram and fluoxetine in a simultaneous assay using high-performance liquid
      chromatography (HPLC). Over a 1-year period, we studied 97 patients (63 females)
      with depressive syndrome who were subdivided into 3 main diagnostic groups. Fifty
      two patients were smokers, the mean age was 39.9 years and the mean weight was
      72.4 kg; 40 patients were taking trazodone alone, 41 trazodone in combination
      with citalopram and 16 patients trazodone in combination with fluoxetine.
      RESULTS: The use of citalopram and fluoxetine in combination with trazodone had
      no significant impact on trazodone serum levels, and the same was true for
      differences in body weight and smoking behavior. On the other hand, age and sex
      had a significant influence on the pharmacokinetic pattern of trazodone, causing
      higher concentrations in females and in older patients. Since the polypharmacy
      investigated did not change the serum levels of trazodone, we assume that there
      is no metabolic interaction between trazodone and citalopram and trazodone and
      fluoxetine. We observed none of the adverse effects which might have been
      expected, including dizziness, severe headache, daytime sedation, fatigue or the
      serotonin syndrome even in a mild form. CONCLUSION: A "double-tracked"
      antidepressive treatment using trazodone and the SSRIs citalopram and fluoxetine
      is associated with a wide safety margin.

PMID- 15180174
TI  - Cyclosporine bioequivalence study: quantification using fluorescence polarization
      immunoassay (FPIA) and radioimmunoassay (RIA).
AB  - OBJECTIVE: The aim of study was to compare the bioavailability of 2 cyclosporine
      capsule formulations (100 mg; Sigmasporin Microoral from Novaquimica Divisao
      Nature's Plus Farmaceutica Ltd., Brazil, as test formulation and Sandimmune
      Neoral from Novartis Biociencias S.A., Brazil, as reference formulation) in 24
      healthy male volunteers. METHODS: The study was open, randomized, with a 2-period
      crossover, a 1-week washout interval between doses. Blood samples were obtained
      over a 12-hour interval after each oral administration of cyclosporine (2
      capsules of 100 mg of each formulation). Cyclosporine blood concentrations were
      quantified using a fluorescence polarization immunoassay (FPIA) method provided
      by Abbott Axsym System and Cyclo-Trac SP. Whole-blood radioimmuoassay (RIA) kit
      was provided by DiaSorin. These assays provided concentration-time curves for
      cyclosporine in blood concentration from which the following pharmacokinetic
      parameters were obtained: AUC(last), AUC(inf), Cmax. RESULTS: Geometric mean and
      90% confidence intervals (CI) of Microoral/Neoral as percent ratios were 94.5%
      (90.8-98.4%) for AUC(last), 93.8% (89.7-98.1%) for AUC(inf), and 98.1% (94.5
      101.8%) for Cmax when cyclosporine was determined using FPIA and 96.1% (91.9 to
      100.6%) for AUC(last), 95.2% (90.2-100.5%) for AUC(inf), and 99.4% (96.4-102.4%)
      for Cmax using RIA. CONCLUSION: Since the 90% CI for Cmax, AUC(last) and AUC(inf)
      ratio were within the 80-125% interval proposed by US-FDA, it is concluded that
      Sigmasporin Microoral 100 mg capsule formulation is bioequivalent to Sandimmune
      Neoral 100 mg capsule formulation with regard to both rate and the extent of
      absorption.

PMID- 15180175
TI  - Novel understanding of pathophysiology and potential intervention in acute
      pancreatitis based on studies of gene-modified mice.

PMID- 15180176
TI  - Selective bloodletting for severe ulcerative colitis.

PMID- 15180177
TI  - Selective approach in the treatment of esophageal perforations.
AB  - BACKGROUND: Treatment of esophageal perforation remains controversial and
      recommendations vary from initially non-operative to aggressive surgical
      management. Several factors are responsible for this life-threatening event,
      which has led to more individualized treatment ensuring adequate
      pleuromediastinal drainage with sufficient irrigation. We analyzed our data,
      evaluating morbidity and mortality in this selective approach. METHODS: During
      1985 to 2001, 17 of the 38 patients with esophageal perforation treated in our
      hospital underwent primarily a thoracotomy, wide drainage and debridement of
      chest/ mediastinum and enteral hyperalimentation. Twenty-one patients (55%)
      initially were treated non-operatively (NPO, nasogastric tube, hyperalimentation,
      antibiotics and chest tube), but surgery was required in 9 patients (43%).
      RESULTS: Most perforations were iatrogenic (45%; 17/38) followed by spontaneous
      perforations (32%; 12/38). Cervical perforations were managed earlier (< 24 h)
      than thoracic tears, 8/10 (80%) and 17/28 (61%) respectively. Initial
      conservative treatment failed in all spontaneous ruptures and more in thoracic
      lesions (62%) than in cervical lesions (13%). Most patients with thoracic
      perforations and 'free' intrathoracic contamination underwent primary surgery.
      Surgery with adequate drainage (n = 23) was based on signs of sepsis, empyema and
      progression of pneumomediastinum/thorax. Mortality occurred in one patient (3%),
      initially treated conservatively. Median intensive care and duration of
      hospitalization were not different between the conservative (5 and 7 days,
      respectively) and the primary surgical approach (21 and 27 days, respectively),
      but were higher after secondary surgery (13 and 50 days, respectively).
      CONCLUSIONS: Spontaneous esophageal perforations require early surgical
      exploration with drainage and irrigation of mediastinum and pleural cavity, while
      most iatrogenic lesions can be managed conservatively. Cervical perforations can
      be treated adequately non-operatively, but thoracic perforations often require
      surgical intervention.

PMID- 15180178
TI  - Ileal brake failure in streptozotocin-induced diabetic rat.
AB  - BACKGROUND: Diabetes mellitus frequently alters gastrointestinal function, but
      the pathophysiology of the diabetic gut has not been fully elucidated. Our aim
      was to characterize the enterogastric modulation of gastric emptying in an
      experimental model of diabetic rat and to determine the putative consequences of
      impaired regulation on glycaemic control. METHODS: Studies were performed in
      streptozotozin-induced diabetic and control groups of male Sprague-Dawley rats.
      In rats fitted with chronic ileal cannulae, gastric emptying of a peptide meal
      was measured during ileal infusion of either lipids (ileal brake) or saline. The
      influence of the ileal brake mechanism on blood glucose levels after oral
      administration of a glucose solution was also evaluated. RESULTS: Diabetic rats
      exhibited a precipitous gastric emptying (80% +/- 3% versus 57% +/- 3% in
      controls; P < 0.05). Ileal lipids delayed gastric emptying in control (38 +/- 4%;
      P < 0.05 versus ileal saline) but not in diabetic animals (77 +/- 5%; N.S. versus
      ileal saline). As the ileal brake contributes to the management of postprandial
      blood glucose levels (114 +/- 4.9 mg/dL after ileal lipids versus 134 +/- 7.8
      mg/dL after ileal saline in control rats; P < 0.05), the failure of this
      mechanism in diabetic rats worsens glycaemic control after feeding (455 +/- 20.4
      mg/dL after ileal lipids versus 399 +/- 8.7 mg/dL after ileal saline; P < 0.05).
      CONCLUSION: Experimental diabetes impairs the ileal brake mechanism and disturbs
      gastric emptying. These abnormalities may contribute to difficult glycaemic
      control.

PMID- 15180179
TI  - Villous tip intraepithelial lymphocytes as markers of early-stage coeliac
      disease.
AB  - BACKGROUND: An investigation was conducted to determine whether the density of
      small-intestinal villous tip intraepithelial lymphocytes would be of value in
      clinical practice in uncovering early-stage coeliac disease. METHODS: Villous
      tip, CD3+ and gammadelta+ intraepithelial lymphocytes were counted in patients
      with definite early-stage coeliac disease without villous atrophy, in classic
      coeliac disease with manifest mucosal lesion and in non-coeliac controls with
      normal mucosal structure. Villous tip analysis was made of haematoxylin-eosin
      specimens and CD3+ and gammadelta+ of immunohistochemical stainings from frozen
      samples. RESULTS: The villous tip intraepithelial lymphocyte count was
      statistically significantly higher in patients with early-stage coeliac disease
      than in non-coeliac controls. The sensitivity of this method to detect untreated
      coeliac disease with normal villous architecture was 0.84; the specificity was
      0.88. This method proved superior to CD3+ analysis and was at least as good as
      gammadelta+ analysis in detecting early-stage coeliac disease. In detecting
      classic coeliac disease, villous tip analysis also reached a higher sensitivity
      than CD3+ and gammadelta+ cells. CONCLUSIONS: Villous tip analysis seems to
      distinguish early coeliac from non-specific changes, thus providing a valuable
      tool in routine practice, especially when borderline findings are involved. Its
      value appears to be similar to counting of gammadelta+ cells, which, however,
      requires frozen biopsy samples.

PMID- 15180180
TI  - Postoperative on-line monitoring with intraperitoneal microdialysis is a
      sensitive clinical method for measuring increased anaerobic metabolism that
      correlates to the cytokine response.
AB  - BACKGROUND: Visceral ischaemia and cytokine release are early stages in the
      development of shock and multiorgan failure. Because of lack of methods to
      measure anaerobic metabolism or visceral hypoxia in the early phase, diagnosis is
      not usually established until shock and organ failure are evident. METHODS:
      Nineteen patients were studied postoperatively after major abdominal
      gastrointestinal surgery. A microdialysis catheter was placed intraperitoneally
      before closure of the abdomen. Analysis of glucose, pyruvate and lactate was
      performed every second hour and the ratio between lactate and pyruvate was
      calculated. Peritoneal fluid was collected from a peritoneal drainage for
      analysis of tumour necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10).
      RESULTS: Sixteen of the patients had a normal postoperative course; the
      lactate/pyruvate ratio started at the level of 20 immediately postoperatively and
      decreased significantly during the first 45 postoperative hours (P = 0.007). A
      similar pattern was recorded for peritoneal TNF-alpha, which decreased
      correspondingly (P = 0.003). A correlation coefficient of 0.303 (P < 0.001 )
      between lactate/pyruvate ratio and TNF-alpha was found. After an initial short
      increase, IL-10 decreased over time (P < 0.001). Three of the patients had
      abnormalities in the microdialysis results, cytokines and clinical outcome. These
      patients are presented separately. CONCLUSIONS: A normal postoperative course
      results in a decrease in the intraperitoneal lactate/pyruvate ratio, TNF-alpha
      and IL-10. A correlation between the intraperitoneal lactate/pyruvate ratio and
      TNF-alpha was found which suggests that intraperitoneal microdialysis is a
      sensitive, indirect method in analysing the postoperative intraperitoneal
      inflammatory response. A complicated postoperative course was preceded by
      increase of the peritoneal lactate/pyruvate ratio interpreted as splanchnic
      hypoxia and also an increased TNF-alpha level.

PMID- 15180181
TI  - Mast cells and eosinophils have a potential profibrogenic role in Crohn disease.
AB  - BACKGROUND: Mast cells and eosinophils have an important role in allergic
      inflammation and probably also in chronic inflammatory diseases resulting in
      fibrosis, such as Crohn disease where fibrosis is present as strictures. The
      involvement of mast cells and eosinophils in Crohn disease fibrosis was
      investigated. METHODS: Biopsies from diseased foci were stained for mast cells,
      eosinophils, anti-collagen type IV and VIII, laminin and alpha-smooth muscle
      actin (alpha-SMA) (IHC). Fibroblasts outgrown from the biopsies and a normal
      fetal intestinal fibroblast line were cultured in the presence of the human mast
      cell line HMC-1, or of human peripheral blood eosinophil (MACS, purity > 98%)
      sonicates, or of selected mediators. Fibroblast proliferation (3H-thymidine),
      collagen synthesis ([3H]-proline) and collagen gel contraction were evaluated.
      RESULTS: Mast cells were present in all the biopsies and only faintly positive
      for extra cellular matrix (ECM) products. Pronounced eosinophilia was detected in
      only two cases. Mast cell sonicates increased both Crohn disease (alpha-SMA
      positive) and control fibroblast proliferation, decreased collagen production and
      increased collagen gel contraction. Eosinophil sonicates increased fibroblast
      proliferation, gel contraction and collagen production. TNF-alpha decreased
      collagen production. Histamine, tryptase and chymase had no influence.
      CONCLUSIONS: These in vitro data show that mast cells and eosinophils could be
      involved in modulating Crohn disease fibrosis by directly influencing intestinal
      fibroblast properties.

PMID- 15180182
TI  - Diagnosing irritable bowel syndrome: poor agreement between general practitioners
      and the Rome II criteria.
AB  - BACKGROUND: The new guidelines for diagnosing irritable bowel syndrome (IBS) in
      clinical practice recommend the use of the Rome II criteria. In this study the
      agreement between general practitioners (GPs) and the Rome II criteria for
      diagnosing of IBS and functional bowel disorders (FBD) is examined. METHODS:
      Consecutive patients in general practice were asked to report on abdominal
      complaints, for which they had consulted or wanted to consult a GP. Patients with
      such complaints completed a questionnaire based on the Rome II criteria for FBD.
      After consultations, the GPs reported their diagnoses on the abdominal
      complaints. RESULTS: Of 3097 screened patients, 553 patients were diagnosed by
      their GP and had complete data in the questionnaire. Of these patients, 107 had
      IBS according to the GPs and 209 had IBS according to the Rome II criteria
      (agreement 58%, kappa 0.01 (CI: -0.06; 0.09)). Agreement on IBS and FBD in
      patients without organic disease, without reflux or dyspepsia and in patients
      with a verified diagnosis was 45%-58%, with kappa values from -0.02 to 0.13. IBS
      and FBD cases were diagnosed by the Rome II criteria more often than by the GPs
      in all these groups of patients (P < 0.001). In patients with diagnostic
      discrepancies concerning IBS, 'stress-related symptoms' was predictive of a
      diagnosis of IBS made by the GPs only (OR 2.17 (CI: 1.1; 4.2)). CONCLUSIONS: This
      study shows poor agreement in the diagnosis of IBS between GPs and the Rome II
      criteria. Therefore, current knowledge about IBS based on strict criteria is not
      necessarily transferable to patients with IBS in general practice.

PMID- 15180184
TI  - Incidence and prognosis of gastric cancer in a population-based cohort survey:
      the Hisayama study.
AB  - BACKGROUND: No population-based cohort studies have been undertaken to evaluate
      the incidence and prognosis of gastric cancer. The purpose of this investigation
      was to clarify the incidence and fatal prognosis of gastric cancer and to
      determine the factors that contribute to the prognosis in a general Japanese
      population in Hisayama using a prospective study design. METHODS: From 1988 to
      1998 a total of 2605 subjects aged 40 years or older with no history of
      gastrectomy or gastric cancer were followed-up prospectively after a health
      examination. The diagnosis of gastric cancer was based on clinical records or
      autopsy findings. RESULTS: During the follow-up period, 76 subjects developed
      gastric cancer. The age-adjusted incidence of gastric cancer for men (4.9 per
      1000 person-years) was 4-fold higher than that for women (1.2, P < 0.05). In men,
      the incidence of gastric cancer increased with advancing age, but this trend was
      not observed in women. The age- and sex-adjusted 5-year survival rate was
      significantly higher in cancers of the middle third of the stomach than in those
      of the upper third of the stomach. The survival rate was higher in cancers of
      well-differentiated adenocarcinoma than in those of the other histological types.
      There were no cases of cancer-related death among the early gastric cancers
      during the follow-up period. CONCLUSIONS: Our data suggest that men are at higher
      risk of gastric cancer than women in the general Japanese population. Clinical
      stage, histological type, and site of cancer in the stomach contribute to a fatal
      prognosis.

PMID- 15180183
TI  - Treatment of anaemia in inflammatory bowel disease with iron sucrose.
AB  - BACKGROUND: Inflammatory bowel disease (IBD)-associated anaemia usually responds
      to intravenous iron. If not, additive treatment with erythropoietin has been
      proposed. The objective of the present retrospective study was to evaluate the
      effectiveness of treatment with iron sucrose alone. METHODS: Sixty-one patients
      with IBD and anaemia (average haemoglobin 97 g/L) were treated with iron sucrose
      (iron dose 1.4 +/- 0.5 g). The indications for iron sucrose were poor response
      and/or intolerance to oral iron. Treatment response was defined as an increase in
      haemoglobin of > or = 20 g/L or to normal haemoglobin levels (> or = 120 g/L).
      Two independent investigators retrospectively assessed laboratory variables,
      clinical findings, and concomitant medication. RESULTS: Two patients were
      transferred to other hospitals after treatment and therefore could not be
      evaluated. Fifty-four of the remaining 59 patients (91%) responded within 12
      weeks. Sixty percent of the patients had responded within 8 weeks. Five patients
      had no or only a partial response to iron sucrose of which three had prolonged
      gastrointestinal blood losses. Eight patients with normal or elevated levels of
      ferritin could be considered to have anaemia of chronic disease, and all of them
      responded to iron sucrose. During a follow-up period of 117 +/- 85 (4-291) (mean
      +/- s (standard deviation) (range)) weeks 19 patients (32%) needed at least one
      second course of iron sucrose because of recurrent disease. CONCLUSIONS: Anaemia
      associated with IBD can be successfully treated with intravenously administered
      iron sucrose, provided that bowel inflammation is treated adequately and enough
      iron is given. Treatment with iron sucrose is safe. Follow-up of haemoglobin and
      iron parameters to avoid further iron deficiency anaemia is recommended.

PMID- 15180185
TI  - Expression patterns of cell cycle and apoptosis-related genes in a multidrug
      resistant human colon carcinoma cell line.
AB  - BACKGROUND: An in vitro multidrug resistance (MDR) system from a human colonic
      cancer cell line (SW620-MDR) has been established. To further study the
      mechanisms at molecular level and prevention of multidrug resistance in clinical
      practice, it was demonstrated that the expressions of several apoptosis-related
      and cell cycle regulator genes were changed in the cells. METHODS: A multidrug
      resistant colonic cell line (SW620-MDR) was established, and the Atlas human cDNA
      expression array was used for studying the pattern of gene expression in this
      cell line. Furthermore, Northern hybridization or real-time PCR analysis
      confirmed the pattern of gene expression. RESULTS: In the SW620-MDR cell line the
      pro-apoptosis genes, CASP4, BIK, PDCD2, and TACE were expressed with decreased
      levels, and the antiapoptosis genes CD27-L and IGFBP2 were over-expressed.
      Furthermore, the cell cycle regulator genes such as CDK6, CCND1, CDC27HS,
      CDC16HS, Wee1Hu, MAPKK1, and IGFBP6 were expressed with decreased levels in the
      drug-resistant cell line. CONCLUSIONS: It is worthwhile investigating whether the
      differentially expressed pattern of the aforementioned genes exists in the drug
      resistant cancer specimens, and to further understand their functions in the
      cancer drug-resistance mechanism.

PMID- 15180186
TI  - Polyamine biosynthesis in relation to K-ras and p-53 mutations in colorectal
      carcinoma.
AB  - BACKGROUND: Polyamines are important polycations found in high concentrations in
      gastrointestinal neoplasms, and ornithine decarboxylase is the key enzyme in
      their biosynthesis. Also genes with oncogenic potential (e.g. K-ras and p53)
      contribute to neoplastic transformation by modifying normal cellular
      proliferation and differentiation. Our aim was to evaluate the ornithine
      decarboxylase activity and polyamine levels in samples of colorectal carcinoma
      and uninvolved surrounding mucosa from 86 patients (52 men and 34 women) showing
      different patterns of K-ras/p53 mutations. METHODS: Polyamines were evaluated by
      high performance liquid chromatography. Ornithine decarboxylase activity was
      determined using the radiometric method. K-ras and p53 mutations were
      investigated by PCR followed by restriction fragment length polymorphism (PCR
      RFLP) and single strand conformational polymorphism (PCR-SSCP), respectively.
      Multiple linear regression analysis was used to analyse relationships among
      polyamine biosynthesis, clinical-pathological variables and K-ras/p53 mutations.
      RESULTS: ODC activity and polyamine levels were significantly higher in
      neoplastic samples than in normal surrounding mucosa. K-ras codon 12 mutation was
      found in 25/86 patients (29.1%) and p53 gene mutation in 41/86 (47.7%). Polyamine
      biosynthesis was significantly higher in cancers showing K-ras mutation, either
      with or without p53 mutation [K-ras(+)/p53(-) and K-ras(+)/p53(+)], compared to
      samples with K-ras wild type [K-ras(-)/p53(-) and K-ras(-)/p53(+)]. Multiple
      linear regression analysis confirmed this finding. CONCLUSIONS: The present study
      provides evidence of a close relationship between K-ras mutation and polyamine
      biosynthesis in human colorectal carcinoma in a way that is largely p53
      independent. In addition, our data support the hypothesis of different pathways
      in colorectal tumorigenesis reflecting different combinations of biochemical
      parameters and genetic alterations.

PMID- 15180187
TI  - Hepatitis B virus X protein (HBx)-induced apoptosis in HuH-7 cells: influence of
      HBV genotype and basal core promoter mutations.
AB  - BACKGROUND: Hepatitis B virus (HBV) infection is a serious, world-wide problem.
      HBV genotype and basal core promoter (BCP) mutations affect the clinical course
      of HBV-infected patients. BCP mutations also lead to mutations at HBV X protein
      (HBx) codons 130/131. The functional significance of naturally occurring variants
      of human HBx remains largely unknown. The purpose of the study was to investigate
      whether HBV genotypes or double mutations affect HBx-induced apoptosis. METHODS:
      We constructed genotype A, B, C, and D HBx expression vectors and HBx expression
      vectors with double mutations at HBx codons 130K and 131V or positions 130M and
      131I using site-directed mutagenesis. A transient expression system in HuH-7
      cells was established and this model was utilized to address the effect of HBx on
      cell viability. RESULTS: HBx-transfected cells showed a dose-dependent decrease
      in cell viability by MTS assay. A subset of cells expressing HBx underwent
      apoptosis according to terminal transferase enzyme-mediated end labeling of DNA
      and caspase-3 activity. This study demonstrated that HBx can induce cell death by
      apoptosis in a dose-dependent manner and that HBV genotypes and double mutations
      did not affect HBx-induced apoptosis. CONCLUSIONS: HBV genotypes and mutation of
      two amino acids directly adjacent to the conserved Kunitz domain essential for
      transcription activating activity of HBx did not change the pro-apoptotic
      activity of HBx. Further study is needed to determine whether HBV genotypes and
      double mutations have any effect on the function of HBx.

PMID- 15180188
TI  - Effect of terlipressin on blood volume distribution in patients with cirrhosis.
AB  - BACKGROUND: Patients with cirrhosis and portal hypertension have an altered blood
      volume distribution and a hyperdynamic systemic circulation. Terlipressin is
      known to reduce portal pressure by decreasing splanchnic inflow, but its effect
      on the blood volume distribution is unknown. The aim of the study was to
      investigate changes in regional blood volume distribution and systemic
      haemodynamics after administration of terlipressin to patients with cirrhosis.
      METHODS: Blood volume distribution was determined in 13 patients with cirrhosis
      and portal hypertension by a dual-head gamma-camera technique and systemic
      haemodynamics was measured before and after intravenous administration of
      terlipressin (2 mg). RESULTS: Terlipressin increased the blood volume in the
      thorax region (+6.0%, P < 0.002) and the liver region (+12.2%, P < 0.002),
      whereas blood volume in the splanchnic region remained unchanged. Systemic
      vascular resistance (SVR) and mean arterial blood pressure increased after
      terlipressin (+34 and +21%, P < 0.001). The increase in liver blood volume
      correlated directly with the increase in SVR (r = 0.88. P < 0.001). CONCLUSIONS:
      Terlipressin ameliorates the hyperdynamic circulation, increases thorax and liver
      blood volumes, but produces no effect on the splanchnic blood volume. Besides
      decreasing the splanchnic inflow, terlipressin may affect portal pressure by
      causing vasodilatation of intrahepatic vessels.

PMID- 15180189
TI  - Validation of intramural intestinal microdialysis as a detector of intestinal
      ischaemia.
AB  - BACKGROUND: The purpose of this study was to validate intestinal microdialysis as
      a detector of intestinal ischaemia using measurements of glucose, lactate and
      glycerol from the jejunal wall. METHODS: Based on a previous study, the cut-off
      levels for the presence of regional intestinal ischaemia were defined for
      microdialysis glucose, lactate, glycerol and the lactate/glucose ratio. Changes
      of 60% in the metabolic compounds measured after 100 min were defined as the cut
      off level for ischaemia. The cut-off levels were tested in a randomized, single
      blinded study. Ten pigs were used; occlusive ischaemia was performed by clamping
      a segment of the mesentery to the intestine. Four catheters were inserted per
      pig, two in the ischaemic segment and two in the non-ischaemic segment. All
      catheters were numbered, randomly allocated and inserted in the intestine by the
      staff at the institute and unknown to the investigators. RESULTS: One pig was
      excluded because the clamping was insufficient. Technical problems with the
      catheters were registered in 15% of cases owing to damage of the microdialysis
      membrane, dislocation, or incorrect placement. The predictive values of presence
      of ischaemia for glucose, lactate, glycerol and the lactate/glucose ratio were:
      0.91, 1,0.85 and 0.92, respectively. CONCLUSION: Using a 60% cut-off limit
      measured after 100 min, intestinal ischaemia can be detected and excluded using
      intestinal microdialysis, but some technical problems remain that need further
      investigation.

PMID- 15180190
TI  - Variegate porphyria presenting with acute autonomic dysfunction, intussusception
      and renal infarction.
AB  - A 48-year-old man presented with abdominal pain, constipation and irritability
      one month after starting phenytoin treatment for a generalized seizure. He was
      hypertensive, tachycardic (BP 174/98, heart rate (HR) 100 bpm supine) and
      hypovolaemic. Abdominal CT demonstrated transient jejunal intussusception and
      infarction of the left kidney. Urinary porphobilinogen levels were increased and
      genetic analysis confirmed the diagnosis of variegate porphyria. Because of
      ongoing postural hypotension, the patient underwent further autonomic
      investigations. Levels of blood pressure (MBP), HR and muscle sympathetic
      activity (MSNA) were increased during the acute attack compared to recovery (131
      versus 105 mmHg, 100 versus 60 bpm, 88 versus 26 bursts min(-1)). HR and MSNA did
      not increase during phase II Valsalva, whereas stroke volume (SV) decays were
      exaggerated (deltaMBP-56 versus 0-31 mmHg and SV 25% versus 40% baseline).
      Baroreflex failure causing increased sympathetic activity, decreased sympathetic
      and parasympathetic rapid responses, loss of splanchnic capacitance and renal
      salt wasting were the likely mechanisms for postural hypotension. Increased
      sympathetic activity may also have caused intussusception and focal renal
      vasoconstriction, both of which may be underdiagnosed causes of abdominal pain in
      acute porphyria.

PMID- 15180191
TI  - Health promotion begins at the breast.

PMID- 15180192
TI  - Smoking cessation counseling for pregnant women who smoke: scientific basis for
      practice for AWHONN's SUCCESS project.
AB  - OBJECTIVES: To review the literature addressing smoking cessation in pregnant
      women. To develop the project protocol for the Association of Women's Health,
      Obstetric and Neonatal Nurse's (AWHONN) 6th research-based practice project
      titled "Setting Universal Cessation Counseling, Education and Screening Standards
      (SUCCESS): Nursing Care of Pregnant Women Who Smoke." To evaluate the potential
      of systematic integration of this protocol in primary care settings in which
      women seek care at the preconception, pregnant, or postpartum stages. LITERATURE
      SOURCES: Computerized searches in MEDLINE and CINAHL, as well as references cited
      in articles reviewed. Key concepts in the searches included low-birth-weight
      infants and effects of prenatal smoking on the infant and the effects of
      preconception and prenatal smoking cessation intervention on premature labor and
      birth weight. LITERATURE SELECTION: Comprehensive articles, reports, and
      guidelines relevant to key concepts and published after 1964 with an emphasis on
      new findings from 1996 through 2002. Ninety-eight citations were identified as
      useful to this review. LITERATURE SYNTHESIS: Tobacco use among pregnant women and
      children's exposure to tobacco use (secondhand smoke) are associated with
      pregnancy complications such as placental dysfunction (including previa or
      abruption), preterm labor, premature rupture of membranes, spontaneous abortions,
      and decreased birth weight and infant stature. Neonates and children who are
      exposed to secondhand smoke are at increased risk for developing otitis media,
      asthma, other respiratory disorders later in childhood; dying from sudden infant
      death syndrome; and learning disorders. The "5 A's" intervention and use of
      descriptive statements for smoking status assessment were synthesized into the
      SUCCESS project protocol for AWHONN's 6th research-based practice project.
      CONCLUSIONS: The literature review generated evidence that brief, office-based
      assessment, client-specific tobacco counseling, skill development, and support
      programs serve as an effective practice guideline for clinicians. Implementation
      and evaluation of the guideline is under way at a total of 13 sites in the United
      States and Canada.

PMID- 15180193
TI  - Comparison of self-reported smoking and urinary cotinine levels in a rural
      pregnant population.
AB  - OBJECTIVES: (a) to assess the accuracy of self-reported smoking status in
      pregnant women from rural and small metropolitan statistical areas who stated
      they were smokers at the onset of pregnancy, (b) to compare the characteristics
      of these women who self-reported a nonsmoker status at the first prenatal visit
      with those who reported a smoker status, and (c) to determine the characteristics
      that predict self-reported smoking status and positive/negative urinary cotinine
      assays. SETTING: Seven private obstetric offices serving rural and small
      metropolitan statistical areas in upstate New York. PARTICIPANTS: A convenience
      sample of 94 pregnant women who stated they were smokers at the onset of their
      pregnancies. Their mean age was 23 years and mean level of education was 11.9
      years; 95% were White, 65% were single, and 65% were Medicaid-funded. DESIGN:
      Descriptive correlational design. At the first prenatal visit, the sensitivity
      and specificity of smoking and nonsmoking status were determined by comparing
      self-reports of smoking status with urinary cotinine assays. Data were also
      analyzed for relationships among demographic variables and for predictors of
      smoking status and urinary cotinine. RESULTS: The discordance rate between self
      reports of smoking status and urinary cotinine assays at the first prenatal visit
      for the total sample was 16.6%, significant at p < .001, chi-square = 27.80, df =
      1. Based on biochemical assays of >200 ng/ml of cotinine indicating active
      smoking, 34.7% of women who denied smoking (specificity of 65.3%) and 10.4% of
      women who stated that they smoked (sensitivity of 89.5%) inaccurately reported
      their status (significant at p < .001). The number of cigarettes smoked per day
      was positively correlated with age, gravidity, parity, and number of smokers in
      the household. Gravidity and the number of smokers in the household were
      significant predictors of positive self-report of smoking status and of positive
      urinary cotinine assay. CONCLUSION: These results substantiate the unreliability
      of self-report on smoking status in the pregnant population and in women who are
      recent quitters. Such findings have implications for clinical practice, such as
      (a) changes are necessary in how the prenatal interview assesses past and present
      tobacco use, (b) pregnant smokers who are multigravidae and who live with other
      smokers need more tailored interventions, and (c) more research is needed on how
      self-report can be ethically and efficiently validated.

PMID- 15180194
TI  - Domestic violence and trauma care in teenage pregnancy: does paternal age make a
      difference?
AB  - OBJECTIVE: To determine whether teenagers partnered with adult men were more
      likely to report domestic violence and trauma-related care during pregnancy than
      teenagers partnered with male peers. DESIGN: Nonexperimental, descriptive
      comparative design. SETTING: Postpartum unit in a large, urban teaching hospital.
      PARTICIPANTS: English-speaking teenagers who recently delivered a live infant.
      METHODS: Semistructured interviews lasting from 30 minutes to 2 hours.
      INSTRUMENTS: The Abuse Assessment Screen, the Danger Assessment Scale. MAIN
      OUTCOME MEASURES: Domestic violence and trauma-related care during pregnancy.
      RESULTS: Teenagers with adult partners were not more likely to report domestic
      violence or seek trauma-related care during pregnancy than teenagers with peer
      age partners. CONCLUSION: Researchers, policy makers, and health care providers
      should continue to address violence occurring among pregnant teenagers by
      identifying subgroups who may be at increased risk of abuse.

PMID- 15180195
TI  - Validity and reliability of the neonatal skin condition score.
AB  - OBJECTIVE: To demonstrate the validity and reliability of the Neonatal Skin
      Condition Scale (NSCS) used in the Association of Women's Health, Obstetric and
      Neonatal Nurses (AWHONN) and the National Association of Neonatal Nurses (NANN)
      neonatal skin care evidence-based practice project. SETTING: NICU and well-baby
      units in 27 hospitals located throughout the United States. PARTICIPANTS: Site
      coordinators (N = 27) and neonates (N = 1,006) observed during both the pre and
      postimplementation phases of the original neonatal skin care project. METHOD: To
      assess reliability, two consecutive NSCS assessments on a single infant were
      analyzed. Site coordinators were contacted after the original project was
      concluded. Sites indicating that a single nurse scored all infant skin
      observations provided data that were used to evaluate intrarater reliability.
      Sites using more than one nurse to score skin observations provided data that
      were used to assess interrater reliability. To assess validity, the following
      variables were used from the original data set: the Neonatal Skin Condition Scale
      (NSCS), with three subscales for dryness, erythema, and breakdown; birth weight
      in grams; number of skin score observations for each infant; and the prevalence
      of infection, defined as a positive blood culture. RESULTS: For intrarater
      reliability, 16 sites used a single nurse for all NSCS assessments; total NSCS
      assessments 475. For interrater reliability, 11 sites used multiple raters; total
      assessments 531. The NSCS demonstrated adequate reliability for each of the three
      subscales and for the total score, with the percent agreement between scores
      ranging from 68.7% to 85.4% (intrarater) and 65.9% to 89% (interrater); all
      Kappas were significant at p < .001 and were in the moderate range for
      reliability. The validity of the NSCS was demonstrated by the findings that
      smaller infants were 6 times more likely to have erythema (chi2(6) = 109.55, p <
      .0001), and approximately twice as likely to have the most severe breakdown
      (chi2(6) = 108.01, p < .0001). Infants with more observations (longer length of
      stay) had higher skin scores (odds ratio = 1.21, p < .0001), and an increased
      probability of infection was noted for infants with higher skin scores (odds
      ratio = 2.25, p < .0001). CONCLUSIONS: The Neonatal Skin Condition Score (NSCS)
      is reliable when used by single and multiple raters to assess neonatal skin
      condition, even across weight groups and racial groups. Validity of the NSCS was
      demonstrated by confirmation of the relationship of the skin condition scores
      with birth weight, number of observations, and prevalence of infection.

PMID- 15180196
TI  - Fathers' perceptions of the immediate postpartal period.
AB  - PURPOSE: To describe the perceptions of first-time fathers regarding critical
      moments of the immediate postpartum period. DESIGN: Qualitative study. SETTING:
      Data were collected through semistructured interviews with the fathers, using the
      critical incident technique; this was done in their home, within the first 12
      days following the birth of their child. PARTICIPANTS: Sample consisted of 13
      first-time fathers. RESULTS: A qualitative analysis allowed for the
      identification of five domains, five categories, and 12 subcategories of critical
      incidents within the first 96 hours of the postpartum period. The five domains of
      incidents relate to self and others: as individuals, as a couple, and as parents
      in relationship with the environment and with the nursing personnel. On the basis
      of a combined score of fathers' presence on the maternity ward, we were able to
      define three subgroups. All groups of fathers were sensitive to interactions with
      their baby and with the nurses. Highly involved fathers reported not feeling
      supported by the hospital environment policies in regard to engaging in behaviors
      that could favor their involvement with their baby. CONCLUSIONS: Increased
      awareness of fathers' experiences during the immediate postpartum period will
      enable nurses to respond more effectively to the fathers' needs.

PMID- 15180197
TI  - The influence of age on symptoms of perimenopause.
AB  - OBJECTIVE: To identify differences in the occurrence and severity of symptoms
      related to perimenopause in women ages 30 to 50 and to determine which of the
      symptoms were recognized as due to perimenopause and discussed with a health care
      professional. DESIGN: Descriptive exploratory research design using a structured
      questionnaire. PARTICIPANTS: A sample of women (N = 418) employed in institutions
      of higher learning and a health care facility. MAIN OUTCOME MEASURES: The
      Menopause Symptom List was a 132-question survey used to identify occurrence and
      severity of symptoms in perimenopausal women, their recognition of the symptoms,
      and their level of discussion with a health care professional regarding the
      symptoms. One-way analysis of variance measures were applied to determine the
      differences between age groups and perimenopausal symptomology. RESULTS: For both
      the measurement scales of frequency and severity of perimenopausal symptoms, the
      mean score increased as age increased. Significant differences were found between
      the age groups for the number of occurrences of sleeplessness, moodiness (p <
      .05) and depression, and poor concentration (p < .005). Significant differences
      in severity of symptoms were seen between age groups for depression (p < .05) and
      poor concentration (p < .005). Depressed feelings, headaches, moodiness, and
      palpitations were the symptoms most frequently discussed with health care
      providers. CONCLUSIONS: Although the vaso-somatic symptom of headache ranked
      first for severity, the most frequently reported symptoms were psychological or
      general somatic in nature. Despite a proliferation of health education materials,
      the subjects in this study did not recognize many symptoms of perimenopause. The
      results of this study suggest that education and anticipatory guidance for
      perimenopausal women should begin with women in their 30s. With many symptoms
      occurring as early as age 35, recognition of symptoms can greatly reduce the
      discomfort and fears that women experience during the perimenopausal transition.

PMID- 15180198
TI  - Factor V Leiden mutation in pregnancy.
AB  - Normal maternal adaptation to pregnancy significantly increases the risk for
      thrombus formation. Inherited thrombophilias further increase risk for deep
      venous thrombosis and adverse outcome in pregnancy. Factor V Leiden mutation is
      the most common inherited thrombophilia, occurring in approximately 5% of the
      White and 1% of the Black populations. Nurses should be knowledgeable about
      screening for and diagnosis of factor V Leiden mutation, risk reduction
      counseling, recommended care of the affected patient, and implications of
      anticoagulant therapy during the perinatal period.

PMID- 15180199
TI  - Role transitions for new clinical leaders in perinatal practice.
AB  - New clinical leaders are transitioning to their roles in a demanding and short
      staffed profession where change is constant and finances are uncertain. For
      successful role transition in the specialty of perinatal nursing, both new
      leaders and their mentors must understand the attributes of potential leaders,
      the role of mentoring, and the need for clearly articulated expectations. This
      article discusses these processes in the context of the considerable skill set
      required for leadership in nursing today. The similarities and differences
      between the roles of manager and leader are discussed.

PMID- 15180200
TI  - Growing future leaders: developing perinatal managers from within.
AB  - Internal leadership development is a pressing issue in nursing because of the
      powerful influence of unit-level leaders/managers on staff nurse retention, the
      excessive costs of replacing this level of leadership as well as the costs of
      replacing staff, and the difficulty of finding strong candidates for both staff
      and leadership positions. This article offers a process of leadership development
      for frontline managers to be conducted within the facility. Models from the
      business community are helpful in constructing possibilities for internal
      development programs in nursing. Three courses, their content, and the
      experiential learning projects associated with didactic content are described.

PMID- 15180202
TI  - Nursing leadership in the boardroom.
AB  - It is critical that nurse leaders, including chief nurse executives and service
      line directors, be part of the institutional decision-making process about
      resource allocation, strategic direction, and planning for the future. Nurse
      leaders can use numerous strategies to influence decisions made in the boardroom
      that affect the women's service line, including perinatal and women's health.
      These strategies include building on the importance of women's services to the
      organization, working in collaboration with senior leaders and key physician
      leaders, marketing, and reaching out to governing boards with information. Nurse
      leaders must continue to prepare for the future to thrive in the increasingly
      complex health care environment.

PMID- 15180201
TI  - Leadership in nursing informatics.
AB  - Nursing informatics is a 21st century science with great potential for improving
      the quality, safety, and efficiency of health care. Perinatal, neonatal, and
      women's health nurses have an opportunity to contribute and lead in informatics.
      Leaders must learn about current informatics issues from essential resources,
      including the literature, professional organizations, and education programs, to
      develop successful strategies for innovation, collaboration, and implementation.
      Most important, nurses must be accountable for humanizing the use of technology
      using a nursing model.

PMID- 15180203
TI  - Growing and characterizing one-dimensional crystals within single-walled carbon
      nanotubes.
AB  - Single-walled carbon nanotubes (SWNTs) have been used as growth templates for
      spatially confined crystal growth. The comparative crystallization and high
      resolution transmission electron microscopy imaging properties of simple binary
      halides formed by the alkali iodides MI (M = Li, K, Na, Rb and Cs) within SWNTs
      are described. The most common structure type observed within SWNTs was the
      rocksalt archetype, although CsI was observed to form both body-centred cubic
      (bcc) and rocksalt structure types. ThCl4 was found to form a chain structure of
      Th[Cl]8 polyhedra. HgI2 crystallized within nanotubes with ultra-narrow (i.e. 0.8
      nm) capillaries was observed to form helical 2 x 1 layer crystals.

PMID- 15180204
TI  - Effects of heat and electron irradiation on the melting behavior of Al-Si alloy
      particles and motion of the Al nanosphere within.
AB  - In situ heating and electron-beam irradiation in the transmission electron
      microscope were performed to study melting of Al-11.6 at.% Si alloy submicron
      particles supported on an amorphous-C thin film. It was found that electron
      irradiation could be used to melt the particles, even when the hot-stage specimen
      holder was kept at a much lower temperature than the bulk melting point (i.e. the
      eutectic temperature) of the particles. The critical current densities required
      to achieve partial melting increased linearly with the incident electron-beam
      energy for a given temperature. Comparison between this behavior and analytical
      calculations indicates that melting under electron-beam irradiation is caused by
      a temperature rise due to electron thermal spikes in the particles and poor
      thermal conduction away from the particles. The motion of the crystalline Al
      nanosphere inside the partially molten particles was also investigated, using the
      electron beam to both stimulate and observe the motion of the nanosphere. The
      irregular motion observed was quantified as antipersistent fractional Brownian
      motion. Analysis of possible phenomena contributing to the motion demonstrates
      that the incident electrons provide the fractional force that moves the Al
      nanosphere, and that gravity and the oxide shell on the partially molten particle
      cause the antipersistent behavior. Another interesting phenomenon observed in
      this study was that the crystalline Al nanosphere inside the partially molten Al
      Si alloy particle followed a focused electron beam as it was moved about on the
      partially molten particle. This observation suggests that it may be possible to
      manipulate metallic nanospheres inside opaque liquids using an electron beam.

PMID- 15180205
TI  - Electron holographic mapping of two-dimensional doping areas in cross-sectional
      device specimens prepared by the lift-out technique based on a focused ion beam.
AB  - Recently, electron holography has been successfully applied to analyze two
      dimensional (2D) dopant distribution in semiconductor devices with high
      resolution and high sensitivity. The preparation of proper specimens is a
      fundamental step for the practical application of electron holography in the
      semiconductor industry. Therefore, it is important to explore a reliable and
      quick specimen preparation method. In our current work, we have tried to use the
      lift-out technique based on a focused ion beam, to fabricate cross-sectional CMOS
      device specimens for electron holographic observation. Using the lift-out
      technique, specimens with a large area and uniform thickness can be prepared
      directly from integrated circuit wafers in a very short time. Specimens with a
      complex and unknown dopant distribution were examined using off-axis electron
      holography. In the reconstructed phase images, the different 2D doping areas in a
      CMOS device, such as source, drain, well and substrate, were revealed
      successfully. The advantages and disadvantages of the technique are discussed.

PMID- 15180206
TI  - Identification of crack path of inter- and transgranular fractures in sintered
      silicon nitride by in situ TEM.
AB  - Inter- and/or transgranular crack paths in sintered silicon nitride (Si3N4)
      during fracture were investigated by in situ straining experiments in a
      transmission electron microscope at room temperature, using a high-precision
      micro-indenter. By this technique, cracks introduced in an in situ manner were
      observed to propagate in the grain interior and along grain boundaries. High
      resolution electron microscopy (HREM) observation revealed that the crack
      propagation takes place at an interface between Si3N4 grains and an intergranular
      glassy film (IGF) in the case of intergranular fractures. According to the
      results by previous molecular dynamics simulations, a number of dangling bonds
      are present at the Si3N4/IGF interface, which should result in the observed
      fracture behavior at the interface. On the other hand, the crack path introduced
      during transgranular fracture of Si3N4 grains was found to be sharp and straight.
      The observed crack propagated towards [1120] inside the Si3N4 grain with the
      crack surface parallel to the (1100) plane. The HREM observations of crack walls
      revealed them to be atomically flat. The atomic termination of the crack walls
      was identified in combination with image simulations based on atomic models of
      the cleaved crack walls.

PMID- 15180207
TI  - Direct observation of a stacking fault in Si(1 - x)Ge(x) semiconductors by
      spherical aberration-corrected TEM and conventional ADF-STEM.
AB  - Spherical aberration (C(S))-corrected transmission electron microscopy (TEM) and
      annular dark-field scanning TEM (ADF-STEM) are applied to high-resolution
      observation of stacking faults in Si(1 - x)Ge(x) alloy films prepared on a
      Si(100) buffer layer by the chemical vapor deposition method. Both of the images
      clarify the individual nature of stacking faults from their directly
      interpretable image contrast and also by using image simulation in the case of
      the C(S)-corrected TEM. Positions of the atomic columns obtained in the ADF-STEM
      images almost agree with a projection of the theoretical model studied by Chou et
      al. (Phys. Rev. B 32(1985): 7979). Comparison between the C(S)-corrected TEM and
      ADF-STEM images shows that their resolution is at a similar level, but directly
      interpretable image contrast is obtained in ultrathin samples for C(S)-corrected
      TEM and in slightly thicker samples for ADF-STEM.

PMID- 15180208
TI  - Determination of absolute thickness and mean free path of thin foil specimen by
      zeta-factor method.
AB  - The zeta-factor method is applied to the thickness determination of thin
      amorphous specimens where the convergent-beam electron diffraction method is not
      applicable. Characteristic X-ray intensities are first measured using standard
      specimens in order to determine zeta-factors. These zeta-factors are then used to
      determine local thicknesses of an amorphous Si and an amorphous Al alloy.
      Electron energy-loss spectroscopy (EELS) spectra are acquired at the same
      positions as for the X-ray measurements. Thus, using the thicknesses measured
      from the zeta-factor method, the electron mean-free path is determined through
      the EELS log-ratio method. The mean free path is measured as a function of the
      collection semi-angle, beta, and specimen thickness, and it is also compared with
      theoretical values. Furthermore, the mean free path of amorphous Si is compared
      with that of the crystalline Si.

PMID- 15180209
TI  - Detection of iron-oxide layer on the surface of iron nitride using high
      resolution electron microscopy and Fourier filtering.
AB  - High-resolution electron microscopy (HREM) was used to detect the surface Fe3O4
      iron-oxide layer formed on [011] Fe4N iron nitride due to electron irradiation in
      the transmission electron microscope. The existence of a surface oxide layer was
      confirmed by both image processing and through-focus observation. Images of the
      iron oxide were revealed using the process of fast Fourier transformation (FFT)
      of experimental HREM images, filtering of the FFT patterns and inverse FFT. By
      through-focus observation, HREM images of iron oxide were obtained based on the
      tuning of contrast transfer function. Fourier filtering is effective for
      examining the beginning of phase transformation, because at this stage the
      diffraction spots of iron oxide are too weak to be detected. At the time when the
      iron oxide layer has developed to some extent, through-focus observation is
      useful to obtain an image of oxide layers.

PMID- 15180210
TI  - Microstructure of metal-filled carbon nanotubes.
AB  - Catalysts are usually required to produce carbon nanotubes (CNTs) and play
      important roles during the growth process. Any catalysts that remain after
      processing are expected to add extra properties and removal of the catalysts is
      usually required to achieve the original properties of CNTs. Recently, CNTs have
      been filled incidentally by catalysts, such as Pb, Sn, Ni and Bi. This has led to
      success in obtaining additional properties and a few models have been proposed to
      describe the encapsulating mechanisms. In the present study, CNTs were filled
      with palladium by a microwave plasma-assisted chemical vapor deposition method.
      Detailed structural and compositional investigations of these metal-filled CNTs
      were carried out by transmission electron microscopy to elucidate the growth
      mechanisms.

PMID- 15180211
TI  - Electron microscopy observation of interface in diffusion-bonded copper joint.
AB  - The microstructure at the interface of diffusion-bonded joints of oxygen-free
      high-conductivity copper for two kinds of surface conditions, with and without
      argon ion bombardment treatment, was investigated using scanning and high
      resolution transmission electron microscopy and energy-dispersive X-ray
      spectroscopy. The results showed that argon ion bombardment effectively removed
      the surface oxide film layer and lowered the height of the surface asperity, so
      that inclusion formation was decreased and void shrinkage time was shortened at
      the interface of the bonded copper joints, and the tensile strength of diffusion
      bonded copper joints was improved obviously.

PMID- 15180212
TI  - Atom-selective imaging and mechanical atom manipulation using the non-contact
      atomic force microscope.
AB  - We succeeded in distinguishing between oxygen and silicon atoms on an oxygen
      adsorbed Si(111)7 x 7 surface, and also distinguished between silicon and tin
      atoms on Si(111)7 x 7-Sn intermixed and Si(111) square root(3) x square root(3)
      Sn mosaic-phase surfaces using non-contact atomic force microscopy (NC-AFM) at
      room temperature. Atom species of individual atoms are specified from the number
      of each atom in NC-AFM images, the tip-sample distance dependence of NC-AFM
      images and/or the surface distribution of each atom. Further, based on the NC-AFM
      method but using soft nanoindentation, we achieved two kinds of mechanical
      vertical manipulation of individual atoms: removal of a selected Si adatom and
      deposition of a Si atom into a selected Si adatom vacancy on the Si(111)7 x 7
      surface at 78 K. Here, we carefully and slowly indented a Si atom on top of a
      clean Si tip apex onto a predetermined Si adatom to remove the targeted Si adatom
      and onto a predetermined Si adatom vacancy to deposit a Si atom, i.e. to repair
      the targeted Si adatom vacancy. By combining the atom-selective imaging method
      with two kinds of mechanical atom manipulation, i.e. by picking up a selected
      atom species and by depositing that atom one by one at the assigned site, we hope
      to construct nanomaterials and nanodevices made from more than two kinds of atom
      species in the near future.

PMID- 15180213
TI  - Optical characterization of individual semiconductor nanostructures using a
      scanning tunneling microscope.
AB  - By injecting low-energy minority carriers from the tip of a scanning tunneling
      microscope (STM) and analyzing the light emitted from the tip-sample gap of the
      STM, it is possible to study the optical and electronic properties of individual
      semiconductor nanostructures with an extremely high spatial resolution close to
      the atomic scale. This technique has been applied to investigate the transport
      properties of hot electrons injected into AlGaAs/GaAs quantum well structures and
      the optical properties of single self-assembled InAs/AlGaAs quantum dots. The
      physical principles, usefulness and future expectations of this novel technique
      are discussed.

PMID- 15180214
TI  - Novel local density of state mapping technique for low-dimensional systems.
AB  - A novel local density of state (LDOS) probing method for low-dimensional electron
      systems is proposed. By applying a two-dimensional fast Fourier transform to a
      real-space image obtained by scanning tunneling microscopy (STM), visualization
      of a complementary image in k-space can be realized. Especially, low-dimensional
      Fermi contours can be extracted by applying the k-space imaging to real-space
      images containing sufficient LDOS information around the Fermi level. To realize
      a more enhanced LDOS visualization in both spaces, we have proposed the use of
      special materials for STM tips, which have relatively large LDOSs at the Fermi
      level. To demonstrate this idea, several kinds of STM tips (Ag, Au, W and Nb)
      with different types of LDOSs were developed. An Au(111)-(22 x square root(3))
      reconstructed surface, where Shockley surface-state electrons form a nearly free
      electron gas, was selected as a test sample for the LDOS extraction.
      Visualization of standing waves in the surface LDOS modulated by herringbone
      reconstruction was attempted using the various types of STM tips. Significant
      effects of the LDOSs of the STM tips were clarified.

PMID- 15180215
TI  - Scattering-type near-field optical microscopy.
AB  - A highly promising tool for nanoscale material characterization exploits local
      optical/infrared light scattering simultaneously with standard atomic force
      microscopy imaging. Thus, both the topography and the local optical/infrared
      properties of a sample surface can be mapped at better than 20 nm spatial
      resolution.

PMID- 15180216
TI  - Nano-optical probing of exciton wave-functions confined in a GaAs quantum dot.
AB  - We have enhanced the performance of near-field scanning optical microscopy (NSOM)
      in terms of the spatial resolution and the sensitivity in signal detection. A
      careful preparation of an aperture-NSOM probe provides us with a spatial
      resolution as high as 30 nm in fluorescence imaging spectroscopy. We have applied
      this technique to map out the center-of-mass wave functions of an exciton
      confined in a GaAs quantum dot (a monolayer-high island formed in a quantum
      well). The spatial profile of the exciton emission, which reflects the shape of
      the island, differs from that of biexciton emission, due to different
      distributions of the polarization field for the exciton and biexciton
      recombinations. A theoretical calculation of the spatial distribution of the
      polarization field quantitatively reproduced the experimental result.
      Furthermore, mapping of an excited state wave-function with a node structure is
      also demonstrated. The novel technique can be extensively applied to wave
      function engineering in the design and fabrication of quantum devices.

PMID- 15180217
TI  - Cathodoluminescence study of one-dimensional free-standing widegap-semiconductor
      nanostructures: GaN nanotubes, Si3N4 nanobelts and ZnS/Si nanowires.
AB  - Luminescence properties of one-dimensional free-standing widegap-semiconductor
      nanostructures were characterized by means of cathodoluminescence (CL). GaN
      nanopipes, alpha-Si3N4 nanobelts and ZnS/Si nanowires were fabricated by a
      catalyst-free method, namely grown in an induction furnace from powders. After
      the observation of morphology by scanning electron microscopy as well as the
      confirmation of their crystal structures by transmission electron microscopy,
      their CL spectra and images were observed. The CL spectra mapping as well as the
      monochromatic CL imaging revealed the variation of the luminescence spectra of
      different nanowires as well as that along a single wire. These results revealed
      the optical features of nanostructures.

PMID- 15180218
TI  - Observation of polarization property in near-field optical imaging by a
      polarization-maintaining fiber probe.
AB  - We fabricated an original near-field scanning optical microscopy (NSOM) fiber
      probe made of polarization-maintaining and attenuation-reducing (PANDA)-type
      polarization-maintaining optical fiber, and observed the polarization property of
      propagation light in a polymer optical waveguide. The distribution of the
      transmission coefficient in polarization angles through this NSOM probe showed
      that the linear polarization is maintained in the two crossing directions: the
      fast and slow axes. The polarization degree parallel to the slow axis decreases
      from 1000:1 to 2:1 by bending the fiber probe and the decrease is independent of
      the bending direction. Using this PANDA-type NSOM probe, we investigated the
      polarization property of periodic intensity modulation. It was found that the
      intensity modulation was observed clearly with the electric vector parallel to
      the radius direction of the waveguide, but was observed vaguely with the electric
      vector perpendicular to the radius direction.

PMID- 15180219
TI  - Exercise reduces sick leave in patients with non-acute non-specific low back
      pain: a meta-analysis.
AB  - OBJECTIVES: To investigate whether exercise alone or as a part of a
      multidisciplinary treatment reduces sick leave in patients with non-specific non
      acute low back pain. METHODS: A meta-analysis of randomized controlled trials was
      performed. A qualitative analysis of the sick leave results was performed
      applying pre-defined levels of evidence. In studies comparing exercise with usual
      care, pooled effect sizes were computed. RESULTS: Fourteen trials were identified
      allowing 22 comparisons between treatments. The qualitative and the quantitative
      analysis showed strong evidence that exercise reduces sick days during the first
      follow-up year, the effect size (95% confidence interval) was -0.24 ( -0.36, 
      0.11). In a subgroup of studies on the treatment of severely disabled patients (>
      90 sick days under usual care) the effect size was -0.30 (-0.42, -0.17). The
      effect size of the number of patients receiving a disability allowance was small
      and not significant. CONCLUSION: The reviewed trials provide strong evidence that
      exercise significantly reduces sick days during the first follow-up year.

PMID- 15180220
TI  - Possible interpretation of subjective complaints in patients with spontaneous
      subarachnoid haemorrhage.
AB  - OBJECTIVE: To analyse factors related to subjective non-cognitive and cognitive
      complaints in patients with spontaneous subarachnoid haemorrhage. SUBJECTS:
      Twenty-seven patients with subarachnoid haemorrhage and 27 age-, sex- and
      education-matched healthy controls. METHODS: A battery of cognitive tests
      measuring visuo-spatial abilities, verbal abilities, and fine-motor skill, Brief
      Social Support Questionnaire, and Life Orientation Scale were individually
      presented to all participants. RESULTS: Cognitive complaints were related to low
      social support but not to cognitive performance. Complaints about headaches and
      dizziness were also related to decreased cognitive performance. Above-normal
      optimistic life-orientation was related to the absence of complaints in patients
      with subarachnoid haemorrhage. Healthy participants were best discriminated from
      patients with subarachnoid haemorrhage by less satisfactory social support system
      and decreased fine motor skills in the latter group. CONCLUSION: Change in social
      support network may be an important resource for increasing quality of life in
      patients with subarachnoid haemorrhage not only through help provided by
      supporters but also indirectly, through increasing subjective well-being. The
      absence of subjective complaints in patients with subarachnoid haemorrhage is not
      necessarily related to better objective condition but rather to inadequately
      optimistic life orientation.

PMID- 15180221
TI  - Older people's use of powered wheelchairs for activity and participation.
AB  - OBJECTIVE: The aims of this study were to investigate outcomes of older people's
      use of powered wheelchairs and risk factors for negative outcomes. DESIGN: The
      study was a cross-sectional interview-study including 111 powered wheelchair
      users over 65 years of age. RESULTS: All participants used their powered
      wheelchair in the summer; nearly all users regarded it as important and found
      that it gave them independence. The wheelchair made activity and participation
      possible for the users. The most frequent activity in the summer was going for a
      ride, and in the winter it was shopping. However, some could not use the
      wheelchair for visits, and supplementary travel modes are called for. Users who
      could not walk at all or who could not transfer without assistance were more
      likely not to be able to carry out prioritized activities. Furthermore, other
      risk factors for negative outcomes and need for further research were identified.
      CONCLUSION: The use of powered wheelchairs is a relevant societal intervention in
      relation to older people with limited walking ability in order to make activity
      and participation possible. It is likely that a larger proportion of older people
      could benefit from this intervention, in particular if current practices are
      improved taking activity and participation outcomes into consideration.

PMID- 15180222
TI  - Musculoskeletal pain in adults with cerebral palsy compared with the general
      population.
AB  - OBJECTIVE: To examine prevalence and localization of musculo-skeletal pain in
      adults with cerebral palsy compared with the general population and to
      investigate variables potentially associated with pain. DESIGN: A postal survey.
      SUBJECTS: Persons with cerebral palsy and no intellectual disabilities, 18 years
      or more, living in Norway. METHODS: A multidimensional questionnaire, including
      items on musculo-skeletal pain, was sent to 766 adults with cerebral palsy.
      RESULTS: In total 406 persons responded, 49% females and 51% males age range 18
      72 years (mean 34 years). All categories of cerebral palsy were represented.
      Nearly one-third of the adults with cerebral palsy had chronic pain, vs 15% in
      the general population. Mean scores of domain of bodily pain on Short Form 36
      were significantly lower from an earlier age in adults with cerebral palsy. Back
      pain was the most common in both groups. Pain in adults with cerebral palsy was
      significantly associated with gender, chronic fatigue, low life satisfaction and
      deteriorating physical function. CONCLUSION: Musculo-skeletal pain is a
      pronounced problem in adults with cerebral palsy from an early age, and should be
      addressed specifically in the follow-up programs, and in further clinical studies
      on potential causal pathways.

PMID- 15180223
TI  - Evaluation of changes in occupational performance among patients in a pain
      management program.
AB  - OBJECTIVES: The aims of this study were to evaluate changes in occupational
      performance among chronic pain patients after a pain management program and to
      explore relationships between these changes and demographic and clinical factors,
      psychosocial functioning and psychological well-being. SUBJECTS: 188 consecutive
      patients were included. METHODS: Changes were registered by using Canadian
      Occupational Performance Measure, Multidimensional Pain Inventory and
      Psychological General Well-Being Index. RESULTS: There were statistically
      significant positive changes in occupational performance. Patients with sickness
      compensation had significantly higher changes in occupational performance than
      those without sickness compensation. The patients with a profile group as
      interpersonally distressed had statistically significant higher change scores on
      occupational performance than the adaptive coper group. Furthermore, increases in
      changes on general activity level, general health, and vitality and decreases in
      pain severity were associated with positive changes on perceived occupational
      performance and performance satisfaction. CONCLUSION: Changes in occupational
      performance, psychological well-being and psychosocial functioning seem all to be
      of relevance in the evaluation of pain management programs. Psychosocial profiles
      and sickness compensation has relevance for directions on changes in occupational
      performance, whereas other demographic and clinical factors do not.

PMID- 15180224
TI  - A specific arm-interval exercise program could improve the health status and
      walking ability of elderly patients after total hip arthroplasty: a pilot study.
AB  - OBJECTIVE: To investigate the influence of an arm-interval exercise program for
      the upper limbs on health status and walking ability in elderly patients after
      total hip arthroplasty. DESIGN: A randomized controlled investigation. After
      surgery, a control group started a general rehabilitation program, and a training
      group combined it with an arm-interval exercise program. SUBJECTS: Fourteen
      patients (age 75.1 +/- 4.8 years) were randomly assigned to the control group (n
      = 7) and the training group (n = 7). METHODS: A Western Ontario and MacMaster
      University (WOMAC) Osteoarthritis Index was completed and an incremental exercise
      test on an arm crank ergometer was also performed 1 month before (T(-1)) and 2
      months after surgery (T2). Moreover, a 6-minute walk test was performed at T2.
      RESULTS: Both groups significantly improved all dimensions of WOMAC, except in
      WOMAC physical function subscale in the control group. The training group covered
      a significantly longer distance in the walking test than the control group and
      also presented significantly higher VO2 peak value at T2. Correlation analyses
      indicate that VO2 peak value and the distance covered in the 6-minute walking
      test were significantly associated with functional status. After calculating the
      ratio distance covered/score at WOMAC physical function, we observed a
      significantly higher ratio value in the training group than in the control group.
      CONCLUSION: Preliminary results indicate that the improvement in physical fitness
      and functional status of the training group seems to be associated with better
      health status.

PMID- 15180225
TI  - What's all that noise? The effect of co-morbidity on health outcome questionnaire
      results after knee arthroplasty.
AB  - BACKGROUND: We modified the Charnley Classification for hips to facilitate its
      use with knee arthroplasty patients and investigated what affect the different
      classes of co-morbidity had on the results of a spectrum of outcome
      questionnaires. PATIENTS AND METHODS: 3600 patients from the Swedish Knee
      Arthroplasty Registry were surveyed by post with a variety of questionnaires
      ranging from multiple-item general health, to a single-item knee arthroplasty
      specific questionnaire. All patients also completed a co-morbidity questionnaire,
      from which a modified Charnley Classification was generated for each patient. We
      then investigated the correlation and relationship between the results of the
      questionnaires and the different classes of co-morbidity. RESULTS: The results of
      the questionnaires tested varied significantly by Charnley Class, regardless of
      the specificity of the questionnaire used. INTERPRETATION: We suggest that co
      morbidity should be taken into account in outcome studies utilizing general
      health or disease/site specific questionnaires.

PMID- 15180226
TI  - High survival rate of hydroxyapatite-coated hip prostheses: 100 consecutive hips
      followed for 10 years.
AB  - We followed 100 consecutive primary total hip replacements with a proximal
      hydroxyapatite coating for 10 years. No patient was lost to follow-up. 29
      patients (32 hips) died before the 10-year follow-up was done; none of their hips
      had been revised. Thigh pain on activity occurred in 3 hips. We found no
      radiographic signs of loosening of the femoral components. In course of time the
      location of dense bone around the femoral stem, which would suggest implant/bone
      stress transfer, moved distally in 51 of 67 stems after 10 years. No linear or
      distal osteolysis occurred around the stem. Revision of 1 stem was performed
      because of thigh pain, but it was found fixed to bone proximally, while 3 cups
      were revised because of acetabular osteolysis. The 10-year survival of the stem
      and cup, using revision or pending revision as endpoint, was 100% (95% CI: 99
      100) and 97% (95% CI: 94-99), respectively.

PMID- 15180227
TI  - Micro-wear features on unique 100-Mrad cups: two retrieved cups compared to hip
      simulator wear study.
AB  - We studied the micro-wear phenomena of unique, extensively cross-linked
      polyethylene cups (cross-linked with 1,000 kGy-irradiation) that had been used
      briefly in Japan. Two retrievals (at 15 years) came from the Japanese "SOM" hip
      system (implanted 1971-78). These were compared to a set of 0 kGy and 500-1,500
      kGy cups run in our hip simulator. The polyethylene cups that had not been cross
      linked had the greatest wear. The worn areas had a burnished appearance and were
      clearly separated from the unworn region by a distinct ridge-line. The worn areas
      had lost all machine tracks, showed a large amount of UHMWPE 'flow', and long PE
      fibrils. The associated surface rippling was degraded. These features were
      considered synonymous with severe polyethylene wear. In contrast, the worn areas
      in the very cross-linked cups had a visibly matte surface and no ridge-line.
      Micro-examination showed that the machine tracks were still present. Ripple
      formations were less obvious than in the cups that were not cross-linked,
      polyethylene surface fibrils were scarcer and all the fibrils were much smaller
      than in the cups that were not crosslinked. Our two retrieved cups and the
      simulator cups confirmed the greater wear-resistance of very cross-linked
      polyethylene. It should also be noted that the SOM cup design and processing were
      unique and differed greatly from that of modern polyethylene cups.

PMID- 15180228
TI  - Total hip replacement in younger patients: survival rate after avascular necrosis
      of the femoral head.
AB  - BACKGROUND: A high risk of loosening has been reported in replacements performed
      because of avascular necrosis. PATIENTS AND METHODS: To study cementless total
      hip replacement (THR) in younger patients with avascular necrosis (AVN), we
      analyzed retrospectively the outcome in 129 cases: 46 Mittelmeier monobloc
      ceramic hips (22 cases with AVN), and 83 Zweymuller total hip systems (35 cases
      with AVN) clinically and radiographically. RESULTS: At follow-up, 17 Mittelmeier
      prostheses (10 AVN) and 4 Zweymuller prostheses (none with AVN) had been revised.
      The diagnosis did not affect the implant survival, but the Zweymuller THR fared
      better than the Mittelmeier system. The main reason for revision of Mittelmeier
      implants was aseptic loosening, 3 of 4 Zweymuller revisions were necessary due to
      polyethylene wear. This difference was confirmed by the radiographic evaluation
      of the still intact implants: Zweymuller THR showed better values for signs of
      osseointegration, radiolucent lines around the implants and migration, but more
      acetabular wear. None of these differences was affected by the AVN diagnosis.
      INTERPRETATION: We could not confirm that AVN is a risk factor in total hip
      replacement.

PMID- 15180229
TI  - Changes in load-bearing area after Ganz periacetabular osteotomy evaluated by
      multislice CT scanning and stereology.
AB  - BACKGROUND: We used a stereologic method based on 3D CT scanning to estimate the
      projected load-bearing surface in the hip joint. PATIENTS AND METHODS: 6 normal
      hip joints and 6 dysplastic hips were examined. The latter were CT-scanned before
      and after periacetabular osteotomy. RESULTS: We found that the average area of
      the projected load-bearing surface of the femoral head preoperatively was 7.4
      (6.5-8.4) cm2 and postoperatively 11 (9.8-14) cm2, which was similar to the load
      bearing surface in the normal control group. We performed double measurements and
      the coefficient of error of the mean was estimated at 1.6%. Due to
      overprojection, an overestimation of about 3.8% on the projected load-bearing
      surface occurred. Consequently, the stereologic method proved to be precise and
      unbiased. INTERPRETATION: Our findings indicate that this method is of value for
      monitoring the load-bearing area in the hip joint of patients undergoing
      periacetabular osteotomy.

PMID- 15180230
TI  - An age-related medullary expansion can have implications for the long-term
      fixation of hip prostheses.
AB  - BACKGROUND: Diaphyseal bone loss occurs mainly at the endosteal surface in the
      medullary cavity. Since the menopause is followed by an increase in bone loss,
      the size of the medullary cavity should theoretically increase during the
      postmenopausal period. If so, this might affect the long-term fixation of hip
      prostheses. PATIENTS AND METHODS: This 19-year prospective study evaluated bone
      loss and geometrical changes in 112 women, all premenopausal at baseline. Bone
      mineral density (BMD) and skeletal geometry, with special reference to the size
      of the medullary cavity, were estimated every other year by single-photon
      absorptiometry at the cortical site of the distal radius. RESULTS: After
      menopause, a decrease of 1.7 (95% CI 1.6-1.8)% occurred in the BMD every year,
      while an increase of 0.9 (0.8-1.0)% in the medullary width (endosteal width) too
      place every year. The annual change in BMD was inversely correlated with the
      annual change in the medullary width (r = -0.5, p < 0.001). The quartile of women
      with the largest BMD loss had a greater medullary expansion than the quartile of
      women with the least BMD loss (p < 0.001). INTERPRETATION: If the age-related
      expansion of the radial medullary cavity is a general phenomenon, this may have
      implications for the long-term fixation of hip prostheses.

PMID- 15180231
TI  - Comparison of various vacuum mixing systems and bone cements as regards
      reliability, porosity and bending strength.
AB  - BACKGROUND: There are several vacuum mixing systems on the market which are
      arbitrarily used with various bone cements in clinical work. Hardly any studies
      have been done on the performance and handling of these systems in combination
      with different cement brands. MATERIAL AND METHODS: We therefore tested 6 vacuum
      mixing systems (Palamix, Summit, Cemvac, Optivac, Vacumix, MixOR) in combination
      with 6 cement brands (Palacos R, Simplex P, CWM 1, CWM 2000, Palamed G,
      VersaBond) concerning their reliability, user-friendliness, porosity and bending
      strength. RESULTS: Our study indicated that each system has weak points. The
      preparation of the mixed cement for gun injection can present problems. If cement
      collection under vacuum fails, porosity is increased. Manual collection without a
      vacuum carries the risk of intermixing air. For comfortable and effective
      retrograde cement application, cement guns should have a stable connection with
      the cartridge and a high piston stroke. There are marked differences between the
      systems as regards overall porosity when all tested cements are considered (range
      2-18%), and between the cements when all tested systems are considered (range 2
      17%). All test samples exceeded the required bending strength of 50 MPa,
      according to ISO 5833. Palaces specimens showed excessive plastic deformation in
      the bending test. INTERPRETATION: There are better and worse mixing system/cement
      combinations for a given system and a given cement. Systems with cement
      collection under vacuum reduce porosity best.

PMID- 15180232
TI  - Gentamicin concentrations in diagnostic aspirates from 25 patients with hip and
      knee arthroplasties.
AB  - BACKGROUND: There is little information on long-term release of antibiotics from
      impregnated bone cement. PATIENTS AND METHODS: We assayed joint fluids obtained
      for diagnostic purposes from 25 patients for the presence of gentamicin. All
      patients had presented with failing or painful joints up to 20 years following
      primary hip or knee arthroplasty, using gentamicin-impregnated cement. RESULTS:
      Gentamicin was detected in the joint fluids from 9 of 15 patients with knee
      prostheses and 4 of 10 patients with hip prostheses. The concentrations ranged
      from 0.06 mg/L to 0.85 mg/L with no significant differences in concentration
      between the patients with hip or knee prostheses, or the type of prosthesis. We
      found no relationship between the gentamicin concentration and the time after
      primary arthroplasty. INTERPRETATION: Although most concentrations were below the
      levels required to inhibit susceptible pathogens, we conclude that gentamicin
      release around failing implants may lead to false negative cultures in some
      patients and provide selective pressure for the emergence of resistance where
      infection is present in others.

PMID- 15180233
TI  - Early individualized postoperative occupational therapy training in 100 patients
      improves ADL after hip fracture: a randomized trial.
AB  - BACKGROUND: It is not clear whether occupational therapy is of value for hip
      fracture patients. PATIENTS AND METHODS: In a randomized trial we studied the
      effects of an early, individualized, postoperative occupational training (OT)
      program on the ability of hip fracture patients to perform ADL and IADL.
      Secondary endpoints were self-reported fear of pain and pain when performing ADL
      and IADL. The need for technical aids and/or home adaptations was also
      investigated. 100 eligible patients (aged > or = 65 years, with independent
      residence) were randomized 50:50 to an OT or control group (conventional care).
      During their hospital stay, members of the OT group received individual daily
      training which included the use of technical aids. Before discharge, the
      occupational therapist paid a home visit together with the patient. All patients
      were assessed 2-4 days after surgery, at discharge and after 2 months, using the
      Klein-Bell ADL scale and a modified version of the Disability Rating Index.
      RESULTS: At discharge, the OT group had better ability to dress, to take care of
      personal hygiene and bathing activities independently, and to make toilet visits.
      Age, sex, type of fracture or length of stay at the hospital made no significant
      contribution to explaining the better ADL ability on discharge. After 2 months,
      all patients had regained their ADL and IADL abilities. Half of the patients
      required technical aids and adaptations in their homes. INTERPRETATION:
      Individualized OT-training speed up the ability of patients to perform ADL, thus
      enhancing the likelihood of patients returning to independent living and reducing
      the need for postoperative care at home.

PMID- 15180234
TI  - How reliable are reliability studies of fracture classifications? A systematic
      review of their methodologies.
AB  - Two independent reviewers performed a search in MEDLINE and EMBASE for fracture
      classification reliability studies. Data were obtained on classifications, image
      modalities, fracture selection processes, sample sizes and their justification,
      type and number of raters, practical issues for the classification sessions,
      statistical methods, and results. A 10-item checklist was devised for quality
      assessment of methodologies. 44 studies assessing 32 fracture classification
      systems were included. We found a wide variation of methodologies. For instance,
      the median number of raters was 5 (2-36) and the median number of fractures was
      50 (10-200). This selection was considered representative in 17/44 of the
      studies. The true distribution of classification categories was estimated in 9
      studies. The kappa coefficient was mostly used (39/44) to quantify the raters'
      agreement. Methodological issues are discussed. Given limitations in the use and
      interpretation of kappa coefficients, investigators should consider alternative
      methods that focus upon the accuracy of the classification systems. The
      development and adoption of a systematic methodological approach to the
      development and validation of fracture classification systems is needed.

PMID- 15180235
TI  - Fracture rate in a population-based sample of men in Reykjavik.
AB  - The population-based Reykjavik Heart Study, started in 1967, aims at finding and
      evaluating risk factors for cardiovascular diseases. It included 4,137 men born
      between 1907 and 1934 and we examined all fractures recorded in these subjects
      from January 1977 until the end of December 2000, or death. Their mean age at the
      start of this study was 54 (42-69) years and the mean follow-up time 19 years. We
      examined the patients' records, including those from the Radiological Departments
      in all Reykjavik hospitals and the only out-patient accident clinic in Reykjavik.
      Old fractures and those caused by a malignancy were excluded. The intensity of
      the trauma was estimated from E-numbers. Altogether 1,531 fractures were recorded
      in 939 (23%) persons. A low-energy trauma caused 53% of all fractures. 612 had a
      single fracture during this period. 323 had two or more fractures--a 53% risk of
      sustaining additional fractures. The fracture incidence increased by 40% in each
      10-year period. Fractures of the ribs were commonest (246), followed by those of
      the hand (241). 135 were hip fractures, 75% caused by low-energy trauma. The
      fracture rate was 20 per 1000 persons year--i.e., similar to that in other
      studies.

PMID- 15180236
TI  - Pharmacological treatment of osteopenia induced by gastrectomy or ovariectomy in
      young female rats.
AB  - BACKGROUND: Both gastrectomy (GX) and ovariectomy (OVX) induce osteopenia in man
      and experimental animals. The present study addresses the question--can
      alendronate, estrogen or parathyroid hormone (PTH) be used to treat established
      GX- or OVX -evoked osteopenia? METHODS: Rats were GX-, OVX- or SHAM-operated 8
      weeks before starting the treatment with drugs. Each group was then treated for 8
      weeks with 50 microg/kg/day alendronate, 10 microg/kg/day estrogen or 75
      microg/kg/day PTH(1-84); n = 8 rats/group. Peripheral Quantitative Computed
      Tomography (pQCT) was used to measure trabecular bone mineral density (BMD) and
      various cortical bone parameters. RESULTS: At killing, 16 weeks after surgery, GX
      and OVX rats had a greatly reduced trabecular BMD in the metaphysis of the distal
      femur (GX -44% and OVX -55%). Alendronate increased the trabecular BMD by 44% in
      GX rats and by 64% in OVX rats, while PTH increased it by 51% and 115%,
      respectively. However, estrogen increased the trabecular BMD in GX rats (35%),
      but not in OVX rats (15%, not significant). Cortical bone parameters were
      adversely (but moderately) affected by GX, but not by OVX or by treatment with
      the three drugs. INTERPRETATION: Alendronate, estrogen and PTH restored the
      trabecular bone loss in rats with an established GX-evoked osteopenia. In
      contrast, alendronate and PTH, but not estrogen, restored the trabecular bone
      loss after OVX. Hence, the mechanism underlying GX-evoked bone loss differs from
      that underlying OVX-evoked bone loss. The ability of alendronate, estrogen and
      PTH to reverse the GX-evoked osteopenia in the rat may be of clinical interest
      when dealing with bone loss in humans after GX.

PMID- 15180237
TI  - Chondrocyte cloning in aging and osteoarthritis of the hip cartilage:
      morphometric analysis in transgenic mice expressing bovine growth hormone.
AB  - An arthritic disorder resembling human osteoarthritis occurs in transgenic mice
      expressing the fusion gene coding for bovine growth hormone (bGH). In these
      animals, we performed a morphometric evaluation of cellular density, clonal
      density and the relationship between both parameters in articular cartilage.
      These parameters were determined in the femoral head of bGH (+) mice at 1, 6 and
      12 months of age and compared to values in the control mice. The transgenic mouse
      showed a reduction in cellular density of the superficial and middle zones of the
      articular cartilage with age. In the uncalcified cartilage at 6 and 12 months of
      age, cellular density was significantly lower in age-matched transgenic mice than
      in the control group. In the former, the changes in cellular density were
      accompanied by a gradual reduction in the clonal density in the superficial and
      middle zones. The clonal density/cellular density ratio was similar in transgenic
      mice and the control group at 12 months of age. These findings indicate that
      these transgenic mice develop an osteoarthritic process characterized by loss of
      cellularity and a gradual decline in chondrocyte cloning in the superficial and
      middle zones.

PMID- 15180238
TI  - Faster integration of human allograft bone than of the bovine substitute Lubboc:
      non-randomized evaluation of 20 cases with benign tumors or tumor-like
      conditions.
AB  - In 20 patients, we studied healing and time for complete integration of human
      cancellous bone allografts and the bovine substitute Lubboc on plain radiographs.
      They were all operated on because of benign tumors or tumor-like conditions, and
      followed until integration of the graft or for at least 1 year after operation.
      The median follow-up was 10 (2-40) months. Allografts showed a better integration
      than the bovine substitute. We conclude that allografts are to be preferred for
      these indications.

PMID- 15180239
TI  - Initially neglected tissue interposition after reduction of posterior hip
      dislocation in a child--a case report.

PMID- 15180240
TI  - Distraction with external fixator for contractures of proximal interphalangeal
      joints: good outcome in 10 cases.
AB  - We present a new and simple technique for the treatment of proximal
      interphalangeal (PIP) joint contractures by mini Orthofix external fixator
      without open surgery. The technique was tested on 10 patients. We found that the
      fixator is easy to apply and effective in reducing contractures of the PIP joint
      by soft tissue distraction.

PMID- 15180241
TI  - Identification of the RP1 and RP10 (IMPDH1) genes causing autosomal dominant RP.

PMID- 15180243
TI  - An integrated genetic approach to identify candidate genes for human chromosome
      6q-linked retinal disorders.

PMID- 15180244
TI  - Mouse genetic approaches to access pathways important in retinal function.
AB  - The laboratory mouse is a premier research tool for understanding human biology
      and disease. With the availability of the first complete draft sequences of the
      mouse genome and ongoing large scale screens for new mouse mutations to serve as
      novel models, the usefulness of the mouse will only increase. The vision research
      field, in particular, which has identified many human diseases for which no
      models are yet available, will benefit from the newly developed tools in mouse
      molecular genetics.

PMID- 15180245
TI  - Retinal degenerative disorders in Southern Africa: a molecular genetic approach.

PMID- 15180242
TI  - On the role of IMPDH1 in retinal degeneration.

PMID- 15180246
TI  - Comparing rod and cone function with fundus autofluorescence images in retinitis
      pigmentosa.

PMID- 15180247
TI  - A modified protocol for the assessment of visual function in patients with
      retinitis pigmentosa.
AB  - BACKGROUND: The assessment of visual function for retinitis pigmentosa routinely
      includes: electroretinography, visual acuity and visual field-testing. Patients
      with retinitis pigmentosa sometimes complain of changes in visual function, which
      are not paralleled by routine eye tests. AIMS AND OBJECTIVES: To determine which
      visual function test or group of tests can predict reliably perceived visual
      function in patients with retinitis pigmentosa METHODS: Subjects with progressive
      retinitis pigmentosa are recruited from the Ocular genetics program of The
      Hospital for Sick Children and Mount Sinai Hospital, Toronto. Subjects will be
      tested four times over the over the period of one year. On each visit they
      undergo following tests- 1) Central visual acuity (VA) using the crowded logMAR
      acuity chart, 2) Contrast Sensitivity (CS) using Pelli-Robson contrast
      sensitivity chart, 3) Visual field test (VF) using Humphrey (10-2), 4) Color
      vision using Mollon-Reffin 'minimalist' test and 5) Subjective visual function
      questionnaire testing near and global perceived visual function respectively.
      RESULTS: Phase I (baseline and visit I measure) results are reported. Total of
      sixty-eight patients with mean age of 41 years, age range of twelve to sixty
      seven were tested. Of these thirty-one were males and thirty-seven were females.
      Repeat testing correlation was high (r>0.8, p<0.05) for all parameters between
      baseline visit and visit I. The near perceived visual function correlated best
      with the combination of visual acuity and contrast sensitivity. The global
      perceived visual function correlated best with combination of visual field and
      visual acuity. Objective measure of central visual function (HVF 10-2) correlated
      best with contrast sensitivity. DISCUSSION: The addition of contrast sensitivity
      and Humphrey visual field to routine visual assessment should improve the quality
      of the longitudinal data of visual function recorded on these patients. Patients
      will be re- tested at six months and one-year interval. To date of the sixty
      eight subjects twenty-seven have returned for their six-month visit (phase II).

PMID- 15180248
TI  - Prenatal human ocular degeneration occurs in Leber's Congenital Amaurosis (LCA1
      and 2).

PMID- 15180249
TI  - Leber congenital amaurosis--genotyping required for possible inclusion in a
      clinical trial.

PMID- 15180250
TI  - Treatment of cystoid macular edema related to retinitis pigmentosa with
      intravitreal triamcinolone acetonide: case report.

PMID- 15180252
TI  - Progressive pathways in age-related macular degeneration.

PMID- 15180251
TI  - Proteomic approaches to understanding age-related macular degeneration.
AB  - Microdissection methods have been developed for isolating drusen and Bruch's
      membrane from human eyes. Comparative proteomic studies of these isolates from
      normal and AMD donors were pursued for clues to the biochemical pathways involved
      in the pathogenesis of AMD. A total of 129 potential drusen proteins were
      identified by LC MS/MS and immunocytochemical analyses have confirmed drusen
      localization for approximately 16% of the proteins. The most common drusen
      proteins appear to be TIMP-3, clusterin, vitronectin and serum albumin. Western
      blot analysis suggests that carboxyethyl pyrrole-protein adducts derived from
      docosahexaenoate-containing lipids are more abundant in AMD than in normal
      tissues. Abnormal protein cross-links and advanced glycation end products were
      also observed in drusen and Bruch's membrane. Lipid oxidation products and
      oxidative protein modifications may be causally involved in drusen formation and
      Bruch's membrane thickening.

PMID- 15180253
TI  - Tissue inhibitor of metalloproteinases-3 and Sorsby fundus dystrophy.

PMID- 15180254
TI  - Investigations of RPE cells of choriodal neovascular membranes from patients with
      age-related macula degeneration.

PMID- 15180255
TI  - Retinal and choroidal alterations following photodynamic therapy.

PMID- 15180256
TI  - Usher syndrome: correlation between visual field size and maximal ERG response b
      wave amplitude.

PMID- 15180257
TI  - The cellular function of the usher gene product myosin VIIa is specified by its
      ligands.

PMID- 15180258
TI  - Mouse models for Usher syndrome 1B.
AB  - Photoreceptor cell degeneration was not detected in any of the shaker1 alleles,
      except for a small but significant loss of photoreceptor cells found in
      Myo7a(4626SB/4626SB) mice that were also homozygous mutant for Cdh23v. Perhaps
      greater and/or faster photoreceptor cell loss that is dependent on mutant Myo7a
      can be effected by having additional mutant USH1 genes in the genetic background.
      In any case, it is argued that shaker1 mice are a useful model for testing USH1B
      gene therapy, due to the presence of mutant phenotypes other than photoreceptor
      cell death.

PMID- 15180259
TI  - Screen for usher syndrome 1B mutations in the ovine myosin VIIa gene.

PMID- 15180260
TI  - Photoreceptor intersegmental transport and retinal degeneration: a conserved
      pathway common to motile and sensory cilia.

PMID- 15180261
TI  - Inherited retinal dystrophy in Mer knockout mice.

PMID- 15180262
TI  - Mouse models of human retinal disease caused by expression of mutant rhodopsin. A
      valuable tool for the assessment of novel gene therapies.

PMID- 15180263
TI  - Evaluation of inner retinal structure in the aged RCS rat.

PMID- 15180264
TI  - The intact Xenopus laevis eye rudiment: a quasi-in vivo system for the study of
      retinal development and degenerations.

PMID- 15180265
TI  - Streptozotocin-induced diabetes--a rat model to study involvement of retinal cell
      types in the onset of diabetic retinopathy.

PMID- 15180266
TI  - A2E, a fluorophore of RPE lipofuscin: can it cause RPE degeneration?

PMID- 15180267
TI  - Bright light induces retinal degeneration by a transducin-independent mechanism.

PMID- 15180269
TI  - Light-induced photoreceptor damage triggers DNA repair: differential fate of rods
      and cones.
AB  - Intense light triggers cell death in cones and rods by two distinct mechanisms:
      rapid, necrosis-like cell death occurs in cones; prolonged, apoptotic death is
      displayed by rods. However, the areas of cone and rod loss coincide, suggesting
      some interrelationship. DNA fragmentation in rods occurs in two waves. Our
      evidence suggests a repair mechanism that triggers up-regulation of the enzyme
      DNA polymerase beta, implying a rod-specific mechanism that initially attempts
      DNA repair, but which subsequently fails, resulting in a second wave of damage
      leading to apoptotic rod cell death. This study suggests two different but
      coincidental pathways lead to photoreceptor death. Definition of these two
      pathways could suggest useful pharmacologic sites toward which compounds could be
      targeted to promote cell survival in damaging retinal degenerative diseases. In
      addition, maintenance or enhancement of existing in-house repair mechanisms could
      provide additional approaches for the rescue of neurons with stress-induced
      nuclear damage.

PMID- 15180268
TI  - Does constitutive phosphorylation protect against photoreceptor degeneration in
      Rpe65-/- mice?
AB  - Despite the presence of this virgin opsin, Rpe65-/- rods are behaving like dark
      adapted rods. These results argue that opsin which has not been exposed to 11-cis
      retinal and is constitutively phosphorylated, does not generate the activity
      generally associated with the bleached apoprotein. However, increased light
      independent activation of transducin (due to bleached opsin) could be
      demonstrated after the addition of exogenous 11-cis retinal. We hypothesize that
      free opsin in the Rpe65-/- rods does not cause degeneration of rods by
      constitutive activation of the phototransduction cascade; but rather rods may die
      due to other causes such as the impairment of RPE function due to excess
      unprocessed retinyl-esters in the RPE.

PMID- 15180270
TI  - Mitochondrial deletions in normal and degenerating rat retina.
AB  - Photoreceptor death by apoptosis is the central pathology of most forms of
      retinal degeneration. Mitochondria play key roles in apoptosis, releasing both
      signals which induce apoptosis (cytochrome c, caspases) and signals which inhibit
      apoptosis (Bcl-2). Because mitochondria are the site of oxidative metabolism they
      are also a major site of formation of the toxic oxygen intermediates which form
      as oxygen is recruited into the oxidative phosphorylation pathway. Previous
      studies have shown that deletions in mtDNA accumulate in postmitotic tissues
      (central nervous, muscle) and that their accumulation is accelerated by oxidative
      stress (such as hypoxia) (Takeda et al. 1996; Lee et al. 1994; Merril et al.
      1996; Englander et al. 1999). It seems possible therefore that mitochondria are a
      site at which oxidative stress induces the death of retinal neurones. This study
      investigates the accumulation of mtDNA deletions in the rat retina, in both
      normal (non-degenerative) and degenerative strains. Deletions were undetectable
      in Sprague-Dawley albino rats (24 months) but were detected at 15 months in the
      rapidly degenerating RCS strain. The appearance of deletions in the RCS strain,
      in which retinal oxygen tension is known to rise as the degeneration progresses,
      gives support to the ideas that oxidative stress is a factor in mtDNA deletions,
      and in the progress of the late stages of the degeneration.

PMID- 15180271
TI  - Quantitative PCR analysis of FosB mRNA expression after short duration oxygen and
      light stress.
AB  - Quantitative polymerase chain reaction (QPCR) was used to examine changes in FosB
      mRNA expression in models of oxygen and light stress to the retina. C57BL/6 mice
      or Sprague-Dawley (SD) albino rats were subjected to several experimental
      paradigms: short-term light or oxygen stress, extended hyperoxia (75% oxygen), or
      a model of oxygen-induced retinopathy (OIR). Control animals were subjected to
      room air and 5 lux cyclic light. FosB expression dramatically increases in
      response to light stress as well as in a model of OIR, but not in response to
      sustained 75% oxygen. These data suggest that both hypoxia and light stress
      induce expression of FosB in the retina.

PMID- 15180272
TI  - Metabolic modulation of visual sensitivity.

PMID- 15180273
TI  - Mitochondrial uncoupling proteins: regulators of retinal cell death.

PMID- 15180274
TI  - Energy depletion hypothesis for retinitis pigmentosa.

PMID- 15180275
TI  - Functional studies of AIPL1: potential role of AIPL1 in cell cycle exit and/or
      differentiation of photoreceptors.

PMID- 15180276
TI  - Photoreceptor degeneration in Pro23His and S334ter transgenic rats.

PMID- 15180277
TI  - Retinal degeneration caused by mutations in TULP1.

PMID- 15180278
TI  - Towards understanding the function of the tubby gene family in the retina.

PMID- 15180279
TI  - Identification of downstream mechanisms involved in PEDF'S activity in the retina
      by large scale gene expression profiling.

PMID- 15180280
TI  - The nob mutation does not protect against light-induced retinal degeneration.

PMID- 15180281
TI  - The phagocytosis of os is mediated by the PI3-kinase linked tyrosine kinase
      receptor, mer, and is stimulated by GAS6.

PMID- 15180282
TI  - Role of alphavbeta5 integrin in regulating phagocytosis by the retinal pigment
      epithelium.

PMID- 15180283
TI  - Comparative study of cathepsin D and S in rat IPE and RPE cells.

PMID- 15180284
TI  - Isolation and culture of primary mouse retinal pigmented epithelial cells.

PMID- 15180285
TI  - Regulation of the visual cycle: retinol dehydrogenase and retinol fluorescence
      measurements in vertebrate retina.

PMID- 15180286
TI  - Melatonin enhances retinoic acid induction of cone arrestin gene expression in
      retinoblastoma cells.

PMID- 15180287
TI  - Regulation of retinal phosphoinositide 3-kinase activity in p85alpha-subunit
      knockout mice.

PMID- 15180288
TI  - Peripherin/rds in skate retina.

PMID- 15180289
TI  - XIAP protects photoreceptors from n-methyl-n-nitrosourea-induced retinal
      degeneration.

PMID- 15180290
TI  - Neuroprotective effect of estrogen upon retinal neurons in vitro.

PMID- 15180291
TI  - Transgenic rd mice harboring axokine gene by Rpe65 gene promoter does not rescue
      photoreceptor degeneration.

PMID- 15180292
TI  - Marrow stromal cells (MSC): a species comparison.

PMID- 15180293
TI  - Gene therapy for Leber congenital amaurosis.

PMID- 15180294
TI  - Functional and structural evaluation after AAV.RPE65 gene transfer in the canine
      model of Leber's congenital amaurosis.

PMID- 15180295
TI  - Assessment of rAAV-mediated gene therapy in the Rpe65-/- mouse.

PMID- 15180296
TI  - Muller cell transduction by AAV2 in normal and degenerative retinas.

PMID- 15180297
TI  - Virus-mediated secretion gene therapy--a potential treatment for ocular
      neovascularization.

PMID- 15180298
TI  - Insulin receptor substrate proteins and diabetes.
AB  - The discovery of insulin receptor substrate (IRS) proteins and their role to link
      cell surface receptors to the intracellular signaling cascades is a key step to
      understanding insulin and insulin-like growth factor (IGF) action. Moreover, IRS
      proteins coordinate signals from the insulin and IGF receptor tyrosine kinases
      with those generated by proinflammatory cytokines and nutrients. The IRS2-branch
      of the insulin/IGF signaling cascade has an important role in both peripheral
      insulin response and pancreatic beta-cell growth and function. Dysregulation of
      IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during
      peripheral insulin resistance. IRS protein signaling is down regulated by serine
      phosphorylation or proteasome-mediated degradation, which might be an important
      mechanism of insulin resistance during acute injury and infection, or chronic
      stress associated with aging or obesity. Understanding the regulation and
      signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal
      new strategies to prevent or cure diabetes and other metabolic diseases.

PMID- 15180299
TI  - Synthesis of silicon traceless linker for solid-phase reaction.
AB  - The silicon linker is the foremost traceless linker used in solid-phase
      reactions. Hydrogen fluoride (HF) or trifluoroacetic aicd (TFA) can remove the
      silicon linker with the silicon atom being replaced by a hydrogen atom. In this
      experiment, the linkers 1c and 2d, which are the most useful in solid-phase
      reactions, were synthesized. Linker 1c is composed of seven linearly linked
      carbons and linker 2d includes an oxygen atom in the linear carbon chain to
      increase the solvation capacity. The carboxylic acid component of linker 1c and
      2d forms an amide or ester bond with resin. The synthesized linkers 1c and 2d
      could be utilized in constructing a chemical compound library that includes
      indole, benzodiazepine and phenothiazine (aromatic ring compounds).

PMID- 15180300
TI  - Anti-platelet pentacyclic triterpenoids from leaves of Campsis grandiflora.
AB  - Five pentacyclic triterpenoids, oleanolic acid (1), hederagenin (2), ursolic acid
      (3), tormentic acid (4) and myrianthic acid (5), were isolated from the methanol
      extract of the leaves of Campsis grandiflora, and structures of the compounds
      were established by the spectroscopic methods. Compounds 2, 3, 4, and 5 were
      isolated for the first time from the genus Campsis. All of the compounds (IC50:
      45.3, 32.8, 82.6, 42.9 and 46.2 microM respectively) were as equivalently
      inhibitive as acetylsalicylic acid (IC50: 57.0 microM) on epinephrine induced
      platelet aggregation.

PMID- 15180301
TI  - Phenolic and furan type compounds isolated from Gastrodia elata and their anti
      platelet effects.
AB  - Nine phenolic (1-9) and two furan type (10, 11) compounds, were isolated from the
      methanolic extract of the tuber of Gastrodia elata Blume (Orchidaceae) in the
      course of continuing search for platelet anti-aggregating plant components.
      Compound 1 was identified as 4,4'-dihydroxybenzyl sulfone, a novel compound for
      the best of our knowledge. Compound 10, 5-hydroxymethyl-2-furancarboxaldehyde,
      was isolated for the first time from this plant. Compound 1 (IC50; 83 microM) was
      about four times more inhibitory to U46619 induced aggregation than ASA (IC50;
      340 microM). Compound 9, 4,4'-dihydroxy-dibenzylether, (IC50; 5 microM, 3 microM
      and 33 microM, respectively) was 10-80 fold more potent than ASA (IC50; 420
      microM, 53 microM and 340 microM respectively) to collagen, epinephrine and
      U46619 induced aggregation, although it is less active than ASA to AA induced
      aggregation.

PMID- 15180302
TI  - Flavonoids and aromatic compounds from the rhizomes of Zingiber zerumbet.
AB  - Repeated column chromatography of the CHCl3-soluble fraction of Zingiber zerumbet
      led to the isolation and identification of two aromatic compounds, p
      hydroxybenzaldehyde (1) and vanillin (2), and six kaempferol derivatives,
      kaempferol-3,4',7-O-trimethylether (3), kaempferol-3-O-methylether (4),
      kaempferol-3,4'-O-dimethylether (5), 4''-O-acetylafzelin (6), kaempferol-3-O-(4-O
      acetyl-alpha-L-rhamnopyranoside)], 2'',4''-O-diacetylafzelin (7), kaempferol-3-O
      (2,4-O-diacetyl-alpha-L-rhamnopyranoside)], and 3'',4''-O-diacetylafzelin (8),
      kaempferol-3-O-(3,4-O-diacetyl-alpha-L-rhamnopyranoside)]. The structures of 1-8
      were identified by analysis of spectroscopic data as well as by comparison with
      published values. This is the first report on the isolation of compounds 1-3 from
      this plant.

PMID- 15180303
TI  - Flavonol glycosides from the aerial parts of Aceriphyllum rossii and their
      antioxidant activities.
AB  - The methanol extract obtained from the aerial parts of Aceriphyllum rossii
      (Saxifragaceae) was fractionated into ethyl acetate (EtOAc), n-BuOH and H2O
      layers through solvent fractionation. Repeated silica gel column chromatography
      of EtOAc and n-BuOH layers afforded six flavonol glycosides. They were identified
      as kaempferol 3-O-beta-D-glucopyranoside (astragalin, 1), quercetin 3-O-beta-D
      glucopyranoside (isoquercitrin, 2), kaempferol 3-O-alpha-L-rhamnopyranosyl (1-
      >6)-beta-D-glucopyranoside (3), quercetin 3-O-alpha-L-rhamnopyranosyl (1-->6)
      beta-D-glucopyranoside (rutin, 4), kaempferol 3-O-[alpha-L-rhamnopyranosyl (1-
      >4)-alpha-L-rhamnopyranosyl (1-->6)-beta-D-glucopyranoside] (5) and quercetin 3-O
      [alpha-L-rhamnopyranosyl (1-->4)-alpha-L-rhamnopyranosyl (1-->6)-beta-D
      glucopyranoside] (6) on the basis of several spectral data. The antioxidant
      activity of the six compounds was investigated using two free radicals such as
      the ABTS free radical and superoxide anion radical. Compound 1 exhibited the
      highest antioxidant activity in the ABTS [2,2-azinobis-(3-ethylbenzothiazoline-6
      sulfonic acid)] radical scavenging method. 100 mg/L of compound 1 was equivalent
      to 72.1+/-1.4 mg/L of vitamin C, and those of compounds 3 and 5 were equivalent
      to 62.7+/-0.5 mg/L and 54.3+/-1.3 mg/L of vitamin C, respectively. And in the
      superoxide anion radical scavenging method, compound 5 exhibited the highest
      activity with an IC50 value of 17.6+/-0.3 microM. In addition, some physical and
      spectral data of the flavonoids were confirmed.

PMID- 15180304
TI  - Regulation of c-fos and c-jun gene expression by lipopolysaccharide and cytokines
      in primary cultured astrocytes: effect of PKA and PKC pathways.
AB  - The effects of lipopolysaccharide (LPS) and several cytokines on the c-fos and c
      jun mRNA expression were examined in primary cultured astrocytes. Either LPS (500
      ng/mL) or interferon-gamma (IFN-gamma; 5 ng/mL) alone increased the level of c
      fos mRNA (1 h). However, tumor necrosis factor-alpha (TNF-alpha; 10 ng/mL) or
      interleukin-1beta (IL-1beta; 5 ng/mL) alone showed no significant induction of
      the level of c-fos mRNA. TNF-alpha showed a potentiating effect in the regulation
      of LPS-induced c-fos mRNA expression, whereas LPS showed an inhibitory action
      against IFN-gamma-induced c-fos mRNA expression. LPS, but not TNF-alpha, IL-1beta
      and IFN-gamma, increased the level of c-jun mRNA (1 h). TNF-alpha and IFN-gamma
      showed an inhibitory action against LPS-induced c-jun mRNA expression. Both
      phorbol 12-myristate 13-acetate (PMA; 2.5 mM) and forskolin (FSK; 5 mM) increased
      the c-fos and c-jun mRNA expressions. In addition, the level of c-fos mRNA was
      expressed in an antagonistic manner when LPS was combined with PMA. When LPS was
      co-treated with either PMA or FSK, it showed an additive interaction for the
      induction of c-jun mRNA expression. Our results suggest that LPS and cytokines
      may be actively involved in the regulation of c-fos and c-jun mRNA expressions in
      primary cultured astrocytes. Moreover, both the PKA and PKC pathways may regulate
      the LPS-induced c-fos and c-jun mRNA expressions in different ways.

PMID- 15180305
TI  - Role of the Fas/Fas ligand death receptor pathway in ginseng saponin metabolite
      induced apoptosis in HepG2 cells.
AB  - This research team found in previous studies, that the ginseng saponin metabolite
      IH901 induces apoptosis in HepG2 cells via a mitochondrial-mediated pathway,
      which resulted in the activation of caspase-9 and subsequently of caspase-3 and 
      8. Based on these results, the involvement of the Fas/Fas ligand (FasL) death
      receptor pathway, in IH901-induced apoptosis in HepG2 cells, was investigated.
      Levels of Fas and the Fas ligand (FasL) mRNA or protein were not increased by
      IH901, rather they were decreased significantly at 18 h post treatment. Soluble
      FasL (sFasL) was detectable by immunoprecipitation analysis in the medium of
      HepG2 cells treated with IH901. Increased levels of sFasL were inversely
      correlated with the levels of FasL. Preincubation of HepG2 cells with
      antagonistic anti-Fas antibody showed little protective effect, if any, on IH901
      induced cell death. At a 30 microM (24 and 48 h) and 40 microM (24 h)
      concentration of IH901, the cytotoxic effect of IH901 was less then 50%, anti-Fas
      antibody prevented IH901-induced cell death. However, at a 60 microM (24 and 48
      h) and 40 microM (48 h) concentration of IH901, cell death rates were about 80%
      or more and most of the chemopreventive and chemotherapeutic effects of IH901
      were manifested. Blocking the Fas receptor did not influence IH901-induced cell
      death. These results indicate that the Fas/FasL system is engaged, but not
      required for IH901-induced cell death, at pharmacologically significant
      concentrations.

PMID- 15180306
TI  - Histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in
      HepG2 cells.
AB  - The expression of CYP3A4 gene is induced by a variety of structurally unrelated
      xenobiotics including the antibiotic rifampicin, pregnenolone 16-carbonitrile
      (PCN), and endogenous hormones, that might mediate through steroid and xenobiotic
      receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4
      gene expression have not been understood. In order to gain the insight of the
      molecular mechanism of CYP3A4 gene expression, study has been undertaken to
      investigate if the histone deacetylation is involved in the regulation of CYP3A4
      gene expression by proximal promoter in human hepatoma HepG2 cells. Also we have
      investigated to see if SXR is involved in the regulation of CYP3A4 proximal
      promoter activity in human hepatoma HepG2 cells. HepG2 cells were transfected
      with a plasmid pCYP3A4-Luc containing approximately 1 kb of the CYP3A4 proximal
      promoter region (-863 to +64 bp) in front of a reporter gene, luciferase, in the
      presence or absence of pSAP-SXR. In HepG2 cells, CYP3A4 inducers, such as
      rifampicin, PCN and RU486 showed minimal stimulation of CYP3A4 proximal promoter
      activity in the absence of SXR and histone deacetylase (HDAC) inhibitors. 4
      Dimethylamino-N-[4-(2-hydroxycarbamoylvinyl)benzyl]benzamide (IN2001), a new
      class HDAC inhibitor significantly increased CYP3A4 proximal promoter activity
      over untreated control cells and rifampicin concomitant treatment with IN2001
      increased further CYP3A4 proximal promoter activity that was stimulated by
      IN2001. The results of this study demonstrated that both HDAC inhibitors and SXR
      are essential to increase of CYP3A4 proximal promoter activity by CYP3A4 inducers
      such as PCN, rifampicin, and RU486. Especially SXR seems to be important for the
      dose dependent response of CYP3A4 inducing chemicals to stimulate CYP3A4 proximal
      promoter activity. Also this data suggested that HDAC inhibitors seemed to
      facilitate the CYP3A4 proximal promoter to be activated by chemicals.

PMID- 15180307
TI  - Trichostatin A, a histone deacetylase inhibitor stimulate CYP3A4 proximal
      promoter activity in Hepa-I cells.
AB  - Cytochrome P450 3A4 (CYP3A4) is the most abundant CYPs in human liver, comprising
      approximately 30% of the total liver CYPs contents and is involved in the
      metabolism of more than 60% of currently used therapeutic drugs. However, the
      molecular mechanisms underlying regulation of CYP3A4 gene expression have not
      been understood. Thus, this study has been carried out to gain the insight of the
      molecular mechanism of CYP3A4 gene expression, investigating if the histone
      deacetylation is involved in the regulation of CYP3A4 gene expression by proximal
      promoter. Also SXR was investigated to see if they were involved in the
      regulation of CYP3A4 proximal promoter activity. Hepa-I cells were transfected
      with a plasmid containing approximately 1 kb of the human CYP3A4 proximal
      promoter region (863 to +64 bp) cloned in front of a reporter gene, luciferase,
      in the presence or absence of SXR. Transfected cells were treated with CYP3A4
      inducers such as rifampicin, PCN and RU 486, in order to examine the regulation
      of CYP3A4 gene expression in the presence or absence of trichostatin A (TSA). In
      Hepa-I cells, CYP3A4 inducers increased modestly the luciferase activity when TSA
      was co-treated, but this increment was not enhanced by SXR cotransfection. Taken
      together, these results indicated that the inhibition of histone deacetylation
      was required to SXR-mediated increase in CYP3A4 proximal promoter region when
      rifampicin, or PCN was treated. Further a trans-activation by SXR may demand
      other species-specific transcription factors.

PMID- 15180308
TI  - Identification of expressed sequence tags of genes expressed highly in the
      activated hepatic stellate cell.
AB  - Expressed sequence tags (ESTs) were generated from two 3'-directed cDNA libraries
      constructed from quiescent and activated rat hepatic stellate cell (HSC) to
      analyze the expression profiles of active genes in both cells. From quiescent and
      activated HSC, 694 ESTs and 779 ESTs, respectively, were obtained after excluding
      those having shorter than 30 bp. Among ESTs obtained from quiescent and activated
      HSC, 68 and 73 kinds of ESTs (186 clones and 236 clones), respectively, appeared
      more than once, implying that their genes are expressed highly in each cell type.
      52 among 73 ESTs appeared only in the activated HSC, 47 among 68 ESTs only in the
      normal HSC, and 21 in both cells. The genes of these 52 ESTs were assumed to be
      expressed more highly in the activated HSC. To confirm the high expression of
      genes of which the ESTs appeared more than twice in the activated HSC, northern
      hybridization was carried out with RNAs derived from rat normal and fibrotic
      liver using each of 18 EST DNAs as probe. 13 ESTs showed more intense bands with
      RNA isolated from the fibrotic liver than normal liver. From these results, we
      confirm the positive correlation between abundance of transcript in activated
      HSCs and the expression level in fibrotic liver. The expression profile of the
      transcripts serves as an important tool in understanding the biological
      properties of HSC.

PMID- 15180309
TI  - Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer
      cells.
AB  - Ginseng has an anti-cancer effect in several cancer models. This study was to
      characterize active constituents of ginseng and their effects on proliferation of
      prostate cancer cell lines, LNCaP and PC3. Cell proliferation was measured by
      [3H]thymidine incorporation, the intracellular calcium concentration by a dual
      wavelength spectrophotometer system, effects on mitogen-activated protein (MAP)
      kinases by Western blotting, and cell attachment and morphologic changes were
      observed under a microscope. Among 11 ginsenosides tested, ginsenosides Rg3 and
      Rh2 inhibited the proliferation of prostate cancer cells. EC50s of Rg3 and Rh2 on
      PC3 cells were 8.4 microM and 5.5 microM, respectively, and 14.1 microM and 4.4
      microM on LNCaP cells, respectively. Both ginsenosides induced cell detachment
      and modulated three modules of MAP kinases activities differently in LNCaP and
      PC3 cells. These results suggest that ginsenosides Rg3 and Rh2-induced cell
      detachment and inhibition of the proliferation of prostate cancer cells may be
      associated with modulation of three modules of MAP kinases.

PMID- 15180310
TI  - Microtubule inhibitory effects of various SJ compounds on tissue culture cells.
AB  - SJ compounds (SJ8002 and related compounds) are a group of novel anticancer
      agents (Cho, Chung, Lee, Kwon, Kang, Joo, and Oh. PCT/KR02/00392). To explore the
      anticancer mechanism of these compounds, we examined the effect of SJ8002 on
      microtubules of six human cell lines. At a high concentration (2 microg/mL),
      SJ8002 effectively disrupted microtubules of the six cell lines within 1 h. At
      lower concentrations (0.05 to approximately 1.0 microg/mL), the antimicrotubule
      activity of SJ8002 varied defending on cell lines. The inhibition of in vitro
      polymerization of pure tubulin by SJ8002 suggested that SJ8002 acts on free
      tubulin, inhibits the polymerization of tubulin dimer into microtubules, and
      hence induces the depolymerization of microtubules.

PMID- 15180311
TI  - Inhibition of contact dermatitis in animal models and suppression of
      proinflammatory gene expression by topically applied flavonoid, wogonin.
AB  - Wogonin (5,7-dihydroxy-8-methoxyflavone) is a down-regulator of cyclooxygenase-2
      and inducible nitric oxide synthase expression, contributing to anti-inflammatory
      activity in vivo. For further characterization of modulatory activity on
      proinflammatory gene expression in vivo, the effect of wogonin was examined in
      this experiment using animal models of skin inflammation. By topical application,
      wogonin inhibited an edematic response as well as proinflammatory gene expression
      against contact dermatitis in mice. Wogonin inhibited ear edema (19.4-22.6%) at
      doses of 50-200 microg/ear and down-regulated interleukin-1beta induction (23.1%)
      at 200 microg/ear in phenol-induced simple irritation. Wogonin (2x50-2x200
      microg/ear) also inhibited edematic response (51.2-43.9%) and down-regulated
      proinflammatory gene expression of cyclooxygenase-2, interleukin-1beta,
      interferon-gamma, intercellular adhesion molecule-1 and inducible nitric oxide
      synthase with some different sensitivity against picryl chloride-induced delayed
      hypersensitivity reaction. All these results clearly demonstrate that wogonin is
      a down-regulator of proinflammatory gene expression in animal models of skin
      inflammation. Therefore, wogonin may have potential for a new anti-inflammatory
      agent against skin inflammation.

PMID- 15180312
TI  - Efficacy of brown seaweed hot water extract against HCl-ethanol induced gastric
      mucosal injury in rats.
AB  - Effect of pre-treatment with hot water extract of marine brown alga Sargassum
      polycystum C.Ag. (100 mg/kg body wt, orally for period of 15 days) on HCl-ethanol
      (150 mM of HCl-ethanol mixture containing 0.15 N HCl in 70% v/v ethanol given
      orally) induced gastric mucosal injury in rats was examined with respect to lipid
      peroxides, antioxidant enzyme status, acid/pepsin and glycoproteins in the
      gastric mucosa. The levels of lipid peroxides of gastric mucosa and volume,
      acidity of the gastric juice were increased with decreased levels of antioxidant
      enzymes and glycoproteins were observed in HCl-ethanol induced rats. The rats pre
      treated with seaweed extract prior to HCl-ethanol induction reversed the depleted
      levels of antioxidant enzymes and reduced the elevated levels of lipid peroxides
      when compared with HCl-ethanol induced rats. The levels of glycoproteins and
      alterations in the gastric juice were also maintained at near normal levels in
      rats pre-treated with seaweed extract. The rats given seaweed extract alone did
      not show any toxicity, which was confirmed by histopathological studies. These
      results suggest that the seaweed extract contains some anti-ulcer agents, which
      may maintain the volume/acidity of gastric juice and improve the gastric mucosa
      antioxidant defense system against HCl-ethanol induced gastric mucosal injury in
      rats.

PMID- 15180313
TI  - Gossypin protects primary cultured rat cortical cells from oxidative stress- and
      beta-amyloid-induced toxicity.
AB  - The present study investigated the effects of gossypin, 3,3',4',5,7,8
      hexahydroxyflavone 8-glucoside, on the toxicity induced by oxidative stress or
      beta-amyloid (Abeta) in primary cultured rat cortical cells. The antioxidant
      properties of gossypin were also evaluated by cell-free assays. Gossypin was
      found to inhibit the oxidative neuronal damage induced by xanthine/xanthine
      oxidase or by a glutathione depleting agent, D,L-buthionine (S,R)-sulfoximine. In
      addition, gossypin significantly attenuated the neurotoxicity induced by Abeta(25
      35). Furthermore, gossypin dramatically inhibited lipid peroxidation initiated by
      Fe2+ and ascorbic acid in rat brain homogenates. It also exhibited potent radical
      scavenging activity generated from 1,1-diphenyl-2-picrylhydrazyl. These results
      indicate that gossypin exerts neuroprotective effects in the cultured cortical
      cells by inhibiting oxidative stress- and Abeta-induced toxicity, and that the
      antioxidant properties of gossypin may contribute to its neuroprotective actions.

PMID- 15180314
TI  - Quality evaluation of Alismatis Rhizoma by high performance liquid
      chromatography.
AB  - The quality of Alismatis Rhizoma was evaluated by reversed-phase high performance
      liquid chromatographic method. Alisol B 23-acetate was used as a standard marker
      for evaluation. This component was fully separated from the other components in
      the plant extracts on a ODS column. Identification of alisol B 23-acetate was
      carried out by comparing the LC/MS spectrum of separated peak from the extract
      with that of standard. Alisol B 23-acetate contents in Alismatis Rhizoma obtained
      from several herbal markets were varied from 0.15% to 0.56%.

PMID- 15180315
TI  - The dynamics of Wuchereria bancrofti infection: a model-based analysis of
      longitudinal data from Pondicherry, India.
AB  - This paper presents a model-based analysis of longitudinal data describing the
      impact of integrated vector management on the intensity of Wuchereria bancrofti
      infection in Pondicherry, India. The aims of this analysis were (1) to gain
      insight into the dynamics of infection, with emphasis on the possible role of
      immunity, and (2) to develop a model that can be used to predict the effects of
      control. Using the LYMFASIM computer simulation program, two models with
      different types of immunity (anti-L3 larvae or anti-adult worm fecundity) were
      compared with a model without immunity. Parameters were estimated by fitting the
      models to data from 5071 individuals with microfilaria-density measurement before
      and after cessation of a 5-year vector management programme. A good fit, in
      particular of the convex shape of the age-prevalence curve, required inclusion of
      anti-L3 or anti-fecundity immunity in the model. An individual's immune
      responsiveness was found to halve in approximately 10 years after cessation of
      boosting. Explanation of the large variation in Mf-density required considerable
      variation between individuals in exposure and immune responsiveness. The mean
      life-span of the parasite was estimated at about 10 years. For the post-control
      period, the models predict a further decline in Mf prevalence, which agrees well
      with observations made 3 and 6 years after cessation of the integrated vector
      management programme.

PMID- 15180316
TI  - Sequence variation of the cytochrome b gene of various human infecting members of
      the genus Leishmania and their phylogeny.
AB  - The Cytochrome b (Cyt b) gene has proved to be useful for identification and
      classification of many mammals and plants. In order to evaluate the utility of
      this gene for discrimination of Leishmania parasites as well as for exploring
      their phylogenetic relationships, we determined the nucleotide sequences of the
      Cyt b gene from 13 human-infecting Leishmania species (14 strains) from the New
      and Old Worlds. The Cyt b genes, approximately 1080 base pairs, were found to be
      A/T rich, and their 5' terminal-editing regions were highly conserved. The
      nucleotide sequence variation among them was enough to discriminate parasite
      species; 245 nucleotide positions were polymorphic and 190 positions were
      parsimony informative. The phylogenetic relationships based on this gene, showed
      good agreement with the classification of Lainson & Shaw (1987) except for the
      inclusion of L. (L.) major in the L. (L.) tropica complex and the placement of L.
      tarentolae in another genus. These data show that the Cyt b gene is useful for
      phylogenetic study of Leishmania parasites.

PMID- 15180317
TI  - Antioxidant enzymes in intramolluscan Schistosoma mansoni and ROS-induced changes
      in expression.
AB  - Killing of intramolluscan schistosomes by host haemocytes is mediated by reactive
      oxygen metabolites. Hence, defence against oxidative damage is essential for the
      parasite to survive. In this study, expression of three key antioxidant enzymes,
      superoxide dismutase (EC 1.15.1.1), glutathione peroxidase (EC 1.11.1.9) and
      glutathione-S-transferase (EC 2.5.1.18) was determined in Schistosoma mansoni
      miracidia, sporocysts and cercariae. Stage-dependent expression of these enzymes
      was shown to be regulated at the transcriptional level. Second, the influence on
      enzyme expression of reactive oxygen species (ROS) and of haemocytes from
      schistosome-resistant and -susceptible host snails was determined. Generation of
      ROS by xanthine/xanthine oxidase resulted in increased transcript levels for all
      three enzymes. Addition of hydrogen peroxide induced a significantly increased
      expression of GPx and SOD but not GST. Snail haemocytes induced an up-regulation
      of SOD and GPx at 12 and 18 h post-exposure, respectively. Susceptible haemocytes
      elicited a stronger induction of transcript expression than resistant haemocytes.
      After 36-48 h, SOD remained up-regulated in sporocysts encapsulated by haemocytes
      from susceptible hosts, whereas a down-regulation of SOD and GPx occurred in
      schistosomes encapsulated by haemocytes from resistant snails. These observations
      indicate that schistosomes express elevated levels of antioxidant enzymes in
      interaction with haemocytes from susceptible snail hosts in which they survive.
      On the other hand, haemocytes of resistant snails may interfere with reactive
      oxygen detoxification via down-regulation of schistosome antioxidant enzymes,
      thus shifting the balance towards parasite killing.

PMID- 15180318
TI  - Questing height of nymphs of the bush tick, Haemaphysalis longicornis, and its
      closely related species, H. mageshimaensis: correlation with body size of the
      host.
AB  - The questing height (i.e. ambush height) of ticks on a plant plays an important
      role in host selection. To test the hypothesis that the questing height of ticks
      in a locality had adapted to the body size of the host in that locality, we
      examined the questing height of nymphs of the ticks, Haemaphysalis longicornis
      and H. mageshimaensis, at 7 locations in Japan. Sika deer, Cervus nippon, is the
      primary host of these ticks and there is considerable geographical variation in
      the body size of sika deer. Multiple regression analysis revealed that the
      questing height in the field was influenced by the height of the plants and by
      the body size of deer at a location. However, the questing height of ticks at
      some locations may have been constrained by the height of the plants and might
      not be the same as their intrinsic questing height. When ticks were placed in
      vertical glass tubes in the laboratory, the questing height of ticks from a
      locality was correlated with the mean body size of deer at that locality.
      Therefore, the prominent cue determining the questing height of H. longicornis
      and H. mageshimaensis seems to be the body size of the host deer.

PMID- 15180319
TI  - A preliminary phylogenetic analysis of the Capsalidae (Platyhelminthes:
      Monogenea: Monopisthocotylea) inferred from large subunit rDNA sequences.
AB  - Phylogenetic relationships within the Capsalidae (Monogenea) were examined using
      large subunit ribosomal DNA sequences from 17 capsalid species (representing 7
      genera, 5 subfamilies), 2 outgroup taxa (Monocotylidae) plus Udonella caligorum
      (Udonellidae). Trees were constructed using maximum likelihood, minimum evolution
      and maximum parsimony algorithms. An initial tree, generated from sequences 315
      bases long, suggests that Capsalinae, Encotyllabinae, Entobdellinae and
      Trochopodinae are monophyletic, but that Benedeniinae is paraphyletic. Analyses
      indicate that Neobenedenia, currently in the Benedeniinae, should perhaps be
      placed in a separate subfamily. An additional analysis was made which omitted 3
      capsalid taxa (for which only short sequences were available) and all outgroup
      taxa because of alignment difficulties. Sequence length increased to 693 bases
      and good branch support was achieved. The Benedeniinae was again paraphyletic.
      Higher-level classification of the Capsalidae, evolution of the Entobdellinae and
      issues of species identity in Neobenedenia are discussed.

PMID- 15180320
TI  - Behaviour and development of Elasmosoma sp. (Neoneurinae: Braconidae:
      Hymenoptera), an endoparasite of Formica ants (Formicidae: Hymenoptera).
AB  - The behaviour and development of Elasmosoma sp., near pergandei Ashm.
      (Neoneurinae: Braconidae: Hymenoptera), a parasite of the ant, Formica
      obscuriventris clivia Creighton, was studied in a coastal sand dune habitat in
      central Oregon over a 2-year period. Female wasps oviposited into the abdomen of
      major worker ants after alighting briefly on the host. Embryonic development of
      the wasp occurred inside the serosal membrane or trophamnion of the egg in the
      abdomen of the ant host. First instar wasp larvae possessed a large head capsule
      with falcate mandibles, 11 ventral body lobes, an elongate tail and a dorsally
      located anus. Second instar larvae were unspecialized and lacked the large head
      capsule, elongate tail and paired ventral body lobes. Third instar larvae were
      hymenopteriform with a distinct head capsule. Cocoon formation and adult
      emergence is described. Observations on the percentage parasitism and altered
      behaviour of parasitized ants are presented. The association between neoneurine
      wasps and ants is a well-balanced system that has been in existence for at least
      40 million years.

PMID- 15180322
TI  - Cysteine proteinase activities in the fish pathogen Philasterides dicentrarchi
      (Ciliophora: Scuticociliatida).
AB  - This study investigated protease activities in a crude extract and in vitro
      excretion/secretion (E/S) products of Philasterides dicentrarchi, a ciliate fish
      parasite causing economically significant losses in aquaculture. Gelatin/SDS-PAGE
      analysis (pH 4, reducing conditions) detected 7 bands with gelatinolytic activity
      (approximate molecular weights 30-63 kDa) in the crude extract. The banding
      pattern observed in analysis of E/S products was practically identical, except
      for 1 low-molecular-weight band detected in the crude extract but not in the E/S
      products. In assays with synthetic peptide p-nitroanilide substrates, the crude
      extract hydrolysed substrates characteristic of cysteine proteases, namely Z-Arg
      Arg pNA, Bz-Phe-Val-Arg pNA and Z-Phe-Arg pNA. These activities were strongly
      inhibited by the cysteine protease inhibitor E-64 and by Ac-Leu-Val-Lys aldehyde,
      a potent inhibitor of cysteine proteases of the cathepsin B protease subfamily.
      The proteases present in the crude extract degraded both type-I collagen and
      haemoglobin in vitro, consistent with roles in tissue invasion and nutrition
      respectively. Again, E-64 completely (collagen) or markedly (haemoglobin)
      inhibited this degradation. Finally, the histolytic activity of the ciliate in
      turbot fibroblast monolayers was strongly reduced in the presence of E-64,
      confirming the importance of secreted cysteine proteinases in the biology of
      Philasterides dicentrarchi.

PMID- 15180321
TI  - The potential signalling pathways which regulate surface changes induced by
      phytohormones in the potato cyst nematode (Globodera rostochiensis).
AB  - It has been demonstrated that the surface lipophilicity of the plant-parasitic
      nematode Globodera rostochiensis decreases when infective larvae are exposed to
      the phytohormones indole-3-acetic acid (auxin) or kinetin (cytokinin). In the
      present study, it was shown that inhibition of phospholipase C (PLC) or
      phosphatidylinositol 3 kinase (PI3-kinase) reversed the effect of phytohormones
      on surface lipophilicity. The signalling pathway(s) involved in surface
      modification were investigated using 'caged' signalling molecules and stimulators
      or inhibitors of different signalling enzymes. Photolysis of the 'caged'
      signalling molecules, NPE-caged Ins 1,4,5-P3, NITR-5/AM or caged-cAMP to liberate
      IP3, Ca2+ or cAMP respectively, decreased the surface lipophilicity. Activation
      of adenylate cyclase also decreased the surface lipophilicity. In contrast,
      inhibition of PI3-kinase using Wortmannin, LY-294002 or Quercetin, and inhibition
      of PLC using U-73122 all increased the surface lipophilicity. Two possible
      signalling pathways involved in phytohormone-induced surface modification are
      proposed.

PMID- 15180323
TI  - Genetic variability in cysteine protease genes of Haemonchus contortus.
AB  - To increase the existent genetic variability in cysteine proteases, a
      polymorphism study was performed in Haemonchus contortus by comparing 2 different
      strains of the parasite: North American (NA) and Spanish (SP) strains. For this
      purpose, the polymorphism of 5 previously reported genes (AC-1, AC-3, AC-4, AC-5
      and GCP-7) were analysed by PCR-SSCP and sequencing procedures. Based on the SSCP
      results, a total of 20 different alleles were identified for the 5 loci assessed.
      Except locus AC-5, all the loci were polymorphic. Loci AC-1, AC-3, AC-4 and GCP-7
      showed 5, 8, 2 and 4 alleles, respectively. The allelic frequencies ranged from
      0.0070 to 0.8560 and were significantly different between strains. In addition,
      nucleotide diversity analyses showed a significant variation within and between
      strains. The variations in the nucleotide sequence of the different alleles were
      translated in some cases into changes in the amino acid sequence. Evidence of
      genetic variability in cysteine proteases from two different strains of H.
      contortus for the same set of genes had not been previously reported.

PMID- 15180324
TI  - Sexual transmission of a nematode parasite of Wood Mice (Apodemus sylvaticus)?
AB  - Sexual transmission occurs commonly in microparasites such as viruses and
      bacteria, but this is an unusual transmission route for macroparasites. Here we
      present evidence which suggests that a nematode parasite of Wood Mice (Apodemus
      sylvaticus) may be sexually transmitted and we have classified the nematode using
      molecular data. Wood Mice were collected annually in the course of work on their
      reproductive physiology. Larval nematodes were found in the epididymides of 19.6%
      of males. It seems likely that they would be transmitted to females at
      ejaculation. To identify these larval nematodes, which we were unable to do using
      morphological features, we sequenced the 18S rDNA. Sequence comparisons with the
      molecular phylogeny of Blaxter et al. (1998) demonstrated that they were bursate
      nematodes (Order Strongylida). The relationships between strongylid taxa were
      poorly resolved by 18S rDNA. However, both distance and parsimony analyses
      grouped the nematode with the superfamily Metastrongylidea in a clade containing
      Filaroides and Angiostrongylus sp. Importantly, the sequences were distinct from
      those of Heligmosomoides polygyrus and Angiostrongylus dujardini, two common
      strongylid nematodes of Apodemus. We were therefore unable positively to identify
      these worms by matching their sequences with those from morphologically
      identifiable adult strongylid nematodes infecting Apodemus. These results
      demonstrate that an as yet unidentified strongylid is quite commonly found in
      large numbers in the male reproductive tract of Wood Mice. Further work is
      required to understand the biology and transmission dynamics of this interesting
      system.

PMID- 15180325
TI  - Echinococcus granulosus strain differentiation based on sequence heterogeneity in
      mitochondrial genes of cytochrome c oxidase-1 and NADH dehydrogenase-1.
AB  - Genetic analyses of Echinococcus granulosus isolates from different intermediate
      host species have demonstrated substantial levels of variation for some genotype
      (strain) clusters. To determine the range of genetic variability within and
      between genotypes we amplified and cloned partial cox1 and nadh1 genes from 16
      isolates of E. granulosus from 4 continents. Furthermore, we sequenced different
      clones from a PCR product to analyse the intra-individual genetic variance. The
      findings showed a moderate degree of variance within single isolates and a
      significant degree of variance between the cluster of genotypes G1-G3 (sheep,
      Tasmanian sheep and buffalo strain), genotypes G4 (horse strain) and G5 (cattle
      strain) and the cluster of the genotypes G6 (camel strain) and G7 (pig strain).
      The variance of up to 2.2% within genotypes was relatively low compared with that
      of 4.3-15.7% among genotypes. The present results indicate that a re-examination
      of the classification of 5 genotypes of Echinococcus is warranted. Hence, our
      data highly support a re-evaluation of the taxonomy of the clades G1-G3, G4, G5,
      G6/7 and G8 (cervid strain) within the genus Echinococcus.

PMID- 15180327
TI  - Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia
      inducible VEGF plasmid for ischemic disease.
AB  - PURPOSE: Gene therapy using vascular endothelial growth factor (VEGF) is a new
      potential treatment of ischemic disease. To be safe and effective, VEGF
      expression should be enhanced locally in ischemic tissue. In this study, we
      identified the cis-regulatory element for the hypoxia induction of the RTP801
      promoter. In addition, pRTP801-VEGF was evaluated as a therapeutic plasmid in
      vitro. METHODS: The cis-regulatory element for hypoxia induction was identified
      by deletion and mutation analyses. Antisense oligonucleotide co-transfection
      assay was performed to evaluate the role of Sp1. pRTP801-VEGF was constructed by
      the insertion of the RTP801 promoter into the VEGF plasmid. The hypoxia-inducible
      expression of VEGF was evaluated by in vitro transfection assay. RESULTS: In
      luciferase assay, the region between -495 and -446 was responsible for the
      hypoxia-induced transcription. The mutation of the Sp1 site in this region
      reduced hypoxia-induced transcription. In addition, co-transfection with
      antisense Sp1 oligonucleotide suggests that hypoxia induction of the RTP801
      promoter is mediated by Sp1. In vitro transfection showed that pRTP801-VEGF had
      higher VEGF expression than pEpo-SV-VEGF. In addition, VEGF expression by pRTP801
      VEGF was induced under hypoxia. CONCLUSIONS: With strong basal promoter activity
      and induction under hypoxia, pRTP801-VEGF may be useful for gene therapy for
      ischemic disease.

PMID- 15180328
TI  - Characterization of the cellular localization, expression level, and function of
      SNP variants of MRP2/ABCC2.
AB  - PURPOSE: The presence of single nucleotide polymorphisms (SNPs) has been reported
      for multidrug resistance-associated protein 2 (MRP2/ABCC2). The purpose of the
      current study was to characterize the localization, expression level, and
      function of MRP2 variants. METHODS: The expression and cellular localization of
      the wild-type and three kinds of reported SNP variants of MRP2 molecules were
      analyzed in LLC-PK1 cells after infection with the recombinant Tet-off
      adenoviruses. Their function was determined by using the isolated membrane
      vesicles from the infected LLC-PK1 cells. RESULTS: The transport activity for
      E217betaG, LTC4, and DNP-SG, normalized by the expression level of MRP2, was
      similar between the wild-type, V417I, and A1450T MRP2s. The transport activity of
      S789F MRP2 was slightly higher than that of wild-type MRP2. However, the
      expression level of S789F and A1450T MRP2 proteins was significantly lower
      compared with the wild-type and V417I MRP2. In addition, although the wild-type
      and V417I MRP2 were exclusively localized in the apical membrane, S789F and
      A1450T MRP2 were located in the apical membrane and also in the intracellular
      compartment. CONCLUSIONS: These results suggest that the most frequently observed
      V417I substitution may not affect the in vivo function of MRP2, whereas the much
      less frequently observed S789F and A1450T may be associated with the reduced in
      vivo function.

PMID- 15180329
TI  - Correction of permeability with pore radius of tight junctions in Caco-2
      monolayers improves the prediction of the dose fraction of hydrophilic drugs
      absorbed by humans.
AB  - PURPOSE: To improve predictions of fraction dose absorbed (Fa) for hydrophilic
      drugs, a correction of paracellular permeability using the pore radius of tight
      junctions (TJs) in Caco-2 monolayers was performed. METHODS: The apparent
      permeability coefficient (P9app)) of drugs was measured using the Caco-2 assay
      and the parallel artificial membrane permeation assay (PAMPA), and values were
      corrected with the pore radius of TJs. RESULTS: An equation for calculating the
      pore radius of TJs from the P(app) of lucifer yellow was obtained. The optimal
      pore radius of TJs in Caco-2 monolayers for predicting human Fa was calculated to
      be 7 A. The correlation between the actual and predicted Fa was improved by using
      the P(app) corrected with the pore radius of TJs. Permeability in the PAMPA,
      which was corrected using the pore radius and membrane potential, was well
      correlated with that in the Caco-2 assay. Most of the hydrophilic drugs tested in
      this study were absorbed mainly through the paracellular pathway. CONCLUSIONS:
      The results suggest the necessity of optimizing paracellular permeation for the
      prediction of Fa, and also the importance of the paracellular pathway to the
      absorption of hydrophilic drugs. This method might contribute to the setting of
      appropriate dosages and the development of hydrophilic drugs.

PMID- 15180326
TI  - The complexities of hepatic drug transport: current knowledge and emerging
      concepts.
AB  - Recently, hepatic transport processes have been recognized as important
      determinants of drug disposition. Therefore, it is not surprising that
      characterization of the hepatic transport and biliary excretion properties of
      potential drug candidates is an important part of the drug development process.
      Such information also is useful in understanding alterations in the hepatobiliary
      disposition of compounds due to drug interactions or disease states. Basolateral
      transport systems are responsible for translocating molecules across the
      sinusoidal membrane, whereas active canalicular transport systems are responsible
      for the biliary excretion of drugs and metabolites. Several transport proteins
      involved in basolateral transport have been identified including the Na(+)
      taurocholate co-transporting polypeptide [NTCP (SLC10A1)], organic anion
      transporting polypeptides [OATPs (SLCO family)], multidrug resistance-associated
      proteins [MRPs (ABCC family)], and organic anion and cation transporters [OATs,
      OCTs (SLC22A family)]. Canalicular transport is mediated predominantly via P
      glycoprotein (ABCB1), MRP2 (ABCC2), the bile salt export pump [BSEP (ABCB11)],
      and the breast cancer resistance protein [BCRP (ABCG2)]. This review summarizes
      current knowledge regarding these hepatic basolateral and apical transport
      proteins in terms of substrate specificity, regulation by nuclear hormone
      receptors and intracellular signaling pathways, genetic differences, and role in
      drug interactions. Transport knockout models and other systems available for
      hepatobiliary transport studies also are discussed. This overview of
      hepatobiliary drug transport summarizes knowledge to date in this rapidly growing
      field and emphasizes the importance of understanding these fundamental processes
      in hepatic drug disposition.

PMID- 15180330
TI  - Transport screening of drug cocktails through an in vitro blood-brain barrier: is
      it a good strategy for increasing the throughput of the discovery pipeline?
AB  - PURPOSE: The objective of the current study was to investigate whether blood
      brain barrier (BBB) permeability studies in vitro could be accelerated by running
      several compounds together in the same experiment. METHODS: To address this
      question, we compared the transport of six compounds run separately with the
      results of the same compounds run together (cocktails). RESULTS: The study
      clearly demonstrated that the outcome of the experiments were totally different
      depending on the strategy used. Furthermore, the study highlights the importance
      of having the resistance to drug transport offered by filters without cells under
      control, as the filter membrane itself can be the rate-limiting step for some
      compounds; in addition, there is always a potential risk of interactions between
      molecules in cocktails as well as drug-drug interaction at the level of BBB
      transporters. In this study, the presence of several P-glycoprotein substrates in
      the drug cocktail was found to cause breakdown of the BBB. CONCLUSIONS: The
      results demonstrate that unless a strategy that involves running several
      compounds in the same experiment is properly validated, the results are of little
      predictive value.

PMID- 15180331
TI  - Characterization and modulation of the transferrin receptor on brain capillary
      endothelial cells.
AB  - PURPOSE: The expression level of the transferrin receptor (TfR) on brain
      capillary endothelial cells (BCECs) and the endocytosis of 125I-transferrin (125I
      Tf) by this receptor was investigated. Furthermore, the influence of iron, the
      iron scavenger deferoxamine mesylate (DFO), astrocytic factors, a GTP-ase
      inhibitor (tyrphostin-A8, T8), lipopolysaccharide (LPS), and the radical
      scavenger N-acetyl-L-cysteine (NAC) on the TfR expression was studied to gain
      insight in the use and optimization of the TfR for drug targeting to the brain.
      METHODS: Experiments were performed with primary cultured bovine BCECs that were
      incubated with 125I-Tf at 4 degrees C (to determine binding) or at 37 degrees C
      (to determine endocytosis) in the absence or presence of the modulators. For full
      saturation curves in the absence or presence of iron or DFO, analysis was
      performed with a population approach using NONMEM, allowing us to estimate a
      single value for affinity (Kd, concentration of 50% receptor occupancy) and
      separate values for maximum receptor occupancy (B(max). RESULTS: On BCECs, the
      TfR is expressed extracellularly (B(max) of 0.13 fmol/microg cell protein), but
      also has a large intracellular pool (total B(max) of 1.37 fmol/microg cell
      protein), and is actively endocytosing Tf via clathrin-coated vesicles. At 4
      degrees C, a Kd of 2.38 microg/ml was found, whereas the Kd at 37 degrees C was
      5.03 microg/ml. Furthermore, DFO is able to increase both the extracellular as
      well as the total binding capacity to 0.63 and 3.67 fmol/microg cell protein,
      respectively, whereas it had no influence on Kd. B(max) at 37 degrees C after DFO
      preincubation was also increased from 0.90 to 2.31 fmol/microg cell protein.
      Other modulators had no significant influence on the TfR expression levels,
      though LPS increased cellular protein concentrations after 2-h preincubation.
      CONCLUSIONS: The TfR is expressed on BCECs and actively endocytoses Tf, making it
      a suitable target for drug delivery to the bloodbrain barrier and the CNS. DFO up
      regulates the TfR expression level, which may influence targeting efficiency.

PMID- 15180332
TI  - Ocular pharmacokinetic/ pharmacodynamic modeling for bunazosin after instillation
      into rabbits.
AB  - PURPOSE: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model for an alpha1
      blocker (bunazosin) after instillation. The PK/PD model can predict both the drug
      concentrations in various ocular tissues and the hypotensive effect. METHODS:
      Bunazosin concentrations were determined with High Performance Liquid
      Chromatography (HPLC) in tear fluid, the aqueous humor, cornea, and iris-ciliary
      body after instillation or ocular injection into the anterior chamber in rabbits.
      After instillation of bunazosin in rabbits, intraocular pressure (IOP) was also
      determined with a pneumatic tonometer. The PK/PD parameters were estimated by
      fitting the concentration-time profiles and the hypotensive effect-time profiles
      to the developed PK/PD models using the MULTI (RUNGE) program. RESULTS: On the
      basis of the concentration-time profiles of bunazosin, a PK model, including
      seven compartments, was developed for examining the behavior of bunazosin after
      instillation. Then, two PK/ PD models for hypotensive effect of bunazosin were
      developed using an indirect response (model A) and the relationship between IOP
      and aqueous humor flow (model B). These models well described the concentration
      time profiles and hypotensive effect-time profiles of bunazosin after
      instillation. CONCLUSIONS: This study is the first trial to develop a PK/PD model
      for an antiglaucoma agent using an indirect response and the relationship between
      IOP and aqueous humor flow.

PMID- 15180333
TI  - Analysis of pharmacokinetics, pharmacodynamics, and pharmacogenomics data sets
      using VizStruct, a novel multidimensional visualization technique.
AB  - PURPOSE: Data visualization techniques for the pharmaceutical sciences have not
      been extensively investigated. The purpose of this study was to evaluate the
      usefulness of VizStruct, a multidimensional visualization tool, for applications
      in pharmacokinetics, pharmacodynamics, and pharmacogenomics. METHODS: The
      VizStruct tool uses the first harmonic of the discrete Fourier transform to map
      multidimensional data to two dimensions for visualization. The mapping was used
      to visualize several published pharmacokinetic, pharmacodynamic, and
      pharmacogenomic data sets. The VizStruct approach was evaluated using simulated
      population pharmacokinetics data sets, the data from Dalen and colleagues (Clin.
      PharmacoL Ther. 63:444-452, 1998) on the kinetics of nortriptyline and its 10
      hydroxynortriptyline metabolite in subjects with differing number of copies of
      the CYP2D6, and the gene expression profiling data of Bohen and colleagues (Proc.
      Natl. Acad. Sci. USA 100:1926-1930, 2003) on follicular lymphoma patients
      responsive and nonresponsive to rituximab. RESULTS: The VizStruct mapping
      preserves the key characteristics of multidimensional data in two dimensions in a
      manner that facilitates visualization. The mapping is computationally efficient
      and can be used for cluster detection and class prediction in pharmaceutical data
      sets. The VizStruct visualization succinctly summarized the salient similarities
      and differences in the nortriptyline and 10-hydroxynortriptyline pharmacokinetic
      profiles in subjects with increasing number of CYP2D6 gene copies. In the
      simulated population pharmacokinetic data sets, it was capable of discriminating
      the subtle differences between pharmacokinetic profiles derived from 1- and 2
      compartment models with the same area under the curve. The two-dimensional
      VizStruct mapping computed from a subset of 102 informative genes from the Bohen
      and colleagues data set effectively separated the rituximab responder, rituximab
      nonresponder, and control subject groups. CONCLUSIONS: The VizStruct approach is
      a computationally efficient and effective approach for visualizing complex,
      multidimensional data sets. It could have many useful applications in the
      pharmaceutical sciences.

PMID- 15180334
TI  - Urinary excretion: does it accurately reflect relative differences in
      bioavailability/systemic exposure when renal clearance is nonlinear?
AB  - PURPOSE: The purpose of this study was to assess the influence of nonlinear renal
      clearance on the ability of urinary excretion data to accurately determine
      relative differences in systemic exposure and bioavailability. METHODS: Serum
      concentration and urinary excretion-time profiles were simulated assuming an open
      one-compartmental model with first-order absorption, linear nonrenal clearance,
      and either linear or nonlinear renal clearance (saturable secretion). Renal
      clearance comprised 5% or 95% of total clearance. Doses were varied over a 100
      fold range (10-fold decrease/increase from the reference dose). Relative systemic
      exposures were based on the ratios of AUC and C(max) and the corresponding ratios
      of cumulative amount excreted in urine (A(e)) and the maximum urinary excretion
      rate. Relative bioavailability was based on the ratios of A(e) and the test to
      reference dose (D(ratio)). RESULTS: When renal clearance was linear and urinary
      excretion data were used to assess relative systemic exposure and relative
      bioavailability, no significant errors in accuracy were observed. However, when
      renal clearance was nonlinear, errors in the accuracy of estimation of relative
      bioavailability (Clr =5% only) and relative systemic exposure ranged from -53% to
      +125%; minimal error in accuracy existed in the estimation of relative
      bioavailability when Clr = 95% (-3% to +6%). CONCLUSIONS: Prior to the use of
      urinary excretion data to assess relative systemic exposure or bioavailability,
      the relationship between serum concentration and renal clearance should be
      established.

PMID- 15180335
TI  - Comparison of the use of liver models for predicting drug clearance using in
      vitro kinetic data from hepatic microsomes and isolated hepatocytes.
AB  - PURPOSE: To compare three liver models (well-stirred, parallel tube, and
      dispersion) for the prediction of in vivo intrinsic clearance (CL(int)), hepatic
      clearance (CLh). and hepatic availability (Fh) of a wide range of drugs in the
      rat using in vitro data from two in vitro sources. METHODS: In vitro CL(int) was
      obtained from studies using isolated rat hepatocytes (35 drugs) or rat liver
      microsomes (52 drugs) and used to predict in vivo CL(int) using reported scaling
      factors, and subsequently CLh and Fh were predicted based on the three liver
      models. In addition, in vivo CL(int) values were calculated from the reported
      values of CLh based on each of the three models. RESULTS: For all of the
      parameters, predictions from hepatocyte data were consistently more accurate than
      those from microsomal data. Comparison of in vitro and in vivo CL(int) values
      demonstrated that the dispersion model and the parallel tube model were
      comparable and more accurate (less bias, more precise) than the well-stirred
      model. For CLh and Fh prediction, the three models performed similarly.
      CONCLUSIONS: Considering the statistics of the predictions for three liver
      models, the use of parallel tube model is recommended for the evaluation of in
      vitro CL(int) values both from microsomes and hepatocytes. However, for the
      prediction of the in vivo drug (hepatic) clearance from in vitro data, as there
      are minimal differences between the models, the use of the well-stirred liver
      model is recommended.

PMID- 15180336
TI  - In vitro and in vivo pharmacoscintigraphic evaluation of ibuprofen hypromellose
      and gelatin capsules.
AB  - PURPOSE: To evaluate the in vitro and in vivo characteristics of hypromellose
      (HPMC) capsules prepared using a gellan gum and potassium gelling system compared
      to conventional hard gelatin capsules. METHODS: The in vitro dissolution of
      ibuprofen gelatin and HPMC capsules was determined using the USP and TRIS buffers
      at pH 7.2. The effect of pH and composition of the media was determined using a
      model drug that is soluble throughout the pH range 1.2 to 7.2. In an 11 subject
      four-way crossover study, the gastrointestinal performance of ibuprofen gelatin
      and HPMC capsule formulations was evaluated using scintigraphy and
      pharmacokinetics following fasted and fed dosing. RESULTS: Acid conditions and
      the presence of K+ cations hinder HPMC capsule opening, whereas in water,
      dissolution is identical to that of gelatin. These effects are related to the
      nature of the gel network that is formed in the presence of cations. No
      significant difference in esophageal transit was observed. Although the in vivo
      opening times of HPMC capsules were longer than for their gelatin counterparts,
      no significant difference in the regulatory important pharmacokinetic metrics of
      C(max) and AUC was found between ibuprofen, gelatin and HPMC capsules.
      CONCLUSIONS: The in vitro performance of HPMC capsules differ from gelatin, which
      will require modification to dissolution testing methodology for certain drugs.
      However, for the class II BCS drug ibuprofen, the two capsule types were not
      statistically different when comparing AUC and C(max) values, which suggests that
      the in vitro differences have reduced in vivo relevance.

PMID- 15180337
TI  - Uptake of melatonin into the cerebrospinal fluid after nasal and intravenous
      delivery: studies in rats and comparison with a human study.
AB  - PURPOSE: To investigate the possibility of direct transport of melatonin from the
      nasal cavity into the cerebrospinal fluid (CSF) after nasal administration in
      rats and to compare the animal results with a human study. METHODS: Rats (n = 8)
      were given melatonin both intranasally in one nostril (40 microg/rat) and
      intravenously by bolus injection (40 microg/rat) into the jugular vein using a
      Vascular Access Port. Just before and after drug administration, blood and CSF
      samples were taken and analyzed by HPLC. RESULTS: Melatonin is quickly absorbed
      in plasma (T(max) = 2.5 min) and shows a delayed uptake into CSF (T(max) = 15
      min) after nasal administration. The melatonin concentration-time profiles in
      plasma and CSF are comparable to those after intravenous delivery. The
      AUC(CSF)/AUC(plasma) ratio after nasal delivery (32.7 +/- 6.3%) does not differ
      from the one after intravenous injection (46.0 +/- 10.4%), which indicates that
      melatonin enters the CSF via the blood circulation across the blood-brain
      barrier. This demonstrates that there is no additional transport via the nose-CSF
      pathway. These results resemble the outcome of a human study. CONCLUSIONS: The
      current results in rats show that there is no additional uptake of melatonin in
      the CSF after nasal delivery compared to intravenous administration. This is in
      accordance with the results found in humans, indicating that animal experiments
      could be predictive for the human situation when studying nose-CSF transport.

PMID- 15180338
TI  - Chitosan nanoparticles as new ocular drug delivery systems: in vitro stability,
      in vivo fate, and cellular toxicity.
AB  - PURPOSE: To assess the potential of chitosan (CS) nanoparticles for ocular drug
      delivery by investigating their interaction with the ocular mucosa in vivo and
      also their toxicity in conjunctival cell cultures. METHODS: Fluorescent (CS-fl)
      nanoparticles were prepared by ionotropic gelation. The stability of the
      particles in the presence of lysozyme was investigated by determining the size
      and their interaction with mucin, by measuring the viscosity of the mucin
      dispersion. The in vivo interaction of CS-fl nanoparticles with the rabbit cornea
      and conjunctiva was analyzed by spectrofluorimetry and confocal microscopy. Their
      potential toxicity was assessed in a human conjunctival cell line by determining
      cell survival and viability. RESULTS: CS-fl nanoparticles were stable upon
      incubation with lysozyme and did not affect the viscosity of a mucin dispersion.
      In vivo studies showed that the amounts of CS-fl in cornea and conjunctiva were
      significantly higher for CS-fl nanoparticles than for a control CS-fl solution,
      these amounts being fairly constant for up to 24 h. Confocal studies suggest that
      nanoparticles penetrate into the corneal and conjunctival epithelia. Cell
      survival at 24 h after incubation with CS nanoparticles was high and the
      viability of the recovered cells was near 100%. CONCLUSIONS: CS nanoparticles are
      promising vehicles for ocular drug delivery.

PMID- 15180339
TI  - Involvement of P-glycoprotein in the transport of saquinavir and indinavir in rat
      brain microvessel endothelial and microglia cell lines.
AB  - PURPOSE: Membrane-bound efflux transporters, such as P-glycoprotein (P-gp), may
      limit the brain entry and distribution of HIV-1 protease inhibitors and be in
      part responsible for HIV-1-associated dementia treatment failure. The purpose of
      this study was to characterize the transport properties of saquinavir and
      indinavir in a brain microvessel endothelial cell line and in microglia, the
      immune cells of the brain and primary HIV-1 cellular target. METHODS: Biochemical
      and transport studies were performed in an immortalized rat brain endothelial
      cell line (RBE4), a rat microglia cell line (MLS-9), and a P-gp overexpressing
      Chinese hamster ovary cell line (CHRC5). RESULTS: Western blot analysis using the
      P-gp monoclonal antibody C219 detected a single band at approximately 170 to 180
      kDa (a size previously reported for P-gp) in all cell lines. Cellular
      accumulation of [14C]saquinavir and [3H]indinavir by RBE4, MLS-9, and CHRC5
      monolayers was significantly enhanced in the presence of P-gp inhibitors, HIV-1
      protease inhibitors, the ATPase inhibitor sodium azide, and the ATP depleting
      agent 2',4'-dinitrophenol respectively. [14C]Saquinavir and [3H]indinavir efflux
      from both cell systems was rapid and significantly reduced in the presence of
      PSC833. CONCLUSIONS: These results provide evidence for P-gp mediated transport
      of saquinavir and indinavir in RBE4 and MLS-9 and suggest that this transporter
      can restrict, at least in part, the permeation of HIV-1 protease inhibitors at
      both the brain barrier site and in brain parenchyma.

PMID- 15180340
TI  - Predicting P-glycoprotein effects on oral absorption: correlation of transport in
      Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo.
AB  - PURPOSE: Cell-based permeability screens are widely used to identify drug-P
      glycoprotein (PGP) interaction in vitro. However, their reliability in predicting
      the impact of PGP on human drug pharmacokinetics is poorly defined. The aim was
      to determine whether a quantitative relationship exists between PGP-mediated
      alterations in Caco-2 permeability and oral pharmacokinetics in mice. METHODS:
      Two indicators of drug efflux were measured in Caco-2 for a group of 10
      compounds, the ratio of A-B and B-A transport (R9B-A/A-B)) and the ratio of A-B
      transport in the presence and absence of a PGP inhibitor, GF120918 (R(GF)). These
      data were correlated with ratios of oral plasma levels in either mdr1a(-/-) or
      mdr1a/1b(-/-) and wild-type mice (R(KO/WT in vivo)) calculated from literature
      data on these compounds. RESULTS: A significant, positive correlation (r2 = 0.8,
      p < 0.01) was observed between RGF and R(KO/WT in vivo). In contrast, R(B-A/A-B),
      a more commonly used in vitro measure, showed a much weaker correlation with in
      vivo data (r2 = 0.33, p = 0.11). A strong correlation with R(GF) was also
      observed after correction of in vivo data for PGP effects on IV clearance.
      CONCLUSION: The increase in A-B drug permeability following inhibition of PGP in
      Caco-2 allows a reasonable prediction of the likely in vivo impact that PGP will
      have on plasma drug levels after oral administration.

PMID- 15180341
TI  - Control of blood glucose by novel GLP-1 delivery using biodegradable triblock
      copolymer of PLGA-PEG-PLGA in type 2 diabetic rats.
AB  - PURPOSE: The incretin hormone glucagon-like peptide-1 (GLP-1) is a promising
      candidate for treatment of type 2 diabetes mellitus. However, plasma half-life of
      GLP-1 is extremely short, thus multiple injections or continuous infusion is
      required for therapeutic use of GLP-1. Therefore, we investigated a new delivery
      system as a feasible approach to achieve sustained GLP-1 release for a 2-week
      period. METHODS: A water-soluble, biodegradable triblock copolymer of poly [(DL
      lactide-co-glycolide)-b-ethylene glycol-b-(DL-lactide-coglycolide)] (ReGel) was
      used in this study as an injectable formulation for controlled release of GLP-1.
      GLP-1 was formulated into ReGel as insoluble zinc complex to stabilize GLP-1
      against aggregation and slow down release. The GLP-1 release profile was
      monitored in vitro and in vivo. Zucker Diabetic Fatty rats were administered
      subcutaneously with the GLP-1 formulation. The concentration of GLP-1, insulin,
      and glucose was monitored every day after the GLP-1 administration. RESULTS: The
      GLP-1 release from ReGel formulation in vitro and in vivo showed no initial burst
      and constant release for 2 weeks. Animal study demonstrated that the plasma
      insulin level was increased, and the blood glucose level was controlled for 2
      weeks by one injection of ReGel/ ZnGLP-1 formulation. CONCLUSIONS: It is
      concluded that one injection of zinc-complexed GLP-1 loaded ReGel can be used for
      delivery of bioactive GLP-1 during a 2-week period. Because this new delivery
      system is biocompatible and requires twice-a-month injection, it can improve
      patient compliance and cost-effectiveness.

PMID- 15180342
TI  - Sustained intravesical drug delivery using thermosensitive hydrogel.
AB  - PURPOSE: Direct instillation of drug solutions into the bladder through a
      urethral catheter (i.e., intravesical therapy) evades systemic adverse effects of
      drugs used for bladder diseases. However, conventional vehicles for these drugs
      fail to extend duration of drug exposure in the bladder beyond the first voiding
      of urine postinstillation. The current study seeks to overcome the aforementioned
      inherent limitation of intravesical drug administration by using thermosensitive
      hydrogel as a matrix for sustained intravesical drug delivery. METHODS: Under
      halothane anesthesia, normal adult female Sprague-Dawley rats were catheterized
      with PE-50 tubing to instill either 0.02% w/v solution of fluorescein
      isothiocyanate (FITC) or the same amount of FITC in a 30% w/v dispersion of
      thermosensitive [Poly(ethylene glycol)-Poly[lactic acid-co-glycolic acid]
      Poly(ethylene glycol)) (PEG-PLGA-PEG) polymer in a 0.1 M phosphate buffer. After
      instillations, rats were kept in metabolic cages for urine collection.
      Fluorescence emanating from FITC was measured in the urine at various time points
      up to 24 h after instillation. A rat model of cyclophosphamide-induced cystitis
      was chosen for the efficacy study using misoprostol as a model drug entrapped in
      the thermosensitive hydrogel in place of FITC. Efficacy of hydrogel containing
      misoprostol was compared against rat groups instilled with saline, hydrogel, and
      misoprostol independently. RESULTS: Prolonged drug exposure to the bladder
      afforded by hydrogel was evident from the time course of FITC elimination in the
      urine and by the green fluorescence of FITC seen at the bladder surface when
      isolated 24 h after instillation. Rats instilled with free FITC voided almost all
      of the fluorescence in the urine within the first 8 h, whereas rats instilled
      with hydrogel encapsulated FITC showed sustained release up to 24 h after
      instillation. Using a cyclophosphamide-induced cystitis model, rats instilled
      with misoprostol, a synthetic PGE1 analog, showed significantly reduced frequency
      of urine voiding (p < 0.05) as compared to the rats instilled with saline.
      Histological examination of the urothelium showed near normal morphology in rats
      instilled with misoprostol in hydrogel, whereas extensive tissue damage was
      observed in rats instilled with saline. CONCLUSION: Our study showed that PEG
      PLGA-PEG polymer could be used as a viable sustained drug delivery system for
      intravesical therapy of diseases of the bladder such as cystitis using
      misoprostol.

PMID- 15180343
TI  - A method for oral DNA delivery with N-acetylated chitosan.
AB  - PURPOSE: The gastrointestinal tract poses a variety of morphological and
      physiological barriers to the expression of a target gene. In this work, N
      acetylated chitosan is used as a gene delivery carrier for solving this problem.
      METHODS: Plasmid DNAs carrying the lacZ gene and interluekin-10 (IL-10) gene were
      mixed with N-acetylated chitosan. The N-acetylated chitosan/plasmid DNA complex
      was mixed into a food paste to feed mice. The transport and distribution
      characteristics of the plasmid along the intestinal mucosa were identified by
      beta-galactosidase assay. In addition, the stomach and intestines were subjected
      to analysis for the production of IL-10. RESULTS: The efficiency of N-acetylated
      chitosan-mediated gene delivery to the intestines was observed to be higher than
      that of chitosan alone. In particular, this result was most significant in the
      case of the duodenum, where the LacZ gene was expressed most effectively through
      the use of N-acetylated chitosan. It was also demonstrated that the IL-10 gene
      was successfully transferred to intestines through this method. CONCLUSIONS: A
      plasmid DNA was able to be orally delivered to the intestines using N-acetylated
      chitosan as a carrier. Thus, we have developed a dietary dose system for
      delivering a DNA vaccine for treating gastrointestinal diseases.

PMID- 15180344
TI  - Transdermal iontophoresis of rotigotine across human stratum corneum in vitro:
      influence of pH and NaCl concentration.
AB  - PURPOSE: The aim of this study was to characterize the influence of pH and NaCl
      concentration on the transdermal iontophoretic transport of the dopamine receptor
      agonist rotigotine across human stratum corneum (HSC). METHODS: Rotigotine
      transport was studied in vitro in side by side diffusion cells according to the
      following protocol: 6 h of passive diffusion, 9 h of iontophoresis, and 5 h of
      passive diffusion. A current density of 0.5 mA cm(-2) was used. The influence of
      donor phase pH (4, 5, and 6) and different concentrations of NaCl (0.07 and 0.14
      M) on rotigotine iontophoretic flux were examined. The acceptor phase was
      phosphate-buffered saline (PBS) at pH 7.4 except in one series of experiments
      aimed to study the effects of rotigotine solubility on its iontophoretic
      transport. In this study, PBS at pH 6.2 was used. In separate studies. 14C
      mannitol was used as a marker to determine the role of electro-osmosis during
      iontophoresis. RESULTS: The estimated iontophoretic steady-state flux (Flux(ss))
      of rotigotine was influenced by the pH of the donor solution. At a drug donor
      concentration of 0.5 mg ml(-1), the iontophoretic flux was 30.0 +/- 4.2 nmol cm(
      2) h(-1) at pH 6 vs. 22.7 +/- 5.5 nmol cm(-2) h(-1) at pH 5. However, when the
      donor concentration was increased to 1.4 mg ml(-1), no significant difference in
      iontophoretic rotigotine transport was observed between pH 5 and 6. Increase of
      NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine
      Flux(ss) from 22.7 +/- 5.5 nmol cm(-2) h(-1) to 14.1 +/- 4.9 nmol cm(-2) h(-1).
      The contribution of electro-osmosis was estimated less than 17%. Probably due to
      the lipophilic character of the drug, impeding the partitioning of rotigotine
      from HSC to the acceptor compartment, steady-state transport was not achieved
      during 9 h of iontophoresis. CONCLUSIONS: Both pH and NaCl concentration of the
      donor phase are crucial on the iontophoretic transport of rotigotine. Electro
      repulsion is the main mechanism of the iontophoretic transport of rotigotine.

PMID- 15180346
TI  - Modeling and monitoring of polymorphic transformations during the drying phase of
      wet granulation.
AB  - PURPOSE: The purpose of this work was to monitor polymorphic transformations of
      glycine during the drying phase of a wet granulation and model the polymorphic
      conversions using a time-based reconciliation model. METHODS: Near-infrared
      spectroscopy (NIR) was used for quantitation of polymorphs, and X-ray powder
      diffraction (XRPD) was used for qualitative analysis of polymorphs. RESULTS: The
      data show that the faster the granulation was dried, the more kinetic trapping of
      the metastable alpha-glycine polymorph, as predicted by reconciliation of the
      time scales of both the drying rate and the rate of the solution-mediated
      conversion. CONCLUSIONS: By knowing basic properties of the drug substance
      (solubility of the polymorphic forms and the rate of the solution-mediated
      conversion), processing conditions, such as the drying rate, can be adjusted to
      anticipate and prevent potential polymorphic transformations.

PMID- 15180345
TI  - On-line visualization of dye diffusion in fresh unfixed human skin.
AB  - PURPOSE: The purpose of the current study was to develop a new method to examine
      the diffusion in fresh unfixed human skin on-line. METHODS: Full thickness skin
      samples were cut perpendicular to the skin surface (cutting plane facing upwards)
      with a new cutting device forming part of the final diffusion cell. The donor
      solution contained 0.1 mg/ml Bodipy FL C5 (moderately lipophilic) dissolved in
      citric acid buffer, pH 5.0, and the acceptor phase consisted of phosphate
      buffered saline, pH 7.4. Images were taken with confocal laser scanning
      microscopy (CLSM) every 10 min for 8 h. RESULTS: This new method enabled for the
      first time visualization of concentration profiles in different skin layers
      simultaneously as a function of time. For this model penetrant, Bodipy FL C5
      showed that the lower stratum corneum layer constitutes the greatest barrier to
      diffusion. Furthermore, there is preferred partitioning of this probe in
      epidermis vs. either stratum corneum or dermis. CONCLUSIONS: The on-line
      diffusion cell in combination with CLSM is a promising tool to study diffusion
      processes of dyes in fresh unfixed skin on-line. The method has the potential to
      access deeper skin layers as well as to visualize diffusion processes in cells.

PMID- 15180347
TI  - Effect of aging on the physical properties of amorphous trehalose.
AB  - PURPOSE: The purpose of this investigation was i) to study the effect of physical
      aging on crystallization and water vapor sorption behavior of amorphous anhydrous
      trehalose prepared by freeze-drying, and ii) to determine the effects of water
      sorption on the relaxation state of the aged material. METHODS: Freeze-dried
      trehalose was aged at 100 dgrees C for varying time periods to obtain samples
      with different degrees of relaxation. The glass transition temperature (Tg) and
      enthalpic relaxation were determined by differential scanning calorimetry, and
      the rate and extent of water uptake at different relative humidity values were
      quantified using an automated vapor sorption balance. RESULTS: Annealing below
      the Tg caused nucleation in the amorphous trehalose samples, which decreased the
      crystallization onset temperature on subsequent heating. However, no
      crystallization was observed below the Tg even after prolonged annealing.
      Physical aging caused a decrease in the rate and extent of water vapor sorption
      at low relative humidity values. Moreover, the water sorption removed the effects
      of physical aging, thus effectively causing enthalpic recovery in the aged
      samples. This recovery occurred gradually in the glassy phase and was not
      associated with a glass to rubber transition. We believe this aging reversal to
      be due to volume expansion during water sorption in the amorphous structure.
      CONCLUSIONS: Thermal history of amorphous materials is a crucial determinant of
      their physical properties. Aging of amorphous trehalose led to nucleation below
      the Tg, and decrease in rate and extent of water sorption. Sorption of water
      resulted in irreversible changes in the relaxation state of the aged material.

PMID- 15180348
TI  - A new wet conductivimetric method to estimate the drug percolation threshold.
AB  - PURPOSE: The main objectives of this work are to study the behavior of fluid
      imbibition into a consolidated matrix through a wet invasive conductivimetric
      technique, to investigate if the changes in the behavior observed can be related
      to the drug percolation threshold, and to use this technique for its estimation.
      METHODS: Matrix tablets were prepared using five sieving fractions of KCl and
      Eudragit RS-PM. In vitro release assays were carried out on 45 batches. The drug
      percolation thresholds were estimated following the method of Leuenberger and
      Bonny, and the results were compared to the obtained employing the
      conductivimetric technique described in this paper. RESULTS: The wet
      conductivimetric technique and the standard method provided similar results for
      the estimation of the percolation threshold. The presented technique also
      provides quantitative information about the consolidated matrix. CONCLUSIONS: A
      new apparatus has been developed for the study of the conductivimetric behavior
      of matrix tablets during water uptake. This technique provides measurable
      parameters of fluid penetration and can be used to estimate the drug percolation
      threshold, providing similar results to the Leuenberger and Bonny method and
      being clearly faster.

PMID- 15180349
TI  - Polymer blends used for the coating of multiparticulates: comparison of aqueous
      and organic coating techniques.
AB  - PURPOSE: The purpose of this study was to use polymer blends for the coating of
      pellets and to study the effects of the type of coating technique (aqueous vs.
      organic) on drug release. METHODS: Propranolol HCl-loaded pellets were coated
      with blends of a water-insoluble and an enteric polymer (ethyl cellulose and
      Eudragit L). Drug release from the pellets as well as the mechanical properties,
      water uptake, and dry weight loss behavior of thin polymeric films were
      determined in 0.1 M HCI and phosphate buffer, pH 7.4. RESULTS: Drug release
      strongly depended on the type of coating technique. Interestingly, not only the
      slope, but also the shape of the release curves was affected, indicating changes
      in the underlying drug release mechanisms. The observed effects could be
      explained by the higher mobility of the macromolecules in organic solutions
      compared to aqueous dispersions, resulting in higher degrees of polymer-polymer
      interpenetration and, thus, tougher and less permeable film coatings. The
      physicochemical properties of the latter were of major importance for the control
      of drug release, which was governed by diffusion through the intact polymeric
      films and/or water-filled cracks. CONCLUSIONS: The type of coating technique
      strongly affects the film microstructure and, thus, the release mechanism and
      rate from pellets coated with polymer blends.

PMID- 15180350
TI  - Oxaliplatin degradation in the presence of chloride: identification and
      cytotoxicity of the monochloro monooxalato complex.
AB  - PURPOSE: To study the degradation of oxaliplatin in chloride media and evaluate
      the cytotoxicity of oxaliplatin in normal and chloride-deficient medium. METHODS:
      The products of the reaction of oxaliplatin with chloride were separated on a
      Hypercarb S column with a mobile phase containing 40% methanol in 0.05 M ammonia
      and subjected to electrospray ionization mass spectrometry. The cytotoxicity of
      oxaliplatin in normal and chloride-deficient medium was evaluated by 30-min
      incubations on human colon adenocarcinoma cells (HT-29). RESULTS: We identified a
      new intermediate degradation product, the monochloro monooxalato complex
      ([Pt(dach)oxCl]-) and the final product. the dichloro complex (Pt(dach)Cl2), by
      liquid chromatography-mass spectrometry. [Pt(dach)oxCl]- was found as the
      negative ion, M-, at m/z 431, and the positive ion, [M+2H]+, m/z 433. Pt(dach)Cl2
      was found as the negative ion, [M-H]-, m/z 377, and the positive ion, [M+NH4]+,
      m/z 396. The fast initial degradation of oxaliplatin can be coupled to the fast
      formation of [Pt(dach)oxCl]-. In the cytotoxic assay, the cell survival was not
      affected by the chloride levels. CONCLUSIONS: [Pt(dach)oxCl]-, a new
      transformation product of oxaliplatin, has been identified. Its in vitro
      cytotoxic effect does not appear to exceed that of oxaliplatin.

PMID- 15180351
TI  - Probiotics reduce the CD34+ hemopoietic precursor cell increased traffic in
      allergic subjects.
AB  - An increased traffic of circulating CD34+ Hemopoietic Precursors Cells (HPC) is
      an important feature of systemic allergic inflammation. Bacteria and bacterial
      products are capable of stimulating the transcription of the maturational
      cytokines IL12 and IFNs through the activation of Toll-Like-Receptor and the
      subsequent nuclear translocation of the NF-kappaB factor. In this study the
      probiotics differentiation/maturational effect potential on CD34+ HPC has been
      investigated. Fourteen consecutive subjects, 9M and 5F, aged 6-48, with clinical
      symptoms of asthma and /or conjunctivitis, rhinitis, urticaria, atopic
      dermatitis, food allergy and irritable bowel syndrome were enrolled. Allergen
      specific serum IgE were found in twelve patients. Flow-cytometric measurement of
      peripheral blood CD34dim/bright HPC values were assessed before and after 30 days
      of therapy, consisting in the oral administration of one sachet a day of ENDOLAC
      (UCB Pharma, Turin, Italy). Each sachet contained a mixture of Lactobacillus
      acidophilus, L. delbrueckii and Streptococcus thermophilus for a total of 1 x
      10(9) live bacteria. Circulating CD34+ cell values significantly (p < 0.001)
      reduced after the treatment. ENDOLAC, thus, may improve the efficacy of the
      standard treatments of allergic diseases.

PMID- 15180352
TI  - Immediate hypersensitivity to chlorhexidine: literature review.
AB  - Chlorhexidine, an antiseptic belonging to family of biguanides, is used
      extensively in the medical and surgical environment. Late onset hypersensitivity
      and eczema occur regularly and are well documented events. Conversely, immediate
      hypersensitivity, sometimes taking the form of acute urticaria that can result in
      anaphylactic shock, is rarer. These manifestations can occur during contact of
      the skin or mucosa with chlorhexidine. Out of the fifty case reports of
      chlorhexidine-related anaphylaxis published worldwide over the past ten years,
      fifteen occurred during surgery. Signs generally appear from 15 to 45 minutes
      after the start of anesthesia. If there is any suspicion of immediate allergy to
      chlorhexidine, prick-tests or even intradermal reaction (IDR) techniques are
      highly recommended. In the event of confirmed allergy to chlorhexidine, strict
      eviction is required, bearing in mind that over a hundred medicinal products
      currently on the French market contain chlorhexidine.

PMID- 15180353
TI  - Is Anti Cyclic citrullinated peptide a useful laboratory test for the diagnosis
      of rheumatoid arthritis?
AB  - AIM OF THE STUDY: To evaluate Anti Cyclic citrullinated peptide (anti-CCP) and
      Rheumatoid Factor (RF) sensitivity and specificity in patients with Rheumatoid
      Arthritis (RA). MATERIALS AND METHODS: Anti-CCP and RAtest for the assessment of
      RF have been tried out in 35 patients with RA and in a group of 42 patients whose
      hands were affected by arthralgic/arthritis-like symptoms. RESULTS: Sensitivity
      of anti-CCP was 71,4% with 95,2% of specificity. RAtest sensitivity was 91,4%
      with specificity of 31%. Anti-CCP and RAtest both positive showed an overall
      71.4% sensitivity and 95.2% specificity; sensitivity was 91.4% and specificity
      was 31.0%, if at least RAtest or anti-CCP resulted positive, The positive
      predictive value of the two test performed together was 97.0%, higher than that
      of anti-CCP (71.4%) and RAtest (88.5%9) alone. The negative predictive value of
      the two test performed together was 30.9% similar to that of the RAtest performed
      alone (30.9%). All patients affected by HCV related chronic liver disease were
      negative for anti-CCP test; 12/14 of them had RAtest positive. CONCLUSIONS: Anti
      CCP antibody has a diagnostic specificity higher than RF. Anti-CCP and RA tests
      together prove to have the some specificity as anti-CCP alone and a lower
      sensitivity. Sensitivity is better when at least either RAtest or anti-CCP
      results positive. The best positive predictive value is obtained performing both
      anti-CCP and RAtest. Anti-CCP is a useful laboratory marker to confirm the
      diagnosis of rheumatoid arthritis; it seems to be very important to differentiate
      patients with RA from those with HCV related arthritis.

PMID- 15180354
TI  - Efficacy and safety of specific immunotherapy to mosquito bites.
AB  - BACKGROUND: Adverse effects of mosquito bites are often very unpleasant and need
      a treatment. OBJECTIVE: To evaluate the efficacy of specific immunotherapy
      (S.I.T) with an extract of the whole body of the mosquito Aedes communis. METHOD:
      Twenty patients having strong local immediate and delayed reactions with in many
      cases also an allergic rhinitis, were selected. A similar control group was
      included. In all these patients skin tests, RASTs and nasal provocation tests
      were carried out with an extract of Aedes communis and a battery of the commonest
      allergens in our area including two insects : Blatella germanica (german
      cockroach) and Gasterophilus intestinalis (horse fly). The specific immunotherapy
      was carried out by the conventionnal subcutaneous route. RESULTS: After 18 months
      of S.I.T all the patients reported the disappearance of local reactions and
      symptoms of allergic rhinitis, which was correlated with a statistically
      improvement of symptom and drug consumption scores and a decrease of allergenic
      reactivity by the nasal provocation test. CONCLUSIONS: S.I.T with an extract of
      Aedes communis produced after 18 months of treatment a significant improvement of
      allergic symptoms, a decrease of symptom and drug consumption scores and of
      allergen specific nasal reactivity. S.I.T in mosquito bite allergy appears to be
      effective and safe in the treatment of both cutaneous and respiratory symptoms.

PMID- 15180355
TI  - Position paper: controversial and unproven diagnostic procedures for food
      allergy.

PMID- 15180356
TI  - Mizolastine and fexofenadine modulate cytokine pattern after nasal allergen
      challenge.
AB  - Allergen specific nasal challenge (ASNC) is an optimal model to study the
      pathophysiological mechanisms sustaining allergic inflammation, particularly the
      cytokine pattern. Antihistamines have been accepted as a highly effective therapy
      for allergic rhinitis. The aim of this double blind, randomised, placebo
      controlled study was the evaluation of symptoms and cytokines, during the early
      phase, after a single dose of mizolastine (10 mg), fexofenadine (120 mg) or
      placebo, using the model of ASNC. A total of 30 patients with allergic rhinitis
      underwent nasal challenge 6 hours after treatment. The following parameters were
      evaluated 30 minutes after ASNC (i.e. early phase): nasal symptoms (rhinorrhea,
      itching, sneezing, obstruction), and cytokine pattern, including IL1, IL6, and
      TNFalpha. Mizolastine was associated with early phase reduction of: i) clinical
      symptoms (p < 0.03), ii) cyotkine levels of IL1 (p = 0.003), IL6 (p < 0.007), and
      TNF_ (p < 0.003) in comparison with placebo group. Fexofenadine significantly
      inhibited IL6 (p < 0.004) and TNFalpha (p < 0.004) levels in comparison with
      placebo. The present findings demonstrate that mizolastine exerts a significant
      effect on early phase events, reducing symptoms and pro-inflammatory cytokines.
      Fexofenadine reduces TNFalpha and IL6 levels only. These effects appear to be
      clinical relevant for mizolastine.

PMID- 15180357
TI  - Some doubts of the allergist.
AB  - The authors examine and discuss some controversial points of allergologic
      literature concerning immunomodulation, pathogenesis, hygiene hypothesis, mixture
      of vaccines and treatment schedules.

PMID- 15180358
TI  - Posidonia oceanica as a biomonitor of trace elements in the Gulf of Naples:
      temporal trends by lepidochronology.
AB  - Levels of Hg, Cd, Pb, Cu, Zn, Fe, and Mn were assessed by using Posidonia
      oceanica as a bioindicator in the Gulf of Naples (southern Italy).
      Lepidochronology, which enables retroactive dating of scales and rhizomes of this
      seagrass, was combined with atomic spectrometry to assess temporal trends of
      trace elements in dated scales and rhizomes over a 10-year period.
      Lepidochronology occasionally has been used to monitor Hg in dated scales, but
      never has been used to determine concentrations of other trace elements in dated
      rhizomes. Data were compared between various structural parts of seagrass and
      between sampling sites. Concentrations of some elements found in dated scales or
      rhizomes showed a similar trend in most of the sites; increasing for Hg and Cu
      and decreasing for Pb, Fe, and Zn. Contaminant levels indicated by seagrass
      meadows varied from metal to metal. Concentrations of Hg, Cd, and Pb fell within
      the ranges measured in other areas considered to have low levels of heavy metal
      pollution, whereas Cu, Mn, and Zn had higher concentrations only in some years.
      However, on the basis of other studies, none of the sampling sites are considered
      to have high contamination levels.

PMID- 15180359
TI  - The influence of pH and salinity on the toxicity of heavy metals in sediment to
      the estuarine clam Ruditapes philippinarum.
AB  - An approach is presented for determining the influence of two key variables, pH
      and salinity (S), on the toxicity of four common heavy metals bound to sediments
      in estuaries. Two samples of environmental sediment taken from two estuaries in
      southern Spain (the Huelva estuary and the Guadalquivir River estuary), together
      with a dilution of toxic mud from the Aznalcollar (Spain) mining spill (April
      1998) were used to determine their toxicity at different values of pH (6.5, 7.5,
      and 8.5) and salinity (10, 20, and 30) on the estuarine clam Ruditapes
      philippinarum. Two different endpoints, sublethal, indicated by clam reburial
      (median effective burial time [ET50]), and relative mortality (median lethal
      concentration [LC50]), were used to quantify the toxicity associated with the
      heavy metals. Neither salinity nor pH was found to influence the toxic responses
      measured by the behavioral endpoint (ET50). However, a strong effect on the LC50
      related to pH and salinity was detected, with the toxicity of the heavy metals
      being increased at low values of both variables (pH = 6.5 and S = 10). The
      mechanism of heavy metals uptake through water may explain this influence of pH
      and salinity on the lethal toxicity detected. The results show differences in the
      toxicity of these heavy metals bound to sediments depending on whether the origin
      of metal contamination is chronic or acute.

PMID- 15180360
TI  - Valve closure response to uranium exposure for a freshwater bivalve (Corbicula
      fluminea): quantification of the influence of pH.
AB  - Laboratory experiments were carried out to analyze the first valve closure
      response of a freshwater bivalve (Corbicula fluminea) exposed to uranium during a
      5-h period. Experiments were performed in a well-defined artificial water at two
      pH values, 5.5 and 6.5, with a noninvasive method of valve recording. Sensitivity
      thresholds, based on percentage of bivalve that close their valves in a given
      time, were determined. Response thresholds depended on the total uranium
      concentration, integration time of response (fast responses could only be
      observed for the highest concentrations), and pH. The bivalve is much more
      sensitive to total uranium concentration at pH 5.5 than pH 6.5. The minimal
      sensitivity threshold determined, expressed as the uranium concentration inducing
      the valve closure of 50% of the bivalves, was 0.05 micromol/L at pH 5.5 after 5 h
      of exposure. Moreover, higher concentrations of the free ion UO2(2-) are required
      at pH 5.5 than at pH 6.5 to illicit the same response. Two hypotheses can be
      proposed, that UO2(2-) is not the only detected species or that competition
      exists between H- and UO2(2-) for binding sites.

PMID- 15180361
TI  - Effects of dissolved organic carbon concentration and source, pH, and water
      hardness on chronic toxicity of copper to Daphnia magna.
AB  - The effects of pH (5.3-8.7), water hardness (CaCO3 at 25-500 mg/L), dissolved
      organic carbon (DOC) concentration (1.6-18.4 mg/L), and DOC source on the chronic
      toxicity of copper to Daphnia magna were investigated by using a multifactorial,
      central composite test design. Natural dissolved organic matter (DOM) was
      collected at three sites in Belgium and The Netherlands by using reverse osmosis.
      For a total number of 35 toxicity tests performed, 21-d no-observed-effect
      concentrations (NOECs) of copper based on reproduction ranged from 29.4 to 228
      microg/L and 21-d concentrations of copper causing 50% reduction of reproduction
      (EC50s) ranged from 41.5 to 316 microg/L. Statistical analysis revealed that DOC
      concentration and pH had a significant effect on copper toxicity but hardness (at
      the levels tested) did not. In general, an increase in pH or DOC resulted in a
      linear increase of 21-d NOEC and EC50 values. All DOMs (originating from three
      different sources) reduced copper toxicity to the same extent. Multiple linear
      regression analysis on the results of all 35 toxicity tests revealed that DOC
      concentration is the most important factor for chronic toxicity of copper to D.
      magna, explaining about 60% of the observed variability, whereas pH only
      explained about 15% of the observed variability. Regression models were developed
      (with DOC and pH as parameters) that were capable of predicting NOECs and EC50s
      within a factor of 1.9 from observed NOEC and EC50 values obtained with eight
      natural surface waters spiked with copper. Until future research further
      elucidates the mechanisms underpinning the observed bioavailability relations,
      these empirical regression models can become a first simple tool for regulatory
      applications.

PMID- 15180362
TI  - Effects of acid mine drainage on larval Chironomus (Diptera, Chironomidae)
      measured with the Multispecies Freshwater Biomonitor.
AB  - The abandoned Sao Domingos mine (Portugal) offers a pH and metal gradient of acid
      mine drainage (AMD), and is an ideal model for ecotoxicological studies. Short
      term 24-h bioassays with water from the AMD (pH 3.3, 4.4, and 5.5, and control)
      were performed with fourth instars of Chironomus in the laboratory and in situ
      (AMD at pH 5.5) in artificial flow-through channels. This was compared to
      reference water acidified to the respective pH values (acid only). Behavioral
      stress responses were monitored online with the Multispecies Freshwater
      Biomonitor (MFB). The exposure to AMD and acid only was in the sublethal range
      (mortality 0-20%). The use of MFB chambers did not affect survival. Stress
      behavior of Chironomus consisted mainly of decreased locomotory activity in AMD
      and increased activity in acid-only tests, indicating that the metals in the AMD
      played a role as stress factor. Field exposure in the AMD mixing zone (pH 5.5)
      generated similar activity as in the corresponding laboratory exposure.

PMID- 15180363
TI  - Physicochemical and toxicological studies on 4-chloro-3,5-dinitrobenzoic acid in
      aqueous solutions.
AB  - Physicochemical characterization of hazardous compounds often is required for the
      development of structure-reactivity correlations. Physical, chemical, and
      toxicological properties of target pollutants require determination for an
      efficient application of wastewater treatments. In the present work, we chose a
      chloro-nitro-aromatic derivative (4-chloro-3,5-dinitrobenzoic acid [CDNBA]), as a
      model compound on which to perform physicochemical and toxicological studies.
      Several properties of CDNBA are not available in the literature, although many
      aromatic nitro-compounds are considered hazardous materials. Measurements of
      solubility in water, acid dissociation constant, and kinetic parameters for the
      nucleophilic substitution of chlorine atom in alkaline media are reported. We
      also performed cytotoxicity studies of CDNBA and ultraviolet-irradiated CDNBA
      solutions. From the analysis of CDNBA solubility in water at different
      temperatures, an enthalpy of solution of 23.2 +/- 2.5 kJ/mol was found. The study
      of the acid dissociation constant Kc by using conductivity measurements and the
      modified Gran's method yielded values for the equilibrium constant Ka of 2.36 x
      10(-3) and 2.26 x 10(-3), respectively. The bimolecular rate constant for the
      reaction of CDNB- and hydroxyl ion (HO) measured at room temperature and 0.1 M of
      ionic strength was 5.92/M x s, and the activation energy for this process was
      70.7 +/- 3.4 kJ/mol. Cytotoxicity assays with aqueous suspensions of Tetrahymena
      pyriformis showed lethal effects due to the pH change induced by CDNBA. On the
      other hand, in buffered solutions, a value of 104.47 microM was observed for the
      median effective concentration, that is, the concentration of CDNBA at which the
      proliferation was restricted to one half of the blank. Irradiation of CDNBA
      solutions increased the toxicity, suggesting the formation of intermediate
      products with higher cytotoxicity effects.

PMID- 15180364
TI  - Fate of veterinary antibiotics in a macroporous tile drained clay soil.
AB  - The environment may be exposed to veterinary medicines administered to livestock
      through the application of organic fertilizers to land. For other groups of
      substances that are applied to agricultural land (e.g., pesticides), preferential
      flow in underdrained clay soils has been identified as an extremely important
      mechanism by which pollution of surface waters can occur. This study, therefore,
      was performed to investigate the fate of three antibiotics from the sulfonamide,
      tetracycline, and macrolide groups. Pig slurry was applied to a field in arable
      production in two consecutive years and the fate of the compounds was monitored
      in the soil and drainage water. Both sulfachloropyridazine and oxytetracycline
      were detected in soil at concentrations up to 365 and 1691 microg/kg,
      respectively. Subsequently, peak concentrations of the two substances in
      drainflow were 613.2 and 36.1 microg/L, although mass losses to the receiving
      water were less than 0.5%. In contrast, tylosin was not detected at all. These
      findings could be explained by the persistence and sorption characteristics of
      the antibiotics, while preferential flow via desiccation cracks and worm channels
      to the tile drains was found to be the most important route for translocation of
      the chemicals. Thus, when the soil was disced prior to slurry application, losses
      were reduced significantly. It is evident that processes governing pesticide fate
      also apply to veterinary antibiotics.

PMID- 15180365
TI  - Effect of sediment on the fate of metolachlor and atrazine in surface water.
AB  - In aquatic environments, pesticides can partition between the dissolved phase and
      particulate phase depending on the type of suspended sediment present and the
      physical and chemical properties of the pesticides and water. Particulate matter
      and sediment can alter the bioavailability of contaminants to organisms and
      therefore influence their toxicity and availability for microbial degradation.
      Experiments were conducted to determine the degradation of atrazine (6-chloro-N
      ethyl-N'-(1-methylethyl)-1,3,5-triazine-2.4-diamine) and metolachlor (2-chloro-N
      (2-ethyl-6-methylphenyl)-N-(methooxyprop-2-yl)acetamide) in surface water, and to
      evaluate the contribution of sediment to their dissipation. Sediment
      significantly reduced concentrations of atrazine and metolachlor in the surface
      water as a result of greater degradation, evident by increased quantities of
      degradates in the surface water, and the partitioning of the herbicide or
      herbicide degradates in the sediment. First-order 50% dissipation time (DT50)
      values for atrazine and metolachlor were 42 and 8 d in the surface water-sediment
      incubation systems, which were almost four times less than the DT50s calculated
      for the sediment-free systems. The results of this research illustrate the
      importance of sediment in the fate of pesticides in surface water. Greater
      comprehension of the role of sediment to sequester or influence degradation of
      agrichemicals in aquatic systems will provide a better understanding of the
      bioavailability and potential toxicity of these contaminants to aquatic
      organisms.

PMID- 15180366
TI  - Identification of in vitro estrogen and androgen receptor agonists in North Sea
      offshore produced water discharges.
AB  - The estrogen receptor (ER) agonist potency of offshore produced water discharges
      was examined via bioassay-directed chemical analysis. The in vitro estrogen
      receptor (ER) and androgen receptor (AR) agonist potency of five produced water
      samples collected from oil-production platforms in the British and Norwegian
      sectors of the North Sea was determined by using the yeast estrogen and androgen
      screens. Produced water samples were extracted in situ on the production
      platforms by using large-volume solid-phase extraction. All five extracts tested
      positive for the presence of ER agonists, whereas no AR agonist activity could be
      detected. By using the yeast estrogen screen assay in association with bioassay
      directed fractionation, attempts were made to identify the ER agonist compounds
      present in the produced water extracts. The fractionation procedure used cyano
      amino-bonded silica normal-phase high-performance liquid chromatography to
      isolate estrogenic compounds from produced water extract followed by full-scan
      gas chromatography-electron-impact mass spectrometry (GC-(EI)MS) to identify
      them. Isomeric mixtures of C1 to C5 and C9 alkylphenols contributed to the
      majority of the ER agonist potency measured in the samples.

PMID- 15180367
TI  - Distribution of atrazine into three chemical fractions: impact of sediment depth
      and organic carbon content.
AB  - The fate and transport of organic contaminants in aquatic sediments are impacted
      largely by microbial degradation and sorption to organic matter. Atrazine, a pre
      emergent herbicide, has the potential to contaminate groundwater because of its
      slight water solubility, long half-life, and sorption to organic matter.
      Mineralization and distribution of 14C-atrazine into three chemical fractions
      were monitored over time in surface and subsurface coastal aquatic sediments of
      different land use. Sediments were extracted with an organic solvent followed by
      an alkali hydrolysis, and 14C activity was measured in the aqueous, solvent, and
      basic fractions (representing nonsorbed compounds, loosely sorbed compounds, and
      humic or fulvic acid bound compounds, respectively). Limited mineralization of
      atrazine occurred (< 4%). The 14C activity in the aqueous and basic fractions
      increased over time, was greater in surface versus subsurface sediments, and was
      positively correlated with sediment organic carbon (SOC) content, indicating
      greater biological and chemical activity. Total 14C recovered ranged from 50 to
      90%, was less in surface versus subsurface sediments, and was not correlated with
      SOC after 80 d. These results suggest that in native aquatic surface sediments,
      atrazine sorption plays a major role, whereas in subsurface sediments atrazine
      may be available for degradation and transport to shallow groundwater.

PMID- 15180368
TI  - Assessment of mercury in waters, sediments, and biota of New Hampshire and
      Vermont Lakes, USA, sampled using a geographically randomized design.
AB  - We report on mercury (Hg) contamination in waters, sediments, and biota of
      Vermont and New Hampshire (USA) lakes measured during 1998-2000, using a
      geographically randomized design. Waters and sediments of 92 lakes were sampled
      for mercury, methylmercury, and ancillary parameters. Yellow perch (Perca
      flavescens) muscle tissues were analyzed for mercury on 47 of these lakes.
      Interannual variation in mercury was limited; only epilimnetic Hg was elevated by
      approximately 1.5 ng/L in 1998 over remaining years because of wet weather.
      Aqueous total and methylmercury concentrations were elevated in both dystrophic
      and eutrophic lakes over other types. Yellow perch tissue concentrations were
      elevated by 0.218 microg/g in dystrophic lakes over other types and were very low
      in eutrophic lakes. Fish tissue mercury concentrations showed no relationship to
      hypolimnetic or sediment mercury or methylmercury. A statistical model indicated
      that yellow perch tissues in 40.2 +/- 13% of lakes were likely to exceed the U.S.
      Environmental Protection Agency (U.S. EPA) methylmercury criterion of 0.3
      microg/g, and yellow perch from New Hampshire were twice as likely to exceed the
      criterion as those from Vermont. Results of this study provide a regional-scale
      baseline against which the success of future reductions in mercury emissions can
      be assessed.

PMID- 15180369
TI  - Estrogenicity in bile of juvenile rainbow trout as measure of exposure and
      potential effects of endocrine disruptors.
AB  - Estrogenicity in the bile of juvenile rainbow trout exposed to effluents from
      municipal sewage treatment plants and various industries was assayed by using a
      recombinant yeast strain containing the human estrogen receptor alpha gene.
      Estrogenicity in bile also was measured after deconjugation of steroids to
      provide an estimate of the exposure and as an endpoint for potential effects on
      the organism. In unexposed fish or fish exposed for three weeks at control
      localities, 0.5 to 9 ng of estradiol equivalents (EEq) were found per gram of
      bile (ng EEq/g bile). Fish exposed for three weeks in cages placed in the
      receiving waters near outlets of municipal effluent had an average activity of 26
      ng EEq/g bile. Fish exposed to undiluted sewage water in aquaria had a bile
      estrogenicity of 51 to 87,000 ng EEq/g bile. Unconjugated estrogens contributed
      only 8% or less to the estrogenicity in bile of fish exposed to municipal
      effluents. Municipal sewage effluents were more estrogenic than the industrial
      effluents that were investigated. Estrogenicity in bile was compared to that in
      extracts of wastewater by using the same receptor assay, and to vitellogenin
      induction in the plasma of the same fish. Bile estrogenicity proved to be a
      useful and sensitive (internal) measure of exposure and indicated its potential
      for the display of biological effects as a complement or replacement of more
      laborious assays.

PMID- 15180370
TI  - Application of toxicity identification evaluation procedures for characterizing
      produced water using the tropical mysid, Metamysidopsis insularis.
AB  - Toxicity identification evaluations (TIEs) were performed on seven produced water
      (PW) effluents from inland discharge facilities operated in Trinidad and Tobago,
      a Caribbean tropical country with one of the oldest commercial oil industries in
      the world. The research was performed to determine the presence and magnitude of
      toxicity and characterize which toxicants are responsible for observed effects.
      Marine effluent toxicity characterizations with Metamysidopsis insularis revealed
      high whole acute toxic-unit response for produced water ranged from 8.1 to > 17.0
      acute toxic-unit (initial toxicity test) and 5.7 to 1,111 acute toxic-unit
      (baseline toxicity test). Toxicity test results for all sites except one, which
      had the highest toxicity, are comparative with similar studies on produced water.
      The toxicological causality of this complex mixture differed for each PW with
      nonpolar organics being consistently toxic in all samples. Other potential
      toxicants contributing to overall toxicity to a much lesser extent were metals,
      ammonia, and volatile organic compounds. With the use of sodium thiosulfate and
      filtration manipulations for only PW6 sample, there was very slight reduction in
      toxicity; therefore, oxidants and filterable materials were not a great
      contributing factor. Whole effluent toxicity also can be attributed to ionic
      imbalance and the very stable oil-in-water emulsion that consists of fine oil
      droplets (less than 0.1-10 microm with an average diameter of 2.5 microm). This
      investigation is the first of its type in Trinidad and demonstrates clearly the
      applicability of this test method and local test species for evaluating complex
      effluents in tropical environments.

PMID- 15180371
TI  - Evaluation of the protective effects of reactive sulfide on the acute toxicity of
      silver to rainbow trout (Oncorhynchus mykiss).
AB  - Acute 96-h toxicity tests were performed with juvenile rainbow trout
      (Oncorhynchus mykiss) exposed to AgNO3 in either the absence or the presence of
      100 nM reactive sulfide to evaluate the protective effect of aqueous sulfides
      against ionic Ag toxicity. The sulfide was presented in the form of zinc sulfide
      (ZnS) clusters under oxic conditions. Silver was lost from the water column
      during the course of the experiment, so mean measured Ag concentrations were used
      to generate all median lethal concentration (LC50) data. The system was
      complicated in that Ag2S precipitated because of the need for large amounts of Ag
      to obtain lethal effects in the presence of ZnS. Some of the losses of Ag could
      be explained by complexation with ZnS and formation of solid Ag2S. Other losses
      were probably the result of partial adsorption to exposure-chamber walls or to
      complexation with ligands or functional groups within organic material produced
      by the fish. The LC50 (95% confidence interval) values generated using measured
      concentrations for total Ag were 139 (122-162) nM in the absence of sulfide and
      377 (340-455) nM in the presence of 100 nM sulfide. The LC50 values generated
      using measured concentrations from filtered (pore size, 0.45 microm) water
      samples were 122 (105-145) nM in the absence of sulfide and 225 (192-239) nM in
      the presence of 100 nM sulfide. These results suggest a stoichiometric protection
      of sulfides up to a 2:1 ratio of Ag:sulfide. Greater accumulation of Ag at the
      gills was measured in fish exposed to AgNO3 in the presence of sulfide.

PMID- 15180372
TI  - Comparison of two screening bioassays, based on the frog sciatic nerve and yeast
      cells, for the assessment of herbicide toxicity.
AB  - Two different test systems, one based on the isolated sciatic nerve of an
      amphibian and the other on a microbial eukaryote, were used for the assessment of
      herbicide toxicity. More specifically, we determined the deleterious effects of
      increasing concentrations of herbicides of different chemical classes
      (phenoxyacetic acids, triazines, and acetamides), and of 2,4-dichlorophenol (2,4
      DCP), a degradation product of the herbicide 2,4-dichlorophenoxyacetic acid (2,4
      D), on electrophysiological parameters and the vitality of the axons of the
      isolated sciatic nerve of the frog (Rana ridibunda) and on the growth curve of
      the yeast Saccharomyces cerevisiae based on microtiter plate susceptibility
      assays. The no-observed-effect-concentration (NOEC), defined as the maximum
      concentration of the tested compound that has no effect on these biological
      parameters, was estimated. In spite of the different methodological approaches
      and biological systems compared, the NOEC values were identical and correlated
      with the lipophilicity of the tested compounds. The relative toxicity established
      here, 2,4-DCP > alachlor, metolachlor >> metribuzin > 2,4-D, 2-methyl-4
      chlorophenoxyacetic acid (MCPA), correlates with the toxicity indexes reported in
      the literature for freshwater organisms. Based on these results, we suggest that
      the relatively simple, rapid, and low-cost test systems examined here may be of
      interest as alternative or complementary tests for toxicological assessment of
      herbicides.

PMID- 15180373
TI  - Mysid crustaceans as potential test organisms for the evaluation of environmental
      endocrine disruption: a review.
AB  - Anthropogenic chemicals that disrupt the hormonal systems (endocrine disruptors)
      of wildlife species recently have become a widely investigated and politically
      charged issue. Invertebrates account for roughly 95% of all animals, yet
      surprisingly little effort has been made to understand their value in signaling
      potential environmental endocrine disruption. This omission largely can be
      attributed to the high diversity of invertebrates and the shortage of fundamental
      knowledge of their endocrine systems. Insects and crustaceans are exceptions and,
      as such, appear to be excellent candidates for evaluating the environmental
      consequences of chemically induced endocrine disruption. Mysid shrimp (Crustacea:
      Mysidacea) may serve as a viable surrogate for many crustaceans and have been put
      forward as suitable test organisms for the evaluation of endocrine disruption by
      several researchers and regulatory bodies (e.g., the U.S. Environmental
      Protection Agency). Despite the long-standing use of mysids in toxicity testing,
      little information exists on their endocrinology, and few studies have focused on
      the potential of these animals for evaluating the effects of hormone-disrupting
      compounds. Therefore, the question remains as to whether the current standardized
      mysid endpoints can be used or adapted to detect endocrine disruption, or if new
      procedures must be developed, specifically directed at evaluating hormone
      regulated endpoints in these animals. This review summarizes the ecological
      importance of mysids in estuarine and marine ecosystems, their use in toxicity
      testing and environmental monitoring, and their endocrinology and important
      hormone-regulated processes to highlight their potential use in assessing
      environmental endocrine disruption.

PMID- 15180374
TI  - Assessing behavioral toxicity with Caenorhabditis elegans.
AB  - Behavior, even in simple metazoans, depends upon integrated processes at the
      subcellular, cellular, and organismal level, and thus is susceptible to
      disruption by a broad spectrum of chemicals. Locomotor behavior (movement) of the
      small free-living nematode Caenorhabditis elegans has proven to be useful in
      assessing toxicity. Recently reported observations suggest that behavioral change
      (reduced movement) occurs after 4 h of exposure to heavy metals, and that with
      abbreviated exposure, the concentration-response relationship for Pb (a known
      neurotoxic metal) differs from that for Cu. In this study, movement was evaluated
      after 4-h exposures for nine compounds from three chemical classes: organic
      pesticides, organic solvents, and heavy metals. Concentration-dependent reduction
      of movement was observed for all test compounds with the exception of
      mebendazole, for which test concentrations were limited by solubility. Within
      each chemical class, movement was more sensitive to the neurotoxic compounds than
      to substances not believed to be neurotoxic, as evidenced by behavioral effective
      concentration to reduce average worm movement to 50% of the control movement
      values (e.g., levamisole and chlorpyrifos < mebendazole, ethanol and acetone <
      dimethylsulfoxide, and Pb and Al < Cu). These observations are discussed as they
      relate to the use of acute behavioral tests in assessing general chemical
      toxicity, and the enhanced value of 4-h testing for the detection of neural
      toxicants.

PMID- 15180375
TI  - A comparative study on the relationship between acetylcholinesterase activity and
      acute toxicity in Daphnia magna exposed to anticholinesterase insecticides.
AB  - Acetylcholinesterase (AChE) activity was measured in Daphnia magna that had been
      exposed to four organophosphates (OPs; parathion, chlorpyrifos, malathion, and
      acephate) and one carbamate (propoxur) for 48 h. These results were related to
      acute toxicity (median effective concentration [EC50] for immobility). For the
      four OPs, the EC50s were 7.03 pM, 3.17 pM, 10.56 pM, and 309.82 microM,
      respectively. The EC50 for propoxur was 449.90 pM. Reduction in AChE activity was
      directly related to an increase in immobility in all chemicals tested. However,
      the ratio between the EC50 and the AChE median inhibiting concentration ranged
      from 0.31 to 0.90. A 50% reduction in AChE activity generally was associated with
      detrimental effects on mobility. However, for acephate, high levels of AChE
      inhibition (70%) were observed in very low concentrations and were not associated
      with immobility. In addition, increasing the concentration of acephate further
      had a slight negative effect on AChE activity but a strong detrimental effect on
      mobility. Binding sites other than AChE possibly are involved in acephate
      toxicity to D. magna. Our findings demonstrate different associations between
      AChE inhibition and toxicity when different chemicals are compared. Therefore,
      the value of using AChE activity as a biomarker in D. magna will be dependent on
      the chemical tested.

PMID- 15180376
TI  - Effect of dissolved organic matter source on acute copper toxicity to Daphnia
      magna.
AB  - The protective effect of dissolved organic matter (DOM) on metal toxicity to
      aquatic organisms has been reported by numerous authors. Bioavailability models
      such as the biotic ligand model (BLM) thus account for this factor to predict
      metal toxicity to aquatic organisms. Until now, however, few attempts have been
      made to assess the effect of the DOM source on metal speciation and toxicity and,
      accordingly, on BLM predictions. The aims of this study were to investigate to
      what extent DOMs differ in their ability to decrease acute copper toxicity to the
      cladoceran Daphnia magna and to evaluate if ultraviolet (UV) absorbance
      measurements may be a simple and effective method to incorporate DOM variability
      into the acute Cu-BLM for D. magna. Acute toxicity tests were carried out in
      artificial test water enriched with DOMs isolated from six locations in Europe
      and North America and in seven natural European surface waters. The acute Cu-BLM
      for D. magna was then used to estimate the copper complexing capacity of each DOM
      (expressed as % active fulvic acid, %AFA). A factor of 6 difference was observed
      between the lowest and the highest copper complexing capacity. A significant
      linear relationship was observed between the UV-absorbance coefficient at 350 nm
      (epsilon350) and the %AFA. Linking this relationship to the acute Cu-BLM resulted
      in a significant improvement of the predictive capacity of this BLM. Without
      accounting for this relationship, 90% of the predicted 48-h 50% effective
      concentrations (EC50) were within a factor of 2 of the observed EC50s; taking
      this relationship into account, 90% of the EC50s were predicted with an error of
      less than factor 1.3. The present study and other studies seem to indicate that
      UV absorbance may be a good measure of biologically and toxicologically relevant
      differences in copper binding behavior of DOM.

PMID- 15180377
TI  - Eiders (Somateria mollissima) obtain nodularin, a cyanobacterial hepatotoxin, in
      Baltic Sea food web.
AB  - Nodularin (NODLN) is a cyclic pentapeptide hepatotoxin produced by the
      cyanobacterium Nodularia spumigena, which occurs regularly in the Baltic Sea
      during the summer season. Nodularia blooms have caused several animal kills in
      the Baltic Sea area, and NODLN has been found in mussels and fish caught from the
      northern Baltic Sea in 1996 to 2002. We analyzed liver samples of common eider
      (Somateria mollissima) for NODLN by enzyme-linked immunosorbent assay (ELISA) and
      liquid chromatography/mass spectrometry (LC-MS). Eiders feed extensively on
      mussel and can be exposed to NODLN by contaminated mussels. Fifteen eiders were
      shot and collected from three different sites in the western Gulf of Finland
      (northern Baltic Sea) in August and September 2002. Analyses by ELISA and LC-MS
      showed that eider liver samples contained 3 to 180 microg NODLN/kg dry weight and
      0.1 to 5.8 microg NODLN/liver (dry wt). This is the first documentation of NODLN
      in seabirds and additional evidence for the transfer of NODLN in different parts
      of the Baltic Sea food web.

PMID- 15180378
TI  - A relationship between gill silver accumulation and acute silver toxicity in the
      freshwater rainbow trout: support for the acute silver biotic ligand model.
AB  - Rainbow trout were exposed to a range of silver concentrations (as AgNO3) in
      flowing synthetic soft water (0.05 mM Na+, 0.05 mM Cl-, 0.05 mM Ca2+, 0.02 mM
      Mg2+, 0.02 mM K+, pH 7.0, approximately 0.7 mg C/L dissolved organic carbon, 10
      mg CaCO3/L, 10 +/- 2 degrees C) to investigate a possible relationship between
      short-term gill silver accumulation (3 h or 24 h) and acute silver toxicity (96-h
      mortality). We also investigated potential relationships between gill silver
      accumulation and inhibition of Na+ uptake plus inhibition of gill Na+K(+)
      adenosine triphosphatase (ATPase) activity. The 96-h median lethal concentration
      (LC50) values were 13.3 microg total Ag L(-1) and 3.3 microg dissolved Ag L(-1).
      A relationship was demonstrated between 3-h and 24-h gill silver accumulation and
      96-h mortality. A relationship also was demonstrated between gill silver
      accumulation and inhibition of Na+ uptake at 24 h of exposure. No relationship
      between gill silver accumulation and inhibition of gill Na+K(+)-ATPase activity
      was found. The 96-h median lethal gill accumulation (LA50) values of 129 (at 3 h)
      and 191 ng g(-1) (at 24 h) and a conditional equilibrium binding constant of 8.0
      for Ag+ binding to the gills were calculated. These observations support use of
      the silver biotic ligand model (BLM) as a regulatory tool to predict acute silver
      toxicity.

PMID- 15180379
TI  - Influence of 4-nonylphenol on the structure of nematode communities in freshwater
      microcosms.
AB  - We investigated the effect of 4-nonylphenol (NP) on nematode communities in the
      sediment of freshwater microcosms. Seven treatments were dosed with various
      concentrations of NP over a period of six weeks by using a controlled-release
      method (NPI-NP7; maximum sediment concentrations: 0.29-3.37 mg/kg dry wt). Four
      microcosms were not exposed to NP and served as controls. Nematode communities
      were analyzed over a period of 15 weeks, including sampling dates before, within,
      and after the NP application. Communities were characterized in terms of total
      nematode abundance and species diversity (Shannon index and evenness), as well as
      composition of species, feeding types, and different life-history strategists
      (maturity index [MI]). Species composition was analyzed by using a multivariate
      method (principal response curves). Total nematode abundance and species
      diversity were not affected in any of the NP-treated microcosms. However, in the
      highest dosed treatment, NP-induced changes in the nematode communities occurred.
      Species and feeding types composition, as well as the MI, were affected in the
      postapplication period, with species composition being altered most clearly. In
      the highest dosed treatment, deposit-feeding species, classified as colonizers
      (Eumonhystera), increased in dominance, whereas epistrate feeders and chewers
      (Prodesmodora and Tobrilus) decreased in relative abundance compared to the
      control.

PMID- 15180380
TI  - Effect of maternal exposure to tributyltin on reproduction of the pearl oyster
      (Pinctada fucata martensii).
AB  - We examined the effect of tributyltin (TBT) on reproduction of the pearl oyster
      (Pinctada fucata martensii). In a maternal exposure test, five female pearl
      oysters were exposed to TBT at measured concentrations of 0 (control), 0.092, or
      0.191 microg/L at 25 degreesC for one week, and the embryo developmental success
      (the ratio of normal D-larvae to all larvae) was measured. The embryo
      developmental success was significantly decreased in the 0.191-microg/L treatment
      group (65.5%) compared to that in the control group (82.5%; p = 0.031).
      Concentrations of TBT in the ovary reached 0.088 microg/g in the 0.191-microg/L
      treatment group. In a waterborne exposure test, inseminated eggs were exposed to
      TBT at measured concentrations of 0 (control), 0.020, 0.045, 0.091, 0.192, or
      0.374 microg/L for 24 h. The embryo developmental success also was significantly
      decreased in the 0.192-microg/L treatment group (78.3%; p = 0.020) and no
      development at all was observed in the 0.374-microg/L treatment group compared
      with that in the control group (95.4%). These results clearly demonstrate that
      TBT accumulating in the bodies of bivalves has the potential to inhibit
      reproduction.

PMID- 15180381
TI  - Effects of vertebrate hormones on development and sex determination in Daphnia
      magna.
AB  - Daphnia (Crustacea) are extensively used as model organisms in ecotoxicology;
      however, little is known regarding their endocrine system. This study examines
      Daphnia vulnerability to vertebrate hormones. Twelve natural or synthetic
      vertebrate hormones were screened for activity on developmental and reproductive
      processes in Daphnia magna. Natural hormones tested included: beta-estradiol,
      gonadotropin, hydrocortisone, insulin, melatonin, progesterone, somatostatin,
      testosterone, and thyroxine at concentrations ranging from 1 to 100 microg/L.
      Synthetic hormones tested included diethylstilbestrol (estrogenic), R-1881
      (androgen), and ICI-182,780 (antiestrogen); all hormones were screened with a 6-d
      assay. Additionally, progesterone, insulin, testosterone, and thyroxine were
      screened for 25 d. Diethylstilbestrol decreased D. magna growth rate while
      thyroxine increased it. Short-term testosterone exposure reduced D. magna
      fecundity; however, long-term exposure did not, potentially indicating
      testosterone hydroxylation with long-term exposure. Hormones commonly considered
      sex-hormones (estrogens and androgens) in vertebrates do not appear to control
      sexual differentiation in D. magna; however, several vertebrate hormones do
      affect reproduction and development in D. magna making D. magna a potentially
      useful tool in monitoring for the presence of these hormones or compounds that
      mimic them.

PMID- 15180383
TI  - Responses of nontarget Lepidoptera to Foray 48B Bacillus thuringiensis var.
      kurstaki on Vancouver Island, British Columbia, Canada.
AB  - Impacts of a gypsy moth (Lymantria dispar) eradication program on native,
      nontarget Lepidoptera were assessed in 1999, on southeastern Vancouver Island
      (BC, Canada). The microbial insecticide Bacillus thuringiensis var. kurstaki
      (Btk) was applied aerially over two areas totalling 12,805 ha on May 8, May 19,
      and June 8, 1999, at a dosage of 50 billion international units in 4.0 L/ha.
      Lepidoptera were collected from two host plant species: Garry oak (Quercus
      garryana) and common snowberry (Symphoricarpos albus). Lepidopteran larvae were
      collected from common snowberry foliage at 24 urban parks and from Garry oak
      foliage at 28 oak-dominated habitats, representing 12 and 14 replicates,
      respectively, of two treatments: unsprayed (reference) and sprayed (treatment).
      Prespray data were collected from March 25 to May 6 for S. albus, and from April
      26 to May 6 for Q. garryana. Postspray data were collected from May 10 through
      June 15 for S. albus and from May 10 to July 6 for Q. garryana. The 15 most
      abundant lepidopteran species were analyzed statistically. However, the majority
      of species were collected infrequently, and, therefore were pooled for
      statistical analysis. After the Btk spray applications, 11 of the individual
      species and groups of uncommon species were found to be significantly less
      abundant in the treatment sites than in the reference sites. The effects of
      sample date were statistically significant on almost all groups of Lepidoptera
      analyzed, both before and after Btk spray applications, indicating temporal
      variation in lepidopteran abundance. Significant variation in diversity of
      members of the Lepidoptera, as a result of Btk spray application, was not
      detected on S. albus or Q. garryana. However, results showed significant
      variation in lepidoptera richness and abundance on both host plant species.

PMID- 15180382
TI  - Testosterone and energy metabolism in the estuarine mysid Neomysis integer
      (Crustacea: Mysidacea) following exposure to endocrine disruptors.
AB  - A diverse set of reference compounds suspected of having an endocrine-disrupting
      mode of action (i.e., testosterone, flutamide, ethinylestradiol, precocene,
      nonylphenol, fenoxycarb, and methoprene) were tested for acute toxicity to the
      estuarine mysid Neomysis integer (Crustacea: Mysidacea). Neomysis integer was
      very sensitive to all tested compounds, with 96-h median lethal concentrations in
      a narrow range between 0.32 and 1.95 mg/L. The pesticides methoprene and
      fenoxycarb, both synthetic insect juvenile hormone analogs, were most toxic to N.
      integer. In addition, the short-term sublethal effects of methoprene and
      nonylphenol (an estrogen agonist) on the energy and steroid metabolism of N.
      integer were evaluated. Both compounds significantly affected energy and
      testosterone metabolism of N. integer at concentrations below acute toxicity
      levels. Energy consumption in methoprene- and nonylphenol-exposed mysids was
      significantly induced at 100 microg/L, resulting in a lower cellular energy
      allocation in these animals. Testosterone phase I metabolism was affected at 10
      microg/L, whereas glycosylation was the most important phase II pathway affected
      in mysids exposed to 100 microg/L of both compounds. Methoprene exposure resulted
      in a concentration-dependent increase in the metabolic androgenization ratio.
      Mysids exposed to nonylphenol at 10 microg/L had a significantly higher metabolic
      androgenization ratio. The present study indicates that energy and testosterone
      metabolism of mysids, as endpoints, are able to detect endocrine-disruptive
      activity of chemicals after short-term exposure to environmentally realistic
      levels of endocrine disruptors.

PMID- 15180384
TI  - Effects of methoprene, its metabolites, and breakdown products on retinoid
      activated pathways in transfected cell lines.
AB  - Methoprene (isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate) is
      an insect juvenile hormone agonist that blocks metamorphosis in some insects.
      Recent evidence suggests that a metabolite, methoprene acid, activates vertebrate
      retinoid X receptors (RXRs), and may interfere with retinoic acid-regulated
      developmental processes. Methoprene, methoxy-methoprene acid, and two major
      breakdown products were tested for their ability to interfere with retinoid
      regulated pathways when using transfected cells. The CV-1 cells were transiently
      transfected with genes encoding RXRs and response elements attached to luciferase
      reporters, and retinoic acid-sensitive F9 cells were stably transfected with
      retinoic acid receptor (RAR)/RXR response elements attached a lacZ reporter (Sil
      REM/beta-gal-NEO). Experiments confirmed that methoxy-methoprene acid acted as a
      ligand for RXRs and was capable of activating transcription through RAR/RXR
      response elements. However, neither methoprene nor the breakdown products, 7
      methoxycitronellal and 7-methoxycitronellic acid, activated transcription in
      transfected CV-1 or F9 cells. Methoprene and methoxy-methoprene acid may
      interfere with the conversion of all-trans-retinol and all-trans-retinaldehyde to
      all-trans-retinoic acid in the F9-derived cell line. Methoprene was as effective
      as the retinol dehydrogenase inhibitor citral in blocking the retinol-induced
      transcription of RAR/RXR-regulated reporter genes, whereas methoxy-methoprene
      acid blocked transcription stimulated by retinaldehyde.

PMID- 15180385
TI  - Morphological responses of Daphnia pulex to Chaoborus americanus kairomone in the
      presence and absence of metals.
AB  - Daphnia pulex neonates develop neck teeth in the presence of predatory kairomone
      from Chaoborus americanus that are fed D. pulex. These neck teeth reduce the
      susceptibility of the neonates to predation. Evidence suggests that aqueous
      metals interfere with chemical communication in fish. The objective of our study
      was to determine if Cu or Ni at environmentally relevant concentrations affects
      predatory kairomone response in D. pulex. To test this possibility, D. pulex were
      placed in increasing waterborne concentrations of Cu or Ni in the presence or
      absence of predatory kairomone. Both Cu and Ni reduced neck tooth induction in D.
      pulex neonates in the presence of predatory kairomone. Copper had a significant
      nonlinear effect on neck tooth length consistent with a hormetic response, where
      neck tooth length was highest at 5 microg/L Cu, but not significantly different
      than 0 microg/L Cu at higher Cu concentrations. A Ni concentration of 200
      microg/L caused D. pulex to become hypersensitive to Chaoborus regardless of
      Chaoborus' diet, leading to increased neck tooth number but decreased neck tooth
      length. Neither Ni nor Cu produced any significant effects on body length or
      brood size. These results suggest that metal inhibition of neck tooth induction
      probably occurs along the signal transduction pathway. Impairment of chemosensory
      response to predatory chemical cues may have widespread ecological consequences
      in aquatic systems contaminated by metals.

PMID- 15180386
TI  - Micronucleus induction in gill cells of green-lipped mussels (Perna viridis)
      exposed to mixtures of polycyclic aromatic hydrocarbons and chlorinated
      pesticides.
AB  - Different groups of green-lipped mussels (Perna viridis) were exposed to the same
      net amount of a genotoxicant mixture of four polycyclic aromatic hydrocarbons
      ([PAHs]; anthracene, fluoranthene, pyrene, and benzo[a]pyrene) and four
      organochlorine pesticides ([OCs]; alpha-hexachlorocyclohexane (HCH), aldrin,
      dieldrin, and p,p'-DDT) for four weeks under different regimes that simulated
      various scenarios of fluctuating toxicant levels in the marine environment.
      Micronucleus (MN) formation in gill cells was studied at the end of each week.
      Micronucleus frequencies increased with continual addition of genotoxicants, and
      did not diminish significantly under conditions of either gradually decreasing
      concentrations or cessation of exposure for one to two weeks, suggesting that the
      MN response may persist over relatively long exposure periods. An almost two-fold
      higher mean MN frequency was recorded in a chronic exposure group than in an
      acute group that had received the same net nominal dose of genotoxicants,
      indicating that chronic exposure may lead to a greater genotoxic impact than
      acute exposure. The results suggested that in field studies, MN response should
      be monitored at multiple time points in order to elucidate the effects of
      potentially fluctuating toxicant levels. Finally, MN formation was positively
      correlated with both nominal contaminant levels and tissue levels of the
      genotoxicants. These findings suggest that MN responses can be a sensitive
      indicator of exposure to relatively low levels of genotoxicants and that MN
      response in mussel gill cells can be a stable biomarker of genotoxicity.

PMID- 15180388
TI  - Time-dependent lethal body residues for the toxicity of pentachlorobenzene to
      Hyalella azteca.
AB  - The study examined the temporal response of Hyalella azteca to pentachlorobenzene
      (PCBZ) in water-only exposures. Toxicity was evaluated by calculating the body
      residue of PCBZ associated with survival. The concentration of PCBZ in the
      tissues of H. azteca associated with 50% mortality decreased from 3 to 0.5
      micromol/g over the temporal range of 1 to 28 d, respectively. No significant
      difference was observed in the body residue calculated for 50% mortality when the
      value was determined using live or dead organisms. Metabolism of PCBZ was not
      responsible for the temporal response because no detectable PCBZ
      biotransformation occurred over an exposure period of 10 d. A damage assessment
      model was used to evaluate the impact and repair of damage by PCBZ on H. azteca.
      The toxicokinetics were determined so that the temporal toxicity data could be
      fit to a damage assessment model. The half-life calculated for the elimination of
      PCBZ averaged approximately 49 h, while the value determined for the half-life of
      damage repair from the damage assessment model was 33 h.

PMID- 15180387
TI  - Effects of the antifungal imidazole ketoconazole on CYP1A and CYP3A in rainbow
      trout and killifish.
AB  - The use of N-substituted imidazoles is widespread, and imidazole and triazole
      fungicides have been detected in the aquatic environment and shown to
      bioaccumulate in fish. We have investigated effects of the model imidazole,
      ketoconazole, on drug-metabolizing cytochrome P450 (CYP) forms. We focused on
      cytochrome P4501A (CYP1A) and cytochrome P4503A (CYP3A) expression and activities
      in juvenile rainbow trout and in adult killifish. The CYP1A expression (mRNA,
      protein) and activity was induced in rainbow trout, whereas in killifish no
      effect of ketoconazole on CYP1A protein expression was observed. A biphasic dose
      response relationship was observed between ketoconazole exposure and hepatic
      CYP1A-mediated ethoxyresorufin O-deethylase (EROD) activity in rainbow trout in
      vitro and in vivo, implying that higher doses of ketoconazole inhibit CYP1A
      activities. Slight induction of CYP3A protein levels was observed in rainbow
      trout exposed in vivo to ketoconazole. However, the CYP3A-mediated benzyloxy-4
      [trifluoromethyl]-coumarin (BFC) O-debenzyloxylase activity was reduced in
      rainbow trout and killifish treated with ketoconazole. In vitro inhibition
      studies confirmed that ketoconazole was a potent inhibitor of both CYP3A and
      CYP1A enzyme activities in these species. This study showed that ketoconazole
      induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced
      effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in
      rainbow trout and in killifish.

PMID- 15180389
TI  - Environmental risk assessment of six human pharmaceuticals: are the current
      environmental risk assessment procedures sufficient for the protection of the
      aquatic environment?
AB  - In this study, exposure and ecotoxicity data of six human pharmaceuticals
      (carbamazepine, clofibric acid, diclofenac, ofloxacin, propranolol, and
      sulfamethoxazole) were collected, including our own experimental data and
      literature data. From this data collection, the two-tiered European draft
      guideline on the environmental risk assessment of human pharmaceuticals was
      tested. Measured environmental concentrations in effluents from France and in
      effluents and surface waters from Germany were compared to the predicted
      environmental concentrations (PECs) in both countries. In a similar manner,
      predicted no-effect concentrations (PNECs) derived from acute data and PNECs
      derived from chronic data were estimated for each pharmaceutical and
      corresponding PEC/PNEC ratios then were compared in both countries. Globally,
      results demonstrated that all environmental concentrations (predicted or
      measured) for each considered pharmaceutical exceeded the 10-ng/L cutoff value,
      which requires the implementation of the second-tier assessment based on
      ecotoxicity data. Moreover, the six pharmaceuticals showed a relatively limited
      acute toxicity, and carbamazepine and propranolol were inaccurately identified as
      having negligible risks under the current European draft procedure. Such results
      lead to discussion of the actual procedure on pharmaceuticals, especially on the
      need of appropriate ecotoxicity tests.

PMID- 15180390
TI  - Visual encoding mechanisms and their relationship to text presentation
      preference.
AB  - This study was designed to investigate the importance of spatial encoding in
      reading, with particular emphasis on visuo-spatial encoding mechanisms. Thirty
      one school children participated in the first study in which they were measured
      on their ability to solve a centrally presented spatial encoding task, as well as
      their sensitivity to the frequency doubling illusion across the retina. We found
      that both spatial frequency doubling sensitivity and performance in the spatial
      encoding task were correlated with reading, however these tasks were unrelated to
      each other. Furthermore, frequency doubling sensitivity was correlated with
      contextual reading, but not single-word reading, while the central spatial
      encoding task was correlated with both reading tasks. These findings may have
      functional implications for text presentation preference. Accordingly, in
      Experiment 2 we demonstrated that children with poor FDT sensitivity read more
      accurately when words were presented singularly rather than in a whole-text
      format. In conclusion, we suggest that contextual reading may depend upon two
      separate and functionally distinct visual encoding mechanisms--one central,
      important for the spatial discrimination of letters within words, and the other,
      a spotlighting mechanism important for spatial localization within a body of
      text. While both mechanisms may constrain reading efficiency, neither mechanism
      enforces an absolute limit on reading ability.

PMID- 15180391
TI  - Implications of articulatory awareness in learning literacy in English as a
      second language.
AB  - The articulatory awareness task, which was found by Griffiths and Frith (2002) to
      discriminate ex-dyslexic from non-dyslexic adults, was given to three groups of
      Japanese college students with different English reading abilities. Two
      unexpected results emerged: (1) Articulatory awareness performance was generally
      poor across the groups, thereby suggesting that poor articulatory awareness is
      not unique to dyslexia but rather to reading difficulty in general, and (2) There
      was a weak but significant positive correlation between articulatory awareness
      and English reading ability. Implications are that while articulatory awareness
      may not function only in dyslexia, it is embedded in a complex information
      processing network involving reading acquisition. Specifically, a revised
      Articulatory Awareness Deficit Hypothesis is formulated, which states that poor
      articulatory awareness is part of articulation difficulty associated with poor
      phonological awareness that in turn tends to underlie dyslexia and reading
      difficulty.

PMID- 15180392
TI  - On the development of low-level auditory discrimination and deficits in dyslexia.
AB  - Absolute auditory thresholds, frequency resolution and temporal resolution
      develop with age. It is still discussed whether low-level auditory performance is
      of clinical significance--specifically, for delayed maturation of central
      auditory processing. Recently, five new auditory tasks were used to study the
      development of low-level auditory discrimination. It was found that the
      development lasts up to the age of 16-18 years (on an average). Very similar
      tasks were now used with 432 controls and 250 dyslexic subjects in the age range
      of 7-22 years. For both groups the performance in one of the tasks was not
      related to the performance in another task indicating that the five tasks
      challenge independent subfunctions of auditory processing. Surprisingly high
      numbers of subjects were classified as low performers (LP), because they could
      not perform one or the other task at its easiest level and no threshold value
      could be assigned. For the dyslexics the incidence of LP was considerably
      increased in all tasks and age groups as compared with the age matched controls.
      The development of dynamic visual and optomotor functions and the corresponding
      deficits in dyslexia are discussed in relation to the auditory data presented
      here.

PMID- 15180393
TI  - The effect of practice on low-level auditory discrimination, phonological skills,
      and spelling in dyslexia.
AB  - Phonological awareness is believed to play a major role in the auditory
      contribution to spelling skills. The previous paper reports low-level auditory
      deficits in five different subdomains in 33-70% of the dyslexics. The first study
      of this paper reports the results of an attempt to improve low-level auditory
      skills by systematic daily practice of those tasks that had not been passed in
      previous diagnostic sessions. The data of 140 dyslexics indicate that the average
      number of unsolved tasks can be reduced from 3 of 5 to 1 of 5. The success rates
      have values of 70-80% for intensity and frequency discrimination and for gap
      detection, but reach only 36% for time-order judgement and 6% for side-order
      judgement. The second study reports that successful low-level auditory training
      transfers completely to language-related phonological skills and also to spelling
      with the largest profit in spelling errors due to poor auditory analysis. Control
      groups (waiting and placebo) did not exhibit significant improvements. It is
      concluded that low-level auditory deficits should be considered and improved by
      practice in order to give the dyslexics more phonological help when trying to
      transfer what they hear to spelling.

PMID- 15180394
TI  - The effects of an audio-visual training program in dyslexic children.
AB  - A research project was conducted in order to investigate the usefulness of
      intensive audio-visual training administered to children with dyslexia involving
      daily voicing exercises. In this study, the children received such voicing
      training (experimental group) for 30 min a day, 4 days a week, over 5 weeks. They
      were assessed on a reading task before and after the training. A significant
      benefit to the experimental group was found after training. These preliminary
      results underline the role of the phonological components of dyslexia.

PMID- 15180395
TI  - International disease monitoring, January to March 2004.

PMID- 15180396
TI  - Risk of foot-and-mouth disease associated with proximity in space and time to
      infected premises and the implications for control policy during the 2001
      epidemic in Cumbria.
AB  - An analysis was made that calculated the risk of disease for premises in the most
      heavily affected parts of the county of Cumbria during the foot-and-mouth disease
      epidemic in the UK in 2001. In over half the cases the occurrence of the disease
      was not directly attributable to a recently infected premises being located
      within 1.5 km. Premises more than 1.5 km from recently infected premises faced
      sufficiently high infection risks that culling within a 1.5 km radius of the
      infected premises alone could not have prevented the progress of the epidemic. A
      comparison of the final outcome in two areas of the county, south Penrith and
      north Cumbria, indicated that focusing on controlling the potential spread of the
      disease over short distances by culling premises contiguous to infected premises,
      while the disease continued to spread over longer distances, may have resulted in
      excessive numbers of premises being culled. Even though the contiguous cull in
      south Penrith appeared to have resulted in a smaller proportion of premises
      becoming infected, the overall proportion of premises culled was considerably
      greater than in north Cumbria, where, because of staff and resource limitations,
      a smaller proportion of premises contiguous to infected premises was culled.

PMID- 15180397
TI  - Pharmacokinetics of amoxycillin and the rate of depletion of its residues in
      pigs.
AB  - Six pigs were used in a two-period crossover study to investigate the
      pharmacokinetics of amoxycillin after single intravenous and oral doses of 20
      mg/kg bodyweight. Twelve pigs were used to study the residues of the drug in
      muscle, kidney, liver and fat after they had received daily oral doses of 20
      mg/kg amoxycillin for five days. The mean (sd) elimination half life (t1/2beta)
      and mean residence time of amoxycillin in plasma were 3.38 (0.30) and 3.54 (0.43)
      hours, respectively, after intravenous administration and 4.13 (0.50) and 4.47
      (0.30) hours, respectively, after oral administration. After oral administration,
      the maximum plasma concentration (Cmax) was 7.37 (0.42) microg/ml and it was
      reached after 0.97 (0.29) hours. Six days after the last oral dose, the mean
      concentration of amoxycillin in the pigs' kidneys was 21.38 ng/g and in the liver
      it was 12.32 ng/g, but no amoxycillin could be detected in fat or muscle; the
      concentrations of amoxycillin in edible tissues were less than the European Union
      maximal residue limit of 50 microg/kg.

PMID- 15180398
TI  - Detection of toxoplasmosis in experimentally infected goats by PCR.
AB  - PCR was used to diagnose toxoplasmosis in two pairs of Barbari goats infected by
      oral administration of doses of either 10(4) or 10(5) oocysts of Toxoplasma
      gondii. Blood and lymph node aspirates were collected from the infected goats and
      control goat at intervals, and tissues were also collected from a fetus that was
      aborted and a doe that died during the trial. Both processed and unprocessed
      samples were used for the PCR, using primers directed to the multicopy B1 gene.
      None of the blood samples was positive, but a specific signal was obtained from
      the lymph node aspirates after partial DNA extraction. Direct PCR of the lung,
      muscle and mesenteric lymph node of the doe and lung tissue of the aborted fetus
      yielded the target fragment. The simplified PCR protocols, including partial DNA
      extraction and direct assay of lung tissue, were effective for the diagnosis of
      toxoplasmosis.

PMID- 15180399
TI  - Identification and treatment of dermatophilosis in a Cumbrian cattle herd.

PMID- 15180400
TI  - XX/XY chromosome chimaerism in a Border terrier.

PMID- 15180401
TI  - DACTARI: results from the first year.

PMID- 15180402
TI  - Angiostrongylus infection in a dog in north-west England.

PMID- 15180403
TI  - Eradication of low pathogenicity avian influenza of the H7N3 subtype from Italy.

PMID- 15180404
TI  - Cryptosporidium oocysts in white-cheeked bulbuls.

PMID- 15180405
TI  - Molecular wheel B8(2-) as a new inorganic ligand. photoelectron spectroscopy and
      ab initio characterization of LiB8(-).
AB  - The bare B(8) cluster was previously reported to be a D(7h) molecular wheel with
      a triplet group state. The B(8)(2-) dianion was predicted to be a closed-shell
      singlet and double aromatic D(7h) molecular wheel. Here we report the
      experimental observation of B(8)(2-) stabilized by a Li(+) cation in LiB(8)(-)
      and its experimental characterization using photoelectron spectroscopy.
      Theoretical searches lead to a C(7v) LiB(8)(-) global minimum structure, and its
      calculated photodetachment transitions are in good agreement with the
      experimental values. Except for a small out-of-plane distortion due to the
      asymmetric Li(+) capping, the B(8)(2-) unit in LiB(8)(-) is nearly identical to
      the bare B(8)(2-), suggesting it is a robust and stable structural unit and may
      be used as a new ligand and building block in chemistry.

PMID- 15180406
TI  - Microwave assisted stereoselective synthesis of cis-substituted TinIV
      phthalocyanine dicarboxylates. application as corrosion inhibitors.
AB  - Two PcSn(IV) dicarboxylate molecules were obtained through efficient microwave
      methodology with the aim to test them as corrosion inhibitors in the oil
      industry. The compounds were characterized by elemental analysis, IR, UV-vis,
      (1)H, (13)C NMR, and X-ray diffraction. The relative configuration of the two
      carboxylates is cis, placing the fatty acid moieties on the same face of the
      phthalocyanine macrocycle. In the solid-state the tin atoms possess square
      antiprismatic octacoordinated geometries. Both tin phthalocyanines were tested as
      corrosion inhibitors for hydrogen sulfide corrosive media showing a chemisorption
      process of the nanocap motifs on the metallic surface. Apparently, the length of
      the hydrophobic chain contributes significantly to the inhibition efficiency, in
      the sense that shorter chains increase the efficiency.

PMID- 15180407
TI  - Low temperature induced synthesis of TiN nanocrystals.
AB  - TiN nanocrystals were successfully prepared through the direct reaction between
      TiCl(4) and NaNH(2) induced at 300 degrees C. The yield based on Ti is
      approximately 80%. X-ray powder diffraction indicated that the product was cubic
      TiN with a lattice constant of a = 4.243 A. Transmission electron microscopy
      revealed that nanocrystalline TiN with a diameter of 10 nm or so and extremely
      long straight rods were synthesized. The possible formation mechanism was also
      proposed.

PMID- 15180408
TI  - Structure and dynamics of dinuclear zirconium(IV) complexes.
AB  - We have determined by X-ray crystallography the structures of three dinuclear
      zirconium(IV) complexes containing the heptadentate ligand dhpta (where H(5)dhpta
      = 1,3-diamino-2-propanol-N,N,N',N'-tetraacetic acid, 1) and different
      countercations: K(2)[Zr(2)(dhpta)(2)].5H(2)O (2.5H(2)O),
      Na(2)[Zr(2)(dhpta)(2)].7H(2)O.C(2)H(5)OH (3.7H(2)O.C(2)H(5)OH), and
      Cs(2)[Zr(2)(dhpta)(2)].H(5)O(2).Cl.4H(2)O (4.H(5)O(2).Cl.4H(2)O). In the K(I)
      complex 2, crystallized from water, the two Zr(IV) ions are 3.5973(4) A apart and
      bridged via two alkoxo groups (average Zr-O 2.165 A). Each Zr(IV) is eight
      coordinate and also bound to two N atoms (average Zr-N 2.448 A), and four
      carboxylate O atoms (average Zr-O 2.148 A). The two dhpta ligands in the
      dinuclear unit have different conformations. One face of the complex contains an
      array of 14 oxygen atoms and interacts strongly with the two K(I) ions, one of
      which is 6-coordinate, the other 8-coordinate, which are 3.922(4) A apart and
      bridged by a carboxylate O and by two water molecules. The structures of the
      dinuclear anion [Zr(2)(dhpta)(2)](2-) in the Na(I) complex 3 and in the Cs(I)
      complex 4 are essentially identical to that found in complex 2, although the
      alkali metal ions coordinate differently to the oxygen-rich face. All Zr(IV) ions
      have a distorted triangulated dodecahedral geometry. Although the crystal
      structure of complex 2 does not indicate the presence of acidic protons, in 4 an
      [H(5)O(2)](+) unit is strongly H-bonded to an oxygen atom of a coordinated
      carboxylate group. 1D and 2D (1)H and (13)C NMR spectroscopic and potentiometric
      studies reveal two deprotonations with pK(a) values of 9.0 and 10.0. At low pH,
      two carboxylate groups appear to undergo protonation accompanied by chelate ring
      opening, and the complex exhibits dynamic fluxional behavior in which the two
      magnetically nonequivalent dhpta ligands exchange at a rate of 11 s(-1) at pH
      3.30, 298 K, as determined from 2D EXSY NMR studies. Ligand interchange is not
      observed at high pH (>11). The same crystals of complex 2 were obtained from
      solutions at pH 3 or 12. The dynamic configurational change is therefore mediated
      by the aqueous solvent.

PMID- 15180409
TI  - A detailed study of the vapochromic Behavior of [Tl[Au(C6Cl5)2]]n.
AB  - The linear-chain polymer [Tl[Au(C(6)Cl(5))(2)]](n), 1, reacts in the solid state
      and in solution with different volatile organic compounds such as
      tetrahydrofuran, acetone, tetrahydrothiophene, 2-fluoropyridine, acetonitrile,
      acetylacetone, and pyridine. Solid-state exposure of 1 to vapors of the above
      VOCs produces a selective and reversible change in its color that is perceptible
      to the human eye and even deeper under UV irradiation, allowing 1 to function as
      a sensor for these VOCs. Heating the samples exposed to the VOCs for a few
      minutes at 100 degrees C regenerates the original material without degradation,
      even after several exposure/heating cycles. The reversibility is further
      confirmed by X-ray powder diffraction measurements of complex 1 before and after
      exposure to vapors and again after heating the samples. The products obtained by
      reactions of complex 1 with the above VOCs as ligands in solution contain
      extended linear chains of alternating gold and thallium centers with two
      molecules of the organic ligands attached to each thallium atom. The
      stoichiometry of these materials has been confirmed by single-crystal X-ray
      diffraction as [Tl(THF)(2)[Au(C(6)Cl(5))(2)]](n), 3, and
      [Tl(acacH)(2)[Au(C(6)Cl(5))(2)]](n), 5. Comparison of FT-IR, UV-vis, and
      luminescence spectra at room temperature and at 77 K of the solid samples of
      complexes 2-9 with the spectra of complex 1 after its exposure to VOCs suggests
      interaction occurs between the organic VOCs and thallium in each case.
      Thermogravimetric analyses data indicate that all the thallium centers in these
      derivatives of complex 1 are neither fully nor equally coordinatively saturated.
      The materials formed appear to be intermediates between complex 1 with no VOCs
      attached and complexes 3-9 which contain two organic ligands coordinated to each
      thallium. A crystal structure analyses of one of these intermediates,
      [Tl(THF)(0.5)[Au(C(6)Cl(5))(2)]](n), 1.0.5THF, confirms this. Density functional
      calculations are in accord with the observed experimental results. Analysis
      reveals a substantial participation of the metal atoms in transitions that give
      rise to the observed emissions. Crystallographic data are as follows. For
      1.0.5THF: triclinic, P1, a = 8.9296(1) A, b = 11.2457(1) A, c = 21.2465(3) A,
      alpha = 96.7187(7) degrees, beta = 92.5886(6) degrees, gamma = 98.5911(8)
      degrees, V = 2090.87(4) A(3), and Z = 2. For 3: monoclinic, P2(1)/c, a =
      26.4163(6) A, b = 12.1619(2) A, c = 28.0813(6) A, alpha = 90 degrees, beta =
      161.9823(6) degrees, gamma = 90 degrees, V = 2790.51(10) A(3), and Z = 4. For 5:
      monoclinic, P2(1)/c, a = 9.8654(2) A, b = 29.8570(5) A, c = 11.6067(2) A, alpha =
      90 degrees, beta = 114.5931(6) degrees, gamma = 90 degrees, V = 3108.64(10) A(3),
      and Z = 4.

PMID- 15180410
TI  - Synthesis, structure, and characterization of a cubic thallium cluster phase of
      the Bergman type, Na13(Cd-0.70Tl-0.30)27.
AB  - Samples of Na(13)(Cd(1-x)Tl(x))(27) crystallize with a cubic Bergman-type Im3
      structure (formerly called the R-phase) (Z = 4, a approximately 15.92 A) and
      exhibit a small phase width, 0.24 < x < 0.33. The crystal structure exhibits a
      Cd/Tl (=M) network of concentric empty M(12) and Cd(12) icosahedra and M(60)
      buckyball clusters, with the sodium cations in the annuli between clusters. The
      compound is unusually electron deficient with respect to electron counting rules
      applied to most Bergman phases with less electropositive cations, and because of
      the sodium component it is probably better described as an electron-poor Zintl
      phase. The new compound is metallic according to both EHTB band calculations for
      the anion and the measured resistivities and magnetic susceptibilities. Site
      preferences observed for Na, Cd, and Tl among the seven crystallographic sites
      are consistent with their relative Mulliken electron populations.

PMID- 15180411
TI  - Arachno, nido, and closo aromatic isomers of the Li6B6H6 molecule.
AB  - We analyzed chemical bonding in low-lying isomers of the recently computationally
      predicted B(6)H(6)Li(6) molecule. According to our calculations the benzene-like
      B(6)H(6)Li(6) (D(2h), (1)A(1g)) arachno structure with the planar aromatic
      B(6)H(6)(6-) anion is the most stable one. A nido isomer with two aromatic
      B(6)H(6)(4-) (pentagonal pyramid) and Li(3)(+) (triangular) moieties, which can
      be considered as derived from the global minimum structure through a two-electron
      intramolecular transfer from B(6)H(6)(6-) to three Li(+) cations, was found to be
      10.7 kcal/mol higher in energy. A closo isomer with three aromatic moieties
      (octahedral B(6)H(6)(2-) and two Li(3)(+)) was found to be 31.3 kcal/mol higher
      in energy than the global minimum. Another isomer with three aromatic moieties
      (two B(3)H(3)(2-) and Li(3)(+)) was found to be substantially higher in energy
      (74.4 kcal/mol). Thus, the intramolecular electron transfers from the highly
      charged B(6)H(6)(6-) anion to cations are not favorable for the B(6)H(6)Li(6)
      molecule, even when a formation of three-dimensional aromatic B(6)H(6)(2-) anion
      and two sigma-aromatic Li(3)(+) cations occurs in the closo isomer.

PMID- 15180412
TI  - Electron-transfer chemistry of Ru-linker-(heme)-modified myoglobin: rapid
      intraprotein reduction of a photogenerated porphyrin cation radical.
AB  - We report the synthesis and characterization of RuC7, a complex in which a heme
      is covalently attached to a [Ru(bpy)(3)](2+) complex through a -(CH(2))(7)-
      linker. Insertion of RuC7 into horse heart apomyoglobin gives RuC7Mb, a Ru(heme)
      protein conjugate in which [Ru(bpy)(3)](2+) emission is highly quenched. The rate
      of photoinduced electron transfer (ET) from the resting (Ru(2+)/Fe(3+)) to the
      transient (Ru(3+)/Fe(2+)) state of RuC7Mb is >10(8) s(-1); the back ET rate (to
      regenerate Ru(2+)/Fe(3+)) is 1.4 x 10(7) s(-1). Irreversible oxidative quenching
      by [Co(NH(3))(5)Cl](2+) generates Ru(3+)/Fe(3+): the Ru(3+) complex then oxidizes
      the porphyrin to a cation radical (P*+); in a subsequent step, P*+ oxidizes both
      Fe(3+) (to give Fe(IV)=O) and an amino acid residue. The rate of intramolecular
      reduction of P*+ is 9.8 x 10(3) s(-1); the rate of ferryl formation is 2.9 x
      10(3) s(-1). Strong EPR signals attributable to tyrosine and tryptophan radicals
      were recorded after RuC7MbM(3+) (M = Fe, Mn) was flash-quenched/frozen.

PMID- 15180413
TI  - Dawson type heteropolyanions. 3. Syntheses and 31P, 51V, and 183W NMR structural
      investigation of octadeca(molybdo-tungsto-vanado)diphosphates related to the
      [H2P2W12O48]12- anion.
AB  - The synthesis and multinuclear NMR characterization of mixed molybdenum-vanadium
      tungsten polyoxometalates [P(2)Mo(x)V(y)W(18-(x+y))O(62)](n-) (x + y < or = 8)
      related to the Dawson structure are reported. The mixed species are obtained from
      the hexavacant anion [H(2)P(2)W(12)O(56)](12-) by successive condensation and
      hydrolysis reactions. The strategy of synthesis is mainly based on the steric
      control of hydrolysis reactions by the nature and the strength of the base, the
      relative kinetic lability of molybdenum and tungsten in hydrolysis reactions, and
      the conservation of the framework when vacant sites are refilled by new metal
      atoms. Rather good values of (31)P chemical shift variations can be predicted by
      an additive model taking into account the contribution of substituting groups,
      depending on their position in the structure. The influence of Mo/W and V/W
      substitutions on (183)W chemical shifts of the remaining W atoms has been
      discussed and seems to be preferentially passed on through corner junctions.

PMID- 15180414
TI  - Investigation of transition metal-imido bonding in M(NBut)2(dpma).
AB  - A complete series down group 6 of the formula M(NBu(t))(2)(dpma) has been
      synthesized, where dpma is N,N-di(pyrrolyl-alpha-methyl)-N-methylamine. A fourth
      complex, Mo(NAr)(2)(dpma) (4), was also prepared, where Ar is 2,6
      diisopropylphenyl. All four of these complexes display geometries in the solid
      state best described as square pyramidal with one imido ligand occupying the
      axial position and the other an equatorial site. In all cases, the axial imido
      ligand has a significantly smaller M-N(imido)-C bond angle with respect to the
      equatorial multiple-bond substituent. From the (1)H, (13)C, and (14)N NMR
      spectra, the axial (bent) imido appears to be more electron-rich than the
      equatorial and linear imido, with the differences becoming less pronounced down
      the column. The angular deformation energies for the axial imido ligands were
      studied by DFT in order to discern if and to what extent imido bond angles were
      important energetically. The electronic energies associated with straightening
      the axial imido ligand, while holding the remainder of the molecule at the ground
      state geometry, for the Cr, Mo, and W derivatives were calculated as 4.5, 2.7,
      and 2.0 kcal/mol, respectively. A straight-line plot is found for deformation
      energies versus estimated electronegativity of the group 6 metals in the +6
      oxidation state. The study suggests that the electronic differences between metal
      imido ligands of different angles are quite small; however, the effects may be
      more pronounced for metal centers with higher electronegativity, e.g. Cr(VI) with
      electron-withdrawing ligands.

PMID- 15180415
TI  - Eclipsed M2X6 compounds exhibiting very short metal-metal triple bonds.
AB  - The preparation, characterization, and electronic structure of homoleptic
      complexes of molybdenum and tungsten bridged by bis(alkylamido)phenylboranes,
      M(2)[RN-B(Ph)-NR](3) (M = Mo, R = Et (1), (i)Pr (2); M = W, R = Et (3), (i)Pr
      (4)), are described. These triple metal-metal bond species (i) exhibit a nearly
      eclipsed ligand geometry and (ii) possess the shortest metal-metal bonds of
      neutral dimolybdenum and ditungsten M(2)X(6) complexes observed to date (d(Mo-Mo)
      = 2.1612(6) A (1); d(W-W) = 2.2351(7) A (4)).

PMID- 15180416
TI  - Synthesis of carbaalane halogen derivatives.
AB  - The carbaalane halogen derivatives [(AlX)(6)(AlNMe(3))(2)(CCH(2)CH(2)SiMe(3))(6)]
      (X = F (9), Cl (7), Br (10), I (11)) were prepared in toluene from
      [(AlH)(6)(AlNMe(3))(2)(CCH(2)CH(2)SiMe(3))(6)] (6) and BF(3).OEt(2), BX(3) (X =
      Br, I), Me(3)SnF, and Me(3)SiX (X = Cl, Br, I), respectively. A partially
      halogenated product [(AlH)(2)(AlX)(4)(AlNMe(3))(2)(CCH(2)CH(2)SiMe(3))(6)] (12)
      (X = Cl (approximately 40%), Br (approximately 60%)) was obtained from 5 and
      impure BBr(3). [(AlH)(6)(AlNMe(3))(2)(CCH(2)Ph)(6)] (5) was converted to
      [(AlX)(6)(AlNMe(3))(2)(CCH(2)Ph)(6)] (X = F (13), Cl (14), Br (15), I (16)) using
      BF(3).OEt(2) and Me(3)SiX (X = Cl, Br, I), respectively. The X-ray single-crystal
      structures of 11.C(6)H(6), 12.3C(7)H(8), 13.6C(7)H(8), and 15.4C(7)H(8) were
      determined. Compounds 7 and 9-11 are soluble in benzene/toluene and could be well
      characterized by NMR spectroscopy and MS (EI) spectrometry. The results
      demonstrate the facile substitution of the hydridic hydrogen atoms in 5 and 6 by
      the halides with different reagents.

PMID- 15180417
TI  - Alkaline side-coordination strategy for the design of nickel(II) and nickel(III)
      bis(1,2-diselenolene) complex based materials.
AB  - The deprotonated form of the pyrazine-2,3-diselenol (pds) ligand, pds(2-), reacts
      with Ni(II) inorganic salts to form the nickel compounds
      [Ni(II)(pds)(2)](nBu(4)N)(2) (1), [Ni(II)(pds)(2)]Na(2).2H(2)O (2), and
      [Ni(III)(pds)(2)](2)Na(2).4H(2)O (3), depending on the reaction conditions. They
      are characterized by NMR, EPR, UV-vis, and IR spectroscopies, elemental analysis,
      cyclic voltammetry, and X-ray crystallography. The crystal structure of compound
      3 shows the formation of segregated stacks of Ni(pds)(2-) units, with a strong
      dimerization along the stacks. The stacked fashion of the crystal packing was
      expected since the supramolecular forces of the alkaline side coordination to the
      pyrazine moieties dominate, as happens in the recently reported analogous copper
      system [Cu(III)(pds)(2)]Na.2H(2)O. The structure of 2 further emphasizes the
      alkaline coordination as the dominating supramolecular event, and an orthogonal
      array of 2D layers is observed. The absence of alkaline cations in complex 1 is
      reflected in a crystal packing with isolated complex Ni(pds)(2)(2-) units. The
      dimerization found in the paramagnetic Ni(III) complex 3 promotes a very strong
      antiferromagnetic interaction, leading to a singlet ground state.

PMID- 15180418
TI  - Hydrocarbyl ligand "tuning" of the PtII/IV redox potential.
AB  - The potentially tridentate macrocycle [2.1.1]-(2,6)-pyridinophane (L) enables the
      transient LPt(II)(CH(3))(+) to cleave the C-H bond of two molecules of C(6)F(5)H.
      The resulting product has two aryl groups on Pt but, in contrast to
      nonfluorinated analogue, varies in its location of the cleaved H, as is evident
      from the two products (HL(+))Pt(II)R(2) and (eta(3)-L)Pt(IV)H(R)(2)(+). At
      equilibrium, the related example where R = CH(3) is purely the Pt(IV) redox
      isomer, which with R = C(6)H(5) shows detectable populations of both isomers, and
      with R = C(6)F(5) is purely the pyridine-protonated (HL(+))Pt(II) redox isomer.
      All species show a hydrogen bond from the pyridinium proton to Pt(II). Consistent
      with the idea that electron-withdrawing R makes platinum(II) more resistant to
      oxidation (i.e., a proton on Pt), and thus less Bronsted basic, the (1)J(PtH)
      coupling constant falls in the series R = Me (90 Hz), R = C(6)H(5) (86 Hz), and R
      = C(6)F(5) (63 Hz).

PMID- 15180419
TI  - Terminal ligand influence on the electronic structure and intrinsic redox
      properties of the [Fe4S4]2+ cubane clusters.
AB  - We used photoelectron spectroscopy (PES) to study how the terminal ligands
      influence the electronic structure and redox properties of the [4Fe-4S] cubane in
      several series of ligand-substituted analogue complexes: [Fe(4)S(4)Cl(4
      x)(CN)(x)](2-), [Fe(4)S(4)Cl(4-x)(SCN)(x)](2-), [Fe(4)S(4)Cl(4-x)(OAc)(x)](2-),
      [Fe(4)S(4)(SC(2)H(5))(4-x)(OPr)(x)](2-), and [Fe(4)S(4)(SC(2)H(5))(4-x)Cl(x)](2-)
      (x = 0-4). All the ligand-substituted complexes gave similar PES spectral
      features as the parents, suggesting that the mixed-ligand coordination does not
      perturb the electronic structure of the cubane core significantly. The terminal
      ligands, however, have profound effects on the electron binding energies of the
      cubane and induce significant shifts of the PES spectra, increasing in the order
      SC(2)H(5)(-) --> Cl(-) --> OAc(-)/OPr(-) --> CN(-) --> SCN(-). A linear
      relationship between the electron binding energies and the substitution number x
      was observed for each series, indicating that each ligand contributes
      independently and additively to the total binding energy. The electron binding
      energies of the gaseous complexes represent their intrinsic oxidation energies;
      the observed linear dependence on x is consistent with similar observations on
      the redox potentials of mixed-ligand cubane complexes in solution. The current
      study reveals the electrostatic nature of the interaction between the [4Fe-4S]
      cubane core and its coordination environment and provides further evidence for
      the electronic and structural stability of the cubane core and its robustness as
      a structural and functional unit in Fe-S proteins.

PMID- 15180420
TI  - [Mn2(AsS4)4]8- and [Cd2(AsS4)2(AsS5)2]8-: discrete clusters with high negative
      charge from alkali metal polythioarsenate fluxes.
AB  - The reaction of Mn and Cd in alkali metal polythioarsenate fluxes afforded four
      new compounds featuring molecular anions. K(8)[Mn(2)(AsS(4))(4)] (I) crystallizes
      in the monoclinic space group P2/n with a = 9.1818(8) A, b = 8.5867(8) A, c =
      20.3802(19) A, and beta = 95.095(2) degrees. Rb(8)[Mn(2)(AsS(4))(4)] (II) and
      Cs(8)[Mn(2)(AsS(4))(4)] (III) both crystallize in the triclinic space group P1
      with a = 9.079(3) A, b = 9.197(3) A, c = 11.219(4) A, alpha = 105.958(7) degrees,
      beta = 103.950(5) degrees, and gamma = 92.612(6) degrees for II and a = 9.420(5)
      A, b = 9.559(5) A, c = 11.496(7) A, alpha = 105.606(14) degrees, beta =
      102.999(12) degrees, and gamma = 92.423(14) degrees for III. The discrete dimeric
      [Mn(2)(AsS(4))(4)](8-) clusters in these compounds are composed of two octahedral
      Mn(2+) ions bridged by two [AsS(4)](3-) units and chelated each by a [AsS(4)](3-)
      unit. Rb(8)[Cd(2)(AsS(4))(2)(AsS(5))(2)] (IV) crystallizes in P1 with a =
      9.122(2) A, b = 9.285(2) A, c = 12.400(3) A, alpha = 111.700(6) degrees, beta =
      108.744 degrees, and gamma = 90.163(5) degrees. Owing to the greater size of Cd
      compared to Mn, the Cd centers in this compound are bridged by [AsS(5)](3-)
      units. The [Cd(2)(AsS(4))(4)](8-) cluster is a minor component cocrystallized in
      the lattice. These compounds are yellow in color and soluble in water.

PMID- 15180421
TI  - Coordination polymers with carborane anions: silver dinitrile complexes.
AB  - Crystalline materials have been isolated and characterized from mixing the silver
      carborane salts Ag(CB(11)H(12)) or Ag[Co(C(2)B(9)H(11))(2)] with nitrile ligands,
      either terminal acetonitrile or potentially bridging alkanedinitriles. Most of
      the complexes showed B-H...Ag interactions between the silver center and
      carborane anion. [Ag(acetonitrile)(2)(CB(11)H(12))] has a hexagonal network
      structure. [Ag(malonitrile)(2)(CB(11)H(12))] is a discrete dimeric complex, while
      [Ag(4)(succinonitrile)(5)(CB(11)H(12))(4)],
      [Ag(glutaronitrile)(2)][Co(C(2)B(9)H(12))(2)], and
      [Ag(glutaronitrile)[Co(C(2)B(9)H(11))(2)]] all show coordination chain
      structures. The carborane anions in [Ag(adiponitrile)[Co(C(2)B(9)H(11))(2)]]
      bridge between Ag centers to give a 3D CdSO(4)-related coordination polymer. The
      structure of [Ag(malonitrile)(2)](BF(4)) was also determined to have an unusual
      chiral diamondoid structure with a skewed 2-fold interpenetration.

PMID- 15180422
TI  - Electrochemical, spectroscopic, and structural evidence for the mild hydrolysis
      of tetracyanoethylene, TCNE, to form the 2,3,3-tricyanoacrylamidate ligand:
      isolation of an unexpected quadruply-bonded polymeric material
      [Mo2(O2CCMe3)3((NC)2CC(CN)CONH)]infinity.
AB  - Under strictly anhydrous conditions, no reaction occurs between
      Mo(2)(O(2)CCMe(3))(4) and tetracyanoethylene, TCNE, at room temperature, but
      after addition of 1 equiv of water, a reaction proceeds to form
      [Mo(2)(O(2)CCMe(3))(3)((NC)(2)CC(CN)CONH)], 1. The compound contains a quadruple
      bonded Mo(2) unit and the 2,3,3-tricyanoacrylamidate anion as a ligand (TC3A), a
      very unusual hydrolyzed form of TCNE. Two different solid-state structures were
      obtained after crystallization of 1. Crystals obtained from CH(2)Cl(2) consist of
      a two-dimensional network, and crystals grown from a C(6)H(6) solution form a 1-D
      chain motif. In both cases, the TC3A ligand acts as a polydentate ligand
      involving a bidentate OCN bridging unit and two CN groups. The electrochemical
      and spectroscopic (IR, UV/vis/near-IR, NMR, EPR) properties of 1 support the
      formulation in solution as a discrete 1:1 complex of the TC3A donor ligand and a
      Mo(2) unit with no charge transfer. The coordinated TC3A ligand exhibits redox
      properties similar to those of free TCNE.

PMID- 15180423
TI  - Organometallic early lanthanide clusters: syntheses and X-ray structures of new
      monocyclopentadienyl complexes.
AB  - The reaction of Ln(BH(4))(3)(THF)(3) or LnCl(3)(THF)(3) with 1 equiv of KCp*'
      ligand (Cp' = C(5)Me(4)n-Pr) afforded the new monocyclopentadienyl complexes
      Cp*'LnX(2)(THF)(n) (X = BH(4), Ln = Sm, n = 1, 1a, Ln = Nd, n = 2, 1b; X = Cl, Ln
      = Sm, n = 1, 3a) and [Cp*'LnX(2)](n') (X = BH(4), n' = 6, Ln = Sm, 2a, Ln = Nd,
      2b; X = Cl, Ln = Nd, 4b). All these compounds were characterized by elemental
      analysis and (1)H NMR. Crystals of mixed borohydrido/chloro-bridged
      [Cp*'(6)Ln(6)(BH(4))(12-x))Cl(x)(THF)(n')] (x = 10, n' = 4, Ln = Sm, 2a', Ln =
      Nd, 2b'; x = 5, n = 2, Ln = Sm, 2a' ') were also isolated. Compounds 2a, 2b, 2a',
      2b', and 2a'' were structurally characterized; they all exhibit a hexameric
      structure in the solid state containing the [Cp*(3)Ln(3)X(5)(THF)] building
      block. The easy clustering of THF adducts first isolated is illustrative of the
      well-known bridging ability of the BH(4) group. Hexameric 2a was found to be
      unstable in the presence of THF vapors; this may be correlated to the opening of
      unsymmetrical borohydride bridges observed in the molecular structure.

PMID- 15180424
TI  - DFT study of the geometry and energy order of the low singlet and triplet states
      of [d4-eta5-CpMo(CO)2X] 16-electron complexes (X = halogen, CN, H, and CH3).
AB  - DFT methods have been used to investigate the dependence of the geometry and
      energy order of the low energy states of [d(4)-eta(5)-CpMo(CO)(2)X] 16-electron
      complexes on X (X = halogen, CN, H and CH(3)). The calculations use a double-zeta
      plus polarization valence basis set on all atoms and utilize relativistic ECPs on
      Mo and the heavier halogens. In every case two singlet and two triplet electronic
      states have been considered and minimized at the B3LYP level. For X = Cl,
      additional calculations were carried out at the BPW91, CCSD(T), and CASSCF
      levels. In the C(s) point group, the singlet states are from the
      (1a')(2)(1a'')(2) and (1a')(2)(2a')(2) configurations of the valence d(4)
      electrons of the metal, and are denoted (1)A'-a and (1)A'-b, respectively. The
      triplet species are for the lowest (3)A'' and (3)A' states from the
      (1a')(2)(2a')(1)(1a'')(1) and (1a'')(2)(1a')(1)(2a')(1) d(4) configurations. For
      all substituents, the geometry of both the singlet and triplet states is found to
      distort substantially from the uniform 3-leg piano-stool structural motif, a
      behavior that can be related to Jahn-Teller effects. When X is a halogen or a
      methyl, (1)A'-b is predicted to be lower than (1)A'-a, while the reverse order of
      these two singlet states is calculated for X = H and CN. For all substituents
      (3)A' is substantially higher than (3)A''. In turn, the energy of (3)A'' is
      calculated to be comparable to the lower singlet state of each complex. Attempts
      are made to rationalize some of these results using qualitative MO theory.

PMID- 15180425
TI  - Crystal structure and spectroscopic properties of CsVO2SO4.
AB  - Dark crystals of the V(V) compound CsVO(2)SO(4), suitable for X-ray
      investigations have been obtained from the catalytically important Cs(2)S(2)O(7)
      V(2)O(5) system. By cooling of the mixture with the composition X(V)2(O)5 = 0.5,
      some crystals were obtained in the otherwise glassy sample. The compound
      crystallizes in the orthorhombic space group Pbca with a = 6.6688(13) A, b =
      10.048(2) A, and c = 17.680(4) A at 20 degrees C and Z = 8. It contains a
      coordination sphere with a short V-O bond of 1.595(2) A and trans to this the
      closest VO distance at 3.4 A and four equatorial V-O bonds in the range 1.725(1)
      1.984(2) A. The deformation of the VO(6) octahedron is thus much more pronounced
      compared to other known oxo sulfato V(V) compounds, and the coordination
      polyhedron of V(V) should be regarded as a tetragonal pyramid with the vanadium
      atom in the center. Each VO(2)(+) group is coordinated to the neighboring groups
      by oxygen and sulfate double bridges in a zigzag structure where two sulfate
      oxygens virtually remain uncoordinated-one is found at the very long nonbonding V
      O distance from the neighboring chain. This is the first time that we find
      pentacoordination of vanadium in the 12 different V(III), V(IV), and V(V)
      compounds examined so far. The FTIR and Raman spectra of the compound are in
      agreement with the simple formula unit of the investigated compound.

PMID- 15180426
TI  - Chalcogen-chalcogen bonds in edge-sharing square-planar d8 complexes. Are they
      possible?
AB  - A theoretical study of the formation of X-X bonds in complexes with the general
      formula [M(2)(mu-X)(2)L(4)] (M = group 10 and X = group 16 elements) having d(8)
      transition-metal atoms is presented. The existence of two energy minima for some
      complexes, with short and long X-X distances, is shown by density functional
      theory calculations, and the factors responsible for it are analyzed, including a
      strong influence of the nature of the metals and ligands on the relative
      stability of the two isomers. The influence of the bite angle of chelating
      terminal ligands and the nature of the donor atom on the relative stabilities of
      the two isomers are also discussed.

PMID- 15180427
TI  - Linkage isomerism in nitrite reduction by cytochrome cd1 nitrite reductase.
AB  - Nitrite reduction by cytochrome cd(1) nitrite reductase (cd(1)NIR) is currently
      accepted to involve coordination of the nitrite nitrogen atom to the ferrous d(1)
      heme. Here, density functional theory results are reported on the previously
      unexplored O-binding of nitrite to ferrous and ferric cd(1)NIR. Although the N
      isomer (nitro) is energetically favored over the O-nitrite (nitrito), even one
      single strong hydrogen bond may provide the energy required to put the two
      isomers on level terms. When hydrogen bonding existent at the cd(1)NIR active
      site is accounted for in the computational model, the O-nitrite isomer is found
      to spontaneously protonate and thus yield a ferric-hydroxo species, liberating
      nitric oxide. An O-nitrite ferrous cd(1)NIR complex appears to be an
      energetically feasible intermediate for nitrite reduction. O-Coordination would
      offer an advantage since the end product of nitrite reduction would be a ferric
      hydroxo/water complex, rather than the more kinetically inert iron-nitrosyl
      complex implied by the N-nitrite mechanism.

PMID- 15180428
TI  - A convenient synthesis of new isolable phosphaalkenes using the base-induced
      rearrangement of secondary vinylphosphines.
AB  - The secondary vinylphosphines Ar(F)P(H)C(R)[double bond]CH(2) [2a, Ar(F) = 2,6
      (CF(3))(2)C(6)H(3), R = CH(3); 2b, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = C(6)H(5);
      2c, Ar(F) = 2,4,6-(CF(3))(3)C(6)H(2), R = CH(3)] were prepared by treating the
      corresponding dichlorophosphine Ar(F)PCl(2) (1) with H(2)C[double bond]C(R)MgBr.
      In the presence of catalytic base (DBU or DABCO) the vinylphosphines (2a-c)
      undergo quantitative 1,3-hydrogen migration over 3 d to give stable and isolable
      phosphaalkenes Ar(F)P=C(R)CH(3) (3a, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = CH(3);
      3b, Ar(F) = 2,6-(CF(3))(2)C(6)H(3), R = C(6)H(5); 3c, Ar(F) = 2,4,6
      (CF(3))(3)C(6)H(2), R = CH(3)). Under analogous conditions, only 90% conversion
      is observed in the base-catalyzed rearrangement of MesP(H)C(CH(3))[double
      bond]CH(2) to MesP[double bond]C(CH(3))(2). Presumably, the increase in acidity
      of the P-H group when electron-withdrawing groups are employed (i.e. 2a-c) favors
      quantitative rearrangement to the phosphaalkene tautomer (3a-c). Thus, the double
      bond migration reaction is a convenient and practical method of preparing new
      phosphaalkenes with C-methyl substituents.

PMID- 15180430
TI  - Density functional theory investigation of the active site of Fe-hydrogenases.
      systematic study of the effects of redox state and ligands hardness on structural
      and electronic properties of complexes related to the [2Fe](H) subcluster.
AB  - Density functional theory has been used to investigate complexes related to the
      [2Fe](H) subcluster of [Fe]-hydrogenases. In particular, the effects on
      structural and electronic properties of redox state and ligands with different
      sigma-donor pi-acceptor character, which replace the cysteine residue coordinated
      to the [2Fe](H) subcluster in the enzyme, have been investigated. Results show
      that the structural and electronic properties of fully reduced Fe(I)Fe(I)
      complexes are strongly affected by the nature of the ligand L, and in particular,
      a progressive rotation of the Fe(d)(CO)(2)(CN) group, with a CO ligand moving
      from a terminal to a semibridged position, is observed going from the softest to
      the hardest ligand. For the partially oxidized Fe(I)Fe(II) complexes, two isomers
      of similar stability, characterized either by a CO ligand in a terminal or
      bridged position, have been observed. The switching between the two forms is
      associated with a spin and charge transfer between the two iron atoms, a feature
      that could be relevant in the catalytic mechanism of dihydrogen activation. The
      structure of the fully oxidized Fe(II)Fe(II) models is extremely dependent on the
      nature of the L ligand; one CO group coordinated to Fe(d) switches from terminal
      to bridging position going from complexes characterized by neutral to anionic L
      ligands.

PMID- 15180429
TI  - Electronic spectroscopy, photophysical properties, and emission quenching studies
      of an oxidatively robust perfluorinated platinum porphyrin.
AB  - The highly electron-deficient, beta-octafluorinated meso
      tetrakis(pentafluorophenyl)-porphyrin (H(2)F(28)TPP) was metalated with platinum
      to afford the oxidatively robust luminophore [PtF(28)TPP], and its X-ray
      structure shows that the porphyrin core exists in a slightly saddle-shaped
      conformation. The absorption spectrum of [PtF(28)TPP] in CH(2)Cl(2) displays a
      near-UV Soret band (B) at 383 nm (epsilon = 2.85 x 10(5) dm(3) mol(-1) cm(-1))
      and two visible Q(1,0) and Q(0,0) bands at 501 (epsilon = 1.45 x 10(4) dm(3) mol(
      1) cm(-1)) and 533 (epsilon = 1.36 x 10(4) dm(3) mol(-1) cm(-1)) nm,
      respectively. These absorption bands of [PtF(28)TPP] are blue-shifted from those
      in [PtF(20)TPP] (390, 504, and 538 nm, respectively) and [PtTPP] (401, 509, and
      539 nm, respectively). Excitation of [PtF(28)TPP] (complex concentration = 1.5 x
      10(-6) mol dm(-3)) in dichloromethane at the Soret or Q(1,0) or Q(0,0) band gave
      a phosphorescence with peak maximum at 650 nm (lifetime = 5.8 micros) and a weak
      shoulder at 712 nm. Both the emission lifetime and quantum yield vary with
      solvent polarity, and plots of tau versus E(K) and Phi versus E(K) (where E(K) is
      the empirical solvent polarity parameter based on the hypsochromic shift of the
      longest wavelength absorption of the [Mo(CO)(4)[(C(5)H(4)N)HC[double
      bond]NCH(2)C(6)H(5)]] complex with increasing solvent polarity; see: Kamlet, M.
      J.; Abboud, J. L. M.; Taft, R. W. Prog. Phys. Org. Chem. 1981, 13, pp 485-630)
      show linear correlation, indicating that the emission is sensitive to the local
      environment/medium. Electrochemical studies on [PtF(28)TPP] by cyclic voltammetry
      showed no porphyrin-centered oxidation at potential < or = 1.5 V versus
      Ag/AgNO(3), demonstrating that [PtF(28)TPP] is more resistant toward oxidation
      than [PtF(20)TPP] (E(1/2) = 1.33 V) and [PtTPP] (E(1/2) = 0.97 V). The porphyrin
      centered reduction of [PtF(28)TPP] occurs at -0.75 and -1.18 V, which is
      anodically shifted from those at -1.06 and -1.55 V in [PtF(20)TPP], and -1.51 V
      in [PtTPP], respectively. The excited-state reduction potential of [PtF(28)TPP]
      is estimated to be 1.49 V versus Ag/AgNO(3). Over 97% of the emission intensity
      of [PtF(28)TPP] was retained after irradiation with a high power mercury arc lamp
      (500 W) for 14 h, compared to 90% and 12% for [PtF(20)TPP] and [PtTPP],
      respectively; hence, [PtF(28)TPP] exhibits superior photostability. Quenching of
      the emission of [PtF(28)TPP] by oxygen, alcohol, catechol, and butylamine reveals
      that [PtF(28)TPP] is an oxidatively robust material with medium-sensitive
      photoluminescence properties.

PMID- 15180431
TI  - The reactions of tellurium tetrahalides with triphenylphosphine under ambient
      conditions.
AB  - The reactions of tellurium tetrahalides and triphenylphosphine in tetrahydrofuran
      have been carried out under ambient conditions and afford
      [(Ph(3)PO)(2)H](2)[Te(2)X(10)] [X = Cl (1), Br (2)] and
      [(Ph(3)PO)(3)(OH(3)])(2)[TeI(6)] (4). The X-ray structures of 1 and 2 show that
      they are isostructural and contain discrete [Te(2)X(10)](2-) anions exhibiting
      octahedral coordination around both tellurium atoms with one shared edge and
      [Ph(3)POH...OPPh(3)](+) cations that show strong hydrogen bonds (the O...O
      distances are 2.399 and 2.404 A for 1 and 2, respectively). The compound 4 is
      built up with discrete octahedral hexaiodotellurate anions and
      [(Ph(3)PO)(3)(OH(3))](+) cations. The reaction of TeBr(4) and PPh(3) also results
      in the formation of formally zwitterionic Ph(3)PO(CH(2))(4)TeBr(4) (3). This
      reaction involves an unprecedented THF ring opening in which the oxygen atom
      becomes bonded to the phosphorus atom of triphenylphosphine and the carbon atom
      at the other end of the five-atomic chain becomes bonded to the tellurium atom of
      TeBr(4). The ring opening of the solvent THF is also taking place in the reaction
      involving tellurium tetraiodide, as indicated by the formation of C(4)H(8)TeI(2)
      (5). The reaction may initially lead to Ph(3)PI(2) that reacts with THF yielding
      Ph(3)PO and ICH(2)(CH(2))(2)CH(2)I. The latter species reacts with elemental
      tellurium producing 5. Depending on the conditions upon crystallization, two
      polymorphs of C(4)H(8)TeI(2) (5a and 5b) are observed. While the molecular
      structures of the two forms are virtually identical, their packing and
      intermolecular contacts are different. Two further minor products (6a and 6b)
      were isolated in the reaction of TeI(4) and PPh(3): Both are formally 1:1 adducts
      of 5 and TeI(4), but they differ considerably in their structures. 6a can be
      formulated as [C(4)H(8)TeI(+)](2)[Te(2)I(10)(2-)] and 6b as
      [C(4)H(8)TeI(+)](2)(TeI(3)(+))(2)(I(-))(4). The latter compound exhibits
      framework similar to that of the tetramers in gamma- and delta-TeI(4).

PMID- 15180432
TI  - Anion binding with a tripodal amine.
AB  - Binding studies of the tren-based amine, L (N,N',N' '-tris(2
      benzylaminoethyl)amine), with inorganic anions and two crystal structures,
      [H(3)L][H(2)PO(4)](3).H(3)PO(4) and [H(3)L][Br](3), are reported. NMR titration
      results indicate that the ligand binds H(2)PO(4)(-) and HSO(4)(-) more strongly
      than NO(3)(-) and halides. In the crystal structure of the phosphate complex, the
      ligand is triprotonated with the three arms pointing outward in a trigonal-planar
      like arrangement. Four phosphate species are associated with the receptor, and
      have been assigned as three H(2)PO(4)(-) counterions located between each of the
      tren arms, and an additional H(3)PO(4) molecule above the quasi-planar tren. The
      structure of the bromide complex is slightly different, although again the tren
      receptor is triprotonated and quasi-planar, but in this case C(2v)-like symmetry
      is seen with two of the arms pointed in the same direction with a bromide ion in
      between. The other two bromides lie outside of the tren arms.

PMID- 15180433
TI  - Dimeric (tris(tert-butyl)silyl)phosphanyl (tris(tert-butyl)silyl)phosphanediyl
      gallane: a molecule with a Ga-P-Ga heteroallyl system.
AB  - The metathesis reaction of potassium (tris(tert-butyl)silyl)phosphanide with
      GaCl(3) in a molar ratio of 1:1 leads to the formation of
      [Cl(2)GaP(H)Si(t)Bu(3)](2) (1) as a mixture of cis and trans isomers with very
      large (1)J(P,H) and (2)J(P,P) coupling constants. The molecular structure of 1
      shows a Ga(2)P(2) cycle with nearly planar coordinated phosphorus atoms under
      neglection of the hydrogen atoms and Ga-P distances of 239 pm. The reaction of
      GaCl(3) with 3 equiv of potassium (tris(tert-butyl)silyl)phosphanide as well as
      the reaction of 1 with 2 equiv of KP(H)Si(t)Bu(3) yields [(t)Bu(3)SiP(H)Ga(mu
      PSi(t)Bu(3))](2) (2). The central moiety comprises a four-membered Ga(2)P(2)
      cycle with one planar P atom and extremely short Ga-P bonds of approximately 226
      pm, the other being in a pyramidal environment with an angle sum of 298.4
      degrees. The structure of 2 can be described as a GaPGa heteroallyl system which
      is bonded to a phosphanidyl substituent. This idea and its dependency on the
      steric demand of the trialkylsilyl groups are investigated by DFT calculations on
      different isomers of 2.

PMID- 15180434
TI  - Maintenance of midgut epithelial cells from Dendroctonus valens (Coleoptera:
      Scolytidae) in vitro.
AB  - This article describes the culture of epithelial cells from anterior and
      posterior midgut regions of adult Dendroctonus valens. Culture conditions were
      established, and cell adherence was improved by means of a new technique that
      allowed the cells to grow between two glass coverslips. Cytoplasmic projections
      occur as anterior midgut cells grow to confluence; these projections were not
      observed in cells of the posterior midgut. The optimal culture medium for the
      maintenance of these epithelial cells was Roswell Park Memorial Institute 1640
      medium at 25 degrees C. Cells in Grace's medium died in 24 h. Cultures did not
      require CO(2) atmosphere, but culture development was favored by the
      microaerophilic environment and the dark conditions in which the cells were
      grown, between the coverslips.

PMID- 15180435
TI  - Increased activity of the calcineurin-nuclear factor of activated T cells pathway
      in squirrel monkey B-Lymphoblasts identified by PowerBlot.
AB  - New World primate-derived cell lines were instrumental in identifying the primary
      factors causing glucocorticoid resistance in these primate species. Their use is
      expanding because it has been recognized that some of these cell lines exhibit
      differential sensitivity to retroviral infection. To enhance their utility as
      cell models, we have further characterized one of these cell lines, squirrel
      monkey-derived B-lymphoblast (SML) cells, using PowerBlot. PowerBlot is a high
      throughput, proteomic screen designed to identify differentially expressed
      proteins. We compared proteins expressed in SML cells and in a human B
      lymphoblast (HL) cell line. We found that, relative to HL cells, SML cells
      overexpress the calcineurin-activated transcription factor nuclear factor of
      activated T cells 1 (NFAT-1), which exists in a cyclosporine A (CsA)-sensitive
      dephosphorylated, constitutively active state. We show that there is increased
      binding of NFAT-1 to deoxyribonucleic acid and greater activity of an NFAT
      sensitive human interleukin-2 (IL-2) promoter-luciferase reporter gene in SML
      compared with activity in HL cells. The increased NFAT activity does not likely
      result from calcium-dependent activation of calcineurin because cytosolic calcium
      levels were not different in SML and HL cells. Rather, SML cells express a
      truncated form of the catalytic subunit of calcineurin that we propose is
      responsible for the increased activity of the NFAT pathway. Thus, these novel
      findings first uncovered by a proteomic screen will enhance the value of these
      New World primate cell lines as "experiments of nature" to gain insight into
      mechanisms of NFAT activation.

PMID- 15180436
TI  - Induction of osteoblast aggregation, detachment, and altered integrin expression
      by bear serum.
AB  - Animal models have long been used to elucidate the mechanisms responsible for
      osteoporosis in humans. The American black bear, an animal that does not
      experience extensive bone loss normally associated with long-term immobilization
      (when hibernating), may provide an insight into the nature of the pathogenesis of
      the disease. Circulating growth and differentiation factors present in the serum
      may facilitate continued proliferation of bone-forming cells. The aim of our
      study was to determine the effects of bear serum on human osteoblasts when
      cultured for extended periods of time. Unexpectedly, exposure to the bear serum
      in vitro led to the detachment of osteoblasts from the surface of the culture
      plate after 3 d of incubation. The osteoblasts pulled off the polystyrene surface
      in sheets and aggregated into floating conglomerations of viable cells. In
      contrast, osteoblasts cultured in fetal calf serum maintained adherence to the
      surface of the culture plate. Detachment of osteoblasts propagated in bear serum
      was time dependent and was associated with an increased expression of integrins
      compared with osteoblasts propagated in fetal calf serum, as indicated by reverse
      transcriptase-polymerase chain reaction and immunostaining.

PMID- 15180437
TI  - Enhancement of lipid bodies during differentiation of skeletal myofibroblasts of
      rat's fetus in vitro.
AB  - Fibroblasts in vitro can acquire myofibroblast phenotype by the development of
      several biochemical and morphological properties of smooth muscle cells,
      particularly the expression of alpha-smooth muscle actin. These cells play a
      major role in inflammatory responses and in wound repair through their production
      of growth factors, cytokines, and other soluble mediators. Lipid bodies (LB) are
      lipid-rich cytoplasmic inclusions and have been recognized as specialized
      intracellular domains involved in the formation of paracrine mediators of
      inflammation. The aim of the present study was to investigate the occurrence and
      distribution of LB during differentiation of rat fetus skeletal fibroblasts into
      myofibroblasts in vitro. Primary cultures of fibroblasts were obtained from
      skeletal muscles of 18-d-old Wistar strain rat fetus by enzymatic dissociation.
      At 1-7 d, the cells were stained with Nile red vital dye to identify LB and then
      observed under a Zeiss CLSM-310. Our results showed that there was an accentuated
      increase in the number of LB during the differentiation of skeletal fibroblasts
      into myofibroblasts and that these inclusions were scattered at the cytoplasm.

PMID- 15180439
TI  - [Blue Rubber Bled Nevus syndrome: three cases].

PMID- 15180438
TI  - Explant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice.
AB  - We have established an explant-cell culture system for mammary gland tumors from
      c-myc oncogene-expressing transgenic mice and potentially other transgenic
      strains. By coating culture dish surfaces with fetal bovine serum and using
      culture media supplemented with low serum and growth factors, the mammary tumor
      specimens could be maintained in culture for over 3 mo. Throughout the culture
      period, the explants produced abundant outgrowths of epithelial cells. As the
      outgrowths of epithelial cells filled the dishes, the explants were serially
      transferred from one dish to another-a process that could be repeated at least
      six times, thus providing a continuous supply of primary tumor cells. This
      culture system provides a useful tool for studying the biology of mouse mammary
      gland tumors and possibly tumors from other organ sites.

PMID- 15180440
TI  - Inflammatory bowel disease in Spain: problems grow.

PMID- 15180441
TI  - A population-based study on the incidence of inflammatory bowel disease in Oviedo
      (Northern Spain).
AB  - OBJECTIVE: to assess the incidence of inflammatory bowel disease in Oviedo
      (Northern Spain), and to describe the clinical features of new patients. PATIENTS
      AND METHODS: a prospective population-based study was made at the Health Area IV,
      Principality of Asturias (Oviedo, 312,324 inhabitants). All new diagnosed
      patients with inflammatory bowel disease were registered over a 2-year period.
      RESULTS: a total of 85 patients were included, 47 of these with ulcerative
      colitis (UC), 37 with Crohns disease (CD), and 1 with undetermined colitis. The
      overall adjusted incidence rate of UC and CD per 105 inhabitants between 15-64
      years was 9.1 (95% CI: 5-13.1) and 7.5 (95% CI: 3.8-11.2), respectively. The
      global male/female ratio was 0.9, without significant differences between both
      diseases. CD patients were younger than those with UC (33 +/- 15 years vs 45 +/-
      20 years; p < 0.05). Mostly, CD patients were diagnosed at an age younger than 35
      years (65%), while UC patients were diagnosed at an age between 25 and 64 years
      (81%). Disease extension in UC was proctitis in 11%, left-side colitis in 53% and
      extensive colitis in 36%. With respect to CD, the ileo-colonic form predominated
      (49%), followed by the ileal (40%) and colonic (11%) forms; an inflammatory,
      stenotic and fistulous pattern was seen in 54, 22 and 24% of patients,
      respectively. CONCLUSIONS: in our area, the incidence of CD is similar to that in
      other Northern European countries, while UC has a lower incidence. CD mainly
      affects young people, while UC predominates in middle-aged patients. At
      diagnosis, UC is predominantly localized, the ileo-colonic form and an
      inflammatory pattern being most frequent in CD patients.

PMID- 15180442
TI  - Biliopancreatic tumors: patient survival and quality of life after palliative
      treatment.
AB  - OBJECTIVES: to analyse survival and quality of life of patients with malignant
      obstructive jaundice after palliative treatment, comparing endoscopic stent
      insertion and palliative surgical (palliative resection and bypass surgical).
      PATIENTS AND METHOD: eighty and seven patients were included in a trial. They
      were distributed to endoscopic stent (50) and palliative surgical (37). It
      analysed survival, quality of life and comfort index of jaundiced patients. The
      good quality of life was defined by absence of jaundice, pruritus and cholangitis
      after the initial treatment. RESULTS: the median survival of the patients treated
      to endoscopic stent was 9,6 months whereas the patients to surgical treatment
      survived a median of 17 months. The time free of disease was 4 months in stented
      patients and 10,5 months in surgical patients. There was no significant
      difference in comfort index between the two groups (stented 34%, surgical 42,5%)
      Neither was there significant difference in survival and quality of life between
      palliative resection and bypass surgery. CONCLUSIONS: despite the survival and
      time free of disease being better in surgical patients, there was no significant
      difference in overall quality of life between the two groups. The survival and
      quality of life are the same after palliative resection as after bypass surgery,
      for this should not be performed routinely or to justify resection as a debulking
      procedure.

PMID- 15180443
TI  - Safety and efficacy of argon plasma coagulator ablation therapy for flat
      colorectal adenomas.
AB  - INTRODUCTION: argon-plasma coagulation (APC) has been used safely and
      efficaciously in multiple settings including colon polyp treatment. The aim of
      this study was to evaluate APC efficacy and safety in the treatment of flat
      colorectal adenomas. MATERIALS AND METHODS: APC ablation was prospectively
      performed and evaluated in 22 consecutive patients with colorectal adenomas, 11
      of which had large sessile adenomas that were treated with piecemeal polypectomy
      and APC ablation of residual adenomatous tissue, whereas the remaining eleven
      patients with flat or carpet-like adenomas were only treated with APC. The mean
      initial longitudinal extension of adenomas to be treated with APC was 22 mm
      (range, 20 to 40 mm). RESULTS: the mean age of patients was 70 years. Adenomas
      were found most frequently in the rectum (50%) and cecum (23%). Complete ablation
      was achieved in 90.9% of adenomas. Recurrence was observed in 20% of patients,
      all of them in the rectum, after a mean follow-up period of 16.3 months (range, 8
      to 35). All recurrences were managed satisfactorily. No major complications were
      seen. CONCLUSIONS: argon plasma coagulator ablation of flat colorectal adenomas
      is an efficacious and safe technique, specially in the right colon, but results
      must be confirmed in controlled trials with a higher number of patients.

PMID- 15180444
TI  - Influence of the surgical manipulation of the colon in colonic induced
      carcinogenesis in rats.
AB  - AIM: to investigate the influence of different experimental manipulations in a
      model of colonic experimental carcinogenesis with pharmacological induction in
      the rat. EXPERIMENTAL DESIGN: a total of 90 Sprague-Dawley male rats, divided
      into three groups, were used: non-surgical (n = 30); surgical with colonic trauma
      (n = 20), and surgical with colo-colonic anastomosis (n = 40). Carcinogenic
      induction was carried out with 1-2 dimethylhydrazine dihydrochloride. Colonic
      adenocarcinomas were identified and the number of tumors, as well as tumoral
      surface and percentage of tumoral surface was established. One-way ANOVA and Chi
      square were employed for the statistical analysis. RESULTS: the number of tumors
      was greater in the surgical group than in the control group, and tumors
      preferentially developed around the manipulated colon. Surface and tumoral
      percentage were greater in the surgical group than in the control group, being
      also greater in the anastomosis group than in the group with colonic trauma.
      Within anastomosis groups, a greater tumor surface and percentage was found in
      the group with titanium than in the group with reabsorbable material.
      CONCLUSIONS: the experimental manipulation of the colon in rats enhances drug
      induced colon carcingenesis. The creation of an anastomosis further increases the
      carcinogenic process compared with simulated anastomosis. This process is also
      enhanced by the quantity of suture material included in the anastomosis, and by
      the non-reabsorbable nature of the materials used in the anastomotic line.

PMID- 15180445
TI  - Fever, pain in righ hypochondrium and liver mass with central calcification.

PMID- 15180446
TI  - Diffuse cavernous hemangioma of the rectum: an atypical cause of rectal bleeding.
AB  - OBJECTIVE: cavernous hemangioma of the rectosigmoid colon is a rare disease, with
      no more than 200 cases reported in the literature. The rectosigmoid is the most
      common site of this disease in the gastrointestinal tract. CASE REPORT: we report
      the case of a 31-year-old male with recurrent episodes of rectal bleeding, who
      was finally diagnosed of diffuse cavernous hemangioma of the rectum. The tumor,
      of 12 x 10 x 9 cm in size, occupied the rectum to the margin of the anal
      sphincter. A surgical procedure was ruled out because of the inability to carry
      out a safe anastomosis while preserving anal sphincters. DISCUSSION: rectal
      hemangiomas are less frequent vascular malformations. The clinical presentation
      of a cavernous hemangioma of the rectum is usually acute, recurrent or chronic
      rectal bleeding. Other symptoms stem from the possible compression or invasion of
      adjacent structures, such as lumbar or perianal pain, metrorrhage, hematuria,
      etc. This diagnosis is commonly made in younger patients. Colonoscopy is without
      doubt the diagnostic technique of choice, and it allows to establish the
      localization, morphology, and total extension of the lesion; its characteristic
      image is a red-purplish nodule with great vascular congestion. According to the
      opinion of most authors, biopsy is not advisable during colonoscopy, since
      imaging techniques are sufficient for an accurate diagnosis, and the risk of
      bleeding while manipulating this lesion is not negligible. Computed tomography
      and particularly magnetic resonance imaging, given their high precision to
      delimit the lesion and its relations to adjacent structures, are imaging studies
      that are mandatory before surgical treatment. Other techniques such as selective
      angiography, barium enema, gastrointestinal transit, and upper-tract endoscopy
      may be supplementary and help locate more lesions along the gastrointestinal
      tract. Failure to recognize the exact diagnosis and extent of diffuse cavernous
      hemangioma may lead to failed surgical treatment and severe complications.
      Complete surgical excision of the lesion with a sphincter-saving procedure is the
      primary mode of treatment: conservative proctectomy with coloanal anastomosis.

PMID- 15180447
TI  - [Intestinal pseudoobstruction and severe lower gastroinstestinal haemorrhage due
      to amiloidosis].

PMID- 15180448
TI  - [Askin's tumor with sigmoid metastasis].

PMID- 15180449
TI  - Common and uncommon features of rheumatoid arthritis and chronic obstructive
      pulmonary disease: clues to a future therapy.
AB  - Over the last decade it has become apparent that common pathogenic mechanisms are
      shared between many human chronic inflammatory diseases of unrelated pathology
      and manifestation. These mechanisms include common inflammatory networks that
      control tissue destructive and repair processes and their study is of major
      therapeutic potential as recently demonstrated for TNFalpha. Thus, early studies
      in rheumatoid arthritis defined TNFalpha as a major therapeutic target, the
      blockade of which was subsequently proved to be of great efficacy in the clinic.
      This paved the way for the successful blockade of TNFalpha in various other
      diseases including Crohn's disease, psoriasis, spondyloarthropathies and juvenile
      arthritis, although no similar networks with anti-TNFalpha at their apex had
      previously been demonstrated. In this article, we review the current knowledge of
      the pathogenic mechanisms involved in rheumatoid arthritis and chronic
      obstructive pulmonary disease with particular emphasis on the role of
      inflammatory cytokines, chemokines, and tissue degrading enzymes as revealed by
      studies in the laboratory and the clinic. Direct comparison of these mechanisms
      may provide clues for a future therapy for these painful and incurable diseases.

PMID- 15180450
TI  - Hyperferritinaemia without iron overload: pathogenic and therapeutic
      implications.
AB  - It is not unusual to meet increased levels of ferritinaemia in patients
      apparently healthy. Among other causes of hyperferritinaemia, recently was
      described the Hereditary Hyperferritinemia Cataract Syndrome, a genetic condition
      characterized by increased serum ferritin values without iron overload and
      bilateral nuclear cataract, both of early onset. It has been demonstrated that
      single or double point mutations or deletions in the stem-loop structure of the
      iron regulatory element (I.R.E.) located in the 5 untranslated regions of the
      ferritin L-subunit gene (19q13.1) are responsible for the upregulation of
      ferritin. This overexpression only for the L-chain gives rise to typical piles in
      several tissues. When this altered ferritin accumulates in lens it causes
      bilateral nuclear cataracts, that is the peculiar sign of this syndrome. It is
      essential to differentiate true iron overload from Hereditary Hyperferritinaemia
      Cataract Syndrome (H.H.C.S.), because these patients rapidly develop iron
      deficient anaemia when venosectioned. Here we describe a case report about a 40
      years old healthy female blood donor who presented isolated hyperferritinaemia
      without iron overload, in the absence of concomitant pathologies. Anamnestic,
      biochemical, instrumental and clinical investigations led us to diagnose
      H.H.C.S., a pathology first described in 1995. From 1995 to date about 40 cases
      concerning patients showing the characteristics of this syndrome from Europe,
      USA, and Australia were described. Biochemical, genetical and clinical
      investigations led finally to understand every matter of this pathology,
      providing conclusive and exhaustive explanations.

PMID- 15180451
TI  - Regulators of G protein signaling: potential drug targets for controlling
      cardiovascular and immune function.
AB  - Heterotrimeric G-protein-coupled receptors (GPCRs) mediate a wide variety of
      organismal functions ranging from vision, olfaction, and gustation to the
      development and physiology of the cardiovascular, neuronal, and immune system.
      Naturally they are targets of a large number of therapeutic drugs. The regulators
      of G protein signaling (RGS) are a family of diverse proteins that regulate the
      GPCR-mediated signaling pathways principally by acting as GTPase activating
      proteins (GAPs) for the alpha subunit of the heterotrimeric G-proteins. Certain
      members of the RGS family contain multiple domains and motifs that mediate
      interactions with other signaling molecules, thus linking GPCR-dependent and GPCR
      independent signaling pathways. Because of their ability to fine-tune vital GPCR
      mediated processes and recent findings linking them to brain disorders, retinitis
      pigmentosa, and cancer RGS proteins have become excellent candidates for new drug
      discovery. The focus of this review is to discuss the roles of the RGS proteins
      in the development and normal physiology of cardiovascular and immune system, and
      to explore their potential as drug targets useful for the treatment of
      pathological conditions of the cardiovascular and immune systems.

PMID- 15180452
TI  - The pathobiology of osteoarthritis and the rationale for using the chondroitin
      sulfate for its treatment.
AB  - Structure-modifying osteoarthritis (OA) drugs are agents that reverse, retard, or
      stabilize the pathology of OA, thereby providing symptomatic relief in the long
      term treatment. The objective of this review is to evaluate the literature on
      chondroitin sulfate (CS) with respect to the pathobiology of OA to ascertain
      whether this agent should be classified as a symptomatic slow-acting drug
      (SYSADOA), a compound that has a slow onset of action and improve OA symptoms
      after a couple of weeks. CS exhibits a wide range of biological activities and
      from a pharmacological point of view it produces a slow but gradual decrease of
      the clinical symptoms of OA and these benefits last for a long period after the
      end of treatment. Many literature data show that CS could have an anti
      inflammatory activity and a chondroprotective action by modifying the structure
      of cartilage. These properties are also related to the oral adsorption of this
      molecule as high-molecular mass compounds having clusters of sulfate groups and
      high charge density capable of exert their chondroprotective activity in vivo.

PMID- 15180453
TI  - Therapeutic implications of immune-endocrine interactions in the critically ill
      patients.
AB  - The existence of an immune-endocrine interaction has been demonstrated decades
      ago. An immunomodulatory effect was reported for a wide range of hormones. The
      best known example for this interaction is the glucocorticoids released by the
      adrenal cortex. Apart of the glucocorticoids several hormones and
      neurotransmitters released by these systems are capable of altering immune
      functions. This includes the catecholamines epinephrine, norepinephrine and
      dopamine, the pituitary hormone prolactin, and the adrenal hormone
      dehydroepiandrosterone (DHEA). Several pathological states are paralleled by an
      activation of the endocrine system leading to an increased hormone release. In
      line with this an elevated release of catecholamines, of prolactin, and of DHEA
      has been demonstrated after major surgery, during systemic inflammation and
      following trauma hemorrhage. Furthermore, due to their pharmacologic properties
      several neurotransmitters are used as pharmaceutical agents to stabilize
      cardiovascular function or to prevent organ failure (e.g. epinephrine,
      norepinephrine, dopamine). Several pharmacological substances interact with the
      release of immunomodulatory hormones (e.g. metoclopramid and prolactin, dopamine
      and prolactin) and some hormones are available as over-the counter self
      medications like DHEA. Therefore, alterations of the serum concentrations of
      these hormones may affect the immunocompetence of the organism and may thereby
      affect the clinical course of critically ill patients. The clinical and
      pharmacological implications of this complex relationship between the endocrine
      and the immune system will be provided on the background of a review of the
      recent literature and of our research work.

PMID- 15180454
TI  - Treatment of inflammatory and paraproteinemic neuropathies.
AB  - Acquired demyelinating and inflammatory neuropathies encompass a number of acute
      and chronic autoimmune conditions characterized by variable degrees of clinical
      involvement. These disorders, including Guillain-Barre syndrome (GBS), chronic
      inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor
      neuropathy (MMN), and paraprotein-associated neuropathy, have an overall annual
      incidence of 2-4/100,000 worldwide and are potentially treatable. Over the last
      few years, several investigations have helped clarify the pathogenesis of immune
      neuropathies and the definition of molecular targets involved in these diseases,
      thus providing firmer grounds for treatment with classical immunosuppressive
      drugs and new biological agents. In GBS and related variants, which are
      characterized by cellular inflammation and alterations of the blood-nerve
      barrier, randomized clinical trials show that plasma exchange (PE) and
      intravenous immunoglobulin (IVIg) are equally effective as disease-modifying
      treatments, although IVIg has been adopted as the favourite treatment in most
      centres. In CIDP, controlled clinical trials have established the efficacy of
      oral prednisone, PE and IVIg, with intermittent IVIg treatment or corticosteroids
      being usually preferred. Adding azathioprine can help keep lower the required
      dose of prednisone, while other immunosuppressive agents, such as
      cyclophosphamide and cyclosporin A may have side effects, limiting their use to
      selected cases. Currently, the efficacy of interferon beta and alfa is under
      evaluation. Controlled trials support the view that IVIg is the treatment of
      choice in MMN. Patients resistant to IVIg administration may benefit of
      treatments which deplete B cells, such as cyclophosphamide and rituximab.
      Demyelinating neuropathies associated with circulating paraproteins are
      clinically heterogeneous, depending on the reactivity and type of the monoclonal
      (M) protein. In many cases, neuropathies associated with IgM M proteins are not
      treated because of their slow progression. In patients with a disabling or rapid
      progression, small trials have shown short-term benefits from IVIg or PE.
      Recently, fludarabine and rituximab have been reported as beneficial in selected
      cases.

PMID- 15180455
TI  - Flt3 ligand bioactivity and pharmacology in neoplasia.
AB  - Fms-like tyrosine kinase 3 ligand (Flt3L) has multiple effects on the
      hematopoietic and immune systems. Further, preclinical studies have suggested
      potential therapeutic activity against cancer. Flt3L is a potent hematopoietic
      cytokine, capable of stimulating the expansion and differentiation of
      hematopoietic progenitor and stem cells. Administration of Flt3L mobilizes
      hematopoietic cells from the bone marrow (BM) into the blood, lymphoid organs,
      and parenchymal tissues. This mobilization activity, especially effective in
      combination with granulocyte colony stimulating factor (G-CSF), has stimulated
      studies of Flt3L in hematopoietic stem cell (HSC) transplantation. In addition to
      its effects on hematopoietic stem and progenitor cells, Flt3L has been shown to
      increase the frequency and number of dendritic cells (DCs) within the circulatory
      system and solid organs. DC expansion by Flt3L has been the focus of preclinical
      and clinical studies on antigen (Ag) specific T-cell mediated immunity. The
      mechanism for the augmentation of T-cell mediated immunity has yet to be
      completely identified, although Flt3L's ability to expand DCs in lymphoid and non
      lymphoid tissues is involved. This expansion occurs primarily with DCs, which
      secrete interleukin (IL) 12. Consistent with the expansion of this DC population,
      treatment with Flt3L enhances T-cell mitogenesis and preferentially induces type
      1 T-cell responses. However, the DCs resulting from Flt3L administration are
      immature, leading in some studies to the induction of tolerance. This review
      focuses on the effects of Flt3L on DCs and other effector populations, and on its
      potential activity as a therapeutic agent for cancer, alone and in combination
      with vaccines.

PMID- 15180456
TI  - Activins, myostatin and related TGF-beta family members as novel therapeutic
      targets for endocrine, metabolic and immune disorders.
AB  - Activins and inhibins were first identified by virtue of their ability to
      regulate follicle-stimulating hormone (FSH) secretion from the anterior
      pituitary. Activins are also powerful regulators of gonadal functions. However,
      the physiological functions of activins are not restricted to reproductive
      tissues. Activins are involved in apoptosis of hepatocytes and B cells, fibrosis,
      inflammation and neurogenesis. Activins are regarded as novel drug targets since
      blocking activins would provide benefits by preventing apoptosis, fibrosis,
      inflammation and growth of several cancers. Activins are members of the
      transforming growth factor-beta (TGF-beta) family, which has numerous peptide
      growth and differentiation factors including activins, bone morphogenetic
      proteins (BMPs), growth and differentiation factors (GDFs) and TGF-betas. Among
      them, GDF8 is also known as myostatin and is structurally related to activins.
      Myostatin is specifically expressed in the skeletal muscle lineage and is a
      candidate for muscle chalone negatively regulating the growth of myoblasts.
      Myostatin is regarded as a good drug target since therapeutics that modulate
      skeletal muscle growth would be useful for disease conditions such as muscular
      dystrophy, sarcopenia, cachexia and even diabetes. Recent studies have revealed
      that activins and myostatin signal through activin type II receptors (ActRIIA and
      ActRIIB) and their activities are regulated by extracellular binding proteins,
      follistatins and follistatin-related gene (FLRG). Furthermore, signaling of
      activins, myostatin and related ligands is also controlled by intracellular
      receptor-interacting proteins by novel mechanisms. In this review, I would like
      to show the current progress in the field emphasizing the importance of activins
      and myostatin as novel drug targets for immune, endocrine and metabolic
      disorders.

PMID- 15180457
TI  - Vaccine therapy for hepatitis B virus carrier.
AB  - Despite the presence of an effective prophylactic vaccine since 1982, more than
      350 million people of the world are now chronically infected with hepatitis B
      virus (HBV). In one scenario, a considerable numbers of chronic HBV carrier would
      eventually develop serious complications like liver cirrhosis and hepatocellular
      carcinoma. In another, chronic HBV carriers would be permanent sources of HBV
      infection and transmit HBV to uninfected healthy individuals. Taken together,
      chronic HBV infection represents a major global public health problem, especially
      in the developing nations of the Asia and Africa, where most of the chronic HBV
      carriers reside. Unfortunately, there is no good curative therapy approach for
      these patients. The prospect of treatment of chronic HBV infection by antiviral
      agents like type-1 interferons and lamivudine is not satisfactory due to their
      low efficacy, considerable side effects and high costs. Vaccine therapy, an
      immune therapy, has recently shown considerable optimism for treating patients
      with chronic HBV infection. In this review, we will first describe the
      pathogenesis of chronic HBV carrier state to provide scientific and ethical
      rationales of vaccine therapy in chronic HBV carriers. Next, we will summarize
      the information that has been compiled from ongoing clinical trials of vaccine
      therapy in chronic HBV carrier. Finally, we will discuss the mechanism of action
      of vaccine therapy in patients with chronic HBV infection and HBV transgenic
      mice, a murine model of chronic HBV carrier state. This information will be
      valuable for developing next generation therapeutic vaccines for the management
      of chronic HBV infection.

PMID- 15180458
TI  - Two orthogonal approaches to overcome multi-drug resistant HIV-1s: development of
      protease inhibitors and entry inhibitors based on CXCR4 antagonists.
AB  - The development of novel drugs active against multi-drug resistant (MDR) HIV-1
      strains is urgently required. HIV protease inhibitors and reverse transcriptase
      inhibitors constitute two categories of important drugs, which have greatly
      improved the clinical treatment of HIV-infected patients by their cocktail use
      designated as highly active anti-retroviral therapy (HAART). By combinatorial
      chemistry involving substructure units contained in known HIV protease
      inhibitors, we found effective protease inhibitors, TYA5 and TYB5, which showed
      potent anti-HIV activity even against MDR strains. Selection of drug-resistant
      viruses is also decreased when these new agents are tested in vitro.
      Subsequently, introduction of an (E)-alkene dipeptide isostere into TYB5 led to
      the development of a pure non-peptide protease inhibitor, TYB1. We have also
      studied the development of effective inhibitors for blocking HIV-entry into host
      cells based on recent discovery of an HIV entry mechanism involving the viral
      usage of chemokine receptors as coreceptors, CXCR4 and CCR5. We developed highly
      selective CXCR4 antagonists, T22 and T140 (18-mer and 14-mer peptides,
      respectively), which strongly suppress T-cell line-tropic HIV-1 (X4-HIV-1) entry
      through their specific binding to CXCR4. Recently, molecular-size reduction of
      T140 yielded low molecular weight CXCR4 antagonists, which might be more useful
      leads to drug-like structures. In this review, we discuss the development of two
      types of anti-HIV agents, protease inhibitors and CXCR4 antagonists, which would
      improve clinical AIDS chemotherapy.

PMID- 15180459
TI  - Antiviral properties of quinolone-based drugs.
AB  - Quinolones represent an important class of broad-spectrum antibacterials, the
      main structural features of which are a 1,4 dihydro-4-oxo-quinolinyl moiety
      bearing an essential carboxyl group at position 3. Quinolones inhibit prokaryotic
      type II topoisomerases, namely DNA gyrase and, in a few cases, topoisomerase IV,
      through direct binding to the bacterial chromosome. Based on the hypothesis that
      these drugs could also bind to the viral nucleic acids or nucleoprotein
      complexes, several quinolone derivatives were tested for their antiviral
      activity. Indeed, antibacterial fluoroquinolones were shown to be effective
      against vaccinia virus and papovaviruses; these preliminary results prompted the
      synthesis of modified quinolones to optimize antiviral action and improve
      selectivity index. The introduction of an aryl group at the piperazine moiety of
      the fluoroquinolone shifted the activity from antibacterial to antiviral, with a
      specific action against HIV. The antiviral activity seemed to be related to an
      inhibitory effect at the transcriptional level, and further evidence suggested a
      mechanism of action mediated by inhibition of Tat functions. Substitution of the
      fluorine at position 6 with an amine group to give aryl-piperazinyl-6-amino
      quinolones improved the activity and selectivity against HIV-1: the most potent
      compound of this series was shown to inhibit virus replication through
      interference with Tat-TAR interaction. A comprehensive SAR investigation was
      performed based on additional chemical intervention to the quinolone template
      moiety, such as the introduction of nucleoside derivative functions. The
      information gained so far will be useful for future rational drug design aimed at
      developing new compounds with optimized antiviral activity.

PMID- 15180460
TI  - Candida and candidiasis: the cell wall as a potential molecular target for
      antifungal therapy.
AB  - The fungal species Candida albicans is an opportunistic pathogen, which causes
      serious infections in humans, particularly in immunocompromised patients.
      Depending on the underlying host defect, C. albicans causes a variety of
      infections, ranging from superficial mucocutaneous candidiasis to life
      threatening disseminated infections. Both the limited spectrum of antifungal
      drugs currently in clinical use and the emergence of resistances make necessary
      the development of new effective antifungal drugs with minimal side effects;
      however, such a research is limited by the small number of specific target sites
      identified to date. The cell wall is a fungal specific dynamic structure
      essential to almost every aspect of the biology and pathogenicity of C. albicans.
      Its structure confers physical protection and shape to fungal cells, and as the
      most external part of the fungus, the cell wall mediates the interaction with the
      host, including adhesion to host tissues and modulation of the host anti-Candida
      immune response. Consequently, the fungal cell wall can be considered as a
      suitable target for development of new antifungal compounds. Therefore two
      distinct types of potential cell wall-related targets can be envisaged, according
      to their mode of action in inhibiting infection: (i) inhibition of cell wall
      biogenesis, which may impair cell wall integrity and thus cell viability, and
      (ii) modification of host-fungus interactions by inhibiting or blocking putative
      virulence factors, which may impair host colonization and progress of the
      infectious process. Antibodies specific to cell wall antigens may protect against
      infection by a variety of mechanisms and may evolve into save antifungal agents.

PMID- 15180461
TI  - Determining and overcoming resistance to HIV protease inhibitors.
AB  - HIV protease represents a major target for development of antiviral therapeutics.
      The introduction of HIV protease (PR) inhibitors (PIs) to clinical practice and
      the application of highly active antiretroviral therapy resulted in decreased
      mortality and prolonged life expectancy of HIV-positive patients. However, the
      high polymorphism of HIV leads to rapid selection of viral variants resistant
      towards the inhibitors. Such resistant PR variants have developed in HIV-positive
      patients after treatment with any of the eight PIs approved for clinical use. In
      this review we overview (i) the methods for the identification and assessment of
      viral resistance in HIV positive patients, and (ii) the approaches medicinal
      chemists take to overcome it. Rational antiviral therapy brings about the need
      for quantitative assessment of the level of drug resistance development in the
      course of the treatment. At present, two main approaches are taken: in genotypic
      assays the viral sequences are PCR amplified, sequenced and changes in the viral
      gene sequence known to be associated with reduced drug sensitivity are
      identified, while phenotypic assays test the ability of a virus to grow in the
      presence of a drug or combination of drugs. The advantages and drawbacks of these
      methods, as well as their relevance for the therapy are discussed. We also review
      the efforts to design second-generation PIs, capable of potently inhibiting multi
      resistant HIV-1 PR species, using structure-assisted design of the compounds
      targeted to the active site, as well as alternative approaches with compounds
      binding to other domains of the PR molecule.

PMID- 15180462
TI  - Aminoglycoside nephrotoxicity.
AB  - The main constraints to the administration of aminoglycosides (AG) are risks of
      nephrotoxicity and ototoxicity, which can lead to renal and vestibular failure.
      AG accumulation in the kidney may be related to the dosing schedule. As a result,
      administration of larger doses on a less frequent basis may reduce the drug
      accumulation in the renal cortex. Many methods have been proposed to reduce AG
      nephrotoxicity. (1) Molecular modeling and analog synthesis could lead to
      intrinsically less toxic AG but this approach is time consuming and expensive.
      Protective approaches such as the co-administration of polyaspartic acid or
      defferoxamine appear to be very promising in clinical practice. (2) Population
      pharmacokinetic computer programs, used to control AG serum concentrations, are
      correct predictors of efficacy but the estimated concentrations in the second
      compartment are not reliable predictors of nephrotoxicity because they do not
      take into account non-linear processes such as the AG uptake in the renal cortex
      or the tubuloglomerular feedback. (3) Finally, modelling the AG nephrotoxicity
      with probabilistic approaches and/or with deterministic approaches seems to be
      very promising. These two approaches appear to be not competitive but very
      complementary in clinical practice. The probabilistic model can be used to
      predict nephrotoxicity at the beginning the treatment. The deterministic model
      can be used to simulate and control nephrotoxicity when it is already unfolding
      and the treatment must be given for a long period of time.

PMID- 15180463
TI  - Novel tissue and cell type-specific gene/drug delivery system using surface
      engineered hepatitis B virus nano-particles.
AB  - The hepatitis B virus (HBV) surface antigen (HBsAg) L particle is a hollow nano
      scale particle. HBsAg L particles have many properties that make them useful for
      in vivo gene transfer vectors and drug delivery systems. Gene therapy so far has
      required the in vivo pinpoint delivery of genetic materials into the target
      organs and cells. Gene transfer by HBsAg L particles might be an attractive
      method, since their tropism is the same as that of HBV. The HBsAg L particles are
      able to deliver therapeutic payloads with high specificity to human hepatocytes.
      In addition, the specificity of L particle can be altered by displaying various
      cell-binding molecules on the surface. Our results indicate that the L particle
      is suitable for a cell- and tissue-specific gene/drug transfer vector. In this
      review, we discuss HBsAg L particles as a gene/drug transfer vector and its
      potential for the treatment of infectious diseases.

PMID- 15180464
TI  - Epidemiology of psoriasis.
AB  - The prevalence of psoriasis is relatively high in the general population, ranging
      between 0.6% and 4.8%, mainly as a result of chronicity and the absence of a
      cure. Although genetic-environmental interaction has been proposed as a model for
      the causation of psoriasis, the evidence for environmental factors is rather
      scarce. Risk factors, which have been documented in epidemiological studies
      include smoking, alcohol consumption, diet, infection, drugs, and stressful life
      events. Psoriasis affects the quality of life to substantial degree. Apart from a
      few cross-sectional surveys of large series of psoriatic patients, there have
      been no formal studies of the natural history and prognosis of established
      psoriasis. By imposing methodologic control and a numerate approach, epidemiology
      can offer a major contribution to understand psoriasis.

PMID- 15180465
TI  - The psoriasis genetics as a model of complex disease.
AB  - Psoriasis [OMIM*177900] is a common, chronic and papulosquamous inflammatory skin
      disease affecting approximately 2% of Caucasian. However, this disorder is rare
      among Japanese, Eskimos, West Africans and North American blacks and very
      uncommon in North American and South American natives. The causes for these
      variations are likely to be both genetic and environmental. Population-based
      studies and twin studies indicate that psoriasis is a heritable disease with a
      polygenic mode of inheritance with variable penetrance. Independent genome-wide
      scans have suggested the involvement of a large number of chromosomal regions
      (loci), and many candidate genes have been proposed. We discuss genetic
      approaches to the disease, results and interpretations of relevant studies, as
      well as future perspectives. Understanding the genetic basis of psoriasis will
      represent a major advance in our understanding of the disease and will reveal
      novel disease-specific biologic pathways.

PMID- 15180466
TI  - Immunopathogenesis of psoriasis.
AB  - Psoriasis is characterized by sustained T cell activation by antigen-presenting
      cells (APCs) in the lesions, and by a deviation of T cell differentiation to type
      1 helper T and type 1 cytotoxic T cells, although no specific antigens have yet
      been determined. These characteristics are at least promoted by decreased IL-10
      expression and the increased IL-12 expression observed in both the skin and
      stimulated peripheral blood mononuclear cells of psoriatic patients. Some of the
      cytokines produced by activated T cells are suspected to stimulate the
      proliferation of psoriatic keratinocytes. Among them, interferon-gamma is the
      most likely candidate, although interferon-gamma does not promote the growth of
      normal keratinocytes. In addition to the abnormal proliferation, psoriatic
      keratinocytes show abnormal differentiation and resistance to apoptosis. So far,
      however, it is still unknown whether these phenotypic and functional
      characteristics of psoriatic keratinocytes are only the consequences of the
      stimulation by activated T cells or are at least based on an inherent
      susceptibility. Recently, it has become clear that chemokines derived from
      activated keratinocytes or endothelial cells play a crucial role in recruiting T
      cells in the skin and inducing the neutrophilic infiltration that leads to the
      formation of subcorneal pustules (Munro's microabscess). Finally, recent
      developments in the detection and analysis of gene expression have revealed the
      molecules responsible for these steps. Some of them have become target molecules
      for the treatment of psoriasis. And indeed, it has become possible now to treat
      patients with new, innovative drugs.

PMID- 15180467
TI  - Established treatments of psoriasis.
AB  - Psoriasis is a complex disease with a spectrum of clinical manifestations.
      Psoriasis may express as a few coin-sized erythemato-squamous plaques up to
      widespread disease covering the entire body surface (erythrodermic psoriasis).
      Psoriasis may present as a few stable plaques or unstable disease, rapidly
      relapsing after treatment. Some patients may respond excellently to topical
      treatments whereas other patients may be difficult to manage, showing treatment
      resistance even to the systemic treatments. Therefore, a spectrum of treatments
      is available to individualize care of psoriasis. In this chapter the available
      treatments are presented. The vast majority of patients is treated with topical
      treatments, with vitamin D(3)analogs and topical corticosteroids as the first
      line treatments. Tazarotene is an alternative for vitamin D(3) treatment if this
      treatment fails. In some special cases, dithranol and tar treatment may be used.
      Phototherapy with UVB and photochemotherapy (PUVA) are indicated in patients not
      responding sufficiently to topical treatment. However, chronic exposure, in
      particular to photochemotherapy implies an increased risk for photo-
      carcinogenicity. Systemic treatments including methotrexate, cyclosporin,
      acitretin and fumarates are indicated in patients who cannot be managed with
      topical treatments or phototherapy, either for treatment resistance or cumulative
      toxicity. In this article the opportunities and limitations of the available
      treatments are presented.

PMID- 15180468
TI  - T-cell-targeted biologicals for psoriasis.
AB  - Psoriasis is now accepted as a T-cell-mediated disease and that targeting of T
      cell function and/or trafficking is a logical approach to therapy. As a
      consequence of recombinant DNA technologies biologic therapies are synthesisable
      in sufficient quantities for clinical use. The original proof of concept for T
      cell-targeted therapies in psoriasis came with the demonstration that anti-CD4
      monoclonal antibodies were effective. Progress is such that two T-cell-directed
      biologicals - alefacept and efalizumab - have recently been approved in the
      U.S.A. for the treatment of psoriasis. In addition to providing new therapies the
      T-cell-targeted biologicals with their selective approach can be used as
      sophisticated tools to dissect out and help our understanding of key
      pathomechanisms in psoriasis; the non - efficacy of anti - E-selectin is a case
      in point. It is likely that the most appropriate place for T-cell-directed
      biologicals in the management of chronic plaque psoriasis will be for
      maintenance, rather than induction, of remission. This is a reflection of mode of
      action and relative safety for long-term administration.

PMID- 15180469
TI  - Targeting selectin functions in the therapy of psoriasis.
AB  - As leukocytes play a primary role in the immunopathogenesis of psoriasis, it is a
      reasonable assumption that preventing those cells from localizing to the sites of
      cutaneous inflammation can stop the disease process. Selectins, a family of three
      single-chain transmembrane adhesion molecules, which bind to carbohydrate
      moieties displayed on other cells, are pivotally involved in the initial steps of
      leukocyte recruitment, i.e. tethering and rolling along the endothelial lining of
      blood vessels. Thus, compounds impairing selectin functions have been developed
      to treat inflammatory disorders, such as psoriasis. Potential strategies to
      interfere with selectin functions include direct inhibition through monoclonal
      antibodies or small-molecule compounds, transcriptional regulation of selectin
      expression, and modulation of the post-transcriptional glycosylation of selectin
      ligands. More than a dozen different compounds targeting selectin functions are
      currently under development, several of which have shown promising effects on
      leukocyte recruitment and the therapy of inflammatory conditions under
      experimental conditions. However, based on preclinical and early clinical
      investigations, it appears that in some cases specifically targeting the function
      of single selectins may not be sufficient to effectively interrupt the
      inflammatory cascade. This is, at least in part, due to considerable redundancies
      and overlaps in the functions of the selectins, a notion that is corroborated by
      the apparently more pronounced therapeutic efficacy of some compounds with
      broader activity against several selectins. Overall, while targeting selectin
      functions promises rather selective and pathogenesis-based therapeutic approaches
      against psoriasis, the clinical value of such strategies, alone or in combination
      with other therapies, remains to be seen.

PMID- 15180470
TI  - Chemokines and chemokine receptors as targets in the therapy of psoriasis.
AB  - Chemokines are members of a superfamily of small, cytokine-like, chemotactic
      proteins that have recently been shown to critically regulate leukocyte
      trafficking. Accumulating evidence indicates that the chronically relapsing
      inflammatory skin disease psoriasis represents a T cell-mediated disease. Thus,
      the understanding of the underlying mechanisms of memory T cell homing to the
      skin may provide promising targets for the development of novel therapeutics.
      Here results of recent studies associating chemokines with a psoriatic phenotype
      and delineating their role in the recruitment of memory T cells to the skin are
      discussed.

PMID- 15180471
TI  - Targeting tumor necrosis factor-alpha in the therapy of psoriasis.
AB  - Tumor necrosis factor-alpha (TNF-alpha) plays a fundamental role in the
      initiation and persistence of skin inflammation in psoriasis. The best evidence
      of the essential activity of this cytokine in the pathogenesis of psoriasis came
      from the observation that selective TNF-alpha blockers are dramatically effective
      in the therapy of this disease. The TNF-alpha inhibitors, infliximab and
      etanercept, have been employed with success in moderate to severe psoriasis and
      in psoriatic arthritis in randomized controlled trials. Anti-TNF-alpha
      biologicals induce rapid disease resolution and long-lasting remission,
      suggesting that they may alter the natural course of the disease. Further studies
      are warranted to more precisely establish the biological bases of the action of
      anti-TNF-alpha agents, better define which subgroup of patients can benefit most
      from this treatment, and the modalities of combination therapy with other
      antipsoriatic agents. Many other TNF-alpha inhibitors have been developed but
      none of them has been yet used in the therapy of psoriasis. Major limitations to
      the use of selective TNF-alpha blockers include the reactivation of latent
      tuberculosis, the risk of opportunistic infections, the development of specific
      antibodies, which is associated with a reduced duration of response to treatment,
      and the high cost.

PMID- 15180472
TI  - Interleukin-10: an important immunoregulatory cytokine with major impact on
      psoriasis.
AB  - Interleukin (IL)-10 is a pluripotent cytokine with effects on numerous cell
      populations, in particular circulating and resident immune cells as well as
      epithelial cells. With its potent immunoregulatory capacities its main biological
      function seems to be the limitation and termination of inflammatory responses.
      Thus its low level expression found in psoriasis may have pathophysiological
      relevance for this immune disease. Remarkably, induction of IL-10 expression was
      found by conventional antipsoriatic therapies, supporting the hypothesis that IL
      10 may be a key cytokine in psoriasis and that application of this cytokine
      itself may have therapeutic effects. In first clinical trials in patients with
      established psoriasis IL-10 showed moderate antipsoriatic effects and was well
      tolerated. Moreover, long term application in psoriatic patients remission showed
      that IL-10 therapy decreases the incidence of relapse and prolongs the disease
      free interval. The immunological effects observed during these clinical studies
      together with in vitro observations suggests that IL-10 exerts its antipsoriatic
      activity by effects on different cell populations including antigen presenting
      cells and T-cells (lasting type 1/ type 2 cytokine balance shift), but not
      through direct effects on keratinocytes. In conclusion IL-10 seems to have major
      importance in psoriasis. Further investigations, in particular multicenter,
      placebo-controlled, double blind trials are required to fully determine whether
      IL-10 application will become a successful antipsoriatic therapy.

PMID- 15180473
TI  - Immune deviation strategies in the therapy of psoriasis.
AB  - The experience with biologicals in currently available animal models suggest that
      inflammatory autoimmune disease depend on IFN-gamma-producing T helper (Th)
      cells. Deletion of T cells improves most of these autoimmune diseases but bears
      the risks of general immunosuppression. Alternatively, selective deviation of the
      inflammatory, disease-inducing Th cells into an anti-inflammatory Th cell
      phenotype may be a promising strategy to treat inflammatory autoimmune diseases,
      such as psoriasis, rheumatoid arthritis, multiple sclerosis or autoimmune
      diabetes. The common feature of these organ-specific autoimmune diseases is the
      close association with IFN-gamma-producing Th1 cells, which recognize organ
      specific antigens and orchestrate the cells and mediators that ultimately cause
      the tissue damage. Even though the autoantigens recognized in psoriasis remain
      enigmatic, it has been the first Th1-mediated autoimmune disease successfully
      treated in humans by immune deviation. The basis of such an immune intervention
      therapy has been established in experimental mice with model diseases of multiple
      sclerosis, rheumatoid arthritis or autoimmune diabetes. In all these autoimmune
      diseases clinical improvement was associated with the skewing of IFN-gamma
      producing autoantigen-specific Th1 cells into an IL-4 dominated Th2 phenotype.
      Such Th2 cells are still reactive to the autoantigen but provide a different
      cytokine pattern. The most powerful cytokines capable of inducing anti
      inflammatory Th2 cells are IL-4 itself or IL-11. Interestingly, another agent
      that has been used for decades in the therapy of psoriasis in some European
      countries, fumaric acid esters (FAE), seems also to induce immune deviation. This
      review focuses on the potential immune deviating strategies based on the use of
      IL-4, IL-11 or FAE in the therapy of psoriasis, the effects of these agents on
      the immune system, potential risks and future perspectives for therapeutic
      intervention by immune deviation replacing immunosuppression.

PMID- 15180474
TI  - New vitamin D analogs in psoriasis.
AB  - Psoriasis is a common inflammatory and hyperproleferative skin disease
      characterized by infiltrated plaques of the skin and may involve nails, scalp and
      intertreginous areas. Recent years of research has shown that psoriasis can be
      treated topically with analogs of vitamin-D(3). Impaired differentiation and
      increased proliferation of epidermal keratinocytes are key features in psoriatic
      lesions together with a local activation of T lymphocytes. Evidence has
      accumulated that analogs of vitamin D(3) increase differentiation and inhibit
      proliferation of keratinocytes. Topical treatment with analogs of vitamin D(3)
      have in a number of trials shown improvement of psoriasis. Vitamin D analogs show
      the same efficacy as potent topical corticosteroids and do not produce skin
      atrophy during long-term therapy. Vitamin D analogs can be used both as
      monotherapy and in combination with topical corticosteroids, UVB, PUVA,
      acitretin, methotrexate and cyclosporine. The vitamin D(3) analog calcipotriol
      has been investigated in most detail and is available as an ointment, a cream and
      as a scalp solution. From clinical studies involving several thousands of
      patients, it can be concluded that calcipotriol is efficacious, safe and well
      tolerated even on a long term basis.

PMID- 15180475
TI  - Peroxisome proliferator-activated receptors as new molecular targets in
      psoriasis.
AB  - While psoriasis is upon the age of biological treatments, additional researches
      have led to other new therapies for psoriasis, including targets aimed at nuclear
      receptors. PPARs are members of the nuclear-hormone-receptor superfamily,
      including retinoid receptors and vitamin D receptors. Recent works have
      highlighted the role of PPARs, which transduce a wide variety of signals into a
      set of cellular responses at the level of gene transcription, as critical
      regulators of cutaneous homeostasis in regulating differentiation, proliferation,
      and inflammatory responses of the skin. PPAR agonists or antagonists may
      therefore, hold promise as interesting compounds for the treatment of various
      epidermal disorders characterized by inflammation, hyperproliferation and
      aberrant differentiation, such as psoriasis.

PMID- 15180476
TI  - Histone deacetylase inhibitors in psoriasis therapy.
AB  - Psoriasis is recognised as a multifactorial disease with inflammatory,
      proliferative, angiogenic and genetic components contributing to the pathology.
      The disease, which may vary in intensity, remains clinically unmet although there
      have been several recent advances that have had a substantial impact on
      suffering. Histone deacetylase inhibitors represent a new class of therapeutic
      agent, initially developed for oncology, which prevent cell proliferation and
      induce differentiation. Here we discuss the possible application of HDAC
      inhibitors to psoriasis, focussing particularly on their anti-proliferative and
      anti-inflammatory activity. Our view, based upon the emerging clinical properties
      of HDAC inhibitors, reflects the growing recognition that HDAC inhibitors will be
      important therapeutic agents in diseases other than cancer.

PMID- 15180477
TI  - Small conductance Ca2+-activated K+ channels as targets of CNS drug development.
AB  - In most central neurons, small conductance Ca(2+)-activated K(+) channels (SK
      channels) contribute to afterhyperpolarizations (AHPs), which control neuronal
      excitability. The medium AHP has pharmacological properties similar to
      recombinant SK channels, consistent with the hypothesis that SK channels generate
      this afterhyperpolarization component. It is still unclear how recombinant SK
      channels are functionally related to the slow AHP component. Cloned SK channels
      are heteromeric complexes of SK channel subunits and calmodulin. The channels are
      activated by Ca(2+) binding to calmodulin that induces conformational changes
      resulting in channel opening. Channel deactivation is the reverse process brought
      about by dissociation of Ca(2+) from calmodulin. In the mammalian brain, the
      three SK channel subunits (SK1-3) display partially overlapping distributions.
      Most of the higher brain regions such as the neocortex and hippocampus show
      expression of both genes encoding SK1 and SK2 channels, whereas phylogenetically
      older brain regions such as the thalamus, basal ganglia, cerebellum, and
      brainstem show high levels of SK3 gene expression. At present, it is still
      unclear whether native SK channels are generated as heteromeric or homomeric
      channels. Peptide toxins such as apamin and scyllatoxin, as well as organic
      compounds such as quaternary salts of bicuculline, dequalinium, UCL 1684 and UCL
      1848 serve as non-specific SK channel blockers. The only known exceptions so far
      are the scorpion toxin tamapin and the peptide inhibitor Lei-Dab(7), which bind
      preferentially to SK2. Electrophysiological and behavioral studies indicate that
      blockade of SK channels by apamin increases excitability, lowers the threshold
      for the induction of synaptic plasticity, and facilitates hippocampus-dependent
      memory. The potential value of pharmacological SK channel modulation in various
      pathological states such as increased epileptiform activity, cognitive
      impairment, pain, mood disorders and schizophrenia will be discussed.

PMID- 15180478
TI  - The NR2B subtype of NMDA receptor: a potential target for the treatment of
      alcohol dependence.
AB  - Ethanol is a small molecule acting on several neurotransmitter systems in the
      brain. Accumulating evidences suggest that the primary excitatory--i.e. the
      glutamatergic--neurotransmitter system is a particularly important site of
      ethanol's action. Several studies showed that ethanol is a potent and selective
      inhibitor of the N-methyl-D-aspartate (NMDA) receptors and prolonged ethanol
      exposition leads to a compensatory "up-regulation" of these receptors resulting
      in enhanced NMDA receptor-mediated functions after removal of ethanol. These
      alterations are supposed to contribute to the development of ethanol tolerance,
      dependence as well as the acute and delayed signs of ethanol withdrawal. In
      recent papers, alterations in subunit composition of NMDA receptors were reported
      after long term ethanol exposure. mRNA and/or protein levels of NR2A and NR2B
      types of subunits were found elevated both by in vivo and in vitro experiments.
      Our results showed that especially the NR2B subunit expression is increased in
      cultured hippocampal and cortical neurones after 3 days of intermittent ethanol
      treatment. According to the high calcium permeability, the increased agonist
      sensitivity and the relatively slow closing kinetics of NMDA ion channels
      composed of NR2B subunits, the above mentioned changes may underlie the enhanced
      NMDA receptor activation observed after long term ethanol exposure. Accordingly,
      we have tested NR2B subunit selective NMDA receptor antagonists in primary
      cultures of rat cortical neurones pre-treated with ethanol intermittently for 3
      days and found that these compounds potently inhibited the neurotoxic effect of
      ethanol withdrawal. Hypothesising the involvement of enhanced NR2B subunit
      expression in development of alcohol dependence and withdrawal symptoms and
      considering the tolerable side effect profile of the NR2B subunit selective NMDA
      receptor antagonists, the NR2B type of NMDA receptor subunit may serve as a
      possible drug target in pharmacological interventions for alcoholism. The aim of
      this review is to give an update on the role of altered structure and function of
      NMDA receptors after ethanol exposure and to summarise the recent data about the
      activity of NR2B subunit selective NMDA receptor antagonists in model systems
      related to alcoholism.

PMID- 15180480
TI  - Methods for providing therapeutic agents to treat damaged spiral ganglion
      neurons.
AB  - Sensorineural hearing loss, characterized by damage to sensory hair cells and/or
      associated nerve fibers is a leading cause of hearing disorders throughout the
      world. To date, treatment options are limited and there is no cure for damaged
      inner ear cells. Because the inner ear is a tiny organ housed in bone deep within
      the skull, access to the inner ear is limited, making delivery of therapeutic
      agents difficult. In recent years scientists have investigated a number of growth
      factors that have the potential to regulate survival or recovery of auditory
      neurons. Coinciding with the focus on molecules that may restore function are
      efforts to develop novel delivery methods. Researchers have been investigating
      the use of mini osmotic pumps, viral vectors and stem cells as a means of
      providing direct application of growth factors to the inner ear. This review
      summarizes recent findings regarding the molecules that may be useful for
      restoring damaged spiral ganglion neurons, as well as the advantages and
      disadvantages of various delivery systems.

PMID- 15180479
TI  - AMPA receptor potentiators for the treatment of CNS disorders.
AB  - Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)
      receptors mediate most of the excitatory neurotransmission in the mammalian
      central nervous system and also participate in forms of synaptic plasticity
      thought to underlie memory and learning, and the formation of neural networks
      during development. Molecular cloning techniques have shown that the AMPA
      receptor family is composed of four different subunits named GluR1-4 or GluRA-D
      (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely
      tetramers generated by the assembly of one or more of these subunits, yielding
      homomeric or heteromeric receptors. Additional complexity among AMPA receptors is
      conferred by alternative splicing of RNA for each subunit giving rise to flip and
      flop variants. Clinical and experimental data have suggested that positive
      modulation of AMPA receptors may be therapeutically effective in the treatment of
      cognitive deficits. Several classes of AMPA receptor potentiators have been
      reported, including pyrroliddones (piracetam, aniracetam), benzothiazides
      (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently
      biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules
      enhance cognitive function in rodents, which appears to correlate with increased
      hippocampal activity. In addition, clinical studies have suggested that AMPA
      receptor modulators enhance cognitive function in elderly subjects, as well as
      patients suffering from neurological and psychiatric disorders. Several
      independent studies have suggested that AMPA receptors can increase BDNF
      expression by both calcium-dependent and independent pathways. For example,
      recent studies have shown that AMPA receptors interact with the protein tyrosine
      kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase
      (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in
      addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor
      activation can increase the expression of BDNF in vitro and in vivo. This may
      account for activity of AMPA receptor potentiators in rodent models predictive of
      antidepressant activity (forced swim and tail suspension tests). The increase in
      neurotrophin expression also may contribute to the functional, neuroprotective
      and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into
      the substantia nigra. In conclusion, several potent, selective and systemically
      active AMPA receptor potentiators have been reported. Data indicate that these
      molecules modulate glutamatergic transmission, enhance synaptic transmission,
      long-term potentiation (LTP) and increase neurotrophin expression. Therefore,
      these AMPA receptor potentiators offer an exciting new class of drugs with
      potential for treating (1) cognitive impairment associated with Alzheimer's
      disease and schizophrenia, (2) depression, (3) slowing the progression and
      potentially enhancing recovery from Parkinson's disease.

PMID- 15180481
TI  - The mechanism of action of antidepressants: a unitary hypothesis based on
      transport-p.
AB  - Endogenous depression is a common mental illness which is associated with
      significant morbidity and mortality. Tricyclic antidepressants and their newer
      derivatives are the main treatment for this disease. However, there are serious
      deficiencies in the use of existing antidepressants for the treatment of
      depressive illness. An obstacle in the development of better antidepressants is
      that the mechanism of the therapeutic action of these compounds is unknown. The
      prevailing view is that antidepressants exert their therapeutic effect by
      inhibiting the pre-synaptic re-uptake of the neurotransmitter amines,
      noradrenaline and serotonin. However, there are objections to this hypothesis.
      Transport-P is a new factor in this field; it is an antidepressant-sensitive,
      proton-dependent, V-ATPase linked uptake process for amines in peptidergic
      neurones. It differs from other uptake processes in its anatomical location in
      post-synaptic (peptidergic) neurones, in its functional properties and in the
      structure of its ligands. Therapeutic concentrations of antidepressants are
      active at Transport-P. This review describes a hypothesis which postulates that
      antidepressants exert a therapeutic effect by an action on Transport-P [1].
      According to this hypothesis, Transport-P accumulates antidepressants in
      acidified vesicles in post-synaptic neurones. The normal function of the vesicles
      is to degrade internalised post-synaptic receptors. As their amine groups are
      basic, the antidepressants tend to neutralise the acidity of the vesicles. This
      slows the rate of degradation of post-synaptic receptors, and makes post-synaptic
      neurones more responsive to the excitatory actions of neurotransmitter amines.
      This hypothesis resolves the problems with the pre-synaptic re-uptake hypothesis
      and offers a unitary explanation for hitherto inexplicable observations. If the
      hypothesis is correct, compounds which act as potent and selective ligands for
      Transport-P would have a more rapid onset of action and would represent an
      advance in the treatment of depressive illness. The data on Transport-P which are
      described in this article are derived entirely from the work of the author who is
      not aware of any other research groups working on Transport-P. Therefore, the
      amount of work which has been done so far is relatively limited. The evidence on
      which the hypothesis is based is derived from work on alpha(1) adrenoceptors in
      hypothalamic, peptidergic neurones. There are large gaps in the evidence which
      would be required to support a mechanistic hypothesis: for example, the
      serotonergic system, which is likely to be involved in depressive illness, has
      not been investigated. Further, no attempt has been made so far to address the
      applicability of the phenomena which were observed in the hypothalamus to other
      brain regions which may be involved in depressive illness. Nevertheless, the
      hypothesis, as it stands at present, appears to solve problems which have been
      inexplicable on the basis of the pre-synaptic re-uptake hypothesis. More work is
      required to determine the validity of the solutions which are proposed in this
      review.

PMID- 15180482
TI  - Antipsychotic drugs: evolving mechanisms of action with improved therapeutic
      benefits.
AB  - One of the conundrums of neuropharmacology is to understand the therapeutic
      mechanisms of action of antipsychotic drugs. Every drug with antipsychotic
      activity is a dopamine (DA) D(2)-like receptor antagonist and therefore this
      function is critical to reducing psychotic symptoms. However, the actions of the
      archetypal atypical antipsychotic drug clozapine go beyond antipsychotic effects
      because the drug is efficacious in treating psychotic symptoms that do not
      respond to drugs mainly directed at antagonizing the DA D(2) receptor, has
      benefits in cognition and has recently been shown to reduce levels of suicide. A
      growing understanding of the mechanisms of clozapine and other atypical
      antipsychotic drugs suggests that both partial and inverse agonism, as well as
      receptor antagonism, at specific neurotransmitter receptors is required to give
      full therapeutic benefits. It is, therefore, timely to review the evolving nature
      of the mechanisms of action of different antipsychotic drugs.

PMID- 15180483
TI  - Programmed axon death, synaptic dysfunction and the ubiquitin proteasome system.
AB  - Axons are essential, vulnerable and often irreplaceable so it is essential to
      understand how they are lost in neurodegenerative disease. Recent data link the
      mechanism of injury-induced Wallerian degeneration to that of axon death in CNS
      and PNS disease. The neuroprotective gene Wld(S) delays Wallerian degeneration,
      CNS axonal dystrophy, 'dying-back' pathology and to a lesser extent synapse loss,
      despite the different causes and morphologies of degeneration. These findings
      validate Wallerian degeneration as a model to understand and prevent mechanisms
      of axon and synapse loss in neurodegenerative disorders. The existence of a gene
      that alters Wallerian degeneration suggests it is a regulated program of axon
      death normally held back by axonal inhibitors, similar in principle to apoptosis.
      The Wld(S) protein and proteasome inhibitor experiments implicate the ubiquitin
      proteasome system (UPS) in Wallerian degeneration. However, the site of UPS
      involvement and the molecular events remain unclear because the UPS is highly
      compartmentalized in neurons, affecting complex and sometimes conflicting
      processes in nuclei, axons, growth cones and synapses. Proteasome inhibitors are
      blunt tools for studying such a complex system and they are also particularly
      toxic to axons and alter synapse function. In contrast, Wld(S) acts on a specific
      step, leaving mice healthy with normal development and behavior. This also makes
      it an attractive drug target. We need to understand which UPS step is blocked in
      which neuronal compartment, and to define the pathway in order to develop new
      strategies to block axon pathology.

PMID- 15180484
TI  - Astrocytic adrenoceptors: a major drug target in neurological and psychiatric
      disorders?
AB  - Considerable attention has recently been paid to astrocyte functions, which are
      briefly summarized. A large amount of data is available about adrenoceptor
      expression and function in astrocytes, some of it dating back to the 1970's and
      some of it very recent. This material is reviewed in the present paper. The brain
      is innervated by noradrenergic fibers extending from locus coeruleus in the brain
      stem, which in turn is connected to a network of adrenergic and noradrenergic
      nuclei in the medulla and pons, contributing to the control of (nor)adrenergic,
      serotonergic, dopaminergic and cholinergic function, both in the central nervous
      system (CNS) and in the periphery. In the CNS astrocytes constitute a major
      target for noradrenergic innervation, which regulates morphological plasticity,
      energy metabolism, membrane transport, gap junction permeability and
      immunological responses in these cells. Noradrenergic effects on astrocytes are
      essential during consolidation of episodic, long-term memory, which is reinforced
      by beta-adrenergic activation. Glycogenolysis and synthesis of glutamate and
      glutamine from glucose, both of which are metabolic processes restricted to
      astrocytes, occur at several time-specific stages during the consolidation.
      Astrocytic abnormalities are almost certainly important in the pathogenesis of
      multiple sclerosis and in all probability contribute essentially to inflammation
      and malfunction in Alzheimer's disease and to mood disturbances in affective
      disorders. Noradrenergic function in astrocytes is severely disturbed by chronic
      exposure to cocaine, which also changes astrocyte morphology. Development of
      drugs modifying noradrenergic receptor activity and/or down-stream signaling is
      advocated for treatment of several neurological/psychiatric disorders and for
      neuroprotection. Astrocytic preparations are suggested for study of mechanism(s)
      of action of antidepressant drugs and pathophysiology of mood disorders.

PMID- 15180485
TI  - Non-invasive assessment of atherosclerosis risk.
AB  - The reasons to measure atherosclerosis include 1) risk stratification and
      prediction; 2) evaluation of patient response to interventions; and 3)
      identification of novel genetic, cellular and molecular determinants of risk.
      Atherosclerosis can be quantified non-invasively using the increasingly reliable
      and precise modalities described in this issue, which include ultrasound and
      magnetic resonance imaging. While each modality assesses "atherosclerosis", the
      particular morphological entities captured may reflect different aspects of
      atherogenesis with different biological determinants. For instance, among carotid
      ultrasound determinations, intima-media thickness (IMT) may reflect medial
      hypertrophy from hypertension, while plaque volume and stenosis and calcium
      deposition may additionally reflect foam cell proliferation, scarring and/or
      thrombosis. Clarifying the biological and clinical correlates of images may guide
      the choice of modality for specific applications. In addition, these tools are
      presently used to assess structures at a single time point. However, using them
      to follow temporal changes may further enhance their value. In this regard,
      certain modalities, such as ultrasound assessment of carotid plaque area or
      volume, may be more sensitive than others, such as assessment of IMT, for
      detecting temporal changes in atherosclerosis. Combining modalities--and adding
      new biomarkers of disease--may be necessary to grasp the full complex vascular
      phenotypic picture--"phenomics"--of both individual subjects and groups of
      patients. In evaluating new determinants and novel therapies, it will be
      important to consider the biology and clinical correlates of a specific measured
      atherosclerosis phenotype in order to select the most appropriate modality.

PMID- 15180486
TI  - Carotid intima media thickness and beyond.
AB  - Atherosclerosis evolves from the vascular wall. The initial build-up starts at
      the inner layers of the intima media complex of the artery. To track these phases
      of the beginning of disease requires a technique that can reliably detect and
      follow the extent and severity non-invasively over time. The artery that is
      accessible and indicative for the process of atherosclerosis is the carotid
      artery. The Quantitative assessment of the Intima Media Thickness (IMT) using
      ultrasound is safe, validated and portable, is inexpensive, and can be used in
      multicenter studies. IMT coupled with an interactive large multi-ethnic may
      provide a reliable tool to predict the likelihood of cardiovascular complications
      like myocardial infarction or stroke. QIMT combines the quantitative analyses and
      assessment of the far wall of the common carotid artery in a specific area,
      proximal to the bulb, that includes a fully automatic algorithm interacting with
      an ethnically diverse database. Many new and exciting applications where the
      underlying disease has an impact on cardiovascular disease have been added to its
      cardiovascular current use. The standardization of the whole procedure from image
      acquisition, transport of images, computerized assessment of images and
      interactive assessment for a specific individual is critical in its new and
      expanded role. Unfortunately the vast majority of the current systems do not
      adhere to these requirements, leading to a false sense of security when a value
      is provided. Given the lack of standardization in most IMT programs, a new valid
      standard is urgently needed, with the dissemination of these new concepts of
      application happens. The QIMT method of assessment of the far wall of the common
      carotid artery is validated, reproducible and the preferred method proposed for
      standardization. Different specialties should be approached and contribute in the
      expansion of its use, as opposed to the current trend to limit QIMT to specific
      healthcare areas.

PMID- 15180487
TI  - Atherosclerotic plaque characterization by MR imaging.
AB  - The MR imaging of carotid artery and aortic plaque has undergone significant
      improvement in the last decade. Early studies utilizing ex vivo specimens and
      spin echo or fast spin echo imaging, led to the conclusion that T2-weighting was
      the best single contrast to characterize carotid plaque morphology. On these
      images, the fibrous plaque appears bright and the lipid core is dark; thrombus
      can have variable intensity. There can be an overlap in T2w signal intensities
      among the various plaque components, which can be partially offset by the use of
      qualitative or multi-spectral analysis of multiple contrast images. With
      improvements in coil design, sequence design, main field and gradient
      capabilities, accurate in vivo differentiation and measurement of these various
      plaque components should be possible in a few years. Carotid and aortic plaque
      burden can be accurately measured in vivo today; ongoing longitudinal studies
      should lead to a better understanding of the relationship between plaque burden
      and the risk of thromboembolic complications, as well as the effect of diet and
      drug therapy in hyperlipidemic patients. With these developments in place or soon
      to be available, MR imaging of the diseased carotid artery and aortic wall may
      prove to be even more important than MR angiography or other current clinical
      tests.

PMID- 15180488
TI  - 3D ultrasound imaging of the carotid arteries.
AB  - Although ultrasonography is an important cost-effective imaging modality,
      technical improvements are needed before its full potential is realized for
      accurate and reproducible monitoring of carotid disease and plaque burden. 2D
      viewing of 3D anatomy, using conventional ultrasonography limits our ability to
      quantify and visualize carotid disease and is partly responsible for the reported
      variability in diagnosis and monitoring of disease progression. Efforts of
      investigators have focused on overcoming these deficiencies by developing 3D
      ultrasound imaging techniques that are capable of acquiring B-mode, color Doppler
      and power Doppler images of the carotid arteries using existing conventional
      ultrasound systems, reconstructing the information into 3D images, and then
      allowing interactive viewing of the 3D images on inexpensive desktop computers.
      In addition, the availability of 3D ultrasound images of the carotid arteries has
      allowed the development of techniques to quantify plaque volume and surface
      morphology as well as allowing registration with other 3D imaging modalities.
      This paper describes 3D ultrasound imaging techniques used to image the carotid
      arteries and summarizes some of the developments aimed at quantifying plaque
      volume and morphology.

PMID- 15180489
TI  - Electron beam tomography as a non invasive method to monitor effectiveness of
      antiatherosclerotic therapy.
AB  - Coronary artery calcification has long been known to be associated with
      atherosclerosis and is intimately associated with atherosclerotic plaque
      development. Similarly, aortic valve degeneration and calcification appears to
      follow a pathophysiologic process very similar to atherosclerosis. Newer
      noninvasive technologies such as Electron Beam Tomography (EBT) allow the
      practicing physician to accurately detect and quantify cardiovascular
      calcification. It has recently become apparent that coronary calcium is an
      excellent marker of risk for myocardial infarction and sudden death in an
      individual patient and that aortic valve sclerosis is associated with high risk
      of coronary events. Besides identification and quantification of cardiovascular
      calcification, the EBT technology has also been employed to accurately measure
      the rate of progression of coronary calcification and it could become a very
      helpful tool to gauge effectiveness of therapy instituted to halt the progression
      of atherosclerosis. In this article we present a review of the studies published
      to date on the use of EBT imaging to gauge the effects of medical therapy on
      coronary and valvular calcification.

PMID- 15180490
TI  - Image-based computational fluid dynamics: a new paradigm for monitoring
      hemodynamics and atherosclerosis.
AB  - Complex blood flow dynamics are thought to play a key role in the development and
      treatment of atherosclerosis; however, the exact nature of this role is
      incompletely understood owing to the practical difficulties associated with
      measuring important local hemodynamic factors, notably wall shear stresses, in
      vivo. Only recently has it become possible to consider mapping these hemodynamic
      factors in a prospective, patient-specific manner via the coupling of in vivo
      medical imaging and computational fluid dynamics (CFD) modelling. CFD models
      derived from intravascular ultrasound have already been used to elucidate the
      role that hemodynamic forces play in mechanical and pharmacological interventions
      for coronary atherosclerosis. CFD models derived from magnetic resonance imaging
      and three-dimensional ultrasound provide a less invasive window into more
      superficial vessels such as the carotid bifurcation, and thus are promising tools
      for clarifying the role of, and eventually exploiting, purported local geometric
      and hemodynamic risk factors for atherosclerosis and its response to therapeutic
      options. Efforts to improve the ease and robustness with which these models are
      constructed have led to concomitant improvements in accuracy and precision, data
      for which are presented to facilitate estimation of sample sizes for future
      studies. Current limitations and anticipated future directions for these powerful
      new tools are discussed.

PMID- 15180491
TI  - Cytochrome P450 gene polymorphism and cancer.
AB  - Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs
      and environmental chemicals. Several CYP enzymes metabolically activate
      procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an
      association between CYP enzyme activity and the risk to develop several forms of
      cancer. Research carried out in the last decade demonstrated that several CYP
      enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications
      and deletions. As genotyping procedures became available for most human CYP, an
      impressive number of association studies on CYP polymorphisms and cancer risk
      were conducted. Here we review the findings obtained in these studies regarding
      CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6,
      CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent
      evidences for association between CYP polymorphisms and lung, head and neck, and
      liver cancer were reported. Controversial findings suggest that colorectal and
      prostate cancers may be associated to CYP polymorphisms, whereas no evidences for
      a relevant association with breast or bladder cancers were reported. We summarize
      the available information related to the association of CYP polymorphisms with
      leukaemia, lymphomas and diverse types of cancer that were investigated only for
      some CYP genes, including brain, esophagus, stomach, pancreas, pituitary,
      cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This
      review discusses on causes of heterogeneity in the proposed associations,
      controversial findings on cancer risk, and identifies topics that require further
      investigation. In addition, some recommendations on study design, in order to
      obtain more conclusive findings in further studies, are provided.

PMID- 15180492
TI  - Cytochrome P450 in neurological disease.
AB  - Advances in a multitude of disciplines support an emerging role for cytochrome
      P450 enzymes and their metabolic substrates and end-products in the pathogenesis
      and treatment of central nervous system disorders, including acute
      cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such
      as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis
      and psychiatric disorders, including anxiety and depression. The neural tissue
      contains its own unique set of P450 genes that are regulated in a manner that is
      distinct from their molecular regulation in peripheral tissue. Furthermore, brain
      P450s catalyze the formation of important brain signaling molecules, such as
      neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A
      and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics
      and environmental neurotoxins. These unique characteristics allow this family of
      proteins and their metabolites to perform such vital functions in brain as
      neurotrophic support, neuroprotection, control of cerebral blood flow,
      temperature control, neuropeptide release, maintenance of brain cholesterol
      homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter
      levels and other functions important in brain physiology, development and
      disease.

PMID- 15180493
TI  - Cytochrome P450 regulation and drug biotransformation during inflammation and
      infection.
AB  - The expression of cytochrome P450 and related biotransformation is altered during
      the operation of host defense mechanisms. This has major implications in
      inflammation and infection when the capacity of the liver and other organs to
      handle drugs is severely compromised. In most cases individual cytochrome P450
      forms are down regulated at the level of gene transcription with a resulting
      decrease in the corresponding mRNA, protein and enzyme activity. The loss in drug
      metabolism is channeled predominantly through the production of cytokines which
      ultimately modify specific transcription factors. Other proposed mechanisms that
      apply to specific cytochrome P450s involve post translational steps including
      enzyme modification and increased degradation. When inflammatory responses are
      confined to the brain there is a loss of cytochrome P450 not only in the brain
      but also in peripheral tissues. This involves a yet to be identified mode of
      signaling between the brain and periphery but it does involve the production of
      cytokines from a peripheral source. In clinical medicine there are numerous
      examples of a decreased capacity to handle drugs during infections and disease
      states that involve an inflammatory component. This often results in altered drug
      responses and increased toxicities. Inflammation mediated alterations in the
      metabolism of endogenous compounds can lead to altered physiology. Changes in
      drug handling capacity during inflammation/infection will continue to be one of
      the many factors that complicate therapeutics.

PMID- 15180494
TI  - Role of cytochrome P450 metabolites of arachidonic acid in hypertension.
AB  - Considerable evidence has accumulated over the last decade implicating a role of
      cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) in the
      pathogenesis of hypertension. Indeed, 20-hydroxyeicosatetraenoic acid (20-HETE)
      is produced by vascular smooth muscle (VSM) cells and is a potent vasoconstrictor
      that depolarizes VSM by blocking large conductance Ca+-activated K2+ channels. In
      contrast, epoxyeicosatrienoic acids (EETs) are synthesized by the vascular
      endothelium and have opposite effects on VSM (hyperpolarization and
      vasodilatation). Inhibition of the synthesis of 20-HETE attenuates myogenic tone
      and autoregulation of blood flow and modulates vascular responses to vasodilators
      (NO and CO) and vasoconstrictors (angiotensin II, endothelin). In the kidney, 20
      HETE inhibits sodium transport in the proximal tubule by blocking Na+-K+-ATPase
      activity. In the thick ascending limb of the loop of Henle, 20-HETE inhibits Na+
      K+-2Cl- transport, in part, by blocking a 70 pS apical K+ channel. EETs are
      produced in the proximal tubule where they inhibit Na+-H+ exchange and in the
      collecting duct where they inhibit sodium and water transport. Numerous studies
      have established that the formation of EETs and 20-HETE and the expression of CYP
      enzymes are altered in the kidney in many genetic and experimental animal models
      of hypertension and in some forms of human hypertension. However, the functional
      significance of these changes remains to be determined. Given the importance of
      this pathway in the control of renal function and vascular tone, it is likely
      that alterations in the renal formation of CYP-dependent metabolites of AA will
      be shown to participate in the development of hypertension in many of these
      models.

PMID- 15180495
TI  - Effect of hypoxia on cytochrome P450 activity and expression.
AB  - In the last three decades, numerous reports have shown that patients with chronic
      pulmonary disease and with heart failure with hypoxemia cleared drugs at a lower
      rate than healthy volunteers. As a consequence decreased clearance, drug toxicity
      is frequent in these patients. The reduction in drug clearance is due to a
      decrease in activity of cytochrome P450 isoforms, partly associated to the
      hypoxemia. With in vivo animal models, acute moderate hypoxia (PaO2 of around 35
      50 mm Hg) reduces the clearance of drugs biotransformed by CYP1A1, CYP1A2,
      CYP2B6, CYP2C9, CYP2C19 and CYP2E1, although hypoxia does not affect the
      clearance of drugs biotransformed by CYP3A6. Ex vivo and in vitro experiments
      demonstrate that hypoxia down-regulates CYP1A1, CYP1A2, CYP2B6, CYP2C9 and
      CYP2C19, decrease preceded by a reduction in activity. On the other hand, acute
      moderate hypoxia up-regulates CYP3A6. The changes in protein expression are
      preceded by modifications in the mRNA coding for the proteins. The effect of
      hypoxia on hepatic cytochrome P450 is carried out by serum mediators, e.g.
      interferon-gamma, interleukin-1beta, and interleukin-2 are responsible for the
      decrease in activity and in expression of cytochrome P450 isoforms, and
      erythropoietin accounts for the increase in CYP3A6. Probably several mechanisms
      underlie and contribute to the decrease in activity and down-regulation of
      cytochrome P450 isoforms by hypoxia, e.g. reducing potentiation factors, inducing
      repressor elements and activating negative regulatory elements. The up-regulation
      of CYP3A6 implies a PTK- and p42/44MAPK-dependent stabilization/activation,
      nuclear translocation of HIF-1 and AP-1, binding to CYP3A6 promoter, and
      transactivation of the gene to induce CYP3A6 expression.

PMID- 15180496
TI  - Cytochrome P450 and liver diseases.
AB  - Cytochrome P-450 (CYPs) are involved in the metabolism of drugs, chemicals and
      endogenous substrates. The hepatic CYPs are also involved in the pathogenesis of
      several liver diseases. CYP-mediated activation of drugs to toxic metabolites
      induces hepatotoxicity. Well-known examples include acetaminophen and halothane.
      In some instances, covalent binding of the toxic metabolite to CYP leads to the
      formation of anti-CYP antibodies and immune-mediated hepatotoxicity (hydralazine,
      tienilic acid). Anti-CYP2D6 antibodies are also present in the serum of patients
      with type II autoimmune hepatitis, but the mechanism leading to their presence
      and their pathogenic significance remains unclear. Several studies support a role
      for CYP2E1 in the pathogenesis of alcoholic liver disease and non-alcoholic
      steatohepatitis. In these conditions, enhanced CYP2E1 activity is associated with
      lipid peroxidation and the production of reactive oxygen species with secondary
      damage to cellular membranes and mitochondria. Because of its ability to activate
      carcinogens, a role for CYP2E1 as a cofactor for hepatocellular carcinoma has
      also been postulated. On the other hand, drug metabolism is impaired in patients
      with liver disease, particularly that mediated by CYPs. The content and activity
      of CYP1A, 2C19 and 3A appear to be particularly vulnerable to the effect of liver
      disease while CYP2D6, 2C9 and 2E1 are less affected. The pattern of CYPs
      isoenzymes alterations also differs according to the etiology of liver disease. A
      strong relationship between the activity of CYPs and the severity of cirrhosis
      has been demonstrated, but the usefulness of measuring CYP activity to assess
      hepatic functional reserve remains uncertain.

PMID- 15180497
TI  - Novel approaches for targeted cancer therapy.
AB  - The clinical use of chemotherapeutic agents against malignant tumors is
      successful in many cases but suffers from major drawbacks. One drawback is lack
      of selectivity, which leads to severe side effects and limited efficacy; and
      another is the emergence/selection of drug-resistance. To limit non-specific
      toxicity and to improve the efficiency of cancer therapy, "tumor markers", which
      are proteins generally overexpressed on the surface of tumor cells, can be
      selectively targeted. Growth factor receptors are one of the most extensively
      studied tumor markers. The implication of growth factor receptors in the
      pathogenesis and evolution of cancer has clearly been established and therefore,
      provides a rationale for therapeutic intervention. The targeting of cytotoxic
      substances to tumor markers with "magic bullets" is an old idea that raised high
      expectations but also disappointment. Over the past decade, newly gained
      understanding of mechanisms for targeted therapy have brought new hopes.
      Pharmacological agents that selectively target and block the action of growth
      factors and their receptors have been attempted, such as monoclonal antibodies
      (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to
      drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in
      free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes
      encapsulated drugs, and small molecule inhibitors. This review will focus on
      current developments of selective targeting and bypassing drug resistance in the
      management of growth factor receptor-overexpressing tumors.

PMID- 15180498
TI  - Signaling pathways responsible for cancer cell invasion as targets for cancer
      therapy.
AB  - Migration of cancer cells is one of the key factors responsible for cancer
      metastasis. The elucidation of mechanisms responsible for the highly invasive
      potential of cancer cells can help to identify specific targets for the treatment
      of cancer patients. Highly invasive cancers are usually characterized by aberrant
      activity of specific intra- or extracellular molecules such as protein kinases,
      phosphatases, transcriptional factors, proteolytic enzymes, and others. Protein
      kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) are responsible for the
      constitutive activity of transcriptional factors NF-kappaB and AP-1 in some of
      the highly invasive cancers. Furthermore, NF-kappaB and AP-1 control the
      expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR),
      and expression of both uPA and uPAR correlates with invasive cancer cell
      phenotype and poor prognosis. The inhibition of PKC and PI3K signaling (through
      NF-kappaB and AP-1) suppressed the secretion of uPA, resulting in the inhibition
      of motility of highly invasive breast cancer cells. Therefore, inhibition of
      specific target molecules in common signaling pathway(s) responsible for
      metastatic spread can have potential clinical relevance. This review will
      summarize different approaches to targeting distinct signaling molecules involved
      in cancer invasion and metastasis.

PMID- 15180499
TI  - Functional antagonism between NF-kappaB and nuclear receptors: implications in
      carcinogenesis and strategies for optimal cancer chemopreventive interventions.
AB  - Hyper-activation of nuclear factor kappa B (NF-kappaB) is germane to
      carcinogenesis by its fundamental implication in cellular de-differentiation and
      proliferation, the subversion of apoptosis, the promotion of neo-angiogenesis,
      invasive growth and metastases. Conversely, the expression of multiple nuclear
      receptors (NRs), arbiters of cellular differentiation, decreases with progressive
      carcinogenesis. This review is a conceptual discussion of evidence to support NF
      kappaB as the nexus between carcinogenesis and decreased NR expression.
      Furthermore, it synthesizes the thesis and antithesis of NR function in
      carcinogenesis and expounds on the functional antagonism between NRs and NF
      kappaB as a basis for the chemopreventive activity of NR ligands. Finally,
      strategies for optimal chemopreventive interventions with NR ligands are
      discussed.

PMID- 15180500
TI  - Microfilament actin remodeling as a potential target for cancer drug development.
AB  - Actin was first identified in non-muscle cells only about three decades ago, and
      at about the same time, it was found that actin filaments were disrupted in the
      malignant transformed cells. The actin network is a rather complex, yet important
      structural and functional system of all eukaryotic cells. Actin filaments provide
      the basic infrastructure for maintaining cell morphology and functions such as
      adhesion, motility, exocytosis, endocytosis, and cell division. Growing evidence
      from this laboratory and others shows that alterations of actin polymerization,
      or actin remodeling, plays a pivotal role in regulating the morphologic and
      phenotypic events of a malignant cell. Actin remodeling is the result of
      activation of oncogenic actin signaling pathways (e.g., Ras and Src), or
      inactivation of several important actin-binding proteins that have tumor
      suppressor functions (e.g., gelsolin). Distinctive protein expression patterns of
      some of these genes in cancer and progressive carcinogenic processes have been
      observed. It has become evident that actin dynamics are regulated by a complex
      interplay of the small GTPase proteins of Ras superfamily Rac, Rho, and Cdc42,
      and efforts to develop specific inhibitors for these small G proteins as
      anticancer drug are underway. In this review we will discuss how actin remodeling
      is altered in the malignant transformation process, the functional significance
      of actin alteration in association with malignant phenotypes, and the approaches
      of targeting actin remodeling for chemopreventive and chemotherapeutic drug
      development. Approaches including using nature products directly modulating actin
      polymerization, using inhibitors of actin pathway small G proteins, and using
      gene-augmentation for actin binding proteins will be discussed. In addition, the
      concept of using F/G-actin ratio as a surrogate marker for actin-pathway based
      therapy will also be introduced.

PMID- 15180501
TI  - Vitamin E analogues: a new class of inducers of apoptosis with selective anti
      cancer effects.
AB  - In spite of unrelenting effort, the net incidence of neoplastic diseases appears
      not to have been curbed. While some types of cancer have been suppressed
      significantly, others are either stagnating or on the increase. Therefore, the
      need for a cure is imperative, in particularly a drug or combination of drugs
      that would be selective for malignant cells, i.e. with as low secondary toxicity
      as possible. Recent data strongly suggest that analogues of vitamin E, epitomised
      by the most studied alpha-tocopheryl succinate (alpha-TOS), may meet the need for
      the coveted drugs with a selective anti-neoplastic effect. The reasons for this
      optimism are reviewed in this article.

PMID- 15180502
TI  - Potent chemopreventive agents against pancreatic cancer.
AB  - Development of pancreatic cancers is clinically so silent in general that at the
      time of diagnosis, the vast majority of cases are incurable with a very poor
      prognosis. Therefore, effective preventive approaches against this aggressive
      disease are urgently required. Experimentally, carcinogenesis process is assumed
      to consist of at least two stages named initiation and promotion. Using a two
      stage model of hamster pancreatic carcinogenesis, we have reported stage-specific
      inhibitory effects by a number of potent cancer chemopreventive agents. Among
      them, phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables,
      remarkably blocked the initiation phase of pancreatic as well as lung
      carcinogenesis in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP).
      However, PEITC failed to affect both pancreatic and lung carcinogenesis when
      given during the post-initiation (promotion) phase of carcinogenesis. In
      contrast, our recent study clearly demonstrated that a cyclooxygenase (COX)-2
      inhibitor substantially protects against BOP-induced pancreatic tumors in
      hamsters in line with decrease in cell proliferative activity of pancreatic ducts
      when given in the post-initiation phase. Interestingly, trypsin inhibitors
      inhibited both initiation and post-initiation phases of BOP-induced pancreatic
      carcinogenesis although they are known to induce hyperplastic acinar lesions in
      the rat pancreas. Taken together with these data, our review is aimed at looking
      over mechanistic insights into potent chemopreventive agents against pancreatic
      cancer.

PMID- 15180503
TI  - Description, distribution, activity and phylogenetic relationship of ribosome
      inactivating proteins in plants, fungi and bacteria.
AB  - Ribosome-Inactivating Proteins (RIPs) are enzymes that trigger the catalytic
      inactivation of ribosomes and other substrates. They are present in a large
      number of plants and have been found also in fungi, algae and bacteria. RIPs are
      currently classified as type 1, those formed by a single polypeptide chain with
      the enzymatic activity, and type 2, those formed by 2 types of chains, i.e. A
      chains equivalent to a type 1 RIPs and B chains with lectin activity. Type 2 RIPs
      usually contain the formulae A-B, (A-B)2 and less frequent (A-B)4 and polymeric
      forms of type 2 RIPs lectins. RIPs are broadly distributed in plants, and are
      present also in fungi, bacteria, at least in one alga; recently RIP-type activity
      has been described in mammalian tissues. The highest number of RIPs has been
      found in Caryophyllaceae, Sambucaceae, Cucurbitaceae, Euphorbiaceae,
      Phytolaccaceae and Poaceae. However there are no systematic screening studies to
      allow generalisations about occurrence. The most known activity of RIPs is the
      translational inhibitory activity, which seems a consequence of a N-glycosidase
      on the 28 S rRNA of the eukaryotic ribosome that triggers the split of the
      A(4324) (or an equivalent base in other ribosomes), which is key for translation.
      This activity seems to be part of a general adenine polynucleotide glycosylase
      able to act on several substrates other than ribosomes, such as tRNA, mRNA, viral
      RNA and DNA. Other enzymatic activities found in RIPs are lipase, chitinase and
      superoxide dismutase. RIPs are phylogenetically related. In general RIPs from
      close families share good amino acid homologies. Type 1 RIPs and the A chains of
      type 2 RIPs from Magnoliopsida (dicotyledons) are closely related. RIPs from
      Liliopsida (monocotyledons) are at the same time closely related and distant from
      Magnoliopsida. Concerning the biological roles played by RIPs there are several
      hypotheses, but the current belief is that they could play significant roles in
      the antipathogenic (viruses and fungi), stress and senescence responses. In
      addition, roles as antifeedant and storage proteins have been also proposed.
      Future research will approach the potential biological roles played by RIPs and
      their use as toxic effectors in the construction of immunotoxins and conjugates
      for target therapy.

PMID- 15180504
TI  - The structure of ribosome inactivating proteins.
AB  - Ribosome Inactivating Proteins, RIPs, depurinate an invariant adenine from the
      28S rRNA of eukaryotic ribosomes; they have evolved to near enzymatic perfection
      for this task. The N-glycosidase fold is conserved in plant and bacterial
      enzymes. RIPs can form complexes with cell surface recognition proteins that
      dramatically increase the cytotoxicity of the molecule.

PMID- 15180505
TI  - Genetics of ribosome-inactivating proteins.
AB  - Ribosome-inactivating proteins (RIPs) are a heterogeneous group of enzymes found
      mainly in plants and a few bacteria that possess N-glycosidase activity on
      ribosomes and a related polynucleotide adenosine glycosidase activity on naked
      nucleic acids. They encompass single enzymatic chains, heterodimeric toxic
      lectins and related agglutinins. Plants commonly produce several RIP isoforms
      encoded by multi-gene families. The toxic lectins possess adaptations related to
      their cytotoxic role.

PMID- 15180506
TI  - The genetics and properties of cereal ribosome-inactivating proteins.
AB  - Plants contain proteins that are capable of inactivating ribosomes, commonly
      referred to as Ribosome Inactivating Proteins (RIPs). These particular plant
      proteins have received attention in biological and biomedical research because of
      their unique biological activities towards animals and human cells as cell
      killing agents. Some of the best-characterised RIPs have been isolated from
      exotic plants, but they have also been found in cereals and other food crops.
      Cereals contain, in general, RIPs in the endosperm protein pool: they share a
      high similarity with all the other RIPs retaining, however, characteristic
      features forming a distinct class which diversified significantly during
      evolution. They appear to be involved in quite different physiological roles,
      such as defence against pathogens and/or involved in regulatory and developmental
      processes. This review aims to provide a critical assessment to work related to
      cereal RIP with particular emphasis to the maize RIPs.

PMID- 15180507
TI  - Ribosome-inactivating proteins: entry into mammalian cells and intracellular
      routing.
AB  - To catalytically-modify ribosomes in vivo, ribosome-inactivating proteins
      produced by plants must enter susceptible mammalian cells in order to reach their
      substrates in the cytosol. This review primarily focuses on the biosynthesis,
      mechanism of cell entry and intracellular trafficking of ricin, the most
      thoroughly studied ribosome-inactivating protein in this respect.

PMID- 15180508
TI  - Cytotoxicity and toxicity to animals and humans of ribosome-inactivating
      proteins.
AB  - The toxicity to cells and animals of type 1 and toxic and non-toxic type 2
      Ribosome-Inactivating Proteins (RIP) is discussed in correlation with their
      catalytic activity, resulting in ribosome inactivation and apoptosis. The
      symptoms and histopathological lesions induced by RIP to animals and humans is
      also reviewed.

PMID- 15180509
TI  - Antiviral activity of ribosome inactivating proteins in medicine.
AB  - Pokeweed antiviral protein and several other ribosome inactivating proteins are
      effective against a broad range of viruses. Recent results have shown that their
      enzymatic activity is not limited to depurination of the large rRNA, they can
      depurinate other nucleic acids, including viral RNAs. Antiviral activity of RIPs
      is summarized here in light of their novel activities and recent developments in
      the field.

PMID- 15180510
TI  - Immunotoxins and other conjugates: preparation and general characteristics.
AB  - Targeted toxins represent an invaluable tool offering a wide range of potential
      applications, both in experimental models and in the clinics. Here we will review
      several aspects related to the preparation and properties of carrier molecule
      toxin heteroconjugates and fusion toxins.

PMID- 15180511
TI  - Immunotoxins and other conjugates: pre-clinical studies.
AB  - A wide variety of conjugates containing RIPs, of either chemical or recombinant
      type, have been made and tested against dangerous cells in vitro and in animal
      models. Many of these pre-clinical studies will be reviewed here dividing them on
      the basis of the target cell and the surface molecule specifically recognized.

PMID- 15180512
TI  - Immunotoxins and neuropeptide-toxin conjugates experimental applications.
AB  - The use of targeted toxins in research applications has recently grown
      considerably. The ability to remove a few specific cells, even when surrounded by
      different populations, has given scientists a powerful tool for the understanding
      of systems biology. The use of targeted toxins in research is rich and varied;
      here we limit ourselves to describe some of those exciting results that
      researchers have made in the neurosciences.

PMID- 15180519
TI  - Proteasomes: a complex story.
AB  - Protein degradation in eukaryotic cells is important for regulation of
      metabolism, progression through the division cycle, in cell signalling pathways,
      and in mammals also for generation of antigen fragments for presentation on the
      major histocompatibility complex (MHC) class I. Most cell proteins are degraded
      via the ubiquitin/proteasome pathway where an elaborate enzyme system recognises
      the protein substrates and marks them for destruction by attachment of a chain of
      ubiquitin. The substrates are then bound to 26S proteasomes, unfolded, and
      threaded into the cylindrical central part of the 26S proteasome, where they are
      cleaved to peptides. Recently many proteins, which associate with proteasomes,
      have been found. One of them controls the cellular contents of proteasomes by
      regulating their synthesis. Others ubiquitylate substrates or transfer substrates
      to proteasomes. Others again seem to unfold the substrates or release ubiquitin
      and glycans from them during degradation, stabilise proteasomes, regulate their
      cellular localisation, and modify their activity. It therefore appears that
      proteasomes are centres in macromolecular clusters, which degrade cell proteins
      in a tightly regulated manner.

PMID- 15180520
TI  - Proteasome function in antigen presentation: immunoproteasome complexes, Peptide
      production, and interactions with viral proteins.
AB  - Proteasomes are the major nonlysosomal protein degradation machinery in
      eukaryotic cells and they are largely responsible for the processing of antigens
      for presentation by the MHC class I pathway. This review concentrates on recent
      developments in the area of antigen processing. Specialized proteasomes called
      immunoproteasomes and an 11S regulator of proteasomes (PA28) are induced by
      interferon-gamma, but it is not entirely clear why changes in proteasome
      structure are beneficial for antigen presentation. Different proteasome complexes
      have distinct subcellular distributions and subtle differences in cleavage
      specificity. Thus it is likely that the efficiency of production of MHC class I
      binding peptides varies in different locations. Immunoproteasome subunits are
      enriched at the ER where TAP transports peptides for association with newly
      synthesized MHC class I molecules. There is recent evidence to suggest that
      antigen presentation from viral expression vectors, or from peptides that are
      either delivered by bacterial toxins or derived from signal peptides, require
      proteasome activity for generation of the correct C-terminus of the epitope. The
      correct N-terminus may be generated by recently identified ER associated
      aminopeptidases. A number of viral protein interactions with proteasome subunits
      have been reported and such interactions may interfere with host anti-viral
      defenses and also contribute to mechanisms of cell transformation.

PMID- 15180521
TI  - Ubiquitin-protein ligases--novel therapeutic targets?
AB  - Intracellular protein degradation is a tightly regulated process that in many
      cases is controlled by protein ubiquitylation. The ubiquitin pathway is a major
      route by which cells not only remove normal proteins at the appropriate time but
      also abnormally folded normal or mutant, cytoplasmic and membrane, proteins. This
      has led to a major impetus to identify constituents of the pathway. The key
      components that regulate substrate ubiquitylation are the ubiquitin-protein
      ligases. Ligases come in many forms, from single proteins to very large
      multiprotein complexes. Specificity of targeting can be modulated by the
      requirement for post-translational modifications such as phosphorylation,
      hydroxylation or oxidation of the substrate and, in some cases, the ligase
      itself. The requirement for substrate modification prior to ubiquitylation allows
      the same ligase to target different substrates within the same cell at different
      times. Abnormal intracellular protein processing is a common feature of many
      human diseases including neurodegenerative diseases and cancer. It may not
      represent the causative factor that initiates the disease process but may be a
      downstream regulator of the toxic effect. These abnormalities often arise from
      the loss of a key protein-protein interaction. As a consequence, mutated proteins
      can have very different half-lives from their normal counterparts. This can
      affect the levels of their activity and/or lead to the formation of protein
      aggregates (inclusion bodies/aggresomes). In this review, we aim to highlight
      examples of diseases where abnormal protein ubiquitylation is proposed to be a
      key regulator of the disease process. The recent success of the proteasome
      inhibitor Bortezomib (PS-341) for treatment of relapsed, refractory myeloma
      suggests that the modulation of individual ubiquitin-protein ligase activities
      with synthetic agents may represent a novel approach that has enormous potential
      for the treatment of a wide range of diseases.

PMID- 15180522
TI  - Cullin-based ubiquitin ligase and its control by NEDD8-conjugating system.
AB  - Several studies have examined the importance of ubiquitin-like posttranslational
      modifiers (which consist of an unexpectedly large family). Of these, NEDD8 (also
      called Rub1, related to ubiquitin 1) with a high homology to ubiquitin is
      covalently linked to all members of cullin (Cul)-family proteins through an
      enzymatic cascade analogous to ubiquitylation. Cul-family proteins are scaffold
      proteins for a wide series of ubiquitin-protein ligase complexes, such as SCFs
      (Skp1, Cul-1, Roc1, and F-box proteins), which regulate the degradation of broad
      range of cellular proteins. Unlike ubiquitin, which mostly acts as a degradation
      signal for the target proteins, NEDD8 acts as an activation signal for Cul-family
      proteins; i.e., Cul-based ubiquitin-protein ligases. Accordingly, the NEDD8
      conjugation pathway regulating Cul-protein function is responsible for a diverse
      array of biologically important processes, such as the cell cycle progression,
      signalling cascades and developmental programs. Furthermore, recent studies have
      revealed that the COP9/Signalosome complex interacts physically and genetically
      with Cul-family proteins, and catalyzes deconjugation of NEDD8 ligated to Cul
      family proteins. This review summarizes recent advances in biochemical and
      genetic studies on how the NEDD8-modifying system regulates Cul-family proteins
      and their physiology.

PMID- 15180523
TI  - The COP9 signalosome: mediating between kinase signaling and protein degradation.
AB  - The COP9 Signalosome (CSN), a highly conserved eight-subunit complex, is found in
      all higher eukaryotes. It contains eight core subunits, named CSN1-8, in order of
      decreasing molecular weight. The CSN is structurally similar to the regulatory
      lid of 26S proteasome and the eukaryotic translation initiation factor eIF3. CSN
      is also now known to play an essential role in signaling processes controlling
      many aspects of plant and Drosophila development. Taken together, the various
      genetic studies demonstrate that the CSN is involved at the nexus between
      multiple signal inputs and a variety of downstream regulatory cascades
      controlling specific aspects of cellular differentiation. Research in various
      organisms has converged onto the notion that CSN is biochemically linked to
      ubiquitin-dependent protein degradation. Other proposed roles for the CSN include
      regulating eIF3 and kinase signaling. CSN is itself is both a target for kinase
      activity and associates with and coordinates activity of kinases. CSN-associated
      kinases. This kinase activity further regulates the ubiquitin-dependent
      degradation of various transcription factors. This review concentrates on the
      proposed activity of the CSN as a regulator of protein phosphorylation.

PMID- 15180524
TI  - Deubiquitinating enzymes: their functions and substrate specificity.
AB  - Conjugation of one or more molecules of ubiquitin to target proteins can signify
      one of several fates, including degradation by the 26S proteasome, or trafficking
      via the secretory or endocytic pathways. Whereas much attention in recent years
      has focussed on the mechanisms of forming these different ubiquitin conjugates,
      far less is known about the removal of ubiquitin, which is performed by
      deubiquitinating enzymes (DUBs). While it has been appreciated for some 10 years
      that DUBs constitute large gene families in eukaryotes, and known for much longer
      that ubiquitination is a reversible process, information on the exact role of
      DUBs has been slow in coming. This review will attempt to summarise results from
      the last few years that shows that DUBs are an essential regulatory step of both
      protein degradation by the proteasome, and of other ubiquitin-dependent
      processes, by virtue of their ability to regulate protein ubiquitination in a
      target-specific manner.

PMID- 15180526
TI  - Targeting MAPK signalling: Prometheus' fire or Pandora's box?
AB  - MAPK (Mitogen Activated Protein Kinase) pathways mediate fundamental biological
      processes and have moved into the limelight of drug discovery during the past
      decade. Here we review the biochemistry and biology of MAPK signalling with a
      focus on ERK, JNK and p38. We summarise current drug discovery efforts and
      clinical trials. Further, we critically discuss the rationale behind current
      strategies of using MAPK pathways as drug targets and suggest new approaches that
      take the complexity of MAPK signalling networks into account.

PMID- 15180525
TI  - Flt3 receptor tyrosine kinase as a drug target in leukemia.
AB  - The hematopoietic class III receptor tyrosine kinase (RTK) Flt3 (Flk2, STK1) has
      recently received much attention as a potential drug target. Activation of Flt3
      by different types of mutations plays an important role for proliferation,
      resistance to apoptosis, and prevention of differentiation of leukemic blasts in
      acute myeloid leukemia (AML). At least one type of such mutations - an internal
      tandem duplication in the Flt3 juxtamembrane domain (Flt3-ITD) - has been
      associated with an unfavorable prognosis. Signal transduction of Flt3 involves
      activation of several conserved pathways, including the RAS/MAP-Kinase and the
      phosphoinositide-3-kinase/Akt signaling cascades. Transforming versions of Flt3
      exhibit altered signaling, for example a very pronounced activation of STAT5,
      ultimately resulting in alternate profiles of gene expression and cell
      transformation. Selective inhibitors of Flt3 tyrosine kinase activity have the
      potential to suppress aberrant Flt3 signaling. Although highly homologous to
      other class III RTKs, Flt3 is resistant to the phenylaminopyrimidine STI571
      (Gleevec, Imatinib), a potent inhibitor of other RTKs in the family, such as the
      PDGFbeta-receptor or c-Kit. STI571 binding to Flt3 is prevented by the
      phenylalanine 691 side-chain in the ATP binding center and mutating this site to
      threonine renders the corresponding Flt3 mutant sensitive to STI571. Compounds of
      several other structural families, including the quinoxaline AG1296, the bis(1H-2
      indolyl)-1-methanone D-65476, the indolinones SU5416 and SU11248, the
      indolocarbazoles PKC412 and CEP-701, and the piperazonyl quinazoline CT53518, are
      potent inhibitors of Flt3 kinase. They exhibit different selectivity profiles,
      both with respect to other kinases and among wildtype Flt3 and its activated
      versions. These compounds hold promise as novel drugs against AML and as probes
      for understanding activation mechanisms and signaling pathways in the class III
      RTK family.

PMID- 15180527
TI  - MEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in
      tumors.
AB  - The Ras-Raf-MEK-ERK intracellular signaling cascade can be activated in response
      to a variety of extracellular stimuli. Growth factor binding to extracellular
      receptors results in activation of Ras, which in turn interacts with and
      activates Raf, leading to the phosphorylation of the dual specificity kinase MEK
      (MAP kinase kinase) on two distinct serine residues. MEK possesses a number of
      unique biochemical and biological features that make it an attractive target from
      an anticancer drug development perspective. The identification and subsequent
      testing of highly selective small molecule inhibitors of MEK have served to re
      enforce the long held belief that the MEK/ERK module plays a critical role in
      controlling a number of cellular events that are critical to tumor cell growth
      and survival. We have witnessed advancement of the first MEK-targeted clinical
      drug candidate into clinical trials with the entry of CI-1040. The evaluation of
      sufficiently potent and selective MEK inhibitors in well-designed clinical trials
      is critical for ultimate validation of MEK as a molecular-based anticancer drug
      target.

PMID- 15180529
TI  - The role of protein kinase C-alpha (PKC-alpha) in cancer and its modulation by
      the novel PKC-alpha-specific inhibitor aprinocarsen.
AB  - As our understanding of tumorigenesis increases, interference with the various
      signaling pathways of tumor cells has become an attractive approach to arresting
      tumor cell growth and overcoming chemoresistance. Among many intracellular
      signaling proteins, protein kinase C (PKC) isoenzymes have been identified as
      possible targets to render tumor cells more susceptible to apoptosis and growth
      arrest. We review the known biology of the alpha-isoenzyme of PKC in different
      cancers to provide a rational approach for developing targeted therapies using
      PKC modulators, including aprinocarsen, an antisense oligonucleotide (ASO)
      against PKC-alpha.

PMID- 15180528
TI  - Phosphoinositide 3-kinases as targets for therapeutic intervention.
AB  - Phosphoinositide 3-kinases (PI3K) represent a family of intracellular signaling
      proteins, which control a variety of important cellular functions such as
      proliferation, apoptosis and migration. Recent findings suggest an involvement of
      PI3K in the pathogenesis of numerous diseases including cancer, heart failure and
      autoimmune/inflammatory disorders. This review summarizes the current knowledge
      of the emerging therapeutic value of PI3K as targets for the intervention of
      several pathological disorders and in particular focusing on oncogenesis. A brief
      introduction on the molecular and biochemical features of these signaling
      proteins will be followed by a depiction of signaling interactions of PI3K in a
      cellular context. PI3K dependent signaling involved in the control of cell
      growth, proliferation, survival and cytoskeletal remodeling and the link to
      cellular dysfunctions will be discussed. Further we will summarize the phenotypic
      consequences by genetic targeting PI3K signaling in mice. In its final part this
      review outlines challenges and activities considering PI3K as targets for
      therapeutic intervention and progress in the development of first generation
      small molecule inhibitors.

PMID- 15180530
TI  - G protein-coupled receptors and their signaling pathways: classical therapeutical
      targets susceptible to novel therapeutic concepts.
AB  - In recent years, new strategies in cancer therapy have been developed targeting
      key signaling molecules in the receptor tyrosine kinase signal transduction
      pathway. In contrast, most therapeutical concepts to manipulate G protein-coupled
      receptors (GPCR)-mediated disorders are still limited to the use of receptor
      specific agonists or antagonists. Visible progress in the understanding of GPCR
      signaling complexity, especially the detection of several families of highly
      target- and cell-specific regulator proteins of GPCRs, G proteins, and effector
      components may open new horizons to develop novel therapeutical concepts
      targeting GPCR signaling elements. Thus, this review will focus on different
      molecular levels that may be of particular interest in terms of new drug
      development such as: (i) GPCR subtypes, allosteric binding sites, dimerization
      and constitutive activity, the use of RAMPs (receptor-activity-modifying
      proteins) and RASSLs (receptor activated solely by synthetic ligands); (ii) AGS
      (activators of G protein signaling) and RGS (regulators of G protein signaling)
      proteins which modify G protein activity; (iii) the high diversity of isozymes
      involved in the generation, signal transmission, and degradation of second
      messenger molecules.

PMID- 15180531
TI  - Monitoring therapy with gene expression profiling reveals physiological
      differences in drug action.
AB  - Gene expression profiling has become a versatile tool for biomedical research,
      which allows the assessment of a wide variety of basic questions in cellular
      regulation, in particular when a large number of molecular parameters have
      changed. There are various applications in drug research for which gene
      expression profiling is a very suitable approach. This includes: target
      identification, target validation, validation of drug specificity and monitoring
      of drug action during therapy. The focus of this article is the therapy
      monitoring and the interpretation of the gene expression profiles in respect to
      physiological differences of drug action. As an example, we will discuss changes
      in gene expression in blood samples from CML patients treated with the tyrosine
      kinase inhibitor (imatinib mesylate) and compare the observed effects on gene
      expression with the effects of IFNalpha treatment. In comparison with other
      examples of therapy monitoring the potential of this application of gene
      expression profiling for optimizing individual therapy will be discussed.

PMID- 15180532
TI  - Tumor intracellular redox status and drug resistance--serendipity or a causal
      relationship?
AB  - Reducing tumor load by therapeutic induction of cell death in the transformed
      phenotype is the desirable goal of most chemotherapeutic regimens. Despite the
      tremendous strides made in our understanding of mechanisms that endow tumor cells
      with the ability to evade execution signals, development of chemo-resistance is
      still a major obstacle in the successful management of the disease. A host of
      factors have been implicated in the acquisition of the resistant phenotype, such
      as activation of drug efflux pumps, overexpression of proteins that inhibit cell
      death, absence of critical members of the death circuitry, and selective loss of
      cell cycle checkpoints. Consequently, it is now well established that the process
      of carcinogenesis is not only a result of an increase in cells' proliferative
      capacity, but a product of increased proliferation and defective or diminished
      cell death signaling. To that end, one of the critical determinants of cellular
      response to exogenous stimuli is the cellular redox status. Intracellular
      generation of reactive oxygen species (ROS) is tightly regulated by the intrinsic
      anti-oxidant defense systems. Despite the conventional dogma that ROS are harmful
      to the cell, experimental evidence over the last decade or so bear witness to the
      fact that ROS also play an important role as signaling molecules in diverse
      physiological processes. Indeed, low levels of intracellular ROS have been linked
      to cellular proliferation and cell cycle progression, which provides an
      explanation for the pro-oxidant state invariably associated with the transformed
      phenotype. Coupled to that are recent observations implicating pro-oxidant
      intracellular milieu in tumor cells' resistance to cell death signals delivered
      through the cell surface receptor or upon exposure to chemotherapeutic drugs.
      These studies provide convincing evidence to support a direct or indirect role
      for intracellular superoxide anion in creating an intracellular milieu non
      permissive for cell death execution. Thus a novel approach to enhancing tumor
      cell sensitivity to chemotherapy-induced cell death would be to favourably tailor
      the cytosolic milieu to allow efficient apoptotic execution. Here we present a
      brief discussion on the role of ROS in cell growth and differentiation, and more
      specifically address the issue of chemo-resistance from the standpoint of
      cellular redox status.

PMID- 15180533
TI  - Hirudo medicinalis: avascular tissues for clear-cut angiogenesis studies?
AB  - Basic studies on angiogenesis in normal and pathologic conditions, as well as
      research on drugs or genes/proteins that stimulate or regulate the angiogenic
      process, can rely on an increasing number of experimental models. Among non
      mammalian models, Zebrafish is adopted by an increasing number of research
      groups. Moreover, angiogenesis and vasculogenesis in invertebrates like the leech
      Hirudo medicinalis share a high degree of similarity with the same processes
      occurring in humans, both under the structural/functional and biochemical points
      of view. Interestingly, Hirudo angiogenic growth factor receptors respond to
      corresponding human/mammalian recombinant growth factors and cytokines; in
      addition, Hirudo endogenous angiogenic growth factors and receptors react with
      antibodies against their human/mammalian counterparts. Furthermore, as it will be
      shown in this review, Hirudo has the unique advantage of having a virtually
      avascular muscular body wall, whereas the reliability of such a peculiar feature
      as a model for physiologically vascularised mammalian tissues has to be
      thoroughly investigated. Hirudo has proven so far to allow unambiguous, clear-cut
      studies on the angiogenic potential of gene-products or drugs, as well as on the
      anti-angiogenic compounds. This article will review the biology of angiogenesis
      in Hirudo and the data so far collected on angiogenesis stimulation/modulation in
      this model; an example describing a study on the biological activity of a naked
      DNA vector for angiogenesis gene therapy will also be provided.

PMID- 15180534
TI  - Rational drug design of multifunctional phosphoramidate substituted nucleoside
      analogs.
AB  - This review focuses on our approach to the study of the effect of a series of
      phosphoramidate substituted nucleoside analogs on model systems for cancer, HIV
      and fertility. This approach allowed the development of compound WHI-07, an
      arylphosphoramidate derivative of zidavudine. This compound is a multifunctional
      agent showing potent activity in the above mentioned model systems. Our rational
      drug design provided such a powerful derivative with all the necessary
      characteristic of a drug candidate. Importantly, we have experimental evidence
      that each of the groups associated with the molecular frame of WHI-07 imparts the
      multifunctional ability for this agent. In addition, we have also suggested a
      possible biological pathway for WHI-07 including various products with their
      therapeutic targets that are formed during the course of its metabolism inside
      the cell. We also propose which individual moieties in the structure of WHI-07
      are responsible for the biological activity from the formation of these
      metabolites. A detailed structure-activity relationship is presented in the
      review in connection with various structural modifications of the agent.
      Application of this active agent in animal models shows the potential usefulness
      of this agent as a drug candidate. We further plan to utilize gene-chip
      technology to identify new targets and modes of action using microarrays to
      measure expression changes in thousands of gene products. In conclusion, we have
      demonstrated the power of multifunctional drug design to discover drugs to combat
      various diseases. We believe this is the future direction of the drug discovery
      process.

PMID- 15180535
TI  - Modulation of the Fcepsilon receptor I signaling by tyrosine kinase inhibitors:
      search for therapeutic targets of inflammatory and allergy diseases.
AB  - Mast cells and basophils are major effector cells in the immunoglobulin E (IgE)
      dependent allergic reactions as well as in the innate immunity. They are
      distributed throughout the body and, upon allergen exposure, are stimulated via
      the high affinity IgE receptor (FcepsilonRI) to release several pro-inflammatory
      mediators such as leukotrienes, immunoregulatory cytokines and histamine.
      FcepsilonRI-mediated signaling is initiated by tyrosine phosphorylation of
      FcepsilonRI subunits by Src family kinase Lyn, which is followed by an activation
      of Syk/Zap family kinase Syk. The activated kinases then in turn phosphorylate
      and activate other enzymes [phospholipase Cgamma (PLCgamma) isoforms,
      phosphatidylinositol-3 kinase (PI3K) isoforms, protein kinase C (PKC) isoforms,
      Bruton's tyrosine kinase (Btk) and others], adaptors [linker for activation of T
      cells (LAT), Cbl, Grb2 and others] and GTP exchange factors/GTPases (Vav, Ras,
      Rho, and others), and subsequently induce the mobilization of stored and
      extracellular Ca(2+). These and other biochemical events lead within seconds and
      minutes to the secretory response and later to the production of chemokines. This
      review is focused on the use of tyrosine kinase inhibitors specific for Src
      family kinases (PP1/PP2, SU6656 and CT5269), Syk kinase (piceatannol, ER-27319
      and BAY 61-3606) and Btk (terreic acid and LFM-A13) for a modulation of
      FcepsilonRI-mediated signaling in mast cells. Potential use of the inhibitors in
      the treatment of inflammatory and allergy diseases as well as future directions
      in the development of highly specific tyrosine kinases inhibitors of new
      generations and their use in an intended modulation of mast cell signaling are
      discussed.

PMID- 15180536
TI  - The spleen tyrosine kinase (Syk) in human disease, implications for design of
      tyrosine kinase inhibitor based therapy.
AB  - The spleen tyrosine kinase Syk is an enigmatic protein tyrosine kinase functional
      in a number of diverse cellular processes. It is best known as a non receptor
      protein tyrosine kinase involved in signal transduction in cells of hematopoietic
      origin and plays a crucial role in signaling in most of these cells. It is
      involved in B and T-cell function, platelet aggregation, mast cell signaling,
      neutrophils and macrophages. Recently it has been found in tissues outside of the
      hematopoietic lineage. Perhaps the most interesting non-traditional role of Syk
      is that of a potential tumor suppressor in breast cancer. Absence of Syk protein
      in primary breast tumors is correlated with poor outcomes. Syk deficient cells
      have increased motility which is restored to normalcy by replacement with wild
      type Syk. Syk also associates with the actin and tubulin cytoskeleton and is an
      alpha-tubulin kinase. The central role that Syk has in a number of cellular
      processes makes it an ideal starting point for broad therapeutic targeting.

PMID- 15180537
TI  - Src: regulation, role in human carcinogenesis and pharmacological inhibitors.
AB  - The cellular signaling machinery is a complex network of cross-talking proteins
      that enables dynamic communication between upstream causal factors and downstream
      effectors. Non-receptor tyrosine kinases, including Src, are the intermediates of
      signal transfer, controlling pathways as diverse as cell growth, death,
      differentiation, migration, and genome maintenance. When expressed as viral genes
      these proteins are potent carcinogens. Furthermore, analogous genetic alterations
      are observed, albeit not frequently, in human tumors. In a variety of tumors
      including those derived from the colon and breast, Src is either over expressed
      or constitutively active in a large percentage of patients. Increased expression
      or activity of Src correlates with the stage and metastatic potential of some
      neoplasia. The detailed knowledge of Src activation facilitates rational design
      of drugs that potentially interfere with either binding of ATP or substrate
      peptides. Several existing inhibitors are available as lead compounds for further
      development of Src inhibitors.

PMID- 15180538
TI  - Therapeutic potential of inhibiting Bruton's tyrosine kinase, (BTK).
AB  - BTK (Bruton's tyrosine kinase) is a member of the TEC family of tyrosine kinases
      that plays a central but diverse modulatory role in various cellular processes.
      The unique role of BTK in a multitude of signaling pathways, its function as a
      dual regulator of apoptosis and its involvement in a number of developmental
      processes makes BTK a desirable target for potential anti-cancer, anti
      inflammatory and anti-viral agents as well as other treatments. The biochemistry
      and signaling networks of BTK were well described in numerous detailed reviews
      written by members of our team and others before us. Therefore in this particular
      review we are going to concentrate on the possible practical application of
      previously obtained knowledge to specific diseases and disorders.

PMID- 15180539
TI  - Therapeutic potential of Janus kinase 3 (JAK3) inhibitors.
AB  - Here we discuss the therapeutic potential of Janus kinase 3 (JAK3) inhibitors as
      a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory,
      anti-allergic, anti-thrombotic and anti-leukemic properties. JAKs are abundantly
      expressed in primary leukemic cells from children with ALL (acute lymphoblastic
      leukemia) and are crucial for signals regulating apoptosis. Additional roles for
      JAK3 in mast cell-mediated immediate hypersensitivity reactions, autoimmune
      disorders and platelet function have recently been described. The preclinical
      studies on JAK3 inhibitors revealed their clinical potential as anti-leukemic
      agents with anti-thrombotic, anti-allergic and immunosuppressive properties.
      Results from multiple preclinical experimental model systems of autoimmune
      diabetes, pancreatic islet transplantation, solid organ transplantation, allergy,
      thrombosis and bone marrow transplantation are discussed in the context of the
      clinical need for new immunomodulatory agents with such properties.

PMID- 15180540
TI  - A novel class of HIV-1 inhibitors that targets the viral envelope and inhibits
      CD4 receptor binding.
AB  - BMS-378806 is a prototype of a new class of small molecule HIV-1 inhibitors that
      blocks viral attachment to cells. This compound exhibits potent inhibitory
      activity against a panel of HIV-1 laboratory and clinical isolates (M- and T
      tropic), selective for HIV-1 and inactive against HIV-2, SIV and a panel of other
      viruses. BMS-378806 exhibits no significant cytotoxicity and displays many
      attractive pharmacological properties such as low protein binding, minimal serum
      effect on anti-HIV-1 potency, good oral bioavailability in animal species and a
      clean safety profile in initial animal toxicology studies. The compound binds to
      gp120 and blocks the attachment of the HIV-1 envelope protein to cellular CD4
      receptors via a specific and competitive mechanism. BMS-378806 binds directly to
      gp120 at an approximately 1:1 stoichiometry, with a binding affinity similar to
      that of soluble CD4. Further confirmation that this class of compounds targets
      the envelope in infected cells was obtained through the isolation of resistant
      variants and the mapping of resistance substitutions to the HIV-1 envelope. In
      particular, two substitutions, M426L and M475I, are situated at or near the CD4
      binding pocket of gp120. Recombinant HIV-1 carrying these two substitutions
      demonstrated significantly reduced susceptibility to inhibition. Using these HIV
      1 gp120 resistant variants and gp120/CD4 contact site mutants, the potential BMS
      378806 target site was localized to a specific region within the CD4 binding
      pocket of gp120. Together, the data show that BMS-378806 is the first of a new
      class of HIV inhibitors with the potential to become a valued addition to our
      current repertoire of antiretroviral drugs.

PMID- 15180541
TI  - CD4 down-modulating compounds with potent anti-HIV activity.
AB  - The use of HAART with double or triple drug combinations has significantly
      improved the survival of AIDS patients. However, the emergence of virus-drug
      resistance and both short- and long-term drug-related side effects are among the
      main reasons for continuing the development of new classes of effective anti-HIV
      drugs that target the replicative cycle at different sites. In recent years,
      tremendous progress has been made in understanding HIV-1 entry, a multistep
      process that comprises viral attachment, coreceptor interactions and fusion. The
      mechanistic insight gained from these studies has enabled the design of specific
      agents that can inhibit each step in the HIV entry process. The successful
      results from clinical trials with enfuvirtide (T-20), the first approved entry
      inhibitor, indicate that targeting of HIV entry will soon be an important
      component of antiretroviral therapy and further encourage the development of
      effective entry inhibitors. In this article the recent developments of
      therapeutic agents endowed with inhibitory properties against the binding of the
      HIV envelope glycoprotein gp120 to the CD4 receptor (e.g., PRO 542, BMS-378806,
      TNX-355, PRO 2000 and CV-N) are briefly outlined. Major focus is placed on the
      anti-HIV activity of cyclotriazadisulfonamides (CADA), a novel class of compounds
      with a unique mode of action by down-modulating the CD4 receptor in lymphocytic
      and monocytic cells.

PMID- 15180542
TI  - HIV-1 gp41 as a target for viral entry inhibition.
AB  - The recent success of the fusion inhibitor T-20 (enfuvirtide) in clinical studies
      has ushered in a new chapter in the development of anti-HIV-1 therapeutics. T-20
      is the first FDA-approved drug that targets the viral transmembrane protein gp41.
      This protein, along with gp120, promotes viral entry through a coordinated
      cascade of conformational transitions that lead to the fusion of the HIV-1 and
      target cell membranes. The interaction of gp120 with CD4 and a chemokine receptor
      stimulates gp41 to extend and bridge the space between the virus and cell.
      Subsequently, gp41 collapses into a trimer-of-hairpins structure that brings the
      viral and cellular membranes into close proximity necessary for fusion.
      Enfuvirtide targets the gp41 amino-terminal region exposed in the transient
      extended state, blocking the ultimate collapse into the trimer-of hairpins and
      inhibiting membrane fusion. The vulnerability of this transient extended state
      has stimulated the development of new agents, ranging from small molecules to
      large proteins, that bind to gp41 and inhibit its structural transformations. The
      discovery and characterization of these inhibitors have not only led to new
      antiviral strategies, but have also shed light on the accessibility of gp41
      epitopes that might play a role in HIV-1 vaccine development.

PMID- 15180543
TI  - High throughput screening and characterization of HIV-1 entry inhibitors
      targeting gp41: theories and techniques.
AB  - The gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope
      glycoprotein plays an important role in HIV-1 entry and severs as an attractive
      target for development of HIV-1 entry inhibitors, a new class of anti-HIV drugs.
      Triggered by gp120 binding to CD4 and a coreceptor, gp41 undergoes a conformation
      shift from a native prefusogenic state to a fusogenic state, in which the N
      terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) associate to form
      a six-helix bundle, representing the fusion-active gp41 core. Any compound that
      disrupts the gp41 six-helix bundle formation may inhibit the gp41-mediated
      membrane fusion, thereby blocking HIV-1 entry into target cells. Peptides derived
      from the gp41 NHR and CHR regions, designated N- and C-peptides, can interact
      with the counterpart regions in gp41 and interfere with the six-helix bundle
      formation between the viral NHR and CHR region, thus inhibiting fusion of the
      virus with the target cell. One of the C-peptides, T-20 (brand name: Fuzeon), was
      recently approved by the US FDA as the first HIV entry inhibitor which can be
      used for treatment of AIDS patients who fail to respond to the current
      antiretroviral drugs, e.g., the reverse transcriptase inhibitors and protease
      inhibitors. The limitations of T-20 include lack of oral availability and high
      cost of production. Thus it is essential to develop small molecule HIV-1 entry
      inhibitors targeting gp41. This review summarizes the newly developed techniques
      for high throughput screening (HTS) and characterization of the HIV-1 entry
      inhibitors targeting gp41. The theories behind these techniques are also
      discussed. It is expected that the "drug-like" compounds with potent HIV-1 fusion
      inhibitory activity will be identified in the near future and used as leads for
      development of the low molecular weight HIV-1 entry inhibitors for the
      chemotherapy of HIV-1 infection and AIDS.

PMID- 15180544
TI  - HIV-resistance to viral entry inhibitors.
AB  - An increasing number of human immunodeficiency virus (HIV)-infected patients have
      detectable viraemia despite treatment with multiple-drug combinations or have
      developed resistance to all available classes of antiretroviral therapy. HIV
      entry has become an important pharmacological target. Enfuvirtide is the first
      HIV entry inhibitor to be approved for the treatment of drug-experienced patients
      but several other agents are progressing through preclinical and clinical trials.
      However, because different entry inhibitors target different parts of the entry
      process their combined effects could be synergistic or generate different
      distinct profiles of drug-resistance. The HIV envelope glycoprotein that drives
      HIV entry is highly variable. Its plasticity allows HIV to escape the immune
      system and its variability is associated with HIV tropism, fitness and
      replicative capacity. Thus, mutations that confer resistance to entry inhibitors
      will modify these parameters. Therapeutic strategies that aim at blocking virus
      entry may also be used to alter the natural evolution of HIV in an unprecedented
      way. Here, we will describe the structure and function of the envelope
      glycoprotein complex that constitute the basis for the emergence of resistance to
      HIV entry inhibitors, review those HIV entry inhibitors for which drug-resistance
      has been evaluated and discuss the interplay between viral resistance to
      inhibitors of HIV entry and the pathogenicity of HIV and AIDS.

PMID- 15180545
TI  - Effects of HIV-1 entry inhibitors in combination.
AB  - Inhibiting the HIV-1 entry process offer a new therapeutic target and the hope to
      potentialize our current treatments against wild-type or drug-resistant viruses.
      Several inhibitors of CD4, co-receptor CCR5 or CXCR4 and fusion are at various
      levels of clinical development. How best to use this class of drugs in our
      therapeutic arsenal remains to be defined. It is likely that these compounds will
      not be used as monotherapy. Therefore, it is important to evaluate how these
      drugs will interact among themselves as well as with antiretrovirals from other
      classes. Drug interactions can range from synergy to antagonism depending on
      factors including binding affinity, drug concentrations, and pharmacokinetics. In
      the case of entry inhibitors, one must also consider that the entry of HIV-1 into
      the cell is a multi-step process that involve cumulative events which are
      interdependent. Furthermore, polymorphism both in the coreceptors and in gp120,
      the density of coreceptors, and the binding site of the drug may also affect
      efficacy. Therefore it is difficult to predict how blocking one step of the
      process will affect the subsequent one without carefully studying interactions of
      each potential combination in an in vitro system. So far, studies of interactions
      between fusion inhibitors and coreceptor inhibitors have shown a high level of
      synergy. Similar studies performed with two co-receptor inhibitors have shown
      results varying from synergy to high antagonism depending on the viral isolate
      and the compounds used. In the following chapter, we will review some concepts of
      mechanisms that may affect these interactions.

PMID- 15180546
TI  - Single molecule techniques for biomedicine and pharmacology.
AB  - The present review gives a short summary on techniques useful for single molecule
      research, describes experiments on in vitro single molecule detection and
      reactions of single molecules and finally reports on the behavior of single
      molecules and single virus particles in living cells. One experiment on single
      molecule enzyme kinetics of lactate dehydrogenase, an enzyme used in the
      diagnosis of heart attacks and one experiment on restriction analysis of
      individual DNa molecules are described in some detail. Where it is possible, the
      relevance to pharmacology and biomedicine is emphasized, often as a perspective
      or suggestion for experiments, since in this young field of science a not too
      large variety of experiments have indeed already been devoted directly to drug
      action.

PMID- 15180547
TI  - Single-molecule spectroscopy studies of conformational change dynamics in
      enzymatic reactions.
AB  - Protein conformational dynamics, often associated with static and dynamic
      inhomogeneities, plays a crucial role in biomolecular functions. It is extremely
      difficult to characterize such inhomogeneous dynamics in an ensemble-averaged
      measurement, especially when the protein involves in a multiple-step complex
      chemical reaction, such as an enzymatic reaction. Single-molecule spectroscopy is
      a powerful approach to analyze protein conformational dynamics in real time under
      physiological conditions, providing dynamic perspectives on a molecular-level
      understanding of protein structure-function mechanisms. In this minireview, we
      discuss our recent studies on single-molecule enzymatic reaction dynamics and
      protein conformational dynamics of the T4 lysozyme hydrolyzation reaction of a
      polysaccharide by a combined approach of single-molecule spectroscopy, molecular
      dynamics simulation, and theoretical modeling. Detailed characterization of the
      complex enzymatic reaction dynamics identified the nature of the inhomogeneity
      and revealed multiple intermediate conformational states associated with the
      enzyme-substrate complex formation in the multiple-step enzymatic reaction.

PMID- 15180548
TI  - Single-molecule spectroscopy for nucleic acid analysis: a new approach for
      disease detection and genomic analysis.
AB  - Recently developed single-molecule spectroscopy (SMS) permits the analysis of
      fluorescent mixtures one molecule at a time. SMS methods provide the means to
      make rapid measurements on small, complex samples without the need for
      separations and target amplification enabling a new class of ultrasensitive
      nucleic acid assays. Here we give a brief overview of the current state of the
      art of SMS nucleic acid analysis and discuss ongoing work in our laboratory on
      two-color single-molecule fluorescence detection of specific nucleic acid
      sequences. In the future, two-color SMS nucleic acid assays will be used for a
      variety of applications including: gene expression analysis, disease detection
      and genomics.

PMID- 15180549
TI  - Applications of single-molecule detection to the analysis of pathogenic DNA.
AB  - We have devised a new technique based on single fluorescent molecule detection
      for the analysis of specific sequences of DNA. The method consists of
      synthesizing a fluorescent reporter molecule using a polymerase extension
      reaction and labeled nucleotides. The fluorescent reporter products are analyzed
      in a laser-based single-molecule detection system. We have applied this method to
      the detection of pUC19 and Bacillus anthracis DNA targets. We expect that this
      method will have applications in rapid detection and identification of DNA from
      pathogens as well as other sources, and that it will be used for processing of
      large number of samples in a short period of time.

PMID- 15180550
TI  - Using photoinduced charge transfer reactions to study conformational dynamics of
      biopolymers at the single-molecule level.
AB  - This mini-review describes how single-molecule sensitive fluorescence resonance
      energy transfer (FRET) and photoinduced electron transfer (PET) reactions can be
      successfully applied to monitor conformational dynamics in biopolymers. Single
      pair FRET experiments are ideally suited to study conformational dynamics
      occurring on the nanometer scale, e.g. during protein folding or unfolding. In
      contrast, conformational dynamics with functional significance, for example
      occurring in enzymes at work, often appear on much smaller spatial scales of up
      to several Angstroms. Our results demonstrate that selective PET-reactions
      between fluorophores and amino acids or DNA nucleotides represent a versatile
      tool to measure small-scale conformational dynamics in biopolymers on a wide
      range of time scales, extending from nanoseconds to seconds, at the single
      molecule level. That is, the monitoring of conformational dynamics of biopolymers
      with temporal resolutions comparable to those within reach using new techniques
      of molecular dynamic simulations. Furthermore, we demonstrate that the strong
      distance dependence of charge separation reactions on the sub-nanometer scale can
      be used to develop conformationally flexible PET-biosensors. These sensors enable
      the detection of specific target molecules in the sub-picomolar range and allow
      one to follow their molecular binding dynamics with temporal resolution.

PMID- 15180551
TI  - Time-resolved confocal fluorescence imaging and spectrocopy system with single
      molecule sensitivity and sub-micrometer resolution.
AB  - We present novel technical features and results from a two channel confocal
      fluorescence lifetime microscope, which allows to efficiently investigate
      fluorescence dynamics down to the single molecule level. The MicroTime 200 time
      resolved fluorescence microscope offers a multicolor excitation where different
      picosecond diode lasers are used. For imaging and positioning purposes we utilize
      a compact Piezo scanner which allows, due to a novel scanning algorithm and
      synchronisation technique, a superior movement and positioning accuracy. The data
      acquisition is completely based on time-correlated single photon counting, where
      every photon is detected and stored individually with its specific timing
      information (Time-Tagged Time-Resolved mode). This multiparameter data
      acquisition scheme offers the opportunity to analyse the parameter dependencies
      in a multitude of different ways. Standard intensity analysis can be used to
      reconstruct 2D-images or the temporal evolution (time trace) of the fluorescence
      of a single spot. The information from the two distinct detector channels
      additionally allows to investigate the polarisation of the emitted light or its
      spectral composition, for example for analysis of Fluorescence Resonance Energy
      Transfer (FRET). The timing information down to a picosecond scale offers the
      possibility not only to reconstruct fluorescence decay constants of each pixel
      for the purpose of Fluorescence Lifetime Imaging (FLIM) but also to analyze the
      fluorescence fluctuation correlation function of any single spot of interest. The
      flexible multichannel detector scheme enables in this case also a cross
      correlation between spectrally separated parts of the emission light, or even
      identical parts of the fluorescence to eliminate detector artifacts. The photon
      arrival coincidence analysis can also be expanded in the sub-ns range to study
      fluorescence antibunching in the fluorescence emission of single molecules. The
      ability of combining these different pieces of temporal information allows the
      construction of extremely powerful analysis methods and assays. We demonstrate a
      variety of these capabilities with results obtained from fluorescently labeled
      latex beads, biological samples, and single molecules excited in the blue or red
      wavelength region.

PMID- 15180561
TI  - Retinoids and receptor interacting protein 140 (RIP140) in gene regulation.
AB  - Retinoids exert pleiotropic effects in various biological processes by binding to
      their nuclear receptors, the retinoic acid receptors (RARs) and retinoid X
      receptors (RXRs), to regulate gene transcription. Apo-RARs and RXRs repress
      target gene expression by recruiting corepressors to the target DNA, triggering
      chromatin condensation by the action of histone deacetylases present in the
      corepressor complexes. In contrast, holo-RARs and RXRs recruit coactivators, some
      known to encode histone acetyl transferases, which trigger histone
      hyperacetylation, chromatin decondensation, and ultimately gene activation.
      Receptor interacting protein 140 (RIP140) represents a novel RAR/RXR coregulator
      that suppresses vitamin A-regulated gene expression in a retinoid- dependent
      manner. This review addresses the action of different retinoid ligands on gene
      expression, the molecular mechanisms underlying RAR/RXR-mediated gene regulation,
      and the unique properties of RIP140 as a novel retinoid hormone-dependent
      negative coregulator for RAR- and RXR-mediated gene regulation.

PMID- 15180562
TI  - Blocking Ca2+entry: a way to control cell proliferation.
AB  - Ca(2+) signalling is involved in virtually all cellular processes: among the
      others, it controls cell survival, proliferation and death regulating a plethora
      of intracellular enzymes located in the cytoplasm, nucleus and organelles.
      Changes in the cytosolic free Ca(2+) concentration may be due either to release
      from the intracellular Ca(2+) stores or to influx from the extracellular medium,
      through the opening of plasma membrane calcium-permeable channels. In particular,
      Ca(2+) entry from the extracellular space is a mechanism able to sustain long
      lasting intracellular Ca(2+) elevations: this signal, activated by many growth
      factors and mitogens in normal and tumoral tissues, is linked to DNA
      transcription and duplication, finally leading to cell proliferation. In the last
      years many informations have been provided about the transduction mechanisms
      related to Ca(2+) entry induced by mitogenic factors, mostly binding to tyrosine
      kinase receptors, but also to G-protein coupled ones. Nevertheless, some key
      points remain to be fully clarified: among them, the molecular structure of the
      Ca(2+) channels involved, their regulation by intracellular messengers, and the
      modes through which specificity is achieved. The increasing knowledge on Ca(2+)
      entry-dependent control of proliferation may provide a more satisfactory
      understanding of pathological alterations, including cancer progression and
      angiogenesis. A detailed description of the mechanisms that trigger Ca(2+) entry,
      and in particular the definition of calcium-permeable channels and their
      modulators at the molecular levels, will greatly improve our possibility to take
      advantage of Ca(2+) entry regulation as a therapeutic approach for the control of
      cell proliferation, designing antibodies or molecules with low side effects and
      specific channel blocker functions. The review will focus on this topic.

PMID- 15180552
TI  - Ultra-sensitive fluorescence reader for bioanalysis.
AB  - Recent advances in the development of new microscopical techniques with single
      molecule sensitivity have given access to essentially new types of information on
      biological systems. In this review, basic methodological concepts of ultra
      sensitive microscopy are presented and characterized, with focus on their
      applicability for a bioanalytical instrument. Measurements on artificial lipid
      bilayers were used to evaluate the feasibility of this novel technology. First
      examples of single molecule microscopy on cell membranes revealed new basic
      insights into the lateral organization of the plasma membrane.

PMID- 15180563
TI  - Heme oxygenase-1: a novel therapeutic target in oxidative tissue injuries.
AB  - Oxidative stresses such as oxidant stimuli, inflammation, exposure to
      xenobiotics, or ionizing irradiation provoke cellular protective responses,
      principally involving transcriptional activation of genes encoding proteins which
      participate in the defense against oxidative tissue injuries. Excess of free
      heme, which is released from hemeproteins under such conditions, may constitute a
      major threat because it can catalyze the formation of reactive oxygen species
      (ROS). Exposure of mammalian cells to oxidative stimuli induces heme oxygenase-1
      (HO-1), the rate-limiting enzyme in heme degradation, as well as a 33-kDa heat
      shock protein. In various model systems, HO-1 induction confers protection on
      tissues from further injuries, while the abrogation of its induction accelerates
      cellular injuries. In this article, we review recent advances in the regulatory
      mechanism of ho-1 gene expression and the role of HO-1 in various models of
      experimental oxidative tissue injuries, and its potential therapeutic
      implications.

PMID- 15180564
TI  - The design of drug candidate molecules as selective inhibitors of therapeutically
      relevant protein kinases.
AB  - The human genome encompasses some 2,000 proteins that utilize adenosine 5'
      triphosphate (ATP) in one way or another and some 500 of these are protein
      tyrosine and protein-serine/threonine kinases (PTKs & PSTKs). Substrate
      phosphorylation by these enzymes is nature's predominant molecular way of
      organizing cellular signal transduction and regulating biochemical processes in
      general. It is not surprising, therefore, that abnormal phosphorylation of
      cellular proteins is a hallmark of disease and that there has been a growing
      interest in the use of kinase inhibitors as drugs. In fact the search for such
      agents has recently culminated in the approval of the first kinase inhibitor
      drugs for medical use. Although it has been demonstrated exhaustively that potent
      and structurally diverse ATP-antagonistic small molecule kinase inhibitors can be
      found through mass screening and structure-guided design, the question of
      biochemical, cellular, and in vivo selectivity of such inhibitors remains much
      less clear. Here the medicinal chemistry of kinase inhibitors is reviewed
      critically with particular emphasis on target selectivity and specificity.
      Approaches based on chemical genomics, combinatorial target-guided ligand
      assembly, computational chemistry, and structural biology techniques, which aim
      at classifying both inhibitors and kinase targets, are given special emphasis.
      The various strategies in which differences in biochemical mechanism of kinase
      function can be exploited in order to attain selective inhibition are also
      discussed. Furthermore, recent developments in the design of inhibitors to
      selected individual validated therapeutic kinase targets, including cell cycle
      kinases and receptor PTKs, etc. are summarised.

PMID- 15180565
TI  - Electron-capture mass spectrometry: a powerful tool in biomedical trace level
      analysis.
AB  - This review focuses on the advances in electron capture mass spectrometry.
      Electron-capture (EC) is a sensitive ionisation technique for mass spectrometry
      providing selectivity towards electrophoric compounds. Recent advances in
      instrumentation have led to a more widespread application of this method in
      biomedical and pharmaceutical analysis. After a brief introduction to EC-mass
      spectrometry (MS), potential targets for EC-MS analysis are defined and
      enhancement of sensitivity by electrophoric derivatisation is discussed. A wide
      range of applications is selected, including prostanoid analysis in biomedical
      systems (with the oxidative stress indicators isoprostanes) and the trace level
      analysis of endogenous low-molecular weight compounds. Application to the trace
      level gas chromatography-negative ion chemical ionization MS (GC-NICI-MS)
      analysis of complex glucuronides is also demonstrated, as well as a wide range of
      drugs analysed in human blood. The review should point out the versatility and
      unique sensitivity of the technique, making it useful for basic research in
      medicinal chemistry, as well as clinical diagnosis, pharmaceutical and
      toxicological applications.

PMID- 15180566
TI  - Inhibition of insulin secretion as a new drug target in the treatment of
      metabolic disorders.
AB  - The pattern of insulin release is crucial for regulation of glucose and lipid
      haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas
      excessive insulin release can give rise to serious metabolic disorders, such as
      nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and
      might also be closely associated with development of type 2 diabetes and obesity.
      Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance
      and impaired insulin release, i.e. reduced first phase insulin release and
      decreased insulin pulse mass. The beta cell function of patients with type 2
      diabetes slowly declines and will ultimately result in beta cell failure and
      increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity
      and cardiovascular disorders, forms the metabolic syndrome. It has been possible
      to improve beta cell function and viability in preclinical models of type 1 and
      type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical
      studies have furthermore indicated that inhibitors of insulin release will be of
      benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells
      secrete insulin in response to increased metabolism and by stimulation of
      different receptors. The energy status of the beta cell controls insulin release
      via regulation of open probability of the ATP sensitive potassium (K(ATP))
      channels to affect membrane potential and the intracellular calcium concentration
      [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular
      targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin
      release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic
      receptors, cholecystokinin receptors and adrenergic receptors. Although the
      relationship between hyperinsulinemia and certain metabolic diseases has been
      known for decades, only a few inhibitors of insulin release have been
      characterized in vitro and in vivo. These include the K(ATP) channel openers
      diazoxide and NN414 and the somatostatin receptor agonist octreotide.

PMID- 15180567
TI  - In silico prediction models for blood-brain barrier permeation.
AB  - The ability to permeate across the blood brain barrier (BBB) is essential for
      drugs acting on the central nervous system (CNS). Thus, for speeding up the drug
      discovery process in the CNS-area, it is of great importance to develop systems
      that allow rapid and inexpensive screening of the BBB-permeability properties of
      novel lead compounds or at least small subsets of combinatorial CNS-libraries. In
      this field, in silico prediction methods gain increasing importance. Starting
      with simple regression models based on calculation of lipophilicity and polar
      surface area, the field developed via PLS methods to grid based approaches (e.g.
      VolSurf). Additionally, the use of artificial neural networks gain increasing
      importance. However, permeation through the BBB is also influenced by active
      transport systems. For nutrients and endogenous compounds, such as amino acids,
      monocarboxylic acids, amines, hexoses, thyroid hormones, purine bases and
      nucleosides, several transport systems regulating the entry of the respective
      compound classes into the brain have been identified. The other way round there
      is striking evidence that expression of active efflux pumps like the multidrug
      transporter P-glycoprotein (P-gp) on the luminal membrane of the brain capillary
      endothelial cells accounts for poor BBB permeability of certain drugs.
      Undoubtedly, P-gp is an important impediment for the entry of hydrophobic drugs
      into the brain. Thus, proper prediction models should also take into account the
      active transport phenomena.

PMID- 15180568
TI  - Trichostatin A-like hydroxamate histone deacetylase inhibitors as therapeutic
      agents: toxicological point of view.
AB  - Modulation of chromatin structure through histone acetylation/deacetylation is
      known to be one of the major mechanisms involved in the regulation of gene
      expression. Two opposing enzyme activities determine the acetylation state of
      histones: histone acetyltransferases (HATs) and histone deacetylases (HDACs),
      respectively acetylating or deacetylating the epsilon-amino groups of lysine
      residues located in the amino-terminal tails of the histones. In general,
      transcriptionally active chromatin is associated with hyperacetylated histones,
      whilst silenced chromatin is linked to hypoacetylated histones. A number of
      structurally divergent classes of HDAC inhibitors have been identified. They have
      been shown to induce cell cycle arrest, terminal differentiation and/or apoptosis
      in various cancer cell lines and inhibit tumor growth in animals. In particular,
      the reversible HDAC inhibitor Trichostatin A (TSA) and its hydroxamate analogues
      can effectively and selectively induce tumor growth arrest at very low
      concentrations (nano- to micromolar range). They form a group of so-called
      promising antitumor agents of which some are currently under clinical trial.
      Since the selection of a molecule for further drug development requires a balance
      of biological potency, safety and pharmacokinetics, it is of paramount importance
      to elucidate the pharmacokinetic and toxicological properties of these HDAC
      inhibitors before they can be considered as potential new drugs. Primary
      hepatocytes and their cultures are well-differentiated in vitro models and can be
      used to study simultaneously the biological effects of HDAC inhibitors and their
      biotransformation. The present review provides a state-of-the-art of our current
      knowledge of the pharmacological and toxicological effects on proliferating cells
      of TSA and its hydroxamate-based structural analogues. Besides a theoretical
      basis, an overview of the experimental results, obtained by the authors using
      primary rat hepatocytes as an in vitro model, is given.

PMID- 15180569
TI  - Polyene macrolide antibiotic biosynthesis.
AB  - Polyenes constitute a large class of natural metabolites produced by giant
      multifunctional enzymes in a process resembling fatty acid biosynthesis. Like
      fatty acids, polyene macrolides and other polyketides are assembled by
      decarboxylative condensations of simple carboxylic acids. But while fatty acid
      intermediates are fully reduced, polyene macrolide intermediates suffer the
      suppression of reduction or dehydration reactions at given biosynthetic steps. In
      the last years, much progress has been made in our understanding of the linear
      and modular organization of the gene clusters, and the enzymes encoded by them,
      responsible for the biosynthesis of these macrocyclic metabolites. This know-how
      about the rules that govern polyene chain growth has provided the basis for the
      first rational manipulations of these fascinating systems for the production of
      engineered derivatives and promises a new era of novel polyene development, which
      will hopefully yield new molecules with improved pharmacological properties.

PMID- 15180570
TI  - Organoselenium compounds as potential therapeutic and chemopreventive agents: a
      review.
AB  - Selenium is an essential trace element. It is, however toxic at concentration
      little above which is required for health. Selenium is incorporated into proteins
      as selenocysteine, the 21(st) amino acid. Selenoproteins are found in bacteria,
      archaea and eukaryotes. Biochemical and physicochemical properties of selenium
      result in the unique redox characteristics of selenocysteine and its use in
      antioxidant enzymes. In this context of a redox reaction is the reduction of
      reactive oxygen metabolites by glutathione peroxidases, helping to maintain
      membrane integrity, reduces the oxidative damage to lipids, lipoproteins, and
      DNA. Selenium has structural and enzymatic roles. Selenium influences a number of
      endocrine processes, most notably, those involved in thyroid hormone synthesis
      and metabolism. Se is needed for the proper functioning of the immune system, a
      role in viral suppression, AIDS, and also is implicated in delaying the aging
      process. Its deficiency has been linked to a number of disorders such as heart
      disease, diabetes, and diseases of the liver, and it is required for sperm
      motility and may reduce the risk of miscarriage. Se supplementation has recently
      moved from the realm of correcting nutritional deficiencies to one of
      pharmacological intervention, especially in the clinical domain of cancer
      chemoprevention. During the last few years, a tremendous effort has been directed
      toward the synthesis of stable organoselenium compounds that could be used as
      antioxidants, enzyme modulators, antitumor, antimicrobials, antihypertensive
      agents, antivirals and cytokine inducers. The biochemistry and pharmacology of
      selenium-based compounds are subjects of intense current interest, especially
      from the point of view of public heath. The purpose of this review is to discuss
      the recent pharmacological applications of organoselenium compounds as
      therapeutic agents in the treatment of several diseases.

PMID- 15180571
TI  - Chemical and biological characterization and clinical evaluation of botanical
      dietary supplements: a phase I red clover extract as a model.
AB  - Botanical dietary supplements, as compared with nutritional supplements or single
      component pharmaceutical drugs, are typically less-refined preparations derived
      from bulk plant material and, as such, require a modified approach to their
      development, production, and evaluation. An integrated, multidisciplinary team of
      scientific and clinical investigators is required in order to develop high
      quality phytomedicines and rigorously evaluate their safety and efficacy.
      Research on botanicals involves unique challenges as plant source materials
      frequently vary in chemical content and may contain unwanted pesticides, heavy
      metals, contaminant plant species, or other adulterants. Ideally, a botanical
      formulation should be standardized, both chemically and biologically, by a
      combination of analytical techniques and bioassays. This combination approach
      provides multiple measures by which reproducible quality and efficacy of
      botanical supplements may be achieved, and is particularly useful for botanical
      products for which the active compound(s) have not yet been identified. Safety
      and toxicity should be evaluated during the supplement development process in
      both in vitro and in vivo systems. A number of liquid chromatography-mass
      spectrometry methods can aid in the assessment of purity, bioavailability,
      toxicity, metabolism, and molecular target profiling of botanical extracts.
      Clinical investigators must appreciate the complexity of multi-component
      phytomedicines and adjust trial protocols accordingly. This review highlights
      practical considerations of value to basic science and clinical investigators
      engaged in the study of botanical supplements. Lessons and examples are drawn
      from the authors' experience in designing and developing a red clover (Trifolium
      pratense L.) standardized extract for evaluation in Phase I and Phase II clinical
      trials.

PMID- 15180572
TI  - Natural products in the process of finding new drug candidates.
AB  - Natural derived or originated compounds still play a major role as drugs, and as
      lead structures for the development of synthetic molecules. About 50% of the
      drugs introduced to the market during the last 20 years are derived directly or
      indirectly from small biogenic molecules. In the future, natural products will
      continue to play a major role as active substances, model molecules for the
      discovery and validation of drug targets. A multidisciplinary approach to drug
      discovery involving the generation of truly novel molecular diversity from
      natural product sources, combined with total and combinatorial synthetic
      methodologies provides the best solution to increase the productivity in drug
      discovery and development. Screening for new drugs in plants implies the
      screening of extracts for the presence of novel compounds and an investigation of
      their biological activities. It is currently estimated that approximately 420,000
      plant species exist in nature. For the purpose of lead discovery, or for the
      scientific validation of a traditional medicinal plant or a phytopharmaceutical,
      active principals in complex matrices need to be identified. Therefore, the
      interfacing of biological and chemical assessment becomes the critical issue.
      Drug discovery from plants can be guided by epidemiologic studies facilitated
      with computer assisted HPLC microfractionation and microplate technology.
      Epidemiologic studies have shown that high dietary flavonoid intake may be
      associated with decreased risk for cardiovascular disease. Chlamydia pneumoniae
      is a common human pathogen and epidemiological and clinical studies have shown a
      connection between chronic C. pneumoniae infection, atherosclerosis and the risk
      of myocardial infarction. We will present here the detection of natural compounds
      active against C. pneumoniae as an example.

PMID- 15180573
TI  - Authentication of medicinal plants using molecular biology techniques to
      compliment conventional methods.
AB  - Medicinal plants have become extremely popular in the United States as botanical
      supplements, herbal medicines and sources of lead compounds for pharmaceutical
      development. It is estimated that in 1997 Americans used or consumed 5.1 billion
      US dollars worth of herbal medicines. For the protection of consumers,
      authentication of medicinal plants is a critical issue. Ideally, authentication
      should occur from the harvesting of the plant material to the final product.
      Unfortunately there is no single or superior method to assure 100 percent
      authentication during the entire process, but the goal can be achieved through
      the application of a variety of different methodologies. The whole process starts
      with good voucher specimens that act as reference material and to prove chain of
      custody. Macroscopic and microscopic examinations can be used as rapid and
      inexpensive identification techniques. Chemical analysis is by far the best
      method for the detection of contaminants and can be an excellent method for plant
      identification. Each of these methodologies has limitations and more analytical
      methods are needed to assist in the authentication process. Molecular biology
      offers an assortment of techniques that can be very useful for authentication of
      medicinal plants. This review covers various aspects of authentication methods,
      with special emphasis on molecular biology techniques.

PMID- 15180574
TI  - Efficacy, chemistry and pharmacology of chinese herbal medicine for allergic
      rhinitis.
AB  - An extensive literature search identified six randomized controlled clinical
      trials in which the efficacy of Chinese herbal medicine had been investigated for
      the treatment of allergic rhinitis. Although four of these trials had
      methodological flaws, the therapeutic outcomes of all six have been reviewed. One
      of two trials considered to be of high quality was concerned with the treatment
      of seasonal allergic rhinitis and the other with perennial allergic rhinitis. It
      is considered that all six studies demonstrated various degrees of alleviation of
      the symptoms of allergic rhinitis. No serious side effects were reported in any
      of the trials. A number of the herbs in the Chinese herbal formulae used in the
      trials, and/or their constituent compounds have been reported to possess anti
      allergic, anti-inflammatory or immune modulation activity. Such actions include
      inhibition of the release or action of mast cell mediators such as histamine,
      inhibition of inflammation induced by chemical agents, and modulation of serum
      IgE levels or of lymphocyte and/or macrophage activity. An aqueous, unresolved
      extract of the herbal formula used in one of the six trials has been reported to
      exhibit a range of pharmacological actions relevant to the treatment of allergic
      rhinitis. Essential oils, lignans, flavonoids and saponins are chemical classes
      that are frequently represented in individual herbs of the six Chinese herbal
      formulae used in the trials. The chemical structures characterising these classes
      of compound and the pharmacological actions of these and other constituents of
      the herbs, relevant to allergic rhinitis, have been reviewed.

PMID- 15180575
TI  - Immunomodulatory and antimicrobial effects of some traditional chinese medicinal
      herbs: a review.
AB  - The current practice of ingesting phytochemicals to support the immune system or
      to fight infections is based on centuries-old tradition. We review reports on
      seven Chinese herbs, (Aloe vera Mill. (Aloaceae), Angelica species
      (Umbelliferae), Astragalus membranaceus Bunge. (Leguminosae), Ganoderma lucidum
      (Fr.) Karst. (Ganodermataceae), Panax ginseng C.A Mey. (Araliaceae), Scutellaria
      species (Lamiaceae) and Zingiber officinale Rosc. (Zingiberaceae) with emphasis
      to their immunomodulatory and antimicrobial activities. While some of these
      herbaceous plants have a direct inhibitory effect on microbial organisms, we
      observe that each plant has at least one compound that selectively modulates
      cells of the immune system. The successful derivation of pure bioactive compounds
      from Ganoderma lucidum, ginseng and Zingiber officinale supports the traditional
      practice of using these plants to stimulate the immune system. As many modern
      drugs are often patterned after phytochemicals, studying the influence of each
      compound on immune cells as well as microbes can provide useful insights to the
      development of potentially useful new pharmacological agents.

PMID- 15180576
TI  - Traditional remedies for fertility regulation.
AB  - Plants have been used worldwide for treatment of various human ailments since
      antiquity. Their use is still quite prevalent in developing countries in the form
      of traditional/folkloric system of medicine. Intensive chemical and
      pharmacological studies on traditional/folkloric medicinal plants during the last
      5 decades have led to the validation of traditional claims in many cases and
      facilitated identification of their active principles. The active principles have
      provided leads in the development of several life saving drugs, which are in
      clinical use today. A large number of these plants are used for birth control in
      different countries. The present review has, therefore, been planned to provide
      an account of the investigations carried out on traditional/folkloric plants used
      for fertility regulation. The status of scientific validations of their anti
      fertility potential and identification of active principles during the last 28
      years are discussed. The literature survey shows that approximately 318 different
      plants are in traditional/folkloric use worldwide, of which 227 plants are of
      Indian origin. So far, 74 plants have been screened for their anti-fertility
      potential, 48 of them have been found to be effective. Active principles of about
      15 plants have been identified during the period under review.

PMID- 15180578
TI  - Cytotoxic natural products from Formosan plants and marine organisms.
AB  - Cytotoxic natural products isolated from Formosan plants and marine organisms
      till December, 2002, by local scientists or Taiwanese researchers have been
      reviewed. A total of about 200 compounds belonging to six types of chemical
      structures are listed or/and described in this article. Several compounds with
      special or selective activity have been described in more details. Some structure
      activity relationships for the compounds of the same skeleton are drawn to
      clarify the possible pharmacophores.

PMID- 15180577
TI  - Antimicrobial and chemopreventive properties of herbs and spices.
AB  - Herbs and spices have been used for generations by humans as food and to treat
      ailments. Scientific evidence is accumulating that many of these herbs and spices
      do have medicinal properties that alleviate symptoms or prevent disease. A
      growing body of research has demonstrated that the commonly used herbs and spices
      such as garlic, black cumin, cloves, cinnamon, thyme, allspices, bay leaves,
      mustard, and rosemary, possess antimicrobial properties that, in some cases, can
      be used therapeutically. Other spices, such as saffron, a food colorant;
      turmeric, a yellow colored spice; tea, either green or black, and flaxseed do
      contain potent phytochemicals, including carotenoids, curcumins, catechins,
      lignan respectively, which provide significant protection against cancer. This
      review discusses recent data on the antimicrobial and chemopreventive activities
      of some herbs and spices and their ingredients.

PMID- 15180579
TI  - Natural medicine: the genus Angelica.
AB  - More than 60 species of medicinal plants belong to the genus Angelica (Family:
      Apiaceae). Many of these species have long been used in ancient traditional
      medicine systems, especially in the far-east. Various herbal preparations
      containing Angelica species are available over-the-counter, not only in the far
      eastern countries, but also in the western countries like USA, UK, Germany, etc.
      For centuries, many species of this genus, e.g. A. acutiloba, A. archangelica, A.
      atropupurea, A. dahurica, A. japonica, A. glauca, A. gigas, A. koreana, A.
      sinensis, A. sylvestris, etc., have been used traditionally as anti-inflammatory,
      diuretic, expectorant and diaphoretic, and remedy for colds, flu, influenza,
      hepatitis, arthritis, indigestion, coughs, chronic bronchitis, pleurisy, typhoid,
      headaches, wind, fever, colic, travel sickness, rheumatism, bacterial and fungal
      infections and diseases of the urinary organs. Active principles isolated from
      these plants mainly include various types of coumarins, acetylenic compounds,
      chalcones, sesquiterpenes and polysaccharides. This review evaluates the
      importance of the genus Angelica in relation to its traditional medicinal uses,
      alternative medicinal uses in the modern society and potential for drug
      development, and summarises results of various scientific studies on Angelica
      species or Angelica-containing preparations for their bioactivities including,
      antimicrobial, anticancer, antitumour, analgesic, anti-inflammatory,
      hepatoprotective, nephroprotective, etc.

PMID- 15180580
TI  - Therapeutic constituents and actions of Rubus species.
AB  - Rubus species (family Rosaceae) have been cultivated for centuries for their
      fruits. These and other parts of the plants have been used traditionally for
      therapeutic purposes. This article highlights these and the potential they can
      offer. The constituents reported in the various species and those demonstrated to
      exhibit pharmacological properties have been reviewed. In the search for
      biologically active compounds, one of the most frequently documented species of
      the genus is the raspberry plant R. idaeus, the leaves of which have been used
      traditionally as a uterine relaxant and stimulant during confinement, for the
      treatment of diarrhoea and similar enteric disorders and as an astringent.
      Investigations of other Rubus species have been conducted in the last twenty-five
      years, and have shown possible application for a wide range of indications,
      including bacterial infections, anxiety, pain and inflammation.

PMID- 15180581
TI  - Herb-drug interactions: an evidence based approach.
AB  - The increasing use of herbal medicinal products (HMPs) in the community where
      people are also receiving prescription medicines suggests that adverse herb-drug
      interactions may be of significant public health consequence. The evidence
      available to guide practitioners in decision making is complex and consists of a
      range of sources including adverse event database entries, spontaneous or case
      reports, in vivo and in vitro drug metabolism studies, and in vivo drug
      interaction studies in healthy subjects and patients. In the absence of further
      rigorous studies to assess the clinical significance of herb-drug interactions,
      an evidence-based appraisal of the current literature is essential to guide
      practitioners involved in patient care.

PMID- 15180582
TI  - Gene therapy for heart transplantation-associated acute rejection,
      ischemia/reperfusion injury and coronary arteriosclerosis.
AB  - Acute cardiac allograft rejection is still a major complication after heart
      transplantation. Acute rejection usually responds to conventional
      immunosuppressants, however, the nonspecific nature of the immunosuppression and
      the toxicities of the drugs can be life threatening and may compromise the
      recipient's quality of life. In addition, cardiac allograft arteriosclerosis or
      chronic rejection limits the long-term survival of recipients. Such conditions
      cannot be prevented with conventional therapies. To overcome acute and chronic
      rejection of cardiac allograft as well as ischemia/reperfusion injury associated
      with organ preservation many novel approaches have been proposed. Gene
      transfection of the donor organ during organ preservation is an attractive
      method, because the transfected genes would not affect recipients and treatment
      could be delivered specifically to the site of inflammation. This method could be
      useful to prevent graft failure without systemic adverse effects. Here we shall
      review current advances in gene therapies to prevent and treat organ failure of
      transplanted allografts.

PMID- 15180583
TI  - Gene therapy for restenosis--what now, what next?
AB  - Late luminal loss after coronary angioplasty has resisted pharmacological and
      physical attempts at prevention for over twenty years. As a consequence of the
      resistance of restenosis to traditional therapeutic approaches it has become a
      popular target for DNA-based treatment modalities. In this review we consider
      what is currently known of the basic pathophysiology of restenosis and briefly
      outline the previous attempts to influence the long-term outcome after coronary
      intervention. We then discuss the animal models of vascular injury that have been
      used for studies of gene therapy and the vectors that have been applied to the
      setting of vascular gene transfer before considering the many studies in which
      the effects of specific gene transfer have been studied in the setting of
      vascular injury. These transgenes are considered in four broad groupings: those
      that act by the suppression of cellular proliferation in the vessel wall; those
      that inhibit cell migration; anti-thrombotic transgenes; and transgenes that have
      multiple effects within the vessel. We finally consider why, although more than
      eight years have passed since publication of the first studies of gene transfer
      to inhibit the vascular responses to endoluminal injury, little progress has been
      made in translating gene therapy for restenosis into the human setting. Principle
      reasons for the disappointingly slow clinical implementation of gene therapy for
      restenosis are an incomplete understanding of the vascular biology of restenosis,
      the difficulty of translating findings in animal models into the human setting
      and the technical difficulties incumbent upon localised gene delivery into
      coronary arteries.

PMID- 15180584
TI  - The HVJ-envelope as an innovative vector system for cardiovascular disease.
AB  - Recently promising results of gene therapy clinical trials have been reported for
      treatment of peripheral vascular and cardiovascular diseases using various
      angiogenic growth factors and other therapeutic genes. Viral vector and non-viral
      vector systems were employed in preclinical studies and clinical trials.
      Adenoviral vector and naked plasmid have been used most in the clinical studies.
      HVJ (hemagglutinating virus of Japan or Sendai virus)-liposome vector, a hybrid
      non-viral vector system with fusion of inactivated HVJ virus particle and
      liposome, has developed and demonstrated high transfection efficiency in
      preclinical studies of many different disease models, including a wide range of
      cardiovascular disease models. However, some limitations exist in the HVJ
      liposome technology, especially in the scalability of its production. Recently an
      innovative vector technology, HVJ envelope (HVJ-E) has been developed as a non
      viral vector, consisting of HVJ envelope without its viral genome, which is
      eliminated by a combination of inactivation and purification steps. HVJ-E is able
      to enclose various molecule entities, including DNA, oligonucleotides, proteins,
      as single or multiple therapeutic remedies. The therapeutic molecule-included HVJ
      E vector can transfect various cell types in animals and humans with high
      efficiency. In this review, vector technology for cardiovascular disease and the
      biology of HVJ-E vector technology is discussed.

PMID- 15180585
TI  - Getting to the heart of the matter: exploring opportunities for gene therapy
      treatment of dystrophic cardiomyopathy.
AB  - Muscular dystrophies are broadly classed as skeletal muscle disease entities of
      genetic origin. Accordingly, the development and application of gene therapy
      treatment modalities has focused on skeletal muscle gene replacement.
      Irrespective of this generalization, most forms of dystrophy are accompanied by
      progressive cardiomyopathy and cardiac involvement in muscular dystrophies is now
      recognized as an independent risk for patient morbidity. In this review, we
      summarize the available murine strains most suitable for modeling the dystrophic
      myocardium and discuss the use of adenoviral based vector systems as the
      preferred gene delivery vehicle for modulating dystrophic cardiomyopathy.

PMID- 15180586
TI  - Therapeutic angiogenesis using hepatocyte growth factor (HGF).
AB  - HGF is a mesenchyme-derived pleiotropic factor, which regulates cell growth, cell
      motility, and morphogenesis of various types of cells and is thus considered a
      humoral mediator of epithelial-mesenchymal interactions responsible for
      morphogenic tissue interactions during embryonic development and organogenesis.
      Although HGF was originally identified as a potent mitogen for hepatocytes, it
      has also been identified as a member of angiogenic growth factors. Interestingly,
      the presence of its specific receptor, c-met, is observed in vascular cells and
      cardiac myocytes. In addition, among growth factors, the mitogenic action of HGF
      on human endothelial cells was most potent. Recent studies have demonstrated the
      potential application of HGF to treat cardiovascular diseases such as peripheral
      vascular disease, myocardial infarction and cerebrovascular disease. In this
      review, we will discuss a potential therapeutic strategy using HGF in
      cardiovascular disease.

PMID- 15180587
TI  - Gene therapy approaches for cardiovascular diseases.
AB  - Cardiovascular diseases are one of the main causes of mortality in Western
      countries. Gene therapy is emerging as a potential strategy for the treatment of
      cardiovascular diseases, such as peripheral arterial disease, ischemic heart
      disease, restenosis after angioplasty, vascular bypass graft occlusion and
      transplant-associated coronary artery disease. Since the initial experiments more
      than one decade ago, remarkable progress has been made in the field of gene
      transfer and human clinical trials are underway. In here we give an overview of
      available gene transfer strategies describing several delivery routes and
      currently used vectors in animal studies and clinical trials. Hereby we want to
      focus on new approaches including the potential combination of gene therapy with
      cell therapy and tissue engineering, gene silencing and recently developed
      techniques for targeting genes to the vascular wall and the myocardium.

PMID- 15180588
TI  - Clinical use of intracoronary gene transfer of fibroblast growth factor for
      coronary artery disease.
AB  - Anginal symptoms due to myocardial ischemia continue to affect millions of
      patients despite ongoing improvements in the diagnosis and treatment of coronary
      artery disease. Revascularization therapy with percutaneous coronary
      interventions and coronary artery bypass graft surgery can be highly effective in
      eligible subjects, but many patients are suboptimal candidates due to various
      factors, which include diffuse vascular disease, poor ventricular function and
      failure of prior procedures. Introduction of vascular growth factors to the heart
      to promote angiogenesis and collateral vessel formation has emerged as an
      alternative strategy for the relief of myocardial ischemia in these patients.
      Early preclinical work demonstrated that gene transfer of fibroblast growth
      factor using an E1-deleted adenovirus vector via intracoronary injection could
      safely reverse stress-induced ischemic ventricular dysfunction with no
      discernible evidence of inflammatory response. The AGENT trial established that
      intracoronary administration of Ad5FGF-4 could be performed with reasonable
      safety to patients with coronary artery disease, and that a one-time dose could
      provide an anti-ischemic effect out to 12 weeks of evaluation. Further evaluation
      of the efficacy and safety of Ad5FGF-4 is now being conducted in two simultaneous
      multicenter, randomized, double-blind, placebo-controlled pivotal trials in the
      United States and the European Union, with planned enrollment of approximately
      1000 treated subjects. The primary efficacy variable in the trial will be changed
      in treadmill exercise duration at 12 weeks compared to baseline. Secondary
      efficacy variables include the rate of all-cause mortality and coronary events
      (non-fatal myocardial infarction, and unplanned hospitalization and
      revascularization due to myocardial ischemia) up to 1 year.

PMID- 15180589
TI  - (Hypo-) accommodation mini symposium; starlight test.

PMID- 15180590
TI  - Hyperopia, accommodative dysfunction and reading.

PMID- 15180591
TI  - Substrates of negative accommodation.
AB  - Negative accommodation refers to a unique phenomenon, sparsely documented in rare
      individuals, whereby evanescent increases in vision (described as "flashes" of
      clear vision) accompany a decrease in the overall plus power of the eye.
      Complementing less than a handful of dated studies, a few recent personal
      communications from eye care clinicians claim to have objectively assessed
      negative accommodation (e.g., by retinoscopy). Whereas negative accommodation may
      explain informal accounts claiming occasional improved visual acuity in
      uncorrected myopes, its mode of operation is not established. We sketch a
      potential mechanism by which negative accommodation may operate, if it exists.

PMID- 15180592
TI  - Pseudo-false positive eye/vision photoscreening due to accommodative
      insufficiency. A serendipitous benefit for poor readers?
AB  - BACKGROUND: Children whose eyes and vision are otherwise normal and who should
      screen negatively as normals, but who fail to compensate for their normal mild
      hyperopia (i.e. by normally accommodating, or rather actually failing to
      accommodate) will generate hyperopic crescents in a photoscreen test that can be
      interpreted as "positive" (for pathology) because high and asymmetric levels of
      hyperopia are common risk factors for amblyopia. This would therefore usually be
      considered a "false positive" and no further care would be offered. However, this
      failure to compensate, may in fact be a pathological disorder, accommodative
      insufficiency, making this apparently "false positive" situation actually a
      actually a "false-positive-false- negative positive test", or more simply a
      "false- false positive test". METHODS: The Alaska Blind Child Discovery Project
      photoscreened just under 16,000 children referring 6% as "positive", of which,
      after examination, the false positive rate was just 6% of those referred (0.4% of
      the total number screened). RESULTS: Ten (42%) of the 24 false positives had
      evidence of accommodative insufficiency inspite of only average (for age) amounts
      of cycloplegic hyperopia and a lag of accommodation on dynamic retinoscopy. Eight
      of the 10 were boys of kindergarten age. Most of these subsequently benefitted
      from prescription and use of reading glasses of low plus sphere correction.
      CONCLUSION: About 0.15% of photoscreened children, or 2.5% of those screening
      positive, and 42% (10/24) found initially on exam to be falsely positive,
      yielding hyperopic interpretations despite low and usually acceptably normal for
      age amounts of hyperopia, are in fact suffering from a pathological accommodative
      insufficiency. Identification of such false- false positives by a combination of
      photoscreening and dynamic retinoscopy may be used to determine which students
      might be helped with enforced reading glasses. Confirmatory exams on photoscreen
      positive-hyperopia cases should include an assessment of accommodation to
      identify these children.

PMID- 15180593
TI  - Duration and effect of single-dose atropine: paralysis of accommodation in
      penalization treatment of functional amblyopia.
AB  - BACKGROUND AND PURPOSE: Atropine dilates the pupil and paralyzes the ciliary
      muscle accommodation, blurring vision, and therefore is an effective penalization
      of the sound eye in the treatment of functional amblyopia of the other eye. The
      degree of blur induced is a function of the amount of the patient's uncorrected
      hyperopia and the distance from the eye of the viewed material or object. Another
      factor determining effectiveness of atropine penalization is the duration of the
      effect of the atropine. It is the purpose of this study to investigate these
      factors. METHODS: Six normal children underwent complete eye exam with
      cycloplegic refraction several days before deliberate instillation of atropine 1%
      in the sound, or right eye. Distance and near acuity was then tested after 30
      minutes, and on subsequent days. Additional data points were derived by placing
      known minus lenses in front of the tested eye. In addition, we also studied one
      successfully treated amblyopic patient when he terminated chronic daily atropine
      in his normal, sound eye. RESULTS: Atropine initially produced a linear reduction
      in logMAR acuity (blur) at distance of about 0.2 logMAR lines per diopters of
      uncorrected hyperopia. The magnitude of the blur was greater for near, but the
      effect of increased hyperopia was slightly greater for distance measurements.
      This blurring of acuity lasted just less than 48 hours for normal subjects, and
      just over 48 hours following prompt cessation of chronic daily atropine in that
      one subject. Regression formulae were derived relating uncorrected hyperopia and
      time interval following atropine cessation on distance and near acuity in
      children of amblyopic age range. CONCLUSION: The degree of penalization is highly
      dependent on the uncorrected hyperopic refractive error. A significant
      penalization effect is present only for one day or so. Daily atropine is
      therefore indicated for penalization. To better tailor penalization therapy to
      target sound eye acuity blur, these formulae and graphs can be used,
      specifically, in addition, to determine the amount of deliberate spectacle
      hyperopic undercorrection to maximize the penalization effect.

PMID- 15180594
TI  - The remnants of crossed fixation observed in teenaged children with esotropia.
AB  - PURPOSE: To report 2 cases of teenage children with esotropia from a much earlier
      age, displaying remnants of crossed fixation with special reference to
      Helmholtz's theory that each eye is controlled independently and Hering's Law of
      equal innervation. CASE REPORTS: Case 1 had paretic and partially accommodative
      esotropia that was first observed at 11 months of age; and Case 2 had
      accommodative esotropia with an onset at age 3 years. Both cases had
      hypermetropia and good corrected visual acuity in both eyes. They were able to
      fixate independently with each eye but the dominant eye always controls their
      fixation and they believe they are using only their dominant eye; however, their
      non-dominant eye was used to viewing objects in the opposite field (crossed
      fixation). Both cases maintained good binocular alignment at distance with either
      surgery and glasses (Case 1) or glasses alone (Case 2). However, their esotropia
      increased through the early teenage years leading both patients to undergo
      surgery at this later age: Case 1 at 17 years of age and Case 2 at 19 years of
      age. Post-surgical Starlight testing showed that their binocular visual fields
      improved. CONCLUSION: Crossed fixation exists in esotropia (even in acquired
      accommodative esotropia) and as the patient ages, one eye becomes dominant
      leaving the non-dominant eye to fix only in crossed gaze. These cases support
      Helmholtz's theory that each eye is controlled independently and that binocular
      coordination is learned.

PMID- 15180596
TI  - The ethics of rewarded kidney donation.

PMID- 15180597
TI  - Proteomics and urine analysis: a potential promising new tool in urology.

PMID- 15180598
TI  - The 'learning curve' in surgery: what is it, how do we measure it and can we
      influence it?

PMID- 15180595
TI  - Electrostatic interactions of domain III stabilize the inactive conformation of
      mu-calpain.
AB  - The ubiquitous mu- and m-calpains are Ca2+-dependent cysteine proteases. They are
      activated via rearrangement of the catalytic domain II induced by cooperative
      binding of Ca2+ to several sites of the molecule. Based on the crystallographic
      structures, a cluster of acidic residues in domain III, the acidic loop, has been
      proposed to function as part of an electrostatic switch in the activation
      process. Experimental support for this hypothesis was obtained by site-directed
      mutagenesis of recombinant human mu-calpain expressed with the baculovirus system
      in insect cells. Replacing the acidic residues of the loop individually with
      alanine resulted in an up to 7-fold reduction of the half-maximal Ca2+
      concentration required for conformational changes (probed with 2-p
      toluidinylnapthalene-6-sulphonate fluorescence) and for enzymic activity. Along
      with structural information, the contribution of individual acidic residues to
      the Ca2+ requirement for activation revealed that interactions of the acidic loop
      with basic residues in the catalytic subdomain IIb and in the pre-transducer
      region of domain III stabilize the structure of inactive micro-calpain.
      Disruption of these electrostatic interactions makes the molecule more flexible
      and increases its Ca2+ sensitivity. It is proposed that the acidic loop and the
      opposing basic loop of domain III constitute a double-headed electrostatic switch
      controlling the assembly of the catalytic domain.

PMID- 15180599
TI  - More should be done to prevent the harmful effects of long-term androgen ablation
      therapy in prostate cancer.

PMID- 15180600
TI  - A re-assessment of the role of combined androgen blockade for advanced prostate
      cancer.

PMID- 15180601
TI  - Practical management issues in bilateral testicular cancer.

PMID- 15180602
TI  - Male-factor infertility: do we really need urologists? A gynaecological view.
AB  - The Royal College of Obstetricians and Gynaecologists state that male factor
      infertility is responsible for up to 25% of all cases of infertility and may
      contribute in a further 25%. Where the role of the urologist ends and
      gynaecologist begins in these couples is a matter of debate. We therefore discuss
      the management of these couples and the need for a multidisciplinary approach.

PMID- 15180603
TI  - Buccal mucosal urethroplasty: is it the new gold standard?
AB  - Whilst techniques for urethral reconstruction have developed in the past few
      decades the quest for an ideal substitute continues. We critically review the
      literature on buccal mucosal grafts for substitution urethroplasty, to determine
      the efficacy and complications arising from its use. Buccal mucosal grafts have
      proved to be a versatile substitute for strictures attributable to a wide range
      of causes. Placing the graft dorsally appears to be more successful than
      ventrally and was successful in 96% of cases; after treating complex urethral
      strictures with two-stage procedures about a quarter of patients required a
      revision after the first stage with fewer complications then when skin was used
      as a substitute. Thus, buccal mucosa is most likely to become the new gold
      standard for substitution urethroplasty and longer term results with its use are
      eagerly awaited.

PMID- 15180604
TI  - Consensus statement on urethral trauma.

PMID- 15180605
TI  - Concurrent radical retropubic prostatectomy and inguinal hernia repair through a
      modified Pfannenstiel incision.
AB  - OBJECTIVE: To describe a technique for concurrent radical retropubic
      prostatectomy (RRP) and inguinal hernioplasty, using a modified Pfannenstiel
      incision. PATIENTS AND METHODS: RRP is usually done through a midline lower
      abdominal incision but some patients with localized prostate cancer have an
      inguinal hernia. Concurrent inguinal hernia repair at the time of RRP with the
      usual method is only possible by either a preperitoneal mesh repair or formal
      hernioplasty, requiring an additional incision(s). A 10-12 cm Pfannenstiel
      incision is made along the pubic hairline centred over the pubic symphysis, and a
      'Y'-shaped incision in the rectus sheath. The rectus muscle is split vertically
      along the midline, followed by RRP. After removing the prostate and completing
      the anastomosis, the surgeon identifies the inguinal canal along the inferior and
      lateral aspect of the transverse incision and uses a formal tension-free
      hernioplasty with a 3 x 5 cm polypropylene mesh. We used this technique in
      fifteen concurrent inguinal hernioplasties (two bilateral hernias and thirteen
      unilateral) at the time of RRP, with no additional incisions, using the formal
      tension-free Lichtenstein technique. One patient with bilateral hernias had a
      right indirect inguinal hernia, and all the remaining men had a direct inguinal
      hernia. RESULTS: All patients were discharged 2 days after surgery, with no
      complications associated with the procedure and no recurrences; however, the
      follow-up was short (mean 5.5 months). CONCLUSION: A modified Pfannenstiel
      incision is ideal for concurrent RRP and inguinal hernioplasty, providing
      excellent exposure of the pelvic structures and allowing the surgeon to use a
      formal tension-free mesh hernioplasty through the same incision. Wound healing
      and cosmetic results are excellent.

PMID- 15180606
TI  - Comparison of clinical and pathological features in African-American and
      Caucasian patients with localized prostate cancer.
AB  - OBJECTIVE: To examine patient characteristics, prostate specific antigen (PSA)
      levels, and established preoperative and pathological prognostic factors to
      determine differences between Caucasian and African-American patients with
      localised prostate cancer, as it remains controversial whether African-American
      men present with more aggressive disease. PATIENTS AND METHODS: One hundred
      consecutive patients (aged 53-76 years) undergoing radical retropubic
      prostatectomy (RRP) at an equal-access tertiary-care centre were retrospectively
      reviewed. All patients had preoperative PSA levels, a physical examination
      (including clinical staging), and sextant biopsy. Insurance information was also
      collected. The same urological oncologist determined clinical staging and
      performed all the RRPs, and the same genitourinary pathologist determined the
      Gleason grade for biopsies and surgical specimens, pathological stage, percentage
      of tumour involvement, and specimen weight. African-American and Caucasian
      patients were compared for PSA, clinical stage, pathological stage, biopsy and
      pathological Gleason grade, organ confinement, margin status and specimen weight.
      Using preoperative and pathological data, both groups were also compared for over
      and under-staging and -grading. The Wilcoxon rank test with P < 0.05 was used to
      determine statistically significant differences. RESULTS: African-American
      patients were more likely to be Medicaid or self-insured than Caucasian patients.
      Age, biopsy grade and clinical stage were not significantly different between the
      groups. African-American patients presented with a mean PSA level of 11.9 ng/mL
      and Caucasians with a mean of 8.5 ng/mL (P = 0.03). When clinical and biopsy data
      were compared with pathological data there were no differences between the groups
      in under/over-grading or under/over-staging. African-American patients had larger
      prostates per surgical specimen than their Caucasian counterparts (59.3 g vs 51.6
      g, respectively; P = 0.04). CONCLUSIONS: In a referred, equal-access system,
      African-American patients presented with higher serum PSA levels and had larger
      prostates in the surgical specimen. However, African-American patients did not
      present at an earlier age or with higher Gleason grade or clinical stage, nor
      were pathological grade and stages higher. Other pathological features were no
      different. African-American patients were not under- or over-staged or under- or
      over-graded more than their Caucasian counterparts. This retrospective study does
      not suggest that African-American men present with more aggressive disease.

PMID- 15180607
TI  - Relationship of erythrocyte membrane polyunsaturated fatty acids and prostate
      specific antigen levels in Jamaican men.
AB  - OBJECTIVE: To investigate the relationship between erythrocyte membrane
      polyunsaturated fatty acid (PUFA) and serum prostate- specific antigen (PSA)
      levels in Jamaican men, as there may be an association between prostate cancer
      incidence and dietary fatty acids, and prostate cancer incidence in Jamaica is
      among the highest in the world. PATIENTS AND METHODS: Blood from 107 Jamaican men
      was analysed for 32 individual fatty acids and PSA levels. Special attention was
      given to correlations between Omega3 and Omega6 PUFAs and PSA. Data were analysed
      using standard linear regression methods. RESULTS: The mean PSA was 18.6 ng/mL
      (normal 0-4.0); for age groups of 51-60, 61-70 and 71-80 years the levels were
      14, 26 and 23 ng/mL, respectively. Eicosapentaenoic acid (Omega3) levels
      decreased as PSA exceeded 10 ng/mL (P = 0.02). Arachidonic acid (Omega6) levels
      decreased as PSA was < 2 ng/mL (P = 0.02). Linoleic acid (Omega6) levels
      decreased in men with PSA levels of 2-10 ng/mL (P = 0.04). In men with a PSA of >
      10 ng/mL there was a positive correlation between the ratio of Omega6 to Omega3
      PUFAs and PSA (P = 0.036); there was also a negative correlation between the
      ratio of Omega3 to Omega6 PUFAs and PSA (P = 0.08). When the ratio of Omega3
      PUFAs over the products of Omega6 PUFAs were used, this trend was significant (P=
      0.03). CONCLUSIONS: Increased levels of Omega6 PUFAs and the ratio of
      Omega6/Omega3 PUFAs in Jamaican men are associated with an increased mean PSA
      level and risk of prostate cancer. Additional studies are needed to establish a
      causal link between dietary fatty acid intake and the development of prostate
      cancer in Jamaican men.

PMID- 15180609
TI  - Effect of peripheral biopsies in maximising early prostate cancer detection in 8
      , 10- or 12-core biopsy regimens.
AB  - OBJECTIVE: To assess the cancer detection rate per individual core biopsy in a 12
      core protocol and develop an optimal biopsy regimen for detecting early prostate
      cancer. PATIENTS AND METHODS: The study included 445 new patients who had a 12
      core transrectal ultrasonography (TRUS)-guided prostatic biopsy over a 40-month
      period. The 12- core biopsy protocol included parasagittal sextant and six
      peripheral biopsies. The cancer detection rate per individual core was evaluated
      to give an optimal biopsy protocol. RESULTS: Prostate cancer was detected in 142
      patients (31.9%). Parasagittal sextant biopsy would have failed to detect 40
      (28.2%) of the cancers. Among the various possible biopsy protocols, the optimum
      10-core biopsy strategy excluding the parasagittal mid-zone biopsies from the 12
      core protocol achieved a cancer detection rate of 98.6%. CONCLUSION: The cancer
      detection rate increased from 71.8% for parasagittal sextant biopsies to 88.7% by
      adding peripheral basal biopsies (8-biopsy protocol); 98.6% of cancers in the
      series would have been detected with a 10-biopsy strategy omitting the
      parasagittal mid-zone biopsies. Thus we recommend a 10-core protocol
      incorporating six peripheral biopsies in patients with elevated age- specific
      prostate-specific antigen levels (2.6-10.0 ng/mL) for maximising cancer
      detection.

PMID- 15180608
TI  - Bupivacaine provides rapid, effective periprostatic anaesthesia for transrectal
      prostate biopsy.
AB  - OBJECTIVE: To examine the effectiveness of the longer acting agent bupivacaine in
      providing periprostatic anaesthesia during transrectal ultrasonography (TRUS)
      guided biopsy, as the periprostatic injection of lidocaine has been shown to
      significantly alleviate the pain of this procedure. PATIENTS AND METHODS: Seventy
      five patients were randomized to receive a periprostatic injection with either
      bupivacaine, a lidocaine/bupivacaine (1/1) combination, or no local anaesthesia.
      Immediately before biopsy 5 mL of the anaesthetic was injected under TRUS
      guidance into the periprostatic nerves bilaterally. After taking a 10-core biopsy
      the patients were given a visual analogue scale (VAS; 0-10) to assess their pain
      during the procedure. RESULTS: The mean VAS scores were 2.04 in the bupivacaine
      group and 4.46 in the control (no local anaesthetic) group (P < 0.001).
      CONCLUSIONS: Bupivicaine provides significant, immediate periprostatic
      anaesthesia for TRUS biopsy.

PMID- 15180610
TI  - Predictors of androgen independence in metastatic prostate cancer.
AB  - OBJECTIVE: To assess the factors that influence the onset of androgen
      independence (AI, which heralds a dismal outcome) in patients with metastatic
      prostate carcinoma. PATIENTS AND METHODS: The records of 361 consecutive patients
      with prostate carcinoma diagnosed and treated in the authors' institution from 1
      January 1996 to 31 December 1999 were reviewed retrospectively; 92 with
      metastatic prostate carcinoma were assessed (median age 71.0 years, range 42-93).
      Patients were included if they developed metastatic disease from prostate cancer
      at the time of diagnosis. The nadir for prostate specific antigen (PSA) level was
      defined as the date of the lowest PSA level after hormonal therapy, and AI was
      defined as the date of the third consecutive PSA increase above the nadir value
      by any threshold. RESULTS: The median Gleason sum was 8 and the modal Gleason
      score 4 + 5. The median (range) pretreatment PSA level was 274.0 (1.3-2179)
      ng/mL. Of the 92 men, 57 (62%) attained a nadir PSA, including 23 with a nadir of
      < 2 ng/mL; 32 (35%) progressed to AI within 2 years and 27% reached a nadir PSA
      but did not develop AI. The mean (sd) time from diagnosis to the nadir PSA was
      13.7 (11.8) months, while the mean time from diagnosis to progression to AI was
      30.3 (15.6) months. Univariate analysis showed that a nadir PSA level after
      treatment of >/= 1 ng/mL (P = 0.0128) was an early predictor of progression to
      AI; a nadir PSA level of >/= 2 ng/mL (P = 0.0216) was a predictor of poor overall
      survival. CONCLUSION: Failure to attain a nadir PSA of < 1 ng/mL after treatment
      predicts progression to AI and a nadir PSA of > 2 ng/mL predicts poorer overall
      survival. The development of skeletal events predicts the onset of AI but occurs
      late in the disease and is unsuitable as an early prognostic marker.

PMID- 15180611
TI  - Patients with bladder and lung cancer: a long-term outcome analysis.
AB  - OBJECTIVES: To report on patient characteristics, stage of disease and long-term
      outcome and prognosis of patients with dual bladder and lung cancers, as there is
      an established increased risk of smoking-related second primary cancers,
      especially lung cancer, developing in patients with bladder cancer. PATIENTS AND
      METHODS: We reviewed our hospital tumour registry database from 1990 to 2002, and
      identified 27 patients who had both bladder and lung cancers among 1038 with
      bladder cancer and 2427 with lung cancer. Seventeen patients had bladder cancer
      detected before lung cancer (group 1), and the remaining 10 had lung cancer
      diagnosed first (group 2). RESULTS: Group 1 and 2 were comparable in terms of
      patients' characteristics, mean interval between cancer detection and their use
      of tobacco. Group 1 patients had a tendency towards more invasive lung cancer at
      diagnosis than had group 2 patients (11/17 vs 2/10 stage >/= IIB, respectively; P
      = 0.082). The mean follow-up was 49.8 and 64.5 months for groups 1 and 2,
      respectively (not significant). The mean (sd) interval to death from the date of
      diagnosis of lung cancer was 18 (17) months for group 1 and 65 (42) months for
      group 2 (P < 0.05). CONCLUSIONS: Patients with bladder and lung cancer who have
      lung cancer detected first have a lower lung cancer stage and higher overall
      survival rate than patients diagnosed with bladder cancer first.

PMID- 15180612
TI  - Papillary urothelial neoplasm of low malignant potential: reliability of
      diagnosis and outcome.
AB  - OBJECTIVE: To determine the ability of pathologists to reproducibly diagnose a
      newly defined lesion, i.e. the papillary urothelial neoplasm of low malignant
      potential (PUNLMP) using the published criteria, defined by the 1998 World Health
      Organisation/International Society of Urological Pathology (WHO/ISUP)
      classification system; in addition, debate remains about the clinical behaviour
      of these lesions, thus the rates of recurrence and progression of PUNLMP lesions
      were assessed and compared with low-grade papillary urothelial carcinomas (LG
      PUC) and high-grade (HG-PUC) over a 10-year follow-up. PATIENTS AND METHODS:
      Forty-nine cases of superficial bladder cancer (G1-3 pTa) representing an initial
      diagnosis of transitional cell carcinoma made in 1990 were identified and re
      graded using the 1998 WHO/ISUP classification by two pathologists. Inter-observer
      agreement was assessed using Cohen weighted kappa statistics. After re
      classification the clinical follow-up was reviewed retrospectively, and episodes
      of recurrence and progression recorded. RESULTS: The inter-observer agreement was
      moderate, regardless of whether one (kappa 0.45) or two (kappa 0.60) pathologists
      were used to grade these lesions. Re-classification identified 12 PUNLMP, 28 LG
      PUC and nine HG-PUC. PUNLMP lesions recurred in 25% (3/12) of cases; no
      progression was documented. Recurrence rates were 75% (21/28) and 67% (6/9) for
      LG- and HG-PUC, respectively, and progression rates were 4% (1/28) and 22% (2/9).
      CONCLUSION: The 1998 WHO/ISUP classification of urothelial neoplasms can be
      reproducibly applied by pathologists, with a moderate level of agreement. There
      is evidence that PUNLMP lesions have a more indolent clinical behaviour than
      urothelial carcinomas. However, the risk of recurrence and progression remains,
      and clinical monitoring of these patients is important.

PMID- 15180613
TI  - The use of Raman spectroscopy to identify and characterize transitional cell
      carcinoma in vitro.
AB  - OBJECTIVE: To determine whether Raman spectroscopy can be used to differentiate
      between normal, inflammatory and malignant bladder pathologies in vitro, and
      secondly if it can used to grade and stage transitional cell carcinoma (TCC).
      MATERIALS AND METHODS: In all, 1525 Raman spectra were measured from 75 bladder
      samples comprising normal bladder, cystitis, carcinoma in situ (CIS), TCC and
      adenocarcinoma. Multivariate analysis was applied to the spectral dataset to
      construct diagnostic algorithms; these were then tested for their ability to
      determine the histological diagnosis of each sample from its Raman spectrum.
      RESULTS: The diagnostic algorithms could be used to accurately differentiate
      among the pathological groups, in particular, a three-group algorithm
      differentiated among normal bladder, cystitis and TCC/CIS with sensitivities and
      specificities of > 90%. Algorithms could also accurately characterize TCC in
      terms of splitting them into low (G1/G2) or high (G3) grade and superficial (pTa)
      or invasive (pT1/pT2) stage. CONCLUSION: Raman spectroscopy can be used to
      accurately identify and grade/stage TCC in vitro. The technique therefore shows
      promise for use as an objective method to assist the pathologist in assessing
      bladder pathologies. Raman spectroscopy also has potential to provide immediate
      pathological diagnoses during surgical procedures. Following the promising
      results of this in vitro study, in vivo cystoscopic studies are planned.

PMID- 15180614
TI  - Characterization of bone metastases in patients with renal cell cancer.
AB  - OBJECTIVE: To characterize the clinical features of bone metastases in patients
      with renal cell carcinoma (RCC) treated with interleukin-2 therapy. Bone lesions
      contribute to significant morbidity and mortality, and although present in up to
      half of patients with RCC, their behaviour and response to therapy have not been
      well characterized. PATIENTS AND METHODS: We evaluated skeletal metastases in 19
      patients with bone lesions who received either moderate- or high-dose interleukin
      2 therapy. Data on bone disease, including location and number of bone lesions,
      need for bone-specific therapies and use of pain medications, were noted. The
      response of bone lesions to interleukin-2 was compared with the response of other
      systemic metastatic sites. RESULTS: Skeletal metastases resulted in significant
      morbidity by causing pain (75%) and other complications requiring surgical and/or
      radiotherapeutic intervention (94%) before beginning interleukin-2 therapy. In
      most patients the response of bone lesions to interleukin-2 was similar to that
      in their other systemic sites. Treatment with interleukin-2 had no significant
      effect on the requirement for pain medication for bone pain. However, it may have
      prevented skeletal complications requiring surgery or radiotherapy. None of the
      patients had hypercalcaemia; there was no significant association between bone
      metastases and elevated alkaline phosphatase levels. CONCLUSIONS: Skeletal
      metastases are a significant contributor to morbidity among patients with RCC.
      Bone lesions respond similarly to interleukin-2 therapy as other systemic sites.
      Bisphosphonates appear promising for these predominantly osteolytic lesions.

PMID- 15180615
TI  - Risk behaviours and benign prostatic hyperplasia.
AB  - OBJECTIVE: To identify risk factors for benign prostatic hyperplasia (BPH).
      SUBJECTS AND METHODS: Medical history data, including reported urological
      conditions and treatments, and risk factor data were collected from 34 694
      participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer
      Screening Trial, a randomized controlled trial designed to evaluate methods for
      the early detection of cancer. RESULTS: Asian men had the lowest risks (odds
      ratio, 95% confidence interval) for nocturia (0.7, 0.5-0.9), physician-diagnosed
      BPH (0.3, 0.2-0.5) and transurethral prostatectomy (TURP, 0.2, 0.1-0.6), while
      risks for Whites and Blacks were similar for most measures of BPH. Greater
      alcohol intake was associated with decreased nocturia (P trend = 0.002), BPH (P
      trend < 0.001) and TURP (P trend < 0.001). Current tobacco use was associated
      with decreased nocturia (0.8, 0.7-0.9), BPH (0.7, 0.6-0.8) and TURP (0.6, 0.4
      0.8) but dose-response patterns were weak. CONCLUSION: Asian-Americans have the
      lowest risk of clinical BPH. Alcohol and possibly cigarettes are related to a
      lower risk for BPH.

PMID- 15180616
TI  - The cost of clinically significant urinary storage symptoms for community
      dwelling adults in the UK.
AB  - OBJECTIVES: To estimate the cost of clinically significant urinary storage
      symptoms (CSUSS), including costs borne by the National Health Service (NHS) and
      individuals, in terms of the use of goods and services in community-dwelling
      adults. SUBJECTS AND METHODS: The subjects were community-dwelling adults aged
      >/= 40 years and living in Leicestershire. The prevalence of CSUSS was estimated
      using a postal questionnaire with a randomly selected sample of 23 182
      respondents. The costs associated with CSUSS were estimated using home interviews
      with 613 cases with and 523 subjects without CSUSS. Cases were defined on the
      basis of urinary symptoms of leakage, urgency, frequency and nocturia.
      Willingness-to-pay was used to measure intangible costs as an indicator of the
      value of alleviating symptoms. RESULTS: The estimated total annual cost to the
      NHS for treating CSUSS cases in community-dwelling adults was pound 536 million
      at 1999/2000 prices ( pound 303 million and pound 233 million for men and women,
      respectively). The total value of costs borne by individuals was estimated to be
      pound 207 million ( pound 29 million and pound 178 million for men and women,
      respectively). This gives total annual costs related to the use of services of
      pound 743 million. There were large intangible costs borne by individuals
      estimated to be pound 669 million ( pound 301 and pound 368 million for men and
      women) for the UK in terms of willingness-to-pay. CONCLUSIONS: The costs of CSUSS
      in the community amounted to approximately 1.1% of overall NHS spending for
      1999/2000. Personally borne and intangible costs are also large and important
      components of the costs of CSUSS. There are large gender differences in the
      proportion of costs borne by the NHS, i.e. 91% of male and 57% of female costs.

PMID- 15180617
TI  - Nocturia and depression.
AB  - OBJECTIVE: To assess the possible relationship between major depression (MD) and
      nocturia. SUBJECTS AND METHODS: An unselected group of adult men and women,
      living in the city of Ostersund, Sweden, were sent a postal questionnaire
      containing questions on somatic and mental health, sleep, sleepiness and
      nocturia. For depression diagnostics the Major Depression Inventory (MDI) was
      used. RESULTS: The mean (sd) ages of the men and women were 48.0 (18.2) and 50.1
      (19.1) years, respectively. Two or more nocturnal micturition episodes occurred
      in 15.6% of the men and 16.5% of the women. In a multiple logistic regression
      analysis independent correlates (with 95% confidence intervals) for >/= 2
      nocturnal voids in men were: MD 6.5 (2.6-15.6); health, fair vs good, 1.8 (1.0
      3.9); health, poor vs good, 2.7 (1.1-4.8); age, 60-74 vs 18-29, 3.6 (1.5-8.4) and
      age >/= 75 vs 18-29 6.7 (2.6-17.4); and in women: MD 2.8 (1.3-6.3); health, fair
      vs good, 1.9 (1.1-3.2); health, poor vs good, 4.3 (2.6-8.2); age, 60-74 vs 18-29,
      3.8 (1.8-7.8), and age >/= 75 vs 18-29, 8.6 (4.0-18.6). Age < 60 years was
      deleted by the logistic model in both sexes. CONCLUSION: MD is associated with a
      six-fold increase in nocturia in men and a three-fold increase in women, after
      accounting for age and health. Possible pathogenetic mechanisms of this
      relationship may involve both increased nocturnal diuresis via a disturbed 24-h
      rhythm of antidiuretic hormone secretion, and a decrease in nocturnal bladder
      capacity through a central and/or peripheral serotonergic effect.

PMID- 15180618
TI  - The 24-h frequency-volume chart in adults reporting no voiding complaints:
      defining reference values and analysing variables.
AB  - OBJECTIVE: To determine the variables (e.g. voiding frequency, voided volumes,
      urine production) and their mutual relationships and differences between age
      groups and genders, using a frequency-volume chart (FVC) in an adult population
      (representing all age groups) who denied having any voiding complaints. SUBJECTS
      AND METHODS: In all, 1152 men and women aged > 20 years completed a 24-h FVC;
      registration started with the first voided volume in the morning and concluded
      with the first voided volume the next morning. The time of voiding and volume
      were both recorded, and bedtime hours noted. Each participant claimed to have no
      voiding complaints. The statistical analysis was aimed at discerning the
      relationships between the FVC variables, gender and age. RESULTS: There was a
      linear increase in mean 24-h voiding frequency and nocturia in men, from 6.0 and
      0.5 in the third decade to 8.5 and 1.6 in those aged > 70 years. Contrary to men,
      in women the mean 24-h frequency declined slightly in the older decades; it
      increased from 6.9 in the third to 8.2 in the sixth, declining to 7.8 in those
      aged > 70 years. Nocturia in women increased linearly, although slower than in
      men, from 0.7 in the third decade to 1.4 in those aged > 70 years. The mean
      volume/void decreased significantly in both genders, from 313 to 209 mL in men,
      and from 274 to 240 mL in women. The mean 24-h volume was 1718 and 1762 mL in men
      and women, respectively. For both genders there was a strong linear association
      between 24-h urine production and voided volumes. CONCLUSION: The volume/void and
      maximum voided volume decreased significantly with age in both sexes, but more
      prominently in men. As a result, in men the frequency increased with age,
      probably reflecting subclinical changes associated with the development of
      prostatic enlargement. In contrast to men the frequency in women increased
      initially and decreased in the older groups. A higher 24-h urine production was
      associated with a higher mean volume/void.

PMID- 15180619
TI  - Prevention of recurrent bacterial cystitis by intravesical administration of
      hyaluronic acid: a pilot study.
AB  - OBJECTIVES: To assess the effect of bladder instillations of hyaluronic acid (HA)
      on the rate of recurrence of urinary tract infection (UTI). PATIENTS AND METHODS:
      Forty women (mean age 35 years) with a history of recurrent UTI received
      intravesical instillations of HA (40 mg in 50 mL phosphate-buffered saline) once
      weekly for 4 weeks then once monthly for 4 months. The UTI status was assessed
      over a prospective follow-up of 12.4 months and compared with the rates of UTI
      before instillation, determined by a retrospective review of patient charts
      covering 15.8 months. RESULTS: After HA treatment no patients had a UTI during
      the 5-month treatment phase and 28 (70%) were recurrence-free at the end of the
      follow-up. The mean (sd) rate of UTI per patient-year was 4.3 (1.55) before
      treatment and 0.3 (0.55) afterward (P < 0.001). The median time to recurrence
      after HA treatment was 498 days, compared with 96 days beforehand (P < 0.001).
      The tolerability was excellent, as side-effects were limited to nine patients who
      reported mild bladder irritation; no patient interrupted the treatment.
      CONCLUSIONS: In this preliminary study, bladder instillations of HA had a
      significant effect on the rate of UTI in women with a history of recurrent UTIs.
      The bladder instillation of HA is an acceptable and promising therapeutic
      alternative in patients with recurrent UTI. Expanded placebo controlled clinical
      trials examining this application of HA are currently underway.

PMID- 15180620
TI  - Urodynamic findings before and after noninvasive management of bladder calculi.
AB  - OBJECTIVES: To determine the most frequent urodynamic observations associated
      with bladder calculi, and to assess whether the presence of calculi alters these
      observations. PATIENTS AND METHODS: Fifty patients with bladder stones were
      included in a prospective study in which two urodynamic tests were used, one at
      inclusion and another once the patient was stone- free after treatment by
      noninvasive methods (mainly extracorporeal shockwave lithotripsy). RESULTS: The
      results from the urodynamic evaluation with the stone in the bladder were:
      bladder outlet obstruction in 51%, detrusor overactivity in 68%, detrusor under
      activity in 10%, and a normal study in 18%. There were no significant differences
      between the urodynamic study before or after treatment in maximum flow rate and
      postvoid residual volume, detrusor overactivity and detrusor pressure at maximum
      flow. CONCLUSIONS: Conversely to what has been accepted for years, bladder
      calculi are not always associated with bladder outlet obstruction and the
      urodynamic results are not influenced by the presence of bladder stones during
      the urodynamic testing.

PMID- 15180621
TI  - An open-label, randomized, flexible-dose, crossover study to assess the
      comparative efficacy and safety of sildenafil citrate and apomorphine
      hydrochloride in men with erectile dysfunction.
AB  - OBJECTIVE: To compare the efficacy and safety of sildenafil and apomorphine in
      the treatment of men with erectile dysfunction (ED). PATIENTS AND METHODS: In
      all, 139 men with ED who were naive to treatment were entered into an open-label
      crossover trial with two treatment periods, each of 8 weeks, separated by a 2
      week washout period. Men were randomized to receive either sildenafil then
      apomorphine or apomorphine then sildenafil, and were allowed to titrate the dose
      on both drugs. The primary endpoint was the erectile function (EF) domain of the
      International Index of Erectile Function (IIEF), and other endpoints included
      diary data, the other domains of the IIEF, overall assessment questions and the
      Erectile Dysfunction Index of Treatment Satisfaction (EDITS) questionnaire.
      RESULTS: The EF domain score after treatment was 25.2 for sildenafil and 15.9 for
      apomorphine. The treatment difference of the adjusted means was 9.3 points (95%
      confidence interval 7.6-11.1; P < 0.001). After sildenafil the successful
      intercourse rate was 75%, vs 35% for apomorphine (P < 0.001), and the EDITS
      scores were 82.5 for sildenafil and 46.8 for apomorphine (P < 0.001). Of the men,
      96% expressed a preference for sildenafil as a treatment for their ED. The side
      effect profiles for both drugs were in keeping with published data. CONCLUSION:
      By all measurable endpoints sildenafil was superior to apomorphine in this open
      label crossover study of men with ED who were naive to therapy

PMID- 15180622
TI  - The efficacy and safety of tadalafil: an update.
AB  - OBJECTIVE: To provide an update on the efficacy and safety of tadalafil, a
      phosphodiesterase-5 inhibitor, in the treatment of erectile dysfunction (ED).
      PATIENTS AND METHODS: In all, 2102 men (mean age 56 years) with mild-to-severe ED
      of various causes were randomized to placebo or tadalafil, taken as needed with
      no food restrictions, at fixed 'on-demand' doses of 10 or 20 mg in 11 randomized,
      double-blind, placebo-controlled trials lasting 12 weeks. The three co-primary
      outcomes were changes from baseline in the erectile function domain of the
      International Index of Erectile Function (IIEF) and the proportion of 'yes'
      responses to questions 2 and 3 of the Sexual Encounter Profile (SEP). Additional
      efficacy instruments included a Global Assessment Question (GAQ). RESULTS:
      Compared with placebo, tadalafil gave significantly better outcomes. Patients
      receiving either dose of tadalafil had a significant mean improvement of 6.5 and
      8.6, respectively, in the IIEF erectile function domain score from baseline (P <
      0.001 vs placebo). At both doses the mean success rate for intercourse attempts
      (SEP-Q3) was 58% and 68%, respectively, compared with 31% in the placebo group (P
      < 0.001), and 71% and 84% reported improved erections at the endpoint (GAQ), vs
      33% on placebo (P < 0.001). Tadalafil was effective up to 36 h after dosing and
      was effective regardless of disease severity and causes, and in patients of all
      ages. The most frequent adverse events were headache, dyspepsia, back pain and
      myalgia. CONCLUSION: Tadalafil was an effective and well-tolerated treatment for
      ED.

PMID- 15180623
TI  - Does the cause of obstructive azoospermia affect the outcome of intracytoplasmic
      sperm injection: a meta-analysis.
AB  - OBJECTIVE: To define whether the outcome of intracytoplasmic sperm injection
      (ICSI) using sperm surgically retrieved from men with obstructive azoospermia
      (OA) depends on the cause of obstruction. PATIENTS AND METHODS: We first analysed
      our data and then used a meta-analysis of published data (including ours) to
      compare the outcome of ICSI in OA, classified in terms of congenital and acquired
      causes. The present study comprised 82 couples who underwent 127 ICSI cycles
      using surgically retrieved sperm. The cause was classified as congenital
      bilateral absence of vas deferens (CBAVD, in 20), after vasectomy (56),
      infective/inflammatory (21), noninfective (24) and ejaculatory (five). Five
      reports (687 cycles) including the present were identified as suitable for meta
      analysis. RESULTS: Analysis of the present data showed that fertilization and
      live-birth rates were highest in men with a previous vasectomy and no infective
      cause (vasectomy 51% and 23%; not infective 53% and 29%, respectively) and lowest
      in men with infective or inflammatory causes. There was no difference in outcome
      if the sperm was fresh or frozen, or whether epididymal or testicular. Meta
      analysis comparing congenital (CBAVD) and acquired causes showed a significantly
      increased fertilization rate (95% confidence interval, 0.84-1) with acquired
      causes. Meta-analysis of the three papers reporting delivery outcome showed no
      difference in live-birth rate but a significantly higher miscarriage rate in the
      congenital group (relative risk 2.67). CONCLUSION: In ICSI cycles in men with OA
      the cause appears to influence the outcome, but outcome is not affected by
      whether the retrieved sperm is fresh, frozen, epididymal or testicular. The meta
      analysis suggested a higher fertilization rate and lower miscarriage rate in
      acquired causes of OA.

PMID- 15180624
TI  - Dorsal buccal mucosal graft urethroplasty by a ventral sagittal urethrotomy and
      minimal-access perineal approach for anterior urethral stricture.
AB  - OBJECTIVE: To present the technique of dorsal buccal mucosal graft urethroplasty
      through a ventral sagittal urethrotomy and minimal access perineal approach for
      anterior urethral stricture. PATIENTS AND METHODS: From July 2001 to December
      2002, 12 patients with a long anterior urethral stricture had the anterior
      urethra reconstructed, using a one-stage urethroplasty with a dorsal onlay buccal
      mucosal graft through a ventral sagittal urethrotomy. The urethra was approached
      via a small perineal incision irrespective of the site and length of the
      stricture. The penis was everted through the perineal wound. No urethral
      dissection was used on laterally or dorsally, so as not to jeopardize the blood
      supply. RESULTS: The mean (range) length of the stricture was 5 (3-16) cm and the
      follow-up 12 (10-16) months. The results were good in 11 of the 12 patients. One
      patient developed a stricture at the proximal anastomotic site and required
      optical internal urethrotomy. CONCLUSION: Dorsal buccal mucosal graft
      urethroplasty via a minimal access perineal approach is a simple technique with a
      good surgical outcome; it does not require urethral dissection and mobilization
      and hence preserves the blood supply.

PMID- 15180625
TI  - Laparoscopic live-donor nephrectomy: modifications for developing nations.
AB  - OBJECTIVE: To describe modifications to laparoscopic live-donor nephrectomy
      (LLDN) to make it more cost-effective for developing countries; LLDN was
      developed as a better alternative to conventional donor nephrectomy, with
      advantages of an earlier return to normal activities and smaller scars, but is
      not popular in developing countries because of high cost of disposable items.
      PATIENTS AND METHODS: From January 2000 to January 2002, 148 LLDNs were
      performed, of which two used a hand-assisted technique, 17 the standard
      technique, 79 a modified laparoscopically assisted cost-saving approach and 50 by
      the modified technique. In the latter approach the kidney was delivered through a
      6-8 cm anterior subcostal flank incision. In last 50 patients we further modified
      the technique, clipping the hilum using endoclips and delivering the kidney by
      holding the lateral pararenal fat through a 5 cm iliac fossa incision. RESULTS:
      The mean age, operative duration, warm ischaemia time, blood loss, analgesic
      requirements, pain score and hospital stay were comparable among the various
      techniques used. Re-exploration was required in four patients (bleeding in two,
      trocar-induced bowel injury in two). Immediate complications after surgery
      occurred in 20% of patients. Using endoclips, the cost was considerably reduced,
      from $400 to $290. The iliac fossa incision was aesthetically pleasing and more
      acceptable to patients. CONCLUSION: These modifications are relevant in the
      context of a developing nation, as they provide all the benefits of LLDN at
      reduced cost and with better cosmetic results.

PMID- 15180626
TI  - Percutaneous stone surgery in the obese: outcome stratified according to body
      mass index.
AB  - OBJECTIVE: To report our experience of percutaneous surgery for treating renal
      pelvicalyceal stones over 6 years, to show that this approach is feasible and
      safe in obese and morbidly obese patients, as the prevalence of obesity and stone
      disease has risen in the last 20 years. PATIENTS AND METHODS: We retrospectively
      reviewed the results of 223 percutaneous nephrolithotomies (PCNLs) by one
      urologist between 1995 and 2001. Patients were stratified into four groups
      according to the World Health Organization classification of body mass index
      (BMI), i.e. <25, 25-29.9 (overweight), 30-39.9 (obese) and > 40 kg/m(2) (morbidly
      obese). The outcomes of surgery in these four groups were compared. RESULTS:
      There were no statistically significant differences in operative duration,
      decrease in haemoglobin concentration, postoperative analgesic use, hospital stay
      and stone-free rates; nor was there a higher complication rate in patients who
      were obese. CONCLUSION: The outcome of PCNL is independent of the patients' BMI
      and results can be favourable in most patients. We therefore advocate treating
      obese patients with symptomatic stone disease based on individual status, using
      percutaneous surgery where appropriate.

PMID- 15180627
TI  - Risk factors for renal cysts.
AB  - OBJECTIVE: To examine the risk factors for renal cysts in a large population
      based health survey, as we previously reported that the prevalence of renal cyst
      increases with age, there is a difference in incidence between the sexes and
      other studies show an association between renal cysts and hypertension. SUBJECTS
      AND METHODS: Data were collected on 17 914 individuals who participated in a
      multiphase health-screening programme at our institution in 2000. Ultrasonography
      was used for diagnosing renal cysts. Logistic analysis was used to examine
      various risk factors for renal cyst, including sex, age, serum creatinine,
      hypertension, hypercholesterolaemia, diabetes mellitus, and smoking habits.
      Hypertension was defined as a systolic blood pressure of > 140 mmHg, a diastolic
      blood pressure of > 90 mmHg, or current use of antihypertensive medication. In 45
      patients with renal cysts who were followed for a mean (range) of 6 (4-7) years
      the sequential changes in the size of the cysts and the systolic blood pressure
      were plotted in relation to age. The relationship of the mean changes in these
      variables was also examined. RESULTS: The prevalence of renal cysts was 9.9%,
      ranging from 3.8% for subjects in their third decade to 18.5% in their sixth.
      Cysts were detected in 13.0% of men and 5.8% of women (P < 0.001). The mean serum
      creatinine was 83 mg/L in those with cysts and 76 mg/L in those without (P <
      0.001); the respective mean systolic blood pressure was 123 and 118 mmHg (P <
      0.001). Multivariate logistic regression analysis showed that age (P < 0.001),
      sex (P < 0.001), hypertension (P = 0.0022) and serum creatinine (P = 0.021) had a
      significant influence on the occurrence of renal cysts. Enlargement of the cysts
      was not correlated with the increase in blood pressure. CONCLUSIONS: The risk
      factors for a renal cyst are age, male gender, renal dysfunction and
      hypertension. Hypertension might cause renal dysfunction, which leads to the
      development of renal cysts.

PMID- 15180628
TI  - Coping with bladder exstrophy: diverse results from early attempts at functional
      urinary tract surgery.
AB  - OBJECTIVES: To report the long-term surgical outcome in a group of patients with
      bladder exstrophy treated from 1960 to 1982, and to assess physical health,
      social integration and sexual function, as attempts at functional closure during
      the development of this surgery resulted in patients with differing surgical
      status of the genitourinary organs. PATIENTS AND METHODS: A review of medical
      record archives revealed 36 patients; of these, seven had died, six were
      untraceable and six declined to participate, leaving 15 evaluable subjects (seven
      men and eight women, mean age at follow-up, 35 years). Data were collected from
      medical records and direct interviews were conducted using a semi-structured
      questionnaire, after obtaining informed consent. The Short Form-36 (SF-36) v2
      Health Survey instrument was used to assess health and well-being. RESULTS: Three
      patients have retained the use of their bladder, and 11 had initial bladder
      closure but required (at a mean age of 3.1 years) various urinary diversions.
      Eight patients had a pelvic osteotomy. Of 27 functioning renal units, 25 are in
      reasonable to good condition. Six men and six women had genital reconstruction.
      Four men are capable of penetrative intercourse and ejaculate; six women manage
      penetrative intercourse and five have orgasms. All patients attended mainstream
      school and 13 achieved examination success. Nine patients took vocational
      training and 11 work full-time. Five patients are married and five are in long
      term relationships. Two men have achieved three pregnancies and one women has had
      a child. The mean total SF-36 score (maximum 3600) was 2763 in men and 2235 in
      women. CONCLUSIONS: Surgery for bladder exstrophy has been developing for more
      than 40 years and the legacy of early attempts at functional closure is a
      population of adults who have a diversity of lower urinary tracts, good
      preservation of renal function overall and acceptable sexual function. They are
      usually robust, healthy and well-adjusted individuals functioning well in
      society, often in full-time employment and long-term relationships. Adolescent
      follow-up must be clearly focused, incorporating a multidisciplinary team
      approach to facilitate a seamless transition into adulthood.

PMID- 15180629
TI  - Predictive risk factors for chronic renal failure in primary high-grade vesico
      ureteric reflux.
AB  - OBJECTIVE: To evaluate and define the risk factors predictive of chronic renal
      failure (CRF) in children with severe bilateral primary vesico-ureteric reflux
      (VUR), observed within the first year of life and with a long follow-up. PATIENTS
      AND METHODS: The study comprised 50 patients presenting with grade 3-5 bilateral
      VUR diagnosed in the first year of life; 12 were suspected prenatally and
      confirmed shortly after birth, before any urinary tract infection (UTI). The mean
      (range) follow-up was 6.3 (1-16) years. The variables considered within the first
      year of life were: gender, prenatal diagnosis with no UTI, number of febrile
      UTIs, serum creatinine and urea nitrogen levels, metabolic acidosis, proteinuria,
      24-h urine output, hypertension, bilateral renal length on ultrasonography and
      renal scarring on renal scintigraphy. CRF was defined as a creatinine clearance
      of <80 mL/min/1.73 m(2) at the last follow-up. The results were assessed using
      univariate and multivariate analyses (backward-stepwise multiple regression) of
      the selected variables. RESULTS: CRF was detected at the last follow-up in 27
      patients (54%), all boys, while renal function was normal in 23 (46%; seven
      girls). None of the 12 patients with prenatal diagnosis had UTI, but six had CRF.
      Febrile UTI was the presenting symptom in 38 (76%) patients and 17 (34%) of them
      had renal scarring. There was no significant difference between the prenatally
      detected VUR and febrile UTI group in the outcome as CRF. The univariate and
      multiple regression analysis showed that the first serum creatinine threshold of
      >6 mg/L before 1 year old was the most significant risk factor for CRF (P <
      0.001; odds ratio 1.25). CONCLUSIONS: Children with primary bilateral high-grade
      VUR and a serum creatinine of > 6 mg/L in the first year of life have a
      significant risk of developing CRF in the long-term. Prenatal diagnosis and
      postnatal febrile UTI do not modify the outcome for renal function.

PMID- 15180630
TI  - Transurethral incision of duplex system ureteroceles in neonates: does it
      increase the need for secondary surgery in intravesical and ectopic cases?
AB  - OBJECTIVE: To evaluate the relevance of ureterocele ectopia and associated reflux
      on the outcome of duplex system ureteroceles (DSU) after neonatal transurethral
      incision (TUI). PATIENTS AND METHODS: The study included 41 neonates with a
      diagnosis of DSU; the ureterocele was ectopic in 24 (58%). Before TUI, vesico
      ureteric reflux (VUR) was present in 13 lower moieties (32%) and seven
      contralateral ureters (17%). TUI was always performed within the first month of
      life. The follow-up and management were tailored for each patient from the
      findings at ultrasonography, voiding cysto-urethrography and renal scintigraphy.
      Results of intravesical and ectopic DSU were compared using Fisher's exact test.
      RESULTS: TUI was effective in allowing ureteric decompression in all but one
      patient (2.4%). After TUI, VUR ceased in six lower ipsilateral moieties and in
      two contralateral ureters, while new VUR occurred in three contralateral kidneys.
      De novo VUR in the punctured moiety appeared in 13 cases (32%). Nine upper poles
      were not functioning. Twenty-one patients (51%) required secondary surgery.
      Ureteric reimplantation was indicated exclusively for reflux in the punctured
      moiety in only in two cases (5%), while in a further two iatrogenic reflux in a
      nonfunctioning upper moiety required total heminephro-ureterectomy. There was no
      significant difference between intravesical and ectopic ureteroceles in the
      occurrence of VUR in the punctured moiety, rate of nonfunctioning upper poles or
      need for secondary surgery. CONCLUSIONS: About half of the patients with a DSU
      need secondary surgery, but this is rarely indicated for de novo reflux in the
      punctured moiety only. The need for secondary surgery was greater whenever there
      was associated reflux before endoscopic incision. There was no difference in the
      outcome of intravesical and ectopic ureteroceles and such distinction seems no
      longer to be of clinical relevance.

PMID- 15180631
TI  - Ureteric calculi in children: preliminary experience with holmium:YAG laser
      lithotripsy.
AB  - OBJECTIVE: To determine the efficacy and safety of holmium:YAG laser lithotripsy
      in children with ureteric calculi. PATIENTS AND METHODS: Between 1999 and 2003,
      28 ureteroscopic laser procedures were carried out on 26 children (14 boys and 12
      girls, mean age 6.5 years) with ureteric calculi. The mean (range) stone size was
      1.21 (0.4-2.2) cm. At ureteroscopy the calculi were in the upper ureter in six
      (23%), mid-ureter in five (19%) and lower ureter in 15 (58%) patients. A rigid 8
      F ureteroscope was used and the Ho:YAG laser energy delivered at 0.6-1.4 J and 6
      10 Hz. All patients were evaluated after 3 months with intravenous urography to
      confirm stone clearance and to exclude ureteric stricture formation. RESULTS: The
      overall stone-free rate was 92% (24 children) after 28 ureteroscopic procedures.
      Stones were completely cleared in 83%, 80% and 100% of the procedures in the
      upper, mid- and lower ureters, respectively. In two children the procedure
      failed; they were salvaged by ureterolithotomy in one and extracorporeal
      shockwave lithotripsy in the other. During the procedures, a ureteric perforation
      was caused by several factors, including a technically difficult procedure and
      higher laser energy. At the mean (range) follow-up of 18 (3-39) months, low grade
      vesico-ureteric reflux was detected in two children, and there were no ureteric
      strictures in any. CONCLUSION: Holmium:YAG laser lithotripsy is an efficient and
      safe treatment for ureteric calculi in children.

PMID- 15180632
TI  - Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated
      bladder.
AB  - OBJECTIVE: To explore the influence of intracellular cAMP on phasic activity in
      the isolated bladder (phasic rises in intravesical pressure associated with waves
      of contraction and local stretches that can be activated by muscarinic or
      nicotinic agonists), as it has been argued that this activity underlies
      nonmicturition contractions, and that it contributes to the generation and
      modulation of afferent nerve activity. MATERIALS AND METHODS: Isolated whole
      bladders from female guinea pigs (270-300 g) were cannulated via the urethra and
      suspended in a chamber containing oxygenated Tyrode solution at 33-35 degrees C.
      Bladder pressure was recorded and pharmacological agents added to the solution
      bathing the abluminal surface of the bladder. RESULTS: Forskolin (1-3 micro
      mol/L), an activator of adenyl cyclase, reduced the frequency and amplitude of
      the phasic activity induced by the muscarinic agonist arecaidine (300 nmol/L).
      There were similar changes in frequency and amplitude in bladders exposed to the
      nonspecific phosphodiesterase (PDE) inhibitor iso-butyl-methyl-xanthene (IBMX).
      The actions of specific PDE inhibitors were explored to assess which isoenzymes
      might be responsible for regulating phasic activity. ENHA (PDE-2), zaprinast (PDE
      5, -6, -8, -9 and -11) and siguazodan (PDE-3) had no effect. Zardavarine (PDE-3, 
      4) and Ro 20-1724 (PDE-4) reduced both the frequency and amplitude of the phasic
      activity. Nerve-mediated rises in intravesical pressure were also inhibited by Ro
      20-1724, and the inhibition was more pronounced at 6.5 Hz than at 30 Hz
      stimulation. Ro 20-1724 inhibited nerve-mediated fluctuations induced by
      prolonged (200 s) stimulation at 6.5 Hz. CONCLUSION: The mechanisms influencing
      the frequency of agonist-induced phasic activity in the isolated bladder are
      slowed by cAMP. Degradation of intracellular cAMP in the cells responsible for
      phasic activity appears to involve primarily PDE-4. The importance of these
      observations in relation to the overall physiological regulation of the bladder
      are discussed, and the possible importance of these findings in the development
      of pharmacological strategies to modulated bladder activity reviewed.

PMID- 15180633
TI  - Identification of multidrug resistance-associated protein 1 and glutathione as
      multidrug resistance mechanisms in human prostate cancer cells:
      chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine.
AB  - OBJECTIVE: To assess the involvement of the multidrug resistance-associated
      protein 1 (MRP1) and the glutathione pathway in the multidrug resistant (MDR)
      phenotype of prostate cancer in vitro. MATERIALS AND METHODS: Chemoselection of
      human prostate cancer cell lines PC3 and DU145 with etoposide resulted in the
      resistant cell lines PC3-R and DU-R. Resistance against etoposide, doxorubicin
      and vincristine, and its reversal with leukotriene D4 antagonists MK-571 and
      zafirlukast, and buthionine sulfoximine (BSO), was assessed using tetrazolium-dye
      viability assays. Western blot analysis of MRP1 expression and glutathione
      content were measured, and MRP1 function assessed in fluorescence assays.
      RESULTS: MRP1 was increased in the MDR models; the glutathione content was
      significantly higher in PC3-R but there was no increase in glutathione in DU-R.
      Adding non-toxic doses of MK-571, zafirlukast or BSO significantly increased the
      sensitivity of the MDR models to cytotoxic drugs. MRP1 function was inhibited
      with MK-571 in the MDR models. CONCLUSION: MRP1 and glutathione mediate MDR in
      newly developed prostate cancer models.

PMID- 15180634
TI  - The expression of thrombospondin-1 in benign prostatic hyperplasia and prostatic
      intraepithelial neoplasia is decreased in prostate cancer.
AB  - OBJECTIVE: To evaluate the immunohistochemical expression of thrombospondin
      (TSP), a potent inhibitor of angiogenesis, in human benign prostatic hyperplasia
      (BPH) and prostate cancer. MATERIALS AND METHODS: The expression of TSP-1, TSP-2
      and CD36 receptor was assessed in 73 tissue specimens using immunohistochemistry;
      specimens were from 32 patients with BPH, seven with prostatic intraepithelial
      neoplasia (PIN) and 34 with cancer. RESULTS: Immunohistochemistry showed that all
      39 patients with BPH and PIN had TSP-1-positive glands. In contrast, none of the
      34 patients with cancer had positive TSP-1 staining in the cancer tissue. All 73
      patients were positive for TSP receptor CD36 and negative for TSP-2. CONCLUSIONS:
      TSP is expressed in BPH, down-regulated in PIN and absent in prostate cancer
      tissue. This may indicate that TSP is important in prostate cancer progression.
      Further studies are needed to understand the significance of these findings for
      the malignant transformation of the prostate gland.

PMID- 15180635
TI  - P2X and P2X receptor expression in human bladder urothelium and changes in
      interstitial cystitis.
AB  - OBJECTIVE: To investigate whether the expression of P2X(3) receptors (implicated
      in the pathophysiology of pain) is altered in human bladder urothelium from
      patients with interstitial cystitis (IC, a major symptom of which is pain), and
      as P2X(2) receptors can be co-expressed with P2X(3) receptors, to assess their
      expression also. PATIENTS AND METHODS: Bladder tissue samples were collected from
      patients undergoing cystectomy or radical prostatectomy. Patients with IC were
      diagnosed using the international criteria. RNA protein expression levels of both
      receptors were evaluated using reverse transcription-polymerase chain reaction
      (PCR), real-time quantitative PCR and Western blot analysis. RESULTS: P2X(2) was
      expressed in the human urothelium, in a glycosylated form. There was less gene
      expression of P2X(3) in IC urothelium, whereas P2X(2) gene expression was
      unchanged. This contrasted with the protein expression, which was increased for
      both P2X(2) and P2X(3). CONCLUSION: This is the first report of the expression of
      the P2X(2) receptor in human bladder urothelium. There was greater protein
      expression of both P2X(2) and P2X(3) in IC bladder urothelium which did not
      directly correlate with the gene expression. Changes in expression of P2X(2) and
      P2X(3) receptors may contribute to the pain that patients with IC have, and might
      provide novel drug targets.

PMID- 15180636
TI  - Urological research within the pharmaceutical industry: back to basics?

PMID- 15180637
TI  - Intracorporeal uretero-enteric anastomoses during laparoscopic continent urinary
      diversion.

PMID- 15180638
TI  - A new concept for active ureteric occlusion during percutaneous
      nephrolithotripsy: the 'counter-flow' principle.

PMID- 15180641
TI  - A novel way of controlling rectal bleeding after transrectal ultrasonography
      guided prostate biopsies.

PMID- 15180642
TI  - Broadening the criteria for avoiding staging bone scans in prostate cancer: a
      retrospective study of patients at the royal marsden hospital.

PMID- 15180643
TI  - An improved technique for controlling bleeding during simple retropubic
      prostatectomy.

PMID- 15180644
TI  - Lifelong premature ejaculation: from authority-based to evidence-based medicine.

PMID- 15180645
TI  - Repeating the measurement of prostate-specific antigen in symptomatic men can
      avoid unnecessary prostatic biopsy.

PMID- 15180646
TI  - Purse-string suture for partial nephrectomy.

PMID- 15180647
TI  - A randomized crossover study to evaluate RO 115-1240, a selective alpha1A/1L
      adrenoceptor partial agonist in women with stress urinary incontinence.

PMID- 15180648
TI  - The purse-string suture in nephron-sparing surgery for renal cell carcinoma.

PMID- 15180649
TI  - Vasovasostomy.

PMID- 15180653
TI  - Editor's comment.

PMID- 15180654
TI  - Latent pattern mixture models for informative intermittent missing data in
      longitudinal studies.
AB  - A frequently encountered problem in longitudinal studies is data that are missing
      due to missed visits or dropouts. In the statistical literature, interest has
      primarily focused on monotone missing data (dropout) with much less work on
      intermittent missing data in which a subject may return after one or more missed
      visits. Intermittent missing data have broader applicability that can include the
      frequent situation in which subjects do not have common sets of visit times or
      they visit at nonprescheduled times. In this article, we propose a latent pattern
      mixture model (LPMM), where the mixture patterns are formed from latent classes
      that link the longitudinal response and the missingness process. This allows us
      to handle arbitrary patterns of missing data embodied by subjects' visit process,
      and avoids the need to specify the mixture patterns a priori. One assumption of
      our model is that the missingness process is assumed to be conditionally
      independent of the longitudinal outcomes given the latent classes. We propose a
      noniterative approach to assess this key assumption. The LPMM is illustrated with
      a data set from a health service research study in which homeless people with
      mental illness were randomized to three different service packages and measures
      of homelessness were recorded at multiple time points. Our model suggests the
      presence of four latent classes linking subject visit patterns to homeless
      outcomes.

PMID- 15180655
TI  - Nonignorable missingness in matched case-control data analyses.
AB  - Matched case-control data analysis is often challenged by a missing covariate
      problem, the mishandling of which could cause bias or inefficiency. Satten and
      Carroll (2000, Biometrics56, 384-388) and other authors have proposed methods to
      handle missing covariates when the probability of missingness depends on the
      observed data, i.e., when data are missing at random. In this article, we propose
      a conditional likelihood method to handle the case when the probability of
      missingness depends on the unobserved covariate, i.e., when data are nonignorably
      missing. When the missing covariate is binary, the proposed method can be
      implemented using standard software. Using the Northern Manhattan Stroke Study
      data, we illustrate the method and discuss how sensitivity analysis can be
      conducted.

PMID- 15180656
TI  - Estimating mean response as a function of treatment duration in an observational
      study, where duration may be informatively censored.
AB  - After a treatment is found to be effective in a clinical study, attention often
      focuses on the effect of treatment duration on outcome. Such an analysis
      facilitates recommendations on the most beneficial treatment duration. In many
      studies, the treatment duration, within certain limits, is left to the discretion
      of the investigators. It is often the case that treatment must be terminated
      prematurely due to an adverse event, in which case a recommended treatment
      duration is part of a policy that treats patients for a specified length of time
      or until a treatment-censoring event occurs, whichever comes first. Evaluating
      mean response for a particular treatment-duration policy from observational data
      is difficult due to censoring and the fact that it may not be reasonable to
      assume patients are prognostically similar across all treatment strategies. We
      propose an estimator for mean response as a function of treatment-duration policy
      under these conditions. The method uses potential outcomes and embodies
      assumptions that allow consistent estimation of the mean response. The estimator
      is evaluated through simulation studies and demonstrated by application to the
      ESPRIT infusion trial coordinated at Duke University Medical Center.

PMID- 15180657
TI  - Inference for the proportional hazards model with misclassified discrete-valued
      covariates.
AB  - We consider the Cox proportional hazards model with discrete-valued covariates
      subject to misclassification. We present a simple estimator of the regression
      parameter vector for this model. The estimator is based on a weighted least
      squares analysis of weighted-averaged transformed Kaplan-Meier curves for the
      different possible configurations of the observed covariate vector. Optimal
      weighting of the transformed Kaplan-Meier curves is described. The method is
      designed for the case in which the misclassification rates are known or are
      estimated from an external validation study. A hybrid estimator for situations
      with an internal validation study is also described. When there is no
      misclassification, the regression coefficient vector is small in magnitude, and
      the censoring distribution does not depend on the covariates, our estimator has
      the same asymptotic covariance matrix as the Cox partial likelihood estimator. We
      present results of a finite-sample simulation study under Weibull survival in the
      setting of a single binary covariate with known misclassification rates. In this
      simulation study, our estimator performed as well as or, in a few cases, better
      than the full Weibull maximum likelihood estimator. We illustrate the method on
      data from a study of the relationship between trans-unsaturated dietary fat
      consumption and cardiovascular disease incidence.

PMID- 15180658
TI  - Analyzing time-to-event data in a clinical trial when an unknown proportion of
      subjects has experienced the event at entry.
AB  - In some clinical trials, where the outcome is the time until development of a
      silent event, an unknown proportion of subjects who have already experienced the
      event will be unknowingly enrolled due to the imperfect nature of the diagnostic
      tests used to screen potential subjects. For example, commonly used diagnostic
      tests for evaluating HIV infection status in infants, such as DNA PCR and HIV
      Culture, have low sensitivity when given soon after infection. This can lead to
      the inclusion of an unknown proportion of HIV-infected infants into clinical
      trials aimed at the prevention of transmission from HIV-positive mothers to their
      infants through breastfeeding. The infection status of infants at the end of the
      trial, when they are more than a year of age, can be determined with certainty.
      For those infants found to be infected with HIV at the end of the trial, it
      cannot be determined whether this occurred during the study or whether they were
      already infected when they were enrolled. In these settings, estimates of the
      cumulative risk of the event by the end of the study will overestimate the true
      probability of event during the study period and hypothesis tests comparing two
      or more intervention strategies can also be biased. We present inference methods
      for the distribution of time until the event of interest in these settings, and
      investigate issues in the design of such trials when there is a choice of using
      both imperfect and perfect diagnostic tests.

PMID- 15180659
TI  - Erosion of regression effect in a survival study.
AB  - Lack of persistence, or erosion, of the regression effect is an alternative to
      proportional hazards of particular interest in many medical applications. Such a
      departure from proportional hazards is often the most likely direction in which
      the model may be inadequate. Questions such as, is the effect of treatment only
      transitory or to what extent does an initially measured prognostic variable
      maintain its impact, frequently arise. In the context of a simple changepoint
      model, we propose a test of the null hypothesis of proportional hazards against
      the specific alternative of erosion of the regression effect. The particular
      changepoint model used can be viewed as a first approximation to a more complex
      reality, an approximation that enables us to avoid specifically modeling the
      functional form that any erosion might take. Practical guidelines for carrying
      out the test are provided. The approach is illustrated in the context of a study
      on risk factors for breast cancer survival.

PMID- 15180660
TI  - Selecting factors predictive of heterogeneity in multivariate event time data.
AB  - In multivariate survival analysis, investigators are often interested in testing
      for heterogeneity among clusters, both overall and within specific classes. We
      represent different hypotheses about the heterogeneity structure using a sequence
      of gamma frailty models, ranging from a null model with no random effects to a
      full model having random effects for each class. Following a Bayesian approach,
      we define prior distributions for the frailty variances consisting of mixtures of
      point masses at zero and inverse-gamma densities. Since frailties with zero
      variance effectively drop out of the model, this prior allocates probability to
      each model in the sequence, including the overall null hypothesis of homogeneity.
      Using a counting process formulation, the conditional posterior distributions of
      the frailties and proportional hazards regression coefficients have simple forms.
      Posterior computation proceeds via a data augmentation Gibbs sampling algorithm,
      a single run of which can be used to obtain model-averaged estimates of the
      population parameters and posterior model probabilities for testing hypotheses
      about the heterogeneity structure. The methods are illustrated using data from a
      lung cancer trial.

PMID- 15180661
TI  - Best linear unbiased allele-frequency estimation in complex pedigrees.
AB  - Many types of genetic analyses depend on estimates of allele frequencies. We
      consider the problem of allele-frequency estimation based on data from related
      individuals. The motivation for this work is data collected on the Hutterites, an
      isolated founder population, so we focus particularly on the case in which the
      relationships among the sampled individuals are specified by a large, complex
      pedigree for which maximum likelihood estimation is impractical. For this case,
      we propose to use the best linear unbiased estimator (BLUE) of allele frequency.
      We derive this estimator, which is equivalent to the quasi-likelihood estimator
      for this problem, and we describe an efficient algorithm for computing the
      estimate and its variance. We show that our estimator has certain desirable small
      sample properties in common with the maximum likelihood estimator (MLE) for this
      problem. We treat both the case when parental origin of each allele is known and
      when it is unknown. The results are extended to prediction of allele frequency in
      some set of individuals S based on genotype data collected on a set of
      individuals R. We compare the mean-squared error of the BLUE, the commonly used
      naive estimator (sample frequency) and the MLE when the latter is feasible to
      calculate. The results indicate that although the MLE performs the best of the
      three, the BLUE is close in performance to the MLE and is substantially easier to
      calculate, making it particularly useful for large complex pedigrees in which MLE
      calculation is impractical or infeasible. We apply our method to allele-frequency
      estimation in a Hutterite data set.

PMID- 15180662
TI  - Measuring the relative information in allele-sharing linkage studies.
AB  - In the context of allele-sharing methods, this article investigates ways of
      measuring the information in the marker data relative to the amount of
      information that would have been available if the identity-by-descent (IBD)
      process were known. Such measures are needed to decide whether new markers can
      substantially modify the evidence for excess sharing. We propose new measures
      that take advantage of the properties of the exponential model introduced by Kong
      and Cox (1997, American Journal of Human Genetics61, 1179-1188). These measures
      are related to Fisher Information and hence are also efficiency measures. Large
      sample and small-sample properties of the new and previously proposed measures of
      information are examined.

PMID- 15180663
TI  - Modeling microarray data using a threshold mixture model.
AB  - An important goal of microarray studies is the detection of genes that show
      significant changes in expression when two classes of biological samples are
      being compared. We present an ANOVA-style mixed model with parameters for array
      normalization, overall level of gene expression, and change of expression between
      the classes. For the latter we assume a mixing distribution with a probability
      mass concentrated at zero, representing genes with no changes, and a normal
      distribution representing the level of change for the other genes. We estimate
      the parameters by optimizing the marginal likelihood. To make this practical,
      Laplace approximations and a backfitting algorithm are used. The performance of
      the model is studied by simulation and by application to publicly available data
      sets.

PMID- 15180664
TI  - Bayesian sample size determination for prevalence and diagnostic test studies in
      the absence of a gold standard test.
AB  - Planning studies involving diagnostic tests is complicated by the fact that
      virtually no test provides perfectly accurate results. The misclassification
      induced by imperfect sensitivities and specificities of diagnostic tests must be
      taken into account, whether the primary goal of the study is to estimate the
      prevalence of a disease in a population or to investigate the properties of a new
      diagnostic test. Previous work on sample size requirements for estimating the
      prevalence of disease in the case of a single imperfect test showed very large
      discrepancies in size when compared to methods that assume a perfect test. In
      this article we extend these methods to include two conditionally independent
      imperfect tests, and apply several different criteria for Bayesian sample size
      determination to the design of such studies. We consider both disease prevalence
      studies and studies designed to estimate the sensitivity and specificity of
      diagnostic tests. As the problem is typically nonidentifiable, we investigate the
      limits on the accuracy of parameter estimation as the sample size approaches
      infinity. Through two examples from infectious diseases, we illustrate the
      changes in sample sizes that arise when two tests are applied to individuals in a
      study rather than a single test. Although smaller sample sizes are often found in
      the two-test situation, they can still be prohibitively large unless accurate
      information is available about the sensitivities and specificities of the tests
      being used.

PMID- 15180665
TI  - Bayesian isotonic regression and trend analysis.
AB  - In many applications, the mean of a response variable can be assumed to be a
      nondecreasing function of a continuous predictor, controlling for covariates. In
      such cases, interest often focuses on estimating the regression function, while
      also assessing evidence of an association. This article proposes a new framework
      for Bayesian isotonic regression and order-restricted inference. Approximating
      the regression function with a high-dimensional piecewise linear model, the
      nondecreasing constraint is incorporated through a prior distribution for the
      slopes consisting of a product mixture of point masses (accounting for flat
      regions) and truncated normal densities. To borrow information across the
      intervals and smooth the curve, the prior is formulated as a latent
      autoregressive normal process. This structure facilitates efficient posterior
      computation, since the full conditional distributions of the parameters have
      simple conjugate forms. Point and interval estimates of the regression function
      and posterior probabilities of an association for different regions of the
      predictor can be estimated from a single MCMC run. Generalizations to categorical
      outcomes and multiple predictors are described, and the approach is applied to an
      epidemiology application.

PMID- 15180666
TI  - Bayesian analysis of serial dilution assays.
AB  - In a serial dilution assay, the concentration of a compound is estimated by
      combining measurements of several different dilutions of an unknown sample. The
      relation between concentration and measurement is nonlinear and heteroscedastic,
      and so it is not appropriate to weight these measurements equally. In the
      standard existing approach for analysis of these data, a large proportion of the
      measurements are discarded as being above or below detection limits. We present a
      Bayesian method for jointly estimating the calibration curve and the unknown
      concentrations using all the data. Compared to the existing method, our estimates
      have much lower standard errors and give estimates even when all the measurements
      are outside the "detection limits." We evaluate our method empirically using
      laboratory data on cockroach allergens measured in house dust samples. Our
      estimates are much more accurate than those obtained using the usual approach. In
      addition, we develop a method for determining the "effective weight" attached to
      each measurement, based on a local linearization of the estimated model. The
      effective weight can give insight into the information conveyed by each data
      point and suggests potential improvements in design of serial dilution
      experiments.

PMID- 15180667
TI  - Accounting for multiplicities in assessing drug safety: a three-level
      hierarchical mixture model.
AB  - Multiple comparisons and other multiplicities are among the most difficult of
      problems that face statisticians, frequentists, and Bayesians alike. An example
      is the analysis of the many types of adverse events (AEs) that are recorded in
      drug clinical trials. We propose a three-level hierarchical mixed model. The most
      basic level is type of AE. The second level is body system, each of which
      contains a number of types of possibly related AEs. The highest level is the
      collection of all body systems. Our analysis allows for borrowing across body
      systems, but there is greater potential-depending on the actual data-for
      borrowing within each body system. The probability that a drug has caused a type
      of AE is greater if its rate is elevated for several types of AEs within the same
      body system than if the AEs with elevated rates were in different body systems.
      We give examples to illustrate our method and we describe its application to
      other types of problems.

PMID- 15180668
TI  - A cautionary note on the robustness of latent class models for estimating
      diagnostic error without a gold standard.
AB  - Modeling diagnostic error without a gold standard has been an active area of
      biostatistical research. In a majority of the approaches, model-based estimates
      of sensitivity, specificity, and prevalence are derived from a latent class model
      in which the latent variable represents an individual's true unobserved disease
      status. For simplicity, initial approaches assumed that the diagnostic test
      results on the same subject were independent given the true disease status (i.e.,
      the conditional independence assumption). More recently, various authors have
      proposed approaches for modeling the dependence structure between test results
      given true disease status. This note discusses a potential problem with these
      approaches. Namely, we show that when the conditional dependence between tests is
      misspecified, estimators of sensitivity, specificity, and prevalence can be
      biased. Importantly, we demonstrate that with small numbers of tests, likelihood
      comparisons and other model diagnostics may not be able to distinguish between
      models with different dependence structures. We present asymptotic results that
      show the generality of the problem. Further, data analysis and simulations
      demonstrate the practical implications of model misspecification. Finally, we
      present some guidelines about the use of these models for practitioners.

PMID- 15180669
TI  - A conditional Markov model for clustered progressive multistate processes under
      incomplete observation.
AB  - Clustered progressive chronic disease processes arise when interest lies in
      modeling damage in paired organ systems (e.g., kidneys, eyes), in diseases
      manifest in different organ systems, or in systemic conditions for which damage
      may occur in several locations of the body. Multistate Markov models have
      considerable appeal for modeling damage in such settings, particularly when
      patients are only under intermittent observation. Generalizations are necessary,
      however, to deal with the fact that processes within subjects may not be
      independent. We describe a conditional Markov model in which the clustering in
      processes within subjects is addressed by the use of multiplicative random
      effects for each transition intensity. The random effects for the different
      transition intensities may be correlated within subjects, but are assumed to be
      independent for different subjects. We apply the mixed Markov model to a
      motivating data set of patients with psoriatic arthritis, and characterize the
      progressive course of damage in joints of the hand. A generalization to
      accommodate a subpopulation of "stayers" and extensions which facilitate
      regression are indicated and illustrated.

PMID- 15180670
TI  - Assessing the goodness-of-fit of hidden Markov models.
AB  - In this article, we propose a graphical technique for assessing the goodness-of
      fit of a stationary hidden Markov model (HMM). We show that plots of the
      estimated distribution against the empirical distribution detect lack of fit with
      high probability for large sample sizes. By considering plots of the univariate
      and multidimensional distributions, we are able to examine the fit of both the
      assumed marginal distribution and the correlation structure of the observed data.
      We provide general conditions for the convergence of the empirical distribution
      to the true distribution, and demonstrate that these conditions hold for a wide
      variety of time-series models. Thus, our method allows us to compare not only the
      fit of different HMMs, but also that of other models as well. We illustrate our
      technique using a multiple sclerosis data set.

PMID- 15180671
TI  - A population pharmacokinetic model with time-dependent covariates measured with
      errors.
AB  - We propose a population pharmacokinetic (PK) model with time-dependent covariates
      measured with errors. This model is used to model S-oxybutynin's kinetics
      following an oral administration of Ditropan, and allows the distribution rate to
      depend on time-dependent covariates blood pressure and heart rate, which are
      measured with errors. We propose two two-step estimation methods: the second
      order two-step method with numerical solutions of differential equations
      (2orderND), and the second-order two-step method with closed form approximate
      solutions of differential equations (2orderAD). The proposed methods are
      computationally easy and require fitting a linear mixed model at the first step
      and a nonlinear mixed model at the second step. We apply the proposed methods to
      the analysis of the Ditropan data, and evaluate their performance using a
      simulation study. Our results show that the 2orderND method performs well, while
      the 2orderAD method can yield PK parameter estimators that are subject to
      considerable biases.

PMID- 15180672
TI  - Self modeling with flexible, random time transformations.
AB  - Methods for modeling sets of complex curves where the curves must be aligned in
      time (or in another continuous predictor) fall into the general class of
      functional data analysis and include self-modeling regression and time-warping
      procedures. Self-modeling regression (SEMOR), also known as a shape invariant
      model (SIM), assumes the curves have a common shape, modeled nonparametrically,
      and curve-specific differences in amplitude and timing, traditionally modeled by
      linear transformations. When curves contain multiple features that need to be
      aligned in time, SEMOR may be inadequate since a linear time transformation
      generally cannot align more than one feature. Time warping procedures focus on
      timing variability and on finding flexible time warps to align multiple data
      features. We draw on these methods to develop a SIM that models the time
      transformations as random, flexible, monotone functions. The model is motivated
      by speech movement data from the University of Wisconsin X-ray microbeam speech
      production project and is applied to these data to test the effect of different
      speaking conditions on the shape and relative timing of movement profiles.

PMID- 15180673
TI  - Testing separability in spatial-temporal marked point processes.
AB  - Nonparametric tests for investigating the separability of a spatial-temporal
      marked point process are described and compared. It is shown that a Cramer-von
      Mises-type test is very powerful at detecting gradual departures from
      separability, and that a residual test based on randomly rescaling the process is
      powerful at detecting nonseparable clustering or inhibition of the marks. An
      application to Los Angeles County wildfire data is given, in which it is shown
      that the separability hypothesis is invalidated largely due to clustering of
      fires of similar sizes within periods of up to 3.9 years.

PMID- 15180674
TI  - Adaptive two-stage designs for single-arm phase IIA cancer clinical trials.
AB  - The main purpose of a phase IIA trial of a new anticancer therapy is to determine
      whether the therapy has sufficient promise against a specific type of tumor to
      warrant its further development. The therapy will be rejected for further
      investigation if the true response rate is less than some uninteresting level and
      the test of hypothesis is powered at a specific target response rate. Two-stage
      designs are commonly used for this situation. However, in many situations
      investigators often express concern about uncertainty in targeting the
      alternative hypothesis to study power at the planning stage. In this article,
      motivated by a real example, we propose a strategy for adaptive two-stage designs
      that will use the information at the first stage of the study to either reject
      the therapy or continue testing with either an optimistic or a skeptic target
      response rate, while the type I error rate is controlled. We also introduce new
      optimal criteria to reduce the expected total sample size.

PMID- 15180675
TI  - Multiple testing to establish superiority/equivalence of a new treatment compared
      with k standard treatments for unbalanced designs.
AB  - In clinical studies, multiple superiority/equivalence testing procedures can be
      applied to classify a new treatment as superior, equivalent (same therapeutic
      effect), or inferior to each set of standard treatments. Previous stepwise
      approaches (Dunnett and Tamhane, 1997, Statistics in Medicine16, 2489-2506;
      Kwong, 2001, Journal of Statistical Planning and Inference 97, 359-366) are only
      appropriate for balanced designs. Unfortunately, the construction of similar
      tests for unbalanced designs is far more complex, with two major difficulties:
      (i) the ordering of test statistics for superiority may not be the same as the
      ordering of test statistics for equivalence; and (ii) the correlation structure
      of the test statistics is not equi-correlated but product-correlated. In this
      article, we seek to develop a two-stage testing procedure for unbalanced designs,
      which are very popular in clinical experiments. This procedure is a combination
      of step-up and single-step testing procedures, while the familywise error rate is
      proved to be controlled at a designated level. Furthermore, a simulation study is
      conducted to compare the average powers of the proposed procedure to those of the
      single-step procedure. In addition, a clinical example is provided to illustrate
      the application of the new procedure.

PMID- 15180676
TI  - Circular distributions based on nonnegative trigonometric sums.
AB  - A new family of distributions for circular random variables is proposed. It is
      based on nonnegative trigonometric sums and can be used to model data sets which
      present skewness and/or multimodality. In this family of distributions, the
      trigonometric moments are easily expressed in terms of the parameters of the
      distribution. The proposed family is applied to two data sets, one related with
      the directions taken by ants and the other with the directions taken by turtles,
      to compare their goodness of fit versus common distributions used in the
      literature.

PMID- 15180677
TI  - Cutpoint selection for categorizing a continuous predictor.
AB  - This article presents a new approach for choosing the number of categories and
      the location of category cutpoints when a continuous exposure variable needs to
      be categorized to obtain tabular summaries of the exposure effect. The optimum
      categorization is defined as the partition that minimizes a measure of distance
      between the true expected value of the outcome for each subject and the estimated
      average outcome among subjects in the same exposure category. To estimate the
      optimum partition, an efficient nonparametric estimate of the unknown regression
      function is substituted into a formula for the asymptotically optimum
      categorization. This new approach is easy to implement and it outperforms
      existing cutpoint selection methods.

PMID- 15180678
TI  - A multiple-record systems estimation method that takes observed and unobserved
      heterogeneity into account.
AB  - We present a model to estimate the size of an unknown population from a number of
      lists that applies when the assumptions of (a) homogeneity of capture
      probabilities of individuals and (b) marginal independence of lists are violated.
      This situation typically occurs in epidemiological studies, where the
      heterogeneity of individuals is severe and researchers cannot control the
      independence between sources of ascertainment. We discuss the situation when
      categorical covariates are available and the interest is not only in the total
      undercount, but also in the undercount within each stratum resulting from the
      cross-classification of the covariates. We also present several techniques for
      determining confidence intervals of the undercount within each stratum using the
      profile log likelihood, thereby extending the work of Cormack (1992,
      Biometrics48, 567-576).

PMID- 15180679
TI  - Biplots for multifactorial analysis of distance.
AB  - Many data sets in practice fit a multivariate analysis of variance (MANOVA)
      structure, but do not accord with MANOVA assumptions for their analysis. One way
      forward is to calculate the matrix of dissimilarities or distances between every
      pair of individuals, and then to conduct an analysis of distance on the resulting
      data. Various metric scaling plots can be used to interpret the results of the
      analysis. However, developments to date of this approach have focused mainly on
      the individuals in the sample, and little attention has been paid to the
      assessment of influence of the original variables on the results. The present
      article attempts to rectify this omission. We discuss the inclusion of biplots on
      all forms of metric scaling representations in the analysis of distance. Exact
      biplots will often be nonlinear so we propose a simple linear approximation, and
      contrast it with other simple linear possibilities. An example from ecology
      illustrates the methodology.

PMID- 15180680
TI  - Small-sample inference for the comparison of means of log-normal distributions.
AB  - We propose a likelihood-based test for comparing the means of two or more log
      normal distributions, with possibly unequal variances. A modification to the
      likelihood ratio test is needed when sample sizes are small. The performance of
      the proposed procedures is compared with the F-ratio test using Monte Carlo
      simulations.

PMID- 15180681
TI  - The analysis of placement values for evaluating discriminatory measures.
AB  - The idea of using measurements such as biomarkers, clinical data, or molecular
      biology assays for classification and prediction is popular in modern medicine.
      The scientific evaluation of such measures includes assessing the accuracy with
      which they predict the outcome of interest. Receiver operating characteristic
      curves are commonly used for evaluating the accuracy of diagnostic tests. They
      can be applied more broadly, indeed to any problem involving classification to
      two states or populations (D= 0 or 1). We show that the ROC curve can be
      interpreted as a cumulative distribution function for the discriminatory measure
      Y in the affected population (D= 1) after Y has been standardized to the
      distribution in the reference population (D= 0). The standardized values are
      called placement values. If the placement values have a uniform(0, 1)
      distribution, then Y is not discriminatory, because its distribution in the
      affected population is the same as that in the reference population. The degree
      to which the distribution of the standardized measure differs from uniform(0, 1)
      is a natural way to characterize the discriminatory capacity of Y and provides a
      nontraditional interpretation for the ROC curve. Statistical methods for making
      inference about distribution functions therefore motivate new approaches to
      making inference about ROC curves. We demonstrate this by considering the ROC-GLM
      regression model and observing that it is equivalent to a regression model for
      the distribution of placement values. The likelihood of the placement values
      provides a new approach to ROC parameter estimation that appears to be more
      efficient than previously proposed methods. The method is applied to evaluate a
      pulmonary function measure in cystic fibrosis patients as a predictor of future
      occurrence of severe acute pulmonary infection requiring hospitalization.
      Finally, we note the relationship between regression models for the mean
      placement value and recently proposed models for the area under the ROC curve
      which is the classic summary index of discrimination.

PMID- 15180682
TI  - Sensitivity of Bayes estimators to hyper-parameters with an application to
      maximum yield from fisheries.
AB  - Priors are seldom unequivocal and an important component of Bayesian modeling is
      assessment of the sensitivity of the posterior to the specified prior
      distribution. This is especially true in fisheries science where the Bayesian
      approach has been promoted as a rigorous method for including existing
      information from previous surveys and from related stocks or species. These
      informative priors may be highly contested by various interest groups. Here,
      formulae for the first and second derivatives of Bayes estimators with respect to
      hyper-parameters of the joint prior density are given. The formula for the second
      derivative provides a correction to a previously published result. The formulae
      are shown to reduce to very convenient and easily implemented forms when the
      hyper-parameters are for exponential family marginal priors. For model parameters
      with such priors it is shown that the ratio of posterior variance to prior
      variance can be interpreted as the sensitivity of the posterior mean to the prior
      mean. This methodology is applied to a nonlinear state-space model for the
      biomass of South Atlantic albacore tuna and sensitivity of the maximum
      sustainable yield to the prior specification is examined.

PMID- 15180683
TI  - Multivariate regression trees for analysis of abundance data.
AB  - Multivariate regression tree methodology is developed and illustrated in a study
      predicting the abundance of several cooccurring plant species in Missouri Ozark
      forests. The technique is a variation of the approach of Segal (1992) for
      longitudinal data. It has the potential to be applied to many different types of
      problems in which analysts want to predict the simultaneous cooccurrence of
      several dependent variables. Multivariate regression trees can also be used as an
      alternative to cluster analysis in situations where clusters are defined by a set
      of independent variables and the researcher wants clusters as homogeneous as
      possible with respect to a group of dependent variables.

PMID- 15180684
TI  - Confidence interval for rate ratio in a 2 x 2 table with structural zero: an
      application in assessing false-negative rate ratio when combining two diagnostic
      tests.
AB  - In this article, we consider problems with correlated data that can be summarized
      in a 2 x 2 table with structural zero in one of the off-diagonal cells. Data of
      this kind sometimes appear in infectious disease studies and two-step procedure
      studies. Lui (1998, Biometrics54, 706-711) considered confidence interval
      estimation of rate ratio based on Fieller-type, Wald-type, and logarithmic
      transformation statistics. We reexamine the same problem under the context of
      confidence interval construction on false-negative rate ratio in diagnostic
      performance when combining two diagnostic tests. We propose a score statistic for
      testing the null hypothesis of nonunity false-negative rate ratio. Score test
      based confidence interval construction for false-negative rate ratio will also be
      discussed. Simulation studies are conducted to compare the performance of the new
      derived score test statistic and existing statistics for small to moderate sample
      sizes. In terms of confidence interval construction, our asymptotic score test
      based confidence interval estimator possesses significantly shorter expected
      width with coverage probability being close to the anticipated confidence level.
      In terms of hypothesis testing, our asymptotic score test procedure has actual
      type I error rate close to the pre-assigned nominal level. We illustrate our
      methodologies with real examples from a clinical laboratory study and a cancer
      study.

PMID- 15180686
TI  - General ranked set sampling with cost considerations.
AB  - Nahhas, Wolfe, and Chen (2002, Biometrics58, 964-971) considered optimal set size
      for ranked set sampling (RSS) with fixed operational costs. This framework can be
      very useful in practice to determine whether RSS is beneficial and to obtain the
      optimal set size that minimizes the variance of the population estimator for a
      fixed total cost. In this article, we propose a scheme of general RSS in which
      more than one observation can be taken from each ranked set. This is shown to be
      more cost-effective in some cases when the cost of ranking is not so small. We
      demonstrate using the example in Nahhas, Wolfe, and Chen (2002, Biometrics58, 964
      971), by taking two or more observations from one set even with the optimal set
      size from the RSS design can be more beneficial.

PMID- 15180698
TI  - Heritability of C-reactive protein and association with apolipoprotein E
      genotypes in Japanese Americans.
AB  - Numerous studies have demonstrated that increased C-reactive protein (CRP) levels
      predict coronary heart disease, stroke, peripheral vascular disease, and
      diabetes, and are associated with features of the metabolic syndrome. Only three
      previous studies have investigated the heritability of CRP levels, primarily in
      samples of Caucasian families. The purpose of the present study was to estimate
      the magnitude of genetic influences on CRP levels, and to examine potential
      associations between variation in the APOE gene and CRP levels, using a sample of
      562 individual Japanese Americans from 68 extended kindreds. In general,
      correlation coefficients between first-degree relatives for CRP were
      approximately 0.2, and spouse correlations did not differ from zero, consistent
      with genetic influences. Heritability estimates were approximately 0.3 (p <
      0.01), even with adjustment for factors known to influence CRP levels. A
      significant relationship was seen between unadjusted CRP levels and APOE
      genotypes (p = 0.02), with the highest mean CRP level among epsilon2 carriers
      (1.20 mg/L), and nearly the same mean levels among epsilon3/epsilon3 subjects and
      epsilon4 carriers (0.72 and 0.74 mg/L, respectively). However, this relationship
      was diminished with adjustment for covariates (p = 0.07). These results
      demonstrate the presence of both genetic and environmental effects on CRP levels
      among Asian Americans, and additional studies are needed to determine if the APOE
      gene contributes to these genetic influences.

PMID- 15180699
TI  - Molecular analysis of GAA repeats and four linked bi-allelic markers in and
      around the frataxin gene in patients and normal populations from India.
AB  - Friedreich ataxia (FRDA), the most common type of ataxia worldwide, is an
      autosomal recessive disease. Homozygous expansion of GAA repeats in the first
      intron of the frataxin gene constitute the major type of mutation that causes the
      disease. The prevalence of FRDA in diverse ethnic populations of India has not
      been widely studied. We have studied the distribution of polymorphic GAA repeats
      in the frataxin gene among 6 clinically diagnosed patients and 160 ethnically
      matched normal individuals, to gather information on the prevalence of FRDA in
      the eastern part of India. Homozygous expansion in the range of 250-730 GAA
      repeats was detected among the patients. Among normal individuals, we observed a
      unimodal distribution of GAA repeats, consisting of 10 different alleles ranging
      from 7 to 16 GAA repeats, where the 9 repeat allele had maximal frequency. Only
      5.9% of all chromosomes were found to harbour >12 GAA repeats. Haplotype analysis
      using closely linked four bi-allelic markers in and around the frataxin gene
      indicated that 66.7% of the expanded alleles harbour the ATCC haplotype that has
      been reported worldwide. This haplotype was present in 53.3% of the chromosomes
      with >12 GAA repeats, and accounted for only 3.8% of chromosomes with 7 to 12 GAA
      repeats. We found one novel haplotype, ACCT, among the expanded alleles as well
      as among normal individuals, though at low frequency; this haplotype may be
      characteristic of Indian populations.

PMID- 15180700
TI  - Age related changes in 5-methylcytosine content in human peripheral leukocytes
      and placentas: an HPLC-based study.
AB  - The goal of the present study was to investigate inter-individual and age
      dependent variation of global DNA methylation in human tissues. In this work, we
      examined 5-methyldeoxycytidine ((met)C) content by HPLC in human peripheral blood
      leukocytes obtained from 76 healthy individuals of ages varying from 4 to 94
      years (yr), and 39 human placentas from various gestational stages. The HPLC
      analysis revealed a significant variation of (met)C across individuals and is
      consistent with the previous findings of age-dependent decrease of global
      methylation levels in human tissues. The age-dependent decrease of (met)C was
      relatively small, but statistically highly significant (p= 0.0002) in the aged
      group (65.9 +/- 8.9 [mean age +/- SD] yr; n = 22) in comparison to the young
      adult group (19.3 +/- 1.4 yr; n = 21). Males showed a subtle but statistically
      significant higher mean (met)C content than females. In contrast to the
      peripheral blood samples, DNA extracted from placentas exhibited gestational
      stage-dependent increase of methylation levels that appeared to inversely
      correlate with the expression levels of human endogenous retroviruses. These data
      may be helpful in further studies of DNA methylation, such as inheritance of
      epigenetic patterns, environment-induced changes, and involvement of epigenetic
      changes in disease.

PMID- 15180701
TI  - Mitochondrial DNA and Y-chromosome variation in the caucasus.
AB  - We have analyzed mtDNA HVI sequences and Y chromosome haplogroups based on 11
      binary markers in 371 individuals, from 11 populations in the Caucasus and the
      neighbouring countries of Turkey and Iran. Y chromosome haplogroup diversity in
      the Caucasus was almost as high as in Central Asia and the Near East, and
      significantly higher than in Europe. More than 27% of the variance in Y
      haplogroups can be attributed to differences between populations, whereas mtDNA
      showed much lower heterogeneity between populations (less then 5%), suggesting a
      strong influence of patrilocal social structure. Several groups from the highland
      region of the Caucasus exhibited low diversity and high differentiation for
      either or both genetic systems, reflecting enhanced genetic drift in these small,
      isolated populations. Overall, the Caucasus groups showed greater similarity with
      West Asian than with European groups for both genetic systems, although this
      similarity was much more pronounced for the Y chromosome than for mtDNA,
      suggesting that male-mediated migrations from West Asia have influenced the
      genetic structure of Caucasus populations.

PMID- 15180702
TI  - Mitochondrial DNA heterogeneity in Tunisian Berbers.
AB  - Berbers live in groups scattered across North Africa whose origins and genetic
      relationships with their neighbours are not well established. The first
      hypervariable segment of the mitochondrial DNA (mtDNA) control region was
      sequenced in a total of 155 individuals from three Tunisian Berber groups and
      compared to other North Africans. The mtDNA lineages found belong to a common set
      of mtDNA haplogroups already described in North Africa. Besides the autochthonous
      North African U6 haplogroup, a group of L3 lineages characterized by the
      transition at position 16041 seems to be restricted to North Africans, suggesting
      that an expansion of this group of lineages took place around 10500 years ago in
      North Africa, and spread to neighbouring populations. Principal components and
      the coordinate analyses show that some Berber groups (the Tuareg, the Mozabite,
      and the Chenini-Douiret) are outliers within the North African genetic landscape.
      This outlier position is consistent with an isolation process followed by genetic
      drift in haplotype frequencies, and with the high heterogeneity displayed by
      Berbers compared to Arab samples as shown in the AMOVA. Despite this Berber
      heterogeneity, no significant differences were found between Berber and Arab
      samples, suggesting that the Arabization was mainly a cultural process rather
      than a demographic replacement.

PMID- 15180703
TI  - Standardizing a composite measure of linkage disequilibrium.
AB  - The maximum and minimum are obtained for a composite measure of linkage
      disequilibrium used with genotypic data when the phase of double heterozygotes
      cannot be determined. These bounds are used to standardize the composite measure
      in the same way used for D', the standardized gametic measure of linkage
      disequilibrium. Standardization produces a measure which lies between -1 and 1,
      and allows comparison of linkage disequilibrium between populations. The method
      is illustrated using two loci in the CASR gene.

PMID- 15180704
TI  - Further investigation of linkage disequilibrium SNPs and their ability to
      identify associated susceptibility loci.
AB  - There is currently considerable interest in the use of single-nucleotide
      polymorphisms (SNPs) to map disease susceptibility genes. The success of this
      method will depend on a number of factors including the strength of linkage
      disequilibrium (LD) between marker and disease loci. We used a data set of SNP
      genotypings in the region of the APOE disease susceptibility locus to investigate
      the likely usefulness of SNPs in case-control studies. Using the estimated
      haplotype structure surrounding and including the APOE locus, and assuming a
      codominant disease model, we treated each SNP in turn as if it were a disease
      susceptibility locus and obtained, for each disease locus and markers, the
      expected likelihood ratio test (LRT) to assess disease association. We were
      particularly interested in the power to detect association with the
      susceptibility polymorphism itself, the power of nearby markers to detect
      association, and the ability to distinguish between the susceptibility
      polymorphism and marker loci also showing association. We found that the expected
      LRT depended critically on disease allele frequencies. For disease loci with a
      reasonably common allele we were usually able to detect association. However, for
      only a subset of markers in the close neighbourhood of the disease locus was
      association detectable. In these cases we were usually, but not always, able to
      distinguish the disease locus from nearby associated marker loci. For some
      disease loci, no other loci demonstrated detectable association with the disease
      phenotype. We conclude that one may need to use very dense SNP maps in order to
      avoid overlooking polymorphisms affecting susceptibility to a common phenotype.

PMID- 15180705
TI  - The Sib TDT adjusted for age of disease onset.
AB  - Since the Sib-TDT (Spielman & Ewens, 1998) ignores age of disease onset, there
      could be loss of power in detecting linkage. In this article, we propose an
      adjustment for age of onset using the Cox Proportional Hazard Model (Cox, 1972)
      with the marker allele as a covariate. The test statistic for linkage is
      identical to the traditional Sib-TDT. Monte-Carlo simulations are performed under
      different disease models to assess the increase in power of the age-adjusted Sib
      TDT compared to the traditional Sib-TDT. We extend our method to multiallelic
      markers. An application using data on Alzheimer's Disease is also presented.

PMID- 15180706
TI  - Notes on the maximum likelihood estimation of haplotype frequencies.
AB  - The maximum likelihood estimation (MLE) is one of the most popular ways to
      estimate haplotype frequencies of a population with genotype data whose linkage
      phases are unknown. The MLE is commonly implemented in the use of the Expectation
      Maximization (EM) algorithm. It is known that the EM algorithm carries the risk
      that an estimator may converge erroneously to one of the local maxima or saddle
      points of the likelihood surface, resulting in serious errors in the MLE of
      haplotype frequencies. In this note, by theoretical treatments we present the
      necessary and sufficient conditions that the local maxima or saddle points on the
      likelihood surface appear. As a rule of thumb, that the difference between the
      coupling and repulsive haplotype frequencies in phase known individuals is 3/2
      times larger than the frequency of phase ambiguous individuals is the sufficient
      condition that the likelihood surface is unimodal. Moreover, we present the
      analytic solution to the biallelic two-locus problem, and construct a general
      algorithm to obtain the global maximum.

PMID- 15180707
TI  - Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined
      immunodeficiency associated with alopecia in southern Italy population.
AB  - Genetic alterations of the FOXN1 transcription factor, selectively expressed in
      thymic epithelia and skin, are responsible in both mice and humans for the
      Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T
      transition in exon 5 resulting in the nonsense mutation R255X, and was detected
      in two probands originated from a small community in southern Italy. In this
      community, four additional children affected with congenital alopecia died in
      early childhood because of severe infections. In this study, we report on the
      screening for this mutation in 30% of the village population. This analysis led
      us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843
      inhabitants screened. A genealogical study revealed that these subjects,
      belonging to 39 families, were linked in an extended 7-generational pedigree
      comprising 483 individuals. Through the archival database a single ancestral
      couple, born at the beginning of the 19th century, was identified. To confirm the
      ancestral origin of the mutation we genotyped two microsatellite markers,
      D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three
      haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a
      single ancestral origin for the mutation R255X.

PMID- 15180708
TI  - The genetic basis for sex differences in human behaviour: role of the sex
      chromosomes.
AB  - The nature of the mechanisms underlying observed sex differences in human
      behaviour continues to be debated. This review concentrates on the thesis that
      genes on the sex chromosomes other than those directly controlling sex
      determination, and whose functions are, at least in part, independent from
      hormonal influences, play a significant role in determining gender differences in
      behaviour. To provide an adequate basis for examining this issue, the current
      understanding of the nature of sex determination, differences in behaviour and
      the influences of sex hormones are evaluated. The possible contribution to
      behavioural differences of those X-linked genes which escape inactivation, or
      which may be subjected to imprinting, is discussed. The review concludes with a
      summary of the genetic basis for two sexually disparate types of behaviour.

PMID- 15180709
TI  - Hepatitis C with normal liver enzymes: to treat or not to treat. Pro: most
      patients should be treated.

PMID- 15180710
TI  - Hepatitis C with normal liver enzymes: to treat or not to treat. Con: most
      patients should not be treated.

PMID- 15180711
TI  - Hepatitis C with normal liver enzymes: to treat or not to treat. A balancing
      view: a decision to be shared with patients.

PMID- 15180712
TI  - Informed consent: not just for procedures anymore.
AB  - The ethical and legal requirement to obtain informed consent prior to performing
      a procedure or administering a treatment derives from the concept of personal
      (patient) autonomy. The competent patient, after receiving appropriate disclosure
      of the material risks of the procedure or treatment, understanding those risks,
      the benefits, and the alternative approaches, makes a voluntary and uncoerced
      informed decision to proceed. This article will present a general overview of the
      modern concept of informed consent as a process (mutual communication) rather
      than an event (document signing). The historical evolution of this concept and
      the legal rulings that have shaped the requirements of informed consent will be
      cited. The benefits of informed decision making as a communication and risk
      management tool are presented. This review is intended as general information,
      and not as legal advice, which should be sought from a health-care attorney.

PMID- 15180713
TI  - Gastroesophageal reflux disease poorly responsive to single-dose proton pump
      inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux, or
      both?
AB  - OBJECTIVES: Studies using ambulatory pH and esophageal bile reflux monitoring
      (Bilitec) have shown that both acid reflux and duodeno-gastro-esophageal reflux
      (DGER) frequently occur in patients with gastroesophageal reflux disease (GERD).
      A subset of patients with GERD has persistent reflux symptoms in spite of
      standard doses of proton pump inhibitors (PPIs). The aim of the present study was
      to investigate the role of acid and DGER in patients with reflux disease poorly
      responsive to PPIs. METHODS: Sixty-five patients (32 men, 44 +/- 2 yr) without
      Barrett's esophagus and with persistent heartburn or regurgitation during
      standard PPI doses were studied. They underwent upper gastrointestinal endoscopy
      and simultaneous 24-h ambulatory pH and Bilitec monitoring while PPIs were
      continued. RESULTS: Thirty-three patients (51%) had persistent esophagitis. Seven
      patients (11%) had only pathological acid exposure, 25 (38%) had only
      pathological DGER exposure, and 17 (26%) had pathological exposure to both acid
      and DGER. Acid exposure under PPI was positive in only 37%, but adding Bilitec
      increased the diagnoses of persistent reflux to 75%. Patients with persistent
      esophagitis had similar acid exposure, but significantly higher DGER exposure
      than those without esophagitis. The highest prevalence of esophagitis was found
      in patients with pathological exposure to both acid and DGER; symptoms did not
      differ according to the type of reflux. CONCLUSIONS: Combined pH and Bilitec
      monitoring is superior to pH monitoring alone in demonstrating ongoing
      pathological reflux in patients with medically poorly responsive reflux disease.

PMID- 15180714
TI  - "Refractory GERD": acid, nonacid, or not GERD?
AB  - Gastroesophageal reflux disease (GERD) is a common condition with 44% of
      Americans surveyed reporting heartburn at least once a month and 20% once a week
      (1, 2). However, despite major advances in our understanding of this disease,
      management of GERD is still a challenge. Proton pump inhibitors (PPIs) are more
      effective than H2-receptor antagonists (H2RA) in the initial healing of erosive
      esophagitis, which provide symptom relief and maintenance (3). Due to its
      established efficacy and safety, PPI treatment is used as the initial "test" in
      diagnosing GERD in the absence of bleeding, anemia, weight loss, or dysphagia. A
      single dose of PPI provides adequate symptom relief in most patients; however,
      dose escalation to twice a day may be needed in some. Patients unresponsive to
      PPI therapy are often labeled as having "refractory GERD." However, this term is
      poorly defined and has a different meaning in different countries. More
      importantly, the cause of "refractory GERD" is poorly understood.

PMID- 15180715
TI  - Complete elimination of reflux symptoms does not guarantee normalization of
      intraesophageal and intragastric pH in patients with gastroesophageal reflux
      disease (GERD).
AB  - BACKGROUND: Acid plays a significant role in the development of gastroesophageal
      reflux symptoms, such as heartburn and regurgitation. It is generally assumed
      that acid suppressive therapy improves or eliminates symptoms by normalizing
      intraesophageal pH. AIMS: The aim of this article was to assess the efficacy of
      proton-pump inhibitors (PPIs) in normalizing intraesophageal and intragastric pH
      in patients with GERD without Barrett's esophagus (BE) rendered symptom free by
      therapy. METHODS: Patients were evaluated by dual-sensor 24-h pH monitoring while
      receiving PPI therapy for complete control of GERD symptoms. Analyses of
      intraesophageal and intragastric pH profiles were then made. RESULTS: Fifty
      patients, 39 men and 11 women, with GERD, without BE, were studied. All tolerated
      PPIs well and were asymptomatic at the time of the study. Fifty percent of
      patients had abnormal intraesophageal pH profiles despite adequate symptom
      control on PPIs, which was associated with significant breakthrough of
      intraesophageal acid control in both the upright and supine positions. Low
      intragastric pH correlated highly with intraesophageal acid reflux only in
      patients with persistent abnormal esophageal acid exposure (p= 0.001).
      CONCLUSIONS: Fifty percent of patients with GERD without BE continue to exhibit
      pathologic GERD and low intragastric pH despite PPI therapy that achieves
      complete reflux symptom control.

PMID- 15180716
TI  - Acid inhibition in GERD-how much is enough?
AB  - Gastric acid plays a fundamental role in the development of mucosal injury and
      symptoms in gastro-esophageal reflux disease(GERD). In this issue of the Journal,
      Milkes et al report the inability of proton pump inhibitor (PPIs) therapy to
      "normalize" 24-hour intraesophageal pH parameters despite good symptom control.
      Twenty-five of fifty H. pylori negative patients with chronic uncomplicated GERD
      failed to normalize their pH parameters. Failure of esophageal acid control
      correlated with inadequate gastric acid inhibition. These findings are
      provocative and interesting but difficult to reconcile against a large body of
      evidence supporting the superior therapeutic efficacy of PPIs in symptom control,
      healing of esophagitis, and decreasing the rate of dilations in patients with
      GERD. No information is provided regarding the status of the esophageal mucosa in
      patients failing to achieve normalization of pH values. This raises the question
      about the clinical significance of this finding: i.e., does the lack of
      normalization of esophageal pH parameters correlate with esophageal epithelial
      damage (endoscopically visible injury) or complications of the disease? The
      patient population for this study was highly selected, thus the true prevalence
      of this observation for the large pool of patients with GERD remains unknown.
      Despite this and other limitations, the study will likely stimulate further
      research to examine ultimately how much acid inhibition-and for how long-is
      critical to the healing of GERD and to prevent the complications of the disease.

PMID- 15180717
TI  - Physical and pH properties of gastroesophagopharyngeal refluxate: a 24-hour
      simultaneous ambulatory impedance and pH monitoring study.
AB  - OBJECTIVES: Frequency occurrence of nonacidic and nonliquid reflux events in the
      pharynx has not been systematically studied. The aim of the present study was to
      characterize the physical (liquid, gas, and mixed gas/liquid) and pH properties
      of the gastroesophagopharyngeal refluxate. METHODS: We performed a total of 31 24
      h simultaneous ambulatory pharyngoesophageal impedance and pH recordings in 11
      GERD patients, 10 patients with reflux-attributed laryngitis, and 10 healthy
      controls. RESULTS: On average, the total number of reflux events (all kinds) in
      the pharynx was less than half of that in the proximal esophagus (18 +/- 4 vs 50
      +/- 4, p < 0.01). Most of the pharyngeal reflux events were gas events and were
      observed in all three studied groups. Prevalence of these gas reflux events
      ranged between 0 and 74. The number of gas reflux events accompanied by a minor
      pH drop in laryngitis patients (1 (0-36)) was significantly higher than those in
      GERD and controls (0 (0-2) and 0 (0-1), respectively, p < 0.05). There was no
      significant difference in the number of nonacidic gas reflux events among the
      three groups (GERD: 10 (2-57), laryngitis: 11.5 (0-51), controls: 10.5 (0-27)).
      Impedance recording identified a total number of 566 events in the pharynx. Of
      these, a total of 563 events were compatible with gas reflux events, 101 events
      were accompanied by minor drops in intrapharyngeal pH, whereas 460 events were
      not accompanied by any pharyngeal pH change. CONCLUSIONS: Concurrent impedance
      and pH recordings detect significantly more events qualifying as reflux in the
      pharynx than pH recordings alone. A substantial majority of these events are
      gaseous refluxes both with and without minor pH drops. Gas reflux events with
      weak acidity appear to be more common among patients with reflux-attributed
      laryngeal lesions compared to GERD patients and controls.

PMID- 15180718
TI  - Combined multichannel intraluminal impedance and manometry clarifies esophageal
      function abnormalities: study in 350 patients.
AB  - BACKGROUND: Combined multichannel intraluminal impedance and esophageal manometry
      (MII-EM) is a technique that uses an FDA-approved device allowing simultaneous
      evaluation of bolus transit (MII) in relation to pressure changes (EM). METHODS:
      During a 9-month period, beginning from July 2002 through March 2003, we
      prospectively performed combined MII-EM on all patients referred for esophageal
      function testing. Each patient received 10 liquid and 10 viscous swallows.
      Manometric findings were reported based on criteria described by Spechler and
      Castell for liquid swallows. MII findings were reported as having normal bolus
      transit if >/=80% (8/10) of liquid and >/=70% (7/10) of viscous swallows had
      complete bolus transit. RESULTS: Three-hundred fifty studies were evaluated from
      patients with a variety of symptoms having the following manometric diagnoses:
      normal manometry (125), achalasia (24), scleroderma (4), ineffective esophageal
      motility (IEM) (71), distal esophageal spasm (DES) (33), nutcracker esophagus
      (30), hypertensive lower esophageal sphincter (LES) (25), hypotensive LES (5),
      and poorly relaxing LES (33). None of the patients with achalasia and scleroderma
      had normal bolus transit. Fifty-one percent of patients with IEM and 55% of
      patients with DES had normal bolus transit while almost all (more than 95%)
      patients with normal esophageal manometry, nutcracker esophagus, poorly relaxing
      LES, hypertensive LES, and hypotensive LES had normal bolus transit. Dysphagia
      occurred most often in patients with incomplete bolus transit on MII testing.
      CONCLUSION: Esophageal body pressures primarily determine bolus transit with
      isolated LES abnormalities appearing to have little effect on esophageal
      function. MII clarifies functional abnormalities in patients with abnormal
      manometric studies.

PMID- 15180719
TI  - Esophageal impedance monitoring: the ups and downs of a new test.
AB  - Impedance monitoring was first proposed as a method for gastrointestinal motility
      10 yr ago. It detects changes in resistance to current flow when a bolus
      traverses an electrode pair, and can distinguish liquid (low-impedance) from gas
      (high-impedance) boluses (1). Electrode pairs placed at multiple sites on a
      standard solid-state esophageal manometry catheter can track antegrade bolus
      transit through the esophagus to correlate with manometry findings. In contrast,
      the electrode pairs placed at multiple sites on a standard pH probe can track
      retrograde bolus transit from the stomach to the esophagus to correlate with pH.
      This issue of The American Journal of Gastroenterology contains reports that
      relate to each of these two distinct applications of impedance monitoring.

PMID- 15180720
TI  - Re-examination of the cost-effectiveness of surgical versus medical therapy in
      patients with gastroesophageal reflux disease: the value of long-term data
      collection.
AB  - OBJECTIVES: For patients with reflux esophagitis, long-term therapeutic options
      include proton pump inhibitor (PPI) therapy and/or antireflux surgery. An earlier
      cost-effectiveness analysis concluded that at 5 yr, medical therapy was less
      expensive but similarly effective to fundoplication, but the results were
      sensitive to estimates on quality of life and long-term medication usage, which
      were derived from "expert opinion." Recently, data from randomized controlled
      trials addressing these variables have become available. We have incorporated
      these new data into a revised Markov model to examine the cost-effectiveness of
      surgical versus medical therapy in patients with severe reflux esophagitis.
      METHODS: A Markov simulation model was constructed using specialized software
      (DATA PRO 4.0, Williamstown, MA). Total expected costs and quality-adjusted life
      years were calculated for long-term medical therapy and for laparoscopic Nissen
      fundoplication. Probabilities were obtained from the medical literature using
      Medline. Procedural and hospitalization costs used were the average Medicare
      reimbursements at our institution. Medication costs were the average wholesale
      price. The analysis was extended over a 10-yr time horizon at a discount rate of
      3%. RESULTS: The discounted analysis shows that medical therapy is associated
      with total costs of 8,798 dollars and 4.59 quality-adjusted life-years, whereas
      the surgical strategy is more expensive (10,475 dollars) and less effective (4.55
      quality-adjusted life-years). The results were robust to most one-way sensitivity
      analyses. CONCLUSIONS: Long-term medical therapy with proton pump inhibitors is
      the preferred strategy for patients with gastroesophageal reflux disease and
      severe esophagitis. Our study highlights the importance of using primary, patient
      derived data rather than expert opinion.

PMID- 15180721
TI  - Complexities of managing achalasia at a tertiary referral center: use of
      pneumatic dilatation, Heller myotomy, and botulinum toxin injection.
AB  - PURPOSE: The purpose of this study is to describe the results and complexity of
      treatment for achalasia patients presenting to a single esophagologist at a
      tertiary referral center and to make treatment recommendations based on this
      experience. METHODS: Retrospective chart review of achalasia patients treated
      between 1994 and 2002. Symptoms, manometric and timed barium esophagram results,
      and treatments/outcome at CCF determined. RESULTS: 232 patients (51% male, mean
      age = 53) were evaluated. Untreated patients (n = 184): Pneumatic dilatation (PD)
      used in 111 patients. Symptoms and barium emptying improved in 86% and 54%,
      respectively. Nineteen (17%) patients required subsequent Heller myotomy (HM).
      Perforation rate: 3/111 (2.7%) patients. 16% required proton-pump inhibitor (PPI)
      for GERD. HM was used in 72 patients (81% laparoscopic). Symptoms and barium
      emptying improved in 89% and 44%, respectively. PPI required in 53%. Botulinum
      toxin (Botox) was used in 39 older patients (mean age = 71); symptom improvement
      lasted for a mean 6.2 months, with frequent need for repeated injection (mean:
      1.7, range: 1-7). About 43% required additional treatment with a different
      modality. Esophagectomy was done in three patients. Patients with prior surgery
      (n = 48): PD (n = 10) achieved symptom and barium emptying improvement in 67% and
      11%, comparable to redo HM (n = 21) with 57% symptom improvement and 38% improved
      emptying. Esophagectomy required in eight patients. CONCLUSIONS: Successful
      management of achalasia can be complex and may require more than one treatment
      modality. PD and HM are presently the best treatments for untreated achalasia
      with similar efficacy but greater PPI use after surgery. Both are less successful
      after prior HM.

PMID- 15180722
TI  - Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a
      multicenter report of normal values from 60 healthy volunteers.
AB  - OBJECTIVES: Impedance monitoring is a new diagnostic method for gastroesophageal
      reflux disease (GERD) where multiple impedance electrode pairs are placed on a
      standard pH catheter. It detects reflux of a liquid and/or gas bolus into the
      esophagus, as well as its distribution, composition, and clearing. The aim of
      this collaborative study is to define normal values for 24-h ambulatory
      simultaneous impedance and pH monitoring (24-h Imp-pH), and compare bolus
      parameters by impedance monitoring to changes in [H(+)] measured by pH
      monitoring. METHODS: Sixty normal volunteers without GER symptoms underwent 24-h
      Imp-pH with impedance measured at six sites (centered at 3, 5, 7, 9, 15, and 17
      cm above lower esophageal sphincter) and pH 5 cm above the LES. Reflux detected
      by impedance was characterized by the pH probe as either acid, weakly acidic,
      nonacid, or superimposed acid reflux. Proximal reflux was defined as reflux that
      reached the impedance site 15 cm above the LES. RESULTS: Reflux frequency was
      common upright (median-27, 25th and 75th quartile-16, 42), but rare recumbent
      (median-1; 0, 4). A median of 34% (14%, 49%) of upright reflux reached the
      proximal esophagus. There was a similar number of mixed composition (liquid +
      gas; 49%) and liquid-only reflux (51%). Acid reflux was two-fold more common than
      weakly acidic reflux (p < 0.001). Superimposed acid reflux and nonacid reflux
      were rare. Acid neutralization to pH 4 took twice as long as volume clearance
      measured by impedance. CONCLUSIONS: Combining impedance and pH monitoring
      improves the detection and characterization of GER. This study characterizes the
      frequency, duration, and extent of reflux in health and provides normal values
      for 24-h Imp-pH for future comparison with GERD patients.

PMID- 15180723
TI  - Assessment of health state utilities and quality of life in patients with
      malignant esophageal Dysphagia.
AB  - OBJECTIVES: Palliation of terminal conditions such as malignant dysphagia must
      take into account individual preferences for aggressive or nonaggressive care,
      with a focus on quality of life. Despite this, there are very few data on
      patients' preferences for palliative therapy. This study is designed to
      quantitatively determine individual preferences for palliation of malignant
      dysphagia using health state utilities (HSU). METHODS: HSU were measured using
      three methods: time trade-off (TTO), visual analog scale (VAS), and the EQ-5D.
      Patients with esophageal cancer were asked to rate their own state of health and
      of three standardized scenarios of local, regional, and metastatic disease.
      RESULTS: Fifty patients with esophageal cancer were enrolled. Using the TTO
      method, the utilities of their own health state were 0.80 (95% CI 0.59-0.99) for
      localized, 0.54 (0.37-0.70) for regional, and 0.52 (0.32-0.71) for metastatic
      cancer showing no significant difference in mean utility scores for the three
      staging groups. VAS and EQ5D gave statistically similar values to TTO. Patients
      consistently rated their own utility better than the utility of standardized
      scenarios with similar stage and prognosis. Independent of their staging,
      patients with high dysphagia scores rated their utility worse than patients with
      low dysphagia scores. CONCLUSIONS: These results confirm the perceived poor state
      of health of patients with esophageal cancer and are substantially lower than
      previous estimates in operated patients. Cost-effectiveness models must take into
      account significant differences between patients' assessment of their own state
      of health, and that of a "societal" perspective of others with a similar disease.
      All three methods provided similar estimates. Given the ease of use of VAS and EQ
      5D, these methods may be preferable to TTO.

PMID- 15180724
TI  - Empiric treatment with high and standard dose of omeprazole in general practice:
      two-week randomized placebo-controlled trial and 12-month follow-up of health
      care consumption.
AB  - OBJECTIVES: Patients with acid-related symptoms in general practice are often
      treated empirically with a standard dose of proton pump inhibitors (PPIs). The
      effect of higher doses is not known. The study compared the immediate symptom
      relieving as well as the long-term effect of standard and double dose of
      omeprazole in such patients. METHODS: Consecutive patients with dyspeptic
      symptoms, normally treated by the general practitioner with PPIs or H2-blockers
      were randomized to treatment with omeprazole 40 mg, 20 mg, or placebo in the
      morning for 2 wk. Patients with alarm symptoms, IBS, and PPI-treated patients
      were excluded. Dyspeptic symptoms and Helicobacter pylori status were recorded.
      The study endpoint was complete relief of the dyspeptic symptoms, which initiated
      the consultation. Relapse rates and health-care consumption were recorded during
      12-month observation. RESULTS: Eight hundred and twenty-nine patients were
      randomized. Complete relief of the predominant symptom was obtained by 66%, 63%,
      and 35% in patients treated with omeprazole 40 mg, 20 mg, and placebo,
      respectively. No difference was found comparing H. pylori-positive and -negative
      patients. Relapse rates were high and health-care consumption during 12 months
      was related to the treatment outcome, but not to the omeprazole dose or the H.
      pylori status. CONCLUSIONS: Compared to placebo, omeprazole 40 mg and 20 mg were
      equally and significantly better in relieving acid-related symptoms; the numbers
      needed-to-treat (NNT) were 3.2 (40 mg) and 3.7 (20 mg). Relief of the dyspeptic
      complaint was followed by significantly reduced health-care consumption during 12
      month observation.

PMID- 15180725
TI  - Treat the patients' main dyspepsia complaint, not the ROME criteria.
AB  - This pragmatic, primary care study by Meineche-Schmidt in patients with presumed
      acid-related uninvestigated dyspepsia showed that a standard dose of omeprazole
      20 mg daily was significantly more effective than a placebo in treating their
      self-worded main dyspepsia complaint. As a higher dose of omeprazole 40 mg daily
      was not more effective, the standard dose should be used. In this study, 9% of
      the patients had sole reflux-like symptoms while the rest had other accompanying
      symptoms and would be considered to have dyspepsia. In fact, patients had on
      average more than five symptoms. Patients do not know that there is a controversy
      about whether to call their symptoms GERD or dyspepsia; they just know that they
      want to feel better. As no initial investigations were made, patients could have
      a variety of possible diagnoses such as gastroesophageal reflux disease, ulcer
      disease, or functional dyspepsia. The recent CADET-PE study showed that if
      patients had endoscopic abnormalities, these were findings such as esophagitis
      that would be appropriately treated with acid suppression. That study also
      reconfirmed that symptoms do not predict endoscopic findings and do not make a
      diagnosis. Thus, the approach suggested in this study to treat patients based on
      their main symptom complaint is practical and effective.

PMID- 15180726
TI  - Mucosal concentrations of proinflammatory cytokines and chemokines at gastric
      cardia: implication of Helicobacter pylori infection and gastroesophageal reflux.
AB  - OBJECTIVES: The pathogenesis of carditis remains unclear, although
      gastroesophageal reflux disease (GERD) and Helicobacter pylori infection have
      been proposed. Little is known about the profile of proinflammatory cytokines and
      chemokines in the pathogenesis of carditis. METHODS: We studied 28 patients with
      GERD and 40 controls. Two biopsy specimens were taken endoscopically from the
      cardiac mucosa within 5 mm from the squamocolumnar junction; one was snap frozen
      for measurement of mucosal levels of interleukin 1beta (IL-1beta), tumor necrosis
      factor-alpha, IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), regulated
      on activation normal T-cell expressed and presumably secreted (RANTES) by enzyme
      linked immunosorbent assays, while another was processed for histopathology. H.
      pylori infection was assessed by serology, rapid urease test, and histology with
      Giemsa staining. Samples were taken from the cardia of 18 H. pylori-positive
      patients, before and after eradication treatment. RESULTS: Carditis was
      significantly associated with H. pylori infection, but not GERD. IL-8, MCP-1, and
      RANTES levels were significantly higher in cardiac mucosa of patients with
      carditis than in those without it and in patients with than without H. pylori
      infection. IL-8 concentrations were significantly associated with the degree of
      neutrophil infiltration within the cardiac mucosa and decreased after cure of the
      infection. Mucosal MCP-1 and RANTES levels correlated positively with the grades
      of mononuclear cell infiltration and IL-1beta concentrations. CONCLUSION: Our
      results indicate that chemokines produced locally in the cardiac mucosa may be
      involved in the development of H. pylori-associated carditis.

PMID- 15180727
TI  - Endoscopic ultrasound and fine-needle aspiration of unexplained bile duct
      strictures.
AB  - OBJECTIVES: The aim of this study was to assess the utility of endoscopic
      ultrasound (EUS) with fine-needle aspiration (FNA) in patients with unexplained
      common bile duct strictures after endoscopic retrograde cholangiopancreatography
      (ERCP) and intraductal tissue sampling. METHODS: Records were reviewed for all
      subjects undergoing EUS for evaluation of unexplained bile duct strictures at our
      institution. 40 subjects had either a final histologic diagnosis (24) or no
      evidence of malignancy after at least 1 yr of follow-up (16). RESULTS: The
      finding of a pancreatic head mass and/or an irregular bile duct wall had
      sensitivity for malignancy of 88%, specificity of 100%, positive predictive value
      of 100%, and negative predictive value of 84%. Bile duct wall thickness >/=3 mm
      had a sensitivity for malignancy of 79%, specificity of 79%, positive predictive
      value of 73%, and negative predictive value of 80%. Sensitivity of EUS FNA for
      malignancy was 47% with specificity 100%, positive predictive value 100%, and
      negative predictive value 50%. CONCLUSIONS: Sonographic features may be more
      sensitive than EUS FNA for diagnosis of unexplained bile duct strictures and
      include presence of a pancreatic mass, an irregular bile duct wall, or bile duct
      wall thickness > 3 mm. EUS FNA cytology is specific but insensitive for
      diagnosis. EUS improves the diagnosis of otherwise unexplained bile duct
      strictures.

PMID- 15180728
TI  - Screening flexible sigmoidoscopy using an upper endoscope is better tolerated by
      women.
AB  - BACKGROUND: Flexible sigmoidoscopy (FS) is a commonly used method for colorectal
      cancer screening. Women are more likely than men to have a FS with a limited
      depth of insertion, in part due to differences of anatomy and perception of pain.
      AIM: The objective of this prospective single-blinded randomized clinical study
      is to assess satisfaction in women undergoing screening FS using an upper
      endoscope (E, diameter 9.8 mm) versus a standard sigmoidoscope (S, diameter 13.3
      mm) as measured by pain and discomfort and overall satisfaction using a validated
      survey instrument. Secondary endpoints of FS efficacy included the depth of
      insertion of the instrument, frequency of polyp detection, and complication rate.
      RESULTS: A total of 160 asymptomatic women undergoing screening FS were entered
      over a 4-month period (July through November 2002). All procedures were performed
      by two experienced physician assistants. The two groups were of similar age (E =
      57.5, S = 58.2, p= 0.579) and had a similar rate of previous abdominal surgery (E
      = 51.2%, S = 45.0%, p= 0.428) or hysterectomy (E = 34.2%, S = 26.3%, p= 0.274).
      Depth of insertion of the scope was 54.5 cm (+/-9.2 cm) with the E and 51.6 cm
      (+/- 10.3 cm) with the S (p= 0.058). Polyps were found more frequently in the
      study group (18.3%) compared with the control group (p= 10.2%) though this did
      not reach statistical significance (p= 0.131). Overall satisfaction with FS was
      similar in both groups (p= 0.694) but pain and discomfort were less in the
      patients undergoing FS using the E (p= 0.006). Controlling for age and previous
      surgery the differences in pain scores remained significant (p= 0.035).
      Endoscopist assessment of procedure difficulty (p= 0.726) and complication rates
      (p= 0.614) was equivalent. Controlling for the presence of polyps, the total
      duration for the procedure was 7.2 min in the E group and 5.7 min in the S group
      (p= 0.008). There were no significant differences between women with and without
      hysterectomy on either overall satisfaction or pain and discomfort. CONCLUSION:
      Screening FS in women using an upper endoscope is a feasible approach to
      colorectal cancer screening. Patients screened with an upper endoscope reported
      less pain and discomfort compared to standard sigmoidoscope while overall
      satisfaction did not differ. The trend toward increased polyp detection in
      patients undergoing FS with an upper endoscope may be related to a more thorough
      examination due to less patient discomfort and/or an increased depth of insertion
      of the upper endoscope. Thinner, more flexible endoscopes should be considered
      when performing screening FS in women.

PMID- 15180729
TI  - An initial investigation of bispectral monitoring as an adjunct to nurse
      administered propofol sedation for colonoscopy.
AB  - BACKGROUND AND AIMS: Bispectral (BIS) monitoring has been used to evaluate depth
      of sedation in intensive care and surgical patients. We sought to explore its
      utility as a monitoring device for nurse-administered propofol sedation (NAPS)
      during colonoscopy. METHODS: Fifty consecutive patients (ASA I or II) receiving
      NAPS for outpatient colonoscopy were evaluated. BIS scores, sedation scores, and
      propofol dosing were correlated. The nurses assessed the usefulness of BIS by
      questionnaire. RESULTS: The mean (SD) dose of propofol required to produce a BIS
      value </= 60 was 109.4 (43.9) mg and an Observer's Assessment of
      Alertness/Sedation (OAA/S) score of 1 (deep sedation) was 91.4 (44.8) mg (p <
      0.0001). The mean times required to achieve BIS values </= 60 (188 +/- 147.1 s)
      and </= 70 (164.3 +/- 95.1 s) were significantly longer than the mean time
      required to achieve an OAA/S of 1 (117.4 +/- 93.0 s, p= 0.0007). Similarly,
      during the recovery phase, there was a lag time of 197.9 s between mean (SD) time
      required from the last dose of propofol to an OAA/S of 5 (372.1 +/- 197.1 s) and
      the mean (SD) time required from the last dose of propofol to a BIS value >/= 90
      or return to baseline (570 +/- 279.9 s, p < 0.0001). The mean (SD) BIS value in
      the maintenance phase of sedation was 58.9 (8.53), with a range of 22-88. Nurses
      administering propofol rated the usefulness of BIS at a mean of 2.85 (maximum
      usefulness scored as 4) in guiding the dosing of propofol sedation during the
      maintenance phase of sedation. No patient required mask ventilation or
      endotracheal intubation. CONCLUSIONS: The BIS index in its current version is not
      useful in titrating boluses of propofol to an adequate level of sedation, because
      there is a substantial lag time between decrease of BIS scores to <70 and OAA/S
      scores indicative of deep sedation. There is also a substantial lag time between
      recovery of alertness and return of BIS scores to normal. A controlled trial of
      whether BIS values can assist in avoiding unnecessary propofol dosing during the
      maintenance phase of sedation appears warranted.

PMID- 15180731
TI  - GP73 and liver disease: a (Golgi) complex enigma.
AB  - Newly synthesized proteins in the lumen and the membrane of the endoplasmic
      reticulum are transported to the Golgi apparatus, where posttranslational
      modification of proteins and lipids occurs, commonly by the addition of
      carbohydrate residues. The Golgi apparatus is also the major sorting center of
      the cell; proteins proceed from this organelle to lysosomes, secretory granules,
      or the plasma membrane, according to signals encoded within their amino acid
      sequences and three-dimensional structures. A growing number of resident membrane
      proteins have been identified in the last few years, but the function of many of
      these proteins remains poorly characterized to date. In this issue, as a
      continuation of their previous studies, Fimmel and colleagues report that GP73
      protein is overexpressed in a variety of acute and chronic liver diseases. In
      contrast to their previous studies, they show expression of GP73 in sinusoidal
      lining cells, and suggest that activated stellate cells may be a potential source
      of this protein. In the current study, the authors do not provide any new insight
      on the function and role of this protein in liver disease. The widespread
      expression of this protein in many diverse acute and chronic conditions suggests
      that the measurement of this protein is unlikely to be very useful for
      etiological diagnosis or staging, but it may prove to be a marker of liver
      disease. However, a better understanding of the role of this protein may provide
      more insights into the pathogenesis of liver injury and progression.

PMID- 15180730
TI  - Disease- and cell-specific expression of GP73 in human liver disease.
AB  - OBJECTIVES: GP73, a Golgi membrane protein, is expressed at high levels in
      hepatocytes of patients with decompensated cirrhosis. Its expression in other
      forms of liver disease has not been investigated. Therefore, we studied GP73
      expression in patients with noncirrhotic liver disease. METHODS: GP73 expression
      was detected immunohistochemically and by immunofluorescence microscopy in
      patients with acute hepatitis of various etiologies, autoimmune hepatitis,
      chronic HCV infection, and alcoholic liver disease. In order to quantitate
      hepatocyte GP73 expression, an immunohistochemical scoring system was developed,
      and validated by a direct comparison with GP73 protein levels as determined by
      Western blotting. RESULTS: GP73 immunostaining and Western blotting data were
      highly correlated, demonstrating the suitability of the immunohistochemical
      scoring system to quantitate hepatocyte GP73 expression. Hepatocyte GP73
      expression was increased in patients with acute and autoimmune hepatitis.
      Treatment of autoimmune hepatitis was associated with a normalization of GP73
      expression, indicating that the initial upregulation was reversible. Increased
      levels of GP73 expression were also noted in chronic HCV infection and alcoholic
      liver disease. Under these conditions, GP73 levels were correlated with disease
      stage but not grade. GP73 immunoreactivity was occasionally detected in alpha-SMA
      positive, sinusoidal lining cells, suggesting activated stellate cells as a
      potential source of GP73. CONCLUSIONS: Hepatocyte GP73 levels are upregulated in
      acute hepatitis and during the progression of liver disease to cirrhosis. This
      expression pattern suggests the presence of two regulatory mechanisms, the first
      triggered during acute hepatocellular injury, the second during the progression
      of chronic liver disease.

PMID- 15180732
TI  - Amantadine therapy for chronic hepatitis C: a dose escalation study.
AB  - OBJECTIVES: Amantadine reduces liver transaminase levels in some patients with
      chronic hepatitis C at doses of 200 mg daily and may improve the sustained
      virological response (SVR) when given with interferon and ribavirin. The primary
      purpose of the present investigation was to study the safety and toxicity of
      higher doses of amantadine in subjects who previously failed or were intolerant
      to interferon. The secondary aim was to test the efficacy of higher dose of
      amantadine against hepatitis C. METHODS: An open-labeled prospective study was
      conducted starting with amantadine 200 mg daily and increasing to 500 mg daily
      while monitoring for safety, toxicity, and efficacy. An amantadine blood level
      exceeding 1,600 ng/ml was considered toxic requiring dose reduction. The
      patient's symptoms, laboratory tests, and quality of life were monitored.
      RESULTS: One hundred patients enrolled in the study. Normalization of alanine
      aminotransferase (ALT) for each dose was as follows: 200 mg (35%), 300 mg (49%),
      400 mg (53%), and 500 mg (56%). The incidence of toxic amantadine plasma levels
      increased with dose, i.e., 200 mg (0%), 300 mg (6%), 400 mg (27%), and 500 mg
      (49%). The frequency and severity of arthralgias and fatigue improved at all
      dosages administered. No changes in the occurrence or severity of headache,
      insomnia, or depression were reported. Serious adverse events included myocardial
      infarction and suicide attempt. Other side effects included impotence, confusion,
      alopecia, and hoarseness. CONCLUSIONS: Amantadine given at a dose of 300 mg daily
      is safe, and significantly lowers ALT blood levels more than 200 mg daily. The
      enzyme response rate does not significantly improve above 300 mg, but toxicity
      increases.

PMID- 15180733
TI  - Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable
      pruritus in patients with primary biliary cirrhosis.
AB  - BACKGROUND AND AIMS: Pruritus is a distressing symptom in patients with primary
      biliary cirrhosis, and when uncontrollable it is an indication for liver
      transplantation. Since pruritus can result from unknown substances that
      accumulate systemically as a consequence of impaired biliary secretion, we have
      assessed whether a new extracorporeal albumin dialysis (ECAD) procedure, the
      molecular-adsorbing recirculating system-MARS, has any effect on pruritus of
      cholestasis. METHODS: Four patients with primary biliary cirrhosis and resistant
      pruritus were treated with two 7-h ECAD sessions 1 day apart. Pruritus was
      recorded from 15 days before the first session, before and after each session,
      and during the follow-up using a visual analogue scale (VAS). Standard liver
      tests as well as serum bile acid levels were also measured. RESULTS: There was a
      clear association between ECAD treatment and relief of itching, which promptly
      disappeared in two patients, or decreased markedly in the other two. One patient
      was free of pruritus for 18 months except for short periods with mild pruritus.
      The second patient experienced amelioration of itching, which almost disappeared
      completely and recurred mildly 4 months later. In the other two patients pruritus
      was alleviated markedly after ECAD but gradually recurred. These two patients
      were treated again 9 and 7 months later with favorable effects on pruritus. The
      scratching skin lesions improved or disappeared in parallel with the alleviation
      of itching. The albumin dialysis procedure did not result in liver test changes,
      except for circulating bile acids, which decreased in all the patients. No
      significant adverse effects were observed. CONCLUSIONS: The ECAD procedure seems
      to be an effective alternative for the treatment of patients with pruritus of
      cholestasis who do not respond to other therapeutic methods.

PMID- 15180734
TI  - Reduced expression of chemokine receptors on peripheral blood lymphocytes in
      patients with hepatocellular carcinoma.
AB  - OBJECTIVES: Hepatocellular carcinoma (HCC) is a rapidly progressive malignancy.
      Chemokine receptors are important mediators of lymphocyte migration in cancer.
      This study evaluated expression of chemokine receptors on lymphocytes of HCC
      patients. METHODS: Chemokine receptor expression on peripheral blood lymphocytes
      (PBL) was determined by flow cytometry and RT-PCR. Tumor infiltrating lymphocytes
      (TIL) and adjacent nontumor liver infiltrating lymphocytes (NIL) were also
      studied. RESULTS: The expressions of CCR5, CCR6, and CXCR3 on PBL were
      significantly reduced in HCC patients compared with normal controls, which
      occurred concurrently with increased expression of the chemokine receptors in TIL
      and NIL. Reduced expression of CXCR3 on PBL correlated with large tumor size and
      advanced tumor stage. The reduced chemokine receptor expression was consistent
      with the reduced mRNA levels and intracellular protein levels in PBL. HCC
      patients exhibited lower proportions of CD4(+) and CD8(+) T cells with CCR5,
      CCR6, and CXCR3 expression on PBL, which occurred concurrently with the increased
      expression of these chemokine receptors on TIL and NIL. The reduced CCR6 and
      CXCR3 expression on PBL correlated with the reduced memory phenotype in
      circulation and increased memory phenotype in liver. Furthermore, CCR5-expressing
      memory T cells were increased in liver compartment compared with circulation.
      CONCLUSION: This study demonstrated that reduced chemokine receptor expression on
      PBL was concurrent with increased chemokine receptor expression on both TIL and
      NIL in HCC. The results demonstrated the role of chemokine receptors in
      recruitment of lymphocytes from peripheral blood to HCC. The findings have
      important implications in understanding of immunopathogenesis of HCC.

PMID- 15180735
TI  - A prospective randomized observer-blind 2-year trial of azathioprine monotherapy
      versus azathioprine and olsalazine for the maintenance of remission of steroid
      dependent ulcerative colitis.
AB  - OBJECTIVE: The aim of this prospective study was to assess whether the
      coadministration of azathioprine (AZA) and olsalazine is superior to AZA
      monotherapy in maintaining remission of steroid-dependent ulcerative colitis
      (UC). METHODS: Patients with steroid-dependent UC in remission were randomized to
      receive AZA alone (2.2 mg/kg) or in combination with olsalazine (0.5 g tid).
      Remission was defined as steroid withdrawal, an Ulcerative Colitis Clinical
      Activity Index (UCCAI) score of <2, an Ulcerative Colitis Disease Activity Index
      (UCDAI) score of 0, and a negative colonoscopy and histology. Patients were
      followed in the outpatient clinic every month for 2 yr. The study protocol
      included 1) monthly clinical examination, assessment of UCCAI, hematological and
      biochemical tests, and compliance with treatment; 2) a sigmoidoscopy and
      completion of inflammatory bowel disease quality-of-life questionnaire (IBD-Q)
      and UCDAI every 3 months; and 3) total colonoscopy with biopsies at the end of
      the first and second year of the trial. RESULTS: Seventy patients were randomized
      to receive AZA alone (n = 34) or with olsalazine (n = 36). Three patients in each
      group developed side effects or could not comply with treatment and were
      withdrawn from the study. Three patients receiving AZA relapsed after the first
      year of the study and three after the second year of the study (19%). In the
      combination therapy group four patients relapsed after the first year of study
      and two after the second year of the study (18%). Relapse rates were not
      significant whether analyzed by intention-to-treat or per protocol. There were no
      significant differences between groups in time to relapse or discontinuation of
      treatment, UCCAI, UCDAI, or IBD-Q scores. However, the number of adverse events
      and the cost of treatment were significantly higher, whereas compliance with
      treatment was poorer in the combination therapy. CONCLUSION: Patients with
      steroid-dependent UC successfully maintained in remission on AZA are not in need
      of 5-aminosalicylic acid compounds.

PMID- 15180736
TI  - Psychological stress and inflammatory bowel disease: a follow-up study in parents
      who lost a child in Denmark.
AB  - OBJECTIVES: Little is known about the association between psychological stress
      and the risk of inflammatory bowel disease (IBD). This study aimed to examine
      whether the death of a child is related to the development and exacerbation of
      IBD in bereaved parents. METHODS: We undertook a follow-up study based on
      national registers. All 21,062 parents who lost a child (younger than 18 yr) from
      1980 to 1996 in Denmark were included in the exposed cohort, and 293,745 parents
      matched on family structure were selected randomly from the general population to
      the unexposed cohort. Cox's proportional-hazards regression models were used to
      evaluate the relative risks (RRs) of first IBD hospitalization in the exposed
      parents, compared to the unexposed. Poisson regression models were fitted to
      estimate the frequency of IBD readmission between the exposed and the unexposed
      IBD parents. We used Wilcoxon tests to compare the mean duration of
      hospitalizations in the two groups of patients. RESULTS: There were 32 prevalent
      IBD patients at the study entry in the exposed cohort and 451 prevalent cases in
      the unexposed cases. We observed 301 incident cases of Crohn's disease (20 in the
      exposed, 281 in the unexposed) and 766 incident cases of ulcerative colitis (51
      in the exposed, 715 in the unexposed). The RRs of first hospitalization for
      Crohn's disease and ulcerative colitis were 0.97 (95% CI = 0.62-1.53) and 1.01
      (95% CI = 0.76-1.34), respectively. For incident or prevalent IBD patients, we
      did not observe any differences in the frequency or duration of hospitalization
      in the exposed and unexposed patients. CONCLUSIONS: Our findings do not support
      an association between psychological stress and the development of IBD in young
      to-middle-aged adults.

PMID- 15180737
TI  - NOD2/CARD15 genotype and phenotype differences between Ashkenazi and Sephardic
      Jews with Crohn's disease.
AB  - OBJECTIVE: NOD2/CARD15 has been identified as a major susceptibility gene for
      Crohn's disease (CD). Three mutations, Arg702Trp, Gly908Arg, and Leu1007fsinsC,
      are associated with CD. The incidence and prevalence rate of inflammatory bowel
      diseases is two- to four-fold higher in Ashkenazi Jews as compared to non-Jewish
      Caucasians. The aim of this study was to determine the significance of the
      NOD2/CARD15 mutations in Jewish CD patients in Israel, and more specifically, to
      compare the significance of the mutations to the expression of CD in the
      Ashkenazi and Sephardic Jewish populations. METHODS: Allele frequencies of the
      mutations were determined in 180 Jewish CD patients, 73 ulcerative colitis
      patients, and 159 ethnically matched controls. Variants were detected using
      allele-specific PCR and restriction enzyme digestion assay. Demographic and
      phenotypic characterizations of the CD patients were determined. RESULTS: The
      carrier rate of the three mutations in the entire Jewish Israeli CD cohort is
      41.1% versus 10.7% in controls (p < 0.0001). The Ashkenazi Jewish CD patients
      have an increased carrier rate compared to Sephardic Jews (47.4%vs 27.45%, p=
      0.034). Association analyses in Ashkenazi Jews reveal odds ratios of 10.5, 9, and
      4.8 for carriage of Gly908Arg, Arg702Trp, and Leu1007fsinsC mutations,
      respectively. Significantly higher rates of smoking, family history of
      inflammatory bowel diseases, and extraintestinal manifestations were found among
      the Sephardic CD patients. CONCLUSIONS: NOD2/CARD15 CD-associated mutations
      confer increased risk mainly to the Ashkenazi Jewish CD patients in Israel. This
      suggests that NOD2/CARD15 mutations could contribute to the higher incidence and
      prevalence rates of CD among Ashkenazi Jews.

PMID- 15180738
TI  - A population-based estimate of the extent of colorectal cancer screening in
      Ontario.
AB  - BACKGROUND/OBJECTIVE: The incidence and mortality rates for colorectal cancer
      (CRC) in Canada are among the highest in the world. For individuals >/=50 yr, CRC
      screening is effective in reducing both CRC incidence and mortality. The goal of
      this research was to conduct a Canadian population-based study of the use of
      tests and procedures to evaluate the large bowel to estimate the extent of CRC
      screening. METHODS: We identified an inception cohort of all residents of Ontario
      aged 50-59 on January 1, 1995, without a previous history of CRC or large-bowel
      evaluation by five tests or procedures: fecal occult blood test (FOBT), barium
      enema, rigid sigmoidoscopy, flexible sigmoidoscopy, and colonoscopy. We followed
      these individuals to December 31, 2000, identified all tests received, and
      determined the proportion that received one or more tests or procedures of each
      type. Data were obtained from three sources: the Ontario Health Insurance Plan
      (OHIP) database, the Canadian Institute for Health Information-Discharge Abstract
      Database (CIHI-DAD), and the Registered Persons Database (RPDB). RESULTS: We
      identified 982,443 individuals in our inception cohort without prior CRC or large
      bowel evaluation. The proportion that had at least one test or procedure was less
      than 10% for each type. The largest proportion (9.3%) had one or more FOBTs.
      Classified according to the initial test received, 14.5% had a non-endoscopic
      test (FOBT, barium enema) and 6% had an endoscopic test (rigid sigmoidoscopy,
      flexible sigmoidoscopy, colonoscopy). The majority (79.5%) had no test or
      procedure to evaluate the large bowel. CONCLUSION: An extraordinarily low
      proportion (<20.5%) of screen-eligible 50-59-yr-old men and women in Ontario were
      screened for CRC during a 6-yr follow-up. Given the high burden of CRC in Canada
      a major opportunity exists to improve the health of Canadians by increasing our
      screening efforts.

PMID- 15180739
TI  - Community-based screening by colonoscopy or computed tomographic colonography in
      asymptomatic average-risk subjects.
AB  - OBJECTIVES: Visualizing the entire colorectum in screening is an advantage of
      colonoscopy, and also computed tomographic (CT) colonography, another potentially
      suitable screening test. Our objective was to compare screening CT colonography
      and colonoscopy in an asymptomatic average-risk population, and to determine
      whether providing a choice of tests increased participation. METHODS: One
      thousand and four hundred subjects from the general community, randomly selected
      from the parliamentary electoral roll, were allocated one of three screening
      groups: colonoscopy, CT colonography, or a choice of these tests, and were sent
      an institutional letter of invitation. Those with symptoms, colorectal cancer in
      first-degree relatives, or colonoscopy within 5 yr were ineligible. Outcome
      measures were participation, acceptability of screening, and yield for advanced
      colorectal neoplasia in participants. RESULTS: Of the subjects, 24.9% were
      ineligible; the overall participation rate was 18.2% (184/1,009). Participation
      in each screening group was not different. Both tests were accompanied by the
      same high levels of acceptability; most participants found colonoscopy (87%) and
      CT colonography (67%, p < 0.001) less unpleasant than expected. About 29% (26/89)
      CT colonography subjects had a positive screening test. The yield of advanced
      colorectal neoplasia was 8.7% (95% CI 5-14%), with no difference in yield between
      tests. CONCLUSION: Colorectal neoplasia screening by colonoscopy or CT
      colonography was associated with modest participation, high levels of
      acceptability, and similar yield for advanced colorectal neoplasia. Providing a
      choice of test did not increase participation.

PMID- 15180740
TI  - Impact of coexisting irritable bowel syndrome on symptoms and pathophysiological
      mechanisms in functional dyspepsia.
AB  - Epidemiological studies suggest considerable overlap between functional dyspepsia
      (FD) and irritable bowel syndrome (IBS). AIM: The aim of the present study was to
      investigate whether coexisting IBS is also associated with symptom pattern or
      pathophysiology in FD. METHODS: In 309 consecutive FD patients (207 women, age 42
      +/- 0.8 yr), questionnaires were used to assess the dyspepsia symptom pattern and
      the Rome II criteria for IBS. The overall symptom severity was calculated adding
      the severity score (0-3, 0 = absent, 3 = severe) of eight dyspepsia symptoms. All
      patients underwent Helicobacter pylori testing, gastric barostat to determine
      sensitivity to distention and accommodation to a meal, and gastric emptying
      breath test. RESULTS: Fifty-four percent of the patients had FD alone, whereas
      46% had FD + IBS. FD + IBS patients were more likely to be female (75%vs 60%, p <
      0.01) and to have a greater weight loss (5.4 +/- 0.6 vs 3.5 +/- 0.4 kg, p <
      0.05). Coexisting IBS did not increase the risk of having any of the dyspeptic
      symptoms but the overall symptom severity was significantly higher in FD + IBS
      (12.4 +/- 0.4 vs 9.8 +/- 0.3, p < 0.01). FD + IBS patients had a lower threshold
      for first perception (2.9 +/- 0.3 vs 3.8 +/- 0.3 mmHg, p < 0.05) and for
      discomfort (7.9 +/- 0.4 vs 9.5 +/- 0.5 mmHg, p < 0.05) and a greater prevalence
      of hypersensitivity to gastric distention (44%vs 28%, p < 0.05). Gastric
      emptying, accommodation to a meal, and prevalence of H. pylori infection did not
      differ in the two groups. CONCLUSION: About half of the FD patients fulfill the
      Rome II criteria for IBS. FD + IBS is more prevalent in female patients and is
      associated with a higher weight loss, with greater overall symptom severity, and
      with hypersensitivity to distention.

PMID- 15180741
TI  - Evaluation of liver fibrosis: a concise review.
AB  - The diagnosis of liver fibrosis has traditionally relied on liver biopsy.
      However, recent studies have suggested that there can be up to a 33 % error in
      the diagnosis of cirrhosis. In this article, we review the current status of
      liver biopsy as a gold standard for the diagnosis of liver fibrosis and discuss
      the radiological and serum tests that have been proposed as potential adjuncts or
      alternatives to biopsies. Indirect markers of liver fibrosis which reflect
      alterations in liver function and or inflammation are discussed as well as more
      direct markers of liver fibrosis. The limitations of utilization of these markers
      for both cross-sectional diagnosis of fibrosis and monitoring disease progression
      or regression are discussed.

PMID- 15180742
TI  - Colonic toxicity of administered drugs and chemicals.
AB  - Although uncommon, medication-induced colonotoxicity is important to recognize
      because medication cessation generally leads to prompt clinical improvement,
      while medication continuation results in disease exacerbation. This review
      categorizes the association between medications and colonotoxicity as "well
      established" or "probable," according to the following criteria: total number of
      reported cases, number of different research groups reporting an association,
      experimental and pharmacologic evidence of an association, and validity of an
      association in each reported case. Cocaine, ergotamine, estrogen, sodium
      polystyrene, alosetron, amphetamines, pseudoephedrine, and vasopressin are
      associated with colonic ischemia. The mechanisms include vasospasm,
      thrombogenesis, and shunting of blood from mesenteric vessels. Narcotics,
      phenothiazines, vincristine, atropine, nifedipine, and tricyclic antidepressants
      are associated with colonic pseudo-obstruction. The mechanisms include
      antagonizing prokinetic neurotransmitters, stimulating antikinetic
      neurotransmitters, promoting dysmotility, relaxing smooth muscle, and injuring
      enteric neurons. Numerous antibiotics are associated with pseudomembranous
      colitis; ampicillin is associated with hemorrhagic colitis; chemotherapy is
      associated with neutropenic colitis; and deferoxamine is associated with Yersinia
      enterocolitis. Mechanisms of these toxicities include altering normal bowel
      flora, weakening immunologic defenses, promoting microorganism virulence, and
      mucosal injury. Gold compounds, nonsteroidal antiinflammatory drugs, alpha
      methyldopa, salicylates, and sulfasalazine are associated with an inflammatory or
      cytotoxic colitis. The mechanisms include direct mucosal cytotoxicity,
      antimetabolite effects, or drug allergy. Nonsteroidal antiinflammatory drugs,
      cyclo 3 fort, flutamide, lansoprazole, and ticlopidine are associated with
      lymphocytic colitis. The mechanisms include immunologic activation or attenuated
      immunologic defenses. Chronic cathartic use leads to colonic hypomotility and
      abdominal distention. Intrarectally administered corrosive compounds can produce
      a toxic colitis.

PMID- 15180743
TI  - Upper GI symptoms in patients with irritable bowel syndrome.

PMID- 15180745
TI  - Prevalence of ileo-colonic ulcerative lesions in chronic NSAIDs users.

PMID- 15180746
TI  - Ethics of PEG tubes-Jewish and Islamic perspectives.

PMID- 15180747
TI  - Thioguanine-induced symptomatic thrombocytopenia.

PMID- 15180748
TI  - Sorbital H2 breath testing when screening for malabsorption/ intolerance and
      untreated celiac disease: understanding the dose and concentration issues.

PMID- 15180749
TI  - Serial testing and conditional independence: a reply to Scoglio et al.

PMID- 15180750
TI  - Through-the-endoscope technique for retrieval of impacted biliary baskets with
      trapped stones.

PMID- 15180753
TI  - Recent advances in pathogenesis and management of hypereosinophilic syndromes.
AB  - Idiopathic hypereosinophilic syndrome is a largely heterogeneous disorder defined
      until now as persistent marked hypereosinophilia of unknown origin generally
      complicated by end-organ damage. Recent studies clearly indicate that many
      patients fulfilling the diagnostic criteria of this syndrome can now be
      classified as presenting one of two major disease variants: the
      myeloproliferative or the lymphocytic variant. Research in cellular and molecular
      biology has provided firm evidence for the existence of discrete hematological
      disorders underlying these variants, questioning the pertinence of continued
      reference to 'idiopathic' hypereosinophilic syndrome in such patients.
      Furthermore, identification of these variants has a number of prognostic and
      therapeutic implications that must be taken into consideration for adequate
      management of these patients.

PMID- 15180754
TI  - Standardization of food challenges in patients with immediate reactions to foods-
      position paper from the European Academy of Allergology and Clinical Immunology.

PMID- 15180755
TI  - Anti-IgE: a significant breakthrough in the treatment of airway allergic
      diseases.

PMID- 15180756
TI  - Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in
      patients with poorly controlled (moderate-to-severe) allergic asthma.
AB  - BACKGROUND: Patients with poorly controlled asthma have greater morbidity and
      mortality. This study evaluated the efficacy and tolerability of omalizumab in
      patients with poorly controlled, moderate-to-severe allergic asthma. METHODS:
      This was a randomized, open-label, multicentre, parallel-group study. A total of
      312 patients (12-73 years) receiving >/=400 microg/day (adolescent) or >/=800
      microg/day (adult) inhaled beclomethasone dipropionate, or equivalent were
      included. Patients received best standard care (BSC) with or without omalizumab
      [at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks] for 12 months. RESULTS: The
      annualized mean number of asthma deterioration-related incidents was reduced from
      9.76 with BSC alone (n = 106) to 4.92 per patient-year with omalizumab (n = 206)
      (P < 0.001). Mean clinically significant asthma exacerbation rates were 2.86 and
      1.12 per patient-year, respectively (P < 0.001). Omalizumab-treated patients
      (41.4%) required rescue medication <1 day/week compared with 20.7% for BSC alone
      (P < 0.001). Omalizumab improved absolute forced expiratory volume in 1 s
      (FEV(1)) compared with BSC alone (2.48 and 2.28 l, respectively; P < 0.05) and
      reduced symptom scores relative to BSC alone (decrease of 6.5 and 0.7
      respectively; P < 0.001). Omalizumab was well-tolerated. CONCLUSIONS: Omalizumab
      administered as add-on therapy to BSC benefits patients with poorly controlled,
      moderate-to-severe allergic asthma.

PMID- 15180757
TI  - Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in
      patients with concomitant allergic asthma and persistent allergic rhinitis:
      SOLAR.
AB  - BACKGROUND: Anti-IgE therapy could be particularly beneficial for patients with
      concomitant disease as it targets a common factor in both diseases. The aim of
      this study was to evaluate the efficacy and safety of omalizumab in patients with
      concomitant moderate-to-severe asthma and persistent allergic rhinitis. METHODS:
      This multicentre, randomized, double-blind, parallel-group, placebo-controlled
      trial evaluated the safety and efficacy of omalizumab. A total of 405 patients
      (12-74 years) with a stable treatment (>/= 400 microg budesonide Turbuhaler) and
      >/= 2 unscheduled medical visits for asthma during the past year or >/= 3 during
      the past 2 years were enrolled. Patients received omalizumab (>/= 0.016 mg/kg/IgE
      [IU/ml] per 4 weeks) or placebo for 28 weeks. RESULTS: Fewer patients treated
      with omalizumab experienced asthma exacerbations (20.6%) than placebo-treated
      patients (30.1%), P = 0.02. A clinically significant (>/= 1.0 point) improvement
      in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life
      Questionnaire occurred in 57.7% of omalizumab patients compared with 40.6% of
      placebo patients (P < 0.001). Omalizumab reduced Wasserfallen symptom scores for
      asthma (P = 0.023), rhinitis (P < 0.001) and the composite asthma/rhinitis scores
      (P < 0.001) compared with placebo. Serious adverse events were observed in 1.4%
      of omalizumab-treated patients and 1.5% of placebo-treated patients. CONCLUSION:
      Omalizumab is well tolerated and effective in preventing asthma exacerbations and
      improving quality of life in patients with concomitant asthma and persistent
      allergic rhinitis.

PMID- 15180758
TI  - Type I latex allergy in health care workers with latex-induced contact urticaria
      syndrome: a follow-up study.
AB  - BACKGROUND: Latex allergy is an important occupational health issue among health
      care workers (HCWs). Secondary prevention in sensitized/allergic individuals
      involves avoiding exposure to NRL products. AIMS OF THE STUDY: The aim of this
      follow-up study is to determine the long-term health consequences in HCWs with
      type I latex allergy with latex-related contact urticaria syndrome, of providing
      appropriate information and practical avoidance education. METHODS: Seventeen
      HCWs with latex-induced contact urticaria syndrome, as ascertained by the glove
      use test, were investigated. Initial and follow-up visits included: a detailed
      questionnaire, skin prick test (SPT) with glove eluates and with commercial latex
      extract, SPT with common inhalant and food extracts, serum specific
      immunoglobulin (Ig)E to latex and some foods and the glove use test. RESULTS: On
      re-examination, 11 (64.7%) subjects showed positive SPTs to extemporaneous
      extract and 10 (58.8%) patients showed a positive SPT to commercial extract. Of
      the nine patients with detectable levels of serum latex specific IgE at first
      evaluation, four (44.4%) became negative and four were assigned to at least one
      class lower. Only one (11.1%) employee had higher radioallergosorbent test values
      than those at the latex allergy diagnosis. At follow-up, the 17 individuals had
      positive latex challenge results, although the duration of exposure causing a
      reaction increased. CONCLUSION: Our study shows that preventive measures are
      sufficient to induce a reduction of sensitization. Continued avoidance is needed
      to prevent re-sensitization or adverse reactions on re-exposure.

PMID- 15180759
TI  - Characterization of B- and T-cell responses and HLA-DR4 binding motifs of the
      latex allergen Hev b 6.01 (prohevein) and its post-transcriptionally formed
      proteins Hev b 6.02 and Hev b 6.03.
AB  - BACKGROUND: Multiple immunoglobulin E (IgE)-binding proteins in natural rubber
      latex extracts have been identified. In the case of Hev b 6 a differentiation was
      made between the precursor protein prohevein (Hev b 6.01) and its two post
      transcriptionally formed proteins, the N-terminal hevein (Hev b 6.02) and the C
      terminal domain (Hev b 6.03). All three components act as independent allergens.
      The aim of this study was a detailed analysis of the T-cell responses and the IgE
      binding capacity of Hev b 6.01, Hev b 6.02 and Hev b 6.03 by using these
      allergens as recombinant maltose-binding fusion (MBP) proteins and the usage of
      synthetic modified hevein peptides. METHODS: Latex-allergic health care workers
      (HCWs) suffering from rhinitis, conjunctivitis, contact urticaria and/or asthma
      with increased specific IgE-antibodies to latex were tested for their IgE-binding
      capacity and T-cell reactivity (by proliferation response) to the recombinant MBP
      rHev b 6.01, MBP-rHev b 6.02, MBP-rHev b 6.03, to native Hev b 6.02, to modified
      hevein peptides and wheat germ agglutinin (WGA). For testing of the human
      leucocyte antigen (HLA) class II restriction of MBP-rHev b 6.01 induced
      peripheral blood mononuclear cell (PBMC) responses, monoclonal antibodies against
      HLA-DR, HLA-DP or HLA-DQ were added. RESULTS: Seventeen of 18 (94%) serum samples
      from latex-allergic HCWs had increased levels of specific IgE to MBP-rHev b 6.01,
      16 (89%) to MBP-rHev b 6.02 and 13 (72%) to MBP-rHev b 6.03. A significant
      difference existed between the specific IgE-values of MBP-rHev b 6.02 and MBP
      rHev b 6.03 (P < 0.01). Proliferation responses of PBMC of the same 18 latex
      allergic patients were positive for MBP-rHev b 6.01 and MBP-rHev b 6.03 in 83 and
      67% of the tested PBMC suspension, whereas the proliferation responses induced
      with MBP-rHev b 6.02 or native Hev b 6.02 were very low (5.6 and 22.2%). Sera
      from nine additional latex-allergic patients showed specific IgE binding to the
      native Hev b 6.02, but none of these sera showed specific IgE binding to the
      modified Hev b 6.02-peptides [whereby all eight cysteine residues were
      substituted by serine (C --> S) or by alanine (C --> A)]. Proliferation responses
      induced by the modified Hev b 6.02 peptides were not significantly different from
      that induced by Hev b 6.02. Potential HLA-DR4Dw4(DRB1*0401)-restricted T-cell
      epitopes of Hev b 6.01 predicted by two computer algorithms were only found in
      the Hev b 6.03-part of Hev b 6.01. CONCLUSION: In the Hev b 6.01 precursor the
      regions responsible for IgE binding and those for inducing the T-cell
      proliferation responses are settled in different parts of the protein. The Hev b
      6.02 domain is responsible for IgE binding and carries discontinuous B-cell
      epitopes whereas Hev b 6.03 is a better inducer of a proliferation response and
      contains HLA-DR4-binding motifs.

PMID- 15180760
TI  - Increased prevalence of latex-sensitization among children with chronic renal
      failure.
AB  - BACKGROUND: Type-I-allergy to natural rubber latex (NRL) has been shown to be
      more prevalent among certain groups of patients. Children suffering from chronic
      renal failure (CRF) could be a suspected risk group because of their intense
      exposure to latex through catheters, gloves and anesthetic equipment during
      frequent hospitalizations from early life on. We investigated the prevalence of
      latex-sensitization among this group of patients and sought to identify risk
      factors. METHODS: Ninety-three patients (mean age 10.5 years) suffering from CRF
      were assessed by questionnaire-based history (details on renal disease, number
      and kind of surgical procedures, family and personal history of atopic diseases,
      allergic reactions to NRL, and the use of pacifiers) and by measurement of total
      and latex-specific serum immunoglobulin (Ig)E. RESULTS: Ten of 93 (10.8%)
      patients showed elevated latex-specific IgE-levels. One of 10 patients reported
      clinical symptoms to latex-allergen, but no allergic reactions to NRL during
      medical care were reported. Sensitized patients were significantly more likely to
      be atopic, reflected by a positive history of other allergies as well as elevated
      total serum IgE-levels, and had a significantly higher number of urogenital
      surgeries (P = 0.02 in all cases, Fisher's exact and Wilcoxon test,
      respectively). CONCLUSION: This study demonstrates that children with CRF are at
      increased risk of latex-hypersensitivity. Significant associations with atopy and
      repeated surgeries were observed. Larger studies are required to elucidate
      whether these children are also at increased risk of anaphylaxis and therefore
      deserve preventive measures.

PMID- 15180761
TI  - Antigen characterization of major cork moulds in Suberosis (cork worker's
      pneumonitis) by immunoblotting.
AB  - BACKGROUND: We characterized by immunoblotting the antigenicity of the most
      frequent fungi colonizing cork during its industrial processing, Penicillium
      glabrum and Chrysonilia sitophila. Penicillium glabrum is the main causative
      agent of Suberosis, a hypersensitivity pneumonitis of cork workers. Chrysonilia
      sitophila induces both IgE sensitization and occupational asthma in the wood
      processing industry. METHODS: Serum-specific IgG, IgG4 and IgE to P. glabrum and
      C. sitophila from nine cork workers with hypersensitivity pneumonitis (HP) and
      seven with asthma (four with occupational asthma) were analysed by
      immunoblotting. RESULTS: Both HP and asthmatic patients' sera showed
      immunoreactivity to several proteins resolved in the specific immunoblot strips.
      The frequency of specific IgG recognition to 12-13.5 and 33 kDa proteins of P.
      glabrum was significantly higher in HP patients. The sera of HP patients had
      significantly higher specific IgG recognition to 16 and 51-55 kDa proteins of C.
      sitophila. There was no specific IgE recognition in the sera of HP or asthmatic
      patients to both fungi. CONCLUSIONS: Different patterns of antibody reactivity to
      P. glabrum and C. sitophila are seen in cork workers with hypersensitivity
      pneumonitis or asthma. The 12-13.5 and 33 kDa proteins of P. glabrum and the 16
      and 51-55 kDa proteins of C. sitophila may be major antigens in Suberosis.

PMID- 15180762
TI  - Alternaria spores at different heights from the ground.
AB  - BACKGROUND: Alternaria tenuis (Alt) is one of the main allergens in pediatric
      age. In temperate climates, airborne Alt spores are detectable from May to
      November with peaks in late summer and autumn. Sensitized children display
      symptoms even in the absence of airborne Alt spores. Alt spore concentration, as
      well as pollen, is usually detected by fixed devices located on the roof of a
      building at a height of 10-20 m. The aim of the current study is to find out
      whether ground-level (50 cm) Alt spore concentrations are different from those at
      roof-top level, even during low-concentration periods. METHODS: Alt samples were
      taken simultaneously using a Hirst fixed volumetric collector (FVC) placed on a
      15 m-high roof and by a portable volumetric collector (PVC). Firstly, the results
      of FVC and PVC, both placed on the roof-top, were compared to verify the
      correlation coefficient of the two samplers. Subsequently, the PVC was placed 50
      cm above the ground in a courtyard (30 samplings) and in private green areas (50
      samplings). The results were compared by statistical analysis (Student's t-test
      or K-S test). RESULTS: The values of the 20 samples taken jointly in summer time
      (FVC 195 +/- 134 spores/m(3); PVC = 134 +/- 131 spores/m(3)) showed a good
      correlation between the two samplers (r = 0.850; P < 0.01), with a correction
      factor equal to 1.177. 1. Thirty samples obtained in summer and winter when the
      PVC was positioned in an enclosed courtyard directly below the FVC showed no
      significant difference (PVC, 181 +/- 194 spores/m(3); FVC, 152 +/- 145
      spores/m(3); P = 0.221). 2. Fifty samples taken by PVC placed in private green
      areas in a low-concentration period, showed significantly higher concentrations
      than by FVC: PVC, 531 +/- 925 spores/m(3); FVC, 25 +/- 51 spores/m(3) (K-S test:
      P < 0.0001). In particular, 33 samples taken in winter when Alt counts by FVC
      were <10 spores/m(3) still demonstrated highly significant differences: PVC, 398
      +/- 961 spores/m(3); FVC, 2.0 +/- 2 spores/m(3) (K-S test: P < 0.0001).
      CONCLUSION: Our results lead to the conclusion that Alt spore concentration is
      significantly higher at ground level in the presence of vegetation, even when the
      spore concentration is very low (<10 spores/m(3)). These results further suggest
      that the individual's exposure to Alt, especially in the case of children, is
      underestimated by samples taken at roof-top level by FVC.

PMID- 15180763
TI  - Importance of including Blomia tropicalis in the routine diagnosis of Venezuelan
      patients with persistent allergic symptoms.
AB  - BACKGROUND: Blomia tropicalis is a common mite found in the house dust of many
      tropical countries including Venezuela. The prevalence of skin test and specific
      serum immunoglobulin (Ig)E reactivity to B. tropicalis in Venezuela has not been
      previously evaluated. METHODS: In the present study we evaluated the skin
      reactivity by skin prick test and specific IgE by a multiple antigen blot assay,
      against B. tropicalis and Dermatophagoides pteronyssinus, in a group of 115
      subjects who attended the Allergy Clinic of the Institute of Biomedicine,
      Caracas, Venezuela, and we studied possible cross reactions between similar
      proteins of these two mites. RESULTS: One hundred and six patients with
      persistent allergic respiratory symptoms showed a positive skin prick test to at
      least one of the mite extracts, with the frequency of positive reactions to B.
      tropicalis being as high as to D. pteronyssinus. Twelve patients reacted only to
      D. pteronyssinus and 13 different patients only to B. tropicalis. Specific IgE to
      each of the mite extracts was found with similar frequency, and the results
      coincided with the skin test reactivity. CONCLUSIONS: The study indicated the
      importance of including B. tropicalis in routine diagnostic testing in tropical
      and sub-tropical situations.

PMID- 15180764
TI  - Allergic inflammation induced by a Penicillium chrysogenum conidia-associated
      allergen extract in a murine model.
AB  - BACKGROUND: Recent evidence has shown that viable conidia from the fungus
      Penicillium chrysogenum induce allergic effects in mice. The present study was
      conducted to determine the specific allergic dose response of C57BL/6 mice to the
      protease extract, Pen ch, isolated from viable P. chrysogenum conidia. METHODS:
      Mice were treated with primary intraperitoneal (IP) injections of 10 or 100
      microg of Pen ch adsorbed to alum, followed by weekly IP injections of 0.1, 1.0,
      or 10.0 microg Pen ch with alum for 4 weeks, and with 10.0 microg of Pen ch by
      intranasal (IN) inoculations the final 2 weeks before killing. RESULTS:
      Intraperitoneal injections of 10 and 100 microg of Pen ch for 5 weeks followed by
      2 weeks of IN instillation of 10 microg induced significant increases of total
      serum immunoglobulin (Ig)E and IgG(1). Bronchoalveolar lavage cell counts
      revealed increased numbers of eosinophils and neutrophils. Histopathological
      examination of lungs detected perivascular inflammation by eosinophils and
      neutrophils and increased mucous production. CONCLUSIONS: The data presented in
      this study indicate that sensitization to protease allergens released by viable
      P. chrysogenum conidia in vivo induce a strong allergic inflammatory response in
      a murine model, which could have implications for people exposed to high levels
      of conidia of this organism.

PMID- 15180765
TI  - Rupatadine 10 mg and ebastine 10 mg in seasonal allergic rhinitis: a comparison
      study.
AB  - BACKGROUND: The aim of this study is to establish the efficacy and safety of
      rupatadine vs ebastine and placebo in the treatment of seasonal allergic rhinitis
      (SAR). Rupatadine is a new second generation H(1)-antihistamine with once-daily
      dosing that may provide better control of symptoms than the currently used H(1)
      receptor blockers because of its dual pharmacological profile (anti-PAF and anti
      H(1)). METHODS: In a multicentre study, 250 patients with SAR were included in a
      double-blind, randomized, parallel-group and placebo-controlled study. Patients
      received either rupatadine 10 mg, ebastine 10 mg or placebo once daily for 2
      weeks. The main efficacy outcome was based on the patient's record of severity of
      nasal symptoms (sneezing, nasal itching, runny nose and nasal obstruction) and
      nonnasal symptoms (conjunctival itching, tearing and pharyngeal itching). The
      daily total symptom score (DTSS) was the mean of the DSS recorded for each of the
      seven symptoms assessed, and the mean DTSS (mDTSS) was the mean of the DTSS
      values for each study day. RESULTS: Significant differences in mDTSS were
      detected between rupatadine and placebo (33% lower for rupatadine group; P =
      0.005) after 2 weeks of treatment. The TSS for rupatadine were 22% lower than for
      ebastine, although the differences were not statistically significant. No serious
      adverse events were reported during the study period. CONCLUSIONS: Rupatadine 10
      mg once daily was clearly superior to placebo in alleviating the symptoms of SAR
      over a 2-week period. In comparison with ebastine, rupatadine shows a trend
      towards a better profile as regard several secondary efficacy variables.

PMID- 15180766
TI  - A bispecific antibody against human IgE and human FcgammaRII that inhibits
      antigen-induced histamine release by human mast cells and basophils.
AB  - BACKGROUND: FcgammaRIIB are low-affinity immunoglobulin (Ig)G receptors that we
      previously demonstrated to negatively regulate IgE-induced mast cell activation
      when coaggregated with FcepsilonRI. Here, we engineered and characterized a
      bispecific reagent capable of coaggregating FcgammaRIIB with FcepsilonRI on human
      mast cells and basophils. METHODS: A bispecific antibody was constructed by
      chemically crosslinking one Fab' fragment against human IgE and one Fab' fragment
      against human FcgammaRII. This molecule was used to coaggregate FcepsilonRI with
      FcgammaRII on human mast cells and basophils sensitized with human IgE
      antibodies, and the effect of coaggregation was examined on mediator release upon
      challenge with specific antigen. RESULTS: When used under these conditions, this
      bispecific antibody not only failed to trigger the release of histamine by IgE
      sensitized cells, but it also prevented specific antigen from triggering
      histamine release. Comparable inhibitions were observed with mast cells and
      basophils derived in vitro from cord blood cells and with peripheral blood
      basophils. CONCLUSIONS: The bispecific antibody described here is the prototype
      of similar molecules that could be used in new therapeutic approaches of allergic
      diseases based on the coaggregation of activating receptors, such as FcepsilonRI,
      with inhibitory receptors, such as FcgammaRIIB, that are constitutively expressed
      by mast cells and basophils.

PMID- 15180767
TI  - Does my partner cause my allergy?
AB  - BACKGROUND: The study of partners can help to understand the impact of
      environmental influences on the development of allergies. We aimed to test the
      hypothesis that subjects whose partners have hay fever are at increased risk for
      the same disease and that the risk increases with the time subjects live together
      with an affected partner. METHODS: A nested unmatched case-control study was
      performed in a random sample of 4261 inhabitants, aged 25-74 years, of the City
      of Augsburg, Germany, and two adjacent counties. Using standardized computer
      assisted face-to-face interviews, we determined the risk of doctor-diagnosed hay
      fever in subjects who lived together with a partner having the same disease as
      opposed to subjects living with an unaffected partner. Furthermore, the risk of
      doctor-diagnosed hay fever depending on the time the subjects had lived together
      with an affected partner was calculated. RESULTS: After adjustment for age, sex,
      parental predisposition and social status, the risk of hay fever was more than
      double in subjects who lived together with a partner having the same disease
      (odds ratio, OR(adj.), 2.41; 95% confidence interval, CI, 1.48-3.92). If subjects
      lived together with an affected partner, the risk of developing the disease
      increased with the time the partners lived together (1-11 years, OR 1; 12-23
      years, OR 1.8; 24-35 years, OR 7.4; 36-54 years, OR 13.7). CONCLUSION: The risk
      of developing hay fever is significantly elevated in subjects who live together
      with a partner having the same disease. The risk further increases with the time
      the partners live together. This points to important shared environmental
      influences or behaviours and raises speculations on a transmissible cause.

PMID- 15180768
TI  - Diagnostic approach to anaphylaxis by carrot, related vegetables and horsetail
      (Equisetum arvense) in a homemaker.

PMID- 15180769
TI  - Acute urticaria induced by hyoscine butylbromide.

PMID- 15180770
TI  - Tolerance induction to rofecoxib in a patient with Bartter's syndrome.

PMID- 15180771
TI  - Delayed reaction urticaria due to trimebutine.

PMID- 15180772
TI  - Elastic encasing material for mattresses may be a hidden source of occupational
      latex exposure in health care facilities.

PMID- 15180773
TI  - Bridging the mental health research gap in low- and middle-income countries.

PMID- 15180774
TI  - Long-term outcome of pediatric obsessive-compulsive disorder: a meta-analysis and
      qualitative review of the literature.
AB  - OBJECTIVE: To review the extant literature on the long-term outcome of
      child/adolescent-onset obsessive-compulsive disorder (OCD). METHOD: Medline and
      Psychlit databases were systematically searched for articles regarding long-term
      outcomes of child/adolescent-onset OCD. Meta-analysis regression was applied to
      evaluate predictors and persistence of OCD. RESULTS: Sixteen study samples (n = 6
      132; total = 521 participants) in 22 studies had follow-up periods ranging
      between 1 and 15.6 years. Pooled mean persistence rates were 41% for full OCD and
      60% for full or subthreshold OCD. Earlier age of OCD onset (z = -3.26, P =
      0.001), increased OCD duration (z = 2.22, P = 0.027) and in-patient vs. out
      patient status (z = 2.94, P = 0.003) predicted greater persistence. Comorbid
      psychiatric illness and poor initial treatment response were poor prognostic
      factors. Although psychosocial function was frequently compromised, most studies
      lacked comprehensive outcome measures. CONCLUSION: Long-term persistence of
      pediatric OCD may be lower than believed. Future studies should include broader
      measures of outcome including symptomatic persistence and functional impairment
      in multiple domains.

PMID- 15180775
TI  - Insight into current symptoms of schizophrenia. Association with frontal cortical
      function and affect.
AB  - OBJECTIVE: Examine whether frontal lobe dysfunction or affective experiences
      correlates with lack of symptom awareness in schizophrenia. METHOD: A total of
      122 consecutive adult schizophrenia outpatients were assessed cross-sectionally
      with standard rating scales of psychopathology and of insight, and underwent
      neuropsychological assessment with a battery of tests sensitive to frontal lobe
      dysfunction. Correlational analyses were used to determine relationships between
      variables. RESULTS: About 62% of patients had at least partial awareness of
      symptoms. Anxiety correlated modestly with insight into the abnormal nature of
      positive and negative symptoms. No cognitive variable was significantly
      correlated with symptom awareness. CONCLUSION: The pathological nature of
      symptoms is better recognized by patients who experience dysphoric affect.
      Neither severity of psychotic symptoms nor frontal lobe cognitive deficits
      correlates to symptom awareness. Lack of insight, which can be partial for
      symptoms of the illness, might be a non-reducible symptom of schizophrenia.

PMID- 15180776
TI  - A randomized comparison of group cognitive-behavioural therapy and group
      psychoeducation in patients with schizophrenia.
AB  - OBJECTIVE: Although the efficacy of cognitive-behavioural therapy (CBT) in
      schizophrenia has been established in a number of studies, no information is
      available on the differential efficacy of CBT in comparison with patient
      psychoeducation (PE). METHOD: Eighty-eight in-patients with schizophrenia were
      randomized to receive a therapy envelope of 8 weeks including either 16 sessions
      group CBT or eight [correction] sessions group PE treatment. Assessments took
      place at baseline, post-treatment and 6 month follow-up. RESULTS: Patients, who
      received CBT were significantly less rehospitalized than patients in the PE group
      during the follow-up period. On a descriptive level, CBT resulted in lower
      relapse rates and higher compliance ratings at post-treatment and at follow-up
      than PE. Both forms of therapy led to significant psychopathological improvement
      at post-treatment and at follow-up. CONCLUSION: The brief group CBT intervention
      showed some superiority to the PE programme, which could be of considerable
      clinical and economical importance.

PMID- 15180777
TI  - Neurological soft signs discriminating mood disorders from first episode
      schizophrenia.
AB  - OBJECTIVE: To investigate the specificity of neurological soft signs (NSS) for
      first episode schizophrenia compared with mood disorders. METHOD: We assessed NSS
      in a sample of 60 healthy controls, 191 first episode psychosis patients and 81
      mood disorder patients. We used a principle component analysis to identify
      dimensions of NSS. We subsequently investigated the specificity of these
      dimensions for schizophrenia and their relationships with medication and symptom
      scores. RESULTS: We identified five dimensions; coordination disorders, movement
      disorders, increased reflexes, dyskinesia and catatonia. These dimensions were
      related to neural circuits associated with schizophrenia and mood disorders and
      included the fronto-striatal-thalamic and the fronto-cerebellar pathway. The
      movement disorder dimension, which was suggestive for the involvement of the
      fronto-striatal-thalamic pathway, was specific for first episode schizophrenia
      independent from medication. CONCLUSION: NSS are the result of circuitry
      dysfunctions rather than overall dysfunction and a particular set of NSS shows
      specificity for schizophrenia.

PMID- 15180778
TI  - Delivering cognitive therapy to people with psychosis in a community mental
      health setting: an effectiveness study.
AB  - OBJECTIVE: Cognitive therapy (CT) has been shown to be an efficacious treatment
      for persistent psychotic symptoms. However, there is some debate regarding
      whether this is transportable to real life clinical settings. This study aimed to
      evaluate the effectiveness of CT for psychosis in a community mental health team
      (CMHT) setting. METHOD: Patients referred for CT for psychosis were
      naturalistically allocated (determined by the availability of a therapist) to CT
      or waiting-list (WL)/treatment-as-usual (TAU). Outcome assessments were performed
      at WL, pre-CT, post-CT and 1-year follow-up. Data from 59 patients were analysed.
      RESULTS: Random effects regression analyses showed there was a significant
      improvement, attributable to CT, on most outcome measures, and that many of the
      symptomatic improvements were maintained at follow-up. Wilcoxon signed ranks
      tests indicated that there was a significant reduction in psychiatric hospital
      use following CT. CONCLUSION: These results confirm that CT is an effective
      treatment for psychosis that is generalizable to a community setting.

PMID- 15180779
TI  - Impaired spatial working memory in adults with attention-deficit/hyperactivity
      disorder: comparisons with performance in adults with borderline personality
      disorder and in control subjects.
AB  - OBJECTIVE: This study investigated a previous claim that working memory may be
      'particularly impaired' in adult attention-deficit/hyperactivity disorder (ADHD),
      compared with other psychiatric disorders which affect frontal lobe-mediated
      executive functions. METHOD: Performance on spatial working memory (SWM) and two
      additional tasks were investigated for adult patients selected on the basis of
      DSM-IV ADHD (n = 19), adult patients selected on the basis of borderline
      personality disorder (BPD) (n = 19), and non-clinical control subjects (n = 19).
      Groups were matched for age, verbal IQ and gender. RESULTS: Analysis of variance
      showed that the ADHD group had significant impairment of SWM performance relative
      to the non-clinical controls. Although there was a trend towards impairment in
      the BPD group relative to non-clinical controls, this did not reach significance.
      CONCLUSION: The results are consistent with the claim that aspects of working
      memory are 'particularly impaired' in adult ADHD. Also, the BPD group had a
      longer deliberation time for one of the additional tasks, compared with the ADHD
      group, which indicated that the patient groups may have different patterns of
      neuropsychological impairments.

PMID- 15180780
TI  - Development of neuropsychiatric symptoms in poststroke patients: a cross
      sectional study.
AB  - OBJECTIVE: The study aimed to characterize neuropsychiatric symptomatology and
      its evolution in a large group of poststroke patients during their first year.
      METHOD: The Neuropsychiatric Inventory (NPI) was administered to a sample of 124
      poststroke patients, divided into three independent groups on the basis of time
      from stroke (2, 6 and 12 months). The controls were 61 healthy subjects. RESULTS:
      A wide range of neuropsychiatric symptoms was found significant in the poststroke
      population: mostly depression (61%), irritability (33%), eating disturbances
      (33%), agitation (28%), apathy (27%) and anxiety (23%). Modifications in terms of
      greater depression, anxiety, irritability and eating disturbances evolved in the
      year following stroke. Other symptoms were significantly present depending on
      time from stroke. Clear relations with other clinical and demographic variables
      were also found. CONCLUSION: Neuropsychiatric symptoms constitute an important
      part of comorbidity in stroke patients; thus, suitable assessment tools may
      improve clinical understanding of these patients.

PMID- 15180781
TI  - Longitudinal diagnostic efficiency of DSM-IV criteria for obsessive-compulsive
      personality disorder: a 2-year prospective study.
AB  - OBJECTIVE: To examine the longitudinal diagnostic efficiency of the DSM-IV
      criteria for obsessive-compulsive personality disorder (OCPD). METHOD: At
      baseline, criteria and diagnoses were determined using diagnostic interviews, and
      blinded assessments were performed 24 months later with 550 participants.
      Diagnostic efficiency indices (conditional probabilities, total predictive power,
      and kappa) were calculated for each criterion determined at baseline, using the
      independent OCPD diagnosis at follow-up as the standard. RESULTS: Longitudinal
      diagnostic efficiencies for the OCPD criteria varied; findings suggested the
      overall predictive utility of 'preoccupied with details', 'rigid and stubborn',
      and 'reluctant to delegate'. CONCLUSION: These findings suggest the predictive
      validity of three cognitive-interpersonal OCPD criteria.

PMID- 15180782
TI  - Patient and direct-care staff body mass index in a state mental hospital:
      implications for management.
AB  - OBJECTIVE: Obesity is a major problem among chronically psychotic patients.
      METHOD: We assessed body mass index (BMI) of chronically psychotic patients on
      admission to a state mental hospital and in follow-up. We also compared patient
      BMI to staff BMI. RESULTS: The initial patient BMI (26.4 +/- 5.8 kg/m2) was in
      the overweight range. The patient BMI (29.1 +/- 5.8 kg/m2) increased (P < 0.0001)
      on follow-up and almost reached the level of obesity. Staff BMI (35.1 +/- 8.6
      kg/m2) was in the obese range with 64.9% meeting criteria of obesity and 29.9%
      meeting criteria of morbid obesity. African-American women made up 84.5% of
      clinical-care staff and constitute the race-sex mix most vulnerable to obesity in
      the US. Morbid obesity (BMI > or = 40 kg/m2) was five times more common among
      these African-American female clinical-care staff than among African-American
      women in the general US population. CONCLUSION: Our findings may have treatment
      implications for chronically psychotic patients at risk for obesity.

PMID- 15180785
TI  - Galvanizing mental health research in low- and middle-income countries: role of
      scientific journals.

PMID- 15180783
TI  - A case study in the treatment of dementia with Lewy bodies.
AB  - OBJECTIVE: To describe the assessment and treatment of an elderly woman with
      parkinsonism, progressive memory and cognitive deficits, and visual
      hallucinations. METHOD: The patient presented with a 10-year history of hand
      tremors, an 8-year history of short-term memory problems, and a 3-4-year history
      of visual hallucinations. Treatment with donepezil and rivastigmine
      (successively) did not produce the desired benefits. Then she was started on
      galantamine 4 mg b.i.d. (escalated to 8 mg b.i.d.). RESULTS: The patient's social
      interaction improved and cognitive decline appeared to be stabilized;
      hallucinations and agitation were also better controlled. CONCLUSION: By current
      criteria, this subject would be labeled as having Parkinson's disease with
      dementia, although she exhibited the core features of dementia with Lewy body
      disease. As suggested in previous studies, cholinesterase inhibitors may be
      effective in treating psychotic symptoms; however, all currently available agents
      may not be equally effective.

PMID- 15180788
TI  - Measurement of coronary flow reserve in isolated hearts from mice.
AB  - AIM: Langendorff-perfused murine hearts are increasingly used in cardiovascular
      research, but coronary cardiovascular haemodynamics vary considerably from one
      research group to another. The aim of this study was to establish an isolated,
      retrogradely perfused mouse heart preparation for the simultaneous measurement of
      left ventricular haemodynamics and of coronary flow (CF). METHODS: Heart rate was
      controlled by right atrial pacing (480 beats min(-1)) and heart temperature was
      kept constant. Accurate flow values of <0.5 mL min(-1) could be determined, and
      this methodology was then used to study the stability of this preparation, as
      well as coronary response to vasoactive drugs and to short-term ischaemia.
      RESULTS: The CF and maximum systolic pressure were well maintained over a 2-h
      perfusion period, both showing a 10% decline per hour. Sodium-nitroprusside
      (endothelium-independent) and adenosine (endothelium-dependent) increased CF
      relatively modest (30-50% above baseline values). Short-term no-flow ischaemia
      caused a transient 40-50% increase in CF on reperfusion. Peak reflow occurred
      approximately 15 s after start of reperfusion and flow returned to baseline
      during the following 1-2 min. Increased coronary blood flow following infusion of
      vasoactive drugs (nitroprusside or adenosine) or short-term ischaemia were
      associated with minor changes in ventricular pressure development. CONCLUSIONS:
      Blood flow and haemodynamics can readily be determined in this isolated perfused
      mouse heart model, but CF reserve is relatively small, compared with blood
      perfused organs.

PMID- 15180789
TI  - Muscle dysfunction during exercise of a single skeletal muscle in rats with
      congestive heart failure is not associated with reduced muscle blood supply.
AB  - AIM: Inadequate muscle blood flow is a possible explanation for reduced fatigue
      resistance in patients with congestive heart failure (CHF). METHODS: In rats with
      post-infarction CHF we electrically stimulated the soleus muscle (SOL) in situ
      with intact blood supply. Contractile properties, blood flow, high-energy
      phosphates and metabolites were measured during 30 min of intermittent
      stimulation, and in addition capillarization of SOL was recorded. RESULTS: During
      stimulation, SOL contracted more slowly in rats with CHF compared with sham
      operated rats. However, the blood flow in SOL was unaltered and capillary density
      was maintained in CHF rats. Further, the content of ATP, ADP, AMP, NAD, CrP, P(i)
      and lactate in SOL was not different between the groups. CONCLUSION: The cause of
      contractile dysfunction in a single exercising skeletal muscle in rats with CHF
      cannot be explained simply by reduced blood supply. In addition, absence of
      changes in high-energy phosphates and metabolites indicate that the oxidative
      metabolism of SOL is intact in rats with CHF.

PMID- 15180790
TI  - Hydralazine treatment alters body composition in the rabbit model of obesity.
AB  - AIMS: While hydralazine is commonly used as monotherapy in animal studies, its
      potential side effects are seldom acknowledged. Purported side effects occur from
      sympathetic and renin-angiotensin system activation, and include tachycardia,
      oedema, and nausea. We hypothesized that these side effects would alter body
      composition by increasing body water and/or decreasing body fat. METHODS: Female
      New Zealand White rabbits were divided into lean and obese control and
      hydralazine-treated groups. Lean rabbits ate a maintenance diet for 12 weeks;
      obese rabbits ate an ad lib high fat diet. Hydralazine was administered at 6 and
      10-14 mg kg(-1) day(-1) for lean and obese hydralazine groups, respectively. Body
      composition was determined using triplicate 2-3 g samples of whole body
      homogenate, and analysed using 2 x 2 ANOVA for diet vs. hydralazine effects.
      RESULTS: Hydralazine-treated animals had lower body fat (15.7 +/- 1.1 and 21.8 +/
      1.0%, respectively) and higher body water (59.8 +/- 0.8 and 55.4 +/- 0.6%,
      respectively) compared with controls. While obese controls were heavier than
      obese hydralazine-treated animals (5.12 +/- 0.09 vs. 4.73 +/- 0.11 kg,
      respectively) and had greater overall feed consumption (13.5 +/- 0.4 vs. 11.8 +/-
      0.4 kg, respectively), a subsequent analysis using subsets that did not differ in
      body weight or feed consumption yielded the same conclusions. Plasma adrenaline
      and noradrenaline did not differ between control and hydralazine-treated groups.
      CONCLUSIONS: Use of hydralazine to control blood pressure alters body
      composition. Direct or indirect effects of hydralazine may impact physiological
      systems under study. Alterations in adipose tissue may be of particular concern
      because of its endocrine function.

PMID- 15180791
TI  - Effects of ageing on the energy balance of food-restricted rats.
AB  - AIMS: Age can alter energy balance by decreasing the resting metabolic rate. Food
      restriction can also change energy balance by decreasing energy expenditure as a
      mechanism of energy conservation. We investigated the influence of food
      restriction on the energy balance of rats at different ages. METHODS: Wistar EPM
      1 female rats were used at ages of 3, 9, 15 and 21 months. At each age, two food
      intake schedules were provided: control (ad libitum) and food restriction (50%).
      Animals remained under these schedules for 30 days, and throughout this period
      body weight, food intake, and stool collection were controlled daily. On the 30th
      day, animals were killed, blood was collected and the carcasses and faeces were
      processed for analysis by pump calorimetry. Blood glucose, T(3), T(4) and rT(3)
      levels were determined. RESULTS: Food restriction reduced energy gain and gross
      food efficiency of animals at different ages, but more so in older animals. Food
      restricted rats also had lower energy expenditure than controls. This reduction
      was about 40% of the energy expenditure of control animals irrespective of age.
      Water content increased and fat content decreased in the carcass of food
      restricted animals. Serum T(3) and T(4) levels were lower in food-restricted
      animals pointing out to a major role of thyroid hormones in the mechanism of
      energy conservation exhibited by food-restricted animals. CONCLUSIONS: The
      mechanism of energy conservation takes place in all restricted animals and is
      very important for survival and for species preservation, mainly in aged animals
      in which food restriction is frequently aggravated by senescence-related organic
      disorders.

PMID- 15180792
TI  - Effect of chronic wheel running on the fatty acid composition of phospholipids
      and triacylglycerols in rat serum, skeletal muscle and heart.
AB  - AIM: The purpose of this study was to examine the effects of long-term wheel
      running on the fatty acid composition of phospholipids (PL) and triacylglycerols
      (TG) in rat serum, skeletal muscle (soleus and extensor digitorum longus) and
      heart. METHODS: To this end, the relevant tissues of 11 trained male Wistar rats
      were compared with those of 14 untrained ones. RESULTS: There were several
      significant differences between the two groups regarding the concentrations and
      percentages of individual fatty acids in serum PL and TG, with most differences
      appearing in the fatty acid distribution of PL. Monounsaturated fatty acids of
      muscle PL were significantly lower in the trained rats. Estimated elongase
      activity was significantly higher, whereas Delta(9)-desaturase activity was
      significantly lower in the trained muscles. Monounsaturated fatty acids of PL
      were also significantly lower in the trained hearts. The fatty acid composition
      of PL in the skeletal muscles and the heart adapted to training in a comparable
      manner, whereas most of the changes in the fatty acid profile of TG were tissue
      dependent. Judging from the magnitude of the effect sizes and the percentage
      differences between trained and untrained animals, there were many large effects
      of chronic exercise on the fatty acid composition of the tissues examined.
      CONCLUSION: Long-term wheel running modified the fatty acid profile of PL and TG
      in rat serum, skeletal muscle and heart, and could thus be considered as a
      modulator of tissue fatty acid composition.

PMID- 15180793
TI  - Long-term endurance training does not prevent the age-related decrease in left
      ventricular relaxation properties.
AB  - AIM: Diastolic filling dynamics in the long-term endurance trained elderly has
      previously been examined by transmitral flow velocity, which has been shown to be
      preload dependent. The aim of this study was to assess the effect of long-term
      endurance training on left ventricular (LV) relaxation in older individuals by
      using pulsed tissue Doppler imaging. METHODS: Fourteen master athletes with a
      history of intensive long-term endurance training, 14 aged-matched sedentary
      controls and 15 young adult men underwent standard Doppler echocardiography and
      pulsed Doppler tissue imaging, performed in four-chambers apical view, by placing
      a sample volume at the level of the mitral annulus. RESULTS: Stroke volume was
      significantly higher and heart rate lower in master athletes compared with aged
      matched sedentary subjects. Transmitral Peak E velocity and ratio E/A were
      significantly higher in master athletes, but did not reach the values of young
      men. Peak LV wall motion during the early filling phase, an index of LV
      relaxation, were significantly higher in young men than in both groups of older
      individuals. However, similar values were obtained between master athletes and
      sedentary counterparts. CONCLUSIONS: Our data provide evidence that long-term
      training does not reduce the age-related decline in LV relaxation properties in
      humans. This finding implies that other mechanisms, such as increased LV filling
      pressures due to expanded blood volume, are probably responsible for the higher
      contribution of early diastolic filling to LV filling in master athletes compared
      with their sedentary counterparts. However this hypothesis needs to be confirmed.

PMID- 15180794
TI  - Morphological changes in rat hindlimb muscle fibres during recovery from disuse
      atrophy.
AB  - AIM: The present study attempted to use HE staining to clarify morphological
      changes in muscle fibres during recovery from disuse muscle atrophy. METHODS:
      Disuse muscle atrophy was induced by suspending 7-week-old male Wistar rats by
      their tails for 5 weeks (hindlimb unloading or HU group). Histological changes in
      the soleus muscle (SOL) during the recovery process were examined and compared
      with those in control rats who were raised freely without unloading (C group).
      RESULTS: Wet muscle mass and muscle cross-sectional area per fibre of SOL in the
      HU group were 52 +/- 5 and 22 +/- 5% of those in the C group, respectively.
      Muscle atrophy was largely attributable to decreases in the size of muscle
      fibres, rather than to muscle fibre damage or loss. Muscle mass in the HU group
      increased quickly after reloading, but recovery of cross-sectional area per fibre
      was slow, with mean area in the HU group measuring 69 +/- 10% of that in the C
      group even after 5 weeks of reloading. After 1, 2 and 5 weeks of reloading,
      incidences of muscle fibres displaying central nuclei (regenerated muscle fibres)
      were 7.4 +/- 2.4, 7.2 +/- 6.3 and 19.2 +/- 14.5%, respectively. CONCLUSION: These
      findings suggest that recovery of muscle fibres atrophied by disuse involves not
      only growth of atrophied muscle fibres, but also regeneration of muscle fibres.
      Cross-sectional areas recovery of atrophied muscle fibres thus continues after
      increases of muscle mass.

PMID- 15180795
TI  - Time-course changes in VEGF expression and capillarity in the early stage of
      exercise training with Co treatment in rat skeletal muscles.
AB  - AIM: Cobalt administration was reported to mimic hypoxia. This study was designed
      to examine the time-course changes in vascular endothelial growth factor (VEGF)
      expression and capillary geometry in skeletal muscles during endurance training
      with CoCl(2) administration in female Wistar rats. METHODS: Exercise training by
      running lasted for up to 10 days at 25 m min(-1) on a 20% gradient, 15-42 min
      day(-1). Rats in the Co(2+)-treated groups drank water containing 0.01% CoCl(2).
      Serial frozen sections were stained for alkaline phosphatase and
      dipeptidylpeptidase IV to identify capillary profiles and VEGF-A protein.
      RESULTS: In the soleus muscle, the density of VEGF-positive capillaries (VEGF
      cap) was significantly increased after 6 and 10 days of the Co(2+) administration
      (by 27 and 65% respectively) while the capillary-to-fibre ratio (C : F) first
      increased after 10 days. The training with Co(2+) significantly increased VEGF
      cap by 69, 44 and 60%, respectively, after 3, 6 and 10 days. The VEGF-cap was
      significantly increased after 6 and 10 days of training alone by 38 and 58%,
      respectively. In a similar extent, both training groups with and without Co(2+)
      showed a significant increase in the C : F ratio after 6 and 10 days.
      CONCLUSIONS: The present results suggest that activation of the cellular oxygen
      sensing mechanism induced by Co(2+) administration slightly facilitates an
      expression of VEGF but does not facilitate exercise-induced microvascular
      remodelling in hind-leg muscles.

PMID- 15180796
TI  - Coexpression after electroporation of plasmid mixtures into muscle in vivo.
AB  - AIM: Muscle is perhaps the most frequently considered tissue for non-viral gene
      therapy, in particular after gene transfer by electroporation. Expression in
      muscle is stable, but since the cell turnover is so slow incorporation in the
      host genome is not required. This raises interesting practical and theoretical
      questions related to the behaviour of the transgenic DNA under such conditions.
      METHODS: We have investigated expression of reporter genes from plasmid mixtures
      electroporated into the extensor digitorum longus (EDL) muscle in mice in order
      to assess the degree of coexpression. RESULTS: Under conditions where the
      reporter is easily identified the coexpression rate was 100%, as none of 287
      fibres from five different muscles expressing blue fluorescent protein (BFP)
      failed to express green fluorescent protein (GFP). With other reporter
      combinations the rate was lower, but this we attribute to marginal sensitivity
      for fluorescent proteins, or from reporter protein degradation for beta
      galactosidase. CONCLUSIONS: The high degree of coexpression suggests that a large
      copy number takes part in the final transcription with this system. The finding
      also enhances the usefulness of muscle and electroporation for gene therapy and
      experimental biology.

PMID- 15180797
TI  - Glycogen debranching enzyme is associated with rat skeletal muscle sarcoplasmic
      reticulum.
AB  - AIMS: Gel electrophoresis revealed a band of molecular weight approximately 160
      000 Da associated with the skeletal muscle sarcoplasmic reticulum (SR) vesicle
      preparations. This investigation sought to examine glycogen debranching enzyme
      associated with skeletal muscle SR. METHODS: Sarcoplasmic reticulum samples were
      also taken from muscle whose glycogen content had been reduced either via
      stimulation of the sciatic nerve or alpha-amylase treatment of muscle
      homogenates. RESULTS: The stimulation protocol reduced whole muscle glycogen by
      86% (7.4 +/- 0.4 vs. 1.0 +/- 0.3 microg mg(-1) wet mass, P < or = 0.05). Glycogen
      associated with the SR was reduced by 82% in the stimulation protocol (533 +/- 82
      vs. 96 +/- 7 microg mg(-1) protein) and by 94% in alpha-amylase treatment (493 +/
      11 vs. 29 +/- 2 microg mg(-1) protein), respectively. Gel electrophoresis and
      Western blots revealed that the content of glycogen debranching enzyme was
      reduced by approximately 53% as a result of muscle stimulation and by
      approximately 46% in alpha-amylase treatment (P < or = 0.05). In addition,
      glycogen debranching enzyme activity was reduced by 61% in stimulated samples
      compared with control (20.3 +/- 1.0 vs. 8.0 +/- 1.2 nmol mg(-1) min(-1),
      respectively), a value consistent with reductions observed from gel
      electrophoresis and Western blots. CONCLUSION: These results confirm that similar
      to glycogen phosphorylase, glycogen debranching enzyme is associated with the
      skeletal muscle SR and is dissociated under exercise conditions.

PMID- 15180798
TI  - Effects of oxytocin in normal man during low and high sodium diets.
AB  - AIM: We tested the hypothesis that oxytocin in normal man causes natriuresis by
      means of nitric oxide and/or atrial natriuretic peptide. METHODS: Normal male
      subjects were investigated after 4 days of sodium controlled diets (30 mmol
      sodium chloride day(-1), n = 8 or 230 mmol sodium chloride day(-1), n = 6).
      Oxytocin was infused intravenously (1 pmol kg(-1) min(-1) for 240 min). RESULTS:
      Mean arterial blood pressure, heart rate and glomerular filtration rate by
      clearance of chromium-labelled ethylenediaminetetraacetate remained stable.
      Plasma oxytocin increased from 2 to 3 pg mL(-1) to around 50 pg mL(-1). Oxytocin
      decreased urine flow (4.2 +/- 0.2--0.75 +/- 0.11 and 4.6 +/- 1.3-1.4 +/- 0.6 mL
      min(-1), low- and high-salt diet, respectively). During low-salt conditions,
      oxytocin reduced sodium and potassium excretion (11 +/- 2--4 +/- 2 and 93 +/- 19-
      42 +/- 3 micromol min(-1), respectively). Plasma renin, angiotensin II,
      aldosterone and renal excretion of metabolites of nitric oxide (nitrate and
      nitrite) all decreased. Plasma atrial natriuretic peptide and cyclic guanosine
      monophosphate were unchanged. A similar pattern was obtained during high-salt
      conditions but in this case the antinatriuresis was not different from that
      occurring during the corresponding time control series. CONCLUSIONS: The data
      reject the hypothesis. In contrast, we found significant antinatriuretic,
      antikaliuretic and antidiuretic effects, which were not mediated by the renin
      angiotensin-aldosterone system, atrial natriuretic peptide, systemic
      haemodynamics, or processes increasing urinary excretion of metabolites of nitric
      oxide. The natriuretic effect of oxytocin found in laboratory animals is species
      specific.

PMID- 15180799
TI  - Analysis of ET-A and ET-B receptors using an isolated perfused rat lung
      preparation.
AB  - AIMS AND METHODS: The pulmonary and vascular effects of endothelin-1 receptor
      activation were studied in isolated perfused and ventilated lung preparations
      from rat. The responses to endothelin-1 (ET-1) and the endothelin B (ET(B))
      receptor agonist sarafotoxin 6c (S6c) were characterized using the endothelin A
      (ET(A))-receptor antagonist FR 139317, the ET(B)-receptor antagonist BQ 788 and
      the combined ET(A)/ET(B)-receptor antagonist Bosentan. The respiratory parameter
      airway conductance (G(aw)) and the vascular parameter perfusion flow were
      analysed simultaneously. RESULTS: Concentration-response curves for ET-1
      administered intra-arterially revealed that its most potent effect was on the
      vascular side while S6c had a more potent effect on airway conductance. ET-1,
      given as a bolus dose intra-arterially (100 microL of 0.2 nM), induced a strong-
      and long-lasting contraction of the vasculature while only a less pronounced
      contraction was seen in the airways. Neither of the antagonists had a significant
      effect per se on G(aw) or perfusion flow. FR 139317 reduced the effect of ET-1 on
      perfusion flow by about 50%, while airway conductance was augmented. BQ 788
      enhanced the decrease in perfusion flow by ET-1 while G(aw) was not influenced.
      The combined ET(A)/ET(B) antagonist Bosentan powerfully prevented the ET-1
      induced decrease in G(aw) but did not alter its reduction in perfusion flow.
      CONCLUSIONS: The potent effect of ET-1 on the vascular side of the lung is
      mediated mainly through ET(A) receptors, whereas both ET(A) and ET(B) receptors
      are involved in G(aw) in the rat lung.

PMID- 15180800
TI  - Steroid treatment for relapses in multiple sclerosis - the evidence urges shared
      decision-making.
AB  - OBJECTIVES: Therapy of acute relapses in multiple sclerosis with corticosteroids
      (CC) remains uncertain with respect to route, dosage and effectiveness. This
      makes the treatment of relapses a clinical field where 'shared decision-making
      (SDM)' could be of advantage for the patients. A prerequisite for SDM is the
      provision of evidence-based information for the patients. The British General
      Medical Council (GMC) has published ethical guidelines on seeking patients'
      consent for medical interventions, formulating topics of information patients
      need in order to make an informed treatment decision. METHODS: Medical databases
      were searched for evidence on the treatment of acute relapses with CC. RESULTS:
      The available evidence on relapse treatment is ambiguous and weak. It does not
      provide enough evidence to sufficiently inform patients following the topics
      formulated by the GMC. CONCLUSION: Good evidence is lacking, supporting the
      concept of SDM in the therapy of relapses.

PMID- 15180801
TI  - Factors influencing quality of life in multiple sclerosis patients: disability,
      depressive mood, fatigue and sleep quality.
AB  - OBJECTIVES: In a series of 504 patients with multiple sclerosis (MS), quality of
      life (QOL) and its main clinical and demographic determinants were assessed in
      comparison with healthy individuals. MATERIALS AND METHODS: A postal
      questionnaire with self-completed measures of disability (Expanded Disability
      Status Scale, EDSS), QOL (Quality of Life Index, QLI), depressive mood (Self
      rating Depression Scale, SDS), fatigue severity (Fatigue Severity Scale, FSS) and
      sleep quality (Pittsburgh Sleep Quality Index, PSQI) was sent to this sample of
      MS patients. RESULTS: Most patients were severely disabled; almost half were
      mildly to severely depressed, suffering from reduced sleep quality and/or
      fatigue. The multiple sclerosis patients had significantly lower QLI scores than
      healthy controls. EDSS and SDS scores were found to be predictors of global QLI
      score. Regarding the different QLI domains, mean SDS scores remained predictive
      for all QLI items, while mean EDSS, PSQI and FSS scores were only predictive for
      physical domains. CONCLUSION: Our study clearly demonstrates that depressive mood
      is the main factor influencing QOL. The disability status, fatigue and reduced
      sleep quality have an impact mainly on physical domains of life quality.

PMID- 15180802
TI  - A cluster of multiple sclerosis cases in Lysvik in the Swedish county of
      Varmland.
AB  - OBJECTIVES: When surveying the county of Varmland in Sweden in order to determine
      the prevalence of multiple sclerosis (MS), we observed an aggregation of MS cases
      originating from the parish of Lysvik in the local region called Fryksdalen. Our
      intention was to analyse this cluster thoroughly, confirming the MS diagnosis and
      seeing if a hereditary or environmental background was plausible. METHODS: The
      medical files were studied and the cases were classified by a neurologist
      according to Poser's criteria. Hereditary factors were analysed. RESULTS: Sixteen
      living cases of MS were found, either living in the parish (n = 6) or born or
      raised there and had later moved to another place (n = 10). All patients had
      clinically definite MS. Eleven patients had relatives with MS, all of these being
      descendants of the Suhoinen family. Another two cases were Suhoinen descendants
      who did not have relatives with MS. Other common ancestors were also identified.
      Two cases were adopted. Eleven deceased MS patients from Lysvik were found, 10 of
      them had Suhoinen ancestry. CONCLUSION: We report a cluster of MS cases with a
      common ancestry indicating heredity for MS in 85% of the cases. Lysvik is a
      parish where Finnish immigration was pronounced in the 17th century and there has
      been inbreeding to a certain extent through marriage between cousins. Thus, we
      interpret this aggregation as possibly being genetically based, and neurogenetic
      studies are now being performed. However, as two of the cases were adopted
      environmental factors must also be considered.

PMID- 15180803
TI  - The relapse rate of multiple sclerosis changes during pregnancy: a cohort study.
AB  - OBJECTIVE: To evaluate the influence of pregnancy and puerperium on the relapse
      rate of multiple sclerosis (MS). METHODS: We determined retrospectively the
      yearly mean relapse rate (MRR) during pregnancies occurring in the course of
      relapsing-remitting MS. We compared the MRR of pregnancy-time with that of non
      pregnancy time by paired t-test. Relative risk (RR) of relapses during the
      pregnancy-time was also compared with that of non-pregnancy time by chi(2)
      analysis and 95% confidence intervals. RESULTS: From a population of 351 women
      affected by clinically definite MS, only 70 reported pregnancies during their
      relapsing-remitting phase of MS for a total of 98 pregnancies. Both MRR (P =
      0.006) and RR (RR = 0.63, 95% CI = 0.40-0.94) decreased during the three
      trimesters of pregnancy. RR increased in the first 3 months of puerperium,
      although this was not statistically significant (RR = 1.36, 95% CI = 0.79-2.20).
      CONCLUSION: Our study confirms that in MS the relapse rate decreases throughout
      pregnancy and increases during puerperium. This suggests a complex interplay
      between hormonal and immune factors.

PMID- 15180804
TI  - Seizures among families of Indian probands with different epileptic syndromes.
AB  - OBJECTIVES: To investigate the contribution of hereditary factors in the
      causation of different epilepsy syndromes. MATERIAL AND METHODS: Occurrence of
      seizures among first- and second-degree relatives of 5628 Indian probands with
      epilepsy, and 3357 probands with non-epilepsy neurological disorders (who acted
      as control population) was documented. Syndromic concordance between epilepsy
      probands and affected relatives was investigated. RESULTS: Twenty percent
      epilepsy probands (1129) had affected relatives. Relatives of epilepsy probands
      were more often affected compared with relatives of non-epilepsy probands (OR:
      3.4). Probands with some epilepsy syndromes more often had a positive family
      history. Relatives of younger probands were at greater risk of having epilepsy.
      Sibs were more often affected compared with other first- and second-degree
      relatives (OR: 1.3 and 4.6). Sibs having generalized epilepsies and syndromes and
      febrile convulsions (FC) were at greater odds of syndromic concordance with
      probands compared with second-degree relatives. Sibs and second-degree relatives
      having idiopathic/cryptogenic epilepsy had greater odds for concordance compared
      with those with symptomatic epilepsies. CONCLUSIONS: One-fifth of probands with
      all types of epileptic syndromes have family history of seizures. Familial risk
      of epilepsy correlated with the epilepsy syndrome among probands and their age at
      presentation. Risk of relatives being affected varied as a function of the
      relation with probands. Concordance of epilepsy syndromes varied both as a
      function of the epilepsy syndrome and relation with the probands.

PMID- 15180805
TI  - Familiarity with, knowledge of, and attitudes toward epilepsy in residents of
      Seoul, South Korea.
AB  - BACKGROUND AND PURPOSE: The aim of this study was to investigate the perceptions
      of epilepsy in Seoul, South Korea, a country where social stigma toward epilepsy
      is still pronounced. METHODS: We randomly selected 1000 persons living in Seoul
      and performed telephone interviews regarding public awareness, knowledge, and
      attitudes toward epilepsy. RESULTS: Among 1000 respondents, the 92% who had read
      or heard about epilepsy became the subjects of the study. Word of mouth was most
      often referenced as a source of knowledge (78%). Forty-seven percentage believed
      that epilepsy is inheritable, whereas 5% thought that epilepsy is a mental
      illness. Marriage of their children to an epileptic person, childbearing by women
      with epilepsy, and employing a person with epilepsy were opposed by more than 50%
      of respondents. The reasons for the negative attitudes were that epilepsy was
      hereditary and untreatable (P < 0.05, respectively). CONCLUSIONS: Our study
      revealed that there still remains negative attitudes regarding the marriage,
      childbearing, and employment of persons with epilepsy, which may stem from
      misconceptions about the cause and treatability of epilepsy, possibly due in part
      to the influence of herbal medicine, and South Korea's ethnic homogeneity. Public
      health education either through media or school health education is urgently
      needed to improve knowledge about, and attitudes toward epilepsy.

PMID- 15180806
TI  - Effects of pulsed electromagnetic fields on cognitive processes - a pilot study
      on pulsed field interference with cognitive regeneration.
AB  - BACKGROUND: Due to the ubiquitous use of cellular phones much has been speculated
      on secondary effects of electromagnetic irradiation emitted by those.
      Additionally, several studies have reported vegetative alterations as well as
      effects on the neuronal and molecular levels in humans. Here, using a psycho
      physiological test paradigm, we examined effects of exposure to pulsed
      electromagnetic fields on cognitive performance. MATERIALS AND METHODS: In 11
      volunteers, we tested cognitive processing under field exposure (GSM standard)
      and under field-free conditions. To examine the hypothesized effect of pulsed
      fields, we applied an auditory discrimination task and determined the
      participant's current 'Order Threshold' value. Following a first test cycle, the
      volunteers had to relax for 50 min while being, or not, exposed to pulsed
      electromagnetic fields. Subsequently, the test was repeated. Data acquired before
      and after the resting phase were compared from both experimental conditions.
      RESULTS: We found that nine of the 11 test participants (81.8%) showed worse
      results in their auditory discrimination performance upon field exposure as
      compared with control conditions. Group data comparison revealed a statistical
      significance of P = 0.0105. CONCLUSION: We could show that the participants'
      cognitive performance was impaired after exposure to pulsed electromagnetic
      fields. With regard to this finding, we recommend that the use of cellular phones
      should be restricted generally and in particular in respect of physical hazard of
      high-risk groups, e.g. elderly, children and ill people.

PMID- 15180807
TI  - Limited utility of interictal apparent diffusion coefficient in the evaluation of
      hippocampal sclerosis.
AB  - OBJECTIVE: Quantitative measurement of diffusion has been studied as an
      independent parameter for the identification and characterization of abnormal
      hippocampi and temporal lobes in epileptic patients. MATERIAL AND METHODS: In
      order to study the diagnostic value of magnetic resonance diffusion weighted
      imaging (DWI) and the apparent diffusion coefficient (ADC) from the temporal
      region, interictal DWI and ADC values were prospectively obtained from both
      hippocampal areas and temporal lobes bilaterally and compared between 19 normal
      volunteers and 20 medial temporal lobe epilepsy (MTLE) patients. RESULTS: In all
      patients, visual assessment of DWI failed to lateralize the lesion. However, the
      overall correct lateralization rate of interictal ADC was 100% (20/20) if the
      side with the higher ADC value was considered to be abnormal. Comparison of the
      MTLE lesion side values with those of the normal volunteers revealed that the ADC
      values measured from the hippocampal areas and temporal lobes of the MTLE
      patients were significantly higher than those from the normal volunteers on the
      lesion side (P < 0.05) and also on the contralateral side although not
      statistically significant. The absolute differences between the ADC values of the
      higher and lower side, in both the hippocampus and the temporal lobe, were not
      significant among the normal volunteers and the MTLE patients. CONCLUSION:
      Although the correct lateralization rate of interictal ADC in the MTLE patients
      was 100%, the application of elevated ADC value as a diagnostic criteria for MTLE
      was disappointing because such elevation in ADC values was not limited only to
      the ipsilateral temporal region but also in the contralateral side in MTLE.

PMID- 15180808
TI  - Cognitive and affective status in mild hypothyroidism and interactions with L
      thyroxine treatment.
AB  - OBJECTIVES: While clinical hypothyroidism is associated with frank
      neuropsychological and affective alterations and is considered one of the causes
      of reversible dementia, the occurrence of these alterations and their treatment
      in mild hypothyroidism (MH) remains a controversial issue. Our aim was therefore
      to evaluate cognitive and psychological functions in a selected population of
      recently-diagnosed MH patients with minor subjective symptoms. MATERIALS AND
      METHODS: Thirty-six MH women (mean age 51.9 +/- 13.5 years) were observed after a
      careful assessment had excluded subjects with neurological, psychiatric and/or
      somatic disorders, or confounding conditions. The subjects were evaluated for
      thyroid function and tested with an extensive battery of neuropsychological tests
      and psychological rating scales, in basal conditions and after 6 months of L
      thyroxine treatment. RESULTS: Baseline neuropsychological performance was within
      the normal range, while an age-dependent reduction was found in attentive
      function. After L-thyroxine treatment, an increase in serum fT4 was detected in
      parallel with thyroid stimulating hormone (TSH) reduction. Verbal fluency and
      depression scores showed a slight improvement. A positive correlation was found
      between TSH reduction and improved mood scores. CONCLUSION: From the analysis of
      the results, treatment of asymptomatic MH would seem advisable in order to re-set
      hormonal levels and, particularly in older subjects, to protect the brain against
      the potential risk of cognitive and affective dysfunctions.

PMID- 15180809
TI  - Progression of multiple sclerosis is associated with exon 1 CTLA-4 gene
      polymorphism.
AB  - OBJECTIVES: Multiple sclerosis (MS) is a chronic demyelinating disease of the
      central nervous system which is widely believed to have a T-cell-mediated
      etiology. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) antigen molecule plays a
      key role in the downregulation of T-cell responses. To examine the genetic
      association of the CTLA-4 gene locus with MS, we analyzed an exon 1 (A49G)
      transition. MATERIAL AND METHODS: One hundred and fifty-two MS patients and 154
      controls were examined. The A/G transition was genotyped by a polymerase chain
      reaction followed by labeling with a SNaPshot kit and detection using a capillary
      genetic analyzer. RESULTS: The genotype, allele and phenotype frequencies did not
      differ significantly between MS patients and controls. Those MS patients with AA
      and AG genotypes had 4.36 times greater risk of progressing from the relapsing
      remitting to the secondary progressive form of the disease than those with the GG
      genotype. CONCLUSION: The results of our study indicate that CTLA-4 (A49G) exon 1
      polymorphism is associated with MS progression.

PMID- 15180810
TI  - A non-syndromic hearing loss caused by very low levels of the mtDNA A3243G
      mutation.
AB  - We described a patient with progressive non-syndromic hearing loss (NSHL)
      harboring the A3243G mutation in the mitochondrial DNA (mtDNA). Muscle biopsy
      showed scattered ragged-red, cytochrome c oxidase negative fibers, whereas the
      biochemical analysis of the mitochondrial respiratory chain complexes was normal.
      Restriction fragment length polymorphism (RFLP) analysis showed A3243G mtDNA
      transition, present at very low in patient's muscle (3%) and in urinary sediments
      (1%), and not detectable in blood and buccal mucosa. The patient was submitted to
      a bilateral cochlear implantation with post-operative excellent hearing and
      communicative outcomes. Our findings indicate that A3243G mutation may be
      responsible both for SHL and NSHL, may be depending on the levels of mutated
      mtDNA. Patients with hearing loss due to mtDNA mutations should be considered as
      good candidates for cochlear implantation.

PMID- 15180811
TI  - A review of research related to blood transfusion in Canada, 2000-2002.
AB  - The former National Blood Safety Council undertook a comprehensive review of
      blood transfusion research in Canada for the years 2000 through 2002. Data were
      acquired by direct contact with agencies which support such research and by
      searches of the relevant websites. Total grant support increased markedly over
      the 3-year period, from 4.1 million dollars to 18.5 million dollars. Publicly
      funded granting agencies, biopharmaceutical companies, the blood services and the
      province of Ontario were major supporters. Much smaller amounts were granted from
      charitable organizations. Clinical research attracted the majority of the
      funding, although a larger number of projects were basic science in nature. Most
      research was carried out in the provinces of Ontario, Quebec and British
      Columbia. Although we have not assessed the productivity of blood-related
      research, it appears that substantial amounts of funding were allocated to these
      projects between 2000 and 2002. These data may provide a helpful perspective to
      investigators in transfusion medicine elsewhere, who may also be assessing the
      relative priority given to this field of research in their own countries.

PMID- 15180812
TI  - Trustworthiness of information about blood donation and transfusion in relation
      to knowledge and perceptions of risk: an analysis of UK stakeholder groups.
AB  - There is evidence that the public perceive blood transfusion as risky, and there
      is a growing literature exploring factors associated with perceived transfusion
      risk. One contributory factor might be the types of information different key
      stakeholders (e.g. general practitioners, anaesthetists, health/life style
      journalists and blood donors) rely on for information. This article addresses
      four unanswered questions about transfusion/donation risk, namely (1) do
      different stakeholder groups perceive different sources of information as more or
      less trustworthy, (2) to what extent is the perceived trustworthiness related to
      levels of knowledge and perceived risk, (3) is optimistic bias observed across
      the stakeholder groups, and (4) is knowledge related to levels of perceived risk
      across the stakeholder groups? A questionnaire survey was used to assess the
      trustworthiness of sources of information, perceived risk and knowledge. Four
      stakeholder groups were examined, namely (1) blood donors (n = 250), (2) general
      practitioners (n = 88), (3) anaesthetists (n = 143) and (4) medical journalists
      (n = 20). The results showed that (1) judgements of trustworthiness vary as a
      function of stakeholder groups, and (2) it is what people think they know rather
      than what they actually know that is related to judgements of trustworthiness and
      perceptions of risk. Judgements of trustworthiness are generally unrelated to
      perceptions of risk, and all stakeholder groups show optimistic bias. The
      implications of these findings for risk communication, specifically relating to
      transfusion medicine, are discussed.

PMID- 15180813
TI  - Evaluation of processing characteristics of photochemically treated pooled
      platelets: target requirements for the INTERCEPT Blood System comply with routine
      use after process optimization.
AB  - To ensure good performance of pathogen inactivation with the INTERCEPT blood
      system, specific target requirements must be met for platelet dose, volume,
      plasma content and residual red blood cells (RBCs) prior to photochemical
      treatment (PCT). A two-arm in vitro study was conducted to compare quality
      parameters of pooled platelet concentrates (PCs), either treated (test units) or
      nontreated (control units). PCs meeting European requirements were evaluated with
      reference to their compliance with INTERCEPT guard bands. Of 50 PCs (25 tests and
      25 controls) meeting European quality requirements, 24% (three test and three
      controls units) did not reach INTERCEPT requirements, particularly in terms of
      sufficient volumes and RBC contamination. The buffy-coat optimization procedure
      assessed prior to this study ensured plasma contents well within target limits of
      30 to 45%. Due to PCT-related in-process loss of 11% in volume (34.38 +/- 3.94)
      and in platelet dose (0.41 +/- 0.14), the mean platelet dose was significantly (P
      < 0.001) lower in test units: 3.1 +/- 0.3 versus 3.6 +/- 0.4 x 10(11). After
      treatment, six of the overall 25 test units (25%) would not have met the European
      guideline for platelet dose (3.0 x 10(11)). Before implementation of techniques
      for pathogen reduction, each centre should optimize processing steps during a
      validation procedure to ensure PC complying with INTERCEPT targets before and
      European targets after treatment. Besides buffy-coat optimization for sufficient
      plasma reduction, centrifugation profiles need to be optimized as well to prevent
      PC with low volumes and, in particular, with higher than acceptable RBC
      contamination.

PMID- 15180814
TI  - Transfusion-related acute lung injury caused by two donors with anti-human
      leucocyte antigen class II antibodies: a look-back investigation.
AB  - Transfusion-related acute lung injury (TRALI) is considered as one of the most
      important complications of blood transfusion. Previous look-back investigations
      have revealed unrecognized cases. We report two cases of TRALI in brief and the
      outcomes of transfusion in the recipients of previous components from the
      implicated donors. This look-back investigation was a retrospective case-note
      study assessing whether there were any untoward events associated with the
      previous transfusions. 18 patients were identified as having received a blood
      component transfusion from one of the two donors with anti-human leucocyte
      antigen (HLA) antibodies to antigens occurring frequently in the local
      population. One of the five patients receiving a unit of fresh frozen plasma had
      an evidence of TRALI, which was not diagnosed at the time. A second patient, who
      had been HLA typed and who carried a full match of antigens for the antibody
      specificities of the plasma received, had no evidence of a reaction. There were
      no documented reactions in 13 recipients of red cells in optimal additive (OA)
      solution. Cases of TRALI may go unrecognized. Not all patients with
      antibody/antigen concordance will develop clinical signs. Red cells in OA
      solution from donors with anti-HLA antibodies appear to have a low risk of
      causing clinically evident lung damage.

PMID- 15180815
TI  - Improvement in fresh frozen plasma transfusion practice: results of an outcome
      audit.
AB  - Blood components have been in use in clinical practice for many decades now. In
      spite of fairly clear guidelines regarding their use, inappropriate prescriptions
      for components are still rampant. We undertook this work to assess the
      appropriateness of fresh frozen plasma (FFP) transfusions in our hospital. A
      prospective audit of 504 transfusion orders for 1761 FFP units was conducted over
      a 6-month period which was followed by a re-audit of 294 FFP prescriptions for
      961 units. In the initial audit, we identified 304 (60.3%) prescriptions which
      were inappropriate according to the British Committee for Standardization in
      Hematology (BCSH) guidelines. The re-audit performed after an educational
      campaign among clinicians showed a reduction in inappropriate requests by 26.6%.
      The specific areas of misuse were FFP transfusions in patients with
      hypoproteinaemic states (40.5%), anaemia (36.5%), bleeding without coagulation
      factor deficiency (10.2%) and volume depletion (9.2%). A significant 50.3% of
      requests in the initial audit and 38.4% in the re-audit were for single- or two
      unit transfusions, which were subtherapeutic. FFP transfusions carry the same
      risks to the patients as any other blood component. Prescribers of these
      transfusions need to be aware of the clinical setting where their use is
      appropriate. Local hospital transfusion committees can play a vital role in
      overseeing transfusion practices to ensure optimal use of blood/component
      therapy.

PMID- 15180816
TI  - Morganella morganii causing fatal sepsis in a platelet recipient and also
      isolated from a donor's stool.
AB  - Bacterial contamination of blood products causes significant patient morbidity
      and mortality. Contaminated platelet transfusion is a frequent cause of
      bacteraemia and sepsis because of the storage conditions of platelets. A fatal
      case of Morganella morganii platelet transfusion associated with sepsis is
      described, along with procedures traced back to the isolation of M. morganii from
      a donor's stool. Molecular typing was performed, and the same M. morganii strain
      was found in blood and post-mortem organ cultures of platelet recipient and
      platelet bag and in the donor's stool. The route of contamination is unknown. The
      contamination could be due to either insufficient venipuncture site disinfection
      or the donor's transient bacteraemia. Patient died 5 days after the transfusion.

PMID- 15180817
TI  - Large volume polymerized haemoglobin solution in a Jehovah's Witness following
      abruptio placentae.
AB  - Severe anaemia, with haemoglobin (Hb) levels < or =3 g dL(-1), is associated with
      mortality rates of 50-95%. Although accepted transfusion targets have been
      debated in the literature (Carson et al., 2002; Practice guidelines for blood
      component therapy. 1996; Consensus Conference. 1988; Hebert et al., 1999), few
      would argue the risks associated with Hb levels less than 5 g dL(-1) in
      critically ill patients. In patients who are unable to receive red blood cell
      transfusions, the utility of Hb solutions is an attractive solution. We describe
      a Jehovah's Witness patient who exemplifies the marked physiologic derangements
      of severe anaemia and subsequent clinical resolution with large volume
      polymerized human Hb transfusion. The Hb-based oxygen carrier, PolyHeme, provided
      adequate oxygen transport, acting as a bridge until endogenous production could
      compensate for red cell loss. Practicing physicians need to be aware of current
      therapeutic options for use in these complicated patients.

PMID- 15180818
TI  - Annual costs of blood transfusion.

PMID- 15180820
TI  - Man, mouse and Duffy genotype-phenotype-specific pharmacokinetics of monocyte
      chemotactic protein-1.

PMID- 15180821
TI  - Prevalence of human T-cell lymphotropic virus-I/II-indeterminate reactivities in
      a Greek blood bank population.

PMID- 15180823
TI  - Regulating actin dynamics at membranes: a focus on dynamin.
AB  - Dynamin, the large guanosine triphosphatase, is generally considered to have a
      key role in deforming membranes to create tubules or vesicles. Dynamin,
      particularly dynamin2 isoforms, also are localized with actin filaments, often at
      locations where cellular membranes undergo remodeling. Perturbing dynamin
      function interferes with endocytic traffic and actin function. Thus, dynamin may
      regulate actin filaments coordinately with its activities that remodel membranes.
      This review will highlight recent observations that provide clues to mechanisms
      whereby dynamin might coordinate membrane remodeling and actin filament dynamics
      during endocytic traffic, cell morphogenesis and cell migration.

PMID- 15180824
TI  - Actin and microtubules in cell motility: which one is in control?
AB  - The cytoskeleton is composed of three distinct elements: actin microfilaments,
      microtubules and intermediate filaments. The actin cytoskeleton is thought to
      provide protrusive and contractile forces, and microtubules to form a polarized
      network allowing organelle and protein movement throughout the cell. Intermediate
      filaments are generally considered the most rigid component, responsible for the
      maintenance of the overall cell shape. Cytoskeletal elements must be coordinately
      regulated for the cell to fulfill complex cellular functions, as diverse as cell
      migration, cell adhesion and cell division. Coordination between cytoskeletal
      elements is achieved by signaling pathways, involving common regulators such as
      the Rho guanosine-5'-triphosphatases (GTPases). Furthermore, evidence is now
      accumulating that cytoskeletal elements participate in regulating each other. As
      a consequence, although their functions seem well defined, they are in fact
      overlapping, with actin playing a role in membrane trafficking and microtubules
      being involved in the control of protrusive and contractile forces. This
      cytoskeletal crosstalk is both direct and mediated by signaling molecules. Cell
      motility is a well-studied example where the interplay between actin and
      microtubules appears bidirectional. This leads us to wonder which, if any,
      cytoskeletal element leads the way.

PMID- 15180826
TI  - Novel secretory vesicle proteins essential for membrane fusion display
      extracellular-matrix domains.
AB  - Exocytotic mutants can be obtained in Paramecium that affect the organization of
      the fusion machinery, visible by electron microscopy. The site of action of the
      genes in the plasma membrane, cytosol or secretory compartment can easily be
      determined in such mutants. Functional complementation cloning of exocytotic
      mutants specifically affected in the secretory compartment, nd2-1 and nd169-1,
      reported here, and the previously studied nd7-1, led to the discovery of a set of
      novel proteins that display PSI and EGF domains, normally found in extracellular
      matrix proteins and involved in transmembrane signaling. The structure of one of
      these proteins, Nd2p, and of the product of a paralog found in the genome Nd22p,
      corresponds to that of type I membrane receptors, generally involved in protein
      and vesicle sorting. Our characterization suggests that the proteins we have
      identified are required to indicate the presence of a mature secretory vesicle to
      the plasma membrane, to prepare the machinery for fusion. We propose to name this
      novel subclass of receptors VEMIF, for Vesicular Extracellular-Matrix-like
      proteins Involved in preparing membrane Fusion.

PMID- 15180825
TI  - Chemical genetic screening identifies sulfonamides that raise organellar pH and
      interfere with membrane traffic.
AB  - Chemical genetics seeks to identify small molecules that afford functional
      dissection of cell biological pathways. Previous screens for small molecule
      inhibitors of exocytic membrane traffic yielded the identification and
      characterization of several compounds that block traffic from the Golgi to the
      cell surface as well as transport from the endoplasmic reticulum to the Golgi
      network [Feng et al. Proc Natl Acad Sci USA 2003;100:6469-6474; Yarrow et al.
      Comb Chem High Throughput Screen 2003;6:279-286; Feng et al. EMBO Reports 2004:
      in press]. Here, we screened these inhibitors for potential effects on endocytic
      membrane traffic. Two structurally related sulfonamides were found to be potent
      and reversible inhibitors of transferrin-mediated iron uptake. These inhibitors
      do not block endoplasmic reticulum-to-Golgi transport, but do disrupt Golgi-to
      cell surface traffic. The compounds are members of a novel class of sulfonamides
      that elevate endosomal and lysosomal pH, down-regulate cell surface receptors,
      and impair recycling of internalized transferrin receptors to the plasma
      membrane. In vitro experiments revealed that the sulfonamides directly inhibit
      adenosine triphosphate (ATP) hydrolysis by the V-ATPase and that they also
      possess a potent proton ionophore activity. While maintenance of organellar pH is
      known to be a critical factor in both endocytosis and exocytosis, the precise
      role of acidification, beyond the uncoupling of ligands from their receptors,
      remains largely unknown. Identification of this novel class of sulfonamide
      inhibitors provides new chemical tools to better understand the function of
      organelle pH in membrane traffic and the activity of V-ATPases in particular.

PMID- 15180827
TI  - Fractionation and characterization of kinesin II species in vertebrate brain.
AB  - Recent research on kinesin motors has outlined the diversity of the superfamily
      and defined specific cargoes moved by kinesin family (KIF) members. Owing to the
      difficulty of purifying large amounts of native motors, much of this work has
      relied on recombinant proteins expressed in vitro. This approach does not allow
      ready determination of the complement of kinesin motors present in a given
      tissue, the relative amounts of different motors, or comparison of their native
      activities. To address these questions, we isolated nucleotide-dependent,
      microtubule-binding proteins from 13-day chick embryo brain. Proteins were
      enriched by microtubule affinity purification, then subjected to velocity
      sedimentation to separate the 20S dynein/dynactin pool from a slower sedimenting
      KIF containing pool. Analysis of the latter pool by anion exchange chromatography
      revealed three KIF species: kinesin I (KIF5), kinesin II (KIF3), and KIF1C
      (Unc104/KIF1). The most abundant species, kinesin I, exhibited the expected long
      range microtubule gliding activity. By contrast, KIF1C did not move microtubules.
      Kinesin II, the second most abundant KIF, could be fractionated into two pools,
      one containing predominantly A/B isoforms and the other containing A/C isoforms.
      The two motor species had similar activities, powering microtubule gliding at
      slower speeds and over shorter distances than kinesin I.

PMID- 15180828
TI  - Amphiphysin is a component of clathrin coats formed during synaptic vesicle
      recycling at the lamprey giant synapse.
AB  - Amphiphysin is a protein enriched at mammalian synapses thought to function as a
      clathrin accessory factor in synaptic vesicle endocytosis. Here we examine the
      involvement of amphiphysin in synaptic vesicle recycling at the giant synapse in
      the lamprey. We show that amphiphysin resides in the synaptic vesicle cluster at
      rest and relocates to sites of endocytosis during synaptic activity. It
      accumulates at coated pits where its SH3 domain, but not its central clathrin/AP
      2-binding (CLAP) region, is accessible for antibody binding. Microinjection of
      antibodies specifically directed against the CLAP region inhibited recycling of
      synaptic vesicles and caused accumulation of clathrin-coated intermediates with
      distorted morphology, including flat patches of coated presynaptic membrane. Our
      data provide evidence for an activity-dependent redistribution of amphiphysin in
      intact nerve terminals and show that amphiphysin is a component of presynaptic
      clathrin-coated intermediates formed during synaptic vesicle recycling.

PMID- 15180829
TI  - pH-independent endocytic cycling of the chemokine receptor CCR5.
AB  - Following agonist activation, the chemokine receptor CCR5 is internalised through
      clathrin-coated pits and delivered to recycling endosomes. Subsequently, ligand-
      free and resensitised receptors are recycled to the cell surface. Currently
      little is known of the mechanisms regulating resensitisation and recycling of
      this G-protein coupled receptor. Here we show that raising the pH of endocytic
      compartments, using bafilomycin A, monensin or NH(4)Cl, does not significantly
      affect CCR5 endocytosis, recycling or dephosphorylation. By contrast, these
      reagents inhibited recycling of another well-characterised G protein coupled
      receptor, the beta(2)-adrenergic receptor, following agonist-induced
      internalisation. CCR5-bound RANTES (CCL5) and MIP-1beta (CCL4) only exhibit pH
      dependent dissociation at pH < 4.0, below the values normally found in endocytic
      organelles. Although receptor-agonist dissociation is not dependent on low pH,
      the subsequent degradation of released chemokine is inhibited in the presence of
      reagents that raise endosomal pH. Our data show that exposure to low pH is not
      required for RANTES or MIP-1beta dissociation from CCR5, or for recycling of
      internalised CCR5 to the cell surface.

PMID- 15180831
TI  - Radiation-induced optic neuropathy: still no treatment.

PMID- 15180830
TI  - Dense core vesicle dynamics in Caenorhabditis elegans neurons and the role of
      kinesin UNC-104.
AB  - We have developed a model system in Caenorhabditis elegans to perform genetic and
      molecular analysis of peptidergic neurotransmission using green fluorescent
      protein (GFP)-tagged IDA-1. IDA-1 represents the nematode ortholog of the
      transmembrane proteins ICA512 and phogrin that are localized to dense core
      secretory vesicles (DCVs) of mammalian neuroendocrine tissues. IDA-1::GFP was
      expressed in a small subset of neurons and present in both axonal and dendritic
      extensions, where it was localized to small mobile vesicular elements that at the
      ultrastructural level corresponded to 50 nm electron-dense objects in the
      neuronal processes. The post-translational processing of IDA-1::GFP in transgenic
      worms was dependent on the neuropeptide proprotein convertase EGL-3, indicating
      that the protein was efficiently targeted to the peptidergic secretory pathway.
      Time-lapse epifluorescence microscopy of IDA-1::GFP revealed that DCVs moved in a
      saltatory and bidirectional manner. DCV velocity profiles exhibited multiple
      distinct peaks, suggesting the participation of multiple molecular motors with
      distinct properties. Differences between velocity profiles for axonal and
      dendritic processes furthermore suggested a polarized distribution of the
      molecular transport machinery. Study of a number of candidate mutants identified
      the kinesin UNC-104 (KIF1A) as the microtubule motor that is specifically
      responsible for anterograde axonal transport of DCVs at velocities of 1.6
      microm/s-2.7 microm/s.

PMID- 15180832
TI  - The promise and challenges of personalized medicine for eye diseases.

PMID- 15180833
TI  - Panoptic versus conventional ophthalmoscope.
AB  - BACKGROUND: The 'ease of use' and accuracy in measurement of the vertical optic
      cup/disc ratio (VCDR) was compared between the conventional direct ophthalmoscope
      (CO) and Panoptic direct ophthalmoscope (PO) in a group of 'naive' first year
      medical students to determine which would be more suitable for non
      ophthalmologists. METHODS: In this quasi-randomized method comparison study,
      eight students received an introductory session on ophthalmoscopy then examined
      18 eyes (9 left, 9 right) with each ophthalmoscope in a private practice. The
      subjects were the eight students themselves plus two other subjects. Each subject
      (n = 10) had one eye dilated. Students determined a VCDR and a subjective score
      of 'ease of use' on a scale of 1 (difficult) to 10 (easy). A consultant
      ophthalmologist (GAG) determined the benchmark VCDR for each eye with each
      ophthalmoscope. RESULTS: Of 288 eye examinations, there were 111 measurements of
      VCDR using the CO (47 undilated, 64 dilated), and 140 measurements using the PO
      (75 undilated, 65 dilated). Differences in the students' estimated VCDR and the
      benchmark were similar for the CO and PO (P = 0.67). 'Ease of use' was scored in
      288 eyes and the median score was higher in the PO overall (CO: median 8, IQR 6
      9; PO median 9, IQR 8-10; P < 0.0001), and within each session (P < 0.0001 for
      each session). CONCLUSIONS: Medical students found the PO much easier to use,
      with accuracy of rating the VCDR similar to the CO. This comparison would support
      the wider use of the PO amongst medical students, general practitioners and other
      primary care providers.

PMID- 15180834
TI  - Attitudes towards and perceptions of visual loss and its causes among Hong Kong
      Chinese adults.
AB  - BACKGROUND: As part of a study of visual function among Hong Kong Chinese adults,
      their attitudes and perceptions related to visual loss were examined. These
      included fear of visual loss, negative functional impacts of visual loss, the
      relationship between ageing and visual loss and help-seeking behaviours related
      to visual loss. Demographic factors associated with these variables were also
      studied. METHODS: The study population were people aged 40 and above randomly
      selected from the Shatin district of Hong Kong. The participants underwent eye
      examinations that included visual acuity, intraocular pressure measurement,
      visual field, slit-lamp biomicroscopy and ophthalmoscopy. The primary cause of
      visual disability was recorded. The participants were also asked about their
      attitudes and perceptions regarding visual loss using a structured questionnaire.
      RESULTS: The prevalence of bilateral visual disability was 2.2% among adults aged
      40 or above and 6.4% among adults aged 60 or above. Nearly 36% of the
      participants selected blindness as the most feared disabling medical condition,
      which was substantially higher than conditions such as dementia, loss of limbs,
      deafness or aphasia. Inability to take care of oneself (21.0%), inconvenience
      related to mobility (20.2%) and inability to work (14.8%) were the three most
      commonly mentioned 'worst impact' effects of visual loss. Fully 68% of the
      participants believed that loss of vision is related to ageing. A majority of
      participants would seek help and advice from family members in case of visual
      loss. CONCLUSIONS: Visual function is perceived to be very important by Hong Kong
      Chinese adults. The fear of visual loss is widespread and particularly affects
      self-care and functional abilities. Visual loss is commonly seen as related to
      ageing. Attitudes and perceptions in this population may be modified by
      educational and outreach efforts in order to take advantage of preventive
      measures.

PMID- 15180836
TI  - Refractive status and the 5-year incidence of age-related maculopathy: the Blue
      Mountains Eye Study.
AB  - This study aimed to assess the longitudinal association between refraction and 5
      year incident age-related maculopathy (ARM) in the Blue Mountains Eye Study
      population. The dataset included 3654 participants aged 49+ (82.4% of eligible)
      examined at baseline (1992-1994), and 2335 (75.1% of survivors) examined after 5
      years. Retinal photograph grading followed the International ARM Classification.
      Incident ARM was assessed using a side-by-side comparison. Refraction was
      performed using autorefraction with subjective refinement. Spherical equivalent
      was calculated from spherical plus half the cylindrical power. After adjusting
      for age, sex and smoking, no association was found between baseline spherical
      equivalent and 5-year incident late or early ARM. Hyperopic right eyes had
      slightly higher incident rates for late (0.8%) and early (6.3%) ARM, compared
      with myopic (0.4% and 4.1%, respectively) or emmetropic (0.5% and 5.0%,
      respectively) right eyes. After multivariable adjustment, this study found no
      significant association between hyperopia and the 5-year incidence of late or
      early ARM. Left eyes or the combined data from both eyes had similar findings.

PMID- 15180835
TI  - Prospective randomized evaluation of diode-laser and cryotherapy in prethreshold
      retinopathy of prematurity.
AB  - PURPOSE: To study the efficacy of indirect diode laser photocoagulation and
      cryotherapy in prethreshold retinopathy of prematurity (ROP). METHODS: Thirty-six
      eyes of 18 premature infants less than 34 weeks gestational age and/or less than
      1600 g birth weight with prethreshold ROP were prospectively randomized to
      treatment with either indirect laser photocoagulation or cryotherapy.
      Prethreshold ROP was defined as any stage of ROP in zone I with plus disease; or
      stage 3 with three or more contiguous clock hours or five or more total clock
      hours of involvement of retina in zone II with plus disease but less than
      threshold disease. Regression of the ROP was assessed for a minimum period of 6
      months. RESULTS: Regression of ROP occurred in all 36 eyes (100%) in both groups.
      CONCLUSIONS: Excellent results are achieved if ROP is treated at the prethreshold
      stage with both indirect laser photocoagulation and cryotherapy. Although laser
      has definite advantages, cryotherapy can be considered as an alternative modality
      of treatment in developing countries due to economic reasons.

PMID- 15180837
TI  - Assessment of optic nerve head topographic parameters with a confocal scanning
      laser ophthalmoscope.
AB  - AIM: To assess the disc area, age, sex, laterality (side of the eyes) and
      refractive error dependent differences in optic nerve head topographic parameters
      in a normal population. METHODS: Optic nerve head topographic analysis of both
      eyes of 551 healthy Turkish subjects aged 11-75 years (1102 eyes) was performed
      using a confocal scanning laser ophthalmoscope, the Heidelberg Retinal Tomograph
      II (HRT II). The effects of disc size, sex, laterality (side of the eyes), age
      and refractive error on optic nerve head topographic parameters were assessed.
      Subjects were divided into three different age groups (<30 years, 30-60 years,
      >60 years) and three different disc area groups (<2.00 mm(2), 2.00-2.25 mm(2),
      >2.25 mm(2)). Disc area, topography standard deviation and a total of 12
      topographic parameters were calculated by HRT II for each subject. Statistical
      analysis was performed using Student's t-test, multiple regression analysis,
      Tukey-HSD test, anova and Pearson's correlation coefficient. RESULTS: A total of
      543 subjects (298 women and 245 men) were included in the study. The mean disc
      area of the subjects was 2.12 +/- 0.47 mm(2) (range 1.16-4.98 mm(2)). The mean
      refractive error of the subjects was -0.58 +/- 1.71 D (range -4.75 D to +4.25 D).
      The mean cup shape measure was -0.21 +/- 0.07 (95% confidence interval -0.07 to 
      0.35). The disc area was significantly correlated with all of the topographic
      parameters but two; namely, the cup shape measure and the height variation
      contour. Significant age-related differences were detected in four parameters
      (mean retinal nerve fibre layer [RNFL] thickness, disc area, cup-to-disc area
      ratio, cup area) and significant sex-related differences were detected three
      parameters (mean RNFL thickness, height variation contour, RNFL cross-sectional
      area). However, there were no significant differences in any of the parameters
      for laterality and refractive error. The parameter cup shape measure did not
      correlate with any of the five variables investigated. CONCLUSION: Cup shape
      measure was the only optic nerve head topographic parameter that was independent
      of age, sex, disc area, laterality and the refractive error. It seems to be a
      promising parameter in evaluation and comparison of the optic discs of normal
      subjects, with different disc area, age, sex, refraction error and laterality, as
      being independent of the main variation factors of the disc topography.

PMID- 15180838
TI  - Menstrual cycle dependent changes in blue-on-yellow visual field analysis of
      young diabetic women with severe non-proliferative diabetic retinopathy.
AB  - PURPOSE: To evaluate menstrual cycle dependent changes on blue-on-yellow visual
      fields of diabetic women, and to compare the results with those of healthy women.
      METHODS: Left eyes of 93 normally menstruating women were included in the study,
      comprising 45 with type-1 diabetes mellitus and severe non-proliferative diabetic
      retinopathy and 48 healthy controls. All subjects underwent baseline complete
      ocular examination and achromatic visual field analysis. Blue-on-yellow visual
      field tests (short-wavelength automated perimetry) were performed in both
      follicular (days 7-10 of the cycle) and luteal phases (days 3-6 before the
      bleeding) of two consecutive menstrual cycles. Visual field analyses were
      performed using Humphrey Field Analyser II with full threshold, central 30-2
      program. Visual fields were divided into four regions: superior temporal,
      inferior temporal, superior nasal and inferior nasal. Visual field mean
      sensitivity (MS) was calculated for all regions separately. RESULTS: The mean
      ages of diabetic and control subjects were not significantly different (P >
      0.05). Mean MS values of the diabetic group were significantly lower than that of
      the control group (P < 0.05). Control subjects did not demonstrate any menstrual
      cycle dependent changes in MS values (P > 0.05). However, diabetic women
      demonstrated a significant decrease in MS values in the luteal phase (P < 0.05).
      The decrease in MS was most marked in the nasal visual field (P < 0.05).
      CONCLUSION: Young diabetic women demonstrated a significant depression in visual
      field threshold sensitivity in the luteal phase of the menstrual cycle. Nasal
      visual fields are more prone to have menstrual cycle dependent threshold
      sensitivity depression. This should be taken into consideration in the clinical
      assessment of women with advanced diabetes who are at risk of glaucomatous optic
      neuropathy.

PMID- 15180839
TI  - Effect of check size and stimulation rate on blue-yellow multifocal visual evoked
      potentials.
AB  - BACKGROUND: To determine the effect of different stimulus frame rates and check
      sizes on blue-yellow multifocal visual evoked potentials (mVEP). METHODS:
      Subjects were examined at the Save Sight Institute at the University Sydney.
      Experiment 1 involved five adult subjects who underwent binocular stimulation by
      the Accumap multifocal objective perimeter. The eyes were stimulated with a
      cortically scaled dartboard pattern consisting of isoluminant blue and yellow
      checks. These were arranged in three concentric rings extending to an
      eccentricity of 26 degrees in the visual field. The stimulus pattern was driven
      by binary sequences resulting in pseudorandom binary exchange of two opposite
      checkerboard patterns at each of the 32 sites in the visual field. The mVEP were
      recorded at two different rates of display of the pattern stimulus. In experiment
      2, mVEP were tested on 10 normal subjects. Each of the 36 stimulation sites
      contained a checkerboard pattern of 20, 30, 42 or 56 checks/site, the stimulation
      pattern was displayed at the optimum rate found in experiment 1. The size of the
      checks was inversely proportional to the number of checks per site. RESULTS: In
      experiment 1, the slow frame rate significantly increased the average amplitude
      throughout the field tested by 50 +/- 10.1% (P = 0.001). Latency was
      significantly shortened by 6.3% (P < 0.01). In experiment 2, the average
      amplitude peaked at 30 checks per segment; however, this was only calculated to
      be significantly different from the smallest check size (F(crit range 4,27) =
      0.09 P < 0.05, anova, Tukey's T method). A similar difference was found in ring 1
      (F(crit range 4,27) = 0.09, P < 0.05, anova, Tukey's T method). In ring 2,
      however, there was also a significant difference between 56 checks and 20, 30 and
      42 (F(crit range 4,27) = 0.09, anova, P < 0.05). Altering the check sizes did not
      significantly affect the amplitudes in ring 3. The latencies were not
      significantly modified by altering check size at any eccentricity. CONCLUSIONS:
      These findings suggest that slowing the stimulation rate and displaying 30 checks
      per stimulation segment optimizes the blue-yellow mVEP stimulus.

PMID- 15180840
TI  - In vivo confocal microscopic characteristics of iridocorneal endothelial
      syndrome.
AB  - PURPOSE: To analyse five cases of iridocorneal endothelial (ICE) syndrome and
      describe the microstructural characteristics observed by in vivo confocal
      microscopy. METHODS: All five subjects presented with clinical characteristics
      suggestive of ICE syndrome and were examined clinically by Orbscan II pachymetry
      and by in vivo confocal microscopy. At least 600 sequential digital confocal
      images throughout the z-axis were analysed qualitatively and quantitatively for
      each cornea. RESULTS: Clinically, all subjects presented with: minimal to
      moderate corneal oedema, focal to diffuse 'beaten metal' appearance of the
      corneal endothelium, and varying degrees of iris atrophy. Three subjects had a
      history of elevated intraocular pressure. In vivo confocal microscopy highlighted
      two main patterns of endothelial change: small cells (mean maximal diameter of
      13.6 +/- 1.5 micro m), with indistinct borders and very bright and prominent,
      uniform nuclei (two subjects) and larger, epithelioid-like cells (mean maximal
      diameter of 26.6 +/- 5.5 micro m), with irregular borders and non-homogenous,
      diversely shaped nuclei (three subjects). Different degrees of alteration of
      stromal structure, very prominent corneal nerves and unusual syncytia of
      keratocytes were also observed. Significant oedema of the basal epithelium with
      increased reflectivity of the intercellular spaces was prominent in all cases.
      CONCLUSIONS: Although ICE syndrome is considered to be primarily an endothelial
      disease, in vivo confocal microscopy demonstrated structural alterations
      throughout the entire cornea even in clinically mild cases. The ability of in
      vivo confocal microscopy to localize and accurately measure various elements in
      different corneal layers will assist differentiation of various presentations of
      ICE syndrome as this technique becomes increasingly available in clinical
      practice.

PMID- 15180841
TI  - Increase in cataract surgery prevalence from 1992-1994 to 1997-2000: analysis of
      two population cross-sections.
AB  - BACKGROUND: Monitoring temporal changes in the demand for and provision of
      cataract surgery will be useful to health planners to meet resource needs and to
      estimate likely costs. The aim of this report was to compare the prevalence of
      cataract surgery in two population cross-sections of the Blue Mountains Eye Study
      (BMES), over an interval of around 6 years. METHODS: Cross-section I (n = 3654;
      mean age 66.2 years) consisted of BMES I participants (1992-1994). Cross-section
      II (n = 3509; mean age 66.7 years) consisted of BMES II (5-year) participants (n
      = 2335) plus persons who had moved into the area and age category since BMES I (n
      = 1174), so were newly eligible (1997-2000). Cataract surgery history was
      collected during interview and confirmed at examination. RESULTS: Over this 6
      year period, there was a 32% increase in cataract surgery prevalence from 6.0% to
      7.9%, or from 6.0% to 7.7% after age standardization. The increase in eye
      specific prevalence was 43% (from 4.4% to 6.3%). It was more marked among persons
      aged 80+ years and for bilateral (from 12.3% to 19.9%) than unilateral surgery
      (from 10.7% to 11.8%). Best-corrected visual acuity (mean letters read correctly)
      after surgery (43 and 44 letters, respectively) was similar between cross
      sections I and II. CONCLUSIONS: The findings from a representative older
      population confirm that prevalent cataract surgery has increased substantially
      over the average 6-year period, from 1992-1994 to 1997-2000.

PMID- 15180842
TI  - Effects of binocular form deprivation on the excitatory post-synaptic currents
      mediated by N-methyl-D-aspartate receptors in rat visual cortex.
AB  - PURPOSE: To investigate the effects of binocular form deprivation (BFD) on the
      excitatory post-synaptic currents (EPSCs) mediated by the N-methyl-D-aspartate
      (NMDA) receptor (NMDA-EPSCs), and the proportion of NMDA-EPSCs relative to
      glutamate receptor currents (glutamate-EPSCs) in rat visual cortex. METHODS:
      Binocular form deprivation was achieved by suturing the eyelids of Wistar rats at
      postnatal day (PD) 14, before eye-opening. Visual cortical slices (300 micro m)
      were prepared from normal and BFD Wistar rats aged PD 14, 21 and 28. Recordings
      were obtained in slices from layer II to IV using the whole-cell patch-clamp
      technique. Glutamate-EPSCs were isolated in the presence of bicuculline
      methiodide (20 micro mol/L) in the bathing medium, and NMDA-EPSCs were isolated
      with a combination of bicuculline methiodide (20 micro mol/L) and 6-cyano-7
      nitroquinoxaline-2,3-dione (CNQX, 20 micro mol/L). In addition, D,L-2-amino-5
      phosphonovalerate (AP-5, 20 micro mol/L) was applied to study the NMDA-only
      mediated currents. For each cell, the ratio of peak NMDA to glutamate EPSCs was
      calculated. RESULTS: During visual development, the decay time constant of NMDA
      EPSCs became shorter after eye-opening in normal rats (F = 5.949, P <0.05; PD 28
      vs PD 14, P = 0.027), but not in rats with BFD (P > 0.05). The weighted time
      constant of NMDA-EPSCs in the visual cortex became shorter after the rats' eyes
      were opened in the normal group (F(2,37) = 4.727, P = 0.015; PD 28 vs PD 14, P =
      0.035), but not in the BFD group (P > 0.05). However, the rise time constant and
      peak value of NMDA-EPSCs showed no significant changes in normal and BFD groups
      (P > 0.05). The ratio of NMDA-EPSCs to glutamate-EPSCs became gradually smaller
      with age in the normal rats (F = 4.661, P < 0.05; PD 28 vs PD 14, P = 0.025), but
      not in the BFD group (P > 0.05). CONCLUSIONS: These studies reveal that the
      proportion of NMDA-EPSCs relative to glutamate-EPSCs and the decay time constant
      of NMDA-EPSCs are influenced by BFD. These changes may reflect important
      experience-dependent modifications of neuronal synapses in visual cortex.

PMID- 15180843
TI  - Iris melanoma: pathology, prognosis and surgical intervention.
AB  - A case of an iris melanoma in a 58-year-old woman is described. The clinical and
      pathological findings are discussed, highlighting the correlations between
      histopathology and prognosis for iris melanoma, which differ markedly from
      choroidal melanoma. The mixed cellular pathology of this iris melanoma
      (containing both spindle B cells and epithelioid cells) carries a higher
      metastatic rate than tumours composed exclusively of either. This contrasts with
      choroidal melanoma, where the presence of epithelioid cells is the strongest
      pathological marker for a poor prognosis. The ocular outcome that can be achieved
      with local surgical excision of a well-delineated iris melanoma that does not
      involve the angle is discussed.

PMID- 15180844
TI  - Pathological features of surgically excised polypoidal choroidal vasculopathy
      membranes.
AB  - The histopathological features are reported of surgically excised specimens from
      five patients with polypoidal choroidal vasculopathy, which had been diagnosed by
      indocyanine green angiography. On stereomicroscopy, four of the five cases
      demonstrated large choroidal arterioles with an inner elastic layer. Disruption
      of the inner elastic layer and arteriosclerotic changes of the vessels were
      identified by light microscopy. Transmission electron microscopy demonstrated
      increased deposition of basement membrane-like material, together with collagen
      fibres, in the arteriolar walls. This study indicates that large choroidal
      arterioles and venules can be found in excised specimens from patients with
      polypoidal choroidal vasculopathy and arteriosclerosis is an important
      pathological feature.

PMID- 15180845
TI  - Fatigable ptosis and pseudoretraction caused by myasthenia gravis.
AB  - The case is presented of a 59-year-old woman with myasthenia gravis. Fatigable
      ptosis and pseudoretraction caused by the myasthenia gravis are illustrated in a
      series of clinical photographs.

PMID- 15180846
TI  - Myopia: precedents for research in the twenty-first century.
AB  - The myopic eye is generally considered to be a vulnerable eye and, at levels
      greater than 6 D, one that is especially susceptible to a range of ocular
      pathologies. There is concern therefore that the prevalence of myopia in young
      adolescent eyes has increased substantially over recent decades and is now
      approaching 10-25% and 60-80%, respectively, in industrialized societies of the
      West and East. Whereas it is clear that the major structural correlate of myopia
      is longitudinal elongation of the posterior vitreous chamber, other potential
      correlates include profiles of lenticular and corneal power, the relationship
      between longitudinal and transverse vitreous chamber dimensions and ocular
      volume. The most potent predictors for juvenile-onset myopia continue to be a
      refractive error </=+0.50 D at 5 years of age and family history. Significant and
      continuing progress is being made on the genetic characteristics of high myopia
      with at least four chromosomes currently identified. Twin studies and genetic
      modelling have computed a heritability index of at least 80% across the whole
      ametropic continuum. The high index does not, however, preclude an environmental
      precursor, sustained near work with high cognitive demand being the most likely.
      The significance of associations between accommodation, oculomotor dysfunction
      and human myopia is equivocal despite animal models that have demonstrated that
      sustained hyperopic defocus can induce vitreous chamber growth. Recent optical
      and pharmaceutical approaches to the reduction of myopia progression in children
      are likely precedents for future research, for example progressive addition
      spectacle lens trials and the use of the topical M1 muscarinic antagonist
      pirenzepine.

PMID- 15180847
TI  - In vivo confocal microscopy of Thygeson's superficial punctate keratitis.
AB  - A 56-year-old Chinese man diagnosed with Thygeson's keratitis by clinical
      biomicroscopy was examined using a tandem scanning confocal microscope. Among
      normal superficial epithelial cells, clumps of markedly enlarged epithelial cells
      were identified. Multiple highly reflective filamentary structures were observed
      in the deeper layers. Most of these lesions were linear; some demonstrated curled
      ends and others demonstrated branching lesions with 'sprouts'. No inflammatory
      cells were evident in the areas of corneal stroma sampled. In vivo confocal
      microscopy may be helpful in the diagnosis of Thygeson's superficial keratitis.
      To the best of our knowledge, we report the first in vivo confocal images of
      focal desquamation of epithelium and intraepithelial hyper-reflective linear
      lesions in English literature.

PMID- 15180848
TI  - Tapioca melanoma of the iris mimicking a vascular tumour: a clinicopathological
      correlation.
AB  - Although vascular iris processes are usually benign, they may be a clinical
      manifestation of iris melanoma, and this should be considered in the differential
      diagnosis. The case is reported of a 20-year-old man with a highly vascularized
      tapioca melanoma of the left iris without involvement of the anterior chamber
      angle or ciliary body, but with observed growth tendency. Sector iridectomy was
      performed 2 months after first examination. In addition, two separate floating
      tumour nodules were observed in the anterior chamber angle at 6 o'clock and were
      removed by aspiration. After 1 year follow up, no recurrence of melanoma cells
      was observed. In tapioca iris melanomas, diagnostic differentiation from
      congenital, inflammatory, vascular and neoplastic iris processes is required.
      Careful biomicroscopic examination of the iris in patients with vascular iris
      tumours may help the ophthalmologist to identify malignant iris melanomas
      (tapioca type) and plan appropriate surgical treatment.

PMID- 15180849
TI  - Optic neuropathy secondary to radiotherapy for nasal melanoma.
AB  - Optic neuropathy is a rare but important complication of radiotherapy used in the
      treatment of cancers of the head and neck, usually resulting in rapidly
      progressive blindness in one or both eyes. The case is presented of a 77-year-old
      woman with bilateral optic neuropathy resulting in blindness, secondary to
      radiotherapy for a melanoma of the nasal cavity. The onset of optic neuropathy
      occurred 9 months post-radiotherapy, at a cumulative dose of 6000 rad. The left
      eye was first involved, with the right eye becoming involved within 2 weeks.
      Despite treatment with oral anticoagulation and high dose intravenous
      methylprednisolone, there was progressive deterioration resulting in bilateral
      optic atrophy, with final visual acuities of perception of light in the right eye
      and no perception of light in the left eye. This case demonstrates that oral
      anticoagulation was ineffective in the treatment of progressive radiation-induced
      optic neuropathy.

PMID- 15180850
TI  - Visual loss despite anticoagulation in radiation-induced optic neuropathy.
AB  - Radiation therapy to the brain may produce necrosis and loss of function months
      after completion of the treatment. The case is presented of a 62-year-old man who
      developed radiation-induced optic neuropathy 2 years after treatment for a glioma
      of the left temporal lobe, despite being on anticoagulation therapy. Although
      anticoagulation appears to be beneficial in cerebral radiation necrosis, its
      usefulness in the treatment of radiation-induced optic neuropathy is unclear.

PMID- 15180851
TI  - Progressive visual loss in a patient with presumed temporal arteritis despite
      treatment: how to make the diagnosis.
AB  - Giant cell (temporal) arteritis is a severe potentially fatal systemic vasculitis
      characterized by focal involvement of the cranial arteries resulting in ischaemic
      arterial occlusion. The case is presented of a 75-year-old woman with presumed
      giant cell arteritis and normal bilateral temporal artery biopsies. Despite a
      seemingly adequate course of systemic steroid therapy, the patient developed
      sudden catastrophic vision loss. Cerebral angiography and ultrasonography were
      useful investigations to determine the most appropriate artery to biopsy to
      confirm the diagnosis of giant cell arteritis.

PMID- 15180852
TI  - Anterior uveitis in a child with Takayasu's arteritis.
AB  - Takayasu's arteritis is a rare idiopathic arteriopathy that produces narrowing
      and eventually closure of affected blood vessels. Ocular symptoms typically occur
      late in the disease process in those individuals who have severe involvement of
      the aortic arch and the carotid arteries. Visual loss typically occurs as a
      result of either systemic hypertension or concomitant ocular hypo-perfusion. We
      describe an unusual case of Takayasu's arteritis presenting in a child who
      complained of painful blurred vision. In this individual, no carotid artery
      disease was identified on vascular imaging and no evidence of impairment of
      ocular perfusion was demonstrable. Vision loss in this instance was due to
      anterior uveitis and cystoid maculopathy. These are atypical and rarely described
      features of Takayasu's arteritis. The patient responded well to anti-inflammatory
      treatment and his symptoms resolved. The clinical significance of these findings
      are discussed and the relevant literature reviewed.

PMID- 15180853
TI  - Isolated trochlear nerve palsy as a presenting feature of primary polycythemia
      rubra vera.
AB  - A case is reported where the onset of vertical diplopia secondary to a trochlear
      nerve palsy occurred as the presenting feature of polycythemia rubra vera. This
      may be the first report of an isolated trochlear nerve palsy secondary to
      polycythemia rubra vera and infarction of the fascicle or nerve.

PMID- 15180854
TI  - Central retinal vein occlusion associated with liquorice ingestion.

PMID- 15180855
TI  - AMD: to supplement or not?

PMID- 15180856
TI  - Extramedullary plasmocytoma with local amyloidosis presenting as a lump on the
      lip.

PMID- 15180857
TI  - Aortic thrombus with Aspergillus in a patient with refractory acute
      myelomonocytic leukaemia.

PMID- 15180858
TI  - Guidelines on the diagnosis and management of AL amyloidosis.

PMID- 15180859
TI  - Adverse prognostic significance of CD20 positive Reed-Sternberg cells in
      classical Hodgkin's disease.
AB  - The prognostic significance of CD20 positive classical Hodgkin's disease (cHD) is
      uncertain. All cHD cases referred to the Memorial Sloan-Kettering Cancer Center
      (MSKCC) were retrospectively identified (5/92-11/00); the samples were
      immunostained, and clinical data ascertained. Cases were re-reviewed without
      knowledge of clinical outcome. Univariate and multivariate analyses were
      performed 248 patients had cHD: 28 CD20(+) (11%); 220 CD20(-). All clinical
      characteristics were comparable except haemoglobin level at presentation. With a
      median follow-up of 29.2 months, significant prognostic factors in multivariate
      analysis were: CD20 positivity, elevated white blood cell count (WBC) and low
      absolute lymphocyte count for time-to treatment failure (TTF); and for overall
      survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and
      age >/=45 years. TTF was significantly poorer for ABVD-treated patients with
      CD20(+) cHD as compared with CD20(-) cHD. Among 167 patients treated at MSKCC,
      both TTF (P < 0.0001) and OS (P = 0.017) were significantly decreased in CD20(+)
      patients as compared with CD20(-) cHD. CD20(+) cHD is a poor prognostic factor
      for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large
      prospective trial is needed to confirm these findings.

PMID- 15180860
TI  - Novel loss-of-function mutations of the haematopoiesis-related transcription
      factor, acute myeloid leukaemia 1/runt-related transcription factor 1, detected
      in acute myeloblastic leukaemia and myelodysplastic syndrome.
AB  - AML1/RUNX1, which encodes a transcription factor essential for definitive
      haematopoiesis, is a frequent target of leukaemia-associated chromosome
      translocations. Point mutations of this gene have also recently been associated
      with leukaemia and myelodysplastic syndrome (MDS). To further define the
      frequency and biological characteristics of AML1 mutations, we have examined 170
      cases of such diseases. Mutations within the runt-domain were identified in five
      cases: one of de novo acute myeloid leukaemia (AML) and four of MDS. Where
      multiple time point samples were available, mutations were detected in the
      earliest samples, which persisted throughout the disease course. Of the five
      mutations, one was a silent mutation, two were apparent loss-of-function
      mutations caused by N-terminal truncation, and two were insertions, I150ins and
      K168ins, which preserved most of the AML1 DNA-binding domain. Both AML1 molecules
      with insertion mutations were non-functional in that they were unable to rescue
      haematological defects in AML1-deficient mouse embryonic stem cells. In addition,
      activating mutations of N-ras, deletion of chromosome 12p, or inactivation of
      TP53 accompanied some of the AML1 mutations. Together, these observations
      strongly suggest that one-allele inactivation of AML1 serves as an initial or
      early event that plays an important role in the eventual development of overt
      diseases with additional genetic alterations.

PMID- 15180861
TI  - Phenotypic and functional characterization of monocyte-derived dendritic cells in
      chronic lymphocytic leukaemia patients: influence of neoplastic CD19 cells in
      vivo and in vitro.
AB  - Dendritic cells (DCs) are the most potent antigen-presenting cells and are
      therefore an attractive option as antigen carriers in vaccination protocols.
      Chronic lymphocytic leukaemia (CLL) represents a potential good target for these
      approaches. The present study was designed to investigate the feasibility of
      generating in vitro fully functional DCs from peripheral blood (PB) monocytes of
      CLL patients at different phases of the disease. Although functional DCs could be
      obtained from CLL samples, in patients with active disease the expression of some
      co-stimulatory molecules appeared to be reduced. In contrast, DCs from CLL
      patients in remission showed no difference from those of normal controls.
      Moreover, patients with active disease produced DCs with reduced allostimulatory
      ability when compared with normal ones, whereas the functional capacities
      appeared to be restored in CLL DCs from remission patients. To more precisely
      assess the possible inhibitory effect of CLL cells on DC development, the
      influence of autologous leukaemic CD19(+) cells on the generation of monocyte
      derived CLL DCs in vitro was investigated. The addition of CLL neoplastic cells
      markedly affected monocyte-derived DC maturation. In conclusion, monocytes from
      CLL patients with active disease give rise to DCs, which show phenotypic and
      functional defects that are not observed in remission CLL patients. These results
      need to be taken into account in the design of DC-based immunotherapeutic
      approaches in CLL.

PMID- 15180862
TI  - Microarray transcript profiling distinguishes the transient from the acute type
      of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a
      specific discriminating marker.
AB  - Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing
      neoplasia specific to Down's syndrome (DS), affecting up to 10% of DS neonates.
      In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia
      (AMKL) at 2-4 years of age. The TMD and AMKL blasts are morphologically and
      immuno-phenotypically identical, and have the same acquired mutations in GATA1.
      We performed transcript profiling of nine TMD patients comparing them with seven
      AMKL patients using Affymetrix HG-U133A microarrays. Similar overall transcript
      profiles were observed between the two conditions, which were only separable by
      supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified
      the expression of selected differing genes, with statistical significance (P <
      0.05) by Student's t-test. The Taqman differences were also reproduced on TMD and
      AMKL blasts sorted by a fluorescence-activated cell sorter. Among the significant
      differences, CDKN2C, the effector of GATA1-mediated cell cycle arrest, was
      increased in AMKL but not TMD, despite the similar level of GATA1. In contrast,
      MYCN (neuroblastoma-derived oncogene) was expressed in TMD at a significantly
      greater level than in AMKL. MYCN has not previously been described in
      leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific
      marker for AMKL blasts, with no expression in TMD. This study provides markers
      discriminating TMD from AMKL-M7 in DS. These markers have the potential as
      predictive, diagnostic and therapeutic targets. In addition, the study provides
      further clues into the pathomechanisms discerning self-regressive from the
      progressive phenotype.

PMID- 15180863
TI  - Either interleukin-12 or interferon-gamma can correct the dendritic cell defect
      induced by transforming growth factor beta in patients with myeloma.
AB  - The poor response to immunotherapy in patients with multiple myeloma (MM)
      indicates that a better understanding of any defects in the immune response in
      these patients is required before effective therapeutic strategies can be
      developed. Recently we reported that high potency (CMRF44(+)) dendritic cells
      (DC) in the peripheral blood of patients with MM failed to significantly up
      regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in
      response to an appropriate signal from soluble trimeric human CD40 ligand. This
      defect was caused by transforming growth factor beta(1) (TGFbeta(1)) and
      interleukin (IL)-10, produced by malignant plasma cells, and the defect was
      neutralized in vitro with anti-TGFbeta(1). As this defect could impact on
      immunotherapeutic strategies and may be a major cause of the failure of recent
      trials, it was important to identify a more clinically useful agent that could
      correct the defect in vivo. In this study of 59 MM patients, the relative and
      absolute numbers of blood DC were only significantly decreased in patients with
      stage III disease and CD80 up-regulation was reduced in both stage I and stage
      III. It was demonstrated that both IL-12 and interferon-gamma neutralized the
      failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause
      a change in the distribution of DC subsets that were predominantly myeloid
      (CD11c+ and CDw123-) suggesting that there would be a predominantly T-helper cell
      type response. The addition of IL-12 or interferon-gamma to future immunotherapy
      trials involving these patients should be considered.

PMID- 15180864
TI  - Haematopoetic stem cell transplantation for refractory autoimmune cytopenia.
AB  - This study describes the outcome of patients receiving haematopoietic stem cell
      transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The
      registry of the European Group of Blood and Marrow Transplantation holds data on
      36 patients receiving 38 transplants, the first transplant was autologous for 27
      and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia
      (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5);
      immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4;
      allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or
      thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding
      disease having failed multiple prior treatments. Among 26 evaluable patients
      mobilized for autologous HSCT, three died of treatment-related causes, one died
      of disease progression, seven were non-responders, six patients had transient
      responses and nine had continuous partial or complete remission. Of the seven
      evaluable patients receiving allogeneic HSCT, one died of treatment-related
      complications, one with transient response died of progressive disease and five
      had a continuous response. Autologous and allogeneic HSCT may induce a response
      in a subset of patients with autoimmune cytopenia of long duration albeit at the
      price of considerable toxicity.

PMID- 15180866
TI  - Treatment of isolated central nervous system relapse in high-risk lymphoid
      malignancy with allogeneic bone marrow transplantation and extended intrathecal
      therapy.
AB  - We performed allogeneic bone marrow transplantation (BMT) with an extended period
      of post-transplant intrathecal (IT) chemotherapy for five patients with acute
      lymphoblastic leukaemia and non-Hodgkin's lymphoma who had relapsed in the
      central nervous system either in the very early phase or more than twice. Post
      transplant IT was scheduled for a total of 12 doses over 18 months. One patient
      was found to have subclinical leucoencephalopathy. Disease relapse occurred in
      one patient and the other patients remained in complete remission for 39-196
      months post-BMT. The estimated event-free survival was 80 +/- 17.9% (standard
      error).

PMID- 15180865
TI  - Etoposide, methylprednisolone, cytarabine and cisplatin successfully cytoreduces
      resistant myeloma patients and mobilizes them for transplant without adverse
      effects.
AB  - Myeloma remains incurable with a median survival of 4 years, but outcome can be
      improved by the use of high-dose therapy. We used the etoposide,
      methylprednisolone, cytarabine and cisplatin (ESHAP) regimen as second-line
      therapy in 42 newly diagnosed myeloma patients who had failed vincristine,
      adriamycin and dexamethasone (VAD)- type therapy (n = 36), responded to first
      line treatment but persisted in having significant residual marrow plasmacytosis
      (n = 5) or failed prior stem cell harvesting (n = 1), with the dual aim of
      improving disease response and mobilizing peripheral blood stem cells. Fourteen
      of 21 (67%) patients with no change or progressive disease after VAD responded to
      ESHAP; seven of 12 (58%) patients with minor response converted to partial
      response. Marrow plasmacytosis fell from a median of 52% at diagnosis to 23.5%
      after primary therapy and to15% after ESHAP. ESHAP chemotherapy was well
      tolerated. There were 11 admissions due to febrile neutropenia (n = 7), nausea
      and vomiting (n = 2), pneumonia (n = 1) and perforated bowel (n = 1). Renal
      function deteriorated in 13 of 42 patients after ESHAP, but none required renal
      support. ESHAP mobilization was performed in 32 patients of whom 87% achieved a
      CD34(+) yield >2 x 10(6)/kg. In all, 38 patients proceeded to high-dose therapy.
      The overall survival for all patients was 62% at 4 years following ESHAP. We
      conclude that ESHAP has acceptable toxicity and efficient stem cell mobilizing
      capability, effectively cytoreduced this chemoresistant group of patients, and
      did not appear to adversely affect transplant outcome.

PMID- 15180867
TI  - Interest of transjugular liver biopsy in adult patients with haemophilia or other
      congenital bleeding disorders infected with hepatitis C virus.
AB  - Liver histology is important for prognosis and treatment strategy in patients
      with hepatitis C. We report a 10-year experience of transjugular liver biopsy
      (TJLB) in patients with haemophilia and other congenital bleeding disorders (CBD)
      in terms of safety, efficiency and therapeutic consequences. TJLB was proposed to
      patients who were regularly followed for CBD, and were hepatitis C virus (HCV)
      positive by polymerase chain reaction. Patients with inhibitors or who were human
      immunodeficiency virus (HIV) positive with CD4 cells <0.2 x 10(9)/l or with
      evidence of liver failure were excluded. TJLB was performed during a short
      hospitalization with factor replacement. Between 1992 and 2002, 88 TJLB were
      performed in 69 of 151 adult HCV patients (39% HIV positive). CBD was haemophilia
      A in 68% and haemophilia B in 24%. Few mild adverse events were recorded.
      Histology was assessable in 78 of 88 procedures (89%). Twenty-nine (37%) cases
      demonstrated minimal change (METAVIR A </= 1 and F </= 1). Extended fibrosis or
      cirrhosis was recorded in 23 procedures (26%), all in patients whose infection
      period was longer than 20 years. No relationship between liver histology, HIV
      status or HCV genotype was found. TJLB appears to be safe and useful in HCV
      patients with CBD. One-third of patients had minimal histological changes and
      could avoid systematic anti-HCV treatment.

PMID- 15180868
TI  - Platelet degranulation and monocyte-platelet complex formation are increased in
      the acute and convalescent phases after ischaemic stroke or transient ischaemic
      attack.
AB  - Flow cytometric studies suggest that platelets are activated in ischaemic stroke
      or transient ischaemic attack (TIA). However, few studies have measured
      circulating leucocyte-platelet complexes in this patient population. Whole blood
      flow cytometry was used to quantify the expression of CD62P-, CD63-, and PAC1
      binding, and the percentages of leucocyte-platelet complexes in acute (1-27 d, n
      = 79) and convalescent (79-725 d, n = 70) ischaemic cerebrovascular disease (CVD)
      patients compared with controls without CVD (n = 27). We performed a full blood
      count, and measured plasma levels of soluble P-selectin, soluble E-selectin, and
      von Willebrand factor antigen (VWF:Ag) as additional markers of platelet and/or
      endothelial cell activation. The median percentage CD62P expression and the
      median percentage monocyte-platelet complexes were higher in both acute and
      convalescent CVD patients than controls (P </= 0.02). The mean white cell count
      and mean VWF:Ag levels were significantly elevated in the acute and convalescent
      phases after ischaemic stroke or TIA (P </= 0.02). Otherwise, there was no
      significant increase in any other marker of platelet or endothelial activation in
      CVD patients. There was a positive correlation between the percentage expression
      of CD62P and the percentages of both neutrophil-platelet and monocyte-platelet
      complexes in the acute phase, and the percentages of all leucocyte-platelet
      complexes in the convalescent phase after ischaemic CVD. This study provides
      evidence for ongoing excessive platelet and/or endothelial activation in
      ischaemic CVD patients despite treatment with antithrombotic therapy.

PMID- 15180869
TI  - Anti-sickling effect of MX-1520, a prodrug of vanillin: an in vivo study using
      rodents.
AB  - Vanillin, a food additive, covalently binds with sickle haemoglobin (Hb S),
      inhibits cell sickling and shifts the oxygen equilibrium curve towards the left.
      These effects would potentially benefit patients with sickle cell disease (SCD).
      However, vanillin has no therapeutic effect if given orally because orally
      administered vanillin is rapidly decomposed in the upper digestive tract. To
      overcome this problem, a vanillin prodrug, MX-1520, which is biotransformed to
      vanillin in vivo, was synthesized. Studies using transgenic sickle mice, which
      nearly exclusively develop pulmonary sequestration upon exposure to hypoxia,
      showed that oral administration of MX-1520 prior to hypoxia exposure
      significantly reduced the percentage of sickled cells in the blood. The survival
      time under severe hypoxic conditions was prolonged from 6.6 +/- 0.8 min in
      untreated animals to 28.8 +/- 12 min (P < 0.05) and 31 +/- 7.5 min (P < 0.05) for
      doses of 137.5 and 275 mg/kg respectively. Intraperitoneal injection of MX-1520
      to bypass possible degradation in the digestive tract showed that doses as low as
      7 mg/kg prolonged the survival time and reduced the percentage of sickled cells
      during hypoxia exposure. These results demonstrate the potential for MX-1520 to
      be a new and safe anti-sickling agent for patients with SCD.

PMID- 15180870
TI  - Four new cases of stomatin-deficient hereditary stomatocytosis syndrome:
      association of the stomatin-deficient cryohydrocytosis variant with neurological
      dysfunction.
AB  - This report concerns congenitally Na(+)-K(+) leaky red cells of the 'hereditary
      stomatocytosis' class. Three new isolated cases and one new pedigree are
      described, and one previously reported case is expanded. In all cases, Western
      blotting of red cell membranes revealed a deficiency in the 32 kDa membrane
      protein, stomatin. All showed pronounced cation leaks at 37 degrees C with
      markedly abnormal intracellular Na(+) and K(+) concentrations, like all other
      such stomatin-deficient cases. Consistent with recent findings in two previously
      described British pedigrees, immunocytochemistry demonstrated that the deficiency
      of stomatin was not complete. On typical blood films, some red cells showed
      positive stomatin immunoreactivity, while most were negative, although in one
      case only a minority were negative. All platelets and neutrophils were stomatin
      positive. The cases differed markedly between themselves with regard to the
      temperature dependence of the passive leak to K(+). Three showed a simple
      monotonic temperature dependence, while two showed a minimum at around 20-25
      degrees C, such that the cells were extremely leaky at 0 degrees C, giving the
      phenotype known as 'cryohydrocytosis'. These patients are the only two known
      cases of stomatin-deficient cryohydrocytosis. Both showed a congenital syndrome
      of mental retardation, seizures, cataracts and massive hepatosplenomegaly,
      probably defining a new haemato-neurological syndrome.

PMID- 15180871
TI  - Elevated circulating endothelial membrane microparticles in paroxysmal nocturnal
      haemoglobinuria.
AB  - We analysed endothelial cell membrane microparticles (ECMP) in the peripheral
      blood of patients with paroxysmal nocturnal haemoglobinuria (PNH) (n = 9),
      aplastic anaemia (AA) (n = 10), sickle cell disease (SCD) (n = 8), and healthy
      donors (HD) (n = 11). There was no clinically manifested thrombosis in the PNH or
      AA group, except one cured thrombophlebitis (PNH), while all SCD patients had a
      history of vaso-occlusive crises. We used three-colour flow cytometry with blood
      cell-specific antibodies and antibodies to endothelial antigens CD105 and CD144.
      Phosphatidylserine-positive microparticles were detected using the annexin V
      binding (AVB) assay. The population of CD105+AVB+ ECMP was significantly (P <
      0.05) higher in SCD (median: 0.568 x 10(9)/l; 25-75th percentile range: 0.351
      0.976 x 10(9)/l) and PNH (0.401 x 10(9)/l; 0.19-0.441 x 10(9)/l) patients when
      compared with AA (0.122 x 10(9)/l; 0.061-0.172 x 10(9)/l) or HD (0.180 x 10(9)/l;
      0.137-0.217 x 10(9)/l) group. Even more pronounced differences were observed in
      ECMP exhibiting a marker of inflammatory stimulation CD54 (CD105+CD54+).
      Similarly, ECMP that exhibited endothelial specific and proteolysis-sensitive
      antigen CD144 were increased in SCD and PNH, but not in AA. Elevated CD54+ ECMP
      may reflect the inflammatory status of endothelial cells in SCD and PNH, while
      CD144+ ECMP could indicate continuous endothelial stimulation and/or injury.
      Analysis of circulating ECMP appears promising to provide useful information on
      the status of the vascular endothelium in PNH and SCD.

PMID- 15180872
TI  - Biological and clinical features of T-biphenotypic acute leukaemia: report from a
      single centre.

PMID- 15180873
TI  - Association of the 1513C polymorphism in the P2X7 gene with familial forms of
      chronic lymphocytic leukaemia.

PMID- 15180874
TI  - Severe factor XI deficiency caused by compound heterozygosity.

PMID- 15180875
TI  - Long-term improvement of anaemia in a patient with aplastic anaemia by short-term
      administration of pegylated recombinant human megakaryocyte growth and
      development factor.

PMID- 15180877
TI  - British Association of Dermatologists, 84th Annual Meeting, 6-9 July 2004,
      Belfast, United Kingdom. Abstracts.

PMID- 15180890
TI  - Roles of B cells in rheumatoid arthritis.
AB  - B lymphocytes play several critical roles in the pathogenesis of rheumatoid
      arthritis. They are the source of the rheumatoid factors and anticitrullinated
      protein antibodies, which contribute to immune complex formation and complement
      activation in the joints. B cells are also very efficient antigen-presenting
      cells, and can contribute to T cell activation through expression of
      costimulatory molecules. B cells both respond to and produce the chemokines and
      cytokines that promote leukocyte infiltration into the joints, formation of
      ectopic lymphoid structures, angiogenesis, and synovial hyperplasia. The success
      of B cell depletion therapy in rheumatoid arthritis may depend on disruption of
      all these diverse functions.

PMID- 15180891
TI  - Targeting B cells for the treatment of rheumatoid arthritis.
AB  - The role of B cells in rheumatoid arthritis (RA) has been debated for decades.
      However, recent clinical trial data indicating that depletion of B cells in RA
      patients is of therapeutic benefit has validated the importance of this cell type
      in the pathogenesis of the disease. Elucidation of the molecular basis of B cell
      development and activation has allowed the identification of a number of possible
      therapeutic targets that are appealing for drug development. This review
      discusses briefly a number of these molecules and the rationale for targeting
      them for the treatment of RA.

PMID- 15180892
TI  - Safety of rituximab in the treatment of B cell malignancies: implications for
      rheumatoid arthritis.
AB  - The chimeric anti-CD20 monoclonal antibody rituximab has been used extensively in
      the treatment of B cell malignancies, and more recently it has emerged as a
      potential treatment for rheumatoid arthritis (RA), via selective B lymphocyte
      depletion. Experience in oncology shows that rituximab is well tolerated in a
      variety of settings, with mild-to-moderate infusion related reactions following
      the first infusion being the most common adverse event. Current data suggest that
      the safety profile of rituximab in patients with RA is similar to that in
      oncology, but that the adverse events are less frequent and less severe in
      patients with RA.

PMID- 15180893
TI  - B cell depletion in autoimmune disease.
AB  - The CD20 cell marker appears early in the process of B cell development. In this
      review we focus on the results of attempts to utilize B cell depletion based on
      the use of a chimeric monoclonal antibody (MAb) specific for human CD20,
      rituximab, for the treatment of patients with autoimmune diseases. In 1997,
      rituximab was approved for the treatment of low-grade B cell non-Hodgkin's
      lymphoma. Following these encouraging results, rituximab started to be used
      experimentally in other diseases presumed to be due to B cell pathology. The
      first autoimmune disease to be treated effectively was chronic idiopathic
      thrombocytopaenia. More recent success has been demonstrated in patients with
      rheumatoid arthritis and systemic lupus erythematosus.

PMID- 15180894
TI  - B cell abnormalities in systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease
      characterized by the differentiation of short- and long-lived immunoglobulin
      secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal
      centers and plasma cells secreting autoantibodies have been observed in lupus
      nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes
      that affect differentiation and survival of plasma cells, such as those that
      influence activation, proliferation, cytokine and chemokine
      secretion/responsiveness, and apoptosis of the T and B cells that are involved in
      humoral immunity generated in germinal centers, as well as genes that are
      involved in presentation and clearance of apoptotic material and autoantigens by
      antigen presenting cells and other phagocytes. Emerging data have demonstrated
      that B lymphocytes are active participants in humoral immune responses that lead
      to T-dependent and T-independent differentiation of immunoglobulin-secreting
      plasma cells by homotypic CD154-CD40 interactions as well as continued
      stimulation by B cell activating factor through B cell maturation antigen, B cell
      activating factor receptor and transmembrane activater.

PMID- 15180896
TI  - Pseudomyxoma extraperitonei occurring 35 years after appendicectomy: a case
      report and review of literature.
AB  - BACKGROUND: Pseudomyxoma peritonei is a rare condition consisting of mucinous
      ascites, most commonly arising from mucinous tumors of the appendix and
      occasionally from the ovary. Very rarely mucinous implants arise in the
      retroperitoneum without any intra-peritoneal involvement. This has been termed as
      pseudomyxoma extraperitonei. CASE PRESENTATION: We report a case of a 57 year old
      man who developed pseudomyxoma extraperitonei, 35 years after undergoing an
      appendicectomy for a perforated appendix. CONCLUSIONS: Pseudomyxoma
      extraperitonei has been previously reported, however we report the longest
      incubation period of 35 years for this condition.

PMID- 15180895
TI  - Post-ovulatory ageing and egg quality: a proteomic analysis of rainbow trout
      coelomic fluid.
AB  - BACKGROUND: In fish, oocyte post-ovulatory ageing is associated with egg quality
      decrease. During this period, eggs are held in the body cavity where they bath in
      a semi-viscous liquid known as coelomic fluid (CF). CF components are suspected
      to play a role in maintaining oocyte fertility and developmental competence (egg
      quality). However, CF proteic composition remains poorly studied. Thus rainbow
      trout CF proteome was studied during the egg quality decrease associated with
      oocyte post-ovulatory ageing. METHODS: High resolution two-dimensional gel
      electrophoresis was used to analyze the proteome of rainbow trout (Oncorhynchus
      mykiss) CF in relationship with the egg quality decrease associated with oocyte
      post-ovulatory ageing. A first experiment was performed using CF pools
      originating from 17 females sampled at ovulation as well as 7, 14 and 21 days
      later. These observations were verified using a second set of CF pools
      originating from 22 females sampled 5 and 16 days following ovulation. RESULTS:
      Approximately 200 protein spots of 10-105 kDa molecular mass and 3-10 pI were
      detected in CF samples. Several protein spots, while undetected at the time of
      ovulation, exhibited a progressive and strong accumulation in CF during post
      ovulatory ageing. After silver-staining and Matrix-Assisted Laser Desorption Time
      Of Flight (MALDI-TOF) mass spectrometer analysis, some of these protein spots
      were identified as lipovitellin II fragments. CONCLUSIONS: These observations
      suggest that egg protein fragments accumulate in the CF during the post-ovulatory
      period and could therefore be used to detect egg quality defects associated with
      oocyte post-ovulatory ageing.

PMID- 15180898
TI  - Geovisualization to support the exploration of large health and demographic
      survey data.
AB  - BACKGROUND: Survey data are increasingly abundant from many international
      projects and national statistics. They are generally comprehensive and cover
      local, regional as well as national levels census in many domains including
      health, demography, human development, and economy. These surveys result in
      several hundred indicators. Geographical analysis of such large amount of data is
      often a difficult task and searching for patterns is particularly a difficult
      challenge. Geovisualization research is increasingly dealing with the exploration
      of patterns and relationships in such large datasets for understanding underlying
      geographical processes. One of the attempts has been to use Artificial Neural
      Networks as a technology especially useful in situations where the numbers are
      vast and the relationships are often unclear or even hidden. RESULTS: We
      investigate ways to integrate computational analysis based on a Self-Organizing
      Map neural network, with visual representations of derived structures and
      patterns in a framework for exploratory visualization to support visual data
      mining and knowledge discovery. The framework suggests ways to explore the
      general structure of the dataset in its multidimensional space in order to
      provide clues for further exploration of correlations and relationships.
      CONCLUSION: In this paper, the proposed framework is used to explore a
      demographic and health survey data. Several graphical representations
      (information spaces) are used to depict the general structure and clustering of
      the data and get insight about the relationships among the different variables.
      Detail exploration of correlations and relationships among the attributes is
      provided. Results of the analysis are also presented in maps and other graphics.

PMID- 15180897
TI  - Cardiovascular disease risk factors among children of different socioeconomic
      status in Istanbul, Turkey: directions for public health and nutrition policy.
AB  - OBJECTIVES: The aim of the current study was to examine the influence of
      socioeconomic status (SES) on physiological (lipid profile, obesity indices) and
      behavioral (dietary habits, physical activity) cardiovascular disease (CVD) risk
      factors among primary schoolchildren in Istanbul. DESIGN: Cross sectional study.
      SETTING: One private school and two public schools from different SES districts
      in Istanbul. PARTICIPANTS: 510 randomly selected children aged 12 and 13 years
      old (257 boys, 253 girls). RESULTS: The prevalence of overweight (15.2%) and the
      energy intake (p < 0.001 and p < 0.05 for boys and girls respectively) were found
      to be higher for the middle/high SES group for both genders. Regarding
      biochemical indices, middle/high SES children had higher values of High Density
      Lipoprotein-cholesterol (HDL-C) (p < 0.001 and p < 0.05 for boys and girls
      respectively) and lower values of TC/HDL-C ratio and LDL-C/HDL-C ratio (p < 0.05
      and p < 0.001 for boys and girls respectively). This could be attributed to the
      higher physical activity levels observed for middle/ high SES children (p <
      0.001). CONCLUSION: The findings of the current study revealed a coexistence of
      both overweight and higher energy intake in middle/high SES children, as well as
      a coexistence of underweight and lower physical activity levels in low SES
      children. These observations should guide the public health policy in developing
      appropriate intervention strategies to efficiently tackle these health and social
      issues early in life.

PMID- 15180899
TI  - Simultaneous storage of medical images in the spatial and frequency domain: a
      comparative study.
AB  - BACKGROUND: Digital watermarking is a technique of hiding specific identification
      data for copyright authentication. This technique is adapted here for
      interleaving patient information with medical images, to reduce storage and
      transmission overheads. METHODS: The patient information is encrypted before
      interleaving with images to ensure greater security. The bio-signals are
      compressed and subsequently interleaved with the image. This interleaving is
      carried out in the spatial domain and Frequency domain. The performance of
      interleaving in the spatial, Discrete Fourier Transform (DFT), Discrete Cosine
      Transform (DCT) and Discrete Wavelet Transform (DWT) coefficients is studied.
      Differential pulse code modulation (DPCM) is employed for data compression as
      well as encryption and results are tabulated for a specific example. RESULTS: It
      can be seen from results, the process does not affect the picture quality. This
      is attributed to the fact that the change in LSB of a pixel changes its
      brightness by 1 part in 256. Spatial and DFT domain interleaving gave very less
      %NRMSE as compared to DCT and DWT domain. CONCLUSION: The Results show that
      spatial domain the interleaving, the %NRMSE was less than 0.25% for 8-bit encoded
      pixel intensity. Among the frequency domain interleaving methods, DFT was found
      to be very efficient.

PMID- 15180900
TI  - Statics and dynamics of malaria infection in Anopheles mosquitoes.
AB  - The classic formulae in malaria epidemiology are reviewed that relate
      entomological parameters to malaria transmission, including mosquito survivorship
      and age-at-infection, the stability index (S), the human blood index (HBI),
      proportion of infected mosquitoes, the sporozoite rate, the entomological
      inoculation rate (EIR), vectorial capacity (C) and the basic reproductive number
      (R0). The synthesis emphasizes the relationships among classic formulae and
      reformulates a simple dynamic model for the proportion of infected humans. The
      classic formulae are related to formulae from cyclical feeding models, and some
      inconsistencies are noted. The classic formulae are used to to illustrate how
      malaria control reduces malaria transmission and show that increased mosquito
      mortality has an effect even larger than was proposed by Macdonald in the 1950's.

PMID- 15180901
TI  - Ionic self-complementarity induces amyloid-like fibril formation in an isolated
      domain of a plant copper metallochaperone protein.
AB  - BACKGROUND: Arabidopsis thaliana copper metallochaperone CCH is a functional
      homologue of yeast antioxidant ATX1, involved in cytosolic copper transport. In
      higher plants, CCH has to be transported to specialised cells through
      plasmodesmata, being the only metallochaperone reported to date that leaves the
      cell where it is synthesised. CCH has two different domains, the N-terminal
      domain conserved among other copper-metallochaperones and a C-terminal domain
      absent in all the identified non-plant metallochaperones. The aim of the present
      study was the biochemical and biophysical characterisation of the C-terminal
      domain of the copper metallochaperone CCH. RESULTS: The conformational behaviour
      of the isolated C-domain in solution is complex and implies the adoption of mixed
      conformations in different environments. The ionic self-complementary peptide
      KTEAETKTEAKVDAKADVE, derived from the C-domain of CCH, adopts and extended
      conformation in solution with a high content in beta-sheet structure that induces
      a pH-dependent fibril formation. Freeze drying electron microscopy studies
      revealed the existence of well ordered amyloid-like fibrils in preparations from
      both the C-domain and its derivative peptide. CONCLUSION: A number of proteins
      related with copper homeostasis have a high tendency to form fibrils. The
      determinants for fibril formation, as well as the possible physiological role are
      not fully understood. Here we show that the plant exclusive C-domain of the
      copper metallochaperone CCH has conformational plasticity and forms fibrils at
      defined experimental conditions. The putative influence of these properties with
      plant copper delivery will be addressed in the future.

PMID- 15180902
TI  - Adult Wilms' tumor with calcification untreated for 5 years--a case report.
AB  - BACKGROUND: Wilms' tumor is rarely found in adults and there are no established
      treatment guidelines for such tumors in adults. Whereas calcification is a common
      finding in neuroblastoma, it is considered uncommon in Wilms' tumor. CASE
      PRESENTATION: We report a case of adult Wilms' tumor with calcification in a 22
      year-old man. He had been initially referred to our hospital with a chief
      complaint of right flank pain 5 years previously, when abdominal computed
      tomography had revealed focal calcification at the upper pole of the right
      kidney. Although we planned further assessment, he did not revisit our hospital
      again until 5 years later, again because of right flank pain. Ultrasound and
      computed tomography scan revealed a large mass lesion with calcification in the
      right kidney, invasive to the hepatic lobe. The patient underwent curative right
      nephrectomy and partial right hepatic lobectomy. Pathological analysis
      demonstrated a nephroblastoma (Wilms' tumor) with predominant epithelial
      histology infiltrating the hepatic lobe. The patient has been well without tumor
      recurrence for 15 months after surgery. CONCLUSIONS: Calcification may be a sign
      of slow tumor growth and possibly a favorable prognosis in cases of adult Wilms'
      tumor.

PMID- 15180903
TI  - Seasonality and trend in blood lead levels of New York State children.
AB  - BACKGROUND: Environmental exposure to lead remains a significant health problem
      for children. The costs of lead exposure in children are estimated to be
      considerably more than other childhood diseases of environmental origin. While
      long-term trends in blood lead levels (BLLs) among children are declining,
      seasonal variation persists. Cross-sectional studies have found a peak in summer
      months. Part of this variation may be due to increased exposure to lead paint on
      window sills and through increased contact with soils containing lead during the
      summer. The current study represents the largest published population-based study
      on seasonality and trends in the BLLs of children to date. In addition, the
      results offer a comparison of recent data on seasonality of BLLs in New York
      State children, to studies conducted over the past three decades. METHODS:
      262,687 New York State children born between 1994 and 1997 were screened for
      blood lead within 2 weeks of their first or second birthdays. Time series
      analyses of blood lead data from these children were conducted to study the
      seasonality and trends of BLLs. RESULTS: Children's blood lead values showed a
      distinct seasonal cycle on top of a long-term decreasing trend. The geometric
      mean BLL declined by about 24% for children born between 1994 and 1997. The
      prevalence of elevated BLLs in two-year-olds was almost twice that in one-year
      olds over the time period. Nearly twice as many children had elevated BLLs in the
      late summer compared to late winter/early spring. In this and previous cross
      sectional studies, the amount of seasonality as a proportion of the mean ranged
      between 15% and 30%. CONCLUSION: Pediatricians should be aware of the seasonality
      of BLLs. For example, if a two-year-old receives a borderline result during the
      winter, it is possible that the levels would have been higher if he had been
      tested during the summer. However, physicians should continue to screen children
      at their normally scheduled well-child visits rather than delaying until
      summertime and possibly postponing the discovery of an elevated BLL. Age, season,
      and time trends still need to be considered in lead studies and result
      interpretation.

PMID- 15180904
TI  - Autoantibodies against retinal proteins in paraneoplastic and autoimmune
      retinopathy.
AB  - BACKGROUND: Autoimmune retinal degeneration may occur in patients who present
      with sudden or, less commonly, subacute loss of vision of retinal origin,
      associated with an abnormal ERG, through the action of autoantibodies against
      retinal proteins. Often the patients are initially diagnosed with or suspected of
      having a paraneoplastic retinopathy (PR), such as cancer-associated retinopathy
      (CAR). However, there is limited information on the occurrence, the specificity
      of autoantibodies in these patients, and their association with clinical
      symptoms. METHODS: Sera were obtained from 193 retinopathy patients who presented
      with clinical symptoms resembling PR or autoimmune retinopathy (AR), including
      sudden painless loss of vision, typically associated with visual field defects
      and photopsias, and abnormal rod and/or cone responses on the electroretinogram
      (ERG). Sera were tested for the presence of anti-retinal autoantibodies by
      Western blot analysis using proteins extracted from human retina and by
      immunohistochemistry. Autoantibody titers against recoverin and enolase were
      measured by ELISA. RESULTS: We identified a higher prevalence of anti-retinal
      autoantibodies in retinopathy patients. Ninety-one patients' sera (47.1%) showed
      autoantibodies of various specificities with a higher incidence of antibodies
      present in retinopathy patients diagnosed with cancer (33/52; 63.5%; p = 0.009)
      than in retinopathy patients without cancer (58/141; 41.1%). The average age of
      PR patients was 62.0 years, and that of AR patients was 55.9 years.
      Autoantibodies against recoverin (p23) were only present in the sera of PR
      patients, autoantibodies against unknown p35 were more common in patients with
      AR, while anti-enolase (anti-p46) autoantibodies were nearly equally distributed
      in the sera of patients with PR and those with AR. In the seropositive patients,
      the autoantibodies persisted over a long period of time--from months to years. A
      rebound in anti-recoverin autoantibody titer was found to be associated with
      exacerbations in visual symptoms but not in the recurrence of cancer. When
      compared to sera from healthy subjects, autoantibodies against retinal proteins
      from both groups of patients were cytotoxic to retinal cells, indicating their
      pathogenic potential. CONCLUSIONS: These studies showed that patients with sudden
      or subacute, unexplained loss of vision of retinal origin have anti-retinal
      antibodies in a broad range of specificity and indicate the need for autoantibody
      screening. Follow-up tests of antibody levels may be useful as a biomarker of
      disease activity associated with worsening of vision. Moreover, the heterogeneity
      in autoantibody specificity may explain the variation and complexity of clinical
      symptoms in retinopathy patients.

PMID- 15180905
TI  - Analysis of neonatal mortality:is standardizing for relative birth weight biased?
AB  - BACKGROUND: Infant mortality has traditionally been analyzed as a function of
      birth weight and birth weight-specific mortality. Often, however, when comparing
      two populations, the population with higher overall mortality has lower mortality
      at low birth weights and a reversed pattern at higher birth weights. Methods
      standardizing birth weight, such as the "relative birth weight", have been
      proposed to eliminate these crossover effects, but such methods do not account
      for the separate contributions to birth weight of gestational age and fetal
      "growth." METHODS: Using data for singleton U.S. Blacks (n = 3,683,572) and
      Whites (n = 18,409,287), we compared neonatal mortality, gestational age, and the
      difference between the observed birth weight and the optimal birth weight (the
      weight at which neonatal mortality was lowest) among Black and White infants at
      the same relative birth weight. RESULTS: At relative birth weights below zero,
      gestational ages were, on average, 2.4 +/- 1.5 (mean +/- standard deviation)
      weeks shorter for Blacks than for Whites for the same relative birth weight. At
      relative birth weights above zero, no differences were observed in gestational
      age, but the optimal birth weight occurred at a much higher relative birth weight
      in Whites than in Blacks (4150 vs. 3550 g). CONCLUSIONS: Our results suggest that
      comparisons of neonatal mortality between groups using "relative" birth weight
      may be potentially biased by differences in gestational age at low birth weights,
      and by the distance from the optimal birth weight at higher birth weights.

PMID- 15180906
TI  - Coronavirus 3CLpro proteinase cleavage sites: possible relevance to SARS virus
      pathology.
AB  - BACKGROUND: Despite the passing of more than a year since the first outbreak of
      Severe Acute Respiratory Syndrome (SARS), efficient counter-measures are still
      few and many believe that reappearance of SARS, or a similar disease caused by a
      coronavirus, is not unlikely. For other virus families like the picornaviruses it
      is known that pathology is related to proteolytic cleavage of host proteins by
      viral proteinases. Furthermore, several studies indicate that virus proliferation
      can be arrested using specific proteinase inhibitors supporting the belief that
      proteinases are indeed important during infection. Prompted by this, we set out
      to analyse and predict cleavage by the coronavirus main proteinase using
      computational methods. RESULTS: We retrieved sequence data on seven fully
      sequenced coronaviruses and identified the main 3CL proteinase cleavage sites in
      polyproteins using alignments. A neural network was trained to recognise the
      cleavage sites in the genomes obtaining a sensitivity of 87.0% and a specificity
      of 99.0%. Several proteins known to be cleaved by other viruses were submitted to
      prediction as well as proteins suspected relevant in coronavirus pathology.
      Cleavage sites were predicted in proteins such as the cystic fibrosis
      transmembrane conductance regulator (CFTR), transcription factors CREB-RP and OCT
      1, and components of the ubiquitin pathway. CONCLUSIONS: Our prediction method
      NetCorona predicts coronavirus cleavage sites with high specificity and several
      potential cleavage candidates were identified which might be important to
      elucidate coronavirus pathology. Furthermore, the method might assist in design
      of proteinase inhibitors for treatment of SARS and possible future diseases
      caused by coronaviruses. It is made available for public use at our website:
      http://www.cbs.dtu.dk/services/NetCorona/.

PMID- 15180907
TI  - Evaluation of several lightweight stochastic context-free grammars for RNA
      secondary structure prediction.
AB  - BACKGROUND: RNA secondary structure prediction methods based on probabilistic
      modeling can be developed using stochastic context-free grammars (SCFGs). Such
      methods can readily combine different sources of information that can be
      expressed probabilistically, such as an evolutionary model of comparative RNA
      sequence analysis and a biophysical model of structure plausibility. However, the
      number of free parameters in an integrated model for consensus RNA structure
      prediction can become untenable if the underlying SCFG design is too complex.
      Thus a key question is, what small, simple SCFG designs perform best for RNA
      secondary structure prediction? RESULTS: Nine different small SCFGs were
      implemented to explore the tradeoffs between model complexity and prediction
      accuracy. Each model was tested for single sequence structure prediction accuracy
      on a benchmark set of RNA secondary structures. CONCLUSIONS: Four SCFG designs
      had prediction accuracies near the performance of current energy minimization
      programs. One of these designs, introduced by Knudsen and Hein in their PFOLD
      algorithm, has only 21 free parameters and is significantly simpler than the
      others.

PMID- 15180908
TI  - Multiclass discovery in array data.
AB  - BACKGROUND: A routine goal in the analysis of microarray data is to identify
      genes with expression levels that correlate with known classes of experiments. In
      a growing number of array data sets, it has been shown that there is an over
      abundance of genes that discriminate between known classes as compared to
      expectations for random classes. Therefore, one can search for novel classes in
      array data by looking for partitions of experiments for which there are an over
      abundance of discriminatory genes. We have previously used such an approach in a
      breast cancer study. RESULTS: We describe the implementation of an unsupervised
      classification method for class discovery in microarray data. The method allows
      for discovery of more than two classes. We applied our method on two published
      microarray data sets: small round blue cell tumors and breast tumors. The method
      predicts relevant classes in the data sets with high success rates. CONCLUSIONS:
      We conclude that the proposed method is accurate and efficient in finding
      biologically relevant classes in microarray data. Additionally, the method is
      useful for quality control of microarray experiments. We have made the method
      available as a computer program.

PMID- 15180909
TI  - pdb-care (PDB carbohydrate residue check): a program to support annotation of
      complex carbohydrate structures in PDB files.
AB  - BACKGROUND: Carbohydrates are involved in a variety of fundamental biological
      processes and pathological situations. They therefore have a large pharmaceutical
      and diagnostic potential. Knowledge of the 3D structure of glycans is a
      prerequisite for a complete understanding of their biological functions. The
      largest source of biomolecular 3D structures is the Protein Data Bank. However,
      about 30% of all 1663 PDB entries (version September 2003) containing
      carbohydrates comprise errors in glycan description. Unfortunately, no software
      is currently available which aligns the 3D information with the reported
      assignments. It is the aim of this work to fill this gap. RESULTS: The pdb-care
      program http://www.glycosciences.de/tools/pdb-care/ is able to identify and
      assign carbohydrate structures using only atom types and their 3D atom
      coordinates given in PDB-files. Looking up a translation table where systematic
      names and the respective PDB residue codes are listed, both assignments are
      compared and inconsistencies are reported. Additionally, the reliability of
      reported and calculated connectivities for molecules listed within the HETATOM
      records is checked and unusual values are reported. CONCLUSION: Frequent use of
      pdb-care will help to improve the quality of carbohydrate data contained in the
      PDB. Automatic assignment of carbohydrate structures contained in PDB entries
      will enable the cross-linking of glycobiology resources with genomic and
      proteomic data collections.

PMID- 15180910
TI  - Current trends in the cardiovascular clinical trial arena (I).
AB  - The existence of effective therapies for most cardiovascular disease states,
      coupled with increased requirements that potential benefits of new drugs be
      evaluated on clinical rather than surrogate endpoints, makes it increasingly
      difficult to substantiate any incremental improvements in efficacy that these new
      drugs might offer. Compounding the problem is the highly controversial issue of
      comparing new agents with placebos rather than active pharmaceuticals in drug
      efficacy trials. Despite the recent consensus that placebos may be used ethically
      in well-defined, justifiable circumstances, the problem persists, in part because
      of increased scrutiny by ethics committees but also because of considerable
      lingering disagreement regarding the propriety and scientific value of placebo
      controlled trials (and trials of antihypertensive drugs in particular).The
      disagreement also substantially affects the most viable alternative to placebo
      controlled trials: actively controlled equivalence/noninferiority trials. To a
      great extent, this situation was prompted by numerous previous trials of this
      type that were marked by fundamental methodological flaws and consequent false
      claims, inconsistencies, and potential harm to patients.As the development and
      use of generic drugs continue to escalate, along with concurrent pressure to
      control medical costs by substituting less-expensive therapies for established
      ones, any claim that a new drug, intervention, or therapy is "equivalent" to
      another should not be accepted without close scrutiny. Adherence to proper
      methods in conducting studies of equivalence will help investigators to avoid
      false claims and inconsistencies. These matters will be addressed in the third
      article of this three-part series.

PMID- 15180911
TI  - Lateralized concomitants of human handedness.
AB  - Literature was reviewed concerning lateral asymmetries of brain and behavior in
      normal and pathological populations of left-and right-handers. Cerebral
      asymmetries of structure and function are less pronounced in left-handers as a
      group than in right-handers as a group, and variability is greater in left
      handers.

PMID- 15180912
TI  - A neo-Piagetian investigation of the serial position effect in children's motor
      learning.
AB  - Children's serial motor skill acquisition was studied within a neo-Piagetian
      framework. High and low M-processors performed on a curvilinear repositioning
      task. A primacy-recency effect was evidenced for both groups on the age-related
      task, while a recency effect occurred for only the high M-processors on the task
      one stage beyond the developmental processing capacity of the subjects. High M
      processors were more accurate and less variable than low M-processors. Although
      low M-processors performed better on the more complex task than on the simpler
      one, their performance never exceeded that of the high M-processors. Implications
      of these results for future research were discussed.

PMID- 15180913
TI  - Retention characteristics of movement rate information.
AB  - The retention characteristics of fast and slow movements were investigated in two
      experiments. Experiment 1 examined the reproduction of either fast or slow
      preselected movement rates after 0-sec rest, 15-sec rest or a 15-sec filled
      delay. Both fast and slow movement rates were rehearsable. Experiment 2 examined
      reproduction accuracy after subjects were required to perform a competing
      secondary task during the production of fast and slow movements. Although the
      secondary task degraded the reproduction of slow movements, it had no apparent
      effect upon the reproduction of fast movements. These results were interpreted as
      indicating partial support for Jones' (1974) notion of central monitoring of
      efference, and suggested that the contribution of proprioceptive feedback to
      movement control varies as a function of movement rate.

PMID- 15180914
TI  - Levels of processing and the coding of position cues in motor short-term memory.
AB  - The present study investigated the appropriateness of the levels-of-processing
      framework of memory for explaining retention of information in motor short-term
      memory. Subjects were given labels descriptive of the positions to be remembered
      by the experimenter (EL), were given no labels (NL), or provided their own labels
      (SL). A control group (CONT) was required to count backwards during the
      presentation of the criterion positions. The inclusion of a 30-sec filled
      retention interval as well as 0-sec and 30-sec unfilled retention intervals
      tested a prediction by Craik and Lockhart (1972), when attention is diverted from
      an item, information will be lost at a rate appropriate to its level of
      processing - that is, slower rates for deeper levels. Groups EL and SL had
      greater accuracy at recall for all three retention intervals than groups CONT and
      NL. In addition, there was no significant increase in error between 30-sec
      unfilled and 30-sec filled intervals for groups EL and SL, while there was a
      significant increase in error for groups CONT and NL. The data were interpreted
      in terms of Craik and Lockhart's (1972) levels-of-processing approach to memory.

PMID- 15180915
TI  - Fitts' law as a function of system dynamics and target uncertainty.
AB  - Fins' law was found to hold for discrete movements executed by subjects
      controlling the velocity of a cursor with a control stick The slope of movement
      time versus index of difficulty was approximately twice as large as for a
      comparable position control system. Target uncertainty also increased the slope
      of total time versus index of difficulty, and this effect is interpreted in terms
      of adaptive tuning of the human movement system.

PMID- 15180916
TI  - The role of verbal estimates of movement error in ballistic skill acquisition.
AB  - The role of verbal estimates of movement error in a ballistic movement task was
      investigated. Two groups performed a rapid linear movement timing task for 50
      trials with KR followed by 50 trials without KR. Group I was required to give a
      verbal estimate of movement time immediately after the task, while Group II was
      not. Verbal labeling of movement error did not augment performance when KR was
      present. When KR was withdrawn, however, Group I maintained performance, but
      Group II's response accuracy declined. Implications for current motor learning
      theories are discussed.

PMID- 15180917
TI  - Visuomotor coordination and intermanual transfer for a proprioceptive reaching
      task.
AB  - Two experiments were conducted to determine the role of head constraint, whether
      present or absent and arm exposure type (terminal or continuous) on the
      production of intermanual transfer to two types of visual distortion. Experiment
      1 investigated intermanual transfer to binocular, lateral prism displacement
      where the prism base orientation for both eyes was in the same direction.
      Experiment 2 determined whether intermanual transfer could be produced to squint
      prism viewing where the prism base orientation for each eye was in an opposite
      direction (base-out prisms). In both experiments transfer was produced when
      either head movement during prism exposure was unconstrained or when a terminal
      arm exposure was employed. Maximal transfer was produced when both of these
      conditions were employed.

PMID- 15180918
TI  - Shifts in attention demands and motor program utilization during motor learning.
AB  - The relationship between changes in the level of motor program utilization and
      attention demand during the learning of a motor task was examined. The primary
      task involved an 86-cm horizontal arm movement which subjects attempted to
      complete coincident with the end of a 360 degrees sweep of a clock hand. A
      secondary task performed with the opposite limb required a rapid button press to
      an auditory probe stimulus presented at various temporal locations within each
      trial. Control subjects performed either the primary task or the secondary task
      alone, while experimental subjects performed both tasks in combination. Schmidt's
      (1972) index of preprogramming was used to measure the level of motor program
      utilization, while probe reaction time reflected the attention demand of the
      primary task. There was a stable level of motor programming over four consecutive
      days of practice (100 trials a day), but a general decrease in attention demand.
      Implications for an expansion of the concept of the motor program were discussed.

PMID- 15180919
TI  - Cigarette smoke extract inhibits angiogenesis of pulmonary artery endothelial
      cells: the role of calpain.
AB  - Angiogenesis is an integral part of both the pulmonary inflammatory response to
      chronic exposure to cigarette smoke and the lung tissue remodeling associated
      with cigarette smoke-induced chronic obstructive pulmonary disease (COPD). To
      investigate the role of angiogenesis in the pathogenesis of COPD, we evaluated
      the effect of cigarette smoke extract (CSE) on angiogenesis of pulmonary artery
      endothelial cells (PAEC). Incubation of PAEC with 2.5-10% CSE resulted in a dose
      dependent inhibition of endothelial monolayer wound repair. CSE also caused
      inhibition of tube formation on Matrigel, migration in a Boyden chamber, and
      proliferation of PAEC. Because calpain, a family of calcium-dependent
      intracellular proteases, mediates cytoskeletal signaling in endothelial motility,
      we explored the role of calpain in the CSE-induced inhibition of endothelial
      angiogenesis. Incubation of CSE resulted in a dose-dependent decrease in calpain
      activity. Calpain inhibitor-1, a specific inhibitor of calpain, potentiates
      inhibitory effect of CSE on the endothelial monolayer wound repair, tube
      formation, cell migration, and cell proliferation. Transfection of PAEC with
      antisense oligodeoxyribonucleotides of calpastatin, the major endogenous calpain
      inhibitor, prevented CSE-induced increase in calpastatin protein content and CSE
      induced decreases in calpain activity. It also prevented CSE-induced decreases in
      monolayer wound repair, tube formation, and migration. These results suggest that
      CSE attenuates angiogenesis of PAEC and the mechanism involves inhibition of
      calpain. Impaired angiogenesis may impede the repair process in the lungs of
      cigarette smokers and contribute to the altered structural remodeling observed in
      the lungs of patients with cigarette smoke-related COPD.

PMID- 15180920
TI  - Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular
      mechanisms.
AB  - Resveratrol (3,4',5-trihydroxystilbene) is a polyphenolic stilbene found in the
      skins of red fruits, including grapes, that may be responsible for some of the
      health benefits ascribed to consumption of red wine. Resveratrol has been shown
      to have antioxidant properties and can act as an estrogen agonist. This study
      examined the anti-inflammatory effects of resveratrol on human airway epithelial
      cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin,
      inhibited IL-8 and granulocyte-macrophage colony-stimulating factor release from
      A549 cells. Neither the estrogen receptor antagonist tamoxifen nor the
      glucocorticoid antagonist mifepristone altered the inhibitory effect of
      resveratrol. The mechanism of resveratrol action was investigated further using
      luciferase reporter genes stably transfected into A549 cells. Resveratrol and
      quercetin inhibited NF-kappaB-, activator protein-1-, and cAMP response element
      binding protein-dependent transcription to a greater extent than the
      glucocorticosteroid dexamethasone. These compounds also had no significant effect
      on acetylation or deacetylation of core histones. Resveratrol, but not estradiol
      or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide
      synthase expression and nitrite production (IC50 = 3.6 +/- 2.9 microM) in human
      primary airway epithelial cells. Resveratrol also inhibited granulocyte
      macrophage colony-stimulating factor release (IC50 = 0.44 +/- 0.17 microM), IL-8
      release (IC50 = 4.7 +/- 3.3 microM), and cyclooxygenase-2 expression in these
      cells. This study demonstrates that resveratrol and quercetin have novel
      nonsteroidal anti-inflammatory activity that may have applications for the
      treatment of inflammatory diseases.

PMID- 15180921
TI  - Endothelium-derived reactive oxygen species and endothelin-1 attenuate NO
      dependent pulmonary vasodilation following chronic hypoxia.
AB  - Vasodilatory responses to exogenous nitric oxide (NO) are diminished following
      exposure to chronic hypoxia (CH) in isolated, perfused rat lungs. We hypothesized
      that both endothelium-derived reactive oxygen species (ROS) and endothelin-1 (ET
      1) mediate this attenuated NO-dependent pulmonary vasodilation following CH. To
      test this hypothesis, we examined vasodilatory and vascular smooth muscle (VSM)
      Ca2+ responses to the NO donor spermine NONOate in UTP-constricted, isolated
      pressurized small pulmonary arteries from control and CH rats. Consistent with
      our previous findings in perfused lungs, we observed attenuated NO-dependent
      vasodilation following CH in endothelium-intact vessels. However, in endothelium
      denuded vessels, responses to spermine NONOate were augmented in CH rats compared
      with controls, thus demonstrating an inhibitory influence of the endothelium on
      NO-dependent reactivity following CH. Whereas both the ROS scavenger tiron and
      the ETA receptor antagonist BQ-123 augmented NO-dependent reactivity in
      endothelium-intact vessels from CH rats, neither fully restored vasodilatory
      responses to those observed following endothelium denudation in vessels from CH
      rats. In contrast, the combination of tiron and BQ-123 or the nonselective ET
      receptor antagonist PD-145065 enhanced NO responsiveness in endothelium-intact
      vessels from CH rats similar to that observed following endothelium denudation.
      We conclude that both endothelium-derived ROS and ET-1 attenuate NO-dependent
      pulmonary vasodilation following CH. Furthermore, CH augments pulmonary VSM
      reactivity to NO.

PMID- 15180922
TI  - The role of von Hippel-Lindau tumor suppressor protein and hypoxia in renal clear
      cell carcinoma.
AB  - The majority of kidney cancers are caused by the mutation of the von Hippel
      Lindau (VHL) tumor suppressor gene. VHL protein (pVHL) is part of an E3 ubiquitin
      ligase complex called VEC that is composed of elongin B, elongin C, cullin 2,
      NEDD8, and Rbx1. VEC targets a hypoxia-inducible factor (HIF) transcription
      factor for ubiquitin-mediated destruction selectively in the presence of oxygen.
      In the absence of wild-type pVHL, as in VHL patients or in the majority of
      sporadic clear cell renal cell carcinomas, HIF-responsive genes are
      inappropriately activated even under normoxia. Recent insights into the molecular
      mechanisms regulating the function of pVHL, and thereby HIF, in the context of
      kidney cancer are the focus of this review.

PMID- 15180923
TI  - Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms
      of action.
AB  - Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an imperative
      role in tubular repair and regeneration after acute renal injury. Growing
      evidence indicates that HGF is also an endogenous renoprotective factor that
      possesses a potent antifibrotic ability. HGF prevents the initiation and
      progression of chronic renal fibrosis and inhibits transforming growth factor
      (TGF)-beta(1) expression in a wide variety of animal models. In vitro, HGF
      counteracts the action of TGF-beta(1) in different types of kidney cells,
      resulting in blockade of the myofibroblastic activation from interstitial
      fibroblasts and glomerular mesangial cells, as well as inhibition of the
      mesenchymal transition from tubular epithelial cells. Recent studies reveal that
      HGF antagonizes the profibrotic actions of TGF-beta(1) by intercepting Smad
      signal transduction through diverse mechanisms. In interstitial fibroblasts, HGF
      blocks activated Smad-2/3 nuclear translocation, whereas it specifically
      upregulates the expression of the Smad transcriptional corepressor SnoN in
      tubular epithelial cells. In glomerular mesangial cells, HGF stabilizes another
      Smad corepressor, TGIF, by preventing it from degradation. Smad corepressors bind
      to activated Smad-2/3 and sequester their ability to transcriptionally activate
      TGF-beta target genes. This article reviews recent advances in our understanding
      of the cellular and molecular mechanisms underlying HGF inhibition of renal
      fibrosis.

PMID- 15180925
TI  - Upregulation of macula densa cyclooxygenase-2 expression is not dependent on
      glomerular filtration.
AB  - Although the regulation of cyclooxygenase-2 (COX-2) expression in the kidney
      cortex has been extensively characterized, the physiological control mechanisms
      of COX-2 expression at the level of the kidney and at the level of the tubular
      cells are not well understood. Based on the current hypothesis that tubular salt
      transport might be a crucial regulator of COX-2 expression, this study aimed to
      determine the impact of salt delivery to the tubules (glomerular filtration) for
      the regulation of COX-2 in the kidney cortex in vivo. To this end, glomerular
      filtration of the right kidney was abrogated by the ligation of the right ureter
      of male Sprague-Dawley rats. After 1 wk of ligation, the animals were treated
      with subcutaneous infusions of furosemide (12 mg x kg(-1) x day(-1)) or with a
      low-salt or a high-salt diet (0.02% wt/wt; 8% wt/wt), and COX-2 as well as renin
      mRNA expression were determined in the ligated and the nonligated contralateral
      kidney. During ureteral ligation, hydronephrosis developed with a reduction of
      medullary mass, while the cortex was preserved. Expressions of the Na-K-2Cl
      cotransporter isoforms A and B were both reduced in the hydronephrotic cortex to
      70 and 35% of the corresponding contralateral intact kidney. Despite the
      abrogation of glomerular filtration, detected by inulin clearance measurements,
      renocortical COX-2 mRNA abundance was stimulated by furosemide treatment (3.2
      fold) or low-salt diet (2.9-fold) to similar degrees compared with the intact
      contralateral kidney (2.7-fold for both treatments), whereas a high-salt diet did
      not significantly suppress COX-2 mRNA in the macula densa region of either
      kidney. Renin mRNA expression was regulated strictly in parallel in both kidneys,
      a low-salt diet or furosemide treatment stimulating and a high-salt diet
      suppressing it. We conclude from these findings that salt delivery to the tubules
      is not an essential requirement for the upregulation of COX-2 by salt deficiency
      or by loop diuretics in the rat kidney cortex nor is it for chronic stimulation
      of renin mRNA expression.

PMID- 15180924
TI  - The dopamine precursor L-dihydroxyphenylalanine is transported by the amino acid
      transporters rBAT and LAT2 in renal cortex.
AB  - The intrarenal autocrine-paracrine dopamine (DA) system is critical for Na(+)
      homeostasis. l-Dihydroxyphenylalanine (l-DOPA) uptake from the glomerular
      filtrate and plasma provides the substrate for DA generation by the renal
      proximal tubule. The transporter(s) responsible for proximal tubule l-DOPA uptake
      has not been characterized. Renal cortical poly-A(+) RNA injected into Xenopus
      laevis oocytes induced l-DOPA uptake in a time- and dose-dependent fashion with
      biphasic K(m)s in the millimolar and micromolar range and independent of inward
      Na(+), K(+), or H(+) gradients, suggesting the presence of low- and high-affinity
      l-DOPA carriers. Complementary RNA from two amino acid transporters yielded l
      DOPA uptake significantly above water-injected controls the rBAT/b(0,+)AT dimer
      (rBAT) and the LAT2/4F2 dimer (LAT2). In contradistinction to renal cortical poly
      A(+), l-DOPA kinetics of rBAT and LAT2 showed classic Michaelis-Menton kinetics
      with K(m)s in the micromolar and millimolar range, respectively. Sequence
      specific antisense oligonucleotides to rBAT or LAT2 (AS) caused inhibition of
      rBAT and LAT2 cRNA-induced l-DOPA transport and cortical poly-A(+)-induced
      arginine and phenylalanine transport. However, the same ASs only partially
      blocked poly-A(+)-induced l-DOPA transport. In cultured kidney cells, silencing
      inhibitory RNA (siRNA) to rBAT significantly inhibited l-DOPA uptake. We conclude
      that rBAT and LAT2 can mediate apical and basolateral l-DOPA uptake into the
      proximal tubule, respectively. Additional l-DOPA transport mechanisms exist in
      the renal cortex that remain to be identified.

PMID- 15180926
TI  - Development of biomarkers in multiple sclerosis.
AB  - Multiple sclerosis is a complex disease, as several pathophysiological processes
      (including inflammation, demyelination, axonal damage and repair mechanisms)
      participate in the disease process. Furthermore, as new pathological evidence
      reveals, these processes are not uniformly represented across patient populations
      but can selectively predominate in individual patients, thus contributing to the
      heterogeneity in phenotypic expression of the disease, its prognosis and response
      to therapies. While the armamentarium of available therapies for multiple
      sclerosis broadens, little is known about factors that predict treatment response
      in individual patients to a specific drug. More importantly, we are beginning to
      understand that, analogous to cancer therapy, the successful therapeutic strategy
      in multiple sclerosis might ultimately involve the combination of different
      therapeutics targeting several dominant pathophysiological processes. The
      development of these process-specific therapies will be impossible without the
      use of biomarkers that reflect the targeted process, can select patient
      population in which the targeted process is prevailing and can aid during the
      more rapid screening of therapeutic agents in the early phase of their
      development. This review summarizes the general concepts of biomarkers and their
      potential use as surrogate endpoints and tailors these concepts to specific
      applications in multiple sclerosis research.

PMID- 15180927
TI  - Automatic annotation of organellar genomes with DOGMA.
AB  - The Dual Organellar GenoMe Annotator (DOGMA) automates the annotation of
      organellar (plant chloroplast and animal mitochondrial) genomes. It is a Web
      based package that allows the use of BLAST searches against a custom database,
      and conservation of basepairing in the secondary structure of animal
      mitochondrial tRNAs to identify and annotate genes. DOGMA provides a graphical
      user interface for viewing and editing annotations. Annotations are stored on our
      password-protected server to enable repeated sessions of working on the same
      genome. Finished annotations can be extracted for direct submission to GenBank.

PMID- 15180928
TI  - Protein complex prediction via cost-based clustering.
AB  - MOTIVATION: Understanding principles of cellular organization and function can be
      enhanced if we detect known and predict still undiscovered protein complexes
      within the cell's protein-protein interaction (PPI) network. Such predictions may
      be used as an inexpensive tool to direct biological experiments. The increasing
      amount of available PPI data necessitates an accurate and scalable approach to
      protein complex identification. RESULTS: We have developed the Restricted
      Neighborhood Search Clustering Algorithm (RNSC) to efficiently partition networks
      into clusters using a cost function. We applied this cost-based clustering
      algorithm to PPI networks of Saccharomyces cerevisiae, Drosophila melanogaster
      and Caenorhabditis elegans to identify and predict protein complexes. We have
      determined functional and graph-theoretic properties of true protein complexes
      from the MIPS database. Based on these properties, we defined filters to
      distinguish between identified network clusters and true protein complexes.
      CONCLUSIONS: Our application of the cost-based clustering algorithm provides an
      accurate and scalable method of detecting and predicting protein complexes within
      a PPI network.

PMID- 15180929
TI  - An entity tagger for recognizing acquired genomic variations in cancer
      literature.
AB  - VTag is an application for identifying the type, genomic location and genomic
      state-change of acquired genomic aberrations described in text. The application
      uses a machine learning technique called conditional random fields. VTag was
      tested with 345 training and 200 evaluation documents pertaining to cancer
      genetics. Our experiments resulted in 0.8541 precision, 0.7870 recall and 0.8192
      F-measure on the evaluation set.

PMID- 15180930
TI  - Java Treeview--extensible visualization of microarray data.
AB  - Open source software encourages innovation by allowing users to extend the
      functionality of existing applications. Treeview is a popular application for the
      visualization of microarray data, but is closed-source and platform-specific,
      which limits both its current utility and suitability as a platform for further
      development. Java Treeview is an open-source, cross-platform rewrite that handles
      very large datasets well, and supports extensions to the file format that allow
      the results of additional analysis to be visualized and compared. The combination
      of a general file format and open source makes Java Treeview an attractive choice
      for solving a class of visualization problems. An applet version is also
      available that can be used on any website with no special server-side setup.

PMID- 15180931
TI  - lga972: a cross-platform application for optimizing LD studies using a genetic
      algorithm.
AB  - lga972 is a user-friendly cross-platform application with a graphical interface
      for determining the design features of two-stage genetic linkage disequilibrium
      studies that minimize the genotyping burden.

PMID- 15180932
TI  - Picky: oligo microarray design for large genomes.
AB  - MOTIVATION: Many large genomes are getting sequenced nowadays. Biologists are
      eager to start microarray analysis taking advantage of all known genes of a
      species, but existing microarray design tools were very inefficient for large
      genomes. Also, many existing tools operate in a batch mode that does not assure
      best designs. RESULTS: Picky is an efficient oligo microarray design tool for
      large genomes. Picky integrates novel computer science techniques and the best
      known nearest-neighbor parameters to quickly identify sequence similarities and
      estimate their hybridization properties. Oligos designed by Picky are
      computationally optimized to guarantee the best specificity, sensitivity and
      uniformity under the given design constrains. Picky can be used to design arrays
      for whole genomes, or for only a subset of genes. The latter can still be
      screened against a whole genome to attain the same quality as a whole genome
      array, thereby permitting low budget, pathway-specific experiments to be
      conducted with large genomes. Picky is the fastest oligo array design tool
      currently available to the public, requiring only a few hours to process large
      gene sets from rice, maize or human.

PMID- 15180933
TI  - Visualizations for taxonomic and phylogenetic trees.
AB  - MOTIVATION: Despite substantial efforts to develop and populate the back-ends of
      biological databases, front-ends to these systems often rely on taxonomic
      expertise. This research applies techniques from human-computer interaction
      research to the biodiversity domain. RESULTS: We developed an interactive node
      link tool, TaxonTree, illustrating the value of a carefully designed interaction
      model, animation, and integrated searching and browsing towards retrieval of
      biological names and other information. Users tested the tool using a new, large
      integrated dataset of animal names with phylogenetic-based and classification
      based tree structures. These techniques also translated well for a tool,
      DoubleTree, to allow comparison of trees using coupled interaction. Our
      approaches will be useful not only for biological data but as general portal
      interfaces.

PMID- 15180935
TI  - Transmembrane proteins in the Protein Data Bank: identification and
      classification.
AB  - MOTIVATION: Integral membrane proteins play important roles in living cells.
      Although these proteins are estimated to constitute 25% of proteins at a genomic
      scale, the Protein Data Bank (PDB) contains only a few hundred membrane proteins
      due to the difficulties with experimental techniques. The presence of
      transmembrane proteins in the structure data bank, however, is quite invisible,
      as the annotation of these entries is rather poor. Even if a protein is
      identified as a transmembrane one, the possible location of the lipid bilayer is
      not indicated in the PDB because these proteins are crystallized without their
      natural lipid bilayer, and currently no method is publicly available to detect
      the possible membrane plane using the atomic coordinates of membrane proteins.
      RESULTS: Here, we present a new geometrical approach to distinguish between
      transmembrane and globular proteins using structural information only and to
      locate the most likely position of the lipid bilayer. An automated algorithm
      (TMDET) is given to determine the membrane planes relative to the position of
      atomic coordinates, together with a discrimination function which is able to
      separate transmembrane and globular proteins even in cases of low resolution or
      incomplete structures such as fragments or parts of large multi chain complexes.
      This method can be used for the proper annotation of protein structures
      containing transmembrane segments and paves the way to an up-to-date database
      containing the structure of all known transmembrane proteins and fragments
      (PDB_TM) which can be automatically updated. The algorithm is equally important
      for the purpose of constructing databases purely of globular proteins.

PMID- 15180934
TI  - Supervised machine learning techniques for the classification of metabolic
      disorders in newborns.
AB  - MOTIVATION: During the Bavarian newborn screening programme all newborns have
      been tested for about 20 inherited metabolic disorders. Owing to the amount and
      complexity of the generated experimental data, machine learning techniques
      provide a promising approach to investigate novel patterns in high-dimensional
      metabolic data which form the source for constructing classification rules with
      high discriminatory power. RESULTS: Six machine learning techniques have been
      investigated for their classification accuracy focusing on two metabolic
      disorders, phenylketo nuria (PKU) and medium-chain acyl-CoA dehydrogenase
      deficiency (MCADD). Logistic regression analysis led to superior classification
      rules (sensitivity >96.8%, specificity >99.98%) compared to all investigated
      algorithms. Including novel constellations of metabolites into the models, the
      positive predictive value could be strongly increased (PKU 71.9% versus 16.2%,
      MCADD 88.4% versus 54.6% compared to the established diagnostic markers). Our
      results clearly prove that the mined data confirm the known and indicate some
      novel metabolic patterns which may contribute to a better understanding of
      newborn metabolism.

PMID- 15180936
TI  - A spline function approach for detecting differentially expressed genes in
      microarray data analysis.
AB  - MOTIVATION: A primary objective of microarray studies is to determine genes which
      are differentially expressed under various conditions. Parametric tests, such as
      two-sample t-tests, may be used to identify differentially expressed genes, but
      they require some assumptions that are not realistic for many practical problems.
      Non-parametric tests, such as empirical Bayes methods and mixture normal
      approaches, have been proposed, but the inferences are complicated and the tests
      may not have as much power as parametric models. RESULTS: We propose a weakly
      parametric method to model the distributions of summary statistics that are used
      to detect differentially expressed genes. Standard maximum likelihood methods can
      be employed to make inferences. For illustration purposes the proposed method is
      applied to the leukemia data (training part) discussed elsewhere. A simulation
      study is conducted to evaluate the performance of the proposed method.

PMID- 15180937
TI  - Bayesian integrated functional analysis of microarray data.
AB  - MOTIVATION: The statistical analysis of microarray data usually proceeds in a
      sequential manner, with the output of the previous step always serving as the
      input of the next one. However, the methods currently used in such analyses do
      not properly account for the fact that the intermediate results may not always be
      correct, then leading to cumulating error in the inferences drawn based on such
      steps. RESULTS: Here we show that, by an application of hierarchical Bayesian
      methodology, this sequential procedure can be replaced by a single joint
      analysis, while systematically accounting for the uncertainties in this process.
      Moreover, we can also integrate relevant functional information available from
      databases into such an analysis, thereby increasing the reliability of the
      biological conclusions that are drawn. We illustrate these points by analysing
      real data and by showing that the genes can be divided into categories of
      interest, with the defining characteristic depending on the biological question
      that is considered. We contend that the proposed method has advantages at two
      levels. First, there are gains in the statistical and biological results from the
      analysis of this particular dataset. Second, it opens up new possibilities in
      analysing microarray data in general.

PMID- 15180938
TI  - Reconstruction of gene networks using Bayesian learning and manipulation
      experiments.
AB  - MOTIVATION: The analysis of high-throughput experimental data, for example from
      microarray experiments, is currently seen as a promising way of finding
      regulatory relationships between genes. Bayesian networks have been suggested for
      learning gene regulatory networks from observational data. Not all causal
      relationships can be inferred from correlation data alone. Often several
      equivalent but different directed graphs explain the data equally well.
      Intervention experiments where genes are manipulated can help to narrow down the
      range of possible networks. RESULTS: We describe an active learning algorithm
      that suggests an optimized sequence of intervention experiments. Simulation
      experiments show that our selection scheme is better than an unguided choice of
      interventions in learning the correct network and compares favorably in running
      time and results with methods based on value of information calculations.

PMID- 15180939
TI  - A statistical framework for the design of microarray experiments and effective
      detection of differential gene expression.
AB  - MOTIVATION: Microarray experiments generate a high data volume. However, often
      due to financial or experimental considerations, e.g. lack of sample, there is
      little or no replication of the experiments or hybridizations. These factors
      combined with the intrinsic variability associated with the measurement of gene
      expression can result in an unsatisfactory detection rate of differential gene
      expression (DGE). Our motivation was to provide an easy to use measure of the
      success rate of DGE detection that could find routine use in the design of
      microarray experiments or in post-experiment assessment. RESULTS: In this study,
      we address the problem of both random errors and systematic biases in microarray
      experimentation. We propose a mathematical model for the measured data in
      microarray experiments and on the basis of this model present a t-based
      statistical procedure to determine DGE. We have derived a formula to determine
      the success rate of DGE detection that takes into account the number of
      microarrays, the number of genes, the magnitude of DGE, and the variance from
      biological and technical sources. The formula and look-up tables based on the
      formula, can be used to assist in the design of microarray experiments. We also
      propose an ad hoc method for estimating the fraction of non-differentially
      expressed genes within a set of genes being tested. This will help to increase
      the power of DGE detection. AVAILABILITY: The functions to calculate the success
      rate of DGE detection have been implemented as a Java application, which is
      accessible at
      http://www.le.ac.uk/mrctox/microarray_lab/Microarray_Softwares/Microarray_Softwar
      s.htm

PMID- 15180940
TI  - STAR: an algorithm to Search for Tandem Approximate Repeats.
AB  - MOTIVATION: Tandem repeats consist in approximate and adjacent repetitions of a
      DNA motif. Such repeats account for large portions of eukaryotic genomes and have
      also been found in other life kingdoms. Owing to their polymorphism, tandem
      repeats have proven useful in genome cartography, forensic and population
      studies, etc. Nevertheless, they are not systematically detected nor annotated in
      genome projects. Partially because of this lack of data, their evolution is still
      poorly understood. RESULTS: In this work, we design an exact algorithm to locate
      approximate tandem repeats (ATR) of a motif in a DNA sequence. Given a motif and
      a DNA sequence, our method named STAR, identifies all segments of the sequence
      that correspond to significant approximate tandem repetitions of the motif. In
      our model, an Exact Tandem Repeat (ETR) comes from the tandem duplication of the
      motif and an ATR derives from an ETR by a series of point mutations. An ATR can
      then be encoded as a number of duplications of the motif together with a list of
      mutations. Consequently, any sequence that is not an ATR cannot be encoded
      efficiently by this description, while a true ATR can. Our method uses the
      minimum description length criterion to identify which sequence segments are ATR.
      Our optimization procedure guarantees that STAR finds a combination of ATR that
      minimizes this criterion. AVAILABILITY: for use at http://atgc.lirmm.fr/star

PMID- 15180941
TI  - Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous
      cell carcinoma of the head and neck.
AB  - p73, a novel p53 homolog, has some p53-like activity and plays an important role
      in modulating cell-cycle control, apoptosis and cell growth. p73 regulates
      differentiation of head and neck squamous epithelium, and changes in p73 may lead
      to the development of squamous cell carcinoma of the head and neck (SCCHN). Two
      linked non-coding exon 2 polymorphisms (designated as G4C14-to-A4T14) were
      identified recently but their functional relevance is unknown. We hypothesized
      that this p73 polymorphism plays a role in the etiology of SCCHN. Therefore, in
      this hospital-based case-control study of 708 patients newly diagnosed with SCCHN
      and 1229 cancer-free controls, we evaluated the association between the p73 AT
      variant allele and risk of SCCHN. The controls were frequency-matched to the
      cases by age (+/-5 years), sex and smoking status, and all subjects were non
      Hispanic whites. Our results showed that the frequencies of variant AT allele and
      genotypes were more common in the cases than in the controls (P = 0.029 and P =
      0.009, respectively). Compared with the GC/GC genotype, the variant genotypes
      (GC/AT + AT/AT) were associated with a statistically significantly increased risk
      for SCCHN [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.10-1.60].
      Further stratification analyses by age, sex, smoking and alcohol status and by
      cancer sites within the head and neck region indicated that this significantly
      increased risk was more pronounced in younger (< or =50 years) individuals
      (adjusted OR = 1.70; 95% CI, 1.19-2.43), women (1.61; 1.09-2.37), current smokers
      (1.77; 1.25-2.51) and patients with oral cancer (1.54; 1.15-2.07). Our results
      suggest that this p73 polymorphism may be a risk marker for genetic
      susceptibility to SCCHN.

PMID- 15180942
TI  - Non-steroidal anti-inflammatory drug activated gene (NAG-1) expression is closely
      related to death receptor-4 and -5 induction, which may explain sulindac sulfide
      induced gastric cancer cell apoptosis.
AB  - Non-steroidal anti-inflammatory drugs (NSAIDs) are powerful chemopreventive
      agents in various cancers. They act by inhibiting cyclooxygenase (COX) activity,
      or through other mechanisms. NSAID-activated gene (NAG-1) has antitumorigenic and
      pro-apoptotic activities, but the mechanisms of NAG-1-induced apoptosis are
      poorly understood. Here we examined whether NAG-1 expression is induced in
      gastric cancer cells treated with NSAIDs, and the effect of NAG-1 expression on
      cell death. NAG-1 cDNA was transfected into SNU601 cells, and the relation
      between the ectopic expression of NAG-1 and death receptor-4 (DR-4) and DR-5
      levels was studied. We found that NAG-1 expression was strongly induced in SNU601
      cells, which lack endogenous COX-2, by sulindac sulfide, and that this was
      closely related with increased apoptosis and decreased cell viability. Moreover,
      temporal expressions of DR-4 and DR-5 induced by sulindac sulfide were similar to
      that of NAG-1. Most SNU601 cells transfected with NAG-1 cDNA did not survive
      during expansion. Forced NAG-1 expression significantly induced apoptosis and DR
      4 and DR-5 expression. We conclude that NAG-1 expression is closely related to DR
      4 and DR-5 induction, which could provide a mechanistic basis for the apoptotic
      effect of COX inhibitors in gastric cancer cells.

PMID- 15180943
TI  - Comparison of the chemopreventive efficacies of garlic powders with different
      alliin contents against aflatoxin B1 carcinogenicity in rats.
AB  - Garlic (Allium sativum) is well known for its beneficial effects on health and
      particularly for its chemopreventive potential against cancer. The present study
      was designed to compare the chemopreventive efficacies of several garlic powders
      with various levels of alliin, a precursor of active sulfur compounds. For this
      purpose we used the medium-term hepatocarcinogenesis protocol (resistant
      hepatocyte model), which allows the detection of preneoplasic foci expressing the
      placental form of glutathione S-transferase (GST-P) as an end-point. Rats were
      fed diets containing three garlic powders (5% of the diet) with various alliin
      contents for 3 weeks. Garlic powders were obtained from bulbs grown on soils with
      different levels of sulfur fertilization. During the period of garlic feeding
      hepatocarcinogenesis was initiated by administration of 10 i.p. injections of
      0.025 mg/kg body weight aflatoxin B1 (AFB1). The rats were later submitted to 2
      acetylaminofluorene treatment and partial hepatectomy, and GST-P foci were
      detected and quantified. Consumption of diets containing garlic powders decreased
      the appearance and size of hepatic GST-P foci. A strong reduction was observed in
      rats fed garlic containing the highest level of alliin. In addition, increased
      alliin content of the garlic powder was associated with a proportional decrease
      in the number and area of preneoplastic foci. Elsewhere, garlic powder ingestion
      increased hepatic ethoxyresorufin deethylase, glutathione S-transferase and UDP
      glucuronosyl transferase activities while no modification of nifedipine oxidase
      activity was found. We also observed an increase in the levels of GST A5 and AFB1
      aldehyde reductase. It is suggested that garlic partly exerts its
      anticarcinogenic effects through increasing enzymes involved in AFB1
      detoxification. This study highlights the possibility of controlling the
      cultivation conditions to improve the chemopreventive efficacy of garlic.

PMID- 15180944
TI  - Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma
      model: a p53-independent mitochondrial-mediated apoptotic mechanism.
AB  - The effects of lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A
      reductase, were studied in a mouse model of metastatic mammary cancer carrying a
      p53 mutation. Mice bearing mammary tumors, induced by inoculation of syngeneic
      BALB/c mice with BJMC3879 cells, were treated with lovastatin at 0, 25 and 50
      mg/kg three times a week. Tumor volumes were significantly reduced in a dose
      dependent manner throughout the 6 week study and were associated with both a
      decrease in DNA synthesis and an increase in apoptosis. The high dose of
      lovastatin also inhibited lung metastasis. In a corollary in vitro study, flow
      cytometric analyses of lovastatin-treated mammary cancer cells additionally
      showed cell cycle arrest at G1 phase and decreases in S and G2/M phases. Laser
      scanning cytometric analyses further demonstrated that cancer cells in S and G2/M
      were particularly susceptible to the effects of lovastatin. Transmission electron
      microscopic evaluation of TUNEL-confirmed apoptotic bodies in lovastatin-treated
      mammary carcinoma cells revealed many free 3'-OH ends of DNA in condensed
      chromatin within fragmented nuclei that occasionally assumed a characteristic
      half-moon shape. Consistent with initiation of apoptosis, cellular caspase-8,
      caspase-9 and caspase-3 activities were elevated in lovastatin-treated cells. The
      mitochondrial membrane potential was also decreased, with subsequent release of
      cytochrome c. However, lovastatin-induced cell death was significantly reduced by
      the broad spectrum caspase inhibitor z-VAD-fmk, as well as the caspase-9
      inhibitor z-LEHD-fmk and the caspase-3 inhibitor z-DEVD-fmk, but not by the
      specific caspase-8 inhibitor z-IETD-fmk. Since immunoelectron microscopy showed
      translocation of Bax to the mitochondria in lovastatin-treated cells, lovastatin
      induced apoptosis may, therefore, be ultimately dependent on Bax induction of
      cytochrome c release. These results suggest that lovastatin may be useful as an
      adjuvant therapy in breast cancers containing p53 mutations due to its ability to
      both suppress DNA synthesis and induce p53-independent mitochondria-mediated
      apoptosis.

PMID- 15180945
TI  - Destructive cycles: the role of genomic instability and adaptation in
      carcinogenesis.
AB  - Classical theories of carcinogenesis postulate that the accumulation of several
      somatic mutations is responsible for oncogenesis. However, these models do not
      explain how non-mutagenic carcinogens cause cancer. In addition, known mutation
      rates appear to be insufficient to account for observed cancer rates. Moreover,
      the current theory doesn't easily account for the long latencies observed in
      human cancers. Proponents of an aneuploidy-driven theory of carcinogenesis
      suggest that genomic instability has a causative role in carcinogenesis. In
      support of this theory, pre-neoplastic cells frequently display genomic
      instability while normal cells do not. Data obtained from a variety of model
      organisms have revealed that disruption of the cell cycle controls required for
      homeostasis results in the acquisition of genomic instability. Subsequently, this
      genomic instability becomes self-propagating via 'destructive cycles' and
      provides a medium for cellular selection and adaptation. Genomic instability
      allows numerous genetic and epigenetic alterations to accumulate during
      carcinogenesis without markedly changing phenotype until they are qualitatively
      or quantitatively sufficient to be selectively advantageous in the tumor
      microenvironment. Observations of adaptation in tumor cell populations and
      application of chaos theory may help elucidate the mechanism that drives the
      enormous genetic heterogeneity observed in tumors and provide insights into the
      development of new therapeutic cancer interventions and treatments.

PMID- 15180946
TI  - A novel splice-site variant of the base excision repair gene MYH is associated
      with production of an aberrant mRNA transcript encoding a truncated MYH protein
      not localized in the nucleus.
AB  - The MYH gene encodes a DNA glycosylase involved in the excision repair of
      adenines paired with 8-hydroxyguanines, a major component of oxidative DNA
      damage, and bi-allelic germline MYH mutations have been reported to predispose
      individuals to multiple colorectal adenomas and carcinoma. To determine whether
      the MYH gene is involved in gastric carcinogenesis, we examined blood specimens
      from 20 Japanese familial gastric cancer (GC) patients for MYH mutations by
      polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP)
      analysis followed by direct sequencing. Bi-allelic germline MYH mutations were
      not found in any of the specimens, but in addition to four known variants, a
      novel splice-site variant, IVS10-2A > G (c.892-2A > G), was found in two patients
      as its heterozygote. Reverse transcription-PCR analysis revealed that the IVS10
      2A > G variant caused the production of an aberrant mRNA transcript encoding a
      truncated MYH protein. Immunofluorescence analysis showed that the wild-type MYH
      protein, but not the variant-type, is localized in the nucleus. We then searched
      for the IVS10-2A > G variant in 128 digestive tract cancer patients by PCR with
      confronting two-pair primers, and eight cancers from six patients with the IVS10
      2A/G genotype were identified. However, no other germline MYH mutations or
      inactivation of the remaining wild-type allele was detected. We next tested the
      presumed correlation of the IVS10-2G allele with GC risk in a case-control study
      of 148 GC cases and 292 controls, but no significant difference in the
      distribution of the IVS10-2A > G variant was found between the cases and
      controls. Interestingly, the homozygote for the IVS10-2G allele was found in one
      GC case, but not in any controls. These results suggested that the ability to
      repair 8-hydroxyguanine in nuclear DNA may differ among Japanese individuals due
      to the splicing abnormality based on the MYH IVS10-2A > G variant, and that the
      bi-allelic IVS10-2A > G variation may be responsible for the occurrence of GC.

PMID- 15180947
TI  - Pre-S mutant surface antigens in chronic hepatitis B virus infection induce
      oxidative stress and DNA damage.
AB  - Ground glass hepatocytes (GGHs) are the historic hallmarks for the hepatocytes in
      the late and non-replicative stages of hepatitis B virus (HBV) infection. We have
      identified type I and type II GGHs that contain two mutant types of large HBV
      surface antigens (HBsAg) with deletions over the pre-S1 and pre-S2 regions,
      respectively. These pre-S mutant HBVsAg accumulate in endoplasmic reticulum (ER),
      resulting in strong ER stress. Type II GGHs often appear in hepatic nodules in
      the late phases of HBV infection and proliferate in clusters, suggesting that
      these mutant pre-S1/S2 HBsAg may be involved in HBV-related hepatocarcinogenesis,
      associated with ER stress. In this study, we investigated the potential genomic
      instability imposed by pre-S mutant HBsAg. Based on the analysis of comet assays,
      we found that the pre-S1 and pre-S2 mutant HBsAg caused oxidative stress and DNA
      damage. The DNA repair gene ogg1 was greatly induced by over-expression of pre-S
      mutant HBsAg. Induction of the DNA repair gene ogg1 was also detected in the pre
      S2 HBsAg transgenic mice, as well as the type II GGHs from patients with
      hepatocellular carcinoma, strongly suggesting that the pre-S mutant HBsAg
      contributes to the oxidative DNA damage to hepatocytes. In addition, the mutation
      rates in the X-linked hprt gene were enhanced in mouse hepatoma ML1-4a cells,
      which constitutively expressed the pre-S1/S2 HBsAg. These results indicate that
      pre-S1/S2 mutant HBsAg, which make up GGHs, induce oxidative DNA damage and
      mutations in hepatocytes in the late stages of HBV infection.

PMID- 15180948
TI  - Molecular cues to implantation.
AB  - Successful implantation is the result of reciprocal interactions between the
      implantation-competent blastocyst and receptive uterus. Although various cellular
      aspects and molecular pathways of this dialogue have been identified, a
      comprehensive understanding of the implantation process is still missing. The
      receptive state of the uterus, which lasts for a limited period, is defined as
      the time when the uterine environment is conducive to blastocyst acceptance and
      implantation. A better understanding of the molecular signals that regulate
      uterine receptivity and implantation competency of the blastocyst is of clinical
      relevance because unraveling the nature of these signals may lead to strategies
      to correct implantation failure and improve pregnancy rates. Gene expression
      studies and genetically engineered mouse models have provided valuable clues to
      the implantation process with respect to specific growth factors, cytokines,
      lipid mediators, adhesion molecules, and transcription factors. However, a
      staggering amount of information from microarray experiments is also being
      generated at a rapid pace. If properly annotated and explored, this information
      will expand our knowledge regarding yet-to-be-identified unique, complementary,
      and/or redundant molecular pathways in implantation. It is hoped that the
      forthcoming information will generate new ideas and concepts for a process that
      is essential for maintaining procreation and solving major reproductive health
      issues in women.

PMID- 15180949
TI  - Testosterone effects on the breast: implications for testosterone therapy for
      women.
AB  - Androgens have important physiological effects in women. Postmenopausal androgen
      replacement, most commonly as testosterone therapy, is becoming increasingly
      widespread. This is despite the lack of clear guidelines regarding the diagnosis
      of androgen insufficiency, optimal therapeutic doses, and long-term safety data.
      With respect to the breast specifically, there is the potential for exogenous
      testosterone to exert either androgenic or indirect estrogenic actions, with the
      latter potentially increasing breast cancer risk. In experimental studies,
      androgens exhibit growth-inhibitory and apoptotic effects in some, but not all,
      breast cancer cell lines. Differing effects between cell lines appear to be due
      primarily to variations in concentrations of specific coregulatory proteins at
      the receptor level. In rodent breast cancer models, androgen action is
      antiproliferative and proapoptotic, and is mediated via the androgen receptor,
      despite the potential for testosterone and dehydroepiandrosterone to be
      aromatized to estrogen. The results from studies in rhesus monkeys suggest that
      testosterone may serve as a natural endogenous protector of the breast and limit
      mitogenic and cancer-promoting effects of estrogen on mammary epithelium.
      Epidemiological studies have significant methodological limitations and provide
      inconclusive results. The strongest data for exogenous testosterone therapy comes
      from primate studies. Based on such simulations, inclusion of testosterone in
      postmenopausal estrogen-progestin regimens has the potential to ameliorate the
      stimulating effects of combined estrogen-progestin on the breast. Research
      addressing this is warranted; however, the number of women that would be required
      for an adequately powered randomized controlled trial renders such a study
      unlikely.

PMID- 15180950
TI  - Androgens and bone.
AB  - Loss of estrogens or androgens increases the rate of bone remodeling by removing
      restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes
      a focal imbalance between resorption and formation by prolonging the lifespan of
      osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as
      well as estrogens, maintain cancellous bone mass and integrity, regardless of age
      or sex. Although androgens, via the androgen receptor (AR), and estrogens, via
      the estrogen receptors (ERs), can exert these effects, their relative
      contribution remains uncertain. Recent studies suggest that androgen action on
      cancellous bone depends on (local) aromatization of androgens into estrogens.
      However, at least in rodents, androgen action on cancellous bone can be directly
      mediated via AR activation, even in the absence of ERs. Androgens also increase
      cortical bone size via stimulation of both longitudinal and radial growth. First,
      androgens, like estrogens, have a biphasic effect on endochondral bone formation:
      at the start of puberty, sex steroids stimulate endochondral bone formation,
      whereas they induce epiphyseal closure at the end of puberty. Androgen action on
      the growth plate is, however, clearly mediated via aromatization in estrogens and
      interaction with ERalpha. Androgens increase radial growth, whereas estrogens
      decrease periosteal bone formation. This effect of androgens may be important
      because bone strength in males seems to be determined by relatively higher
      periosteal bone formation and, therefore, greater bone dimensions, relative to
      muscle mass at older age. Experiments in mice again suggest that both the AR and
      ERalpha pathways are involved in androgen action on radial bone growth. ERbeta
      may mediate growth-limiting effects of estrogens in the female but does not seem
      to be involved in the regulation of bone size in males. In conclusion, androgens
      may protect men against osteoporosis via maintenance of cancellous bone mass and
      expansion of cortical bone. Such androgen action on bone is mediated by the AR
      and ERalpha.

PMID- 15180951
TI  - Biological, physiological, pathophysiological, and pharmacological aspects of
      ghrelin.
AB  - Ghrelin is a peptide predominantly produced by the stomach. Ghrelin displays
      strong GH-releasing activity. This activity is mediated by the activation of the
      so-called GH secretagogue receptor type 1a. This receptor had been shown to be
      specific for a family of synthetic, peptidyl and nonpeptidyl GH secretagogues.
      Apart from a potent GH-releasing action, ghrelin has other activities including
      stimulation of lactotroph and corticotroph function, influence on the pituitary
      gonadal axis, stimulation of appetite, control of energy balance, influence on
      sleep and behavior, control of gastric motility and acid secretion, and influence
      on pancreatic exocrine and endocrine function as well as on glucose metabolism.
      Cardiovascular actions and modulation of proliferation of neoplastic cells, as
      well as of the immune system, are other actions of ghrelin. Therefore, we
      consider ghrelin a gastrointestinal peptide contributing to the regulation of
      diverse functions of the gut-brain axis. So, there is indeed a possibility that
      ghrelin analogs, acting as either agonists or antagonists, might have clinical
      impact.

PMID- 15180952
TI  - The diagnosis and medical management of advanced neuroendocrine tumors.
AB  - Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms that
      originate from endocrine glands such as the pituitary, the parathyroids, and the
      (neuroendocrine) adrenal, as well as endocrine islets within glandular tissue
      (thyroid or pancreatic) and cells dispersed between exocrine cells, such as
      endocrine cells of the digestive (gastroenteropancreatic) and respiratory tracts.
      Conventionally, NETs may present with a wide variety of functional or
      nonfunctional endocrine syndromes and may be familial and have other associated
      tumors. Assessment of specific or general tumor markers offers high sensitivity
      in establishing the diagnosis and can also have prognostic significance. Imaging
      modalities include endoscopic ultrasonography, computed tomography and magnetic
      resonance imaging, and particularly, scintigraphy with somatostatin analogs and
      metaiodobenzylguanidine. Successful treatment of disseminated NETs requires a
      multimodal approach; radical tumor surgery may be curative but is rarely
      possible. Well-differentiated and slow-growing gastroenteropancreatic tumors
      should be treated with somatostatin analogs or alpha-interferon, with
      chemotherapy being reserved for poorly differentiated and progressive tumors.
      Therapy with radionuclides may be used for tumors exhibiting uptake to a
      diagnostic scan, either after surgery to eradicate microscopic residual disease
      or later if conventional treatment or biotherapy fails. Maintenance of the
      quality of life should be a priority, particularly because patients with
      disseminated disease may experience prolonged survival.

PMID- 15180953
TI  - RAGE- and TGF-beta receptor-mediated signals converge on STAT5 and p21waf to
      control cell-cycle progression of mesangial cells: a possible role in the
      development and progression of diabetic nephropathy.
AB  - The molecular events associated with acute and chronic exposure of mesangial
      cells (MC) to hyperglycemia were evaluated. We found that, unlike high glucose
      (HG) and Amadori adducts, advanced glycation end products (AGE) and transforming
      growth factor-beta (TGF-beta) induced p21waf expression and accumulation of MC in
      G0/G1. TGF-beta1 blockade inhibited AGE-mediated collagen production but only
      partially affected AGE-induced p21waf expression and cell-cycle events,
      indicating that AGE by binding to AGE receptor (RAGE) per se could control MC
      growth. Moreover, AGE and TGF-beta treatment led to the activation of the signal
      transduction and activators of transcription (STAT)5 and the formation of a
      STAT5/p21SIE2 complex. The role of STAT5 in AGE- and TGF-beta-mediated p21waf
      expression and growth arrest, but not collagen production, was confirmed by the
      expression of the dominant negative STAT5 (DeltaSTAT5) or the constitutively
      activated STAT5 (1*6-STAT5) constructs. Finally, in p21waf-/- fibroblasts both
      AGE and TGF-beta failed to inhibit cell-cycle progression. A potential in vivo
      role of these mechanisms was sustained by the increasing immunoreactivity for the
      activated STAT5 and p21(waf) in kidney biopsies from early to advanced stage of
      diabetic nephropathy. Our data indicate that AGE- and TGF-beta-mediated signals,
      by converging on STAT5 activation and p21waf expression, may regulate MC growth.

PMID- 15180954
TI  - Vitamin A status significantly alters nuclear factor-kappaB activity assessed by
      in vivo imaging.
AB  - Our study aimed to investigate, in vivo, the relationship between vitamin A
      status and NF-kappaB activity, a transcription factor central in regulating
      inflammatory and immune responses. We used a novel transgenic murine NF-kappaB
      luciferase reporter model that enabled molecular imaging of NF-kappaB activity in
      live mice via an intensified image-capture apparatus. Whole-body luminescence,
      which reflects overall NF-kappaB activity, was elevated 2.2-fold in vitamin A
      deficient (VAD) mice compared with control mice. Specifically, NF-kappaB activity
      in VAD mice was increased 1.8-fold in the lymph nodes and 1.4-fold in the thymus
      and, NF-kappaB induction in UVB radiation-exposed skin was also enhanced in VAD
      mice compared with control mice. The administration of all-trans retinoic acid to
      VAD mice resulted in a transient reduction in NF-kappaB activity and, conversely,
      a single dose of the RAR-pan-antagonist, AGN 194310, administered to control
      mice, led to a marked, transient induction of whole-body luminescence. Our
      results suggest that vitamin A status, and vitamin A itself, affects NF-kappaB
      activity in vivo and that the elevated NF-kappaB activity in VAD may be a
      mechanism underlying some of the features of VAD syndrome.

PMID- 15180955
TI  - Local cyclin-dependent kinase inhibition by flavopiridol inhibits coronary artery
      smooth muscle cell proliferation and migration: Implications for the
      applicability on drug-eluting stents to prevent neointima formation following
      vascular injury.
AB  - In-stent restenosis is a hyperproliferative disease which can be successfully
      treated by drug-eluting stents releasing compounds that exhibit cell-cycle
      inhibitory properties to inhibit coronary smooth muscle cell (CASMC)
      proliferation and migration, resembling the key pathomechanisms of in-stent
      restenosis. Cyclin-dependent kinases (CDK) are key regulators of the eukaryotic
      cell cycle. CDK activity may be blocked by novel compounds such as flavopiridol.
      Therefore, CDK inhibitors are attractive drugs to be used for the local
      prevention of in-stent restenosis. In this study, we demonstrate that
      flavopiridol leads to potent inhibition of CASMC proliferation and migration.
      Molecular effects on cell-cycle regulatory mechanisms and distribution were
      evaluated by post-transcriptional assessment of distinct cyclins and cyclin
      dependent kinase inhibitor (CKI) levels and flow cytometry. Cellular necrosis and
      apoptosis was assessed in CASMC and coronary endothelial cells. Flavopiridol
      induced a potent antiproliferative effect by cell-cycle inhibition in G1 and G2/M
      and led to increased protein levels of CKIs p21cip1 and p27kip1 as well as p53 in
      CASMC. Hyperphosphorylation of retinoblastoma protein was abrogated and mitogen
      mediated smooth muscle cell migration significantly reduced. No accelerated
      cytotoxicity or increased apoptosis was detectable. Flavopiridol-coated stents,
      implanted in rat carotid arteries, led to significant decrease of neointima
      formation. As proof of principle, our results demonstrate that stents eluting CDK
      inhibitors such as flavopiridol effectively inhibit neointima formation.
      Therefore, this new class of therapeutics may be suitable for further clinical
      investigations on drug-eluting stents to prevent in-stent restenosis.

PMID- 15180956
TI  - Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse
      ventral mesencephalon and the product promotes production of dopaminergic neurons
      from embryonic stem cell-derived nestin-positive cells.
AB  - Neural stem cells are promising candidates for donor cells in neural
      transplantation. However, the mechanism by which neural stem cells differentiate
      into neurons is not well understood. In the present study, a serial analysis of
      gene expression (SAGE) was carried out to generate a gene file of neural stem
      (progenitor) cells from the mouse ventral mesencephalon. Among the 15,815 tags
      investigated, the mRNA of the housekeeping genes (elongation factor 1-alpha,
      ATPase subunit 6, GAPDH, actin), laminin receptor 1, HSP 70, pleiotrophin, and
      nestin were highly expressed. Because pleiotrophin (PTN) exhibits mitogenic and
      trophic effects on neural development and exhibits trophic effects on survival of
      dopaminergic (DAergic) neurons, we investigated the role of PTN in neurogenesis,
      especially to DAergic neurons. Here, we show that PTN increased the production of
      tyrosine hydroxylase (TH)-positive neurons from embryonic stem (ES) cell-derived
      nestin-positive cells. The expression of Nurr1 mRNA was enhanced by PTN. L-dopa
      in the culture medium was increased by PTN. This effect was as strong as with
      sonic hedgehog. Data suggest that PTN mRNA is highly expressed in neural stem
      (progenitor) cells of mouse ventral mesencephalon, and PTN promotes the
      production of DAergic neurons from ES cell-derived nestin-positive cells.

PMID- 15180957
TI  - Cysteine/cystine couple is a newly recognized node in the circuitry for biologic
      redox signaling and control.
AB  - Redox mechanisms function in control of gene expression, cell proliferation, and
      apoptosis, but the circuitry for redox signaling remains unclear. Cysteine and
      methionine are the only amino acids in proteins that undergo reversible
      oxidation/reduction under biologic conditions and, as such, provide a means for
      control of protein activity, protein-protein interaction, protein trafficking,
      and protein-DNA interaction. Hydrogen peroxide and other reactive oxygen species
      (ROS) provide a mechanism to oxidize signaling proteins. However, oxidation of
      sulfur-containing side chains of cysteine and methionine by ROS can result in
      oxidation states of sulfur (e.g., sulfinate, sulfonate, sulfone) that are not
      reducible under biologic conditions. Thus, mechanisms for oxidation that protect
      against over-oxidation of these susceptible residues and prevent irreversible
      loss of activity would be advantageous. The present study shows that the steady
      state redox potential of the cysteine/cystine couple (Eh = -145 mV) in cells is
      sufficiently oxidized (>90 mV) relative to the GSH/GSSG (-250 mV) and thioredoxin
      (Trx1, -280 mV) redox couples for the cysteine/cystine couple to function as an
      oxidant in redox switching. Consequently, the cysteine/cystine couple provides a
      means to oxidize proteins without direct involvement of more potent oxidants. A
      circuitry model incorporating cysteine as a redox node, along with Trx1 and GSH,
      reveals how selective interactions between the different thiol/disulfide couples
      and reactive protein thiols could differentially regulate metabolic functions.
      Moreover, inclusion of cysteine/cystine as a signaling node distinct from GSH and
      Trx1 significantly expands the redox range over which protein thiol/disulfide
      couples may operate to control physiologically relevant processes.

PMID- 15180959
TI  - Slow spontaneous secretion from single large dense-core vesicles monitored in
      neuroendocrine cells.
AB  - Hormones are released from cells by passing through an exocytotic pore that forms
      after vesicle and plasma membrane fusion. In stimulated exocytosis vesicle
      content is discharged swiftly. Although rapid vesicle discharge has also been
      proposed to mediate basal secretion, this has not been studied directly. We
      investigated basal hormone release by preloading fluorescent peptides into single
      vesicles. The hormone discharge, monitored with confocal microscopy, was compared
      with the simultaneous loading of vesicle by FM styryl dye. In stimulated vesicles
      FM 4-64 (4 microM), loading and hormone discharge occurs within seconds. In
      contrast, in approximately 50% of spontaneously releasing vesicles, the vesicle
      content discharge and the FM 4-64 loading were slow (approximately 3 min). These
      results show that in peptide secreting neuroendocrine cells the elementary
      vesicle content discharge differs in basal and in stimulated exocytosis. It is
      proposed that the view dating back for some decades, which is that, at rest, the
      vesicle discharge of hormones and neurotransmitters is similar to that occurring
      after stimulation, needs to be extended. In addition to the classical paradigm
      that secretory capacity of a cell is determined by controlling the probability of
      occurrence of elementary exocytotic events, one will have to consider activity
      modulation of elementary exocytotic events as well.

PMID- 15180958
TI  - Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds
      proliferative demand.
AB  - The relationship between growth factor-dependent cell growth and proliferation
      and the up-regulation of cellular metabolism required to support these processes
      remains poorly defined. Here, we demonstrate that cell growth, proliferation, and
      glucose metabolism are coordinately regulated by interleukin-3 (IL-3) in cytokine
      dependent cells. Surprisingly, glycolytic activity is stimulated to a greater
      extent than would be expected based on the rate of cell growth or proliferation.
      IL-3 signaling exerts a direct effect on glycolytic commitment independent of
      cell growth control. These results are not restricted to IL-3 as the cytokines IL
      7 and IL-2 have similar effects on glucose metabolism when assayed in factor
      dependent cell lines or primary lymphocytes, respectively. Growth factor
      stimulation leads cells to consume less oxygen and produce more lactate per
      glucose, indicative of conversion from oxidative to glycolytic metabolism. The
      enforced rate of glucose metabolism is in excess of that required to support cell
      growth; accordingly, if extracellular glucose is reduced, cells retain the
      ability to grow and proliferate by derepressing oxidative metabolism. These data
      suggest that the high rate of glycolysis observed in response to growth factor
      stimulation is a primary effect rather than a homeostatic response to increased
      cell growth.

PMID- 15180960
TI  - Transcriptional profiling of dysplastic lesions in K14-HPV16 transgenic mice
      using laser microdissection.
AB  - In the K14-HPV16 transgenic mouse model of human papillomavirus (HPV)-associated
      squamous cell cancers, HPV16 E6 and E7 oncogenes and E1 and E2 regulatory genes
      are driven by the K14 keratinocyte-specific promoter. HPV transcription varies
      within the different layers of the epithelium. The correlation between HPV
      transcription patterns and disease pathogenesis is not well understood.
      Understanding these patterns is critical to designing and testing new HPV
      specific therapeutic strategies. We examined HPV gene expression in homogenous
      populations of cells microdissected from the stratum basale, stratum spinosum,
      and stratum corneum of lesions from the transgenic mice using PALM microlaser
      technology. RNA extracted from each cell layer was subjected to two-step gene
      specific RT-PCR and real-time quantitative nested PCR. To ensure specific
      amplification of spliced transcripts, the primers used for real-time nested PCR
      spanned the splice sites. High levels of E2 were detected in the basal and supra
      basal layers of hyperplastic and dysplastic lesions. E7 and E6* levels increased
      significantly over time in stratum basale and stratum spinosum. E6** was
      expressed at much lower levels. We showed that the transgenic mice express
      correctly spliced E2 transcripts and are suitable as a preclinical model to test
      a therapeutic strategy using transcriptional regulation by the E2 protein.

PMID- 15180961
TI  - Regulation of endothelial glutathione by ICAM-1: implications for inflammation.
AB  - The role of glutathione (GSH) in inflammation is largely discussed from the
      context of providing reducing equivalents to detoxify reactive oxygen and
      nitrogen species. Inflammation is now recognized to be an underlying cause of
      many vascular diseases including atherosclerosis, a disease in which endothelial
      GSH concentrations are decreased. However, mechanisms that control GSH levels are
      poorly understood. Key players in the inflammatory process are endothelial
      adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1). This
      adhesion molecule is present constitutively and can be induced by a variety of
      inflammatory stimuli. In this study, using mouse aortic endothelial cells (MAEC)
      deficient in ICAM-1, we demonstrate a novel interplay between constitutive ICAM-1
      and cellular GSH. Deficiency of ICAM-1 was associated with an approximately
      twofold increase in total GSH content. Inhibiting glutamate-cysteine ligase
      (GCL), the enzyme that catalyses the rate-limiting step in GSH biosynthesis,
      prevented the increase in GSH. In addition, the catalytic subunit of GCL was
      increased (approximately 1.6-fold) in ICAM-1 deficient relative to wild-type
      cells, suggesting that constitutive ICAM-1 represses GCL expression. Furthermore,
      the ratio of reduced (GSH) to oxidized (GSSG) glutathione was also increased
      suggesting a role for ICAM-1 in modulating cellular redox status. Interestingly,
      increasing cytosolic GSH in wild-type mouse endothelial cells decreased
      constitutive ICAM-1, suggesting the presence of an inverse and reciprocal
      pathway. To test the effects of inducible ICAM-1 on GSH, cells were stimulated
      with the proinflammatory cytokine TNF-alpha. TNF-alpha stimulated production of
      ICAM-1, which was however not associated with induction of GSH. In contrast,
      supplementation of endothelial cells with GSH before TNF-alpha addition,
      inhibited induction of ICAM-1. These data suggest a novel regulatory pathway
      between constitutive ICAM-1 and GSH synthesis in the endothelium and are
      discussed in the context of modulating the inflammatory response.

PMID- 15180963
TI  - Activity of complex III of the mitochondrial electron transport chain is
      essential for early heart muscle cell differentiation.
AB  - During development of the heart, mitochondria proliferate within cardiomyocytes.
      It is unclear whether this is a response to the increasing energy demand or
      whether it is part of the developmental program. To investigate the role of the
      electron transport chain (ETC) in this process, we used transgenic murine
      embryonic stem (ES) cells in which the green fluorescent protein gene is under
      control of the alpha-myosin heavy chain promoter (alpha-MHC), allowing easy
      monitoring of cardiomyocyte differentiation. Spontaneous contraction of these
      cells within embryoid bodies (EBs) was not affected by inhibition of the ETC,
      suggesting that early heart cell function is sufficiently supported by anaerobic
      ATP production. However, heart cell development was completely blocked when
      adding antimycin A, an inhibitor of ETC complex III, before initiation of
      differentiation, whereas KCN did not block differentiation, strongly suggesting
      that specifically complex III function rather than mitochondrial ATP production
      is necessary for early heart cell development. When the underlying mechanism was
      examined, we noticed that antimycin A but not KCN lead to inhibition of
      spontaneous intracellular Ca++ oscillations, whereas both substances decreased
      mitochondrial membrane potential, as expected. We postulate that mitochondrial
      complex III activity is necessary for these Ca++ oscillations, which in turn are
      a prerequisite for cardiomyocyte differentiation.

PMID- 15180962
TI  - A recombinant antibody increases cardiac contractility by mimicking phospholamban
      phosphorylation.
AB  - Many cardiovascular disease states end in progressive heart failure. Changes in
      intracellular calcium handling, including a reduced activity of the sarcoplasmic
      reticulum calcium pump (SERCA), contribute to this contractile dysfunction. As
      the regulatory protein phospholamban can inhibit the calcium pump, we evaluated
      it as a potential target to improve cardiac function. In this study, we describe
      a recombinant antibody-based protein (PLN-Ab) that binds to the cytoplasmic
      domain of phospholamban. Fluorescence resonance energy transfer (FRET) studies
      suggest that PLN-Ab mimics the effects of phospholamban phosphorylation. PLN-Ab
      accelerated the decay of the calcium transient when expressed in neonatal rat and
      adult mouse ventricular cardiac myocytes. In addition, direct injection of
      adenovirus encoding PLN-Ab into the diabetic mouse heart enhanced contractility
      when measured in vivo by echocardiography and in ex vivo Langendorff perfused
      hearts. The PLN-Ab provides a novel therapeutic approach to improving
      contractility through in vivo expression of an antibody inside cardiac myocytes.

PMID- 15180964
TI  - Serum response factor is a critical requirement for VEGF signaling in endothelial
      cells and VEGF-induced angiogenesis.
AB  - Angiogenesis, new capillary blood vessel formation, is essential for embryonic
      development, wound healing, and cancer growth. Vascular endothelial growth factor
      (VEGF) induces angiogenesis by activating endothelial cell migration and
      proliferation. Serum response factor (SRF) is a transcription factor important
      for embryonic development and activation of immediate early gene expression. The
      roles of SRF in endothelial cell biology and angiogenesis have not been explored.
      Here we demonstrate that SRF is a downstream mediator of VEGF signaling in
      endothelial cells and a critical requirement for VEGF-induced angiogenesis.
      Knockdown of SRF protein levels in human and rat endothelial cells abolished VEGF
      induced in vitro angiogenesis, impaired endothelial cell migration and
      proliferation, and inhibited VEGF-induced actin polymerization and immediate
      early gene expression. Injection of SRF antisense expression plasmid into gastric
      ulcers in rats significantly inhibited in vivo angiogenesis in granulation
      tissue. Mechanistically, this study also revealed that VEGF promotes SRF
      expression and nuclear translocation and increases SRF binding activity to DNA in
      endothelial cells through both Rho-actin and MEK-ERK dependent signaling
      pathways. These findings have potential therapeutic implications, e.g., local
      anti-SRF treatment may inhibit angiogenesis crucial for tumor growth.

PMID- 15180965
TI  - Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells.
AB  - Interleukin-23, a recently described cytokine produced by activated antigen
      presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40
      subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is
      distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL
      17 secretion from activated CD4+ T cells, and stimulating the proliferation of
      memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known
      immunomodulator, on the production of IL-23 by bone marrow- derived dendritic
      cells (BM-DCs). Our results indicate that PGE2 increases the production of
      functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2
      induces both the expression of p19 and p40, without affecting p35 expression. The
      effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked
      by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces
      IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of
      PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the
      pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL
      23 inducing activity of PGE2 in a synergistic manner. Recent studies described
      both pro- and anti-inflammatory effects of PGE2, and our results suggest an
      additional mechanism for its pro-inflammatory role, particularly significant for
      autoimmune diseases, such as rheumatoid arthritis.

PMID- 15180966
TI  - Role of high expression levels of CXCR4 in tumor growth, vascularization, and
      metastasis.
AB  - Hormone refractory metastatic prostate cancer remains an incurable disease. We
      found that high expression levels of the chemokine receptor CXCR4 correlated with
      the presence of metastatic disease in prostate cancer patients. Positive staining
      for CXCL12, the ligand for CXCR4, was mainly present in the tumor-associated
      blood vessels and basal cell hyperplasia. Subcutaneous xenografts of PC3 and
      22Rv1 prostate tumors that overexpressed CXCR4 in NOD/SCID mice were two- to
      threefold larger in volume and weight vs. controls. Moreover, blood vessel
      density, functionality, invasiveness of tumors into the surrounding tissues, and
      metastasis to the lymph node and lung were significantly increased in these
      tumors. Neutralizing the interactions of CXCL12/CXCR4 in vivo with CXCR4 specific
      antibodies inhibited the CXCR4-dependent tumor growth and vascularization. In
      vitro, CXCL12 induced the proliferation and VEGF secretion but not migration of
      PC3 and 22Rv1 cells overexpressing CXCR4. Similar effects of CXCR4 overexpression
      on tumor growth in vivo were also noted in two breast cancer lines, suggesting
      that the observed effect of CXCR4 is not unique to prostate tumor cells. Thus
      high levels of the chemokine receptor CXCR4 induce a more aggressive phenotype in
      prostate cancer cells and identify CXCR4 as a potential therapeutic target in
      advanced cases of metastatic prostate cancer.

PMID- 15180968
TI  - A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity
      as a novel treatment for Parkinson's disease and related disorders.
AB  - Convergent biochemical and genetic evidence suggests that the formation of alpha
      synuclein (alpha-syn) protein deposits is an important and, probably, seminal
      step in the development of Parkinson's disease (PD), dementia with Lewy bodies
      (DLB) and multiple system atrophy (MSA). It has been reported that transgenic
      animals overexpressing human alpha-syn develop lesions similar to those found in
      the brain in PD, together with a progressive loss of dopaminergic cells and
      associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn
      self-aggregation could, therefore, provide a novel approach to treating the
      underlying cause of these diseases. We synthesized a library of overlapping 7-mer
      peptides spanning the entire alpha-syn sequence, and identified amino acid
      residues 64-100 of alpha-syn as the binding region responsible for its self
      association. Modified short peptides containing alpha-syn amino acid sequences
      from part of this binding region (residues 69-72), named alpha-syn inhibitors
      (ASI), were found to interact with full-length alpha-syn and block its assembly
      into both early oligomers and mature amyloid-like fibrils. We also developed a
      cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine
      peptide delivery system. This ASID peptide was able to inhibit the DNA damage
      induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial
      PD-associated mutation. ASI peptides without this delivery system did not reverse
      levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased
      (P<0.0005) the number of cells stained positive for Bcl-2, while significantly
      (P<0.05) decreasing the percentage of cells stained positive for BAX. These short
      peptides could serve as lead compounds for the design of peptidomimetic drugs to
      treat PD and related disorders.

PMID- 15180967
TI  - Differential expression of nitric oxide synthases (NOS 1-3) in human skeletal
      muscle following exercise countermeasure during 12 weeks of bed rest.
AB  - Adaptive changes of major body systems in astronauts during spaceflight can be
      simulated by strict anti-orthostatic head-down tilt (HDT) bed rest (BR), a ground
      based microgravity (microG) model that provides a meaningful opportunity to study
      atrophy mechanisms and possible countermeasures under controlled experimental
      conditions. As nitric oxide (NO) signaling is linked to muscle activity, we
      investigated altered expression of the three major isoforms of nitric oxide
      synthase (NOS 1-3) at cellular compartments during prolonged HDT BR without
      (control group) and with resistance exercise interventions (exercise group) using
      a flywheel ergometer (FWE). Atrophy detected in mixed (fast-slow) m. vastus
      lateralis (VL) and slow-type m. soleus (SOL) myofiber Types I and II (minus 35
      40% of myofiber cross-sectional area) was prevented by FWE training. Concomitant
      to muscle atrophy, reduced NOS 1 protein and immunostaining was found in VL not
      in SOL biopsies. In trained VL, NOS 1 protein and immunostaining at myofibers II
      were significantly increased at the end of BR. Exercise altered NOS 2/caveolin 3
      co-immunostaining patterns of subsarcolemmal focal accumulations in VL or SOL
      myofibers, which suggests reorganization of sarcolemmal microdomains. In trained
      VL, increased capillary-to-fiber (C/F) ratio and NOS 3 protein content were
      documented. Activity-linked NO signaling may be widespread in skeletal muscle
      cellular compartments that may be directly or indirectly impacted by adequate
      exercise countermeasure protocols to offset the negative effects induced by
      disuse, immobilization, or extended exposure to microgravity.

PMID- 15180969
TI  - Nonnutritive swallowing and respiration relationships in preterm lambs.
AB  - The aim of the present study was to assess the effects of the different states of
      alertness on 1) nonnutritive swallowing (NNS) frequency, 2) the relationship
      between NNS and the respiratory cycle, and 3) the association of NNS with
      spontaneous apneas. Recordings of sleep states, diaphragm and laryngeal
      constrictor electrical activity, nasal flow, electrocardiogram, respiratory
      inductance plethysmography, and pulse oximetry were obtained from six preterm
      lambs without sedation. Analysis of 2,468 NNS showed that 1) NNS frequency was
      higher during quiet wakefulness and active sleep (AS) than in quiet sleep; 2) in
      all states of alertness, a greater number of NNS (38%) were preceded and followed
      by an inspiration; 3) although NNS and central apneas were rarely coincidental,
      AS appeared to favor their association; and 4) most obstructive apneas occurred
      in AS and were coincidental with bursts of NNS. Compared with results in full
      term lambs, premature birth does not modify the NNS-respiratory coordination.
      However, AS in preterm lambs is characterized by a higher association of NNS
      bursts with obstructive apneas.

PMID- 15180970
TI  - Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training
      induced changes in glucose tolerance indexes.
AB  - A polymorphism in the IL-6 gene, a G-to-C substitution 176 bp upstream of the ATG
      translation initiation site, has been associated with diabetes prevalence and
      insulin resistance. Interventions including exercise training are frequently used
      to modify cardiovascular disease risk factors. Consequently, this project
      examined associations between the IL-6 -174 genotype and oral glucose tolerance
      test outcomes in 50- to 75-yr-old sedentary men and postmenopausal women before
      and after aerobic exercise training. Among the 87 individuals who started the
      study, 56 were retested after 6 mo of aerobic exercise training. Subject
      characteristics at baseline did not differ between the IL-6 genotype groups with
      the exception of fasting glucose, which was higher (P = 0.02, covariates age,
      gender, and ethnicity) in the CC genotype group. The training-induced change in
      glucose area under the curve during the oral glucose tolerance test varied
      between the IL-6 -174 genotype groups (P = 0.05, covariates age, gender,
      ethnicity, baseline glucose area under the curve, and percent body fat change)
      with a significant decrease occurring only in the GG genotype group. Insulin
      outcomes did not differ among the groups at baseline or after training. Training
      induced changes in weight, percent body fat, maximal oxygen consumption, fasting
      glucose, and an insulin sensitivity index also changed similarly among the
      genotype groups. In conclusion, fasting glucose and the extent to which glucose
      tolerance changes with exercise training may be influenced by the IL-6 -174 gene
      polymorphism.

PMID- 15180971
TI  - Initial phase of maximal voluntary and electrically stimulated knee extension
      torque development at different knee angles.
AB  - We investigated the capacity for torque development and muscle activation at the
      onset of fast voluntary isometric knee extensions at 30, 60, and 90 degrees knee
      angle. Experiments were performed in subjects (n = 7) who had high levels (>90%)
      of activation at the plateau of maximal voluntary contractions. During maximal
      electrical nerve stimulation (8 pulses at 300 Hz), the maximal rate of torque
      development (MRTD) and torque time integral over the first 40 ms (TTI40) changed
      in proportion with torque at the different knee angles (highest values at 60
      degrees ). At each knee angle, voluntary MRTD and stimulated MRTD were similar (P
      < 0.05), but time to voluntary MRTD was significantly longer. Voluntary TTI40 was
      independent (P > 0.05) of knee angle and on average (all subjects and angles)
      only 40% of stimulated TTI40. However, among subjects, the averaged (across knee
      angles) values ranged from 10.3 +/- 3.1 to 83.3 +/- 3.2% and were positively
      related (r2 = 0.75, P < 0.05) to the knee-extensor surface EMG at the start of
      torque development. It was concluded that, although all subjects had high levels
      of voluntary activation at the plateau of maximal voluntary contraction, among
      subjects and independent of knee angle, the capacity for fast muscle activation
      varied substantially. Moreover, in all subjects, torque developed considerably
      faster during maximal electrical stimulation than during maximal voluntary
      effort. At different knee angles, stimulated MRTD and TTI40 changed in proportion
      with stimulated torque, but voluntary MRTD and TTI40 changed less than maximal
      voluntary torque.

PMID- 15180972
TI  - Endothelial cells as early sensors of pulmonary interstitial edema.
AB  - We studied responses of endothelial and epithelial cells in the thin portion of
      the air-blood barrier to a rise in interstitial pressure caused by an increase in
      extravascular water (interstitial edema) obtained in anesthetized rabbits
      receiving saline infusion (0.5 ml.kg(-1).min(-1) for 3 h). We obtained
      morphometric analyses of the cells and of their microenvironment (electron
      microscopy); furthermore, we also studied in lung tissue extracts the biochemical
      alterations of proteins responsible for signal transduction (PKC, caveolin-1) and
      cell-cell adhesion (CD31) and of proteins involved in membrane-to-cytoskeleton
      linkage (alpha-tubulin and beta-tubulin). In endothelial cells, we observed a
      folding of the plasma membrane with an increase in cell surface area, a doubling
      of plasmalemma vesicular density, and an increase in cell volume. Minor
      morphological changes were observed in epithelial cells. Edema did not affect the
      total plasmalemma amount of PKC, beta-tubulin, and caveolin-1, but alpha-tubulin
      and CD-31 increased. In edema, the distribution of these proteins changed between
      the detergent-resistant fraction of the plasma membrane (DRF, lipid microdomains)
      and the rest of the plasma membrane [high-density fractions (HDFs)]. PKC and
      tubulin isoforms shifted from the DRF to HDFs in edema, whereas caveolin-1
      increased in DRF at the expense of a decrease in phosphorylated caveolin-1. The
      changes in cellular morphology and in plasma membrane composition suggest an
      early endothelial response to mechanical stimuli arising at the interstitial
      level subsequently to a modest (approximately 5%) increase in extravascular
      water.

PMID- 15180973
TI  - Epinephrine infusion increases adipose interleukin-6 gene expression and systemic
      levels in humans.
AB  - Exercise increases IL-6 mRNA in subcutaneous adipose tissue; however, the
      immediate signal for the IL-6 induction is unknown. We, therefore, explored the
      possible role of epinephrine in the induction of IL-6 in adipose tissue.
      Subcutaneous adipose tissue biopsies and blood samples were obtained from eight
      healthy men (mean age 27 yr, mean height 184 cm, mean weight 83 kg) in response
      to epinephrine infusion or in response to saline infusion. The rate of
      epinephrine infusion was such that circulating epinephrine concentrations
      mimicked that typically seen during exercise. The level of IL-6 mRNA in
      subcutaneous adipose tissue increased 26-fold (95% confidence interval, 9- to 166
      fold) at 3 h of epinephrine infusion compared with controls (P=0.028). In
      addition, plasma levels of IL-6 increased in response to epinephrine infusion (P
      <0.001). However, epinephrine did not affect the IL-6 receptor mRNA. In
      conclusion, epinephrine acutely increases IL-6 mRNA levels in subcutaneous
      adipose tissue as well as circulating IL-6 levels in healthy men.

PMID- 15180974
TI  - Physiological characterization of human ovarian cancer cells in a rat model of
      intraperitoneal antineoplastic therapy.
AB  - Destruction of cancer cells by therapies directed against new molecular targets
      requires their effective delivery to the tumor. To study diffusion and convection
      of intraperitoneal (ip) therapy to ip tumors, we established a new athymic rat
      (RNU) model with ovarian tumor cells (SKOV3 and OVCAR3) implanted in the
      abdominal wall. The model simulates metastatic tumor and facilitates the
      measurement of physiological parameters that govern transport forces. CD31
      immunohistochemistry revealed unique patterns of angiogenesis, with a tissue
      averaged vascular volume of approximately 0.01 ml/g for each tumor. The
      extracellular volume (SKOV3: 0.54 +/- 0.11 ml/g, n=5; OVCAR3: 0.61 +/- 0.03, n=5)
      was over twice that of the adjacent normal muscle (0.22 +/- 0.06 ml/g, n=5).
      Intravenous-injected antibody tumor clearance was two to three times that of
      muscle. Interstitial pressures were higher than normal tissue with a median of 10
      15 mmHg. Quantitative autoradiography of frozen tissue slices from rats exposed
      to ip solutions containing [14C]mannitol or 125I-immunoglobulin G (trastuzumab)
      was performed to determine transport of small and large molecules. With ip
      pressure of 0-6 mmHg, both mannitol and immunoglobulin G displayed steep
      concentration profiles close to the tumor surface with limited penetration deeper
      within the tumor tissue; antibody penetration was significantly affected by ip
      pressure. These results demonstrated effects of molecular size, ip pressure, the
      limited but highly permeable tumor vasculature, and the expanded interstitium on
      drug penetration from the peritoneal cavity. In conclusion, we have characterized
      physical and chemical parameters that determine transport of therapeutic agents
      in our unique tumor-bearing rat model.

PMID- 15180975
TI  - Central inhibition of the aortic baroreceptors-heart rate reflex at the onset of
      spontaneous muscle contraction.
AB  - Animals decerebrated at the precollicular-premammillary body level exhibit
      spontaneous locomotion without any artificial stimulation. Our laboratory
      reported that the cardiovascular and autonomic responses at the onset of
      spontaneous locomotor events are evoked by central command, generated from the
      caudal diencephalon and the brain stem (Matsukawa K, Murata J, and Wada T. Am J
      Physiol Heart Circ Physiol 275: H1115-H1121, 1998). In this study, we examined
      whether central command and/or a reflex resulting from muscle afferents modulates
      arterial baroreflex function using a decerebrate cat model. The baroreflex was
      evoked by stimulating the aortic depressor nerve (ADN) at the onset of
      spontaneous muscle contraction (to test the possible influence of central
      command) and during electrically evoked contraction or passive stretch (to test
      the possible influence of the muscle reflex). When the ADN was stimulated at
      rest, heart rate and arterial blood pressure decreased by 40 +/- 2 beats/min and
      11 +/- 1 mmHg, respectively. The baroreflex bradycardia was attenuated to 55 +/-
      4% at the onset of spontaneous contraction. The attenuating effect on the
      baroreflex bradycardia was not observed at the onset and middle of electrically
      evoked contraction or passive stretch. The depressor response to ADN stimulation
      was identical among resting and any muscle interventions. The inhibition of the
      baroreflex bradycardia during spontaneous contraction was seen after beta
      adrenergic blockade but abolished by muscarinic blockade, suggesting that the
      bradycardia is mainly evoked through cardiac vagal outflow. We conclude that
      central command, produced within the caudal diencephalon and the brain stem,
      selectively inhibits the cardiac component, but not the vasomotor component, of
      the aortic baroreflex at the onset of spontaneous exercise.

PMID- 15180976
TI  - Reperfusion injury in skeletal muscle is reduced in inducible nitric oxide
      synthase knockout mice.
AB  - Inducible nitric oxide synthase (iNOS) participates in many pathological events,
      and selective inhibition of iNOS has been shown to reduce ischemia-reperfusion
      (I/R) injury in different tissues. To further confirm its role in this injury
      process, I/R injury was observed in denervated cremaster muscles of iNOS
      deficient (iNOS-/-) and wild-type mice. After 3-h ischemia and 90-min
      reperfusion, blood flow in reperfused muscle was 80 +/- 8.5% (mean +/- SE) of
      baseline at 10-min reperfusion and completely returned to the preischemia
      baseline after 20 min in iNOS-/- mice. In contrast, blood flow was 32 +/- 7.4% at
      10 min and increased to 60 +/- 20% of the baseline level at 90 min in wild-type
      mice (P < 0.001 vs. iNOS-/- mice at all time points). The increased muscle blood
      flow in iNOS-/- mice was associated with significantly less vasospasm in all
      three sizes of arterial vessel size categories. The weight ratio to the
      contralateral muscle not subjected to I/R was greater in wild-type mice (173 +/-
      11%) than in iNOS-/- mice (117 +/- 3%; P < 0.01). Inflammation and neutrophil
      extravasation were also more severe in wild-type mice. Western blot analysis
      demonstrated an absence of iNOS protein band in iNOS-/- mice and upregulation of
      iNOS protein expression in wild-type mice. Our results confirm the importance of
      iNOS in I/R injury. Upregulated iNOS exacerbates I/R injury and appears to be a
      therapeutic target in protection of tissues against this type of injury.

PMID- 15180977
TI  - Hypoxic reduction in cellular glutathione levels requires mitochondrial reactive
      oxygen species.
AB  - When exposed to hypoxia (1.5% O2), several cell types have been shown to increase
      production of reactive O2 species derived from the mitochondrial electron
      transport chain (mtROS). The general physiological consequences of hypoxic mtROS
      production are not completely understood, although several groups have
      demonstrated that mtROS promote the stabilization and activity of hypoxia
      inducible factor-1alpha (HIF-1alpha) transcription factor, alter cardiac myocyte
      contractility, and modulate Na+-K+-ATPase activity. To investigate the effects of
      hypoxia-induced mtROS on general cellular oxidative metabolism, we measured the
      levels of glutathione, a major cellular antioxidant, in response to hypoxic
      treatment. Our data indicate that HEK293 and Hep3B cells exposed to 1.5% O2
      exhibit a time-dependent decrease in cellular glutathione stores and concomitant
      inhibition of glutathione biosynthesis, which correlates to impaired transport of
      the substrate cystine. Using a combination of ROS scavengers, mitochondrial
      electron transport inhibitors, and mitochondrial DNA-deficient rho0 cells, we
      demonstrate that this decrease in cellular glutathione levels is mediated by
      hypoxia-induced mtROS. Intriguingly, this effect is also inhibited by
      cyclohexamide but is not dependent on HIF-mediated transcription. Overall, these
      data suggest a novel HIF-independent role for mitochondrial ROS in regulating
      glutathione synthesis, and hence cellular oxidative homeostasis, during hypoxic
      exposure.

PMID- 15180978
TI  - Burn trauma alters calcium transporter protein expression in the heart.
AB  - We have shown previously that burn trauma produces significant cardiac
      dysfunction, which is first evident 8 h postburn and is maximal 24 h postburn.
      Because calcium handling by the cardiomyocyte is essential for cardiac function,
      one mechanism by which burn injury may cause cardiac abnormalities is via calcium
      dyshomeostasis. We hypothesized that major burn injury alters cardiomyocyte
      calcium handling through changes in calcium transporter expression. Sprague
      Dawley rats were given either burn injury or no burn injury (controls).
      Cardiomyocyte intracellular calcium and sodium were quantified at various times
      postburn by fura 2-AM or sodium-binding benzofuran isophthalate fluorescent
      indicators, respectively. In addition, hearts freeze-clamped at various times
      postburn (2, 4, 8, and 24 h) were used for Western blot analysis using antibodies
      against the sarcoplasmic reticulum calcium-ATPase (SERCA), the L-type calcium
      channel, the ryanodine receptor, the sodium/calcium exchanger, or the sodium
      potassium-ATPase. Intracellular calcium levels were elevated significantly 8-24 h
      postburn, and intracellular sodium was increased significantly 4 through 24 h
      postburn. Expression of SERCA was significantly reduced 1-8 h postburn, whereas L
      type calcium-channel expression was diminished 1 and 2 h postburn (P < 0.05) but
      returned toward control levels 4 h postburn. Ryanodine receptor protein was
      significantly reduced at 1 and 2 h postburn, returning to baseline by 4 h
      postburn. Sodium/calcium exchanger expression was significantly elevated 2 h
      postburn but was significantly reduced 24 h postburn. An increase in sodium
      potassium-ATPase expression occurred 2-24 h postburn. These data confirm that
      burn trauma alters calcium transporter expression, likely contributing to
      cardiomyocyte calcium loading and cardiac contractile dysfunction.

PMID- 15180979
TI  - Neural coupling between upper and lower limbs during recumbent stepping.
AB  - During gait rehabilitation, therapists or robotic devices often supply physical
      assistance to a patient's lower limbs to aid stepping. The expensive equipment
      and intensive manual labor required for these therapies limit their availability
      to patients. One alternative solution is to design devices where patients could
      use their upper limbs to provide physical assistance to their lower limbs (i.e.,
      self-assistance). To explore potential neural effects of coupling upper and lower
      limbs, we investigated neuromuscular recruitment during self-driven and
      externally driven lower limb motion. Healthy subjects exercised on a recumbent
      stepper using different combinations of upper and lower limb exertions. The
      recumbent stepper mechanically coupled the upper and lower limbs, allowing users
      to drive the stepping motion with upper and/or lower limbs. We instructed
      subjects to step with 1) active upper and lower limbs at an easy resistance level
      (active arms and legs); 2) active upper limbs and relaxed lower limbs at easy,
      medium, and hard resistance levels (self-driven); and 3) relaxed upper and lower
      limbs while another person drove the stepping motion (externally driven). We
      recorded surface electromyography (EMG) from six lower limb muscles. Self-driven
      EMG amplitudes were always higher than externally driven EMG amplitudes (P <
      0.05). As resistance and upper limb exertion increased, self-driven EMG
      amplitudes also increased. EMG bursts during self-driven and active arms and legs
      stepping occurred at similar times. These results indicate that active upper limb
      movement increases neuromuscular activation of the lower limbs during cyclic
      stepping motions. Neurologically impaired humans that actively engage their upper
      limbs during gait rehabilitation may increase neuromuscular activation and
      enhance activity-dependent plasticity.

PMID- 15180980
TI  - Expression of leukemia inhibitory factor and its receptor is not altered in the
      decidua and chorionic villi of human anembryonic pregnancy.
AB  - BACKGROUND: Uterine expression of leukemia inhibitory factor (LIF) is absolutely
      essential for mouse, and critical for human, embryo implantation. However LIF is
      not required for post-implantation development of mouse embryo. The objective of
      this study was to examine the role of LIF system in post-implantation stage of
      human pregnancy. METHODS: Tissues from 25 patients with anembryonic pregnancy
      (AP; blighted ovum) and 25 matched patients with normal pregnancy (NP) were
      collected. LIF and its receptor beta (LIF-Rbeta) expression in the decidua and
      chorionic villi were analyzed by semi-quantitative reverse transcription and
      polymerase chain reaction (RT-PCR), real-time quantitative PCR and
      immunohistochemical study. RESULTS: LIF mRNA levels were not different either
      between different tissues (decidua vs chorionic villi) or between different
      patients (NP vs AP). LIF-Rbeta mRNA levels were significantly higher in chorionic
      villi than in decidua but were not different between NP and AP.
      Immunohistochemical staining supported these findings and showed a predominate
      expression of LIF-Rbeta in the trophoblast cells. CONCLUSIONS: This study
      concluded that at early human post-implantation stage, LIF is produced from both
      decidua and chorionic villi and may exert its major action on trophoblasts. A
      baseline expression of LIF and LIF-Rbeta is probably needed for early pregnancy,
      but AP cannot be accounted for by the defective expression of either LIF or LIF
      Rbeta in most circumstances.

PMID- 15180981
TI  - The relationship between pregnancy outcome and smooth endoplasmic reticulum
      clusters in MII human oocytes.
AB  - BACKGROUND: During ICSI, we occasionally observe pronucleus sized translucent
      vacuoles. We investigated why these vacuoles occur and determined the effect on
      pregnancy outcome. METHODS: Translucent vacuole-positive oocytes and the
      corresponding cohort were examined by transmission electron microscopy (TEM) and
      histochemical staining with DiI and ER-Tracker. Stimulation methods, hormonal
      levels, patients' condition and grade of transferred embryos were compared
      between vacuole-positive and vacuole-negative cycles. RESULTS: By TEM, we
      confirmed that the vacuoles were tubular-type smooth endoplasmic reticulum
      clusters (sERCs). Numerous small sERCs were also observed in the oocytes from the
      same cohort. Veeck's grades of transferred embryos were higher in sERC-positive
      cycles and fertilization rate was similar to those of sERC-negative cycles.
      However, in sERC-positive cycles, significantly lower pregnancy and higher
      biochemical pregnancy rates were shown. Serum estradiol levels on the day of hCG
      administration were significantly higher in sERC-positive cycles. CONCLUSIONS:
      The presence of sERCs is associated with lower chances of successful pregnancy,
      even in sERC-negative oocytes from the same cohort that are transferred along
      with the sERC-positive oocytes. High estradiol levels could be one of the causes
      of sERC formation.

PMID- 15180982
TI  - Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in
      human molybdenum cofactor biosynthesis.
AB  - The human proteins MOCS1A and MOCS1B catalyze the conversion of a guanosine
      derivative to precursor Z during molybdenum cofactor biosynthesis. MOCS1A shares
      homology with S-adenosylmethionine (AdoMet)-dependent radical enzymes, which
      catalyze the formation of protein and/or substrate radicals by reductive cleavage
      of AdoMet through a [4Fe-4S] cluster. Sequence analysis of MOCS1A showed two
      highly conserved cysteine motifs, one near the N terminus and one near the C
      terminus. MOCS1A was heterologously expressed in Escherichia coli and purified
      under aerobic and anaerobic conditions. Individual mutations of the conserved
      cysteines to serine revealed that all are essential for synthesis of precursor Z
      in vivo. The type and properties of the iron-sulfur (FeS) clusters were
      investigated using a combination of UV-visible absorption, variable temperature
      magnetic circular dichroism, resonance Raman, Mossbauer, and EPR spectroscopies
      coupled with iron and acid-labile sulfide analyses. The results indicated that
      anaerobically purified MOCS1A is a monomeric protein containing two oxygen
      sensitive FeS clusters, each coordinated by only three cysteine residues. A redox
      active [4Fe-4S](2+,+) cluster is ligated by an N-terminal CX(3)CX(2)C motif as is
      the case with all other AdoMet-dependent radical enzymes investigated thus far. A
      C-terminal CX(2)CX(13)C motif that is unique to MOCS1A and its orthologs
      primarily ligates a [3Fe-4S](0) cluster. However, MOCS1A could be reconstituted
      in vitro under anaerobic conditions to yield a form containing two [4Fe-4S](2+)
      clusters. The N-terminal [4Fe-4S](2+) cluster was rapidly degraded by oxygen via
      a semistable [2Fe-2S](2+) cluster intermediate, and the C-terminal [4Fe-4S](2+)
      cluster was rapidly degraded by oxygen to yield a semistable [3Fe-4S](0) cluster
      intermediate.

PMID- 15180983
TI  - The FAD-shielding residue Phe1395 regulates neuronal nitric-oxide synthase
      catalysis by controlling NADP+ affinity and a conformational equilibrium within
      the flavoprotein domain.
AB  - Phe(1395) stacks parallel to the FAD isoalloxazine ring in neuronal nitric-oxide
      synthase (nNOS) and is representative of conserved aromatic amino acids found in
      structurally related flavoproteins. This laboratory previously showed that
      Phe(1395) was required to obtain the electron transfer properties and calmodulin
      (CaM) response normally observed in wild-type nNOS. Here we characterized the
      F1395S mutant of the nNOS flavoprotein domain (nNOSr) regarding its physical
      properties, NADP(+) binding characteristics, flavin reduction kinetics, steady
      state and pre-steady-state cytochrome c reduction kinetics, and ability to shield
      its FMN cofactor in response to CaM or NADP(H) binding. F1395S nNOSr bound
      NADP(+) with 65% more of the nicotinamide ring in a productive conformation with
      FAD for hydride transfer and had an 8-fold slower rate of NADP(+) dissociation.
      CaM stimulated the rates of NADPH-dependent flavin reduction in wild-type nNOSr
      but not in the F1395S mutant, which had flavin reduction kinetics similar to
      those of CaM-free wild-type nNOSr. CaM-free F1395S nNOSr lacked repression of
      cytochrome c reductase activity that is typically observed in nNOSr. The combined
      results from pre-steady-state and EPR experiments revealed that this was
      associated with a lesser degree of FMN shielding in the NADP(+)-bound state as
      compared with wild type. We conclude that Phe(1395) regulates nNOSr catalysis in
      two ways. It facilitates NADP(+) release to prevent this step from being rate
      limiting, and it enables NADP(H) to properly regulate a conformational
      equilibrium involving the FMN subdomain that controls reactivity of the FMN
      cofactor in electron transfer.

PMID- 15180984
TI  - Tic32, an essential component in chloroplast biogenesis.
AB  - Chloroplast protein import across the inner envelope is facilitated by the
      translocon of the inner envelope of chloroplasts (Tic). Here we have identified
      Tic32 as a novel subunit of the Tic complex. Tic32 can be purified from
      solubilized inner envelope membranes by chromatography on Tic110 containing
      affinity matrix. Co-immunoprecipitation experiments using either Tic32 or Tic110
      antisera indicated a tight association between these polypeptides as well as with
      other Tic subunits, e.g. Tic40, Tic22, or Tic62, whereas the outer envelope
      protein Toc75 was not found in this complex. Chemical cross-linking suggests that
      Tic32 is involved late in the overall translocation process, because both the
      precursor form as well as the mature form of Rubisco small subunit can be
      detected. We were unable to isolate Arabidopsis null mutants of the attic32 gene,
      indicating that Tic32 is essential for viability. Deletion of the attic32 gene
      resulted in early seed abortion because the embryo was unable to differentiate
      from the heart stage to the torpedo stage. The homology of Tic32 to short-chain
      dehydrogenases suggests a dual role of Tic32 in import, one as a regulatory
      component and one as an important subunit in the assembly of the entire complex.

PMID- 15180985
TI  - MalK, the ATP-binding cassette component of the Escherichia coli maltodextrin
      transporter, inhibits the transcriptional activator malt by antagonizing inducer
      binding.
AB  - MalK, the ATP-binding cassette component of the Escherichia coli maltodextrin
      transporter, has long been known to control negatively the activity of MalT, a
      transcriptional activator dedicated to the maltose regulon. By using a
      biochemical approach and the soluble form of MalK as a model substrate, we
      demonstrate that MalK alone inhibits transcription activation by MalT in a
      purified transcription system. The inhibitory effect observed in vitro is
      relieved by maltotriose and by two malT mutations and one malK mutation known to
      interfere with MalT repression by MalK in vivo. MalK interacts directly with the
      activator in the absence of maltotriose but not in the presence of maltotriose.
      Conversely, MalK inhibits maltotriose binding by MalT. Altogether, these data
      strongly suggest that MalK and maltotriose compete for MalT binding. Part, if not
      all, of the MalK-binding site is located on DT1, the N-terminal domain of MalT.
      All of these features indicate that MalK inhibits MalT by the same mechanism as
      two other proteins, MalY and Aes, that also act as negative effectors of MalT by
      antagonizing maltotriose binding by MalT. These results offer new insights into
      the mechanism by which gene regulation can be accomplished by the ATPase
      component of a bacterial ATP-binding cassette-type importer.

PMID- 15180986
TI  - Crystal structure of human eIF3k, the first structure of eIF3 subunits.
AB  - eIF3k, the smallest subunit of eukaryotic initiation factor 3 (eIF3), interacts
      with several other subunits of eIF3 and the 40 S ribosomal subunit. eIF3k is
      conserved among high eukaryotes, including mammals, insects, and plants, and it
      is ubiquitously expressed in human tissues. Interestingly, eIF3k does not exist
      in some species of yeast. Thus, eIF3k may play a unique regulatory role in higher
      organisms. Here we report the crystal structure of human eIF3k, the first high
      resolution structure of an eIF3 component. This novel structure contains two
      distinct domains, a HEAT (named for Huntington, elongation factor 3, A subunit of
      protein phosphatase 2A, target of rapamycin) repeat-like HAM (HEAT analogous
      motif) domain and a winged-helix-like WH domain. Through structural comparison
      and sequence conservation analysis, we show that eIF3k has three putative protein
      binding surfaces and has potential RNA binding activity. The structure provides
      key information for understanding the structure and function of the eIF3 complex.

PMID- 15180987
TI  - Linking receptor-mediated endocytosis and cell signaling: evidence for regulated
      intramembrane proteolysis of megalin in proximal tubule.
AB  - Megalin, a member of the low density lipoprotein receptor gene family, is
      required for efficient protein absorption in the proximal tubule. Recent studies
      have shown that the low density lipoprotein receptor-related protein, another
      member of this gene family, is proteolytically processed by gamma-secretase
      implying a role for low density lipoprotein receptor-related protein in a
      Notchlike signaling pathway. This pathway has been shown to involve: 1)
      metalloprotease-mediated ectodomain shedding and gamma-secretase-mediated
      intramembrane proteolysis of some receptors. Experiments were performed to
      determine whether megalin undergoes similar processing. By immunocytochemistry,
      immunoblotting, and a fluorogenic enzyme assay presenilin-1 (required for gamma
      secretase activity) and gamma-secretase activity were found in the brush border
      of proximal kidney tubules where megalin is localized. Using a fluorogenic
      peptide containing an amyloid precursor protein gamma-secretase cleavage site and
      Compound E, a specific gamma-secretase inhibitor, we found high levels of gamma
      secretase activity in renal brush border membrane vesicles. Immunoblotting
      analysis of renal microsomes and opossum kidney proximal tubule (OKP) cells using
      antibodies directed to the cytosolic domain of megalin showed a 35-40-kDa,
      membrane-associated, carboxyl-terminal fragment of megalin (MCTF). When cells
      were incubated with 200 nm phorbol 12-myristate 13-acetate, the appearance of the
      MCTF increased 2.5-fold and was blocked by metalloprotease inhibitors. When the
      cells were incubated with gamma-secretase inhibitor Compound E, it caused a 2
      fold increase in MCTF. Finally, incubating the cells with 1 microm vitamin D
      binding protein resulted in a 25% increase in the appearance of the MCTF. In
      summary, the MCTF is produced by protein kinase C regulated, metalloprotease
      mediated ectodomain shedding and is the substrate for gamma-secretase. We
      postulate that the enzymatic processing of megalin represents part of a novel
      ligand-dependent signaling pathway in the proximal tubule that links receptor
      mediated endocytosis with cell signaling.

PMID- 15180988
TI  - The bafilomycin/concanamycin binding site in subunit c of the V-ATPases from
      Neurospora crassa and Saccharomyces cerevisiae.
AB  - The vacuolar H+-ATPase is inhibited with high specificity and potency by
      bafilomycin and concanamycin, macrolide antibiotics with similar structures. We
      previously reported that mutation at three residues in subunit c of the vacuolar
      ATPase from Neurospora crassa conferred strong resistance to bafilomycin but
      little or no resistance to concanamycin (Bowman, B. J., and Bowman, E. J. (2002)
      J. Biol. Chem. 277, 3965-3972). We have identified additional mutated sites in
      subunit c that confer resistance to bafilomycin. Furthermore, by subjecting a
      resistant mutant to a second round of mutation we isolated strains with increased
      resistance to both bafilomycin and concanamycin. In all of these strains the
      second mutation is also in subunit c, suggesting it forms at least part of the
      concanamycin binding site. Site-directed mutagenesis of the gene encoding subunit
      c in Saccharomyces cerevisiae showed that single mutations in each of the
      residues identified in one of the double mutants of N. crassa conferred
      resistance to both bafilomycin and concanamycin. Mutations at the corresponding
      sites in the VMA11 and VMA16 genes of S. cerevisiae, which encode the c' and c"
      subunits, did not confer resistance to the drugs. In all, nine residues of
      subunit c have been implicated in drug binding. The positions of these residues
      support a model in which the drug binding site is a pocket formed by helices 1,
      2, and 4. We hypothesize that the drugs inhibit by preventing the rotation of the
      c subunits.

PMID- 15180989
TI  - Replication protein A and the Mre11.Rad50.Nbs1 complex co-localize and interact
      at sites of stalled replication forks.
AB  - In response to replicative stress, cells relocate and activate DNA repair and
      cell cycle arrest proteins such as replication protein A (RPA, a three subunit
      protein complex required for DNA replication and DNA repair) and the MRN complex
      (consisting of Mre11, Rad50, and Nbs1; involved in DNA double-strand break
      repair). There is increasing evidence that both of these complexes play a central
      role in DNA damage recognition, activation of cell cycle checkpoints, and DNA
      repair pathways. Here we demonstrate that RPA and the MRN complex co-localize to
      discrete foci and interact in response to DNA replication fork blockage induced
      by hydroxyurea (HU) or ultraviolet light (UV). Members of both RPA and the MRN
      complexes become phosphorylated during S-phase and in response to replication
      fork blockage. Analysis of RPA and Mre11 in fractionated lysates
      (cytoplasmic/nucleoplasmic, chromatin-bound, and nuclear matrix fractions) showed
      increased hyperphosphorylated-RPA and phosphorylated-Mre11 in the chromatin-bound
      fractions. HU and UV treatment also led to co-localization of hyperphosphorylated
      RPA and Mre11 to discrete detergent-resistant nuclear foci. An interaction
      between RPA and Mre11 was demonstrated by co-immunoprecipitation of both protein
      complexes with anti-Mre11, anti-Rad50, anti-NBS1, or anti-RPA antibodies.
      Phosphatase treatment with calf intestinal phosphatase or lambda-phosphatase not
      only de-phosphorylated RPA and Mre11 but also abrogated the ability of RPA and
      the MRN complex to co-immunoprecipitate. Together, these data demonstrate that
      RPA and the MRN complex co-localize and interact after HU- or UV-induced
      replication stress and suggest that protein phosphorylation may play a role in
      this interaction.

PMID- 15180990
TI  - Differential regulation of islet-specific glucose-6-phosphatase catalytic subunit
      related protein gene transcription by Pax-6 and Pdx-1.
AB  - Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is
      selectively expressed in islet beta cells and is a major autoantigen in a mouse
      model of type I diabetes. The analysis of IGRP-chloramphenicol acetyltransferase
      (CAT) fusion gene expression through transient transfection of islet-derived
      betaTC-3 cells revealed that a promoter region, located between -273 and -254, is
      essential for high IGRP-CAT fusion gene expression. The sequence of this promoter
      region does not match that for any known islet-enriched transcription factor.
      However, data derived from gel retardation assays, a modified ligation-mediated
      polymerase chain reaction in situ footprinting technique and a SDS-polyacrylamide
      separation/renaturation procedure led to the hypothesis that this protein might
      be Pax-6, a conclusion that was confirmed by gel supershift assays. Additional
      experiments revealed a second non-consensus Pax-6 binding site in the -306/-274
      IGRP promoter region. Pax-6 binding to these elements is unusual in that it
      appears to require both its homeo and paired domains. Interestingly, loss of Pax
      6 binding to the -273/ -246 element is compensated by Pax-6 binding to the -306/
      274 element and vice versa. Gel retardation assays revealed that another islet
      enriched transcription factor, namely Pdx-1, binds four non-consensus elements in
      the IGRP promoter. However, mutation of these elements has little effect on IGRP
      fusion gene expression. Although chromatin immunoprecipitation assays show that
      both Pax-6 and Pdx-1 bind to the IGRP promoter within intact cells, in contrast
      to the critical role of these factors in beta cell-specific insulin gene
      expression, IGRP gene transcription appears to require Pax-6 but not Pdx-1.

PMID- 15180991
TI  - Mitochondrial function is required for hydrogen peroxide-induced growth factor
      receptor transactivation and downstream signaling.
AB  - The transactivation of growth factor receptors is an early event in H(2)O(2)
      induced signaling, although proximal targets in this process remain unclear. We
      found that inhibition of flavin- or heme-containing proteins eliminated H(2)O(2)
      induced transactivation of the epidermal growth factor receptor and stimulation
      of its downstream targets, JNK and Akt. Inhibition of mitochondrial function with
      rotenone, antimycin A, KCN, carbonylcyanide-m-chlorophenylhydrazone, or
      oligomycin reproduced this effect, as did generation of mitochondrial DNA
      deficient (pseudo-rho(0)) cells. Mitochondrial function had no role in JNK
      activation in response to UV irradiation or tumor necrosis factor-alpha. The
      impact of mitochondrial function on H(2)O(2)-induced growth factor
      transactivation was ubiquitous and applied to both the vascular endothelial
      growth factor (VEGF)-2 receptor and the platelet-derived growth factor-beta
      receptor in endothelium and fibroblasts, respectively. In contrast, ligand
      induced growth factor activation was unrelated to mitochondrial function. Growth
      factor receptor transactivation and its downstream signaling in response to
      H(2)O(2) appeared to involve redox-sensitive mitochondrial events as they were
      abrogated by a mitochondrial-targeted antioxidants but not their nontargeted
      counterparts. Functionally, we found that mitochondrial-targeted antioxidants
      inhibited H(2)O(2)-induced apoptosis and cell death but had no effect with UV
      irradiation. These data establish a novel role for the mitochondrion as a
      proximal target specific to H(2)O(2)-induced signaling and growth factor
      transactivation.

PMID- 15180992
TI  - Role of sphingosine-1-phosphate phosphatase 1 in epidermal growth factor-induced
      chemotaxis.
AB  - Sphingosine-1-phosphate (S1P) is the ligand for a family of specific G protein
      coupled receptors that regulate a wide variety of cellular functions, including
      cytoskeletal rearrangements and cell motility. Because of the pivotal role of
      S1P, its levels are low and tightly regulated in a spatial-temporal manner
      through its synthesis catalyzed by sphingosine kinases and degradation by an S1P
      lyase and specific S1P phosphatases (SPP). Surprisingly, down-regulation of SPP-1
      enhanced migration toward epidermal growth factor (EGF); conversely,
      overexpression of SPP-1, which is localized in the endoplasmic reticulum,
      attenuated migration toward EGF. To determine whether the inhibitory effect on
      EGF-induced migration was because of decreased S1P or increased ceramide as a
      consequence of acylation of increased sphingosine by ceramide synthase, we used
      fumonisin B1, a specific inhibitor of ceramide synthase. Although fumonisin B1
      blocked ceramide production and increased sphingosine, it did not reverse the
      negative effect of SPP-1 expression on EGF- or S1P-induced chemotaxis. EGF
      activated the epidermal growth factor receptor to the same extent in SPP-1
      expressing cells, yet ERK1/2 activation was impaired. In agreement, PD98059, an
      inhibitor of the ERK-activating enzyme MEK, decreased EGF-stimulated migration.
      We next examined the possibility that intracellularly generated S1P might be
      involved in activating a G protein-coupled S1P receptor important for EGF
      directed migration. Treatment with pertussis toxin to inactivate Galpha(i)
      suppressed EGF-induced migration. Moreover, expression of regulator of G protein
      signaling 3, which inhibits S1P receptor signaling and completely prevented
      ERK1/2 activation mediated by S1P receptors, not only reduced migration toward
      S1P but also markedly reduced migration toward EGF. Collectively, these results
      suggest that metabolism of S1P by SPP-1 is important for EGF-directed cell
      migration.

PMID- 15180993
TI  - An RNA-binding domain in the thyroid hormone receptor enhances transcriptional
      activation.
AB  - Thyroid hormone plays important roles in development, differentiation, and
      metabolic homeostasis by binding to nuclear thyroid hormone receptors, which
      regulate target gene expression by interacting with DNA response elements and
      coregulatory proteins. We show that thyroid hormone receptors also are single
      stranded RNA binding proteins and that this binding is functionally significant.
      By using a series of deletion mutants, a novel RNA-binding domain was localized
      to a 41-amino acid segment of thyroid hormone receptor alpha1 between the second
      zinc finger and the ligand-binding domain. This RNA-binding domain was necessary
      and sufficient for thyroid hormone receptor binding to the steroid receptor RNA
      activator (SRA). Although SRA does not bind directly to steroid receptors, it has
      been identified as a steroid receptor coactivator, and was thought not to be a
      coactivator for thyroid hormone receptors. However, transfection studies revealed
      that SRA enhances thyroid hormone induction of appropriate reporter genes and
      that the thyroid hormone receptor RNA-binding domain is important for this
      enhancement. We conclude that thyroid hormone receptors bind RNA through a novel
      domain and that the interaction of this domain with SRA, and perhaps other RNAs,
      enhances thyroid hormone receptor function.

PMID- 15180994
TI  - Effectors of lysine 4 methylation of histone H3 in Saccharomyces cerevisiae are
      negative regulators of PHO5 and GAL1-10.
AB  - Post-translational modifications of histone amino-terminal tails are a key
      determinant in gene expression. Histone methylation plays a dual role in gene
      regulation. Methylation of lysine 9 of histone H3 in higher eukaryotes is
      associated with transcriptionally inactive heterochromatin, whereas H3 lysine 4
      methylation correlates with active chromatin. Methylation of lysine 4 of H3 via
      Set1, a component of the Saccharomyces cerevisiae COMPASS complex, is regulated
      by the transcriptional elongation Paf1-Rtf1 and histone ubiquitination Rad6-Bre1
      complexes, which are required for the expression of a subset of genes. This
      suggests that lysine 4 methylation of histone H3 may play an activating role in
      transcription; however, the mechanism of Set1 function remains unclear. We show
      here that H3 lysine 4 methylation also negatively regulated gene expression, as
      strains without Set1 showed enhanced expression of PHO5, wherein chromatin
      structure plays an important transcriptional regulatory role. Di- and
      trimethylation of H3 lysine 4 was detected at the PHO5 promoter, and a strain
      expressing a mutant version of histone H3 with lysine 4 changed to arginine,
      (which cannot be methylated) exhibited PHO5 derepression. Moreover, PHO5 was
      derepressed in strains that lacked components of either the Paf1-Rtf1 elongation
      or Rad6-Bre1 histone ubiquitination complexes. Lastly, PHO84 and GAL1-10
      transcription was also increased in set1Delta cells. These results suggest that
      H3 methylation at lysine 4, in conjunction with transcriptional elongation, may
      function in a negative feedback pathway for basal transcription of some genes,
      although being a positive effector at others.

PMID- 15180996
TI  - Arabidopsis thaliana glutamate-cysteine ligase: functional properties, kinetic
      mechanism, and regulation of activity.
AB  - In plants, glutathione accumulates in response to different stress stimuli as a
      protective mechanism, but only limited biochemical information is available on
      the plant enzymes that synthesize glutathione. Glutamatecysteine ligase (GCL)
      catalyzes the first step in glutathione biosynthesis and plays an important role
      in regulating the intracellular redox environment. Because the putative
      Arabidopsis thaliana GCL (AtGCL) displays no significant homology to the GCL from
      bacteria and other eukaryotes, the identity of this protein as a GCL has been
      debated. We have purified AtGCL from an Escherichia coli expression system and
      demonstrated that the recombinant enzyme catalyzes the ATP-dependent formation of
      gamma-glutamylcysteine from glutamate (Km = 9.1 mm) and cysteine (Km = 2.7 mm).
      Glutathione feedback inhibits AtGCL (Ki approximately 1.0 mm). As with other GCL,
      buthionine sulfoximine and cystamine inactivate the Arabidopsis enzyme but with
      inactivation rates much slower than those of the mammalian, bacterial, and
      nematode enzymes. The slower inactivation rates observed with AtGCL suggest that
      the active site differs structurally from that of other GCL. Global fitting
      analysis of initial velocity data indicates that a random terreactant mechanism
      with a preferred binding order best describes the kinetic mechanism of AtGCL.
      Unlike the mammalian GCL, which consists of a catalytic subunit and a regulatory
      subunit, AtGCL functions and is regulated as a monomeric protein. In response to
      redox environment, AtGCL undergoes a reversible conformational change that
      modulates the enzymatic activity of the monomer. These results explain the
      reported posttranslational change in AtGCL activity in response to oxidative
      stress.

PMID- 15180995
TI  - The cell-specific expression of endothelial nitric-oxide synthase: a role for DNA
      methylation.
AB  - The basis for the endothelial cell-restricted expression of endothelial nitric
      oxide synthase (eNOS) is not known. While transgenic promoter/reporter mice
      demonstrated endothelium cell-specific eNOS expression, we found robust
      expression of episomal eNOS promoter/reporter constructs in cell types that do
      not express the native eNOS transcript. To explore the mechanism underlying this
      differential activity pattern of chromatin-versus episome-based eNOS promoters,
      we examined the methylation status of 5'-regulatory sequences of the human eNOS
      gene. DNA methylation differed dramatically between endothelial and
      nonendothelial cell types, including vascular smooth muscle cells. This same cell
      type-specific methylation pattern was observed in vivo in endothelial and
      vascular smooth muscle cells of the mouse aorta at the native murine eNOS
      promoter. We addressed the functional consequences of methylation on eNOS
      transcription using transient transfection of in vitro methylated
      promoter/reporter constructs and found that methylated constructs exhibited a
      marked decrease in the synergistic action of Sp1, Sp3, and Ets1 on eNOS promoter
      activity. The addition of methyl-CpG-binding protein 2 further reduced the
      transcriptional activity of methylated eNOS constructs. Importantly, chromatin
      immunoprecipitation demonstrated the presence of Sp1, Sp3, and Ets1 at the native
      eNOS promoter in endothelial cells but not in vascular smooth muscle cells.
      Finally, robust expression of eNOS mRNA was induced in nonendothelial cell types
      following inhibition of DNA methyltransferase activity with 5-azacytidine,
      demonstrating the importance of DNA methylation-mediated repression. This report
      is the first to show that promoter DNA methylation plays an important role in the
      cell-specific expression of a constitutively expressed gene in the vascular
      endothelium.

PMID- 15180997
TI  - Calcium-induced matrix metalloproteinase 9 gene expression is differentially
      regulated by ERK1/2 and p38 MAPK in oral keratinocytes and oral squamous cell
      carcinoma.
AB  - Matrix metalloproteinases (MMPs) play an important role in the invasive behavior
      of a number of cancers including oral squamous cell cancer (OSCC), and increased
      expression of MMP-9 is correlated with invasive and metastatic OSCC. Because
      calcium is an important regulator of keratinocyte function, the effect of
      modulating extracellular calcium on MMP-9 expression in OSCC cell lines was
      evaluated. Increasing extracellular calcium induced a dose-dependent increase in
      MMP-9 expression in immortalized normal and premalignant oral keratinocytes, but
      not in two highly invasive OSCC cell lines. Differential activation of MAPK
      signaling was also induced by calcium. p38 MAPK activity was down-regulated,
      whereas ERK1/2 activity was enhanced. Pharmacologic inhibition of p38 MAPK
      activity or expression of a catalytically inactive mutant of the upstream kinase
      MAPK kinase 3 (MKK3) increased the calcium induced MMP-9 gene expression,
      demonstrating that p38 MAPK activity negatively regulated this process.
      Interestingly blocking p38 MAPK activity enhanced ERK1/2 phosphorylation,
      suggesting reciprocal regulation between the ERK1/2 and p38 MAPK pathways.
      Together these data support a model wherein calcium-induced MMP-9 expression is
      differentially regulated by the ERK1/2 and p38 MAPK pathways in oral
      keratinocytes, and the data suggest that a loss of this regulatory mechanism
      accompanies malignant transformation of the oral epithelium.

PMID- 15180998
TI  - Crystal structure of Bacillus subtilis guanine deaminase: the first domain
      swapped structure in the cytidine deaminase superfamily.
AB  - Guanine deaminase, a key enzyme in the nucleotide metabolism, catalyzes the
      hydrolytic deamination of guanine into xanthine. The crystal structure of the 156
      residue guanine deaminase from Bacillus subtilis has been solved at 1.17-A
      resolution. Unexpectedly, the C-terminal segment is swapped to form an
      intersubunit active site and an intertwined dimer with an extensive interface of
      3900 A(2) per monomer. The essential zinc ion is ligated by a water molecule
      together with His(53), Cys(83), and Cys(86). A transition state analog was
      modeled into the active site cavity based on the tightly bound imidazole and
      water molecules, allowing identification of the conserved deamination mechanism
      and specific substrate recognition by Asp(114) and Tyr(156'). The closed
      conformation also reveals that substrate binding seals the active site entrance,
      which is controlled by the C-terminal tail. Therefore, the domain swapping has
      not only facilitated the dimerization but has also ensured specific substrate
      recognition. Finally, a detailed structural comparison of the cytidine deaminase
      superfamily illustrates the functional versatility of the divergent active sites
      found in the guanine, cytosine, and cytidine deaminases and suggests putative
      specific substrate-interacting residues for other members such as dCMP
      deaminases.

PMID- 15180999
TI  - Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are
      independent of peroxisome proliferator-activated receptor-alpha.
AB  - Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of
      monounsaturated fatty acids, which are required for normal rates of synthesis of
      triglycerides, cholesterol esters, and phospholipids. Mice with a targeted
      disruption of the stearoyl-CoA desaturase 1 (SCD1) isoform are protected against
      diet and leptin deficiency-induced adiposity, have increased energy expenditure,
      and have up-regulated expression of hepatic genes encoding enzymes of fatty acid
      beta-oxidation. Because peroxisome proliferator-activated receptor-alpha
      (PPARalpha) is a key transcription factor that induces the transcription of fatty
      acid beta-oxidation and thermogenic genes, we hypothesized that the increased
      fatty acid oxidation observed in SCD1 deficiency is dependent on activation of
      the PPARalpha pathway. Here we show that mice nullizygous for SCD1 and PPARalpha
      are still protected against adiposity, have increased energy expenditure, and
      maintain high expression of PPARalpha target genes in the liver and brown adipose
      tissue. The SCD1 deficiency rescued hepatic steatosis of the PPARalpha(-/-) mice.
      The SCD1 mutation increased the phosphorylation of both AMP-activated protein
      kinase and acetyl-CoA carboxylase, thereby increasing CPT activity and
      stimulating the oxidation of liver palmitoyl-CoA in the PPARalpha null mice. The
      findings indicate that the reduced adiposity, reduced liver steatosis, increased
      energy expenditure, and increased expression of PPARalpha target genes associated
      with SCD1 deficiency are independent of activation of the PPARalpha pathway.

PMID- 15181000
TI  - The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A
      resolution.
AB  - The structure of human P450 2C9 complexed with flurbiprofen was determined to 2.0
      A by x-ray crystallography. In contrast to other structurally characterized P450
      2C enzymes, 2C5, 2C8, and a 2C9 chimera, the native catalytic domain of P450 2C9
      differs significantly in the conformation of the helix F to helix G region and
      exhibits an extra turn at the N terminus of helix A. In addition, a distinct
      conformation of the helix B to helix C region allows Arg-108 to hydrogen bond
      with Asp-293 and Asn-289 on helix I and to interact directly with the carboxylate
      of flurbiprofen. These interactions position the substrate for regioselective
      oxidation in a relatively large active site cavity and are likely to account for
      the high catalytic efficiency exhibited by P450 2C9 for the regioselective
      oxidation of several anionic non-steroidal anti-inflammatory drugs. The structure
      provides a basis for interpretation of a number of observations regarding the
      substrate selectivity of P450 2C9 and the observed effects of mutations on
      catalysis.

PMID- 15181001
TI  - Regulation of malonyl-CoA concentration and turnover in the normal heart.
AB  - The goal of this study was to test the relationship between malonyl-CoA
      concentration and its turnover measured in isolated rat hearts perfused with
      NaH(13)CO(3). This turnover is a direct measurement of the flux of acetyl-CoA
      carboxylation in the intact heart. It also reflects the rate of malonyl-CoA
      decarboxylation, i.e. the only known fate of malonyl-CoA in the heart. Conditions
      were selected to result in stable malonyl-CoA concentrations ranging from 1.5 to
      5 nmol.g wet weight-(1). The malonyl-CoA concentration was directly correlated
      with the turnover of malonyl-CoA, ranging from 0.7 to 4.2 nmol.min(-) (1).g wet
      weight(-1) (slope = 0.98, r(2) = 0.94). The V(max) activities of acetyl-CoA
      carboxylase and of malonyl-CoA decarboxylase exceeded the rate of malonyl-CoA
      turnover by 2 orders of magnitude and did not correlate with either concentration
      or turnover of malonyl-CoA. However, conditions of perfusion that increased
      acetyl-CoA supply resulted in higher turnover and concentration, demonstrating
      that malonyl-CoA turnover is regulated by the supply of acetyl-CoA. The only
      condition where the activity of malonyl-CoA decarboxylase regulated malonyl-CoA
      kinetics was when the enzyme was pharmacologically inhibited, resulting in
      increased malonyl-CoA concentration and decreased turnover. Our data show that,
      in the absence of enzyme inhibitors, the rate of acetyl-CoA carboxylation is the
      main determinant of the malonyl-CoA concentration in the heart.

PMID- 15181002
TI  - Redox reactions of the iron-sulfur cluster in a ribosomal RNA methyltransferase,
      RumA: optical and EPR studies.
AB  - An unprecedented [4Fe-4S] iron-sulfur cluster was found in RumA, the enzyme that
      methylates U1939 in Escherichia coli 23 S ribosomal RNA (Agarwalla, S., Kealey,
      J. T., Santi, D. V., and Stroud, R. M. (2002) J. Biol. Chem. 277, 8835-8840; Lee,
      T. T., Agarwalla, S., and Stroud, R. M. (2004) Structure 12, 397-407).
      Methyltransferase reactions do not involve a redox step. To understand the
      structural and functional roles of the cluster in RumA, we have characterized
      redox reactions of the iron-sulfur cluster. As isolated aerobically, RumA
      exhibits a visible absorbance maximum at 390 nm and is EPR silent. It cannot be
      reduced by anaerobic additions of dithionite. Photoreduction by
      deazariboflavin/EDTA gives EPR spectra, the quantity (56% of S = 1/2 species) and
      details (g(av) approximately 1.96-1.93) of which indicate a [4Fe-4S](1+) cluster
      in the reduced RumA. Oxidation of RumA by ferricyanide leads to loss of the 390
      nm band and appearance of lower intensity bands at 444 and 520 nm. EPR spectra of
      ferricyanide-oxidized RumA show a fraction (<8%) of the FeS cluster trapped in
      the [3Fe-4S](1+) form (g(av) approximately 2.011) together with unusual radical
      like spectrum (g' values 2.015, 2.00, and 1.95). RumA also reacts with nitric
      oxide to give EPR spectra characteristic of the protein-bound iron dinitrosyl
      species. Oxidation of the cluster leads to its decomposition and that could be a
      mechanism for regulating the activity of RumA under conditions of oxidative
      stress in the cell. Sequence data base searches revealed that RumA homologs are
      widespread in various kingdoms of life and contain a conserved and unique iron
      sulfur cluster binding motif, CX(5)CGGC.

PMID- 15181004
TI  - Fungal metabolic model for type I 3-methylglutaconic aciduria.
AB  - Aspergillus nidulans catabolizes Leu to acetyl-CoA and acetoacetate through a
      pathway homologous to that used by humans. Fungal hlyA encodes a bifunctional
      polypeptide comprising the last two enzymes in this pathway, 3-methylglutaconyl
      CoA hydratase and 3-hydroxy-3-methylglutaryl-CoA lyase. hlyA transcription is
      specifically induced by Leu. A Delta hlyA mutation removing the complete 3
      methylglutaconyl-CoA hydratase C-terminal domain prevents growth on Leu but not
      on lactose or other amino acids and, in agreement with the predicted enzyme
      function, leads to Leu-dependent accumulation of 3-methylglutaconic acid in the
      culture supernatant. These data represent a formal demonstration in vivo of the
      specific involvement of 3-methylglutaconyl-CoA hydratase in Leu catabolism. Type
      I 3-methylglutaconic aciduria patients deficient in 3-methylglutaconyl-CoA
      hydratase show urinary excretion of 3-methylglutaconic acid and, in contrast to
      the other three types of methylglutaconic acidurias, 3-hydroxyisovaleric acid
      excretion. Gas chromatography-mass spectrometry analysis revealed an accumulation
      of both diagnostic compounds in Delta hlyA culture supernatants, illustrating
      that the metabolic consequences of equivalent inborn errors of metabolism are
      conserved from fungi to humans. Using our fungal type I 3-methylglutaconic
      aciduria model, we show that metabolites accumulating in the deficient strain are
      toxic, although less so than those accumulating in a Delta mccB strain deficient
      for the upstream enzyme 3-methylcrotonyl-CoA carboxylase. Diagnostic metabolite
      accumulation is Leu concentration-dependent, in agreement with the ability of Leu
      intake restriction to reduce the levels of offending metabolites. Delta mccB and
      Delta hlyA mutations show additive Leu toxicities. The double mutant accumulates
      3-methylglutaconic acid, which can therefore be synthesized through 3
      methylcrotonyl-CoA carboxylase-dependent and -independent reactions.

PMID- 15181003
TI  - The dual nature of the wheat xylanase protein inhibitor XIP-I: structural basis
      for the inhibition of family 10 and family 11 xylanases.
AB  - The xylanase inhibitor protein I (XIP-I) from wheat Triticum aestivum is the
      prototype of a novel class of cereal protein inhibitors that inhibit fungal
      xylanases belonging to glycoside hydrolase families 10 (GH10) and 11 (GH11). The
      crystal structures of XIP-I in complex with Aspergillus nidulans (GH10) and
      Penicillium funiculosum (GH11) xylanases have been solved at 1.7 and 2.5 A
      resolution, respectively. The inhibition strategy is novel because XIP-I
      possesses two independent enzyme-binding sites, allowing binding to two glycoside
      hydrolases that display a different fold. Inhibition of the GH11 xylanase is
      mediated by the insertion of an XIP-I Pi-shaped loop (Lalpha(4)beta(5)) into the
      enzyme active site, whereas residues in the helix alpha7 of XIP-I, pointing into
      the four central active site subsites, are mainly responsible for the reversible
      inactivation of GH10 xylanases. The XIP-I strategy for inhibition of xylanases
      involves substrate-mimetic contacts and interactions occluding the active site.
      The structural determinants of XIP-I specificity demonstrate that the inhibitor
      is able to interact with GH10 and GH11 xylanases of both fungal and bacterial
      origin. The biological role of the xylanase inhibitors is discussed in light of
      the present structural data.

PMID- 15181005
TI  - Nox3 regulation by NOXO1, p47phox, and p67phox.
AB  - gp91(phox) (Nox2), the catalytic subunit of the superoxide-generating respiratory
      burst oxidase, is regulated by subunits p47(phox) and p67(phox). Nox1, a homolog
      of gp91(phox), is regulated by NOXO1 and NOXA1, homologs of p47(phox) and
      p67(phox), respectively. For both Nox1 and gp91(phox), an organizer protein
      (NOXO1 or p47(phox)) cooperates with an activator protein (NOXA1 or p67(phox)) to
      regulate the catalytic subunit. Herein, we investigate the subunit regulation of
      Nox3 compared with that of other Nox enzymes. Nox3, like gp91(phox), was
      activated by p47(phox) plus p67(phox). Whereas gp91(phox) activity required the
      protein kinase C activator phorbol myristate acetate (PMA), Nox3 activity was
      already high without PMA, but was further stimulated approximately 30% by PMA.
      gp91(phox) was also activated by NOXO1/NOXA1 and required PMA for high activity.
      gp91(phox) regulation required an intact activation domain in the activator
      protein, as neither p67(phox)(V204A) nor NOXA1(V205A) were effective. In
      contrast, p67(phox)(V204A) was effective (along with p47(phox)) in activating
      Nox3. Unexpectedly, Nox3 was strongly activated by NOXO1 in the absence of NOXA1
      or p67(phox). Nox3 activity was regulated by PMA only when p47(phox) but not
      NOXO1 was present, consistent with the phosphorylation-regulated autoinhibitory
      region in p47(phox) but not in NOXO1. Deletion of the autoinhibitory region from
      p47(phox) rendered this subunit highly active in the absence of PMA toward both
      gp91(phox) and Nox3, and high activity required an activator subunit. The unique
      regulation of Nox3 supports a model in which multiple interactions with
      regulatory subunits stabilize an active conformation of the catalytic subunit.

PMID- 15181006
TI  - Weak base permeability characteristics influence the intracellular sequestration
      site in the multidrug-resistant human leukemic cell line HL-60.
AB  - A number of organelles contained within mammalian cells have been implicated in
      the selective sequestration of chemical entities including drug molecules.
      Specifically, weakly basic molecules have been shown to selectively associate
      with either the mitochondrial compartment or lysosomes; however, the structural
      basis for this differentiation has not been understood. To investigate this, we
      have identified a series of seven weakly basic compounds, all with pK(a) near
      neutrality, which have different sequestration sites within the multidrug
      resistant HL-60 human leukemic cell line. Three of the compounds were selectively
      sequestered into the mitochondria of the cells, whereas the remainder were
      predominantly localized within lysosomes. Using specific chemical inhibitors to
      disrupt either mitochondrial or lysosomal accumulation capacity, we demonstrated
      that accumulation of these compounds into respective organelles are not
      competitive processes. Comparison of the permeability characteristics of these
      compounds as a function of pH revealed striking differences that correlate with
      the intracellular sequestration site. Only those compounds with significantly
      reduced permeability in the ionized state relative to the un-ionized state had
      the capacity to accumulate within lysosomes. Alternatively, those compounds with
      relatively pH-insensitive permeability selectively accumulated into mitochondria.
      Using novel quantitative assays for assaying drug accumulation into subcellular
      organelles, we demonstrated a correlation between these permeability
      characteristics and the lysosomal versus mitochondrial accumulation capacity of
      these compounds. Together, these results suggest that the selective accumulations
      of weakly basic compounds in either lysosomes and mitochondria occur via
      exclusive pathways governed by a unique permeability parameter.

PMID- 15181008
TI  - Phosphoglycerate mutase-derived polypeptide inhibits glycolytic flux and induces
      cell growth arrest in tumor cell lines.
AB  - The putative tumor metastasis suppressor protein Nm23-H1 is a nucleoside
      diphosphate kinase that exhibits a novel protein kinase activity when bound to
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In this study we show that the
      glycolytic enzyme phosphoglycerate mutase B (PGM) becomes phosphorylated in the
      presence of the Nm23-H1.GAPDH complex in vitro. Mutation of His-10 in PGM
      abolishes the Nm23-H1.GAPDH complex-induced phosphorylation. Nm23-H1, GAPDH, and
      PGM are known to co-localize as shown by free flow isoelectric focusing. In
      association with Nm23-H1 and GAPDH, PGM could be activated by dCTP, which is a
      substrate of Nm23-H1, in addition to the well known PGM activator 2,3
      bisphosphoglycerate. A synthetic cell-penetrating peptide (PGMtide) encompassing
      the phosphorylated histidine and several residues from PGM (LIRHGE) promoted
      growth arrest of several tumor cell lines, whereas proliferation of tested non
      tumor cells was not influenced. Analysis of metabolic activity of one of the
      tumor cell lines, MCF-7, indicated that PGMtide inhibited glycolytic flux,
      consistent with in vivo inhibition of PGM. The specificity of the observed effect
      was further determined experimentally by testing the effect of PGMtide on cells
      growing in the presence of pyruvate, which helps to compensate PGM inhibition in
      the glycolytic pathway. Thus, growth of MCF-7 cells was not arrested by PGMtide
      in the presence of pyruvate. The data presented here provide evidence that
      inhibition of PGM activity can be achieved by exogenous addition of a
      polypeptide, resulting in inhibition of glycolysis and cell growth arrest in cell
      culture.

PMID- 15181007
TI  - Cyclooxygenase-1-dependent prostaglandin synthesis modulates tumor necrosis
      factor-alpha secretion in lipopolysaccharide-challenged murine resident
      peritoneal macrophages.
AB  - Comprehensive studies of prostaglandin (PG) synthesis in murine resident
      peritoneal macrophages (RPM) responding to bacterial lipopolysaccharide (LPS)
      revealed that the primary PGs produced by RPM were prostacyclin and PGE(2).
      Detectable increases in net PG formation occurred within the first hour, and
      maximal PG formation had occurred by 6-10 h after LPS addition. Free arachidonic
      acid levels rose and peaked at 1-2 h after LPS addition and then returned to
      baseline. Cyclooxygenase-2 (COX-2) and microsomal PGE synthase levels markedly
      increased upon exposure of RPM to LPS, with the most rapid increases in protein
      expression occurring 2-6 h after addition of the stimulus. RPM constitutively
      expressed high levels of COX-1. Studies using isoform-selective inhibitors and
      RPM from mice bearing targeted deletions of ptgs-1 and ptgs-2 demonstrated that
      COX-1 contributes significantly to PG synthesis in RPM, especially during the
      initial 1-2 h after LPS addition. Selective inhibition of either COX isoform
      resulted in increased secretion of tumor necrosis factor-alpha (TNF-alpha);
      however, this effect was much greater with the COX-1 than with the COX-2
      inhibitor. These results demonstrate autocrine regulation of TNF-alpha secretion
      by endogenous PGs synthesized primarily by COX-1 in RPM and suggest that COX-1
      may play a significant role in the regulation of the early response to
      endotoxemia.

PMID- 15181009
TI  - Stripping down the mitochondrial cholesterol hydroxylase system, a kinetics
      study.
AB  - The origin of steroid hormones in mammals is cholesterol that is metabolized by
      the mitochondrial CYP11A1 system. The cytochrome P450 is fed with reduction
      equivalents via a small electron transfer chain consisting of NADPH, adrenodoxin
      reductase, and adrenodoxin. Though the redox behavior of the individual protein
      components has been studied previously, the kinetics of the system in its
      entirety has not yet been analyzed. In this study we combine surface plasmon
      resonance experiments to determine the binding constants for the different pairs
      of redox partners with measurements of the pre-steady-state kinetics of the
      different reaction steps of this system and steady-state kinetics. We could
      correlate the individual protein-protein interactions with the effect of distinct
      reduction-oxidation steps on the overall catalytic activity of the CYP11A1
      system. For the first time, we were able to follow the reduction of each of the
      protein components of this system within one measurement when we mixed all
      oxidized protein components with NADPH. These measurements allowed the
      determination of the individual apparent rate constants for the reduction of all
      three proteins involved. In addition, variation of the ionic strength in these
      experiments revealed different optimum salt concentrations for the reduction of
      adrenodoxin reductase and adrenodoxin, respectively, and unraveled dramatically
      changing reduction rates of CYP11A1 by adrenodoxin.

PMID- 15181010
TI  - Localization of a catalytic intermediate bound to the FeMo-cofactor of
      nitrogenase.
AB  - Nitrogenase catalyzes the biological reduction of N(2) to ammonia (nitrogen
      fixation) as well as the reduction of a number of alternative substrates,
      including acetylene (HC identical with CH) to ethylene (H2C=CH2). It is known
      that the metallocluster FeMo-cofactor located within the nitrogenase MoFe protein
      component provides the site of substrate reduction, but the exact site where
      substrates bind and are reduced on the FeMo-cofactor remains unknown. We have
      recently shown that the alpha-70 residue of the MoFe protein plays a significant
      role in defining substrate access to the active site; alpha-70 approaches one
      face of the FeMo-cofactor, and when valine is substituted by alanine at this
      position, the substituted nitrogenase is able to accommodate a reduction of the
      larger alkyne propargyl alcohol (HC identical with CCH(2)OH, propargyl-OH).
      During this reduction, a substrate-derived intermediate can be trapped on the
      FeMo-cofactor resulting in an S = 1/2 spin system with a novel electron
      paramagnetic resonance spectrum. In the present work, trapping of the propargyl
      OH-derived or propargyl amine (HC identical with CCH(2)NH(2), propargyl-NH(2))
      derived intermediates is shown to be dependent on pH and the presence of
      histidine at position alpha-195. It is concluded that these catalytic
      intermediates are stabilized and thereby trapped by H-bonding interactions
      between either the-OH group or the-NH(3)(+)group and the imidazole epsilon-NH of
      alpha-195(His). Thus, for the first time it is possible to establish the location
      of a bound substrate-derived intermediate on the FeMo-cofactor. Refinement of the
      binding mode and site was accomplished by the use of density functional and force
      field calculations pointing to an eta(2) coordination at Fe-6 of the FeMo
      cofactor.

PMID- 15181011
TI  - Transcriptional repressor DREAM interacts with thyroid transcription factor-1 and
      regulates thyroglobulin gene expression.
AB  - Tissue-specific gene expression depends on the interaction between tissue
      specific and general transcription factors. DREAM is a Ca2+-dependent
      transcriptional repressor widely expressed in the brain where it participates in
      nociception through its control of prodynorphin gene expression. In the
      periphery, DREAM is highly expressed in the thyroid gland, the immune system, and
      the reproductive organs. Here, we show that DREAM interacts with thyroid-specific
      transcription factor TTF-1 and regulates the expression of the thyroglobulin (Tg)
      gene. The mechanism also involves binding of DREAM to the thyroglobulin promoter
      and blockage of TTF-1-mediated transactivation. The TSH/cAMP pathway and Ca2+
      signaling regulate DREAM-mediated transcriptional repression of the thyroglobulin
      gene. Furthermore, chromatin immunoprecipitation experiments in FRTL-5 cells
      confirmed that Tg is a bona fide target gene for DREAM transrepression in thyroid
      follicular cells.

PMID- 15181012
TI  - Functional domains of Brevibacillus thermoruber lon protease for oligomerization
      and DNA binding: role of N-terminal and sensor and substrate discrimination
      domains.
AB  - Lon protease is a multifunctional enzyme, and its functions include the
      degradation of damaged proteins and naturally short lived proteins, ATPase and
      chaperone-like activities, as well as DNA binding. A thermostable Lon protease
      from Brevibacillus thermoruber WR-249 (Bt-Lon) has been cloned and characterized
      with an N-terminal domain, a central ATPase domain that includes a sensor and
      substrate discrimination (SSD) domain, and a C-terminal protease domain. Here we
      present a detailed structure-function characterization of Bt-Lon, not only
      dissecting the individual roles of Bt-Lon domains in oligomerization, catalytic
      activities, chaperone-like activity, and DNA binding activity but also describing
      the nature of oligomerization. Seven truncated mutants of Bt-Lon were designed,
      expressed, and purified. Our results show that the N-terminal domain is essential
      for oligomerization. The truncation of the N-terminal domain resulted in the
      failure of oligomerization and led to the inactivation of proteolytic, ATPase,
      and chaperone-like activities but retained the DNA binding activity, suggesting
      that oligomerization of Bt-Lon is a prerequisite for its catalytic and chaperone
      like activities. We further found that the SSD is involved in DNA binding based
      on gel mobility shift assays. On the other hand, the oligomerization of Bt-Lon
      proceeds through a dimer <--> tetramer <--> hexamer assembly model revealed by
      chemical cross-linking experiments. The results also showed that hydrophobic
      interactions may play important roles in the dimerization of Bt-Lon, and ionic
      interactions are mainly responsible for the assembly of hexamers.

PMID- 15181013
TI  - Solution structure of Cox11, a novel type of beta-immunoglobulin-like fold
      involved in CuB site formation of cytochrome c oxidase.
AB  - Cytochrome c oxidase assembly process involves many accessory proteins including
      Cox11, which is a copper-binding protein required for Cu incorporation into the
      Cu(B) site of cytochrome c oxidase. In a genome wide search, a number of Cox11
      homologs are found in all of the eukaryotes with complete genomes and in several
      Gram-negative bacteria. All of them possess a highly homologous soluble domain
      and contain an N-terminal fragment that anchors the protein to the membrane. An
      anchor-free construct of 164 amino acids was obtained from Sinorhizobium
      meliloti, and the first structure of this class of proteins is reported here. The
      apoform has an immunoglobulin-like fold with a novel type of beta-strand
      organization. The copper binding motif composed of two highly conserved cysteines
      is located on one side of the beta-barrel structure. The apoprotein is monomeric
      in the presence of dithiothreitol, whereas it dimerizes in the absence of the
      reductant. When copper(I) binds, NMR and extended x-ray absorption fine structure
      (EXAFS) data indicate a dimeric protein state with two thiolates bridging two
      copper(I) ions. The present results advance the knowledge on the poorly
      understood molecular aspects of cytochrome c oxidase assembly.

PMID- 15181014
TI  - Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte
      insulin signaling.
AB  - Many proinflammatory cytokines and hormones have been demonstrated to be involved
      in insulin resistance. However, the molecular mechanisms whereby these cytokines
      and hormones inhibit insulin signaling are not completely understood. We observed
      that several cytokines and hormones that induce insulin resistance also stimulate
      SOCS3 expression in 3T3-L1 adipocytes and that SOCS3 mRNA is increased in adipose
      tissue of obese/diabetic mice. We then hypothesized that SOCS3 may mediate
      cytokine- and hormone-induced insulin resistance. By using SOCS3-deficient
      adipocytes differentiated from mouse embryonic fibroblasts, we found that SOCS3
      deficiency increases insulin-stimulated IRS1 and IRS2 phosphorylation, IRS
      associated phosphatidylinositol 3-kinase activity, and insulin-stimulated glucose
      uptake. Moreover, lack of SOCS3 substantially limits the inhibitory effects of
      tumor necrosis factor-alpha to suppress IRS1 and IRS2 tyrosine phosphorylation,
      phosphatidylinositol 3-kinase activity, and glucose uptake in adipocytes. The
      ameliorated insulin signaling in SOCS3-deficient adipocytes is mainly due to the
      suppression of tumor necrosis factor-alpha-induced IRS1 and IRS2 protein
      degradation. Therefore, our data suggest that endogenous SOCS3 expression is a
      key determinant of basal insulin signaling and is an important molecular mediator
      of cytokine-induced insulin resistance in adipocytes. We conclude that SOCS3
      plays an important role in mediating insulin resistance and may be an excellent
      target for therapeutic intervention in insulin resistance and type II diabetes.

PMID- 15181015
TI  - The P34G mutation reduces the transforming activity of K-Ras and N-Ras in NIH 3T3
      cells but not of H-Ras.
AB  - Ras proteins (H-, N-, and K-Ras) operate as molecular switches in signal
      transduction cascades controlling cell proliferation, differentiation, or
      apoptosis. The interaction of Ras with its effectors is mediated by the effector
      binding loop, but different data about Ras location to plasma membrane subdomains
      and new roles for some docking/scaffold proteins point to signaling specificities
      of the different Ras proteins. To investigate the molecular mechanisms for these
      specificities, we compared an effector loop mutation (P34G) of three Ras isoforms
      (H-, N-, and K-Ras4B) for their biological and biochemical properties. Although
      this mutation diminished the capacity of Ras proteins to activate the Raf/ERK and
      the phosphatidylinositol 3-kinase/AKT pathways, the H-Ras V12G34 mutant retained
      the ability to cause morphological transformation of NIH 3T3 fibroblasts, whereas
      both the N-Ras V12G34 and the K-Ras4B V12G34 mutants were defective in this
      biological activity. On the other hand, although both the N-Ras V12G34 and the K
      Ras4B V12G34 mutants failed to promote activation of the Ral-GDS/Ral A/PLD and
      the Ras/Rac pathways, the H-Ras V12G34 mutant retained the ability to activate
      these signaling pathways. Interestingly, the P34G mutation reduced specifically
      the N-Ras and K-Ras4B in vitro binding affinity to Ral-GDS, but not in the case
      of H-Ras. Thus, independently of Ras location to membrane subdomains, there are
      marked differences among Ras proteins in the sensitivity to an identical mutation
      (P34G) affecting the highly conserved effector-binding loop.

PMID- 15181016
TI  - Connexin43 interacts with NOV: a possible mechanism for negative regulation of
      cell growth in choriocarcinoma cells.
AB  - The gap junction protein connexin43 (Cx43) is thought to be involved in growth
      control in several tissues. Using the doxycycline inducible tet-on system, we
      generated human malignant trophoblast Jeg3 cells transfected with either Cx40,
      Cx43, or C-terminal truncated Cx43 (trCx43). Cx43, but not Cx40 or trCx43,
      displayed a reduced cell growth of Jeg3 cells in vitro and tumor growth in nude
      mice, suggesting a role of the C terminus of Cx43 in growth regulation. Using
      gene array analysis, the growth regulator NOV (CCN3), a member of the CCN gene
      family, was found to be up-regulated only in the Cx43-transfected cells.
      Validation by reverse transcriptase-PCR confirmed an up-regulation of the NOV
      transcript exclusively upon Cx43 induction. In contrast to Cx40 or trCx43,
      induction of Cx43 led to a switch in localization of NOV from the nucleus to the
      cell membrane, where it is colocalized with Cx43. Coimmunoprecipitation showed a
      binding of NOV to the C terminus of Cx43 in vitro as well as in transfected
      cells. Jeg3 cells transfected only with NOV revealed that NOV itself acts as a
      growth regulator. We suggest that Cx43 is able to regulate cell growth via an up
      regulation of NOV transcription, a change in localization of the NOV protein and
      a binding of NOV to the C terminus of Cx43.

PMID- 15181019
TI  - The epidemic of obesity.
AB  - As the obesity epidemic spreads, concern about the significant health and
      economic consequences has also grown. Obesity has been linked to a variety of
      chronic diseases, almost 300,000 deaths each year, and 117 billion dollars in
      direct and indirect annual costs in the United States alone. In this article we
      review the recent trends in overweight and obesity, summarize the lifestyle
      factors that influence the increasing prevalence of obesity, and discuss the
      health and economic impact of the obesity epidemic.

PMID- 15181017
TI  - Spermatocyte/spermatid-specific thioredoxin-3, a novel Golgi apparatus-associated
      thioredoxin, is a specific marker of aberrant spermatogenesis.
AB  - Mammalian germ cells are endowed with a complete set of thioredoxins (Trx), a
      class of redox proteins located in specific structures of the spermatid and sperm
      tail. We report here the characterization, under normal and pathological
      conditions, of a novel thioredoxin with a germ line-restricted expression
      pattern, named spermatocyte/spermatid-specific thioredoxin-3 (SPTRX-3). The human
      SPTRX-3 gene maps at 9q32, only 50 kb downstream from the TRX-1 gene from which
      it probably originated as genomic duplication. Therefore, human SPTRX-3 protein
      comprises a unique thioredoxin domain displaying high homology with the
      ubiquitously expressed TRX-1. Among the tissues investigated, Sptrx-3 mRNA is
      found exclusively in the male germ cells at pachytene spermatocyte and round
      spermatid stages. Light and electron microscopy show SPTRX-3 protein to be
      predominately located in the Golgi apparatus of pachytene spermatocytes and round
      and elongated spermatids, with a transient localization in the developing
      acrosome of round spermatids. In addition, increased levels of SPTRX-3, possibly
      caused by overexpression, are observed in morphologically abnormal human
      spermatozoa from infertile men. In addition, SPTRX-3 is identified as a novel
      postobstruction autoantigen. In this report, we propose that SPTRX-3 can be used
      as a specific marker for diverse sperm and testis pathologies. SPTRX-3 is the
      first thioredoxin specific to the Golgi apparatus, and its function within this
      organelle might be related to the post-translational modification of proteins
      required for germ cell-specific functions, such as acrosomal biogenesis.

PMID- 15181020
TI  - Insulin resistance syndrome in children.
AB  - The insulin resistance syndrome (syndrome X, metabolic syndrome) has become the
      major health problem of our times. Associated obesity, dyslipidemia,
      atherosclerosis, hypertension, and type 2 diabetes conspire to shorten life
      spans, while hyperandrogenism with polycystic ovarian syndrome affect the quality
      of life and fertility of increasing numbers of women. Whereas a growing number of
      single genetic diseases affecting satiety or energy metabolism have been found to
      produce the clinical phenotype, strong familial occurrences, especially in
      racially prone groups such as those from the Indian subcontinent, or individuals
      of African, Hispanic, and American Indian descents, together with emerging
      genetic findings, are revealing the polygenetic nature of the syndrome. However,
      the strong lifestyle factors of excessive carbohydrate and fat consumption and
      lack of exercise are important keys to the phenotypic expression of the syndrome.
      The natural history includes small for gestational age birth weight, excessive
      weight gains during childhood, premature pubarche, an allergic diathesis,
      acanthosis nigricans, striae compounded by gynecomastia, hypertriglyceridemia,
      hepatic steatosis, premature atherosclerosis, hypertension, polycystic ovarian
      syndrome, and focal glomerulonephritis appearing increasingly through adolescence
      into adulthood. Type 2 diabetes, which develops because of an inherent and/or an
      acquired failure of an insulin compensatory response, is increasingly seen from
      early puberty onward, as is atheromatous disease leading to coronary heart
      disease and stroke. A predisposition to certain cancers and Alzheimer's disease
      is also now recognized. The looming tragedy from growing numbers of individuals
      affected by obesity/insulin resistance syndrome requires urgent public health
      approaches directed at their early identification and intervention during
      childhood. Such measures include educating the public on the topic, limiting the
      consumption of sucrose-containing drinks and foods with high carbohydrate and fat
      contents, and promoting exercise programs in our nation's homes and schools.

PMID- 15181021
TI  - The pediatric obesity epidemic: causes and controversies.
AB  - Obesity in children and adolescents has reached alarming proportions in the
      United States. Nutritional surveys do not indicate a significant increase in
      caloric intake in children and adolescents over the last 3 decades, although
      caloric intake has increased recently in adolescent females. Dietary fat has also
      been falling. There is no conclusive evidence linking physical inactivity to the
      obesity epidemic, and longitudinal studies indicate that physical inactivity may
      be the result of obesity rather than its cause. Hence, attention should be
      focused on dietary carbohydrate. Carbohydrate intake has increased as a result of
      the decrease in dietary fat. Indirect evidence also indicates that the quality of
      carbohydrate has been changing, so that American children are eating more
      carbohydrates with a higher glycemic index. It is proposed that high-glycemic
      index diets lead to excessive weight gain as a consequence of postprandial
      hyperinsulinemia. Low-glycemic-index diets lower postprandial insulin levels and
      insulin resistance. It seems likely that diets restricted in sweetened sodas and
      noncitrus juices and containing ample whole grains, vegetables, and fruit could
      have a major impact on the prevalence of pediatric obesity.

PMID- 15181022
TI  - Adipose tissue as an endocrine organ.
AB  - Adipose tissue is a complex, essential, and highly active metabolic and endocrine
      organ. Besides adipocytes, adipose tissue contains connective tissue matrix,
      nerve tissue, stromovascular cells, and immune cells. Together these components
      function as an integrated unit. Adipose tissue not only responds to afferent
      signals from traditional hormone systems and the central nervous system but also
      expresses and secretes factors with important endocrine functions. These factors
      include leptin, other cytokines, adiponectin, complement components, plasminogen
      activator inhibitor-1, proteins of the renin-angiotensin system, and resistin.
      Adipose tissue is also a major site for metabolism of sex steroids and
      glucocorticoids. The important endocrine function of adipose tissue is emphasized
      by the adverse metabolic consequences of both adipose tissue excess and
      deficiency. A better understanding of the endocrine function of adipose tissue
      will likely lead to more rational therapy for these increasingly prevalent
      disorders. This review presents an overview of the endocrine functions of adipose
      tissue.

PMID- 15181023
TI  - Proopiomelanocortin and energy balance: insights from human and murine genetics.
AB  - Proopiomelanocortin (POMC) undergoes extensive and tissue-specific
      posttranslational processing to yield a range of biologically active peptides.
      Historically, the most clearly defined roles of these peptides are in the control
      of adrenal steroidogenesis by corticotroph-derived ACTH and skin pigmentation by
      alphaMSH. However, a rapidly expanding body of work has established that POMC
      derived peptides synthesized in neurons of the hypothalamus play a central role
      in the control of energy homeostasis. We review how inherited abnormalities in
      POMC synthesis and processing and defects in the action of POMC-derived peptides
      in both humans and mice have helped shape our current understanding of the
      importance of the melanocortin system in human energy balance.

PMID- 15181024
TI  - Adiponectin: A novel adipokine linking adipocytes and vascular function.
AB  - Cardiovascular disease accounts for an overwhelming proportion of the morbidity
      and mortality suffered by patients with obesity and type 2 diabetes mellitus, and
      recent work has elucidated several potential mechanisms by which increased
      adiposity enhances cardiovascular risk. Excess adipose tissue, especially in
      certain compartments, leads to reduced insulin sensitivity in metabolically
      responsive tissues, which is frequently associated with a set of cardiovascular
      risk factors, including hyperinsulinemia, hypertension, dyslipidemia, and glucose
      intolerance. Increasing attention has also been paid to the direct vascular
      effects of plasma proteins that originate from adipose tissue, especially
      adiponectin, which exhibits potent antiinflammatory and antiatherosclerotic
      effects. This brief review will summarize recent work on the vascular actions of
      adiponectin, which complements the growing body of information on its insulin
      sensitizing effects in glucose and lipid metabolism. Adiponectin is now a
      recognized component of a novel signaling network among adipocytes, insulin
      sensitive tissues, and vascular function that has important consequences for
      cardiovascular risk.

PMID- 15181025
TI  - Metabolic and body composition factors in subgroups of obesity: what do we know?
AB  - Obesity is thought to be a heterogeneous disorder with several possible
      etiologies; therefore, by examining subtypes of obesity we attempt to understand
      obesity's heterogeneous nature. The purpose of this review was to investigate the
      roles of metabolic, body composition, and cardiovascular disease risk in subtypes
      of obesity. We briefly consider two subtypes of obesity that have been identified
      in the literature. One subset of individuals, termed the metabolically healthy,
      but obese (MHO), despite having large amounts of fat mass compared with at risk
      obese individuals shows a normal metabolic profile, but remarkably normal to high
      levels of insulin sensitivity. Preliminary evidence suggests that this could be
      due at least in part to lower visceral fat levels and earlier onset of obesity. A
      second subset, termed the metabolically obese, but normal weight (MONW), present
      with normal body mass index, but have significant risk factors for diabetes,
      metabolic syndrome, and cardiovascular disease, which could be due to higher fat
      mass and plasma triglycerides as well as higher visceral fat and liver content.
      We also briefly consider the potential role of adipose and gastrointestinal
      hormonal profiles in MHO and MONW individuals, which could lead to a better
      understanding of potential factors that may regulate their body composition. This
      information will eventually be invaluable in helping us understand factors that
      predispose to or protect obese individuals from metabolic and cardiovascular
      disease. Collectively, a greater understanding of the MHO and MONW individual has
      important implications for therapeutic decision making, the characterization of
      subjects in research protocols, and medical education.

PMID- 15181026
TI  - The gut and regulation of body weight.
AB  - Signals generated by the gastrointestinal tract are able to regulate appetite and
      influence body weight. Ghrelin is an orexigenic peptide produced by the stomach.
      Satiety signals derived from the intestine and pancreas include peptide YY,
      pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and
      cholecystokinin. Signals from the gut and adipose tissue are integrated in the
      central nervous system to provide energy homeostasis. Knowledge of the body's
      control of appetite is important because we strive to combat obesity in man.

PMID- 15181027
TI  - Medical consequences of obesity.
AB  - Obesity is an epidemic disease that threatens to inundate health care resources
      by increasing the incidence of diabetes, heart disease, hypertension, and cancer.
      These effects of obesity result from two factors: the increased mass of adipose
      tissue and the increased secretion of pathogenetic products from enlarged fat
      cells. This concept of the pathogenesis of obesity as a disease allows an easy
      division of disadvantages of obesity into those produced by the mass of fat and
      those produced by the metabolic effects of fat cells. In the former category are
      the social disabilities resulting from the stigma associated with obesity, sleep
      apnea that results in part from increased parapharyngeal fat deposits, and
      osteoarthritis resulting from the wear and tear on joints from carrying an
      increased mass of fat. The second category includes the metabolic factors
      associated with distant effects of products released from enlarged fat cells. The
      insulin-resistant state that is so common in obesity probably reflects the
      effects of increased release of fatty acids from fat cells that are then stored
      in the liver or muscle. When the secretory capacity of the pancreas is
      overwhelmed by battling insulin resistance, diabetes develops. The strong
      association of increased fat, especially visceral fat, with diabetes makes this
      consequence particularly ominous for health care costs. The release of cytokines,
      particularly IL-6, from the fat cell may stimulate the proinflammatory state that
      characterizes obesity. The increased secretion of prothrombin activator inhibitor
      1 from fat cells may play a role in the procoagulant state of obesity and, along
      with changes in endothelial function, may be responsible for the increased risk
      of cardiovascular disease and hypertension. For cancer, the production of
      estrogens by the enlarged stromal mass plays a role in the risk for breast
      cancer. Increased cytokine release may play a role in other forms of
      proliferative growth. The combined effect of these pathogenetic consequences of
      increased fat stores is an increased risk of shortened life expectancy.

PMID- 15181028
TI  - Race/ethnic issues in obesity and obesity-related comorbidities.
AB  - The prevalence of obesity is increasing among all age and racial groups in the
      United States. There is, however, a disproportionate rise in the prevalence of
      obesity among African-Americans and Hispanic/Mexican Americans. Obesity is a
      major contributor to the insulin resistant syndrome (IRS), a condition of
      multiple metabolic abnormalities that is a precursor to type 2 diabetes, and
      confers a high risk for cardiovascular events. The estimated prevalence of IRS is
      also greater in Mexican Americans and African-Americans than in Caucasians. The
      IRS is identifiable in children, and as with adults, there are racial differences
      in its expression even at a young age. The obesity-associated diseases, including
      diabetes and hypertension, are found at higher rates within the minority races
      compared with Caucasians. However, there are differences, in that obesity-related
      hypertension occurs at higher rates among African-Americans, and obesity-related
      diabetes occurs at higher rates among Mexican Americans. Race/ethnic differences
      in lifestyle behaviors and economic disadvantage may account for some of the race
      disparity in obesity-related diseases and disease outcomes. Environmental
      factors, however, do not explain all of the race disparity in disease expression,
      indicating that there are genetic/molecular factors that are operational as well.

PMID- 15181029
TI  - Obesity, metabolic syndrome, and cardiovascular disease.

PMID- 15181030
TI  - Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type
      2 diabetes and familial combined hyperlipidemia in coronary artery disease risk.
AB  - Regional body fat distribution has an important influence on metabolic and
      cardiovascular risk factors. Increased abdominal (visceral) fat accumulation is a
      risk factor for coronary artery disease (CAD), dyslipidemia, hypertension,
      stroke, and type 2 diabetes. The recent emphasis on treatment of the dyslipidemia
      of the metabolic syndrome (hypertriglyceridemia, reduced high-density
      lipoprotein, and increased small, dense low-density lipoprotein particle number)
      has compelled practitioners to consider lipid-lowering therapy in a greater
      number of their patients, as one in two individuals over age 50 has the metabolic
      syndrome. Individuals with the metabolic syndrome typically have normal low
      density lipoprotein cholesterol levels, and current lipid-lowering guidelines may
      underestimate their cardiovascular risk. Two subgroups of patients with the
      metabolic syndrome are at particularly high risk for premature CAD. One,
      individuals with type 2 diabetes, accounts for 20-30% of early cardiovascular
      disease. The second, familial combined hyperlipidemia, accounts for an additional
      10-20% of premature CAD. Familial combined hyperlipidemia is characterized by the
      metabolic syndrome in addition to a disproportionate elevation of apolipoprotein
      B levels. The measurement of fasting glucose and apolipoprotein B, in addition to
      the fasting lipid profile, can help to estimate CAD risk in patients with the
      metabolic syndrome.

PMID- 15181031
TI  - Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution.

PMID- 15181032
TI  - Pharmacological approaches to weight reduction: therapeutic targets.

PMID- 15181034
TI  - Central fat mass versus peripheral fat and lean mass: opposite (adverse versus
      favorable) associations with arterial stiffness? The Amsterdam Growth and Health
      Longitudinal Study.
AB  - Central and peripheral fatness seem to confer opposite (i.e. adverse vs.
      protective) effects on cardiovascular risk, but how this occurs is not clear. In
      addition, the role of peripheral lean mass needs to be elucidated. We therefore
      investigated, in 336 (175 women) 36-yr-old and apparently healthy adults, the
      relationship between trunk fat, peripheral fat, and peripheral lean mass on the
      one hand, and estimates of stiffness of three large arteries on the other. Body
      composition was assessed by dual-energy x-ray absorptiometry. Arterial properties
      were assessed by ultrasound imaging. We found that 1) trunk fat was positively
      (i.e. adversely) associated with stiffness of the carotid and femoral arteries,
      whereas peripheral fat was inversely (i.e. favorably) associated with stiffness
      of the brachial and the carotido-femoral segment; 2) peripheral lean mass was
      positively associated with arterial diameter and carotid compliance and inversely
      associated with stiffness of the carotido-femoral segment; and 3) after
      adjustment for the other body composition variables, the above-mentioned
      associations remained, but peripheral fat in addition became, if anything,
      favorably associated with stiffness of the femoral artery. We conclude that trunk
      fat is adversely associated with large artery stiffness, whereas some degree of
      protection is conferred by peripheral fat and lean mass.

PMID- 15181033
TI  - Body size and ethnicity are associated with menstrual cycle alterations in women
      in the early menopausal transition: The Study of Women's Health across the Nation
      (SWAN) Daily Hormone Study.
AB  - The dynamics of reproductive hormones that characterize the menopausal transition
      (perimenopause) are incompletely understood, particularly in non-Caucasian women.
      The Study of Women's Health across the Nation (SWAN) is a multiethnic cohort
      study of 3302 women at seven sites who were aged 42-52 yr at baseline. All
      participants are seen annually to assess a variety of endpoints. A subcohort of
      848 women undergoes further investigation of their daily patterns of reproductive
      hormones in the Daily Hormone Study (DHS). DHS enrollees annually complete a
      daily collection of first morning voided urine for an entire menstrual cycle or
      up to 50 d (whichever comes first). Chemiluminescent assays measured urinary LH
      and FSH, as well as metabolites of estradiol [estrone conjugates (E1c)] and
      progesterone [pregnanediol glucuronide (Pdg)]. Cycles were assessed for evidence
      of luteal activity and day of luteal transition using previously developed
      algorithms. Midreproductive-aged women who underwent similar daily urinary
      analyses served as historical controls. Correlates of cycle features were
      identified. Eight hundred thirty-three cycles were evaluable and had complete
      data on covariates. Six hundred seventy-four (80.9%) cycles had evidence of
      luteal activity, and 159 (19.1%) did not. Women who were at least 49 yr old were
      less likely to have cycles with luteal activity and had more variable cycle
      length, higher total-cycle FSH, and lower total-cycle Pdg. Compared with heavier
      women, those with body mass index less than 25 kg/m2 had shorter cycles and
      higher total-cycle LH, FSH, and Pdg but not E1c. Chinese- and Japanese-American
      women had overall lower adjusted total-cycle E1c excretion. Smoking was not
      significantly associated with cycle length or hormones. When compared with cycles
      of younger control women, the cycles of the SWAN DHS participants had higher
      gonadotropins, lower total integrated Pdg, and E1c levels that were not
      different, which suggests that the ovary retains sensitivity to elevated FSH in
      the early menopausal transition. In this cross-sectional study of women over age
      42 who are premenopausal or in the early menopausal transition, there were
      important differences in the characteristics of cycles related to age, body mass
      index, and ethnicity. Comparisons to younger women indirectly support the inhibin
      hypothesis, which proposes that the initiating event in the menopausal transition
      is the loss of inhibin negative feedback on FSH secondary to a diminished
      follicular reserve.

PMID- 15181035
TI  - Association of the polycystic ovary syndrome with genomic variants related to
      insulin resistance, type 2 diabetes mellitus, and obesity.
AB  - We have evaluated the possible association of polycystic ovary syndrome (PCOS)
      with 15 genomic variants previously described to influence insulin resistance,
      obesity, and/or type 2 diabetes mellitus. Seventy-two PCOS patients and 42
      healthy controls were genotyped for 15 variants in the genes encoding for
      paraoxonase (three variants), plasma cell differentiation antigen glycoprotein,
      human sorbin and SH3 domain containing 1, plasminogen activator inhibitor-1,
      peroxisome proliferator-activated receptor-gamma2, protein tyrosine phosphatase
      1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and
      IGF2 receptor. Compared with controls, PCOS patients were more frequently
      homozygous for the -108T variant in paraoxonase (36.6% vs. 9.5%; P = 0.002) and
      homozygous for G alleles of the ApaI variant in IGF2 (62.9% vs. 38.1%; P =
      0.018). Paraoxonase is a serum antioxidant enzyme and, because -108T alleles
      result in decreased paraoxonase expression, this increase in oxidative stress
      might result in insulin resistance. G alleles of the ApaI variant in IGF2 may
      increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen
      secretion. In conclusion, the paraoxonase -108 C-->T variant and the ApaI
      polymorphism in the IGF2 gene are associated with PCOS and might contribute to
      increased oxidative stress, insulin resistance, and hyperandrogenism in this
      prevalent disorder.

PMID- 15181036
TI  - Opposing influences of prenatal and postnatal weight gain on adrenarche in normal
      boys and girls.
AB  - Associations between low birth weight and higher adrenal androgen secretion
      before puberty have yet only been reported in case-control studies in girls. We
      examined the influence of birth weight and early postnatal weight gain on
      overnight-fasting adrenal androgen and cortisol levels in 770 children from a
      large normal United Kingdom birth cohort at age 8 yr. In univariate analyses,
      adrenal androgen levels were inversely related to birth weight sd score in each
      sex [dehydroepiandrosterone sulfate in boys: regression coefficient (B) = -2.5
      microg/dl/SD; 95% confidence interval (CI), -4.7 to -0.2; in girls: B = -3.8
      microg/dl/SD; 95% CI, -6.2 to -1.4; androstenedione in boys: B = -0.15
      nmol/liter/sd, 95% CI, -0.25 to -0.6; in girls: B = -0.13 nmol/liter/SD; 95% CI, 
      0.24 to -0.02). In multivariate analyses, both lower birth weight and larger
      current body weight predicted higher adrenal androgen levels (P < 0.005 for all
      comparisons). Allowing for current weight, children who showed rapid postnatal
      weight gain between 0 and 3 yr had higher dehydroepiandrosterone sulfate (P =
      0.002) and androstenedione (P = 0.004) levels at 8 yr. In contrast, cortisol
      levels were unrelated to birth weight or current body size. In summary, the
      relationship between lower birth weight and higher childhood adrenal androgen
      levels was continuous throughout the range of normal birth weights, and was
      similar in boys and girls. Adrenal androgen levels were highest in small infants
      who gained weight rapidly during early childhood. We suggest that higher adrenal
      androgen secretion could contribute to links between early growth and adult
      disease risks, possibly by enhancing insulin resistance and central fat
      deposition.

PMID- 15181037
TI  - Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the
      production of IL-1 receptor antagonist by human adipose tissue.
AB  - Adipose tissue is the source of production and site of action of several pro- and
      antiinflammatory cytokines. We have recently shown that white adipose tissue
      (WAT) is a major producer of the antiinflammatory IL-1 receptor antagonist (IL
      1Ra). Because IL-1Ra serum levels are elevated 7-fold in human obesity and an
      excess of this protein has been implicated in the acquired resistance to leptin
      and insulin, we investigated the regulation of IL-1Ra in human WAT. We
      demonstrate that IL-1Ra is mainly produced by adipocytes, rather than the stromal
      fraction of WAT, and that IL-1alpha and beta, as well as interferon-beta (IFN
      beta), strongly up-regulate the expression and secretion of IL-1Ra in WAT.
      Moreover, human WAT expresses the receptors and proteins known to be required for
      the action of IL-1 (IL-1 receptor type I, IL-1 receptor accessory protein) and
      IFN-beta (IFN-alpha/beta receptor subunits 1 and 2). Finally, human WAT actively
      secretes these regulatory cytokines, suggesting that they up-regulate IL-1Ra
      through a local autocrine/paracrine action, which is hypothesized to play a
      regulatory role in adipogenesis and metabolism.

PMID- 15181038
TI  - Circulating ghrelin is sensitive to changes in body weight during a diet and
      exercise program in normal-weight young women.
AB  - Ghrelin is directly involved with short-term regulation of energy balance.
      Although circulating levels of ghrelin are elevated in anorexia nervosa and
      reduced in obesity, the role of ghrelin in regulating long-term energy balance in
      healthy women has not been investigated. We examined the effects of a 3-month
      energy deficit-imposing diet and exercise intervention on circulating ghrelin in
      normal-weight, healthy women. Body composition, resting metabolic rate, and serum
      ghrelin were measured at pre-, mid-, and postintervention in controls (n = 7),
      who performed no exercise, and exercising women who remained weight stable (n =
      5) or lost weight (n = 10). Exercise training occurred five times per week, and
      subjects were fed a specific diet. Ghrelin significantly increased over time (770
      +/- 296 to 1322 +/- 664 pmol/liter) in the weight-loss group compared with the
      controls and the weight-stable group (P < 0.05). Changes in ghrelin were
      negatively correlated with changes in body weight (r = -0.61; P < 0.05). Body
      fat, body weight, and resting metabolic rate significantly decreased in the
      weight-loss group before the increase in ghrelin. These findings suggest that
      ghrelin responds in a compensatory manner to changes in energy homeostasis in
      healthy young women, and that ghrelin exhibits particular sensitivity to changes
      in body weight.

PMID- 15181039
TI  - Adiponectin relationship with lipid metabolism is independent of body fat mass:
      evidence from both cross-sectional and intervention studies.
AB  - Adiponectin influences insulin sensitivity and lipid metabolism, but it is not
      clear whether these effects are correlated with fat mass or distribution. We
      studied the relationship between plasma adiponectin and leptin levels, insulin
      sensitivity, and serum lipids by a cross-sectional study (n = 242 subjects) and
      by an intervention study (95 of 242) to evaluate the effect of weight loss (WL).
      Considering all subjects both together and subdivided into nonobese (n = 107) and
      obese (n = 135) groups, plasma adiponectin, but not plasma leptin, was
      significantly (P < 0.01) correlated with insulin sensitivity [homeostasis model
      assessment of insulin-resistance index (HOMAIR), insulin sensitivity index (ISI)
      at oral glucose tolerance test, and clamp in 115 of 242 individuals], high
      density lipoprotein cholesterol, and triglycerides. These relationships were
      still significant (P < 0.01) after adjusting for age, gender, body mass index
      (BMI), and ISI. After WL (-16.8 +/- 0.8%), plasma adiponectin increased, and
      plasma leptin decreased (P < 0.0001 for both). Their changes (Delta) were
      significantly correlated with Delta-BMI (P < 0.05 for both). Delta-Adiponectin,
      but not Delta-leptin, significantly (P < 0.001) correlated with Delta-high
      density lipoprotein cholesterol and Delta-triglycerides; these correlations were
      independent of age, gender, Delta-BMI, and Delta-ISI (P < 0.005). In conclusion,
      both cross-sectional and intervention studies indicate that plasma adiponectin
      level correlates with serum lipids independently of fat mass. The intervention
      study also suggests that adiponectin increase after WL is correlated with serum
      lipid improvement independently of insulin sensitivity changes.

PMID- 15181040
TI  - Leptin hormonal kinetics in the fed state: effects of adiposity, age, and gender
      on endogenous leptin production and clearance rates.
AB  - Leptin is an adipocyte-secreted hormone that regulates energy homeostasis and
      neuroendocrine function. Replacement therapy with recombinant methionyl human
      leptin (r-metHuLeptin) improves obesity, insulin resistance, hyperlipidemia, and
      neuroendocrine dysfunction associated with low-leptin states. We administered
      three doses of r-metHuLeptin (0.1, 0.3, and 1.0 mg/kg) to healthy subjects to
      determine r-metHuLeptin pharmacokinetics in the fed state, to determine
      endogenous leptin production and clearance rates, and to study the effects of
      age, body mass index, gender, and race on r-metHuLeptin pharmacokinetics. We
      detected no dose-dependent effects on elimination half-life (t(1/2)), dose
      normalized area under the curve (nAUC(0- infinity)), total body clearance (CL),
      or volume of distribution at steady state. The mean t(1/2), CL, and volume of
      distribution at steady state of r-metHuLeptin are 3.4 +/- 1.5 h, 79 +/- 16
      ml/kg.h, and 150 +/- 39 ml/kg, respectively. Older subjects have a higher nAUC(0-
      infinity) (P = 0.003) and tend to have a decreased leptin production rate (Rsyn)
      and CL (P = 0.01). Increased body mass index is associated with higher baseline
      endogenous leptin levels (P < 0.0001), higher Rsyn (P < 0.0001), and longer
      t(1/2) (P = 0.008). Females have significantly greater baseline endogenous leptin
      levels and Rsyn than males (P < 0.0001). In summary, the leptin production rate
      is increased in females and with increasing adiposity, whereas leptin clearance
      is decreased with increasing adiposity, and nAUC(0- infinity) is increased with
      age. Elucidation of leptin pharmacokinetic parameters allows the accurate
      calculation of exogenous leptin replacement doses for humans in the fed state.

PMID- 15181041
TI  - Serum haptoglobin: a novel marker of adiposity in humans.
AB  - Haptoglobin (Hp) is a glycoprotein involved in the acute phase response to
      inflammation. Our previous findings indicate that Hp mRNA and protein are present
      in the adipose tissue of rodents and that Hp gene expression is up-regulated in
      obese models. The aim of the present study was to establish whether Hp could be
      considered a marker of obesity in humans. In 312 subjects, serum Hp was
      correlated directly with body mass index (BMI), leptin, C-reactive protein (CRP),
      and age. In a multivariate stepwise regression analysis, BMI and CRP were
      independent determinants of serum Hp in females, with BMI having the strongest
      effect. CRP and age were independent determinants of serum Hp in males, although
      explaining only a modest percentage of the total variability. Serum Hp was
      positively associated with body fat, as assessed by dual-energy x-ray
      absorptiometry, both in female and in male groups. The level of significance
      improved when serum Hp was analyzed against fat mass adjusted for lean mass.
      Finally, Northern and Western blot analyses performed in biopsies of sc abdominal
      fat from 20 obese individuals showed the presence of Hp mRNA and protein in the
      human adipose tissue. In conclusion, serum Hp constitutes a novel marker of
      adiposity in humans, and the adipose tissue likely contributes to determine its
      levels.

PMID- 15181042
TI  - Adiponutrin: A new gene regulated by energy balance in human adipose tissue.
AB  - Adiponutrin is a newly identified nonsecreted adipocyte protein regulated by
      changes in energy balance in rodents. We documented the influence of energy
      balance modification on adiponutrin gene expression in humans. We investigated
      the mRNA expression in sc adipose tissue of nonobese women and in obese women
      during 2-d very low-calorie diet (VLCD) and subsequent refeeding as well as
      before and after a VLCD of 3 wk (21-d VLCD). The adiponutrin mRNA levels of the
      nonobese and obese women were not different (P > 0.05). Two-day VLCD reduced the
      average level of adiponutrin mRNA expression by 36% (P = 0.0016), whereas
      refeeding elevated the mRNA level by 31% (P = 0.004). The 3-wk VLCD caused a
      dramatic 58% fall of the adiponutrin mRNA expression level (P = 0.001). The mRNA
      level was negatively correlated with fasting glucose (Rho = -0.62; P < 0.0001),
      and subjects with high adiponutrin mRNA level had an increased insulin
      sensitivity. Compared with other adipocyte proteins such as leptin and
      adiponectin, adiponutrin mRNA did not show correlation with either adiposity
      indexes or with leptin or adiponectin mRNAs. These results indicate that
      adiponutrin gene expression in humans is highly regulated by changes in energy
      balance.

PMID- 15181043
TI  - Angiotensin II-induced effects on adipose and skeletal muscle tissue blood flow
      and lipolysis in normal-weight and obese subjects.
AB  - The present study was designed to investigate the effects of angiotensin II (Ang
      II) on adipose and skeletal muscle tissue blood flow and lipolysis in normal
      weight and obese subjects using the microdialysis technique. Microdialysis probes
      were placed in the abdominal sc adipose tissue left and right from the umbilicus
      and in the gastrocnemius muscle of both legs in eight normal-weight and eight
      obese men. Probes were consecutively perfused with 1.0 nM Ang II, 1.0 microM Ang
      II, and 1.0 microM Ang II + 48 microM hydralazine or with Ringer solution
      (control). Ethanol and glycerol concentrations in the dialysate were measured as
      an indicator of local blood flow and lipolysis, respectively. Ang II caused an
      increase in ethanol outflow/inflow ratio, compared with baseline values both in
      adipose tissue (average of both groups, Ang 1.0 nM: 0.03 +/- 0.01, P = 0.02; Ang
      1.0 microM: 0.05 +/- 0.01, P < 0.01) and muscle (average of both groups, Ang 1.0
      nM: 0.02 +/- 0.01, P = 0.09; Ang 1.0 microM: 0.04 +/- 0.01, P = 0.01), indicating
      a decrease in local blood flow. These effects were not significantly different in
      obese and normal-weight subjects. The decrease in local blood flow was
      accompanied by unchanged interstitial glycerol concentrations in adipose tissue
      (except during the supraphysiological dose) and skeletal muscle, suggesting that
      Ang II inhibits lipolysis in both tissues. Thus, the present data suggest that
      Ang II decreases local blood flow in a dose-dependent manner and inhibits
      lipolysis both in adipose and skeletal muscle tissue. These effects were not
      significantly different in obese and normal-weight subjects in both tissues.

PMID- 15181044
TI  - Adiponectin, inflammation, and the expression of the metabolic syndrome in obese
      individuals: the impact of rapid weight loss through caloric restriction.
AB  - Severe obesity increases the prevalence of the metabolic syndrome, and moderate
      acute weight loss with a very low-calorie diet in obese subjects with the
      metabolic syndrome leads to significant metabolic benefits. Adiponectin has been
      implicated in both the pathogenesis of obesity-related insulin resistance and
      increased inflammation. We analyzed the relationship of the adipocyte-derived
      hormone adiponectin with indices of inflammation, adiposity, and insulin
      resistance in obese subjects with (MS+, n = 40) and without (MS-, n = 40) the
      metabolic syndrome and examined the acute effects of rapid weight loss. MS+
      subjects had significantly lower adiponectin (7.6 +/- 0.6 vs. 10.4 +/- 0.6
      microg/ml; P = 0.003) and significantly higher TNF-alpha (3.3 +/- 0.2 vs. 2.8 +/-
      0.3 pg/ml; P = 0.004) levels compared with MS- subjects matched for age and body
      mass index. Plasma adiponectin and TNF-alpha levels were inversely related to the
      number of metabolic syndrome factors in a stepwise manner. After 4-6 wk of weight
      loss, there was marked improvement in glucose, insulin, leptin, and
      triglycerides, whereas adiponectin and TNF-alpha concentrations did not change.
      Thus, increases in plasma levels of adiponectin or reductions in TNF-alpha are
      not required for marked improvements in glucose/insulin and lipid metabolism with
      acute weight loss.

PMID- 15181045
TI  - Diet-induced weight loss is associated with an improvement in beta-cell function
      in older men.
AB  - Although weight loss in older subjects has been shown to improve insulin
      sensitivity, it is unclear what effect this lifestyle intervention has on beta
      cell function. To determine whether diet-induced weight loss can improve beta
      cell function in older subjects, we studied 19 healthy male subjects (age, 65.4
      +/- 0.9 yr; body mass index, 30.9 +/- 0.6 kg/m2; mean +/- SEM) before and after a
      3-month 1200-kcal/d diet. The insulin sensitivity index (SI) was quantified using
      Bergman's minimal model. The acute insulin response to glucose (AIRg) and the
      maximal glucose-potentiated insulin response (AIRmax) were determined and then
      adjusted for SI (SI x AIRg and SI x AIRmax), thus providing measures of beta-cell
      function. Subjects demonstrated significant weight loss (95.6 +/- 2.4 to 86.1 +/-
      2.5 kg; P < 0.001). Both fasting plasma glucose [97.3 +/- 1.6 to 95.1 +/- 1.3
      mg/dl (5.4 +/- 0.09 to 5.3 +/- 0.07 mM); P = 0.05] and insulin [18.5 +/- 1.3 to
      12.2 +/- 1.0 microU/ml (110.9 +/- 7.7 to 73.5 +/- 5.9 pM); P < 0.001] levels
      decreased. With weight loss, SI increased [1.59 +/- 0.24 to 2.49 +/- 0.32 x 10(
      4) min(-1)/(microU/ml) (2.65 +/- 0.4 to 4.15 +/- 0.5 x 10(-5) min(-1)/pM); P <
      0.001], whereas both AIRg [63.4 +/- 13.4 to 51.0 +/- 10.7 microU/ml (380 +/- 80
      to 306 +/- 64 pM); P < 0.05] and AIRmax [314 +/- 31.4 to 259.9 +/- 33.4 microU/ml
      (1886 +/- 188 to 1560 +/- 200 pM); P < 0.05] decreased. Overall beta-cell
      function improved (SI x AIRg, 9.63 +/- 2.28 to 12.78 +/- 2.58 x 10(-3) min(-1), P
      < 0.05; and SI x AIRmax, 51.01 +/- 9.2 to 72.69 +/- 13.4 x 10(-3) min(-1), P <
      0.05). Thus, the weight loss-associated improvements in both insulin sensitivity
      and beta-cell function may explain the beneficial effects of a lifestyle
      intervention on delaying the development of diabetes in older subjects.

PMID- 15181046
TI  - Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in
      human adipose tissue.
AB  - The global epidemic of obesity has heightened the need to understand the
      mechanisms that underpin its pathogenesis. Clinical observations in patients with
      Cushing's syndrome have highlighted the link between cortisol and central
      obesity. However, although circulating cortisol levels are normal or reduced in
      obesity, local regeneration of cortisol, from inactive cortisone, by 11beta
      hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been postulated as a
      pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose
      tissue in human obesity are debated in the literature, global inhibition of
      11betaHSD1 improves insulin sensitivity. We have determined the effects of
      significant weight loss on cortisol metabolism and adipose tissue 11betaHSD1
      expression after 10-wk ingestion of a very low calorie diet in 12 obese patients
      (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). All
      patients achieved significant weight loss (14.1 +/- 1.3% of initial body weight).
      Total fat mass fell from 41.8 +/- 1.9 to 32.0 +/- 1.7 kg (P < 0.0001). In
      addition, fat-free mass decreased (64.4 +/- 3.4 to 58.9 +/- 2.9 kg; P < 0.0001)
      and systolic blood pressure and total cholesterol also fell [systolic blood
      pressure, 135 +/- 5 to 121 +/- 5 mm Hg (P < 0.01); total cholesterol, 5.4 +/- 0.2
      to 4.8 +/- 0.2 mmol/liter (P < 0.05)]. The serum cortisol/cortisone ratio
      increased after weight loss (P < 0.01). 11betaHSD1 mRNA expression in isolated
      adipocytes increased 3.4-fold (P < 0.05). Decreased 11betaHSD1 activity and
      expression in obesity may act as a compensatory mechanism to enhance insulin
      sensitivity through a reduction in tissue-specific cortisol concentrations.
      Inhibition of 11betaHSD1 may therefore be a novel, therapeutic strategy for
      insulin sensitization.

PMID- 15181047
TI  - Comparison of a low-fat diet to a low-carbohydrate diet on weight loss, body
      composition, and risk factors for diabetes and cardiovascular disease in free
      living, overweight men and women.
AB  - Overweight and obese men and women (24-61 yr of age) were recruited into a
      randomized trial to compare the effects of a low-fat (LF) vs. a low-carbohydrate
      (LC) diet on weight loss. Thirty-one subjects completed all 10 wk of the diet
      intervention (retention, 78%). Subjects on the LF diet consumed an average of
      17.8% of energy from fat, compared with their habitual intake of 36.4%, and had a
      resulting energy restriction of 2540 kJ/d. Subjects on the LC diet consumed an
      average of 15.4% carbohydrate, compared with habitual intakes of about 50%
      carbohydrate, and had a resulting energy restriction of 3195 kJ/d. Both groups of
      subjects had significant weight loss over the 10 wk of diet intervention and
      nearly identical improvements in body weight and fat mass. LF subjects lost an
      average of 6.8 kg and had a decrease in body mass index of 2.2 kg/m2, compared
      with a loss of 7.0 kg and decrease in body mass index of 2.1 kg/m2 in the LC
      subjects. The LF group better preserved lean body mass when compared with the LC
      group; however, only the LC group had a significant decrease in circulating
      insulin concentrations. Group results indicated that the diets were equally
      effective in reducing systolic blood pressure by about 10 mm Hg and diastolic
      pressure by 5 mm Hg and decreasing plasminogen activator inhibitor-1 bioactivity.
      Blood beta-hydroxybutyrate concentrations were increased in the LC only, at the 2
      and 4-wk time points. These data suggest that energy restriction achieved by a
      very LC diet is equally effective as a LF diet strategy for weight loss and
      decreasing body fat in overweight and obese adults.

PMID- 15181048
TI  - Changes in muscle myostatin expression in obese subjects after weight loss.
AB  - Myostatin is a member of transforming growth factor-beta superfamily that plays
      an important inhibitory role during muscle development; in fact mutations of
      myostatin gene result in a hypermuscular phenotype. Moreover myostatin-deficient
      mice have a significant reduction in fat depots and a depression of adipogenesis.
      Little is known about myostatin function in muscle growth regulation in humans
      and in particular during caloric restriction. In the present work we quantified
      by real-time RT-PCR myostatin expression in muscle biopsies of a group of
      morbidly obese patients before and after weight loss obtained by biliopancreatic
      diversion (BPD). The patients reduced body weight by 38.9%, mostly due to fat
      mass loss, showing also a significant reduction in the 24-hour EE as assessed by
      the respiratory chamber. Myostatin mRNA levels result clearly decreased after
      weight loss, suggesting a role in counteracting the progressive decline of muscle
      mass after BPD. Myostatin may provide therefore another mechanistic explanation
      for the control of energy partitioning between protein and fat, working against
      muscle wasting. Our data suggest that myostatin might represent an important
      regulator of skeletal muscle size also in conditions of food restriction in obese
      subjects.

PMID- 15181049
TI  - Evidence for a potent antiinflammatory effect of rosiglitazone.
AB  - We have recently demonstrated a potent antiinflammatory effect of troglitazone,
      an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and a
      partial agonist of PPARalpha in both the nondiabetic obese and diabetic obese
      subjects. We have now investigated the antiinflammatory actions of rosiglitazone,
      a selective PPARgamma agonist. Eleven nondiabetic obese subjects and 11 obese
      diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6
      wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after
      the cessation of rosiglitazone). Eight obese subjects and five obese diabetic
      subjects were also included in the study as control groups. Fasting blood samples
      were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear
      factor kappaB (NFkappaB)-binding activity in mononuclear cells, plasma monocyte
      chemoattractant protein-1 (MCP-1), TNF-alpha, soluble intercellular adhesion
      molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured.
      Blood glucose concentration changed significantly at 6 wk only in the obese
      diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin
      concentration decreased significantly at 6 wk in both groups. NFkappaB-binding
      activity in mononuclear cell nuclear extract fell in both obese and obese
      diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in
      plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-alpha and SAA
      concentrations were inhibited significantly in the obese group (P < 0.05) but not
      in the obese diabetic subjects. NFkappaB-binding activity and plasma MCP-1, CRP,
      SAA, and TNF-alpha did not change in the obese and obese diabetic control groups.
      We conclude that rosiglitazone, a selective PPARgamma agonist, exerts an
      antiinflammatory effect at the cellular and molecular level, and in plasma. These
      observations may have implications for atherogenesis in the long term in subjects
      treated with rosiglitazone and possibly other thiazolidinediones.

PMID- 15181050
TI  - Distinguishing the antihypertensive and electrolyte effects of eplerenone.
AB  - In two clinical trials on the antihypertensive effects of the mineralocorticoid
      receptor antagonist eplerenone 397 essential hypertensives were dose titrated
      (50, 100, and 200 mg/d) over successive 4-wk periods until they reached target
      blood pressure levels. Of the total, 44% reached target on 50 mg/d, 17% on 100
      mg/d, and 19% on 200 mg/d, with 20% failing to do so despite stepwise dose
      increases. At each dose level, those who reached target (responders) were
      compared with those who did not (nonresponders), with three major findings.
      First, at each dose level, the blood pressure fall in responders (systolic, 16-20
      mm Hg; diastolic, approximately 15 mm Hg) was markedly more than mean values in
      nonresponders (systolic, 2-5 mm Hg; diastolic, 1-3 mm Hg). Second, sensitivity to
      eplerenone varied widely across the population studied in terms of blood pressure
      reduction. Third, there was no difference in plasma [K+] levels between
      responders and nonresponders at any dose level. We interpret these data as
      evidence for the major antihypertensive effect of eplerenone being via mechanisms
      other than those involving epithelial electrolyte and fluid transport. The modest
      (< or =0.2 mEq/liter at 200 mg/d) mean elevation in plasma [K+] suggests that
      titration to effect rather than forced titration may minimize the risk of
      hyperkalemia, even where relatively high (100-200 mg/d) doses of the specific
      mineralocorticoid receptor antagonist eplerenone may ultimately be required.

PMID- 15181051
TI  - The investigation of insulin resistance in patients with idiopathic hirsutism.
AB  - Hirsutism, which is characterized by excessive growth of terminal hair in a male
      pattern, is a common clinical condition in women. It may result from various
      causes including polycystic ovary syndrome, nonclassic adrenal hyperplasia,
      adrenal or ovarian tumors, or it may be idiopathic. Idiopathic hirsutism (IH) is
      considered to be one of the most common forms of hirsutism. Although not
      universal, insulin resistance and hyperinsulinemia have been demonstrated in
      women with polycystic ovary syndrome. Because there are not enough data showing
      whether patients with IH also have insulin resistance, we intended to investigate
      the presence/absence of insulin resistance in women with IH. Thirty-two women
      with IH [mean age, 24.8 +/- 1.2 yr; body mass index (BMI), 24.6 +/- 0.8 kg/m2]
      and 17 healthy women (mean age, 25.8 +/- 0.6 yr; BMI, 22.5 +/- 0.6 kg/m2) were
      included in the study. Eight of 32 patients with IH had BMI higher than 30 kg/m2.
      The presence of insulin resistance was investigated by using basal insulin
      levels, the oral glucose tolerance test, the i.v. insulin tolerance test, and the
      homeostasis model assessment (HOMA) score in both groups. Six (18.7%) patients
      had impaired glucose tolerance (IGT). Overall, patients with IH had significantly
      (P < 0.05) higher basal insulin levels (10.5 +/- 1.1 mU/liter vs. 5.7 +/- 0.9
      mU/liter) and HOMA scores (2.0 +/- 0.2 vs. 1.1 +/- 0.2) and lower plasma glucose
      disappearance rate values (5.2 +/- 0.2 vs. 6.0 +/- 0.3) than control subjects.
      However, patients with IGT were notably more obese than the patients with a
      normal glucose tolerance test. Analyses after omitting the patients with IGT
      showed that there was still a significant (P < 0.05) difference in terms of basal
      insulin levels and HOMA scores. Six of eight (75%) obese patients with IH showed
      IGT. These data suggest that IH is associated with insulin resistance and an
      increased prevalence of IGT in obese patients.

PMID- 15181052
TI  - The prevalence and features of the polycystic ovary syndrome in an unselected
      population.
AB  - Notwithstanding the potential public health impact of the polycystic ovary
      syndrome (PCOS), estimates regarding its prevalence are limited and unclear.
      Between July 1998 and October 1999, 400 unselected consecutive premenopausal
      women (18-45 yr of age) seeking a preemployment physical at the University of
      Alabama at Birmingham were studied (223 Black, 166 White, and 11 of other races).
      Evaluation included a history and physical examination, a modified Ferriman
      Gallwey hirsutism score, and serum screening for hyperandrogenemia,
      hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal
      hyperplasia. PCOS was diagnosed by the presence of the following: 1)
      oligoovulation, 2) hyperandrogenemia and/or hirsutism (modified Ferriman-Gallwey
      score > or = 6), and 3) the exclusion of related disorders. Confirmed PCOS was
      established in those individuals whose evaluation was complete and indicative of
      PCOS, and possible PCOS was established when the hormonal evaluation was not
      complete or was unavailable, but the clinical phenotype was otherwise suggestive
      of the disorder. The individual probability of PCOS in women with possible PCOS
      was assigned a weight based on the findings in similar subjects whose evaluation
      was complete, and the total number of PCOS cases arising from these individuals
      was calculated (i.e. individual probability of PCOS x total number of subjects in
      the group). The cumulative prevalence of PCOS in our population was 6.6% (26.5 of
      400), including 15 subjects among the 347 women completing their evaluation and a
      calculated prevalence of 11.5 subjects among the remainder. The prevalence rates
      of PCOS for Black and White women were 8.0 and 4.8%, respectively, not
      significantly different. These data from a large representative unselected
      population support the concept that PCOS is the most common endocrine abnormality
      of reproductive-aged women in the United States.

PMID- 15181053
TI  - Adipose tissue metabolites and insulin resistance in nondiabetic Asian Indian
      men.
AB  - Obesity-related insulin resistance is associated with changes in adipose tissue
      release of leptin, adiponectin, and nonesterified fatty acids (NEFAs). We have
      previously described that persons originating from the Indian subcontinent (Asian
      Indians) manifest excessive insulin resistance even in the absence of obesity.
      Therefore, in this study, we tested the hypothesis that nondiabetic, insulin
      resistant Asian Indians differ from less insulin-resistant Caucasians of similar
      age and body composition in adipose tissue production of leptin and adiponectin,
      and in suppression of plasma NEFA concentrations during hyperinsulinemia. Seventy
      nine Asian Indian men were compared with 61 Caucasian men. Higher plasma NEFAs
      and leptin in Asian Indians (P < 0.0001 and P = 0.003 for NEFAs and leptin,
      respectively) and lower plasma concentrations of adiponectin (P = 0.009) were not
      explained by body fat content and distribution. Oral glucose tolerance test
      studies revealed that Caucasian men had greater suppression of plasma NEFAs than
      Asian Indian men. We conclude that plasma concentrations of the adipose tissue
      metabolites leptin and NEFAs are higher and that of adiponectin is lower in
      insulin-resistant Asian Indians compared with more insulin-sensitive Caucasians.
      These differences may contribute to the excessive prevalence of type 2 diabetes
      and cardiovascular disease in nonobese Asian Indians.

PMID- 15181054
TI  - Comparison of efficacy of spironolactone with metformin in the management of
      polycystic ovary syndrome: an open-labeled study.
AB  - We compared the efficacy of spironolactone (50 mg/d) with metformin (1000 mg/d)
      after random allocation in 82 adolescent and young women with polycystic ovary
      syndrome (PCOS) on body mass index (BMI), waist-to-hip ratio, blood pressure,
      menstrual cyclicity, hirsutism, hormonal levels, glycemia, and insulin
      sensitivity at baseline and at the 3rd and 6th months of treatment. Sixty-nine
      women who completed the follow-up had a mean age of 22.6 +/- 5.0 yr and mean BMI
      of 26.8 +/- 4.0 kg/m2. The number of menstrual cycles in the spironolactone and
      metformin groups increased from 6.6 +/- 2.1 and 5.7 +/- 2.3 at baseline to 9.0 +/
      1.9 and 7.4 +/- 2.6 at 3rd month and to 10.2 +/- 1.9 and 9.1 +/- 2.0/ year at
      the 6th month (P = 0.0037), respectively. The hirsutism score decreased from 12.9
      +/- 3.2 and 12.5 +/- 4.9 at baseline to 10.1 +/- 3.1 and 11.4 +/- 4.1 at the 3rd
      month and to 8.7 +/- 1.9 and 10.0 +/- 3.3 at the 6th month, respectively. Both
      groups showed improvement in glucose tolerance and insulin sensitivity, although
      the metformin effect was significant in the latter. Serum LH/FSH and testosterone
      decreased in both groups. BMI, waist-to-hip ratio, and blood pressure did not
      change with either drug. We conclude that both drugs are effective in the
      management of PCOS. Spironolactone appears better than metformin in the treatment
      of hirsutism, menstrual cycle frequency, and hormonal derangements and is
      associated with fewer adverse events.

PMID- 15181055
TI  - Menopause transition: Annual changes in serum hormonal patterns over the
      menstrual cycle in women during a nine-year period prior to menopause.
AB  - To examine the hormonal characteristics of menstrual cycles in healthy women
      approaching menopause, serum hormone profiles were investigated annually in this
      longitudinal study of 13 healthy women between 4 and 9 yr before menopause and
      the year of the menopause. Serum FSH, LH, estradiol, progesterone, total inhibin,
      inhibins A and B, and prolactin were determined in blood samples collected
      annually three times weekly for 4 wk beginning with the onset of menses.
      Menstrual bleeding diaries covering this 4- to 9-yr period were also collected
      allowing the prospective identification of the final menstrual period. A change
      in serum hormone patterns was observed in cycles approaching menopause,
      exemplified by an increasing number of cycles of prolonged length with a
      prolonged follicular phase resulting in a failure to detect a luteal phase rise
      in serum progesterone within the 4-wk collection period. These prolonged cycles
      (designated B cycles based on a previous work) were analyzed separately and
      compared with the remaining ovulatory (D) cycles. No B cycles were identified in
      any women earlier than 27 cycles from menopause. The proportion of B cycles
      increased as menopause approached, reaching 62% in the last 10 cycles. The
      proportion of D cycles decreased accordingly. The B cycles during the initial 4
      wk collection period were characterized by elevated FSH, LH, FSH/inhibin A and
      FSH/inhibin B ratios, and longer duration, although cycle length/subject was not
      significantly different presumably due to the small number of B cycles. The D
      cycles showed no changes in hormonal profiles over the 4- to 9-yr time period.
      These data indicate that there is a time-related change in the character of
      menstrual cycles as menopause approaches, with an increasing proportion of cycles
      observed with prolonged follicular phases that may either be delayed ovulatory
      cycles or anovulatory cycles. The increase in the proportion of B cycles with
      elevated early follicular phase FSH levels and low inhibin/FSH ratios toward
      menopause provides a basis for the apparent early increase in serum FSH and
      decrease in serum inhibins observed previously in studies of the menopause
      transition based on sampling confined to the follicular phase only. The data
      amplify and clarify current concepts of the endocrine basis of the menopause
      transition.

PMID- 15181056
TI  - Prolactin and prostate hypertrophy: a pilot observational, prospective, case
      control study in men with prolactinoma.
AB  - In experimental models, prolactin (PRL) displays independent hypertrophic effects
      on the prostate. To investigate whether hyperprolactinemia is associated with
      prostate enlargement in humans, we designed this open, prospective, case-control
      study enrolling 20 men with prolactinoma (aged 34 +/- 10 yr) and 20 age-matched
      healthy men. The endocrine profile and prostate transrectal ultrasonography were
      performed before and after 12 and 24 months of cabergoline treatment in the
      patients and at study entry and after 24 months in the controls. The patients had
      lower serum testosterone, dihydrotestosterone (DHT), and IGF-I levels and
      prostate volume (15.4 +/- 3.5 vs. 19.6 +/- 5.1 ml; P < 0.001) and higher PRL
      levels and prostate-specific antigen density than controls. There was no
      difference in prostate and transitional zone volumes between patients with
      normoandrogenemia (n = 8) or hypoandrogenemia (n = 12). After 12 and 24 months of
      treatment, PRL, testosterone, and DHT levels were normal in all cases, as were
      IGF-I and IGF-binding protein-3 levels. After 24 months, prostate volume was
      comparable to that in controls (21.7 +/- 4.5 vs. 22.5 +/- 4.7 ml). There were no
      changes in prostate structure throughout the study period in either the patients
      or the controls. In conclusion, in young men with prolactinoma PRL excess is
      unlikely to have effects on the prostate per se, because it is accompanied by low
      testosterone and DHT levels that produce the major effects.

PMID- 15181057
TI  - Volumetric bone density at the femoral neck as a common measure of hip fracture
      risk for men and women.
AB  - Measurements of bone density using dual-energy x-ray absorptiometry are generally
      based on the areal projection, which incompletely accounts for size. The larger
      areal bone density in older men compared with older women is primarily due to
      their larger bone size, conferring a biomechanical advantage that may be a major
      factor contributing to lower hip fracture rates. The aim of this study was to
      evaluate estimated volumetric bone density at the hip in men and women with and
      without fractures to better determine the role of estimated volumetric density
      vs. size in hip fracture risk. This prospective population-based study compared
      852 women and 635 men without fractures with 73 women and 23 men with hip
      fractures. As expected, areal bone mineral density (BMD) and cross-sectional area
      were lower in women than men, and areal bone density was lower in those with hip
      fractures compared with nonfracture subjects. However, estimated volumetric BMD
      was the only parameter, apart from age, that was the same in women and men both
      without hip fractures (0.31 +/- 0.06 and 0.31 +/- 0.06 g/cm3, respectively) and
      with hip fractures (0.25 +/- 0.04 and 0.26 +/- 0.04 g/cm3, respectively). Using
      the World Health Organization 2.5 SD cut-off for osteoporosis for hip fracture
      prediction, estimated volumetric BMD was more sensitive than areal BMD in men (70
      vs. 43%; P = 0.04) and similar to that in women, in whom sensitivity was similar
      for both areal (73%) and estimated volumetric (78%) BMD cut-offs. Thus, men and
      women have hip fractures at the same estimated femoral neck volumetric BMD, which
      is largely independent of the size artifact inherent in areal BMD. This aspect of
      estimated femoral neck volumetric BMD suggests that it can provide a single
      measure that could be used in men and women. It needs further exploration for a
      role in assessment of hip fracture risk across the sexes and particularly in men.

PMID- 15181058
TI  - Myocardial blood flow and flow reserve in response to hormone therapy in
      postmenopausal women with risk factors for coronary disease.
AB  - Estrogen has beneficial effects on markers of coronary heart disease (CHD) risk,
      but may increase overall CHD events. The effects of hormone therapy on vascular
      endothelial function have been mixed, and require further assessment. We studied
      the myocardial blood flow (MBF) response to postmenopausal combination hormone
      therapy (CHT) in postmenopausal women with risk factors for CHD. We performed
      dynamic [13N]ammonia positron emission tomography in 15 postmenopausal women in a
      7-month placebo-controlled crossover trial of continuous conjugated equine
      estrogen/cyclical micronized progesterone. MBF was measured at rest, after
      sympathetic stimulation with the cold pressor test (CPT), and after i.v.
      adenosine infusion, to determine baseline, endothelium-dependent, and maximal
      flows, respectively. Response to CPT was neutral in all women at baseline (-0.51
      +/- 27%). Adenosine induced a marked increase in MBF (161 +/- 111%). Treatment
      with 3 months of combined estrogen/progestin CHT did not change CPT or adenosine
      MBF responses. Myocardial flow reserve was unchanged as well. In this group of
      postmenopausal women at higher cardiovascular risk, no association was found
      between CHT assignment and change in MBF. Further study is needed to clarify the
      effects of CHT on the endothelium of women with presumably diseased vasculature.

PMID- 15181059
TI  - Determinants of survival in treated acromegaly in a single center: predictive
      value of serial insulin-like growth factor I measurements.
AB  - We evaluated survival after optimal treatment for acromegaly and assessed the
      predictive effects of different remission criteria for survival in 164
      consecutive acromegalic patients, treated by transsphenoidal surgery and adjuvant
      therapy between 1977 and 2002. The goal of treatment was a mean GH less than 5
      mU/liter, a normal glucose-suppressed GH, and a normal IGF-I for age in all
      patients. Surgery initially cured 108 patients (66%). Adjuvant therapy for
      persistent disease was given to 49 patients. At the end of follow-up (mean, 12.3
      yr), remission rates for surgery and multimodality treatment were 54% and 90%,
      respectively. In 2033 person-years of follow-up, 28 of 164 patients died,
      resulting in an observed:expected mortality ratio of 1.3 (confidence interval,
      0.87-1.87). Significant predictors for survival were the duration of disease and
      the postoperative glucose-suppressed GH. The effects of these predictors became
      less significant with increasing follow-up duration. A time-dependent effect on
      survival was observed for serial IGF-I concentrations, but not for serial GH
      concentrations. Of the three remission criteria, IGF-I was the only one to be
      significantly associated with survival in this study, with a relative risk of
      4.78 for an elevated as opposed to a normal IGF-I concentration.

PMID- 15181060
TI  - Early adrenocortical recovery after glucocorticoid therapy in children with
      leukemia.
AB  - The duration of glucocorticoid-induced inhibition that occurs in the hypothalamic
      pituitary-adrenal (HPA) axis after discontinuation of treatment is controversial.
      The main objective of this prospective study was to evaluate the inhibition of
      the HPA axis by dexamethasone in children and adolescents with acute lymphoid
      leukemia. Thirty-five patients (median age of 6.9 yr) were evaluated. A stimulus
      test with ovine CRH (1 microg/kg) was performed before the introduction of
      dexamethasone (6 mg/m2.d for 28 d), in the 8th and 28th days of glucocorticoid
      therapy, and 48 h and 1 month after discontinuation of glucocorticoid therapy.
      Suppression of the basal secretion as well as the maximum concentration of ACTH
      occurred during glucocorticoid therapy (P < 0.01). The pituitary function before
      the introduction of dexamethasone was similar to the one seen 48 h and 1 month
      after withdrawing it. Suppression of the adrenal function was detected during
      glucocorticoid therapy, which persisted for 48 h after the steroid was removed
      from treatment (P < 0.01). One month after ceasing the administration of the
      glucocorticoid, the adrenal function was similar to that before glucocorticoid
      therapy. According to these results, a clinical and laboratory follow-up of the
      HPA axis in the month after the cessation of dexamethasone therapy is suggested
      to determine glucocorticoid replacement.

PMID- 15181061
TI  - A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels
      in elderly men: effects on bone metabolism.
AB  - Current evidence suggests that estrogen plays a dominant role in determining bone
      mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19
      gene have been associated with low bone mass in young males. We previously
      reported an association between a TTTA repeat polymorphism in intron 4 of the
      CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the
      role of this polymorphism as a genetic determinant of BMD in a sample of elderly
      males who were recruited by direct mailing and followed longitudinally for 2 (n =
      300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight,
      nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal
      distribution of alleles, with two major peaks at seven and 11 repeats and a very
      low distribution of the nine-repeat allele. Men with a high-repeat genotype
      (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers,
      higher estradiol levels, and a lower rate of BMD change than men with a low
      repeat genotype (<nine repeats). The association with BMD was not significant in
      the subgroup of patients with high body mass index (>25), suggesting that the
      effect of CYP19 genotypes on bone may be masked by the increase in fat mass.
      Moreover, the high-repeat genotype was less represented, although not
      significantly, in the vertebral fracture group with respect to the nonvertebral
      fracture group. Functional in vitro analysis after incubation with [3H]
      androstenedione showed a higher aromatase activity in fibroblasts from subjects
      with a high-repeat genotype than in fibroblasts from subjects with a low-repeat
      genotype. In conclusion, differences in estrogen levels due to polymorphism at
      the aromatase CYP19 gene may predispose men to increased age-related bone loss
      and fracture risk.

PMID- 15181062
TI  - Lack of defects in androgen production in children with hypospadias.
AB  - Formation of the male urethra requires the synthesis of testosterone, its
      activation to dihydrotestosterone (DHT) in genital skin, and binding of DHT to
      the androgen receptor. Defects in any of those steps can cause hypospadias. To
      determine whether defects exist in the production of androgens in individuals
      with hypospadias, we examined enzymatic function of 3beta-hydroxysteroid
      dehydrogenase (3betaHSD), P450c17 (17alpha-hydroxylase and 17,20 lyase activity),
      and type 3 17betaHSD. Sixty-eight subjects participated in the study: 48 patients
      had hypospadias, and 20 had normal male genitalia. Subjects were stratified into
      groups based on age and severity of hypospadias, as defined by location of the
      urethral meatus after correction of penile curvature. Hormonal values in boys
      with hypospadias were compared by nonparametric analysis with those in age
      matched controls. Controls excluded individuals with cryptorchidism, micropenis,
      known endocrine defects, or receiving steroid supplementation. Morning fasting
      serum levels of pregnenolone, progesterone, 11-deoxycorticosterone, 17
      hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol,
      dehydroepiandrosterone, androstenedione, androstenediol, testosterone, and DHT
      were determined. To focus on the proximal steps in androgen biosynthesis, 12
      individuals with hypospadias underwent standard ACTH stimulation. No significant
      differences in the androgen precursors and metabolites were found between
      controls and individuals with hypospadias. The response to ACTH was variable
      without a significant difference between the patients with different degrees of
      hypospadias and/or published controls. These data indicate that enzymatic defects
      in the steroidogenic steps from cholesterol to DHT are not a common etiology of
      hypospadias. Routine abnormalities in the androgen biosynthetic pathway are an
      unlikely cause of any degree of hypospadias in boys without accompanying
      cryptorchidism or genital malformations.

PMID- 15181063
TI  - Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a
      clinical, endocrinological, metabolic pilot study.
AB  - The aim of this study was to investigate the effects of the new estro-progestinic
      containing the antimineralcorticoid progestogen drospirenone (DRSP) in women with
      polycystic ovary syndrome (PCOS). Fifteen hirsute PCOS patients were treated with
      30 microg ethinyl estradiol plus 3 mg DRSP for 12 cycles. Ultrasonographic pelvic
      exams, evaluation of hirsutism scores, and hormonal and lipid profile assays were
      performed at baseline and after three, six, and 12 cycles of treatment. An oral
      glucose tolerance test and euglycemic hyperinsulinemic clamp were also performed,
      except at the third cycle. The treatment was well tolerated, and all women
      attained satisfactory cycle control. Hirsutism significantly improved from the
      sixth cycle onward. Body weight and fat distribution as well as blood pressure
      remained stable throughout the treatment. Plasma levels of LH, testosterone,
      SHBG, and, consequently, the free androgen index significantly fell from the
      third cycle on. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone
      significantly decreased after six cycles. The treatment did not affect
      glycoinsulinemic homeostasis. A trend toward an increase was seen for total
      cholesterol, triglycerides, and high- and low-density lipoproteins (HDL and LDL)
      plasma concentrations, although all parameters remained within the normal range.
      No modifications in total cholesterol/HDL and HDL/LDL ratios were induced by the
      therapy. The ethinyl estradiol/DRSP combination seems to be effective in
      ameliorating clinical and hormonal features of PCOS.

PMID- 15181064
TI  - The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first
      24 hours of postnatal life.
AB  - The purpose of this study was to measure serum T4, free T4, TSH, T3, rT3, T4
      sulfate, and thyroxine binding globulin at four time points within the first 24 h
      of life (cord and 1, 7, and 24 h) in infants between 24 and 34 wk gestation. The
      infants were subdivided into gestational age groups: 24-27 wk (n = 22); 28-30 wk
      (n = 26); and 31-34 wk (n = 24). The TSH surge in the first hour of postnatal
      life was markedly attenuated in infants of 24-27 wk gestation [8 compared with 20
      (28-30 wk) and 23 mU/liter (31-34 wk)]. T4 levels in the most immature group
      declined over the first 24 h, whereas levels increased in the more mature groups
      [mean cord and 24-h levels: 65 and 59 (NS) vs. 70 and 84 (P < 0.002) vs. 98 and
      125 (NS) nmol/liter]. Free T4 and T3 showed only small, transient increases in
      the most immature group and progressively larger and sustained increases in the
      other gestational groups. rT3 and T4 sulfate levels in cord serum were higher in
      the most immature infants, and in all groups levels decreased initially and then
      variably increased. The features of a severely attenuated or failed hypothalamic
      pituitary-thyroid response to delivery critically define this 24- to 27-wk group
      as distinct from more mature preterm infants.

PMID- 15181066
TI  - Effects of testosterone on mood, aggression, and sexual behavior in young men: a
      double-blind, placebo-controlled, cross-over study.
AB  - The prospects of wider application of testosterone (T) in novel indications such
      as male contraception have prompted renewed interest in the investigation of
      nonreproductive actions and safety of androgens. This study investigated
      potential changes in mood and behavior in response to elevations in circulating T
      concentrations produced by the new long-acting preparation, T undecanoate (TU).
      Twenty-eight eugonadal men were randomized into one of two treatment groups: A1)
      active, receiving 1000 mg TU i.m. followed by A2) washout, followed by A3)
      placebo, receiving 4 ml castor oil i.m.; B1) placebo, 4 ml castor oil i.m.; B2)
      washout followed by B3) active, receiving 1000 mg TU i.m.. Mood, self- and
      partner-reported physical and verbal aggression, anger, hostility, irritability,
      assertiveness, self-esteem, and sexual function were assessed. A single injection
      of 1000 mg TU i.m. increased plasma T concentrations from 20.7 +/- 1.5 to 37.5 +/
      2.2 nmol/liter at wk 1 and 31.6 +/- 1.5 nmol/liter at wk 2, and estradiol from
      74.0 +/- 4.9 to 120.4 +/- 10.7 pmol/liter at wk 1, and 100.0 +/- 6.3 pmol/liter
      at wk 2. The T increment was associated with detectable but minor mood changes.
      Increased circulating T was associated with significant increases in anger
      hostility from baseline (mean score = 7.48) to wk 2 (mean score = 10.71)
      accompanied by an overall reduction in fatigue-inertia (treatment = 6.21 vs.
      placebo = 7.84). TU treatment did not increase aggressive behavior or induce any
      changes in nonaggressive or sexual behavior. Changes in estradiol were not
      associated with any behavioral alterations. Our results suggest that exogenous TU
      induced elevation of circulating T, to the range likely to be used in hormonal
      male contraception, has limited psychological effects. Future research should
      investigate the implications of these minor mood changes.

PMID- 15181065
TI  - Ghrelin increases energy intake in cancer patients with impaired appetite: acute,
      randomized, placebo-controlled trial.
AB  - There is a pressing need for more effective appetite-stimulatory therapies for
      many patient groups including those with cancer. We have previously demonstrated
      that the gastric hormone ghrelin potently enhances appetite in healthy
      volunteers. Here, we performed an acute, randomized, placebo-controlled, cross
      over clinical trial to determine whether ghrelin stimulates appetite in cancer
      patients with anorexia. Seven cancer patients who reported loss of appetite were
      recruited from oncology clinics at Charing Cross Hospital. The main outcome
      measures were energy intake from a buffet meal during ghrelin or saline infusion
      and meal appreciation as assessed by visual analog scale. A marked increase in
      energy intake (31 +/- 7%; P = 0.005) was observed with ghrelin infusion compared
      with saline control, and every patient ate more. The meal appreciation score was
      greater by 28 +/- 8% (P = 0.02) with ghrelin treatment. No side effects were
      observed. The stimulatory effects of ghrelin on food intake and meal appreciation
      seen in this preliminary study suggest that ghrelin could be an effective
      treatment for cancer anorexia and possibly for appetite loss in other patient
      groups.

PMID- 15181067
TI  - Pharmacological treatment of insulin resistance at two different stages in the
      evolution of type 2 diabetes: impact on glucose tolerance and beta-cell function.
AB  - The purpose of this study was to compare the impact of treating insulin
      resistance with a thiazolidinedione drug before vs. at the onset of diabetes on
      glucose levels and beta-cell function. Nondiabetic Hispanic women of Mexican or
      Central American descent with prior gestational diabetes mellitus (GDM) were
      randomized to troglitazone (early intervention), 400 mg/d, or placebo (later
      intervention). Women who developed diabetes were placed on open-label
      troglitazone. Glucose tolerance, insulin resistance, and beta-cell function were
      measured at randomization, at the diagnosis of diabetes, and 8 months post trial
      to determine the long-term impact of the two treatment strategies on glucose
      levels and beta-cell function. During a mean follow-up of 4.3 yr between baseline
      and posttrial tests, glucose tolerance (oral glucose tolerance test glucose area,
      P = 0.04) and insulin resistance (MINMOD SI, P = 0.02) worsened more in women
      randomized to late intervention (n = 69) than to early intervention (n = 57).
      Insulin secretion (acute insulin response in the iv glucose tolerance test, P =
      0.09) and beta-cell compensation for insulin resistance (disposition index, P =
      0.07) also tended to worsen more in the late intervention group. Among women in
      the late intervention group who developed diabetes, oral glucose tolerance test
      glucose area (P = 0.0001) and beta-cell function (P < or = 0.04) deteriorated
      significantly during development of diabetes on placebo and then did not change
      significantly (P > 0.50) during treatment with troglitazone and posttreatment
      washout. In high-risk Hispanic women, amelioration of insulin resistance can
      stabilize glycemia at the time diabetes develops. These findings highlight the
      role of insulin resistance in the genesis of progressive beta-cell dysfunction
      during the evolution of type 2 diabetes.

PMID- 15181068
TI  - The relationship of fasting serum radioimmune insulin levels to incident coronary
      heart disease in an insulin-treated diabetic cohort.
AB  - It is not known whether insulin levels, in the setting of insulin treatment, are
      an independent risk factor for coronary heart disease (CHD). We studied a cohort
      of 116 insulin-treated individuals, 65 yr or older, who were followed for 5.6-9
      yr. All were free of CHD at baseline. There were 47 incident CHD events. In Cox
      proportional hazards modeling, with fasting immune-reactive insulin levels as a
      continuous variable, the hazard ratio for CHD was statistically significant (P <
      0.0001). When insulin levels were divided into intervals, those in the third
      interval [43-150 microU/ml (258-900 pmol/liter)] had an adjusted 30% increased
      relative risk (95% confidence interval, 0.57, 2.98) compared with those in the
      first interval [<20 microU/ml (<120 pmol/liter)]. Those in the fourth interval
      [151-400 microU/ml (906-2400 pmol/liter)] had an adjusted 5.6-fold increased risk
      (2.3-13.1; P < 0.0001). Approximately 15% of the cohort had such elevated insulin
      levels. Immune-reactive insulin levels were strongly correlated with specific
      insulin, proinsulin, and insulin antibody levels. Markedly elevated fasting
      immune-reactive insulin levels were an independent risk factor for CHD in this
      study of insulin-treated older adults. These observational findings should be
      confirmed through larger prospective studies, given their implications for
      insulin therapy.

PMID- 15181069
TI  - The economic implications of three biochemical screening algorithms for
      pheochromocytoma.
AB  - Pheochromocytoma is a rare, life-threatening condition. Using a modeling
      technique, we studied the economic implications of detection strategies for
      pheochromocytoma (third-party payer perspective). The diagnostic efficacy of
      biochemical tests was based on Mayo Clinic Rochester data. In all hypothetical
      algorithms, positive biochemical tests were followed by abdominal computerized
      tomography and, if negative, metaiodobenzylguanidine scintigraphy. In each
      hypothetical algorithm, imaging would be indicated after positive biochemical
      testing as follows: algorithm A, fractionated plasma metanephrine measurements
      above the laboratory reference range; or algorithm B, abnormal measurements of 24
      h urinary total metanephrines or catecholamines. In algorithm C, subjects with
      fractions of plasma metanephrine at or above 0.5 nmol/liter or normetanephrine at
      or above 1.80 nmol/liter would undergo imaging, whereas those with values between
      the reference range and these cutoffs would undergo 24-h urinary measurements
      (total metanephrines and fractionated catecholamines) and be imaged if positive.
      We determined that, if 100,000 hypertensive patients (including 500 patients with
      pheochromocytoma) were tested, algorithm A (measurement of fractionated plasma
      metanephrines alone) would detect 489 pheochromocytoma patients at a cost of 56.6
      million dollars, whereas B (24-h urinary measurements) would detect 457
      pheochromocytoma patients for 39.5 million dollars, and C (combination of
      measurements of fractionated plasma metanephrines and urines) would detect 478
      patients for 28.6 million dollars. None of the screening strategies for
      pheochromocytoma described are affordable if implemented on a routine basis in
      extremely low-risk patients. However, algorithm C may be the least costly, and at
      a reasonable level of sensitivity, for subjects in whom the suspicion of disease
      is moderate.

PMID- 15181070
TI  - Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new
      diagnostic tool for papillary thyroid cancer.
AB  - Numerous biomolecular markers have been studied to improve the accuracy of fine
      needle aspiration biopsy (FNAB) in the diagnostic and prognostic evaluation of
      thyroid tumors, but none of them has yet become clinically useful. The recently
      discovered BRAF mutation, which occurs specifically in papillary thyroid cancers
      (PTC) with a high prevalence and is associated with poor clinicopathological
      outcomes, has the potential to be a useful diagnostic and prognostic marker for
      PTC. In the present study, we investigated whether detection of BRAF mutation on
      FNAB specimens was technically possible and could be used as an adjunct
      diagnostic tool with routine FNAB. Evaluation of a new colorimetric mutation
      detection method demonstrated 100% sensitivity and 100% specificity in comparison
      with conventional DNA sequencing as the "gold standard" in a large pool of DNA
      samples from various primary thyroid tumor specimens and cell lines. We found
      this novel technique even more sensitive in detecting BRAF mutation on FNAB
      specimens than conventional sequencing. In a series of 48 patients undergoing
      thyroidectomy, mostly for thyroid cancer or for suspicion of cancer, we performed
      preoperative FNAB and, using the colorimetric mutation detection method,
      identified BRAF mutation on the cytological specimens. Prospective analysis
      showed that 50% of the nodules that proved to be PTC on surgical histopathology
      were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were
      no false positive findings. Thus, we have demonstrated the usefulness of BRAF
      mutation detection on FNAB specimens that can help diagnose and identify those
      PTC patients who may need more aggressive surgical treatment and vigilant
      clinical monitoring.

PMID- 15181071
TI  - Serum inhibin B and follicle-stimulating hormone levels as tools in the
      evaluation of infertile men: significance of adequate reference values from
      proven fertile men.
AB  - Inhibin B and FSH levels in 289 idiopathic infertile men were compared with
      reference materials consisting of 303 proven fertile men (reference group 1) and
      307 healthy men from the general population with unknown fertility status
      (reference group 2). The diagnostic power of these two serum markers of
      spermatogenesis was evaluated by the use of receiver operating characteristic
      plot analysis, and an example of how both markers can be used simultaneously in a
      bivariate reference chart is presented. Inhibin B levels were significantly lower
      and FSH levels were significantly higher in the infertile men, compared with
      either reference group, but with significant overlap, especially with reference
      group 2. Nevertheless, approximately 50% of the infertile men had an inhibin B or
      FSH, respectively, below the 2.5 percentile or above the 97.5 percentile of
      reference group 1, whereas only approximately 25% of the infertile men had an
      inhibin B or FSH, respectively, below the 2.5 percentile or above the 97.5
      percentile of reference group 2. Fourteen and 11% of reference group 2 had an
      inhibin B or FSH, respectively, below the 2.5 percentile or above the 97.5
      percentile of reference group 1, suggesting that a significant number of
      individuals from the general population with unknown fertility but otherwise
      healthy may actually be subfertile. In conclusion, 1) proven fertile men
      constitute the most appropriate reference group in the evaluation of the FSH
      inhibin B axis; the sensitivity of these markers to identify infertility
      increased by approximately 20% when fertile men rather than men from the general
      population were used as control group; 2) FSH alone had a slightly higher
      positive predictive value than inhibin B alone, but the positive predictive value
      were highest when both markers of spermatogenesis were used in an inhibin B/FSH
      ratio; and 3) a bivariate reference chart is a valuable objective tool in the
      simultaneous evaluation of FSH and inhibin B as two interrelated markers.

PMID- 15181072
TI  - Interleukin-4 stimulates papillary thyroid cancer cell survival: implications in
      patients with thyroid cancer and concomitant Graves' disease.
AB  - IL-4, a pleiotropic cytokine mainly produced by activated helper T lymphocytes
      type 2 (Th2), is known to protect thyroid cells from autoimmune damage. Acting
      via its receptors (IL-4Ralpha), IL-4 has antiproliferative and apoptotic effects
      in many malignancies. Its effect in thyroid cancer is unknown. We found that
      surgical specimens of thyroid carcinomas express both IL-4Ralpha and IL-4 in the
      majority of cases. Thyroid glands affected by Graves' disease also express IL-4.
      We also studied a panel of eight thyroid cancer cell lines from different
      histotypes and found that thyroid cancer cells express high levels of IL-4Ralpha
      although they do not express IL-4. We then compared the biological effects of IL
      4 in TPC-1, a thyroid cancer cell line, and in MCF-7 breast cancer cells. IL-4
      very weakly stimulated thyroid cancer cell proliferation, but it was very
      effective in protecting thyroid cancer cells from apoptosis induced by
      staurosporin. The protective effect of IL-4 was similar in magnitude to that of
      IGF-I and was associated with up-regulation of the antiapoptotic molecule Bcl-2
      and weak down-regulation of the proapoptotic molecule Bax. Moreover, IL-4
      slightly potentiated the survival effect of IGF-I. In contrast, IL-4 reduced
      growth and induced apoptosis in MCF-7 cells. Taken together, these findings
      suggest that thyroid cancer cells receive significant protection from apoptosis
      by IL-4 produced in the thyroid gland by activated T lymphocytes when concomitant
      Graves' disease is present.

PMID- 15181073
TI  - Angiogenesis and lymphangiogenesis in parathyroid proliferative lesions.
AB  - Angiogenesis and lymphangiogenesis are involved in tumoral growth and metastatic
      spread. There is little information on angiogenesis and no available data on
      lymphangiogenesis in parathyroid glands (PTG). Using immunohistochemistry for
      CD34, LYVE-1 (specific markers for vascular and lymphatic endothelium,
      respectively), vascular endothelial growth factor (VEGF)-A, VEGF-C, and
      fibroblast growth factor (FGF)-2, this study analyzes microvascular density
      (MVD), lymphatic vascular density (LVD), and expression of angiogenic and
      lymphangiogenic growth factors in 13 normal PTG, 77 parathyroid adenomas (PTA),
      and 17 primary parathyroid hyperplasia (PPH). MVD was higher in PPH and PTA,
      compared with PTG (P < 0.001). There was no difference in VEGF-A expression among
      groups. In contrast, FGF-2 expression was higher in PPH, compared with PTA and
      PTG (P < 0.0001). FGF-2 scores and MVD were significantly correlated (r = 0.43).
      LVD did not differ among groups, and VEGF-C expression was unrelated to LVD.
      There was no relationship between MVD and tumor behavior (adenoma size, PTH, or
      calcium). In conclusion, this study shows increased angiogenesis in parathyroid
      proliferative lesions compared with normal glands and suggests that FGF-2 is
      proangiogenic in parathyroid tissue. In PTA, tumor behavior is not related to
      angiogenic phenotype. This is the first demonstration of lymphatic vessels in
      PTG, but the lack of correlation with VEGF-C expression suggests that VEGF-C is
      not the primary lymphangiogenic factor.

PMID- 15181074
TI  - Expression of extracellular matrix metalloproteinase inducer in human placenta
      and fetal membranes at term labor.
AB  - Matrix metalloproteinases (MMPs) are the main mediators of extracellular matrix
      (ECM) degradation during human parturition. However, the mechanisms involved in
      regulation of MMP production during parturition remain poorly understood.
      Recently, an extracellular matrix metalloproteinase inducer (EMMPRIN) has been
      shown to play a key role, as a local regulator, in stimulating MMP production in
      cancer systems. Whether EMMPRIN is expressed and stimulates MMP production in
      human placenta and fetal membranes is presently unknown. In this study, we
      investigated the expression of EMMPRIN at the levels of mRNA and protein in human
      term placenta and fetal membranes with or without labor. Western blot analysis
      showed that EMMPRIN protein was detected in term placenta and fetal membranes at
      two molecular masses of 40 and 65 kDa (glycosylated protein) and one of
      approximately 30 kDa (nonglycosylated protein). The ratio of 65 kDa EMMPRIN to
      total EMMPRIN significantly increased (P < 0.05) in term labor chorio-decidua and
      amnion compared with nonlabor chorio-decidua and amnion. Immunohistochemical
      analysis revealed that EMMPRIN was expressed in placental syncytiotrophoblast,
      amniotic epithelial cells, trophoblast cells of chorion laeve, and decidua
      parietalis. EMMPRIN was also detected at the mRNA level using RT-PCR in cultured
      placental syncytiotrophoblast, amniotic epithelial cells, and chorionic
      trophoblast cells. We conclude that human placenta and fetal membranes express
      EMMPRIN, with the potential to stimulate MMP production, thereby facilitating
      fetal membrane rupture and leading to detachment of the placenta and fetal
      membranes from the maternal uterus at the time of parturition.

PMID- 15181075
TI  - Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys:
      Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear
      factor-1beta gene due to germline mosaicism.
AB  - Mutations in the gene coding for hepatocyte nuclear factor-1beta (HNF-1beta) have
      been known to cause a form of maturity-onset diabetes of the young (MODY5), which
      is usually characterized by dominantly inherited adolescence-onset diabetes
      mellitus associated with renal cysts. This report, however, describes recurrence
      of a novel missense mutation in the HNF-1beta gene, S148W (C443G), in two sibs,
      one with neonatal diabetes mellitus and the other with neonatal polycystic,
      dysplastic kidneys leading to early renal failure. The former patient had only a
      few small renal cysts with normal renal functions, and the latter had only a
      transient episode of hyperglycemia, which resolved spontaneously. Interestingly,
      both parents were clinically unaffected, and PCR restriction fragment length
      polymorphism analysis showed that the mother was a low-level mosaic of normal and
      mutant HNF-1beta, which suggested that the recurrence was caused by germline
      mosaicism. This is the first report of permanent neonatal diabetes mellitus
      caused by a mutation of the HNF-1beta gene as well as the first report of
      germline mosaicism of this gene. In addition, the two cases described here show
      that additional factors, genetic or environmental, can have a significant
      influence on the phenotypic expression of HNF-1beta mutations.

PMID- 15181076
TI  - 15-hydroxyprostaglandin dehydrogenase and cyclooxygenase 2 messenger ribonucleic
      acid expression and immunohistochemical localization in human cervical tissue
      during term and preterm labor.
AB  - Here we have examined the enzymes cyclooxygenase (COX)-2 and 15
      hydroxyprostaglandin dehydrogenase (15-OH PGDH) in pregnant human cervix. In
      biopsies taken transvaginally after preterm and term elective cesarean sections
      and vaginal deliveries, the levels of mRNA coding for COX-2 and 15-OH PGDH were
      assessed by Northern blotting. The cellular localization of the COX-2 and 15-OH
      PGDH proteins was determined by immunohistochemical analysis. COX-2 and 15-OH
      PGDH mRNAs were expressed at detectable levels in the cervical biopsies from all
      four groups of subjects. At cesarean sections (unripe cervix), the level of 15-OH
      PGDH mRNA was significantly higher than the level in the ripe cervix at the time
      of partus, irrespective of the gestational length. In contrast, the level of COX
      2 mRNA was similar in all subjects. Immunoreactivity of COX-2 and 15-OH PGDH was
      expressed by activated fibroblasts. The present investigation documents the
      expression and cellular localization of COX-2 and 15-OH PGDH in the preterm and
      term pregnant human cervix. This observation indicates that both preterm and term
      cervical ripening is associated with decreased degradation of prostaglandins.

PMID- 15181077
TI  - Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and
      Brunzell syndrome: phenotype variability suggests important modifier effects.
AB  - Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder
      caused by mutations in AGPAT2 and Gng3lg. We screened for mutations in AGPAT2 and
      Gng3lg in 26 families with CGL and one family with Brunzell syndrome. We found
      mutations in either AGPAT2 or Gng3lg in all but four probands, including three
      novel mutations in AGPAT2, A712T (Lys215X), IVS3-1G-->C, and C636A (Phe189X). In
      three siblings with Brunzell syndrome, we identified a splice site mutation (IVS4
      2A-->G) in AGPAT2, showing that AGPAT2 mutations can also cause Brunzell
      syndrome. Eighteen CGL patients from 15 families from the same region of
      northeastern Brazil were homozygous for a frameshift mutation (669insA of
      AF05149) in Gng3lg. Despite having the same mutation, the subjects had widely
      divergent clinical manifestations. In our subjects, there did not appear to be
      any distinguishing clinical characteristics between CGL subjects with AGPAT2 or
      Gng3lg mutations with the exception of mental retardation in carriers of Gng3lg.
      In summary, mutations in AGPAT2 and Gng3lg are approximately equally represented
      in CGL; despite harboring the same Gng3lg mutation, subjects may have widely
      divergent clinical manifestations, suggesting modifying influences of other genes
      and/or environment; and Brunzell syndrome may be caused by a mutation in AGPAT2.

PMID- 15181078
TI  - Low-density lipoprotein particle size and its regulatory factors in school
      children.
AB  - Small low-density lipoprotein (LDL) particles are more atherogenic than larger
      LDL particles. To help prevent atherosclerotic coronary heart diseases, it may be
      useful to understand risk factors during childhood. In the present study, we
      evaluated LDL size and its relationship to other risk factors for atherosclerotic
      coronary heart disease. LDL size was measured by 2-15% gradient gel
      electrophoresis in 586 Japanese children (316 boys and 270 girls). Plasma lipids,
      apolipoproteins (apo), glucose, and insulin were also determined by conventional
      methods. Pattern B (LDL size < 25.5 nm) was found in 10.8% of boys and 4.4% of
      girls. Children with pattern B had a higher body mass index (BMI) and insulin
      resistance and a more atherogenic lipoprotein profile [higher triglycerides,
      higher apoB, and lower high-density lipoprotein cholesterol (HDL-C)] than
      children with pattern A (LDL size > or = 25.5 nm). BMI, insulin resistance, and
      plasma concentrations of triglycerides, glucose, and insulin decreased and plasma
      concentrations of HDL-C and apoA-I increased as LDL size increased. HDL-C and
      insulin in boys, and BMI, HDL-C, and apoA-I in girls predicted 22.9 and 28.1% of
      the variability of LDL size, respectively. LDL size was correlated with BMI and
      plasma concentrations of HDL-C, apoA-I, and insulin. Although the contribution of
      these parameters to LDL size in children was less than that in adults,
      improvement of these parameters by changes in lifestyle might be important for
      preventing the development of atherosclerosis even in children.

PMID- 15181079
TI  - CYP7B generates a selective estrogen receptor beta agonist in human prostate.
AB  - In human prostate, dehydroepiandrosterone (DHEA) is a substrate for two major
      metabolic pathways that produce functionally opposing sex steroids. In one
      pathway, DHEA is converted into potent androgens such as testosterone and 5alpha
      dihydrotestosterone. In the other, DHEA is metabolized to 7alpha-hydroxy-DHEA
      (7HD). Recently, CYP7B, a novel P450 enzyme originally characterized in mouse
      brain and expressed in rodent prostate, has been found to be responsible for all
      extrahepatic 7alpha-hydroxylase activity. In this study, we have investigated the
      expression and function of this novel enzyme in human prostate. We have used
      reverse transcription combined with PCR and mRNA in situ hybridization to
      determine and localize the expression of CYP7B mRNA in human benign prostatic
      hyperplasia. High levels of CYP7B mRNA were localized in the epithelial cells
      together with estrogen receptor beta (ERbeta). 7alpha-Hydroxylation was the major
      metabolic fate of DHEA in human prostate. Furthermore, we have shown that human
      prostate epithelial cells in primary culture maintain a high level of 7alpha
      hydroxylase activity, which was enhanced by coculture with stroma cells. To
      investigate the functional relevance of CYP7B expression to sex-steroid action in
      prostate, we used transient transfections and ligand binding assay to determine
      the ability of 7HD to bind and activate the sex-steroid receptors: androgen
      receptor, ERalpha, and ERbeta. 7HD specifically activates ERbeta-mediated
      transcription, mimicking the effects of 17beta-estradiol, but has no impact on
      ERalpha and androgen receptor. Given that DHEA, and its sulfate, circulate at
      micromolar concentrations, there is a clear possibility that CYP7B generates
      sufficient 7HD to activate ERbeta over and above that achieved with very low
      concentrations of intraprostatic 17beta-estradiol. In conclusion, our study
      suggests that CYP7B catalyzes oxysterol 7alpha-hydroxylation within the human
      prostate epithelium. By this reaction, an ERbeta-specific agonist, 7HD, is
      produced. Therefore, CYP7B may be a novel regulator of the androgens/estrogenic
      balance within the prostate.

PMID- 15181080
TI  - Testosterone metabolic clearance and production rates determined by stable
      isotope dilution/tandem mass spectrometry in normal men: influence of ethnicity
      and age.
AB  - The metabolic clearance rate (MCRT) and production rate (PRT) of testosterone (T)
      were measured using constant infusion of trideuterated (d3) T and quantitating
      serum d3T by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Serum
      unlabeled T (d0T) was measured by LC-MS-MS, and serum total T (d3T + d0T) was
      measured by RIA. Mean MCRR (measured by LC-MS-MS) in young white men (1272 +/-
      168 liters/d) was not significantly different from young Asian men (1070 +/- 166
      liters/d). Mean PRT was also not significantly different between the two ethnic
      groups (whites, 9.11 +/- 1.11 mg/d; Asians, 7.22 +/- 1.15 mg/d; P = 0.19 using
      d0T data). Both the mean MCRR (812 +/- 64 liters/d; P < 0.01) and the PRT (3.88
      +/- 0.27 mg/d; P < 0.001) were significantly lower in middle-aged white men when
      compared with their younger counterparts. The mean MCRR and PRR calculated using
      serum total T or d0T data showed a diurnal variation, with levels at midday
      significantly higher than those measured in the evening in the young (MCRT, P <
      0.01; PRT, P < 0.001) and to a lesser extent in the older men (MCRT, P < 0.05;
      PRT, P < 0.05 using total T and P < 0.001 using d0T data). We conclude that using
      LC-MS-MS to detect d3T in serum after constant infusion of stable isotope-labeled
      T allows the measurements of MCRT and PRT, which can be used to study androgen
      metabolism repeatedly after physiological or pharmacological interventions.

PMID- 15181081
TI  - Insulin sensitivity in women with polycystic ovary syndrome.
AB  - The aim of our study was to compare insulin sensitivity in lean and obese
      European polycystic ovary syndrome (PCOS) women with lean healthy women. We
      performed the euglycemic hyperinsulinemic clamp in 83 women with PCOS [53 lean
      with body mass index (BMI) of 21.5 +/- 1.8 kg/m2 and 30 obese with BMI of 29.6 +/
      3.7 kg/m2] and in 15 healthy women with BMI of 21.6 +/- 1.8 kg/m2 to determine
      glucose disposal (M) and the insulin sensitivity index (ISI). Statistical
      evaluation was done using Kruskal-Wallis ANOVA followed by Kruskal-Wallis
      multiple-comparison z-value test. The basal blood glucose was significantly
      higher in lean and obese PCOS women than in controls (P < 0.02). Fasting insulin
      was significantly higher in both lean and obese PCOS women than in controls (P <
      0.000001). Obese PCOS women were more insulin resistant than controls (P < 0.02
      for M and P < 0.0008 for ISI); lean PCOS women did not differ from controls in M
      or ISI. Posthepatic insulin delivery was significantly higher in both lean and
      obese PCOS women compared with controls (P < 0.000008). We conclude that lean
      PCOS women are not more insulin resistant than healthy controls. Insulin
      hypersecretion, on the other hand, is present even in lean PCOS women.

PMID- 15181082
TI  - Lipoprotein remnants and endothelial dysfunction in the postprandial phase.
AB  - The objective of this work was to study whether changes in remnant lipoprotein
      (RLP) plasma levels during the postprandial phase relate to alterations of the
      endothelial function. Fasted patients (15 moderately dyslipidemic men) were given
      an oral fat load (OFL), and blood samples were collected before the OFL ingestion
      (T0) and 2, 4, 6, and 8 h (T2, T4, T6, T8) thereafter. Endothelial function,
      determined as flow-mediated dilatation (FMD) of the brachial artery, was assessed
      at the same time points. Triglyceridemia peaked between T4 (5.48 +/- 0.64
      mmol/liter) and T6 (5.34 +/- 0.89 mmol/liter) and decreased at 8 h (4.36 +/- 0.87
      mmol/liter) after the OFL. FMD decreased significantly 6 h after the OFL
      consumption (from 16.03 +/- 1.32% to 11.53 +/- 1.42%, P < 0.01). Cholesterol in
      RLPs increased steadily up to 6 h and decreased at 8 h (T0 0.53 +/- 0.10, T6 0.81
      +/- 0.11, T8 0.73 +/- 0.13 mmol/liter). Fasting levels of triglycerides and
      cholesterol-RLPs (C-RLPs) correlated significantly with FMD at baseline. The
      decrease in endothelial function at 6 h also significantly correlated with the
      area under the curve of triglycerides (R = 0.53, P = 0.04). Postprandial C-RLPs
      (area under the curve), however, showed the best correlation with the decrease of
      FMD (R = 0.63, P = 0.012). The correlation persisted in a multivariate analysis.
      We concluded that C-RLPs contribute significantly to the endothelial dysfunction
      occurring during the postprandial lipemia.

PMID- 15181083
TI  - Negative relationship between fasting plasma ghrelin concentrations and ad
      libitum food intake.
AB  - Ghrelin is a novel GH secretagogue with orexigenic effects. We hypothesized that
      high fasting plasma ghrelin concentrations (FxGhr) might predict high ad libitum
      food intake. FxGhr were measured in 30 normoglycemic subjects: 15 Pima Indians (8
      male/7 female; age, 32 +/- 7 yr; body weight, 87 +/- 21 kg; mean +/-sd) and 15
      Caucasians (12 male/3 female, 36 +/- 8 yr, 94 +/- 26 kg) in energy balance for 3
      d before testing. Subjects then self-selected their food ad libitum for the
      following 3 d. Mean daily energy intake (DEI) was calculated from the weight of
      foods consumed and expressed as a percent of weight maintenance energy needs.
      FxGhr were twice as high in Caucasians as in Pima Indians (103 +/- 53 vs. 52 +/-
      18 fmol/ml, P < 0.001) and remained higher after adjustment for age, gender, and
      body weight (P < 0.0001). Neither DEI, nor percent of weight maintenance energy
      needs, nor percent of calories from fat differed between the races. In both
      groups, FxGhr were negatively correlated with DEI (r = -0.61, P = 0.01; r = 
      0.54, P = 0.04, respectively). These negative relationships were not explained by
      interindividual differences in age, gender, or body weight. This unexpected
      finding that low FxGhr predict ad libitum food intake suggests that the role of
      endogenous ghrelin in the regulation of energy homeostasis remains uncertain.

PMID- 15181084
TI  - Protective effect of paraoxonase activity in high-density lipoproteins against
      erythrocyte membranes peroxidation: a comparison between healthy subjects and
      type 1 diabetic patients.
AB  - High-density lipoproteins (HDL) plays a key role in the protection against
      oxidative damage of lipoprotein and biological membranes. The aim of the present
      study was to investigate the relationship between the antioxidant role of HDL and
      the HDL-paraoxonase (PON) activity in healthy subjects and in type 1 diabetic
      patients. Moreover, the ability of HDL of controls and diabetic patients to
      protect and/or repair biological membranes from oxidative damage was studied. HDL
      were isolated from 31 type 1 diabetic patients and 31 sex- and age-matched
      healthy subjects and immediately used to evaluate lipid hydroperoxides and HDL
      PON activity. Erythrocyte membranes obtained from healthy subjects were oxidized
      with 2,2-azo-bis(2-aminidinopropane)dihydrochloride and then incubated in the
      presence of HDL isolated from healthy or type 1 diabetic subjects, with
      measurements of membrane lipid hydroperoxides before and after the incubation.
      HDL from type 1 diabetic patients showed higher levels of lipid hydroperoxides
      and a lower activity of HDL-PON than healthy subjects. Moreover, HDL of type 1
      diabetic patients protected less efficiently erythrocyte membranes against
      oxidative damage compared with HDL from healthy subjects. A negative correlation
      was found between HDL-PON activity and the levels of hydroperoxides of HDL,
      confirming the relationship between PON and lipid peroxidation and suggesting
      that subjects with low PON activity are more exposed to oxidative damage than
      subjects with high PON activity. The ability of HDL to protect erythrocyte
      membranes was positively correlated with HDL-PON activity and negatively
      correlated with the levels of lipid hydroperoxides of HDL of healthy subjects.
      These results confirm a linkage between PON activity and lipid peroxidation of
      lipoproteins and suggest that the ability of HDL to protect erythrocyte membranes
      might be related to the PON activity. It might be hypothesized that the decrease
      of PON activity in diabetic patients and the lower HDL protective action against
      membrane peroxidation could contribute to acceleration of arteriosclerosis in
      type 1 diabetes mellitus.

PMID- 15181085
TI  - Dietary fructose reduces circulating insulin and leptin, attenuates postprandial
      suppression of ghrelin, and increases triglycerides in women.
AB  - Previous studies indicate that leptin secretion is regulated by insulin-mediated
      glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin
      secretion, we hypothesized that meals high in fructose would result in lower
      leptin concentrations than meals containing the same amount of glucose. Blood
      samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2
      randomized days during which the subjects consumed three meals containing 55, 30,
      and 15% of total kilocalories as carbohydrate, fat, and protein, respectively,
      with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or
      glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two
      treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and
      insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption.
      The area under the curve for leptin during the first 12 h (-33 +/- 7%; P <
      0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak -
      nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl
      day. In addition, circulating levels of the orexigenic gastroenteric hormone,
      ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl
      meal (P < 0.01), but postprandial suppression of ghrelin was significantly less
      pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced
      a rapid and prolonged elevation of plasma triglycerides compared with the HGl day
      (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key
      signals to the central nervous system in the long-term regulation of energy
      balance, decreases of circulating insulin and leptin and increased ghrelin
      concentrations, as demonstrated in this study, could lead to increased caloric
      intake and ultimately contribute to weight gain and obesity during chronic
      consumption of diets high in fructose.

PMID- 15181086
TI  - Association of the (AU)AT-rich element polymorphism in PPP1R3 with hormonal and
      metabolic features of polycystic ovary syndrome.
AB  - Insulin resistance, a key factor in the pathogenesis of polycystic ovary syndrome
      (PCOS), is associated with a reduction in activation of muscle glycogen synthase.
      A 5-bp insertion-deletion polymorphism in the (AU)AT-rich element (ARE) within
      the 3'-untranslated region of the gene encoding the muscle-specific glycogen
      targeting subunit of protein phosphatase 1 (PPP1R3) has been associated with
      insulin resistance and type 2 diabetes. The present study was undertaken to
      examine the relationship of the ARE polymorphism with clinical and hormonal
      characteristics of women with PCOS. We studied 186 women with PCOS who had
      undergone a standard 75-g oral glucose tolerance test and measurement of serum
      androgen and SHBG levels. Among the largest cohort of nondiabetic subjects
      (Caucasian, n = 112), the presence of the deletion allele (ARE-2) was associated
      with insulin resistance and hyperandrogenemia. There was no association of the
      ARE polymorphism with body mass index or blood glucose concentration during the
      oral glucose tolerance test. Subjects who were homozygous for the insertion
      allele (ARE-1/1) had a mean insulin area under the curve (99,116 +/- 6,625
      pmol/liter.min) that was significantly lower than that in either the heterozygous
      (ARE-1/2) (132,195 +/- 12,340 pmol/liter.min) or homozygous (ARE-2/2) (164,661 +/
      24,219 pmol/liter.min) deletion groups. In addition, ARE-1/1 subjects had
      significantly lower serum concentrations of dehydroepiandrosterone sulfate
      compared with ARE-2/2 subjects (4.2 +/- 0.3 vs. 6.6 +/- 0.7 micromol/liter) and a
      trend toward lower levels of free testosterone (78.8 +/- 6.5 vs. 114.1 +/- 30.8
      pmol/liter). Studies of diabetic and nondiabetic PCOS women of other racial and
      ethnic backgrounds will be necessary to assess the impact of this and other
      variants in PPP1R3 upon the phenotype and natural history of women with PCOS.

PMID- 15181087
TI  - Age-related analysis of inhibin A, inhibin B, and activin a relative to the
      intercycle monotropic follicle-stimulating hormone rise in normal ovulatory
      women.
AB  - Previous studies have reported that the monotropic rise in FSH in older women is
      associated with decreased inhibin B and/or A levels and increased levels of
      activin A. Whereas most investigators have found decreased follicular-phase
      inhibin B, the roles of inhibin A and activin A as modulators of the FSH rise are
      unclear. The objectives of this study were to determine whether deficiencies in
      circulating levels of inhibin A, inhibin B, and/or activin A exist during the
      intercycle interval in ovulatory older (age, 40-45 yr; n = 16), compared with
      younger women (age, 20-25 yr; n = 13). Blood samples were obtained daily
      throughout one menstrual cycle and the follicular phase of the subsequent cycle
      and were analyzed for LH, FSH, estradiol, inhibin A and B, and activin A. Despite
      significant FSH elevation, no deficiencies in inhibin A, activin A, or estradiol
      were detected in older subjects. In fact, inhibin A was significantly higher in
      older participants during the intercycle phase (P = 0.01), whereas inhibin B was
      significantly lower. Thus, the monotropic rise in FSH does not appear to result
      from changes in inhibin A or activin A, supporting the concept that inhibin B
      plays a critical role in mediating the FSH rise in older women.

PMID- 15181088
TI  - 17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines
      correlates with heat shock protein 90 levels.
AB  - Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes growth
      factor receptors and signaling molecules. Disruption of this action inhibits the
      MAPK and phosphatidylinositol-3 kinase cascades and can induce cancer cell death.
      The goal of this study was to determine whether thyroid cancer cells are
      sensitive to the cytotoxic effects of 17-allylamino-17-demethoxygeldanamycin (17
      AAG), an Hsp90 inhibitor in clinical trials, and to determine predictors of this
      response. Papillary (NPA), follicular (WRO), and anaplastic (ARO) thyroid cancers
      were incubated with 17-AAG in vitro. Surprisingly, the ARO cells were most
      sensitive to the cytotoxic effects of this agent. Conversely, all cell lines
      displayed similar responses to specific blockers of phosphatidylinositol-3 kinase
      and MAPK kinase (LY294002 and U0126, respectively). Western blot demonstrated
      that the NPA cells that were most resistant to 17AAG-induced cytotoxicity had the
      lowest levels of Hsp90 and were the only cells with persistent levels of Akt
      protein. Interestingly, even the WRO and ARO cell lines that were sensitive to 17
      AAG-induced cell death did not undergo apoptosis. These data suggest that
      sensitivity of thyroid cancer cells to 17-AAG-induced cytotoxicity relates to
      Hsp90 levels rather than histological subtype and that thyroid cancer cells have
      a reduced apoptotic response to 17-AAG.

PMID- 15181089
TI  - Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling
      proteins in omental but not subcutaneous human adipocytes.
AB  - Visceral adiposity is associated with insulin resistance and type 2 diabetes.
      This study explores the metabolic differences between s.c. and visceral fat
      depots with respect to effects in vitro of glucocorticoids and insulin on glucose
      uptake. Adipocytes from human s.c. and omental fat depots were obtained during
      abdominal surgery in 18 nondiabetic subjects. Cells were isolated, and metabolic
      studies were performed directly after the biopsies and after a culture period of
      24 h with or without dexamethasone. After washing, basal and insulin-stimulated
      [14C]glucose uptake as well as cellular content of insulin signaling proteins and
      glucose transporter 4 (GLUT4) was assessed. Omental adipocytes had an
      approximately 2-fold higher rate of insulin-stimulated glucose uptake compared
      with s.c. adipocytes (P < 0.01). Dexamethasone treatment markedly inhibited (by
      approximately 50%; P < 0.05) both basal and insulin-stimulated glucose uptake in
      omental adipocytes but had no consistent effect in s.c. adipocytes. The cellular
      content of insulin receptor substrate 1 and phosphatidylinositol 3-kinase did not
      differ significantly between the depots, but the expression of protein kinase B
      (PKB) tended to be increased in omental compared with s.c. adipocytes (P = 0.09).
      Dexamethasone treatment decreased the expression of insulin receptor substrate 1
      (by approximately 40%; P < 0.05) and PKB (by approximately 20%; P < 0.05) in
      omental but not in s.c. adipocytes. In contrast, dexamethasone pretreatment had
      no effect on insulin-stimulated Ser473 phosphorylation of PKB. GLUT4 expression
      was approximately 4-fold higher in omental than s.c. adipocytes (P < 0.05).
      Dexamethasone treatment did not alter the expression of GLUT4. In conclusion,
      human omental adipocytes display approximately 2-fold higher glucose uptake rate
      compared with s.c. adipocytes, and this could be explained by a higher GLUT4
      expression. A marked suppression is exerted by glucocorticoids on glucose uptake
      and on the expression of insulin signaling proteins in omental but not in s.c.
      adipocytes. These findings may be of relevance for the interaction between
      endogenous glucocorticoids and visceral fat in the development of insulin
      resistance.

PMID- 15181091
TI  - Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in
      isolated endocrine tumors.
AB  - Activating mutations of the Gsalpha gene are detected in different endocrine
      tumors, such as GH-secreting adenomas and toxic thyroid adenomas, and in
      hyperfunctioning glands from patients with McCune-Albright syndrome (MAS). There
      is increasing evidence that the Gsalpha gene is subjected to imprinting control
      and that Gsalpha imprinting plays a key role in the pathogenesis of different
      human diseases. The aim of this study was to investigate the presence of a parent
      specificity of Gsalpha mutations in 10 patients affected with MAS and 12 isolated
      tumors (10 GH-secreting adenomas, one toxic thyroid adenoma, and one
      hyperfunctioning adrenal adenoma). The parental origin of Gsalpha mutations was
      assessed by evaluating NESP55 and exon 1A transcripts, which are monoallelically
      expressed from the maternal and paternal alleles, respectively. By this approach,
      we demonstrated that in isolated GH-secreting adenomas, as well as in MAS
      patients with acromegaly, Gsalpha mutations were on the maternal allele. By
      contrast, the involvement of other endocrine organs in MAS patients was not
      associated with a particular parent specificity, as precocious puberty and
      hyperthyroidism were present in patients with mutations on either the maternal or
      the paternal allele. Moreover, isolated hyperfunctioning thyroid and adrenal
      adenomas displayed the mutation on the maternal and paternal alleles,
      respectively. These data confirm the importance of Gsalpha imprinting in the
      pituitary gland and point out the high degree of tissue specificity of this
      phenomenon.

PMID- 15181090
TI  - Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on
      social and sexual behavior in female macaques.
AB  - Medroxyprogesterone acetate (MPA) commonly is used in contraception and hormone
      replacement therapy. However, little is known about its effects within the
      central nervous system. Using ovariectomized pigtail macaques (Macaca
      nemestrina), we evaluated the potential for MPA to antagonize estradiol (E2)
      effects on female sociosexual behavior. Subjects (n = 6) were treated
      sequentially with placebo, E2 alone, E2 + progesterone (P4), and E2 + MPA. The
      order of treatments was balanced among subjects, and equimolar quantities of P4
      and MPA were administered. During each treatment period, female sexual initiation
      rates, anxiety-related behavior, and aggression were recorded. Treatment with E2
      alone induced a substantial rise in female sexual initiation rates. Although
      concurrent P4 treatment failed to significantly inhibit sexual behavior, MPA
      treatment markedly antagonized E2's effects. Neither the E2-only nor the E2 + P4
      treatment had an impact on aggression rates, but the E2 + MPA treatment induced a
      significant rise in this behavior. Both MPA and P4 counteracted the effect of E2
      on measures of anxiety. These findings suggest that MPA antagonizes certain
      behavioral effects of E2 that may be beneficial to women, and that it does so
      more profoundly or in ways that endogenous P4 does not. The marked increase in
      aggression seen during MPA treatment suggests that production of negative affect
      may be a particularly serious side effect of MPA.

PMID- 15181092
TI  - Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase
      (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors.
AB  - The human aldose reductase, AKR1B1, participates in glucose metabolism and
      osmoregulation and is supposed to play a protective role against toxic aldehydes
      derived from lipid peroxidation and steroidogenesis that could affect cell
      growth/differentiation when accumulated. Adrenal gland is a major site of
      expression of AKR1B1, and we asked whether changes in its expression could be
      associated with adrenal disorders. Therefore, we examined AKR1B1 gene expression
      in human fetal adrenals, adrenocortical cell line, and tumors and compared the
      results with the expression of steroidogenic genes (StAR and CYP11A) and
      regulators of adrenal cortex development [steroidogenic factor-1 (SF-1) and
      dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the
      X chromosome, gene 1 (DAX1)]. Using specific antibodies, Northern blotting, and
      enzymatic assays, we present evidences that AKR1B1 detectable in 15-wk-old fetal
      glands is regulated by cAMP in NCI-H295 cells and thus that AKR1B1 is
      functionally related to the ACTH-responsive murine akr1b7/mvdp gene rather than
      to its direct ortholog, the mouse aldose reductase akr1b3 gene. Although low DAX1
      expression in aldosterone-producing adenomas (n = 5) was confirmed (P < 0.05), no
      correlation was found between the expression of all other genes and the tumors
      endocrine activity. In contrast, relative abundance of AKR1B1 mRNA was decreased
      in adrenocortical carcinomas (n = 5; mean +/- sem, 0.95 +/- 0.2) when compared
      with adenomas (n = 12; 9.29 +/- 3.05; P < 0.001). Most (seven of eight)
      adrenocortical carcinomas (19.0 +/- 5.4) had very low relative AKR1B1 protein
      levels when compared with benign tumors (cortisol-producing adenomas, n = 5, 63.0
      +/- 9.8; nonfunctional adenomas, n = 5, 58.0 +/- 10.4; aldosterone-producing
      adenomas, n = 4, 65.3 +/- 7.7; P < 0.001), Cushing's hyperplasia (n = 5, 54.6 +/-
      5.3; P < 0.01), or normal adrenals (n = 4; 37.1 +/- 5.3; P < 0.001). These
      properties provide the first evidence that expression of cAMP-regulated AKR1B1 is
      decreased in adrenocortical cancer. This might take part in adrenal tumorigenesis
      and could be investigated as a marker of malignancy for the diagnosis of adrenal
      tumors.

PMID- 15181093
TI  - Type II gonadotropin-releasing hormone stimulates p38 mitogen-activated protein
      kinase and apoptosis in ovarian cancer cells.
AB  - Recent results indicate that a novel second form of GnRH, GnRH-II, has an
      antiproliferative effect on ovarian and endometrial cancer cells and might be
      considered as a possible therapy for gynecological tumors. However, the mechanism
      of the GnRH-II-induced antiproliferative effect is not known. The p38 MAPK, one
      of the stress-activated protein kinases, is activated by diverse cellular stress
      and proinflammatory cytokines. In this study, the effect of GnRH-II on the
      activation of p38 MAPK was investigated, and its possible role in the regulation
      of cell proliferation and apoptosis was further examined in the human ovarian
      cancer cell line, OVCAR-3. Treatment with GnRH-II (100 nM) resulted in an
      activation of p38 MAPK in a time-dependent manner. A significant activation of
      p38 MAPK was observed at 2, 5, 10, and 15 min after GnRH-II treatment. The
      activation of p38 MAPK by GnRH-II was reversed in the presence of a specific
      inhibitor of p38 MAPK, SB203580 (1 microM). The transcription factor, activator
      protein-1, was activated (1.5-fold) by GnRH-II and attenuated in the presence of
      SB203580 (1 microM). Treatment with GnRH-II (1 nM, 100 nM, 10 microM) for 2, 4,
      and 6 d resulted in an inhibition of cell growth in OVCAR-3 cells as determined
      by thymidine incorporation assay. The effect of GnRH-II (100 nM) on cell
      proliferation was blocked by pretreatment with SB203580 (1 microM). Furthermore,
      a significant increase of apoptosis (1.6-fold) was observed after GnRH-II
      treatment, which was also reversed by pretreatment with SB203580 (1 microM).
      Taken together, these results indicate that p38 MAPK is involved in the GnRH-II
      induced inhibition of cell growth through activator protein-1 activation, which
      may be related to induction of apoptosis in ovarian cancer cells.

PMID- 15181094
TI  - The novel somatostatin ligand (SOM230) regulates human and rat anterior pituitary
      hormone secretion.
AB  - Currently available somatostatin analogs predominantly bind to the somatostatin
      receptor subtype (SSTR)2 subtype, and control GH and IGF-I secretion in
      approximately 65% of patients with acromegaly, their efficacy relating to
      receptor density and subtype expression. SOM230 is a somatostatin ligand with
      high affinity to four SSTR subtypes. In primary cultures of rat pituicytes,
      SOM230 dose-dependently inhibited GH release (P = 0.002) with an IC50 of 1.2 nM.
      Ten nanomoles SOM230 inhibited GH and TSH release by 40 +/- 7% (P < 0.001) and 47
      +/- 21% (P = 0.09), respectively. No effect of SOM230 was observed on prolactin
      (PRL) or LH release. In cultures of human fetal pituitary cells, SOM230 inhibited
      GH secretion by 42 +/- 9% (P = 0.002) but had no effect on TSH release. SOM230
      inhibited GH release from GH-secreting adenoma cultures by 34 +/- 8% (P = 0.002),
      PRL by 35 +/- 4% from PRL-secreting adenomas (P = 0.01), and alpha-subunit
      secretion from nonfunctioning pituitary adenomas by 46 +/- 18% (P = 0.34). In
      contrast, octreotide inhibited GH, PRL, and alpha-subunit from the respective
      adenoma by 18 +/- 12 (P = 0.39), 22 +/- 4 (P = 0.04), and 20 +/- 10% (P = 0.34).
      In all culture systems, no significant difference in the inhibitory action of
      SOM230, octreotide, and somatostatin 14 on hormone release was observed. SOM230,
      similar to somatostatin, has high-affinity binding to SSTR1, 2, 3, and 5 and, in
      keeping with this, has an equivalent inhibitory effect on pituitary hormone
      secretion. As a consequence of its broader binding profile, SOM230 is likely to
      find clinical utility in treating tumors resistant to SSTR-2-preferential
      analogs.

PMID- 15181095
TI  - Recombinant human chorionic gonadotropin but not dihydrotestosterone alone
      stimulates osteoblastic collagen synthesis in older men with partial age-related
      androgen deficiency.
AB  - Several randomized trials of androgen supplementation in older men have been
      undertaken. However, the relative contributions of testosterone (T) and estrogens
      on bone metabolism in aging men are controversial. Within the setting of two
      double-blind, placebo-controlled studies, we evaluated the effect of
      dihydrotestosterone (DHT) and recombinant human chorionic gonadotropin (rhCG) on
      bone turnover in healthy, community-dwelling older men with partial androgen
      deficiency (total T < or = 15 nmol/liter). In the first study, 35 men (age 68.3
      +/- 6.8 yr; baseline T, 13.9 +/- 3.3 nmol/liter) were randomized to receive
      either daily transdermal DHT (n = 17) or placebo for 3 months. In the second
      study, 40 men (age 67.4 +/- 5.4 yr; baseline T, 11.4 +/- 2.2 nmol/liter) were
      randomized to receive either rhCG s.c. (n = 20), two injections weekly, or
      placebo for 3 months. The following parameters were measured before, monthly
      during, and 1 month after treatment: serum T, estradiol (E2), and LH; markers of
      bone formation, serum amino-terminal propeptide of type I procollagen (S-PINP)
      and osteocalcin; markers of bone resorption, serum carboxyterminal cross-linked
      telopeptide of type I collagen and urinary deoxypyridinoline. Compared with
      placebo, treatment with DHT significantly increased serum DHT and suppressed LH
      and T levels, whereas E2 concentrations and markers of bone turnover did not
      change. In contrast, rhCG therapy significantly increased both T and E2, with the
      increases in E2 being supraphysiological. At the same time, rhCG significantly
      increased S-PINP concentrations with peak levels after 1 month (Delta40%; P =
      0.02 compared with placebo). In contrast, serum osteocalcin and carboxyterminal
      cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels
      did not change. The change in S-PINP levels correlated with the change in E2
      levels (r = 0.59; P = 0.02) but not with a change in T. We conclude that in older
      men with partial age-related androgen deficiency, rhCG treatment stimulates
      osteoblastic collagen formation proportionally to increased E2 concentrations but
      does not alter markers of mature osteoblastic function or bone resorption. In
      contrast, treatment with a pure, nonaromatizable androgen (DHT) has no effect on
      bone turnover despite a 20-fold increase in serum levels. Bone resorption was not
      accelerated during unchanged (DHT) or increased (rhCG) E2 levels, suggesting that
      minimal E2 levels are needed to maintain stable resorption, although direct
      androgen receptor-mediated effects cannot be excluded. If androgen
      supplementation is required for aging men, aromatizable androgens with sufficient
      endogenous estrogenic activity may have the most beneficial effects on bone.

PMID- 15181096
TI  - Liver receptor homolog-1 regulates the expression of steroidogenic acute
      regulatory protein in human granulosa cells.
AB  - Steroidogenic acute regulatory protein (StAR) plays a critical role in the
      initial step of steroid hormone synthesis. In the present study, we investigated
      the role of liver receptor homolog-1 (LRH-1) and dosage-sensitive sex reversal,
      adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX-1)
      in the regulation of StAR gene expression in human granulosa cell tumor cells. We
      also examined the effect of protein kinase A (PKA) signaling pathway on the
      expression of StAR in the presence of LRH-1 and DAX-1. Cell transfection,
      mutation analysis, and EMSA were performed. LRH-1 significantly induced StAR
      promoter activity in a concentration-dependent manner. This induction was further
      augmented in the presence of PKA agonist. Using deletion analysis, we
      demonstrated LRH-1 binding site at -105/-95. Mutation of this site resulted in a
      significant decrease in the StAR promoter activity. Using EMSA, the ability of
      this cis-element to bind LRH-1 was confirmed. DAX-1 inhibited LRH-1-stimulated
      StAR promoter activity in a concentration-dependent manner. This inhibition was
      also maintained in the presence of PKA stimulation. Our results demonstrated that
      LRH-1 plays a critical role in the induction of StAR gene expression. We
      hypothesize that LRH-1 could be the major transcription factor responsible for
      the rapid and significant increase in ovarian StAR gene expression after
      ovulation.

PMID- 15181097
TI  - Postprandial response of plasma ghrelin levels to various test meals in relation
      to food intake, plasma insulin, and glucose.
AB  - Ghrelin is an orexigenic gastric hormone that decreases in peripheral blood after
      carbohydrate-rich meals but increases after protein ingestion. In the present
      study plasma ghrelin was determined together with hunger and satiety ratings and
      with insulin and glucose concentrations after the ingestion of satiating
      quantities of carbohydrate-, fat-, protein-, fruit-, and vegetable-rich meals in
      14 healthy subjects. Four hours later, standardized sandwiches were consumed.
      After carbohydrate, ghrelin decreased, whereas fat, protein, fruit, and vegetable
      ingestion significantly increased ghrelin levels. Considering all test meals, no
      significant correlation existed between changes of ghrelin levels and satiety
      ratings (r = 0.05; not significant), whereas a significant inverse relationship
      was observed between plasma ghrelin and insulin levels (r = -0.44; P < 0.001).
      During the second meal, sandwich consumption was significantly greater after the
      preceding fruit and vegetable meals, which was significantly correlated with the
      fourth-hour increase of ghrelin (r = 0.44; P < 0.001). In conclusion, after an
      overnight fast, ghrelin release depends on the ingested macronutrients and is
      most likely not a major regulator of acute food intake, although it is of greater
      importance for the recurrence of hunger and subsequent meal size.

PMID- 15181098
TI  - Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin
      resistant obese men.
AB  - Glucagon-like peptide-1-(7-36)-amide (GLP-1) is involved in satiety control and
      glucose homeostasis. Animal studies suggest a physiological role for GLP-1 in
      water and salt homeostasis. This study's aim was to define the effects of GLP-1
      on water and sodium excretion in both healthy and obese men. Fifteen healthy
      subjects and 16 obese men (mean body mass index, 36 kg/m2) were examined in a
      double-blind, placebo-controlled, crossover study to demonstrate the effects of a
      3-h infusion of GLP-1 on urinary sodium excretion, urinary output, and the
      glomerular filtration rate after an i.v. 9.9-g salt load. Infusion of GLP-1
      evoked a dose-dependent increase in urinary sodium excretion in healthy subjects
      (from 74 +/- 8 to 143 +/- 18 mmol/180 min, P = 0.0013). In obese men, there was a
      significant increase in urinary sodium excretion (from 59 to 96 mmol/180 min, P =
      0.015), a decrease in urinary H+ secretion (from 1.1 to 0.3 pmol/180 min, P =
      0.013), and a 6% decrease in the glomerular filtration rate (from 151 +/- 8 to
      142 +/- 8 ml/min, P = 0.022). Intravenous infusions of GLP-1 enhance sodium
      excretion, reduce H+ secretion, and reduce glomerular hyperfiltration in obese
      men. These findings suggest an action at the proximal renal tubule and a
      potential renoprotective effect.

PMID- 15181099
TI  - Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine
      response to acylated ghrelin in humans.
AB  - Ghrelin possesses strong GH-releasing activity but also other endocrine
      activities including stimulation of PRL and ACTH secretion, modulation of insulin
      secretion and glucose metabolism. It is assumed that the GH secretagogue (GHS)
      receptor (GHS-R) 1a mediates ghrelin actins provided its acylation in Serine 3;
      in fact, acylated ghrelin only is able to exert endocrine activities. Acylated
      ghrelin (AG) is present in serum at a 2.5 fold lower concentration than
      unacylated ghrelin (UAG). UAG, however, is not biologically inactive; it shares
      with AG some non-endocrine actions like cardiovascular effects, modulation of
      cell proliferation and even some influence on adipogenesis. Thus, these actions
      are likely to be mediated by GHS-R subtypes able to bind ghrelin independently of
      its acylation. In order to further clarify whether UAG is really devoid of any
      endocrine action, we studied the interaction of the combined administration of AG
      and UAG (1.0 microg/kg i.v.) in 6 normal young volunteers (age [mean +/- SE]:
      25.4 +/- 1.2 yr; BMI: 22.3 +/- 1.0 kg/m2). As expected, AG induced marked
      increase (p < 0.01) in circulating GH, PRL, ACTH and cortisol levels. AG
      administration was also followed by a decrease in insulin levels (-285.4 +/- 64.8
      mU*min/l; p < 0.05) and an increase in plasma glucose levels (1068.4 +/- 390.4
      mg*min/dl; p < 0.01). UAG alone did not induce any change in these parameters.
      UAG also failed to modify the GH, PRL, ACTH and cortisol responses to AG.
      However, when UAG was co-administered together with AG, no significant change in
      insulin (-0.5 +/- 40.9 mU*min/l) and glucose levels (455.9 +/- 88.3 mg*min/dl)
      was recorded anymore, indicating that the insulin and glucose response to AG has
      been abolished by UAG. In conclusion, non-acylated ghrelin does not affect the
      GH, PRL, and ACTH response to acylated ghrelin but is able to antagonize the
      effects of acylated ghrelin on insulin secretion and glucose levels. These
      findings indicate that unacylated ghrelin is metabolically active and is likely
      to counterbalance the influence of acylated ghrelin on insulin secretion and
      glucose metabolism. As GHS-R1a is not bound by unacylated ghrelin, these findings
      suggest that GHS receptor subtypes mediate the metabolic actions of both acylated
      and unacylated ghrelin.

PMID- 15181100
TI  - Growth hormone (GH) replacement in women in relation to their endogenous GH
      secretion.

PMID- 15181101
TI  - Seed-specific promoters direct gene expression in non-seed tissue.
AB  - The organ specificity of four promoters that are known to direct seed-specific
      gene expression was tested. Whereas the phaseolin (phas)- and legumin B4 (leB4)
      promoters were from genes encoding 7S and 11S globulins from Phaseolus vulgaris
      and Vicia faba, respectively, the usp- and the sbp-promoters were from non
      storage protein genes of V. faba. The expression of different promoter-reporter
      gene fusions was followed either by RT-PCR or by registering the reporter enzyme
      activity in organs of transgenic tobacco, pea, narbon bean, or linseed. In
      addition to seeds, the promoters directed reporter gene expression in pollen and
      in seed coats. USP-, vicilin- and legumin-mRNA were detected by RT-PCR in pollen
      of Pisum sativum and V. faba. Expression during microsporogenesis and
      embryogenesis seems to be a general character of various seed protein genes.

PMID- 15181102
TI  - Determining protein identity from sieve element sap in Ricinus communis L. by
      quadrupole time of flight (Q-TOF) mass spectrometry.
AB  - The phloem transport system is a complex tissue that primarily carries
      photoassimilate from source to sink. Its function depends on anucleate sieve
      elements (SE) supported by companion cells (CC). In this study, SE sap was
      sampled and the protein identity of soluble proteins was determined with the aim
      of understanding the function of proteins within the conduit. Unlike many plants,
      SE sap exudes from incisions in the bark of Ricinus communis and, although there
      is a greater possibility of contamination from tissues other than SE, sap can be
      obtained in sufficient quantities to separate proteins using 2D electrophoresis.
      Spots were excised for trypsin digest, then analysed by quadrupole time of flight
      (Q-TOF) mass spectrometry (MS) and database searched to determine sequence
      identity. Overall, 18 proteins were identified in the SE-enriched sap. Proteins
      identified that have not previously been identified directly from SE sap included
      a glycine-rich RNA-binding protein, metallothionein, phosphoglycerate mutase, and
      phosphopyruvate hydratase. The potential role of the identified protein in SE
      function is discussed. The protein identification in this study provides a first
      step towards the goal of a greater understanding of the function of proteins
      within the SE.

PMID- 15181103
TI  - Constitutive expression of EIL-like transcription factor partially restores
      ripening in the ethylene-insensitive Nr tomato mutant.
AB  - Climacteric fruit ripening is regulated by the phytohormone ethylene. ETHYLENE
      INSENSITIVE3 (EIN3) is a transcription factor that functions downstream from the
      ethylene receptors in the Arabidopsis ethylene signal transduction pathway. Three
      homologues of the Arabidopsis EIN3 gene have been identified in tomato,
      Lycopersicon esculentum, EIN3-like or LeEIL, LeEIL1, LeEIL2, and LeEIL3. These
      transcription factors have been proposed to be functionally redundant positive
      regulators of multiple ethylene responses. In order to test the role of such
      factors in the ethylene signal transduction pathway during ripening, EIL1 fused
      to green fluorescent protein (GFP) has been over-expressed in the ethylene
      insensitive non-ripening Nr mutant of tomato. Increased levels of LeEIL1
      compensated for the normally reduced levels of LeEIL1 in the Nr mutant, and
      transgenic Nr plants that exhibited high-level constitutive expression of
      LeEIL1GFP phenotypically resembled wild-type plants, the fruit ripened and the
      leaves exhibited epinasty, unlike Nr plants. The EIL1GFP fusion protein was
      located in the cell nuclei of ripe tomato fruit. The mRNA profile of these plants
      showed that the expression of certain ethylene-dependent ripening genes was up
      regulated, including polygalacturonase and TOMLOX B. However, not all ripening
      genes and ethylene responses, such as seedling triple response, were restored.
      These results demonstrate that expressing candidate genes in the Nr ethylene
      insensitive background is a valuable general approach for testing the role of
      putative downstream components in the ethylene-signalling pathway.

PMID- 15181104
TI  - Hydraulic architecture of plants of Helianthus annuus L. cv. Margot: evidence for
      plant segmentation in herbs.
AB  - The hydraulic architecture of sunflower (Helianthus annuus L. cv. Margot) was
      studied in terms of the partitioning of the hydraulic conductance (Kleaf) of
      leaves inserted at progressively more apical nodes both in growing plants (GP)
      and in plants at full anthesis (mature plants, MP). Leaf conductance to water
      vapour (gL), leaf water potential (PsiL), leaf water potential at zero turgor
      (Psi tlp), and leaf osmotic potential at full turgor (pi0) were also measured.
      Sunflower plants showed gL and Kleaf values significantly increasing in the
      acropetal direction, while PsiL of basal leaves was significantly more negative
      than that of distal leaves; Psi tlp markedly decreased in the acropetal direction
      in MP so that leaves of MP retained increasingly more turgor the more apical they
      were. This hydraulic pattern, already present in very young plants (GP), strongly
      favours apical leaves. These data suggest that the progressive leaf dieback
      starting from the stem base, as observed when the inflorescence of sunflower
      reached maturity, might be due to time-dependent loss of hydraulic conductance.
      In fact, Kleaf loss was correlated with PsiL drop and stomatal closure. Leaf
      dehydration was aggravated by solute exportation from the basal towards the
      apical leaves, as revealed by the acropetal decrease of pi0. Kleaf was shown to
      be linearly and positively related to the prevailing ambient irradiance during
      plant growth, thus suggesting that leaf hydraulics is very sensitive to
      environmental conditions. It was concluded that the pronounced apical dominance
      of some sunflower cultivars is determined, among other factors, by plant
      hydraulic architecture.

PMID- 15181105
TI  - Maintaining exponential growth, solution conductivity, and solution pH in low
      ionic-strength solution culture using a computer-controlled nutrient delivery
      system.
AB  - Studies of plant nutrient requirements in solution culture have often used
      nutrient concentrations many-fold higher than levels found in fertile soils,
      creating an artificial rooting environment that can alter patterns of nutrient
      acquisition. The relative addition rate (RAR) technique addresses this problem by
      providing nutrients in exponentially increasing quantities to plant roots in
      solution culture. A computer-controlled RAR nutrient delivery system has been
      developed to reduce workload and to facilitate more frequent nutrient additions
      (4x daily) than is possible with manual additions. In initial experiments, a
      minimum background solution containing 500 microM nitrogen and all other
      essential nutrients in optimal proportions was required for the healthy growth of
      Triticum aestivum. This requirement was reduced to 50 microM nitrogen when
      calcium in the background solutions was increased to 400 microM. Varying the
      abundance of ammonium and nitrate in both background and delivery solutions
      provided a means of controlling plant-induced pH changes in growth solutions. In
      optimized solutions, plant relative growth rates (RGR) in the order of 0.2 g g(
      1) plant d(-1) were maintained over a 22 d experimental period. Variation in RARs
      provided a means of growing plants with varying RGRs under relatively constant
      conditions of solution electrical conductivity and pH.

PMID- 15181106
TI  - Uptake and translocation of phytochemical 2-benzoxazolinone (BOA) in radish seeds
      and seedlings.
AB  - The molecular aspects of phytochemical interactions between plants, especially
      the process of phytochemical translocation by the target plant, remain
      challenging for those studying allelopathy. 2-Benzoxazolinone (BOA) is a natural
      chemical produced by rye (Secale cereale) and is known to have phytotoxic effects
      on weed seeds and seedlings. The translocation of BOA into target plants has been
      poorly investigated. Therefore, the total absorption of [ring U 14C] BOA was
      estimated by oxidizing whole seedlings of Raphanus sativus cv. for 8 days and
      quantifying the radioactivity. Non-radiolabelled BOA in seedlings was also
      estimated by HPLC. BOA applied at 10(-3) M was readily taken up by germinated
      radish at a rate of 1556 nmol g(-1) FW. At these same concentrations, BOA reduced
      radish germination by 50% and caused a delay in radicle elongation. Exogenous BOA
      was responsible for the observed germination inhibition. At a concentration of
      10(-5) M, BOA was taken up by germinated seeds (31 nmol g(-1) FW), but this
      quantity did not affect radish germination. Labelled BOA was not mineralized in
      the culture medium during seedling growth as no 14CO2 was recovered. Both 10(-3)
      and 10(-5) M BOA were translocated into radish organs, mainly into roots and
      cotyledons. These organs were then identified as potential physiological target
      sites. Cotyledons remained the target sink (44% of the total radioactivity). The
      kinetics of BOA uptake at 10(-3) and 10(-5) M in radish seedlings was identical:
      BOA accumulation was proportional to its initial concentration. A comparison
      between radioactivity and HPLC quantification for 10(-3) M BOA indicated that BOA
      (along with some metabolites) could effectively be recovered in radish organs
      using chromatography.

PMID- 15181107
TI  - Changes in pit membrane porosity due to deflection and stretching: the role of
      vestured pits.
AB  - The effect of increasing pressure difference (DeltaP) on intervessel pit membrane
      porosity was studied in two angiosperm tree species with differing pit
      architecture. Fraxinus americana L. possesses typical angiosperm bordered pit
      structure while Sophora japonica L. exhibits well-developed vestures in
      intervessel pit chambers. It was hypothesized (a) that large DeltaP across
      intervessel pits would cause the deflection of pit membranes in the stems of F.
      americana resulting in significant increases in porosity and thus lower
      cavitation thresholds, and (b) that the presence of vestures would prevent the
      deflection of pit membranes in S. japonica. To determine if the porosity of pit
      membranes increased under mechanical stress, suspensions of colloidal gold, 5 nm
      and 20 nm in diameter, were perfused across intervessel pit membranes at DeltaP
      ranging from 0.25 MPa to 6.0 MPa. The effect of increasing DeltaP on membrane
      porosity was also tested by comparing air seeding thresholds (Pa) in stems
      perfused with water or a solution with lower surface tension. Air seeding and
      colloidal gold experiments indicated that pit membrane porosity increased
      significantly with DeltaP in F. americana. In S. japonica, increases in
      permeability to colloidal gold with DeltaP were small and maximum pore diameters
      predicted from Pa were independent of DeltaP, suggesting that vestures limited
      the degree to which the membrane can be deflected from the centre of the pit
      cavity. This provides the first experimental evidence that vestures reduce the
      probability of air seeding through pit membranes.

PMID- 15181108
TI  - The role of soil microbes in plant sulphur nutrition.
AB  - Chemical and spectroscopic studies have shown that in agricultural soils most of
      the soil sulphur (>95%) is present as sulphate esters or as carbon-bonded sulphur
      (sulphonates or amino acid sulphur), rather than inorganic sulphate. Plant
      sulphur nutrition depends primarily on the uptake of inorganic sulphate. However,
      recent research has demonstrated that the sulphate ester and sulphonate-pools of
      soil sulphur are also plant-bioavailable, probably due to interconversion of
      carbon-bonded sulphur and sulphate ester-sulphur to inorganic sulphate by soil
      microbes. In addition to this mineralization of bound forms of sulphur, soil
      microbes are also responsible for the rapid immobilization of sulphate, first to
      sulphate esters and subsequently to carbon-bound sulphur. The rate of sulphur
      cycling depends on the microbial community present, and on its metabolic
      activity, though it is not yet known if specific microbial species or genera
      control this process. The genes involved in the mobilization of sulphonate- and
      sulphate ester-sulphur by one common rhizosphere bacterium, Pseudomonas putida,
      have been investigated. Mutants of this species that are unable to transform
      sulphate esters show reduced survival in the soil, indicating that sulphate
      esters are important for bacterial S-nutrition in this environment. P. putida S
      313 mutants that cannot metabolize sulphonate-sulphur do not promote the growth
      of tomato plants as the wild-type strain does, suggesting that the ability to
      mobilize bound sulphur for plant nutrition is an important role of this species.

PMID- 15181109
TI  - Dimethylsulphoniopropionate (DMSP) and related compounds in higher plants.
AB  - Dimethylsulphoniopropionate (DMSP) is produced in high concentrations in many
      marine algae, but in higher plants only in a few salt marsh grasses of the genus
      Spartina, in sugar canes (Saccharum spp.), and in the Pacific strand plant
      Wollastonia biflora (L.) DC. The high concentrations found in higher plants (up
      to 250 micromol g(-1) dry weight) suggest an important role, but though many
      functions have been suggested (including methylating agent, detoxification of
      excess sulphur, salt tolerance, and herbivore deterrent), its actual functions
      remain unclear. The fact that the ability to produce DMSP in high concentrations
      is found in species that have no taxonomic or ecological relationship suggests
      that the compound evolved independently and serves different functions in
      different plants. This is supported by observations that DMSP in W. biflora
      behaves differently from that in Spartina species. While DMSP concentrations in
      W. biflora have been found to increase with increasing salinity, suggesting a
      role in osmotic control, such a relationship has not been found for DMSP in
      Spartina species. Recent observations on tissue culture showed that, while
      undifferentiated tissue of W. biflora produced DMSP, such material of Spartina
      alterniflora Loisel. did not. Ongoing studies with tissue culture of both species
      have opened up new avenues of research on DMSP in higher plants, ultimately to
      elucidate the functions of this enigmatic compound.

PMID- 15181110
TI  - Elemental sulphur as an induced antifungal substance in plant defence.
AB  - Man's oldest fungicide has probably long functioned in this role in plants, as a
      natural component of induced antifungal defence. Elemental sulphur (S(0)) is the
      only inorganic phytoalexin and the only phytoalexin produced by so many different
      taxa. S(0) (detected by GC-MS as (32)S(8)) is produced in representative species
      of Sterculiaceae (cocoa), Solanaceae (tomato, tobacco), Malvaceae (cotton), and
      Leguminosae (French bean) in response to xylem-invading fungal and bacterial
      pathogens. Production was more rapid and intensive in disease-resistant
      genotypes. Gene expression for S(0) production may be xylem-specific as S(0) was
      not present in leaves of six species undergoing hypersensitivity to Pseudomonas
      syringae. Anomalously, high constitutive S(0) levels occurred in leaves of
      Arabidopsis and Brassica oleracea. S(0) was highly toxic (ED(50) 1-3 microg ml(
      1)) to many fungal pathogens representing ascomycetes, basidiomycetes, and
      deuteromycetes, but not to an oomycete, Phytophthora, or to bacteria. Levels in
      cocoa and tomato xylem and Arabidopsis leaves were potentially inhibitory, but in
      other interactions were below theoretically toxic concentrations. However, S(0)
      accumulation is highly localized, suggesting that the element is produced in
      sufficient amounts, at the right time and place to be effective. SEM-EDX revealed
      S in tomato and cocoa xylem walls, xylem parenchyma, and vascular gels and
      tyloses, all sites appropriate to counter vascular pathogenic Verticillium
      dahliae. Transient increases in sulphate, glutathione and cysteine occurred in
      tomato xylem. The sulphate may reflect the over-expression of sulphate
      transporters, but the thiols might be possible precursors. Analysis of
      differential gene expression should reveal what may be a novel biosynthetic
      pathway of S(0) formation in eukaryotes.

PMID- 15181111
TI  - Regulated gene expression by glucocorticoids in cultured Virginia pine (Pinus
      virginiana Mill.) cells.
AB  - The effects of six glucocorticoids (dexamethasone, hydrocortisone, 6
      methylprednisolone, prednisolone, prednisone, and triamcinolone) on inducible
      gene expression, based on the chimaeric transcriptional activator GVG and carried
      by the binary expression vector pINDEX3-m-gfp5-ER, were evaluated in transgenic
      Virginia pine cell cultures. The concentration that activated GVG transcription
      factor activity, the level of inducible m-gfp5-ER expression, and the kinetics of
      inducible m-gfp5-ER expression were determined for each glucocorticoid.
      Transgenic cells produced green fluorescence upon blue light excitation after
      treatment with prednisolone, prednisone, 6-methylprednisolone, dexamethasone,
      triamcinolone, and hydrocortisone. Green fluorescence was observed at 6-12 h
      after treatment of all six glucocorticoids at concentrations of 1, 3, 5, and 10
      mg l(-1). Differential expression of gfp was confirmed by northern blot analysis
      and by quantitative fluorescence analyses of confocal images taken by a LSM 510
      Laser Scanning Microscope. Fresh and dry weight increases of transgenic cell
      cultures were not affected by all six glucocorticoids at concentrations of 0.1,
      0.5, 1, 3, and 5 mg l(-1). It is shown that triamcinolone had the most potent
      effect on the GVG system. Different glucocorticoids can therefore be used to
      regulate the GVG transcriptional activator and to induce gene expression in
      transgenic plant cells, and this property could be useful in establishing an
      optimum system of transgene regulation.

PMID- 15181112
TI  - Differential expression of the nitrite reductase gene family in tobacco as
      revealed by quantitative competitive RT-PCR.
AB  - Tobacco (Nicotiana tabacum L. cv. Xanthi XHFD8) possesses four nitrite reductase
      (NiR) genes: nii1, nii2, nii3, and nii4. Their differential expression in leaves
      and roots was investigated by quantitative competitive RT-PCR using gene-specific
      primer pairs. These results appear to contradict existing views on the expression
      of these NiR genes: (i) the mRNA of each of the four NiR genes was
      distinguishable both in leaves and roots; (ii) nitrate treatment increased nii1
      and nii3 mRNA in leaves and roots by at least 4-fold (at least 5-fold in nii2 and
      nii4 mRNA); and (iii) the steady-state levels of nii1 and nii3 mRNA were almost
      the same in leaves (6-7 x 10(5) and about 3 x 10(6) copies microg(-1) of total
      RNA before and after nitrate treatment, respectively) and in roots (3-4 x 10(4)
      and 3-6 x 10(5) copies microg(-1) of total RNA before and after nitrate
      treatment, respectively). Very similar relationships were obtained for the steady
      state levels of nii2 and nii4 mRNA in roots (2-4 x 10(5) and 8 x 10(6) copies
      microg(-1) of total RNA before and after nitrate treatment, respectively), and in
      leaves (5-9 x 10(4) and 4 x 10(5) copies microg(-1) of total RNA before and after
      nitrate treatment, respectively). These results demonstrate that nii1 and nii3
      transcripts are a dominating, but not exclusive, NiR mRNA in leaves, and the same
      is true for nii2 and nii4 transcripts in roots.

PMID- 15181113
TI  - Exhibit hall is a highlight of SNM 2004 annual meeting.

PMID- 15181114
TI  - USP general chapter <797> pharmaceutical compounding-sterile preparations.

PMID- 15181115
TI  - The potential impact of usp general chapter <797> on procedures and requirements
      for the preparation of sterile radiopharmaceuticals.

PMID- 15181116
TI  - Combined guide to NRC compliance now available.

PMID- 15181117
TI  - Pioneering Nuclear Medicine in Buffalo, NY.

PMID- 15181119
TI  - SNM leadership update.

PMID- 15181120
TI  - SNMTS leadership update.

PMID- 15181125
TI  - 18F-FDG PET in rheumatoid arthritis: there still is a long way to go.

PMID- 15181126
TI  - GLUT1 expression in tissue and (18)F-FDG uptake.

PMID- 15181127
TI  - Statistical parametric mapping of (99m)Tc-ECD SPECT in idiopathic Parkinson's
      disease and multiple system atrophy with predominant parkinsonian features:
      correlation with clinical parameters.
AB  - Statistical parametric mapping was performed to investigate differences in
      regional cerebral blood flow (rCBF) between patients with idiopathic Parkinson's
      disease (IPD), patients with multiple system atrophy (MSA), and healthy
      volunteers. In addition, a voxel-based covariance analysis was performed with
      disease-specific parameters and clinical patient data such as disease duration,
      medication, and clinical subscores. METHODS: For this purpose, (99m)Tc
      ethylcysteine dimer (ECD) SPECT was performed on 81 IPD patients (50 men, 31
      women; age, 62.6 +/- 10.2 y), 15 MSA patients (9 men, 6 women; age, 61.5 +/- 9.2
      y), and 44 age- and sex-matched healthy volunteers (27 men, 17 women; age, 59.2
      +/- 11.9 y). RESULTS: Significant hypoperfusion was observed in IPD compared with
      healthy subjects in a symmetric subcortical-cortical network including the basal
      ganglia, thalami, prefrontal and lateral frontal cortex, and parietooccipital
      cortex (voxel P value P(height) < 0.001, corrected for multiple comparisons). For
      MSA, only symmetric hypoperfusion was seen in the putamen and thalamus with
      respect to healthy subjects and to IPD (P(height) < 0.01, corrected). Prolonged
      disease duration or higher Hoehn and Yahr stage results in hypoperfusion of the
      posterior associative cortex. There is a negative correlation between perfusion
      of the caudate heads and limbic system and the standardized dosage of dopamine
      agonists in the patients with PD, whereas for MSA a bilateral decrease in putamen
      activity was noted (P(height) < 0.001, uncorrected). Cognitive performance was
      positively correlated with limbic perfusion and inversely correlated with
      posterior associative cortical areas, but not with prefrontal regions.
      CONCLUSION: Voxel-based analysis of (99m)Tc-ECD perfusion SPECT shows detailed
      differences between IPD and MSA, which may be of use in the differentiation of
      both disease entities, and is able to elucidate cerebral perfusion correlates of
      disease severity, dopamine agonist medication, and cognitive performance.

PMID- 15181128
TI  - Reduced blood flow and preserved vasoreactivity characterize oxygen
      hypometabolism due to incomplete infarction in occlusive carotid artery diseases.
AB  - Recent studies have clarified that hemodynamically compromised patients are at
      high risk for subsequent stroke. The acetazolamide test is widely used to detect
      the patients with hemodynamic compromise due to occlusive carotid artery disease.
      Previous studies have suggested that patients with impaired reactivity to
      acetazolamide had an increased oxygen extraction fraction (OEF) on PET. However,
      the underlying pathophysiology has not been defined in patients with reduced
      blood flow and preserved reactivity to acetazolamide due to carotid occlusive
      diseases regardless of a normal appearance on MRI. This study aimed to clarify
      hemodynamic and metabolic parameters in such patients, using (15)O gas and (11)C
      flumazenil (FMZ) PET. METHODS: Our study included 15 patients who had reduced
      cerebral blood flow (CBF) and preserved cerebrovascular reactivity (CVR) to
      acetazolamide in the ipsilateral middle cerebral artery territory due to
      occlusive carotid diseases on N-isopropyl-p-(123)I-iodoamphetamine ((123)I-IMP)
      SPECT. We determined the CBF, cerebral metabolic rate for oxygen (CMRO(2)),
      cerebral blood volume (CBV), and OEF using (15)O gas PET. The binding potential
      for (11)C-FMZ was also measured in 5 patients. All patients were medically
      treated and followed-up during a mean period of 2.7 y. RESULTS: (15)O gas PET
      scans revealed that the ipsilateral CBF and CMRO(2) were reduced to 80% +/- 11%
      (P < 0.0001) and 78% +/- 8% (P < 0.0001) of the contralateral side, respectively.
      However, there was no significant side-to-side difference in the CBV and OEF. The
      ipsilateral binding potential for (11)C-FMZ was also significantly reduced to 82%
      +/- 2% of the contralateral side (P < 0.05), being very similar to the asymmetry
      of the CBF and CMRO(2). No patients suffered further ischemic stroke in the
      ipsilateral hemisphere during the follow-up period. CONCLUSION: Our results
      strongly suggest that a reduced CBF and a normal CVR characterize oxygen
      hypometabolism probably due to ischemia-related neuronal loss-namely, incomplete
      infarction. Such an ischemic lesion is not hemodynamically compromised and is at
      very low risk for a subsequent ischemic stroke even if the patient is medically
      treated.

PMID- 15181129
TI  - Influence of angiographic collateral circulation on myocardial perfusion in
      patients with chronic total occlusion of a single coronary artery and no prior
      myocardial infarction.
AB  - The functional role of various angiographic grades for coronary collaterals
      remains controversial. The aim of this study was to assess the influence of the
      Rentrop angiographic grading of coronary collaterals on myocardial perfusion in
      patients with single-vessel chronic total occlusion (CTO) and no prior myocardial
      infarction (MI). METHODS: The study included 56 patients with single-vessel CTO
      and no prior MI who underwent rest-stress myocardial perfusion SPECT and coronary
      angiography within 6 mo. All patients had angiographic evidence of coronary
      collaterals. Patients were divided according to the Rentrop classification: Group
      I had grade 1 or 2 (n = 25) and group II had grade 3 collaterals (n = 31).
      RESULTS: Group I had a higher frequency of resting regional wall motion
      abnormalities on left ventriculography (52.6% vs. 19.2% [P = 0.019]). The mean
      perfusion scores of the overall population showed severe and extensive stress
      perfusion defects (summed stress score of 14.1 +/- 7.1 and summed difference
      score of 12.9 +/- 6.9) but minimal resting perfusion defects (summed rest score
      of 1.0 +/- 2.7). No perfusion scores differed between the 2 groups. The perfusion
      findings suggested that chronic stunning rather than hibernation is the principal
      cause of regional wall motion abnormalities in these patients. CONCLUSION: In the
      setting of single-vessel CTO and no prior MI, coronary collaterals appear to
      protect against resting perfusion defects. Excellent angiographic collaterals may
      prevent resting regional wall motion abnormalities but do not appear to protect
      against stress-induced perfusion defects.

PMID- 15181130
TI  - Assessment of disease activity in rheumatoid arthritis with (18)F-FDG PET.
AB  - The aim of this study was to assess synovitis by (18)F-FDG PET in an individual
      joint analysis and in a global analysis of rheumatoid arthritis (RA) disease
      activity and to compare (18)F-FDG PET parameters with clinical, biologic, and
      sonographic (US) rheumatoid parameters. METHODS: Three hundred fifty-six joints
      were assessed in 21 patients with active RA: the knees in all subjects and either
      wrists as well as metacarpophalangeal and proximal interphalangeal joints in 13
      patients, or ankles and the first metatarsophalangeal joints in the remaining 8
      patients. PET analysis consisted of a visual identification of (18)F-FDG uptake
      in the synovium and measurements of standardized uptake values (SUVs).
      Independent assessors performed the clinical and US examinations. RESULTS: PET
      positivity was found in 63% of joints, whereas 75%, 79%, and 56% were positive
      for swelling, tenderness, and US analysis, respectively. Both the rate of PET
      positive joints and the SUV increased with the number of positive parameters
      present (swelling, tenderness, US positivity) and with the synovial thickness.
      The mean SUV was significantly higher in joints where a power Doppler signal was
      found. In a global PET analysis, the number of PET-positive joints and the
      cumulative SUV were significantly correlated with the swollen and tender joint
      counts, the patient and physician global assessments, the erythrocyte
      sedimentation rate and C-reactive protein serum levels, the disease activity
      score and the simplified disease activity index, the number of US-positive
      joints, and the cumulative synovial thickness. CONCLUSION: (18)F-FDG PET is a
      unique imaging technique that can assess the metabolic activity of synovitis and
      measure the disease activity in RA.

PMID- 15181131
TI  - Preoperative assessment of postoperative remnant liver function using
      hepatobiliary scintigraphy.
AB  - Hepatic resection is the therapy of choice for malignant and symptomatic benign
      hepatobiliary tumors. The concept of remnant liver volume (RLV) has been
      introduced and can be assessed with CT. However, inhomogeneous liver function
      distribution and a lack of correlation between morphologic hypertrophy and
      functional recovery fuelled the enthusiasm for functional imaging. The aim of the
      present study was to assess liver function reserve (LFR) and remnant liver
      function (RLF) before and after major liver surgery with hepatobiliary
      scintigraphy (HBS) and to compare scintigraphic results with volumetric CT data
      and indocyanine-green (ICG) clearance test results. Furthermore, HBS was used to
      assess functional recovery of liver function, and results were compared with
      volumetric data. METHODS: Fifteen patients with a partial liver resection were
      included. HBS was performed before, 1 d after, and 3 mo after surgery. ICG
      clearance and CT were performed before and 3 mo after surgery. Liver function
      determined with HBS was compared with ICG and volumetric data. RESULTS: Liver
      function determination using HBS was highly reproducible. A strong positive
      association (r = 0.84) was found between LFR determined with HBS and ICG
      clearance. Little or no association (r = 0.27) was found between CT volumetric
      analysis and corresponding ICG clearance. A strong positive association (r =
      0.95) was found between the RLF determined preoperatively on HBS and the actually
      measured value postoperatively. A weak positive association (r = 0.61) was found
      between functional liver regeneration and liver volume regeneration in the 3 mo
      after partial liver resection. CONCLUSION: HBS offers a unique combination of
      functional liver uptake and excretion with the ability to assess the preoperative
      LFR and to estimate the RLF preoperatively. Determination of the RLF instead of
      the RLV might clarify some of the discrepancies observed in the literature
      between RLV and clinical outcome in patients with an inhomogeneous liver
      function. Finally, liver function regeneration can be monitored using HBS.

PMID- 15181132
TI  - Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG.
AB  - Our aim was to evaluate the use of PET with (11)C-metomidate and (18)F-FDG for
      the diagnosis of adrenal incidentalomas. METHODS: Twenty-one patients underwent
      hormonal screening before dynamic imaging of the upper abdomen with (11)C
      metomidate, and for 19 of these 21 patients, static (18)F-FDG imaging followed.
      Uptake of (11)C-metomidate and (18)F-FDG in incidentalomas was quantified and
      correlated with the hormonal work-up and the mass size on CT (median, 2.5 cm;
      range, 2-10 cm). RESULTS: The final diagnoses were hormonally active adenoma (n =
      7), nonsecretory adenoma (n = 5), adrenocortical carcinoma (n = 1),
      pheochromocytoma (n = 2), benign noncortical tumor (n = 2), normal adrenal (n =
      1), and malignant noncortical tumor (n = 3). Diagnosis was established at surgery
      (n = 9), percutaneous biopsy (n = 4), or follow-up (n = 8). The highest uptake of
      (11)C-metomidate, expressed as standardized uptake value (SUV), was found in
      adrenocortical carcinoma (SUV = 28.0), followed by active adenomas (median SUV =
      12.7), nonsecretory adenomas (median SUV = 12.2), and noncortical tumors (median
      SUV = 5.7). Patients with adenomas had significantly higher tumor-to-normal
      adrenal (11)C-metomidate SUV ratios than did patients with noncortical tumors.
      (18)F-FDG detected 2 of 3 noncortical malignancies but failed to detect adrenal
      metastases from renal cell carcinoma. All inactive and most active adenomas were
      difficult to detect with (18)F-FDG against background activity, whereas both
      pheochromocytomas and adrenocortical carcinoma showed slightly increased uptake
      of (18)F-FDG. There was no correlation between uptake of (11)C-metomidate or
      (18)F-FDG and mass size. CONCLUSION: (11)C-Metomidate is a promising PET tracer
      to identify incidentalomas of adrenocortical origin. (18)F-FDG should be reserved
      for patients with a moderate to high likelihood of neoplastic disease.

PMID- 15181133
TI  - Detection of distant metastases in esophageal cancer with (18)F-FDG PET.
AB  - Standard staging of esophageal and gastroesophageal junction (GEJ) tumors
      substantially lacks accuracy. The aim of this study was to investigate whether
      the addition of PET with (18)F-FDG is a valuable gain in the initial staging.
      METHODS: Between January 1996 and January 2002, (18)F-FDG PET was performed in 74
      patients. Conventional staging included CT in all patients and well-performed
      endoscopic ultrasonography (EUS) in 52 patients. They were compared with (18)F
      FDG PET with pathology and follow-up of suspicious lesions as the gold standard.
      RESULTS: PET identified 70 primary tumors (sensitivity, 95%). Sensitivity to
      identify locoregional metastases was highest for EUS (69%) but was not different
      for CT and PET (44% and 55%, respectively). PET was able to identify distant
      nodal disease in 71% (17/24 patients) compared with 29% (7/24 patients) after
      combined CT/EUS alone (P = 0.021). Sensitivity to detect distant nodal and
      systemic (M1) disease increased with PET (78% vs. 37%; P = 0.012). PET upstaged
      15 patients (15/74; 20%) correctly as M1 disease, missed by CT/EUS, and correctly
      downstaged 4 patients (5%) from M1 to M0 disease. However, false upstaging and
      downstaging was encountered in 5 (7%) and 3 (4%) patients, respectively.
      CONCLUSION: PET improves the currently applied staging of esophageal and GEJ
      tumors, particularly by ameliorating the detection of M1 disease.

PMID- 15181134
TI  - Predictive value for disease progression of serum thyroglobulin levels measured
      in the postoperative period and after (131)I ablation therapy in patients with
      differentiated thyroid cancer.
AB  - The aim of our study was to evaluate and compare in thyroid cancer patients the
      predictive value for disease progression of thyroglobulin (Tg) levels measured
      under thyroid-stimulating hormone (TSH) stimulation, in the postoperative period
      just before (131)I ablative therapy and at the time of control 6-12 mo later.
      METHODS: Two-hundred twelve consecutive patients treated for a well
      differentiated thyroid carcinoma (184 papillary, 28 follicular) with no initial
      distant metastases were retrospectively studied. All patients had a total or near
      total thyroidectomy followed by ablation with 3.7 GBq (131)I. Tg levels were
      determined just before ablative therapy (Tg1) and 6-12 mo later (Tg2). Thresholds
      of 30 and 10 ng/mL were used for Tg1 and Tg2, respectively. Univariate and
      multivariate analyses were performed to assess the predictive value for disease
      progression of the 2 Tg determinations. RESULTS: Thirty patients had a Tg1 level
      > 30 ng/mL. Six to 12 mo later, 30 patients had a Tg2 level > 10 ng/mL, 19 of
      whom had initially a Tg1 level > 30 ng/mL. Disease progression was reported in 20
      patients (9%). Progression-free survival rates were significantly lower in
      patients with a low Tg1 or Tg2 level but the difference was more important with
      Tg2. With univariate analysis, 5 variables were significantly associated with
      disease progression: Tg2, Tg1, node invasion, extrathyroidal extension, and tumor
      size. With multivariate analysis, only Tg2 (odds ratio [OR] = 16.4; 95%
      confidence interval [95% CI] = 5.7-47.4; P < 0.001) and node invasion (OR = 2.7;
      95% CI = 1.0-7.2; P = 0.04) had an independent prognostic value. When only
      initial parameters were considered, Tg1 and node invasion were the 2 independent
      prognostic factors. The OR decreased for Tg1 (OR = 10.1; 95% CI = 4.0-25.7; P <
      0.001) but increased for node invasion (OR = 4.4; 95% CI = 1.7-11.2; P = 0.002).
      CONCLUSION: Among all clinical and tumoral variables, lymph node invasion and
      serum Tg level are 2 important parameters to define the risk of disease
      progression. Although Tg2 appears more significant than Tg1, both Tg levels
      measured under TSH stimulation, in the postoperative period and a few months
      after ablative therapy, have a predictive value. In clinical practice, patients
      at risk can be selected as soon as the initial lymph node status and Tg1 level
      are known.

PMID- 15181135
TI  - PET for the evaluation of pleural thickening observed on CT.
AB  - Early discrimination between benign and malignant pleural diseases is vital for
      the treatment and prognosis of a patient. Imaging is traditionally performed with
      CT or MRI, with an accuracy of 50%-75%. PET has proven to be superior as a
      diagnostic tool in several malignancies. In this prospective study, PET results
      in patients with pleural abnormalities on CT were compared with histologic
      results. METHODS: Eligible patients had pleural thickening on CT and were
      medically fit for surgical diagnostic procedures. All patients underwent PET.
      Qualitative assessment led to a PET score of 1 (definitely normal), 2 (probably
      normal), 3 (probably abnormal), or 4 (definitely abnormal). PET scores of 1 or 2
      indicated a negative PET finding, whereas PET scores of 3 or 4 indicated a
      positive PET finding. Pathologic verification techniques included
      thoracocentesis, thoracoscopy, or open pleural biopsy at thoracotomy. RESULTS:
      Thirty-two patients were enrolled, 19 with malignant and 13 with benign pleural
      disease. PET was true positive in 18 and true negative in 12 patients, with an
      accuracy and negative predictive value of 94% and 92%, respectively. PET was
      false negative in a patient with a slowly growing malignant solitary fibrous
      tumor and false positive in a patient with infectious pleuritis. Median
      standardized uptake values calculated for 7 patients with malignant and benign
      pleural diseases were 6.28 and 1.69, respectively. Patients with a PET score of 1
      or 2 survived significantly longer than patients with a PET score of 3 or 4.
      CONCLUSION: Qualitative assessment of pleural thickening with PET accurately
      discriminates between malignant and benign pleural thickening, with a high
      accuracy and negative predictive value.

PMID- 15181136
TI  - Overexpression of Glut1 in lymphoid follicles correlates with false-positive
      (18)F-FDG PET results in lung cancer staging.
AB  - The evaluation of mediastinal lymph node involvement in non-small cell lung
      carcinoma (NSCLC) is very important for the selection of surgical candidates. PET
      using (18)F-FDG has remarkably improved mediastinal staging in NSCLC. However,
      false (18)F-FDG PET results remain a problem. This study was undertaken to
      identify histologic and immunohistochemical differences between cases showing
      false and true results of mediastinal lymph node involvement assessed by (18)F
      FDG PET. METHODS: Preoperative (18)F-FDG PET examinations were performed on 62
      patients with NSCLC, and mediastinal lymph node sampling was done at thoracotomy
      or mediastinoscopy. In 111 lymph nodes, the size, glucose transporter 1 (Glut1)
      expression, grade of follicular hyperplasia, and involved proportion of tumor
      were examined and compared with the (18)F-FDG PET findings. RESULTS: Lymphoid
      follicular cells were strongly positive for the expression of Glut1. The grade of
      follicular hyperplasia in false-positive lymph nodes was higher than that in true
      negative nodes (P < 0.001). The Glut1 expression of metastatic tumors was higher
      in true-positive nodes than that in false-negative nodes (P < 0.001). Metastatic
      squamous cell carcinomas showed stronger Glut1 expression than adenocarcinomas
      and no false-negative results on (18)F-FDG PET. On the other hand, metastatic
      adenocarcinomas exhibited focal and weak Glut1 expression with frequent false
      negative results. CONCLUSION: The results of this study indicate that (a).
      lymphoid follicular hyperplasia with Glut1 overexpression may have a causal
      relationship with high (18)F-FDG uptake of false-positive nodes and (b). the
      lower expression of Glut1 in metastatic tumors, such as adenocarcinomas, might be
      responsible for false-negative lymph nodes.

PMID- 15181137
TI  - Radionuclide gastroesophageal motor studies.
AB  - Disorders of the upper digestive tract have a high impact on modern society, in
      terms of both direct and indirect health care costs and of social burden. The
      most common presenting symptom is either dysphagia or dyspepsia. Discriminating
      specific diagnoses within this wide group of diseases requires sound clinical
      judgment and application of procedures to distinguish organic from nonorganic
      disease and to further characterize the functional or motility disturbance of
      nonorganic diseases. Non-radionuclide-based diagnostic techniques include both
      noninvasive tests (upper gastrointestinal barium series, ultrasonography, and
      breath test for gastric emptying) and invasive procedures (fiberoptic endoscopy,
      esophagogastroduodenoscopy, pharyngeal manometry, stationary esophageal
      manometry, 24-h pH monitoring, esophageal biliary reflux monitoring, multichannel
      intraluminal impedance, and electrogastrography). Some of these techniques are
      not well tolerated by patients or not widely available. Radionuclide
      transit/emptying scintigraphy provides a means of characterizing exquisite
      functional abnormalities with a set of low-cost procedures that are easy to
      perform and widely available, entail a low radiation burden, closely reflect the
      physiology of the tract under evaluation, are well tolerated and require minimum
      cooperation by patients, and provide quantitative data for better intersubject
      comparison and for monitoring response to therapy. Despite the relatively low
      degree of standardization both in the scintigraphic technique per se and in image
      processing, these methods have shown excellent diagnostic performance in several
      function or motility disorders of the upper digestive tract. Dynamic scintigraphy
      with a radioactive liquid or semisolid bolus provides important information on
      both the oropharyngeal and the esophageal phases of swallowing, thus representing
      a useful complement or even a valid alternative to conventional invasive tests
      (such as stationary esophageal manometry) for evaluating abnormalities of
      oropharyngoesophageal transit. Clinical applications of esophageal transit
      scintigraphy include disorders such as nutcracker esophagus, esophageal spasm,
      noncardiac chest pain of presumed esophageal origin, achalasia, esophageal
      involvement of scleroderma, and gastroesophageal reflux and monitoring of
      response to therapy (either medical or surgical treatment of disease-for example,
      organic disease such as esophageal cancer). Scintigraphy with a radiolabeled test
      meal represents the gold standard for evaluating gastric emptying, whereas more
      recent radionuclide methods include dynamic antral scintigraphy and gastric SPECT
      for assessing gastric accommodation. Clinical applications of gastric-emptying
      scintigraphy include, among others, evaluation of patients with dyspepsia and
      evaluation of gastric function in various systemic diseases affecting gastric
      emptying. The present review includes the proposal of clinical algorithms for
      evaluating patients with the main disorders of the upper digestive tract. These
      algorithms, originally derived from available literature, have been developed on
      the basis of a vast clinical experience in conjunction with the specialists more
      deeply involved in the care of patients with such disorders (medical and surgical
      gastroenterologists and nuclear medicine physicians). The role of radionuclide
      gastroesophageal motor studies is clearly identified in the various steps of
      patients' management, from the initial diagnostic approach to functional
      characterization to postoperative follow-up or monitoring of medical therapy.

PMID- 15181138
TI  - Common artifacts in PET myocardial perfusion images due to attenuation-emission
      misregistration: clinical significance, causes, and solutions.
AB  - Misregistration between attenuation and emission images causes artifactual
      abnormalities on cardiac PET images that result in false-positive defects. This
      study determines the frequency and mechanisms of misregistration artifacts,
      identifies their predictors, and validates a method for their routine clinical
      identification, prevention, or correction. METHODS: We performed 1177 consecutive
      diagnostic myocardial perfusion PET studies using 1 of 3 protocols: (a). 3
      initial consecutive measured attenuation correction (MAC) scans, followed by
      resting and dipyridamole emission scans; (b). an initial MAC scan (early MAC),
      followed by emission scans; and (c). a MAC attenuation scan obtained after
      emission scans (late MAC). Emission images were manually shifted to obtain
      coregistration with attenuation and reconstructed again using shifted emission
      data that eliminated artifactual defects. Measurements on PET images included
      heart size, heart and diaphragm displacement after dipyridamole, objective
      quantitative misregistration of attenuation and emission images, and size or
      severity of image defects before and after shifting emission images. RESULTS: Of
      1,177 rest-dipyridamole PET perfusion studies, 252 (21.4%) had artifactual
      defects due to attenuation-emission misregistration. By shifting emission images,
      quantitative severity and size of misregistration and artifactual defects
      significantly decreased (P < 0.001) with visual normalization. Artifactual
      defects were predicted by horizontal plane misregistration (odds ratio [OR] =
      1.545, confidence intervals [CI] = 1.113-2.145, P = 0.009), body mass index (OR =
      2.659, CI = 1.032-6.855, P = 0.043), and whole heart area in the horizontal plane
      at rest (OR = 1.096, CI = 1.018-1.179, P = 0.015). Quantitative misregistration
      was predicted by diaphragm displacement between rest and dipyridamole (P = 0.001,
      CI = 0.158-0.630), body mass index (P = 0.005, CI = 0.202-1.124), and whole heart
      area in the horizontal plane at rest (P = 0.004, CI = -0.144 to -0.028).
      Diaphragm displacement was significantly larger for obese compared with lean
      patients (P = 0.027) during the initial 10 min of the imaging protocol.
      CONCLUSION: Misregistration of attenuation and emission images is common in
      cardiac PET imaging and causes artifactual defects predicted by diaphragmatic
      displacement, body mass index, and heart size. Multiattenuation imaging sequences
      and manual, visually optimized coregistration of attenuation and emission images
      substantially eliminate artifacts for reliably identifying mild perfusion defects
      of early nonobstructive coronary atherosclerosis as the basis for intense
      lifestyle and pharmacologic treatment.

PMID- 15181139
TI  - Imaging characteristics of a 3-dimensional GSO whole-body PET camera.
AB  - A whole-body 3-dimensional PET scanner using gadolinium oxyorthosilicate (GSO)
      crystals has been designed to achieve high sensitivity and reduced patient
      scanning time. This scanner has a diameter of 82.0 cm and an axial field of view
      of 18 cm without interplane septa. The detector comprises of 4 x 6 x 20 mm(3) GSO
      crystals coupled via an optically continuous light guide to an array of 420
      photomultiplier tubes (39-mm diameter) in a hexagonal arrangement. The patient
      port diameter is 56 cm, and 2.86-cm (1.125 in.) thick lead shielding is used to
      fill in the region up to the detector ring. METHODS: Performance measurements on
      the scanner were made using the National Electrical Manufactures Association
      (NEMA) NU 2-2001 procedures. Additional counting rate measurements with a large
      phantom were performed to evaluate imaging characteristics for heavier patients.
      The image-quality torso phantom with hot or cold spheres was also measured as a
      function of counting rate to evaluate different techniques for randoms and
      scatter subtraction as well as to determine an optimum imaging time. RESULTS: The
      transverse and axial resolutions near the center are 5.5 and 5.6 mm,
      respectively. The absolute sensitivity of this scanner measured with a 70-cm-long
      line source is 4.36 cps/kBq, whereas the scatter fraction is 40% with a 20 x 70
      cm line source cylinder. For the same cylinder, the peak noise equivalent count
      (NEC) rate of 30 kcps at an activity concentration of 9.25 kBq/mL (0.25 micro
      Ci/mL) leads to a 7% increase in the peak NEC value. A significant reduction in
      the peak NEC is observed with a larger 35 x 70 cm line source cylinder. Image
      quality measurements show that the small 10-mm sphere in the NEMA NU 2-2001 image
      quality phantom is clearly visible in a scan time of 3 min, and there is no
      noticeable degradation in image contrast at high activity levels. CONCLUSION:
      This whole-body scanner represents a new generation of 3D, high-sensitivity, and
      high-performance PET cameras capable of producing high-quality images in <30 min
      for a full patient scan. The use of a pixelated GSO Anger-logic detector leads to
      a high-sensitivity scanner design with good counting rate capability due to the
      reduced light spread in the detector and fast decay time of GSO. The light
      collection over the detector is fairly uniform, leading to a good energy
      resolution and, thus, reduced scatter in the collected data due to a tight energy
      gate.

PMID- 15181140
TI  - Isolating effects of microscopic nonuniform distributions of (131)I on labeled
      and unlabeled cells.
AB  - Radiopharmaceuticals are generally distributed nonuniformly in tissue. At the
      microscopic level, only a fraction of the cells in tissue are labeled.
      Consequently, the labeled cells receive an absorbed dose from radioactivity
      within the cell (self-dose) as well as an absorbed dose from radioactivity in
      surrounding cells (cross-dose). On the other hand, unlabeled cells only receive a
      cross-dose. This work uses a novel approach to examine the lethal effects of
      microscopic nonuniformities of (131)I individually on the labeled and unlabeled
      cells. METHODS: A multicellular tissue model was used to investigate the
      lethality of microscopic nonuniform distributions of (131)I. Mammalian cells
      (V79) were dyed with CFDA-SE (carboxy fluorescein diacetate succinimidyl ester)
      and labeled with (131)I-iododeoxyuridine ((131)IdU). The dyed labeled cells were
      then mixed with equal numbers of unlabeled cells, and 3-dimensional tissue
      constructs (4 x 10(6) cells) were formed by centrifugation in a small tube. This
      resulted in a uniform distribution of (131)I at the macroscopic level but
      nonuniform distribution at the multicellular level, wherein 50% of the cells were
      labeled. The multicellular clusters were maintained at 10.5 degrees C for 72 h to
      allow (131)I decays to accumulate. The clusters were then dismantled and the
      labeled (dyed) and unlabeled (undyed) cells were separately seeded for colony
      formation using a fluorescence-activated cell sorter. RESULTS: The unlabeled
      cells, which received only a cross-dose, exhibited a mean lethal dose D(37) of
      4.0 +/- 0.3 Gy. In contrast, the labeled cells received both a self-dose and a
      cross-dose. Isolating the effects of the self-dose resulted in a D(37) of 1.2 +/-
      0.3 Gy, which was about 3.3 times more toxic per unit dose than the cross-dose.
      The reason for these differences appears to be primarily related to the higher
      relative biological effectiveness of the self-dose delivered by (131)IdU compared
      with the cross-dose. Theoretical modeling of the killing of labeled and unlabeled
      cells was achieved by considering the cellular self-doses and cross-doses.
      CONCLUSION: Cellular self-doses and cross-doses play an important role in
      determining the biological response of tissue to microscopic nonuniform
      distributions of (131)I. Prediction of the biological response requires that both
      self-doses and cross-doses be considered along with their relative lethality per
      unit dose.

PMID- 15181141
TI  - High-dose (131)I-tositumomab (anti-CD20) radioimmunotherapy for non-Hodgkin's
      lymphoma: adjusting radiation absorbed dose to actual organ volumes.
AB  - Radioimmunotherapy (RIT) using (131)I-tositumomab has been used successfully to
      treat relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Our approach to
      treatment planning has been to determine limits on radiation absorbed dose to
      critical nonhematopoietic organs. This study demonstrates the feasibility of
      using CT to adjust for actual organ volumes in calculating organ-specific
      absorbed dose estimates. METHODS: Records of 84 patients who underwent
      biodistribution studies after a trace-labeled infusion of (131)I-tositumomab for
      RIT (January 1990 and April 2003) were reviewed. Serial planar gamma-camera
      images and whole-body NaI probe counts were obtained to estimate (131)I-antibody
      source-organ residence times as recommended by the MIRD Committee. The source
      organ residence times for standard man or woman were adjusted by the ratio of the
      MIRD phantom organ mass to the CT-derived organ mass. RESULTS: The mean radiation
      absorbed doses (in mGy/MBq) for our data using the MIRD model were lungs = 1.67;
      liver = 1.03; kidneys = 1.08; spleen = 2.67; and whole body = 0.3; and for CT
      volume-adjusted organ volumes (in mGy/MBq) were lungs = 1.30; liver = 0.92;
      kidneys = 0.76; spleen = 1.40; and whole body = 0.22. We determined the following
      correlation coefficients between the 2 methods for the various organs: lungs,
      0.49 (P = 0.0001); liver, 0.64 (P = 0.004); kidneys, 0.45 (P = 0.0004); spleen,
      0.22 (P = 0.0001); and whole body, 0.78 (P = 0.0001), for the residence times.
      For therapy, patients received mean (131)I administered activities of 19.2 GBq
      (520 mCi) after adjustment for CT-derived organ mass compared with 16.0 GBq (433
      mCi) that would otherwise have been given had therapy been based only using
      standard MIRD organ volumes-a statistically significant difference (P = 0.0001).
      CONCLUSION: We observed large variations in organ masses among our patients. Our
      treatments were planned to deliver the maximally tolerated radiation dose to the
      dose-limiting normal organ. This work provides a simplified method for
      calculating patient-specific radiation doses by adjusting for the actual organ
      mass and shows the value of this approach in treatment planning for RIT.

PMID- 15181142
TI  - Radiolabeling, biodistribution, and dosimetry of (123)I-mAb 14C5: a new mAb for
      radioimmunodetection of tumor growth and metastasis in vivo.
AB  - This study reports on the in vitro evaluation, biodistribution, and dosimetry of
      (123)I-labeled monoclonal antibody (mAb) 14C5, a new antibody-based agent
      proposed for radioimmunodetection of tumor growth and metastasis in vivo.
      METHODS: (123)I-mAb 14C5 was prepared by direct iodination and tested for
      stability in vitro. Binding assays were performed on human SK-BR-3 and HeLa
      carcinoma cells to investigate the antigen expression, antibody affinity, and
      kinetics of tracer binding. For the biodistribution and dosimetry study, 3- to 4
      wk-old NMRI mice were injected intravenously with (123)I-mAb 14C5 (148.0 +/- 7.4
      kBq per mouse) and killed at preset time intervals. Organs, blood, urine, and
      feces were counted for radioactivity uptake, and the data were expressed as the
      percentage injected dose per gram tissue (%ID/g tissue) or %ID. The MIRDOSE3.0
      program was applied to extrapolate the estimated absorbed radiation doses for
      various organs to the human reference adult. RESULTS: (123)I-mAb 14C5 was
      obtained in radiochemical yields of 85.0% +/- 2.5% and radiochemical purities
      were >97%. The iodinated antibody demonstrated good in vitro stability with 93.6%
      +/- 0.1% of (123)I-mAb 14C5 remaining intact at 24 h after radiolabeling. (123)I
      mAb 14C5 bound to SK-BR-3 cells (dissociation constant [K(d)] approximately 0.85
      +/- 0.17 nmol/L) and HeLa cells (K(d) approximately 1.71 +/- 0.17 nmol/L) with
      nanomolar affinity and high specificity, whereas both cell types exhibited a high
      CA14C5 antigen expression (maximum number of binding sites [B(max)] = 40.6 +/-
      5.2 and 57.1 +/- 9.6 pmol/L, respectively). In mice, (123)I-mAb 14C5 accumulated
      primarily in lungs (20.4 %ID/g), liver (15.1 %ID/g), and kidneys (11.1 %ID/g)
      within 5 min after injection. A delayed uptake was observed in stomach (12.8
      %ID/g) and urinary bladder (8.7 %ID/g) at 3 and 6 h, respectively, after
      injection. Radioactivity clearance was predominantly urinary, with 44.9 +/- 4.5
      %ID excreted during the initial 48 h after administration (cumulative amount).
      The highest absorbed radiation doses determined for the human reference adult
      were received by the urinary bladder wall (0.1200-0.1210 mGy/MBq), liver (0.0137
      0.0274 mGy/MBq), uterus (0.0196-0.0207 mGy/MBq), and lower large intestine wall
      (0.0139-0.0258 mGy/MBq). The average effective dose resulting from a single
      (123)I-mAb 14C5 injection was estimated to be 0.017-0.022 mSv/MBq. CONCLUSION:
      (123)I-mAb 14C5 shows good in vitro biologic activity and favorable
      biodistribution properties for imaging carcinomas of different origin and
      provides an acceptable radiation dose to the patient.

PMID- 15181143
TI  - Discrepant recovery course of sympathetic neuronal function and beta
      adrenoceptors in rat hearts after reperfusion following transient ischemia.
AB  - Cardiac sympathetic neuronal function is closely coupled with beta-adrenoceptors
      and adrenergic signaling. However, the recovery process of sympathetic neuronal
      function and beta-adrenoceptors after reperfusion following transient ischemia is
      not fully understood. Accordingly, this study was performed to investigate serial
      changes in sympathetic neuronal function and beta-adrenoceptors after transient
      myocardial ischemia. METHODS: The left coronary artery of male Wister rats was
      ligated for 15 min followed by reperfusion. A dual-tracer method of (131)I
      metaiodobenzylguanidine ((131)I-MIBG) and (125)I-iodocyanopindolol ((125)I-ICYP)
      was used to assess cardiac sympathetic neuronal function and beta-adrenoceptor
      density on days 1, 3, 7, 14, and 28 after reperfusion. Myocardial norepinephrine
      (NE) content in ischemic regions (IR) and in remote regions (RR) and hemodynamic
      indices were determined. Using a membrane preparation of the rat heart after
      reperfusion, the maximum specific binding (B(max)) of beta-adrenoceptors was
      compared with (125)I-ICYP accumulation. RESULTS: The maximum value of the rate of
      change in left ventricular (LV) pressure (dP/dt(max)) tended to decrease on day 1
      after reperfusion but recovered thereafter. Myocardial NE content was
      significantly reduced in IR compared with RR on day 1 (272 +/- 49 vs. 487 +/- 93
      ng/g, P < 0.01), and the decrease became more severe on day 14 (36 +/- 19 vs. 489
      +/- 132 ng/g, P < 0.01) and day 28 (37 +/- 14 vs. 455 +/- 216 ng/g, P < 0.01).
      Decrease in the IR-to-RR uptake ratio of (131)I-MIBG was modest on day 1 (0.64 +/
      0.12) and became more severe on days 7 and 14 (0.38 +/- 0.12 and 0.35 +/- 0.13,
      respectively). This reduction was partially restored on day 28 (0.50 +/- 0.18).
      In contrast, the IR-to-RR uptake ratio of (125)I-ICYP was severely decreased
      until day 3 (0.60 +/- 0.13 on day 1 and 0.54 +/- 0.19 on day 3) and recovered
      thereafter. On day 3, B(max) was significantly lower in IR than in RR (83 +/- 17
      vs. 100 +/- 12 fmol/mg, P < 0.05), but the dissociation constant did not differ
      between the 2 regions. CONCLUSION: The recovery course of cardiac (131)I-MIBG
      uptake after reperfusion following transient ischemia is quite different from
      that of (125)I-ICYP. Simultaneous scintigraphic portrayal of beta-adrenoceptors
      together with (131)I-MIBG would provide useful information regarding adrenergic
      system signaling in patients with coronary artery disease.

PMID- 15181144
TI  - Imaging apoptosis with (99m)Tc-annexin-V in experimental subacute myocarditis.
AB  - 99mTc-Annexin-V (ANX), which allows in vivo detection of apoptotic cells, is
      potentially a promising noninvasive tool to diagnose myocarditis. To test this
      assumption, we compared the myocardial uptake of ANX (imaging and quantitative
      autoradiography) in experimental subacute myocarditis (Wistar Bonn/Kobori rats
      [WBN/Kob]) and in normal Wistar rats. WBN/Kob is an inbred strain of Wistar rat
      in which myocardial injury mimicking subacute catecholamine-induced myocarditis
      spontaneously develops (course duration, 18 mo). The apoptotic myocardial rates
      were determined by immunohistochemical studies. METHODS: Fourteen WBN/Kob rats (8
      10 mo old) and 12 control rats were injected with ANX (7.4 MBq/100 g). Ten-minute
      anterior planar thoracic images (matrix, 128 x 128) were obtained using a pinhole
      collimator, 1 and 4 h after injection. Heart-to-lung activity ratios were
      calculated on the scintigrams. Four hours after ANX injection, quantitative
      autoradiography of myocardial slices was performed, as well as histologic studies
      with hematoxylin-eosin and with a staining assay specific for apoptotic cells.
      RESULTS: Heart-to-lung activity ratios were higher in WBN/Kob rats than in
      control rats on 4-h images (2.07 +/- 0.07 vs. 1.66 +/- 0.06, P = 0.0007).
      Autoradiographic studies showed moderate diffuse, homogeneous myocardial ANX
      uptake significantly higher in WBN/Kob rats than in control rats: 54 +/- 4 versus
      37 +/- 3 counts/mm(2) (P < 0.007). The apoptotic rate, evaluated with an
      apoptotic cell-staining assay, was 0.51% +/- 0.14% of cells in WBN/Kob rats
      versus 0.0042% +/- 0.0008% in control rats (P < 0.008). CONCLUSION: Compared with
      control rats, rats with subacute myocarditis mimicking catecholamine-induced
      myocarditis showed increased ANX myocardial uptake. This suggests a potential
      role for ANX imaging in the diagnosis of myocarditis.

PMID- 15181145
TI  - Amplification targeting: a modified pretargeting approach with potential for
      signal amplification-proof of a concept.
AB  - Conventional nuclear medicine imaging with large radiolabeled molecules such as
      antitumor antibodies suffers from slow localization and clearance. Pretargeting
      is under active investigation as an alternative using either
      (strept)avidin/biotin, bispecific antibodies, or oligomers. However, only the use
      of oligomers such as phosphorodiamidate morpholinos (MORFs) in pretargeting
      offers the potential of signal amplification at the target. Amplification
      targeting is a multistep procedure with the potential to greatly improve target
      localization of radioactivity (and eventually drugs) through the intermediate use
      of polymers conjugated with multiple copies of oligomers. OBJECTIVE: This study
      was conducted to prove the concept in vivo in tumored mice of amplfication
      targeting. METHODS: Nude mice bearing LS174T tumors received in order: the anti
      CEA antibody MN14 conjugated with MORF, a polymer conjugated with multiple copies
      of complementary MORFs (cMORFs), and, finally, (99m)Tc-MORF. RESULTS: In tumored
      animals, dual radiolabels ((99m)Tc and (111)In) were used to demonstrate that,
      after 18 h, about 25% of antibody MORFs in tumor were targeted with polymeric
      cMORFs and, after 3 h, about 12% of the polymeric cMORFs in tumor were targeted
      with (99m)Tc-MORF. Therefore, hybridization in tumor in both cases (i.e.,
      polymeric cMORF to antibody MORF and radiolabeled MORF to polymeric cMORF) was
      surprisingly efficient given the barriers to targeting in vivo and the
      competition between targeting and clearance. Moles of radiolabeled MORF
      accumulating in tumor were more than tripled for study animals receiving all 3
      injections compared with control animals not receiving the antibody or the
      polymer. Furthermore, MORF expression (on antibody) and cMORF expression (on
      polymer) were rapidly lost in normal organs such as liver, spleen, and kidneys
      but not in tumor, thus improving the target-to-nontarget ratios. CONCLUSION:
      Although signal amplification has not yet been convincingly demonstrated and
      amplification targeting will require further studies for optimization, the
      concept has now been shown to be feasible.

PMID- 15181146
TI  - Cooking annexin V: a simple 1-pot procedure to destroy its phosphatidylserine
      binding activity.

PMID- 15181147
TI  - Gene silencing of CENP-E by small interfering RNA in HeLa cells leads to
      missegregation of chromosomes after a mitotic delay.
AB  - Centromeric protein-E (CENP-E) is a kinesin-like motor protein required for
      chromosome congression at prometaphase. Functional perturbation of CENP-E by
      various methods results in a consistent phenotype, i.e., unaligned chromosomes
      during mitosis. One unresolved question from previous studies is whether cells
      complete mitosis or sustain mitotic arrest in the presence of unaligned
      chromosomes. Using RNA interference and video-microscopy, we analyzed the dynamic
      process of mitotic progression of HeLa(H2B)-GFP cells lacking CENP-E. Our results
      demonstrate that these cells initiated anaphase after a delayed mitotic
      progression due to the presence of unaligned chromosomes. In some dividing cells,
      unaligned chromosomes are present during anaphase, causing nondisjunction of some
      sister chromatids producing aneuploid daughter cells. Unlike in Xenopus extract,
      the loss of CENP-E in HeLa cells does not impair gross checkpoint activation
      because cells were arrested in mitosis in response to microtubule-interfering
      agents. However, the lack of CENP-E at kinetochores reduced the
      hyperphosphorylation of BubR1 checkpoint protein during mitosis, which may
      explain the loss of sensitivity of a cell to a few unaligned chromosomes in the
      absence of CENP-E. We also found that presynchronization with nocodazole
      sensitizes cells to the depletion of CENP-E, leading to more unaligned
      chromosomes, longer arrest, and cell death.

PMID- 15181148
TI  - p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress.
AB  - G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their
      entry into mitosis, with the concomitant risks of oncogenic transformation.
      According to the current model, signals elicited by DNA damage prevent mitosis by
      inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic
      regulator. We now show that normal human fibroblasts use additional mechanisms to
      block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA
      damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This
      nuclear retention, which strictly depends on association with endogenous p21,
      prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well
      as its recruitment to the centrosome. In p21-deficient normal human fibroblasts
      and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could
      be readily detected at the centrosome in response to DNA damage. Therefore, in
      normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle
      arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21
      directly prevents mitosis by inactivating and maintaining the inactive state of
      mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic
      cyclins, further contributes to the establishment of a permanent G2 arrest.

PMID- 15181149
TI  - p53 localization at centrosomes during mitosis and postmitotic checkpoint are ATM
      dependent and require serine 15 phosphorylation.
AB  - We recently demonstrated that the p53 oncosuppressor associates to centrosomes in
      mitosis and this association is disrupted by treatments with microtubule
      depolymerizing agents. Here, we show that ATM, an upstream activator of p53 after
      DNA damage, is essential for p53 centrosomal localization and is required for the
      activation of the postmitotic checkpoint after spindle disruption. In mitosis,
      p53 failed to associate with centrosomes in two ATM-deficient,
      ataxiatelangiectasia-derived cell lines. Wild-type ATM gene transfer
      reestablished the centrosomal localization of p53 in these cells. Furthermore,
      wild-type p53 protein, but not the p53-S15A mutant, not phosphorylatable by ATM,
      localized at centrosomes when expressed in p53-null K562 cells. Finally, Ser15
      phosphorylation of endogenous p53 was detected at centrosomes upon treatment with
      phosphatase inhibitors, suggesting that a p53 dephosphorylation step at
      centrosome contributes to sustain the cell cycle program in cells with normal
      mitotic spindles. When dissociated from centrosomes by treatments with spindle
      inhibitors, p53 remained phosphorylated at Ser15. AT cells, which are unable to
      phosphorylate p53, did not undergo postmitotic proliferation arrest after
      nocodazole block and release. These data demonstrate that ATM is required for p53
      localization at centrosome and support the existence of a surveillance mechanism
      for inhibiting DNA reduplication downstream of the spindle assembly checkpoint

PMID- 15181150
TI  - The RCP-Rab11 complex regulates endocytic protein sorting.
AB  - Rab 11 GTPase is an important regulator of endocytic membrane traffic. Recently,
      we and others have identified a novel family of Rab11 binding proteins, known as
      Rab11-family interacting proteins (FIPs). One of the family members, Rab coupling
      protein (RCP), was identified as a protein binding to both Rab4 and Rab11
      GTPases. RCP was therefore suggested to serve a dual function as Rab4 and Rab11
      binding protein. In this study, we characterized the cellular functions of RCP
      and mapped its interactions with Rab4 and Rab11. Our data show that RCP interacts
      only weakly with Rab4 in vitro and does not play the role of coupling Rab11 and
      Rab4 in vivo. Furthermore, our data indicate that the RCP-Rab11 complex regulates
      the sorting of transferrin receptors from the degradative to the recycling
      pathway. We therefore propose that RCP functions primarily as a Rab11 binding
      protein that regulates protein sorting in tubular endosomes.

PMID- 15181151
TI  - Splicing factor hSlu7 contains a unique functional domain required to retain the
      protein within the nucleus.
AB  - Precursor-mRNA splicing removes the introns and ligates the exons to form a
      mature mRNA. This process is carried out in a spliceosomal complex containing
      >150 proteins and five small nuclear ribonucleoproteins. Splicing protein hSlu7
      is required for correct selection of the 3' splice site. Here, we identify by
      bioinformatics and mutational analyses three functional domains of the hSlu7
      protein that have distinct roles in its subcellular localization: a nuclear
      localization signal, a zinc-knuckle motif, and a lysine-rich region. The zinc
      knuckle motif is embedded within the nuclear localization signal in a unique
      functional structure that is not required for hSlu7's entrance into the nucleus
      but rather to maintain hSlu7 inside it, preventing its shuttle back to the
      cytoplasm via the chromosomal region maintenance 1 pathway. Thus, the zinc
      knuckle motif of hSlu7 determines the cellular localization of the protein
      through a nucleocytoplasmic-sensitive shuttling balance. Altogether, this
      indicates that zinc-dependent nucleocytoplasmic shuttling might be the possible
      molecular basis by which hSlu7 protein levels are regulated within the nucleus.

PMID- 15181152
TI  - Does a sentinel or a subset of short telomeres determine replicative senescence?
AB  - The proliferative life span of human cells is limited by telomere shortening, but
      the specific telomeres responsible for determining the onset of senescence have
      not been adequately determined. We here identify the shortest telomeres by the
      frequency of signal-free ends after in situ hybridization with telomeric probes
      and demonstrate that probes adjacent to the shortest ends colocalize with
      gammaH2AX-positive DNA damage foci in senescent cells. Normal BJ cells growth
      arrest at senescence before developing significant karyotypic abnormalities. We
      also identify all of the telomeres involved in end-associations in BJ fibroblasts
      whose cell-cycle arrest at the time of replicative senescence has been blocked
      and demonstrate that the 10% of the telomeres with the shortest ends are involved
      in >90% of all end-associations. The failure to find telomeric end-associations
      in near-senescent normal BJ metaphases, the presence of signal-free ends in 90%
      of near-senescent metaphases, and the colocalization of short telomeres with DNA
      damage foci in senescent interphase cells suggests that end-associations rather
      than damage signals from short telomeres per se may be the proximate cause of
      growth arrest. These results demonstrate that a specific group of chromosomes
      with the shortest telomeres rather than either all or only one or two sentinel
      telomeres is responsible for the induction of replicative senescence.

PMID- 15181153
TI  - NG2 proteoglycan promotes endothelial cell motility and angiogenesis via
      engagement of galectin-3 and alpha3beta1 integrin.
AB  - The NG2 proteoglycan is expressed by microvascular pericytes in newly formed
      blood vessels. We have used in vitro and in vivo models to investigate the role
      of NG2 in cross-talk between pericytes and endothelial cells (EC). Binding of
      soluble NG2 to the EC surface induces cell motility and multicellular network
      formation in vitro and stimulates corneal angiogenesis in vivo. Biochemical data
      demonstrate the involvement of both galectin-3 and alpha3beta1 integrin in the EC
      response to NG2 and show that NG2, galectin-3, and alpha3beta1 form a complex on
      the cell surface. Transmembrane signaling via alpha3beta1 is responsible for EC
      motility and morphogenesis in this system. Galectin-3-dependent oligomerization
      may potentiate NG2-mediated activation of alpha3beta1. In conjunction with recent
      studies demonstrating the early involvement of pericytes in angiogenesis, these
      data suggest that pericyte-derived NG2 is an important factor in promoting EC
      migration and morphogenesis during the early stages of neovascularization.

PMID- 15181156
TI  - High-throughput functional genomics identifies genes that ameliorate toxicity due
      to oxidative stress in neuronal HT-22 cells: GFPT2 protects cells against
      peroxide.
AB  - We describe a novel genetic screen that is performed by transfecting every
      individual clone of an expression clone collection into a separate population of
      cells in a high-throughput mode. We combined high-throughput functional genomics
      with experimental validation to discover human genes that ameliorate cytotoxic
      responses of neuronal HT-22 cells upon exposure to oxidative stress. A collection
      of 5,000 human cDNAs in mammalian expression vectors were individually
      transfected into HT-22 cells, which were then exposed to H(2)O(2). Five genes
      were found that are known to be involved in pathways of detoxification of
      peroxide (catalase, glutathione peroxidase-1, peroxiredoxin-1, peroxiredoxin-5,
      and nuclear factor erythroid-derived 2-like 2). The presence of those genes in
      our "hit list" validates our screening platform. In addition, a set of candidate
      genes was found that has not been previously described as involved in
      detoxification of peroxide. One of these genes, which was consistently found to
      reduce H(2)O(2) -induced toxicity in HT-22, was GFPT2. This gene is expressed at
      significant levels in the central nervous system (CNS) and encodes glutamine
      fructose-6-phosphate transaminase (GFPT) 2, a rate-limiting enzyme in hexosamine
      biosynthesis. GFPT has recently also been shown to ameliorate the toxicity of
      methylmercury in Saccharomyces cerevisiae. Methylmercury causes neuronal cell
      death in part by protein modification as well as enhancing the production of
      reactive oxygen species (ROS). The protective effect of GFPT2 against H(2)O(2)
      toxicity in neuronal HT-22 cells may be similar to its protection against
      methylmercury in yeast. Thus, GFPT appears to be conserved among yeast and men as
      a critical target of methylmercury and ROS-induced cytotoxicity.

PMID- 15181154
TI  - Microtubule-dependent movement of late endocytic vesicles in vitro: requirements
      for Dynein and Kinesin.
AB  - Our previous studies demonstrated that fluorescent early endocytic vesicles
      prepared from rat liver after injection of Texas red asialoorosomucoid contain
      asialoglycoprotein and its receptor and move and undergo fission along
      microtubules using kinesin I and KIFC2, with Rab4 regulating KIFC2 activity (J.
      Cell Sci. 116, 2749, 2003). In the current study, procedures to prepare
      fluorescent late endocytic vesicles were devised. In addition, flow cytometry was
      utilized to prepare highly purified fluorescent endocytic vesicles, permitting
      validation of microscopy-based experiments as well as direct biochemical
      analysis. These studies revealed that late vesicles bound to and moved along
      microtubules, but in contrast to early vesicles, did not undergo fission. As
      compared with early vesicles, late vesicles had reduced association with
      receptor, Rab4, and kinesin I but were highly associated with dynein, Rab7,
      dynactin, and KIF3A. Dynein and KIF3A antibodies inhibited late vesicle motility,
      whereas kinesin I and KIFC2 antibodies had no effect. Dynamitin antibodies
      prevented the association of late vesicles with microtubules. These results
      indicate that acquisition and exchange of specific motor and regulatory proteins
      characterizes and may regulate the transition of early to late endocytic
      vesicles. Flow cytometric purification should ultimately facilitate detailed
      proteomic analysis and mapping of endocytic vesicle-associated proteins.

PMID- 15181155
TI  - Rab22a regulates the recycling of membrane proteins internalized independently of
      clathrin.
AB  - Plasma membrane proteins that are internalized independently of clathrin, such as
      major histocompatibility complex class I (MHCI), are internalized in vesicles
      that fuse with the early endosomes containing clathrin-derived cargo. From there,
      MHCI is either transported to the late endosome for degradation or is recycled
      back to the plasma membrane via tubular structures that lack clathrin-dependent
      recycling cargo, e.g., transferrin. Here, we show that the small GTPase Rab22a is
      associated with these tubular recycling intermediates containing MHCI. Expression
      of a dominant negative mutant of Rab22a or small interfering RNA-mediated
      depletion of Rab22a inhibited both formation of the recycling tubules and MHCI
      recycling. By contrast, cells expressing the constitutively active mutant of
      Rab22a exhibited prominent recycling tubules and accumulated vesicles at the
      periphery, but MHCI recycling was still blocked. These results suggest that
      Rab22a activation is required for tubule formation and Rab22a inactivation for
      final fusion of recycling membranes with the surface. The trafficking of
      transferrin was only modestly affected by these treatments. Dominant negative
      mutant of Rab11a also inhibited recycling of MHCI but not the formation of
      recycling tubules, suggesting that Rab22a and Rab11a might coordinate different
      steps of MHCI recycling.

PMID- 15181157
TI  - Molecular basis of slow activation of the human ether-a-go-go related gene
      potassium channel.
AB  - The human ether-a-go-go related gene (HERG) encodes the pore forming alpha
      subunit of the rapid delayed rectifier K(+) channel which is central to the
      repolarization phase of the cardiac action potential. HERG K(+) channels have
      unusual kinetics characterized by slow activation and deactivation, yet rapid
      inactivation. The fourth transmembrane domain (S4) of HERG, like other voltage
      gated K(+) channels, contains multiple positive charges and is the voltage sensor
      for activation. In this study, we mutated each of the positively charged residues
      in this region to glutamine (Q), expressed the mutant and wild-type (WT) channels
      in Xenopus laevis oocytes and studied them using two-electrode voltage clamp
      methods. K525Q channels activated at more hyperpolarized potentials than WT,
      whereas all the other mutant channels activated at more depolarized potentials.
      All mutants except for R531Q also had a reduction in apparent gating charge
      associated with activation. Mutation of K525 to cysteine (C) resulted in a less
      dramatic phenotype than K525Q. The addition of the positively charged MTSET to
      K525C altered the phenotype to one more similar to K525Q than to WT. Therefore it
      is not charge per se, but the specific lysine side chain at position 525, that is
      crucial for stabilizing the closed state. When rates of activation and
      deactivation for WT and mutant channels were compared at equivalent total
      (chemical + electrostatic) driving forces, K525Q and R528Q accelerated activation
      but had no effect on deactivation, R531Q slowed activation and deactivation,
      R534Q accelerated activation but slowed deactivation and R537Q accelerated
      deactivation but had no effect on activation. The main conclusions we can draw
      from these data are that in WT channels K525 stabilizes the closed state, R531
      stabilizes the open state and R534 participates in interactions that stabilize
      pre-open closed states.

PMID- 15181158
TI  - Expression of several cytoskeletal proteins in ovine cerebral arteries:
      developmental and functional considerations.
AB  - Cytoskeleton proteins play important roles in regulating vascular smooth muscle
      (VSM) contraction and relaxation. We tested the hypotheses that the expression
      levels of several of these proteins change significantly during the course of
      development, and that these changes contribute to age-related changes in
      contractile responses. In cerebral arteries from 95-day (d) gestation and 140-d
      fetus, newborn lambs, and adult sheep, by Western immunoblot (n= 5 for each age)
      we quantified the relative expression of alpha-actin, alpha-tubulin, cyclophilin
      A, and proliferating cell nuclear antigen (PCNA). In addition, we examined middle
      cerebral artery tension responses to phenylephrine (PHE) stimulation in the
      absence or presence of cytochalasin D (3 x 10(-7)m) and nocodazole (3 x 10(-6)m),
      inhibitors of alpha-actin and alpha-tubulin polymerization, respectively. The
      expression levels of alpha-actin and cyclophilin A varied little during the
      course of development. In contrast, alpha-tubulin expression was approximately
      2.5-fold greater in both fetal age groups as compared to adult. Also, as compared
      to adult and as expected, expression of PCNA was several-fold greater in cerebral
      arteries of the 95-d fetus (x8), 140-d fetus (x 5), and newborn (x 3). In both
      adult and fetal middle cerebral artery, cytochalasin D-induced inhibition of
      actin polymerization decreased PHE-induced contraction, to approximately 60 and
      approximately 40% of control, respectively (despite no significant change in
      expression level). In contrast, alpha-tubulin inhibition by nocodazole showed
      little effect on PHE-induced tension (in spite of the age-related decrease in
      expression). In conclusion, expression levels of alpha-actin, a thin filament
      protein involved in contraction, remained relatively constant during the course
      of development, as did the effects of inhibition of its polymerization on
      contractility. In contrast, alpha-tubulin, important in intracellular protein
      trafficking, showed a significant age-related decrease in expression and played a
      relatively minor role in contractility. The present studies suggest that other
      cytoskeletal structural proteins and/or elements of pharmaco-mechanical coupling
      are important to developmental differences in cerebrovascular contractility. In
      addition, the relatively constant expression levels of alpha-actin and
      cyclophilin A with development, suggest that these are useful internal standards
      for studies of cytosolic protein expression.

PMID- 15181159
TI  - Autocrine control of neuronal excitability.

PMID- 15181161
TI  - Changes in contractile activation characteristics of rat fast and slow skeletal
      muscle fibres during regeneration.
AB  - Damaged skeletal muscle fibres are replaced with new contractile units via muscle
      regeneration. Regenerating muscle fibres synthesize functionally distinct
      isoforms of contractile and regulatory proteins but little is known of their
      functional properties during the regeneration process. An advantage of utilizing
      single muscle fibre preparations is that assessment of their function is based on
      the overall characteristics of the contractile apparatus and regulatory system
      and as such, these preparations are sensitive in revealing not only coarse, but
      also subtle functional differences between muscle fibres. We examined the Ca(2+)-
      and Sr(2+)-activated contractile characteristics of permeabilized fibres from rat
      fast-twitch (extensor digitorum longus) and slow-twitch (soleus) muscles at 7, 14
      and 21 days following myotoxic injury, to test the hypothesis that fibres from
      regenerating fast and slow muscles have different functional characteristics to
      fibres from uninjured muscles. Regenerating muscle fibres had approximately 10%
      of the maximal force producing capacity (P(o)) of control (uninjured) fibres, and
      an altered sensitivity to Ca(2+) and Sr(2+) at 7 days post-injury. Increased
      force production and a shift in Ca(2+) sensitivity consistent with fibre
      maturation were observed during regeneration such that P(o) was restored to 36
      45% of that in control fibres by 21 days, and sensitivity to Ca(2+) and Sr(2+)
      was similar to that of control (uninjured) fibres. The findings support the
      hypothesis that regenerating muscle fibres have different contractile activation
      characteristics compared with mature fibres, and that they adopt properties of
      mature fast- or slow-twitch muscle fibres in a progressive manner as the
      regeneration process is completed.

PMID- 15181160
TI  - P2X receptor subtype-specific modulation of excitatory and inhibitory synaptic
      inputs in the rat brainstem.
AB  - The role of P2 receptors in synaptic transmission to the rat medial nucleus of
      the trapezoid body (MNTB) was studied in an in vitro brain slice preparation.
      Whole-cell patch recordings were made and spontaneous synaptic responses studied
      under voltage clamp during application of P2X receptor agonists. ATPgammaS (100
      microm) had no effect on holding current, but facilitated spontaneous excitatory
      postsynaptic current (sEPSC) frequency in 41% of recordings and facilitated
      spontaneous inhibitory postsynaptic currents (sIPSCs) in 20% of recordings. These
      were blocked by the P2 receptor antagonist suramin (100 microm). alpha,beta-meATP
      also facilitated sEPSC and sIPSC frequency, while l-beta,gamma-meATP facilitated
      only sIPSCs. The sEPSC facilitation by ATPgammaS was blocked by TTX (but did not
      block facilitation of sIPSCs). sEPSC facilitation was blocked by PPADS (30
      microm) and the selective P2X(3) receptor antagonist A-317491 (3 microm),
      suggesting that modulation of sEPSCs involves P2X(3) receptor subunits.
      alpha,beta-meATP-facilitated sIPSCs were also recorded in wild-type mouse MNTB
      neurones, but were absent in the MNTB from P2X(1) receptor-deficient mice
      demonstrating a functional role for P2X(1) receptors in the CNS.

PMID- 15181162
TI  - Altered neurotransmitter control of reflex vasoconstriction in aged human skin.
AB  - Cutaneous vasoconstriction (VC) in response to cooling is attenuated in older
      humans; however, mechanisms underlying this functional decline remain unclear.
      The present study tested the hypothesis that the contributions of noradrenaline
      (NA) and sympathetic cotransmitters to reflex-mediated cutaneous VC are altered
      with age. In 11 young (18-26 years) and 11 older (61-77 years) men and women,
      forearm skin blood flow was monitored at three sites using laser Doppler
      flowmetry (LDF) while mean skin temperature was lowered from 34 to 30.5 degrees C
      using a water-perfused suit. Cutaneous vascular conductance (CVC; LDF/mean
      arterial pressure) was expressed as percentage change from baseline (%
      DeltaCVC(base)). Solutions of yohimbine + propranolol (Y + P), bretylium tosylate
      (BT), and lactated Ringer solution were infused via intradermal microdialysis at
      each LDF site to antagonize alpha- and beta-adrenoceptors, block sympathetic
      release of NA and cotransmitters, and act as control, respectively. During
      cooling, VC was attenuated at the control site in older subjects compared to
      young subjects (-16 +/- 3 versus-34 +/- 4% DeltaCVC(base), P < 0.001). Y + P
      attenuated VC in young subjects (-13 +/- 8% DeltaCVC(base), P < 0.001 versus
      control) and abolished VC in older subjects (0 +/- 3% DeltaCVC(base), P > 0.9
      versus baseline). BT completely blocked VC in both age groups. Cutaneous VC in
      young subjects is mediated by both NA and sympathetic cotransmitter(s); however,
      reflex VC in aged skin is attenuated compared to young and appears to be mediated
      solely by NA.

PMID- 15181163
TI  - Plasticity of the beta cell insulin secretory competence: preparing the
      pancreatic beta cell for the next meal.
AB  - It is well established that the acute rise in plasma glucose and in the incretin
      hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide
      1 (7-36) amide (GLP-1), as occurs during a meal, is of pivotal importance in
      regulating the minute-to-minute output of insulin from pancreatic beta cells. In
      addition to this well studied acute effect, both glucose and incretin hormones
      have been recently observed to determine the future secretory responsiveness of
      the cells. Such plasticity of the insulin secretory competence would imply that
      glucose and incretins not only act during the present meal, but also help to
      prepare the beta cells to function during the subsequent meal. Evidence
      supporting this hypothesis is growing as a result of physiological studies of
      cultured beta cells (either primary cells or beta cell lines), as well as from an
      increasing number of large-scale gene expression studies, exploring
      transcriptional and post-transcriptional events in genes regulated by glucose and
      incretins. On the basis of this hypothesis, one can speculate that genetic or
      environmental disturbances of plasticity of the insulin secretory competence is
      one aspect of beta cell dysfunction that can contribute to the aetiology of type
      2 diabetes.

PMID- 15181164
TI  - Relaxation from a voluntary contraction is preceded by increased excitability of
      motor cortical inhibitory circuits.
AB  - Termination of a muscle contraction is as important a part of movement as muscle
      activation yet the mechanisms responsible are less well understood. In the
      present experiments we examined the possible role of intracortical inhibitory
      circuits in terminating a 20% maximum isometric contraction of the first dorsal
      interosseous muscle (FDI) in eight healthy subjects. Subjects performed the task
      simultaneously with both hands and received single or pairs (at an interstimulus
      interval of 3 ms to evaluate short interval intracortical inhibition, SICI) of
      transcranial magnetic stimuli (TMS) via a focal coil over the motor hand area of
      the left hemisphere at different times before and after the onset of relaxation.
      The amplitude of the motor-evoked potential (MEP) following a single or a pair of
      TMS pulses was measured in the right FDI and plotted relative to the onset of
      relaxation as estimated from the surface electromyogram (EMG) of the left FDI.
      MEPs were larger during contraction than after relaxation whereas SICI was absent
      during contraction and reappeared after relaxation. We found that in all
      subjects, the time course of MEP changes during relaxation was closely fitted by
      a Boltzmann sigmoidal curve which allowed us to estimate the mean MEP amplitudes
      as well as the ratio of the amplitudes after single or pairs of TMS pulses
      (i.e.%SICI) at any time in the task. The data showed that the amplitude of MEPs
      to single pulse TMS had started to decline at about the same time as the onset of
      EMG silence. Furthermore, the size of the MEPs evoked by paired pulses decreased
      up to 30 ms beforehand. The latter suggests that an increase in SICI occurs prior
      to the onset of MEP changes, and hence that increased cortical inhibition may
      play a role in suppressing corticospinal excitability during relaxation. A
      subsidiary experiment showed that the time relations of changes in SICI and MEP
      were unchanged by a period of 10 min training on the task.

PMID- 15181165
TI  - Human forearm position sense after fatigue of elbow flexor muscles.
AB  - After a period of eccentric exercise of elbow flexor muscles of one arm in young,
      adult human subjects, muscles became fatigued and damaged. Damage indicators were
      a fall in force, change in resting elbow angle and delayed onset of soreness.
      After the exercise, subjects were asked to match the forearm angle of one arm,
      whose position was set by the experimenter, with their other arm. Subjects
      matched the position of the unsupported reference arm, when this was unexercised,
      with a significantly more flexed position in their exercised indicator arm.
      Errors were in the opposite direction when the reference arm was exercised. The
      size of the errors correlated with the drop in force. Less consistent errors were
      observed when the reference arm was supported. A similar pattern of errors was
      seen after concentric exercise, which does not produce muscle damage. The data
      suggested that subjects were using as a position cue the perceived effort
      required to maintain a given forearm angle against the force of gravity. The fall
      in force from fatigue after exercise meant more effort was required to maintain a
      given position. That led to matching errors between the exercised and unexercised
      arms. It was concluded that while a role for muscle spindles in kinaesthesia
      cannot be excluded, detailed information about static limb position can be
      derived from the effort required to support the limb against the force of
      gravity.

PMID- 15181166
TI  - Characterization of release-independent short-term depression in the juvenile rat
      hippocampus.
AB  - Short-term depression strongly influences neuronal activity in cerebral circuits
      and contributes to low-pass temporal filtering of information. In this work, we
      show that synaptic depression evoked by stimulation of commissural-Schaffer
      collateral afferents at 10 Hz is associated with a reduction of the fibre volley.
      This depression of action potentials is also evident in the absence of
      extracellular Ca(2+), which underlies its release-independent nature. In
      addition, this reduction of the excitability is independent of failures in action
      potential propagation since increasing the distance between the stimulus and
      recording electrodes does not alter this effect. Whole-cell recordings show that
      tetanic stimulation at supraminimal intensity induces action potential failures
      preceded by changes in the repolarization rate of the action potentials leading
      the membrane potential to hyperpolarized values. This activity-dependent
      hyperpolarization was blocked by ouabain, an indication of the important role of
      the Na(+)-K(+)-ATPase in this process. Then again, an alteration of the firing
      threshold was observed when action potentials were elicited either by somatic
      current injection or by synaptic stimulation, which indicates that this mechanism
      could alter the EPSP-spike coupling in these cells. The results suggest that
      these factors act together to reduce gradually the safety factor for action
      potential generation and to produce failures in action potential initiation; in
      fact, experiments made at twice the supraminimal intensity show a dramatic
      decrease in the rate of these failures. Taken together, the results suggest the
      existence of a release-independent component of short-term depression that is
      related to failures in action potential initiation.

PMID- 15181167
TI  - Expression of the sodium-myo-inositol cotransporter SMIT2 at the apical membrane
      of Madin-Darby canine kidney cells.
AB  - Myo-inositol is a compatible osmolyte used by cells which are challenged by
      variations in extracellular osmolarity, as in the renal medulla. In order to
      accumulate large quantities of this polyol, cells rely on Na(+)-dependent
      transporters such as SMIT1. We have recently identified a second Na(+)-myo
      inositol cotransporter, SMIT2, which presents transport characteristics
      corresponding to those recently described for the apical membrane of renal
      proximal tubules. In order to further characterize this transport system, we
      transfected Madin-Darby canine kidney (MDCK) cells with rabbit SMIT2 cDNA and
      selected a stable clone with a high expression level. The accumulation of
      radiolabelled myo-inositol by this cell line is 20-fold larger than that seen in
      native MDCK cells. The affinity for myo-inositol of MDCK cells transfected with
      SMIT2 is slightly lower (K(m)= 334 microm) than that found in voltage-clamped
      Xenopus laevis oocytes expressing SMIT2 (K(m)= 120 microm). Transport studies
      performed using semipermeable filters showed complete apical targeting of the
      SMIT2 transporter. This apical localization of SMIT2 was confirmed by transport
      studies on purified rabbit renal brush border membrane vesicles (BBMVs). Using a
      purified antibody against SMIT2, we were also able to detect the SMIT2 protein
      (molecular mass = 66 kDa) in Western blots of BBMVs purified from SMIT2
      transfected MDCK cells. SMIT2 activity was also shown to be stimulated 5-fold
      when submitted to 24 h hypertonic treatment (+200 mosmol l(-1)). The SMIT2-MDCK
      cell line thus appears to be a promising model for studying SMIT2 biochemistry
      and regulation.

PMID- 15181168
TI  - Probing the pore of the auditory hair cell mechanotransducer channel in turtle.
AB  - Hair cell mechano-electric transducer (MET) channels play a pivotal role in
      auditory and vestibular signal detection, yet few data exist regarding their
      molecular nature. Present work characterizes the MET channel pore, a region whose
      properties are thought to be intrinsically determined. Two approaches were used.
      First, the channel was probed with antagonists of candidate channel subtypes
      including: cyclic nucleotide-gated channels, transient receptor potential
      channels and gap-junctional channels. Eight new antagonists were identified. Most
      of the effective antagonists had a partially charged amine group predicted to
      penetrate the channel pore, antagonizing current flow, while the remainder of the
      molecule prevented further permeation of the compound through the pore. This
      blocking mechanism was tested using curare to demonstrate the open channel nature
      of the block and by identifying methylene blue as a permeant channel blocker. The
      second approach estimated dimensions of the channel pore with simple amine
      compounds. The narrowest diameter of the pore was calculated as 12.5 +/- 0.8 A
      and the location of a binding site approximately 45% of the way through the
      membrane electric field was calculated. Channel length was estimated as
      approximately 31 A and the width of the pore mouth at < 17 A. Each effective
      antagonist had a minimal diameter, measured about the penetrating amine, of less
      than the pore diameter, with a direct correlation between IC(50) and minimal
      diameter. The IC(50) was also directly related to the length of the amine side
      chains, further validating the proposed pore blocking mechanism. Data provided by
      these two approaches support a hypothesis regarding channel permeation and block
      that incorporates molecular dimensions and ion interactions within the pore.

PMID- 15181169
TI  - Light-evoked current responses in rod bipolar cells, cone depolarizing bipolar
      cells and AII amacrine cells in dark-adapted mouse retina.
AB  - Light-evoked excitatory cation current (DeltaI(C)) and inhibitory chloride
      current (DeltaI(Cl)) of rod and cone depolarizing bipolar cells (DBC(R)s and
      DBC(C)s) and AII amacrine cells (AIIACs) in dark-adapted mouse retinal slices
      were studied by whole-cell voltage-clamp recording techniques, and the cell
      morphology was revealed by Lucifer yellow fluorescence with a confocal
      microscope. DeltaI(C) of all DBC(R)s exhibited similar high sensitivity to 500 nm
      light, but two patterns of DeltaI(Cl) were observed in DBC(R)s with slightly
      different axon morphology. At least two types of DBC(C)s were identified: one
      with axon terminals ramified in 70-85% of the depth of the inner plexiform layer
      (IPL) and DBC(R)-like DeltaI(C) sensitivity, whereas the other with axon
      terminals ramified in 55-75% of IPL depth and much lower DeltaI(C) sensitivity.
      The relative rod/cone inputs to DBCs and AIIACs were analysed by comparing the
      DeltaI(C) and DeltaI(Cl) thresholds and dynamic ranges with the corresponding
      values of rods and cones. On average, the sensitivity of a DBC(R) to the 500 nm
      light is about 20 times higher than that of a rod. The sensitivity of an AIIAC is
      more than 1000 times higher than that of a rod, suggesting that AIIAC responses
      are pooled through a coupled network of about 40 AIIACs. Interactions of rod and
      cone signals in dark-adapted mouse retina appear asymmetrical: rod signals spread
      into the cone system more efficiently than cone signals into the rod system. The
      mouse synaptic circuitry allows small rod signals to be highly amplified, and
      effectively transmitted to the cone system via rod-cone and AIIAC-DBC(C)
      coupling.

PMID- 15181170
TI  - Twinkle and POLG defects enhance age-dependent accumulation of mutations in the
      control region of mtDNA.
AB  - Autosomal dominant and/or recessive progressive external ophthalmoplegia
      (ad/arPEO) is associated with mtDNA mutagenesis. It can be caused by mutations in
      three nuclear genes, encoding the adenine nucleotide translocator 1, the
      mitochondrial helicase Twinkle or DNA polymerase gamma (POLG). How mutations in
      these genes result in progressive accumulation of multiple mtDNA deletions in
      post- mitotic tissues is still unclear. A recent hypothesis suggested that mtDNA
      replication infidelity could promote slipped mispairing, thereby stimulating
      deletion formation. This hypothesis predicts that mtDNA of ad/arPEO patients will
      contain frequent mutations throughout; in fact, our analysis of muscle from
      ad/arPEO patients revealed an age-dependent, enhanced accumulation of point
      mutations in addition to deletions, but specifically in the mtDNA control region.
      Both deleted and non-deleted mtDNA molecules showed increased point mutation
      levels, as did mtDNAs of patients with a single mtDNA deletion, suggesting that
      point mutations do not cause multiple deletions. Deletion breakpoint analysis
      showed frequent breakpoints around homopolymeric runs, which could be a signature
      of replication stalling. Therefore, we propose replication stalling as the
      principal cause of deletion formation.

PMID- 15181171
TI  - Inhibition of human breast carcinoma proliferation, migration, chemoinvasion and
      solid tumour growth by DNAzymes targeting the zinc finger transcription factor
      EGR-1.
AB  - DNAzymes (synthetic catalytic DNA) have emerged as a new class of nucleic acid
      based gene silencing agent. Using DNAzymes targeting the human mRNA of the
      immediate-early gene and C2H2-class zinc finger transcription factor early growth
      response-1 (EGR-1), we demonstrate here that EGR-1 plays an indispensable role in
      breast cancer proliferation, migration, chemoinvasion and xenograft growth in
      nude mice. DNAzyme inhibition of these tumorigenic processes and EGR-1 protein
      expression in breast carcinoma cells is sequence-specific and EGR-1 transcription
      independent. These agents inhibit breast carcinoma cell migration and
      chemoinvasion in microchemotaxis chambers and solid tumour growth in athymic nude
      mice. Thus, DNAzymes targeting specific genes can inhibit multiple key
      tumorigenic processes in vitro and in vivo and may serve as useful anti-cancer
      agents.

PMID- 15181172
TI  - The Drosophila Bruno paralogue Bru-3 specifically binds the EDEN translational
      repression element.
AB  - We reported in our previous work that the EDEN-dependent translational repression
      of maternal mRNAs was conserved between Drosophila and Xenopus. In Xenopus, this
      repression is achieved through the binding of EDEN to the Bruno-like factor, EDEN
      BP. We show in the present work that the Drosophila Bruno paralogue, the 45 kDa
      Bru-3 protein (p45), binds specifically to the EDEN element and acts as a
      homodimer. We describe for the first time a previously undetected 67 amino acid
      domain, found in the divergent linker region, the lsm domain (lsm stands for
      linker-specific motif). We propose that the presence of this domain in a subset
      of the Bruno-like proteins, including Bru-3, EDEN-BP and CUG-BP but not Bruno nor
      its other paralogue Bru-2, might be responsible for specific RNA recognition.
      Interestingly, comparative structural analyses using threaders and molecular
      modelling suggest that the new domain might be distantly related to the first RNA
      recognition motif of the Drosophila sex-lethal protein (sxl). The phylogenetic
      analyses and the experimental data based on its specific binding to the EDEN
      element support the conclusion that Bru-3 is an EDEN-BP/CUG-BP orthologue.

PMID- 15181173
TI  - NMR solution structure of a parallel LNA quadruplex.
AB  - The solution structure of a locked nucleic acid (LNA) quadruplex, formed by the
      oligomer d(TGGGT), containing only conformationally restricted LNA residues is
      reported. NMR and CD spectroscopy, as well as molecular dynamics and mechanic
      calculations, has been used to characterize the complex. The molecule adopts a
      parallel stranded conformation with a 4-fold rotational symmetry, showing a right
      handed helicity and the guanine residues in an almost planar conformation with
      three well-defined G-tetrads. The thermal stability of Q-LNA has been found to be
      comparable with that of [r(UGGGU)]4, while a T(m) increment of 20 degrees C with
      respect to the corresponding DNA quadruplex structure [d(TGGGT)]4 has been
      observed. The structural features of the LNA quadruplex reported here may open
      new perspectives for the biological application of LNAs as novel versatile tools
      to design aptamer or catalyst oligonucleotides.

PMID- 15181174
TI  - Sequence-specific Rho-RNA interactions in transcription termination.
AB  - The bacteriophage lambda tR1 terminator encodes a region of the nascent cro
      transcript containing RNA residues recognized by termination factor Rho. To
      identify ribonucleotide-protein interactions contributing to termination, a
      library of reporter gene plasmids was constructed containing predominantly single
      nucleotide substitutions in a 24 nt region previously shown to be critical for
      efficient termination. Screening 16 822 bacterial transformants identified 110
      terminator mutants, most of which contained two or more nucleotide substitutions.
      Although the vast majority of single base changes did not reduce tR1 function, 11
      specific single-nucleotide substitutions at eight positions interspersed in the
      upstream part of the target region (5'-ATAACCCCGCTCTT ACACATTCCA-3') did reduce
      termination. About half of these substitutions also reduced Rho-dependent
      termination on cro gene templates transcribed by purified RNA polymerase,
      indicating specific residues critical for optimal terminator function. Other
      termination defects were not reproduced in these in vitro assays, and likely
      resulted from indirect effects of altering interactions between tR1 and
      additional cellular factors capable of attenuating Rho function. Our results
      indicate that while Rho is able to recognize a wide variety of similar rut site
      sequences by interacting with alternate nucleotides at critical positions,
      interactions with specific individual ribonucleotides of the tR1 transcript
      provide highly efficient Rho-dependent termination.

PMID- 15181175
TI  - LNA/DNA chimeric oligomers mimic RNA aptamers targeted to the TAR RNA element of
      HIV-1.
AB  - One of the major limitations of the use of phosphodiester oligonucleotides in
      cells is their rapid degradation by nucleases. To date, several chemical
      modifications have been employed to overcome this issue but insufficient efficacy
      and/or specificity have limited their in vivo usefulness. In this work
      conformationally restricted nucleotides, locked nucleic acid (LNA), were
      investigated to design nuclease resistant aptamers targeted against the HIV-1 TAR
      RNA. LNA/DNA chimeras were synthesized from a shortened version of the hairpin
      RNA aptamer identified by in vitro selection against TAR. The results indicate
      that these modifications confer good protection towards nuclease digestion.
      Electrophoretic mobility shift assays, thermal denaturation monitored by UV
      spectroscopy and surface plasmon resonance experiments identified LNA/DNA TAR
      ligands that bind to TAR with a dissociation constant in the low nanomolar range
      as the parent RNA aptamer. The crucial G, A residues that close the aptamer loop
      remain a key structural determinant for stable LNA/DNA chimera-TAR complexes.
      This work provides evidence that LNA modifications alternated with DNA can
      generate stable structured RNA mimics for interacting with folded RNA targets.

PMID- 15181176
TI  - Genome-wide identification of genes likely to be involved in human genetic
      disease.
AB  - Sequence analysis of the group of proteins known to be associated with hereditary
      diseases allows the detection of key distinctive features shared within this
      group. The disease proteins are characterized by greater length of their amino
      acid sequence, a broader phylogenetic extent, and specific conservation and
      paralogy profiles compared with all human proteins. This unique property pattern
      provides insights into the global nature of hereditary diseases and moreover can
      be used to predict novel disease genes. We have developed a computational method
      that allows the detection of genes likely to be involved in hereditary disease in
      the human genome. The probability score assignments for the human genome are
      accessible at http://maine.ebi. ac.uk:8000/services/dgp.

PMID- 15181177
TI  - Demonstration of a universal surface DNA computer.
AB  - A fundamental concept in computer science is that of the universal Turing
      machine, which is an abstract definition of a general purpose computer. A general
      purpose (universal) computer is defined as one which can compute anything that is
      computable. It has been shown that any computer which is able to simulate Boolean
      logic circuits of any complexity is such a general purpose computer. The field of
      DNA computing was founded in 1994 by Adleman's solution of a 7-bit instance of
      the Hamiltonian path problem. This work, as well as most of the subsequent
      experimental and theoretical investigations in the area, focused primarily upon
      the solution of NP-complete problems, which are a subset of the larger universal
      class of problems. In the present work a surface DNA computer capable of
      simulating Boolean logic circuits is demonstrated. This was done by constructing
      NOR and OR gates and combining them into a simple logic circuit. The NOR gate is
      one of the universal gates in Boolean logic, meaning that any other logic gate
      can be built from it alone. The circuit was solved using DNA-based operations,
      demonstrating the universal nature of this surface DNA computing model.

PMID- 15181178
TI  - Endogenous retroviral syncytin: compilation of experimental research on syncytin
      and its possible role in normal and disturbed human placentogenesis.
AB  - Placental syncytin was first described in the year 2000 as a fusogenic
      glycoprotein originally derived from a human endogenous retroviral envelope gene.
      Although the presence of stable integrated retroviral elements within the human
      genome has been known for many years, their biological significance is still
      obscure and has usually been designated as irrelevant or even harmful. Syncytin,
      however, demonstrates tissue-specific expression and distinctive receptor
      interaction during trophoblast cell differentiation and syncytium formation.
      These findings indicate an involvement of syncytin in the development of the
      human placenta. Disturbances in placental architecture leading to severe
      placental dysfunction, such as pre-eclampsia, may therefore be discussed as a
      consequence of an altered syncytin system. We evaluate the hypothesis that
      syncytin is essential for human placenta formation and may also have played an
      important role in human placental evolution.

PMID- 15181179
TI  - Mutations in the coding region of the FOXL2 gene are not a major cause of
      idiopathic premature ovarian failure.
AB  - Premature ovarian failure (POF) is a heterogeneous disorder whose aetiology is
      still unknown. Recently, the autosomal FOXL2 gene, highly expressed in the adult
      ovary, has been correlated with the disorder. FOXL2 mutations, causing a
      truncation of the FOXL2 protein in the forkhead domain or in the poly-Ala tract
      lead to blepharophimosis-ptosis-epicanthus-inversus syndrome associated with POF
      (BPES I). Interestingly, in two out of 70 idiopathic POF patients, a 30 bp
      deletion (898-927del) and a missense mutation (1009T-->A) were identified. To
      further evaluate the correlation between POF and FOXL2 mutations, 120
      phenotypically normal women affected by POF were analysed by direct sequencing of
      the FOXL2 coding region. The analysis did not reveal any mutation in the 240
      analysed chromosomes, indicating that mutations in the FOXL2 coding region are
      rarely associated with non-syndromic POF.

PMID- 15181180
TI  - Atypical auditory event-related potentials in preterm infants during the first
      year of life: a possible sign of cognitive dysfunction?
AB  - We assessed auditory event-related potentials in small-for-gestational-age (SGA;
      850 +/- 258 g, 28.9 +/- 3.3 gestational wk; n = 15) and appropriate for
      gestational age (AGA; 1014 +/- 231 g, 26.9 +/- 1.9 gestational wk; n = 20)
      preterm infants and healthy term infants (n = 22). An oddball paradigm was used
      with a harmonic tone of 500-Hz frequency as the standard and of 750-Hz frequency
      as the deviant stimulus. The preterm infants were studied at 40 gestational wk
      and at 6 and 12 mo of corrected age, and the control subjects were studied at 2-4
      d and at 3, 6, 9, 12, and 15 mo of age. The peaks of interest were the main
      positive peak (P350), the negative peaks at 250 ms (N250) and 650 ms (Nc), and
      the mismatch negativity at 200 ms (MMN). At term, the P350 in the preterm infants
      was similar to that of the newborn control subjects. In response to the deviant,
      the Nc was smaller in the SGA than in the AGA (P < 0.02) and control (P < 0.005)
      infants. The N250 amplitude was also lower in the SGA infants. At 12 mo, the MMN
      was observed in the control but not in the preterm infants, whose broad
      difference positivity correlated with the Bayley developmental index. The
      decreased Nc and N250 peaks in the SGA infants may suggest an increased risk for
      cognitive dysfunction. The broad difference positivity at 1 y of age may indicate
      atypical cortical auditory processing. Whether cognitive dysfunction can be
      predicted by these findings needs to be assessed in a study with extended follow
      up.

PMID- 15181181
TI  - Dose response to aerosolized perflubron in a neonatal swine model of lung injury.
AB  - Aerosolized perfluorocarbon (PFC) improves gas exchange, lung mechanics, and
      pulmonary artery pressure. The objective of this intervention was to study the
      dose-response effect to aerosolized perfluorooctylbromide (PFOB; perflubron,
      LiquiVent, Alliance Pharmaceutical Corp.) in surfactant-depleted piglets. After
      induction of lung injury by saline lavage, 25 newborn piglets were randomly
      assigned to receive 0, 1.25, 2.5, 5.0, or 7.5 mL/kg aerosolized PFOB per hour. A
      2-h therapy period was followed by a 3-h observation period. In all animals,
      respiratory support was performed with intermittent mandatory ventilation. After
      aerosol treatment and 3 h of observation, arterial oxygen pressure was similarly
      improved in the 2.5-, 5.0-, and 7.5-mL. kg(-1). h(-1) aerosol-PFOB groups and
      higher compared with the 1.25-mL. kg(-1). h(-1) aerosol-PFOB (P < 0.01) and the
      control groups (P < 0.001). Compared with the control group, arterial carbon
      dioxide pressure was significantly reduced with 2.5-, 5.0-, and 7.5-mL. kg(-1).
      h(-1) aerosol-PFOB (P < 0.001). Treatment with 1.25 mL. kg(-1). h(-1) aerosol
      PFOB did not significantly affect arterial carbon dioxide pressure. The 20%
      terminal dynamic compliance/dynamic compliance was significantly improved in the
      groups that received 2.5, 5.0, and 7.5 mL. kg(-1). h(-1) aerosol-PFOB compared
      with control animals. Mean pulmonary artery pressure was lower after therapy with
      5.0 and 7.5 mL. kg(-1). h(-1) aerosol-PFOB (P < 0.01) than in the control group.
      IL-1beta gene expression in lung tissue was significantly reduced with PFOB 1.25
      mL. kg(-1). h(-1). In summary, aerosolized PFOB improved terminal dynamic
      compliance, pulmonary gas exchange, and pulmonary artery pressure in a dose
      dependent manner. In terms of oxygenation and lung mechanics, the optimum dose
      was between 2.5 and 5 mL. kg(-1). h(-1).

PMID- 15181182
TI  - A neuroblastoma-selective suicide gene therapy approach using the tyrosine
      hydroxylase promoter.
AB  - In this study, selective expression of therapeutic transgenes was evaluated in
      neuroblastoma cells. Promoter fragments of the genes for neuron-specific enolase
      (NSEp), tyrosine hydroxylase (THp), and dopamine-beta-hydroxylase (DBHp) were
      studied in neuroblastoma and nonneuronal cell lines by transient transfection
      experiments using fluorescence-activated cell sorting (FACS) analysis of enhanced
      green fluorescent protein (egfp) and luciferase (luc+) assay. Both reporter gene
      assays revealed a neuroblastoma-selective expression mediated by NSEp and THp,
      whereas DBHp was active only in a murine neuroblastoma cell line. Reporter gene
      expression by NSEp in neuroblastoma cells was markedly higher than expression by
      THp, but NSEp also showed considerable background activity in nonneuronal cells.
      THp-driven expression of egfp was 35-fold higher in human neuroblastoma MHH-NB11
      compared with nonneuronal HeLa cells. Thus, THp was chosen for a neuroblastoma
      selective suicide gene therapy approach using the herpes simplex virus type 1
      thymidine kinase (HSV-tk)/ganciclovir (GCV) system. A retrovirus vector that
      contained an expression cassette of a HSV-tk/egfp fusion gene and THp in
      antisense orientation was generated. Stably transduced human neuroblastoma cells
      and nonneuronal cell lines were generated, and HSV-tk/egfp expression was
      measured by FACS and GCV cytotoxicity assay. There was a 2.2-fold difference in
      green fluorescence and a 1.4-fold difference in cell killing between the human
      neuroblastoma MHH-NB11 and HeLa cells after HSV-tk/egfp gene transfer. The
      overall difference in THp-HSV-tk/egfp-mediated cell killing between neuroblastoma
      and nonneuronal tumor cell lines was statistically significant (P = 0.001). In
      conclusion, the present study demonstrated the feasibility of a neuroblastoma
      selective gene therapy approach using the THp/HSV-tk/egfp expression cassette.

PMID- 15181183
TI  - A dual stable isotope tracer method for the measurement of surfactant disaturated
      phosphatidylcholine net synthesis in infants with congenital diaphragmatic
      hernia.
AB  - The aim of the study was to measure for the first time in humans surfactant
      disaturated-phosphatidylcholine (DSPC) net synthesis and kinetics by using a
      novel, dual stable isotope tracer approach. Ten infants with congenital
      diaphragmatic hernia [CDH; birth weight, 3.4 +/- 0.2; gestational age, 39.8 +/-
      0.4 wk] and 6 age-matched control subjects with no lung disease (birth weight,
      3.2 +/- 0.3 kg; gestational age, 39.1 +/- 1.1 wk), all of whom were admitted to
      the neonatal intensive care unit (Padua, Italy), were studied. All infants
      received simultaneously an intratracheal (carbon-13 di-palmitoyl
      phosphatidylcholine) and an i.v. (deuterated palmitic acid) stable isotope
      tracer. Isotopic enrichment curves of DSPC from sequential tracheal aspirates
      were analyzed by mass spectrometry. DSPC kinetic data were expressed as mean +/-
      SEM and compared by the Mann-Whitney test. DSPC net synthesis from plasma
      palmitate was nearly identical in infants with CDH and control subjects (8.6 +/-
      2.2 and 8.1 +/- 1.5 mg. kg(-1). d(-1); P = 0.7). DSPC apparent pool size was 36.7
      +/- 7.5 and 58.5 +/- 9.1 mg/kg (P = 0.07) and half-life was 26.7 +/- 4.5 and 50.3
      +/- 9.7 h (P = 0.03) in infants with CDH and control subjects, respectively. Both
      DSPC turnover and percentage of catabolism/recycling significantly correlated
      with duration of mechanical ventilation. In conclusion, the measurements of net
      DSPC synthesis and catabolism/recycling were reported for the first time in
      humans. Mean net DSPC synthesis was approximately 8 mg. kg(-1). d(-1). No
      significant differences were found between control subjects and infants with CDH.
      DSPC turnover was faster in infants with CDH, presumably reflecting an increased
      DSPC catabolism/recycling. Whether this may ultimately lead to a secondary
      surfactant deficiency in infants with CDH is still to be ascertained.

PMID- 15181184
TI  - Differential maturation of the innate immune response in human fetuses.
AB  - Newborns and especially preterm infants show a unique susceptibility to severe
      bacterial infections that cause significant morbidity and mortality. As very few
      data are available on innate immune functions in human fetuses, we conducted a
      comprehensive study to investigate the expression of several adhesion molecules
      essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L).
      Furthermore, phagocytic activity, generation of respiratory burst products, and
      production of several proinflammatory cytokines were assessed. Various functions
      of the fetal innate immune system were demonstrated to be essentially different
      from those observed in term neonates or adults. Expression of several surface
      markers was significantly diminished on fetal granulocytes. Furthermore, a
      significantly reduced phagocytic activity of fetal granulocytes and monocytes was
      found, contrasted by an enhanced generation of reactive oxygen products. In
      addition, we demonstrate that significant numbers of fetal monocytes are capable
      of the production of proinflammatory cytokines in response to stimulation.
      However, the pattern of cytokine production is different from the more mature
      individuals: the number of IL-6- and tumor necrosis factor-alpha-positive
      monocytes were significantly diminished, whereas more IL-8-producing monocytes
      were found compared with adults. The results of our study add significantly to
      our understanding of the maturation and impairment of the innate immune response.

PMID- 15181185
TI  - Production of granulomatous inflammation in lungs of rat pups and adults by
      Sephadex beads.
AB  - Granulomatous inflammation is a process that involves mononuclear leukocytes as
      well as other inflammatory cells. The heterogeneity of its appearance may be due
      to the variety of cytokines and chemokines that are involved. In this study, we
      compared granuloma formation and bronchoalveolar leukocyte differential in the
      lungs of rats (2- and 8-wk-old) that were treated intravenously with Sephadex
      beads. In addition, the kinetics of cytokine and chemokine production was
      determined in these groups. In adults, the beads caused lung granulomas
      associated with infiltration of eosinophils and neutrophils and increased
      eosinophil and neutrophil counts in the bronchoalveolar lavage fluid within 16 h.
      In pups, the granulomas were formed slowly and did not reach the size achieved in
      adults. Eosinophils and neutrophils were sparsely found in the periphery of the
      granulomas, even at 32 h. Pups were also unable to respond rapidly to Sephadex
      bead treatment with eosinophil and neutrophil infiltration in the bronchoalveolar
      lavage fluid. Tumor necrosis factor-alpha was significantly increased in both
      groups, but the cytokine was lower in pups than in adults. Interferon-gamma and
      eotaxin were increased only in adults, and IL-4 and regulated on activation,
      normal T cell expressed, and secreted was increased only in pups. In conclusion,
      the i.v. administration of Sephadex beads produced granulomatous inflammation in
      the lungs of adult rats, but pups were unable to respond as rapidly to the
      treatment. In addition, the difference in response between the two age groups was
      associated with the kinetics of cytokine and chemokine production.

PMID- 15181186
TI  - A history of pediatric specialties: the development of pediatric cardiology.
AB  - Pediatric cardiology, as a discipline, arose from early descriptive studies of
      congenital cardiac defects. The development of the stethoscope allowed some
      clinical diagnoses to be made during life. Cardiology as a medical specialty was
      limited, mainly, to internists. When Robert Gross ligated a patent ductus in
      1938, pediatric cardiology, as a discipline, was born. Physiologic studies,
      angiography, and the development of extracorporeal circulation allowed congenital
      cardiac lesions previously considered a curiosity to be diagnosed and treated
      successfully. The few pediatricians who were interested in cardiology taught
      themselves, and soon pediatric cardiology training programs developed. By 1961,
      pediatric cardiology became the first subspecialty board in pediatrics. The past
      60 y has brought enormous progress. Cardiac ultrasound, color-flow Doppler, and
      magnetic resonance imaging have made diagnostic cardiac catheterization almost
      unnecessary. Instead, interventional cardiac catheterization rapidly developed
      and is already able to replace surgery in the treatment of a number of cardiac
      defects. The first 50 y of cardiology has been focused on patient care,
      education, and clinical research, but the last 10 y has added exciting, basic
      research discoveries, which are elucidating the cause of cardiac defects with
      hope for prevention in the future. As a discipline, pediatric cardiology has
      always required a team-pathologists, physiologists, cardiologists, surgeons,
      intensivists, interventionists, and anesthesiologists-all playing an important
      role in the treatment of children with cardiac problems. Today the geneticists,
      molecular biologists, and other basic scientists are joining the team to ensure
      an exciting future for pediatric cardiology and the children yet to be born.

PMID- 15181187
TI  - Linearity versus cross-talk: biological models and the role of the Society for
      Pediatric Research in the 21st century.

PMID- 15181188
TI  - Introduction of David G. Nathan and the 2003 John Howland Award.

PMID- 15181189
TI  - Pancreatic lipase and its related protein 2 are regulated by dietary
      polyunsaturated fat during the postnatal development of rats.
AB  - The developmental gene expression of pancreatic lipase (PL) and its related
      proteins (PLRP1 and PLRP2) is anticoordinate. It is unknown whether dietary fat
      regulates the expression of these proteins in the preweanling stage. For
      determining the regulation of development and diet on PL, PLRP1, and PLRP2 as
      early as the suckling period, pregnant (Sprague-Dawley) rats consumed from day 15
      (d15) of pregnancy through d9 of lactation a purified low (11% of energy)
      safflower oil diet [low-fat (LF)]. From d9 of lactation, dams and their
      respective pups were fed LF, medium-fat (MF; 40% of energy), or high-fat (HF; 67%
      of energy) safflower oil diets to d56. Milk fatty acid content had 15- to 100
      fold less C:10 and 2.6- to 3.3-fold more C18:2 in MF and HF groups. Diet (LF < MF
      = HF; P < 0.002), postnatal development (d15 < d21 < d28 = d56; P < 0.001), and
      interaction of diet x development significantly affected PL activity starting as
      early as d15. PL mRNA levels showed a parallel effect of diet (LF < HF = MF; P <
      0.013) and development (P < 0.001). Both PLRP1 and PLRP2 mRNA levels were
      significantly affected by development (P < 0.001) and had an anticoordinate
      pattern compared with PL expression (d15 > d21 > d28). Reported for the first
      time is the significant down-regulation of PLRP2 mRNA levels by high
      polyunsaturated fat in suckling (d15) rats. In conclusion, PL and PLRP2 gene
      expression is regulated anticoordinately by the amount of dietary polyunsaturated
      fat starting as early as the preweanling phase of development.

PMID- 15181190
TI  - Interleukin-8/CXCL8 forms an autocrine loop in fetal intestinal mucosa.
AB  - IL-8/CXC ligand (CXCL) 8 is ingested in high concentrations by the human
      fetus/neonate with amniotic fluid and human milk, and is also produced
      constitutively by intestinal epithelial cells (IEC). We have shown that
      recombinant human IL-8/CXCL8 (rhIL-8/CXCL8) protects cultured IEC against tumor
      necrosis factor (TNF)-alpha and cycloheximide-induced cytotoxicity. In view of
      its constitutive production, we hypothesized that IL-8/CXCL8 might play an
      autocrine role in fetal enterocyte maintenance. In this study, we measured IL
      8/CXCL8 mRNA concentrations in fetal intestine (11-22 wk gestation), sought the
      presence of the protein by immunohistochemistry in fetal stomach and intestine (9
      24 wk), measured IL-8/CXCL8 in neonatal gastric secretions, and studied
      constitutive and stimulated IL-8/CXCL8 expression in cultured IEC. We found that
      IL-8/CXCL8 is consistently transcribed and expressed in fetal intestinal tissue,
      in a developmentally regulated inverse relationship with gestational maturation.
      The cognate receptors for IL-8/CXCL8 are also expressed abundantly in the fetal
      intestine, and, therefore, we sought to determine whether the expressed IL
      8/CXCL8 would complete an autocrine loop. Neutralization of IL-8/CXCL8 resulted
      in increased cell death in cultured IEC in the presence of TNF-alpha. This effect
      is specifically mediated through the CXCR2 receptors. We speculate that IL
      8/CXCL8 secretion during cytotoxic stress reflects a cellular self-defense
      mechanism.

PMID- 15181191
TI  - Intrauterine hyperglycemia increases insulin binding sites but not glucose
      transporter expression in discrete brain areas in term rat fetuses.
AB  - Diabetic pregnancy results in several metabolic and hormonal disorders, both in
      the embryo and the fetus of different species, including humans. Insulin is a
      potent modulator of brain development and is suggested to promote the
      differentiation and maturation of hypothalamic or related extrahypothalamic
      structures, which are directly involved in neural inputs to the pancreas. Because
      these structures are known to be specifically responsive both to insulin and
      glucose, we examined the effects of 48-h hyperglycemic clamps in unrestrained
      pregnant rats on insulin binding and glucose transporter expression in
      hypothalamic and extrahypothalamic-related areas of their fetal offspring. The
      main result was an increase in insulin binding in the ventromedial hypothalamic
      nucleus (VMH), the arcuate nucleus (AN), and the lateral hypothalamus (LH), and
      in the nucleus of the tractus solitarius (NTS) for extrahypothalamic areas (+30%
      in the VMH, +37% in the AN, +25.8% in the LH, and +37.3% in the NTS). The
      deleterious effect of brain hyperinsulinism during the late gestational stage
      does not seem to act through glucose transporter (GLUT) expression, inasmuch as
      no relationship between GLUT level and hyperinsulinism in brain areas could be
      observed. The specific increase in insulin binding in areas involved in the
      nervous control of metabolism could be a factor in the increased glucose
      intolerance and impairment of insulin secretion that was previously observed in
      the adult rats from hyperglycemic mothers.

PMID- 15181192
TI  - Immune responses to strenuous exercise and carbohydrate intake in boys and men.
AB  - Few studies describe immune responses to exercise in children, compared with
      adults, and none have investigated the influence of carbohydrate (CHO) intake. We
      hypothesized less perturbation and a faster recovery of the immune system with
      exercise in children, regardless of supplemental energy. Twelve boys (9.8 +/- 0.1
      y) and 10 men (22.1 +/- 0.5 y) cycled for 60 min at 70% o(2max) while drinking 6%
      CHO (CHO-T) or flavored water (FW-T). Blood samples were collected before (PRE),
      immediately after (POST), and 60 min after (REC) exercise. Boys, compared with
      men, had smaller (p < 0.05) increases in total leukocytes (28% versus 38%),
      natural killer (NK) cells (78% versus 236%), and NK T cells (42% versus 128%) at
      POST, averaged across beverage trials. Exercise did not increase tumor necrosis
      factor-alpha (TNF-alpha), but significantly (p < 0.05) increased IL-6 in men
      (189%), but not in boys (11%). In both trials, lymphocytes and T cells at REC
      were suppressed (p < 0.05), relative to PRE, in men (-21%), but not in boys (4%).
      IL-6 remained elevated ( p< 0.001) in men at REC, with no change from POST in
      boys. In boys, but not in men, CHO significantly (p < 0.05) attenuated increases
      in neutrophil, lymphocyte, and NK cell counts at POST. Neutrophils at REC in CHO
      T were lower (p < 0.05) than in FW-T in men ( approximately 25%) and in boys (
      approximately 17%). CHO had no effect on TNF-alpha or IL-6 in either group. Our
      results indicate a distinct pattern of the immune response to exercise and CHO
      intake in boys, compared with men.

PMID- 15181193
TI  - Zinc metabolism in adolescents with Crohn's disease.
AB  - Low serum zinc concentrations have been reported in Crohn's disease (CD) and
      overt zinc deficiency has been described, but little is known about the effect of
      CD on zinc metabolism in adolescents. The aim of this study was to measure zinc
      absorption, endogenous fecal zinc excretion, urinary zinc excretion, and zinc
      balance in children with stable CD and in matched controls. Subjects were 15
      children, ages 8-18 y, with stable CD, and 15 healthy matched controls. Subjects
      were adapted to diets providing 12 mg/d elemental zinc for 2 wk, and then
      admitted for a 6-d metabolic study. Stable zinc isotopes were given intravenously
      and orally, and urine and feces collected for 6 d. Fractional zinc absorption,
      endogenous fecal zinc excretion, and zinc balance were calculated using
      established stable isotope methods. In subjects with CD, zinc absorption (10.9%
      +/- 6.1 versus 23.4 +/- 15.8, p = 0.008) and plasma zinc concentration (0.85
      mg/dL +/- 0.15 versus 1.25 +/- 0.35, p = 0.004) were significantly reduced,
      compared with controls. Despite this, there were no significant differences in
      endogenous fecal zinc excretion (2.0 mg +/- 1.5 versus 1.5 +/- 1.5, p = 0.34) or
      urinary zinc excretion (0.9 mg +/- 0.7 versus 1.0 +/- 0.7, p = 0.47). Zinc
      balance was significantly lower in CD (-1.5 mg +/- 1.5) than in controls (+0.6 mg
      +/- 3.1, p < 0.0001). In conclusion, adolescents with CD have significantly
      reduced zinc absorption. Despite this, they were unable to reduce endogenous
      fecal zinc excretion to restore normal zinc balance and had a significantly worse
      zinc balance and lower plasma zinc concentration than controls.

PMID- 15181195
TI  - Long-term enzymatic and phenotypic correction in the phenylketonuria mouse model
      by adeno-associated virus vector-mediated gene transfer.
AB  - Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a
      deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine
      leads to severe mental and psychomotor retardation, and hypopigmentation of skin
      and hair. Low-phenylalanine diet therapy can prevent irreversible damage if
      instituted from birth. However, poor compliance with the strict lifelong dietary
      therapy leads to various neurologic and behavioral problems. To develop a safe
      and promising gene therapy method for PKU, we investigated whether a recombinant
      adeno-associated virus could be used as a PAH gene transfer vector to reduce the
      excessive phenylalanine level in the PKU mouse model. A recombinant adeno
      associated virus vector encoding the human PAH gene (rAAV-hPAH), driven by EF1
      alpha promoter, was infused into PAH-deficient mice, Pah(enu2), via the hepatic
      portal vein. Two weeks after injection, the plasma phenylalanine level
      dramatically decreased to 360 microM in male PKU mice, accompanied by the coat
      color changing to black. The mean plasma phenylalanine level of untreated PKU
      mice was 1800 microM. The PAH enzyme activities of treated mice increased to 10
      17% of wild-type mice. No signs of liver toxicity were observed after gene
      transfer. The biochemical and phenotypic corrections were sustained for up to 25
      wk (25-wk detection period). In contrast, the treatment was less effective in
      female PKU mice. These results indicate that recombinant adeno-associated virus
      vector-mediated gene therapy can be a useful therapeutic candidate for patients
      with PKU. Further studies are needed to clarify the differences in PKU
      pathogenesis in males and females, and to explore alternative administration
      routes besides hepatic portal vein injection.

PMID- 15181196
TI  - Acceptance of the 2003 John Howland Award: a journey in clinical research.

PMID- 15181194
TI  - Nuclear factor kappa B activation in human cord blood mononuclear cells.
AB  - The immunologic signals participating in immune responses early in life have not
      been completely elucidated. Regarding the characterization of neonatal cells,
      little is known concerning the activity of transcription factor nuclear factor
      kappa B (NF-kappaB), which regulates inflammatory genes and cytokine production.
      The aim of this study was to characterize NF-kappaB activation in cord blood
      mononuclear cells (CBMC). We analyzed the potential association of NF-kappaB
      activity with lymphocyte proliferation and influences on cytokine secretion in
      the early immune system. To determine the contribution of a disease whereby
      inheritance may impact neonatal immunity, we assessed the influence of maternal
      allergic disease on NF-kappaB regulation and cytokine secretion. CBMC from
      healthy newborns were isolated and stimulated with mitogen (n = 28). Nuclear
      extracts were analyzed by electrophoretic mobility shift assay, cytokine
      secretion by ELISA. FISH analysis excluded relevant maternal contamination of
      CBMC. All samples showed a positive lymphoproliferative response, and NF-kappaB
      activity was both increased and decreased after mitogen stimulation. Increased NF
      kappaB activation was significantly associated with decreased TNF-alpha secretion
      (median 6.1 versus 50.3 pg/mL) in unstimulated CBMC. Mitogen stimulation resulted
      in increased NF-kappaB activity with a trend to increased IL-13 production.
      Maternal allergic disease was associated with higher TNF-alpha (median 982 versus
      173 pg/mL) and IL-13 secretion (median 1328 versus 1120 pg/mL) after mitogen
      stimulation. Together, NF-kappaB activity is differentially activated in cord
      blood and associated with a distinct cytokine pattern. Whether differential NF
      kappaB activity in cord blood is related to the subsequent development of immune
      diseases requires further investigation.

PMID- 15181197
TI  - Artificial rearing of mouse pups: development of a mouse pup in a cup model.
AB  - Artificial rearing of rat pups has been used in the investigation of the neonatal
      gut. We propose to adapt the model of artificially rearing rat pups for use in
      mouse pups, thereby allowing the use of transgenic animals for our research. We
      hypothesized that gastrostomy catheters may be placed successfully into neonatal
      mouse pups and that the pups may be artificially reared without significant
      alterations in their growth or intestinal development. Gastrostomy tubes are
      placed into 5-d-old mouse pups [artificially reared (AR); n = 32], and the mice
      are fed rodent milk substitute. Littermate pups [maternally reared (MR); n = 22]
      are used as controls. After 5 d, pups are killed and their organs are harvested.
      Intestinal villus measurements, protein content, and DNA content are determined.
      Data are reported as mean +/- SEM, compared with appropriate statistical methods,
      and significance is determined at P < 0.05. Initial weights and lengths are not
      different between the two groups, but after 5 d, MR pups weigh more than their AR
      counterparts (5.0 +/- 0.13 versus 4.1 +/- 0.14 g, MR versus AR; P < 0.01).
      However, the pups' length and the intestinal villus height-to-width ratios,
      protein, and DNA content are not different between the MR and AR pups. To our
      knowledge, this is the first report of artificially rearing mouse pups.
      Development of this technique will permit nutritional manipulation in neonatal
      mice, a mammalian model wherein the genome is sequenced and transgenic mutants
      are available.

PMID- 15181198
TI  - Positive end expiratory pressure during resuscitation of premature lambs rapidly
      improves blood gases without adversely affecting arterial pressure.
AB  - Positive end expiratory pressure (PEEP) is important for neonatal ventilation but
      is not considered in guidelines for resuscitation. Our aim was to investigate the
      effects of PEEP on cardiorespiratory parameters during resuscitation of very
      premature lambs delivered by hysterotomy at approximately 125 d gestation (term
      approximately 147 d). Before delivery, they were intubated and lung fluid was
      drained. Immediately after delivery, they were ventilated with a Drager Babylog
      plus ventilator in volume guarantee mode with a tidal volume of 5 mL/kg. Lambs
      were randomized to receive 0, 4, 8, or 12 cm H(2)O of PEEP. They were ventilated
      for a 15-min resuscitation period followed by 2 h of stabilization at the same
      PEEP. Tidal volume, peak inspiratory pressure, PEEP, arterial pressure, oxygen
      saturation, and blood gases were measured regularly, and respiratory system
      compliance and alveolar/arterial oxygen differences were calculated. Lambs that
      received 12 cm H(2)O of PEEP died from pneumothoraces; all others survived
      without pneumothoraces. Oxygenation was significantly improved by 8 and 12 cm
      H(2)O of PEEP compared with 0 and 4 cm H(2)O of PEEP. Lambs with 0 PEEP did not
      oxygenate adequately. The compliance of the respiratory system was significantly
      higher at 4 and 8 cm H(2)O of PEEP than at 0 PEEP. There were no significant
      differences in partial pressure of carbon dioxide in arterial blood between
      groups. Arterial pressure was highest with 8 cm H(2)O of PEEP, and there was no
      cardiorespiratory compromise at any level of PEEP. Applying PEEP during
      resuscitation of very premature infants might be advantageous and merits further
      investigation.

PMID- 15181199
TI  - Cerebral structure and metabolism and long-term outcome in small-for-gestational
      age preterm neonates.
AB  - In the present study, we compared brain development and metabolism of small-for
      gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants using
      proton magnetic resonance spectroscopy ((1)H-MRS). We tested the hypothesis that
      intrauterine growth retardation caused by placental insufficiency is associated
      with changes in cerebral metabolism and is followed by an adverse
      neurodevelopmental outcome at the age of 2 y. Twenty-six AGA and 14 SGA (birth
      weight <P 2.3) preterm infants with no major ultrasound abnormalities were
      enrolled prospectively. At 32 and 41 wk postmenstrual age, (1)H-MRS and magnetic
      resonance imaging were performed. For (1)H-MRS, a volume of interest was placed
      in the basal ganglia and in the periventricular white matter. Using echo times of
      31 and 144 ms N-acetylaspartate/choline (NAA/Cho), lactate/Cho, myo-inositol/Cho
      (mI/Cho), and glutamate-glutamine-gamma-aminobutyric acid/Cho (Glx/Cho) ratios
      were compared between AGA and SGA groups. Griffiths' developmental quotient (DQ)
      values were assessed at 24 mo corrected age. Griffiths' DQ (AGA, 104 +/- 10; SGA,
      99 +/- 9) and brain development assessed using magnetic resonance imaging showed
      no significant differences between both AGA and SGA groups, and NAA/Cho, Lac/Cho,
      mI/Cho, and Glx/Cho ratios were not significantly different between the groups.
      NAA/Cho ratios increased from 32 to 41 wk, whereas mI/Cho ratios decreased in
      both groups. No differences in cerebral metabolism, brain development, and DQ
      values between AGA and severely SGA infants could be demonstrated.

PMID- 15181200
TI  - The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic
      acid-driven mitochondrial localization.
AB  - Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The
      function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative
      stress, leading to the suggestion that DJ-1 is protective under these conditions.
      We addressed whether this represents a posttranslational modification at cysteine
      residues by systematically mutating cysteine residues in human DJ-1. WT or C53A
      DJ-1 was readily oxidized in cultured cells, generating a pI 5.8 isoform, but an
      artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in
      crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was
      promoted by the crystallization procedure. In addition, oxidation-induced
      mitochondrial relocalization of DJ-1 and protection against cell death were
      abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against
      neuronal death, and that this is signaled by acidification of the key cysteine
      residue, C106.

PMID- 15181201
TI  - AtCAND1, a HEAT-repeat protein that participates in auxin signaling in
      Arabidopsis.
AB  - Auxin affects many aspects of plant growth and development. We previously used
      chemical genetics to dissect auxin-signaling mechanisms and identified a small
      molecule, sirtinol, that constitutively activated auxin signaling (Y. Zhao et al.
      [2003], Science 301: 1107-1110). Here we describe the isolation,
      characterization, and cloning of an Arabidopsis mutant Atcand1-1 that emerged
      from a genetic screen for mutants insensitive to sirtinol. Loss-of-function
      mutants of AtCAND1 were resistant to sirtinol and auxin, but not to gibberellins
      or brassinolide. Atcand1 displayed developmental phenotypes similar to those of
      axr1, namely, short petioles, downwardly curling leaves, short inflorescence, and
      reduced fertility. AtCAND1 is homologous to human CAND1, a protein that is
      composed almost entirely of HEAT-repeat units and has been implicated in
      regulating the assembly and disassembly of the SCF protein degradation machinery.
      Taken together with previous biochemical studies, this work helps to elucidate
      the roles of AtCAND1 in protein degradation and auxin signaling.

PMID- 15181202
TI  - 16,17-dihydro gibberellin A5 competitively inhibits a recombinant Arabidopsis GA
      3beta-hydroxylase encoded by the GA4 gene.
AB  - Ring D-modified gibberellin (GA) A5 and A20 derivatives are structurally similar
      to GA20 and GA9 (the precursors to growth-active GA1 and GA4) and, when applied
      to higher plants, especially grasses, can reduce shoot growth with concomitant
      reductions in levels of growth-active GAs and increases in levels of their
      immediate 3-deoxy precursors. The recombinant Arabidopsis GA 3beta-hydroxylase
      (AtGA3ox1) protein was used in vitro to test a number of ring D-modified GA
      structures as possible inhibitors of AtGA3ox1. This fusion protein was able to
      3beta-hydroxylate the 3-deoxy GAs, GA9 and GA20, to GA4 and GA1, respectively,
      and convert the 2,3-didehydro GA, GA5, to its 2,3-epoxide, GA6. Michaelis-Menten
      constant (Km) values of 1.25 and 10 microM, respectively, were obtained for the
      GA9 and GA20 conversions. We utilized the enzyme's ability to convert GA20 to GA1
      in order to test the efficacy of GA5, 16,17-dihydro GA5 (dihydro GA5), and a
      number of other ring D-modified GAs as inhibitors of AtGA3ox activity. For the
      exo-isomer of dihydro GA5, inhibition increased with the dose of dihydro GA5,
      with Lineweaver-Burk plots showing that dihydro GA5 changed only the Km of the
      enzyme reaction, not the V(max), giving a dissociation constant of the enzyme
      inhibitor complex (Ki) of 70 microM. Other ring D-modified GA derivatives showed
      similar inhibitory effects on GA1 production, with 16,17-dihydro GA20-13-acetate
      being the most effective inhibitor. This behavior is consistent with dihydro GA5,
      at least, functioning as a competitive substrate inhibitor of AtGA3ox1. Finally,
      the recombinant AtGA3ox1 fusion protein may be a useful screening tool for other
      effective 3beta-hydroxylase inhibitors, including naturally occurring ones.

PMID- 15181203
TI  - Purification and characterization of enzymes exhibiting beta-D-xylosidase
      activities in stem tissues of Arabidopsis.
AB  - This work describes the purification and characterization of enzymes that exhibit
      beta-d-xylosidase activity in stem tissues of Arabidopsis. This is the first
      detailed investigation that concerns the characterization of catalytic properties
      and sequence identity of enzymes with beta-D-xylosidase activities in a
      dicotyledonous plant. Three different enzymes, ARAf, XYL4, and XYL1 with apparent
      molecular masses of 75, 67, and 64 kD, respectively, were purified to
      homogeneity. ARAf was identified as a putative alpha-L-arabinofuranosidase, and
      XYL4 and XYL1 as putative beta-D-xylosidases using matrix-assisted laser
      desorption ionization time of flight. ARAf belongs to family 51 and XYL4 and XYL1
      to family 3 of glycoside hydrolases. ARAf and XYL1 have highest specificity for p
      nitrophenyl-alpha-L-arabinofuranoside and XYL4 for p-nitrophenyl-beta-D
      xylopyranoside and natural substrates such as xylobiose and xylotetraose. XYL4
      was shown to release mainly D-Xyl from oat spelt xylan, rye arabinoxylan, wheat
      arabinoxylan, and oligoarabinoxylans. ARAf and XYL1 can also release D-Xyl from
      these substrates but less efficiently than XYL4. Moreover, they can also release
      L-Ara from arabinoxylans and arabinan. Overall, the results indicate that XYL4
      possesses enzymatic specificity characteristic for a beta-D-xylosidase, while
      ARAf and XYL1 act as bifunctional alpha-L-arabinofuranosidase/beta-D-xylosidases.
      Analysis of the activity of these three enzymes in stem tissues at different
      stages of development has shown that young stems possess the highest activities
      for all three enzymes in comparison to the activities of the enzymes present in
      stems at older stages of development. High enzyme activities are most likely
      related to the necessary modifications of cell wall structure occurring during
      plant growth.

PMID- 15181204
TI  - Gene expression signatures from three genetically separable resistance gene
      signaling pathways for downy mildew resistance.
AB  - Resistance gene-dependent disease resistance to pathogenic microorganisms is
      mediated by genetically separable regulatory pathways. Using the GeneChip
      Arabidopsis genome array, we compared the expression profiles of approximately
      8,000 Arabidopsis genes following activation of three RPP genes directed against
      the pathogenic oomycete Peronospora parasitica. Judicious choice of P. parasitica
      isolates and loss of resistance plant mutants allowed us to compare the responses
      controlled by three genetically distinct resistance gene-mediated signaling
      pathways. We found that all three pathways can converge, leading to up-regulation
      of common sets of target genes. At least two temporal patterns of gene activation
      are triggered by two of the pathways examined. Many genes defined by their early
      and transient increases in expression encode proteins that execute defense
      biochemistry, while genes exhibiting a sustained or delayed expression increase
      predominantly encode putative signaling proteins. Previously defined and novel
      sequence motifs were found to be enriched in the promoters of genes coregulated
      by the local defense-signaling network. These putative promoter elements may
      operate downstream from signal convergence points.

PMID- 15181205
TI  - Molecular characterization of an Arabidopsis gene encoding a phospholipid
      specific inositol polyphosphate 5-phosphatase.
AB  - Phosphoinositides are important molecules that serve as second messengers and
      bind to a complex array of proteins modulating their subcellular location and
      activity. The enzymes that metabolize phosphoinositides can in some cases serve
      to terminate the signaling actions of phosphoinositides. The inositol
      polyphosphate 5-phosphatases (5PTases) comprise a large protein family that
      hydrolyzes 5-phosphates from a variety of inositol phosphate and phosphoinositide
      substrates. We previously reported the identification of 15 putative 5PTase genes
      in Arabidopsis and have shown that overexpression of the At5PTase1 gene can alter
      abscisic acid signaling. At5PTase1 and At5PTase2 have been shown to hydrolyze the
      5-phosphate from inositol phosphate substrates. We have examined the substrate
      specificity of the At5PTase11 protein, which is one of the smallest predicted
      5PTases found in any organism. We report here that the At5PTase11 gene encodes an
      active 5PTase enzyme that can only dephosphorylate phosphoinositide substrates
      containing a 5-phosphate. In addition to hydrolyzing known substrates of 5PTase
      enzymes, At5PTase11 also hydrolyzes the 5-phosphate from phosphatidylinositol
      (3,5) bisphosphate. We also show that the At5PTase11 gene is regulated by
      abscisic acid, jasmonic acid, and auxin, suggesting a role for phosphoinositide
      action in these signal transduction pathways.

PMID- 15181206
TI  - Intracellular localization of Arabidopsis sulfurtransferases.
AB  - Sulfurtransferases (Str) comprise a group of enzymes widely distributed in
      archaea, eubacteria, and eukaryota which catalyze the transfer of a sulfur atom
      from suitable sulfur donors to nucleophilic sulfur acceptors. In all organisms
      analyzed to date, small gene families encoding Str proteins have been identified.
      The gene products were localized to different compartments of the cells. Our
      interest concerns the localization of Str proteins encoded in the nuclear genome
      of Arabidopsis. Computer-based prediction methods revealed localization in
      different compartments of the cell for six putative AtStrs. Several methods were
      used to determine the localization of the AtStr proteins experimentally. For
      AtStr1, a mitochondrial localization was demonstrated by immunodetection in the
      proteome of isolated mitochondria resolved by one- and two-dimensional gel
      electrophoresis and subsequent blotting. The respective mature AtStr1 protein was
      identified by mass spectrometry sequencing. The same result was obtained by
      transient expression of fusion constructs with the green fluorescent protein in
      Arabidopsis protoplasts, whereas AtStr2 was exclusively localized to the
      cytoplasm by this method. Three members of the single-domain AtStr were localized
      in the chloroplasts as demonstrated by transient expression of green fluorescent
      protein fusions in protoplasts and stomata, whereas the single-domain AtStr18 was
      shown to be cytoplasmic. The remarkable subcellular distribution of AtStr15 was
      additionally analyzed by transmission electron immunomicroscopy using a
      monospecific antibody against green fluorescent protein, indicating an attachment
      to the thylakoid membrane. The knowledge of the intracellular localization of the
      members of this multiprotein family will help elucidate their specific functions
      in the organism.

PMID- 15181207
TI  - Cell cycle modulation in the response of the primary root of Arabidopsis to salt
      stress.
AB  - Salt stress inhibits plant growth and development. We investigated the importance
      of cell cycle regulation in mediating the primary root growth response of
      Arabidopsis to salt stress. When seedlings were transferred to media with
      increasing concentrations of NaCl, root growth rate was progressively reduced. At
      day 3 after transfer of seedlings to growth medium containing 0.5% NaCl the
      primary roots grew at a constant rate well below that prior to the transfer,
      whereas those transferred to control medium kept accelerating. Kinematic analysis
      revealed that the growth reduction of the stressed roots was due to a decrease in
      cell production and a smaller mature cell length. Surprisingly, average cell
      cycle duration was not affected. Hence, the reduced cell production was due to a
      smaller number of dividing cells, i.e. a meristem size reduction. To analyze the
      mechanism of meristem size adaptation prior to day 3, we investigated the short
      term cell cycle events following transfer to saline medium. Directly after
      transfer cyclin-dependent kinase (CDK) activity and CYCB1;2 promoter activity
      were transiently reduced. Because protein levels of both CDKA;1 and CDKB1;1 were
      not affected, the temporary inhibition of mitotic activity that allows adaptation
      to the stress condition is most likely mediated by posttranslational control of
      CDK activity. Thus, the adaptation to salt stress involves two phases: first, a
      rapid transient inhibition of the cell cycle that results in fewer cells
      remaining in the meristem. When the meristem reaches the appropriate size for the
      given conditions, cell cycle duration returns to its default.

PMID- 15181208
TI  - Arabidopsis trehalose-6-phosphate synthase 1 is essential for normal vegetative
      growth and transition to flowering.
AB  - In resurrection plants and yeast, trehalose has a function in stress protection,
      but the absence of measurable amounts of trehalose in other plants precludes such
      a function. The identification of a trehalose biosynthetic pathway in angiosperms
      raises questions on the function of trehalose metabolism in nonresurrection
      plants. We previously identified a mutant in the Arabidopsis trehalose
      biosynthesis gene AtTPS1. Plants homozygous for the tps1 mutation do not develop
      mature seeds (Eastmond et al., 2002). AtTPS1 expression analysis and the spatial
      and temporal activity of its promoter suggest that this gene is active outside
      the seed-filling stage of development as well. A generally low expression is
      observed in all organs analyzed, peaking in metabolic sinks such as flower buds,
      ripening siliques, and young rosette leaves. The arrested tps1/tps1 embryonic
      state could be rescued using a dexamethasone-inducible AtTPS1 expression system
      enabling generation of homozygous mutant plants. When depleted in AtTPS1
      expression, such mutant plants show reduced root growth, which is correlated with
      a reduced root meristematic region. Moreover, tps1/tps1 plants are retarded in
      growth and remain generative during their lifetime. Absence of Trehalose-6
      Phosphate Synthase 1 in Arabidopsis plants precludes transition to flowering.

PMID- 15181209
TI  - Trehalose mediated growth inhibition of Arabidopsis seedlings is due to trehalose
      6-phosphate accumulation.
AB  - Trehalose-6-phosphate (T6P) is required for carbon utilization during Arabidopsis
      development, and its absence is embryo lethal. Here we show that T6P accumulation
      inhibits seedling growth. Wild-type seedlings grown on 100 mm trehalose rapidly
      accumulate T6P and stop growing, but seedlings expressing Escherichia coli
      trehalose phosphate hydrolase develop normally on such medium. T6P accumulation
      likely results from much-reduced T6P dephosphorylation when trehalose levels are
      high. Metabolizable sugars added to trehalose medium rescue T6P inhibition of
      growth. In addition, Suc feeding leads to a progressive increase in T6P
      concentrations, suggesting that T6P control over carbon utilization is related to
      available carbon for growth. Expression analysis of genes from the Arabidopsis
      trehalose metabolism further supports this: Suc rapidly induces expression of
      trehalose phosphate synthase homolog AtTPS5 to high levels. In contrast, T6P
      accumulation after feeding trehalose in the absence of available carbon induces
      repression of genes encoding T6P synthases and expression of T6P phosphatases. To
      identify processes controlled by T6P, we clustered expression profile data from
      seedlings with altered T6P content. T6P levels correlate with expression of a
      specific set of genes, including the S6 ribosomal kinase ATPK19, independently of
      carbon status. Interestingly, Suc addition represses 15 of these genes, one of
      which is AtKIN11, encoding a Sucrose Non Fermenting 1 (SNF1)-related kinase known
      to play a role in Suc utilization.

PMID- 15181211
TI  - Interaction between wall deposition and cell elongation in dark-grown hypocotyl
      cells in Arabidopsis.
AB  - A central problem in plant biology is how cell expansion is coordinated with wall
      synthesis. We have studied growth and wall deposition in epidermal cells of dark
      grown Arabidopsis hypocotyls. Cells elongated in a biphasic pattern, slowly first
      and rapidly thereafter. The growth acceleration was initiated at the hypocotyl
      base and propagated acropetally. Using transmission and scanning electron
      microscopy, we analyzed walls in slowly and rapidly growing cells in 4-d-old dark
      grown seedlings. We observed thick walls in slowly growing cells and thin walls
      in rapidly growing cells, which indicates that the rate of cell wall synthesis
      was not coupled to the cell elongation rate. The thick walls showed a
      polylamellated architecture, whereas polysaccharides in thin walls were axially
      oriented. Interestingly, innermost cellulose microfibrils were transversely
      oriented in both slowly and rapidly growing cells. This suggested that
      transversely deposited microfibrils reoriented in deeper layers of the expanding
      wall. No growth acceleration, only slow growth, was observed in the cellulose
      synthase mutant cesA6(prc1-1) or in seedlings, which had been treated with the
      cellulose synthesis inhibitor isoxaben. In these seedlings, innermost
      microfibrils were transversely oriented and not randomized as has been reported
      for other cellulose-deficient mutants or following treatment with
      dichlorobenzonitrile. Interestingly, isoxaben treatment after the initiation of
      the growth acceleration in the hypocotyl did not affect subsequent cell
      elongation. Together, these results show that rapid cell elongation, which
      involves extensive remodeling of the cell wall polymer network, depends on normal
      cellulose deposition during the slow growth phase.

PMID- 15181210
TI  - GCR1 can act independently of heterotrimeric G-protein in response to
      brassinosteroids and gibberellins in Arabidopsis seed germination.
AB  - Signal recognition by seven-transmembrane (7TM) cell-surface receptors is
      typically coupled by heterotrimeric G-proteins to downstream effectors in
      metazoan, fungal, and amoeboid cells. Some responses perceived by 7TM receptors
      in amoeboid cells and possibly in human cells can initiate downstream action
      independently of heterotrimeric G-proteins. Plants use heterotrimeric G-protein
      signaling in the regulation of growth and development, particularly in hormonal
      control of seed germination, but it is not yet clear which of these responses
      utilize a 7TM receptor. Arabidopsis GCR1 has a predicted 7TM-spanning domain and
      other features characteristic of 7TM receptors. Loss-of-function gcr1 mutants
      indicate that GCR1 plays a positive role in gibberellin- (GA) and brassinosteroid
      (BR) regulated seed germination. The null mutants of GCR1 are less sensitive to
      GA and BR in seed germination. This phenotype is similar to that previously
      observed for transcript null mutants in the Galpha-subunit, gpa1. However, the
      reduced sensitivities toward GA and BR in the single gcr1, gpa1, and agb1
      (heterotrimeric G-protein beta-subunit) mutants are additive or synergistic in
      the double and triple mutants. Thus, GCR1, unlike a typical 7TM receptor,
      apparently acts independently of the heterotrimeric G-protein in at least some
      aspects of seed germination, suggesting that this alternative mode of 7TM
      receptor action also functions in the plant kingdom.

PMID- 15181212
TI  - A novel family of cys-rich membrane proteins mediates cadmium resistance in
      Arabidopsis.
AB  - Cadmium (Cd) is a widespread pollutant that is toxic to plant growth. However,
      only a few genes that contribute to Cd resistance in plants have been identified.
      To identify additional Cd(II) resistance genes, we screened an Arabidopsis cDNA
      library using a yeast (Saccharomyces cerevisiae) expression system employing the
      Cd(II)-sensitive yeast mutant ycf1. This screening process yielded a small Cys
      rich membrane protein (Arabidopsis plant cadmium resistance, AtPcrs). Database
      searches revealed that there are nine close homologs in Arabidopsis. Homologs
      were also found in other plants. Four of the five homologs that were tested also
      increased resistance to Cd(II) when expressed in ycf1. AtPcr1 localizes at the
      plasma membrane in both yeast and Arabidopsis. Arabidopsis plants overexpressing
      AtPcr1 exhibited increased Cd(II) resistance, whereas antisense plants that
      showed reduced AtPcr1 expression were more sensitive to Cd(II). AtPcr1
      overexpression reduced Cd uptake by yeast cells and also reduced the Cd contents
      of both yeast and Arabidopsis protoplasts treated with Cd. Thus, it appears that
      the Pcr family members may play an important role in the Cd resistance of plants.

PMID- 15181213
TI  - The transcriptional innate immune response to flg22. Interplay and overlap with
      Avr gene-dependent defense responses and bacterial pathogenesis.
AB  - Animals and plants carry recognition systems to sense bacterial flagellin.
      Flagellin perception in Arabidopsis involves FLS2, a Leu-rich-repeat receptor
      kinase. We surveyed the early transcriptional response of Arabidopsis cell
      cultures and seedlings within 60 min of treatment with flg22, a peptide
      corresponding to the most conserved domain of flagellin. Using Affymetrix
      microarrays, approximately 3.0% of 8,200 genes displayed transcript level changes
      in flg22 elicited suspension cultures and seedlings. FLARE (Flagellin Rapidly
      Elicited) genes mostly encode signaling components, such as transcription
      factors, protein kinases/phosphatases, and proteins that regulate protein
      turnover. Approximately 80% of flg22-induced genes were also up-regulated in
      Arabidopsis seedlings treated with cycloheximide. This suggests that many FLARE
      genes are negatively regulated by rapidly turned-over repressor proteins. Twenty
      one tobacco Avr9/Cf-9 rapidly elicited (ACRE) cDNA full-length sequences were
      used to search for their Arabidopsis orthologs (AtACRE). We identified either
      single or multiple putative orthologs for 17 ACRE genes. For 13 of these ACRE
      genes, at least one Arabidopsis ortholog was induced in flg22-elicited
      Arabidopsis suspension cells and seedlings. This result revealed a substantial
      overlap between the Arabidopsis flg22 response and the tobacco Avr9 race-specific
      defense response. We also compared FLARE gene sets and genes induced in basal or
      gene-for-gene interactions upon different Pseudomonas syringae treatments, and
      infer that Pseudomonas syringae pv tomato represses the flagellin-initiated
      defense response.

PMID- 15181214
TI  - Characterization of an ultraviolet B-induced lipase in Arabidopsis.
AB  - An Arabidopsis expressed sequence tag clone, 221D24, encoding a lipase has been
      characterized using an antisense approach. The lipase gene is expressed during
      normal growth and development of Arabidopsis rosette leaves but is down-regulated
      as the leaves senesce. When plants are exposed to sublethal levels of UV-B
      radiation, expression of the lipase is strongly up-regulated. The lipase protein
      is localized in the cell cytosol and is present in all organs of Arabidopsis
      plants. Recombinant lipase protein produced in Escherichia coli preferentially
      hydrolyzed phospholipids, indicating that the gene encodes a phospholipase.
      Transgenic plants in which lipase expression is suppressed showed enhanced
      tolerance to UV-B stress but not osmotic stress and were unable to up-regulate PR
      1 expression when irradiated with UV-B. The observations collectively indicate
      that the lipase is capable of deesterifying membrane phospholipids and is up
      regulated in response to UV-B irradiation.

PMID- 15181216
TI  - SARS: market, toilet, hospital, and laboratory.

PMID- 15181215
TI  - Homology modeling of representative subfamilies of Arabidopsis major intrinsic
      proteins. Classification based on the aromatic/arginine selectivity filter.
AB  - Major intrinsic proteins (MIPs) are a family of membrane channels that facilitate
      the bidirectional transport of water and small uncharged solutes such as
      glycerol. The 35 full-length members of the MIP family in Arabidopsis are
      segregated into four structurally homologous subfamilies: plasma membrane
      intrinsic proteins (PIPs), tonoplast intrinsic proteins (TIPs), nodulin 26-like
      intrinsic membrane proteins (NIPs), and small basic intrinsic proteins (SIPs).
      Computational methods were used to construct structural models of the putative
      pore regions of various plant MIPs based on homology modeling with the atomic
      resolution crystal structures of mammalian aquaporin 1 and the bacterial glycerol
      permease GlpF. Based on comparisons of the narrow selectivity filter regions (the
      aromatic/Arg [ar/R] filter), the members of the four phylogenetic subfamilies of
      Arabidopsis MIPs can be classified into eight groups. PIPs possess a uniform ar/R
      signature characteristic of high water transport aquaporins, whereas TIPs are
      highly diverse with three separate conserved ar/R regions. NIPs possess two
      separate conserved ar/R regions, one that is similar to the archetype, soybean
      (Glycine max) nodulin 26, and another that is characteristic of Arabidopsis
      NIP6;1. The SIP subfamily possesses two ar/R subgroups, characteristic of either
      SIP1 or SIP2. Both SIP ar/R residues are divergent from all other MIPs in plants
      and other kingdoms. Overall, these findings suggest that higher plant MIPs have a
      common fold but show distinct differences in proposed pore apertures, potential
      to form hydrogen bonds with transported molecules, and amphiphilicity that likely
      results in divergent transport selectivities.

PMID- 15181217
TI  - Out-patient chronic pain service in Hong Kong: prospective study.
AB  - OBJECTIVE: To examine the profile and referral pattern of patients attending an
      out-patient pain management service in Hong Kong. DESIGN: Prospective cross
      sectional survey. SETTING: Regional public hospitals, Hong Kong. PATIENTS: All
      patients attending out-patient pain management clinics in the New Territories
      East public hospitals between 1 September and 31 December 2002. MAIN OUTCOME
      MEASURES: Demographic profiles, referring specialty, pain diagnosis, pain sites,
      duration and severity of pain, treatment modality, litigation, compensation, and
      social welfare status. Data were collected using a standardised questionnaire.
      RESULTS: Two hundred and forty-eight patients were interviewed. Most patients
      (70%) were middle-aged, with 21% over 60 years. Seventy-nine percent of patients
      were referred to the clinics either from orthopaedic surgeons (64.1%), general
      and other surgeons (14.9%), or general practitioners (3.6%). The median (range)
      duration of pain was 2.3 (0.08-26.7) years. The most common pain diagnoses were
      musculoskeletal back pain (46.4%) and neuropathic pain (27.8%). A total of 11.3%
      of the patients had two pain diagnoses, while 40.7% complained of pain in more
      than one location. Pain in the limbs was the most frequent complaint followed by
      the head, neck, and back. Approximately 38% of patients had tried four or more
      treatment modalities. Oral medication was the most common method (86.7%) of pain
      relief treatment. More than half of the patients had also tried physiotherapy and
      traditional Chinese medicine. Approximately 37% of the patients were unemployed,
      while 31% were receiving social security subsidy. Eighty-six patients had pain
      associated with a work-related injury, and of these patients, 80% were involved
      in compensation claims. CONCLUSIONS: The profile of patients referred to the pain
      management clinics was complex. Patients were mainly referred from specialists.
      The economic implication in this group of patients is likely to be significant as
      many patients utilised multiple treatment modalities, were unemployed and on
      social welfare benefits, and were involved in compensation and litigation
      proceedings.

PMID- 15181218
TI  - Features predicting adverse outcomes of status epilepticus in childhood.
AB  - OBJECTIVE: To examine variables that might predict abnormal outcome of status
      epilepticus among children. DESIGN: Retrospective study. SETTING: Regional
      hospital, Hong Kong. PATIENTS: All children younger than 15 years who were
      admitted to the paediatric intensive care unit with status epilepticus between
      1997 and 2002. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes. RESULTS: Two
      of the 25 patients died, resulting in a mortality rate of 8%. No deaths were due
      to status epilepticus itself. No patient with febrile or idiopathic status
      epilepticus developed epilepsy. Neurological deterioration was observed in a
      quarter (six of 23) of the survivors. Symptomatic aetiology (acute or remote) and
      refractory status epilepticus were associated with adverse outcomes (P<0.05).
      Young age at status epilepticus (<12 months) and duration of status epilepticus
      (>60 minutes) tended to be more frequent among those who developed adverse
      outcome. Rectal diazepam was given before hospital arrival in only four patients.
      CONCLUSIONS: Paediatric patients with status epilepticus who had normal
      neurodevelopmental status before the onset of an attack and who did not sustain
      an acute insult to the central nervous system or have progressive encephalopathy,
      had favourable outcomes. Prompt use of rectal diazepam or buccal midazolam
      administered by caretakers or paramedics should be encouraged.

PMID- 15181219
TI  - Pain and disability in a group of Chinese elderly out-patients in Hong Kong.
AB  - OBJECTIVE: To investigate the relationship between musculoskeletal pain and
      disability among a group of geriatric out-patients. DESIGN: Consecutive case
      series. SETTING: Regional hospital, Hong Kong. PARTICIPANTS: Attendees at a
      geriatric specialist out-patient clinic from October 2002 to February 2003. MAIN
      OUTCOME MEASURES: Pain duration, location, intensity, and frequency; use of
      analgesics; ability to identify the cause of pain; disability (Barthel index) and
      Lawton Instrumental Activities of Daily Living scale score; depressive symptoms
      (Geriatric Depression Scale score); and self-reported sleep quality. RESULTS: Of
      the 749 respondents, 461 (61.5%) had experienced pain in the previous 2 weeks.
      Among these patients, 51.3% had received a pain-relieving drug. Compared with
      men, women reported a higher pain intensity (5.87 versus 5.26; P=0.001), had a
      lower Barthel index (96.0 versus 97.9; P=0.005), and had a lower score on the
      Lawton Instrumental Activities of Daily Living scale (42.19 versus 44.52;
      P=0.008). Multivariate logistic regression showed that the presence of pain was
      associated with female sex (odds ratio=2.25), poor self-rated health (0.69), and
      depression (1.54). CONCLUSION: Pain is a common problem among the elderly
      population, but it is not associated with physical disability, and only half of
      the patients received analgesics. The study provides information for health care
      workers to develop strategies to better assess and manage pain problems among
      elderly people.

PMID- 15181220
TI  - Use of an electronic barcode system for patient identification during blood
      transfusion: 3-year experience in a regional hospital.
AB  - OBJECTIVE: To evaluate the use of an electronic barcode system for patient
      identification during blood transfusion. DESIGN: Retrospective study. SETTING:
      Regional hospital, Hong Kong. PATIENTS: For all patients requiring blood
      transfusion between May 1999 and April 2002, with the exception of patients in
      the psychiatric wards and the accident and emergency department, a portable, hand
      held scan-and-print electronic device was used to verify and document patients'
      identity at two critical points of transfusion: blood sampling for the
      compatibility test and blood administration. MAIN OUTCOME MEASURES: Scope of use
      of the electronic device, cost, effectiveness, staff compliance, problems and
      solution for improvement. RESULTS: In the first 3 years of hospital-wide use of
      the new device, no incidents of blood transfusion to wrong patients, or wrong
      labelling of blood samples, occurred with 41,00 blood sampling procedures and
      administration of 27 000 units of blood. Blood sampling took 6 minutes to
      complete with the use of the electronic device-similar to that taken by the
      conventional second-checker system. Among hospital staff, the compliance rate of
      using the new device approached 90%. Battery problems occurred in 12% of episodes
      of use of the device. CONCLUSIONS: The electronic barcode system was effective in
      reducing human error related to bedside transfusion procedures. The future goal
      is to tailor-make a more efficient device with additional functions.

PMID- 15181221
TI  - Reliability of Hong Kong Chinese version of the Patient-rated Forearm Evaluation
      Questionnaire for lateral epicondylitis.
AB  - OBJECTIVE: To determine the reliability and validity of a dedicated assessment
      tool for lateral epicondylitis after translation into Hong Kong Chinese. DESIGN:
      Cross-sectional study. SETTING: District hospital, Hong Kong. PATIENTS: Seventy
      four patients, 12 of whom were bilingual, were recruited (total of 82 elbows).
      MAIN OUTCOME MEASURES: Translation equivalence and reliability were measured with
      the test-retest method. Validity was measured against the Roles and Maudsley
      outcome score and mean maximal grip strength. RESULT: The Patient-rated Forearm
      Evaluation Questionnaire had high English-Chinese equivalence (Spearman's rho
      correlation coefficient=0.926; P<0.001). It was also very reliable (intraclass
      correlation coefficient=0.99; P<0.001). Validity according to the Roles and
      Maudsley outcome score and mean of maximal grip strength was significant
      (P<0.01). CONCLUSION: The Hong Kong Chinese version of Patient-rated Forearm
      Evaluation Questionnaire is a reliable and valid assessment tool for chronic
      lateral epicondylitis. Its equivalence to the original English version makes
      outcome assessment across cultural barrier feasible.

PMID- 15181222
TI  - Wireless capsule endoscopy in Chinese patients with suspected small bowel
      diseases.
AB  - OBJECTIVE: To evaluate the use of wireless capsule endoscopy in Chinese patients.
      DESIGN: Retrospective analysis. SETTING: University teaching hospital, Hong Kong.
      PATIENTS: Twenty-eight patients who had undergone wireless capsule endoscopy
      between December 2002 and December 2003. MAIN OUTCOME MEASURES: Diagnoses
      according to findings of capsule endoscopy and complications from the procedure.
      RESULTS: The mean age of the 28 patients (15 men and 13 women) was 60.0 (standard
      deviation, 18.3) years. The indications for capsule endoscopy were obscure gastro
      intestinal bleeding (n=16), unexplained iron-deficiency anaemia (n=9), and
      recurrent abdominal pain (n=3). Half of the patients had abnormal endoscopy
      findings that may account for their presenting symptoms. The most common
      abnormality was angioectasia of the small bowel. Small bowel ulcers and erosions
      were also noted in three patients with obscure bleeding. In contrast, none of the
      patients with recurrent abdominal pain had abnormal capsule endoscopy. No
      complications arose from the procedure. CONCLUSIONS: Wireless capsule endoscopy
      is a safe and useful mode of investigation for the diagnosis of obscure gastro
      intestinal bleeding in Chinese patients.

PMID- 15181223
TI  - Epilepsy in Hong Kong: a literature review.
AB  - OBJECTIVE: To review data on the causes, clinical features, and management of
      patients with epilepsy in Hong Kong. DATA SOURCES: MEDLINE and Chinese Current
      Medical Contents were used to search the literature. A manual search of the Hong
      Kong Medical Journal, Hong Kong Practitioner, and Chinese Medical Journal (1982
      2002) was also undertaken. STUDY SELECTION: Key words for the literature search
      were 'epilepsy' and 'Hong Kong'. DATA EXTRACTION: All relevant articles in
      English or in Chinese language were reviewed. DATA SYNTHESIS: Overall, disease
      characteristics and the response to both medical and surgical treatments of
      epilepsy among local Chinese patients with epilepsy was found to be comparable to
      that reported for patients in western countries. Knowledge of epilepsy among the
      general population was more limited than expected from the international
      literature, and attitudes to epilepsy relatively more negative, adding to the
      psychosocial burden for people with epilepsy. CONCLUSION: Further research in
      Hong Kong on aspects of epileptology is indicated with a view to developing more
      innovative and effective therapy.

PMID- 15181224
TI  - Use of ophthalmic medications during pregnancy.
AB  - OBJECTIVES: To review potential risks of eye medications to the mother and her
      foetus. DATA SOURCES: PubMed search for all relevant articles (1966 to 2003).
      STUDY SELECTION: All types of publication that documented potential risks of eye
      medications during pregnancy. The following key words were used: pregnancy,
      fetus, teratogenicity, eye, ocular, ophthalmic, glaucoma, antibiotics, anti
      inflammatory, and corticosteroids. DATA EXTRACTION: All relevant articles
      including original articles, review papers, case studies, and relevant book
      chapters were extracted and reviewed. DATA SYNTHESIS: Whether ophthalmic
      medications can be used during pregnancy is a very important issue; yet, limited
      information on the subject exists in the literature. Topically applied eye
      medications that give rise to systemic side-effects are of particular concern to
      both patients and doctors. Various ophthalmic anti-infective preparations and
      ophthalmic corticosteroids have shown to cause teratogenicity in animal studies.
      Furthermore, anti-glaucoma drugs pose potential risks to the foetus if they are
      absorbed systemically. This article examines the association between the main
      groups of ophthalmic medication and their possible adverse effects on the mother
      and the foetus. Recommendations for the treatment of pregnant patients with eye
      diseases are also discussed. CONCLUSION: The risk of giving ophthalmic drugs to
      pregnant women is low. Doctors should be cautious when prescribing drugs for
      pregnant women and consult experts in the field when in doubt.

PMID- 15181225
TI  - Use of hair analysis in the diagnosis of heavy metal poisoning: report of three
      cases.
AB  - We report three paediatric cases of suspected heavy metal poisoning that
      presented with non-specific symptoms. Hair samples of the three patients were
      sent overseas for analysis; results showed abnormal levels of many elements,
      including some heavy metals. A diagnosis of heavy metal poisoning was made and
      chelation therapy was offered to each patient. Blood levels for some heavy metals
      were subsequently checked and all were within the normal range. The original
      diagnosis of heavy metal poisoning was therefore not substantiated. The patients
      did not have a history of exposure to heavy metals or specific clinical features
      of heavy metal poisoning. The non-invasive nature of hair analysis is tempting,
      but the validity of such testing in diagnosing heavy metal poisoning is
      questionable.

PMID- 15181226
TI  - Corticosteroid therapy in a Chinese patient with nephropathy associated with
      human immunodeficiency virus infection.
AB  - A 52-year-old man with 6 years' history of human immunodeficiency virus infection
      who was receiving highly active antiretroviral therapy presented with acute renal
      failure and nephrotic syndrome. Renal biopsy revealed features consistent with
      nephropathy associated with human immunodeficiency virus infection. Treatment
      consisted of intravenous methylprednisolone followed by oral prednisolone. The
      patient's renal function improved, although proteinuria persisted. Human
      immunodeficiency virus-associated nephropathy is very rare in Asian populations
      and is more common among blacks. To the best of our knowledge, this is the first
      documented case of nephropathy associated with human immunodeficiency virus
      infection occurring in Hong Kong.

PMID- 15181227
TI  - Multiple endocrine neoplasia type 2B in a Chinese patient.
AB  - Multiple endocrine neoplasia type 2B syndrome is rarely reported in Chinese
      patients. A 25-year-old Chinese male presented with full-blown clinical features
      of this syndrome, including bilateral phaeochromocytomas, medullary thyroid
      carcinoma, and characteristic phenotypic features. One-stage surgical treatment
      was performed and subsequent genetic analysis confirmed a point mutation at codon
      918 in exon 16 of the RET proto-oncogene. The mutation was arising de novo as
      there was no corresponding mutation found in both his parents or younger sister.
      Data published to date suggest there is no difference in the genetic and
      pathophysiologic basis, nor clinical characteristics of multiple endocrine
      neoplasia type 2B in Chinese patients. As the disease can be lethal, early
      diagnosis by prompt recognition of the characteristic phenotypic features
      followed by surgical treatment should improve the outcome. Family screening is
      essential to identify at-risk family members for prophylactic treatment.

PMID- 15181228
TI  - A case of cerebellar hypoplasia in a Chinese infant with osteogenesis imperfecta.
AB  - We report a unique case of unilateral cerebellar hypoplasia in a young Chinese
      girl with osteogenesis imperfecta type IV. Magnetic resonance imaging showed mild
      basilar invagination and impression. Although unilateral cerebellar hypoplasia
      and osteogenesis imperfecta may have been coincidental diagnoses, we propose
      possible mechanisms for unilateral cerebellar hypoplasia secondary to
      osteogenesis imperfecta. For example, cerebellar hypoplasia may have been because
      of vascular disruption or direct compression to the posterior circulation in
      utero. Foetuses with osteogenesis imperfecta are more susceptible to the above
      risks compared to the normal foetus because of associated craniocervical
      anomalies and a poorly ossified skull.

PMID- 15181229
TI  - Extrusion of a coil from the internal carotid artery through the middle ear.

PMID- 15181230
TI  - Pitfalls in practice.

PMID- 15181231
TI  - Can liver toxicity occur at repeated borderline supratherapeutic doses of
      paracetamol?

PMID- 15181232
TI  - Unnecessary phobia of paracetamol.

PMID- 15181234
TI  - Minimally invasive parathyroidectomy for regional hospitals.

PMID- 15181235
TI  - Homer/Vesl proteins and their roles in CNS neurons.
AB  - Since their initial discovery in 1997, Homer/Vesl proteins have become
      increasingly investigated as putative regulators of receptor and ion-channel
      function in the central nervous system. Within a relatively brief period,
      numerous research reports have described manifold effects of Homer proteins,
      including the modulation of the trafficking of type I metabotropic glutamate
      receptors (mGluRs), axonal pathfinding, mGluR coupling to calcium and potassium
      channels, agonist-independent mGluR activity, ryanodine receptor regulation,
      locomotor activity, and behavioral plasticity. This review summarizes our current
      knowledge on the induction, expression, and structure of the various forms of
      Homer proteins, as well as their roles in neuronal function. In addition, we
      provide an outlook on novel developments with regard to the involvement of Homer
      1a in hippocampal synaptic function.

PMID- 15181236
TI  - Thioredoxin as a neurotrophic cofactor and an important regulator of
      neuroprotection.
AB  - Oxidative stress has been implicated in the pathogenesis of a wide variety of
      neuronal diseases, including ischemic neuronal injury, Alzheimer's disease, and
      Parkinson's disease. Thioredoxin reduces exposed protein disulfides and couples
      with peroxiredoxin to scavenge reactive oxygen species. Nerve growth factor (NGF)
      has profound effects on neurons, including promotion of survival and
      differentiation via multiple signaling pathways. As for the NGF-induced neurite
      outgrowth, the CREB-cAMP responsive element (CRE) pathway is important to the
      activation of immediate-early genes such as c-fos. Thioredoxin is upregulated by
      NGF through ERK and the CREB-CRE pathway in PC12 cells. Thioredoxin is necessary
      for NGF signaling through CRE leading to c-fos expression and also plays a
      critical role in the NGF-mediated neurite outgrowth in PC12 cells. Therefore,
      thioredoxin appears to be a neurotrophic cofactor that augments the effect of NGF
      on neuronal differentiation and regeneration. NGF acts also as a neuronal
      survival factor. Previous reports showed that thioredoxin exerts a cytoprotective
      effect in the nervous system. The cytoprotective effect is mediated by enhancing
      the action of NGF, via the regulation of antiapoptotic signaling, or through its
      antioxidative stress activity.

PMID- 15181237
TI  - Functional diversity of ventral midbrain dopamine and GABAergic neurons.
AB  - Recent findings indicate that VTA and SN dopaminergic (DA) and GABAergic neurons
      form subpopulations that are divergent in their electrophysiological features,
      vulnerability to neurodegeneration, and regulation by neuropeptides. This
      diversity can be correlated with the anatomical organization of the VTA and SN
      and their inputs and outputs. In this review we describe the heterogeneity in ion
      channels and firing patterns, especially burst firing, in subpopulations of
      dopamine neurons. We go on to describe variations in vulnerability to neurotoxic
      damage in models of Parkinson's disease in subgroups of DA neurons and its
      possible relationship to developmental gene regulation, the expression of
      different ion channels, and the expression of different protein markers, such as
      the neuroprotective marker calbindin. The electrophysiological properties of
      subgroups of GABAergic midbrain neurons, patterns of expression of protein
      markers and receptors, possible involvement of GABAergic neurons in a number of
      processes that are usually attributed exclusively to dopaminergic neurons, and
      the characteristics of a subgroup of neurons that contains both dopamine and GABA
      are also discussed.

PMID- 15181238
TI  - Calcium dependence of native metabotropic glutamate receptor signaling in central
      neurons.
AB  - Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that
      are distributed throughout the brain and play important roles in regulation of
      synaptic efficacy. Some studies report that mGluRs heterologously expressed in
      nonneuronal cells are sensitive not only to glutamate but also to extracellular
      Ca2+ (Ca2+o). We studied the Ca2+o-sensitivity of native mGluRs in mammalian
      central neurons. In cerebellar Purkinje cells that naturally express type-1 mGluR
      (mGluR1), physiological levels of Ca2+o (around 2 mM) activate mGluR1-mediated
      intracellular Ca2+ mobilization. The activation of the native mGluR1 response to
      Ca2+o appears to be slower than that to glutamate. Ca2+o (2 mM) also augments
      glutamate analog-evoked, native mGluR1-mediated inward cation current and
      intracellular Ca2+o mobilization. Detailed analysis of this effect suggests that
      Ca2+o modulates the glutamate responsiveness of native and heterologously
      expressed mGluR1s in different manners. These findings suggest that Ca2+o may
      enhance the basal level and glutamate responsiveness of neuronal mGluR signaling
      in vivo.

PMID- 15181242
TI  - Apolipoprotein E knockout mice as a model of behavioral dysfunction.

PMID- 15181240
TI  - Neurotrophins as mediators of drug effects on mood, addiction, and
      neuroprotection.
AB  - The induction of synthesis or release of endogenous neurotrophic factors in the
      brain by low-molecular-weight drugs could be a feasible alternative for the
      direct administration of neurotrophic factors for the treatment of central
      nervous system disorders. Recent data suggest that several drugs already in
      clinical use increase the synthesis, release, or signaling of neurotrophins.
      Antidepressant drugs increase the synthesis and signaling of brain-derived
      neurotrophic factor (BDNF), and BDNF signaling appears to be both sufficient and
      necessary for the antidepressant-induced behavioral effects. Furthermore,
      neurotrophins and other neurotrophic factors play a role in the acute and chronic
      responses produced by addictive drugs. Moreover, several neuroprotective drugs
      influence neurotrophin synthesis or signaling, although the significance of these
      effects is still unclear. These findings reveal a wider role for neurotrophic
      factors in drug action than has previously been expected, and they suggest that
      neurotrophin-induced trophic responses in neuronal connectivity and plasticity
      may be involved in the mechanism of action of several classes of CNS drugs.
      Improved assay systems are needed for the systematic screening of the effects of
      putative neuroprotective drugs on the synthesis, release, and signaling of
      neurotrophic factors, and for the evaluation of the functional role of these
      factors in the action of novel drug candidates.

PMID- 15181239
TI  - Proteomic approach to studying Parkinson's disease.
AB  - Parkinson's disease is a common age-related neurodegenerative disease
      characterized pathologically by a loss of dopaminergic neurons in the substantia
      nigra with resultant depletion of striatal dopamine and presence of Lewy bodies
      in the remaining neurons. The Lewy body contains numerous functional and
      structural proteins, including alpha-synuclein and ubiquitin; aggregation of
      alpha-synuclein is thought to be important in Lewy body formation as well as
      neurodegeneration, although the detailed mechanisms remain to be defined.
      Increasing evidence has suggested that mitochondrial dysfunction, increased
      oxidative stress, and dysfunction of the ubiquitin-proteasome system may be
      involved in alpha-synuclein aggregation, Lewy body formation, and
      neurodegeneration. However, how these processes are related to each other is not
      fully understood, given that there are Parkinsonian animal models as well as
      human diseases with significant nigral neurodegeneration regardless of whether
      Lewy bodies form or not. This review summarizes the current related research
      fields and proposes a proteomic approach to investigate the mechanisms that may
      dictate alpha-synuclein aggregation, Lewy body formation, and neurodegeneration.

PMID- 15181241
TI  - Mechanisms of dendritic maturation.
AB  - The highly complex geometry of dendritic trees is crucial for neural signal
      integration and the proper wiring of neuronal circuits. The morphogenesis of
      dendritic trees is regulated by innate genetic factors, neuronal activity, and
      external molecular cues. How each of these factors contributes to dendritic
      maturation has been addressed in the developing nervous systems of animals
      ranging from insects to mammals. The results of such investigations have shown
      that the contribution of intrinsic and extrinsic factors and activity, however,
      appear to be weighted differentially in different types of neurons, in different
      brain areas, and especially in different species. Moreover, it appears that
      dozens of molecules have been found to regulate dendritic maturation, but it is
      almost certain that each molecule plays only a specific role in this formidable
      cooperative venture. This article reviews our current knowledge and understanding
      of the role of various factors in the establishment of the architecture of mature
      dendritic trees.

PMID- 15181243
TI  - Apolipoprotein E4 as a target for developing new therapeutics for Alzheimer's
      disease.
AB  - The identification of factors that influence the onset or progression of the
      sporadic form of Alzheimer's disease (AD) is a key step toward understanding its
      mechanism(s) and developing successful rational therapies. The apoE genotype has
      been identified as a powerful risk factor for AD that may account for as much as
      50% of the sporadic form of the disease. As the major risk factor for late-onset
      AD, apolipoprotein E4 (apoE4) should be considered a good target for AD drug
      discovery. However, despite knowing for over a decade that apoE4 is detrimental
      to the disease process, we still remain uncertain about the molecular mechanisms
      subserving the risk-factor activity of apoE4. This, coupled with the fact that we
      know relatively little about the function(s) of apoE in brain, has presented a
      barrier to developing apoE-based therapeutics for AD. Progress has been made in
      understanding the neurobiology of apoE; a number of potentially overlapping
      functions have been ascribed, which include lipid transport, neuronal repair,
      dendritic growth, maintenance of synaptic plasticity, and anti-inflammatory
      activities. Until the gaps are filled in our understanding of the pathogenic
      function(s) of apoE4, therapeutic strategies targeting this protein will lag
      behind the development of other AD therapies. Putative pathological functions, or
      risk-factor activities, of apoE4 include its role in beta-amyloid deposition,
      neurofibrillary tangle formation, synaptic loss, lipid dysfunction,
      neuroinflammation, and oxidative stress.

PMID- 15181244
TI  - APOE genotype effects on Alzheimer's disease onset and epidemiology.
AB  - The risk of developing Alzheimer's disease (AD) is tied most closely to age and
      appears to follow Gompertzian kinetics. However, specific genetic factors are
      also linked closely to AD, and the apolipoprotein E (APOE) genotype accounts for
      as much of 50% of the attributable risk for AD in many populations. This paper
      reviews the onset, diagnosis, and epidemiology of AD, specifically with regard to
      the APOE genotype and the interaction of the genotype with age.

PMID- 15181246
TI  - Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer's
      disease.
AB  - There is now a large body of evidence suggesting that apolipoprotein E (apoE)
      genotype is the single most important genetic risk factor for the most common
      (sporadic) form of Alzheimer's disease. Yet in proportion to the total number of
      investigations in this field, relatively few groups are studying the contribution
      of this cholesterol-binding protein to disease risk and severity. Of those that
      are, a major focus is on the impact of apoE on amyloid-related mechanisms of
      disease. I argue here that apoE should be considered a major culprit in its own
      right, not simply in a supporting role. The argument is based on several lines of
      evidence, including the fact that apoE is associated with both plaques and
      tangles, the overwhelming evidence for genetic risk of the disease attributed to
      apoE, increasing evidence that apoE might also modify risk of other
      nonamyloidogenic neurological diseases, neurotoxicity attributed to apoE and/or
      proteolytic fragments of apoE, negative consequences of transgenic expression of
      apoE4 in mice, and genetic evidence for polymorphisms that increase both apoE
      expression and disease risk, regardless of isoform.

PMID- 15181245
TI  - ApoE-dependent plasticity in Alzheimer's disease.
AB  - The contribution of neuroplasticity to Alzheimer's disease (AD) is supported by
      important effects of apoE on both the pathology of AD and the environmental and
      developmental factors influencing its etiologies. The earlier age of onset of
      apoE4 AD patients could be caused by defects in apoE-related compensatory repair
      mechanisms. The role of apoE in stimulating neuronal regeneration like neurite
      sprouting has received much support, with apoE4 consistently showing defects both
      in vitro and in vivo and in AD. In addition, growing evidence indicates that the
      reduced sprouting activity of apoE4 represents a gain-of-negative function; that
      is, apoE3-stimulated sprouting increases with increasing apoE3 dose, while any
      neurite sprouting with apoE4 is decreased with increasing apoE4 dose. Clearly,
      the dose responses for all relevant apoE activities need evaluation, as well as
      determination of the physiologically relevant doses in the brain. Because apoE4
      plays a major role in the risk and onset of AD for approximately 50% of AD cases,
      therapies that target the mechanism of this increased risk would greatly impact
      AD prevalence. Possible targets include apoE expression levels and regulation,
      and apoE protein structure or gene replacement. The gain-of-negative function of
      apoE4 in neurite sprouting, or any apoE4-specific activity, could have important
      clinical implications for the pharmacogenetic efficacy of therapeutic drugs that
      impact or target apoE expression or activity. Some therapeutic drugs, including
      estrogen that can regulate apoE levels, show apoE isotype-dependent efficacy in
      AD therapy. Other candidate drugs that could modulate apoE expression include
      antioxidants, anti-inflammatories, and statins. The contribution of apoE4 to drug
      efficacy may distinguish mechanisms of disease onset from those of progression,
      since the pleiotropic effects of apoE and its isotypes raise the strong
      possibility that the isotypes differ in the mechanism by which they contribute to
      AD etiology.

PMID- 15181248
TI  - A dual role for apolipoprotein e in neuroinflammation: anti- and pro-inflammatory
      activity.
AB  - Chronically activated glia associated with amyloid plaques might contribute to
      neuronal dysfunction in Alzheimer's disease (AD) through generation of
      neuroinflammatory molecules. Apolipoprotein E (apoE), also found associated with
      amyloid plaques, has been hypothesized to serve an anti-inflammatory role in the
      CNS through its ability to modulate beta-amyloid (Abeta)-induced glial
      activation. To further characterize the effect of apoE on inflammation, we
      examined the ability of exogenously added human apoE3 and apoE4 to modulate neuro
      inflammatory responses of cultured rat glia. Apolipoprotein E3 (apoE3) and apoE4
      suppressed oligomeric Abeta-induced production of inducible nitric oxide synthase
      and cyclo-oxygenase-2, supporting an anti- inflammatory role for apoE. Exogenous
      apoE also inhibited Abeta-induced production of endogenous apoE. However,
      exogenous apoE in the absence of Abeta stimulated production of the pro
      inflammatory cytokine interleukin-1beta in an isoform-dependent manner, with
      apoE4 inducing a significantly greater response than apoE3. These data support
      the idea that Abeta stimulation of glial apoE limits neuroinflammation but that
      overproduction of apoE by activated glia might exacerbate inflammation. In
      addition, the observation that apoE4 has more robust pro-inflammatory activity
      than apoE3 provides a mechanistic link between the APOE4 allele and AD, and
      suggests potential apoE-based therapeutic strategies.

PMID- 15181247
TI  - Apolipoprotein E: diversity of cellular origins, structural and biophysical
      properties, and effects in Alzheimer's disease.
AB  - Apolipoprotein E4 (apoE4) is a major risk factor for Alzheimer's disease (AD).
      Several hypotheses have been proposed to explain the association of the APOE
      epsilon4 allele with AD; however, the mechanisms underlying this association are
      largely unknown. Initially, apoE was thought to be synthesized primarily by
      astrocytes but not by neurons in the brain. However, subsequent studies have
      demonstrated that central nervous system neurons also express apoE under diverse
      physiological and pathological conditions. Detailed studies of the structure and
      biophysical properties of apoE isoforms have demonstrated unique properties
      distinguishing apoE4 from apoE3. Because the structural and biophysical
      properties of a protein determine how it functions under normal and abnormal
      conditions, apoE4, with its multiple cellular origins and multiple structural and
      biophysical properties, might contribute to the pathology of AD through several
      different mechanisms. Some of these mechanisms might be suitable targets for the
      development of new treatments for AD.

PMID- 15181249
TI  - Insulin-degrading enzyme, apolipoprotein E, and Alzheimer's disease.
AB  - Insulin-degrading enzyme (IDE) is a protease that degrades insulin and the beta
      amyloid (Abeta) peptide implicated in Alzheimer's disease (AD). Hence, factors
      that influence IDE expression or IDE activity toward Abeta are potentially
      relevant to the etiology of AD. Hippocampal IDE mRNA levels are lower on average
      in subjects with an APOE epsilon4 allele, suggesting that the genetic risk
      conferred by APOE epsilon4 may be mediated in part by this allele's effect on IDE
      expression. Other factors that influence IDE may be relevant in non-epsilon4
      carriers. For example, insulin, a competitive inhibitor of IDE activity toward
      Abeta, may be elevated in non-epsilon4 cases. We here report IDE gene promoter
      region variants that are associated with AD in subjects without an epsilon4
      allele. If these promoter region variants prove to affect expression levels, they
      may be relevant to disease as well. Further investigation of the relationship
      between APOE genotype, IDE genetic variants, and the expression and activity of
      hippocampal IDE is warranted.

PMID- 15181250
TI  - Cholesterol efflux as a critical component of Alzheimer's disease pathogenesis.
AB  - The risk of Alzheimer's disease and the levels of amyloid deposition are altered
      by factors associated with high cholesterol levels. When cells have high levels
      of cholesterol, they induce an efflux system of to maintain a proper cholesterol
      equilibrium. In the brain, cholesterol is converted to 24S hydroxycholesterol by
      the enzyme Cyp46. 24S hydroxycholesterol promotes gene transcription through
      interactions with LXR. We have found that in cells derived from the brain, two
      proteins important for cholesterol efflux, ABCA1 and apoE, are induced by this
      system. Furthermore, we have found that pharmacologic induction of LXR also
      induced secreted Abeta levels, particularly levels of Abeta42. We suggest that
      the risk of amyloid deposition associated with high cholesterol may be through
      induction of the LXR system.

PMID- 15181251
TI  - Apolipoprotein E as a target for developing new therapeutics for Alzheimer's
      disease based on studies from protein, RNA, and regulatory region of the gene.
AB  - Alzheimer's disease (AD), the most common form of dementia, is a progressive,
      degenerative disorder of the central nervous system. The major hallmarks of AD
      include selective neuronal cell death and the presence of amyloid deposits and
      neurofibrillary tangles. Apolipoprotein E (ApoE) has also been shown to
      colocalize with these neuropathological lesions. Here is reviewed the role of
      ApoE in AD. The human ApoE gene has three alleles (epsilon2, epsilon3, epsilon4)
      all products of the same gene. The epsilon3-allele accounts for the majority of
      the ApoE gene pool (approximately 70-80%), the epsilon4-allele accounts for 10
      15% and the epsilon2 allele for 5-10%. Inheritance of the epsilon4-allele
      strongly increases the risk for developing AD at an earlier age. Functions of
      ApoE include cholesterol transport, neuronal repair, dendritic growth and anti
      inflammatory activities. Putative pathological functions or "risk-factor
      activities" of ApoE-epsilon4 include its role in promoting amyloid accumulation,
      neurotoxicity, oxidative stress and neuro fibrillary tangles.ApoE mRNA is most
      abundant in the liver followed by the brain, where it is synthesized and secreted
      primarily by astrocytes. ApoE protein and mRNA are further detected in cortical
      and hippocampal neurons in humans. ApoE gene expression is induced by brain
      injury in some neurons and upregulated in astrocytes during aging. In AD, an
      increased ApoE mRNA was reported in the hippocampus. The risk for AD has been
      reported to correlate with transcriptional activity of the ApoE gene. Binding
      sites for putative transcriptional factors (TF), such as AP-1, AP-2 and NF
      kappaB, are present in the ApoE promoter. The promoter also contains sites for
      the inflammatory response transcription factors IL-6 RE-BP, MED1, STAT1 and
      STAT2. A functional peroxisome-proliferator-activated receptor gamma (PPARgamma)
      has been detected in the ApoE/ApoCI intergenic region. ApoE mRNA levels were
      shown to be regulated by ciglitazone, a PPARgamma inducer. Certain statin drugs
      may also affect ApoE promoter activity. Two distal enhancers that specify ApoE
      gene expression in macrophages were identified. These results have implications
      for the regulation of ApoE gene expression, which plays an important role in the
      development of AD. The interaction of different transcription factors with the
      regulatory region of the ApoE gene is important to understand the
      neuroinflammatory process seen in AD.

PMID- 15181252
TI  - ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure
      and function.
AB  - Abnormalities in the processing of amyloid precursor protein to amyloid-beta
      (Abeta) are causal factors, and the presence of the epsilon4 allele of
      apolipoprotein E (apoE) is the primary risk factor for Alzheimer's disease (AD).
      Based, at least in part, on these genetics, the potential structural and
      functional interactions between these two proteins are the focus of our research.
      To understand the nature of the physical interactions between apoE and Abeta, we
      initially utilized gel-shift assays to demonstrate that native apoE2 and E3
      (associated with lipid particles) form an SDS-stable complex with Abeta that is
      more abundant than the apoE4:Abeta complex. We further demonstrated that
      exogenous apoE3 but not E4 prevents Abeta-induced neurotoxicity by a process that
      requires apoE receptors. In addition, both exogenous apoE3 and E4 prevent Abeta
      induced, glial-mediated inflammation, also via a process that requires apoE
      receptors. These functional effects all occur at a molar ratio of apoE to Abeta
      of 1:30. Because the biological activities for both apoE and Abeta are profoundly
      influenced by their isoform and conformation, respectively, we further
      investigated the idea that apoE3 and E4 differentially interact with particular
      aggregation species of Abeta1-42. Our overall hypothesis is that apoE has two
      general functions in relation to Abeta. First, apoE interacts with oligomeric
      Abeta via an apoE receptor-mediated process to inhibit neurotoxicity and
      neuroinflammation (apoE3 > apoE4) a process possibly related to binding and
      clearance of apoE3:oligomer complexes. Second, apoE facilitates the deposition of
      Abeta as amyloid (apoE4 > apoE3). We will continue to investigate the effect of
      apoE isoform and Abeta conformation on the structural and functional interactions
      between these two proteins in relation to the pathogenesis of AD.

PMID- 15181253
TI  - In vivo effects of ApoE and clusterin on amyloid-beta metabolism and
      neuropathology.
AB  - The epsilon4 allele of apolipoprotein E APOE is a risk factor for Alzheimer's
      disease (AD) and cerebral amyloid angiopathy (CAA), and the epsilon2 allele is
      associated with a decreased risk for AD. There is strong evidence to suggest that
      a major, if not the main, mechanism underlying the link between apoE and both AD
      and CAA is related to the ability of apoE to interact with the amyloid-beta
      (Abeta) peptide and influence its clearance, aggregation, and conformation. In
      addition to a number of in vitro studies supporting this concept, in vivo studies
      with amyloid precursor protein (APP) transgenic mice indicate that apoE and a
      related molecule, clusterin (also called apolipoprotein J), have profound effects
      on the onset of Abeta deposition, as well as the local toxicity associated with
      Abeta deposits both in the brain parenchyma and in cerebral blood vessels. Taken
      together, these studies suggest that altering the expression of apoE and
      clusterin in the brain or the interactions between these molecules and Abeta
      would alter AD pathogenesis and provide new therapeutic avenues for prevention or
      treatment of CAA and AD.

PMID- 15181254
TI  - Apolipoprotein E dose-dependent modulation of beta-amyloid deposition in a
      transgenic mouse model of Alzheimer's disease.
AB  - Susceptibility to the development of Alzheimer's disease (AD) is increased for
      individuals harboring one or more apolipoprotein E4 (apoE4) alleles. Even though
      several isoform-specific effects of apoE have been identified, the relationship
      between biochemical function and risk factor assessment remains unknown. Our
      previous studies have demonstrated that there is an equilibrium between cerebral
      spinal fluid (CSF) and plasma beta-amyloid (Abeta) and that amyloid plaques can
      modify this equilibrium. Trafficking of soluble central nervous system (CNS)
      Abeta is a very dynamic system that almost certainly is modulated by Abeta
      binding proteins. Altered trafficking of the Abeta peptide might have a dramatic
      consequence as to whether the peptide is metabolized or begins to deposit within
      the brain. To gain a better understanding of the molecular mechanisms by which
      apoE influences AD pathogenesis and/or Abeta trafficking, we developed PDAPP
      transgenic mice that express different levels of human apoE3. Analysis of the
      soluble CNS pools of Abeta in young mice showed an apoE3 dose-dependent decrease
      in Abeta levels (E3-/- > E3-/- > E3+/+). In addition to the dose-dependent
      effects on soluble Abeta, by 15 mo of age there were highly significant
      differences in the amount of deposited Abeta between the genotypes (E3-/- > E3-/-
      > E3+/+). These data indicate that apoE3 provides a dose-dependent protective
      effect against Abeta deposition. This study suggests that increasing human apoE
      levels in brain might be a possible therapeutic target for preventing AD.

PMID- 15181255
TI  - Discordance in DXA male reference ranges.
AB  - Previous studies have reported discordance in female lumbar spine and proximal
      femur dual-energy X-ray absorptiometry (DXA) reference ranges. Although the
      NHANES III reference range is recommended for the proximal femur in males and
      females, there are no published data in men on the concordance or otherwise of
      the different manufacturer-specific lumbar spine bone mineral density (BMD)
      reference ranges. Potentially, the use of different reference populations by
      different manufacturers could result in inconsistencies in the diagnosis of
      osteopenia or osteoporosis. We compared lumbar spine BMD, as well as T-scores and
      Z-scores, in 45 men scanned using Lunar DPXL and Norland Excel densitometers. The
      BMD measured by the two instruments was highly correlated (lumbar spine: r =
      0.99, p < 0.0001). However, the two instruments assigned significantly different
      BMD T-scores. These differences relate primarily to the different standard
      deviations employed in the calculations. There were also significant differences
      when BMD was expressed with respect to age-matched values (Z-scores). This study
      shows that in men, as previously demonstrated in women, two commonly used DXA
      instruments provide comparable lumbar spine standardized BMD, but there are
      significant differences in derived T-scores because of differences in the
      manufacturer-specific reference ranges. Standardization of lumbar spine reference
      ranges in men should be a high priority.

PMID- 15181256
TI  - Osteoporosis prevalence in men varies by the normative reference.
AB  - Controversy surrounds which normative data should be used to estimate
      osteoporosis prevalence in men. Prevalence estimates may vary significantly when
      different normative standards are applied. Five normative datasets (NHANES female
      norms, local female norms, Hologic densitometer manufacturer female norms, NHANES
      male norms, Hologic male norms) were used to estimate the prevalence of
      osteoporosis by World Health Organization diagnostic criteria in a study
      population of 311 consecutive men between the age of 30 and 91 (mean 60.3 yr)
      referred to an outpatient osteoporosis center between January 1996 and December
      1998. Statistically significant variations were seen in osteoporosis prevalence
      measured at three anatomical sites. The greatest relative variation was seen for
      the total femur, where osteoporosis prevalence ranged from 7.0% (NHANES and
      Hologic female norms) to 15.6% (NHANES male norms). The least relative variation
      was seen at the lumbar spine, where prevalence ranged from 18.1% (Hologic female
      norms) to 29.6% (local female norms). When considering osteoporosis at any site,
      prevalence was lowest (23.5%) based on Hologic female norms and highest (35.8%)
      based on local female norms. Interpretation of prevalence data should include an
      assessment of how normative standards influence reporting of the population at
      high risk of fracture.

PMID- 15181257
TI  - Identification of men with reduced bone density at the lumbar spine and femoral
      neck using BMD of the os calcis.
AB  - We assessed the utility of os calcis (OC) bone mineral density (BMD) measurements
      to identify men with low BMD at the lumbar spine (LS) and femoral neck (FN). BMD
      was measured by dual X-ray absorptiometry (DXA). Receiver operator
      characteristics (ROC) analysis was applied to determine the risk of osteoporosis
      at the lumbar spine or femoral neck. [A total of 230 men with an average age of
      59 yr were studied.] The most common reasons for referral were fracture (47%) and
      steroid use (46%). Twenty-six percent were osteoporotic at the LS, 21% at the FN,
      and 15% at the OC. Optimal classification with respect to osteoporotic
      measurements at the LS or FN was obtained at an OC T-score of -1.9 (BMD = 0.45
      g/cm2). Osteoporosis was only weakly related to a simple cumulative risk factor
      score, but was strongly related to a T-score OC categorized into quartiles.
      Regression analysis of BMD on the major risk factors alone explained only 17% of
      the variance in BMD at the LS and 5% at the FN. The combination of the T-score at
      the OC, age, and weight provided the best model. BMD OC is superior to risk
      factors alone in the clinical evaluation and selection of men referred for axial
      densitometry.

PMID- 15181258
TI  - Impact of using the ultradistal radius region of interest on diagnostic
      classification.
AB  - World Health Organization (WHO) criteria using T-scores for classifying patients
      as normal, osteopenic, or osteoporotic are based on bone mineral density (BMD,
      g/cm2) of the lumbar spine and hip and bone mineral content (BMC) (BMC, g) at the
      distal and midradius. There is no consensus on whether other forearm regions of
      interest (ROIs) can be used with the WHO criteria. Because the ultradistal radius
      region of interest (UDR) has a greater ratio of trabecular to cortical bone than
      midshaft portions of the radius, it is possible that more patients would be
      classified as osteoporotic if the UDR is measured. The objective of this study
      was to determine the prevalence of osteoporosis when using T-scores from the UDR
      in addition to PA lumbar spine, proximal femur (hip), and the radius 33% ROI.
      Retrospective data were obtained from three centers with differing patient
      demographics, thus reducing bias as a result of patient characteristics. Data
      were used only from patients who had a spine, hip, and forearm scan on the same
      day. Central dual-energy X-ray absorptiometry (DXA) systems included a GE Lunar
      DPX-L, DPX IQ, and Prodigy and a Hologic Delphi. Hologic data were for the
      ultradistal radius + ulna ROI (UDRU). Diagnostic classification (using the WHO T
      score criteria) was made excluding and including the UDR and UDRU T-scores, in
      addition to lumbar spine (L2-L4 or L1-L4), hip (femoral neck, greater trochanter,
      or total), and the radius 33% ROI. The lowest T-score from any ROI determined the
      classification. For all GE Lunar patients (n = 409 women; age range: 20-96 yr),
      the distribution of normal, osteopenic, osteoporotic not using the UDR was 94
      (23%), 170 (42%), and 145 (36%), respectively. The distribution when using the
      UDR was 67 (16%), 137 (33%), and 205 (50%), respectively. The difference in the
      ratio of normal + osteopenic versus osteoporotic when excluding and including the
      UDR T-scores was significant (p < 0.0001; two-tailed Fisher's exact test). For
      all Hologic patients (n = 153 women; age range: 44-93 yr), the distributions were
      32 (21%), 66 (43%), and 55 (36%) not using and 31 (20%), 64 (42%), and 58 (38%),
      respectively, using the UDRU (not statistically significantly different). The
      group mean T-scores were lowest for the UDR compared to the spine and hip with GE
      Lunar but not Hologic patients.

PMID- 15181259
TI  - Image-based micro-finite-element modeling for improved distal radius strength
      diagnosis: moving from bench to bedside.
AB  - Although osteoporosis is characterized by quantitative (mass) and qualitative
      (structural) changes, standard clinical techniques (dual-energy X-ray
      absorptiometry, DXA) only measure the former. Three-dimensional micro-finite
      element (micro-FE) models based on high-resolution images can account for
      structural aspects as well, and it has recently been shown that an improved
      prediction of distal radius strength is possible with micro-FE analysis. A
      clinical application of this technique, however, is limited by its high imaging
      and computational demands. The objective of this study is to investigate if an
      improved prediction of bone strength can be obtained as well when only a small
      part of the radius is used for micro-FE modeling. Images of a 1-cm region of the
      metaphysis of the distal radius of 54 cadaver arms (mean age: 82 +/- 9 SD) made
      with a three-dimensional peripheral quantitative computed tomography (pQCT)
      device at 165- micro m resolution formed the basis for micro-FE models that were
      used to predict the bone failure load. Following imaging, specimens were
      experimentally compressed to failure to produce a Colles'-type fracture. Failure
      loads predicted from micro-FE analyses agreed well with those measured
      experimentally (R2 = 0.66, p < 0.001). Lower correlations were observed with bone
      mass (R2 = 0.48, p < 0.001) and microstructural parameters (R2 = 0.47, p <
      0.001). Hence, even when only a small region is modeled, micro-FE analysis
      provides an improved prediction of radius strength.

PMID- 15181260
TI  - Application of magnetic resonance imaging to evaluation of femoral neck structure
      in growing girls.
AB  - Conventional density measures by dual-energy X-ray absorptiometry (DXA) are
      confounded by increases in bone size and do not assess bone geometry. We assessed
      precision of magnetic resonance imaging (MRI) and used MRI, DXA, and hip
      structure analysis (HSA) to assess 7-mo changes in bone structure at the femoral
      neck in 18 prepubertal girls. At baseline, girls were 10.4 (0.5) yr, 144.0 (8.2)
      cm, and 35.2 (7.0) kg, on average. Total bone and cortical cross-sectional area
      (ToA and CoA) were calculated from high-resolution T1-weighted MRI oblique axial
      images of the femoral neck. We used proximal femur DXA scans (Hologic QDR-4500)
      and the HSA program to estimate bone cross-sectional area (CSA), and calculate
      section modulus. MRI precision was determined by scanning 10 volunteers (13-46 yr
      old) three times with and without repositioning. Precision (CVrms) was 2% for ToA
      and 7% for CoA. Significant correlations were observed between FN area and MRI
      derived ToA (r = 0.57, p = 0.013) and CoA (r = 0.47, p = 0.050). There were
      significant positive changes over 7 mo by both methods. In conclusion, MRI
      provides useful information on femoral neck bone area in children. The
      reproducibility of cortical dimensions at the femoral neck needs improvement
      through technical modifications and appropriate analysis software.

PMID- 15181261
TI  - Multislice computed tomography of the distal radius metaphysis: relationship of
      cortical bone structure with gender, age, osteoporotic status, and mechanical
      competence.
AB  - We explore the relationship of region-specific densitometric and geometry-based
      (cortical) parameters at the distal radial metaphysis with gender, age, and
      osteoporotic status, using multislice computed tomography (CT). We specifically
      test the hypothesis that these parameters can improve the prediction of
      mechanical strength of the distal radius vs bone mass (bone mineral content
      [BMC]). The BMC was determined in 56 forearm specimens with peripheral dual
      energy X-ray absorptiometry (DXA). Trabecular and cortical density and geometric
      properties of the metaphyseal cortex were determined using multislice CT and
      proprietary image analysis software. Specimens were tested to failure in a fall
      simulation, maintaining the integrity of the elbow joint and hand. Women
      displayed significantly lower failure strength (-34%), BMC (-35%), trabecular
      density (-26%), and cortical area (-12%) than men. The reduction of trabecular
      density with age and osteoporotic status was stronger than that of cortical
      density or thickness. DXA explained approx 50% (r2) of the variability in bone
      failure loads. This proportion was slightly increased (55%) when adding geometry
      based parameters. The study suggests that high-resolution tomographic
      measurements with current clinical imaging methodology can marginally improve the
      prediction of mechanical failure strength. Further efforts are required to
      improve spatial resolution for determining metaphyseal cortical properties
      clinically.

PMID- 15181262
TI  - Estimation of femoral head bone density using magnetic resonance imaging:
      comparison between men with and without hip osteoarthritis.
AB  - Bone changes are thought to be one important etiological element in the
      pathogenesis of hip osteoarthritis (OA). The magnetic resonance imaging (MRI)
      derived T2* relaxation time has been shown to provide information about bone
      mineral status of the femoral neck. The aim of this study was to test the
      hypothesis that the MRI-derived T2* relaxation time of the proximal femur in hip
      OA differs from that seen in healthy subjects. Based on the American College of
      Rheumatology criteria regarding classification of the OA of the hip, 27 men (aged
      47-64 yr) with unilateral or bilateral hip OA and 30 age-matched randomly
      selected healthy men were studied. Bone mineral density (BMD), bone mineral
      content (BMC), and bone width of the femoral neck were measured with dual-energy
      X-ray absorptiometry (DXA). Subsequently, T2* measurements were performed with a
      1.5-T scanner (Siemens Magnetom 63SP; Erlangen, Germany). A single 10-mm-thick
      coronal slice was generated on the femur, with a repetition time of 60 ms and
      nine echo times (4-20 ms) to derive T2* values. T2* measurements were performed
      from the different region of interests (ROIs) from the femoral neck and head. T2*
      relaxation times showed significant negative correlations with BMC, BMD (r = 
      0.401 to -0.794; p < 0.05-0.001). T2* relaxation time values revealed no
      significant differences between the groups in the femoral neck and in the head of
      the femur, whereas it was 12% lower (p < 0.01) in OA subjects than in controls in
      acetabulum. There were no significant differences in the T2* relaxation time
      values between the radiographic OA subgroups. Our findings suggest that hip OA is
      not associated with an increase of BMD in the femoral neck or in the head of the
      femur.

PMID- 15181263
TI  - Characteristics of long bone DXA reference data in Hong Kong Chinese.
AB  - With the increasing number of geriatric long bone fractures, the establishment of
      long bone reference BMD data is desirable for the accurate diagnosis of
      osteoporosis, study of fracture mechanics, implant design, and indications for
      augmentation of fracture fixation with biomaterials. We report the normal
      reference bone mineral density (BMD) and bone mineral content (BMC) at three
      femoral sites (proximal, diaphyseal, and distal) in 106 male and 93 female Hong
      Kong Chinese aged 12 to 80, measured with dual-energy X-ray absorptiometry (DXA).
      The length and width of the femur were also measured. The results suggest that
      males reached peak bone mass earlier than females and the value was also higher
      in all measured sites. After reaching the peak bone mass, bones lost BMD faster
      in females. The age-related annual bone loss (in BMD) calculated with a
      regression model in female subjects were, on average, 3.3, 4.0, and 3.0 times
      higher than those in males at the diaphyseal, proximal, and distal regions,
      respectively. The decrease in BMD and BMC occurred slightly earlier in the
      proximal and distal regions than the diaphysis in both sexes. The male femur was
      significantly longer than that of the female in all age groups after 20 yr of age
      and remained unchanged with advancing age. The femoral width in females showed an
      increasing trend from adolescence. Our study provides reference data for the
      changes in diaphyseal BMC and BMD associated with aging. The age-related changes
      in the femoral diameter in females might attenuate the negative impact on
      fracture risk as a result of decreasing BMD with age.

PMID- 15181264
TI  - Ultrasound parameters and markers of bone turnover in hyperthyroidism: a
      longitudinal study.
AB  - Hyperthyroid patients are characterized by accelerated bone turnover leading to
      bone mass loss. The aim of this study was to assess changes in quantitative
      ultrasound [QUS] parameters, bone mineral density (BMD), and biochemical markers
      of bone turnover in patients prior to and after the onset of hyperthyroid
      treatment. A 2-yr longitudinal study was performed on 10 women recently diagnosed
      with Grave's disease after starting antithyroid therapy. Six patients were
      postmenopausal. All patients showed evidence of thyrotoxicosis as indicated by
      suppressed serum TSH and high levels of total serum thyroxine. They received
      antithyroid therapy (methimazole and/or 131I radiodine). QUS parameters were
      measured using an Achilles ultrasound unit and BMD was assessed by dual-energy X
      ray absorptiometry (DXA). Thyroid hormones and markers of bone turnover were
      determined at baseline and 6, 12, and 24 mo after the onset of
      treatment.Stiffness, broadband ultrasound attenuation (BUA), and speed of sound
      (SOS) were low at baseline compared to normal values for the same age range and
      increased after 2 yr of treatment. A significant increase in BMD of the lumbar
      spine, total skeleton, and skeletal regions (legs) was also observed after
      treatment. Recovery of stiffness was almost complete at 12 mo. No significant
      elevation was observed between 12 and 24 mo. Stiffness increased 7.6%, 10.4%, and
      10.4% after 6 mo (p < 0.02), after 1 yr (p < 0.02), and after 2 yr, respectively.
      No significant increase in SOS and BUA was observed between 12 and 24 mo.
      Furthermore, recovery of total skeleton and lumbar spine BMD continued throughout
      the study. Successful antithyroid therapy produced a rapid increase in QUS
      parameters (Stiffness) and spine BMD and femoral neck during the first year of
      treatment and a slower increment in total skeleton (up to 24 mo). Overall, ad
      integrum restitution was not observed in QUS or BMD.

PMID- 15181265
TI  - Accuracy and precision of peripheral quantitative computed tomography
      measurements at the tibial metaphysis.
AB  - The ability of 29 peripheral quantitative computed tomography (pQCT) software
      analysis modes at defining cortical from trabecular bone at three tibial
      metaphyseal regions was evaluated using five cadaveric tibiae. The accuracy of
      pQCT was determined by comparing the bone mineral content (BMC) with the ash
      weight. The precision of the pQCT scanner was calculated using repeated
      measurements. All the analysis modes had a good accuracy when measuring total
      bone area and a poor accuracy when measuring cortical bone area at the proximal
      5% and distal 4% regions. For trabecular bone measured at all three regions and
      cortical bone area measured at the proximal 10% region, the Stratec peel mode 5
      was the most accurate analysis mode. Highly significant correlations (r = 0.71
      0.98) and a moderate accuracy error (coefficient of variation [CV] = 5-22%) was
      found between ash weight and BMC when using this mode. The precision of bone
      mineral density (BMD) measurements was good (total, CV = 2-5%; trabecular, CV = 2
      5%; cortical, CV = 4-6%). pQCT is a moderately accurate, precise method of
      measuring trabecular and total BMD at the tibial metaphysis. The authors
      recommend caution when interpreting results for cortical BMD, as cortical area
      measurements at the metaphyseal region are less accurate and less precise.

PMID- 15181266
TI  - Use of recombinant cytokines for optimized induction of antiviral immunity
      against SIV in the nonhuman primate model of human AIDS.
AB  - Outbreaks of infectious diseases such as HIV and the much televised and attention
      getting outbreaks of diseases such as Ebola, Hantaviruses, and the most recent
      outbreak of SARS have induced a significant new interest in the formulations and
      more importantly the science of vaccinology, which has previously to a large
      extent been conducted empirically. Our laboratory has focused on the use of
      recombinant nonhuman primate cytokines as adjunctive therapies for inducing
      antigen-specific immune responses in monkeys because most recombinant human
      cytokines appear to be immunogenic. This article provides a summary of our work
      with such cytokines, which includes attempts to define optimum dosing schedules
      that lead to optimal primary and lasting memory antigen-specific immune
      responses.

PMID- 15181267
TI  - The expression of HLA-DO (H2-O) in B lymphocytes.
AB  - HLA-DO (H2-O in mice) is a nonpolymorphic transmembrane alphabeta heterodimer
      encoded in the class II region of the major histocompatibility complex (MHC). It
      is expressed selectively in B lymphocytes and thymic medullary epithelial cells.
      DO forms a stable complex with the peptide-loading catalyst HLA-DM in the
      endoplasmic reticulum (ER); in the absence of DM, DO is unstable. During
      intracellular transport and distribution in the endosomal compartments, the ratio
      of DO to DM changes. In primary B cells, only approx 50% of DM molecules are
      associated with DO. DO appears to regulate the peptide-loading function of DM in
      the MHC class II antigen-presentation pathway. Although certain discrepancies are
      present, results from most studies indicate that DO (as well as H2-O) inhibits DM
      (H2-M) function; this inhibition is pH-dependent. As a consequence, DO restrains
      presentation of exogenous antigens delivered through nonreceptor-mediated
      mechanisms; in addition, DO alters the peptide repertoire that is associated with
      cell-surface class II molecules. The biological function of DO remains obscure,
      partially because of the lack of striking phenotypes in the H2-O knockout mice.
      Results from recent studies indicate that DO expression in B cells is dynamic,
      and highly regulated during B-cell development and B-cell activation, suggesting
      that the physiological role of DO is to tailor the antigen presentation function
      of the B-lineage cells to meet their primary function at each stage of B-cell
      development and maturation. Further investigations are needed in this direction.

PMID- 15181269
TI  - Evolution of HLA antibody detection: technology emulating biology.
AB  - New technological advances in the field of histocompatibility have provided an
      approach to systematically address the specificity of positive lymphocyte
      crossmatches. These approaches can now confirm whether a positive crossmatch is
      (or is not) due to class I and/or class II antibodies directed against donor HLA
      antigens. The information gained from the application of these sensitive and
      specific technologies can be used to predict crossmatch results for highly
      sensitized patients. In summary, these emerging technologies have provided the
      tools to reliably determine the clinical relevance of a positive lymphocyte
      crossmatch.

PMID- 15181268
TI  - Defining the parameters necessary for T-cell recognition of ligands that vary in
      potency.
AB  - Identification of the mechanisms by which a T cell is able to sense ligands of
      varying strength, such as those that mediate tumor growth, viral evasion, and
      autoimmunity, is a major goal of T-cell activation studies. In recent years,
      parameters important for T-cell activation by strong ligands (agonists) are
      beginning to be characterized. Here, we review our current work on the factors
      that are critical for T-cell activation by ligands that differ in potency,
      typified by full agonists, weak agonists, partial agonists, and antagonists.
      Furthermore, we discuss mechanisms contributing to the lack of a full range of
      effector functions observed in T cells following their stimulation by suboptimal
      ligands. Finally, we present strategies for the design of peptide-based therapies
      to control activation of polyclonal, autoreactive T-cell populations.

PMID- 15181270
TI  - Intestinal epithelial cell regulation of mucosal inflammation.
AB  - The intestinal epithelium serves as one of human's primary interfaces with the
      outside world. This interface is very heavily colonized with bacteria and yet
      permits absorption of life-sustaining nutrients while protecting the tissues
      below from microbial onslaught. Although the gut epithelium had been classically
      thought to achieve this function primarily by functioning as a passive, albeit
      highly selective, barrier, research over the last decade has demonstrated that in
      fact the epithelium plays a very active role in protecting the host from the
      bacteria that colonize it. As a consequence of its mediation of mucosal immunity,
      intestinal epithelial dysfunction appears to be central to diseases associated
      with aberrant gut mucosal immune responses such as inflammatory bowel disease
      (IBD). This article reviews: (1) how the gut epithelium participates in
      regulating innate immune inflammatory responses to enteric pathogens, (2) how
      these responses may regulate the adaptive immune system, (3) mechanisms that may
      resolve acute inflammation, and (4) how epithelial dysfunction may participate in
      regulating both the active and chronic phases of IBD.

PMID- 15181271
TI  - Tracking dendritic cells in vivo: insights into DC biology and function.
AB  - Dendritic cells (DCs) play a vital role in the generation of immune responses,
      participating both in innate immunity as well as in the initiation of adaptive
      immunity. However, study of this rare cell population in vivo has been hampered
      by their low frequency as well as by inadequate means to track antigen-bearing
      DCs. Our laboratory has developed a novel strategy to genetically tag these DCs
      in the skin, and to monitor their migration from the periphery to the draining
      lymph nodes. These studies have provided new insights into the frequency of DC
      migration, the longevity of DCs in the lymphoid organs, as well as the ability of
      these DCs to function as antigen-presenting cells. Furthermore, the potential
      applications of this technique include the ability to evaluate DC function after
      silencing of specific genes.

PMID- 15181272
TI  - Qa-1, a nonclassical class I histocompatibility molecule with roles in innate and
      adaptive immunity.
AB  - Qa-1, a nonclassical class I histocompatibility molecule expressed in mice,
      predominantly assembles with a single nonameric peptide, Qdm, derived from the
      signal sequence of certain class Ia molecules. The Qa-1/Qdm complex is the
      primary ligand for CD94/NKG2A inhibitory receptors expressed on a major fraction
      of natural killer (NK) cells. Cells become susceptible to killing by NK cells
      under conditions where surface expression of the Qa-1/Qdm inhibitory ligand is
      reduced. The CD94/NKG2 "missing-self" recognition system serves as mechanism for
      removing cells that have abnormalities in the intracellular machinery required
      for assembly and expression of class I-peptides complexes, as a consequence of
      viral infection, for example. Despite its highly focused peptide-binding
      specificity, Qa-1 also has a capacity to act as an antigen-presentation molecule
      for CD8+ T cells. It appears that a small subpopulation of these T cells
      undergoes positive selection by interaction with Qa-1 in the thymus, and they
      maintain their specificity for Qa-1 after maturation. The role of these unusual T
      cells in adaptive immune responses remains to be defined.

PMID- 15181273
TI  - Gammadelta T cells play an essential role in several forms of tolerance.
AB  - Gammadelta T cells were discovered in the mid-1980s, but the antigens they
      recognize and the biological functions they mediate are poorly understood.
      Although gammadelta T cells have the capacity to augment immunity to certain
      infections and kill certain tumor cells, they are generally not required for
      development of antibody responses, for graft rejection, or for development of
      autoimmune diseases. Nevertheless, gammadelta T cells accumulate at sites of
      inflammation induced by infection, tumor growth, and autoimmune lesions, where
      they have been shown to reduce the inflammatory reaction and tissue damage. In
      this review, we summarize the evidence that gammadelta T cells play an important
      role in the induction of various forms of tolerance.

PMID- 15181274
TI  - Ocular immune privilege and CTL tolerance.
AB  - The introduction of antigens into the anterior chamber (AC) of the eye, an immune
      privileged site, induces immune responses that effectively eliminate ocular
      pathogens while minimizing tissue damage that can cause blindness. This
      specialized immune response, termed AC associated immune deviation (ACAID) is
      thought to be an evolutionary compromise to preserve the delicate microanatomy of
      the eye while maintaining ocular immune responses. The injection of soluble
      antigen in the AC of mice results in systemic tolerance characterized by reduced
      priming for antigen-specific delayed-type hypersensitivity (DTH) and cytotoxic T
      lymphocyte (CTL) responses. Similarly, the injection of histo incompatible tumors
      into the AC of mice reduces priming for DTH responses specific to minor antigens.
      However, robust tumor-specific CTL responses are induced systemically following
      this treatment that are capable of eliminating a subsequent injection of the same
      tumors in the skin or the opposite eye. Interestingly, CTL responses induced by
      administration of tumors in the AC fail to eliminate the primary ocular tumor. In
      this review, we compare and contrast CTL responses generated by the injection of
      soluble or tumor-associated antigens in the AC and discuss mechanisms employed to
      induce ocular CTL tolerance.

PMID- 15181275
TI  - Immunity to influenza: the challenges of protecting an aging population.
AB  - Influenza viruses cause annual epidemics and occasional pandemics of acute
      respiratory disease. Improved vaccines that can overcome the decline in immune
      function with aging and/or can induce broader immunity to novel pandemic strains
      are a high priority. To design improved vaccines for the elderly, we need to
      better understand the effects of age on both innate and adaptive immunity. In a
      murine model, we have determined that defects in antigen-presenting cell (APC)
      expression of pattern-recognition molecules, co-stimulatory molecules, and
      cytokine production may play an important role in the reduced clonal expansion of
      T cells in aging. The use of immunomodulators such as adjuvants may overcome some
      of the defects of aging immunity and may also be useful in the development of
      improved vaccines for avian influenza A subtypes that pose a pandemic threat.
      Several novel strategies including the use of ISCOM-formulated vaccines, mucosal
      delivery, or DNA vaccination provided cross-subtype protection that could provide
      an important component of immunity in the event of a pandemic.

PMID- 15181276
TI  - Transcriptional control of thymocyte positive selection.
AB  - Thymocyte development proceeds through multiple regulated checkpoints to ensure
      that the mature T-cell population is useful for recognition of self major
      histocompatibility complex (MHC) molecules, but not overtly autoreactive.
      Developing cells pass the positive selection checkpoint when the T-cell receptor
      (TCR) on immature thymocytes engages self peptide/MHC with low affinity. The
      resulting signal transduction initiates migration, survival, maturation, allelic
      exclusion, and lineage commitment. The changes in gene expression necessary for
      all of these cellular events are controlled by transcription factors responsive
      to signals in immature thymocytes. Recent progress has defined a small group of
      transcription factors that can be clearly linked to regulation of gene expression
      during positive selection.

PMID- 15181277
TI  - Pathogen-host standoff: immunity to polyomavirus infection and neoplasia.
AB  - Polyomaviruses establish persistent infection in a variety of hosts, including
      humans, where they pose an oncogenic threat under conditions of depressed immune
      function. Control of persistent infection by these DNA tumor viruses requires
      continuous immunosurveillance by functionally competent antiviral CD8+ T cells.
      Repetitive antigen encounter by these T cells, however, often leads to their
      deletion or inactivation. Elucidation of the in vivo mechanisms that sustain
      antigen-specific CD8+ T-cell effector activity in the face of persistent antigen
      is essential for devising immunotherapeutic strategies against viral oncogenesis.

PMID- 15181278
TI  - Reflections on CD8 T-cell activation and memory.
AB  - CD8 T cells contribute to clearance and long-term protection following acute
      infection with certain viruses, bacteria, and protozoa, and may play an important
      role in tumor immunity. Primary adaptive CD8 T-cell responses have been
      conceptually divided into four phases: activation, expansion, contraction, and
      memory. We summarize each phase of the response, and discuss recent advances in
      our understanding of the development and maintenance of CD8 T-cell memory.

PMID- 15181280
TI  - Bacterial inhibition of eukaryotic pro-inflammatory pathways.
AB  - Eukaryotic cells perceive and respond to microbes, both pathogenic and commensal,
      by activation of signaling cascades such as the NF-kappaB pathway. Induction of
      such pathways leads to the upregulation of a program of gene expression that
      mediates pro-inflammatory and anti-apoptotic effector proteins. This host
      response is usually effective in clearing or controlling an infection. For
      pathogens (and potentially, symbionts) to continue their lifecycle, it is
      necessary to evade or repress these cellular responses. There has been recent
      interest in bacteria that can inhibit pro-inflammatory pathways, in some cases by
      the actions of soluble effector proteins secreted via a Type III secretion
      system. Certain effector proteins with this function possess enzymatic activity
      toward ubiquitin and related molecules. Ubiquitination is an increasingly
      recognized regulatory modification in eukaryotic cells, and microbial effectors
      that modulate this key host system may have diverse effects on infected cells and
      mediate many aspects of eukaryotic-prokaryotic interactions.

PMID- 15181279
TI  - Insights into the role of host genetic and T-cell factors in resistance to HIV
      transmission from studies of highly HIV-exposed Thais.
AB  - Studies of resistance to HIV-1 transmission are likely to be valuable for the
      design of vaccines and other efforts to prevent HIV. Here, we review the T-cell
      and genetic factors associated with resistance to HIV-1 transmission in studies
      of highly exposed but persistently seronegative (HEPS) women from northern
      Thailand. Women were enrolled in two sex-worker studies and in a discordant
      couple study. We performed Cr51 cytotoxic T lymphocyte (CTL), interferon-gamma
      (IFN-gamma) ELISPOT, and proliferation assays as well as genetic studies,
      including HLA-class I typing. CTL and ELISPOT studies showed a skewing of T-cell
      responses to conserved HIV-1 proteins in HEPS, but not in HIV-1-seropositive
      women. T-cell responses were extremely long-lived in some HEPS women. In the two
      sex-worker studies, HLA-A11 was associated with resistance to HIV-1 transmission.
      These data provide promise for the ability of CTL to control HIV and emphasize
      the importance of developing HIV vaccines that stimulate strong, long-lasting
      Tcell responses.

PMID- 15181281
TI  - Modulating TH1/TH2 responses with microbes, dendritic cells, and pathogen
      recognition receptors.
AB  - The adaptive immune system has evolved different types of immune responses, each
      one effective against a given class of pathogen. For example, Th1 and Th2
      responses represent two qualitatively different types of immune responses that
      are preferentially effective against intracellular microbes and helminths,
      respectively. Since the original description of Th1 and Th2 T-cell clones (1), we
      have learned much about the cytokines that influence the type of Th response.
      Thus, interleukin-4 (IL-4) is known to induce IL-4 production in T cells;
      conversely IL-12 and interferon-gamma (IFN-gamma) are known to induce IFN-gamma
      production by T cells. However, the original sources of these cytokines in vivo
      are less clear. Recent developments from several labs point to a potential role
      for dendritic cells (DCs) in orchestrating this decision making process. Here, we
      present our current view of DC development, and then review the evidence for two
      opposing concepts: (1) that distinct subsets of DCs are predetermined to
      differentially bias the T-helper response; and (2) that microbes and the local
      microenvironment are potent modulators of DC function. Thus, nature appears to
      have evolved different mechanisms to regulate immune responses via DCs.

PMID- 15181282
TI  - Anti-CD137 antibodies in the treatment of autoimmune disease and cancer.
AB  - CD137 (4-1BB), is an inducible T-cell costimulatory receptor and a member of the
      tumor necrosis factor receptor (TNFR) superfamily. It is expressed on activated T
      cells and activated natural killer (NK) cells, but is constitutively expressed on
      a population of splenic dendritic cells (DCs). The natural counter receptor for
      CD137 is 4-1BB ligand, a member of the TNF superfamily that is weakly expressed
      on naive or resting B cells, macrophages, and DCs. Upon activation, the level of
      4-1BBL expression increases on these cells. In T cells CD137-induced signals lead
      to the recruitment of TRAF family members and activation of several kinases,
      including ASK-1, MKK, MAPK3/ MAPK4, p38, and JNK/SAPK. Kinase activation is then
      followed by the activation and nuclear translocation of several transcription
      factors, including ATF-2, Jun, and NF-kappaB. CD137-mediated T-cell costimulation
      as measured by enhanced proliferation and cytokine production can be induced by
      anti-CD137 monoclonal antibodies (MAbs) or by employing immobilized 4-1BB ligand.
      In addition to augmenting suboptimal TCR-induced proliferation, CD137-mediated
      signaling protects T cells, and in particular, CD8+ T cells from activation
      induced cell death (AICD). Although studies with CD137-deficient or 4-1BBL
      deficient mice failed to demonstrate any loss of essential immunological
      function, or other noteworthy deficits, we have found that 4-1BBL-deficient mice
      failed to generate a strong antiviral immune response following lymphocytic
      choriomeningitis virus (LCMV) peptide vaccination. We further found that although
      compromised, the immune response to LCMV vaccination in these mice could be fully
      restored by injecting them with anti-CD137 MAbs at the time of vaccination.
      Finally, we have found that injecting normal mice with anti-CD137 MAbs had
      profound effects on their ability to develop immune responses to allo- and
      autoantigens. The results of these studies discussed in this article provide a
      rationale for assessing the potential use of anti-CD137 MAbs for therapeutic
      purposes.

PMID- 15181283
TI  - Separating antiviral and GVHD activities of donor T cells prior to bone marrow
      transplantation.
AB  - Approaches to speed immune reconstitution following bone marrow transplantation
      (BMT) or peripheral-blood hematopoietic stem-cell transplantation (HSCT) could
      markedly reduce morbidity and mortality, particularly following partially major
      histocompatibility complex (MHC)-matched related donor (PMRD) transplants.
      However, it is critical to simultaneously eliminate the subpopulation of donor T
      cells that are alloreactive with the recipient and may produce graft-vs-host
      disease (GVHD). In this article, we discuss a number of promising cellular
      engineering approaches that could be applied to this problem, including the use
      of veto cells, regulatory T-cell subsets, and psoralen-treated donor lymphocytes.
      Emphasis is placed on whether these approaches can simultaneously transfer broad
      spectrum immunity to the recipient without producing GVHD.

PMID- 15181284
TI  - Functional regulation of human neutrophil Fc gamma receptors.
AB  - Interaction between Fc receptors expressed on phagocytic cells and antibodies
      play a critical role in innate immune response. Interestingly, immune cells such
      as neutrophils, monocytes, and dendritic cells (DCs) express multiple Fc
      receptors for IgG (FcgammaR) with overlapping ligand specificity. These receptors
      compete for the same ligand on the target and are known to transduce positive and
      negative signals to the same cell, depending on presence of type of signaling
      motif in their cytoplasmic domain. Neutrophils, the first line of defense against
      bacterial infection and the major phagocytic cell in the blood, express two types
      of FcgammaRs depending on the species. In humans, the neutrophils co-express
      immunoreceptor tyrosine-based activation motif (ITAM) containing CD32A and
      glycosyl-phosphatidyl inositol (GPI)-anchored CD16B, which is in contrast to co
      expression of ITAM containing CD16A and ITIM containing CD32B in mouse
      neutrophils. Recent studies in gene knockout mice have demonstrated that the
      negative signaling by CD32B plays a critical role in preventing immune complex
      (IC)-mediated autoimmune diseases by regulating the activation signal delivered
      by CD16A. However, it is not known how the function of ITAM signaling CD32A is
      regulated in human neutrophils. Recent observations from our laboratory suggest
      that in human neutrophils, the CD32A receptor is regulated at the ligand-binding
      stage. Using a CD16B-deficient donor, we found that the CD32A expressed on
      resting neutrophils is unable to bind ligand; however, once neutrophils are
      activated with fMLP, a bacterial chemotactic peptide, the CD32A is functionally
      active in binding ligand. We also observed that this regulation is neutrophil
      specific phenomenon. These observations suggest that FcgammaR can be regulated by
      distinct mechanisms and factors such as membrane-anchoring, cell-specific
      signaling, and avidity modulation that may be coordinately involved in regulating
      the function of human FcgammaR. Because neutrophils may be activated during
      infectious and inflammatory diseases, the knowledge of functional regulation of
      FcgammaR will be useful in designing therapies for many autoimmune diseases.

PMID- 15181285
TI  - Cancer vaccine development: protein transfer of membrane-anchored cytokines and
      immunostimulatory molecules.
AB  - Many tumor cells escape host-immune recognition by the downregulation or lack of
      immunostimulatory molecules. Expression of immunostimulatory molecules on tumor
      cells by gene transfer can be used to induce an antitumor immune response.
      However, we have previously shown that protein transfer of glycosyl
      phosphatidylinositol (GPI)-linked costimulatory molecules is a successful
      alternative to traditional gene transfer in preparing such a tumor vaccine.
      Vaccination with membranes modified by protein transfer to express GPI-linked
      B7.1 (CD80), a costimulatory adhesion molecule, induces protective immunity in
      mice and allogeneic antitumor T-cell proliferation in humans in vitro. Our goal
      is to develop an optimal tumor vaccine using tumor membranes modified by protein
      transfer to target and stimulate antigen-presenting cells (APCs) and T cells. We
      have investigated the efficacy of expressing GPI-anchored cytokine molecules on
      the surface of tumor cells. Expression of interleukin-12 (IL-12) on tumor-cell
      membranes in a GPI-anchored form induces a strong antitumor immune response that
      is comparable to the effects of secretory IL-12. Because many cytokines act
      synergistically, we are testing the membrane expression and immunostimulatory
      effects of cytokines individually as well as in combination to determine
      potential complementary effects of coexpression on the antitumor immune response.
      Ultimately, the protein-transfer vaccination may be used in humans alone or in
      multimodal combination therapies to induce tumor regression and to serve as a
      protective measure to prevent postsurgical secondary metastases.

PMID- 15181287
TI  - Cell-cycle dysregulation in the immunopathogenesis of AIDS.
AB  - For a number of years the pathogenesis of AIDS was thought to be essentially
      related to direct human immunodeficiency virus (HIV)-mediated killing of CD4+ T
      cells. More recently, attention has shifted to pathogenic models that emphasize
      the role of generalized immune system activation and the excess apoptosis of
      uninfected T cells in inducing HIV-associated CD4+ T-cell depletion. The main
      focus of our research is to better define the determinants and the consequences
      of these "indirect" mechanisms of immunodeficiency by studying both HIV-infected
      patients and nonhuman primates infected with simian immunodeficiency virus (SIV).
      We have discovered that pathogenic models of retroviral infections of primates
      (i.e., HIV infection in humans and SIV infection in rhesus macaques) are
      associated with the presence of a set of perturbations of normal cell-cycle
      control in T lymphocytes. These perturbations, to which we collectively refer to
      as cell-cycle dysregulation, or CCD, may represent an important biological link
      between chronic immune activation and excess apoptosis and therefore may play a
      significant role in the pathogenesis of AIDS. A better understanding of the
      determinants and consequences of CCD may pave the way for the introduction of new
      therapeutic strategies to be used in addition to standard antiretroviral therapy
      in HIV-infected patients.

PMID- 15181286
TI  - Initiation and resolution of mucosal inflammation.
AB  - Antigens entering the body through the mucosal surface are screened by a highly
      developed immune system comprised not only of traditional lymphoid cells but also
      epithelial cells, fibroblasts, and antigen-presenting cells (APCs). For example,
      in the intestinal tract, gut-associated lymphoid tissue (GALT) is tolerant to the
      approx 400 separate commensal strains residing mainly in the colon, but also
      retains the capacity to detect and remove virulent bacteria before they infect
      systemically. This review summarizes recent work characterizing the molecular
      mechanisms involved in acute and chronic intestinal inflammation. We will also
      describe a natural murine pathogen, Citrobacter rodentium, which is being used to
      explore the host response to enteric pathogens and the resulting immunopathology.

PMID- 15181288
TI  - Reconstructing immunity after allogeneic transplantation.
AB  - A major goal of our research is to reduce the graft-vs-host disease (GVHD)
      activity of allogeneic donor T cells in bone marrow transplantation (BMT), while
      preserving graft-vs-tumor (GVT) effects. Using ex vivo immunosuppressive
      strategies and cell-separation techniques to modulate the graft prior to
      transplantation, we examined the roles of different donor immune cells on GVHD
      and GVT effects in allogeneic mouse models. Our results demonstrate that donor
      memory CD4 T cells facilitate posttransplant immunological reconstitution without
      causing GVHD, whereas transplantation of equal numbers of donor naive CD4 T cells
      leads to fatal GVHD. The initial events of donor T cells interacting with antigen
      presenting cells (APCs) in the transplant recipient appear to be critical to the
      development of GVT, GVHD, or anergy to alloantigens. In the setting of clinical
      BMT, increased numbers of donor type 2 dendritic cells (DCs) were associated with
      an increased rate of posttransplant relapse, and decreased rates of chronic GVHD.
      In a mouse transplant model, manipulation of the DC content of bone marrow grafts
      was achieved by depletion of CD11b+ cells. Mice transplanted with CD11b- depleted
      marrow showed enhanced posttransplant expansion of memory T cells with markedly
      improved GVT activity and limited GVHD compared to recipients of unmanipulated
      marrow. A model that differentiates GVT from GVHD based on interaction of T-cell
      subsets with DC subsets is proposed.

PMID- 15181289
TI  - Chemokine receptors and leukocyte trafficking in the mucosal immune system.
AB  - The CC chemokine receptors CCR6, CCR9, and CCR10 all contribute to the
      positioning of leukocytes at mucosal locations. Mucosal epithelial cells are
      major sources of the chemokine ligands for each of these receptors, although the
      pattern of expression of the individual ligands differs at distinct mucosal
      sites. CCR6 is expressed by most B cells, subsets of CD4 and CD8 memory T cells,
      and subsets of dendritic cells (DCs). Absence of CCR6 in mice leads to abnormal
      expansion of intestinal intraepithelial T cells and lamina propria T cells,
      smaller Peyer's patches, and defects in IgA-mediated responses to oral antigens
      and pathogens. CCR9 is present on thymocytes, most intestinal intraepithelial
      lymphocytes, and other types of intestine-homing T cells. CCR10 is found on skin
      homing T cells and also directs IgA-producing plasma cells into mucosal sites.
      This review discusses the role of these chemokine receptors in homeostatic
      regulation of the mucosal immune system.

PMID- 15181292
TI  - Pre-school education.

PMID- 15181291
TI  - Identification and characterization of CD8+ suppressor T cells.
AB  - It has long been appreciated that certain subsets of T cells are capable of
      suppressing immune reactions. Initially, such T cells were described as CD8+
      suppressor T cells (Ts) and there is a vast body of research spanning 30 years
      that describes the immunobiology of CD8+ Ts. However, studies on CD8+ Ts have
      suffered from the inability to distinguish CD8+ Ts from CD8+ T cells of other
      phenotypes. Here we present a brief history of CD8+ Ts, a review of recent
      progress distinguishing CD8+ Ts as a unique subset of CD8+ T cells, and an
      overview of the evolving immunological context in which CD8+ Ts function.

PMID- 15181293
TI  - The role of zinc in child health in developing countries: taking the science
      where it matters.

PMID- 15181290
TI  - The role of gamma/delta T cells in immunity to infection and regulation of
      inflammation.
AB  - The role of gamma/delta T cells in immunity to bacterial infection and control of
      inflammation is discussed. Special emphasis is placed on the use of murine models
      in which various aspects of immune function can be monitored in the absence of
      gamma/delta T cells. Issues discussed include the response to and control of
      cytokine production by gamma/delta T cells. Especially relevant is the apparent
      paradox that gamma/delta T cells play both pro-inflammatory and antiinflammatory
      roles in response to infection.

PMID- 15181294
TI  - Slow versus fast enteral feed advancement in very low birth weight infants: a
      randomized control trial.
AB  - OBJECTIVE: To evaluate the tolerance of rapid advancement of enteral feeds in
      VLBW babies. SETTING: Tertiary teaching hospital. DESIGN: Randomized controlled
      trial. METHODS: All stable neonates with birth weight less than 1250 grams were
      included in the study. The primary outcome variable was the time taken to achieve
      full enteral feeds (defined as 180 ml/kg/day). The secondary outcome variables
      were incidence of Necrotizing enterocolitis (NNEC) and incidence of apnea. At 48
      hours, the infants were randomized into the slow advancement group (enteral feeds
      advanced by increments of 15 ml/kg/day) or fast advancement group (enteral feeds
      advanced by increments of 30 ml/kg/day). The monitoring during feeding included
      daily weight record, two hourly abdominal girth charting, gastric aspirates,
      apnea, time taken to reach full enteral feedings and for NNEC. RESULTS: There
      were 53 infants who were enrolled for the study (27 in the fast advancement group
      and 26 in the slow advancement group). In the fast advancement group, 20 percent
      completed the trial; whereas 14 (53.8 percent;) in the slow advancement group
      completed the study. The two groups were comparable for birth weights,
      gestational age, sex, intrauterine growth status, Apgar and CRIB scores. The
      infants in the fast group reached full enteral intake of 180 ml/kg/day
      significantly earlier (10 +/- 1.8 days) than in the slow group (14.8 +/- 1.5
      days). The two groups were comparable for episodes of feed intolerance, apnea,
      NNEC. Infants in the fast group regained birth weight significantly earlier
      (median 18 days) than in the slow advancement group (median 23 days).
      CONCLUSIONS: Stable VLBW neonates can tolerate rapid advancements of enteral
      feeding without increased risk of adverse effects.

PMID- 15181295
TI  - IAP National Task Force for Childhood Prevention of Adult Diseases: insulin
      resistance and Type 2 diabetes mellitus in childhood.
AB  - Type 2 diabetes mellitus (DM) has traditionally been considered a disease of
      adults. However, in the last 2 decades, it is increasingly being reported in
      children and adolescents. Obesity is a strong correlate, and the increasing
      prevalence of obesity and poor physical activity is precipitating type 2 DM at
      younger ages in the ethnic groups at risk. Indians and other South Asians are
      among the ethnic groups particularly prone to insulin resistance and type 2 DM,
      the other racial groups being some American Indian tribes like the Pima Indians,
      Mexican Americans,Pacific Islanders and African Americans,among others. The WHO
      has predicted that India will have the greatest number of diabetic individuals in
      the world by the year 2025. Type 2 DM starting during adolescence puts the
      individual at risk for major morbidity and even mortality right during the
      productive years of life. The microvascular complications of DM (nephropathy,
      retinopathy, neuropathy) are brought on at an early age. In addition, type 2 DM
      and obesity are two components of a metabolic syndrome of insulin resistance, the
      other features of which include hypertension, dyslipidemia and hypercoagulability
      of blood. All these conditions together increase the risk for cardiovascular and
      cerebrovascular mortality and morbidity (i.e., myocardial infarction and stroke).
      The resulting economic burden will be enormous. Type 2 DM and the insulin
      resistance syndrome are to a large extent preventable. Adoption of a healthy
      eating and physical activity pattern has resulted in decreasing the development
      of DM in a few recent studies from various parts of the world. A concerted,multi
      pronged effort is needed, involving the general public, pediatricians and general
      physicians, teachers and schools, the media,the government and professional
      medical bodies, to generate a momentum towards the goal of prevention of type 2
      DM and the insulin resistance syndrome in the young population of India.

PMID- 15181296
TI  - Continuous positive airway pressure - a gentler approach to ventilation.
AB  - Continuous positive airway pressure (CPAP) has become a useful modality in
      management of respiratory distress, especially in preterm babies. Main
      indications for use of CPAP are respiratory distress syndrome (RDS) and apnea of
      prematurity. It decreases the need of invasive and costly mechanical ventilation.
      This review details the physiological effects of CPAP, its methods of delivery,
      and its need in a country like India. It also describes the guidelines for
      initiating and weaning CPAP. The review concludes that use of CPAP in respiratory
      distress syndrome is associated with lower rates of failed treatment, decreased
      incidence of chronic lung disease and lower overall mortality, specially in
      infants with birth weight above 1500 grams. Early use of CPAP is more beneficial,
      Surfactant and CPAP act in conjunction for babies with RDS. CPAP is a low-cost,
      simple and noninvasive option for a country like India, where most places lack
      facilities of mechanical ventilation. Systematic reviews, randomized and quasi
      randomized trials by searching MEDLINE and the Cochrane Library formed the basis
      of this update.

PMID- 15181297
TI  - Differentiation of Fanconi anemia from idiopathic aplastic anemia by induced
      chromosomal breakage study using mitomycin-C (MMC).
AB  - This study was conducted to differentiate between Fanconi anemia (FA) and
      "idiopathic" aplastic anemia on the basis of induced chromosomal breakage study
      with mitomycin C (MMC). MMC-stress test was conducted on peripheral blood
      lymphocytes from 29 patients with aplastic anemia. Ten patients with very high
      percentage of chromosomal breakage and four patients exhibiting somatic mosaicism
      were diagnosed as FA on the basis of chromosomal breakage study. Six of these
      patients exhibited congenital anomalies at presentation while another eight
      lacked such anomalies or had minor physical problems. The present study
      illustrates that MMC stress test provides an unequivocal means of differentiation
      between Fanconi anemia and 'idiopathic' aplastic anemia. Further, the study,
      first of its kind from India, stresses on the need for conducting this test in
      all aplastic anemia cases, even those without congenital anomalies, for accurate
      and timely diagnosis of Fanconi anemia to implement appropriate therapy.

PMID- 15181298
TI  - Zinc status in well nourished Bangladeshi children suffering from acute lower
      respiratory infection.
AB  - This study was done to investigate the association of zinc status of well
      nourished Bangladeshi children with Acute Lower Respiratory Infection (ALRI). In
      this case control study, simultaneous estimation of serum and hair zinc was
      performed in 35 well nourished children, aged 6-60 months suffering from ALRI and
      38 normal matched controls. Serum zinc was low in children suffering from ALRI as
      compared to control (90 +/- 51 pg/dL vs 176 +/- 98 pg/dL, OR: 6, 95% CI: 1.83,
      19.66;P <0.05) children. Hair zinc was also found significantly low in children
      suffering from ALRI as compared to control (158 + 48 1g/g vs 247 154 pg/g, OR: 3,
      95% CI: 1.46, 10.04, P < 0.05). We conclude that Bangladeshi children suffering
      from pneumonia, have decreased levels of serum and hair zinc.

PMID- 15181299
TI  - Amitraz poisoning: clinical and laboratory findings.
AB  - Amitraz is an insecticide/acaricide of formamidine pesticides used worldwide to
      control ectoparasites in animals. Amitraz poisoning is a rare disorder
      characterized by central nervous system (CNS) and respiratory depression,
      bradycardia, hypotension, hypothermia, hyperglycemia,nausea and vomiting.
      Poisoning may occur either by oral inhalation and dermal route. In this study, we
      present seven pediatric patients with amitraz poisoning. The initial symptoms
      were unconsciousness, dizziness and vomiting; and emerged within 30-150 minutes.
      The length of stay in the intensive care unit (ICU) was between 18-62 hours.

PMID- 15181300
TI  - Blood zinc levels in children hospitalized with severe pneumonia: a case control
      study.
AB  - A case control study was conducted in a referral and teaching hospital in North
      India on children aged 2 months to 5 years, to compare blood zinc levels in 50
      cases of severe pneumonia and 50 age,sex and nutritional status matched controls.
      Mean blood Zinc levels in cases and controls was 376.1 ug/dL + 225.73 and 538.52
      microg/dL +/- 228.0 respectively ( P value 0.0003). In logistic regression model
      severe pneumonia was associated with lower blood zinc level, use of biomass fuel
      and isolation of H. Influenzae from nasopharyngeal swab. Cotrimoxazole resistant
      S. pneumoniae were isolated from 95% of cases and 41.2 % of controls (P = 0.
      0004). Therefore, the role of zinc in treatment of severe pneumonia should be
      investigated.

PMID- 15181301
TI  - Near-triploid acute lymphoblastic leukemia with TEL/AML1 translocation.
AB  - An 11-year-old girl was diagnosed as B-precursor acute lymphoblastic leukemia
      (ALL) with co-expression of myeloid antigens. Cytogenetic analysis revealed a
      near-triploid (75-82 chromosomes/cell) abnormal chromosomal complement.
      Fluroscent in situ hybridization studies indicated presence of TEL/AMLI fusion
      genes. We discuss the prognostic relevance of TEL/AML1 in this rare near-triploid
      subtype of ALL.

PMID- 15181302
TI  - Moyamoya syndrome.
AB  - We report a new association of coloboma of the iris and optic disc and eczema of
      the skin in child who developed stroke due to Moyamoya syndrome.

PMID- 15181303
TI  - Opsoclonus myoclonus syndrome: response to plasmapheresis.
AB  - An 18-month-old with idiopathic opsomyoclonus, refractory to therapy with ACTH,
      corticosteroids, and clonazepam received plasmapheresis along with oral
      corticosteroids and azathioprine. The subject improved dramatically following
      this treatment. Anticerebellar antibodies were detected from the plasma in this
      patient and in a two and a half year-old girl with cerebellar ataxia secondary to
      an adrenal ganglioneuroma.

PMID- 15181304
TI  - Intractable psychogenic sneezing: two case reports.
AB  - Sneezing is usually the physiologic response to nasal irritation but intractable
      paroxysmal sneezing is very uncommon. Majority of cases of intractable sneezing
      are reported among adolescents and are psychogenic in origin. We report two
      adolescent girls with intractable paroxysmal sneezing in whom the removal of
      psychogenic stressors resulted incomplete remission.

PMID- 15181305
TI  - Pneumococcal subdural empyema in young infants.
AB  - We report three young infants including a neonate with fulminant pneumococcal
      subdural effusion.

PMID- 15181306
TI  - Neonatal lupus erythematosus.

PMID- 15181307
TI  - Fourniers gangrene.

PMID- 15181308
TI  - Smith-Lemli-Opitz syndrome.

PMID- 15181309
TI  - Basal and stimulated growth hormone levels in children with cirrhotic disorders.

PMID- 15181310
TI  - Association of clomiphene with iniencephaly.

PMID- 15181311
TI  - Survey of school health and absenteeism in Lucknow.

PMID- 15181312
TI  - Bedside clue to bilateral partial nasal obstruction in a neonate.

PMID- 15181313
TI  - Partial glossectomy for lingual edema following injury.

PMID- 15181316
TI  - Treatment of neonatal candidiasis with liposomal amphotericin B.

PMID- 15181314
TI  - Artemether in children with severe Malaria.

PMID- 15181320
TI  - Defining the mandate of tuberculosis research in a postgenomic era.
AB  - The identification of Mycobacterium tuberculosis by Robert Koch in 1882 as the
      causative agent of tuberculosis, the release of the drug rifampicin in 1970 and
      the sequencing of the M. tuberculosis genome in 1998 are three major events that
      have revolutionized tuberculosis research. In spite of these breakthroughs, the
      continued status of tuberculosis as the largest killer amongst infectious
      diseases is an issue of major concern. Although directly observed short course
      chemotherapy exists to treat the disease, the emergence of drug-resistant strains
      has severely threatened the efficacy of the treatment. The recent sequencing of
      the M. tuberculosis genome holds promise for the development of new vaccines and
      the design of new drugs. This is all the more possible when the information from
      the genome sequence is combined with proteomics and structural and functional
      genomics. Such an integrated approach has led to the birth of a new field of
      research christened 'postgenomics' that holds substantial promise for the
      identification of novel drug targets and the potential to aid the development of
      new chemotherapeutic compounds to treat tuberculosis. The challenge before the
      scientific community therefore lies in elucidation of the wealth of information
      provided by the genome sequence and its translation into the design of novel
      therapies for the disease. All the major developments in the field of
      tuberculosis research after the sequencing of the M. tuberculosis genome will be
      discussed in this review.

PMID- 15181321
TI  - Selenium in the treatment of head and neck lymphedema.
AB  - OBJECTIVE: To investigate the impact of selenium in the treatment of lymphedema
      of the head and neck region after radiotherapy alone or in combination with
      surgery. SUBJECTS AND MATERIALS: Between June 1996 and June 2001 a total of 36
      cancer patients (29 male, 7 female; median age 61 years) were treated with
      selenium for persistent, extensive or progressive lymphedema of the head and neck
      region. Twenty had interstitial endolaryngeal edema associated with stridor and
      dyspnea. All patients received 350 microg/m(2) body surface sodium selenite
      medication p.o. daily (total dose 50 microg per day) for a period of 4-6 weeks
      after radiotherapy. The optimal effect of the selenium treatment was assessed
      after 4 weeks of therapy using the Miller score system. A visual analogue scale
      on a scale of 0-10 was used to assess the patient's quality of life prior to and
      after selenium. RESULTS: 75% of the patients had an improvement of the Miller
      score of one stage or more. The self-assessment of quality of life using the
      visual analogue scale improved significantly after selenium treatment with a
      reduction of 4.4 points (p < 0.05). Of the 20 patients with endolaryngeal edema
      tracheostomy was not necessary in 13 patients (65%), but 5 and 2 received a
      temporary or permanent tracheostomy, respectively. No episode of erysipelas was
      observed in all study patients. CONCLUSION: Our results suggest a short positive
      effect of sodium selenite on secondary head and neck lymphedema caused by
      radiotherapy alone or in combination with surgery.

PMID- 15181322
TI  - The bacteriology of the supragingival plaque of child dental patients in Kuwait.
AB  - OBJECTIVE: To investigate the bacterial flora of the gingival plaques of
      pediatric dental patients in order to establish baseline data for future studies
      on the complex microbiota of the oral cavity of this group of child dental
      patients. SUBJECTS AND METHODS: Forty subjects, aged 3-12 years, were enrolled
      and investigated after informed consent was obtained. During the patients' first
      visit to the dental clinic supragingival plaque samples were collected from the
      gingival area of buccal and lingual tooth surfaces of all primary and permanent
      molar teeth using sterile curettes. Serially diluted samples were inoculated onto
      a set of selective and nonselective media and then incubated at the appropriate
      atmospheric conditions and temperatures. Representative colonies of isolates were
      identified by standard methods, including hemolytic characteristics on blood agar
      and profiling on API 20S and API 20A as appropriate. RESULTS: A total of 183
      isolates (123 aerobes and 60 anaerobes) were recovered from the 40 patients with
      a mean count of 3 per sample of aerobes compared to 1.5 per sample for the
      anaerobes. Streptococcus sanguis was the predominant aerobic species (23.6%)
      isolated from 29 (72.5%) of the 40 patients, followed by Streptococcus mitis,
      19.5 and 60%, Streptococcus salivarius, 17.1 and 52.5% and Streptococcus mutans,
      17.1 and 52.5%. The frequency of isolation of anaerobic bacteria was Prevotella
      spp. 50% from 30 (75%) of the 40 patients, Fusobacterium spp., 18.3 and 27.5%,
      Bacteroides spp., Porphyromonas spp. and Peptostreptococcus spp., 6.7 and 10%,
      6.7 and 10%, and 5 and 7.5%, respectively. Prevotella intermedia was the single
      most common species. CONCLUSION: The results show that there were more
      aerobic/facultative anaerobic bacteria than the obligate anaerobes in the dental
      plaque of the pediatric dental patients in Kuwait. The high prevalence of the
      pioneering streptococci as well as black-pigmented Prevotella spp. and
      Fusobacterium spp. indicates that the dental plaques of the children were in the
      developing stage, a precursor to the development of periodontal diseases.

PMID- 15181324
TI  - Hodgkin's disease: Kuwait experience.
AB  - OBJECTIVE: To describe histologic subtypes, clinical presentation and treatment
      outcome of Hodgkin's lymphoma in Kuwait. SUBJECTS AND METHOD: Patients older than
      15 years, diagnosed with Hodgkin's lymphoma between 1980 and 1998, were included
      in this retrospective analysis. Data were collected using a standardized form
      that included demographics, histologic subtypes, clinical presentation, stage,
      extranodal involvement, treatment modality and follow-up. Histology reports were
      obtained from hospital records. RESULTS: There were 83 (59%) males and 57 (41%)
      females. Dominant histologic subtypes were nodular sclerosis 65 (46.4%) and mixed
      cellularity 42 (30%). Constitutional symptoms were reported by 54 (38.6%) of the
      cases. Two thirds (64%) of the cases were advanced. Primary extranodular
      involvement included liver (8%), gastrointestinal tract (7%), lung and bone
      marrow (4% each). Disease-free survival according to treatment groups were:
      radiotherapy alone 100%, chemotherapy alone 88%, and combined modality 65%. The 5
      year Kaplan-Meier estimates of overall disease-free survival was 84%. CONCLUSION:
      In the cohort of 137 patients with Hodgkin's disease the treatment with combined
      radiotherapy and chemotherapy had a remarkable outcome. However, evaluation of
      long-term treatment complications is needed.

PMID- 15181323
TI  - Role of iodine-131 MIBG scanning in the management of paediatric patients with
      neuroblastoma.
AB  - OBJECTIVES: To evaluate the role of iodine-131 metoiodobenzylguanidine (iodine
      131 MIBG) scanning in the management of paediatric patients with neuroblastoma.
      SUBJECTS AND METHODS: Forty-three iodine-131 MIBG scans were performed on 26
      children, 18 male and 8 female, ranging in age from 8 months to 11 years. Bone
      scan, computed tomography (CT) images and findings of bone marrow biopsy were
      compared with the iodine-131 MIBG scan findings. RESULTS: Of the 26 patients, 18
      (69%) showed abnormal iodine-131 MIBG avidity and were proven to have a neural
      crest tumour on histology. The remaining 8 (31%) patients had normal iodine-131
      MIBG scans, and histology showed a malignancy other than a neural crest tumour.
      Iodine-131 MIBG scans showed the primary site in 16 of 17 patients while CT
      showed 14 primary sites. In follow-up studies, the results were as follows:
      iodine-131 MIBG showed no evidence of disease in 4 compared with 3 on CT,
      persistent disease in 2 on iodine-131 MIBG and 4 on CT; recurrence in 1 on iodine
      131 MIBG and 0 on CT; MIBG scans detected double the number of bony lesions
      compared with bone scans. The findings on iodine-131 MIBG scans and bone marrow
      biopsy were in agreement in 16/18 cases. Patients in whom iodine-131 MIBG scans
      showed disease resolution had better clinical outcomes. CONCLUSION: The findings
      indicate that iodine-131 MIBG scanning is useful for the diagnosis, staging,
      evaluation of response to therapy and detection of recurrences in patients with
      neuroblastoma. It exhibited a clear advantage over CT in detecting the primary
      site and soft issue metastases and was also superior to bone scanning in
      detecting skeletal metastases. It also reliably demonstrated bone marrow
      involvement.

PMID- 15181325
TI  - Radioanatomical measurements of the medullary cavity of the humerus in Kuwait:
      ethnic differences and clinical implications for fracture fixation.
AB  - OBJECTIVE: To compare the difference in diameter of the medullary cavity of the
      humerus in Arab and South Asian patients in Kuwait. SUBJECTS AND METHODS: In 46
      patients (29 Arab, 17 South Asian) treated at Al-Razi Hospital, Kuwait, for
      diaphyseal fracture of the humerus, the medullary cavity of the humerus on the
      radiographs of the uninjured (contralateral side) was examined. Bone density was
      also measured. Statistical significance was calculated by parametric and
      nonparametric test using SPSS package. RESULTS: South Asians had a significantly
      narrower medullary cavity (p < 0.05) and higher cortical indices (p < 0.05) than
      Arabs, and also a narrower external diameter of the humerus at levels 5 and 6 (p
      < 0.05). CONCLUSION: In cases of fracture of the humerus, radiographic
      measurements of the diameter of the medullary cavity of the uninjured side were
      essential in selecting the appropriate fixation device.

PMID- 15181326
TI  - Time course from first symptom to the treatment of lung cancer in the Eastern
      Black Sea Region of Turkey.
AB  - OBJECTIVES: To determine the delay between the onset and the diagnosis and
      treatment of patients with lung cancer in two cancer centres in the Eastern Black
      Sea Region of Turkey. SUBJECTS AND METHODS: The records of 226 patients (217
      males, 9 females) were evaluated retrospectively for the dates noted for the
      onset of symptoms, first presentation to a physician, histopathological diagnosis
      and start of treatment. The median time intervals from the appearance of the
      first symptom to definitive diagnosis and treatment were calculated. RESULTS: The
      patients presented to their physicians 30 (range 2-365) days after their
      complaints began. The time that elapsed between admission and histopathological
      diagnosis and between the diagnosis and initiation of therapy were 8 (range 1
      210) and 17.5 days (range 0-206), respectively. The median time span from
      presentation to treatment was 30 days (range 1-253). There were no significant
      time interval differences between onset of symptoms and first presentation and
      the subsequent diagnostic and therapeutic processes for histopathology, stage of
      the tumour and treatment procedures (p > 0.05). CONCLUSION: Reasons for the
      delayed treatment of lung cancer patients were late presentation to the physician
      and the long time interval between tissue diagnosis and treatment. This delay was
      mostly associated with a large number of patients and delayed appointments for
      imaging procedures--the result of organisational problems within the health
      services of Turkey.

PMID- 15181327
TI  - Seroepidemiological and microbiological study of brucellosis in Kuwait.
AB  - OBJECTIVE: The primary objective of the study was to determine the prevalence of
      brucellosis and the antimicrobial susceptibility pattern of local Brucellae
      isolates in the Infectious Diseases Hospital, Kuwait. SUBJECTS AND METHODS: A
      single serum sample was collected from each of 1,836 patients of different
      nationalities from January 2000 to December 2001. Any patient with a provisional
      diagnosis of fever or brucellosis had a standard tube agglutination (STA) test
      for the quantitation of Brucella antibodies. Blood cultures were done in 166 of
      455 patients with significant STA titers, using the Bactec system. Antimicrobial
      susceptibility testing of 123 isolates of Brucella spp. was done against 8
      antimicrobial agents. RESULTS: A total of 455 serum samples (24.8%) having an STA
      titer of > or =1:160 were presumptively diagnosed as cases of brucellosis. The
      peak isolation was in April and May. Brucella spp. were isolated from 123 blood
      cultures (74.1%). The blood culture isolation rate was significantly higher in
      patients with an STA titer of >/=1:1,280 than in those with an STA titer of
      </=1:160 (p < 0.05). Antimicrobial susceptibility testing showed good in vitro
      activity of tetracycline, gentamicin, amikacin, streptomycin and ciprofloxacin
      against all isolates. Azithromycin had good anti-Brucella activity against only
      42% of the isolates, while rifampicin and trimethoprim-sulfamethoxazole showed
      low in vitro anti-Brucella activity against 8 and 25% of the isolates,
      respectively. CONCLUSION: Brucellosis is quite common in Kuwait. Kuwaiti and
      Bangladeshi nationals were most affected. Significant titers on the STA test were
      detected in 24.8% of serum samples. Good in vitro activity against all isolates
      was found with tetracycline, gentamicin, amikacin, ciprofloxacin and
      streptomycin, and low activity with azithromycin, rifampicin and trimethoprim
      sulfamethoxazole.

PMID- 15181328
TI  - Estrogen receptor profiles: changes in mouse and rat mammary tumors by treatment
      with selective estrogen receptor modifiers.
AB  - OBJECTIVE: The aim of this work was to analyze the effect of estradiol (E(2)),
      medroxyprogesterone and the two selective estrogen receptor modulators (SERMs)
      (tamoxifen (Tam) and raloxifene (Ral)) on the estrogen receptor (ER) conformers
      profile performed by size exclusion HPLC in relation to hormone dependence of
      mammary tumors. MATERIALS AND METHODS: Two types of mammary tumors were studied:
      tumors transplanted in BALB/c mice that are medroxyprogesterone acetate (MPA)
      dependent for growth, and tumors induced in Sprague-Dawley rats by
      intraperitoneal injection of N-nitroso-N-methylurea (NMU). Tumors from mice
      treated with MPA, E(2), Tam or Ral and NMU-treated rats were analyzed and
      compared to that of control. RESULTS: The tumor conformer profiles were as
      follows: control and MPA-treated mice showed only one peak (oligomeric form);
      E(2)-treated mice also showed only one peak (dimer); Tam-treated mice showed one
      peak corresponding to a possible proteolytic fragment, and Ral-treated mice
      showed two peaks (oligomeric and a possible proteolytic fragment). On the other
      hand, NMU-induced mammary tumors from rats showed three peaks (oligomeric,
      monomeric and proteolytic). CONCLUSION: Our findings may indicate that SERMs
      affect the aggregation state of ER and thereby its ability to modulate genomic
      transcription mechanisms related to growth rate.

PMID- 15181329
TI  - Benign acute childhood myositis.
AB  - OBJECTIVE: To evaluate the clinical and laboratory findings of benign acute
      childhood myositis. SUBJECTS AND METHODS: Six children, 1 girl and 5 boys, aged 3
      9 years, were admitted to Karadeniz Technical University Paediatric Neurology
      Department in Trabzon, Turkey, with the diagnosis of benign acute childhood
      myositis in January and February 2002. The clinical and laboratory findings on
      the patients were analysed. RESULTS: Serum creatine kinase and aspartate
      aminotransferase levels were increased in all cases. Two patients had leucopenia.
      Viral studies were negative. All the patients had a good outcome, and full
      recovery was achieved within 12 h to 3 days. CONCLUSION: Benign acute childhood
      myositis is a self-limiting disease with a good prognosis. Pediatricians and
      pediatric neurologists must be aware of this condition to avoid unnecessary
      investigations and to differentiate this condition from other causes of acute
      onset of inability to walk. It may occur in epidemics mainly in the wintertime,
      suggesting a viral aetiology.

PMID- 15181330
TI  - Vascular injuries caused by orthopaedic screws. A case report.
AB  - OBJECTIVE: To describe 3 cases of vascular injuries due to orthopaedic
      procedures. CLINICAL PRESENTATION AND INTERVENTION: Of 242 vascular injuries, 3
      were due to orthopaedic screws. The 1st patient presented with a late
      complication (after 3 years) of an orthopaedic screw placed in close proximity to
      the axillary artery that with time got eroded and leaked to form a false aneurysm
      which later caused embolisation to the arm and limb ischaemia. The 2nd and 3rd
      cases were due acute ischaemia following the orthopaedic procedures. Both were
      injuries to the popliteal artery, one after a long screw and the other after
      drilling the tibia. The aneurysm of the 1st case was resected, the screw was
      removed and a reversed segment of the right long saphenous vein was used to
      repair the axillary artery. In the 2nd patient, a bypass of the left popliteal
      artery to the tibio-peroneal trunk was performed using a reversed 12-cm-long
      saphenous vein graft retrieved from the right thigh. In the 3rd patient, the
      right popliteal vein was ligated, and a reversed 25-cm-long saphenous vein graft
      retrieved from the left thigh was used for a femoro-popliteal bypass. For the 3
      patients, postoperative recovery was unremarkable. Pulses were present within 6
      10 months of follow-up. CONCLUSIONS: Whenever limb vascularity is compromised
      after an orthopaedic procedure, a high index of suspicion for an arterial injury
      should be exercised and prompt referral to the vascular service is mandatory.
      Repair of injured vessels with a saphenous vein graft provides excellent long
      term results.

PMID- 15181331
TI  - Giant cell arteritis of the breast.
AB  - OBJECTIVE: To report a rare case of giant cell arteritis of the breast in a 56
      year-old woman. CLINICAL PRESENTATION AND INTERVENTION: The patient presented
      with tenderness in the upper outer quadrant of the left breast, in the absence of
      any constitutional symptoms. A diagnosis of giant cell arteritis was made only
      after surgical wedge excision of the affected breast quadrant. She returned 6
      weeks later with tenderness in the upper inner medial quadrant of the same
      breast, with a raised erythrocyte sedimentation rate. She has since been referred
      to the rheumatologist for further management. CONCLUSION: The diagnosis of giant
      cell arteritis of the breast was made only after pathological examination of the
      excised breast tissue. This study focused attention on the need to be aware of
      systemic conditions that may present as localised lesions of the breast and to
      maintain a high index of clinical suspicion in order to adequately investigate
      them and perhaps avoid unnecessary radical surgical intervention such as
      mastectomy.

PMID- 15181332
TI  - Prevalence and distribution of root caries in Pomerania, North-East Germany.
AB  - The aim of this study was to assess the prevalence and distribution of root
      caries in the adult population of Pomerania, Germany. The study sample comprised
      6,267 randomly selected subjects who were scheduled for examination from 1997 to
      2001 (population-based cross-sectional study, response rate: 69%, age range 20-79
      years). 499 edentulous persons were excluded from the dental examination (12%)
      performed according to WHO guidelines (1997). In the statistical analysis,
      frequency distributions, means and median values were calculated and subdivided
      for different age groups. The percentage of exposed and affected root surfaces
      increased with age (root caries index 4.6-10.6%). The mean number of
      carious/filled root surfaces (RDFS) rose from 0.4 per person (25-34 years) to 2.3
      (55-64 years) and dropped for seniors due to the low number of retained teeth.
      Fillings comprised the largest proportion of the RDFS (69.5%). Most
      caries/fillings were found on buccal surfaces, the highest rate in mandibular
      premolars. With about half of over-45-year-olds having at least one
      carious/filled root surface and increasing number of retained teeth in seniors,
      root caries is a relevant and probably growing disease in Pomerania and East
      Germany.

PMID- 15181333
TI  - Intra-oral acid production associated with eating whole or pulped raw fruits.
AB  - The hypotheses that raw fruits, whether whole or pulped, were cleared rapidly
      from the mouth and that the sugars in the whole and pulped fruits are fermented
      with equal efficiency to acids by the oral microflora were tested in this study.
      Groups of 7-9 adult subjects chewed 10 g of raw, whole or pulped fruit (apple,
      banana, orange, pear and pineapple) for 1 min and whole, unstimulated saliva
      samples were collected during the following 60-min interval. Each saliva sample
      was assayed for the concentrations of fruit-derived sugars (glucose, fructose and
      sucrose), fruit-derived acids (malic and citric) and acids which may be produced
      as a result of bacterial fermentation (acetic, lactic, formic and succinic). We
      found the fruit-derived sugars were rapidly cleared from the mouth (within 5
      min). The major bacterially produced acids were lactic and succinic, which
      reached maximum concentrations in the 5-min sample. There was no significant
      difference, within a fruit, in the salivary levels of any of the sugars or acids
      between the raw whole or raw pulped forms. In light of these findings it seems
      unwise to assume that fruits may be consumed without consideration of their
      acidogenic potential.

PMID- 15181334
TI  - Evaluation of several techniques for the detection of secondary caries adjacent
      to amalgam restorations.
AB  - The objective of this study was to determine the ability of several techniques to
      detect natural secondary caries adjacent to proximal class II amalgam
      restorations. Two sites were selected and marked on each of 50 human extracted
      posterior teeth. Three examiners visually characterized each site independently
      for signs of demineralization (VI), ditching presence (VD), and color change, and
      utilized light-induced fluorescence (QLF), and infrared laser fluorescence (LF)
      techniques. The teeth were sectioned through the selected sites, and the severity
      of each lesion was determined by confocal laser scanning microscopy (CLSM) as the
      'gold standard'. Agreement among examiners was assessed using weighted kappa
      statistics and showed fair to moderate correlation with all techniques.
      Sensitivity, specificity, positive predictive value (PPV), negative predictive
      value and accuracy were determined by utilizing three arbitrary CLSM thresholds.
      Higher sensitivity was indicated by the QLF and LF than by VI. For PPV and
      accuracy, QLF and LF showed values higher or similar to VI. Low sensitivity was
      found for VD. The results obtained in this study suggest that LF and QLF may
      improve the ability to detect early secondary caries around amalgam restorations.

PMID- 15181335
TI  - Assessment of two 'low-tech' genetic health care procedures performed by prenatal
      care providers in Washington state: implications for future policy development
      activities.
AB  - Equity in health care demands that patients be treated fairly, impartially and
      with justice. Health care professionals and others have long been aware of the
      concept of equity, and the many inequities that exist in our health care system.
      As part of our analysis of postpartum data collected between 1993 and 1996 by the
      Washington Pregnancy Risk Assessment Monitoring System (PRAMS) from self
      administered patient surveys, we explored equity as it pertains to two 'low-tech'
      prenatal genetic health care procedures: (1) whether or not prenatal care
      providers asked their patients about a family history of birth defects/genetic
      disorders, and (2) whether or not prenatal care providers talked to their
      patients about prenatal testing for birth defects/genetic disorders. Overall,
      about 80% of pregnant women reported that they had been asked about their family
      history of birth defects/genetic disorders, and about 85% said that their
      prenatal care provider(s) had talked to them about prenatal testing. Maternal
      characteristics associated with a lower likelihood of receiving these two low
      tech genetic health care procedures appeared to be young maternal age, and low
      education and income levels, regardless of where women with these attributes
      received their prenatal care (e.g. community, migrant, health department or
      military health care clinics, private physicians, or health maintenance
      organizations).

PMID- 15181336
TI  - First-cousin matings and congenital heart disease in Saudi Arabia.
AB  - BACKGROUND: Consanguinity may be a risk factor that contributes to congenital
      heart disease in an inbred population, particularly among first cousins; with
      high rates of intermarriage between relatives, consanguinity is associated with
      congenital heart disease particularly among first cousins. PATIENTS AND METHODS:
      This study examines a group of 1,028 consecutive congenital heart disease (CHD)
      patients identified through the Congenital Heart Disease Registry at King Faisal
      Specialist Hospital in Riyadh, Saudi Arabia. Families were interviewed by an
      Arabic-speaking data collector for information on consanguinity and demographic
      data. After exclusions for nonavailability, data were collected on 949 cases and
      the proportions of first-cousin consanguinity in the study sample were compared
      to national population data. A z test of proportions was utilized to test the
      hypothesis that there are higher proportions of first-cousin consanguinity in the
      study sample of congenital heart patients than in the general population.
      FINDINGS: Data indicate that the proportion of first-cousin matings among CHD
      patients is significantly higher than that of first-cousin intermarriages
      reported in the general population (p < 0.001). Regional breakdowns of the data
      substantiate significant differences (p < 0.001) in the proportions of first
      cousin consanguinity in the study sample compared to the general population.
      INTERPRETATION: In a population with a high degree of inbreeding, consanguinity
      may exacerbate underlying genetic risk factors, particularly for offspring of
      first-cousin matings. This finding has public health implications for genetic
      counseling and prevention of some cardiac malformations.

PMID- 15181337
TI  - Preconceptional screening of couples for carriers of cystic fibrosis: a
      prospective evaluation of effects, costs and savings for different mutation
      detection methods.
AB  - OBJECTIVE: The aim of this study was to perform a prospective evaluation of the
      effects, costs and savings of a preconceptional screening programme of couples
      for carriers of cystic fibrosis (CF). METHODS: A decision model for both single
      entry two-step (SETS) and double-entry two-step (DETS) couple screening was
      constructed. Two mutation detection methods were considered: allele-specific
      oligonucleotide (ASO) hybridisation screening of 32 mutations, with a sensitivity
      of 90%, and denaturing gradient gel electrophoresis (DGGE), with a sensitivity of
      98%. In our model, the following combinations were used: (1) ASO for both steps;
      (2) DGGE for both steps, and (3) ASO for the first step and DGGE for the second
      step. The model is demonstrated using figures from the Netherlands, where there
      is a carrier frequency of 1:30. We estimated the value of different choices and
      probabilities in a decision tree and determined the costs of screening for CF and
      the costs of the illness itself. RESULTS: We found that with most of the
      combinations of mutation detection methods, SETS couple screening could offer
      positive net savings in the Netherlands. The ASO/DGGE combination resulted in the
      highest net savings. DETS couple screening for all combinations, including
      testing with DGGE in both steps, did not show a positive cost-savings balance at
      all, not even with an uptake rate of 100%. The maximum number of carrier couples
      identified when screening 100,000 couples with the ASO/DGGE combination was 98
      (SETS). This could result in about 25 fewer children born with CF each year in
      the Netherlands, under the following assumptions: (1) each couple has two
      children and 10% of couples are unable to have children; (2) of detected carrier
      couples, 15% decide not to have children and 85% make use of prenatal diagnosis;
      (3) of those fetuses diagnosed with CF, 80% are aborted, and (4) prenatal
      diagnosis carries a 0.75% risk of iatrogenic abortion. CONCLUSIONS: The results
      of this evaluation show that there are no financial objections to the
      preconceptional screening of couples in the Netherlands when the above-mentioned
      assumptions apply; thus, further evaluation can concentrate on the balance of the
      non-economic consequences of screening for participants and for society.

PMID- 15181338
TI  - Carrier testing program in a high-risk cystic fibrosis population from
      northeastern Italy. Active recruitment of relatives via probands' parents.
AB  - OBJECTIVE: To assess the practicability and monitor the results of an active
      carrier testing program among relatives of cystic fibrosis (CF) patients.
      METHODS: Parents of CF patients in the Veneto and Trentino regions of
      northeastern Italy were asked to help recruit relatives aged between 18 and 45
      years for CF mutation testing. RESULTS: Of 409 enrolled CF parents, 59.6% agreed
      to send to the CF Center family composition data of relatives up to the third
      degree, and 28.8% recruited relatives to carrier testing, providing names and
      addresses of those who, being contacted, expressed a willingness to be tested.
      The participation of parents was higher if they were young and had a child
      recently diagnosed with CF. Recruiting parents indicated 333 close relatives
      (59%) for testing. When contacted by the CF Center, 170 of these 333 (51%)
      attended for testing. The percentage of close relatives who spontaneously asked
      for the test was 5.4% before the carrier testing program started; it rose to
      25.3% following the introduction of the active strategy. CONCLUSIONS: The
      participation of the parents of CF patients is an important factor affecting the
      utilization of testing by relatives. Besides this, the influence of a favorable
      medical and cultural context (participation of gynecologists and family doctors
      in testing programs, genetic education of the general population) has to be
      considered.

PMID- 15181339
TI  - Glycogen storage disease type II: birth prevalence agrees with predicted genotype
      frequency.
AB  - OBJECTIVES: To compare the overall birth prevalence of diagnosed glycogen storage
      disease type II (GSD II) with the predicted frequency based on mutation
      screening, in order to determine whether GSD II is an underdiagnosed condition,
      and to analyze which medical disciplines recognize GSD II. METHODS: Retrospective
      data on all enzymatic diagnoses of GSD II were collected from diagnostic labs
      throughout the Netherlands, covering the period from January 1, 1972 to December
      31, 1996. Age-specific diagnostic incidence rates were calculated for the entire
      study period. By adding together the diagnostic incidences for all age groups, we
      calculated the birth prevalence of diagnosed GSD II and compared these figures
      with the predicted frequency based on mutation screening in a random sample from
      the general population. The medical specialization of the referring clinicians
      was also recorded. RESULTS: GSD II was diagnosed in 154 individuals, including 11
      prenatal diagnoses. The birth prevalences of the various phenotypes were
      1/101,000 (infantile form), 1/720,000 (juvenile form) and 1/53,000 (adult form).
      The birth prevalence of the adult and infantile phenotype together was 1/35,000.
      Eighty-two percent of the patients were diagnosed in university hospitals. Of the
      patients with infantile GSD II, 71% were diagnosed by a pediatrician, whereas
      most patients with adult GSD II were diagnosed by a neurologist (80%).
      CONCLUSIONS: There is no evidence for the underdiagnosis of GSD II in the
      Netherlands, as the calculated birth prevalences of the disease are consistent
      with previous predictions based on mutation screening in a random sample of
      newborns. The worldwide birth prevalence of the disease may well be higher than 1
      in 100,000. GSD II is mainly diagnosed in university hospitals.

PMID- 15181340
TI  - Birth defect and risk factor surveillance in the northern and southwestern
      Netherlands.
AB  - OBJECTIVE: To survey the associations between several risk factors and birth
      defects, in order to detect potential new teratogens. METHODS: Data of the two
      Dutch European Registration of Congenital Anomalies (EUROCAT) registries
      collected before January 1, 1998 were used to perform chi2 tests for a large
      number of risk factors and birth defects. Defects caused by chromosomal or
      monogenic disorders were analyzed separately. RESULTS: Cross-tabulations of 80
      groups of birth defects with 303 risk factors were studied. Of these, 126
      combinations had a p value under 0.05, and 34 had a p value under 0.001. Of these
      34 associations, some are known in the literature, some were found before in the
      same databases and some were new associations. CONCLUSIONS: This is a good method
      for generating new hypotheses for associations between risk factors and birth
      defects. It can be a start for new, more in-depth studies of potential
      teratogens.

PMID- 15181341
TI  - Qualifications of public health geneticists?
AB  - Public health genetics is a rapidly emerging field that is not well defined. One
      way of helping to define the field is to describe the competences of the
      professionals who participate in it. The information presented here attempts to
      define the knowledge base, skills, and attitudes needed to be a public health
      geneticist. It is hoped that this information will be used to create a uniform
      definition of public health genetics, and also help education programs train
      individuals who want to participate in the field.

PMID- 15181342
TI  - Knowledge about medical genetics in health care.
AB  - Effective genetic services depend upon co-operation between medical geneticists
      and many different non-geneticist professionals to ensure that the most
      appropriate patients are referred to geneticists and that those that require long
      term care receive it. Important determinants of the quality of genetic services
      are the knowledge that professionals have about clinical genetics and the
      equitable distribution of adequately resourced genetic centres. Consequently, we
      have investigated in a European context how much clinically relevant genetics non
      geneticists know, how competent non-geneticists are in counselling their own
      patients, how well equipped specialist genetic centres are, who refers to genetic
      centres and what they refer and who offers continuing care to patients and
      families whose problems are not resolvable at a limited genetic clinic visit.

PMID- 15181343
TI  - Susceptibility of several strains of mice to Echinostoma hortense infection.
AB  - Susceptibilities of 5 different mice strains, including C3H/HeN, BALB/c, C57BL6,
      FvB and ICR, to Echinostoma hortense infection, was evaluated. The worm expulsion
      rate, worm size and egg production were observed from 1 to 8 weeks after
      infection with 30 metacercariae. C3H/HeN and ICR mice showed the highest worm
      maturation rates. The worm recovery rate and the number of eggs per gram (EPG) of
      feces was also higher in C3H/HeN and ICR mice than in BALB/c, C57BL6, and FvB
      mice. It is suggested that E. hortense is highly infectious to ICR and C3H/HeN
      mice, but not to the other strains of mice. Based on the results obtained, we
      believe that the susceptibility of different mouse strains to E. hortense
      infection is dependent on the genetic and immunologic background of mice.

PMID- 15181344
TI  - Enzymatic N-glycan analysis of 31 kDa molecule in plerocercoid of Spirometra
      mansoni (sparganum) and its antigenicity after chemical oxidation.
AB  - A highly specific antigenic protein of 31 kDa from plerocercoid of Spirometra
      mansoni (sparganum) was obtained by gelatin affinity and Mono Q anion-exchange
      column chromatography. The purified 31 kDa protein was subjected to N-glycan
      enzymatic digestion for structural analysis. The relative electrophoretic
      mobility was analyzed by SDS-PAGE, before and after digestion. On SDS-PAGE after
      enzymatic digestion, the 31 kDa protein showed a molecular shift of approximately
      2 kDa, which indicated the possession of complex N-linked oligosaccharides (N
      glycosidase F sensitive) but not of high-mannose oligosaccharides (endo-beta-N
      acetylglucosaminidase H, non-sensitive). Chemically periodated 31 kDa protein
      showed statistically non-significant changes with human sparganosis sera by
      enzyme linked immunosorbent assay (ELISA). Therefore, the dominant epitopes of
      the 31 kDa molecule in human sparganosis were found to be mainly polypeptide,
      while N-glycans of the antigenic molecule in sparganum was minimal in anti
      carbohydrate antibody production.

PMID- 15181345
TI  - Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates.
AB  - The plasmepsins are the aspartic proteases of malaria parasites. Treatment of
      aspartic protease inhibitor inhibits hemoglobin hydrolysis and blocks the
      parasite development in vitro suggesting that these proteases might be exploited
      their potentials as antimalarial drug targets. In this study, we determined the
      genetic variations of the aspartic proteases of Plasmodium vivax (PvPMs) of wild
      isolates. Two plasmepsins (PvPM4 and PvPM5) were cloned and sequenced from 20 P.
      vivax Korean isolates and two imported isolates. The sequences of the enzymes
      were highly conserved except a small number of amino acid substitutions did not
      modify key residues for the function or the structure of the enzymes. The high
      sequence conservations between the plasmepsins from the isolates support the
      notion that the enzymes could be reliable targets for new antimalarial
      chemotherapeutics.

PMID- 15181346
TI  - Infection status of intestinal parasites in children living in residential
      institutions in Metro Manila, the Philippines.
AB  - A small scale survey was performed to know the infection status of intestinal
      parasite in children of the residential institutions and street communities in
      Metro Manila, Philippines. A total of 284 stool samples from 11 institutions and
      3 street communities was examined by the formalin-ether concentration method. The
      scotch tape anal swab was adapted to 121 children to investigate the infection
      status of Enterovius vermicularis. It was found out that 62.0% of the children
      examined were positive for one or more intestinal parasites. Multiple infections
      were observed in 34.2% of the children. Among 172 children who gave detail
      information, the prevalence for Ascaris lumbricoides, Trichuris trichiura, and
      hookworm was 36.0%, 44.8%, and 7.0% respectively. Of the children examined, 47.7%
      were found to be harboring parasitic protozoans such as Entamoeba histolytica,
      Giardia lamblia, and Blastocystis hominis. The most prevalent of these protozoans
      was B. hominis with an infection rate of 40.7%. The prevalence of these
      infections among children living in institutions was relatively high. More
      efforts should be made to implement anthelminthic programs including bi-annual
      follow-up treatments.

PMID- 15181347
TI  - Molecular phylogenic location of the Plagiorchis muris (Digenea, Plagiorchiidae)
      based on sequences of partial 28S D1 rDNA and mitochondrial cytochrome C oxidase
      subunit I.
AB  - To determine the molecular phylogenic location of Plagiorchis muris, 28S D1
      ribosomal DNA (rDNA) and mitochondrial cytochrome C oxidase subunit I (mtCOI)
      were sequenced and compared with other trematodes in the family Plagiorchiidae.
      The 28S D1 tree of P. muris was found to be closely related to those of P.
      elegans and other Plagiorchis species. And, the mtCOI tree also showed that P.
      muris is in a separate clade with genus Glypthelmins. These results support a
      phylogenic relationship between members of the Plagiorchiidae, as suggested by
      morphologic features.

PMID- 15181348
TI  - Modification of carbohydrate compositions of 31/36 kDa proteins of plerocercoids
      (sparganum) of Spirometra mansoni grown in different intermediate hosts.
AB  - We purified specific 31/36 kDa antigenic molecules from sparganum in different
      intermediate hosts (snakes and mice) and analyzed their monosaccharide
      compositions. Compositional analysis showed that glucose and mannose
      concentrations were 2-3 fold higher in the 31/36 kDa molecule purified from
      snakes than those from mice. This result implies that antigenic glycoproteins of
      sparganum from snakes might be modified in mammalian sparganosis with respect to
      their carbohydrate composition.

PMID- 15181349
TI  - Immunolocalization of the 150 kDa protein in cyst fluid of Taenia solium
      metacestodes.
AB  - The 150 kDa protein of cyst fluid (CF) of Taenia solium metacestodes was purified
      by ammonium sulfate fractionation and Superose 6 HR gel filtration
      chromatography. The purified protein consisted of three subunits (15, 10 and 7
      kDa proteins), which were analyzed with the use of a 7.5-15% gradient sodium
      dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Immunofluorescence
      study was carried out by using immunize specific polyclonal antibody. Positive
      reactions were noticed at bladder walls, calcareous corpuscles, granules of cyst
      fluid and some host tissue surrounding the bladder wall of the metacestodes.
      These results suggest that the 150 kDa protein was secreted into host tissues,
      inducing immune responses in the host, and it may play important roles in the
      cellular physiology of the parasites.

PMID- 15181350
TI  - Genotype and animal infectivity of a human isolate of Cryptosporidium parvum in
      the Republic of Korea.
AB  - Cryptosporidium parvum oocysts were isolated from a child suffering from acute
      gastroenteritis and successfully passaged in a calf and mice (designated
      hereafter SNU-H1) in the Republic of Korea; its molecular genotype has been
      analyzed. The GAG microsatellite region was amplified by a polymerase chain
      reaction (PCR), with a 238 base pair product, which is commonly displayed in C.
      parvum. The isolate was shown to be a mixture of the genotypes 1 (anthroponotic)
      and 2 (zoonotic). To study its infectivity in animals, 2 calves and 3 strains of
      mice were infected with the SNU-H1; in these animals, the propagation of both
      genotypes was successful. In immunosuppressed (ImSP) BALB/c and C57BL/6 mice the
      number of oocysts decreased after day 10 post-infection (PI); but in ImSP ICR
      mice, they remained constant until day 27 PI. The results show that both the C.
      parvum genotypes 1 and 2 can be propagated in calves and ImSP mice.

PMID- 15181351
TI  - What is an optometrist?

PMID- 15181355
TI  - Reliability and validity of the Melbourne Edge Test and High/Low Contrast Visual
      Acuity chart.
AB  - PURPOSE: The purposes of the study were to investigate the test-retest
      reliability and the validity of new versions of the Melbourne Edge Test (MET) and
      the High/Low Contrast Visual Acuity (H/LCVA) chart and to investigate the
      agreement between the original and new versions. METHODS: The MET original
      photographic version, MET new light box version, H/LCVA Chart original
      photographic version, H/LCVA Chart new printed version, and the Pelli-Robson
      chart were administered twice to one eye of 22 subjects with low vision and 20
      soft contact lenses wearers. RESULTS: For the low vision group, the test-retest
      95% limits of agreement were +/- 5.2 dB for the MET new light box version and +/-
      0.39 logarithm of the minimum angle of resolution (logMAR) for the LCVA component
      of the H/LCVA new printed version. For the soft contact lens group, the test
      retest 95% limits of agreement were +/- 2.1 dB for the MET new light box version
      and +/- 0.26 logMAR for the LCVA component of the H/LCVA new printed version.
      Moderate to high correlations were obtained between contrast sensitivity tests,
      thus providing evidence of validity. Scores obtained for the new test versions
      were significantly higher than the original versions (p < 0.01). CONCLUSIONS: Of
      all the tests administered, the MET original photographic version and the Pelli
      Robson Chart had the highest test-retest reliability for the low vision group.
      For the soft contact lens group, the H/LCVA original version (low contrast
      letters, 18% Weber) and the Pelli-Robson Chart had the highest reliability.

PMID- 15181354
TI  - Association of visual field loss and mobility performance in older adults:
      Salisbury Eye Evaluation Study.
AB  - PURPOSE: To determine the association between visual field loss and orientation
      and mobility (O&M) performance in a population-based sample of older adults and
      to identify the specific regions of the visual field that are most strongly
      associated with O&M performance. METHODS: A population-based sample of 1504
      persons between the ages of 72 to 92 was enrolled in the third round of Salisbury
      Eye Evaluation. Monocular visual fields (60 degrees radius) were tested with the
      81-point, single intensity (24 dB) screening test strategy on the Humphrey Field
      Analyzer. Binocular visual fields were estimated from a combination of the
      monocular fields. The number of points missed was calculated for the overall
      visual field and for 3 non-overlapping regions: central (< or = 20 degrees
      radius), upper- and lower-peripheral visual fields. Orientation and mobility
      performance was evaluated by walking speed, number of bumps, and number of
      orientation errors on a circuitous, 32.8-m course seeded with obstacles. Log
      linear regressions and linear regressions, adjusting for age, gender, body mass,
      height, cognitive and general health status, were performed. RESULTS: Loss in the
      overall visual field was associated with an increase in the number of bumps and
      decrease in walking speed. Visual field loss was not associated with the number
      of orientation errors. Out of the three visual field sub-regions that we tested,
      in terms of percentage of loss, the central and lower peripheral regions showed
      comparable decrements in walking speed and the central region was most strongly
      associated with number of bumps. CONCLUSIONS: The loss in visual field, which
      occurs with aging, is associated with a decline in mobility performance. Walking
      speed decreases, and the number of bumps into obstacles increases, with decreases
      in the visual field. The number of orientation errors is not associated with the
      loss in visual field that occurs with aging.

PMID- 15181356
TI  - Prevalence of myopia in local and international schools in Hong Kong.
AB  - PURPOSE: This study aims to investigate genetic and environmental influences on
      physiological myopia by studying the difference in myopia prevalence between
      local schools and international schools in Hong Kong. METHODS: Vision screening
      was carried out in local and international schools for students 13 to 15 years
      old. Types of refractive error were identified by visual acuity measurement, the
      presence of spectacles, a simple refraction, and the use of plus and minus
      ophthalmic lenses. RESULTS: Three local schools and six international schools
      participated in the study. Two hundred eighty-nine students were from the local
      schools, and 789 students were from the international schools. Prevalence of
      myopia at the local schools ranged from 85 to 88%, whereas it ranged from 60 to
      66% in the international schools. Students in the international schools were
      subdivided into Chinese origin, white, mixed Chinese, and Asian. Prevalence of
      myopia was highest in the Chinese group (82.8%) and lowest in the white group
      (40.5%). There was no age or gender difference in the prevalence of myopia.
      CONCLUSIONS: Hong Kong Chinese students had a higher prevalence of myopia
      regardless of whether they studied in local or international schools when
      compared with other ethnic groups, such as whites. This further supports a
      genetic input into myopia development.

PMID- 15181357
TI  - Clinical evaluation of the Topcon BV-1000 automated subjective refraction system.
AB  - BACKGROUND: The BV-1000 is a new instrument that performs binocular
      autorefraction and subjective refraction. The aim of the study was to evaluate
      the accuracy of the BV-1000 compared with subjective refraction without
      cycloplegia and the repeatability of the BV-1000 in subjects without cycloplegia.
      METHODS: BV-1000 binocular autorefraction (mean of three measures) and automated
      subjective refraction was performed on 100 eyes and compared with practitioner
      subjective refraction. After BV-1000 assessment, the result was modified by the
      investigator in the form of a binocular addition; the practitioner was masked as
      to the result of the BV-1000. Repeatability was evaluated by comparing the test
      retest data on 40 eyes. Refraction data were converted into Fourier component
      terms: mean spherical equivalent (MSE), J0, J45, and vector dioptric difference
      (VDD). RESULTS: Mean difference of MSE (BV-1000 subjective vs. practitioner) was
      0.05 +/- 0.35 D (p = 0.13), whereas after binocular addition, the mean difference
      in MSE was -0.01 +/- 0.21 D (p = 0.67). The mean difference of MSE (BV-1000
      objective vs. practitioner) was +0.10 +/- 0.37 D (p < 0.05). Mean difference in
      J0 and J45 was -0.03 +/- 0.12 D (p = 0.09) and -0.02 +/- 0.10 D (p = 0.06),
      respectively. More than 95% of cylinder powers were within +/- 0.50 D. The median
      VDD was 0.35 D (range, 1.38 D; interquartile range, 0.31) for comparisons of BV
      1000 subjective refraction and the practitioner. A median VDD of 0.25 D (range,
      1.06 D; interquartile range, 0.16) was found after binocular addition correction.
      There was no statistically significant difference (p = 0.73) in spherical
      intereye difference between BV-1000 subjective and subjective refraction. Mean
      spherical intereye difference (spherical balancing error) between the BV-1000 and
      practitioner subjective refraction was -0.02 +/- 0.24 D. Repeatability as
      described by the mean difference between occasions for MSE was found to be -0.06
      +/- 0.19 D, -0.02 +/- 0.08 D for J0, and -0.03 +/- 0.07 D for J45. CONCLUSIONS:
      The subjective refraction routine within the BV-1000 improves the results of
      simultaneous binocular autorefraction data. The BV-1000 provides an accurate and
      repeatable measure of subjective refraction after binocular addition.

PMID- 15181358
TI  - Evaluation of an automated subjective refractor.
AB  - PURPOSE: To test the validity and repeatability of an automated subjective
      refractor compared with subjective refraction performed by clinicians. Corrected
      visual acuity was used to compare the validity of each technique. METHODS: On
      each of two visits separated by at least 1 week, the following were measured in
      60 naive subjects (mean age, 33 +/- 11 years): automated objective refraction
      (AOR) and automated subjective refraction (ASR) with the Topcon BV-1000,
      subjective refraction by one of two doctors (DR), and monocular visual acuity
      with the ASR and DR findings. Repeatability of refraction was calculated as the
      95% limits of agreement (LoA) between same-mode measurements from the two visits.
      The validity of the ASR compared with DR was determined two ways: as the 95% LoA
      between the two measures and as the mean visual acuity measured with each
      prescription. RESULTS: The DR and AOR had similar repeatability: 95% LoA = -0.49
      to +0.46 D and -0.51 to +0.45 D, respectively. The ASR had poorer repeatability
      with 95% LoA of -0.70 to + 0.71 D. Because of a calibration (offset) error in the
      right eye path of the BV-1000, the ASR of the right eye yielded refractions +0.26
      +/- 0.41 D higher than the DR. For the right eye, visual acuity was 3.42 +/- 6.09
      letters better with the DR than with the ASR, consistent with this calibration
      error. For the left eye, visual acuity was 1.20 +/- 5.20 letters better for the
      DR. CONCLUSIONS: Doctor-performed refractions are more valid and repeatable than
      the ASR performed with the BV-1000, although the differences are small. When
      calibrated, the BV-1000 gives similar visual acuity values to the DR, although
      the visual acuity for the DR is more repeatable.

PMID- 15181359
TI  - Will visual discomfort among visual display unit (VDU) users change in
      development when moving from single vision lenses to specially designed VDU
      progressive lenses?
AB  - PURPOSE: Three types of progressive additions lenses (PAL) specially designed for
      VDU-work and one single vision lens were compared in a prospective field study.
      The aim was to investigate if these progressive lenses created a difference in
      the development of visual discomfort compared to single vision lenses when
      working on an optimized VDU-workstation. METHODS: The study had a prospective,
      parallel group design, with four groups of VDU-workers. Approximately 40 subjects
      in each group, selected after careful task analysis with special attention
      towards the visual angles and distances to the work tasks. The groups were
      followed over one year. A questionnaire concerning visual conditions, working
      conditions, discomfort in different body areas, the status of the subjects'
      optometric corrections, psychological factors both at work and at home, amount,
      frequency and duration of VDU-work etc. was filled in before the intervention,
      after six months and after one year. No other contact was made with the subjects.
      The VDU-lenses included were Interview (Essilor), Gradal RD (Zeiss) and Technica
      (American Optical). Pain intensity and duration were assessed on a 100 mm Visual
      Analogue Scale (VAS) before the intervention, and six and twelve months after the
      intervention. All subjects were given a complete optometric examination. RESULTS:
      Only small changes in the development of headache and visual discomfort were
      registered. However, the subjective evaluation of area of clear vision and
      overall satisfaction was significantly improved for the Interview and Gradal RD
      lens (p < 0.05). There were no significant changes for Technica and single vision
      lenses. CONCLUSION: Lens designs that cover viewing distances from near and out
      to approximately 2 meters work well compared to lens designs trying to cover
      greater range of clear vision. When tasks analysis shows that single vision
      correction may be used, this is still an acceptable solution.

PMID- 15181360
TI  - Correlation analysis of the optics of progressive addition lenses.
AB  - PURPOSE: To investigate the relations between selected key optical parameters and
      the sizes of the clear viewing areas of progressive addition lenses (PALs).
      METHODS: The optics of 28 PALs (plano with +2.00 D add) currently on the market
      were measured with a Rotlex Class Plus lens analyzer. Horizontal cross sections
      were analyzed in 1 mm vertical steps with respect to the fitting cross. Distance,
      intermediate, and near viewing zone widths and areas were calculated from the
      measurements. The maximum amount of unwanted astigmatism, minimum zone width
      (0.50 DC limit), and maximum power rate in the corridor were also recorded for
      each lens. Correlation coefficients were determined for all relations. RESULTS:
      Each of the three viewing zone areas had a significant negative relation with the
      other (r of -0.4 to -0.8), indicating design tradeoff. Maximum power rate was
      significantly related to minimum zone width (r = -0.695), which was significantly
      related to maximum astigmatism (r = -0.616), but there was not a significant
      relation between maximum power rate and maximum astigmatism. Higher power rates
      and narrower minimum zones were significantly related to smaller intermediate and
      larger near zones (r = 0.4 to 0.9). Maximum astigmatism was related to distance
      zone width (r = 0.42) and to intermediate zone size (r = -0.4 to -0.56), but not
      significantly related to near viewing zone. Power rate and astigmatism each vary
      relatively uniformly across each lens. CONCLUSIONS: The fundamental relation
      appears to be between power rate and zone width, each of which is highly related
      to sizes of the intermediate and near viewing zones. The maximum amount of
      astigmatism is related to zone width, but not to maximum power rate. The amount
      of astigmatism is unrelated to the size of the near zone. The pattern of
      correlations between the optical and viewing zone parameters help identify the
      underlying optical relations of PALs.

PMID- 15181361
TI  - The effect of LASIK on best-corrected high-and low-contrast visual acuity.
AB  - PURPOSE: To evaluate the effects of laser in situ keratomileusis (LASIK) and
      LASIK with concurrent astigmatic keratectomy (LASIK/AK) on high- and low-contrast
      visual acuity. METHODS: The setting was a university refractive surgery practice.
      Patients were recruited from those undergoing LASIK or LASIK/AK for myopia (>1.00
      D spherical equivalent) between May 1996 and August 1997. All subjects were at
      least 21 years of age. Testing occurred preoperatively and 3 and 6 months after
      LASIK. Main outcome measures were best spectacle-corrected, high- and low
      contrast visual acuity. RESULTS: For all subjects, there was a significant effect
      of surgery on nondilated low-contrast visual acuity (repeated measures two-way
      analysis of variance, p < 0.0001). Tukey's posthoc analysis showed that
      preoperative low-contrast visual acuity scores were significantly different from
      3-month [0.08 logarithm of the minimum angle of resolution (logMAR)] and 6-month
      (0.11 logMAR) scores for patients undergoing LASIK and LASIK/AK. Under dilated
      conditions, there was a significant effect of surgery for high- and low-contrast
      visual acuity (analysis of variance, p < 0.0001 for both). Only changes in low
      contrast visual acuity were clinically meaningful [LASIK, visual acuity reduction
      of 0.1 logMAR (1 line); LASIK/AK, visual acuity reduction of 0.15 logMAR (1.5
      lines)]. When considering high and low myopes separately (LASIK only), the level
      of myopia had a significant effect on the visual acuity after surgery (analysis
      of variance, p = 0.01). Preoperative, dilated, low-contrast visual acuity scores
      for high myopes were significantly different from 3-month (0.14 logMAR) and 6
      month (0.13 logMAR) scores. No differences were noted for low myopes.
      CONCLUSIONS: Clinically meaningful postoperative changes in low-contrast visual
      acuity were noted in patients undergoing LASIK and LASIK/AK under natural and
      dilated conditions. Postoperative, dilated, low-contrast visual acuity scores
      were significantly worse than preoperative scores for high myopes, but remained
      unchanged for low myopes.

PMID- 15181362
TI  - Retinal nerve fiber loss in high- and normal-tension glaucoma by optical
      coherence tomography.
AB  - PURPOSE: To compare the pattern of retinal nerve fiber layer (RNFL) damages in
      high-tension and normal-tension primary chronic open-angle glaucoma using optical
      coherence tomography (OCT). METHODS: Age- and refractive error-matched patients
      with normal-tension glaucoma (NTG) (n = 38) and high-tension glaucoma (HTG) (n =
      48) and normal subjects (n = 48) were recruited. All subjects underwent complete
      eye examinations and OCT RNFL assessments. RESULTS: No statistically significant
      difference was found between eyes with HTG and NTG for any OCT RNFL thickness
      parameters (p > 0.05). Inferotemporal thickness values were significantly lower
      than the superotemporal thickness values in both glaucoma groups (p < 0.001), but
      no difference was observed in the normal group. Compared with the results from
      normal subjects, several OCT parameters, including average, superior, inferior,
      inferotemporal, and superotemporal values, were significantly lower in patients
      with HTG and NTG (p < 0.01). CONCLUSIONS: A mixture of diffuse RNFL damage
      (superotemporal and inferotemporal regions) and local damage in inferotemporal
      region was observed in patients with HTG and NTG, suggesting that HTG and NTG may
      undergo same pathological process.

PMID- 15181363
TI  - Critical flicker fusion frequency: relation to resting systolic blood pressure.
AB  - OBJECTIVE: Past studies have shown that a number of factors, both acute and
      chronic, influence individual differences in critical flicker fusion frequency
      (CFF). In this study, we assessed whether CFF co-varied with resting systolic
      blood pressure (SBP). METHODS: SBP and CFF were assessed in one session in 221
      subjects (mean age, 19.6 +/- 2.5 years), and SBP and CFF were assessed over 10
      sessions in 12 subjects. CFF values were determined psychophysically using a 570
      nm circular 1 degrees test field centrally fixated. Blood pressure was determined
      with an automated sphygmomanometer. RESULTS: There was a significant (p < 0.0002)
      positive relation between CFF and SBP for the larger sample (n = 221).
      Significant within-subject relations were found for 6 of the 12 subjects tested
      repeatedly. CONCLUSIONS: The combination of results strongly suggests that CFF
      and resting SBP are positively related.

PMID- 15181364
TI  - Effects of dominant and nondominant eyes in binocular rivalry.
AB  - PURPOSE: To investigate the relation between sighting and sensory eye dominance
      and attempt to quantitatively examine eye dominance using a balance technique
      based on binocular rivalry. METHODS: The durations of exclusive visibility of the
      dominant and nondominant eye target in binocular rivalry were measured in 14
      subjects. The dominant eye was determined by using the hole-in-card test
      (sighting dominance). In study 1, contrast of the target in one eye was fixed at
      100% and contrast of the target in the other eye was varied from 100% to 80% to
      60% to 40% to 20%, when using rectangular gratings of 1, 2, and 4 cycles per
      degree (cpd) at 2 degrees, 4 degrees , and 8 degrees in size. In study 2,
      contrast of the target in the nondominant eye was fixed at 100% and contrast of
      the target in the dominant eye was varied from 100% to 80% to 60% to 40% to 20%,
      when using a rectangular grating of 2 cpd at 4 degrees in size. RESULTS: In study
      1, the total duration of exclusive visibilities of the dominant eye target; that
      is, the target seen by the eye that had sighting dominance was longer compared
      with that of the nondominant eye target. When using rectangular gratings of 4
      cpd, mean total duration of exclusive visibility of the dominant eye target was
      statistically longer than that of the nondominant eye target (p < 0.05). In study
      2, reversals (in which duration of exclusive visibility of the nondominant eye
      becomes longer than the dominant eye when the contrast of the dominant eye target
      is decreased) were observed for all contrasts except for 100%. CONCLUSIONS: The
      dominant sighting eye identified by the hole-in-card test coincided with the
      dominant eye as determined by binocular rivalry. The contrast at which reversal
      occurs indicates the balance point of dominance and seems to be a useful
      quantitative indicator of eye dominance to clinical applications.

PMID- 15181365
TI  - Unwrapping Hartmann-Shack images from highly aberrated eyes using an iterative B
      spline based extrapolation method.
AB  - PURPOSE: When the wavefront aberrations of the eye are measured with a Hartmann
      Shack (HS) sensor, the resulting spot pattern must be unwrapped, that is, for
      each lenslet the corresponding spot must be identified. This puts a limitation on
      the measurable amount of aberrations. To extend the range of an HS sensor, a
      powerful unwrapping algorithm has been developed. METHODS: The unwrapping
      algorithm starts by connecting the central HS spots to the central lenslets. It
      then fits a B-spline function through a least squares estimate to the deviations
      of the central HS spots. This function is then extrapolated to find the expected
      locations of HS spots for the unconnected lenslets. The extrapolation is
      performed gradually in an iterative manner; the closest unconnected lenslets are
      extrapolated and connected, and then the B-spline function is least squares
      fitted to all connected HS spots and extrapolated again. RESULTS: Wavefront
      aberrations from eyes with high aberrations can be successfully unwrapped with
      the developed algorithm. The dynamic range of a typical HS sensor increases 3.5
      to 13 times compared with a simple unwrapping algorithm. CONCLUSIONS: The
      implemented algorithm is an efficient unwrapping tool and allows the use of
      lenslets with a low numerical aperture and thus gives a relatively higher
      accuracy of measurements of the ocular aberrations.

PMID- 15181366
TI  - Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic
      clonic seizures in WAG/Rij rats.
AB  - Generalized epileptic seizures produce widespread physiological changes in the
      brain. Recent studies suggest that "generalized" seizures may not involve the
      whole brain homogeneously. For example, electrophysiological recordings in
      WAG/Rij rats, an established model of human absence seizures, have shown that
      spike-and-wave discharges are most intense in the perioral somatosensory cortex
      and thalamus, but spare the occipital cortex. Is this heterogeneous increased
      neuronal activity matched by changes in local cerebral blood flow sufficient to
      meet or exceed cerebral oxygen consumption? To investigate this, we performed
      blood oxygen level-dependent functional magnetic resonance imaging (fMRI)
      measurements at 7T with simultaneous electroencephalogram recordings. During
      spontaneous spike-wave seizures in WAG/Rij rats under fentanylhaloperidol
      anesthesia, we found increased fMRI signals in focal regions including the
      perioral somatosensory cortex, known to be intensely involved during seizures,
      whereas the occipital cortex was spared. For comparison, we also studied
      bicuculline-induced generalized tonic-clonic seizures under the same conditions,
      and found fMRI increases to be larger and more widespread than during spike-and
      wave seizures. These findings suggest that even in regions with intense neuronal
      activity during epileptic seizures, oxygen delivery exceeds metabolic needs,
      enabling fMRI to be used for investigation of dynamic cortical and subcortical
      network involvement in this disorder.

PMID- 15181367
TI  - Evaluation of simplified kinetic analyses for measurement of brain
      acetylcholinesterase activity using N-[11C]Methylpiperidin-4-yl propionate and
      positron emission tomography.
AB  - The applicability of two reference tissue-based analyses without arterial blood
      sampling for the measurement of brain regional acetylcholinesterase (AChE)
      activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated
      in 12 healthy subjects. One was a linear least squares analysis derived from
      Blomqvist's equation, and the other was the analysis of the ratio of target
      tissue radioactivity relative to reference-tissue radioactivity proposed by
      Herholz and coworkers. The standard compartment analysis using arterial input
      function provided reliable quantification of k3 (an index of AChE activity)
      estimates in regions with low (neocortex and hippocampus), moderate (thalamus),
      and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12%
      to 19%. However, the precise k3 value in the striatum, where AChE activity is the
      highest, was not obtained. The striatum was used as a reference because its time
      radioactivity curve was proportional to the time integral of the arterial input
      function. Reliable k3 estimates were also obtained in regions with low-to
      moderate AChE activity with a COV of less than 21% by striatal reference
      analyses, though not obtained in the cerebellum. Shape analysis, the previous
      method of direct k3 estimation from the shape of time-radioactivity data, gave k3
      estimates in the cortex and thalamus with a somewhat larger COV. In comparison
      with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the
      linear analysis and a moderate underestimation by 2% to 13% in the Herholz method
      were observed, which were appropriately explained by the results of computer
      simulation. In conclusion, simplified kinetic analyses are practical and useful
      for the routine analysis of clinical [11C]MP4P studies and are nearly as
      effective as the standard analysis for detecting regions with abnormal AChE
      activity.

PMID- 15181368
TI  - Altered biosynthesis of neuropeptide processing enzyme carboxypeptidase E after
      brain ischemia: molecular mechanism and implication.
AB  - In this study, using both in vivo and in vitro ischemia models, the authors
      investigated the impact of brain ischemia on the biosynthesis of a key
      neuropeptide-processing enzyme, carboxypeptidase E (CPE). The response to brain
      ischemia of animals that lacked an active CPE was also examined. Combined in situ
      hybridization and immunocytochemical analyses for CPE showed reciprocal changes
      of CPE mRNA and protein, respectively, in the same cortical cells in rat brains
      after focal cerebral ischemia. Western blot analysis revealed an accumulation of
      the precursor protein of CPE in the ischemic cortex in vivo and in ischemic
      cortical neurons in vitro. Detailed metabolic labeling experiments on ischemic
      cortical neurons showed that ischemic stress caused a blockade in the proteolytic
      processing of CPE. When mice lacking an active CPE protease were subjected to a
      sublethal episode of focal cerebral ischemia, abundant TUNEL-positive cells were
      seen in the ischemic cortex whereas only a few were seen in the cortex of wild
      type animals. These findings suggest that ischemia has an adverse impact on the
      neuropeptide-processing system in the brain and that the lack of an active
      neuropeptide-processing enzyme exacerbates ischemic brain injury.

PMID- 15181369
TI  - Glucosylceramide synthase activity and ceramide levels are modulated during
      cerebral ischemia after ischemic preconditioning.
AB  - After 24-hour middle cerebral artery occlusion (MCAO) in spontaneously
      hypertensive rats, brain ceramide level increased from baseline reached 595%
      (ischemic core) and 460% (perifocal/penumbral areas); brain glucosylceramide
      synthase (GCS) activities in these areas simultaneously decreased by 70% and 50%,
      respectively. Ten-minute MCAO preconditioning significantly attenuated 24-hour
      MCAO-induced ceramide accumulation by 40% to 60% in ischemic core and perifocal
      areas, and GCS activities improved by 60% to 70% in both areas. Thus, potentially
      toxic levels of brain ceramide induced by MCAO were attenuated to intermediate
      levels in preconditioned animals; brain GCS activity was relatively preserved. In
      ischemic tolerance, GCS appears to modulate otherwise high levels of brain
      ceramide.

PMID- 15181370
TI  - Origin of PACAP-immunoreactive nerve fibers innervating the subarachnoidal blood
      vessels of the rat brain.
AB  - The subarachnoidal cerebral blood vessels of the rat are innervated by nerve
      fibers containing different neuropeptides, e.g. pituitary adenylatecyclase
      activating polypeptide (PACAP). PACAP dilates brain arterioles and
      immunohistochemical studies of the rat have indicated that PACAP binds to a VPAC1
      receptor in the cerebral vasculature of this species. We have investigated the
      perikaryal origin of the nerve fibers innervating the subarachnoidal blood
      vessels of the rat by combined retrograde tracing with Fluorogold and
      immunohistochemistry. The in vivo neuronal retrograde tracings were done by
      injection of 2% Fluorogold in water into the subarachnoidal space in the area of
      the middle cerebral artery. The retrograde transported tracer was detected by use
      of an antibody against Fluorogold. One week after the injections, the animals
      were vascularly perfused with Stephanini's fixative and labeled perikarya were
      found bilaterally in the trigeminal, sphenopalatine, and otic ganglia. The
      retrograde Fluorogold tracings were combined with immunohistochemistry for PACAP
      using a mouse monoclonal antibody and the biotinylated tyramide amplification
      system. Double labeled perikarya containing both Fluoro-gold and PACAP were found
      predominantly in the trigeminal ganglion, and only rarely in the otic and
      sphenopalatine ganglion. Summarizing, our retrograde tracings combined with
      immunohistochemistry indicate that the perikarya in the trigeminal ganglion are
      the main origin of PACAPergic nerve fibers projecting to the cerebral vasculature
      of the rat.

PMID- 15181372
TI  - Augmented delayed infarct expansion and reactive astrocytosis after permanent
      focal ischemia in apolipoprotein E4 knock-in mice.
AB  - Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4
      (4/4)-knock-in (KI) mice, we aimed to examine whether an apoE isoform-specific
      exacerbation of delayed infarct expansion occurs after permanent middle cerebral
      artery occlusion (pMCAO). Compared with 2/2- or 3/3-KI mice, 4/4-KI mice
      exhibited significantly larger infarct volumes and worse neurologic deficits
      after pMCAO, with no significant differences between the latter two groups.
      Infarct volume in 4/4-KI mice was significantly increased from 1 to 5 days after
      pMCAO, whereas that in 2/2- or 3/3-KI mice was not significantly altered. DNA
      fragmentation in the peri-infarct area as detected by terminal deoxynucleotidyl
      transferase-mediated deoxyuridine triphosphatenick end-labeling was increased to
      a similar degree in all of the KI mice by 5 days after pMCAO, with no significant
      differences among the mouse groups. At every time-point examined, human apoE was
      most markedly expressed in the peri-infarct area, with similar immunoreactivity
      among the three lines of KI mice. The glial fibrillary acidic protein
      immunoreactive burden in the peri-infarct area was progressively increased
      through 7 days in 4/4-KI mice, but not in 2/2- or 3/3-KI mice. Taken together,
      these data show that the apoE4 isoform acts to aggravate delayed infarct
      expansion and peri-infarct reactive astrocytosis during the subacute phase of
      pMCAO in genetically engineered apoE-KI mice.

PMID- 15181371
TI  - Epsilon protein kinase C mediated ischemic tolerance requires activation of the
      extracellular regulated kinase pathway in the organotypic hippocampal slice.
AB  - Ischemic preconditioning (IPC) promotes brain tolerance against subsequent
      ischemic insults. Using the organotypic hippocampal slice culture, we conducted
      the present study to investigate (1) the role of adenosine A1 receptor (A1AR)
      activation in IPC induction, (2) whether epsilon protein kinase C (epsilonPKC)
      activation after IPC is mediated by the phosphoinositol pathway, and (3) whether
      epsilonPKC protection is mediated by the extracellular signal-regulated kinase
      (ERK) pathway. Our results demonstrate that activation of A1AR emulated IPC,
      whereas blockade of the A1AR during IPC diminished neuroprotection. The
      neuroprotection promoted by the A1AR was also reduced by the epsilonPKC
      antagonist. To determine whether epsilonPKC activation in IPC and A1AR
      preconditioning is mediated by activation of the phosphoinositol pathway, we
      incubated slices undergoing IPC or adenosine treatment with a phosphoinositol
      phospholipase C inhibitor. In both cases, preconditioning neuroprotection was
      significantly attenuated. To further characterize the subsequent signal
      transduction pathway that ensues after epsilonPKC activation, mitogen-activated
      protein kinase kinase was blocked during IPC and pharmacologic preconditioning
      (PPC) (with epsilonPKC, NMDA, or A1AR agonists). This treatment significantly
      attenuated IPC- and PPC-induced neuroprotection. In conclusion, we demonstrate
      that epsilonPKC activation after IPC/PPC is essential for neuroprotection against
      oxygen/glucose deprivation in organotypic slice cultures and that the ERK pathway
      is downstream to epsilonPKC.

PMID- 15181373
TI  - Translation-state analysis of gene expression in mouse brain after focal
      ischemia.
AB  - Confounding any genome-scale analysis of gene expression after cerebral ischemia
      is massive suppression of protein synthesis. This inefficient translation
      questions the utility of examining profiles of total transcripts. Our approach to
      such postischemic gene profiling in the mouse by microarray analysis was to
      concentrate on those mRNAs bound to polyribosomes. In our proof-of-principle
      study, polysomally bound and unbound mRNAs were subjected to microarray analysis:
      of the 1,161 transcripts that we found to increase after ischemia, only 36% were
      bound to polyribosomes. In addition to the expected increases in heat-shock
      proteins and metallothioneins, increases in several other bound transcripts
      involved in the promotion of cell survival or antiinflammatory behavior were
      noted, such as CD63 (Lamp3), Lcn2 (lipocalin-2), Msn (moesin), and UCP2
      (uncoupling protein 2), all of which showed increases in cognate protein by
      Western blotting. The list of heretofore nonfunctionally annotated transcripts
      (RIKEN clones/ESTs) that increased appeared to be novel. How some transcripts are
      selected in ischemic brain for translation into protein, while others are
      rejected, is not clear. The length of the 5'-UTR in the ischemically induced
      transcripts that occur in the NCBI RefSeq database did not indicate any general
      tendency to be more than 200 nt, nor to be longer than the 5'-UTRs of the unbound
      transcripts. Thus, the presence of a complex 5'-UTR region with internal ribosome
      entry sites (IRES) or polypyrimidine tracts (TOP) does not appear to be the basis
      of selection for translation in ischemic brain.

PMID- 15181374
TI  - Leukocyte-endothelium interactions during permanent focal cerebral ischemia in
      mice.
AB  - The contribution of leukocyte infiltration to brain damage after permanent focal
      cerebral ischemia and the underlying molecular mechanisms are still unclear.
      Therefore, the aim of this study was to establish a mouse model for the
      visualization of leukocytes in the cerebral microcirculation in vivo and to
      investigate leukocyte-endothelial interaction (LEI) after permanent middle
      cerebral artery occlusion (MCAO). Sham-operated 129/Sv mice showed physiologic
      LEI in pial venules as observed by intravital fluorescent microscopy. Permanent
      focal cerebral ischemia induced a significant increase of LEI predominantly in
      pial venules. The number of rolling and adherent leukocytes reached 36.5 +/-
      13.2/100 microm x min and 22.5 +/- 7.9/100 microm x min, respectively at 120
      minutes after MCAO (P = 0.016 vs. control). Of note, rolling and adherent
      leukocytes were also observed in arterioles of ischemic animals (7.3 +/- 3.0/100
      microm x min rolling and 3.0 +/- 3.6/100 microm x min adherent). Capillary
      density was not different between groups. These results demonstrate that
      leukocytes accumulate in the brain not only after transient but also after
      permanent focal cerebral ischemia and may therefore contribute to brain damage
      after stroke without reperfusion.

PMID- 15181375
TI  - Olfactory response in the temporal cortex of the elderly measured with near
      infrared spectroscopy: a preliminary feasibility study.
AB  - The pathway for the olfactory response may be affected at an early stage of
      Alzheimer's disease. Measurement of the olfactory response in the elderly is
      therefore of particular interest. In this feasibility study, near-infrared
      spectroscopy was used to measure the olfactory response in 21 patients aged 56 to
      79 years. Eight subjects had no memory complaints whereas 13 had subjective
      memory complaints, mild cognitive impairment, or very mild Alzheimer's disease.
      The optodes were placed over the temporal lobe, with the emitting optode over the
      pole and the receiving optode over the superior gyrus. The response to vanilla
      (1% in sterile H2O) in a test tube held immediately beneath the nostrils was
      compared to the response to sterile H2O only. Four control subjects had a clearly
      definable response with increased oxyhemoglobin and decreased deoxyhemoglobin
      bilaterally. The response was measured as the sum of the deviation of oxygenated
      and deoxygenated hemoglobin from baseline mean. With a cut-off determined after
      examination of responses to vanilla and sham stimulus, group difference was
      significant for response to vanilla (chi2 test, P = 0.03). Response amplitudes to
      vanilla in the patient group were within the range of those to sham stimuli.

PMID- 15181376
TI  - Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor
      translocation after focal ischemia in the rat.
AB  - Apoptosis plays a critical role in many neurologic diseases, including stroke.
      Cytochrome c release and activation of various caspases are known to occur after
      focal and global ischemia. However, recent reports indicate that caspase
      independent pathways may also be involved in ischemic damage. Apoptosis-inducing
      factor (AIF) is a novel flavoprotein that helps mediate caspase-independent
      apoptotic cell death. AIF translocates from mitochondria to nuclei where it
      induces caspase-independent DNA fragmentation. Bcl-2, a mitochondrial membrane
      protein, protects against apoptotic and necrotic death induced by different
      insults, including cerebral ischemia. In the present study, Western blots
      confirmed that AIF was normally confined to mitochondria but translocated to
      nuclei or cytosol 8, 24, and 48 hours after onset of ischemia. Overall, AIF
      protein levels also increased after stroke. Confocal microscopy further
      demonstrated that nuclear AIF translocation occurred in the peri-infarct region
      but not in the ischemic core where only some cytosolic AIF release was observed.
      Our data also suggest that AIF translocated into nuclei after cytochrome c was
      released into the cytosol. Bcl-2 transfection in the peri-infarct region blocked
      nuclear AIF translocation and improved cortical neuron survival.

PMID- 15181377
TI  - Neuroprotection of ischemic brain by vascular endothelial growth factor is
      critically dependent on proper dosage and may be compromised by angiogenesis.
AB  - Vascular endothelial growth factor (VEGF) is currently considered a potential
      pharmacologic agent for stroke therapy because of its strong neuroprotective and
      angiogenic capacities. Nonetheless, it is unclear how neuroprotection and
      angiogenesis by exogenous VEGF are related and whether they are concurrent
      events. In this study, the authors evaluated by stereology the effect of VEGF on
      neuronal and vascular volume densities of normal and ischemic brain cortices of
      adult male Sprague-Dawley rats. Ischemia was induced by a 4-hour occlusion of the
      middle cerebral artery. Low, intermediate, and high doses of VEGF165 were infused
      through the internal carotid artery for 7 days by an indwelling osmotic pump. The
      low and intermediate doses, which did not induce angiogenesis, significantly
      promoted neuroprotection of ischemic brains and did not damage neurons of normal
      brains. In contrast, the high dose that induced angiogenesis showed no
      neuroprotection of ischemic brains and damaged neurons of normal brains. These
      findings suggest that in vivo neuroprotection of ischemic brains by exogenous
      VEGF does not necessarily occur simultaneously with angiogenesis. Instead,
      neuroprotection may be greatly compromised by doses of VEGF capable of inducing
      angiogenesis. Stroke intervention efforts attempting to induce neuroprotection
      and angiogenesis concurrently through VEGF monotherapy should be approached with
      caution.

PMID- 15181378
TI  - Negative functional response to sensory stimulation and its origins.
AB  - Functional imaging studies typically give prominence to positive responses.
      However, negative changes that accompany activation-induced positive responses
      are not yet clearly understood. The authors investigated the origin of sustained
      negative CBF responses that accompanied positive CBF changes. Measurements were
      made in the rat somatosensory cortex in response to whisker stimulation using
      laser-Doppler imaging. Flux images indicative of CBF were obtained at rest and
      during whisker stimulation with a spatial resolution of 200 microm. Large and
      intermediate blood vessels in the cortical surface exhibiting high flux values
      were clearly resolved. This greatly reduced the contamination of the tissue pixel
      volume with macroscopic blood vessels. Regions that responded positively to
      whisker stimulation were from areas with intermediate to low baseline flux and
      distinctly away from high flux areas. Stimulation-induced change in signal
      intensity was the largest in pixels with low baseline flux, presumably from
      tissue and microvessels. Simultaneously, a sustained decrease in signal intensity
      was observed in regions with high baseline flux values. The temporal coherence,
      macrovascular origin, lesser trial-to trial variability, and complete absence of
      the negative CBF response in the microvascular regions suggest that it may be
      purely hemodynamic in nature.

PMID- 15181380
TI  - Transcultural issues in mood and anxiety disorders: a focus on Japan.
AB  - Accurate comparisons of the prevalence of psychiatric disorders across Eastern
      and Western cultures are difficult and limited by methodological problems.
      Nevertheless, using standardized diagnostic and evaluation techniques, recent
      surveys have suggested that depression and anxiety disorders exist in all
      countries and cultures examined thus far, although variations in the prevalence
      rates and symptomatology may exist. This article discusses the influence and
      impact that culture can have on recognizing and treating mood and anxiety
      disorders, with a particular focus on Japan. Over the last 20 years, studies have
      consistently reported an increase in mental illness in Japan, especially symptoms
      of depression and anxiety. While such symptoms have had an adaptive cultural role
      in the past, current social and economic changes in Japan have turned any
      adaptive advantage into a potentially significant disadvantage, with a major
      impact on the capacity of individuals to function adequately. The situation is
      compounded by the fact that Japanese patients are reluctant to openly discuss
      disturbances of mood, since these are considered to be indicative of personal
      weakness rather than treatable medical conditions. Reluctance to discuss personal
      mental health hinders timely recognition and appropriate treatment.

PMID- 15181381
TI  - Making advances where it matters: improving outcomes in mood and anxiety
      disorders.
AB  - Mood and anxiety disorders are among the most prevalent psychiatric illnesses and
      are associated with considerable morbidity and mortality. Selective serotonin
      reuptake inhibitors (SSRIs) are safe and effective treatments for major
      depression and anxiety disorders, and have become the most widely prescribed
      antidepressants worldwide. However, several issues limit SSRI treatment outcomes.
      Although SSRIs have a wider therapeutic margin and a milder side-effect profile
      compared to earlier antidepressants, even minor SSRI side effects can have a
      major impact on treatment outcomes by interfering with patient compliance. Nausea
      is one of the most common early SSRI side effects, and advances in SSRI delivery
      systems can diminish this. A controlled-release formulation of paroxetine targets
      the site of absorption for a more distal region of the small intestine, thereby
      avoiding the stimulation of upper gastrointestinal serotonin receptors that
      mediate nausea. The sustained-release characteristics also reduce the amplitude
      in blood level peaks and troughs, which may lead to diminished side effects and
      enhanced efficacy. Sexual side effects and weight gain are important sustained
      SSRI side effects, which affect compliance during continuation and maintenance
      phases of treatment. Several strategies address SSRI sexual side effects,
      including the use of adjunctive medication and/or manipulations in the scheduling
      of drug administration. Depression negatively impacts the management of many
      medical illnesses, including cardiovascular disease, cancer, and infectious
      diseases. The recognition and treatment of depression leads to improved outcomes
      in the management of breast cancer. Prophylactic SSRI treatment significantly
      reduces the incidence of interferon-associated depression and enhances completion
      rates in malignant melanoma.

PMID- 15181382
TI  - Pharmacologic differences among the SSRIs: focus on monoamine transporters and
      the HPA axis.
AB  - Depression is a widespread and serious disorder that afflicts an estimated 13.1
      to 14.2 million adults in the United States each year. Even more compellingly,
      the lifetime prevalence rate of depression in the US has recently been estimated
      to include 16.2% of adults (21% women, 13% men), or >32.6 million people. There
      are multiple putative "causes" of depression, with approximately one-third of an
      individual's propensity for unipolar depression due to genetic vulnerability,
      while the remaining two-thirds is due to environmental factors. Although the
      selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to
      mainly act by selectively binding to the serotonin (5-HT) transporter to block
      reuptake of 5-HT from the synapse into the presynaptic nerve terminal, thereby
      increasing synaptic serotonin concentrations, some of the SSRIs also exhibit
      other neuropharmacologic effects. One such example is the high affinity for
      paroxetine in blocking norepinephrine reuptake. Another is the inhibition of
      dopamine reuptake by sertraline. In depression, hyperactivity of corticotropin
      releasing factor (CRF)--producing neurons contribute to the well-characterized
      hypothalamic-pituitary-adrenal axis hyperactivity of depression. Increased
      activity of extrahypothalamic CRF circuits are believed to contribute to several
      depressive symptoms. Treatment and certain SSRIs have been shown to reduce the
      activity of CRF neurons and may contribute to their therapeutic action. Each SSRI
      apparently has its own unique pharmacologic properties that likely underlie their
      observed differences in clinical use.

PMID- 15181383
TI  - Determinants of repeated-sprint ability in well-trained team-sport athletes and
      endurance-trained athletes.
AB  - AIM: To examine the importance of peak .VO(2) in determining repeated-sprint
      ability (RSA), we recruited 20 well-trained females (10 team-sport athletes and
      10 endurance-trained runners; mean SD peak .VO(2): 3.3+/-0.2 L x min(-1)) who
      were homogenous with respect to peak .VO(2) (mean difference = 0.05 L x min(-1)).
      METHODS: Tests consisted of a RSA cycle test (5 x 6-s max sprints every 30 s) and
      a peak .VO(2) test. Venous and capillary blood was sampled immediately before and
      after the 5 x 6-s cycle test for the determination of hypoxanthine concentration
      ([Hx]), lactate concentration ([La-]) and pH; blood buffer capacity (beta(blood))
      was also estimated. RESULTS: The team-sport athletes had significantly higher
      peak power for the 1(st) sprint (P(1); W x kg(-1)), total work for 5 x 6-s
      sprints (W(tot); J x kg(-1)) and power decrement across the 5 sprints (P(dec)),
      (p<0.05). There were also significant between-group differences for post-test
      values of [Hx], [La-] and pH (p<0.05). While there was no significant difference
      in beta(blood) between the 2 groups (p=0.10), there was a moderate effect
      (d=0.77). CONCLUSION: These results suggest that factors in addition to peak
      .VO(2) are likely to be important for RSA.

PMID- 15181384
TI  - Physiological variables to use in the gender comparison in highly trained
      runners.
AB  - AIM: The aims of this investigation were to compare physiological characteristics
      between highly trained middle-distance and marathon male (n=17) and female (n=11)
      runners; to determine the most suitable variables to use in the gender comparison
      in these subjects, considering physical difference between genders; and to
      indicate some of the best predictors of performance in running events in which
      oxidative metabolism prevails. METHODS: Subjects performed a progressive maximal
      exercise on the treadmill to determine maximal oxygen uptake (VO(2max)) and
      velocities corresponding to a blood lactate concentration of 4 mmol x L(-1)
      (upsilon(OBLA)) and to the lactate threshold (upsilon(LT)). Cost of running (Cr)
      and maximal aerobic velocity (upsilon(a max)) were calculated from VO(2)
      measurements. RESULTS: Males presented higher VO(2max), upsilon(a max),
      upsilon(OBLA), upsilon(LT), and VO(2) @ upsilon(OBLA) and upsilon(LT) (p<0.001),
      but females had higher upsilon(OBLA) and upsilon(LT) (p<0.01) expressed as
      %VO(2max). upsilon(a max) correlated with performance time relative to the world
      record in both, females (r=-0.77, p<0.01) and males (r=-0.58, p<0.05); and
      upsilon(LT) with performance only in males (r=-0.59, p<0.05). CONCLUSION: In
      conclusion, female athletes seemed to compensate partly their aerobic profile
      with higher %VO(2max) @ u(OBLA) and u(LT), suggesting that both maximal and
      submaximal physiological variables should be considered when evaluating and
      comparing highly trained athletes of both genders. upsilon(a max) is one of the
      best predictors of performance in running events in which oxidative metabolism
      prevails.

PMID- 15181385
TI  - Development and validation of a sport-specific exercise protocol for elite youth
      soccer players.
AB  - AIM: The aims of the current study were, firstly, to quantify the motion
      characteristics of professional youth soccer players and, secondly, to develop
      and validate a soccer-specific exercise protocol (SSEP). METHODS: The motion
      characteristics of 12 first team members and 12 scholars (under 19s), signed to
      an English Premiership club were determined via motion analysis. Motion profiles
      from the analysis were then used to develop a SSEP for a non-motorised treadmill.
      Validity of the protocol was checked with 6, healthy, male soccer players who
      completed the SSEP and, on a separate occasion, a soccer match. Heart rates were
      recorded during both trials, in addition, capillary blood and expired air samples
      were taken, and RPE recorded, during the SSEP. RESULTS: Youth team players
      covered 10274+/-609 m, compared to 9741+/-882 m by the first team players
      (t=1.72, p>0.05; 95% CI for the difference = -1174 m to 109 m). The trend for
      greater mean distance covered by youth players could be attributed to the
      distances covered while jogging and running. Mean heart rate response was 166+/-9
      beatsxmin(-1) during match play and 166+/-12 beatsxmin(-1) during the SSEP
      (t=0.164, p>0.05). Mean .VO(2) during the SSEP was 70+/-3% of .VO(2max). Blood
      lactate concentration fell from a mean value of 5.37+/-1.15 mmol x L(-1) during
      the first half to 4.74+/-1.25 mmol x L(-1) during the 2(nd) half (t=2.52,
      p<0.05). CONCLUSION: The findings of this study suggest that the protocol
      developed induced a similar physiological load to soccer match play and provides
      the opportunity to study the physiological demands of soccer.

PMID- 15181386
TI  - Effect of moderate exercise on excess post-exercise oxygen consumption and
      catecholamines in young women.
AB  - AIM: The purpose of this study was to examine the effects of moderate exercise on
      the magnitude and duration of excess post-exercise oxygen consumption (EPOC) and
      catecholamine concentrations in 7 young women. METHODS: The subjects performed 30
      or 60 minutes of exercise (30-ME and 60-ME, respectively) on separate days at an
      intensity of 60% of maximal oxygen uptake on a cycle ergometer. The glucose,
      epinephrine and norepinephrine in the plasma, and free fatty acids and glycerol
      in the serum were measured at the end of the 60 min of the rest period before
      each exercise, immediately after the performance of each exercise and 30 min, 1,
      2 and 24 h time points after each exercise. RESULTS: EPOC lasted for 46.1+/-25.4
      and 116.1+/-79.8 min after the 30- and 60-ME, respectively. Corresponding total
      EPOC were 2636+/-1125 and 5208+/-1880 ml, respectively. The mean differences were
      statistically significant (p<0.05 each). The serum free fatty acids significantly
      increased immediately after the 60-ME. The serum glycerol was significantly
      increased immediately after the 30-ME and was also significantly increased
      immediately after and 30 min time point after the 60-ME. The plasma epinephrine
      and norepinephrine significantly increased immediately after the 30- and 60-ME,
      respectively. The plasma epinephrine at the 30 min time point after the 60-ME
      significantly correlated with the magnitude (r=0.955) and duration (r=0.897) of
      EPOC. Norepinephrine at the 30 min time point after the 60-ME also significantly
      correlated with the magnitude (r=0.774) of EPOC. CONCLUSION: The results indicate
      that longer duration exercise results in a greater and longer EPOC, and the
      plasma catecholamines may possibly contribute to EPOC in young women. Although,
      the overall magnitude of EPOC is small, if exercise frequency and compliance are
      strong, some long term benefits may accrue.

PMID- 15181387
TI  - Effects of 8 days acclimation on biological and performance response in a
      tropical climate.
AB  - BACKGROUND: This study was designed to determine the acclimation process elicited
      by exposure to a tropical climate. METHODS: Nine triathletes performed 3 outdoor
      indirect continuous running multistage tests in both thermoneutral and tropical
      conditions. Before travelling to the tropical area (Martinique Island, FWI), the
      triathletes performed the thermoneutral test (TN) in 14 degrees C and 45% rh
      conditions. The tropical tests were performed 2 and 8 days after arrival (T2 and
      T8, performed at a mean environmental temperature of 33.4 degrees C and 75.5%
      rh). The day before T8, blood samples were drawn for biochemical analysis. During
      each test, tympanic temperature, sweat rate, weight loss, heart rate (HR), and
      performance were recorded. RESULTS: The results demonstrated that: 1) the mean
      tympanic temperature was greater in T2 (p<0.001) and T8 (p<0.01) than in TN; 2)
      the mean sweat rate was significantly greater (p<0.001) in T2 and T8 than in TN
      and significantly greater in T8 than in T2 (p<0.03); 3) the weight loss after
      trials was significantly greater (p<0.001) in T2 and T8 than in TN and in T8 than
      in T2 (p<0.04); 4) the mean HR and the HR at rest were significantly greater in
      T2 than in TN (p<0.001) and T8 (p<0.005); 6) significant reductions were observed
      in T8 vs TN in red cell count (p<0.05) and plasma proteins (p<0.04), the
      consequence of a 7.5% plasma volume expansion; and 7) the performance was
      significantly lower in both T2 (p<0.02) and T8 (p<0.03) than in TN. CONCLUSIONS:
      We concluded that 8 days exposure to hot/wet conditions induced impairments in
      physiological responses and performance that were still evident on the 8th day.
      Further and longer outdoor studies are needed to investigate if return to optimal
      performance levels after adaptation to hot/wet conditions is possible.

PMID- 15181388
TI  - Multicompartment model to assess body composition in professional water polo
      players.
AB  - AIM: The aim of this study was to compare differences between skinfold
      thicknesses (SK), bioelectrical impedance analysis (BIA), a 2-compartment model
      (2C), and 2, 3-compartment models (3C) of percent body fat (%BF) assessment with
      a 4-compartment model (4C) in professional water polo athletes. METHODS: Ten male
      subjects, 18 to 29 years of age, participated in this study. Under water
      weighing, deuterium dilution, and dual-energy X-ray absorptiometry (DXA) were
      used to provide the required values for the models. The two, 3C models used were
      established by Withers et al. (3C-W) and by the DXA manufacturers (3C-DXA). 4C
      was also established by Withers et al. RESULTS: There were no significant
      differences between 2C, 3C-W, and 3C-DXA when compared with 4C (criterion model).
      There were no significant differences between 2C and 3C-W. %BF was significantly
      greater using 2C compared with 3C-DXA. %BF derived from SK and BIA were
      significantly greater than all other METHODS: 4C was best correlated with 3C-W
      (R2=0.998), followed by 2C (R2=0.806), 3C-DXA (R2=0.5071), SK (R2=0.2945), and
      BIA (R2=0.2377). CONCLUSION: We conclude that 2C and 3C-W assess %BF equally as
      well as 4C; however, SK and BIA significantly over-estimated %BF in water polo
      athletes.

PMID- 15181389
TI  - Postexercise increase of free fatty acids. A qualitative indicator for free fatty
      acid utilisation during exercise?
AB  - AIM: The purpose of this study was to verify the hypothesis that the postexercise
      increase (PEI) of plasma free fatty acid (FFA) concentrations after cessation of
      exercise is a suitable qualitative indicator for the FFA utilisation during the
      foregoing exercise. METHODS: Fourteen, 17 and 23 healthy subjects participated in
      3 test series performing several prolonged exercise protocols (PEP) on a bicycle
      ergometer. During and after cessation of the PEP heart frequency, lactate and FFA
      were measured. RESULTS: Fasting resulted in an increase of PEI (90%, p<0.05) and
      the synergistic use of upper body muscles during cycling caused a significant
      rise of PEI compared to "regular" cycling (39%, p<0.01). Increasing workload step
      by step produced continuously rising PEI (p<0.05), only from 42% to 50% of
      maximal workload PEI decreased by 17% (p=n.s.). CONCLUSION: The results support
      the hypothesis that PEI is a suitable qualitative indicator for FFA utilisation
      during a foregoing exercise. Furthermore the results indicate that there is a
      maximum of FFA utilisation in the legs at 40% of maximum workload during cycling
      and that the upper body muscles contribute substantially to total body FFA
      turnover at high inten-sities, an aspect to which possibly too little attention
      has been paid to when quantifying FFA turnover during cycling.

PMID- 15181390
TI  - Low back pain in competitive rhythmic gymnasts.
AB  - AIM: It has been reported that rhythmic gymnasts are at risk of suffering from
      low back injuries, because of repetitive lumbar hyperextensions. On the other
      hand, this sport requires features of leanness, muscular strength and flexibility
      that should represent protective factors for back pain. METHODS: This cross
      sectional study aimed to assess the prevalence of low back pain in 67 club-level
      competitive rhythmic gymnasts aged 13-19 years. A standardized questionnaire was
      used to evaluate back-pain symptoms. Anthropometric measurements, time spent in
      physical activity, psychological testing results, smoking habits and age of
      menarche were recorded. One hundred and four age-matched general females served
      as control group. RESULTS: Low back pain complaints were reported by 7 rhythmic
      gymnasts and by 27 controls (10.4% vs 26.0%, p<0.05); the prevalent location of
      back pain was bilateral in gymnasts and central in controls. Gymnasts had lower
      body weight, body mass index, fat body mass and delayed menarche. The females
      with low-back pain displayed higher body weight, body mass index, fat body mass,
      age, a greater smoking habit and more anxious/depressive behaviour, both in the
      gymnast and in the control group. CONCLUSION: Competitive, club-level rhythmic
      gymnasts show a reduced prevalence of low back-pain. Being younger in age, having
      greater leanness, not smoking, displaying less anxious/depressive behaviour, and
      developing increased muscle strength and flexibility, all can represent
      preventive factors for low back pain. This study suggests that rhythmic
      gymnastics is not a discipline at increased risk of low back pain.

PMID- 15181391
TI  - Postexercise hypotension and hemodynamics: the role of exercise intensity.
AB  - AIM: Although postexercise hypotension (PEH) has already been extensively
      demonstrated, the influence of exercise intensity on its magnitude and mechanisms
      is still controversial. METHODS: Twenty-three normotensive subjects were
      submitted to a control (45 minutes of rest) and 3 exercise sessions (cycle
      ergometer, 45 minutes at 30%, 50% and 75% of .VO(2peak)) to investigate the role
      of exercise intensity on PEH. Blood pressure (BP - auscultatory), heart rate (HR 
      ECG), and cardiac output (CO - CO2 rebreathing) were measured before and after
      the control and exercise sessions. RESULTS: Systolic BP decreased significantly
      after exercise at 50% and 75% of .VO(2peak). Diastolic BP increased significantly
      during the control session, did not change after exercise at 30% of .VO(2peak),
      and decreased significantly after exercise at 50% and 75% of .VO(2peak). This
      fall was greater and longer after more intense exercise. CO and systemic vascular
      resistance (SVR) responses were similar between sessions, CO increased whereas
      SVR decreased significantly. Stroke volume (SV) increased and heart rate (HR)
      decreased following control and exercise at 30% of .VO(2peak) whereas SV
      decreased and HR increased after exercise at 50% and 75% of .VO(2peak).
      CONCLUSION: PEH is greater and longer after more intense exercise. BP profile is
      followed by a decrease in SVR and an increase in CO, what was not influenced by
      previous exercise. The increase in CO is caused by an increase in SV after rest
      and low intensity exercise and by an increase in HR after moderate and more
      intense aerobic exercise.

PMID- 15181392
TI  - Effects of successive running and cycling on the release of atrial natriuretic
      factor in highly trained triathletes.
AB  - AIM: To evaluate the influence of successive running and cycling on both exercise
      induced arterial hypoxemia (EIAH) and atrial natriuretic factor (ANF) release, 5
      triathletes performed 2 separate exercise trials. METHODS: One trial consisted of
      a 20-min+20-min successive cycle-run exercise (C(1)-R(2)) and the other consisted
      of a 20-min+20-min successive run-cycle exercise (R(1)-C(2)). Arterial
      oxygenation (PaO(2)) and ANF were determined at pre-exercise, at the end of each
      20-min segment of exercise and after 10 min of recovery. RESULTS: EIAH was noted
      during C(1)-R(2) and R(1)-C(2) trials. A higher EIAH was observed during running
      compared with cycling performed in the 1(st) position (R(1) vs C(1)) in the
      succession. In contrast, no difference was observed between successive running
      and successive cycling (R(2) vs C(2)), (-10.6+/-7.0 vs -15.6+/-4.0 mmHg for C(1)
      R(2) and -20.9+/-6.0 vs -16.2+/-2.4 mmHg for R(1)-C(2)). ANF showed no difference
      between cycling and running performed in first position, whereas a significantly
      lower ANF was observed during successive cycling compared with successive running
      (C(2) vs R(2)) (19.9+/-3.72 vs 36.2+/-6.4 pmol.L(-1)). During recovery, neither
      PaO(2) nor ANF plasma returned to baseline level after either trial. CONCLUSION:
      This study provides new information on some of the physiological modifications
      that occur during multi-sports. Specifically, the impact of the modality of the
      successive exercise on ANF release and body fluid regulation was observed.
      Cycling as the successive exercise seems to cause lower ANF release than does
      running.

PMID- 15181393
TI  - Physical activity in young and elderly subjects.
AB  - AIM: In the current recommendations for energy intake of different countries as
      well as in the international WHO recommendations for energy intake it is assumed
      that the elderly are less physically active than young adults. Therefore, the aim
      of the present study was to compare physical activity patterns and physical
      activity level (PAL) of young and elderly subjects. METHODS: In 178 female (age
      67.8+/-5.7 y, BMI 26.4+/-3.7 kg/m(2)) and 107 male (age 66.9+/-5.1 y, BMI 26.3+/
      3.1 kg/m(2)) participants of the longitudinal study on nutrition and health
      status in an aging population of Giessen, Germany as well as in a young age group
      consisting of 154 women (age 24.8+/-3.0 y, BMI 21.0+/-2.2 kg/m(2)) and 68 men
      (age 26.8+/-3.4 y, BMI 23.3+/-2.4 kg/m(2)) different activities like occupational
      work, housework, gardening, walking and sports were assessed by a questionnaire.
      Energy expenditure of the different activities was calculated using multipliers
      for resting metabolic rate (RMR) according to the WHO. The same multipliers were
      used for young and elderly subjects. RMR was measured by indirect calorimetry
      after an overnight fast. PAL of the subjects was calculated as total energy
      expenditure divided by RMR. RESULTS: Young adults did more occupational work and
      performed more sports than elderly subjects. In contrast elderly women did more
      housework in comparison to young women, and elderly men walked more than young
      men. Both elderly women and men did more gardening than young women and men. In
      elderly women, PAL was significantly higher in comparison to young women, whereas
      PAL of young and elderly men did not differ significantly. CONCLUSION: The
      results indicate that despite different activity patterns, the young-old do not
      necessarily show a lower PAL than young subjects.

PMID- 15181394
TI  - The characteristics and effects of motivational music in exercise settings: the
      possible influence of gender, age, frequency of attendance, and time of
      attendance.
AB  - AIM: The purpose of the present study was to investigate the characteristics and
      effects of motivational music in British gymnasia. The secondary purpose was to
      determine whether the characteristics and effects of motivational music were
      invariant in relation to gender, age, frequency of gymnasium attendance, and the
      time of day at which exercise participants attended gymnasia. METHODS:
      Participants (n=532) from 29 David Lloyd Leisure exercise facilities across
      Britain responded to a questionnaire that was designed to assess music
      preferences during exercise via 2 open-ended questions and 1 scaled-response
      item. RESULTS: A content analysis of the questionnaire data yielded 45 analytic
      properties that were grouped into the following categories: specific music
      factors, general music factors, music programme factors, delivery factors,
      televisual factors, personal factors, contextual factors, and psychophysical
      response factors. The relative incidence of these analytic properties across
      gender groups (male/female), age groups (16-26 y, 27-34 y, 35-45 y, 46+ y),
      frequency of attendance groups (low, medium, high), and time of attendance groups
      (morning, afternoon, evening) was tested by use of chi(2) analyses. Of the
      personal variables tested, age exerted the greatest influence on musical
      preference during exercise; older participants expressed a preference for
      quieter, slower, and generally less overtly stimulative music. CONCLUSION: Music
      programmes that are prescribed to accompany exercise should be varied in terms of
      musical idiom and date of release. Such programmes will account for the
      preferences of different groups of exercise participants that attend gymnasia at
      different times of the day. Further, the music chosen should be characterised by
      a strong rhythmical component.

PMID- 15181395
TI  - Neuromuscular effects of three training methods in ageing women.
AB  - AIM: The present study aimed to compare the effects of 3 strength development
      methods on muscular mass and muscular strength in healthy ageing women. METHODS:
      Thirty-two healthy women, 62 to 75 years old were randomised into 3 groups. The 3
      groups performed 4 sessions a week of strength development for 6 weeks. The 1(st)
      group (SC) climbed up and down 300 stairs per session. The 2(nd) group (ES)
      followed an electrostimulation programme on the quadriceps muscles. The 3(rd)
      group (SC+ES) combined stair climbing with electrostimulation. Before and after
      the 3 programmes, the muscular mass of the leg was assessed using a biphotonic
      absorptiometry machine. Isometric (angle 20 degrees and 100 degrees ) and
      isokinetic (60 degrees /s and 240 degrees /s) knee extension torque was measured
      using an isokinetic dynamometer. RESULTS: None of the programmes changed the
      muscular mass. All 3 groups increased isometric (angle 20 degrees, p<0.001; angle
      100 degrees, p<0.003) and isokinetic (60 degrees /s, p<0.0001; 240 degrees /s,
      p<0.0001) knee extension torque. None of the programmes appeared more efficient
      than the others for muscular mass or muscular strength. CONCLUSION: Six weeks of
      activity (SC, ES or SC+ES) improved the isometric and dynamic muscular strength
      in ageing healthy women. However, this period was too short to change the
      muscular mass. None of the activities presented a real advantage over the others
      in ageing women.

PMID- 15181396
TI  - Vigorous exercise training is not associated with prevalence of ventricular
      arrhythmias in elderly athletes.
AB  - AIM: Physical activity, when vigorous, is not devoided of arrhythmic risk. Since
      the risk of developing arrhythmias increase as an otherwise healthy person ages,
      the question arises as to whether high intensity physical activity could be
      dangerous in the elderly person. The present study addressed the incidence of
      arrhythmias in elderly athletes in comparison to age-matched control subjects.
      METHODS: We studied 49 male athletes engaged in various sport disciplines, mean
      age 62.3+/-2.3 and 24 sedentary or moderately physically active healthy males,
      mean age 62.9+/-1.7 years (Controls). All subjects underwent 2-D, M-mode and
      Doppler echocardiographic examination, resting ECG and exercise stress test
      followed by 24-hour electrocardiographic monitoring. RESULTS: No pathological
      findings were detected in both experimental groups at echocardiographic
      examination. Exercise performance was greater in athletes than controls (206.9+/
      5.2 vs 156.3+/-12 watt, p<0.01). During exercise test, no significant between
      groups difference was detected in the incidence of ventricular arrhythmias, that
      is multiple premature ventricular contractions (MPVC), polymorphous premature
      ventricular contractions (PPVC) and repetitive premature ventricular contractions
      (RPVC). No subject featured horizontal or downsloping ST segment depression in
      both groups. At 24-hour electrocardiographic monitoring the incidence of the
      overall number of premature ventricular contractions was significantly greater in
      controls than athletes (87.0% vs 63.3%, p<0.05), whereas no significant
      difference were detected in the incidence of discrete ventricular arrhythmias
      between athletes (4.1% MPVC, 14.3% PPVC, 8.2% couplets) and controls (0.5% MPVC,
      16.7% PPVC, 12.5% couplets). CONCLUSION: These finding indicate that in elderly,
      otherwise healthy, athletes vigorous training even to competition does not result
      in a greater incidence of ventricular arrhythmias, although caution should be
      made for a careful preparticipation evaluation.

PMID- 15181398
TI  - Plasma leptin responses to prolonged sculling in female rowers.
AB  - AIM: Plasma leptin concentrations are reduced in the presence of a negative
      energy balance. The purpose of this study was to investigate the effects of a
      prolonged single endurance rowing training session on plasma leptin
      concentrations in female rowers. METHODS: Ten female college level single scull
      rowers participa-ted in this study. Venous blood samples were obtained during the
      early follicular phase of the menstrual cycle immediately before and after on
      water rowing lasting about 2 h (7518+/-293 s; distance covered 18.9+/-1.4 km;
      heart rate 150+/-7 beats. min(-1)). RESULTS: Blood lactate concentration did not
      change significantly during sculling training session (from 1.6+/-0.4 to 1.9+/
      0.5 mmol. L(-1)) indicating that training was performed at moderate intensities.
      Leptin values were significantly reduced immediately after prolonged rowing by a
      mean 44% and no further changes occurred during the first 2 h of recovery.
      Insulin and glucose values were also decreased immediately after prolonged
      rowing. A further reduction in insulin was seen during the 2(nd) hour of
      recovery. No further changes occurred during the first 2 h of recovery in glucose
      concentration. Plasma leptin concentrations immediately after (r=-0.64), and 30
      min (r=-0.66) and 2 h (r=-0.64) after an endurance rowing training session were
      related (p<0.05) to the distance covered. No such relation was observed for other
      measured blood biochemical parameters. Leptin also correlated with insulin
      measured at different time points after endurance training (r>0.64; p<0.05).
      Regression analyses demonstrated a positive relationship between total body fat
      mass and plasma leptin (R(2)>0.70; p<0.001) regardless of sampling time in female
      rowers. CONCLUSION: Our findings indicate that a prolonged low-intensity rowing
      training session results in an energy deficit beyond the threshold that is
      necessary to reduce plasma leptin concentration without changing body fat mass in
      female rowers. It was suggested that plasma leptin could be regarded as a signal
      for metabolic reaction to endurance rowing training session and following
      recovery in female endurance athletes.

PMID- 15181397
TI  - The muscle strength and bone density relationship in young women: dependence on
      exercise status.
AB  - AIM: Numerous studies report an association between muscle strength and bone
      mineral density (BMD) in young and older women. However, the participants are
      generally non-athletes, thus it is unclear if the relationship varies by exercise
      status. Therefore, the purpose was to examine the relationships between BMD and
      muscle strength in young women with markedly different exercise levels. METHODS: 
      EXPERIMENTAL DESIGN: cross-sectional. SETTING: a University research laboratory.
      PARTICIPANTS: 18 collegiate gymnasts and 22 age- and weight-matched
      recreationally active control women. MEASURES: lumbar spine, femoral neck, arm,
      leg and whole body BMD (g/cm(2)) were assessed by dual X-ray absorptiometry. In
      addition, lumbar spine and femoral neck bone mineral apparent density (BMAD,
      g/cm(3)) was calculated. Handgrip strength and knee extensor and flexor torque
      (60 degrees /s) were determined by dynamometry, and bench press and leg press
      strength (1-RM) using isotonic equipment. RESULTS: BMD at all sites and bench
      press, leg press and knee flexor strength were greater in gymnasts than controls
      (p<0.001). In controls, knee extensor torque was significantly correlated to
      femoral neck, limb and whole body BMD (r=0.47-0.55, p<0.05), leg press strength
      was associated with limb and whole body BMD (r=0.52-0.74, p<0.05), and bench
      press strength with arm BMD (r=0.50, p=0.019). In partial correlations
      controlling for weight, leg press strength was related to leg and whole body BMD
      (r=0.46-0.63, p<0.05). There was no association between muscle strength and BMD
      in gymnasts. CONCLUSION: These results suggest that the association between
      muscle strength and BMD in young women is dependent on exercise status. The
      osteogenic effect of increased mechanical loading associated with gymnastics
      training likely contributes to the dissociation of the relationship in gymnasts.

PMID- 15181399
TI  - [Various genetic cardiac diseases predispose to arrhythmias and the risk of
      sudden death].
AB  - Identification of underlying genetic factors has added to understanding of
      arrhythmogenic triggers and determinants of sudden death. Many factors
      (medications, bradycardia, temperature changes) during general anesthesia could
      precipitate malignant dysrhythmia in these patients. Criteria for risk
      stratification for surgical patients are not available: we can only extrapolate
      information collected from medical patients. We describe 4 patients with
      suspected Brugada syndrome (only one was confirmed) during genera anesthesia and
      propose an anesthesiologic management during operation and for the postoperative
      period (36 hours).

PMID- 15181400
TI  - Xenon, a modern anaesthesia gas.
AB  - Xenon is an interesting anesthetic as it appears to lack negative inotropicy and
      vasodilatation, giving great advantages to both patients with limited
      cardiovascular reserve or those who require hemodynamic stability. It has low
      toxicity and is not teratogenic. Xenon gives rapid induction and recovery, due to
      its low blood/gas partition coefficient (0.15), and has a MAC of 63%. Several
      vitro studies showed that Xenon may protect neural cells against ischaemic
      injury. Its low blood solubility can take to diffusion hypoxia if Xenon is not
      substituted by 100% oxygen at the end of anesthesia. It has been shown that,
      compared to other anesthetic regimens, Xenon anesthesia produces the highest
      regional blood flow in the brain, liver, kidney and intestine. In conclusion, the
      most important positive effects of Xenon are cardiovascular stability, cerebral
      protection and favourable pharmacokinetics. Negative points are high cost and the
      limited number of ventilators supplying Xenon.

PMID- 15181401
TI  - [Cardiac protection is a clinical evidence].
AB  - AIM: Anaesthetics may have protective effect against myocardial ischemia. We
      aimed to investigate if sevoflurane administration could exert myocardial
      protection during following coronary occlusion in patients with coronary artery
      disease. METHODS: a). EXPERIMENTAL DESIGN: prospective, randomized study. b).
      SETTING: University Hospital, cardiac surgical operative theatre. c). PATIENTS:
      42 patients with coronary artery disease, scheduled to undergo coronary surgery.
      INCLUSION CRITERIA: severe coronary stenosis of anterior descending coronary
      artery; no collateral flow on angiography; at least two normokinetic segments in
      the myocardial region supplied by the vessel being bypassed. PATIENTS were
      randomized to receive (group S) or not (group C) sevoflurane administration for
      15 min just before coronary occlusion. d). INTERVENTIONS: Transoesophageal Tissue
      Doppler echocardiographic examination of myocardial systolic and early diastolic
      velocities in both groups basally and 60 s after coronary occlusion by the
      surgeon. e). MEASURES: systolic and early diastolic velocities were registered by
      Tissue Doppler from a long-axis view of the interventricular septum or the
      anterior wall of the left ventricle. RESULTS: In group C a significant reduction
      of systolic and diastolic intramyocardial velocities was found during myocardial
      ischemia due to coronary occlusion. CONCLUSION: Treatment with sevoflurane before
      coronary occlusion seem effective in reducing functional myocardial impairment
      due to ischemia.

PMID- 15181402
TI  - Critical bleeding in surgery: conventional therapy and new prospects.
AB  - Perioperative bleeding is one of the most frequent complications of surgery.
      Management of bleeding consists of local control (surgical or endoscopic
      hemostasis), measures to retain adequate circulation and proper transfusion
      procedures. In this review we will discuss various agents with a prohemostatic
      potential and their efficacy to reduce perioperative blood loss. Desmopressin
      increase the plasma concentration of Von Willebrand factor giving an augmentation
      of primary hemostasis. The use of recombinant activated factor VII is based on
      the evidence that activation of coagulation in vivo predominantly proceeds by the
      tissue factor/factor VII (a) pathway. Agents that exerts anti-fibrinolytic
      activity are aprotinin and the group of lysine analogues. The prohemostatic
      effect is due to inhibition of fibrinolysis and to a protective effect on
      platelets. Prohemostatic therapy may achieve an improvement of hemostasis, by
      amelioration of primary hemostasis, stimulation of fibrin formation or inhibition
      of fibrinolysis and seems to be effective in reducing perioperative blood loss
      and transfusion requirements.

PMID- 15181403
TI  - [Anesthesia and concomitant pathologies: anesthesia in the elderly patient].
AB  - With the increase in the average age of the population, more and more older
      persons undergo surgery. Major surgery, cardiovascular, orthopaedic and abdominal
      interventions expose the elderly patient to a significant risk for postoperative
      morbidity and mortality. This is not only related to the advanced age of these
      subjects, which is a recognized independent risk factor, but also to the aging
      process itself and to the greater prevalence of heart and lung diseases affecting
      this population segment. An important role is also played by the so-called
      physiologic modification found in subjects without recognized illnesses. Reduced
      organ function reserve requires accurate preoperative assessment that takes into
      account cardiovascular reserve and physiologic and pathologic alterations in the
      respiratory system that may predispose the patient to hypoxemia and favour the
      development of postoperative infection. Moreover, alterations in pharmacokinetics
      and pharmacodynamics require individualized drug dosing. Particular attention
      should also be directed at the prevention of postoperative cognitive disorders
      that favour the development of complications and negatively affect postoperative
      recovery of body function.

PMID- 15181404
TI  - Anesthetic considerations in patients with chronic pulmonary diseases.
AB  - AIM: Increasing age and co-morbidities of patients admitted for surgery impose
      new challenges on the anesthesiologist. METHODS: Review of current literature
      regarding the perioperative management of patients with chronic pulmonary
      disease. RESULTS: If patients are treated adequately, surgery can be safely
      performed under regional and general anaesthesia. Major risk factors include type
      of surgery, type and duration of anesthesia, general health status and smoking
      history, but not certain lung function parameters. Regional anesthesia remains
      the first choice for intra- and postoperative care, and if general anesthesia is
      necessary, early extubation should be achieved. Non-invasive ventilation could be
      a possible alternative in weaning failure. CONCLUSION: Assessing the functional
      status of patients admitted to surgery remains a difficult task, and in patients
      identified at risk by clinical examination additional spirometry and blood gases
      may be helpful. If there are signs of respiratory failure, the anaesthetist
      should monitor the patient closely and invasively, yet there is no reason to deny
      any patient a substantially beneficial operation.

PMID- 15181405
TI  - Allergy and anaphylaxis in anaesthesia.
AB  - Immediate hypersensitivity reactions to anaesthetic and associated agents used
      during the perioperative period have been reported with increasing frequency in
      most developed countries. Most reactions are of immunologic origin (IgE mediated,
      anaphylaxis) or related to direct stimulation of histamine release (anaphylactoid
      reactions). The incidence of anaphylaxis is estimated between 1 in 10000 and 1 in
      20000 anaesthesia, and any drug administered in the perioperative period can
      potentially produce life-threatening immune-mediated hypersensitivity reactions.
      Neuromuscular blocking agents (NMBAs), latex and antibiotics represent the most
      frequently involved substances. However, anaphylactic reactions cannot be
      clinically distinguished from non-immune mediated reactions which account for 30%
      to 40% of hypersensitivity reactions. Therefore, any suspected anaphylactic
      reaction must be extensively investigated using combined peroperative and
      postoperative testing to confirm the nature of the reaction, the responsibility
      of suspected drugs and to provide precise recommendations for future anaesthetic
      procedures. These investigations include plasma histamine, tryptase and specific
      IgE concentration determination at the time of the reaction, and skin tests 6
      weeks later. In addition, since no specific treatment has been shown to reliably
      prevent the occurrence of anaphylaxis, allergy assessment must be performed in
      all high-risk patients. The need for proper epidemiological studies and the
      relative complexity of allergy investigation should be underscored. They
      represent an incentive for further development of allergo-anaesthesiology
      clinical networks to provide expert advice for anaesthetists and allergologists.

PMID- 15181406
TI  - Auditory evoked potentials.
AB  - Auditory evoked potentials (AEPs) are an electrical manifestation of the brain
      response to an auditory stimulus. Mid-latency auditory evoked potentials (MLAEPs)
      and the coherent frequency of the AEP are the most promising for monitoring depth
      of anaesthesia. MLAEPs show graded changes with increasing anaesthetic
      concentration over the clinical concentration range. The latencies of Pa and Nb
      lengthen and their amplitudes reduce. These changes in features of waveform are
      similar with both inhaled and intravenous anaesthetics. Changes in latency of Pa
      and Nb waves are highly correlated to a transition from awake to loss of
      consciousness. MLAEPs recording may also provide information about cerebral
      processing of the auditory input, probably because it reflects activity in the
      temporal lobe/primary cortex, sites involved in sounds elaboration and in a
      complex mechanism of implicit (non declarative) memory processing. The coherent
      frequency has found to be disrupted by the anaesthetics as well as to be
      implicated in attentional mechanism. These results support the concept that the
      AEPs reflects the balance between the arousal effects of surgical stimulation and
      the depressant effects of anaesthetics. However, AEPs aren't a perfect measure of
      anaesthesia depth. They can't predict patients movements during surgery and the
      signal may be affected by muscle artefacts, diathermy and other electrical
      operating theatre interferences. In conclusion, once reliability of the AEPs
      recording became proved and the signal acquisition improved it is likely to
      became a routine feature of clinical anaesthetic practice.

PMID- 15181407
TI  - [Possible and proved benefits of peridural analgesia].
AB  - Regional anesthesia is supposed to be of some help in improving the outcome of
      surgical patients. Actually this assumption is largely accepted, even if clear
      scientific demonstrations have not been obtained. At present there are data
      showing the advantages, as to survival and complications, especially for major
      orthopedic surgery. These data have been shown by important and clarifying meta
      analyses. Unfortunately, for other types of surgery, advantages have been
      scarcely demonstrated, due to the low number of patients involved in clinical
      trials. Anyway, it is underlined that regional anesthesia, and especially
      epidural block, is much more convenient for the patients than general anesthesia.
      It seems also convenient from the economic point of view, since the pharmaco
      economic studies present in the literature showed the possibility to save money,
      using regional anesthesia and regional analgesia.

PMID- 15181408
TI  - Locoregional anesthesia and agents interfering with haemostasis.

PMID- 15181409
TI  - Surgical treatment of end stage emphysema.
AB  - Emphysematous changes are common in the general population. A significant number
      of these patients requires surgical interventions. Lung volume reduction surgery
      (LVRS) rapidly gained popularity without a sufficient evidence of beneficial
      outcome; the presumed mechanism of improvement in lung function is secondary to
      re-expansion of more normal, underlying compressed lung. The NETT study proposed
      to evaluate effectiveness of medical treatment vs LVRS in patients with severe
      bilateral emphysema. Complete results of the NETT study are unknown yet, but
      there are evidences of beneficial effects of LVRS, at least in a short term. The
      anesthetic management of these patients includes the continuation of the
      bronchodilator therapy till surgery, the use of steroids and antisialologue. Pain
      relief must be optimal and mobilization must be early. One lung ventilation is an
      absolute necessity, achieved with double lumen tube insertion.

PMID- 15181410
TI  - Methods of lung separation.
AB  - During video assisted thoracoscopy (VAT) the lung should be well collapsed. When
      the separation of the lungs is strictly indicated, use of difficult tube, such as
      double lumen tube (DLT) or Univent tube cannot be avoided, despite the presence
      of a difficult airway. If a patient has a recognized difficult airway, awake
      intubation with fiberoptic bronchoscopy can be attempted with Univent tube, DLT
      or with single lumen tube (SLT). If failure to provide a lung separation could
      result in a life-threatening situation, there are 2 possibilities to provide a
      one lung ventilation (OLV) when a SLT is in place: a tube exchanger can be used
      to position a DLT or a bronchial blocker (BB) can be directed through the SLT in
      the bronchus. The most used BB is a Fogarty embolectomy catheter. More recently a
      new BB has been approved by FDA: the Cohen Flexitip Endobronchial Blocker. The
      most important feature of the blocker is its flexible soft tip that allows to
      direct it in the desired bronchus. The blocker contains a lumen that allows
      suctioning of the lung to facilitate deflation, suctioning of secretion and
      insufflation of oxygen. In summary, the clinician should be able to master
      different methods of lung separation and make him/her self familiar with the
      available devices.

PMID- 15181411
TI  - [Antifungal descalation or scalation therapy?].

PMID- 15181412
TI  - [Infection surveillance in intensive care units. Preliminary results of a
      multicenter GiViTI study in 71 Italian ICUs].
AB  - AIM: Infection surveillance and control in ICU is believed to be a means to
      improve the quality of assistance. The importance of this activity is supported
      by both epidemiological (rate and severity of infection in ICU) and economic
      (efficiency, cost-benefit and cost-effectiveness analysis) evaluations. Many
      authors thinks that infection surveillance and control should be performed with a
      routine tool in order to obtain remarkable data without too much time loss, and
      used by many ICUs, in order to compare the data. METHODS: A prospective
      observational study in 71 Italian ICUs participating in GiViTi. All patients
      admitted in each ICU during 6 month (except those discharged alive within 48
      hours from admission) were enrolled and surveyed. Demographic and clinical data,
      data relating to nosocomial and at admission infections, risk factors,
      responsible micro-organisms, antibiotics use and outcome were collected. RESULTS:
      A total of 5814 patients (98% of eligible patients) were surveyed. The overall
      incidence of infected patients was 43%. The incidence of patients with nosocomial
      infection was 18% (1062 patients). Pneumonia, bacteraemia and urinary tract were
      the main sites. The major isolated micro-organism responsible of infection were
      staphylococcus (29.7%) and pseudomonas (16.2). Only 17% of all patients was not
      treated with antibiotics, and 72% of patients without infection was treated with
      antibiotics. CONCLUSION: These preliminary data confirm the importance of
      infection in ICU and the need of continuous surveillance. We propose a tool that
      can be useful for continuous and multicentric infection surveillance in ICU.

PMID- 15181413
TI  - Prevention of nosocomial infection in the ICU setting.
AB  - The aim of this review is to focus the epidemiology and preventing measures of
      nosocomial infections that affect the critically ill patients. Most of them (over
      80%) are related to the device utilization needed for patient life support but
      responsible for such complications as ventilator-associated pneumonia (VAP),
      catheter-related bloodstream infections (CRBSI), surgical site infections (SSI)
      and urinary tract infections (UTI). General recommendations include staff
      education and use of a surveillance program with a restrictive antibiotic policy.
      Adequate time must be allowed for hand washing and barrier precautions must
      always be used during device manipulation. The routine changing of central
      catheters is not necessary and increases costs; it is necessary to decrease the
      handling of administration sets, to use a more careful insertion technique and
      less frequent set replacement. Specific measures for VAP prevention are: 1). use
      of multi-use, closed-system suction catheters; 2). no routine change of the
      breathing circuit; 3). lubrication of the the endotracheal tube cuff with a water
      soluble gel; 4). maintenance of patient in semi-recumbent position to improve
      chest physiotherapy. Specific measures for UTI prevention include: 1). use of a
      catheter-valve instead of a standard drainage system; 2). use of a silver-alloy,
      hydro gel-coated latex urinary catheter instead of uncoated catheters. By
      implementing effective preventive measures and maintaining strict surveillance of
      ICU infections, we hope to affect the associated morbidity, mortality, and cost
      that our patients and society bare. More clinical trials are needed to verify the
      efficacy of prevention measures of ICU infections.

PMID- 15181414
TI  - [Protein C and coagulation in sepsis].
AB  - The last few years have clarified the tight link between inflammation and
      coagulation. In addition to the identification of new regulatory mechanisms of
      the coagulation system and of an explosive number of mediators of inflammation,
      it is now clear that the existence of a positive feed-back between inflammation
      and coagulation leads to reciprocal activation of both pathways. Plasma levels of
      acute phase proteins involved in coagulation and fibrinolysis are elevated during
      inflammation, while natural anticoagulant mechanisms are depressed. Pro
      inflammatory cytokines "activate" cell membranes exposed to flowing blood
      (endothelium, platelets, monocytes, neutrophils) which from physiologically inert
      or anticoagulant become procoagulant. Increased tissue factor expression results
      in increased thrombin formation within the microcirculation. Thrombin is central
      to fibrin deposition but it also plays a key role in cell-mediated mechanisms
      involving inflammation, cell proliferation and activation of the natural
      anticoagulant protein C. Depression of natural anticoagulant mechanisms,
      occurring in severe sepsis, results in uncontrolled thrombin formation, with pro
      inflammatory activity prevailing, and the feed-back loop of inflammation and
      coagulation ultimately leading to multi-organ failure. However, both in the
      clinical setting and in animal experiments, heparin or direct anticoagulants have
      shown no effect on survival even if blocking fibrin deposition. Organ failure is
      only partially due to the thrombotic occlusion of the microcirculation, while
      other mechanisms of endothelial damage are probably more relevant in the
      development of ischemia. The endothelium is central to the maintenance of the
      natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C
      system, in addition to dumping thrombin formation, specifically modulates
      inflammation by cell signaling. This system is markedly depressed in severe
      sepsis. The infusion of activated protein C, or restoring normal levels of
      protein C within the circulation - depending on the individual bleeding risk are
      powerful tools to treat the endothelitis responsible for the clinical sequelae of
      severe sepsis.

PMID- 15181415
TI  - [Use of protein C concentrate in adult patients with severe sepsis and septic
      shock].
AB  - AIM: The aim of this study is to describe the first experiences on the use of
      protein C concentrate (PC) in adult patients with severe sepsis and septic shock
      and clinical contraindications to activated protein C (APC). On the basis of the
      effectiveness demonstrated by the activated form in sepsis and of the encouraging
      results expressed in literature of protein C concentrate (PC) mainly about
      meningococcus fulminating infections, we carried out an observational study on
      protein C concentrate (PC) with 28-day follow-up and a daily analysis of the
      hemato-chemical and clinical parameters. Particular attention was paid to the
      variations in the PC plasma levels, to the modifications of the coagulation
      system, to the SOFA score as well as to the safety under bleeding risk
      conditions. METHODS: The study included 7 patients (5 females and 2 males) either
      with severe sepsis (2). or septic shock (5); one of them had DIC, with PC plasma
      levels less than 50%. APC could not be administered because of clinical reasons.
      Patients' mean age was 60.5 years (43-78), the average SAPS II 52.2 (36-72), the
      pathologies leading to sepsis were lung infections (3). and peritonitis (4). The
      average time elapsed between the onset of the organ failure and the beginning of
      treatment with PC was 27.7 hours (12-42). RESULTS: Mortality on day 28 was 42.8%
      (3 deaths), in all patients the PC plasma levels were brought again to the
      physiological values. Among the biochemical parameters recorded during the PC
      infusion, was observed in particular a significant decrease of PDFs, a general
      rise of the platelet count, and a reduction of the lactic acid levels. No adverse
      reaction or bleeding complication were seen, even if most of the patients'
      coagulation was altered or at risk due to neurological problems or repeated
      surgery. CONCLUSION: In our small number of patients, protein C concentrate has
      proven to be safe and particularly useful in the control of the coagulopathy
      triggered and sustained by sepsis.

PMID- 15181416
TI  - [Use of protein C concentrate in critical conditions: clinical experience in
      pediatric patients with sepsis].
AB  - The coagulation disturbance, typical of septic conditions, is associated to a
      reduction of clotting factors in plasma with an "acquired" deficiency (from
      consumption) of protein C. As observed with "purpura fulminans" in neonates
      affected by congenital protein C deficiency, administration of protein C
      concentrate has proved to reduce thrombotic manifestations and to improve
      morbidity and mortality of children with septic shock. The Protein C concentrate
      is presently utilized as a therapy for patients with a congenital deficiency of
      protein C and several papers in the literature support the efficacy of protein C
      concentrate in the treatment of children with meningococcus septicemia, with the
      aim of correcting the acquired protein C deficiency often seen in septic
      conditions and shown to be strongly correlated to a higher morbidity and
      mortality. Protein C, given as a plasma concentrate, can exert its therapeutic
      actions only after activation once in the blood stream: clinical trials with the
      use of protein C concentrate failed to show any increased risk of bleeding or
      related disorders. At our PICU 8 children, with sepsis, septic shock and purpura
      have been treated with protein C concentrate (Ceprotin); because the plasma
      protein C level was lower than the normal range (mean value 0.32 IU/ml, range
      0.11-0.6 IU/ml). Six children have shown a rapid response to all therapeutic
      efforts and survived without sequelae and two are died. No adverse reaction was
      observed during and after Ceprotin administration to all patients.

PMID- 15181417
TI  - Ethyl pyruvate: a novel treatment for sepsis and shock.
AB  - Pyruvic acid is a simple 3 carbon a-keto-monocarboxylic acid. Recognition that
      pyruvate is an effective scavenger of reactive oxygen species (ROS) prompted
      investigators to use it as therapeutic agent for various pathological conditions
      that are thought to be mediated by redox dependent phenomena, like myocardial,
      intestinal or hepatic ischemia/reperfusion-induced injury. Ethyl Pyruvate showed
      to be more effective and safer than equimolar doses of sodium pyruvate. Ethyl
      Pyruvate showed to have anti-inflammatory effects. In animal models Ethyl
      Pyruvate improved hyperpermeability and bacterial translocation due to
      endotoxemia and improved the development of renal disfunction as well as some of
      the morphological findings of kidney injury. The pharmacological basis for the
      anti-inflammatory effects of EP remains to be explained. It is plausible that EP
      mediates suppression of NF-KB activation and secretion of NO and of pro
      inflammatory cytokines.

PMID- 15181418
TI  - [Analgesia, sedation and neuromuscular block in pediatric intensive care units:
      present procedures and recent progress].
AB  - Anxiolysis and pain control are a duty for physicians and must be treated very
      carefully in the Pediatric Intensive Care Units, although it is very difficult to
      assess them: in critically ill children sedatives and/or analgesic medications
      are routinely provided and titrated to obtain a satisfactory level of sedation,
      but different evaluation scores are needed to discriminate between light or
      inadequate and deep or excessive sedation, especially when the clinical
      examination is unavailable. It is usual to associate a benzodiazepin with an
      opioid, more often Midazolam and Morphine or Fentanyl; other drugs as Propofol,
      Clonidine and Ketamine have specific indications, brief painful procedures and
      weaning from long periods of sedation to avoid withdrawal. Sometimes it can be
      useful to add a neuromuscular blocking agent to help mechanical ventilation.
      Adverse sedation events are relatively frequent, associated with drug overdoses
      and drug interactions, particularly when 3 or more drugs are used: all class of
      medications and all routes of administration are involved.

PMID- 15181419
TI  - [Ex utero intrapartum technique].
AB  - Upper airway obstruction of a neonate constitutes an emergency. The ex utero
      intrapartum technique (EXIT) is a procedure for safely managing airway
      obstruction at birth, in which placental support is maintained until the airway
      is evaluated and secured. The anaesthetist is involved in preventing uterine
      contractions that impair oxygenation of the foetus and cause placental
      separation, in providing foetal anaesthesia to help airway manipulations, in
      maintaining foetal pattern of circulation, in preventing and treating maternal
      hypotension and in resuscitating the neonate. General anaesthesia with high
      concentration of inhalational agents is preferred as it provides surgical
      tocolysis and foetal anaesthesia. Additional uterine relaxation may be obtained
      using tocolytic drugs like nitroglycerin or beta-adrenergic agonists. During EXIT
      the foetus is delivered only as far as the shoulders or thorax leaving the cord
      entirely in utero to maximize the duration of placental support and to minimize
      heat and water loss. In this position foetal airway is examined and secured,
      which may involve tracheal intubation, bronchoscopy or tracheostomy. The
      umbilical cord is divided and the neonate is completely delivered only after the
      airway has been secured. With EXIT, a potential life-threatening emergency at
      birth can be managed like an elective procedure that can improve the prognosis
      for foetuses with airway obstruction.

PMID- 15181420
TI  - [Mortality in pediatric anesthesia].
AB  - In last the 50 years many studies have described the causes of mortality. In
      newborns and infants between 5 and 6 months the risk is higher. The heart is not
      developed as in older/grown child and these infants need more oxygen than the
      older ones. Probably, the interaction or interference of positive pressure
      ventilation with the neonatal circulation is an important cause leading to this
      pathology. In many studies the authors have identified this risk in the
      administration of alothane. A more comprehensive literature is needed about
      sevoflurane in order to know if it is effective. The incidence of complications
      with an was twice higher than the incidence with a pediatric anesthetists. In the
      50s, there have been many changes in our operational METHODS: Actually, we need
      more randomized and controlled studies to answer the question oh what is the
      cause of mortality and what we will be able to do in the future to prevent infant
      mortality in the operation room.

PMID- 15181421
TI  - Neuropathic pain in children.
AB  - The International Association for the Study of Pain (IASP) defines neuropathic
      pain as being caused by a lesion or dysfunction of the nervous system.
      Characteristics that would define neuropathic pain and differentiate it from
      other types of pain include: pain and sensory symptoms that persist beyond the
      healing period; presence, in variable degree, of neurological sensory signs
      manifesting as negative and positive sensory phenomena; presence, in variable
      degree, of other neurological signs, including motor, manifesting as negative and
      positive motor phenomena or autonomic signs. Many of the conditions causing
      neuropathic pain in adults are rare in children, but some forms of neuropathic
      pain do affect children and adolescents as complex regional pain syndrome or
      phantom limb pain. Treatment strategies that have demonstrated to be efficacious
      in adults have been extrapolated to be used in children, including medications,
      nerve blocks, physical therapy, and behavioral medicine. A multidisciplinary
      program that combines all of these approaches provides the best chance of relief.

PMID- 15181422
TI  - Postoperative analgesia in infants and children: new developments.
AB  - Nowadays, postoperative pain control in infants and children is a big challenge.
      The only effective solution is a multidisciplinary work with accurate guidelines,
      starting from the preoperative period throughout the surgery and arriving at the
      postoperative period. The approach must be scientific, based on the recent
      studies and research. In recent years, there has been a renaissance in regional
      anesthesia in children, in part because of a greater concern about postoperative
      pain management in young patients, and in part because of technical advances in
      equipment to perform the blocks. In fact several techniques and routes can be
      used for pain treatment but all have side effects. We await data from the use of
      COX2 inhibitors, surely the future of NSAIDs, with valid anti-inflammatory action
      and fewer side effects in children. When possible/not controindicated, regional
      analgesia is often the best choice. Recently continuous peripheral infusion is
      successfully applied in infants and children, due to its safety, efficacy and
      well limited localisation of analgesia. All the variety of peripheral nerve
      blocks used in adults can be used in pediatrics. The indications to place a
      catheter for a continouos peripheral nerve blocks are the followings: major
      orthopedic procedures; the procedure is scheduled to last more than two hours;
      congenital malformation of foot or hand; fracture reduction; traction of femur
      fracture; when postoperative pain therapy is necessary for several days; painful
      physical therapy. The commonly performed continuous peripheral blocks in children
      are the brachial plexus block (parascalene or axillary), the femoral nerve block,
      the fascia iliaca block, the sciatic nerve block with the lateral or with the
      popliteal approach. In these last two years also our group performed several
      continuous peripheral nerve blocks particularly axillary, femoral and sciatic for
      major orthopedic surgery and trauma. In our institution, we use a bolus dose of
      0.5-1 ml/kg (depending on the nerve to be blocked) of ropivacaine 0.2% or
      levobupivacaine 0.25% with clonidine 2 microg/kg and then in infants older than 6
      months and children we use a continuous infusion of 0.1-0.3 ml/kg/h of 0.2%
      ropivacaine or 0.25% levobupivacaine with clonidine 3 microg/kg/24h for 48-72
      hours. For older children doses and concentrations are usually the same used in
      adults.

PMID- 15181423
TI  - [Territorial emergency: physician or nurse?].
AB  - This study was conceived to assess a pattern of Italian prehospital critical care
      team, especially referring to the advanced life support (ALS) rescue team.
      Function and management of ALS rescue team and its relationship with other
      members of the emergency medical system (intra hospital physician, basic life
      support team, general practitioner) are analysed; stress is laidon the knowledge,
      the background and the complexity of the emergency procedures. The benefit of 2
      major prehospital options of the ALS team, composed by 1 physician and 1 nurse
      staffing or by 2 trained nurse staffing, is discussed; the importance of
      educational programs for ambulance teams, a comparison of cost-effectiveness and
      the number of emergency teams availability is underlined. The authors, finally
      emphasize the advantages of a territorial coverage with an integrated system of
      ambulances staffed with specially trained rescuers or technicians, ambulances
      with rescuers and nurses, and ALS teams staffed with emergency physician and 1
      nurse (integrated or not with ambulances with 2 trained nurses), being perfectly
      capable to face up any background in pre-hospital emergency medicine setting.

PMID- 15181424
TI  - [The assessment of nursing workload].
AB  - The measurement of nursing workload first began in the 1970s, because of the need
      for determining severity of illness and cost-effectiveness in the intensive care
      unit. In the following decades, the need for more specific tools for assessing
      nursing workload brought to the development of scoring systems more focused on
      nursing activities. We will briefly review the scoring systems validated since
      1974. TISS-Therapeutic Intervention Scoring System elaborated by Cullen in 1974
      is based on 57 therapeutic procedures and was designed to assess the severity of
      illness in the ICU. Each intervention scores 1 to 4. Patients are grouped in 5
      classes. It was not sufficiently validated and was abandoned. However it first
      introduced the idea of "patient point managed per nurse". TISS update was
      elaborated by Keene in 1983. The therapeutic procedures were increased to 76. It
      was assumed that a single nurse can manage 40/50 points per day. Though not
      validated, it became the most used tool to assess complexity of treatment and
      nurse/patient ratio. However many of these items are obsolete and frequently
      related to the severity of illness rather than to specific nursing interventions.
      PRN-Project Research of Nursing was elaborated by EROS during 1980-1987. Points
      are assigned to each nursing activity according to their frequency, duration,
      need for more than one nurse, etc. It results quite time consuming, thus
      unsuitable for routine use. OMEGA elaborated in 1986 describes 86 therapeutic
      interventions, grouped in 3 categories, measured at the end of ICU stay, thus
      representing a measure of global workload and use of resources. TOSS-Time
      Oriented Score System was elaborated by GIRTI in 1991. This score was studied and
      tested in Italy. It represents a direct temporal evaluation of nursing workload.
      The score is expressed in minutes. It is reliable and relatively simple, and has
      been validated on over 2 700 ICU patients. TISS 28 was elaborated by Miranda in
      1996. It represents a simplified and updated version of the original TISS,
      proposed to assess the nursing workload. The authors stated that a nurse can deal
      with 46 points over the 24 hours. NEMS-Nine Equivalents of nursing Manpower use
      Score was elaborated by Miranda in 1997. It was derived from TISS and TISS28.
      Only 9 items, related to specific organ support, nursing and
      diagnostic/therapeutic interventions inside or outside the ICU, are considered.
      These items were weighted by multivariate analysis, obtaining a score comparable
      to the TISS28 score. Each nurse can deal with 45/50 points per day. NAS-Nursing
      Activity Score was elaborated by Miranda in 2003. It was derived from TISS28,
      aiming at the description of nursing activities not necessarily correlated to the
      severity of illness. It describes 81% of the nursing time, compared to 43% of
      TISS 28. In conclusion, many scoring systems have been proposed to describe
      nursing workload, both directly (as with TOSS and PRN) or through severity and
      complexity of treatment (TISS, TISS 28, NAS and NEMS). These scores represent the
      instruments to assess the correct use of ICU resources.

PMID- 15181425
TI  - [Identification of the patient with sepsis].
AB  - Sepsis may be defined as a clinical syndrome caused by an organism's response to
      infection. The complex alterations triggered by the infection include
      inflammation and systemic coagulopathy in the absence of effective fibrinolysis.
      Possible manifestations vary in entity and severity, ranging from systemic
      inflammatory response syndrome (SIRS) to septic shock and multiorgan dysfunction
      syndrome (MODS). The nurse can play a fundamental role in the timely recognition
      of SIRS and in the early identification of the onset of signs of organ damage. In
      this way, an additional aid to establishing diagnosis can be provided and
      targeted treatment instituted. Following a brief presentation of the
      pathophysiology and epidemiology of sepsis, the manifestations and attendant
      risks are described, the most appropriate monitoring methods and the main nursing
      tasks in treating sepsis are discussed. We present the results of our experience
      in identifying patients with sepsis through the application of selection criteria
      adopted from clinical studies on the use of activated protein C.

PMID- 15181426
TI  - [Hand hygiene in intensive care].
AB  - Hand hygiene represents the main way to prevent and/or at least reduce nosocomial
      infection incidence. In this paper we discuss this "hot topic" through both the
      analysis of CDC guide lines and the data resulting from a questionnaire survey
      sent to health care workers, eventually corroborated by their direct observation.
      From literature data and our survey result analyses, we are more than convinced
      that the winning strategies for a slow but progressive improvement of hand
      washing practice and compliance are (i). using a product able to decontaminate
      hands very quickly and without needing water; (ii). the health care worker
      awareness of hand hygiene and compliance feed-back importance. From our
      questionnaire survey as well as from our direct observation, we found a very low
      (5.6%) compliance of our hospital health care workers to CDC guidelines for hand
      washing. This may be justified above all by ward logistical and structural
      problems, as only 55% of sinks are located inside patient rooms, but also because
      there is a lacking of knowledge of new CDC suggested practices and
      decontaminating products. Health care worker specific training and the choice of
      an alcoholic antiseptic disinfectant, allowed us to significantly increase their
      compliance to proper practices in hand washing and hygiene, showing their
      interest in such an important and delicate matter.

PMID- 15181427
TI  - [The fluid balance in the critically ill patient].
AB  - AIM: In the critically ill patient the hemodynamic management is essential.
      Usually the hemodynamic status is estimated by the measurement of the
      intravascular pressure or volume and by computing the fluid balance, while the
      change in body weight estimates the total body water. The fluid balance is
      computed by subtracting the fluid output to the input. Although the input
      (fluids, drugs, infusion.) are well known, the output are difficult to correctly
      compute, because they depend on several factors such as the body-room
      temperature, amount of humidity and may change with time. Aim of this study was
      to prospectively evaluate the accuracy of the fluid balance compared to the body
      weight measured by a dedicated mattress (Hill-Rom). METHODS: Fifteen critically
      ill patients were enrolled (mean age of 63.2+/-19.7 years, body mass index of
      24.9+/-3.5 kg/m2) and the measurements were computed every 8 hours. The data were
      analyzed by the Bland-Altman test. RESULTS: Four-hundred and seventy-two
      measurements for a mean intensive care stay of 12.3.+/-7.3 days were computed.
      The Bland-Altamn showed a great inaccuracy, because the agreement (the difference
      between the 2 methods) was poor with a standard deviation of 1 840 L. CONCLUSION:
      Although the fluid balance was not accurate, the only body weight without any
      intravascular measurement is not helpful for a correct clinical hemodynamic
      management of the patient.

PMID- 15181429
TI  - Stability of a cannulated screw versus a Kirschner wire for the proximal
      crescentic osteotomy of the first metatarsal: a biomechanical study.
AB  - The purpose of this study was to compare the stability of a Kirschner wire (K
      wire) versus a single cannulated screw for fixation of the proximal crescentic
      first metatarsal osteotomy. Seven matched pairs of fresh-frozen human cadaver
      first metatarsal specimens were dissected out en bloc at the first metatarsal
      medial cuneiform complex; right and left specimens were randomized as to
      fixation. In screw specimens, a cannulated screw was mounted from the proximal
      medial side of the metatarsal, traversing osteotomy and engaging the lateral
      diaphyseal cortical bone. In the corresponding specimen, a K-wire was placed from
      the distal medial metatarsal cortex oriented as close to the longitudinal
      metatarsal axis as possible. Using a materials testing machine, a continuous load
      was applied to the plantar aspect of the metatarsal head at a rate of 5 mm/min
      until a displacement of 10 mm was reached. The following parameters were
      measured: initial stiffness of the entire specimen, stiffness of the osteotomy,
      the force required to create a 1-mm displacement, the force required to create a
      0.15-mm gap across the osteotomy, and the ultimate force to create the 10-mm
      displacement. Both specimen and osteotomy stiffness were found to be
      significantly higher for screw fixation versus the K-wire (P <.05). Although
      there was also a difference in the force-to-failure load in favor of screw
      fixation, this result was found not found to be statistically significant.

PMID- 15181430
TI  - Flexible flatfoot treatment with arthroereisis: radiographic improvement and
      child health survey analysis.
AB  - This study was designed to ascertain if there was a statistically significant
      correction in the foot and to determine the overall health of a child after an
      arthroereisis procedure. Thirty-seven patients (67 feet) who had undergone
      Maxwell-Brancheau arthroereisis were retrospectively reviewed at an average of
      18.4 months after surgery. The pre- and postoperative lateral talo-first
      metatarsal and talar declination and the anteroposterior talo-first metatarsal
      and talocalcaneal angles were measured by using an X-Caliper device (Eisenlohr
      Technologies, Davis, CA); significance was determined with a t test. Child health
      questionnaire answers were calculated and converted to a 0 to 100 scaled score
      and statistically compared with population norms by using a single-sample t test.
      The lateral radiographic average preoperative talo-first metatarsal and talar
      declination angles were 11.3 and 27.5, respectively, and were 3.7 and 21.9,
      respectively, postoperatively. The preoperative average anteroposterior talo
      first metatarsal and talocalcaneal angles were 13.8 and 25.6, respectively, and
      were 6.4 and 19.4, respectively, postoperatively. The t test showed the
      postoperative angles had a statistically significant (P <.01) change from the
      preoperative angles. The results of the Child health questionnaire of our 34
      pediatric patients (92%) showed scores in 3 domains (role emotional behavior,
      global behavior, parent time) that were better than population norms, and there
      was no difference in the remaining domains.

PMID- 15181431
TI  - Early weightbearing after first metatarsophalangeal joint arthrodesis: a
      retrospective observational case analysis.
AB  - A retrospective observational study was performed to determine if early
      ambulation compromised healing in patients who underwent primary first
      metatarsophalangeal joint arthrodesis. The records of 42 patients undergoing 47
      fusions were evaluated to determine time to radiographic union, time to clinical
      union, and return to regular shoes. Results showed that patients achieved
      clinical healing at an average of 5.6 weeks, and showed distinct signs of
      radiographic union at an average 6.1 weeks. The mean time for return to athletic
      shoes was 6.23 weeks. The patient population reviewed had a 100% radiographic and
      clinical union rate. These results reinforce the idea that early ambulation is a
      viable option in patients undergoing primary first metatarsophalangeal joint
      arthrodesis.

PMID- 15181432
TI  - The Cole midfoot osteotomy: a retrospective review of 11 procedures in 8
      patients.
AB  - This article presents the results of a retrospective chart and radiographic
      review of 11 feet (8 patients) that underwent a Cole midfoot osteotomy from
      February 1998 through October 2000 at the Western Pennsylvania Hospital. The
      average time to follow-up was 23 months (range, 11 to 29.5 months). A 100% bony
      union rate was achieved, with an average time to radiographic union of 2.3 months
      (range, 1.2 to 4.5 months). The average time until full weightbearing was 3.3
      months (range, 2 to 4.25 months). The average preoperative talo-first metatarsal
      angle on an anteroposterior radiograph was 8.60 degrees and 8.64 degrees on the
      lateral radiograph. The average postoperative change was 3.50 degrees (P =.03) on
      the anteroposterior radiograph and 16.82 degrees (P =.003) on the lateral
      radiograph. At the final follow-up visit, all patients were independently active
      and were able to wear conventional shoe gear. A postoperative questionnaire was
      completed by 5 of 8 patients (8 of 11 feet) at a mean 21 months (range, 13 to
      29.5 months) postoperatively. Of these patients, 4 of 5 patients (7 of 8 feet)
      would recommend this surgery to others. No major complications were reported in
      this study. These results suggest that the Cole midfoot osteotomy is a reasonable
      procedure to consider for correcting pes cavus deformities with the apex in the
      midfoot.

PMID- 15181433
TI  - Peritalar dislocations: a retrospective study of 18 cases.
AB  - The purpose of this study is to retrospectively evaluate 18 consecutive cases of
      peritalar dislocations referred to our department during a period of 25 years and
      to delineate the factors influencing long-term prognosis. There were 13 (73%)
      medial and 5 (27%) lateral dislocations. Six patients (33%) suffered an open
      injury, including 2 of 13 (15%) medial and 4 of 5 (80%) lateral dislocations.
      Associated fractures involving the hindfoot or forefoot were noted in 7 feet,
      including 3 of 5 lateral dislocation cases. Reduction was accomplished under
      general anesthesia; in no case was open reduction necessary. In 4 of 6 open
      injuries with associated fractures, temporary fixation with Kirschner wires was
      performed. Patients were immobilized in a plaster cast for 4 weeks, or for 6
      weeks in the presence of fracture, followed by weightbearing as tolerated. At a
      mean follow-up of 10.2 years (range, 4 to 26 years), 10 patients (56%) showed
      excellent results; all had sustained a closed medial low-energy dislocation.
      There were 3 cases (17%) with fair results and 5 cases (28%) with poor results.
      Forty-five percent of patients showed a restriction of activity, a reduction of
      subtalar range of motion, and moderate or severe radiographic signs of hindfoot
      degenerative arthritis. There were no cases of talar avascular necrosis, and in
      no case was secondary surgery necessary. Lateral dislocation and open medial
      dislocations with concomitant fractures showed a greater potential for poor
      prognosis. The results were independent from period of cast immobilization,
      suggesting that 4 to 6 weeks of immobilization provides acceptable long-term
      results.

PMID- 15181434
TI  - The use of external fixation for treatment of the acute Jones fracture: a
      retrospective review of 10 cases.
AB  - The purpose of this retrospective clinical study was to evaluate the clinical
      outcome of patients who underwent external fixation of acute Jones fractures.
      There were 10 patients with a mean age of 25.2 years; 9 of the patients were
      actively involved in athletics. Chart and radiograph review showed the mean
      clinical and radiographic healing times to be 5.7 and 6.5 weeks, respectively.
      Patients returned to preinjury activity levels at a mean 9 weeks postoperatively.
      Complications included 1 case each of localized cellulitis, asymptomatic
      nonunion, and refracture. Telephone inquiry performed at a mean 46 months
      postoperatively determined all patients to be pain-free and continuing to
      participate at their preinjury activity levels. External fixation is quick and
      easy to perform and provides a viable alternative to intramedullary screw
      fixation of Jones fractures in the young, active patient.

PMID- 15181435
TI  - Distal tibial aneurysmal bone cyst treatment by using a proximal fibular
      autologous bone graft: a case report.
AB  - A case of an aneurysmal bone cyst that involved the distal tibia and medial
      malleolus with erosion of the medial cortex in a 22-year-old woman is presented.
      The patient was surgically treated by curettage and bone grafting along with
      reconstruction of the distal tibia by using ipsilateral proximal fibula. At the 2
      year follow-up, the patient had full, painless range of motion and complete
      incorporation of the fibular graft. The authors discuss the different treatment
      options for benign tumors of the distal tibia and the advantages of using
      proximal fibula as an autologous bone graft in the reconstruction of medial
      malleolus.

PMID- 15181436
TI  - Tarsal tunnel syndrome caused by epineural ganglion of the posterior tibial
      nerve: report of 2 cases and review of the literature.
AB  - Ganglia within the posterior tibial nerve is a rare condition. The authors report
      2 cases of epineural ganglion of the posterior tibial nerve, causing tarsal
      tunnel syndrome. Both cases presented with numbness on the plantar surface of the
      foot. Magnetic resonance imaging showed the presence of the cyst within the
      tarsal tunnel. During surgery, these cysts were found within the epineurium of
      the posterior tibial nerve and were successfully removed without damage to nerve
      fibers. Both patients were free of symptoms after surgery. Ganglion cysts in the
      peripheral nerve are either intrafascicular or epineural. Intrafascicular ganglia
      present beneath the epineurium and involve the nerve fibers, whereas epineural
      ganglia are located in the epineurium and do not involve the nerve fibers. A
      review of the literature discusses these concepts. The authors suggest that
      epineural ganglion should be clinically distinctive from an intrafascicular
      ganglion because of the differences in surgical treatment, postoperative nerve
      function, and the recurrence rate.

PMID- 15181437
TI  - Hemangiopericytoma of the navicular: a case report.
AB  - Hemangiopericytoma is a tumor of vascular origin usually found in the soft
      tissue. Manifestation in bone is extremely rare and are most commonly located in
      the pelvis and the lower extremity. This is the first case of hemangiopericytoma
      in the bone of the foot known to the authors. This article shows the presenting
      findings and the surgical treatment. At 13 months after the final surgery, there
      was no evidence of tumor recurrence.

PMID- 15181438
TI  - Osteochondritis dissecans of the talus treated with the mosaicplasty technique: a
      case report.
AB  - The authors present the use of osteochondral autografting with mosaicplasty
      technique performed on a 20-year-old man for a large osteochondral talar dome
      lesion. The patient had sustained a right ankle sprain many times while playing
      rugby football. The lesion measured 15 mm in diameter and encompassed more than
      one-third of the articular surface. After exposing the talus to a medial
      malleolar osteotomy, 3 osteochondral grafts taken from the medial femoral condyle
      of the ipsilateral knee were press-fit into the lesion. One year postoperatively,
      the patient has returned to playing rugby football. Radiographically, there was
      incorporation of the grafts. The authors believe that the mosaicplasty technique
      presents a promising new option in the treatment of osteochondritis dissecans of
      the talus.

PMID- 15181439
TI  - Percutaneous plating of the distal tibia.

PMID- 15181440
TI  - A technique for proximal first metatarsal osteotomy for hallux valgus repair.

PMID- 15181447
TI  - Three-dimensional images for surgical plan of giant sacral schwannoma.
AB  - OBJECTIVE: Documentation of three-dimensional (3D) images of a giant sacral
      schwannoma with intrapelvic expansion. SETTING: Nagoya University, Nagoya, Japan.
      RESULTS: 3D computed tomography (3D CT) showed a destructed bony region clearly.
      3D CT angiography clarified the positional relationship between tumor and iliac
      arteries. Resection procedure was safely completed based on these 3D evaluations.
      CONCLUSION: 3D images were helpful to make a surgical plan and to complete this
      complicated resection combined with sacroiliac reconstruction.

PMID- 15181448
TI  - Spontaneous corynebacterium discitis in a patient with chronic renal failure.
AB  - STUDY DESIGN: Case report describing spontaneous Corynebacterium diptheria
      discitis in a patient with chronic renal failure. OBJECTIVES: To describe this
      very rare form of discitis and the results of surgical and antibiotic therapy.
      SETTING: University Department of Neurosurgery, Turkey. CASE REPORT: A 55-year
      old man with chronic renal failure presented with acute low-back pain. Lumbar
      magnetic resonance imaging (MRI) suggested discitis and osteomyelitis at the L5
      S1 level. The L5-S1 disc was operated upon and the discectomy material was sent
      for pathological and microbiological analysis. RESULTS: Pathological examination
      revealed infection and bacterial culture grew C. diptheria. The patient was
      prescribed combination antibiotic therapy with vancomycin, a third-generation
      cephalosporin, and rifampicin. Clinical status improved after 8 weeks of therapy.
      Lumbar MRI revealed remission of the discitis and osteomyelitis after 10 months
      of follow-up. CONCLUSION: Chronic renal failure patients with low-back pain
      should be investigated for spinal infection. These individuals are prone to low
      grade infection in the form of discitis or osteomyelitis. Corynebacterium
      subspecies rarely cause spontaneous discitis. This case is interesting because of
      the unusual causal organism and the occurrence of discitis in the setting of
      chronic renal failure.

PMID- 15181450
TI  - HIF activation by pH-dependent nucleolar sequestration of VHL.
AB  - Hypoxia and acidosis occur in a wide variety of physiological and pathological
      settings that include muscle stress, tumour development and ischaemic disorders.
      A central element in the adaptive response to cellular hypoxia is HIF (hypoxia
      inducible factor), a transcription factor that activates an array of genes
      implicated in oxygen homeostasis, tumour vascularization and ischaemic
      preconditioning. HIF is activated by hypoxia, but undergoes degradation by the
      VHL (von Hippel-Lindau) tumour suppressor protein in the presence of oxygen.
      Here, we demonstrate that hypoxia induction or normoxic acidosis can neutralize
      the function of VHL by triggering its nucleolar sequestration, a regulatory
      mechanism of protein function that is observed rarely. VHL is confined to
      nucleoli until neutral pH conditions are reinstated. Nucleolar sequestration of
      VHL enables HIF to evade destruction in the presence of oxygen and activate its
      target genes. Our findings suggest that an increase in hydrogen ions elicits a
      transient and reversible loss of VHL function by promoting its nucleolar
      sequestration.

PMID- 15181449
TI  - PTOP interacts with POT1 and regulates its localization to telomeres.
AB  - Telomere maintenance has been implicated in cancer and ageing, and requires
      cooperation between a multitude of telomeric factors, including telomerase, TRF1,
      TRF2, RAP1, TIN2, Tankyrase, PINX1 and POT1 (refs 1-12). POT1 belongs to a family
      of oligonucleotide-binding (OB)-fold-containing proteins that include Oxytricha
      nova TEBP, Cdc13, and spPot1, which specifically recognize telomeric single
      stranded DNA (ssDNA). In human cells, the loading of POT1 to telomeric ssDNA
      controls telomerase-mediated telomere elongation. Surprisingly, a human POT1
      mutant lacking an OB fold is still recruited to telomeres. However, the exact
      mechanism by which this recruitment occurs remains unclear. Here we identify a
      novel telomere protein, PTOP, which interacts with both POT1 and TIN2. PTOP binds
      to the carboxyl terminus of POT1 and recruits it to telomeres. Inhibition of PTOP
      by RNA interference (RNAi) or disruption of the PTOP-POT1 interaction hindered
      the localization of POT1 to telomeres. Furthermore, expression of the respective
      interaction domains on PTOP and POT1 alone extended telomere length in human
      cells. Therefore, PTOP heterodimerizes with POT1 and regulates POT1 telomeric
      recruitment and telomere length.

PMID- 15181451
TI  - Correlation between karyotype and quantitative immunophenotype in acute
      myelogenous leukemia with t(8;21).
AB  - Acute myelogenous leukemia with t(8;21) is a distinct clinicopathologic entity in
      which the malignant myeloblasts display a characteristic pattern of surface
      antigen expression. Quantitative analysis of surface marker expression in
      patients with this chromosomal abnormality compared to acute myelogenous leukemia
      patients with a different karyotype has not been reported. From 305 consecutive
      newly diagnosed acute myelogenous leukemia patients underwent immunophenotyping
      and cytogenetic analysis at our center; 16 patients (5.2%) had a t(8;21).
      Fluorescence intensity values were obtained, using a set of reference microbeads,
      by conversion of mean channel fluorescence to molecular equivalent of soluble
      fluorochrome. Patients with t(8;21) displayed higher levels of CD34, HLA-DR and
      MPO expression (P < 0.001 for each) and lower levels of CD13 (P = 0.03) and CD33
      (P = 0.02) expression. In order to study the sensitivity, specificity and
      predictive value of these markers, molecular equivalent of soluble fluorochrome
      thresholds were statistically determined. The statistically established threshold
      for each of the individual markers (CD34 > 60.5 x 10(3), HLA-DR > 176.1 x 10(3),
      MPO > 735.1 x 10(3), CD13 < 24.3 x 10(3) and CD33 < 17.3 x 10(3)) had a
      sensitivity of 100%, a specificity of 62-92% and a positive predictive value of 7
      45%. In multivariate analysis, two quantitative patterns (CD34 > 60.5 x 10(3) and
      MPO > 176.1 x 10(3); CD33 < 17.3 x 10(3) and MPO > 176.1 x 10(3)) had a
      sensitivity, specificity and positive predictive value of 100%. These aberrant
      phenotypic patterns might help identify patients with t(8;21) at diagnosis and
      could be useful in minimal residual disease monitoring.

PMID- 15181452
TI  - Microdissection genotyping of gliomas: therapeutic and prognostic considerations.
AB  - Molecular anatomic pathology represents the blend of traditional morphological
      methods and the multigene approach to determine cancer-related gene alterations
      for diagnostic and prognostic purposes. Microdissection genotyping was utilized
      to characterize 197 gliomas with targeted microdissection of 2-7 areas spanning
      the spectrum of histologic types and grades. The methodology described herein is
      complementary to the existing realities of pathology practice. The technique
      utilizes paraffin-embedded fixative-treated tissue of small sample size after the
      primary morphological examination by the pathologist. Molecular information
      derived from microdissection genotyping in combination with the traditional
      histological information, results in an enhanced understanding of glioma
      formation and biological progression leading to improvements in diagnosis and
      prediction of prognosis. In all, 100% or 32 of 32 cases with at least partial
      treatment response was observed in neoplasms possessing the 1p or 1p/19q loss.
      The 19q loss alone without coexisting 1p showed no improvement in treatment
      response. Gliomas lacking 1p loss with only allelic loss involving 3p, 5q, 9p,
      10q and 17p showed unfavorable outcome of only 35%, or six of 17 cases with
      treatment response. In addition, the determination of fractional allelic loss
      (favorable/unfavorable), was a very good independent predictor of biological
      behavior. These findings emphasize the importance of determining the cumulative
      pattern of mutational damage on 16 distinct sites or more, especially in the
      presence of 1p loss which in isolation or in combination with 19q is a favorable
      prognostic factor for therapeutic response.

PMID- 15181453
TI  - Loss of heterozygosity of chromosome 9p and loss of p16INK4A expression are
      associated with malignant gastrointestinal stromal tumors.
AB  - Gastrointestinal stromal tumors GISTs are distinctive KIT-positive mesenchymal
      neoplasms. The genetic alterations leading to the malignant behavior of these
      tumors are not well characterized. In this study, 21 cases of GISTs (eight low
      malignant potential, nine primary malignant and four intra-abdominal recurrences)
      were characterized by immunohistochemistry and evaluated for loss of
      heterozygosity of the short arm of chromosome 9, using six microsatellite
      markers. Loss of heterozygosity with at least one microsatellite marker at 9p
      region was a common finding in high-risk GISTs (malignant and recurrent group)
      but was absent in the low malignant potential group. Recurrent GISTs showed more
      frequent deletions than their primary tumors. All cases with loss of
      heterozygosity showed deletions at 9p21. Similarly, all low malignant potential
      GISTs were immunoreactive for p16, whereas malignant tumors were negative for
      p16. These results suggest that loss of p16(INK4A) gene on 9p may contribute to
      the progression and/or malignant transformation of GISTs.

PMID- 15181454
TI  - The V599E BRAF mutation is uncommon in biliary tract cancers.
AB  - Activating point mutations of the BRAF oncogene have been identified in several
      solid tumors, most commonly in cutaneous melanomas and papillary carcinomas of
      the thyroid. A specific point mutation--V599E--accounts for the overwhelming
      majority of these mutational events. We explored the frequency of the V599E BRAF
      mutation in biliary tract cancers. In all, 62 archival biliary tract cancers,
      including 15 gallbladder cancers, 15 extrahepatic, and 10 intrahepatic
      cholangiocarcinomas from the United States, and 22 gallbladder carcinomas from
      Chile were analyzed for the V599E mutation of the BRAF gene using three distinct
      methods: direct sequencing, a primer extension method (Mutector assay), and the
      highly sensitive quantitative Gap Ligase Chain Reaction. The common V599E
      mutation was not identified in any of the 62 biliary cancer samples using these
      three methods of detection. The V599E somatic mutation of the BRAF gene is absent
      in biliary tract cancers, at least in the two geographic populations (United
      States and Chile) examined. Activation of the RAS/RAF/MAP kinase pathway in
      biliary tract cancers is likely to be secondary to oncogenic RAS mutations, or
      due to mutations of the BRAF gene at nucleotide positions not explored in the
      current study.

PMID- 15181455
TI  - Cardiolipin and its metabolites move from mitochondria to other cellular
      membranes during death receptor-mediated apoptosis.
AB  - We previously reported that during death receptor-mediated apoptosis, cardiolipin
      (CL) relocates to the cell surface, where it reacts with autoantibodies from
      antiphospholipid syndrome sera. Here, we analysed the intracellular distribution
      of CL and its metabolites during the early phase of cell death signalling
      triggered by Fas stimulation in U937 cells and mouse liver. We found a
      redistribution of mitochondrial CL to the cell surface by using confocal
      microscopy and flow cytometry. Mass spectrometry revealed that CL and its
      metabolites relocated from mitochondria to other intracellular organelles during
      apoptosis, with a conversion into non-mitochondrial lipids. Concomitantly,
      cytosolic Bid relocated to the light membranes comprised in fraction P100,
      including the plasma membrane and associated vesicular systems. A direct Bid-CL
      interaction was demonstrated by the observation that CL and monolysoCL
      coimmunoprecipitated with Bid especially after Fas stimulation, suggesting a
      dynamic interaction of the protein with CL and its metabolites.

PMID- 15181456
TI  - Galectin-1beta, a natural monomeric form of galectin-1 lacking its six amino
      terminal residues promotes axonal regeneration but not cell death.
AB  - We previously identified a novel N-terminally processed form of galectin-1,
      galectin-1beta (Gal-1beta) whose expression was induced by DeltaFosB. In the
      present study, the biochemical properties and biological functions of Gal-1beta
      were compared with the full-length form of galectin-1 (Gal-1alpha). We first
      purified recombinant mouse Gal-1alpha and beta (rmGal-1alpha, beta) to near
      homogeneity. The rmGal-1alpha exists as a monomer under oxidized conditions and
      forms a dimer under reduced conditions, while the rmGal-1beta exists as a monomer
      regardless of redox conditions. The affinity of rmGal-1beta to beta-lactose was
      approximately two-fold lower than that of rmGal-1alpha under reduced conditions.
      The viability of Jurkat cells efficiently decreased when they were exposed to
      rmGal-1alpha, however, rmGal-1beta barely induced such a reduction. In contrast,
      both rmGal-1alpha and rmGal-1beta exhibited an equivalent capacity to promote
      axonal regeneration from the dorsal root ganglion explants. Our results suggest
      that the biochemical properties of rmGal-1beta determine its biological
      functions.

PMID- 15181457
TI  - A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal
      transdifferentiation.
AB  - Epithelial-mesenchymal transdifferentiation (EMT) is a critical morphogenic event
      that occurs during embryonic development and during the progression of various
      epithelial tumors. EMT can be induced by transforming growth factor (TGF)-beta in
      mouse NMuMG mammary epithelial cells. Here, we demonstrate a central role of
      helix-loop-helix factors, E2A and inhibitor of differentiation (Id) proteins, in
      TGF-beta-induced EMT. Epithelial cells ectopically expressing E2A adopt a
      fibroblastic phenotype and acquire migratory/invasive properties, concomitant
      with the suppression of E-cadherin expression. Id proteins interacted with E2A
      proteins and antagonized E2A-dependent suppression of the E-cadherin promoter.
      Levels of Id proteins were dramatically decreased by TGF-beta. Moreover, NMuMG
      cells overexpressed Id2 showed partial resistance to TGF-beta-induced EMT. Id
      proteins thus inhibit the action of E2A proteins on the expression of E-cadherin,
      but after TGF-beta stimulation, E2A proteins are present in molar excess of the
      Id proteins, thus over-riding their inhibitory function and leading to EMT.

PMID- 15181458
TI  - The source of heme for vascular heme oxygenase I: heme uptake in rat aorta.
AB  - During the last decade, heme oxygenase (HO) and carbon monoxide (CO) have
      garnered substantial research interest in terms of cell and organ regulation,
      especially as they bear on the central nervous system, organ transplantation, and
      the cardiovascular system. While the enzymatic mechanism, substrates, and
      products of HO are well known, it is not clear whether the cardiovascular system
      derives its supply of the heme substrate through de novo synthesis or uptake from
      the extracellular milieu. The objective of the present study was to test the
      latter possibility in rat aorta and to determine the influence of plasma proteins
      that bind heme in vivo, viz. hemopexin and albumin. Aortic tissue was exposed to
      [14C]heme in vitro, and the concentration and time dependence of heme uptake was
      assessed. The presence of hemopexin or albumin in the incubation medium
      dramatically decreased heme uptake by the aorta. Heme uptake by aortic tissue was
      not altered after induction of HO-1, which would be expected to increase tissue
      heme demand. In summary, the rat, isolated aorta was capable of obtaining heme
      from its external milieu, but this was obtunded in the presence of the plasma
      proteins hemopexin or albumin. For normal physiological situations, heme uptake
      may not be a usual source of substrate for vascular HO and hemoenzymes such as
      nitric oxide synthase, soluble guanylyl cyclase, and cyclooxygenase.

PMID- 15181459
TI  - The source of heme for vascular heme oxygenase II: de novo heme biosynthesis in
      rat aorta.
AB  - Heme is an essential prosthetic group or substrate for many proteins, including
      hemoglobin, and hemo enzymes such as nitric oxide synthase, soluble guanylyl
      cyclase, and heme oxygenase (HO). HO is responsible for the breakdown of heme
      into equimolar amounts of biliverdin, iron, and carbon monoxide, the latter of
      which is thought to play a role in the regulation of vascular tone. It is not
      clear whether the source of heme for cardiovascular functions is derived from
      uptake from the extracellular milieu or synthesis. In this study, we tested the
      hypothesis that blood vessels obtain their supply of heme for HO through de novo
      synthesis. Adult male Sprague-Dawley rat aorta was incubated at 37 degrees C in
      Krebs' solution with 1 micro M [14C]delta-aminolevulinic acid (ALA). [14C]ALA
      uptake was linear for about 30 min and reached a plateau at approximately 100
      min. The radioactivity was incorporated into porphyrins and heme as determined by
      esterification of 14C-labelled metabolites and thin-layer chromatography. The
      first and rate-limiting step of heme biosynthesis is catalyzed by ALA synthase
      (ALA-S), the activity of which was determined in rat aorta using a radiometric
      assay, approximately 250 nmol x (g wet mass)(-1) x h(-1). Inducing HO-1 in rat
      aorta with S-nitroso-N-acetylpenicillamine (500 micro M) did not increase ALA-S
      activity as compared with basal activity levels of the enzyme. It appears that
      there is a sufficient amount of heme available under basal ALA-S activity
      conditions to meet the increased demand for heme resulting from HO-1 induction.
      These observations indicate that the complete enzymatic pathway for de novo heme
      biosynthesis resides in rat aorta and furthermore indicate that de novo heme
      synthesis is capable of supplying a substantial portion of the heme substrate for
      HO in the aorta.

PMID- 15181460
TI  - Physiological involvement of placental endothelin-1 and prostaglandin F2alpha in
      uteroplacental circulatory disturbance in pregnant rats exposed to heat stress.
AB  - Several studies suggest that heat stress affects placental functions including
      uteroplacental circulation, subsequently leading to pregnancy failure and birth
      weight reduction. To clarify the involvement of endothelin and placental
      prostaglandin (PG) systems in the uteroplacental circulation during heat stress,
      we examined the effects of i.v. administration of the endothelin receptor
      antagonist bosentan and the cyclooxygenase inhibitor indomethacin on
      uteroplacental blood flow and on placental PGE2 and PGF2alpha levels and their
      13,14-dyhydro-15-keto-metabolites (PGEM and PGFM, respectively) in heat-exposed
      or non-heat-exposed pregnant rats. The administration of bosentan or indomethacin
      did not change uteroplacental blood flow in non-heat-exposed pregnant rats. In
      contrast, heat reduced uteroplacental blood flow in pregnant rats, but the
      reduction was reversed by the administration of bosentan or indomethacin before
      heat exposure. Heat did not change placental PGE2 or PGEM levels, but in pregnant
      rats it increased placental PGF2alpha and PGFM levels, which were reversed by
      bosentan or indomethacin. Our results suggest that the activation of placental
      endothelin receptor and PGF2alpha systems are involved in the uteroplacental
      circulatory disturbances produced by heat. PGF2alpha systems activated by heat
      may be involved in the vasoconstricting effects of endothelin-A and -B receptors
      during heat exposure.

PMID- 15181461
TI  - Immediate constraint-induced movement therapy causes local hyperthermia that
      exacerbates cerebral cortical injury in rats.
AB  - Constraint-induced movement therapy (CIMT), which involves restraint of the
      nonimpaired arm coupled with physiotherapy for the impaired arm, lessens
      impairment and disability in stroke patients. Surprisingly, immediate ipsilateral
      forelimb immobilization exacerbates brain injury in rats. We tested whether
      immediate ipsilateral restraint for 7 days aggravates injury after a
      devascularization lesion in rats. Furthermore, we hypothesized that ipsilateral
      restraint aggravates injury by causing hyperthermia. In experiment 1, each rat
      received two lesions, one in the motor cortex and one in the visual cortex.
      Ipsilateral restraint increased only the motor cortex lesion. In additional rats,
      no differences in core temperature occurred after ipsilateral or contralateral
      restraint. Thus, ipsilateral restraint does not aggravate injury by a systemic
      side effect. In experiment 2, we hypothesized that ipsilateral restraint causes
      hyperthermia in the region surrounding the initial cortical lesion. Brain
      temperature, measured via telemetry, was significantly higher (approximately 1
      degrees C for 24 h) with ipsilateral restraint. A third experiment similarly
      found that ipsilateral restraint aggravates injury and causes local cortical
      hyperthermia and that contralateral restraint with externally induced mild
      hyperthermia aggravates injury. In conclusion, immediate ipsilateral restraint
      aggravates injury apparently by localized events that include hyperthermia.
      Caution must be exercised in applying early CIMT to humans, as hyperthermia is
      detrimental.

PMID- 15181462
TI  - Spinal excitation and inhibition decrease as humans age.
AB  - Although changes in the soleus H-reflex (an electrical analog of the tendon jerk)
      with age have been examined in a number of studies, some controversy remains.
      Also, the effect of age on inhibitory reflexes has received little attention. The
      purpose of this paper was to examine some excitatory and inhibitory reflexes
      systematically in healthy human subjects having a wide range of ages. We
      confirmed that both the maximum H-reflex (Hmax) and the maximum M-wave (Mmax)
      (from direct stimulation of motor axons) decrease gradually with age. The
      decrease in Hmax was larger so the Hmax/Mmax ratio decreased dramatically with
      age. Interestingly, the modulation of the H-reflex during walking was essentially
      the same at all ages, suggesting that the pathways that modulate the H-reflex
      amplitude during walking are relatively well preserved during the aging process.
      We showed for the first time that the short-latency, reciprocal inhibitory
      pathways from the common peroneal nerve to soleus muscle and from the tibial
      nerve to the tibialis anterior muscle also decreased with age, when measured as a
      depression of ongoing voluntary activity. These results suggest that there may be
      a general decrease in excitability of spinal pathways with age. Thus, the use of
      age-matched controls is particularly important in assessing abnormalities
      resulting from disorders that occur primarily in the elderly.

PMID- 15181464
TI  - Gold sodium thiomalate improves membrane potential impaired by high-frequency
      stimulation.
AB  - Effects of gold sodium thiomalate (GSTM) on membrane potential and tetanus
      tension were examined to elucidate whether the gold compound improves mechanical
      and electrical muscle dysfunction produced by continuous repeated stimulation of
      frog skeletal muscles. Continuous stimulation (50 Hz for 2 min, 0.05 ms pulse
      duration) to the sartorius muscle depolarized the membrane, decreased action
      potential amplitude, and prolonged action potential duration. GSTM (0.1 mM),
      unlike thiomalic acid (0.1 mM), markedly decreased impairment of these electrical
      parameters produced during the stimulation period. In the presence of 500
      units/mL of catalase, fatigue stimulation still lengthened by 1.5-fold the half
      duration of the action potential after a 5-min rest. The prolongation was,
      however, smaller than that in controls (no catalase). Application of both
      catalase and GSTM led to no further changes in action potential compared with the
      application of catalase alone. GSTM did not affect resting tension of single toe
      muscle fibers though it suppressed the maximum tension after continuous
      stimulation. These findings suggest that GSTM can inhibit excitable dysfunction
      of skeletal muscles subjected to continuous stimulation and that such protective
      effects of GSTM may be partially mediated by H2O2.

PMID- 15181463
TI  - Positive inotropism in mammalian skeletal muscle in vitro during and after
      fatigue.
AB  - We tested the hypothesis that positive inotropic factors decrease fatigue and
      improve recovery from fatigue in mammalian skeletal muscle in vitro. To induce
      fatigue, we stimulated mouse soleus and extensor digitorum longus (EDL) to
      perform isometric tetanic contractions (50 impulses x s(-1) for 0.5 s) at 6
      contractions x min(-1) for 60 min in soleus and 3 contractions x min(-1) for 20
      min in EDL. Muscles were submerged in Krebs-Henseleit bicarbonate solution
      (Krebs) at 27 degrees C gassed with 95% nitrogen - 5% carbon dioxide (anoxia).
      Before and for 67 min after the fatigue period, muscles contracted at 0.6
      contractions x min(-1) in 95% oxygen - 5% carbon dioxide (hyperoxia). We added a
      permeable cAMP analog (N6, 2'-O-dibutyryladenosine 3':5'-cyclic monophosphate at
      10(-3) mol x L(-1) (dcAMP)), caffeine (2 x 10(-3) mol x L(-1), or Krebs as
      vehicle control at 25 min before, during, or at the end of the fatigue period. In
      soleus and EDL, both challenges added before fatigue significantly increased
      developed force but only caffeine increased developed force when added during the
      fatigue period. At the end of fatigue, the decrease in force in challenged
      muscles was equal to or greater than in controls so that the force remaining was
      the same or less than in controls. EDL challenged with dcAMP or caffeine at any
      time recovered more force than controls. In soleus, caffeine improved recovery
      except when added before fatigue. With dcAMP added to soleus, recovery was better
      after challenges at 10 min and the end of the fatigue period. Thus, increased
      intracellular concentrations of cAMP and (or) Ca2+ did not decrease fatigue in
      either muscle but improved recovery from fatigue in EDL and, in some conditions,
      in soleus.

PMID- 15181465
TI  - Effect of age on mechanical properties of rat mesenteric small arteries.
AB  - With aging, large arteries become stiffer and systolic blood pressure
      consequently increases. Less is known, however, about the age-related change in
      mechanics of small resistance arteries. The aim of this study was to determine
      whether aging plays a role in the stiffening of the small mesenteric arteries of
      rats. Intra-arterial systolic, diastolic, mean and pulse pressures were measured
      in male Wistar rats aged 2, 4, 15 and 26 months. The passive mechanical
      properties of the wall of isolated perfused and pressurized arterial segments of
      mesenteric small arteries were also investigated. Intra-arterial systolic,
      diastolic and mean blood pressures tended to decrease with age and were
      significantly lower in the oldest rats (26-month-old group). Pulse pressure was
      significantly higher in the 15- and 26-month-old groups than in the two younger
      groups. Under isobaric conditions, increasing age is associated with an outward
      hypertrophic remodeling of the mesenteric arteries. Under relaxed conditions,
      incremental distensibility in response to increasing intravascular pressure did
      not change with aging. As a function of strain (under isometric conditions),
      stress shifted to the left as age increased, indicating an age-related vascular
      stiffening. Under isobaric conditions or in relation to wall stress, the elastic
      modulus was greater in the adult 15-month-old rats than in the younger rats.
      These findings suggest that distensibility seems to be preserved with aging,
      despite stiffness of the wall components, probably by arterial wall geometric
      adaptation, which limits the pulse pressure damage. It is interesting to note
      that elastic modulus in mesenteric arteries from the oldest rats (26-month-old),
      examined in relation to wall stress and intravascular pressure, did not differ
      from that of the youngest rats, thus suggesting that elasticity of wall
      components had been restored.

PMID- 15181466
TI  - Toxic effect of chloromycetin on the ultrastructures of the motor neurons of the
      Chinese tree shrew (Tupaia belangeri).
AB  - This paper describes the toxic effects of chloromycetin on the motor neurons of
      the Chinese tree shrew (Tupaia belangeri chinensis) with horse radish peroxidase
      (HRP) as the labeling enzyme. When chloromycetin was administered orally at 2.5
      mg/kg (body weight)/day for 3 days, Chinese tree shrews showed evidence of
      neurotoxicity. This included damage in cortical motor neuron synapses ending on
      neurons of the red nucleus and the ultrastructural changes in the mitochondria
      such as swelling of these organelles and blurring of their cristae. There was an
      increase of the mitochondrial matrix density and of the thickness of the synaptic
      membranes. These observations indicate that chloromycetin can lead to
      ultrastructural change of terminals of the cortical motor axons, and that Chinese
      tree shrews are sensitive animal model for chloromycetin neurotoxicity.

PMID- 15181467
TI  - Rapid biphasic arteriolar dilations induced by skeletal muscle contraction are
      dependent on stimulation characteristics.
AB  - To test the hypothesis that measurable changes in microvasculature dilation occur
      in response to a single short-duration tetanic contraction, we contracted three
      to five skeletal muscle fibres of the hamster cremaster muscle microvascular
      preparation (in situ) and evaluated the response of an arteriole overlapping the
      active muscle fibres. Arteriolar diameter (baseline diameter = 16.4 +/- 0.9 micro
      m, maximum diameter = 34.7 +/- 1.2 micro m) was measured before and after a
      single contraction resulting from a range of stimulus frequencies (4, 10, 20, 30,
      40, 60, and 80 Hz) within a 250- or 500-ms train. Four and 10 Hz produced a
      significant dilation at 2.9 +/- 0.4 and 6.5 +/- 2.8 s, respectively, within a 250
      ms train and 3.0 +/- 0.2 and 6.1 +/- 1.3 s, respectively, within a 500-ms train.
      Biphasic dilations were observed within a 250-ms train at 20 Hz (at 3.9 +/- 0.9
      and 22.1 +/- 4.3 s), 30 Hz (at 2.7 +/- 0.3 and 17.5 +/- 2.9 s), and 40 Hz (at 3.8
      +/- 0.4 and 23.2 +/- 2.6 s) and within a 500-ms train at 20 Hz (at 4.8 +/- 0.4
      and 31.9 +/- 3.8 s) and 30 Hz (at 3.4 +/- 0.3 and 27.6 +/- 3.0 s). A single
      dilation was observed within a 250-ms train at 60 Hz (at 5.1 +/- 0.7 s) and 80 Hz
      (at 14.2 +/- 3.3 s) and within a 500-ms train at 40 Hz (at 9.9 +/- 3.2 s), 60 Hz
      (at 7.9 +/- 2.1 s), and 80 Hz (at 13.4 +/- 4.0 s). We have shown that a single
      contraction ranging from a single twitch (4 Hz, 250 ms) to fused tetanic
      contractions produces significant arteriolar dilations and that the pattern of
      dilation is dependent on the stimulus frequency and train duration.

PMID- 15181468
TI  - Protective role of heme oxygenase in the blood vessel wall during atherogenesis.
AB  - Several lines of evidence suggest that antioxidant processes and (or) endogenous
      antioxidants inhibit proatherogenic events in the blood vessel wall. Heme
      oxygenase (HO), which catabolizes heme to biliverdin, carbon monoxide, and
      catalytic iron, has been shown to have such antioxidative properties. The HO-1
      isoform of heme oxygenase is ubiquitous and can be increased several fold by
      stimuli that induce cellular oxidative stress. Products of the HO reaction have
      important effects: carbon monoxide is a potent vasodilator, which is thought to
      play a role in modulation of vascular tone; biliverdin and its by-product
      bilirubin are potent antioxidants. Although HO induction results in an increase
      in catalytic free iron release, the enhancement of intracellular ferritin protein
      through HO-1 has been reported to decrease the cytotoxic effects of iron.
      Oxidized LDL has been shown to increase HO-1 expression in endothelial and smooth
      muscle cell cultures, and during atherogenesis. Further evidence of HO-1
      expression associated with atherogenesis has been demonstrated in human, murine
      and rabbit atherosclerotic lesions. Moreover, genetic models of HO deficiency
      suggest that the actions of HO-1 are important in modulating the severity of
      atherosclerosis. Recent experiments in gene therapy using the HO gene suggest
      that interventions aimed at HO in the vessel wall could provide a novel
      therapeutic approach for the treatment or prevention of atherosclerotic disease.

PMID- 15181469
TI  - Conformational change and inactivation of arginine kinase from shrimp
      Feneropenaeus chinensis in oxidized dithiothreitol solutions.
AB  - The effect of oxidized dithiothreitol (DTT) on the conformation and function of
      arginine kinase from shrimp Feneropenaeus chinensis was investigated with the
      methods of intrinsic fluorescence, ANS fluorescence, size exclusion
      chromatography (SEC), sodium dodecyl sulfate - polyacrylamide gel electrophoresis
      (SDS-PAGE), and activity assay. The excess molecular oxidized dithiothreitol
      could result in a loss of activity and conformational change of arginine kinase.
      The oxidized arginine kinase was characterized by monitoring the changes of
      fluorescence emission wavelength (excitation wavelength: 295 nm) and the
      intensity of 1-anilino-8-naphthalenesulfonate (ANS) binding (excitation
      wavelength: 380 nm) to the protein. The results of fluorescence spectra showed
      that the presence of oxidized DTT could result in a marked change in the enzyme
      tertiary structure. The conformational changes of native and oxidized arginine
      kinase are induced by the presence of the full set of transition state analog
      (TSA) components. The results of size exclusion chromatography and SDS-PAGE
      indicated that no disulfide bond was formed among the protein molecules in the
      oxidized-DTT solution.

PMID- 15181470
TI  - Characterization of glycine N-methyltransferase from rabbit liver.
AB  - The enzymatic properties of glycine N-methyltransferase from rabbit liver and the
      effects of endogenous adenosine nucleosides, nucleotides and methyltransferase
      inhibitors were investigated using a photometrical assay to detect sarcosine with
      o-dianisidine as a dye. After isolation and purification the denatured enzyme
      showed a two-banded pattern by SDS-PAGE. The enzyme was highly specific for its
      substrates with a pH-optimum at pH 8.6. Glycine N-methyltransferase exhibits
      Michaelis-Menten kinetics for its substrates, S-adenosylmethionine and glycine,
      respectively. The apparent Km and Vmax values were determined for both the
      substrates, the other substrate being present at saturating concentrations. The
      enzyme was strongly inhibited in the presence of S-adenosylhomocysteine, 3
      deazaadenosine, and 5'-S-isobutylthio-5'-deoxyadenosine. All other inhibitors
      investigated, adenosine, 2'-deoxyadenosine, aciclovir, and 5'-N
      ethylcarboxamidoadenosine were poor inhibitors of the methylation reaction.
      Adenine nucleotides and vidarabin were without effect on the enzymatic activity.
      Based on the kinetic data glycine N-methyltransferase from rabbit liver exhibits
      appreciable activity at physiological S-adenosylmethionine and S
      adenosylhomocysteine levels.

PMID- 15181471
TI  - Maintenance of Epstein-Barr virus-derived episomal vectors in the murine Sp2/0
      myeloma cell line is dependent upon exogenous expression of human EBP2.
AB  - Vectors carrying the origin of replication (oriP) and driving expression of the
      EBNA-1 protein from Epstein-Barr virus (EBV) replicate as extrachromosomal
      episomes in human cells. Whether these vectors can be maintained as episomes in
      murine cells is still controversial. Here we demonstrate that EBNA-1 expression
      alone was unable to maintain episomal expression of an EBV-based vector in the
      murine Sp2/0 cell line. However, we were able to obtain long-term episome
      maintenance in Sp2/0 cells after exogenously expressing human EBP2 by genetic
      engineering. Our results provide further evidence for the fundamental role of
      human EBP2 in episomal maintenance of EBV-based vectors. Moreover, we demonstrate
      that EBV-based vectors can be successfully used in cells presumably incompetent
      for episomal maintenance.

PMID- 15181472
TI  - Expression of iNOS gene in macrophages stimulated with 17beta-estradiol is
      regulated by free intracellular Ca2+.
AB  - 17Beta-estradiol has potent Ca2+ ionophore capability and its signaling in
      macrophages is mediated through binding to surface and genomic receptors,
      resulting in transient nitric oxide (NO) elaboration. We decided to examine if
      the transient release of NO is due to Ca2+ influx pattern or the quenching effect
      of superoxide (*O2-) through peroxynitrite formation. Differential chelation of
      intracellular Ca2+ ([Ca2+]i) showed that NO generation was favored by [Ca2+]i
      concentration of 237 nM. Application of an estrogen receptor antagonist ICI 182
      780 resulted in attenuation of estradiol mediated NO release. Studies directed at
      identifying the possible role of *O2-; in the attenuation of NO showed no
      supportive evidence. Inhibition of extracellular Ca2+ channel or extracellular
      and intracellular Ca2+ channels showed data consistent with a case for optimum
      Ca2+ influx signal favoring iNOS gene expression, accompanied by an elevation in
      iNOS protein. These data show that Ca2+ influx pattern determines macrophage NO
      elaboration.

PMID- 15181473
TI  - Bioenergetic remodeling during cellular differentiation: changes in cytochrome c
      oxidase regulation do not affect the metabolic phenotype.
AB  - Myogenesis induces mitochondrial proliferation, a decrease in reactive oxygen
      species (ROS) production, and an increased reliance upon oxidative
      phosphorylation. While muscles typically possess 20%-40% excess capacity of
      cytochrome c oxidase (COX), undifferentiated myoblasts have only 5%-20% of the
      mitochondrial content of myotubes and muscles. We used two muscle lines (C2C12,
      Sol8) and 3T3-L1 pre-adipocytes to examine if changes in COX regulation or
      activity with differentiation cause a shift in metabolic phenotype (i.e., more
      oxidative, less glycolytic, less ROS). COX activity in vivo can be suppressed by
      its inhibitor, nitric oxide, or sub-optimal substrate (cytochrome c)
      concentrations. Inhibition of nitric oxide synthase via L-NAME had no effect on
      the respiration of adherent undifferentiated cells, although it did stimulate
      respiration of myoblasts in suspension. While cytochrome c content increased
      during differentiation, there was no correlation with respiratory rate or
      reliance on oxidative metabolism. There was no correlation between COX specific
      activity and oxidative metabolism between cell type or in relation to
      differentiation. These studies show that, despite the very low activities of COX,
      undifferentiated myoblasts and pre-adipocytes possess a reserve of COX capacity
      and changes in COX with differentiation do not trigger the shift in metabolic
      phenotype.

PMID- 15181474
TI  - Retinoic acid-inducible gene-I is induced by interferon-gamma and regulates the
      expression of interferon-gamma stimulated gene 15 in MCF-7 cells.
AB  - Retinoic acid-inducible gene-I (RIG-I) is a member of the DExH box family
      proteins, which have diverse roles in regulation of gene expression and cellular
      functions. We found RIG-I mRNA and protein were expressed in MCF-7 human breast
      cancer cells stimulated with interferon-gamma (IFN-gamma). This effect of IFN
      gamma was observed in concentration- and time-dependent manners, and IFN-gamma
      also induced promoter activity of RIG-I. Transfection of GFP-RIG-I cDNA into MCF
      7 cells resulted in the expression of RIG-I protein in cytoplasm. Overexpression
      of RIG-I induced the upregulation of IFN-gamma stimulated gene 15, which has the
      potential to amplify the immunomodulatory effects. We conclude that IFN-gamma
      induces the expression of RIG-I, which may play a role in the immunological
      effects of IFN-gamma.

PMID- 15181475
TI  - An analysis of mismatched duplex DNA unzipping through a bacterial nanopore.
AB  - A 50-base Guide strand was synthesized that consisted of a central 10-base probe
      sequence flanked by two tracts of 20 adenine residues. Target sequences of 10
      bases containing up to three mismatches were prepared and hybridized to the Guide
      strand in 1 M KCl. The transport of these constructs through single alpha
      hemolysin pores was analysed by measuring the current blockade as a function of
      time. Complementary dsDNA takes significantly longer (840 +/- 60 micro s) to pass
      through the pore than a sequence of the same length containing a single (590 +/-
      45 micro s) and a double (270 +/- 50 micro s) mismatch. Constructs involving
      three mismatches were indistinguishable from Guide ssDNA transport (120 +/- 30
      micro s). The results suggest that dsDNA must unzip as it is transported through
      the nanopore. Duplexes containing mismatches unzip more quickly and can be
      distinguished from those with perfect complementarity.

PMID- 15181476
TI  - Suppression subtractive hybridization coupled with microarray analysis to examine
      differential expression of genes in virus infected cells.
AB  - High throughput detection of differential expression of genes is an efficient
      means of identifying genes and pathways that may play a role in biological
      systems under certain experimental conditions. There exist a variety of
      approaches that could be used to identify groups of genes that change in
      expression in response to a particular stimulus or environment. We here describe
      the application of suppression subtractive hybridization (SSH) coupled with cDNA
      microarray analysis for isolation and identification of chicken transcripts that
      change in expression on infection of host cells with a paramyxovirus. SSH was
      used for initial isolation of differentially expressed transcripts, a large-scale
      validation of which was accomplished by microarray analysis. The data reveals a
      large group of regulated genes constituting many biochemical pathways that could
      serve as targets for future investigations to explore their role in paramyxovirus
      pathogenesis. The detailed methods described herein could be useful and adaptable
      to any biological system for studying changes in gene expression.

PMID- 15181478
TI  - Upper extremity movement pattern of a common drinking task in well elderly women:
      A pilot study.
AB  - Retraining of the upper limb during neurological rehabilitation often involves
      preparatory therapeutic exercises of concentric and eccentric nature embedded in
      purposeful activity. However, empirical baseline studies are lacking to justify
      efficacy of such training. The purpose of this study was to determine the effect
      of concentric and eccentric exercises on upper extremity movement pattern in
      healthy elderly persons during a common daily functional task. Nine young women
      aged between 22 and 23 years and nine elderly women between 70 and 78 years
      participated in the musculoskeletal study of lifting a cup of water to sip and
      then lowering the cup back to a table. Two-dimensional forearm movement
      kinematics and associated electromyography from biceps and triceps were analysed.
      Forearm motor performance in the elderly participants were slower and needed more
      corrections compared to the younger participants. The electromyography revealed
      that lifting and lowering movements were accomplished by concentric and eccentric
      muscle firing in the biceps. However, in the elderly the muscle responses were
      varied suggesting a possible decline in object-related visuomotor co-ordination
      with age. The results indicate that movement patterns and muscular response
      decline in elderly people during preparatory therapeutic exercises embedded in
      purposeful activity. The effect of therapeutic exercises on upper limb functional
      performance needs to be further investigated in patient populations to explore
      the effectiveness of embedded therapeutic exercises in movement retraining. Small
      sample number limits the results of the study to be generalized. In addition,
      future studies should measure movement of more limb and hand segments to gain
      understanding of the total upper extremity performance during the task.

PMID- 15181477
TI  - Detection of hCG Responsive Expression of the Steroidogenic Acute Regulatory
      Protein in Mouse Leydig Cells.
AB  - The steroidogenic acute regulatory (StAR) protein, a novel mitochondrial protein,
      is involved in the regulation of steroid hormone biosynthesis through its
      mediation of the intramitochondrial transport of the steroid substrate,
      cholesterol, to the cytochrome P450 cholesterol side chain cleavage (P450scc)
      enzyme. The expression of StAR protein is regulated by cAMP-dependent signaling
      in steroidogenic cells. During the course of our studies in mouse Leydig cells,
      we employ several methods for studying the regulation of StAR protein expression
      by human chorionic gonadotropin (hCG). A sensitive quantitative reverse
      transcription and polymerase chain reaction (RT-PCR) was utilized for determining
      StAR mRNA expression. Stimulation of mLTC-1 mouse Leydig tumor cells with hCG
      resulted in the coordinate regulation of StAR mRNA expression and progesterone
      accumulation in a time-response manner. The validity and accuracy of quantitative
      RT-PCR results in mLTC-1 cells were verified by a competitive PCR approach and
      were further confirmed in primary cultures of isolated mouse Leydig cells.
      Immunoblotting studies demonstrated an increase in the levels of the StAR protein
      in a concentration dependent manner following hCG stimulation in mLTC-1 cells.
      Northern hybridization analysis revealed three StAR transcripts, all of which
      were of sufficient size to encode functional StAR protein, and which were
      coordinately expressed in response to hCG. Collectively, the experimental
      approaches utilized in the present investigation allow for the demonstration and
      characterization of hCG mediated regulation of StAR mRNA and StAR protein
      expression in mouse Leydig cells.

PMID- 15181479
TI  - Functional capacity evaluation reports for clients with personal injury claims: A
      content analysis.
AB  - Functional capacity evaluations (FCEs) for personal injury claimants are
      rigorously scrutinized by the stakeholders because of their financial
      implications. This study examined 51 medico-legal FCE reports for clients all of
      whom suffered with spinal pain attributed to a motor vehicle accident. The FCEs
      were completed by 14 occupational therapists. Content analysis of the FCE reports
      identified categories and sub-categories of objective and subjective information
      on which occupational therapists reported. They included employment, activities
      of daily living, pain, functional physical capacities and job demands.
      Recommendations included the suitability of current and future jobs. However, the
      reasoning behind occupational therapists' recommendations in the FCE reports was
      frequently not stated. This content analysis demonstrated that these detailed FCE
      reports had a consistent focus on work capacity; further, the researchers suggest
      refinements to FCE reporting practices so that findings, recommendations and
      predictions about work outcomes for clients are interpreted clearly and
      realistically.

PMID- 15181480
TI  - Evaluation of the mentor-mentee relationship in an occupational therapy
      mentorship programme.
AB  - Mentor group relationships in an occupational therapy university curriculum were
      investigated. In phase I, mentors (n = 23) and mentees (n = 124) were surveyed
      over a four year period. In phase II, 14 mentees from the same time period were
      surveyed after graduation. It was found that mentors and mentees surveyed agreed
      that their mentor group leader displayed more mentoring (i.e. ongoing partnership
      for guidance and support) than coaching (i.e. short-term relationship for
      providing feedback on areas requiring change) characteristics, and most agreed
      that, post-graduation, their mentor group leader had been a mentor to them.
      Mentees viewed their mentors predominantly as a role model or counsellor and
      emphasized knowledge, experience, guidance, and support as desirable attributes
      of a mentor. Contact with mentors for resources, support, or job-related purposes
      continued after graduation for more than half of mentees. Some mentees reported
      that peer mentoring had also occurred. Limitations of the study include the small
      sample size in Phase II and some aspects of survey design. Future areas of
      research identified include studying the development of the relationship over
      time (i.e. pre-, mid-way, and post-programme), comparing relationships between
      mentors and mentees who have similar versus dissimilar expectations for the
      programme, further examining peer mentoring or group relationships, and
      continuing post-graduation surveys with a larger sample size for increased
      reliability.

PMID- 15181481
TI  - Cross-cultural adaptation of the Sensory Profile: establishing linguistic
      equivalency of the Hebrew version.
AB  - In the process of translating assessment tools from one language to another,
      researchers often run the risk of altering the intended meaning of the test
      items, and consequently affecting the validity of the assessment tool. In this
      study, the accuracy of a Hebrew translation of the Sensory Profile (Dunn, 1999)
      was validated. A multi-step process, based on back-translation and the bilingual
      method was undertaken to examine whether the Hebrew translation was
      linguistically equivalent to the original Sensory Profile. Quantitative and
      qualitative measures were used to detect and explain inconsistencies in the
      translation. The analysis of the back-translation revealed that the discrepancies
      found in a number of items stemmed from inaccurate translation or back
      translation, erroneous substitution, omission, or addition of words/phrases, and
      from substitution of words/phrases because there was no equivalent in the Hebrew
      language. Of the 59 back-translated items, which were not linguistically
      equivalent to the original Sensory Profile items, only 12 items generated
      inconsistent responses by the bilingual parents. Overall, the responses of the
      bilingual parents to the Hebrew and the English version were inconsistent in 26
      of the 125 Sensory Profile items. The coefficient alpha values in all sections of
      the Hebrew version (except for section N) were above.70, indicating a good
      overall reliability. Based on proposed criteria, results indicate that the Hebrew
      translation of the Sensory Profile is accurate. Inconsistencies found in a number
      of items may relate to connotation effect, language effect, and measurement
      errors.

PMID- 15181482
TI  - Toward better probing for hypomania of bipolar-II disorder by using Angst's
      checklist.
AB  - The reliability of the diagnosis of bipolar-II disorder (BP-II) is still a
      problem. Semi-structured interviews by clinicians might partly overcome this
      problem. The aims of this study were to find the degree of agreement in the
      diagnosis of BP-II between the Structured Clinical Interview for DSM-IV (SCID)
      and a semi-structured interview based on Angst's hypomania checklist (Angst et
      al., 2003), and to assess the priority among hypomanic symptoms for the diagnosis
      of BP-II. Remitted depression outpatients (N = 102) were interviewed during a
      follow-up visit using th Structured Clinical Interview for DSM-IV (SCID), and
      then with Angst's semi-structured interview, following DSMIV criteria. Bipolar I
      (BP-I) patients were excluded. Using the SCID, 29 patients were diagnosed BP-II,
      26 BP-I, and 47 major depressive disorder (MDD). By the semi-structured interview
      69 patients were diagnosed BP-II, 33 MDD, and none BP-I. Agreement for the
      diagnosis of BP-II between the two interviews was 53.9% (k = 0.18). Re-analysis,
      after deleting the SCID question on the impact on functioning (DSM-IV unclear
      boundary between BP-I and BP-II), increased agreement to 78.4% (k = 0.55).
      Elevated mood and overactivity (increased goal-directed activity) had th lowest
      agreement (k = 0.46 0.49). For predicting BP-II, overactivity had the highest
      sensitivity (94.2%), whil elevated mood had a sensitivity of 84.0%. Multivariate
      analysis for predicting BP-II (diagnosed by semi-structured interview), including
      all DSM-IV hypomanic symptoms, found that mood change and overactivity were the
      only independent predictors. Overactivity plus at least three symptoms (as
      suggested by Angst and Gamma, 2002) were present in 71 patients, of whom 91.5%
      also met DSM-IV criteria for hypomania. Overactivity and elevated mood were
      strongly associated (but not overactivity and irritability). Findings may support
      a diagnosis of BP-II based on Angst's semi-structured interview versus the fully
      structured SCID interview. While DSM-IV always requires mood change for the
      diagnosis of hypomania, the present findings may suggest that overactivity could
      have the same priority, as suggested by Angst et al. (2003) and by Akiskal et al.
      (1977, 2001, 2003).

PMID- 15181483
TI  - A longitudinal evaluation of two-year outcome in a community-based mental health
      service using graphical chain models. The South-Verona Outcome Project 9.
AB  - The 2-year outcome of 178 patients attending a community-based mental health
      service was assessed from a multidimensional perspective. The study investigated:
      (1) the effect of disease-related characteristics (such as diagnosis and illness
      duration) and of a series of outcome variables measured at baseline (global
      functioning, psychopathology, social disability, quality of life and satisfaction
      with services) on total costs of care over 2 years; and (2) the effect of costs
      of care and outcome variables measured at baseline on the corresponding outcome
      variables at 2 years. To gain insight into the multivariate longitudinal
      dependencies among variables, we used graphical Gaussian chain models, a new
      multivariate method that analyses the relationship between continuous variables
      taking into account the effect of antecedent and intervening variables, to reveal
      not only direct but also indirect correlations. Outcome variables showed the
      tendency to segregate, both at baseline and follow-up, into two distinct groups:
      a clinician-rated dimension (given by global functioning, social disability and
      psychopathology) and a patient-rated dimension (given by service satisfaction and
      subjective quality of life). Higher costs at 2 years were predicted by higher
      psychopathology at baseline, diagnosis of psychosis and longer duration of
      illness. Baseline values for each variable were the main predictors of the
      corresponding values at two years. Improvement in satisfaction with life at
      follow-up was experienced in those subjects with a lower functioning at baseline.
      This study throws some light on the complex relationships between clinical,
      social and economic variables affecting the medium-term outcome of mental health
      care.

PMID- 15181484
TI  - Use of resampling to select among alternative error structure specifications for
      GLMM analyses of repeated measurements.
AB  - Autocorrelated error and missing data due to dropouts have fostered interest in
      the flexible general linear mixed model (GLMM) procedures for analysis of data
      from controlled clinical trials. The user of these adaptable statistical tools
      must, however, choose among alternative structural models to represent the
      correlated repeated measurements. The fit of the error structure model
      specification is important for validity of tests for differences in patterns of
      treatment effects across time, particularly when maximum likelihood procedures
      are relied upon. Results can be affected significantly by the error specification
      that is selected, so a principled basis for selecting the specification is
      important. As no theoretical grounds are usually available to guide this
      decision, empirical criteria have been developed that focus on mode fit. The
      current report proposes alternative empirical criteria that focus on bootstrap
      estimates of actual type I error an power of tests for treatment effects. Results
      for model selection before and after the blind is broken are compared. Goodness
      of-fit statistics also compare favourably for models fitted to the blinded or
      unblinded data, although the correspondence to actual type I error and power
      depends on the particular fit statistic that is considered.

PMID- 15181485
TI  - Screening for personality disorder: a comparison of personality disorder
      assessment by patient and informants.
AB  - The Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II
      Version 2.0) is becoming the most favoured instrument to measure personality
      disorder but takes up to an hour to complete. The Standardized Assessment of
      Personality (SAP), an informant-based measure, takes 10 to 15 minutes to
      complete. Both instruments have been validated independently. This study aimed to
      determine whether the SAP is a suitable screening instrument for personality
      disorder as measured by the SCID-II. Fifty-seven psychiatric patients were
      assessed for personality disorder using both the SAP and the SCID-II. The SAP
      assessments were conducted blind to the results of the SCID-II assessments.
      Agreement between the two instruments in this population was low (kappa = 0.3).
      The level of agreement differed between personality disorder categories, ranging
      from kappa = 0.4 (antisocial) to 0.1 (narcissistic). In this population of
      patients, the SAP proved to be a poor screen for the SCID-II. The study
      highlights the discrepancy between informant and self-report assessments for
      personality disorder.

PMID- 15181486
TI  - Symptom development and timing of menarche: a longitudinal study.
AB  - Self-reported somatic complaints among females were studied cross sectionally at
      age 15 and 43, an longitudinally between these two ages. Specifically, the
      relationship between symptom development and timing of menarche was considered.
      The sample consisted of 477 females representing the general Swedish population.
      All the included symptoms were significantly related to each other at both ages.
      There was also longitudinal correlational stability for all the studied symptoms.
      Moreover, symptoms at age 15 were associated with early menarcheal timing.
      Pattern analyses of the studied symptoms were conducted with roots in person
      oriented methodology. These results revealed structural as well as individual
      stability in patterns of symptom reporting for nearly 30 years. That is, similar
      configurations of symptoms were found at both ages, and it was the same females
      who reported being either symptom free or reporting a high symptom load at both
      ages. At age 15 fewer early maturing females than expected by chance reported
      being symptom free, whereas more of the late maturing females than expected
      reported being symptom free. However, there were no effects of menarcheal timing
      on symptom reporting at age 43.

PMID- 15181487
TI  - Double-blind, randomized, acyclovir-controlled, parallel-group trial comparing
      the safety and efficacy of famciclovir and acyclovir in patients with
      uncomplicated herpes zoster.
AB  - This randomized, double-blind, parallel-group study compared the efficacy and
      safety of famciclovir administered at 250 mg thrice daily with acyclovir 800 mg 5
      times daily for the treatment of acute uncomplicated herpes zoster in
      immunocompetent adults. A total of 55 patients participated in this trial. Twenty
      seven patients (49.1%) were randomized into the famciclovir plus placebo
      treatment group and 28 (50.9%) into the acyclovir plus placebo group. Six of the
      55 patients did not complete the study. Two of these patients were in the
      famciclovir plus placebo group and dropped out due to deviation from the study
      protocol. Four patients in the acyclovir plus placebo group did not complete the
      study protocol due to adverse events (n = 2), deviation from the protocol (n =
      1), or loss to follow-up (n = 1). Treatment was initiated within 72 h of onset of
      the zoster rash and was continued for 7 days. When treatment was initiated within
      72 h, famciclovir was as effective as acyclovir for healing the cutaneous lesion,
      as indicated by the time to full crusting, loss of acute phase pain, loss of
      vesicles, and loss of crusts. Famciclovir was well tolerated and had a more
      favorable adverse event profile compared to acyclovir. Constipation, hematuria,
      and glycosuria were the most commonly reported adverse events, but only
      constipation was considered to have a possible relationship to the treatment. In
      conclusion, famciclovir, administered less frequently and at lower unit doses
      than acyclovir, is an effective treatment for uncomplicated herpes zoster.

PMID- 15181488
TI  - Prognostic implications of myoclonic jerk in children with enterovirus infection.
AB  - To determine the prognostic value of myoclonic jerk in children with enterovirus
      71 (EV71) infection, a retrospective study was conducted on 665 enterovirus
      culture-confirmed patients admitted to Chang Gung Children's Hospital from
      January 2000 to September 2001. The mean age was 35.0 months +/- 32.2 months,
      ranging from 1 day to 15 years and 416 (62.6%) of them were male. Among these
      patients, 140 (21.1%) had EV71 isolated, and 150 (22.6%) had myoclonic jerk.
      Fifty one percent (72/140) of EV71 cases and only 15% (78/525) of non-EV71 cases
      had myoclonic jerk (p<0.001). The age of enterovirus patients with myoclonic jerk
      was younger than that of patients without myoclonic jerk (23.2 +/- 17.6 vs 38.4
      +/- 34.6 months, p=0.005). The hospitalization and fever durations were
      significantly longer in the EV71 group than in the non-EV71 group (8.3 +/- 13 vs
      4.2 +/- 2.7 days, p<0.001; 5.9 +/- 4.8 vs 4.2 +/- 3.0 days, p=0.009,
      respectively). Patients with myoclonic jerk also had higher percentages of severe
      illness, and neurologic sequelae (20% and 9%, respectively) than those without
      myoclonic jerk (5% and 1%, respectively) [p<0.001]. The positive predictive
      values of myoclonic jerk for EV71 infection, severe cases, and neurologic
      sequelae were 0.48, 0.20, and 0.09, respectively; the negative predictive values
      for severe cases and neurologic sequelae were 0.95 and 0.99, respectively. This
      study demonstrated that myoclonic jerk and EV71 infection are both independently
      associated with more severe disease and higher incidence of neurologic sequelae.

PMID- 15181489
TI  - Different familial association patterns of autoimmune diseases between juvenile
      onset systemic lupus erythematosus and juvenile rheumatoid arthritis.
AB  - The aim of this study was to determine if the prevalence of autoimmune disorders
      in the relatives of patients with systemic lupus erythematosus (SLE) is greater
      than that of relatives of patients with juvenile rheumatoid arthritis (JRA).
      Interviews were used to obtain histories of the following autoimmune disorders
      among living or deceased first-, second-, and third-degree relatives of 91 SLE
      and 110 JRA families: ankylosing spondylitis, SLE, rheumatoid arthritis (RA),
      JRA, multiple sclerosis, juvenile dermatomyositis, Sjogren's syndrome, myasthenia
      gravis, psoriasis, and thyroid diseases. There were statistically significant
      differences between the SLE and JRA probands in mean age and gender ratio (19.1
      +/- 4.8 vs 14.0 +/- 5.5 years; M (male)/F (female): 17/74 vs 62/48, p<0.005). The
      prevalence rate of autoimmune diseases in relatives of SLE families (20.9%) was
      greater than in JRA families (11.8%), but not statistically significantly so. The
      mean age (18.0 +/- 5.3 vs 14.0 +/- 4.3 years), mean age at diagnosis (13.4 +/-
      4.3 vs 7.9 +/- 3.9 years) and gender ratio (F/M, 16/3 vs 5/8) of the patients
      with affected relatives between these 2 groups all had statistically significant
      differences. A higher prevalence of SLE in relatives was found in SLE families
      than in JRA cases. Furthermore, this study revealed a higher incidence of
      autoimmune disorders among second- and third-degree relatives of SLE or JRA
      probands versus first-degree ones, especially sisters (including 1 pair of twins)
      and the maternal aunt in SLE families. These data demonstrate that the prevalence
      of autoimmune disorders in the relatives of patients with SLE is greater than
      those of relatives of patients with JRA. This suggests that clinically different
      autoimmune phenotypes may share common susceptibility genes, which may act as
      risk factors for autoimmunity.

PMID- 15181490
TI  - Clinical features of influenza A and B in children and association with myositis.
AB  - Influenza virus is among the most common causes of respiratory illness, which may
      manifest as a range of conditions, from mild upper respiratory tract infection to
      bronchiolitis and pneumonia. Acute childhood myositis associated with influenza
      occurs mostly in influenza B infection. In this retrospective study, we analyzed
      the characteristics of 197 children with influenza virus treated from January
      2000 to December 2001. Among them, 73 children had influenza A infection and 124
      had influenza B infection. Influenza A virus outbreaks occurred in January 2000,
      July 2001, and December 2001, while influenza B virus outbreaks occurred from
      March 2000 to May 2000 and from December 2000 to February 2001. The most common
      clinical manifestations of influenza A and influenza B virus infection included
      fever, cough, and rhinorrhea. These infections also frequently manifested as
      laryngo-tracheobronchitis, pneumonia, and unexplained fever, which led to
      hospitalization. The most common clinical diagnosis was upper respiratory tract
      infection. The rates of benign acute childhood myositis in influenza A and
      influenza B were 5.5% and 33.9%, respectively. Creatine kinase levels were
      elevated in most myositis cases and boys were more commonly affected. Acute
      childhood myositis was more commonly seen in influenza B infection.

PMID- 15181491
TI  - Salmonella enterica serotype Choleraesuis infection in a medical center in
      northern Taiwan.
AB  - This retrospective study was conducted in order to determine the clinical and
      microbiologic features of infection with Salmonella enterica serotype
      Choleraesuis. Between March 1999 and December 2002, 55 patients with 66 isolates
      were enrolled for analysis. The ratio of males to females was 2.2:1. Most
      patients were older than 60 years (56%) and had underlying diseases (78%), such
      as diabetes mellitus, malignancy, and peptic ulcer. Fever (85%) was the most
      common clinical manifestation, followed by abdominal pain/fullness (31%). The
      gastrointestinal manifestations, including nausea/vomiting or diarrhea, accounted
      for only 13% and 11% of patients, respectively. S. enterica serotype Choleraesuis
      was extremely invasive, with a high predilection to cause bacteremia (78% of the
      isolates were from blood). Various types of metastatic focal infections were
      found, including infected arterial aneurysm, osteomyelitis, septic arthritis,
      urinary tract infection and wound infection. The crude mortality rate was 18% (10
      deaths in 55 cases). Nearly all isolates were susceptible to the third-generation
      cephalosporins. A higher resistance rate to commonly used antimicrobial agents
      was found with ampicillin (85%, 56/66), trimethoprim-sulfamethoxazole (81%,
      40/49), chloramphenicol (96%, 47/49), and ciprofloxacin (49%, 30/61). In view of
      the emergence of fluoroquinolone resistance, the third-generation cephalosporins
      appear to be the best choice for treatment of invasive infections caused by this
      organism.

PMID- 15181492
TI  - Acute hepatitis with or without jaundice: a predominant presentation of acute Q
      fever in southern Taiwan.
AB  - Acute Q fever was previously regarded as an uncommon infectious disease in Taiwan
      but has been increasingly recognized recently. Acute febrile illness, hepatitis,
      and pneumonia are the 3 most common manifestations of this condition, whereas
      jaundice is rarely reported among patients with acute Q fever. We report 2 cases
      of acute Q fever with jaundice and multi-organ involvement. The first patient
      presented with fever, severe headache, and acute abdomen necessitating laparotomy
      and was complicated with acute cholestatic hepatitis, acute non-oliguric renal
      failure and disseminated intravascular coagulation. The second patient had acute
      cholestatic hepatitis and thrombocytopenia, and the latter was likely related to
      the infection of bone marrow by Coxiella burnetii, as evidenced by the presence
      of C. burnetii DNA detected by nested polymerase chain reaction. The incidence
      and clinical significance of hyperbilirubinemia was also determined by review of
      medical records of 35 cases of acute Q fever cases diagnosed serologically at
      National Cheng Kung University Hospital from 1994 to 2001. All had biochemical
      hepatitis and 23% had hyperbilirubinemia (serum bilirubin > or =2 mg/dL). The
      febrile course before admission and the period between the initiation of
      effective medication to defervescence were longer in patients with
      hyperbilirubinemia than in patients without hyperbilirubinemia, although this
      difference was not significant. Our results suggest that the predominant
      presentation of acute Q fever in southern Taiwan is acute febrile illness with
      hepatitis and that jaundice is not uncommon. Due to the clinical polymorphism of
      acute Q fever, the threshold of surveys for C. burnetii infections should be low
      for febrile patients with elevated transaminases or hyperbilirubinemia of unknown
      cause.

PMID- 15181493
TI  - Changing characteristics of typhoid fever in Taiwan.
AB  - Typhoid fever, a systemic disease caused by Salmonella typhi, is classically
      characterized by fever and abdominal symptoms. Although now considered uncommon,
      it seems to have re-emerged in Taiwan in recent years. We conducted a
      retrospective study of the clinical characteristics and microbiologic findings in
      24 confirmed cases of typhoid fever treated over a 7-year period at a medical
      center in northern Taiwan. There were 11 males and 13 females, including 15
      adults (over 18 years in age) and 9 children. Their mean age was 24.7 years
      (range, 9 months to 58 years). Twelve patients had recently returned from abroad,
      mostly from Southeast Asia. The most common complaints were fever (24/24),
      diarrhea (18/24), abdominal pain (10/24), and cough (10/24). The average duration
      of fever before diagnosis was 14.1 days, with a maximum of 30 days. Relative
      bradycardia was noted in 6 patients. Leukopenia was noted in 2 patients. S. typhi
      was isolated from blood culture in 20 cases, from stool culture in 3 cases, and
      from bone marrow culture in 1 case. Widal test was only positive initially in
      7/18 cases. Fever of unknown origin was the most common initial diagnosis.
      Typhoid or enteric fever was impressed initially in only 2 cases. Almost all
      isolates of S. typhi were susceptible to antibiotics currently used for typhoid
      fever, with only 1 isolate resistant to chloramphenicol. All patients survived
      after antibiotic treatment. Only 1 patient developed recurrence after a 10-day
      course of ceftriaxone. In conclusion, the diagnosis of typhoid fever is often
      challenging due to non-specific symptoms and lack of an immediate confirmatory
      test. It is important to include this disease in the differential diagnosis of
      febrile patients with abdominal symptoms.

PMID- 15181494
TI  - Fungal peritonitis in peritoneal dialysis patients: effect of fluconazole
      treatment and use of the twin-bag disconnect system.
AB  - Fungal peritonitis is an uncommon but potentially life-threatening complication
      for patients undergoing continuous ambulatory peritoneal dialysis. This
      retrospective study evaluated the efficacy of fluconazole in fungal peritonitis
      treatment and the incidence of fungal peritonitis in different peritoneal
      dialysis disconnect systems. Fungal peritonitis was caused by Candida species in
      67% of episodes. The most common pathogen in this series was Candida parapsilosis
      (29%), followed by Candida albicans (14%). One patient (5%) died within 1 month
      after admission for treatment of fungal peritonitis. Only 1 patient (5%) in this
      series could resume peritoneal dialysis. Treatment with fluconazole alone has an
      effect comparable to intraperitoneal (IP) amphotericin B alone or IP amphotericin
      B combined with oral or intravenous fluconazole. The incidence of fungal
      peritonitis in patients who used the spike, Y-set, and UV antiseptic systems was
      5.69, 6.20, and 2.93 times, respectively, as frequent as that of fungal
      peritonitis in patients who used the twin-bag disconnect system.

PMID- 15181495
TI  - The hyperimmunoglobulin E syndrome.
AB  - Hyperimmunoglobulin E syndrome is a primary immunodeficiency disease
      characterized by markedly high titers of serum immunoglobulin E (IgE), chronic
      eczema, recurrent staphylococcal infections, pneumatoceles, reduced neutrophil
      chemotaxis, and variable impaired T cell function. There are no clinical tools
      for diagnosis and definitive laboratory investigation. Variability of
      presentation makes it easy to confuse the diagnosis with that of severe atopy or
      other rare immunodeficiencies. We report a case of a 6-year-old boy with
      hyperimmunoglobulin E syndrome with recurrent methicillin-resistant
      Staphylococcus aureus furunculosis. Physical examination revealed a peculiar
      facial appearance, pruritic dermatitis, and furunculosis over the scalp, neck,
      and back. Laboratory investigation revealed mild leukocytosis with eosinophilia,
      a very high immunoglobulin E level, defective neutrophil chemotaxis, and impaired
      lymphocyte proliferation to anti-CD3/CD28 monoclonal antibodies. The boy was
      discharged without incident after 2 weeks of antibiotic therapy and debridement.

PMID- 15181496
TI  - Community-acquired methicillin-resistant Staphylococcus aureus liver abscess in a
      patient with end-stage renal disease.
AB  - Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections
      are an emerging problem. Although most liver abscesses are caused by Escherichia
      coli and Klebsiella pneumoniae, S. aureus can occasionally be isolated as the
      pathogenic organism. Liver abscess caused by MRSA is rarely reported. Here, we
      report a case of liver abscess due to MRSA in a 34-year-old man with end-stage
      renal disease and a 13-year history of hemodialysis treatment.

PMID- 15181497
TI  - Mycoplasma pneumoniae infection presenting as neutropenia, thrombocytopenia, and
      acute hepatitis in a child.
AB  - Extrapulmonary manifestations of Mycoplasma pneumoniae pneumonia are uncommon and
      include hematologic, gastrointestinal, musculoskeletal, dermatologic, and
      neurologic complications. We report a case of serologically-confirmed M.
      pneumoniae infection complicated by severe neutropenia, thrombocytopenia, and
      hepatitis. The presence of antiplatelet and antineutrophil antibodies suggested
      that these autoantibodies caused the cytopenias. The disease had an acute course
      and the patient recovered after steroid treatment. This case indicates that
      neutropenia, thrombocytopenia and hepatitis are possible clinical manifestations
      of M. pneumoniae infection.

PMID- 15181498
TI  - Neonatal lupus erythematosus with cholestatic hepatitis.
AB  - Neonatal lupus erythematosus is an uncommon passive autoimmune disease in which
      there is transplacental passage of anti-Ro/SSA and/or anti-La/SSB or anti-U1RNP
      maternal autoantibodies. Its common clinical manifestations include cardiac
      disease, notably congenital heart block, cutaneous lupus lesions, and hematologic
      problems. During the past decade, it has become clear that hepatobiliary disease
      may also occur as a manifestation of neonatal lupus erythematosus. We report a
      case of neonatal lupus erythematosus in a male infant who had lupus hepatitis
      with jaundice in addition to cutaneous lupus, anemia, and thrombocytopenia. Other
      diseases in the differential diagnosis of conjugated hyperbilirubinemia,
      including metabolic, infectious, and inherited anatomic conditions were all ruled
      out. The infant had a high titer of antinuclear antibodies (titer 1:640) with a
      speckled pattern, anti-Ro/SSA and anti-La/SSB antibodies, and no anti-dsDNA
      antibodies. Treatment with prednisolone (2 mg/kg/day) for 14 days resulted in
      dramatic improvement of the thrombocytopenia. Hemoglobin and bilirubin returned
      to normal 2 months later, and transaminases were normal by 10 months of age.

PMID- 15181499
TI  - Surgical options for the treatment of venous ulcers.
AB  - Venous ulcers are a difficult problem for both patient and physician. Healing of
      venous ulcers with compression therapy and elevation, although usually
      successful, often takes months. Some venous ulcers do not heal with conservative
      therapy, or if they do, can often recur. Proper evaluation of the lower extremity
      venous system, usually with noninvasive imaging, is essential in planning any
      surgical intervention. In the appropriate patient, a number of surgical options
      are available to achieve ulcer healing and/or to prevent recurrence. These
      options include ablation of superficial reflux, perforator interruption, deep
      venous reconstruction, and endovenous procedures.

PMID- 15181500
TI  - Endoluminal repair of ruptured abdominal aortic aneurysms under local anesthesia:
      initial experience.
AB  - Open surgical repair is the standard treatment for a ruptured infrarenal
      abdominal aortic aneurysm (rAAA). This approach is associated with mortality
      rates of up to 70%, with significant surgery-related morbidity among survivors.
      In selected patients, endoluminal repair (ER) of an rAAA under local anesthesia
      may allow emergent aneurysm repair with reduced perioperative stress, ideally
      resulting in improved outcomes. The authors report their initial experience using
      a commercially available bifurcated endoluminal stent-graft to treat patients
      with rAAA under local anesthesia. Five of 8 patients (63%) with rAAA in a 1-year
      interval (June 2000-May 2001) were treated with ER. Criteria for ER were the
      following: (1) suitable aortic anatomy based on preoperative computed tomography
      (CT) imaging and (2) a hemodynamic state not requiring immediate aortic control.
      Mean size of ER rAAAs was 8 cm. Four of 5 patients underwent ER under local
      anesthesia. All 5 ER patients survived the initial surgery, and 4 patients
      survived to discharge. The expired patient was a Jehovah's Witness who had a
      successful ER but was profoundly anemic postoperatively and refused transfusion.
      On postoperative CT imaging, no endoleaks were noted and no AAA enlargement had
      occurred. In a selected but significant subset of rAAA patients, emergent repair
      using a commercially available bifurcated endograft under local anesthesia is
      feasible, and clinical outcomes are acceptable. These promising initial results
      suggest that a further evaluation of the role of endoluminal repair in the
      treatment of ruptured infrarenal AAAs is warranted.

PMID- 15181501
TI  - Reflux from thigh to calf, the major pathology in chronic venous ulcer disease:
      surgery indicated in the majority of patients.
AB  - The aim of this study was to define the underlying anatomical and
      pathophysiological conditions in limbs with venous ulcers in order to get
      information for the most appropriate treatment selection. Ninety-eight limbs (83
      patients, 59 men), with active chronic venous ulcers, were analyzed
      retrospectively and classified according to the CEAP (clinical, etiological,
      anatomical, and pathophysiological) classification. Duplex-ultrasound was
      performed in all patients, while air-plethysmography and venography were
      performed selectively on potential candidates for deep venous reconstruction.
      Sixty-six ulcers were primary in origin and 32 were secondary. Reflux was present
      in all limbs except 1. Isolated reflux in 1 system (superficial = 3, deep = 4,
      perforator = 3) was seen in 10 legs (10%), while incompetence in all 3 systems
      was seen in 51 legs (52%). Superficial reflux with or without involvement of
      other systems was seen in 84 legs (86%), 72 legs (73%) had deep reflux with or
      without involvement of other systems, and incompetent perforator veins were
      identified in 79 limbs (81%). Axial reflux (continuous reverse flow from the
      groin region to below knee) was found in 77 limbs (79%). The femoral vein was the
      single most common deep venous segment in which either reflux or obstruction was
      found. Axial distribution of disease was found in the majority of cases and no
      patient had isolated deep venous incompetence below knee. Primary disease was the
      predominant etiologic cause and reflux was the main pathophysiological finding.
      Practically all patients were found to have 1 or more sites of reflux or
      obstruction that could benefit from operative treatment.

PMID- 15181502
TI  - Percutaneous venous valve bioprosthesis: initial observations.
AB  - Chronic deep venous insufficiency remains a major health problem in the United
      States and worldwide. Selected patients benefit from direct deep vein valve
      repair or valve transplantation; however, most are not candidates for these
      procedures. Experience with the bovine monocusp venous valve surgically inserted
      into the common femoral vein (CFV) demonstrates potential benefit and good long
      term patency. A venous valve placed distal to the CFV via percutaneous access has
      great appeal and potential for further improving venous hemodynamics, as well as
      reducing ambulatory venous hypertension and ulceration. Two patients were treated
      with a percutaneous venous valve bioprosthesis as part of a Phase I trial. The
      primary objective was to evaluate the safety, patency, and efficacy of the
      percutaneous venous valve bioprosthesis to restore competency to the deep venous
      system.

PMID- 15181503
TI  - In-vitro evaluation of a new inferior vena cava filter-the stent-filter.
AB  - Inferior vena cava filters are indicated for the prevention of pulmonary embolism
      when anticoagulation using heparin has failed or is contraindicated. The aim of
      this study was to assess in an in-vitro setting the efficiency of a new inferior
      vena cava filter to intercept emboli. The new filter, stent-filter, was inserted
      into a pulsating flow circuit. Then thrombi were produced by introducing sheep's
      blood into silicon tubes with 3 mm diameter. A combination of 9% saline solution
      with 40% glycerol was used as the isosmotic fluid in the circuit. A total of 150
      thrombi were introduced into the circuit in 3 stages of 50 events each. The flow
      rate in each of the 3 stages was altered; initially a rate of 1.0 liter per
      minute was chosen, and after this, it was increased to 1.5 liters and finally 2.0
      liters per minute. The percentage of interceptions was used for statistical
      analysis. In the in-vitro experiment, the filter captured 94%, 90%, and 92% of
      the thrombi at flow rates of 1.0, 1.5, and 2.0 liters per second, respectively.
      In conclusion the new filter was effective in the interception of the thrombi
      when it was evaluated in in-vitro conditions.

PMID- 15181504
TI  - Reevaluation of temporary transvenous cardiac pacemaker usage during carotid
      angioplasty and stenting: a safe and valuable adjunct.
AB  - Although many current series document the safety of carotid angioplasty and
      stenting procedures (CAS), several acknowledge clinically significant hemodynamic
      disturbances in 25-71% of patients. We report herein the safety and efficacy of
      prophylactic percutaneous temporary transvenous cardiac pacemaker insertion
      during CAS for the prevention of hemodynamic changes. At a community-based
      institution, 48 patients undergoing 51 attempted CAS procedures from March 1999
      to August 2002 for carotid artery occlusive disease were retrospectively
      reviewed. Thirty-one percent of patients had procedures performed for either
      recurrent disease or a history of neck radiation; 62.5% had significant coronary
      disease. Temporary transvenous pacemakers were inserted as an adjunctive
      procedure in the authors' CAS protocol. The pacers were set to capture a heart
      rate decrease below 60 beats per minute. Demographics, cardiac risk, and outcomes
      were analyzed. CAS was successfully performed in 96% (49 lesions). In the intent
      to-treat group, the patients had a mean age of 71 +/-9 years and angiographic
      stenoses of 88 +/-8%, with 29% having symptomatic lesions. Significant
      bradycardia or asystole to trigger ventricular pacing occurred in 11 (22%)
      procedures, thus, triggering ventricular pacing. Pharmacologic support for
      concomitant hypotension was temporarily necessary in only 4 (8%) cases. No
      patient required prolonged pacing or medication therapy following CAS. Neither
      presence of carotid-related symptoms nor disease etiology was related to need for
      intraprocedural pacing. Furthermore, there was no occurrence of pacemaker failure
      or other complication secondary to venous catheterization. Hemodynamic changes
      may occur during mechanical dilation of the carotid artery and bulb, with reports
      in the literature of the need for prolonged pharmacologic support. In selected
      patients, the prophylactic placement of a transvenous pacemaker is a safe,
      feasible, and expeditious method to treat periprocedural hemodynamic changes with
      a decrease in additional pharmacologic support during CAS.

PMID- 15181505
TI  - Abdominal wall hernias after open abdominal aortic aneurysm repair: prospective
      radiographic detection and clinical implications.
AB  - The purpose of this study was to evaluate the prevalence of radiographically
      detected abdominal wall defects (AWD) after open abdominal aortic aneurysm (AAA)
      repair and to correlate it with prospectively gathered clinical information. Fine
      collimation, high-resolution, serial follow-up computed tomography (CT) scans for
      99 patients in the control group of the Guidant Ancure device trial were
      reviewed. CT scans were obtained at 12, 24, 36, 48, and 60 months. AWDs, defined
      as discontinuity of the fascial layer with protrusion of abdominal contents, were
      identified. Clinical information regarding AWDs was retrieved from the study
      registry. The prevalence of AWD exceeds 20% and plateaus at 24 months. Eight
      patients (8%) had clinical evidence of ventral incisional hernias. One patient
      underwent repair, but no other patient developed hernia incarceration or
      intestinal obstruction or required additional procedures related to the AWD. AWDs
      are radiographic findings occurring frequently after open AAA repair.
      Radiographic evaluation is more sensitive than clinical observation for detection
      of ventral hernias. Clinical events and reinterventions related to these
      radiographic abnormalities are rare.

PMID- 15181506
TI  - Hand-assisted laparoscopic aorto-aortic bypass: initial experience in a porcine
      model.
AB  - Videoscopic surgical techniques have been developed to reduce morbidity of open
      aortic reconstructions. The advantage of hand-assisted laparoscopic surgery
      (HALS) technique is the introduction of the surgeon's hand into the peritoneal
      cavity. The aims of this study were to assess the feasibility and to examine the
      learning curve, limitations, and pitfalls of the HALS technique to perform aortic
      reconstruction in a porcine model for training purposes. HALS aorto-aortic 8 mm
      polytetrafluoroethylene (PTFE) interposition grafts were placed in 12 pigs.
      Proficiency was judged by measuring operative time points, satisfactory
      completion of the operation, and the need to convert to open procedure. The
      strength of the relationship between order number in which a procedure was
      performed and the various surgical time point measures was described with the
      Spearman rank correlation. HALS aortic grafting was successful in the last 8
      pigs. The first 2 pigs required conversion to open repair, and the graft of the
      third and fourth animals occluded early. Median operative time was 115 minutes
      (range: 75 to 205), median intestinal retraction time was 28 minutes (range: 10
      to 40), median aortoiliac dissection time was 30 minutes (range: 20 to 60), and
      median aortic cross-clamp time was 48 minutes (range: 35 to 82). The Spearman
      rank correlations and p values between the order of the procedure and the
      intestinal retraction time, aortoiliac dissection time, clamping time, and total
      operative time were -0.62 (0.06), -0.47 (0.17), -0.69 (0.03), and -0.83 (0.03),
      respectively. HALS facilitates intestinal retraction and completion of
      laparoscopic aortoiliac dissection. It offers adequate exposure in pigs for
      aortic grafting and allows open sutured aortic anastomosis. The learning curve
      for HALS aortic surgery in a porcine model is short and within reach of surgeons
      with standard laparoscopic surgery skills, since no laparoscopic suturing is
      required. Training on this porcine model may be an efficient and safe way to
      introduce surgeons to HALS for aortoiliac reconstruction.

PMID- 15181507
TI  - Outcome from traumatic injury of the portal and superior mesenteric veins.
AB  - Traumatic injuries to the portal vein (PV) and superior mesenteric vein (SMV) are
      rare and carry a high mortality rate, and the best approach and method of repair
      is still subject to debate. The objective of the present study was to analyze
      risk factors for mortality in portal and superior mesenteric venous injuries. A
      retrospective analysis of 18 patients during a 5-year period was performed.
      Mechanism of injury, shock upon admission, Revised Trauma Score (RTS), Injury
      Severity Score (ISS), intraoperative fluid requirements, classification of venous
      injury severity, and associated injuries were analyzed as potential predictors of
      outcome. All patients were male, 9 were victims of gunshot wounds, and 11 were in
      shock at the time of admission. Eight patients sustained PV, and 12 sustained SMV
      injuries. The great majority of patients had more than 1 associated injury and
      61% had an associated vascular injury. Mortality rate correlated with injury
      severity. Overall mortality rate was 72%. Nonsurvivors had higher ISS than
      survivors (24 +/-0.4 and 20 +/-1.7, respectively; p = 0.006). Uncontrollable
      intraoperative hemorrhage was the cause of death in 5 of 13 patients (38.4%). Six
      patients died during the postoperative period from complications of prolonged
      shock and multiple organ failure, and 2 died of sepsis. The physiologic status
      upon admission, the number of associated injuries, and the severity of the
      vascular injury are the most important factors related to mortality in PV and SMV
      injuries.

PMID- 15181508
TI  - Endovascular treatment of an endoleak causing rupture of a previously bypassed
      popliteal aneurysm. A case report.
AB  - Enlargement of a previously bypassed popliteal aneurysm is rare. However, the
      possibility exists for persistent aneurysm expansion via geniculate collaterals.
      The authors report herein a patient who underwent successful endovascular
      treatment of a ruptured popliteal aneurysm that had been previously bypassed and
      presumably excluded.

PMID- 15181509
TI  - Spontaneous dissection of common iliac artery. A case report.
AB  - Spontaneous dissection of the iliac artery is very rare but known as a
      complication of high-energy traumatic injuries and has been reported in
      connection with pregnancy, collagen diseases, and alpha-1-antitrypsin deficiency.
      The authors report a 42-year-old man with an acute dissection of the common iliac
      artery during exercise. Groin pain and claudication were the early symptoms.
      Computerized angiotomography was diagnostic. Operative iliac artery
      reconstruction was performed. A prerelease control computed tomography
      examination showed a dissection of the distal aorta and left iliac artery. To
      their knowledge, the combination of the 2 dissections has not been previously
      published.

PMID- 15181510
TI  - Mega-aneurysmal degeneration of a saphenous vein graft following infrainguinal
      bypass. A case report.
AB  - True aneurysm formation in infrainguinal autologous vein grafts is rare. The
      authors report a case of a patient presenting with extensive aneurysmal
      degeneration of a femoropopliteal bypass vein graft 13 years after the original
      operation and 8 years after graft revision and thrombolysis for acute occlusion.
      Over a 2-year period, the vein graft aneurysm expanded from 2.7 to 4.5 cm maximal
      diameter. He underwent exclusion and partial resection of the vein graft aneurysm
      with placement of a new femoropopliteal bypass using reversed saphenous vein from
      the contralateral leg. Histopathologic examination of the aneurysm revealed
      intimal fibrosis, medial degeneration, and inflammation. This case and review of
      the literature suggests that true infrainguinal vein graft aneurysms occur
      infrequently and massive aneurysm degeneration is even more uncommon. Because of
      the rarity of true infrainguinal vein graft aneurysms, their etiology remains
      unclear.

PMID- 15181511
TI  - Adventitial cystic disease of the external iliac vein presenting with deep venous
      thrombosis. A case report.
AB  - Adventitial cystic disease of the venous system is a rare occurrence with only 8
      reported cases in the world literature. The most commonly involved segment has
      been the common femoral vein, resulting in luminal compromise and presenting with
      extremity swelling. Painless swelling of the right lower extremity in a 37-year
      old man was diagnosed as iliofemoral thrombosis by duplex examination.
      Thrombolysis revealed smooth luminal defects of the external iliac vein, which
      prompted surgical exploration. Iliofemoral thrombectomy exposed multiloculated
      adventitial cysts of the distal external iliac vein. The preferred surgical
      intervention in the literature has been transadventitial or transluminal
      evacuation of the mucoid cysts with removal of cystic wall. These are excellent
      options when there is no associated venous thrombosis, wall thickening, or
      persistent venous stenosis after drainage. This is the first reported case
      associated with deep venous thrombosis. In this situation resection of the
      involved segment followed by venous reconstruction might be the preferred option.

PMID- 15181512
TI  - Failed angioplasty of a popliteal artery stenosis secondary to cystic adventitial
      disease--a case report.
AB  - The purpose of this case review is to describe treatment options for arterial
      occlusive disease secondary to a popliteal cyst. The occurrence of this disease
      is significantly less than atherosclerosis as the cause of claudication. The
      clinical presentation, natural history, and treatment options are reviewed.

PMID- 15181513
TI  - Primary aorto/iliac-enteric fistula-report of 6 new cases.
AB  - The management of patients with vascular-enteric fistulas remains a challenging
      diagnostic and therapeutic problem for the vascular surgeon. Although fortunately
      quite a rare cause of gastrointestinal bleeding, reported mortality and
      amputation rates are very high. Fistulas between major vascular structures and
      the gastrointestinal tract are classified as either primary or secondary. Primary
      fistulas occur most commonly between an aortic aneurysm and the distal duodenum,
      while secondary fistulas occur following erosion of prosthetic material into the
      bowel following aortic reconstruction. The authors report 6 new cases of primary
      aortoenteric fistula: A malignant aortoenteric fistula in a patient with advanced
      metastatic squamous cell carcinoma involving the infrarenal aorta and duodenum, 4
      cases of primary aortoenteric fistulas in patients with abdominal aortic
      aneurysms, and 1 iliac-enteric fistula secondary to a common iliac aneurysm. The
      diagnosis is often difficult to make, and although it was considered in 4
      patients preoperatively, the diagnosis was not made until the time of laparotomy
      in all of these patients. Three patients were treated with an in-situ vascular
      graft, 2 others had the distal abdominal aorta oversewn and axillobilateral
      femoral bypass performed, and in the case involving the malignancy, the patient
      underwent primary aortic repair owing to the extent of the tumor process
      prohibiting aortic reconstruction. Three patients had primary closure of the
      intestine performed, and 3 required bowel resection and primary anastomosis. The
      overall 30-day mortality rate was 50% as 3 patients died in the early
      postoperative period and the remaining 3 patients survived to be discharged from
      hospital. One patient (17%) required bilateral above-knee amputations. Treatment
      of patients with vascular-enteric fistulas is a difficult problem, often
      associated with delayed diagnosis and high morbidity and mortality rates.
      Successful surgical management can be achieved with primary closure of the
      intestinal tract and an in-situ vascular graft or extraanatomic bypass.

PMID- 15181514
TI  - The economics of healthcare litigation.

PMID- 15181515
TI  - Pap smear screening for cervical cancer in Singapore: issues to consider.

PMID- 15181516
TI  - Launching the Singapore Medical Journal CME programme.

PMID- 15181518
TI  - Biostatistics 203. Survival analysis.

PMID- 15181519
TI  - The pivotal role of the pathology laboratory in the context of a Singapore
      cervical cancer screening programme.
AB  - Singapore is poised to implement a national cervical screening programme and
      pathology laboratories have a pivotal role to play. This review describes the
      laboratory examination of Pap smears and the importance of providing a first
      class service. This will require sufficient experienced cyto-technologists and
      pathologists. There also needs to be a mechanism in place to monitor all stages
      of the Pap smear, from the time it is taken until it is reported. The Bethesda
      System for reporting Pap smears, new smear collection devices, liquid-based
      specimens, use of computer screening and other measures to enhance laboratory
      standards, are also discussed.

PMID- 15181520
TI  - Endoscopic extraperitoneal inguinal hernia repair: a series of 182 repairs.
AB  - INTRODUCTION: The local experience of endoscopic totally-extraperitoneal hernia
      repair in a major teaching hospital is reviewed. METHODS: Between 1997 and 2003,
      141 consecutive patients underwent 182 totally-extraperitoneal hernia repairs for
      inguinal hernia. 100 patients had unilateral hernia and 41 patients had bilateral
      hernias. The mean age was 51 years (range 20 to 83 years). RESULTS: The mean
      operation duration was 70 minutes. Bilateral repairs took 24 percent longer than
      for unilateral repairs (82 versus 66 minutes). However, the mean operative
      duration for the last 55 (30 percent) cases decreased to 55 minutes. Four
      patients (2.8 percent) had conversion to open surgery and ten patients had minor
      complications, mostly groin seroma that resolved. Overall, there were seven
      hernia recurrences (3.8 percent) in the series. However, no hernia recurrence was
      present in the last 63 patients (45 percent). Recurrences were higher when the
      mesh was not anchored than when the mesh was fixed with a tacking device (p value
      is less than 0.01). The mean inpatient hospital stay was 1.4 days. Of the last 30
      patients (21 percent), 70 percent were performed as outpatients. CONCLUSION:
      Endoscopic extraperitoneal hernia repair offers the appropriate patient a viable
      alternative to open hernia surgery. To achieve good results, adequate cases
      should be performed to overcome the learning curve, and the mesh should be
      anchored to the inguinal floor to prevent recurrences.

PMID- 15181521
TI  - Laparoscopic ventral hernia repair: local experience.
AB  - INTRODUCTION: Laparoscopic ventral hernia repair (LVHR) is a recent development
      that has been shown to be an effective way of treating ventral hernias. We
      present the first local series of LVHR with a review of the literature on
      laparoscopic ventral herniorrhaphy. METHODS: We retrospectively reviewed all our
      patients who underwent laparoscopic surgery for ventral hernias from December
      1998 to May 2002. Results of LVHR such as operative time, length of hospital
      stay, complications and recurrence rates were evaluated. RESULTS: Twenty patients
      underwent LVHR. There were 16 female and four male patients. The average age was
      54 years. The mean fascial defect was 46 square cm. An ePTFE Mesh was used in all
      the patients except for one patient who had a prolene mesh. The mean operative
      time was 117 minutes and the hospital stay was two days. There were two minor
      complications and no major complications. With a mean follow-up period of 14.9
      months, the recurrence rate was 5.0 percent with a single recurrence at four
      months. CONCLUSION: Our initial experience with this modality shows that LVHR a
      feasible option with great potential in both treatment success and reduction of
      surgical morbidity.

PMID- 15181522
TI  - Comparison of the effectiveness of detecting diabetic eye disease: diabetic
      retinal photography versus ophthalmic consultation.
AB  - INTRODUCTION: This study determines the accuracy of reading a Polaroid retinal
      photograph in the diabetic retinal photography programme as compared to a
      clinical fundal examination in the diagnosis of diabetic retinopathy. METHODS: A
      prospective study recording the additional findings obtained from clinical
      examination of the eye using indirect ophthalmoscopy and slit lamp biomicroscopy
      in a restructured tertiary hospital serving an urban community was performed.
      RESULTS: Seventy-eight eyes in 39 diabetic patients were reviewed by an
      ophthalmologist for diabetic changes seen on fundus photography. The sensitivity
      of diabetic retinal photography in diagnosing diabetic eye conditions was 91.6
      percent, with a specificity of 99.8 percent and a positive predictive value of
      95.6 percent. The degree of agreement kappa was 0.94. CONCLUSION: The use of
      diabetic retinal photographs to screen for diabetic eye disease achieved a high
      sensitivity by capturing diabetic retinal lesions. It was comparable to an
      examination performed by the ophthalmologist. With appropriate training, the
      person reading the diabetic retinal photographs can accurately diagnose diabetic
      eye conditions.

PMID- 15181523
TI  - Does right leg require extra protection? Five-year review of type 3 open
      fractures of the tibia.
AB  - INTRODUCTION: Open fracture of the tibia is very common among motorcyclists. The
      morbidity associated with this injury is well-documented as treatment of severe
      open fractures is very difficult. There is currently no study done in the
      literature to see the relationship between fracture severity and the side of the
      injury. METHODS: We reviewed 239 patients with open fractures of the tibia
      admitted to our institution from 1998 to 2002. RESULTS: From 241 tibias studied,
      150 (62.2 percent) involved the right side and 91 (37.8 percent) involved the
      left side. Statistical analysis showed that there was a significant difference in
      the severity of open fracture between the sides of fracture. Less severe injury
      (grades 1 and 2 fractures) was associated with injury of the left tibia and
      severe injury (grades 3A, B and C fractures combined) was associated with right
      tibia fracture. CONCLUSION: Since the right leg was more exposed to the injury,
      it is imperative to protect the limb. This may reduce the overall incidence and
      severity of tibia fractures.

PMID- 15181524
TI  - Rapidly-progressive bronchiolitis obliterans organising pneumonia.
AB  - Bronchiolitis obliterans organising pneumonia is a clinicopathological syndrome
      characterised by indolent course of flu-like illness followed by cough, dyspnoea
      and fever, and responds well to steroid treatment. We describe a 76-year-old
      woman who presented with a short three-day history and progressed rapidly to
      respiratory failure. She was successfully treated with high-dose steroids.

PMID- 15181525
TI  - Malignant rhabdoid tumour of the brain.
AB  - Rhabdoid tumour is a rare childhood tumour with poor prognosis. We report a 13
      month-old Malay girl suffering from this tumour that was located at the left
      fronto-temporo-parietal region of the brain. Computed tomography showed a large
      irregular enhancing mass that caused obstructive hydrocephalus. The tumour did
      not reduce in size after three operations and finally the patient succumbed to
      the disease four months after diagnosis.

PMID- 15181526
TI  - Pitfalls of gynaecological ultrasonography.
AB  - Pitfalls in gynaecological ultrasonography may arise during acquisition of
      images, processing and interpretation. Physical interactions between the
      ultrasound and body structures may produce artifacts. Physiological processes
      such as functional ovarian cysts may mimic lesions. Different pathological
      processes may produce similar ultrasonographical appearances. To minimise errors
      in interpretation of gynaecological ultrasonography, one needs to be aware of the
      limitations of ultrasonography, and the similarities in the appearances of
      various physiological and pathological processes.

PMID- 15181527
TI  - Clinics in diagnostic imaging (98). Heterotopic pregnancy with an intrauterine
      blighted ovum and a live tubal ectopic pregnancy.
AB  - A 26-year-old woman who was six weeks amenorrhoeic presented with vaginal
      spotting and mild abdominal pain. She had been coming to the 24 hours women's
      clinic at two-day intervals for the past week with the same symptoms.
      Ultrasonography two days ago showed one intrauterine gestational sac (IUGS) with
      a yolk sac within. Her pregnancy was clomiphene-related. Repeat transvaginal
      ultrasonography during this admission showed an IUGS, together with a left live
      tubal ectopic pregnancy. Heterotopic pregnancies used to be a rare entity. Now,
      given the increasing rise in assisted reproduction techniques, there should be a
      high index of suspicion for heterotopic pregnancy as this would impact upon
      clinical management. The ultrasonographical features of heterotopic pregnancy and
      its differential diagnoses are discussed.

PMID- 15181528
TI  - Penile metastasis from rectal carcinoma.

PMID- 15181534
TI  - A novel genetic modifier of p53, mop1, results in embryonic lethality.
AB  - The heterogeneity that occurs in the tumor spectrum and latency in Li-Fraumeni
      syndrome (LFS) patients with inherited mutations in p53 suggest risk modifiers at
      loci other than the major gene. We developed a mouse model to investigate these
      risk modifiers. Inbred CE/J mice, which succumb to multiple types of tumors
      similar to those found in LFS, were crossed with the p53-null 129/Sv (129
      Trp53(tm1Tyj)) mouse. In this cross, we uncovered evidence for a genetic modifier
      of p53, mop1, based on an unexpected mix of genotypes in the F2 progeny from
      Mendelian expectations. A model in which a recessive CE/J allele in combination
      with p53 heterozygosity or homozygosity results in lethality most closely fits
      the data. Using simple-sequence length polymorphism analysis of the entire
      genome, we identified a putative chromosomal region for this modifier of p53 on
      mouse chromosome 11 centromeric to p53.

PMID- 15181535
TI  - An ENU-induced mutation in AP-2alpha leads to middle ear and ocular defects in
      Doarad mice.
AB  - One of the advantages of N-ethyl- N-nitrosourea (ENU)-induced mutagenesis is
      that, after randomly causing point mutations, a variety of alleles can be
      generated in genes leading to diverse phenotypes. For example, transcription
      factor AP-2alpha ( Tcfap2a) null homozygote mice show a large spectrum of
      developmental defects, among them missing middle ear bones and tympanic ring.
      This is the usual occurrence, where mutations causing middle ear anomalies
      usually coincide with other abnormalities. Using ENU-induced mutagenesis, we
      discovered a new dominant Tcfap2a mutant named Doarad ( Dor) that has a missense
      mutation in the PY motif of its transactivation domain, leading to a misshapen
      malleus, incus, and stapes without any other observable phenotype. Dor homozygous
      mice die perinatally, showing prominent abnormal facial structures and ocular
      defects. In vitro assays suggest that this mutation causes a "gain of function"
      in the transcriptional activation of AP-2alpha. These mice enable us to address
      more specifically the developmental role of Tcfap2a in the eye and middle ear and
      are the first report of a mutation in a gene specifically causing middle ear
      abnormalities, leading to conductive hearing loss.

PMID- 15181536
TI  - Mouse testis transcriptome revealed using serial analysis of gene expression.
AB  - We applied serial analysis of gene expression (SAGE) to the mouse testis to
      reveal the global gene expression profile and to identify senescence-dependent
      changes in that profile. A total of 61,929 SAGE tags, including 19,323 unique
      tags, were obtained from 3- and 29-month-old BDF1 mice and 14-month-old SAMP1
      mice. Genes highly expressed in the testis included those associated with
      spermatogenesis, protein metabolism, energy metabolism, growth and
      differentiation, and signal transduction. Testes from old mice of both strains
      appeared atrophied. Morphological examination of aged testes revealed extremely
      thin seminiferous epithelia and significantly decreased numbers of spermatids and
      spermatocytes. Despite the physical deterioration, no gross changes in the gene
      expression profile were apparent in the testes of old BDF1 mice. However, in 14
      month-old SAMP1 mice, protamine 2 gene transcription was approximately 50% lower
      than in BDF1 mice. This reduction may be associated with the oligozoospermia and
      early decline in reproductive performance of SAMP1 mice. Our SAGE results are the
      first quantitative gene expression profile of the mouse testis and provide a
      reliable transcriptome reference for this organ.

PMID- 15181537
TI  - A novel mouse Chromosome 2 congenic strain with obesity phenotypes.
AB  - Linkage studies have identified many chromosomal regions containing obesity genes
      in mice. However, only a few of these quantitative trait loci (QTLs) have been
      used to guide the production of congenic mouse strains that retain obesity
      phenotypes. We seek to identify chromosomal regions containing obesity genes in
      the BSB model of spontaneous obesity because the BSB model is a multigenic
      obesity model. Previous studies identified QTLs on Chromosomes (Chrs) 2, 6, 7,12,
      and 15. BSB mice are made by backcross of lean C57BL/6J x Mus spretus. F(1)s were
      backcrossed to C57BL/6J mice to produce BSB progeny. We have constructed a new
      BSB cross and produced congenic mice with obesity phenotypes by marker-directed
      selection called B6.S- D2Mit194- D2Mit311. We found a highly significant QTL for
      percentage body lipid on Chr 2 just proximal to the Agouti locus. Chr 2 congenics
      were constructed to determine whether the main effects would be detectable. We
      observed highly significant linkage of the Chr 2 congenic containing Agouti and
      containing markers distal to D2Mit311 and proximal to D2Mit194. Thus, this
      congenic contains approximately 14.6 cM or 30 Mb (about 1.1% of the spretus mouse
      genome) and several hundred genes. The obesity phenotype of the QTL is retained
      in the congenic. The congenic can now be used to model the genetic and
      physiological basis for a relatively simple, perhaps monogenic, obesity.

PMID- 15181538
TI  - Identification of a congenic mouse line with obesity and body length phenotypes.
AB  - Our primary objective was to discover simplified mouse models corresponding to
      human obesity linkages. We used the B10.UW- H3(b) we Pax1(un) a(t)/Sn (B10.UW)
      congenic strain, a subcongenic strain with a reduced UW strain donor region, and
      their C57BL/10SnJ background strain. The congenic and subcongenic UW strain donor
      regions are on mouse Chr 2. We measured body length [anal-nasal (AN) length],
      summed fat depot weights normalized for body weight (Adiposity Index, AI), and
      percentage of body weight that is lipid. The B10.UW congenic and subcongenic
      strains have significantly smaller AN lengths ( p < 0.0001) and have a
      significantly lower AI and percentage of body weight as fat than the background
      strain ( p < 0.0001). In an F(2) intercross of the congenic and background
      strains, AN and AI were both linked to the distal half of the donor region with
      LOD scores greater than 19 and 5, respectively. F(2) haplotypes identified a
      minimal region for AN linkage of 0.8 megabases (Mb) that is estimated to express
      four genes in the current Celera mouse genome assembly. We narrowed the most
      likely location of the obesity gene to 15 Mb whose homologous genes are all
      located on human Chr 20 in the region surrounding the centromere. Since a
      previous study identified human obesity linkage peaking near the centromere, then
      the B10.UW mice may exhibit obesity due to the homologous gene.

PMID- 15181539
TI  - Genetic complexity of an obesity QTL ( Fob3) revealed by detailed genetic
      mapping.
AB  - Obesity is proving to be a serious health concern in the developed world as well
      as an unwanted component of growth in livestock production. While recent advances
      in genetics have identified a number of monogenic causes of obesity, these are
      responsible for only a small proportion of human cases of obesity. By divergent
      selection for high and low fat content over 60 generations, we have created Fat
      (F) and Lean (L) lines of mice that represent a model of polygenic obesity
      similar to the situation in human populations. From previous crosses of these
      lines, four body fat quantitative trait loci (QTL) were identified. We have
      created congenic lines (F(chr15L)), by recurrent marker-assisted backcrossing, to
      introgress the QTL region with the highest LOD score, Fob3 on Chr 15, from the L
      Iine into the F-line background. We have further mapped this QTL by progeny
      testing of recombinants, produced from crosses between the F-line and congenic
      F(chrl5L) mice, showing that the Fob3 QTL region is a composite of at least two
      smaller effect QTL-the proximal QTL Fob3a is a late-onset obesity QTL, whereas
      the distal Fob3b is an early-onset obesity QTL.

PMID- 15181540
TI  - Fine mapping of a murine growth locus to a 1.4-cM region and resolution of linked
      QTL.
AB  - Previous work identified a QTL affecting murine size (particularly tail length)
      in a cross between C57BL/6J and DBA/2J mice and refined its location to an 8-cM
      region between D1Mit30 and D1Mit57. The present study used recombinant progeny
      testing to fine map this QTL. Individuals from a partially congenic strain
      carrying chromosomes recombinant between D1Mit30 and D1Mit57 were mated to
      DBA/2J, generating 942 progeny. Two QTL affecting 10-week tail length were
      identified in this population: one at 9.7 cM distal to D1Mit30 (the position
      estimated in previous work), and another of smaller effect near D1Mit30. A second
      population ( n = 787) was generated by mating siblings from the progeny test
      population that were heterozygous for the same segment of chromosome, including
      only recombinants between D1Mit265 and D1Mit57. In the latter population, two QTL
      were also identified: one at 10.2 cM distal to D1Mit30, and another of smaller
      effect at the distal end of the mapped region (at D1Mit150). When the two
      populations were analyzed together, the estimated location of the central QTL was
      10.2 cM distal to D1Mit30 and there was marginally significant evidence of the
      distal QTL. The central QTL explained approximately 7% of the phenotypic
      variance, and the 95% confidence interval for its position (determined by
      bootstrapping) was a 1.4-cM region, approximately the region from D1Mit451 to
      D1Mit219. The central QTL also affected tail length and body mass at 3 and 6
      weeks of age, but to a lesser degree than 10-week tail length.

PMID- 15181541
TI  - A prevalent POLG CAG microsatellite length allele in humans and African great
      apes.
AB  - The human nuclear gene for the catalytic subunit of mitochondrial DNA polymerase
      gamma ( POLG) contains within its coding region a CAG microsatellite encoding a
      polyglutamine repeat. Previous studies demonstrated an association between length
      variation at this repeat and male infertility, suggesting a mechanism whereby the
      prevalent (CAG)(10) allele, which occurs at a frequency of >80% in different
      populations, could be maintained by selection. Sequence analysis of the POLG CAG
      microsatellite region of more than 1000 human chromosomes reveals that virtually
      all allelic variation at the locus is accounted for by length variation of the
      CAG repeat. Analysis of POLG from African great apes shows that a prevalent
      length allele is present in each species, although its exact length is species
      specific. In common chimpanzee ( Pan troglodytes) a number of different sequence
      variants contribute to the prevalent length allele, strongly supporting the idea
      that the length of the POLG microsatellite region, rather than its exact
      nucleotide or amino acid sequence, is what is maintained. Analysis of POLG in
      other primates indicates that the repeat has expanded from a shorter, glutamine
      rich sequence, present in the common ancestor of Old and New World monkeys.

PMID- 15181542
TI  - IDID: inherited diseases in dogs: web-based information for canine inherited
      disease genetics.
AB  - The domestic dog ( Canis familiaris) shows greater phenotypic variation than any
      other mammal. A corollary of this variation has been the recognition of more
      naturally occurring inherited diseases in dogs than have been cataloged in any
      other species apart from man. Recent catalogs list more than 370. A searchable
      Web-based database "Inherited Diseases in Dogs" (http://www.vet.cam.ac.uk/idid)
      has been developed. It catalogs diseases and conditions of dogs which are likely
      to be transmitted wholly or partly through a genetic mechanism, together with
      breeds in which they have been described. It contains disease listings and short
      descriptions, genetic and molecular genetic summaries where known, and connects
      to entry points to the literature on each disease.

PMID- 15181543
TI  - In response: Teaching testicular examination.

PMID- 15181544
TI  - New research assessment of selected psychometric properties of nonstandard ABFP
      ITE scales.

PMID- 15181545
TI  - Medical decision-making risk management based on aeronautical model.

PMID- 15181546
TI  - Professionalism: part II -- teaching and assessing the learner's professionalism.

PMID- 15181547
TI  - Your life on film: teaching continuity to residents through powerpoint and
      videotaped interviews.
AB  - Residents often lack the context they need to care for challenging patients. We
      developed a curriculum using videotapes of patient visits to teach (1). knowing
      the patient's context, (2). time: the key to trust, (3). reciprocity in the
      patient-doctor relationship, and (4). overcoming resistance to care. This
      teaching was most effective when the patient was interviewed by his/her own
      resident physician, when a particular patient was shown over time, and when
      contrasting different methods of dealing with behaviors common to two patients
      was demonstrated. Residents rated conferences in the "excellent" range and
      demonstrated a deeper appreciation of the elements of continuity.

PMID- 15181549
TI  - Chiari and me.

PMID- 15181550
TI  - Subjectifying the patient: creative writing and the clinical encounter.

PMID- 15181551
TI  - Using a modified nominal group technique as a curriculum evaluation tool.
AB  - The modified nominal group technique (NGT) is a useful and practical course
      evaluation tool that complements existing methods such as evaluation forms,
      surveys, pretests and posttests, focus groups, and interviews. The NGT's unique
      contribution to the evaluation process is the semi-quantitative, rank-ordered
      feedback data obtained on learners' perceptions of a course's strengths and
      weaknesses. In this paper, we demonstrate through a worked example how to use a
      modified NGT as a course evaluation tool in medical education.

PMID- 15181552
TI  - The current state of colonoscopy training in family medicine residency programs.
AB  - BACKGROUND AND OBJECTIVES: The US Preventive Services Task Force has recommended
      that all adults ages 50 and over be screened for colorectal cancer. Colonoscopy
      is the most accurate screening procedure, but the feasibility of colonoscopy as a
      screening tool is limited by the number of physicians trained to perform it. This
      study determined the current state of colonoscopy training in US family medicine
      residency programs. METHODS: We surveyed program directors of all Accreditation
      Council for Graduate Medical Education-approved family medicine residency
      programs regarding colonoscopy training. RESULTS: The response rate was 94% (426
      of 455). Forty-eight percent (n=201) of directors reported that their program
      offered colonoscopy training, but only 18% (n=75) of all respondents had actually
      trained one or more residents to do colonoscopies. Nationally, the mean number of
      colonoscopies performed per resident was 42.6 +/- 3.9. Regional differences were
      reported; residents trained in the western United States performed a mean of 69.8
      +/- 12.8 colonoscopies per resident. Gastroenterologists in hospital-based
      gastroenterology suites trained approximately 75% of family medicine residents.
      Fifteen percent (n=64) of directors reported that 133 (4%) of their July 2002
      graduates sought credentials to perform colonoscopy. CONCLUSIONS: Only a minority
      of family medicine graduates seek credentials to perform colonoscopy, and
      significant regional differences in training exist.

PMID- 15181553
TI  - Career influence of an international health experience during medical school.
AB  - BACKGROUND AND OBJECTIVES: International health (IH) experiences are popular
      among medical students and may influence career choices. The International Health
      Fellowship Program (IHFP) consisted of preparatory coursework and field
      experience in a developing country. We conducted a survey 4-7 years later to
      assess the career influence of IHFP participation. METHODS: Fellows completed a
      questionnaire regarding training, practice setting, patient population, further
      international work, and knowledge and attitudes about IH. RESULTS: Surveys were
      completed by 42 (70%) fellows; 31% spend most of their time working with
      underserved populations, 67% have been involved in community health projects, 74%
      practice primary care, 29% have an MPH degree, 57% have done further work in
      developing countries, while 90% named one or more barriers to further IH
      experiences. Knowledge and attitudes about IH were largely retained. Most fellows
      (67%) believed the IHFP influenced their careers. CONCLUSIONS: Most fellows felt
      that IHFP participation had a positive influence on their careers. While a
      causative relationship cannot be inferred, fellows demonstrate a strong
      preference to work with underserved populations and engage in community service
      activities. Compared with US physicians, IHFP fellows are more likely to practice
      primary care and obtain MPH degrees. Medical schools that seek to produce
      graduates with these qualities should make efforts to increase quality IH
      opportunities for their students.

PMID- 15181554
TI  - Emergency contraception: knowledge and attitudes of family medicine providers.
AB  - BACKGROUND AND OBJECTIVES: Emergency contraception (EC) is an underutilized
      method of preventing unplanned pregnancy. This study assessed family physicians'
      and nurse providers' knowledge, attitudes, and beliefs about EC. METHODS: A cross
      sectional survey was distributed to faculty, residents, and clinic nurses in a
      Midwestern department of family medicine. Data were analyzed using Statistical
      Package for the Social Sciences. Statistical significance was tested by chi
      square test, Student's t test, and Mann-Whitney U test where appropriate.
      RESULTS: Seventy-eight providers participated (response rate 81%). Seventy-four
      percent of physicians have prescribed EC in the past, with an average of 3.2
      (range 0-10) times in the last year. The majority of providers reported that they
      were familiar with indications (96%) and protocols (78%) for prescribing EC, yet
      knowledge inaccuracies were identified. Overall attitudes regarding EC were
      positive. CONCLUSIONS: Although the majority of participating providers were
      willing to prescribe EC and had generally favorable attitudes toward it, rates of
      providing this therapy were low. There was a discrepancy between providers'
      perceived and actual knowledge about EC. Interventions targeting
      misunderstandings might help reduce missed opportunities to provide EC.

PMID- 15181555
TI  - Family support and diet barriers among older Hispanic adults with type 2
      diabetes.
AB  - BACKGROUND AND OBJECTIVES: Diet plays an important role in the management of
      diabetes, and a suboptimal diet is a commonly identified problem. Family support
      may be important in overcoming barriers to good diet. We conducted this study to
      examine the role of the family in overcoming barriers to diet self-care among
      older Hispanic patients with diabetes. METHODS: We performed a cross-sectional
      survey of 138 older Hispanic adults seeking care at an outpatient university
      clinic. Patients reported on their perception of family functioning, family
      support for diet, and barriers to diet self-care. RESULTS: Level of family
      functioning was related to family support for diet self-care, and family support
      for diet was related to perceived barriers to diet self-care. Scores for family
      support were higher for those who perceived their family as functional compared
      to those who perceived their family as mildly dysfunctional or dysfunctional. As
      family support for diet increased, perceived barriers to diet self-care
      decreased. CONCLUSIONS: To fully understand difficulties encountered by older
      Hispanic adults with adherence to a diabetic diet, primary care physicians should
      explore the role of family support and family functioning. For those with poorly
      functioning families or low levels of family support, family-level interventions
      may need to be considered.

PMID- 15181556
TI  - Childhood immunization refusal: provider and parent perceptions.
AB  - BACKGROUND AND OBJECTIVES: Parental concerns may contribute to immunization
      refusals and low infant immunization rates. Little knowledge is available about
      how often and why parents refuse immunizations for their children. This study was
      conducted to estimate, based on reports from health care providers and parents,
      the frequency of and reasons for immunization refusal. METHODS: In 1998, we
      conducted 32 focus groups of parents and providers in six cities. We then mailed
      a survey to a random sample of private practice family physicians and
      pediatricians and public health nurses who immunize children. The overall survey
      response rate was 77%, and the final sample size was 544. RESULTS: Focus group
      findings indicated that parents rarely refused vaccines but occasionally resisted
      specific vaccines. Parents who were unsure about vaccinating were open to
      discussions about vaccines with a trusted provider. Most of these parents agreed
      to immunize after discussing concerns with their provider. In a subsequent survey
      of providers, respondents estimated that they immunized a mean of 3536 (median
      1560) children annually. The reported mean number of refusals per 1000 children
      age >18 years immunized was 7.2 (median 0.4), with varicella vaccine being the
      most commonly refused. Means did not vary by region or specialty. Providers
      indicated that fear of side effects heard about from media/word of mouth was the
      most commonly expressed reason for parents to refuse vaccines (52%). Religious
      (28%) or philosophical (26%) reasons or belief that the disease was not harmful
      (26%) were less common reasons. Providers reported that few parents refused
      because of anti-government sentiment (8%). CONCLUSIONS: Providers indicate low
      vaccine refusal rates within offices of traditional primary care providers and in
      public health clinics. Strategies for efficient provider-patient communication
      are needed to address parental concerns about vaccines.

PMID- 15181557
TI  - Geographic retrofitting: a method of community definition in community-oriented
      primary care practices.
AB  - Community definition is an important aspect of community health work in general
      and community-oriented primary care (COPC) in particular. Yet, community
      definitions are often nonspecific, relying on geopolitical boundaries or local
      presumptions about patient populations. Such definitions are an impediment to the
      precise application of sociodemographic or health status data to community health
      problems or to targeted community organizing. This paper describes a technique
      called "geographic retrofitting" that has proved useful in establishing a
      rigorous definition of a practice's community based on current patterns of health
      care by the community. It also demonstrates how this approach, used in
      conjunction with geographic information systems software, facilitates more
      powerful capabilities in community characterization and intervention.

PMID- 15181558
TI  - Interest in family medicine: 1982 revisited?

PMID- 15181559
TI  - Old doc, new challenges: correctional medicine.

PMID- 15181560
TI  - Prevention of mother-to-child transmission of HIV-1 through breast-feeding: past,
      present, and future.

PMID- 15181561
TI  - Late postnatal transmission of HIV-1 in breast-fed children: an individual
      patient data meta-analysis.
AB  - BACKGROUND: We analyzed individual patient data to determine the contribution of
      late postnatal transmission to the overall risk of mother-to-child transmission
      of human immunodeficiency virus type 1 (HIV-1) and the timing and determinants of
      late postnatal transmission. METHODS: Eligible trials were conducted where breast
      feeding was common; included >/=2 HIV-1 tests by 3 months, and, if follow-up
      continued, >/=2 tests at 3-12 months; and regularly assessed infant-feeding
      modality. Data on children born before January 2000 were analyzed. RESULTS: Of
      4085 children from 9 trials (breast-fed singletons for whom HIV-1 testing was
      performed), 993 (24%) were definitively infected (placebo arms, 25.9%; treatment
      arms, 23.4%; P=.08). Of 539 children with known timing of infection, 225 (42%)
      had late postnatal transmission. Late postnatal transmission occurred throughout
      breast-feeding. The estimated hazard function for time to late postnatal
      transmission was roughly constant. The cumulative probability of late postnatal
      transmission at 18 months was 9.3%. The overall risk of late postnatal
      transmission was 8.9 transmissions/100 child-years of breast-feeding and was
      significantly higher with lower maternal CD4(+) cell counts and male sex.
      CONCLUSIONS: Late postnatal transmission contributes substantially to overall
      mother-to-child transmission of HIV-1. The risk of late postnatal transmission is
      generally constant throughout breast-feeding, and late postnatal transmission is
      associated with a lower maternal CD4(+) cell count and male sex. Biological and
      cultural mechanisms underlying the association between sex and late postnatal
      transmission should be further investigated. Interventions to decrease
      transmission of HIV-1 through breast-feeding are urgently needed.

PMID- 15181562
TI  - Complete protection of neonatal rhesus macaques against oral exposure to
      pathogenic simian-human immunodeficiency virus by human anti-HIV monoclonal
      antibodies.
AB  - Because milk-borne transmission of human immunodeficiency virus (HIV) diminishes
      the benefits of perinatal antiviral drug therapy in developing countries, we have
      developed a new strategy to prevent postnatal and, possibly, intrapartum virus
      transmission in a primate model. Eight neonatal rhesus macaques were exposed
      orally to pathogenic simian-human immunodeficiency virus (SHIV); 4 neonates were
      then given intramuscular postexposure prophylaxis with 3 anti-HIV human
      neutralizing monoclonal antibodies (nMAbs) with potent cross-clade and cross
      group neutralization activity. Untreated infants experienced high viral RNA
      levels and CD4(+) T-cell losses and died (median survival time, 5.5 weeks). In
      contrast, all 4 nMAb-treated neonates were protected from infection (P=.028);
      their plasma, peripheral blood mononuclear cells, and lymph nodes remained virus
      negative for >1 year. These data are important for designing clinical trials in
      human neonates and have general implications for AIDS vaccine development, as the
      epitopes recognized by the 3 nMAbs are conserved among diverse primary isolates.

PMID- 15181564
TI  - Alterations in the C-terminal region of the HIV-1 accessory gene vpr do not
      confer clinical advantage to subjects receiving nucleoside antiretroviral
      therapy.
AB  - The C terminus of the human immunodeficiency virus type 1 (HIV-1) accessory
      protein vpr acts in viral cell cycle arrest, nuclear localization, and apoptosis.
      Polymorphisms in this region are described in series of long-term nonprogression
      cases. We determined vpr sequences of archived baseline specimens from 96
      participants in a historical trial of single- versus double-nucleoside reverse
      transcriptase inhibitors. These sequences were then analyzed by study-entry and 
      outcome characteristics such as baseline absolute CD4(+) T cell count, prior
      treatment, CD4(+) T cell response, and clinical endpoints. Frequency of C
      terminal mutations did not correlate to any measures of disease intensity.
      Changes in that portion of vpr did not attenuate disease.

PMID- 15181563
TI  - The epidemiology of antiretroviral drug resistance among drug-naive HIV-1
      infected persons in 10 US cities.
AB  - BACKGROUND: The prevalence and characteristics of persons with newly diagnosed
      human immunodeficiency virus (HIV) infections with or without evidence of
      mutations associated with drug resistance have not been well described. METHODS:
      Drug-naive persons in whom HIV had been diagnosed during the previous 12 months
      and who did not have acquired immune deficiency syndrome were sequentially
      enrolled from 39 clinics and testing sites in 10 US cities during 1997-2001.
      Genotyping was conducted from HIV-amplification products, by automated
      sequencing. For specimens identified as having mutations previously associated
      with reduced antiretroviral-drug susceptibility, phenotypic testing was
      performed. RESULTS: Of 1311 eligible participants, 1082 (83%) were enrolled and
      successfully tested; 8.3% had reverse transcriptase or major protease mutations
      associated with reduced antiretroviral-drug susceptibility. The prevalence of
      these mutations was 11.6% among men who had sex with men but was only 6.1% and
      4.7% among women and heterosexual men, respectively. The prevalence was 5.4% and
      7.9% among African American and Hispanic participants, respectively, and was
      13.0% among whites. Among persons whose sexual partners reportedly took
      antiretroviral medications, the prevalence was 15.2%. CONCLUSIONS: Depending on
      the characteristics of the patients tested, HIV-genotype testing prior to the
      initiation of therapy would identify a substantial number of infected persons
      with mutations associated with reduced antiretroviral-drug susceptibility.

PMID- 15181565
TI  - Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute
      cryptococcal meningitis.
AB  - We conducted a phase 2, double-blind, placebo-controlled study to evaluate the
      safety and antifungal activity of adjuvant recombinant interferon (rIFN)- gamma
      1b in patients with acquired immunodeficiency syndrome and acute cryptococcal
      meningitis. Patients received 100 or 200 microg of rIFN- gamma 1b or placebo,
      thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin
      B, with or without flucytosine, followed by therapy with fluconazole. End points
      included conversion of cerebrospinal fluid fungal cultures from positive to
      negative at 2 weeks, resolution of symptoms, and survival. Among 75 patients, 2
      week culture conversion occurred in 13% of placebo recipients, 36% of rIFN- gamma
      1b (100 microg) recipients, and 32% of rIFN- gamma 1b (200 microg) recipients.
      There was a trend toward improved combined mycologic and clinical success in rIFN
      gamma 1b recipients (26% vs. 8%; P=.078). Therapy with rIFN- gamma 1b was well
      tolerated, and there was no apparent influence on serial CD4 cell counts and
      human immunodeficiency virus load measurements. Adjunctive therapy with rIFN-
      gamma 1b holds promise for patients with acute cryptococcal meningitis and
      warrants further study.

PMID- 15181566
TI  - Cyclic shedding of HIV-1 RNA in cervical secretions during the menstrual cycle.
AB  - The association between hormone fluctuations during the menstrual cycle and human
      immunodeficiency virus type 1 (HIV-1) RNA shedding in cervical and vaginal
      secretions was examined daily for 17 HIV-1-seropositive women, for the duration
      of 1 cycle. Serum levels of RNA were evaluated 3 times/week. A marginally
      significant positive correlation between serum levels of progesterone and serum
      levels of HIV-1 RNA (P=.04) was observed. Cervical virus levels were
      significantly correlated with the number of days from the midcycle surge in
      luteinizing hormone (LH) (P=.008). The lowest levels of cervical HIV-1 RNA were
      present at the LH surge, and this nadir was followed by an increase in virus
      levels that reached a maximum before the start of menses. In contrast, there was
      no significant association between the number of days from the LH surge and the
      level of HIV-1 RNA in vaginal secretions (P=.4). These data support the
      hypothesis that the level of HIV-1 RNA in cervical secretions is influenced by
      the menstrual cycle, and they suggest that the risk of heterosexual transmission
      of HIV-1 may increase as menses is approached.

PMID- 15181567
TI  - Increased adhesion molecule and chemokine receptor expression on CD8+ T cells
      trafficking to cerebrospinal fluid in HIV-1 infection.
AB  - BACKGROUND: The central nervous system (CNS) is a recognized target for human
      immunodeficiency virus type 1 (HIV-1). CD8(+) T cells may mediate viral clearance
      from the CNS but also may contribute to immune-mediated neuronal damage. METHODS:
      Using 4- and 6-color flow cytometry, we investigated the role of adhesion
      molecules (very late antigen [VLA]-4 [ alpha 4 beta 1 integrin] and leukocyte
      function antigen [LFA]-1 [ alpha L beta 2 integrin]) and chemokine receptors
      (CXCR3 and CCR5) in CD8(+) T cell migration to cerebrospinal fluid (CSF) during
      HIV-1 infection. RESULTS: CD8(+) T cells trafficking to CSF were uniformly VLA
      4(high), LFA-1(high). CCR5 expression was significantly enhanced in T cells from
      CSF, compared with those from blood (P<.001), including HIV-1-specific CD8(+) T
      cells, and most T cells from CSF expressed both CXCR3 and CCR5. Interferon
      inducible protein (IP)-10 (CXCL10) levels in CSF were significantly increased in
      HIV-1-positive individuals, relative to IP-10 levels in control subjects
      (P=.007), and a positive correlation was found between IP-10 levels and virus
      load in CSF (r2=.777; P=.0007). CONCLUSIONS: These findings suggest that LFA-1,
      CCR5 and CXCR3, and IP-10 play an important role in lymphocyte trafficking to CSF
      during HIV-1 infection. These observations suggest a "push-pull" model, in which
      lymphocyte extravasation is driven by lymphocyte activation, expression of
      adhesion molecules, and increased vascular permeability and is coupled with
      chemokine-mediated trafficking to inflammatory sites in the CNS.

PMID- 15181568
TI  - Phase 1 evaluation of 3 highly immunogenic prime-boost regimens, including a 12
      month reboosting vaccination, for malaria vaccination in Gambian men.
AB  - Successful vaccination against intracellular pathogens, including liver-stage
      Plasmodium falciparum, will require induction of strong antigen-specific T
      lymphocyte responses. The multiple epitope (ME)-thrombospondin-related adhesion
      protein (TRAP) construct includes CD8(+) and CD4(+) T cell epitopes from pre
      erythrocytic P. falciparum antigens fused in-frame to the entire pre-erythrocytic
      antigen TRAP. Three carriers for this construct--plasmid DNA and 2 recombinant
      nonreplicating poxviruses (modified vaccinia virus Ankara [MVA] and fowlpox
      strain 9 [FP9])--were administered at 3-week intervals in a heterologous prime
      boost combination to 29 Gambian men aged 18-45 years. Doses of DNA ME-TRAP, MVA
      ME-TRAP, and FP9 ME-TRAP were 2 mg and 1.5x10(8) and 1x10(8) plaque-forming
      units, respectively. DNA ME-TRAP was injected intramuscularly; MVA ME-TRAP and
      FP9 ME-TRAP were injected intradermally. There were no clinically relevant
      laboratory abnormalities and no severe or serious adverse events related to
      vaccination. DNA/MVA and FP9/MVA regimens were the most potent inducers of
      circulating effector T cells seen to date in sub-Saharan Africa. Twelve months
      after the final vaccination, a single booster vaccination expanded the effector T
      cell pool to a similar or higher magnitude than that after the primary
      vaccinations. These results highlight optimized combination regimens with general
      relevance to the development of vaccines targeting intracellular pathogens.

PMID- 15181569
TI  - Molecular evaluation of the natural history of asymptomatic parasitemia in
      Ugandan children.
AB  - We assessed the prevalence and natural history of malarial parasitemia by use of
      microscopy and polymerase chain reaction (PCR) in 314 asymptomatic children in
      Kampala, Uganda. The prevalence of asymptomatic parasitemia was 17% by microscopy
      and 47% by PCR. Children with parasitemia identified by microscopy had a 5-fold
      higher rate of subsequent symptomatic malaria, compared with children without
      detectable parasitemia. Children with parasitemia identified by PCR alone had a
      similar rate of subsequent symptomatic malaria, compared with children without
      detectable parasitemia. Among microscopy-positive children who later developed
      symptomatic malaria, 47% had strains identical to those identified at enrollment,
      and the proportion of symptomatic episodes due to persistent strains remained
      high for 3 months. Among the PCR-positive/microscopy-negative children, only 17%
      had identical genotyping patterns at the onset of symptomatic malaria, with most
      of these episodes occurring during the first month. Asymptomatic parasitemia
      detected by microscopy, but not by PCR, strongly predicted subsequent clinical
      malaria, often due to persistent infection.

PMID- 15181570
TI  - DNA phasing by TA dinucleotide microsatellite length determines in vitro and in
      vivo expression of the gp91phox subunit of NADPH oxidase and mediates protection
      against severe malaria.
AB  - Reactive oxygen intermediates (ROIs) play a major role in the nonspecific innate
      immune response to invading microorganisms, such as Plasmodium falciparum. In a
      search for genetic markers that determine differences in production of ROI, we
      detected a highly polymorphic region of dinucleotide TA repeats approximately 550
      bp upstream of the NADPH oxidase gp91(phox) subunit promoter. We genotyped 183
      matched Gabonese children with severe or mild malaria. Repeat lengths TA(11) and
      TA(16) differed significantly in frequency between mild and severe infection,
      which suggests protection against severe malaria. Both repeat lengths showed
      lower levels of NADPH oxidase and promoter activities, which can be explained by
      a cyclic trend in TA repeat length with a period of approximately 5, which
      indicates the necessity of correct DNA phasing between 2 possible control regions
      in the promoter. We provide a molecular model of how DNA phasing generated by TA
      dinucleotide polymorphisms may influence the expression level and protect against
      severe malaria.

PMID- 15181571
TI  - Monocyte activation and T cell inhibition in Plasmodium falciparum-infected
      placenta.
AB  - BACKGROUND: During healthy pregnancy, T helper (Th) 1-type and inflammatory-type
      responses are down-regulated, and Th2-type and proinflammatory-type responses
      predominate. In Plasmodium falciparum-infected females, these responses induce
      enhanced production of tumor necrosis factor- alpha and interferon- gamma.
      METHODS: To assess the respective implication of monocytes and T cells in this
      placental immunomodulation, we cocultured cells from delivering females living in
      an area where malaria is endemic. Monocytes and T cells from both peripheral and
      intervillous blood were crossed in in vitro cultures, to compare the
      proliferative response to several antigens. Moreover, monocyte cell-surface
      molecules were quantified by flow cytometry. RESULTS: Coculture results confirmed
      placental immunomodulation and suggested that the most affected cells are not the
      intervillous monocytes, which are as able to present the antigen as the
      peripheral monocytes, but the intervillous T cells. Monocyte staining showed
      significant increases in human leukocyte antigen D-related, CD54, CD80, and CD86
      surface markers in intervillous blood, compared with peripheral blood, which
      suggests a relative activation of monocytes in the placenta. CONCLUSION: A state
      of T cell deactivation and monocyte activation is present at delivery. The T cell
      deactivation in reaction to purified protein derivative could be explained by the
      presence of local T cell immunoregulatory factors.

PMID- 15181572
TI  - Serodiagnostic studies in an immunocompetent individual infected with
      Encephalitozoon cuniculi.
AB  - Little is known about the prevalence and clinical significance of infection with
      Encephalitozoon species in immunocompetent individuals. In the present study, by
      using indirect immunofluorescence technique (IFAT), Western blot, and recombinant
      antigens of the spore wall (SWP1) and polar tube (PTP1, PTP2, and PTP3 ), we
      analyzed the IgG antibody response of a laboratory worker who was infected with
      Encephalitozoon cuniculi. Serum samples were analyzed 1, 20, 32, and 38 months
      after infection. After 1 month, by use of IFAT, only spore-wall antigens were
      recognized, an antibody reaction that changed toward both the spore wall and
      polar tube in the following months. By use of Western blot analysis, a
      characteristic pattern that recognized multiple bands was noticed. Reaction
      against SWP1 was present in all 4 serum samples. The IgG response against PTP1,
      PTP2, and PTP3 was not detectable 1 month after infection, but became evident in
      the follow-up serum samples. Serum samples showed cross-reactivity with the spore
      wall of Encephalitozoon hellem and Encephalitozoon intestinalis, but only little
      cross-reactivity with the polar tube of these parasites. This is the first study
      to our knowledge that provides full details about the antibody response against a
      specified Encephalitozoon species in an immunocompetent person. The results
      strongly encourage the development and use of reliable serodiagnostic methods,
      which will provide information about the prevalence and clinical significance of
      Encephalitozoon species infection in humans.

PMID- 15181573
TI  - Differential expression of a virulence factor, the trans-sialidase, by the main
      Trypanosoma cruzi phylogenetic lineages.
AB  - The clinical outcome of Chagas disease is highly variable, mainly because of the
      heterogeneity of Trypanosoma cruzi, a parasite for which 2 major phylogenetic
      groups (I and II) were recently defined. Epidemiological and immunological data
      indicate that the prevalence of T. cruzi II in patients living in the southern
      cone of South America correlates with the alterations caused by Chagas disease.
      We report here that infection with T. cruzi II isolates induces 100% mortality in
      mice, in contrast to infection with T. cruzi I isolates, in which almost all mice
      enter the chronic phase even when a 1000-fold higher inoculum is administered.
      Trypomastigotes from T. cruzi II strains express and shed significantly higher
      amounts of trans-sialidase than do those from the T. cruzi I lineage.
      Disorganization of the thymus histoarchitecture associated with the circulating
      enzyme was observed after infection with T. cruzi II strains, in contrast to
      transient thymus lesions found in mice infected with T. cruzi I strains.
      Therefore, trans-sialidase becomes the first T. cruzi virulence factor identified
      that is differentially expressed by the main parasite groups and that contributes
      to their contrasting behaviors.

PMID- 15181574
TI  - Distribution of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 in
      maternal saliva and breast milk in Zambia: implications for transmission.
AB  - BACKGROUND: The seroprevalence of Kaposi sarcoma-associated herpesvirus
      (KSHV)/human herpesvirus 8 (HHV-8) in sub-Saharan Africa suggests that multiple
      routes of transmission exist. In the present study, we examined 2 possible routes
      of mother-to-child transmission, through breast milk and saliva, during the first
      6 months after delivery. METHODS: The prevalence of HHV-8 DNA in the breast-milk
      cells (n=75), milk supernatant (n=56), colostrum (n=2), and saliva cells (n=65)
      of HHV-8-seropositive mothers who recently gave birth was examined. Polymerase
      chain reaction analysis was performed for the detection of HHV-8 in cross
      sectional samples isolated at 2, 4, and 6 months after delivery. RESULTS: None of
      the 75 breast-milk samples but 2 of the colostrum samples that were analyzed
      contained HHV-8 DNA at a limit of detection of approximately 1 HHV-8 copy/10(4)
      cellular genomes, whereas Epstein-Barr virus DNA and HIV-1 DNA were detected in
      16 and 22 samples, respectively. Analysis of 65 saliva cell samples, which were
      obtained from mothers who also provided milk samples, revealed that 19 of the
      samples had detectable HHV-8 DNA. Viral DNA was found at all time points, but the
      presence of viral DNA in saliva was independent of maternal HIV-1 serostatus (chi
      2=0.33; P=.57). CONCLUSIONS: Our findings demonstrate the lack of HHV-8 DNA in
      the breast milk of seropositive mothers, and they suggest that contact with
      breast milk is not a likely source of horizontal transmission of virus to infants
      in sub-Saharan Africa.

PMID- 15181575
TI  - Heterogeneity of risk factors and antibody profiles in epstein-barr virus genome
      positive and -negative hodgkin lymphoma.
AB  - BACKGROUND: Hodgkin lymphoma (HL) tumors that contain the Epstein-Barr virus
      (EBV) genome may differ etiologically from EBV-negative HL tumors. METHODS: A
      case-case study examining heterogeneity of risk factors between disease subgroups
      compared personal characteristics and EBV antibodies between 95 EBV-positive and
      303 EBV-negative patients with HL. RESULTS: We confirmed previous associations of
      EBV-positive HL with older age, male sex, and mixed-cellularity (MC) histological
      subtypes. EBV-positive patients were less educated and more likely to have smoked
      cigarettes and had more prevalent and higher EBV antibody titers, compared with
      EBV-negative patients. After adjustment for all independent risk factors, those
      most strongly associated with EBV-positive HL were histological subtypes (odds
      ratio [OR] for MC vs. nodular sclerosis histology, 3.2; 95% confidence interval
      [CI], 1.4-7.2), elevated anti-viral capsid antigen level (OR, 3.1; 95% CI, 1.6
      6.0), and less education (OR, 0.7; 95% CI, 0.5-1.0). Cigarette smoking and a low
      anti-Epstein-Barr nuclear protein (EBNA) 1 : anti-EBNA-2 ratio were also
      marginally associated with EBV-positive HL. CONCLUSIONS: EBV-positive HL is more
      common among individuals who have markers of diminished cellular immunity and an
      abnormal EBV antibody response. EBV appears to participate in the etiology of EBV
      positive HL but may not be involved in EBV-negative HL.

PMID- 15181576
TI  - Possible role of neonatal infection with the asymptomatic reassortant rotavirus
      (RV) strain I321 in the decrease in hospital admissions for RV diarrhea,
      Bangalore, India, 1988-1999.
AB  - We sought to determine the proportion of rotavirus (RV) infections among children
      with severe diarrhea in Bangalore, India, and to determine the role of neonatal
      infection with the asymptomatic RV strain I321 in protection against subsequent
      RV diarrhea. At 2 major hospitals, there was a >42% decrease in diarrhea-specific
      admissions during the study period. At 6 hospitals, asymptomatic infections were
      found in 25%-50% of neonates, when screening was performed randomly, and in >58%
      of neonates, when screening was performed daily, with the majority of infections
      occurring within the first 7 days of life. All the RVs found in asymptomatic
      neonates were strain I321. A 24-month follow-up of a cohort of 44 children who
      had been neonatally infected with strain I321 and 28 children who had not
      (control group) revealed comparable rates of RV detection but a marked decrease
      in the number of RV diarrhea episodes in the strain I321-infected group (2.3%),
      compared with the control group (39.3%) (P<.0001). This preliminary study
      suggests a possible association between neonatal infection with strain I321 and
      protection against subsequent RV illness.

PMID- 15181577
TI  - Rotavirus immunoglobulin a responses stimulated by each of 3 doses of a
      quadrivalent human/bovine reassortant rotavirus vaccine.
AB  - A quadrivalent precursor to the pentavalent rotavirus vaccine candidate RotaTeq
      was evaluated in a 3-dose, 439-subject study. To determine immunogenicity, the
      quantity of rotavirus immunoglobulin A (IgA) in stool specimens obtained, at 1 of
      10 study sites, from 37 placebo and 37 vaccine recipients was measured. None of
      the placebo recipients showed a clinically important (>/=3-fold) increase in
      stool rotavirus IgA, whereas 31 vaccine recipients showed an increase after at
      least 1 dose of vaccine. In total, 16, 19, and 15 vaccine recipients had
      increases after 1, 2, and 3 doses, respectively, indicating that a 3-dose regimen
      increased the immune response elicited by this vaccine.

PMID- 15181578
TI  - Human T cell lymphotropic virus (HTLV) type-1-specific CD8+ T cells: frequency
      and immunodominance hierarchy.
AB  - Human T cell lymphotropic virus type 1 (HTLV-1) causes HTLV-1-associated
      myelopathy/tropical spastic paraparesis (HAM/TSP). We used interferon- gamma
      enzyme-linked immunospot assays with overlapping peptides spanning the entire
      HTLV-1 proteome to test whether the HTLV-1-specific CD8(+) T cells differed
      significantly in frequency or immunodominance hierarchy between patients with
      HAM/TSP and asymptomatic carriers and whether the frequency correlated with
      provirus load. Tax was the immunodominant target antigen. There was no
      significant qualitative or quantitative difference in the HTLV-1-specific CD8(+)
      T cell response between the 2 groups. Virus-specific CD8(+) T cell frequency
      alone does not indicate the effectiveness of the cytotoxic T lymphocyte response
      in controlling provirus load at equilibrium.

PMID- 15181579
TI  - Development of pathogenicity-driven definitions of outcomes for a field trial of
      a killed oral vaccine against enterotoxigenic Escherichia coli in Egypt:
      application of an evidence-based method.
AB  - BACKGROUND: To design an efficacy trial of a killed oral vaccine against
      enterotoxigenic Escherichia coli (ETEC) diarrhea in Egyptian children, we derived
      for ETEC diarrhea an empirical definition that increased the probability that
      diarrhea associated with excretion of ETEC was caused by the detected ETEC.
      METHODS: We conducted a cohort study of 397 Egyptian children <24 months old and
      monitored them until they were 3 years old. Vaccine-preventable (VP) ETEC was
      defined as ETEC expressing >/=1 of the toxin- (heat-labile [LT] toxin) and
      colonization-factor antigens (CFA I, II, and IV) in the vaccine. RESULTS:
      Although fecal excretion of VP-ETEC was highly associated with diarrhea,
      excretion of LT-ETEC per se was not related to diarrhea (adjusted odds ratio
      [OR(A)], 1.16 [95% confidence interval [CI], 0.90-1.49]). The fecal excretion of
      antigenic types of VP-ETEC other than LT-ETEC (non-LT VP-ETEC) was highly
      associated with diarrheal symptoms (OR(A), 3.91 [95% CI, 2.78-5.49]; P<.001), and
      this association was greater for nonbloody than for bloody diarrhea. CONCLUSIONS:
      Because the vaccine had been anticipated to protect primarily against symptomatic
      ETEC diarrhea, these results indicate that the primary-outcome definition of ETEC
      diarrhea for the trial should be restricted to nonbloody diarrheal episodes
      associated with fecal excretion of non-LT VP-ETEC.

PMID- 15181580
TI  - Inhibition of the tissue factor/factor VIIa pathway does not influence the
      inflammatory or antibacterial response to abdominal sepsis induced by Escherichia
      coli in mice.
AB  - BACKGROUND: Anticoagulants have gained increasing attention for the treatment of
      sepsis. Inhibition of the tissue factor (TF)/factor (F) VIIa pathway has been
      shown to attenuate the activation of coagulation and to prevent death in a
      primate model of sepsis caused by gram-negative bacteria. METHODS: To determine
      the role of the TF/FVIIa complex in the host response to peritonitis, mice
      received an intraperitoneal injection of live Escherichia coli with or without
      concurrent treatment with recombinant nematode anticoagulant protein c2 (rNAPc2),
      a selective inhibitor of the TF/FVIIa pathway. RESULTS: Peritonitis was
      associated with an increase in the expression of TF at the tissue level and
      activation of coagulation, as reflected by elevated levels of thrombin
      antithrombin complexes and by increased fibrin(ogen) deposition in the liver and
      lungs. rNAPc2 strongly attenuated this procoagulant response but did not
      influence the inflammatory response (histopathology, leukocyte recruitment to the
      peritoneal cavity, and cytokine and chemokine levels). Moreover, rNAPc2 did not
      alter bacterial outgrowth locally or dissemination of the infection, and survival
      was not different between rNAPc2-treated mice and control mice. CONCLUSIONS:
      These data suggest that TF/FVIIa activity contributes to the activation of
      coagulation during E. coli peritonitis but does not play a role in the
      inflammatory response or antibacterial host defense.

PMID- 15181581
TI  - Incomplete correlation of serum vibriocidal antibody titer with protection from
      Vibrio cholerae infection in urban Bangladesh.
AB  - The serum vibriocidal antibody is the only recognized predictor of protection
      from cholera, but no seroepidemiological data have been gathered since the
      emergence of Vibrio cholerae O139. We assessed the association between the
      vibriocidal antibody titer and protection from cholera in an endemic setting.
      Although a higher baseline vibriocidal titer correlated with protection from V.
      cholerae O1, infection still developed in some contacts with very high titers. No
      association between baseline vibriocidal titer and protection from V. cholerae
      O139 infection was found. Our findings suggest that the vibriocidal antibody is
      an incomplete predictor of protection from V. cholerae infection.

PMID- 15181582
TI  - Virulence potential of the staphylococcal adhesin CNA in experimental arthritis
      is determined by its affinity for collagen.
AB  - BACKGROUND: Staphylococcus aureus is a major cause of bacterial arthritis, which
      often results in severe joint damage. CNA, a collagen adhesin of S. aureus, was
      shown to be a virulence factor in several animal models. However, the precise
      molecular mechanism by which CNA contributes to virulence remains unclear.
      METHODS: We examined the role of the collagen-binding function of CNA in a mouse
      model of septic arthritis by comparing the virulence of isogenic strains of S.
      aureus expressing (1) wild-type CNA, (2) a truncated form of CNA (CNA35) with a
      higher affinity for collagen than the wild type, (3) CNA35 containing a single
      point mutation resulting in loss of collagen binding, (4) CNA lacking the
      collagen-binding domain, and (5) the collagen-binding domain of ACE (adhesin of
      collagen from Enterococcus faecalis). RESULTS AND CONCLUSIONS: The results
      provide, for the first time, direct evidence that the virulence of CNA depends on
      its collagen-binding ability. Collagen binding facilitated early colonization of
      the joints of mice. Furthermore, the virulence potential of the adhesin is
      determined by the adhesin's affinity for its ligand, as well as its binding
      kinetics.

PMID- 15181583
TI  - Standard nomenclature for the superantigens expressed by Staphylococcus.
AB  - The International Nomenclature Committee for Staphylococcal Superantigens
      proposes an international procedure for the designation of newly described
      superantigens and putative superantigens, a procedure that will be compatible
      with the new age of genomics.

PMID- 15181586
TI  - Developing an accreditation system.

PMID- 15181587
TI  - The American Veterinary Medical Association Council on Education (COE)
      Accreditation.

PMID- 15181585
TI  - BSE: how does it impact veterinary education?

PMID- 15181588
TI  - The AVMA COE accreditation site visit.

PMID- 15181589
TI  - Accreditation of veterinary schools in Australia and New Zealand.
AB  - Veterinary schools in Australia and New Zealand are assessed for accreditation
      purposes every six years by the Veterinary Schools Accreditation Advisory
      Committee (VSAAC), which is a standing committee of the Australasian Veterinary
      Boards Council (AVBC).1 Prior to undertaking an assessment, VSAAC requests a Self
      Evaluation Report from the school and subsequently spends a week on site to
      collect additional information. The committee also takes into consideration other
      quality assurance procedures within the university and aims for a process that
      complements other evaluation activities. Internal evaluation procedures within
      VSAAC are designed to reflect the process and outcomes of each visit and lead to
      annual revisions of the publication Policies, Procedures and Guidelines
      publication. The committee has close links with the Royal College of Veterinary
      Surgeons (RCVS), and there is a routine exchange of observers on all visits in
      the United Kingdom and Australasia. In recent years VSAAC has become increasingly
      interested in looking at ways to place greater emphasis on the outcomes of
      veterinary education and, eventually, to reduce our reliance on input measures.
      There has been good progress in identifying desirable attributes for veterinary
      graduates, but further work is needed to establish the reliability of assessment
      procedures. The Australasian accreditation system is very supportive of recent
      moves to achieve greater compatibility of veterinary accreditation systems in
      different parts of the world because we believe it has the potential to assist
      globalization of animal disease control and veterinary education.

PMID- 15181590
TI  - Accreditation of veterinary schools in the United Kingdom and the European Union:
      the process, current issues and trends, and future concerns.

PMID- 15181591
TI  - The accreditation system for colleges of veterinary medicine in Mexico and a
      comparison with the AVMA system.
AB  - This article reviews the evolution of veterinary medicine in Mexico in order to
      explain the foundation of the National Council for Veterinary Medicine Education
      (CONEVET). This institution performs college accreditation and professional
      certification procedures in the country. The accreditation process for colleges
      of veterinary medicine in Mexico is described, and the results obtained to this
      point are presented. A comparative analysis of veterinary education in Mexico and
      the United States is also presented. The veterinary college accreditation
      processes of the two countries are compared and their differences analyzed.

PMID- 15181592
TI  - The critical role of outcomes assessment in veterinary medical accreditation.

PMID- 15181593
TI  - Comparison of accreditation practices and standards of US schools of medicine and
      veterinary medicine.
AB  - There are 126 medical education programs leading to the MD degree in the United
      States, and 16 in Canada, that are accredited by the Liaison Committee on Medical
      Education (LCME). This article summarizes the current policies and procedures
      used by the LCME and traces their historical development. The external factors
      that have acted to influence accreditation in the United States, such as
      recognition of accreditation agencies by the US Department of Education, are then
      described. Finally, comparisons are drawn between the accreditation systems for
      medical education and veterinary medical education programs.

PMID- 15181594
TI  - Outcomes assessment as a component of good educational practice.

PMID- 15181595
TI  - Veterinary school admission interviews, part 3: strategies for increasing
      interview validity.
AB  - The veterinary school admission interview is a widely used selection tool, yet
      concerns persist about its reliability, validity, and cost. Relative to medicine,
      optometry, and dentistry schools, veterinary schools have been more likely to
      conduct panel interviews and to fix the interview's weight in selection
      decisions, strategies that increase interview validity. This article provides
      strategies for further increasing the veterinary school interview's validity.
      Interview reliability and validity studies point to key strategies the veterinary
      school admissions committee can implement before the interview: (1) establishing
      the interview's purpose(s); (2) conducting a "job" analysis to identify desirable
      candidate skills, knowledge, and attributes; (3) developing a structured and
      panel interview where interviewers, if possible, are blind to other admission
      data; (4) training interviewers; (5) setting a reasonable interview schedule; and
      (6) determining methods for analyzing applicant data. During the interview,
      interviewers should proceed through a structured series of steps: (1) open the
      interview with a specified agenda; (2) probe for information using structured
      questions and anchored rating scales; (3) close the interview to allow for
      candidate questions; and (4) evaluate the interview data. After the interview,
      the admissions committee should (1) analyze the interview data within and across
      interviewers and (2) analyze the data across all selection tools in order to
      assign relative weights to the selection tools.

PMID- 15181596
TI  - Implementing a simulated client program: bridging the gap between theory and
      practice.
AB  - INTRODUCTION: This paper outlines the design and implementation of an innovative
      communication skills training program at the Ontario Veterinary College (OVC).
      Based upon the body of research in human medical education reporting effective
      results through the use of standardized patients (SPs) for this type of training,
      an experiential learning laboratory using simulated clients (SCs) and patients
      was introduced to first-year veterinary students. METHOD: One hundred and four
      first-year students were assigned to 12 groups of eight or nine students plus a
      facilitator. Each student interacted with a simulated client and a patient while
      being observed by peers and a facilitator. The Calgary-Cambridge Observation
      Guide (CCOG) was used to guide students and facilitators with performance
      standards and feedback. Assessment strategies were utilized. RESULTS:
      Implementation of this program required extensive resources, including funding,
      expertise, facilitator training, time allotment in an already overburdened
      curriculum, and administrative and faculty support. Preliminary assessment
      revealed high student and facilitator satisfaction. The potential of this program
      for student education and assessment was recognized, and it will be expanded in
      years 2 and 3 of the DVM (Doctor of Veterinary Medicine) curriculum. CONCLUSIONS:
      Medical educators have created resources, including skills checklists and
      experiential learning modalities, that are highly applicable to veterinary
      medical education. Ongoing evaluation of the program is essential to determine
      whether we are meeting expectations for communication competency in veterinary
      medicine.

PMID- 15181597
TI  - Levels of continuing veterinary medical education program evaluation: assessing a
      course on dairy reproductive management.
AB  - There are four different levels of continuing education program evaluation:
      participant perceptions of the program or course; participant competence with new
      skills, knowledge, and abilities; participant performance or change in behavior;
      and health care or client outcomes, such as resultant changes in patient care or
      herd/flock production performance. The purpose of this article is to describe
      different levels of evaluation and demonstrate some methods used in evaluating a
      continuing veterinary medical education (CVME) course in dairy reproductive
      management. Participants' learning needs were assessed using learning stage
      theory and a pre-test of knowledge. Post-program assessments included a test of
      knowledge, a satisfaction survey, a commitment to change, and self-reported
      behavior change. The results of the evaluation indicate that self-reports of
      learning needs do not necessarily reflect actual needs and that satisfaction with
      a course does not necessarily indicate behavior change. Providers of CVME must
      recognize the value of program evaluation, as well as the advantages and
      disadvantages of different evaluation methods.

PMID- 15181598
TI  - Gender differences and the definition of success: male and female veterinary
      students' career and work performance expectations.
AB  - This article addresses the challenges that gender performance expectations create
      within the veterinary profession. An investigation of veterinary students'
      perceptions of the essential characteristics that define successful veterinarians
      and veterinary students, and the gender differences within these definitions, is
      described. Because previous research supports the premise that the standards
      required for success differ for males and females, it is likely that male and
      female veterinary students possess different career expectations and definitions
      of career success. The ramifications of these differences are explored, and
      proposed strategies to address this issue, in the form of student support
      services, are discussed.

PMID- 15181599
TI  - Training the veterinary public health workforce: a review of educational
      opportunities in US veterinary schools.
AB  - This article presents the results of an Internet-based review conducted in
      January and February 2003 to assess the educational opportunities available in
      veterinary public health, epidemiology, and preventive medicine at the 27
      veterinary schools in the United States. Most professional veterinary curricula
      are designed to train students for careers as highly qualified private
      practitioners, although there is an increased need for veterinary perspectives
      and contributions in the public health sector. The future of veterinary public
      health relies on the opportunities available in education to teach and encourage
      students to pursue a career of public service. The results of this review
      indicate the availability of a wide variety of required courses, electives, and
      post-graduate training programs to veterinary students in the United States.
      Veterinary students are exposed to a median of 60 hours of public health,
      epidemiology, and preventive medicine in required stand-alone courses in these
      areas. Four veterinary schools also have required rotations for senior students
      in public health, preventive medicine, or population medicine. Contact time for
      required public health, epidemiology, and preventive medicine courses ranges from
      30 to 150 contact hours. Advanced training was available in these subjects at 79%
      of the 27 schools. Greater collaboration between veterinary schools, schools of
      public health, and the professional public health community will increase
      exposure to and opportunities in public health to all future veterinarians.

PMID- 15181600
TI  - Models for teaching career development and practice management.

PMID- 15181601
TI  - The Zodiak workshop: an innovative model for teaching financial management
      through partnership with industry.
AB  - The National Commission on Veterinary Economic Issues (NCVEI) is working to
      enhance the non-technical skills, knowledge, aptitudes, and attitudes (SKAs) of
      veterinarians. This report describes the development of an innovative model for
      teaching the principles of financial management as they apply to the veterinary
      practice. Zodiak: The Game of Business Finance and Strategy is a "business
      literacy" game in which players work together in small teams (generally four
      people) to run a fictional multi-million-dollar company called Zodiak Industries
      for three "years" in order to learn principles of business finance and strategy.
      After finishing the 4.5-hour game, participants spend the rest of the workshop
      making the right "Connections"-exercises designed to connect what they have
      learned to business strategies, financial statements, and operational tactics
      drawn from veterinary practice. Issues addressed for the veterinary practice,
      with parallels drawn to Zodiak, included return on owner investment in a
      veterinary practice (vs. salary drawn by owner veterinarians); pricing (setting
      prices, price elasticity of demand, and relationships between volume, quality,
      and price); human resources and operations management as they relate to
      profitability and efficiency; cash flow and management of accounts receivable;
      and commonly used financial benchmarks. Workshop venues have included Michigan
      State University, The Ohio State University, the University of Illinois, and
      Purdue University. Financial and in-kind support were provided through
      partnership with Pharmacia Animal Health (now Pfizer Animal Health) and Hill's
      Pet Nutrition, Inc. Through course evaluations, participants generally rated the
      workshop high as an educational experience and indicated that the most important
      things learned were related to financial management (principles, terminology, and
      methods). The most enjoyable aspects of the workshop tended to be group
      discussions, teamwork, the dynamic/interactive environment, and the "game"
      atmosphere. Based on these experiences, the Zodiak workshop provides a useful
      model for teaching career development and practice management topics to
      veterinary students. The business simulation in a workshop format was especially
      useful for teaching these "non-mainstream" topics, as traditional classroom
      lecture approaches might not have engaged students sufficiently to achieve
      effective learning. In addition, the partnership developed between academia and
      industry offered substantial benefits to both parties. Similar educational
      approaches should be considered for additional aspects of the non-technical SKAs.

PMID- 15181602
TI  - Optimizing cancer chemotherapy and hormonal therapy: the key role of supportive
      agents. Introduction.

PMID- 15181603
TI  - Anemia impact and management: focus on patient needs and the use of
      erythropoietic agents.
AB  - Anemia is a common complication associated with cancer and cancer treatment. As
      many as 50% to 60% of cancer patients will develop this condition. Fatigue is a
      major symptom of anemia and is a primary complaint in patients with cancer.
      Fatigue can be debilitating for patients, reducing their ability to work,
      decreasing physical and emotional well-being, and interfering with cognitive
      ability, all of which can lead to anxiety and depression. Despite the high
      incidence of the disease and the extent of its impact on the cancer patient,
      anemia remains underdiagnosed and undertreated. Erythropoietic proteins offer a
      valuable alternative to standard transfusion therapy, and there is increasing
      evidence that, in addition to raising hemoglobin levels, these therapeutic agents
      can lead to improvements in quality of life and patient-reported outcomes. The
      impact of anemia correction on survival is under investigation; a body of
      evidence suggests a possible benefit, although this has recently been challenged.
      There is a strong need for increased awareness of cancer-related anemia and the
      consequences of its lack of treatment.

PMID- 15181604
TI  - New erythropoietic proteins: rationale and clinical data.
AB  - Anemia is a common condition in patients with cancer. Patients who develop severe
      anemia are frequently treated with red blood cell transfusions. However, the
      benefits are transient and associated with a number of risks (such as infection
      and immunosuppression). An alternative treatment option, recombinant human
      erythropoietin (rHuEPO) was introduced into the clinical setting more than a
      decade ago. Today, rHuEPO is increasingly being used to treat anemic patients
      with cancer. However, despite the well-documented clinical benefits of rHuEPO
      therapy, it has not been universally adopted as a routine treatment in the
      oncology setting and there remains an unmet need for an effective and convenient
      anemia treatment for cancer patients. Longer-acting versions of rHuEPO would
      avoid the need for frequent injections, increase biological activity and,
      potentially, the clinical efficacy of rHuEPO. One agent, darbepoetin alfa, is now
      available for the treatment of anemia in patients with cancer who are receiving
      chemotherapy, another agent, pegylated-epoetin beta, is in phase II trials, and
      additional compounds are in early stages of preclinical and clinical development.
      This review focuses on the available clinical experience with such agents and
      discusses how dose- and schedule-finding studies are optimizing their clinical
      use to maximize patient benefits.

PMID- 15181605
TI  - Dose-dense chemotherapy in breast cancer and lymphoma.
AB  - Adjuvant combination chemotherapy reduces the risk of relapse and death for
      patients with invasive breast cancer and adds to the benefits obtained with
      hormonal treatment. Generally, anthracycline-containing regimens are superior to
      non-anthracycline regimens, treatments longer than 6 months are not advantageous
      and high-dose chemotherapy regimens, which require autologous hematopoietic stem
      cell support, have not proved consistently superior. The development and
      evaluation of the taxanes was highly anticipated as they have shown high levels
      of efficacy while appearing to be non-cross-resistant with partially non
      overlapping toxicities. A role for taxanes in the adjuvant or neoadjuvant setting
      is now widely acknowledged, although they are not currently approved for
      treatment of early breast cancer in Europe. In patients with aggressive lymphoma
      who receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
      chemotherapy, 40% to 70% of patients attain a complete remission, depending on
      risk factors such as age and extranodal involvement. Second- and third-generation
      regimens like m-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide), Pro
      MACE-CytaBOM (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide,
      cytarabine, bleomycin, vincristine, methotrexate), and MACOP-B (methotrexate with
      leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone,
      bleomycin) have largely failed to improve treatment outcome. The use of
      monoclonal anti-CD20 antibodies or dose escalation have shown promising results
      in improving relapse-free and survival rates. In patients with breast cancer, the
      key Cancer and Leukemia Group B 9741 trial showed that dose-dense doxorubicin,
      cyclophosphamide, and paclitaxel chemotherapy with granulocyte colony-stimulating
      factor (G-CSF), repeated every 2 weeks, is superior to the same regimen
      administered at standard 3-weekly intervals. In lymphoma, dose-dense CHOP
      chemotherapy has shown superiority over standard CHOP regimens, particularly in
      elderly patients with aggressive non-Hodgkin's lymphoma. G-CSF factor is
      essential to enable the administration of dose-dense chemotherapy and any
      reduction in its use leads to significant increases in infectious complications.
      Current evidence suggests that dose-dense chemotherapy, enabled by G-CSF, is an
      important breakthrough in the evolution of chemotherapy for breast cancer and
      lymphoma.

PMID- 15181606
TI  - Neulasta (pegfilgrastim): a once-per-cycle option for the management of
      chemotherapy-induced neutropenia.
AB  - Neutropenia is a significant hematologic complication induced by cytotoxic
      chemotherapy. The clinical consequences of chemotherapy-induced neutropenia are
      often severe and can be potentially life-threatening. Patients who develop
      febrile neutropenia often need to be hospitalized, reducing their quality of life
      and increasing costs. Neutropenia can also compromise the ability to deliver
      chemotherapy at the full dose and on schedule. To help prevent the occurrence of
      neutropenia, patients with a high risk of developing chemotherapy-related
      infections may be given prophylactic colony-stimulating factors. Filgrastim is a
      recombinant human granulocyte colony-stimulating factor that has been widely used
      (in over 3 million patients) for over 12 years in the management of neutropenia.
      Pegfilgrastim is an approved, long-acting, next generation of granulocyte colony
      stimulating factor that has similar clinical benefits to filgrastim but has novel
      pharmacokinetic properties. Pegfilgrastim shows at least comparable safety and
      efficacy to filgrastim, with the added benefit of simplified once-per
      chemotherapy-cycle dosing. In addition, two randomized, controlled pivotal trials
      have shown that a single dose of pegfilgrastim given once per cycle led to a
      lower observed incidence of febrile neutropenia following myelosuppressive
      chemotherapy, compared with daily injections of filgrastim. Clinical trials are
      currently expanding the clinical experience with pegfilgrastim in a variety of
      solid tumors and hematologic malignancies. In addition to prevention of
      chemotherapy-induced neutropenia in 21- and 28-day regimens, future studies are
      examining the suitability of pegfilgrastim in dose-dense therapy and other cancer
      settings.

PMID- 15181607
TI  - Mucosal damage: a major risk factor for severe complications after cytotoxic
      therapy.
AB  - The oral and gastrointestinal mucosa is frequently damaged during chemotherapy
      and radiotherapy in patients with cancer, leading to a high incidence of
      mucositis (ie, oral, esophageal, lower gastrointestinal tract mucositis).
      Patients with mucositis often experience considerable pain and discomfort.
      Furthermore, neutropenic patients with mucositis have an increased risk of
      potentially life-threatening infections as well as prolonged hospital stays.
      Mucositis may also require that subsequent chemotherapy or radiotherapy doses be
      reduced, thereby potentially compromising the efficacy of cancer therapy.
      Standard care for oral mucositis is based on effective oral hygiene, appropriate
      analgesia, infection management, and parenteral nutrition when needed; few other
      approaches have been shown to be effective. The evaluation of new options to
      treat and prevent mucositis rather than control the symptoms is therefore an
      urgent priority. A comprehensive understanding of the complex pathobiology of
      mucositis will help to identify potential targets for new drugs. Promising
      investigational approaches have recently emerged. These include fibroblast growth
      factor-20, which is effective in animal models of chemotherapy/radiation-induced
      mucosal toxicity, and is being investigated in clinical studies. The candidate
      that is most advanced in terms of drug development is recombinant human
      keratinocyte growth factor (rHuKGF; palifermin), which in phase III clinical
      trials was shown to reduce the severity and duration of oral mucositis and
      improve clinical sequelae.

PMID- 15181610
TI  - Infection, immune function, and functional gut disorders.

PMID- 15181611
TI  - Ethnicity and hepatitis C virus infection.

PMID- 15181613
TI  - Racial differences in liver inflammation and fibrosis related to chronic
      hepatitis C.
AB  - BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is more prevalent in black
      compared with white Americans. However, the natural course of HCV in black
      patients has not been defined. METHODS: We performed a retrospective comparison
      of initial liver tests, HCV genotype and viral load, and liver histology findings
      in 87 black and 136 white American chronic hepatitis C patients who were
      evaluated at the University of Maryland between 1995 and 1998. The liver biopsy
      examinations were interpreted by using the Knodell Histologic Activity Index
      (HAI) criteria. RESULTS: Black HCV patients were older (46.3 vs. 43.3 yr; P =
      0.004) and were more likely to be infected with HCV genotype 1 (95% vs. 75%). The
      modes of HCV transmission, estimated duration of HCV infection, and prevalence of
      alcohol abuse were similar in the 2 groups. Yet, black patients had lower mean
      total HAI scores (7.6 vs. 8.7; P = 0.021), periportal hepatocyte necrosis scores
      (P = 0.021), and liver fibrosis scores (P = 0.049). In keeping with less hepatic
      necroinflammatory activity, black patients had a lower mean serum alanine
      transaminase (ALT) level (85.5 vs. 122.7; P = 0.002). Black patients also had
      lower serum iron levels (P = 0.009). There were no racial differences in the
      prevalence of increased iron studies and hepatic iron loading. CONCLUSIONS: Black
      chronic HCV patients have milder liver necroinflammation and fibrosis than white
      patients with similar HCV duration. These differences in liver histology were not
      explained by a variance in hepatic iron loading.

PMID- 15181612
TI  - Hepatitis C in a Los Angeles public hepatitis clinic: demographic and biochemical
      differences associated with race-ethnicity.
AB  - BACKGROUND & AIMS: The goal of this study was to uncover possible racial-ethnic
      differences in hepatitis C presentation in an urban hepatitis clinic. METHODS: We
      surveyed the clinic summary cards of patients with antibodies to hepatitis C
      virus (HCV) seen from 1993 to 2000 for demographic and laboratory data. RESULTS:
      A total of 1271 HCV patients were categorized into 4 major racial-ethnic groups
      consisting of 95 Asian, 232 African American, 323 Caucasian, and 621 Latino
      patients. The latter showed significantly higher serum alanine transaminase
      (ALT), aspartate transaminase, and bilirubin levels (P < 0.0001) and lower serum
      albumin levels (P < 0.01) compared with all other racial-ethnic groups. Latinos
      had the lowest rate of hepatitis B coinfection (2.4%) and were significantly less
      likely to have normal serum ALT levels (P = 0.0002) compared with other groups.
      Asian patients were 10 years older than other racial-ethnic groups and were
      significantly more likely to be coinfected with hepatitis B virus (HBV) (P =
      0.004). Asian patients also had an equal distribution of infected men and women
      whereas all other groups showed a male predominance. Injection drug use was a
      negligible cause of hepatitis C in Asian patients, but a prevalent exposure in
      Caucasian patients of both sexes and in African American and Latino men was seen.
      Transfusion was more prevalent in Asian and Latino patients. CONCLUSIONS:
      Hepatitis C risk factors, sex distribution, and coinfection with hepatitis B vary
      by race-ethnicity. Latino patients showed statistically significant biochemical
      differences in ALT, aspartate transaminase, bilirubin, and albumin levels
      compared with all other racial-ethnic groups. Further studies are required to
      determine the possible causes for these biochemical differences.

PMID- 15181614
TI  - A comparison of the spectrum of chronic hepatitis C virus between Caucasians and
      African Americans.
AB  - BACKGROUND & AIMS: Differences in hepatitis C virus (HCV)-related liver disease
      between Caucasians and African Americans remain controversial. METHODS: We
      performed a retrospective analysis of 302 consecutive inmates in the Virginia
      Department of Corrections evaluated for HCV between October 1998 and July 2002.
      All subjects were anti-HCV positive, HCV treatment naive, human immunodeficiency
      virus and HBV negative, and had compensated liver disease. RESULTS: The mean age
      of the cohort was 41 years; they were 91% male and 51% Caucasian. The mean ALT
      level was 94 U/L, 49% had a normal ALT level, and 80% were genotype 1. The mean
      Knodell histologic activity index (HAI) was 7.03, with bridging fibrosis in 18%
      and cirrhosis in 6%. When analyzed by race, the mean ALT level (106 vs. 79 U/L; P
      = 0.01), proportion with normal ALT level (46% vs. 57%; P = 0.06), and proportion
      with genotype 1 (67% vs. 94%; P < 0.001) were different between Caucasians and
      African Americans, respectively. Although the HAI and proportion with bridging
      fibrosis/cirrhosis were similar between groups, African Americans had lower
      piecemeal necrosis (1.41 vs. 1.72; P = 0.034) and fibrosis (1.12 vs. 1.40; P =
      0.047) scores compared to Caucasians. Multivariate analysis demonstrated that
      age, ALT, and race were significant independent variables associated with total
      HAI, piecemeal necrosis, and fibrosis scores. CONCLUSIONS: Although the overall
      spectrum of liver disease is similar, African Americans have less piecemeal
      necrosis and lower fibrosis scores independent of age and ALT compared with
      Caucasians.

PMID- 15181615
TI  - Helicobacter pylori eradication improves pre-existing reflux esophagitis in
      patients with duodenal ulcer disease.
AB  - BACKGROUND & AIMS: There has been significant controversy over the relationship
      between Helicobacter pylori infection and reflux esophagitis. We investigated the
      effects of eradicating H. pylori on the reflux esophagitis found in patients with
      peptic ulcers. METHODS: Prospective posteradication evaluations were conducted
      yearly in 162 H. pylori-positive patients who had reflux esophagitis together
      with peptic ulcer disease (4 women and 158 men, mean age = 49.1 yr). The Los
      Angeles classification of the patients' esophagitis was: grade A, 90; grade B,
      63; and grade C, 9. The follow-up evaluations began 1 to 2 months after
      completion of the eradication treatment (mean time of follow-up = 22 mo), and
      consisted of endoscopy and an interview focusing on heartburn. RESULTS: Six
      patients were withdrawn from the study because of adverse drug reactions or a
      failure to regularly keep their appointments. After eradication therapy, we
      observed endoscopically that reflux esophagitis had improved in 87 (55.8%) of the
      156 patients. The improvement rate was significantly higher in patients cured of
      infection (60.8%) than in those with persistent H. pylori infection (38.9%) (P =
      0.04). Body mass index (odds ratio = 0.86, 95% confidence interval [CI] = 0.76
      0.97), cure of infection (3.68, 95% CI = 1.56-8.69), the absence of a hiatal
      hernia (3.90, 95% CI = 1.83-8.28), and an ulcer located in the duodenum (2.75,
      95% CI = 1.33-5.70) were identified as significant independent factors for the
      improvement of reflux esophagitis. CONCLUSIONS: In patients with reflux
      esophagitis associated with duodenal ulcer, a significant improvement in pre
      existing reflux esophagitis was noted after H. pylori eradication.

PMID- 15181616
TI  - Immunochromatographic sticks for tissue transglutaminase and antigliadin antibody
      screening in celiac disease.
AB  - BACKGROUND & AIMS: We investigated two 1-step immunochromatographic visual assays
      based on human recombinant tissue-transglutaminase (t-TG) as an alternative to
      enzyme-linked immunosorbent assays (ELISAs) for celiac disease (CD) screening.
      METHODS: We used a tissue-transglutaminase (t-TG) stick, which detected
      immunoglobulin A/G (IgA/G) antibodies to t-TG, and a t-TG/antigliadin antibodies
      (AGA) stick, which detected IgA antibodies to both t-TG and AGA, as well as t-TG
      and AGA ELISAs, to determine t-TG and AGA antibodies in untreated celiac patients
      with subtotal villous atrophy. A total of 142 children (3 IgA-deficient sera) and
      30 adults, and 140 controls (normal mucosa; 121 children and 19 adults), plus 23
      sera from pediatric CD patients in remission were assayed. RESULTS: For pediatric
      patients, with the t-TG stick we obtained a sensitivity of 97.1% and a
      specificity of 99.0%, and in adults, 83.3% and 100%, respectively. The t-TG/AGA
      stick displayed a sensitivity of 95.7% and a specificity of 99.0% for t-TG and a
      sensitivity of 89.2% and a specificity of 95.8% for AGA in children, and a
      sensitivity of 80% and a specificity of 100% for t-TG and a sensitivity of 83.3%
      and a specificity of 100% for AGA in adults. Results were comparable with the
      corresponding ELISAs. CONCLUSIONS: The 2 visual assays are efficient for CD
      screening as an alternative to ELISAs. They are simple to handle and to
      interpret. By the combined use of the 2 sticks, IgA-deficient patients can be
      identified as positive in the t-TG (IgG/A) but negative in the t-TG/AGA (IgA)
      stick.

PMID- 15181617
TI  - Early predictors of severe lower gastrointestinal bleeding and adverse outcomes:
      a prospective study.
AB  - BACKGROUND & AIMS: Unlike in upper tract bleeding, prognostic factors for ongoing
      or recurrent bleeding from the lower gastrointestinal tract have not been well
      defined. The aim of this study was to identify risk factors for severe lower
      gastrointestinal bleeding and for significant adverse outcomes. METHODS: All
      patients seeking attention at a university emergency department for
      gastrointestinal bleeding were prospectively identified during a 3-year period.
      Ninety-four of 448 (21%) admitted patients had lower gastrointestinal bleeding.
      Clinical predictors available in the first hour of evaluation were recorded. The
      primary outcome, severe lower gastrointestinal bleeding, was defined as gross
      blood per rectum after leaving the emergency department associated with either
      abnormal vital signs (systolic blood pressure < 100 mm Hg or heart rate >
      100/min) or more than a 2-unit blood transfusion during the hospitalization.
      Significant adverse outcomes, including death, were tabulated. RESULTS: Thirty
      seven patients (39%) had severe lower gastrointestinal bleeding. Independent risk
      factors for severe lower gastrointestinal bleeding were initial hematocrit </=35%
      (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.2-16.7); presence of
      abnormal vital signs (systolic blood pressure < 100 mm Hg or heart rate >
      100/min) 1 hour after initial medical evaluation (OR, 4.3; 95% CI, 1.4-12.5); and
      gross blood on initial rectal examination (OR, 3.9; 95% CI, 1.2-13.2). Nineteen
      patients (20%) experienced a significant adverse outcome, including 3 deaths. The
      main independent predictor of adverse outcomes was severe lower gastrointestinal
      bleeding (OR, 5.3; 95% CI, 1.7-16.5). CONCLUSIONS: Risk factors are available in
      the first hour of evaluation in the emergency department to identify patients at
      risk for severe lower gastrointestinal bleeding. Severe lower gastrointestinal
      bleeding is a significant risk factor for global adverse outcomes.

PMID- 15181618
TI  - Abdominal MRI after enteroclysis or with oral contrast in patients with suspected
      or proven Crohn's disease.
AB  - BACKGROUND & AIMS: Diagnostic results of magnetic resonance (MR) enteroclysis
      correlate highly with those from conventional enteroclysis; nevertheless,
      intubation of the patient and positioning of an intestinal tube is still
      necessary for the examination, which is often remembered as the most embarrassing
      part of the examination by the patient. A more comfortable and highly sensitive
      examination of the small bowel therefore would increase patient acceptance for
      recurring examinations, which are often necessary, for example, in patients with
      Crohn's disease. This study evaluates the diagnostic efficacy of abdominal MR
      imaging (MRI) of the small bowel after drinking contrast agent only compared with
      conventional enteroclysis and abdominal MRI performed after enteroclysis in
      patients with suspected or proven Crohn's disease. METHODS: Twenty-one patients
      with Crohn's disease referred for conventional enteroclysis underwent abdominal
      MRI after enteroclysis. Additionally, 1 to 3 days before or after these
      examinations, abdominal MRI was performed using only orally administered
      contrast. All MRI examinations were performed using a 1.5T scanner. RESULTS: All
      pathological findings on conventional enteroclysis were shown correctly with MRI
      after enteroclysis and MRI after oral contrast only. Additional information by
      MRI was obtained in 6 of 21 patients. No statistically significant differences
      were found in assessing the diagnostic efficacy of the 3 examinations.
      CONCLUSIONS: Abdominal MRI with oral contrast only can be used as a diagnostic
      tool for evaluation of the small bowel in patients with Crohn's disease and has
      the potential to replace conventional enteroclysis as follow-up.

PMID- 15181619
TI  - Distal intestinal obstruction syndrome in adults with cystic fibrosis.
AB  - BACKGROUND & AIMS: With the improved survival of patients with cystic fibrosis
      (CF), gastrointestinal complications become more evident in adults with this
      condition. The aims of this study were to determine the prevalence and clinical
      features of distal intestinal obstruction syndrome (DIOS) and its relationship
      with the cystic fibrosis transmembrane conductance regulator (CFTR) genotype in
      an adult CF population. METHODS: Cross-sectional study was conducted in an adult
      CF cohort. RESULTS: Among 171 adults with CF (mean age, 28.9 years), 27 patients
      (15.8%) reported 43 episodes of DIOS. No significant association was found
      between DIOS and a history of meconium ileus. The first episode of DIOS occurred
      in adulthood in 21 cases (77.8%). DIOS recurred in 13 patients (48.1%). All
      patients who developed DIOS had pancreatic insufficiency. Pulmonary function was
      significantly more altered in patients with DIOS than in the other patients, but
      pancreatic insufficiency and age might act as confounding factors. DIOS occurred
      in 21.9% of patients with a severe CFTR genotype and in only 2.4% of patients
      with a mild CFTR genotype (P < 0.005). CONCLUSIONS: DIOS is frequent in adults
      with CF with a severe CFTR genotype and/or advanced-stage pulmonary disease. The
      relative contributions of malabsorption and impaired intestinal secretion in the
      development of DIOS are discussed.

PMID- 15181620
TI  - Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W
      mutation.
AB  - BACKGROUND & AIMS: Cystic fibrosis (CF) results from abnormal production of
      sticky mucus, which obstructs many organs. In most cases, the pancreas is
      severely compromised, but 10%-15% of patients with CF have pancreas sufficiency
      (PS) and are subject to develop pancreatitis. The aim of this study is to
      determine which specific genotypes lead to the development of pancreatitis in
      patients with CF. METHODS: We used prospective data collected by the Cystic
      Fibrosis Foundation and performed a nested case-control study with all patients
      who reported at least 1 episode of pancreatitis constituting the cases. We used
      logistic regression to assess the association between pancreatitis and genotype
      and the Kaplan-Meier method to estimate the cumulative incidence of pancreatitis
      for selected genotypes. RESULTS: Three hundred sixty-four of 17,871 genotyped
      patients with CF (2.0%) reported at least 1 episode of pancreatitis. Only 0.9% of
      12,997 patients with genotypes generally associated with pancreas insufficiency
      reported pancreatitis against 11.9% of 868 patients carrying at least 1 mild CF
      mutation generally associated with PS. The greatest rate of pancreatitis (19.0%)
      was observed for patients carrying an R334W mutation: 48% of these 79 patients
      were Hispanic and 13 patients were living in Puerto Rico. CONCLUSIONS: Of all
      patients with CF, those carrying an R334W mutation have the greatest risk for
      developing pancreatitis. This mutation is found mostly in Hispanic patients with
      CF living in Puerto Rico. There are no current data to determine whether
      asymptomatic carriers of the R334W mutation are at greater risk for developing
      pancreatitis or whether this mutation is frequent in Hispanics with idiopathic
      pancreatitis.

PMID- 15181621
TI  - Signs and symptoms of pancreatic cancer: a population-based case-control study in
      the San Francisco Bay area.
AB  - BACKGROUND & AIMS: Pancreatic cancer usually does not cause definitive symptoms
      until survival is severely compromised. Prevention and early detection are
      urgently needed. Our aim was to collect and analyze data in a population-based
      study on signs and symptoms of disease reported by patients with pancreatic
      cancer and control participants to contribute to earlier detection and better
      prognosis. METHODS: A supplemental symptoms questionnaire was administered to 120
      consecutive patients with pancreatic cancer who were part of a larger population
      based case-control study conducted in the San Francisco Bay Area between 1994 and
      2001. One hundred eighty age- and sex-matched population-based control
      participants also were queried about the same symptoms reported by at least 5% of
      patients with pancreatic cancer. RESULTS: Most signs and symptoms occurred within
      3 years before diagnosis with pancreatic cancer (cases) and interview (controls).
      Many signs and symptoms were more likely to have been reported by patients
      compared with control participants and included appetite loss (odds ratio [OR],
      41; 95% confidence interval [CI], 14-120), pale stools (OR, 31; 95% CI, 7.3-134),
      abdominal pain (OR, 30; 95% CI, 9.1-101), jaundice (OR, 20; 95% CI, 8.0-49),
      unusual bloating (OR, 20; 95% CI, 5.9-67), unusual belching (OR, 17; 95% CI, 3.9
      75), weight loss (OR, 12; 95% CI, 5.2-28), dark urine (OR, 10; 95% CI, 2.9-36),
      constipation (OR, 7.3; 95% CI, 2.0-26), diarrhea (OR, 5.6; 95% CI, 2.0-16),
      itching (OR, 5.0; 95% CI, 2.3-11), fatigue (OR, 3.8; 95% CI, 2.0-7.3), altered
      ability to sleep (OR, 2.9; 95% CI, 1.3-6.3), and unusual heartburn (OR, 2.3; 95%
      CI, 1.2-4.5). CONCLUSIONS: Our results show that signs and symptoms likely to be
      indicators of pancreatic cancer occur substantially more often among patients
      with pancreatic cancer than among population-based controls. The large magnitude
      of the risk estimates indicate that common gastrointestinal symptoms may assist
      clinicians in earlier diagnosis of pancreatic cancer and perhaps affect survival.

PMID- 15181622
TI  - Exploring how to tell the truth and preserve hope: can a balance between
      communication and empathy be calculated?
AB  - BACKGROUND & AIMS: When told the harsh truth about severe disease, a patient
      might despair and lose all hope. Without knowing the truth, however, the patient
      cannot participate in decision making and adjust life according to his illness.
      The present study aims to analyze the relationships between hope and truth in the
      decision on how much information to disclose to a patient with severe
      gastrointestinal disease. METHODS: The decision analysis is based on the economic
      concepts of indifference curves and utility function. An inverse linear
      relationship exists between hope and truth; as more truth becomes revealed, the
      amount of hope declines. The utility function and the corresponding indifference
      curve of hope plotted versus truth describe the patient's personal choices among
      different combinations of hope and truth. The optimal choice among various
      combinations of hope and truth corresponds with the point at which the inverse
      hope-truth line meets the indifference curve. RESULTS: In situations in which
      hope drops steeply as more medical facts are being revealed, the utility to the
      patient is maximized with less truth being told. With a less pronounced truth
      related decline in hope, utility is maximized at higher levels of truth, and,
      occasionally, utility is maximized only after all medical facts have been
      disclosed. The lesser the impact of truth on hope, the more truth is being
      tolerated. CONCLUSIONS: A caring gastroenterologist trying to optimize his/her
      patient's well-being should try to assess the potential influence of truth on the
      patient's psyche and dispense it accordingly.

PMID- 15181624
TI  - Minimally invasive diagnosis of Peutz-Jeghers syndrome.

PMID- 15181625
TI  - Automated structure elucidation of two unexpected products in a reaction of an
      alpha,beta-unsaturated pyruvate.
AB  - The reaction between an alpha,beta-unsaturated pyruvate and ethyl diazoacetate
      (EDA) yielded two unexpected products. The structures of these products were
      determined by automated elucidation of the chemical structures using
      spectroscopic inputs of a series of 1D and 2D NMR data using the computer program
      ACD/Structure Elucidator, StrucEluc. The formation of these products is
      rationalised. Their structures were also confirmed by x-ray crystallography.

PMID- 15181626
TI  - Reorientational dynamics of p-sulfonatocalix[4]arene and of its La(III) complex
      in water.
AB  - The reorientational dynamics of p-sulfonatocalix[4]arene and of its La(III)
      complex in deuterated water were studied by 1H NMR longitudinal relaxation rates.
      It is shown that the relaxation is purely dipolar in the non-extreme narrowing
      regime. The distance between the geminal protons could be determined from the NMR
      data, giving good agreement with the values generally used in correlation time
      calculations. The correlation times show an Arrhenius behaviour in good agreement
      with previously reported data from 13C measurements for a similar uncomplexed
      calixarene. The Arrhenius energies of activation are identical for the
      uncomplexed and the complexed calixarenes, suggesting a reorientational motion
      strongly dependent on the structure of the water cage around the complex. This is
      also in agreement with a complexation of the La(III) cation in the second sphere
      of solvation of the sulfonate groups, as shown by molecular dynamics simulations.

PMID- 15181627
TI  - Conformation analysis and molecular mobility of ethylene and tetrafluoroethylene
      copolymer using solid-state 19F MAS and 1H --> 19F CP/MAS NMR spectroscopy.
AB  - The changes in the conformation and molecular mobility accompanied by a phase
      transition in the crystalline domain were analyzed for ethylene (E) and
      tetrafluoroethylene (TFE) copolymer, ETFE, using variable-temperature (VT) solid
      state 19F magic angle spinning (MAS) and 1H --> 19F cross-polarization (CP)/MAS
      NMR spectroscopy. The shifts of the signals for fluorines in TFE units to higher
      frequency and the continuing decrease and increase in the T1rho(F) values suggest
      that conformational exchange motions exist in the crystalline domain between 42
      and 145 degrees C. Quantum chemical calculations of magnetic shielding constants
      showed that the high-frequency shift of TFE units should be induced by trans to
      gauche conformational changes at the CH2-CF2 linkage in the E-TFE unit. Although
      the 19F signals of the crystalline domain are substantially overlapped with those
      of the amorphous domain at ambient probe temperature (68 degrees C), they were
      successfully distinguished by using the dipolar filter and spin-lock pulse
      sequences at 145 degrees C. The dipolar coupling constants for the crystalline
      domain, which can be estimated by fitting the dipolar oscillation behaviors in
      the 1H --> 19F CP curve, showed a significant decrease with increasing
      temperature from 42 to 145 degrees C. This is due to the averaging of 1H-19F
      dipolar interactions originating from the molecular motion in the crystalline
      domain. The increase in molecular mobility in the crystalline domain was clearly
      shown by VT T1rho(F) and 1H --> 19F CP measurements in the phase transition
      temperature range.

PMID- 15181629
TI  - Heteronuclear selective refocusing 2D NMR experiments for the spectral analysis
      of enantiomers in chiral oriented solvents.
AB  - We report the use of carbon-proton heteronuclear selective refocusing 2D NMR
      experiments dedicated to the spectral analysis of enantiomers dissolved in weakly
      ordering chiral liquid crystalline solvents. The method permits the extraction of
      carbon-proton residual dipolar couplings for each enantiomer from a complex or
      unresolved proton-coupled 13C spectral patterns. Illustrative examples are
      analysed and discussed. It is shown that an accurate determination of
      enantiomeric excess is possible.

PMID- 15181628
TI  - Solution structure of the palladium(II) complex of 1,4,7,10-tetrathiacyclododec-2
      ene-2,3-dicarbonitrile.
AB  - The solution structure of the Pd(II) complex of mn-12-S4 was studied in detail by
      NMR spectroscopy. The stoichiometry of the complex was determined by 1H NMR
      titration experiments. 3J(H,H) coupling constants were extracted from the 2D J
      resolved NMR spectrum of the complex providing information concerning the S-C-C-S
      torsional angles. Further conclusions about the conformation of [Pd(mn-12
      S4)](BF4)2 were drawn from experimental NOEs. The results of the NMR study were
      corroborated by molecular modelling.

PMID- 15181630
TI  - Adducts of Rh2[MTPA]4 with some phosphine chalcogenides: nature of binding and
      ligand exchange.
AB  - Adducts of four phosphine chalcogenides with the chiral dirhodium complex ([Rh
      Rh]) were investigated by variable-temperature 1H and 31P NMR spectroscopy in
      order to compare their properties as axial ligands. Whereas the selenide (1) and
      the sulfide (2) are strong ligands with electrostatic attraction and, in
      addition, a significant orbital (HOMO-LUMO) interaction, the phosphine oxide
      compounds (P=O) bind primarily via electrostatic attraction and are relatively
      weak donors. Moreover, the overall bond strength in these adducts depends on
      steric congestion around the P=O group.

PMID- 15181631
TI  - 1H and 13C NMR spectral assignments and conformational analysis of 14 19-nor
      neoclerodane diterpenoids.
AB  - Unambiguous and complete assignments of 1H and 13C NMR chemical shifts for 14 19
      nor-neoclerodane diterpenoids, nine of them isolated from natural sources and
      five other synthetic derivatives, are presented. The assignments are based on 2D
      shift-correlated (1H,1H-COSY, 1H,13C-gHSQC and 1H,13C-gHMBC) and NOE experiments.
      The conformations of rings A and B of these compounds are supported by the
      3J(H,H) values and they agree with the low-energy conformations obtained by semi
      empirical calculations. Moreover, the data obtained in this work for 2
      acetoxyteucvidin and a semisynthetic 18-aldehyde derivative indicate that the
      configuration at C-2 of the former and at C-10 of the latter must be reversed
      with respect to those reported previously.

PMID- 15181632
TI  - Complete NMR elucidation of a novel trishomocubane hydantoin and its mono- and
      bis-t-Boc protected derivatives.
AB  - The syntheses of a novel trishomocubane hydantoin and its mono- and bis-protected
      t-Boc derivatives are described. The less nucleophilic N-3' nitrogen of the
      hydantoin ring is protected first when treated with di-tert-butyl dicarbonate (t
      Boc anhydride), possibly owing to steric hindrance by the bulky trishomocubane
      cage skeleton. More basic conditions were required to form the bis-protected t
      Boc hydantoin with the same reagent. The structures of these novel compounds were
      elucidated with 2D NMR techniques. The proton spectrum of the trishomocubane
      skeleton is complex owing to major overlap of proton signals. A high-level DFT
      calculation was used to determine some of the crucial interatomic positions,
      which assisted with the elucidation of the structures. The assignment of proton
      and carbon signals of the three structures is described and it differs
      significantly from each other and also from the trishomocubanol precursor. The
      bis-Boc hydantoin is required for a more facile hydrolysis to the corresponding
      trishomocubane amino acid at room temperature.

PMID- 15181633
TI  - High-resolution NMR spectroscopic trends and assignment rules of metal-free,
      metallated and substituted corroles.
AB  - Major advances over the last few years have facilitated the synthesis of a large
      variety of meso-only substituted corroles that display interesting catalytic,
      therapeutic and photophysical properties. This work is the first to study
      extensively the NMR spectral characteristics of both metallated and non
      metallated triarylcorroles in various organic solvents and provide guidelines for
      easy and reliable assignments of 1D 1H spectra from trends of J coupling
      constants and chemical shifts. An excellent correlation is found between C=C bond
      lengths derived from 3J(H,H) values and experimental lengths determined by x-ray
      crystallography of the same molecules. The nuclear Overhauser effect provides a
      robust 1D 1H NMR tool for determining the selectivity of electrophilic
      substitutions. Variable-temperature NMR and isotopic labelling reveal a single
      preferred tautomerization state and unsymmetric ring orientations at -70 degrees
      C. The beta-pyrrole protons demonstrate long-range heteronuclear couplings with
      the coordination core (15N) and with the ortho-19F nuclei of the meso-carbon aryl
      rings. In sum, application of multinuclear magnetic resonance to corroles and
      their metal complexes, through the compilation of chemical shifts and J couplings
      and the recognition of trends therein, provides basic information essential to
      reliable spectral assignments. Additionally, the conclusions drawn about the
      structures of corroles and the electron densities at various positions of the
      corrole macrocycle resulting from the application of high-resolution NMR
      techniques are of importance to an in-depth understanding of the molecular
      interactions and processes of this relatively new and rapidly expanding class of
      compounds.

PMID- 15181634
TI  - Differential protonation and dynamic structure of doxylamine succinate in
      solution using 1H and 13C NMR.
AB  - A protonation and dynamic structural study of doxylamine succinate, a 1:1 salt of
      succinic acid with dimethyl-[2-(1-phenyl-1-pyridin-2-yl-ethoxy)ethyl]amine, in
      solution using one- and two-dimensional 1H and 13C NMR experiments at variable
      temperature and concentration is presented. The two acidic protons of the salt
      doxylamine succinate are in 'intermediate' exchange at room temperature, as
      evidenced by the appearance of a broad signal. This signal evolves into two
      distinct signals below about -30 degrees C. A two-dimensional 1H-1H double
      quantum filtered correlation experiment carried out at -55 degrees C shows
      protonation of one of the acidic protons to the dimethylamine nitrogen. A two
      dimensional rotating frame 1H-1H NOE experiment at the same temperature reveals
      that the other proton remains with the succinate moiety. Comparison of the 1H and
      13C chemical shifts and the 13C T1 relaxation times of the salt with those of the
      free base further substantiate the findings.

PMID- 15181635
TI  - Acceleration of carbon-13 spin-lattice relaxation times in amino acids by
      electrolytes.
AB  - Measurements of the enhancement, by various electrolytes, of the spin-lattice
      relaxation time of carbon-13 at different locations in a number of amino acids
      are reported. Spin-lattice relaxation times T1 of all the carbons in amino acids
      generally tend to decrease with increase in the concentration of electrolytes,
      the largest effects often being observed for the charged carboxylate groups of
      the amino acids. Carboxylic carbons in amino acids are the sensitive 'acceptor'
      of the 13C spin-lattice relaxation accelerating effects offered by electrolytes,
      and the 13C spin-lattice relaxation accelerating ability of electrolytes
      decreases in the order Mg(ClO4)2 > MgCl2 > CaCl2 > NaCl > KCl > LiClO4 > NaOH.
      The mechanisms of the observed phenomena are discussed in terms of intermolecular
      interaction, paramagnetic impurities in electrolytes and other mechanisms; large
      contributions of intermolecular interactions with electrolytes are present on
      complex formation between amino acids and metal ions and the incoming
      'unsaturation' of the primary solvation shell of cations with the increase in
      electrolyte concentration.

PMID- 15181636
TI  - Structural assignment of regioisomeric 3-[2- or 5-anilino-2
      (alkylamino)phenyl]propanoic acids, 2H-1,4-benzothiazin-3(4H)-ones and 2,3
      dihydro-1,5-benzothiazepin-4(5H)-ones by 1D NOE and gHMBC NMR techniques.
AB  - The 1H and 13C NMR spectra of compounds 1-11 and 16-22 in CDCl3 and DMSO-d6
      solutions allowed structural assignment to regioisomers 1/5 and 2/6 and their
      regioselective cyclization products 16-18 utilizing one- and two-dimensional NMR
      techniques (APT, DEPT, NOE difference, COSY, NOESY, HETCOR and gHMQC, gHMBC).
      Temperature-dependent 1H NMR spectra of 8-anilino-5-(4-methyl-2-pentyl)-2,3
      dihydro-1,5-benzothiazepin-4(5H)-one (18) indicated a free energy of activation
      (deltaG++) of ca 17 kcal mol(-1) for interconversion between rotamers. The 1H and
      13C NMR spectra of 20 and 22 containing two chiral centers exhibit duplication of
      several signals, indicating the existence of two diastereomeric forms. The
      structure of 4 was unambiguously confirmed by x-ray crystallography.

PMID- 15181637
TI  - Complete assignments of 1H and 13C NMR data for 10 phenylethanoid glycosides.
AB  - Ten phenylethanoid glycosides, including two new ones, isolated from the aerial
      parts of the mangrove plant Acanthus ilicifolius were identified. The first
      complete assignments of the 1H and 13C NMR chemical shifts for these glycosides
      were achieved by means of 2D NMR techniques, including 1H-1H COSY, TOCSY, HSQC
      and HMBC spectra.

PMID- 15181638
TI  - NMR characterization of new 10-membered-ring macrolactones and
      dihydrobenzophenazine-5-one, oxidized derivatives of benzo[a]phenazines.
AB  - Peroxidation of the phenazine of beta-lapachone using m-ClC6H4CO3H-CH2Cl2
      furnished a macrolactone with a rigid 10-membered ring, and the corresponding N
      oxide, along with a dihydrobenzophenazine-5-one. All of the new compounds were
      fully characterized by spectroscopic methods, with the unambiguous assignment of
      the hydrogens and carbon NMR signals for the N-oxide, with the aid of 2-D NMR,
      mainly COSY, HMQC, HSQC and HMBC. For the other two compounds some signals could
      not be assigned owing to their own intrinsic features.

PMID- 15181639
TI  - Precis of Edwin G. Conklin's JEZ article, "Mosaic Development in Ascidian Eggs".

PMID- 15181640
TI  - Regrowth of the stalk of the sea lily, Metacrinus rotundus (Echinodermata:
      Crinoidea).
AB  - Sea lilies are critical to understanding the evolution of the echinoderm body
      plan, because they are the only extant group whose adults possess a stalk, a
      prevalent feature in the radiation of a number of primitive echinoderm lineages.
      Extensive crown regeneration ability has been reported in Metacrinus rotundus,
      but the regenerative potential of the stalk has never been determined in any
      species of sea lilies. In this study, we show that M. rotundus whose stalks have
      been completely excised are capable of stalk regeneration. The process is similar
      to the growth of the original stalk, but much slower, and the regenerated stalks
      are not morphologically identical to the original stalk. Since stalk
      regeneration, in contrast to well-studied regeneration events, probably requires
      little additional activation of morphogenetic programs, we refer to the stalk
      regeneration phenomenon as "stalk regrowth" to distinguish it as a special form
      of regeneration. Since specimens whose entire stalk below the basal plates had
      been removed were able to regrow, the basal plates, and probably the aboral nerve
      center within them, are essential for stalk regrowth. Sea lily stalk regrowth is
      described in detail, and the evolution of feather stars is discussed in light of
      the growth pattern of the sea lily stalk.

PMID- 15181641
TI  - Progesterone determination in Iberian red deer by time-resolved fluorometry: an
      alternative method to RIA.
AB  - The validation for Iberian red deer of a commercially available Time-resolved
      fluoroimmunoassay (TR-FIA) designed for analysis of progesterone in human beings
      was carried out. Intra-assay coefficients of variation ranged from 3.6% to 7.4%,
      while inter-assay coefficients of variation varied from 5.2% to 15.5%. Accuracy,
      evaluated by comparing results yielded by TR-FIA with those obtained from a
      validated radioimmunoassay (RIA) in the measurement of 14 samples, provided a
      high regression coefficient (R(2)= 0.93). Different progesterone concentrations
      added to pool plasma showed percentages of recovery that ranged between 102.6%
      and 82.48%. The limit of detection was 0.102 nmol/L. The results obtained
      indicate that the present method is suitable for the measurement of progesterone
      in female Iberian red deer.

PMID- 15181642
TI  - Growth enhancement and food conversion efficiency of transgenic fish Labeo
      rohita.
AB  - Three family lines of fast growing transgenic rohu Labeo rohita (rohu) were
      generated by electroporated-sperm-mediated transfer of the vectors harboring CMV
      promoter or grass carp beta-actin promoter fused to endogenous rohu GH (rGH)
      cDNA. The gene transfer efficiency was 25%. The transgenic rohu (family line 1)
      with CMV promoter showed a growth enhancement of four times normal size, whereas
      those (family lines 2 and 3) generated with beta-actin promoter grew 4.5 and 5.8
      times faster than their respective control siblings. Southern analysis confirmed
      the transgene extrachromosomal (Te) persistence until the 60th week in family 1.
      The individuals of family lines 2 and 3, however, showed integration (Ti), as
      well as persistence as extrachromosomal copies (Te) until the age of 30 weeks.
      Mosaicism of the transgene was shown at the levels of its presence and
      expression. The ectopic expression of rGH mRNA was confirmed by RT-PCR. Feeding
      experiments revealed that the transgenic rohu ate food at a lower rate but grew
      more efficiently than their control siblings.

PMID- 15181643
TI  - Survival capacity of haploid-diploid goldfish chimeras.
AB  - In teleosts, haploidy has been considered to be inviable due to the expression of
      abnormalities during embryogenesis, but the recent report of live haploid-diploid
      mosaic fish suggests the probable improvement of survival capacity by adding
      diploid cells or tissues to haploid embryos. In order to examine such
      possibilities, two types of haploid-diploid goldfish chimeric embryos were
      produced by transplantation of blastoderm between the normally fertilized diploid
      and the artificially induced gynogenetic haploid: the haploid-base chimera with
      the diploid upper half on the haploid lower half blastoderm and the diploid-base
      chimera with the haploid upper half on the diploid lower half blastoderm.
      Fluorescent detection of FITC-labeled cells, subsequent histochemical detection
      of biotin-labeled haploid cells and flow-cytometrical detection of both haploid
      and diploid cells proved successful induction of the haploid-diploid chimera.
      Both types of chimeric embryos demonstrated much better survival capacity than
      pure haploid individuals, but all the haploid-base chimeras died before 10 days
      after fertilization due to the expression of edema, whereas several diploid-base
      chimeras survived until 16 months after fertilization when the experiment was
      ended. This concluded diploid-base chimeras became viable by adding diploid cells
      to haploid embryos. However, the proportion of transplanted haploid cells was
      reduced and the distribution of these cells was limited to certain organs because
      survivors exhibited haploid cells only in brain, eye and/or skin. These results
      suggest possible elimination of haploid cells from the organs originated from
      ectoderm.

PMID- 15181644
TI  - Clonal diploid sperm of the diploid-triploid mosaic loach, Misgurnus
      anguillicaudatus (Teleostei:Cobitidae).
AB  - The loach Misgurnus anguillicaudatus comprises diploid, triploid and diploid
      triploid mosaic individuals in a wild population of the Hokkaido island, Japan.
      Previous studies revealed the presence of a cryptic clonal lineage among diploid
      loaches, which is maintained by uniparental reproduction of genetically identical
      diploid eggs. In the present study, we analyzed distribution and genetic status
      of diploid and triploid cells in infrequent mosaic males. Flow cytometry,
      microsatellite genotyping and DNA fingerprinting verified that mosaic males
      consisted of diploid cells with genotypes identical to the natural clone and
      triploid cells with diploid genomes of the clonal lineage plus haploid genome
      from sperm nucleus of the father. Thus, the occurrence of diploid-triploid
      mosaicism might be caused by accidental fertilization of a diploid blastomere
      nucleus with haploid sperm after the initiation of clonal development of
      unreduced eggs. Such mosaic males produced fertile sperm with diploid DNA
      content. The experimental cross between normal diploid female and diploid
      triploid mosaic male gave rise to the appearance of triploid progeny which
      exhibited two microsatellite alleles identical to the clonal genotype and one
      allele derived from the normal female. In DNA fingerprinting, such triploid
      progeny gave not only all the DNA fragments from the clone, but also other
      fragments from the normal female. Induced androgenesis using UV irradiated eggs
      and sperm of the mosaic male gave rise to the occurrence of diploid individuals
      with paternally derived microsatellite genotypes and DNA fingerprints, absolutely
      identical to the natural clonal lineage. These results conclude that the diploid
      triploid mosaic male produced unreduced diploid sperm with genetically identical
      genotypes. The spermatogenesis in the clonal diploid cells under the mosaic
      condition suggests that triploid male somatic cells might transform genetically
      all-female germ cells to differentiate into functionally male gametes. The
      discovery of the mosaic male producing unreduced sperm suggests the theoretical
      occurrence of triploids and other polyploids by the syngamy of such paternally
      derived diploid gametes.

PMID- 15181645
TI  - Molecular cloning of a putative membrane form guanylyl cyclase from the crayfish
      Procambarus clarkii.
AB  - Available data indicate that crustacean hyperglycemic hormone (CHH) stimulates
      membrane-bound guanylyl cyclase (GC), producing cyclic guanosine 3',5'
      monophosphate, which in turn mediates the effect of CHH on carbohydrate
      metabolism. In the present study, we report the cloning of a cDNA (PcGC-M2)
      encoding a putative membrane form GC from the muscle of the crayfish, Procambarus
      clarkii. Analysis of the deduced amino acid sequence shows that PcGC-M2 contains
      the signature domains characteristic of membrane form GCs, including an
      extracellular ligand-binding domain, a single transmembrane, and intracellular
      kinase-like and cyclase catalytic domains. In addition, a C-terminal domain of
      247 residues is present following the cyclase catalytic domain. PcGC-M2 is most
      closely related (33% identity) to a Drosophila membrane form GC (DrGC-1), and an
      Anopheles gambiae membrane form GC (AgaGC); the three GCs also share a similar
      distribution pattern of conserved cysteine residues in the extracellular domain.
      The PcGC-M2 transcript is expressed in several CHH target tissues, including
      muscle, hepatopancreas, heart, ovary, testis, and gill, suggesting that PcGC-M2
      may participate in the signaling cascade activated by CHH.

PMID- 15181646
TI  - Seasonal effects of dehydration on glucose mobilization in freeze-tolerant chorus
      frogs (Pseudacris triseriata) and freeze-intolerant toads (Bufo woodhousii and B.
      cognatus).
AB  - It has been hypothesized that freeze-tolerance in anurans evolved from a
      predisposition for dehydration tolerance. To test this hypothesis, we dehydrated
      summer/fall-collected and winter acclimated freeze-tolerant chorus frogs and
      dehydration-tolerant, but freeze-intolerant, Woodhouse's and Great Plains toads
      to 25% and 50% body water loss (BWL). Following treatments, we measured glucose,
      glycogen, and glycogen phosphorylase and glycogen synthetase (summer/fall only)
      activities in liver and leg muscle. Hepatic glucose levels were not significantly
      altered by dehydration in either summer/fall-collected frogs or toads.
      Conversely, winter acclimated frogs did show an increment (2.9-fold) in hepatic
      glucose with dehydration, accompanied by a reduction in hepatic glycogen levels.
      Winter acclimated toads did not mobilize hepatic glucose in response to
      dehydration. Further, hepatic glycogen and phosphorylase activities did not vary
      in any consistent manner with dehydration in winter toads. Mean leg muscle
      glucose values were elevated at 50% BWL relative to other treatments,
      significantly so compared to 25% BWL for summer/fall-collected frogs. The pattern
      of hepatic glucose mobilization with dehydration in winter frogs is consistent
      with that in other freeze-tolerant frog species, and provides additional support
      for the hypothesis that freezing tolerance evolved from a capacity for
      dehydration tolerance. However, the lack of hepatic glucose mobilization in
      response to dehydration in fall frogs suggests that a seasonal component to
      dehydration-induced regulation of glucose metabolism exists in chorus frogs.
      Furthermore, the absence of a dehydration-induced mobilization of hepatic glucose
      at both seasons in toads suggests that this dehydration response is not universal
      for terrestrial anurans.

PMID- 15181647
TI  - alpha-Tubulin and acetylated alpha-tubulin during ovarian follicle
      differentiation in the lizard Podarcis sicula Raf.
AB  - During most of the previtellogenic oocyte growth, the follicular epithelium of
      the lizard Podarcis sicula shows a polymorphic structure, due to the presence of
      different follicle cells. These include small cells which divide and move from
      the periphery of the follicle to the oocyte surface, intermediate cells which
      represent an initial step in the process of cell enlargement, and large pyriform
      cells engaged in the transport of different materials to the oocyte through
      intercellular bridges. We have studied, by immunolocalization and immunoblotting,
      the localization of alpha-tubulin and its acetylated form in different follicle
      cells and in the oocyte during the main steps of ovarian follicle
      differentiation. Our results indicate that alpha-tubulin is present in all
      follicle cells at different stages of ovarian follicle differentiation, while its
      acetylated form is detectable exclusively in the small proliferating and
      migrating follicle cells. In pyriform cells, alpha-tubulin is localized around
      the nucleus, extends to the cell apex, and crosses the zona pellucida into the
      oocyte cortex. The presence of acetylated tubulin in the small follicle cells may
      be related to the proliferation and/or migration of these cells. The absence of
      acetylated tubulin form in the cytoplasm of intermediate and pyriform cells can
      be related to the colocalization of alpha-tubulin with the keratin cytoskeleton
      in these cells, as detected by confocal microscopy. We have also identified the
      colocalization of alpha-tubulin with keratin in the cortical region of the
      oocyte, in particular when the cortex is engaged in the uptake of the yolk
      proteins.

PMID- 15181648
TI  - Influence of photoperiod and temperature on reproductive mode in the Brine
      shrimp, Artemia franciscana.
AB  - Brine shrimp, Artemia, exhibit two modes of reproduction: oviparity (diapause
      cyst production) and ovoviviparity (live larvae release). Environmental
      conditions determining these developmental routes are poorly understood, so we
      investigated the effects of photoperiod and temperature on reproductive mode.
      Nauplii of A. franciscana were hatched from cysts produced in the Great Salt
      Lake, Utah, and raised in 2% natural sea salt water under photoperiods of 24, 14,
      12, or 10 h at 28 degrees or 20 degrees C. Mating pairs of mature shrimp were
      isolated and reared continuously under those conditions. The mode of reproduction
      shown by each pair was determined daily throughout their life span, and found to
      be greatly affected by photoperiod, and less influenced by temperature. The
      relative degree of oviparity increased as the photoperiod became shorter at both
      temperatures. In contrast, the degree of ovoviviparity was higher as the
      photoperiod became longer at both temperatures. The critical photoperiod appears
      to be between 12 and 14 h. For all photoperiods examined, the degree of oviparity
      was higher at 28 degrees C than at 20 degrees C, whereas the degree of
      ovoviviparity was greater at 20 degrees C than at 28 degrees C.

PMID- 15181649
TI  - Medicines and the drug control treaties: is buprenorphine for opioid addiction at
      risk of being lost?
AB  - Over the past century, a worldwide system for the control of drugs with abuse
      potential has developed through the adoption of a series of international
      treaties. The important multilateral conventions currently in force are the
      United Nations Single Convention on Narcotic Drugs, 1961 (Single Convention), the
      United Nations Convention on Psychotropic Substances, 1971 (Psychotropic
      Convention) and the United Nations Convention Against Illicit Traffic in Narcotic
      Drugs and Psychotropic Substances, 1988. From the beginning, the aim of these
      drug control treaties has been to control the abuse and trafficking of substances
      with abuse potential while assuring that the availability of these drugs for
      medical and scientific purposes is not unduly restricted. There is activity in
      the World Health Organization and the International Narcotics Control Board to
      determine whether the international control of buprenorphine, a partial mu-opioid
      agonist used as an analgesic and for the treatment of opioid addiction, should be
      changed from the Psychotropic Convention to the Single Convention. This change
      would result in the classification and regulation of buprenorphine as a narcotic
      drug rather than a psychotropic substance. Such a move is unwarranted medically
      and scientifically and would provoke increased controls on buprenorphine that
      would fundamentally disrupt the medical practice of pain management and opioid
      replacement therapy around the world. The negative impact of inappropriate
      regulatory controls when licensed medicines come under such scrutiny are
      described.

PMID- 15181650
TI  - Verbal working memory deficits in current and previous users of MDMA.
AB  - Previous research suggests that MDMA users are impaired in various aspects of
      cognitive functioning, however, it remains unclear whether they might experience
      deficits in established measures of verbal working memory functioning. In the
      present study current and previous MDMA users were compared with non-users on
      verbal working memory measures including reading and computation span. Both user
      groups were found to be impaired on the computation span measure while current
      users also exhibited impairment in reading span. The MDMA-related deficit on the
      computation span measure remained significant following the introduction of
      statistical controls for the potentially confounding effects of cannabis and
      other drugs. The results are discussed in the context of recent research on
      executive processes. It is suggested that MDMA may produce differential effects
      on specific components within a fractionated executive system.

PMID- 15181651
TI  - The effect of a herbal medicine (Mao-to) for the prevention of interferon-induced
      psychiatric complications in chronic hepatitis C: a pilot study.
AB  - OBJECTIVE: To evaluate the efficacy of a herbal medicine (Mao-to) on psychiatric
      complications caused by IFN, and to examine the relationship between depression
      and microcirculation. METHODS: Twelve patients with chronic hepatitis C and a
      past history of IFN-induced depression were enrolled in this study. Their mental
      state was evaluated by the self-rating depression scale (SDS)> or =40, or M-R of
      the Cornell medical index (CMI)> or =10. Each patient received a daily dose of 6
      million units of IFN-beta for 8 weeks, and Mao-to was given orally four times a
      day during the IFN-beta course. RESULTS: All patients in this study completed a
      full course of IFN. Mean CMI scores (M-R) had significantly decreased at the end
      of the treatment. Mean erythrocyte aggregability and erythrocyte deformability
      had also significantly decreased at the end of treatment. CONCLUSION: Mao-to
      might be useful for preventing the incidence of depression in patients with
      chronic hepatitis C being treated with IFN. The mechanism by which Mao-to
      prevents depression is suggested to be through the improvement of
      microcirculation.

PMID- 15181652
TI  - Enhanced cognitive performance and cheerful mood by standardized extracts of
      Piper methysticum (Kava-kava).
AB  - The acute effects of the herbal anxiolytic Kava-kava (Piper methysticum G.
      Forster) on emotional reactivity and cognitive performance were investigated in a
      double-blind randomized placebo-controlled trial involving healthy volunteers.
      Subjects' reports of mood change were assessed with the state-trait-cheerfulness
      inventory, which measures the three concepts of cheerfulness, seriousness and bad
      mood as both traits and states. Cognitive performance was examined with the
      Sperling partial report and the Sternberg item recognition task, which were used
      as an index for visual attention and short-term memory processing. The intake of
      a single dose of Kava extract (300 mg; p.o.) led to an increase in state
      cheerfulness, while the phytopharmacon did not influence state seriousness and
      bad mood. The mood-elevating effects of Kava were most prominent in trait
      cheerful subjects, indicating that trait cheerfulness moderated the drug-induced
      increase in cheerful mood. Furthermore, Kava improved the accuracy and the speed
      of performing the partial report and the item recognition task, indicative of a
      beneficial effect of the phytopharmacon on visual attention and short-term memory
      retrieval, respectively. Thus, unlike conventional benzodiazepine-type
      anxiolytics, which tend to impair cognitive performance and to increase the
      occurrence of negative affective states, Kava is a potent anxiolytic agent,
      which, additionally, can facilitate cognitive functioning and can increase
      positive affectivity related to exhilaration.

PMID- 15181653
TI  - Decrease of the platelet 5-HT2A receptor function by long-term imipramine
      treatment in endogenous depression.
AB  - BACKGROUND: Animal studies have found that many antidepressants induce decreases
      in both the density and the functional activity of the serotonin 2A (5-HT2A)
      receptor subtype. However, the extrapolation of findings to humans has been
      inconclusive. A physiological platelet response mediated by this receptor, the
      serotonin-amplified platelet aggregation, was measured to study whether long-term
      antidepressant treatment induces changes in 5-HT2A receptor functioning in
      endogenous depressed patients. METHOD: The percentage of serotonin-amplified
      platelet aggregation to adenosine diphosphate (ADP) was studied in 15 untreated
      patients with major depressive disorder (DSM-IV) with endogenous features
      (Newcastle scale). This index was used as an indirect measurement of the
      functional status of platelet 5-HT2A receptors. Aggregation studies were repeated
      once remission of the symptoms was achieved during treatment with imipramine (150
      300 mg/day). A group of 15 concurrent normal subjects was used as a control.
      RESULTS: A statistically significant decrease (p = 0.038) in the percentage of
      serotonin-amplified platelet aggregation to ADP was observed when remission was
      achieved (after 145 +/- 27 days). CONCLUSIONS: The results showed a decrease in a
      platelet functional response mediated by 5-HT2A receptors following effective
      imipramine treatment, suggesting that desensitization or down-regulation of the 5
      HT2A receptor function could be linked to the therapeutic effect of some
      antidepressants. The data also support the use of platelet aggregometry as a
      surrogate measurement of antidepressant action, particularly in intra-subject
      designs.

PMID- 15181655
TI  - A preliminary study of the comparative effects of olanzapine and risperidone on
      cognition in schizophrenia.
AB  - The aim of this study was to compare the effects of olanzapine and risperidone on
      cognitive functions in patients with schizophrenia. The subjects were
      schizophrenic outpatients, all meeting DSM-IV diagnostic criteria for
      schizophrenia and already treated with risperidone. In the experimental group
      (15), risperidone was changed to olanzapine to be administered for 8 weeks.
      Risperidone was maintained without a change in the daily dose in the control
      group (13). The assessment of clinical symptoms and cognitive functions in both
      groups was made at baseline and at 8 weeks. The experimental group relative to
      the control group showed significant improvement in five items such as immediate
      and delayed recall of verbal memory, verbal fluency, visual memory and total
      error of executive function. Although these data are preliminary, they could
      suggest the possibility of cognitive benefits from treatment with olanzapine
      relative to risperidone. These findings did not appear to be mediated by changes
      in clinical symptoms and side effects.

PMID- 15181654
TI  - Drug utilization review of risperidone for outpatients in a tertiary referral
      hospital in Singapore.
AB  - BACKGROUND: Risperidone has been used in Singapore for schizophrenia since 1996.
      However, little information is available on its utilization pattern. OBJECTIVE:
      To examine the risperidone utilization pattern in the Psychiatric Outpatient
      Clinic of the National University Hospital. METHOD: Medical records of all
      outpatients with schizophrenia prescribed with risperidone from 1 September1999
      to 31 August 2000 were reviewed. RESULTS: A total of 417 risperidone
      prescriptions were dispensed for 130 outpatients (50 male, 80 female) during the
      study period. The mean +/- SD daily doses for prescriptions and for patients were
      2.3 +/- 1.3 mg and 2.1 +/- 1.1 mg, respectively. Among these patients, 28 (21.5%)
      received at least one concomitant conventional antipsychotic and 71 (54.6%)
      received a concomitant anti-Parkinsonian agent. Logistic regression analysis
      suggested that a higher risperidone dose was associated with the greater
      probability of anti-Parkinsonian agent usage. CONCLUSIONS: The mean risperidone
      dose during the study period was towards the lower end of recommendation for
      schizophrenia. Further study is warranted to confirm and explain the pattern of
      low-dose risperidone, and the high use of concomitant conventional antipsychotics
      and anti-Parkinsonian agents in Singapore. Elucidation of these would provide a
      valuable insight for the management of Asian patients with schizophrenia using
      risperidone. However, the current data indicate that the practice of using a
      lower dose of risperidone could represent better affordability and an improved
      cost-effectiveness ratio of risperidone compared with conventional antipsychotics
      in Asian patients.

PMID- 15181656
TI  - Combination of ziprasidone and clozapine in treatment-resistant schizophrenia.
AB  - In cases of treatment-resistant schizophrenia the combined application of
      antipsychotic drugs often becomes necessary. Clozapine has been combined
      successfully with other atypical antipsychotic drugs such as risperidone or
      amisulpride in the past. We report the difficult treatment of a 28-year-old
      schizophrenic woman. Psychotic symptoms were found resistant to monotherapy with
      clozapine or ziprasidone. In contrast, combined application led to a marked
      improvement in both positive and negative symptoms of schizophrenia along with a
      decrease of side effects.The reported combination is a promising option in cases
      of treatment-resistant schizophrenia and should be further evaluated in
      prospective studies.

PMID- 15181657
TI  - First-episode psychosis after taking an extract of Hypericum perforatum (St
      John's Wort).

PMID- 15181658
TI  - Travel insurance and medical evacuation.

PMID- 15181659
TI  - Travel insurance and medical evacuation.

PMID- 15181660
TI  - Cytogenetic studies allow distinction among different benign fibro-osseous
      lesions of bone.

PMID- 15181661
TI  - Intranasal steroid sprays in the treatment of rhinitis is one better than
      another?

PMID- 15181662
TI  - Does urine alkalinization increase salicylate elimination? If so, why?
AB  - Urine alkalinization is a treatment regimen that increases poison elimination by
      the administration of intravenous sodium bicarbonate to produce urine with a pH >
      or = 7.5. Experimental and clinical studies confirm that urinary alkalinization
      increases salicylate elimination, although the mechanisms by which this occurs
      have not been elucidated. The conventional view is that ionisation of a weak
      acid, such as salicylic acid, is increased in an alkaline environment. Since the
      ionisation constant (pKa) is a logarithmic function then, theoretically, a small
      change in urine pH will have a disproportionately larger effect on salicylate
      clearance. Hence, elimination of salicylic acid by the kidneys is increased
      substantially in alkaline urine. However, as salicylic acid is almost completely
      ionised within physiological pH limits, alkalinization of the urine could not,
      therefore, significantly increase the extent of ionisation further and the
      conventional view of the mechanism by which alkalinization is effective is
      patently impossible. Further experimental studies are required to clarify the
      mechanisms by which urine alkalinization enhances salicylate elimination.

PMID- 15181663
TI  - Abrin poisoning.
AB  - Abrin is a toxic protein obtained from the seeds of Abrus precatorius (jequirity
      bean), which is similar in structure and properties to ricin. Abrin is highly
      toxic, with an estimated human fatal dose of 0.1-1 microgram/kg, and has caused
      death after accidental and intentional poisoning. Abrin can be extracted from
      jequirity beans using a relatively simple and cheap procedure. This satisfies one
      criterion of a potential chemical warfare agent, although the lack of large scale
      production of jequirity seeds means that quantity is unavailable for ready mass
      production of abrin for weapons. This contrasts with the huge cultivation of
      Ricinus seeds for castor oil production. At the cellular level, abrin inhibits
      protein synthesis, thereby causing cell death. Many of the features observed in
      abrin poisoning can be explained by abrin-induced endothelial cell damage, which
      causes an increase in capillary permeability with consequent fluid and protein
      leakage and tissue oedema (the so-called vascular leak syndrome). Most reported
      cases of human poisoning involve the ingestion of jequirity beans, which
      predominantly cause gastrointestinal toxicity. Management is symptomatic and
      supportive. Experimental studies have shown that vaccination with abrin toxoid
      may offer some protection against a subsequent abrin challenge, although such an
      approach is unlikely to be of benefit in a civilian population that in all
      probability would be unprotected.

PMID- 15181664
TI  - Human parathion poisoning. A toxicokinetic analysis.
AB  - The mortality rate of suicidal parathion poisoning is particularly high, the
      onset of fulminant cholinergic signs, and the patients frequently present to the
      emergency physician with life-threatening symptoms. Despite this uniformity,
      subsequent clinical course differs significantly among patients, mostly not as a
      result of different delays in treatment or insufficiency of primary care.
      Probably, the differences depend on the amount of poison absorbed and/or the
      disposition of the active poison, paraoxon. We followed the toxicokinetics of
      parathion and tried to quantify the actual poison load. To this end, we monitored
      parathion-intoxicated patients (patients requiring artificial ventilation) for
      plasma levels of parathion and paraoxon along with the activity of erythrocyte
      acetylcholinesterase and its reactivatability. Plasma obidoxime concentrations
      were followed as well as the cumulative urinary para-nitrophenol conjugate
      excretion as a measure of total poison load. All patients received a standard
      obidoxime scheme of a 250 mg bolus dose intravenously, followed by continuous
      infusion with 750 mg per 24 hours as long as reactivation could be expected
      (usually 1 week). All other treatment was instituted as judged by the physician.
      It was recommended to use atropine at low doses to achieve dry mucous membranes,
      no bronchoconstriction and no bradycardia. Usually 1-2 mg/h were sufficient.
      Seven selected cases are presented exemplifying toxicokinetic peculiarities. All
      patients were severely intoxicated, while the amount of parathion absorbed varied
      widely (between 0.12 and 4.4 g; lethal dose 0.02-0.1 g) and was generally much
      lower than anticipated from the reports of relatives. It remains open whether the
      discrepancies between reports and findings were due to exaggeration or to
      effective decontamination (including spontaneous vomiting, gastric lavage and
      activated charcoal). Absorption of parathion from the gastrointestinal tract was
      sometimes retarded, up to 5 days, resulting in fluctuating plasma profiles. The
      volume of distribution at steady-state (Vdss) of parathion was around 20 L/kg.
      Post-mortem analysis in one patient revealed a 66-fold higher parathion
      concentration in fat tissue compared with plasma, 16 days after ingestion.
      Biotransformation of parathion varied widely and was severely retarded in one
      patient receiving fluconazole during worsening of renal function, while
      phenobarbital (phenobarbitone) sedation (two cases) had apparently no effect. The
      proportion of plasma parathion to paraoxon varied from 0.3-30, pointing also to
      varying paraoxon elimination, as illustrated by one case with particularly low
      paraoxonase-1 activity. Obidoxime was effective at paraoxon concentrations below
      0.5 microM, provided aging was not too advanced. This concentration correlated
      poorly with the paration concentration or the poison load. The data are discussed
      in light of the pertinent literature.

PMID- 15181665
TI  - The role of oximes in the management of organophosphorus pesticide poisoning.
AB  - The number of intoxications with organophosphorus pesticides (OPs) is estimated
      at some 3,000,000 per year, and the number of deaths and casualties some 300,000
      per year. OPs act primarily by inhibiting acetylcholinesterase (AChE), thereby
      allowing acetylcholine to accumulate at cholinergic synapses, disturbing
      transmission at parasympathetic nerve endings, sympathetic ganglia, neuromuscular
      endplates and certain CNS regions. Atropine is the mainstay of treatment of
      effects mediated by muscarine sensitive receptors; however, atropine is
      ineffective at the nicotine sensitive synapses. At both receptor types,
      reactivation of inhibited AChE may improve the clinical picture. The value of
      oximes, however, is still a matter of controversy. Enthusiastic reports of
      outstanding antidotal effectiveness, substantiated by laboratory findings of
      reactivated AChE and improved neuromuscular transmission, contrast with many
      reports of disappointing results. In vitro studies with human erythrocyte AChE,
      which is derived from the same single gene as synaptic AChE, revealed marked
      differences in the potency and efficacy of pralidoxime, obidoxime, HI 6 and HLo
      7, the latter two oximes being considered particularly effective in nerve agent
      poisoning. Moreover, remarkable species differences in the susceptibility to
      oximes were revealed, requiring caution when animal data are extrapolated to
      humans. These studies impressively demonstrated that any generalisation regarding
      an effective oxime concentration is inappropriate. Hence, the 4 mg/L concept
      should be dismissed. To antagonise the toxic effects of the most frequently used
      OPs, pralidoxime plasma concentrations of around 80 mumol/L (13.8 mg/L
      pralidoxime chloride) should be attained while obidoxime plasma concentrations of
      10 mumol/L (3.6 mg/L obidoxime chloride) may be sufficient. These concentrations
      should be maintained as long as circulating poison is expected to be present,
      which may require oxime therapy for up to 10 days. Various dosage regimens exist
      to reach this goal. The most appropriate consists of a bolus short infusion
      followed by a maintenance dosage. For pralidoxime chloride, a 1 g bolus over 30
      minutes followed by an infusion of 0.5 g/h appears appropriate to maintain the
      target concentrtion of about 13 mg/L (70 kg person). For obidoxime chloride, the
      appropriate dosage is a 0.25 g bolus followed by an infusion of 0.75 g/24 h.
      These concentrations are well tolerated and keep a good portion of AChE in the
      active state, thereby retarding the AChE aging rate. AChE aging is particularly
      rapid with dimethyl phosphoryl compounds and may thwart the effective
      reactivation by oximes, particularly in suicidal poisoning with excessive doses.
      In contrast, patients with diethyl OP poisoning may particularly benefit from
      oxime therapy, even if no improvement is seen during the first days when the
      poison load is high. The low propensity to aging with diethyl OP poisoning may
      allow reactivation after several days, when the poison concentration drops.
      Rigorous testing of the benefits of oximes is only possible in randomised
      controlled trials with clear stratification according to the class of pesticides
      involved, time elapsed between exposure and treatment and severity of cholinergic
      symptoms on admission.

PMID- 15181666
TI  - Pharmaceutical drug overdose case reports. From the World Literature.
AB  - All pharmaceutical drugs have the potential to be misused or wrongly
      administered, which can result in toxic amounts of drug being ingested. To help
      you keep up-to-date with the latest data on outcomes and management of overdoses,
      both accidental and intentional, we have selected the following case reports
      recently published in the international medical literature and summarised in
      Reactions Weekly. Any claim of first report has been verified by a search of the
      Adisbase (a proprietary database of Adis International) and Medline. In addition,
      the World Health Organization (WHO) Adverse Drug Reaction database is also
      searched. This database, maintained by the Uppsala Monitoring Centre in Sweden,
      is the largest and most comprehensive adverse drug reaction source in the world,
      with information obtained from the National Centres of over 70 affiliate
      countries.

PMID- 15181667
TI  - Individualism and the ethics of research on humans.

PMID- 15181668
TI  - From informed consent to substituted judgment: decision-making at the end-of
      life.

PMID- 15181669
TI  - Social restrictions on informed consent: research ethics and medical decision
      making.

PMID- 15181670
TI  - Consent to HIV testing and consequentialism in health care ethics.

PMID- 15181671
TI  - The promise of empirical research in the study of informed consent theory and
      practice.

PMID- 15181672
TI  - Reconstructing healthcare in a global marketplace.

PMID- 15181673
TI  - Globalization impacts the healthcare organization of the 21st century. Demanding
      new ways to market product lines successfully.
AB  - Healthcare is, and will continue to be, impacted by unrelenting forces
      transforming the healthcare system. The Internet (computers and
      telecommunication) makes it possible for patients to communicate globally on
      healthcare issues, and they are more educated about wellness, disease prevention,
      and medical treatments. This age of information also offers telehealth, which
      continues to alter the doctor-patient relationship, as well as disease
      management. The world as we know it changes daily. From the drastically changing
      demographic composition of the social order to rapidly emerging new technologies,
      the world of healthcare today is more expansive--an important dimension that
      nurse executives must recognize in order to lead their organizations in a new
      global marketplace. When historians chronicle the events that impacted the 21st
      century, they are certain to highlight the world's increasing consciousness of
      its interdependence. Abundant evidence will be found in literature that speaks to
      "globalization" when describing cultural, economic, environmental, and political
      issues. This unprecedented interconnectedness of healthcare across the globe will
      include nurse executive leadership talents.

PMID- 15181674
TI  - New technology continues to invade healthcare. What are the strategic
      implications/outcomes?
AB  - Healthcare technology continues to advance and be implemented in healthcare
      organizations. Nurse executives must strategically evaluate the effectiveness of
      each proposed system or device using a strategic planning process. Clinical
      information systems, computer-chip-based clinical monitoring devices, advanced
      Web-based applications with remote, wireless communication devices, clinical
      decision support software--all compete for capital and registered nurse salary
      dollars. The concept of clinical transformation is developed with new models of
      care delivery being supported by technology rather than driving care delivery.
      Senior nursing leadership's role in clinical transformation and healthcare
      technology implementation is developed. Proposed standards, expert group action,
      business and consumer groups, and legislation are reviewed as strategic drivers
      in the development of an electronic health record and healthcare technology. A
      matrix of advancing technology and strategic decision-making parameters are
      outlined.

PMID- 15181675
TI  - Consumer trust in healthcare organizations is waning. How will 21st century
      leaders bridge the gap?
AB  - Consumer trust in healthcare is crucial to the health and healing of individuals.
      This article explores the current status of consumer trust in healthcare and
      proposes several approaches to regaining trust that has been lost.

PMID- 15181676
TI  - An aging population with chronic disease compels new delivery systems focused on
      new structures and practices.
AB  - Patients now, more than ever, need reassurance that they are indeed the focus of
      the healthcare team. Patients enter the healthcare system knowing that there are
      worldwide shortages of key personnel, that physicians can no longer afford
      malpractice coverage and are many times practicing "defensive medicine," and that
      there are reported issues in terms of patient safety that may affect their own
      care within a hospital setting. With inpatient care becoming increasingly focused
      on "curing" via application of new and advanced technologies, patients are
      beginning to ask the question "Does anyone care?" To answer that question,
      Baptist Hospital of Miami, part of Baptist Health South Florida, committed to the
      hospital-wide implementation of a new model of practice. In this model, a patient
      care facilitator (PCF) becomes the primary point person for the patient during
      their stay. Each PCF leads a "Twelve Bed Hospital," a smaller segment of the
      patient care center where staff work with the PCF to make the whole inpatient
      experience more personalized. Initial results of the pilot implementation are
      promising. Research is underway to assess the overall effects of this practice
      model on continuity of care, patient safety, satisfaction, efficiency, and
      effectiveness of patient care.

PMID- 15181677
TI  - Globalization's costs to healthcare. How can we pay the bill?
AB  - As people become ever more globally mobile and electronic communication permeates
      ever more remote areas of the world, healthcare reaps both benefits and burdens.
      Instantaneous communication and worldwide collegial collaboration are
      contributing solutions to complex biologic and technologic healthcare challenges.
      Patients are able to access healthcare expertise in distant sites through
      telehealth modalities, as well as through direct contact. Affordable, accessible
      air transportation renders world society highly and rapidly mobile.
      Concomitantly, both new and previously remote diseases are spreading in epidemics
      and pandemics. Both the financial cost and the cost in human lives lost during
      the time required to uncover the etiology of a new disease and develop
      efficacious diagnostic and therapeutic modalities to control it can be
      astronomical. How can society pay the bills when economies around the world are
      struggling for stability? A new model for reimbursement of the financial burden
      incurred by epidemics or pandemics is proposed. In addition, nurse executives are
      encouraged to invest in preparedness, rather than risk the financial and human
      cost of being unprepared.

PMID- 15181678
TI  - Culture diversity/a mobile workforce command creative leadership, new
      partnerships, and innovative approaches to integration.
AB  - Today's healthcare environment requires that nursing leaders meet the needs of a
      growing multicultural workforce and patient population. Cultural factors may be
      overlooked as healthcare delivery becomes increasingly dominated by
      technological, economic, and social changes. Through creative leadership, the
      chief nurse executive (CNE) can encourage staff to pay closer attention to
      cultural factors that will impact on patient, staff, and hospital outcomes. The
      CNE can begin by enhancing his/her own multicultural competency, building these
      competencies in his/her staff, and then empowering staff to respect and
      accommodate cultural differences. An understanding to transcultural nursing
      theory can enhance the development and maintenance of a multicultural
      perspective. The use of Madeline Leininger's Culture Care modalities can assist
      staff in making culturally competent decisions and in implementing actions. This
      article will provide an overview of one community hospital's experiences in
      integrating a multicultural perspective to better meet the needs of specific
      patient populations.

PMID- 15181679
TI  - Global licensure. New modalities of treatment and care require the development of
      new structures and systems to access care.
AB  - As healthcare continues to be impacted by unrelenting external forces that are
      transforming the healthcare system and the practice of nursing, attention must be
      paid to the impact of electronic technologies in shaping professional practice,
      regulation, the national interstate practice model, and the global marketplace.
      Emerging innovations in practice and education will challenge existing laws and
      regulations. Maintaining open communication among major stakeholders and working
      collaboratively to shape a preferred future will enhance practice and meet
      consumer expectations. An analysis of the challenges to the scope of practice in
      the global marketplace is explored. Medicine of the future will not be based on
      blood and guts, but on bits and bytes (Pfizer J. 2001;5(2):20-25).

PMID- 15181680
TI  - Role of research in reconstructing global healthcare for the 21st century.
AB  - Nursing as the largest healthcare discipline is central within every healthcare
      system worldwide. This centrality provides the unique opportunity and the express
      responsibility for the creation of new knowledge through research in
      reconstructing global healthcare in the 21st century. International nursing
      research requires collaboration among culturally diverse team members and data
      collection with multilingual participants. The critical role of ethical research
      is exemplified by the diverse cultural norms. Language translation of not only
      the words but also their meanings is paramount to the relevant application of the
      study results. Institutions and schools of nursing in developed countries must
      acknowledge and act on the opportunities available and necessary for global
      collaboration afforded through the technological resources of the 21st century.
      Clinical nursing scholars who are the expert care providers must be involved in
      the conduct and application of research if any reconstruction of global
      healthcare is to succeed.

PMID- 15181681
TI  - Global informing. Impact and implications of technology in a global marketplace.
AB  - Although information technology is the foundation of global healthcare, its
      ultimate success as an enabler rests on balancing its potential against the
      problems it can create. This article examines the impact and implications of
      technology in a global marketplace, detailing key organizational, cultural, and
      clinical issues.

PMID- 15181683
TI  - Physician pay remains flat, but bonuses rise.

PMID- 15181682
TI  - Bush vs. Kerry: upcoming election offers real debate on health care.

PMID- 15181684
TI  - Will pay for performance programs introduce a new set of problems?

PMID- 15181685
TI  - 'All together now...'. Care coordination strikes right chord.

PMID- 15181686
TI  - Pharmacist care. An idea whose time is still coming.

PMID- 15181687
TI  - 'Random gifts of information' should never be ignored.

PMID- 15181688
TI  - Will providers seek new contracts as consumer-directed plans grow?

PMID- 15181689
TI  - Advances in migraine management: implications for managed care organizations.
AB  - Migraine headache is a disabling disease that poses a significant societal
      burden. Stratified care and early intervention are current strategies for
      migraine management. It has been shown that early treatment with triptans in
      select patients can improve treatment outcomes. Triptans are selective 5-HT
      receptor agonists that are specific and effective treatments in the management of
      migraine, and they meet the acute treatment goal of rapid relief with minimal
      side effects. Triptans are associated with improved quality of life. Factors such
      as speed of onset, need for a second triptan dose, and patient satisfaction
      should be considered in the selection of a specific triptan treatment.
      Appropriate treatment can decrease costs. The patient's migraine history and
      response to prior therapy should be considered when selecting acute treatment.
      Cost-effectiveness models can be used to understand the effect of treatment
      choices on health care budgets. The direct cost per migraine episode, driven
      primarily by the need for rescue medications, is important to include in economic
      models. All aspects of effectiveness (efficacy, tolerability, and cost) should be
      considered to reduce overall managed care expenditures for migraine treatment.
      The improved clinical profiles of the triptans provide substantial value to
      managed care organizations.

PMID- 15181690
TI  - Depression programs might provide an edge.

PMID- 15181691
TI  - New agents regulating tyrosine kinase can be used against several cancers.

PMID- 15181692
TI  - Health care security trumps federal tax cuts.

PMID- 15181693
TI  - Obesity epidemic creates demand for online solutions.

PMID- 15181694
TI  - Groundbreaking study links physical activity with lower costs.
AB  - There is finally evidence to suggest that increased physical activity can slash
      health care costs almost immediately. Further, experts speculate that even a
      modest program aimed at encouraging exercise may be enough to make a big
      difference in health outcomes as well as the bottom line.

PMID- 15181695
TI  - Employers return to wellness to stem rising health care costs.
AB  - While many payers have yet to embrace the concept of DM, there are also those on
      the other end of the spectrum ready to try interventions aimed at preventing or
      at least delaying the development of chronic disease. And vendors are emerging to
      answer this demand. Consider the solution offered by one Phoenix-based
      organization that has been specifically designed for implementation at the
      workplace.

PMID- 15181696
TI  - A new opportunity for savings: identifying patients with low-risk CHF.
AB  - CHF is one of the most common reasons for admission to the hospital, yet there is
      evidence that many of these patients do not need hospital-level care. Now there
      is a new tool to help clinicians determine which patients can safely be treated
      at home. And investigators suggest the potential savings are huge.

PMID- 15181697
TI  - Celebrate Florence Nightingale and nursing.

PMID- 15181698
TI  - Grassroots efforts do change policy.

PMID- 15181699
TI  - The holistic heart--a pathway to healing.

PMID- 15181700
TI  - Holistic nurses lead the way at Three Rivers Community Hospital.

PMID- 15181701
TI  - Compressive strength of glass ionomer cements with dental antibacterial agents.
AB  - Glass ionomer cements have been suggested for obturating carious teeth that have
      been prepared with dental hand instruments. In such cases, carious dentine may be
      inadvertently or deliberately left in situ. The residual bacteria may, over time,
      lead to secondary caries and restoration failure. Benefit may be gained from
      combining antibacterial agents with the glass ionomer cement to control residual
      bacteria. The aim of this study was to investigate the effects on the compressive
      strength of glass ionomer cement combined with oral antibacterial agents.
      Cationic antibacterial agents; chlorhexidine hydrochloride, cetylpyridinium
      chloride and cetrimide were added to the powder and benzalkonium chloride, a
      liquid, to the liquid of Fuji IX glass ionomer cement. These were prepared to
      concentrations of 1, 2 and 4 per cent by weight of the glass ionomer cement and
      compared to Fuji IX with no antibacterial agent. Test specimens were subjected to
      a compressive force to failure. Multiple analysis of variance showed highly
      significant reductions in compressive strength (p < 0.01) between the test
      materials and control group apart from one per cent benzalkonium chloride.
      Increasing concentration of the antibacterial agent had increasing adverse
      effects on the physical properties. The addition of the antibacterial agents
      tested to Fuji IX reduces the seven-day compressive strength which may affect the
      clinical performance of the material.

PMID- 15181702
TI  - Penetrating stab wound injuries to the face.
AB  - Penetrating knife blade injuries to the maxillofacial region are quite rare, with
      retained knife blades even rarer. Associated vascular, ocular, ductal,
      neurosurgical injuries should be identified and treated accordingly. Appropriate
      special investigations included plain radiographs and angiograms, which were used
      in establishing the proximity of the foreign object to the arterial supply to the
      head and neck. The impacted blade should be removed in theatre. Ten patients with
      this injury are discussed.

PMID- 15181703
TI  - From didactic teaching to participatory learning. An innovative approach.
AB  - A course in Public Oral Health is currently offered by the Division of Public
      Oral Health (POH) to students in their final (6th year) of study for the degree
      of Bachelor of Dental Science. A fundamental aspect of this project was to shift
      the teaching methods from didactic to a participatory, student-centred approach,
      based on current local and international trends in medical, dental and general
      education. In 1999 the course covering core Public Health topics was presented
      over a period of 20 weeks to 49 students who were divided into three groups.
      Staff members were trained in participatory, student-centred teaching methods. An
      evaluation of students and staff was conducted at the end of the course. Results
      show that students were satisfied with the teaching methods employed and
      commended the Division on the organisation of the course. Students were unhappy
      with the amount of reading required in preparation for weekly seminars. They felt
      that the course was inappropriately positioned in their final year of study, due
      to pressure of achieving quotas for the clinical courses. Nevertheless, the main
      objectives of the Public Oral Health course were achieved through the adoption of
      a participatory, student-centred teaching approach.

PMID- 15181704
TI  - Salivary glands: applied anatomy and clinical correlates.
AB  - The major salivary glands include the paired parotid, submandibular and
      sublingual glands. Salivary glands act as accessory digestive glands and produce
      a secretion referred to as saliva. Saliva has lubricating, cleansing, digestive
      and antimicrobial properties. The parotid is the largest salivary gland and
      saliva is secreted into the mouth via the parotid duct (Stensen's duct). The
      submandibular gland lies inferior to the body of the mandible and is susceptible
      to sialolithiases. Drainage is via the duct of the submandibular gland (Wharton's
      duct) into the floor of the mouth on either side of the lingual frenulum. The
      sublingual glands are situated under the mucosa in the floor of the mouth, on the
      sides of the tongue. These glands are in relationship to important nerves in the
      surrounding tissue. Disease processes such as chronic intraparenchymal
      sialolithiasis and neoplastic changes frequently mandate surgical removal of the
      underlying salivary gland. Detailed, applied knowledge of anatomy on a regional
      basis is required to avoid inadvertent nerve damage during surgery and resulting
      litigation.

PMID- 15181705
TI  - General practitioner's radiology case 19.

PMID- 15181706
TI  - Abdominal gunshot wounds--current status of selective non-operative management.

PMID- 15181707
TI  - Substance abuse and major trauma in Johannesburg.
AB  - INTRODUCTION: The abuse of alcohol and drugs is a major public health problem and
      intoxication is one of the most important risk factors for violence and other
      causes of injury. The aim of the current study was to evaluate the prevalence of
      drug and alcohol use associated with injury in adult trauma patients in an inner
      city trauma unit in Johannesburg. METHODS: A cohort of 105 adult trauma patients
      admitted to our university trauma unit and its allied medicolegal laboratory were
      studied in order to provide prospective data and enable us to correlate the
      prevalence and type of substance abuse with the demographics and injury patterns
      after major trauma. RESULTS: Forty-five patients required resuscitation at the
      Johannesburg Hospital Trauma Unit (JHTU) and 60 patients were examined at the
      Johannesburg Medicolegal Laboratory (JMLL), giving a total of 105 patients. Blood
      alcohol concentration (BAC) was positive in 59% of the patients. The average BAC
      in the trauma unit patients was 37 mmol/l (0.17 g/dl), more than three times the
      legal limit for driving. Of the patients 43.7% were positive for urinary
      cannabis; women were statistically significantly more likely to have taken
      cannabis than men (p = 0.039). There was no difference in rates of exposure to
      cannabis or alcohol in patients who were the victims of interpersonal violence
      compared with the victims of accidents (p = 0.17). Only 3 patients had taken
      other drugs of abuse; 2 had taken Mandrax (methaqualone) and 1 amphetamine.
      CONCLUSION: Alcohol and cannabis are commonly misused by trauma patients in
      Johannesburg; the degree of misuse of other drugs appears to be low. Intoxication
      is a significant risk factor for violence and accidents and the resultant
      injuries are a massive burden on our society. Doctors have a responsibility to
      highlight the association between substance misuse and trauma and should also
      attempt to persuade individual trauma patients to reduce future alcohol
      consumption.

PMID- 15181708
TI  - Penetrating abdominal trauma.
AB  - Penetrating abdominal trauma (PAT) is seen daily in our trauma ward. We present a
      retrospective study of the patients managed in our hospital (Polokwane Hospital,
      Limpopo) from January 1999 to March 2000. Epidemiology, mechanism of injury,
      patterns of injury, management, morbidity and overall mortality were recorded for
      analysis. Morbidity and mortality were commonly associated with peritonitis and
      multiple organ dysfunction syndrome.

PMID- 15181709
TI  - Use and care of an endotracheal/tracheostomy tube cuff--are intensive care unit
      staff adequately informed?
AB  - BACKGROUND: There is an apparent high incidence of tracheal stenosis in the
      Bloemfontein area. The aim of this study was to determine intensive care unit
      (ICU) staff knowledge of the use and care of endotracheal and tracheostomy tube
      cuffs. METHODS: One hundred and twelve qualified nurses, working in 11 different
      ICUs, were asked to complete an anonymous questionnaire regarding
      endotracheal/tracheostomy tube cuffs. RESULTS: The results highlight the
      following three areas of concern: (i) there was an overall misconception in 38%
      of the respondents that the function of the cuff was to secure the tube in
      position in the trachea to prevent self-extubation; (ii) accurate regulation of
      cuff pressure was not routine practice in any of the ICUs; and (iii) only half of
      the respondents felt their training regarding cuff care management was
      sufficient. CONCLUSIONS: ICU staff had misconceptions regarding the function and
      care of endotracheal/tracheostomy tube cuffs. The concept of a higher cuff
      pressure for better stabilisation of the tube is probably an important factor
      that could have caused the increase in tracheal stenosis in the Bloemfontein
      area. Critical care nursing needs to emphasise the use of current techniques,
      discourage routine cuff deflation, and encourage collaboration with ICU
      physicians on standards of care. A protocol that could be used in the ICUs
      regarding the use and care of an endotracheal/tracheostomy tube cuff is proposed.

PMID- 15181710
TI  - Disseminated nocardiosis masquerading as abdominal tuberculosis.
AB  - A 32-year-old patient was admitted with a community-acquired pneumonia. She had
      clinical evidence of AIDS and chest X-ray features consistent with pulmonary
      tuberculosis. While in the ward she developed an acute abdomen necessitating
      laparotomy, at which a diagnosis of abdominal tuberculosis was made. Sputum and
      intraoperative pus specimens grew a multiresistant Nocardia brasiliensis.
      Microbiological investigations for tuberculosis were negative. The patient died
      after a short ICU admission from multiple organ dysfunction syndrome.

PMID- 15181711
TI  - [Oral surgery in general dental practice 2. Preface].
AB  - In two issues of the journal, some surgical treatments which can be delivered by
      a dentist with special skills on this topic, are discussed. This second issue
      concentrates on interventions occurring less frequently or not treated by every
      dentist in general practice. It concerns dental traumas, eruption disorders,
      removal of a hypertrophied frenulum of the upper lip and reconstructive
      preprosthetic surgery. Finally, some complications of dentoalveolar surgery are
      discussed.

PMID- 15181712
TI  - [Dentoalveolar traumatology].
AB  - The dentist will be confronted unexpectedly with a dentoalveolar trauma patient.
      This patient has to be seen immediately and has to be treated adequately. The
      risk of overlooking trauma-related signs when examining these patients, can be
      minimized by following a strict protocol. This article describes a protocol for
      examination and treatment of a patient with a dentoalveolar trauma. The prognosis
      after treatment of the trauma is discussed. Also some recommendations regarding
      aftercare and prevention are presented.

PMID- 15181713
TI  - [Eruption disturbances].
AB  - Eruption disturbances of teeth should not be considered as a curiosity.
      Acquaintance with these phenomena should form a substantial component of the
      dentist's, orthodontist's and oral and maxillofacial surgeon's basic expertise.
      Early detection of these disturbances followed by treatment in due time, can
      minimise progressive negative effects, such as the development of severe
      malocclusion. Treatment modalities are described.

PMID- 15181714
TI  - [A too short superior labial frenum].
AB  - A too short superior labial frenum is quite normal in babies and little children.
      Usually, the strong frenum disappears at twelve years of age. Before considering
      surgical intervention beyond this age, one should exclude the presence of a tooth
      size or arch length discrepancy, a mesiodens or a severe dysgnathia. In this
      article the consequences of a too short superior labial frenum and its treatment
      are discussed.

PMID- 15181715
TI  - [Reconstructive preprosthetic surgery 1. Corrections of soft tissues and bone].
AB  - The aim of reconstructive preprosthetic surgery is the creation of an environment
      of hard and soft tissue which is favourable to the function of an aesthetically
      optimal prosthesis, with or without oral implants. In this paper, various
      preprosthetic surgical treatments for correcting soft and hard tissues are
      discussed.

PMID- 15181716
TI  - [Reconstructive preprosthetic surgery 2. Pre-implantologic surgery].
AB  - Reconstructive preprosthetic surgery is, amongst others, aimed at the creation of
      an environment which is favourable to the construction of an implant supported
      prosthesis. Not in all cases the pre-existent volume of bone is sufficient to
      place an implant in the planned position. In this paper various techniques to
      augment local bone defects for reliable implant placement are described.

PMID- 15181717
TI  - [Complications during and after dentoalveolar surgery].
AB  - In dentistry complications are undesirable adventures provoked by oral health
      care delivery. If there is any risk of a complication, the patient needs to be
      informed before treatment. Occurrence of complications can be minimized by
      adequate diagnostics and planning sufficient time for treatment. The most common
      complications during and after dentoalveolar surgery are discussed, such as
      complications during or after producing local anaesthesia, nerve injuries,
      complications during or after tooth extraction, aspiration, jaw luxation,
      disturbed wound healing, and complications during or after implantation
      procedures.

PMID- 15181718
TI  - [New boundaries].

PMID- 15181719
TI  - [A moment for oral microbes].

PMID- 15181720
TI  - [Life threatening hyperkalemia: the value of the electrocardiogram].
AB  - In two men, aged 19 and 64, with chronic renal insufficiency and subacute
      symptoms of malaise and weakness of the leg muscles, broad QRS complexes were
      seen in the ECG. The younger patient developed an asystole and resuscitation was
      unsuccessful. His blood potassium level was found to be 8.3 mmol/l. The older
      patient recovered after administration of calcium gluconate. His blood potassium
      level was found to be 8.5 mmol/l. An 80-year-old woman who was taking various
      drugs because of heart failure also complained of muscle weakness. Her blood
      potassium level was 7.2 mmol/l and her ECG showed narrow complexes. She recovered
      without calcium gluconate after a change in medication. Hyperkalemia is a
      potentially life-threatening electrolyte disorder that may require immediate
      treatment. The changes in the ECG, especially widening of the QRS complexes, are
      the most important clues to the severity of the hyperkalemia. A treatment
      protocol based on ECG changes may reduce the mortality in these patients.

PMID- 15181721
TI  - [Sepsis, a complicated syndrome with major medical and social consequences].
AB  - Severe sepsis is a life-threatening complication of infection. Due to associated
      organ-failure treatment in an Intensive Care Unit is usually indicated. Since
      sepsis is defined by the combination and progression of clinical events, correct
      definitions are essential to enable good comparison between study results and
      determination of suitable treatment. Severe sepsis is associated with a mortality
      of 20-60% and decreases the health-related quality of life in survivors. It is
      estimated that annually in the Netherlands 9000 patients are admitted to an
      Intensive Care Unit with severe sepsis. Direct medical costs of severe sepsis are
      estimated at [symbol: see text] 19,500 per patient. Costs correlate strongly with
      the length of stay. Annually Euro dollar 168,6 million is spent on severe sepsis,
      which represents 0.5% of all health-care costs and 1.7% of the annual hospital
      budget in the Netherlands.

PMID- 15181722
TI  - [Causes and consequences of cognitive decline in the very elderly; the 'Leiden 85
      plus Study'].
AB  - In view of the absolute and relative increase in the number of oldest old, it is
      important to identify the causes and consequences of disease in this group. One
      of the areas of focus in the 'Leiden 85-plus Study', a population-based
      prospective study amongst 85-year-olds in the Dutch town of Leiden, is therefore
      to study the causes and consequences of cognitive decline in the very elderly.
      Cognitive impairment is the main threat to independence in the oldest old; 85
      year-old people with impaired cognitive function (prevalence: 35%) have a ten
      times greater risk of being limited in their activities of daily life. If this
      cognitive impairment could be prevented, a large proportion of the independence
      limitations in the general population could be prevented (population attributable
      risk: 70%). Limitations in cognitive functioning are strongly associated with the
      incidence of cardiovascular disease, as well as with a lower average HDL
      cholesterol concentration and signs of inflammation. Vascular factors appear to
      be closely related to development of cognitive impairment in very elderly.
      Therefore, future therapeutic research will have to demonstrate to what extent
      influencing the cardiovascular risk factors can lead to the prevention of
      cognitive decline in the very elderly.

PMID- 15181723
TI  - [Diagnostic image (189). A man with a tongue disorder. Black hairy tongue].
AB  - In a 59-year-old man with a swallowing problem and loss of weight, who used
      fluoxetine because of depression, gastroscopy revealed a black hairy structure on
      the dorsum of the tongue, known as black hairy tongue.

PMID- 15181724
TI  - [Sensitivity and speed of cell and tissue pre-diagnosis among breast cancer
      patients undergoing primary surgical treatment in two hospitals, determined with
      the aid of PALGA data].
AB  - OBJECTIVE: Result and process testing of cell and tissue diagnostics, including
      the sentinel-gland procedure, executed on patients who underwent a primary
      surgical intervention for mammary carcinoma. DESIGN: Retrospective. METHOD: In a
      group of 191 women who underwent 192 primary surgical interventions for breast
      cancer in 2002, data from the Pathological-Anatomical National Computerised
      Archive (PALGA) were examined with regard to which form of cell or tissue
      diagnosis was used and in how many stages the cancer diagnosis was
      morphologically established with sufficient certainty. RESULTS: In three-quarters
      of the women the diagnosis 'cancer' was established with certainty in the first
      stage. When the initial diagnosis was made using fine-needle cytological
      puncture, 35 of the 81 women had to undergo a second diagnostic test; with
      histological tests using needle biopsies this was 10 out of 92. The false
      negative chance of fine-needle cytological tests was 13% (95% CI: 8-22) and for
      tests involving large-core needle biopsies 14% (95% CI: 8-23). A delay in
      treatment of more than 4 months occurred in 6 women due to the cancer being
      missed. A sentinel-gland procedure was performed on 58% of the women. In 33 women
      who underwent pre-operative ultrasound with fine-needle cytological testing of
      the axillary glands, the sensitivity for axillary gland metastases was 74% (95%
      CI: 53-87). CONCLUSION: Looked at in terms of the practical guideline for
      diagnosis of breast cancer the cell and tissue diagnoses were adequate, but the
      standards prescribed in that guideline for the chances of a false-negative (5%)
      were exceeded.

PMID- 15181725
TI  - [Angiosarcoma following breast-conserving therapy].
AB  - Two women with breast cancer, 59 and 72 years of age, were treated by means of
      breast-conserving surgery and radiotherapy. At the age of 66 and 77,
      respectively, discolouration of the skin was seen in the treated breast. Punch
      biopsy did not show secondary malignancy. Diagnostic (deeper) excisional biopsy
      revealed angiosarcoma. Ablation of the breast was performed in both patients. The
      younger woman, however, had a recurrence four months later that was treated with
      wide local excision and omentum-plasty. The older woman died two years after the
      ablation as a result of haematogenous metastases. Knowledge of the symptoms and
      diagnostic pitfalls of radiotherapy-induced angiosarcoma after breast-conserving
      treatment is important in the follow-up of breast-cancer patients. Histological
      diagnosis of a biopsy taken at sufficient depth is indicated when a secondary
      angiosarcoma is suspected.

PMID- 15181726
TI  - [Megacolon during treatment with lactulose].
AB  - Two female patients aged 88 and 82 who were being treated for constipation with
      lactulose, developed life-threatening dilatation of the bowel. Both underwent
      surgery. One of them was found to have cancer of the bowel; she had an uneventful
      postoperative recovery. No mechanical abnormalities were found in the second
      patient but she died due to respiratory insufficiency following aspiration.
      Lactulose is one of the most frequently prescribed laxatives. In the colon it is
      metabolized by bacteria into short-chain fatty acids, hydrogen and carbon
      dioxide. The resulting production of gas in the colon can contribute to a non
      toxic megacolon, particularly in patients with delayed intestinal passage.

PMID- 15181727
TI  - [Beta-blocking drugs indicated in patients with heart failure].

PMID- 15181728
TI  - [The practice guideline 'Hypertension' (third revision) from the Dutch College of
      General Practitioners; a response from the perspective of internal medicine].

PMID- 15181729
TI  - [Breast cancer and the use of the hormones around the menopause].

PMID- 15181730
TI  - [The measures proposed by the Dutch Healthcare Inspectorate after the death of
      Sylvia Millecam and her treatment by practitioners of alternative medicine].

PMID- 15181731
TI  - [Routine funduscopic examination in hypertensive patients not useful].

PMID- 15181732
TI  - [Bizarre advertisements by hospitals in the Dutch Journal of Medicine].

PMID- 15181733
TI  - [Viral co-infections in hepatitis C: HBV, HBV-C/HGV and TTV studies].
AB  - BACKGROUND/AIMS: The prevalence of co-infections with hepatitis B virus (HBV) and
      novel hepatitis viruses GBV-C (Hepatitis G virus, HGV) and TT virus (TTV) in
      chronic hepatitis C (HCV) infection has been studied. In patients with chronic
      hepatitis C and in asymptomatic healthy HCV carriers, the influence of these
      agents on the course of HCV infection was assessed. METHODS: a total of 110 HCV
      positive individuals, among them 77 patients with chronic hepatitis C--50 of them
      treated with interferon (IFN)--and 33 HCV carriers with normal alanine
      aminotransferase have been investigated. HBV-DNA, HGV RNA and TTV DNA were
      detected by PCR, to determine HBsAg and anti-HBc ELISA technic has been used.
      RESULTS: In the healthy population, the prevalence of anti-HCV was 0.3%, HBsAg
      0.09%, anti-HBc 2.5%, HGV RNA 8.0% and TTV DNA 18.5%, respectively. In chronic
      hepatitis C HBsAg (accompanied with HBV-DNA) occurred in 1.29%, anti-HBc 25.97%,
      HGV RNA in 9.09% and TTV DNA in 40.25% of cases. In IFN-treated patients with
      sustained remission, the frequency of TTV was 20% vs. 45.7% found in non
      responders. Among asymptomatic HCV-carriers, the prevalence of anti-HBc was
      27.27%, HGV RNA 9.09% and TTV DNA 75.7% respectively. CONCLUSIONS: Neither
      previous HBV infection, nor HGV RNA and TTV DNA had apparent effect on the course
      of chronic HCV infection. TTV was detected with the lowest frequency in persons
      with sustained remission due to IFN, suggesting antiviral effect of IFN on TTV.

PMID- 15181734
TI  - [Use of DNA-chips technology in colorectal cancer].
AB  - The examination of gene expression in colorectal cancer may develop the bases of
      early diagnosis and of individual therapeutic strategies. With the few cDNA
      microarray examinations in colorectal cancer the expression of hundreds and
      thousands of genes were studied, although both the sample collection and the
      final results showed differences. Beside the exposition of the practical
      advantages of the chip technology our aims are the standardization of the
      currently available data in the international scientific literature and the
      description of the results in a comprehensible way. To summarize one can say that
      gene expression examinations in colorectal cancer show the accentuated role in
      carcinogenesis of not only the tumor suppressor, apoptosis- or cell-cycle
      regulation related genes, but of some mitochondrial, metabolic and cell-cell or
      cell-extracellular matrix conjunction gene families.

PMID- 15181735
TI  - [Treatment of atrial fibrillation in a Hungarian hospital department of
      cardiologic internal medicine at the turn of the millennium].
AB  - INTRODUCTION: The atrial fibrillation is a severe and frequent disease, which
      influences greatly the patients' quality of life. Only a few Hungarian studies
      exist which discuss the physicians' own experiences in its treatment. AIM: The
      description of the experiences acquired in an internal medicine department with
      cardiological profile during the treatment based on the actual guidelines and the
      review of the results of one year follow-up. METHOD: Retrospective analysis of
      the data of patients treated with atrial fibrillation between 1 january 1999 and
      31 december 2001 and a one year follow-up was performed. The age, gender, success
      in cardioversion, the antiarrhythmic therapy at the discharge and the
      modification in it during the first year were evaluated. RESULTS: During the 3
      years long period 1115 patients with atrial fibrillation were admitted (53.9%
      female, 46.1% male, the mean age was 72.0 +/- 10.4 years), 391 of whom were
      discharged with sinus rhythm. In 193 cases (49%) a spontaneous cardioversion was
      observed. 120 electrical (31%) and 78 pharmacological (20%) cardioversions were
      performed. The electrical form was carried out in 42 cases with acute atrial
      fibrillation (in 36 of them successfully) and in 100 cases as an elective
      procedure, in 84 successfully. Pharmacological cardioversion was made in 39 acute
      cases with the administration of propafenone (in 29 ones successfully) and in 57
      elective cases with quinidine + beta-blocker + magnesium (in 49 ones
      successfully). For the maintenance of sinus rhythm in the 38.8% of cases
      amiodarone, 24.0% propafenone, 19.9% sotalol, 10.7% beta-blocker, 0.8% quinidine,
      0.5% prajmaline was administered, and 5.1% of the patients didn't receive any
      special treatment. During the one year follow-up from the 391 patients 261
      remained on sinus rhythm, in 81 cases (21%) the return of the atrial fibrillation
      was diagnosed (in 57 of them a successful cardioversion was performed again), 11
      patients (3%) died and 38 (9%) were lost for observation. At the time of the one
      year control 57.8% of patients treated with amiodarone, 61.7% of those treated
      with propafenone, 67.9% with sotalol and 35.7% with beta-blocker remained on
      sinus rhythm. The amiodarone was omitted in 17 cases because of its side effects.
      CONCLUSIONS: The treatment of the atrial fibrillation has to be performed
      individually taking into account the guidelines, the comorbidity, the time of the
      beginning of rhythm disorder, the patients' present other drugs and the former
      antiarrhythmic therapy. A continuous and consistent follow-up of these patients
      is crucial.

PMID- 15181736
TI  - [Cutaneous symptoms of zinc deficiency in adults].
AB  - Malabsorption is frequently accompanied by skin symptoms, which are the most
      likely first manifestation of the disease. Skin lesions are mainly due to the
      deficiency of zinc, different vitamins, minerals, essential aminoacids, and other
      nutrients. The present paper demonstrates 3 patients with different types of skin
      symptoms primarily related to zinc deficiency, which occur in gastrointestinal
      diseases and alcohol abuse (acrodermatitis enteropathica, eczema craquele,
      hyperpigmentation).

PMID- 15181737
TI  - [Treatment of cataracts].

PMID- 15181738
TI  - [Treatment of thyroiditis].

PMID- 15181739
TI  - [Position statement of the Hungarian Medical and Health Education Society
      regarding the the Bologna Proposal].

PMID- 15181740
TI  - [Urologic complications as a reason of recurrent urinary tract infections in
      patients after renal transplantation].
AB  - Urinary tract infections are the most frequent complications after renal
      transplantation. A retrospective study was conducted in patients treated after
      renal transplantation. We paid special attention to urinary tract infection
      connected with urologic complications and other urologic diseases.

PMID- 15181741
TI  - [Does beta-2 microglobulin measurement play role in diagnostics of childhood
      malignancies?].
AB  - beta 2-Microglobulin (beta 2-M) measurement acts as an important diagnostic tool
      of some lymphoproliferative disorders in adults. Its significance as a marker of
      disease activity in pediatric malignancies has not been evaluated yet. The aim of
      this study was to determine the clinical significance of the pre-treatment serum
      levels of beta 2-M in children suffering from neoplastic disease. The study was
      conducted in 61 children (28 girls and 33 boys) aged from 2.0 to 16.9 years at
      the time of disease diagnosis. The study group consisted of 6 common types of
      childhood malignancies: acute lymphoblastic leukemia (ALL--22 patients), acute
      nonlymphoblastic leukemia (ANLL--3), Hodgkin's disease (HD--12), non-Hodgkin's
      lymphomas (NHL--6) and malignant solid tumors: Wilms' tumor (Tu Wilms--10) and
      soft tissue sarcomas (SA--8). The control group consisted of 30 healthy children.
      Different behavior of beta 2-Microglobulin levels depending on histological type
      of the neoplasm was observed. The pre-treatment levels of analyzed marker in
      children with lymphoproliferative disorders (acute leukemias and lymphomas) were
      significantly elevated as compared to the levels in the healthy controls (median:
      2.90 vs. 2.05 mg/L, p < 0.001). On the contrary, in patients with malignant solid
      tumors (Wilms tumor and soft tissue sarcomas) the median levels of beta 2-M at
      diagnosis were within normal range. Elevated values of serum beta 2-M were stated
      in the majority (67%) of patients with lymphoproliferative disorders and in 39%
      of patients with malignant solid tumors. CONCLUSIONS: beta 2-Microglobulin may
      serve as an additional diagnostic marker in children with leukemias and
      lymphomas. Measurement of serum beta 2-M seems to have no clinical value in the
      diagnostics of pediatric malignant solid tumors.

PMID- 15181742
TI  - [Endoscopic dilatation of benign gastrointestinal anastomotic stenosis with
      hydraulic balloon].
AB  - Incidence of postoperative anastomotic stenosis range from 5 to 30 percent though
      most of them are not clinically relevant. Strictures of gastrointestinal tract
      (GI) within reach of the endoscope may be treated successfully with dilatation.
      The aim of the study was to evaluate the technique of endoscopic balloon
      dilatation in the treatment of GI anastomotic strictures. The procedure of
      endoscopic dilatation was performed in 17 patients with obstruction due to the
      postoperative stricture of anastomosis. In 11 patients stenoses were localized in
      the lower and in 6 patients in the upper digestive tract. In all cases the
      stricture was caused by scar tissue and had benign character (confirmed by
      computed tomography and biopsy). Endoscopic hydraulic balloon dilatation was
      performed using a pressure of 2 atm. All dilatations of the upper digestive tract
      strictures were successful with immediate relieve of symptoms. In 4 patients with
      high grade stenoses after low anterior resection of the rectum anastomotic
      strictures did not dilate after endoscopic treatment. No complications of
      endoscopic dilatations were observed. Endoscopic balloon dilatation is useful in
      the treatment of symptomatic gastrointestinal anastomotic stenosis, but good
      results are expected only in low grade strictures.

PMID- 15181743
TI  - Evaluation of antioxidant enzymes activity and concentration of non-enzymatic
      antioxidants in human brain tumours.
AB  - The purpose of our research was to assess the activity of GSH-Px, GSSG-R, SOD-1
      and concentration of GSH, Vit.C and reactive substances with thiobarbituric acid,
      in brain tumours with Ist, IInd, IIIrd and IVth levels of biological malignancy.
      The research was conducted in 105 samples obtained from patients undergoing
      surgery in the Department of Neurosurgery of the Medical University of Bialystok
      between the years 1996-2001. The obtained values of the above enzyme activities
      and the concentration of the examined substances in brain tumours were compared
      to the control values determined in 15 samples of histopathology unchanged nerve
      tissue. THE RESULTS: The increase in all enzymes activities in brain tumours is
      statistically significant (p < 0.05) as compared to the control level in normal
      nerve tissue alto a significant decrease (p < 0.05) of the GSH and ascorbate
      concentration and a significant increase (p < 0.05) in the level of
      thiobarbituric acid-reactive substances in the examined brain tumours was found
      in comparison to the concentration of the above substances in normal nerve
      tissue.

PMID- 15181744
TI  - [Assessment of apolipoprotein E genotype in Parkinson disease patients with and
      without dementia].
AB  - The aim of our study was evaluation of the relationship between apolipoprotein E
      (APO E) genotype and the clinical parameters in Parkinson's disease (PD) with and
      without dementia. 104 PD patients were evaluated and within this group two
      subgroups were formed: 51 PD patients (25 males, 26 females; mean age: 70.4 +/-
      6.03 years) with dementia and 53 (31 males, 22 females; mean age: 62.5 +/- 8.57
      years) without dementia. The estimation of APO E genotype was executed by means
      of Polymerase Chain Reaction. The Unified Parkinson's Disease Rating Scale was
      used to quantify the severity of PD. Cognitive functions were assessed according
      to the Mini Mental State Examination. APO E genotype and allele frequencies did
      not differ between demented and nondemented parkinsonian patients.

PMID- 15181745
TI  - [Surgical treatment of gastric mesenchymal tumors].
AB  - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of
      the gastrointestinal tract. From January 1998 to December 2000 in the Department
      od Digestive Tract Surgery 294 patients were operated on neoplasms of the
      stomach. In 12 patients (4%) gastric mesenchymal tumor was diagnosed (GMT) (9 W,
      3 M). Median age was 50 years (15-71). All patients with diagnosis of tumor in
      the abdominal cavity underwent operation. Median diameter of tumor was 6 cm (2
      28). We performed following operations: total gastric resection--1, partial
      gastric resection--2, wedge gastric resection--9. Postoperative complications
      occurred in 3 patients (25%). No hospital deaths were observed. In all cases
      diagnosis was established during or after operation based on histopathological
      examination of resected tumor. In 10 patients GIST was diagnosed and in 2-
      schwannoma. Follow-up has lasted for 12-48 months. At the present among 12
      patients 11 (92%) are alive without recurrence of the disease. In 1 patient
      recurrence occurred after 18 months postoperatively which caused his death.
      CONCLUSIONS: Gastric mesenchymal tumors are diagnosed mostly during or after
      operation based on histopathological examination of resected tumor. Extent of
      gastric resection does not influence results of treatment in benign neoplasms.

PMID- 15181746
TI  - [Leptin concentration in umbilical cord blood and maternal blood].
AB  - We investigated leptin concentration in umbilical cord blood of 51 newborns (mean
      5.71 +/- 3.28 ng/ml) and in maternal blood (mean 22.11 +/- 10.95 ng/ml). Leptin
      concentration in 20 preterm infants (mean 4.73 +/- 2.15 ng/ml) was significantly
      lower (p < 0.05) than in full-term newborns (mean 6.34 +/- 2.08 ng/ml) and tended
      to increase according to gestational age and birth weight. We suggested leptin
      concentration had a role in intrauterine development.

PMID- 15181747
TI  - [Malignant neoplasms of the small intestines].
AB  - The paper contains a retrospective study of 12 cases of malignant small bowel
      tumors observed and treated in the Department of Oncological Chemotherapy of
      Medical University of Silesia. The authors presented the most common symptoms,
      typical diagnostic procedures and the difficulties in the diagnostics of small
      bowel neoplasms.

PMID- 15181748
TI  - [Mandibular fractures--retrospective study].
AB  - Between the years 1988 and 1997 1222 patients with mandible fractures were
      treated in the Department of Dental and Maxillofacial Surgery at Medical
      University in Lublin. Majority of them were male patients aged 19-40. In most
      cases fractures were caused by assault (55%) and traffic accidents (29.9%)
      frequently related to earlier consumption of alcohol. Among 702 from 1222 treated
      patients mandible fractures were accompanied by other injuries and that is both
      of bones structure and also of soft tissues.

PMID- 15181749
TI  - [Evaluation of magnetostimulation effectiveness in physiotherapy--questionnaire
      research].
AB  - The anonymous questionnaires which had been filled in by patients were analysed
      after the end of the magnetostimulation applied with Viofor JPS. The applicator
      in form of a mattress with maximum induction 45 microT was used. In the analysed
      group of 1742 patients, 5% of patients suffered from rheumatoid arthritis, 16%
      from central nervous system illnesses, 9% from injuries, 1.5% from allergies, 2%
      from infections, 5.4% from vessel illnesses, 1% from skin illnesses. 0.5% of the
      patients used monotherapy. 8% suffered from radicular symptoms, 30.7% from
      pseudoradicular symptoms, 17.4% from arthrosis, and 3.4% patients suffered from
      migraines and headaches. The complete abatement of complaints or the improvement
      was noted in 95.5% of patients, no improvement in 4.3% and 0.2% of patients
      became worse--82% of deteriorated patients were the ones that suffered from
      infections. The strongest analgesic action and the most frequent abatement were
      noted in patients after injuries and patients with headaches.

PMID- 15181750
TI  - [Pathologic changes in the tongue as signs of systemic diseases].
AB  - The tongue is an organ easy for examination. Pathological changes of the tongue
      are of local or systemic origin and may accompany many systemic diseases or
      precede them. The paper shows shortly normal anatomy and function of the tongue
      and the most common pathological changes in the course of systemic diseases. Also
      we discussed the aspects of early diagnosis and oncological prophylaxis. The aim
      of the study was to concentrate on cooperation between different specialists to
      undertake both local and systemic treatment to provide better care of the
      patient. The paper was based on literature and our own observations.

PMID- 15181751
TI  - [Genetic aspect of Dupuytren's diseases].
AB  - Dupuytren's disease is a connective tissue disorder leading to the shortening of
      the palmar aponeurosis and progressive digital flexion deformity. Despite decades
      of both scientific and clinical investigations the precise etiology and tissue
      origin of Dupuytren's disease remains unclear. Several authors focused their
      studies on the genetics of Dupuytren's disease and postulated either autosomal
      dominant or autosomal recessive mode of inheritance. The limited number of
      members of families affected with the disease makes it difficult to determine the
      mode of inheritance. A particular difficulty is the late age of the onset of
      Dupuytren's disease, which in most cases limits examination to two generations.
      Age-related, dominant inheritance is a mode favored by several authors whereas
      others consider autosomal recessive inheritance as a possible explanation for
      sporadic cases of Dupuytren's disease. A gene that increases susceptibility to
      the disease may do so by rendering the tissue more sensitive to the effects of
      environmental exposures. This article summarizes current studies on various modes
      of inheritance in Dupuytren's disease.

PMID- 15181752
TI  - [The use of retinoids in dermatology].
AB  - Retinoids--new agents derived from vitamin A have initiated a new era in therapy
      of many skin diseases. They are highly effective medicines used in the treatment
      of severe forms of psoriasis. Also they are administered in many forms of acne,
      as alternative drugs do not exist. Moreover, retinoids show antineoplastic
      activity. They are also effective in the symptomatic treatment of the congenital
      keratinization disorder syndromes. The recent development of retinoids combined
      with the growth of expertise with regard to the biological function and
      mechanisms of retinoid receptors, are likely to improve the present therapeutic
      methods and to reveal new potentials regarding the use of retinoids in the
      therapy of many skin disorders.

PMID- 15181753
TI  - [Ciclesonid--new generation of inhaled glucocorticosteroid].
AB  - Inhaled corticosteroids with long acting beta 2-mimetics have become the mainstay
      of therapy for patients with asthma. The clinical and biological activity of the
      inhaled corticosteroids expressed as anti-inflammatory effect depends on their
      bioavailability, receptor affinity, lipophility, half-life terminal elimination
      and molecule value. Ciclesonide as a novel corticosteroid itself is inactive and
      used as prodrug form and needs to be cleaved by pulmonary esterases to acquire
      anti-inflammatory activity. Due to its quick initial activity, long clinical
      effectiveness in dose range of 100-800 micrograms/day, rather mild side effects,
      Ciclesonide is efficacious as a local potency anti-inflammatory drug.

PMID- 15181754
TI  - [Genetic aspects of colorectal carcinogenesis].
AB  - Colorectal cancer (CRC) is one of the most common forms of cancer and the second
      leading cause of death in Poland. Most cases of CRC are sporadic but a small
      percentage occurs in heritable syndromes such as dominant autosomal adenomatous
      and hamartomatous polyposis syndromes and hereditary nonpolyposis colorectal
      cancers. In a majority of cases CRCs are thought to develop in a step wise
      progression from normal epithelium through polyp form to carcinoma. Many genetic
      changes are observed in this process like inactivation of the tumor suppressor
      genes as well as the activation of specific oncogenes. Molecular biological
      studies have shown mutations of p53, Apc, k-ras and/or changes in proteins like
      APC and DNA microsatellite instability or loss of heterozygosity. For several
      years now great progress in this field and new concepts of screening strategies
      and therapeutic options have been made (gene therapy).

PMID- 15181756
TI  - [Effectiveness of splenectomy in high-risk patients needing surgery].
AB  - Splenectomy is a useful method of treatment in some hematological disorders
      (congenital microspherocytosis, ITP, hypersplenism). However in many clinical
      situations the unclear prognostic factors, bad patient's condition or non-typical
      disease's course may impede the decision to splenectomize. We present a history
      of three successfully splenectomized patients. In each of reported cases the
      complicated course required detailed disease and treatment analysis. Our results
      indicate that splenectomy should be considered as a therapeutic option in the
      thrombocytopenic patients. This group of patients should be immediately referred
      to specialized centres.

PMID- 15181755
TI  - [Chronic anal fissure--conservative or surgical treatment?].
AB  - Chronic anal fissure is one of the most common anus diseases. The main ailments
      reported by the sick are: stubborn pain connected with defecation and bleeding.
      Etiopathogenesis of this disease has not been exactly explained yet. The most
      important factors are anodermal blood flow disturbances and excessive cramp of
      internal anal sphincter (IAS). Lateral sphincterotomy is the main way of
      treatment. However, a very dangerous complication as a stool incontinence may
      occur. As far as a pharmacological treatment is concerned, nitric oxide donors,
      calcium channel antagonist and botulinum toxin have been used. In some patients
      threatened with stool incontinence botulinum toxin may be used as an alternative
      way of treatment right after surgical treatment. Other ways of conservative
      treatment seem to be less effective due to the side effects and the frequency of
      repeating doses. The view on the etiopathogenesis of anal fissure, the ways of
      surgical treatment and the mechanism of activity of drugs used in the
      conservative treatment are presented in this paper.

PMID- 15181757
TI  - [Oral cavity infantile myofibromatosis in older children].
AB  - Infantile myofibromatosis (IM) is a rare condition that usually occurs in
      newborns and young children under the age of 2 years. Three cases of IM in older
      children are presented. Clinical, morphological and immunohistochemical features
      of the lesions are described. The lesions appeared as solitary, fast growing oral
      tumors. Infantile myofibromatosis rises the oncological concern and requires
      differentiation with benign and malignant soft tissue tumors as well as juvenile
      and infantile fibromatosis.

PMID- 15181758
TI  - [Renal cell carcinoma metastases to nose and paranasal sinuses presenting as
      recurrent epistaxis].
AB  - Distant metastases in head and neck region are very uncommon. Nasal bleeding was
      the first symptom in a patient with metastasis from renal cell carcinoma. Nasal
      tumour biopsy revealed renal carcinoma to be the primary lesion. Initially the
      patient refused surgery and nephrectomy was performed 8 months later. MR scans
      demonstrated diffuse intracranial invasion which made complete removal
      impossible. Potential routes of renal carcinoma spread are presented. Renal cell
      carcinoma should be considered in the diagnosis of nose and paranasal tumours.
      Epistaxis can be the first symptom of renal carcinoma metastasis to the nose and
      paranasal sinuses.

PMID- 15181759
TI  - [Glomus tumor of the thumb].
AB  - The article presents a case of 42-year-old patient with Recklinghausen disease
      treated in the outpatient clinic for 5 years for hyperaesthesia of a thumb. On
      physical examination the thumb was painful but smooth, soft with no features of
      infection. Neuralgia and Raynaud syndrome were suspected. Additional
      investigations did not show significant abnormalities, however, successive forms
      of conservative treatment (including denervation of the thumb) were not
      successful. Instant, persistent pain caused by even a slight touch or thermal
      changes suggested glomus tumor of the thumb. Physical examination did not confirm
      a lump typical in this disease. Finally partial resection of the digital pulp was
      performed, which led to complete recovery. Histopathological examination
      confirmed glomus tumor of the thumb.

PMID- 15181761
TI  - Leadership in health care. Challenges and new roles for the future.

PMID- 15181760
TI  - Characteristics of emergency departments serving high volumes of safety-net
      patients: United States, 2000.
AB  - OBJECTIVE: This report describes hospital, community, and patient factors
      associated with emergency departments (EDs) whose case loads are driven by
      "safety-net" populations. The study also explores the relationship between safety
      net burden and receipt of Medicaid Disproportionate Share Hospital (DSH) Program
      funds. METHODS: Linked data were analyzed from the 2000 National Hospital
      Ambulatory Medical Care Survey (NHAMCS), Area Resource File, and reports of
      Medicaid DSH payments to hospitals. NHAMCS ED visit data were aggregated to the
      hospital ED level (n = 376). Hospital sampling weights were used to produce
      national estimates of hospital EDs. Hospitals were classified into high vs. low
      safety-net burden based on the percent of ED visits where the expected source of
      payment was Medicaid or uninsured (self-pay or no charge). High- and low-burden
      EDs were compared along five domains: hospital characteristics; community
      factors; patient mix; diagnosis mix using Billings' profiling algorithm; and
      condition severity, visit content, and outcome. RESULTS: Approximately one-third
      (36.1 percent) of U.S. EDs were classified as high safety-net burden provides.
      Hospitals located in the South were more likely to have a high ED safety-net
      burden (61.3%). High-burden EDs saw a higher percentage of cases that were either
      nonurgent or emergent, but primary care treatable. EDs high in uninsured burden
      were not necessarily high in Medicaid burden. Fewer than half of high-burden EDs
      received DSH payments. CONCLUSIONS: High safety-net burden is not necessarily
      offset by public funding. The vast majority of EDs that serve high proportions of
      uninsured patients do not receive such compensation.

PMID- 15181762
TI  - Obesity: public health enemy number one.

PMID- 15181763
TI  - Indian culture and nutrition.

PMID- 15181764
TI  - Online scheduling applications may improve customer satisfaction, but setup is
      not always easy.

PMID- 15181765
TI  - University of Michigan Health System considers patient messaging options.

PMID- 15181766
TI  - Portals build a loyal audience and provide a service to the community.

PMID- 15181767
TI  - Baptist Healthcare System organizes to involve wide range of employees in Web
      site development decisions.

PMID- 15181768
TI  - Nurses can promote environmental health.

PMID- 15181769
TI  - No care for the caregivers.

PMID- 15181770
TI  - Where's the money?
AB  - Small, rural hospitals don't necessarily need to put off needed renovations or
      the purchase of new technology or equipment. Contrary to what administrators and
      trustees might think, size and location does not preclude small rurals from
      obtaining needed capital.

PMID- 15181771
TI  - Who should pay for the uninsured?
AB  - Do hospitals charge the uninsured more? With more than 43 million Americans
      lacking health care coverage, all stakeholders are more challenged than ever to
      pay for charity care.

PMID- 15181772
TI  - Using your Web site as an accountability tool.

PMID- 15181773
TI  - Preserving dignity and access to care. The Broadlawns Model for the Uninsured.

PMID- 15181774
TI  - Developing a treatment philosophy.
AB  - Developing a philosophy is an excellent way to begin a dental career. Many
      dentists reading this column already are well into practice and may have
      developed a philosophy without realizing it. It is important to reflect on that
      philosophy and even write it down to clarify the direction you would like your
      practice to take. Our experience in consulting to more than 7,500 practices has
      shown that many dentists completely change the direction and vision for their
      practice when the philosophy is clearly established and documented. This change
      often gives these dentists greater profitability and the opportunity to retire at
      an earlier age.

PMID- 15181775
TI  - Understanding the limitations of dental radiographs--implications for soft-tissue
      management programs.

PMID- 15181776
TI  - Clinical indications as a basis for ordering extraoral imaging studies.
AB  - Extraoral imaging exams can be an important diagnostic tool for a wide variety of
      pathologies ranging from bone and mineral disorders, to metabolic disorders,
      genetic abnormalities, and soft-tissue calcifications such as carotid artery
      calcification. This article reviews a number of disorders that may manifest in
      the head and neck region and provides information on how the disorders in
      question may appear on an extraoral radiograph. It then presents an approach to
      using clinical indications as a basis for determining when to order extraoral
      imaging studies.

PMID- 15181777
TI  - Endodontic retreatment possibilities: evaluation, limitations, and
      considerations.

PMID- 15181778
TI  - Warming up to composites.
AB  - Patient demand for composite restorations has increased dramatically over the
      past decade. Anterior composites, for teeth that are visible when smiling, have
      been the standards of practice for many years. For the less visible teeth, it is
      estimated that the 50% mark for composite restorations in the posterior region
      was surpassed in 2000.

PMID- 15181779
TI  - Efficacy of full-mouth disinfection vs quadrant root planing.
AB  - This article addresses the capability of full-mouth disinfection, full-mouth root
      planing, and partial-mouth disinfection to improve periodontal health. A basic
      premise of full-mouth therapy (full-mouth disinfection or full-mouth root
      planing) is to eradicate or diminish bacterial reservoirs in the mouth that could
      impede optimal healing or initiate periodontal disease or disease progression.
      Several investigations conducted at one university indicated that full-mouth
      disinfection and full-mouth root planing achieved greater therapeutic
      improvements compared with partial-mouth disinfection regarding decreased probing
      depths, gained clinical attachment, diminished bleeding from probing, and reduced
      subgingival microflora. In contrast, other studies from 2 treatment centers
      demonstrated that there were no statistically significant differences when the
      effectiveness of quadrant-by-quadrant root planing was compared with full-mouth
      root planing and full-mouth disinfection regarding probing depth reduction, gains
      of clinical attachment, and impact on the magnitude and quality of the immune
      response. Theoretically, full-mouth therapy could decrease the number of patent
      visits and allow more efficient use of treatment time. Furthermore, no major
      adverse reactions to full-mouth root planing with or without adjunctive
      chemotherapy are evident. Nevertheless, small study populations and
      noncorroborating data from different treatment centers indicate that more
      clinical trials are required to determine whether full-mouth therapy provides
      clinically relevant improvements compared with partial-mouth disinfection.

PMID- 15181780
TI  - Vaccines: the conflict between efficacy and public concerns--Part 2.

PMID- 15181781
TI  - Using BisCover surface sealant/polish on direct and indirect composite and
      bisacrylic provisional restorations.

PMID- 15181782
TI  - [Intervention with selective serotonin reuptake inhibitors (SSRI) in depressed
      children and adolescents].

PMID- 15181783
TI  - [Trial of time processing training in children with reading and spelling
      disorders].
AB  - OBJECTIVE: It has been suggested that training in temporal processing may
      significantly improve language processing and reading skills. However,
      improvement effects of training on language impairment or dyslexia have not been
      proven so far. In the present study a temporal processing training was evaluated.
      METHOD: The participants of the present study were 42 children (5th graders) of a
      special school for children with reading and spelling problems. Children of one
      class (n = 21) were assigned to a training group (n = 21), the other class to a
      control group. Children in the training group took part in a training program
      consisting of auditory and visual order threshold and sound localisation tasks,
      over a period of eight weeks. We determined the order thresholds, sound
      localisation ability and reading and spelling performance of all children before
      and after the training period. Six months later all subjects were re-tested.
      RESULTS: Auditory and visual order thresholds decreased significantly more in the
      training group than in the control group. However, these changes were not
      accompanied by improvements in reading or spelling skills. CONCLUSIONS: In the
      present study no training effects on reading and writing performance were
      observed by using a program including temporal processing tasks. It is
      questionable whether training programs of temporal processing are useful methods
      in therapy of dyslexic children.

PMID- 15181784
TI  - [Effect of temperament, effect of alcohol expectancies and peer group on amount
      of drinking and alcohol-related problems in adolescence].
AB  - OBJECTIVE: The purpose of this longitudinal study was to investigate the
      relationship between temperament (novelty seeking, harm avoidance and reward
      dependence), alcohol expectancies, membership in a deviant/substance-using
      peergroup and drinking behaviour of adolescents drawn from a general population.
      METHODS: 147 adolescents about 15 years of age were interviewed and completed
      several self-rating questionnaires. We gathered additional information by
      interviewing their parents. One year after the initial assessment the adolescents
      only were interviewed and given questionnaires again. RESULTS: Adolescents with
      alcohol problems at the time of the second interview reported less harm
      avoidance, less reward dependence, and were more likely to be a member of a
      deviant/substance-using peergroup a year before, compared to offspring without
      alcohol problems. Furthermore, they held more positive alcohol expectancies than
      adolescents without alcohol problems. Taking into account the quantity of alcohol
      consumed per occasion, all results were confirmed, but temperament did not
      predict the extend of alcohol consumed after one year. CONCLUSIONS: Alcohol
      expectancies and peer group deviance/substance-use are strongly associated to
      alcohol problems and the amount of alcohol consumed. Therefore, they should be
      the focus of prevention and intervention in this age group.

PMID- 15181785
TI  - [Prevalence of psychiatric symptoms and comorbid conditions in 3- to 5-year-old
      children: results of the Braunschweig Kindergarten Study].
AB  - OBJECTIVES: To analyze the frequency of behavioral and emotional problems and
      comorbidity of kindergarten children in Braunschweig as rated by their parents.
      METHOD: The analysis is part of the Braunschweiger Kindergartenstudie. In a
      sample of N = 809 children aged three to six the parents rated their children
      using a modified version of the Child Behavior Checklist/CBCL 4-18. RESULTS: The
      prevalence rates range from 0.5% to 5.0%. The most frequent behavioral problems
      in kindergarten children were aggressive behavior and attention problems,
      followed by social problems. The study also provides bidirectional comorbidity
      rates. CONCLUSION: Finally the prevalence rates and the implications of the
      findings for prevention of behavioral problems in children are discussed.

PMID- 15181786
TI  - [Chromosome 22q11 deletion syndrome and its relevance for child and adolescent
      psychiatry. An overview of etiology, physical symptoms, aspects of child
      development and psychiatric disorders].
AB  - 22q11.2 deletion syndrome is the most common interstitial deletion syndrome in
      humans. Patients with this syndrome can show a variety of somatic symptoms,
      especially characteristic facial abnormalities, heart defects, thymic hypo- or
      aplasia and velopharyngeal dysfunction with or without cleft palate.
      Disturbancies in motor, language, cognitive and social development are typical,
      as well as psychiatric disorders. Psychiatric disorders in children and
      adolescents are mostly attention-deficit/hyperactivity disorder, affective
      disorders, and autism spectrum problems. Schizophrenia in adults seems to be
      caused by 22q11.2 deletion in about 2% of all patients. We review current
      knowledge about etiology, physical features, developmental aspects and
      psychiatric comorbidity in 22q11.2 deletion syndrome as well as possible
      therapeutic interventions. Clinical criteria for genetic examinations on 22q11.2
      deletion in children and adolescents with psychiatric disorders are defined.
      Until now 22q11.2 deletion is underdiagnosed in this population--despite of its
      clinical relevance.

PMID- 15181787
TI  - [Typical benign epilepsy potentials in childhood (Rolandic spikes)-
      neurobiological and neuropsychological symptoms and their clinical significance
      in child and adolescent psychiatry].
AB  - INTRODUCTION: Rolandic epilepsy is the most frequent epileptic syndrome in
      childhood, electroencephalographically characterized by focal sharp waves, so
      called rolandic spikes (benign epileptiform discharges of childhood). These
      discharges occur in about 1.5 to 2.4% of children; only 10% of them suffer from
      epileptic seizures. METHODS: This paper reviews genetic, epidemiological,
      radiological, neurophysiologic, metabolic and neuropsychological findings in
      children with rolandic discharges. RESULTS: The epileptologic course is
      favorable, seizures and EEG features usually resolve completely at puberty. In
      contrast to former assumptions, symptoms range from infrequent seizures to
      neuropsychological deficits and behavior problems, even in children without overt
      seizures. The impact of rolandic spikes on the development of affected children
      and their behavior is unclear. Two models try to elucidate the relation between
      EEG discharges and neuropsychological disorders. The first regards
      neuropsychological disturbances as transient cognitive impairment due to
      epileptiform discharges; the second model strengthens the role of a hereditary
      impairment of brain maturation. CONCLUSIONS: The benefit of pharmacotherapy for
      treating neuropsychiatric symptoms in children with rolandic spikes but without
      overt seizures remains to be clarified.

PMID- 15181788
TI  - Healthcare facilities discharge hazardous pharmaceutical waste.

PMID- 15181789
TI  - IHEEM must evolve and lead. Interview by Nicholas Marshal.

PMID- 15181790
TI  - Debating project sustainability.
AB  - Three Construction Industry Environmental Forum workshops, held in Edinburgh,
      London and Manchester towards the end of last year, focused on a range of key
      issues concerning the delivery of appropriate sustainability performance in PFI
      projects.

PMID- 15181791
TI  - Helping to improve patient outcomes.
AB  - Delegates attending the forthcoming International Federation of Hospital
      Engineering Congress in Florida will undoubtedly closely focus again on how the
      healthcare environment, and range of non-clinical services provided within it,
      contribute to positive patient outcomes. This article draws attention to some key
      issues which were examined at the IFHE Congress in Bergen two years ago and which
      continue to rank as highly important.

PMID- 15181793
TI  - Whole life-cycle costs examined.

PMID- 15181792
TI  - Concordat facilitates key collaboration.

PMID- 15181794
TI  - Delivering real change for patients.

PMID- 15181795
TI  - Tackling the moisture menace.

PMID- 15181796
TI  - Developing high quality training.

PMID- 15181797
TI  - Products and technologies must be 'green'.

PMID- 15181798
TI  - Low-coherence Michelson interferometric fiber-optic multiplexed strain sensor
      array: a minimum configuration.
AB  - A minimum configuration Michelson fiber-optic low-coherence interferometric quasi
      distributed sensing system is proposed that permits absolute length measurement
      in remote reflective sensor arrays. The sensor's reflective signal
      characteristics have been analyzed, and the relationship between intensities of
      light and number of sensors is given for evaluation of multiplexing potential.
      The proposed sensing scheme will be useful for the measurement of strain
      distribution. An important application may be strain monitoring in smart
      structures. Experimentally, four-sensor array has been demonstrated.

PMID- 15181799
TI  - Image aberrations in optical three-dimensional measurement systems with fringe
      projection.
AB  - In optical shape measurement systems, systematic errors appear as a result of
      imaging aberrations of the lens assemblies in the cameras and projectors. A
      mathematical description of this effect is intended to correct the whole
      measurement area with a few independent coefficients. We apply the ideas of
      photogrammetry to one- and two-dimensional fringe projection techniques. We also
      introduce some new terms for close-range applications and telecentric objectives.
      Further, an algorithm for distance-dependent corrections is introduced. Also, we
      describe a new method with which to determine coefficients of aberration with an
      optimization-based method.

PMID- 15181800
TI  - Generic method for aero-optic evaluations.
AB  - The effect of aerodynamic flow on the performance of an airborne optical system
      is becoming a critical issue in the development of electro-optic systems. A novel
      technique for aero-optic calculations that is based on commercially available
      software is presented. The optically relevant data from the computational fluid
      dynamics results are transformed into an index-of-refraction field and introduced
      as an input to the optical code. The data do not necessarily have to be presented
      in analytical form; instead it is introduced in a most general form as a discrete
      set of values located at a nonuniform grid of points. The modified quadratic
      Shepard method has been adopted for data interpolation, enabling a simple
      interface with virtually any software output. Several numerical simulations that
      demonstrate the technique are presented.

PMID- 15181801
TI  - Phase object data obtained from defocused laser speckle displacement.
AB  - An optical technique that is based on defocused digital speckle photography is
      proposed for the evaluation of phase objects. Phase objects are different kinds
      of transparent or semi-transparent media that allow light to be transmitted. A
      phase object inserted in a laser speckle field introduces speckle displacement,
      from which information about the object may be extracted. It is shown that one
      may use speckle displacements to determine both the phase gradients and the
      positions of phase objects. As an illustration the positions and focal lengths of
      two weak lenses have been derived from defocused laser speckle displacement.

PMID- 15181802
TI  - Phase object data obtained by pulsed TV holography and defocused laser speckle
      displacement.
AB  - Transient events in optically transparent media occur in many engineering
      applications. Using pulsed TV holography to capture a laser speckle field
      propagated through an optical disturbance makes it possible to obtain both the
      position and the phase gradients of the disturbance. The technique depends on the
      fact that speckles transmitted through an optical disturbance will be displaced
      by an amount that depends on the relation of the defocus to the object. First the
      speckle field is captured holographically, without and with disturbance present.
      Then the recorded fields are numerically refocused in a computer to a number of
      different focal planes. With a cross-correlation technique a number of speckle
      displacement fields are obtained, and from them the data about the disturbance
      are obtained. So far the technique has been shown to work for thin objects.

PMID- 15181803
TI  - Interferometric analysis of nanostructured surface profiles: correcting material
      dependent phase shifts.
AB  - We present a technique to correct interferometry for the material-dependent phase
      shift that accompanies reflection. Such corrections are needed for nanometer
      accuracy of surfaces that are not of homogeneous composition. We adapt the
      general theory of reflection from surfaces in which there are irregular and
      unresolved areas of several materials to treat the specific case in which only
      two materials are present, as is the case for many practical applications. We
      show, for the approximation of a large numerical aperture that collects all
      reflected light, how measurements of three quantities, together with known values
      of the optical constants, allow determination of the material-dependent phase
      shift at each position on the surface. We demonstrate with numerical simulation,
      appropriate to measuring a surface of alumina in which optically unresolved
      titanium carbide granules are embedded, that our approach also succeeds, with
      nanometer accuracy, when the numerical aperture is small. The method is discussed
      for use with a miniature interferometric phase sensor, but it has application to
      any interferometer.

PMID- 15181804
TI  - Shock-wave propagation and cavitation bubble oscillation by Nd:YAG laser ablation
      of a metal in water.
AB  - A highly sensitive fiber-optic sensor based on optical beam deflection is applied
      for investigating the propagation of a laser-induced plasma shock wave, the
      oscillation of a cavitation bubble diameter, and the development of a bubble
      collapse-induced shock wave when a Nd:YAG laser pulse is focused upon an aluminum
      surface in water. By the sequence of experimental waveforms detected at different
      distances, the attenuation properties of the plasma shock wave and of the bubble
      collapse-induced shock wave are obtained. Besides, based on characteristic
      signals, both the maximum and the minimum bubble radii at each oscillation cycle
      are determined, as are the corresponding oscillating periods.

PMID- 15181805
TI  - Fabrication and analysis of a Fabry-Perot cavity with a micromechanical wet
      etching process.
AB  - We present a novel low-cost and batch fabrication method to fabricate a Fabry
      Perot (FP) cavity with a micromechanical wet-etching process, through which FP
      cavities can be achieved with a cavity length of from several micrometers to tens
      of micrometers. The parallelism of mirror elements can be well achieved without
      electrostatic control. The quality of an etched surface can be greatly improved
      by the oxidation polish process. FP cavities with a finesse of approximately 50
      are achieved. Analysis shows that the effective finesse is dominated mainly by
      the quality of the etched surface.

PMID- 15181806
TI  - Precise determination of the complex optical constant of mica.
AB  - We present a general method for extracting optical constants n and k plus film
      thickness t of weakly absorbing materials that exhibit film thicknesses in the
      micrometer range. This method utilizes the simultaneous fit of multiple
      transmission measurements of different film thicknesses and employs the
      constraint that the frequencies of the corresponding measured interference
      patterns in the nonabsorbing wavelength region have to be matched by means of n,
      its derivative n' at a certain value E0, and t. Applying this method in practice,
      we calculate, in two different, independent ways, the optical constants of
      muscovite mica at 330-800 nm for thicknesses that range from approximately 5 to
      approximately 160 microns.

PMID- 15181807
TI  - Optical properties of scandium films in the far and the extreme ultraviolet.
AB  - The optical properties of thin Sc films deposited in ultrahigh-vacuum conditions
      have been investigated in the 6.7-174.4-nm spectral range. We measured
      transmittance and multiangle reflectance in situ in the 53.6-174.4 nm spectral
      range and used these measurements to obtain the complex refractive index of a Sc
      film at every individual wavelength investigated. Transmittance measurements were
      made of Sc samples that were deposited over grids coated with a support C film.
      The transmittance and the extinction coefficient of Sc films at wavelengths
      shorter than 30 nm were measured ex situ. The ex situ samples were protected with
      an additional top C film before their removal from vacuum. To our knowledge,
      these are the first optical measurements of Sc films reported in the spectral
      ranges cited.

PMID- 15181808
TI  - Efficient method for the reduction of large piston errors in segmented-mirror
      telescopes.
AB  - Phase discontinuity sensing (PDS) is one of two successful approaches to segment
      phasing that are currently in use at the Keck telescopes, but it has only a
      limited capture range. We describe and present numerical simulations of a
      broadband version of the current (narrowband) PDS algorithm that can extend the
      capture range from 0.4 to 40 microns. Like the original algorithm, the new
      broadband PDS algorithm requires no special-purpose hardware but only a high
      resolution area detector operating in the 2-3-microns range. The potential
      application of this algorithm to extremely large telescopes is also discussed.

PMID- 15181809
TI  - Practical realization of high-speed photodisplacement imaging by use of parallel
      excitation and parallel heterodyne detection: a numerical study.
AB  - A new parallel photodisplacement technique that achieves extremely high
      throughput imaging is proposed, and its practical realization is studied
      numerically. In this technique, a linear region of photothermal displacement is
      excited by use of a line-focusing intensity-modulated laser beam and detected
      with a parallel heterodyne interferometer in which a charge-coupled device linear
      image sensor is used. Because of the integration and sampling effects of the
      sensor, the interference light is spatiotemporally multiplexed. To extract the
      photodisplacement component from the multiplexed sensor signal, a scheme of phase
      shifting light integration under an undersampling condition is proposed for
      parallel interferometry. The frequencies of several control signals, including
      the heterodyne beat signal, modulation signal, and sensor gate signal, are
      optimized so as to eliminate undesirable components, allowing only the
      displacement component to be extracted. Preliminary numerical simulation results
      show that the proposed technique has the potential to perform photodisplacement
      imaging more than 10,000 times faster than conventional photoacoustic microscopy.

PMID- 15181810
TI  - Design and analysis of an adaptive board-to-board dynamic holographic
      interconnect.
AB  - We describe the design and analysis of an adaptive free-space optical
      interconnect between two circuit boards in a standard electronic backplane. An
      array of vertical-cavity surface-emitting lasers is used as the transmitter, and
      this communicates with a detector array on the receiver circuit board. Routing is
      achieved with a holographic crossbar that has a ferroelectric liquid-crystal
      spatial light modulator to display binary phase computer-generated holograms. A
      detailed analysis of a 48-channel interconnect designed to operate at 1
      (Gbytes/s)/channel indicates that such a switch will operate successfully given
      typical components and card misalignments.

PMID- 15181811
TI  - Generalized confocal imaging systems for free-space optical interconnections.
AB  - A generalized confocal imaging system, which is composed of two confocal lenses
      and one field lens, is proposed for free-space optical interconnections. Unlike
      in a conventional 4-f system, both the object distance and the image distance can
      be almost arbitrarily chosen. This advantage is especially important for
      practical setups in which the object distance and the image distance cannot be
      designed to be the same. As a concrete example, we have designed and
      experimentally tested a planar-integrated micro-optical imaging system. The
      result is in good agreement with the theoretical prediction. Similarly to the
      conventional 4-f imaging system and the light-pipe imaging system, the system
      proposed here can also be used as one important part of a hybrid imaging setup.

PMID- 15181812
TI  - Fiber Bragg grating location by a side-scatter technique based on cladding-mode
      coupling.
AB  - At wavelengths slightly shorter than the normal resonance for a fiber Bragg
      grating, radiation can be coupled into cladding and radiation modes that become
      visible external to the fiber. We describe experimental measurements on a fiber
      Bragg grating under broadband illumination, showing the axial variation and
      angular distribution of side-scattered radiation. The scattering signal can
      locate the grating position subject to an offset in the backscatter direction.
      The spectrum of scattered radiation is consistent with a published theoretical
      model of mode coupling by a grating in a finite cladding fiber.

PMID- 15181813
TI  - Y-branch spot-size converter for a buried silica waveguide with large index
      difference.
AB  - Coupling loss occurs between a standard single-mode fiber and a silica waveguide
      when the difference between the refractive indices of the core and the cladding
      of the silica waveguide is high. We designed a Y-branch structure for use as a
      spot-size converter to reduce this coupling loss. The structure was tested with a
      three-dimensional beam-propagation method and was shown to exhibit a
      significantly reduced coupling loss, a low polarization-dependent loss, and a
      good tolerance of imprecision in fabrication. No additional fabrication steps are
      required for this proposed spot-size converter.

PMID- 15181814
TI  - Measurement of the chi (2) tensors of KTiOPO4, KTiOAsO4, RbTiOPO4, and RbTiOAsO4
      crystals.
AB  - We use the separated-beams method to measure the second-order nonlinear optical
      tensors of the crystals KTiOPO4, KTiOAsO4, RbTiOPO4, and RbTiOAsO4 for second
      harmonic generation of 1064-nm light. Our results agree well with most previous
      measurements but have improved precision.

PMID- 15181815
TI  - Sellmeier dispersion for phase-matched terahertz generation in ZnGeP2.
AB  - A Sellmeier dispersion of zinc germanium diphosphide (ZnGeP2) crystal has been
      formulated to determine the phase-matching characteristics of the crystal for the
      generation of coherent tunable terahertz radiation by difference-frequency mixing
      techniques. The results computed with the formulated Sellmeier dispersion provide
      an excellent fit to the experimental data.

PMID- 15181816
TI  - Monitoring of ethylene by a pulsed quantum cascade laser.
AB  - We report on the development and performance of a gas sensor based on a quantum
      cascade laser operating at a wavelength of approximately 10 microns to measure
      ethylene (C2H4) concentrations by use of a rotational component of the
      fundamental nu 7 band. The laser is thermoelectrically cooled and operates in a
      pulsed mode. The influence of pulse-to-pulse fluctuations is minimized by use of
      a reference beam and a single detector with time discriminating electronics. Gas
      absorption is recorded in a 100-m optical path-length astigmatic Herriott cell.
      With a 10-kHz pulse repetition rate and an 80-s total acquisition time, a noise
      equivalent sensitivity of 30 parts per billion has been demonstrated. The sensor
      has been applied to monitor C2H4 in vehicle exhaust as well as in air collected
      in a high-traffic urban tunnel.

PMID- 15181817
TI  - Design and characterization of the balloon-borne Michelson Interferometer for
      Passive Atmospheric Sounding (MIPAS-B2).
AB  - MIPAS-B2 is a balloon-borne limb-emission sounder for atmospheric research. The
      heart of the instrument is a Fourier spectrometer that covers the mid-infrared
      spectral range (4-14 microns) and operates at cryogenic temperatures. Essential
      for this application is the sophisticated line-of-sight stabilization system,
      which is based on an inertial navigation system and is supplemented with an
      additional star reference system. The major scientific benefit of the instrument
      is the simultaneous detection of complete trace gas families in the stratosphere
      without restrictions concerning the time of day and viewing directions. The
      specifications, the design considerations, the actual realization of the
      instrument, and the results of characterization measurements that have been
      performed are described.

PMID- 15181818
TI  - Timing and diplomacy are keys to CT scans in the emergency department.
AB  - Patients needing abdominal computed tomography (CT) scans can back up in your ED
      if you don't employ strategies to move them out fast. Consider reducing the use
      of contrast studies. Liberal use of antiemetics can help with ingesting solution.
      Work closely with radiology to reduce waiting time.

PMID- 15181819
TI  - [Constructing the tumor cell vaccine based on homologous matrix metalloproteinase
      2 and exploring its effects].
AB  - OBJECTIVE: To construct the tumor cell vaccine based on homologous matrix
      metalloproteinase-2 (MMP-2), and explore its anti-tumor effects. METHODS: The
      tumor cell vaccine was constructed by transfecting chicken MMP-2 to tumor cells.
      MTT colorimetric assay was used to evaluate the activation of the transfectants.
      Then we observed the formative tumor response in vivo and evaluated the effects
      of the tumour cell vaccine in immunized mice rechallenged with parental cells.
      RESULTS: Using RT-PCR, we picked out the cell strain with the highest expression
      level from the transfectants. The MTT colorimetric assay revealed that the
      transfectants increased the expression of the MMP-2 of tumor cells while they did
      not change the trend of tumor cells' growth. And in animal experiments the
      vaccine was preliminarily found to be effective for inhibiting the tumour growth
      and prolonging the survival time of animals. CONCLUSION: We have constructed the
      tumor cell vaccine based on homologous matrix metalloproteinase-2. The
      experiments demonstrated that breaking the immune tolerance of MMP-2 by means of
      active immunity should be a useful approach to cancer therapy.

PMID- 15181820
TI  - [Serological screening of xenogeneic antigens from rat testis].
AB  - OBJECTIVE: It is the intent of this study to analyzed the rat testis library by
      employing a modified SEREX (serological analysis of recombinant cDNA expression
      library) approach to find the xenogeneic homologous tumor antigens which could be
      useful in developing cancer vaccines. METHODS: The screening serum was obtained
      from the immunized rabbits with human ovarian cancer cells, and 10 positive
      clones were isolated from the rat testis cDNA library using SEREX technology.
      RESULTS: We found these 10 clones encoded seven different proteins by means of
      bioinformatic analysis. Among them, OV-2 and OV-4 encode proteins related to
      carcinoma in human, yet OV-6 and OV-7 are novel and their encoded proteins remain
      unknown. CONCLUSION: This study indicates that the utilization of xenogeneic
      immunized serum in the serological screening of xenogeneic homologous tumor
      antigens may expand the application of traditional SEREX technology.

PMID- 15181821
TI  - [Construction of pcDNA-BLC and expression of BLC in tumor cells].
AB  - OBJECTIVE: To establish a stable transformants of B-lymphocyte chemoattractant
      (BLC) with the eukaryotic expression vector for investigation of its anti-tumor
      function further. METHODS: The BLC full-length cDNA was amplified by RT-PCR from
      the total RNA isolated from the spleen of mouse. After sequence determination,
      the BLC full-length cDNA was cloned into the eukaryote expression vector pcDNA3.1
      (+), the resulted recombinant was designated as pcDNA-BLC. Then pcDNA-BLC was
      transfected into murine tumor cell line colon 26 by LIPOFECTIN. The stable
      transformants were selected by G418 and identified by immunoblot assay. The
      bioactivity of BLC was confirmed by chemotaxis assay. RESULTS: The recombinant
      pcDNA-BLC was successfully constructed. The stable transformants of BLC can
      express the bioactive BLC in tumor cell lines. CONCLUSION: The stable
      transformants can stably express BLC in tumor cell lines. These stable
      transformants will be useful for further study of the BLC biological effect on
      tumor and for the development of cancer vaccine.

PMID- 15181822
TI  - [Study on the gene mutation of quinolone-resistant Mycobacterium tuberculosis
      isolated from Sichuan Province].
AB  - OBJECTIVE: To investigate the molecular mechanism of quinolone-resistance of M.
      tuberculosis and characterize the gene mutation in Sichuan Province. METHODS:
      Susceptibility of the clinical isolates to quinolones (ofloxacin, ciprofloxacin
      and sparfloxacin) was tested by the absolute concentration method. GyrA gene
      quinolone reasistance-determining region (QRDR) mutations M. tuberculosis were
      detected with PCR-SSCP and DNA sequencing. RESULTS: Of 68 clinical isolates of M.
      tuberculosis, 25 high-resistant, 11 low-resistant and 10 sensitive isolates were
      noted to have abnormal gyrA SSCP profile and different gyrA sequences from the
      standard strain H37Rv, and 14 sensitive and 8 low-resistant isolates were found
      with no mutation of gyrA gene. DNA sequencing unveiled Ser-->Thr mutation at
      codon 95, Asp-->Gly at codon 94, Ala-->Val at codon 90, and Ala-->Val at codon
      83. CONCLUSION: This study confirmed the strong correlation between the quinolone
      resistance and the mutation of gyrA gene, which might be a major molecular
      mechanism of quinolone-resistance in M. tuberculosis. The types of mutations
      exhibit no difference between Sichuan Province and other areas in China.

PMID- 15181823
TI  - [Inhibition of malignant ascites with endostatin adenoviral vector].
AB  - OBJECTIVE: To evaluate the therapeutical effect of endostatin adenoviral vector
      on malignant ascites and compare it with the combined effect of ad-endostatin and
      DDP. METHODS: We transfected SKOV3 cells with ad-endostatin to inhibit human
      umbilical vein endothelial cells (HUVEC) proliferation. Then we administered ad
      endostatin intraperitoneally in BALB/c mice to detect the serum endostatin
      expression and in the mice with malignant ascites to evaluate the therapeutic
      efficacy. RESULTS: Recombinant endostatin inhibited HUVEC proliferation.
      Endostatin was expressed in serum after intraperitoneal injection of ad
      endostatin. The effects of endostatin on inhibition of the ascites accumulation
      and peritoneal capillary permeability, on demotion of VEGF protein level and
      microvascular density in tumor tissues, on reduction of the number of red cells
      and tumor cells counted in malignant ascites, and on prolongation of mice
      survival were significant in two different malignant ascites. Furthermore, the
      combination of ad-endostatin with DDP increased the therapeutic efficacy.
      CONCLUSION: These data suggested that endostatin gene therapy may represent a
      potential new treatment for malignant ascites, and the therapeutic efficacy can
      be enhanced by a combination of ad-endostatin with chemotherapy.

PMID- 15181824
TI  - [Effects of Radix Salviae Miltiorrhizae on the PMN-EC adhesion in vitro at the
      early stage of endotoxemia].
AB  - OBJECTIVE: To evaluate the effects of Radix Salviae Miltiorrhizae (RSM) on the
      PMN-EC adhesion in vitro at the early stage of endotoxemia, and to probe into the
      mechanism there in involved. METHODS: The rabbit endotoxemia model was made, and
      one group was treated with RSM injection (2 ml/kg) instantly and 24 h after the
      modeling of endotoxemia. PMN-EC adhesion rate, adhesion molecule (CD11a/CD18 and
      CD11b/CD18) and TNF-alpha level were measured instantly, 2 h, 4 h, 8 h, 16 h, 24
      h and 48 h after endotoxemia modeling. RESULTS: It was found that after the
      modeling of endotoxemia, the levels of CD11a/CD18, CD11b/CD18 and PMN-EC adhesion
      rate instantly increased in the endotoxemia group and RSM group, they went up to
      the peak at 4 h in the endotoxemia group, and at 2 h, 4 h, 8 h, 16 h, 24 h and 48
      h, they were markedly lower in the RSM group than in the endotoxemia group (P <
      0.05). The TNF-alpha level in the endotoxemia group began to increase 2 h after
      the modeling and reached to the peak at 8 h, with its level still higher than
      normal at 48 h, while the RSM group had lower level of TNF-alpha at all time
      points(P < 0.05). CONCLUSION: The data from this animal experiment indicate that
      Radix Salviae Miltiorrhizae can decrease PMN-EC adhesion rate and the levels of
      CD11a/CD18, CD11b/CD18 and TNF-alpha in case of endotoxemia so as to improve the
      microcirculation.

PMID- 15181825
TI  - [Effect of titanium particles loading on the viability of mesenchymal stem cells
      after osteoblastic induction].
AB  - OBJECTIVE: To assess the effect of titanium particles on the proliferation of
      rMSCs after osteoblastic induction. METHODS: MTT-assay and Confocal Laser
      Scanning Microscopy are utilized to detect rMSCs' proliferation rate and
      morphologic variety. RESULTS: It was found that Ti particles loading suppressed
      the proliferation of osteogenesis behavior of rMSCs, but the down-regulation
      effect varied in different circle diameter, different concentration and different
      loading duration of Ti particles. Especially, among three different particles,
      the submicron Ti particles (0.9 micron) had the most suppressive effect on rMSCs.
      Under the same diameter condition, the inhibitory effect induced by Ti particles
      loading showed a manner dependent on the particles concentration and exposure
      duration. The reductive response from 1 g/L Ti was the earliest and most intense
      one to come forth. And the lower the concentration was in use, the weaker would
      be the reductive response. Furthermore, with the elongation of exposure to Ti
      particles, proliferation was steadily decreasing and its lowest level was at 32 h
      of exposure. CONCLUSION: These findings demonstrated that Ti particles loading
      could suppress the viability of rMSCs' osteoblastic differentiation in a manner
      dependent on the circle diameter, particles concentration, and treatment time.

PMID- 15181826
TI  - [The interrelationships between serum triglyceride, total cholesterol and HDL
      subpopulations].
AB  - OBJECTIVE: To assess the influence of serum triglyceride (TG) level and total
      cholesterol (TC) level on the change of the contents of serum HDL subpopulations.
      METHODS: The apolipoprotein (apo) A-I contents of serum HDL subpopulations in 289
      subjects were determined by two-dimensional gel electrophoresis associated with
      immunodetection method. RESULTS: Analysis of the data on the serum TG levels in
      subjects revealed that the apoA-I contents of pre beta 1-HDL, pre beta 2-HDL,
      HDL3b and HDL3a increased with the increase of TG level, whereas the apoA-I
      contents of HDL2a and HDL2b decreased. By comparison with the data of normal TG
      group, the apoA-I contents of pre beta 1-HDL and HDL3b in the high TG and very
      high TG groups were significantly higher, whereas those of HDL2b were
      significantly lower in the high TG and very high TG groups. Analysis of the data
      on the serum TC levels in subjects revealed that the apoA-I contents of pre beta
      1-HDL, pre beta 2-HDL, HDL2c and HDL3b increased with the increase of TC level,
      while the apoA-I contents of HDL2b decreased. As compared with the data of TC
      desirable group, the apoA-I contents of pre beta 1-HDL, HDL3c and HDL3b were
      significantly higher in the high TC group. CONCLUSION: With the increase of serum
      TG or TC, there is a general shift toward small-sized HDL in subjects. Besides,
      the change of serum TG level is a more important factor influencing the
      components of HDL subpopulations, compared with the change of serum TC level.

PMID- 15181827
TI  - [The expression of matrix metalloproteinase-2 and -9 in cervical cancer and a
      study of their relationship].
AB  - OBJECTIVE: To detect the expressions of matrix metalloproteinase-2 (MMP-2) and
      matrix metalloproteinase-9 (MMP-9) in cervical cancer and their correlation with
      clinicopathologic features. METHODS: With the use of specific monoclonal antibody
      to human MMP-2 and MMP-9, the formalin-fixed and paraffin-embedded specimens of
      62 invasive carcinomas of cervix uteri, 5 carcinomas in situ, 10 normal cervical
      epithelia and 10 lymph node metastases were detected by immunohistochemical
      method. RESULTS: MMP-2 and MMP-9 protein expressions in tumor and peritumoral
      stromal cells were enhanced in invasive carcinoma, compared to those in carcinoma
      in situ and controls (P < 0.05). There was a low correlation between MMP-2 and
      MMP-9 (r = 0.34, P < 0.01); the expression level of MMP-9 was higher than MMP-2.
      The protein expressions of MMP-2 and MMP-9 did not correlate with tumor stage,
      histological grade or pathological subtype. MMP-9 was correlated with lymph node
      metastasis and lymphovascular space invasion. CONCLUSION: The over-expression of
      matrix metalloproteinase-2 and -9 was correlated with invasive behaviour of
      cervical cancer, MMP-9 was significantly correlated with the lymph node
      metastasis, it might become a useful prognostic indicator for early cervical
      cancer.

PMID- 15181828
TI  - [Relationship of oncogene C-erbB2 expression to ER, PR and PS2 in breast cancer
      and its prognostic significance].
AB  - OBJECTIVE: To explore the expression of oncogene C-erbB2 in breast cancer, its
      relationship to estrogen receptor (ER), progesterone receptor (PR) and PS2 and
      the prognostic significance. METHODS: The expression of oncogene C-erbB2 in 245
      cases with breast cancer was detected with immunohistochemical technique (LsAB).
      RESULTS: Expression of oncogene C-erbB2 was found in 60% cases of breast cancer.
      Tumors positive for C-erbB2 were 45.19% and 71.55% in ER positive group and ER
      negative group respectively, while tumors positive for C-erbB2 were 48.08% and
      70.43% in PR positive group and PR negative group respectively. The expression of
      the C-erbB2 was 23.26% in group of PS2 positive and 50.75% in group of PS2
      negative (P < 0.05). No significant association of C-erbB2 expression with age
      and tumor size was noted(P > 0.05), but its expression in breast cancer was
      correlated with advanced clinical stage, high histological grade, axillary lymph
      node involvement (P < 0.05). CONCLUSION: C-erbB2 would be helpful to the
      evaluation of prognosis and treatment in breast cancer.

PMID- 15181829
TI  - [Induction of apoptosis of cultured hepatocarcinoma cell by essential oil of
      Artemisia Annul L].
AB  - OBJECTIVE: To know whether the essential oil of Artemisia annul L. can induce
      apoptosis of cultured hepatocarcinoma cell SMMC-7721. METHODS: Hepatocarcinoma
      cells were treated by the essential oil of Artemisia annul L. while positive
      control was treated by hydroxycamptothecine (HPT) and negative or mock control
      was treated by normal saline (NS). Induction of the apoptosis was analyzed by
      using flow cytometry (FCM), light microscope and electronic microscope, Giemsa's
      stain and DNA pattern after drug treatment. RESULTS: After the treatment of the
      cells with 100 micrograms/ml essential oil of Artemisia annul L. for 24 hours,
      the morphological changes of classic apoptosis such as condensation of cytoplasm,
      fragmentation of nuclear chromatin, and apoptosis body were seen. The sub-G1 peak
      was exhibited by FCM, and the DNA ladder pattern was observed. CONCLUSION: These
      findings demonstrated that the essential oil of Artemisia annul L. could induce
      apoptosis of cultured SMMC-7721.

PMID- 15181830
TI  - [Study on the inducible expression of toll-like receptors in human bladder cell
      line].
AB  - OBJECTIVE: To investigate and compare the expression of Toll-like receptors
      (TLRs) in human bladder cells under the stimulus of Escherichia coli (E. coli)
      versus that under the stimulus of Bacillus Calmette-Guerin (BCG). METHODS: Human
      bladder cancer cell line T24 was cultured for 1 hour under the stimuli of various
      doses (bacillus-cell ratio) of E. coli and BCG respectively. The levels of
      expression of TLR-2 and TLR-4 mRNA in T24 cells were assessed by RT-PCR method.
      RESULTS: By comparison with control, there was no difference observed on the
      expression of either TLR-2 or TLR-4 in T24 cells under the stimulus of E. coli.
      The expression level of either TLR-2 or TLR-4 was increased under the stimulus of
      BCG in a dose-dependent manner. The effects reached the highest level when the
      dose of BCG was 10 bacilli per cell. CONCLUSION: There exist different expression
      patterns of TLRs in bladder transitional cells under the different stimuli of E.
      coli and BCG respectively.

PMID- 15181831
TI  - [Regulative effect of STAT1 on inflammation of lung tissue in bleomycin-induced
      rat interstitial pulmonary fibrosis].
AB  - OBJECTIVE: To investigate the role of signal transducer and activator of
      transcription 1 (STAT1) in alveolar macrophage (AM) in bleomycin-induced rat
      pulmonary fibrosis. METHODS: Fifty adult female Wistar rats were randomly divided
      into two groups. The rats of BLM group were intratracheally instilled with
      bleomycin (BLM), and those of the control group with normal saline(NS). The
      kinetic change of STAT1 activation and the intercellular adhesion molecule-1
      (ICAM-1) expression in AM were examined. RESULTS: STAT1 was slightly activated in
      AM of NS group. After bleomycin treatment, the STAT1 activation of AM
      significantly increased on day 1, reached the peak value on day 7, and then
      gradually decreased, yet it remained significantly above the value of the NS
      group on day 28 (P < 0.05). There were a few positive staining cells for ICAM-1
      expression in AM of NS group. After intratracheal instillation of bleomycin, the
      number of positive staining cells for ICAM-1 expression significantly increased
      on day 1, reached the peak value on day 7, gradually decreased from then on, but
      still it was higher than that of the NS group on day 28 (P < 0.05). There was a
      significant correlation between STAT1 activation and ICAM-1 expression in AM (r =
      0.913, P < 0.01); moreover, ICAM-1 expression in AM was significantly correlated
      with the degree of inflammation in lung tissue (r = 0.947, P < 0.01). CONCLUSION:
      STAT1 was found abnormally activated in AM in bleomycin-induced rat interstitial
      pulmonary fibrosis (IPF). The abnormal STAT1 activation may play a role in the
      pathogenesis of acute alveolitis and pulmonary fibrosis.

PMID- 15181832
TI  - [Study of beta 1-integrin in neonatal rats with ischemic renal injury].
AB  - OBJECTIVE: To study the change of beta 1-integrin in neonatal rats with ischemic
      renal injury. METHODS: Twenty-four neonatal rats weighing from 30 to 40 g were
      chosen. Anesthesia was carried out by peritoneal injection of nembutal-sodium
      solution (4 mg/100 g). Renal ischemic injury model was induced by clamping the
      left renal pedicle for different periods of time. The kidneys of normal neonatal
      rats were functioned as the control group. Immunofluorescence technique was used
      to detect the location of beta 1-integrin in kidney, especially in cortex.
      RESULTS: In control group, beta 1-integrin subunit was found to be located mainly
      in the basal membrane of tubular epithelial cell. After 10 minutes of ischemia,
      immunostaining highlighted the broken basement membranes of the experiment
      groups. The longer the ischemia continued, the more the broken points we
      observed. There were significant differences between the experiment groups and
      the control group. Yet, no significant difference in the IOD value of beta 1
      integrin was seen between the 10-min-ischemia and 30-min-ischemia groups.
      CONCLUSION: Under physiological condition, beta 1-integrin is distributed over
      the basal membrane of the tubular epithelial cell of neonatal rat. Ischemic
      injury can cause the changes of beta 1-integrin which may be the reason of
      exfoliation and depolarization of tubular epithelia cell.

PMID- 15181833
TI  - [The changes of beta 1-integrin and its mRNA distribution in renal tubular
      epithelial cells during kidney ischemia/reperfusion injury in neonatal rats].
AB  - OBJECTIVE: By studying the distribution and expression of beta 1-integrin and its
      mRNA in renal tubular epithelial cell at different ischemia/reperfusion time
      phases we probe the role of beta 1-integrin in I/R injury of neonatal animals.
      METHODS: The neonatal SD rat ischemia/reperfusion model was set up.
      Immunofluorescent staining and in situ hybridization (ISH) were used to show the
      distribution and expression of beta 1-integrin with its mRNA in renal tubular
      epithelial cells and the quantities of beta 1-integrin and its mRNA were counted
      by ImagePlus-Pro system. RESULTS: 1. beta 1-integrin was located at the basal
      plasma membrane in normal renal tubular epithelial cells. After ischemia for 0.5
      h, the redistribution was not significant. After reperfusing for 0.5 h, beta 1
      integrin began to move onto the lateral and apex surfaces of cells. This kind of
      change was most apparent after reperfusion for 2 h and was accompanied with
      reduced expression and destruction of renal tubular. No positive dying was seen
      in the lumen. The regeneration started 24 hours post-ischemia. beta 1-integrin
      was redistributed onto the basal plasma membrane. After reperfusion for 120
      hours, the regeneration ended, but the expression did not gain the normal level.
      2. The mRNA of beta 1-integrin was mainly expressed in the cell plasma. Its
      expression was increased while reperfusion for 0.5 h to 2 h and was still above
      normal level after 24 h to 120 h of reperfusion. CONCLUSION: The distribution of
      beta 1-integrin was "depolarized" and its expression was reduced. But the level
      of mRNA was raised, which indicated that during ischemia/reperfusion injury,
      there were mechanisms that influenced the distribution and synthesis of beta 1
      integrin at the same time.

PMID- 15181834
TI  - [Pathological changes and apoptosis of brain cells in rat embryo suffering from
      intrauterine hypoxia-ischemic injury].
AB  - OBJECTIVE: To observe the pathological changes of fetal rat brain cells caused by
      transient intrauterine ischemia in pregnant rats. METHODS: The uterine arteries
      of the pregnant rats at 17 days of gestation were clamped for 30 min in the
      experimental group, the samples were collected 24, 48 and 72 hours respectively
      after the clamping of artery, respectively. In control group, the pregnant rat's
      abdomens were cut open and closed but the uterine arteries were kept intact; the
      samples were collected 24, 48 and 72 hours after the sham operation,
      respectively. The pathological changes of brain tissues were observed under light
      microscope by HE, Nissl, cholinesterase staining, sequential TUNEL technique, and
      by electron microscopy as well. RESULTS: The edema, degeneration of neural cells
      and the hemorrhage of brain were observed in experimental group. The Nissl bodies
      and the activity of cholinesterase decreased. The apoptosis cells appeared 24
      hours after hypoxia-ischemia injury and increased progressively with time.
      CONCLUSION: Uterine hypoxia and ischemia can cause severe damage to neural cells
      of fetal rat.

PMID- 15181835
TI  - [Three-dimensional finite element analysis of maxillary canine during the tooth
      translation movement].
AB  - OBJECTIVE: To find the characteristic of the stress distribution in the
      periodontal tissue during maxillary canine distal translation. METHODS: The model
      was implemented numerically by means of the 3-dimensional finite element method
      (FEM) and was used to simulate orthodontic tooth translation movements. The
      finite element model was loaded with defined force systems. And the stresses at
      0, 7, 14, and 21 days of loaded distal force and moment in maxillary canine were
      calculated. RESULTS: During the whole distal translation of canine, 1. the stress
      in alveolar bone was higher than that in peridontal ligament; 2. the stresses in
      the cervical region were higher than those in the apical region of the alveolar
      bone and periodontal tissues; 3. the stresses in the cervical, medium and apical
      regions of periodontal tissue were on the decline, and the stress in cervical
      region declined faster than that in apical region. On the 21st day the stresses
      in the cervical, medium and apical regions were similar. CONCLUSION: The 3-D FEM
      analysis revealed that alveolar bone loss could be most likely to happen during
      the initial stage of the tooth movement, and the data from this study mihgt be
      helpful to orthodontists in selecting an appropriate device of force systems to
      control the initial loading during orthodontic treatment.

PMID- 15181836
TI  - [Influence of loops on the torsion stiffness of rectangular wire].
AB  - OBJECTIVE: To study the influence of loops on the torsion stiffness of
      rectangular wire. METHODS: The torsion moments and angles of 0.018 inch x 0.025
      inch rectangular orthodontic arch wires in single 0.022 inch bracket of the first
      maxillary incisor were measured with a torsion measurement apparatus, and the
      measured values were analyzed by two-way ANOVA. The wires included straight
      stainless steel rectangular wires, and 3.5 mm, 7 mm, 10.5 mm, 14 mm high vertical
      loop wires, and 3 mm, 6 mm, 9 mm, 12 mm long horizontal loop wires. RESULTS: 1.
      The torsion stiffnesses of straight wire and vertical and horizontal loop wires
      were 4.909, 4.544, 4.137, 3.851, 3.454, 3.448, 3.024, 2.686, 2.378 N.mm/degree
      respectively. 2. The arch wires will be twisted 19.143 degrees, 19.377 degrees,
      19.851 degrees, 20.949 degrees, 21.632 degrees, 21.812 degrees, 22.418 degrees,
      23.254 degrees, 24.316 degrees respectively to obtain 20 N.mm force. CONCLUSION:
      The design of loop can reduce the torsion stiffness of rectangular wire. Compared
      with the length of loop, the shape of loop has more important effect on the
      reduction of torsion stiffness. The horizontal loop design as a factor for the
      control of the tongue is more effective than the vertical loop design.

PMID- 15181837
TI  - [Effect of tea polyphenol on the demineralization and remineralization of enamel
      in vitro].
AB  - OBJECTIVE: To investigate the effect of tea polyphenol (TP) on the mineralization
      behaviour of enamel in two sterile, in vitro systems. METHODS: In the
      demineralization study, sound enamel sections were pH-cycled. Treatments were
      2000 mg/L TP, 200 mg/L TP, 2000 mg/L TP + 100 mg/L fluoride, 100 mg/L fluoride,
      and deionized water. In the remineralization study, surface-softened enamel was
      used and pH-cycled as above. Test treatments were 2000 mg/L TP, 2000 mg/L TP +
      250 mg/L fluoride, 250 mg/L fluoride, and deionized water. The acidic buffers
      were retained for calcium analysis. The enamel was analysed before and after pH
      cycling by microhardness. RESULTS: In the demineralization study, the calcium
      depletion rates(CDR) were (0.43 +/- 0.05), (0.49 +/- 0.006), (0.21 +/- 0.02),
      (0.21 +/- 0.03) and (0.50 +/- 0.11) microgram/(mm2.h) respectively. The Knoop
      hardness values(KHV) percent reduction were 94.19 +/- 3.50, 96.62 +/- 0.63, 74.74
      +/- 4.09, 77.79 +/- 3.11 and 97.32 +/- 4.03 respectively. There were no
      significant differences within either the TP-only groups or the fluoride groups,
      but the fluoride groups were significantly more efficacious than the TP-only
      groups (P < 0.05). In the remineralization study, the KHV percent increase were 
      11.96 +/- 10.1, -21.32 +/- 11.3, -49.52 +/- 24.6 and -4.24 +/- 8.51 respectively.
      Notably more remineralization was observed in the fluoride group. There were no
      significant differences between the other groups (P > 0.05). CONCLUSION: The data
      of this in vitro study suggest that TP has no effect on de/remineralization of
      enamel blocks and there is no synergetic action of TP and fluoride in a sterile
      system. This finding supports the proposition that tea polyphenols exert an anti
      caries effect via an anti-microbial mode-of-action.

PMID- 15181838
TI  - [Expression of soluble intercellular adhesion molecule-1 in peri-implant sulcular
      fluid].
AB  - OBJECTIVE: To investigate the expression of soluble intercellular adhesion
      molecule-1(sICAM-1) in peri-implant sulcular fluid (PISF) of different health
      conditions. METHODS: According to the health condition and plaque adhesion around
      dental implant, 51 titanium implants of 30 partly edentulous patients were
      divided into 3 groups: healthy group(H), gingivalis group(G) and peri-implantitis
      group(P). The clinical parameters included peri-implant pocket depth(PPD),
      gingival blood index (GBI), modified plaque index (mPLI) and sICAM-1. We used
      periopaper strips to collect PISF and an ELISA technique to measure the levels of
      sICAM-1. RESULTS: The PPD levels of H, G and P groups were (2.64 +/- 1.00) mm,
      (3.65 +/- 0.60) mm and (4.39 +/- 1.46) mm respectively. The sICAM-1 levels in the
      three groups were (348.10 +/- 313.27) ng/ml, (898.30 +/- 501.14) ng/ml and
      (1149.36 +/- 1035.78) ng/ml. The sICAM-1 levels of PISF in the inflammatory
      groups and plaque adhesion groups were significantly higher than that in the
      healthy group and non-plaque adhesion group (P < 0.05). The PPD level in
      inflammatory groups was also significantly higher than that in healthy group.
      CONCLUSION: Both the patients with peri-implantitis and the healthy controls
      showed the presence of sICAM-1 in PISF. Plaque accumulation might trigger the up
      regulation of sICAM-1 levels, and the onset of inflammation would enhance the up
      trend.

PMID- 15181839
TI  - [Photodegradation of nonylphenol in water].
AB  - OBJECTIVE: To investigate the environmental degradation process of
      nonylphenol(NP): METHODS: The NP was detected by HPLC, and the system of
      ultraviolet light, ferrous ion and hydrogen peroxide was used to promote photo
      degradation of NP in water. RESULTS: The maximal photo-degradation of NP occurred
      at the 5.0 mg/L of Fe2+, pH 2.5 and 1 ml/L of H2O2, the environmental factors in
      order of importance to promoting the photo-degradation of NP were: illumination
      time, initial concentration of NP, pH value, concentration of H2O2, concentration
      of Fe2+. CONCLUSION: The system of ultraviolet light, ferrous ion and hydrogen
      peroxide was effective in promoting the photo-degradation of NP.

PMID- 15181840
TI  - [Behavioral features of men who have sex with men].
AB  - OBJECTIVE: This behavioral surveillance survey in Sichuan province was aimed to
      gain an insight into the behavioral features related to HIV prevalence among men
      who have sex with men (MSM). METHODS: The pilot survey was initiated in the year
      from September to December, 2003. Two cities, Chengdu and Nanchong, were selected
      as the surveillance sites. All behavioral data were collected by a special
      questionnaire. Convenience sampling and snowball sampling techniques were applied
      to recruit participants in 5 types of places where MSM appeared more often.
      RESULTS: Most of the participants sexed only with male partners, and the most
      common ways of intercourse for MSM were anal sex, mouth sex and masturbation. The
      cases of multiple sex partners existed generally in MSM. The median partner
      numbers for anal sex and mouth sex were 4.4 and 4.2 respectively. There were 491
      MSM (84.7%) who had sexed with male partners 6 months before, in which 68.6% of
      them sexed with non-commercial regular male partners, 66.2% with non-commercial
      non-regular male partners, and 20.4% with commercial male partners. Condom use
      with different male partners varied significantly. The proportions of consistent
      condom use with non-commercial regular, non-commercial non-regular, and
      commercial male partners were 15.8%, 16.3% and 32.3% respectively. 1.9% of
      participants reported they had had the experience of injecting drug and 18.3% of
      participants reported they had been tested for HIV antibody 12 months before.
      CONCLUSION: High risk behaviors such as multiple sex partners, unprotected anal
      sex, commercial sex, and injecting drug use among the MSM population in the two
      cities were unveiled broadly.

PMID- 15181841
TI  - [Survey of behaviors and knowledge about HIV/AIDS among intravenous drug users at
      a city in Sichuan Province].
AB  - OBJECTIVE: To understand high risk behaviors related to HIV/AIDS and the
      intravenous drug users' knowledge about HIV/AIDS. METHODS: Forty-eight
      intravenous drug users (IDUs) were interviewed by using questionnaires. RESULTS:
      The survey showed that 75% of the subjects were male, 83.3% of their educational
      levels were below junior middle school, and most of them lived in cities(83.0%),
      having no occupation or having special occupation. The age at the beginning of
      drug use was 11 years old, the ages in cities were earlier than those in the
      countryside (F = 3.898, P = 0.029). For the reasons of using drug, 58.1% of IDUs
      did so through curiosity; 57.1% of IDUs had ever shared the syringes and needles
      with others, 62.5% of them shared with fixed people. 79.5% of the IDUs had casual
      sex partners, and 68.75% had multiple sex partners, but only less than 40% of
      them used condoms when having sex with casual partner. CONCLUSION: There are many
      high risk factors related to the IDUs' drug addiction and sex behaviors which can
      facilitate the transmission of HIV.

PMID- 15181842
TI  - [The effect of tripterygium wilfordii polyglycosidium on the compound action
      potential of skeletal muscle in experimental animals with myasthenia gravis].
AB  - OBJECTIVE: To observe and analyze the direct effect of tripterygium wilfordii
      polyglycosidium (TWP) on the activity of skeletal muscle in experimental animals
      with myasthenia gravis (EAMG). METHODS: C57BL/6 mice were used. After sieving
      EAMG animals, we observed and compared the variation of the attenuation
      percentage of compound action potential of gastrocnemius muscle and pronator
      teres muscle of EAMG before and after the muscle specimens being immersed in the
      breeding ground of TWP solution. Such variation of attenuation percentage was
      taken as an indicator of the direct effect of TWP on skeletal muscle. RESULTS: 1.
      Evident influence of TWP on the attenuation percentage of compound action
      potential of gastrocnemius muscle was observed (P < 0.05), and apparent decrease
      of the attenuation percentage could be seen one and a half hours after the muscle
      was immersed [(14 +/- 36)% before treatment, (-40 +/- 24)% after treatment]; 2.
      The influence of TWP on the attenuation percentage of compound action potential
      of pronator teres muscle was noted (P < 0.05), and an apparent decline of the
      attenuation percentage could be observed one and a half hours after the muscle
      was immersed[(17 +/- 25)% before treatment, (-17 +/- 10)% after treatment]; 3.
      There was no distinctive difference between the gastrocnemius muscle and pronator
      teres muscle in respect of their attenuation percentages of compound action
      potential. CONCLUSION: TWP has direct remedial effect on the activity of skeletal
      muscle of EAMG.

PMID- 15181843
TI  - [Applying distortion product otoacoustic emission in testing human sensory
      hearing loss].
AB  - OBJECTIVE: To probe into the application of distortion product otoacoustic
      emission (DPOAE) test in human sensory hearing loss (SHL) research using lower
      stimulus parameter L1 = 65 dB, L2 = 50 dB. METHODS: Elicitation rate, size of
      DPOAE and correlation between DPOAE and pure tone auditory threshold were
      analyzed, and then the sensitivity and specificity were calculated. RESULTS:
      DPOAE was elicited in all of the hearing normal controls (25 subjects, 50 ears).
      In SHL cases (40 patients, 53 ears), DPOAE was elicited in 51 ears at 4 kHz and 6
      kHz, and in 53 ears at 1 kHz and 2 kHz. The DPOAE size at each frequency in the
      normal group was higher than that in the SHL group (P < 0.05). A negative
      correlation between DPOAE size and pure tone auditory threshold was revealed by
      means of Spearman rank sum test. The sensitivity and specificity of DPOAE for
      testing SHL were better than those in literature reports. CONCLUSION: The DPOAE
      elicited by lower stimulus parameter mainly reflects the function of outer hair
      cells of inner ear, and thus it may provide some guidance or information for
      clinical diagnosis and treatment of SHL.

PMID- 15181844
TI  - [Effects of different respiratory rates on PaCO2 and plasma potassium
      concentration].
AB  - OBJECTIVE: To observe the effects of different respiration rates on the CO2
      partial pressure and plasma potassium concentration during general anesthesia.
      METHODS: Forty-two surgical patients under general anesthesia with normal
      preoperative arterial CO2 partial pressure and plasma potassium concentration
      were randomized into 2 groups. After intubation, all patients were placed on the
      mechanical ventilator (Ohmeda 210 anesthesia machine) with tidal volume 10 ml/kg
      and oxygen flow rate 1.5 L/min. Initial respiratory rate of group I patients was
      set to 12 times per minute for 30 minutes, and then was adjusted according to
      calculation with 0.3 x PaCO2. Respiratory rate of group II patients was set to 8
      times per minute. Blood samples were collected for arterial blood gas analysis
      preoperatively, and 30 and 60 minutes after intubation. Linear regression was
      used to analyze the relationship between PaCO2 and plasma with K+ concentration
      and Student's t test was used to test the differences at different time points.
      An overall alpha of 0.05 was considered significant for the outcome variables.
      RESULTS: In two groups, PaCO2 (mmHg) was related with K+ concentration (mmol/L)
      (P < 0.05) at all time points. 30 minutes after intubation, PaCO2 and K+
      concentration significantly decreased (P < 0.05) and recovered to preoperative
      level after the respiratory rate being adjusted [(to 8.85 +/- 0.73) times/min]
      for another 30 minutes in group I. No significant difference in respect to PaCO2
      and K+ concentration was found between any two time points in group II.
      CONCLUSION: Traditional ventilation with VT 10 ml/kg and RR 12-15 times/min will
      probably produce hyperventilation and hypokalemia.

PMID- 15181845
TI  - [Genetic study on 27 children with beta-thalassemia major and their parents in
      Sichuan area].
AB  - OBJECTIVE: This genetic analysis on 27 children with beta-thalassemia major and
      their parents was performed in an attempt to elucidate the characteristics of
      gene mutations, and to improve the early diagnosis and prevention of this disease
      in Sichuan area. METHODS: The hematologic studies of beta-thalassemia included
      the osmotic fragility of erythrocyte determined by brine osmosis method, the HbF
      qualitatively determined by one minute anti-alkaline method, the HbA2 assayed by
      acetyl-cellulose membrane electrophoresis and eluate photometric method, and the
      total hemoglobin measured by the ferric-cynade method. DNA was extracted from
      peripheral white blood cell with standard method (phenol-chloroform extract).
      Multiple allele specific polymerase chain reaction (MASPCR) was used for targeted
      DNA amplification and gene mutation analysis. RESULTS: It was found that the most
      common mutants in Sichuan area were CD17 (A-->T), CD41-42 (-TTCT) and IVS II -654
      (C-->T). Their percentages were 43.64%, 36.36% and 14.54%, respectively.
      CONCLUSION: MASPCR method is a simple, effective and inexpensive method for
      genetic diagnosis of beta-thalassemia major. We identified 3 most common mutants
      in Sichuan by using MASPCR.

PMID- 15181846
TI  - [Clinical application of linkage analysis for vWD family].
AB  - OBJECTIVE: To explore the application of amplified fragment length polymorphism
      (amp-FLP) of short tandem repeat (STR) within intron 40 of vWF gene in the gene
      diagnosis and genetic consulting service for von Willebrand disease (vWD).
      METHODS: We isolated DNA from the blood of members in 8 families with vWD,
      measured the relative parameters of vWD simultaneously; and amplified the
      fragment length polymorphism of two loci (nt1890-1990 and nt2215-2380) within
      intron 40 of vWF gene using PCR. The RCR products were analyzed by means of
      polyacrylamide gel electrophoresis (PAGE) and silver staining. RESULTS: Five
      types of amp-FLP were identified on nt1890-1990 and nt2215-2380 respectively.
      Haplotypes could be identified to link with defective vWF gene in these families.
      CONCLUSION: Combination of PCR and PAGE is a fast and practical method for
      carrying out family analysis of inherited disease; nt1980-1990 and nt2215-2380 of
      vWF gene are two ideal genetic labels in linkage analysis and hereditary
      consultation of vWD family.

PMID- 15181847
TI  - [Effectiveness of urokinase used in combination with batroxobin (DF-521) in rat
      model of focal cerebral ischemia-reperfusion].
AB  - OBJECTIVE: This study was designed to use urokinase (UK) in combination with
      batroxobin in thrombolytic therapy so as to see whether batroxobin(DF-521) would
      be effective for neuroprotection. METHODS: The model of right middle cerebral
      artery occlusion (MCAO) in male SD rats was established. 120 rats were randomized
      into 9 groups, namely control group, sham control group, and groups that were
      treated with batroxobin and urokinase together or separately. Each group
      comprised 15 rats. Intracranial bleeding, infarct volume ratio and neurological
      function were observed. RESULTS: Intracranial bleeding was found in 5 rats of the
      UK 5000 U/kg group, in 4 rats of the UK 5000 U/kg (2 h) + DF-521 5 BU/kg (2 h)
      group, and in only 1 rat of the UK 5000 U/kg (2 h) + DF-521 5 BU/kg (1 h) group.
      Cerebral infarct volume ratio was obviously reduced in 5 BU/kg batroxobin group.
      No difference was observed in neurological deficit scores. CONCLUSION: 5000 U/kg
      urokinase increased the risk of intracranial hemorrhage in rat MCAO model.
      Batroxobin either used separately or in combination with urokinase would not
      increase the risk of intracranial hemorrhage in rat MCAO model.

PMID- 15181848
TI  - [Gliquidon induced-desensitization of pancreatic beta cells and the partial
      reversion of responsiveness after the desensitization of exposure to drug in
      normal and STZ type 2 diabetic rats].
AB  - OBJECTIVE: To test if gliquidone (gli) induces beta cells desensitization as
      other sulfonylurea (Su) and the features of the reversion of responsiveness.
      METHODS: An obese type 2 diabetic (DM2) rat model was developed, for which low
      dose streptozocin (STZ, 25 mg/L) was injected i.p. into Wistar rats followed by
      high sucrose-fat diet feeding for 8 weeks as described previously. Islet cells
      from normal and DM2 rats were isolated and cultured over 24 h in a medium with or
      without gli and the static Ins secretion at various time intervals were measured
      by RIA. These islet cells either untreated or pre-treated for 24 h with various
      dosages of gli (500; 1000; 1500 ng/ml) were perifused by a column perifusion
      system. Ins release in response to the corresponding doses of gli was evaluated.
      RESULTS: Insulin secretion decreased remarkably under the static stimuli to DM2
      islets, compared with that of the normal controls (P < 0.05). Insulin secretion
      in normal islets in response to 500 and 1000 ng/ml gli rose to a peak level at
      the second hour, and then declined with the time, but the islets did not respond
      to 1500 ng/ml gli. Gli pre-treated islets gave no response to acute gli stimuli.
      Short term (10 min) removal of the islets from gli-exposure could not reverse the
      responsiveness; however, after the exposure to gli being discontinued for 20 h,
      desensitization could be reverted completely in use of 500 ng/ml gli; partially
      in use of 1000 ng/ml gli; but not in use of 1500 ng/ml gli. CONCLUSION: The
      results indicated that the exposure of beta cell to gli at various concentrations
      induced selective desensitization of the beta cell to gli stimuli; and the
      desensitization could be reverted completely or partially after the exposure
      being discontinued for 20 h to 500 ng/ml and 1000 ng/ml but not to 1500 ng/ml
      gli, respectively. The restoration of the response of beta cell to gli stimuli
      was dose-dependent and time-dependent.

PMID- 15181849
TI  - [Effect of L-arginine on the changes of cerebral microcirculation following
      craniocerebral missile wound at early stage in cats].
AB  - OBJECTIVE: To study the alterations of cerebral microcirculation and the effect
      of L-Arginine after craniocerebral missile wound (CMW) at early stage in cats.
      METHODS: The CMW animal model in cat was constructed by Carey method. Altogether
      12 mongrel cats with either sex were divided into the CMW group and the L
      Arginine treatment group. The caliber (D), velocity (V) and blood flow (Q) of
      pial microvessels and pathological examination of brain tissue at 10 min before
      CMW and from 5 min to 5 h after CMW were evaluated in each group. RESULTS: 1. In
      CMW group, although the Da, Va and Qa of pial arteriole decreased from 5 to 20
      minutes, Da and Qa elevated at 90 minutes after CMW. There were no significant
      changes in the Dv of pial venule, but the levels of Vv and Qv were lower at 5 min
      and 20 min after CMW. Qv increased from 45 min to 3 h after CMW. The pial venules
      were in congestion situation. 2. In the L-Arginine treatment group, the pial
      aterioles persistently dilated after CMW. The blood flow of pial aterioles
      increased at 20 min after CMW and the higher level lasted 5 h. Similarly, the
      dilation of pial venules was observed, and the blood flow increased at 20 min
      after the injury, followed by venules constriction temporarily. 3. Petechial
      hemorrhage, microthrombosis and nerve cell swelling were found in the cortex on
      the opposite side of the trauma area. The pathological changes were less severe
      in the L-Arginine treatment group than those in the CMW group. CONCLUSION: At the
      early stage after CMW, there are obstructions to cerebral microcirculation, which
      induce brain ischemia, hypoxia and secondary failure of cerebral function. The
      mechanism by which L-Arginine alleviates the impaired cerebral microcirculation
      may lie in the vascular activation of L-Arginine-NO system.

PMID- 15181850
TI  - [Study on the TIL and NK of IL-2 injected via pelvic retroperitoneal space in
      gynecological cancer patient].
AB  - OBJECTIVE: To verify the feasibility and effect of biotherapy instituted via
      pelvic retroperitoneal space on gynecological cancer. METHODS: Injecting IL-2
      (and/or) 5-Fu through a tube installed in the pelvic retroperitoneal space.
      Counting the subpopulation of T cell and NK of lymph-nodes of pelvis after the
      drugs being by FCM. RESULTS: The numbers of CD3+, CD4+, CD8+, CD25+ and NK cells
      in treatment group were significantly higher than those in the control group. And
      the numbers of these cells in the IL-2 + 5-Fu group were significantly higher
      than those in the 5-Fu group. The CD25+ and NK cell numbers in the IL-2 group
      were significantly higher than those in the 5-Fu group (P < 0.05). CONCLUSION:
      The IL-2 injected via pelvic retroperitoneal space can promote the activity,
      development and infiltrating of T cell and NK cell in the tumor tissue.

PMID- 15181851
TI  - [Influence of illuminance on the photo-reaction rate order of nitrofurazone
      solution].
AB  - OBJECTIVE: To explore the relationship between the illuminance and the observed
      order of reaction of photodegradation of nitrofurazone solution. METHODS:
      Studying the observed order of reaction of photodegradation of nitrofurazone
      solution exposed to light with three illuminance values at three concentration
      values respectively. RESULTS: The observed order of reaction of photodegradation
      increased with the decrease of concentration when the illuminance kept constant
      and, on the other hand, the observed order increased with the increase of
      illuminance when the concentration kept constant. CONCLUSION: The observed order
      of reaction of photodegradation of nitrofurazone solution depends on both the
      concentration of the drug and the illuminance of the incident light.

PMID- 15181852
TI  - [Measurements of the flux densities of static magnetic fields generated by two
      types of dental magnetic attachments and their retentive forces].
AB  - OBJECTIVE: To measure and analyze the flux densities of static magnetic fields
      generated by two types of commonly used dental magnetic attachments and their
      retentive forces, and to provide guidance for the clinical application of
      magnetic attachments. METHODS: A digital Gaussmeter was used to measure the flux
      densities of static magnetic fields generated by two types of magnetic
      attachments, under four circumstances: open-field circuit; closed-field circuit;
      keeper and magnet slid laterally for a certain distance; and existence of air gap
      between keeper and magnet. The retentive forces of the magnetic attachments in
      standard closed-field circuit, with the keeper and magnet sliding laterally for a
      certain distance or with a certain air gap between keeper and magnet were
      measured by a tensile testing machine. RESULTS: There were flux leakages under
      both the open-field circuit and closed-field circuit of the two types of magnetic
      attachments. The flux densities on the surfaces of MAGNEDISC 800 (MD800) and
      MAGFIT EX600W (EX600) magnetic attachments under open-field circuit were 275.0 mT
      and 147.0 mT respectively. The flux leakages under closed-field circuit were
      smaller than those under open-field circuit. The respective flux densities on the
      surfaces of MD800 and EX600 magnetic attachments decreased to 11.4 mT and 4.5 mT
      under closed-field circuit. The flux density around the magnetic attachment
      decreased as the distance from the surface of the attachment increased. When
      keeper and magnet slid laterally for a certain distance or when air gap existed
      between keeper and magnet, the flux leakage increased in comparison with that
      under closed-field circuit. Under the standard closed-field circuit, the two
      types of magnetic attachments achieved the largest retentive forces. The
      retentive forces of MD800 and EX600 magnetic attachments under the standard
      closed-field circuit were 6.20 N and 4.80 N respectively. The retentive forces
      decreased with the sliding distance or with the increase of air gap between
      keeper and magnet. CONCLUSION: The magnetic attachments have flux leakages. When
      they are used in patients' oral cavities, if keeper and magnet are not attached
      accurately, the flux leakage will increase, and at the same time the retentive
      force will decrease. Therefore the keeper and magnet should be attached
      accurately in clinical application.

PMID- 15181854
TI  - [Establishment of methods of mechanical dissociation and culture of spiral
      ganglion neurons in postnatal mice].
AB  - OBJECTIVE: To conduct a study on the methods for establishing a cytological model
      of mechanical dissociation and culture of spiral ganglion neurons (SGNs) in
      postnatal mice. METHODS: The spiral ganglion neurons were taken from 1-6-day old
      mice for primary culture. The morphology and the process of axon were observed by
      use of an inverted/phase contrast microscope. Immunocytochemical identification
      was performed using fluorescent microscopy. RESULTS: In the state of primary
      culture in vitro, the SGNs were found to have good cell morphology and axon
      regeneration power, the surviving cells of SGN(5-7 d) amounted to (78.10 +/-
      4.33)/cm2 and the survival period was 7-14 d. CONCLUSION: We successfully
      established the methods of mechanical dissociation and culture of SGN cytological
      model; the cell amount and survival period of SGNs were able to meet the
      requirement of cytological experiments.

PMID- 15181853
TI  - [Comparing two kinds of labeled streptavidin biotin methods and selecting the
      best antigen retrieval method].
AB  - OBJECTIVE: To compare two kinds of labeled streptavidin biotin(LsAB) methods and
      provide the optimal method of antigen retrieval. METHODS: The alkaline
      phosphatase(AP) LsAB method and the horseradish peroxidase (HRP) LsAB method were
      used to stain anti-tryptase in paraffin embedding tissue of patients with chronic
      obstructive pulmonary disease (COPD) and their staining effects were compared.
      The antigens were repaired by high pressure cooking, tryptin digestion and
      microwave, and the repairing effects were compared. RESULTS: The backgrounds of
      stained sections were more distinct and the color distinction of nucleus and
      positive signal were brighter by AP-LsAB, compared with those by HRP-LsAB; the
      repairing effect of high pressure cooking was better than the repairing effect of
      tryptin digestion and than that of microwave. CONCLUSION: AP-LsAB and high
      pressure cooking retrieval were recommended for use in immunohistochemical
      staining of pulmonary inflammatory tissue.

PMID- 15181855
TI  - [Comparison of three methods for quantitative analysis of LPO in different
      biological samples].
AB  - OBJECTIVE: To explore the optimized methods for detecting lipid peroxide (LPO) in
      biological samples and the reference value of LPO in human plasma. METHODS: Three
      most commonly adopted methods were used for detecting LPO in different biological
      samples simultaneously, and then their linearity, accuracy, precision, stability
      and detecting efficiency were compared. The methods were FOX assay, Modified
      iodometric assay and TBARS assay. The standard curve (linearity evaluation), rate
      of sample recovery (accuracy evaluation), reproducibility (precision evaluation),
      stability of reading number (stability evaluation), as well as the detected
      values of LPO in different sample systems by three methods simultaneously
      (detecting efficiency) were evaluated. The sample systems were: isolated low
      density lipoprotein (LDL), supernatant of cell culture, and human plasma.
      RESULTS: When applied to detecting LPO in the isolated LDL sample system, FOX
      assay was found to have the most sensitive detecting efficiency, good accuracy
      and precision. When applied to detecting LPO in the supernatant of cell culture
      and human plasma sample systems, the Modified iodometric assay and TBARS assay
      showed better function than FOX assay; the rate of sample recovery of FOX assay
      61.92% +/- 2.92% was obviously lower as compared with 99.00% +/- 2.65% of
      modified iodometric assay and 101.63% +/- 12.00% of TBARS assay; and the
      reproducibility of FOX assay 19.15% was also lower as compared with 4.36% of
      Modified iodometric assay and 3.14% of TBARS assay. The three methods all showed
      fine linearity and stability. The values of LPO concentration in normal human
      plasma were (14.189 +/- 4.889) mumol/L by Modified iodometric assay and (0.936 +/
      0.462) mumol/L by TBARS assay; these values were close to those in other
      reports. CONCLUSION: FOX assay was found to be most sensitive in the three
      methods for measurement of LPO in a relative pure sample system (such as isolated
      LDL). In complex sample system, however, the Modified iodometric assay and TBARS
      assay showed better function. The authors suggest that suitable method be chosen
      according to the nature of sample, that more than one method be chosen for plasma
      LPO assay in the same planned analysis, and that Modified iodometric assay and
      TBARS assay be worth the first choice.

PMID- 15181856
TI  - [Detection of pentachlorophenol in biomaterial using HPLC].
AB  - OBJECTIVE: To develop a method of detecting pentachlorophenol in biomaterial.
      METHODS: The samples were extracted by ether, and the characters of the high
      performance liquid chromatography (HPLC) method were studied. RESULTS: A method
      for the detection of pentachlorophenol in fish tissue samples was set up with the
      conditions of chromatography as follows: the compounds are separated on Hypersil
      ODS column(4.6 mm i.d. x 150 mm, 5 microns) and eluted with methanol which
      contains 2 g/L NH4Ac (20:80) using 305 nm as the detecting wavelength, the
      recovery of method being 76%, the linear range 0.042 microgram/g-1.344
      micrograms/g, and the correlation coefficient 0.9994, the limit of quantification
      0.014 microgram/g. Finally, pentachlorophenol was successfully detected in the
      fish tissue samples. CONCLUSION: The method has been proven useful in the
      forensic cases involved in the poisoning of pentachlorophenol.

PMID- 15181858
TI  - Healers at war.

PMID- 15181859
TI  - Risperidone long-acting injection: a brief overview.

PMID- 15181857
TI  - [Clinical and pathological analyses of lipoprotein glomerulopathy].
AB  - OBJECTIVE: To investigate the clinical and pathological characteristics of
      lipoprotein glomerulopathy. METHODS: We retrospectively analyzed 3 cases of
      lipoprotein glomerulopathy. RESULTS: The 3 patients, 1 male and 2 females, were
      young Hans. They were admitted to our hospital because of edema. Patient 1 had a
      positive family history. Her proteinuria ranged between 0.8-1.5 g/d, her serum
      albumin levels were below the normal lower limit, and she was afflicted with
      anemia. Patient 2 was found having slightly increased serum creatinine,
      hypertension, and increased total cholesterol and triglyceride level. The kidneys
      of patient 3 were enlarged. Increments of glomerular size and capillary lumen
      space were observed under microscope. Bioptic specimens of the patients' kidneys
      displayed extensive prominent lucent casts in the capillary lumen, which were
      stained as pale mesh-like substance and were not stained by silver impregnation.
      Immunofluorescence microscopy revealed faint immunoglobulin deposit. These casts
      were stained positive for apoE. CONCLUSION: Lipoprotein glomerulopathy is
      pathologically characterized by extensive glomerular capillary casts which are
      stained positive for apoE, and clinically it is characterized by edema,
      proteinuria, hypoalbuminaemia and anemia.

PMID- 15181860
TI  - Modernizing the South Dakota State Medical Association: streamlining and
      simplifying the association for more relevance and effectiveness.

PMID- 15181861
TI  - Infectious mononucleosis presenting as postpartum fever.
AB  - Infectious Mononucleosis and pregnancy are common conditions seen by
      obstetricians and family physicians. However, infectious mononucleosis in the
      postpartum period has not been reported in the literature. A 20 year-old woman
      presented with a four-day history of fever of 40 degrees C, and chills at her six
      week postpartum visit, which prompted an evaluation of the cause of the fever.
      The atypical presentation of mononucleosis in this patient delayed the eventual
      diagnosis. Although Infectious Mononucleosis has not been mentioned in the
      literature as a cause of postpartum fever, it is likely more common than
      realized. For that reason the evaluation of Infectious Mononucleosis and
      postpartum fever are discussed.

PMID- 15181862
TI  - [The impact of low-dose aspirin therapy on umbilical and middle cerebral artery
      blood flow in pregnancy complicated by idiopathic intrauterine growth
      restriction].
AB  - AIM: Intrauterine growth restriction and its treatment still constitute a major
      clinical problem in perinatology. Since low doses of aspirin could improve the
      utero-placental circulation (by shifting the prostacyclin/thromboxane A2
      balance), we have evaluated the impact of low-dose aspirin treatment of IUGR
      during pregnancy on umbilical (UA) and middle cerebral artery (MCA) blood flow.
      MATERIAL AND METHODS: The study comprised 32 pregnant women with idiopathic fetal
      intrauterine growth restriction (IUGR) diagnosed during pregnancy on the basis of
      ultrasound examination of biometric parameters (BPD, FL, AC). All the patients
      were treated only by low-dose aspirin (1.5 mg/kg) for 8-14 days. The: fetal
      biometry and calculation of blood flow indices (S/D, RI, PI) in umbilical and
      middle cerebral artery were performed before and after treatment. RESULTS: Mean
      values of all biometric parameters of the fetuses measured before and after
      treatment did not show statistically important differences (AC-borderline
      significantly). Umbilical artery blood flow indices calculated after the
      treatment were slightly lower and MCA indices slightly higher, as compared to
      those before the treatment. Cerebro-placental ratio changed from 1.37 to 1.63
      (borderline significantly). CONCLUSIONS: IUGR treatment by low-dose aspirin had
      beneficial but non-significant impact on umbilical and middle cerebral artery
      blood flow. Since the number of subjects in this study was relatively small,
      further clinical studies are necessary to evaluate the effectiveness of IUGR
      treatment by low dose aspirin.

PMID- 15181863
TI  - [Twin pregnancies and their outcome at the Department of Obstetrics and
      Gynecology, Institute of Mother and Child in Warsaw, in the period of 1993-2000].
AB  - OBJECTIVE: The aim of this study was to analyse the course of twin pregnancies
      delivered at the Department of Obstetrics and Gynaecology, Institute of Mother
      and Child in Warsaw, from 1993 to 2000. MATERIALS AND METHODS: The medical
      documentation of women with twin pregnancy was looked into. Such parameters as
      mode of conception, maternal age and parity were taken into account. The data
      concerning the duration of pregnancy, mode of delivery, birth weight and
      condition of newly born infants were retrospectively reviewed. RESULTS: There a
      total of 232 (1.46%) twin pregnancies out of 15,869 births. A gradual increase in
      absolute number of twin deliveries and a relative increase of multiple
      pregnancies due to the use of assisted reproduction techniques was observed. The
      tendency to end twin pregnancies by caesarean section was detected. Although the
      perinatal care improved over the years, a small decrease of mean gestational age
      at delivery was observed. No significant difference in neonatal outcome in
      relation to the mode of delivery in researched material was noticed. CONCLUSIONS:
      The number of twin pregnancies due to the use of assisted reproduction techniques
      is on the increase. A percentage of women delivering for the first time has risen
      among women with twin pregnancy. Twin pregnancies are often ended by caesarean
      section and the frequency of caesarean sections has increased over time.

PMID- 15181864
TI  - [Clinical condition of newborns from water birth at the Perinatology Clinic,
      Institute Of Gynecology and Obstetrics of the Medical University in Lodz, in the
      years 1996-2001].
AB  - OBJECTIVE: The objective of the paper was the estimation of the babies from the
      water births. DESIGN: The comparison of newborns from water births to neonates
      from conventional deliveries. MATERIALS AND METHODS: Mature babies, who were born
      in the Clinics of Perinatology in the Institute of Gynecology and Obstetrics of
      the Medical University in Lodz, in the years 1996-2001. Neonates whose mothers
      were living in Lodz district were taken into consideration and datas were gained
      from the medical documentation. RESULTS: Women who delivered in water were mainly
      intellectual and primiparas. Among the newborns from water births many of them
      got from 8 to 10 points by Apgar score (92.9%), and only 7.1% were estimated for
      6 to 7 points. Birth weight in babies from water deliveries varied from 2300
      grams to 4050 grams and the majority (59.5%) was composed of newborns weighting
      3500 grams or more. Birth weight from 2500 grams to 3499 grams referred to 33.3%
      of the babies. In the control group from conventional deliveries, estimation by
      Apgar score was similar, but the body mass equal or higher than 3500 grams was
      seen only in 19.7% and the majority--80.3% was composed of babies with lower
      birth weight (2500 g-3499 g). The clinical condition of all the newborns
      delivered in water was good; they were healthy and only one baby suffered from
      inborn pneumonia, and another one from diaper dermatitis. There were no perinatal
      traumas in analysed babies. CONCLUSION: Taking into consideration such parameters
      as high Apgar score estimation, good clinical condition and absence of traumas,
      water delivery is to be judged as the advantageous one for newborns.

PMID- 15181865
TI  - [Comparison of sexual behavior after total or subtotal hysterectomy].
AB  - OBJECTIVES: Sexual life after supracervical or total hysterectomy is still
      controversial. DESIGN: The aim of study was to compare the impact of hysterectomy
      on frequency and quality of a woman's sexual life in women after supracervical vs
      total hysterectomy with nonmalignant conditions. MATERIAL AND METHODS: A total of
      539 women after total hysterectomy performed in Department of Gynecology in
      Gdansk and 65 women after supracervical hysterectomy operated in the hospital in
      Kartuzy in 1990-2000 were interviewed about symptoms as well as advantages and
      disadvantages after hysterectomy. RESULTS: There was no statistical difference
      between those groups comparing: sexual desire, dyspareunia, frequency of sexual
      relation, orgasm, vaginal dryness after operation. CONCLUSION: Total hysterectomy
      is recommended in benign conditions of uterine because of risk of cancer in the
      cervical stump after supracervical hysterectomy.

PMID- 15181867
TI  - [Preliminary evaluation of synthetic materials used in gynecologic operations
      through the vagina].
AB  - OBJECTIVES: The aim of the study was to evaluate the outcomes of meshes' use in
      gynecological vaginal operations. DESIGN: A prospective analysis of early
      postoperative results and complications. MATERIALS AND METHODS: All patients were
      operated on in Gynecological Department of District Hospital in Rzeszow. The
      investigated group consisted of 37 women suffering from pelvic organ prolapse.
      The degree of prolapse was evaluated with modified Baden Walker scale before
      procedure and three months after operation. Operations with use of synthetic
      materials (anterior and posterior colporraphy) were performed parallel with other
      gynecological procedures. The results of operations were compared to control
      group matched according to the age and parity. The control group consisted of
      patients operated on because of genital organs disorders excluding genital
      prolapse. RESULTS: The reduction of genital prolapse degree was found in all
      patients. In 3/4 of them it was degree 0 in Baden-Walker modified scale.
      CONCLUSIONS: The synthetic materials may be used in gynecological vaginal surgery
      together with conventional procedures. The advantages of operations with meshes'
      use are high efficacy and small number of complications.

PMID- 15181866
TI  - [Hysteroscopy in cases of abnormal uterine bleeding and abnormal ultrasonographic
      findings of uterine cavity-own experience].
AB  - OBJECTIVES: In the paper authors present indications and results of using
      diagnostic and operative hysteroscopy in the clinical practise and compare
      histological result with introductory diagnosis of ultrasonography and
      hysteroscopy. MATERIALS AND METHODS: In period of 01.06.1998-01.09.2002 148
      hysteroscopy were done with in 58 diagnostic and 90 operative histeroscopies.
      Received material was sent to histological research. RESULTS: non-pathologic
      change was diagnosed in 37 women, 43 endometrial polyps, 20 submucous myomas, 5
      polyps and myomas together. CONCLUSIONS: 1. Most often observed change in
      intrauterine pathology were endometrial polyps and submucous myomas. 2. In a few
      cases only hysteroscopy let us discover the reason of pathological bleedings from
      the uterus. 3. hysteroscopy has become the method necesary in some cases of
      gynaecological pathology.

PMID- 15181868
TI  - [Conservative treatment of 12-week cervical pregnancy].
AB  - A cervical pregnancy is very rare form of ectopic pregnancy. Usually it is
      associated with unexpected occurrence hemorrhage from the cervix. For this reason
      the treatment for a cervical pregnancy very often requires an abdominal
      hysterectomy. To avoid hysterectomy several conservative methods of termination
      have been used. In this paper has been reported the case of 29 years old woman
      with a 12-week cervical pregnancy. She had been treated (methotrexate and
      potassium chloride application, ligation of the uterine arteries, local
      haemostatic sutures) before evacuation products of conception from the cervix.
      Post-operative period was uneventful. After a 9 day of postoperative stay the
      woman was discharged. These behaviour allowed for save of uterus and preserve
      future fertility.

PMID- 15181869
TI  - [Unusual late recurrence of cervix uteri carcinoma in colon].
AB  - A rare case of SCC of the colorectal region is reported. A 64-year-old Polish
      woman with a past history of early stage (IA) SCC of the cervix 6 years
      previously suffered sudden onset of tenesmus and additional symptoms like pain on
      defecation and blood in the stool were present. In the ulcerated tumor located 15
      cm from the anal verge, SCC, which was histologically similar to that of primary
      lesion, was observed. Female was treated with total mesorectal excision (TME).
      Primary SCC of the colorectal region is very rare. Female secondary SCC of this
      region, caused by tumor metastasis, especially by metastasis from the cervical
      cancer was not observed before. The present case draws attention to the
      possibility of late recurrence of cervical cancer, even in cases treated
      radically in early stages.

PMID- 15181870
TI  - [Etiology of intrauterine growth retardation. Part I: placental-fetal
      interrelationship disorder].
AB  - Intrauterine growth retardation (IUGR) increases a risk of perinatal
      complications and may carry a negative influence on a later baby's mental and
      physical development. Poorer function revealed by many vital organs seems to be
      the effect of their lower mass and their relative immaturity. In the first part
      of a paper the authors discuss two groups of factors thought to be responsible
      for IUGR. The first one has been related to the fetal status-genetic anomalies,
      other primary developmental defects and different growth patterns.

PMID- 15181871
TI  - [Etiology of intrauterine growth retardation. Part II: maternal disorders].
AB  - The second part of discussion incorporates maternal conditions influencing the
      risk of intrauterine growth retardation. Special attention was paid to the
      systemic abnormalities, and those pregnancy related, known for their links with
      affected placenta-uterine barrier or otherwise related to abnormal fetal growth.
      Both social and environmental groups of factors potentially influencing prenatal
      development have been discussed.

PMID- 15181872
TI  - [Hyperhomocysteinemia and pregnancy complications].
AB  - Homocysteine (Hcy) is a sulfur-containing amino acid produced when methionine is
      demethylated. The majority of Hcy undergoes transsulfuration to cysteine by
      cystathionine beta-synthase (CBS), of which vitamin B6 (pyridoxine) is an
      essential cofactor. The remainder of Hcy is remethylated by methionine synthase
      (MS), of which vitamin B12 (cobalamin) is an essential cofactor along with
      methylenetetrahydrofolate (MTHF). MTHF is generated by the enzyme MTHFR-reductase
      (MTHFR). High levels of Hcy can result from a variety of aquired factors
      (deficiency of vitamins B6, B12 and folic acid, high meat diet, smoking and
      others) or genetic (abnormalities of methionine--homocysteine metabolism).
      Hyperhomocysteinemia is associated with premature atherosclerosis and venous
      thromboembolism; so called "cholesterol of XXI. age". Results of many studies
      suggest that hyperhomocysteinemia, homozygous state for MTHFR gene mutation,
      folate deficiency are probably risk factors for recurrent fetal loss,
      intrauterine fetal death, thrombo-embolic disease in pregnancy, neural tube
      defects and congenital cardiac malformation at infants and other placental
      diseases (pre-eclampsia, placental abruption and intrauterine growth restriction
      IUGR). Those irregularities are very interesting and important for obstetricians
      and gynecologists. The plasma homocysteine values can be modulated by vitamins,
      vitamin B6 and folic acid in particular. The potential for research and possible
      prevention in this area is immense.

PMID- 15181874
TI  - [Oxygen transfer and consumption in human placenta exposed to variable magnetic
      fields in vitro].
AB  - The initial investigations concerning the influence of variable magnetic fields
      (MF) on transfer and oxygen consumption in isolated human cotyledon in vitro were
      performed. Ten dual closed perfusion of the human cotyledon were conducted in
      each group. The control group was not exposed to magnetic fields. In studied
      groups cotyledons were exposed to magnetic field: in the group B1 (B = 2 mT, f =
      50 Hz), and in the group B2 (B = 5 mT, f = 50 Hz) for 180 min. Obtained results
      may suggest that variable magnetic field (B = 5 mT, f = 50 Hz) cause decrease of
      oxygen consumption in human placenta in 120 and 150 min of experiment.

PMID- 15181873
TI  - [The cost of newborns transportation to the referral centers in comparison to the
      cost of the transport in-utero].
AB  - OBJECTIVES: The purpose of the study was to estimate the costs of newborns
      transportation to the referral center, due to congenital malformation and to
      compare theses costs with transfer in utero, after detection of anomalies by
      screening ultrasound. MATERIALS AND METHODS: Analysis of newborns data from
      Pediatric Cardiology Clinic and Intensive Therapy Clinic from the Polish Mother's
      Memorial Hospital (2000-2002). Ambulance transportation, helicopter
      transportation and air-plane transportation were calculated and compared with the
      costs of three ultrasound seans per pregnancy. RESULTS: Transfer in utero was 5 x
      cheaper than newborns transportation by ambulance, 28 x cheaper than by
      helicopter and 42 x cheaper than by air-plane. CONCLUSIONS: Assuming that only
      every second congenital malformation would be detected prenatally by ultrasound,
      Polish Health System could safe circa 13 min zlotych.

PMID- 15181875
TI  - [Nuchal translucency measurement--non invasive ultrasound screening for fetal
      abnormalities. Part I].
AB  - OBJECTIVE: Fetal abnormalities are the most common cause of perinatal and
      postnatal death and infant handicap. In the last years came into being many
      diagnostic methods making possible--precise and accurate diagnosis of fetal
      malformation. DESIGN: Estimation the value of the screening test for fetal
      abnormalities based on the nuchal translucency measurement between 10-14th week
      of pregnancy. MATERIAL AND METHODS: A group of 675 women with singleton
      pregnancies undergoing first trimester nuchal translucency measurement. Nuchal
      translucency thickness was measured by transvaginal ultrasound examination
      according to Nicolaides. Derived risks were then calculated. RESULTS: When we
      used a risk of 1:250 as the cutoff to define a positive result on the screening
      test, the rate of detection of fetal abnormalities was 100%, with a false
      positive rate of 1.3%. CONCLUSION: First trimester nuchal translucency
      measurement is an effective method of screening for fetal abnormalities
      (obstetrical high-risk group).

PMID- 15181876
TI  - [Nuchal translucency measurement--non invasive ultrasound screening for fetal
      abnormalities. Part II].
AB  - OBJECTIVE: There is well established association between increased nuchal
      translucency and chromosomal abnormality. DESIGN: To investigate a new method of
      screening for fetal abnormalities on the basis of maternal age and fetal nuchal
      translucency thickness in the first and second term of pregnancy. METHODS: A
      group of 650 pregnant women from the 10th week of pregnancy until childbirth has
      been put under examination. Nuchal translucency thickness was measured by
      transvaginal ultrasound examination according to Nicolaides in the first
      trimester of pregnancy and by transabdominal ultrasound examination between 15
      19th week of pregnancy. Derived risk were then calculated. RESULTS: There were 8
      chromosomal and 1 structural defects. When we used a risk of 1:250 as the cutoff
      to define a positive result on the screening test, the rate of detection of fetal
      abnormalities was 100%, with a false positive rate 0.7%. CONCLUSION: This study
      suggests a benefit in combining maternal age-related risk together with NT
      measurement in the first and second trimester of pregnancy. Such kind of test
      could also be helpful in twin pregnancies.

PMID- 15181877
TI  - [Combination of screening tests for fetal abnormalities in the first and second
      pregnancy trimesters].
AB  - OBJECTIVE: Screening for fetal abnormalities in the second trimester of
      pregnancy, based on the concentrations of various markers in serum and maternal
      age, has become widely used in the past decade. In the first trimester fetal
      malformations are associated with high values for fetal NT. DESIGN: We propose a
      new screening method in which measurements obtained during both trimesters are
      integrated to provide a single estimate of a woman's risk of having a pregnancy
      affected by genetic syndrome. MATERIAL AND METHODS: Study groups comprised 775
      pregnant women where examinations were done between 11th-14th and 15th-19th
      pregnancy weeks. Nuchal translucency thickness was measured by ultrasound
      examination in both trimesters of pregnancy. AFP, -HCG and oestriol were measured
      by ELISA assays. Derived risks were then calculated. RESULTS: Eight fetal
      aneuploidies were diagnosed. When we used a risk of 1:250 as the cutoff to define
      a positive result on the integrated test, the rate of detection of fetal
      abnormalities was 100%, with a false positive rate of 0.6%. CONCLUSION:
      Integrated test, which is a combination of the ultrasound examination and the
      triple test allows to achieve high sensitivity and the decrease in the percentage
      of false positive results, which leads to the reduction in the number of
      amniocentesis to be performed.

PMID- 15181878
TI  - [New vessels formation within intramural leiomyomata].
AB  - OBJECTIVES: The vessels of uterine leiomyomata seem to control the growth of the
      tumour. The aim of the study was to analyze the angioarchitecture of intramural
      leiomyomata and to observe vascular sprouting of the growing vessels in these
      tumors. MATERIAL AND METHODS: 28 myomatous uteri collected upon autopsy were
      injected via afferent vessels with Mercox resin and corroded after polymerisation
      of the resin. RESULTS: Two types of tumour vascularization were distinguished:
      tumors with few vessels invading the leiomyoma with few side branches and tumours
      with dense vascular "capsule" which was a source of small vessels supplying the
      tumour. Vascular sprouts were observed in majority of studied tumors.
      CONCLUSIONS: Pre-existing vessels undergo regression and new vessels grow from
      the periphery, as well as new vessels arise in the process of angiogenesis within
      the tumors.

PMID- 15181880
TI  - [Disseminated peritoneal leiomyomatosis--case report and literature review].
AB  - Leiomyomatosis peritonealis disseminata(LPD) is a rare smooth muscle pathology,
      characterized by the presence of multiple tumors in peritoneal cavity mimicking a
      malignant process with metastases. The diagnosis may be difficult in some cases
      as the results of ultrasonography and CT imaging may suggest malignancy. The
      final diagnosis was made on biopsy and pathologic examination performed during
      surgery. Exposure to estrogens probably plays the main etiologic role. In this
      report we describe the diagnostic difficulties and the clinical course of LPD in
      45 year old women. The surgical treatment consisted on hysterectomy and removal
      of multiple nodules located in intestinal serosa. The additional hormonal
      treatment with GnRh agonist was applied. This report documents the possibility of
      effective surgical and hormonal treatment.

PMID- 15181879
TI  - [The effectiveness and acceptability of oral contraceptives (Logest), containing
      20 micrograms ethinylestradiol and 75 micrograms gestodene].
AB  - OBJECTIVES: The aim of the study was to evaluate the efficacy and acceptability
      of the use of oral contraceptives Logest, containing 20 micrograms
      ethinylestradiol and 75 micrograms gestodene (in one tablet). DESIGN:
      Observational study (during the period of six months) on the healthy women
      visiting gynecological clinics and asking for establishment of contraception with
      the use of oral contraceptives. MATERIALS AND METHODS: The observation was
      carried out on 800 patients who were included (with use including/excluding
      criteria) to the study. The study was carried out during the period of October
      1999-March 2001. Patients were asked to use the Logest intermittently during the
      period of 6 months (21 days of administration followed by 7 days break, and than
      again 21 days of administration etc). The administration of Logest was followed
      up. Basic examination and qualification for the use of oral contraceptive was
      taken during the first visit. Re-examinations were taken after 3 and 6 month of
      usage of the study drug. RESULTS: High efficacy, good tolerance and acceptability
      of Logest administration was observed. Neither cases of non effectiveness, nor
      serious adverse events, during the Logest administration were reported.
      CONCLUSIONS: 95.7% of the patients which completed the study, declared that the
      oral contraception with use of Logest was "very well accepted" or "well
      accepted".

PMID- 15181881
TI  - [Choriogonadotropin measurements--critical assessment of new diagnostic
      possibilities].
AB  - In the human blood and urine there are different antigen forms of
      choriogonadotropin including nonnicked hCG, nicked hCG, free subunit, free
      subunit, nicked free, core fragment hCG, hyperglycosylated hCG, nicked hCG
      missing the subunit C-terminal peptide, asialo hCG, residues 92-145,
      alternatively nicked hCG--cleaved at 43-44 or 44-45 and others. The authors
      discuss the value of hCG measurements in the diagnosis of normal pregnancy,
      pathological pregnancy, Down syndrome screening and oncology: gestational
      trophoblastic disease, testicular, bladder, digestive tract and other cancers.
      Special consideration is given to false positive values--phantom hCG--and the
      consequences of needless therapy.

PMID- 15181882
TI  - [Photodynamic diagnosis and therapy in gynecology--current knowledge].
AB  - Photodynamic diagnosis (PDD) is a new method based on the detection of different
      forms of fluorescence of tissues after previous administration of
      photosensitizers. The photosensitizer is gathered in the pathological tissue at
      much higher concentration than in the healthy tissue, thus the fluorescence
      differs. Localizing wrong fluorescence allows precise choosing of the spot to
      collect tissue for histopathological or cytological study. Photodynamic therapy
      (PDT) is a technique in which tissue is irradiated with light after the use of a
      photosensitizing drug that produces singlet oxygen, which has a cytotoxic effect.
      The authors describe new trends in photodynamic diagnosis and treatment of some
      vulvar epithelial diseases (VIN, lichen sclerosus, condylomata acuminata) and
      cervical intraepithelial neoplasia. They describe photodynamic method in their
      own studies: diagnosis and treatment of lichen sclerosus and diagnosis of uterine
      cervix cancer.

PMID- 15181883
TI  - [Cervical carcinoma and pregnancy--guidelines for the diagnosis and treatment: a
      proposal].
AB  - The paper presents a proposal of guidelines for diagnosis and management of
      cervical carcinoma associated with pregnancy based on the analysis of
      contemporary references regarding the topic.

PMID- 15181884
TI  - [Ovarian tumors in pregnancy--proposals of diagnosis and treatment].
AB  - We present the review of the literature and the proposals of the exact diagnosing
      and therapy of the ovarian tumors complicating pregnancy. The incidence of
      ovarian tumors in pregnant women is estimated on 1/1000 deliveries. The
      coexistence of an ovarian tumor with pregnancy presents problems to both the
      clinician (obstetrician, oncologist) and the patient. Depending of the increasing
      uterus during pregnancy, the appropriate diagnosis of adnexal mass is based on
      the initial pelvic and ultrasound examination. Most of ovarian tumors in pregnant
      women are asymptomatic and when they are unsuspicious simple cysts or cystic
      teratomas the conservative management is recommended. In cases of complex masses
      and/or torsion, rupture, hemorrhage the surgical intervention by laparotomy (in
      some cases laparoscopy) is required. The possibility of malignancy and its
      therapeutic implications (hysterectomy, salpingo-oophorectomy, delay to delivery)
      must be discussed with the patient and her family (the lives of two human beings
      together are affected).

PMID- 15181885
TI  - Further evidence for a QTL influencing body mass index on chromosome 7p from a
      genome-wide scan in Dutch families.
AB  - Obesity is a rapidly growing threat to public health, driven by the increased
      occurrence of high caloric diets and sedentary lifestyles. Within this
      environment, genetic influences may largely determine inter-individual
      differences in obesity-related traits. To map genes involved in weight
      regulation, we performed a genome-wide linkage scan for body mass index (BMI), a
      reliable measure of total body fat, in 192 Dutch families including 315 twins and
      210 siblings with data on BMI. Using variance components linkage analysis,
      regions with LOD-scores greater than 2 were observed on 6p25.1 (LOD-score, 2.13)
      and 7p21.1 (LOD-score, 2.40). LOD-scores higher than 1 were found on chromosomes
      3, 13, 15 and 21. Of note, evidence for the putative quantitative trait locus for
      BMI on 7p was obtained previously from such diverse populations as Mexican
      Americans, Asians and Nigerians, suggesting that the underlying genes may effect
      weight regulation in diverse environments. An obvious positional candidate in the
      7p linkage region is the gene encoding neuropeptide Y (NPY) that controls satiety
      and food intake.

PMID- 15181887
TI  - [The Prosper-Study: practical consequences?].

PMID- 15181886
TI  - [Acute and chronic-constrictive pericarditis].
AB  - Acute pericarditis is an inflammatory disease of the pericardium of variable
      etiology. A viral infection may sometimes precede symptoms but frequently the
      etiology re-mains unknown (idiopathic pericarditis). The disease is typically
      associated with left-sided chest pain and ECG abnormalities mimicking acute
      myocardial infarction. At physical examination the characteristic finding is a
      pericardial friction rub. A pericardial effusion of varying extent may be present
      or develop in the course of the disease. Pericardial tamponade, which may develop
      insidiously, represents a life-threatening complication. Pathophysiologically,
      filling of the cardiac chambers is impeded resulting in orthopnea, tachycardia,
      and eventually shock. Emergency pericardiocentesis is the treatment of choice.
      Constrictive pericarditis is the result of a chronic inflammation of the
      pericardium. Clinically it is characterized by dyspnea during exercise, symptoms
      of right heart failure and typical hemodynamic findings. Treatment primarily
      includes surgical removal of the thickened pericardium.

PMID- 15181888
TI  - Research into complementary medicine: some future challenges.

PMID- 15181889
TI  - Japan's toxic past resurfaces.

PMID- 15181890
TI  - Echinacea no cure-all for kids.

PMID- 15181891
TI  - Why males are more at risk for melanoma.

PMID- 15181892
TI  - The Maze procedure for the treatment of atrial fibrillation: a minimally invasive
      approach.
AB  - OBJECTIVES: The standard Maze procedure has proven to be extremely effective in
      curing atrial fibrillation in thousands of patients worldwide. Until now it has
      required a median sternotomy and cardiopulmonary bypass. In order to simplify the
      standard approach, a minimally invasive technique was developed. We have recently
      applied this minimally invasive Maze procedure in 72 patients. METHODS: The
      technique is dependent on the use of cryosurgery and the total number of
      atriotomies has been decreased from twelve to four. In addition to performing the
      Maze procedure, 32% of patients have had concomitant surgery via the minimally
      invasive approach including mitral valve repair/replacement and tricuspid valve
      repair. RESULTS: Perioperative morbidity is improved following the minimally
      invasive approach in comparison to the standard approach with the incidence of
      temporary perioperative arrhythmias being decreased by 50%. The long-term
      recurrence of atrial fibrillation is 2.4% following the minimally invasive Maze
      procedure and 2.2% following the standard Maze procedure. The incidence of
      pacemaker requirements following the standard Maze procedure is 20% but only 6%
      following the minimally invasive Maze procedure. Both right atrial and left
      atrial transport function have been documented in 100% of patients following the
      minimally invasive Maze procedure. CONCLUSIONS: We believe that the minimally
      invasive Maze procedure is a substantial improvement over the standard approach
      in terms of patient morbidity while preserving the effectiveness of the Maze
      procedure in curing atrial fibrillation.

PMID- 15181893
TI  - [Urethral valve resection with rectal perforation].

PMID- 15181895
TI  - Recent publications in Hematological Oncology.

PMID- 15181894
TI  - Transitional care for older adults: a cost-effective model.
AB  - Although the quality of care in hospitals and ambulatory settings is undergoing
      more scrutiny, far less attention has focused on the care patients receive as
      they move from one setting to another. Older patients who transition from
      hospital to home are particularly vulnerable: many of these patients have
      multiple health problems that continue beyond discharge. In response,
      investigators at the University of Pennsylvania developed a model of care
      delivered by nurse experts who follow vulnerable elders though their
      hospitalization and monitor their progress at home. This Issue Brief summarizes
      more than a decade of research on this model of transitional care and its effects
      on the costs and quality of care for hospitalized elderly patients.

PMID- 15181897
TI  - Endocrine-related resources from the National Institutes of Health.

PMID- 15181896
TI  - [An alcohol addict with chronic obstructive lung disease and hematemesis].

PMID- 15181898
TI  - [Acute gastrointestinal bleeding caused by a ruptured splenic artery aneurysm].
AB  - BACKGROUND: Splenic artery aneurysms are rare. Symptoms vary from none to acute
      abdominal pain. Gastrointestinal bleeding is a very rare symptom, but may occur
      in case of rupture. CASE REPORT: A 69-year-old woman was admitted for
      haematemesis. A ruptured splenic artery aneurysm was found. The aneurysm had
      ruptured into the pancreatic duct, causing gastrointestinal bleeding via the
      papilla of Vater. The patient's aneurysm was treated successfully with
      endovascular embolisation. DISCUSSION: Selective arteriography is diagnostic for
      splenic artery aneurysms. Endovascular treatment with embolisation of the
      aneurysm is the treatment of choice. When duodenoscopy is done in the case of
      rupture to the pancreatic duct it is mandatory to inspect the papilla of Vater
      for a sufficient period of time in order to see the bleeding from the papilla.
      Although rare, a splenic artery aneurysm should be considered in the assessment
      of patients with diffuse abdominal pain or gastrointestinal bleeding of unknown
      origin.

PMID- 15181899
TI  - Administrative detention of food for human or animal consumption under the Public
      Health Security and Bioterrorism Preparedness and Response Act of 2002. Final
      rule.
AB  - The Food and Drug Administration (FDA) is issuing a final regulation that
      provides procedures for the detention of an article of food, if an officer or
      qualified employee of FDA has credible evidence or information indicating that
      such article presents a threat of serious adverse health consequences or death to
      humans or animals ("administrative detention"). The final rule implements the
      Public Health Security and Bioterrorism Preparedness and Response Act of 2002
      (the Bioterrorism Act), which authorizes the use of administrative detention and
      requires regulations establishing procedures for instituting on an expedited
      basis certain enforcement actions against perishable food subject to a detention
      order.

PMID- 15181900
TI  - All together now...

PMID- 15181901
TI  - New environments, versatile genomes.

PMID- 15181902
TI  - Syphilis.

PMID- 15181903
TI  - Osteonecrosis and bisphosphonates: correlation versus causation.

PMID- 15181904
TI  - Brush biopsy: false negative results.

PMID- 15181906
TI  - Long-range planning for oral and maxillofacial surgery: limits and needs.

PMID- 15181905
TI  - Diagnosing primary and secondary Sjogren's syndrome.

PMID- 15181907
TI  - [Primary biliary cirrhosis. Chief symptoms: fatigue, pruritus, occasionally
      hepatomegaly].

PMID- 15181908
TI  - [Optical and physiological limits of wavefront-controlled keratectomy].
AB  - According to optical diffraction theory, a visual acuity of 20/3.5 is possible in
      human eyes with pupil diameters larger than 6 mm. This theoretical value cannot
      be obtained in practice - in fact visual acuity is limited by the scale of the
      mosaic of the retinal cones. Anatomical data and the model by Helmholtz-Hering
      suggest that visual acuity of humans cannot be substantially higher than 20/10.
      Many young adult reach this visual acuity with their normal spectacles or contact
      lens correction. The human eye has higher-order aberrations which can be measured
      with a Hartmann-Shack aberrometer. A partial correction of these aberrations is
      possible by means of wavefront-controlled keratectomy and customized corneal
      ablation. A perfect eye completely free of ocular aberrations cannot be created
      by customized refractive surgery as, for example chromatic aberration cannot be
      corrected and the strength of ocular aberrations depends on the state of
      accomodation and varies with time.

PMID- 15181909
TI  - "I am not a supporter of simplistic explanations...", an interview with Zhores
      Medvedev. Interview by Lily Huschtscha.

PMID- 15181910
TI  - [Expert opinion problems in the evaluation of osteomyelitis].
AB  - Cases of osteomyelitis can be differentiated according to hematogenous
      (endogenous), and post-traumatic (exogenous) forms. Both types can lead to
      considerable permanent damage or recur even after a fairly long time. In the
      formulation of an expert opinion to assess cases of osteomyelitis, the foremost
      question concerns a possible error in treatment or clarification of a connection
      to a postulated trauma. The present article describes aspects of expert opinions
      on cases of osteomyelitis of the long bones, spinal column, and in children. In
      addition to potential claims for compensation for harm caused by permanent
      damage, other conceivable sequelae such as fistula carcinoma or amyloidosis are
      relevant for expert opinions. In contrast, substantiated clarification of the
      causality of a triggering traumatic event is essentially important for
      recognition of claims against accident insurance companies.

PMID- 15181911
TI  - Papulonodular genital growths in an HIV-infected woman.

PMID- 15181912
TI  - Speculations on why some lab rodent pathogens continue to be prevalent.

PMID- 15181913
TI  - Managing inspections: guidance to biomedical research facilities.

PMID- 15181914
TI  - Occupational health and safety in the care and use of nonhuman primates--an ILAR
      report.

PMID- 15181915
TI  - Common problems encountered by IACUCs--one chair's perspective.

PMID- 15181916
TI  - Designing your new animal facility, part I.

PMID- 15181917
TI  - IAT and AALAS.

PMID- 15181918
TI  - [Chronic lymphocytic leukemia (CLL). Chief symptoms: frequently asymptomatic,
      lymphadenopathy, splenomegaly].

PMID- 15181920
TI  - Fighting feral pigs.

PMID- 15181921
TI  - Cats, dogs and veterinarians--do the numbers stack up?

PMID- 15181922
TI  - What stories should veterinarians be telling?

PMID- 15181923
TI  - Exotic Animal Disease Bulletin. Australian bat lyssavirus (ABL).

PMID- 15181924
TI  - The role of animal technicians.

PMID- 15181925
TI  - Vaccine clarication.

PMID- 15181926
TI  - Inefficacy of selegiline in treatment of canine pituitary-dependent
      hyperadrenocorticism.
AB  - OBJECTIVE: To evaluate selegiline, a monoamine oxidase-B inhibitor, for treating
      dogs with pituitary-dependent hyperadrenocorticism. DESIGN: Prospective clinical
      trial using client-owned dogs with pituitary-dependent hyperadrenocorticism
      treated at The University Veterinary Centre, Sydney, from September 1999 to July
      2001. PROCEDURE: Eleven dogs with pituitary-dependent hyperadrenocorticism
      treated with selegiline were monitored at days 10, 30 and 90 by clinical
      examination, tetracosactrin stimulation testing, urinary corticoid:creatinine
      ratio measurement and client questionnaire. Endogenous adrenocorticotropic
      hormone measurements were also performed on most dogs on days 0 and 90. No dog
      treated with selegiline had satisfactory control of disease. CONCLUSION:
      Selegiline administration was safe and free of side-effects at the doses used,
      but did not satisfactorily control disease in pituitary-dependent
      hyperadrenocorticism affected dogs.

PMID- 15181927
TI  - Radiographic changes in elbow dysplasia following ulnar osteotomy--a case report
      and review of the literature.
AB  - This case report describes the results of bilateral elbow arthrotomy and a
      unilateral ulnar osteotomy in a 10-month-old dog with bilateral elbow dysplasia.
      Fragmented coronoid processes were removed from both joints via bilateral medial
      arthrotomies. On the right side an ulnar osteotomy was also performed using a
      caudolateral approach. Bilateral flexed lateral elbow radiographs taken before
      surgery and 5 months postoperatively were assessed for changes in osteophyte size
      on the anconeal process, caudal epicondylar ridge and radial head. Osteophytes on
      the anconeal process and caudal epicondylar ridge disappeared over the
      postoperative period in the joint that received an ulnar osteotomy. In the
      contralateral joint the size of the oesteophytes on the anconeal process and
      caudal epicondylar ridge increased in size during the same period.

PMID- 15181928
TI  - Facilitated ankylosis of the distal interphalangeal joint in a foal.
AB  - A 3-month-old Quarter Horse colt sustained a penetrating injury over the coronary
      band on the right forelimb resulting in an articular bone sequestrum and septic
      arthritis of the distal interphalangeal joint. Despite aggressive treatment for
      septic arthritis, severe osteoarthritis and ongoing sepsis resulted in persistent
      lameness. Facilitated ankylosis of the distal interphalangeal joint was performed
      using a combination of open surgical debridement, placement of an autogenous
      cancellous bone graft and stabilisation within a transfixation cast. Bony
      ankylosis of the joint was observed radiographically 7 weeks following surgery.
      Evaluation of the horse 30 months following surgery revealed complete fusion of
      the middle and distal phalanges, and the distal sesamoid bone. The horse is
      pasture sound and is used as a breeding stallion. This report describes the
      surgical approach and case management employed to achieve facilitated ankylosis
      as a treatment for unresolved septic arthritis of the distal interphalangeal
      joint. This is the first report of successful facilitated ankylosis of the distal
      interphalangeal joint in a foal.

PMID- 15181929
TI  - Chemical arthrodesis of the distal tarsal joints using sodium monoiodoacetate in
      104 horses.

PMID- 15181930
TI  - Identification of a new prion strain in cattle--is there more than one form of
      BSE?

PMID- 15181931
TI  - Glycosylation of prion strains in transmissible spongiform encephalopathies.
AB  - This is a review of prion replication in the context of the cell biology of
      membrane proteins especially folding quality control in the endoplasmic reticulum
      (ER). Transmissible spongiform encephalopathies, such as scrapie and BSE, are
      infectious lethal diseases of mammalian neurons characterised by conversion of
      the normal membrane protein PrPC to the disease-associated conformational isomer
      called PrPSc. PrPSc, apparently responsible for infectivity, forms a number of
      different conformations and specific N-glycosylation site occupancies that
      correlate with TSE strain differences. Dimerisation and specific binding of PrPc
      and PrPSc seems critical in PrPSc biosynthesis and is influenced by N
      glycosylation and disulfide bond formation. PrPsc can be amplified in vitro but
      new glycosylation cannot occur in cell free environments without the special
      conditions of microsome mediated in vitro translation, thus strain specific
      glycosylation of PrPSc formed in vitro in the absence of these conditions must
      take place by imprintation of PrPc from existing glycosylation site-occupancies.
      PrPSc formed in cell free homogenates is not infectious pointing to events
      necessary for infectivity that only occur in intact cells. Such events may
      include glycosylation site occupancy and ER folding chaperone activity. In the
      biosynthetic pathway of PrPSc, early acquisition of sensitivity of the GPI anchor
      to phospholipase C can be distinguished from the later acquisition of protease
      resistance and detergent insolubility. By analogy to the co-translational
      formation of the MHC I loading complex, it is postulated that PrPSc or its
      specific peptides could imprint nascent PrPc chains thereby ensuring its own
      folds and the observed glycosylation site occupancy ratios of strains.

PMID- 15181932
TI  - Toxic effects of mebendazole at high dose on the haematology of red-legged
      pademelons (Thylogale stigmatica).
AB  - OBJECTIVE: To investigate the effects of mebendazole at high dose on the
      haematology of macropods. Experimental. PROCEDURE: Five red-legged pademelons
      (Thylogale stigmatica) were dosed orally with mebendazole at 50 mg/kg/d for 5 to
      6 days. Two control pademelons were dosed with water. Regular blood samples were
      taken for haematology over 20 days. RESULTS: All four treated pademelons sampled
      at 5 days developed severe leucopenia and neutropenia, moderate lymphopenia,
      thrombocytopenia, eosinopenia and monocytopenia, as well as bone marrow aplasia
      within 5 to 11 days after the first mebendazole dose. Four pademelons died
      unexpectedly or became ill and were euthanased 5 to 11 days after the first dose
      while the other animal recovered after 5 days of illness. Necropsy revealed
      systemic infection with opportunistic enteric bacteria, non-suppurative
      inflammation in tissues, haemorrhage and ulceration of the gastrointestinal
      tract. CONCLUSIONS: Red-legged pademelons rapidly develop bone-marrow aplasia and
      subsequent septicaemia after administration of high doses of mebendazole.
      Mebendazole at high doses should not be used for macropods.

PMID- 15181933
TI  - Comparison of the analgesic effects of xylazine in sheep via three different
      administration routes.
AB  - OBJECTIVE: To examine the influence of administration route on the analgesic
      effects of identical doses of xylazine in sheep. A prospective, linear,
      randomised laboratory study. PROCEDURE: The analgesic response to the
      administration of 2.5 mg of the alpha2 agonist xylazine either intravenously,
      intramuscularly or subcutaneously was assessed using an analgesia testing method
      based upon a learned response to a painful electrical stimulus. RESULTS:
      Intravenous administration achieved the most rapid onset and highest peak
      analgesic values of all administration methods, but was characterised by a
      shorter duration of action (25 min). Intramuscular and subcutaneous
      administration resulted in a longer duration of action (40 min) and a greater
      total analgesic response. CONCLUSION: For the routine management of acute pain,
      intramuscular administration provided the best combination of onset, duration and
      total analgesic response of the routes examined. The absence of adverse side
      effects, such as sedation, normally associated with the administration of alpha2
      agonists should also encourage the use of this method as a simple and effective
      means of providing significant analgesia in the sheep.

PMID- 15181934
TI  - Effect of tunicamycin on peripheral nerves in the guinea pig.

PMID- 15181935
TI  - Measures used to assess frozen-thawed semen in Australian livestock semen
      processing centres.

PMID- 15181936
TI  - Radiologic case study. Patellar tendon rupture.

PMID- 15181937
TI  - The perception and reality of diversity in orthopedics.

PMID- 15181938
TI  - Closed reduction with intramedullary fixation for midclavicular fractures.

PMID- 15181939
TI  - Lateral femoral line: a technique for easy insertion of newer femoral
      reconstruction nails.

PMID- 15181940
TI  - Viscosupplementation for osteoarthritis of the knee.

PMID- 15181941
TI  - Adverse effects of voriconazole.

PMID- 15181942
TI  - CT-free computer-assisted total knee arthroplasty versus the conventional
      technique: radiographic results of 100 cases.

PMID- 15181943
TI  - The mini incision: routine approach.

PMID- 15181944
TI  - The mini incision uni: more for less?

PMID- 15181945
TI  - Primary total hip arthroplasty for treatment of a geriatric acetabulum fracture.

PMID- 15181946
TI  - Bone transplantation.

PMID- 15181947
TI  - Cement penetration using a tibial punch cement pressurizer in total knee
      arthroplasty.
AB  - This study describes a new tibial cement punch pressurizer to enhance cement
      penetration into the metaphyseal cancellous bone of the tibial plateau. Thirty
      knees of 15 patients undergoing simultaneous bilateral total knee arthroplasty
      (TKA) were randomly selected to receive the tibial cement punch pressurizer on
      one side, with the opposite side serving as control. Using computerized and
      radiographic evaluation of both knees 2 weeks postoperatively, the punch
      pressurizer achieved 132 times better penetration of the cement. The tibial punch
      cement pressurizer offers a simple technique to provide reliable cement
      penetration and tibial component fixation in TKA.

PMID- 15181948
TI  - A survey of orthopedic surgeons regarding DVT prophylaxis in foot and ankle
      trauma surgery.
AB  - This study hypothesized that thromboembolism in patients with foot and ankle
      trauma is higher than currently recognized, and that prophylaxis varies among
      surgeons. A questionnaire sent to members of two orthopedic specialty societies
      surveyed the use of thromboembolic prophylaxis over 1 year. Most did not use
      preoperative prophylaxis. Postoperatively, 44% of surgeons used prophylaxis, most
      commonly sequential compression devices and low molecular weight heparin. This
      survey suggests that thromboembolic prophylaxis is used by < 50% of surgeons
      treating foot and ankle trauma. The reported cases of thromboembolism in this
      study underline the need for a prospective investigation.

PMID- 15181949
TI  - Magnetic resonance imaging in the evaluation of infantile torticollis.
AB  - This retrospective study assessed the use of magnetic resonance imaging (MRI) in
      58 infants with infantile torticollis. Eighteen patients had nonmuscular causes
      of torticollis (group 1); MRI identified lesions in 16 patients. Of 40 patients
      with a diagnosis of congenital muscular torticollis (group 2), 28 had a normal
      MRI. Five patients had asymmetry of the sternocleidomastoid without noticeable
      signal changes. Seven patients showd evidence of fibromatosis colli. Asymmetry of
      the posterolateral skull consistent with plagiocephaly was common. Magnetic
      resonance imaging did not alter treatment of group 2. Findings of compartment
      syndrome of sternocleidomastoid were inconsistent. Magnetic resonance imaging is
      not recommended for asymptomatic patients with infantile torticollis.

PMID- 15181950
TI  - Total joint replacement in patients with dementia syndromes: a report of thirteen
      cases.
AB  - The hospital course and clinical outcomes of 14 joint replacement surgeries in 13
      patients with dementia syndromes were evaluated. Eight patients were disoriented
      postoperatively. Complications included slow progress in physical therapy,
      getting out of bed unattended, aggressive behavior, pulling out an intravenous or
      Foley catheter, and falling out of bed. Three patients were unable to comprehend
      their movement restrictions, resulting in one dislocated hip from bending and
      twisting. Eleven of twelve joints available for follow-up were believed to be
      painless and functional. One patient was inactive due to fractures secondary to
      osteoporosis. Although complications arise from patients' disoriented status,
      total joint replacement relieves pain, and the patients' relatives indicated
      satisfaction with the results of the surgery. The family of a patient with
      dementia syndrome must be actively involved in all aspects of care after total
      joint replacement.

PMID- 15181951
TI  - An extreme case of basilar invagination in rheumatoid arthritis of the cervical
      spine.

PMID- 15181952
TI  - Posterior arm and deltoid compartment syndrome after vitamin B12 injection.

PMID- 15181953
TI  - [Health care reform in Lebanon...or the return to the principle fundamentals of
      medicine].

PMID- 15181954
TI  - Molecular fingerprinting of multidrug-resistant Mycobacterium tuberculosis
      strains in Beirut reveals genetic diversity and father to daughter transmission.
AB  - The typing of six consecutive multidrug-resistant Mycobacterium tuberculosis
      strains isolated from patients with tuberculosis (TB) at the American University
      of Beirut Medical Center, was performed by touchdown double-repetitive-element
      (DRE)-PCR. The isolates exhibited four distinct patterns in DRE-PCR with three
      isolates exhibiting unique patterns and three isolates yielded similar DNA
      fragment patterns (cluster pattern). Only two of the three cluster isolates
      exhibited identical patterns as revealed by restriction fragment length
      polymorphism (RFLP) targeting specific mutations in the rpoB and katG genes that
      confer resistance to rifampin and isoniazid, respectively. A direct
      epidemiological linkage for the two isolates exhibiting genotypic relatedness was
      also established as the isolates were recovered from a 33-year-old man and his 8
      year-old daughter. The data show that transmission of multidrug-resistant M.
      tuberculosis strains is contributing to the emergence of drug-resistant TB in
      Beirut. Combining DRE-PCR with RFLP at the rpoB and katG genes could provide a
      powerful means for investigating the spread of multidrug-resistant M.
      tuberculosis strains in Lebanon.

PMID- 15181955
TI  - [Dermatitis artefacta. Report of seven cases].
AB  - BACKGROUND: Dermatitis artefacta is a self-induced chronic disease in which the
      responsibility for the lesions is uniformly denied by the patient. The latter is
      not aware of the reason for self-destruction. The diagnosis of such a condition
      is difficult because of multiple clinical aspects and the fear of missing an
      organic disease. CASE REPORTS: We report on seven cases of dermatitis artefacta
      with a chronic recurrent course. The cutaneous findings, the means involved in
      provoking lesions, the treatment modalities as well as the patients'
      psychological profile may vary from one case to another. DISCUSSION: Criteria for
      diagnosis and management are discussed and compared with literature data. An
      inappropriate approach may cause the loss of the patient and the recurrence of
      the lesions. Psychotherapy is indicated even though prognosis is poor.

PMID- 15181956
TI  - [Cirrhosis and renal failure: the influence of creatinine value on prognosis].
AB  - Renal failure in cirrhosis has multiple etiologies and numerous aggravating
      factors with evidence of worsening of prognosis. Our study was performed on 130
      cirrhotic patients hospitalized in HDF between January 1st, 1994, and December
      31st, 1999. We have evaluated the causes of renal failure and the relation of
      different aggravating factors with the onset of renal failure. Causes of renal
      failure included drug-induced renal failure, organic nephropathy, pre-renal
      azotemia, acute tubular necrosis and hepato-renal syndrome. Among the aggravating
      factors, lactulose was found to alter renal function (p = 0.0175). We studied the
      survival with respect to the serum creatinine levels and to the severity of liver
      disease. Three-year survival was respectively 59% and 42% in case of Child A and
      Child B patients with creatinine lower than 90 micromol/L. No three-year
      survivors were noted in these subsets of patients when creatinine level was
      higher than 90 micromol/L (p = 0.0247 and p = 0.0121 respectively). No difference
      in survival was noted in Child C cirrhosis. The occurrence of renal failure is a
      factor of bad prognosis in cirrhotic patients irrespective of Child's
      classification. In patients with Child A and Child B cirrhosis, a serum
      creatinine level higher than 90 micromol/L is a bad prognostic factor with a
      significantly decreased survival rate. This factor does not affect survival in
      Child C cirrhosis because of mortality related to cirrhosis complications.

PMID- 15181957
TI  - [Handicap and rehabilitation in hospitalized hemodialized patients: study of 20
      patients].
AB  - Twenty hemodialyzed patients, received rehabilitation while they were
      hospitalized. They were all handicapped in the beginning; when they left the
      hospital, 10 patients were completely independent, six needed help at home and 4
      were completely dependent. The authors search, from their own practice, the
      etiologies of handicap with hemodialyzed patients and how to prevent this
      handicap, with the target of giving to their patients the best quality of life.
      The rehabilitation is very important in the strategies of global care of these
      patients.

PMID- 15181958
TI  - Anthrax: a review.

PMID- 15181959
TI  - Imaging of uncommon and rare benign solid liver tumors.
AB  - In this article, we attempted to present an overview of uncommon and rare benign
      solid liver tumors. Table I summarizes some clinical and imaging characteristic
      features with a suggested diagnostic work-up and management. While clinical
      history and certain radiologic appearances can help making a confident diagnosis
      in some of these tumors, the majority requires histologic examination for a
      definitive diagnosis.

PMID- 15181960
TI  - Perforation of the rectum and colon during barium enema examination. Report of
      four cases.
AB  - BACKGROUND: The barium enema examination (BEE) is an important diagnostic study
      and considered to be safe without adverse effects. Perforation of the bowel is
      rare but is the most frequent complication of BEE and can be life-threatening.
      STUDY DESIGN: We report four cases of barium extravasation due to BEE treated at
      our institution, three rectal perforations and one perforation in the descending
      colon. RESULTS: The four patients underwent surgery because signs of peritonitis
      developed. Two of them recovered and two died from multiple organ failure.
      CONCLUSION: Perforation of the colon and rectum during BEE constitutes a surgical
      emergency in most cases. Prompt recognition and management are vital in
      decreasing morbidity and mortality.

PMID- 15181961
TI  - [Endoscopic treatment of Dieulafoy's lesion. A case report and review of the
      literature].
AB  - Dieulafoy's lesion is a rare and important cause of gastrointestinal hemorrhage.
      It is a relatively large artery which lies in close proximity to the mucosal
      surface. Hemorrhage is often torrential and life threatening. Endoscopy is the
      most sensitive diagnostic test. Many reports described successful hemostasis
      utilizing a variety of endoscopic modalities in > 95% of cases. We report an
      upper gastrointestinal hemorrhage in a patient with Dieulafoy lesion treated
      successfully by injection, and a literature review.

PMID- 15181962
TI  - A U.S. perspective on the adverse reactions from traditional Chinese medicines.
AB  - BACKGROUND: Traditional Chinese medicines (TCM) are popular in the United States
      and Asian and non-Asian consumers are using the product for disease treatment and
      health prevention. As more people are using TCM products, there are increased
      reports on adverse reactions. This review will focus on adverse reactions due to
      TCM as reported in the literature. METHODS: The review is based on MedLine search
      of literatures using keywords including: herbs, herbal, traditional Chinese
      medicines with toxicity, adverse effects, death, drug interaction and
      pharmacokinetic. In addition, specific searches were performed using the above
      keywords with the common name and the scientific name of the plant product.
      RESULTS: The causes of adverse reactions associated with TCM are diverse. They
      include variability in active/toxic ingredients due to growing conditions, use of
      inherent toxic herbs causing toxicity, overdose of herbs, drug-herb interactions
      especially with pharmaceuticals that have narrow therapeutic index, coexisting
      diseases, and idiosyncratic reactions like allergy, hepatitis and anaphylaxis.
      Other adverse reactions can be due to manufacturing and quality problems causing
      adulteration, misidentification, substitution of one herb with another,
      variability in the amount of active ingredients, use of pharmaceuticals without
      identifying on the labels, improper processing and preparation, and
      contamination. CONCLUSIONS: To minimize the adverse reactions from TCM and
      protect the public, there must be adequate laws and regulations to ensure that
      products are manufactured with the highest standards. Manufacturers should be
      licensed by regulatory agency and manufactured under good manufacturing practice.
      TCM products must be evaluated for their safety before marketing. Proper labeling
      and good surveillance systems shall ensure the protection of the consumers.

PMID- 15181963
TI  - Intravenous busulfan as preparative regimen in pediatric patients receiving
      hematopoietic stem cell transplantation: the preliminary experience in Taiwan.
AB  - BACKGROUND: Some studies have proved that intravenous busulfan with
      cyclophosphamide (used as a component of conditioning regimens for hematopoietic
      stem cell transplantation) is safer and has fewer complication than oral busulfan
      in adults, whereas the same proof in pediatric patients is only limited, with no
      reported data so far from Asian countries. In this study, we aimed to evaluate
      the efficacy and complications of IV busulfan in pediatric patients. METHODS:
      Three pediatric patients with acute myeloid leukemia were treated by intravenous
      busulfan combined with cyclophosphamide to compare retrospectively with the
      treatment with oral busulfan plus intravenous cyclophosphamide in another three
      pediatric cases having transplantation in the same institute. RESULTS: The
      results showed that the intravenous busulfan-based regimen had better compliance
      and less adverse effects including mucositis, hepatic toxicity, transplant
      related hepatic veno-occlusive disease, and acute graft-versus-host disease than
      oral busulfan-based treatment. CONCLUSIONS: The conditioning regimen of
      intravenous busulfan combined with cyclophosphamide is an acceptable alternative
      for pediatric patients with hematological malignancies in Taiwan. The long-term
      benefit and adverse effects of intravenous busulfan should be further explored.

PMID- 15181964
TI  - Prescription patterns of hypertension--National Health Insurance in Taiwan.
AB  - BACKGROUND: Hypertension is a universal disease. Treatment patterns of
      hypertension provide valuable information for clinicians. Therefore, we present
      the patterns of antihypertensive medications in Taiwan by their pharmacological
      classifications, breaking down by patients' ages and genders. METHODS: A
      descriptive and cross-sectional analysis was performed. Claims from the National
      Health Insurance of Taiwan were used and included all ambulatory cares of 21
      million people from July 1, 1997 to June 30, 1998. A total of 9,717,960 visits
      with 16,595,030 matched records of antihypertensive medications were obtained.
      Hypertensive medications were divided into 5 main categories; monotherapy and
      multiple therapy were defined and discussed separately. Frequency and proportion
      of utilization of antihypertensive medication were charted and figured. RESULTS:
      The most frequently prescribed antihypertensive medications were: calcium
      antagonists: 5,332,527 records (54.9% of enrolled visits); beta-blockers:
      4,230,843 records (43.5%); angiotensin converting enzyme inhibitors (ACEIs):
      3,057,009 records (31.5%); diuretics: 2,255,838 records (23.2%); and "others":
      1,647,100 records (16.9%). Regardless of gender, the top 2 prescription patterns
      were calcium antagonists and beta-blockers for monotherapy, beta-blockers +
      calcium antagonists and ACEIs + calcium antagonists for multiple therapy.
      CONCLUSIONS: Although Taiwan is a country with National Health Insurance,
      patterns of pharmacologic treatment of hypertension in Taiwan are close to those
      in the US, not to those of countries in Europe. Also, these treatments were
      tailored to the conditions of the patients.

PMID- 15181965
TI  - Clinical experience in the management of neovascular glaucoma.
AB  - BACKGROUND: Neovascular glaucoma (NVG) is a devastating ocular disease with poor
      prognosis. The ideal surgical procedure has yet to be determined. In this study,
      the clinical course and visual outcome of NVG and their fellow eyes were
      investigated and the most appropriate management was also evaluated. METHODS: The
      study was conducted retrospectively consisting of NVG in-patients of Taipei
      Veterans General Hospital who were under the care of the same glaucoma specialist
      between January, 1998 and September, 2000. All patients had a minimal follow-up
      period of 6 months. RESULTS: The total number of patients enrolled was 35 (number
      of eyes enrolled was 35) with mean age of 66.4 +/- 12.3 years. The underlying
      cause was diabetes mellitus in 29 patients and central retinal vein occlusion in
      6 patients. Twelve (34.3%) eyes had initial intraocular pressure (IOP) of over 60
      mmHg. Only 1 (2.9%) eye had initial visual acuity better than 6/60. Four lesion
      eyes were able to receive panretinal photocoagulation whereas 31 eyes received
      panretinal cryotherapy. For IOP reducing procedures, 15 eyes received
      trabeculectomy, and 16 received Diode trans-scleral cyclophotocoagulation (TSCP).
      At the final visit, 20 eyes (trabeculectomy group: 11 and Diode TSCP group: 9)
      were able to maintain an IOP < or = 21 mmHg. Of these eyes, 15 (trabeculectomy
      group: 8 and Diode TSCP group: 7) were able to maintain or improve their vision.
      Of the remaining 4 eyes, 2 had cyclocryotherapy and 2 had trabeculectomy followed
      by Diode TSCP. IOP were controlled in these 4 eyes but none were able to maintain
      stable vision. Among the 34 fellow eyes with stable IOP, 32 were able to maintain
      stable vision. CONCLUSIONS: Trabeculectomy and Diode TSCP provided no
      statistically significant difference in IOP control (p = 0.32) and visual outcome
      (p = 0.59) in our patient group. More randomized, prospective trials are needed
      to define the most effective treatment for NVG.

PMID- 15181966
TI  - Nocturnal enuresis in older adults.
AB  - BACKGROUND: Nocturnal enuresis is uncommon in older adults. The paucity of
      literature about this problem prompts us to review our cases to determine the
      management strategy. METHODS: Six older adults, including 2 females and 4 males,
      were evaluated for refractory nocturnal enuresis. Only 2 of them had minor
      daytime urge symptom. Most of them had failed in the treatment using
      anticholinergics and/or alpha-adrenergic blocker. Evaluation consisted of
      detailed medical history, voiding diary, and urodynamic studies. Clinical follow
      up persisted for 12 months. We define nocturnal polyuria as nighttime urine
      amount being more than 35% of total daily urine amount. Bladder outlet
      obstruction in men was diagnosed based on the definition described by
      International Continence Society. RESULTS: The average age was 71 years (range 61
      84). The average duration of the symptom was 3.1 months (range 0.5-6). Two
      patients had bladder outlet obstruction. Four patients used hypnotics for
      insomnia, which might result in difficult awakening on bladder distension.
      Nocturnal polyuria was found in 3 patients. Most patients had multiple factors
      contributing to their nocturnal enuresis except 1, who was found to have an
      enlarged prostate with chronic bladder distension. Specific treatments were given
      based on the causes for each patient. Hypnotics were discontinued for a certain
      meanwhile in some patients. Nocturnal polyuria was managed with afternoon
      diuretic or bedtime desmopressin. Bedtime anticholinergic agent was used in
      patients with detrusor overactivity. The patient with enlarged prostate and
      urinary retention was managed with indwelling catheter followed by elective
      transurethral prostatectomy. All patients were dry in the night following the
      treatment. CONCLUSIONS: Nocturnal enuresis in older adult is usually multi
      factorial. Hypnotic usage and nocturnal polyuria are frequently overlooked.
      Detailed investigation is necessary to identify the causes. Tailored treatment
      may achieve satisfactory results.

PMID- 15181967
TI  - Inguinal hernia after radical retropubic prostatectomy--experience of Kaohsiung
      Veterans General Hospital.
AB  - BACKGROUND: Radical retropubic prostatectomy is a potentially curative treatment
      for localized prostate cancer. This study aimed to examine the incidence of
      developing inguinal hernia after radical retropubic prostatectomy and its
      possible factors. METHODS: From November 1990 to April 2002, there were 222
      patients in Kaohsiung Veterans General Hospital who underwent radical retropubic
      prostatectomy and pelvic lymph node dissection for localized prostate cancer.
      Another 200 patients with prostate cancer who did not receive surgical
      intervention were enrolled as the control group. The medical charts were reviewed
      with an emphasis on the possible mechanisms causing inguinal hernia. RESULTS: The
      period of follow-up ranged from 2 to 137 months, with a median of 54 months.
      There were a total of 15 (6.7%) patients who developed inguinal hernia after
      radical retropubic prostatectomy and pelvic lymph node dissection in our
      hospital. Post-prostatectomy anastomotic stricture was noted in 7 (46%) patients.
      Ten patients (67%) developed indirect type inguinal hernia. Only 4 (2%) inguinal
      hernias were found in the control group. CONCLUSIONS: The incidence of inguinal
      hernia among patients undergoing radical retropubic prostatectomy and pelvic
      lymph node dissection was higher than that among patients without operation. Post
      operative anastomotic stricture was the most important predisposing factor in the
      current study.

PMID- 15181968
TI  - Early gastric MALT lymphoma.
AB  - The endoscopic findings of mucosa-associated lymphoid tissue (MALT) lymphoma were
      classified into exophytic and infiltrative types by Palmer and Seifert. Normal
      appearing gastric MALT lymphoma is quite uncommon, and only one case had been
      reported in the literature. Here we report the case of a 49-year-old woman who
      underwent esophagogastroduodenoscopy for health screening. Endoscopy revealed
      indistinct follicular gastritis mucosal change and a duodenal ulcer scar, and
      random biopsy was taken from her stomach to check for the presence of
      Helicobacter pylori (H. pylori). Biopsy revealed chronic gastritis with H.
      pylori, and atypical lymphoid infiltration highly suggestive of MALT lymphoma.
      Polymerase chain reaction study using primers specific for immunoglobulin heavy
      chain gene showed a clonal B cell lymphoproliferation consistent with MALT
      lymphoma. Treatment with amoxicillin, clarithromycin, and omeprazole for H.
      pylori rendered complete resolution of the disease. In conclusion, follicular
      gastritis may be a high-risk condition that gives rise to MALT lymphoma, and
      further investigation is indicated.

PMID- 15181969
TI  - Isolated oculomotor nerve palsy due to head injury.
AB  - Traumatic isolated oculomotor nerve palsy with negative imaging studies is
      extremely rare. We reported such a case who after head injury had normal brain
      computerized tomography (CT), magnetic resonance imaging (MRI), and angiography.
      The absence of other neurological signs and normal brain MRI indicated the lesion
      was most likely within the subarachnoid space, as the other important structures
      near the third nerve, such as the brainstem, cavernous sinus and orbit, were
      undamaged. The prognosis of traumatic oculomotor palsy is usually poor. Generally
      speaking, patients experience more rapid and complete recovery of ptosis than of
      extraocular movements, while pupillary size and light reflex show the least
      degree of recovery. Further case collections with modern imaging studies are
      needed to clarify the mechanisms and clinical characteristics associated with
      this phenomenon.

PMID- 15181970
TI  - Hyaline-vascular variant of Castleman's disease mimicking a gastric submucosal
      tumor.
AB  - Castleman's disease is a rare lymphoproliferative disorder with unknown
      underlying cause. Three histologic variants (hyaline-vascular, plasma cell and
      mixed) as well as 2 clinical groups (localized and multicentic) have been
      described. Most patients with the hyaline-vascular variant are asymptomatic other
      than localized pressure from the mass. Hyaline-vascular Castleman's disease was
      commonly found as intrathoracic presentation. Extrathoracic lesions have been
      reported in the retroperitoneum, mesentery, central nervous system, orbit,
      pelvis, neck, axilla, and skeletal muscles. Herein, we report a case of hyaline
      vascular Castleman's disease mimicking a gastric submucosal leiomyoma that has
      rarely been reported in English literature review. The lesion was not actually
      developing from the stomach, however, the clinical presentation was mimicking a
      submucosal gastric tumor. Furthermore, the patient in this case had both chronic
      hepatitis C and splenosis. The relationship between the underlying diseases and
      the development of the CD deserves further investigations.

PMID- 15181971
TI  - The challenge of diagnosing psoas abscess.
AB  - Diagnosing psoas abscess in patients with low back pain might be hampered by
      their atypical symptoms. We describe a case in which a 39-year-old retired
      provost marshal presented to our emergency facility with acute onset of low back
      pain following an episode of lumbar strain during a flight. His initial computed
      tomography of lumbar spine and abdominal sonography were inconclusive. Two weeks
      later, he was admitted to our rehabilitation unit for similar symptoms. One day
      later, leukocytosis and elevated c-reactive protein following rising body
      temperature were found. Fever of unknown origin (FUO) was impressed after series
      of laboratory studies. However, an inflammatory gallium scan performed 2 weeks
      later due to persistent fever revealed active infection in the L4 vertebra and
      soft tissue of the L5 paraspinal region. MRI was then performed and demonstrated
      abnormal enhancement at the bodies of the L2 and L3 vertebrae, prevertebral soft
      tissue and bilateral psoas muscles. A CT-guided percutaneous aspiration of 10 cc
      yellowish pus was attained, which yielded no pathogens. His symptoms subsided 1
      week after being given appropriate antibiotics. This case showed the importance
      of nuclear scanning and MRI in patients with low back pain and FUO. It also
      suggests that repeated imaging study and/or other modality should be considered
      when the initial imaging result is not compatible with the clinical presentation
      of psoas abscess, which was initially missed by image studies.

PMID- 15181972
TI  - Cytogenetics and molecular pathology in cancer diagnostics.
AB  - The importance of cytogenetic and molecular genetic changes in cancer diagnostics
      has long been recognized. Especially chromosomal translocations have an
      established role in diagnosis, prognosis, and prediction of response to treatment
      in hematologic malignancies. Today some leukemias are classified according to
      cytogenetic changes. Characterized translocations have provided instrumental
      clues to understanding of molecular mechanisms of cancer, which in turn have
      enabled development of molecularly targeted treatments. This paper reviews the
      diagnostic significance of novel cytogenetic and molecular genetic techniques in
      human malignancies. Not only in hematologic malignancies and sarcomas but also in
      neurogenic tumors and carcinomas numerous diagnostically, prognostically,
      predictively and therapeutically important genetic changes have been described
      over the past few years, and novel genetic markers are discovered at a rapidly
      growing rate. New methods and characterized specific genetic markers have opened
      a new era also in detection of minimal residual cells.

PMID- 15181973
TI  - Does leptin link sleep loss and breathing disturbances with major public
      diseases?
AB  - Leptin is best known as a regulator of energy homeostasis, but it also interacts
      with sleep and breathing. Leptin secretion increases at night and decreases
      during the day. The circadian secretory profile of leptin is determined both by
      the hypothalamic circadian pacemaker and sleep-wake cycle. Leptin is also a
      powerful respiratory stimulant. Serum leptin levels are higher in obstructive
      sleep apnoea syndrome but lower during extended sleep deprivation in healthy
      subjects or in narcolepsy. Abnormalities in serum leptin concentrations have
      recently been linked with deleterious effects on weight control, cardiovascular
      health and glucose regulation. Since sleep curtailment and sleep-disordered
      breathing are epidemics of the modern society, better understanding of leptin
      pathophysiology could open new perspectives to pathophysiology of major public
      diseases, including obesity and metabolic syndrome.

PMID- 15181974
TI  - Role of angiogenic growth factors in transplant coronary artery disease.
AB  - Transplant coronary artery disease (TxCAD) as a manifestation of chronic
      rejection is a major limitation to long-term survival of heart transplant
      recipients. Although the exact molecular and cellular mechanisms contributing to
      neointimal formation are unknown, it has been generally believed that smooth
      muscle cells (SMC) of donor origin migrate from the media into the subendothelial
      layer of the vascular wall, where SMC proliferate and synthesize extracellular
      matrix resulting in intimal thickening. However, recent observations indicate
      that hematopoietic and vascular progenitor cells derived from recipient bone
      marrow may contribute to the arteriosclerotic lesion formation in the coronary
      arteries of the transplant. On the other hand, studies on postnatal hematopoiesis
      indicate that angiogenic growth factors such as vascular endothelial growth
      factor (VEGF) and angiopoietin-1 (Ang1) may regulate the recruitment of these
      cells into distant organs. Furthermore, embryonic VEGFR-2 /CD34+ stem cells may
      serve as vascular progenitor cells and their differentiation into endothelial
      cells and SMC may be regulated by VEGF and platelet-derived growth factor (PDGF),
      respectively. In this review, we discuss the role of angiogenic growth factors
      such as VEGF, Ang, and PDGF in the recruitment of hematopoietic and vascular
      progenitor cells in TxCAD and suggest novel therapies targeted at homing,
      differentiation and proliferation of these cells in the allograft.

PMID- 15181975
TI  - Comparison of mechanisms after post-hoc analyses of the drotrecogin alfa
      (activated) and antithrombin III trials in severe sepsis.
AB  - Severe sepsis is a heterogeneous syndrome in a heterogeneous population. The
      current scheme of classification does not enable distinction between systemic
      inflammatory response syndrome, sepsis and severe sepsis on the basis of the
      underlying biochemical, immunological and abnormal coagulation features.
      Planning, implementation and assessment of results of intervention studies on
      severe sepsis thus present enormous challenges. Two such studies were published
      in the year 2001. The study investigating the drug drotrecogin alfa (activated)
      was positive in the day-28 mortality endpoint; however, post-hoc analyses have
      raised controversies regarding the manner in which the study was carried out, the
      consistency of results presented, and the suggested mechanism of action. On the
      other hand, the KyberSept study that investigated antithrombin III reported
      negative results for the day-28 mortality endpoint, despite correct performance
      of the study. This, however, was not interpreted to mean proof of therapeutic
      inefficacy of administering antithrombin III and post-hoc analyses raise the
      suspicion of an undesirable drug interaction between antithrombin III and
      heparin. Apparently, neither of the sepsis studies meets the criteria which lie
      at the basis of critical assessment of the success or failure of clinical trials
      that could more significantly affect clinical treatment decisions.

PMID- 15181976
TI  - Orphan G protein-coupled receptors: targets for new therapeutic interventions.
AB  - With the completion of the human genome, many genes will be uncovered with
      unknown functions. The 'orphan' G protein coupled receptors (GPCRs) are examples
      of genes without known functions. These are genes that exhibit the seven helical
      conformation hallmark of the GPCRs but that are called 'orphans' because they are
      activated by none of the primary messengers known to activate GPCRs in vivo. They
      are the targets of undiscovered transmitters and this lack of knowledge precludes
      understanding their function. Yet, because they belong to the supergene family
      that has the widest regulatory role in the organism, the orphan GPCRs have
      generated much excitement in academia and industry. They hold much hope for
      revealing new intercellular interactions that will open new areas of basic
      research which ultimately will lead to new therapeutic applications. However, the
      first step in understanding the function of orphan GPCRs is to 'deorphanize'
      them, to identify their natural transmitters. Here we review the search for the
      natural primary messengers of orphan GPCRs and focus on two recently deorphanized
      GPCR systems, the melanin-concentrating hormone (MCH) and prolactin-releasing
      peptide (PrRP) systems, to illustrate the strategies applied to solve their
      function and to exemplify the therapeutic potentials that such systems hold.

PMID- 15181977
TI  - Seropositivity of hepatitis B e antigen and hepatocellular carcinoma.
AB  - Chronic infection with hepatitis B virus (HBV) is an important clinical problem
      due to its worldwide distribution and potential of adverse sequelae including
      hepatocellular carcinoma (HCC). Hepatitis B e antigen (HBeAg) is a biomarker of
      active viral proliferation in hepatocytes and infectivity. The prevalence of
      HBeAg among subjects chronically infected with HBV decreases with the increase in
      age. Case series studies have found a lowest seroprevalence of HBeAg in HCC
      patients compared with patients affected with chronic hepatitis B and liver
      cirrhosis. Case-control studies have shown a significantly higher seroprevalence
      of HBeAg in HCC cases than matched controls. A recent long-term follow-up study
      has shown a significantly elevated HCC risk for seropositives of both hepatitis B
      surface antigen (HBsAg) and HBeAg compared with seropositives of HBsAg only and
      seronegatives. The biological gradient remained in further stratification
      analyses by serum level of alanine transaminase and status of liver cirrhosis
      detected by ultrasonography. The cumulative HCC risk from age 30 to 70 years has
      been estimated to be 87% for those who were persistently seropositive on HBsAg
      and HBeAg, 12% for those with persistent seropositivity of HBsAg only, and 1% for
      those who were seronegative on HBsAg and HBeAg.

PMID- 15181978
TI  - Cardiovascular autonomic regulation in patients with 3243A > G mitochondrial DNA
      mutation.
AB  - BACKGROUND: Patients with the 3243A > G mutation in mitochondrial DNA (mtDNA)
      have an increased risk for cardiovascular morbidity and mortality. The function
      of the autonomic nervous system has not been evaluated in these patients.
      PATIENTS AND METHODS: Indices of 24-hour heart rate variability (HRV) and
      baroreflex sensitivity (BRS) were measured in 28 patients with 3243A > G. The
      results were compared to controls matched with respect to age, sex, the presence
      of hypertension and diabetes mellitus and the use of cardiac medication.
      Conventional time and spectral domain indices and fractal correlation properties
      of HRV were analysed. RESULTS: In spectral analysis of HRV, the ultra-low and
      very-low-frequency spectral components were lower in the patients than the
      controls (P < 0.05 for both). Furthermore, the short-term fractal scaling
      exponent was lower in the patients with 3243A > G compared to the controls (1.16
      +/- 0.18 versus 1.28 +/- 0.13, P < 0.01). No significant associations were found
      between the HRV indices and the other characteristics of the patients with 3243A
      > G, such as the presence of diabetes or left ventricular hypertrophy, left
      ventricular systolic function, the severity of the disease or the degree of 3243A
      > G heteroplasmy. CONCLUSIONS: Patients with the 3243A > G mutation in mtDNA have
      abnormalities in the spectral and fractal characteristics of HRV suggesting
      altered cardiac autonomic regulation. The abnormalities are not clearly
      associated with clinical manifestations related to 3243A > G suggesting that
      mitochondrial dysfunction may affect the autonomic regulatory systems more
      directly.

PMID- 15181979
TI  - Neuropeptide Y and Y2-receptor are involved in development of diabetic
      retinopathy and retinal neovascularization.
AB  - BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent
      endothelium-derived angiogenic factor and a vascular mitogen. We have studied the
      role of the functional leucine7 to proline7 polymorphism of the signal peptide
      region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor
      for diabetic retinopathy. In addition, we investigated the role of the NPY Y2
      receptor as a putative mediator of angiogenic NPY signaling in the retina.
      METHODS: Frequencies of proline7 (Pro7) carriers in the prepro-NPY were
      determined in type 1 and type 2 diabetes patients having retinopathy, in type 2
      diabetes patients without retinopathy and in healthy control subjects. The role
      of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated
      in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA
      antisense oligonucleotide. RESULTS: The carriers having Pro7 in the preproNPY are
      markedly over-represented among type 2 diabetes patients with retinopathy
      compared to type 2 diabetes patients without retinopathy and to the population
      control. Neonatal exposure to hyperoxia resulted in development of retinal
      neovascularization that was prevented in Y2(-1-) -mice, and significantly
      inhibited in rats treated with the Y2-receptor antisense oligonucleotide.
      CONCLUSIONS: NPY and Y2-receptor play important roles in diabetic retinopathy and
      retinal neovascularization and are thus potential new targets for drug molecules
      for treatment of retinopathy.

PMID- 15181980
TI  - Characterization of the signature of subwavelength variation from far-field
      irradiance.
AB  - The dynamic signature of the subwavelength variation of a slit is shown to be
      determinable from far-field irradiance with a precision of better than 1 nm. One
      can increase the efficiency of measurement of the subwavelength's signature by
      adjusting the detection width over which the subwavelength variation is detected.
      The subwavelength variation of a rectangular aperture was also examined to show
      the general feasibility.

PMID- 15181981
TI  - Talbot effect in a quadratic-index medium studied with two-variable Hermite
      polynomials and entangled states.
AB  - We have found the new eigenmodes, two-variable Hermite polynomials, exist in
      propagating plane waves in quadratic-index media and that a two-dimensional
      Talbot effect can be demonstrated with these modes.

PMID- 15181982
TI  - All propagation modes of large-core multimode optical fibers with an arbitrary
      core profile.
AB  - Plastic optical fibers are typical large-core multimode optical fibers. High
      bandwidth graded-index plastic optical fibers, which support a great number of
      propagation modes compared with conventional silica-glass multimode optical
      fibers, were developed in the 1990s. However, because they support a great number
      of propagation modes, their modal analyses have been limited to the WKB analysis.
      We obtain all the propagation modes of a convex-index large-core multimode
      optical fiber by use of the finite-element method, which has a strong advantage
      for arbitrary core profiles.

PMID- 15181983
TI  - Zoned microstructure fiber for low-dispersion waveguiding and coupling to
      photonic crystals.
AB  - We describe a zoned microstructure fiber that exhibits low dispersion and
      virtually zero spherical aberration because of its optimized piecewise Gaussian
      index profile. We present results of a nine-zone design that has an average
      refractive index of 2.3, a refractive-index contrast of 0.1, a first zone radius
      of 1.67 microm, and a maximum core radius of 5 microm. It has an in-fiber focal
      length of 8.88 microm and can focus light to a spot size of radius 315 nm,
      facilitating efficient coupling between single-mode fiber and photonic crystals.

PMID- 15181984
TI  - Non-Maxwellian probability density function of fibers with lumped polarization
      mode dispersion elements.
AB  - We give an analytical expression for the probability density function of the
      differential group delay for a concatenation of Maxwellian fiber sections and an
      arbitrary number of lumped elements with constant and isotropically oriented
      birefringence. When the contribution of the average squared of the constant
      birefringence elements is a significant fraction of the total, we show that the
      outage probability can be significantly overestimated if the probability density
      function of the differential group delay is approximated by a Maxwellian
      distribution.

PMID- 15181985
TI  - Understanding multipeak phenomena in actively Q-switched fiber lasers.
AB  - Dynamics of split pulses in actively Q-switched fiber lasers are numerically
      investigated, and the mechanism that produces multipeak phenomena (MPP) is
      precisely illustrated. It is shown that the first transient pulse in a cavity is
      initiated by the quick switching of a Q-switching element, which actually injects
      part of the amplified spontaneous emission into the laser cavity in the form of a
      pulse. Then the multipeak structures are related to the evolution of the
      perturbation caused by the switching and are determined by the rise time of the
      switching and by conditions of photon density and population inversion.

PMID- 15181986
TI  - Ultraviolet high-spectral-resolution Rayleigh-Mie lidar with a dual-pass Fabry
      Perot etalon for measuring atmospheric temperature profiles of the troposphere.
AB  - We report what is believed to be the first demonstration of measurement of
      tropospheric temperature profiles in daytime by use of a high-spectral-resolution
      Rayleigh-Mie lidar at an eye-safe wavelength of 355 nm. Atmospheric temperature
      is determined from the linewidth of the Rayleigh spectrum. Two Rayleigh signals
      are detected with Fabry-Perot etalon filters with a dual-pass optical layout. The
      Mie signal is detected with a third etalon filter for correcting the Mie
      component in the Rayleigh signals. The temperature statistical uncertainties are
      below 1 K up to a height of 3 km in nighttime and 2 km in daytime with a
      relatively compact system that uses laser energy of 180 mJ and a 25-cm telescope.
      Good agreement between lidar and radiosonde measurements is obtained.

PMID- 15181987
TI  - Quantitative detection of singlet O2 by cavity-enhanced absorption.
AB  - A method for the practical determination of the absolute concentration of single
      (a1delta(g)) oxygen is discussed. The method is based on sensitive off-axis
      integrated-cavity-output spectroscopy (ICOS). Off-axis ICOS allows narrowband,
      continuous-wave lasers to be used in conjunction with optical cavities to record
      sensitive absorption measurements. The details of the method as well as
      spectroscopic data confirming the first observation of the (1, 0) band of the
      b1sigma(g)(+) - a1delta(g) Noxon system are presented. The absolute transition
      probabilities for the b1sigma(g)(+) - a1delta(g) Noxon system, which are not
      known precisely from experiments, are determined by quantum chemistry theory.

PMID- 15181988
TI  - Channel plasmon-polariton in a triangular groove on a metal surface.
AB  - One-dimensional localized plasmons (channel polaritons) guided by a triangular
      groove on a metal substrate are investigated numerically by means of a finite
      difference time-domain algorithm. Dispersion, existence conditions, and
      dissipation of these waves are analyzed. In particular, it is demonstrated that
      the localization of the predicted plasmons in acute grooves may be substantially
      stronger than what is allowed by the diffraction limit. As a result, the
      predicted waves may be significant for the development of new subwavelength
      waveguides and interconnectors for nano-optics and photonics.

PMID- 15181989
TI  - Sensitivity of quantum-dot semiconductor lasers to optical feedback.
AB  - The sensitivity of quantum-dot semiconductor lasers to optical feedback is
      analyzed with a Lang-Kobayashi approach applied to a standard quantum-dot laser
      model. The carriers are injected into a quantum well and are captured by, or
      escape from, the quantum dots through either carrier-carrier or phonon-carrier
      interaction. Because of Pauli blocking, the capture rate into the dots depends on
      the carrier occupancy level in the dots. Here we show that different carrier
      capture dynamics lead to a strong modification of the damping of the relaxation
      oscillations. Regions of increased damping display reduced sensitivity to optical
      feedback even for a relatively large alpha factor.

PMID- 15181990
TI  - Efficient 1645-nm Er:YAG laser.
AB  - We report a resonantly fiber-laser-pumped Er:YAG laser operating at the eye-safe
      wavelength of 1645 nm, exhibiting 43% optical efficiency and 54% incident slope
      efficiency and emitting 7-W average power when repetitively Q switched at 10 kHz.
      To our knowledge, this is the best performance (conversion efficiency and average
      power) obtained from a bulk solid-state Q-switched erbium laser. At a 1.1-kHz
      pulse repetition frequency the laser produces 3.4-mJ pulses with a corresponding
      peak power of 162 kW. Frequency doubling to produce 822.5-nm, 4.7-kW pulses at 10
      kHz was performed to demonstrate the laser's utility.

PMID- 15181991
TI  - Dynamics of a self-Q-switched fiber laser with a Rayleigh-stimulated Brillouin
      scattering ring mirror.
AB  - Backward light scattering can cause passive Q switching in fiber lasers. We
      propose a self-consistent description of the laser dynamics. Our model
      quantitatively reproduces the temporal structure of pulsation and is also
      attractive for analysis of laser stability and statistics. The validity of the
      model is directly verified in an experiment.

PMID- 15181992
TI  - Stabilization of femtosecond laser frequency combs with subhertz residual
      linewidths.
AB  - We demonstrate that femtosecond laser frequency combs (FLFCs) can have a subhertz
      linewidth across their entire emission spectra when they are phase locked to a
      reference laser with a similarly narrow linewidth. Correspondingly, the coherence
      time of the comb components relative to the reference laser can be of the order
      of a few seconds. Thus we are able to detect high-contrast spectral
      interferograms at up to 10-s integration time between two FLFCs locked to a
      common optical reference.

PMID- 15181993
TI  - Isotropic photonic gaps in a circular photonic crystal.
AB  - We investigated the optical properties of a circular photonic crystal (CPC) for
      which the distance between lattices was systematically distributed. The
      transmission spectra of CPC composed of alumina cylinders were examined in the
      frequency region from 0 to 20 GHz. We show that photonic gaps are obtained not
      only in CPCs but also in phase-shifted CPCs. The isotropic photonic gaps are
      evidenced by changes in the incident angle of a millimeter wave.

PMID- 15181994
TI  - In vivo measurement of the local optical properties of tissue by use of
      differential path-length spectroscopy.
AB  - We demonstrate the capability of differential path-length spectroscopy (DPS) to
      determine the local optical properties of tissue in vivo. DPS measurements on
      bronchial mucosa are analyzed and yield information on the local blood
      oxygenation, blood content, average microvessel diameter, and wavelength
      dependence of the reduced scattering coefficient. Our data collected to date show
      that cancerous bronchial mucosa has a lower capillary oxygenation and a larger
      average capillary diameter than normal bronchial mucosa.

PMID- 15181996
TI  - Ultracompact biochemical sensor built with two-dimensional photonic crystal
      microcavity.
AB  - We report an experimental demonstration of an ultracompact biochemical sensor
      based on a two-dimensional photonic crystal microcavity. The microcavity,
      fabricated on a silicon-on-insulator substrate, is designed to have a resonant
      wavelength (lambda) near 1.5 microm. The transmission spectrum of the sensor is
      measured with different ambient refractive indices ranging from n = 1.0 to n =
      1.5. From observation of the shift in resonant wavelength, a change in ambient
      refractive index of delta(n) = 0.002 is readily apparent. The correspondence
      between absolute refractive index and resonant wavelength agrees with numerical
      calculation to within 4% accuracy. The evaporation of water in a 5% glycerol
      mixture is also used to demonstrate the capability for in situ time-resolved
      sensing.

PMID- 15181995
TI  - Second-harmonic optical coherence tomography.
AB  - Second-harmonic optical coherence tomography, which uses coherence gating of
      second-order nonlinear optical responses of biological tissues for imaging, is
      described and demonstrated. Femtosecond laser pulses were used to excite second
      harmonic waves from collagen harvested from rat tail tendon and a reference non
      linear crystal. Second-harmonic interference fringe signals were detected and
      used for image construction. Because of the strong dependence of second-harmonic
      generation on molecular and tissue structures, this technique imparts contrast
      and resolution enhancement to conventional optical coherence tomography.

PMID- 15181997
TI  - Generation of all-solid-state, high-power continuous-wave 213-nm light based on
      sum-frequency mixing in CsLiB6O10.
AB  - Achievement of more than 100 mW of pure continuous-wave deep-ultraviolet
      radiation at 213 nm has been demonstrated in an efficient all-solid-state laser
      system that uses two Brewster-cut CsLiB6O10 (CLBO) crystals. The first crystal is
      used for 266-nm generation by external resonant doubling of 532-nm radiation from
      a frequency-doubled Nd:YVO4 laser. Subsequent sum-frequency mixing is performed
      in a second CLBO crystal placed in a diode-pumped Nd:YAG laser cavity to mix the
      single-pass 266-nm output with circulating 1064-nm light.

PMID- 15181998
TI  - Flexible alteration of optical nonlinearities of iodine charge-transfer complexes
      in solutions.
AB  - The type of donor used is found to influence greatly the optical nonlinearities
      of iodine charge-transfer (CT) complexes in solutions for several solvents. The
      magnitude and sign changes of nonlinear absorption of iodine CT complexes for
      different solvents as donors are observed, which implies the transition from
      saturable absorption to reverse saturable absorption. Compared with C60 in
      toluene, iodine CT complexes with toluene and benzene demonstrate larger reverse
      saturable absorption. Meanwhile, flexible alteration of optical nonlinearities is
      easily obtained by adjusting the mixture ratio of different solvents, yielding a
      prospective means of constructing a nonlinear medium with a large nonlinear
      coefficient.

PMID- 15181999
TI  - Parametric amplification of soliton steering in optical lattices.
AB  - We report on the effect of parametric amplification of spatial soliton swinging
      in Kerr-type nonlinear media with longitudinal and transverse periodic modulation
      of the linear refractive index. The parameter areas are found where the soliton
      center motion is analogous to the motion of a parametrically driven pendulum.
      This effect has potential applications for controllable soliton steering.

PMID- 15182000
TI  - Optical phase conjugation and pseudolinear transmission.
AB  - We describe the use of optical phase conjugation (OPC) to suppress intrachannel
      nonlinearities that limit pseudolinear transmission. We show that OPC combined
      with appropriate dispersion mapping is effective in suppressing intrachannel
      nonlinearities, even in the absence of signal-power evolution symmetry that is
      generally required by OPC to compensate fiber nonlinearity. An increase in signal
      power by 5.5 dB is observed when a single OPC is used for 40-Gbit/s pseudolinear
      transmission over 32 x 100 km of passive-fiber spans.

PMID- 15182002
TI  - High-power femtosecond fiber-feedback optical parametric oscillator based on
      periodically poled stoichiometric LiTaO3.
AB  - We demonstrate a synchronously pumped high-gain optical parametric oscillator
      with feedback through a fiber, using a passively mode-locked Yb:YAG thin-disk
      laser as a pump source. We obtain as much as 19-W average signal power at a
      wavelength of 1.45 microm in 840-fs pulses and 7.8 W of idler power at 3.57
      microm. The repetition rate of the pulses is 56 MHz, and the transverse beam
      quality of the generated signal is M2 < 1.6.

PMID- 15182001
TI  - Second-harmonic generation in resonant waveguide gratings incorporating ionic
      self-assembled monolayer polymer films.
AB  - Experimental results on resonantly excited second-harmonic generation (SHG) in a
      periodic ionically self-assembled monolayer (ISAM) film are reported. A double
      layer guided-mode resonance filter (GMRF) structure is coated with 40 bilayers of
      pyrlium-based chi(2) ISAM thin film and excited with the fundamental of a Nd:YAG
      laser. Enhanced second-harmonic conversion in the ISAM film is achieved because
      of the local field enhancement associated with the fundamental resonating leaky
      mode. This method of SHG is particularly promising, as the ISAM films under
      investigation exhibit anomalous dispersion that may be applied for phase matching
      to improve nonlinear conversion efficiency.

PMID- 15182003
TI  - Effects of polarization-mode dispersion on fiber-based parametric amplification
      and wavelength conversion.
AB  - We present a vector theory of four-wave mixing in optical fibers and use it to
      discuss the effect of polarization-mode dispersion (PMD) on the performance of
      parametric amplifiers and wavelength converters. We show that PMD distorts the
      gain spectrum and makes it less uniform than that expected in the absence of
      residual birefringence. PMD also induces large fluctuations in the amplified or
      wavelength-converted signal.

PMID- 15182004
TI  - Multicolor lattice solitons.
AB  - We report on the existence of multicolor solitons supported by periodic lattices
      made from quadratic nonlinear media. Such lattice solitons bridge the gap between
      continuous solitons in uniform media and discrete solitons in strongly localized
      systems and exhibit a wealth of new features. We discovered that, in contrast to
      uniform media, multipeaked lattice solitons are stable. Thus they open new
      opportunities for all-optical switching based on soliton packets.

PMID- 15182005
TI  - Terahertz-pulse generation by photoionization of air with laser pulses composed
      of both fundamental and second-harmonic waves.
AB  - Intense radiation in the terahertz (THz) frequency range can be generated by
      focusing of an ultrashort laser pulse composed of both a fundamental wave and its
      second-harmonic field into air, as reported previously by Cook et al. [Opt. Lett.
      25, 1210 (2000)]. We identify a threshold for THz generation that proves that
      generation of a plasma is required and that the nonlinearity of air is
      insufficient to explain our measurements. An additional THz field component
      generated in the type I beta-barium borate crystal used for second-harmonic
      generation has to be considered if one is to avoid misinterpretation of this kind
      of experiment. We conclude with a comparison that shows that the plasma emitter
      is competitive with other state-of-the-art THz emitters.

PMID- 15182006
TI  - Nonlinear space-time dynamics of ultrashort wave packets in water.
AB  - We have monitored the space-time transformation of a 150-fs pulse undergoing self
      focusing and filamentation in water, by means of the nonlinear gating technique.
      We have observed that pulse splitting and subsequent recombination apply to axial
      temporal intensity only, whereas the space-integrated pulse profile preserves its
      original shape.

PMID- 15182007
TI  - Multiple filamentation induced by input-beam ellipticity.
AB  - We provide what is to our knowledge the first experimental evidence that multiple
      filamentation (MF) of ultra-short pulses can be induced by input beam
      ellipticity. Unlike noise-induced MF, which results in complete beam breakup, the
      MF pattern induced by small input beam ellipticity appears as a result of
      nucleation of annular rings surrounding the central filament. Moreover, our
      experiments show that input beam ellipticity can dominate the effect of noise
      (transverse modulational instability), giving rise to predictable and highly
      reproducible MF patterns. The results are explained with a theoretical model and
      simulations.

PMID- 15182008
TI  - Broadband polarization correction with programmable liquid-crystal modulator
      arrays.
AB  - We demonstrate a novel method of parallel, multiwavelength state-of-polarization
      (SOP) correction. Using a new liquid-crystal modulator array design, we are able
      to rotate the distorted input SOP spectrum to a fixed linear state on a
      wavelength-by-wavelength basis. We report experimental correction of up to 25.5
      dB polarization-dependent loss over a 13-nm bandwidth around 1550 nm.

PMID- 15182009
TI  - Lensless digital holographic microscope with light-emitting diode illumination.
AB  - We demonstrate the operation of a digital in-line microscope with LED
      illumination. We show with a practical example that, for typical setups, the
      limited temporal coherence and the spatial incoherence of the source do not
      affect the resolving power of the system. On the contrary, important advantages
      are obtained in terms of signal-to-noise ratio and alignment simplification.

PMID- 15182010
TI  - Doubly resonant single-layer bandpass optical filters.
AB  - A bandpass filter based on guided-mode resonance effects in a single-layer
      periodic waveguide is presented. Strong refractive-index modulation is used to
      support the excitation of a resonance pair in which leaky waveguide mode TE0 is
      excited by the second diffraction order and TE2 by the first diffraction order.
      It is shown that one resonance provides a broad low-transmission band, whereas
      the other supplies the transmission peak through its asymmetrical line shape. A
      bandpass filter with central wavelength at 1.55 microm is presented to
      demonstrate this concept.

PMID- 15182011
TI  - Phase modulation by polarization recording in bacteriorhodopsin: application to
      phase-shifting interferometry.
AB  - A novel phase-control method with application to phase-shifting interferometry is
      presented. The linear polarization state of an external (green) light beam is
      recorded on a bacteriorhodopsin film, and this polarization state is read by a
      circular polarized (red) laser beam. By reading the bacteriorhodopsin film, the
      original (red) wave reverses its circularity and becomes phase shifted by an
      amount that is dependent on the polarization of the external (green) beam. This
      method of phase control can be applied in a two-beam interferometer in which the
      test and reference waves are orthogonally polarized, which allows one to obtain
      phase modulation without moving parts inside the interferometer.

PMID- 15182012
TI  - Subkilohertz linewidths measured by heterodyne-detected coherent population
      trapping in sodium vapor.
AB  - Subkilohertz spectroscopy by coherent population trapping (CPT) has been
      performed in Na atomic vapor. The system employs a frequency-swept acousto-optic
      modulator for bichromatic excitation as well as a heterodyne-lock-in detection
      technique that permits the direct measurement of the CPT dispersion curves at a
      good signal-to-noise ratio. A CPT linewidth of -400 Hz was measured as well as a
      steep refractive-index dispersion of as much as 3.3 x 10(-10) Hz(-1),
      corresponding to a group velocity of 1800 m/s.

PMID- 15182013
TI  - Achieving multifrequency mode entanglement with ultraslow multiwave mixing.
AB  - We propose a scheme to achieve the entanglement of N photon modes (frequency
      modes) with perfectly efficient ultraslow multiwave mixing in a cold atomic
      medium. In addition, the method provides an efficient approach to realizing
      frequency tunability.

PMID- 15182014
TI  - Optical dipole trap inside a laser resonator.
AB  - We report the first realization, to our knowledge, of an optical dipole trap
      inside the active resonator of a laser. The concept, which is demonstrated with a
      CO2 laser (lambda = 10.6 microm), combines the advantages of optical power
      enhancement (up to 1.3-kW peak power) with the intrinsic stability of laser
      intensity as a result of the feedback of the active laser medium. Two kinds of
      trapping geometries are presented: a Gaussian trap in a transverse TEM00 mode and
      a boxlike transverse confinement in a superposition of transverse modes. In
      addition, longitudinal superlattices are created by two-frequency operation of
      the laser. Transfer efficiencies of up to 50% from a cesium magneto-optical trap
      are achieved. Storage times (7 = 0.3 s) are mainly limited by the background gas
      pressure. Possible sources of additional loss of atoms are discussed.

PMID- 15182015
TI  - Quasi-monocyclic near-infrared pulses with a stabilized carrier-envelope phase
      characterized by noncollinear cross-correlation frequency-resolved optical
      gating.
AB  - Precise characterization of noncollinear optical parametric amplifier idler
      pulses that have bandwidths of more than an octave with a center wavelength at
      990 nm was demonstrated. The method employed was cross-correlation frequency
      resolved optical gating with broadband sum-frequency mixing to take advantage of
      the idler's angular dispersion. Compression to near the transform limit was
      achieved to produce quasi-monocyclic near-infrared pulses by use of a deformable
      membrane mirror.

PMID- 15182016
TI  - Absolute measurement of a long, arbitrary distance to less than an optical
      fringe.
AB  - A scheme is proposed for high-precision, absolute length measurement for an
      arbitrary optical distance of a few meters to beyond 10(6) m. The approach
      utilizes a phase-stabilized femtosecond laser to provide both incoherent, time-of
      flight information and coherent, fringe-resolved interferometry. Such a combined
      measurement capability allows an optical wavelength resolution to be achieved for
      absolute length measurement over a large dynamic range.

PMID- 15182017
TI  - Choosing scientific patrimony: Sir Ronald Ross, Alphonse Laveran, and the
      mosquito-vector hypothesis for malaria.

PMID- 15182018
TI  - 'The illusion of an explanation': the concept of hereditary disease, 1770-1870.

PMID- 15182019
TI  - Institutionalizing biochemistry: the Enzyme Institute at the University of
      Wisconsin.

PMID- 15182020
TI  - Medicine in art: Self-portrait with Adelaide, Queen of Great Britain and Ireland,
      an unrecorded drawing by Jonathan Martin, Bethlehem Hospital, 1830.

PMID- 15182021
TI  - The social history of British medicine: an essay review.

PMID- 15182022
TI  - Recent dissertations in the history of medicine.

PMID- 15182023
TI  - [Paroxysmal acne].
AB  - Contrasting with the chronic evolution of acne vulgar, other types of acne are
      characterized by paroxysmal outbreaks. They can be endogenous or exogenous in
      origin. Each of these two groups can be further divided into separate entities.

PMID- 15182024
TI  - [Paroxismal reactions of the scalp].
AB  - The scalp is a unique site of the human body that may exhibit some particular
      physiopathological reactions. A few manifestations are paroxysmal. The main ones
      are the acute pruritus of pediculosis, and the pruritus at onset of dandruff or
      seborrhoeic dermatitis. One must add the telogen effuvium after solar exposure or
      during the post-partum, and the anagen dystrophic alopecia following
      chemotherapy. Other paroxysmal events include acute canitia and alopecia areata.

PMID- 15182025
TI  - [Angina].
AB  - The medical history is the cornerstone of the diagnosis of chest pain. In
      presence of angina like symptoms, the diagnosis of coronary artery disease must
      be assertained by rest and exercise ECG, eventually coupled with a stress echo or
      scintigraphy. Coronary angiography remains the ultimate diagnostic procedure
      despite recent advances in CT scan or MRI technologies. Beside symptomatic
      treatment aiming to reduce metabolic demand by medication or to improve
      revascularisation by surgery or percutaneous intervention, the actual therapeutic
      approach involves therapies aiming to stop atherosclerosis such as strict
      correction of coronary risk factors, use of statines, ACE inhibitors and
      antiplatelet agents.

PMID- 15182026
TI  - [Ventricular arrhythmias].
AB  - Tachycardias arise from an arrhythmogenic substrate triggered by a random factor
      (generally an extrasystole) and modulated by the autonomic nervous system. The
      three components are interactive, but their intensity and conjunction vary
      continuously. During the last decade, major achievements have been made to
      clarify definition and classification of data reported in the literature, helping
      our understanding of the mechanisms of ventricular arrhythmias. Nowadays, the
      pathophysiology of cardiac arrhythmias is well-known at the cellular and
      molecular ion channel activity. The progress of epidemiology and molecular
      genetics have allowed a better knowledge of the genotype-phenotype correlation in
      young patients presenting syncopes due to torsades de pointes or polymorphic
      ventricular tachychardia episodes which may degenerate into ventricular
      fibrillation and cause sudden death. The data of numerous large prospective
      randomised studies have led to more rational treatments with the progressive
      withdrawal of class I antiarrhythmics and their replacement by betablocking
      agents. The surgical approach of ventricular tachycardia has been overcome by the
      automatic implantable defibrillator and in some well-defined clinical situations,
      catheter ablation is used.

PMID- 15182027
TI  - [Acute cardiogenic pulmonary edema].
AB  - Acute cardiogenic pulmonary oedema frequently occurs in clinical practice,
      frequently in an old patient. It consists in acute respiratory distress related
      to rapid development of transsudative fluid within the lung interstitium and
      alveolar accumulation. It requires rapid assessment and therapy to prevent
      progression to respiratory failure and cardiovascular collapse. The pathogenesis
      and identification of the underlying disease process are essential for optimal
      medical approach. The aetiology is multiple.

PMID- 15182029
TI  - [Boerhaave's syndrome].
AB  - Spontaneous rupture of the oesophagus, so called Boerhaave's syndrome, still
      remains a surgical emergency. Early diagnosis governs the appropriate repair and
      the vial prognosis.

PMID- 15182028
TI  - [Abdominal aortic rupture].
AB  - Abdominal aortic rupture is sometimes paroxystic. More often, the rupture process
      takes hours, even days. Surgical efficiency is dependant on an early diagnosis.

PMID- 15182031
TI  - [Treatment of exacerbated asthma].
AB  - Asthma exacerbations constitute a common medical emergency, which in the past has
      been shown to be poorly managed. Although its management has recently improved,
      it remains suboptimal. For instance, acute life-threatening asthma is still
      responsible for 2000 death each year in France. More than two thirds of deaths
      should be avoided by a prompt and adjusted treatment. Initial assessment of the
      severity of the exacerbation is fundamental. The clinical story, physical
      examination and objective measurement of airflow obstruction by peak flow meter
      should permit to quickly establish an adapted treatment. The aim of this paper
      is, once general considerations about clinical approach and currently used
      treatments have been made, to propose a home and a hospital-based management of
      the asthma exacerbations.

PMID- 15182030
TI  - [Paroxysmal dyspnoea in a healthy individual: the spontaneous pneumothorax].
AB  - In a healthy individual, a dyspnoea of abrupt onset raises the suspicion of a
      spontaneous pneumothorax. The clinical examination and standard chest X-ray
      usually permit the correct diagnosis. The risk of reccurence can be assessed by
      the clinical history and examination. The functional consequences (which can be
      lethal) and the risk of recurrence will guide the short- and long-term therapy.

PMID- 15182032
TI  - [Excruciating flank pain: "acute renal colic"].
AB  - The classic presentation of acute renal colic is the sudden onset of very severe
      pain in the flank primarily caused by the acute ureteral obstruction. The
      diagnosis is often made on clinical symptoms only, although confirmatory exams
      are generally performed because many others significant disorders may present
      with symptom of flank pain that mimics renal colic. Life threatening emergency
      such as abdominal aortic aneurysm must be ruled out. While non contrast CT has
      become the standard imaging modality, in some situations, a plain abdominal
      radiograph associated with a renal ultrasound or a contrast study such as
      intravenous pyelogram may be preferred. Hematuria is frequently present on urine
      analysis. The usual therapy represented by analgesic and nonsteroidal anti
      inflammatory drugs should be started as soon as possible. Size and location of
      the stone are the most important predictors of spontaneous passage. Uncontrolled
      pain by medical therapy, fever, oligo-anuria suggest complicated stone disease.
      Such conditions require emergency treatment by drainage or stone extraction.
      Although recurrent stone rate is important, extensive metabolic explorations are
      not recommended after an uncomplicated first episode. Nevertheless fluid intake
      is encouraged and a stone chemical analysis should be performed whenever
      possible.

PMID- 15182033
TI  - [Urolithiasis in children and adolescents].
AB  - Urolithiasis is rare in children. Contrary to adults, the great majority have an
      identifiable predisposing cause, metabolic, infectious or structural. Those
      causes often coexist. A complete assessment for all these factors is thus always
      indicated. Symptoms are often non-specific. The diagnosis must be considered in
      case of intense abdominal pain. The majority of urolithiasis in children are
      radiopaque. Ultrasonography looks for impairment of the urinary flow, signs of
      underlying uropathy and nephrocalcinosis. Non contrast spiral CT scan is more
      sensitive for soft stones and ureteral stones. Morphoconstitutional analysis of
      the calculi provides essential information on etiology, limitating further
      metabolic evaluation. If the stone seems unlikely to pass spontaneously, extra
      corporeal shock wave lithotripsy is the first-line treatment for the great
      majority of children. Recurrence is common. Long-term medical treatment is
      essential. The first step is to maintain a high urine output by increasing water
      intake. Long-term prognosis is dependent on early diagnosis and on compliance to
      treatment.

PMID- 15182034
TI  - [Ocular vasospastic syndrome].
AB  - Vasospasm can have many different causes and can occur in a variety of diseases
      as well as in otherwise healthy subjects. We distinguish between primary
      vasospastic syndrome and secondary vasospasm. The term "vasospastic syndrome"
      summarizes the symptoms of patients having such a spasm to stimuli like cold or
      emotional stress. Patients with primary vasospastic syndrome tend to suffer from
      cold hands, low blood pressure, migraine and silent myocardial ischemia. The
      ocular vasospastic syndrome is clearly associated, among other manifestations,
      with glaucomatous optic neuropathy and non arteritic anterior ischemic optic
      neuropathy. The ocular vasospasm leads to a compromised autoregulation, and
      therefore sensitizes the eye to intraocular pressure or to a decrease in blood
      pressure. A variation in ocular perfusion may lead to an increase in free oxygen
      radicals and in glutamate. This may finally induce apoptosis cascade in retinal
      ganglion cells. Valuable diagnostic tools are nailfold capillary microscopy and
      angiography, but probably the best indicator is an increased plasma level of
      endothelin-1. The role of calcium channel blockers, magnesium, endothelin and
      glutamate antagonists are discussed.

PMID- 15182035
TI  - [Acute glaucoma crisis].
AB  - Acute glaucoma crisis is an emergency in ophthalmology. Ocular and systemic
      clinical signs are typical and due to a paroxystic and severe increase of
      intraocular pressure. It is a biometric disease: little eye with a big lens. Main
      factors triggering the acute crisis are: stress, sympathicomimetics,
      parasympathicomimetics and parasympathicolytics drugs. Treatment is surgical:
      iridectomy, cataract extraction, trabeculectomy or combined surgery.

PMID- 15182036
TI  - [Reactive hypoglycaemia, a mysterious, insidious but non dangerous critical
      phenomenon].
AB  - Numerous individuals complain of malaise attributed to hypoglycaemia. However,
      the diagnosis of hypoglycaemia is rarely documented and most often overstated.
      Reactive hypoglycaemia in the postprandial state is rather exceptional. The
      diagnosis relies upon the measurement of plasma glucose concentration (< 3 mmol/l
      or 55 mg/dl) at the time of the malaise. Reactive hypoglycaemia is generally
      associated with adrenergic symptoms and, less often, with cognitive disturbances.
      Importantly, a plasma glucose concentration below 3 mmol/l during an oral glucose
      tolerance test is not sufficient to decide that the patient suffers from reactive
      hypoglycaemia. Treatment is based on dietary advices including frequent small
      split meals and limitation of carbohydrates with high glycaemic index. Acarbose,
      a specific inhibitor of gut alpha-glucosidase enzymes, may be helpful in case of
      diet failure. As compared with true reactive hypoglycaemia, a postprandial
      hyperadrenergic reaction without real concomitant hypoglycaemia is much more
      prevalent. Careful anamnesis may suspect such a diagnosis, but other diagnoses
      such as panic attack or vasovagal reaction should be excluded. Treatment is
      purely symptomatic and essentially empiric.

PMID- 15182037
TI  - [Epileptic and non-epileptic paroxysmal phenomenons in the child].
AB  - In neuropediatry, paroxysmal phenomenons characteristic of the child can be of an
      epileptic or non epileptic origin. A correct clinical diagnosis has to be done
      straightaway in order to best select the complementary exams, establish the
      prognosis and decide the treatment. We will describe the clinical presentation of
      the main paroxysmal phenomenons found in children.

PMID- 15182038
TI  - [Ezetimibe (Ezetrol)].
AB  - Ezetimibe (Ezetrol), recently launched in Belgium by Merck Sharp& Dohme and
      Schering Plough, is presented as 10 mg tablets. It belongs to a new class of
      lipid-lowering agents that selectively inhibit the intestinal absorption of
      cholesterol and phytosterols. Its mechanism of action results in a synergistic
      cholesterol-lowering effect together with a statin that inhibits cholesterol
      synthesis by the liver. Ezetimibe, at a daily dose of 10 mg, is indicated, in
      combination with a statin, as adjuvant treatment to diet in patients with primary
      hypercholesterolaemia (homozygote or heterozygote familial form and non-familial
      polygenic form) not well controlled with a statin alone. In case of statin contra
      indication or intolerance, ezetimibe can be used in monotherapy. Its tolerance
      profile is excellent. Statin-ezetimibe combination allows to significantly reduce
      total and LDL cholesterol levels and increases the percentage of
      hypercholesterolaemic patients who will reach the target levels recommended in
      the international guidelines against atherosclerosis. However, such a combination
      should still prove its efficacy in reducing cardiovascular morbidity and
      mortality in large prospective clinical trials.

PMID- 15182039
TI  - [Valdecoxib (Bextra)].
AB  - Valdecoxib (Bextra tablets of 10 mg and 20 mg) is a new non steroidal
      antiinflammatory drug (NSAID) that selectively inhibits COX-2 isoform of cyclo
      oxygenase. It is indicated for the symptomatic treatment of osteoarthritis or
      rheumatoid arthritis (10 to 20 mg once a day) and for the treatment of primary
      dysmenorrhea (40 mg once a day). Valdecoxib is as efficacious as conventional non
      COX-2 selective NSAIDs, but offers the advantage of a much better
      gastrointestinal tolerance. Valdecoxib has a prodrug that can be administered
      intravenously or intramuscularly (parecoxib, Dynastat) and has been developed for
      the short-term treatment of postsurgical pain.

PMID- 15182040
TI  - [Indications for out-of-hospital thromboprophylaxis].
AB  - In the last decade the performance of an adequate perioperative prophylaxis for
      venous thromboembolism (VTE) has become an established in-hospital measure.
      Although new antithrombotic drugs (oral thrombin inhibitors, fondaparinux) could
      reduce the incidence of perioperative VTE the absolute number remains high. In
      contrast to the widely accepted in-hospital perioperative prophylaxis, it is
      still unclear whether prophylaxis has to be prolonged after the hospital stay
      ("out-of-hospital prophylaxis"). In this review we will demonstrate by evaluation
      of recent studies and recommendations that a prolonged out-of-hospital
      prophylaxis for venous thromboembolism can further reduce the incidence of VTE
      after surgery, mainly orthopaedic surgery, e.g. endoprothetic joint replacement.
      At present low molecular weight heparins (LMWH) may be most effective and exhibit
      a low risk for major bleeding. Similar studies with other antithrombotics and
      other types of surgery are still missing. Finally the medico-legal aspects
      concerning postoperative in-hospital and extended prophylaxis are discussed.

PMID- 15182041
TI  - [Standards and perspectives in locoregional hyperthermia].
AB  - The term "hyperthermia" summarises different procedures of raising the
      temperature of a tumour-loaded tissue to a temperature of 40-43 degrees C. In
      this context, locoregional procedures (radiative/capacitive local, interstitial
      and regional hyperthermia; endoluminal hyperthermia), hyperthermic perfusion
      techniques (hyperthermic peritoneal and isolated limb perfusion), and whole-body
      hyperthermia differ with regard to their indication, expenditure of application,
      and evidence of efficacy. All hyperthermia techniques have in common that they
      have no sufficient antineoplastic activity alone in the temperature range below
      43-45 degrees C, but act in a synergistic way with radiotherapy and certain
      cytotoxic drugs. 14 out of 18 published randomised trials on hyperthermia as an
      adjunct to standard radio- or chemotherapy refer to locoregional approaches.
      Particular progress has been made in regional radiofrequency hyperthermia, where
      novel multiantenna-applicators and their integration into MR-applicators ("hybrid
      systems") have recently been introduced into clinical practice. In addition,
      combinations of hyperthermia with novel technologies (magnetic fluid
      hyperthermia, thermosensitive liposomes, immunotherapy, gene targeting) are
      imminent. We here give a critical update on the proven indications of the
      different locoregional hyperthermia approaches and on the current clinical and
      technological progress in this field.

PMID- 15182042
TI  - The clinical diagnostic accuracy rate regarding the immediate cause of death in a
      hospitalized geriatric population; an autopsy study of 1594 patients.
AB  - BACKGROUND: In the geriatric population the autopsy rate is low, leading to
      mortality statistics often based on clinical diagnoses alone. OBJECTIVES: To
      determine the clinical diagnostic accuracy rate regarding the immediate cause of
      death (CDARCD), the number of major underlying diseases and sole diagnoses, and
      general data about the immediate cause of death in geriatric hospitalized
      patients. METHODS: The autopsy proven immediate cause of death was compared with
      the clinical diagnosis in 1594 patients over 69 years of age. Based on the
      autopsy protocols, the mean number of major underlying diseases and sole
      diagnoses were calculated. The immediate cause of death was classified into six
      groups: cardiovascular disease (CVD), malignant neoplasms (MN), bronchopulmonary
      disease (BPD), fatal pulmonary embolism (PE), miscellaneous (M), and marantic
      atrophy (MA). RESULTS: The overall CDARCD was 52.5%, being highest in MN (65.0%),
      followed by CVD (56.0%), MA (50%), BPD (48.3%), M (44.3%), and PE (26.7%). The
      most common cause of death was CVD (35.8%), followed by MN (24.3%), BPD (19.8%),
      PE (10.6%), M (7.7%) and MA (1.9%). The mean number of major underlying diseases
      and sole diagnoses was 2.0 and 14.4 respectively. CONCLUSIONS: The low CDARCD in
      our study strongly indicates the need for autopsy when reliable mortality
      statistics are desired.

PMID- 15182043
TI  - [Psychosocial characteristics in persons who often change their
      psychotherapists].
AB  - This study was performed on a clinic group of patients (n = 1000, 83.9%
      responder) to test characteristics of persons who switched psychotherapists on
      three or more occasions (n = 74). Compared with the group of minor variation,
      these patients had higher rates of psychosomatic symptoms, lower systemic
      operativeness, a dissatisfying sexuality, tended towards alcohol and
      pharmaceutical abuse, and had significant higher exposure in infancy to violence
      and sexual abuse (all p < 0.01 after Bonferroni correction). Psychosocial factors
      including early experience in forming relationships in addition to current
      factors appear to play a decisive role in a person's dropout liability as well as
      the attitude to therapy.

PMID- 15182045
TI  - Culture counts...but how.

PMID- 15182044
TI  - [Physicians working part-time].
AB  - In order to ensure the best possible medical care and high-quality research,
      hospital medical staff must be well educated and highly motivated. Part-time work
      can help to provide good human resources. Moreover, part-time jobs are often
      necessary as a means of juggling work and family responsibilities. The aim of
      this study was to illustrate the legal and educational groundwork for part-time
      work for physicians in Austria and to outline the advantages and drawbacks of
      part-time work. In March 2003, all medical doctors working part-time at hospitals
      in the Austrian state of the Tyrol (n = 60) were surveyed by means of a written
      questionnaire with the aim of finding out their motives for taking a part-time
      job as well as the positive and negative aspects involved. The response rate was
      nearly 70% (n = 40). Most of the part-time hospital physicians were female. The
      vast majority chose part-time employment in order to better balance family and
      job. Problems involved in part-time work are legal issues (part-time employment
      does not always qualify for medical training), the comparatively low salary and
      the fewer career opportunities. All respondents agreed that patient care,
      teaching and research are not compatible on a part-time basis. Another negative
      aspect is the generally strong time pressure experienced in part-time jobs.
      Despite these negative aspects of working part-time, advantages are considered
      more important, especially the better balancing of job and family and the
      possibility of an important early professional reintegration. Better acceptance
      of part-time jobs would help to make part-time work more attractive. An important
      improvement is associated with the forthcoming changes in the laws governing part
      time work and medical training.

PMID- 15182046
TI  - The family's role in person-centered care: practice considerations.
AB  - Effective implementation of person-centered care requires a shared understanding
      and commitment to make it a reality by administrative personnel, direct care
      providers, and residents and their family members. Long-term care facilities must
      seek ways to engage residents' families in person-centered care through its
      training, policies, care planning, and documentation. Doing so may require
      revisions to policies and work practices, and ongoing leadership efforts to
      maintain this care framework within the realities of staff turnover and
      regulatory requirements. Developing protocols and procedures that facilitate
      family members' communication with staff and build consensus and shared values
      will result in a system that represents and honors the unique perspectives,
      values, and needs of each resident receiving care. It is important for facility
      leadership to set the tone for acknowledging the importance of family involvement
      in person-centered care by modeling acceptance of concerns and criticisms as
      valid and by acknowledging that direct care providers, residents, and their
      family members have a voice in care decisions. Such an approach has the greatest
      chance of success in promoting person-centered care and the shared values
      necessary to ensure its successful implementation.

PMID- 15182047
TI  - Rational emotive behavior therapy: disputing irrational philosophies.
AB  - This article provides an overview of the concepts and techniques of rational
      emotive behavior therapy to distinguish it from cognitive-behavioral therapy.
      Rational emotive behavior therapy proposes that psychological disturbance is
      largely created and maintained through irrational philosophies consisting of
      internal absolutistic demands. This therapy strives to produce sustained and
      profound cognitive, emotive, and behavioral change through active, vigorous
      disputation of underlying irrational philosophies.

PMID- 15182048
TI  - Staff & client perceptions of unit quality: a pilot study.
AB  - This pilot study compared psychiatric health care team members' perceptions of
      unit quality with discharged clients' perceptions of quality of care received on
      the unit. The staff members were from four different service units in one acute
      care psychiatric facility. The study used the Perceptions of Unit Quality (PUQ)
      scale, a valid and reliable outcome measurement instrument, developed by
      Cronenwett. Most quality assurance instruments that exist have focused on
      individual caregivers' or service-specific views of quality, but the PUQ scale
      allows quality assurance data that represent team performance to be described
      through team perceptions of quality. Results of this pilot study suggest that use
      of the PUQ scale, in conjunction with clients' perceptions of unit quality, may
      be a legitimate approach in continuous quality improvement efforts in psychiatric
      mental health care centers.

PMID- 15182049
TI  - Orally disintegrating olanzapine: a possible alternative to injection of
      antipsychotic drugs.
AB  - 1. The orally disintegrating formulation of olanzapine dissolves rapidly on
      contact with saliva. 2. In certain cases, orally disintegrating olanzapine may be
      administered, instead of injection of an antipsychotic agent. 3. Orally
      disintegrating olanzapine is intended to deliver a dose analogous to regular
      olanzapine tablets.

PMID- 15182050
TI  - Recording human globin gene variation.

PMID- 15182051
TI  - Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non
      ionic surfactant in the management of acute chest syndrome.
AB  - Acute chest syndrome (ACS) is the most common cause of death in patients with
      sickle cell anemia. Its management is primarily palliative. We performed a Phase
      I evaluation of purified poloxamer 188 (a non-ionic surfactant) in the management
      of ACS. Forty-three patients with sickle cell disease and ACS were treated with
      doses as high as 2960 mg/day by continuous intravenous (IV) infusion. The maximum
      tolerated dose has not been identified. No evidence of renal toxicity or other
      limiting adverse events were found. One adult patient died due to sepsis and
      adult respiratory distress syndrome, which were unrelated to treatment. Poloxamer
      188 is safe to administer to patients with ACS, and preliminary data suggest that
      it may shorten its duration and the length of hospitalization in a dose related
      manner. Children appeared to benefit more than adults. The data and safety
      profile justify further studies with purified poloxamer 188 in the treatment of
      ACS.

PMID- 15182052
TI  - Hb Cardarelli [beta86(F2)Ala-->Pro]: a new unstable and hyperaffine variant in
      association with beta(+)-thalassemia.
AB  - Hb Cardarelli [beta86(F2)Ala-->Pro] is a new unstable and high oxygen affinity
      variant found in several members of a family from Naples, Southern Italy. A
      detailed structural and functional characterization of the variant was performed
      on two subjects, at both the protein and DNA level. The first patient exhibited
      43% of the variant hemoglobin (Hb) without major hematological problems. The
      proband showed 82% of the abnormal Hb in association with beta(+)-thalassemia
      (thal) that caused relevant erythrocytosis requiring frequent phlebotomies.
      Structural investigation of the Hb variant by mass spectrometric methodologies
      identified the amino acid replacement as Ala-->Pro at beta86. The corresponding
      DNA mutation GCC-->CCC at codon 86 of the beta-globin gene was assessed by both
      DNA sequencing and amplification refractory mutation system (ARMS) techniques.
      Functional studies carried out on whole blood and diluted hemolysates from both
      patients demonstrated increased oxygen affinity, decreased Bohr effect, reduced
      heme-heme interaction and nearly halved 2,3-diphosphoglycerate (2,3-DPG) and
      chloride effects.

PMID- 15182053
TI  - Spectrum of hemoglobinopathies in Orissa, India.
AB  - Five hundred and 20 cases (279 males; 241 females), referred for anemia, with a
      wide age range, from different parts of the state of Orissa, India, were
      investigated to evaluate the extent of the prevalence of hemoglobinopathies
      (sickle cell disorders and thalassemias) by analyzing the associated hemoglobin
      (Hb) profiles, Hb genotypes, as well as the clinical and hematological
      parameters. We found sickle cell trait (Hb AS) in 131 cases (62 males; 69
      females), homozygous sickle cell anemia in 49 cases (34 males; 15 females) and Hb
      S-beta thalassemia (S-beta-thal) in 17 cases (nine males; eight females). There
      were also 46 cases (32 males; 14 females) of beta-thal major, 103 cases (51
      males; 52 females) of beta-thal trait, six cases (four males; two females) of Hb
      E trait [beta26(B8)Glu-->Lys; GAG-->AAG], and 17 cases (12 males; five females)
      of Hb E-beta-thal (E-beta-thal). A large proportion of these anomalies were found
      among the general caste people rather than among the tribal population which
      constitutes 22% of the total population in this state. Hb E was found mainly in
      higher castes like Khandayat and Karan, residing in the coastal region of Orissa.
      This study provides comprehensive data on the spectrum of hemoglobinopathies in
      this state.

PMID- 15182054
TI  - Cardiac involvement in beta-thalassemia major and beta-thalassemia intermedia.
AB  - The forms and severity of cardiac complications were investigated in patients
      with asymptomatic thalassemia intermedia and thalassemia major by M-mode, bi
      dimensional echocardiography (ECHO) and echo-Doppler. Twenty-eight patients of
      both sexes with beta-thalassemia intermedia (beta-TI), mean age 23.2 +/- 6.3
      years, untransfused or minimally transfused, were compared to 42 age- and sex
      matched subjects with thalassemia major, who were regularly treated with
      hemotransfusive therapy [pre-transfusion hemoglobin (Hb) values 9.5 +/- 0.9 g/dL]
      and iron chelation. All patients were splenectomized. Age and sex matched healthy
      control subjects were randomly selected. beta-Thalassemia major (beta-TM)
      patients showed a marked reduction in contractile state and a milder left
      ventricular (LV) enlargement than beta-TI patients. Cardiac output (CO) and
      cardiac index (CI) were increased in both groups of patients but appeared
      significantly higher in beta-TI patients with consequent altered LV diastolic
      function indices. In addition, beta-TI patients had reduced indices of pulmonary
      artery flow related to long-term chronic anemia rather than iron overload. The
      progressive rise in CO and CI casts doubts on the current management of beta-TI
      syndromes.

PMID- 15182055
TI  - A new variant with two amino acid substitutions: Hb S-Cameroon [beta6(A3)Glu-
      >Val;beta90(F6)Glu-->Lys].

PMID- 15182056
TI  - A rare 33 bp in-frame deletion (alpha63-74 or alpha64-74 or alpha65-75) in the
      alpha1-globin gene causing alpha(+)-thalassemia: a second observation.
AB  - The most frequent defects resulting in alpha-thalassemia (thal) include large
      deletions that remove one or both of the duplicated alpha-globin genes on
      chromosome 16. Less commonly, alpha-thal mutations involve single nucleotide
      substitutions or micro-deletions, leading either directly to decreased alpha
      globin chain synthesis by the affected allele, or indirectly through production
      of hyperunstable variant alpha-globin chains. Here we describe the
      characterization of a 33 bp in-frame deletion within the alpha1-globin gene, in a
      woman with hematological findings consistent with an alpha-thal trait. The amino
      acids predicted to be missing as a result of the 33 bp deletion are at the end of
      the E helix and the EF corner of the alpha-globin protein chain, and are not
      normally involved in the heme contact, although it is presumed that alpha-globin
      chain folding and hemoglobin (Hb) formation will be disrupted. The observation of
      inclusion and Heinz bodies indicates the synthesis of some abnormal Hb (or globin
      chains). An identical mutation has been previously observed in a single case, a
      Canadian individual of Greek descent, indicating that it is a rare mutation, and
      probably of the same origin. Possible mechanisms underlying the mutation at the
      DNA level are discussed.

PMID- 15182057
TI  - Two cases of compound heterozygosity for Hb Hekinan [alpha27(B8)Glu-->Asp
      (alpha1)] and alpha-thalassemia in Thailand.
AB  - Two unrelated cases of compound heterozygosity for Hb Hekinan [alpha27(B8)Glu-
      >Asp (alpha1) and alpha-thalassemia have been found in Thailand. Mutations were
      established at protein level by peptide mapping and at the DNA level by direct
      sequence analysis. Proband S.S. had genotype - -SEA/alpha2(A)alpha1Hekinan,
      betaA/betaE, while an unrelated proband, S.J., is the first case described with
      the genotype - -SEA/alpha2(A)alpha1Hekinan, betaA/betaA. Both alpha1Hekinan
      mutations were located in the alpha1 locus. Hb Hekinan could not be accurately
      estimated by HPLC, since it was poorly separated from Hb A. However IEF gave good
      separation of Hb Hekinan and Hb A, leading to estimates of Hb Hekinan (alpha
      Hekinan 2/beta A 2 and alpha Hekinan 2/beta E 2) level as 40-43% of total Hb.

PMID- 15182059
TI  - Beta-globin gene cluster haplotypes linked to the betaS gene in western India.
AB  - The present survey, which involves 70 sickle cell anemia patients from Gujarat
      and Maharashtra revealed a high prevalence of the typical Arab-Indian haplotype
      (91.5 %). Six atypical haplotypes, including a Cameroon one were also found.
      Correlation of these various haplotypes with HbF expression was studied.

PMID- 15182058
TI  - Thalassemia intermedia due to co-inheritance of beta0/beta(+)-thalassemia and (- 
      SEA) alpha-thalassemia/Hb Westmead [alpha122(H5)His > Gln (alpha2)] in a Chinese
      family.
AB  - Two brothers from a Chinese family with beta-thalassemia intermedia who harbor
      both alpha- and beta-globin gene defects are described. They are both compound
      heterozygous for codons 41/42 (-CTTT) beta0-thalassemia and nt - 28 (A > G)
      beta(+)-thalassemia mutations together with concurrent (- -SEA) alpha-thalassemia
      (SEA) deletion. One sibling also harbors Hb Westmead, giving an unusual genotype
      of beta0/beta(+)-thalassemia and (- -SEA) alpha-thalassemia/Hb Westmead. With
      respect to the age at presentation and transfusion requirement, this subject
      shows a milder clinical phenotype than his brother, most probably explainable by
      the presence of Hb Westmead in addition to the SEA deletion, which causes a
      further amelioration of the alpha-chain excess and hence a less severe disease.
      For areas with high prevalence of both alpha- and beta-thalassemia mutations,
      their interactions should always be considered in genotype phenotype correlation.
      Moreover, routine laboratory diagnostic strategy for non-deletional alpha-globin
      gene mutations in the Chinese may need to include Hb Westmead, as it is a common
      alpha-globin gene mutation in our population apart from Hb Constant Spring and Hb
      Quong Sze.

PMID- 15182060
TI  - The phenotype of sheep hemoglobins containing distinct alpha chains is influenced
      by beta chain genotype.
AB  - In sheep carrying simultaneously extra alpha-globin genes (triplications and
      quadruplications) and two alpha-chain allelic variants, a gradient of decreasing
      expression of the downstream genes was previously reported. We show here that in
      these sheep the proportions of the normal and variant Hbs reflect not only the
      position effect, but also the differential affinity of one of the alpha variants
      for the betaA and betaB allelic chains.

PMID- 15182061
TI  - [Clinical applications of brain natriuretic peptide testing].
AB  - Natriuretic peptide hormones are a family of vasoactive peptides with many
      favorable physiological properties and have emerged as useful markers in
      cardiovascular disease. In particular, brain natriuretic peptide (BNP) is a
      cardiac neurohormone secreted by the cardiac ventricles as a response to
      ventricular volume expansion, pressure overload and resultant increased wall
      tension, directly correlated with both left ventricular filling and pulmonary
      wedge pressure. It is nowadays considered an important diagnostic tool, adding
      information to clinical judgment in the evaluation of patients with acute
      dyspnea, and a useful guide to the treatment of chronic heart failure. Moreover,
      the prognostic value of BNP has been established in several studies, both in
      postmyocardial infarction patients with asymptomatic left ventricular dysfunction
      and in patients with overt heart failure. Furthermore it has been shown that BNP
      could also predict sudden death and offer an additive and easily obtainable tool
      for risk stratification of patients with chronic heart failure. This paper
      summarizes the current evidence concerning the use of this peptide in a variety
      of clinical scenarios.

PMID- 15182062
TI  - [Clinical significance of the assessment of endothelial function].
AB  - Endothelium-derived nitric oxide is not only a potent vasodilator but also
      inhibits platelet aggregation, vascular smooth muscle cell migration and
      proliferation, monocyte adhesion and adhesion molecule expression, thus
      protecting the vessel wall from the development of atherosclerosis and
      thrombosis. Major cardiovascular risk factors are associated with endothelial
      dysfunction, which involves enhanced production of oxygen free radicals, that can
      destroy nitric oxide and reduce its availability, and release of endothelium
      derived contracting factors including prostanoids and endothelin-1. Endothelial
      dysfunction is a promoter of atherosclerotic and thrombotic damage and in
      prospective studies on patients with high cardiovascular risk impaired
      endothelium-dependent vasodilation is associated with an increased incidence of
      cardiovascular events. However, endothelial function cannot yet be included among
      the surrogate endpoints which need to be measured for cardiovascular risk
      stratification. This limitation springs from the fact that available tests to
      assess endothelium-dependent vasodilation are invasive or, if noninvasive, they
      have no sufficient sensitivity and specificity to be proposed for clinical
      practice. Moreover, no study is available demonstrating that reversal of
      endothelial dysfunction, which can be obtained by appropriate treatment, is
      independently associated with a better clinical outcome. However it is
      conceivable that in the future, by the utilization of a non-invasive method such
      as the determination of brachial artery flow-mediated dilation, large-scale
      multicenter trials might provide a definitive answer to the real prognostic value
      of endothelial dysfunction, in terms of cardiovascular risk and therapeutic
      approach.

PMID- 15182063
TI  - [The effects of implementation of heart failure guidelines in the Pordenone
      province: analysis of the results following databases of the regional health
      guide system].
AB  - BACKGROUND: The aim of this study was to evaluate the effects of heart failure
      guideline implementation in the Pordenone province area, by using the regional
      health system databases. METHODS: We created the provincial registry of
      hospitalization for heart failure and we defined a set of indicators to assess
      the adequate use of the hospital facility, the correct use of diagnostic
      instruments, the appropriate use of medications, the in-hospital, 6-month and 1
      year mortality rates. RESULTS: Up to December 31, 2002, 2977 subjects, living in
      the Pordenone province area, were hospitalized for heart failure (10.4 for 1000
      inhabitants). Repeated hospitalizations in the years have percentage values
      oscillating at around 20%. The average length of hospitalization appeared
      declining, ranging from 11.1 days in 2000 to 10.3 days in 2002. The in-hospital
      death rate varied between 16-17%. The cumulative death rate within 6 months
      (33.2%) and 1 year (41.0%) of hospitalization resulted rather high, also
      considering the patients' advanced mean age (79 years). The percentage of
      patients who underwent an echocardiogram as outpatients in the previous year
      increased from 5.7% in 2000 to 13.1% in 2002. As for therapy, an increase in the
      percentage of patients treated with ACE-inhibitors (from 44.6 to 50.2%), sartans
      (from 8.2 to 11.7%), beta-blockers (from 11.7 to 16.7%) and diuretics (from 66.4
      to 68.5%) was evident from 2000 to 2001. A mild reduction in the percentage of
      patients treated with digitalis (from 35.0 to 33.8%) and with calcium antagonists
      (from 22.4 to 20.9%) was also noted. CONCLUSIONS: The results of this study show
      that it is possible to use some indicators in evaluating the effects of guideline
      implementation in heart failure, by using the regional health system data. The
      final goal is to gradually involve all the professionals in the different phases
      of the natural course of heart failure patients, particularly the general
      practitioners.

PMID- 15182064
TI  - [Comorbidity in surgical myocardial revascularization: risk factors or
      contraindications for surgery].
AB  - BACKGROUND: The worsening evolution of patients undergoing surgical myocardial
      revascularization makes it difficult the stratification of the preoperative
      mortality risk, a correct evaluation of results and the comparison of results of
      different centers. The aim of the study was to evaluate the prognostic weight of
      comorbidity in surgical myocardial revascularization. METHODS: We evaluated the
      characteristics of preoperative morbidity in 4999 patients who underwent surgical
      myocardial revascularization during four different periods (1979-1980, 1991-1992,
      1994-1998, 1999-2002). We also evaluated the in-hospital results. RESULTS: By
      comparing the four different periods, an increase in older age, female sex,
      comorbidity, three-vessel disease, and severe left ventricular dysfunction was
      observed. Surgical mortality decreased to 2.3%. Multivariate analysis of the 1999
      2002 period showed that only renal insufficiency was a risk factor for in
      hospital mortality. CONCLUSIONS: Although the preoperative risk is higher,
      nowadays hospital mortality is reduced thanks to new cardiac-surgical techniques
      and approaches that increasing the capacity of controlling comorbidity in the pre
      , intra- and postoperative course. For a correct decision-making process it is
      crucial to assess how much comorbidity may influence the long-term follow-up in
      these patients independently of surgical myocardial revascularization.

PMID- 15182065
TI  - [Effects of two Sicilian red wines on some cardiovascular risk factors].
AB  - BACKGROUND: The aim of this study was to evaluate whether Sicilian red wine
      consumption is associated with a lower cardiovascular risk. METHODS: Forty-eight
      subjects of both sexes (age range 35-65 years) nondrinkers or rarely drinkers of
      moderate red wine intake were selected. Subjects were divided into two groups
      (group A and group B), assigned to receive with a crossover design 250 ml/die
      (during the meals) of one of two types of Sicilian red wines (Nero d'Avola and
      Etna Torrepalino respectively). At all visits (-15 days, basal, +4 and +8 weeks)
      the following parameters were measured: blood glucose, total cholesterol and
      triglycerides (by enzyme kit methods, Boehringer Mannheim, Milan, Italy), HDL
      cholesterol (by selective precipitation with dextran-magnesium chloride), LDL
      cholesterol (by calculation with the Friedewald formula), LDL/HDL ratio,
      apolipoproteins A1 and B (by radial immunodiffusion, Behring Institute, Scoppito,
      Italy), lipoprotein(a) (ELISA, Technoclone, Vienna, Austria), plasma C-reactive
      protein (high-sensitivity, Dade Behring, Marburg, Germany), D-dimer (Turbiquant,
      Dade Behring), factor VII (coagulant activity, Dade Behring), plasminogen
      activator inhibitor antigen (ELISA), tissue-type plasminogen activator antigen
      (ELISA), fibrinogen (coagulant), oxidized LDL antibody (ELISA), total plasma
      antioxidant capacity (FRAP method). RESULTS: At the end of the red wine intake
      period, HDL cholesterol was significantly increased (p < 0.01) and the LDL/HDL
      ratio was significantly decreased (p < 0.05) in both study groups, while
      apolipoprotein A1 was significantly increased (p < 0.05) only in group A. In both
      group A and group B fibrinogen (p < 0.01 and p < 0.005, respectively), factor VII
      (p < 0.01 and p < 0.05, respectively), plasma C-reactive protein (p < 0.005 and p
      < 0.05, respectively) and oxidized LDL antibody (p < 0.05) were significantly
      decreased, while tissue-type plasminogen activator (p < 0.005), plasminogen
      activator inhibitor (p < 0.005) and total plasma antioxidant capacity (p < 0.005)
      were significantly increased. CONCLUSIONS: Our results show a positive effect of
      these Sicilian red wines on many risk factors, suggesting a moderate consumption
      of red wine in the adult population as a component of the Mediterranean diet.

PMID- 15182066
TI  - [The unbearable lightness of myocardial infarction].

PMID- 15182067
TI  - [Giant aneurysm of a saphenous vein graft with fistulization into the right
      atrium: differential diagnosis and treatment].
AB  - The aneurysm of an aortocoronary saphenous vein graft is a rare but potentially
      fatal complication of coronary artery bypass grafting. This case came to our
      observation after a single episode of hypotension, followed by dyspnea in a man
      previously operated on for coronary artery bypass grafting. A para-hilar mass was
      found on routine roentgenogram. The spiral computed tomographic scan was
      suggestive for aortic pseudoaneurysm. The correct diagnosis was obtained by
      cardiac catheterization showing a giant graft aneurysm determining compression
      and fistulous communication into the right atrium. The difficult diagnosis and
      the surgical treatment are discussed.

PMID- 15182068
TI  - [Recommendations on hypertension in childhood: the Child Project].

PMID- 15182069
TI  - [Cardiac surgery in developing countries: myth or reality?].

PMID- 15182070
TI  - [Results of 17 months' surgical experience in the Cardiological Centre of Phnom
      Penh (CCPP). The challenge of sanitation in a developing country].
AB  - The authors report the preliminary results of the first 17 months' experience at
      the Cardiological Centre of Phnom-Penh (CCPP), set up by the initiative of the
      "Chaine de l'Espoir" organisation. The CCPP has only two operative theatres, 8
      intensive care beds and 32 hospital beds. During the 17 months, 1193 patients
      under 30 years of age were examined. Nine hundred and five had cardiac disease.
      Three hundred and twenty-two patients underwent surgery for congenital and
      valvular heart disease. The commonest operated congenital lesions were left-to
      right shunts (71%) and tetralogy of Fallot (24%). In the valvular group, 53% had
      mitral insufficiency, 40% had mitral stenosis and 7% had aortic insufficiency.
      The selection of patients and surgical strategy depended on the economic
      constraints specific to developing countries: --strict selection of operable
      patients: exclusion of severe pulmonary hypertension, left ventricular
      dysfunction or cachexia and neonates with complex congenital heart disease; -
      simple, effective and low cost surgical procedures are preferred, repair in the
      majority of cases, preference given to valvuloplasty over valve replacement. The
      quality of the results with low morbid-mortality, justifies the creation of such
      cardiac surgical centres; surgery must be accompanied by strict measures of
      prevention of endemic rheumatic fever which remains a major public health
      problem.

PMID- 15182071
TI  - [Comparison of the radial and femoral arterial approaches for coronary
      angioplasty in acute myocardial infarction].
AB  - AIM: As compared to the femoral approach, the use of radial arterial access has
      been demonstrated to reduce the incidence of access site bleeding complications
      in staged procedures. The purpose of this study was to evaluate clinical outcomes
      comparing radial and femoral approaches in the treatment of acute myocardial
      infarction with emergency angioplasty. METHODS: Between September 1999 and
      December 2002, we prospectively enrolled 162 consecutive patients undergoing
      primary angioplasty with abciximab (n=127) or rescue angioplasty after
      thrombolysis failure (n=35) comparing in a non-randomized plan radial (n=87) and
      femoral (n=75) access. RESULTS: Cannulation time (from patient arrival at the
      catheterization laboratory to the effective placement of arterial sheath) and
      procedural time was not significantly different in radial and femoral groups
      (respectively 8.5 +/- 5.2 vs 9.0 +/- 5.8 minutes, p=0.81, and 42 +/- 28 vs 44 +/-
      27 min, p=0.74). Nevertheless, time of radiation (23.1 +/- 11 min vs 16.5 +/-
      10.9 min; p=0.01) and dose-area product (229 +/- 133 vs 151 +/- 86 Gy.cm2,
      p=0.01) were significantly higher in the radial group. Angiographic success rate
      is comparable in both groups. Freedom from ischemic recurrent events at 1-month
      follow-up occurred in 84 (96%) and 69 (92%) patients in the radial and femoral
      groups, respectively (p=0.12). There were no major access site bleeding
      complications in the radial group, as opposed to six (8%) in the femoral group
      (p=0.01) all requiring transfusions and surgical repair necessary in four.
      Uncomplicated clinical course occurred in 83 (92%) of patients in the radial
      group and 65 (85%) in the femoral group (p=0.03). Total hospital length of stay
      was significantly higher in the femoral group (5.9 +/- 2.1 days vs 3.5 +/- 1.2
      days; p=0.009). CONCLUSION: In patients with acute myocardial infarction treated
      with coronary angioplasty, the transradial access is efficacious with fewer major
      access site complications than transfemoral access. Transradial approach produces
      a shorter length of stay, as compared to the transfemoral approach although with
      longer times of radiation and higher dose area-product.

PMID- 15182072
TI  - [Malignant hypertension. Case series of 42 patients].
AB  - One could expect that malignant hypertension would belong to the history.
      Unfortunately, this complication has not been eradicated even though many
      physicians have already forgot it. The hypertension care units are still
      confronted to it, and even the arrival of the renin-angiotensin system blockers
      have changed the prognosis of those patients, an adequate management on emergency
      remains mandatory in order to avoid in particular the evolution to renal failure.
      By reporting a series of 42 patients included in a period of 7 years, we aimed to
      remind the presentation of this severe pattern of hypertension and the basics of
      its management.

PMID- 15182073
TI  - [Prosthetic valve thrombosis in pregnancy. A single-center study of 12 cases].
AB  - Pregnancy in women with mechanical prosthetic heart valves carried an increased
      risk of thromboembolic complications due to changes in haemostasis. Prosthetic
      valve thrombosis is a serious complication resulting in high mortality. Ten
      patients from 20 to 38 years of age had 12 thromboses of mechanical heart
      prostheses during pregnancy. The prosthesis was mitral in 8 cases and aortic in 4
      cases. The prosthesis was a ball valve in 1 case, a tilting disc in 3 cases and
      bi-leaflet in 8 cases. Initial emergency treatment was surgical in 3 cases and
      medical in 9 cases (thrombolysis in 7 cases and simple heparin therapy in 2
      cases). Secondary surgery was carried out in one patient after failure of heparin
      therapy. There was one death in the surgical group (4 cases, 25%) and 30% foetal
      mortality in the surviving women. In the thrombolysis group (7 cases), two women
      died (28%) after failure of treatment. Both patients had mitral valve prostheses
      and were in cardiogenic shock. Three women, of the other 5 thrombolysed cases,
      were able to complete their pregnancies and had healthy babies with no foetal
      mortality. No per-thrombolytic embolic complications were observed. However,
      there was one severe bleeding complication which was successfully managed by
      surgical drainage. Finally, a global success rate of 75% (9 out of 12 patients)
      and a mortality of 30% (3 maternal deaths in the 10 patients--all with mitral
      valve protheses) were observed irrespective of the therapeutic protocol used.
      Thrombosis is the most life-threatening complication for women with prosthetic
      heart valve during pregnancy. Emergency surgery for valve replacement or
      thrombectomy is the commonest treatment. Trombolysis is classically limited by
      the risk of haemorrhagic and thromboembolic complications reported in the
      literature. In this study, thrombolysis was effective in the 71% of cases with a
      low risk of haemorrhagic complications.

PMID- 15182075
TI  - [Aspirin resistance 2003: a review of the literature].
AB  - Despite the development of new molecules, aspirin remains a mainstay of the
      antiplatelet therapy, indispensable for the secondary prevention of
      cardiovascular events. The therapeutic used is based on the platelet aggregation
      inhibition induced by aspirin. The concept of aspirin resistance corresponds to a
      total or almost total absence of the platelet aggregation inhibition generally
      observed in vitro under aspirin. The frequency of this resistance depends on the
      platelet aggregation test used and the population studied. In a population with
      stable coronary disease treated in the long term with 160 to 325 mg of aspirin
      daily, 8 to 35% of patients are non-responders. Many hypothesis on the mechanisms
      of the lack of antiplatelet effect of aspirin are under investigation. The
      clinical implication of the in vitro antiplatelet effect resistance of aspirin
      has recently been evidenced by a relative risk of cardiovascular events at two
      years at 3. This would support an individual adaptation of the anti-platelet
      therapy.

PMID- 15182074
TI  - [Quantification of longitudinal myocardial velocities by Doppler tissue imaging
      during dobutamine echocardiography].
AB  - Doppler tissue imaging has been suggested to be a valuable method for the
      diagnosis of myocardial ischaemia during dobutamine echocardiography. The authors
      studied this mode of investigation in 49 consecutive patients (average age 60 +/-
      12 years) referred for dobutamine stress echocardiography and who had undergone
      coronary angiography. The stress echo was carried out according to a standard
      protocol (5 to 40 m g/kg/min +/- atropine) with additional acquisition of 3
      apical views (4, 2 and 3 chambers) with colour Doppler tissue imaging. Analysis
      of systolic and diastolic myocardial velocities was performed afterwards from
      digitised data. The different Doppler tissue parameters were measured in 12 left
      ventricular segments (excluding the apical segments) for each dosage of
      dobutamine: peak systolic velocity (S), Q-S duration, systolic velocity time
      integral (ITVS), peak early diastolic velocity (E), peak end diastolic velocity
      (A). These parameters were analysed throughout the stress for each segment
      without significant coronary stenosis to define normal values. ROC curves were
      constructed to determine threshold values of relative changes of velocity
      (between maximal dobutamine dosage and basal conditions) to improve detection of
      ischaemia in a segment with coronary stenosis (vessel diameter reduction > or =
      70%). Similar diagnostic performances were observed with different systolic and
      diastolic parameters. The feasibility of measurement of diastolic velocities was,
      however, reduced (from 29% to 49%). The diagnostic accuracy of each parameter was
      the same for each vessel territory. A satisfactory concordance was observed
      between 2D echocardiography and Doppler tissue imaging for the detection of
      significant coronary stenosis in an analysis by vascular territory. The authors
      conclude that analysis of myocardial velocities during dobutamine stress
      echocardiography is feasible. It may be a useful complement for the detection of
      coronary stenosis during pharmacological stress echocardiography.

PMID- 15182076
TI  - [New concepts on the physiopathology and therapy of aortic stenosis].
AB  - Calcified "degenerative" aortic stenosis is currently the most common
      valvulopathy in industrialised countries. In the course of the last decade,
      experimental studies have allowed a better understanding of the physiopathology
      of this vavlulopathy. The latest development is the evidence for the initiation
      and progression of this disease, similar to those described for atherosclerosis.
      Lipid disturbances, in particular hypercholesterolaemia, constitute an important
      factor in the initiation of valvular lesions, but also in aortic orifice
      calcification. Certain preliminary clinical studies are in favour of the
      significance of statins for slowing the progression of aortic stenosis. This
      potential beneficial effect requires confirmation by randomised prospective
      studies and raises hopes for medical therapy in order to avoid the evolution of
      ordinary aortic sclerosis into tight calcified aortic stenosis.

PMID- 15182077
TI  - [Cardiotoxicity associated with trastuzumab (herceptin). An undesired effect
      leads towards a model of cardiac insufficiency].
AB  - Anticancer chemotherapy continues to advance. One of the new therapeutic
      orientations is the targeting of receptors which regulate the tumoral activity of
      the malignant cells. Trastuzumab is the prototype of these new chemotherapeutic
      agents. It is a monoclonal antibody directed against a tyrosine kinase receptor
      related to the EGF (Epidermal Growth Factor): the HER receptor. This receptor is
      also present in myocardial cells. Blockade of this myocardial receptor could
      cause severe cardiotoxicity about which some information is available but which
      continues to pose many problems. This data should be known as cardiologists will
      be consulted before the prescription of Trastuzumab and could also be confronted
      by these cardiotoxic effects. Precise physiopathological explanations have
      already been published from experimental studies which show the deleterious
      effects of the suppression of certain HER receptors on the heart. These studies
      not only explain all the clinical signs of Trastuzumab's cardiotoxicity but also
      suggest ways of preventing and treating some of these cases of cardiac failure.

PMID- 15182079
TI  - [Administrative procedures in cases of medical errors: the jurisdiction of the
      hospitalist].
AB  - The administrative jurisdiction is, with the exception of free practice within
      hospitals, that which judges whether actions of hospital doctors are at fault,
      and evaluates the harm done to the plaintiff. After a reminder of the
      fundamentals of medical liability as regards the administration, a short update
      on private practice in hospital, and the notion of fault being separate from the
      hospital function, the author analyses the important elements such as the concept
      of the preliminary decision and the status of the expert, and then a number of
      characteristic elements of this type of procedure, stressing in particular the
      absolute necessity of a perfectly kept hospital medical record.

PMID- 15182078
TI  - [Identifying myocardial ischaemia in diabetics. SFC/ALFEDIAM joint
      recommendations].

PMID- 15182081
TI  - [Diagnosis of acute myocardial infarction using multislice computed tomography in
      emergency room].
AB  - Managing chest pain in emergency remains a diagnostic challenge because of the
      speediness and the accuracy that request. The authors report the case of a 40
      years old patient admitted for chest pain with suspected aortic dissection.
      Multislice computed tomography (sixteen-slice CT) was performed at the patient's
      admission, initial diagnosis was rapidly corrected, showing both and accurately
      show both antero-septal defect perfusion and an acute occlusion of the proximal
      left anterior descending artery. Angioplasty was performed in emergency within
      the 6 first hours after onset of the symptoms. Multislice computed tomography was
      able to identify accurately not only the chest pain etiology but also to show the
      culprit artery, leading to quick and oriented percutaneous coronary intervention.

PMID- 15182080
TI  - [Two cases of malignant tumors of the inferior vena cava].
AB  - The malignant tumors of the inferior vena cava are rare. Their prognosis is bad.
      We report two cases of a 17-year-old and 46-year-old woman presenting the one an
      intimal sarcoma of the inferior vena cava and the other a metastatic of
      adenocarcinoma whose primary tumor was not identified. The aortic wall was
      invaded in both patients. The ureter repulsed in first case, was invaded in
      second case. The treatment consisted on resection of the tumor including the
      aortic wall with vein closure in both patients, with right nephrectomy in second
      patient. In the two cases, a prosthetic reconstruction of the arterial integrity
      was attempted with aortobiiliac bypass. The two patients died after relapse
      tumorous to the 6th month in first patient and by multisystem organ failure 5th
      day post-operative in second. Through these two personal cases, we try to point
      out the difficult problem of diagnosis that put these tumors and their bad
      prognosis despite an improvement of treatment.

PMID- 15182082
TI  - [Contribution of Ancient Egypt to cardiovascular medicine].
AB  - As early as the Old Kingdom, 3,000 years before J.C., the Egyptians worked out
      the principles of medicine starting from their clinical observations and the
      description of the effectiveness of some remedies on the noted disorders. The
      originality of the Egyptian medicine was to try to offer rational explanations to
      the noted clinical expressions. They were the first to establish the importance
      of the pulse and its relationship with the contractions of the heart. Egyptians,
      authors of the first known book of cardiology the "treaty of the heart" in the
      Ebers papyrus, incontestably deserve the title of pioneers of the cardiology.

PMID- 15182083
TI  - Phillip Sharp--Nobel Prize for discovery of "split genes".

PMID- 15182084
TI  - Primary percutaneous coronary intervention without nearby surgical capability: a
      reassuring response from rural America.

PMID- 15182085
TI  - Burial by sand: summer play gone awry.

PMID- 15182086
TI  - Menopause and hot flashes: no easy answers to a complex problem.

PMID- 15182087
TI  - Percutaneous coronary intervention for ST-segment and non-ST-segment elevation
      myocardial infarction at hospitals with and without on-site cardiac surgical
      capability.
AB  - OBJECTIVE: To compare the safety and efficacy of percutaneous coronary
      intervention (PCI) for acute myocardial infarction performed at a hospital
      without cardiac surgical capability with PCI performed for acute myocardial
      infarction at a center with on-site surgery. PATIENTS AND METHODS: We included
      patients with acute myocardial infarction in whom PCI was performed from March 1,
      2000, through May 31, 2002, at a community hospital (Immanuel St Joseph's)
      without on-site surgery. The procedural success, in-hospital adverse cardiac
      events, and 6-month follow-up were compared with those of PCI performed for acute
      myocardial infarction in matched controls from January 1, 2000, through February
      28, 2002, at a center with cardiac surgery (Saint Marys Hospital). RESULTS: One
      hundred sixty patients (and 160 matched controls) underwent PCI for acute
      myocardial infarction. The procedural success rate was high and similar for the 2
      groups (96% vs 95%; P=.79). In-hospital mortality, Q-wave myocardial infarction,
      and target vessel revascularization were low and similar for the 2 groups. No
      patient was referred for emergency coronary artery bypass graft surgery for
      failed PCI. Six-month survival from all-cause mortality was 96% for the Immanuel
      St Joseph's group and 94% for the Saint Marys Hospital group (P=.92). Subgroup
      analysis of patients with primary PCI for ST-segment elevation acute myocardial
      infarction revealed high procedural success and low and similar rates of major
      cardiac adverse events in the 2 groups. CONCLUSION: This study shows that PCI for
      acute myocardial infarction can be performed safely and effectively in a
      community hospital without on-site cardiac surgery.

PMID- 15182088
TI  - Lower urinary tract symptoms and sexual dysfunction in community-dwelling men.
AB  - OBJECTIVES: To evaluate the cross-sectional association between lower urinary
      tract symptoms (LUTS) severity and sexual function in a population-based sample
      of men and the extent to which this association might be explained by age.
      SUBJECTS AND METHODS: Subjects in The Olmsted County Study of Urinary Symptoms
      and Health Status Among Men (55% participation rate) included 2115 white men aged
      40 to 79 years; subjects were recruited on January 1, 1990, from a random sample
      identified through the Rochester Epidemiology Project. At baseline in 1990 and
      biennially thereafter, these men completed a self-administered questionnaire that
      assessed LUTS severity with questions similar to those of the American Urological
      Association Symptom Index. At the 6-year follow-up, 11 previously validated
      questions about male sexual function from the Brief Sexual Function Inventory
      were added. RESULTS: Overall, each of the sexual function domains (sexual drive,
      erectile function, ejaculatory function, problem assessment, and overall sexual
      satisfaction) was inversely associated with the severity of LUTS, with Spearman
      correlation coefficients ranging from -0.21 to -0.31 (all P<.001). In age
      adjusted analyses, the ejaculatory function and problem assessment domains were
      most strongly associated with overall LUTS severity, whereas the association with
      sexual drive was substantially diminished. Little difference was noted in the
      magnitude of association between sexual function and either obstructive or
      irritative symptoms. CONCLUSIONS: The cross-sectional data suggest that sexual
      function is inversely associated with LUTS severity and that this association is
      only partially attributable to the confounding effects of age.

PMID- 15182089
TI  - Outcomes of patients with reduced exercise capacity at time of exercise
      echocardiography.
AB  - OBJECTIVE: To characterize the prognostic implications of exercise
      echocardiography in patients who have reduced exercise capacity at the time of
      testing. PATIENTS AND METHODS: We examined the outcomes of 941 patients at the
      Mayo Clinic in Rochester, Minn, between January 1, 1990, and December 31, 1995,
      who had reduced exercise capacity on exercise echocardiography (women, <5
      metabolic equivalents; men, <7 metabolic equivalents) and evaluated the potential
      association between clinical, electrocardiographic, and echocardiographic
      variables and outcomes for patients with normal vs abnormal exercise
      echocardiograms. We used variables of independent prognostic value to estimate
      cardiac risk. RESULTS: For patients with normal exercise echocardiograms (n=282),
      the rate of cardiac death or nonfatal myocardial infarction was 09% per person
      year of follow-up, and previous coronary revascularization was the only predictor
      of the time to cardiac event. For patients with abnormal exercise echocardiograms
      (n=659), the cardiac event rate was 4.4%. Independent predictors of outcome were
      exercise left ventricular (LV) ejection fraction (risk ratio, 1.44 per 10%
      decrement; 95% confidence interval, 1.2-1.7; P<.001) and an increase or no change
      in LV end-systolic size in response to exercise (risk ratio, 2.22; 95% confidence
      interval, 1.2-4.1; P=.01). CONCLUSION: Exercise echocardiographic findings have
      important prognostic implications for patients who have reduced exercise capacity
      on testing. Echocardiographic descriptors of LV systolic function and dysfunction
      obtained immediately after exercise can be used to stratify cardiac risk of
      patients who do not achieve a level of exercise ordinarily considered to be of
      "diagnostic" value.

PMID- 15182090
TI  - Chronic noncancer pain rehabilitation with opioid withdrawal: comparison of
      treatment outcomes based on opioid use status at admission.
AB  - OBJECTIVE: To study differences in treatment outcomes between patients with
      chronic noncancer pain taking vs those not taking maintenance opioids at
      admission to a pain rehabilitation program. PATIENTS AND METHODS: A nonrandomized
      2-group prepost design was used to compare 356 patients admitted to the Mayo
      Comprehensive Pain Rehabilitation Center from January 2002 to December 2002 at
      admission and discharge by opioid status at admission. Measures of pain severity,
      interference due to pain, perceived life control, affective distress, activity
      level, depression, and catastrophizing (an exaggerated negative mental set
      associated with actual or anticipated pain experiences) were used to compare
      opioid and nonopioid groups. The patients entered a 3-week intensive outpatient
      multidisciplinary pain rehabilitation program designed to improve adaptation to
      chronic noncancer pain. The program uses a cognitive-behavioral model and
      incorporates opioid withdrawal. RESULTS: More than one third of patients
      (135/356) were taking opioids daily at admission. At completion of the program,
      all but 3 of the 135 patients had successfully discontinued opioid treatment. No
      significant pretreatment differences were found between the opioid and nonopioid
      group regarding demographics, pain duration, treatment completion, or all outcome
      variables, including pain severity. Significant improvement was noted at
      discharge for all outcome variables assessed regardless of opioid status at
      admission. CONCLUSION: Patients with symptomatically severe and disabling pain
      while taking maintenance opioid therapy can experience significant improvement in
      physical and emotional functioning while participating in a pain rehabilitation
      program that incorporates opioid withdrawal.

PMID- 15182091
TI  - Anticipated impact of drug-eluting stents on referral patterns for coronary
      artery bypass graft surgery: a population-based angiographic analysis.
AB  - OBJECTIVES: To determine the clinical and angiographic characteristics of
      patients who underwent coronary artery bypass graft (CABG) surgery before the
      availability of drug-eluting stents (DES) and to project the potential impact of
      percutaneous coronary intervention using DES. PATIENTS AND METHODS: We reviewed
      the coronary angiograms obtained between March 1999 and December 2001 of 192
      consecutive patients from Olmsted County, Minnesota, who had undergone isolated
      CABG surgery for the first time. Three interventional cardiologists categorized
      the patients into 1 of 4 groups on the basis of technical feasibility of complete
      revascularization by percutaneous coronary intervention with DES. RESULTS: The
      study population consisted primarily of men (78%), with a mean age of 67 years.
      Of the 192 patients, 58 (30%) had diabetes mellitus, and 124 (65%) had 3-vessel
      disease. Twelve patients (6%) had lesions suitable for stents that matched the
      inclusion criteria for DES in recently published trials; 77 (40%) had lesions
      suitable for stents but had lesion characteristics not included in the initial
      DES trials. Thirty-two patients (17%) had target lesions considered technically
      difficult, but feasible, for stent placement. Seventy-one patients (37%) had
      lesions unsuitable for percutaneous coronary intervention (75% of these due to
      chronic occlusions) with the current stent delivery technology. CONCLUSION: This
      population-based analysis suggests that only a small proportion of patients
      undergoing CABG surgery meets the strict angiographic eligibility criteria for
      DES on the basis of recent trials. However, up to 46% of current CABG patients
      may ultimately undergo conversion to DES. The remaining 54% of this patient
      population may still not be ideal candidates for DES with the current stent
      delivery technology.

PMID- 15182092
TI  - Accidental burials in sand: a potentially fatal summertime hazard.
AB  - Accidental burial in sand is a tragically unrecognized risk associated with a
      popular childhood recreational activity. We describe 4 boys, aged 10 to 13 years,
      who were accidentally buried by sand. One boy died after his self-made tunnel in
      a sandbox collapsed. In a separate incident at a construction site, 1 boy died,
      and 2 were injured after a 30-foot sandpile collapsed as they ran down the
      embankment; all 3 were buried by the sand. In both incidents, play was
      unsupervised, and burial was sudden and complete. The calculated weight of the
      sand exceeded the expected maximal muscle effort of the chest, leading to
      traumatic asphyxiation secondary to restrictive compression of the chest. Only 15
      accidental burials have been reported in the literature. To our knowledge, this
      is the first report describing children who died of respiratory asphyxia due to
      overwhelming thoracic compression after sand burial. Greater awareness by public
      health and safety officials at beaches, sandboxes, sandpiles, and natural play
      areas may prevent potentially lethal accidents.

PMID- 15182093
TI  - Measuring hot flashes: summary of a National Institutes of Health workshop.
AB  - The etiology and mechanism of hot flashes remain incompletely understood. Future
      studies of hormonal and neurologic systems may provide promising leads to improve
      our understanding of the basic phenomenon and perhaps also shed light on the
      placebo effect. However, this is likely a complex undertaking. Critical to this
      effort is the ability to reliably identify when a hot flash has occurred. The
      leading objective measure in use today--sternal skin conductance monitoring--has
      some limitations in ambulatory settings. However, a more severe limitation is the
      inability of sternal skin conductance to provide any information on duration,
      intensity, and interference with activities. Ultimately, researchers desire a
      convenient and cost-effective sensor for monitoring hot flashes without
      cumbersome electrodes that might become compromised if a subject experiences
      extensive sweating or takes a shower and one that can capture data continuously
      for relatively long periods of observation. However, researchers also need well
      characterized methods for collecting self-reported data. If the primary concern
      is helping women with hot flashes find relief, then subjective measures collected
      through diaries or interviews cannot be dismissed. Given the importance of this
      information, it would make sense to undertake methodologic research to ensure
      that the best possible systems are used to collect valid and reliable
      information. The factors that we want to measure with respect to hot flashes are
      likely to change over time as more is learned about the underlying phenomenon.
      This will probably be an evolutionary process, one involving decisions about what
      biological factors will be most useful for the task at hand, what technologies
      might be available or easily adaptable, which measures should be bundled together
      to maximize the precision of data collected with the available technology, and
      the analysis of the data to generate new hypotheses and perhaps the need for new
      measurement tools. Investigators face several challenges when considering the
      design of studies of hot flashes. Substantial placebo effects and small sample
      sizes have produced studies with equivocal findings. The placebo effect, while
      remarkable in its dimensions in some studies of hot flash interventions, is not
      understood. Distinguishing placebo effects from the natural dissipation of
      symptoms over time would be extremely helpful. Similarly, the ability to induce a
      placebo effect to reduce the discomfort and annoyance associated with hot flashes
      might be helpful. The use of neuroimaging technology offers potential for greater
      understanding of the placebo effect. The group concluded that better measures of
      hot flashes require improved knowledge in several areas: The physical processes
      underlying hot flashes, which will identify additional factors to measure and the
      factors that influence the perception and reporting of hot flashes. Improved
      sternal skin conductance systems, with additional tools to be developed when
      other factors of hot flashes are identified. The performance characteristics of
      questionnaires and diaries to collect self-reported data on hot flash frequency.
      Improved and validated instruments for collecting data on intensity and
      interference with daily activities. The mechanism(s) of action of placebo, which
      may also help distinguish natural attrition of symptoms from placebo effect.
      Animal models to elucidate triggers and mechanisms of hot flashes and to screen
      potential treatments. Investigators interested in studying hot flashes face
      complex issues. The incomplete understanding of the basic physiology underlying
      hot flashes clearly calls for further work in this area. Some mechanistic studies
      cannot be conducted with human subjects; thus, animal models are needed. Animal
      models could be particularly helpful for understanding the neurobiology of hot
      flashes and perhaps placebo effects. Bringing scientists together from different
      fields would appear to be a promising approach to moving this area forward.
      Scientific advances are being made increasingly at the interfaces of traditional
      disciplines, and approaches to science are becoming more integrative. Finding
      appropriate collaborators from other disciplines is not necessarily easy, and
      meeting a collaborator from another discipline is only the first step in building
      a multidisciplinary research team. Effective teams begin with compelling reasons
      for their existence, but further incentives must be developed to ensure full
      realization of their potential. The success of team science depends on
      individuals who are comfortable with boundary-crossing activities. Working as
      part of a team that is seeking solutions to complex problems requires a
      willingness to work in an interdisciplinary environment, to collaborate with
      different types of organizations, and to recognize the importance of a variety of
      roles in the project. It is likely that a multidisciplinary approach to hot flash
      research would be helpful given the number of physiologic, clinical, and
      behavioral factors involved. For example, psychologists and sociologists could
      contribute to identifying factors that may influence the placebo effect, such as
      pill color; developing and validating questionnaire items and diary formats;
      ascertaining the effect of mode of data collection on the quality of the
      resulting data; and determining the best ways to provide information to subjects.
      However, if they were part of a multidisciplinary team that included basic
      scientists, clinicians, and bioengineers, different questions might be asked, and
      better tools might be developed to collect both subjective and objective data on
      hot flashes. The increasing emphasis on collaborative science is also embraced at
      the NIH level. Since May 2002, the NIH has been engaged in a series of activities
      collectively known as the "NIH Roadmap," whose goal, in keeping with the NIH
      mission of uncovering new knowledge about the prevention, detection, diagnosis,
      and treatment of disease and disability, is to accelerate both the pace of
      discovery in these key areas and the translation of therapies from bench to
      bedside. The timing of this workshop to assess measures of hot flashes appears
      auspicious for several reasons. First, the issue of refining and validating self
      reported measures of symptoms through the use of biomarkers and multidisciplinary
      research teams is consonant with an NIH Roadmap initiative. Second, the new
      National Institute for Biomedical Imaging and Bioengineering at the NIH offers
      impetus for linking biomedical, social, and behavioral scientists with
      bioengineers to assess and improve existing technology or develop new
      technologies to collect data on physiological markers specific to hot flashes.
      Third, people are already purchasing and using CAM modalities or are resuming
      hormone therapy for relief of hot flashes, and they and their clinicians are
      eager for and deserve more information on the safety and efficacy of these
      remedies.

PMID- 15182094
TI  - Erectile dysfunction and cardiovascular disease.
AB  - Cardiovascular disease and erectile dysfunction (ED) are closely interrelated
      disease processes. Erectile dysfunction reportedly affects 10 million to 20
      million men in the United States and more than 100 million men worldwide. Each
      year, about 500,000 persons in the United States survive a myocardial infarction,
      and an estimated 11 million have existing cardiovascular disease, making the
      issue of sexual function and cardiac disease relevant to many patients. We
      explore the relationship between ED and the presence of cardiovascular disease in
      the general population. We also review the prevalence and pathophysiological
      associations of ED and cardiovascular disease. The risks of sexual activity for
      patients with cardiovascular disease are discussed, as are prevention and
      treatment strategies for ED in this patient population.

PMID- 15182095
TI  - Manipulation of central nervous system plasticity: a new dimension in the care of
      neurologically impaired patients.
AB  - Research in the neurosciences in recent decades has shown that the central
      nervous system is not a structurally static organ as was believed previously, but
      instead is a dynamic system that constantly undergoes structural and functional
      reorganization. The term brain plasticity refers to the constant cellular and
      intercellular modifications that occur during normal development and after
      neurologic injury and result in changes in neurologic function. The discovery
      that central nervous system plasticity after injury can be directed toward
      functional improvement with use of specific modalities has opened up a new
      dimension in the care of the neurologically impaired patient, termed restorative
      neurology.

PMID- 15182096
TI  - The morality of unenabled embryo use--arguments that work and arguments that
      don't.

PMID- 15182097
TI  - Schistocytes on the peripheral blood smear.

PMID- 15182098
TI  - Advances in screening, diagnosis, and treatment of breast cancer.
AB  - Breast cancer is the most common cancer in women in the United States; this year,
      approximately 215,900 new cases will be diagnosed. Mammography remains the
      cornerstone of screening, with technologies such as ultrasonography and magnetic
      resonance imaging having an increasingly defined role. Improved risk assessment
      and prevention strategies have been implemented, and current research in these
      areas includes better identification of patients at risk, the use of aromatase
      inhibitors and other agents to reduce risk, and the use of surrogate markers.
      Breast cancer staging has been optimized recently; also, local management of
      breast cancer, adjuvant systemic therapies, and treatment of patients with
      advanced disease have been evolving. Advances in screening, diagnosis, and
      treatment of breast cancer continue to influence our approach to patients with
      this disease. Many improvements have been made as well in supportive care,
      including increased tolerability of therapy and notable amelioration of disease
      symptoms.

PMID- 15182099
TI  - 44-year-old man with fatigue and anemia.

PMID- 15182101
TI  - Recombinant activated factor VII for treatment of enoxaparin-induced bleeding.

PMID- 15182100
TI  - Left ventricular rupture associated with Takotsubo cardiomyopathy.
AB  - A 70-year-old woman was admitted to the hospital with chest discomfort after
      quarreling with her neighbors. Electrocardiography revealed ST-segment elevation
      in leads I, II, III, aVL, aVF, and V2 through V6. Coronary angiography
      demonstrated normal arteries, but left ventriculography showed apical akinesis
      and basal hyperkinesis. Takotsubo cardiomyopathy was diagnosed on the basis of
      these characteristic findings. The creatine kinase and creatine kinase-MB
      concentrations were elevated at admission and reached maximum levels 6 hours
      after admission. The plasma level of brain natriuretic peptide was 10.7 pg/mL
      (reference range, <18.4 pg/mL) on the first hospital day. ST-segment elevation in
      leads I, II, III, aVL, aVF, and V2 through V6 persisted at 72 hours after
      admission. On the third hospital day, sudden rupture of the left ventricle
      occurred, and despite extensive resuscitation efforts, the patient died.
      Takotsubo cardiomyopathy presents in a manner similar to that of acute myocardial
      infarction, but ventricular systolic function usually returns to normal within a
      few weeks. To our knowledge, this is the first reported case of fatal left
      ventricular rupture associated with takotsubo cardiomyopathy. We suggest that
      takotsubo cardiomyopathy may be a newly recognized cause of sudden cardiac death.

PMID- 15182102
TI  - From parallel to perpendicular: getting "straightened out" with levodopa therapy.

PMID- 15182103
TI  - Trimethobenzamide in elderly patients.

PMID- 15182104
TI  - Trimethoprim-sulfamethoxazole--induced methemoglobinemia in an HIV-infected
      patient.

PMID- 15182105
TI  - Iron overload and hepatic fibrosis.

PMID- 15182106
TI  - Incidence of bronchiolitis-associated hospitalization among children in Olmsted
      County, Minnesota.

PMID- 15182107
TI  - Hypertension control--an old song resung.

PMID- 15182108
TI  - The study of hypertension in China.

PMID- 15182109
TI  - ALLHAT: a critical assessment.
AB  - The ALLHAT study has attracted considerable attention in the media and in the
      research community, partly due to the study's unexpected and controversial
      conclusions. However, the study has several serious shortcomings. The primary end
      points in ALLHAT were negative and the conclusions are based entirely on
      secondary end-points and subgroup analyses. Moreover, there is good reason for
      skepticism concerning the findings on heart failure in ALLHAT, because of
      ambiguity in the diagnosis, lack of information on blood pressure and absence of
      a "washout" period. The study design was severely flawed and does not reflect
      clinical reality. Also, blood pressure differences between groups severely
      complicate interpretation. From a patient perspective in ALLHAT, there are drug
      safety concerns with the thiazides, as there was evidence of excess diabetes
      development. The ALLHAT results are difficult to generalize and have limited
      relevance in European settings. Thus, the ALLHAT study suffers from several major
      shortcomings and there is a huge body of evidence that contradicts the ALLHAT
      interpretations.

PMID- 15182110
TI  - HYDRA: possible determinants of unsatisfactory hypertension control in German
      primary care patients.
AB  - The Hypertension and Diabetes Screening and Awareness (HYDRA) study is a cross
      sectional point-prevalence study performed in September 2001; 45,125 primary care
      attendees were recruited from a representative nationwide sample of 1912 primary
      care practices in Germany. Around 42% of all patients presenting in these
      practices had hypertension (WHO definition). In approximately 70% of these
      patients, hypertension was diagnosed by doctors and 84% of diagnosed patients
      were on antihypertensive medication, but in less than 30% of treated patients was
      blood pressure controlled (< 140/90 mmHg). The control rate in all patients
      presenting with hypertension (including those patients unrecognized) was as low
      as 19%. The present analysis aimed to find explanations for this unsatisfactory
      outcome of hypertension control. The main finding was that the rate of diagnosis
      of hypertension is alarmingly low in young people, probably due to insufficient
      blood pressure screenings. The data further indicated that doctors still set
      their target of treatment according to outdated guidelines and that doctors still
      orientate their treatment primarily with regard to the diastolic pressure. These
      insights into the causes of unsatisfactory hypertension control may help to
      direct future educational programmes designed to improve hypertension management
      specifically to these deficits and thereby to improve control rates.

PMID- 15182111
TI  - High screening blood pressure is related to sympathetic nervous system activity
      and insulin resistance in healthy young men.
AB  - The cardiovascular metabolic syndrome is characterized by the presence of several
      cardiovascular risk factors, including blood pressure (BP) elevation. We aimed to
      study the relation between mental stress, plasma catecholamines, BP and BP
      responses to mental stress in healthy young Caucasian men selected from different
      levels of screening BP. We included 98 men with high and 22 men with normal
      screening BP. They were examined at baseline in the laboratory, during a
      hyperinsulinemic, isoglycemic glucose clamp and during mental stress. At baseline
      in the laboratory, the men with high screening BP were characterized by elevated
      BP (p < 0.005) and plasma catecholamines (p < 0.05), but unaltered serum lipid
      levels compared to men with normal screening BP. After 2 h rest the differences
      almost disappeared, but could be reproduced during a mental arithmetic stress
      test. The men with elevated screening BP had significantly higher fasting glucose
      (p = 0.01) and lower insulin sensitivity (p < 0.005). In a multiple regression
      model, norepinephrine during mental stress (R2 = 0.10, p < 0.05) was the main
      variable to retrospectively explain allocation to the normal or high screening BP
      group. In conclusion, young healthy men with elevated screening BP are
      characterized by increased sympathetic activity and insulin resistance.
      Norepinephrine during mental stress is the main variable to explain allocation to
      the normal or elevated screening BP group. We have shown that one single
      screening BP measurement predicts insulin resistance and elevated fasting glucose
      in this cohort.

PMID- 15182112
TI  - Autonomic nervous system and microvascular alterations in normotensives with a
      family history of hypertension.
AB  - Autonomic nervous system and microvascular alterations at pre-hypertensive stage
      of hypertension have still not been fully elucidated. We aimed at addressing
      central and local influences on microvascular reactivity at pre-hypertensive
      stage of hypertension. To that end, we studied microvascular reactivity in 59
      normotensives with a family history of hypertension and 46 controls. We measured
      laser-Doppler flow on the finger nailfold skin in the resting condition, after an
      8-min occlusion of digital arteries and during local nitroglycerin application.
      Finger pressure, pulse and ECG were monitored by a Finapres device. Heart rate
      power spectral analysis was performed using Fast Fourier transformation.
      Baroreflex sensitivity was estimated by the sequence method. Normotensives with a
      family history of hypertension showed higher systolic pressure, decreased high
      frequency power of the heart rate variability spectrum and reduced baroreflex
      sensitivity in the resting condition as well as decreased fundamental frequency
      of laser-Doppler flow oscillations during nitroglycerin application. We conclude
      that normotensives with a family history of hypertension exhibit altered
      sympathovagal balance with decreased parasympathetic activity at the cardiac
      level as well as increased myogenic microvascular reactivity.

PMID- 15182113
TI  - Prevalence and determinants of left ventricular hypertrophy and remodelling
      patterns in hypertensive patients: the St. Petersburg study.
AB  - OBJECTIVE: The primary aim of the present study was to determine the prevalence
      of left ventricular hypertrophy (LVH) in hypertensive patients with the use of
      different threshold values and also to assess the distribution of left
      ventricular (LV) geometry patterns verified by two different methods of relative
      wall thickness (RWT) calculation. The secondary aim was to evaluate the impact of
      different demographic determinants into prevalence of LVH and remodelling
      patterns. PATIENTS AND METHODS: A cross-sectional study in a population-based
      sample of 734 essential hypertensives from the primary care clinic was
      undertaken. Echocardiography was performed and analysed by trained observers. The
      LV posterior wall thickness (PWd), interventricular septum (IVSd) and LV mass
      index (LVMI) were measured. The following criteria for LVH definition were used:
      LVMI >125 g/m2 and 134/110 g/m2, and >131/110 and 116/104 g/m2 in males/females,
      respectively. The RWT was calculated as a 2PWd/LVDD or PWd + IVSd/LVDD, where
      LVDD is the LV internal dimension at the end of diastole. The values exceeding
      0.45 were considered evidence for concentric remodelling. RESULTS: Prevalence of
      LVH ranged from 52.2 to 72.2% by the use of different threshold for LVH
      definition. It was shown that the LVH estimation without sex-specific criteria
      underestimates the prevalence of LVH in women and overestimates it in men. The
      prevalence of concentric LVH and concentric remodelling was higher when the IVSd
      was included in the RWT calculation. Only one-quarter of patients were free from
      morphological alterations and eccentric LVH was as frequently observed as
      concentric LVH. Sex, obesity stage and type as well as hypertension level and
      duration contributed to LVH level and remodelling pattern. CONCLUSIONS: The use
      of different threshold values can significantly influence the assessment of
      prevalence of LVH in hypertension. The "mild" criteria, to our opinion, can
      overestimate the prevalence of structural LV remodelling, while implementation of
      sex-specific criteria for the definition of LVH increases the sensitivity of the
      method. In any way, eccentric LVH is as common for hypertension as a concentric
      LVH, the proportion of the latter increasing with age and more frequently
      observed in males. Concomitant obesity, in particular abdominal, significantly
      increases LVH prevalence.

PMID- 15182115
TI  - Clinical value of ambulatory blood pressure monitoring.

PMID- 15182114
TI  - Increase in systemic blood pressure during intra-arterial PD123319 infusion:
      evidence for functional expression of angiotensin type 2 receptors in normal
      volunteers.
AB  - The functional existence of angiotensin type 2 (AT2) receptors in healthy humans
      is uncertain. A double-blind, randomized, crossover study was performed comparing
      forearm vascular responses to intrabrachial arterial PD123319 (a selective AT2
      receptor antagonist, 10 microg/min) in healthy young, non-smoking volunteers
      following 1 week of telmisartan therapy (40-80 mg once daily) and 1 week of
      placebo therapy. No significant difference was found in baseline mean arterial
      pressure between telmisartan and placebo treatment. Baseline forearm blood flow
      (FBF) was significantly higher during telmisartan (2.69 +/- 1.28 ml/s) therapy
      than during placebo (1.86 +/- 0.75 ml/s). PD123319 did not alter FBF on either
      telmisartan or placebo therapy. However, significant increases in mean arterial
      pressure were observed during intra-brachial arterial infusions of PD123319
      (p=0.003) during both placebo (80 +/- 9 to 92 +/- 17 mmHg) and telmisartan (80 +/
      11 to 90 +/- 14 mmHg) therapy suggesting the presence of functional AT2
      receptors, possibly in locations other than the forearm resistance vessels. Intra
      brachial arterial infusion of PD123319 (10 microg/min) has significant systemic
      effects, which appear more prominent than local changes in FBF and which are not
      influenced by angiotensin type 1 receptor blockade.

PMID- 15182116
TI  - Harlequin ichthyosis: a case study.
AB  - The most severe manifestation of congenital ichthyosis presents itself in the
      form known as harlequin ichthyosis. Harlequin ichthyosis is characterized by a
      profound thickening of the fetal skin. Affected infants are born with a thick
      "horny shell" of dense, waxy, platelike scales with deep, irregular fissures
      covering the body. Contraction of the extremities is seen, along with deformities
      of the ears, eyes, mouth, and digits. This "armor" limits movement and
      compromises the skin's barrier defense, leaving the newborn at risk for metabolic
      abnormalities and infection. A case study of our unit's experience is provided.

PMID- 15182117
TI  - Perinatal corticosteroids: a review of the research. Part II: Postnatal
      administration.
AB  - Postnatal corticosteroids are often administered during the neonatal intensive
      care unit stay to reduce the risk and severity of chronic lung disease (CLD) in
      preterm infants. In 2002, the American Academy of Pediatrics Committee on Fetus
      and Newborn and the Canadian Paediatric Society Fetus and Newborn Committee
      jointly advised against the routine use of systemic dexatmethasone for the
      prevention of CLD in very low birth weight infants. The objective of this review
      is to present evidence-based research and expert opinion to provide the neonatal
      clinician with current information regarding dexamethasone use with premature
      infants. This article serves to inform neonatal clinicians about the benefits and
      potential adverse neurosensory risks of this treatment option.

PMID- 15182118
TI  - End-tidal CO2 verification of endotracheal tube placement in neonates.
AB  - Endotracheal tubes are misplaced more often than one may think, and the
      consequences of not quickly detecting and correcting the error can be
      catastrophic. In the pediatric and adult populations, end-tidal CO2 verification
      of endotracheal tube placement is considered to be the standard of care. An
      understanding and use of the technology available are essential for all health
      care professionals to allow them to provide optimum care for their patients.

PMID- 15182120
TI  - Threat of violence from families.

PMID- 15182119
TI  - Randomized controlled trial of kangaroo care: cardiorespiratory and thermal
      effects on healthy preterm infants.
AB  - PURPOSE: To determine the safety and effects on healthy preterm infants of three
      continuous hours of kangaroo care (KC) compared to standard NICU care by
      measuring cardiorespiratory and thermal responses. DESIGN: Randomized controlled
      trial-pretest-test-posttest control group design. SAMPLE: Twenty-four healthy
      preterm infants (33-35 weeks gestation at birth) nearing discharge. Eleven of the
      infants received KC; 13 received standard NICU care. MAIN OUTCOME VARIABLES:
      Heart rate, respiratory rate, oxygen saturation, and abdominal skin temperature
      were manually recorded every minute. Apnea, bradycardia, periodic breathing, and
      regular breathing were captured continuously on a pneumocardiogram printout.
      Three consecutive interfeeding intervals (three hours each) on one day
      constituted the pretest, test, and posttest periods. RESULTS: Mean
      cardiorespiratory and temperature outcomes remained within clinically acceptable
      ranges during KC. Apnea, bradycardia, and periodic breathing were absent during
      KC. Regular breathing increased for infants receiving KC compared to infants
      receiving standard NICU care.

PMID- 15182121
TI  - Neonatal thrombosis.

PMID- 15182122
TI  - Reliability and validity: Part II.
AB  - Determining measurement reliability and validity involves complex processes.
      There is usually room for argument about most instruments. It is important that
      the researcher clearly describes the processes upon which she made the decision
      to use a particular instrument, and presents the evidence available showing that
      the instrument is reliable and valid for the current purposes. In some cases, the
      researcher may need to conduct pilot studies to obtain evidence upon which to
      decide whether the instrument is valid for a new population or a different
      setting. In all cases, the researcher must present a clear and complete
      explanation for the choices, she has made regarding reliability and validity. The
      consumer must then judge the degree to which the researcher has provided adequate
      and theoretically sound rationale. Although I have tried to touch on most of the
      important concepts related to measurement reliability and validity, it is beyond
      the scope of this column to be exhaustive. There are textbooks devoted entirely
      to specific measurement issues if readers require more in-depth knowledge.

PMID- 15182123
TI  - Why are we trimming peripherally inserted central venous catheters?

PMID- 15182125
TI  - Early detection of prostate cancer in the ESRD population.
AB  - BACKGROUND: There are currently no prostate cancer screening guidelines specific
      to the end-stage renal disease (ESRD) population. With this in mind, we evaluated
      the clinical usefulness of digital rectal examination (DRE), serum total prostate
      specific antigen (PSA), prostate-specific antigen density (PSAD) and transrectal
      ultrasound (TRUS) in predicting prostate cancer in men with ESRD. METHODS: Fifty
      male ESRD patients age 40 years and older with no prior history of prostate
      cancer were enrolled in the study. All patients underwent PSA measurement and a
      DRE followed by a TRUS. PSAD was calculated as the total PSA divided by the
      prostate volume. Ultrasound-guided prostate biopsies were performed on any
      patient with 1 or more of the following abnormal findings: a nodule detected on
      DRE; an abnormal TRUS; PSA > 4.0 ng/ml, or a PSAD > 0.15 ng/ml/cm3. RESULTS:
      Abnormal findings were detected in 19 patients. Two (4%) had an abnormal DRE, 3
      (6%) had PSA > 4.0 ng/ml, 3 (6%) had PSAD > 0.15 ng/ml/cm3 and 16 (32%) had
      abnormal findings on TRUS. Three patients had 2 abnormal findings and 1 had 3. Of
      the 15 prostate biopsies performed, 4 (27%) revealed prostate cancer and 3 (20%)
      high-grade prostatic intraepithelial neoplasm (HGPIN) comprising 8% and 6%,
      respectively, of the studied population. Of the 4 patients diagnosed with
      prostate cancer, none had abnormal DRE, 2 (50%) had PSA > 4.0 ng/ml (sensitivity
      = 66.7% and PPV = 50% (p = 0.236)), 3 (75%) had PSAD > 0.15 ng/ml/cm3
      (sensitivity = 100% and PPV = 75% (p < 0.018)), and 3 (75%) had abnormal findings
      on TRUS (sensitivity = 30% and PPV = 75% (p = 1.000)). CONCLUSION: Routine
      screening with PSA and DRE does not seem sensitive enough to predict the presence
      of the disease. Although TRUS detected abnormalities in 16 patients (32%),
      sensitivity was very low (30%). In our patients, PSAD increased the sensitivity
      and positive predictive value (PPV) of detecting prostate cancers compared to PSA
      alone.

PMID- 15182124
TI  - Undertreatment of hyperlipidemia in a cohort of United States kidney dialysis
      patients.
AB  - BACKGROUND: Application of national guidelines regarding cardiovascular disease
      risk reduction to kidney dialysis patients is complicated by the conflicting
      observations that dialysis patients have a high risk of atherosclerotic
      cardiovascular disease (ASCVD), but dialysis patients with higher serum
      cholesterol have lower mortality rates. Actual treatment patterns of
      hyperlipidemia are not well studied. METHODS: We assessed the prevalence,
      treatment and control of hyperlipidemia in this high-risk patient population from
      1995 - 1998. We measured low-density lipoprotein cholesterol, treatment with a
      lipid-lowering agent, and prevalence of hyperlipidemia as defined by the National
      Cholesterol Education Program (NCEP), Adult Treatment Panel (ATP) II guidelines
      in 812 incident hemodialysis (HD), and peritoneal dialysis (PD) patients from
      dialysis clinics in 19 states throughout the United States. RESULTS:
      Hyperlipidemia was present in 40% of HD and 62% of PD patients. Among subjects
      with hyperlipidemia, 67% of HD and 63% of PD patients were untreated and only 22%
      of HD and 14% of PD patients were treated and controlled. Those who entered the
      study in 1997 or 1998, those with diabetes, males and Caucasians were more likely
      to be treated and controlled, whereas subjects on PD and those with ASCVD were
      less likely to be treated and controlled. CONCLUSION: These data suggest that
      high rates of undertreatment exist in the United States ESRD dialysis population.
      Whether improved rates of treatment will result in decreased cardiovascular
      disease events needs to be tested in randomized clinical trials.

PMID- 15182126
TI  - Effect of propranolol on heart rate variability in patients with end-stage renal
      disease: a double-blind, placebo-controlled, randomized crossover pilot trial.
AB  - BACKGROUND: Low heart rate variability (HRV) is an independent risk factor of
      cardiac mortality in patients with end-stage renal disease (ESRD). It has been
      explained by uremic parasympathetic neuropathy. Sympathetic overactivity can also
      reduce HRV. Our aim was to determine whether there is vagal activity in ESRD
      patients that is masked by sympathetic activity. METHODS: The effect of
      propranolol on HRV was examined in 13 patients with ESRD, aged 20.1 +/- 7.6 years
      without diabetes. All patients were given intravenous propranolol (0.05 mg/kg)
      once and placebo once in a randomized, double-blind way, with an interval of 6.6
      days (mean, range: 2-9). Propranolol was administered before hemodialysis
      treatment, after 40 minutes supine resting period. HRV was registered for 10
      minutes, during supine, before and after the injection. Patients' HRV data were
      compared to that of 29 age-matched healthy controls. RESULTS: Initially, both
      high-(HFV) and low-frequency (LFV) bands of heart rate variability were lower in
      ESRD patients compared to controls (p < 0.001 for both). Propranolol resulted in
      a significant increase of HFV (propranolol: AlgHFV = 0.182 (0.027 - 0.337),
      placebo: deltalgHFV = -0.029 (-0.128 - +0.070); p = 0.032). Elevation of LFV was
      not significant. Six patients had an elevated plasma norepinephrine and/or
      epinephrine level. Plasma dopamine level was elevated in all but 1 patient (mean:
      432 pmol/l, 95% CI: 320-543) and showed an inverse relationship with the increase
      of IgHFV secondary to propranolol (r = -0.66, p = 0.014). CONCLUSIONS: Low HFV of
      ESRD patients can be improved by beta-adrenergic blockade. It demonstrates that
      there is some vagal activity in ESRD that is masked by sympathetic activity.
      Therefore, altered sympathovagal balance of ESRD patients should be taken into
      consideration in the assessment of vagal uremic neuropathy.

PMID- 15182127
TI  - Effect of advanced glycation end products on endotoxin-induced TNF-alpha, IL
      1beta and IL-8 in human peripheral blood mononuclear cells.
AB  - BACKGROUND/AIMS: Advanced glycated end products (AGE) are endogenous proteins
      that have formed covalent complexes with sugars by a nonenzymatic process. Being
      proinflammatory molecules, AGE are thought to contribute to chronic systemic and
      local inflammatory processes associated with pathological changes in various
      diseases. In patients with end-stage renal disease, AGE are believed to play a
      role in the progression of atherosclerosis and worsening of renal failure. In
      patients receiving hemodialysis, AGE are thought to contribute to the
      inflammatory components of the therapy, particularly in diabetic patients.
      METHODS: In the present study, AGE were produced using 5% human serum albumin
      (HSA) and 50% glucose, both used for intravenous infusion into humans and both
      released after strict control for endotoxin content. The presence of AGE formed
      by HSA and glucose was confirmed using 2 independent assays. The inflammatory
      properties of these AGE were assessed using synthesis and release of the
      proinflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF) and
      IL-8, a chemokine. RESULTS: Alone, AGE did not induce these cytokines from
      peripheral blood mononuclear cells (PBMC) obtained from 14 healthy human donors.
      However, in the presence of 1 or 10 ng/ml of endotoxin, AGE augmented the
      production of IL-1 and TNF above that induced by endotoxin alone. Although the
      amount of augmentation of LPS-induced cytokines by AGE varied between the blood
      donors, the response was consistently observed and reached statistical
      significance. The augmentation of cytokine production was confirmed using AGE
      prepared with different lots of HSA and glucose. CONCLUSION: These results
      demonstrate that in the strict absence ofendotoxins, AGE are formed that do not
      stimulate cytokine production from PBMC of healthy donors, however, AGE
      significantly augment the synthesis and release of proinflammatory cytokine in
      the presence of low concentrations of endotoxins. The data suggest that renal
      replacement therapies should consider the role of microbial products in
      potentiating the biological consequences of naturally formed AGE and their
      potential to contribute to systemic and local inflammation in renal replacement
      therapies. Therefore, although the formation of AGE is unavoidable, excluding
      microbial products during renal replacement therapy should reduce the
      pathological consequences of AGE.

PMID- 15182128
TI  - Variable parathyroid hormone(1-84)/carboxylterminal PTH ratios detected by 4
      novel parathyroid hormone assays.
AB  - AIM: Parathyroidhormone (PTH) measurement is important in the evaluation of bone
      disease in patients with chronic renal failure. Large carboxyl-terminal PTH
      fragments (C-PTH) cross-react with second-generation PTH assays, lead to an
      overestimation of biologically active PTH, and are evaluated by a combination of
      second- and third-generation PTH assays. The aim of our study was to examine
      whether the use of 4 different PTH assays of putatively same specificity leads to
      comparable results detecting C-PTH fragments. SUBJECTS AND METHODS: In 70 chronic
      dialysis patients, total PTH and PTH(1-84) were measured in parallel by 4 novel
      PTH assays (Nichols Advantage Intact PTH and Bio-Intact PTH Chemiluminescence
      Assay, Nichols Institute Diagnostics, USA, DUO Total and CAP PTH IRMA,
      Scantibodies Laboratory, USA). The C-PTH concentration was quantitated by
      subtracting PTH(1-84) from total PTH. Consecutively, the PTH(1-84)/C-PTH ratio
      was calculated. RESULTS: Nichols Intact PTH and DUO Total PTH assays were highly
      correlated (r = 0.985), as well as Nichols Bio-Intact and DUO CAP assays (r =
      0.984). However, total PTH values measured by the Nichols assay were 30% higher
      (median (range): 185 (9.9 - 2,332) versus 130 (2.3 - 1,271.1) pg/ml, p < 0.01).
      PTH(1-84) values, measured by the Nichols Bio-Intact PTH assay were 8% higher
      compared to the Scantibodies CAP assay (median (range): 79.6 (7.5 - 1,060.9)
      versus 73.7 (4.4 - 918.9) pg/ml, p = NS). Thirty-six patients had a ratio < 1
      measured by the Nichols assays, whereas only 8 patients showed the same ratio
      when measured by the Scantibodies assays. In 28 patients (40%), contradictory
      PTH(1-84)/C-PTH ratios were found, showing a ratio < 1 when measured by the
      Nichols assays, but > 1 when the Scantibodies assays were used. CONCLUSION: In
      conclusion, our results suggest that the PTH(1-84)/C-PTH ratio cannot be equally
      used as a predictor of bone turnover when different PTH assays are used.
      Depending on those assays, differences in total PTH values mathematically lead to
      varying amounts of C-PTH fragments resulting in variable, even contradictory
      PTH(1-84)/C-PTH ratios.

PMID- 15182129
TI  - Vascular abnormalities in patients with autosomal dominant polycystic kidney
      disease--the influence on arteriovenous fistula creation.
AB  - AIM: Patients with autosomal dominant polycystic kidney (ADPKD) present a number
      of vascular abnormalities, including cerebral aneurysms, heart valve lesions,
      coarctations of aorta and abdominal aortic aneurysms. The aim of our study was to
      investigate whether vascular abnormalities that occur in wrist vessels, make
      native arteriovenous fistula creation difficult in this group of patients.
      PATIENTS AND METHODS: The problem was analyzed retrospectively in 783 patients
      with chronic kidney failure who had had arteriovenous fistula created in our
      centre in the period between 1991 and 2001. ADPKD was the cause of terminal renal
      failure in 57 patients (7.3%). These were 31 men and 26 women aged 28 - 69 years
      (52 +/- 16 years on average). RESULTS: A difference between left and right radial
      artery diameters and a narrow radial artery (below 2 mm), unsuitable for fistula
      creation, occurred in 12% of patients with ADPKD and in 0.38% of other patients.
      Instead of a cephalic vein in the typical place, a few small vessels were present
      in 14% of patients with ADPKD and in 2.17% of patients with other causes of renal
      failure. CONCLUSION: Our experience shows a higher incidence of wrist vascular
      abnormalities in patients with ADPKD. This decreases the possibility of wrist
      native arteriovenous fistula creation in this group of patients.

PMID- 15182130
TI  - Lower erythropoietin and iron supplementation are required in hemodialysis
      patients with hepatitis C virus infection.
AB  - BACKGROUND: Chronic hepatitis C virus (HCV) infection is a common infectious
      agent in chronic hemodialysis (HD) patients. In this prospective case-control
      study, we aimed to investigate the influence of chronic HCV infection on
      erythropoietin (EPO) and iron requirement in HD patients. PATIENTS AND METHODS:
      49 HD patients (24 male, 25 female, mean age 47 +/- 15 years) were included. The
      mean time spent on dialysis was 39 +/- 38 months, and follow-up time was 1 year
      for this study. Biochemical analyses and complete blood counts together with iron
      status of the patients (transferrin saturation and serum ferritin levels) were
      measured monthly. Highly sensitive C-reactive protein (hs-CRP) levels were
      measured within 3-month intervals. Endogenous EPO levels were measured by enzyme
      linked immunoassay 2 weeks after cessation of EPO treatment. RESULTS: Eleven of
      the HD patients (22%) were anti-HCV(+). There was no difference in age, sex, time
      on dialysis, distribution of primary renal diseases, predialytic BUN, Kt/V,
      albumin and i-PTH levels between HCV(+) and (-) patients. Anti-HCV-positive
      patients required significantly lower weekly doses of EPO (87 +/- 25 IU/kg vs 129
      +/- 11 IU/kg, p = 0.042) and iron (16.8 +/- 12.2 mg vs 32.6 +/- 16.1 mg, p =
      0.02) replacement than anti-HCV(-) group; hs-CRP levels were similar between
      study groups. Serum endogenous EPO levels were significantly higher in HCV(+)
      patients than HCV(-) HD patients (9.43 +/- 6.47 mU/ml vs 3.59 +/- 2.08 mU/ml, p =
      0.008). CONCLUSION: Anti-HCV(+) HD patients had higher serum EPO levels and
      required less EPO and iron replacement as compared to anti-HCV(-) patients.
      Because of the changes in iron metabolism, iron treatment should be carefully
      administered in HD patients with HCV.

PMID- 15182132
TI  - Renal transplantation in a C-ANCA(+) patient with Behcet disease and rapidly
      progressive glomerulonephritis.
AB  - Behcet's disease (BD) is a chronic, relapsing, inflammatory disorder, and the
      underlying histophatological lesion is vasculitis of unknown cause. Some case
      reports of BD with positive C-ANCA titers have been reported, but only 2 case
      reports have documented the association of ANCA-associated glomerulonephritis
      (GN) and BD, and no renal transplantation cases have been described. We report
      such a case. A 27-year-old male was referred for consultation due to acute renal
      failure. Seven years before, BD was diagnosed. At the time of consultation he
      suffered from uveitis and generalized arthralgias. The serum creatinine was 14
      mg/dl and urinalysis showed 4+ protein and microscopic hematuria. Results of
      serological tests were normal. The ANCA PR 3 titer was 1:100 of cytoplasmic
      pattern. A renal biopsy showed a rapidly progressive type III glomerulonephritis.
      In spite of immunosuppressive therapy with cyclophosphamide and high steroid
      doses, renal function did not recover and hemodialysis therapy was initiated. One
      year later, the patient underwent a renal transplantation. Follow-up was
      absolutely normal, and 5 years after transplantation, renal function persisted to
      be normal, without urinary abnormalities and signs of reactivation of original
      disease, except for occasional arthralgias. C-ANCA titer was decreased and
      remained stable (<1:30). He is now receiving maintenance immunosupression with
      cyclosporin and prednisone. This report shows the long-term successful renal
      transplantation in a patient with ANCA-associated glomerulonephritis and BD. The
      success of renal transplant in BD with renal involvement is encouraging and
      should be pursued.

PMID- 15182131
TI  - Remission of nephrotic syndrome after thalidomide therapy in a patient with
      Castleman's disease.
AB  - Castleman's is an uncommon lymphoproliferative disorder secondary to lymphoid
      follicle hyperplasia and marked capillary proliferation with endothelial
      hyperplasia. This illness can be associated with glomerulonephritis (GN). Here,
      we report a case with steroid-dependent nephrotic syndrome secondary to
      proliferative mesangial glomerulonephritis in a patient with Castleman's disease,
      that was diagnosed several years before. Considering the involvement of IL-6 in
      Castleman's disease we treated the patient with thalidomide obtaining the
      remission of the nephrotic syndrome. Our experience suggests a possible role of
      thalidomide in the treatment of glomerular pathology when a role of IL-6 is
      hypothesized.

PMID- 15182133
TI  - Maxillary brown tumor and uremic leontiasis ossea in a patient with chronic renal
      insufficiency.
AB  - Findings of renal osteodystrophy in cranial bones are not uncommon and include
      osteomalacia, osteosclerosis, erosion of the cortical bone, brown tumors and
      resorption of the lamina dura. However, massive thickening of the cranial vault
      and facial bones, called uremic leontiasis ossea, have been reported very rare.
      In the present article, we describe the case of an uncooperative female patient
      with a brown tumor, involving the left maxillary sinus and massive thickening of
      the cranial vault and facial bones, secondary to severe secondary
      hyperparathyroidism during 8 years of regular hemodialysis treatment.

PMID- 15182134
TI  - Acute non-cardiogenic pulmonary edema in a 2003 French Puumala virus case:
      cautions and corrections.

PMID- 15182135
TI  - Change in the circadian rhythm of blood pressure in pseudo-hypoaldosteronism type
      2 in response to thiazide diuretics.

PMID- 15182136
TI  - Assessing culture, context, power differences, and psychological development when
      delivering health care to foreign-born adolescents.

PMID- 15182137
TI  - Finding gold in the muddy waters of public health reports.

PMID- 15182138
TI  - Bronchiectasis: not an orphan disease in the East.
AB  - Bronchiectasis is a common disease in the developing world. While the aetiology
      of bronchiectasis is diverse, many patients suffer from idiopathic disease.
      Although the pathogenesis of bronchiectasis is poorly understood, there are three
      distinct pathogenic elements, namely infection, inflammation and enzymatic
      actions. These interact to perpetuate airway destruction in many cases. There are
      four patient stereotypes: rapidly progressive, slowly progressive, indolent
      disease and haemoptysis-predominant. The diagnosis of bronchiectasis is best made
      with high resolution computed tomography, which should be followed by delineation
      of aetiology and evaluation of disease severity. Management of bronchiectasis is
      unsatisfactory and there are no disease-modifying drugs or treatment guidelines.
      Specific therapy to correct an underlying defect should be instituted whenever
      possible, although established disease often continues to deteriorate
      relentlessly. Treatment with prolonged, high-dose antibiotics is useful for
      exacerbations and probably also for some severely affected patients with frequent
      exacerbations who habour Pseudomonas aeruginosa in their airways. Commencement of
      long-term nebulised aminoglycoside, elective in-patient intravenous antibiotic
      therapy, long-term oral antibiotic or low-dose macrolide therapy requires special
      considerations. Inhaled corticosteroid therapy reduces chemokine expression in
      bronchiectasis in vivo, and may be useful for some patients. For severely
      affected patients, the use of non-invasive positive-pressure ventilation with
      supplementary oxygen sometimes helps. The lack of enthusiasm about bronchiectasis
      has already resulted in a lack of research in the treatment of this frustrating
      disease, and such research needs to be encouraged.

PMID- 15182139
TI  - Predicting completion of treatment among foreign-born adolescents treated for
      latent tuberculosis infection in Los Angeles.
AB  - SETTING: Two health clinics in Los Angeles County, California. OBJECTIVE: To
      identify factors associated with completion of care among foreign-born
      adolescents treated for latent tuberculosis infection (LTBI). DESIGN: A total of
      766 low-income adolescents (79% participation rate), including 610 foreign-born,
      were recruited. In prospective face-to-face interviews, data were obtained on
      socio-demographic and lifestyle characteristics, psychosocial factors and clinic
      related variables. Medical chart data were abstracted regarding clinic
      appointment keeping and completion of treatment. Univariate and multivariate
      logistic regression analyses were performed to identify factors associated with
      completion of care. RESULTS: Foreign-born adolescents were more likely to
      complete care than US-born adolescents, with 82% completion of care rate. In
      logistic regression analyses after controlling for age, medication taking
      behavior (OR 1.26, 95%CI 1.15-1.39), living with both parents (OR 1.74, 95%CI
      1.02-2.97), sexual intercourse (OR 0.66, 95%CI 0.36-1.19) and speaking mostly or
      only English with parents (OR 0.39, 95%CI 0.15-1.03) were independently
      associated with completion of care. CONCLUSION: These findings contribute to our
      understanding of the factors that may explain why some adolescents complete care
      whereas others do not. They provide supportive evidence that tailored
      intervention programs should be developed to support the screening and completion
      of treatment of foreign-born adolescents.

PMID- 15182140
TI  - Acceptance of screening and completion of treatment for latent tuberculosis
      infection among refugee claimants in Canada.
AB  - SETTING: Primary care clinic for refugee claimants, Montreal, Canada. OBJECTIVES:
      To identify factors linked to the acceptance of the tuberculin skin test (TST),
      and assess completion of treatment for latent tuberculosis infection (LTBI).
      DESIGN: Asylum seekers consulting for a medical complaint or medical immigration
      examination between February and October 1999 were assessed for eligibility.
      Personal and clinical information was gathered prospectively by questionnaire.
      Hospital files were reviewed to assess completion of LTBI treatment. RESULTS: In
      our study, 296 subjects (72.4% of 409 eligible) were offered TST, of whom 227
      accepted (76.7%). Of these, 49 (24.9%) had a TST > or = 10 mm and 24 (49%)
      completed 6 months of LTBI treatment. Logistic regression models showed that
      patients who had never had a TST (OR 3.2, 95%CI 1.34-7.6) or had no temporary
      exclusion criteria (OR 4.0, 95%CI 1.6-9.9) were more likely to accept TST.
      Perceiving tuberculosis as a severe disease (OR 0.29, 95%CI 0.09-0.91) and
      consulting for an immigration examination (OR 0.42, 95%CI 0.18-0.98) was
      associated with refusal of TST. Increasing age was found to be independently
      associated with a positive TST (OR 1.06, 95%CI 1.01-1.12). Variability in the
      proportion of positive results was found between TST readers. CONCLUSION: This
      study supports the feasibility of screening refugee claimants for LTBI during
      medical consultation and of developing organizational links to ensure completion
      of LTBI treatment.

PMID- 15182141
TI  - Risk of infection with Mycobacterium tuberculosis in Malawi: national tuberculin
      survey 1994.
AB  - OBJECTIVE: To estimate the annual risk of tuberculosis infection among
      schoolchildren in Malawi. METHODS: A school survey was conducted in twelve
      randomly selected districts in Malawi. Children in standard 1-4 and aged 6-11
      years were eligible. Tuberculin skin testing was performed according to World
      Health Organization/International Union Against Tuberculosis and Lung Disease
      guidelines. RESULTS: Of the 17123 eligible children, 80% were tested. Of those
      tested 79% were read. The prevalence of infection according to various criteria
      was 9-12% in children without bacille Calmette-Guerin (BCG) scar. The prevalence
      of reactions of 10 mm or more was lower in girls than in boys, increased with
      age, and was higher in those with than in those without BCG scar. The annual risk
      of infection was estimated to be within the range 0.6-1.4%. CONCLUSION: Annual
      risk of infection in Malawi was in the order of 1%. This study is expected to
      provide valuable baseline information for an assessment of the impact of human
      immunodeficiency virus (HIV) on tuberculosis transmission in Malawi.

PMID- 15182142
TI  - Prescriptions and dosages of anti-tuberculosis drugs in the National Tuberculosis
      Control Programme of Malawi.
AB  - SETTING: All 44 non-private hospitals in Malawi treating pulmonary tuberculosis
      (PTB) patients with an oral regimen (0.5RHZE/1.5R3H3Z3E3/6HE). OBJECTIVES: In new
      smear-positive PTB patients, to determine whether: 1) numbers of tablets were
      correctly prescribed according to pre-treatment weights, and 2) medication
      dosages were adequate, too low or too high. DESIGN: Retrospective review of TB
      registers and TB treatment cards for patients registered with new smear-positive
      PTB between 1 October and 31 December 2001. RESULTS: Of 1970 patients aged > or =
      15 years, 1211 (62%) had treatment cards and pre-treatment weights. Incorrect
      prescriptions were given to 88 (7%), and many of these received dosages of anti
      tuberculosis drugs that were too high or too low. For those receiving correct
      prescriptions, daily treatment in the initial and continuation phases was
      generally associated with adequate dosages of drugs. However, in the initial
      intermittent phase, between 3% and 40% of patients received anti-tuberculosis
      drug dosages that were too low. CONCLUSION: A small percentage of patients
      receive incorrect prescriptions, which can be resolved by training and
      supervision. In those receiving correct prescriptions, intermittent treatment
      provides dosages that are sometimes too low. Weight bands for intermittent
      treatment should be re-examined.

PMID- 15182143
TI  - Retrospective descriptive study of adult tuberculosis in Wuhan, China.
AB  - OBJECTIVE: To determine the rate and associated factors of adult tuberculosis
      (TB) in the central Chinese city of Wuhan. DESIGN: A retrospective descriptive
      study of 417 patients registered for TB treatment from 1 January to 31 December
      2001. RESULTS: The mean age of admission was 38.47 (median 35) years, with males
      aged 20-40 years mostly affected; 191 (45.8%) TB patients were classified as
      smear-positive, 221 (53%) smear-negative and for five (1.2%) the sputum results
      were not known. Of all admissions, 43 (10.32%) were retreatment cases and 50
      (11.99%) were diagnosed as extra-pulmonary TB. All patients were treated under
      the DOTS strategy, with 391 (93.76%) cures, five (1.2%) treatment completed, five
      (1.2%) treatment failures, four (0.96%) deaths, three (0.72%) defaults and nine
      (2.16%) transfers out. Cure was associated with age (chi2 = 3.92, P < 0.05), but
      not with sex, retreatment TB, extra-pulmonary TB, type of treatment regimen, BCG
      status or delay in treatment (P > 0.05). CONCLUSION: DOTS provides high TB cure
      rates. The reasons for the low detection rates, high retreatment rates and the
      increasing number of young adults affected by TB need further elucidation. For
      these purposes, routine human immunodeficiency virus screening and sputum culture
      for multidrug-resistant tuberculosis and case detection may be required.

PMID- 15182144
TI  - Decreasing tuberculosis case fatality in England and Wales, 1988-2001.
AB  - SETTING: Despite declining tuberculosis mortality per head of population, there
      was little change in tuberculosis case fatality in England and Wales from 1974 to
      1987. OBJECTIVE: To determine the trend in tuberculosis case fatality for England
      and Wales from 1988 to 2001. DESIGN: Annual deaths to notifications ratios (DNRs)
      for tuberculosis were calculated using published notification and mortality data,
      and analysed by age group and three disease sites (central nervous system [CNS],
      respiratory and other). DNRs for seven disease sites (miliary, bone and joint,
      CNS, respiratory, genitourinary, gastrointestinal and other) were calculated for
      1998 and 1999 combined, using additional data from the enhanced tuberculosis
      surveillance programme. RESULTS: DNR for all ages and disease sites combined fell
      from 9.26% in 1988 to 5.59% in 2001 (r = -0.90; 95%CI -0.97 - -0.70). DNRs for
      1998-1999 combined were 41% for miliary disease, 17% for bone and joint disease,
      8% for CNS disease, 7% for respiratory disease, 2% for genitourinary and
      gastrointestinal disease and 0.6% for other disease. CONCLUSIONS: Some of the
      decrease in DNRs may be due to improving notification rates. True declines in
      overall case fatality reflect increases in the proportion of tuberculosis
      patients in younger age groups and with low mortality extra-pulmonary disease.

PMID- 15182145
TI  - Preventing drug-resistant tuberculosis with a fixed dose combination of isoniazid
      and rifampin.
AB  - SETTING: Los Angeles County Department of Health Services. OBJECTIVE: To
      determine how well a self-administered fixed dose combination of isoniazid and
      rifampin (CombinedHR) prevents acquired drug resistance to Mycobacterium
      tuberculosis despite treatment interruptions. DESIGN: Self-administered
      CombinedHR was given to approximately 75% of patients and directly observed
      therapy or separate drugs to 25%. Three quarters of the patients completed the
      prescribed treatment. We determined 1) how many patients had two drug-susceptible
      cultures 3 or more months apart as a measure of drug-susceptible failure or
      relapse, 2) how many patients whose initial culture was drug-susceptible had a
      subsequent drug-resistant culture as a measure of acquired drug resistance, and
      3) what treatment regimen was taken by each patient who developed acquired drug
      resistance. RESULTS: Among 5337 drug-susceptible tuberculosis patients who were
      known or presumed to be human immunodeficiency virus (HIV) negative, 152 (2.84%)
      treatment failures or relapses occurred, of which 25 (0.47%) developed acquired
      drug resistance. Among approximately 4000 cases taking CombinedHR and primarily
      CombinedHR, drug resistance occurred in only eight cases (0.2%), and a total of
      12 cases (0.3%) when patients with indeterminate treatment histories were added.
      CONCLUSIONS: Treatment with self-administered CombinedHR results in minimal
      acquired drug resistance in HIV-seronegative tuberculosis cases despite modest
      rates of incomplete treatment.

PMID- 15182146
TI  - Psychiatric issues in the management of patients with multidrug-resistant
      tuberculosis.
AB  - INTRODUCTION: Psychiatric issues present a challenge in the treatment of patients
      with multidrug-resistant tuberculosis (MDR-TB). Both baseline psychiatric
      disorders and development of psychiatric complications related to anti
      tuberculosis drugs and psychosocial factors require aggressive management.
      SETTING: A community-based non-governmental health organization in Lima, Peru.
      OBJECTIVE: To review the literature for psychiatric complications associated with
      anti-tuberculosis medications, to describe the incidence and prevalence of
      depression, anxiety and psychosis among individuals receiving MDR-TB therapy, and
      to detail the management approach used in this cohort. METHODS: A retrospective
      case series was performed among the first 75 patients to receive individualized
      MDR-TB therapy in Lima, Peru, between 1996 and 1999. RESULTS: Baseline depression
      and baseline anxiety were observed in respectively 52.2% and 8.7% of this cohort.
      Most individuals with baseline depression experienced improvement of depressive
      symptoms during the course of TB therapy. The incidence of depression, anxiety
      and psychosis during MDR-TB treatment was 13.3%, 12.0% and 12.0%, respectively.
      While the majority of individuals with depression, anxiety and psychosis required
      psychiatric pharmacotherapy, cycloserine was successfully continued in all but
      one case. CONCLUSION: Psychiatric comorbidities are not a contra-indication to
      MDR-TB therapy. Management of psychiatric complications is possible without
      compromising anti-tuberculosis treatment.

PMID- 15182147
TI  - Surveillance of Mycobacterium tuberculosis susceptibility to second-line drugs in
      Hong Kong, 1995-2002, after the implementation of DOTS-plus.
AB  - OBJECTIVE: To determine the trend in changes in susceptibility of Mycobacterium
      tuberculosis strains, including to second-line drugs, from patients with a
      history of previous anti-tuberculosis (TB) treatment in a 'DOTS-Plus' programme.
      METHODS: A retrospective survey of centralised M. tuberculosis laboratory records
      of all culture-positive cases over an 8-year period. The drug susceptibility of
      the isolates was determined using the absolute concentration method. Isolates
      obtained from patients with a history of previous treatment were further analysed
      for trends of changes in susceptibility to first- and second-line drugs. RESULTS:
      Of 1921 patients with a previous history of treatment and positive cultures, 1425
      (74.2%) had isolates susceptible to all four first-line drugs, while 176 (9.2%)
      were multidrug-resistant (MDR-TB). For the MDR-TB group, 101 (57.4%) isolates
      were sensitive to all second-line drugs, while 30 (17.0%) were resistant to three
      or more second-line drugs. CONCLUSION: In a DOTS-Plus programme environment where
      there is strict control on use of second-line drugs, the prevalence of MDR-TB is
      low amongst retreatment cases and the prudent use of second-line drugs in a
      population with well functioning DOTS-Plus programme does not generate super
      resistant strains. In circumstances where most retreatment strains are still
      susceptible and good laboratory support for detection of MDR cases is available,
      retreatment using first-line drugs is feasible.

PMID- 15182148
TI  - Residual lung damage after completion of treatment for multidrug-resistant
      tuberculosis.
AB  - SETTING: Limpopo Province, South Africa. OBJECTIVE: To assess the residual lung
      damage of patients who completed treatment for multidrug-resistant tuberculosis
      (MDR-TB). DESIGN: Chest radiograph and lung function tests were performed at the
      end of treatment. The radiographs were read by two independent observers who
      attributed a zonal score of between 0 and 18, depending on the extent of
      radiographic abnormalities (opacification or cavitation), counted the number of
      visible cavities and measured the diameter of the largest cavity. RESULTS: The
      mean zonal score was 6.5. Cavitation was present in more than half of the
      patients. Of 33 patients, 31 (94%) had abnormal lung function tests. The median
      FEV1 was 63% and FVC was 57% of the predicted value. Restrictive and combined
      restrictive-obstructive lung function patterns were the predominant
      abnormalities. CONCLUSIONS: Residual lung damage in MDR-TB patients who completed
      treatment is common and extensive. This may increase the risk of relapse of
      tuberculosis and reduce the quality of life and life expectancy of these
      patients. Additional efforts are warranted to diagnose MDR-TB early to reduce the
      extent of residual lung damage. Close follow-up of MDR-TB patients completing
      treatment will have to be ensured to detect relapses.

PMID- 15182149
TI  - Evaluation of a new automated, rapid, colorimetric culture system using solid
      medium for laboratory diagnosis of tuberculosis and determination of anti
      tuberculosis drug susceptibility.
AB  - SETTING: Department of Microbiology and Clinical Microbiology, Gulhane Military
      Medical Academy, Ankara, Turkey, a tertiary referral hospital in a region endemic
      for tuberculosis. OBJECTIVE: To evaluate the performance of the Dio-TK Culture
      System (CS), a new, rapid, automated colorimetric culture system. DESIGN: Dio-TK
      CS results were compared with routinely used Lowenstein Jensen (LJ) medium and
      Bactec 460 TB. RESULTS: In this study, 449 specimens, mostly sputum samples
      obtained from 348 patients, were evaluated. Mycobacteria were isolated from 31
      (6.9%), 23 (5.1%), 18 (4.0%) and 21 (4.7%) of the specimens using Bactec 12B, LJ,
      Dio-TK Medium and Dio-TK SLC (selective), respectively. The mean time to
      detection of growth of 13 isolates by Bactec 12B, Dio-TK Medium, Dio-TK SLC and
      LJ medium was respectively 8.9, 15.1, 17.0 and 26.1 days. CONCLUSION: Dio-TK may
      be a practical and rapid culture system for daily use. However, the manufacturer
      should improve the system to minimise the effects of manipulation errors.
      Comparative studies with a larger number of isolates are needed to standardise
      drug concentrations used in anti-tuberculosis drug susceptibility testing.

PMID- 15182150
TI  - Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients
      in an infectious diseases reference hospital, Buenos Aires, Argentina.
AB  - SETTING: An Argentinean reference hospital specialising in infectious diseases.
      OBJECTIVE: To assess the outcomes of all human immunodeficiency virus (HIV)
      negative multidrug-resistant tuberculosis (MDR-TB) patients referred to or
      diagnosed at Hospital Muniz. DESIGN: Clinical study for the period 1996-1999,
      with follow-up until June 2002. RESULTS: One hundred and forty-one adult patients
      (52.5% female) with resistance to two to seven drugs were studied. Fifty patients
      (35.5%) had not been treated previously. The most frequently used second-line
      drugs were 5-F-quinolones, cycloserine and ethionamide in susceptibility based
      individually tailored three- to five-drug regimens. Hospital admission was
      associated with treatment success. Forty-five episodes of severe toxicity
      occurred. Treatment was successful in 51.8% of cases, but follow-up of 73
      patients yielded 11.9% relapse. The mortality rate was 19.1% and default was
      19.9%. Logistic regression analysis was statistically significant for treatment
      success in relation to patient admission, residence and resistance pattern.
      CONCLUSION: The burden of MDR-TB in this setting--prolonged infection, treatment
      cost and difficulties, low rates of cure and treatment adherence and high rates
      of fatality and relapse--can be improved by strengthening TB control programme
      activities and fighting against poverty and HIV/AIDS.

PMID- 15182151
TI  - The epidemiological profile of tuberculosis in southern Brazil in times of AIDS.
AB  - SETTING: Urban area in southern Brazil. OBJECTIVE: To investigate human
      immunodeficiency virus (HIV) co-infection among new cases of tuberculosis
      recorded in 2000 in Porto Alegre, Brazil. DESIGN: Cross-sectional population
      based study. RESULTS: Among 1713 new tuberculosis cases, HIV testing was not
      available for 29.8% and results were unknown for 1.8%. Of 1171 with known
      results, 47% had HIV co-infection. HIV seropositivity was 44% higher in males.
      The 15-59 years age group had 3.4 times more seropositive cases than the group
      aged >59 years. Individuals with <8 years of schooling presented 57% more co
      infection. HIV positivity was twice as frequent in extra-pulmonary and combined
      forms of tuberculosis as in pulmonary forms. Hospitalization was 2.4 times more
      common in HIV-positive individuals. The overall cure rate was 69.8%, while in co
      infected patients it was 43.9%. The determinants of risk of death from
      tuberculosis included <8 years of schooling (PR 2.2, 95%CI 1.2-3.7), HIV
      seropositivity (PR 8.0, 95%CI 5.0-12.9), combined pulmonary and extra-pulmonary
      tuberculosis (PR 1.7, 95%CI 1.2-2.5) and diagnosis during admission rather than
      in out-patient clinics (PR 5.4, 95%CI 2.9-10.1). CONCLUSIONS: The co-occurrence
      of tuberculosis and HIV/AIDS indicates a need to integrate the control programs
      for these two diseases. The health care system should invest in early diagnosis
      and adherence to treatment for both diseases.

PMID- 15182152
TI  - Screening for tuberculosis in adults with advanced HIV infection prior to
      preventive therapy.
AB  - It is important to exclude tuberculosis prior to preventive therapy, but this can
      be difficult in patients with symptomatic human immunodeficiency virus (HIV)
      disease. Patients with clinically advanced HIV disease were screened for active
      tuberculosis using a symptom questionnaire, measured weight loss, chest
      radiography, sputum microscopy and culture prior to receiving tuberculosis
      preventive therapy. Tuberculosis was diagnosed in 11 of 129 patients screened. A
      simple screening instrument of two or more of the symptoms measured weight loss,
      cough, night sweats or fever, had a sensitivity of 100% and specificity of 88.1%,
      and positive and negative predictive values of 44% and 100%, respectively.

PMID- 15182153
TI  - Undiagnosed pulmonary tuberculosis deaths in rural South Africa.
AB  - This research explores death from pulmonary tuberculosis (PTB) using a verbal
      autopsy (VA) tool within the established Agincourt Health and Demographic
      Surveillance System site in South Africa's rural northeast. Previous work on
      active case finding in the area highlighted a modest burden of undiagnosed PTB in
      the community. This VA research confirms the existence of undiagnosed PTB deaths,
      with 13 (46%) of 28 PTB deaths among the permanent adult population (n = 38,251)
      going undetected by the health service. There was a median duration of coughing
      in the community of 16 weeks among these undiagnosed PTB deaths. As most
      undiagnosed cases present to the health service at some point during their
      illness, intervention strategies to support early diagnosis at this level can
      only be re-emphasised by this work.

PMID- 15182154
TI  - Effectiveness of urban community volunteers in directly observed treatment of
      tuberculosis patients: a field report from Haryana, North India.
AB  - A tuberculosis (TB) unit covering a population of 600000 in Gurgaon District of
      Haryana State, India, where the DOTS-based RNTCP has been implemented since April
      2000. Treatment success rate, as recorded in the TB register, of new sputum smear
      positive patients receiving directly observed treatment (DOT) from community
      volunteers was comparable with that of patients receiving DOT from government
      health workers (78% vs. 77%). The proportion of patients with community
      volunteers increased significantly with time (13% in 2000 to 25% in 2002), even
      in the absence of financial incentives. In this model of community volunteer
      involvement in an urban TB control programme, the primary responsibility for
      returning late patients to treatment was with the staff of the District TB
      Centre.

PMID- 15182155
TI  - Alveolar microlithiasis and immunological disorders.

PMID- 15182156
TI  - Outcome of directly observed therapy for tuberculosis in Yokohama City, Japan.

PMID- 15182157
TI  - Epidemiology and prevention of skin and soft tissue infections.
AB  - Staphylococcus aureus and Streptococcus pyogenes remain the 2 major organisms
      responsible for most common skin and soft tissue infections. While methicillin
      resistant S aureus (MRSA) typically is considered a hospital-acquired organism,
      outbreaks of community-acquired MRSA are being reported. Simple interventions can
      reduce the spread of this infection. Erysipelas is a streptococcal syndrome with
      high morbidity. The epidemiology has changed, with an increasing number of cases
      involving the lower extremities. Risk factors for erysipelas can be identified,
      which allow clinicians to target patients at high risk for recurrent disease.
      Although staphylococci and streptococci are the predominant cutaneous pathogens,
      enterococci and gram-negative organisms account for a significant proportion of
      skin infections.

PMID- 15182158
TI  - Common pathogens and differential diagnosis of skin and soft tissue infections.
AB  - The major organisms responsible for skin infections are Staphylococcus aureus and
      Streptococcus pyogenes. To produce a disease state, both organisms must overcome
      the body's natural defenses, adhere to the skin, invade the tissue, and
      proliferate. Often, endogenous skin microflora can lead to systemic infections,
      especially in immunocompromised individuals. The differential diagnosis of skin
      infections is key to successful therapy and requires a thorough knowledge of the
      patient's clinical history and immune status. Laboratory analysis often can
      assist in the pathogenic differentiation. Examples of common skin infections are
      illustrated herein.

PMID- 15182159
TI  - Antibiotics: what's new?
AB  - In addition to the traditional antibiotic choices for skin and skin structure
      infections, such as beta-lactams, macrolides, and clindamycin, newer broad
      spectrum antibiotics are available to treat resistant pathogens that can cause
      severe infections. The pharmacologic profiles of 3 newer classes of these
      antibiotics are reviewed briefly, and the role of these agents in treating skin
      and skin structure infections is discussed.

PMID- 15182160
TI  - Overview of cefdinir: pharmacokinetics, safety, and efficacy in the treatment of
      uncomplicated skin and skin structure infections.
AB  - Uncomplicated skin and skin structure infections commonly are caused by
      Staphylococcus aureus and Streptococcus pyogenes. Cefdinir, an extended spectrum,
      third-generation cephalosporin is a safe and effective means of treating skin
      infections caused by these organisms, as well as many gram-negative pathogens.
      This article summarizes the pharmacokinetics, dosing schedule, adverse event
      profile, and efficacy data for cefdinir in adult and pediatric, populations in
      the treatment of uncomplicated skin and skin structure infections.

PMID- 15182161
TI  - Staphylococcal resistance and oral cephalosporins for skin and skin structure
      infections.
AB  - The common classification of cephalosporins into "generations," based on their
      activity toward gram-positive and gram-negative organisms, does not adequately
      reflect the differences among these drugs, especially for newer, broad-spectrum
      antibiotics. Thus, clinicians need to understand the complete spectrums of
      activity for these drugs to treat patients effectively and minimize the
      development of drug resistance.

PMID- 15182162
TI  - Classification of diabetic foot infections.
AB  - The treatment of diabetic foot ulcers is first determined by the presence or
      absence of infection. Whereas noninfected ulcers typically respond to pressure
      relief and debridement, the treatment of infected ulcers depends on the degree of
      systemic involvement and the type and number of invading pathogens. This is the
      basis of the new classification system proposed by the Infectious Diseases
      Society of America and briefly described herein. The full report should be
      available later this year in Clinical Infectious Diseases.

PMID- 15182164
TI  - Impetigo in pediatrics.
AB  - Impetigo is a common skin infection in children. If not treated promptly, it can
      spread rapidly through a student population and become a significant health
      problem. Whereas uncomplicated, localized lesions typically are treated with
      topical mupirocin, widespread infections involving multiple pathogens require
      systemic treatment with a cephalosporin or a beta-lactamase-resistant antibiotic.

PMID- 15182163
TI  - The dermatologist's role in managing skin and soft tissue infections.
AB  - Dermatologists are often the first point of care for patients with skin and soft
      tissue bacterial infections. First, physical examination and patient history are
      central points of assessment to determine severity of infection, pathogen
      involved, and appropriate course of action. As preexisting conditions may exert a
      role both in the etiology of an infection and in the choice of antibiotic therapy
      prescribed, the clinician must be aware of the right questions to ask to achieve
      a complete diagnostic picture. Finally, the clinician should have a good
      understanding of the drugs most appropriate for different pathogens and have
      clear expectations of how quickly the infection should respond to therapy.

PMID- 15182165
TI  - Skin and soft tissue infections in special populations.
AB  - Skin infections often develop in children, immunosuppressed patients, and
      patients with chronic conditions such as diabetes. Commonly encountered cutaneous
      infections are described herein, and treatments are briefly discussed.
      Photographs of infections provide assistance with differential diagnosis.

PMID- 15182167
TI  - The managed care approach to placing a drug on formulary.
AB  - The placement of a drug on a health plan's formulary is important to ensure
      patient access to the best therapeutic options. Unfortunately, cost is too often
      a defining attribute that determines whether or not a drug is placed on
      formulary. Multitiered formularies represent one method for managing costs while
      still providing access to more expensive medications. Creating a niche for a
      product is one way that drug companies may be able to obtain formulary
      acceptance.

PMID- 15182166
TI  - Compliance with antibiotics.
AB  - Several factors influence the clinician's choice of antimicrobial therapy. While
      efficacy and toxicity can be important discriminators in the treatment of skin
      and soft tissue infections, patient compliance with antibiotic medication is a
      key component to successful therapy. The general parameters affecting compliance
      are discussed herein, and antibiotic-specific factors affecting compliance are
      discussed briefly.

PMID- 15182168
TI  - Therapeutic benefits from targeting of ADAM family members.
AB  - Members of the ADAM (a disintegrin and metalloproteinase) family of proteolytic
      enzymes are implicated in the processing of many single transmembrane-bound
      proteins ranging from cell surface receptors to growth factors and cytokines.
      Because of the biological significance of these processing events, a recurring
      theme in studying ADAM biology is that they are involved in physiological
      processes that can go awry and lead to disease states. This review provides a
      comprehensive look at ADAM family members and their role in pathology and
      provides a pathway for determining whether an enzyme is a physiological
      convertase for a given protein. In addition, ADAMs are discussed as potential
      therapeutic targets.

PMID- 15182169
TI  - Identification of a novel protonation pattern for carboxylic acids upon Q(B)
      photoreduction in Rhodobacter sphaeroides reaction center mutants at Asp-L213 and
      Glu-L212 sites.
AB  - In the reaction center from the photosynthetic purple bacterium Rhodobacter
      sphaeroides, light energy is rapidly converted to chemical energy through coupled
      electron-proton transfer to a buried quinone molecule Q(B). Involved in the
      proton uptake steps are carboxylic acids, which have characteristic infrared
      vibrations that are observable using light-induced Fourier transform infrared
      (FTIR) difference spectroscopy. Upon formation, Q(B)(-) induces protonation of
      Glu-L212, located within 5 A of Q(B), resulting in a IR signal at 1728 cm(-1).
      However, no other IR signal is observed within the classic absorption range of
      protonated carboxylic acids (1770-1700 cm(-1)). In particular, no signal for Asp
      L213 is found despite its juxtaposition to Q(B) and importance for proton uptake
      on the second electron-transfer step. In an attempt to uncover the reason behind
      this lack of signal, the microscopic electrostatic environment in the vicinity of
      Q(B) was modified by interchanging Asp and Glu at the L213 and L212 positions.
      The Q(B)(-)/Q(B) FTIR spectrum of the Asp-L212/Glu-L213 swap mutant in the 1770
      1700 cm(-1) range shows several distinct new signals, which are sensitive to
      (1)H/(2)H isotopic exchange, indicating that the reduction of Q(B) results in the
      change of the protonation state of several carboxylic acids. The new bands at
      1752 and 1747 cm(-1) were assigned to an increase of protonation in response to
      Q(B) reduction of Glu-L213 and Asp-L212, respectively, based on the effect of
      replacing them with their amine analogues. Since other carboxylic acid signals
      were observed, it is concluded that the swap mutations at L212 and L213 affect a
      cluster of carboxylic acids larger than the L212/L213 acid pair. Implications for
      the native reaction center are discussed.

PMID- 15182170
TI  - Glutathione induces helical formation in the carboxy terminus of human
      glutathione transferase A1-1.
AB  - The structure and dynamic properties of the C-terminal region of the human class
      alpha glutathione transferase A1-1 have been investigated with high-resolution
      NMR methods. On the basis of crystallographic and fluorescence measurements, this
      13-residue segment of the enzyme is presumed to be disordered in the unliganded
      enzyme. When the product or product analogue is bound, a C-terminal alpha-helix
      is observed in crystal structures. Conflicting data exists regarding the
      structure of this region when one of the substrates, glutathione (GSH), is bound.
      The NMR studies presented here show that in the unliganded protein, this region
      of the protein samples different conformations, most likely an ensemble of helix
      like structures. Addition of either GSH or the conjugate between GSH and
      ethacrynic acid (EASG) causes this segment to become a stable alpha-helix. In the
      GSH complex, the ends of this helix exhibit dynamic behavior on both the
      millisecond and nanosecond time scales. In contrast, there is no evidence of
      millisecond dynamics in the EASG complex. The ligand-induced ordering of the
      enzyme reduces the intrinsic affinity of the enzyme for its product, facilitating
      enzymatic turnover.

PMID- 15182171
TI  - An alternative mechanism of bioluminescence color determination in firefly
      luciferase.
AB  - Beetle luciferases (including those of the firefly) use the same luciferin
      substrate to naturally display light ranging in color from green (lambda(max)
      approximately 530 nm) to red (lambda(max) approximately 635 nm). In a recent
      communication, we reported (Branchini, B. R., Murtiashaw, M. H., Magyar, R. A.,
      Portier, N. C., Ruggiero, M. C., and Stroh, J. G. (2002) J. Am. Chem. Soc. 124,
      2112-2113) that the synthetic adenylate of firefly luciferin analogue D-5,5
      dimethylluciferin was transformed into the emitter 5,5-dimethyloxyluciferin in
      bioluminescence reactions catalyzed by luciferases from Photinus pyralis and the
      click beetle Pyrophorus plagiophthalamus. 5,5-Dimethyloxyluciferin is constrained
      to exist in the keto form and fluoresces mainly in the red. However,
      bioluminescence spectra revealed that green light emission was produced by the
      firefly enzyme, and red light was observed with the click beetle protein. These
      results, augmented with steady-state kinetic studies, were taken as experimental
      support for mechanisms of firefly bioluminescence color that require only a
      single keto form of oxyluciferin. We report here the results of mutagenesis
      studies designed to determine the basis of the observed differences in
      bioluminescence color with the analogue adenylate. Mutants of P. pyralis
      luciferase putative active site residues Gly246 and Phe250, as well as
      corresponding click beetle residues Ala243 and Ser247 were constructed and
      characterized using bioluminescence emission spectroscopy and steady state
      kinetics with adenylate substrates. Based on an analysis of these and recently
      reported (Branchini, B. R., Southworth, T. L., Murtiashaw, M. H., Boije, H., and
      Fleet, S. E. (2003) Biochemistry 42, 10429-10436) data, we have developed an
      alternative mechanism of bioluminescence color. The basis of the mechanism is
      that luciferase modulates emission color by controlling the resonance-based
      charge delocalization of the anionic keto form of the oxyluciferin excited state.

PMID- 15182172
TI  - Structure and dynamics of lipoplex formation examined using two-photon
      fluorescence cross-correlation spectroscopy.
AB  - The conditions required to form transfectable lipoplexes have been extensively
      studied [Zuhorn, I. S., and Hoekstra, D. (2002) J. Membr. Biol. 189, 167-179].
      However, to date, experiments have not addressed either the order of events of
      lipoplex formation in solution or the maximum number of DNA molecules per vesicle
      in stable single-vesicle lipoplexes. In this study, we have employed two-photon
      excitation fluorescence correlation spectroscopy (TPE-FCS) and two-photon
      fluorescence cross-correlation spectroscopy (TPE-XCS) to examine both
      fluorescence-labeled DNA and cationic vesicle structure and dynamics
      simultaneously. The dependence of large aggregated lipoplex formation on DNA-to
      cationic lipid charge ratio was determined, as was the maximum number of 40 bp
      double-stranded DNA oligonucleotides able to bind to a single vesicle.

PMID- 15182173
TI  - Mapping backbone dynamics in solution with site-directed spin labeling: GCN4-58
      bZip free and bound to DNA.
AB  - In site-directed spin labeling, a nitroxide-containing side chain is introduced
      at selected sites in a protein. The EPR spectrum of the labeled protein encodes
      information about the motion of the nitroxide on the nanosecond time scale, which
      has contributions from the rotary diffusion of the protein, from internal motions
      in the side chain, and from backbone fluctuations. In the simplest model for the
      motion of noninteracting (surface) side chains, the contribution from the
      internal motion is sequence independent, as is that from protein rotary
      diffusion. Hence, differences in backbone motions should be revealed by comparing
      the sequence-dependent motions of nitroxides at structurally homologous sites. To
      examine this model, nitroxide side chains were introduced, one at a time, along
      the GCN4-58 bZip sequence, for which NMR (15)N relaxation experiments have
      identified a striking gradient of backbone mobility along the DNA-binding region
      [Bracken et al. (1999) J. Mol. Biol. 285, 2133]. Spectral simulation techniques
      and a simple line width measure were used to extract dynamical parameters from
      the EPR spectra, and the results reveal a mobility gradient similar to that
      observed in NMR relaxation, indicating that side chain motions mirror backbone
      motions. In addition, the sequence-dependent side chain dynamics were analyzed in
      the DNA/protein complex, which has not been previously investigated by NMR
      relaxation methods. As anticipated, the backbone motions are damped in the DNA
      bound state, although a gradient of motion persists with residues at the DNA
      binding site being the most highly ordered, similar to those of helices on
      globular proteins.

PMID- 15182174
TI  - Sterol carrier protein-2 directly interacts with caveolin-1 in vitro and in vivo.
AB  - HDL-mediated reverse-cholesterol transport as well as phosphoinositide signaling
      are mediated through plasma membrane microdomains termed caveolae/lipid rafts.
      However, relatively little is known regarding mechanism(s) whereby these lipids
      traffic to or are targeted to caveolae/lipid rafts. Since sterol carrier protein
      2 (SCP-2) binds both cholesterol and phosphatidylinositol, the possibility that
      SCP-2 might interact with caveolin-1 and caveolae was examined. Double
      immunolabeling and laser scanning fluorescence microscopy showed that a small but
      significant portion of SCP-2 colocalized with caveolin-1 primarily at the plasma
      membrane of L-cells and more so within intracellular punctuate structures in
      hepatoma cells. In SCP-2 overexpressing L-cells, SCP-2 was detected in close
      proximity to caveolin, 48 +/- 4 A, as determined by fluorescence resonance energy
      transfer (FRET) and immunogold electron microscopy. Cell fractionation of SCP-2
      overexpressing L-cells and Western blotting detected SCP-2 in purified plasma
      membranes, especially in caveolae/ lipid rafts as compared to the nonraft
      fraction. SCP-2 and caveolin-1 were coimmunoprecipitated from cell lysates by
      anti-caveolin-1 and anti-SCP-2. Finally, a yeast two-hybrid assay demonstrated
      that SCP-2 directly interacts with caveolin-1 in vivo. These interactions of SCP
      2 with caveolin-1 were specific since a functionally related protein,
      phosphatidyinositol transfer protein (PITP), colocalized much less well with
      caveolin-1, was not in close proximity to caveolin-1 (i.e., >120 A), and was not
      coimmunoprecipitated by anti-caveolin-1 from cell lysates. In summary, it was
      shown for the first time that SCP-2 (but not PITP) selectively interacted with
      caveolin-1, both within the cytoplasm and at the plasma membrane. These data
      contribute significantly to our understanding of the role of SCP-2 in cholesterol
      and phosphatidylinositol targeted from intracellular sites of synthesis in the
      endoplasmic reticulum to caveolae/lipid rafts at the cell surface plasma
      membrane.

PMID- 15182175
TI  - Nucleotide exchange from the high-affinity ATP-binding site in SecA is the rate
      limiting step in the ATPase cycle of the soluble enzyme and occurs through a
      specialized conformational state.
AB  - We have characterized the kinetic and thermodynamic consequences of adenine
      nucleotide interaction with the low-affinity and high-affinity nucleotide-binding
      sites in free SecA. ATP binds to the hydrolytically active high-affinity site
      approximately 3-fold more slowly than ADP when SecA is in its conformational
      ground state, suggesting that ATP binding probably occurs when the enzyme is in
      another conformational state during the productive ATPase/transport cycle. The
      steady-state ATP hydrolysis rate is equivalent to the rate of ADP release from
      the high-affinity site under a number of conditions, indicating that this process
      is the rate-limiting step in the ATPase cycle of the free enzyme. Because
      efficient protein translocation requires at least a 100-fold acceleration in the
      ATPase rate, the rate-limiting process of ADP release from the high-affinity site
      is likely to play a controlling role in the conformational reaction cycle of
      SecA. This release process involves a large enthalpy of activation, suggesting
      that it involves a protein conformational change, and two observations indicate
      that this conformational change is different from the well-characterized
      endothermic conformational transition believed to gate the binding of SecA to
      SecYEG. First, nucleotide binding to the low-affinity site strongly inhibits the
      endothermic transition but does not reduce the rate of ADP release. Second,
      removal of Mg(2+) from an allosteric binding site on SecA does not perturb the
      endothermic transition but produces a 10-fold acceleration in the rate of ADP
      release. These divergent effects suggest that a specialized conformational
      transition mediates the rate-limiting ADP-release process in SecA. Finally, ADP,
      2'-O-(N-methylanthraniloyl)-adenosine-5'-diphosphate (MANT-ADP), and adenosine 5'
      O-(3-thiotriphosphate) (ATP-gamma-S) bind with similar affinities to the high
      affinity site and also to the low-affinity site as inferred from their consistent
      effects in inhibiting the endothermic transition. In contrast, adenosine 5'
      (beta,gamma-imino)triphosphate (AMPPNP) shows 100-fold weaker affinity than ADP
      for the high-affinity site and no detectable interaction with the low-affinity
      site at concentrations up to 1 mM, suggesting that this nonhydrolyzable analogue
      may not be a faithful mimic of ATP in its interactions with SecA.

PMID- 15182176
TI  - Two apolipoprotein E mimetic peptides, ApoE(130-149) and ApoE(141-155)2, bind to
      LRP1.
AB  - LRP1 is a cell surface receptor responsible for clearing some 30 known ligands.
      We have previously shown that each of the three complete LDL receptor-homology
      domains of the LRP1 extracellular domain (sLRPs) binds apoE-enriched beta-VLDL
      particles. Here we show that two peptides from the N-terminal receptor binding
      domain of apoE, which are known to elicit a number of different cellular
      responses, bind to LRP1. Solution binding assays show that the two peptides,
      apoE(130-149) and apoE(141-155)(2), interact with each of the sLRPs (2, 3, and
      4). Each peptide was found to exhibit the same solution binding characteristics
      as apoE-enriched beta-VLDL particles. Surface plasmon resonance analyses of the
      sLRP-apoE peptide interaction show that both peptides bind the sLRPs with K(D)
      values in the 100 nM range, a value similar to the effective concentration
      required for observation of the cellular responses. Consistent with results from
      mutagenesis studies of binding of apoE to LDLR, apoE(130-149,Arg142Glu) bound
      with a K(D) similar to that of the wild-type sequence, while apoE(130
      149,Lys143Glu) showed a 10-fold decrease in K(D). Each of the peptides bound
      heparin, and heparin competed for sLRP binding.

PMID- 15182177
TI  - Design of peptoid analogue dimers and measure of their affinity for Grb2 SH3
      domains.
AB  - This paper describes the design of the highest affinity ligands for Grb2 SH3
      domains reported so far. These compounds were designed by combining N-alkyl amino
      acid incorporation in a proline-rich sequence with subsequent dimerization of the
      peptoid sequence based on structural data and molecular modeling. Optimization of
      the linker size is discussed, and the N-alkyl amino acid incorporation into both
      monomeric halves is reported. Because the affinity for Grb2 of the optimized
      compounds was too high to be measured using the fluorescent modifications that
      they induce on the Grb2 emission spectrum, a competition assay was developed. In
      this test, Grb2 is pulled down from a cellular extract by the initial VPPPVPPRRR
      peptide bound to Sepharose beads. In the presence of competitors, the test
      quantifies the amount of Grb2 displaced from the beads. It has enabled us to
      determine a K(i) value in the 10(-10) M range for the highest affinity Grb2
      peptoid analogue dimer.

PMID- 15182178
TI  - Biochemical and structural basis for partially redundant enzymatic and
      transcriptional functions of DCoH and DCoH2.
AB  - An inherited form of diabetes, maturity-onset diabetes of the young type 3
      (MODY3), results from mutations in the transcriptional activator, hepatocyte
      nuclear factor-1alpha (HNF1alpha). Transcription by HNF1alpha is stimulated by
      the bifunctional coactivator DCoH (dimerization cofactor of HNF1). Strikingly, an
      HNF1alpha deletion in mice causes more severe phenotypes than a DCoH deletion. It
      has been hypothesized that a DCoH homolog, DCoH2, partially complements the DCoH
      deletion. To test this idea, we determined the biochemical properties and the 1.6
      A-resolution crystal structure of DCoH2. Like DCoH, DCoH2 forms a tetramer,
      displays pterin-4alpha-carbinolamine dehydratase activity, and binds HNF1alpha in
      vivo and in vitro. DCoH and DCoH2 adopt identical folds with structural
      differences confined largely to the protein surfaces and the tetramer interface.
      In contrast to the hyperstable DCoH tetramer, DCoH2 readily disproportionates and
      forms a 2:2 complex with HNF1 in vitro. Phylogenetic analysis reveals six major
      subfamilies of DCoH proteins, including unique DCoH and DCoH2 branches in
      metazoans. These results suggest distinct roles for DCoH and DCoH2. Differences
      in conserved surface residues could mediate binding to different effectors. We
      propose that HNF1alpha binding kinetics may distinguish regulation by DCoH2,
      under thermodynamic control, from regulation by DCoH, under kinetic control.

PMID- 15182180
TI  - Transthyretin aggregation under partially denaturing conditions is a downhill
      polymerization.
AB  - The deposition of fibrils and amorphous aggregates of transthyretin (TTR) in
      patient tissues is a hallmark of TTR amyloid disease, but the molecular details
      of amyloidogenesis are poorly understood. Tetramer dissociation is typically rate
      limiting for TTR amyloid fibril formation, so we have used a monomeric variant of
      TTR (M-TTR) to study the mechanism of aggregation. Amyloid formation is often
      considered to be a nucleation-dependent process, where fibril growth requires the
      formation of an oligomeric nucleus that is the highest energy species on the
      pathway. According to this model, the rate of fibril formation should be
      accelerated by the addition of preformed aggregates or "seeds", which effectively
      bypasses the nucleation step. Herein, we demonstrate that M-TTR amyloidogenesis
      at low pH is a complex, multistep reaction whose kinetic behavior is incompatible
      with the expectations for a nucleation-dependent polymerization. M-TTR
      aggregation is not accelerated by seeding, and the dependence of the reaction
      timecourse is first-order on the M-TTR concentration, consistent either with a
      dimeric nucleus or with a nonnucleated process where each step is bimolecular and
      essentially irreversible. These studies suggest that amyloid formation by M-TTR
      under partially denaturing conditions is a downhill polymerization, in which the
      highest energy species is the native monomer. Our results emphasize the
      importance of therapeutic strategies that stabilize the TTR tetramer and may help
      to explain why more than eighty TTR variants are disease-associated. The
      differences between amyloid formation by M-TTR and other amyloidogenic peptides
      (such as amyloid beta-peptide and islet amyloid polypeptide) demonstrate that
      these polypeptides do not share a common aggregation mechanism, at least under
      the conditions examined thus far.

PMID- 15182179
TI  - Roles for cysteine residues in the regulatory CXXC motif of human mitochondrial
      branched chain aminotransferase enzyme.
AB  - The redox-active dithiol/disulfide C315-Xaa-Xaa-C318 center has been implicated
      in the regulation of the human mitochondrial branched chain aminotransferase
      isozyme (hBCATm) [Conway, M. E., Yennawar, N., Wallin, R., Poole, L. B., and
      Hutson, S. M. (2002) Biochemistry 41, 9070-9078]. To explore further the
      mechanistic details of this CXXC center, mutants of the Cys residues at positions
      315 and 318 of hBCATm were individually and in combination converted to alanine
      or serine by site-directed mutagenesis (C315A, C315S, C318A, C318S, C315/318A,
      and C315/318S). The effects of these mutations on cofactor absorbance, secondary
      structures, steady-state kinetics, and sensitivity toward hydrogen peroxide
      (H(2)O(2)) treatment were examined. Neither the UV-visible spectroscopic studies
      nor the circular dichroism data showed any major perturbations in the structure
      of the mutants. Kinetic analyses of the CXXC mutant proteins indicated primarily
      a modest reduction in k(cat) with no significant change in K(m). The largest
      effect on the steady-state kinetics was observed with the C315 single mutants, in
      which substitution of the thiol group resulted in a reduced k(cat) (to 26-33% of
      that of wild-type hBCATm). Moreover, the C315 single mutants lost their
      sensitivity to oxidation by H(2)O(2). The kinetic parameters of the C318 mutants
      were largely unaffected by the substitutions, and as with wild-type hBCATm,
      reaction of the C318A mutant protein with H(2)O(2) resulted in the complete loss
      of activity. In the case of oxidized C318A, this loss was largely irreversible on
      incubation with dithiothreitol. Mass spectrometry and dimedone modification
      results revealed overoxidation of the thiol group at position 315 to sulfonic
      acid occurring via a sulfenic acid intermediate in the H(2)O(2)-treated C318A
      enzyme. Thus, C315 appears to be the sensor for redox regulation of BCAT
      activity, whereas C318 acts as the "resolving cysteine", allowing for reversible
      formation of a disulfide bond.

PMID- 15182181
TI  - Dual functional roles of ATP in the human mitochondrial malic enzyme.
AB  - Human mitochondrial malic enzyme is a regulatory enzyme with ATP as an inhibitor.
      Structural studies reveal that the enzyme has two ATP-binding sites, one at the
      NAD(+)-binding site in the active center and the other at the exo site in the
      tetramer interface. Inhibition of the enzyme activity is due to the competition
      between ATP and NAD(+) for the nucleotide-binding site at the active center with
      an inhibition constant of 81 microM. Binding of the ATP molecule at the exo site,
      on the other hand, is important for the maintenance of the quaternary structural
      integrity. The enzyme exists in solution at neutral pH and at equilibrium of the
      dimer and tetramer with a dissociation constant (K(TD)) of 0.67 microM. ATP, at a
      physiological concentration, shifts the equilibrium toward tetramer and decreases
      the K(TD) by many orders of magnitude. Mutation of a single residue Arg542 at the
      tetrameric interfacial exo site resulted in dimeric mutants. ATP thus has dual
      functional roles in the mitochondrial malic enzyme.

PMID- 15182182
TI  - Gln212, Asn270, and Arg301 are critical for catalysis by adenylosuccinate lyase
      from Bacillus subtilis.
AB  - In adenylosuccinate lyase from Bacillus subtilis, Gln(212), Asn(270), and
      Arg(301) are conserved and located close to the succinyl moiety of docked
      adenylosuccinate. We constructed mutant enzymes with Gln(212) replaced by Glu and
      Met, Asn(270) by Asp and Leu, and Arg(301) by Gln or Lys. The wild-type and
      mutant enzymes were expressed in Escherichia coli and purified to homogeneity.
      The specific activities of the Q212M and the 270 and 301 mutant enzymes were
      decreased more than 3000-fold as compared to the wild type. Only Q212E retained
      sufficient activity for determination of its kinetic parameters: V(max) was
      decreased approximately 1000-fold, and K(m) was increased 6-fold, as compared to
      the wild-type enzyme. Adenylosuccinate binding studies of the other mutants
      revealed greatly weakened affinities that contributed to, but did not account
      entirely for, the loss of activity. These mutant enzymes did not differ greatly
      from the wild-type enzyme in secondary structure or subunit association state, as
      shown by circular dichroism spectroscopy and light-scattering photometry.
      Incubation of pairs of inactive mutant enzymes led to reconstitution of some
      functional sites by subunit complementation, with recovery of up to 25% of the
      specific activity of the wild-type enzyme. Subunit complementation occurs only if
      the two mutations are contributed to the active site by different subunits. Thus,
      mixing Q212E with N270L enzyme yielded a specific activity of approximately 20%
      of the wild-type enzyme, while mixing Q212M with R301K enzyme did not restore
      activity. As supported by computer modeling, the studies presented here indicate
      that Gln(212), Asn(270), and Arg(301) are indispensable to catalysis by
      adenylosuccinate lyase and probably interact noncovalently with the carboxylate
      anions of the substrates 5-aminoimidazole-4(N-succinylocarboxamide)ribonucleotide
      and adenylosuccinate, optimizing their bound orientations.

PMID- 15182183
TI  - Defining the binding site of homotetrameric R67 dihydrofolate reductase and
      correlating binding enthalpy with catalysis.
AB  - R67 dihydrofolate reductase (DHFR) is a novel protein that possesses 222
      symmetry. A single active site pore traverses the length of the homotetramer.
      Although the 222 symmetry implies that four symmetry-related binding sites should
      exist for each substrate as well as each cofactor, isothermal titration
      calorimetry (ITC) studies indicate only two molecules bind. Three possible
      combinations include two dihydrofolate molecules, two NADPH molecules, or one
      substrate with one cofactor. The latter is the productive ternary complex. To
      evaluate the roles of A36, Y46, T51, G64, and V66 residues in binding and
      catalysis, a site-directed mutagenesis approach was employed. One mutation per
      gene produces four mutations per active site pore, which often result in large
      cumulative effects. Conservative mutations at these positions either eliminate
      the ability of the gene to confer trimethoprim resistance or have no effect on
      catalysis. This result, in conjunction with previous mutagenesis studies on K32,
      K33, S65, Q67, I68, and Y69 [Strader, M. B., et al. (2001) Biochemistry 40, 11344
      11352; Hicks, S. N., et al. (2003) Biochemistry 42, 10569-10578; Park, H., et al.
      (1997) Protein Eng. 10, 1415-1424], allows mapping of the active site surface.
      Residues for which conservative mutations have large effects on binding and
      catalysis include K32, Q67, I68, and Y69. These residues form a stripe that
      establishes the ligand binding surface. Residues that accommodate conservative
      mutations that do not greatly affect catalysis include K33, Y46, T51, S65, and
      V66. Isothermal titration calorimetry studies were also conducted on many of the
      mutants described above to determine the enthalpy of folate binding to the R67
      DHFR.NADPH complex. A linear correlation between this DeltaH value and log
      k(cat)/K(m) is observed. Since structural tightness appears to be correlated with
      the exothermicity of the binding interaction, this leads to the hypothesis that
      enthalpy-driven formation of the ternary complex in these R67 DHFR variants plays
      a strong role in catalysis. Use of the alternate cofactor, NADH, extends this
      correlation, indicating preorganization of the ternary complex determines the
      efficiency of the reaction. This hypothesis is consistent with data suggesting
      R67 DHFR uses an endo transition state (where the nicotinamide ring of cofactor
      overlaps the more bulky side of the substrate's pteridine ring).

PMID- 15182184
TI  - Manipulation of the active site loops of D-hydantoinase, a (beta/alpha)8-barrel
      protein, for modulation of the substrate specificity.
AB  - We previously proposed that the stereochemistry gate loops (SGLs) constituting
      the substrate binding pocket of D-hydantoinase, a (beta/alpha)(8)-barrel enzyme,
      might be major structural determinants of the substrate specificity [Cheon, Y.
      H., et al. (2002) Biochemistry 41, 9410-9417]. To construct a mutant D
      hydantoinase with favorable substrate specificity for the synthesis of
      commercially important non-natural amino acids, the SGL loops of the enzyme were
      rationally manipulated on the basis of the structural analysis and sequence
      alignment of three hydantoinases with distinct substrate specificities. In the
      SGLs of D-hydantoinase from Bacillus stearothermophilus SD1, mutations of
      hydrophobic and bulky residues Met 63, Leu 65, Phe 152, and Phe 159, which
      interact with the exocyclic substituent of the substrate, induced remarkable
      changes in the substrate specificities. In particular, the substrate specificity
      of mutant F159A toward aromatic substrate hydroxyphenylhydantoin (HPH) was
      enhanced by approximately 200-fold compared with that of the wild-type enzyme.
      Saturation mutagenesis at position 159 revealed that k(cat) for aromatic
      substrates increased gradually as the size of the amino acid side chain
      decreased, and this seems to be due to reduced steric hindrance between the bulky
      exocyclic group of the substrate and the amino acid side chains. When site
      directed random mutagenesis of residues 63 and 65 was conducted with the wild
      type and mutant F159A, the selected enzymes (M63F/L65V and L65F/F159A) exhibited
      approximately 10-fold higher k(cat) values for HPH than the wild-type
      counterpart, which is likely to result from reorganization of the active site for
      efficient turnover. These results indicate that the amino acid residues of SGLs
      forming the substrate binding pocket are critical for the substrate specificity
      of D-hydantoinase, and the results also imply that substrate specificities of
      cyclic amidohydrolase family enzymes can be modulated by rational design of these
      SGLs.

PMID- 15182185
TI  - Design and characterization of helical peptides that inhibit the E6 protein of
      papillomavirus.
AB  - The E6 protein from HPV type 16 binds proteins containing a seven-residue leucine
      containing motif. Previous work demonstrated that peptides containing the
      consensus sequence are a mixture of alpha-helix and unstructured conformations.
      To design monomeric E6-binding peptides that are stable in aqueous solution, we
      used a protein grafting approach where the critical residues of the E6-binding
      motif of E6-associated protein, E6AP, LQELLGE, were incorporated into exposed
      helices of two stably folded peptide scaffolds. One series was built using the
      third zinc finger of the Sp1 protein, which contains a C-terminal helix. A second
      series was built using a Trp-cage scaffold, which contains an N-terminal helix.
      The chimeric peptides had very different activities in out-competing the E6-E6AP
      interaction. We characterized the peptides by circular dichroism spectroscopy and
      determined high-resolution structures by NMR methods. The E6-binding consensus
      motif was found to be helical in the high-quality structures, which had backbone
      root-mean-square deviations of less than 0.4 A. We have successfully grafted the
      E6-binding motif into two parent peptides to create ligands that have biological
      activity while preserving the stable, native fold of their scaffolds. The data
      also indicate that conformational change is common in E6-binding proteins during
      the formation of the complex with the viral E6 protein.

PMID- 15182186
TI  - Correlation of an adenine-specific conformational change with the ATP-dependent
      peptidase activity of Escherichia coli Lon.
AB  - Escherichia coli Lon, also known as protease La, is a serine protease that is
      activated by ATP and other purine or pyrimidine triphosphates. In this study, we
      examined the catalytic efficiency of peptide cleavage as well as intrinsic and
      peptide-stimulated nucleotide hydrolysis in the presence of hydrolyzable
      nucleoside triphosphates ATP, CTP, UTP, and GTP. We observed that the k(cat) of
      peptide cleavage decreases with the reduction in the nucleotide binding affinity
      of Lon in the following order: ATP > CTP > GTP approximately UTP. Compared to
      those of the other hydrolyzable nucleotide triphosphates, the ATPase activity of
      Lon is also the most sensitive to peptide stimulation. Collectively, our kinetic
      as well as tryptic digestion data suggest that both nucleotide binding and
      hydrolysis contribute to the peptidase turnover of Lon. The kinetic data that
      were obtained were further put into the context of the structural organization of
      Lon protease by probing the conformational change in Lon bound to the different
      nucleotides. Both adenine-containing nucleotides and CTP protect a 67 kDa
      fragment of Lon from tryptic digestion. Since this 67 kDa fragment contains the
      ATP binding pocket (also known as the alpha/beta domain), the substrate sensor
      and discriminatory (SSD) domain (also known as the alpha-helical domain), and the
      protease domain of Lon, we propose that the binding of ATP induces a
      conformational change in Lon that facilitates the coupling of nucleotide
      hydrolysis with peptide substrate delivery to the peptidase active site.

PMID- 15182187
TI  - Calmodulin involvement in stress-activated nuclear localization of albumin in JB6
      epithelial cells.
AB  - We report that albumin is translocated to the nucleus in response to oxidative
      stress. Prior measurements have demonstrated that in concert with known
      transcription factors albumin binds to an antioxidant response element, which
      controls the expression of glutathione S-transferase and other antioxidant
      enzymes that function to mediate adaptive cellular responses [Holderman, M. T.,
      Miller, K. P., Dangott, L. J., and Ramos, K. S. (2002) Mol. Pharmacol. 61, 1174
      1183]. To investigate the mechanisms underlying this adaptive cell response, we
      have identified linkages between calcium signaling and the nuclear translocation
      of albumin in JB6 epithelial cells. Under resting conditions, albumin and the
      calcium regulatory protein calmodulin (CaM) co-immunoprecipitate using antibodies
      against either protein, indicating a tight association. Calcium activation of CaM
      disrupts the association between CaM and albumin, suggesting that transient
      increases in cytosolic calcium levels function to mobilize intracellular albumin
      to facilitate its translocation into the nucleus. Likewise, nuclear translocation
      of albumin is induced by exposure of cells to hydrogen peroxide or a phorbol
      ester, indicating a functional linkage between reactive oxygen species, calcium,
      and PKC-signaling pathways. Inclusion of an antioxidant enzyme (i.e., superoxide
      dismutase) blocks nuclear translocation, suggesting that the oxidation of
      sensitive proteins functions to coordinate the adaptive cellular response. These
      results suggest that elevated calcium transients and associated increases in
      reactive oxygen species contribute to adaptive cellular responses through the
      mobilization and nuclear translocation of cellular albumin.

PMID- 15182188
TI  - Reversible refolding of the diphtheria toxin T-domain on lipid membranes.
AB  - The catalytic domain of diphtheria toxin (DT) is translocated across endosomal
      membranes by the T-domain (DTT) in response to acidification. Understanding the
      energetics of translocation, besides clarifying the mechanism of translocation,
      should provide insights into general principles of membrane protein stability and
      assembly. As a first step, we have evaluated the energetics of DTT binding to
      lipid vesicles using three single-cysteine mutants (L350C, Q369C, and Y280C)
      labeled with a 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) fluorophore sensitive to
      polarity changes. Remarkably strong association with the vesicles was detected
      for all mutants, even at pH 7 at which DTT is believed to be in a fully folded
      membrane-incompetent state. Lowering the pH in the presence of anionic membranes
      resulted in a strong but reversible increase in emission of NBD-labeled mutants,
      consistent with reversible membrane insertion. This reversibility permitted free
      energies of DTT interactions with vesicles to be determined for the first time.
      Free energy values for the three mutants ranged from -8 to -10 kcal mol(-1) at pH
      4.3 and from -7 to -8 kcal mol(-1) at pH 7. Insights into the disposition of DTT
      on membranes were obtained using a novel hydropathy analysis that considers the
      relative free energies of transmembrane and interfacial interactions as a
      function of pH. This analysis suggests that interactions at the membrane
      interface dominate pH-triggered insertion of DTT, implying that the folding
      pathway involves interfacial intermediates.

PMID- 15182189
TI  - Structural characterization of fish egg vitelline envelope proteins by mass
      spectrometry.
AB  - The extracellular coat, or vitelline envelope (VE), of rainbow trout
      (Oncorhynchus mykiss) eggs consists of three proteins, called VEalpha (M(r)
      approximately 52 kDa), VEbeta (M(r) approximately 48 kDa), and VEgamma (M(r)
      approximately 44 kDa). Each of these proteins is related to mammalian egg zona
      pellucida (ZP) glycoproteins ZP1-3 and possesses an N-terminal signal sequence, a
      ZP domain, and a protease cleavage site near the C-terminus. VEalpha and VEbeta
      also have a trefoil domain. All three proteins possess a relatively large number
      of cysteine residues (VEalpha, 18; VEbeta, 18; VEgamma, 12), of which 8 are
      present in the ZP domain and 6 are present in the trefoil domain of VEalpha and
      VEbeta. Here, several types of mass spectrometry were employed, together with gel
      electrophoresis of chemical and enzymatic digests, to identify intramolecular
      disulfide linkages, as well as the N- and C-terminal amino acids of VEalpha,
      VEbeta, and VEgamma. Additionally, these methods were used to characterize two
      high molecular weight proteins (HMWPs; M(r) > 110 kDa) of rainbow trout VEs that
      are heterodimers of individual VE proteins. These analyses have permitted
      assignment of disulfide linkages and identification of N- and C-terminal amino
      acids for the VE proteins and determination of the protein composition of two
      forms of HMWPs. These experiments provide important structural information about
      fish egg VE proteins and filaments and about structural relationships between
      extracellular coat proteins of mammalian and nonmammalian eggs.

PMID- 15182190
TI  - Mid- to low-frequency Fourier transform infrared spectra of S-state cycle for
      photosynthetic water oxidation in Synechocystis sp. PCC 6803.
AB  - Flash-induced Fourier transform infrared (FTIR) difference spectra for the four
      step S-state cycle and the effects of global (15)N- and (13)C-isotope labeling on
      the difference spectra were examined for the first time in the mid- to low
      frequency (1200-800 cm(-1)) as well as the mid-frequency (1700-1200 cm(-1))
      regions using photosystem (PS) II core particles from cyanobacterium
      Synechocystis sp. PCC 6803. The difference spectra clearly exhibited the
      characteristic vibrational features for each transition during the S-state
      cycling. It is likely that the bands that change their sign and intensity with
      the S-state advances reflect the changes of the amino acid residues and protein
      matrices that have functional and/or structural roles within the oxygen-evolving
      complex (OEC). Except for some minor differences, the trends of S-state
      dependence in the 1700-1200 cm(-1) frequency spectra of the PS II cores from
      Synechocystis were comparable to that of spinach, indicating that the structural
      changes of the polypeptide backbones and amino acid side chains that occur during
      the oxygen evolution are inherently identical between cyanobacteria and higher
      plants. Upon (13)C-labeling, most of the bands, including amide I and II modes
      and carboxylate stretching modes, showed downward shifts; in contrast, (15)N
      labeling induced isotopic shifts that were predominantly observed in the amide II
      region. In the mid- to low-frequency region, several bands in the 1200-1140 cm(
      1) region were attributable to the nitrogen- and/or carbon-containing group(s)
      that are closely related to the oxygen evolution process. Specifically, the
      putative histidine ligand exhibited a band at 1113 cm(-1) which was affected by
      both (15)N- and (13)C-labeling and showed distinct S-state dependency. The light
      induced bands in the 900-800 cm(-1) region were downshifted only by (13)C
      labeling, whereas the bands in the 1000-900 cm(-1) region were affected by both
      (15)N- and (13)C-labeling. Several modes in the mid- to low-frequency spectra
      were induced by the change in protonation state of the buffer molecules
      accompanied by S-state transitions. Our studies on the light-induced spectrum
      showed that contributions from the redox changes of Q(A) and the non-heme iron at
      the acceptor side and Y(D) were minimal. It was, therefore, suggested that the
      observed bands in the 1000-800 cm(-1) region include the modes of the amino acid
      side chains that are coupled to the oxidation of the Mn cluster. S-state
      dependent changes were observed in some of the bands.

PMID- 15182191
TI  - Characterization of YvcC (BmrA), a multidrug ABC transporter constitutively
      expressed in Bacillus subtilis.
AB  - The involvement of transporters in multidrug resistance of bacteria is an
      increasingly challenging problem, and most of the pumps identified so far use the
      protonmotive gradient as the energy source. A new member of the ATP-binding
      cassette (ABC) family, known in Bacillus subtilis as YvcC and homologous to each
      half of mammalian P-glycoprotein and to LmrA of Lactococcus lactis, has been
      studied here. The yvcC gene was constitutively expressed in B. subtilis
      throughout its growth, and a knockout mutant showed a lower rate of ethidium
      efflux than the wild-type strain. Overexpression of yvcC in Escherichia coli
      allowed the preparation of highly enriched inverted-membrane vesicles that
      exhibited high transport activities of three fluorescent drugs, namely, Hoechst
      33342, doxorubicin, and 7-aminoactinomycin D. After solubilization with n-dodecyl
      beta-D-maltoside, the hexahistidine-tagged YvcC was purified by a one-step
      affinity chromatography, and its ability to bind many P-glycoprotein effectors
      was evidenced by fluorescence spectroscopy experiments. Collectively, these
      results showed that YvcC is a multidrug ABC transporter functionally active in
      wild-type B. subtilis, and YvcC was therefore renamed BmrA for Bacillus multidrug
      resistance ATP. Besides, reconstitution of YvcC into liposomes led to the
      highest, vanadate-sensitive, ATPase activity reported so far for an ABC
      transporter. Interestingly, such a high ATP hydrolysis proceeds with a positive
      cooperativity mechanism, a property only found so far with ABC importers.

PMID- 15182192
TI  - Interaction model for anthracycline activity against DNA topoisomerase II.
AB  - DNA topoisomerase II (Top2) is an essential nuclear enzyme and a target of very
      effective anticancer drugs including anthracycline antibiotics. Even though
      several aspects of drug activity against Top2 are understood, the drug receptor
      site is not yet known. Several Top2 mutants have altered drug sensitivity and
      have provided information of structural features determining drug action. Here,
      we have investigated the sensitivity to three closely related anthracycline
      derivatives of yeast Top2 bearing mutations in the CAP-like domain and integrated
      the findings with computer models of ternary drug-enzyme-DNA complexes. The
      results suggest a model for the anthracycline receptor wherein a drug molecule
      has specific interactions with the cleaved DNA as well as amino acid residues of
      the CAP-like domain of an enzyme monomer. The drug molecule is intercalated into
      DNA at the site of cleavage, and interestingly, drug-enzyme contacts involve one
      side of the four-ring chromophore and the side chain of the anthracycline
      molecule. The findings may explain several established structure-activity
      relationships of antitumor anthracyclines and may thus provide a framework for
      further developments of effective Top2 poisons.

PMID- 15182193
TI  - Repair kinetics of trans-4-hydroxynonenal-induced cyclic 1,N2-propanodeoxyguanine
      DNA adducts by human cell nuclear extracts.
AB  - trans-4-Hydroxynonenal (HNE) is a major peroxidation product of omega-6
      polyunsaturated fatty acids. The reaction of HNE with DNA produces four
      diastereomeric 1,N(2)-gamma-hydroxypropano adducts of deoxyguanosine (HNE-dG);
      background levels of these adducts have been detected in tissues of animals and
      humans. There is evidence to suggest that these adducts are mutagenic and
      involved in liver carcinogenesis in patients with Wilson's disease and in other
      human cancers. Here, we present biochemical evidence that in human cell nuclear
      extracts the HNE-dG adducts are repaired by the nucleotide excision repair (NER)
      pathway. To investigate the recognition and repair of HNE-dG adducts in human
      cell extracts, we prepared plasmid DNA substrates modified by HNE. [(32)P]
      Postlabeling/HPLC determined that the HNE-dG adduct levels were approximately
      1200/10(6) dG of plasmid DNA substrate. We used this substrate in an in vitro
      repair-synthesis assay to study the complete repair of HNE-induced DNA adducts in
      cell-free extracts. We observed that nuclear extracts from HeLa cells
      incorporated a significant amount of alpha[(32)P]dCTP in DNA that contained HNE
      dG adducts by comparison with UV-irradiated DNA as the positive control. Such
      repair synthesis for UV damage or HNE-dG adducts did not occur in XPA cell
      nuclear extracts that lack the capacity for NER. However, XPA cells complemented
      with XPA protein restored repair synthesis for both of these adducts. To verify
      that HNE-dG adducts in DNA were indeed repaired, we measured HNE-dG adducts in
      the post-repaired DNA substrates by the [(32)P]-postlabeling/HPLC method, showing
      that 50-60% of HNE-dG adducts were removed from the HeLa cell nuclear extracts
      after 3 h at 30 degrees C. The repair kinetics indicated that the excision rate
      is faster than the rate of gap-filling/DNA synthesis. Furthermore, the HNE-dG
      adduct isomers 2 and 4 appeared to be repaired more efficiently at early time
      points than isomers 1 and 3.

PMID- 15182194
TI  - Identification of hydrophobic interactions between proteins and lipids: free
      fatty acids activate phospholipase C delta1 via allosterism.
AB  - Lipids are well recognized ligands that bind to proteins in a specific manner and
      regulate their function. Most attention has been placed on the headgroup of
      phospholipids, and little is known about the role of the acyl chains in mediating
      any effects of lipids on proteins. In this report, free fatty acids (FFA) were
      found to bind and activate phospholipase C delta1(PLC delta1). The unsaturated
      FFA arachidonic acid (AA) and oleic acid were able to stimulate PLC delta1 up to
      30-fold in a dose-dependent manner. The saturated FFA stearic acid and palmitic
      acid were less efficacious than unsaturated FFA, activating the enzyme up to 8
      fold. The mechanism of activation appears to be due to a change in K(m) for
      substrate; 50 microM arachidonate reduced the K(m) for the soluble PLC substrate
      diC(4)PI from 1.7 +/- 0.6 mM to 0.24 +/- 0.04 mM (7-fold reduction). V(max) was
      not significantly altered. PLC delta1 bound to sucrose-loaded vesicles that
      contained AA in a concentration-dependent manner. A fragment of PLC delta1 that
      encompasses the EF-hand domain also bound to micelles containing AA using
      nondenaturing PAGE. This same fragment also inhibited AA activation of PLC delta1
      in a competition assay. These results suggest that the function of the EF-hand
      domain of PLC delta1 is to bind lipid and to allosterically regulate catalysis.
      These results also suggest that esterified and nonesterified fatty acids can bind
      to and regulate protein function, identifying a functional role for hydrophobic
      interactions between lipids and proteins.

PMID- 15182195
TI  - On the mechanism of a mutated and abnormally functioning gamma-aminobutyric acid
      (A) receptor linked to epilepsy.
AB  - A recent report indicates that a lysine-to-methionine mutation (K289M) in the
      gamma2 subunit of a human gamma-aminobutyric acid neurotransmitter receptor, the
      GABA(A) receptor, is linked to generalized epilepsy with febrile seizures [Baulac
      et al. (2001) Nat. Genet. 28, 46-48]. This mutation caused a decreased current
      response to GABA [Baulac et al. (2001) Nat. Genet. 28, 46-48]. Here we determine
      changes that occur in the mechanism of opening and closing of transmembrane
      channels formed by the GABA(A) receptor as a result of this mutation. The K289M
      mutation was introduced into the gamma2L subunit of the rat GABA(A) receptor, and
      the mutated subunit was coexpressed with the alpha1 and beta2 subunits in HEK293
      cells. Transient kinetic techniques suitable for investigating reactions on cell
      surfaces with a microsecond-to-millisecond time resolution [Hess, G. P., and
      Grewer, C. (1998) Methods Enzymol. 291, 443-473] were used. They allow one to
      determine not only the channel-opening probability and rates of receptor
      desensitization but also the opening and closing rates of the mutated GABA(A)
      receptor channel. The channel-opening equilibrium constant of the mutated
      receptor was found to be 5-fold lower than that of the wild type. We calculated
      that this decrease in the channel-opening equilibrium accounts for the
      dysfunction of the mutated receptor. We discuss how a knowledge of the mechanism
      of the mutated receptor indicates an approach for alleviating this dysfunction.

PMID- 15182196
TI  - Desensitization and internalization of metabotropic glutamate receptor 1a
      following activation of heterologous Gq/11-coupled receptors.
AB  - In this study we characterized the heterologous desensitization and
      internalization of the metabotropic glutamate receptor 1 (mGluR1) splice variants
      mGluR1a and mGluR1b following activation of endogenous G(q/11)-coupled receptors
      in HEK293 cells. Agonist activation of M1 muscarinic acetylcholine or P2Y1
      purinergic receptors triggered the PKC- and CaMKII-dependent internalization of
      mGluR1a. In co-immunoprecipitation studies, both glutamate and carbachol
      increased the association of GRK2 with mGluR1a. Co-addition of the protein kinase
      C (PKC) inhibitor GF109203X and the Ca(2+) calmodulin-dependent kinase II
      (CaMKII) inhibitor KN-93 blocked the ability of glutamate and carbachol to
      increase the association of GRK2 with mGluR1a. Glutamate also increased the
      association of GRK2 with mGluR1b, whereas carbachol did not. However, unlike
      mGluR1a, glutamate-stimulated association of GRK2 with mGluR1b was not reduced by
      PKC/CaMKII inhibition. Pretreatment of cells expressing mGluR1a or mGluR1b with
      carbachol rapidly desensitized subsequent glutamate-stimulated inositol phosphate
      accumulation. The carbachol-induced heterologous desensitization and
      internalization of mGluR1a was blocked by LY367385, an mGluR1a antagonist with
      inverse agonist activity. Furthermore, LY367385 blocked the ability of carbachol
      to increase the association of GRK2 with mGluR1a. On the other hand, LY367385 had
      no effect on the carbachol-induced desensitization and internalization of the
      nonconstitutively active mGluR1b splice variant. These results demonstrate that
      the internalization of mGluR1a, triggered homologously by glutamate or
      heterologously by carbachol, is PKC/CaMKII-, GRK2-, arrestin-, and clathrin
      dependent and that PKC/CaMKII activation appears to be necessary for GRK2 to
      associate with mGluR1a. Furthermore, the heterologous desensitization of mGluR1a
      is dependent upon the splice variant being in an active conformation.

PMID- 15182197
TI  - EHD2 interacts with the insulin-responsive glucose transporter (GLUT4) in rat
      adipocytes and may participate in insulin-induced GLUT4 recruitment.
AB  - Insulin-induced GLUT4 recruitment to the plasma membrane involves GLUT4
      trafficking through multiple subcellular compartments regulated by multiple
      proteins, many of which are yet to be identified. Here we describe a 65 kDa
      protein found in purified GLUT4 vesicles of rat adipocytes as a potential GLUT4
      traffic regulatory protein. On the basis of MALDI-TOF MS, RT-PCR, gene cloning,
      protein sequencing, and immunoreactivity data, we identified this protein as
      EHD2, a member of the EH domain-containing proteins that have been implicated in
      vesicle trafficking. EHD2 in rat adipocytes was 85% membrane-associated,
      including approximately 10% in immunopurified GLUT4 vesicles. This association of
      EHD2 with GLUT4 vesicles occurred in PM and three distinct endosomal fractions
      and was not significantly affected by cellular insulin treatment. In co
      immunoprecipitation experiments, however, EHD2 physically interacted with GLUT4
      in each of these fractions, and cellular insulin treatment selectively enhanced
      this interaction in an endosomal fraction thought to contain GLUT4 exocytic
      vesicles. EHD2 also interacted with the clathrin adaptor middle chain subunit
      micro(1), micro(2), and rCALM in GST pull-down experiments. Significantly, an
      affinity-purified EHD2 antibody and a peptide corresponding to the EHD2 sequence
      Glu(428)-Glu(535) drastically (by 75% and 35%, respectively) suppressed the
      insulin-induced increase in the plasma membrane GLUT4 contents in SLO
      permeabilized rat adipocytes without affecting the basal GLUT4 distribution.
      These findings strongly suggest that EHD2 interacts with GLUT4 in rat adipocytes
      and may play a key role in insulin-induced GLUT4 recruitment to the plasma
      membrane.

PMID- 15182198
TI  - 1,4-Benzoquinone is a topoisomerase II poison.
AB  - Benzene is a human carcinogen that induces hematopoietic malignancies. It is
      believed that benzene does not initiate leukemias directly, but rather generates
      DNA damage through a series of phenolic metabolites, especially 1,4-benzoquinone.
      The cellular consequences of 1,4-benzoquinone are consistent with those of
      topoisomerase II-targeted drugs. Therefore, it has been proposed that the
      compound initiates specific leukemias by acting as a topoisomerase II poison.
      This hypothesis, however, has not been supported by in vitro studies. While 1,4
      benzoquinone has been shown to inhibit topoisomerase II catalysis, increases in
      enzyme-mediated DNA cleavage have not been reported. Because of the potential
      involvement of topoisomerase II in benzene-induced leukemias, we re-examined the
      effects of the compound on DNA cleavage mediated by human topoisomerase IIalpha.
      In contrast to previous reports, we found that 1,4-benzoquinone was a strong
      topoisomerase II poison and was more potent in vitro than the anticancer drug
      etoposide. DNA cleavage enhancement probably was unseen in previous studies due
      to the presence of reducing agents in reaction buffers and the incubation of 1,4
      benzoquinone with the enzyme prior to the addition of DNA. 1,4-Benzoquinone
      increased topoisomerase II-mediated DNA cleavage primarily by enhancing the
      forward rate of scission. In vitro, the compound induced cleavage at DNA sites
      proximal to a defined leukemic chromosomal breakpoint and displayed a sequence
      specificity that differed from that of etoposide. Finally, 1,4-benzoquinone
      stimulated DNA cleavage by topoisomerase IIalpha in cultured human cells. The
      present findings are consistent with the hypothesis that topoisomerase IIalpha
      plays a role in the initiation of specific leukemias induced by benzene and its
      metabolites.

PMID- 15182199
TI  - Contribution of the esterified amino acid to the binding of aminoacylated tRNAs
      to the ribosomal P- and A-sites.
AB  - Crystallographic studies suggest that the esterified amino acid of aminoacyl tRNA
      make contacts with the ribosomal A-site but not in the P-site. Biochemical
      evidence indicating a thermodynamic contribution of the esterified amino acid to
      binding aminoacyl-tRNA to either the ribosomal P- and A-sites has been
      inconsistent, partly because of the labile nature of the aminoacyl linkage and
      the long times required to reach equilibrium. Measuring the association and
      dissociation rates of deacylated and aminoacylated tRNAs to the A-site and P-site
      of E. coli ribosomes afforded an accurate estimate of the contribution of the
      amino acid. While esterified phenylalanine or methionine has no effect on the
      affinity of tRNA to the P-site, an esterified pheylalanine stabilizes binding to
      the A-site by 7 kJ/mol, in agreement with the contacts observed in the X-ray
      crystal structure. In addition, it was shown that the presence of an esterified
      amino acid in one ribosomal site does not affect the binding of an aa-tRNA to the
      other site.

PMID- 15182200
TI  - Sp1-targeted inhibition of gene transcription by WP631 in transfected
      lymphocytes.
AB  - The binding of Sp1 transcription factor to DNA is considered a potential target
      for small ligands designed to interfere with gene transcription. We attempted to
      distinguish the direct inhibition of the Sp1-binding to DNA in vivo (cell
      culture) from more indirect effects due to the network of pathways that modulate
      cell cycle progression, which may decrease transcription without direct
      interference with Sp1-DNA interactions. We tested whether the Sp3 protein, whose
      putative binding sequence overlaps the Sp1 site, can inhibit Sp1-activated
      transcription and interfere with drug-DNA interactions. A well-characterized
      model system consisting of a wtGLUT1 (wild-type glucose transporter 1) gene
      promoter, or a mutated mut2GLUT1 promoter, linked to a CAT (chloramphenicol
      acetyltransferase) reporter gene, was used to analyze the effects of
      overexpressed Sp1 and Sp3 transcription factors in transiently transfected Jurkat
      T lymphocytes. Bisanthracycline WP631, a potent inhibitor of Sp1-activated
      transcription in vitro, was assayed for its ability to specifically inhibit
      transcription in transfected Jurkat T lymphocytes. The mut2GLUT1 promoter was
      used to further discriminate between the WP631 interference with Sp1-DNA
      complexes and Sp3-induced inhibition, since the Sp3-binding site is canceled in
      this promoter and replaced by a high-affinity binding site for WP631.

PMID- 15182201
TI  - Allosteric modification of factor XIa functional activity upon binding to
      polyanions.
AB  - The effects of several polyanions on the hydrolysis of the chromogenic substrate
      L-pyroglutamyl-L-prolyl-L-arginyl-p-nitroaniline (S-2366) and on the activation
      of factor IX by factor XIa have been investigated. Two forms of dextran sulfate
      (M(r) approximately 500000 and M(r) approximately 10000, DX10) and two forms of
      heparin (64 disaccharide units, M(r) approximately 14000, and hypersulfated
      heparin, S-Hep, M(r) approximately 12000) inhibited both factor XIa amidolytic
      activity and factor IX activation in a concentration-dependent manner. The
      inhibitory effect was not due to binding of either substrate by the polyanions
      since only a decrease in V(max) without any effect on K(m) was observed in
      kinetic assays. Steric inhibition is unlikely since the concentrations of
      polyanions required for inhibition of small peptide hydrolysis were lower than
      those required for macromolecular substrate cleavage. In contrast, an allosteric
      inhibitory mechanism was supported by an enhancement of the dansyl fluorescence
      of 5-(dimethylamino)-1-(naphthalenesulfonyl)glutamylglycylarginyl- (DEGR-) factor
      XIa observed when the fluorophore was in complex with either DX10 or S-Hep.
      Moreover, in the presence of a polyanion the fluorophore was far more resistant
      to quenching by acrylamide. These results provide compelling evidence that factor
      XIa binding to the polyanions, dextran sulfate and heparin, results in inhibition
      of the enzyme by an allosteric mechanism.

PMID- 15182202
TI  - The nature of the hydrophobic n-alkanol binding site within the C1 domains of
      protein kinase Calpha.
AB  - The activator-binding sites within the C1 domains of protein kinase C (PKC) are
      also able to bind alcohols and anesthetics. In this study, the nature of the
      interaction of these agents with the hydrophobic region within the C1 domains was
      investigated and a structure-activity relationship for the alcohol effects was
      obtained. The effects of a series of n-alkanols on PKCalpha activity, determined
      using an in vitro assay system that lacked lipids, were found to be a nonlinear
      function of the chain length. In the absence of phorbol ester or diacylglycerol,
      1-octanol potently activated PKCalpha in a concentration-dependent manner, while
      1-heptanol was completely without effect, despite differing by one methylene
      unit. The minimal structural requirement for the activating effect corresponded
      to R-CH(OH)-(CH(2))(n)-CH(3), where R = H or an alkyl group and n >or= 6.
      Consistent with this, 2-octanol, for which n = 5, was without effect on the
      activity, even though this alcohol is only marginally less hydrophobic than 1
      octanol, whereas 2-nonanol, for which n = 6, was able to produce activity.
      Importantly, it was found that PKCalpha was activated to a greater extent by R-2
      nonanol than by the S enantiomer. The potentiation of phorbol ester-induced,
      membrane-associated PKCalpha activity by long-chain n-alkanols reported
      previously (Slater, S. J., Kelly, M. B., Larkin, J. D., Ho, C, Mazurek, A,
      Taddeo, F. J., Yeager, M. D., Stubbs, C. D. (1997) J. Biol. Chem. 272, 6167
      6173), was also found here for nonmembrane associated PKC, indicating that this
      effect is an intrinsic property of the enzyme rather than a result of membrane
      perturbation. Overall, the results suggest that the alcohol-binding sites within
      the C1 domains of PKCalpha contain spatially distinct hydrophilic and hydrophobic
      regions that impose a high degree of structural specificity on the interactions
      of alcohols and other anesthetic compounds, as well as diacylglycerols and
      phorbol esters.

PMID- 15182203
TI  - Characterization of Mycobacterium tuberculosis NAD kinase: functional analysis of
      the full-length enzyme by site-directed mutagenesis.
AB  - NAD kinase is the only known enzyme catalyzing the formation of NADP, a coenzyme
      implicated in most reductive biosynthetic reactions and in many antioxidant
      defense systems. Despite its importance, nothing is known regarding its structure
      or mechanism of catalysis. Mycobacterium tuberculosis NAD kinase has been
      overexpressed in Escherichia coli and purified to homogeneity. The molecular and
      kinetic properties of the enzyme resulted in significant differences from those
      reported by others on a proteolytically degraded form of the protein. Indeed the
      full-length enzyme displays an allosteric behavior and shows a strict preference
      for inorganic polyphosphate as the phosphate donor. It is inhibited by the
      reaction product NADP and by both NADH and NADPH. The mycobacterial enzyme shares
      with all other known NAD kinases a highly conserved region (spanning residues 189
      210), particularly rich in glycines, which differs from the primary sequences of
      all previously identified nucleotide-binding sites. Alanine-scanning mutagenesis
      performed on 11 conserved residues within this domain revealed its importance in
      catalysis. A total of 6 of 11 mutated proteins completely lost the enzymatic
      activity while retaining the same oligomeric state of the wild-type protein, as
      demonstrated by gel-filtration analysis. Substitutions of S199 and G208 with
      alanine rendered enzyme versions with reduced activity. Their kinetic
      characterization, performed on purified proteins, revealed kinetic parameters
      toward ATP and polyphosphate similar to those of the wild-type enzyme. On the
      contrary, when the kinetic analysis was performed by using NAD as the variable
      substrate, significant differences were observed with respect to both the
      allosteric behavior and the catalytic efficiency, suggesting that the mutated
      region is likely involved in NAD binding.

PMID- 15182204
TI  - L-Aspartate semialdehyde and a 6-deoxy-5-ketohexose 1-phosphate are the
      precursors to the aromatic amino acids in Methanocaldococcus jannaschii.
AB  - No orthologs are present in the genomes of the archaea encoding genes for the
      first two steps in the biosynthesis of the aromatic amino acids leading to 3
      dehydroquinate (DHQ). The absence of these genes prompted me to examine the
      nature of the reactions involved in the archaeal pathway leading to DHQ in
      Methanocaldococcus jannaschii. Here I report that 6-deoxy-5-ketofructose 1
      phosphate and l-aspartate semialdehyde are precursors to DHQ. The sugar, which is
      derived from glucose 6-P, supplies a "hydroxyacetone" fragment, which, via a
      transaldolase reaction, undergoes an aldol condensation with the l-aspartate
      semialdehyde to form 2-amino-3,7-dideoxy-D-threo-hept-6-ulosonic acid. Despite
      the fact that both hydroxyacetone and hydroxyacetone-P were measured in the cell
      extracts and confirmed to arise from glucose 6-P, neither compound was found to
      serve as a precursor to DHQ. This amino sugar then undergoes a NAD dependent
      oxidative deamination to produce 3,7-dideoxy-d-threo-hept-2,6-diulosonic acid
      which cyclizes to 3-dehydroquinate. The protein product of the M. jannaschii
      MJ0400 gene catalyzes the transaldolase reaction and the protein product of the
      MJ1249 gene catalyzes the oxidative deamination and the cyclization reactions.
      The DHQ is readily converted into dehydroshikimate and shikimate in M. jannaschii
      cell extracts, consistent with the remaining steps and genes in the pathway being
      the same as in the established shikimate pathway.

PMID- 15182205
TI  - The region adjacent to the highly immunogenic site and shielded by the middle
      domain is responsible for self-oligomerization/client binding of the HSP90
      molecular chaperone.
AB  - We here investigated the mechanism of self-oligomerization of the 90-kDa heat
      shock protein (HSP90) molecular chaperone, because it is known that this
      oligomerization reflects the client-binding activity. The transition temperatures
      for the self-oligomerization of the full-length forms of human HSP90alpha and
      HtpG (bacterial HSP90), i.e., 45 and 60 degrees C, respectively, were identical
      to those for the dissociation of the recombinant N domain (residues 1-400 of
      human HSP90alpha and residues 1-336 of HtpG in our definition) from the remainder
      of the molecule. The N domain of human HSP90alpha expressed in Escherichia coli
      was oligomeric, and the oligomerization activity was localized within residues
      311-350, i.e., C-terminally adjacent to the highly immunogenic site (residues 291
      304). Particularly, residues 341-350 were critical on oligomerization. On the
      other hand, residues 289-389 were indispensable for the interaction with the M
      domain (residues 401-618) of the molecule. Oligomer formation of the N domain was
      efficiently suppressed by its extension until Lys546, i.e., residues 401-546,
      which is required for the interaction with the N domain. Among highly conserved
      amino acids at residues 289-400, Trp297, Pro379, and Phe384 were essential for
      the interaction with the M domain. With these observations taken together, we
      propose as the activation mechanism of HSP90 molecular chaperone that heat stress
      induces the liberation of the oligomerization/client-binding site of residues 311
      350 by disrupting the intramolecular interaction between residues 289-389 and 401
      546.

PMID- 15182206
TI  - The mechanism of action of the fragile histidine triad, Fhit: isolation of a
      covalent adenylyl enzyme and chemical rescue of H96G-Fhit.
AB  - The human fragile histidine triad protein Fhit catalyzes the Mg(2+)-dependent
      hydrolysis of P(1)-5'-O-adenosine-P(3)-5'-O-adenosine triphosphate, Ap(3)A, to
      AMP and ADP. The reaction is thought to follow a two-step mechanism, in which the
      complex of Ap(3)A and Mg(2+) reacts in the first step with His96 of the enzyme to
      form a covalent Fhit-AMP intermediate and release MgADP. In the second step, the
      intermediate Fhit-AMP undergoes hydrolysis to AMP and Fhit. The mechanism is
      inspired by the chain-fold similarities of Fhit to galactose-1-phosphate
      uridylyltransferase, which functions by an analogous mechanism, and the
      observation of overall retention in configuration at phosphorus in the action of
      Fhit (Abend, A., Garrison, P. N., Barnes, L. D., and Frey, P. A. (1999)
      Biochemistry 38, 3668-3676). Direct evidence in support of this mechanism is
      reported herein. Reaction of Fhit with [8,8'-(3)H]-Ap(3)A and denaturation of the
      enzyme in the steady state leads to protein-bound tritium corresponding to 11% of
      the active sites. Similar experiments with the poor substrate MgATP leads to 0.9%
      labeling. The mutated protein H96G-Fhit is completely inactive against MgAp(3)A.
      However, it is chemically rescued by free histidine. H96G-Fhit also catalyzes the
      hydrolysis of adenosine-5'-phosphoimidazolide, AMP-Im, and of adenosine-5'
      phospho-N-methylimidazolide, AMP-N-MeIm. The hydrolyses of AMP-Im and of AMP-N
      MeIm by H96G-Fhit are thought to represent chemical rescue of the covalent Fhit
      AMP intermediate. Wild-type Fhit is also found to catalyze the hydrolyses of AMP
      Im and of AMP-N-MeIm nearly as efficiently as the hydrolysis of MgAp(3)A. The
      results indicate that Mg(2+) in the reaction of Ap(3)A is required for the first
      step, the formation of the covalent intermediate Fhit-AMP, and not for the
      hydrolysis of the intermediate in the second step.

PMID- 15182208
TI  - Guidelines for community-acquired pneumonia: are they reflected in practice?
AB  - Community-acquired pneumonia (CAP) is common, costly, and clinically serious.
      Several national and international practice guidelines have been developed to
      promote more appropriate, cost-effective care for patients with CAP. This article
      compares and contrasts eight international practice guidelines for the management
      of CAP, describes the extent to which recommendations are reflected in practice,
      and proposes explanations for non-adherence to guidelines. We found consistency
      in recommendations across all the guidelines for the management of patients with
      CAP requiring intensive care. In this setting, all guidelines recommend chest
      radiography, sputum Gram stain and culture, blood cultures, testing for
      Legionella pneumophila, and timely administration of antibiotics active against
      both typical (i.e. Streptococcus pneumoniae, Hemophilus influenzae) and atypical
      organisms (i.e. Legionella spp., Mycoplasma pneumoniae, and Chlamydia
      pneumoniae). Recommendations for the management of the average inpatient with
      pneumonia were more variable, with the greatest differences between the North
      American and European guidelines. The North American guidelines (in contrast to
      European ones), recommended empiric treatment of typical and atypical organisms
      in all inpatients. There were also differences in policies regarding the
      necessity of chest radiography, sputum studies, and serologic testing. Some
      guidelines explicitly embrace the use of prediction rules to inform the decision
      to hospitalize, while others do not. Some of these admission decision algorithms
      focus on identifying low risk patients, while others are most concerned with high
      risk patients. There was also considerable variation in the specificity and
      operationalization of clinical criteria for switching from parenteral to oral
      antibiotics or judging appropriateness for discharge. Many recommendations for
      key management decisions tended to lack explicit, objective, and actionable
      criteria that could be easily implemented in real world practice. Review of the
      pneumonia literature revealed that physician performance of guideline-recommended
      best practices is often suboptimal. Administration of timely antibiotics (< or =8
      hours of presentation) and use of first-line antibiotics occurred in 75-85% and
      18-79% of cases, respectively. Collection of blood cultures within 24 hours of
      presentation and prior to administration of antibiotics was achieved in 69-83%
      and 63-82% of cases, respectively. Screening the eligibility of CAP patients for
      hospital-based pneumococcal and influenza vaccination occurred on average in 11
      and 14% of hospitalizations, respectively, in the US. Lack of awareness of
      guidelines, conflicting advice among them, and lack of specific, objective,
      actionable recommendations most likely contribute to nonadherence to CAP
      guidelines. Increased attention to these factors will be needed if professional
      society practice guidelines are to fulfill their promise as tools for improving
      the quality and outcomes of care for patients with pneumonia.

PMID- 15182207
TI  - Functional reconstitution into proteoliposomes and partial purification of a rat
      liver ER transport system for a water-soluble analogue of
      mannosylphosphoryldolichol.
AB  - Mannosylphosphoryldolichol (Man-P-Dol) is synthesized on the cytosolic leaflet of
      the rough endoplasmic reticulum (ER), and functions as a mannosyl donor in the
      biosynthesis of Glc(3)Man(9)GlcNAc(2)-P-P-Dol after being translocated to the
      lumenal leaflet. An assay, based on the transport of Man-P-citronellol (Man-P
      Dol(10)), a water-soluble analogue of Man-P-Dol(95), into sealed microsomal
      vesicles, has been devised to identify protein(s) (flippases) that could mediate
      the thermodynamically unfavorable movement of Man-P-Dol between the two leaflets
      of the ER. To develop a defined system for the systematic investigation of the
      properties of the Man-P-Dol(10) transporter, and as an initial step toward
      purification of the protein(s) involved in the transport of Man-P-Dol(10), the
      activity has been solubilized from rat liver microsomes with n-octyl-beta-D
      glucoside and reconstituted into proteoliposomes (approximately 0.1 microm in
      diameter). The properties of the reconstituted Man-P-Dol(10) transport system are
      similar to the Man-P-Dol(10) uptake activity in microsomal vesicles from rat
      liver. Man-P-Dol(10) transport into reconstituted proteoliposomes is time
      dependent, reversible, saturable, and stereoselective. The direct role of ER
      proteins in the functionally reconstituted transport system is supported by the
      inhibitory effects of trypsin treatment, 4,4'-diisothiocyanatostilbene-2,2'
      disulfonic acid (DIDS), or diethylpyrocarbonate (DEPC). Solubilization and
      functional reconstitution are shown to provide an experimental approach to the
      partial purification of the protein(s) mediating the transport process.

PMID- 15182209
TI  - Nitric oxide synthase inhibition: therapeutic potential in asthma.
AB  - Nitric oxide (NO) is synthesized from L-arginine in the human respiratory tract
      by enzymes of the NO synthase (NOS) family. Levels of NO in exhaled air are
      increased in asthma, and measurement of exhaled NO has been advocated as a
      noninvasive tool to monitor the underlying inflammatory process. However, the
      relation of NO to disease pathophysiology is uncertain, and in particular the
      fundamental question of whether it should be viewed primarily as beneficial or
      harmful remains unanswered. Exogenously administered NO has both bronchodilator
      and bronchoprotective properties. Although it is unlikely that NO is an important
      regulator of basal airway tone, there is good evidence that endogenous NO release
      exerts a protective effect against various bronchoconstrictor stimuli. This
      response is thought to involve one or both of the constitutive NOS isoforms,
      endothelial NOS (eNOS) and neuronal NOS (nNOS). Therefore, inhibition of these
      enzymes is unlikely to be therapeutically useful in asthma and indeed may worsen
      disease control. On the other hand, the high concentrations of NO in asthma,
      which are believed to reflect upregulation of inducible NOS (iNOS) by
      proinflammatory cytokines, may produce various deleterious effects. These include
      increased vascular permeability, damage to the airway epithelium, and promotion
      of inflammatory cell infiltration. However, the possible effects of iNOS
      inhibition on allergic inflammation in asthma have not yet been described and
      studies in animal models have yielded inconsistent findings. Thus, the evidence
      to suggest that inhibition of iNOS would be a useful therapeutic strategy in
      asthma is limited at present. More definitive information will require studies
      combining agents that potently and specifically target individual NOS isoforms
      with direct measurement of inflammatory markers.

PMID- 15182210
TI  - Redefining treatment in COPD: new directions in bronchodilator therapy.
AB  - COPD is a growing international health concern and it is estimated that by the
      year 2020 it will rank fifth as a cause of disability worldwide. In response to
      this problem, the World Health Organization and the US National Institutes of
      Health convened a panel of experts to draft a consensus strategy to treat
      patients with COPD. Called the Global Initiative for Chronic Obstructive Lung
      Disease (GOLD) guidelines, they are designed to define and stage the severity of
      COPD, make recommendations for treatment, and to expand global awareness of the
      disease. The GOLD guidelines describe a multimodality approach to provide optimal
      care for the COPD patient population. This includes respiratory and
      rehabilitative therapy, nutrition services, psychosocial counseling, and surgical
      care. Bronchodilators form the cornerstone of pharmacologic treatment for COPD.
      These medications can significantly lessen dyspnea, enhance quality of life,
      increase airflow, and improve exercise performance. While bronchodilators
      decrease airway resistance and lessen hyperinflation in patients with COPD, they
      have not been shown to influence the decline in FEV1 over time or improve
      survival in this patient population. Recently, long-acting beta2-adrenoceptor
      agonists (beta2-agonists) such as formoterol and salmeterol and anticholinergic
      medications including tiotropium bromide have been developed which may further
      improve symptom management in COPD patients. This article discusses
      bronchodilator pharmacologic therapy for patients with COPD focusing on beta2
      agonists, anticholinergics, and methylxanthines in the light of the recent GOLD
      consensus statements.

PMID- 15182211
TI  - Chronic rhinosinusitis: management for optimal outcomes.
AB  - Chronic rhinosinusitis is characterized by nasal purulence accompanied by
      malaise, postnasal drip and nasal dryness or crusting. It is a condition that is
      very difficult to treat and can be very disabling to the patients. A clinical
      diagnosis is based on history and evaluation with endoscopy, and computerized
      tomographic scanning. The etiology of chronic rhinosinusitis is multifactorial
      and comprises a vicious cycle of pathophysiological, anatomical, and constitutive
      factors. Predisposing factors include ciliary impairment, allergy, nasal
      polyposis, and immune deficiency. Treatment is aimed at reducing mucosal
      inflammation and swelling, controlling infection, and restoring aeration of the
      nasal and sinus mucosa. The choice of treatment is influenced by many factors
      including past medication, duration of symptoms and the presence of allergy/nasal
      polyps. Pharmacologic treatment, with local or systemic corticosteroids such as
      mometasone furoate, fluticasone propionate, beclometasone dipropionate or oral
      prednisolone coupled with nasal lavage with isotonic saline solutions are the
      cornerstones of disease management. Systemic antibiotics including
      amoxicillin/clavulanic acid, ciprofloxacin, clarithromycin, and
      trimethoprim/sulfamethoxazole (cotrimoxazole) are often administered to patients
      with chronic sinusitis and underlying bacterial infection. In patients with
      underlying allergy, additional treatment with antihistamines should be
      considered. Aeration of the sinuses may temporarily be improved with local nasal
      decongestants such as oxymetazoline. If symptoms persist after aggressive medical
      treatment, surgery should be considered. Surgery should be functional and involve
      widening the natural drainage openings of the sinuses and preserving the ciliated
      epithelium as much as possible. In the case of nasal polyposis surgery is more
      aggressive involving removal of the diseased polypous mucosa. It is recommended
      that medical treatment should be continued post sinus surgery.

PMID- 15182212
TI  - Obstructive sleep apnea syndrome in children: a state-of-the-art review.
AB  - Snoring and obstructive sleep apnea are a frequent problem not only in adults,
      but also in children and adolescents, as can be seen from current epidemiological
      data. The epidemiology, etiology, diagnosis, and management of obstructive sleep
      apnea syndrome (OSAS) in adults have been adequately established on the basis of
      evidential data. As a result of this, both physicians and the public are
      increasingly aware of OSAS in adults. Although there are numerous parallels
      between pediatric and adult OSAS, the situation in children differs that in
      adults. There is a greater variety of symptoms in children with OSAS, diagnosis
      is often more difficult with serious consequences for growth and development of
      children. Treatment of OSAS in children is also different from that of the adult
      patient. There are many possible causes for the development of obstructive sleep
      apnea in children. These include hypertrophy of the tonsils and syndromes such as
      Down syndrome, Pickwickian syndrome, Prader-Willi syndrome or Marfan syndrome.
      OSAS can, however, also be the result of obesity, midfacial dysplasia, retro- or
      micrognathia, allergic rhinitis or muscular dystrophy. Epidemiological data
      presented in the literature concerning the incidence of OSAS in children is
      extremely varied. This wide range is probably due to the fact that snoring may be
      misdiagnosed as OSAS. The diagnosis of OSAS in children may only be made by
      considering clinical history (such as rate of growth, tendency to fall asleep
      during the day, sleep disturbances, susceptibility to infection, etc.),
      polysomnography (if possible during several nights) and accompanying instrumental
      diagnosis including cephalometry or laryngoscopy. One of the problems of
      polysomnography in childhood is that performance and interpretation of the
      results have not yet been standardized or evaluated for different age groups.
      Treatment depends on the cause of OSAS and require multidisciplinary management
      involving the pediatrician, pediatric or adolescent psychiatrist, ear, nose, and
      throat specialist, maxillofacial surgeons, and neurosurgeons. Adenotonsillectomy
      (ATE) is the therapy generally chosen if the child has adenoidal vegetations
      and/or tonsillar hypertrophy. Corrective surgery is possible for rare
      malformation syndromes. Nocturnal masks for continuous positive airway nasal
      pressure or procedures for mask respiration are effective in children, but are
      only used in exceptional cases, such as when ATE is contraindicated or when
      symptoms of OSAS remain after surgery. The success of pharmacological treatment
      of OSAS in children has not been evaluated in controlled clinical trials.

PMID- 15182213
TI  - Hospital-acquired pneumonia in critically ill patients: mortality risk
      stratification upon onset.
AB  - STUDY OBJECTIVES: To identify, in patients experiencing hospital-acquired
      pneumonia (HAP), prognostic factors present at disease onset and build an
      algorithm capable of stratifying mortality risk upon HAP onset. DESIGN:
      Observational cohort from January 1994 to December 2001. SETTING: One intensive
      care unit (ICU) from a university-affiliated, urban teaching hospital. PATIENTS:
      All consecutive patients exhibiting bacteriologically documented HAP either on
      ICU admission or during ICU stay. INTERVENTIONS: Data collection and multivariate
      analysis using Chi-Square Automatic Interaction and Detection technique. RESULTS:
      168 patients were studied. The overall mean mortality rate was 49.4%. Upon onset
      of HAP, five independent variables allowed binary stratification of mortality
      risk. These consisted of underlying diseases (nonfatal versus ultimately and
      rapidly fatal diseases), Simplified Acute Physiology Score II (less than versus >
      or =37), platelet count (less than versus > or =150,000/mm3), chest x-ray
      involvement (1 versus >1 lobe), and PaO2/FiO2 (less than versus > or =167 mm Hg).
      A branching algorithm consisting of these five variables identified patients with
      HAP at both low (<35%) and high (>75%) risk of mortality. CONCLUSION: Mortality
      in ICU patients with HAP may be predicted early, upon onset of HAP, by the
      cumulative use of prognostic factors in an algorithm.

PMID- 15182215
TI  - The National Service Framework for Older People: England's approach to ending age
      discrimination in services and therapeutics.
AB  - In 1997, the new Labour Government in the UK embarked on an ambitious programme
      of reform. One of the key changes has been the publication of a series of
      National Service Frameworks. The National Service Framework for Older People
      (NSFOP) sets out a 10-year programme that has as its principal standard rooting
      out age discrimination. Together with its companion documents, a series of robust
      milestones and standards are set out that have to be met. Although generally
      welcomed by the profession, the NSFOP has been criticised by some because it
      mandates the initiation of new 'intermediate care' services that may be seen as
      denying older people the opportunity for admission to mainstream hospital care.
      Monitoring tools covering both procedures and prescribing have been developed.
      The government-produced frameworks mirror guidelines produced by the profession
      and include a number of prescribing recommendations, e.g. the use of
      antihypertensives and aspirin (acetylsalicylic acid) in the prevention of stroke,
      and the use of calcium, vitamin D and bisphosphonates in the treatment of
      osteoporosis. In tackling age discrimination, both direct and indirect barriers
      to effective prescribing need to be considered. The evidence base on the
      effectiveness of medication in older people is more limited due to the previous
      systematic exclusion of older people from clinical trials. The consequent lack of
      evidence of efficacy, coupled with perhaps a natural reluctance to prescribe
      potentially toxic medication, may lead to underprescribing. Other indirect causes
      of age discrimination may include difficulties for older people attending
      hospitals for drug monitoring, and the difficulties of translating the results of
      trials into meaningful endpoints that older patients can understand and thus make
      valid decisions about whether they wish to take the particular drug or not. At
      the same time as the NSFOP argues against age discrimination, other government
      policies may operate in a contradictory manner. Examples include the trend to
      make drugs available over the counter in pharmacies and for which the patient has
      to pay rather than receive them free, the restriction of some prescription-only
      drugs from the health service, and the need for referral to specialist services
      for some drugs, e.g. sildefanil, which older people may be reluctant to access.
      Successfully combating age discrimination is likely to require a regulatory
      framework, continued monitoring, tackling indirect forms of discrimination, as
      well as embedding antidiscrimination policies in all facets of health education.

PMID- 15182214
TI  - Over-the-counter analgesics in older adults: a call for improved labelling and
      consumer education.
AB  - The use of analgesics increases with age and on any given day 20-30% of older
      adults take an analgesic medication. Over-the-counter (OTC) analgesics are
      generally well tolerated and effective when taken for brief periods of time and
      at recommended dosages. However, their long-term use, use at inappropriately high
      doses, or use by persons with contraindications may result in adverse effects,
      including gastrointestinal haemorrhage, cardiovascular toxicity, renal toxicity
      and hepatotoxicity. Many OTC drugs are also available through a prescription, for
      a broader range of indications and for longer durations of use and wider dose
      ranges, under the assumption that healthcare providers will help patients make
      safe choices about analgesics. Safe and effective use of medications is one of
      the greatest challenges faced by healthcare providers in medicine. More than 60%
      of people cannot identify the active ingredient in their brand of pain reliever.
      Additionally, about 40% of Americans believe that OTC drugs are too weak to cause
      any real harm. As a result of a recent US FDA policy, the conversion of
      prescription to OTC medications will result in a 50% increase of OTC medications.
      To reduce the risks of potential adverse effects from OTC drug therapy in older
      adults, we propose that the use of analgesics will be enhanced through the use of
      patient and healthcare provider education, as well as improved labelling of OTC
      analgesics. Improved labelling of OTC analgesics may help consumers distinguish
      common analgesic ingredients in a wide variety of preparations and facilitate
      informed decisions concerning the use of OTC drugs.

PMID- 15182216
TI  - Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies
      for prevention.
AB  - Achieving target glycaemic goals while avoiding hypoglycaemia is a major
      challenge in the management of elderly patients with diabetes mellitus. Repeated
      episodes of hypoglycaemia may cause extreme emotional distress in such patients,
      even when the episodes are relatively mild. Moreover, evidence is mounting that
      hypoglycaemia among elderly patients is a very real and costly health concern.
      The strongest predictors of severe hypoglycaemia in the elderly are advanced age,
      recent hospitalisation and polypharmacy. Education is the key to preventing
      recurrent or severe hypoglycaemia. As such, there should be close coordination of
      care between the patient, physician and all other healthcare providers in
      identifying the cause of hypoglycaemia in elderly patients, and appropriate steps
      should be taken to prevent further episodes. Prevention of hypoglycaemia has the
      potential to improve psychosocial aspects of elderly health, including enhanced
      quality of life, boosted confidence, improved compliance with antidiabetic
      regimens and avoidance of long-term complications. Since the elderly population
      represents a unique group, it is imperative to focus on the aetiologies that are
      exclusive to this group. Advanced age itself is a risk factor for hypoglycaemia,
      and elderly patients with comorbidities are at increased risk when they are
      hospitalised. Elderly patients with diabetes often have compromised renal
      function, which intereferes with drug elimination and thus predisposes them to
      prolonged life-threatening hypoglycaemia. In addition, patients on five or more
      prescription medications are prone to drug-associated hypoglycaemia. Although
      sulfonylurea-associated hypoglycaemia is common, drugs such as ACE inhibitors and
      nonselective beta-adrenoceptor antagonists can also predispose patients to
      hypoglycaemia. Greater attention should be paid to the avoidance of hypgolycaemia
      in nursing home residents. Recurrent hypoglycaemia in elderly patients is not
      only detrimental to achieving good glycaemic control, it is also a substantial
      economic burden. Once the causes of hypoglycaemia have been identified, it is
      crucial to formulate and institute a prevention plan. Firstly, global evaluation
      of the patient should be carried out to identify possible predisposing risk
      factors. Secondly, target glycaemic goals should be tailored to each patient.
      Thirdly, selection of antidiabetic agents should be judicious, then patients and
      family should be educated to recognise and treat hypoglycaemia. Finally,
      coordinated care should be provided to identify, treat and prevent hypoglycaemia.

PMID- 15182217
TI  - Time course of response to antidepressants in late-life major depression:
      therapeutic implications.
AB  - In the treatment of depression, there is considerable interest in the time course
      of response and, in particular, the speed with which individuals recover from
      depressive episodes. Examination of the time course and speed of response is
      critical for assessing the usefulness of specific treatments. However, while this
      issue has received attention in mid-life adult populations, it has received
      little consideration in the context of late-life major depression. The synthesis
      of empirical reports indicates that, while older adults with depression seem to
      respond with the same speed as mid-life adults, several factors have consistently
      been associated with reduced speed of response to antidepressant treatment,
      including greater severity of depressive symptoms and co-occurring anxiety
      symptoms. Limited evidence suggests that sleep impairment and genetic factors
      (e.g. presence of the s allele of the serotonin transporter gene promoter region)
      may also be associated with reduced speed of response. Some factors have
      consistently been found to be unrelated to speed of response (demographic
      characteristics, nonpsychiatric physical illnesses) whereas other factors have
      only mixed evidence supporting any effect (psychosocial and other clinical
      factors). While there is little work available to date, some evidence suggests
      that time course and speed of response affect longer-term outcomes of depression
      pharmacotherapy; thus, older adults with more rapid versus slower patterns of
      response may differ in the types of maintenance treatment needed to avert
      additional depressive episodes. None of potential strategies for accelerating
      speed of response have been clearly shown to be effective in late-life
      depression. Future treatment studies for late-life depression should routinely
      consider not only overall efficacy of a given pharmacotherapy (i.e. total rate of
      response), but time course and speed of response. To this end, new investigations
      must be designed to overcome the methodological limitations of prior studies that
      have examined time course and they should include a range of potential covariates
      and outcomes of between-patient differences in speed of response. Better
      understanding of factors related to such differences may suggest new intervention
      strategies to accelerate response.

PMID- 15182218
TI  - SSRIs and intraocular pressure modifications: evidence, therapeutic implications
      and possible mechanisms.
AB  - SSRIs are the most commonly prescribed antidepressant drugs, in part because of
      their favourable safety profile compared with older antidepressants. However, the
      widespread use of SSRIs leads to an increased occurrence of rare adverse effects.
      This review, based on data from published experimental research, clinical studies
      and case reports, describes the role of serotonin in the control of intraocular
      pressure (IOP) and the evidence for IOP modifications in patients receiving
      SSRIs. In a small percentage of patients with depression, the cause of SSRI
      withdrawal has been the occurrence of ill-defined visual disturbances. It can be
      speculated that in some of these patients, the iatrogenic ocular alterations
      could have been due to changes in IOP. There have also been a limited number of
      case reports of acute attacks of glaucoma occurring during treatment with SSRIs.
      Although causality is not exactly specified, the relationship between SSRIs and
      this ocular adverse event is strongly implied. Nevertheless, in a small clinical
      study assessing the effect of a single dose of fluoxetine on IOP, the drug was
      shown to increase this parameter, although the effect was asymptomatic. The
      clinical signs of unexpected adverse drug effects are often disregarded, with the
      exception of those characterised by serious symptoms (such as acute angle-closure
      glaucoma in the case of IOP modifications). Also, the distribution of
      iridocorneal angle configurations in the general population implies that an
      adverse effect on IOP will be pauci- or asymptomatic in most patients
      (intermittent, sub-acute or progressive angle-closure glaucoma). As a result, it
      is likely that the incidence of SSRI-related IOP modifications is underestimated.
      Until the involvement of SSRIs in IOP modifications is better understood,
      ophthalmological consultations should be considered before starting and during
      treatment with any SSRI in patients with glaucomatous risk factors, especially
      those who are elderly.

PMID- 15182220
TI  - New formulations of existing antidepressants: advantages in the management of
      depression.
AB  - For nearly 50 years, antidepressant drugs have been the first-line treatment for
      various forms of depression. Despite their widespread use, these medications have
      significant shortcomings, in particular problems of patient compliance due to
      adverse effects. The introduction of new formulations of existing antidepressant
      medications may provide patients with benefits in terms of convenience of use. As
      a consequence, improvements in compliance may lead to better antidepressant
      efficiency.An orally disintegrating formulation of mirtazapine (mirtazapine
      SolTab), a once-weekly formulation of fluoxetine, an enantiomer-specific
      formulation of citalopram (escitalopram), an extended-release formulation of
      venlafaxine (venlafaxine XR), a controlled-release formulation of paroxetine
      (paroxetine CR) and intravenous formulations of some of the newer antidepressants
      have all been evaluated in limited clinical trials. In this article, a review of
      the pharmacokinetics and clinical evaluations of these formulations is presented.
      While there do not appear to be major clinical advantages for the new
      formulations in terms of antidepressant efficacy, none of them is less
      efficacious than their older counterpart. Indeed, some of the new formulations
      are more acceptable to patients (fluoxetine once-weekly, paroxetine CR), others
      have pharmacokinetic advantages (venlafaxine XR, paroxetine CR), while others may
      have a faster onset of effect (mirtazapine SolTab, intravenous formulations).
      Further evaluation of some formulations is still required (mirtazapine SolTab,
      fluoxetine once-weekly), while others (venlafaxine XR, escitalopram) are finding
      widespread acceptance in clinical practice.

PMID- 15182219
TI  - Pharmacotherapy of alcohol dependence: a review of the clinical data.
AB  - Over the last 20 years, the role of adjuvant pharmacotherapy in optimising
      outcome in rehabilitation programmes for alcohol-dependent patients has become
      increasingly evident. New avenues for rational drug treatment have arisen from
      better understanding of the neurobiological substrates of alcohol dependence,
      including adaptive changes in amino acid neurotransmitter systems, stimulation of
      dopamine and opioid peptide systems, and, possibly, changes in serotonergic
      activity. Disulfiram, naltrexone and acamprosate are currently the only
      treatments approved for the management of alcohol dependence. However, there is
      still no unequivocal evidence from randomised controlled clinical trials that
      disulfiram improves abstinence rates over the long term. Aversive therapy with
      disulfiram is not without risk for certain patients, and should be closely
      supervised. Both naltrexone and acamprosate improve outcome in rehabilitation of
      alcohol-dependent patients, but seem to act on different aspects of drinking
      pathology. Naltrexone is thought to decrease relapse to heavy drinking by
      attenuating the rewarding effects of alcohol. However, data from the naltrexone
      clinical trial programme are somewhat inconsistent, with several large studies
      being negative. Acamprosate is believed to maintain abstinence by blocking the
      negative craving that alcohol-dependent patients experience in the absence of
      alcohol. The clinical development programme has involved a large number of
      patients and studies, of which the vast majority have shown a beneficial effect
      of acamprosate on increasing abstinence rates. Both drugs are generally well
      tolerated; nausea is reported by around 10% of patients treated with naltrexone,
      while the most frequent adverse effect reported with acamprosate is diarrhoea.
      Another opioid receptor antagonist, nalmefene, has shown promising activity in
      pilot studies, and may have a similar profile to naltrexone. Data from studies of
      SSRIs in alcohol dependence are somewhat heterogeneous, but it appears that these
      drugs may indirectly improve outcome by treating underlying depression rather
      than affecting drinking behaviour per se. Similarly, the anxiolytic buspirone may
      act by ameliorating underlying psychiatric pathology. Dopaminergic neuroleptics,
      benzodiazepines and antimanic drugs have not yet demonstrated evidence of
      activity in large controlled clinical trials. Trials with drugs acting at
      serotonin receptors have yielded disappointing results, with the possible
      exception of ondansetron. Because the biological basis of alcohol dependence
      appears to be multifactorial, the future of management of alcoholism may be
      combination therapy, using drugs acting on different neuronal pathways, such as
      acamprosate and naltrexone. Pharmacotherapy should be used in association with
      appropriate psychosocial support and specific treatment provided for any
      underlying psychiatric comorbidities.

PMID- 15182222
TI  - Properties of neurotoxic peptides related to the Bri gene.
AB  - Familial British dementia, a rare autosomal dominant neurodegenerative disorder,
      shares features with Alzheimer's disease, including amyloid plaque deposits,
      neurofibrillary tangles, neuronal loss,progressive dementia, but clinically
      presents with additional physical defects [1,2]. A mutation in the termination
      codon of the BRI gene produces a BRI precursor protein 11 amino acids longer than
      the wild-type protein [3,4]. Mutant and wild-type precursor proteins both may
      undergo furin cleavage between residues 243 and 244, producing a peptide of 34
      amino acids in the case of ABri and 23 amino acids long in the case of the wild
      type peptide. The ABri 4kDa peptide is the main component of the amyloid deposits
      found in familial British dementia brains. A decamer duplication in the 3- region
      of the BRI gene originates the peptide Adan that is associated with dementia in
      Familial Danish dementia (FDD), similar to BDD clinically, but with additional
      hearing and eyesight loss [5]. The resulting reading frame is extended to 277
      amino acid residues, and cleavage by furin releases a peptide of 34 residues,
      which is identical to Abri and WT in its N-terminal 22-residues, but contains a
      distinct C-terminal 10 residues composed of mainly hydrophobic residues. Here we
      demonstrate that C-terminal extensions of Abri and Adan are required to elongate
      initially-formed dimers to neurotoxic soluble oligomers and fibrils. In contrast,
      the shorter wild-type peptide does not aggregate under the same conditions and is
      not toxic. Conformational analyses indicate triple-beta-sheet structures. Soluble
      nonfibrillar oligomers of oxidised ABri and reduced Adan were observed in
      solution (pH7.4) of peptides prior to the appearance of mature fibrils.

PMID- 15182223
TI  - Oligomers on the brain: the emerging role of soluble protein aggregates in
      neurodegeneration.
AB  - Extracellular fibrous amyloid deposits or intracellular inclusion bodies
      containing abnormal protein fibrils characterize many different neurodegenerative
      diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), dementia
      with Lewy bodies, multiple system atrophy, Huntington's disease, and the
      transmissible 'prion' dementias. There is strong evidence from genetic,
      transgenic mouse and biochemical studies to support the idea that the
      accumulation of protein aggregates in the brain plays a seminal role in the
      pathogenesis of these diseases. How monomeric proteins ultimately convert to
      highly polymeric deposits is unknown. However, studies employing, synthetic, cell
      derived and purified recombinant proteins suggest that amyloid proteins first
      come together to form soluble low n-oligomers. Further association of these
      oligomers results in higher molecular weight assemblies including so-called
      'protofibrils' and 'ADDLs' and these eventually exceed solubility limits until,
      finally, they are deposited as amyloid fibrils. With particular reference to AD
      and PD, we review recent evidence that soluble oligomers are the principal
      pathogenic species that drive neuronal dysfunction.

PMID- 15182221
TI  - Interferon-beta-1b: a review of its use in relapsing-remitting and secondary
      progressive multiple sclerosis.
AB  - Interferon-beta-1b (Betaseron, Betaferon) is a non-glycosylated recombinant human
      interferon-beta approved for high-frequency, subcutaneous (SC) administration in
      the treatment of multiple sclerosis (MS). Its mechanism of action is unknown, but
      may involve modulation of the autoimmune pathogenic processes of MS. In a
      randomised, double-blind trial in patients with relapsing-remitting MS (RRMS), SC
      interferon-beta-1b 250 micro g (8 million International Units [MIU]) every other
      day reduced the annual relapse rate and increased the proportion of relapse-free
      patients compared with placebo. It also reduced relapse severity,
      hospitalisations, and disease activity assessed by magnetic resonance imaging
      (MRI), and increased the time to first relapse. Progression of disability showed
      a trend towards reduction relative to placebo and baseline, but did not reach
      statistical significance. SC interferon-beta-1b 250 micro g every other day was
      shown in a randomised trial to be superior to intramuscular (IM) interferon-beta
      1a 30 micro g (6 MIU) once weekly with respect to reductions in relapse-related
      parameters, disability progression and MRI-assessed disease activity. In patients
      with secondary progressive MS (SPMS), SC interferon-beta-1b 250 micro g every
      other day slowed progression of the disease relative to placebo in one
      randomised, double-blind trial, but not in another. In both studies, interferon
      beta-1b 250 micro g recipients had fewer relapses and less MRI-assessed disease
      activity than placebo recipients. The difference in primary outcome may reflect
      differences in patient entry criteria. Interferon-beta-1b is generally well
      tolerated and the common adverse events (e.g. injection site reactions, asthenia
      and an influenza-like symptom complex) are clinically manageable. In a randomised
      trial, the tolerability of SC interferon-beta-1b 250 micro g every other day was
      generally similar to that of IM interferon-beta-1a 30 micro g once weekly, except
      for higher incidences of injection site reactions and neutralising anti
      interferon-beta antibodies with SC interferon-beta-1b. In conclusion, SC
      interferon-beta-1b 250 micro g every other day reduces the frequency and severity
      of relapses and MRI measures of disease activity and may delay the progression of
      disability in RRMS. The drug appeared to be more effective than, and as well
      tolerated as, IM interferon-beta-1a 30 micro g once weekly. Interferon-beta-1b
      also has positive effects on relapse rates and disease activity in patients with
      SPMS, although its effects on disease progression remain uncertain. The drug is
      generally well tolerated, and the common adverse events are clinically
      manageable. Thus, interferon-beta-1b is a valuable first-line therapy for
      patients with RRMS and a potentially useful option in those with SPMS.

PMID- 15182225
TI  - Polyglutamine and neurodegeneration: structural aspects.
AB  - Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused
      by proteins with expanded polyQ regions. Although the pathological mechanisms of
      these diseases have not yet been elucidated, the processes of protein misfolding
      and aggregation seem to be a direct cause of neurodegeneration. Detailed
      structural information on polyQ proteins is therefore essential in order to
      understand the mechanisms underlying pathogenesis and to design therapeutic
      strategies. In the past decade, several studies have investigated the structural
      properties of polyQ proteins and the molecular basis of aggregation and fibre
      formation. The results obtained in these studies are reviewed here.

PMID- 15182224
TI  - Alpha-synuclein and the pathogenesis of Parkinson's disease.
AB  - Lesions known as Lewy bodies (LBs) and Lewy neurites (LNs) characterise brains of
      Parkinson's disease (PD) patients. Intracellular aggregation of alpha-synuclein
      (alpha-syn) appears to play a key role in the generation of LBs and LNs. Such
      aggregation in the presence of redox metals may initiate Fenton reaction-mediated
      generation of reactive oxygen species (ROS). ROS thus generated may result in
      cytotoxic mechanisms such as the induction of DNA single-strand breaks.

PMID- 15182226
TI  - Experimental approaches to TSE prevention via inhibition of prion formation.
AB  - Transmissible spongiform encepahalopathies (TSEs) are fatal diseases that damage
      the central nervous system. TSEs are unique in that they may be inherited,
      infectious or spontaneous. The central pathogenic agent is thought to be a
      conformationally distinct form (PrP(Sc;)) of the endogenous prion
      protein(PrP(c)), which is high in beta-sheet content and is resistant to
      proteases; infectivity is thought to involve formation of PrP(Sc) via imprinting
      of abnormal conformation on the normal form of the protein (PrP(c)) by seeds of
      PrP(Sc). A number of compounds found to inhibit the conversion of PrP(c) to
      PrP(Sc) have been proposed as therapeutics to halt TSEs.

PMID- 15182227
TI  - Induction of cellular oxidative stress by the beta-amyloid peptide involved in
      Alzheimer's disease.
AB  - Beta-amyloid, the 39-43 amino acid peptide fragment originating from amyloid
      precursor protein, is today, generally accepted as the biological entity
      responsible for causing the debilitating human disorder Alzheimer's disease.
      Understanding the exact biological effects of beta-amyloid in vitro and in vivo
      is clearly important to provide therapeutic strategies for the disease. Recent in
      vitro studies have focused on the production of reactive oxygen species by
      aggregating beta-amyloid, but the cellular effects of beta-amyloid induced
      reactive oxygen species production have not been fully elucidated.

PMID- 15182228
TI  - Alpha-synuclein aggregation.
AB  - Alpha-synuclein is a major component of Lewy bodies in Parkinson's disease and is
      found associated with several other forms of dementia. As with other
      neurodegenerative diseases, the ability of alpha-synuclein to aggregate and form
      fibrillar deposits seems central to its pathology. We have defined a sequence
      within the NAC region of alpha-synuclein that is necessary for aggregation.
      Exploitation of chemically modified analogues of this peptide may produce
      inhibitors of aggregation.

PMID- 15182229
TI  - PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling
      complex.
AB  - mAKAP (muscle-selective A-kinase-anchoring protein) co-ordinates a cAMP-sensitive
      negative-feedback loop comprising PKA (cAMP-dependent protein kinase) and the
      cAMP-selective PDE4D3 (phosphodiesterase 4D3). In vitro and cellular experiments
      demonstrate that PKA-phosphorylation of PDE4D3 on Ser-13 increases the affinity
      of PDE4D3 for mAKAP. Our data suggest that activation of mAKAP-anchored PKA
      enhances the recruitment of PDE4D3, allowing for quicker signal termination.

PMID- 15182230
TI  - Catalytic and structural contributions for glutathione-binding residues in a
      Delta class glutathione S-transferase.
AB  - Glutathione S-transferases (GSTs) are dimeric proteins that play a major role in
      cellular detoxification. The GSTs in mosquito Anopheles dirus species B, an
      important malaria vector in South East Asia, are of interest because they can
      play an important role in insecticide resistance. In the present study, we
      characterized the Anopheles dirus (Ad)GST D3-3 which is an alternatively spliced
      product of the adgst1AS1 gene. The data from the crystal structure of GST D3-3
      shows that Ile-52, Glu-64, Ser-65, Arg-66 and Met-101 interact directly with
      glutathione. To study the active-site function of these residues, alanine
      substitution site-directed mutagenesis was performed resulting in five mutants:
      I52A (Ile-52-->Ala), E64A, S65A, R66A and M101A. Interestingly, the E64A mutant
      was expressed in Escherichia coli in inclusion bodies, suggesting that this
      residue is involved with the tertiary structure or folding property of this
      enzyme. However, the I52A, S65A, R66A and M101A mutants were purified by
      glutathione affinity chromatography and the enzyme activity characterized. On the
      basis of steady-state kinetics, difference spectroscopy, unfolding and refolding
      studies, it was concluded that these residues: (1) contribute to the affinity of
      the GSH-binding site ('G-site') for GSH, (2) influence GSH thiol ionization, (3)
      participate in kcat regulation by affecting the rate-limiting step of the
      reaction, and in the case of Ile-52 and Arg-66, influenced structural integrity
      and/or folding of the enzyme. The structural perturbations from these mutants are
      probably transmitted to the hydrophobic-substrate-binding site ('H-site') through
      changes in active site topology or through effects on GSH orientation. Therefore
      these active site residues appear to contribute to various steps in the catalytic
      mechanism, as well as having an influence on the packing of the protein.

PMID- 15182232
TI  - Multiplex PCR-single-base extension genotyping of multiple glutathione S
      transferase polymorphisms.
AB  - Identification of genetic polymorphisms has recently gained increased interest,
      since they can be used as markers to identify the genes that predispose to
      disease. This emerging role of genetic polymorphism in clinical association has
      created the need for high-throughput genotyping methodologies. The present study
      describes the development of an SBE (single-base extension) methodology for the
      parallel identification of genetic polymorphisms in glutathione S-transferase
      genes, a superfamily of phase II drug-metabolizing enzymes. Oligonucleotide PCR
      primers were designed for simultaneous amplification of GSTM1, GSTP1 and GSTT1
      gene loci SBE primers were also designed to be specific for each loci and to stop
      one nucleotide 5'-upstream of the polymorphic location. A specific tag was
      associated with each SBE primer to guarantee further discrimination by length.
      After simultaneous amplification of the target gene loci from genomic DNA
      extracted from human blood samples, SBE reactions were performed with
      fluorescently labelled dideoxynucleotide triphosphates. Individual genotypes were
      identified after separation of each tag-SBE probe by PAGE. The multiplex/SBE
      methodology was validated with previously genotyped DNA samples extracted from 21
      individuals and it was used in a blind assay to genotype additional 64
      individuals. The results show that SBE leads to the same results as the current
      'gold standard' restriction-fragment-length-polymorphism-based genotyping
      methodologies, since SBE is a robust and accurate genotyping methodology that
      enables the parallel identification of multiple polymorphisms in the same
      reaction.

PMID- 15182231
TI  - Mammalian and Drosophila cells adhere to the laminin alpha4 LG4 domain through
      syndecans, but not glypicans.
AB  - We have previously shown that the LG4 (laminin G-like) domain of the laminin
      alpha4 chain is responsible for the significantly higher affinity of the alpha4
      chain to heparin than found for other alpha chains [Yamaguchi, Yamashita, Mori,
      Okazaki, Nomizu, Beck and Kitagawa (2000) J. Biol. Chem. 275, 29458-29465]; four
      basic residues were identified to be essential for this activity [Yamashita, Beck
      and Kitagawa (2004) J. Mol. Biol. 335, 1145-1149]. By creating GST (glutathione S
      transferase)-fused LG1, LG2, LG4 and LG5 proteins, we found that only LG4 is
      active for the adhesion of human HT1080 cells, human umbilical vein endothelial
      cells and Drosophila haemocytes Kc167 with a half-saturating concentration of 20
      microg/ml. Adhesion was counteracted by treatment of the cells with heparin,
      heparan sulphate and heparitinase I. Upon mutating the four basic residues
      essential for heparin binding within LG4, the adhesion activity was abolished.
      Pull-down experiments using glutathione beads/GST-fusion proteins indicate a
      direct interaction of LG4 with syndecan-4, which might be the major receptor for
      cell adhesion. Neither the release of glypican-1 by treating human cells with
      phosphatidylinositol-specific phospholipase C nor targeted knockdown of dally or
      dally-like protein impaired the cell-adhesion activity. As the LG4-LG5 domain of
      the alpha4 chain is cleaved in vivo from the main body of laminin-8
      (alpha4beta1gamma1), we suggest that the heparan sulphate proteoglycan-binding
      activity of LG4 is significant in modulating the signalling of Wnt,
      Decapentaplegic and fibroblast growth factors.

PMID- 15182233
TI  - Glycosynthase-catalysed formation of modified polysaccharide microstructures .
AB  - Glycosynthases are mutant glycosidases, genetically engineered to catalyse the
      synthesis of oligosaccharides. A study by Faijes et al. in this issue of the
      Biochemical Journal has expanded the ability of glycosynthases to catalyse the
      polymerization of carbohydrates to form unnatural oligosaccharide products that
      can attain unique crystalline forms. These findings reinforce the potential of
      glycosynthases as interesting and important tools for the enzymic synthesis of
      novel carbohydrates with specific and controlled structures.

PMID- 15182234
TI  - Insulin signalling: putting the 'G-' in protein-protein interactions.
AB  - Cell signalling via receptor tyrosine kinases, such as the insulin receptor, and
      via heterotrimeric G-proteins, such as Galpha(i), Galpha(s) and Galpha(q) family
      members, constitute two of most avidly studied paradigms in cell biology. That
      elements of these two populous signalling pathways must cross-talk to achieve
      proper signalling in the regulation of cell proliferation, differentiation and
      metabolism has been anticipated, but the evolution of our thinking and the
      analysis of such cross-talk have lagged behind the ever-expanding troupe of
      players and the recognition of multivalency as the rule, rather than the
      exception, in signalling biology. New insights have been provided by Kreuzer et
      al. in this issue of the Biochemical Journal, in which insulin is shown to
      provoke recruitment of Galpha(i)-proteins to insulin-receptor-based complexes
      that can regulate the gain of insulin-receptor-catalysed autophosphorylation, a
      proximal point in the insulin-sensitive cascade of signalling. Understanding the
      convergence and cross-talk of signals from the receptor tyrosine kinases and G
      protein-coupled receptor pathways in physical, spatial and temporal contexts will
      remain a major challenge of cell biology.

PMID- 15182235
TI  - N-terminal pro-atrial natriuretic peptide (N-ANP) and N-terminal pro-B-type
      natriuretic peptide (N-BNP) in the prediction of death and heart failure in
      unselected patients following acute myocardial infarction.
AB  - Elevated plasma natriuretic peptide levels after AMI (acute myocardial
      infarction) are associated with adverse outcome. The aim of the present study was
      to examine the relationship of plasma N-ANP (N-terminal pro-atrial natriuretic
      peptide) and N-BNP (N-terminal pro-B-type natriuretic peptide) with mortality and
      heart failure following AMI. We studied 403 patients with AMI. Blood was sampled
      for measurement of N-ANP and N-BNP on a single occasion between 72 and 96 h after
      symptom onset. Natriuretic peptide levels were related to all-cause mortality and
      heart failure episodes. During follow up (median, 462 days; range 5-764), 43
      (10.7%), 25 (6.2%) and 49 (12.2%) patients suffered death, heart failure
      hospitalization and outpatient heart failure respectively. Only N-BNP (P <
      0.0005), N-ANP (P = 0.005) and previous AMI (P = 0.016) were independently
      predictive of death. N-BNP, but not N-ANP, predicted 30-day mortality. N-ANP, but
      not N-BNP, predicted mortality after 30 days. N-BNP was the better predictor of
      heart failure. N-ANP and N-BNP were above the median in 35 and 38 respectively,
      of 43 patients who later died. N-ANP, N-BNP, or both were above the median in 41
      out of 43 patients. Of 25 patients hospitalized with heart failure, N-ANP and N
      BNP was above the median in 20 and 24 respectively, and one or other was elevated
      in all cases. Above-median N-ANP predicted 36 and N-BNP predicted 41 out of 49
      episodes of outpatient heart failure. One or other peptide was above the median
      in 45 out of 49 patients. Our results indicate that N-BNP predicts 30-day and N
      ANP >30-day mortality. We conclude that consideration of both N-ANP and N-BNP
      identifies a greater number of patients at risk of death or heart failure than
      either peptide alone.

PMID- 15182236
TI  - Diminished L-arginine bioavailability in hypertension.
AB  - L-Arginine is the precursor of NO (nitric oxide), a key endogenous mediator
      involved in endothelium-dependent vascular relaxation and platelet function.
      Although the concentration of intracellular L-arginine is well above the Km for
      NO synthesis, in many cells and pathological conditions the transport of L
      arginine is essential for NO production (L-arginine paradox). The present study
      was designed to investigate the modulation of L-arginine/NO pathway in systemic
      arterial hypertension. Transport of L-arginine into RBCs (red blood cells) and
      platelets, NOS (NO synthase) activity and amino acid profiles in plasma were
      analysed in hypertensive patients and in an animal model of hypertension. Influx
      of L-arginine into RBCs was mediated by the cationic amino acid transport systems
      y+ and y+L, whereas, in platelets, influx was mediated only via system y+L.
      Chromatographic analyses revealed higher plasma levels of L-arginine in
      hypertensive patients (175+/-19 micromol/l) compared with control subjects (137+/
      8 micromol/l). L-Arginine transport via system y+L, but not y+, was significantly
      reduced in RBCs from hypertensive patients (60+/-7 micromol.l(-1).cells(-1).h(
      1); n=16) compared with controls (90+/-17 micromol.l(-1).cells(-1).h(-1); n=18).
      In human platelets, the Vmax for L-arginine transport via system y+L was 86+/-17
      pmol.10(9) cells(-1).min(-1) in controls compared with 36+/-9 pmol.10(9) cells(
      1).min(-1) in hypertensive patients (n=10; P<0.05). Basal NOS activity was
      decreased in platelets from hypertensive patients (0.12+/-0.02 pmol/10(8) cells;
      n=8) compared with controls (0.22+/-0.01 pmol/10(8) cells; n=8; P<0.05). Studies
      with spontaneously hypertensive rats demonstrated that transport of L-arginine
      via system y+L was also inhibited in RBCs. Our findings provide the first
      evidence that hypertension is associated with an inhibition of L-arginine
      transport via system y+L in both humans and animals, with reduced availability of
      L-arginine limiting NO synthesis in blood cells.

PMID- 15182237
TI  - Factors influencing child witnesses.
AB  - This study elucidates how professional intervention can influence children's
      abilities to report accurately about abuse experiences. Based on knowledge
      acquired through previous research and the present case study, the study shows
      how methods of information acquisition used during preliminary investigations can
      negatively affect child reports. The case study emanates from a larger study of
      193 allegedly sexually abused children. Examination of these police interviews
      shows that 55 children were interviewed more than once and their reports were
      exposed to possible professional influences before and during the preliminary
      investigation. The case study reveals the inadequate management of a child
      witness. The findings indicate that police officers and psychologists should
      avoid suggestive interventions and co-ordinate their efforts during the
      preliminary investigation in order to safeguard the children's as well as the
      suspects' legal interests. This paper points out the need for implementing
      interview interventions that can enhance children's abilities to report
      accurately about abuse experiences.

PMID- 15182238
TI  - Work values among the unemployed: changes over time and some gender differences.
AB  - Work involvement (psychological identification with work in general) has
      generally been considered as a stable, dispositional characteristic, although
      some studies of unemployment have contradicted this view. Using longitudinal data
      from a Swedish representative sample (n= 888), this study examines employment
      status change (e.g. from work to unemployment) and work values development in a
      15-month time period. Furthermore, the relationship between employment status
      change and well-being is explored, with a special focus on the roles played by
      work values and gender differences. Results indicated that work values are fairly
      stable over 15 months. As expected, the long-term unemployed (mostly active job
      seekers) had higher measures of work involvement after 15 months. Further, no
      gender difference was found with regard to work involvement but females were more
      likely to agree that there is an entitlement to work. Becoming unemployed was
      associated with negative health effects, but only among unemployed men.

PMID- 15182239
TI  - Testing Antonovsky's sense of coherence (SOC) scale among Swedish physically
      active older people.
AB  - In Antonovsky's salutogenic theory, the major concept sense of coherence (SOC) is
      constituted of three core components called comprehensibility, manageability, and
      meaningfulness. Several scales that are intended to measure SOC are available and
      used by researchers in health and caring sciences all over the world. When using
      a scale, evidence of its quality in different study groups is needed in order to
      get reliable and valid data. The aim of this study was to test reliability and
      construct validity of the Swedish version of Antonovsky's original 29-item sense
      of coherence (SOC) scale in a group of physically active older people. The scale
      was tested with a convenience sample of 140 physically active older individuals,
      who took part in different fitness-training groups in eastern Sweden. Reliability
      was assessed as item to total correlations and with the Cronbach's alpha
      coefficient. Construct validity was assessed with the known groups technique,
      confirmatory factor analysis, and with logistic regression analysis. The results
      showed that in the studied group of older individuals, the instrument was a very
      reliable tool with a Cronbach's alpha coefficient of 0.92. Construct validity of
      the scale was supported by the fact that the global concept sense of coherence
      was found to be hierarchically organized in a model that consisted of the three
      core components of comprehensibility, manageability, and meaningfulness.
      Furthermore, perceived health could be explained to some degree by sense of
      coherence, but even more by comprehensibility, in both cases independently of
      chronological age. The results clearly corroborated Antonovsky's theory.

PMID- 15182240
TI  - Internet addiction: characteristics of a questionnaire and prevalence in
      Norwegian youth (12-18 years).
AB  - The use of the Internet has increased considerably during the last few years, and
      there are also some clinical observations that some people 'get hooked', and
      develop an Internet addiction. An epidemiological study was performed in a
      representative sample of the Norwegian youth population (N= 3,237; response rate
      45.2%). The proportion not using Internet was only 4.9%, while 35.8% were non
      frequent users, and 49.6% (1,591) were frequent (weekly) users. They used the
      Internet on the mean 4.3 hours a week. A mean of 1.98% (boys 2.42%, girls 1.51%)
      could be described as having an 'Internet addiction' according to the criteria in
      the Diagnostic Questionnaire of Young (1998), and an additional 8.68% (in sum
      10.66) were considered to have an at-risk Internet use (boys 9.21%, girls 8.13%).
      If these proportions were calculated on individuals who used the Internet
      frequently, 4.02% fulfilled 5 criteria, and an additional 17.66% 3-4 criteria,
      giving quite high figures of problematic Internet use (in sum 21.68). The
      different diagnostic criteria gave a broad range of affirmative answers (from
      0.4% to 27.9%). The results have important implications for further studies of
      prevalence, implementation of preventive measures, and the development of
      treatment approaches for Internet addiction.

PMID- 15182241
TI  - Emotional effects of startling background music during reading news reports: The
      moderating influence of dispositional BIS and BAS sensitivities.
AB  - We examined the moderating influence of dispositional behavioral inhibition
      system (BIS) and behavioral activation system (BAS) sensitivities on the
      relationship of startling background music with emotion-related subjective and
      physiological responses elicited during reading news reports, and with memory
      performance among 26 adult men and women. Physiological parameters measured were
      respiratory sinus arrhythmia (RSA), electrodermal activity (EDA), and facial
      electromyography (EMG). The results showed that, among high BAS individuals, news
      stories with startling background music were rated as more interesting and
      elicited higher zygomatic EMG activity and RSA than news stories with non
      startling music. Among low BAS individuals, news stories with startling
      background music were rated as less pleasant and more arousing and prompted
      higher EDA. No BIS-related effects or effects on memory were found. Startling
      background music may have adverse (e.g., negative arousal) or beneficial effects
      (e.g., a positive emotional state and stronger positive engagement) depending on
      dispositional BAS sensitivity of an individual. Actual or potential applications
      of this research include the personalization of media presentations when using
      modern media and communications technologies.

PMID- 15182242
TI  - Maternal sensitivity behavior and infant crying, fussing and contented behavior:
      the effects of mother's experienced social support.
AB  - Maternal sensitivity behavior, mother's experienced difficulties, experienced
      social support, and the amount of infant's crying, fussing and contented behavior
      were studied when the infants were 3 and 12 months of age. Fifty-seven Finnish
      low-risk mothers' sensitivity behavior was assessed by the Parent-Child Early
      Relational Assessment method. Infant's crying behavior was assessed by the Baby's
      Day Record and by the Crying Patterns Questionnaire. The Social Support
      Questionnaires (SSQ 1 and 2) were used to evaluate mother's experienced
      difficulties and support. The infants of More Sensitive (MS) mothers were more
      contented than those with Less Sensitive (LS) mothers. The MS mothers experienced
      fewer difficulties with their infants and experienced more support from their
      best friend and their husband than LS mothers. In addition, some gender
      differences were found concerning infant behavior.

PMID- 15182243
TI  - Review of studies evaluating psychotherapy in bulimia nervosa: the influence of
      research methods.
AB  - The purpose of the study was to test if design and research methods of studies
      predict outcome results of bulimia nervosa. Fifty-seven articles on outcome of
      bulimia nervosa were found through MEDLINE and PSYCHINFO databases and 25 were
      included in the statistical analysis. Percentages of patients with a good outcome
      ranged from 24% to 74% with a mean of 51.1%. The variables best predicting
      outcome were time to follow-up and number of symptoms evaluated in definition of
      good outcome whereas dropout, design of studies, treatments, and sample
      characteristics did not predict significantly. The implications of these findings
      are discussed.

PMID- 15182244
TI  - The influence of rumination and defensiveness on negative affect in response to
      experimental stress.
AB  - Previous experiments investigating the influence of rumination on negative affect
      have often manipulated the timing and content of rumination, which may be
      problematic as rumination is phenomenologically experienced as uncontrollable. In
      the present experiment, rumination was not manipulated, but measured as an
      individual tendency before the experiment. Furthermore, it was tested whether
      defensiveness would reduce the higher degree of negative affect often associated
      with rumination. Fifty-six participants completed questionnaires measuring
      rumination and defensiveness and participated in a phrase completion task, rating
      negative affect before and after the task. Correlational analyses showed that
      rumination was positively associated (p < 0.05) with affect responses (r range =
      0.35-0.61), whereas defensiveness was negatively associated with affect responses
      (r range =-0.27-0.32). Four groups of high and low rumination and defensiveness
      scorers were created using median splits. An ANOVA showed that scoring high on
      defensiveness did not reduce the negative affect experienced by high ruminating
      participants.

PMID- 15182245
TI  - The enactment effect is due to more than guesses and beliefs.
AB  - Three experiments examined whether the enactment effect - that is, higher recall
      of enacted than of corresponding non-enacted information - might be explained by
      guessing rates and performance expectancies. Experiment 1 checked whether the
      guessing rate of target items would be higher as a result of a narrowed sampling
      space defined by the enactment condition. By means of pre-experimental
      instructions, the subjects in Experiments 2 and 3 were induced to expect
      respectively a positive enactment effect, a negative enactment effect, or no
      difference in amount of recall of enacted and non-enacted materials. Experiment 2
      had a within-subject design, Experiment 3 a between-subject design. The
      experiments failed to support the proposed explanations.

PMID- 15182246
TI  - Fairness heuristic theory is an empirical framework: a reply to Arnadottir.
AB  - In this article on fairness heuristic theory, we point out some important flaws
      in Arnadottir's (2002) claim that fairness heuristic theory is "not empirical,"
      by which Arnadottir meant that theory's predictions are knowable a priori, and
      are not contingent upon circumstances. To this end, we demonstrate that
      empirically testing effects predicted by fairness heuristic theory was and is
      important because this showed that the theory's propositions are not necessarily
      knowable a priori and are contingent upon circumstances. This implies that,
      according to Arnadottir's definition, fairness heuristic theory clearly is an
      empirical framework. It would have been helpful if Arnadottir had studied the
      fairness literature more thoroughly (as this would have easily revealed fairness
      heuristic theory to be not knowable a priori and to be contingent upon
      circumstances) and also if she had pointed out which of our studies fail to
      follow her line of reasoning. Our reply was written not as an attempt to defend
      fairness heuristic theory as we applaud, indeed are honored by, attempts to
      scrutinize our work in progress. Our only aim here was to point at some important
      flaws in the Arnadottir article, because we think these will hamper rather than
      advance the science of psychology of justice.

PMID- 15182247
TI  - Distinct functions of Vav1 in JNK1 activation in Jurkat T cells versus non
      haematopoietic cells.
AB  - Vav1, the 95-kDa protein encoded by the vav1 proto-oncogene, is expressed
      exclusively in haematopoietic cells, where it becomes phosphorylated on tyrosine
      residues in response to antigen receptor ligation. Vav1 was found to act as a
      Rac1-specific guanine nucleotide exchange factor and to activate c-Jun N-terminal
      kinase (JNK1) in vitro and in ectopic expression systems using non-haematopoietic
      cells. Here, we studied the role of Vav1 in JNK1 activation in T cells versus non
      haematopoietic cells. Vav1 overexpression activated JNK1 in COS7 and 293T cells
      but not in Jurkat T lymphocytes. In contrast, constitutively activated Rac1
      efficiently stimulated JNK1 in both cell types under the same conditions. Vav1
      did function in T cells because it clearly stimulated the activity of a nuclear
      factor of activated T-cell reporter plasmid in the same cells. Moreover, Vav1
      induction of JNK1 in T cells required coexpression with calcineurin. This
      cooperation was cell type specific because it was not observed in COS7 or 293T
      cells. In contrast, Vav1 did not cooperate with calcineurin to activate either
      extracellular signal-regulated kinase 2 or p38. These findings demonstrate that
      Vav1 alone is a poor activator of the JNK1 pathway in T cells and emphasize the
      importance of studying the physiological functions of Vav1 in haematopoietic
      cells.

PMID- 15182248
TI  - Marked prolongation of murine cardiac allograft survival using recipient immature
      dendritic cells loaded with donor-derived apoptotic cells.
AB  - We investigated whether recipient dendritic cells (DCs), pretreated with nuclear
      factor-kappaB oligodeoxyribonucleotide decoy (NF-kappaB ODN decoy) and loaded
      with ultraviolet B-irradiated donor apoptotic splenocytes (Apo-SCs), were able to
      induce murine cardiac allograft tolerance. Heterotopic vascularized heart
      transplantation was performed from BALB/c to C57BL/6 mice, and recipients
      (C57BL/6) were given one injection of recipient DCs pretreated with NF-kappaB ODN
      decoy and loaded with donor (BALB/c) apoptotic SCs (decoy Apo-SCs DCs) through
      the portal vein at 7 days, before heart transplantation in the absence of
      immunosuppression. The cardiac allograft survival time and the expressive levels
      of intragraft cytokine genes [interleukin (IL)-2, IL-10, and interferon-gamma]
      were evaluated. Our results indicated that injection of decoy Apo-SCs DCs
      significantly prolonged vascularized heart allograft survival and led to skewing
      of intragraft cytokine expression towards T helper 2 (IL-10). The mechanisms can
      be useful for therapy of allograft rejection with minimization of systemic
      immunosuppression.

PMID- 15182249
TI  - Endolysosomal processing of exogenous antigen into major histocompatibility
      complex class I-binding peptides.
AB  - An alternative endolysosomal pathway has recently been suggested for the
      processing of MHC-I-binding peptides, and peptide/MHC-I complexes have been
      demonstrated in this compartment. However, it remains unclear where in the
      antigen-presenting cells such peptides are processed, in the endolysosomes
      themselves or in the proteasomal complex. Here, we have investigated this using
      monoclonal antibodies specific for the immunodominant SIINFEKL/Kb complex (25-D1)
      or for the carbohydrate part of Db- or Kb-binding glycopeptides in combination
      with inhibitors for classical and endolysosomal MHC-I-processing pathways.
      Alternative processing was detected in both wt and TAP1(-/-) immature DC (iDC) as
      the expression of SIINFEKL/Kb complexes on the surface of OVA-treated cells in
      the presence of Brefeldin A (BFA) or lactacystin and their absence in the
      presence of the lysosomotropic amines ammonium chloride, chloroquine and
      methylamine. Internalized Db- and Kb-binding glycopeptides, detected with high
      specificity using an anti-galabiose (Gal2) monoclonal antibody, were found to
      appear on the cell surface of BFA-treated cells after intracellular MHC-I
      binding. Peptide exchange in Kb was demonstrated as the gradual appearance of
      SIINFEKL/Kb complexes on BFA-treated cells which earlier had been saturated with
      another Kb-binding peptide. Our data support the presence of a fully functional
      endolysosomal processing pathway in iDC guided by the chaperone function of MHC-I
      molecules.

PMID- 15182250
TI  - Anti-inflammatory cytokines induce lipopolysaccharide tolerance in human
      monocytes without modifying toll-like receptor 4 membrane expression.
AB  - Toll-like receptor 4 (TLR4) participates in innate immunity by detecting
      lipopolysaccharides (LPS) of Gram-negative bacterial cell walls. TLR4 macrophage
      expression in mice is modulated by LPS. This fact constitutes, at least
      partially, the molecular basis for LPS tolerance. Very recently, the effect of
      interferon-gamma (IFN-gamma), a pro-inflammatory cytokine, has been described on
      TLR4 membrane expression of human monocytes. IFN-gamma up-regulates TLR4
      expression and antagonizes the LPS-induced TLR4 down-regulation. These data
      prompted us to study the expression of membrane TLR4 in human mono- cytes in
      which LPS tolerance was induced by LPS and by anti-inflammatory cytokines
      [interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1)]. Data
      concerning this latter model, and more specifically, the effect of anti
      inflammatory cytokines over TLR4 expression, are not available at present. We
      show here that membrane TLR4 expression in human monocytes falls after LPS
      exposure. The effect was prolonged for 12 h, but then expression returned to
      normal levels. The incubation of human monocytes with IL-10, TGFbeta1 or a
      mixture of both induces no alterations in membrane TLR4 expression. However,
      these cytokines are able to substitute the tolerizing LPS exposure in order to
      induce LPS tolerance. Our data help to achieve a better understanding of the way
      cytokines control the cellular expression of TLR.

PMID- 15182251
TI  - Red blood cells inhibit proliferation and stimulate apoptosis in human lung
      fibroblasts in vitro.
AB  - Cell proliferation and apoptosis are both important mechanisms for the regulation
      of tissue homeostasis. For instance, proliferation is crucial in wound repair,
      whereas apoptosis is important for removal of damaged cells and resolution of
      inflammation. Imbalance between cell proliferation and apoptosis can therefore
      lead to pathological conditions and disease. In inflammatory and fibrotic lung
      disorders, red blood cells (RBCs) can interact with fibroblasts and connective
      tissue. In the present study, we therefore hypothesized that the presence of RBCs
      can affect fibroblast proliferation and apoptosis. Human foetal lung fibroblasts
      (HFL-1) were cultured in the presence or absence of purified whole RBCs and RBC
      conditioned media. RBC significantly decreased fibroblast proliferation as
      determined both by DNA content analysis (Hoechst 33258 staining, P < 0.01; WST-1,
      P < 0.001) and BrdU incorporation. After treatment with staurosporine (STS) for
      48 h, apoptosis was determined by TUNEL and propidium iodide staining followed by
      flow cytometry analysis. RBCs augmented STS-induced apoptosis (median: 46.4%;
      range 12.0-90.4) compared to control cells (median 26.2%; range 7.1-45.5). Thus,
      our data indicate that the presence of RBCs affects both fibroblast proliferation
      and susceptibility to undergo apoptosis. Our findings therefore suggest a role
      for RBCs in regulating fibroblast homeostasis after tissue injury.

PMID- 15182252
TI  - Utility of the housekeeping genes 18S rRNA, beta-actin and glyceraldehyde-3
      phosphate-dehydrogenase for normalization in real-time quantitative reverse
      transcriptase-polymerase chain reaction analysis of gene expression in human T
      lymphocytes.
AB  - The accuracy of 18S rRNA, beta-actin mRNA and glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) mRNA as indicators of cell number when used for
      normalization in gene expression analysis of T lymphocytes at different
      activation stages was investigated. Quantitative real-time reverse transcriptase
      polymerase chain reaction was used to determine the expression level of 18S rRNA,
      beta-actin mRNA, GAPDH mRNA and mRNA for six cytokines in carefully counted
      samples of resting human peripheral blood mononuclear cells (PBMCs), intestinal
      lymphocytes and PBMCs subjected to polyclonal T-cell activation. The 18S rRNA
      level in activated and resting PBMCs and intestinal lymphocytes was essentially
      the same, while the levels of beta-actin and GAPDH mRNAs fluctuated markedly upon
      activation. When isolated gammadeltaTCR(+), CD4(+) and CD8(+) subpopulations were
      studied, 18S rRNA levels remained unchanged after 21 h of activation but
      increased slightly after 96 h. In contrast, there was a 30-70-fold increase of
      GAPDH mRNA/cell in these cell populations upon activation. Cytokine analysis
      revealed that only normalization to 18S rRNA gave a result that satisfactorily
      reflected their mRNA expression levels per cell. In conclusion, 18S rRNA was the
      most stable housekeeping gene and hence superior for normalization in comparative
      analyses of mRNA expression levels in human T lymphocytes.

PMID- 15182253
TI  - A discrepancy between liquid phase and gel phase assays for evaluation of total
      complement activity and some possible explanations.
AB  - This study was conducted to investigate the frequency and origin of discrepant
      assay results between two haemolytic assays which both measure activity of the
      classical pathway of complement (CH50) by haemolysis of sheep red blood cells
      (SRBCs). One is conducted in gel phase using undiluted sera and the other in
      liquid phase with sera in 1/100 dilution. The majority of discrepant readings are
      observed as low or absent haemolysis in the gel phase, with values within or
      above the normal range in the liquid phase. The incidence of discrepant assay
      readings was evaluated in 300 samples. Furthermore, 28 samples showing the most
      discrepant readings were investigated further for disturbing factors. Factors
      evaluated in the test sera were mannose-binding lectin, C-reactive protein (CRP),
      immune complexes, antibodies to SRBCs, rheumatoid factor and immunoglobulin A
      (IgA) and IgG anti-C1q antibodies. The results showed that discrepant readings
      are present in 10% of the 300 samples and false low gel assay readings account
      for 6.3%. The majority (68%) of the discrepant samples contained a heat-stable
      inhibiting factor, and the main mediators found were elevated levels of IgA anti
      C1q antibodies and antibodies to SRBCs. This could indicate a clinically relevant
      factor in the test sera but can also result from the difference in assay design.

PMID- 15182254
TI  - Identification of a type 1 diabetes-associated CD4 promoter haplotype with high
      constitutive activity.
AB  - CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes
      mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen
      responses of CD4(+) T cells. We previously found linkage between a CD4
      1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we
      screened the human CD4 promoter for mutations and identified three frequent
      single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C.
      The SNPs are in strong linkage disequilibrium (LD) and association with the CD4
      1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes, of which
      four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129
      individuals) and found evidence for linkage and association of a CD4 (A4(-1188)T(
      1050)G(-521)C(-181)) haplotype to T1DM. In reporter studies, we show that (1) the
      T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2)
      the CD4-181G variant encodes higher stimulated promoter activity than the CD4
      181C variant. This difference is in part neutralized in the frequently occurring
      CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report
      functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity
      and the identification of a novel CD4 haplotype with high constitutive promoter
      activity that is linked and associated with T1DM.

PMID- 15182255
TI  - Circulating cytokines in primary Sjogren's syndrome determined by a multiplex
      cytokine array system.
AB  - Plasma cytokines play an important role in the pathogenesis of Sjogren's syndrome
      (SS) by initiating and perpetuating various cellular and humoural autoimmune
      processes. The aim of the present study was to describe a broad spectrum of T
      cell and B-cell cytokines, growth factors, chemokines and molecules that could
      contribute to cell death in SS. A novel protein array system was utilized to
      measure simultaneously the levels of 25 plasma cytokines of patients with primary
      SS and healthy individuals. Furthermore, we correlated these plasma cytokine
      levels with potential laboratory and clinical parameters related to disease
      activity in SS. A subset of plasma cytokines [e.g. interleukin-1beta (IL-1beta),
      IL-6, CXCL8 (IL-8), IL-12 p40, IL-15, tumour necrosis factor-alpha (TNF-alpha),
      epidermal growth factor, CCL4 (MIP-1beta), CCL2 (MCP-1), CCL11 (Eotaxin), CCL5
      (RANTES), TNF-RI and TNF-RII] was found to significantly differ between patients
      and controls. Also, distinct populations of cytokines were found to differentiate
      between patients with normal versus elevated ESR or IgG levels and patients with
      the presence or absence of extra-glandular manifestations (EGMs). Our results
      support the assumption that the multiplex cytokine array system can be
      successfully utilized in the diagnosis and disease management of SS. Furthermore,
      it may provide a powerful tool in the design of individualized anticytokine
      therapies.

PMID- 15182257
TI  - Unmatched sequences in public databases - exemplified by tuberculin-active
      protein.

PMID- 15182256
TI  - Interleukin-10-modulated immature dendritic cells control the proinflammatory
      environment in multiple sclerosis.
AB  - Multiple sclerosis (MS) is a disabling, inflammatory, demyelinating disease of
      the central nervous system considered to be mediated by autoreactive T cells.
      Dendritic cells (DC), being professional antigen-presenting cells, play a pivotal
      role in the decision between T-cell activation and anergy. It has been suggested
      that mature DC (mDC) induce immunity, whereas immature DC (imDC) have the
      potential to induce tolerance. In this study, we investigated the effects of
      autologous imDC versus autologous mDC on lymphocytes with respect to the
      expression of functionally important cell-surface molecules and production of
      cytokines. Our aims were to investigate whether the maturation status of DC
      differs between MS and healthy controls (HC) and to explore whether the effects
      of DC on T-cell responses differ between MS and HC. DC were generated from
      adherent blood mononuclear cells from patients with MS and HC. imDC were obtained
      by culture with either granulocyte-macrophage colony-stimulating factor (GM-CSF)
      + interleukin-4 (IL-4) or GM-CSF + IL-4 + IL-10. mDC were obtained by adding
      lipopolysaccharide to DC cultures. Upon coculture with autologous lymphocytes,
      mDC activated the autologous T cells as reflected by increased CD25 and cytotoxic
      T-lymphocyte antigen-4 expression on CD4(+) T cells together with the increased
      production of both T helper 1 (Th1) (IL-2 and interferon-gamma) and Th2 (IL-10
      and IL-4) cytokines. Unmodulated naive imDC induced the production of only IL-4.
      An exposure of imDC to IL-10 induced the production of IL-4 as well as IL-10 by
      autologous lymphocytes. We hypothesize that such imDC are important in
      controlling the proinflammatory environment in vivo in patients with MS.

PMID- 15182262
TI  - Japanese chest physicians face hopes and enigmas of gefitinib, a molecular
      targeting drug for lung cancer.

PMID- 15182263
TI  - Management of malignant pleural effusions.
AB  - Malignant pleural effusion is a common clinical problem. Evacuation of the
      pleural fluid and prevention of its reaccumulation are the main aims of
      management. Pleurodesis should be attempted early, although considerable practice
      variations exist in the way it is performed. There is a lack of consensus among
      respiratory physicians worldwide on the optimal method and agent for pleurodesis.
      Talc remains the most commonly used pleurodesing compound in most countries.
      While talc produces a higher success rate than other compounds, it generates more
      side-effects. The association between talc and ARDS continues to be debated.
      Ambulatory small-bore pleural catheter drainage followed by intrapleural
      instillation of a pleurodesing agent is increasingly accepted as an alternative
      to conventional in-patient pleurodesis. Development of novel methods to control
      pleural fluid formation should be made a high priority in future pleural
      research.

PMID- 15182264
TI  - Pneumothorax.
AB  - Spontaneous pneumothoraces can occur without obvious underlying lung disease
      (primary) or in patients with known underlying lung disease (secondary).
      Management guidelines for spontaneous pneumothorax have been published by major
      professional organizations, but awareness and application among clinicians seems
      poor. First episodes of primary spontaneous pneumothorax can be managed with
      observation if the pneumothorax is small. If the pneumothorax is large or if the
      patient is symptomatic, manual aspiration via a small catheter or insertion of a
      small-bore catheter coupled to a Heimlich valve or water-seal device, should be
      performed. In general, definitive measures to prevent recurrence are recommended
      after the first recurrence of the pneumothorax, and can be achieved by medical
      (e.g. talc) or surgical (video-assisted thoracic surgery) pleurodesis. Secondary
      pneumothoraces should be treated with chest tube drainage followed by pleurodesis
      after the first episode to minimize any risk of recurrence. Traumatic
      pneumothoraces may be occult (not seen on an initial CXR) or non-occult. The
      majority are treated by placement of a chest tube. Selected patients may be
      treated conservatively, with approximately 10% of these patients eventually
      requiring chest tube placement. Iatrogenic pneumothoraces have a myriad of causes
      with transthoracic lung needle biopsy being most common. Transthoracic needle
      biopsy-related pneumothoraces have CT findings that can predict their occurrence
      and the need for chest tube placement. Iatrogenic pneumothoraces, regardless of
      cause, may be managed by observation or small bore chest tube placement,
      depending upon patient stability and the size of the pneumothorax.

PMID- 15182265
TI  - The process of introducing a tobacco curriculum in medical school.
AB  - Medical students have poor knowledge of cigarette-related diseases and tend to
      increase tobacco use as they progress through their course. The aims of this
      review are to describe the process of developing a tobacco curriculum, present a
      model of implementation, and apply the model to China. The process of developing,
      revising and implementing a tobacco curriculum called the Smokescreen Education
      Program (SEP) for medical students is described. It comprises a lecture and six
      part tutorial. Dissemination of the SEP occurred through doctors who translated
      and introduced the tobacco curriculum into different countries and through the
      conduct of workshops. A six-point model of implementation was developed that
      included defining the extent of the tobacco problem in medical schools,
      developing a flexible curriculum on tobacco, developing networks in countries,
      working as a resource, and following up after training and evaluating success.
      The model is applied to China. The SEP was developed over a decade and has led to
      the development of a practical model of dissemination.

PMID- 15182266
TI  - Outcome of coronavirus-associated severe acute respiratory syndrome using a
      standard treatment protocol.
AB  - OBJECTIVE: There is so far no consensus on the optimal treatment strategy for the
      coronavirus-associated severe acute respiratory syndrome (SARS). We aimed to
      analyse the outcomes of a standard treatment strategy comprising antibiotics, a
      combination of ribavirin, a 3-week step-down course of corticosteroids, and the
      possibility of pulsed methylprednisolone rescue in the event of deterioration.
      METHODOLOGY: This was a prospective cohort study performed at a major public
      funded hospital in Hong Kong. Eighty-eight World Health Organisation/Centers for
      Disease Control and Prevention probable cases of SARS (97% laboratory-confirmed)
      were treated with a standard protocol previously reported. Seventy-one patients
      treated de novo were analysed in detail with regard to time to clinical
      stabilization after combination treatment, requirement of additional therapy
      (pulsed methylprednisolone; assisted ventilation); and final outcomes (recovery,
      mortality). RESULTS: The mean age was 42. Twenty-one patients (24%) had
      comorbidities. Three of 71 treated de novo recovered with antibiotics alone. The
      remaining 68 received combination treatment at a mean of 5.8 days after symptom
      onset, of whom 30 subsequently required pulsed methylprednisolone rescue
      (independent predictors: older age and higher LDH) and 18 required assisted
      ventilation (independent predictors: older age, higher oxygen requirement and
      creatinine level). Their median time to clinical stabilization was 8.0 days after
      combination treatment (independent predictor for longer time to stabilization:
      median age of 41 or above). Common complications were hyperglycaemia (58%),
      pneumo-mediastinum/thoraces (13%), psychiatric manifestations (7%) and ventilator
      associated pneumonia (2%). One patient (1%) died of SARS-related respiratory
      failure. All-cause mortality was 3.4%, occurring in patients aged > 65 years
      only. None of the discharged survivors required continuation of oxygen therapy.
      CONCLUSIONS: This standard treatment protocol resulted in overall satisfactory
      outcomes. Randomized controlled trial is suggested to confirm its efficacy.

PMID- 15182267
TI  - Polymorphism of the promoter region of prostacyclin synthase gene in chronic
      thromboembolic pulmonary hypertension.
AB  - OBJECTIVE: Decreased expression of prostacyclin synthase (PGIS) is observed in
      the lung vasculature of patients with pulmonary arterial hypertension and the
      biosynthesis of prostacyclin (PGI2) may be impaired in chronic thromboembolic
      pulmonary hypertension (CTEPH). Whether it is genetically determined or develops
      as the disease progresses is unclear. A variable-number tandem repeat (VNTR)
      polymorphism has been detected in the 5'-upstream promoter region of the PGIS
      gene. It has been demonstrated that the alleles vary in size from three to seven
      repeats of nine base pairs, and transcriptional activity increased with the
      number of repeats. The purpose of the present study was to elucidate the
      association between the VNTR polymorphisms of the PGIS gene and CTEPH in Japanese
      subjects. METHODOLOGY: Ninety patients with CTEPH and 144 control subjects were
      investigated for the presence of VNTR polymorphisms. Sixty-two blood samples were
      obtained from CTEPH patients and the plasma concentrations of prostacyclin and
      thromboxane A2 metabolites were measured. RESULTS: VNTR polymorphisms in the
      prostacyclin synthase gene were grouped into L alleles (five, six and seven
      repeats) and S alleles (three and four repeats). The overall distribution of the
      alleles and genotypes were not significantly different between CTEPH patients and
      the control subjects. The patients with the LL genotype had higher plasma
      concentrations of 6-keto-prostaglandin F1alpha than patients with the LS and SS
      genotypes. CONCLUSIONS: Our results suggested that the specific VNTR polymorphism
      in the 5'-upstream promoter region of the PGIS gene regulated prostacyclin
      production, but did not seem to be associated with the development of CTEPH in
      this patient population.

PMID- 15182268
TI  - Pulmonary fibrosis in myeloperoxidase antineutrophil cytoplasmic antibody
      associated vasculitides.
AB  - OBJECTIVE: The association of pulmonary fibrosis (PF) with myeloperoxidase
      antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitides has not
      been well documented. The aim of this study was to assess the clinicopathological
      characteristics of PF in patients who tested positive for MPO-ANCA. METHODOLOGY:
      In this study, 31 patients (17 males and 14 females; mean age, 69 years)
      diagnosed as having PF with positive MPO-ANCA levels ranging from 10 to 840 EU
      with a mean of 112.5 EU, were evaluated clinicopathologically. RESULTS: Among 31
      patients with PF, 22 had underlying systemic diseases such as collagen vascular
      diseases, while nine had unknown aetiology. Evidence of glomerulonephritis was
      demonstrated in 14 patients. The clinical features were a history of dry cough
      and/or fine crackles in all 31 patients. Chest CT scans showed honeycombing in
      the lung bases in 26 patients. The histopathological features of the diseased
      lung tissues in all 11 autopsied cases were compatible with the usual
      interstitial pneumonia (UIP) pattern. Vasculitis was confirmed in bronchial
      arteries and/or pulmonary arterioles in five patients. The mortality was as high
      as 13 of the 31 patients. The causes of death were: deterioration of PF in five
      (two of whom were associated with pulmonary haemorrhage), lung cancer in two,
      pneumonia in four, and digestive tract bleeding in two. The survival rates in PF
      with MPO-ANCA-negative collagen vascular diseases, cryptogenic fibrosing
      alveolitis (CFA), and PF with positive MPO-ANCA, were compared. The 5-year
      survival rate in PF with positive MPO-ANCA was worse than in PF with MPO-ANCA
      negative collagen vascular diseases and was the same for CFA. CONCLUSION:
      Although there was no correlation between MPO-ANCA titres and the activity of PF,
      this study demonstrated that the presence of positive MPO-ANCA was an unfavorable
      prognostic factor in patients with PF.

PMID- 15182269
TI  - The effect of chest wall restriction on exercise capacity.
AB  - OBJECTIVE: Subjects with restrictive pulmonary disease exhibit a decreased
      exercise capacity compared to non-diseased subjects, as do subjects in certain
      workplace situations, for example when wearing bullet-proof vests. The purpose of
      this study was to examine the effects of varying degrees of chest wall
      restrictive loading on exercise performance. We have designed and validated a
      chest wall restrictor that mimics the elastic loading occurring in some disease
      states and some occupational situations. METHODOLOGY: In this study, 18 subjects
      performed five graded maximal cycling tests while wearing the device at four
      different inflation pressures (0, 20, 40, and 60 mmHg). RESULTS: Maximal values
      of oxygen uptake (VO2max), minute ventilation (VImax), tidal volume (VT at max)
      and breathing frequency (fB at max) were monitored, as was the time to maximal
      exercise (TTM). VO2, VI, VT, and fB were also measured at three submaximal loads.
      The results showed that VO2max, VImax, TTM, and VT at max were significantly
      decreased, while fB at max was maintained. At submaximal loads, the ventilatory
      parameters VT, and fB were altered with load, but VI and VO2 were not affected by
      load. CONCLUSIONS: These results indicate that the wearing of this device
      decreases variables associated with maximal exercise, and that the decreases are
      related to the degree of chest wall restriction. Furthermore, submaximal exercise
      ventilation was minimally altered, with an increase in fB and a decrease in VT
      associated with increasing restrictive loads. Submaximal oxygen uptake was not
      affected by breathing restriction.

PMID- 15182270
TI  - Post-hyperventilation hypoxaemia is due to alteration of ventilation and
      perfusion matching.
AB  - OBJECTIVE: The aim of this study was to investigate the mechanisms of post
      hyperventilation hypoxia. METHODOLOGY: Seven healthy male volunteers, aged 29.1
      +/- 1.4 years, underwent two 10-min periods of voluntary hyperventilation to
      pulmonary end tidal CO2 values of 20 mmHg (severe hyperventilation), or 30 mmHg
      (moderate hyperventilation). Post-hyperventilation, the arterial oxygen
      saturation, VE and arterial blood gas values were measured. Sleep was excluded by
      EEG monitoring. RESULTS: Maximal hypoxaemia occurred in proportion to severity of
      hyperventilation; at approximately 5 min post-hyperventilation Pao2 fell to 64 +/
      7 mmHg (severe hyperventilation) and 72 +/- 6 mmHg (moderate hyperventilation)
      from 97 +/- 3 mmHg at baseline. Hypoxaemia persisted beyond the time of
      normalization of Paco2 and HCO3. On another occasion, a N2 washout test was
      performed after severe hyperventilation, which excluded bronchoconstriction.
      CONCLUSION: Relative hypoventilation may partly explain post-hyperventilation
      hypoxaemia, but by excluding bronchoconstriction and periodic breathing, we have
      demonstrated that most of the hypoxaemia must have been due to alteration of
      pulmonary blood flow distribution causing a fall in V/Q ratio.

PMID- 15182271
TI  - Methylprednisolone reduces airway microvascular permeability but not airway
      resistance induced by N-formylmethionine leucyl-phenylalanine in the rabbit.
AB  - OBJECTIVE: The aim of this study was to determine the effect of corticosteroids
      on the increase in airway microvascular permeability (MVP) and airway resistance
      induced by N-formylmethionine leucyl-phenylalanine in the rabbit. METHODOLOGY:
      After pretreatment with methylprednisolone (for 1 day or 1 week) rabbits were
      nebulized with N-formylmethionine leucyl-phenylalanine and MVP was assessed using
      the Evans blue dye technique (on the trachea, bronchi and bronchioles), while
      airway resistance was measured using a volume displacement plethysmograph.
      RESULTS: There were no significant differences in airway resistance between the
      steroid treated group and the control group for either steroid treatment regime.
      The degree of extravasation of Evans blue dye was significantly inhibited in the
      bronchioles after both the 1-day and 1-week treatment with methylprednisolone.
      There were no significant differences in MVP in the trachea or bronchi between
      the treated groups and the control groups. CONCLUSION: These results show that
      methylprednisolone can significantly reduce N-formylmethionine leucyl
      phenylalanine-induced MVP without affecting airway resistance.

PMID- 15182272
TI  - Adverse effects of short-acting beta-agonists: potential impact when anti
      inflammatory therapy is inadequate.
AB  - BACKGROUND: Short-acting beta-agonists (SABAs) are associated with reduced lung
      function and increased bronchial hyper-responsiveness. Earlier studies have
      failed to show that these changes are clinically important when SABAs are taken
      regularly in modest doses. However, some patients use SABAs to excess, especially
      with deteriorating asthma. Our aim was to establish whether adverse effects of
      SABAs are greater at higher than normal doses and after withdrawing inhaled
      corticosteroid (ICS) therapy. METHODOLOGY: This was a randomized controlled
      study. The treatments were salbutamol/ipratropium 100 microg/20 microg/puff or
      ipratropium 20 microg/puff, each 12 puffs daily. Phase 1 was of 2 weeks duration.
      During phase 2 ICS were withdrawn until loss of control (LOC) occurred. RESULTS:
      During phase 1 the mean FEV1 fell by 9.3% with salbutamol (0.26 L; 95% C.I. 0.13,
      0.39), but by only 1.6% with ipratropium (0.05 L; 95% C.I. -0.06, 0.16; P =
      0.006). During phase 2 FEV1 fell by a further 18.9% with salbutamol (0.54 L; 95%
      C.I. 0.39, 0.69), but by only 10.5% (0.33 L; 95% C.I. 0.17, 0.49; P = 0.032) with
      ipratropium. Time to LOC was significantly shorter with salbutamol (8.9 days)
      compared to ipratropium (16.8 days; P = 0.03). CONCLUSION: Adverse changes in
      lung function with SABA appear to be greater with higher doses and increasing
      airway inflammation. This highlights the risks of excessive SABA use in patients
      who neglect ICS therapy and/or who rely on 'relievers'.

PMID- 15182273
TI  - Central and obstructive sleep apnoea during ascent to high altitude.
AB  - OBJECTIVE: The aim of the study was to investigate the relationship between
      central sleep apnoea (CSA) at high altitude and arterial blood gas tensions, and
      by inference, ventilatory responsiveness. METHODOLOGY: Fourteen normal adult
      volunteers were studied by polysomnography during sleep, and analysis of awake
      blood gases during ascent over 12 days from sealevel to 5050 m in the Nepal
      Himalayas. RESULTS: Thirteen subjects developed CSA. Linear regression analysis
      showed tight negative correlations between mean CSA index and mean values for
      sleep SaO2, PaCO2 and PaO2 over the six altitudes (r2 > or = 0.74 for all, P <
      0.03). Paradoxically there was poor correlation between the individual data for
      CSA index and those parameters at the highest altitude (5050-m) where CSA was
      worst (r2 < 0.12 for all, NS), possibly due to variation in degree of
      acclimatization between subjects. In addition, CSA replaced mild obstructive
      sleep apnoea during ascent. Obstructive sleep apnoea index fell from 5.5 +/-
      6.9/h in rapid eye movement sleep at sealevel to 0.1 +/- 0.3/h at 5050 m (P <
      0.001, analysis of variance), while CSA index rose from 0.1 +/- 0.3/h to 55.7 +/-
      54.4/h (P < 0.001). CONCLUSION: There was a general relationship between
      decreasing PaCO2 and CSA, but there were significant effects from variations in
      acclimatization that would make hypoxic ventilatory response an unreliable
      predictor of CSA in individuals.

PMID- 15182274
TI  - Long-term effectiveness of an inpatient pulmonary rehabilitation program for
      elderly COPD patients: comparison between young-elderly and old-elderly groups.
AB  - OBJECTIVE: To evaluate the long-term effects of pulmonary rehabilitation in
      elderly COPD patients, we monitored patients for 1 year after they completed a 2
      week inpatient pulmonary rehabilitation program. We also compared the effects of
      pulmonary rehabilitation on young-elderly (age 65-74 years) and old-elderly (age
      75 years or over) COPD patients. METHODOLOGY: Fifty-nine elderly COPD patients
      (mean age 72.8 years) were studied. They underwent a comprehensive 2-week
      inpatient pulmonary rehabilitation program incorporating 10 exercise sessions,
      each of which included endurance training of the lower extremities, peripheral
      muscle conditioning training of the upper and lower extremities, and stretching,
      along with various education sessions. The effects of pulmonary rehabilitation
      were evaluated at 3, 6, and 12 months after completion of the program. RESULTS:
      Overall, patient health-related quality of life (HRQoL) as assessed by a QoL
      scale, and dyspnoea as assessed by an oxygen cost diagram, improved significantly
      over the 12-month period. Exercise capacity assessed by a 6-min walking distance
      test (6MWD) was similarly significantly improved. However, there was some fall
      off in terms of the distance walked 12 months after pulmonary rehabilitation. The
      improvements in exercise capacity, dyspnoea, and HRQoL did not differ between the
      two groups, with the exception that the 6MWD (P < 0.01) and the QoL scale (P <
      0.05) at 3 months post-pulmonary rehabilitation were significantly higher in the
      old-elderly group. CONCLUSIONS: Pulmonary rehabilitation is an effective
      treatment in terms of improving dyspnoea, exercise capacity and HRQoL in elderly
      COPD patients, and the benefits are almost comparable for young-elderly and old
      elderly patients.

PMID- 15182275
TI  - The relative survival of COPD patients on long-term oxygen therapy in Australia:
      A comparative study.
AB  - OBJECTIVE: The survival of patients with COPD on long-term oxygen therapy (LTOT)
      has been studied using both univariate and multivariate procedures. There has
      been only one previous report of relative survival. Relative survival takes into
      account the risk of death due to increasing age. The objective of this study was
      to determine the relative survival of a group of South Australian patients
      prescribed home oxygen therapy for COPD. METHODOLOGY: A method proposed by
      Hakulinen was used to determine relative survival. The results were compared with
      the relative survival of a similar group of French COPD patients. RESULTS: A
      total of 505 COPD patients (249 males, 256 females) were included in the survival
      analysis. Relative survival corrected for life expectancy was 78.1%, 56.7%, 23.1%
      and 1.1% at 1, 2, 5 and 10 years, respectively, which was less than that reported
      in a recent French study of comparable patients. Our patients were similar with
      respect to age, severity of hypoxaemia and oxygen usage to those in the French
      study. CONCLUSIONS: Using relative survival analysis, Australian LTOT patients
      with COPD have worse outcomes than some European patients. Factors contributing
      to the excess mortality in South Australian COPD patients need to be
      investigated.

PMID- 15182276
TI  - Addition of montelukast versus double dose of inhaled budesonide in moderate
      persistent asthma.
AB  - BACKGROUND: Although current guidelines suggest the use of inhaled
      corticosteroids as the first line therapy in persistent asthma, the concerns
      about high-dose corticosteroids may limit their usage. We aimed to investigate
      the efficacy of inhaled budesonide plus oral montelukast versus a double dose of
      inhaled budesonide. METHODOLOGY: Thirty patients with moderate asthma took part
      in the study. Following a 2-week run in period, the patients were randomized into
      two groups to receive 400 microg/day of inhaled budesonide plus 10 mg/day of
      montelukast (BUD + M group) or 800 microg/day of inhaled budesonide (high BUD
      group). The patients were evaluated at 2-week intervals (during a total treatment
      period of 6 weeks) for symptom scores, asthma exacerbations, lung function, use
      of short-acting beta2 agonist, blood eosinophil counts and adverse events.
      RESULTS: At the end of the study, morning and daytime symptom scores were
      significantly reduced within the groups. Although there was a significant
      decrease in the frequency of short-acting beta2 agonist use in the BUD + M group,
      the decrease in the high BUD group was not significant. During the study period,
      no patient in either group experienced an asthma exacerbation. Blood eosinophil
      levels significantly declined in both the BUD + M (0.87 +/- 0.31%) and high BUD
      groups (0.67 +/- 0.29%) as compared with baseline levels (BUD + M = 2.60 +/-
      0.65%, high BUD group = 2.60 +/- 0.47%; P < 0.05). CONCLUSION: Our results
      suggest that the addition of montelukast to low-dose inhaled budesonide is as
      effective as a double dose of inhaled budesonide in asthma control.

PMID- 15182277
TI  - Effect of low-dose theophylline on airway inflammation in COPD.
AB  - OBJECTIVE: Recent studies have shown that theophylline may exert anti
      inflammatory effects on neutrophils. We undertook to assess the effect of
      theophylline on airway inflammation in COPD. METHODOLOGY: We performed a 4-week
      randomized double-blind, placebo-controlled study in 11 theophylline-naive
      patients with mild to moderate COPD. After a 1-week run-in period, six subjects
      were administered 400 mg/day theophylline (Theodur; Nikken Chemicals Co. Ltd,
      Tokyo, Japan) for 4 weeks, while five subjects were administered a placebo.
      Induced sputum was obtained before and after the run-in period and then after 2
      and 4 weeks of treatment. Cell differential count and levels of interleukin-8,
      matrix metalloproteinase-9, neutrophil elastase (NE), myeloperoxidase (MPO),
      alpha1-antitrypsin (alpha1-AT), leukotriene B4 and tissue inhibitor of
      metalloproteinases-1 (TIMP-1) were assessed. RESULTS: No variable was
      significantly different during the run-in period or with placebo treatment. In
      contrast, theophylline treatment significantly decreased NE and MPO levels at 4
      weeks, although the cell differential count did not change appreciably as a
      result of treatment. CONCLUSION: These results suggest that 4 weeks of
      theophylline treatment attenuates neutrophil-associated inflammation in the
      airways of mild to moderate COPD patients. However, the clinical benefits remain
      to be determined.

PMID- 15182278
TI  - Chlamydia pneumoniae and newly diagnosed asthma: a case-control study in 1 to 6
      year-old children.
AB  - OBJECTIVE: The aim of the study was to evaluate the association between
      antibodies to Chlamydia pneumoniae and the onset of asthma in children.
      METHODOLOGY: In 1996-2000, 122 children aged 1-6 years, who were treated for new
      asthma as inpatients or outpatients in our hospital, were recruited. For each
      patient, two controls, matched by age, sex and municipality, were randomly
      selected from the same population. In 2000, 104 serum samples were available from
      patients (85%) and 120 from controls (49%) for microimmunofluorescence (MIF)
      assay for C. pneumoniae and C. trachomatis antibodies, and for enzyme immunoassay
      (EIA) for C. pneumoniae antibodies. RESULTS: In EIA, the median IgG
      concentrations were 20 EIU (EIA units) in the patients, and 16 EIU in the
      controls. IgG was positive (> 30 EIU) in 37 (36%) patients and in 36 (31%)
      controls. IgA was positive (> 12 EIU) in four (4%) patients and in eight (7%)
      controls. In MIF, four (4%) patients and seven (6%) controls were IgG positive,
      and seven were also IgA positive. IgM antibodies were detected in four children
      by EIA, and in none by MIF. CONCLUSION: IgG antibodies to C. pneumoniae, though
      common in 1 to 6-year-old children as detected by EIA, did not differ between
      newly diagnosed asthma patients and controls in this case-control study.

PMID- 15182279
TI  - Respiratory function testing: the impact of respiratory scientists on the
      training and support of primary health care providers.
AB  - OBJECTIVE: In rural Australia access to doctors is limited, access to respiratory
      physicians even more so and these are the traditional sources of lung function
      testing. The aim of this study was to assess the feasibility of training and
      supporting existing rural primary healthcare providers in lung function testing
      as a screening and monitoring mechanism due to the shortage of healthcare
      professionals capable of providing such a service. METHODOLOGY: As pharmacists
      are readily accessible healthcare professionals, they were trained in spirometry
      measurement and supported with ongoing quality assurance by respiratory
      scientists. Spirometers were provided to the pharmacists. People purchasing
      respiratory medications or responding to advertising about the service were
      tested after giving informed consent. Spirometic assessments were assessed for
      accuracy and reproducibility. Participants' spirometry results were reviewed and
      those with abnormal test results were referred to their doctor. RESULTS:
      Pharmacists were able to competently develop the skills necessary for providing
      spirometry measurement as a screening and monitoring technique. The level of
      competence exceeded that reported in previously published studies. Pharmacists
      were able to successfully identify spirometry results within the normal range.
      CONCLUSIONS: Training and supporting accessible healthcare professionals to
      provide lung function testing increases access in areas of need and has
      implications for respiratory morbidity and mortality in such settings.

PMID- 15182281
TI  - Occult pneumomediastinum in a SARS patient presenting as recurrent chest pain and
      acute ECG changes mimicking acute coronary syndrome.
AB  - OBJECTIVE: Severe acute respiratory syndrome (SARS) is a newly emergent disease
      due to a novel coronavirus, which caused outbreaks worldwide. METHODOLOGY: We
      report a SARS patient who had developed recurrent chest pain and acute T-wave
      inversion over the precordial leads on electrocardiography (ECG). RESULTS: She
      developed progressive subcutaneous emphysema a few days later. Her CXR showed
      features suggestive of pneumomediastinum, which was confirmed by high-resolution
      CT scan of the thorax. CONCLUSION: Pneumomediastinum should be considered in SARS
      patients as a possible cause of chest pain and ECG changes that mimic acute
      coronary syndrome.

PMID- 15182280
TI  - Protease inhibitor phenotypes and serum alpha-1-antitrypsin levels in patients
      with COPD: a study from Hong Kong.
AB  - OBJECTIVE: Many studies have suggested that an imbalance of protease activation
      and inhibition might result in COPD with emphysema. Levels of alpha-1-antitrypsin
      (alpha1-AT), the key protease inhibitor, are genetically determined by alleles
      that present in many phenotypes/subtypes, some of which are associated with
      deficiency of the protein. We prospectively evaluated the prevalence of the
      protease inhibitor (Pi) alleles and phenotypes together with the serum alpha1-AT
      levels in Chinese patients with COPD. METHODOLOGY: The study population comprised
      356 patients with COPD. The male-to-female ratio was 4 : 1 with a mean age of
      72.4 years (range 44-93 years). Isoelectric focusing was used for Pi
      phenotyping/subtyping. The frequencies of Pi alleles and phenotypes were compared
      with the frequencies in 1085 healthy unrelated Chinese control subjects. The
      serum alpha1-AT levels were measured by the Cobas Fara assay. RESULTS: PiZ was
      not detected. No significant difference in distribution of PiM
      phenotypes/subtypes between patients with COPD and healthy controls was observed,
      except for M1M3 and M2M3. There was also a significant difference in the
      proportion of variant S and F alleles between the disease group and the control
      population. CONCLUSION: The low prevalence of deficiency Pi phenotypes/subtypes
      suggests a lack of contribution of alpha1-AT deficiency to the pathogenesis of
      COPD in Chinese patients. The strategy of launching an alpha1-AT deficiency
      detection program among COPD patients, based on the recommendation of the World
      Health Organization, may not be readily applicable in our local setting.

PMID- 15182282
TI  - Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient
      with acromegaly.
AB  - Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a
      rare disorder that most often presents clinically as obliterative bronchiolitis,
      but has also been associated with ectopic corticotropin syndrome. We describe a
      49-year-old lifetime non-smoking female with longstanding cough, progressive
      exertional dyspnoea, and fixed airflow limitation, who presented with acromegaly.
      Head magnetic resonance imaging revealed a pituitary microadenoma and open lung
      biopsy revealed a multifocal proliferation of neuroendocrine cells which were
      immunopositive for both corticotropin and growth hormone-releasing hormone. To
      our knowledge, this is the first report of acromegaly associated with IDHPNC, and
      supports the possibility that IDHPNC may fall at one extreme of the spectrum of
      disorders encountered in multiple endocrine neoplasia type 1.

PMID- 15182283
TI  - Clinical features of Q fever pneumonia.
AB  - The aim of the study was to assess the clinical features of Q fever pneumonia in
      Japan. Four cases of Q fever pneumonia (a female aged 21 and males aged 53, 74
      and 87 years) who were diagnosed using the PanBio ELISA test kit, were assessed
      and their clinical features are described. The frequency of Q fever pneumonia
      among our cases of community-acquired pneumonia was 1.4% (4/284). A 21-year-old
      female had a typical case of the disease with (i) a history of owning a cat, (ii)
      onset with fever and dry cough, (iii) multiple soft infiltrative shadows on CXR,
      (iv) a normal white blood cell count, and (v) good response to clarithromycin.
      The pneumonias in the other three cases were considered mixed infections with
      bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. Their
      clinical features included the following: (i) an elderly person with an
      underlying disease, (ii) onset with fever and purulent sputum, (iii) coarse
      crackles on auscultation, (iv) infiltrative shadows and pleural effusion on CXR,
      (v) increased white blood cells with elevated BUN and hyponatraemia, and (vi)
      modest responses to combined therapy with carbapenem and minocycline. Our
      observations suggest that two types of pneumonia caused by Coxiella burnetti
      exist; one with the usual features of atypical pneumonia, and the other
      presenting with the clinical features of bacterial pneumonia in the elderly due
      to mixed bacterial infection.

PMID- 15182284
TI  - Mycobacterium smegmatis pneumonia.
AB  - Mycobacterium smegmatis is a non-tuberculous mycobacterium that is usually
      associated with soft tissue or wound infections in humans. Pulmonary infections
      secondary to this pathogen are rarely seen and occur only in patients with an
      underlying condition, such as lipoid pneumonia. This report presents the first
      case of M. smegmatis pneumonia in an otherwise healthy individual who had no
      predisposing condition.

PMID- 15182285
TI  - A case of idiopathic pulmonary alveolar proteinosis accompanied by T-cell
      receptor gene rearrangement in bronchoalveolar lavage fluid cells.
AB  - We describe a case of a patient with idiopathic pulmonary alveolar proteinosis
      (PAP), who had an elevated serum level of antigranulocyte-macrophage colony
      stimulating factor (anti-GM-CSF) antibody accompanied by T-cell receptor gene
      rearrangements in BAL fluid cells. Histopathological examination of the lung
      excluded lymphoma but revealed PAP and silicosis. There was no detectable serum
      anti-GM-CSF antibody in 50 outpatients with advanced silicosis who did not have
      PAP, suggesting that anti-GM-CSF antibody is directly linked to PAP but not to
      silicosis. We speculate that monoclonal expansion of a T-cell population may play
      a role in the production of anti-GM-CSF antibody and the development of PAP.

PMID- 15182286
TI  - Specific localization of macrophages in pregnant bovine caruncles.
AB  - The objective of this study was to evaluate the distribution and phagocytotic
      function of macrophages in bovine caruncles during pregnancy. Pregnant Holstein
      caruncles obtained at a slaughterhouse and by Caesarean section just before the
      onset of parturition were used. Macrophages in these caruncles were observed
      immunohistochemically and histochemically. Macrophages were present in the
      parenchyma of caruncles throughout pregnancy. The macrophages were irregular in
      shape, and exhibited thin, long processes along the main and intermediate septa
      of caruncles. Macrophages increased as the gestation period progressed. Acid
      phosphatase activity of the macrophages appeared at 5-6 months of gestation and
      remained until the end of gestation period. In particular, macrophages showed
      strong acid phosphatase activity at the peripheral region of the caruncles just
      facing the chorionic villi. In addition, they were conglomerated in the
      hyperplastic prominences of caruncles. These results indicate that caruncle
      macrophages maintain the appropriate size and shape of each caruncle during
      pregnancy.

PMID- 15182287
TI  - In vitro capacitation and acrosome reaction of dog spermatozoa can be feasibly
      attained in a defined medium without glucose.
AB  - Incubation of dog spermatozoa in a medium without glucose and in the presence of
      lactate and pyruvate (l-CCM) for 4 h at 38.5 degrees C in a 5% CO(2) atmosphere
      induced in vitro capacitation of these cells. This was verified after the
      combined specific capacitation-like changes in percentages of viability and
      altered acrosomes, motility characteristics, sperm location of reactivity against
      Pisum sativum, Arachis hypogaea and Helix pomatia lectins and the tyrosine
      phosphorylation pattern. Furthermore, a feasible acrosome reaction (AR) was
      induced when spermatozoa incubated in l-CCM for 4 h were further co-incubated for
      1 h with canine oocytes. This was demonstrated by AR-like changes in percentages
      of viability, altered acrosomes, motility characteristics and sperm location of
      reactivity against P. sativum, A. hypogaea and H. pomatia lectins. All these
      results clearly indicate that in vitro capacitation, and subsequent AR, can be
      feasibly achieved without the presence of sugars. This ability can be related to
      the specific characteristics of energy-metabolism regulation reported in dog
      spermatozoa.

PMID- 15182288
TI  - Ultrasonography and cystic hyperplasia-pyometra complex in the bitch.
AB  - Cystic endometrial hyperplasia-pyometra complex is the most frequent and
      important endometrial disorder encountered in bitches. The pathogenesis of the
      disease is related to the activity of progesterone [Feldman and Nelson, Canine
      and Feline Endocrinology and Reproduction (1996) W.B. Saunders, Philadelphia].
      Cystic endometrial hyperplasia (CEH) is an abnormal response of the bitch's
      uterus to ovarian hormones [De Bosschere et al. Theriogenology (2001) 55, 1509].
      CEH is considered by many authors to be an exaggerated response of the uterus to
      chronic progestational stimulation during the luteal phase of the oestrous cycle,
      causing an abnormal accumulation of fluid within the endometrial glands and
      uterine lumen (De Bosschere et al. 2001). The resulting lesions of pyometra are
      due to the interaction between bacteria and hormones. The aim of this study was
      to evaluate if transabdominal uterine ultrasonography can be a useful and
      reliable diagnostic method to confirm Dow's [Veterinary Record (1958) 70, 1102]
      and De Bosschere's histopathological classification of CEH-pyometra complex. The
      study was carried out on 45 bitches with pyometra, 10 purebreds and 35
      crossbreeds, 1-15 years old, 20% of which had whelped at least once. None of
      these animals had received exogenous oestrogen or progesterone treatment. On
      admission the 45 animals were in the luteal phase of the oestrus cycle. Clinical
      signs, blood parameters, uterine ultrasonography, bacterial swabs and uterine
      histopathological results were recorded. Results suggest that ultrasonographic
      examination is a useful and reliable tool for the diagnosis of cystic endometrial
      hyperplasia.

PMID- 15182289
TI  - Evidence of damage in cryopreserved and fresh bovine embryos using the Tunel
      technique.
AB  - The objective of the present study was to evaluate the quality of bovine embryos
      cryopreserved in different years in Chiapas, Mexico. The embryos were obtained
      from a government institution (FIMEGEN) dedicated to promoting embryo transfer
      among dual-purpose cattle farmers. Forty-three embryos frozen in 1988, 1989, 2000
      and 2002 were analysed with the Tunel technique to detect programmed cell death
      (apoptosis). Eleven fresh embryos were used as controls. Analysis of variance was
      used in embryos stored in the different years with averages tested using Tukey's
      test. Student's t-test was employed to compare fresh and frozen cells. Embryos
      with shorter storage time presented a lower number (p < 0.001) of Tunel-positive
      cells compared with embryos stored for longer time. On the contrary, when
      comparing the number of apoptotic cells between frozen and fresh embryos a higher
      number of positive cells (p < 0.05) were found in the former. The present results
      suggest that the cryopreservation per se caused damage that compromises the
      viability of the embryo. Another explanation for the lower pregnancy rate found
      in the tropics could be irreversible damage caused by poor storage technique in
      these large operations.

PMID- 15182290
TI  - Influences of follicular size on parthenogenetic activation and in vitro heat
      shock on the cytoskeleton in cattle oocytes.
AB  - The availability of cow ovaries from the slaughterhouse has been very limited in
      Taiwan. To maximize the use of cow ovaries for research purposes, whole ovary
      dissection was performed and the developmental competence of the oocytes derived
      from different sizes of follicles was assessed by the rates of in vitro
      maturation (IVM) and parthenogenetic activation of the oocytes in Experiment 1
      (Exp 1). Cumulus-oocyte complexes (COCs) derived from small (1-2 mm) and large (3
      8 mm) follicles were subjected to standard IVM culture for 24 h. Mature oocytes
      were selected and then parthenogenetically activated using A23187 (5 microm, 5
      min) or thimerosal (200 microm, 10 min) alone or combined with 6
      dimethylaminopurine (2.5 mm and 3.5 h, respectively). Activation rates of the
      oocytes, neither from the large nor small follicles, were affected by different
      activation treatments (single or combined stimuli). Whereas maturation rates for
      the oocytes from large follicles were superior to those from small follicles in
      both the single (59% vs 45%) and combined treatments (76% vs 40%; p < 0.05). To
      understand how prolonged heat shock (HS) influences cytoskeletal configurations
      of mature bovine oocytes, in Experiment 2 (Exp 2), matured oocytes derived from
      large follicles were randomly allocated to different durations of HS treatments
      at 41.5 degrees C for 0 (C0h, control, n = 12), 1 (HS1h, n = 28), 2 (HS2h, n =
      31), and 4 h (HS4h, n = 30). An additional control group was cultured for 4 h
      without HS (38.5 degrees C, 4 h, n = 35). Alterations in nuclear structures,
      microtubules (MTs), and microfilaments (MFs) of the oocytes were examined.
      Abnormalities in the chromosomes, spindle MTs and the percentages of oocytes with
      cytoplasmic MTs increased with time of HS treatment. The intensity of the MF
      distribution in the HS oocytes was also altered. Significant changes in the
      cytoskeleton after HS may be associated with the reduced development under
      hyperthermia and, perhaps, with the low pregnancy rates of the animals during hot
      seasons.

PMID- 15182291
TI  - Effect of exogenous progesterone on post-thaw capacitation and acrosome reaction
      of bovine spermatozoa.
AB  - The aim of this work was to study the effect of progesterone (P4) on capacitation
      and acrosome reaction (AR) of post-thaw bovine spermatozoa in vitro. Spermatozoa
      were incubated (0-180 min) in capacitation medium supplemented with 0, 0.1, 1.0
      and 10.0 microg/ml of P4. At different time intervals aliquots were taken to
      determine sperm plasma membrane lipid destabilization, or capacitation (AR
      induced by lysophosphatidylcholine) in spermatozoa. The second experiment aimed
      to study the effects of P4, as potential inducer of AR in heparin-capacitated
      spermatozoa. The acrosomal status and viability of spermatozoa were evaluated
      under an epifluorescence microscope using Ethidium homodimer/peanut agglutinin
      fluorescein isothiocyanate staining method. Plasma membrane scrambling in
      spermatozoa was assessed by a flow cytometer, using merocyanine staining. The
      results show that P4 at the concentrations used had no negative effects on sperm
      viability. Progesterone significantly enhanced sperm capacitation (p < 0.001),
      but had no effect on plasma membrane lipid stability (p > 0.05) and did not
      significantly increase the AR of heparin-capacitated spermatozoa (p > 0.05).
      Progesterone displayed its effects in a dose-dependent manner with a maximum
      effect of 10 microg/ml P4 at 180 min of incubation. The results demonstrate that
      in cryopreserved bovine semen, P4 acts as capacitating, but not as an AR-inducing
      agent.

PMID- 15182292
TI  - Telomerase activity in swamp buffalo (Bubalus bubalis) oocytes and embryos
      derived from in vitro fertilization, somatic cell nuclear transfer and
      parthenogenetic activation.
AB  - The objective of this study was to examine the telomerase activity in swamp
      buffalo oocytes and pre-implantation stage embryos derived from in vitro
      fertilization (IVF), somatic cell nuclear transfer (NT) and parthenogenetic
      activation (PA). Immature and mature oocytes, and embryos at the 2-4 cell, 8-16
      cell, morula and blastocyst stages produced by IVF, NT and PA were collected and
      the telomerase activity was assayed by using a Telomerase PCR ELISA kit.
      Telomerase activity was detected in all developmental stages evaluated from
      immature oocytes to blastocyst stage embryos. Telomerase activity was detected in
      higher amounts in immature as compared with mature oocytes (p < 0.05). Embryos
      derived from NT showed a profile of telomerase activity similar to that of IVF.
      In IVF and NT embryos, telomerase activity was low in the 2-4 cell and 8-16 cell
      stages, but the activity significantly increased (p < 0.05) at the morula stage,
      reaching its highest level at the blastocyst stage. In PA embryos, low levels of
      telomerase activity were detected from the 2-4 cell to the morula stage, and the
      highest level of telomerase activity was found at the blastocyst stage.
      Telomerase activity in NT blastocysts is higher than that derived from IVF and
      the activity is highest in PA blastocysts. These results suggest that the
      successful reprogramming of telomerase activity in buffalo NT embryos follow a
      pattern similar to that in embryos derived from IVF and PA.

PMID- 15182294
TI  - Characterization and localization of membrane vesicles in ejaculate fractions
      from the ram, boar and stallion.
AB  - Membrane vesicles, separated by differential centrifugation from the seminal
      plasma, were detected in the sperm-rich ejaculate fractions of four boars and
      three stallions, and in the whole ejaculates of seven rams. The volume and
      percentage of vesicles, determined by a stereological technique, were higher in
      the sperm-rich than in the post-sperm-rich fractions of the boar and stallion
      ejaculates, and no vesicles were detected in the pre sperm-rich fractions.
      Vesicles were examined by transmission electron microscopy (TEM) and scanning
      electron microscopy (SEM). For boar, stallion and ram semen, the mean (+/-
      s.e.m.) vesicle diameters were 130.9 +/- 3.22 (range 18-577), 164.1 +/- 4.42
      (range 15-671) and 159.7 +/- 2.92 nm (range 22-986), respectively, although they
      were not significantly different (p = 0.709). The vesicles had approximately
      round (TEM) or spherical shape (SEM), were surrounded by single, double or multi
      laminar membranes, and were trapped within ample amorphous material, sometimes
      containing short, flattened membranous elements. The majority of the vesicles had
      a clear interior but some contained granule-dense material. Ram membrane
      vesicles, purified from ultracentrifuged plasma by size exclusion chromatography,
      kept their round shape and the amorphous material was less evident compared with
      the sections taken before purification. This is the first report to identify
      seminal plasma membrane vesicles in the different fractions of ejaculated semen
      in the boar and stallion, and confirms their presence in ram seminal plasma. The
      origin and function of these vesicles are yet to be elucidated.

PMID- 15182293
TI  - Age-related variation of plasma concentrations of skatole, androstenone,
      testosterone, oestradiol-17 beta, oestrone sulphate, dehydroepiandrosterone
      sulphate, triiodothyronine and IGF-1 in six entire male pigs.
AB  - This study describes the age-related variation in boar taint compounds, skatole
      and androstenone, and testosterone, oestradiol-17 beta (E17 beta), oestrone
      sulphate (ES), dehydroepiandrosterone sulphate (DHEAS), triiodothyronine (T(3))
      and insulin-like growth factor-1 (IGF-1) in six boars. Three pairs of littermates
      of crossbred entire male pigs (from three Yorkshire x Duroc dams and one
      Hampshire sire) were included. Blood samples were taken at the age of 9-15 weeks
      and thereafter at weekly intervals from the age of 20-32 weeks. Plasma
      concentrations of skatole, androstenone, testosterone, E17 beta, ES, DHEAS, T(3)
      and IGF-1 were measured. We found that skatole levels in boars increased at the
      age around puberty after an increase in the levels of testicular steroids. Levels
      of skatole were not associated with the levels of sex steroids, T(3) and IGF-1.
      However, the increased level of testicular steroids is probably the underlying
      factor needed for high skatole levels to occur although the specific mechanism
      leading to increased skatole levels remains unknown.

PMID- 15182295
TI  - Influence of CRH and ACTH administration on endocrine profile and ovulation in
      sows.
AB  - Grouping of sows is a stressful event until the ranking is established. The
      purpose of this study was to simulate stress by repeated administration of
      porcine corticotropin releasing hormone (CRH) and adrenocorticotropic hormone
      (ACTH)/tetracosactide and to study its influence on endocrine profile and
      ovulation. Four multiparous sows were used and blood was collected every 2 h from
      the onset of pro-oestrus until 12 h after ovulation. The first oestrus after
      weaning was used to check ovulation and acclimate the sows to their environment.
      The second oestrus after weaning was used as control. At their third oestrus CRH
      (0.6 microg/kg) and at their fourth oestrus ACTH (5 microg/kg) were given every 4
      h from onset of oestrus until ovulation. The total 'area under the curve' of
      cortisol was twofold larger in two of four sows during the CRH treatment period,
      and two- to fourfold larger (p < or = 0.05) during the ACTH treatment period,
      compared with the corresponding control period. In three sows, there was no clear
      effect of either CRH or ACTH on the levels of oestradiol 17beta, luteinizing
      hormone (LH) or on the timing of ovulation. One sow was different in all hormonal
      patterns and also in the timing of ovulation. In all four sows, ACTH treatment
      lowered the baseline level of prostaglandin F(2 alpha)-metabolite. Therefore, we
      conclude that stage of the oestrous cycle seems to be of importance when
      investigating the influence of exogenous administration of CRH/ACTH on hormonal
      pattern and ovulation time in the sow.

PMID- 15182296
TI  - Effect of gestational age and fetal position on the possibility and accuracy of
      ultrasonographic fetal gender determination in dairy cattle.
AB  - The possibility and accuracy of transrectal ultrasonographic determination of
      foetal gender were studied by identifying and locating the genital tubercle,
      scrotum or mammary gland in 15 dairy cows at 49-168 days post-breeding.
      Ultrasound examinations were performed weekly. Each examination was made without
      references to the results of the examinations in the previous weeks. At each
      examination, an attempt was made to view the foetus in frontal, cross-sectional,
      and sagittal planes. The expected foetal gender was compared with that observed
      at birth. Gestational age affected significantly the possibility of foetal gender
      determination. The possibility of foetal gender determination increased from
      26.7% at day 49 to 100% at day 56 of gestation. Between days 56 and 98, foetal
      gender determination was possible in all cases. Thereafter, the ability to
      determine foetal gender decreased with development of pregnancy and was
      impossible in all cases by days 161 and 168. The overall accuracy of foetal
      gender determination was 97.3%. Foetal gender determination between days 49 and
      63 depended on the location of the genital tubercle in a frontal view of the
      foetus. By day 70, all foetal positions could be used for foetal gender
      determination. However, by progress of gestation, the usefulness of frontal view
      for sex determination decreased, while that of cross-sectional view increased.
      Accordingly, the best time for foetal gender determination in dairy cattle is
      between days 56 and 98 of pregnancy.

PMID- 15182297
TI  - Intra-uterine insemination in farm animals and humans.
AB  - Artificial insemination (AI) is the oldest and currently most common technique in
      the assisted reproduction of animals and humans. The introduction of AI in farm
      animals was forced by sanitary reasons and the first large-scale applications
      with a commercial goal were performed in cattle in the late 1930s of last
      century. After the Second World War, cryopreservation of semen facilitated
      distribution and AI was mainly performed for economic reasons, especially in
      dairy cattle industry. In humans however, AI was initially performed in cases of
      physiological and psychological sexual dysfunction, but later on also in cases of
      infertility caused by immunological problems. Currently, the most common
      indications for intra-uterine insemination (IUI) in humans are unexplained
      infertility and male subfertility. In these cases, IUI is considered as the
      treatment of the first choice, before more invasive techniques such as in vitro
      fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) are used. In
      contrast with humans, the quantity and quality of semen produced by farm animals
      is much higher and permits dilution and production of several insemination doses
      per ejaculate. However, with the introduction of sex-sorted semen in farm
      animals, the same problem of low-quality semen as in humans has arisen. In
      cattle, pigs and horses, conventional insemination with low numbers of sex-sorted
      spermatozoa results in a significant decrease in fertility. To improve the
      fertility rates with this semen, new insemination techniques have been developed
      in order to deposit spermatozoa closer to the site of fertilization. In sows and
      mares the advantage of utero-tubal junction (UTJ) insemination has already been
      proven; however, in cattle it is still under investigation. In this review, the
      differences and similarities in the application of AI between animals and humans
      are discussed and as AI in farm animals is most successful in cattle, the
      situation in this species is elaborated the most.

PMID- 15182298
TI  - Glutamate-induced elevations in intracellular chloride concentration in
      hippocampal cell cultures derived from EYFP-expressing mice.
AB  - The homeostasis of intracellular Cl(-) concentration ([Cl(-)](i)) is critical for
      neuronal function, including gamma-aminobutyric acid (GABA)ergic synaptic
      transmission. Here, we investigated activity-dependent changes in [Cl(-)](i)
      using a transgenetically expressed Cl(-)-sensitive enhanced yellow-fluorescent
      protein (EYFP) in cultures of mouse hippocampal neurons. Application of glutamate
      (100 microm for 3 min) in a bath perfusion to cell cultures of various days in
      vitro (DIV) revealed a decrease in EYFP fluorescence. The EYFP signal increased
      in amplitude with increasing DIV, reaching a maximal response after 7 DIV.
      Glutamate application resulted in a slight neuronal acidification. Although EYFP
      fluorescence is sensitive to pH, EYFP signals were virtually abolished in Cl(-)
      free solution, demonstrating that the EYFP signal represented an increase in [Cl(
      )](i). Similar to glutamate, a rise in [Cl(-)](i) was also induced by specific
      ionotropic glutamate receptor agonists and by increasing extracellular [K(+)],
      indicating that an increase in driving force for Cl(-) suffices to increase [Cl(
      )](i). To elucidate the membrane mechanisms mediating the Cl(-) influx, a series
      of blockers of ion channels and transporters were tested. The glutamate-induced
      increase in [Cl(-)](i) was resistant to furosemide, bumetanide and 4,4'
      diisothiocyanato-stilbene-2,2'-disulphonic acid (DIDS), was reduced by
      bicuculline to about 80% of control responses, and was antagonized by niflumic
      acid (NFA) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We conclude
      that membrane depolarization increases [Cl(-)](i) via several pathways involving
      NFA- and NPPB-sensitive anion channels and GABA(A) receptors, but not through
      furosemide-, bumetanide- or DIDS-sensitive Cl(-) transporters. The present study
      highlights the vulnerability of [Cl(-)](i) homeostasis after membrane
      depolarization in neurons.

PMID- 15182299
TI  - Absence of phosphoglucose isomerase-1 in retinal photoreceptor, pigment
      epithelium and Muller cells.
AB  - Macroarray analysis was used to compare equal amounts of cDNA from wild-type and
      rd/rd (retinal degeneration) mice, collected at P90 when photoreceptor
      degeneration is virtually complete. A stronger signal for the glycolytic enzyme
      phosphoglucose isomerase (Gpi1) was observed in the rd/rd sample.
      Extracellularly, Gpi1 may act as a cytokine, independently described as
      neuroleukin and autocrine motility factor. Retinal Gpi1 expression was
      investigated by Northern and Western blot analysis and immunohistochemistry.
      Double-labelling was performed with antibodies against Gpi1 and calbindin-D,
      glutamine synthetase, RPE65, calretinin and ultraviolet opsin in order to provide
      positive cell type identification. Northern and Western blots showed double
      expression levels per microgram of RNA and protein, respectively, in the rd/rd
      retina compared with wild-type. However, the total amount of Gpi1 protein per
      retina was indistinguishable. Gpi1 immunoreactivity was found in ganglion,
      amacrine, horizontal and bipolar cells, but not in rods, cones, pigment
      epithelium and Muller cells. This distribution explains why the absolute amounts
      of Gpi1 protein were not appreciably different between wild-type and the rd/rd
      phenotype, where rods and cones are absent, whilst the relative contribution of
      Gpi1 to the total protein and RNA pools differed. Some extracellular
      immunoreactivity was observed in the photoreceptor matrix around cones in freshly
      fixed tissue only, which could possibly reflect a role as a cytokine. We propose
      that glycolysis in Gpi1-negative cells proceeds entirely through the pentose
      phosphate pathway, creating NADPH at the cost of organic carbon. We hypothesize
      that the unique metabolic needs of photoreceptors justify this trade-off.

PMID- 15182301
TI  - Development of the mouse hypothalamo-neurohypophysial system in the munc18-1 null
      mutant that lacks regulated secretion.
AB  - The hypothalamo-neurohypophysial system (HNS) is composed of hypothalamic
      magnocellular neurons and neural lobe pituicytes that accommodate the nerve
      terminals. Here we have investigated if the communication of the peptidergic
      neurons of the HNS with neighbouring cells plays a role in the development and
      assembly of the HNS. We employed munc18-1-deficient mice, which completely lack
      neurotransmitter secretion. Morphological and immunohistological analysis of the
      HNS in these mutant embryos during brain development showed that this peptidergic
      system was formed normally during early embryogenesis. However, the development
      arrested at embryonal day 14.5, the stage when terminal differentiation has to
      take place. The peptidergic neurons targeted axons in the correct direction, but
      few arrived at their final location and the neurons were not maintained in later
      stages. The pituicytes in the neural lobe of the pituitary were generated, but
      failed to organize normally. Our results indicate that peptide gene expression,
      axon outgrowth and migration are intrinsic developmental events in these
      peptidergic neurons, that are initiated in the munc18-1 null mutant. The further
      expansion and the integration of outgrowing axon terminals with neural lobe
      pituicytes requires munc18-1-dependent processes, probably exocytosis, at
      multiple levels. Firstly, to maintain and propagate neuronal outgrowth and
      guidance, and secondly, to control the cellular organization of the pituicytes.
      Thus, the communication between the outgrowing neurons and the pituicytes could
      serve to integrate these two cell types to constitute a functional peptidergic
      system.

PMID- 15182300
TI  - Irreversible loss of a subpopulation of cortical interneurons in the absence of
      glutamatergic network activity.
AB  - In the cerebral cortex of mammals, gamma-aminobutyric acid (GABA)ergic neurons
      represent 15-25% of all neurons, depending on the species and area being
      examined. Because converging evidence suggests that activity may play an
      important role in the neuritic maturation and synaptic function of GABAergic
      neurons, it is feasible that activity plays a role in the regulation of the
      proportion of GABAergic neurons. Here we provide direct evidence that early in
      cortical development activity blockade may deplete the network of a subpopulation
      of GABA immunoreactive neurons characterized by their small size and late
      generation in vitro. In a period of time coinciding with the emergence of
      synchronous network activity, the survival and morphological differentiation of
      GABAergic neurons was influenced by long-term blockade of synaptic activity.
      While GABA(A) receptor antagonists had a minor promoting effect on interneuronal
      survival during the second week in vitro, antagonists of ionotropic glutamate
      receptors strongly impaired survival and differentiation of immature GABAergic
      interneurons. Interneuronal loss was more severe when N-methyl-D-aspartate
      receptors were blocked than after blockade of alpha-amino-3-hydroxy-5
      methylisoxazole-4-proprionic acid (AMPA)/kainate receptors. The decrease in the
      density of GABAergic neurons was irreversible, but could be prevented by the
      simultaneous addition of brain-derived neurotrophic factor (BDNF). These results
      suggest that there is a narrow time window during neocortical development when
      glutamatergic activity, and specially NMDA receptor stimulation, is crucial to
      assure survival and maturation of a subpopulation of late developing GABAergic
      interneurons.

PMID- 15182302
TI  - Neuronal activation of Ras regulates synaptic connectivity.
AB  - A synRas mouse model was used expressing constitutively activated Ha-Ras (Val12
      mutation) in neurons to investigate the role of Ras-MAPkinase signalling for
      neuronal connectivity in adult brain. Expression of the transgene in the cortex
      of these mice starts after neuronal differentiation is completed and allows to
      directly investigate the effects of enhanced Ras activity in differentiated
      neurons. Activation of Ha-Ras induced an increase in soma size which was
      sensitive to MEK inhibitor in postnatal organotypic cultures. Adult cortical
      pyramidal neurons showed complex structural rearrangements associated with an
      increased size and ramification of dendritic arborization. Dendritic spine
      density was elevated and correlated with a twofold increase in number of
      synapses. In acute brain slices of the somatosensory and of the visual cortex,
      extracellular field potentials were recorded from layer II/III neurons. The input
      output relation of synaptically evoked field potentials revealed a significantly
      higher basal excitability of the transgenic mice cortex compared to wild-type
      animals. In whole cell patch clamp preparations, the frequency of AMPA receptor
      mediated spontaneous excitatory postsynaptic currents was increased while the
      ratio between NMDA and AMPA-receptor mediated signal amplitude was unchanged. A
      pronounced depression of paired pulse facilitation indicated that Ras contributes
      to changes at the presynaptic site. Furthermore, synRas mice showed an increased
      synaptic long-term potentiation, which was sensitive to blockers of NMDA
      receptors and of MEK. We conclude that neuronal Ras is a common switch of
      plasticity in adult mammalian brain sculpturing neuronal architecture and
      synaptic connectivity in concert with tuning synaptic efficacy.

PMID- 15182303
TI  - Postnatal emergence of mature release properties in terminals of rat fast- and
      slow-twitch muscles.
AB  - Motor nerve terminals in adult mammalian slow-twitch muscles have lower levels of
      spontaneous and evoked neurotransmitter release than terminals in fast-twitch
      muscles. These reflect adaptive differences, allowing terminals in slow
      (postural) muscles to sustain release during the prolonged firing trains
      experienced in vivo. Here we ask whether these differences in terminal release
      properties in Sprague-Dawley rat extensor digitorum longus (EDL, fast) and soleus
      (slow) muscles reflect their early cytodifferentiation in the embryo or whether
      they might be adaptations to their distinct mature activity patterns, which
      emerge around two weeks postnatally. We find that the mature pattern of
      differences in release arise through co-ordinated increases in presynaptically
      dependent release properties (quantal content, spontaneous release frequency and
      evoked potential amplitude), beginning at three weeks, which are particularly
      substantial in EDL. In contrast, other synaptic properties are either
      consistently greater in the same muscle throughout development (evoked potential
      kinetics, muscle fibre diameter) or display no systematic muscle type-dependent
      differences (terminal area, input resistance, spontaneous release amplitude).
      Thus, the emergence of adaptive differences in terminal release properties
      correlates with the differentiation of locomotor activity patterns in postnatal
      rat hindlimb muscles.

PMID- 15182304
TI  - Phasic bursts in rat magnocellular neurosecretory cells are not intrinsically
      regenerative in vivo.
AB  - Vasopressinergic hypothalamic magnocellular neurosecretory cells fire in phasic
      bursts. Burst initiation involves summation of postsynaptic potentials to
      generate action potentials. Action potentials are each followed by a nonsynaptic
      depolarizing after-potential that summates temporally to generate a plateau
      potential and so sustain activity throughout the burst. It is unknown whether
      this plateau potential exceeds spike threshold in vivo to cause intrinsic
      regenerative firing or simply approaches threshold to increase the probability
      that excitatory postsynaptic potentials will trigger further action potentials.
      Here we show that pharmacological blockade of ionotropic glutamatergic
      transmission by microdialysis application of kynurenic acid into the supraoptic
      nucleus of anaesthetized rats prevents spontaneous bursts and bursts (after
      discharge) evoked by short trains of antidromically stimulated action potentials
      in magnocellular neurosecretory cells. Even during prolonged depolarization
      induced by 1 m NaCl infusion, kynurenic acid microdialysis application still
      blocked after-discharge. The ability of kynurenic acid to block after-discharge
      during osmotic stimulation was not caused by an unmasking of inhibitory
      postsynaptic potentials as kynurenic acid was equally effective in the presence
      of the ionotropic gamma-aminobutyric acid receptor antagonist, bicuculline, nor
      did it result from inhibition of plateau potential amplitude as this was
      unaffected by kynurenic acid and bicuculline in vitro, as was after-discharge
      evoked in vitro. We conclude that phasic bursts are nonregenerative in vivo but
      rather require continued excitatory synaptic input activity superimposed upon a
      subthreshold plateau potential to sustain burst activity.

PMID- 15182305
TI  - The therapeutic window after spinal cord injury can accommodate T cell-based
      vaccination and methylprednisolone in rats.
AB  - Immune system activity has traditionally been considered harmful for recovery
      after spinal cord injury (SCI). Recent evidence suggests, however, that immune
      activity--and specifically autoimmune activity--is evoked by the insult, is
      beneficial if properly regulated and is amenable to boosting. Thus, for example,
      vaccination with an altered peptide ligand derived from myelin basic protein
      reduces the progressive degeneration of neurons that escaped the initial insult,
      thereby promoting recovery after SCI. As the steroid drug methylprednisolone (MP)
      is currently the only treatment available for patients with SCI, our purpose in
      the present study was to examine the mutual compatibility of the two treatments
      within the post-traumatic therapeutic window. We show, using rats of two
      different strains, that if MP is injected concomitantly with the therapeutic
      vaccination, the beneficial effect of the vaccination is diminished. However, if
      MP is given immediately after the insult and the vaccination 48 h later, MP does
      not detract from the beneficial effect of the vaccination. These results
      demonstrate that the therapeutic window after SCI can accommodate immediate
      administration of MP plus a delayed therapeutic vaccination.

PMID- 15182306
TI  - Endocannabinoid transport tightly controls 2-arachidonoyl glycerol actions in the
      hippocampus: effects of low temperature and the transport inhibitor AM404.
AB  - The control of endocannabinoid actions on cortical neurons by a putative carrier
      mediated uptake is still poorly understood at the level of synaptic transmission.
      We investigated the effect of an endocannabinoid, 2-arachidonoyl glycerol (2-AG),
      on inhibitory postsynaptic currents (IPSCs) in hippocampal slices under
      physiological conditions, and when uptake was altered by a selective blocker or
      lower temperature. Bath application of 2-AG (20 micro m) caused a 40% reduction
      in the amplitude of IPSCs evoked in the perisomatic region of CA1 pyramidal
      neurons at room temperature; this effect could be blocked by a specific CB(1)
      receptor antagonist, AM251. By contrast, a smaller (20%) but significant
      suppression of inhibitory transmission was found by 2-AG at 33-35 degrees C. This
      reduced blocking effect at physiological temperature could be brought back to 40%
      by coapplying the endocannabinoid uptake blocker, AM404 (10 or 20 micro m) with 2
      AG. In parallel experiments, we measured [(3)H]2-AG uptake at different
      temperatures in primary cultures prepared from cortical neurons. These data
      confirmed a striking inhibition of [(3)H]2-AG uptake at room temperature compared
      with values observed at 37 degrees C. Uptake could be significantly modified by
      anandamide, 2-AG and AM404, suggesting a common transporter for the two
      endocannabinoids. These findings together demonstrate the presence of an
      effective endocannabinoid uptake in cortical neurons, which could considerably
      alter the spatial and temporal constraints of endocannabinoid signalling at
      physiological temperature, and which may critically change the interpretation of
      findings at room temperature.

PMID- 15182307
TI  - Brain virus burden and indoleamine-2,3-dioxygenase expression during lentiviral
      infection of rhesus monkey are concomitantly lowered by 6-chloro-2',3'
      dideoxyguanosine.
AB  - Increased kynurenine pathway metabolism has been implicated in the aetiology of
      lentiviral encephalopathy. Indoleamine-2,3-dioxygenase (IDO) initiates the
      increased production of kynurenine pathway metabolites like quinolinic acid
      (QUIN). QUIN itself is elevated in AIDS-diseased monkey and human brain
      parenchyma and cerebrospinal fluid at levels excitotoxic for neurons in vitro.
      This study investigates the cellular origin of IDO biosynthesis in the brain of
      rhesus monkeys infected with simian immunodeficiency virus (SIV) and explores the
      effects of CNS-permeant antiretroviral treatment. IDO transcript and protein were
      absent from the brain of non-infected and SIV-infected asymptomatic monkeys. IDO
      biosynthesis was induced in the brain of monkeys exhibiting AIDS. Nodule and
      multinucleated giant cell-forming macrophages were the main sources of IDO
      synthesis. Treatment with the lipophilic 6-chloro-2',3'-dideoxyguanosine
      suppressed IDO expression in the brain of AIDS-diseased monkeys. The
      effectiveness of this treatment was confirmed by the reduction of virus burden
      and SIV-induced perivascular infiltrates, mononuclear nodules and multinucleated
      giant cells. Our data demonstrate that brain IDO biosynthesis is induced in a
      subset of monocyte-derived cells, depends on viral burden and is susceptible to
      antiretroviral treatment. Thus, IDO induction is associated with reversible overt
      inflammatory events localized to areas of active viral replication in the SIV
      infected brain.

PMID- 15182308
TI  - Intracuneate mechanisms underlying primary afferent cutaneous processing in
      anaesthetized cats.
AB  - The cutaneous primary afferents from the upper trunk and forelimbs reach the
      medial cuneate nucleus in their way towards the cerebral cortex. The aim of this
      work was twofold: (i) to study the mechanisms used by the primary afferents to
      relay cutaneous information to cuneate cuneolemniscal (CL) and noncuneolemniscal
      (nCL) cells, and (ii) to determine the intracuneate mechanisms leading to the
      elaboration of the output signal by CL cells. Extracellular recordings combined
      with microiontophoresis demonstrated that the primary afferent cutaneous
      information is communicated to CL and nCL cells through AMPA, NMDA and kainate
      receptors. These receptors were sequentially activated: AMPA receptors
      participated mainly during the initial phase of the response, whereas kainate-
      and NMDA-mediated activity predominated during a later phase. The involvement of
      NMDA receptors was confirmed by in vivo intracellular recordings. The cutaneous
      evoked activation of CL cells was decreased by GABA and increased by glycine
      acting at a strychnine-sensitive site, indicating that glycine indirectly affects
      CL cells. Two subgroups of nCL cells were distinguished based on their
      sensitivity to iontophoretic ejection of glycine and strychnine. Overall, the
      results support a model whereby the primary afferent cutaneous input induces a
      centre-surround antagonism in the cuneate nucleus by activating (via AMPA, NMDA
      and kainate receptors) and disinhibiting (via serial glycinergic-GABAergic
      interactions) a population of CL cells with overlapped receptive fields that at
      the same time inhibit (via GABAergic cells) other neighbouring CL cells with
      different receptive fields.

PMID- 15182309
TI  - Tonic regulation of satiety by 5-HT receptors in the mouse: converging evidence
      from behavioural and c-fos immunoreactivity studies?
AB  - Activation of 5-HT(1B) receptors is thought to play an important role in the
      inhibitory influence of serotonin on feeding behaviour and body weight in
      mammals. Earlier studies have shown that 5-HT(1B)-knockout (KO) mice eat more and
      are heavier than wild-type (WT) controls and that the selective 5-HT(1B) receptor
      agonist CP-94,253 reduces food intake in food-deprived mice. Here we characterize
      the behavioural effects of both CP-94,253 and the selective 5-HT(1B) receptor
      antagonist SB224289 on feeding and other behaviours within the behavioural
      satiety sequence, and also report a c-fos mapping study using CP-94,253. CP
      94,253 produced a dose-dependent suppression of food intake with a profile
      consistent with a selective effect on feeding behaviour. These effects were
      absent or reduced in 5-HT(1B)-KO mice and in WT mice pretreated with SB224289.
      SB224289 administered alone enhanced food intake consistent with impaired
      satiation; a similar effect was apparent in 5-HT(1B)-KO mice compared to WT. CP
      94,253 induced c-fos in a range of structures previously implicated in the
      expression of feeding behaviour. These results suggest that the activation of 5
      HT(1B) receptors is an important component of endogenous satiation mechanisms in
      the mouse.

PMID- 15182310
TI  - Behavioral training interferes with the ability of gonadal hormones to increase
      CA1 spine synapse density in ovariectomized female rats.
AB  - Estradiol benzoate (EB) has repeatedly been shown to increase hippocampal CA1
      spine synapse density in ovariectomized female rats. Although this increase has
      been assumed to enhance memory, a direct link between increased spine synapse
      density and memory has not been demonstrated. Furthermore, while androgens, such
      as testosterone propionate (TP) and dihydrotestosterone (DHT), also increase
      spine synapse density in females, their effects on memory have yet to be
      investigated. In the present study, ovariectomized female rats were given two
      injections, 24 h apart, of sesame oil (control), 10 microg EB, 500 microg TP or
      500 microg DHT. Forty-eight hours after the second injection, rats were tested in
      a 1-day spatial Morris water maze task and then immediately perfused for analysis
      of CA1 spine synapse density (using electron microscopy and unbiased stereology).
      In the spatial acquisition phase of testing, EB, but not TP or DHT, significantly
      impaired memory relative to controls. Hormone treatment did not affect spatial
      retention or performance in the non-spatial phase of testing. In contrast to
      previous work, spine synapse density was not increased by EB, TP or DHT. We
      therefore examined a new set of EB-treated females, only half of which were water
      maze tested. Consistent with previous work, EB significantly increased spine
      synapse density among behaviorally naive females. In contrast, spine synapse
      densities did not differ among behaviorally tested control and EB females,
      although they were higher than behaviorally naive controls. These data indicate
      that 1-day water maze testing can eliminate the hormone-induced increases in CA1
      spine synapse density typically observed in behaviorally naive females.

PMID- 15182311
TI  - DREAM ablation selectively alters THC place aversion and analgesia but leaves
      intact the motivational and analgesic effects of morphine.
AB  - DREAM (downstream regulatory element antagonistic modulator) is a novel
      transcriptional repressor for the prodynorphin gene, and genetic deletion of
      DREAM in mice results in a phenotype of ongoing analgesia by virtue of its effect
      on opioid gene expression. In the present study, we evaluated the motivational
      effects of opioids (morphine), cannabinoids [Delta(9)-tetrahydrocannabinol (THC)]
      and cocaine in mice lacking the dream gene (dream(-/-)). The aversive effects of
      THC were potentiated in dream(-/-) mice in a kappa-opioid receptor-dependent
      fashion, whereas morphine reward and the aversive effects of morphine withdrawal
      remained intact. The rewarding and aversive effects of cocaine were likewise
      unperturbed in dream(-/-) mice. Moreover, the aversive properties of lithium
      chloride and naloxone were unaffected by the absence of DREAM, indicating that
      the effect of DREAM on THC-induced dysphoria is not due to a general involvement
      in the behavioral response to aversive stimuli. Additionally, physical dependence
      to morphine and the locomotor-sensitizing effects of cocaine were unaltered in
      these animals. Finally, whereas the absence of DREAM reduced the analgesic
      efficacy of THC, morphine analgesia was unaffected in dream(-/-) mice.

PMID- 15182312
TI  - Reminder effects: the molecular cascade following a reminder in young chicks does
      not recapitulate that following training on a passive avoidance task.
AB  - Memory traces, once established, are no longer sensitive to disruption by
      metabolic inhibitors. However, memories reactivated by reminder are once again
      vulnerable, in a time-dependent manner, to amnestic treatment. To determine
      whether the metabolic events following a reminder recapitulate those following
      initial training we examined the temporal dynamics of amnesia induced by the
      protein synthesis inhibitor anisomycin and the glycosylation inhibitor 2
      deoxygalactose. The effects of both were transient and dependent on time of
      reminder post-training and time of injection relative to reminder, and differed
      from those following initial training. 2-[(14)C]-deoxyglucose uptake increased in
      two brain regions, the intermediate medial hyperstriatum ventrale (IMHV) and
      lobus parolfactorius (LPO) following reminder as it did following training, but
      the increase was bilateral rather than confined to the left hemisphere and was
      more marked in LPO than IMHV. C-fos expression after reminder was increased only
      in the LPO, the chick brain region associated with a late phase of memory
      processing and recall. Thus although, like initial consolidation, memory
      processing after reminder is sensitive to inhibitors of protein synthesis and
      glycosylation, the temporal and pharmacological dynamics indicate differences
      between these two processes.

PMID- 15182313
TI  - An impaired neocortical Ih is associated with enhanced excitability and absence
      epilepsy.
AB  - Neuronal subthreshold excitability and firing behaviour are markedly influenced
      by the activation and deactivation of the somato-dendritic hyperpolarization
      activated cation current (Ih). Here, we evaluated possible contributions of Ih to
      hyperexcitability in an animal model of absence seizures (WAG/Rij rats). We
      investigated pyramidal neurons of the somatosensory neocortex, the site of
      generation of spike-wave discharges. Ih-mediated functions in neurons from
      WAG/Rij rats, Wistar rats (sharing the same genetic background with WAG/Rij, but
      less epilepsy-prone) and ACI rats (an inbred strain, virtually free of seizures)
      were compared. We complemented whole-cell recordings from layer 2-3 pyramidal
      neurons with immunohistochemistry, Western blot and RT-PCR analysis of the h
      channel subunits HCN1-4. The fast component of Ih activation in WAG/Rij neurons
      was significantly reduced (50% reduction in the h-current density) and four times
      slower than in neurons from nonepileptic Wistar or ACI rats. The results showing
      decreases in currents corresponded to a 34% reduction in HCN1 protein in the
      WAG/Rij compared to the Wistar neocortex, but HCN1 mRNA showed stable expression.
      The other three Ih subunit mRNAs and proteins (HCN2-4) were not affected. The
      alterations in Ih magnitude and kinetics of gating in WAG/Rij neurons may
      contribute to augmented excitatory postsynaptic potentials, the increase in their
      temporal summation and the facilitation of burst firing of these neurons because
      each of these effects could be mimicked by the selective Ih antagonist ZD 7288.
      We suggest that the deficit in Ih-mediated functions may contribute to the
      development and onset of spontaneously occurring hyperexcitability in a rat model
      of absence seizures.

PMID- 15182314
TI  - An investigation of the role of auditory cortex in sound localization using
      muscimol-releasing Elvax.
AB  - Lesion studies suggest that primary auditory cortex (A1) is required for accurate
      sound localization by carnivores and primates. In order to elucidate further its
      role in spatial hearing, we examined the behavioural consequences of reversibly
      inactivating ferret A1 over long periods, using Elvax implants releasing the
      GABA(A) receptor agonist muscimol. Sub-dural polymer placements were shown to
      deliver relatively constant levels of muscimol to underlying cortex for >5
      months. The measured diffusion of muscimol beneath and around the implant was
      limited to 1 mm. Cortical silencing was assessed electrophysiologically in both
      auditory and visual cortices. This exhibited rapid onset and was reversed within
      a few hours of implant removal. Inactivation of cortical neurons extended to all
      layers for implants lasting up to 6 weeks and throughout at least layers I-IV for
      longer placements, whereas thalamic activity in layer IV appeared to be
      unaffected. Blockade of cortical neurons in the deeper layers was restricted to <
      or = 500 microm from the edge of the implant, but was usually more widespread in
      the superficial layers. In contrast, drug-free Elvax implants had little
      discernible effect on the responses of the underlying cortical neurons. Bilateral
      implants of muscimol-Elvax over A1 produced significant deficits in the
      localization of brief sounds in horizontal space and particularly a reduced
      ability to discriminate between anterior and posterior sound sources. The
      performance of these ferrets gradually improved over the period in which the
      Elvax was in place and attained that of control animals following its removal.
      Although similar in nature, these deficits were less pronounced than those caused
      by cortical lesions and suggest a specific role for A1 in resolving the spatial
      ambiguities inherent in auditory localization cues.

PMID- 15182315
TI  - Interaction between the neuromagnetic responses to sound energy onset and pitch
      onset suggests common generators.
AB  - The pitch-onset response (POR) is a negative component of the auditory evoked
      field which is elicited when the temporal fine structure of a continuous noise is
      regularized to produce a pitch perception without altering the gross spectral
      characteristics of the sound. Previously, we showed that the latency of the POR
      is inversely related to the pitch value and its amplitude is correlated with the
      salience of the pitch, suggesting that the underlying generators are part of a
      pitch-processing network [Krumbholz, K., Patterson, R.D., Seither-Preisler, A.,
      Lammertmann, C. & Lutkenhoner, B. (2003) Cereb. Cortex,13, 765-772]. The source
      of the POR was located near the medial part of Heschl's gyrus. The present study
      was designed to determine whether the POR originates from the same generators as
      the energy-onset response (EOR) represented by the N100m/P200m complex. The EOR
      to the onset of a noise, and the POR to a subsequent transition from noise to
      pitch, were recorded as the time interval between the noise onset and the
      transition varied from 500 to 4000 ms. The mean amplitude of the POR increased by
      approximately 5.9 nA.m with each doubling of the time between noise onset and
      transition. This suggests an interaction between the POR and the EOR, which may
      be based on common neural generators.

PMID- 15182316
TI  - Neural correlates of error detection and error correction: is there a common
      neuroanatomical substrate?
AB  - Successful behaviour requires error detection resulting in remedial actions, such
      as immediate error correction. The present event-related functional magnetic
      resonance imaging study in humans examined the neural correlates of error
      detection and error correction using a speeded modified flankers task. In order
      to investigate corrective behaviour, participants were randomly divided into two
      groups. The correction instructed group was asked to correct all encountered
      errors immediately. The correction not instructed group was unaware that
      corrective responses were recorded. The intention to correct errors significantly
      increased the correction rate. Brain activations correlating with error detection
      were isolated in the rostral cingulate zone and in the pre-supplementary motor
      area, supporting their important role in error processing. Error correction
      activated similar brain regions, suggesting a common neuroanatomical substrate.
      Additional activations were found in the parietal cortex, representing an
      interconnected cortical network, which processes somatosensory information of
      tactile stimuli.

PMID- 15182317
TI  - Synchronization of gamma oscillations increases functional connectivity of human
      hippocampus and inferior-middle temporal cortex during repetitive visuomotor
      events.
AB  - Do recency processes associated with repetitive sensorimotor events modulate the
      magnitude and functional coupling of brain rhythmicity in human temporal cortex?
      Intracranial stereo electroencephalographic activity (SEEG; 256 Hz sampling rate)
      was recorded from hippocampus, and inferior (BA20) and middle (BA21) temporal
      cortex in four epilepsy patients. The repetitive events were represented by
      predicted imperative somatosensory stimuli (CNV paradigm) triggering hand
      movements ("repetitive visuomotor") or counting ("repetitive counting"). The non
      repetitive events were "rare" (P3 paradigm) somatosensory stimuli triggering hand
      movements ("non-repetitive visuomotor") or counting ("non-repetitive counting").
      Brain rhythmicity was indexed by event-related desynchronization/synchronization
      (ERD/ERS) of SEEG data, whereas the functional coupling was evaluated by spectral
      SEEG coherence between pairs of the mentioned areas. The frequency bands of
      interest were theta (4-8 Hz), alpha (8-12 Hz), beta (14-30 Hz), and gamma (32-46
      Hz). Compared to the non-repetitive events, the "repetitive visuomotor" events
      showed a significant beta and gamma ERS in the hippocampus and a significant
      theta ERD in the inferior temporal cortex. Furthermore, the "repetitive
      visuomotor" events induced a task-specific significant gamma coherence among the
      examined areas. These results suggest that recency processes do modulate the
      magnitude and functional coupling of brain rhythmicity (especially gamma) in the
      human temporal cortex.

PMID- 15182318
TI  - Intracortical inhibition and facilitation upon awakening from different sleep
      stages: a transcranial magnetic stimulation study.
AB  - Intracortical facilitation and inhibition, as assessed by the paired-pulse
      transcranial magnetic stimulation technique with a subthreshold conditioning
      pulse followed by a suprathreshold test pulse, was studied upon awakening from
      REM and slow-wave sleep (SWS). Ten normal subjects were studied for four
      consecutive nights. Intracortical facilitation and inhibition were assessed upon
      awakening from SWS and REM sleep, and during a presleep baseline. Independently
      of sleep stage at awakening, intracortical inhibition was found at 1-3-ms
      interstimulus intervals and facilitation at 7-15-ms interstimulus intervals.
      Motor thresholds were higher in SWS awakenings, with no differences between REM
      awakenings and wakefulness, while motor evoked potential amplitude to
      unconditioned stimuli decreased upon REM awakening as compared to the other
      conditions. REM sleep awakenings showed a significant increase of intracortical
      facilitation at 10 and 15 ms, while intracortical inhibition was not affected by
      sleep stage at awakening. While the dissociation between motor thresholds and
      motor evoked potential amplitudes could be explained by the different
      excitability of the corticospinal system during SWS and REM sleep, the heightened
      cortical facilitation upon awakening from REM sleep points to a cortical motor
      activation during this stage.

PMID- 15182319
TI  - Prefrontal-subcortical dissociations underlying inhibitory control revealed by
      event-related fMRI.
AB  - Using event-related fMRI, this study investigated the neural dynamics of response
      inhibition under fluctuating task demands. Fourteen participants performed a
      GO/NOGO task requiring inhibition of a prepotent motor response to NOGO events
      that occurred as part of either a Fast or Slow presentation stream of GO stimuli.
      We compared functional activations associated with correct withholds (Stops)
      required during the Fast presentation stream of stimuli to Stops required during
      the Slow presentation stream. A predominantly right hemispheric network was
      activated across conditions, consistent with previous studies. Furthermore, a
      functional dissociation of activations between conditions was observed. Slow
      Stops elicited additional activation in anterior dorsal and polar prefrontal
      cortex and left inferior parietal cortex. Fast Stops showed additional activation
      in a network that included right dorsolateral prefrontal cortex, insula and
      dorsal striatum. These results are discussed in terms of our understanding of the
      impact of preparation on the distributed network underlying response inhibition
      and the contribution of subcortical areas, such as the basal ganglia, to
      executive control processes.

PMID- 15182320
TI  - The role of V5 (hMT+) in visually guided hand movements: an fMRI study.
AB  - Electrophysiological studies in animals suggest that visuomotor control of
      forelimb and eye movements involves reciprocal connections between several areas
      (striate, extrastriate, parietal, motor and premotor) related to movement
      performance and visuospatial coding of movement direction. The extrastriate area
      MT [V5 (hMT+) in humans] located in the "dorsal pathway" of the primate brain is
      specialized in the processing of visual motion information. The aim of our study
      was to investigate the functional role of V5 (hMT+) in the control of visually
      guided hand movements and to identify the corresponding cortex activation
      implicated in the visuomotor tasks using functional magnetic resonance imaging.
      Eight human subjects performed visually guided hand movements, either
      continuously tracking a horizontally moving target or performing ballistic
      tracking movements of a cursor to an eccentric stationary target while fixating a
      central fixation cross. The tracking movements were back-projected onto the
      screen using a cursor which was moved by an MRI-compatible joystick. Both
      conditions activated area V5 (hMT+), right more than left, particularly during
      continuous tracking. In addition, a large-scale sensorimotor circuit which
      included sensorimotor cortex, premotor cortex, striatum, thalamus and cerebellum
      as well as a number of cortical areas along the intraparietal sulcus in both
      hemispheres were activated. Because activity was increased in V5 (hMT+) during
      continuous tracking but not during ballistic tracking as compared to motion
      perception, it has a pivotal role during the visual control of forelimb movements
      as well.

PMID- 15182321
TI  - Sleep deprivation impairs hippocampus-mediated contextual learning but not
      amygdala-mediated cued learning in rats.
AB  - Prolonged sleep deprivation results in cognitive deficits. In rats, for example,
      sleep deprivation impairs spatial learning and hippocampal long-term
      potentiation. We tested the effects of sleep deprivation on learning in a
      Pavlovian fear conditioning paradigm, choosing a sleep deprivation paradigm in
      which REM sleep was completely prevented and non-REM sleep was strongly
      decreased. During conditioning, rats were given footshocks, either alone or
      paired with a tone, and tested 24 h later for freezing responses to the
      conditioning context, and to the tone in a novel environment. Whereas control
      animals had robust contextual learning in both background and foreground
      contextual conditioning paradigms, 72 h of sleep deprivation before conditioning
      dramatically impaired both types of contextual learning (by more than 50%)
      without affecting cued learning. Increasing the number of footshocks did not
      overcome the sleep deprivation-induced deficit. The results provide behavioural
      evidence that REM/non-REM sleep deprivation has neuroanatomically selective
      actions, differentially interfering with the neural systems underlying contextual
      learning (i.e. the hippocampus) and cued learning (i.e. the amygdala), and
      support the involvement of the hippocampus in both foreground and background
      contextual conditioning.

PMID- 15182322
TI  - Regional expression of RGS4 mRNA in human brain.
AB  - Regulators of G-protein signalling (RGS) proteins are a recently discovered class
      of proteins that modulate G-protein activity. More than 20 RGS proteins have been
      identified and are expressed throughout the body and brain. In particular, RGS4
      appears to regulate dopamine receptor function and has been implicated in several
      dopamine related diseases, including schizophrenia. This study presents an
      extensive examination of the regional distribution of RGS4 mRNA in postmortem
      human brain. Using in situ hybridization, the expression levels of RGS4 mRNA were
      determined in human hemicoronal (Talairach sections +8 and -20) brain sections.
      In the rostral slice (Talairach +8) highest levels were found in the inferior
      frontal cortex, the superior frontal, and the cingulate cortex. Slightly lower
      levels were found in the insular cortex and inferior temporal cortex. The
      caudate, putamen and nucleus accumbens had lower levels. In the caudal slice (
      20), the cortical layers showed the highest levels, with moderate levels observed
      in the parahippocampal gyrus, low levels in the CA-pyramidal region, and almost
      undetectable levels in the thalamus. In the frontal cortex a dense band was
      apparent near one of the inner layers of the cortex. In conclusion, RGS4 mRNA
      distribution in human postmortem tissue from normal persons was very dense in
      most cortical layers examined, with lower density in the basal ganglia and
      thalamus.

PMID- 15182323
TI  - Human MHC class I chain related (MIC) genes: their biological function and
      relevance to disease and transplantation.
AB  - Major histocompatibility complex (MHC) class I chain related (MIC) molecules show
      homology with classical human leukocyte antigen (HLA) molecules, but they do not
      combine with beta2 microglobulin, do not bind peptide and are not expressed on
      normal circulating lymphocytes. In response to stress, MIC proteins are expressed
      on the cell surface of freshly isolated gastric epithelium, endothelial cells and
      fibroblasts and engage the activating natural killer cell receptor NKG2D, which
      is found on many cells within the immune system. Despite the highly polymorphic
      nature of MIC genes, only one polymorphic position has been identified that
      appears to affect the binding of NKG2D. Alleles with a methionine at codon 129
      have a 10-50-fold greater capacity to complex NKG2D than alleles with a valine at
      this position. Renal and pancreatic grafts with evidence of both acute and
      chronic rejection have been shown to express MIC proteins, and anti-MIC
      antibodies have been identified in the serum of these patients. Some MIC
      molecules which are expressed by tumours appear to shed and solubilize in plasma.
      This soluble form of MIC engages cells expressing NKG2D, rendering them inactive,
      and impairs tumour cytolysis. Similarly, a protein encoded by human
      cytomegalovirus (CMV) prevents MICB surface expression and subsequent NKG2D
      interaction. Whereas the benefit of solid organ transplantation may be hindered
      by the expression of MIC molecules on grafts, tumours and viruses may take
      advantage of the expression of MIC molecules on transformed and virus-infected
      cells in order to evade this recognition pathway.

PMID- 15182324
TI  - Alport syndrome: HLA association and kidney graft outcome.
AB  - Alport syndrome (AS) is a genetic disease of type IV collagen involving non
      homogeneous patterns of inheritance characterized clinically by the presence of
      progressive haematuric nephritis leading to end-stage renal disease (ESRD),
      hearing loss and/or ophthalmologic abnormalities. The aim of this study was to
      investigate, in a cohort of AS patients who had undergone a kidney graft (KG) or
      who were still on a waiting list for a KG, (a) whether there is a correlation
      between AS and HLA antigen expression, and (b) long-term graft outcome in
      transplant patients. The AS cohort was represented by 34 ESRD patients, of whom
      25 received a KG and the remaining nine were still on a waiting list. AS
      transplant patients represented 2.78% of 899 first KGs performed at our centre
      (Transplantation Department at S. Martino Hospital, Genoa) between 1983 and 2002.
      Grafts were procured from cadaveric donors in 18 cases and from living, related
      donors in seven cases. All AS transplant patients had a post-transplant follow-up
      period of at least 12 months. Results showed that: (i) the frequency of the HLA
      DRB1*16 antigen was significantly increased in the whole AS cohort as compared to
      128 healthy subjects (HS) (corrected P-value 0.0026; relative risk 7.20) as well
      as to 232 non-AS ESRD patients on a waiting list for KG (corrected P-values
      0.0156; relative risk 4.67); (ii) 5- and 10-year graft survivals in the AS
      transplant patients were 80 and 73%, respectively, and did not differ from those
      of a control group represented by 25 non-AS KG recipients matched for sex, age,
      number of HLA mismatches and immunosuppressive treatment. Increased frequency of
      HLA-DRB1*16 in AS patients may reflect a linkage disequilibrium with genes coding
      for collagen synthesis.

PMID- 15182325
TI  - Evaluating association and transmission of eight inflammatory genes with Viliuisk
      encephalomyelitis susceptibility.
AB  - Since the discovery of Viliuisk encephalomyelitis (VE) in 1887, scientists have
      tried to understand the natural history and aetiology of this endemic
      neurological disorder among the native Sakha population of Central Siberia.
      Familial aggregation and segregation analysis suggested a genetic influence on VE
      incidence. However, recent studies have implicated an unknown virus, possibly
      from the alpha herpesvirus family, as a possible cause for this disease. As VE is
      a neurological disease characterized by the inflammatory reactions systematically
      observed in the spinocerebellar fluid and in the brain tissue of deceased
      patients, we examined 17 single nucleotide polymorphisms (SNPs) across seven
      inflammation-related candidate gene regions, including chemokine receptors type 2
      and 5 (CCR2/CCR5), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, IL
      10, stromal cell-derived factor (SDF) and chemokine regulated upon activation,
      normal T-cell expressed and presumably secreted (RANTES). Our main objective was
      to analyse the degree of genetic association between VE and candidate genes that
      have been previously implicated in other inflammatory diseases. Samples were
      collected from 83 affected families comprising 88 verified VE cases, 156 family
      members, and an additional 69 unrelated, unaffected inhabitants of the same
      geographical area. This collection included substantially all of the cases that
      are currently on the VE Registry. The experimental design included both case
      control and transmission/disequilibrium test (TDT)-based familial association
      analyses. None of 17 SNPs analysed was significantly associated with VE
      occurrence. Exclusion of these eight genes based on the lack of association has
      important implications for identifying the disease agent, as well as prescribing
      therapy and understanding Viliuisk encephalomyelitis.

PMID- 15182326
TI  - CA microsatellite polymorphism of the nuclear factor kappa B1 gene in celiac
      disease.
AB  - In the present work, we investigate the possible effect of a CAn microsatellite
      polymorphism in the nuclear factor kappa B1 (NFKB1) gene on predisposition to
      celiac disease (CD). Seventy-eight Spanish families with CD were genotyped using
      a polymerase chain reaction (PCR)-fluorescent method, and the transmission
      patterns of different CAn alleles were analysed. Furthermore, in order to type
      the CAn polymorphism more accurately, samples between 126 and 144 bp were cloned
      and sequenced. A trend of association with the 132-bp allele was found (P =
      0.02). This allele was more frequently transmitted to affected sibs, although the
      results of statistical tests were not significant after correction for multiple
      comparisons. After sequencing, we found that the 132-, 138- and 142-bp alleles
      had two As at the end of the CA microsatellite, with the other alleles presenting
      the described pattern (NCB1 nucleotide U60337) for the microsatellite repeats.
      These results suggest that the NFKB1 CAn microsatellite does not play a major
      role in CD susceptibility. In addition, a more detailed molecular
      characterization of the CA microsatellite is described.

PMID- 15182327
TI  - Polymorphisms in the genes encoding interferon-gamma and interferon-gamma
      receptors in multiple sclerosis.
AB  - Genome screens suggest that several genes, each contributing to a small extent,
      are involved in multiple sclerosis (MS) susceptibility. Simultaneous analysis of
      related genes may improve the power to detect such small effects. Interferon
      gamma (IFN-gamma), mediating its effects through the IFN-gamma receptor, is a
      pleiotropic, pro-inflammatory cytokine for which a detrimental effect on the
      course of MS has been reported. The role of IFN-gamma receptor 1 (IFNGR1) and IFN
      gamma receptor 2 (IFNGR2) gene polymorphisms has not been studied in MS, and, for
      the IFNG gene polymorphism there is only one previous study, which incorporates
      clinical, but not imaging, data. The aim of this study was to investigate whether
      polymorphisms in the IFNG and IFNGR1 and IFNGR2 genes are associated with
      susceptibility to MS, or disease characteristics, as defined by clinical and
      imaging criteria. Genotypes for IFNG, IFNGR1 and IFNGR2 were determined in 509
      patients with MS and in 193 healthy controls. Patient files were reviewed for
      disease course, age at onset of disease, and rate of progression. Serial magnetic
      resonance imaging (MRI) data were available for 107 patients. No significant
      differences in the distribution of IFNG, IFNGR1 and IFNGR2 genotype and allele
      frequencies were found between patients and controls. A progressive, as opposed
      to a relapsing, onset was significantly more frequent in carriers of the IFNGR2
      allele Arg64 (P = 0.028). Moreover, IFNGR2 allele Arg64 carriers had a lower
      black hole ratio than non-carriers (P = 0.016). No other associations with
      clinical parameters, such as age at onset or rate of progression, or with imaging
      parameters, were observed. The IFNG intron 1 gene polymorphism studied is
      unlikely to play a major role in MS susceptibility or disease course. The IFNGR1
      and IFNGR2 gene polymorphisms studied do not exert an important influence on MS
      susceptibility, but allele IFNGR2*Arg64 may be associated with a progressive
      disease onset.

PMID- 15182328
TI  - CTLA-4 gene polymorphism and its association with Graves' disease in the Lebanese
      population.
AB  - Graves' disease is an organ-specific autoimmune disease that has a female
      predominance. It is probably the result of a complex interaction of genetic and
      environmental factors. This disease is characterized by immune system activation,
      evidenced by elevated serum thyroid-specific autoantibodies and lymphocytic
      infiltration of the target organ (the thyroid gland), associated with raised
      levels of circulating activated T lymphocytes. Several reports have demonstrated
      genetic linkage and association between the genetic markers of the CTLA-4 gene on
      chromosome 2q33 and Graves' disease. In order to confirm this association in the
      Lebanese population, a bi-allelic A/G polymorphism at position 49 of CTLA-4 exon
      1 was studied in 34 patients with Graves' disease, and in 38 healthy individuals,
      using polymerase chain reaction-restriction fragment length polymorphism (PCR
      RFLP) analysis. The results showed a significant increase in allele and genotype
      frequencies in patients with Graves' disease compared to controls. This suggests
      that the CTLA-4 gene might play a role in the development of Graves' disease in
      the Lebanese population.

PMID- 15182329
TI  - Structure of the BoLA-DRB3 gene and promoter.
AB  - The cattle major histocompatibility complex (MHC) class II DR gene product is a
      heterodimer encoded by the BoLA-DRA and -DRB3 genes. Several groups have isolated
      cDNA and genomic clones for these genes, but their full genomic organization has
      not been described. We used a combination of long-range polymerase chain reaction
      (PCR), cloning and sequencing to define the organization of the DRB3 gene on
      existing genomic clones and in genomic DNA. We estimate the size of the coding
      region to be 11.4 kbp. Sequencing of full-length PCR clones from two different
      haplotypes confirmed that they carried complete DRB3 genes and allowed the design
      of probes and primers to isolate and characterize the DRB3 promoter and 3' end.
      Fragments carrying the 5' end of the DRB3 gene and its promoter were identified
      on bacterial artificial chromosome (BAC) clones carrying the BoLA-DR genes. A 10
      kbp promoter fragment was subcloned from one clone and a 1.7-kbp region including
      exon 1 and the promoter was sequenced. A 3-kbp fragment encoding exons 4-6 and
      the entire 3' untranslated region of the DRB3 gene was isolated from lambda clone
      A1 and sequenced. This provides us with improved characterization of the
      DRB3*0101 and DRB3*2002 alleles, and also subcloned 5' and 3' flanking regions of
      the polymorphic DRB3 gene for use in functional studies.

PMID- 15182331
TI  - Disease- or therapy-related bone marrow damage cannot be overcome by changes in
      stem cell source or dose in allogeneic transplantation.
AB  - OBJECTIVE: To test whether the functional impairment of the host bone marrow (BM)
      microenvironment pre-existing at the time of transplantation could be overcome by
      the increased content of immature cells in allogeneic peripheral blood stem cell
      transplantation (PBSCT) when compared with bone marrow transplantation (BMT).
      METHODS: Cobble stone area forming cells (CAFC) were assayed in normal BM and BM
      after allogeneic BMT and PBSCT after stable engraftment. Groups were compared by
      two-tailed t-test. RESULTS: While BM from 11 normal controls contained an average
      of 778.8 CAFC-d35 per 10(6) low density bone marrow cells (LDBMC, range 453-1231
      per 10(6) LDBMC), BM from patients after BMT contained an average of 123.7 CAFC
      d35 per 10(6) LDBMC (range 38-257) per 10(6) LDBMC. BM from patients transplanted
      with PBSC after myeloablative conditioning contained 128.3 (range 46-305) CAFC
      d35 per 10(6) LDBMC (P = 0.89 compared with BMT). Similar results were obtained
      when patients after PBSCT with non-myeloablative conditioning were included (P =
      0.62 compared with BMT). CAFC numbers in patients transplanted in early stages of
      myeloid leukaemia (acute myeloid leukaemia first remission, chronic myeloid
      leukaemia first chronic phase) were significantly higher than CAFC numbers in
      patients transplanted in more advanced stages (P = 0.008) or myelodysplastic
      syndrome (P = 0.023). The lowest CAFC numbers were found in two cases of
      retransplantation. CONCLUSION: Our findings indicate that the functional state of
      the BM microenvironment rather than stem cell dose or source is limiting for the
      homing and engraftment of immature haemopoietic cells in clinical
      transplantation.

PMID- 15182332
TI  - Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes
      is essential in causing bone marrow failure in patients with aplastic anemia.
AB  - Aplastic anemia (AA) is regarded as an immunological disorder because of the
      clinical effect of immunosuppressive therapy. Recent studies have reported that
      cytokines play an important role in the development of AA. In the present study,
      we measured levels of T-cell derived intracellular cytokine production in
      peripheral blood and bone marrow (BM) of patients with AA. We demonstrated that
      BM lymphocytes, particularly CD4(+) and CD8(+) T cells, in patients with AA
      produced significantly higher amounts of tumor necrosis factor-alpha (TNF-alpha),
      compared with lymphocytes in normal controls. We have previously reported that
      expression of TNF receptor (R)1 and TNFR2 in the CD34(+) CD38(-) and CD34(+)
      CD38(+) fractions of patients with AA is significantly higher than those in
      normal control. These results indicate that BM stem cells in patients with AA may
      possess high sensitivity to TNF-alpha. This in turn suggests that TNF-alpha
      affects hematopoiesis at an earlier stage in AA patients than in normal controls.
      We strongly support the hypothesis that a simultaneous increase in TNF-alpha
      production by BM lymphocytes and sensitivity of stem cells to TNF-alpha leads to
      BM failure in AA.

PMID- 15182333
TI  - Matrix metalloproteinase inhibitor reduces apoptosis induction of bone marrow
      cells in MDS-RA.
AB  - BACKGROUND AND OBJECTIVES: We examined the involvement of apoptosis with
      myelodysplastic syndrome (MDS) accompanied by peripheral cytopenias despite normo
      hypercellular bone marrow. MATERIALS AND METHODS: Bone marrow smears from 31
      patients with MDS-refractory anemia (RA) and five normal controls were stained
      using the in situ end labeling (ISEL) method. Next, the inhibitory effects of a
      caspase-3 inhibitor, matrix metalloproteinase inhibitor (MMPI), anti-tumor
      necrosis factor (TNF)-alpha or anti-Fas antibody upon the apoptosis induction in
      overnight cultures of bone marrow cells from the patients were examined. Further,
      TNF-alpha, transforming growth factor (TGF)-beta and soluble Fas ligand (sFasL)
      concentrations in culture supernatants of the cells were assessed by enzyme
      linked immunosorbent assay (ELISA). RESULTS: The incidence of ISEL-positive cells
      among MDS patients was significantly higher than in normal controls (50.8 +/-
      14.0% vs. 11.3 +/- 2.4%; P < 0.0001). A caspase-3 inhibitor reduced significantly
      the ISEL-positive rates (32.6 +/- 15.2% vs. 50.2 +/- 16.5%; P < 0.0001). Anti-TNF
      alpha or anti-Fas antibody reduced the ISEL-positive rates significantly (28.2 +/
      6.0%, 29.2 +/- 5.8%, vs. 44.2 +/- 3.4%, P < 0.001, P = 0.001, respectively). KB
      R7785 also significantly decreased the ISEL-positive rates (18.0 +/- 9.3% vs.
      43.6 +/- 14.0%; P < 0.0001). The concentration of TNF-alpha was significantly
      reduced by KB-R7785 (P < 0.05), whereas that of TGF-beta was not. Concentration
      of sFasL was under detectable level in the present assay system. The derivatives
      of KB-R7785 that can be administrated orally showed inhibitory effect on
      apoptosis induction as well. CONCLUSIONS: These findings suggest that MMPIs
      inhibits the apoptosis induction of MDS bone marrow cells via the inhibition of
      TNF-alpha and probably sFasL secretion, and that MMPIs can be used to control the
      abnormal induction of apoptosis in MDS.

PMID- 15182334
TI  - WT1 gene expression: useful marker for minimal residual disease in childhood
      myelodysplastic syndromes and juvenile myelo-monocytic leukemia?
AB  - The WT1 gene is considered to be highly expressed in patients with acute myeloid
      leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia and is
      thought to play a key role in maintaining the viability of leukemia cells.
      However, little is known about the WT1 gene expression levels in pediatric
      patients with juvenile myelo-monocytic leukemia (JMML) and myelodysplastic
      syndromes (MDS). We studied WT1 expression in diagnostic bone marrow (BM) and
      peripheral blood (PB) samples of 90 patients with JMML, low grade MDS, advanced
      MDS and myelodysplasia-related AML in BM (n = 20) and PB (n = 18) samples of
      normal healthy volunteer donors.

PMID- 15182335
TI  - Intracellular IFN-gamma expression by CD3+/CD8+ cell subset in B-CLL patients
      correlates with stage of the disease.
AB  - Changes in the cytokine network may be responsible for malignant cell
      accumulation in B-cell chronic lymphocytic leukaemia (B-CLL). Among different
      cytokines of question interferon gamma (IFN-gamma) is indicated to prevent
      malignant cells from entering apoptosis. The aim of the study was to determine
      IFN-gamma production capacity of T-cell subsets and B lymphocytes in B-CLL
      patients in comparison with healthy individuals and during disease progression.
      Forty patients with newly diagnosed, untreated B-CLL and 20 healthy individuals
      were studied. The two- and three-colour flow cytometry techniques were used to
      detect intracellular cytokine expression. We detected statistically significantly
      higher percentage of both CD3+/CD4+/IFN-gamma+ and CD3+/CD8+/IFN-gamma+ in
      patients than in controls (P < 0.001 in both cases). Moreover the percentage of
      CD3+/CD8+/IFN-gamma+ cells correlated with stage of the disease (R = 0.39, P =
      0.01) and parameters of disease progression like lymphocyte count and total
      tumour mass score (R = 0.33, P = 0.03 and R = 0.31, P = 0.04, respectively). By
      contrast, the percentage of CD19+/IFN-gamma+ cells in B-CLL group was lower than
      in controls (P < 0.01). These findings indicate that T-cell populations rather
      than malignant B cells are the source of IFN-gamma in B-CLL patients. The subset
      of CD3+/CD8+ cells expressing IFN-gamma seems to play a special role in the
      disease progression and more precise investigation should elucidate its role as a
      prognostic marker in B-CLL and a target for therapeutic strategies.

PMID- 15182336
TI  - Serum angiogenin is not elevated in patients with early B-cell chronic
      lymphocytic leukemia but is prognostic factor for disease progression.
AB  - The association between angiogenin and cancer progression and poor outcome in
      solid tumors has been documented, but its significance in leukemias has not been
      evaluated. Using an ELISA technique (Quantikine Human Angiogenin Immunoassay; R&D
      Systems), we measured serum angiogenin levels in 77 previously untreated Binet
      stage A B-cell chronic lymphocytic leukemia (CLL) patients. No difference in
      angiogenin serum levels could be found between patients (median: 295 ng/mL;
      range: 74-1700) and 15 age- and sex-matched healthy controls (median: 264 ng/mL;
      range: 29-1835) (P = NS; Mann-Whitney test). Increased angiogenin serum level was
      associated with higher LDH (P = 0.03) and beta2-m (P = 0.007) concentrations.
      However, angiogenin did not reflect the extent of bone marrow (BM) angiogenesis
      as evaluated by microvessel area (P = 0.611), circulating levels of vascular
      endothelial growth factor (VEGF) (P = 0.873) and basic fibroblastic growth factor
      (FGF-2) (P = 0.421). When the 25 patients with available data were stratified
      into the four major cytogenetic categories (normal karyotype, 13q as a sole
      aberration, 12q trisomy, 11q or 17p deletion) and aberrations were compared with
      angiogenin serum levels, no correlation was found (P = 0.651; Kruskall-Wallis
      test). A cut-off of angiogenin serum level corresponding to median (i.e. 330
      ng/mL) or higher identified later upstaging and longer progression-free survival
      (PFS). The 5-yr PFS was 51.5% for patients with angiogenin levels lower than
      median and 85% for patients with higher values [P = 0.03; hazard ratio (HR) =
      2.86; 95% CI: 1.08-6.72]. Although in multivariate analysis only Rai substages (P
      = 0.00001) and peripheral blood lymphocytosis (P = 0.009) retained their
      prognostic significance, angiogenin could be incorporated into the Rai substages
      thus leading to the identification of the following risk categories: (i) stage 0
      (angionenin >330 ng/mL); (ii) stage 0 (angiogenin <330 ng/mL) + stage I-II
      (angiogenin >330 ng/mL); and (iii) stage I-II (angiogenin <330 ng/mL). The 40
      month PFS were as follows: 85%, 65%, 25% (chi(2) for trend = 6.33; d.f. = 1; P =
      0.01). In conclusion, serum angiogenin levels although not increased in
      comparison with healthy controls, may predict clinical outcome of patients with
      early CLL and help to refine Rai's stratification.

PMID- 15182337
TI  - Prevalence of HFE mutations among the Thai population and correlation with iron
      loading in haemoglobin E disorder.
AB  - Co-inheritance of HFE mutations has a substantial role in iron overload in beta
      thalassaemia carriers in north European populations where two HFE mutations,
      C282Y and H63D, are prevalent. In Thailand, there was little information about
      the allele frequency of HFE mutations. It is of interest to determine whether
      such determinants represent a potential risk in developing iron overload as
      nearly 40% of the Thai population carry either one of thalassaemia or
      haemoglobinpathy alleles. A total of 380 normal controls from five different
      regions including Bangkok were screened for the HFE C282Y, H63D and IVS5+1 G-->A
      alleles. In addition, 70 individuals with homozygous haemoglobin E (Hb EE) were
      also tested and their genotypes were correlated with levels of serum ferritin.
      H63D is the major HFE mutation found in the Thai population with an average
      allele frequency of 3% (range 1-5%). One individual was heterozygous for the
      splice site mutation IVS5 + 1 G --> A, and the C282Y allele was not detected. In
      the Hb EE group, five individuals had iron deficiency (ferritin <12 microg/L) and
      the remaining 65 individuals had a wide range of serum ferritin levels of 16-700
      microg/L. Four individuals with Hb EE were heterozygous for the H63D allele. No
      significant difference in serum ferritin level was detected in this group with or
      without the HFE mutation (137.2 +/- 78 vs. 116.3 +/- 128 microg/L). HFE mutations
      are relatively uncommon among the Thai population, and the average allele
      frequency of the ancient H63D mutation is similar to that of other countries in
      this region. Because of their paucity, it appears that these alleles are less
      likely to be responsible for high ferritin levels and iron loading in individuals
      with Hb E related disorders.

PMID- 15182338
TI  - Safety and efficacy of caspofungin and liposomal amphotericin B, followed by
      voriconazole in young patients affected by refractory invasive mycosis.
AB  - OBJECTIVE: Data on the use of combination of liposomal amphotericin B and
      caspofungin followed by voriconazole, as maintenance or further rescue treatment,
      in 10 patients with invasive mycosis are reported. MATERIAL AND METHODS: The
      diagnoses were acute leukemia (7), myelodysplastic syndrome (1) and Hodgkin's
      lymphoma (1). All patients developed an invasive mycosis (proven, 3; probable, 6;
      and possible, 1) refractory to first-line antifungal treatment (liposomal
      amphotericin B in all patients except one who received fluconazole). RESULTS:
      Rescue therapy with a combination of caspofungin and liposomal amphotericin B was
      well tolerated, hypokalemia, and thrombophlebitis being the most common side
      effects. Combination therapy was administered for a median of 17 d, range 6-40.
      Among the nine patients with proven or probable mycosis, one was not evaluated
      because of early death caused by massive hemoptysis whilst in the remaining eight
      patients, the response was classified as complete, stable and failure in four,
      three, and one patients, respectively. Complete response was also observed in
      patient with possible mycosis. Eight of nine patients received voriconazole for a
      median of 75 d, range 42-194. Voriconazole was well tolerated although some drug
      interactions were observed during treatment with methotrexate and digoxin. After
      a median follow-up of 125 d, nine of 10 patients are alive. Overall, a favorable
      response to antifungal treatment (including the case of possible mycosis) was
      obtained in eight of 10 patients. CONCLUSION: These data suggest that medical
      antifungal treatment may be intensified in severely ill patients without
      significantly compromising patient safety. The combination of synergistic
      antifungal drugs as well as their sequential use warrants further investigation
      by a larger randomized controlled study.

PMID- 15182339
TI  - Different efficacy of mycophenolate mofetil as salvage treatment for acute and
      chronic GVHD after allogeneic stem cell transplant.
AB  - OBJECTIVE: The therapeutic options currently available for treating refractory
      graft-vs.-host disease (GVHD) are limited. Therefore, the present study evaluated
      the efficacy of mycophenolate mofetil (MMF) as a salvage treatment for acute and
      chronic GVHD in allograft patients. METHODS: Twenty-six consecutive patients with
      refractory acute (13 patients) or chronic (13 patients) GVHD were enrolled. The
      first-line treatment for all patients with acute GVHD consisted of a combination
      of cyclosporine A (CyA) and steroids, while the first-line treatment for chronic
      GVHD was steroids with or without CyA according to the risk group. MMF was added
      at a dose of 1.5 or 2 g daily and the steroids were tapered in the refractory
      cases. RESULTS: Four (30.8%) of 13 patients with refractory acute GVHD responded
      to MMF. When analyzing the overall results according to the type of acute GVHD,
      improvement was observed in four (30.8%) of 13 skin cases, four (44.4%) of nine
      liver cases, and two (22.9%) of nine gut cases. Ten (76.9%) of 13 patients with
      refractory chronic GVHD responded to MMF. The common side effects were
      gastrointestinal disturbance (26.9%) or infectious complications (23.1%). The
      estimated 2-yr survival rate for patients with acute GVHD and chronic GVHD was
      33.3% and 53.9%, respectively. CONCLUSIONS: MMF would appear to be effective and
      safe for treating refractory chronic GVHD, yet not as effective for treating
      refractory acute gut GVHD. Accordingly, a prospective randomized clinical trial
      is warranted to assess the impact of MMF in the treatment of refractory GVHD.

PMID- 15182340
TI  - Hematologic and molecular spontaneous remission following sepsis in acute
      monoblastic leukemia with translocation (9;11): a case report and review of the
      literature.
AB  - Spontaneous remission in patients with acute myeloid leukemia (AML) is a rarely
      reported phenomenon of usually short duration. The etiology remains unclear, but
      an association with preceding blood transfusions or bacterial infections has been
      reported. Triggered immune responses are suggested to play a potential role in
      the development of spontaneous remission. Acute monocytic leukemia was diagnosed
      in a 61-yr-old male patient. Cytogenetic analysis revealed a sole translocation
      (9;11) (q22;q23) and RT-PCR the MLL/AF9 fusion gene. As a result of the patient's
      reduced performance status and septic condition, cytostatic therapy was withheld.
      No microorganisms could be detected. Hematologic and molecular remission occurred
      after initiating antibiotic therapy without any cytostatic treatment; 29 months
      after the initial diagnosis, he is in complete remission, and excellent physical
      condition. Our report includes a review of the literature since 1985, reporting
      cases of patients with AML and spontaneous remission together with informative
      cytogenetics. Balanced translocations such as in core binding factor (CBF)
      leukemias appear somewhat overrepresented. We speculate that AML-specific T cells
      might be relevant for induction of spontaneous remission and need to be further
      investigated.

PMID- 15182341
TI  - Fulminant bronchiolitis obliterans organizing pneumonia following 2 d of
      treatment with hydroxyurea, interferon-alpha and oral cytarabine ocfosfate for
      chronic myelogenous leukemia.
AB  - A 65-yr-old man developed increasing dyspnea and fulminant respiratory failure 48
      h after introduction of hydroxyurea, oral cytarabine ocfosfate (YNK01) and
      interferon-alpha for treatment of Philadelphia chromosome-positive chronic
      myelogenous leukemia. The chest radiograph showed bilateral patchy infiltrates
      while computed tomography revealed multiple bullas, ground glass opacities, and
      patchy consolidations with possible cavitation. Bronchoscopic examination was
      normal and microbiological tests performed on all biologic fluids were negative.
      The patient did not respond to multiple antibiotic treatment and corticosteroid
      administration and died of progressive respiratory failure 5 d after chemotherapy
      introduction. The postmortem lung examination was consistent with the diagnosis
      of bronchiolitis obliterans organizing pneumonia (BOOP).

PMID- 15182342
TI  - Efficacy and safety of anti-D given by subcutaneous injection to patients with
      autoimmune thrombocytopenia.

PMID- 15182343
TI  - Monoclonal antibodies and cytomegalovirus infections.

PMID- 15182344
TI  - Learning about structure and function of neuronal nicotinic acetylcholine
      receptors. Lessons from snails.

PMID- 15182345
TI  - Physico-chemical characterization and synthesis of neuronally active alpha
      conotoxins.
AB  - The high specificity of alpha-conotoxins for different neuronal nicotinic
      acetylcholine receptors makes them important probes for dissecting receptor
      subtype selectivity. New sequences continue to expand the diversity and utility
      of the pool of available alpha-conotoxins. Their identification and
      characterization depend on a suite of techniques with increasing emphasis on mass
      spectrometry and microscale chromatography, which have benefited from recent
      advances in resolution and capability. Rigorous physico-chemical analysis
      together with synthetic peptide chemistry is a prerequisite for detailed
      conformational analysis and to provide sufficient quantities of alpha-conotoxins
      for activity assessment and structure-activity relationship studies.

PMID- 15182346
TI  - Alpha-conotoxins as tools for the elucidation of structure and function of
      neuronal nicotinic acetylcholine receptor subtypes.
AB  - Cone snails comprise approximately 500 species of venomous molluscs, which have
      evolved the ability to generate multiple toxins with varied and often exquisite
      selectivity. One class, the alpha-conotoxins, is proving to be a powerful tool
      for the differentiation of nicotinic acetylcholine receptors (nAChRs). These
      comprise a large family of complex subtypes, whose significance in physiological
      functions and pathological conditions is increasingly becoming apparent. After a
      short introduction into the structure and diversity of nAChRs, this overview
      summarizes the identification and characterization of alpha-conotoxins with
      selectivity for neuronal nAChR subtypes and provides examples of their use in
      defining the compositions and function of neuronal nAChR subtypes in native
      vertebrate tissues.

PMID- 15182347
TI  - Structure-activity relationships of alpha-conotoxins targeting neuronal nicotinic
      acetylcholine receptors.
AB  - alpha-Conotoxins that target the neuronal nicotinic acetylcholine receptor have a
      range of potential therapeutic applications and are valuable probes for examining
      receptor subtype selectivity. The three-dimensional structures of about half of
      the known neuronal specific alpha-conotoxins have now been determined and have a
      consensus fold containing a helical region braced by two conserved disulfide
      bonds. These disulfide bonds define the two-loop framework characteristic for
      alpha-conotoxins, CCX(m)CX(n)C, where loop 1 comprises four residues (m = 4) and
      loop 2 between three and seven residues (n = 3, 6 or 7). Structural studies,
      particularly using NMR spectroscopy have provided an insight into the role and
      spatial location of residues implicated in receptor binding and biological
      activity.

PMID- 15182348
TI  - Computational approaches to understand alpha-conotoxin interactions at neuronal
      nicotinic receptors.
AB  - Recent and increasing use of computational tools in the field of nicotinic
      receptors has led to the publication of several models of ligand-receptor
      interactions. These models are all based on the crystal structure at 2.7 A
      resolution of a protein related to the extracellular N-terminus of nicotinic
      acetylcholine receptors (nAChRs), the acetylcholine binding protein. In the
      absence of any X-ray or NMR information on nAChRs, this new structure has
      provided a reliable alternative to study the nAChR structure. We are now able to
      build homology models of the binding domain of any nAChR subtype and fit in
      different ligands using docking programs. This strategy has already been
      performed successfully for the docking of several nAChR agonists and antagonists.
      This minireview focuses on the interaction of alpha-conotoxins with neuronal
      nicotinic receptors in light of our new understanding of the receptor structure.
      Computational tools are expected to reveal the molecular recognition mechanisms
      that govern the interaction between alpha-conotoxins and neuronal nAChRs at the
      molecular level. An accurate determination of their binding modes on the neuronal
      nAChR may allow the rational design of alpha-conotoxin-based ligands with novel
      nAChR selectivity.

PMID- 15182349
TI  - Chromatin dynamics at DNA replication, transcription and repair.
AB  - During DNA replication, transcription and DNA repair in eukaryotes, the cellular
      machineries performing these tasks need to gain access to the DNA that is
      packaged into chromatin in the nucleus. Chromatin is a dynamic structure that
      modulates the access of regulatory factors to the genetic material. A precise
      coordination and organization of events in opening and closing of the chromatin
      is crucial to ensure that the correct spatial and temporal epigenetic code is
      maintained within the eukaryotic genome. This review will summarize the current
      knowledge of how chromatin remodeling and histone modifying complexes cooperate
      to break and remake chromatin during nuclear processes on the DNA template.

PMID- 15182350
TI  - Cloning and characterization of the genes encoding toxic lectins in mistletoe
      (Viscum album L).
AB  - Leaves of mistletoe (Viscum album L) contain three toxic lectins (type 2 ribosome
      inactivating proteins) MLI, MLII, and MLIII, differing in molecular mass and
      carbohydrate specificity. Clones, containing sequences of three gene variants
      designated ml1p, ml2p, and ml3p, were obtained using PCR amplification from cDNA
      and from mistletoe genomic DNA. The quantitative ratio of the ml1p, ml2p, and
      ml3p genes in genomic DNA was found to be 1.5 : 1 : 4, respectively, whereas the
      ratio of their mRNA was 50 : 10 : 1. The quantitative prevalence of the ml1p
      transcript correlates well with the observation that MLI is quantitatively
      dominant over MLII and MLIII in the mistletoe extract. The sequences of the
      proteins encoded by the ml1p, ml2p, and ml3p genes are identical to MLI by 98,
      88, and 77%, respectively. The similarity to MLI of the amino acid sequence
      encoded by the gene ml1p, the quantitative prevalent of its mRNA, as well as
      structural properties of the B-chain indicate that the gene, ml1p, corresponds to
      MLI. Western blot analysis of recombinant A-chains encoded by the three variants
      of mlp genes with the monoclonal antibody MNA4 having differential affinity to
      MLI, MLII and MLIII A-chains suggests that the ml2p and ml3p genes correspond to
      MLII and MLIII, respectively. Structural differences in the carbohydrate-binding
      sites of the B-subunits of ML1p, ML2p, and ML3p probably explain the difference
      in sugar specificity of MLI, MLII and MLIII.

PMID- 15182351
TI  - Copper-containing nitrite reductase from Pseudomonas chlororaphis DSM 50135.
AB  - The nitrite reductase (Nir) isolated from Pseudomonas chlororaphis DSM 50135 is a
      blue enzyme, with type 1 and type 2 copper centers, as in all copper-containing
      Nirs described so far. For the first time, a direct determination of the
      reduction potentials of both copper centers in a Cu-Nir was performed: type 2
      copper (T2Cu), 172 mV and type 1 copper (T1Cu), 298 mV at pH 7.6. Although the
      obtained values seem to be inconsistent with the established electron-transfer
      mechanism, EPR data indicate that the binding of nitrite to the T2Cu center
      increases its potential, favoring the electron-transfer process. Analysis of the
      EPR spectrum of the turnover form of the enzyme also suggests that the electron
      transfer process between T1Cu and T2Cu is the fastest of the three redox
      processes involved in the catalysis: (a) reduction of T1Cu; (b) oxidation of T1Cu
      by T2Cu; and (c) reoxidation of T2Cu by NO(2) (-). Electrochemical experiments
      show that azurin from the same organism can donate electrons to this enzyme.

PMID- 15182352
TI  - Kinetics of the inhibition of neutrophil proteinases by recombinant elafin and
      pre-elafin (trappin-2) expressed in Pichia pastoris.
AB  - Elafin and its precursor, trappin-2 or pre-elafin, are specific endogenous
      inhibitors of human neutrophil elastase and proteinase 3 but not of cathepsin G.
      Both inhibitors belong, together with secretory leukocyte protease inhibitor, to
      the chelonianin family of canonical protease inhibitors of serine proteases. A
      cDNA coding either elafin or its precursor, trappin-2, was fused in frame with
      yeast alpha-factor cDNA and expressed in the Pichia pastoris yeast expression
      system. Full-length elafin or full-length trappin-2 were secreted into the
      culture medium with high yield, indicating correct processing of the fusion
      proteins by the yeast KEX2 signal peptidase. Both recombinant inhibitors were
      purified to homogeneity from concentrated culture medium by one-step cationic
      exchange chromatography and characterized by N-terminal amino acid sequencing,
      Western blot and kinetic studies. Both recombinant elafin and trappin-2 were
      found to be fast-acting inhibitors of pancreatic elastase, neutrophil elastase
      and proteinase 3 with k(ass) values of 2-4 x 10(6) m(-1).s(-1), while
      dissociation rate constants k(diss) were found to be in the 10(-4) s(-1) range,
      indicating low reversibility of the complexes. The equilibrium dissociation
      constant K(i) for the interaction of both recombinant inhibitors with their
      target enzymes was either directly measured for pancreatic elastase or calculated
      from k(ass) and k(diss) values for neutrophil elastase and proteinase 3. K(i)
      values were found to be in the 10(-10) molar range and virtually identical for
      both inhibitors. Based on the kinetic parameters determined here, it may be
      concluded that both recombinant elafin and trappin-2 may act as potent anti
      inflammatory molecules and may be of therapeutic potential in the treatment of
      various inflammatory lung diseases.

PMID- 15182353
TI  - Activation of transiently transfected reporter genes in 3T3 Swiss cells by the
      inducers of differentiation/apoptosis--dimethylsulfoxide, hexamethylene
      bisacetamide and trichostatin A.
AB  - Despite decades of investigation, the primary site of action of the prototypical
      inducers of differentiation, dimethylsulfoxide and hexamethylene bisacetamide
      (HMBA), has not been delineated. During studies designed to analyze cis-acting
      elements responsible for induction of stage-specific globin genes, we discovered
      the capacity of HMBA and dimethylsulfoxide to enhance the expression of
      transiently transfected reporter genes derived from globin and nonglobin gene
      promoters, prominently in nonerythroid 3T3 Swiss cells. The action of HMBA and
      dimethylsulfoxide in the transient transfection system resembled that of the
      inhibitor of histone deacetylases (HDACs), trichostatin A (TSA), in that the
      three agents enhanced reporter gene expression (a) regardless of the promoter
      employed, (b) with similar kinetics and (c) with an increase in the steady-state
      level of reporter mRNA. Transiently transfected DNA was assembled rapidly into a
      chromatinized structure in 3T3 cells, suggesting that transcription of reporter
      genes was at least in part repressed by chromatin organization. Nuclear run-on
      analyses indicated that dimethylsulfoxide and HMBA enhanced transcriptional
      initiation of the reporter and p21/WAF1/Cip1 genes. In contrast, TSA produced
      negligible effects on nuclear run-on transcription of these genes. HMBA and
      dimethylsulfoxide did not change the acetylation, phosphorylation, or methylation
      status of histones and did not activate stably transfected genes. Despite these
      differences, the three agents modulated the expression of common sets of cellular
      genes and induced differentiation or apoptosis in intact cells. The findings
      imply that HMBA and dimethylsulfoxide modulate transcription by a mechanism
      independent of histone acetylation.

PMID- 15182354
TI  - 2-Pyrimidinone as a probe for studying the EcoRII DNA methyltransferase-substrate
      interaction.
AB  - EcoRII DNA methyltransferase (M.EcoRII) recognizes the 5' em leader CC*T/AGG em
      leader 3' DNA sequence and catalyzes the transfer of the methyl group from S
      adenosyl-l-methionine to the C5 position of the inner cytosine residue (C*).
      Here, we study the mechanism of inhibition of M.EcoRII by DNA containing 2
      pyrimidinone, a cytosine analogue lacking an NH(2) group at the C4 position of
      the pyrimidine ring. Also, DNA containing 2-pyrimidinone was used for probing
      contacts of M.EcoRII with functional groups of pyrimidine bases of the
      recognition sequence. 2-Pyrimidinone was incorporated into the 5' em leader
      CCT/AGG em leader 3' sequence replacing the target and nontarget cytosine and
      central thymine residues. Study of the DNA stability using thermal denaturation
      of 2-pyrimidinone containing duplexes pointed to the influence of the bases
      adjacent to 2-pyrimidinone and to a greater destabilizing influence of 2
      pyrimidinone substitution for thymine than that for cytosine. Binding of M.EcoRII
      to 2-pyrimidinone containing DNA and methylation of these DNA demonstrate that
      the amino group of the outer cytosine in the EcoRII recognition sequence is not
      involved in the DNA-M.EcoRII interaction. It is probable that there are contacts
      between the functional groups of the central thymine exposed in the major groove
      and M.EcoRII. 2-Pyrimidinone replacing the target cytosine in the EcoRII
      recognition sequence forms covalent adducts with M.EcoRII. In the absence of the
      cofactor S-adenosyl-l-methionine, proton transfer to the C5 position of 2
      pyrimidinone occurs and in the presence of S-adenosyl-l-methionine, methyl
      transfer to the C5 position of 2-pyrimidinone occurs.

PMID- 15182355
TI  - Evidence for two different electron transfer pathways in the same enzyme, nitrate
      reductase A from Escherichia coli.
AB  - In order to clarify the role of cytochrome in nitrate reductase we have performed
      spectrophotometric and stopped-flow kinetic studies of reduction and oxidation of
      the cytochrome hemes with analogues of physiological quinones, using menadione as
      an analogue of menaquinone and duroquinone as an analogue of ubiquinone, and
      comparing the results with those obtained with dithionite. The spectrophotometric
      studies indicate that reduction of the cytochrome hemes varies according to the
      analogue of quinone used, and in no cases is it complete. Stopped-flow kinetics
      of heme oxidation by potassium nitrate indicates that there are two distinct
      reactions, depending on whether the hemes were previously reduced by menadiol or
      by duroquinol. These results, and those of spectrophotometric studies of a mutant
      lacking the highest-potential [Fe-S] cluster, allow us to propose a two-pathway
      electron transfer model for nitrate reductase A from Escherichia coli.

PMID- 15182356
TI  - Modulation of nitric oxide-mediated metal release from metallothionein by the
      redox state of glutathione in vitro.
AB  - Metallothioneins (MTs) release bound metals when exposed to nitric oxide. At
      inflammatory sites, both metallothionein and inducible nitric oxide synthase
      (iNOS) are induced by the same factors and the zinc released from metallothionein
      by NO suppresses both the induction and activity of iNOS. In a search for a
      possible modulatory mechanism of this coexpression of counteracting proteins, we
      investigated the role of the glutathione redox state in vitro because the
      oxidation state of thiols is involved in the metal binding in Cd-S or Zn-S
      clusters found in metallothioneins, and NO also binds to reduced glutathione via
      S-nitrosation. Using a variety of techniques, we found that NO and also ONOO(-)
      mediated metal release from purified MTs is suppressed by reduced glutathione
      (GSH), but not by oxidized glutathione. Considering the millimolar concentrations
      of GSH present in mammalian cells, the metal release from MTs by NO should play
      no role in living systems. Therefore, the fact that it has been observed in vivo
      points to a hitherto unknown mechanism or additional compound(s) being involved
      in this physiologically relevant reaction and as long as this additional factor
      is not found experimental results on the MT-NO interaction should be treated with
      caution. Contrary to the peroxynitrite-induced activation of guanylyl cyclase,
      where GSH is needed, we found that the metal release from metallothionein by
      peroxynitrite is not enhanced, but also suppressed by reduced glutathione. In
      addition, we show that zinc, the major natural metal ligand in mammalian MTs and
      suppressor of iNOS, is released more readily under the influence of NO than
      cadmium, but in contrast to the MT isoform 1, the amount of metal released from
      the beta-domain of MT-2 is comparable to that from the alpha-domain.

PMID- 15182357
TI  - Protection of chylomicron remnants from oxidation by incorporation of probucol
      into the particles enhances their uptake by human macrophages and increases lipid
      accumulation in the cells.
AB  - The effects of protection of chylomicron remnants from oxidation on their uptake
      and induction of lipid accumulation in macrophages were investigated using
      chylomicron remnant-like particles (CRLPs) containing the lipophilic antioxidant
      drug, probucol, and macrophages derived from the human monocyte cell line, THP-1.
      The total lipid content of THP-1 macrophages was markedly higher (x2.2) after 48
      h of incubation of THP-1 macrophages with CRLPs containing probucol (pCRLPs) when
      compared to CRLPs without probucol, and this was because of increases in
      triacylglycerol (x2.3) and cholesterol (x1.8) levels, while cholesteryl ester
      concentrations were not significantly changed. Determination of the uptake of
      CRLPs and pCRLPs by the cells using particles labelled with the fluorescent probe
      1,1'-dioctadecyl-3,3,3'3'-tetramethylindo-carbocyanine perchlorate showed that
      pCRLPs are taken up at a faster rate than CRLPs. The synthesis of
      triacylglycerol, as measured by the incorporation of [(3)H]oleate and
      [(3)H]glycerol, was also increased in macrophages incubated with pCRLPs as
      compared to CRLPs without probucol, but phospholipid and cholesteryl ester
      formation from [(3)H]oleate was unaffected. In addition, no differences between
      the effects of CRLPs and pCRLPs on the expression of mRNA for a range of genes
      believed to be involved in lipoprotein uptake, intracellular lipid metabolism and
      the efflux of cholesterol from macrophages was detected. These results suggest
      that antioxidants carried in chylomicron remnants enhance lipid accumulation in
      macrophages by increasing the rate of uptake of the particles and raising the
      intracellular synthesis of triacylglycerol, but not cholesteryl ester, and that
      these effects are brought about by changes at the post-transcriptional level.
      Antioxidants carried in chylomicron remnants therefore may promote the
      development of atherosclerosis, and this is likely to be particularly important
      in conditions where clearance of remnants from the circulation is delayed.

PMID- 15182358
TI  - Membrane distribution of epidermal growth factor receptors in cells expressing
      different gangliosides.
AB  - Gangliosides have been found to reside in glycosphingolipid-enriched microdomains
      (GEM) of the plasma membrane and to be involved in the regulation of epidermal
      growth factor receptor (EGFr or ErbB1) activity. To gain further insight into the
      mechanisms involved in EGFr modulation by gangliosides, we investigated the
      distribution of EGFr family members in the plasma membrane of CHO-K1 cells, which
      were genetically modified to express different ganglioside molecules or depleted
      of glycolipids. Our data demonstrate that at least four different sets of
      endogenously expressed gangliosides, including GD3, did not have a significant
      effect on EGFr distribution in the plasma membrane. In addition, using confocal
      microscopy analysis we clearly demonstrated that the EGFr co-localizes only to a
      minor extent with GD3. We also explored the endogenous expression, in wild-type
      CHO-K1 cells, of the orphan receptor ErbB2 (which is the preferred
      heteroassociation partner of all other ErbB proteins) and the effect of GD3
      expression on its membrane distribution. Our results showed that CHO-K1 cells
      endogenously express ErbB2 and that expression of the GD3 affected, to some
      extent, the membrane distribution of endogenous ErbB2. Finally, our findings
      support the notion that most EGFr are excluded from GEM, while an important
      fraction of ErbB2 is found to be associated with these microdomains in membranes
      from CHO-K1 cells.

PMID- 15182359
TI  - Expression of the pyrG gene determines the pool sizes of CTP and dCTP in
      Lactococcus lactis.
AB  - The pyrG gene from Lactococcus lactis encodes CTP synthase (EC 6.4.3.2), an
      enzyme converting UTP to CTP. A series of strains were constructed with different
      levels of pyrG expression by insertion of synthetic constitutive promoters with
      different strengths in front of pyrG. These strains expressed pyrG levels in a
      range from 3 to 665% relative to the wild-type expression level. Decreasing the
      level of CTP synthase to 43% had no effect on the growth rate, showing that the
      capacity of CTP synthase in the cell is in excess in a wild-type strain. We then
      studied how pyrG expression affected the intracellular pool sizes of nucleotides
      and the correlation between pyrG expression and nucleotide pool sizes was
      quantified using metabolic control analysis in terms of inherent control
      coefficients. At the wild-type expression level, CTP synthase had full control of
      the CTP concentration with a concentration control coefficient close to one and a
      negative concentration control coefficient of -0.28 for the UTP concentration.
      Additionally, a concentration control coefficient of 0.49 was calculated for the
      dCTP concentration. Implications for the homeostasis of nucleotide pools are
      discussed.

PMID- 15182360
TI  - The effect of HAMP domains on class IIIb adenylyl cyclases from Mycobacterium
      tuberculosis.
AB  - The genes Rv1318c, Rv1319c, Rv1320c and Rv3645 of Mycobacterium tuberculosis are
      predicted to code for four out of 15 adenylyl cyclases in this pathogen. The
      proteins consist of a membrane anchor, a HAMP region and a class IIIb adenylyl
      cyclase catalytic domain. Expression and purification of the isolated catalytic
      domains yielded adenylyl cyclase activity for all four recombinant proteins.
      Expression of the HAMP region fused to the catalytic domain increased activity in
      Rv3645 21-fold and slightly reduced activity in Rv1319c by 70%, demonstrating
      isoform-specific effects of the HAMP domains. Point mutations were generated to
      remove predicted hydrophobic protein surfaces in the HAMP domains. The mutations
      further stimulated activity in Rv3645 eight-fold, whereas the effect on Rv1319c
      was marginal. Thus HAMP domains can act directly as modulators of adenylyl
      cyclase activity. The modulatory properties of the HAMP domains were confirmed by
      swapping them between Rv1319c and Rv3645. The data indicate that in the
      mycobacterial adenylyl cyclases the HAMP domains do not display a uniform
      regulatory input but instead each form a distinct signaling unit with its
      adjoining catalytic domain.

PMID- 15182361
TI  - Genomic organization, tissue distribution and deletion mutation of human
      pyridoxine 5'-phosphate oxidase.
AB  - We used a combined computer and biochemical approach to characterize human
      pyridoxine 5'-phosphate oxidase (PNPO). The human PNPO gene is composed of seven
      exons and six introns, and spans approximately 8 kb. All exon/intron junctions
      contain the gt/ag consensus splicing site. The absence of TATA-like sequences,
      the presence of Sp1-binding sites and more importantly, the presence of CpG
      islands in the regulatory region of the PNPO gene are characteristic features of
      housekeeping genes. Northern blot analyses showed two species of poly(A)(+) RNA
      of approximately 2.4 and approximately 3.4 kb at identical intensity, whereas
      Western blot analysis showed that no protein isoform exists in any of the tissues
      examined. PCR-based analysis led to the idea that two messages are transcribed
      from a single copy gene, and that the size difference is due to differential
      usage of the polyadenylation signal. The major sites of PNPO expression are
      liver, skeletal muscle and kidneys while a very weak signal was detected in lung.
      The mRNA master dot-blot for multiple human tissues provided a complete map of
      the tissue distribution not only for PNPO but also for pyridoxal kinase and
      pyridoxal phosphatase. The data indicate that mRNA expression of all three
      enzymes essential for vitamin B(6) metabolism is ubiquitous but is highly
      regulated at the level of transcription in a tissue-specific manner. In addition,
      human brain PNPO cDNA was expressed in Escherichia coli, and the roles of both
      the N- and C-terminal regions were studied by creating sequential truncation
      mutants. Our results showed that deletion of the N-terminal 56 residues affects
      neither the binding of coenzyme nor catalytic activity.

PMID- 15182362
TI  - Amino acid biosynthesis and metabolic flux profiling of Pichia pastoris.
AB  - Amino acid biosynthesis and central carbon metabolism of Pichia pastoris were
      studied using biosynthetically directed fractional (13)C labeling. Cells were
      grown aerobically in a chemostat culture fed at two dilution rates (0.05 h(-1),
      0.16 h(-1)) with glycerol as the sole carbon source. For investigation of amino
      acid biosynthesis and comparison with glycerol cultivations, cells were also
      grown at 0.16 h(-1) on glucose. Our results show that, firstly, amino acids are
      synthesized as in Saccharomyces cerevisiae. Secondly, biosynthesis of
      mitochondrial pyruvate via the malic enzyme is not registered for any of the
      three cultivations. Thirdly, transfer of oxaloacetate across the mitochondrial
      membrane appears bidirectional, with a smaller fraction of cytosolic oxaloacetate
      stemming from the mitochondrial pool at the higher dilution rate of 0.16 h(-1)
      (for glucose or glycerol cultivation) when compared to the glycerol cultivation
      at 0.05 h(-1). Fourthly, the fraction of anaplerotic synthesis of oxaloacetate
      increases from 33% to 48% when increasing the dilution rate for glycerol supply,
      while 38% is detected when glucose is fed. Finally, the cultivation on glucose
      also allowed qualitative comparison with the flux ratio profile previously
      published for Pichia stipitis and S. cerevisiae grown on glucose in a chemostat
      culture at a dilution rate of 0.1 h(-1). This provided a first indication that
      regulation of central carbon metabolism in P. pastoris and S. cerevisiae might be
      more similar to each other than to P. stipitis.

PMID- 15182363
TI  - Colocalization of insulin receptor and insulin receptor substrate-1 to caveolae
      in primary human adipocytes. Cholesterol depletion blocks insulin signalling for
      metabolic and mitogenic control.
AB  - Caveolae are plasma membrane invaginations with several functions, one of which
      appears to be to organize receptor mediated signalling. Here we report that in
      primary human subcutaneous adipocytes the insulin receptor was localized to
      caveolae by electron microscopy/immunogold detection and by isolating caveolae
      from plasma membranes. Part of insulin receptor substrate 1 (IRS1), the immediate
      downstream signal mediator, was colocalized with the insulin receptor in the
      plasma membrane and caveolae, as demonstrated by immunofluorescence microscopy,
      immunogold electron microscopy, and immunogold electron microscopy of transfected
      recombinant HA-IRS1. In contrast, rat epididymal adipocytes lacked IRS1 at the
      plasma membrane. Depletion of cholesterol from the cells using beta-cyclodextrin
      blocked insulin stimulation of glucose uptake, insulin inhibition of perilipin
      phosphorylation in response to isoproterenol, and insulin stimulation of protein
      kinase B and Map-kinases extracellular signal-related kinase (ERK)1/2
      phosphorylation. Insulin-stimulated phosphorylation of the insulin receptor and
      IRS1 was not affected, indicating that caveolae integrity is required downstream
      of IRS1. In conclusion we show that insulin receptor and IRS1 are both caveolar
      proteins and that caveolae are required for both metabolic and mitogenic control
      in human adipocytes. Our results establish caveolae as foci of insulin action and
      stress the importance of examining human cells in addition to animal cells and
      cell lines.

PMID- 15182364
TI  - Growth-associated protein of 43 kDa (GAP-43) is cleaved nonprocessively by the
      20S proteasome.
AB  - Purified, nonubiquitinated growth-associated protein of 43 kDa (GAP-43) was
      attacked by purified reticulocyte 20S proteasome but not by the 26S proteasome.
      Cleavage yielded 12 N-terminally labelled GAP-43 fragments that could be resolved
      by SDS/PAGE. Inhibitor experiments suggested that proteasome beta1 activity
      yielded the resolved bands and that proteasomebeta5 activity generated
      nonresolvable fragments. Processive degradation, yielding only nonresolvable
      fragments, therefore did not occur. Most of the resolved fragments co-migrated
      with fragments formed in the reticulocyte lysate translation mixture used for GAP
      43 synthesis, which suggested that the fragments were also produced in the
      translation mixture by the endogenous reticulocyte lysate proteasome. Consistent
      with this idea, the addition of proteasome inhibitors to translation mixtures
      blocked fragment production. Ubiquitinated GAP-43 appeared to be the source of
      the fragments in the presence of ATP, and nonubiquitinated GAP-43 the source in
      the absence of ATP. The results therefore suggest that the lack of processing
      seen with the 20S proteasome is not an artefact arising from the way in which the
      20S proteasome was purified. In one purification protocol, the GAP-43 fragments
      formed in translation mixtures co-purified with full-length GAP-43. These
      fragments were digested to nonresolvable products upon addition of purified 20S
      proteasome. Addition of calmodulin or G-actin blocked the consumption of both
      full-length GAP-43 and the co-purified GAP-43 fragments. This showed that the
      resolved fragments can re-enter the proteasome and be cleaved to nonresolvable
      products, indicating that the lack of processivity is not a result of their
      resistance to further proteasome attack. The difficult step therefore appears to
      be the transfer of the large fragments within the proteasome from the beta1 to
      the beta5 activity for further attack.

PMID- 15182365
TI  - Temperature and concentration-controlled dynamics of rhizobial small heat shock
      proteins.
AB  - A hallmark of alpha-crystallin-type small heat shock proteins (sHsps) is their
      highly dynamic oligomeric structure which promotes intermolecular interactions
      involved in subunit exchange and substrate binding (chaperone-like activity). We
      studied the oligomeric features of two classes of bacterial sHsps by size
      exclusion chromatography and nanoelectrospray mass spectrometry. Proteins of both
      classes formed large complexes that rapidly dissociated upon dilution and at
      physiologically relevant heat shock temperatures. As the secondary structure was
      not perturbed, temperature- and concentration-dependent dissociations were fully
      reversible. Complexes formed between sHsps and the model substrate citrate
      synthase were stable and exceeded the size of sHsp oligomers. Small Hsps, mutated
      in a highly conserved glycine residue at the C-terminal end of the alpha
      crystallin domain, formed labile complexes that disassembled more readily than
      the corresponding wild-type proteins. Reduced complex stability coincided with
      reduced chaperone activity.

PMID- 15182366
TI  - NMR solution structure of Cn12, a novel peptide from the Mexican scorpion
      Centruroides noxius with a typical beta-toxin sequence but with alpha-like
      physiological activity.
AB  - Cn12 isolated from the venom of the scorpion Centruroides noxius has 67 amino
      acid residues, closely packed with four disulfide bridges. Its primary structure
      and disulfide bridges were determined. Cn12 is not lethal to mammals and
      arthropods in vivo at doses up to 100 microg per animal. Its 3D structure was
      determined by proton NMR using 850 distance constraints, 36 phi angles derived
      from 36 coupling constants obtained by two different methods, and 22 hydrogen
      bonds. The overall structure has a two and half turn alpha-helix (residues 24
      32), three strands of antiparallel beta-sheet (residues 2-4, 37-40 and 45-48),
      and a type II turn (residues 41-44). The amino-acid sequence of Cn12 resembles
      the beta scorpion toxin class, although patch-clamp experiments showed the
      induction of supplementary slow inactivation of Na(+) channels in F-11 cells
      (mouse neuroblastoma N18TG-2 x rat DRG2), which means that it behaves more like
      an alpha scorpion toxin. This behaviour prompted us to analyse Na(+) channel
      binding sites using information from 112 Na(+) channel gene clones available in
      the literature, focusing on the extracytoplasmic loops of the S5-S6 transmembrane
      segments of domain I and the S3-S4 segments of domain IV, sites considered to be
      responsible for binding alpha scorpion toxins.

PMID- 15182367
TI  - Human salivary alpha-amylase Trp58 situated at subsite -2 is critical for enzyme
      activity.
AB  - The nonreducing end of the substrate-binding site of human salivary alpha-amylase
      contains two residues Trp58 and Trp59, which belong to beta2-alpha2 loop of the
      catalytic (beta/alpha)(8) barrel. While Trp59 stacks onto the substrate, the
      exact role of Trp58 is unknown. To investigate its role in enzyme activity the
      residue Trp58 was mutated to Ala, Leu or Tyr. Kinetic analysis of the wild-type
      and mutant enzymes was carried out with starch and oligosaccharides as
      substrates. All three mutants exhibited a reduction in specific activity (150-180
      fold lower than the wild type) with starch as substrate. With oligosaccharides as
      substrates, a reduction in k(cat), an increase in K(m) and distinct differences
      in the cleavage pattern were observed for the mutants W58A and W58L compared with
      the wild type. Glucose was the smallest product generated by these two mutants in
      the hydrolysis oligosaccharides; in contrast, wild-type enzyme generated maltose
      as the smallest product. The production of glucose by W58L was confirmed from
      both reducing and nonreducing ends of CNP-labeled oligosaccharide substrates. The
      mutant W58L exhibited lower binding affinity at subsites -2, -3 and +2 and showed
      an increase in transglycosylation activity compared with the wild type. The
      lowered affinity at subsites -2 and -3 due to the mutation was also inferred from
      the electron density at these subsites in the structure of W58A in complex with
      acarbose-derived pseudooligosaccharide. Collectively, these results suggest that
      the residue Trp58 plays a critical role in substrate binding and hydrolytic
      activity of human salivary alpha-amylase.

PMID- 15182368
TI  - The crystal structure of Thermoactinomyces vulgaris R-47 alpha-amylase II (TVA
      II) complexed with transglycosylated product.
AB  - Alphan alpha-amylase (TVA II) from Thermoactinomyces vulgaris R-47 efficiently
      hydrolyzes alpha-1,4-glucosidic linkages of pullulan to produce panose in
      addition to hydrolyzing starch. TVA II also hydrolyzes alpha-1,4-glucosidic
      linkages of cyclodextrins and alpha-1,6-glucosidic linkages of isopanose. To
      clarify the basis for this wide substrate specificity of TVA II, we soaked 4(3)
      alpha-panosylpanose (4(3)-P2) (a pullulan hydrolysate composed of two panosyl
      units) into crystals of D325N inactive mutated TVA II. We then determined the
      crystal structure of TVA II complexed with 4(2)-alpha-panosylpanose (4(2)-P2),
      which was produced by transglycosylation from 4(3)-P2, at 2.2-A resolution. The
      shape of the active cleft of TVA II is unique among those of alpha-amylase family
      enzymes due to a loop (residues 193-218) that is located at the end of the cleft
      around the nonreducing region and forms a 'dam'-like bank. Because this loop is
      short in TVA II, the active cleft is wide and shallow around the nonreducing
      region. It is assumed that this short loop is one of the reasons for the wide
      substrate specificity of TVA II. While Trp356 is involved in the binding of Glc
      +2 of the substrate, it appears that Tyr374 in proximity to Trp356 plays two
      roles: one is fixing the orientation of Trp356 in the substrate-liganded state
      and the other is supplying the water that is necessary for substrate hydrolysis.

PMID- 15182370
TI  - Thermodynamic and kinetic analysis of the isolated FAD domain of rat neuronal
      nitric oxide synthase altered in the region of the FAD shielding residue Phe1395.
AB  - In rat neuronal nitric oxide synthase, Phe1395 is positioned over the FAD
      isoalloxazine ring. This is replaced by Trp676 in human cytochrome P450
      reductase, a tryptophan in related diflavin reductases (e.g. methionine synthase
      reductase and novel reductase 1), and tyrosine in plant ferredoxin-NADP(+)
      reductase. Trp676 in human cytochrome P450 reductase is conformationally mobile,
      and plays a key role in enzyme reduction. Mutagenesis of Trp676 to alanine
      results in a functional NADH-dependent reductase. Herein, we describe studies of
      rat neuronal nitric oxide synthase FAD domains, in which the aromatic shielding
      residue Phe1395 is replaced by tryptophan, alanine and serine. In steady-state
      assays the F1395A and F1395S domains have a greater preference for NADH compared
      with F1395W and wild-type. Stopped-flow studies indicate flavin reduction by NADH
      is significantly faster with F1395S and F1395A domains, suggesting that this
      contributes to altered preference in coenzyme specificity. Unlike cytochrome P450
      reductase, the switch in coenzyme specificity is not attributed to differential
      binding of NADPH and NADH, but probably results from improved geometry for
      hydride transfer in the F1395S- and F1395A-NADH complexes. Potentiometry
      indicates that the substitutions do not significantly perturb thermodynamic
      properties of the FAD, although considerable changes in electronic absorption
      properties are observed in oxidized F1395A and F1395S, consistent with changes in
      hydrophobicity of the flavin environment. In wild-type and F1395W FAD domains,
      prolonged incubation with NADPH results in development of the neutral blue
      semiquinone FAD species. This reaction is suppressed in the mutant FAD domains
      lacking the shielding aromatic residue.

PMID- 15182369
TI  - The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin
      converting enzyme and the amyloid precursor protein.
AB  - Numerous transmembrane proteins, including the blood pressure regulating
      angiotensin converting enzyme (ACE) and the Alzheimer's disease amyloid precursor
      protein (APP), are proteolytically shed from the plasma membrane by
      metalloproteases. We have used an antisense oligonucleotide (ASO) approach to
      delineate the role of ADAM10 and tumour necrosis factor-alpha converting enzyme
      (TACE; ADAM17) in the ectodomain shedding of ACE and APP from human SH-SY5Y
      cells. Although the ADAM10 ASO and TACE ASO significantly reduced (> 81%) their
      respective mRNA levels and reduced the alpha-secretase shedding of APP by 60% and
      30%, respectively, neither ASO reduced the shedding of ACE. The mercurial
      compound 4-aminophenylmercuric acetate (APMA) stimulated the shedding of ACE but
      not of APP. The APMA-stimulated secretase cleaved ACE at the same Arg-Ser bond in
      the juxtamembrane stalk as the constitutive secretase but was more sensitive to
      inhibition by a hydroxamate-based compound. The APMA-activated shedding of ACE
      was not reduced by the ADAM10 or TACE ASOs. These results indicate that neither
      ADAM10 nor TACE are involved in the shedding of ACE and that APMA, which
      activates a distinct ACE secretase, is the first pharmacological agent to
      distinguish between the shedding of ACE and APP.

PMID- 15182371
TI  - Mediator is required for activated transcription in a Schizosaccharomyces pombe
      in vitro system.
AB  - RNA polymerase II (RNAPII) requires a set of general transcription factors -
      TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH - to initiate transcription from a
      gene promoter in vitro. General transcription factors have been isolated from
      Saccharomyces cerevisiae, rat, human and Drosophila, and their corresponding
      cDNAs have been cloned. In this report, we describe a reconstituted in vitro
      transcription system that consists of the following preparations of factors from
      the yeast Schizosaccharomyces pombe: affinity-purified RNAPII, TFIIH, and
      recombinant TBP, TFIIB, TFIIE and TFIIF. We show that this system can support
      basal transcription from the adenovirus major late promoter when purified RNAPII
      is used and activated transcription when the RNAPII holoenzyme (RNAPII plus the
      Mediator proteins) is included in the reaction. In contrast, the TATA binding
      protein-associated factors had no effect on transcriptional activation in our Sc.
      pombe system. These results indicate that Sc. pombe uses the same set of general
      transcription factors as other eukaryotes and that the Mediator is involved in
      activated transcription.

PMID- 15182374
TI  - 24th International Symposium on Intensive Care and Emergency Medicine held in
      Brussels, Belgium, 30 March - 2 April 2004. Abstracts.

PMID- 15182373
TI  - Hypoglycemic and anti-lipemic effects of the aqueous extract from Cissus
      sicyoides.
AB  - BACKGROUND: Cissus sicyoides (Vitaceae) is a medicinal plant popularly known in
      Brazil as "cipo-puca, anil-trepador, cortina, and insulina". The plant is used in
      several diseases, including rheumatism, epilepsy, stroke and also in the
      treatment of diabetes. In the present work, we studied the hypoglycemic and anti
      lipemic effects of the aqueous extract prepared from fresh leaves of the plant
      (AECS), in the model of alloxan-induced diabetes in rats. In addition, hepatic
      enzyme levels were also determined. RESULTS: Results showed that the daily
      treatment of diabetic rats with AECS for 7 days (100 and 200 mg/kg, p.o.)
      significantly decreased blood glucose levels in 25 and 22% respectively, as
      compared to the same groups before AECS treatment. No significant changes were
      seen in control diabetic rats before (48 h after alloxan administration) and
      after distilled water treatment. While no changes were seen in total cholesterol
      levels, a significant decrease was observed in plasma triglyceride levels, in the
      alloxan-induced diabetic rats after AECS treatment with both doses, as compared
      to the same groups before treatment. Significant decreases in blood glucose (25%)
      and triglyceride levels (48%) were also observed in the alloxan-induced diabetic
      rats after 4 days treatment with AECS (200 mg/kg, p.o.). Aspartate (AST) and
      alanine (ALT) aminotransferases levels, in diabetic controls and AECS-treated
      rats, were in the range of reference values presented by normal rats.
      CONCLUSIONS: The results justify the popular use of C. sicyoides, pointing out to
      the potential benefit of the plant aqueous extract (AECS) in alternative
      medicine, in the treatment of type 2 diabetes mellitus.

PMID- 15182372
TI  - No evidence of association between Catechol-O-Methyltransferase (COMT) Val158Met
      genotype and performance on neuropsychological tasks in children with ADHD: a
      case-control study.
AB  - BACKGROUND: Several studies have suggested an association between the functional
      Val158Met polymorphism in the Catechol-O-Methyltransferase (COMT) gene and
      neurocognitive performance. Two studies showed that subjects with the low
      activity Met allele performed better on the Wisconsin Card Sorting Test (WCST)
      and another study found an effect on processing speed and attention. METHODS: We
      set out to examine the association between the Val158Met polymorphism and
      performance on neurocognitive tasks including those tapping working memory,
      attention and speed, impulsiveness and response inhibition in a sample of 124
      children with ADHD. Task performance for each genotypic group was compared using
      analysis of variance. RESULTS: There was no evidence of association with
      performance on any of the neurocognitive tasks. CONCLUSIONS: We conclude that
      Val158Met COMT genotype is not associated with neurocognitive performance in our
      sample.

PMID- 15182376
TI  - Abstracts of the 24th European Workshop for Rheumatology Research. Berlin,
      Germany, 26-29 February 2004.

PMID- 15182377
TI  - 3rd World Congress of the Global Arthritis Research Network (GARN): International
      Arthritis Summit. Miyazaki, Japan. 14-17 September 2003. Abstracts.

PMID- 15182378
TI  - What difference does ("good") HRM make?
AB  - The importance of human resources management (HRM) to the success or failure of
      health system performance has, until recently, been generally overlooked. In
      recent years it has been increasingly recognised that getting HR policy and
      management "right" has to be at the core of any sustainable solution to health
      system performance. In comparison to the evidence base on health care reform
      related issues of health system finance and appropriate purchaser/provider
      incentive structures, there is very limited information on the HRM dimension or
      its impact.Despite the limited, but growing, evidence base on the impact of HRM
      on organisational performance in other sectors, there have been relatively few
      attempts to assess the implications of this evidence for the health sector. This
      paper examines this broader evidence base on HRM in other sectors and examines
      some of the underlying issues related to "good" HRM in the health sector.The
      paper considers how human resource management (HRM) has been defined and
      evaluated in other sectors. Essentially there are two sub-themes: how have HRM
      interventions been defined? and how have the effects of these interventions been
      measured in order to identify which interventions are most effective? In other
      words, what is "good" HRM?The paper argues that it is not only the organisational
      context that differentiates the health sector from many other sectors, in terms
      of HRM. Many of the measures of organisational performance are also unique.
      "Performance" in the health sector can be fully assessed only by means of
      indicators that are sector-specific. These can focus on measures of clinical
      activity or workload (e.g. staff per occupied bed, or patient acuity measures),
      on measures of output (e.g. number of patients treated) or, less frequently, on
      measures of outcome (e.g. mortality rates or rate of post-surgery
      complications).The paper also stresses the need for a "fit" between the HRM
      approach and the organisational characteristics, context and priorities, and for
      recognition that so-called "bundles" of linked and coordinated HRM interventions
      will be more likely to achieve sustained improvements in organisational
      performance than single or uncoordinated interventions.

PMID- 15182380
TI  - Surgical correction of buried penis after traffic accident - a case report.
AB  - BACKGROUND: Buried penis, most commonly seen in children, is particularly
      debilitating in adults, resulting in inability to void while standing and it also
      affects vaginal penetration. We report a case of buried penis due to a traffic
      accident, which caused dislocation of the fractured pubic bone that shifted
      inside and pulled the penis by its suspensory ligament. CASE PRESENTATION: A 55
      year-old man was admitted to our hospital with a chief complaint of hidden penis
      while in the sitting position. He had suffered a pelvic fracture in a traffic
      accident four years previously, and his penis was covered with suprapubic fat
      when he was in a sitting position. He was unable to have sexual intercourse. We
      performed a penile lengthening procedure, including inverse V-Y-plasty of the
      dorsal skin of the penile root, suspensory desmotomy and fat removal, under
      general anesthesia. There was a good cosmetic result with satisfactory penile
      erection, which allowed successful sexual intercourse after surgery. CONCLUSION:
      We performed penile elongation surgery with inverse V-Y-plasty of the dorsal skin
      of the penile root, suspensory desmotomy, and fat removal. Surgical treatment of
      buried penis achieves marked aesthetic and functional improvement, and benefits
      the majority of patients, resulting in satisfactory erection and successful
      sexual intercourse.

PMID- 15182379
TI  - Pharmaceutical care for elderly patients shared between community pharmacists and
      general practitioners: a randomised evaluation. RESPECT (Randomised Evaluation of
      Shared Prescribing for Elderly people in the Community over Time)
      [ISRCTN16932128].
AB  - BACKGROUND: This trial aims to investigate the effectiveness and cost
      implications of 'pharmaceutical care' provided by community pharmacists to
      elderly patients in the community. As the UK government has proposed that by 2004
      pharmaceutical care services should extend nationwide, this provides an
      opportunity to evaluate the effect of pharmaceutical care for the elderly.
      DESIGN: The trial design is a randomised multiple interrupted time series. We aim
      to recruit 700 patients from about 20 general practices, each associated with
      about three community pharmacies, from each of the five Primary Care Trusts in
      North and East Yorkshire. We shall randomise the five resulting groups of
      practices, pharmacies and patients to begin pharmaceutical care in five
      successive phases. All five will act as controls until they receive the
      intervention in a random sequence. Until they receive training community
      pharmacists will provide their usual dispensing services and so act as controls.
      The community pharmacists and general practitioners will receive training in
      pharmaceutical care for the elderly. Once trained, community pharmacists will
      meet recruited patients, either in their pharmacies (in a consultation room or
      dispensary to preserve confidentiality) or at home. They will identify drug
      related issues/problems, and design a pharmaceutical care plan in conjunction
      with both the GP and the patient. They will implement, monitor, and update this
      plan monthly. The primary outcome measure is the 'Medication Appropriateness
      Index'. Secondary measures include adverse events, quality of life, and patient
      knowledge and compliance. We shall also investigate the cost of pharmaceutical
      care to the NHS, to patients and to society as a whole.

PMID- 15182381
TI  - Does a perception of increased blood safety mean increased blood transfusion? An
      assessment of the risk compensation theory in Canada.
AB  - BACKGROUND: The risk compensation theory is a widely used concept in transport
      economics to analyze driver risk behaviour. This article explores the feasibility
      of applying the theory in blood transfusion to raise important questions
      regarding the increased blood safety measures and their possible effects on blood
      usage (e.g., the appropriateness in transfusion). Further, it presents the
      findings of a pilot survey of physicians in Canada. DISCUSSION: While studies
      have attempted to define transfusion appropriateness, this article argues that if
      the risk compensation theory holds true for transfusion practice, physicians may
      actually be transfusing more. This may increase the possibility of contracting
      other unknown risks, such as the variant Creutzfeldt-Jakob Disease (vCJD), as
      well as increasing the risk of non-infectious transfusion risks, such as
      transfusion reactions. SUMMARY: A much larger study involving psychosocial
      assessment of physician decision making process to fully assess physician
      behaviour within the context of risk compensation theory and transfusion practice
      in Canada is needed to further explore this area.

PMID- 15182383
TI  - Could glycaemic index be the basis of simple nutritional recommendations?

PMID- 15182384
TI  - Probiotics and colorectal cancer risk.

PMID- 15182385
TI  - Functional dichotomy: glutathione and vitamin E in homeostasis relevant to
      primary open-angle glaucoma.
AB  - Primary open-angle glaucoma (POAG) is a complex chronic neurological disease that
      can result in blindness. The goal of understanding the aetiology of POAG is to be
      able to target effective treatment to individuals who will eventually go blind
      without it. Epidemiological studies of POAG have not specifically addressed the
      possibility that nutrition may play a role in the development of POAG. A handful
      of papers have considered that nutrition may have an impact on POAG patients.
      POAG is not believed to be a 'vitamin-deficiency disease'. The concept of
      'vitamin-deficiency diseases' and the recommended daily allowances have not kept
      pace with the growing understanding of the cellular and molecular functions of
      vitamins and other micronutrients. The aetiology of POAG remains a mystery.
      Discoveries in cell physiology can be assimilated from the literature and applied
      to known homeostatic mechanisms of the eye. In this way the possible roles of
      nutritional components involved in the aetiology of POAG can be described. The
      mechanisms may be subject to many influences in ways that have yet to be defined.
      Two distinct changes in the trabecular meshwork can be identified: trabecular
      meshwork changes that cause intra-ocular pressure to increase and trabecular
      meshwork changes that are directly correlated to optic nerve atrophy. Compelling
      evidence suggests that collagen trabecular meshwork extracellular matrix (ECM)
      remodelling is correlated to increased intraocular pressure in POAG. Elastin
      trabecular meshwork ECM remodelling is correlated to POAG optic nerve atrophy.
      There appear to be two different pathways of ECM remodelling and apoptosis
      induction in POAG. The pathway for collagen remodelling and apoptosis induction
      seems to be exogenously influenced by water-soluble antioxidants, for example,
      glutathione. The pathway for elastin remodelling and apoptosis induction seems to
      be influenced by endogenous lipid-soluble antioxidants, for example, vitamin E.
      Roles can be defined for antioxidants in the two different pathways of ECM
      remodelling and apoptosis induction. This suggests that antioxidants are
      important in maintaining cellular homeostasis relevant to the aetiology of POAG.

PMID- 15182386
TI  - Effect of dietary flavonols on oestrogen receptor transactivation and cell death
      induction.
AB  - Consumption of fruits and vegetables has been associated with cancer prevention;
      flavonoids are widely distributed in plant foods and considered to be the active
      ingredients. Quercetin and kaempferol are two of the most commonly found dietary
      flavonols, and have been reported to prevent cancer. We have previously reported
      that the isoflavone genistein and the flavone baicalein exert differential
      actions on the oestrogen receptor (OR) alpha in HepG2 cells. Because of the
      structural resemblance to both isoflavone and flavone, we examined the effects of
      these dietary flavonols on ORalpha- and ORbeta-specific transactivations and
      their subsequent involvement in inducing MCF-7 cell death. In the present study,
      both quercetin and kaempferol were able to compete for OR binding in a cell-free
      system and were agonistic to ORalpha and -beta expressed in HepG2 cells, while
      some additive effect was observed in the oestrogen response element (ORE)-driven
      transcription when 17beta-oestradiol was co-administered. Since the bcl-2
      promoter contained two ORE, and ORE-driven transcriptional activity and Bcl-2
      mRNA expression were increased by treatment with 10 microm-quercetin or
      kaempferol, it is possible that quercetin and kaempferol might up-regulate Bcl-2
      expression through OR transactivation in MCF-7 cells. Cell death ELISA assay
      performed on MCF-7 cells indicated that an increase of apoptosis occurred at 25
      microm-, but not 10 microm-, quercetin or kaempferol. Indirectly the results
      suggest that OR activation is not sufficient to induce apoptosis and that
      apoptosis is induced despite an increase in Bcl-2 expression.

PMID- 15182387
TI  - The type of sugar moiety is a major determinant of the small intestinal uptake
      and subsequent biliary excretion of dietary quercetin glycosides.
AB  - Quercetin is an important dietary flavonoid with putative beneficial effects in
      the prevention of cancer and CVD. The in vivo bioactivity of quercetin depends on
      its bioavailability, which varies widely between foods. We used an in situ rat
      intestinal perfusion model to study whether differential small intestinal
      hydrolysis of the sugar moiety of five naturally occurring quercetin glycosides
      determines the small intestinal uptake and subsequent biliary excretion of
      quercetin. After 30 min perfusion, a decrease of intact quercetin glycoside in
      perfusate was observed for quercetin-3-O-ss-glucoside (20.9 (sem 1.4) micromol/l)
      and quercetin-4'-O-ss-glucoside (23.5 (sem 1.6) micromol/l), but not of quercetin
      3-O-ss-galactoside, quercetin-3-O-ss-rhamnoside and quercetin-3-O-alpha
      arabinopyranoside. Appearance of free quercetin in perfusate and conjugated
      quercetin metabolites (quercetin, isorhamnetin, and tamarixetin) in portal and
      peripheral plasma and bile were also significantly greater after treatment with
      quercetin-3-O-ss-glucoside or quercetin-4'-O-ss-glucoside compared with any of
      the other glycosides. Thus, the type of sugar moiety is a major determinant of
      the small intestinal absorption of quercetin glycosides, but the position (3 or
      4') of the glucose moiety does not further influence absorption. The poor
      bioavailability of important dietary quercetin glycosides has implications for
      their in vivo bioactivities.

PMID- 15182388
TI  - Quercetin glucosides inhibit glucose uptake into brush-border-membrane vesicles
      of porcine jejunum.
AB  - Recent experimental data point to an interaction of dietary flavonol
      monoglucosides with the intestinal Na-dependent glucose transporter 1 (SGLT1). To
      investigate this interaction in more detail, we performed experiments with SGLT1
      containing brush-border-membrane vesicles (BBMV) from pig jejunum. The flavonol
      quercetin-3-O-glucoside (Q3G) concentration-dependently inhibited Na-dependent
      uptake of radioactively labelled d-glucose into BBMV. Uptake of l-leucine was not
      inhibited by Q3G, indicating a specific interaction of the glucoside with SGLT1.
      Whereas the maximal transport rate of concentration-dependent initial glucose
      uptake was not altered in the presence of Q3G, the constant for half-maximal
      glucose uptake was increased, suggesting a competitive type of inhibition of
      glucose uptake by Q3G. Trans-stimulation experiments suggested the transport of
      Q3G via SGLT1. In addition, Q3G decreased the Na-independent diffusive uptake of
      glucose into BBMV. Other flavonoids were also tested for their inhibitory effect
      on d-glucose uptake. Among the tested quercetin glycosides, only the 4'-O
      glucoside (Q4G) also inhibited Na-dependent glucose uptake into BBMV, whereas the
      3-O-galactoside, the 3-O-glucorhamnoside and the aglycone quercetin itself were
      ineffective. Glucosides of some other flavonoid classes such as naringenin-7-O
      glucoside, genistein-7-O-glucoside and cyanidin-3,5-O-diglucoside were
      ineffective as well. Thus, dietary quercetin monoglucosides, for example, Q3G and
      Q4G, have an impact on intestinal nutrient transporters such as SGLT1 and related
      systems.

PMID- 15182389
TI  - Effect of a methionine-supplemented diet on the blood pressure of Sprague-Dawley
      and deoxycorticosterone acetate-salt hypertensive rats.
AB  - The objectives of the present study were to evaluate the effects of a methionine
      supplemented diet on systolic blood pressure (BP) and vasomotor functions in
      Sprague-Dawley (SD) and deoxycorticosterone acetate (DOCA)-salt hypertensive
      rats. SD and DOCA rats were fed a normal or a methionine (8 g/kg)-supplemented
      diet for 10 weeks. Systolic BP was monitored and plasma homocysteine, methionine
      and cysteine levels were determined at the end of the experiment.
      Vasoconstriction and vasodilatation of aortic rings were measured. The methionine
      supplemented diet induced a greater increase in homocysteinaemia concentration in
      DOCA rats than in SD rats and an increase in plasma cysteine concentration in
      DOCA rats. This diet was associated with an increase in systolic BP in SD rats
      and with a lesser development of DOCA-salt hypertension. An enhanced aortic
      constriction and a decreased responsiveness to acetylcholine, bradykinin and
      sodium nitroprusside in the SD rats fed the methionine-rich diet were consistent
      with the elevated systolic BP. In DOCA rats the increased responsiveness to
      bradykinin was in accordance with the systolic BP-lowering effect. In conclusion,
      the methionine-enriched diet cannot simply be considered as model of
      hyperhomocysteinaemia, since other metabolites and mechanisms seemed to be
      implicated in these complex interactions. The differential vasopressive effect of
      the methionine supplementation in SD and DOCA rats, and in particular the
      lowering of systolic BP obtained with a greater degree of hyperhomocysteinaemia
      in DOCA rats, suggest that more complex interactions exist between
      hyperhomocysteinaemia and BP than the simple positive association described
      previously.

PMID- 15182390
TI  - Viscoelastic properties of the small intestinal and caecal contents of the
      chicken.
AB  - We measured the coefficients of viscosity, shear rates and shear stresses of
      chicken small intestinal and caecal contents, including solid particles, using a
      tube-flow viscometer. The coefficients of viscosity of chicken small intestinal
      and caecal contents were correlated negatively with their shear rates, a
      characteristic typical of non-Newtonian fluids. The coefficient of viscosity of
      the small intestinal contents was lower than that of the caecal contents at a
      shear rate of 1 s(-1). Chicken caecal contents were more viscous than pig caecal
      contents. The exponential relationship between shear stress and shear rate showed
      that chicken small intestinal and caecal contents had an apparent Herschel
      Bulkley fluid nature. These results indicate that solid particles, including uric
      acid crystals, are mainly responsible for the viscosity of the digesta in the
      chicken.

PMID- 15182391
TI  - Comparison of antioxidant activity and bioavailability of tea epicatechins with
      their epimers.
AB  - Canned and bottled tea drinks contain not only green tea epicatechins (GTE),
      namely (-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)
      epigallocatechin (EGC) and (-)-epicatechin (EC), but also four GTE epimers,
      namely (-)-gallocatechin gallate (GCG), (-)-catechin gallate (CG), (-)
      gallocatechin (GC) and (-)-catechin (C). In the present study we examined the
      antioxidant activity and bioavailability of these epimers compared with their
      corresponding precursors. The epimerisation reaction was induced by autoclaving
      GTE extract derived from longjing green tea at 120 degrees C for 20 min.
      Isolation and purification of each GTE and epimer were accomplished by various
      column chromatographic and semi-preparative HPLC techniques. The antioxidant
      activity of each epimer with its corresponding GTE precursor was conducted in the
      three in vitro systems, namely human LDL oxidation, ferric reducing-antioxidant
      power (FRAP), and anti-2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assays.
      The results of all three assays demonstrated that CG had similar antioxidant
      activity with its precursor ECG, while GC was less potent as an antioxidant than
      its precursor EGC. Regarding EGCG and GCG, the antioxidant potency was similar
      for both LDL oxidation and DPPH free radical assays, but GCG was statistically
      less effective than EGCG in the FRAP assay. For EC and C, the latter had less
      anti-free radical activity in the DPPH assay, but in LDL oxidation and FRAP
      assays the antioxidant activity was similar. Oral and intravenous dosing of GTE
      epimer mixture led to increase in total plasma antioxidant capacity in rats. In
      general, both epicatechins and epimers had low bioavailability (0.08-0.31) and
      most of the observed differences between epicatechins and their corresponding
      epimers were small, even if they were statistically significant in some cases. It
      was concluded that the epimerisation reaction occurring in manufacturing canned
      and bottled tea drinks would not significantly affect antioxidant activity and
      bioavailability of total tea polyphenols.

PMID- 15182392
TI  - The effects of dietary lipids on dendritic cells in perinodal adipose tissue
      during chronic mild inflammation.
AB  - The effects of dietary lipids on the abundance of dendritic cells in adipose
      tissue in anatomically defined relationships to chronically inflamed lymph nodes
      were investigated in mature male rats fed plain chow or chow plus 20 % sunflower
      seed or fish oil. The popliteal lymph nodes were stimulated by local subcutaneous
      injection of 20 microg lipopolysaccharide to both hindlegs three times/week for 2
      weeks. The masses of the major adipose depots and the numbers of dendritic cells
      emerging from perinodal adipose tissue and samples 5 and 10 mm from the popliteal
      lymph nodes were measured, and those from omental and mesenteric adipose tissue
      around and remote from lymphoid tissue, and mesenteric and popliteal lymph nodes.
      Dendritic cells were most numerous in the perinodal adipose tissue, with the
      corresponding 'remote' samples containing 25-50 % fewer such cells under all
      conditions studied. Dietary sunflower-seed oil increased the numbers of dendritic
      cells by about 17 % in all adipose samples and fish oil reduced the numbers in
      perinodal tissue by about 5 %. The fish-oil diet diminished responses of the
      intra-abdominal adipose depots to local stimulation of the popliteal node.
      Correlations in dendritic cell numbers were stronger between perinodal samples
      from different depots than between remote and perinodal samples from the same
      depot and after the sunflower-seed-oil diet compared with fish oil. These data
      show that dietary lipids modulate the number of dendritic cells in lymphoid
      tissue-containing adipose depots and support the hypothesis that perinodal
      adipose tissue interacts locally with lymphoid cells.

PMID- 15182393
TI  - The influence of different combinations of gamma-linolenic acid, stearidonic acid
      and EPA on immune function in healthy young male subjects.
AB  - To determine the effects of EPA, stearidonic acid (STA) or gamma-linolenic acid
      (GLA) on immune outcomes, healthy male subjects consumed one of seven oil blends
      for 12 weeks. EPA consumption increased the EPA content of peripheral blood
      mononuclear cells (PBMC). Consumption of GLA (2.0 g/d) in the absence of STA or
      EPA increased di-homo-GLA content in PBMC. Neither STA nor its derivative 20 : 4n
      3 appeared in PBMC when STA (<1.0 g/d) was consumed. However, STA (1.0 g/d), in
      combination with GLA (0.9 g/d), increased the proportion of EPA in PBMC. None of
      the treatments altered neutrophil or monocyte phagocytosis or respiratory burst,
      production of inflammatory cytokines by monocytes, T lymphocyte proliferation or
      the delayed-type hypersensitivity response. Production of cytokines by T
      lymphocytes increased in all groups, with no differences among them. The
      proportion of lymphocytes that were natural killer cells decreased significantly
      in subjects receiving 2.0 g EPA or GLA/d. There were no other effects on
      lymphocyte sub-populations. Plasma IgE concentration decreased in most groups,
      but not in the control group. Plasma IgG2 concentration increased in the EPA
      group. Thus, EPA or GLA at a dose of 2.0 g/d have little effect on key functions
      of neutrophils, monocytes and T lymphocytes, although at this dose these fatty
      acids decrease the number of natural killer cells. At this dose EPA increases
      IgG2 concentrations. STA can increase immune cell EPA status, but at 1.0 g/d does
      not affect human immune function.

PMID- 15182394
TI  - Combination of polydextrose and lactitol affects microbial ecosystem and immune
      responses in rat gastrointestinal tract.
AB  - The effects of various dietary fibres on gut health have been studied extensively
      but their combined effects are scarcely documented. In the present study the
      effects of 2 % (w/w) polydextrose (PDX), 2 % (w/w) disaccharide lactitol, or 2 %
      (w/w) PDX+2 % (w/w) lactitol on gut microflora, microbial metabolism and gut
      immune responses were investigated in rats. Both PDX and lactitol alone had an
      effect on many of the studied parameters, but their combination had stronger than
      additive effects in some parameters. The PDX+lactitol combination altered the
      microbial community structure as seen by a culture-independent method, percentage
      guanine+cytosine (%G+C) profiling, increasing the areas of %G+C 35-39 (P<0.0001)
      and %G+C 45-49 (P=0.0002), and decreasing %G+C 65-74 (P<0.0003). These changes
      were also reflected in the microbial metabolism so that the production of
      biogenic amines and branched volatile fatty acids was significantly reduced, by
      12 (P=0.03) and 50 % (P=0.002), respectively, indicating a shift from
      putrefactive towards saccharolytic metabolism. PDX increased the secretion of IgA
      in the caecum (P=0.007). Secretion of IgA increased even more, almost ten-fold,
      with the combination of PDX+lactitol (P<0.0001) when compared with the control
      group. Lactitol increased the production of butyrate by caecal microbes by two-
      to three-fold when compared with the PDX or control group (P<0.0001). Butyrate is
      a preferred energy source for mucosal cells; thus a boost in the availability of
      energy for immune cells may have still added to the synergistic effects of PDX
      and lactitol on immune cells. It is noteworthy that improvement in the IgA
      secretion occurred without signs of mucosal inflammation.

PMID- 15182395
TI  - Contribution of acetate to butyrate formation by human faecal bacteria.
AB  - Acetate is normally regarded as an endproduct of anaerobic fermentation, but
      butyrate-producing bacteria found in the human colon can be net utilisers of
      acetate. The butyrate formed provides a fuel for epithelial cells of the large
      intestine and influences colonic health. [1-(13)C]Acetate was used to investigate
      the contribution of exogenous acetate to butyrate formation. Faecalibacterium
      prausnitzii and Roseburia spp. grown in the presence of 60 mm-acetate and 10 mm
      glucose derived 85-90 % butyrate-C from external acetate. This was due to rapid
      interchange between extracellular acetate and intracellular acetyl-CoA, plus net
      acetate uptake. In contrast, a Coprococcus-related strain that is a net acetate
      producer derived only 28 % butyrate-C from external acetate. Different
      carbohydrate-derived energy sources affected butyrate formation by mixed human
      faecal bacteria growing in continuous or batch cultures. The ranking order of
      butyrate production rates was amylopectin > oat xylan > shredded wheat > inulin >
      pectin (continuous cultures), and inulin > amylopectin > oat xylan > shredded
      wheat > pectin (batch cultures). The contribution of external acetate to butyrate
      formation in these experiments ranged from 56 (pectin) to 90 % (xylan) in
      continuous cultures, and from 72 to 91 % in the batch cultures. This is
      consistent with a major role for bacteria related to F. prausnitzii and Roseburia
      spp. in butyrate formation from a range of substrates that are fermented in the
      large intestine. Variations in the dominant metabolic type of butyrate producer
      between individuals or with variations in diet are not ruled out, however, and
      could influence butyrate supply in the large intestine.

PMID- 15182396
TI  - Dietary intervention with the probiotics Lactobacillus acidophilus 145 and
      Bifidobacterium longum 913 modulates the potential of human faecal water to
      induce damage in HT29clone19A cells.
AB  - Probiotics reduce the risk of colon cancer by inhibiting carcinogen-induced DNA
      damage in animals, but there are no analogous data in human subjects. To enhance
      knowledge of the effects of probiotics in human subjects, we have investigated
      the genotoxicity of faecal water after dietary intervention with standard yoghurt
      or with probiotic yoghurt, which included the strains Lactobacillus acidophilus
      145 and Bifidobacterium longum 913. Faeces were collected from nine healthy
      volunteers after intervention with probiotic yoghurt or standard yoghurt. Faecal
      water was isolated and incubated with human colon tumour cells HT29clone19A. DNA
      strand breaks, oxidised DNA bases and damage after challenge with H2O2 were
      determined by micro-gel-electrophoresis. Faecal water was genotoxic in comparison
      with NaCl, but protected against H2O2-induced DNA strand breaks. The intervention
      with probiotic yoghurt significantly lowered faecal water genotoxicity compared
      with standard yoghurt. However, probiotic intervention also increased oxidative
      damage; this either reflected prooxidative activity or stimulation of endogenous
      defence systems. Altogether, the balance of effects favoured protection, since
      faecal water from the probiotic group reduced overall genetic damage. Thus, there
      was a reduction of strand break-inducing compounds in human faeces after dietary
      intervention with probiotic bacteria. This protection reflected results from
      previous studies in carcinogen-exposed animals where probiotics reduced DNA
      damage in colon cells.

PMID- 15182397
TI  - Oxidative stress status in an institutionalised elderly group after the intake of
      a phenolic-rich dessert.
AB  - The elderly population undergoes a series of physiological and sociological
      changes common to old age with a high probability of suffering degenerative
      illness and malnutrition. A dessert rich in phenolic compounds has been designed
      by using concentrated juices of grape, cherry, blackberry, blackcurrant and
      raspberry with the aim of it being used as a complementary food in adulthood. In
      the present study, we investigated the effect of the intake of this dessert (a
      jar of 200 g daily for a period of 2 weeks), with an antioxidant activity
      equivalent to ten servings of fruits and vegetables, on several markers of
      oxidative and antioxidant status in DNA and plasma in a group of elderly
      individuals. Non-smoking institutionalised elderly subjects were recruited from a
      pool of volunteers in an old-age home in Murcia (Spain). Twenty-two subjects (six
      men and sixteen women) participated in the study. The study was designed as a
      randomised intervention trial with a period of 2 weeks. At days 1 and 15, blood
      samples were collected to analyse total antioxidant capacity, biochemical
      parameters, antioxidant vitamins, LDL peroxidation, and DNA damage in peripheral
      blood lymphocytes. The conclusion of the present study is that a 2-week
      intervention with our dessert enriched with natural polyphenol compounds in
      elderly individuals does not give enough time to find changes in the antioxidant
      and oxidative status. Also, the view that the marked antioxidant ability of
      polyphenols in vitro does not translate to analogous effects in vivo was
      confirmed. Moreover, a highly oxidative stress status during ageing was
      confirmed, together with the need to perform follow-up nutritional studies to
      improve this situation.

PMID- 15182398
TI  - The effects of fluid restriction on hydration status and subjective feelings in
      man.
AB  - Hydration status and the effects of hypohydration have been the topic of much
      public and scientific debate in recent years. While many physiological responses
      to hypohydration have been studied extensively, the subjective responses to
      hypohydration have largely been ignored. The present investigation was designed
      to investigate the physiological responses and subjective feelings resulting from
      13, 24 and 37 h of fluid restriction (FR) and to compare these with a euhydration
      (EU) trial of the same duration in fifteen healthy volunteers. The volunteers
      were nine men and six women of mean age 30 (sd 12) years and body mass 71.5 (sd
      13.4) kg. Urine and blood samples were collected and subjective feelings recorded
      on a 100 mm verbally anchored questionnaire at intervals throughout the
      investigation. In the EU trial the subjects maintained their normal diet. Body
      mass decreased by 2.7 (sd 0.6) % at 37 h in the FR trial and did not change
      significantly in the EU trial. Food intake in the FR trial (n 10) provided an
      estimated water intake of 487 (sd 335) ml and urinary losses (n 15) amounted to
      1.37 (sd 0.39) litres. This is in comparison with an estimated water intake of
      3168 (sd 1167) ml and a urinary loss of 2.76 (sd 1.11) litres in the EU trial.
      Plasma osmolality and angiotensin II concentrations increased from 0-37 h with
      FR. Plasma volume decreased linearly throughout the FR trial amounting to a 6.2
      (sd 5.1) % reduction by 37 h. Thirst increased from 0-13 h of FR then did not
      increase further (P>0.05). The subjects reported feelings of headache during the
      FR trial and also that their ability to concentrate and their alertness were
      reduced.

PMID- 15182399
TI  - Lipoprotein metabolism in patients with anorexia nervosa: a case-control study
      investigating the mechanisms leading to hypercholesterolaemia.
AB  - Hypercholesterolaemia is a common finding in patients with anorexia nervosa (AN).
      To investigate the type, frequency and pathophysiological mechanisms of changes
      in lipoprotein metabolism in AN we performed a cross-sectional study in fifty
      eight female patients (mean age 24.2 years, BMI 15.3 (sd 1.5) kg/m(2)) and fifty
      eight healthy age-matched controls (CO; BMI 22.2 (sd 1.7) kg/m(2)). Total
      cholesterol and LDL-cholesterol were higher in AN (5.5 (sd 1.3) v. 5.0 (sd 0.8)
      mmol/l, P=0.023; 3.6 (sd 1.1) v. 3.2 (sd 0.7) mmol/l, P=0.025 respectively). LDL
      particles were significantly more enriched in cholesterol and triacylglycerol in
      AN. In multiple regression analysis with LDL-cholesterol as the dependent and
      BMI, total body fat ( %), lathosterol:cholesterol ratio (endogenous cholesterol
      synthesis), 7alpha-hydroxy-4-cholesten-3-one (bile acid synthesis), non
      esterified glycerol, free triiodothyronine and free thyroxine as independent
      variables, BMI was the only significant predictor in CO (R(2) 0.36, overall
      P=0.001). In AN the variability of LDL-cholesterol was significantly predicted by
      total body fat, free thyroxine, BMI, free triiodothyronine and non-esterified
      glycerol (R(2) 0.55, overall P<0.001). Subgroup analysis between restricting (AN
      R) and binge-eating-purging patients (AN-B) indicated that in AN-R changes in
      lipoproteins, BMI and total body fat were more pronounced. AN-R patients had
      lower bile acid synthesis than AN-B (P=0.02). We conclude that elevated
      cholesterol concentrations in AN are generally due to an increase in LDL
      cholesterol, which is mostly determined by the severe loss of body fat and the
      resulting changes in thyroid hormones, increased lipolysis and decreased
      endogenous cholesterol synthesis with resulting decrease in LDL removal. The
      clinical subtype of AN plays a major role in the mechanisms leading to
      hypercholesterolaemia.

PMID- 15182400
TI  - Glycaemic index of selected staples commonly eaten in the Caribbean and the
      effects of boiling v. crushing.
AB  - Integrating information about the glycaemic index (GI) of foods into the
      Caribbean diet is limited by the lack of data. Therefore, we determined the GI of
      eight staple foods eaten in the Caribbean and the effect on GI of crushing
      selected tubers. Groups of eight to ten healthy volunteers participated in three
      studies at two sites. GI was determined using a standard method with white bread
      and adjusted relative to glucose. The mean area under the glucose response curve
      elicited by white bread was similar for the different groups of subjects. In
      study 1, the GI of cassava (Manihot esculenta; 94 (sem 11)) was significantly
      higher than those of breadfruit (Artocarpus altilis; 60 (sem 9)), cooking 'green'
      banana (Musa spp.; 65 (sem 11)) and sadha roti (65 (sem 9)) (P=0.018). There was
      no significant difference in the GI of the foods in study 2: dasheen (Colocasia
      esculenta var. esculenta; 77 (sem 10)), eddoes (Colocasia esculenta var.
      antiquorum; 61 (sem 10)), Irish potato (Solanum tuberosum; 71 (sem 8)), tannia
      (Xanthosoma sagittifolium; 60 (sem 5)) and white yam (Dioscorea alata; 62 (sem
      6)), and, in study 3, crushing did not significantly affect the GI of dasheen,
      tannia or Irish potato. However, when the results from studies 2 and 3 were
      pooled, the GI of dasheen (76 (sem 7)) was significantly greater than that of
      tannia (55 (sem 5); P=0.015) with potato being intermediate (69 (sem 6)). We
      conclude that dasheen and cassava are high-GI foods, whereas the other tubers
      studied and sadha roti are intermediate-GI foods. Given the regular usage of
      cassava and dasheen in Caribbean diets we speculate that these diets would tend
      to be high GI, although this could be reduced by foods such as sadha roti and
      white yam. The range of GI between the staples is sufficiently large that health
      benefits may be accrued by replacing high-GI staples with intermediate-GI staples
      in the Caribbean diet.

PMID- 15182401
TI  - The use of glycaemic index tables to predict glycaemic index of composite
      breakfast meals.
AB  - The applicability of the glycaemic index (GI) in the context of mixed meals and
      diets is still debatable. The objective of the present study was to investigate
      the predictability of measured GI in composite breakfast meals when calculated
      from table values, and to develop prediction equations using meal components.
      Furthermore, we aimed to study the relationship between GI and insulinaemic index
      (II). The study was a randomised cross-over meal test including twenty-eight
      healthy young men. Thirteen breakfast meals and a reference meal were tested. All
      meals contained 50 g available carbohydrate, but differed considerably in energy
      and macronutrient composition. Venous blood was sampled for 2 h and analysed for
      glucose and insulin. Prediction equations were made by regression analysis. No
      association was found between predicted and measured GI. The meal content of
      energy and fat was inversely associated with GI (R(2) 0.93 and 0.88,
      respectively; P<0.001). Carbohydrate content (expressed as percentage of energy)
      was positively related to GI (R(2) 0.80; P<0.001). Using multivariate analysis
      the GI of meals was best predicted by fat and protein contents (R(2) 0.93;
      P<0.001). There was no association between GI and II. In conclusion, the present
      results show that the GI of mixed meals calculated by table values does not
      predict the measured GI and furthermore that carbohydrates do not play the most
      important role for GI in mixed breakfast meals. Our prediction models show that
      the GI of mixed meals is more strongly correlated either with fat and protein
      content, or with energy content, than with carbohydrate content alone.
      Furthermore, GI was not correlated with II.

PMID- 15182403
TI  - Eating behaviours, dietary profile and body composition according to dieting
      history in men and women of the Quebec Family Study.
AB  - The purpose of the present cross-sectional study was to compare eating behaviours
      (cognitive dietary restraint, disinhibition and susceptibility to hunger),
      dietary profile and physiological variables according to the practice of dieting:
      current dieting; history of dieting in the 10-year period that preceded the
      study; no dieting during the same period. Dieting history, anthropometric markers
      of adiposity, RMR, dietary profile (3 d food record) and eating behaviours (three
      factor eating questionnaire) were determined in a sample of 244 men and 352
      women. A greater proportion of women (31.8 %) than men (16.8 %) reported that
      they had been on a diet over the past 10 years (P=0.0001). In both genders,
      current and past dieters had a higher BMI (P<0.05) than non-dieters and current
      dieters had lower reported energy intakes than past dieters and non-dieters (only
      in women) (P<0.05). Current and past dieters also had higher scores for all
      eating behaviours and their subscales (P<0.05; except for susceptibility to
      hunger in men) compared with non-dieters (adjusted for age, reported energy
      intake, percentage of dietary fat, BMI and RMR). Moreover, for each dieting
      history category, women had significantly higher scores for cognitive dietary
      restraint than men (P<0.05). In conclusion, the present study showed that current
      and past dieters had higher scores for cognitive dietary restraint and
      disinhibition compared with non-dieters. As disinhibition has previously been
      associated with a greater risk of subsequent weight gain, interventions aimed at
      preventing an increase in disinhibition may be promising for long-term weight
      maintenance.

PMID- 15182402
TI  - Maximum tolerable dose of red pepper decreases fat intake independently of spicy
      sensation in the mouth.
AB  - Dietary red pepper suppresses energy intake and modifies macronutrient intake. We
      have investigated whether a stimulus in the mouth and the sensation of spiciness
      are necessary for red pepper-induced changes in energy and macronutrient intake
      in human volunteers. In a preliminary test, sixteen Japanese male volunteers
      tasted samples of a soup with graded doses of red pepper in order to define a
      moderate and a maximum tolerable (strong) dose of red pepper. On the day of the
      experiment, a standardised breakfast was given to the volunteers. At lunchtime,
      the subjects ingested one of four experimental soups containing either a placebo,
      a moderate or a strong dose of red pepper plus placebo capsules, or a placebo
      soup plus capsules delivering a strong dose of red pepper. The rest of the meal
      was given ad libitum to all subjects. The amount of food, protein and
      carbohydrate ingested was similar for all conditions. Energy and fat intake were
      similar after the ingestion of the moderate soup compared with placebo. However,
      the strong soup significantly lowered fat intake compared with placebo (P=0.043),
      and ingestion of strong capsules also tended to suppress it (P=0.080). Moreover,
      energy intake after strong soup and capsules tended to be lower than placebo
      (P=0.089 and 0.076, respectively). The present results indicate that the maximum
      tolerable dose is necessary to have a suppressive effect of red pepper on fat
      intake. The main site of the action of red pepper is not in the mouth.

PMID- 15182404
TI  - Dietary sources of vitamin C, vitamin E and specific carotenoids in Spain.
AB  - A cross-sectional study was conducted within the Spanish cohort of the European
      Prospective Investigation in Cancer and Nutrition to assess the principal food
      sources of vitamin C, vitamin E, alpha-carotene, beta-carotene, lycopene, lutein,
      beta-cryptoxanthin and zeaxanthin in an adult Spanish population. The study
      included 41446 healthy volunteers (25812 women and 15634 men), aged 29-69 years,
      from three Spanish regions in the north (Asturias, Navarra and Guipuzcoa) and two
      in the south (Murcia and Granada). Usual food intake was estimated by personal
      interview through a computerized version of a dietary history questionnaire.
      Foods that provided at least two-thirds of the studied nutrients were: fruits
      (mainly oranges) (51 %) and fruiting vegetables (mainly tomato and sweet pepper)
      (20 %) for vitamin C; vegetable oils (sunflower and olive) (40 %), non-citrus
      fruits (10 %), and nuts and seeds (8 %) for vitamin E; root vegetables (carrots)
      (82 %) for alpha-carotene; green leafy (28 %), root (24 %) and fruiting
      vegetables (22 %) for beta-carotene; fruiting vegetables (fresh tomato) (72 %)
      for lycopene; green leafy vegetables (64 %) for lutein; citrus fruits (68 %) for
      beta-cryptoxanthin; citrus fruits (43 %) and green leafy vegetables (20 %) for
      zeaxanthin. In conclusion, the main food sources of nutrients with redox
      properties have been identified in a Mediterranean country. This could provide an
      insight into the interpretation of epidemiological studies investigating the role
      of diet in health and disease.

PMID- 15182405
TI  - Diet, serum homocysteine levels and ischaemic heart disease in a Mediterranean
      population.
AB  - Homocysteine (Hcy) is recognised as a risk factor for IHD. Serum Hcy is
      negatively correlated with serum folate levels, the main sources of which are
      fruits, vegetables and legumes. The present case-control study was designed to
      examine the relationship between serum Hcy levels and IHD and to assess the role
      of dietary factors in the southern Mediterranean population of Crete, Greece.
      Serum Hcy, folate, vitamin B12, creatinine and glucose levels and a full lipid
      profile were measured in 152 patients with established IHD, median age 64 (range
      33-77) years, and 152 healthy control subjects, age- and sex-matched. Dietary
      data were assessed using a 3 d food intake record. Compared with controls,
      patients with IHD had significantly higher daily intakes of vitamin B12 and MUFA
      and significantly lower intakes of carbohydrate, fibre, folate, cholesterol, n-3
      fatty acids and total trans unsaturated fatty acids. Moreover, patients had
      significantly higher serum Hcy, vitamin B12 and creatinine levels, but
      significantly lower folate. Serum folate concentrations in both groups had a
      significant positive correlation with dietary fibre consumption and a significant
      inverse correlation with vitamin B12 intake. IHD patients should be encouraged to
      increase their daily dietary intake of fibre, folate and n-3 fatty acids, which
      are significant components of the traditional Cretan Mediterranean diet. Where
      dietary folate intake is inadequate, folate supplements are recommended to reduce
      elevated Hcy levels.

PMID- 15182406
TI  - Laparoscopic radical prostatectomy - results of 200 consecutive cases in a
      Canadian medical institution.
AB  - PURPOSE: Since Guillonneau and Vallancien reintroduced transperitoneal
      laparoscopic radical prostatectomy in 1998, several other medical institutions in
      Europe have published their series and confirmed that laparoscopic radical
      prostatectomy (LRP) is a feasible and reproducible approach to the management of
      clinically localized prostate cancer; however, there have been few reports from
      North American medical institutions. We now report the results of our first 200
      consecutive cases of LRP in a Canadian Medical Institution. MATERIALS AND METHOD:
      From February/2000 until April/2003, laparoscopic radical prostatectomy was
      performed on 200 out of 205 surgical candidates for radical prostatectomy. There
      were 120 transperitoneal laparoscopic radical prostatectomies (TP-LRP) and 80
      extraperitoneal laparoscopic radical prostatectomies (EP-LRP). TP-LRP was based
      on posterior access to the seminal vesicles whereas EP-LRP was based on trans
      bladder neck approach to the seminal vesicles. Patients' mean age was 63.5 (range
      42-75). Patients were separated into two groups of 100 patients in order to
      assess the impact of the learning curve. RESULTS: There were 147 with pT2 disease
      and 53 with pT3 disease with a positive surgical margin of pT2a (0%), pT2b (20%),
      PT3a (52%) and pT3b (53%) respectively. The overall positive surgical margin rate
      is 27%. The median follow-up is 13 months. There were 111 patients available for
      a one-year follow-up with PSA recurrence-free rate of 95%. The positive surgical
      margin rates for low, intermediate and high-risk categories are 19%, 40%, and 63%
      respectively. The 6-month continence rate available in 160 patients was 88.2%.
      Spontaneous erection was reported in 21 out of the 46 patients (46%) with at
      least 6 months follow-up. The intra-operative and post-operative complication
      rate was 20% for Group 1 and 4% for Group 2 with an overall rate of 8%. The
      overall surgical time was 4.4 hours for Group 1 and 3.3 hours for Group 2. The
      hospital stay was 5.26 days for Group 1 and 2.44 days for Group 2. Transfusion
      rate was 8% for Group 1 and 2% for Group 2. The mean analgesic requirement in the
      last 50 cases was 5.5 mg of morphine with 58% of patients being analgesic-free
      post-operatively. CONCLUSION: Laparoscopic radical prostatectomy is a technically
      demanding procedure with a long and gradual learning curve. The present study
      confirms the impression of other large published series in that it appears to
      offer equivalent oncologic results and functional results when compared with open
      radical prostatectomy. The preservation of potency will require longer follow-up.
      Longer follow-up and large randomized control studies will be required to
      determine its exact role in the surgical management of clinically localized
      prostate cancer.

PMID- 15182407
TI  - The American Urological Association 2003 guideline on management of benign
      prostatic hyperplasia: a Canadian opinion.
AB  - The 2003 American Urological Association (AUA) guideline on management of benign
      prostatic hyperplasia (BPH) was released at the AUA annual meeting in Chicago,
      April 2003 and the diagnosis and treatment recommendations were published later
      in 2003. It is likely that the 2003 AUA guideline on the management of BPH will
      have a profound effect on clinical urologic practice in the USA, but its
      influence on Canadian urological practice will be different because of our
      socialized medical system, manpower issues, availability of expensive technology
      and our unique Canadian perspective. The authors review the 2003 AUA guideline on
      the management of BPH and based on a perspective obtained from recent
      publications, consensus/consultant meetings, focus groups and anecdotal
      experience, attempt to put the recommendations into Canadian context. We conclude
      that the 2003 AUA guideline for the management of BPH is an important document
      that should be studied, evaluated and understood by Canadian urologists. Although
      our perspective is clearly different than our US colleagues, it is likely that
      the guideline will influence the management of BPH in Canada.

PMID- 15182408
TI  - Practice patterns of Canadian urologists in the management of stage I testicular
      seminoma.
AB  - OBJECTIVE: To evaluate the practice patterns of Canadian urologists in the
      management of stage I testicular seminoma. METHODS: A survey was conducted with a
      three-page questionnaire among Canadian urologists between July and November
      2002. RESULTS: The overall response rate was 48%. The total number of completed
      and partially completed questionnaires was 198 and 212, respectively. Ninety-four
      responders described their practice as university-affiliated teaching centre,
      while 118 reported community-based or private practice. All ordered CT
      abdomen/pelvis with either chest x-ray or CT scan of chest for staging
      investigation. Only 1% would order a lymphangiogram. About one third would not
      offer surveillance as a management option for stage I testicular seminoma. When
      asked to rank, in order of preference, three management options (surveillance,
      adjuvant radiotherapy, and adjuvant chemotherapy) under four different clinical
      scenarios varying in perceived relapse risk and the presence/absence of fertility
      preservation concern, the majority selected adjuvant radiotherapy as the
      treatment of choice for a patient with high relapse risk or no fertility concern.
      When a patient had desire to preserve fertility as well as low relapse risk,
      surveillance was chosen as the preferred management strategy. There was no
      significant response difference between academic and community urologists.
      CONCLUSION: There was some variation among Canadian urologists in the management
      of stage I testicular seminoma. The issue of fertility preservation and perceived
      relapse risk were important factors influencing management decisions. There was
      no significant difference between academic and community-based urologists with
      respect to patient volume and management approaches.

PMID- 15182409
TI  - Clinical results of combined epidural and general anesthesia procedure in radical
      prostatectomy management.
AB  - OBJECTIVES: Improvement of radical prostatectomy surgical technique remains an
      objective for urological practice. The aim of this study was to evaluate the
      potential benefit of intra and postoperative epidural versus general anesthesia
      alone. MATERIAL AND METHODS: The authors retrospectively analyzed 62 consecutive
      cases of patients who underwent radical retropubic prostatectomy over a 2-year
      period. The mean age was 65.5 years (51-75). Two groups were selected: group I =
      19 patients, who received epidural anesthesia in association with general
      anesthesia and group II = 43 patients with general anesthesia alone. Both groups
      were similar for ASA score, Body Mass Index, prostate volume, tumor stage and
      Gleason score. Evaluation criteria were operative time, blood loss, postoperative
      pain (analgesics required) and length of hospital stay. Mono and multifactorial
      statistical analysis were performed. RESULTS: Operative time in group I was 189
      mn versus 218 mn for group II (p = 0.01). Significant difference was found
      independent of surgical experience. Moreover, significant blood loss (p = 0.002)
      was observed: 971 ml in group I versus 1840 ml in group II. Also, less blood was
      transfused during surgery in group I: 0.84 blood units transfused versus 2.60
      blood units in group II (p = 0.007). In both groups, hematocrit level remained
      stable during surgery. As regards postoperative pain, an improvement in required
      analgesic level was noted in group I during the initial 48 hours (p = 0.001 for
      day 1; p = 0.032 for day 2). Finally, mean hospital stay was only 9.3 days in
      group I and 12.4 days in group II (p = 0.005). CONCLUSION: Our study suggests
      that improved results can be obtained when epidural anesthesia is associated with
      general anesthesia in radical retropubic prostatectomy intra and postoperative
      management, with a significant reduction in morbidity.

PMID- 15182410
TI  - Priapism as a possible acute side effect of radical radiotherapy for prostate
      cancer.
AB  - We report a case of a 73 year-old male diagnosed with T1 N0 M0 prostate cancer,
      Gleason score 7, undergoing a course of radical radiotherapy using 7600 cGY
      delivered in 38 fractions. Several hours after receiving his 27th fraction, he
      reported experiencing a painful penile erection lasting more than 6 hours. A
      history and several investigations were conducted to determine the etiology of
      this adverse event. Although several possible etiologies were considered, the two
      most likely possibilities were direct prostate-irradiation and/or his use of
      alfuzosin, a novel alpha 1-adrenergic antagonist. A literature search revealed
      one case of priapism secondary to radiotherapy as well as reports of priapism
      associated with drugs similar to alfuzosin.

PMID- 15182411
TI  - Laparoscopic pyeloplasty with simultaneous pyelolithotomy using a flexible
      ureteroscope.
AB  - Laparoscopic pyeloplasty is rapidly becoming the gold standard in the repair of
      adults with uretero-pelvic junction obstruction. Renal calculi are a recognized
      complication of uretero-pelvic junction obstruction and their presence has often
      been used to justify percutaneous nephrolithotomy and endopyelotomy as primary
      treatment. Stones developing secondary to uretero-pelvic junction obstruction
      have been removed through simultaneous laparoscopic pyeloplasty and
      pyelolithotomy, but with rigid laparoscopic instruments access is limited to the
      renal pelvis. As exemplified within this report, endourologic techniques such as
      flexible ureteroscopy can be combined with laparoscopic pyeloplasty to deal with
      complex stone disease and to provide optimal treatment of the patient with a
      uretero-pelvic junction obstruction.

PMID- 15182412
TI  - Posterior urethral valves in Eastern Ontario - a 30 year perspective.
AB  - INTRODUCTION: Posterior urethral valves (PUV) are the most common cause of male
      pediatric obstructive uropathy. Recent advancements in antenatal ultrasound and
      endoscopy have altered the presentation and management of PUV. Herein we describe
      the presentation, management and outcome of PUV patients in Eastern
      Ontario/Western Quebec over the last 3 decades. A comparison analysis of those
      cases identified pre and post widespread utilization of antenatal ultrasound
      diagnosis was performed to discern the clinical evolution of PUV with respect to
      long-term outcome. METHODS: Retrospective systematic chart review of all PUV
      cases diagnosed and treated at the Children's Hospital of Eastern Ontario over
      the last 3 decades. Charts were reviewed for initial presentation, method of
      diagnosis, radiological and clinical findings at diagnosis, initial management,
      and long-term clinical outcome. The evolution of PUV was interpreted by dividing
      the cohort into two groups chronologically delineated by the first case detected
      by antenatal ultrasound in the mid-1980s. These pre- and post- antenatal
      ultrasound eras were compared with respect to the parameters outlined above.
      RESULTS: Fifty-three cases were reviewed - 21 prior to widespread antenatal
      ultrasound screening in the mid-1980s and 32 after. There were 13/53 cases (32%)
      discovered by prenatal ultrasound evidence of hydronephrosis, none prior to 1985.
      VCUG confirmed the diagnosis in all cases. Mean age at presentation in the
      remaining post-natally diagnosed patients was 33 months. Of the cases diagnosed
      post-natally, ultrasound investigation complemented VCUG findings in 19/40 cases
      (47%), whereas IVP was utilized in 14/40 (35%). IVP has not been utilized for
      this purpose since 1987. Overall, 26/53 cases (49%) had documented VUR - 16/26
      (62%) bilateral; 42/53 (79%) had hydronephrosis on ultrasound - 37/42 (88%)
      bilateral; 26/53 (49%) had radiological evidence of renal parenchymal damage at
      diagnosis; 41/53 (77%) cases had a thickened bladder wall on ultrasound at
      diagnosis, and 23/53 (43%) had at least one bladder diverticulum. Techniques of
      initial management comprised: valve ablation 32/53, vesicostomy 11/53, and high
      diversion 10/53. Clinically significant bladder dysfunction was found in 31% of
      cases, ranging from bladder instability to myogenic failure. Globally impaired
      renal function, as determined by significantly elevated serum creatinine levels,
      reduced GFR, or both, was found in 12/53 (23%). 6/53 (11%) progressed to ESRD, of
      which 4 received transplants. Two patients died - one from complications related
      to renal failure. Of the six cases of myogenic bladder failure identified, three
      (50%) had concurrently significant renal impairment. Average length of follow-up
      was 8.3 years, varying between 1 month and 18 years. CONCLUSIONS: The
      presentation of PUV is variable, and currently antenatal detection is the most
      common mode. Despite this, it still does not make up the majority of diagnoses.
      Complete radiological work up should include abdominal and pelvic U/S in
      conjunction with VCUG. Concurrent VUR in 50% of boys mandates suppressive
      antibiotic use. Primary valve ablation remains the gold standard for treatment of
      PUV, with vesicostomy reserved for selected cases. Long-term bladder and renal
      dysfunction is common in this population, and mandates long-term urological and
      nephrological follow-up.

PMID- 15182413
TI  - A prospective randomized trial of 1-day versus 3-day antibiotic prophylaxis for
      transrectal ultrasound guided prostate biopsy.
AB  - PURPOSE: To compare the incidence of infection between a 1 day and a 3 day
      antibiotic prophylaxis regimen for transrectal ultrasound (TRUS) guided prostate
      biopsy in a prospective, randomized open-label trial. MATERIALS AND METHODS: TRUS
      examination was performed in the left lateral decubitus position using a Bruel
      and Kjaer 7 MHz rectal probe. Biopsies were carried out with an 18 gauge Tru-cut
      needle fired by the hand-held Biopsy gun. An average of eight core biopsies
      (range 6 to 12) was taken. From May 15, 2000 to May 16, 2001, 363 patients were
      enrolled in this study. Patients were randomized to receive either 1 day or 3
      days of fluroquinolone antibiotic prophylaxis, consisting of either ciprofloxacin
      or levofloxacin orally. Antibiotics were begun at least 1 hour prior to biopsy.
      Seven days later, telephone follow-up was obtained. RESULTS: Two (0.55%) of the
      363 patients, one in each group, had an episode of sepsis. No urinary tract
      infection was reported. Traumatic complications were only minor and no
      significant difference was observed between both groups: hematospermia (p> 0.4),
      hematuria (p>0.1) and rectorragia (p>0.2) being reported most frequently.
      CONCLUSION: There is no clinically nor statistically significant difference
      between a 1 day and 3 day antibiotic prophylaxis regimen for patients undergoing
      TRUS guided biopsies.

PMID- 15182414
TI  - Agenesis of the bladder with solitary renal dysplasia: management of a
      challenging condition.
AB  - Bladder agenesis is an extremely rare congenital anomaly. We report a case of
      bladder agenesis in a newborn girl with a prolapsing ectopic ureter and solitary
      dysplastic kidney. The classification of this disorder and the management of this
      patient are reviewed.

PMID- 15182415
TI  - Solid pseudopapillary tumor of the pancreas mimicking malignant adrenal
      pheochromocytoma.
AB  - We report a 75-year old woman with clinical, laboratory and imaging
      characteristics suggestive of a malignant left adrenal pheochromocytoma with
      invasion of the tail of the pancreas. The mass involving the tail of the pancreas
      and the left adrenal was excised Detailed histological diagnosis revealed that
      the lesion was a rare exocrine tumor of the pancreas.

PMID- 15182417
TI  - Mechanoenergetic estimation of multiple cross-bridge steps per ATP in a beating
      heart.
AB  - The efficiency from the ventricular O(2) consumption (VO(2)) to the total
      mechanical energy (TME) generated by ventricular contraction has proved
      relatively constant at approximately 35%, independent of the loading and
      contractile conditions in a canine heart. TME is the sum of the external
      mechanical work for ejecting a stroke volume against the afterload and of the
      mechanical potential energy for developing ventricular pressure in each beat. The
      approximately 35% VO(2)-to-TME efficiency indicates an also constant
      approximately 60% ATP-to-TME efficiency in a beating heart, based on the nominal
      approximately 60% VO(2)-to-ATP efficiency in the myocardial oxidative
      phosphorylation. I newly attempted to explain the load-independent approximately
      60% ATP-to-TME efficiency by the recently reported approximately 7-10 nm unitary
      step size and approximately 0.8-1.5 pN unitary force of a cross-bridge (CB) at
      the molecular level in in vitro motility assays. This single CB behavior suggests
      that its unitary cycle could generate a mechanical energy of approximately 0.6
      1.5x10(-20) J at most. From the nominal free energy of approximately 10x10(-20) J
      per ATP, the efficiency from one ATP to the CB unitary cycle would then be
      approximately 6-15%. This low efficiency is only approximately 1/10-1/4 of the
      approximately 60% ATP-to-TME efficiency at the heart level. This discrepancy
      suggests that each CB would repeat the unitary cycle at least approximately 4-10
      times per ATP to achieve the high constant ATP-to-TME efficiency in a beating
      heart. This seems to represent a considerable mechanoenergetic advantage of the
      heart at the integrative heart level as compared to the molecular CB level.

PMID- 15182416
TI  - Physiological regulation of renal sodium-dependent phosphate cotransporters.
AB  - The physiological regulation of renal Pi reabsorption is mediated by renal type
      II Na/Pi cotransporters (type IIa and type IIc). The type IIa transporter is
      regulated, among other factors, by dietary Pi intake and parathyroid hormone
      (PTH). The PTH-induced inhibition of Pi reabsorption is mediated by endocytosis
      of the type IIa transporter from the brush-border membrane and subsequent
      lysosomal degradation. Type IIa is part of the heteromeric protein complexes
      organized by PDZ proteins. Furthermore, during Pi depletion the type IIc Na/Pi
      cotransporter is induced in the apical membrane of proximal tubular cells. The
      type IIc transporter is also regulated by PTH via internalization, but by a
      vesicular transport pathway distinct from that used by the type IIc transporter.
      Studying the mechanisms of type IIa and type IIc transporters has increased the
      understanding of the control of proximal tubular Pi handling and thus of overall
      Pi homeostasis.

PMID- 15182418
TI  - Mechanisms for hypoxia detection in O2-sensitive cells.
AB  - Since O(2) is the bare necessity for multicellular organisms, they develop
      multiple protective mechanisms against hypoxia. Mammals will adapt to hypoxia in
      short and long terms. The short-term responses include enhancement of the
      respiratory and cardiac functions, adrenaline secretion from adrenal medullary
      cells, and pulmonary vasoconstriction, whereas the long-term response is the
      increase in erythropoietin production with the consequent increase in red blood
      cells. Although much work has been done to elucidate molecular mechanisms for
      O(2)-sensing for the last ten years, the majority of the mechanisms remain
      unclear. We will review mechanisms proposed for hypoxia detection in carotid body
      type I cells, pulmonary artery smooth muscle, adrenal medullary cells, and liver
      cells, with the special focus on adrenal medullary cells.

PMID- 15182420
TI  - The effects of aging on somatocardiac reflexes in anesthetized rats.
AB  - Nociceptive cutaneous stimulation produces a reflex tachycardiac response that is
      mediated through the activation of cardiac sympathetic efferents. This response
      includes reflex components of both supraspinal and spinal origin, depending on
      which segmental afferent area is stimulated (for a review see Sato et al.: Rev
      Physiol Biochem Pharmacol 130: 1-328, 1997). We herein examined the effects of
      aging on these supraspinal and spinal reflexes in anesthetized rats that were 4-7
      (young adult), 24-27 (old), and 32-36 (very old) months of age. In central
      nervous system (CNS)-intact animals, we found that the supraspinal tachycardiac
      response induced by the pinching of a hindpaw was well preserved in old rats but
      was significantly attenuated in very old rats, while pinching-induced increases
      in cardiac sympathetic nerve activity were well maintained in both of these rat
      populations. In spinalized animals, spinal-mediated changes in heart rate (HR)
      and cardiac sympathetic nerve activity induced by the pinching of the chest skin
      were well preserved in both old and very old rats. There were no significant
      differences in resting HR among the 3 age groups studied, though the maximum HR
      induced by the beta-adrenergic agonist isoproterenol was reduced with age. The
      beta-receptor-mediated maximum HR was greater than that induced by pinching in
      young adult and old rats, CNS-intact and spinalized rats, and very old spinalized
      rats, while the maximum HR was nearly the same as the pinching-induced HR in CNS
      intact very old rats. These results suggest that both supraspinal and spinal
      neural reflex pathways involved in the cardiac sympathetic response to cutaneous
      pinching are well preserved in older animals. They also suggest that the decline
      in the responsiveness of the heart to beta-adrenergic stimulation results in a
      reduced pinching-induced supraspinal tachycardiac response in very old rats.

PMID- 15182419
TI  - Energetics of middle-distance running performances in male and female junior
      using track measurements.
AB  - The aim of this study was to determine the energetic factors of middle-distance
      running performance in junior elite runners according to gender and by using
      measurements from on-track performances. Fifteen elite runners (8 males and 7
      females) were investigated by means of an incremental test and an all-out run
      over 600 m performed with a 2-d interval. We calculated (1) the aerobic maximal
      power (E(r max aero), in W kg(-1)), including VO(2 max) and the delay of
      attainment of VO(2 max) in the 600 m run; (2) the anaerobic power (E(r max
      anaero)), i.e., the oxygen deficit (J kg(-1)) divided by the duration of the 600
      m run. Despite the difference in race duration (87 +/- 3 vs. 102 +/- 2 s), the
      600 m run was made at the same relative value of the velocity associated with
      VO(2 max) (VVO(2 )max) in males and females (121.6 +/- 7 vs. 120 +/- 8% VO(2
      max), p = 0.7). E(r max aero) explained most of the variance in the performance
      (the personal best performed 8 weeks later) between genders: 65 and 79% over 800
      m (T(800)) and 1,500 m (T(1,500)). For females, E(r max aero) explained most of
      the variance of T(1,500) (r(2) = 0.66), and E(r max anaero) improved this
      prediction (r(2) = 0.84). No energetic factor predicted the performance on 800 m
      run in males. In elite junior athletes, the energetic model with individual data
      measured over an all-out 600 m performed on a track, provides an explanation for
      most of the variance in middle-distance running performances between genders. The
      distinction between aerobic power and anaerobic power allowed an improvement in
      the prediction of middle-distance running performances.

PMID- 15182421
TI  - Pretreatment with tyrosine kinase inhibitor attenuates the reduction of apoptosis
      24 h after ischemic preconditioning.
AB  - We investigated whether ischemic preconditioning (PC) attenuates
      ischemia/reperfusion-induced injury in part by decreasing apoptosis and whether
      tyrosine kinase (TK) can regulate the signaling pathway leading to apoptosis in
      delayed cardioprotection. Six groups of rabbits were studied in the early phase
      (EP) and in the delayed phase (DP): (1) sham-operated control animals were
      received vehicle only (Veh-sham); (2) rabbits that received I.V. genistein (a
      nonspecific TK inhibitor) 10 min before ischemia (Gen-sham); (3) rabbits that
      received I.V. daidzein (an inactive structural analog of genistein) 10 min before
      ischemia (Dzn-sham); (4) rabbits preconditioned with 4 cycles of 5-min occlusion
      of left anterior descending coronary artery (LAD) and 10-min reperfusion (PC);
      (5) rabbits that received I.V. genistein, 10 min before PC (Gen-PC); (6) rabbits
      that received I.V. daidzein 10 min before PC (Dzn-PC). All rabbits underwent 30
      min ischemia followed by 180-min reperfusion. Infarct size in the PC, Gen-PC, and
      Dzn-PC groups in the EP was significantly (p < 0.0001) reduced relative to
      controls Gen and Dzn. Delayed cardioprotection was blocked significantly (p <
      0.0001) by genistein. In the EP, apoptosis was significantly (p < 0.0001)
      decreased in PC, Gen-PC, and Dzn-PC groups relative to controls Gen and Dzn. In
      the DP, a reduction of apoptosis was not seen in the Gen-PC group. This study
      suggests that PC reduces ischemic injury in part by decreasing apoptosis after
      ischemia/reperfusion and also that TK phosphorylation is involved in the signal
      transduction cascade leading to the decline of apoptosis in the DP.

PMID- 15182422
TI  - Noninvasive evaluation of cardiac output during postural change and exercise in
      humans: comparison between the modelflow and pulse dye-densitometry.
AB  - To investigate whether the Model-flow method, by simulating the aortic input
      impedance model from a noninvasive monitoring of arterial blood pressure,
      reflected a reliable measure of cardiac output (CO) during postural change and
      whole-body exercise occurring in daily life, we compared the Modelflow-estimated
      CO with a simultaneous reference determined by the pulse dye-densitometry. Nine
      healthy volunteers performed postural change from supine to upright and dynamic
      stepping exercise. The Modelflow-estimated CO decreased to 4.8 +/- 0.5 l/min,
      from 5.8 +/- 0.6 l/min, during the postural change and increased to 12.8 +/- 1.3
      l/min during a stepping exercise, returning to 5.1 +/- 0.4 l/min at 5 min after
      exercise. When comparing the pooled data of CO during resting and following
      exercise between the Modelflow and pulse dye-densitometry, we found that the
      average CO did not differ between the two estimates and that there was a
      significant correlation between them; the slope of the linear regression line
      corresponded to approximately 1.0. Although such linear relationship was also
      observed in an individual subject, the slope of the regression line varied from
      0.737 to 1.588 among the subjects. The calibration of the Modelflow-estimated CO
      with the dye-densitometry value at supine or upright improved a correlation
      between the two estimates. Thus it is likely that the noninvasive Modelflow
      simulation from arterial blood pressure can provide a reliable estimation of
      group-average cardiac output during postural change and stepping exercise
      occurring in daily life. It will be recommended for a more accurate estimation of
      cardiac output in a given subject to calibrate the Modelflow data with an
      independent measure.

PMID- 15182423
TI  - Face area representation of primary somatosensory cortex in humans identified by
      whole-head magnetoencephalography.
AB  - The feasibility of precise mapping was investigated noninvasively on the face
      component in predominantly unilateral primary somatosensory cortices (SI) in six
      healthy subjects. We recorded somatosensory evoked magnetic fields (SEFs) from
      the SI and secondary somatosensory cortices (SII) following the electrical
      stimulation of six skin sites: the infraorbital foramen, the angle of mouth, the
      upper lip, the lower lip, the mental foramen, and the mandibular angle. The
      median nerve at the wrist was stimulated as a standard of the map. The location
      of the equivalent current dipoles (ECDs) estimated from the distribution of
      magnetic fields was identified on MR images of the brain on each subject. The
      ECDs of the early components of SEF with peaks of 20-30 ms aligned along the SI
      in the hemisphere contralateral to the stimulation site. Late components with
      peaks of 80-150 ms were recorded from the bilateral hemispheres, and their ECDs
      were identified in the SII of the bilateral hemispheres. There was a distinct
      separation between the ECD locations representing discrete sites on the face and
      thumb in the SI of the contralateral hemisphere. Five sites of the face area in
      SI at the contralateral hemisphere were compatible with the conventional
      arrangement of homunculus in one subject. However, the remaining subjects had
      variations in the arrangement. The face area reorganization in the SI is possible
      to be related to the use-dependent cortical plasticity of the individual or to
      the perceptual experience by vision and proprioception.

PMID- 15182424
TI  - Effects of chronic intermittent hypoxia on the hemodynamics of systemic
      circulation in rats.
AB  - We examined the effects of chronic intermittent hypoxia (IH) on the hemodynamics
      of systemic circulation in rat. Chronic IH has no effect on the hemodynamics in
      the normoxia condition, but it could effectively prevent the fall of hemodynamics
      during acute hypoxia.

PMID- 15182425
TI  - Thymus-leukemia antigen (TL) as a major histocompatibility complex (MHC) class Ib
      molecule and tumor-specific antigen.
AB  - Mouse thymus-leukemia antigens (TL) belong to the family of major
      histocompatibility complex (MHC) class Ib antigens and have a unique mode of
      expression, i.e., in contrast to other MHC class Ib or Ia antigens, they are
      found restricted to the intestines in all mouse strains, but also in the thymus
      of certain strains (TL(+) strains). Nevertheless, a proportion of T
      lymphomas/leukemias in strains that do not express TL in the thymus (TL(-)
      strains) feature TL as a tumor antigen. TL was originally defined serologically,
      but subsequently we have succeeded in generating T cell receptor (TCR) and
      cytotoxic T lymphocytes (CTL) recognizing TL. By use of TL tetramers free from
      peptides and transfectants expressing various TL/H-2 chimeric molecules, we have
      been able to show that TL-specific CTL recognize the alpha1/alpha2 domain of TL
      without any additional antigen molecules. We previously reported that one of TL's
      functions in the thymus is positive selection of TCR CTL. Recent studies with TL
      tetramers revealed that they can bind to normal intestinal intraepithelial
      lymphocytes (iIEL) and thymocytes in a CD8-dependent, but TCR/CD3-independent
      manner, while their binding to TL-specific CTL is TCR/CD3- and CD8-dependent. The
      possible significance of these findings in relation to the roles of TL in the
      intestines is discussed. We have long been interested in TL as a model tumor
      antigen which shares characteristics with human differentiation tumor antigens,
      and we have demonstrated that growth of TL(+) lymphoma cells in vivo is
      suppressed by immunization with TL(+) skin or dendritic cells (DC) from TL
      transgenic mice. In addition, anti-tumor effects against TL(+) T lymphomas were
      obtained by adoptive transfer of TL tetramer strongly-positive TL-specific CTLs.

PMID- 15182426
TI  - Gene mutations and altered gene expression in azoxymethane-induced colon
      carcinogenesis in rodents.
AB  - Studies of colon carcinogenesis in animal models are very useful to elucidate
      mechanisms and provide pointers to potential prevention approaches in the human
      situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM),
      we have documented frequent mutations of specific genes. K-ras mutations at codon
      12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large
      adenocarcinomas. In addition, mutations of the beta-catenin gene in its GSK-3beta
      phosphorylation consensus motif could also be identified in many adenomas and
      adenocarcinomas, and altered cellular localization of beta-catenin protein was
      observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined,
      indicating that activation of Wnt signaling by accumulation of beta-catenin is a
      major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene
      mutations of beta-catenin and altered cellular localization of the protein are
      also features of AOM-induced colon tumors in mice. Expression of enzymes
      associated with inflammation, such as inducible nitric oxide synthase (iNOS) and
      the inducible type of cyclooxygenase (COX), COX-2, is increased in AOM-induced
      rat colon carcinogenesis, and overproduction of nitric oxide (NO) and
      prostaglandins is considered to be involved in colon tumor development. We have
      demonstrated that increased expression of iNOS is an early and important event
      occurring in step with beta-catenin alteration in rat colon carcinogenesis.
      Activation of K-ras was also found to be involved in up-regulation of iNOS in the
      presence of inflammatory stimuli. In addition, expression levels of prostaglandin
      E(2) (PGE(2)) receptors may be altered in colon cancers. For example, the EP(1)
      and EP(2) subtypes have been shown to be up-regulated and EP(3) down-regulated in
      AOM-induced colon cancers in rats and mice. EP(1) and EP(4) appear to be involved
      in ACF formation, while alteration in EP(2) and EP(3) is considered to contribute
      to later steps in colon carcinogenesis. Increased expression of some other gene
      products, such as the targets of Wnt/beta-catenin signaling, have also been
      reported. The further accumulation of data with this chemically-induced animal
      colon carcinogenesis model should provide useful information for understanding
      colorectal neoplasia in man.

PMID- 15182427
TI  - Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically
      induced colon carcinogenesis in rats.
AB  - Pomegranate (Punica granatum L.) seed oil (PGO) contains more than 70%
      cis(c)9,trans(t)11,c13-18:3 as conjugated linolenic acids (CLN). Our previous
      short-term experiment demonstrated that seed oil from bitter melon (Momordica
      charantia) (BMO), which is rich in c9,t11,t13-CLN, inhibited the occurrence of
      colonic aberrant crypt foci (ACF) induced by azoxymethane (AOM). In this study,
      we investigated the effect of dietary PGO on the development of AOM-induced
      colonic malignancies and compared it with that of conjugated linoleic acid (CLA).
      To induce colonic tumors, 6-week old male F344 rats were given subcutaneous
      injections of AOM (20 mg/kg body weight) once a week for 2 weeks. One week before
      the AOM treatment they were started on diet containing 0.01%, 0.1%, or 1% PGO or
      1% CLA for 32 weeks. Upon termination of the bioassay (32 weeks) colon tumors
      were evaluated histopathologically. AOM exposure produced colonic adenocarcinoma
      with an incidence of 81% and multiplicity of 1.88 +/- 1.54 at week 32.
      Administration of PGO in the diet significantly inhibited the incidence (AOM +
      0.01% PGO, 44%, P < 0.05; AOM + 0.1% PGO, 38%, P < 0.01; AOM + 1% PGO, 56%) and
      the multiplicity (AOM + 0.01% PGO, 0.56 +/- 0.73, P < 0.01; AOM + 0.1% PGO, 0.50
      +/- 0.73, P < 0.005; AOM + 1% PGO, 0.88 +/- 0.96, P < 0.05) of colonic
      adenocarcinomas, although a clear dose-response relationship was not observed at
      these dose levels. CLA feeding also slightly, but not significantly, reduced the
      incidence and multiplicity of colonic adenocarcinomas. The inhibition of colonic
      tumors by PGO was associated with an increased content of CLA (c9,t11-18:2) in
      the lipid fraction of colonic mucosa and liver. Also, administration of PGO in
      the diet elevated expression of peroxisome proliferator-activated receptor (PPAR)
      gamma protein in the non-tumor mucosa. These results suggest that PGO rich in
      c9,t11,c13-CLN can suppress AOM-induced colon carcinogenesis, and the inhibition
      is associated in part with the increased content of CLA in the colon and liver
      and/or increased expression of PPARgamma protein in the colon mucosa.

PMID- 15182428
TI  - Beta-catenin gene alteration in glandular stomach adenocarcinomas in N-methyl-N
      nitrosourea-treated and Helicobacter pylori-infected Mongolian gerbils.
AB  - The goal of this study was to elucidate whether beta-catenin gene mutations might
      contribute to glandular stomach carcinogenesis in Helicobacter pylori (H.pylori)
      infected Mongolian gerbils. Firstly, exon 3 of gerbil beta-catenin cDNA, a
      mutation hot spot, was cloned and sequenced and found to have 89.3% homology with
      the human form and 95.5% with the rat and mouse forms. Peptide sequence in this
      region was shown to be 100% conserved in these mammals. Then, 45 stomach
      adenocarcinomas induced with N-methyl-N-nitrosourea (MNU) plus H. pylori
      infection and 7 induced with MNU alone were examined for beta-catenin expression
      by immunohistochemistry and for DNA mutations using a combination of
      microdissection and PCR-single strand conformation polymorphism analysis. One
      gastric cancer in the MNU + H. pylori group (2.2%) displayed nuclear (N) beta
      catenin localization, 3 (6.7%) showed cytoplasmic (C) distribution in local
      regions, and 41 (91.1%) demonstrated cell membrane (M) localization. Tumors
      induced by MNU alone showed only membranous beta-catenin localization (7/7).
      Analysis of exon 3 of the beta-catenin gene dem-onstrated all tumors with
      membrane or cytoplasmic staining as well as surrounding normal mucosa (S) to
      feature wild-type beta-catenin. In contrast, the lesion with nuclear staining had
      a missense mutation at codon 34 [GAC (Gly) --> GAA (Glu)] in exon 3 (1/1 = 100%,
      N vs. M, P < 0.05; and N vs. S, P < 0.05). In conclusion, these results suggest
      that beta-catenin may not be a frequent target for mutation in stomach
      carcinogenesis in MNU + H. pylori-treated gerbils.

PMID- 15182429
TI  - Expression of the prolactin-inducible protein (PIP/GCDFP15) gene in benign
      epithelium and adenocarcinoma of the prostate.
AB  - Prolactin-inducible protein (PIP), also known as gross cystic disease fluid
      protein 15, is a predominant secretory protein in various body fluids, including
      saliva, milk and seminal plasma. Immunohistochemistry of this protein has been
      exploited as a clinical marker for breast cancer and Paget's disease. This study
      comparatively examined PIP expression in normal prostate tissues and in
      adenocarcinomas of the prostate. Quantitative real-time RT-PCR revealed low-level
      presence (6%) of PIP mRNA in normal prostate tissue in comparison with the
      seminal vesicle. Indirect immunostaining with monoclonal antibody 3E7 displayed a
      positive sign for benign epithelium in 8 cases (29.6%) among 27 normal specimens;
      however, the incidence significantly increased to 56.1% (37/66) in instances
      involving primary prostate carcinoma tissues of different types. Quantitative RT
      PCR also demonstrated that PIP transcript levels in carcinoma regions were
      significantly higher than corresponding levels in benign regions. These findings
      conclusively showed that benign prostate epithelium expresses PIP at low levels;
      in contrast, PIP is over-expressed in carcinomas of the prostate.

PMID- 15182430
TI  - Prediction of prognosis of estrogen receptor-positive breast cancer with
      combination of selected estrogen-regulated genes.
AB  - Estrogen receptor (ER)-positive breast cancer is a distinct subpopulation of
      breast cancer exhibiting a high response rate to endocrine therapy. However, not
      all ER-positive patients respond to the therapy, and a subgrouping of ER-positive
      patients based on the physiology of estrogen signaling is expected to be useful
      for predicting the prognosis. This study has revealed that selected estrogen
      regulated genes (ERGs) are useful in identification of a poor-prognosis
      population among ER-positive breast cancer patients. First, the expression levels
      of 11 ERGs, selected based on our earlier microarray study in cultured cells,
      were analyzed by means of real-time reverse transcription-PCR in 14 ER-positive
      human breast cancer tissues. The patients were clearly divided into two groups in
      cluster analysis. Then, we examined the expression levels of two representative
      ERGs, histone deacetylase 6 (HDAC6) and insulin-like growth factor binding
      protein 4 (IGFBP-4), in 62 ER-positive patients with immunohistochemistry to
      assess the impact of ERG expression on prognosis (median follow-up 4409 days).
      Positive HDAC6 staining was significantly correlated with a lower disease-free
      survival rate. Moreover, when the expression level of HDAC6 was assessed in
      combination with IGFBP-4 expression in the nucleus, the poor-prognosis patients
      were more accurately identified. This study has identified new candidate ERGs for
      prediction of prognosis, and we suggest that combined assessment of the
      expression levels of these ERGs will contribute to the clinically useful
      stratification of ER-positive breast cancer patients.

PMID- 15182432
TI  - Diagnostic value of serum EBV-DNA quantification and antibody to viral capsid
      antigen in nasopharyngeal carcinoma patients.
AB  - We compared the amount of serum Epstein-Barr virus DNA (EBV-DNA) detected in
      patients with nasopharyngeal carcinoma (NPC) in a high-incidence area,
      represented by Taiwan, and a low-incidence area, represented by Japan, using real
      time quantitative PCR. The median serum EBV-DNA value in 41 Japanese NPC cases
      was 5450 copies/ml, and that in in 23 Taiwanese cases was 2125 copies/ml. The
      median serum EBV-DNA value in all 64 NPC cases was significantly higher than in
      control groups. Using receiver-operating-characteristic (ROC) curves, the
      sensitivity and specificity of EBV-DNA quantification were determined (cut-off
      point, 6.87 copies/ml; sensitivity, 0.855; specificity, 0.885) and compared with
      those of EBV-viral-capsid-antigen (VCA) titers; the results showed that EBV-DNA
      was a more sensitive and specific parameter than EBV-VCA titer. Then, we analyzed
      19 NPC patients in whom recurrence developed (11 Japanese and 8 Taiwanese), and
      26 NPC patients in continuous remission. Although there was no significant
      difference in EBV-DNA values between Japanese and Taiwanese patients, the value
      was significantly higher in the 19 patients with recurrence than in those in
      remission. ROC analysis again revealed a higher diagnostic value of EBV-DNA than
      EBV-VCA. These results suggest EBV-DNA is a more reliable tumor marker than EBV
      VCA in both high-incidence and low-incidence areas of NPC.

PMID- 15182431
TI  - Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia
      with t(1;19)(q23;p13).
AB  - The most common nonrandom translocation found among childhood pre-B acute
      lymphoblastic leukemias (ALL) is t(1;19)(q23;p13), which frequently results in
      fusion of E2A with PBX1. However, rare cases of childhood ALL and various other
      hematological diseases with t(1;19) lack the E2A-PBX1 fusion. Analyzing a cell
      line with pre-B-cell phenotype, TS-2, that carries t(1;19)(q23;p13) but lacks the
      E2A-PBX1 fusion, we successfully cloned the breakpoints, which fell within
      introns of MEF2D and DAZAP1. Both chimeric transcripts, MEF2D-DAZAP1 and DAZAP1
      MEF2D, whose sequences indicated in-frame fusions between MEF2D and DAZAP1, were
      expressed in TS-2 cells and in bone-marrow cells of the patient from whom the TS
      2 was established. MEF2D-DAZAP1 and DAZAP1-MEF2D proteins were both located in
      the nucleus, and MEF2D-DAZAP1 was able to form dimers with MEF2D and HDAC4. In
      addition, exogenous expression of MEF2D-DAZAP1 and DAZAP1-MEF2D promoted the
      growth of HeLa cells. Given the frequency of t(1;19) without the E2A-PBX1 fusion
      in hematological malignancies, we suggest that MEF2D / DAZAP1 rearrangements
      might be involved in the pathogenesis of those diseases.

PMID- 15182433
TI  - A novel mouse model of rectal cancer established by orthotopic implantation of
      colon cancer cells.
AB  - A novel intraluminal colon tumor model was established in mice by intrarectal
      instillation of colon cancer cells followed by short-term induction of colitis by
      an irritant agent. Male BALB/c mice were fed a diet containing 3% (w/w) dextran
      sulfate sodium (DSS) for 7 days to induce colitis, and colon 26 cells (1-2 x
      10(6) cells/mouse) were infused intrarectally after the mice had been deprived of
      food for the last 18 h of DSS treatment. The tumor incidence (%) and size (mean
      volume +/- SD, mm(3)) at the rectal mucosa were 35% (2 +/- 3), 95% (96 +/- 79),
      95% (141 +/- 137) and 94% (325 +/- 270) at 1, 2, 3 and 4 weeks after instillation
      of tumor cells, respectively. Histopathological analyses revealed that a solid
      tumor was formed initially at the rectal mucosa at 1 week after instillation,
      then became invasive into the submucosal and muscular tissues at 3 weeks after
      implantation. Intrarectal instillation of human colon cancer cells, LS174T (1 x
      10(7) cells/mouse), mixed with "Matrigel" (0.5 mg/mouse), an extracellular matrix
      solution, in SCID mice led to formation of rectal tumors at 4 weeks after
      instillation, and immunohistochemical analysis revealed that the tumor cells
      expressed human carcinoembryonic antigen, suggesting that the tumor nodule was
      derived from the instilled LS174T cells. Oral or intravenous administration of a
      camptothecin (CPT) derivative, CPT-11, resulted in a significant reduction in
      tumor incidence and tumor volume in the colon 26-intraluminal implantation
      system. In conclusion, it was suggested that the present intraluminal colon tumor
      model is useful for examination of chemotherapeutic agents and also intraluminal
      factors (dietary compounds, intestinal microflora, etc.) that might function to
      suppress or enhance the growth of colorectal cancer in situ.

PMID- 15182434
TI  - Cytochrome p450 gene expression levels in peripheral blood mononuclear cells in
      comparison with the liver.
AB  - Cytochromes p450 (CYPs) compose a superfamily of similar proteins involved in
      detoxification and elimination, as well as activation of a wide variety of
      compounds. Most CYP family members are localized in the liver. In order to assess
      whether peripheral blood leukocytes (PBL) are available as a surrogate for the
      determination of CYP gene expression levels in the liver, we compared CYP gene
      expression levels in PBL with those in liver tissues from patients with
      hepatocellular carcinoma (HCC). We measured CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9,
      2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 3A4, 3A5, 3A7, 4A11, 4B1 and CYP27 gene
      expressions in PBL and in the liver by real-time reverse-transcription (RT)-PCR.
      We could detect expression of CYP1A1, 1A2, P1B1, 2A6, 2B6 and 2E1 genes in PBL
      and all the genes except for CYP2F1 in the liver. Although gene expression levels
      within each subfamily were closely correlated within PBL and within the liver, a
      clear correlation of gene expression levels between PBL and liver tissues was
      found only for CYP4B1. Although inter-individual variation of the expression
      level of each CYP gene was wide, the induced level was proportional to the basal
      expression level. Therefore, monitoring of CYP gene expression levels in PBL,
      especially those of CYP4B1, could be available as a biomarker for monitoring of
      exposure to environmental pollutants and assessing the associated risk. Compared
      with non-tumor tissue, HCC tissues tended to show overexpression of multiple CYP
      genes, indicating that individualized selection and more effective administration
      of chemotherapeutic agents could perhaps be based on the pattern of CYP
      overexpression.

PMID- 15182435
TI  - Comparative analysis of ATP-binding cassette (ABC) transporter gene expression
      levels in peripheral blood leukocytes and in liver with hepatocellular carcinoma.
AB  - ATP-binding cassette (ABC) transporters comprise a superfamily of similar
      proteins involved in transmembrane transport of various substances. ABC
      transporter family members in the liver participate in bile formation and lipid
      metabolism. In order to assess whether peripheral blood leukocytes (PBL) are
      available as a surrogate for determination of the expression of ABC transporter
      genes in the liver, we compared ABC transporter gene expression levels in PBL
      with those in liver tissues from patients with hepatocellular carcinoma (HCC). We
      measured ABCA1, A2, B1-B4, C1 degrees C5, G1 and G2 gene expression levels in
      PBL, and cancerous and non-cancerous portions of liver from patients with
      hepatocellular carcinoma by means of real time reverse-transcription (RT)-PCR. We
      could not detect ABCC5 expression in any tissue of the liver. Close correlations
      between ABCA2, C1 and G1 in PBL and in non-tumor tissues of the liver were found.
      Compared with the non-tumor part, HCC tissue expressed lower levels of ABCA1, B4
      and G2. We think monitoring of ABCA2, C1 and G1 gene expression levels in PBL
      will be useful for selection of anti-cancer agents and monitoring of drug
      resistance of HCC. Administration of chemotherapeutic agents which are substrates
      of ABCA1, B4 and G2 should be effective for the treatment of HCC.

PMID- 15182436
TI  - In vitro conversion of irinotecan to SN-38 in human plasma.
AB  - Irinotecan is an active cytotoxic agent for various cancers, and is converted to
      SN-38, its most active metabolite, by carboxylesterase converting enzyme (CCE) in
      vivo. Although the primary metabolic site is in the liver, ex vivo studies have
      proven that irinotecan is also converted to SN-38 in intestines, plasma and tumor
      tissues. The present study attempted to elucidate the in vitro conversion
      efficiency in human plasma, and to examine possible inter-individual variability
      and its clinical significance. Plasma samples were taken from 57 patients with
      lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers.
      After addition of 157 mM irinotecan to plasma, time courses of SN-38
      concentration, measured by high-performance liquid chromatography (HPLC), were
      investigated. All subjects showed linear increase in SN-38 concentration during
      the first 60-min period, followed by a plateau. Mean and standard deviation of
      the conversion rate in the first 60 min were 515.9 +/- 50.1 pmol/ml/h (n = 69),
      with a coefficient of variation of 0.097. Although most of the subjects showed
      comparable conversion rates, 3 subjects had significantly higher conversion
      rates. In conclusion, the results of this study suggest that the enzyme activity
      of CCE in human plasma may show inter-individual variability.

PMID- 15182437
TI  - Dependence of chemotherapy response on p53 mutation status in a panel of human
      cancer lines maintained in nude mice.
AB  - In contrast to findings in vitro, the clinical response to anticancer
      chemotherapy is not simply associated with the p53 mutation status. To analyze
      the relationship between the actual response of solid tumors with p53 mutation
      and other biological characteristics, we used a human cancer-nude mouse panel of
      21 lines derived from stomach, colorectal, breast, lung, and liver cancers for
      experimental chemotherapy. We examined the tumor growth rates of the cancer lines
      and the effects of nine drugs in clinical use, namely, mitomycin C (MMC),
      cisplatin (CDDP), nimustine hydrochloride (ACNU), irinotecan (CPT-11),
      cyclophosphamide (CPA), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), a 4:1
      mixture of uracil and FT-207 (UFT), 5'-deoxy-5-fluorouridine (5'-DFUR), and
      adriamycin (ADM), on these tumors. The chemotherapy response was expressed as the
      tumor growth inhibition rate (IR). The genomic DNA sequences of the p53 gene in
      exons 5 through 8 were analyzed in these cancer tissues, and p53 mutations were
      detected in 10 of the 21 cancer lines (48%). Resistance to MMC was observed in
      p53 mutant tumors with smaller IRs than those for wild-type tumors (57.7% vs.
      79.9%, P < 0.03). No significant differences were noted with the other eight
      drugs. To explore the role of the p53 function in the chemotherapy response, we
      calculated the correlation coefficients between chemosensitivity and tumor growth
      rate separately in p53 mutant and wild-type groups. In the p53 wild-type group,
      we found a positive correlation for the following drugs: ADM (P < 0.02), ACNU (P
      < 0.007), CPA (P < 0.011), UFT (P < 0.012), and FT-207 (P < 0.02). In the p53
      mutant group, only CPA (P < 0.003) showed a positive correlation. The kinetics
      suggests that in the wild-type tumors, DNA damage caused by anticancer drugs
      occurs proportionally to the rate of DNA synthesis, and p53-mediated apoptosis is
      subsequently induced. The low frequency of positive correlation in the p53 mutant
      tumors is compatible with the loss of function or malfunction of mutant p53. The
      present results provide kinetic evidence that p53 function affects the response
      to anticancer drugs. Preserved p53 function tended to confer good
      chemosensitivity on rapidly growing tumors. However, the p53 mutation status did
      not seem to be suitable for use as an exclusive indicator to predict the
      chemotherapy response of human cancer xenografts.

PMID- 15182438
TI  - Kigamicin D, a novel anticancer agent based on a new anti-austerity strategy
      targeting cancer cells' tolerance to nutrient starvation.
AB  - Both tolerance to nutrient starvation and angiogenesis are essential for cancer
      progression because of the insufficient supply of nutrients to tumor tissue.
      Since chronic nutrient starvation seldom occurs in normal tissue, cancer's
      tolerance to nutrient starvation should provide a novel target for cancer
      therapy. In this study, we propose an anti-austerity strategy to exploit the
      ability of agents to eliminate cancer cells' tolerance to nutrient starvation. We
      established a simple screening method for agents that inhibit cancer cell
      viability preferentially during nutrient starvation, using PANC-1 cell line
      cultured in nutrient-rich and nutrient-deprived media. After screening over 2000
      culture media of actinomycetes, we identified a new compound, kigamicin D
      (C(48)H(59)NO(19)), which shows preferential cytotoxicity to cancer cells under
      nutrient-deprived conditions, but hardly any cytotoxicity under nutrient-rich
      conditions. Both subcutaneous and oral administration of kigamicin D strongly
      suppressed the tumor growth of several tested pancreatic cancer cell lines in
      nude mice. Moreover, kigamicin D was observed to block the activation of Akt
      induced by nutrient starvation. Therefore, our results suggest that kigamicin D
      be a candidate for implementing our novel concept, anti-austerity, which may
      serve as a new strategy for cancer therapy.

PMID- 15182439
TI  - [Current understanding in definitions and diagnosis of sepsis].

PMID- 15182440
TI  - [Sepsis: challenge and intervention strategy].

PMID- 15182441
TI  - [Multi-center clinical study on the diagnostic criteria for multiple organ
      dysfunction syndrome with illness severity score system].
AB  - OBJECTIVE: To establish the diagnostic criteria for multiple organ dysfunction
      syndrome (MODS) with illness severity score according to the evaluation of
      clinical MODS data from hosptal in Beijing. METHODS: The clinical data from 413
      MODS cases in eight hospitals with III-leve in Beijing was analyzed by multi
      center retrospective cohort study. The significant difference of the each
      descriptor between non-survivor group and survivor group was analyzed, and then
      the significant descriptor was selected as the potential indicator. Based on the
      above analysis, the abnormal range of each descriptor was divided into 4
      intervals, assigned corresponding points, diagnostic criteria for MODS was
      established. RESULTS: Severe infection, major operations, trauma and severe
      pancreatitis were the main etiological factor for MODS. The mortality of MODS in
      hospital was 53.5%, and the mortality rate for 28 days hospitalization was 37.3%.
      The correspondent mortality rate in MODS with 2-6 dysfunction organs was 28.6%
      100.0%. The mortality rate of MODS complicated by the dysfunction of brain,
      cardiovascular system, kidney, and lung was 72.8%, 64.3%, 61.7%, and 54.7%
      respectively. The frequency of machinery ventilation support was 76.0% and the
      frequency of hemodialysis was 8.2%. The script of diagnostic criteria for MODS
      with the illness severity score system was established. The script mainly was
      involved in the evaluation of seven organs or systems, including respiratory
      system, cardiovascular system, kidney, hemologic system, liver and alimentary
      system. Only one parameter was used in each organ, they were FiO(2)/PaO(2),
      systolic blood pressure (SBP), serum creatinine, platelet count, conscious state
      and the defecation status. 0-4 scores were endued with each index according to
      the severity of the illnesses respectively. Every descriptor was 5 points,
      showing 0 point with normal organ function, and 1-4 scores with organ dysfunction
      and aggravation. CONCLUSION: The mortality of MODS in hospitals is 53.5% in
      Beijing. The main etiological factors for MODS still are severe infection, major
      operations, trauma and severe pancreatitis. The diagnostic criteria for MODS with
      the illness severity score and the prognostic evaluation system established might
      have clinical significance and practicability, but further studies with large
      samples are still needed.

PMID- 15182442
TI  - [Changes of intestinal mucosal lymphocyte homing in rats with multiple organ
      dysfunction syndromes].
AB  - OBJECTIVE: To observe the changes of intestinal mucosal lymphocyte homing in rats
      with multiple organ dysfunction syndromes (MODS) and study the role of intestinal
      mucosal lymphocyte play in MODS. METHODS: A rat model of MODS was reproduced by
      occluding the superior mesenteric artery for 45 minutes followed by reperfusion
      for 6 hours. From the fifth hour after reperfusion, intestinal lymph of rats
      (MODS group 1, n=10) was collected for 1 hour. Intestinal lymph was also
      collected from rats of control group 1 (n=6). The population of lymphocytes and
      the percentage of T and B cells were measured in both groups. From the third hour
      after reperfusion, intestinal lymph of rats (MODS group 2, n=6) was collected for
      2 hours. Then, intestinal lymphocytes were labeled with (51)Cr and were infused
      into blood circulation again at the sixth hour of reperfusion. Various organs
      were taken out 1 hour later for measurement of (51)Cr-lymphocytes distribution in
      organs by gamma-counter. Intestinal lymph of control rats (group 2, n=6) was
      collected. Labeled lymphocytes were also infused into blood circulation of rats
      again. RESULTS: The number of lymphocytes from intestinal mucosa migrated into
      blood circulation was decreased, the counts were (0.28+/-0.15)X10(7)/h and
      (2.69+/-0.61)X10(7)/h respectively, while 51 Cr-intestinal lymphocytes homed to
      intestinal mucosa were increased in MODS induced by intestine
      ischemia/reperfusion. At the same time, the levels of endotoxin and tumor
      necrosis factor-alpha (TNF-alpha) in intestinal lymph were also elevated.
      CONCLUSION: Increased homing of intestinal mucosal lymphocyte is involved in MODS
      of rats.

PMID- 15182443
TI  - [Analysis of the early and late gene expression of lipopolysaccharide activated
      macrophages by cDNA microarray].
AB  - OBJECTIVE: To study the early and late changes in mRNA expression in macrophages
      in response to lipopolysaccharide (LPS) with a cDNA microarray approach using the
      Clontech Atlas microarray. METHODS: mRNA was isolated from unstimulated control
      and LPS stimulated murine peritoneal macrophages at 2 hours and 24 hours
      poststimulation, converted to (33)P radiolabeled cDNA, and hybridized to mouse
      array membranes. RESULTS: In macrophages being stimulated for 2 hours, 69 out of
      1 176 genes were found to differ by over 3-fold compared with the control. Among
      them 44 genes were up-regulated and 25 genes were down-regulated. In macrophages
      stimulated for 24 hours, 11 genes were up-regulated and 26 genes were down
      regulated compared with the control. Only 8 genes were identified both at 2 hours
      and at 24 hours poststimulation. The expressions of many genes encoding
      transcription factor, cytokines, cell signaling modulators and apoptosis
      associated proteins were found to have changed. Some genes that were not
      previously linked to this model, such as bric-a-brac (BTB) and cap-n-collar(CNC)
      homology 1(BACH1), early growth response protein 2 (EGR2), E47 interaction
      protein 1 (EIP1), Ngfi-A binding protein 2 (NAB2), myeloblastosis oncogene-like
      protein (MYBL2), neurofibromatosis 1 (NF1), ciliarry neurotropic factor (CNTF)
      and semaphorin 4A (Sema4A). CONCLUSION: This study has allowed us to identify
      genes that may potentially be regulated by LPS at early and late phase in
      macrophages. These may contribute to better understanding of the mechanism
      underlying LPS or bacteria induced inflammatory and immune response following
      infection and trauma.

PMID- 15182445
TI  - [Defensin-5 and Matrilysin mRNA expression in the intestine of scalded rats and
      its relation to bacterial translocation].
AB  - OBJECTIVE: To investigate the effect of burn injury on the expression of rat
      defensin-5 (RD-5) and Matrilysin mRNA in the intestine of scalded rats and to
      determine its relation to bacterial translocation. METHODS: Thirty-two Wistar
      rats were divided randomly into sham injury group (n=8) and burn group (n=24).
      Rats of the burn group were subjected to 30% total body surface area (TBSA) full
      thickness scald injury. At 8, 24 and 72 hours after the injury, the animals (n=8
      at each time point) were sacrificed and ileum was sampled for the determination
      of the expression of RD-5 mRNA and Matrilysin mRNA with reverse transcription
      polymerase chain reaction (RT-PCR) technique. Cultures of mesenteric lymph nodes
      (MLN), liver, spleen and lung were carried out at 24 hours after the injury to
      assess the rate of bacterial translocation to visceral organs,and the
      morphological changes in ileal Paneth cells were observed. RESULTS: The
      expression of RD-5 mRNA was significantly up-regulated at 8 hours when compared
      with control group. It was down-regulated sharply at 24 hours but was still
      higher than control group, and at 72 hours it was down-regulated to a level lower
      than control. On the contrary, the expression of Matrilysin mRNA was up-regulated
      continuously to 72 hours, and it was significantly higher than control. Bacterial
      translocation rate was significantly higher in rats of the burn group at 24 hours
      (58.3%) than in control group (8.3%, P<0.01), but there were no obvious
      morphological changes in ileal Paneth cells at the same time point. CONCLUSION:
      The expressions of both RD-5 mRNA and Matrilysin Mrna are up-regulated in the
      early stage after the injury, but their time phases are different. The phenomenon
      might imply that there is a host protective response against bacterial
      translocation.

PMID- 15182446
TI  - [Protective effect of ketamine against septic shock in rats].
AB  - OBJECTIVE: To investigate the effects and the mechanism of ketamine on
      hemodynamics and pro-inflammatory cytokine levels of plasma in septic shock rats.
      METHODS: Cecal ligation and puncture (CLP) was used to reproduce septic shock
      model. Twenty healthy and male Sprague-Dawlay (SD) rats weighing (225+/-25) g
      were randomly divided into four equal groups: Sham CLP group, CLP group, ketamine
      I (KT I) and ketamine II (KT II) group. Thirty minutes before CLP, normal saline
      (0.9 %) was infused continuously at a rate of 5 ml.kg(-1).h(-1) through the left
      femoral vein cannula in sham CLP and CLP group, and ketamine (5 mg.kg(-1).h(-1)
      and 10 mg.kg(-1).h(-1), respectively) was infused continuously in KT I or KT II
      group. The right femoral artery was cannulated to monitor mean arterial pressure.
      The plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6
      (IL-6) were measured using enzyme-linked immunosorbent assays (ELISA). RESULTS:
      CLP produced progressive hypotension, and a large increase in the plasma TNF
      alpha and IL-6 concentrations. The hemodynamic responses were reversed and the
      cytokine responses were suppressed in ketamine treated animals. CONCLUSION:
      Ketamine administration has protective effect against septic shock in CLP rats.

PMID- 15182448
TI  - [Change in intestinal function in sepsis in rat].
AB  - OBJECTIVE: To study the barrier function, absorption, permeability and
      peristalsis of intestine in sepsis in rats. METHODS: A Wistar rat model of sepsis
      was reproduced by ischemia/reperfusion (I/R) of the intestine combined with
      endotoxin challenge. Animal were randomly divided into normal, I/R 1 hours (I/R
      1), I/R 2 hours (I/R 2), I/R 4 hours (I/R 4) and I/RL groups. The following
      parameters were measured in the experiments: (1) diamin oxidase activity (DAO), D
      lactate and D-xylose levels in blood using spectrophotometry; (2) transit
      function of small intestine; (3) pathological examination of small intestine by
      light microscope. RESULTS: The results showed that plasma DAO activity was
      increased in I/R 1, I/R 4 and I/RL (all P<0.05), and small intestinal tissue DAO
      was decreased in I/R 2 and I/RL (both P<0.05). Negative correlations were found
      between plasma and intestinal DAO (r=-0.909, P<0.001). Plasma D-lactate was
      elevated significantly in I/R 1, I/R 2, and I/RL (all P<0.05). D-xylose content
      was increased at I/R1 and I/RL groups (both P<0.05), and it was significantly
      higher than controls at 3 hours. Similarly, a positive correlation was found
      between plasma DAO activity and plasma D-lactate level (r=0.559, P<0.05).
      CONCLUSION: The intestinal barrier function, absorption function, permeability,
      and transit are impaired after gut ischemia/reperfusion combined with endotoxin
      challenge.

PMID- 15182449
TI  - [Alterations in myocardial function in early stage of sepsis in rabbits].
AB  - OBJECTIVE: To study the alterations in myocardial function in early stage of
      sepsis. METHODS: Twenty rabbits were randomly divided into two groups. In the
      control group (n=10) only laparotomy was done, and in the sepsis group the
      animals received cecal ligation and puncture (CLP). In both groups left
      ventricular catheter was placed via right internal carotid artery. Left
      ventricular systolic peak pressure (LVSP), maximal positive change in filling
      pressure versus time (+dp/dt max), maximal negative change in filling pressure
      versus time (-dp/dt max) were monitored, and serum troponin I (TnI) was measured
      per hour for five times (0, 1, 2, 3, 4 hours after operation). RESULTS: Compared
      to the basic levels, LVSP, +dp/dt max and -dp/dt max decreased significantly an
      hour after CLP in sepsis group (all P<0.05), with the tendency of decrease with
      elapse of time. Serum TnI increased significantly an hour after CLP in sepsis
      group, and continued to increase with the passage of time. In contrast, no
      significant change was observed in control group. CONCLUSION: Cardiac muscle is
      injured, and myocardial systolic and diastolic functions are depressed in early
      stage of sepsis in rabbit model.

PMID- 15182450
TI  - [Anti-endotoxin core glycolipid antibody: the preparation of immune serum of E.
      Coli J5].
AB  - OBJECTIVE: To prepare high titer anti-endotoxin core glycolipid (J5) antibody
      (CGL) for the treatment of Gram-negative bacteremia and septic shock. METHODS:
      Nontoxic bacterial vaccine (50 x 10(12)U/L) against E.Coli O111:B4 mutant strain
      J5 was prepared. J5 bacterial vaccine was injected into rabbits through ear
      marginal vein (saline as control preparation), one time pre three days, totally
      five times. Injected doses were as following: 0.1 ml, 0.2 ml, 0.4 ml, 0.6 ml, and
      0.8 ml. One week after fifth injection, blood samples from heart were collected
      and immune serum was isolated. Indirect clotting test was used to determine the
      titer of antibody and cross reaction. RESULTS: Among 12 immunized rabbits, titers
      of antibody against E. Coli J5 were exceeding 1:1 024 in 6 rabbits, and they had
      cross reaction with various kinds of Gram-negative bacterial endotoxins.
      CONCLUSION: The titer of anti-endotoxin core glycolipid (E.Coli J5) antibody
      prepared by us appears to be high, and it can combine with various kinds of Gram
      negative bacterial endotoxins.

PMID- 15182451
TI  - [Diagnostic value of procalcitonin in sepsis in the elderly].

PMID- 15182452
TI  - [Influence of lipopolysaccharide pretreatment on acute lung injury induced by
      lipopolysaccharide in rats].
AB  - OBJECTIVE: To evaluate the effect of lipopolysaccharide pretreatment on blocking
      the development of lipopolysaccharide (E.Coli O(55):B(5)) induced acute lung
      injury. The activity of nuclear factor-kappaB (NF-kappaB) in alveolar macrophages
      was assessed to elucidate its mechanism. METHODS: Thirty-six Wistar rats were
      divided into three groups: normal saline (A), lipopolysaccharide (B),
      lipopolysaccharide preconditioning (C). Rat model of acute lung injury was
      reproduced by administering intraperitoneally lipopolysaccharide in a dose of 6
      mg/kg. Group A and B served as control. In the test group (group C)
      lipopolysaccharide was given intraperitoneally 0.5 mg/kg, 0.5 mg/kg and 1.0 mg/kg
      consecutively for 3 days before lipopolysaccharide challenge. Four hours after
      lipopolysaccharide/normal saline administration, the animals were killed. Blood
      gas was measured. And total protein of bronchoalveolar lavage fluid (BALF) was
      calculated by measuring the radioactivity of (99)Tc labeled serum albumin.
      Wet/dry ratios of the lungs of each group were determined. The nuclear protein of
      the alveolar macrophages was extracted from BALF, and the activity of NF-kappaB
      was assayed with electrophoretic mobility shift assay (EMSA). Microscopic
      examination of the lung was done. RESULTS: In group C, partial pressure of oxygen
      in artery (PaO(2)) was significantly higher than that in group B, and total
      protein content of BALF was significantly lower in group A and C than that in
      group B. Activity of NF-kappaB in group C was higher than group A and B.
      CONCLUSION: Lipopolysaccharide pretreatment can reduce the severity of acute lung
      injury induced by lipopolysaccharide challenge. This phenomenon may be related
      with change in the activity of NF-kappaB of the alveolar macrophages.

PMID- 15182453
TI  - [Effect of treatment with somatostatin on sepsis in rats].

PMID- 15182455
TI  - [Correlation of serum interleukin-1 and coronary heart disease].

PMID- 15182457
TI  - [Retrospective analysis and evaluation of published articles concerning
      glucocorticoid therapy for ARDS].

PMID- 15182458
TI  - [Study on new methods of gastric tube insertion in patients with mechanical
      ventilation support].

PMID- 15182467
TI  - Effectiveness of a light-weight ice-vest for body cooling while wearing fire
      fighter's protective clothing in the heat.
AB  - The aim of the study was to examine the effects of wearing an ice-vest (ca 1 kg)
      on physiological and subjective responses in fire fighters. The experiments were
      carried out on a treadmill in a hot-dry environment. The physical cooling effect
      of the ice-vest was measured with a thermal manikin. The ice-vest effectively
      reduced skin temperatures under the vest. On average, heart rate was 10 beats/min
      lower, the amount of sweating was reduced by 13%, and subjective sensations of
      effort and warmth were lower during work with the ice-vest compared to work
      without it. Thermal manikin tests indicated that the useful energy available from
      the vest for body cooling was rather high (58%). In conclusion, the ice-vest
      reduces physiological and subjective strain responses during heavy work in the
      heat, and may promote efficient work time by 10%.

PMID- 15182468
TI  - Assessment of future workshop's usefulness as an ergonomics tool.
AB  - This study was carried out to assess Future Workshop (FW) regarding its
      usefulness as a participatory ergonomics method, using a descriptive evaluation
      design analysed by phenomenographical approach. The study was conducted among
      professional cleaners, health care personnel and miners, with a sample of 105
      participating subjects in 8 different FWs. Multiple methods, giving a combination
      of both qualitative and quantitative data, were used for data collection. Good
      involvement of participants was observed during workshops. Evaluations
      immediately after FWs and 3 months later showed a strong relationship with high
      correlation, indicating that the perception of FW participants was very positive.
      Interviews revealed conformity between developed problem identification and
      proposed changes. Participants' own perceptions of FW's influence on creativity
      depict their belief of developed ideas and solutions in order to identify and
      solve workplace problems. FW is considered to be a useful ergonomics tool, and
      its qualities are related to structure and practical performance.

PMID- 15182469
TI  - An analysis of accidents caused by improper functioning of machine control
      systems.
AB  - The scope of this study covers events resulting from improper functioning of
      machine control systems. An accident model providing a basis for formulating a
      checklist for accident analysis has been developed. Data about 700 accidents were
      collected. An analysis has proved that in the group of accidents caused by
      improper functioning of machine control systems, serious accidents happened much
      more frequently as compared to the group of accidents with no relation to the
      control system. The reasons for the majority of incidents caused by improper
      performance of safety functions consist in the errors made by designers. In view
      of that, incorrect behaviour of a worker should be treated as a normal event
      instead of a deviation causing an accident.

PMID- 15182470
TI  - Working conditions and dentists' attitude towards proprioceptive derivation.
AB  - Proprioceptive derivation (Pd), a new method of organising a dentist workstation
      as well as a working procedure, was introduced to Thailand. The aim of this study
      was to assess the working conditions and the attitude to Pd among experienced
      users. Questionnaires were distributed among 12 dentists. The results showed that
      all dentists chose to work in a sitting posture and mostly worked without breaks
      between patients. They spent less time on dental examination and crown and bridge
      therapy tasks. Solving problems in patients with physical limitations resulted in
      a low stress level. Seven dentists (58.3%) always used Pd and liked it. Five
      dentists (41.7%) sometimes used Pd, with 3 of them liking it. Only 2 dentists,
      who sometimes used Pd, did not like it because it could not cover all dental
      tasks and treatment, and it was difficult and complex.

PMID- 15182471
TI  - Cytotoxicity of resorcinol under short- and long-term exposure in vitro.
AB  - Cytotoxicity of resorcinol to 3T3 fibroblast in short- (3 hrs) and long-term (72
      hrs or 6 weeks) exposure was investigated. The effects of resorcinol on cell
      viability (neutral red uptake, NRU assay), mitochondrial function (MTT assay) and
      total cell protein (Kenacid Blue assay) were estimated. As a model for long-term
      exposure an INTEGRA CL 6-WELL bioreactor was used. The concentrations of
      resorcinol producing 20, 50 and 80% inhibition of cell growth in the NRU test
      were lower than in the MTT test after 3 hrs of exposure. The use of an INTEGRA CL
      6-WELL bioreactor allows continuous culturing and exposure to test chemical of
      cells for several weeks, but the strong adhesiveness of fibroblast and forming
      aggregates make it difficult to remove them from chambers. Resorcinol in
      concentration of 1 microg/cm(3) did not decrease the viability of cells to 50% of
      control in long-term exposure in the bioreactor.

PMID- 15182472
TI  - Musculoskeletal symptoms as related to ergonomic factors in Iranian hand-woven
      carpet industry and general guidelines for workstation design.
AB  - Carpet weaving is a high risk occupation for developing musculoskeletal disorders
      (MSDs). The objectives of the present study, which was carried out in the Iranian
      hand-woven carpet industry, were determination of the prevalence of MSD symptoms,
      identification of major factors associated with MSD symptoms and development of
      guidelines for workstation design. 1,439 randomly selected weavers participated
      in this study. A questionnaire was used to collect data on MSD symptoms. The
      results revealed that the prevalence rates for symptoms in different body regions
      were high as compared to the general Iranian population (for neck, back and large
      joints, p <.0001). The results of multivariate analyses showed that major
      ergonomic factors associated with musculoskeletal symptoms were loom type,
      working posture, daily working time and seat type. Based on the results, some
      general guidelines for designing weaving workstations were developed. A prototype
      test showed that the new workstation was acceptable for subject tests and that it
      improved working posture.

PMID- 15182473
TI  - Identification of ergonomic issues that affect workers in oilrigs in desert
      environments.
AB  - The main objective of this research was to conduct an assessment of ergonomic
      related problems in oilrigs in a desert environment. A checklist, physical audit
      and medical records were used in the investigation. The results showed
      significant health, environment and work-related problems that could be
      attributed to ergonomic deficiencies in the work system of the oilrig. Some major
      ergonomic issues identified were hard physical work, back pain, discomfort, hot
      environment, long shift, and diverse schedule. Ninety-four percent of the
      employees perceived the workday as very long, 79% were dissatisfied with the work
      schedule, while 61% of the employees perceived the summer work environment as
      extremely hot. Ergonomics should be considered in the work system design so as to
      reduce or eliminate problems in oilrigs in hot desert environments.

PMID- 15182474
TI  - Speech intelligibility of the callsign acquisition test in a quiet environment.
AB  - This paper reports on preliminary experiments aimed at standardizing speech
      intelligibility of military Callsign Acquisition Test (CAT) using average power
      levels of callsign items measured by the Root Mean Square (RMS) and maximum power
      levels of callsign items (Peak). The results obtained indicate that at a minimum
      sound pressure level (SPL) of 10.57 dBHL, the CAT tests were more difficult than
      NU-6 (Northwestern University, Auditory Test No. 6) and CID-W22 (Central
      Institute for the Deaf, Test W-22). At the maximum SPL values, the CAT tests
      reveal more intelligibility than NU-6 and CID-W22. The CAT-Peak test attained 95%
      intelligibility as NU-6 at 27.5 dBHL, and with CID-W22, 92.4% intelligibility at
      27 dBHL. The CAT-RMS achieved 90% intelligibility when compared with NU-6, and
      87% intelligibility score when compared with CID-W22; all at 24 dBHL.

PMID- 15182475
TI  - Do children have one third less peripheral vision than adults?
AB  - The following report is a case study example of how problematic information can
      invade and percolate through the literature on forensic human factors and
      ergonomics. Initially, a highly doubtful assertion was used to bolster an
      argument made in a legal case of wrongful death. The assertion was supported
      through reference to a number of cited works. When the trail of evidence was
      pursued, however, it became clear that diverse citations had all branched from
      one, single, original and doubtful source. The fundamental issue, whether
      children have one third less peripheral vision than adults turns out to be much
      more complex than the original, simplistic spatial conception suggested. The case
      study illustrates the importance of ascertaining original citations and is yet
      another example of the frustration that often accompanies forensic activity where
      financial and legal concerns frequently over-ride the fundamental search for
      knowledge.

PMID- 15182476
TI  - [Road traffic injury--a global public health problem].

PMID- 15182479
TI  - [Effects of selenium on rat hepatocellular DNA damage, apoptosis and changes of
      cell cycle induced by cadmium in vivo].
AB  - OBJECTIVE: This study was conducted to study the effects of sodium selenite on
      rat hepatocellular DNA damage, apoptosis, changes of cell cycle and DNA relative
      content induced by cadmium chloride in vivo. METHODS: Both sodium selenite at the
      dose of 5 micromol/kg and cadmium chloride at the dose of 5 micromol/kg, 10
      micromol/kg and 20 micromol/kg were given to rats by i.p. and there were 5 male
      SD rats in each group. Hepatocellular DNA damage was measured by the single cell
      gel electrophoresis (or comet assay), hepatocellular apoptosis was measured with
      TUNEL (TdT-mediated dUTP Nick End Labelling) and flow cytometry, DNA relative
      content (DNA(RC)) and cell cycle were detected with flow cytometry. RESULTS: When
      sodium selenite at the dose of 5 micromol/kg acted jointly with cadmium chloride
      at the dose of 5 micromol/kg, 10 micromol/kg and 20 micromol/kg respectively, the
      results showed that selenium reduced the effect of cadmium on DNA damage and
      apoptosis and decreased the rates of DNA damage and the rates of apoptosis
      significantly. Sodium selenite at the dose of 5 micromol/kg increased cell number
      of G(0)/G(1) period decreased by cadmium chloride at the dose of 5 micromol/kg
      and increased cell number of G(2)/M period decreased by cadmium chloride at the
      dose of 10 micromol/kg and 20 micromol/kg. Sodium selenite at the dose of 5
      micromol/kg increased DNA relative content reduced by cadmium chloride at the
      dose of 10 micromol/kg and 20 micromol/kg. CONCLUSIONS: It was suggested that
      selenium at certain doses could antagonize DNA damage, apoptosis, changes of cell
      cycle and DNA relative content induced by cadmium in rat hepatocytes in vivo.

PMID- 15182478
TI  - [Studies on the effects of lead on the growth and differentiation of hippocampal
      neural cells as well as the expression of Oct-2].
AB  - OBJECTIVE: In order to explore the effects of lead on the growth and development
      of cultured hippocampal neural cells and on the expression of Oct-2, the II
      subtype POU domain protein. METHODS: Experiment cell model was established using
      primary culture of hippocampal neural cells from SD rat embryos. Target cells
      were exposed to lead acetate in the different concentrations, i.e. 10(-1), 10(0),
      10(1), 10(2), 10(3) micromol/L, while the control group was given the same
      quantity of the culture medium. The immunohistochemistry method was utilized to
      detect the expressions of Neurofilament (NF) and Glial Fibrillary Acidic Protein
      (GFAP), the markers for neuron and astrocyte, respectively, and the expression of
      Oct-2 as well. RESULTS: The results showed that 10 micromol/L lead acetate
      treatment caused diminishing of neuronal cell body and the decreases of both axon
      lengths and inter-cellular connections. In addition, 1 micromol/L lead acetate
      significantly increased the number of GFAP-positive cells compared with the
      control group (P < 0.05). By image analysis system, 1 micromol/L lead acetate
      treatment was found to induce a statistically significant increase of the
      positive area rate concerning Oct-2 expression in hippocampal neurons and
      astrocytes, while both positive area rate and integral density of light of Oct-2
      expression were found to increase markedly in the groups treated by 10 micromol/L
      lead acetate (P < 0.01). CONCLUSIONS: Lead acetate treatment may contribute to
      the inhibitions of both growth and differentiation of hippocampus neurons, and to
      the stimulation of glial cell hyperplasia simultaneously. In addition, the CNS
      impairments caused by lead is partly correlated with the enhancement of Oct-2
      expression.

PMID- 15182480
TI  - [Effects of tea polyphenols and tea pigments on telomerase activity of HepG2
      cells].
AB  - OBJECTIVE: This study is to investigate the effect of tea polyphenols and tea
      pigments on telomerase activity of human liver cancer cell line, HepG2 cells.
      METHODS: TRAP-PCR-ELISA was applied to investigate the telomerase activity.
      RESULTS: Telomerase was positive in tea polyphenols treated groups, tea pigments
      treated groups and blank control group. Telomerase activities (A(450
      approximately 690) values) were 1.56 and 1.46 in 50 mg/L and 100 mg/L tea
      polyphenols-treated groups, 1.55 and 1.49 in 50 mg/L and 100 mg/L tea pigments
      treated groups, respectively. The results showed that telomerase activity was
      significantly inhibited by tea polyphenols and tea pigments treatment as compared
      with the blank control group (A(450 approximately 690) = 2.11). CONCLUSIONS: Tea
      polyphenols and tea pigments could significantly inhibit telomerase activity of
      HepG2 cells, and telomerase activity may be a useful biomarker for cancer
      chemoprevention.

PMID- 15182482
TI  - [Genetic polymorphism in cytochrome P450 2E1, salted food and colorectal cancer
      susceptibility: a case-control study].
AB  - OBJECTIVE: To investigate PstI allelic variants of cytochrome P450 2E1 (CYP2E1),
      the interaction effect on salted food and their role in risk for colorectal
      cancer. METHODS: The genotypes of CYP2E1 PstI restriction fragment length
      polymorphism were analyzed in 126 colorectal cancer cases and 343 normal
      controls. The unconditional logistic regression was applied to estimate the OR
      and its 95% CI. RESULTS: The CYP2E1 C1/C1, C1/C2 and C2/C2 genotypes were found
      respectively in 61.8%, 35.8% and 2.4% of normal control, similar to rectal cancer
      cases. The percentage of PstI variant genotype (54.9%: 52.9% C1/C2 and 2.0%
      C2/C2) in colon cancer cases was significantly higher than that in controls
      (adjusted OR1.979, 95% CI 1.090 approximately 3.595). Stratified analysis
      suggested an interaction between CYP2E1 C2 allele and salted food. The odds ratio
      (OR) for the CYP2E1 variant genotype, salted food eaten weekly or biweekly and
      eaten every day or every other day were 1.935, 2.122 and 2.315, respectively,
      while those of salted food combined with variant genotype eaten weekly or
      biweekly and eaten every day or every other day were 2.272 and 3.127. The role in
      risk for rectal cancer was different from that for colon cancer. Whatever the
      CYP2E1 genotype is, the risk for rectal cancer came to marked when salted food
      was consumed weekly or biweekly (OR = 2.646 and 2.297, respectively). However,
      none but the combined effect of variant genotype and salted food eaten every day
      or every other day had the notably risk for colon cancer and the odds ratio
      suddenly increased to 4.262 (95% CI 1.395 approximately 13.017), 1.69-fold higher
      than that of wild genotype (P = 0.072). CONCLUSION: The CYP2E1 C2 allele is a
      susceptibility factor for colorectal cancer, especially for colon cancer, and
      there is an apparent gene-environment interaction between the susceptible
      genotype and salted food.

PMID- 15182483
TI  - [Role of telomerase in chrysotile induced malignant transformation of normal
      human embryonic lung fibroblasts].
AB  - OBJECTIVE: To explore the role of telomerase in asbestos dust induced malignant
      transformation of human embryonic lung fibroblasts in vitro. METHODS: Human
      telomerase catalytic subunit (hTERT) was transferred into human embryonic lung
      fibroblasts (HELF). Chrysotile dust at concentration of 2.5 microg/cm(2) was
      added to HELF transduced with and without hTERT (HELF-T+), respectively, and
      their transduced foci were separated. Biological characteristics of the cells,
      telomerase activity, length of telomere and cell growth curve were observed.
      Colony forming test was performed on soft agar to evaluate the nature of
      transformation. RESULTS: The hTERT gene was transferred into HELF steadily, and
      HELF-T+ was established. Malignant transformation occurred in both HELF and HELF
      T+ by asbestos stimulation. Asbestos dusts could induce higher rate of
      transformations in HELF-T+ [(2.08 +/- 1.08)/utensil] than in HELF [(1.08 +/-
      0.10)/utensil], P < 0.05. Telomerase activity in both transformed malignant cells
      and HELF-T+ was higher, as well as the longer length of telomere in them.
      CONCLUSION: Rate of malignant transformation in cells with more activity of
      telomerase and longer length of the telomere was higher after stimulation with
      asbestos, indicating telomerase could play an important role in asbestos induced
      human cells malignant transformation.

PMID- 15182484
TI  - [The comparative study on maturation of metacarpal bone in puberty children
      during their growth spurt period between urban and rural areas].
AB  - OBJECTIVES: To study maturation of the metacarpal bone in puberty children during
      their growth spurt period and its difference between urban and rural areas.
      METHODS: Totally, 560 pupils/students were selected from primary and secondary
      schools in urban and rural areas each, with 35 children in each gender and age
      group, ranging 12 - 15 years of age for boys and 10 - 13 for girls. An X-ray film
      of left hand-wrist site was taken for each of them. Length and width of the
      metacarpal bone were measured and the metacarpal index was calculated. RESULTS:
      Increment of length of the metacarpal bone was great in puberty children both in
      urban and rural areas, (6.26 - 9.31) mm in boys and (5.28 - 9.12) mm in girls.
      Mean length of the metacarpal bone was longer in children of urban areas than
      that of rural ones, regardless of their age and gender. There was significant
      difference in mean length of the metacarpal bone between boys aged 14 - 15 years
      and girls aged 12. Mean width of the metacarpal bone in most children was wider
      in rural areas than that in urban ones. Mean metacarpal index in children was
      higher in urban areas than that in rural ones, with very statistical
      significance, except for girls of 13 year age group. The peak age of metacarpal
      maturation was 1 year earlier in urban areas than in rural ones. CONCLUSIONS:
      Maturation of the metacarpal bone was rapid during puberty growth spurt period,
      with relatively significant difference in urban and rural ares.

PMID- 15182486
TI  - [A cross-sectional study on the changes in dietary behavior stages in resident].
AB  - OBJECTIVE: To explore the possibility of applying the concept of various stages
      of dietary behavior changes in Hangzhou residents. METHODS: The dietary behavior
      was surveyed and analyzed in 1 388 Hangzhou residents with 18 year-old and older
      using the various dietary behavior change model model and stages of change.
      RESULTS: The proportion of Hangzhou residents with unhealthy dietary behavior was
      high and associated with gender and education level. The changes of dietary
      behavior could be divided into 5 stages, i.e. preintention, intention,
      preparation, action and maintenance. These stages of change happen consecutively.
      The changes of unhealthy dietary behavior do not match the improvement of health
      knowledge. Although a significant proportion of the residents understand that it
      is unhealthy to eat too much fat, pickles and high salt food, there are only a
      few of them really take action to reduce the consumption of these foods and to
      consume more milk, fruit and vegetable. CONCLUSIONS: There are multiple factors
      that affect the changes of dietary behavior in people. The changes of dietary
      behavior occur in various consecutive stages. Different intervention measures
      should be applied to people in different dietary behavior changes.

PMID- 15182485
TI  - [A study on occupational stress in commercial workers of a supermarket in
      Yinchuan].
AB  - OBJECTIVE: To study difference in occupational stress between men and women
      commercial workers in a supermarket in Yinchuan, Ningxia. METHODS: Totally, 679
      commercial workers in a supermarket were investigated with questionnaire of
      occupational stress indicator (OSI), matched on age, length of service,
      educational level, marital status and type of work. RESULTS: Score of
      occupational stress factors, relationships, home/work balance and organizational
      atmosphere in women commercial workers was 143.48, 30.86, 20.82 and 15.16,
      respectively, obviously higher than that in men, with 134.89, 28.61, 18.75 and
      13.93, respectively. Score of psychological health and satisfaction in women was
      39.86 and 14.82, respectively, lower than that in men, with 43.84 and 17.66,
      respectively, which indicate that occupational stress in women was more severe
      with a more stressful psychological reaction than in men. Stepwise regression
      analysis showed that the main predicting factor for job satisfaction was personal
      relationships in women, and organizational atmosphere, managerial role and
      workload in men. Those for psychological health was control strategy and
      organizational atmosphere in women, and organizational atmosphere and recognition
      in men, those for physical illness was workload in women and support strategy and
      physical exercises in men, and those for stress level was support strategy in
      women and coping strategy in men. CONCLUSIONS: Women commercial workers
      experienced much more stress, with more severe stress reaction in their work,
      than men did. The main factors affecting occupational stress reaction and level
      of stress in women and men were not quite similar.

PMID- 15182487
TI  - [The effects of pregnancy malnutrition on the development of insulin resistance
      in rat offspring].
AB  - OBJECTIVE: To investigate the effects of pregnancy malnutrition on the occurrence
      of insulin resistance (IR) in rat offspring during adult stage and to find out
      the relationship between TNF-alpha and IR; and to find out a reasonable early
      nutritional intervention measure for the prevention of IR, through giving
      different diets to offspring. METHODS: An IUGR model was built by maternal
      nutrition restriction. 80 newborn IUGR female pups were randomly divided into 4
      groups, the mother rats were given the following diet respectively for 3 weeks
      after delivery, pups were fed by mother milk: (1) The IUGR (intrauterine growth
      retardation) rat model was used and the animals were divided into: IUGR control
      group (group S/N) fed with normal diet, (2) IUGR high-caloric diet group (group
      A), (3) IUGR high-protein and high-caloric diet group (group B) and (4) IUGR high
      protein isocaloric diet group (group C). Each group had 20 pups and another 20
      normal female pups were fed with normal diet as the normal control group (group
      C/N). All pups were weaned at the 4th week of age and fed with normal diet till
      the end of the experiment. At the 12th week (adulthood) and 48th week (senility)
      of life, body weight and length, the fasting blood glucose, insulin
      concentration, TNF-alpha of adipose tissue and body weight were measured. Body
      mass index (BMI), ISI (insulin sensitive index), IRI (insulin resistant index)
      and HBCI (beta cell insulin excretion index) and their correlation to TNF-alpha
      were calculated. RESULTS: At 12th week and 48th week of life, the insulin
      sensitivity of IUGR model group was significantly lower than group C/N, although
      there was no significant difference of body weight between these two groups. TNF
      alpha was negatively correlated with ISI, positively correlated with IRI and no
      relation to HBCI. Group A and B was fatter and developed more severe IR. There
      were no significant differences in ISI, IRI, HBCI and TNF-alpha between group C
      and group C/N. CONCLUSIONS: IUGR offspring of pregnancy malnutrition mother rats
      showed IR at the age of 12th week. TNF-alpha was closely related to the
      occurrence of IR in IUGR pups. IUGR pups fed with high caloric diet or high
      protein and caloric diet at the early postnatal period amplified the metabolic
      abnormality. The high protein isocaloric diet is effective early nutritional
      intervention measure for the prevention of occurrence of IR at adulthood.

PMID- 15182490
TI  - [Effect of static magnetic field on development toxicity of rat embryonic
      midbrain neurons cells].
AB  - OBJECTIVE: To explore the effect of static magnetic field (SMF) on the
      differentiation and proliferation of rat embryonic midbrain neurons cells.
      METHODS: The micromass culture of rat embryonic midbrain neurons cell was applied
      to study the effect of varieties of SMF (1.0, 10.0, 50.0, 100.0, 200.0 mT) and
      FACS. RESULTS: SMF inhibited the differentiation of the cell without affecting
      cell proliferation. The concentration of 50% inhibition of cell differentiation
      (ICD(50)) was 25 mT. The concentration of 50% inhibition of cell differentiation
      (IVD(50)) was 45 mT. CONCLUSIONS: The inhibition of SMF on embryonic midbrain
      neurons cells may be associated with impact of protein syntheses, and lipid
      peroxidation.

PMID- 15182488
TI  - [Effect of niacin on nitric oxide synthase expression in rat lung exposed to
      silica].
AB  - OBJECTIVE: To evaluate the effects of niacin supplemented in diet on temporal
      expression of nitric oxide synthase in rat lung exposed to silica by tissue array
      technology. METHODS: Wistar rats were randomly divided into three experimental
      groups: saline-treated group, silica-treated group, niacin-treated group. There
      are 48 animals in each group. Animal models were established by direct tracheal
      instillation of silica into the rat lungs. Plasma level of niacin was measured by
      high performance liquid chromatography (HPLC). The expression of iNOS protein in
      the paraffin-embedded lung sections was measured with streptavidin/peroxidase
      (SP) immunohistochemistry on tissue microarray and quantified by Image-Pro Plus.
      RESULTS: Plasma level of niacin in niacin-treated group were significantly
      elevated by 5.946 4, 17.422 0, 21.398 0, 16.091 0, 4.414 3 and 7.130 5 mg/L at 1,
      3, 7, 14, 21 and 28 days after instillation of silica, as compared to control and
      silica-treated groups. Seven days after instillation of silica, iNOS integrated
      optical density (IOD) of the lung, total NOS and iNOS activities in bronchial
      alveolar lavage fluid (BALF) supernatant in silica-treated group significantly
      elevated by 273 421, 2.61 kU/L and 1.89 kU/L, respectively, in the saline-treated
      group, with statistical significance. Niacin treatment could significantly
      decrease silica-elevated iNOS integrated optical density (IOD) of the lung, total
      NOS and iNOS activities in BALF supernatant by 248.292, 1.50 kU/L and 0.91 kU/L
      in the silica-treated group, respectively, with statistical significance.
      CONCLUSIONS: It is suggested that treatment with niacin could effectively
      attenuate the over expression of nitric oxide synthase in the rat lung induced by
      silica particles in our study.

PMID- 15182491
TI  - [Construction of a novel Schistosoma japonicum DNA vaccine pBK-Sj14-3-3 and
      studies on its immunoprotection in mice].
AB  - OBJECTIVE: To prepare Sj14-3-3 DNA vaccine and observe its immunoprotection
      against Schistosoma japonicum in mice. METHODS: The Sj14-3-3 gene was amplified
      by reverse transcription-polymerase chain reaction (RT-PCR) and subcloned into
      eukaryotic expression vector pBK. The recombinant plasmid pBK-Sj14-3-3 was
      extracted, purified and inoculated into BALB/c mice by intramuscular injection.
      Mice were attacked by Schistosoma japonicum cercariae and then killed. Adult worm
      and egg were counted, respectively. Diameter of the egg granulomas in the liver
      of infected mice was measured. RESULTS: Electrophoresis on 1% agarose gel showed
      that the product of RT-PCR and the inserted fragment of recombinant plasmid
      digested with EcoR I and Xho I had the same size, about 765 bp, confirming the
      latter was the 14-3-3 encoding gene by nucleotide sequencing. Adult worm load
      declined by 27%, average egg load of per gram (EPG) of the liver tissues by 79%,
      average egg production per couple of adult worm (EPWP) by 51%, and mean diameter
      of egg granulomas by 29% in vaccinated mice. CONCLUSION: The recombinant plasmid
      pBK-Sj14-3-3 was successfully constructed, which had some immunoprotection
      against Schistosoma japonicum in infected mice, indicating its potential to be
      vaccine candidate molecule of Schistosoma japonicum.

PMID- 15182492
TI  - [Application of green fluorescence protein in the detection of E. coli O157:H7 in
      food].
AB  - OBJECTIVE: To introduce green fluorescence protein (GFP) into E. coli O157:H7 and
      improve the detection methods for this bacteria, and to study the kinetics of E.
      coli O157:H7. METHODS: The plasmid pGFP was transferred into E. coli O157:H7. The
      characteristic of the new built O157:H7-pGFP strain was evaluated. Some food
      samples were inoculated with the recombinant strain under certain temperature to
      imitate different storage circumstances. The contaminated E. coli O157:H7 were
      counted after certain time. RESULTS: The pGFP was stable in E. coli O157:H7. The
      E. coli O157:H7-pGFP inoculated in ground poultry meat and pasteurized milk were
      enriched to 35 000 approximately 200 000 times in 12 h under higher storage
      temperature (37 degrees C), whereas the quantity decreased slowly under lower
      temperature (4 degrees C). CONCLUSION: The recombinant strain with the characters
      of ampicillin resistance and green fluorescence under UV 365 nm was a useful tool
      in detection methods improvement and bacteria survival studies.

PMID- 15182493
TI  - [Characteristics of virulence gene in Vibrio parahaemolyticus strains isolated
      from clinical patients and environment in Hangzhou, China].
AB  - OBJECTIVES: To investigate the characteristics of virulence gene in Vibrio
      parahaemolyticus strains isolated from clinical patients and environment in
      Hangzhou, China. METHODS: Thermostable direct hemolysin gene (tdh) and
      thermostable direct hemolysin-related hemolysin gene (trh) were determined in a
      total of 174 strains of V. parahaemolyticus isolated from patients and
      environment (seafood) in Hangzhou area by PCR. RESULTS: The tdh was found in 92
      out of 94 V. parahaemolyticus strains from food poisoning patients and in 33 out
      of 34 strains from sporadic diarrhea patients, and trh was not detected in all
      above clinical strains. Meanwhile the tdh was negative in all V. parahaemolyticus
      strains from environment, and the trh was also negative except one strain with
      urease activity. All strains with trh negative had no the activity of urease.
      CONCLUSIONS: The V. parahaemolyticus strains from food poisoning patients and
      sporadic diarrhea patients are tdh positive and trh negative. The V.
      parahaemolyticus strains with tdh negative and almost trh positive in environment
      might be a potential pathogen in Hangzhou.

PMID- 15182494
TI  - [High-performance liquid chromatography with electrochemical in the detection of
      plasma homocysteine].

PMID- 15182495
TI  - [Emergency injury events and its warning system and emergency treatment].

PMID- 15182496
TI  - [Guideline of prevention and treatment of hepatitis C].

PMID- 15182498
TI  - [General medicine in our old days].

PMID- 15182497
TI  - [Recognition of the national and local differences in bacterial drug resistance].

PMID- 15182499
TI  - [A prospective cohort study of risk factors for ventilator-associated pneumonia
      in intensive care unit].
AB  - OBJECTIVE: To study the risk factors of ventilator-associated pneumonia (VAP) in
      intensive care unit (ICU), in order to offer basic epidemiological data for the
      prevention of VAP in ICU. METHODS: A prospective cohort study on VAP was carried
      out in intubated or tracheotomied patients in ICU of Fudan University Zhongshan
      Hospital from Dec.1999 to Feb. 2001. Single factor analysis and muti-variable
      logistic regression analysis were adopted to identify the possible risk factors
      of VAP. RESULTS: (1) Ninety-eight patients were enrolled in this study, of which
      52 were diagnosed as having VAP. The incidence of VAP was 53.1%. The incidence of
      VAP was 32.4 cases per 1000 intubation days. (2) Single factor analysis showed
      that history of chronic obstructive pulmonary emphysema, use of H2-receptor
      blocker, the days of antibiotic use, the types of antibiotics, enteral feeding,
      APACHEII scores, the duration of mechanic ventilation, pH of gastric juice,
      hypoalbuminemia, tracheotomy, reintubation, colonization of gram negative bacilli
      in oropharynx, and conscious disturbance were related to the occurrence of VAP.
      (3) Multi-variable logistic analysis showed statistical significance in
      combination of over two types of antibiotics (OR = 7.59, 95% CI 4.31 - 38.29),
      reintubation (OR = 4.73, 95% CI 2.33 - 11.67), APACHE II scores over 15 (OR =
      2.02, 95% CI 1.59 - 26.74), pH of gastric juice over 4 (OR = 1.23, 95% CI 1.02 -
      1.54) and prolongation of mechanic ventilation (OR = 1.15, 95% CI 1.01 - 3.75).
      CONCLUSIONS: Various factors contributed to VAP in ICU. Further clinical trials
      are needed for evidence of the above-mentioned possible risk factors.

PMID- 15182500
TI  - [The phenotype and genotype patterns of erythromycin-resistant Streptococcus
      pneumoniae].
AB  - OBJECTIVE: To investigate the resistance phenotypes and genotypes in erythromycin
      resistant Streptococcus (S.) pneumoniae. METHODS: The minimum inhibitory
      concentration (MIC) of erythromycin, clindamycin, penicillin and fluoroquinolones
      against 192 strains of S. pneumoniae was tested with broth microdilution method
      according to the guidelines of the National Committee for Clinical Laboratory
      Standards. Of 148 clinical isolates of erythromycin resistant S. pneumoniae, the
      macrolide resistance phenotypes were observed by the erythromycin-clindamycin
      spiramycin triple-disc test and erythromycin resistance genes were detected by
      polymerase chain reaction. RESULTS: 42.7% S. pneumoniae isolates was resistant
      (intermediate and resistant) to penicillin while the resistance rates to
      erythromycin and clindamycin were 77.6% and 66.7% respectively. The ermB gene,
      being the most prevalent, was detected in 79.1% of the 148 erythromycin-resistant
      strains. The main phenotype (85.1%) of erythromycin-resistant strains was
      constitutive macrolide, lincosamide, and streptogramin B resistance phenotype
      (cMLS). Erythromycin MICs for S. pneumoniae ermB-positive isolates were higher
      than those for mefA-positive isolates. 74.4% of the ermB-positive isolates
      demonstrated erythromycin MICs of > 16.0 micro g/ml, and the erythromycin MICs
      for mefA-positive isolates ranged from 0.5 approximately 4.0 micro g/ml.
      CONCLUSIONS: The resistance rate of S. pneumoniae to erythromycin is high in
      China. The main phenotype is cMLS. Ribosomal modification (ermB gene coded) is
      the main resistance mechanism against erythromycin in S. pneumoniae

PMID- 15182501
TI  - [The relationship between chronic obstructive pulmonary disease and Chlamydiae
      pneumoniae infection].
AB  - OBJECTIVE: To determine the possible association between Chlamydiae pneumoniae
      (Cpn) infection and chronic obstructive pulmonary disease (COPD). METHODS: This
      work comprised of two studies. The first was an animal study which involved 40
      male Wistar rats. The animals were divided into 4 groups, 10 rats in each group.
      They were treated with cigarette smoking alone (group A), cigarette smoking and
      Cpn inoculation (group B), and Cpn inoculation alone (group C), respectively,
      with a group D as the control. After 6 weeks, Cpn DNA in the lung tissue was
      detected by PCR, and pulmonary function of the animals was measured. Lung
      pathological characteristics were scored. In the second study we used PCR to
      detect Cpn DNA in lung tissues from patients with COPD and control group,
      meanwhile Cpn IgG and IgA antibodies were also measured. RESULTS: The animal
      model of COPD was successfully replicated in most rats of group A (88.9%) and all
      of group B (100%). Group A was greater than group B in changes of pulmonary
      function, and higher in pulmonary pathological scores, predominantly in
      inflammatory cell infiltration and proliferation of small airway smooth muscle.
      There were no statistical differences between group C and group D in changes of
      pulmonary function. Pulmonary pathological scores were higher in group C than in
      group D, with statistical value, also predominantly in inflammatory cell
      infiltration and proliferation of small airway smooth muscle. The positive
      incidence of Cpn PCR were 88.9% and 80.0% in group A and C respectively. The
      positive rate of IgG and IgA were 82.4% and 58.8%, respectively. All pulmonary
      biopsy specimens of COPD and control group were negative. CONCLUSIONS: There were
      no direct relationship between COPD with Cpn infection. Infection with Cpn cannot
      induce COPD simply. But it can exacerbated the air obstruction of COPD on the
      bases of pulmonary impairment by cigarette smoking.

PMID- 15182502
TI  - [Chest X-ray features of severe acute respiratory syndrome and clinical staging].
AB  - OBJECTIVE: To establish a clinical staging system for patients with severe acute
      respiratory syndrome (SARS) based on clinical feature, laboratory tests as well
      as dynamic changes of chest X-ray images. METHOD: Dynamic changes of chest X-ray
      images and laboratory tests in 45 SARS patients managed from March to May, 2003
      were analyzed. RESULTS: (1) Chest X-ray image: among 45 cases, 23 were common
      type: the time to appearance of unilateral patched shadow of the lung were 2 to 5
      (2.9 +/- 1.0) days. The time to appearance of bilateral patched shadow of the
      lungs were 2 to 12 (6.9 +/- 2.5) days. The time to appearance of ground glass or
      consolidation in the lung were 6 to 19 (11.0 +/- 2.0) days. The time to the
      beginning of absorption of X-ray changes were 10 to 21 (15.0 +/- 4.1) days. The
      time for chest X-ray image to be absorbed completely were 18 to 46 (25.9 +/- 7.2)
      days. Twenty-two patients were severe type, in which the time to the appearance
      of ground glass of the lung were (9.0 +/- 3.2) days, with no significant
      difference when compared with common type (P < 0.05). However, the time to the
      beginning of absorption and complete absorption were (19.0 +/- 4.6) days (P =
      0.009) and (36.0 +/- 8.1) days (P = 0.001), respectively. Noticeably, the time to
      pan-consolidation of the lung were less than 7 days in 7 fatal cases. (2)
      Laboratory tests: decrease in the number of lymphocytes and T lymphocyte subset
      were seen in the early stage. While the account recovered in 10 to 14 days of
      disease course in the 38 patients who survived, there was no recovery in 7
      patients who died. CONCLUSIONS: SARS can be divided into five stages: incubation
      period 2 to 10 days, prodromal period 1 to 3 days, progressive period 4 to 7
      days, advanced period 8 to 15 days were, convalescent period 16 to 24 days. The
      appearance of pan-consolidation in the lung in less than 7 days and/or unable to
      recover the number of lymphocytes and T lymphocyte subset will be associated with
      poor prognosis.

PMID- 15182503
TI  - [A study of helper T cell (Th)1/Th2 immune response pattern of gammadeltaT cells
      in asthma].
AB  - OBJECTIVE: To explore the mode of immune responses of gammadeltaT cells in asthma
      and the role of gammadeltaT cell subsets in the pathogenesis of asthma. METHODS:
      Wistar rats were sensitized and challenged with ovalbumin to establish an
      asthmatic model (n = 10, for each group). "Attack-panning" method was used to
      culture selective gammadeltaT cells. The percentage of gammadelta T cells among
      cultured cells was determined by flow cytometry. The levels of interleukin (IL)-4
      and interferon-gamma (IFN-gamma) were measured by ELISA. The expression of IL-4
      mRNA and IFN-gamma mRNA was determined by in situ hybridization. RESULTS: In the
      asthmatic group, IL-4 and IFN-gamma were detectable at the same time in cultured
      supernatant of gammadeltaT cells in peripheral blood mononuclear cells (PBMC) or
      broncho-alveolar fluid (BALF), and the level of IL-4 [PBMC: (40.5 +/- 3.7) ng/L,
      BALF: (49.6 +/- 3.1) ng/L] increased as compared with the control group [PBMC:
      (26.1 +/- 2.1) ng/L, BALF: (23.6 +/- 1.7) ng/L; all P < 0.01], while the level of
      IFN-gamma [PBMC: (17.6 +/- 2.5) ng/L, BALF: (28.5 +/- 3.6) ng/L] decreased as
      compared with the control group [PBMC: (24.3 +/- 1.7) ng/L, BALF: (38.4 +/- 2.8)
      ng/L; all P < 0.01]. In the asthmatic group, the percentage of IL-4 mRNA positive
      staining cells [PBMC: (76.2 +/- 7.2)%, BALF: (85.7 +/- 8.4)%] among the
      gammadeltaT cells significantly increased as compared with the control group
      [PBMC: (20.6 +/- 5.3)%, BALF: (25.0 +/- 6.8)%; all P < 0.01], while the
      percentage of IFN-gammamRNA positive-staining cells [PBMC: (30.9 +/- 6.7)%, BALF:
      (41.5 +/- 3.6)%] among the gammadeltaT cells significantly decrease as compared
      with the control group [PBMC: (60.1 +/- 4.2)%, BALF: (53.8 +/- 5.1)%; all P <
      0.01]. CONCLUSIONS: gammadeltaT cells can secrete both IL-4 and IFN-gamma at the
      same time, or there are two subsets of gammadeltaT cells which can secrete either
      IL-4 or IFN-gamma in PBMC or BALF in asthma. Th1/Th2 immune response mode is
      present in gammadeltaT cells of asthma and Th2-cytokine profile predominates.
      gammadeltaT cells is involved in the pathogenesis of asthma.

PMID- 15182504
TI  - [Effects of RNA interference on epidermal growth factor receptor expression in
      SPC-A-1 cells].
AB  - OBJECTIVE: To investigate whether RNA interference (RNAi) induced by small
      interference RNA (siRNA) could suppress epidermal growth factor receptor (EGFR)
      expression in non-small-cell lung carcinoma (NSCLC) cells. METHODS: SPC-A-1 cells
      were transfected using chemically synthesized double stranded RNA (dsRNA)
      formulated with Lipofectamine 2000. The EGFR numbers were determined by both
      Western blot and flow cytometry. The antiproliferative effects of dsRNA-EGFR were
      assessed using cell counts and colony assay. Cell cycle analysis was carried out
      via flow cytometry. The chemosensitivity of transfected cells to cisplatin was
      determined by MTT. RESULTS: Sequence specific siRNAs targeting EGFR down
      regulated EGFR expression significantly. Compared with the control group, dsRNA
      EGFR reduced the cell numbers by 78.3% and decreased the colonies by 66.8%. Cell
      cycle analysis showed that dsRNA-EGFR induced accumulation of cells in G0-G1
      phase by 17.48% with a significant decrease in the percentage of cells in S-phase
      by 19.20% relative to the control. Based on the value of IC50 obtained by Origin
      6.0 software, we concluded that dsRNA-EGFR increased the sensitivity of SPC-A-1
      to cisplatin by seven-fold. CONCLUSIONS: Sequence specific siRNAs targeting EGFR
      was capable of suppressing EGFR expression, and therefore, significantly
      inhibiting cellular proliferation and inducing cell cycle arrest. The finding
      from chemosensitivity assay further revealed that dsRNA-EGFR was associated with
      an addictive or synergistic effect on tumor growth inhibition when combined with
      cisplatin. The successful application of dsRNA-EGFR for inhibition of
      proliferation in EGFR overexpressing cells extends the list of available
      therapeutic modalities in the treatment of human cancer.

PMID- 15182505
TI  - [Expression of DNA excision repair enzymes and lung cancer prognosis].
AB  - OBJECTIVE: To study the expression levels of three DNA damage excision repair
      enzymes: excision repair cross-complementing rodent repair deficiency gene 2
      (ERCC2), uracil DNA glycosylase (UDG), and proliferating cell nuclear antigen
      (PCNA), in different lung tissues and their relationship with lung cancer
      prognosis. METHODS: The expression levels of ERCC2, UDG, and PCNA protein were
      detected using immunohistochemistry method. Cancer tissues and normal tissues
      adjacent to the cancer from 61 cases of lung carcinoma, and tissue samples from
      18 cases of benign lung disease were studied. The relationship among ERCC2, UDG,
      and PCNA expression levels with lung cancer development and prognosis were
      studied using Ridit analysis method. RESULTS: The expression levels of all three
      proteins were not significantly different between cancer tissues and a normal
      tissues adjacent to the cancer (P > 0.05); but significantly different between
      cancer tissues and benign tissues, and between normal tissues adjacent to the
      cancer and benign tissues (P < 0.05). ERCC2 and UDG levels were higher in benign
      tissues than those in cancer and cancer adjacent tissues, while the PCNA level
      was the opposite. Only the UDG level in cancer adjacent normal tissues showed no
      significant difference compared to that of benign tissues (P > 0.05). There were
      no relationship among age, smoke, cancer metastasis, cancer type and ERCC2, UDG,
      PCNA expression levels. ERCC2 also showed no relationship with degree of
      malignancy and cancer size, while UDG and PCNA expression levels were correlated
      with cancer malignancy and cancer size (P < 0.05). Low UDG and high PCNA
      expression levels were correlated with higher malignancy and larger tumors.
      CONCLUSION: The expression levels of ERCC2, UDG and PCNA were significantly
      different in benign lung tissues, lung cancer tissues and lung cancer adjacent
      normal tissues. ERCC2 showed no significant relationship with lung cancer
      prognosis, while patients with low UDG and high PCNA expressions were more likely
      to have higher malignancy and larger tumors. UDG and PCNA were possible markers
      for evaluating lung cancer prognosis.

PMID- 15182506
TI  - [Spectrum of ST-T-wave changes in hereditary long-QT syndrome in Chinese].
AB  - OBJECTIVE: To evaluate the spectrum of ST-T-wave patterns in Chinese patients
      with hereditary long-QT syndrome. METHODS: ECGs of 61 families were studied to
      determine ST-T-wave patterns. Genotypes were identified by sequencing. RESULTS:
      32 cases showed similarity to LQT1, 41 to LQT2 and 2 to LQT3 in ECG, and 3 cases
      could not be classified. QTc of the patients with symptom was (0.547 +/- 0.08)
      sec and that of the patients without symptoms was (0.526 +/- 0.06) sec, both were
      much longer than that of normal members of the families. T wave patterns were
      different in 48 cases at different time. QTc difference in a same person between
      two times or DeltaQTc were as follows: (0.048 +/- 0.057) sec in patients and
      (0.023 +/- 0.017) sec in normal members (P < 0.001). 12 cases of LQT1 and 11
      cases of LQT2 were identified by genotype sequencing. CONCLUSIONS: There are some
      differences in ST-T waves between these Chinese hereditary long-QT syndrome
      patients and European and American patterns. These patients showed greater
      variability in ST-T wave pattern including the changes in the same type, in the
      same pedigree and in the same patients at different time.

PMID- 15182507
TI  - [Evaluation of the quality of life of patients with irritable bowel syndrome].
AB  - OBJECTIVE: To explore and assess the health-related quality of life (HRQOL) of
      irritable bowel syndrome (IBS) patients in the population. METHODS: Random
      clustered sampling involving permanent inhabitants aged 18 - 80 yr was carried
      out under stratification of urban and suburban areas in Guangdong Province.
      Altogether 231 IBS patients fulfilling the Rome II criteria and 636 Non-IBS as
      control were collected. The impact of IBS on HRQOL was evaluated using the
      Chinese version of SF-36. RESULTS: (1) There were no statistically significant
      differences between IBS and Non-IBS groups in aspects of sex, age educational
      level, and distribution according to areas (P > 0.05). (2) IBS patients reported
      significantly poorer HRQOL than controls (Non-IBS) on all SF-36 subscales (P <
      0.05). The patients had poorer HRQOL than the Non-patients, but their differences
      weren't significant (P > 0.05). (3) The scores on all SF-36 subscales were highly
      associated with the frequency of abdominal pain in IBS patients (P < 0.05); They
      were also correlated to degree of effects of IBS symptoms on life reported by IBS
      patients (P < 0.05); The association between the scores and the symptom of
      fatigue which is the most extra-intestinal symptom in IBS was significant (P <
      0.05); (4) Copying style was highly correlated to the eight SF-36 subscales; IBS
      still had a significant impact on patients after partialing out the effect of
      copying style. CONCLUSIONS: IBS symptoms had a negative impact on HRQOL and the
      SF-36 could be adopted to detect the differences between IBS group and Non-IBS
      group, which may be used as an outcome measure in future treatment studies.
      However, the development of IBS-specific measures of quality of life is
      necessary.

PMID- 15182508
TI  - [The mechanism of KAI1 gene in inhibition of metastasis of primary pancreatic
      cancer].
AB  - OBJECTIVE: To study the effect on invasive and motor ability of MiaPaCa II
      pancreatic cancer cell transfected by recombinant plasmid pCMV-KAI1, alteration
      of KAI1 in the transfecting cancer cells, and the metastatic mechanism in the
      malignancy. METHODS: MiaPaCa II pancreatic cancer cell was transfected with pCMV
      KAI1 by liposome, the invasive and gelatinase ability of two pancreatic cancer
      cell lines were analyzed with transwell culture cell and polyacrylamided gel
      electrophoresis (PAGE) before and after KAI1 cDNA transfection. RESULTS: After
      KAI1 cDNA transfected into MiaPaCa II, the migrative ability of passing through
      the membrane filter decreased evidently (P < 0.05). The width of negative
      staining band narrowed, the intensity level of tape weakened through PAGE. These
      results showed that reduced the ability of degrading basement membrane and extra
      cell base and metastasis were influenced after MiaPaCa II pancreatic cancer cells
      were transfected. CONCLUSION: The suppressed invasion and motor function of
      pancreatic cancer cells seems to influence their metastatic ability and thereby
      entrances the malignant potential of pancreatic cancer.

PMID- 15182509
TI  - [Adult-onset latent autoimmune diabetes and autoimmune thyroid disease].
AB  - OBJECTIVE: To investigate the relationship between latent autoimmune diabetes in
      adults (LADA) and thyroid autoimmunity. METHODS: The frequency of thyroid
      peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab) was determined
      with radioimmunoassay in 394 subjects, including 90 LADA, 104 classic type 1
      diabetics (T1DM), 100 type 2 diabetics (T2DM) and 100 controls. Glutamic acid
      decarboxylase antibody (GAD-Ab) was measured with radioligand immunoassay.
      RESULTS: (1) TPO-Ab existed more frequently in LADA (16.7%, 15/90) than in T2DM
      patients (7.0%, 7/100; P < 0.05). The frequency of thyroid antibody (TPO-Ab or TG
      Ab positivity) in LADA and T1DM was 18.9% (17/90) and 25.0% (26/104)
      respectively, being higher than that in the control group (8/100, 8.0%; P <
      0.05). (2) Thyroid antibodies occurred more frequently in LADA patients with
      higher titer of GAD-Ab (GAD-Ab > or = 0.5) than those with lower ones (50.0% vs
      12.5%, P < 0.05). (3) 47.1% (8/17) of LADA patients with thyroid autoimmunity had
      thyroid dysfunction as compared with 17.6% (6/34) in the group without thyroid
      antibodies (P < 0.05). CONCLUSIONS: (1) LADA patients, especially those with high
      titer of GAD-Ab, have high risk for thyroid autoimmunity. (2) The presence of
      thyroid antibody may predict high risk for thyroid dysfunction in LADA patients.
      (3) LADA may be one of the components in autoimmune polyendocrine syndrome.

PMID- 15182511
TI  - [Effects of oxygen enrichment of room air on sleep patterns at high altitude].
AB  - OBJECTIVE: To explore how hypoxia circumstance affects sleep architecture and to
      study the potential use of oxygen enrichment of room air at an altitude of 3700
      m. METHODS: Oxygen concentration was raised to (24.30 +/- 0.88)% in a room with a
      dimension of 4.51 m x 3.32 m x 3.41 m. Twelve men aged 18 to 20 years who had
      stayed at high altitude (3700 m above sea level) for 30 days slept one night in a
      room of ambient air and another night in the oxygen enriched room the order being
      randomized. Their electroencephalograms (EEG) were recorded with CFM-8
      polysomnography. RESULTS: Significantly more time was spent in deep sleep (stages
      III and IV combined, also known as slow-wave sleep) with oxygen enriched than
      ambient air [(19.33 +/- 4.85)% vs (13.67 +/- 3.75)%, P < 0.01 with paired
      comparisons]. The total sleep time [(500.83 +/- 32.94) min vs (470.67 +/- 27.43)
      min, P < 0.05] and the efficient sleep index [(90.33 +/- 2.06)% vs (85.50 +/-
      3.34)%, P < 0.001] were increased in oxygen enriched air. No differences between
      ambient and oxygen enriched air were found in sleep latency the time to fall
      asleep, the number of arousal and sleep shift (the time spent awake after falling
      asleep), but there was a trend toward fewer of these with oxygen treatment.
      CONCLUSIONS: Installing an oxygen-enriched room at high altitude is relatively
      simple and inexpensive, and there will be a promise for improving sleep quality,
      well-being, and work capacity.

PMID- 15182512
TI  - [Evaluation of gastric lavage treatment for severe acute organophosphorus
      pesticides poisoning complicated by respiratory failure requiring mechanical
      ventilation].
AB  - OBJECTIVE: To discuss the measures of gastric lavage for severe acute
      organophosphorus pesticides poison (AOPP) patients complicated with respiratory
      failure and treated with mechanical ventilation. METHODS: 92 cases of respiratory
      failure due to severe AOPP treated with mechanical ventilation were treated for
      gastric lavage with nasal gastric tube or gastrotomy. Patients of each gastric
      lavage method were divided into fasting toxicosis group (fasting group) and post
      meal toxicosis group (post-meal group). RESULTS: When treated for lavage with
      nasal gastric tube, the duration of coma, the time for reaching atropinization
      and the dosage of atropine needed, the total dosage of atropine used, the
      mechanical ventilation time, the time for restoring 50% of the normal value of
      choline esterase, the hospitalization time and charges, the relapse rate, the
      rate of atropine toxicosis and mortality were respectively: 13 (3 - 24) h, 180
      (60 - 290) min, 150 (80 - 310) mg, 300 (90 - 870) mg, 17 (4 - 52) h, (5.0 +/-
      2.3) d, 9 (7 - 18) d, (8080 +/- 2570) yuans, 0, 0, and 4.76% in the fasting
      groups; all the figures were superior to those of the post-meal group with the
      same treatment: 26 (4 - 55) h, 380 (110 - 690) min, 360 (90 - 730) mg, 3610 (1100
      - 9070) mg, 36 (6 - 110) h, (7.8 +/- 3.6) d, 12 (9 - 35) d, (10 720 +/- 3350)
      yuans, 45%, 30%, and 30.00% (P < 0.01 or P < 0.05). There was no obvious
      difference between the fasting group and the post-meal group in curative effect,
      complication occurrence rate and mortality except for the charges when treated
      with gastrotomy. For the post-meal toxicosis patients gastrotomy showed a better
      effect than the nasal gastric tube and there was no difference in charges.
      CONCLUSIONS: It is suggested that severe AOPP patients complicated with
      respiratory failure and treated with mechanical ventilation should hare lavage
      with nasal gastric tube, if they were poisoned in fasting state, but they should
      be washed through gastrotomy if poisoned after meal.

PMID- 15182530
TI  - [HUP98-HOXA9 transgenic mice are susceptible to N-ethyl-N-nitrosourea stimulation
      in leukemogenesis].
AB  - OBJECTIVE: In order to investigate the leukemogenic potential of NUP98-HOXA9
      fusion gene in vivo. METHODS: Molecular cloning technology was used to construct
      NUP98-HOXA9 transgenic plasmid and NUP98-HOXA9 transgenic mice were generated.
      The genotype and phenotype of the NUP98-HOXA9 transgenic mice were analyzed by
      PCR, RT-PCR and colony-forming assay. The effect of N-ethyl-N-nitrosourea (ENU)
      stimulation on the transgenic mice was analyzed by peripheral blood count, bone
      marrow (BM) cells morphology pathological examination. RESULTS: The transgenic
      expression was detected in 5 independent lines of NUP98-HOXA9 transgenic mice,
      but no expected phenotypes was found in 2 year follow-up. Upon ENU stimulation, 2
      of 10 transgenic mice developed myeloid leukemia, suggesting that NUP98-HOXA9
      transgenic mice have increased susceptibility to ENU mutagenesis in
      leukemogenesis. CONCLUSION: The fusion gene expressed in BM cells of NUP98-HOXA9
      transgenic mice. It seems that the expression of the fusion gene is insufficient
      to trigger leukemogenesis. However, the increased susceptibility to ENU
      mutagenesis suggests that NUP98-HOXA9 fusion gene might play a potential role in
      leukemogenesis.

PMID- 15182533
TI  - [Study on the mutation of human telomeric repeat binding factor 1 gene in
      malignant hematopoietic cell lines].
AB  - OBJECTIVE: To detect mutations of human telomeric repeat binding factor 1 (TERF1)
      gene in 11 malignant hematopoietic cell lines, which have positive telomerase
      activity, and evaluate the significance of the mutations. METHODS: Genome
      structure of TERF1 was predicted by using biology information program, and
      verified by PCR and sequencing. Telomerase activity was detected by telomeric
      repeat amplification (TRAP)-ELISA. PCR and sequencing were used to detect
      mutation of each exon of TERF1 in 11 cell lines, including myelogenous leukemia
      cell lines K562, HL-60, U-937, NB4, THP-1, HEL and Dami; lymphoblastic leukemia
      cell lines 6T-CEM, Jurkat and Raji and MDS-RAEB cell line MUTZ-1. Five DNA
      samples from healthy volunteers were detected as normal controls. RESULTS: TERF1
      gene has 10 exons and spans 38.6 kb. All the 11 cell lines showed positive
      telomerase activity. No mutation was found in all exons of TERF1 in the 11 cell
      lines. However, 4 variants were found in intron1, 2 and 8 near exon1, exon2 and
      exon9, respectively. The variants in MUTZ-1 was different from those in leukemia
      cell lines; but no difference was found between the variants in myelogenous and
      lymphoblastic leukemia cell lines. CONCLUSION: TERF1 mutation is probably not
      among the main factors of the gene dysfunction in malignant hematopoietic
      diseases.

PMID- 15182532
TI  - [Gene expression profile of yolk sac and fetal liver in mouse].
AB  - OBJECTIVE: To better understand the mechanisms of the fetal hematopoiesis turn
      over from primitive to definitive hematopoiesis through the expression level of c
      kit(+) and sca-1(+), and major characters of gene expression profile of these
      cells. METHODS: c-kit and sca-1 expression level were monitored with fluorescence
      activated cell sorting (FACS) of the mononuclear cells from mouse yolk sac and
      fetal liver, while gene expression profile was carried out with EST sequencing
      strategy. RESULTS: The Sca-1(+) cells were increased while the c-kit(+) cells
      decreased with the embryonic development. Through profiling the functionally
      identified known genes, most of the highly expressed were globin genes,
      especially of embryonic types. CONCLUSION: The erythropoiesis played a key role
      in early fetal hematopoiesis in mammalian.

PMID- 15182531
TI  - [Development of human myeloid leukemia-like phenotype in NUP98-PMX1 transgenic
      mice].
AB  - OBJECTIVE: In order to investigate the leukemogenic potential of NUP98-PMX1
      fusion gene in vivo. METHODS: NUP98-PMX1 transgenic mice were generated, in which
      the fusion gene was driven by hCG promoter and expressed in myeloid cells at
      early stage of differentiation. Molecular cloning technology was used to
      construct NUP98-PMX1 transgenic plasmid. The genotype and phenotype of the NUP98
      PMX1 transgenic mice were analyzed by PCR, RT-PCR, peripheral blood count (PBC),
      bone marrow (BM) cells morphology and pathological examination. RESULTS: NIH3T3
      cells transfected with NUP98-PMX1 fusion gene grew faster, formed colonies in
      soft agar, and developed tumors in 10 inoculated nude mice. Among 8 disordered
      NUP98-PMX1 transgenic mice, 4 developed myeloid leukemia-like phenotype,
      including 3 resembling human chronic myeloid leukemia. CONCLUSION: NUP98-PMX1 has
      oncogenic activity and plays a crucial role in leukemogenesis.

PMID- 15182534
TI  - [The initiation of G2/M checkpoint by diallyl disulfide requires the activation
      of p38 MAP kinase in HL-60 cells].
AB  - OBJECTIVE: To explore the molecular mechanisms of G(2)/M checkpoint initiated by
      diallyl disulfide (DADS) in HL-60 cells. METHODS: Cell viability was determined
      by MTT assay. Cell cycle was assayed by flow cytometry. The expression of phospho
      p38, Cdc25B and Cdc2, and p38 mRNA were measured by Western blotting and RT-PCR,
      respectively. RESULTS: After treatment with DADS at 5 - 160 micro mol/L for 0 -
      72 h, the growth of HL-60 cells were suppressed in a concentration-dependent
      manner and the inhibitory effect of DADS (20 micro mol/L) was similar to that of
      ATRA (10 nmol/L) (P > 0.05). Incubation of HL-60 cells with DADS (20 micro mol/L)
      for 12 h could activate G(2)/M checkpoint and increase the expression of phospho
      p38 MAPK, followed by the expression of phospho-Cdc25B and phospho-Cdc2 (P <
      0.05). SB202190, a specific inhibitor of p38 MAPK, markedly blocked the
      phosphorylation of p38 MAPK, Cdc25B and Cdc2 (P < 0.05). CONCLUSION: DADS could
      induce the G(2)/M arrest in HL-60 cells which may be involved in the activation
      of p38 MAP kinase.

PMID- 15182535
TI  - [Coculture of dendritic cell with cytokine-induced killer results in a
      significant increase in cytotoxic activity of CIK to tumor cells in vitro and in
      vivo].
AB  - OBJECTIVE: To explore whether coculture of dendritic cells (DC) with cytokine
      induced killer (CIK) lead to an increase of cytotoxicity against tumor cells in
      vitro and in vivo. METHODS: DC and CIK were prepared from human peripheral blood
      mononuclear cells (PBMC) by conventional methods, the DC pulsed with or without
      NB4 leukemia cell lyses (LCL) was cocultured with the CIK (LCL-DC + CIK and DC +
      CIK), CIK was used as control. Cells phenotypes were analyzed by flow cytometry,
      secretion of IFN-gamma was determined by ELISPOT assay, and cytotoxicity was
      assayed in vitro with (51)Cr-release assay. A human leukemia cell NB4-bearing
      nude mice model was established to test in vivo antitumor efficacy and cell
      homing. RESULTS: Compared with CIK, LCL-DC + CIK got a significant increasing of
      proliferation rate [(18.2 +/- 2.1) times vs (11.6 +/- 2.3) times, P < 0.05] and
      CD(3)(+)CD(56)(+) expression rate [(51.05 +/- 2.63)% vs (30.18 +/- 1.45)%, P <
      0.05], and the number of IFN-gamma secreting cells was increased significantly
      [(13.86 +/- 3.28)/10(4) cells vs (8.74 +/- 2.53)/10(4) cells, n = 12, P < 0.05].
      Meanwhile, LCL-DC + CIK led to an increase of cytotoxic activity to NB4, K562,
      and KG1a cells, and showed significant inhibition of the growth of transplanted
      tumor cells and increased tumor free survival rate of nude mice (100% vs 66.7%, P
      < 0.05), DiI labeled LCL-DC + CIK were detected in spleen, lymph node and tumor
      within a week after injection. There was no significant different in antitumor
      activity between LCL-DC + CIK cell and DC + CIK cell. CONCLUSION: Coculture of
      CIK with DCs can promote the effect of CIK against tumor in vitro and in vivo. DC
      CIK is promising as an immuno-therapeutic strategy for patients with leukemia.

PMID- 15182536
TI  - [Up-regulation of transcription factors GATA-1 and GATA-2 induced by Panax
      notoginosides in hematopoietic cells].
AB  - OBJECTIVE: To observe the role of Panax notoginosides (PNS) in up-regulation of
      GATA family transcription factors, and explore intracellular signal pathway of
      PNS in the proliferation of hematopoietic cells. METHODS: Human bone marrow cells
      were incubated with different concentrations of PNS for colony-forming assay.
      Human cell lines HL-60, K562, CHRF-288 and Meg-01 were incubated with PNS (10
      mg/L) for 14 days. The cell nuclear proteins were extracted and analyzed by
      Western blot with antibodies against GATA-1, GATA-2. Electrophoretic mobility
      shift assay (EMSA) and antibody gel supershift assay was performed using (32)P
      labeled GATA consensus oligonucleotide which contains binding site for GATA
      transcription factors. RESULTS: PNS could promote the proliferation of CFU-GM and
      CFU-E and induce the expression of GATA-1, GATA-2. The nuclear proteins of both
      GATA-1 and GATA-2 in K562, CHRF-288 and Meg-01 cells treated by PNS were
      increased by (1.5 - 2.8) and (2.0 - 3.1)-fold over untreated cells respectively.
      GATA binding activity initiated by PNS was apparently elevated to form higher
      density band of GATA-DNA complex. While there was no detectable change in HL-60
      cells before and after PNS treatment. The predominant GATA binding complex was
      mainly attributable to both GATA-1 and GATA-2 proteins being in phosphorylated
      status. CONCLUSION: PNS can induce the synthesis of transcription factors GATA-1
      and GATA-2 and enhance their DNA binding activity, which could play a role in the
      up-regulation of the expression genes related to proliferation and
      differentiation in hematopoietic cells.

PMID- 15182537
TI  - [Second allogeneic transplant for leukemia relapsed after first allogeneic
      transplantation].
AB  - OBJECTIVE: To evaluate the efficacy of second allogeneic hematopoietic stem cell
      transplantation (allo-HSCT) for treatment of leukemia relapsed after first allo
      HSCT. METHODS: Nine patients with relapsed acute leukemia (5 AML, 4 ALL) and one
      with chronic myelogenous leukemia (CML) who showed cytogenetic relapse after
      first allo-HSCT received second allo-HSCT. The median relapse time from the first
      allo-HSCT was 141 days. Conditioning regimens for second allo-HSCT were
      combination chemotherapy based on moderate-dose Ara-C (n = 5), Bu (n = 3),
      conventional-dose Ara-C (n = 1) and Flud/Mel (n = 1). Prophylaxis for acute graft
      versus-host disease (aGVHD) were CsA alone (n = 2), CsA/MTX (n = 1), FK506 (n =
      1), and no prophylaxis in 6. The median number of peripheral blood mononuclear
      cells transfused was 6.1 x 10(8)/kg. RESULTS: Eight cases were evaluable. All of
      them were engrafted and 7 developed aGVHD (grade I 4, grade II 3). The median
      time for absolute neutrophil count (ANC) > 0.5 x 10(9)/L and platelets > 20 x
      10(9)/L were 11 and 12 days, respectively. Five cases developed localized chronic
      GVHD. Of all the 10 cases received second allo-HSCT, 8 died from interstitial
      pneumonia (n = 2), multiple-organ failure (n = 1), sepsis (n = 1), fungous
      pneumonia (n = 1), and leukemia relapse (n = 3), and 2 survived without leukemia
      for +986 and +1913 days, respectively. The leukemia free survival,
      transplantation related mortality and relapse rate at 2 year were 20%, 50% and
      30%, respectively. CONCLUSION: Second allo-HSCT is a therapeutic alternative for
      selected patients with relapsed leukemia after first allo-HSCT.

PMID- 15182539
TI  - [Experimental study on NK cells promoting donor marrow engraftment and
      hematopoietic reconstitution after MHC haploidentical BMT in mice].
AB  - OBJECTIVE: To explore the effect of donor-derived NK cells added to pretreatment
      conditioning regimen on hematopoietic reconstitution after MHC haplotype
      mismatched BMT in mice. METHODS: Murine model of MHC haplotype-mismatched BMT was
      established by using BALB/c(H-2d) x C57BL/6(H-2b) (CB6F(1)(H-2d/b)) mouse as
      recipient, and C57BL/6(H-2b) mouse as donor. Fifty recipient mice were divided
      into 5 groups. The mice in the first three groups were each infused 1 x 10(6), 5
      x 10(5), 2 x 10(5)/mouse donor-derived NK cells, respectively before TBI ((60)Co,
      9.0 Gy) and then conditioned with TBI, followed by infusion of C57BL/6(H-2b) mice
      bone marrow cells four hours later. The mice in the fourth group received TBI
      only, and in the fifth group, TBI and BMT at the some doses as the first three
      groups. Hematopoietic reconstitution, survival time, body weight, histopathology
      of the recipients were followed up. RESULTS: (1) Survival time was (5.15 +/-
      0.66) days for the fourth group, and > 30 days for the other 4 groups. (2)
      Leukocyte and platelet counts at day 10 after BMT were (0.99 +/- 0.22) x 10(9)/L
      and (61.0 +/- 7.27) x 10(9)/L respectively for the fifth group and (2.01 +/-
      0.21) x 10(9)/L, (101.50 +/- 16.34) x 10(9)/L; (1.98 +/- 0.29) x 10(9)/L, (99.50
      +/- 16.41) x 10(9)/L and (1.97 +/- 0.21) x 10(9)/L, (98.0 +/- 16.19) x 10(9)/L
      for the first three groups, respectively. Histopathology displayed no GVHD in all
      the groups. CONCLUSION: Donor-derived NK cells could promote hematopoietic
      reconstitution after MHC haplotype-mismatched BMT in mice.

PMID- 15182552
TI  - [Reinforce the basic and clinical research for anemia].

PMID- 15182540
TI  - [Analysis of methylation status of the promoter of mdr1 gene in K562 and K562/DNR
      cells].
AB  - OBJECTIVE: To analyze the methylation patterns of mdr1 gene promotor in both K562
      cell and K562/DNR cells and the relationship between promotor methylation and P
      gp expression. METHODS: mdr1 gene expression was analyzed by flow cytometry and
      RT-PCR, methylation status of the promotor of mdr1 gene by bisulfite-sequencing
      (including two GC-box). RESULTS: mdr1 gene was found methylated at GC-box and not
      expressed in K562 cells, but unmethylated and expressed respectively in K562/DNR
      cells. CONCLUSION: The methylation patterns of mdr1 gene promotor in K562/DNR and
      K562 cells were different. mdr1 gene silencing was associated with the promotor
      methylation.

PMID- 15182553
TI  - [Apoptosis and proliferation of CD34 positive bone marrow cells in patients with
      polycythemia vera].
AB  - OBJECTIVE: To study the apoptosis and proliferation of CD(34) positive
      (CD(34)(+)) bone marrow cells (BMC) in patients with polycythemia vera (PV).
      METHODS: The expression of Annexin V and Ki67 of the CD(34)(+) BMC in 20 PV
      patients and control cases [10 essential thrombocythemia (ET), 12 normal persons]
      were assessed by bicolor flow cytometry (FCM), and the correlation between
      apoptosis and clinical situation was analysed in PV patients. RESULTS: The
      Annexin V expressions of CD(34)(+) BMC were (15.96 +/- 1.45)% in PV patients and
      (15.53 +/- 1.76)% in ET patients which were lower than that in normal subjects
      [(23.61 +/- 3.89)%, (P < 0.05)]. The Ki67 expression of CD(34)(+) BMC was (48.79
      +/- 11.68)% in PV patients and (49.60 +/- 9.98)% in ET patients, which were
      significantly higher than that in normal controls (33.87 +/- 6.82)%. The ratio of
      apoptosis/proliferation in PV patients was 0.33 +/- 0.10 and in ET patients 0.32
      +/- 0.02 which were significantly lower than that in normal controls 0.72 +/-
      0.11 (P < 0.01). The apoptosis of CD(34)(+) BMC was negatively correlated with
      the hemoglobin (Hb) levels (r = -0.481, P = 0.037), white blood cells (WBC) (r = 
      0.538, P = 0.026) and the numbers of endogenous erythroid colony (EEC) (r = 
      0.632, P = 0.50), and the ratio of apoptosis/proliferation was negatively
      correlated with the Hb (r = -0.537, P = 0.018) and WBC (r = -0.667, P = 0.003) in
      PV patients. CONCLUSION: There were lower apoptosis and higher proliferation in
      CD(34)(+) BMC of PV patients. Lower apoptosis was correlated with the severity of
      the disease.

PMID- 15182554
TI  - [Expression of three kinds of GPI-anchor proteins in paroxysmal nocturnal
      hemoglobinuria, aplastic anemia and myelodysplastic syndromes patients and their
      clinical implications].
AB  - OBJECTIVE: To investigate the expressions of three kinds of glycosyl
      phosphatidylinositol anchor proteins (GPI-AP), the CD(55), CD(59) and CD(87) on
      the peripheral granulocytes and the soluble u-PAR (su-PAR) level in serum from
      patients with paroxysmal nocturnal hemoglobinuria (PNH), aplastic anemia (AA),
      and myelodysplastic syndromes (MDS), and to analyse their clinical implications.
      METHODS: Twenty-two PNH patients, including 4 complicated with thrombotic
      diseases and 5 with AA-PNH syndrome, 30 AA patients, including 9 being severe AA
      (SAA) and 11 chronic AA (CAA), 27 MDS-RA patients, and 20 healthy individuals
      were tested. The expressions of CD(55), CD(59) and CD(87) on peripheral
      granulocytes were analyzed with flow cytometry. Serum su-PAR was assayed by
      ELISA. RESULTS: The CD(55)(+), CD(59)(+) and CD(87)(+) granulocytes in peripheral
      blood of 20 normal controls were all more than 90%. The expressions of three
      kinds of GPI-APs in 22 PNH patients were significantly decreased as compared with
      that in normal controls, AA patients and MDS-RA patients. The serum level of su
      PAR in PNH group was higher than that of the other three groups. The expression
      of CD(87) was significantly decreased in thrombotic PNH patients as compared with
      that in non-thrombotic PNH patients. The expression of CD(87) was significantly
      decreased in AA patients than in normal controls. The expressions of three kinds
      of GPI-APs in 5 AA-PNH syndrome patients were remarkably reduced as compared with
      AA patients, but no significant difference was found for these indexes between AA
      PNH syndrome and PNH patients and between 27 MDS-RA patients and 20 normal
      controls. CONCLUSION: Measurement of CD(55), CD(59) and CD(87) expressions levels
      on the peripheral granulocytes and su-PAR in serum would be alternative
      approaches for diagnosis and differential diagnosis of PNH. Serum level of su-PAR
      may be helpful to monitor thrombosis in PNH patients.

PMID- 15182555
TI  - [Preliminary study of DA or HA regimen chemotherapy for the treatment of
      refractory and relapsed paroxysmal nocturnal hemoglobinuria].
AB  - OBJECTIVE: To observe the efficacy and side effect of DA/HA regimen chemotherapy
      for the treatment of refractory and relapsed paroxysmal nocturnal hemoglobinuria
      (PNH). METHODS: Eight patients with refractory and relapsed PNH were treated with
      DA/HA regimen chemotherapy. Three patients were treated with DA (DNR 40 mg/d,
      i.v.drip, the first and the second day; 20 mg/d, i.v.drip, the third day; Ara-C
      100 mg/d, i.v.drip, for 5 days) and 5 patients with HA (HHT 2 - 3 mg/d, i.v.drip,
      for 5 days; Ara-C 100 mg/d, i.v.drip, for 5 days). RESULTS: All the 8 patients
      responded well: the PNH clone was diminished in five patients. Hemolysis was
      remitted in 6 cases. Five patients showed improvement in hematological
      parameters. The dosage of corticosteroid was decreased in all of them. No serious
      side effect was revealed. CONCLUSION: DA/HA regimen chemotherapy was safe and
      effective for refractory and relapsed PNH patients.

PMID- 15182556
TI  - [Homozygous hemoglobin constant spring in Guangxi province].
AB  - OBJECTIVE: To analyze the relationship between genotype and phenotype of
      homozygous hemoglobin Constant Spring (Hb CS) in Guangxi province, and to explore
      the reasons of missed diagnosis and the methods for screening and diagnosing.
      METHODS: Screening Hb CS by acetate fibrous membrane electrophoresis with
      benzidine staining. Gene mutation of homozygous Hb CS by polymerase chain
      reaction (PCR) and DNA sequencing. RESULTS: Out of the 9 patients, 4 had no
      clinical symptoms, 2 showed mild anemia and splenomegaly, 3 were jaundice.
      Hemoglobin levels were normal or mild anemia. MCVs were normal or reduced.
      Peripheral blood smear of all the patients displayed hypochromia, anisocytosis,
      poikilocytosis and target cells. The quantities of HbA(2) + Hb CS were 4.3% -
      6.72%, while HbA(2) < 2%. Gene analysis confirmed the diagnosis of homozygous Hb
      CS. CONCLUSION: There was quite different in clinical symptoms, hematological
      parameters and hemoglobin quantifications for patients with homozygous Hb CS.
      They might have no clinical and hematological signs and looked like the phenotype
      of Hb H disease. Homozygous Hb CS was very easy to miss diagnosis. Gene analysis
      can be helpful.

PMID- 15182557
TI  - [Study on the T lymphocytes early activation and soluble tumor necrosis factor
      receptor in patients with aplastic anemia].
AB  - OBJECTIVE: To investigate the expression of T cell early activation marker
      (CD(69)) on peripheral CD(4)(+) and CD(8)(+) lymphocytes and serum levels of
      soluble tumor necrosis factor receptor 1 and 2 (sTNF-R1 and sTNF-R2) in serum and
      bone marrow in patients with aplastic anemia (AA) and their pathophysiological
      significance. METHODS: In vitro activation of T lymphocytes was carried out by
      whole blood cell culture containing PHA (20 micro g/ml). The CD(69) expressions
      on CD(4)(+) and CD(8)(+) lymphocytes at 0 h and 4 h after PHA exposure were
      analyzed by two-color flow cytometry. The levels of sTNF-R1 and sTNF-R2 in serum
      and bone marrow were measured by ELISA. RESULTS: The CD(69) expression rates of
      CD(4)(+) and of CD(8)(+) cells in SAA patients were (8.96 +/- 7.23)% and (10.67
      +/- 7.58)%, respectively, and that of CD(8)(+) cells in CAA patients was (7.36 +/
      5.49)% before PHA stimulation. The CD(69) expression rates of CD(4)(+) and of
      CD(8)(+) cells in SAA patients were (71.73 +/- 11.91)% and (61.74 +/- 13.44)% and
      in CAA (59.35 +/- 10.15)% and (48.78 +/- 8.25)% respectively, and were
      significantly elevated after PHA stimulation. CD(69) expression on CD(4)(+) cells
      was much higher than that on CD(8)(+) cells after stimulation. The levels of the
      two sTNF-R (sTNF-R1 and sTNF-R2) in peripheral blood and bone marrow of SAA
      patients were elevated and in the bone marrow of CAA patients were also
      increased. The serum levels of sTNF-R2 were positively related to the CD(69)
      expression rates of CD(8)(+) cells before PHA stimulation. CONCLUSION: Increased
      early activation and activated potentials of T lymphocytes, along with abnormally
      elevated immunologically active molecules might play a major role in the
      pathogenesis of AA.

PMID- 15182559
TI  - [Trisomy 3 in intestinal B-cell lymphoma of mucosa-associated lymphoid tissue
      type].
AB  - OBJECTIVE: To determine the frequency of trisomy 3 in the intestinal B-cell
      lymphoma of mucosa associated lymphoid tissue (MALT) type and to explore the
      relationship between these two. METHODS: Paraffin embedded tissue sections of
      intestinal B-cell lymphomas of MALT type, according to WHO classification, were
      successfully studied. Seven cases were classical MALT lymphoma, being clinically
      low-grade, and one MALT lymphoma with large cell transform, clinically high
      grade. By using biotin labelled DNA probes specific for chromosome 3 centromeric,
      chromosome in situ hybridization (CISH) were performed. Probe for C16 was used as
      the positive reference of the method, and chronic intestinal inflammation as the
      experiment control for detection of C3 copies in tumor cells. RESULTS: Of the 7
      low-grade classical MALT lymphoma, 5 showed trisomy 3 and 2 normal C3. The only
      case of MALT transformed was trisomy 3. The frequency of trisomy 3 in the
      intestinal low-grade lymphoma was 71.4%. CONCLUSION: The frequency of trisomy 3
      in the intestinal low-grade lymphoma is high, indicating that it may be involved
      in the pathogenesis of this disease and may be of value for the diagnosis.

PMID- 15182558
TI  - [Proliferation of bone marrow hematopoietic stem cells and function of T helper
      lymphocytes of patients with immuno-related pancytopenia].
AB  - OBJECTIVES: To explore the proliferative capacity of bone marrow hematopoietic
      stem cells and the function of T helper (Th) lymphocytes of patients with immuno
      related pancytopenia (IRP). METHODS: Twenty-five untreated IRP patients, 15 IRP
      patients in complete remission (CR) and 10 normal controls were studied for in
      vitro yields of CFU-GM, CFU-E and BFU-E from bone marrow mononuclear cells
      (BMMNC). The mRNA expressions of IL-4, IL-10, IFN-gamma and IL-2 genes in
      unstimulated BMMNC from 25 untreated IRP patients,15 IRP patients in CR, 19
      patients with other hematological diseases presenting pancytopenia and 10 normal
      controls were detected by reverse transcription polymerase chain reaction (RT
      PCR). RESULTS: There was no significant difference of the yields of CFU-E, CFU-GM
      or BFU-E among the untreated, and in CR IRP patients and normal controls (P >
      0.05). The mRNA expressions of IL-4 and IL-10 of Th2 cells were significantly
      higher in untreated IRP patients than in the other groups. The mRNA expressions
      of IFN-gamma and IL-2 of the Th1 cells in all IRP patients were not higher than
      those in the other groups. CONCLUSIONS: The cytopenia of IRP patients was not
      caused by the qualitative abnormality of the hematopoietic stem cells but by the
      destruction or suppression of hematopoietic stem cells from certain extrinsic
      insults. The imbalance of Th lymphocytes subtypes and overfunction of Th2
      lymphocytes played important roles in the pathogenetic mechanism of IRP leading
      to increased and overfunctional B lymphocytes, which produced autoantibodies
      destructing or suppressing hematopoiesis in IRP.

PMID- 15182560
TI  - [Detection of TCR-gamma chain gene rearrangement in malignant histiocytosis].
AB  - OBJECTIVE: To investigate the lineage of the malignant cells in malignant
      histiocytosis. METHODS: Polymerase chain reaction with two groups of common
      primers for TCR-gamma gene was used to analyze the malignant cells of 28
      autopsied cases of malignant histiocytosis. RESULTS: Monoclonal TCR-gamma gene
      rearrangements were detected in 12 out of the 28 samples (43%). CONCLUSION: Most
      cases diagnosed as malignant histiocytosis in Southwest China seems to be
      peripheral T-cell lymphomas.

PMID- 15182561
TI  - [Survivin antisense oligonucleotide induces lymphoma cells apoptosis and
      sensitizes the cells to chemotherapy].
AB  - OBJECTIVE: To explore the effect of antisense oligodeoxynucleotide (ASODN) of
      survivin gene on apoptosis and chemotherapy sensitivity of lymphoma cell line
      Raji. METHODS: Anti-survivin phosphorothioate ASODN was synthesized and
      transfected into Raji cells by lipofectin. MTT assay was used to detect
      cytotoxicity. Apoptosis was observed by fluorescence microscopy and flow
      cytometry. Survivin expression was determined by RT-PCR and Western-blotting.
      RESULTS: (1) survivin ASODN inhibited the cells proliferation in a dose and time
      dependent manner. (2) A higher apoptosis rate (33.0%) could be induced in Raji
      cells by survivin ASODN as compared with that induced by the sense
      oligodeoxynucleotide (11.5%) (P < 0.05). (3) The expression of survivin mRNA and
      protein significantly decreased after treatment with survivin ASODN. (4) There
      was a significant increase of cell inhibition rate after exposure to the
      combination of survivin ASODN and Vm26 as compared to Vm26 or survivin ASODN
      alone (both P < 0.05). CONCLUSION: Survivin ASODN is able to inhibit the
      proliferation of Raji cells, induce the apoptosis, and enhance the sensitivity of
      Raji cell to chemotherapy via specific down-regulation of survivin expression.

PMID- 15182577
TI  - [Report of a case of congenital plasminogen activator inhibitor-1 deficiency].
AB  - OBJECTIVE: To report a patient with congenital plasminogen activator inhibitor-1
      (PAI-1) deficiency and explore its molecular mechanism. METHODS: The activities
      of tissue plasminogen activator (tPA), alpha(2) antiplasmin (alpha(2)AP) and PAI
      1 were measured by the methods of chromogenic substrate, the antigens of tPA and
      PAI-1 were measured by ELISA. PAI-1 gene was studied by PCR product sequencing
      and restriction endonuclease ana-lysing. RESULTS: In the present patient, the
      euglobulin clot lysis time was 70 minutes and was corrected to normal range after
      added 50 ng/ml PAI-1 to his plasma. The activities of t-PA, alpha(2)AP, and
      factor were normal; the activity and antigen of PAI-1 in plasma were both
      significantly decreased. Nucleotide sequence analysis revealed that the patient
      had a heterozygous missense mutation in exon 2, a G to A transition at nucleotide
      43. The possibility of gene polymorphism was excluded by restriction endonuclease
      analysing. CONCLUSIONS: It is the first patient with congenital PAI-1 deficiency
      reported in China. The PAI-1 deficiency in the patient may be caused by compound
      heterozygosity, one of which is the G to A transition at nt43, a new mutation in
      congenital PAI-1 deficiency.

PMID- 15182578
TI  - [FXI gene mutations in two pedigrees of congenital clotting factor XI
      deficiency].
AB  - OBJECTIVES: To identify the FXI gene mutations in two Chinese pedigrees of
      congenital factor XI deficiency. METHODS: The peripheral blood samples were
      collected from the probands and their family members and the plasma FXI:C and
      FXI:Ag were determined. All the exons and exon-intron boundries of FXI gene were
      amplified with PCR and sequenced thereafter. RESULTS: A nonsense mutation
      Trp228stop and two missense mutations Glu323Lys and Leu172Pro were disclosed in
      the two pedigrees. All mutations existed in a heterozygous state. CONCLUSION: The
      FXI gene mutations Trp228stop, Glu323Lys and Leu172Pro attribute to the
      pathogenesis of the congenital factor XI deficiency in Chinese. The Leu172Pro is
      identified for the first time.

PMID- 15182579
TI  - [Study of C1423T polymorphism of the von Willebrand factor-cleaving protease gene
      in Chinese Han population].
AB  - OBJECTIVE: The C1423T polymorphism in von Willebrand factor-cleaving protease
      (vWF-cp) gene affects its enzyme activity. The present study was to investigate
      the polymorphism frequency among Chinese Han population and its relevance to
      arterial thrombotic disorders. METHODS: An amplified 366 bp fragment of human vWF
      cp gene was analyzed by Rsa I restriction assay in 400 unrelated individuals
      including 150 with acute ischemic stroke (AIS), 103 with acute myocardial
      infarction (AMI) and 147 age- and gender-matched healthy controls. The resulting
      products were analyzed by 12% polyacrylamide gels electrophoresis and stained
      with ethidium bromide. RESULTS: Twelve cases were C1423T heterozygous, the C1423T
      frequencies were 98.5% and 1.5%, and the heterozygosity and allele frequency were
      3% and 1.5%, respectively, which were remarkably lower than those reported in
      Japanese population. No 1423T/T homozygote was found. Besides, there was no
      significant difference between healthy controls and patients with thrombotic
      disorders. CONCLUSION: C1423T polymorphism is low frequency in both controls and
      patients of Han population.

PMID- 15182580
TI  - [Double heterozygous mutations of non-canonical splice (IVS1a + 5g > a) and
      His348Gln caused inherited coagulation factor VII deficiency].
AB  - OBJECTIVE: To investigate the pathogenesis of inherited coagulation factor VII
      (FVII) deficiency. METHODS: The diagnosis was validated by coagulant parameter
      assay. FVII gene mutations were analysed in the proband by DNA direct sequencing
      of PCR products of all exons, exon-intron boundaries and the 3', 5'untranslated
      sequences. The mutations were confirmed by reverse sequencing. The ectopic
      transcripts of RT-PCR were used to confirm the characteristics of the mutation in
      non-canonical splice site (IVS1a + 5g > a). RESULTS: Double heterozygous
      mutations in the propositus were identified: a T to G mutation at position 10961,
      resulting in His348Gln substitution, a non-canonical splice site (IVS1a + 5g > a)
      mutation, causing the new model of splice and frameshift mutation. CONCLUSION:
      Double heterozygous mutations of His348Gln and IVS1a + 5g > a were identified in
      a propositus, the splicing pattern of the IVS1a + 5g > a mutation was reported
      for the first time.

PMID- 15182581
TI  - [Study of the effect of TF/FVIIa complex on the expression of u-PAR mRNA in human
      ovarian cancer].
AB  - OBJECTIVE: To construct the expression vector of human tissue factor (TF), and
      investigate the influence of TF/coagulant factor VIIa (FVIIa) complex on the
      transcriptional expression of urokinase plasminogen activator (u-PA) and u-PA
      receptor (u-PAR) in human ovarian cancer. METHODS: The human TF cDNA was obtained
      from placenta by RT-PCR and then inserted into eukaryotic expression vector
      pcDNA3 to obtain the TF-pcDNA3 combinant. This combinant was transfected into
      human ovarian cancer cell line A2780 by lipofectamine. Stably-transfected cells
      A2780/TF were screened. A2780 and A2780/TF cell lines were stimulated by FVIIa
      respectively, and the transcriptional levels of u-PA and u-PAR were examined by
      RT-PCR. RESULTS: (1) The constructed product was identified as TF-pcDNA3
      combinant by sequencing. (2) TF was highly expressed not only at transcriptional
      level in the stable-transfected A2780/TF cell (transfected cell 3.91 +/- 0.28,
      untransfected cell 0.97 +/- 0.23, P < 0.01), but also on the membrane of the cell
      surface [transfected cell (48.56 +/- 9.53)%, untransfected cell (2.73 +/- 1.15)%,
      P < 0.01]. (3) The u-PA and u-PAR mRNA levels in A2780 cell line did not change
      significantly after stimulated by FVIIa; (4) While stimulated by FVIIa, the u-PAR
      mRNA levels in A2780/TF cells increased significantly in both dose-dependent and
      time-dependent manner, while the u-PA mRNA levels did not change significantly;
      (5) In the A2780/TF cell line the enhanced expression of u-PAR mRNA by FVIIa was
      significantly inhibited by coincubated with anti-TF antibody. CONCLUSION:
      TF/FVIIa complex could up-regulate the transcription of u-PAR in human ovarian
      cancer cells so as to enhance tumor invasion and metastasis.

PMID- 15182582
TI  - [Clinical and laboratory study of a case of hematidrosis].
AB  - OBJECTIVE: To study the clinical characteristics and pathogenesis of
      hematidrosis. METHODS: Detailed clinical manifestations and natural history of a
      patient with hematidrosis were presented. A series of laboratory examinations
      were performed, and skin pathohistologic features and ultra microscopic
      structures were observed. RESULTS: The episodes of skin bleeding occurred on any
      site of the body spontaneously and promptly. The skin surface bloody
      extravasation has identical cell components as that of peripheral blood. All the
      results of laboratory tests were normal except a positive Trousseau's test. Skin
      pathohistological study revealed some intradermal bleeding and emphraxised
      capillaries. No abnormality was found in sweat glands, hair follicles and
      sebaceous glands. CONCLUSION: The pathological basis for hematidrosis might be a
      distinctive vasculitis.

PMID- 15182583
TI  - [Effect of curcumin on STAT5 signaling molecule in K562 cells].
AB  - OBJECTIVE: To investigate the effect of curcumin on STAT 5 signaling molecule in
      K562 cells and its molecular mechanism of antileukemia. METHODS: Cell
      proliferation was studied by tetrazolium dye assay. The expressions of STAT5 mRNA
      and protein were assayed by in situ hybridization, and Western blotting
      respectively. RESULTS: Curcumin could inhibit K562 cell proliferation in a time-
      and dose-dependent manner. The percentage of STAT5-positive cells was 19% in
      curcunin group, significantly less than 31% of that in K562 cell group (P <
      0.01). The A value of the expression level of STAT5 protein in curcumin group was
      15 266 +/- 769, significantly less than 25 781 +/- 1240 of that in K562 cell
      group (P < 0.01). CONCLUSION: The expressions of STAT5 mRNA and protein in K562
      cells were inhibited by curcumin and curcumin could inhibit K562 cell
      proliferation.

PMID- 15182584
TI  - [Effect of HMBA on differentiation and apoptosis of HL-60 and U937 cells and its
      mechanism].
AB  - OBJECTIVES: To explore the effect of hexamethylene bisacetamide (HMBA) on the
      differentiation and apoptosis of HL-60 and U937 cells, and its mechanism.
      METHODS: Flow cytometry was used to evaluate the expressions of cellular surface
      antigen CD(11b), CD(14), apoptotic marker Annexin V, cell cycle distribution and
      endocytic antigen cyclin D, cyclin E and p27. Changes of c-myc, Rb, Bcl-2 gene
      mRNA levels were detected by RT-PCR. RESULTS: After 72 hours of HMBA treatment,
      CD(11b) expressions increased significantly, apoptosis increased under high-dose
      HMBA, cells were arrested in G(0)/G(1) phase and reduced cyclin E, increased
      cyclin D and p27 were significant in a dose-dependent manner in HL-60 and U937
      cells. RT-PCR showed that c-myc and bcl-2 mRNA was significantly down-regulated
      and Rb mRNA up-regulated in HL-60 and U937 cells. CONCLUSION: HMBA can induce the
      differentiation of HL-60 and U937 cells, while apoptosis of these cell is induced
      only by high dose of HMBA. The possible mechanism of HMBA inducing
      differentiation might be related to the changes of cell cycle regulators and
      certain proliferation and differentiation related genes.

PMID- 15182585
TI  - [Bone marrow morphologic features in patients treated with imatinib for
      Philadelphia chromosome positive chronic myeloid leukemia].
AB  - OBJECTIVES: To assess bone marrow morphologic changes in Philadelphia-chromosome
      positive chronic myeloid leukemia (Ph(+)-CML) patients treated with Imatinib, and
      to evaluate the correlation of the morphologic changes with hematological or
      cytogenetic responses. METHODS: One hundred and seventeen patients with Ph(+)
      CML: 54 in chronic phase but failed to interferon-alpha treatment, 41 in
      accelerated phase, 22 in blastic phase received oral administration of Imatinib
      400 or 600 mg once daily for more than 18 months. RESULTS: All of the patients
      responded to the treatment, including complete hematological response, bone
      marrow response and return to chronic phase, bone marrow cellularity and
      myeloblast count reduced significantly to non-CML picture. Myeloid/erythroid
      ratio and megkaryocyte count were decreased significantly in most patients in
      chronic and accelerated phases (P < 0.05). Bone marrow hypoplasia or aplasia was
      associated with lower cytogenetic response rates in patients in chronic phase
      (58.8% vs 86.5%, P = 0.035), lower complete hematological response in patients in
      accelerated phase (26.3% vs 75.0%, P = 0.004), and 6-month overall survival in
      patients in blastic phase (77.8% vs 16.7%, P = 0.009). Patients in advanced stage
      obtained non-CML marrow picture in 1 month of treatment had better prognosis. 18
      month disease progression rates were lower (25% vs 75%, P = 0.028) and overall
      survival rates higher (75.0% vs 11.8%, P = 0.004) in patients obtained non-CML
      picture marrows than in those with CML marrows picture in accelerated phase.
      Hematological response rate and overall survival of more than 6 months were
      higher in patients with non-CML marrows picture than those with CML marrows
      picture (100.0% vs 40.0%, P = 0.017 and 83.3% vs 26.7%, P = 0.046 respectively)
      in blastic phase. CONCLUSIONS: Normal marrow appearance can be sustained under
      continuous treatment of Imatinib in CML patients who achieved hematological
      responses.

PMID- 15182586
TI  - [Changes of the migration ability of the cord blood CD(34)(+) cells during short
      term ex vivo expansion].
AB  - OBJECTIVE: To study the effect of ex vivo expansion on the migration ability and
      the CXCR4 expression of umbilical cord blood (CB) hematopoietic stem/progenitor
      cells (HSPC). METHODS: CD(34)(+) cells isolated from fresh CB samples were
      cultured in a serum-free and stroma-free culture system. On day 7, 10 and 14,
      CD(34)(+) cells were re-selected from the expanded cells, and the expression of
      CXCR4 and the transmigration ability of these CD(34)(+) cells were evaluated
      respectively and compared with those of the precultured fresh CD(34)(+) cells.
      RESULTS: (1) SDF-1 induced a higher migration percentage of fresh or expanded CB
      CD(34)(+) cells than that of uninduced ones. (2) Both of the uninduced and SDF-1
      induced migrations were slightly reduced in the first week and then much more
      reduced in the second week expansion (P < 0.05). (3) The number of the
      CD(34)(+)CXCR4(+) cells were significantly increased during the culture period,
      but there was a downtrend of CXCR4 expression on CD(34)(+) subset; the expression
      levels on day 10 and 14 were lower than that on day 0. CONCLUSIONS: The expanded
      HSPC would sustain the chemotactic activity during one-week-culture, but with
      further extended culture time their intrinsic homing potential would be partly
      impaired.

PMID- 15182587
TI  - [Study of gene expression profile of chronic myeloid leukemia in chronic and
      blastic phases].
AB  - OBJECTIVE: To study the gene expression profile of chronic myeloid leukemia (CML)
      in chronic and blast phases for providing information about the potential
      mechanisms of blastic crisis. METHODS: The gene expression difference of bone
      marrow mononuclear cells between CML in chronic and in blastic phases was
      examined with DNA array. RESULTS: In the blastic phase, 68 genes were obviously
      up-regulated in the 1176 tested genes. Among the 68 genes, the transcription
      factors accounted for 23.5%, cell surface antigens 22.1%, regulation proteins
      19.1% and others 35.3%. There were 17 genes expressed only in the blastic phase
      and 11 (16.2%) genes related to G protein. CONCLUSIONS: Obvious difference of
      gene expression profile existed between chronic and blastic phases of CML. Up
      regulation of gene expression is one of the characteristics of CML in blastic
      phase. The genes related to G protein may play an important role in the blastic
      transformation of CML.

PMID- 15182589
TI  - [Hematopoietic stem/progenitor cells and phenotypes of lymphocyte subpopulations
      in human placenta].
AB  - OBJECTIVE: To study whether human placenta contains hematopoietic stem/progenitor
      cells (HSPCs), and analyze phenotypes of lymphocyte subpopulations in the
      placenta. METHODS: Nucleated cells from fresh human placenta were analyzed for
      phenotypes of HSPCs and lymphocyte subpopulations by flow cytometry (FCM). And
      CD(34)(+) cells were sorted from human placenta nucleated cells by FCM or
      MiniMACS. RESULTS: (1) CD(34)(+) cells, CD(34)(+)/CD(38)(+) cells, and
      CD(34)(+)/CD(38)(-) cells from a human placenta were 8.8, 4.6 and 11.9 times
      higher than those from umbilical cord blood (UCB), respectively. (2) The yields
      and purity of CD(34)(+) cells isolated from human placenta by FCM sorting system
      were (63.05 +/- 10.14)% and (86.39 +/- 11.27)%, respectively. (3) Lymphocytes, T
      cells (CD(3)(+)/CD(2)(+)), B cells (CD(19)(+)), Th cells (CD(3)(+), CD(4)(+)),
      and Th/Ts ratio in the placenta tissue were apparently lower than those in the
      UCB, while the CD(8)(+)/CD(28)(-) T suppressor cells were higher in the placenta
      than in the UCB. CONCLUSIONS: Human placenta is rich in HSPCs, and has important
      hematopoietic function in ontogeny. It is probable that human placenta would be
      graft resource for HSPCs transplantation. CD(8)(+)/CD(28)(-) T suppressor cells
      might play an important role in feto-maternal immunologic tolerance.

PMID- 15182588
TI  - [Effect of ATRA and DNR on the expression and secretion of VEGF in leukemic
      cells].
AB  - OBJECTIVE: To investigate the expression of VEGF mRNA and secretion of VEGF
      protein in NB4 and HL-60 cells affected by all-trans retinoic acid (ATRA) and
      daunorubincin (DNR) respectively. METHODS: Semi-quantitative RT-PCR and ELISA
      were used to study the expression of VEGF mRNA and secretion of VEGF protein in
      NB4 and HL-60 cell lines treated by ATRA and DNR respectively. RESULTS: VEGF was
      expressed in both NB4 and HL-60 cells. The expression of VEGF mRNA and secretion
      of VEGF protein could be down-regulated by ATRA and DNR respectively in a time
      and dose dependent manner. CONCLUSION: Besides inducing apoptosis and restraining
      proliferation of leukemic cells, ATRA and DNR exerted their anti-leukemia effects
      by reducing angiogenesis via reduction of angiogenic reaction stimulating
      signals.

PMID- 15182597
TI  - Spontaneous coronary artery dissection: an uncommon but dangerous condition.

PMID- 15182598
TI  - Acute coronary syndromes in women: is treatment different? Should it be?
AB  - The vast majority of acute coronary syndrome (ACS) trials conducted over the past
      two decades support the view that women have persistently higher mortality and
      morbidity despite the introduction of new medical therapies and devices. Even
      after adjustment for older age, higher prevalence of diabetes, hypertension,
      heart failure, smaller vessel size, and late presentation, some studies still
      point to a persistent sex disadvantage. Even in contemporary practice, women
      continue to have longer delays in presentation and treatment. Selection bias in
      unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) trials allows
      inclusion of large numbers of women with clinically insignificant coronary
      disease and may mistakenly shift results toward apparent benefit of a less
      aggressive approach. This bias causes further difficulty in determining efficacy
      and safety of new antithrombotic agents such as direct thrombin inhibitors and
      glycoprotein IIb/IIa inhibitors across the spectrum of ACS. In trials of
      UA/NSTEMI, use of objective evidence of ischemia such as elevated troponin
      levels, would greatly assist the determination of efficacy and benefit in women.
      Enrollment of more women in clinical trials and timely sex-specific analysis
      would promote a better understanding of the role of female gender in ACS and
      would facilitate better care of all patients.

PMID- 15182600
TI  - Eplerenone: will it have a role in the treatment of acute coronary syndromes?
AB  - Aldosterone is known to have multiple adverse cardiovascular effects that are
      reminiscent of but independent from angiotensin II. These effects include
      endothelial dysfunction, heightened thrombogenicity, inflammation, and reparative
      fibrosis, and have been described in experimental and human models of aldosterone
      excess. Recently a number of clinical investigations have demonstrated that
      mineralocorticoid receptor (MR) antagonism, even in conditions not traditionally
      associated with systemic activation of the renin-angiotensin II-aldosterone
      pathway, may provide additional benefits above and beyond angiotensin-converting
      enzyme (ACE) inhibition and angiotensin receptor blockade. The Eplerenone
      Neurohormonal Efficacy and Survival Study (EPHESUS) with eplerenone in patients
      who were post-myocardial infarction underscores the additive benefit of such a
      strategy in post-infarction patients that typify an at-risk population for
      recurrent cardiovascular events. The mechanisms operative in acute coronary
      syndromes (ACS), including inflammation, altered hemostasis, and endothelial
      dysfunction, overlap significantly with those seen in the EPHESUS patient
      population. One may therefore hypothesize that MR antagonism with eplerenone may
      be beneficial in patients with ACS. Another advantage of using eplerenone is that
      it offers the advantages of MR antagonism without the side effects due to
      blockade of other nuclear receptors such as the androgen and progesterone
      receptors. If MR blockade is found to be beneficial in patients with ACS, the
      potential reduction in morbidity, mortality, and health care costs are profound.

PMID- 15182599
TI  - Markers to define ischemia: are they ready for prime time use in patients with
      acute coronary syndromes?
AB  - Optimal treatment of patients who present with chest pain is predicated on
      accurate identification of those patients with a cardiac etiology of their
      discomfort. Serial troponins and electrocardiograms are very sensitive for the
      detection of myocardial infarction but they are insensitive for the detection of
      ischemia. There are many analytes that are being actively evaluated for routine
      use to facilitate the identification of patients with myocardial ischemia. At
      present, only one assay is US Food and Drug Administration-approved for the
      exclusion of ischemia; many other analytes are under clinical evaluation and are
      briefly reviewed. At present, none of these analytes are yet appropriate for
      routine clinical use.

PMID- 15182601
TI  - Clopidogrel: how good is it and how does it work?
AB  - Until recently, long-term antiplatelet therapy for the treatment and prevention
      of the complications of atherothrombotic disease was limited to aspirin. Although
      an incredibly cost-effective therapy, in placebo-controlled clinical trials
      approximately 75% of patients at risk continue to experience thrombotic events
      despite chronic aspirin therapy. The availability of the thienopyridines, in
      particular clopidogrel, represents an important addition to the physician's
      armamentarium. A number of clinical trials have confirmed the efficacy of the
      combination of clopidogrel and aspirin therapy compared with aspirin alone, with
      multiple other important large-scale clinical trials currently ongoing. The exact
      mechanism of this benefit is still being elucidated but is clearly related to the
      inhibition of the many consequences of platelet activation--vascular
      inflammation, endothelial dysfunction, and localized angiogenesis/mitogenesis-
      and not just aggregation.

PMID- 15182602
TI  - Antithrombotic therapy and the invasive cardiac catheterization management
      strategy: the intracoronary stenting with antithrombotic regimen cooling-off
      trial.

PMID- 15182603
TI  - Moderate versus aggressive lipid lowering with statins following an acute
      coronary syndrome: the pravastatin or atorvastatin evaluation and infection
      therapy trial.

PMID- 15182604
TI  - Individualizing therapy in acute coronary syndromes: using a multiple biomarker
      approach for diagnosis, risk stratification, and guidance of therapy.
AB  - Patients with non-ST-elevation acute coronary syndromes (ACS) are typically
      grouped together and treated with similar approaches to therapy despite
      tremendous variability in clinical presentation and prognosis. The cardiac
      troponins are biomarkers of myocardial necrosis that have recently been evaluated
      in conjunction with markers of neurohormonal activation such as brain natriuretic
      peptide, and markers of systemic inflammation such as C-reactive protein, to
      further characterize risk in the individual patient presenting with ACS.
      Measurement of biomarkers that reflect different components of the underlying
      pathophysiology appears to provide independent and complementary risk
      stratification information in patients with non-ST-elevation ACS. This review
      summarizes the rationale for a multimarker approach to risk stratification in ACS
      and also discusses other cardiac biomarkers under active investigation. One of
      these of particular interest is soluble CD40 ligand, a biomarker that may not
      only indicate active inflammation and platelet activation associated with ACS,
      but may also exhibit direct prothrombotic properties that mediate early
      atherogenesis, plaque rupture, and thrombosis.

PMID- 15182605
TI  - Current concepts in the antithrombotic management of non-ST-elevation acute
      coronary syndromes.
AB  - The recognition that thrombosis is fundamental to acute coronary syndromes (ACS)
      has inspired the development of novel therapies to inhibit platelet aggregation
      and thrombus formation. Several recent advances have been made in the management
      of patients with non-ST-segment elevation ACS (NSTE ACS) to improve early and
      late clinical outcomes. The research efforts leading to these improvements in
      care have focused on antiplatelet and anticoagulant therapies coupled with early
      invasive treatment options. In particular, ongoing clinical trials seek to refine
      treatment strategies for patients relative to individual risk presentation, the
      availability of facilities for invasive procedures, and the timing of
      revascularization. However, even despite the proven efficacy of currently
      available therapies to reduce the occurrence of death and/or myocardial
      infarction, still many eligible patients with high-risk NSTE ACS do not receive
      such treatments. This review provides a pathophysiologic rationale for
      antithrombotic therapies in ACS, examines the results of recent trials, and
      presents future directions for clinical investigation.

PMID- 15182606
TI  - Use of the early invasive approach in the management of acute coronary syndromes.
AB  - Large randomized clinical trials of early invasive versus conservative strategy
      in patients with non-ST-elevation acute coronary syndromes (NSTE ACS) have been
      published recently. These studies have clearly shown that intermediate and high
      risk patients presenting with NSTE ACS have better outcomes when referred early
      to cardiac catheterization. Patients who are referred early to cardiac
      catheterization have a reduction of death, myocardial infarction, and recurrent
      ischemia, and also have shorter hospital stays. Guidelines recommend referral to
      cardiac catheterization for intermediate and high-risk NSTE ACS patients within
      the first 48 hours of presentation. Despite these recommendations, data from a
      large nationwide registry show that the majority of high-risk patients with NSTE
      ACS are not being managed with an early invasive strategy.

PMID- 15182607
TI  - Transport and centralization of acute coronary syndrome care.
AB  - Primary percutaneous coronary intervention (PCI) is the optimal treatment for
      patients presenting with ST-elevation myocardial infarction (STEMI). But PCI
      facilities are not widely available, and the majority of patients who receive
      reperfusion therapy are treated with thrombolytic therapy. However, with
      significant improvements in the procedural success of PCI, there has been a
      concomitant reduction in the need for emergency bypass surgery and there is
      evidence to support primary PCI without on-site cardiac surgical facilities.
      Others have proposed immediate transfer to a suitable hospital for immediate
      primary PCI. An alternative treatment strategy is facilitated PCI, which might
      combine the early benefits of thrombolysis with the higher patency rates and
      superior clinical outcomes of primary PCI, although this remains unproven.
      Finally, rescue PCI remains a reasonable treatment option for patients with
      failed thrombolysis, but there is insufficient evidence to support this option as
      a preferred treatment strategy for patients with STEMI.

PMID- 15182609
TI  - Morphological observation of immunological alterations in the spleens from
      estrogen receptor deficient mice.
AB  - AIM: To evaluate some immunological parameters in the spleens from estrogen
      receptor(ER) deficient mice. METHODS: Immunohistochemistry and immunofluorescence
      analysis were used in the study. RESULTS: Multiple alterations were found in the
      spleens of ER deficient mice, especially in ERbeta deficient mice, such as
      increased expression of proinflammatory cytokines and inducible nitric oxide
      synthase, elevated number of proliferating splenocytes and increased IgM/IgG
      production. Moreover, The splenocytes lack of ERbeta were resistant towards
      estrogen's suppression on proliferation. The activation of nuclear factor (NF)
      kappaB in ERbeta deficient spleens may account for the above hyperactivity.
      CONCLUSION: ER, especially ERbeta, plays a key role in mediating the modulation
      of immune response by estrogen. ERbeta disruption may increase the sensibility
      towards autoimmune diseases.

PMID- 15182608
TI  - The evaluation and management of dyslipidemia and impaired glucose metabolism
      during acute coronary syndromes.
AB  - Dyslipidemia and hyperglycemia are common among patients presenting with acute
      coronary syndromes (ACS), and patients with ACS and metabolic disorders are at
      increased risk for worse outcomes. Although guidelines for the diagnosis and
      management of dyslipidemia, diabetes, and the metabolic syndrome have been
      published, these guidelines have not specifically focused on the ACS patient
      population. Recent observational registries and clinical trials have advanced the
      appreciation of these disorders in ACS populations and data from these studies
      support aggressive efforts to diagnose and treat dyslipidemia and hyperglycemia
      in patients admitted for ACS.

PMID- 15182610
TI  - [The cloning of human augmentor of liver regeneration-interacting proteins].
AB  - AIM: To screen human augmentor of liver regeneration(hALR)-interacting proteins
      and to explore the mechanisms of hALR in liver regeneration. METHODS: The open
      reading frame of hALR was used to construct the "bait" plasmid and the genes
      encoding hALR-interacting proteins were screened from the human liver cDNA
      library that was pretransformed into yeast Y187 by yeast two-hybrid system.
      Bioinformatic analysis of the sequences of the positive clones were performed.
      RESULTS: The positive clones encoding metallothionein, albumin, selenoprotein
      P,Na/K-ATPase, and 2 unknown proteins were screened out. CONCLUSION: The
      successful cloning of the genes encoding proteins interacting with hALR may pave
      the way for studying the interaction between the above proteins and hALR, and the
      molecular mechanisms of biological effect of hALR.

PMID- 15182611
TI  - [Construction of eukaryotic expression vector of hdll1(ext)-Fc and its expression
      in COS-7 cells].
AB  - AIM: To construct an eukaryotic expression vector pEF-BOSneo-hdll1(ext)-Fc, and
      to express the fusion protein consisting of the extracellular region of delta
      like1 and Fc fragment of human IgG1 in COS-7 cells. METHODS: The extracellular
      region of human delta-like1 was amplified from a human brain cDNA library by PCR.
      The expression vector was constructed by DNA recombination. The recombinant
      plasmid was transfected into COS-7 cells via liposome mediation. The expression
      of the fusion protein was detected by RT-PCR, immunofluorescence assay and
      sandwich ELISA. RESULTS: DNA sequencing and restriction endonuclease digestion
      analysis indicated that the eukaryotic expression vector pEF-BOSneo-hdll1(ext)-Fc
      had been constructed successfully. After recombinant plamid had been transfected
      into COS-7 cells, RT-PCR and DNA sequencing verified that the dll1(ext) gene and
      IgG1Fc gene were fused correctly. The results of immunofluorescence assay were
      positive and the fusion protein could be detected by sandwich ELISA in culture
      supernatant of transfected COS-7 cells. CONCLUSION: hdll1(ext) was successfully
      cloned and expressed in the form of Fc fusion protein, which is helpful for
      further study of the function of Notch pathway.

PMID- 15182612
TI  - [Construction of recombinant vector pEGFP-ANG and expression of angiogenin gene
      in HUVECs].
AB  - AIM: To express the recombinant angiogenin protein in mammalian cells. METHODS:
      Human ANG full-length cDNA was obtained by chemical synthesis. The target gene
      ANG was inserted into eukaryotic expression vector pEGFP-C2. The recombinant
      plasmid was transfected into the human umbilical vein endothelial cells (HUVECs)
      via Lipofectin transfection. The expression of ANG gene in transfected HUVECs was
      detected by fluorescence microscopy and immunohistochemical staining. RESULTS:
      DNA sequencing showed the sequence of the synthetic ANG was correct and amino
      acid sequence of ANG was right. The green fluorescence could be seen in
      transfected HUVECs under fluorescence microscope. Immunohistochemical staining
      detection showed that ANG expressed in transfected cells. CONCLUSION: Human ANG
      full-length cDNA has been obtained. The ANG protein was expressed in mammalian
      cells successfully.

PMID- 15182613
TI  - [The cloning and expression of the truncated human bid gene and its pro-apoptotic
      effect on Hela cells].
AB  - AIM: To explore the expression of the truncated bid gene and its pro-apoptotic
      effect on Hela cells. METHODS: A full-length human bid gene was cloned by RT-PCR
      and confirmed by sequence analysis. By deleting the 60 amino acids of N-terminal
      the truncated bid (tbid) gene was obtained and then inserted into the eukaryotic
      expression vector pIRES2-EGFP. After the tbid gene was transfected into Hela
      cells under lipofectamine mediation, the effect of target gene expression on
      morphology and growth of Hela cells were observed under fluorescence and electron
      microscopes and analysed by TUNEL staining. RESULTS: pIRES2-EGFP containing tbid
      gene was constructed successfully. After Hela cells were transfected with GFP
      expression vector of tbid gene, tbid was expressed which was followed by
      decreased cell fluorescence intensity, poor cell growth, and cell death. Cell
      shrinkage and nuclear condensation, typical apoptotic characteristics, were
      observed by electron microscope observation and Tunel staining. CONCLUSION: The
      expression of tbid can effectively induce apoptosis of Hela cells.

PMID- 15182614
TI  - [Tumor suppression of a constitutively active caspase-3 in the SKBr-3 breast
      carcinoma xenograft mice model].
AB  - AIM: To explore the apoptosis-inducing effect of a constitutively active caspase
      3 molecule on human breast carcinoma SKBr-3 cells. METHODS: A revcaspase-3 gene
      was generated by arranging the coding sequence of the small subunit preceding
      that of the large one, i.e. in a reverse order of the wild-type caspase-3 gene. A
      pcDNA3-revcaspase-3 plasmid was constructed and transfected into SKBr-3 cells,
      and the proapoptotic effect of revcaspase-3 was examined by morphological
      observation of the cells, cell counting and flow cytometry analysis. The in-vivo
      tumor suppression was further evaluated following i.t. administration of pcDNA
      revcaspase-3, while the apoptosis in tumor tissues was assayed using TUNEL.
      RESULTS: The apoptosis of SKBr-3 cells was induced after introduction of the
      revcaspase-3 gene, and tumor growth was strongly suppressed following injection
      of the pcDNA3 vector harboring revcaspase-3 gene. Revcaspase-3 was expressed in
      the cells of tumor tissues and apoptosis of the tumor cells was confirmed by
      TUNEL assays. CONCLUSION: Apoptosis of SKBr-3 cells in a mouse tumor model could
      be induced by in-vivo expression of a revcaspase-3 gene.

PMID- 15182615
TI  - [In-vivo tracing of bone marrow stromal cell differentiating into chondrocytes by
      green fluorescent protein gene transfection].
AB  - AIM: To achieve highly efficient, stable and long-term expression of green
      fluorescent protein(GFP) reporter gene in bone marrow stromal cells(BMSCs) and to
      trace directly the distribution and differentiation of BMSCs in articular
      cartilage defects. METHODS: Recombinant RV-GFP expression vector was constructed
      and transfected into packaging cell PT67. After G418 screening and amplification,
      cell clones producing high level recombinant viruses were obtained and in-vitro
      expanded. The virus supernatant from infected PT67 cell culture was used to
      infect BMSCs directly. Autologous GFP-labeled BMSCs were seeded onto
      biodegradable polymer and implanted into porcine articular cartilage defects. 7
      months later, the repaired tissue was evaluated by confocal microscope. RESULTS:
      The constructed recombinant expression vector RV-GFP was identified by
      restriction digestion. The transfection rates of PT67 cells reached 20%-50%,
      which reached 100% after G418 screening, bright green fluorescence could be seen
      under fluorescence microscope. BMSCs could be transfected successfully by the
      culture supernatant from infected PT67 cells and GFP was expressed efficiently in
      a long-term period. Confocal microscope revealed that GFP-labeled cells existed
      in many neocartilage lacunae after 7 months. CONCLUSIONS: The recombinant vector
      RV-GFP can provide a simple, sensitive and reliable tool to label BMSCs which can
      be used to study cytologic dynamic follow-up in-vivo. BMSCs can differentiate
      into chondrocytes and play an important role in repairing articular cartilage
      defects.

PMID- 15182616
TI  - [The effects of glycyrrhizin-18alpha on the expression of NF-kappaB in the renal
      interstitium of rats with obstructive nephropathy].
AB  - AIM: To investigate the effects of glycyrrhizin-18alpha on the expression of
      nuclear factor-kappaB in the renal interstitium of rats with obstructive
      nephropathy. METHODS: Obstructive nephropathy model of rats was set up by
      unilateral ureteral ligation. The rats were sacrificed 7,14, 28 and 56 days after
      operation. And then specimens were taken from the renal cortex. The morphological
      changes in renal interstitium were observed under light and electron microscopes.
      The expression of nuclear factor-kappaB and type III collagen was detected by
      immunohistochemical staining and analyzed by EIG image analysis system. RESULTS:
      Progressive fibrosis was observed in the renal interstitium of rats with
      obstructive nephropathy. The semi-quantitative analysis indicated that the
      expression level of NF-kappaB and type III collagen in the renal interstitium of
      glycyrrhizin-18alpha treatment and prophylaxis groups was markedly higher than
      that of mock operation group (P<0.01) and remarkably lower than that of normal
      saline control group(P<0.01) 7 days after operation. No significant difference in
      the expression of NF-kappaB and type III collagen was detected between
      glycyrrhizin-18alpha treatment group and prophylaxis group(P>0.05). CONCLUSION:
      Glycyrrhizin-18alpha may prevent renal interstitial fibrosis in obstructive
      nephropathy by down-regulating the expression of NF-kappaB in renal interstitium.

PMID- 15182617
TI  - [Screening anti-adhesion polypeptides from phage peptide library].
AB  - AIM: To screen the active peptides which can suppress adhesion of monocytes to
      endothelial cells(ECs) from a random peptide phage library. METHODS: The ECs
      injured by oxidized low density lipoprotein (ox-LDL) 100 mg/L was used as target
      cells and polypeptides specifically binding to the injured ECs were isolated from
      the phage-displayed peptide library. The positive clones were characterized by
      ELISA, and the amino acid sequences of the peptides were deduced by DNA
      sequencing. Cell counting was used to evaluate the adhesion rate between ECs and
      monocytes. RESULTS: Six positive clones specifically binding to injured EC were
      isolated. Four of them contained a repeated sequence of leucine-leucine. Among
      the four clones, two had an identical sequence, which could reduce the adhesion
      rate of monocytes to ECs by 17%. CONCLUSION: One peptide which can suppress
      adhesion of monocytes to ECs is isolated from a random peptide phage library.

PMID- 15182618
TI  - [Apoptosis and modulatory mechanism of human AHH-1 T lymphocytes induced by gamma
      irradiation].
AB  - AIM: To explore the apoptotic characteristics and modulatory mechanism of human
      AHH-1 T lymphoblast induced by ionizing radiation and provide an experimental
      basis for preventing and treating immune damage in acute radiation sickness.
      METHODS: TdT-mediated dUTP nick end labeling (TUNEL) and May-Grunwald Giemsa
      (MGG) staining, MTT colorimetry and immunohistochemical staining were used to
      detect the T lymphocyte apoptosis, cell survival and the expressions of Bax, Bcl
      XL and caspase-3 proteins. RESULTS: (1) Over a definite dose range, apoptotic
      rate of AHH-1T lymphocytes increased with the elevation of radiation doses, while
      the lymphocytic survival rate decreased sharply, both showing a good dose-effect
      relationship. (2) The expression of apoptosis-accelerating protein Bax enhanced
      obviously with the increase of radiation doses, while apoptosis-inhibiting
      protein Bcl-XL trended to persistent decline. (3)The activity of activated
      apoptosis-executing protein caspase-3 heightened significantly with increased
      radiation doses, which revealed a better corresponding relationship to apoptotic
      rate. CONCLUSION: A great number of apoptotic AHH-1 T cells may be one of major
      accounts for the lymphocyte rapid reduction and depressed organism immune
      function induced by irradiation. Bax, Bcl-XL and caspase-3 proteins play an
      important role in the regulation of radiation-induced T cell apoptosis.

PMID- 15182619
TI  - [Participation of ICAM-1 in the cytotoxicity of TM-TNF-alpha mediated by TNF
      receptor I].
AB  - AIM: To identify membrane-associated molecules involved in the tumoricidal
      cytotoxicity of TM-TNF-alpha and to explore the molecular mechanism underlying
      the tumoricidal cytotoxicity of TM-TNF-alpha and differences of biological
      effects between TM-TNF-alpha and sTNF. METHODS: Antibody blocking test and RT-PCR
      were used to evaluate the role of ICAM-1 and VCAM-1 in the cytotoxicity of TM-TNF
      alpha mediated by TNFR I or TNFR II. RESULTS: After the ICAM-1 expressed on the
      membrane of MCF-7 cells(expressing TNFRI) was blocked, the cytotoxicity of TM-TNF
      alpha to this cell lines decreased significantly, while blocking VCAM-1 had no
      effect. Blocking ICAM-1 or VCAM-1 expressed on the membrane of HL-60
      cells(expressing TNFRII)had no significant effects on the cytotoxicity of TM-TNF
      alpha to this cell lines. CONCLUSION: ICAM-1 participates in the cytotoxicity of
      TM-TNF mediated by TNFRI.

PMID- 15182620
TI  - [Preventive and therapeutic effect of genetic vaccine based on recombinant alpha
      virus against mouse mastocytoma P815].
AB  - AIM: To explore the immunological effect of genetic vaccine based on alpha-virus
      and to seek out better forms of gene vaccines. METHODS: Expression plasmid
      P1A/pSMART2a and packaging plasmid helper were cotransfected into mammalian 293
      cells by calcium phosphate precipitation method and high level of recombinant
      alpha-virus P1A/SFV was prepared. Following identification of rSFV and its
      expression, BALB/c mice were inoculated with rSFV, and the production of antigen
      specific antibody and the cytotoxic effect of CTLs were determined. In the
      preventive and therapeutic experiments, the percents of tumor-free and of
      survival mice immunized with rSFV were observed. RESULTS: The recombinant SFV
      could express correctly in cultured cells. After being inoculated into the mice,
      rSFV could prime stronger CTL response than that in control mice. When the ratio
      of E/T cells was 100:1, the (51)Cr release rate reached 75%. No antibody could be
      detected in mice from all groups. The immunological effect of P1A/SFV among all
      groups was the best in both preventive and therapeutic experiment within
      experimental deadline. On 60th day in preventive experiment, the percent of tumor
      free animal in P1A/SFV group reached 60%, whereas that was only 20% in P1A/pCI
      neogroup. On 60th day in therapeutic experiment, survival rate of mice in P1A/SFV
      group reached 50%, but only 10% mice could survive in all control groups.
      CONCLUSION: Compared with common gene vaccines, the genetic vaccine based on
      recombinant SFV has the best immunological effect, which provides some new
      strategies for clinical genetic therapy of tumors.

PMID- 15182621
TI  - [Cloning and eukaryotic expression of mouse interleukin 21].
AB  - AIM: To clone mouse interleukin 21(mIL-21) gene and construct its eukaryotic
      expression vector. METHODS: mIL-21 cDNA was amplified from ConA-activated mouse T
      cells by RT-PCR. And then the cDNA was cloned into eukaryotic expression plasmid
      pcDNA3.1 to construct recombinant plasmid pcDNA3.1/mIL-21 which was introduced
      into Sp2/0 cells by lipofectin. Expression of mIL-21 gene was detected by RT-PCR
      and NK cytotoxicity assay. RESULTS: Recombinant plasmid pcDNA3.1/mIL-21 was
      constructed correctly and mIL-21 gene was expressed in transfected Sp2/0 cells.
      CONCLUSION: mIL-21 gene was cloned and expressed successfully, which lays the
      foundation for further studying anti-tumor effect of mIL-21 gene therapy in
      animal models.

PMID- 15182622
TI  - [Specific promoter activity of CIITA-pI in dendritic cells].
AB  - AIM: To detect whether CIITA-pI can drive reporter gene expression and its
      specific promoter activity in DCs. METHODS: Luciferase reporter system was used
      to detect 112 bp CIITA-pI specific promoter activity in DCs. RESULTS: CIITA-pI
      could drive expression of reporter gene in DCs but not in HEK 293 cells and its
      promoter activity increased with the maturation of DCs. CONCLUSION: Our work
      provides a basis for further study of targeting DC gene therapy using CIITA-pI as
      DC-specific promoter.

PMID- 15182623
TI  - [The change of the erythrocyte chemokine receptor binding activity in the shock
      stage of burn rats].
AB  - AIM: To investigate the change of the erythrocyte chemokine receptor(ECKR)
      binding activity in the shock stage of burn rats. METHODS: SD rats were randomly
      divided into two group, burn and control groups. In the burn group rats, 30%
      total body surface area (TBSA)were scalded to III degree. The binding activity of
      rat ECKR in the shock stage was detected by ELISA using IL-8 as ligand at various
      time points (0.5, 2, 4, 8, 16, 24 and 48 hours) after burn. RESULTS: Compared
      with control group, the binding activity of rat ECKR declined significantly half
      an hour after burn and maintained at low level for 48 hours (P<0.01). The
      comparison of the binding activity of rat ECKR at various time points after burn
      indicated that the binding activity declined gradually from 2 hours (P<0.01
      0.05), reached lowest value 24 hrs, and then rose significantly 48 hrs after burn
      (P<0.01). CONCLUSION: The ECKR binding activity declined significantly after
      burn, suggesting erythrocytes may participate in the regulation of chemokines and
      play some role in the inflammation.

PMID- 15182625
TI  - [The effects of M-CSF and IL-10 on IL-12 and IL-18 production and expressions of
      HLA-DR and CD80 by human monocytes].
AB  - AIM: To explore the effects of M-CSF and IL-10 on IL-12 and IL-18 production and
      expressions of HLA-DR and CD80 by human peripheral blood monocytes. METHODS:
      Human monocytes were isolated from blood of healthy donors, and cultured with M
      CSF and or IL-10 alone or together. Then the monocytes and culture supernatant
      were collected respectively. IL-12 p40 and IL-18 levels in culture supernatant
      were detected by ELISA and the expressions of CD80 and HLA-DR on the monocytes
      were analyzed by FACS. RESULTS: (1)M-CSF induced secretion of IL-18 by the
      monocytes, while IL-10 inhibited the production of IL-18 and antagonized
      enhancement of LPS-induced IL-18 production by M-CSF. Both M-CSF and IL-10
      inhibited secretion of IL-12 p40 by the monocytes and had a synegistic effect in
      the inhibition. (2)M-CSF could induce while IL-10 inhibited HLA-DR expression.
      Moreover, IL-10 had an antagonistic action on HLA-DR expression induced by M-CSF.
      M-CSF had no influence on CD80 expression, while IL-10 induced CD80 expression.
      CONCLUSION: M-CSF and IL-10 can regulate IL-12 and IL-18 production and HLA-DR
      and CD80 expressions by human monocytes, which may affect the activation and
      differentiation of T cells and T cell-mediated immune response.

PMID- 15182624
TI  - [Construction, expression and antigenicity of bivalent vaccine candidate of human
      Helicobacter pylori].
AB  - AIM: To construct a recombinant vector containing fused gene of heat shock
      protein A(HspA) and outer membrane protein(OMP) with M(r) 18,000, from human
      Helicobacter pylori(Hp) and express the fusion protein in E.coli BL21. METHODS:
      The gene encoding HspA was amplified from Hp chromosome by PCR. After digestion
      with kpn I and BamH I, the HspA gene was inserted into the prokaryotic expression
      vector pET32a(+). After recombinant vectors pET32a(+)/HspA and pET32a(+)/Omp (18)
      were digested with Hind III and BamH I, the pET32a(+)/HspA and 18,000 OMP gene
      segments were recovered through agarose electrophoresis, and connected by T4
      ligase. The recombinant vector pET32a(+)/HspA-Omp(18) was transformed into E.coli
      BL21(DE3). The antigenicity of recombinant fusion protein was analysed by Western
      blot. RESULTS: Enzyme digestion analysis and sequencing showed that the fused
      gene had 891 base pairs. As compared with gene reported in GenBank, there were
      1.15% and 1.26% differences in cloned nucleotide sequence and amino acid sequence
      respectively. SDS-PAGE analysis showed that recombinant vector could be expressed
      in E.coli BL21. The relative molecule mass (M(r)) of expressed fusion protein was
      51x10(3). And soluble expression product accounted for 18.96% of total bacterial
      protein.After purification via Ni-NTA agarose resin, the purity of recombinant
      fusion protein was about 95%. The Western blot analysis showed that recombinant
      fusion protein could be recognized by anti-Hp positive serum and anti-18,000 OMP
      mAb, suggesting that this protein had good antigenicity. CONCLUSION: The fused
      gene of HspA and OMP is cloned and expressed successfully, which lays the
      foundation for development of protein and DNA vaccines and a diagnostic kit of Hp
      infection.

PMID- 15182626
TI  - [Analysis of the change in clonotypes of T cells accumulated in 4 feet joints of
      SKG mice].
AB  - AIM: To understand the relationship between T cell clonotypes and RA invasion
      through clonotypes of analysis of T cells accumulated in 4 feet joints of SKG
      mice. METHODS: Comparative analysis of T cells clonotypes of accumulated in the
      joints of SKG mice, a spontaneous RA mouse model, was carried out by RT-PCR/SSCP
      at the initial and late-stages of RA. RESULTS: The identical rate of Vbeta2 and
      Vbeta8.2 T cell clonotypes in 4 feet joints increased significantly at the late
      stage of RA (72.3% and 60.2%, respectively). CONCLUSION: The T cells with Vbeta2
      or Vbeta8.2 TCR may play an important role in the RA development of SKG mice.

PMID- 15182627
TI  - [The mechanism for up-regulation of HLA-I expression on HepG2 cells by HBV].
AB  - AIM: To explore the mechanism of up-regulation of HLA-I expression on HepG2 cells
      by wild type (WT) and nucleocapsid mutants(L97 and V60) of hepatitis B virus
      (HBV). METHODS: The HBV-stable expression vectors EBO-WT, EBO-L97 and EBO-V60
      were transfected into HepG2 cells via the liposome mediation, respectively. The
      cells were assayed by semi-quantitative RT-PCR for HLA-A gene and antigen
      presentation-related genes LMP2, TAP1, and tapasin mRNA expression. Western blot
      was applied for analysis of HLA-I protein expression in the cells. RESULTS: HepG2
      cells transfected by the 3 HBV expression vectors expressed HLA-A and TAP1, while
      there was no expression of HLA-A and only marginal expression of TAP1 in HepG2
      cells transfected by control vector EBO. The expression level of HLA-A in the
      transfected cells decreased successively in the order of EBO-L97, EBO-WT and EBO
      V60. There was no significant difference in the expression level of TAP1 between
      HepG2 cells transfected by the 3 HBV expression vectors. No detectable expression
      of LMP2 and tapasin was observed for all transfected cells. CONCLUSION: HBV can
      induce the expression of HLA-I molecule and TAP1 in HepG2 cells.

PMID- 15182628
TI  - [Construction of a DNA vaccine against human B cell lymphoma].
AB  - AIM: To construct a DNA vaccine based on surface Ig V(H) gene of tumor cells in
      the human B-cell lymphoma biopsy tissue. METHODS: The V(H) gene fragment was
      amplified by RT-PCR using Ig superfamily primers. Also, the murine monocyte
      chemotactic protein 3(MCP-3) cDNA was cloned. The fusion gene fragment of MCP-3
      gene with V(H) gene was constructed by recombinant PCR and then cloned into the
      eukaryotic expression vector pcDNA3.1 to construct the DNA vaccine plasmid
      pcDNA3.1/MCP-V(H). The vaccine plasmid was transiently expressed in the
      eukaryotic cell line COS-7. RESULTS: The DNA vaccine plasmid was successfully
      constructed and expressed in COS-7 cells in the form of fusion protein MCP-V(H).
      CONCLUSION: The DNA vaccine plasmid pcDNA3.1/MCP-V(H) is constructed and
      expressed successfully, which plays the foundation for further experimental
      research in animal model.

PMID- 15182629
TI  - Generation and characterization of monoclonal antibodies against botulinum
      neurotoxin type A (BoNT/A).
AB  - AIM: To generate the monoclonal antibodies(mAbs) against botulinum neurotoxin
      type A (BoNT/A). METHODS: BALB/c mice were intraperitoneally immunized with
      purified BoNT/A-Hc, and the splenocytes of immunized mice were fused with myeloma
      cells Sp2/0. Hybridoma cells were screened by indirect ELISA and monoclonal
      hybridoma cells was obtained using limited dilution. RESULTS: Three hybridomas,
      named 4A8, 2F7 and 4F2, producing the mAbs against BoNT/A, were successfully
      established, and the titer of ascitic mAbs ranged from 1x10(-4) to 1x10(-6).
      Identification of subclass showed that all the produced mAbs belonged to IgG1.
      4A8 and 4F2 were stable in secreting anti-BoNT/A mAbs through three-month
      continuous culture and showed high specificity to recombinant BoNT/A-Hc and
      native BoNT/A. CONCLUSION: Anti-BoNT/A mAbs we generated have high specificity,
      which laid the foundation for the immunological detection of BoNT/A and clinical
      treatment of botulism in the future.

PMID- 15182630
TI  - [Preparation and characterization of monoclonal antibodies against recombinant
      human NDPK-A].
AB  - AIM: To prepare monoclonal antibodies (mAb) against recombinant human nucleoside
      diphosphate kinase-A(NDPK-A) and characterize their properties. METHODS: BALB/c
      mice were immunized with rhNDPK-A, and mAb was prepared by hybridoma technique.
      Ig subclass and specificity was analysed by double immunodiffusion and western
      blot respectively. The titres of mAbs in ascitic fluid, relative affinity and
      epitopes recognized by mAbs were determined by indirect ELISA. RESULTS: 6
      hybridoma cell lines secreting anti-rhNDPK-A mAbs were obtained. Their Ig
      subclass belonged to IgG1. The titers of 6 mAbs in ascitic fluid were 1x10(-4)
      5x10(-6). Relative affinity of mAbs were 4.5x10(-9)-2.8x10(-10) mol/L. They
      recognized 3 different epitopes on rhNDPK-A molecule. CONCLUSION: 6 mAbs against
      rhNDPK-A have been prepared successfully which provide useful reagent for
      clinical diagnosis and further research.

PMID- 15182631
TI  - [Preparation and characterization of rabbit antibody against human selenoprotein
      P].
AB  - AIM: To prepare rabbit antibody against human selenoprotein P (HSelP) by using
      HSelP expressed in the prokaryotic expression system and identify its
      specificity. METHODS: HSelP gene fragment was expressed in E.Coli via IPTG
      induction and purified through DEAE and Ni-NTA columns sequentially. The purified
      HSelP as immunogen was used to immunize rabbit. The specificity of rabbit anti
      HSelP antibody was analyzed by Western blot. RESULTS: HSelP protein had been
      expressed and purified successfully. The polyclonal anti-HSelP antibody could
      specifically recognize natural HSelP from human serum. CONCLUSION: Polyclonal
      anti-HSelP antibody with high specificity and purity has been prepared by using
      purified HSelP as immunogen, which lays the foundation for further research on
      the function and distribution of HSelP, as well as developing a simple method for
      detecting HSelP.

PMID- 15182632
TI  - [Mannosylation of ligand binding domain 2 of HER-2/neu].
AB  - AIM: To establish a new method for protein mannosylation, which will facilitate
      the study of antigen presentation mediated by mannose receptor. METHODS:
      Recombinant HER-2/neu ligand binding domain 2 (LBD2) was purified through DEAE
      sepharose FF column and cobalt-based affinity resins. LBD2 protein was
      mannosylated in-vitro,and then analyzed by MALDI-TOF-MS and resorcinol-sulfuric
      acid method. RESULTS: The purity of LBD2 obtained was 90%. Analysis of MALDI-TOF
      MS and resorcinol-sulfuric acid method suggested LBD2 was mannosylated.
      CONCLUSION: LBD2 neoglycoprotein has been obtained, which lays the foundation for
      the study of antigen uptake and presentation mediated by mannose receptor and the
      development of tumor vaccine.

PMID- 15182633
TI  - [Cloning full-length homologous cDNAs of pollen allergens in Humulus
      Scandens(Lour.) Merr by degenerate primer].
AB  - AIM: To establish a stable and reliable method for fast cloning homologous genes
      of pollen allergens in allergen-containing plants. METHODS: Degenerate primers
      were designed based on the bioinformatic analysis of numerous allergens available
      from the database. Subsequent amplification of the allergen genes was conducted
      in the weed pollen cDNA pool by a selective PCR profile. Following the truncated
      gene cloning, RACE method was used to isolate full-length cDNA. Gene function was
      deduced by sequence alignment in GenBank database. The degenerate ability of the
      primer was compared with the full-length cDNA sequences. RESULTS: Three full
      length cDNAs were obtained. Sequence analysis showed that these new genes shared
      as high as 79%-85% homology with a large amount of known allergen profilins and
      were hence regarded as members of panallergen profilin family. Comparing these
      genes with the degenerate primers that were initially used in truncated gene
      cloning revealed that alternative nucleotide degeneracy occurred beyond the
      degenerate site predesigned, suggesting that further degeneracy was expanded by
      Touchdown-gradient PCR. CONCLUSION: Cloning of homologous genes or allergen genes
      can be efficiently achieved by using the combination of degenerate primer with
      Touchdown-gradient RT-PCR in the species such as Humulus scandens that has not
      yet been investigated.

PMID- 15182634
TI  - [Construction, expression and biologic activities of two rhIL-6/GM-CSF fusion
      proteins].
AB  - AIM: To construct and express the gene encoding hIL-6/GM-CSF fusion protein.
      METHODS: The genes encoding the two hIL-6/GM-CSF fusion proteins were constructed
      in pBV220 expression vector. Fusion proteins were expressed in E.coli BL-21 and
      purified through Q Sepharose HP ion exchange chromatography and Sephacryl S-200
      gel filtration columns. The biologic activities of the fusion proteins were
      detected by proliferation of hIL-6 dependent cell line B9 and hGM-CSF dependent
      cell line TF1 with MTT assay. RESULTS: Both fusion proteins were expressed in
      E.coli BL-21 in the form of inclusion body. The expression levels were more than
      25% of the total cell lysates. Both fusion proteins were obtained with high
      purity which had both hIL-6 and hGM-CSF biologic activities. CONCLUSION: Two hIL
      6/GM-CSF fusion proteins with high purity and bilolgic activities have been
      acquired successfully.

PMID- 15182635
TI  - [Expression, purification and identification of recombinant human lymphotoxin
      alpha deletant (rhLT-alphaDeltaN27)].
AB  - AIM: To construct prokaryotic expression vector of recombinant human lymphotoxin
      alpha deletant (rhLT-alphaDeltaN27) and express the protein in E.coli. METHODS:
      The rhLT-alphaDeltaN27 gene was amplified by RT-PCR using total RNA extracted
      from Jurkat cells,cloned into prokaryotic expression vector pET-23b, and
      transformed into E.coli BL21(DE3). The recombinant protein was expressed after
      IPTG induction and purified by DEAE Sepharose FF and Phenyl-Sepharose FF.
      RESULTS: The recombinant protein was expressed as inclusion bodies with the yield
      of more than 30% of total bacterial protein. After purification, the purity of
      rhLT-alphaDeltaN27 was 99%, and the biological activity was more than 8x10(7)
      U/mg. Other characteristics of rhLT-alphaDeltaN27, such as relative molecular
      mass(M(r)), pI and N-terminal amino acid sequence, all corresponded to
      theoretical prediction. CONCLUSION: The expression vector of rhLT-alphaDeltaN27
      gene was constructed, and the recombinant protein was expressed in E.coli
      successfully.A method of for purifying rhLT-alphaDeltaN27 was established.

PMID- 15182636
TI  - [Effects of total alkaloids of Tongbiling prescription on Th1 type cytokine
      expression in T lymphocytes].
AB  - AIM: To study the effects of total alkaloid of Tongbiling prescription(TBL) on
      Th1 type cytokine expression in T cells in order to elucidate the anti
      inflammatory mechanism of TBL. METHODS: The lymphocytes were isolated from mouse
      mesenteric lymph nodes and cultured in-vitro. Various concentrations of TBL were
      added to the culture followed by phorbol ester and inomycin treatment and then
      incubated for another 4 hours. The expressions of IFN-gamma and TNF-alpha in the
      lymphocytes were analyzed by flow cytometry. RESULTS: 200 mg/L and 100 mg/L TBL
      could obviously inhibit IFN-gamma and TNF-alpha expressions in T lymphocytes.
      CONCLUSION: Inhibiting Th1 cytokine expression may be one mechanism by which TBL
      can treat rheumatoid arthritis.

PMID- 15182637
TI  - [Cloning, expression and antitumor effect of mouse costimulatory molecule 4
      1BBL].
AB  - AIM: To clone mouse 4-1BBL gene, construct its eukaryotic expression vector, and
      evaluate antitumor activity of the expression product. METHODS: RT-PCR was used
      to amplify mouse 4-1BBL gene from total RNA of C57BL/6 splenocytes stimulated by
      PHA. Then m4-1BBL cDNA was subcloned into eukaryotic expression vector
      pcDNA3.1(+) and transfected into mouse hepatocellular carcinoma cell line Hepa1
      6. The expression of m4-1BBL in transfected cells was detected by RT-PCR,
      indirect immunofluorescence staining, and flow cytometry. Non-adherent
      splenocytes from non-immunized C57BL/6 mice were incubated with mitomycin-treated
      non-transfected Hepa1-6(Hepa1-6-wt) or transfected Hepa1-6 cells (Hepal-6-m4
      1BBL), respectively. Then the lymphocytes were tested for cytotoxic activity to
      Hepa1-6-wt cells. RESULTS: The Hepa1-6 cells transfected by pcDNA3.1(+)-m4-1BBL
      could efficiently express m4-1BBL. As compared with Hepa1-6-wt cells,Hepa1-6-m4
      1BBL cells could induce more efficiently cytotoxic activity of lymphocytes to
      Hepa1-6-wt cells (P<0.01). CONCLUSION: The expression of m4-1BBL by tumor cells
      is effective in inducing antitumor immune response.

PMID- 15182638
TI  - [Immunological up-regulation of cyclophosphamide-treated mice by turtle blood
      extract].
AB  - AIM: To explore the effect of turtle blood extract on murine immune system.
      METHODS: We compared the ratio of CD4(+) helper T cells and CD8(+) T cells, NK
      cell activity, lymphocyte proliferation stimulated by mitogen and capability of
      cytokine secretion of cyclosphophamide-treated mice with or without treatment of
      turtle blood extract. RESULTS: Turtle blood extract-treated mice displayed
      increased CD4(+) helper T cell population, stronger cytotoxicity of NK cells and
      enhanced of ConA-induced lymphocyte proliferation. In addition, the capacity of
      IFN-gamma secretion was dramatically up-regulated in turtle blood extract-treated
      mice group. CONCLUSION: Turtle blood extract can upregulate the immune function
      of cyclosphophamide-treated mouse.

PMID- 15182639
TI  - [Influence of bondage stress on Th1/Th2 cytokines and growth of tumors in mice
      bearing S180 tumor cells].
AB  - AIM: To observe the influence of bondage stress on Th1/Th2 cytokines and growth
      of tumor in mice bearing S180 tumor cells. METHODS: 2 x 10(6) S180 tumor cells
      were injected subcutaneously into the murine right oxter,and bondage stress was
      imposed on mice for 8 hours per day,ten days running. Then T lymphocyte
      proliferation was detected by MTT colorimetry. IFN-gamma and IL-2 secreted by
      splenocytes was measured by mitogen-activating lymphoblast assay and macrophage
      NO production assay. At the same time, the levels of IL-4 and IL-10 in serum were
      detected by ELISA, and the weight of the tumors and thymuses were measured.
      RESULTS: Compared with mice only injected with S180 tumor cells, tumor bearing
      mice suffered from bondage stress showed decreased T lymphocyte proliferation,
      thymus index, and levels of IFN-gamma and IL-2, but increased levels of IL-4 and
      IL-10(P<0.05), and tumor weight (P<0.01). CONCLUSION: Bondage stress could
      aggravate the suppression of cellular immunity in mice bearing S180 tumor and
      promote the T cells to shift towards Th2 type cells, which may be one of the
      mechanisms of promoting tumor growth by bondage stress.

PMID- 15182640
TI  - [Construction of eukaryotic expression vector of murine SLC gene and
      characterization of its chemotactic function].
AB  - AIM: To construct the eukaryotic expression vector of murine SLC gene and study
      the chemotactic function of murine SLC in-vitro and in-vivo. METHODS: Murine SLC
      gene was cloned by RT-PCR from the thymus tissue of a C57BL/6 mouse. Eukaryotic
      expression vector of SLC gene-pcDNA3.1 mSLC was constructed and transfected into
      B16F10 cells by gene gun. Culture supernatant was collected 48 hours after the
      transfection and chemotactic function of expression product to lymphocytes was
      detected by a chemotaxis chamber. SLC expression was detected by RT-PCR.
      Lymphocytic infiltration was observed in SLC gene transfected murine abdominal
      skin. RESULTS: The gene cloned from the C57BL/6 mouse thymus tissue was SLC gene
      Scya21b. Transfected cells expressed SLC mRNA, and culture supernatant of those
      cells had a potent chemotactic function to lymphocytes. Histological examination
      of transfected skin showed obvious lymphocytic infiltration. CONCLUSION: The SLC
      gene was cloned from the mouse thymus tissue and could be expressed in B16F10
      cells. The expression product in-vitro and in-vivo had a remarkable chemotactic
      function to lymphocytes.

PMID- 15182641
TI  - [Cloning of a DnaJ homolog chaperon PBP and its subcellular localization].
AB  - AIM: To isolate and identify a human DnaJ homolog chaperon, PBP, from a human
      skeleton cDNA library, and to analyze its expression and distribution in
      transfected mammalian cells. METHODS: (32)p-dCTP labeled probe hybridization was
      used to screen the human skeleton cDNA library and sequence of the positive
      clones were analyzed. Then PBP gene was transfected into COS-7 cells using
      lipofectamin. PBP expressed in the cells were detected by Western-blot and
      indirect immunofluorescence staining. RESULTS: A full-length(1.5 kb) cDNA of
      peripherin-binding protein (PBP) was identified, which is identical with that of
      mrj. Full length PBP was mainly localized to cytoplasms of COS-7 cells in
      interphase, and to nuclei in mitosis. CONCLUSION: The results indicate that
      besides cooperating with DnaK (HSP70), PBP itself plays an important role as a
      member of DnaJ family. PBP may also be involved in the regulation of cell cycle.

PMID- 15182642
TI  - [Expression and biological activities of TRAIL fusion protein gene].
AB  - AIM: To obtain and express the full-length of TRAIL gene in prokaryocytes.
      METHODS: The full-length of TRAIL gene was amplified from peripheral blood
      cells(PBCs)by RT-PCR and then cloned into the expression vector pGEX-2T. The
      TRAIL-GST was expressed in E.coli. RESULTS: Sequence analysis indicated that the
      sequence of TRAIL gene was identical with that in the GenBank. The TRAIL-GST was
      expressed in E.coli. Expressed product could inhibit the proliferation of KB and
      Hela cells and finally lead to their apoptosis. CONCLUSION: The TRAIL-GST with
      biological activity has been expressed in the prokaryotic system.

PMID- 15182644
TI  - [Establishment and characterization of human alloantigen induced T cell clones].
AB  - AIM: To estabilish and analyze stable human T cell clones cultured in-vitro.
      METHODS: The activated T cells from mixed lymphocyte culture (MLC) were cloned by
      limiting dilution using irradiated PBMCs as feeder cells. T cell clones were then
      characterized by immunofluorescence staining and flow cytometry analysis.
      RESULTS: 16 clones were obtained, of which all but one were alphabetaT cells.
      Among the 15 alphabetaT cell clones, 9 clones belonged to Th subset, including 3
      Th0 and 6 Th2, and 6 clones belonged to Tc subset, including 5 Tc0 and 1 Tc2.
      CONCLUSION: Fifteen human T cell clones were successfully established, which lays
      the foundation for study on markers and function of Tc1 and Tc2 subsets.

PMID- 15182643
TI  - [Preparation and preliminary characterization of soluble HLA-A2-peptide complex].
AB  - AIM: To express HLA-A2 heavy chain (HC) and light chain beta(2m) in bacteria and
      to prepare soluble HLA-A2-peptide complex. METHODS: HC and beta(2m) expressing
      engineering bacteria was induced for 5 h with 0.5 mmol/L IPTG. After sonification
      of the bacteria,crude inclusion body was obtained which was then refined,
      renaturated, ultrafiltrated, and purified by DEAE Sepherose Fast Flow anion
      exchange chromatography. Then HC and beta(2m) were connected with two specific
      peptides, purified through Superdex 75 gel filtration, and identified with mAb
      W6/32 which can recognize native HLA-A2. RESULTS: The expression rates of HC and
      beta(2m) in engineering bacteria was both about 50%. The purity of both
      expression products reached to 95%.Moreover, the two HLA-A2-peptide complexes
      could be recognized by mAb W6/32, even after being stored at 4 degrees Celsius
      for 2 months. CONCLUSION: The two soluble HLA-A2-peptide complexes prepared by us
      are stable and lay the foundation for further research of CTL recognition and
      response.

PMID- 15182645
TI  - [The effect of CTLA4Ig-modified dendritic cells on proliferation and cytotoxicity
      of lymphocytes in-vitro].
AB  - AIM: To study the effect of dendritic cells (DCs) modified by CTLA4Ig on T-cell
      proliferation and the cytotoxic T lymphocyte killer activity. METHODS: The
      expressing vector pG/CTLA4Ig was transfected into DCs via lipofectamine reagent
      mediation. CTLA4Ig fusion protein secreted by DCs in the culture supernatant was
      confirmed by sandwich ELISA and SDS-PAGE. Peripheral blood mononuclear cells
      (PBMC) from C57BL/6 mice (as reaction cells) and DCs modified or unmodified by
      CTLA4Ig (as stimulation cells) were co-cultured for 6 days. MTT colorimetry was
      used to detect lymphocyte proliferation. Lactate dehydrogenase release method and
      sandwich ELISA assay was used to examine the cytotoxic activity and T-cell
      apoptosis. RESULTS: CTLA4Ig fusion protein and DCs modified by CTLA4Ig could
      significantly inhibit lymphocyte proliferation response and cytotoxic activity of
      specific cytotoxic T lymphocytes, and induce T-cell apoptosis, while unmodified
      DCs could markedly induce lymphocyte proliferation response. CONCLUSION: The DCs
      of stably expressing CTLA4Ig fusion protein could not only markedly inhibit T
      cell proliferation and cytotoxic activity of CTL, but also induce T-cell
      apoptosis.

PMID- 15182646
TI  - [Effect of resveratrol alone and its combination with cyclosporin A on the immune
      function of human peripheral blood T lymphocytes].
AB  - AIM: To investigate the effect of resveratrol (Res) alone and its combination
      with cyclosporin A (CsA) on the proliferation of human peripheral blood T
      lymphocytes (hPBTCs), transformation into lymphoblasts, as well as IL-2 and INF
      gamma production. METHODS: The proliferation of hPBTCs was detected by MTT
      colorimetry. The lymphocyte transformation rate was examined by morphologic
      method. The levels of IL-2 and INF-gamma in lymphocyte culture supernatant were
      detected by ELISA. RESULTS: When the concentration of resveratrol was over 2.5
      mg/L, especially 10 mg/L, the proliferation and transformation rate of hPBTCs
      decreased significantly (P<0.05). The levels of IL-2 and INF-gamma in lymphocyte
      culture supernatant reduced markedly (P<0.05), on condition that the
      concentration of resveratrol was over 5 mg/L. The combination of more than 2.5
      mg/L of resveratrol with cyclosporine A had synergism. CONCLUSION: Resveratrol
      can suppress notably the proliferation and transformation of human lymphocytes
      and the combination of resveratrol at a given concentration with cyclosporine A
      can enhance immune suppression.

PMID- 15182647
TI  - [Correlation between activation-induced cytidine deaminase gene polymorphism and
      atopic asthma and plasma IgE in adult].
AB  - AIM: To explore whether the activation-induced cytidine deaminase(AICDA) gene
      8408 C/T polymorphism is related to adult atopic asthma and the level of plasma
      IgE. METHODS: The polymorphism of AICDA gene was detected by PCR and restriction
      fragment length polymorphism (PCR-RFLP). RESULTS: The frequencies of 8408T/T
      genotype had significant difference (P<0.05) between adult asthma patients and
      control group, while the frequencies of T allele between two groups were not
      significantly different. The total plasma IgE level in adult atopic asthma
      patients with 8408T/T genotype was higher than that in the patients with C/C and
      C/T genotypes(P<0.05). CONCLUSION: The 8408 T/T genotype of AICDA is correlated
      with atopic asthma and total plasma IgE level in adult.

PMID- 15182648
TI  - [Dynamic observation of cytokine induced killer cells in peripheral blood from
      patients with chronic hepatitis B].
AB  - AIM: To observe dynamically proliferation and cytotoxicity of cytokine induced
      killer cells (CIKs) in peripheral blood from patients with persistent infection
      of hepatitis B virus. METHODS: Peripheral blood mononuclear cells (PBMCs) were
      isolated routinely from 10 normal volunteers (control group) and 20 patients with
      chronic hepatitis B. PBMCs were co-cultured with IFN-gamma, rhIL-2 and anti-CD3
      mAb to induce CIK cell generation. The expressions of single staining CD3, CD4,
      and CD8, as well as double staining CD4 CD25, CD3 CD56 and CD28 CD95 on CIK cells
      were analyzed by flow cytomctry on 3,6,12,24 and 30 days of co-culture. RESULTS:
      The proliferative level and killer activity of CIK cells from the patients were
      lower than those from control group. The proliferative level, killer activity and
      expressions of above surface markers on CIK cells from the patients at various
      times after co-culture were higher than those before co-culture, and reached peak
      values on 12 days after co-culture. CONCLUSION: The proliferative level and
      killer activity of CIK cells from the patients are lower than that of normal
      people, which may be the reason of persistent development of HBV infection.

PMID- 15182649
TI  - [Cooperative effect of rhIL-2 and adriamycin-magnetic albumin microsphere
      targeting therapy on tumor].
AB  - AIM: To observe the synergistic inhibitory effects of rhIL-2 and adriamycin
      magnetic albumin microsphere(ADM-MAM) targeting therapy on tumor and to explore
      their antitumor mechanism. METHODS: The antitumor activity was observed using the
      tumor weight as index. The killer activity of natural killer (NK) cells and the
      lymphocyte transformation were examined by the LDH release assay and MTT
      colorimetry, respectively. The apoptosis of tumor cells and the expressions of
      p53,Fas and FasL were examined by flow cytometry. The expressions of IL-2 and IL
      12 were determined by RT-PCR. RESULTS: Compared with the control group, in ADM
      MAM targeting therapy group and combination therapy (ADM-MAM and rhIL-2 therapy)
      group, tumor weight, killer activity of NK cells, and the lymphocyte
      transformation;were obviously decreased; while the expression of Fas, FasL, IL-2
      and IL-12 were markedly increased. CONCLUSION: ADM-MAM targeting therapy exerts
      anti-tumor effects with fewer side effects, which can be enhanced when combined
      with rhIL-2 therapy. Such synergistic anti-tumor effects may be realized by
      stimulating the proliferation of T cells and growth of NK cell to enhance
      cellular immunological function.

PMID- 15182650
TI  - [Typing for HLA-DR DNA by polymerase chain reaction with sequence-specific
      primers].
AB  - AIM: To type the HLA-DR DNA for renal transplantation by PCR with sequence
      specific primers (PCR-SSP). METHODS: According to nucleotide sequences of HLA-DR,
      16 pairs of specific primers and a pair of positive control primers were designed
      and synthesized for PCR-SSP. Then HLA-DR sites of 52 donors and recipients for
      renal transplantation were typed by the PCR-SSP. RESULTS: All the samples were
      successfully typed by PCR-SSP with the synthesized primers. The results were
      available within 3 hours after sampling and the accuracy and reproducibility were
      100%. CONCLUSION: Genotyping for HLA-DR sites by PCR-SSP with primers reported
      herein was a simple and accurate technique suitable for clinical application.

PMID- 15182651
TI  - [Significance of detecting urinary monocyte chemotactic peptide-1 in renal
      transplant recipient].
AB  - AIM: To detect the content of monocyte chemotactic peptide-1(MCP-1) and to
      investigate the role of MCP-1 in acute renal graft rejection. METHODS: Urinary
      MCP-1 level was detected by avidin biotin complex(ABC)ELISA. RESULTS: Urinary MCP
      1 levels in renal function stable renal transplantation of recipients and control
      group were (416+/-21) microg/L and (408+/-11) microg/L, respectively. Urinary MCP
      1 level in renal transplantation recipients with acute rejection was (1195+/-58)
      microg/L, which was notably higher than that in control group and renal function
      stable recipients (P<0.01). After anti-rejection treatment, urinary MCP-1 level
      decreased markedly in patients who responded to treatment. CONCLUSION: The
      urinary MCP-1 level is correlated closely with acute renal graft rejection and
      its increase may indicate ongoing acute renal rejection. Detection of urinary MCP
      1 level may contribute to early diagnosis and prognostic judgement of acute graft
      rejection.

PMID- 15182652
TI  - [Preparation and characterization of monoclonal antibodies against rat Nogo
      molecule].
AB  - AIM: To prepare monoclonal antibodies against rat Nogo molecule and study the
      distribution of Nogo in rat central nervous system (CNS). METHODS: Murine mAbs
      were prepared by hybridoma technique. The distribution of Nogo in rat CNS was
      identified by immunofluorescent histochemical staining. RESULTS: Three hybridoma
      cell lines, FMU-Nogo1, FMU-Nogo2 and FMU-Nogo3, secreting mAbs against rat Nogo
      molecule were obtained. The titers of ascitic mAbs reached to 10(-6) and the Ig
      subclass of FMU-Nogo1, FMU-Nogo2 and FMU-Nogo3 was IgG2b(kappa), IgG1(kappa) and
      IgG1(kappa), respectively. Moreover, these mAbs could be used in immunofluoresent
      histochemical staining. The results showed that rat Nogo molecule could be
      detected in Purkinje cell layer and granual layer of rat cerebellum and on
      oligodendrocyte in white matter of rat spinal cord.Furthermore, these mAbs could
      be used in Western blot for detecting Nogo molecule present in rat spinal cord.
      CONCLUSION: Three mAbs against rat Nogo molecule were successfully prepared,
      which can provide a useful tool in research on the structure and functions of
      Nogo molecule in CNS.

PMID- 15182653
TI  - [Cloning and expression of Fab gene of mAb HAb18 against human hepatocellular
      carcinoma].
AB  - AIM: To clone Fab gene of mAb HAb18 against human hepatocellular carcinoma and
      express it in E.coli. METHODS: The cDNAs of kappa chain and Fd of mAb HAb18 were
      amplified by RT-PCR and cloned into prokaryotic expression vector pComb3 which
      was transfected into competent E.coli to express Fab by IPTG induction. The
      specificity of the expressed Fab was tested by ELISA and immunofluorescence
      staining. RESULTS: The Fab gene of mAb HAb18 was successfully amplified and
      expressed in E.coli. The results of competitive ELISA and immunofluorescence
      staining showed that the expressed Fab had specific antigen-binding activity.
      CONCLUSION: HAb18 Fab was prepared successfully, which lays the foundation for
      its further application to diagnosis and therapy of human hepatocellular
      carcinoma.

PMID- 15182654
TI  - [Characterization of neutralizing activity of murine monoclonal antibodies for
      construction of anti-human TNF chimeric antibody].
AB  - AIM: To screen high quality murine monoclonal antibodies (mAb) for construction
      of anti-human TNF chimeric antibody. METHODS: 3 hybridoma cells D2, E6 and F6
      were selected from one group of hybridoma cells secreting anti-human TNF mAbs and
      then ascitic fluids were prepared according to routine protocol. After salted out
      with saturated ammonium sulphate, the mAb (IgG2b) secreted by D2 cells was
      purified through protein A affinity chromatography column. The mAbs (IgG1)
      secreted by E6 and F6 cells were purified through QFF anion exchange
      chromatography column. The titers of 3 mAbs were detected by indirect ELISA
      before and after purification. Inhibition of TNF induced cell death of L929 cells
      and ICAM-1 upregulation on ECV304 cells were assayed as indexes of neutralizing
      activity of the mAbs. RESULTS: ELISA results showed that the titers of 3 mAbs D2,
      E6, and F6 before purification were 1x10(-6 ), 1x10(-7 ), and 1x10(-7 ),
      respectively, and 0.01, 0.002 and 0.002 mg/L after purification, respectively.
      0.16 mg/L D2, 0.40 mg/L E6, or 0.50 mg/L F6 could protect 50% L929 cells from
      cell death induced by 2x10(4) U/L TNF, and the inhibition rates of ICAM-1
      upregulation by 2x10(5) U/L TNF of 1.0 mg/L D2, E6 or F6 were 70.1%, 60.1%, and
      60.1%, respectively. The inhibition rates still reached 60.1%,53.7% and 59.0%,
      respectively, when the concentrations of 3 mAbs D2, E6 and F6 decreased to 0.1
      mg/L. CONCLUSION: 3 mAbs with high titers and neutralizing activities were
      obtained, which paves the way for construction of anti-human TNF chimeric
      antibody.

PMID- 15182655
TI  - [Preparation and identification of the monoclonal antibody against human
      endostatin].
AB  - AIM: To prepare monoclonal antibody against human endostatin for the in depth
      study on the mechanism of anti-tumor effect of endostatin. METHODS: Monoclonal
      antibody specific for endostatin was prepared using hybridoma technique and
      screened with ELISA. Ascites fluids were produced in BALB/c mice following in
      sequentical intraperitoneal injection of pristine and hybridoma cells. The mAb
      was purified by affinify chromatography with protein A sepharose CL-4B. RESULTS:
      One hybridoma cell line 4E7 was established, which could produce mAb against
      human endostatin. The titers of mAb 4E7 in culture supernatant and ascites fluid
      were 1:128-1:516 and 1:10(-4)-1:10(-6), respectively. The mAb 4E7 belonged to
      IgG1 (lambda type). Western blot analysis showed that the mAb 4E7 could react to
      the human endostatin expressed by yeast and E.coli, but it had no cross reaction
      to other cytokines such as bFGF. CONCLUSION: The mAb 4E7 is able to react
      specifically with human endostatin and can be used for further investigation.

PMID- 15182656
TI  - [Cloning, prokaryotic expression of CML66 and preparation of its polyclonal
      antibody].
AB  - AIM: To clone and express CML66 cDNA and to prepare rabbit anti-CML66 antibody.
      METHODS: cDNA isolated from the testis using RT-PCR was cloned into pGEMT. After
      sequencing, the cDNA was inserted into prokaryotic expression vector pET32b(+).
      The recombinant vector was transformed into BL-21(DE3) through electroporation.
      6xHis-tagged CML66 expression was then induced by IPTG. The protein was purified
      through Ni(2+) affinity chromatography column and characterized by SDS-PAGE and
      Western blot. The purified protein was injected into rabbits to prepare
      polyclonal antibody. RESULTS: The cloned cDNA sequence was identical with that
      previously reported. The target protein was successfully purified. And rabbit's
      anti-serum with high titer was obtained. CONCLUSION: We have cloned CML66
      successfully, expressed and purified the protein in E.coli.Furthermore,rabbit
      polyclonal antibody has been obtained.

PMID- 15182657
TI  - [Construction, expression and functional characterization of disulfide-stabilized
      anti-hepatocarcinoma single chain Fv fused with truncated Pseudomonas exotoxin].
AB  - AIM: To prepare fusion protein of disulfide-stabilized anti-hepatocarcinoma
      single chain Fv(dsFv)and truncated Pseudomonas exotoxin(PE38). METHODS: The gene
      encoding the fusion protein was cloned into the prokaryotic expression vector
      pTIG which was then transformed into E.coli origami(DE3). The expressed product
      was purified through Ni-NTA agarose affinity chromatography column. The
      cytotoxicity of the purified dsFv-PE38 was detected by MTT colorimetry. RESULTS:
      The immunotoxin dsFv PE38 was expressed in E.coli origami(DE3) in a soluble form,
      which accounted for nearly 21% of the total bacterial soluble proteins. The
      results of cytotoxic assay showed that the dsFv-PE38 could specifically kill
      hepatocarcinoma cells, while spared the normal hepatic cells. CONCLUSION: The
      immunotoxin dsFv-PE38 may have some potential value in the treatment of
      hepatocarcinoma.

PMID- 15182658
TI  - [The observation of the lymphocyte phenotype change in different lymphoid tissues
      of mice after intranasal immunization with bivalent Shigella vaccines].
AB  - AIM: To observe the changes of lymphocyte phenotype in different lymphoid tissues
      of mice at various time after intranasal immunization with bivalent Shigella
      vaccines. METHODS: BALB/c mice were randomly divided into three groups, 30 mice
      per group. Mice were intranasally immunized respectively with PBS, FSM-2117 or FS
      5416 four times (bacterial number was sequentially 5x10(6), 1x10(7),4x10(7)and
      4x10(7)CFU/mouse) with two week intervals. Lymphocytes in nasal associated
      lymphoid tissue (NALT), nasal passage(NP), spleen or Peyer's patch (PP) were
      isolated on the 7th,30th and 90th day after the last immunization. The phenotype
      of the lymphocytes was detected by FACS. RESULTS: CD3(+) T cells in NALT, NP and
      PP increased significantly on the 7th day after the immunization, in which most
      were CD4(+)T cells. B220(+) cells and CD3(+) T cells increased notably in spleens
      of FSM-2117 group and FS-5416 group, respectively. The same phenotypic changes
      still maintained in the NALT, NP and spleen on the 30th day after immunization,
      but only present in NALT and NP on the 90th day. CONCLUSION: Intranasal
      inoculation with the two bivalent Shigella vaccines can effectively induce immune
      responses in different mucosal sites and systematically which can durate for a
      long time and start to weaken from the tissues distal from nose to those
      proximal.

PMID- 15182659
TI  - [Immunogenicity of DNA vaccine encoding fusion protein of Mycobacterium
      tuberculosis Ag85B and MPT64].
AB  - AIM: To study the immunogenicity of a DNA vaccine encoding fusion protein of
      Mycobacterium tuberculosis Ag85B and MPT64. METHODS: C57BL/6 mice were
      intramuscularly injected respectively with PBS(A group), plasmid vector (B
      group), pcDNA/Ag85B(C group), pcDNA/MPT64(D group), and pcDNA/Ag85B MPT64 (E
      group) for three times with 2 week intervals. The mice were sacrificed 4 weeks
      after the final immunization. The total specific antibody levels were detected by
      ELISA and simultaneously spleen lymphocyte proliferation response to PPD and IFN
      gamma level in culture supernatant of the PPD stimulated spleen lymphocytes was
      measured by MTT colorimetry and ELISA, respectively. RESULTS: The Ag85B, MPT64
      and fusion gene Ag85B MPT64 DNA vaccines could induce anti-PPD antibody
      production as well as antigen specific lymphocyte proliferation and high levels
      of IFN-gamma in immunized mice. CONCLUSION: The Ag85B MPT64 fusion gene can
      induce specific cellular immunity and humoral immunity in immunized mice.

PMID- 15182661
TI  - [Construction and characterization of osteosarcoma 9901 cell cDNA library].
AB  - AIM: To construct human osteosarcoma 9901 cell cDNA expression library for
      screening osteosarcoma-specific antigens. METHODS: Total RNA was extracted from
      human osteosarcoma cell line 9901 and mRNA was purified. cDNA was synthesized by
      reverse transcription, and cDNA fragments larger than 400 bp were ligated with
      dephosphorylated arms of lambdagt11. The recombinants were packaged in-vitro, and
      a small portion of packaged phage was used to infect E.coli Y1090 for titration.
      The size of cDNA inserts and the diversity of library were detected by PCR.
      RESULTS: The osteosarcoma 9901 cell line cDNA library consisting of 1.5x10(6)
      recombinant bacteriophages was constructed. The average length of exogenous
      inserts in the recombinants was about 1.4 kb. CONCLUSION: The cDNA library
      reported herein is suitable for screening osteosarcoma-specific antigens.

PMID- 15182660
TI  - [Changes of telomerase activity and hTERT mRNA expression in the process of
      apoptosis of HL-60 cells induced by arsenic sulfide].
AB  - AIM: To explore the effect of arsenic sulfide on telomerase activity of HL-60
      cells. METHODS: Telomerase activity was determined by PCR-ELISA. The expression
      of hTERT-mRNA was analyzed by semi-quantitative RT-PCR. Flow cytometry was used
      to analyze the cell cycle,apoptosis and CD11b expression of HL-60 cells. RESULTS:
      Treament of HL-60 cells with 0.3-0.6 mg/L arsenic sulfide for 72 h did not induce
      apoptosis of the cells, while 1.5-3.0 mg/L did. Furthermore, 1.5-3.0 mg/L arsenic
      sulfide inhibited the telomerase activity and hTERT-mRNA expression in HL-60
      cells. Proportion of the cells in G2/M phase was increased when being treated
      with arsenic sulfide. 3.0 mg/L arsenic sulfide upregulated CD11b expression in HL
      60 cells from 1.0 % to 6.8%. CONCLUSION: Arsenic sulfide can inhibit telomerase
      activity. The increase of proportion of HL-60 cells in G2/M phase may be related
      to the reduction of telomerase activity. High dosage of arsenic sulfide can
      slightly induce differentiation of HL-60 cells.

PMID- 15182662
TI  - [Liver tissue-specific stable expression of human CD81 molecule].
AB  - AIM: To express stably human CD81 gene on mouse hepatoma cell line Hepa 1-6 using
      liver specific promoter. METHODS: RNA were isolated from human HepG2 cells which
      could be infected with hepatitis C virus. RT-PCR was carried out using human CD81
      gene specific primers. Amplified fragments were cloned into pGEM-T vector.
      Albumin promoter and enhancer which were liver tissue specific were ligated to
      the 5'end of human CD81 gene and SV40 polyA sequence was fused with 3'end of
      CD81. The fused CD81 gene was inserted into eukaryotic expression vector pcDNA3
      to construct a recombinant vector pcDNA3-Alb p-CD81 which was then transfected
      into Hepa 1-6 cells through lipofectamine mediation. Human CD81 mRNA
      transcription and its protein expression were detected by RT-PCR and FACS,
      respectively. RESULTS: Sequence analysis showed that the cloned gene segment was
      human CD81 gene sequence. After transfection, transcripted human CD81 mRNA was
      obtained and human CD81 molecules were expressed stably on Hepa 1-6 cells.
      CONCLUSION: The obtained positive cell clones which stably express HCV receptor
      human CD81 lay the foundation for further study on interactions between HCV
      envelope proteins and human CD81, screening of HCV infection blocking drugs and
      development of HCV infection mouse model.

PMID- 15182663
TI  - [The role of nitric oxide in the cytotoxic effect of macrophages].
AB  - AIM: To explore the role of nitric oxide (NO) in cytotoxicity of macrophages.
      METHODS: 20 mice of Kunming species were divided into two groups. One group were
      injected subcutaneously with rhabdosarcoma cells S180 and the other were normal
      controls. The macrophages in peritoneal lavage fluid of two groups of mice were
      co-cultured with tumor cells K562. L-arginine(L-Arg) or NG nitro L-arginine
      methyleste(L-NAME) was added to the culture medium, and the cytotoxicity of
      macrophages was measured. RESULTS: Macrophages from tumor bearing mice had
      stronger cytotoxicity than those from normal mice. L-Arg increased and L-NAME
      decreased the cytotoxicity of macrophages from tumor bearing mice, but both had
      no effect on the cytotoxicity of macrophages from normal mice. CONCLUSION: NO is
      an effector molecule in cytotoxicity of activated macrophages.

PMID- 15182664
TI  - [Stimulating the expression of macrophage inflammatory protein-2gamma by
      lipopolysaccharide in-vitro].
AB  - AIM: To study the expression level of macrophage inflammatory protein-2gamma(MIP
      2gamma)stimulated by lipopolysaccharide(LPS)in-vitro. METHODS: Murine monocyte
      macrophage like cell line RAW264.7 and BALB/c mice primary kidney cell culture
      were stimulated with LPS. MIP-2gamma mRNA expression level in these cells was
      detected by real time fluorescence quantitative RT-PCR. RESULTS: MIP-2gamma mRNA
      expression level of RAW264.7 cell line increased quickly and reached the peak (7
      times the normal level) within 2 hours after LPS stimulation and dropped to the
      base level within 16 hours, while that of cultured promary kidney cells of BALB/c
      mice elevated about 50 times compared with base level 12 hours following LPS
      stimulation. CONCLUSION: LPS can significantly stimulate the expression of MIP
      2gamma mRNA, suggesting that MIP-2gamma may play some role in inflammatory
      process.

PMID- 15182665
TI  - Preferential localization of glutamate receptors opposite sites of high
      presynaptic release.
AB  - BACKGROUND: The localization of glutamate receptors is essential for the
      formation and plasticity of excitatory synapses. These receptors cluster opposite
      neurotransmitter release sites of glutamatergic neurons, but these release sites
      have heterogeneous structural and functional properties. At the Drosophila
      neuromuscular junction, receptors expressed in a single postsynaptic cell are
      confronted with an array of hundreds of apposed active zones. Hence, this is an
      ideal preparation for the investigation of whether receptor clustering is
      sensitive to the morphological and physiological properties of the apposed active
      zones. RESULTS: To investigate the relationship between the localization of
      glutamate receptors and the properties of the apposed active zones, we
      investigated receptor localization in mutants in which receptors are limited. We
      find that receptors are not uniformly distributed opposite the full array of
      active zones but that some active zones have a disproportionately large share of
      receptors as assayed by receptor levels and response to transmitter. The active
      zones at which receptors preferentially cluster are larger and have a higher
      neurotransmitter release probability than the average active zone. We find a
      similar relationship between glutamate receptor clusters and active-zone size at
      wild-type synapses. CONCLUSIONS: When confronted with an array of active zones,
      glutamate receptors preferentially cluster opposite the largest and most
      physiologically active sites. These results suggest an activity-dependent
      matching of pre- and postsynaptic function at the level of a single active zone.

PMID- 15182666
TI  - ZEN-4/MKLP1 is required to polarize the foregut epithelium.
AB  - BACKGROUND: Epithelial tubes are a key component of organs and are generated from
      cells with distinct apico-basolateral polarity. Here, we describe a novel
      function during tubulogenesis for ZEN-4, the Caenorhabditis elegans ortholog of
      mitotic kinesin-like protein 1 (MKLP1), and CYK-4, which contains a RhoGAP
      (GTPase-activating protein) domain. Previous studies revealed that these proteins
      comprise centralspindlin (a complex that functions during mitosis to bundle
      microtubules), construct the spindle midzone, and complete cytokinesis. RESULTS:
      Our analyses demonstrate that ZEN-4/MKLP1 functions postmitotically to establish
      the foregut epithelium. Mutants that lack ZEN-4/MKLP1 express polarity markers
      but fail to target these proteins appropriately to the cell cortex. Affected
      proteins include PAR-3/Bazooka and PKC-3/atypical protein kinase C at the apical
      membrane domain, and HMR-1/cadherin and AJM-1 within C. elegans apical junctions
      (CeAJ). Microtubules and actin are disorganized in zen-4 mutants compared to the
      wild-type. CONCLUSION: We suggest that ZEN-4/MKLP1 and CYK-4/RhoGAP regulate an
      early step in epithelial polarization that is required to establish the apical
      domain and CeAJ.

PMID- 15182667
TI  - Dynamics of centromere and kinetochore proteins; implications for checkpoint
      signaling and silencing.
AB  - BACKGROUND: The mitotic checkpoint prevents the onset of anaphase before all
      chromosomes are attached to spindle microtubules. The checkpoint is thought to
      act by the catalytic generation at unattached kinetochores of a diffusible "wait
      signal" that prevents anaphase. Mad2 and Cdc20, two candidate proteins for
      components of a diffusible wait signal, have previously been shown to be
      recruited to and rapidly released from unattached kinetochores. RESULTS:
      Fluorescence recovery after photobleaching demonstrated that Mad1, Bub1, and a
      portion of Mad2, all essential mitotic-checkpoint components, are stably bound
      elements of unattached kinetochores (as are structural centromere components such
      as Centromere protein C [CENP-C]). After microtubule attachment, Mad1 and Mad2
      are released from kinetochores and relocalize to spindle poles, whereas Bub1
      remains at kinetochores. CONCLUSIONS: A long residence time at kinetochores
      identifies Bub1, Mad1, and a portion of Mad2 as part of a catalytic platform that
      recruits, activates, and releases a diffusible wait signal that is partly
      composed of the rapidly exchanging portion of Mad2. The release of Mad1 and Mad2,
      but not Bub1, from kinetochores upon attachment separates the elements of this
      "catalytic platform" and thereby silences generation of the anaphase inhibitor
      despite continued rapid cycling of Mad2 at spindle poles.

PMID- 15182669
TI  - The Drosophila F box protein archipelago regulates dMyc protein levels in vivo.
AB  - BACKGROUND: The Myc oncoprotein is an important regulator of cellular growth in
      metazoan organisms. Its levels and activity are tightly controlled in vivo by a
      variety of mechanisms. In normal cells, Myc protein is rapidly degraded, but the
      mechanism of its degradation is not well understood. RESULTS: Here we present
      genetic and biochemical evidence that Archipelago (Ago), the F box component of
      an SCF-ubiquitin ligase and the Drosophila ortholog of a human tumor suppressor,
      negatively regulates the levels and activity of Drosophila Myc (dMyc) protein in
      vivo. Mutations in archipelago (ago) result in strongly elevated dMyc protein
      levels and increased tissue growth. Genetic interactions indicate that ago
      antagonizes dMyc function during development. Archipelago binds dMyc and
      regulates its stability, and the ability of Ago to bind dMyc in vitro correlates
      with its ability to inhibit dMyc accumulation in vivo. CONCLUSIONS: Our data
      indicate that archipelago is an important inhibitor of dMyc in developing
      tissues. Because archipelago can also regulate Cyclin E levels and Notch
      activity, these results indicate how a single F box protein can be responsible
      for the degradation of key components of multiple pathways that control growth
      and cell cycle progression.

PMID- 15182668
TI  - Spindle checkpoint protein dynamics at kinetochores in living cells.
AB  - BACKGROUND: To test current models for how unattached and untense kinetochores
      prevent Cdc20 activation of the anaphase-promoting complex/cyclosome (APC/C)
      throughout the spindle and the cytoplasm, we used GFP fusions and live-cell
      imaging to quantify the abundance and dynamics of spindle checkpoint proteins
      Mad1, Mad2, Bub1, BubR1, Mps1, and Cdc20 at kinetochores during mitosis in living
      PtK2 cells. RESULTS: Unattached kinetochores in prometaphase bound on average
      only a small fraction (estimated at 500-5000 molecules) of the total cellular
      pool of each spindle checkpoint protein. Measurements of fluorescence recovery
      after photobleaching (FRAP) showed that GFP-Cdc20 and GFP-BubR1 exhibit biphasic
      exponential kinetics at unattached kinetochores, with approximately 50%
      displaying very fast kinetics (t1/2 of approximately 1-3 s) and approximately 50%
      displaying slower kinetics similar to the single exponential kinetics of GFP-Mad2
      and GFP-Bub3 (t1/2 of 21-23 s). The slower phase of GFP-Cdc20 likely represents
      complex formation with Mad2 since it was tension insensitive and, unlike the fast
      phase, it was absent at metaphase kinetochores that lack Mad2 but retain Cdc20
      and was absent at unattached prometaphase kinetochores for the Cdc20 derivative
      GFP-Cdc20delta1-167, which lacks the major Mad2 binding domain but retains
      kinetochore localization. GFP-Mps1 exhibited single exponential kinetics at
      unattached kinetochores with a t1/2 of approximately 10 s, whereas most GFP-Mad1
      and GFP-Bub1 were much more stable components. CONCLUSIONS: Our data support
      catalytic models of checkpoint activation where Mad1 and Bub1 are mainly
      resident, Mad2 free of Mad1, BubR1 and Bub3 free of Bub1, Cdc20, and Mps1
      dynamically exchange as part of the diffuse wait-anaphase signal; and Mad2
      interacts with Cdc20 at unattached kinetochores.

PMID- 15182670
TI  - Negative control of circadian clock regulator E4BP4 by casein kinase Iepsilon
      mediated phosphorylation.
AB  - Light-dependent transcriptional regulation of clock genes is a crucial step in
      the entrainment of the circadian clock. E4bp4 is a light-inducible gene in the
      chick pineal gland, and it encodes a bZIP protein that represses transcription of
      cPer2, a chick pineal clock gene. Here, we demonstrate that prolonged light
      period-dependent accumulation of E4BP4 protein is temporally coordinated with a
      delay of the rising phase of cPer2 in the morning. E4BP4 was phosphorylated
      progressively and then disappeared in parallel with induced cPer2 expression.
      Characterization of E4BP4 revealed Ser182, a phosphoacceptor site located at the
      amino-terminal border of the Ser/Thr cluster, which forms the phosphorylation
      motifs for casein kinase 1epsilon (CK1epsilon). CK1epsilon physically associated
      with E4BP4 and phosphorylated it. CK1epsilon-catalyzed phosphorylation of E4BP4
      resulted in proteasomal proteolysis-dependent decrease of E4BP4 levels, while
      E4BP4 nuclear accumulation was attenuated by CK1epsilon in a kinase activity
      independent manner. CK1epsilon-mediated posttranslational regulation was
      accompanied by reduction of the transcriptional repression executed by E4BP4.
      These results not only demonstrate a phosphorylation-dependent regulatory
      mechanism for E4BP4 function but also highlight the role of CK1epsilon as a
      negative regulator for E4BP4-mediated repression of cPer2.

PMID- 15182671
TI  - Repression of primordial germ cell differentiation parallels germ line stem cell
      maintenance.
AB  - In Drosophila, primordial germ cells (PGCs) are set aside from somatic cells and
      subsequently migrate through the embryo and associate with somatic gonadal cells
      to form the embryonic gonad. During larval stages, PGCs proliferate in the female
      gonad, and a subset of PGCs are selected at late larval stages to become germ
      line stem cells (GSCs), the source of continuous egg production throughout
      adulthood. However, the degree of similarity between PGCs and the self-renewing
      GSCs is unclear. Here we show that many of the genes that are required for GSC
      maintenance in adults are also required to prevent precocious differentiation of
      PGCs within the larval ovary. We show that following overexpression of the GSC
      differentiation gene bag of marbles (bam), PGCs differentiate to form cysts
      without becoming GSCs. Furthermore, PGCs that are mutant for nanos (nos), pumilio
      (pum) or for signaling components of the decapentaplegic (dpp) pathway also
      differentiate. The similarity in the genes necessary for GSC maintenance and the
      repression of PGC differentiation suggest that PGCs and GSCs may be functionally
      equivalent and that the larval gonad functions as a "PGC niche".

PMID- 15182672
TI  - Mammalian Scribble forms a tight complex with the betaPIX exchange factor.
AB  - Drosophila Scribble is implicated in the development of normal synapse structure
      and epithelial tissues, but it remains unclear how it plays a role and which
      process it controls. The mammalian homolog of Scribble, hScrib, has a primary
      structure and subcellular localization similar to that of its fly homolog, but
      its function remains unknown. Here we have used tandem mass spectrometry to
      identify major components of the hScrib network. We show that it includes betaPIX
      (also called Cool-1), a guanine nucleotide exchange factor (GEF), and its partner
      GIT1 (also called p95-APP1), a GTPase activating protein (GAP). betaPIX directly
      binds to the hScrib PDZ domains, and the hScrib/betaPIX complex is efficiently
      recovered in epithelial and neuronal cells and tissues. In cerebellar granule
      cell cultures, hScrib and betaPIX are both partially localized at neuronal
      presynaptic compartments. Furthermore, we show that hScrib is required to anchor
      betaPIX at the cell cortex and that dominant-negative betaPIX or hScrib proteins
      can each inhibit Ca2+-dependent exocytosis in neuroendocrine PC12 cells,
      demonstrating a functional relationship between these proteins. These data reveal
      the existence of a tight hScrib/betaPIX interaction and suggest that this complex
      potentially plays a role in neuronal transmission.

PMID- 15182674
TI  - A barrier to lateral diffusion in the cleavage furrow of dividing mammalian
      cells.
AB  - Barriers to diffusion of proteins and lipids play an important role in generating
      functionally specialized regions of the plasma membrane. Such barriers have been
      reported at the base of axons, at the bud neck in Saccharomyces cerevisiae, as
      well as at the tight junctions of epithelia. How diffusion barriers are formed
      and how they effect behavior of both inner and outer leaflets of the bilayer are
      not fully understood. Here, we provide evidence for a cortical barrier to
      diffusion within the cleavage furrow of mammalian cells. Photobleaching-based
      assays were used to measure diffusion of three membrane proteins with differing
      topologies and putative lipid raft association, as well as the lipid analog
      dialkylindocarbocyanine (DiI C18, ), across the cleavage furrow. There was a
      block in diffusion of proteins with a cytosolic domain, but not of proteins
      anchored in the outer leaflet of the PM or of DiI. Diffusion of lipid raft
      proteins in the inner and outer leaflets of the membrane was not directly
      coupled. The distribution of Septin proteins, as opposed to cortical actin, was
      consistent with a functional role in limiting diffusion.

PMID- 15182673
TI  - One picture is worth at least a million neurons.
AB  - How many neurons participate in the representation of a single visual image?
      Answering this question is critical for constraining biologically inspired models
      of object recognition, which vary greatly in their assumptions from few
      "grandmother cells" to numerous neurons in widely distributed networks.
      Functional imaging techniques, such as fMRI, provide an opportunity to explore
      this issue, since they allow the simultaneous detection of the entire neuronal
      population responding to each stimulus. Several studies have shown that fMRI BOLD
      signal is approximately proportional to neuronal activity. However, since it
      provides an indirect measure of this activity, obtaining a realistic estimate of
      the number of activated neurons requires several intervening steps. Here, we used
      the extensive knowledge of primate V1 to yield a conservative estimate of the
      ratio between hemodynamic response and neuronal firing. This ratio was then used,
      in addition to several cautious assumptions, to assess the number of neurons
      responding to a single-object image in the entire visual cortex and particularly
      in object-related areas. Our results show that at least a million neurons in
      object-related cortex and about two hundred million neurons in the entire visual
      cortex are involved in the representation of a single-object image.

PMID- 15182675
TI  - CTCF elements direct allele-specific undermethylation at the imprinted H19 locus.
AB  - The H19 imprinted gene locus is regulated by an upstream 2 kb imprinting control
      region (ICR) that influences allele-specific expression, DNA methylation, and
      replication timing. This ICR becomes de novo methylated during late
      spermatogenesis in the male but emerges from oogenesis in an unmethylated form,
      and this allele-specific pattern is then maintained throughout early development
      and in all tissues of the mouse. We have used a genetic approach involving
      transfection into embryonic stem (ES) cells in order to decipher how the maternal
      allele is protected from de novo methylation at the time of implantation. Our
      studies show that CCCTC binding factor (CTCF) boundary elements within the ICR
      have the ability to prevent de novo methylation on the maternal allele. Since
      CTCF does not recognize its binding sequence when methylated, this reaction does
      not occur on the paternal allele, thus preserving the gamete-derived, allele
      specific pattern. These results suggest that CTCF may play a general role in the
      maintenance of differential methylation patterns in vivo.

PMID- 15182676
TI  - Local factors determine the stabilization of monocular ambiguous and binocular
      rivalry stimuli.
AB  - Perceptual alternation in viewing bistable stimuli can be slowed or halted if the
      stimuli are presented intermittently. Memory of the recent perceptual experience
      has been proposed to explain this stabilization effect. But the nature of this
      "perceptual memory" remains unclear. By using a bistable rotating cylinder and
      two dichoptically presented orthogonal gratings, we explored the features that
      are important for the stabilization by changing a particular feature of the
      stimuli between alternate presentations. For the rotating cylinder, changing its
      color, rotating speed, size, or its stereo depth had no or minimal effect on the
      stabilization of its perceived rotation direction. For binocular rivalry, when
      the two gratings were matched in strength and then swapped between the two eyes
      synchronously with the intermittent presentation, the percepts were usually
      stabilized to one eye. In both cases, perceptual stabilization occurred only if
      the stimuli were presented to the same retinal location. These results suggest
      that the stabilization of monocular bistable stimuli is likely due to the removal
      of local adaptation, insensitive to the features that define the object identity.
      For binocular rivalry, preservation of the direction of interocular suppression
      rather than memory of the stimulus identity accounts for the stabilization
      effect.

PMID- 15182677
TI  - Caenorhabditis elegans-based screen identifies Salmonella virulence factors
      required for conserved host-pathogen interactions.
AB  - A Caenorhabditis elegans-Salmonella enterica host-pathogen model was used to
      identify both novel and previously known S. enterica virulence factors (HilA,
      HilD, InvH, SptP, RhuM, Spi4-F, PipA, VsdA, RepC, Sb25, RfaL, GmhA, LeuO, CstA,
      and RecC), including several related to the type III secretion system (TTSS)
      encoded in Salmonella pathogenicity island 1 (SPI-1). Mutants corresponding to
      presumptive novel virulence-related genes exhibited diminished ability to invade
      epithelial cells and/or to induce polymorphonuclear leukocyte migration in a
      tissue culture model of mammalian enteropathogenesis. When expressed in C.
      elegans intestinal cells, the S. enterica TTSS-exported effector protein SptP
      inhibited a conserved p38 MAPK signaling pathway and suppressed the diminished
      pathogenicity phenotype of an S. enterica sptP mutant. These results show that C.
      elegans is an attractive model to study the interaction between Salmonella
      effector proteins and components of the innate immune response, in part because
      there is a remarkable overlap between Salmonella virulence factors required for
      human and nematode pathogenesis.

PMID- 15182678
TI  - Fighting isolation.
AB  - Cuban scientists have a tough time because of the isolation from the United
      States, but as Michael Gross reports, this has forced successful innovation in
      the biosciences with global potential amongst poorer, third world countries.

PMID- 15182679
TI  - The importance of ignorance.
AB  - The need for people to keep their genetic data confidential is crucial to help
      exploit medical advances, a key British Committee believes. Nigel Williams
      reports.

PMID- 15182680
TI  - The cochlear amplifier.

PMID- 15182681
TI  - Q & A: Till Roenneberg.
AB  - Till Roenneberg is Professor of Chronobiology at the University of Munich. He
      studies the circadian clock from its cellular/molecular mechanisms up to the
      consequences of shift work. He received his education in Munich and London, and
      worked in the 1980s with Woody Hastings at Harvard. Since then, he has built up
      the Centre for Chronobiology at the Munich Medical School. For many years, he has
      coordinated circadian research and education in Germany and in Europe. He is also
      involved in reforming the University curriculum, incorporating problem-based
      approaches. He has received international prizes for both his research and his
      teaching.

PMID- 15182682
TI  - Theory is available light.

PMID- 15182683
TI  - Trout out.

PMID- 15182684
TI  - Frimousse--a spontaneous ascidian mutant with anterior ectodermal fate
      transformation.

PMID- 15182685
TI  - Monastrol stabilises an attached low-friction mode of Eg5.

PMID- 15182686
TI  - Receptor clustering: nothing succeeds like success.
AB  - By experimentally limiting the amount of receptor molecules available in a
      postsynaptic neuron in Drosophila, it has been shown that receptors can
      preferentially cluster opposite active zones with a high release probability.
      This asymmetry in receptor distribution can alter the apparent probability and
      calcium-dependence of neurotransmitter release.

PMID- 15182687
TI  - Supplementary eye field: keeping an eye on eye movement.
AB  - The supplementary eye field has the biggest say in choosing what we look at, but
      has long been an enigma. Recent studies are beginning to make more sense of what
      it actually does.

PMID- 15182688
TI  - Evolution: love thy neighbour.
AB  - Five neighbouring populations of a cichlid fish from Lake Malawi differ in male
      courtship colour. Females show strong mate preferences for male coloration from
      their own populations. This suggests that sexual selection is an important factor
      contributing to speciation in cichlids.

PMID- 15182689
TI  - Morphological diversity: taking the spine out of three-spine stickleback.
AB  - A gene already known to play a crucial developmental role in chick and mouse
      embryos has been fingered as a candidate for naturally occurring variation in
      three-spine stickleback anatomy.

PMID- 15182690
TI  - Cancer cell biology: Myc wins the competition.
AB  - During Drosophila development, cells with elevated levels of the Myc oncoprotein
      grow faster than, and induce cell death in, nearby wild-type cells, suggesting
      how inappropriate Myc over-expression provides cells with a competitive advantage
      that can lead to cancer.

PMID- 15182692
TI  - Ancient DNA: would the real Neandertal please stand up?
AB  - Mitochondrial DNA sequences recovered from eight Neandertal specimens cannot be
      detected in either early fossil Europeans or in modern populations. This
      indicates that, if Neandertals made any genetic contribution at all to modern
      humans, it must have been limited, though the extent of the contribution cannot
      be resolved at present.

PMID- 15182691
TI  - Drosophila development: RNA interference ab ovo.
AB  - A novel protein required for RNA interference in Drosophila, Armitage, was
      identified in a screen for genes involved in embryonic axis formation. In
      armitage mutants, oocyte polarity and the regulation of oskar mRNA translation
      are impaired, suggesting that RNA silencing regulates the first steps of
      Drosophila development.

PMID- 15182693
TI  - Cell motility: Golgi signalling shapes up to ship out.
AB  - In a motile eukaryotic cell, secretory traffic is directed towards the front of
      the cell. New work shows that signals from the Golgi matrix play an important
      part in cell motility by allowing reorientation of the Golgi towards the
      direction of movement.

PMID- 15182695
TI  - The origin of asymmetry: early polarisation of the Drosophila germline cyst and
      oocyte.
AB  - The anterior-posterior axis of Drosophila is established before fertilisation
      when the oocyte becomes polarised to direct the localisation of bicoid and oskar
      mRNAs to opposite poles of the egg. Here we review recent results that reveal
      that the oocyte acquires polarity much earlier than previously thought, at the
      time when it acquires its fate. The oocyte arises from a 16-cell germline cyst,
      and its selection and the initial cue for its polarisation are controlled by the
      asymmetric segregation of a germline specific organelle called the fusome.
      Several different downstream pathways then interpret this asymmetry to restrict
      distinct aspects of oocyte identity to this cell. Mutations in any of the six
      conserved Par proteins disrupt the early polarisation of the oocyte and lead to a
      failure to maintain its identity. Surprisingly, mutations affecting the control
      of the mitotic or meiotic cell cycle also lead to a failure to maintain the
      oocyte fate, indicating crosstalk between the nuclear and cytoplasmic events of
      oocyte differentiation. The early polarity of the oocyte initiates a series of
      reciprocal signaling events between the oocyte and the somatic follicle cells
      that leads to a reversal of oocyte polarity later in oogenesis, which defines the
      anterior-posterior axis of the embryo.

PMID- 15182694
TI  - Wnt signaling: Ig-norrin the dogma.
AB  - Secreted Wnt proteins trigger the intracellular Wnt signaling cascade upon
      engagement of dedicated Frizzled-Lrp receptor complexes. Unexpectedly, a non-Wnt
      ligand for this receptor complex has now been discovered. This novel ligand,
      Norrin, is mutated in the hereditary ocular Norrie syndrome.

PMID- 15182700
TI  - Oocyte maturation and cell cycle control: a farewell symposium for Pr Marcel
      Doree.
AB  - Oocyte maturation and early development have been intensively studied for well
      over 100 years. The earliest theory proposed that after fertilisation and during
      cell division determinants were unequally distributed to control cell fate;
      experimental proof came from using frog eggs (Roux, 1888). After understanding
      the contribution of the nucleus and the chromosomes into cell cycle progression
      using sea urchin eggs (Boveri, 1902), it was the discovery of the cytoplasm
      contribution to the G2/M transition that led the cell cycle community in search
      of the "mitosis-inducing factor", MPF. Yoshio Masui was the first to
      experimentally demonstrate that few nanoliters of cytoplasm taken from a
      metaphase-arrested oocyte and microinjected in a G2-arrested oocyte was able to
      trigger the G2 to metaphase transition (Masui and Markert, 1971). Although the
      way to identify the mitotic factor seemed obvious, it proved very hard and was
      not purified until 1988 (Lohka et al, 1988), then work from a variety of
      organisms including Xenopus, starfish, clams, sea urchins and yeast converged on
      the identification of MPF as a complex of cdc2 and cyclin B (Dunphy et al, 1988;
      Gautier et al., 1988; Draetta et al., 1889; Meijer et al., 1989; Labbe et al.,
      1989; Gautier et al., 1990). Since then, the oocyte and egg extracts developed by
      Lohka and Masui have often been used to study cell cycle events such as nuclear
      envelop formation, chromatin condensation, DNA replication, repair, and
      recombination, Golgi formation, microtubule dynamics, spindle assembly,
      chromosome segregation as well as cell cycle controls.

PMID- 15182701
TI  - How does Xenopus oocyte acquire its competence to undergo meiotic maturation?
AB  - During Xenopus oogenesis, the follicle-enclosed oocyte, arrested at the diplotene
      stage of meiotic prophase, accumulates pre-MPF. Pre-MPF is an heterodimer formed
      of cyclin B2 and Cdc2 protein kinase, which is maintained inactive by inhibitory
      phosphorylations on Thr14 and Tyr15. When the oocyte reaches its full size, it
      becomes competent to respond to progesterone and to activate MPF through a
      positive feedback loop. In this paper, we present experimental data indicating
      that the molecular network involved in the autoamplification loop of MPF is
      progressively established during late oogenesis.

PMID- 15182702
TI  - An overview of the KIN1/PAR-1/MARK kinase family.
AB  - Members of the KIN1/PAR-1/MARK kinase family are conserved from yeast to humans
      and share a similar primary structural organization. Several kinases of this
      family appear to be at the crossroads of various biological functions including
      cell polarity, cell cycle control, intracellular signalisation, microtubules
      stability and protein stability. Here we present an overview of known roles of
      KIN1/PAR-1/MARK kinases including pEg3 a newly identified member which is
      regulated during the cell cycle and is a potential regulator of the cell cycle
      progression. Some common modes of action can be deciphered for this protein
      kinase family.

PMID- 15182703
TI  - Multiple roles of Condensins: a complex story.
AB  - Condensins are pentameric complexes that were initially described as being
      involved in the dynamics of chromosomes during mitosis. It has been recently
      established that two related complexes (Condensin I and Condensin II) contribute
      to this process. An increasing sum of studies, using different approaches in
      various organisms, leads to the paradigm that Condensins are required for the
      correct segregation of replicated chromosomes by cooperating somehow with
      Topoisomerase II in sister chromatid resolution. Depending on species and/or
      experimental studies, these complexes also contribute to some aspects of the
      assembly and compaction of mitotic chromosomes. Recent studies provided evidences
      that Condensins and related complexes also function in non-mitotic processes such
      as replication and transcription. Biochemical studies have highlighted
      mechanistic aspects of Condensin function and initiated a fine functional
      dissection of core and regulatory subunits. However, the exact contribution of
      each subunit remains largely elusive as well as the functional interplay between
      Condensin I and Condensin II.

PMID- 15182704
TI  - Aurora A, meiosis and mitosis.
AB  - The Aurora family kinases are pivotal to the successful execution of cell
      division. Together they ensure the formation of a bipolar mitotic spindle,
      accurate segregation of chromosomes and the completion of cytokinesis. They are
      also attractive drug targets, being frequently deregulated in cancer and able to
      transform cells in vitro. In this review, we summarize current knowledge about
      the three family members, Aur-A, Aur-B and Aur-C. We then focus on Aur-A, its
      roles in mitotic progression, and its emerging roles in checkpoint control
      pathways. Aur-A activity can be controlled at several levels, including
      phosphorylation, ubiquitin-dependent proteolysis and interaction with both
      positive regulators, such as TPX2, and negative ones, like the tumor suppressor
      protein p53. In addition, work in Xenopus oocytes and early embryos has revealed
      a second role for Aur-A, directing the polyadenylation-dependent translation of
      specific mRNAs important for cell cycle progression. This function extends to
      post-mitotic neurons, and perhaps even to cycling somatic cells.

PMID- 15182705
TI  - Imaging molecular interactions by multiphoton FLIM.
AB  - The spatio-temporal localisation of molecular interactions within cells in situ
      and in particular in vivo is of great importance in elucidating the key
      mechanisms in regulation of fundamental process within the cell. Measurements of
      such near-field localisation of protein complexes may be achieved by the
      detection of fluorescence (or Forster) resonance energy transfer (FRET) between
      protein-conjugated fluorophores. The use of fluorescence lifetime imaging
      microscopy (FLIM) to determine both intra- and intermolecular FRET has become an
      important and powerful technique for investigating biological systems. In this
      review we focus on the time-domain-based fluorescence lifetime sensing, using
      time-correlated single photon counting multiphoton microscopy. We give a
      description of the technique, including data acquisition and analysis, and
      discuss the different biological applications of this technology.

PMID- 15182706
TI  - The mitotic spindle and actin tails.
AB  - To segregate their chromosomes, eukaryotic cells rely on a dynamic structure made
      of microtubules: the mitotic spindle. This structure can form in cells lacking
      centrosomes, because their chromosomes also nucleate microtubules. This second
      assembly pathway is observed even in some cells that naturally have centrosomes,
      for example when the centrosomes are ablated by laser surgery. Recent results
      have started to address the complementary question of whether centrosome
      nucleated microtubules alone could sustain the formation of a functional mitotic
      spindle. We wonder in this respect whether lower eukaryotes such as yeasts are
      different from higher eukaryotes such as vertebrates.

PMID- 15182707
TI  - More than G1 or G2 arrest: useful starfish oocyte system for investigating
      skillful MAP kinase.
AB  - During the meiotic cycles in starfish oocytes, MAP kinase (MAPK) is involved in
      the meta-I arrest, the meiosis I to II transition, and the arrest at pronucleus
      stage (G1 and/or G2 phase). The eventual fate, either development or death, of
      mature eggs is also under the control of MAPK. Starfish oocytes are thus a useful
      model system to study multiple functions of skillful MAPK.

PMID- 15182708
TI  - Glyphosate-based pesticides affect cell cycle regulation.
AB  - Cell-cycle dysregulation is a hallmark of tumor cells and human cancers. Failure
      in the cell-cycle checkpoints leads to genomic instability and subsequent
      development of cancers from the initial affected cell. A worldwide used product
      Roundup 3plus, based on glyphosate as the active herbicide, was suggested to be
      of human health concern since it induced cell cycle dysfunction as judged from
      analysis of the first cell division of sea urchin embryos, a recognized model for
      cell cycle studies. Several glyphosate-based pesticides from different
      manufacturers were assayed in comparison with Roundup 3plus for their ability to
      interfere with the cell cycle regulation. All the tested products, Amega, Cargly,
      Cosmic, and Roundup Biovert induced cell cycle dysfunction. The threshold
      concentration for induction of cell cycle dysfunction was evaluated for each
      product and suggests high risk by inhalation for people in the vicinity of the
      pesticide handling sprayed at 500 to 4000 times higher dose than the cell-cycle
      adverse concentration.

PMID- 15182709
TI  - It's all in the assay: a new model for retinotectal topographic mapping.
AB  - Ephrin-As have been implicated as topographic mapping labels in the retinotectal
      system, but the underlying molecular mechanisms for their activities in this
      context remain somewhat mysterious. Hansen et al. (this issue of Neuron)
      developed an assay that reveals new mechanisms for ephrins in topographic mapping
      and suggest a model whereby retinal axons grow and terminate in the tectum via a
      balance of growth promotion and repulsion, with the balance point depending on
      retinal position and concentration of ephrin-As.

PMID- 15182710
TI  - BK channels: the spring between sensor and gate.
AB  - K+ channels contain two main functional domains, an ion-selective pore and a
      sensor that determines whether the cytoplasmic pore gate is open or closed. In
      this issue of Neuron, Niu et al. provide compelling evidence that the link
      between sensor and gate is a remarkably simple mechanical spring.

PMID- 15182711
TI  - Intact frontal memory effect in older age and dementia.
AB  - Older adults and demented patients show preserved functioning on certain tests of
      implicit memory. In this issue of Neuron, Lustig and Buckner demonstrate that
      both groups show comparable repetition-based effects on response time and
      prefrontal activity relative to younger adults.

PMID- 15182712
TI  - Intraflagellar transport genes are essential for differentiation and survival of
      vertebrate sensory neurons.
AB  - Cilia play diverse roles in vertebrate and invertebrate sensory neurons. We show
      that a mutation of the zebrafish oval (ovl) locus affects a component of the
      ciliary transport (IFT) mechanism, the IFT88 polypeptide. In mutant retina, cilia
      are generated but not maintained, producing the absence of photoreceptor outer
      segments. A loss of cilia also occurs in auditory hair cells and olfactory
      sensory neurons. In all three sense organs, cilia defects are followed by
      degeneration of sensory cells. Similar phenotypes are induced by the absence of
      the IFT complex B polypeptides, ift52 and ift57, but not by the loss of complex A
      protein, ift140. The degeneration of mutant photoreceptor cells is caused, at
      least partially, by the ectopic accumulation of opsins. These studies reveal an
      essential role for IFT genes in vertebrate sensory neurons and implicate the
      molecular components of intraflagellar transport in degenerative disorders of
      these cells.

PMID- 15182713
TI  - Retinal axon response to ephrin-as shows a graded, concentration-dependent
      transition from growth promotion to inhibition.
AB  - Ephrin-As act as retinal topographic mapping labels, but the molecular basis for
      two key aspects of mapping remains unclear. First, although mapping is believed
      to require balanced opposing forces, ephrin-As have been reported to be retinal
      axon repellents, and the counterbalanced force has not been molecularly
      identified. Second, although graded responsiveness across the retina is required
      for smooth mapping, a sharp discontinuity has instead been reported. Here, an
      axon growth assay was developed to systematically vary both retinal position and
      ephrin concentration and test responses quantitatively. Responses varied
      continuously with retinal position, fulfilling the requirement for smooth
      mapping. Ephrin-A2 inhibited growth at high concentrations but promoted growth at
      lower concentrations. Moreover, the concentration producing a transition from
      promotion to inhibition varied topographically with retinal position. These
      results lead directly to a mapping model where position within a concentration
      gradient may be specified at the neutral point between growth promotion and
      inhibition.

PMID- 15182714
TI  - Natural variation in the npr-1 gene modifies ethanol responses of wild strains of
      C. elegans.
AB  - Variation in the acute response to ethanol between individuals has a significant
      impact on determining susceptibility to alcoholism. The degree to which genetics
      contributes to this variation is of great interest. Here we show that allelic
      variation that alters the functional level of NPR-1, a neuropeptide Y (NPY)
      receptor-like protein, can account for natural variation in the acute response to
      ethanol in wild strains of Caenorhabditis elegans. NPR-1 negatively regulates the
      development of acute tolerance to ethanol, a neuroadaptive process that
      compensates for effects of ethanol. Furthermore, dynamic changes in the NPR-1
      pathway provide a mechanism for ethanol tolerance in C. elegans. This suggests an
      explanation for the conserved function of NPY-related pathways in ethanol
      responses across diverse species. Moreover, these data indicate that genetic
      variation in the level of NPR-1 function determines much of the phenotypic
      variation in adaptive behavioral responses to ethanol that are observed in
      natural populations.

PMID- 15182715
TI  - Linker-gating ring complex as passive spring and Ca(2+)-dependent machine for a
      voltage- and Ca(2+)-activated potassium channel.
AB  - Ion channels are proteins that control the flux of ions across cell membranes by
      opening and closing (gating) their pores. It has been proposed that channels
      gated by internal agonists have an intracellular gating ring that extracts free
      energy from agonist binding to open the gates using linkers that directly connect
      the gating ring to the gates. Here we find for a voltage- and Ca(2+)-activated K+
      (BK) channel that shortening the linkers increases channel activity and
      lengthening the linkers decreases channel activity, both in the presence and
      absence of intracellular Ca2+. These observations are consistent with a
      mechanical model in which the linker-gating ring complex forms a passive spring
      that applies force to the gates in the absence of Ca2+ to modulate the voltage
      dependent gating. Adding Ca2+ then changes the force to further activate the
      channel. Both the passive and Ca(2+)-induced forces contribute to the gating of
      the channel.

PMID- 15182716
TI  - Modulation of glutamate mobility reveals the mechanism underlying slow-rising
      AMPAR EPSCs and the diffusion coefficient in the synaptic cleft.
AB  - Fast- and slow-rising AMPA receptor-mediated EPSCs occur at central synapses.
      Fast-rising EPSCs are thought to be mediated by rapid local release of glutamate.
      However, two controversial mechanisms have been proposed to underlie slow-rising
      EPSCs: prolonged local release of transmitter via a fusion pore, and spillover of
      transmitter released rapidly from distant sites. We have investigated the
      mechanism underlying slow-rising EPSCs and the diffusion coefficient of glutamate
      in the synaptic cleft (Dglut) at cerebellar mossy fiber-granule cell synapses
      using a combination of diffusion modeling and patch-clamp recording. Simulations
      show that modulating Dglut has different effects on the peak amplitudes and time
      courses of EPSCs mediated by these two mechanisms. Slowing diffusion with the
      macromolecule dextran slowed slow-rising EPSCs and had little effect on their
      amplitude, indicating that glutamate spillover underlies these currents. Our
      results also suggest that under control conditions Dglut is approximately 3-fold
      lower than in free solution.

PMID- 15182717
TI  - Altered cortical synaptic morphology and impaired memory consolidation in
      forebrain- specific dominant-negative PAK transgenic mice.
AB  - Molecular and cellular mechanisms for memory consolidation in the cortex are
      poorly known. To study the relationships between synaptic structure and function
      in the cortex and consolidation of long-term memory, we have generated transgenic
      mice in which catalytic activity of PAK, a critical regulator of actin
      remodeling, is inhibited in the postnatal forebrain. Cortical neurons in these
      mice displayed fewer dendritic spines and an increased proportion of larger
      synapses compared to wild-type controls. These alterations in basal synaptic
      morphology correlated with enhanced mean synaptic strength and impaired
      bidirectional synaptic modifiability (enhanced LTP and reduced LTD) in the
      cortex. By contrast, spine morphology and synaptic plasticity were normal in the
      hippocampus of these mice. Importantly, these mice exhibited specific deficits in
      the consolidation phase of hippocampus-dependent memory. Thus, our results
      provide evidence for critical relationships between synaptic morphology and
      bidirectional modifiability of synaptic strength in the cortex and consolidation
      of long-term memory.

PMID- 15182718
TI  - Precise development of functional and anatomical columns in the neocortex.
AB  - Sensory cortex is ordered into columns, each tuned to a subset of peripheral
      stimuli. To identify the principles underlying the construction of columnar
      architecture, we monitored the development of circuits in the rat barrel cortex,
      using laser-scanning photostimulation analysis of synaptic connectivity,
      reconstructions of axonal arbors, and in vivo whole-cell recording. Circuits
      impinging onto layer 2/3 neurons from layers 4 and 2/3 developed in a monotonic,
      precise progression, with little evidence for transient hyperinnervation at the
      level of cortical columns. Consistent with this, synaptic currents measured in
      layer 2/3 neurons at PND 8, just after these neurons ceased to migrate, revealed
      already spatially well-tuned receptive fields.

PMID- 15182719
TI  - A double dissociation between hippocampal subfields: differential time course of
      CA3 and CA1 place cells for processing changed environments.
AB  - Computational theories have suggested different functions for the hippocampal
      subfields (e.g., CA1 and CA3) in memory. However, it has been difficult to find
      dissociations relevant to these hypothesized functions in investigations of the
      hippocampal correlates of space ("place fields") in freely behaving animals. The
      current study demonstrates a double dissociation between the shifts in the center
      of mass (COM) of the place fields that were simultaneously recorded in CA1 and
      CA3 when familiar cue configurations were dynamically changed over days. The COM
      of CA3 place fields shifted backward in the first experience of the cue-changed
      environment, whereas the COM of CA1 place fields did not display the backward
      shift until the next day. These results support the hypothesis that CA3 plays a
      key role in the rapid formation of representations of new spatiotemporal
      sequences, whereas CA1 may be more important for comparing currently experienced
      sequence information with stored sequences in the CA3 network.

PMID- 15182720
TI  - Neuronal responses related to long-term recognition memory processes in
      prefrontal cortex.
AB  - Much evidence indicates that prefrontal cortex plays an important role in long
      term recognition memory processes. Here, we report primate prefrontal neuronal
      responses carrying information necessary for long-term visual recognition memory.
      The responses of many neurons signaled stimulus familiarity even when the period
      over which stimuli had to be remembered extended to 24 hr. Such responses
      occurred frequently in ventromedial, orbitofrontal, and anterior cingulate but
      not dorsolateral prefrontal cortex. Prefrontal information processing, as
      indicated by the response latencies, started after that in inferior temporal
      cortex and might be related to retrieval processes, as responses were typically
      larger for familiar than for novel stimuli.

PMID- 15182721
TI  - Visual responses on neck muscles reveal selective gating that prevents express
      saccades.
AB  - Express saccades promote the acquisition of visual targets at extremely short
      reaction times. Because of the head's considerable inertia, it is unknown whether
      express saccades are accompanied by a parallel command to the head. Here, by
      recording electromyographic (EMG) activity from monkey neck muscles, we
      demonstrate that visual target presentation elicits time-locked, lateralized
      recruitment of neck muscles at extremely short latencies (55-95 ms). Remarkably,
      such recruitment not only accompanies express saccades, but also precedes
      nonexpress saccades, occasionally by up to 150 ms. These results demonstrate
      selective gating of components of descending commands from the superior
      colliculus to prevent express saccades yet permit recruitment of a head orienting
      synergy. We conclude that such selective gating aids eye-head coordination by
      permitting force development at neck muscles while a decision to commit to a gaze
      shift is being made, optimizing the contribution of the more inertial head to the
      ensuing gaze shift.

PMID- 15182722
TI  - Columnar resolution of blood volume and oximetry functional maps in the behaving
      monkey; implications for FMRI.
AB  - The ultimate goal of high-resolution functional brain mapping is single-condition
      (stimulus versus no-stimulus maps) rather than differential imaging (comparing
      two "stimulus maps"), because the appropriate ("orthogonal") stimuli are rarely
      available. This requires some component(s) of activity-dependent hemodynamic
      signals to closely colocalize with electrical activity, like the early increase
      in deoxyhemoglobin, shown previously to yield high-quality functional single
      condition maps. Conversely, nonlocal vascular responses dominate in cerebral
      blood volume (CBV)-based single-condition maps. Differential CBV maps are largely
      restricted to the parenchyma, implying that part of the CBV response does
      colocalize with electrical activity at fine spatial scale. By removing surface
      vascular activation from optical imaging data, we document the existence of a
      capillary CBV response component, regulated at fine spatial scale and yielding
      single-condition maps exhibiting approximately 100 microm resolution. Blood
      volume and -flow based single-condition functional mapping at columnar level
      should thus be feasible, provided that the capillary response component is
      selectively imaged.

PMID- 15182723
TI  - Interaction between the amygdala and the medial temporal lobe memory system
      predicts better memory for emotional events.
AB  - Emotional events are remembered better than neutral events possibly because the
      amygdala enhances the function of medial temporal lobe (MTL) memory system
      (modulation hypothesis). Although this hypothesis has been supported by much
      animal research, evidence from humans has been scarce and indirect. We
      investigated this issue using event-related fMRI during encoding of emotional and
      neutral pictures. Memory performance after scanning showed a retention advantage
      for emotional pictures. Successful encoding activity in the amygdala and MTL
      memory structures was greater and more strongly correlated for emotional than for
      neutral pictures. Moreover, a double dissociation was found along the
      longitudinal axis of the MTL memory system: activity in anterior regions
      predicted memory for emotional items, whereas activity in posterior regions
      predicted memory for neutral items. These results provide direct evidence for the
      modulation hypothesis in humans and reveal a functional specialization within the
      MTL regarding the effects of emotion on memory formation.

PMID- 15182724
TI  - Preserved neural correlates of priming in old age and dementia.
AB  - Implicit memory, including priming, can be preserved in aging and dementia
      despite impairment of explicit memory. To explore the neural correlates of
      preserved memory ability, whole-brain functional MRI (fMRI) was used during a
      repetition priming paradigm to study 34 young adults, 33 older adults without
      dementia, and 24 older adults in the early stages of dementia of the Alzheimer
      type (DAT). Both older adult groups showed repetition-based response time
      benefits (priming) and changes in activation along inferior frontal gyrus similar
      to those shown by young adults. Across all three groups, repetition-related
      response time reductions correlated with prefrontal activity reductions,
      demonstrating a direct relation between priming and fMRI-measured activity
      change. These results suggest that despite difficulties with deliberate memory,
      both older adults without dementia and those with early-stage DAT can modify
      behavior mediated by prefrontal contributions, making these preserved abilities
      an attractive target for cognitive training and rehabilitation.

PMID- 15182725
TI  - Modulation of ovalbumin-induced Th2 responses by second-generation
      immunomodulatory oligonucleotides in mice.
AB  - Oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG DNAs)
      prevent development of T-helper type 2 (Th2) immune responses and reverse
      established allergic responses in mouse models. We recently reported that second
      generation immunomodulatory oligonucleotides (IMOs) containing novel structures
      (immunomers) and a synthetic immunostimulatory CpR (R=2'-deoxy-7-deazguanosine)
      motif induce the production of distinct cytokine secretion profiles in vitro and
      in vivo. In the present study, we evaluated IMOs containing CpG and CpR motifs to
      modulate allergen-induced Th2 immune responses in prevention and treatment
      models. Mice sensitized and challenged with ovalbumin (OVA) were treated with a
      CpG DNA or an IMO by administration either at the time of OVA sensitization (co
      administration; prevention) or after establishment of an allergic response
      (treatment). Spleens, blood, and lungs were collected and analyzed for immune
      responses. Spleen-cell cultures harvested from OVA-sensitized mice showed a
      significant decrease in Th2 cytokine levels with a concomitant increase in Th1
      cytokine levels only when CpG DNA or IMOs were co-administered with OVA. The co
      administration of CpG DNA or IMOs during OVA sensitization significantly reduced
      serum OVA-specific and total IgE levels in mice. The mice who received CpG DNA or
      IMOs co-administered with OVA showed a small reduction in serum OVA-specific and
      total IgG1 levels and a significant increase in serum OVA-specific and total
      IgG2a levels. Similar results were found in mice with established allergic
      responses who received IMO treatment. IMO treatment also resulted in strong
      inhibition of inflammatory cell infiltration and goblet cell hyperplasia in the
      lungs compared with untreated mice lungs. These data demonstrate that IMOs
      prevent antigen-induced Th2 immune responses when co-administered to mice during
      OVA sensitization and that IMOs reverse established allergic responses induced by
      OVA.

PMID- 15182726
TI  - Trapidil inhibits monocyte CD40 expression by preventing IFN-gamma-induced STAT1
      S727 phosphorylation.
AB  - Trapidil is a triazolopyrimidine that has been found to prevent restenosis after
      vascular injury. Although its precise mode of action is still unclear, several
      biological effects have been described including inhibition of IFN-gamma-induced
      CD40 expression on monocytes. Herein, we investigated the molecular mechanisms by
      which Trapidil exerts this inhibitory action. First, we observed that the
      inhibition of CD40 expression is associated with the suppression of CD40 gene
      transcription, as demonstrated by a clear decrease of CD40 nuclear RNA (nRNA)
      levels and unchanged CD40 mRNA half-life. IFN-gamma-induced CD40 transcription
      has been shown to be mediated by STAT1alpha dimers (p91/p84) which, after nuclear
      translocation, bind to GAS elements present in the promoter of IFN-gamma
      responsive genes. Electrophoresis mobility shift assay (EMSA) with both STAT1
      consensus and CD40 mGAS probes showed that Trapidil did not affect the DNA
      binding ability of STAT1 dimers. STAT1 dimerization and activation are conferred
      by upstream phosphorylation of two amino acid residues of the STAT1 protein. The
      subsequent studies on these two potential STAT1 phosphorylation sites (Tyr701,
      Ser727) revealed that Trapidil attenuated IFN-gamma-induced Ser727 but not Tyr701
      phosphorylation. The inhibition of CD40 transcription by Trapidil could at least
      partially owing to the impaired Ser727 phosphorylation of STAT1, since IFN-gamma
      failed to trigger CD40 expression in U3A S727A cells, a cell line displaying a
      point mutation at the Ser727 site. Collectively, our results indicate that
      phosphorylation of STAT1 at the Ser727 site enhances CD40 transcription and that
      Trapidil might be used as a selective inhibitor that could differentially
      modulate STAT1 target genes.

PMID- 15182727
TI  - Effect of a novel interleukin-5 receptor antagonist, YM-90709 (2,3-dimethoxy-6,6
      dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline), on antigen-induced
      airway inflammation in BN rats.
AB  - Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in
      the allergic inflammation in conditions such as asthma, rhinitis, and atopic
      dermatitis. A newly synthesized compound, YM-90709 (2,3-dimethoxy-6,6-dimethyl
      5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline), was previously reported to
      inhibit the binding of IL-5 to its receptor (R) on human eosinophils and
      eosinophilic HL-60 clone 15 cells. However, it did not inhibit the binding of
      granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptor on the
      same cells. In this study, the intravenous injection of YM-90709 resulted in the
      inhibition of antigen-induced infiltration of eosinophils and lymphocytes, but
      not neutrophils or monocytes, into the bronchoalveolar lavage fluid (BALF) of
      Brown-Norway (BN) rats, with ED50 values of 0.32 mg/kg and 0.12 mg/kg,
      respectively. Two glucocorticoids, dexamethasone and prednisolone, inhibited
      neutrophil, eosinophil, and lymphocyte infiltration into the BALF. However, both
      significantly reduced the number of peripheral blood leukocytes and bone marrow
      leukocytes. In contrast, YM-90709 did not affect the peripheral blood leukocytes
      or the bone marrow leukocytes. These results indicate that, in this model, YM
      90709, which is a novel IL-5 R antagonist, inhibits antigen-induced eosinophil
      and lymphocyte recruitment into the airway, without any suppressive effects on
      peripheral blood leukocytes or bone marrow leukocytes, in contrast to the
      glucocorticoids.

PMID- 15182728
TI  - Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger
      receptor(s) and induces lysosomal damage.
AB  - There is evidence that the chemical modification of proteins (haptens) with
      malondialdehyde-acetaldehyde (MAA) and the immune response to these haptenated
      proteins is associated with the initiation and/or progression of alcohol liver
      disease. Experimentally, proteins modified with MAA induce antibody and T cell
      responses, which are mediated by scavenger receptor(s). Moreover, macrophages
      have been shown to play an important role in processing and presenting MAA
      haptenated proteins in vitro. In vitro, MAA-modified proteins have been shown to
      induce both apoptosis and necrosis in a dose- and cell-type-dependent manner.
      Natural ligands modified by oxidative stress, such as oxidized LDL, similarly
      initiate not only antibody responses, but also cause cell death by disrupting
      lysosomes after binding to scavenger receptors and internalization. We therefore
      investigated the binding, internalization, and lysosomal integrity in a
      macrophage cell line to a MAA-haptenated protein. We demonstrate for the first
      time that MAA-haptenated proteins are preferentially bound by scavenger receptors
      on macrophages, which internalize the ligands and shuttle them to lysosomes.
      Moreover, MAA-haptenated proteins are demonstrated to be associated with a rapid
      dose-dependent disruption in lysosomal integrity, resulting in leakage and
      caspase activation. Similarly, as hen egg lysozyme (HEL)-MAA concentrations
      increased (>31.3 microg/ml), increased levels of apoptosis and a G1/S cell cycle
      checkpoint inhibition were identified. This study identifies mechanisms by which
      MAA-haptenated proteins are taken up by a representative antigen-presenting cell
      and may delineate steps by which MAA-haptenated proteins induce cell death and
      induce their immunogenicity to the carrier protein.

PMID- 15182729
TI  - Lipopolysaccharide-induced paw edema model for detection of cytokine modulating
      anti-inflammatory agents.
AB  - Cytokines are critical to pathogenesis of inflammatory disorders. So inhibition
      of their action provides therapeutic benefits in various diseases. Although
      inhibition of inflammation caused by intraperitoneally administered LPS can
      identify cytokine modulators, this inflammatory test-agent does not allow one to
      determine overall anti-inflammatory potential. Functional characteristics of
      Carrageenan (Cara)-induced edema were valuable for identification of nonsteroidal
      anti-inflammatory drugs (NSAIDS). Hence, the potential of LPS-induced paw
      inflammation was investigated and compared to that by Cara. Stimulation of
      isolated rat peritoneal exudates cells (PEC) with 10 ng/ml LPS, but not Cara,
      induced IL-6 (3.04+/-0.2 ng/ml) and TNFalpha (1.030.09 ng/ml). At least 100 mg/ml
      Cara was necessary for detection of IL-6 (2.03+/-0.1 ng/ml) and TNFalpha
      (0.6+0.09 ng/ml) in PEC. Similar to Cara, subplantar administration of LPS
      induced inflammatory paw edema in rats. LPS, but not Cara, induced TNFalpha
      (2.14+/-0.6 ng/ml) and IL-6 (2.9+/-0.5 ng/ml) in serum at 1 and 3 h,
      respectively, which returned to basal levels by 5 h. LPS-induced serum TNFalpha
      (sTNFalpha) levels closely paralleled paw swelling and its neutralization by anti
      TNFalpha antibody or inhibition by pentoxifylline and nimesulide correlated with
      inhibition of inflammation. Similar to earlier reports, rofecoxib induced
      sTNFalpha at 30 mg/kg and exhibited pro-inflammatory effect by enhancing paw
      swelling. LPS-induced edema provides a useful functional model for identification
      of cytokine modulating anti-inflammatory agents.

PMID- 15182730
TI  - Up-regulation of phospholipase Cgamma1 and phospholipase D during the
      differentiation of human monocytes to dendritic cells.
AB  - Phospholipase C (PLC)gamma and phospholipase D (PLD) play pivotal roles in the
      signal transduction required for various cellular responses, including cell
      proliferation and differentiation. Dendritic cells (DCs), which are professional
      antigen-presenting cells, can be generated from human monocytes by stimulating
      the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) and
      interleukin 4 (IL-4). We investigated whether PLCgamma and PLD expression levels
      can be changed during the differentiation of the human monocytes into DCs. The
      enzymatic activity and protein level of PLC gamma1 were significantly increased
      in the human monocyte-derived DCs by GM-CSF/IL-4, but the protein levels of PLC
      gamma2 were unaltered. Moreover, the enzymatic activity and protein level of
      PLD1b and PLD2 were up-regulated during the differentiation of human monocytes to
      DCs, but those of PLD1a were not changed. A higher phagocytic activity of DCs was
      found to be correlated with the up-regulations of PLCgamma1 and PLD, and the
      phagocytic activity of DCs was inhibited by a PLC-specific inhibitor (U73122) and
      by a phosphatidic acid acceptor (n-butanol), but to be increased by phosphatidic
      acid. Thus, suggesting that PLC and PLD participate in the process. This study
      suggests that the up-regulations of PLCgamma1 and PLD are accompanied by the
      differentiation of monocytes into DCs, which results in increased phagocytic
      activity.

PMID- 15182731
TI  - AM3 inhibits HBV replication through activation of peripheral blood mononuclear
      cells.
AB  - In this report, we have analyzed the effect of AM3, a glycoconjugate of natural
      origin with immunomodulatory properties, which is available under the commercial
      name of Inmunoferon, on hepatitis B virus (HBV) replication in HBV-transfected
      cells. We found that AM3 inhibited HBV RNA expression as well as DNA synthesis
      and viral antigen expression by an indirect mechanism. We found that AM3 lacked
      intrinsic antiviral properties, and that the antiviral effect of the
      glycoconjugate was due to stimulation of secretion of molecules with antiviral
      properties by peripheral blood mononuclear cells. Our data indicate that the
      employment of AM3 as an adjuvant administered simultaneously with conventional
      antiviral drugs may potentiate the endogenous response against viral infection.

PMID- 15182732
TI  - Differential effects of clindamycin on neutrophils of healthy donors and septic
      patients.
AB  - Antibiotics are frequently administered to ICU patients in case of bacterial
      infections. Little is known, however, about the interference of antibiotics with
      neutrophil host defence mechanisms in patients with sepsis and multiple organ
      dysfunction syndrome (MODS). With our study, evidence for differential
      clindamycin effects on neutrophils in healthy donors and septic patients without
      or with MODS was sought. Functional parameters (oxidative response and
      phagocytosis) and fMLP receptor expression were analysed. The study was approved
      by the local ethical board. Venous blood was drawn from healthy donors and septic
      patients. Neutrophils in PBS were incubated with 0, 5, 25 or 125 microg/ml
      clindamycin and analysed flow cytometrically. Neutrophils of patients with sepsis
      and MODS showed a significantly higher basal activation compared to healthy
      donors. Clindamycin application led to a dose-dependent significant suppression
      of the fMLP-induced oxidative response in patients with sepsis and MODS, but not
      in healthy donors or septic patients in the absence of MODS. In patients with
      sepsis and MODS, phagocytosis of Escherichia coli and Staphylococcus aureus was
      significantly suppressed by clindamycin 125 microg/ml. In both other treatment
      groups, clindamycin did not affect phagocytosis. fMLP receptor expression was not
      altered by clindamycin. High-dose clindamycin selectively suppresses functional
      responses of neutrophils in septic patients with MODS. Simultaneously applied
      drugs, such as general anaesthetics, may potentiate this modulation of
      antibacterial defence and inflammation.

PMID- 15182734
TI  - Extracellular ATP inhibits apoptosis and maintains cell viability by inducing
      autocrine production of interleukin-4 in a myeloid progenitor cell line.
AB  - Interleukin-3 (IL-3)-dependent myeloid progenitor cell FDC.P2 is induced to
      undergo apoptotic cell death upon IL-3 depletion. Extracellular adenosine
      triphosphate (ATP) was found to prevent apoptosis and maintain cell viability of
      FDC.P2 cells upon IL-3 withdrawal. The antiapoptotic effect of ATP required
      extracellular Ca2+. Furthermore, FK506, a specific inhibitor of
      calcium/calmodulin-dependent protein phosphatase calcineurin, inhibited the
      antiapoptotic effect of ATP. As one of cytokines whose expression is dependent on
      the activation of calcineurin, interleukin-4 (IL-4) played a critical role in ATP
      mediated cell survival of FDC.P2 cells because neutralizing antibody against IL-4
      effectively abrogated the antiapoptotic activity of ATP. Moreover, ATP treatment
      induced a significant amount of secreted IL-4 that was sufficient to maintain
      cell viability. Taken together, our present results demonstrate that
      extracellular ATP triggers autocrine production of IL-4 through calcium-dependent
      activation of calcineurin and secreted IL-4 substitutes IL-3 in protecting FDC.P2
      cells from apoptosis even in the absence of IL-3.

PMID- 15182733
TI  - Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)
      deoxynojirimycin protects against the inflammatory response in hapten-induced
      colitis.
AB  - Since glycolipid biosynthesis is potentially involved in immunological and
      inflammatory responses, we tested the effect of a novel inhibitor of
      intracellular glycolipid biosynthesis N-(5-adamantane-1-yl-methoxy-pentyl)
      deoxynojirimycin (AMP-DNM) in two hapten-induced colitis models: trinitrobenzene
      sulphonic acid (TNBS)- and oxazolone (4-ethoxymethylene-2phenyl-2oxazoline-5-one;
      Oxa)-induced colitis. AMP-DNM was given either by intraperitoneal injection or
      orally via the diet. Mice treated with AMP-DNM had less severe colitis and a more
      rapid weight recovery, less edema and less wall thickness. Cellular infiltration,
      goblet cell loss and myeloperoxidase (MPO) activity were reduced in colons of AMP
      DNM-treated animals. Intralesional IFN-gamma and IL-18 production were lower in
      mice of the AMP-DNM-treated groups. Furthermore, AMP-DNM treatment reduced the
      serum anti-TNBS and anti-Oxa antibody levels. Our findings show that the
      glycolipid biosynthesis inhibitor AMP-DNM has a strong anti-inflammatory and
      immune suppressive activity on both TNBS- and Oxa-induced colitis. The data also
      provide evidence that glycolipid biosynthesis is involved in the inflammatory
      cascade in these inflammatory bowel disease (IBD) models.

PMID- 15182735
TI  - Protective and anti-arthritic effects of deer antler aqua-acupuncture (DAA),
      inhibiting dihydroorotate dehydrogenase, on phosphate ions-mediated chondrocyte
      apoptosis and rat collagen-induced arthritis.
AB  - The effect of water extract of deer antler aqua-acupuncture (DAA; Cervi
      Pantotrichum Cornu) prepared from the pilose antler of Cervus korean TEMMINCK
      var. mantchuricus Swinhoe (Nokyong in Korean), a traditional immunosuppressive
      and immunoactivating Korean herbal acupuncture [Int. Immunopharm. 3 7 (2003)
      1001] on rat chondrocyte apoptosis was studied. Terminally differentiated
      hypertrophic chondrocytes were isolated from rat costochondrial cartilage and
      cell death was measured in the presence of 3-5 mM phosphate ions (Pi). The effect
      of 10 microg/ml DAA was compared to that of phosphonoformic acid (PFA), a
      competitive inhibitor of the Na-Pi co-transport on Pi-induced apoptosis in
      chondrocytes. A total of 1 mM PFA blocked anion-induced cell death and prevented
      an increase in the cell Pi content. In a parallel study, we determined that the
      DAA also protected chondrocytes from death. On the other hand, the effect of DAA
      was also evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase)
      and tested in the rat collagen-induced arthritis (CIA) model. Female 7-week-old
      Sprague-Dawley rats were used for the evaluation of DAA in the CIA model.
      Arthritis was evaluated by arthritis score, body weight loss, bone destruction
      score. DAA was administered by bilateral Shinsu (B23) acupuncture five times per
      week (10, 20, 30, and 100 microg/kg/day). DAA inhibited rat liver DHO-DHase in
      vitro with Ki = 843 +/- 43 microg/ml. The anti-proliferative effect of DAA was
      caused by cell cycle arrest at the S-phase. Treatment with 300 mg/kg/day of DAA
      completely prevented the development of CIA based on the reduction of the
      arthritis score. The 50% effective dose (ED50) of DAA on arthritis score was 64
      mg/kg. DAA ameliorated body weight loss associated with disease onset. DAA
      suppressed the development of arthritis, even when it was administered after a
      booster immunization of collagen. DAA is a novel immunosuppressant which inhibits
      DHO-DHase and its effects in CIA suggest that it could be useful in the treatment
      of rheumatoid arthritis.

PMID- 15182736
TI  - Adenosine suppresses GABAA receptor-mediated responses in rat sacral dorsal
      commissural neurons.
AB  - The modulatory effect of adenosine on gamma-aminobutyric acid (GABA)-activated
      whole-cell currents were investigated in the neurons acutely dissociated from the
      rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch
      recording configuration under the voltage-clamp conditions. The results showed
      that: (1) GABA acted on GABAA receptor and elicited inward Cl- currents (IGABA)
      at a holding potential (VH) of -40 mV; (2) adenosine suppressed GABA-induced Cl-
      current without affecting the reversal potential of IGABA and the apparent
      affinity of GABA to its receptor; (3) N6-cyclohexyladenosine mimicked the
      suppression effect of adenosine on IGABA, whereas 8-cyclopentyl-1,3
      dipropylxanthine blocked the suppression effect of adenosine; (4) adenosine fails
      to suppress IGABA on the neurons that were pretreated with bisindolylmaleimide I
      (BIM), while after pretreatment with H-89, the inhibitory effect of adenosine on
      IGABA were not affected; (5) the suppression effect of adenosine on IGABA
      remained in the presence of BAPTA-AM. The present results indicate that the
      suppression of adenosine on IGABA is mediated by adenosine A1 receptor and
      through a Ca2+-independent protein kinase C transduction pathway, and that the
      interactions between adenosine and GABA might participate in the modulation of
      nociceptive information transmission at the SDCN.

PMID- 15182737
TI  - Baroreflex control of renal sympathetic nerve activity and spontaneous rhythms at
      Mayer wave's frequency in rats.
AB  - The effects of sedation with pentobarbital sodium (15 mg/kg followed by 15.9+/
      1.2 mg/kg/h, i.v.) on arterial pressure (AP) Mayer waves and accompanying
      oscillations of renal sympathetic nerve activity (RSNA) were examined in rats
      (n=8). As compared with values observed in the conscious state, pentobarbital
      significantly (P<0.05) decreased AP (from 119+/-2 to 93+/-3 mm Hg), heart rate
      (HR; from 427+/-11 to 355+/-11 beats/min) and RSNA (from 1.20+/-0.27 to 0.62+/
      0.13 microV). The baroreflex control of RSNA was analyzed by fitting a sigmoid
      logistic function to changes in RSNA and AP observed during nitroprusside and
      phenylephrine administrations. During pentobarbital infusion, the RSNA-AP
      relationship was reset towards lower AP values, but neither its maximum gain nor
      its gain at resting AP were significantly altered (from 6.3+/-1.0 to 5.8+/-1.4
      and from 3.2+/-0.5 to 3.8+/-1.3 normalized units (n.u.)/mm Hg, respectively).
      Spectral power in the frequency band containing Mayer waves (0.29-0.73 Hz) was
      significantly decreased by pentobarbital for both AP (from 4.65+/-0.90 to 0.95+/
      0.25 mm Hg2) and RSNA (from 1437+/-245 to 488+/-79 n.u.2). This effect was mainly
      secondary to the attenuation of strongly coherent oscillations of both variables
      at approximately 0.4 Hz. Although previous experimental evidence points to a
      major involvement of the sympathetic limb of the arterial baroreceptor reflex in
      the genesis of Mayer waves, the present study indicates that the amplitude of
      these oscillations cannot be used as a quantitative index of sympathetic
      baroreflex sensitivity.

PMID- 15182738
TI  - P2X2 and P2X3 receptor expression in the gallbladder of the guinea pig.
AB  - We investigated for the first time, the distribution pattern of P2X2 and P2X3
      receptors in the gallbladder of the guinea pig using immunohistochemistry. P2X2
      and P2X3 receptor-immunoreactive nerve fibers were observed within the ganglia,
      in the interganglionic connectives, in the muscularis and in the paravascular
      plexus. Immunoreactivity for P2X2 and P2X3 was also observed in most neurons in
      the ganglionated plexus. Double-labeling studies revealed that 58.1% of all P2X2
      positive neurons and 54.3% of all P2X3-positive neurons were found to display
      nitric oxide synthase. Over 90% of the neurons that were immunoreactive for P2X2
      and P2X3 receptor were also immunoreactive for calretinin. We also found that
      30.5% of P2X2- and 32.6% of P2X3-immunoreactive neurons were also immunoreactive
      for vasoactive intestinal peptide. No P2X2- or P2X3- immunoreactive neurons
      stained for calcitonin gene-related peptide; a few calcitonin gene-related
      peptide-immunoreactive nerve fibers also showed immunoreactivity to P2X2 or P2X3
      receptors. These results further demonstrate the neurotransmitter diversity of
      the nerves of the gallbladder and provide an incentive for studies of the actions
      of these compounds in the gallbladder wall.

PMID- 15182739
TI  - Hypercapnia induces long-term changes in postganglionic renal nerve activity in
      the piglet.
AB  - In developing swine, time and frequency domain analyses were used to compare
      changes in discharge features of efferent phrenic and postganglionic renal nerve
      activities evoked by prolonged (1 h) exposure to severe hypercapnia (10% CO2,
      balance O2), before and after combined carotid sinus and aortic depressor nerve
      (CSN-AOD) sectioning. With intact CSN-AOD innervation, respiration-related
      activity in renal nerve discharge was rare (3 of 11 animals) during baseline
      periods with intact innervation, but was observed in most cases (10 of 11
      animals) during baseline following denervation. Renal nerve respiration-related
      activity was recruited by hypercapnic stimulation in animals with intact CSN-AOD
      innervation, and was augmented in denervated animals with ongoing respiratory
      activity. Phrenic nerve discharge was markedly augmented during hypercapnia,
      whether CSN-AOD innervation was intact or not, and it did not exhibit a post
      hypercapnic depression. Autopower spectra of renal nerve activity revealed the
      presence of two coexisting rhythms, 2-6 and 7-13 Hz, which were present whether
      CSN-AOD innervation was intact or not. The hypercapnic-induced increases of
      activity in the 2-6 and 7-13 Hz bands were not comparable, with the latter region
      exhibiting a much more robust response to hypercapnia, especially following CSN
      AOD denervation. Thus, prolonged exposure to hypercapnia evoked changes in renal
      nerve discharge that involved increased coupling to neuronal ensembles shaping
      central inspiratory activity and those generating central sympathetic outflows,
      especially to networks generating 7-13 Hz rhythm. Such changes may permit more
      efficient modulation of innervated structures during exposure to stressors.

PMID- 15182740
TI  - The role of neuronal nitric oxide in the vagal control of cardiac interval of the
      rat heart in vitro.
AB  - The aim of this study was to examine the role of neuronal nitric oxide (NO) on
      vagal regulation of the rat heart in vitro using the neuronal nitric oxide
      synthase (nNOS) inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM). All
      experiments were carried out in the presence of the beta-adrenoreceptor
      antagonist atenolol (4 microM). Right thoracic vagus, or its cardiac branch, was
      stimulated at frequencies of 2, 4, 8, 16 and 32 Hz (pulse duration 1 ms, 20 V,
      for 20 s) before and after addition of TRIM (0.14 mM) and cardiac interval (ms)
      assessed. There was a significant positive linear correlation between cardiac
      interval and vagal frequency giving a slope of 2.76+/-0.8 ms/Hz (slope+/-S.E.
      slope; data pooled from eight rats) which was significantly attenuated following
      TRIM to 0.4+/-0.6 ms/Hz (P<0.05 ANOVA; n=8 rats). Nicotine applied in cumulative
      concentrations (0.03, 0.1, 0.3, 0.5, 1 mM) caused a linear concentration
      dependent increase in cardiac interval, with a slope of 403+/-72 ms/mM (n=10
      rats) which was significantly attenuated after treatment with hexamethonium (28
      microM), to 190+/-36 ms/mM (n=10 rats, P<0.05 ANOVA), and atropine (3 microM)
      100+/-31 ms/mM (n=9 rats, P<0.05 ANOVA) but not following TRIM (0.14 mM) 262+/-48
      ms/mM (n=9 rats, P<0.05 ANOVA). These results suggest that NO facilitates vagal
      effects on the rat heart in vitro by an action at the pre-ganglionic/post
      ganglionic synapse.

PMID- 15182741
TI  - Does sympathetic nerve discharge affect the firing of myelinated cutaneous
      afferents in humans?
AB  - In clinical practise, the notion that some complex regional pain syndromes (CRPS)
      are associated with sympathetic facilitation of nociceptive transmission is
      widespread. However, physiological increases in cutaneous sympathetic nerve
      activity have not been found to influence the firing properties of cutaneous
      polymodal nociceptive (high-threshold mechano-heat sensitive) fibers in human
      subjects. Whether the same applies to low-threshold cutaneous mechanoreceptors is
      not known. Such an effect could be relevant for sympathetic facilitation of
      nociception, given that tactile afferents are implicated in the allodynia
      associated with CRPS. This issue was addressed by recording the responses of
      single cutaneous mechanoreceptors in the glabrous skin of the finger pads to
      constant mechanical stimuli, at rest and during physiological increases in
      cutaneous sympathetic activity produced by arousal stimuli. Unitary recordings
      were made from 17 rapidly adapting (15 FAI and 2 FAII) and 20 slowly adapting (9
      SAI and 11 SAII) afferents located in the finger pads via tungsten
      microelectrodes inserted percutaneously into the median nerve at the wrist in
      nine subjects. A servomotor applied 1 s constant-displacement ramp-and-hold
      indentations to the receptor-bearing digit every 3 s. Displacement and
      compression force were recorded. Blood flow in the finger pad and sweating in the
      palm were measured contralaterally. Increases in cutaneous sympathetic outflow
      caused only modest changes in the spontaneous and compression-evoked firing of
      tactile afferents. These changes were usually (for 26/37 afferents) related to
      the associated decreases in skin blood flow. The latency from the start of the
      ramp stimulus to the onset of firing was inversely correlated to flow (i.e. unit
      response was delayed during vasoconstriction) for 11/31 units (7/15 FAI, 1/2
      FAII, 2/9 SAI, 1/5 SAII), whereas no units showed a positive correlation.
      Compression-evoked firing rates were positively correlated to flow (i.e.
      vasoconstriction reduced firing rates) for 14/31 units (2/15 FAI, 1/2 FAII, 7/9
      SAI, 4/5 SAII), whereas no units showed a negative correlation. 10/11 SAII
      afferents exhibited spontaneous background firing, which increased for 4 and
      decreased for 4 in response to arousal stimuli, presumably reflecting their
      sensitivity to changes in skin stretch associated with sympathetically mediated
      reductions in blood volume in the finger pad. Two afferents showed no change, but
      nor was there significant vasoconstriction in these recordings. Thus, arousal
      stimuli reduced rather than augmented tactile afferent firing. The close relation
      to blood flow for all types of afferents, and the different responses among SAII
      afferents, suggest that sympathetically mediated changes in afferent firing
      properties are indirect, i.e. secondary to changes in the mechanoreceptors'
      tissue environment rather than to a direct sympathetic effect on the endings.

PMID- 15182742
TI  - Stroke volume and sympathetic responses to lower-body negative pressure reveal
      new insight into circulatory shock in humans.
AB  - We measured various hemodynamic responses and muscle sympathetic nerve activity
      (MSNA) in human subjects during a graded lower-body negative pressure (LBNP)
      protocol to test the hypotheses that: (1) reduced stroke volume (SV) is linearly
      related to increased MSNA; and (2) the onset of symptoms of impending
      cardiovascular collapse is associated with hypoadrenergic responses to central
      hypovolemia. We measured heart rates, arterial blood pressures, sympathetic
      neural activity (MSNA; peroneal nerve microneurography), and relative changes (%
      Delta) in SV (thoracic electrical bioimpedance) in 13 men during exposure to
      graded levels of LBNP. After a 12-min baseline data collection period, LBNP was
      initiated at -15 mm Hg for 12 min followed by continuous stepwise increments to 
      30, -45, and -60 mm Hg for 12 min each. Eight subjects completed the LBNP
      protocol (finishers), while the protocol was terminated prematurely during -60 mm
      Hg in five subjects due to onset of symptoms of cardiovascular collapse
      (nonfinishers). Of these subjects, we were able to record MSNA successfully
      throughout the LBNP protocol in four finishers and two nonfinishers. The
      relationship between average change in stroke volume and average change in MSNA
      was linear (% DeltaMSNA=464-3.6 [% DeltaSV], r2=0.98). On average, MSNA was
      greater in the nonfinishers at each level of LBNP compared to finishers, but
      peripheral resistance was lower. Our results support the hypothesis that MSNA
      activation is inversely related and linear to stroke volume reductions during
      central hypovolemia. Sympathetic withdrawal rather than hypoadrenergic function
      may represent a fundamental mechanism for the development of circulatory shock.

PMID- 15182743
TI  - Interaction between paraventricular nucleus and medial septal area on the renal
      effects induced by adrenaline.
AB  - The aim of the present study was to analyze the role of alpha1, alpha2
      adrenoceptors, and the effects of losartan and PD123319 (selective ligands of the
      AT1 and AT2 angiotensin receptors, respectively) injected into the
      paraventricular nucleus (PVN) on the diuresis, natriuresis, and kaliuresis
      induced by administration of adrenaline into the medial septal area (MSA). Male
      Holtzman rats with a stainless steel cannula implanted into the MSA and
      bilaterally into the PVN were used. The administration of adrenaline into the MSA
      increased in a dose-dependent manner the urine, sodium, and potassium excretions.
      The previous administration of prazosin (an alpha1-adrenoceptor antagonist)
      injected into the PVN abolished the above effects of adrenaline, whereas
      yohimbine (an alpha2-adrenoceptor antagonist) doesn't affect the diuresis,
      natriuresis, and kaliuresis induced by adrenaline. Pretreatment with losartan
      into the PVN decreased in a dose-dependent manner the urine, sodium, and
      potassium excretions induced by MSA administration of adrenaline (50 ng), while
      PVN PD123319 was without effect. These results indicate that urinary and
      electrolyte excretion effects induced by adrenaline into the MSA are mediated
      primarily by PVN AT1 receptors. However, the doses of losartan were more
      effective when combined with the doses of PD123319 than given alone, suggesting
      that the urinary, natriuretic, and kaliuretic effects of MSA adrenaline may
      involve activation of multiple angiotensin II receptors subtypes into the PVN.

PMID- 15182745
TI  - Changes in heart rate variability before and after surgery in patients with
      pheochromocytoma.
AB  - We assessed ambulatory blood pressure and heart rate variability in two female
      patients with pheochromocytoma. The ambulatory blood pressure and ECG R-R
      intervals were measured during a 24-h period with a portable recorder before and
      3 weeks after surgery. A power-spectral analysis of R-R intervals was performed
      to obtain the low-frequency (LF) and high-frequency (HF) components. The
      percentage of differences between adjacent normal R-R intervals >50 ms (pNN50)
      was also calculated. In both patients, the plasma epinephrine and norepinephrine
      levels decreased markedly after surgery. The 24-h blood pressures also decreased
      after surgery. In both patients, the 24-h average LF component, HF component, and
      pNN50 decreased after surgery, while the 24-h average LF/HF ratio increased after
      surgery. These results suggest that high circulating catecholamines inhibit
      central sympathetic neural outflow and augment parasympathetic nerve activity in
      patients with pheochromocytoma.

PMID- 15182744
TI  - In vivo assessment of catechol O-methyltransferase activity in rabbit skeletal
      muscle.
AB  - With the use of microdialysis technique in the anesthetized rabbit, we examined
      the catechol O-methyltransferase (COMT) activity at the skeletal muscle
      interstitium. We implanted a dialysis probe into the adductor muscle, and
      monitored dialysate catecholamines and their metabolites with chromatogram
      electrochemical detection. Administration of COMT inhibitor (entacapone)
      decreased dialysate 3-methoxy 4-hydroxyphenylglycol (MHPG) levels. Local
      administration of dihydroxyphenylglycol induced increases in dialysate MHPG
      levels. These increases in dialysate MHPG levels were suppressed by the addition
      of entacapone. The concentration of MHPG in the skeletal muscle dialysate
      corresponded to the COMT activity in the skeletal muscle. Furthermore, local
      administration of norepinephrine or epinephrine increased normetanephrine or
      metanephrine levels in dialysate but not MHPG levels. Skeletal muscle
      microdialysis with local administration of catecholamine offers a new method for
      in vivo assessment of regional COMT activity.

PMID- 15182746
TI  - Workers' compensation: a historical review and description of a legal and social
      insurance system.
AB  - The workers' compensation system is a no-fault legal and social insurance system
      established to address compensation issues that involve work-related injuries and
      illnesses. The system was developed in response to dissatisfaction with common
      law litigation on the parts of injured workers and employers. The history of the
      development of workers' compensation is reviewed, and a general description of
      the system is offered, including discussion of state law and insurance
      structures, benefits and costs, administrative boards/commissions, and the
      federal systems for workers' compensation and related programs. The recent
      history of the workers' compensation system is provided, the recommendations of
      the National Commission on State Workmen's Compensation Laws in 1972 are
      reviewed, and the problems and state-initiated changes in worker's compensation
      that occurred during the 1990s are discussed.

PMID- 15182747
TI  - Factors influencing the costs of workers' compensation.
AB  - This article presents several factors believed to have shaped the costs of
      workers' compensation. Of these factors, the most notable influence on claims
      severity is related to the way medical care is delivered to treat occupational
      injuries and illnesses. Although medical care providers may have some influence
      on the other factors responsible for increased claims severity, such as attorney
      costs and differences in state workers' compensation laws, they have a tremendous
      impact on the way medical care is delivered and its resultant costs. This places
      physicians, nurse practitioners,physical therapists, chiropractors, nurses, and
      physician assistants in a unique role of being able to assist US business in
      improving productivity through a reduction in workers' compensation costs.

PMID- 15182748
TI  - Workers' compensation reform.
AB  - Workers' compensation reform efforts respond to the competing interests of
      business, labor and insurers. Early reforms expanded programs in response to
      inadequate benefits and coverage while in the 1980s and 1990s states responded to
      increasing costs by tightening fee schedules, limiting physician choice,
      restricting eligibility,lowering benefits, and integrating managed care into
      workers' compensation. Although managed care has resulted in significant medical
      savings, the cost of workers' compensation is again rapidly increasing in some
      states, where workers' compensation legislation is again at the center of debate.
      Increasing the use of treatment guidelines, placing limitations on use of
      services, developing more objective criteria for determining level of disability,
      and streamlining dispute resolutions have been offered as solutions. Controlling
      costs alone, however, cannot solve other problems of workers' compensation.
      Future reform efforts will need to focus not only on the costs of the system but
      also its inclusiveness and support of the workers and their families it was
      intended to protect.

PMID- 15182749
TI  - The relationship of workers' compensation to the Americans with Disabilities Act
      and Family and Medical Leave Act.
AB  - This article examines the intersection of workers' compensation laws with the
      Americans with Disabilities Act (ADA) and the Family and Medical Leave Act
      (FMLA). Much ADA and FMLA litigation stems from work-related injuries or
      illnesses. Knowledge of the ADA and FMLA may help prevent workers' compensation
      cases from resulting in costly employment litigation. Employees who are absent
      from work for a work-related condition often have rights under other laws,
      besides workers' compensation laws, such as the ADA and FMLA. Employers need to
      be cognizant of this while addressing these cases. First, the goals of state
      workers' compensation laws and the ADA and FMLA are reviewed. Then specific
      issues involving the intersection of workers' compensation, ADA,and FMLA are
      discussed.

PMID- 15182750
TI  - Managing workers' compensation costs: success of initiatives to change outcomes.
AB  - The cost of workers' compensation health care has been a challenge during the
      past few decades. Various programs have been initiated on the local, state, and
      national levels to address this issue. The purpose of this article is to examine
      some of the programs that have initiated cost control measures. Most of those
      published claim successful outcomes. The initiatives reviewed herein were
      instituted at medical centers in Maryland and Pennsylvania, at casino hotels in
      Nevada, at an occupational health clinic in Ohio, at an electrical union in New
      York State, and at an insurance company. Initiatives in Minnesota and Washington
      State are also described. Sharing the outcomes of initiatives may allow such
      research to be translated into action on a broader scale.

PMID- 15182751
TI  - The Washington state workers' compensation system: a case study.
AB  - Washington State workers' compensation has researched applying managed care in
      workers' compensation through a series of research projects. In 1995 and 1996,
      the managed care project evaluated the impact of managed care on medical
      outcomes, patient satisfaction, and the cost control of medical care and
      disability. The managed care project also evaluated the long-term outcome of the
      cases by reviewing the participants 2 years after the injury. Finally,the managed
      care project evaluated the satisfaction of the employer with managed care. The
      Department of Labor and Industries Centers of Occupational Health and Education
      project currently is evaluating the impact of an occupational medicine
      directed,education-oriented, protocol-guided pilot project.

PMID- 15182752
TI  - Managing workers' compensation costs in the military setting: the Army's story.
AB  - Direct and indirect costs for the Army's workers' compensation payments have
      increased to more than 2 billion US dollars. Increasing attention is putting the
      spotlight on the problems at all levels, and a promising cooperative approach to
      injury prevention and case management is emerging. This article addresses the
      system within which the Army's workers' compensation program operates, provides
      some organizational history, gives an update on current status,and describes what
      is needed for sustained improvement. The onus is on the Army to develop and
      implement strategies that use available data to target high-risk occupations and
      employees to prevent accidents, injuries, and illnesses. Front-line managers bear
      the responsibility for educating the workforce and providing safe workplaces.
      Employees become the beneficiaries, not of medical and compensation benefits but
      of safe and healthy work environments.

PMID- 15182753
TI  - Evidence-based clinical occupational medicine: updating the ACOEM occupational
      medicine practice guidelines.
AB  - In this article, we review the evolution and application of evidence based
      medicine and the results of the literature reviews and syntheses incorporated in
      the second edition of the guidelines. Our intent is to disseminate this
      information to practitioners treating injured workers and those managing and
      financing such care and disability management. Use of proven diagnostic,
      causality, testing,and treatment methods should markedly improve the quality of
      occupational medical care and make that care more cost effective.

PMID- 15182754
TI  - Workers' compensation fraud and the physician.
AB  - Some individuals in the health care system base their actions primarily on
      individual economic incentives rather than ethical and societal standards. These
      actions are considered fraudulent when they can be proven to have violated
      specific laws or statutes and can impact workers' compensation costs. Physicians
      and other health care providers involved in the management of workers'
      compensation claims may have little ability to affect employer or insurer fraud.
      Ethical and efficient practice style, in conjunction with the maintenance of
      clarity and objectivity in the evaluation of patient symptoms, can help to reduce
      the degree to which provider and patient fraud is allowed to develop and
      flourish. In understanding the factors that promote fraudulent behavior and being
      able to recognize and manage such behavior, health care providers may impact the
      perpetuation of fraud and its impact on the workers' compensation system.

PMID- 15182755
TI  - The art of directing a workers' compensation claim: personal observations on the
      role of the workers' compensation claim adjuster.
AB  - Workers' compensation claims are becoming more complex and expensive every day.
      One of the contributing factors for the increase is the aging workforce as well
      as federal legislation such as the Americans with Disabilities Act (ADA) and the
      Family and Medical Leave Act (FMLA). The workforce is aging, mobile, and educated
      about their rights. The key to avoiding spiraling costs is a strong safety and
      claims program that is sponsored by senior management,valued by the employees,
      and implemented by the entire company.

PMID- 15182757
TI  - Workers' compensation costs: still a challenge.
AB  - The workers' compensation system in the United States, comprised of independent
      state based and national programs for federal workers, covers approximately 127
      million workers and has evolved and grown since its inception in 1911. Coverage
      has significantly broadened in scope to allow for the inclusion of most
      occupational injuries and illnesses. The cost of workers' compensation care has
      also increased. Some of the cost drivers have been identified,and various
      approaches have been taken to address medical cost containment. There is a need
      to balance cost control with ensuring benefit adequacy and quality of medical
      care. It is likely that managing workers' compensation costs will continue to be
      a challenge in the foreseeable future. The cost of workers' compensation care
      affects all stakeholders including workers, employers,providers, state workers'
      compensation regulators, legislatures,and insurers. A continued commitment to
      quality, accessibility to care, and cost containment, and being alert to emerging
      issues that can affect these elements, will help ensure that workers are afforded
      accessible, high quality, and cost-effective care.

PMID- 15182756
TI  - Workers' compensation and health and productivity.
AB  - This article presents a conceptual framework that allows the practitioner to
      appreciate the relationship between health status and health interventions and
      productivity in relation to workers' compensation care. Factors important to
      productivity for individual workers are indicated. Some specific applications of
      health and productivity theory to the area of workers' compensation from the
      points of view of the injured worker, the employer, the insurer, and the treating
      physician are described. Finally, alternate ways of looking at these
      relationships using the concept of the human capital are briefly discussed.

PMID- 15182758
TI  - Definitions of terms commonly used in workers' compensation.
AB  - This article provides definitions for the various terms commonly used in the area
      of workers' compensation.

PMID- 15182760
TI  - Experimental animal model for anthracycline-induced heart failure.

PMID- 15182762
TI  - Desmin-free cardiomyocytes and myocardial dysfunction in end stage heart failure.
AB  - Our aim was to evaluate the desmin content in the myocardial tissue of patients
      with end-stage heart failure of ischaemic origin and to assess its role on
      cardiac function. We studied 18 explanted hearts from patients transplanted for
      end-stage heart failure due to ischaemic cardiomyopathy (ICM). Control myocardial
      tissue was obtained from the cardiac biopsies of six women with breast cancer
      taken prior to commencing chemotherapy with anthracyclines, four male donors for
      heart transplantation and two autoptic hearts from patients who died due to non
      cardiac events. Myocardial tissue, obtained from the left ventricle (remote zone
      from infarcted area), was analyzed by light and confocal immunochemistry (desmin)
      microscopy. The desmin content of myocardial tissue was obtained by real-time
      PCR. Cardiac function was evaluated by echocardiographic and right heart
      catheterization data, obtained before heart transplantation. Confocal microscopy
      evaluation showed a significant decrease in the number of desmin-positive
      myocytes (P<0.01) in ICM hearts compared to controls. At real-time PCR
      evaluation, there was a reduction (P<0.01) in desmin content in the ICM patients
      compared to controls. A negative correlation was found between desmin-free
      cardiomyocytes and ejection fraction (EF) (r=-0.834; P<0.02) on echocardiogram. A
      negative relationship (r=-0.688) was also found between desmin-negative myocytes
      and capillary wedge pressure. In conclusion, the myocardial tissue of patients
      with end-stage heart failure of ischaemic origin, shows a decreased number in
      desmin-positive myocytes at immunochemistry evaluation compared to normal
      individuals. This deficiency in cytoskeletal intermediate filament content is
      associated with reduced cardiac function.

PMID- 15182763
TI  - Cardiac chimerism in recipients of peripheral-blood and bone marrow stem cells.
AB  - Multipotent progenitor cells have the ability to differentiate into most somatic
      cell types, including cardiac myocytes. We sought to investigate cardiac
      chimerism after peripheral-blood and bone marrow stem cell transplantation.
      Between 10 and 17 highly polymorphic short tandem repeat (STR) markers were
      assayed in DNA obtained from donors' peripheral blood, recipients' peripheral
      blood before transplantation, and the recipient's heart in every patient. Gender
      and non-gender STR donor alleles were identified in the recipient heart in three
      patients. Using a highly sensitive PCR assay to determine donor and recipient
      genotypes, we confirmed the existence of cardiac chimerism in recipients of
      peripheral-blood and bone marrow stem cells.

PMID- 15182761
TI  - Rabbit model for in vivo study of anthracycline-induced heart failure and for the
      evaluation of protective agents.
AB  - BACKGROUND: Cardiac toxicity associated with chronic administration of
      anthracycline (ANT) antibiotics represents a serious complication of their use in
      anticancer chemotherapy, but can also serve as a useful experimental model of
      cardiomyopathy and congestive heart failure. AIMS: In this study, a model of
      chronic ANT cardiotoxicity induced by repeated i.v. daunorubicin (DAU)
      administration to rabbits was tested. METHODS: Three groups of animals were used:
      (1) control group-10 animals received i.v. saline; (2) 11 animals received DAU (3
      mg/kg, i.v.); (3) 5 animals received the model cardioprotective agent dexrazoxane
      (DEX, 60 mg/kg, i.p.), 30 min prior to DAU. All substances were administered once
      weekly, for 10 weeks. The DAU-induced heart damage and protective action of DEX
      were determined and quantitated with the use of histopathology, invasive
      haemodynamic measurements (e.g. left ventricular pressure changes-dP/dt(max),
      dP/dt(min)), non-invasive systolic function examinations (left ventricular
      ejection fraction, PEP/LVET index) and biochemical analysis of cardiac troponin T
      plasma concentrations. RESULTS: All the employed methods showed unambiguously
      pronounced heart impairment in the DAU group, with the development of both
      systolic and diastolic heart failure, as well as significant reduction of DAU
      cardiotoxicity in DEX-pretreated animals. Other toxicities were acceptable.
      CONCLUSION: The presented model has been approved to be consistent and reliable
      and it can serve as a basis for future determinations and comparisons of chronic
      cardiotoxic effects of various drugs, as well as for the evaluation of potential
      cardioprotectants.

PMID- 15182764
TI  - Studies on intragastric PCO2 at rest and during exercise as a marker of
      intestinal perfusion in patients with chronic heart failure.
AB  - AIMS: The aim of this study was to investigate mesenteric ischaemia by
      determining intragastric PCO(2) (iPCO(2)) with gastric tonometry during rest and
      exercise stress testing in patients with chronic heart failure (CHF). In CHF
      inflammatory immune activation is hypothesized to result from a chronic endotoxin
      challenge due to bacterial translocation of hypoperfused intestinal mucosa.
      METHODS AND RESULTS: In 10 patients with CHF and ten healthy controls a tonometry
      catheter was inserted into the stomach. IPCO(2) was measured at rest and during
      bicycle exercise every 5 min. At rest arterial pCO(2) (aPCO(2)), intragastric
      pCO(2) (iPCO(2)) and the intragastric/arterial gap did not differ between
      patients and controls. During low level exercise (25 W), patients showed an
      increase in iPCO(2) compared to resting iPCO(2), whereas controls did not show an
      increase in iPCO(2) (change in iPCO(2): 12+/-2% vs. 1+/-0.4%, P<0.001). In CHF,
      iPCO(2) during peak exercise was 25+/-3% higher than at rest, compared to
      controls (increase 2+/-1, P<0.0001). CONCLUSIONS: Patients with CHF already at
      low level exercise develop an increase in iPCO(2). This is likely to reflect
      hypoperfusion of the intestinal mucosa, which may contribute to the development
      of bacterial translocation.

PMID- 15182765
TI  - Catecholamines restore myocardial contractility in dilated cardiomyopathy at the
      expense of increased coronary blood flow and myocardial oxygen consumption (MvO2
      cost of catecholamines in heart failure).
AB  - To investigate the metabolic cost of catecholamine use in heart failure, we
      administered intravenous dobutamine or norepinephrine to dogs with moderate and
      severe LV dysfunction until LV contractile function was restored to normal
      levels. Both drugs were associated with significant increases in myocardial O(2)
      consumption, increased coronary blood flow requirements and decreased myocardial
      mechanical efficiency. These mechanisms may contribute to the deleterious effects
      of catecholamines in heart failure.

PMID- 15182767
TI  - Diastolic heart failure. Paroxysmal or chronic?
AB  - Heart failure with preserved systolic function is considered by some to be
      synonymous with diastolic heart failure (DHF). Although recent epidemiological
      studies have suggested that DHF constitutes 30-50% of all patients with heart
      failure, many cardiologists dealing with ambulant heart failure patients on a
      daily basis find that the vast majority of heart failure patients have systolic
      dysfunction. What could be the reasons for this? Referral bias and varying
      diagnostic thresholds and interpretation of results could be one important
      reason. Heart failure with preserved systolic function comprises a heterogeneous
      group of conditions: whilst some patients may truly have DHF, others may have
      heart failure due to subtle systolic dysfunction (noted on tissue Doppler imaging
      of the left ventricular long axis). Other patients actually have pulmonary
      disease, obesity or ischaemic heart disease, and have their symptoms attributed
      to 'diastolic heart failure' on the basis of 'abnormal' mitral diastolic flow
      indices that may, in fact, simply reflect aging. True DHF may be much less
      prevalent than suggested. A further possibility is that heart failure in patients
      with diastolic dysfunction might be paroxysmal rather than chronic. This group of
      patients may present predominantly to acute units like accident and emergency,
      coronary care units and intensive care units and are, therefore unlikely to
      figure prominently in the usual outpatient population of chronic systolic left
      ventricular dysfunction.

PMID- 15182766
TI  - Impact of atrial fibrillation on mortality and readmission in older adults
      hospitalized with heart failure.
AB  - BACKGROUND: Atrial fibrillation is common in older adults with heart failure. It
      is known to adversely affect outcomes. AIM: To examine the associations of atrial
      fibrillation with 4-year mortality and 30-day readmission in older adults
      hospitalized with heart failure. METHODS: Patients were Medicare beneficiaries 65
      years of age and older discharged with a primary diagnosis of heart failure.
      Baseline data were obtained by retrospective chart reviews and data on mortality
      and readmission were obtained from Medicare administrative files. Presence of
      atrial fibrillation was confirmed using electrocardiogram during hospital
      admission. Using Cox proportional hazards models we estimated bivariate and
      multivariable (adjusted for various patient and care covariates) hazards ratios
      (HR) and 95% confidence intervals (CI) for 4-year mortality and 30-day
      readmission of patients with atrial fibrillation compared with those without.
      RESULTS: Patients (n=944) had a mean age (+/-S.D.) of 79 (+/-7) years, 61% were
      women, 18% African-Americans, 25% had atrial fibrillation by admission
      electrocardiogram, 64% died within 4 years, and 8% were readmitted. Patients with
      atrial fibrillation had a 52% increased risk of 4-year mortality (adjusted
      HR=1.52; 95%CI=1.11-2.07). Atrial fibrillation was also associated with higher
      risk of readmission (unadjusted HR=1.64; 95%CI=1.01-2.68). However, the
      association lost its statistical significance after adjustment for various
      patient and care variables (adjusted HR=2.09; 95%CI=0.94-4.65). CONCLUSION:
      Presence of atrial fibrillation was associated with significant increased risk of
      long-term mortality in older adults hospitalized with heart failure and was
      associated with a non-significant higher risk of hospital readmission.

PMID- 15182768
TI  - European reference values for Doppler indices of left ventricular diastolic
      filling.
AB  - The European Study Group on diastolic heart failure requires objective evidence
      of abnormal left ventricular diastolic function to establish the diagnosis of
      diastolic heart failure, which is common in older people. Reference values for
      Doppler indices of transmitral flow, used to assess left ventricular diastolic
      function, have not been reported for people 70 years and over in Europe. The aim
      of this study was to establish reference values for these Doppler indices of
      transmitral flow in older people. A random sample of 355 subjects aged 70 and
      over, living in the community underwent clinical assessment and echocardiography.
      Asymptomatic subjects with no cardiovascular disease and cardiovascular risk
      factors were identified. Measurements of five commonly used Doppler indices of
      transmitral flow from these subjects were obtained and reference range expressed
      as mean+/-2 standard deviations and as percentiles. We have therefore generated
      reference Doppler values of transmitral flow for people aged over 70 in a British
      population.

PMID- 15182769
TI  - Echocardiographic indices of left ventricular diastolic dysfunction in 647
      individuals with preserved left ventricular systolic function.
AB  - BACKGROUND: Knowledge about the occurrence of isolated diastolic dysfunction (DD)
      in the general population is limited. AIMS: This population study was performed
      to assess the frequency and distribution pattern of echocardiographic indices of
      left ventricular (LV) DD in an elderly population aged 50-89 years in which LV
      systolic function is preserved. METHODS AND RESULTS: The study population (n=764)
      recruited from the background population answered a heart failure questionnaire
      and underwent echocardiography. Excluding subjects with a LV ejection fraction
      <50% or atrial fibrillation, diastolic function was evaluated in 647 subjects.
      The frequency of impaired relaxation according to earlier guidelines was 0.5%,
      vs. 2.5% using age- and gender-specific normal values of 'E/A-ratio' and
      'deceleration time'. In a subpopulation of 167 participants, 6.6% had
      'pseudonormalisation'. No difference was found in the frequency of dyspnea in
      subjects with impaired relaxation or 'pseudonormalisation' compared to subjects
      with normal filling pattern. CONCLUSION: The prevalence of LV impaired relaxation
      was highly dependent on the choice of normal (cut-off) values for Doppler
      indices. Furthermore, our findings suggest that either isolated DD is often
      asymptomatic, or that Doppler flow derived parameters as a diagnostic method for
      assessing DD have a low specificity when used as a screening tool in the general
      population.

PMID- 15182770
TI  - Beta-blocker induced bradycardia-should we pace?

PMID- 15182771
TI  - Effect of carvedilol on diastolic function in patients with diastolic heart
      failure and preserved systolic function. Results of the Swedish Doppler
      echocardiographic study (SWEDIC).
AB  - AIM: The purpose of this study was to investigate the effects of carvedilol on
      diastolic function (DF) in heart failure patients with preserved left ventricular
      (LV) systolic function and abnormal DF. PATIENTS AND METHODS: We randomised 113
      patients with diastolic heart failure (DHF) (symptomatic, with normal systolic LV
      function and abnormal DF) into a double blind multi-centre study. The patients
      received either carvedilol or matching placebo in addition to conventional
      treatment. After uptitration, treatment was continued for 6 months. Two
      dimensional and Doppler echocardiography were used for quantification of LV
      function at baseline and at follow-up. Four different DF variables were evaluated
      by Doppler echocardiography: mitral flow E:A ratio, deceleration time (DT),
      isovolumic relaxation time (IVRT) and the ratio of systolic/diastolic pulmonary
      venous flow velocity (pv-S/D). Primary endpoint was change in the integrated
      quantitative assessment of all four variables during the study. RESULTS: Ninety
      seven patients completed the study. A mitral flow pattern reflecting a relaxation
      abnormality was recorded in 95 patients. There was no effect on the primary
      endpoint, although a trend towards a better effect in carvedilol treated patients
      was noticed in patients with heart rates above 71 beats per minute. At the end of
      the study, there was a statistically significant improvement in E:A ratio in
      patients treated with carvedilol (0.72 to 0.83) vs. placebo (0.71 to 0.76),
      P<0.05. CONCLUSIONS: Treatment with carvedilol resulted in a significant
      improvement in E:A ratio in patients with heart failure due to a LV relaxation
      abnormality. E:A ratio was found to be the most useful variable to identify
      diastolic dysfunction in this patient population. This effect was observed
      particularly in patients with higher heart rates at baseline.

PMID- 15182772
TI  - Beneficial effects of carvedilol on angiotensin-converting enzyme activity and
      renin plasma levels in patients with chronic heart failure.
AB  - OBJECTIVE: To assess the effects of carvedilol treatment on the renin-angiotensin
      system in patients with chronic heart failure (CHF). BACKGROUND: Carvedilol
      improves survival of patients suffering from CHF but the effects of the drug on
      angiotensin-converting enzyme (ACE) activity, renin and aldosterone are not well
      characterized in patients receiving an ACE inhibitor. METHODS: A randomized,
      multicenter, double-blind, 6-month, placebo-controlled study of carvedilol vs.
      placebo was conducted in 64 CHF patients. Circulating levels of ACE activity,
      active renin and aldosterone as well as left ventricular diameters and ejection
      fraction by echography were assessed. RESULTS: During the study, left ventricular
      ejection fraction increased from 25+/-11% to 31+/-12% with carvedilol and from
      27+/-12% to 28+/-12% with placebo (P=0.03). This beneficial effect was associated
      with marked blunting of active renin secretion (-53% in the carvedilol group vs.
      13% in the placebo group, P=0.04). ACE activity was reduced by 30% in the
      carvedilol group (P=0.07 vs. placebo). Aldosterone was not changed. CONCLUSION:
      Carvedilol markedly reduced the increase in active renin observed with time
      despite ACE-inhibitors and tended to decrease ACE activity. These findings may in
      part explain the beneficial actions of carvedilol and highlights the profound
      effect of betablockade on renin in patients already receiving ACE-inibitors.

PMID- 15182773
TI  - Tolerability of carvedilol and ACE-Inhibition in mild heart failure. Results of
      CARMEN (Carvedilol ACE-Inhibitor Remodelling Mild CHF EvaluatioN).
AB  - BACKGROUND: Management guidelines for heart failure recommend ACE-I and beta
      blockers. The perception of difficult up-titration might have added to the slow
      uptake of beta-blockers despite their mortality and morbidity benefits. AIMS:
      CARMEN offered a possibility to study safety and tolerability of enalapril
      against carvedilol and their combination. METHODS: Five hundred and seventy-two
      patients were blindly up-titrated on carvedilol (target 25 mg bid) and/or
      enalapril (target 10 mg bid), and continued for 18 months. In the combination
      arm, carvedilol was up-titrated before enalapril. RESULTS: There was no group
      related difference in adverse events during up-titration. Withdrawal rates were
      31, 30 and 30%, and serious adverse events 28, 29 and 34% in the combination,
      carvedilol and enalapril arms. Mortality was similar in all groups (all-cause
      N=14, 14 and 14; cardiovascular N=9, 13 and 14). All-cause and cardiovascular
      hospitalizations occurred in 26, 27 and 32%, and in 12, 16 and 22% in the
      combination, carvedilol and enalapril arms, respectively. CONCLUSION: The safety
      profile was similar in all treatment arms. In contrast to common perception,
      there was no difference in tolerability between the ACE-I and carvedilol. This
      result is even more remarkable as the high prestudy use of ACE-I (65%) might have
      introduced a bias by selecting ACE-I tolerant patients, who were only switched
      from their former ACE-I to enalapril.

PMID- 15182774
TI  - Cardiogenic shock shortly after initial success of cardiac resynchronization
      therapy.
AB  - Cardiac resynchronisation therapy (CRT) has been shown to improve symptoms,
      exercise capacity and left ventricular function, as well as a reduction in
      morbidity/mortality in heart failure patients. Failures following initial success
      of this treatment are mostly related to lead dislodgement. Another entirely
      different reason is presented in this case study.

PMID- 15182775
TI  - Selective intestinal decontamination in advanced chronic heart failure: a pilot
      trial.
AB  - BACKGROUND AND AIMS: Endotoxin, derived from intestinal aerobic Gram-negative
      bacilli (AGNB), could be an important monocyte activator in chronic heart failure
      (CHF). The effect of selective decontamination of the digestive tract (SDD) on
      intracellular monocyte cytokine production, monocyte CD14 expression, circulating
      endotoxin and cytokines, and flow-mediated dilation (FMD) was studied in patients
      with severe CHF. METHODS AND RESULTS: Ten patients with CHF (NYHA class III-IV)
      were enrolled in a non-placebo controlled pilot trial involving the
      administration of SDD (polymyxin B, tobramycin) for 8 weeks. One patient was
      later excluded due to cardiac transplantation. Before treatment, after 4 and 8
      weeks therapy, and 6 weeks post-treatment, monocyte CD14 expression,
      intracellular monocyte production of interleukin-1beta [IL-1beta], interleukin-6
      [IL-6], tumour necrosis factor (TNF)-alpha with and without lipopolysaccharide
      (LPS) stimulation were measured. Concentrations of endotoxin and cytokines (IL
      1beta, IL-6, TNF-alpha) were also determined. AGNB in faeces, intestinal
      endotoxin and FMD were assessed at baseline, after 4 weeks of treatment and 6
      weeks post-treatment. SDD eradicated intestinal AGNB (P<0.00001) and decreased
      faecal endotoxin concentrations (P<0.00001). There was a significant decline in
      monocyte CD14 expression (P=0.03) and in IL-1beta (P=0.0001), IL-6 (P=0.02) and
      TNF-alpha (P=0.0002) production after 4 and 8 weeks of treatment in the basal
      state and for IL-1beta (P=0.008) and IL-6 (P=0.005) after LPS stimulation. FMD
      significantly improved at 4 weeks and returned to baseline after treatment
      discontinuation (P=0.002). Circulating concentrations of endotoxin and cytokines
      remained unchanged. CONCLUSION: Reduction of the intestinal endotoxin pool led to
      a decrease in monocyte CD14 expression and intracellular cytokine production in
      patients with severe CHF. The improvement of peripheral endothelial function
      could be a marker of the anti-inflammatory effect of SDD.

PMID- 15182776
TI  - Comparison of treatment initiation with bisoprolol vs. enalapril in chronic heart
      failure patients: rationale and design of CIBIS-III.
AB  - BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors and beta-blockers are
      standard therapy for chronic heart failure (CHF). beta-blockers are recommended
      to be initiated after ACE-inhibitors, but this order is not evidence based. The
      initiation order may be important since many, especially elderly CHF patients
      cannot tolerate target doses of both. Data suggest that beta-blockers may be more
      important to CHF patients than ACE-inhibitors, especially in early stages of CHF.
      AIMS: To compare the effect on combined death or hospitalisation of initial
      monotherapy with either bisoprolol or enalapril, followed by combination therapy.
      METHODS: One-thousand CHF patients without ACE-inhibitor, beta-blocker or
      angiotensin-receptor-blocker therapy will be randomised 1:1 to monotherapy with
      either enalapril or bisoprolol for 6 months, followed by combined therapy for 6
      18 months. The primary objective is to show non-inferiority for bisoprolol-first
      vs. enalapril-first regarding combined death or hospitalisation. If that is
      shown, superiority for bisoprolol-first will be tested. CONCLUSIONS: If the trial
      shows non-inferiority for bisoprolol-first vs. enalapril-first, the first CHF
      therapy may be chosen based on individual judgement in each patient. If
      bisoprolol-first is superior to enalapril-first, a beta-blocker should be given
      prior to an ACE-inhibitor in CHF, and the paradigm of testing CHF compounds
      against a background of ACE-inhibitor therapy will be challenged.

PMID- 15182777
TI  - Clinical trials update and cumulative meta-analyses from the American College of
      Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and
      cardiac resynchronisation therapy in heart failure.
AB  - This article continues a series of reports on recent research developments in the
      field of heart failure. Key presentations made at the American College of
      Cardiology meeting, held in New Orleans, Louisiana, USA in March 2004 are
      reported. These new data have been added to existing data in cumulative meta
      analyses. The WATCH study randomised 1587 patients with heart failure and left
      ventricular systolic dysfunction to warfarin, aspirin or clopidogrel. The study
      showed no difference between the effects of these agents on mortality or
      myocardial infarction, but hospitalisations for heart failure were higher on
      aspirin (22.2%) compared to warfarin (16.1%). The SCD-HeFT study showed that ICD
      therapy reduced all-cause mortality at 5 years by 23% in patients with
      predominantly NYHA class II heart failure and left ventricular systolic
      dysfunction, but amiodarone was ineffective. The DINAMIT study showed that ICD
      therapy was not beneficial in patients with left ventricular dysfunction after a
      recent MI, even in those with risk factors for arrhythmic death. In CASINO,
      levosimendan improved survival compared with dobutamine or placebo in patients
      with decompensated heart failure. INSPIRE showed that SPECT imaging can be used
      to assess risk early after acute MI safely and accurately. Rimonabant was shown
      to be safe and effective in treating the combined cardiovascular risk factors of
      smoking and obesity. An overview of new developments in cardiac resynchronisation
      therapy (CRT) in heart failure is also reported.

PMID- 15182778
TI  - Observational series of patients treated either with ACE inhibitors and diuretics
      or with a homeopathic Crataegus preparation.

PMID- 15182779
TI  - Efficacy of a homeopathic Crataegus preparation.

PMID- 15182780
TI  - Efficacy of a homeopathic Crataegus preparation.

PMID- 15182781
TI  - Efficacy of a homeopathic Crataegus preparation.

PMID- 15182785
TI  - Antiphospholipid antibodies: recent progresses on their origin and pathogenicity.

PMID- 15182784
TI  - Switching between anti-TNFalpha agents: what is the evidence?

PMID- 15182786
TI  - Pharmacoepidemiology: lessons from real life.

PMID- 15182787
TI  - Making pregnancy safer for patients with lupus.
AB  - Systemic lupus erythematosus is a hormone-dependent disorder predominantly
      affecting young women in whom changes in hormonal activity affect the course of
      the disease. More specifically, pregnancy is associated in 50 to 60% of cases
      with a clinical flare manifesting as renal or hematological symptoms, usually
      during the second or third trimester but occasionally in the postpartal period.
      Patients should be strongly advised to start a pregnancy only if their disease
      has been stable for at least 6 months, and they should be informed of the few
      contraindications. Severe flares are uncommon (10%) and the risk of maternal
      death is now 2 to 3%. The risk of the fetus remains high, however. Thus, fetal
      loss is common, particularly in patients with a lupus anticoagulant, renal
      failure, or arterial hypertension. Preterm birth occurs in 25% to 50% of cases
      and intrauterine growth retardation in 30%. Neonatal lupus with or without
      congenital heart block is exceedingly rare, being seen in the 1% of SLE women who
      have anti-SSA (Ro) and/or SSB (La) antibodies. To ensure a favorable outcome for
      both the mother and the child, the pregnancy should be planned, started during a
      period of disease stability, monitored closely (physical examination, laboratory
      tests, and Doppler ultrasound), and treated as needed (with antimalarial therapy
      throughout the pregnancy). Even with these precautions, however, preterm birth
      remains common.

PMID- 15182788
TI  - Primary hyperparathyroidism and osteoporosis in 2004.
AB  - In patients with primary hyperparathyroidism, a definite diagnosis is the first
      step in the management strategy and relies on appropriately selected and
      carefully interpreted laboratory tests. Parathyroid hormone assays are being
      increasingly performed as part of the routine evaluation of osteoporosis. In this
      setting, laboratory tests are often consistent with primary hyperparathyroidism
      but should be interpreted with caution. Bone mineral density measurements are
      useful for assessing the impact of primary hyperparathyroidism. The recommended
      bone mineral density cutoffs for selecting patients requiring parathyroidectomy
      were lowered in 2003, and the number of surgically treated patients has increased
      as a result. Parathyroidectomy remains the treatment of choice given the low
      mortality associated with this procedure and the absence of pharmacological
      alternatives suitable for long-term use.

PMID- 15182789
TI  - Do primary care physicians have a place in the management of rheumatoid
      arthritis?
AB  - OBJECTIVE: Few recommendations have been issued about the management of
      rheumatoid arthritis (RA), which varies widely across physicians. The primary
      care physician (PCP) plays a unique role as the first physician to evaluate the
      patient. The objective of this study was to evaluate the place of PCPs in the
      management of RA. METHODS: Medline was searched for articles reporting management
      of rheumatoid arthritis in primary care practice. RESULTS: Currently, the goal of
      initiating a disease modifying anti-rheumatic drug (DMARD) early is unrealistic
      for numerous patients. Agreement between PCPs and rheumatologists about the
      diagnosis of RA is only passable, but PCPs tend to overdiagnose RA. Median time
      from symptom onset to second-line treatment was 19 months and the best predictive
      factor for a longer lag time before DMARD prescription was the time from symptom
      onset to the first rheumatologist visit. Moreover, DMARDs are only rarely
      prescribed by PCPs. Some data suggest that the impact of rheumatologists care is
      positive on outcomes but it has to be confirmed by longitudinal, randomized
      studies, with valid outcomes and diagnosis criteria. Recognition of the need for
      timely referral is an important goal in the teaching of students and generalists.
      Moreover, the nature of management differences between rheumatologists and PCPs
      has to be explored. We should also think how to create a better coordination.
      This starts by knowing what are the needs of the PCP (e.g. education, access to
      phone advice or rapid consultation) and by defining common plan if the care
      should be shared. CONCLUSION: Several healthcare professionals, among whom the
      PCP plays a pivotal role, should share the management of RA. PCPs and
      rheumatologists should be encouraged to work together on optimizing the
      management of patients with RA.

PMID- 15182790
TI  - Anti-neutrophil cytoplasmic antibodies in patients with rheumatoid arthritis:
      clinical, biological, and radiological correlations.
AB  - OBJECTIVES: To determine the prevalence and the associations of anti-neutrophil
      cytoplasmic antibodies (ANCA) and subtypes with clinical, biological, and
      radiological findings in patients with rheumatoid arthritis (RA). MATERIALS AND
      METHODS: This is a transversal study of 85 patients with RA (followed in Ibn-i
      Sina Hospital, Ankara University School of Medicine) with disease duration of 8.7
      +/- 6.4 years. Besides clinical, biological, and radiological disease activity
      parameters, ANCA and ANCA against myeloperoxidase (MPO) and proteinase 3 (PR3)
      were examined. RESULTS: The prevalence of ANCA, perinuclear ANCA (p-ANCA) and
      atypical ANCA (a-ANCA) were 18% (15/85 patients), 6% and 12%, respectively. Anti
      MPO was found in six patients while anti-PR3 was not found. No significant
      association could be found between clinical, biological, and radiological disease
      activity assessments and ANCA (including indirect immunoflorescence subtypes).
      Similarly, ANCA were not associated with features suggestive of underlying
      vasculitis (noticed in 11/85 patients), and/or other extra-articular features.
      CONCLUSIONS: Our results confirm that ANCA of various specificities (mainly a
      ANCA) occur in a minority of RA. However, those ANCA were not associated with
      more severe RA, including the 6/85 patients positive for MPO (who were all free
      from vasculitis). The over-representation in RA sera of a-ANCA, as compared to p
      ANCA, should be further studied.

PMID- 15182791
TI  - Hyperprolactinemia in Sjogren's syndrome: a patient subset or a disease
      manifestation?
AB  - OBJECTIVE: To investigate the prevalence of hyperprolactinemia in patients with
      primary Sjogren's syndrome (SS), its clinical significance and its implication to
      our understanding of the disease pathogenesis. MATERIALS AND METHODS: Forty-nine
      patients with primary SS (44 females and five males) age range 37-66 years were
      included in this study. All patients underwent clinical assessment for disease
      manifestations in addition to laboratory assessment for serum prolactin, sex
      hormones and immunological profile. Fifty healthy subjects (44 females and six
      males) of matched age were studied as control group. RESULTS: The mean prolactin
      serum level was significantly higher in SS patients compared to the control group
      (P < 0.01). This significant difference was persistent after subgrouping the
      patients and the controls based on their menstrual history. Hyperprolactinemia
      (>20 ng/ml) was prevalent in 16.3% of SS patients. There was no correlation
      between serum prolactin levels and hormonal status, autoantibodies as well as
      systemic manifestations of the disease. CONCLUSION: Patients with primary SS have
      moderately increased levels of prolactin. Hyperprolactinemia reflects disease
      pathology rather than being present in a subset of patients. The presence of
      elevated prolactin levels was not associated with hormonal status, clinical or
      immunological manifestations of primary SS.

PMID- 15182792
TI  - Outcome of patients with undifferentiated chronic monoarthritis: retrospective
      study of 46 cases.
AB  - OBJECTIVE: To determine the natural history of undifferentiated monoarthritis of
      more than 3 months' duration and to evaluate the usefulness of classic diagnostic
      tools for identifying factors associated with outcomes. METHOD: Retrospective
      study of 46 patients with undifferentiated monoarthritis of more than 3 months'
      duration. RESULTS: Full resolution was the outcome in 50% of cases. Rheumatoid
      arthritis and spondyloarthropathy were the most common diagnoses in the remaining
      patients. HLA-B27 status was the only significant predictor of outcome:
      progression to spondyloarthropathy was significantly more common (P = 0.05) among
      HLA-B27-positive patients. Mean time to full recovery was significantly shorter
      than mean time to disease progression (12 vs. 45 months, P = 0.0015).
      Intraarticular glucocorticoid injections were effective in over 50% of patients.
      Arthritis relief during the month following the injection was associated with
      self-limited disease. The role for magnetic resonance imaging in managing
      patients with undifferentiated monoarthritis remains unclear. CONCLUSION: In
      patients with undifferentiated monoarthritis, the likelihood of a full recovery
      is 50%. The only significant predictor of outcome was positive HLA-B27 status,
      which was associated with progression to spondyloarthropathy.

PMID- 15182793
TI  - Changes in osteoarthritis management by general practitioners in the COX2
      inhibitor era-concomitant gastroprotective therapy.
AB  - OBJECTIVES: Two selective COX2 inhibitors, rofecoxib and celecoxib, were
      introduced on the French market in 2000. We evaluated their use in the treatment
      of osteoarthritis by general practitioners, with special attention to concomitant
      prescription of gastroprotective agents. MATERIAL AND METHODS: The Thales
      Epidemiology Observatory is a medical database compiled by a representative
      sample of 1000 general practitioners in France. We examined the data collected
      during the year before and the year after the introduction of rofecoxib and
      celecoxib on the French market (November 1999-October 2001). During each of the 2
      years of the study period, about 200,000 visits for 70,000 patients were entered
      into the database. RESULTS: COX2 inhibitors were prescribed at a rapidly
      increasing rate during the second year, when they accounted for 38% of the
      prescription volume for nonsteroidal antiinflammatory drugs (NSAIDs) and 25% of
      prescribed medication costs. In some patients, COX2 inhibitors were substituted
      for nonselective NSAIDs, and in others they were used as first-line NSAID
      therapy. On average over the 2-year study period, 22.1% of prescriptions for
      conventional NSAIDs included a prescription for a gastroprotective agent; this
      proportion increased from 18.6% in November 1999 to 24.8% in October 2001. Among
      prescriptions for COX2 inhibitors, 17.5% included a gastroprotective agent.
      CONCLUSION: General practitioners have been prompt to use COX2 inhibitors in the
      treatment of osteoarthritis. However, they have not decreased their use of
      concomitant gastroprotective treatment. Thus, they seem aware that proof of a
      lower long-term risk of gastrointestinal toxicity with COX2 inhibitors is
      lacking, and that elderly patients such as those with osteoarthritis are at high
      risk for gastrointestinal side effects of NSAIDs.

PMID- 15182794
TI  - The anterior center edge angle: a study of 102 volunteers.
AB  - OBJECTIVES: To measure the anterior center edge (VCE) angle that reflects
      anterior coverage of the femoral head. PATIENTS AND METHODS: False profile views
      of both hips of 102 volunteers, 23 male and 79 female, were taken between October
      2000 and October 2001. Radiographs with evidence of degenerative hip disease and
      those with poor image quality were excluded from the study. This left 181
      radiographs. RESULTS: An orthopedic surgeon and a radiologist used a standard
      protractor to examine each of the 181 radiographs twice, at an interval of 24 h.
      The mean VCE angle was 49.27 +/- 7.77 degrees (range, 24.75-68.75), a value
      different from those found in previous studies. No significant intraobserver or
      interobserver differences were found. CONCLUSIONS: Our findings may contribute to
      the determination of a new parameter for evaluating anterior femoral head
      covering. In patients with acetabular dysplasia and deficient anterior coverage,
      this parameter may prove useful for selecting patients for surgery, planning the
      procedure, and evaluating postoperative results.

PMID- 15182795
TI  - Bone metastases revealing primary tumors. Comparison of two series separated by
      30 years.
AB  - OBJECTIVE: To compare two series of patients admitted to a rheumatology
      department for bone metastases 30 years apart and to obtain a pragmatic
      estimation of the percentage of bone metastases revealing cancer. METHODS: The
      recent series was composed of 132 patients seen between 1989 and 1996 and the
      earlier series of 50 patients admitted between 1958 and 1967. All patients were
      admitted to the same rheumatology department for bone metastases from a diagnosed
      or undiagnosed primary. Both series were studied retrospectively. The rate of
      occurrence of each cancer diagnosis was determined in the patients with and
      without known primaries. RESULTS: Among the patients with metastatic disease as
      the first manifestation of cancer, the percentage with lung cancer increased from
      the early to the recent series, particularly among women, whereas the percentages
      with prostate and breast cancer decreased. The primary remained unknown in 27%
      and 38% of patients in the early and recent series, respectively. CONCLUSION:
      Despite the introduction of new investigations, our ability to identify primaries
      responsible for bone metastases does not seem to have improved. However, our data
      should be interpreted with caution since recruitment probably differed between
      the two series.

PMID- 15182796
TI  - Post-fracture osteolysis of the pubic bone simulating a malignancy: report of a
      case.
AB  - Post-fracture osteolysis of the pubic bone is rare. We report a case of a 70-year
      old woman with osteoporosis and a history of radiation therapy 2 years earlier.
      At presentation, she was found to have a bilateral sacral fracture and fractures
      of both pubic rami on one side. The pain persisted, and follow-up radiographs
      showed osteolysis of the pubic rami suggestive of metastatic disease. The
      development of a bony callus within 8 months established the diagnosis of benign
      osteolysis. About 50 cases of osteolysis at fracture sites have been reported to
      date, of which about a dozen occurred after radiation therapy. All the patients
      were elderly women with post-menopausal osteoporosis. Radiation therapy probably
      further increases the risk in this setting. The possibility of osteolysis at
      fracture sites in patients with osteoporosis should be borne in mind to avoid
      unnecessary and burdensome investigations that are costly and cause undue anxiety
      to the patients. Rest is the only effective treatment.

PMID- 15182797
TI  - Idiopathic hypoparathyroidism and adhesive capsulitis of the shoulder in two
      first-degree relatives.
AB  - INTRODUCTION: Primary hypoparathyroidism and adhesive capsulitis of the shoulder
      in the same patient does not seem to have been reported previously. We report two
      cases in first-degree relatives. PATIENTS: Case 1: In 1999, a 41-year-old woman
      experienced seizures simulating epilepsy. She had been treated 5 years earlier
      for idiopathic adhesive capsulitis of both shoulders. Computed tomography of the
      brain showed calcifications in the basal ganglia meeting criteria for Fahr's
      disease, and incipient bilateral cataract was found. A diagnosis of idiopathic
      primary hypoparathyroidism was given. After 1 month of calcium and vitamin D
      supplementation, improvements were noted in the clinical symptoms, laboratory
      test, and electroencephalogram. Case 2: The 70-year-old father of case 1, who had
      an unremarkable medical history, had been receiving treatment for about 2 years
      for adhesive capsulitis of the left shoulder. Routine laboratory tests disclosed
      idiopathic primary hypoparathyroidism. The outcome was favorable with calcium and
      vitamin D supplementation. CONCLUSION: Our cases suggest that there may be a
      common immunological or genetic basis for primary hypoparathyroidism and adhesive
      capsulitis. Alternatively, adhesive capsulitis may be a manifestation of
      hypoparathyroidism. Although genetic factors involved in primary
      hypoparathyroidism have been elucidated, the pathophysiology of the disease
      remains unclear. Finally, a chance association remains possible.

PMID- 15182798
TI  - Osteonecrosis 15 years after femoral neck fracture and long-term low-dose inhaled
      corticosteroid therapy.
AB  - Posttraumatic avascular necrosis of the femoral head typically occurs immediately
      or within a few years after a femoral neck injury, and non-traumatic avascular
      necrosis is often related to systemic glucocorticoid therapy. We report an
      unusual case in which avascular necrosis of the femoral head occurred 15 years
      after a transcervical femoral fracture in a woman with a 20-year history of daily
      inhaled glucocorticoid therapy for chronic bronchitis. She had not taken
      glucocorticoids by any other route and had no other risk factors for
      osteonecrosis. To our knowledge, this is the first report of osteonecrosis
      associated with inhaled glucocorticoid therapy in a patient with a local cause of
      diminished vascular reserve. Inhaled glucocorticoid therapy should be added to
      the list of risk factors for osteonecrosis.

PMID- 15182799
TI  - Multifocal discitis caused by Staphylococcus warneri.
AB  - Staphylococcus warneri is a coagulase-negative staphylococcus that is a normal
      inhabitant of the skin but occasionally causes septicemia and endocarditis. We
      report a case of multifocal discitis caused by S. warneri in an immunocompetent
      patient. Only three cases of spinal S. warneri infections have been reported in
      the literature. They illustrate the atypical clinical presentation, with chronic
      pain of increasing severity in the thoracic or lumbar spine instead of the abrupt
      onset that characterizes S. aureus discitis. In our patient, despite the
      multifocal distribution of the lesions, heretofore unreported, clinical
      presentation suggested common low back pain. This presentation may be ascribable
      to the unique bacteriological characteristics of S. warneri. The case reported
      here illustrates the diagnostic challenges sometime raised by discitis due to
      coagulase-negative staphylococci.

PMID- 15182800
TI  - Leflunomide-induced aseptic meningitis.
AB  - Drug-induced aseptic meningitis is uncommon and occurs primarily in patients with
      autoimmune disease. We report the first known case of leflunomide-induced aseptic
      meningitis, in a patient with rheumatoid arthritis.

PMID- 15182802
TI  - MRI studies of ulnar nerve compression at the wrist.

PMID- 15182801
TI  - Osteoporotic fracture of the dens revealed by cervical manipulation.
AB  - Osteoporotic vertebral fractures selectively affect the thoracolumbar junction,
      usually sparing the cervical spine. A 65-year-old woman with documented
      osteoporotic fractures and chronic alcohol abuse presented with neck pain and
      occipital neuralgia that started after she suddenly flexed then extended her
      neck. Following several sessions of cervical manipulation, her pain became more
      severe, and she was admitted. Imaging studies showed multiple fractures in the
      dens, C6 and C7. These apparently spontaneous fractures suggested a bone tumor,
      for which investigations were negative. Osteoporosis was the only identifiable
      cause. The spinal manipulations probably worsened the lesions which were
      performed by a chiropractor who is not a physician and did not obtain cervical
      spine radiographs before treating the patient. Osteoporosis contraindicates
      spinal manipulation at any level, including the cervical spine.

PMID- 15182803
TI  - Severe refractory hypocalcemia in patients with enteropathy: consider
      hypomagnesemia.

PMID- 15182805
TI  - Selecting compounds for focused screening using linear discriminant analysis and
      artificial neural networks.
AB  - Linear discriminant analysis and a committee of neural networks have been applied
      to recognise compounds that act at biological targets belonging to a specific
      gene family, protein kinases. The MDDR database was used to provide compounds
      targeted against this family and sets of randomly selected molecules. BCUT
      parameters were employed as input descriptors that encode structural properties
      and information relevant to ligand-receptor interactions. The technique was
      applied to purchasing compounds from external suppliers. These compounds achieved
      hit rates on a par with those achieved using known actives for related targets
      when tested for the ability to inhibit kinases at a single concentration. This
      approach is intended as one of a series of filters in the selection of screening
      candidates, compound purchases and the application of synthetic priorities to
      combinatorial libraries.

PMID- 15182806
TI  - Combating bioterrorism with personal computers.
AB  - Using personal computers in a grid is permitting the in silico screening of
      millions of molecules to seek out potential inhibitors of agents that pose
      bioterror threats. Current projects are targeting anthrax and smallpox, but the
      approach has many attractions for investigating any known protein target and its
      inhibition.

PMID- 15182807
TI  - Getting it right: modeling of pH, solvent and "nearly" everything else in virtual
      screening of biological targets.
AB  - "Getting it right" refers to the careful modeling of all elements in the living
      system, i.e. biological macromolecules, ligands and water molecules. In addition,
      careful attention should be paid to the protonation state of ionizable functional
      groups on the ligands and residues at the active site. Computational technology
      based on the empirical HINT program is described to: (1) calculate free energy
      scores for ligand binding; (2) include the implicit and explicit effects of water
      in and around the ligand binding site; and (3) incorporate the effects of global
      and local pH in molecular models. This last point argues for the simultaneous
      consideration of a number of molecular models, each with different protonation
      profiles. Data from recent studies of protein-ligand systems (trypsin, thrombin,
      neuraminidase, HIV-1 protease and others) are used to illustrate the concepts in
      the paper. Also discussed are experimental factors related to accurate free
      energy predictions with this and other computational technologies.

PMID- 15182808
TI  - Modelling in vitro hepatotoxicity using molecular interaction fields and SIMCA.
AB  - There is currently a great deal of interest in creating computational tools for
      predicting the pharmacological properties of drug development candidates, ranging
      from physicochemical properties such as pK(a) and solubility to more complex
      biological properties such as oral bioavailability and toxicity. The limiting
      factor in many cases is a shortage of good data from which to construct training
      sets. In other cases, large amounts of data are available, but they use surrogate
      end-points or are comprised of compounds very different from those usually
      encountered in drug discovery and development. In such cases large training sets
      and global models are not necessarily better than local models based on smaller
      data sets. Such considerations make it as important to examine the available data
      carefully so as to avoid over-interpretation of the models obtained as it is to
      minimise errors in prediction per se. The kinds of complications likely to be
      encountered for in vitro hepatotoxicity modelling are discussed in general terms
      and illustrated in particular by SIMCA analysis of data obtained from assays of
      cultured hepatocytes for a large, structurally diverse data set and a smaller,
      much more focussed one.

PMID- 15182809
TI  - Modelling blood-brain barrier partitioning using Bayesian neural nets.
AB  - We have employed three families of molecular molecular descriptors, together with
      Bayesian regularized neural nets, to model the partitioning of a diverse range of
      drugs and other small molecules across the blood-brain barrier (BBB). The
      relative efficacy of each descriptors class is compared, and the advantages of
      flexible, parsimonious, model free mapping methods, like Bayesian neural nets,
      illustrated. The relative importance of the molecular descriptors for the most
      predictive BBB model were determined by use of automatic relevance determination
      (ARD), and compared with the important descriptors from other literature models
      of BBB partitioning.

PMID- 15182810
TI  - Towards integrated ADME prediction: past, present and future directions for
      modelling metabolism by UDP-glucuronosyltransferases.
AB  - Undesirable absorption, distribution, metabolism, excretion (ADME) properties are
      the cause of many drug development failures and this has led to the need to
      identify such problems earlier in the development process. This review highlights
      computational (in silico) approaches that have been used to identify the
      characteristics of ligands influencing molecular recognition and/or metabolism by
      the drug-metabolising enzyme UDP-gucuronosyltransferase (UGT). Current studies
      applying pharmacophore elucidation, 2D-quantitative structure metabolism
      relationships (2D-QSMR), 3D-quantitative structure metabolism relationships (3D
      QSMR), and non-linear pattern recognition techniques such as artificial neural
      networks and support vector machines for modelling metabolism by UGT are
      reported. An assessment of the utility of in silico approaches for the
      qualitative and quantitative prediction of drug glucuronidation parameters
      highlights the benefit of using multiple pharmacophores and also non-linear
      techniques for classification. Some of the challenges facing the development of
      generalisable models for predicting metabolism by UGT, including the need for
      screening of more diverse structures, are also outlined.

PMID- 15182811
TI  - QSAR and QSPR based solely on surface properties?
AB  - The use of descriptors based on local properties calculated at the molecular
      surface for QSPR models is discussed. It is suggested that descriptors should be
      related to the physical theory of intermolecular interactions and the
      relationship between established surface-based descriptors and the fundamental
      types of intermolecular interaction is discussed. Descriptors based on local
      properties that do not encode the chemical constitution of the molecule directly
      are likely to provide less local QSPR models and favor scaffold hopping. The
      major disadvantage for surface-based descriptors is that they are difficult to
      interpret in the sense of relating predictions to the chemical composition of the
      molecule. This disadvantage must be alleviated by suitable model-interrogation
      techniques.

PMID- 15182812
TI  - The phakomatoses.
AB  - The phakomatoses are a diverse set of disorders related principally by a similar
      tendency to produce patchy manifestations that affect the nervous system and
      various other tissues. All of the disorders involve the occurrence of benign
      neoplasms or hamartomatous growths, and all involve the action of a distinct gene
      that functions as a tumor suppressor. At present, none of the phakomatoses is
      amenable to effective medical treatment, so management is limited to surveillance
      and treatment of progressive lesions. The radiologist plays a key role in this
      management, participating in diagnosis and follow-up of affected patients.

PMID- 15182813
TI  - Neuroimaging findings in neurofibromatosis type 1 and 2.
AB  - Neuroimaging, particularly MR imaging, plays an important role in the diagnosis
      and management of the patient with neurofibromatosis type 1 and 2. These
      phakomatoses are complex disorders affecting multiple cell types and multiple
      systems of the body with a wide range of expression. This article summarizes the
      neuroradiologic central nervous system findings in these neurocutaneous
      disorders.

PMID- 15182814
TI  - Neuroimaging of phakomatoses: Sturge-Weber syndrome, tuberous sclerosis, von
      Hippel-Lindau syndrome.
AB  - This article discusses the imaging characteristics of Sturge-Weber syndrome,
      tuberous sclerosis, and von Hippel-Lindau syndrome.

PMID- 15182815
TI  - The rare phakomatoses.
AB  - This article outlines the clinical, central nervous system, and neuropathologic
      features,pathogenesis, genetics, molecular biology, and neuroimaging
      characteristics of the rare vascular phakomatoses, melanophakomatoses, and
      organoid phakomatoses.

PMID- 15182816
TI  - Genetics of disorders of cortical development.
AB  - Since the advent of MR imaging, cortical malformations have become an
      increasingly recognized cause of epilepsy and neurologic impairment. Improved
      radiographic characterization of cortical malformations has been requisite to
      defining their genetics, and a large portion of these disorders are now known to
      have a genetic basis. Uncovering genetic etiologies has provided insight into
      phenotypic diversity, revealed the importance of de novo mutations, and resulted
      in improved radiographic-genetic correlation. This article provides an overview
      of major cerebral cortical malformations and focuses on the genetic mechanisms of
      their causation.

PMID- 15182817
TI  - Neuroimaging in disorders of cortical development.
AB  - Malformations of cortical development are important causes of developmental delay
      and epilepsy. They are classified by the presumed stage during which normal
      development is interrupted: neuronal proliferation and differentiation, neuronal
      migration, and late migration/cortical organization. This article discusses the
      important malformations in each of these groups, how and why the malformations
      develop, and their imaging findings. A better understanding of these disorders
      helps in genetic counseling of the parents and may help in the treatment of
      associated epilepsy.

PMID- 15182818
TI  - Sonography of the fetal central nervous system.
AB  - This article presents a general overview of fetal sonography and an approach to
      the sonographic evaluation of the fetal central nervous system. Annotated images
      of anomalies of the fetal head, brain, spine, face, and neck are shown.
      Sonographic technique,including the choice of transducers and imaging windows is
      presented. The complementary relationship of fetal neurosonography and fetal MR
      imaging is covered, and the strengths and weaknesses of each modality are
      discussed.

PMID- 15182819
TI  - MR imaging of fetal head and neck anomalies.
AB  - This article describes an approach to imaging of fetal head and neck anomalies.
      Topics include cleft lip and palate, facial clefts, amniotic band sequence,
      micrognathia and retrognathia, ocular and orbital abnormalities,
      craniosynostosis, posterior nuchal translucency, cephaloceles, vascular
      anomalies, and tumors. Some of the more common syndromes are also described.

PMID- 15182820
TI  - Fetal imaging of central nervous system abnormalities.
AB  - Fetal MR imaging is complementary to obstetric ultrasonography. The additional
      information provided by in utero MR imaging may alter prenatal, perinatal, or
      immediate postnatal management. For example, the MR imaging findings may affect
      the decision to continue the pregnancy, change the mode, timing, or location of
      delivery, or modify decisions regarding the necessity of immediate postnatal
      surgery. Finally, the information contributed by MR may permit a better
      assessment of the risk of recurrent defects in subsequent pregnancies.

PMID- 15182821
TI  - A neuroimaging approach to inborn errors of metabolism.
AB  - There are numerous neurodegenerative and neurometabolic disorders of childhood.
      Individually, however, they are quite rare. Some may be seen only once in a
      lifetime at a given medical center, even one devoted to the specialized care of
      children. This article presents the classic neuroimaging features of some of the
      more commonly seen entities and of some of the more recently described metabolic
      disorders.

PMID- 15182822
TI  - Molecular imaging of cell-based therapies.
AB  - This article focuses on molecular imaging of novel cell-based therapies,
      particularly stem cell therapies and the adoptive transfer of immunocytes. The
      animal models,potential clinical applications, and likely future prospects of
      these therapies are discussed in the context of imaging.

PMID- 15182824
TI  - Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase
      inhibitors: where do we stand, where do we go.
AB  - Cytotoxic chemotherapy has only yielded modest gains in survival in lung cancer
      in the past decade. However, the development of agents targeting specific
      signaling pathways that drive carcinogenesis has heralded a major paradigm shift
      in the approach to treatment of cancer. In non-small cell lung cancer (NSCLC),
      many researchers have focused on the epidermal growth factor receptor (EGFR)
      because this protein is present on a relatively high proportion of non-small cell
      lung cancers and its intracellular tyrosine kinase activates a signaling cascade
      that drives tumor growth. Blockade of the EGFR by small molecule inhibitors of
      the tyrosine kinase, such as gefitinib and erlotinib, causes tumor regressions in
      NSCLC. Phase II monotherapy trials of EGFR tyrosine kinase inhibitors in patients
      with previously treated advanced NSCLC demonstrated anti-tumor activity with
      objective response rates of 10-19% with acceptable toxicities and an associated
      improvement in lung cancer symptomatology. Gefitinib is now an FDA approved
      treatment for advanced NSCLC previously treated with platinum and docetaxel-based
      therapies. However, phase III trials of gefitinib and erlotinib in combination
      with chemotherapy doublets have failed to demonstrate a survival advantage when
      compared with chemotherapy alone. It remains unclear why these drugs work so
      effectively in certain patients and so poorly in combination with chemotherapy.
      The goal of ongoing and future investigation is to identify which patients may
      benefit from this new therapeutic approach.

PMID- 15182825
TI  - The prothrombotic state in cancer: pathogenic mechanisms.
AB  - Thrombosis and disseminated intravascular coagulation (DIC) are common
      complications in cancer. Patients with malignancy have a prothrombotic state due
      to the ability of almost all type of cancer cells to activate the coagulation
      system. However, none of the haemostatic markers of coagulation has any
      predictive value for the occurrence of the thrombotic events in one individual
      patient. The pathogenesis of the prothrombotic state in cancer is complex and,
      probably, multifactorial. Prothrombotic factors in malignancy include the tumour
      production of procoagulants (i.e., tissue factor (TF) and cancer procoagulant
      (CP)) and inflammatory cytokines, and the interaction between tumour cells and
      blood (i.e., monocytes/macrophages, platelets) and endothelial cells. Other
      mechanisms of thrombus promotion include some general responses of the host to
      the tumour (i.e., acute phase, inflammation, angiogenesis), decreased levels of
      inhibitors of coagulation, and impaired fibrinolysis. In addition, the
      prothrombotic tendency of cancer patients is enhanced by anticancer therapy, such
      as surgery, chemotherapy, hormone therapy and radiotherapy, by indwelling central
      venous catheter, and by haemodinamic compromise (i.e., stasis). However, not all
      of the mechanisms allowing the prothrombotic state of cancer are entirely
      understood. Therefore, it is presently difficult to rank the relative weight of
      these multiple interactions on the basis of the well-recognised clinical
      evidences of enhanced thrombotic episodes in patients with cancer. In this review
      we attempt to describe the current proposed mechanisms for the pathogenesis of
      the prothrombotic state in cancer patient. A better understanding of these
      mechanisms could help clinicians in the developments of more targeted treatment
      to prevent thromboembolic complications in cancer patient.

PMID- 15182826
TI  - Adult acute myeloid leukaemia.
AB  - The curability of acute myeloid leukaemia (AML) in a fraction of adult patients
      was demonstrated a long time ago. Currently, the probability of cure is
      consistently above fifty per cent in patients with de novo disease expressing
      favourable-risk associated cytogenetic features. Even better, the cure rate
      exceeds 75% in the acute promyelocytic subtype since the introduction of retinoic
      acid-containing regimens. In the meantime, continuing progress in supportive care
      systems and stem cell transplant procedures is making myeloablative therapies,
      when needed, somewhat less toxic-and thereby more effective-than in the recent
      past. Therefore, evidence is accumulating to indicate an improved therapeutic
      trend over the years, with the notable exception of older (>55 years) patients
      with adverse-risk chromosomal aberrations and/or leukemia secondary to
      myelodysplasia or prior cancer-related chemotherapy and/or radiotherapy. This
      review conveys the many facets of this progress, focusing on diagnostic subsets,
      risk classes, newer biological issues and conventional as well as innovative
      therapeutic interventions with or without autologous/allogeneic stem cell
      transplantation.

PMID- 15182827
TI  - Adult acute lymphoblastic leukaemia.
AB  - Acute lymphoblastic leukaemia (ALL) in adults is a relatively rare neoplasm with
      a curability rate around 30% at 5 years. This consideration makes it imperative
      to dissect further the biological mechanisms of disease, in order to selectively
      implement an hitherto unsatisfactory success rate. The recognition of discrete
      ALL subtypes (some of which deserve specific therapeutic approaches, like T
      lineage ALL (T-ALL) and mature B-lineage ALL (B-ALL)) is possible through an
      accurate combination of cytomorphology, immunophenotytpe and cytogenetic assays
      and has been a major result of clinical research studies conducted over the past
      20 years. Two-three major prognostic groups are now easily identifiable, with a
      survival probability ranging from <10 to 20% (Philadelphia-positive ALL) to about
      50-60% (low-risk T-ALL and selected patients with B-lineage ALL). These issues
      are extensively reviewed and form the basis of current knowledge. The second
      major point relates to the emerging importance of studies that reveal a
      dysregulated gene activity and its clinical counterpart. It is now clear that
      prognostication is a complex matter ranging from patient-related issues to
      cytogenetics to molecular biology, including the evaluation of minimal residual
      disease (MRD) and possibly gene array tests. On these bases, the role of a
      correct, highly personalised therapeutic choice will soon become fundamental.
      Therapeutic progress may be obtainable through a careful integration of
      chemotherapy, stem cell transplantation, and the new targeted treatments with
      highly specific metabolic inhibitors and humanised monoclonal antibodies.

PMID- 15182828
TI  - Microbial mats for multiple applications in aquaculture and bioremediation.
AB  - Microbial mats occur in nature as stratified communities of cyanobacteria and
      bacteria, but they can be cultured on large-scale and manipulated for a variety
      of functions. They are complex systems, but require few external inputs. The
      functional uses of mats broadly cover the areas of aquaculture and
      bioremediation. Preliminary research also points to promising uses in agriculture
      and energy production. Regarding aquaculture, mats were shown to produce protein,
      via nitrogen fixation, and were capable of supplying nutrition to tilapia
      (Oreochromis niloticus). Current research is examining the role of mats in the
      nitrification of nutrient-enriched effluents from aquaculture. Most research has
      addressed bioremediation, within which two majors categories of contaminants were
      examined: metals and radionuclides, and organic contaminants. Mats sequester or
      precipitate metals/radionuclides by surface absorption or by conditioning the
      surrounding chemical environment, thus bioconcentrating the metal/radionuclide in
      a small volume. Organic contaminants are degraded and may be completely
      mineralized. For agriculture mats hold promise as a soil amendment and nitrogen
      fertilizer. The use of mats in biohydrogen production has been verified, but is
      in a preliminary phase of development. We propose a comprehensive closed system
      based on microbial mats for aquaculture and waste management.

PMID- 15182829
TI  - Production, characterization and application of a thermostable polygalacturonase
      of a thermophilic mould Sporotrichum thermophile Apinis.
AB  - The production of polygalacturonase (PGase) by Sporotrichum thermophile Apinis in
      stirred submerged fermentation (SmF) was high in comparison with that in static
      conditions. Yeast extract (0.25%) and citrus pectin (2%) at pH 7.0 and 45 degrees
      C supported a high enzyme production in flasks agitated at 200 rpm. An overall
      1.75-fold enhancement in PGase production was achieved as a result of
      optimization. The enzyme was optimally active at pH 7.0 and 55 degrees C, and
      exhibited t(1/2) of 4 h at 65 degrees C. The Km and Vmax values of the enzyme
      (for pectin) were 0.416 mg ml(-1) and 0.52 micromol mg(-1)min(-1), respectively.
      The PGase activity was stimulated by Mn(2+) and Fe(2+), but inhibited strongly by
      Mg(2+), and slightly by Tween 80 and Triton X-100. Among the additives tested,
      beta-mercaptoethanol exerted a strong inhibitory effect, suggesting a critical
      role of disulphide linkages in maintaining a suitable conformation of the enzyme.
      An increase in the yield of banana, grape and apple juices was recorded due to
      the treatment of fruit pulps with the mixture of enzymes (pectinase, xylanases
      and cellulase) of S. thermophile as compared to that with only pectinase. The
      yield of fruit juices did not increase with enhanced titre of cellulase in the
      enzyme mixture.

PMID- 15182830
TI  - Removal of chromate anions from aqueous stream by a cationic surfactant-modified
      yeast.
AB  - The removal of chromate anions (CrO(4)(2-)) from aqueous solution by a cationic
      surfactant-modified yeast was studied in a batch system. Cetyl trimethyl ammonium
      bromide (CTAB) was used for biomass modification; it substantially improved the
      biosorption efficiency. The influences of solution pH, CrO(4)(2-) anion
      concentrations and biomass concentration on the biosorption efficiency were
      investigated. The biosorption of chromate anions by modified yeast was strongly
      affected by pH. The optimum pH for biosorption of CrO(4)(2-) by modified yeast
      was 4.5-5.5. Zeta potential values of modified and unmodified yeast were
      determined at various pH values. Concentrations ranging from 5.2 to 208 mg/l
      Cr(VI) were tested and the biosorptive removal efficiency of the metal ions from
      aqueous solution was more than 99.5%. Freundlich and Langmuir isotherms were used
      to evaluate the data and the regression constants were determined.

PMID- 15182831
TI  - Nutrient removal from farm effluents.
AB  - The objectives of the study were: (i) to examine the efficiency of nutrient
      removal during the treatment of dairy farm effluent in a two-pond system, and
      (ii) to produce an inexpensive but effective nutrient trap which could be
      recycled as a nutrient source or soil mulch. The concentration of chemical oxygen
      demand (COD), biological oxygen demand (BOD), nitrogen (N), phosphorus (P) and
      potassium (K) in a two-pond system used to treat dairy farm effluent was
      monitored over a period of 7 months. The retention of nutrients by two porous
      materials was examined both in the laboratory batch (zeolite and bark) and pilot
      scale field (bark) experiments. The results indicated that biological treatment
      of farm effluents using the two-pond system was not effective in the removal of
      nutrients, which are likely to become pollutant when discharged to waterways.
      Both the bark and zeolite materials were effective in the removal of N, P and K
      from effluent. These materials can be placed in the second (i.e., aerobic) pond
      to treat effluents, which can then be discharged to streams with minimum impact
      on water quality. The nutrient-enriched porous materials can be recycled as a
      source of nutrients and soil conditioner.

PMID- 15182832
TI  - Influence of inoculum on performance of anaerobic reactors for treating municipal
      solid waste.
AB  - The influence of bovine rumen fluid inoculum during anaerobic treatment of the
      organic fraction of municipal solid waste (MSW) was studied in this work. The
      parameters adopted for evaluation were the biostabilization constant of total
      volatile solids (TVS) and the biostabilization time of the chemical oxygen demand
      (COD) applied to the reactors. The work was realized in four anaerobic batch
      reactors of 20 l capacity each, during a period of 365 days. The proportions
      between MSW/inoculum loaded in the reactors were Reactor A (100%/0%), Reactor B
      (95%/5%), Reactor C (90%/10%) and Reactor D (85%/15%). The necessary time for
      biostabilization of half of the applied COD was 459, 347, 302 and 234 days and
      the average of methane concentration in the biogas produced was 3.6%, 13.0%,
      25.0% and 42.6% for Reactors A, B, C and D, respectively. The data obtained
      affirm that the inoculum used substantially improved the performance of the
      process.

PMID- 15182833
TI  - Dechlorination and decolorization of chloro-organics in pulp bleach plant E-1
      effluents by advanced oxidation processes.
AB  - Studies were conducted on the composition of chloro-organics in kraft-pulp bleach
      plant E-1 effluents and their response toward advanced oxidation processes, such
      as UV-, O(2)/UV-, O(3)/UV- and O(3)-H(2)O(2)/UV-photolysis processes with
      irradiation of 254 nm photons. The studies were extended to ozonation and O(3)
      H(2)O(2) oxidation systems in alkaline aqueous solution. The effects of process
      variables included initial pH, addition of oxidant to the UV-photolysis system on
      the decolorization and dechlorination of the chloro-organics the E-1 bleaching
      effluents were also studied. The decolorization and dechlorination rate constants
      are increased in the presence of molecular oxygen in the UV-photolysis systems,
      but are decreased on addition of hydrogen peroxide. The dechlorination rate
      constants are increased appreciably on oxidation with ozone alone and a
      combination of ozone and hydrogen peroxide as compared to those of the
      corresponding UV-photolysis systems under aerial atmosphere.

PMID- 15182834
TI  - Evaluation of chlorines' impact on biofilms on scratched stainless steel
      surfaces.
AB  - Biofilms of a wild type Escherichia coli were grown on 316 stainless steel slides
      in a nutrient starved medium. The stainless steel surfaces were either polished
      to a smooth finish or scribed. The scribes consisted of lines and crosses.
      Biofilm samples were taken after 3, 6, 12, 24 and 48 h of growth. After sampling,
      the slides were soaked in deionized water or 50 or 200 ppm free chlorine prior to
      vital staining. Images were captured and the areas of viable and total biofilm
      were estimated. The individual biofilm patches, circularities, total percentage
      coverage, and viability percentage coverage were analyzed. The biofilms tended to
      increase in size between 6 and 24 h. A 3-6 h old biofilm on a polished stainless
      steel surface detached when 200 ppm sodium hypochlorite was applied. When grown
      in scribes, the circularity decreased up to 24 h, but thereafter increased. As
      the film grew older, it detached with or without a sodium hypochlorite treatment
      from the part of the surface that was polished, but remained in the neighborhood
      of the scribe. Based on the results, we recommend sanitizing at intervals of less
      than 12 h for this and similar strains of bacteria and protection of stainless
      steel surfaces to minimize scratching.

PMID- 15182835
TI  - Adsorbent supplemented biological treatment of pre-treated landfill leachate by
      fed-batch operation.
AB  - Biological treatment of landfill leachate usually results in low COD removals
      because of high chemical oxygen demand (COD), high ammonium-N content and
      presence of toxic compounds. Coagulation-flocculation with lime addition and air
      stripping of ammonia were used as pre-treatment in this study in order to improve
      biological treatability of the leachate. Pre-treated leachate was subjected to
      adsorbent supplemented biological treatment in an aeration tank operated in fed
      batch mode. COD and NH(4)-N removal performances of powdered activated carbon
      (PAC) and powdered zeolite (PZ) were compared during biological treatment.
      Adsorbent concentrations varied between 0 and 5 gl(-1). Percent COD and ammonium
      N removals increased with increasing adsorbent concentrations. Percent COD
      removals with PAC addition were significantly higher than those obtained with the
      zeolite. However, zeolite performed better than the PAC in ammonium-N removal
      from the leachate. Nearly 87% and 77% COD removals were achieved with PAC and
      zeolite concentrations of 2 gl(-1), respectively. Ammonium-N removals were 30%
      and 40% with PAC and zeolite concentrations of 5 gl(-1), respectively at the end
      of 30 h of fed-batch operation.

PMID- 15182836
TI  - Composition of corn and distillers dried grains with solubles from dry grind
      ethanol processing.
AB  - Increase in the demand for ethanol has resulted in growth in the dry grind (DG)
      ethanol industry. In DG processing, the whole corn kernel is fermented, resulting
      in two main coproducts, ethanol and distillers dried grains with solubles (DDGS).
      Marketing of DDGS is critical to the economic stability of DG plants. The
      composition of DDGS can vary considerably; this reduces market value. Factors
      that cause variation in composition need to be evaluated. The objective was to
      determine the relationship between composition of corn and composition of DDGS.
      Samples of corn and DDGS were obtained from a DG ethanol plant and analyzed for
      protein, fat, starch and other nutrients. Concentrations of protein, fiber and
      starch were similar to published data for corn but were higher for DDGS.
      Coefficients of variation for protein fat and fiber concentrations were similar
      for corn and DDGS. There were no significant correlations between concentrations
      of components in corn and those in DDGS. Variation in the composition of DDGS was
      not related to variation in corn composition and probably was due to variation in
      processing streams or processing techniques. This implies that reducing the
      variation in composition of DDG will require modification of processing
      strategies.

PMID- 15182837
TI  - Decolorization of basic, direct and reactive dyes by pre-treated narrow-leaved
      cattail (Typha angustifolia Linn.).
AB  - The efficiency of basic, direct and reactive dye removal from water by narrow
      leaved cattail (NLC) powder treated with distilled water (DW-NLC), 37%
      formaldehyde+0.2 N sulfuric acid (FH-NLC), or 0.1 N sodium hydroxide (NaOH-NLC)
      at various pH levels (3, 5, 7, and 9) was tested. Desorption of the adsorbed dyes
      was also investigated. The type of NLC treatment and pH of the dye solution had
      little effect on removal of basic dyes, and efficiencies ranged from 97% to 99%
      over the range of pH used. Over a wide range of pH levels, all types of treated
      cattail powder had negative charges and probably attracted the basic dyes
      possessing positive charges. Efficiency of removal by the three NLC treatments
      ranged from 37% to 42% for direct dyes and from 22% to 54% for direct dyes at pH
      7. The pH of the dye solution had substantial effects on the efficiency of
      removal in direct and reactive dyes. Dye removal was highest at pH 3, with 99%
      for a direct dye (Sirius Red Violet RL) and 96% for a reactive dye (Basilen Red M
      5B). There was mutual attraction between negatively charged direct dye molecules
      and positively charged molecules on the surface of the FH-treated cattail. In
      tests of desorption of dyes from cattail in distilled water, the desorption
      percentage for FH-NLC after adsorbing basic, direct and reactive dyes was 6%, 10%
      and 35%, respectively, which indicated a chemisorption mechanism for basic and
      direct dyes and some physiosorption for reactive dyes.

PMID- 15182838
TI  - Stabilization of palm oils by using Ficus exasperata leaves in local processing
      methods.
AB  - This work was done to ascertain the efficacy of the local use of Ficus exasperata
      leaves in processing palm oils to improve and stabilize the quality. Palm oils
      were obtained from the ripe fruits of Elaeis guineensis and Elaeis guineensis var
      virescens, including Ficus exasperata leaves in the traditional processing
      procedures--cooking and soaking the fruits in water. Phytochemical analysis of
      the Ficus leaves and the oils were performed. The quality of the oils were
      assessed in terms of saponification, acid and peroxide values, and free fatty
      acid content. Results showed the presence of phenolic compounds, terpenoids,
      alcohols and carbonyl compounds in the leaves. Oil from both oil palm varieties
      contained appreciable amounts of carotenoids, flavonoids and sterols, but only
      the Elaeis guineensis var virescens oil contained saponins. The use of the Ficus
      leaves eliminated saponins and the foaming tendencies of the var virescens oil,
      but reduced the sterol levels and increased the carotenoid levels in the oils
      from both oil palm varieties. Oils processed by soaking of fruits and use of the
      Ficus leaves had slightly greater saponification values, while oils processed by
      cooking of fruit and use of leaves had reduced FFA, acid and peroxide values. The
      use of Ficus exasperata leaves makes for a better stabilized oil with potentially
      good keeping qualities.

PMID- 15182839
TI  - Induction, production, repression, and de-repression of exoglucanase synthesis in
      Aspergillus niger.
AB  - The influence of carbon and nitrogen sources on the production of cellulases was
      investigated. The enzyme production was variable according to the carbon source.
      Levels of beta-cellobiohydrolase (CBH) were minimal in the presence of even low
      concentrations of glucose. Enzyme production was stimulated by other
      carbohydrates. The enzyme is subject to carbon source control by easily
      metabolizable sugars. Wheat bran and cellulose were the most effective promoters
      of beta-cellobiohydrolase and filter paperase (FPase) activities respectively,
      followed by rice bran. Exogenously supplied glucose inhibited the synthesis of
      the enzyme in cultures of A. niger growing on wheat bran. In defined medium with
      cellobiose, the cellobiohydrolase titres were 2- to 110-fold higher with cells
      growing on monomeric sugars and 1.5 times higher than cells growing on other
      disaccharides. It appeared that synthesis of beta-cellobiohydrolase varied under
      an induction mechanism, and a repression mechanism which changed the rate of
      synthesis of beta-cellobiohydrolase and FPase in induced over non-induced
      cultures. In this organism, substantial synthesis of beta-cellobiohydrolase can
      be induced by cellobiose, cellodextrin, cellulose or cellulose and hemi-cellulose
      containing substrates which showed low volumetric substrate uptake rate. The
      organism required limiting concentration of carbon, nitrogen or phosphorous for
      production of beta-cellobiohydrolase and FPase. During growth of A. niger on
      wheat bran, maximum volumetric productivities (Qp) of beta-cellobiohydrolase and
      FPase were 39.6 and 32.5 IU/lh and were significantly higher than the values
      reported for some other potent fungi and bacteria. The addition of actinomycin D
      (a repressor of transcription) and cycloheximide, (a repressor of translation)
      completely repressed CBH/FPase biosynthesis, suggested that the regulation of CBH
      synthesis in this organism occurs at both transcriptional and translational
      level. Thermodynamic studies revealed that the culture exerted protection against
      thermal inactivation when exposed to different fermentation temperatures.

PMID- 15182840
TI  - An economic analysis of leachate purification through willow-coppice vegetation
      filters.
AB  - In this study an economic analysis of the purification of integrated solid waste
      treatment facility leachates through a willow-coppice (Salix) vegetation filter
      in southern Sweden was carried out. Calculations were based on the use of two
      computer models that were initially used in estimating a pump-and-pipe irrigation
      system for a 36-ha willow-coppice plantation to purify an average annual quantity
      of 195,000 m(3) of leachate with an average nitrogen content of 24 g/m(3).
      Results showed that facility leachates could be purified at US dollars 0.34/m(3)
      compared with US dollars 0.62/m(3) for that of conventional leachate treatment at
      a wastewater treatment plant. Furthermore, results revealed that the increased
      income from willow growing and sale of the biomass chips represented only a small
      factor in the overall cost of the purification technique--decreasing purification
      costs to US dollars 0.326/m(3). Sensitivity analyses also demonstrated that,
      because of the large leachate holding pond expense, only a fraction of facility
      leachate should be treated through a vegetation filter.

PMID- 15182841
TI  - Kinetic growth parameters of different amylolytic and non-amylolytic
      Lactobacillus strains under various salt and pH conditions.
AB  - Four Lactobacillus species were studied for their ability to grow at high NaCl
      concentrations and different initial pH values. Lactobacillus plantarum 541 and
      A6 could ferment glucose and produce lactic acid in the presence of 8% salt in
      the medium. For strain 541, the specific rate of lactate production (q(lac)) and
      the yield of lactic acid relative to substrate (Y(p/s)) remained constant,
      whereas the yield of biomass relative to substrate (Y(x/s)) decreased up to 6%
      salt. In contrast, for strain A6, Y(p/s) decreased up to 6% salt whereas Y(x/s)
      did not vary markedly. Combined effects of salt and pH studied through a
      factorial design did not show significant interaction between salt and pH. The pH
      was the dominant factor in glucose fermentation for both the strains. Considering
      overall performance, 4% salt and pH between 6.0 and 6.6 can be taken as
      appropriate conditions, for the use of both strains as starters in processes
      where higher salt concentrations are required.

PMID- 15182842
TI  - Microbiological activities contributing to nitrogen removal with methane: effects
      of methyl fluoride and tungstate.
AB  - When methane (CH(4)) and O(2) are present, nitrogen can be removed from
      wastewater that does not contain other organic carbon sources. In this study,
      microbial activities during methane-dependent denitrification (MDD) were
      investigated by adding inhibitors of methane-oxidation and denitrification.
      Sludge susceptible to MDD showed methane oxidation activity in the presence of
      CH(4) and O(2), and denitrification activity with methanol and acetate under
      anoxic conditions. Methyl fluoride (CH(3)F) is known to inhibit methane
      oxidation. When CH(3)F was present, MDD did not occur, perhaps because methane
      oxidation was inhibited. Tungstate (WO(4)(2-)), a known inhibitor of nitrate
      reduction, also lowered denitrification activity in the sludge, and partly
      inhibited methane oxidation. When WO(4)(2-) was added to the medium, MDD almost
      ceased, perhaps because of a synergic inhibitory effect on denitrification and
      methane oxidation. These results show that both methane oxidation and
      denitrification contribute to MDD.

PMID- 15182843
TI  - Pb2+ removal from aqueous solution using crab shell treated by acid and alkali.
AB  - In order to investigate the process of Pb(2+) removal by crab shell, the effects
      of pretreatment of crab shell with acid and alkali on Pb(2+) removal by crab
      shell were examined. In acid treatment of crab shell with HCl for the
      demineralization of crab shell, Ca(2+) and Mg(2+) in crab shell were largely
      extracted during the acid treatment and the Pb(2+) removal by acid treated crab
      shell was very low. The total released Ca(2+) and Mg(2+) amounts in the alkali
      treated crab shell during Pb(2+) removal were not greatly different from those in
      the untreated crab shell. However, the times to reach an equilibrium state were
      quite shortened by alkali treatment and the reason was explained by transmission
      electron microscope.

PMID- 15182844
TI  - Approaches for creating computer-interpretable guidelines that facilitate
      decision support.
AB  - During the last decade, studies have shown the benefits of using clinical
      guidelines in the practice of medicine. Although the importance of these
      guidelines is widely recognized, health care organizations typically pay more
      attention to guideline development than to guideline implementation for routine
      use in daily care. However, studies have shown that clinicians are often not
      familiar with written guidelines and do not apply them appropriately during the
      actual care process. Implementing guidelines in computer-based decision support
      systems promises to improve the acceptance and application of guidelines in daily
      practice because the actions and observations of health care workers are
      monitored and advice is generated whenever a guideline is not followed. Such
      implementations are increasingly applied in diverse areas such as policy
      development, utilization management, education, clinical trials, and workflow
      facilitation. Many parties are developing computer-based guidelines as well as
      decision support systems that incorporate these guidelines. This paper reviews
      generic approaches for developing and implementing computer-based guidelines that
      facilitate decision support. It addresses guideline representation, acquisition,
      verification and execution aspects. The paper describes five approaches (the
      Arden Syntax, GuideLine Interchange Format (GLIF), PROforma, Asbru and EON),
      after the approaches are compared and discussed.

PMID- 15182845
TI  - Auditing concept categorizations in the UMLS.
AB  - The Unified Medical Language System (UMLS) integrates about 880,000 concepts from
      100 biomedical terminologies. Each concept is categorized to at least one
      semantic type of the Semantic Network. During the integration, it is unavoidable
      that some categorization errors and inconsistencies will be introduced. In this
      paper, we present an auditing technique to find such errors and inconsistencies.
      Our technique is based on an expert reviewing the pure intersections of meta
      semantic types of a metaschema, a compact abstract view of the UMLS Semantic
      Network. We use a divide and conquer approach, handling differently small pure
      intersections and medium to large pure intersections. By using this approach, we
      limit the number of concepts reviewed, for which we expect a high percentage of
      errors. We reviewed all concepts in 657 pure intersections containing one to 10
      concepts. Various kinds of errors are identified and the analysis of the results
      are presented in the paper. Also, we checked the pure intersections containing
      more than 10 concepts for their semantic soundness, where the semantically
      suspicious pure intersections are presented in the paper and their concepts are
      reviewed.

PMID- 15182846
TI  - Prediction of diagnosis in patients with early arthritis using a combined Kohonen
      mapping and instance-based evaluation criterion.
AB  - Rheumatoid arthritis (RA) and spondyloarthropathy (SpA) are the two most frequent
      forms of chronic autoimmune arthritis. These diseases lead to important
      inflammatory symptoms resulting in an important functional impairment. This paper
      introduces a self-organizing artificial neural network combined with a case-based
      reasoning evaluation criterion to predict diagnosis in patients with early
      arthritis. Results show that 47.2% of the sample space can be predicted with an
      accuracy of 84.0% and attaining a high confidence level. 37.7% of the sample
      space is classified with an overall accuracy of 65.0%. The remaining group was
      labeled as "undetermined". A general prediction accuracy of 75.6% is reached,
      exceeding the performance of other approaches such as a backpropagation neural
      network and the Quest decision tree program. Furthermore, by using this new
      method, more specifically case-based reasoning, as a helpful tool to classify
      patients with early arthritis, the possibility of a confidence measure is given,
      indicating a degree of "belief" of the system in its results. This is often an
      important feature when dealing with diagnosis in human patients.

PMID- 15182847
TI  - A quantitative comparison of functional MRI cluster analysis.
AB  - The aim of this work is to compare the efficiency and power of several cluster
      analysis techniques on fully artificial (mathematical) and synthesized (hybrid)
      functional magnetic resonance imaging (fMRI) data sets. The clustering algorithms
      used are hierarchical, crisp (neural gas, self-organizing maps, hard competitive
      learning, k-means, maximin-distance, CLARA) and fuzzy (c-means, fuzzy competitive
      learning). To compare these methods we use two performance measures, namely the
      correlation coefficient and the weighted Jaccard coefficient (wJC). Both
      performance coefficients (PCs) clearly show that the neural gas and the k-means
      algorithm perform significantly better than all the other methods using our
      setup. For the hierarchical methods the ward linkage algorithm performs best
      under our simulation design. In conclusion, the neural gas method seems to be the
      best choice for fMRI cluster analysis, given its correct classification of
      activated pixels (true positives (TPs)) whilst minimizing the misclassification
      of inactivated pixels (false positives (FPs)), and in the stability of the
      results achieved.

PMID- 15182848
TI  - Brain tumor classification based on long echo proton MRS signals.
AB  - There has been a growing research interest in brain tumor classification based on
      proton magnetic resonance spectroscopy (1H MRS) signals. Four research centers
      within the EU funded INTERPRET project have acquired a significant number of long
      echo 1H MRS signals for brain tumor classification. In this paper, we present an
      objective comparison of several classification techniques applied to the
      discrimination of four types of brain tumors: meningiomas, glioblastomas,
      astrocytomas grade II and metastases. Linear and non-linear classifiers are
      compared: linear discriminant analysis (LDA), support vector machines (SVM) and
      least squares SVM (LS-SVM) with a linear kernel as linear techniques and LS-SVM
      with a radial basis function (RBF) kernel as a non-linear technique. Kernel-based
      methods can perform well in processing high dimensional data. This motivates the
      inclusion of SVM and LS-SVM in this study. The analysis includes optimal input
      variable selection, (hyper-) parameter estimation, followed by performance
      evaluation. The classification performance is evaluated over 200 stratified
      random samplings of the dataset into training and test sets. Receiver operating
      characteristic (ROC) curve analysis measures the performance of binary
      classification, while for multiclass classification, we consider the accuracy as
      performance measure. Based on the complete magnitude spectra, automated binary
      classifiers are able to reach an area under the ROC curve (AUC) of more than 0.9
      except for the hard case glioblastomas versus metastases. Although, based on the
      available long echo 1H MRS data, we did not find any statistically significant
      difference between the performances of LDA and the kernel-based methods, the
      latter have the strength that no dimensionality reduction is required to obtain
      such a high performance.

PMID- 15182850
TI  - Reactive oxygen species in immune responses.

PMID- 15182851
TI  - Role of Se-dependent glutathione peroxidases in gastrointestinal inflammation and
      cancer.
AB  - Increase in reactive oxygen species plays an integral part in the inflammatory
      response, and chronic inflammation increases cancer risk. Selenium-dependent
      glutathione peroxidase (GPX) is well recognized for its antioxidant, and thus
      anti-inflammatory, activity. However, due to the multiple antioxidant families
      present in the gastrointestinal tract, it has been difficult to demonstrate the
      importance of individual antioxidant enzymes. Using genetically altered mice
      deficient in individual Gpx genes has provided insight into the physiological
      functions of these genes. Insufficient GPX activity in the mucosal epithelium can
      trigger acute and chronic inflammation. The presence of certain microflora, such
      as Helicobacter species, may affect cancer risk significantly. However, when
      damaged cells have progressed into a precancerous status, increased GPX activity
      may become procarcinogenic, presumably due to inhibition of hydroperoxide
      mediated apoptosis. This review summarizes the current view of GPX in
      inflammation and cancer with emphasis on the GI tract.

PMID- 15182852
TI  - Regulation of T-cell apoptosis by reactive oxygen species.
AB  - To ensure that a constant number of T cells are preserved in the peripheral
      lymphoid organs, the production and proliferation of T cells must be balanced out
      by their death. Newly generated T cells exit the thymus and are maintained as
      resting T cells. Transient disruption of homeostasis occurs when naive T cells
      undergo antigen-induced expansion, a process involving intracellular signaling
      events that lead to T cell proliferation, acquisition of effector functions, and,
      ultimately, either apoptosis or differentiation into long-lived memory cells. The
      last decision point (death vs. differentiation) is a crucial one: it resets
      lymphoid homeostasis, promotes protective immunity, and limits autoimmunity.
      Despite its importance, relatively little is known about the molecular mechanisms
      involved in this cell fate decision. Although multiple mechanisms are likely
      involved, recent data suggest an underlying regulatory role for reactive oxygen
      species in controlling the susceptibility of T cells to apoptosis. This review
      focuses on recent advances in our understanding of how reactive oxygen species
      modulate T-cell apoptosis.

PMID- 15182853
TI  - Dietary chemopreventive compounds and ARE/EpRE signaling.
AB  - Chemoprevention comprises multiple intervention methods using either
      pharmacological or dietary agents to impede, arrest, or reverse carcinogenesis at
      various stages. Development of dietary compounds as potential cancer
      chemopreventive agents is highly desirable, due to their safety, low toxicity,
      and general acceptance as dietary supplements. In this review, potential
      application of the dietary detoxifying enzyme inducers for chemoprevention and
      their relevant signaling events are discussed. Overall, the detoxifying enzyme
      system plays an important role in determining the final fate of
      carcinogens/procarcinogens and their subsequent impact on carcinogenesis. Among
      those positive regulators, phenolic and sulfur-containing compounds are two major
      classes of dietary detoxifying enzyme inducers. Regulation of many detoxifying
      enzymes by dietary chemopreventive compounds is mediated by the antioxidant
      response element (ARE)/electrophile response element (EpRE), which is located in
      the promoter region of related genes. Transcription factor nuclear factor E2
      related factor 2 (Nrf2) binds to the ARE sequence to initiate gene expression. In
      response to treatments of various detoxifying enzyme inducers, several signal
      transduction pathways, including the oxidative stress, mitogen-active protein
      kinase, protein kinase C, and phosphatidylinositol 3-kinase pathways, are
      activated. The consequences of the activation of these signaling cascades,
      whether directly or indirectly, lead to the dissociation of Nrf2 from its
      cytosolic sequester Kelch-like ECH associating protein 1, nuclear translocation,
      and accumulation of Nrf2 protein in the nucleus, and ultimately increase the
      expression level of detoxifying enzymes through transcriptional activation of
      ARE/EpRE in those responsible genes.

PMID- 15182854
TI  - Cadmium induces caspase-independent apoptosis in liver Hep3B cells: role for
      calcium in signaling oxidative stress-related impairment of mitochondria and
      relocation of endonuclease G and apoptosis-inducing factor.
AB  - Cadmium-induced cellular toxicity has been related to necrosis and/or caspase
      dependent apoptosis. In the present study, we show that, on cadmium exposure, the
      human hepatocarcinoma Hep3B cells undergo caspase-independent apoptosis
      associated with nuclear translocation of endonuclease G and apoptosis-inducing
      factor, two mitochondrial apoptogenic proteins. Release of these proteins is
      likely related to calcium-induced alteration of mitochondrial homeostasis.
      Indeed, it was first preceded by a rapid and sustained increase in cytoplasmic
      calcium and then by a coincident loss in mitochondrial membrane potential and
      production of reactive oxygen species. Bapta-AM (acetoxymethyl ester of 5, 5'
      dimethyl-bis (o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), a calcium
      chelator, blocked all these events and prevented cadmium-induced apoptosis.
      Production of reactive oxygen species was inhibited by ruthenium red and
      rotenone, two mitochondrial inhibitors, and by diphenyleneiodonium, a
      flavoprotein inhibitor, which also prevented both loss in mitochondrial membrane
      potential and apoptosis. In addition, Bapta-AM and diphenyleneiodonium were found
      to almost totally block decreased expression of the mitochondrial anti-apoptotic
      nuclear factor-kappaB-regulated bcl-x(L) protein in cadmium-treated cells. Taken
      together, our results show that cadmium induces Hep3B cells apoptosis mainly by
      calcium- and oxidative stress-related impairment of mitochondria, which probably
      favors release of apoptosis-inducing factor and endonuclease G.

PMID- 15182856
TI  - Catalase binds Grb2 in tumor cells when stimulated with serum or ligands for
      integrin receptors.
AB  - Recent studies have demonstrated that H(2)O(2) acts as a second messenger of
      mitogenic signaling and that catalase is under the regulation of PKA and PKC
      signaling. Here we examined whether catalase binds any mitogenic signaling
      molecules. Our results indicated that serum stimulation of HeLa, Caco-2, and LiSa
      2 cells, but not BJ-1 and primary human bronchial epithelial cells, resulted in
      catalase binding to Grb2. Whereas serum deprivation, butyrate, and herbimycin-A
      negatively regulated the binding, an extended culture of confluent Caco-2 cells
      resulted in binding of an additional but as yet unidentified molecule to the Grb2
      catalase complex. Expression of active catalase nearly 15-fold over control level
      in Tet-off HeLa cells substantially increased binding to Grb2, and this was
      sensitive to 3-aminotriazole, a specific catalase inhibitor. Furthermore,
      fibrinogen, fibronectin, and laminin, but not collagen types I to V, hyaluronic
      acid, elastin, insulin, EGF, IGF-I, PDGF, or NGF, resulted in binding similar to
      that of serum. A mutation of tyrosine to phenylalanine at 447 abolished the
      binding capability of catalase to Grb2 in vitro. These results support the view
      that catalase (447)Tyr-Val-Asn-Val binds Grb2 upon phosphorylation in tumor cells
      when stimulated with serum or ligands for integrin receptors. This is the first
      report demonstrating that catalase binds a SH2 domain of the molecule and
      participates in integrin signaling.

PMID- 15182855
TI  - Homocysteine induces oxidative stress by uncoupling of NO synthase activity
      through reduction of tetrahydrobiopterin.
AB  - Hyperhomocysteinemia is a risk factor for cardiovascular diseases that induces
      endothelial dysfunction. Here, we examine the participation of endothelial NO
      synthase (eNOS) in the homocysteine-induced alterations of NO/O(2)(-) balance in
      endothelial cells from human umbilical cord vein. When cells were treated for 24
      h, homocysteine dose-dependently inhibited thrombin-activated NO release without
      altering eNOS phosphorylation and independently of the endogenous NOS inhibitor,
      asymmetric dimethylarginine. The inhibitory effect of homocysteine on NO release
      was associated with increased production of reactive nitrogen and oxygen species
      (RNS/ROS) independent of extracellular superoxide anion (O(2)(-)) and was
      suppressed by the NOS inhibitor L-NAME. In unstimulated cells, L-NAME markedly
      decreased RNS/ROS formation and the ethidium red fluorescence induced by
      homocysteine. This eNOS-dependent O(2)(-) synthesis was associated with reduced
      intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (
      80%) and increased release of 7,8-dihydrobiopterin and biopterin in the
      extracellular medium (+40%). In addition, homocysteine suppressed the activating
      effect of sepiapterin on NO release, but not that of ascorbate. The results show
      that the oxidative stress and inhibition of NO release induced by homocysteine
      depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin
      availability.

PMID- 15182857
TI  - Glutathione content and adaptation to endogenously induced energy depletion in
      Mv1Lu cells.
AB  - Transfection of genes that code for enzymes of energy metabolism provides
      alternative models to study the adaptive response to energy restriction induced
      by endogenous changes instead of by unfavorable environmental conditions.
      Overexpression of the glycolytic enzyme fructose-2,6-bisphosphatase reduced the
      content of fructose 2,6-bisphosphate, inducing energy limitation in the mink lung
      epithelial cell line Mv1Lu. This metabolic stress reduced the ATP available in
      transfected cells by 20%, which downregulated active ion transport and protein
      turnover. Ion homeostasis and cell function require concomitant reductions in
      cell membrane ion permeability and protein damage. Our results indicate that
      glutathione content linked these features of the adaptive response to the
      endogenously induced metabolic downregulation.

PMID- 15182858
TI  - Involvement of lipid peroxidation and organic peroxides in UVA-induced matrix
      metalloproteinase-1 expression.
AB  - Ultraviolet A (UVA) irradiation causes human skin aging and skin cancer at least
      partially through the activation of matrix metalloproteinases (MMPs). MMP-1, the
      interstitial collagenase, is responsible for the degradation of collagen and is
      involved in tumor progression in human skin. The present study uses human skin
      fibroblast cells (FEK4) to investigate the involvement of lipid peroxidation and
      the role of peroxides as possible mediators in MMP-1 activation by UVA.
      Preincubation with the antioxidants butylated hydroxytoluene and Trolox reduced
      UVA-dependent MMP-1 upregulation, suggesting that peroxidation of membrane lipids
      is involved. Blocking the iron-driven generation of lipid peroxides and hydroxyl
      radicals by different iron chelators led to a decrease in UVA-induced MMP-1 mRNA
      accumulation. Moreover, modulation of glutathione peroxidase activity by use of
      the specific inhibitor mercaptosuccinate (MS) or by the depletion of glutathione
      (using buthionine-S, R-sulfoximine, BSO), enhanced the UVA-dependent MMP-1
      response. Finally, UVA irradiation generated a significant increase in
      intracellular peroxide levels which is augmented by pretreatment of the cells
      with BSO or MS. Our results demonstrate that lipid peroxidation and the
      production of peroxides are important events in the signalling pathway of MMP-1
      activation by UVA.

PMID- 15182859
TI  - Characterization of antioxidant and antiglycation properties and isolation of
      active ingredients from traditional chinese medicines.
AB  - There is considerable interest in the isolation of more potent antioxidant
      compounds to treat diseases involving oxidative stress. Thirty-three traditional
      Chinese medicine (TCM) extracts were examined for their antioxidant activity
      using the 2,2'-azinobis[3-ethylbenzothiazoline-6-sulfonate] (ABTS) assay. Five
      extracts with high activity (Cratoxylum cochinchinense, Cortex magnoliae
      officinalis, Psoralea corylifolia L, Curculigo orchioides Gaertn, and Glycyrrhiza
      uralensis Fisch.) were selected for further characterization. C. cochinchinense
      outperformed other extracts in most of the assays tested except phospholipid
      peroxidation inhibition, where P. corylifolia L showed higher activity. C.
      cochinchinense was particularly potent in inhibiting the formation of advanced
      glycation end products on proteins and strongly inhibited hypochlorous acid
      induced DNA damage. We attempted to isolate the active ingredients from C.
      cochinchinense and obtained an extract (YCT) containing at least 90% mangiferin
      as identified by HPLC and mass spectrometry. However, YCT showed significantly
      higher activity in assays of phospholipid peroxidation, inhibition of protein
      glycation, and superoxide (O(2)(?-)) and peroxynitrite (ONOO(-)) scavenging, as
      compared with mangiferin, suggesting that the nonmangiferin constituents of YCT
      contribute to its additional antioxidant activities.

PMID- 15182860
TI  - Mechanism of cell death induced by an antioxidant extract of Cratoxylum
      cochinchinense (YCT) in Jurkat T cells: the role of reactive oxygen species and
      calcium.
AB  - YCT is a semipurified extract from Cratoxylum cochinchinense that has antioxidant
      properties and contains mostly mangiferin. We show here that YCT is selectively
      toxic to certain cell types and investigate the mechanisms of this toxicity in
      Jurkat T cells. By flow cytometric analyses, we show that YCT causes intense
      oxidative stress and a rise in cytosolic Ca(2+). This is followed by a rise in
      mitochondrial Ca(2+), release of cytochrome c, collapse of Deltapsi(m), a fall in
      ATP levels, and eventually cell death. The mechanism(s) of intense oxidative
      stress may involve a plasma membrane redox system, as cell death is inhibited by
      potassium ferricyanide. Cell death has some features of apoptosis (propidium
      iodide staining, externalization of phosphatidylserine, limited caspase-3 and -9
      activities), but there was no internucleosomal DNA fragmentation.

PMID- 15182861
TI  - Formation of phosphatidic acid, ceramide, and diglyceride on radiolysis of
      lipids: identification by MALDI-TOF mass spectrometry.
AB  - By use of matrix-assisted laser desorption/ionization time-of-flight mass
      spectrometry, phosphatidic acid was found to be the main product of gamma
      radiolysis of cardiolipin, phosphatidylinositol, and phosphatidylglycerol. It has
      been shown that gamma irradiation of such glycolipids as cerebroside and
      galactosyl diglyceride leads to formation of ceramide and diglyceride,
      respectively. These findings, combined with those obtained earlier, allowed an
      assumption to be made that, owing to radiation-induced free radical fragmentation
      of lipids in their polar moiety, formation of signaling molecules can occur.

PMID- 15182862
TI  - Multiple deficiencies in antioxidant enzymes in mice result in a compound
      increase in sensitivity to oxidative stress.
AB  - To examine the effect of compound deficiencies in antioxidant defense, we have
      generated mice (Sod2(+/-)/Gpx1(-/-)) that are deficient in Mn superoxide
      dismutase (MnSOD) and glutathione peroxidase 1 (Gpx1) by breeding Sod2(+/-) and
      Gpx1(-/-) mice together. Although Sod2(+/-)/Gpx1(-/-) mice showed a 50% reduction
      in MnSOD and no detectable Gpx1 activity in either mitochondria or cytosol in all
      tissues, they were viable and appeared normal. Fibroblasts isolated from Sod2(+/
      )/Gpx1(-/-) mice were more sensitive (4- to 6-fold) to oxidative stress (t-butyl
      hydroperoxide or gamma irradiation) than fibroblasts from wild-type mice, and
      were twice as sensitive as cells from Sod2(+/-) or Gpx1(-/-) mice. Whole-animal
      studies demonstrated that survival of the Sod2(+/-)/Gpx1(-/-) mice in response to
      whole body gamma irradiation or paraquat administration was also reduced compared
      with that of wild-type, Sod2(+/-), or Gpx1(-/-) mice. Similarly, endogenous
      oxidative stress induced by cardiac ischemia/reperfusion injury led to greater
      apoptosis in heart tissue from the Sod2(+/-)/Gpx1(-/-) mice than in that from
      mice deficient in either MnSOD or Gpx1 alone. These data show that Sod2(+/
      )/Gpx1(-/-) mice, deficient in two mitochondrial antioxidant enzymes, have
      significantly enhanced sensitivity to oxidative stress induced by exogenous
      insults and to endogenous oxidative stress compared with either wild-type mice or
      mice deficient in either MnSOD or Gpx1 alone.

PMID- 15182864
TI  - Vascular disease and inflammation.
AB  - The past decade has witnessed a dramatic shift in the understanding of the causes
      of atherosclerotic vascular disease. What was once considered to be a process of
      abnormal lipid deposition in the vascular wall is now understood to be a dynamic
      inflammatory process from inception through plaque growth, rupture and ultimately
      thrombosis. This article reviews the basic science research that supports this
      growing body of epidemiologic data and discusses the inflammatory markers that
      predict future clinical events,as well as the pharmacologic success in therapies
      that specifically target inflammation.

PMID- 15182863
TI  - Mass spectrometric characterization of the oxidation of the fluorescent lipid
      peroxidation reporter molecule C11-BODIPY(581/591).
AB  - C11-BODIPY(581/591) is a fluorescent lipid peroxidation reporter molecule that
      shifts its fluorescence from red to green when challenged with oxidizing agents,
      i.e., reactive oxygen species (ROS) or reactive nitrogen species (RNS). To
      understand the molecular mechanism responsible for this shift, we studied the
      molecular rearrangements leading to the shift in fluorescence in C11
      BODIPY(581/591). Furthermore, we aimed to determine if these rearrangements were
      dependent on the nature of the applied ROS, in homogenous solution, bilayer
      vesicles, and living cells. C11-BODIPY(581/591) was challenged with various ROS-
      or RNS-generating systems, including peroxynitrite, NO(2)(?), peroxides, and
      hydroxyl, alkoxyl, tyrosyl, and peroxyl radicals. The reaction products were
      subsequently analyzed by means of mass spectrometry. Our results show that the
      initial target for free radical-mediated oxidation is the conjugated diene
      interconnection between the BODIPY core and the terminal phenyl moiety, which
      already explains the shift in fluorescence properties of the probe. After
      oxidative challenge, three different stable products were identified, one of
      which was specific for oxidation by peroxynitrite. The two other stable end
      products had lost the entire phenyl moiety, irrespective of the type of radical
      generating system used. These products were also recovered from Rat-1 fibroblasts
      stressed either by GSH depletion/serum starvation or by exposure to
      peroxynitrite, and were the only C11-BODIPY(581/591) oxidation products
      detectable in these cells.

PMID- 15182865
TI  - Preoperative cardiac evaluation.
AB  - The current standards for preoperative cardiac evaluation and the guidelines
      published by the American College of Cardiology and the American Heart
      Association call for noninvasive or invasive cardiac evaluation in certain
      patients. Perioperative use of beta-adrenergic blockade has been shown to reduce
      cardiac complication rates, diminishing the positive predictive value and the
      likelihood ratio of a positive result of a preoperative cardiac test,unfavorably
      shifting the risk to benefit ratio of preoperative tests and any possible
      therapeutic action that one might take based on the test. A new paradigm might be
      emerging that makes cardiac tests unnecessary except in the highest-risk patients
      identified by clinical variables.

PMID- 15182866
TI  - Noncardiac pulmonary, endocrine, and renal preoperative evaluation of the
      vascular surgical patient.
AB  - Patients who have vascular disease who are to undergo an operation are at risk
      for developing perioperative and postoperative complications caused by coexisting
      diseases. A comprehensive preoperative evaluation is critical in identifying
      these coexisting diseases, and the anesthetic plan might require modification.
      This article focuses on important aspects of the pulmonary, endocrine (diabetes),
      and renal systems during the preoperative evaluation of the vascular surgical
      patient.

PMID- 15182867
TI  - Intraoperative monitoring during vascular surgery.
AB  - The principal objectives of intraoperative monitoring are to improve
      perioperative outcome, facilitate surgery and reduce adverse events, using
      continuously collected data of cardiopulmonary,neurologic and metabolic function
      to guide pharmacologic and physiologic therapy. Although sophisticated and
      reliable apparatus may be used to collect these data they are useless, or even
      harmful, without proper interpretation. This article provides a comprehensive
      overview of recent publications on the history,philosophy, and semantics of
      monitoring.

PMID- 15182868
TI  - Choice of anesthetics.
AB  - The choice of anesthetics for vascular surgical patients is not only determined
      by the kind and extent of the surgical procedure but also by patient
      comorbidities. Frequently, patients have a history of hypertension, peripheral
      vascular and coronary artery disease,cerebrovascular disease, and renal
      impairment. The goal of the chosen anesthetic technique is to protect organ
      function, mainly of the brain and the heart. In some instances regional
      anesthesia might be preferred, but no difference in outcome between the two
      techniques has been shown conclusively. Vascular emergencies are particularly
      challenging for the anesthesiologist, but in recent years the development of
      stent graft insertion has improved the short-term outcome in many of these
      procedures.

PMID- 15182869
TI  - Intraoperative management: carotid endarterectomies.
AB  - The management of anesthesia for patients undergoing carotid endarterectomy is
      challenging and dynamic. Effective management and good outcome requires the
      anesthesiologist's understanding of cerebral physiology, knowledge of neck
      anatomy, and understanding of the rapid pathophysiologic changes that occur
      during carotid artery manipulations. The anesthesiologist must be flexible in the
      management of patients, who frequently have underlying multiorgan pathology and
      cardiovascular compromise. Good communication between the anesthetic and surgical
      teams is needed to avoid irreversible debilitating consequences for the patient.

PMID- 15182870
TI  - Intraoperative management of aortic aneurysm surgery.
AB  - Managing the anesthesia of patients undergoing open aortic surgical repair is a
      great challenge. The anesthesiologist's role in myocardial,renal, and neurologic
      protection is crucial to the patient's overall outcome.Each case presents
      different challenges, and there is no one right way to manage the patient
      intraoperatively.

PMID- 15182871
TI  - Intraoperative management: peripheral vascular surgery.
AB  - Lower extremity atherosclerotic disease affects nearly 10 million people in the
      United States. Recent advances in diagnostic imaging and interventional
      techniques help many patients avoid more invasive surgical procedures. Those
      reaching the operating room, however,represent a distilled subset of patients who
      are prone to significant comorbidities. We outline current treatment strategies
      and discuss anesthetic concerns and techniques for these complex patients.

PMID- 15182872
TI  - Intraoperative management: endovascular stents.
AB  - This article discusses the current state of minimally invasive treatment options
      for a variety of vascular diseases. Advances that have been introduced over the
      last two decades have dramatically changed the practice of vascular surgery and
      anesthesia. The ability to treat pathology, using both intraluminal and
      extraluminal means,has provided vascular surgeons, interventional radiologists,
      and cardiologists with unique treatment options that were not available less than
      a decade ago. Peripheral interventions to treat vascular disease have exploded,
      from 90,000 in 1994 to more than 200,000 in 1997, and endovascular procedures now
      replace almost 50% of traditional open vascular operations.

PMID- 15182875
TI  - Vascular anesthesia.

PMID- 15182873
TI  - Postoperative care of vascular surgery patients.
AB  - Vascular surgery continues to carry one of the highest postoperative morbidity
      and mortality rates. A detailed understanding of postoperative central nervous,
      myocardial, respiratory, and renal pathophysiology potentially helps to improve
      outcome. Current economic constraints, combined with changing intraoperative
      management, prompt inquiry into whether these patients can safely be managed
      outside of an intensive care unit setting. This article reviews whether efforts
      to less invasively manage these patients intraoperatively improves postoperative
      outcome remains under investigation, and what is known about the effects on
      postoperative outcome of regional anesthesia for carotid endarterectomy and
      endovascular treatment of aortic vascular disease.

PMID- 15182876
TI  - Anti-aging medicine--the good, the bad, and the ugly.
AB  - Complementary and alternative medicine has flourished since the beginning of time
      because of a human need to postpone the aging process and to reverse disease.
      Complementary and alternative medicine sells, because in some cases it works as
      well or better than mainstream medicine. In addition, many practitioners of
      complementary medicine understand Hippocrates' aphorism: "It is more important to
      know the person that has the disease than the disease the person has." It is
      important to recognize that spending time with the patient is often as
      therapeutic as drugs. CAM offers patients the time, touch, attention, and level
      of personal interaction that are increasingly uncommon in contemporary medical
      care. There is a major need for large and appropriately designed studies to test
      the effectiveness of complementary techniques. As in other areas of health care,
      studies in the elderly are consistently lacking. With the growing interest in
      CAM, it is important for medical providers to keep an open mind--to both the
      potential benefits and potential harms of alternative treatments. When treatments
      are shown to be dangerous or ineffective, we must educate the public and work to
      remove these therapies from the market place. When treatments are proven
      effective, Western and Eastern medical providers must work together with patients
      to provide the most appropriate and comprehensive health care.

PMID- 15182877
TI  - The use of complementary and alternative medical therapies among older persons
      around the world.
AB  - Defining complementary and alternative medicine (CAM) helps in understanding what
      it offers, why older patients are attracted to and find effectiveness in these
      therapies, and how conventional practitioners can deal with their increasing use.
      The most common definition in United States medical literature is "those
      practices neither taught widely in United States medical schools nor gene-rally
      available in United States hospitals." Patient interviews must include inquiry
      into CAM use; providers need to know about potentially risky therapies.
      Integration of CAM into our health care system, although burdensome in the short
      term, will benefit patients in the long run, where benefit is due. Integration of
      CAM into treatment does not mean acknowledging its effectiveness, but taking
      advantage of any benefits it has to offer.

PMID- 15182878
TI  - Exercise and aging.
AB  - There is increasing evidence that the black box we have referred to as"biologic
      aging" is composed of genetic factors and many types of environmental exposures.
      Some of the most potentially modifiable elements of this syndrome are those
      attributable to disuse or insufficient exposure to certain kinds or intensities
      of physical stressors during the course of the life span. Beneficial adaptations
      to exercise once thought restricted to genetically endowed master athletes now
      are seen to occur just as predictably in frail elders with chronic disease,
      opening the door to vastly improved physical function and associated health
      benefits. Knowledge of the benefits of physical activity, however well
      substantiated, may be necessary, but it is not sufficient to change either
      physician-prescribing habits or the likelihood of adoption and long-term
      adherence to exercise on the part of patients. Ultimately, the penetration of an
      exercise prescription to optimize aging into the most inactive cohorts in the
      community,who have the most to gain from increases in levels of physical activity
      and fitness, will depend on a combination of clear evidence-based guidelines
      coupled with health professional training and behavioral programs tailored to age
      specific barriers and motivational factors.

PMID- 15182879
TI  - Chiropractic and geriatrics: a review of the training, role, and scope of
      chiropractic in caring for aging patients.
AB  - Chiropractors may be well-positioned to play an important role in health
      promotion, injury and disease prevention, and on geriatric care teams, due to
      their practice style and holistic philosophy. The bottom line in aging care is
      that someone in the health-care world must provide health promotion and
      preventive services to older patients before the wave of aged patients profoundly
      overwhelms our health-care system. Chiropractic services are safe and relatively
      low-cost, and patient satisfaction with them is very high. In the managed-care
      environment, time pressures on allopathic providers may preclude them from
      spending sufficient time discussing health promotion and illness prevention with
      their patients. Chiropractic, when paid for out-of-pocket, is not as affected by
      these extreme pressures. With the hands-on nature of chiropractic care, a strong
      doctor-patient relationship is forged in which health and lifestyle
      recommendations may be comfortably and effectively discussed. Relative to
      musculoskeletal care in elderly patients, chiropractic adjustments (spinal
      manipulative therapy) are recommended by the Agency for Health Care Policy and
      Research for the care of acute low back pain, and the American Geriatric Society
      Panel Guidelines for the Management of Chronic Pain state that non-pharmaceutical
      interventions such as chiropractic may be appropriate. Most geriatric health-care
      providers have a limited number of options to offer patients with these
      complaints. Various lower-force chiropractic techniques are available as safe
      alternatives to drugs and surgery for musculoskeletal complaints in the older
      patient. Due to the prevalence of these conditions in older patients, and the
      success of chiropractic in caring for these patients, interdisciplinary geriatric
      health care teams should include the doctor of chiropractic. Chiropractors, well
      trained in health assessment, diagnosis, radiographic studies, health promotion,
      and illness prevention, are well-positioned to provide many primary health-care
      services to aging patients. This is particularly important to a nation that is
      straining to provide adequate geriatric health care in rural areas and areas with
      a shortage of health-care professionals. Continued improvements in geriatric
      education, and an increase in research and publication on chiropractic care of
      the aging patient are essential. As stated by Montes and Johnston in the Journal
      of Health Education: Training, as well as continual upgrading of the competencies
      for health educators, must include ways of dealing with the great disparities in
      health among populations, especially those most vulnerable and underserved.
      Faculty too must be prepared in ... this ever-changing health care delivery
      system. In a rapidly aging society, chiropractors, (along with all health
      professions)must prepare themselves to provide optimal health care to this
      important segment of our society, through excellence in chiropractic education,
      training,and practice.

PMID- 15182880
TI  - Herbal therapies.
AB  - In summary, herbs are commonly used, and it is the physician's responsibility to
      have better documentation of this practice by encouraging patients to report use
      of herbs, and to look for any unusual side effects that can occur in terms of
      herb-drug or herb-herb interactions.

PMID- 15182881
TI  - Vitamins in health and aging.
AB  - The use of various dietary supplements, including vitamins, to prevent or delay
      disease or aging rests for the most part on epidemiological associations. It does
      appear from these data that a diet rich in vitamins is associated with a tendency
      to improved health; however, the results from controlled trials are dismal. The
      discrepancy between different types of studies is probably explained by the fact
      that dietary composition and supplement use is a component in a cluster of
      healthy behaviors. An alternative hypothesis is that there are as-yet-unknown
      essential organic compounds in certain foods. The most prudent approach is to
      recommend a daily intake of fruits and vegetables as a likely source of essential
      nutrients. Failing compliance with a natural source of essential nutrients, and
      in populations at high risk of vitamin deficiency, vitamin supplements should be
      encouraged.

PMID- 15182882
TI  - Hormonal fountains of youth.
AB  - Any hope of a fountain of youth to stop people from getting older is a long way
      off, with science just beginning to understand the complex genetic, physical, and
      hormonal causes of aging. Clearly, modem research has demonstrated that the
      concept of a hormonal fountain of youth is predominantly mythology. The best
      evidence supporting use of hormonal replacement is vitamin D and estrogen
      replacement to prevent hip fractures. Other than that, treatment should be
      limited to hormone replacement in persons who have endocrine disease.

PMID- 15182883
TI  - Cancer in the elderly: is it preventable?
AB  - It is the goal of the American Cancer Society to decrease the mortality from
      cancer by 50% and the incidence of cancer by 25% by the year 2015 in the United
      States. Achieving this goal requires intervention at the primary (incidence) and
      secondary (mortality) prevention stages, and will involve a concerted effort of
      the individual practitioner, governmental agencies, local, state, and national
      interest groups, and the population at large. Primary care practitioners must
      increase their level of enthusiasm for cancer prevention, and actively counsel
      patients about cancer risks and preventive measures. Practitioners should
      encourage inclined patients by providing support and specialty resources, such as
      dieticians, exercise therapists, and smoking and alcohol cessation programs. The
      greatest effort lies in the general population, who must adopt a healthier
      lifestyle, including appropriate diet, smoking cessation, control of obesity, and
      daily exercise. None of these lifestyle changes are easy to embrace, but once
      educated about lifestyle and risk of cancer, people have a powerful incentive to
      change. Continued public awareness campaigns and encouragement from health care
      providers are essential for the success of such programs. The success in smoking
      cessation shows that achieving societal lifestyle changes on a large scale is
      possible. The elderly are especially prone to benefit from primary and secondary
      prevention techniques, and it must not be assumed that only the young will
      realize the benefits of prevention and screening. The association of age and
      cancer risk will always be present, but need not be as consequential as it is
      now. Although cancer prevention may have a limited role in antiaging per se, the
      feasibility of cancer risk reduction has a definite role in aging successfully.

PMID- 15182884
TI  - Antiaging methods and medicines for the memory.
AB  - The interaction of bedside and basic science has led to the identification ofa
      short list of pathological proteins as causal in Alzheimer's disease. AI3P has
      received the most attention, and work with animal models has reinforced the
      evidence that overproduction of ABP causes cognitive impairments. Animal models
      are now being used to discover and develop unique therapeutics directed at
      reversing the deleterious effects of ABP. These models strongly suggest that
      established Alzheimer's disease might be reversible, not just preventable. Animal
      models are also demonstrating that other peptides and proteins can enhance or
      impair cognitive function. These peptides and proteins add further to the list of
      possible therapeutic candidates. Approaches such as these, and not the commercial
      antiaging remedies that have no scientific basis, will eventually provide
      medicine for memory enhancement.

PMID- 15182885
TI  - Free radicals and brain aging.
AB  - We reviewed here the formation of free radicals and its effect physiologically.
      Studies mentioned above have indicated that free radical/ROS/RNS involvement in
      brain aging is direct as well as correlative. Increasing evidence demonstrates
      that accumulation of oxidation of DNA, proteins, and lipids by free radicals are
      responsible for the functional decline in aged brains. Also, lipid peroxidation
      products, such as MDA, HNE, and acrolein, were reported to react with DNA and
      proteins to produce further damage in aged brains. Therefore, the impact of free
      radicals on brain aging is pronounced. It has been estimated that 10,000
      oxidative interactions occur between DNA and endogenously generated free radicals
      per human cell per day, and at least one of every three proteins in the cell of
      older animals is dysfunctional as an enzyme or structural protein, due to
      oxidative modification. Although these estimated numbers reveal that free radical
      mediated protein and DNA modification play significant roles in the deterioration
      of aging brain, they do not imply that free radical damages are the only cause of
      functional decline in aged brain. Nevertheless,although other factors may be
      involved in the cascade of damaging effects in the brain, the key role of free
      radicals in this process cannot be underestimated. This article has examined the
      role and formation of free radicals in brain aging. We propose that free radicals
      are critical to cell damage in aged brain and endogenous, and that exogenous
      antioxidants, therefore, may play effective roles in therapeutic strategies for
      age-related neurodegenerative disorders.

PMID- 15182886
TI  - Ethical and legal issues in antiaging medicine.
AB  - The development of specific antiaging treatments and the emergence of the
      practice of antiaging medicine have created new ethical and legal issues. The
      ultimate desirability of treatments designed to alter human aging is currently an
      actively debated issue that needs to emerge as an issue of public dialogue, given
      the potentially dramatic effect these therapies could have on both individual
      health and societal structure. Current therapies carry many doubts about their
      safety and effectiveness, which makes the practice of antiaging medicine with the
      prescription of these therapies a challenging issue from both a legal and ethical
      perspective. Finally, although the practice of antiaging medicine is not directly
      recognized and regulated by legislation, both anti-aging treatments and practice
      are regulated by emerging state and federal legislation that is evolving to
      address the emerging area of complementary and alternative medicine.

PMID- 15182887
TI  - Anti-aging.

PMID- 15182888
TI  - Problem severity profiles of substance abusing women in European Therapeutic
      Communities: influence of psychiatric problems.
AB  - This article aims to search for a specific female, psychiatric profile based on a
      large European sample of substance dependent clients (828) entering therapeutic
      communities. First, all six areas of functioning of the EuropASI were included,
      using the composite scores to search for gender differences. Next, the
      'psychiatric' status section was selected for further study. A binary logistic
      regression was performed with gender as the dependent variable, and nine
      individual psychiatric items, country, and age as predictors. According to this
      model a number of problem variables could be identified as being reported more
      often by women than by men in therapeutic community treatment. Women are more
      likely to report serious depression, problems in understanding, concentrating or
      remembering, being prescribed medication, and serious thoughts about suicide;
      they have also attempted suicide more often than men. Women find treatment for
      these psychological problems more important than their male counterparts. They
      also have a more severe history of abuse. Women in therapeutic communities may
      need specific treatment interventions for their more severe psychiatric needs.

PMID- 15182889
TI  - Validation of the Addiction Severity Index (ASI) for internet and automated
      telephone self-report administration.
AB  - This study assesses the convergent validity of Internet (Net) and interactive
      voice response (IVR) automated telephone self-report versions of the Addiction
      Severity Index (ASI) relative to the established, clinician-administered (CA)
      ASI. Eighty-eight subjects were recruited from an addiction treatment program to
      complete three ASI assessments. The mean correlation between composite scores
      obtained by Net and IVR and those obtained via clinician interview was.91
      (range.81-.95). For History items, the mean correlation was.77 (range.14-1.00)
      and the mean kappa coefficient was.75 (range.46-1.00). The results demonstrated
      the validity of these self-report Net and IVR versions of the ASI. Self-report
      Net and IVR were rated as "very satisfactory" or "extremely satisfactory" by a
      majority of respondents for ease of use. Automation can reduce the labor costs
      associated with ASI administration and may facilitate longitudinal tracking of
      subjects from home.

PMID- 15182890
TI  - Residential treatment for smokeless tobacco use: a case series.
AB  - We developed and implemented a novel 8-day residential treatment program for
      smokeless tobacco (ST) use. A multidisciplinary team delivered behavioral
      treatment, nicotine patches were adjusted to achieve 100% replacement of baseline
      peak serum nicotine concentrations, and bupropion sustained-release was
      prescribed. Mean participant age (+/- SD) was 47.4 +/- 18.2 years. Mean nicotine
      patch dose at program end was 43.2 mg/day +/- 13.9 (range 14 to 66 mg/d). Median
      percent replacement by serum nicotine concentrations was 86.6% (IQR: 75-113.8%).
      At 1 year, the biochemically-confirmed (urine anabasine <2.0 ng/mL) self-reported
      7-day point prevalence tobacco abstinence rate was 58% (14/24). A residential
      treatment program for ST users may be effective. More research is needed to
      replicate our findings and determine if comparable abstinence rates can be
      achieved with outpatient ST treatment programs using similar behavioral and
      pharmacotherapies.

PMID- 15182891
TI  - Enabling behavior in a clinical sample of alcohol-dependent clients and their
      partners.
AB  - Substance use disorders affect not only the identified client but significant
      others as well. Clinical work and some research suggest that partner responses to
      drinking may either facilitate or hinder treatment acceptance and recovery
      efforts. Female partners of male alcoholics have received much of this attention,
      and have been labeled as codependents or enablers. We administered a clinically
      derived assessment tool, the Behavioral Enabling Scale, to 42 alcoholic clients
      and their partners enrolled in a couples counseling program to determine the
      extent of specific partner behaviors that might reasonably be thought to
      reinforce drinking or hinder recovery. Results indicated that, among other
      findings, the majority of both clients and partners reported the partner took
      over chores or duties from the alcoholic client at some point during the
      relationship, drank or used other drugs with the client, and lied or made excuses
      to others to cover for the drinker. Moreover, particular relationship beliefs
      were associated with higher behavioral enabling scores, providing clear direction
      for cognitive and behavioral interventions. It is argued that efforts to
      understand and treat alcohol dependence will be more productive if partner
      behaviors are incorporated into assessment and intervention procedures.

PMID- 15182892
TI  - Heterogeneity among Latinas and Latinos entering substance abuse treatment:
      findings from a national database.
AB  - The current study examined differences in 30-day and lifetime substance use for a
      sample of Mexican American, Puerto Rican, and Cuban American men and women from
      the Drug Evaluation Network System, a national database on individuals seeking
      substance abuse treatment. There were significant gender and ethnic differences
      in recent and lifetime substance use after controlling for age, years of
      education, employment, medical, and psychological problems. Lifetime and 30-day
      substance use rates found in this study do not coincide with prevalence rates
      found in community samples of Latinas/os, indicating that the patterns of
      substance use may be different among individuals who seek substance abuse
      treatment than among those in the general population. The results of this study
      highlight the heterogeneity of Latinas/os who abuse substances.

PMID- 15182893
TI  - Naltrexone for heroin dependence treatment in St. Petersburg, Russia.
AB  - Naltrexone may be more effective for treating opioid (heroin) dependence in
      Russia than in the U.S. because patients are mostly young and living with their
      parents, who can control medication compliance. In this pilot study we randomized
      52 consenting patients who completed detoxification in St. Petersburg to a double
      blind, 6-month course of biweekly drug counseling and naltrexone, or counseling
      and placebo naltrexone. Significant differences in retention and relapse favoring
      naltrexone were seen beginning at 1 month and continuing throughout the study. At
      the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in
      treatment and had not relapsed as compared to 4 of 25 placebo patients (16%;
      p<0.05). Since heroin dependence is the main way HIV is being spread in Russia,
      naltrexone is likely to improve treatment outcome and help reduce the spread of
      HIV if it can be made more widely available.

PMID- 15182894
TI  - Does pregnancy affect outcome of methadone maintenance treatment?
AB  - Studies of pregnant women receiving methadone maintenance have tended to focus on
      teratogenic, prenatal, and neonatal issues. We are not aware of any controlled
      studies comparing pregnant to non-pregnant heroin-addicted women in methadone
      treatment. This article presents findings from a study examining treatment
      outcome between pregnant and non-pregnant participants in a metropolitan
      methadone-maintenance program. Participants were 51 pregnant women and 51 non
      pregnant women enrolled in a methadone maintenance program between 1994 and 2003.
      Groups were compared on demographic characteristics, psychiatric comorbidity,
      urinalysis results and retention rates. Groups were comparable in terms of most
      demographic characteristics and severity of addiction at intake. Groups did not
      differ significantly in terms of urinalysis results or retention rates. While
      most women reduced their drug use, a majority of both groups continued to use
      illicit drugs at least occasionally. Psychiatric comorbidity was significantly
      different with the non-pregnant group being more psychiatrically disordered.
      Clinical implications are discussed.

PMID- 15182895
TI  - A survey of clinical practices and readiness to adopt evidence-based practices:
      Dissemination research in an addiction treatment system.
AB  - Addiction research is challenged to disseminate evidence-based practices into
      routine clinical settings. The successful adoption of innovation must consider
      issues of fit, such as the characteristics, readiness, and attitudes of
      clinicians in the community. We constructed a survey to assess clinical practices
      and readiness to adopt certain evidence-based practices in addiction treatment
      programs. The instrument was administered to directors (n = 21) and clinicians (n
      = 89) from 24 public addiction treatment programs in New Hampshire (USA).
      Clinicians are more motivated to adopt some evidence-based practices (twelve-step
      facilitation, cognitive behavioral therapy, motivational interviewing, relapse
      prevention therapy) than others (contingency management, behavioral couples
      therapy, pharmacotherapies). Translational strategies for treatment development
      and research dissemination are discussed.

PMID- 15182896
TI  - Network therapy: decreased secondary opioid use during buprenorphine maintenance.
AB  - Network therapy (NT) employs family members and/or friends to support compliance
      with an addiction treatment carried out in office practice. This study was
      designed to ascertain whether NT is a useful psychosocial adjunct, relative to a
      control treatment, for achieving diminished illicit heroin use for patients on
      buprenorphine maintenance. Patients agreeing to randomization to either NT (N =
      33) or medication management (MM, N = 33) were inducted onto short-term
      buprenorphine maintenance and then tapered to zero dose. NT resulted in
      significantly more urine toxicologies negative for opioids than MM (65% vs. 45%)
      and more NT than MM patients (50% vs. 23%) experienced a positive outcome
      relative to secondary heroin use by the end of treatment. The use of NT in office
      practice may therefore improve the effectiveness of eliminating secondary heroin
      use during buprenorphine maintenance. It may also be useful in enhancing
      compliance with an addiction treatment regimen in other contexts.

PMID- 15182897
TI  - Screening of selected indigenous plants of Lebanon for antimicrobial activity.
AB  - The objective of this study is to test in vitro the antimicrobial efficacy of 39
      water and 39 methanol extracts derived from different parts of 27 indigenous wild
      plant species that have been commonly used in Lebanese folk medicine. The
      antimicrobial efficacy was determined using the single disk diffusion method,
      with 10 and 20 microl load extract volume per disc. Nine test microorganisms were
      used namely, Escherichia coli, Proteus sp., Pseudomonas aeruginosa, Shigella
      dysenteria, Salmonella enteritidis, Salmonella typhi, Staphylococcus aureus,
      Streptococcus faecalis, and Candida albicans. Only one water extract out of 39
      derived from whole plant of Alchemilla diademata showed an antimicrobial activity
      against Staphylococcus aureus. The percentage of test organisms that were
      susceptible to 10 most efficacious methanol plant extracts (20 microl/disc) were
      as follows: Achillea damascena whole plant (88.8%), Anthemis scariosa flower
      (88.8%), Cirsium sp. whole plant (88.8%), Centaurea ainetensis flowers (88.8%),
      Hieracium sp. whole plant (88.8%), Origanum libanoticum whole plant (99.9%),
      Ranunculus myosuroudes whole plant (88.8%), Nepata curviflora leaf (88.8%),
      Nepata curviflora stem, and Verbascum leptostychum flower (99.9%). The minimum
      inhibitory concentration (MIC) was determined on plant extracts that showed high
      efficacy against the test organisms. The chance to find antimicrobial activities
      was more apparent in methanol rather than water extracts of the same indigenous
      plants of Lebanon, with higher antimicrobial activities in 20 microl methanol
      extract-discs in comparison to that present in the 10 microl discs (P < 0.05).

PMID- 15182898
TI  - In vitro culture studies of Sutherlandia frutescens on human tumor cell lines.
AB  - Sutherlandia frutescens is a South African herb used traditionally by the natives
      to treat cancer, and more recently to improve the overall health in HIV/AIDS
      patients. Gas chromatography/mass spectrometer profiling and liquid
      chromatographic/mass spectral investigation confirmed and quantified the presence
      of canavanine, GABA and arginine in the herbal preparation used in this study. In
      vitro study demonstrated a concentration dependent effect of Sutherlandia on
      several tumor cell lines, with 50% inhibition (IC50) of proliferation of MCF7,
      MDA-MB-468, Jurkat and HL60 cells at 1/250, 1/200, 1/150 and 1/200 dilutions,
      respectively. Sutherlandia treatment did not induce HL60 differentiation along
      the macrophage/monocyte or granulocyte lineage. It demonstrated antioxidant
      activity in reducing free radical cations with an estimated activity of 0.5
      microl of Sutherlandia extract equivalent to that of 10 microM of Trolox.
      However, it did not significantly suppress lipopolysaccharide stimulated nitric
      oxide production by murine macrophage/monocyte RAW 264.7 cells, nor did it
      significantly inhibit IL-1beta and TNF-alpha mRNA expression in RAW 264.7 cells.
      In conclusion, Sutherlandia ethanolic extract showed a concentration dependent
      antiproliferative effect on several human tumor cell lines but did not show
      significant antioxidant effects. Further studies are needed to explore the
      activities of this multipurpose South African herbal preparation.

PMID- 15182899
TI  - Comparison of two Chinese medical herbs, Huangbai and Qianniuzi, on influence of
      short circuit current across the rat intestinal epithelia.
AB  - Huangbai (Phellodendron spec.) and Qianniuzi (Pharbitis spec.) are two
      traditional Chinese medical herbs used for anti-diarrheal and laxative agents,
      respectively. Ethanol and water extracts of these two herbs were prepared and
      effects of the extracts on ion transport of the rat intestinal epithelia were
      studied. For measuring changes of the short circuit current across the epithelia,
      the rat intestinal epithelia were mounted in the Ussing chamber and attached with
      voltage/current clamp. The intestinal epithelia were firstly activated by serosal
      administration of 5 microM forskolin. As current raised and being stable,
      extracts of these herbs were added, respectively, and changes in the short
      circuit current were recorded. Ethanol extract of Huangbai attenuated the current
      increment; on the contrary, ethanol extract of Qianniuzi augmented the current
      increment additionally. Water extracts of the two herbs showed minor effects on
      the current in comparison to ethanol extracts. The results provide evidences to
      reveal the pharmacological mechanism of the two Chinese medical herbs on the
      intestinal tissue.

PMID- 15182900
TI  - In vitro antiplasmodial activity of extracts and fractions from seven medicinal
      plants used in the Democratic Republic of Congo.
AB  - The in vitro antiplasmodial activity of seven EtOH extracts and twenty fractions
      from the partition of the initial ethanolic extracts from seven African medicinal
      plants used in the Democratic Republic of Congo (DR Congo) for the treatment of
      malaria was evaluated. The most active EtOH extracts (IC50 < 3 microg/ml) were
      those from Cassia occidentalis leaves, Euphorbia hirta whole plant, Garcinia kola
      stem bark and Phyllanthus niruri whole plant. Their respective petroleum ether
      soluble fractions also exhibited an antiplasmodial activity with IC50 < 3
      microg/ml. EtOH extracts from Vernonia amygdalina leaves (5 < IC50 < 10
      microg/ml), Tetracera poggei leaves (10 < IC50 < 50 microg/ml) and Morinda
      morindoides leaves (50 < IC50 < 100 microg/ml) were less active, but their
      petroleum ether fractions exhibited a pronounced antiplasmodial activity (IC50 <
      3 microg/ml). The same observation could also be made for the petroleum ether
      fraction from Cassia occidentalis, Euphorbia hirta, Garcinia kola and Phyllanthus
      niruri. Isoamyl alcohol fractions from Euphorbia hirta, Phyllanthus niruri and
      Vernonia amygdalina showed IC50) values less than 3 microg/ml, and from Cassia
      occidentalis, Garcinia kola, Morinda morindoides and Tetracera poggei between 10
      and 50 microg/ml. The observed antiplasmodial activity may be related to the
      presence of terpenes, steroids, coumarins, flavonoids, phenolic acids, lignans,
      xanthones and anthraquinones.

PMID- 15182901
TI  - The effect of Aloe vera A. Berger (Liliaceae) on gastric acid secretion and acute
      gastric mucosal injury in rats.
AB  - The effect of varying doses of ethanol extract of Aloe vera (Liliaceae) on acute
      gastric mucosal lesions induced by 0.6 M HCl and acid output was studied in the
      pylorus ligated and lumen perfuse rats, respectively. Acid secretion was
      determined by titration of the collected gastric juice to pH 7.0. Intraperitoneal
      injection of Aloe vera, dose dependently inhibited gastric acid secretion. The
      plant was more active as a gastroprotective agent at lower concentration against
      mucosal injury induced by 0.6 M HCl. In conclusion, Aloe vera is endowed with
      gastric acid anti-secretory activity and could protect the gastric mucosa at low
      concentrations against injurious agents.

PMID- 15182902
TI  - New evidences of antimalarial activity of Bidens pilosa roots extract correlated
      with polyacetylene and flavonoids.
AB  - Bidens pilosa is among the several plants used in Brazil to treat malaria. It was
      demonstrated that crude extracts from roots prepared with 80% ethanol by
      percolation are active in vitro against Plasmodium falciparum and the activity is
      correlated with the presence of polyacetylene and flavonoids. This extract was
      submitted to column chromatography with ether and ether methanol (1:1) and two
      fractions, enriched in polyacetylene and flavonoids, respectively, were obtained.
      The extract and the fractions were assessed by HPLC/DAD analysis and antimalarial
      tests in vivo. Ethanol extract showed by HPLC the presence of several peaks for
      polyacetylene and flavonoids, compounds corresponding to quercetin-3,3'-dimethoxy
      7-0-rhamnoglucopyranose and the acetylene 1-phenyl-1,3-diyn-5-en-7-ol-acetate,
      previously identified in this extract. The peaks for flavonoids were absent in
      ether fraction and those ones for polyacetylene in ether:methanol. In in vivo
      tests, ethanol extract caused 36% of reduction of parasitaemia at fifth day, and
      29% at seventh day. Ether:methanol fraction caused 38% of reduction at fifth day
      but was inactive at day 7. The survival of the animals treated with 80% ethanol
      extract was higher than in the fractions. The results showed that the in vivo
      activity of ethanol extract depends on the presence of polyacetylene and
      flavonoids.

PMID- 15182903
TI  - Traditional medicine in north Cote-d'Ivoire: screening of 50 medicinal plants for
      antibacterial activity.
AB  - Sixty-seven crude ethanol extracts from 50 plants (31 families), which are used
      in North Cote-d'Ivoire as traditional remedies for bacterial diseases, were
      screened for in vitro activity against Gram negative (Escherichia coli and
      Pseudomonas aeruginosa) and Gram positive (Staphylococcus aureus, Enterococcus
      faecalis, Streptococcus pyogenes and Bacillus subtilis) bacteria. Thirty-one
      extracts showed antibacterial activity only on Gram positive bacteria. Of these,
      10 extracts from 10 plant species had a promising level of activity against
      bacteria including strains resistant to antibiotics such as aminosides,
      penicillin M, macrolides, lincosamide and streptrogramin B. The most active was
      Erythrina senegalensis DC (Fabaceae) followed by Bobgunnia madagascariensis
      (Desv.) J.H. Kirkbr. & Wiersema (Caesalpinaceae), Waltheria lanceolata R. Br. ex
      Mast. (Sterculiaceae), Uapaca togoensis Pax. (Euphorbiaceae), Ximenia americana
      L. (Olacaceae), Khaya senegalensis (Ders.) A. Juss. (Meliaceae), Lannea acida A.
      Rich. (Anacardiaceae), Cissus populnea Guill. & Perr. (Vitaceae), Keetia hispida
      (Benth.) Bridson (Rubiaceae) and Ficus thonningii (Miq.) A. Rich. (Moraceae).
      This is the first report of the antibacterial potency of these 10 plant species
      on a range of bacteria. The results provided evidence that some of the studied
      plants might indeed be potential sources of new antibacterial agents, also
      against some antibiotic-resistant strains.

PMID- 15182904
TI  - Protective effect of Copaifera langsdorffii oleo-resin against acetic acid
      induced colitis in rats.
AB  - The oleo-resin from Copaifera langsdorffii (Leguminosae) was evaluated in rats on
      acetic acid-induced colitis. Rats were pretreated orally (15 and 2 h) or rectally
      (2 h) before the induction of colitis with copaiba oleo-resin (200 and 400 mg/kg)
      or vehicle (1 ml, 2% Tween 80). Colitis was induced by intracolonic instillation
      of a 2 ml of 4% (v/v) acetic acid solution and 24 h later, the colonic mucosal
      damage was analyzed for the severity of macroscopic colonic damage,
      myeloperoxidase (MPO) activity, and malondialdehyde levels. A significant
      reduction in gross damage score and in wet weight/length ratio of colonic tissue
      were evident in test substance-pretreated animals as compared to vehicle or oleo
      resin alone-treated controls. This effect was confirmed biochemically by a
      reduction in colonic myeloperoxidase activity, the marker of neutrophilic
      infiltration, and by a marked decrease in malondialdehyde level, an indicator of
      lipoperoxidation. Furthermore, microscopical examination revealed the diminution
      of inflammatory cell infiltration, and submucosal edema in the colon segments of
      rats treated with copaiba oleo-resin. The data indicate the protective effect of
      copaiba oleo-resin in the animal model of acute colitis possibly through an
      antioxidant and or anti-lipoperoxidative mechanism.

PMID- 15182905
TI  - Bronchodilatory effect of Portulaca oleracea in airways of asthmatic patients.
AB  - Therapeutic effects of Portulaca oleracea for respiratory diseases are indicated
      in ancient Iranian medical books. The relaxant effect of this plant have also
      been observed on smooth muscle tissue in previous studies. Therefore, in the
      present study, the bronchodilatory effect of the boiled extract of Portulaca
      oleracea in the airway of asthmatic patients was examined. The relaxant effect of
      the orally administered 0.25 ml/kg of 5% boiled extract in comparison with 3
      mg/kg oral theophylline and 200 microg inhaled salbutamol was studied by
      measuring forced expiratory volume in one second (FEV1), peak expiratory flow
      (PEF), maximal mid-expiratory flow (MEF(25-75)), and specific airway conductance
      (sGaw). The FEV1, PEF, MEF(25-75), and sGaw were measured before, administration
      and repeated 15, 30, 60, 90, and 120 min after administration of the oral extract
      and theopylline. For inhaled salbutamol measurements were performed 5, 15, 30,
      and 60 min post-inhalation. Results showed that the boiled extract of Portulaca
      oleracea caused significant increases in all measured pulmonary function tests
      (PFTs), (P < 0.05 to P < 0.01). There was no significant difference between the
      maximum increase in measured PFTs due to the boiled extract and theophylline.
      However, maximum increase in PEF and MEF(25-75) due to the boiled extract were
      significantly lower than those of salbutamol (P < 0.05 for both cases). The onset
      of brochodilatory effect of extract was similar to that of theophylline beginning
      60 min, but the effect of extract decline after 120 min after administration. In
      conclusion, the results of the present study showed that Portulaca oleracea has a
      relatively potent but transient bronchodilatory effect on asthmatic airways.

PMID- 15182906
TI  - A polysaccharide fraction from medicinal herb Prunella vulgaris downregulates the
      expression of herpes simplex virus antigen in Vero cells.
AB  - Herpes simplex viruses (HSV) are pathogenic. With the emergence of drug-resistant
      strains of HSV, new antiviral agents, especially those with different modes of
      action, are urgently needed. Prunella vulgaris L. (Labiatae), a perennial plant
      commonly found in China and Europe, has long been used as a folk medicine to cure
      ailments. In this study, a polysaccharide fraction was prepared from Prunella
      vulgaris (PPV), and its effects on the expressions of HSV-1 and HSV-2 antigens in
      their host Vero cells were investigated with flow cytometry. The HSV antigen
      increased time-dependently in the infected cells, and PPV reduced its expression.
      The effective concentrations of PPV with 50% reductions of the HSV-1 and HSV-2
      antigens were 20.6 and 20.1 microg/ml, respectively. The novelty of PPV is that
      it also reduces the antigen expression of acyclovir-resistant strain of HSV-1.
      After incubations with 25-100 microg/ml of PPV the HSV antigen-positive cells
      were reduced by 24.8-92.6%, respectively, showing that this polysaccharide
      fraction has a different mode of anti-HSV action from acyclovir. Results from
      this study show that PPV is effective against both the HSV-1 and HSV-2
      infections, and flow cytometry offers a quantitative and highly reproducible anti
      HSV drug-susceptibility assay.

PMID- 15182907
TI  - Vasorelaxant effect of the aqueous extract of Ajuga iva in rat aorta.
AB  - The aim of the present study was to investigate the ex vivo and in vitro vascular
      activity of the aqueous extract of Ajuga iva (L.) Schreber (Labiatae) in
      normotensive Wistar rats. Chronic oral administration of the extract of Ajuga iva
      did not significantly affect the systolic blood pressure. In aorta isolated from
      Ajuga iva-treated rats, the contractile response to noradrenaline was depressed
      compared to the responses obtained in aorta from untreated rats but the
      endothelium-dependent relaxation evoked by acetylcholine was not affected. In
      vitro, Ajuga iva extract inhibited the contraction evoked by noradrenaline. The
      addition of Ajuga iva extract during the plateau phase of noradrenaline-evoked
      contraction produced a relaxation that was sensitive to N-nitro-L-arginine. After
      pre-incubation of the artery in the presence of the plant extract, vasorelaxant
      effect was markedly less pronounced. The endothelium-dependent relaxation induced
      by acetylcholine was concentration-dependently blunted in the presence of Ajuga
      iva extract in the bathing solution. This study indicates that the aqueous
      extract of Ajuga iva possesses NO-mediated and NO-independent vasorelaxing
      properties in vitro while only the endothelium-independent effect was observed ex
      vivo.

PMID- 15182908
TI  - Effect of medicinal plant extracts on forced swimming capacity in mice.
AB  - The tonic effect of Cordyceps militaris (CM), Paecilomyces japonia (PJ),
      Phellinus linteus (PL), Ganoderma lucidum (GL), Grifola frondosa (GF), and Panax
      ginseng (PG) was examined based on the forced swimming capacity and the change of
      biochemical parameters in ICR mice. The treatment groups were orally administered
      medicinal plant extracts (500 mg/kg per day), while the control group received
      distilled water for 4 weeks. The swimming times to exhaustion were longer in the
      CM, PJ, and GF groups than in the control group (P < 0.05). Plasma TG levels were
      lower in the treatment groups than in the control group. Plasma glucose levels
      were not significantly different between the control group and each treatment
      group except the PG group. Plasma lactate and ammonia levels of the PJ and GF
      groups were lower than those of the control group (P < 0.05). There were no
      significant differences in the content of liver and gastrocnemius muscle glycogen
      between the control group and each treatment group. In conclusion, PJ and GF
      extracts enhanced the forced swimming capacity of mice by increasing fat
      utilization and by delaying the accumulation of plasma lactate and ammonia.

PMID- 15182909
TI  - Antiulcerogenic activity of ethanol extract of Solanum variabile (false
      "jurubeba").
AB  - The ethanol extract (EE) of the aerial parts of Solanum variabile Mart.
      (Solanaceae) was investigated for its ability to prevent ulceration of the
      gastric and duodenal mucosa at different doses. Its ability to heal chronic ulcer
      processes was also evaluated. When the HCl/ethanol solution was used to induce
      gastric ulcer, the EE produced a significant dose-dependent reduction of lesion
      formation of 51, 74 and 89%, at doses of 250, 500 and 1000 mg/kg, respectively.
      The 100 mg/kg dose had no significant activity. The EE also significantly reduced
      the gastric lesions induced by the combination of indomethacin and bethanechol
      (60 and 72%) at doses of 500 and 1000 mg/kg and also reduced stress-induced
      gastric ulcer (41%) but only at the doses of 1000 mg/g (P < 0.05). The pylorus
      ligature experiment demonstrated that the highest EE dose affected significantly
      the gastric juice parameters by increasing pH values from 4.08 (negative control)
      to 5.42 and decreasing acid output from 7.16 (negative control) to 4.26 mEq.mL,
      4h. A decrease of gastric contents from 370 mg (negative control) to 240 mg was
      also observed. The results obtained in the chronic gastric ulcer model indicated
      that a single oral dose of Solanum variabile (1000 mg/kg) administered for 14
      consecutive days accelerated the ulcer healing by 46% compared to a 55% effect of
      cimetidine. Also, at the dose of 1000 mg/kg, the EE inhibited the onset of
      duodenal lesions by 64%. The data suggest that the EE of Solanum variabile has a
      significant preventive, curative and duodenal anti-ulcer effect.

PMID- 15182910
TI  - In vitro antibradykinin activity of Aloe barbadensis gel.
AB  - When bradykinin-induced contraction of the isolated rat ileum was tested in the
      presence of Aloe barbadensis Mill. (Liliaceae) gel (fraction F-1) and with the
      fraction obtained by precipitation of the F-1 with 55% ammonium sulfate (F-55),
      the maximal responses to bradykinin were reduced by 10 and 22%, respectively.
      Furthermore, purification of the F-55 by filtration through a column of Sephacryl
      (S-500-HR) yielded the F-SH fraction, which inhibited the bradykinin effect by
      60%. Purification of the F-SH fraction, by filtration through a column of
      Sephadex G-100, brought about four new fractions: F-GA, F-GB, F-GC, and F-GD. F
      GB was the only one that showed the bradykinin inhibition effect (67%). Clearly,
      Aloe barbadensis gel contains a material that inhibits the bradykinin effect,
      which might explain the anti-inflammatory properties of Aloe barbadensis.

PMID- 15182911
TI  - Anxiolytic-like actions of leaves of Casimiroa edulis (Rutaceae) in male Wistar
      rats.
AB  - Anxiolytic-like actions of an aqueous extract of the leaves of Casimiroa edulis
      (Ce) La Llave ex Lex. (Rutaceae) were studied in male Wistar rats in the elevated
      plus-maze test, whether effect on locomotion were studied in the open-field task,
      and its possible antidepressant-like actions in the forced swimming task. In the
      elevated plus-maze test, diazepam (Dz) (1.30 mg/kg; P < 0.05) and Casimiroa
      edulis (25.0 mg/kg, P < 0.05; 35.0 mg/kg, P < 0.05) increased open arms
      exploration (i.e., anxiolytic-like action). Doses of 45.0 mg/kg (P < 0.05) and
      55.0 mg/kg (P < 0.05) of Casimiroa edulis reduced locomotion in the elevated plus
      maze test and in the open-field test. In the forced swimming task, desipramine
      (dmi) (32.0 mg/kg; P < 0.05) reduced immobility (i.e., antidepressant-like
      action). Conversely, as compared to control rats, neither diazepam (Dz) (1.30
      mg/kg) nor Casimiroa edulis (25.0 mg/kg) modified immobility in the forced
      swimming task. However, diazepam (P < 0.05) or Casimiroa edulis (P < 0.05), when
      co-administered, canceled the antiimmobility actions of desipramine. In
      conclusion, the leaves of Casimiroa edulis (Rutaceae) produced anxiolytic-like
      actions in male Wistar rats, with several side actions, namely, reduced
      locomotion and neutralization of the antidepressant-like actions of desipramine.

PMID- 15182912
TI  - Cannabis improves night vision: a case study of dark adaptometry and scotopic
      sensitivity in kif smokers of the Rif mountains of northern Morocco.
AB  - Previous reports have documented an improvement in night vision among Jamaican
      fishermen after ingestion of a crude tincture of herbal cannabis, while two
      members of this group noted that Moroccan fishermen and mountain dwellers observe
      an analogous improvement after smoking kif, sifted Cannabis sativa mixed with
      tobacco (Nicotiana rustica). Field-testing of night vision has become possible
      with a portable device, the LKC Technologies Scotopic Sensitivity Tester-1 (SST
      1). This study examines the results of double-blinded graduated THC
      administration 0-20 mg (as Marinol) versus placebo in one subject on measures of
      dark adaptometry and scotopic sensitivity. Analogous field studies were performed
      in Morocco with the SST-1 in three subjects before and after smoking kif. In both
      test situations, improvements in night vision measures were noted after THC or
      cannabis. It is believed that this effect is dose-dependent and cannabinoid
      mediated at the retinal level. Further testing may assess possible clinical
      application of these results in retinitis pigmentosa or other conditions.

PMID- 15182913
TI  - Cardioprotective activity of Hydrocotyle asiatica L. in ischemia-reperfusion
      induced myocardial infarction in rats.
AB  - The alcoholic extract of Hydrocotyle asiatica Linn. (Hydrocotyle asiatica L.)
      whole plant was evaluated for cardioprotective activity against ischemia
      reperfusion induced myocardial infarction in rats. Cardioprotective activity was
      studied by measuring infarct size and estimating lipid peroxide levels in serum
      and heart tissue. A lead II electrocardiogram was monitored at various intervals
      throughout the experiment. A dose (100-1000 mg kg(-1)) dependent reduction in
      percent left ventricle necrosis (PLVN) as well as in lipid peroxide levels was
      observed in rats treated with alcoholic extract of Hydrocotyle asiatica L. orally
      for 7 days compared to control animals. The study strongly suggests the
      cardioprotective activity of Hydrocotyle asiatica L. in limiting ischemia
      reperfusion induced myocardial injury.

PMID- 15182914
TI  - Analysis of strychnine from detoxified Strychnos nux-vomica [corrected] seeds
      using liquid chromatography-electrospray mass spectrometry.
AB  - The content of strychnine from Strychnos nux-vomica [corrected] seeds was
      analyzed and compared to processed seeds by the HPLC-ESI/MS method. Using this
      technique, levels as low as 1 ng of strychnine were detected. In contrast to
      conventional UV detectors, this method also made it possible to discriminate
      brucine. This study resulted in finding the content of strychnine in detoxified
      seeds to be one tenth of unprocessed Strychnos nux-vomica [corrected] seeds.

PMID- 15182915
TI  - Brassica juncea (Rai) significantly prevented the development of insulin
      resistance in rats fed fructose-enriched diet.
AB  - Brassica juncea (BJ; Hindi name: Rai) seeds and Murraya koenigii (MK; English
      names: Curry leaves) leaves, used as food ingredients and also by diabetics in
      India, were assessed in a fructose-mediated non-genetic model of insulin
      resistance. Feeding of fructose rich diet for 30 days resulted in rise in blood
      glucose by 29.4%, insulin by 101.2% and cholesterol by 26.7% indicating
      development of insulin resistance. However, feeding of a fructose diet containing
      10% Brassica juncea seeds powder for 30 days significantly decreased fasting
      serum glucose, insulin and cholesterol levels but did not normalize them. On the
      other hand, a diet containing 15% Murraya koenigii leaves powder failed to exert
      any effect on these parameters. Results of the present study suggests that BJ can
      play a role in management of pre-diabetic state of insulin resistance and should
      be promoted for use in patients prone to diabetes.

PMID- 15182916
TI  - Studies on the in vitro and in vivo hypoglycemic activities of some medicinal
      plants used in treatment of diabetes in Jordanian traditional medicine.
AB  - Ferula persica, Paronychia argentea, and Pistacia atlantica are three of the
      plants widely recommended by the herbalists and used for their hypoglycemic
      activity in Jordan. Aqueous extracts of these plants were tested in vitro for
      their alpha amylase inhibitory activity and in vivo for their hypoglycemic
      activity in normoglycemic and streptozocin-induced hyperglycemic rats. Although
      the three plants were advocated for their hypoglycemic effects in Jordanian
      traditional herbal medicine; none of them showed significant hypoglycemic
      activity compared to the untreated animals. Paronychia argentea and Pistacia
      atlantica showed significant alpha amylase inhibitory activity while Ferula
      persica did not demonstrate any alpha amylase inhibitory activity. The main
      conclusion of this work was the concern over the unjustified claims of the uses
      of some herbal medicine in Jordan and possibly in other countries.

PMID- 15182917
TI  - Pharmacological actions and potential uses of Momordica charantia: a review.
AB  - Since ancient times, plants and herbal preparations have been used as medicine.
      Research carried out in last few decades has certified several such claims of use
      of several plants of traditional medicine. Popularity of Momordica charantia (MC)
      in various systems of traditional medicine for several ailments (antidiabetic,
      abortifacient, anthelmintic, contraceptive, dysmenorrhea, eczema, emmenagogue,
      antimalarial, galactagogue, gout, jaundice, abdominal pain, kidney (stone),
      laxative, leprosy, leucorrhea, piles, pneumonia, psoriasis, purgative,
      rheumatism, fever and scabies) focused the investigator's attention on this
      plant. Over 100 studies using modern techniques have authenticated its use in
      diabetes and its complications (nephropathy, cataract, insulin resistance), as
      antibacterial as well as antiviral agent (including HIV infection), as
      anthelmintic and abortifacient. Traditionally it has also been used in treating
      peptic ulcers, interestingly in a recent experimental studies have exhibited its
      potential against Helicobacter pylori. Most importantly, the studies have shown
      its efficacy in various cancers (lymphoid leukemia, lymphoma, choriocarcinoma,
      melanoma, breast cancer, skin tumor, prostatic cancer, squamous carcinoma of
      tongue and larynx, human bladder carcinomas and Hodgkin's disease). There are few
      reports available on clinical use of MC in diabetes and cancer patients that have
      shown promising results.

PMID- 15182918
TI  - Effects of Biota orientalis extract and its flavonoid constituents, quercetin and
      rutin on serum uric acid levels in oxonate-induced mice and xanthine
      dehydrogenase and xanthine oxidase activities in mouse liver.
AB  - The hypouricemic actions of Biota orientalis (BO) extract and its flavonoid
      constituents quercetin and rutin, were in vivo examined using oxonate-induced
      hyperuricemic mice. Quercetin and rutin, when administered three times orally to
      the oxonate-induced hyperuricemic mice, were able to elicit dose-dependent
      hypouricemic effects. The effects of quercetin and rutin were more potent than
      that of Biota orientalis extract at the same dose of 100 mg/kg. At doses of 50
      mg/kg of quercetin or above, or at doses of 100 mg/kg of rutin or above, the
      serum urate levels of the oxonate-pretreated mice were not different from normal
      mice. In addition, Biota orientalis extract, quercetin and rutin, when tested in
      vivo on mouse liver homogenates, elicited significant inhibitory actions on the
      xanthine dehydrogenase/xanthine oxidase (XDH/XO) activities. The effects of
      quercetin and rutin resulted less potent than that of allopurinol. However,
      intraperitoneal administration at the same scheme did not produce any observable
      hypouricemic effect. These hypouricemic effects are partly due to the inhibition
      of XDH/XO activities in mouse liver. The pharmacological profile of the
      flavonoids is partly different from that of allopurinol. Such hypouricemic action
      and inhibition of the enzyme activity of quercetin and rutin may be responsible
      for a part of the beneficial effects of Biota orientalis extract on hyperuricemia
      and gout. The effects of quercetin and rutin on serum urate levels in
      hyperuricemic mice induced by oxonate and the inhibition of enzyme activities in
      mouse liver are discussed in relation to their absorption and metabolism, and
      their potential application to treat gout and hyperuricemia.

PMID- 15182919
TI  - Anti-inflammatory and related pharmacological activities of the n-BuOH
      subfraction of mushroom Phellinus linteus.
AB  - This study aimed to elucidate the anti-inflammatory and related activities of
      mushroom Phellinus linteus. The results show that the EtOH extract of Phellinus
      linteus (PLE) dose-dependently inhibited the mouse ear edema induced by croton
      oil. Among PLE subfractions, the n-BuOH subfraction showed highest anti
      inflammatory activity in croton oil-induced ear edema test. The n-BuOH
      subfraction also showed highest inhibitory activity on the chick embryo
      chorioallantoic membrane (CAM) angiogenesis in a dose-dependent manner. PLE could
      significantly reduce the number of writhing induced by acetic acid in mice,
      indicating that PLE possesses potent antinociceptive effect mediated by its anti
      inflammatory activity. Mycelial extract of six different Phellinus strains were
      found to contain anti-angiogenic activity in the CAM assay. These results suggest
      that Phellinus linteus has anti-inflammatory and antinociceptive activities, in
      addition to its anti-angiogenic activity.

PMID- 15182920
TI  - Effect of short-term prefeeding and body weight on wheel running and responding
      reinforced by the opportunity to run in a wheel.
AB  - A biobehavioural analysis of activity anorexia suggests that the motivation for
      physical activity is regulated by food supply and body weight. In the present
      experiment, food allocation was varied within subjects by prefeeding food
      deprived rats 0, 5, 10 and 15 g of food before sessions of lever pressing for
      wheel-running reinforcement. The experiment assessed the effects of prefeeding on
      rates of wheel running, lever pressing, and postreinforcement pausing. Results
      showed that prefeeding animals 5 g of food had no effect. Prefeeding 10 g of food
      reduced lever pressing for wheel running and rates of wheel running without a
      significant change in body weight; the effect was, however, transitory.
      Prefeeding 15 g of food increased the animals' body weights, resulting in a
      sustained decrease of wheel running and lever pressing, and an increase in
      postreinforcement pausing. Overall the results indicate that the motivation for
      physical activity is regulated by changes in local food supply, but is sustained
      only when there is a concomitant change in body weight.

PMID- 15182921
TI  - Flavor aversion learning induced by lithium chloride in reptiles but not in
      amphibians.
AB  - Flavor aversion learning occurs when digestive illness follows ingestion of a
      novel food. Such learning has been shown to exist in mammals and birds. In this
      experiment, we looked for flavor aversion learning in amphibians (Bufo
      paracnemis, Pachytriton breviceps) and reptiles (Basiliscus vitattus, B.
      basiliscus, Eumeces schneideri, Mabuya multifasciata). After intake of the novel
      food, the animals received i.p. injection of either lithium chloride (LiCl), an
      effective illness inducer, or a saline solution. A week later, the LiCl injection
      had not affected the food intake of the amphibians whereas in the lizards it had
      produced a strong aversion to the flavor of the novel food. These results are
      consistent with the hypothesis that specific mental capacities emerged with
      reptiles.

PMID- 15182922
TI  - Impulsive choice in inbred strains of mice.
AB  - When humans or non-humans are given a choice between receiving a sooner-smaller
      (SS) reinforcer, or a later-larger (LL) reinforcer, the choice of a SS reinforcer
      represents impulsive choice whereas the choice of a LL reinforcer represents self
      controlled choice. It has been suggested that both biological and genetic factors
      influence impulsive/self-control choice in this paradigm. In the present study,
      the inbred strains of BALB/c, C57BL/6, and DBA/2 mice were given a choice to
      press one of two levers in an operant chamber. Depending on their choice, mice
      received either a smaller reinforcer (one pellet delivered after 6s) sooner (SS)
      or a larger reinforcer (two pellets after 6, 9, 12, 18, or 30s) later (LL). Mice
      preference for the larger reinforcer decreased with longer delays. More
      importantly, the BALB/c mice chose the SS reinforcer more often than the C57BL/6
      mice under the 9- and 12-s delays, and more often than the DBA/2 mice under the 9
      s delay. This indicates that the choice pattern of the BALB/c strain is more
      "impulsive" than the other strains and suggests that specific gene configurations
      influence impulsive choice in mice.

PMID- 15182923
TI  - Discriminations, reversals, and extra-dimensional shifts in the Gottingen
      minipig.
AB  - Gottingen minipigs were trained on a set-shifting procedure involving
      discriminations, reversals, and extra-dimensional shifts. The discriminations
      used were black-white discriminations and right-left discriminations. The initial
      visual and spatial discrimination seemed equally difficult, and only for the
      visual modality was reversal found to be more difficult than the initial
      discrimination. Visual reversal was more difficult than spatial reversal, and a
      larger number of perseverative sessions were found for visual reversal compared
      to spatial reversal. The acquisition of the extra-dimensional shift from the
      visual to the spatial dimension was not inferior to the learning of spatial
      reversal. Neither was the acquisition of the extra-dimensional shift from the
      spatial to the visual dimension inferior to the learning of visual reversal.
      Thus, no evidence was found for attention to stimulus dimensions in
      discrimination learning of the pigs.

PMID- 15182924
TI  - Balancing variable patch quality with predation risk.
AB  - Patch choice is almost always under the influence of multiple factors. Patch
      quality and the threat of predation are two such factors that have been shown to
      influence the foraging decisions of animals. In addition, aspects of patch
      quality may also vary with time, and consequently animals should incorporate
      temporal information to reduce their uncertainty about current patch conditions.
      The temporal weighting rule (TWR), which has been validated in previous studies,
      describes how animals should choose among variable options with the passage of
      time. In this study, we varied an additional factor, predation risk, along with
      certainty about patch yields in a field experiment, utilizing individually
      marked, free-ranging least chipmunks, Tamias minimus. We gave the animals in each
      condition experience at our experimental patches and then recorded patch choices
      a few minutes or one to 2 days later. The results show that animals combined
      perceived predation risk with a progressively shifting assessment of patch
      quality to form estimates of overall patch value as modeled by TWR. Based on the
      information available, the animals' patch choices were, arguably, the most
      adaptive choices.

PMID- 15182925
TI  - Pair bonding and "the widow effect" in female prairie voles.
AB  - We conducted field and laboratory experiments with the well-studied monogamous
      prairie vole, Microtus ochrogaster, to distinguish among three hypotheses for the
      failure of females that lose their mates to bond with a new male ("the widow
      effect"). The reproductive value hypothesis predicts that males prefer young to
      older females because they potentially have a longer reproductive lifespan. The
      mate rejection hypothesis predicts that females will prevent repairing by
      aggressively deterring males that might harm their current offspring. The
      misdirected paternal care hypothesis assumes that females will mate during
      postpartum estrus and thus will be pregnant and/or nursing young throughout the
      breeding season; males will avoid pairing with older females to avoid providing
      care to unrelated offspring and/or because of a delay to the next breeding
      opportunity. Males associated and bred more with older than young females,
      allowing us to reject the reproductive value hypothesis. Our results were
      consistent with the male rejection hypothesis in that females were aggressive
      toward unfamiliar males. Our results were most consistent with the misdirected
      paternal care hypothesis in that once females started breeding, they continued to
      become pregnant and nurse young throughout the study period. Thus, our findings
      suggest that the potential of misdirected paternal care and delayed mating
      opportunity in conjunction with the aggressive behavior of females toward
      unfamiliar males are likely explanations for the lack of repairing for widow
      females.

PMID- 15182926
TI  - Reinforcer concentration effects on a fixed-interval schedule.
AB  - Four rats received training on a mixed FI 30-s FI 150-s schedule, where the
      different FI values were associated with different levers. During baseline, the
      reinforcer was a 30% concentration of condensed milk. During subsequent testing
      sessions, the reinforcer concentration was varied within sessions over values of
      10, 30, 50, and 70%. Measures of behaviour were taken from the FI 30-s lever
      during trials where the reinforcer was delivered for responses on the other
      lever. Increasing the reinforcer concentration which began the interval (a)
      increased the time to start responding in the interval, and (b) increased the
      location of the response peak on the FI 30-s lever (often to values well above
      30s). Response rate at the peak, and spread of the response rate versus time
      function, changed much less with reinforcer concentration. The data are discussed
      relative to predictions derived from Scalar Expectancy Theory, the Behavioural
      Theory of Timing, and the Tuned-trace model.

PMID- 15182927
TI  - Does the terminal-link effect depend on duration or reinforcement rate?
AB  - Preference in concurrent chains for the richer terminal-link schedule becomes
      more extreme as the schedule values increase with their ratio held constant, a
      result known as the terminal-link effect. We report two experiments that attempt
      to determine whether this effect is related to terminal-link duration or the
      overall rate of reinforcement. These variables have been confounded in prior
      studies, but can be separated by comparing variable-duration schedules that end
      after a single reinforcer has been earned, with constant-duration schedules
      during which a variable number of reinforcers may be earned. In Experiment 1, the
      terminal-link effect was obtained with variable-duration schedules when duration
      and overall reinforcement rate were manipulated, but not with constant-duration
      schedules when overall reinforcement rate was changed with duration held
      constant. In Experiment 2, the terminal-link effect was obtained with constant
      duration schedules when duration was manipulated with overall reinforcement rate
      held constant. Taken together, these results show that the terminal-link effect
      depends on changes in terminal-link duration, not overall reinforcement rate (or
      equivalently, average time to reinforcement). This accords with the account of
      the terminal-link effect provided by the contextual choice model [J. Exp. Anal.
      Behav. 61 (1994) 113] but not delay-reduction theory [J. Exp. Anal. Behav. 12
      (1969) 723].

PMID- 15182928
TI  - Flehmen response in bull: role of vaginal mucus and other body fluids of bovine
      with special reference to estrus.
AB  - The present investigation was carried out with a view to evaluate the frequency
      of Flehmen behaviour in bull in response to body fluids of cows in various stages
      of the estrous cycle, in the context of estrus detection. The study was performed
      on free moving bulls under natural conditions. Samples of vaginal mucus, saliva,
      faeces and milk of pro-estrus, estrus and di-estrus stages collected from donor
      cows were rubbed individually onto the genital regions of non-estrus animals
      (dummy cows) and the bulls were observed for 30 min for assessment of Flehmen
      behaviour. The duration of Flehmen behaviour shown by bulls was maximum towards
      the dummy cows receiving estrus sample. Such Flehmen behaviour, however, did not
      occur in bulls in response to the cows receiving samples of other stages. The
      statistical significance was higher (P < 0.001) in exhibiting repeated Flehmen
      behaviour towards estrus as compared to those of pro-estrus and di-estrus. Among
      the various body fluids tested, the exhibition of Flehmen behaviour was
      significantly higher (P < 0.01) in response to estrus vaginal fluid. No response
      was observed on dummy cows (control) to which only water was applied on the
      genital region. The results suggest that vaginal mucus may act as an
      additional/secondary source along with urine in eliciting copulatary behaviour
      and executing coitus in bulls during estrus. The results further suggest that in
      addition to vaginal mucus, other body fluids like saliva, faeces and milk have
      estrus-related odours and are probably involved in bovine bio-communication.

PMID- 15182929
TI  - A method for identifying sounds used in the classification of alarm calls.
AB  - In this study, we present a methodology that identifies acoustic units in
      Gunnison's prairie dog alarm calls and then uses those units to classify the
      alarm calls and bouts according to the species of predator that was present when
      the calls were vocalized. While traditional methods measure specific acoustic
      parameters in order to describe a vocalization, our method uses the variation in
      the internal structure of a vocalization to define possible information
      structures. Using a simple representation similar to that used in human speech to
      identify vowel sounds, a software system was developed that uses this
      representation to recognize acoustic units in prairie dog alarm calls. These
      acoustic units are then used to classify alarm calls and their associated bouts
      according to the species of predator that was present when the alarm calls were
      vocalized. Identification of bouts with up to 100% accuracy was obtained. This
      work represents a first step toward revealing the details of how information is
      encoded in a complex nonhuman communication system. Furthermore, the techniques
      discussed in this paper are not restricted to a database of prairie dog alarm
      calls. They could be applied to any animal whose vocalizations include multiple
      simultaneous frequencies.

PMID- 15182930
TI  - The importance of 'memory' in statistical models for animal feeding behaviour.
AB  - We investigate models for animal feeding behaviour, with the aim of improving
      understanding of how animals organise their behaviour in the short term. We
      consider three classes of model: hidden Markov, latent Gaussian and semi-Markov.
      Each can predict the typical 'clustered' feeding behaviour that is generally
      observed, however they differ in the extent to which 'memory' of previous
      behaviour is allowed to affect future behaviour. The hidden Markov model has
      'lack of memory', the current behavioural state being dependent on the previous
      state only. The latent Gaussian model assumes feeding/non-feeding periods to
      occur by the thresholding of an underlying continuous variable, thereby
      incorporating some 'short-term memory'. The semi-Markov model, by taking into
      account the duration of time spent in the previous state, can be said to
      incorporate 'longer-term memory'. We fit each of these models to a dataset of cow
      feeding behaviour. We find the semi-Markov model (longer-term memory) to have the
      best fit to the data and the hidden Markov model (lack of memory) the worst. We
      argue that in view of effects of satiety on short-term feeding behaviour of
      animal species in general, biologically suitable models should allow 'memory' to
      play a role. We conclude that our findings are equally relevant for the analysis
      of other types of short-term behaviour that are governed by satiety-like
      principles.

PMID- 15182931
TI  - Cytoplasmic membrane polarization in Gram-positive and Gram-negative bacteria
      grown in the absence and presence of tetracycline.
AB  - The ability of numerous diverse compounds and ions to cross the bacterial
      cytoplasmic membrane by diffusion and active transport is highly dependent on
      cytoplasmic membrane fluidity, which can be measured using fluorescent probes to
      estimate membrane polarization values. However, membrane polarization data are
      lacking for most bacterial species. The cytoplasmic membrane polarization values
      for Arthrobacter sp. ATCC 21908, Bacillus cereus NRC 3045, Pseudomonas
      fluorescens R2F, Pseudomonas putida NRC 2986 and Escherichia coli C600 bacterial
      cells were spectrofluorometrically measured over a temperature range from 10 to
      50 degrees C, and in the absence and presence of 1 microg/ml tetracycline, using
      the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) to obtain new
      information on their membrane fluidity. At an assay temperature of 10 degrees C,
      E. coli cells grown in the absence of tetracycline exhibited the highest
      cytoplasmic membrane polarization value (least fluid membrane) of 0.446, followed
      by values of 0.392, 0.371, 0.344 and 0.293, respectively, for B. cereus,
      Arthrobacter sp., P. fluorescens and P. putida. At an assay temperature of 30
      degrees C, the polarization values ranged from 0.357 to 0.288 for cells grown in
      the absence of tetracycline, regardless of the species. B. cereus grown in the
      presence of 1 microg/ml tetracycline had lower polarization values than when
      grown in the absence of this antibiotic at all assay temperatures. Regardless of
      the absence or presence of 1 microg/ml tetracycline in the growth medium, all
      bacterial species generally exhibited a more fluid membrane as the assay
      temperature increased from 10 to 50 degrees C. To our knowledge, these are some
      of the first cytoplasmic membrane polarization values reported for these Gram
      negative and Gram-positive bacteria over a broad temperature range and also for
      cells grown in the presence of tetracycline.

PMID- 15182932
TI  - Incorporation of a high level of vitamin B12 into a vegetable, kaiware daikon
      (Japanese radish sprout), by the absorption from its seeds.
AB  - High level of vitamin B(12) was incorporated into kaiware daikon (Japanese radish
      sprout) by soaking its seeds in B(12) solutions. Vitamin B(12) amount
      incorporated into kaiware daikon increased up to 1.5 microg/g wet sprout with the
      soaking time of seeds in 0-200 microg/ml B(12) solution. Vitamin B(12) could be
      extracted more from the sample heated for a short time than from that of control
      without heat treatment.

PMID- 15182933
TI  - Micropatterned, self-assembled monolayers for fabrication of transfected cell
      microarrays.
AB  - The aim of this study was to develop the cell microarray that allows efficient
      transfer of multiple genes into mammalian cells cultured on the microarray in a
      high-throughput fashion. A microarray was fabricated using a gold-coated glass
      plate having a micropatterned, self-assembled monolayer of alkanethiols carrying
      ionic and nonionic terminal groups. Plasmid DNA and a cationic lipid were loaded
      by alternate electrostatic adsorption to the microspots to obtain a plasmid DNA
      microarray. The loading and the release of lipid-DNA complex were studied by,
      respectively, the fluorescence staining of DNA and the imaging of the microarray
      with a surface plasmon resonance (SPR) apparatus. The transfection efficiency was
      evaluated by directly plating and culturing human embryonic kidney cells onto the
      microarray. The results demonstrated that cells which adhered to the DNA-loaded
      spots were transfected to express the encoded model proteins for several days.
      The chemistry of the monolayers and the number of alternate adsorption cycles had
      large effects on the efficiency of transfection. This may be explained from the
      availability of the lipid-DNA complex to the cells directly contacted. We
      conclude that the micropatterned, self-assembled monolayers greatly facilitate
      regionally defined loading of DNAs and expression of the encoded protein in
      mammalian cells.

PMID- 15182934
TI  - Characterization of the cytotoxic mechanism of Mana-Hox, an analog of manzamine
      alkaloids.
AB  - Mana-Hox is a synthetic analog of manzamines, which are beta-carboline alkaloids
      isolated from marine sponges. Mana-Hox exhibited cytotoxicity against various
      tumor cell lines with the IC(50) range from 1 to 5 microM. Cell cycle
      synchronization and flow cytometric analysis showed that Mana-Hox delayed cell
      cycle progression at mitosis. At the concentration that delayed mitotic
      progression, bipolar spindle with lagged chromosomes and multipolar spindle with
      disorganized chromosomes were detected. The presence of such aberrant mitotic
      cells accompanied by the activation of spindle checkpoint that delayed cells exit
      from mitosis. However, after a short delay, lagged chromosomes were able to
      display in the abnormal metaphase plates, and subsequent cell division resulting
      in chromosome missegregation. Furthermore, the aberrant mitotic cells showed
      lower viability, indicating that Mana-Hox-induced cell death resulting from
      chromosome missegregation. This study is the first to explore cytotoxic mechanism
      of a manzamine-related compound and understand its potential as a lead compound
      for the development of future anticancer agents.

PMID- 15182935
TI  - Expression of cell surface Lewis X and Y antigens and FUT4 mRNA is increased in
      Jurkat cells undergoing apoptosis.
AB  - Cell surface molecules undergo specific changes during apoptosis, including the
      expression of phosphatidylserine (PS) and some proteins and alterations in sugar
      chains. Among the various sugar chains on the cell surface, Lewis X (Le(X)) and
      Lewis Y (Le(Y)) antigens are key determinants for a variety of biological
      processes. We studied the changes in Le(X) and Le(Y) expression in Jurkat cells,
      a human T cell line, during apoptosis. Flow cytometry showed that Le(X) and Le(Y)
      antigen expression was enhanced on the cell surface during apoptosis induced by
      anti-Fas antibody. To clarify the mechanism of enhanced Le(X) and Le(Y)
      expression, we assessed the expression levels of fucosyltransferase (FUT1, 2, 3-5
      6, 4, and 9) mRNAs that are predominantly expressed in Jurkat cells and which are
      considered to form Le(X) and Le(Y). The expression of FUT4 mRNA was up-regulated
      after exposing cells to anti-Fas antibody. Moreover, the increase in Le(X) and
      Le(Y) antigen levels was significantly suppressed by caspase 3 or 8 inhibitors.
      These results indicated that the induction of FUT (mainly FUT4), the gene
      expression of which is mediated by signals downstream of caspase 3, increases
      Le(X) and Le(Y) expression in apoptotic cells.

PMID- 15182936
TI  - Oxygen binding and oxidation reactions of human hemoglobin conjugated to
      carboxylate dextran.
AB  - Human hemoglobin (Hb) conjugated to benzene tetracarboxylate substituted dextran
      produces a polymeric Hb (Dex-BTC-Hb) with similar oxygen affinity to that of red
      blood cells (P(50)=28-29 mm Hg). Under physiological conditions, the oxygen
      affinity (P(50)) of Dex-BTC-Hb is 26 mm Hg, while that of native purified human
      HbA(0) is 14 mm Hg, but it exhibits a slight reduction in cooperativity (n(50)),
      Bohr effect, and lacks sensitivity to inositol hexaphosphate (IHP), when compared
      to HbA(0). Oxygen-binding kinetics, measured by rapid mixing stopped-flow method
      showed comparable oxygen dissociation and association rates for both HbA(0) and
      Dex-BTC-Hb. The rate constant for NO-mediated oxidation of the oxy form of Dex
      BTC-Hb, which is governed by NO entry to the heme pocket, was reduced to half of
      the value obtained for HbA(0). Moreover, Dex-BTC-Hb is only slightly more
      sensitive to oxidative reactions than HbA(0), as shown by about 2-fold increase
      in autoxidation, and slightly higher H(2)O(2) reaction and heme degradation
      rates. Dextran-BTC-based modification of Hb produced an oxygen-carrying compound
      with increased oxygen release rates, decreased oxygen affinity and reduced nitric
      oxide scavenging, desirable properties for a viable blood substitute. However,
      the reduction in the allosteric function of this protein and the lack of apparent
      quaternary T-->R transition may hinder its physiological role as an oxygen
      transporter.

PMID- 15182937
TI  - A single amino acid substitution can shift the optimum pH of DNase I for enzyme
      activity: biochemical and molecular analysis of the piscine DNase I family.
AB  - We purified four piscine deoxyribonucleases I (DNases I) from Anguilla japonica,
      Pagrus major, Cryprus carpio and Oreochromis mossambica. The purified enzymes had
      an optimum pH for activity of approximately 8.0, significantly higher than those
      of mammalian enzymes. cDNAs encoding the first three of these piscine DNases I
      were cloned, and the sequence of the Takifugu rubripes enzyme was obtained from a
      database search. Nucleotide sequence analyses revealed relatively greater
      structural variations among the piscine DNase I family than among the other
      vertebrate DNase I families. From comparison of their catalytic properties, the
      vertebrate DNases I could be classified into two groups: a low-pH group, such as
      the mammalian enzymes, with a pH optimum of 6.5-7.0, and a high-pH group, such as
      the reptile, amphibian and piscine enzymes, with a pH optimum of approximately
      8.0. The His residue at position 44 of the former group is replaced by Asp in the
      latter. Replacement of Asp44 of piscine and amphibian DNases I by His decreased
      their optimum pH to a value similar to that of the low-pH group. Therefore,
      Asp44His might be involved in an evolutionarily critical change in the optimum pH
      for the activity of vertebrate DNases I.

PMID- 15182938
TI  - Activation and inhibition of Candida rugosa and Bacillus-related lipases by
      saturated fatty acids, evaluated by a new colorimetric microassay.
AB  - Research on lipase inhibitors could help in the therapy of diseases caused by
      lipase-producing microorganisms and in the design of novel lipase substrate
      specificities for biotechnology. Here we report a fast and sensitive colorimetric
      microassay that is low-cost and suitable for high-throughput experiments for the
      evaluation of lipase activity and inhibition. Comparison of Candida rugosa
      activity and inhibition with previous HPLC results validated the method, and
      revealed the importance of the reaction mixture composition. The assay was used
      to evaluate the effect of saturated fatty acids on Bacillus-related lipases. Cell
      bound esterases were strongly inhibited by fatty acids, suggesting a negative
      feedback regulation by product, and a role of these enzymes in cell membrane
      turnover. Bacillus subtilis LipA was moderately activated by low concentrations
      of fatty acids and was inhibited at greater concentrations. LipB-like esterases
      were highly activated by myristic and lauric acids and were only slightly
      inhibited by high capric acid concentrations. Such an activation, reported here
      for the first time in bacterial lipases, seems to be part of a regulatory system
      evolved to ensure a high use of carbon sources, and could be related to the
      successful adaptation of Bacillus strains to nutrient-rich environments with
      strong microbial competition.

PMID- 15182939
TI  - Non-covalent interaction between procyanidins and apple cell wall material: Part
      I. Effect of some environmental parameters.
AB  - The adsorption of procyanidins on cell wall material were quantified by bringing
      into contact a solution of procyanidins and a suspension of cell wall material.
      The influence of structural features such as degree of polymerisation (DP) and
      percentage of galloylation (% gall), and of physico-chemical parameters such as
      pH, ionic strength, temperature and presence of ethanol were investigated. The
      amount of procyanidins bound to the cell wall increased with the DP, the % gall,
      and the proportion of (+)-catechin, the last indicating an effect of the
      stereochemistry of the flavan-3-ols. Complex formation between procyanidins and
      cell wall material was not affected by pH in the range 2.2-7 but it was decreased
      by urea, dioxane and ethanol. Adsorption increased with increasing ionic strength
      and decreased with increasing temperature. This indicated that the bonds which
      governed the interaction between procyanidins and cell wall material were weak
      energy bonds of the type hydrogen bond and hydrophobic interaction.

PMID- 15182941
TI  - Overexpression, purification and characterization of the acidic ribosomal P
      proteins from Candida albicans.
AB  - In all eukaryotic cells, acidic ribosomal P-proteins form a lateral protuberance
      on the 60S ribosomal subunit-the so-called stalk-structure that plays an
      important role during protein synthesis. In this work, we report for the first
      time a full-length cloning of four genes encoding the P-proteins from Candida
      albicans, their expression in Escherichia coli, purification and characterization
      of the recombinant proteins. Considerable amino acid sequence similarity was
      found between the cloned proteins and other known fungal ribosomal P-proteins. On
      the basis of their phylogenetic relationship and amino acid similarity to their
      yeast counterparts, the C. albicans P-proteins were named P1A, P1B, P2A and P2B.
      Using three different approaches, namely: chemical cross-linking method, gel
      filtration and two-hybrid system, we analyzed mutual interactions among the C.
      albicans P-proteins. The obtained data showed all the four P-proteins able to
      form homo-oligomeric complexes. However, the ones found between P1B-P2A and P1A
      P2B were dominant forms among the C. albicans P-proteins. Moreover, the strength
      of interactions between particular proteins was different in these two complexes;
      the strongest interactions were observed between P1B and P2A proteins, and a
      significantly weaker one between P1A and P2B proteins.

PMID- 15182940
TI  - Iron release, superoxide production and binding of autologous IgG to band 3
      dimers in newborn and adult erythrocytes exposed to hypoxia and hypoxia
      reoxygenation.
AB  - Iron is released in a desferrioxamine (DFO)-chelatable form when erythrocytes are
      challenged by an oxidative stress. The release is increased when an accelerated
      removal of erythrocytes occurs such as in perinatal period, in which iron release
      is greater in hypoxic than in non-hypoxic newborns. This suggests that an hypoxic
      environment at birth promotes iron release. To test this possibility, iron
      release in a model of hypoxia, hypoxia-reoxygenation and normoxia was studied in
      newborn and adult erythrocytes. In newborn erythrocytes, hypoxia induced a much
      greater iron release compared to an equal period of normoxia. In adult
      erythrocytes, hypoxia also induced a greater iron release as compared to
      normoxia, but it was much lower than that seen with newborn erythrocytes.
      Methemoglobin (MetHb) formation roughly paralleled iron release. The
      phenylhydrazine-promoted superoxide anion (O(2)?(-)) production was greater with
      normoxic but lower with hypoxic erythrocytes from newborns as compared to that
      from adults. This discrepancy between iron release and O(2)?(-) production may be
      explained by the shift towards MetHb in hemoglobin autoxidation. Iron diffusion
      out of the erythrocytes was much higher with hypoxic erythrocytes from newborns
      as compared to that from adults. Also the binding of autologous IgG to band 3
      dimers (AIgGB) is much greater with hypoxic erythrocytes from newborns as
      compared to that from adults, suggesting that the level of iron release is
      related to the extent of band 3 clustering and that hypoxia accelerates removal
      of erythrocytes from bloodstream in in vivo condition.

PMID- 15182942
TI  - Roles of loop C and the loop B-C interval of the nicotinic receptor alpha subunit
      in its selective interactions with imidacloprid in insects.
AB  - To elucidate the mechanism of selective action of imidacloprid on insect
      nicotinic acetylcholine receptors (nAChRs), we examined the roles of loop C and
      the loop B-C interval region in receptor interactions with imidacloprid. The
      P242E mutation in loop C of the Drosophila SAD subunit (the second alpha-like
      Drosophila nicotinic acetylcholine receptor subunit, also called Dalpha2 subunit)
      reduced imidacloprid sensitivity of the SAD-chicken beta2 hybrid nAChR, whereas
      the E219P mutation of the alpha4 subunit increased the imidacloprid sensitivity
      of the alpha4beta2 nAChR. Deletion of the loop B-C interval region from the SAD
      subunit enhanced the effect of the P242E mutation on the SADbeta2 hybrid nAChR,
      suggesting important roles of the regions investigated in the nAChR-imidacloprid
      interactions.

PMID- 15182943
TI  - Allelic variation at the A218C tryptophan hydroxylase polymorphism influences
      agitation and aggression in Alzheimer's disease.
AB  - The behavioural and psychological symptoms of dementia are common, distressing to
      carers, and directly linked to the requirement for institutional care. Symptoms
      of aggression and agitation are particularly difficult for carers to tolerate.
      The origin of these features is unclear although genetic and environmental
      modification of pre-frontal serotonergic circuitry which regulates the control of
      negative emotions is proposed. Following the suggestion that the A218C intronic
      polymorphism of the tryptophan hydroxylase gene influences aggression and anger
      in non-demented individuals, we tested the influence of A218C on symptoms of
      agitation/aggression in 396 Alzheimer's disease patients using the
      Neuropsychiatric Inventory. Overall, 50% of participants experienced
      agitation/aggression in the month prior to interview. It was observed that male
      patients with a history of agitation/aggression were more likely to possess C
      containing genotypes (P = 0.044, OR = 1.65, CI = 0.98-2.76). We conclude that
      aggression in male subjects with Alzheimer's disease may be genetically linked to
      polymorphic variation at the tryptophan hydroxylase gene.

PMID- 15182944
TI  - Cyclooxygenase-2 expression in Schwann cells and macrophages in the sciatic nerve
      after single spinal nerve injury in rats.
AB  - Recent evidence suggested that cyclooxygenase-2 (COX-2) expression in the
      peripheral nerve early after nerve injury might be involved in the development of
      neuropathic pain. Although previous investigators have demonstrated that COX-2 is
      expressed in peripheral nerve at a late phase (2-4 weeks) after nerve injury, COX
      2 up-regulation at an early phase after nerve injury has not been determined.
      Using immunohistochemistry, we observed biphasic increases of COX-2 expression
      after L5 single spinal nerve injury. The first increment of COX-2 positive cells
      was noted 1 day after nerve injury and these cells co-expressed the Schwann cell
      marker S-100. A second increment was noted after 7-14 days and these cells co
      expressed the macrophage marker ED-1. These results suggested that the cellular
      sources of COX-2 expression might be different between the early and late phases
      after nerve injury.

PMID- 15182945
TI  - Halothane depresses C-fiber-evoked windup of deep dorsal horn neurons in mice.
AB  - A progressive increase in the response of a nociceptive spinal neuron to repeated
      electrical C-fiber stimulation reflects a phenomenon called windup. Second order
      neurons in the dorsal horn, as well as motoneurons, can develop windup. Inhaled
      anesthetics act primarily in spinal cord to suppress movement induced by noxious
      stimulation. We hypothesized that halothane would depress neuronal windup in mice
      at concentrations that also prevented movement. We measured windup in deep dorsal
      horn neurons in lumbar spinal cord at 0.75 MAC (the minimum alveolar
      concentration of anesthetic that prevents movement in 50% of subjects in response
      to noxious stimulation), 0.9 MAC, and 1.1 MAC. The change from 0.75 to 0.9 MAC
      did not significantly decrease windup (-11+/-22%), but the change from 0.9 to 1.1
      MAC decreased windup (-35+/-7%, P<0.01). We conclude that halothane depresses
      neuronal windup in the range that prevents movement, and that the effect on
      windup might play a role in halothane's immobilizing action.

PMID- 15182946
TI  - Changes in electrophysiological properties of regenerating rat peripheral nerves
      after crush injury.
AB  - The conduction of action potential in peripheral nerves requires the coordinated
      opening and closing of Na(+) and K(+) channels. In the present study, we used the
      sucrose-gap recording technique to determine the electrophysiological changes of
      the regenerating nerves after sciatic nerve injury by using 4-aminopyridine (4
      AP) and tetraethylammonium (TEA), and lidocaine. 4-AP enhanced the amplitude and
      duration of the compound action potentials (CAPs) of regenerating sciatic nerve
      15 days post crush (15 dpc), and elicited delayed depolarizations (Del-dep) in 38
      dpc and intact groups. Hyperpolarizing afterpotentials elicited by 4-AP were
      completely removed by TEA in both 15 and 38 dpc. Lidocaine effectively blocked
      the CAP amplitude. This blockage was more pronounced in 15 dpc than 38 dpc. This
      agent also exhibited a partial blockage on the Del-dep amplitude. These results
      may indicate that the changes in the activities of 4-AP- and TEA-sensitive K(+)
      channels and slow Na(+) channels may play critical roles in nerve excitability
      and conduction.

PMID- 15182947
TI  - Astragaloside IV protects against ischemic brain injury in a murine model of
      transient focal ischemia.
AB  - Astragalus membranaceus is a herbal medicine that has been used clinically in
      stroke patients in China for decades, but its potential neuroprotective effect
      against ischemic brain injury has not been experimentally tested. In this study,
      we investigated the effect of Astragaloside IV, a purified extract from
      Astragalus membranaceus, in a murine model of focal cerebral ischemia/reperfusion
      produced by transient (1.5 h) middle cerebral artery occlusion. As determined at
      72 h after ischemia, post-ischemic treatment of Astragaloside IV (20 or 40 mg/kg)
      markedly and significantly (P < 0.03 vs. vehicle-treated animals) reduced infarct
      volume. Astragaloside IV treatment also decreased the levels of malondialdehyde,
      an indicator of lipid peroxidation, and increased the levels of the antioxidant
      enzymes glutathione peroxidase and superoxide dismutase in ischemic tissues. The
      results presented here provide the first evidence of a neuroprotective effect of
      Astragaloside IV in the model of ischemic brain injury. We suggest that the anti
      infarction effect by Astragaloside IV may be derived at least in part from its
      antioxidant properties.

PMID- 15182948
TI  - Influence of velocity on the human global postural strategies during the movement
      leading up to the vertical upside-down position.
AB  - The aim of this study was to examine the influence of the velocity on the control
      of the final postural equilibrium in the movement of standing up into upside-down
      vertical posture on the hands. Seven expert gymnasts performed the movement on a
      force plate of large dimensions from which the kinematic of center of mass (CoM)
      was studied. The first result showed that the speed of CoM was increased in the
      vertical axis but did not change in the antero-posterior axis. The second result
      showed a reduction of the duration of the anticipatory postural adjustments (APA)
      conversely to the speed. This was in contrast to the movements performed in the
      natural erect stance. These results suggest firstly that the speed of CoM
      corresponds to a global strategic response linked to the body's posturo-kinetic
      capacity, and secondly that the reduction of the APA seems to be linked to the
      precariousness of the final equilibrium.

PMID- 15182949
TI  - Activation of HIF-1alpha mRNA by hypoxia and iron chelator in isolated rat
      carotid body.
AB  - The hypoxia inducible factor-1alpha (HIF-1alpha) protein level is increased by
      hypoxia and iron chelator (ciclopirox olamine) in isolated rat carotid body (CB)
      and glomus cells. Reverse transcription and polymerase chain reaction (RT-PCR)
      are performed to test whether this increase is caused, at least in part, by
      increased HIF-1alpha gene transcription. HIF-1alpha mRNA levels dose-dependently
      increased and decreased in the rat CBs incubated for 1 h in a medium saturated
      with O(2) levels that were varied around nominally normoxic level of 21% in the 0
      95% range. The iron chelator, ciclopirox olamine (5 microM), stimulated HIF
      1alpha mRNA production under normoxic condition. Thus, in the CB, the main
      systemic O(2)-sensing organ, HIF-1alpha transcription is regulated by O(2) supply
      around the normoxic level; this may contribute to cellular and organismal
      adaptations to chronic changes in ambient O(2).

PMID- 15182950
TI  - Gene expression profiles in the rat central nervous system induced by JP-8 jet
      fuel vapor exposure.
AB  - Jet propulsion fuel-8 (JP-8) is the predominant fuel for military land vehicles
      and aircraft used in the US and NATO. Occupational exposure to jet fuel in
      military personnel has raised concern for the health risk associated with such
      exposure in the Department of Defense. Clinical studies of humans chronically
      exposed to jet fuel have suggested both neurotoxicity and neurobehavioral
      deficits. We utilized rat neurobiology U34 array to measure gene expression
      changes in whole brain tissue of rats exposed repeatedly to JP-8, under
      conditions that simulated possible occupational exposure (6 h/day for 91 days) to
      JP-8 vapor at 250, 500, and 1000 mg/m(3), respectively. Our studies revealed that
      the gene expression changes of exposure groups can be divided into two main
      categories according to their functions: (1). neurotransmitter signaling
      pathways; and (2). stress response. The implications of these gene expression
      changes are discussed.

PMID- 15182951
TI  - Nerve growth factor treatment enhances release of immunoreactive calcitonin gene
      related peptide but not substance P from spinal dorsal horn slices in rats.
AB  - The effect of systemic nerve growth factor (NGF) on neuropeptide content and
      capsaicin-evoked release of neuropeptide from in vitro spinal cord dorsal horn
      slices was examined. Rats were injected subcutaneously every other day with
      murine NGF (mNGF) 1 mg/kg or saline for 7 days, or mNGF 0.1/kg, mNGF 1 mg/kg or
      saline for 13 days. Lumbar dorsal horn slices of the rat spinal cord from all
      groups showed a significant increase in immunoreactive calcitonin gene-related
      peptide (CGRP) release upon exposure to capsaicin. This release was enhanced in
      rats pretreated with mNGF 1 mg/kg for 7 days, but not after 13 days. No
      enhancement was seen after 7 or 13 days in any treatment group for immunoreactive
      substance P release. Upon examination of neuropeptide content in dorsal horn, no
      significant differences were noted between treatment groups. The increased iCGRP
      release from dorsal horn slices suggests a preferential release of CGRP and
      provides further evidence that NGF indirectly plays a role in the modulation of
      inflammation through the regulation of neuropeptide release.

PMID- 15182952
TI  - Preventive effect of antioxidants in MPTP-induced mouse model of Parkinson's
      disease.
AB  - Oxidative stress to dopaminergic neurons is believed to be one of the causes of
      neurodegeneration in Parkinson's disease (PD). It was investigated whether N
      acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) have a
      preventive effect in an oxidative stress-induced model of PD. We found that NAC
      and OTC prevent degradation of PARP during auto-oxidized dopamine- or auto
      oxidized L-DOPA-induced apoptosis in PC12 cells. In an animal model study, NAC
      and OTC showed a preventive effect against MPTP-induced loss of tyrosine
      hydroxylase-positive neurons, and suppressed the nuclear translocation of c-jun N
      terminal kinase (JNK), suggesting that NAC and OTC can prevent MPTP-induced
      apoptosis by suppressing JNK activation. Therefore, these results suggest that
      NAC and OTC can be used as potential agents to prevent the progression of PD.

PMID- 15182953
TI  - Expression of cysteinyl leukotriene receptor 1 in human traumatic brain injury
      and brain tumors.
AB  - Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators. CysLT
      receptor 1 (CysLT(1)) is one of the two CysLT receptors that has been cloned.
      Although the expression of CysLT(1) in the brain has been demonstrated by
      Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains
      unknown. The objective of this study was to examine the distribution of CysLT(1)
      by immunohistochemical analysis in human brains with traumatic injury or tumors.
      CysLT(1) was expressed intensely in the microvascular endothelial cells in both
      normal and abnormal conditions. At 8 days after traumatic injury, microvascular
      regeneration was found and all of the endothelial cells highly expressed
      CysLT(1). In gray and white matters of the normal regions of the brain, CysLT(1)
      was expressed weekly or not at all. However, the CysLT(1) expression increased in
      the neuron- and glial-appearing cells in gray and white matters after traumatic
      brain injury. CysLT(1) was also detected in astrocytoma, ganglioglioma and
      metastatic adenocarcinoma, and the expression in the neuron- and glial-appearing
      cells around brain tumors increased robustly.

PMID- 15182954
TI  - A novel approach employing ultrasound guidance for percutaneous cardiac muscle
      injection to retrograde label rat stellate ganglion neurons.
AB  - Stellate ganglion (SG) neurons provide the main sympathetic innervation to the
      heart and help to regulate cardiac function. The purpose of this study was to
      determine if ultrasound imaging could be employed to retrograde label rat SG
      neurons innervating the heart without employing thoracotomy. In addition,
      electrophysiological experiments were performed to characterize the modulation of
      Ca(2+) channels by neurotransmitters in unlabeled and dye-labeled SG neurons.
      Fluorescence imaging of actutely isolated cells revealed that dye uptake was
      successful within five days following injection of dye in the cardiac muscle.
      Whole-cell voltage-clamp recordings revealed that the majority of the Ca(2+)
      current was carried by N-type Ca(2+) channels. Finally, fluorescence dye uptake
      did not appear to affect the modulation of Ca(2+) currents following exposure of
      SG neurons to norepinephrine, adenosine and neurokinin A. These results
      demonstrate that ultrasound imaging-guided percutaneous injection can be
      effectively employed to retrograde label neurons innervating the heart.

PMID- 15182955
TI  - Differential regulation of CYP1A1 and CYP1B1 expression in resveratrol-treated
      human medulloblastoma cells.
AB  - Resveratrol induces differentiation and Fas-independent apoptosis of
      medulloblastoma cells by a largely unknown mechanism. CYP1A1 and 1B1 are involved
      in resveratrol-mediated tumor suppression but their expression in medulloblastoma
      cells and their relevance to anti-medulloblastoma activity of resveratrol have
      not been described. The statuses of CYP1A1 and 1B1 in UW228-3 medulloblastoma
      cells without and with resveratrol treatments were elucidated in this study with
      ethoxyresorufin O-deethylation assay, followed by RT-PCR, immunocytochemical
      staining and Western blot hybridization. CYP1A1/1B1 enzymatic activity was low in
      UW228-3 cells but became several folds higher upon resveratrol treatments. CYP1A1
      was undetectable and CYP1B1 was expressed in normally cultured cells. Accompanied
      by the increased fraction of apoptosis, enhanced CYP1A1 and downregulated CYP1B1
      were observed in resveratrol-treated cells in time- and dose-related fashions.
      Our results demonstrate for the first time that in the medulloblastoma cell
      system, CYP1A1 upregulation is paralleled with resveratrol-induced
      differentiation and apoptosis, while CYP1B1 may not be an essential element in
      metabolic activation of resveratrol in those cells. CYP1A1 and 1B1 are
      resveratrol response genes and potential chemosensitive markers of
      medulloblastoma cells.

PMID- 15182957
TI  - Ontogeny of the dopamine and serotonin transporters in the rat brain: an
      autoradiographic study.
AB  - Damage to monoaminergic systems during the period of brain development is thought
      to be involved in several neurodevelopmental disorders. We investigated the
      maturation of the dopamine and serotonin transporters in rat cerebral regions
      containing the soma and projections of dopaminergic and serotoninergic neurons in
      an extensive study from the end of embryonic life (E(18)) to adult stages (until
      P(70)). The membrane transporters were measured by quantitative autoradiography
      using specific radioprobes. We demonstrated that the dopamine and serotonin
      transporters have different patterns of development. The dopamine transporter
      density increased from E(18) to P(28) where it reached the adult level and then
      remained stable until P(70). The maturation of serotonin transporters followed a
      triphasic profile in all areas: (i). an increase leading to a peak obtained
      between P(0) and P(14) in cell bodies and at P(21) in nerve endings; (ii). a
      decrease to reach adult levels at P(21) in raphe nuclei and at P(28) in
      projections areas; and (iii). a plateau until P(70). This demonstrated that the
      last week of embryonic life and the first two postnatal weeks are critical
      periods in the development of the dopaminergic and serotoninergic systems at
      which time they could be particularly vulnerable to injury.

PMID- 15182956
TI  - NaoXinQing, an anti-stroke herbal medicine, reduces hydrogen peroxide-induced
      injury in NG108-15 cells.
AB  - NaoXinQing (NXQ) is a patented and approved drug of Traditional Chinese Medicine
      that has been used for years for the treatment of syndrome of apoplexy, but the
      underlying mechanism remains unclear. The present study is designed to
      investigate the effects of NXQ on hydrogen peroxide (H(2)O(2))-induced cell
      damage in NG108-15 cells. Exposure to H(2)O(2) induces apoptosis-like cell
      injury. Preincubation of cells with NXQ alleviated H(2)O(2)-induced cell injury
      and apoptosis. This herb medicine also improves redox imbalance in cells under
      the exposure of H(2)O(2) as indicated by the attenuation in the reduction of
      activities of intracellular endogenous antioxidants, glutathione and glutathione
      peroxidase as well as catalase, and by the decrease in the leak of lactate
      dehydrogenase and the accumulation of malondialdehyde. These results indicate
      that NXQ significantly protects NG108-15 cells against H(2)O(2) challenge by
      improving redox imbalance and inhibiting apoptosis, which might represent
      mechanisms underlying its potential usage in the prevention and treatment of
      syndrome of apoplexy.

PMID- 15182958
TI  - Nitroglycerin induces migraine headache and central sensitization phenomena in
      patients with migraine without aura: a study of laser evoked potentials.
AB  - In migraineurs nitroglycerin (NTG) induces severe delayed headache, resembling
      spontaneous migraine attacks. The aim of the present study was to evaluate NTG
      laser evoked potentials (LEP) features amplitude and pain sensation to laser
      stimuli during NTG-induced headache. Nine patients were selected. Headache was
      induced by oral administration of 0.6 mg of NTG; signals were recorded through
      disk electrodes placed at the vertex and referred to linked earlobes. CO(2)-LEPs
      delivered by stimulation of the dorsum of both hands and the right and left
      supraorbital zones were evaluated after the onset of moderate or severe headache
      resembling spontaneous migraine and at least 72 h after the end of the headache
      phase. Patients exhibited a significant heat pain threshold reduction and an LEPs
      amplitude increment during headache when both the supraorbital zones were
      stimulated. NTG appeared to support a reliable experimental model of migraine,
      based on the neuronal effects on the integrative-nociceptive structures. The LEPs
      facilitation during NTG-induced headache may be subtended by a hyperactivity of
      nociceptive cortex as well as by a failure of pain-inhibitory control.

PMID- 15182960
TI  - Expression of c-Fos-like immunoreactivity in the brain of mice with learned
      helplessness.
AB  - The learned helplessness (LH) developed after repeat inescapable stress is a well
      validated animal model of human major depression and is not species specific. c
      Fos, the protein product of the protooncogene c-fos, is expressed in neurons
      under a variety of stressors and could reflect the regional neuronal activation.
      Using the LH paradigm in mice, we examined c-Fos expression in several brain
      regions related to stress response or major depression. The LH mice showed
      significantly lower c-Fos-like immunoreactivity (FLI) in the hippocampus dentate
      gyrus and the lateral septal nucleus, and higher FLI in the hypothalamic
      paraventricular nucleus compared with the naive mice. Our finding in the mice LH
      model supported previous studies in rats showing that the lateral septal nucleus
      and the hypothalamic paraventricular nucleus are important in LH behaviors. We
      further demonstrated that hippocampus dentate gyrus, a region important for
      learning and major depression, may also be involved in the LH behaviors. These
      related brain regions could provide a basis for further exploration of the
      molecular mechanisms underlying LH behaviors.

PMID- 15182959
TI  - Association study of serotonin-2A receptor gene polymorphism and panic disorder
      in patients from Canada and Germany.
AB  - The T102C serotonin-2A (5-HT2A) receptor gene polymorphism has been studied
      extensively in a number of complex psychiatric conditions with mixed results.
      Recently a genetic association has been described between this polymorphism and
      panic disorder in a Japanese sample. To evaluate the impact of the T102C
      polymorphism in panic disorder we genotyped triad families (panic disorder
      patient and parents), and cases with controls in Canadian and German samples. No
      significant transmission disequilibrium was observed between the alleles of the
      T102C 5-HT2A receptor gene polymorphism and panic disorder, nor was a significant
      excess of either allele found in the case control analysis. Our data suggest thus
      that this polymorphism is unlikely to play a major role in the pathogenesis of
      panic disorder.

PMID- 15182961
TI  - Chronic levodopa intake increases levodopa plasma bioavailability in patients
      with Parkinson's disease.
AB  - Previous pharmacokinetic trials with standard levodopa formulations showed a
      different behavior of levodopa degradation in plasma of patients with Parkinson's
      disease (PD) in various advanced stages. The objective of this trial was to
      compare levodopa plasma metabolism in PD patients with and without previous long
      term levodopa intake after oral intake of a dispensable levodopa/benserazide
      formulation (DLB). The over a 150 min interval computed area under the curve
      values of levodopa plasma levels after DLB administration were significantly
      (ANCOVA: F(1,19) = 7.88, P = 0.01) higher in PD patients with chronic levodopa
      treatment compared to patients without prior levodopa treatment. The maximum
      plasma levodopa concentration did not differ (ANCOVA: F(1.19) = 1.17, P = 0.29).
      Long-term levodopa administration results in an increased levodopa plasma
      bioavailability in PD patients.

PMID- 15182962
TI  - Association of aldehyde dehydrogenase-2 polymorphism with alcoholic
      polyneuropathy in humans.
AB  - Persons who have the Glu-487-->Lys mutation (single nucleotide polymorphism) of
      the aldehyde dehydrogenase-2 (ALDH2) gene have less ability to metabolize the
      alcohol breakdown product acetaldehyde. In order to clarify whether acetaldehyde
      is associated with the pathogenesis of alcoholic polyneuropathy, we compared
      nerve conduction data as well as clinical signs and symptoms of neuropathy
      between alcoholics with ALDH2*2 (Lys-487) heterozygotes and those with ALDH2*1
      (Glu-487) homozygotes. Alcoholics with ALDH2*2 heterozygotes showed significantly
      lower sensory nerve action potential amplitudes of the sural and median nerves
      than those with ALDH2*1 homozygotes, suggesting that the accumulation of
      acetaldehyde due to ALDH2 inactivity is associated with alcoholic polyneuropathy.

PMID- 15182963
TI  - Effects of incubation on solubility and mobility of trace metals in two
      contaminated soils.
AB  - Much research has focused on changes in solubility and mobility of trace metals
      in soils under incubation. In this experiment, changes in solubility and mobility
      of trace metals (Pb, Cu and As) and Fe in two contaminated soils from Tampa,
      Florida and Montreal, Canada were examined. Soils of 30 g were packed in columns
      and were incubated for 3-80 days under water-flooding incubation. Following
      incubation, metal concentrations in pore water (water soluble) and in 0.01 M
      CaCl2 leachates (exchangeable+water soluble) were determined. While both soils
      were contaminated with Pb (1600-2500 mg kg(-1)), Tampa soil was also contaminated
      with As (230 mg kg(-1)). Contrast to the low pH (3.8) of Tampa soil, Montreal
      soil had an alkaline pH of 7.7 and high Ca of 1.6%. Concentrations of Fe(II)
      increased with incubation time in the Tampa soil mainly due to reductive Fe
      dissolution, but decreased in the Montreal soil possibly due to formation of
      FeCO3. The inverse relationship between concentrations of Pb and Fe(II) in pore
      water coupled with the fact that Fe(II) concentrations were much greater than
      those of Pb in pore water may suggest the importance of Fe(II) in controlling Pb
      solubility in soils. However, changes in concentrations of Fe(II), Pb, Cu and As
      in pore water with incubation time were similar to those in leachate, i.e. water
      soluble metals were positively related to exchangeable metals in the two
      contaminated soils. This research suggests the importance of Fe in controlling
      metal solubility and mobility in soils under water-flooded incubation.

PMID- 15182964
TI  - Multi-generation cadmium acclimation and tolerance in Daphnia magna Straus.
AB  - The cladoceran Daphnia magna was acclimated for seven generations to cadmium
      concentrations ranging from 0 (control) to 250 microg/l Cd (corresponding to a
      free ion activity of 4.60 nM Cd2+). Acute and chronic cadmium tolerance as well
      as cadmium accumulation were monitored as a function of acclimation time. After
      two to three generations of acclimation to concentrations ranging from 0.23 to
      1.11 nM Cd2+ increases in acute tolerance were maximal (factor 7.2) and
      significant. Acclimation for seven generations to the same acclimation
      concentrations did result in an increased chronic cadmium tolerance (21 days EC50
      values increased). Organisms acclimated to 1.93 nM Cd2+ were equally or more
      sensitive than non-acclimated daphnids in acute and chronic toxicity tests.
      Cadmium contents in D. magna increased significantly as a function of the
      acclimation concentration. Maximum body burdens of 236+/-30 microg Cd/g dry
      weight were measured in organisms exposed to 4.60 nM Cd2+, but detoxification
      mechanisms were only successful up to 82+/-20 microg Cd/g dry weight as this
      concentration did not cause major decreases in survival and reproduction in
      chronic toxicity tests. As the potential positive effect of acclimation on
      cadmium tolerance disappeared with successive acclimation generations and
      increasing acclimation concentrations, it is concluded that multi-generation
      acclimation studies are important for the evaluation of the long-term effects of
      environmental toxicants.

PMID- 15182965
TI  - The role of glomalin, a protein produced by arbuscular mycorrhizal fungi, in
      sequestering potentially toxic elements.
AB  - Naturally occurring soil organic compounds stabilize potentially toxic elements
      (PTEs) such as Cu, Cd, Pb, and Mn. The hypothesis of this work was that an
      insoluble glycoprotein, glomalin, produced in copious amounts on hyphae of
      arbuscular mycorrhizal fungi (AMF) sequesters PTEs. Glomalin can be extracted
      from laboratory cultures of AMF and from soils. Three different experiments were
      conducted. Experiment 1 showed that glomalin extracted from two polluted soils
      contained 1.6-4.3 mg Cu, 0.02-0.08 mg Cd, and 0.62-1.12 mg Pb/g glomalin.
      Experiment 2 showed that glomalin from hyphae of an isolate of Gigaspora rosea
      sequestered up to 28 mg Cu/g in vitro. Experiment 3 tested in vivo differences in
      Cu sequestration by Cu-tolerant and non-tolerant isolates of Glomus mosseae
      colonizing sorghum. Plants were fed with nutrient solution containing 0.5, 10 or
      20 microM of Cu. Although no differences between isolates were detected, mean
      values for the 20 microM Cu level were 1.6, 0.4, and 0.3 mg Cu/g for glomalin
      extracted from hyphae, from sand after removal of hyphae and from hyphae attached
      to roots, respectively. Glomalin should be considered for biostabilization
      leading to remediation of polluted soils.

PMID- 15182966
TI  - Natural attenuation of trichloroethene and its degradation products at a lake
      shore site.
AB  - Subsurface contamination by trichloroethene (TCE) was detected at a Michigan
      National Priorities List (NPL) site in 1982. The TCE plume resulted from the
      disposal of spent solvent and other chemicals at an industrial facility located
      in the eastern shore of Lake Michigan. TCE degradation products of three
      dichloroethene (DCE) isomers, vinyl chloride (VC) and ethene were present. The
      plume was depleted of oxygen and methanogenic at certain depths. Transects of the
      plume were sampled by slotted auger borings the year after the TCE plume was
      first discovered. Water samples were also taken from lake sediments to a depth of
      12 m about 100 m offshore. Later samples were taken along the shoreline of the
      lake with a hand-driven probe. Later in 1998 water was taken from sediments about
      3-m from the shoreline. The average concentration of each chemical and net
      apparent base coefficient between appropriate pairs of transects between the
      lower site and lakeshore were calculated. Loss rates were then calculated from an
      analytical solution of the two-dimensional advective-dispersive-reactive
      transport equation. Net apparent rate coefficients and a set of coupled reaction
      rate equations were used to extract the apparent loss coefficients. This study
      showed the field evidence for natural attenuation of TCE.

PMID- 15182967
TI  - Long-term effects of submergence and wetland vegetation on metals in a 90-year
      old abandoned Pb-Zn mine tailings pond.
AB  - A Pb-Zn tailings pond, abandoned for approximately 90 years, has been naturally
      colonized by Glyceria fluitans and is an excellent example of long-term metal
      retention in tailings ponds under various water cover and vegetation conditions.
      Shallow/intermittently flooded areas (dry zone) were unvegetated and low in
      organic matter (OM) content. Permanently flooded areas were either unvegetated
      with low OM, contained dead vegetation and high OM, or living plants and high OM.
      It was expected that either water cover or high OM would result in enhanced
      reducing conditions and lower metal mobility, but live plants would increase
      metal mobility due to root radial oxygen loss. The flooded low OM tailings showed
      higher As and Fe mobility compared with dry low OM tailings. In the permanently
      flooded areas without live vegetation, the high OM content decreased Zn mobility
      and caused extremely high concentrations of acid-volatile sulfides (AVS). In
      areas with high OM, living plants significantly increased Zn mobility and
      decreased concentrations of AVS, indicating root induced sediment oxidation or
      decreased sulfate-reduction. This is the first study reporting the ability of
      wetland plants to affect the metal mobility and AVS in long-term (decades),
      unmanaged tailings ponds.

PMID- 15182968
TI  - Contamination of butyltin compounds in Malaysian marine environments.
AB  - Concentration of butyltin compounds (BTs), including tributyltin (TBT),
      dibutyltin (DBT) and monobutyltin (MBT) and total tin (SigmaSn) were determined
      in green mussel (Perna viridis), 10 species of muscle fish and sediment from
      coastal waters of Malaysia. BTs were detected in all these samples ranging from
      3.6 to 900 ng/g wet wt., 3.6 to 210 ng/g wet wt., and 18 to 1400 ng/g dry wt. for
      mussels, fish and sediments, respectively. The concentrations of BTs in several
      locations of this study were comparable with the reported values from some
      developed countries and highest among Asian developing nations. Considerable
      concentration of BTs in several locations might have ecotoxicological
      consequences and may cause concern to human health. The parent compound TBT was
      found to be highest than those of its degradation compounds, DBT and MBT,
      suggesting recent input of TBT to the Malaysian marine environment. Significant
      positive correlation (Spearman rank correlation: r2=0.82, P<0.0001) was found
      between BTs and SigmaSn, implying considerable anthropogenic input of butyltin
      compounds to total tin contamination levels. Enormous boating activities may be a
      major source of BTs in this country, although aquaculture activities may not be
      ignored.

PMID- 15182969
TI  - The influence of season and leaf age on concentrations of radiocaesium (137Cs),
      stable caesium (133Cs) and potassium in Agrostis capillaris.
AB  - The transfer of radioactive caesium from soils to plants has been well
      researched. In contrast there is limited knowledge on natural stable 133Cs and
      its potential role as a predictor for radiocaesium behaviour. In a pot experiment
      with Agrostis capillaris close correlations were found between plant 137Cs and
      plant 133Cs concentrations (R2 90-96%). Season and leaf age had significant
      effects with concentrations increasing 10-30-fold between June and December.
      Simultaneously the plant concentrations of K, the nutrient analogue of Cs,
      decreased to around one third. In the soil the exchangeable fractions of K and
      137Cs declined. No clear relationships were found between 137+133Cs in the plant
      and exchangeable K in the soil. However, at the end of the experiment the K
      content of the above-ground biomass was higher than the exchangeable pool in the
      soil, suggesting that depletion of soil K could be a key factor in the observed
      increase of plant 137+133Cs over time.

PMID- 15182970
TI  - Haloacetic acids in the aquatic environment. Part I: macrophyte toxicity.
AB  - Haloacetic acids (HAAs) are contaminants of aquatic ecosystems with numerous
      sources, both anthropogenic and natural. The toxicity of HAAs to aquatic plants
      is generally uncharacterized. Laboratory tests were conducted with three
      macrophytes (Lemna gibba, Myriophyllum sibiricum and Myriophyllum spicatum) to
      assess the toxicity of five HAAs. Myriophyllum spp. has been proposed as required
      test species for pesticide registration in North America, but few studies have
      been conducted under standard test conditions. The HAAs in the present
      experiments were monochloroacetic acid (MCA), dichloroacetic acid (DCA),
      trichloroacetic acid (TCA), trifluoroacetic acid (TFA) and chlorodifluoroacetic
      acid (CDFA). MCA was the most toxic to Myriophyllum spp. with EC50 values ranging
      from 8 to 12.4 mg/l depending on the endpoint, followed by DCA (EC50 range 62
      722.5 mg/l), TCA (EC50 range 49.5-1702.6 mg/l), CDFA (EC50 range 105.3 to >10,000
      mg/l) and with TFA (EC50 range 222.1 to 10,000 mg/l) the least toxic. Generally,
      L. gibba was less sensitive to HAA toxicity than Myriophyllum spp., with the
      difference in toxicity between them approximately threefold. The range of
      toxicity within Myriophyllum spp. was normally less than twofold. Statistically,
      plant length and node number were the most sensitive endpoints as they had the
      lowest observed coefficients of variation, but they were not the most sensitive
      to HAA toxicity. Toxicological sensitivity of endpoints varied depending on the
      measure of effect chosen and the HAA, with morphological endpoints usually an
      order of magnitude more sensitive than pigments for all plant species. Overall,
      mass and root measures tended to be the most sensitive indicators of HAA
      toxicity. The data from this paper were subsequently used in an ecological risk
      assessment for HAAs and aquatic plants. The assessment found HAAs to be of low
      risk to aquatic macrophytes and the results are described in the second
      manuscript of this series.

PMID- 15182971
TI  - Haloacetic acids in the aquatic environment. Part II: ecological risk assessment.
AB  - Haloacetic acids (HAAs) are environmental contaminants found in aquatic
      ecosystems throughout the world as a result of both anthropogenic and natural
      production. The ecological risk posed by these compounds to organisms in
      freshwater environments, with a specific focus on aquatic macrophytes, was
      characterized. The plants evaluated were Lemna gibba, Myriophyllum spicatum and
      M. sibiricum and the HAAs screened were monochloroacetic acid (MCA),
      dichloroacetic acid (DCA), trichloroacetic acid (TCA), trifluoroacetic acid (TFA)
      and chlorodifluoroacetic acid (CDFA). Laboratory toxicity data formed the basis
      of the risk assessment, but field studies were also utilized. The estimated risk
      was calculated using hazard quotients (HQ), as well as effect measure
      distributions (EMD) in a modified probabilistic ecological risk assessment. EMDs
      were used to estimate HAA thresholds of toxicity for use in HQ assessments. This
      threshold was found to be a more sensitive measure of low toxicity than the no
      observed effect concentrations (NOEC) or the effective concentration (EC10).
      Using both deterministic and probabilistic methods, it was found that HAAs do not
      pose a significant risk to freshwater macrophytes at current environmental
      concentrations in Canada, Europe or Africa for both single compound and mixture
      exposures. Still, HAAs are generally found as mixtures and their potential
      interactions are not fully understood, rendering this phase of the assessment
      uncertain and justifying further effects characterization. TCA in some
      environments poses a slight risk to phytoplankton and future concentrations of
      TFA and CDFA are likely to increase due to their recalcitrant nature, warranting
      continued environmental surveillance of HAAs.

PMID- 15182972
TI  - Comparing aquatic risk assessment methods for the photosynthesis-inhibiting
      herbicides metribuzin and metamitron.
AB  - Three different risk assessment procedures are described that aim to protect
      freshwater habitats from risks of the photosynthesis-inhibiting herbicides
      metribuzin and metamitron. These procedures are (1) the first-tier approach,
      based on standard toxicity tests and the application of an assessment factor, (2)
      the Species Sensitivity Distribution (SSD) approach, based on laboratory tests
      with a wider array of species and the application of a statistical model to
      calculate the HCx (the Hazardous Concentration for x% of the species), and (3)
      the model ecosystem approach, based on the evaluation of treatment-related
      effects in field enclosures. A comparison of the risk assessment procedures
      reveals that the first-tier approach is the most conservative for metamitron and
      metribuzin, and that HC5 values (and even HC10 values) based on acute EC50 values
      of algae and aquatic vascular plants may be used to derive maximum permissible
      concentrations for single applications. For both compounds these HC5 values were
      very similar to the ecological threshold concentrations in the enclosure studies.
      In contrast to model ecosystem experiments, however, HCx values based on lab
      toxicity tests do not provide information on the recovery potential of sensitive
      endpoints and on indirect effects, which may be important for regulatory decision
      making. In the enclosure study, indirect effects of metribuzin on invertebrate
      populations were observed at an exposure concentration that was approximately 20
      times lower than the corresponding HC5 value based on lab toxicity data for
      aquatic invertebrates.

PMID- 15182973
TI  - Arbuscular mycorrhizal fungi can decrease the uptake of uranium by subterranean
      clover grown at high levels of uranium in soil.
AB  - Subterranean clover inoculated or not with the arbuscular mycorrhizal (AM) fungus
      Glomus intraradices was grown on soil containing six levels of 238U in the range
      0-87 mg kg(-1). Increasing U concentration in soil enhanced the U concentration
      in roots and shoots of both mycorrhizal and nonmycorrhizal plants but had no
      significant effects on plant dry matter production or root AM colonization.
      Mycorrhizas increased the shoot dry matter and P concentration in roots and
      shoots, while in most cases, it decreased the Ca, Mg and K concentrations in
      plants. The AM fungus influenced U concentration in plants only in the treatment
      receiving 87 mg U kg(-1) soil. In this case, U concentration in shoots of
      nonmycorrhizal plants was 1.7 times that of shoots of mycorrhizal plants. These
      results suggested that mycorrhizal fungi can limit U accumulation by plants
      exposed to high levels of U in soil.

PMID- 15182974
TI  - Degradation of toxaphene in water during anaerobic and aerobic conditions.
AB  - The degradation of technical toxaphene in water with two kinds of bioreactors
      operating in sequence was studied. One packed bed reactor was filled with Poraver
      (foam glass particles) running at anaerobic conditions and one suspended carrier
      biofilm reactor working aerobically. Chemical oxygen demand (COD), chloride,
      sulphate, pH, dissolved oxygen, total toxaphene and specific toxaphene isomers
      were measured. After 6 weeks approx. 87% of the total toxaphene was degraded
      reaching 98% by week 39. The majority of the conversion took place in the
      anaerobic reactor. The concentrations of toxaphene isomers with more chlorine
      substituents decreased more rapidly than for isomers with less chlorine
      substituents.

PMID- 15182975
TI  - Atmospheric lead deposition to Okefenokee Swamp, Georgia, USA.
AB  - Contamination of the environment from atmospheric deposition during the twentieth
      century is pervasive even in areas ostensibly considered pristine or remote from
      point sources. In this study, Pb concentrations in a 210Pb-dated peat core
      collected from the Okefenokee Swamp, GA were used to assess historical
      contaminant input via atmospheric deposition. Lead isotope ratios were determined
      by dynamic reaction cell ICP-MS (DRC-ICP-MS). Increases in Pb concentration
      occurred in the late nineteenth century and a marked rise in Pb concentrations
      pre-dated the widespread use of leaded gasoline within the US. The 206Pb/207Pb
      ratios of 1.19 during this period were consistent with coal combustion emissions.
      A later increase in Pb concentration, concurrent with a trend toward more
      radiogenic 206Pb/207Pb ratios in gasoline is consistent with an increased input
      of Pb from leaded gasoline emissions. However, it appears that coal combustion
      emissions remain a major source of Pb to the Okefenokee.

PMID- 15182976
TI  - Responses of three grass species to creosote during phytoremediation.
AB  - Phytoremediation of creosote-contaminated soil was monitored in the presence of
      Tall fescue, Kentucky blue grass, or Wild rye. For all three grass species, plant
      growth promoting rhizobacteria (PGPR) were evaluated for plant growth promotion
      and protection of plants from contaminant toxicity. A number of parameters were
      monitored including plant tissue water content, root growth, plant chlorophyll
      content and the chlorophyll a/b ratio. The observed physiological data indicate
      that some plants mitigated the toxic effects of contaminants. In addition, in
      agreement with our previous experiments reported in the accompanying paper
      (Huang, X.-D., El-Alawi, Y., Penrose, D.M., Glick, B.R., Greenberg, B.M., 2004. A
      multi-process phytoremediation system for removal of polycyclic aromatic
      hydrocarbons from contaminated soil. Environ. Poll. doi:
      10.1016/j.envpol.2003.09.031), PGPR were able to greatly enhance
      phytoremediation. PGPR accelerated plant growth, especially roots, in heavily
      contaminated soils, diminishing the toxic effects of contaminants to plants.
      Thus, the increased root biomass in PGPR-treated plants led to more effective
      remediation.

PMID- 15182977
TI  - A multi-process phytoremediation system for removal of polycyclic aromatic
      hydrocarbons from contaminated soils.
AB  - To improve phytoremediation processes, multiple techniques that comprise
      different aspects of contaminant removal from soils have been combined. Using
      creosote as a test contaminant, a multi-process phytoremediation system composed
      of physical (volatilization), photochemical (photooxidation) and microbial
      remediation, and phytoremediation (plant-assisted remediation) processes was
      developed. The techniques applied to realize these processes were land-farming
      (aeration and light exposure), introduction of contaminant degrading bacteria,
      plant growth promoting rhizobacteria (PGPR), and plant growth of contaminant
      tolerant tall fescue (Festuca arundinacea). Over a 4-month period, the average
      efficiency of removal of 16 priority PAHs by the multi-process remediation system
      was twice that of land-farming, 50% more than bioremediation alone, and 45% more
      than phytoremediation by itself. Importantly, the multi-process system was
      capable of removing most of the highly hydrophobic, soil-bound PAHs from soil.
      The key elements for successful phytoremediation were the use of plant species
      that have the ability to proliferate in the presence of high levels of
      contaminants and strains of PGPR that increase plant tolerance to contaminants
      and accelerate plant growth in heavily contaminated soils. The synergistic use of
      these approaches resulted in rapid and massive biomass accumulation of plant
      tissue in contaminated soil, putatively providing more active metabolic
      processes, leading to more rapid and more complete removal of PAHs.

PMID- 15182978
TI  - Strain and force transducers used in human and veterinary tendon and ligament
      biomechanical studies.
AB  - Biomechanical studies often aim at determining the contribution (in terms of load
      or strain) of a tendon or ligament in posture, gesture or locomotion. To this
      end, many transducers have been developed since 30 years. These devices implanted
      within or attached to the inside of the tendon or ligament must be compliant
      enough to measure in vivo the tissue load or strain without interfering with the
      movement of man or animals. They can be transducers with variation of electrical
      resistance (liquid metal strain gauge, buckle transducer, implantable force
      transducer and pressure transducer), variation of magnetic field (Hall effect
      transducer) and variation of light flow (optic fibre). Their use requires surgery
      in order to implant them and it is limited in time because of their invasive
      character and the development of fibrous healing reactions. Besides, the
      transducer dimensions and its position in the tendon can influence the transducer
      output signal. Moreover, the latter may not reflect the behaviour of the tendon
      as a whole but only locally. In addition, a calibration is required in order to
      convert the output signal into a strain or a force. In animals, this calibration
      is generally made by a post-mortem procedure on dissected anatomical specimens;
      in man, an indirect calibration procedure using inverse dynamic calculations is
      generally performed. However, the calibration conditions cannot reproduce exactly
      the in vivo conditions. So far, only invasive transducers have allowed to measure
      strain or force in tendons with all constraints and limits mentioned above.

PMID- 15182979
TI  - The mechanical effects of intervertebral disc lesions.
AB  - OBJECTIVE: To determine the mechanical effect of individual concentric tears,
      radial tears and rim lesions of the intervertebral disc anulus. DESIGN: In vitro
      dynamic mechanical testing of sheep discs comparing the mechanical behaviour
      before and after lesion creation. BACKGROUND: Structural changes to the disc in
      the form of anular lesions are a feature of disc degeneration and degeneration
      has been related to changes in the mechanical function of the disc. However, the
      effect of individual lesions is unknown. METHODS: Fifteen ovine, lumbar disc body
      units were tested in flexion/extension, lateral bending and axial rotation.
      Concentric tears, radial tears and rim lesions were experimentally introduced and
      the motions repeated. The mechanical response after lesion creation was compared
      to the undamaged response. RESULTS: It was found that an anterior rim lesion
      reduced the peak resistive moment produced by the disc in extension, lateral
      bending and axial rotation. Concentric tears and radial tears did not affect the
      peak resistive moment, however, radial tears reduced the hysteresis of response
      in flexion/extension and lateral bending. The neutral zone was not affected by
      the presence of disc lesions. CONCLUSIONS: These results show that rim lesions
      reduce the disc's ability to resist motion. Radial tears change the hysteresis of
      response indicating an altered stress distribution in the disc. RELEVANCE: These
      changes may lead to overloading of the spinal ligaments, muscles and
      zygapophysial joints, possibly damaging these structures. This suggests a
      mechanism for a cycle of degeneration that is instigated by small changes in the
      mechanical integrity of the intervertebral disc.

PMID- 15182980
TI  - Altered patterns of pelvic bone motion determined in subjects with posterior
      pelvic pain using skin markers.
AB  - OBJECTIVE: To determine whether the pattern of pelvic bone motion, determined by
      skin markers, differs between control subjects and subjects with posterior pelvic
      pain. DESIGN: Cross-sectional study of three-dimensional angular and
      translational motion of the innominates relative to the sacrum in two subject
      groups. BACKGROUND: Comparative in vivo analysis of the 3D patterning of pelvic
      motion in subjects with posterior pelvic pain and controls is limited. METHODS:
      Fourteen males with posterior pelvic pain and healthy age and height matched
      controls were studied. A 6-camera motion analysis system was used to determine 3D
      angular and translational motion of pelvic skin markers during standing hip
      flexion. RESULTS: Posterior rotation of the innominate occurred with hip flexion
      in control subjects and pelvic pain subjects as previously reported in the
      literature. On the supporting leg, the innominate rotated posteriorly in controls
      and anteriorly in symptomatic subjects. CONCLUSION: Posterior rotation of the
      innominate, as measured using skin markers during weight bearing in controls may
      reflect activation of optimal lumbo-pelvic stabilisation strategies for load
      transfer. Anterior rotation occurred in symptomatic subjects, suggesting failure
      to stabilise intra-pelvic motion for load transfer. RELEVANCE: This study found
      that posterior rotation of the innominate occurred during weight bearing in
      controls. This movement pattern is thought to optimise stability of the pelvic
      girdle during increased loading. Conversely, anterior rotation occurred in
      symptomatic subjects during weight bearing. This is a non-optimal pattern and may
      indicate abnormal articular or neuromyofascial function during increased vertical
      loading through the pelvis.

PMID- 15182982
TI  - Effects of neck extensor muscles fatigue on balance.
AB  - OBJECTIVE: Measure the effects of cervical extensor muscle isometric contraction
      on cervical surface electromyographic spectral shift and balance in healthy
      subjects. DESIGN: Experimental within-subject design. BACKGROUND: Postural
      instability can be induced by mechanically stimulating cervical muscle spindles.
      Postural changes are also observed in individuals who suffer from chronic neck
      pain or whiplash injury. Furthermore these subjects appear to experience neck
      musculature fatigue more quickly, which in turn not only affects the neck
      function but also seems to affect the balance in a standing posture. METHODS:
      Using a force platform, balance was measured, in 10 blindfolded college students
      before and after isometric voluntary contraction in neck extension at 5% and 25%
      maximum voluntary isometric contraction for a period of 5, 10 and 15 min. Paired
      posturographic data were analysed for differences. Control measurements were
      performed on the same subjects by measuring balance before and after subjects
      sitting quietly for 5, 10 and 15 min without performing isometric contraction.
      RESULTS: The results indicate that a 25% maximal isometric contraction of the
      neck extensors for 10 and 15 min duration produced significant changes in some
      posturographic parameters in young healthy males. Furthermore, this contraction
      also produced a significant cervical muscle electromyography median frequency
      spectrum shift of the lower frequencies. CONCLUSIONS: Balance was affected by 15
      min of 25% maximal isometric contraction of the extensor cervical muscles.
      Posturographic parameters affected are similar to parameters observed in subjects
      that have suffered a whiplash injury. RELEVANCE: This study contributes to our
      understanding of functional aspects of cervical muscle fatigue. The similarity of
      results with other studies performed on subjects suffering from chronic neck pain
      and from whiplash injuries may suggest a similar cause for loss of postural
      control. Ultimately, this may help us in developing objective evaluation
      procedures for subjects suffering from neck complaints.

PMID- 15182981
TI  - Differences in normal and perturbed walking kinematics between male and female
      athletes.
AB  - OBJECTIVE: To identify differences in lower extremity kinematic movement patterns
      between genders during walking through the application of an expected
      perturbation. DESIGN: Randomized limb kinematics were compared between healthy
      active males and females. BACKGROUND: Lower extremity kinematics during jump
      landing and cutting have been implicated as a potential source of the discrepancy
      in anterior cruciate ligament injury rates between genders. Kinematic differences
      between genders have been identified during tasks that are not provocative of
      anterior cruciate ligament injury but do result in increased ligament strain.
      Repetition of movement patterns that increase anterior cruciate ligament strain
      may increase the likelihood they will be reproduced during athletic tasks that
      produce force loads that exceed anterior cruciate ligament tensile strength.
      METHODS: Twenty subjects (10 women, 10 men) classified as a level I or II athlete
      underwent motion analyses while performing self-paced walking trials. Five trials
      were undisturbed, and five each with a platform translating either laterally or
      anteriorly at heel contact. Sagittal, frontal, and transverse hip angles as well
      as sagittal and frontal knee angles were collected during stance. RESULTS:
      Excursions in the frontal and transverse planes were greater at the hip and knee
      for females compared to males in each walking condition. The rate of these
      excursions also occurred more rapidly for females than males. There was no
      difference for joint angles at initial contact between genders, and there was no
      difference in the amount of sagittal plane excursion for the hip and knee when
      comparing genders. CONCLUSIONS: Females demonstrate characteristics during both
      normal and perturbed gait that may potentially contribute to increased anterior
      cruciate ligament strain. Repetition of these potentially harmful movement
      patterns during provocative athletic maneuvers may lead to anterior cruciate
      ligament injury. RELEVANCE: Females exhibit lower extremity kinematic patterns
      that differ from males. Female kinematic patterns may contribute to an increased
      risk for anterior cruciate ligament injury.

PMID- 15182983
TI  - Gait coordination in pregnancy: transverse pelvic and thoracic rotations and
      their relative phase.
AB  - OBJECTIVE: To examine the effects of pregnancy on the coordination of transverse
      pelvic and thoracic rotations during gait. DESIGN: Gait of healthy pregnant women
      and nulligravidae was studied during treadmill walking at predetermined
      velocities ranging from 0.17 to 1.72 m/s. BACKGROUND: pelvis-thorax coordination
      during walking is altered in women with postpartum pregnancy-related pelvic
      girdle pain. This coordination has not been investigated in a healthy pregnant
      population. METHODS: Comfortable walking velocity was established. Amplitudes of
      pelvic and thoracic rotations were calculated. Their coordination was
      characterized by relative Fourier phase and its standard deviation. RESULTS:
      Comfortable walking velocity was significantly reduced. The amplitudes of pelvic
      and thoracic rotations were somewhat reduced, with significantly smaller intra
      individual standard deviations. Also pelvis-thorax relative Fourier phase was
      somewhat smaller, its intra-individual standard deviation was negatively
      correlated with week of pregnancy, and significantly lower at velocities > or =
      1.06 m/s. CONCLUSIONS: The general pattern of gait kinematics in pregnant women
      is very similar to that of nulligravidae. Still, it appears that pregnant women
      experience difficulties in realizing the more anti-phase pelvis-thorax
      coordination that is required at higher walking velocities. RELEVANCE: The
      present study shows that gait in healthy pregnancy is remarkably normal, but some
      differences in pelvis-thorax coordination were detected. In healthy pregnancy,
      anti-phase pelvis-thorax coordination appears difficult, but less so than in
      pregnancy-related pelvic girdle pain. Better understanding of gait in healthy
      pregnancy may provide insight into the gait problems of women with pregnancy
      related pelvic girdle pain.

PMID- 15182984
TI  - Knee joint moments during stair climbing of patients with anterior cruciate
      ligament deficiency.
AB  - OBJECTIVE: To establish the gait adaptations of patients with anterior cruciate
      ligament deficiency during stair ascent. DESIGN: Joint kinematics and kinetics
      during stair climbing were measured in both knees of normal subjects and
      unilateral anterior cruciate ligament deficient patients. BACKGROUND: As there is
      limited research pertaining to activities other than level walking, the purpose
      of the current study was to elucidate the gait of patients with anterior cruciate
      ligament deficiency during stair climbing to determine the effects of the
      deficiency on knee joint motion and moments as compared with normal knee
      function. METHODS: A motion analysis system was used to measure and calculate
      kinematic and kinetic data for six normal subjects and nine patients with
      unilateral anterior cruciate ligament deficiency during stair ascent on a
      specially constructed staircase. Left and right leg data were analysed to reveal
      between-limb differences for each subject. RESULTS: Patients with anterior
      cruciate ligament deficiency displayed a significant (P < 0.05) reduction of up
      to 50% in peak knee flexion moments in their involved knee. In the present study
      where a step height of 15.5 cm was used, peak flexion moments in all subjects'
      limbs occurred at knee flexion angles of about 40 degrees during single limb
      support. CONCLUSION: The current study showed that most patients with an anterior
      cruciate deficient knee adapted their gait during stair ascent. RELEVANCE: As
      stair climbing is a common activity, its effect on gait is relevant to better
      understand appropriate treatment and management strategies of patients with
      anterior cruciate ligament deficient knees.

PMID- 15182985
TI  - How postural behaviour in undisturbed upright stance can be used to assess the
      physical characteristics of various models of ankle orthoses.
AB  - OBJECTIVES: To assess various ankle orthoses presenting different physical
      characteristics. DESIGN: The postural performance in bi-pedal stance of 14
      healthy adults was assessed during four different ankle orthoses conditions.
      BACKGROUND: Resultant ankle stiffness is an important component in undisturbed
      upright postural regulation. METHODS: The centre of pressure displacements issued
      from the force platform were used to compute the horizontal motions of the centre
      of gravity, the controlled variable, and those of the difference between the
      centre of pressure and the vertical projection of the centre of gravity from
      which ankle stiffness can be estimated. Their respective contribution was
      assessed through a frequency analysis and a fractional Brownian motion modelling
      to determine their spatio-temporal linkage and their degree of control. RESULTS:
      Ligacast, the more rigid model, induces the larger decrease, principally in the
      medio-lateral direction, in both centre of pressure minus centre of gravity and
      centre of gravity amplitudes. Dynastab reduces only the centre of pressure minus
      centre of gravity motions in both medio-lateral and antero-posterior directions.
      Lastly, no specific effect was observed for the less rigid Ligaflex for each
      motion and each direction. These effects are mainly explained by a reduction in
      the distance covered until the corrective process is initiated, the corresponding
      time interval being unchanged. In addition, depending on the model, the
      corrective processes appear more or less controlled. CONCLUSIONS: Modulating the
      ankle joint stiffness by using various models of orthoses induces some contrasted
      behaviours, hence suggesting that postural control does not result solely from
      resultant ankle stiffness. RELEVANCE: This data, contributing to the
      understanding of orthotic devices by emphasising their benefits, allows the
      practitioners and physical therapists to take into account the specific effects
      generated by each model.

PMID- 15182986
TI  - Femoroplasty-augmentation of mechanical properties in the osteoporotic proximal
      femur: a biomechanical investigation of PMMA reinforcement in cadaver bones.
AB  - OBJECTIVE: To determine the feasibility of polymethyl-methacrylate injection into
      the osteoporotic proximal femur and its effect on the mechanical properties.
      DESIGN: In vitro pairwise comparison of non reinforced and reinforced bones in a
      load to failure loading mode. BACKGROUND: Hip fractures represent an important
      public healthcare problem. Continued growth in the elderly population will raise
      the incidence of hip fractures and their associated costs dramatically in the
      near future. METHODS: Twenty pairs of osteoporotic femurs were mechanically
      tested either in a single-limb stance configuration or simulating a fall on the
      greater trochanter. From each pair, one femur was augmented with bone cement,
      with the contralateral femur serving as a control. The surface temperature at the
      femoral neck was recorded until twenty minutes after injection. The fracture load
      and the energy absorption were calculated. The Wilcoxon signed rank test was used
      to test for differences in fracture load and energy absorption between the
      reinforced femurs and the native controls. RESULTS: Volumes of 28-41 ml of cement
      (mean, 36 ml) could be injected. The increase of surface temperature at the
      femoral neck ranged from delta18.4 to delta29.8 degrees C. For the single limb
      stance configurations, the peak fracture load was increased by 21%, (P < 0.002)
      and for the simulated fall on the hip by 82%, (P < 0.002). The corresponding
      values for energy absorption were +48%; and +188% (P < 0.002) respectively.
      CONCLUSIONS: The feasibility and mechanical effectiveness of the in vitro
      procedure could be demonstrated. The heat generation due to polymethyl
      methacrylate polymerisation is high. RELEVANCE: Prophylactic reinforcement of the
      femur could become a treatment option to solve the problems with osteoporotic hip
      fractures in patients at risk. Reinforcement materials with less exothermic
      reaction need to be evaluated further and also the feasibility of fracture repair
      after reinforcement.

PMID- 15182987
TI  - Geometric and material nonlinearity in tensioned wires of an external fixator.
AB  - OBJECTIVE: To investigate the fundamental characteristics of a tensioned wire in
      an external fixator. DESIGN: Many factors that may influence the wire performance
      including the change in wire geometry, material hardening and yielding, loading
      and unloading, and levels of pre-tension are considered in order to obtain a
      whole spectrum of the wire characteristics. BACKGROUND: External fixation is
      widely used in the treatment of unstable fractures, limb lengthening, and
      congenital and pathological orthopedic deformities. With the use of tensioned
      wires, external fixation provides attractive features such as minimal
      invasiveness, maximum tailorability, and versatility. These seemingly simple
      wires actually fulfill a very complex duty. To be able to maximize the benefit of
      these wires, it is necessary to know their fundamental characteristics. METHODS:
      A single wire was isolated from an external Ilizarov ring-frame, and nonlinear
      elastic and plastic analyses of the wire were performed using the method of
      finite element analysis. RESULTS: The nonlinear behavior of the wire originates
      not only from the material hardening and yielding but also from the change in its
      geometry. Pre-tension reduces wire deflection, delays the onset of full-plastic
      deformation, and elevates the limiting plastic moment, but at the same time leads
      to early material hardening and yielding. CONCLUSIONS: An entire load-deflection
      curve is necessary when comes to describe the wire performance. To enhance the
      wire performance, further efforts should be directed to exploiting the benefit of
      geometric nonlinearity of the wire. RELEVANCE: The findings will lead to
      refinement of external fixation design and provide engineering information to
      surgeons regarding the application of pre-tension during surgery.

PMID- 15182988
TI  - Intramedullary nails with two lag screws.
AB  - OBJECTIVE: To investigate the structural integrity of intramedullary nails with
      two lag screws, and to give guidance to orthopaedic surgeons in the choice of
      appropriate devices. DESIGN: Alternative designs of the construct are considered,
      and the use of a slotted upper lag screw insertion hole is analysed. BACKGROUND:
      Intramedullary fixation devices with a single lag screw have been known to fail
      at the lag screw insertion hole. Using two lag screws is considered. It has also
      been proposed to use a slot in the nail for the upper lag screw to prevent the
      upper lag screw from sticking. METHODS: Bending and torsion load cases are
      analysed using finite element method. Consideration of both load conditions is
      essential. RESULTS: The results present the overall stiffness of the assembly,
      the load sharing between lag screws, and the possibility for cut-out to occur.
      CONCLUSIONS: While the slot for the upper lag screw might be advantageous with
      regard to the stresses in the lag screws, it could be detrimental for cut-out
      occurring adjacent to the lag screws. RELEVANCE: Comparative analyses demonstrate
      that two lag screws may be advantageous in patients whose cancellous bone quality
      is good and who impose large loads on the lag screw/nail interface. However, the
      use of two screws might pre-dispose to failure by cut-out of the lag screws. The
      addition of a slotted hole for the upper lag screw appears to do nothing
      significant to reduce the risk of such a failure.

PMID- 15182989
TI  - Biomechanical strength of deep-frozen versus lyophilized large cortical
      allografts.
AB  - OBJECTIVE: To compare biomechanical strength of deep-frozen versus lyophilized
      large cortical allografts. DESIGN: In vivo transplantation studies performed in
      tibia of adult cats using 4 cm deep-frozen and lyophilized, gamma-irradiated
      allografts to bridge large cortical defect model. BACKGROUND: Bridging large
      cortical bone defect is a challenging problem. Options include autografts,
      allografts, bioceramics and prostheses. Allografts provide a suitable option.
      METHODS: Forty mature cats were used. A large defect (4 cm) was created in mid
      diaphysis of right tibia. In 16 cats, cortical defect was reconstructed using
      deep-frozen allografts (-80 degrees C) with intra-medullary rodding. In another
      16 cats, lyophilized, gamma-irradiated allografts were used. Observation periods
      include 8, 12, 16 and 24 weeks. The specimens were procured together with
      unoperated legs as controls. Mechanical testing was performed using a materials
      testing machine with torsion test device of up to 500 Nm at speed of 0.18 rpm.
      Parameters studied included maximum torque, torsional stiffness and energy of
      absorption. RESULTS: Deep-frozen allografts did not reach 100% strength,
      achieving only 64% at 6 months. In marked contrast, lyophilized allografts were
      significantly weaker with only 12% maximum torque strength at 6 months.
      Lyophilized allografts were significantly weaker than deep-frozen allografts in
      all observation periods (p < 0.05). CONCLUSION: Deep-frozen allografts did not
      reach 100% normal strength and were significantly weaker than non-vascularised
      autografts. Lyophilized allografts were significantly weaker than deep-frozen
      allografts. RELEVANCE: For the reconstruction of massive cortical bone defects,
      only deep-frozen cortical allografts should be used. Lyophilized allografts are
      not suitable.

PMID- 15182990
TI  - Consolidation responses of delipidized articular cartilage.
AB  - OBJECTIVE: To determine the role of articular cartilage lipids in its load
      bearing function. DESIGN: Normal and delipidised, bovine articular cartilage
      specimens were statically loaded and both the hydrostatic excess pore pressure
      and creep strain were measured. From this the compression stiffness of the
      skeletal structures of both types of matrices was determined. BACKGROUND: It has
      been hypothesized that surfactant injection could relief osteoarthritis, but
      there is no study in the literature relating to the influence of lipids, the main
      ingredients of such products, on cartilage load-carriage. METHODS: Articular
      cartilage specimens were obtained from the patellar grooves of 2-3 year old
      bovine animals. When required specimen delipidization was carried out using
      chloroform/methanol rinsing. Both normal and delipidised samples were loaded in
      the consolidometer and the hydrostatic excess pore pressure and strain were
      measured. RESULTS: The transient patterns of the hydrostatic excess pore pressure
      were similar for both types of tissue, with a relatively insignificant increase
      of 2% in the maximum hydrostatic excess pore pressure of the delipidized samples
      relative to the normal intact specimens. The maximum creep strain of the
      delipidised specimens decreased by 10% on average relative to their normal intact
      counterparts, thereby indicating that delipidization causes stiffening of the
      cartilage matrix. CONCLUSION: The delipidized fluid-saturated articular cartilage
      is stiffer than its intact counterpart with consequence for cartilage compliance
      during function. RELEVANCE: Because osteoarthritis can be accompanied by lipid
      loss in cartilage, this study contributes to the further understanding of the
      disease with potential benefit for treatment.

PMID- 15182991
TI  - Reliability of RT-PCR methods for measuring relative gene expression in mast
      cells.
AB  - Three methods to quantify gene transcript levels in mast cells, real-time RT-PCR,
      competitive RT-PCR and conventional RT-PCR analyses, were compared. Linear
      regression analysis on five gene transcripts revealed that the mRNA levels
      measured by real-time RT-PCR analysis were minimally correlated with those by
      conventional RT-PCR analysis. In addition, differences in the mRNA level between
      samples measured by conventional RT-PCR analysis were smaller than those by real
      time RT-PCR analysis, suggesting that conventional RT-PCR analysis is less
      sensitive at measuring mRNA levels. Results from competitive RT-PCR analysis
      correlated closely with those from real-time RT-PCR analysis. When the
      differences in mRNA level between samples are relatively smaller, however, the
      correlation tended to be weaker. Real-time RT-PCR analysis has higher
      reliability, but is expensive. In contrast, competitive RT-PCR analysis is
      inexpensive, but is weaker at detecting smaller differences in gene transcript
      level between samples. Therefore, the most appropriate analytical method to
      measure mRNA levels should be chosen, depending on the experimental conditions.

PMID- 15182993
TI  - Serum haemolytic complement activities in 11 different MHC (B) typed chicken
      lines.
AB  - To study the relation between serum complement levels and the chicken MHC (B)
      complex, complement haemolytic activity was measured in sera from hens from seven
      pure-bred B-typed White and one Brown Leghorn lines, and three ISA-Warren lines
      that had been divergently selected for antibody responses to sheep red blood
      cells (SRBC). Significant differences occurred in the serum haemolytic complement
      activities, both belonging to the classic (CPW) and the alternative (APW)
      pathways, among the 11 different haplotyped chicken lines. Hens with high CPW and
      high APW titres predominantly displayed the B2 or B21 haplotypes. Chickens with
      low CPW and APW were found in B14 and B15 haplotypes. Haplotype B14 appears to be
      different in complement levels when present into the pure-bred lines or into the
      ISA-Warren line selected for low antibody responses to SRBC. Otherwise, the
      presence of B21 in ISA-Warren line selected for high antibody responses to SRBC
      does not differ with the B21 in the inbred lines (except in the NL-line for CPW
      values). In general the haplotypes B2 and B21 are found in chicken lines with
      enhanced disease resistance, and the B15 haplotype has been connected with
      enhanced disease susceptibility. Our results suggest that levels of haemolytic
      complement activity, either from the classical or from the alternative pathways,
      may underlie part of the immunocompetence ascribed to the MHC (B) complex in
      chickens.

PMID- 15182992
TI  - Modulation by colostrum-acquired maternal antibodies of systemic and mucosal
      antibody responses to rotavirus in calves experimentally challenged with bovine
      rotavirus.
AB  - The effect of colostral maternal antibodies (Abs), acquired via colostrum, on
      passive protection and development of systemic and mucosal immune responses
      against rotavirus was evaluated in neonatal calves. Colostrum-deprived (CD)
      calves, or calves receiving one dose of pooled control colostrum (CC) or immune
      colostrum (IC), containing an IgG1 titer to bovine rotavirus (BRV) of 1:16,384 or
      1:262,144, respectively, were orally inoculated with 105.5 FFU of IND (P[5]G6)
      BRV at 2 days of age. Calves were monitored daily for diarrhea, virus shedding
      and anti-BRV Abs in feces by ELISA. Anti-rotavirus Ab titers in serum were
      evaluated weekly by isotype-specific ELISA and virus neutralization (VN). At 21
      days post-inoculation (dpi), all animals were euthanized and the number of anti
      BRV antibody secreting cells (ASC) in intestinal and systemic lymphoid tissues
      were evaluated by ELISPOT. After colostrum intake, IC calves had significantly
      higher IgG1 serum titers (GMT=28,526) than CC (GMT=1195) or CD calves (GMT<4).
      After BRV inoculation, all animals became infected with a mean duration of virus
      shedding between 6 and 10 days. However, IC calves had significantly fewer days
      of diarrhea (0.8 days) compared to CD and CC calves (11 and 7 days,
      respectively). In both groups receiving colostrum there was a delay in the onset
      of diarrhea and virus shedding associated with IgG1 in feces. In serum and feces,
      CD and CC calves had peak anti-BRV IgM titers at 7 dpi, but IgA and IgG1
      responses were significantly lower in CC calves. Antibody titers detected in
      serum and feces were associated with circulation of ASC of the same isotype in
      blood. The IC calves had only an IgM response in feces. At 21 dpi, anti-BRV ASC
      responses were observed in all analyzed tissues of the three groups, except bone
      marrow. The intestine was the main site of ASC response against BRV and highest
      IgA ASC numbers. There was an inverse relationship between passive IgG1 titers
      and magnitude of ASC responses, with fewer IgG1 ASC in CC calves and
      significantly lower ASC numbers of all isotypes in IC calves. Thus, passive anti
      BRV IgG1 negatively affects active immune responses in a dose-dependent manner.
      In ileal Peyer's patches, IgM ASC predominated in calves receiving colostrum;
      IgG1 ASC predominated in CD calves. The presence in IC calves of IgG1 in feces in
      the absence of an IgG1 ASC response is consistent with the transfer of serum IgG1
      back into the gut contributing to the protection of the intestinal mucosa.

PMID- 15182994
TI  - Hematologic and immunophenotypic factors associated with development of
      Rhodococcus equi pneumonia of foals at equine breeding farms with endemic
      infection.
AB  - Rhodococcus equi causes severe pyogranulomatous pneumonia in foals and in
      immunocompromised people. In mice, both CD4+ and CD8+ T lymphocytes contribute to
      host defense against R. equi, but CD4+ T lymphocytes are required for pulmonary
      clearance of the bacteria. In this prospective study of 208 foals at two equine
      breeding farms with endemic R. equi infections, we collected peripheral blood
      samples at 2 and 4 weeks of age and at the time of diagnosis of R. equi
      pneumonia. Samples were analyzed for concentrations of total and differential
      leukocytes, EqCD4+ and EqCD8+ T lymphocytes, and B lymphocytes. Thirty (14.4%)
      foals developed R. equi pneumonia. At the 2nd week of life, affected foals had
      significantly lower concentrations of white blood cells (WBC) and segmented
      neutrophils, significantly lower proportions of EqCD4+ T lymphocytes, and
      significantly higher proportions of EqCD8+ T lymphocytes. The EqCD4:EqCD8 ratio
      was significantly lower for affected foals. At the 4th week of life, affected
      foals had significantly lower concentrations of segmented neutrophils and EqCD4+
      T lymphocytes than did unaffected foals. The ratio of EqCD4:EqCD8 was
      significantly lower for affected foals. Two- and 4-week-old foals with ratios of
      EqCD4:EqCD8<3 were significantly more likely to develop R. equi pneumonia. There
      was a significant farm effect which diluted our statistical power to detect
      differences; however; after adjusting for the farm effect, 2-week-old foals with
      ratios of EqCD4:EqCD8<3 remained significantly more likely to develop R. equi
      pneumonia. There were no significant differences in immunophenotypic variables
      between affected foals (at the time of diagnosis) and age-matched control foals.
      These data suggest that there are hematologic and immunophenotypic differences
      between affected and unaffected foals during the first 2-4 weeks of life, prior
      to onset of clinical signs of R. equi pneumonia. These differences may represent
      important immunologic mechanisms associated with increased susceptibility of
      individual foals to infection with R. equi. Because there was considerable
      overlap between values for affected and unaffected foals, we cannot yet recommend
      immunophenotyping of foals at endemically-infected farms as a clinically useful
      screening tool to identify foals at increased risk of developing R. equi
      pneumonia.

PMID- 15182996
TI  - TB diagnosis in non-human primates: comparison of two interferon-gamma assays and
      the skin test for identification of Mycobacterium tuberculosis infection.
AB  - In general non-human primates are highly susceptible to infections with
      Mycobacterium tuberculosis which therefore presents an explosive health threat to
      colonies. To screen for M. tuberculosis infections in non-human primates, the
      skin test is routinely used. However, the reliability of this test in primates is
      debatable. The aim of this study was to compare relatively easy in vitro
      diagnostic tests for TB with the skin test for detection of a tuberculosis (TB)
      infection. Two in vitro assays, a whole blood interferon-gamma (WB IFN-gamma)
      assay and in vitro stimulation of isolated lymphocytes (PBMC IFN-gamma) were
      evaluated during both experimental TB infections in macaques as well as during an
      outbreak of TB in a macaque quarantine facility. The WB IFN-gamma assay was also
      evaluated on healthy old and new world monkeys. Our results show that both in
      vitro assays detected TB infection in macaques. All experimentally infected
      animals showed TB-specific responses in both assays. In contrast, several TB
      animals were not diagnosed TB positive using the skin test. In addition, during
      the outbreak in the quarantine facility one animal was not detected using the
      routinely used skin test, but it showed strong positive responses in the WB
      assay. In conclusion, the in vitro assays are a valuable tool for screening non
      human primates for TB infection, especially because the assays cause relatively
      less stress for the animals compared to the skin test and give reproducible and
      reliable results.

PMID- 15182995
TI  - Peptide mapping of feline immunodeficiency virus by IFN-gamma ELISPOT.
AB  - Interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) has become an
      important tool in studying antigen-specific T lymphocyte responses. Soluble
      peptides can be used to map T-cell epitopes, providing information that is useful
      in the design and evaluation of vaccines as well as studies of
      immunopathogenesis. To date, this assay has not been widely utilized in feline
      immunodeficiency virus (FIV) research. We have developed a feline IFN-gamma
      ELISPOT assay and used it to determine FIV-specific T-cell epitopes recognized by
      infected cats. A panel of 331 peptides, 15 amino acids in length and overlapping
      by 10 residues was synthesized. The peptide library spanned the FIV structural
      (Gag), envelope (Env), reverse transcriptase (RT), and open-reading-frame A
      (OrfA) proteins. Initially, 34 pools, containing 7-10 peptides each were screened
      by IFN-gamma ELISPOT against peripheral blood mononuclear cells (PBMC) from eight
      cats chronically infected with the NCSU(1) molecular clone of FIV and four
      uninfected control cats. Individual peptides from pools recognized by FIV+ cats
      were then evaluated and optimal peptides were combined into pools representing
      Gag, Env, RT, and OrfA. A higher percentage of FIV infected cats were identified
      as responders against the peptide pools when using fresh PBMC as compared to
      cryopreserved PBMC. In vitro restimulation of cryopreserved PBMC with the peptide
      pools improved the sensitivity of the assay to similar levels as observed from
      fresh samples. Individual peptides used in the pools were generally found to
      stimulate CD8+ T-cells more efficiently than CD4+ T-cells. Comparison of the
      peptide sequences to representative FIV sequences from clades A-D showed
      conservation was high among Gag and RT peptides, variable among Env peptides and
      low for OrfA peptides. The IFN-gamma ELISPOT assay and FIV-specific peptide pools
      we describe here will be useful in assessing cell-mediated responses to
      experimental FIV vaccines.

PMID- 15182997
TI  - Age-related differences in parameters of feline immune status.
AB  - In order to assess age-related differences in feline immune status, 101 domestic
      short haired cats were assigned to two groups, adult (2-5 years, n=50) and senior
      (10-14 years, n=51). Analyses of leucocyte populations, lymphocyte subsets,
      complement activity, serum immunoglobulins and acute-phase proteins were
      undertaken and revealed significant differences between the two groups. The
      senior group had significantly lower WBC, lymphocyte and eosinophil counts than
      the adult group. Neutrophil, monocyte and basophil counts did not differ between
      the groups. Flow cytometry analysis, in combination with differential WBC data,
      revealed that the absolute values (cells/l) of T-cells, B-cells and natural
      killer (NK) cells were significantly lower in the older animals. While serum
      immunoglobulins IgA and IgM were higher in the senior group when compared with
      the adult group, no significant differences were observed in complement activity
      or in serum acute-phase proteins. Our findings suggest that age-related changes
      to parameters of immune status in the feline model are likely to follow a similar
      pattern to those observed in other long-lived mammalian species.

PMID- 15182998
TI  - Effects of furazolidone pretreatment of Salmonella enteritidis PT4 at sub- and
      suprainhibitory concentrations on phagocytosis and intracellular survival in
      chicken macrophages.
AB  - The antimicrobial effect of the nitrofuran derivative furazolidone at sub- and
      suprainhibitory concentrations on Salmonella enteritidis PT4 and the influence
      with regard to interaction with avian macrophages was investigated in this study.
      Phagocytosis of furazolidone-sensitive (FzS) S. enteritidis with chicken
      macrophages in the presence of furazolidone at concentrations of 1/8, 1/4, 1/2
      and 8x MIC resulted in an increase in the rate of phagocytic killing of
      approximately 3-, 6-, 6.5- and 9-fold, respectively, with 1/2 and 8x MIC
      concentrations producing statistically significant (P<0.05) increases in
      phagocytosis. Treatment of the FzS Salmonella with furazolidone at concentrations
      of 4x and 10x MIC, for 15 min prior to phagocytosis, also significantly (P<0.005)
      increased phagocytic uptake when compared with untreated bacteria. The rate of
      phagocytosis monitored over 90 min was highest between 30 and 60 min with the
      furazolidone pretreated salmonella, compared with the delayed rate of the control
      between 60 and 90 min. Exposure of FzS and FzR strains with suprainhibitory
      concentrations of furazolidone at 4x, 8x and 10x MIC for 30 min prior to
      phagocytosis demonstrated an increase in bacterial killing. Exposure of strains
      to sub-inhibitory concentrations of furazolidone led to an increase in
      chemiluminescence during phagocytosis with macrophages, suggesting an increase in
      oxidative metabolism in the macrophages as a result of an increase in activation
      and phagocytosis. Pretreatment of the strains with suprainhibitory concentrations
      of furazolidone for 30 min prior to phagocytosis demonstrated a similar increase
      in oxidative metabolism in the macrophages. Measurement of the amount of 14C
      furazolidone associated with chicken macrophages was determined over 20 h
      incubation. The level of radioactivity of 14C-furazolidone alone was used to
      estimate the amount of cell-associated nitrofuran when incubated with the
      macrophages by means of regression analysis. Incubation with concentrations of
      16, 32 and 64 microg/ml for 20 h resulted in the cell association of >or=1
      microg/ml of furazolidone, which is the concentration required for the agent to
      exhibit bactericidal activity on furazolidone-sensitive Salmonella strains.
      Furazolidone was able to reduce intracellular salmonella viability at all
      concentrations, but total killing was achieved only with concentrations of >or=8
      microg/ml, which supports the results for furazolidone association with the
      macrophages. This substantiates that the bioactivity of the nitrofuran was not
      inhibited or diminished in the intracellular environment of the macrophage and
      that exposure of salmonella to nitrofurans enhances phagocytosis.

PMID- 15182999
TI  - Passage from India: the first European Veterinary Immunology Workshop.
AB  - The European Veterinary Immunology Group (EVIG) was founded under the auspices of
      the European Federation of Immunologic Societies (EFIS) in 2001, and held its
      first meeting in autumn 2003 in Berlin. Here, we summarize the short history of
      this group, report on the workshop in Berlin and outline some future perspectives
      up to the next meeting scheduled for 2006 in Paris.

PMID- 15183001
TI  - 20th International Neurotoxicology Conference: Emerging Issues in
      Neurotoxicology.

PMID- 15183000
TI  - Identification of key immune mediators regulating T helper 1 responses in swine.
AB  - This publication describes the cloning of full or partial length sequences for
      pig TBX21 (T-bet), MYD88, ICSBP1, CD8A (CD8alpha), CD8B (CD8beta), and CD28
      cDNAs. Real-time PCR assays have been developed for the relative quantitation of
      these products as well as previously characterized transcripts that encode exon A
      containing CD45, HLX1, IRF1, STAT1 and RPL32. When used for examining temporal
      immune gene expression in the liver of Toxoplasma gondii infected pigs, the
      positive regulators of Th1 responses, IRF1, MYD88, and STAT1, were found to be
      expressed prior to the simultaneous upregulation of interferon gamma (IFNG), HLX1
      and TBX21 gene expression. In contrast, in the mesenteric lymph node (MLN), only
      expression of IRF1 and IFNG was significantly upregulated. Based on their
      demonstrated utility in establishing an immune response pathway, these PCR assays
      should be valuable additions to our swine immune toolkit.

PMID- 15183002
TI  - Neuroimaging: strategies to illuminate environment-disease linkages. Session II.
      Summary and research needs.

PMID- 15183003
TI  - Emerging technologies in neurotoxicology: Session III summary and research needs.

PMID- 15183004
TI  - Testing for developmental neurotoxicity: Session VII-A summary and research
      needs.

PMID- 15183005
TI  - Neurotoxicants and synaptic function: Session VII-B summary and research needs.

PMID- 15183006
TI  - Consequences of exposure from persistent organic pollutants (POPs): Session X
      summary and research needs.

PMID- 15183007
TI  - Neuroimaging: new approaches for neurotoxicology.
AB  - Over the last 20 years, the impact of imaging on the clinical sciences is
      unquestionable. It has revolutionized the diagnosis and treatment of disease.
      Interestingly, the use of imaging in preclinical neurotoxicology has been
      relatively negligible. This has been in part due to the lack of knowledge or
      understanding of the capabilities of these powerful technologies. However, some
      of the more immediately applicable imaging approaches could impact the present
      approach to neurotoxicology. In addition, the recent advent of the development of
      imagers specifically for application to small animals will provide the
      opportunity of obtaining information for neurotoxicological risk assessment in a
      more timely and relevant manner. The ability to visualize changes in structure
      and function due to neurotoxic insult in a noninvasive manner is a promising
      direction. Changes in anatomy of soft and hard tissue, metabolism, function and
      gene expression can now be done in both a preclinical and a clinical setting
      using such technologies as magnetic resonance imaging (MRI), magnetic resonance
      imaging microscopy (MRM), and positron emission tomography (PET). This type of
      information is not readily accessible using conventional preclinical
      neurotoxicological procedures and usually requires total destruction of the
      intrinsic structure of the sample of interest. Imaging provides an opportunity to
      produce much of these data in a nondestructive manner and presents the data in a
      three-dimensional format. This permits longitudinal studies of the same subject
      subsequently reducing the number of animals required for studies while providing
      more information. In addition, as these technologies have been primarily
      developed for clinical purposes, they provide an outstanding opportunity for
      cross-species and animal-to-human extrapolation and testing.

PMID- 15183008
TI  - Introduction to PET imaging with emphasis on biomedical research.
AB  - Medical imaging is migrating from anatomic imaging to functional imaging and
      fused anatomic/functional imaging. The technology is being adapted for biomedical
      research using both clinical and small animal scanners. The ability to externally
      image real-time physiologic processes in both normal and deranged conditions,
      including various models to image gene expression, apoptosis, or drug
      biodistribution, has powerful impact on the exploration of biomedical and
      fundamental biological research. Positron emission tomography (PET) has a unique
      ability to not only provide such images but also to do so with high resolution
      (typically 1-2mm resolution for small animal scanners) and to provide both
      relative and absolute quantitation. This technology is revolutionizing biomedical
      and biological research. This article reviews the underlying principles involved
      in this technology, gives a brief history of its development, and then introduces
      the interested researcher to some of the important techniques that could be of
      use.

PMID- 15183009
TI  - Manganese-induced cytotoxicity in dopamine-producing cells.
AB  - Manganese (Mn) is an essential metal that, at excessive levels in the brain,
      produces extrapyramidal symptoms similar to those in patients with Parkinson's
      disease (PD). In the present study, Mn toxicity was characterized in a human
      neuroblastoma (SK-N-SH) cell line and in a mouse catecholaminergic (CATH.a) cell
      line. Mn was demonstrated to be more toxic in the catecholamine-producing CATH.a
      cells (EC50 = 60 microM) than in non-catecholaminergic SK-N-SH cells (EC50 = 200
      microM). To test the hypothesis that the sensitivity of CATH.a cells to Mn is
      associated with their dopamine (DA) content, DA concentrations were suppressed in
      these cells by pretreatment with alpha-methyl-para-tyrosine (AMPT). Treatment for
      24 h with 100 microM AMPT decreased intracellular DA, but offered no significant
      protection from Mn exposure (EC50 = 60 microM). Additional studies were carried
      out to assess if Mn toxicity was dependent on glutathione (GSH) levels. CATH.a
      cells were significantly protected by the addition of 5mM GSH (Mn EC50 = 200
      microM) and 10mM N-acetyl cysteine (NAC) (Mn EC50 = 300 microM), therefore,
      indirectly identifying intracellular ROS formation as a mechanism for Mn
      neurotoxicity. Finally, apoptotic markers of Mn-induced cell death were
      investigated. DNA fragmentation, caspase-3 activation, and apoptosis-related gene
      expression were studied in CATH.a cells. No internucleosomal fragmentation or
      caspase activation was evident, even in the presence of "supraphysiological" Mn
      concentrations. cDNA hydridization array analysis with two differing Mn
      concentrations and time points, identified no noteworthy mRNA inductions of genes
      associated with programmed cell death. In conclusion, DA content was not
      responsible for the enhanced sensitivity of CATH.a cells to Mn toxicity, but
      oxidative stress was implicated as a probable mechanism of cytotoxicity.

PMID- 15183010
TI  - Selective changes in gene expression in cortical regions sensitive to amphetamine
      during the neurodegenerative process.
AB  - Gene expression profiles in several brain regions of adult male rats were
      evaluated following a d-amphetamine (AMPH) exposure paradigm previously
      established to produce AMPH neurotoxicity. Escalating doses of AMPH (5-30 mg/kg)
      were given over the course of 16 h per day in an 18 degrees C environment for 2
      days. This paradigm produces neurotoxicity but eliminates or minimizes the
      hyperthermia and seizure activity that might influence gene expression in a
      manner unrelated to the neurotoxic effects of AMPH. The expression of 1185 genes
      was monitored in the striatum, parietal cortex, piriform cortex and
      posteriolateral cortical amygdaloid nucleus (PLCo) using cDNA array technology,
      and potentially significant changes were verified by RT-PCR. Gene expression was
      determined at time points after AMPH when neurodegeneration was beginning to
      appear (16 h) or maximal (64 h). Expression was also determined 14 days after
      AMPH to find long-term changes in gene expression that might be biomarkers of a
      neurotoxic event. In the parietal cortex there was a two-fold increase in
      neuropeptide Y precursor protein mRNA whereas nerve growth factor-induced
      receptor protein I-A and I-B mRNA decreased 50% at 16 h after the end of AMPH
      exposure. Although these changes in expression were not observed in the PLCo,
      insulin-like growth factor binding protein 1 mRNA was increased two-fold in the
      PLCo at 16 and 64 h after AMPH. Changes in gene expression in the cortical
      regions were all between 1.2- and 1.5-fold 14 days after AMPH but some of these
      changes, such as annexin V increases, may be relevant to neurotoxicity. Gene
      expression was not affected by more than 1.5-fold at the time points in the
      striatum, although 65% dopamine depletions occurred, but the plasma membrane
      associated dopamine transporter and dopamine D2 receptor were decreased about 40%
      in the substantia nigra at 64 h and 14 days post-AMPH. Thus, the 2-day AMPH
      treatment produced a few changes in gene expression in the two-fold range at time
      points 16 h or more after exposure but the majority of expression changes were
      less than 1.5-fold of control. Nonetheless, some of these lesser fold-changes
      appeared to be relevant to the neurotoxic process.

PMID- 15183011
TI  - Brain energy metabolism in a sub-acute rat model of manganese neurotoxicity: an
      ex vivo nuclear magnetic resonance study using [1-13C]glucose.
AB  - Ex vivo high-resolution NMR spectroscopy combined with in vivo injection of [1
      13C]glucose was applied to gain insight into the mechanism(s) leading to energy
      failure in manganese neurotoxicity. In rats treated for 4 days with 50mg/kg
      MnCl(2) (intraperitoneally, i.p.), the concentration of 13C-labeled lactate
      increased to 154% compared to control rats. Changes in the absolute amounts of
      lactate were much less, resulting in increased fractional 13C-enrichments in
      lactate (indicating relative changes of de novo synthesis from glucose via the
      glycolytic pathway) to 143% of control values (P < 0.001). Analysis of samples
      obtained from blood plasma and peripheral organs demonstrate a selective increase
      of lactate synthesis from [1-13C]glucose in the brain, which is released into the
      circulation. In parallel, manganese treatment resulted in stimulation of flux
      through pyruvate dehydrogenase (PDH), leading to accumulation of [4
      13C]glutamate, [4-13C]glutamine and [2-13C]GABA to 168, 247 and 144% of control,
      respectively. The relative flux of glucose through astrocytic pyruvate
      carboxylase (PC), on the other hand, was impaired by manganese, as evident from a
      decreased ratio of [2-13C]/[4-13C]glutamate or [2-13C]/[4-13C] glutamine.
      Consistent with stimulated glucose oxidative metabolism, the fractional 13C
      enrichment in [2-13C]acetyl-CoA entering the tricarboxylic acid (TCA) cycle and
      contributing to glutamate and glutamine synthesis increased to 138 and 156% of
      control, respectively (P < 0.001). In parallel, the TCA cycling ratio increased
      to 134% compared to control rats, prior to the label ending up in glutamate. In
      contrast, glutamine is synthesized mainly during the first TCA cycle turn. The
      present data provide new evidence in support of changes in brain energy
      metabolism playing an important role in manganese neurotoxicity. In particular,
      increased glycolytic flux and lactate synthesis may contribute to the deleterious
      effects of manganese in the brain. Furthermore, stimulated astrocytic glucose
      oxidation and glutamine synthesis may be associated with astrocytic pathology and
      altered astrocytic-neuronal metabolic trafficking in manganese neurotoxicity.

PMID- 15183013
TI  - Presynaptic disruption of transmitter release by lead.
AB  - Low concentrations of inorganic lead ions (Pb2+) disrupt transmitter release by
      causing aberrant augmentation of spontaneous and suppression of evoked release.
      These effects result from high affinity interactions of Pb2+ with the voltage
      gated calcium channels (VGCC) as well as Ca2+ binding proteins which regulate the
      synaptic vesicle mobilization, docking, and exocytosis processes. Augmentation of
      spontaneous release may involve stimulation of vesicle mobilization consequent to
      Pb2+ activation of CaMKII-dependent phosphorylation of synapsin I and/or
      stimulation of asynchronous exocytosis via direct Pb2+ activation of the putative
      exocytotic Ca2+-sensor protein synaptotagmin I. In addition, synergistic
      stimulation of PLC and DAG/Pb2+-dependent activation of PKC may enhance the
      secretagogue effects of Pb2+ by increasing metal sensitivity of exocytosis and/or
      modulating calcium channel activity. In contrast to intracellularly-mediated
      actions of Pb2+ resulting in augmentation of spontaneous release, the inhibition
      of evoked transmitter release by Pb2+ is largely attributable to extracellular
      block of the voltage-gated calcium channels.

PMID- 15183012
TI  - Dieldrin promotes proteolytic cleavage of poly(ADP-ribose) polymerase and
      apoptosis in dopaminergic cells: protective effect of mitochondrial anti
      apoptotic protein Bcl-2.
AB  - Previously, we demonstrated that the organochlorine pesticide dieldrin induces
      mitochondrial depolarization, caspase-3 activation and apoptosis in dopaminergic
      PC12 cells. We also demonstrated that protein kinase Cdelta (PKCdelta), a member
      of a novel PKC family of proteins, is proteolytically activated by caspase-3 to
      mediate apoptotic cell death processes. In the present study, we have further
      characterized the protective effect of the major mitochondrial anti-apoptotic
      protein Bcl-2 against dieldrin-induced apoptotic events in dopaminergic cells.
      Exposure to dieldrin (30-100 microM) produced significant cytotoxicity and
      caspase-3 activation within 3h in vector-transfected PC12 cells, whereas human
      Bcl-2-transfected PC12 cells were almost completely resistant to dieldrin-induced
      cytotoxicity and caspase-3 activation. Also, dieldrin (30-300 microM) treatment
      induced proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), which was
      blocked by pretreatment with caspase-3 inhibitors Z-DEVD-FMK and Z-VAD-FMK.
      Additionally, dieldrin-induced chromatin condensation and DNA fragmentation were
      completely blocked in Bcl-2-overexpressed PC12 cells as compared to vector
      control cells. Together, these results clearly indicate that overexpression of
      mitochondrial anti-apoptotic protein protects against dieldrin-induced apoptotic
      cell death and further suggest that dieldrin primarily alters mitochondrial
      function to initiate apoptotic cell death in dopaminergic cells.

PMID- 15183014
TI  - Presence and functional activity of the aryl hydrocarbon receptor in isolated
      murine cerebral vascular endothelial cells and astrocytes.
AB  - Numerous functions regulated by the central nervous system (CNS) are targeted by
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); however, the cell specific targets
      and mechanisms of toxicity are unknown. Outside of the brain, the peripheral
      vascular endothelium has been identified as a significant cellular target of TCDD
      toxicity resulting in apoptosis, edema, hemorrhaging and vascular dysfunction.
      Possible effects of TCDD in the vascular endothelium of the CNS have not been
      examined. Cellular dysfunction in this endothelium may disrupt function of the
      blood-brain barrier (BBB), which could severely compromise neuronal homeostasis
      and potentiate neurotoxicity. TCDD toxicity is mediated primarily by the aryl
      hydrocarbon receptor (AhR), a ligand activated transcription factor that
      modulates the expression of a large battery of genes. This study examined the
      presence and functional activity of the AhR in response to TCDD in endothelial
      cells and astrocytes, the two primary components of the BBB. Primary mouse
      cortical endothelial cells and astrocytes express the AhR, as shown by
      immunocytochemical and western blot analyses. AhR activity was assessed by time-
      and concentration-dependent analyses of CYP1A1 and CYP1B1 protein expression
      following TCDD treatment. Both CYP1A1 and CYP1B1 proteins were induced in
      endothelial cells after 4 and 8h, respectively, while only CYP1B1 protein
      induction was detected in astrocytes after 16h. The CYP450 protein induction was
      sustained for greater than 72h in both cell types. These changes in protein
      expression were dependent on AhR activity as indicated by the inhibition of these
      responses by a receptor antagonist. Together these data indicate endothelial
      cells and astrocytes are responsive to TCDD through the AhR-mediated pathway and
      therefore could be targets of toxicity.

PMID- 15183015
TI  - The changing view of acrylamide neurotoxicity.
AB  - Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and
      industrial applications: e.g., waste water management, ore processing. In
      addition, ACR is used extensively in molecular laboratories for gel
      chromatography and is present in certain foods that have been prepared at very
      high temperatures. Extensive studies in rodents and other laboratory animals have
      provided evidence that exposure to monomeric ACR causes cellular damage in both
      the nervous and reproductive systems, and produces tumors in certain hormonally
      responsive tissues. Whereas human epidemiological studies have demonstrated a
      significantly elevated incidence of neurotoxicity in occupationally exposed
      populations, such research has not, to date, revealed a corresponding increase in
      cancer risk. Since the announcement by a Swedish research group in April 2002 [J.
      Ag. Food Chem. 50 (2002) 4998] regarding the presence of ACR in potato and grain
      based foods, there has been a renewed interest in the toxic actions of this
      chemical. Therefore, in this review, we consider the different toxic effects of
      ACR. The neurotoxic actions of ACR will be the focal point since neurotoxicity is
      a consequence of both human and laboratory animal exposure and since this area of
      investigation has received considerable attention over the past 30 years. As will
      be discussed, a growing body of evidence now indicates that the nerve terminal is
      a primary site of ACR action and that inhibition of corresponding membrane-fusion
      processes impairs neurotransmitter release and promotes eventual degeneration.
      The electrophilic nature of ACR suggests that this neurotoxicant adducts
      nucleophilic sulfhydryl groups on certain proteins that are critically involved
      in membrane fusion. Adduction of thiol groups also might be common to the
      reproductive and carcinogenic effects of ACR. A final goal of this review is to
      identify data gaps that retard a comprehensive understanding of ACR
      pathophysiological processes.

PMID- 15183016
TI  - Guidelines for developmental neurotoxicity and their impact on organophosphate
      pesticides: a personal view from an academic perspective.
AB  - The appropriate regulation of drugs, chemicals and environmental contaminants
      requires the establishment of clear and accepted guidelines for developmental
      neurotoxicity. Ideally, these guidelines should encompass the ability to assess
      widely disparate classes of compounds through routine tests, with high throughput
      and low cost. Increasingly, however, the progress in primary research from
      academic laboratories deviates from this goal, focusing instead on categorizing
      novel effects of toxicants, development of new testing paradigms, and extension
      of techniques into molecular biology. The differing objectives of academic
      science as opposed to those of regulatory agencies or industry, are driven in
      part, by the priorities of the agencies that fund primary research. Recent work
      on organophosphate pesticides (OPs) such as chlorpyrifos (CPF) illustrate this
      dichotomy. Originally, OPs were thought to affect brain development through their
      ability to elicit cholinesterase inhibition and consequent cholinergic
      hyperstimulation. This common mechanism allowed for parallels to be drawn between
      standard measures of systemic toxicity, gross morphological examinations, and
      exposure testing utilizing an easily-assessed surrogate endpoint, plasma
      cholinesterase activity. In the past decade, however, it has become increasingly
      evident that CPF, and probably other OPs, have direct effects on cellular
      processes that are unique to brain development, and that these effects are
      mechanistically unrelated to inhibition of cholinesterase. The identification and
      pursuit of these mechanisms and their consequences for brain development
      represent new and exciting scientific findings, while at the same obscuring the
      ability to sustain a uniform approach to neurotoxicity guidelines or biomarkers
      of exposure. In the future, a new set of test paradigms, relying on primary work
      in cell culture, invertebrates, or non-mammalian models, followed by more
      targeted examinations of specific processes in mammalian models, may unite
      cutting-edge academic research with the need for establishing flexible guidelines
      for developmental neurotoxicity.

PMID- 15183017
TI  - High manganese levels in milk-based infant formulas.

PMID- 15183019
TI  - Proceedings of the 20th International Neurotoxicology Conference (NTX XX).
      November 18-21, 2002. Little Rock, Arkansas, USA.

PMID- 15183018
TI  - Effects of low-level exposure to inorganic mercury.

PMID- 15183020
TI  - The highs and lows of predicting the weather.

PMID- 15183021
TI  - Two portraits of Edmond Halley.

PMID- 15183022
TI  - Sverre Petterssen and the contentious (and momentous) weather forecasts for D
      Day.

PMID- 15183023
TI  - Sicily or the Sea of Tranquility? Mapping and naming the moon.
AB  - In their race to provide the ultimate guide to the moon, two 17th-century
      astronomers proposed lunar maps and nomenclatures that they hoped would gain
      international currency. But the names we use today were those proposed by the
      Jesuit, a friend of Galileo's persecutors, in a book whose purpose was to refute
      the Copernican system once and for all. We now believe that Riccioli was wrong
      about the universe, but why do we still use his nomenclature? The keys to this
      foundational visual debate in astronomical image-making are the moon maps
      themselves.

PMID- 15183024
TI  - Elements in the history of the Periodic Table.
AB  - Discovery of the Periodic Table was rendered possible only after four decisive
      prerequisites had been achieved. These were (i) the abandonment of the
      metaphysical and occult notions of elements that typified the alchemical era;
      (ii) the adoption of a modern and workable definition of an element; (iii) the
      development of analytical chemical techniques for the isolation of the elements
      and determination of their properties; and (iv) the devising of a means of
      associating each element with a characteristic natural number. The Periodic Table
      made its appearance on cue almost as soon as these preconditions had been
      fulfilled.

PMID- 15183025
TI  - Food of paradise: Tahitian breadfruit and the autocritique of European
      consumption.
AB  - In many ways, Tahiti was central to European colonialism, for it was there that
      European visitors forged a model of primitive nature that served as a comparison
      to, and sometimes critique of, European civilization. Tahiti was also the place
      from which a unique plant, the breadfruit, was brought to European colonies and
      to England and France during the late 18th century, at the behest of naturalists.
      With the breadfruit travelled contrasting perceptions of the Tahitian way of
      life. The autocritique of European lifestyles and the naturalization of the
      breadfruit are closely intertwined. The breadfruit indeed became a radical food
      of the end of the 18th century.

PMID- 15183026
TI  - Two approaches to etiology: the debate over smoking and lung cancer in the 1950s.
AB  - Statisticians R.A. Fisher and Joseph Berkson have become infamous for ending up
      on the "wrong" side of the debate over the evidence linking smoking and lung
      cancer during the 1950s, and scholars have speculated about their personal
      motives in the controversy. But there were many senior biostatisticians and
      epidemiologists voicing similar concerns about the quality of the evidence at the
      time, albeit with less inflammatory rhetoric. This debate occurred during a time
      when epidemiological research methods commonly used today were understood by few
      and were only just beginning to work their way into public health and medicine.
      All of the participants in the debate over smoking and lung cancer saw the need
      for explicit and rigorous standards for evaluating etiological hypotheses, but
      they held conflicting views about what those standards should be. The differing
      opinions on the evidence reflected two different models of etiological research-
      controlled experiment as the crucial, objective test of a causal hypothesis
      versus inferential judgment based on a diverse body of evidence. This debate has
      relevance for current epidemiological practice, as tension between these two
      views still remains.

PMID- 15183027
TI  - Cell culture of clonal ginbuna crucian carp hematopoietic cells: differentiation
      of cultured cells into erythrocytes in vivo.
AB  - We cultivated kidney hematopoietic cells from clonal triploid ginbuna crucian
      carp, Carassius auratus langsdorfii. Proliferating cells from hematopoietic cell
      cultures were harvested and injected into tetraploid hybrids (clonal triploid
      ginbuna and goldfish hybrid) which possess three sets of chromosomes from a
      triploid clone and a haploid set of chromosomes from goldfish (Carassius
      auratus). After injection of cultured triploid cells (donor cells), blood samples
      were obtained from tetraploid hybrids (recipients) every other week. Blood cells
      stained with acridine orange were measured by flow cytometry to trace the
      injected donor cells by means of differences in DNA content. Although
      erythrocytes were not produced in donor cell cultures, such cultures maintained
      precursor cells capable of differentiation into erythrocytes in vivo. After 4-12
      weeks of transplantation, mature erythrocytes derived from the donors were
      observed in the blood circulation of the recipient fish. These results indicated
      that the ginbuna hematopoietic cell culture system is an in vivo situation
      suitable for the study of hematopoietic control mechanisms.

PMID- 15183028
TI  - Self-discrimination in colonial invertebrates: genetic control of allorecognition
      in the hydroid Hydractinia.
AB  - Sessile, colonial invertebrates display the ability to distinguish between their
      own tissues and those of unrelated members of the same species. These
      allorecognition responses play a fundamental role in maintaining the genetic and
      physiological integrity of the colony. While allorecognition responses have been
      observed in all major colonial invertebrate taxa, the genetics of the response
      has been addressed only in the ascidian Botryllus and, more recently, in the
      hydroid Hydractinia. In Botryllus, allorecognition is controlled by a single co
      dominant locus. This review focuses on current developments on the genetics of
      allorecognition in Hydractinia.

PMID- 15183029
TI  - Cellular aspects of allorecognition in the compound ascidian Botryllus
      schlosseri.
AB  - We studied changes in the morphology of morula cells, a common haemocyte type in
      botryllid ascidians, during both the rejection reaction (occurring between
      contacting, genetically incompatible colonies) and fusion (occurring between
      compatible colonies), and in short-term cultures of haemocytes incubated with
      heterologous or autologous blood plasma. In both the rejection reaction and
      haemocyte cultures in the presence of heterologous blood plasma, we observed
      alterations in morula cells, consistent with a degranulation event, and their
      expression of molecules recognised by anti-IL-1-alpha- and anti-TNF-alpha
      antibodies. Anti-cytokine-antibodies markedly reduced the extent of the in vitro
      cytotoxicity, when haemocytes were exposed to heterologous blood plasma. In
      addition, the increase in the production of nitrite ions and the decrease of the
      in vitro cytotoxicity by the nitric oxide synthase inhibitor N(omega)-nitro-L
      arginine methyl ester, suggest the role of nitric oxide in cell death. These
      results provide new clues to understand the process of rejection reaction in
      botryllid ascidians.

PMID- 15183030
TI  - Immulectin-2, a pattern recognition receptor that stimulates hemocyte
      encapsulation and melanization in the tobacco hornworm, Manduca sexta.
AB  - In insects, encapsulation followed by melanization is a major defense mechanism
      against metazoan parasites. However, insects must recognize and differentiate
      nonself before they mount an immune response. Recognition of pathogens in insects
      is accomplished by a set of pattern recognition receptors (PRRs). Binding of PRRs
      to pathogens is linked to a variety of immune responses including phagocytosis,
      nodule formation, encapsulation, and prophenoloxidase activation. So far, little
      is known about how recognition of pathogens by PRRs triggers different immune
      responses. In this article, we report that immulectin-2, a C-type lectin,
      enhances encapsulation and melanization processes in the tobacco hornworm,
      Manduca sexta. Coating of agarose beads with recombinant carboxyl-terminal
      carbohydrate-recognition domain (CRD2-II) of immulectin-2 enhanced encapsulation
      of the beads in vitro by hemocytes and melanization of the beads in vivo in M.
      sexta larvae. Recombinant CRD2-II also directly bound to granular cells and
      oenocytoids, but not to plasmatocytes or spherule cells. Immulectin-2 in
      hemolymph of M. sexta larvae bound to the surface of a nematode, Caenorhabditis
      elegans, and recombinant CRD2-II directly bound to C. elegans and a human
      filarial nematode, Brugia malayi. Binding of CRD2-II to C. elegans enhanced
      melanization of the nematode in vivo. Our results suggest that binding of
      immulectin-2 to the surface of parasites can trigger encapsulation and
      melanization responses in M. sexta.

PMID- 15183031
TI  - Purification and functional assessment of C3a, C4a and C5a of the common carp
      (Cyprinus carpio) complement.
AB  - Promotion of inflammatory response is an important role of the complement system,
      but this kind of function is poorly documented for the lower vertebrates. Here we
      report chemotactic activity of purified anaphylactic fragments derived from the
      complement components C3, C4 and C5 of the common carp. The purified
      anaphylatoxins are two C5a-desArg peptides derived from the C5-I isotype, an
      intact form and a desArg form of C4a from C4-2 isotype, and an intact form and a
      desArg form of C3a from C3-H1 isoform. These were identified by N-terminal
      sequencing, mass spectrometry, and peptide mass fingerprinting. In the chemotaxis
      assay using carp kidney neutrophils, the two C5a-desArg fragments, which are
      probably allotypic variants, showed a potent chemotactic activity at 0.5-1 nM,
      whereas C3a or C4a showed no significant activity. The results suggest that C3a,
      C4a and C5a of bony fish have functionally diverged to the state similar to their
      mammalian homologs.

PMID- 15183032
TI  - Molecular cloning and sequencing of Japanese pufferfish (Takifugu rubripes) NADPH
      oxidase cDNAs.
AB  - The superoxide-producing NADPH oxidase complex of phagocytes plays a crucial role
      in host defenses against microbial infection. NADPH oxidase consists of a
      membrane heterodimeric protein, composed of gp91phox and p22phox, and cytosolic
      proteins, p40phox, p47phox and p67phox. In the present study, cDNAs of all the
      components of NADPH oxidase were cloned from peripheral white blood cells of the
      Japanese pufferfish utilizing the reverse transcription-polymerase chain
      reaction. The sequences of these cDNAs showed that the pufferfish gp91phox,
      p22phox, p40phox, p47phox and p67phox clones contained open reading frames
      encoding 565, 186, 348, 423 and 495 amino acids, respectively. Comparison of the
      deduced amino acid sequences showed that the pufferfish gp91phox, p22phox,
      p40phox, p47phox and p67phox sequences shared 68.0, 61.8, 53.8, 54.7 and 41.9%
      identity with those of human components, respectively. gp91phox has three
      potential N-linked glycosylation sites. gp91phox and p22phox have six and three
      hydrophobic regions, respectively, that are predicted to be transmembrane
      regions. p47phox and p67phox have two potential Src homology 3 domains and
      p40phox has one. The functional domains are highly conserved in many animals,
      though the sequence of the components of the pufferfish showed low homology with
      that of mammals. The Fugu NADPH oxidase genes were expressed in various tissues
      of unstimulated fish. The level of gp91phox, p47phox and p67phox expression were
      high only in the blood and kidney, while p22phox and p40phox were constitutively
      expressed in a wide range of tissues. These results suggest that Japanese
      pufferfish NADPH oxidase components possess functional activities similar to
      those of human.

PMID- 15183033
TI  - Interferon alpha/beta genes from a marsupial, Macropus eugenii.
AB  - This paper describes the cloning of full length marsupial type I interferon (IFN)
      genes and their flanking regions using a genome walking approach and PCR primers
      based on previously isolated partial DNA sequences. We confirm that the two major
      classes of Tammar Wallaby type I IFN genes are homologous with the eutherian IFN
      alpha and IFN-beta gene families. The wallaby IFN genes share a number of
      conserved features with their eutherian counterparts, including codons for
      cysteines at equivalent positions, implying similar secondary structures for the
      encoded proteins, and promoter regions with conserved putative regulatory motifs.
      Moreover, the wallaby genes have AT-rich elements in their flanking sequence
      corresponding to the mRNA 3'-untranslated regions, also implying that, as in
      eutherian mammals, rapid mRNA degradation plays a role in regulating expression
      of these genes. The complex nature of the type I IFN gene families in viviparous
      mammals (eutherians and marsupials) may reflect their recruitment into
      nonimmunological processes and this concept is discussed.

PMID- 15183034
TI  - Reference values for relative numbers of natural killer cells in cattle blood.
AB  - Natural killer (NK) cells have been studied in humans and rodents for almost 30
      years, but little is known about NK cells in other mammals, such as cattle.
      Recently, a monoclonal antibody directed against bovine NKp46, a receptor that is
      expressed exclusively on NK cells, was developed. We have utilized this antibody
      to study the relative numbers of NK cells in blood of 254 cattle at different
      ages. The highest relative number of NK cells was observed in young calves, and
      gradually decreased with age to a bottom level in heifers, followed by a moderate
      increase in adults. Relative numbers of NK cells in cattle were generally lower
      than in humans, but age-related changes in bovine NK cells showed similar
      tendencies as reported in humans. The present material provides a source for
      reference values for NK cells in cattle at various ages.

PMID- 15183035
TI  - Differential migratory properties of mouse, fish, and frog leukocytes treated
      with agonists of opioid receptors.
AB  - Zymosan-induced peritoneal inflammation was inhibited by morphine co-injection in
      mice and fish but not in anuran amphibians. In present experiments, an in vitro
      migration of mouse, goldfish, and frog leukocytes to L15 medium, control serum
      (S) or zymosan-activated serum (ZAS) was recorded following cell preincubation
      with L15 or with agonists of mu, delta, or kappa opioid receptors (morphine,
      deltorphine, or U-50,488H, respectively). In all species, migration of control
      leukocytes was in the order ZAS > S > L15. Pretreatment with morphine or
      deltorphine (but not with U-50,488H) enhanced leukocyte migration to L15 and S in
      each species, while it inhibited migration of mouse and fish (but not frog)
      leukocytes to ZAS, phenomena reversed by specific antagonists of mu and delta
      opioid receptors (CTOP or naltrindole, respectively). It seems that final effects
      of opioids on cell migration are dependent on a species-specific balance between
      up- and down-regulation of leukocyte migration resulted from interplay between
      receptors for opioids and chemotactic factors.

PMID- 15183036
TI  - The polyglutamine tract of androgen receptor: from functions to dysfunctions in
      motor neurons.
AB  - This review summarizes the mechanisms of neurotoxicity associated to androgen
      receptor containing an elongated polyglutamine tract responsible for motor
      neuronal cell death.

PMID- 15183037
TI  - Ghrelin--a hormone with multiple functions.
AB  - Ghrelin is brain-gut peptide with growth hormone-releasing and appetite-inducing
      activities. It is mainly secreted from the stomach mucosa but it is also
      expressed widely in different tissues and therefore may have both endocrine and
      paracrine effects. Ghrelin is the endogenous ligand of the G protein-coupled
      growth hormone secretagogue receptor. In the current review we comprehensively
      summarize (i) the data available regarding the structure, expression pattern and
      regulation of ghrelin and its receptor; (ii) the available information regarding
      the effect of ghrelin on the pituitary hormone axis, appetite regulation, cardiac
      and gastrointestinal function, carbohydrate metabolism, adipose and reproductive
      tissue, cell proliferation and behavioral effects; (iii) experimental and
      clinical data regarding circulating ghrelin levels observed in various
      physiological and pathological conditions; and (iv) data on gene variations of
      ghrelin and its receptor. It is apparent that ghrelin is involved in many more
      processes than originally envisaged, and in particular appears to have relatively
      less relevance to growth hormone physiology and more to the regulation of energy
      fluxes in the organism. Increasing data link ghrelin to the overall control of
      energy use and flow in situations where there is a limitation of energy sources
      and ghrelin appears to play a pivotal role in energy homeostasis.

PMID- 15183038
TI  - Cost-minimization analysis of two algorithms for diagnosing acute pulmonary
      embolism.
AB  - INTRODUCTION: Pulmonary embolism is a common disorder that often requires
      extensive diagnostic testing. We hypothesized that an algorithmic approach to
      diagnosis of pulmonary embolism based upon clinical risk stratification and D
      dimer testing would be less costly than a standard approach. MATERIALS AND
      METHODS: We constructed a decision tree based upon two published algorithms for
      diagnosing acute pulmonary embolism. Branch point probabilities were obtained
      from the best available published literature. Costs were based upon Medicare
      charges. From this we obtained a base-case analysis and conducted sensitivity
      analysis. RESULTS: Our base-case analysis revealed that the cost-per-patient for
      diagnostic testing were US$216.52 for the algorithm based upon pre-test
      probability and D-dimer testing and US$538.62 for the standard algorithm. The
      cost difference per patient evaluated was US$322.10. One- and two-way sensitivity
      analyses did not reveal any instances in which the clinical risk algorithm was
      more costly than the standard algorithm. Two-way sensitivity analysis revealed
      several scenarios in which the standard algorithm would be less costly; however,
      the conditions required for these scenarios are rarely encountered in clinical
      practice. CONCLUSIONS: Costs of testing using an algorithm based on clinical pre
      test probability and D-dimer testing are less than with a standard approach for
      evaluating suspected acute pulmonary embolism. This new algorithm has previously
      been shown to be safe and has the potential for large cost savings if widely
      applied.

PMID- 15183039
TI  - Deep vein thrombosis after elective cesarean section.
AB  - INTRODUCTION: Pregnancy is associated with an overall 5-10 fold increased risk of
      venous thromboembolism (VTE). The absolute risk is highest during and shortly
      after delivery. Although operative delivery further increases the risk of VTE,
      there is no consensus on thromboprophylaxis after an elective cesarean. The aim
      of the present study was to investigate the frequency of symptomatic and
      asymptomatic deep venous thrombosis (DVT) in a low risk cesarean section
      population. MATERIALS AND METHODS: Fifty-nine women undergoing elective cesarean
      section were screened for DVT using triplex Doppler sonography 3-5 days after
      delivery. Markers of activated coagulation were also followed and all women were
      screened for thrombophilia. Postoperative thromboprophylaxis was not given.
      During the same period all cases of symptomatic VTE were also recorded. RESULTS:
      No DVT was detected by ultrasonography and no women developed symptomatic VTE
      during the six weeks follow-up period after delivery. Six women had
      thrombophilia. During the study period, a cesarean section was performed in
      1067/5364 (20%) deliveries. Five of these women (0.47%) developed symptomatic
      pulmonary embolism, and all of these women had additional risk factors for VTE.
      CONCLUSION: The risk of DVT among healthy pregnant women undergoing elective
      cesarean section is low, and general medical thromboprophylaxis is probably not
      justified.

PMID- 15183040
TI  - Allele frequencies of two polymorphisms associated with the factor IX gene in
      Iranian population.
AB  - Indirect genetic diagnosis using polymorphic DNA markers can be useful in large
      scale screening programs, which is technically simpler, more rapid and amenable.
      The main objective of this study was to test the informativeness of two common
      intragenic markers (TaqI and XmnI) in Iranian haemophilia B families to detect
      the carriers by using a strategy that would be accurate and informative, yet less
      expensive compared to direct mutation analysis. The efficacy of these sites has
      been examined in 50 unrelated Iranian haemophilia B families and 50 normal
      females. The method used was polymerase chain reaction/restriction fragment
      length polymorphism (PCR/RFLP), which is economical and the enzymes XmnI and TaqI
      are cheap enough to be accessible in most of laboratories in developing
      countries. Our results show that 25% of X-chromosomes had the restriction site
      for TaqI enzyme. The XmnI site was 21%. The heterozygosity rates for TaqI and
      XmnI polymorphisms were 37% and 38%, respectively. Using the two polymorphisms
      together, the informative rate reached 46%. Taking advantage of TaqI and XmnI
      polymorphisms, carrier detection was performed for seven females with unknown
      status in five haemophilia B families (including one large extended family) with
      positive history. Six of the girls were normal and one was haemophilia B carrier.
      Therefore, carrier detection might be possible for informative Iranian
      haemophilia B families in the familial cases. Additionally, similarities in term
      of heterozygosity rates for these two polymorphic sites were seen between some
      European and Iranian populations.

PMID- 15183042
TI  - The state of platelets preserved in extracorporeal circulation with a
      glycoprotein IIb/IIIa inhibitor.
AB  - INTRODUCTION: Temporary inhibition of platelet function during extracorporeal
      circulation (platelet anesthesia) can preserve platelet count. We hypothesized
      that platelet anesthesia with a glycoprotein IIb/IIIa inhibitor could preserve
      activated platelets. MATERIALS AND METHODS: Fresh human blood from donors was
      recirculated for 120 min in a simulated extracorporeal circuit. Heparin and
      FK633, a short-acting platelet glycoprotein IIb/IIIa inhibitor, were added to
      recirculated blood in one group (group F, n=5) whereas only heparin was used in
      controls (group C, n=5). Blood samples were obtained from the donors, and at 0,
      5, 15, 30, 60, and 120 min of recirculation. Platelet counts, beta
      thromboglobulin, thrombin-antithrombin complex, and aggregation to adenosine
      diphosphate were measured. Flow cytometry was performed for measurement of
      fibrinogen binding, platelet surface expression of P-selectin, and
      microparticles. RESULTS AND CONCLUSIONS: In the FK633 group, platelet counts were
      preserved and beta-thromboglobulin levels remained unchanged, whereas in group C,
      platelet counts decreased significantly and beta-thromboglobulin increased
      significantly from 30 and 60 min, respectively. FK633 inhibited platelet
      aggregation and fibrinogen binding to platelets throughout recirculation. A
      significant difference between groups with respect to microparticle parameters
      and thrombin-antithrombin complex levels was evident by 120 min. P-selectin
      expression increased at 0 min in both groups, and was preserved significantly at
      5 min and reduced at 120 min in group F. Platelet counts were preserved by
      platelet anesthesia during recirculation without platelet activation. These
      results suggest that FK633 inhibits the amplification loop by reducing the
      binding of fibrinogen to glycoprotein IIb/IIIa and platelet aggregation.

PMID- 15183041
TI  - Pharmacodynamic profile of antiplatelet agents: marked differences between single
      versus costimulation with platelet activators.
AB  - BACKGROUND: In pharmacodynamic studies with antiplatelet agents, platelets are
      usually activated in vitro with single agonists (e.g., ADP) solely. We questioned
      whether differences occur between single and combined stimulation of platelets
      [involving the major thrombin-receptors, protease-activated receptors (PAR)1 and
      PAR4], and whether the pharmacodynamic response to common antiplatelet drugs vary
      when a combined stimulus is applied instead of a single agonist. METHODS: We
      investigated the influence of different antiplatelet agents (aspirin [500 mg]) in
      vivo, the P2Y12-antagonist AR-C 69931MX (4 nM) and the GPII/IIIa-antagonist
      (abciximab ([5 microg/ml] in vitro) on the degranulation response (CD62) and
      expression of the activated GPIIb/IIIa-receptor (PAC-1) after stimulation with
      ADP (2 microM), collagen (4 microg/ml), a PAR1-activating peptide (3 microM TRAP)
      and a PAR4-activating peptide (200 microM AYPGKF) alone or in a combination of
      each two agonists by flow cytometry in healthy subjects. RESULTS: (1) Combined
      activation of TRAP with AYPGKF resulted in synergistic CD62 and PAC-1 expression.
      Only AYPGKF but neither TRAP nor ADP acted synergistically with collagen. (2) AR
      C 69931MX inhibited platelet degranulation (CD62) in all inducer combinations
      with ADP or the combination TRAP with AYPGKF. The effect was considerably smaller
      or absent for the combination of collagen with a second inducer. (3) Aspirin
      intake reduced platelet degranulation and PAC-1 expression only for AYPGKF
      costimulation with collagen. CONCLUSION: Because a variety of different agonists
      influence platelet activation and its distinct functions at a time,
      investigations which regard the concert of these agonists might be closer to the
      in vivo situation and better reflect the pharmacodynamic profile of an
      antiplatelet agent than using one single inducing agent.

PMID- 15183043
TI  - A critical role for thrombin in platelet aggregation under high shear stress.
AB  - The serine protease, thrombin, plays a crucial role in both coagulation and
      platelet activation. Anhydrothrombin (AhT) is a catalytically inactive derivative
      of thrombin in which dehydroalanine replaces the active-site serine. AhT retains
      affinity for natural substrates of thrombin and may be a competitive inhibitor of
      thrombin-mediated coagulation and platelet reactions. In the present study,
      thrombelastography showed that AhT not only delayed the onset and the progress of
      the coagulation process but impaired clot strength, indicating that AhT may have
      both anticoagulant and antiplatelet activity. In addition, AhT prolonged the
      activated partial thromboplastin time dose-dependently, but had little effect on
      the prothrombin time, suggesting that its principal activity was mediated in the
      intrinsic coagulation pathway. AhT inhibited thrombin-induced aggregation of
      platelet-rich plasma. Complete inhibition of aggregation was evident at a
      concentration of 1.85 microM AhT. Furthermore, 3.7 microM of AhT almost
      completely abolished shear-induced platelet aggregation in PRP. Interpretation of
      this in vitro study requires confirmation in vivo, but the findings suggest that
      thrombin plays a critical role in shear related platelet mechanisms. AhT may be a
      useful tool for investigating platelet-based coagulation reactions and may
      provide the basis for a novel class of antithrombotic agents.

PMID- 15183044
TI  - Genetic variation in the human thrombomodulin promoter locus and prognosis after
      acute coronary syndrome.
AB  - INTRODUCTION: Endothelial thrombomodulin (TM) plays a critical role in both
      anticoagulation and anti-inflammation. An impaired TM cofactor function or
      reduced TM gene expression could constitute a prethrombotic abnormality leading
      to acute coronary events. Mutations in the TM gene occur, but their functional
      consequences on the expression and activity of the gene are not yet fully
      understood. MATERIALS AND METHODS: We performed a prospective study investigating
      the prevalence of TM mutations in the promoter region in 182 patients with acute
      coronary syndrome as well as in a control group. The patients were followed-up
      after 30 days and after 2 years for acute myocardial infarction (MI) and
      mortality. RESULTS AND CONCLUSIONS: We identified 10 point mutations and 2 small
      deletions: -1861 C/A, -1852 C/G, -1803 G/C, -1752 G/C, -1213/1212 delTT, -1089
      C/G, -1088 C/T, -1083/1082 delCC, -1066 A/C, -801 C/G, -651 A/C and -52 G/A. Two
      of the mutations, -1752 G/C and -1213/1212 delTT, were frequent in the patients
      as well as in the controls, while all the others were rare. The only significant
      finding was that both -1752 G/C and -1213/1212 delTT were associated with a lower
      than normal risk of suffering a clinical event among smokers at 30 days and 2
      years. We did not gain any support for the hypothesis that TM mutations confer an
      increased risk of MI or mortality.

PMID- 15183045
TI  - INR comparison between the CoaguChek Pro PT(N) and a standard laboratory method.
AB  - BACKGROUND: The prothrombin time (PT), also called thromboplastin time ("Quick"),
      is usually measured using citrated plasma from venous blood. Recently, portable
      coagulation monitors have been developed, which measure PT using non
      anticoagulant capillary whole blood from a finger stick. In the present study, we
      compared the International Normalized Ratio (INR) of the standard laboratory
      method (INRven) with the newly developed reagent PT(N) for the CoaguChek Pro
      portable monitor (INRcap) in various patient groups: healthy individuals,
      patients with oral anticoagulation and patients with a deficiency of coagulation
      factor V, factor VII or factor X, respectively. METHODS: One hundred and fifty
      five patients were included in this prospective open comparison study. Capillary
      PT was measured with the portable coagulation monitor CoaguChek Pro using the new
      disposable cartridge PT(N) (containing rabbit brain thromboplastin). In
      comparison, PT was measured using citrated venous plasma and the reagent Innovin
      on the coagulation analyzer STA-R. RESULTS: We found a correlation coefficient of
      0.85 between capillary and venous INR values among the 100 patients with oral
      anticoagulation. The slope of the regression line was 1.4 and the y-intercept is 
      0.65. Agreement between both methods was found to be 80% (95% CI: 72-88%) and the
      standard-agreement was 85% (95% CI: 78-92%). Among the 30 healthy subjects, the
      individual differences between INRven and INRcap were in 4 cases 0, in 21 cases
      0.1 and in 5 cases 0.2. CONCLUSION: The new test cartridge PT(N) was found to be
      a valuable tool for measuring PT among healthy subjects. However, among patients
      with oral anticoagulation, agreement between INRcap measured with the new
      cartridge PT(N) and INRven was only moderate. Our results show that improvements
      are necessary for a more valuable measurement of capillary PT with portable
      coagulation monitors.

PMID- 15183046
TI  - Evaluation of a novel kallikrein inhibitor on hemostatic activation in vitro.
AB  - BACKGROUND: DX-88 is a potent kallikrein inhibitor that is being studied for the
      treatment of hereditary angioedema (HAE) and represents a potential alternative
      to aprotinin in cardiac surgical patients. The current study was designed to
      evaluate in vitro effects of DX-88 on coagulation in comparison with aprotinin.
      METHODS: Blood samples were obtained from consented 12 healthy volunteers. DX-88
      or aprotinin was added to blood at 200 and 800 kallikrein inhibitory units (KIU)
      per milliliter for aprotinin, and at 1.1, 2.2, or 8.8 microg/ml for DX-88.
      Thromboelastography (TEG) was performed using celite, kaolin, or tissue factor
      (TF) activation. Kaolin-based activated clotting times (ACTs) were measured at
      different heparin levels. The whole blood prothrombin time (PT)/PTT values were
      also measured. The endogenous thrombin generation was assessed with a fluorogenic
      assay using platelet-poor plasma (PPP). RESULTS: With celite and kaolin
      activation of TEG, the reaction time was prolonged with DX-88 and aprotinin. With
      tissue factor activation, TEG parameters were not affected. DX-88 caused dose
      dependent kaolin-ACT prolongation that was augmented by increasing doses of
      heparin. DX-88 or aprotinin had no significant effects on the PT values, but PTT
      values were dose-dependently prolonged. Both agents delayed the onset of thrombin
      generation when PTT reagent was used as a trigger, whereas no change was observed
      when tissue factor was used. CONCLUSION: We found that DX-88 delayed contact
      activator induced coagulation without affecting tissue factor mediated
      coagulation. For evaluation of coagulation during DX-88 therapy, the use of PT or
      tissue factor-activated TEG may be preferable.

PMID- 15183047
TI  - Genetic variations in the human TFPI-2 gene and its promoter region by denaturing
      high performance liquid chromatography.

PMID- 15183048
TI  - Polyomaviruses and human cancer: molecular mechanisms underlying patterns of
      tumorigenesis.
AB  - Polyomaviruses are DNA tumor viruses with small circular genomes encoding only
      six proteins including three structural capsid proteins. Despite this simplicity,
      our understanding of the mechanisms of polyomavirus-mediated tumorigenesis is far
      from complete. The archetypal primate polyomavirus, SV40, was isolated more than
      40 years ago and has been used extensively as a model system for the study of
      basic eukaryotic cellular processes such as DNA replication and transcription.
      Two human polyomaviruses have been isolated from clinical samples: JC virus (JCV)
      and BK virus (BKV). In this review, SV40, JCV, and BKV will be compared based on
      what is known about their molecular biology from experiments performed in vitro,
      in cell culture and in laboratory animals. The association of these viruses with
      clinical tumors is discussed along with the possible roles of these
      polyomaviruses in the etiology of human malignant disease.

PMID- 15183049
TI  - Classification of papillomaviruses.
AB  - One hundred eighteen papillomavirus (PV) types have been completely described,
      and a yet higher number of presumed new types have been detected by preliminary
      data such as subgenomic amplicons. The classification of this diverse group of
      viruses, which include important human pathogens, has been debated for three
      decades. This article describes the higher-order PV taxonomy following the
      general criteria established by the International Committee on the Taxonomy of
      Viruses (ICTV), reviews the literature of the lower order taxa, lists all known
      "PV types", and interprets their phylogenetic relationship. PVs are a taxonomic
      family of their own, Papillomaviridae, unrelated to the polyomaviruses. Higher
      order phylogenetic assemblages of PV types, such as the "genital human PVs", are
      considered a genus, the latter group, for example, the genus "Alpha
      Papillomavirus". Lower-order assemblages of PV types within each genus are
      treated as species because they are phylogenetically closely related, but while
      they have distinct genomic sequences, they have identical or very similar
      biological or pathological properties. The taxonomic status of PV types,
      subtypes, and variants remains unchanged and is based on the traditional criteria
      that the sequence of their L1 genes should be at least 10%, 2-10%, and maximally
      2% dissimilar from one another.

PMID- 15183050
TI  - Identification of an octanucleotide motif sequence essential for viral protein,
      DNA, and progeny virus biosynthesis at the origin of DNA replication of porcine
      circovirus type 2.
AB  - A plasmid-based transfection system capable of generating infectious porcine
      circovirus type 2 (PCV2) was established. This system was then used in
      mutagenesis studies to investigate the involvement of a "conserved"
      nonanucleotide (which constitutes a portion of the loop sequence) located at the
      origin of DNA replication of PCV2 with respect to viral protein synthesis, DNA
      self-replication, and progeny virus production. The results demonstrated that an
      octanucleotide (AGTATTAC) embedded in the loop sequence is essential for virus
      replication. This octanucleotide can be further condensed to an essential core
      element (ECE) represented by AxTAxTAC. The positions specified by the indicated
      nucleotides are critical for viral DNA replication and stable infectious virus
      production, and they cannot be substituted by other bases, while the positions
      indicated by x can accept variable bases and yield stable progeny viruses.

PMID- 15183051
TI  - The DNA beta satellite component associated with ageratum yellow vein disease
      encodes an essential pathogenicity protein (betaC1).
AB  - Ageratum yellow vein disease (AYVD) is caused by the geminivirus ageratum yellow
      vein virus (AYVV) and an associated DNA beta satellite. We have mapped a DNA beta
      transcript to a highly conserved open reading frame (betaC1 ORF). The most
      abundant transcript 5'-terminus is located 8 bases upstream of the betaC1 ORF
      putative initiation codon while the transcript terminates at multiple sites
      downstream from the putative termination codon. Disruption of betaC1 protein
      expression by the introduction of an internal nonsense codon prevented infection
      of the AYVV-satellite complex in ageratum and altered the phenotype in Nicotiana
      benthamiana to that produced by AYVV alone although the mutant was maintained in
      systemically infected tissues. Modification of the putative initiation codon to a
      nonsense codon produced an intermediate phenotype in N. benthamiana and a mild
      yellow vein phenotype in ageratum, suggesting that betaC1 protein expression
      could be initiated from an alternative site. N. benthamiana plants containing a
      dimeric DNA beta transgene produced severe developmental abnormalities, vein
      greening, and cell proliferation in the vascular bundles. Expression of betaC1
      protein from a potato virus X (PVX) vector also induced abnormal plant growth.
      Our results demonstrate that the satellite encodes at least one protein that
      plays a major role in symptom development and is essential for disease
      progression in ageratum, the natural host of the AYVD complex.

PMID- 15183052
TI  - Phylogeography and molecular evolution of dengue 2 in the Caribbean basin, 1981
      2000.
AB  - We sequenced the envelope (E) genes of 59 DEN-2 isolates collected from ten
      Caribbean islands, six South American countries, and two Central American
      countries between 1981 and 2000, a period characterized by hyperendemicity and
      increased incidence of severe dengue. Fifty-two isolates belonged to
      "American/Asian" subtype IIIb, possessing a characteristic polar residue at
      envelope aa position 390 (N [n = 48] or S [n = 4]) common to that group. Six
      isolates from Trinidad (1981), Honduras (1991 [4]), and El Salvador (1987) fell
      into the "Native American" subtype V (D at aa 390), and one from Honduras (1986)
      belonged to "Asian" subtype I. The data suggest that after its first isolation in
      the Caribbean in 1981, genotype IIIb spread throughout the Americas and
      effectively replaced subtype V throughout the Caribbean basin. The strain also
      evolved into several distinct lineages, based on substitutions in the E
      glycoprotein (amino acids 91 and 131), two of which were still in circulation in
      2000. Interestingly, a molecular clock did not fit the data well, suggesting that
      other sources of rate variation, such as differential selection or differences in
      effective population sizes, may exist among lineages. Our results indicate the
      importance of large temporal- and geographical-scale phylogenetic studies in
      understanding disease dynamics, particularly where replacements between regions
      can occur.

PMID- 15183053
TI  - Herpesvirus saimiri-encoded proteins Tip and StpC modulate human immunodeficiency
      virus type 1 replication in T-cell lines and lymphocytes independently of viral
      tropism.
AB  - Herpesvirus saimiri (HVS)-transformed T-lymphocytes are permissive for both X4
      and R5 strains of human immunodeficiency virus type 1 (HIV-1). HVS-encoded
      proteins tyrosine-kinase interacting protein (Tip) and saimiri transformation
      associated protein subgroup C (StpC) were previously implicated in altering HIV
      permissiveness. MOLT4 cells expressing StpC or StpC and Tip are permissive for X4
      strains of HIV-1. In contrast, HIV-1 was restricted in MOLT4 cells expressing Tip
      alone. Here we show that MOLT4 cells and primary lymphocytes expressing StpC are
      permissive for R5 strains of HIV-1 while Tip expression restricted R5 strains.
      These results suggest that intracellular immunization with Tip and StpC could be
      developed as models for therapeutic strategies targeting both X4 and R5 strains
      of HIV-1.

PMID- 15183054
TI  - Rescue of influenza virus expressing GFP from the NS1 reading frame.
AB  - In this study, several influenza NS1 mutants were examined for their growth
      ability in interferon (IFN)-deficient Vero cells treated with human interferon
      alpha (IFN-alpha). Mutants with an intact RNA binding domain showed similar
      growth properties as the wild-type virus, whereas viruses carrying an impaired
      RNA binding domain were dramatically attenuated. Relying on the ability of the
      first half of the NS1 protein to antagonize the IFN action, we established a
      rescue system for the NS gene based on the transfection of one plasmid expressing
      recombinant NS vRNA and subsequent coinfection with an IFN sensitive helper virus
      followed by adding of human IFN-alpha as a selection drug. Using this method, a
      recombinant influenza A virus expressing green fluorescence protein (GFP) from
      the NS1 reading frame was rescued. To ensure the posttranslational cleavage of
      GFP from the N-terminal 125 amino acids (aa) of NS1 protein, a peptide sequence
      comprising a caspase recognition site (CRS) was inserted upstream the GFP
      protein. Although a rather long sequence of 275 aa was inserted into the NS1
      reading frame, the rescued recombinant vector appeared to be genetically stable
      while passaging in Vero cells and was able to replicate in PKR knockout mice.

PMID- 15183055
TI  - Pseudotype hepatitis C virus enters immature myeloid dendritic cells through the
      interaction with lectin.
AB  - Dendritic cells (DC) are the most potent antigen-presenting cells that regulate
      immune responses. One of the mechanisms for hepatitis C virus (HCV) persistence
      is the ability of HCV to suppress DC function. Direct HCV infection to blood DC
      has been implicated for DC dysfunction. To clarify the susceptibility of each DC
      subset to HCV, we used pseudotype vesicular stomatitis virus (VSV) coated with
      chimeric HCV envelope glycoproteins (E1 and E2). We demonstrate that pseudotype
      VSV enters myeloid DC (MDC) but not plasmacytoid DC (PDC). The highest efficiency
      of pseudotype VSV entry to MDC was observed when MDC were cultured with GM-CSF.
      Such efficiency decreased when MDC are matured with the treatment of IL-4, CpG
      oligodeoxynucleotide, or CD40 ligand. Mannan inhibited pseudotype VSV entry to
      MDC, but Ca(2+) chelators failed to do so. These results show that pseudotype VSV
      possessing HCV-E1 and E2 enters immature MDC through the interaction with lectins
      in a Ca(2+)-independent manner.

PMID- 15183056
TI  - Attenuation of SARS coronavirus by a short hairpin RNA expression plasmid
      targeting RNA-dependent RNA polymerase.
AB  - Severe acute respiratory syndrome (SARS) is a highly contagious and sometimes a
      lethal disease, which spread over five continents in 2002-2003. Laboratory
      analysis showed that the etiologic agent for SARS is a new type of coronavirus.
      Currently, there is no specific treatment for this disease. RNA interference
      (RNAi) is a recently discovered antiviral mechanism in plant and animal cells
      that induces a specific degradation of double-stranded RNA. Here, we provide
      evidences that RNAi targeting at coronavirus RNA-dependent RNA polymerase (RDRP)
      using short hairpin RNA (shRNA) expression plasmids can specifically inhibit
      expression of extraneous coronavirus RDRP in 293 and HeLa cells. Moreover, this
      construct significantly reduced the plaque formation of SARS coronaviruses in
      Vero-E6 cells. The data may suggest a new approach for treatment of SARS
      patients.

PMID- 15183057
TI  - HIV-1 acute infection env glycomutants designed from 3D model: effects on
      processing, antigenicity, and neutralization sensitivity.
AB  - The human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) has
      evolved to limit its overall immunogenicity by extensive glycosylation. Only a
      few studies dealing with glycosylation sites have taken into account available 3D
      data in a global approach. We compared primary env sequences from patients with
      acute HIV-1 infection. Conserved N-glycosylation sites were placed on the gp120
      3D model. Based on vicinity, we defined glycosylation clusters. According to
      these clusters, we engineered plasmids encoding deglycosylated gp160 mutants. We
      also constructed mutants corresponding to nonclustered glycans or to the full
      deglycosylation of the V1 or V2 loop. After in vitro expression, mutants were
      tested for functionality. We also compared the inhibition of pseudotyped
      particles infection by human-neutralizing sera. Generally, clustered and
      nonclustered mutants were affected similarly. Silencing of more than one glycan
      had deleterious effects, independently of the type of sugar removed. However,
      some mutants were moderately affected by glycans removal suggesting a distinct
      role for these N-glycans. Additionally, compared to the wild-type pseudovirus,
      two of these mutants were neutralized at higher sera dilutions strengthening the
      importance of the location of specific N-glycans in limiting the neutralizing
      response. These results could guide the selection of env mutants with the fewest
      antigenic and functional alterations but with enhanced neutralization
      sensitivity.

PMID- 15183058
TI  - An adenovirus vector with a chimeric fiber derived from canine adenovirus type 2
      displays novel tropism.
AB  - Many clinically relevant tissues are refractory to Ad5 transduction because of
      negligible levels of the primary Ad5 receptor, the coxsackie and adenovirus
      receptor (CAR). Thus, development of Ad vectors that display CAR-independent
      tropism could lead directly to therapeutic gain. The Toronto strain of canine
      adenovirus type 2 (CAV2) exhibits native tropism that is augmented by, but not
      fully dependent upon, CAR for cellular transduction. We hypothesized that an Ad5
      vector containing the nonhuman CAV2 knob would provide expanded tropism and
      constructed Ad5Luc1-CK, an E1-deleted Ad5 vector encoding the fiber knob domain
      from CAV2. Ad5Luc1-CK gene delivery to CAR-deficient cells was augmented up to 30
      fold versus the Ad5 control vector, and correlated with increased cell surface
      binding. Further, we confirmed the importance of cellular integrins to Ad5Luc1-CK
      transduction. Herein, we present the rationale, design, purification, and
      characterization of a novel tropism modified, infectivity-enhanced Ad vector.

PMID- 15183059
TI  - Expression of rabbit IL-4 by recombinant myxoma viruses enhances virulence and
      overcomes genetic resistance to myxomatosis.
AB  - Rabbit IL-4 was expressed in the virulent standard laboratory strain (SLS) and
      the attenuated Uriarra (Ur) strain of myxoma virus with the aim of creating a Th2
      cytokine environment and inhibiting the development of an antiviral cell-mediated
      response to myxomatosis in infected rabbits. This allowed testing of a model for
      genetic resistance to myxomatosis in wild rabbits that have undergone 50 years of
      natural selection for resistance to myxomatosis. Expression of IL-4 significantly
      enhanced virulence of both virulent and attenuated virus strains in susceptible
      (laboratory) and resistant (wild) rabbits. SLS-IL-4 completely overcame genetic
      resistance in wild rabbits. The pathogenesis of SLS-IL-4 was compared in
      susceptible and resistant rabbits. The results support a model for resistance to
      myxomatosis of an enhanced innate immune response controlling virus replication
      and allowing an effective antiviral cell-mediated immune response to develop in
      resistant rabbits. Expression of IL-4 did not overcome immunity to myxomatosis
      induced by immunization.

PMID- 15183060
TI  - Adenovirus type 5 pseudotyped with adenovirus type 37 fiber uses sialic acid as a
      cellular receptor.
AB  - For purposes of gene therapy, the tropism of adenovirus (Ad) serotype 5 vectors
      can be altered with fibers derived from alternative serotypes. However, there is
      currently limited information available on the cellular receptors used by the
      approximately 51 known Ad serotypes. Recently, alpha(2-->3)-linked sialic acid
      (2,3-SA) has been implicated as the cellular receptor for wild-type Ad37.
      However, some studies have demonstrated that wild-type Ad37 uses a 50-kDa protein
      and not sialic acid as its primary receptor for binding of human conjunctival
      cells. The sialic acid receptor has also been shown not to play a major role in
      the infection of these cells by an Ad5 virion pseudotyped with Ad37 fiber
      (Ad5.GFP.DeltaF/37F). In this study, we demonstrate that a similar virus (Ad5F37)
      can indeed use alpha(2-->3)-linked sialic acid as a cellular receptor. We also
      find that the receptor used by Ad5F37 is sensitive to proteases and that Ad5F37
      can use integrin more efficiently than sialic acid for cell entry. Unlike Ad5
      vectors, Ad5F37 does not efficiently employ the coxsackie and adenovirus receptor
      (CAR) to infect cells. Similar to Ad5, Ad5F37 infection of cells that form tight
      junctions can be enhanced by ethylenediaminetetraacetic acid (EDTA). These
      results have implications in the design of pseudotyped adenovirus vectors for
      gene therapy and may have particular use in the treatment of diseases involving
      breakdown of the blood-retinal barrier.

PMID- 15183061
TI  - N-linked glycosylation in the CXCR4 N-terminus inhibits binding to HIV-1 envelope
      glycoproteins.
AB  - CXCR4 is a co-receptor along with CD4 for human immunodeficiency virus type 1
      (HIV-1). We investigated the role of N-linked glycosylation in the N-terminus of
      CXCR4 in binding to HIV-1 gp120 envelope glycoproteins. Gp120s from CXCR4 (X4)
      and CCR5 (R5) using HIV-1 strains bound more efficiently to non-N-glycosylated
      than to N-glycosylated CXCR4 proteoliposomes in a CD4-dependent manner. Similar
      results were observed in binding studies using non-N-glycosylated or N
      glycosylated CXCR4 expressed on cells. Mutation of the N-glycosylation site N11
      in CXCR4 (N11Q-CXCR4) enhanced CD4-dependent binding of X4 and R5 gp120s and
      allowed more efficient entry of viruses pseudotyped with X4 or R5 HIV-1 envelope
      glycoproteins. However, the binding of R5 gp120 to N11Q-CXCR4 and entry of R5 HIV
      1 viruses into cells expressing N11Q-CXCR4 were 20- and 100- to 1000-fold less
      efficient, respectively, than the levels achieved using X4 gp120 or X4 HIV-1
      viruses. Binding of stromal cell-derived factor (SDF)-1alpha, the natural ligand
      of CXCR4, and SDF-1alpha-induced signaling were reduced by the N11Q mutation.
      These findings demonstrate that N-glycosylation at N11 inhibits the binding of
      CXCR4 to X4 and R5 HIV-1 gp120, and provide a better understanding of the
      structural elements of CXCR4 involved in HIV-1 Env-co-receptor interactions.

PMID- 15183062
TI  - A 40 kDa isoform of the type 5 adenovirus IVa2 protein is sufficient for virus
      viability.
AB  - The multifunctional IVa2 protein is essential for adenovirus replication [J.
      Virol. 77 (2003) 3586], but the relative importance of the transcriptional and
      encapsidation functions is unknown. As part of a study of IVa2 function, we
      created a set of mutations in the IVa2 gene in the correct location in the viral
      genome. Unexpectedly, an opal stop codon at position 6 was recovered in virus
      twice. Isolate #2 showed defective viral replication, but produced late proteins
      at almost wild-type levels. Analysis of IVa2 mRNA showed an additional species,
      larger and more abundant than the equivalent wild-type species. It was a hybrid
      of the 5' UTR of L3 23 kDa attached to the IVa2 second exon, so that M75 is the
      5' proximal methionine. This mRNA arises from a corresponding hybrid DNA, present
      in the virus stock. A protein of approximately 40 kDa, consistent with
      translation from the hybrid mRNA, was detected. It is able to bind to the
      packaging sequence and to the MLP downstream elements (DE1/2). Isolate #8 was
      more defective in replication than #2. No hybrid mRNA or DNA was detected, but it
      also produces a 40 kDa isoform, which is present in wild-type-infected cells.
      Mutational analysis of M75 and M101 revealed that the 40 kDa isoform is produced
      by initiation at Met75. This might be the origin of the previously unidentified
      40 kDa factor present in the heterodimer DEF-A, which binds to DE1 and DE2a.

PMID- 15183063
TI  - Envelope glycoproteins are not required for insertion of host ICAM-1 into human
      immunodeficiency virus type 1 and ICAM-1-bearing viruses are still infectious
      despite a suboptimal level of trimeric envelope proteins.
AB  - Previous works have indicated that incorporation of surface glycoprotein into
      retroviruses such as the human immunodeficiency virus type 1 (HIV-1) is not a
      highly specific process because several cellular glycoproteins can be inserted
      within the mature viral particle. The mechanism(s) that govern the acquisition of
      such host constituents have remained so far elusive. In this study, we have
      investigated the role played by the viral envelope (Env) of HIV-1 in the
      acquisition of host intercellular adhesion molecule type I (ICAM-1). ICAM-1
      proteins were still present on viruses carrying much lower levels of gp120/gp41
      due to a mutation in the matrix (MA) domain or on Env-deficient viruses when
      produced in immortalized and primary human cell lines. Interestingly, infectivity
      of an HIV-1 MA mutant that carry a suboptimal amount of Env proteins was restored
      to a certain degree by the presence of ICAM-1 when infection was performed in
      cells expressing an activated form of its natural counter-ligand, LFA-1.

PMID- 15183064
TI  - The tyrosine-based YXXO targeting motif of murine leukemia virus envelope
      glycoprotein affects pathogenesis.
AB  - Retroviruses, such as human and simian immunodeficiency viruses (HIV and SIV),
      and murine leukemia viruses (MuLV), harbor a tyrosine-based motif in the
      intracytoplasmic domain of their envelope glycoprotein. This motif can act as an
      endocytosis signal or as a targeting signal, restricting viral budding at
      specific cell surface membrane domains. In the present study, proviral DNA of the
      ecotropic Cas-Br-E strain of MuLV was modified by substitution or deletion of the
      critical tyrosine residue. Mutant viruses lost basolateral targeting in polarized
      MDCK epithelial cells while expression level of the glycoprotein at the cell
      surface was not affected. This suggests that the tyrosine-based motif in MuLV
      does not act as an endocytosis signal. Only a small delay in the appearance of
      disease was observed in inoculated mice. In contrast, a striking change in the
      pathology was observed with enlarged thymus and lymph nodes in animals inoculated
      with mutant viruses.

PMID- 15183065
TI  - Phosphorylation of the RNA polymerase II carboxyl-terminal domain in human
      cytomegalovirus-infected cells and in vitro by the viral UL97 protein kinase.
AB  - The carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II
      (RNAP II) ordinarily exists in electrophoretically distinct hypophosphorylated
      and hyperphosphorylated forms. Human cytomegalovirus infection induced forms of
      this subunit whose electrophoretic mobilities were intermediate without decreases
      in abundance of the original forms. Phosphatase treatment nearly eliminated the
      intermediate migrating forms. In vitro, the viral protein kinase, UL97,
      phosphorylated this subunit, a recombinant protein containing the CTD, and
      peptides containing the CTD consensus sequence, YSPTSPS. Phosphorylation occurred
      predominantly on serine 5 and was substantially reduced when either serine 2 or 5
      was already phosphorylated. The abundance of the intermediate and
      hypophosphorylated forms was reduced at most twofold during infections in which
      UL97 was genetically or pharmacologically inhibited. These results identify a new
      pattern of RNA polymerase II modification induced by virus infection and a viral
      enzyme that phosphorylates the CTD in vitro, but only possibly in vivo.

PMID- 15183066
TI  - Domains of macaque DC-SIGN essential for capture and transfer of simian
      immunodeficiency virus.
AB  - The C-type lectin DC-SIGN mediates the capture and transfer of simian
      immunodeficiency virus (SIV) from macaque dendritic cells (DCs) to permissive T
      cells. To further identify the determinants in macaque DC-SIGN required for
      capture and transfer of virus, we created mutants containing deletions or point
      mutations in the extracellular domains, and tested their ability to capture and
      transmit SIV. We found that SIV bound to the carbohydrate recognition domain
      (CRD) of macaque DC-SIGN via the envelope protein. In addition, deleting the C
      terminal half of the CRD, or mutating amino acids within this region that contact
      Ca(2+) or mannose, disrupted virion capture activity. However, an N-terminal CRD
      deletion mutant was capable of binding SIV, indicating that this region was not
      necessary for binding. Finally, deletion of the neck domain also reduced the
      capacity for macaque DC-SIGN to capture SIV. Interestingly, ICAM-3, the cellular
      ligand for DC-SIGN, did not bind to any of the DC-SIGN mutants, including mutants
      with amino acid changes in the N-terminal region of the CRD. These data suggest
      that the binding sites for SIV and ICAM-3 may be distinct but overlapping.
      Together, the data demonstrate the importance of both the neck and the CRD of
      macaque DC-SIGN for efficient capture of SIV and binding to ICAM-3.

PMID- 15183067
TI  - Isolation and characterization of the Mason-Pfizer monkey virus p12 protein.
AB  - The Mason-Pfizer monkey virus (M-PMV) Gag protein, precursor to the structural
      proteins of the infectious virion, assembles into immature capsid-like particles
      when expressed at high levels in bacterial cells. Similar capsid-like particles
      can be obtained by in vitro assembly using a high concentration of isolated Gag.
      M-PMV Gag contains a p12 protein that has no corresponding analogues in most
      other retroviruses and has been suggested to contain an internal scaffold domain
      (ISD). We have expressed and purified p12 and the N- and C-terminal halves (Np12
      and Cp12) that are predicted to be structurally independent domains. The behavior
      of these proteins was analyzed using chemical cross-linking, CD spectroscopy, and
      electron microscopy. The N-terminal half of p12 is largely alpha-helical although
      the C-terminal portion lacks any apparent ordered structure. Both p12 and Np12
      form high-order oligomers in vitro and when expressed in E. coli produce
      organized structures that are visible by electron microscopy. Interestingly,
      Cp12, as well as the whole protein, can form dimers in the presence of SDS. The
      data show that both domains of p12 contribute to its ability to multimerize with
      much of this potential residing in its N-terminal part, most probably within the
      leucine zipper-like (LZL) sequence.

PMID- 15183068
TI  - Fusion activity of lipid-anchored envelope glycoproteins of herpes simplex virus
      type 1.
AB  - Expression of the herpes simplex virus type 1 (HSV-1) glycoproteins gB, gD, gH,
      and gL is necessary and sufficient to cause cell fusion. To identify the
      requirements for a membrane-spanning domain in HSV-1 glycoprotein-induced cell
      fusion, we created gB, gD, and gH mutants with transmembrane and cytoplasmic
      domains replaced by a glycosylphosphatidylinositol (gpi)-addition sequence. The
      corresponding gBgpi, gDgpi, and gHgpi proteins were expressed with wild-type
      efficiency at the cell surface and were linked to the plasma membrane via a gpi
      anchor. The gDgpi mutant promoted cell fusion near wild-type gD levels when co
      expressed with gB, gH, and gL in a cell-mixing fusion assay, indicating that the
      gD transmembrane and cytoplasmic domains were not required for fusion activity. A
      plasma membrane link was required for fusion because a gD mutant lacking a
      transmembrane and cytoplasmic domain was nonfunctional for fusion. The gDgpi
      mutant was also able to cooperate with wild-type gB, gH, and gL to form syncytia,
      albeit at a size smaller than those formed in the wild-type situation. The gBgpi
      and gHgpi mutants were unable to promote fusion when expressed with the other
      wild-type viral glycoproteins, highlighting the requirement of the specific
      transmembrane and cytoplasmic domains for gB and gH function.

PMID- 15183069
TI  - Efficient delivery and stable gene expression in a hematopoietic cell line using
      a chimeric serotype 35 fiber pseudotyped helper-dependent adenoviral vector.
AB  - Certain human cell populations have remained difficult to infect with human
      adenovirus (Ad) serotype 5 because of their lack of coxsackievirus B-adenovirus
      receptor (CAR). Native adenovirus fiber compositions, although diverse, cannot
      infect all tissue types. Recently, a chimeric Ad5/35 fiber was created, which
      displays an altered tropism from Ad5. We incorporated this chimeric fiber into a
      helper-dependent (HD) adenovirus vector system and compared HD to E1-deleted
      (E1Delta) vectors by transgene expression, cell transduction efficiency, and
      cytotoxicity. K562 cells were infected approximately 50 times more efficiently
      with the chimeric Ad5/35 fiber compared with the Ad5 fiber. Short-term transgene
      expression was sustained longer from HD Ad5/35 than E1Delta Ad5/35 vector after
      in vitro infection of actively dividing K562 cells. Rapid loss of transgene
      expression from E1Delta Ad5/35 infection was not due to the loss of vector
      genomes, as determined by quantitative real-time PCR (QRT-PCR), or cytotoxicity,
      but rather through a putative silencing mechanism.

PMID- 15183070
TI  - Comparison of four regions in the replicase gene of heterologous infectious
      bronchitis virus strains.
AB  - Infectious bronchitis virus (IBV) produces six subgenomic (sg) mRNAs, each
      containing a 64 nucleotide (nt) leader sequence, derived from the 5' end of the
      genome by a discontinuous process. Several putative functional domains such as a
      papain-like proteinase (PL(pro)), main protease (M(pro)), RNA-dependent RNA
      polymerase (RdRp), and RNA helicase encoded by the replicase gene are important
      for virus replication. We have sequenced four regions of the replicase genes
      corresponding to the 5'-terminal sequence, PL(pro), M(pro), and RdRp domains from
      20 heterologous IBV strains, and compared them with previously published
      coronavirus sequences. All the coronavirus 5'-termini and PL(pro) domains were
      divergent, unlike the M(pro) and the RdRp domains that were highly conserved with
      28% and 48% conserved residues, respectively. Among IBV strains, the 5'
      untranslated region including the leader sequence was highly conserved (>94%
      identical); whereas, the N-terminal coding region and the PL(pro) domains were
      highly variable ranging from 84.6% to 100%, and 77.6% to 100% identity,
      respectively. The IBV M(pro) and RdRp domains were highly conserved with 82.7%
      and 92.7% conserved residues, respectively. The BJ strain was the most different
      from other IBVs in all four regions of the replicase. Phylogeny-based clustering
      based on replicase genes was identical to the antigen-based classification of
      coronaviruses into three groups. However, the IBV strain classification based on
      replicase gene domains did not correlate with that of the type-specific antigenic
      groups. The replicase gene sequences of many IBVs recovered from infected
      chickens were identical to those of vaccine viruses irrespective of serotype,
      suggesting that either there has been an exchange of genetic material among
      vaccine and field isolates or that there is a convergent evolution to a specific
      replicase genotype. There was no correlation between the genotype of any region
      of the replicase gene and pathotype, suggesting that the replicase is not the
      sole determinant of IBV pathogenicity.

PMID- 15183071
TI  - Melatonin and mitochondrial function.
AB  - Melatonin is a natural occurring compound with well-known antioxidant properties.
      In the last decade a new effect of melatonin on mitochondrial homeostasis has
      been discovered and, although the exact molecular mechanism for this effect
      remains unknown, it may explain, at least in part, the protective properties
      found for the indoleamine in degenerative conditions such as aging as well as
      Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries
      such as ischemia-reperfusion. A common feature in these diseases is the existence
      of mitochondrial damage due to oxidative stress, which may lead to a decrease in
      the activities of mitochondrial complexes and ATP production, and, as a
      consequence, a further increase in free radical generation. A vicious cycle thus
      results under these conditions of oxidative stress with the final consequence
      being cell death by necrosis or apoptosis. Melatonin is able of directly
      scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates
      antioxidative enzymes, increases the efficiency of the electron transport chain
      thereby limiting electron leakage and free radical generation, and promotes ATP
      synthesis. Via these actions, melatonin preserves the integrity of the
      mitochondria and helps to maintain cell functions and survival.

PMID- 15183072
TI  - A short note on the nucleolar size and density in apoptotic leukemic granulocytic
      precursors (HL-60 cells).
AB  - The present study was undertaken to provide more information on the nucleolar
      size and density in mononuclear blastic granulocytic precursors represented by HL
      60 cells the proliferation of which was blocked by photodynamic treatment (PDT)
      which induced apoptotic process without preceding terminal maturation. Both the
      nucleolar size and density did not change in apoptotic cells in comparison with
      controls. Thus, large and dense nucleoli in apoptotic cells are not necessarily
      related to the nucleolar biosynthetic or cell proliferation activity.

PMID- 15183073
TI  - Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia
      and lymphoma cells by induction of apoptosis.
AB  - Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used
      Chinese medicinal herbs. Although recent studies have demonstrated its antitumour
      activities on cancer cells in vitro and in vivo, the exact mechanism is not fully
      elucidated. Hence, the objective of this study was to examine the in vitro
      cytotoxic activities of a standardized aqueous ethanol extract prepared from
      Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic
      leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test
      whether the mechanism involves induction of apoptosis. Cell death ELISA was
      employed to quantify the nucleosome production resulting from nuclear DNA
      fragmentation during apoptosis. The present results demonstrated that CV extract
      at 50 to 800 microg/ml dose-dependently suppressed the proliferation of Raji, NB
      4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC50
      values: HL-60 (147.3 +/- 15.2 microg/ml), Raji (253.8 +/- 60.7 microg/ml) and NB
      4 (269.3 +/- 12.4 microg/ml). The extract however did not exert any significant
      cytotoxic effect on normal liver cell line WRL (IC50 > 800 microg/ml) when
      compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming
      the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji
      cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon
      the treatment of CV extract, while no significant nucleosome production was
      detected in extract-treated WRL cells. The CV extract was found to selectively
      and dose-dependently inhibit the proliferation of lymphoma and leukemic cells
      possibly via an apoptosis-dependent pathway.

PMID- 15183074
TI  - Chronopharmacology of oxacalcitriol in 5/6 nephrectomized rats.
AB  - We previously reported on the merits of the chronopharmacological effects of
      1,25(OH) 2 vitaminD3 in 5/6 nephrectomized rats (Tsuruoka et al, Life Scineces
      2002; 71: 1809-1820). In this study, the chronopharmacological effect of 22
      oxacalcitriol (OCT), a newly developed active vitaminD3 analogue with less
      calcemic activity, was evaluated by a single and repeated dosing of the drug. The
      5/6 nephrectomized animals were kept in rooms with a 12-h light/dark cycle.
      Single (12.5 microg/kg, i.v.) and repeated (5 microg/kg, i.v. three times a week
      for 12 weeks) dosing of OCT or vehicle was given at either 2 hours after lights
      on (2HALO) or 14 hours after lights on (14HALO). The severity of hypercalcemia
      and hyperphosphatemia was significantly milder when the drug was given at 14HALO.
      Serum concentrations of total OCT and albumin of the 2HALO and 14HALO trials did
      not differ significantly. The decrease of parathyroid hormone concentration was
      greater in the 14HALO trial while the increase in urinary ratio of Ca to
      creatinine was greater in the 2HALO trial. The suppression of urinary
      deoxypyridinoline excretion, an index of bone resorption capacity of osteoclast,
      and the increase in bone density of both femurs were greater in the 14HALO trial.
      These results suggest that the adverse reactions of OCT were ameliorated and its
      efficacy was enhanced after dosing of the drug at 14HALO. Chronopharmacological
      differences of OCT were more prominent than those seen with other vitamin D
      analogues. Dosing-time-dependent variation in the sensitivity of the drug to
      osteoclast were involved in the mechanisms of these events.

PMID- 15183075
TI  - Modulation of matrix metalloproteinase production from human lung fibroblasts by
      type 4 phosphodiesterase inhibitors.
AB  - Over-expression of matrix metalloproteinases by lung fibroblasts has been blamed
      for much of the tissue destruction associated with airway inflammation. Because
      cyclic AMP is known to regulate fibroblast proliferation, as well as cytokine and
      extracellular matrix protein production, the current study was designed to
      evaluate the ability of three selective phosphodiesterase (PDE) type 4
      inhibitors, rolipram, cilomilast and CI-1044, to inhibit extracellular matrix
      degradation. Using zymography and ELISA, we found that pro-MMP-2 release was
      enhanced following 24 h treatment of human lung fibroblast (MRC-5) with TGF-beta1
      (10 ng/ml) or TNF-alpha (10 ng/ml), whereas PMA (0.02 microM) had no effect. One
      hour of pre-incubation with PDE4 inhibitors (10 microM) induced an inhibition of
      TNF-alpha-stimulated pro-MMP-2 release. Zymography and immunoblotting revealed
      that fibroblasts cultured with PMA or TNF-alpha released increased amounts of pro
      MMP-1, whereas TGF-beta1 had no effect. Incubation with CI-1044 or cilomilast
      significantly prevented the TNF-alpha increase in pro-MMP-1. These results
      suggest that PDE4 inhibitors are effective in inhibiting the pro-MMP-2 and pro
      MMP-1 secretion induced by TNF-alpha and might underline a potential therapeutic
      benefit of selective PDE4 inhibitors in lung diseases associated with abnormal
      tissue remodelling.

PMID- 15183076
TI  - Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene
      lactone parthenolide and N-ethyl maleimide, and on its transactivating potential.
AB  - Sesquiterpene lactones (SLs) are potent anti-inflammatory substances. It was
      previously shown that the anti-inflammatory effect could be partly explained by
      the inhibition of the transcription factor NF-kappaB. Whether they inhibit the
      DNA binding of NF-kappaB, the activation of the IkappaB-kinase, or both is still
      a matter of debate. The data supporting these hypotheses were obtained using
      different cell systems. In this contribution we analyzed the mechanism of the
      sesquiterpene lactone-mediated inhibition using different cell systems, and
      showed that in all the cell lines analyzed, SLs inhibited both NF-kappaB binding
      and the IkappaB-kinase, but that the former played a more preponderant role in
      the inhibition. These results again confirm the importance of cysteine 38 in the
      inhibition and regulation of NF-kappaB's function. Moreover, we compared the
      selectivity of the SL parthenolide with that of N-ethyl maleimide (NEM). We
      showed that NEM directly alkylated p65 as well as p50 of NF-kappaB, whereas SLs
      possess a selectivity towards p65. Finally, we studied the transactivating
      properties of various p65 mutants, to analyze the effect of exchanged cysteine
      residues in the DNA binding domain of NF-kappaB/p65 on its function and
      demonstrated that the transactivating potential of the mutants did not correlate
      with their DNA binding strenght.

PMID- 15183077
TI  - Gender-dependent differences in biological rhythms of mice.
AB  - The advantage of a variable's rhythm resides in its optimal time-phasing. This
      implies that, for a given function, members of a species will strive to exhibit
      identical time-phasing namely, their inter-individual genetic differences will be
      masked. To examine the generality of this assumption we explored if inbred mice
      exhibit gender dependent differences in rhythm parameters of biochemical
      variables. Male and female mice, entrained by exposure to 12:12 light:dark
      illumination were sacrificed, every 3 hours over a 27 hours period. Activities of
      creatine-phosphokinase (CK) and alkaline- phosphatase (AP), white blood cell
      (WBC) counts and urea nitrogen (UN) concentration were determined at each time
      point. For each significant rhythm four parameters were computed: period,
      acrophase, mesor and amplitude. In addition two derived parameters were also
      calculated: relative-amplitude (RA) and the rate of change in RA (CRA) which
      provide information about the slope and width of the peak. Patterns of most
      variables exhibited a compound rhythm containing two significant periodicities.
      Gender dependent differences were documented in the parameters of most rhythms
      indicating that the genetic and physiological differences limit to a certain
      extent the phasing ability of the entraining signals and point to an independent
      control of each of the rhythm parameters.

PMID- 15183078
TI  - Losartan ameliorates progression of glomerular structural changes in diabetic
      KKAy mice.
AB  - Pathological changes in glomerular structure are typically associated with the
      progression of diabetic nephropathy. The involvement of angiotensin II (AII) in
      pathogenesis of diabetic nephropathy has been extensively studied and the
      therapeutic advantages associated with blockade of renin-angiotensin system
      (RAS), primarily with angiotensin converting enzyme (ACE) inhibitors, has been
      well-documented. We studied the effect of RAS blockade with an AII receptor
      antagonist (losartan) vs. an ACE inhibitor (enalapril) on glomerular lesions in
      KKAy mice, a model of type 2 diabetes mellitus. Losartan was administered at 3
      and 10 mg/kg/day and enalapril at 3 mg/kg/day for 14 weeks in the drinking water.
      The doses of losartan at 10 mg/kg/day was expected to be equivalent to 3
      mg/kg/day of enalapril when considering clinical doses for lowering blood
      pressure. The dose of 3 mg/kg/day of losartan was selected to compare the
      efficacy at equivalent dose of enalapril. Histologic observation demonstrated
      suppression of glomerular mesangial expansion and glomerulosclerosis with
      exudative lesion in the 10 mg/kg/day losartan group when compared to the
      untreated diabetic controls. A lesser degree of glomerulosclerosis was also
      observed with losartan and enalapril treatment at 3 mg/kg/day. Ultrastructural
      examination of renal glomeruli from the high dose losartan group revealed a
      decreased degree of effacement and/or irregular arrangement of glomerular
      podocytic foot process. The beneficial effect of RAS inhibition with the AII
      receptor antagonist losartan on diabetic glomerular lesions was clearly
      demonstrated in this study. These findings, therefore, provide mechanistic
      explanation for the clinical utility of losartan for use in the treatment of
      diabetic nephropathy in man.

PMID- 15183079
TI  - Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously
      hypertensive rats: persistent effects after withdrawal.
AB  - Our objective was to examine the effect of chronic treatment with amlodipine on
      blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously
      hypertensive rats and the persistence of such an effect after drug withdrawal. We
      investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine
      given orally for six months and at three months after drug withdrawal. Systolic
      blood pressure was measured using the tail-cuff method. At the end of the study
      period, the heart was excised, the left ventricle was isolated, and the left
      ventricle weight/body weight ratio was calculated as a left ventricular
      hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated
      using an automated image-analysis system on sections stained with Sirius red. Age
      matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive
      controls, respectively. Systolic blood pressure was reduced in the treated SHR in
      a dose-dependent way and after amlodipine withdrawal it increased progressively,
      without reaching the values of the hypertensive controls. Cardiac hypertrophy was
      reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only
      the group treated with 8 mg/kg/day maintained significant differences versus the
      hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and
      this regression persisted with the two highest doses after three months without
      treatment. We concluded that antihypertensive treatment with amlodipine is
      accompanied by a reduction in left ventricular hypertrophy and regression in
      collagen deposition. Treatment was more effective in preventing fibrosis than in
      preventing ventricular hypertrophy after drug withdrawal.

PMID- 15183080
TI  - Assessment of determinants of optimum performance of the CAST-2000 ELISA
      procedure.
AB  - The Cellular Antigen Stimulation Test (CAST), a recent innovation in the
      laboratory detection of allergen sensitivity, is a functional assay based on the
      release of sulphidoleukotrienes (LTs) from allergen-activated circulating
      basophils. The current study was undertaken to establish optimum determinants of
      this procedure. The results demonstrate that treatment of blood with preservative
      free heparin in polypropylene containers, and removal of erythrocytes by
      selective lysis with 0.83% ammonium chloride are excellent alternatives to the
      use of CAST venepuncture tubes and dextran, respectively. Similarly, decreasing
      and increasing the leucocyte concentration by 0.5- and 4-fold, respectively, as
      well as omission of interleukin-3 (IL-3) were also without significant effect.
      However, treatment of leucocyte suspensions with bacterial endotoxin (>1
      microg/ml) activated the release of sulphidoleukotrienes from basophils and/or
      other types of leucocytes. The findings of this study are clearly relevant, both
      with respect to cost and performance, when implementing the CAST in clinical
      immunology laboratories.

PMID- 15183081
TI  - The use of cryopreserved mature trophozoites in assessing antibody recognition of
      variant surface antigens of Plasmodium falciparum-infected erythrocytes.
AB  - Mature stages of Plasmodium falciparum insert variant antigens (VSA) into the
      surface of infected erythrocytes, and antibodies against such antigen provide
      variant-specific protection against malaria. Because mature P. falciparum
      trophozoites normally sequester away from the peripheral circulation, parasites
      for anti-VSA antibody studies are obtained from patients as ring trophozoites,
      cryopreserved, and cultured to maturity when required. However, this process is
      associated with problems of poor recovery from cryopreservation, growth failure
      and variations in time different isolates take to mature after recovery. We
      therefore assessed the use of cryopreserved mature trophozoites in anti-VSA
      assays. Cryopreservation of parasites did not alter their anti-VSA antibody
      reactivity phenotype as determined by agglutination assays or flow cytometry. We
      have therefore demonstrated that cryopreserved mature trophozoites are suitable
      for use in anti-VSA antibody assays. The use of cryopreserved mature trophozoites
      could help to circumvent the problems associated with recovery of cryopreserved
      ring trophozoites.

PMID- 15183082
TI  - Statistical considerations for the design and analysis of the ELISpot assay in
      HIV-1 vaccine trials.
AB  - Effector T lymphocyte responses are considered critical for controlling human
      immunodeficiency virus type-1 (HIV-1) infection. The enzyme-linked immunospot
      (ELISpot) assay has emerged as a primary means of assessing HIV-specific T cell
      responses, and the development of objective methods that distinguish positive and
      negative ELISpot responses while properly controlling the rate of false positives
      is critical. In this paper, we consider several statistical methods that are
      helpful in defining such a positive criterion. Simulation results under a variety
      of scenarios suggest that a permutation-based criterion using a resampling
      adjustment for multiple comparisons yields the desired false positive rate while
      remaining competitive with other potential criteria in terms of sensitivity.
      These results also provide guidance on the effect of the number of experimental
      and negative control replicate wells on assay sensitivity. Application of
      different potential positive criteria using ELISpot assay results from IFN-gamma
      secreting T cells of HIV-1 seropositive and seronegative donors confirmed several
      of the results obtained under simulation. Our findings support the application of
      statistically-based positive criteria such as the permutation-based resampling
      approach in assessing HIV vaccine-induced T cell responses. Moreover, the
      proposed methods have potential utility in related HIV immunopathogenesis studies
      and in non-HIV clinical vaccine trials.

PMID- 15183083
TI  - Methods for exposing multiple cultures of endothelial cells to different fluid
      shear stresses and to cytokines, for subsequent analysis of inflammatory
      function.
AB  - Endothelial cells are conditioned by physicochemical environmental factors,
      including shear stress applied by flowing blood. However, the effects of shear
      conditioning on the functional responses of endothelial cells, such as ability to
      recruit leukocytes, remain uncertain. Here we describe a system for culturing
      multiple samples of endothelial cells under flow for prolonged periods, either at
      different shear stresses, or exposed concurrently to different concentrations of
      cytokines, for instance, tumour necrosis factor-alpha (TNF). The endothelial
      cells were cultured in glass capillaries (microslides) that could be conveniently
      transferred to a flow-based adhesion assay, to test the ability of the cultures
      to support adhesion and migration of flowing leukocytes. Paired control, 'static'
      samples were exposed to the identical medium and culture geometry. We found that
      the type of tubing used in the culture flow circuit and its maintenance at 37
      degrees C were critical design factors, which could influence the response to TNF
      of the static controls which were exposed to recirculated medium. Endothelial
      cells conditioned by culture under flow showed a reduction in response to TNF, as
      judged by ability to induce the capture and migration of neutrophils. We found
      that the higher the shear stress, the weaker the ability to recruit neutrophils.
      This sensitivity to shear stress was greater if the cells were allowed to
      stabilise under static conditions for 24 h, compared to cells exposed to flow
      immediately after seeding. The inhibition of neutrophil recruitment was similar
      for cultures exposed to steady flow or flow with a pulsatile element (flow
      oscillation approximately 20% about the mean). Thus, we have developed a
      versatile culture system which allows investigations of functional modifications
      of endothelial cells and demonstrates the potential sensitivity of inflammatory
      responses to the local fluid environment.

PMID- 15183084
TI  - Rapid and sensitive immunomagnetic-electrochemiluminescent detection of p53
      antibodies in human serum.
AB  - The mutation of tumor suppressor p53 gene is common in malignant tumor. p53
      antibodies are products of immunoresponse against abnormal p53 protein. It has
      been found that p53 antibodies are of importance in tumor's diagnosis, prognosis
      and relapse monitoring. However, current method for detecting p53 antibodies,
      i.e. enzyme-linked immunosorbent assay (ELISA), requires a long time with
      multiple steps, and the assay is only semi-quantitative. In this work, a protocol
      for quantitative detection of p53 antibodies in human serum using immunomagnetic
      electrochemiluminescence (IM-ECL) was devoloped. The immunoassay format consisted
      of a three antibody sandwich in which a biotinylated capture antibody, was banded
      with the commercial p53 protein. A detector antibody was added to bind the p53
      protein at another site. Then, secondary antibody, labeled with ruthenium(II)
      tris-bipyridal, was added and, when bound to the bead immunocompiex, generated
      light in the presence of an excess of tripropylamine. The light was detected and
      measured by the analyzer made by us. Our experimental results indicate that the
      sensitivity of this assay was 10 pg of p53 antibodies per ml of reference serum
      (normal human serum). A stable calibration curve with a wide dynamic range was
      established. The calibration curve was linear from 0.01 to 1000 ng/ml, thus,
      making quantitation possible. An immunologic prozone effect was observed above
      1000 ng p53 antibodies per milliliter of serum. Serum samples from lung and
      nasopharyngeal carcinoma patients were tested using the IM-ECL assay. The
      positive rate of p53 antibodies were 28.6% in lung carcinoma and 8.33% in
      nasopharyngeal carcinoma, respectively. p53 antibody concentration in the
      carcerous human sera were quantified from the calibration curve. In the case of
      lung carcinoma, a trend was found that a higher p53 antibody concentration in the
      serum was likely linked to a higher stage of the cancer. This trend was not found
      in nasopharyngeal carcinoma. The assay uses only 50 microl of sample per test and
      requires a 30-min incubation period in addition to a 50 s acquisition time. This
      assay has several advantages over the commonly used ELISA method in terms of
      sensitivity, linear range, and assay time. Results of the study suggest that IM
      ECL is a feasible method for rapid and sensitive detection of p53 antibodies in
      human serum.

PMID- 15183085
TI  - Novel application of an in vitro technique to the detection and quantification of
      botulinum neurotoxin antibodies.
AB  - Detection of Clostridium botulinum neurotoxin (BoNT) neutralising antibodies is
      currently achieved using the mouse lethality assay (MLA). This technique has
      provided the majority of the data for vaccine development and, with the
      increasing use of BoNT as a therapeutic agent, the MLA is the assay of choice to
      evaluate 'non-responder' antisera. However, the MLA is semi-quantitative and has
      an animal consumption rate that raises ethical concerns. The development of an
      alternative is therefore desirable. Here, we describe an in vitro neuronal
      release assay that may represent such an alternative in terms of both its
      sensitivity and ability to produce quantitative data. Initially recognised in the
      course of assessing a novel vaccine candidate, the suitability of this assay has
      been further explored using an International standard. The results support the
      conclusion that the detection of neutralising antibodies in human sera should be
      attempted using this method.

PMID- 15183086
TI  - Optimization of intracellular cytokine staining for the quantitation of antigen
      specific CD4+ T cell responses in rhesus macaques.
AB  - Standard proliferation assays used for analysis of CD4+ T cell function have
      significant shortcomings, including limited sensitivity, lack of truly
      quantitative readouts and significant variability. We have optimized an
      intracellular cytokine staining (ICS) assay in rhesus macaques which allows us to
      identify virus-specific CD4+ T cells at the single-cell level with high
      sensitivity while reducing background staining to a minimum. A variety of
      parameters were tested to determine the optimal experimental conditions necessary
      for the detection of antigen-specific CD4+ T cells in macaques. Central to our
      optimized protocol was the addition of cross-linked costimulatory anti-CD28 and
      anti-CD49d Mabs, a modification which resulted in up to threefold enhancement of
      the frequency of TNF-alpha-secreting CD4+ T cells following superantigen- or
      antigen-specific stimulation. The ICS protocol was also optimized with respect to
      antigen concentration and duration of antigenic stimulation. These modifications
      resulted in a convenient and highly reproducible assay with intra- and inter
      assay variability of less than 10%. Although cryopreservation of PBMC generally
      led to a 40% to 80% decrease in the frequency of antigen-specific CD4+ T cells
      detected by ICS using stimulation with viral proteins, the use of overlapping
      peptide pools minimized the effects of cryopreservation on ICS responses. The use
      of more sensitive techniques such as ICS permits delineation of antigen-specific
      cells at the single cell level and should provide new insights into pathogen
      specific immune responses in the rhesus macaque model.

PMID- 15183087
TI  - Monitoring leukocyte traffic in vivo into human delayed-type hypersensitivity
      reaction.
AB  - Leukocyte traffic from blood to sites of inflammation has been elaborately
      studied in animal models and in vitro. However, to date, little understanding has
      accumulated on the process in humans in vivo. A noninvasive light confocal
      microscopy technique has enabled us to image leukocyte rolling, arrest and
      transmigrated cells in vivo in human tissues. In the current study, a delayed
      type hypersensitivity (DTH) reaction was elicited in the lower lip of healthy,
      Bacille Calmette-Guerin (BCG)-vaccinated volunteers by injection of respective
      purified protein derivate (PPD), mimicking the classic cutaneous Mantoux
      reaction. Subjects were imaged with real-time confocal microscopy at baseline and
      2, 4, 24 and 48 h after the injection. The number of rolling leukocytes did not
      increase significantly until at 48 h. Even then, rolling cells were seen in only
      a minority (23%) of blood vessels. The frequency of engaged blood vessels was,
      nevertheless, significantly greater than at baseline. As the inflammation
      generated with this challenge was mild, transmigrated leukocytes could be
      detected in the confocal microscopy only occasionally. Histology of biopsies
      taken immediately after imaging at 48 h showed a T cell-dominated leukocyte
      population at the site of the DTH reaction. We have thus developed a method to
      monitor noninvasively leukocyte traffic in vivo in human subjects during the
      classic inflammatory model of delayed-type hypersensitivity reaction.

PMID- 15183088
TI  - A novel method of Multiplexed Competitive Antibody Binning for the
      characterization of monoclonal antibodies.
AB  - We have developed a novel method of high-throughput Multiplexed Competitive
      Antibody Binning (MCAB). Using only a small amount of antibody and antigen, this
      method enables the sorting of a large, complex panel of monoclonal antibodies
      into different bins based on cross-competition for antigen binding. The MCAB
      assay builds on Luminex multiplexing bead-based technology to detect antibody
      competition. Because of its high sensitivity, the MCAB method is immediately
      applicable after identification of antigen-positive mAbs, providing information
      useful for advancing mAb candidates into further testing. The MCAB assay also can
      be used for sorting mAbs into binding groups after screening for functional
      activity.

PMID- 15183089
TI  - Discontinuous Percoll gradient centrifugation combined with immunomagnetic
      separation obviates the need for erythrocyte lysis and yields isolated
      eosinophils with minimal granule abnormalities.
AB  - Isolated blood eosinophils are routinely used to study eosinophil activation
      mechanisms. However, as revealed by ultrastructural analysis, different isolation
      protocols may yield purified eosinophils with marked variability in granule
      electron density. In this study, using eosinophil peroxidase (EPO) histochemistry
      and transmission electron microscopy (TEM), we have compared the morphology of
      eosinophils in immediately fixed whole blood (to represent a morphological
      baseline) with isolated eosinophils purified by a number of protocols.
      Eosinophils in whole blood contained intact specific secondary granules of which
      a few exhibited marginal coarsening of matrix electron density (4% (95% CI: 2 to
      7) altered granules per eosinophil). By contrast, eosinophils purified according
      to standard protocols, which included erythrocyte lysis with either ammonium
      chloride or distilled water, showed moderate to extensive loss in density of
      secondary granule core and/or matrix (NH4Cl: 62% (95% CI: 58 to 66); dH2O: 37%
      (95% CI: 30 to 44) altered granules). Stepwise analysis of eosinophils during the
      cell separation processes indicated that the granule abnormalities seen following
      erythrocyte lysis were further increased following immunomagnetic separation.
      However, when erythrocyte lysis was omitted, by use of a two-layered Percoll
      gradient (1.076 g/ml/1.088 g/ml) to which diluted whole blood was applied
      directly, eosinophils with minimal granule abnormalities (11% (95%CI: 9 to 13)
      altered granules) could be obtained after immunomagnetic separation. In
      conclusion, to obtain eosinophils with granule morphology more closely resembling
      the whole blood baseline phenotype, erythrocyte lysis should be avoided when
      separating eosinophils from human blood. Thus it will be possible to study in
      vitro the early transformation of resting eosinophils into the degranulating
      phenotype found in diseased tissues.

PMID- 15183090
TI  - A rapid flow cytometric method for determining the cellular composition of
      bronchoalveolar lavage fluid cells in mouse models of asthma.
AB  - Mouse models of allergic asthma are increasingly used to study the
      immunopathology of this complex disorder. The degree and type of airway
      inflammation is often studied by determination of differential cell counts on
      cytospins of bronchoalveolar lavage fluid (BALF) cells stained with May-Grunwald
      Giemsa, in which the separation of eosinophils (eos) from neutrophils (neutro)
      and of monocytes (mono) from activated T cells can be quite problematic. In this
      study, we compared differential cell counts based on morphological criteria on
      May-Grunwald Giemsa stained cytospins with a newly developed flow cytometric
      method. BAL fluid cells were identified based on forward and side scatter
      characteristics (FSC and SSC), autofluorescence of macrophages, and simultaneous
      one-step staining with antibodies for T cells (CD3-Cy-Chrome), B cells (B220-Cy
      Chrome), eosinophils (CCR3-PE), and dendritic cells (DCs) (MHCII-FITC, CD11c
      APC). The validity of this flow cytometric determination was tested by
      morphological analysis of flow-sorted cellular subsets. In an animal model of
      ovalbumin-induced asthma, this new method correlated very well with the
      differential counts based on cytospins. Flow cytometric determination of the
      cellular composition of BAL fluid in mouse models of asthma is a rapid and easy
      method that can replace differential cell counts based on morphology.

PMID- 15183091
TI  - Method for large scale isolation, culture and cryopreservation of human monocytes
      suitable for chemotaxis, cellular adhesion assays, macrophage and dendritic cell
      differentiation.
AB  - This paper presents an improved method of isolating, culturing and cryopreserving
      human monocytes in large quantity with high purity using standard laboratory
      centrifuges. Monocytes were isolated from 300 to 360 ml of heparinized human
      blood using a Double Density technique employing Ficoll Isopaque and 46% iso
      osmotic Percoll. Yields of monocytes ranged from 75 to 205 million (from 300 to
      360 ml of blood) with an average purity of 90.6%. The ability of fresh or frozen
      monocytes to adhere to endothelial cells in the presence of oxidized L-alpha-1
      palmitoyl-2-arachidonosyl-sn-glycero-3-phosphocholine (oxPAPC) or
      lipopolysaccharide (LPS) did not differ and no significant difference in response
      to the chemotactic stimulant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)
      was observed. We define a useful method for the culture and differentiation of
      fresh or frozen monocytes isolated by this method, into macrophages as judged by
      morphology, expression of the macrophage marker SRA-1 and induction of
      inflammatory genes TNF-alpha, IL-6 and COX-2. Also, fresh or frozen Double
      Density isolated cells can be successfully differentiated into dendritic cells in
      the presence of GM-CSF and IL-4 as judged by the expression of the hallmark
      surface proteins CD1a and DC-sign and the absence of CD14. This method also
      yields a pure population of lymphocytes.

PMID- 15183092
TI  - ELISPOT cell rescue.
AB  - The enzyme-linked immunospot (ELISPOT) assay is a highly sensitive and
      reproducible method for quantifying T cell-mediated immune responses, and has
      been used to measure antigen-specific responses post-vaccination. While there are
      several advantages of the ELISPOT assay for use in field settings for large-scale
      vaccination trials, blood draw volumes are often limited, and the number of
      antigen-specific responses that can be measured is constrained by the limited
      cell number. We reasoned that it should be possible to salvage and rescue viable
      cells from a completed ELISPOT assay post-incubation, to use for further
      experimentation. Here, we show that cells rescued from an ELISPOT plate after
      assay are viable, and may be used in a second cytokine-producing assay, in a
      proliferation assay, or to provide a source of DNA for genetic studies such as
      human leukocyte antigen (HLA) typing. Rescue of cells after an ELISPOT assay will
      be particularly useful for increasing sample utility and maximizing data
      collection from T cell assays in vaccine trials.

PMID- 15183093
TI  - Human/mouse cross-reactive anti-VEGF receptor 2 recombinant antibodies selected
      from an immune b9 allotype rabbit antibody library.
AB  - Vascular endothelial growth factor (VEGF) and its receptors have been implicated
      in promoting solid tumor growth and metastasis via stimulating tumor-associated
      angiogenesis. Models of murine tumor angiogenesis and receptor-specific
      antibodies are required to evaluate roles of VEGF receptors in mouse models of
      human cancer. Human VEGFR2 (also known as KDR) and murine VEGFR2 (or Flk-1) share
      85% amino acid sequence identity in their extracellular domain. We describe here
      the development of antibodies that cross-react with mouse and human VEGFR2. High
      affinity, species cross-reactive, Fabs specific for KDR/Flk-1 were selected from
      an antibody phage display library generated from an immunized rabbit of b9
      allotype. The selected chimeric rabbit/human Fabs were found to bind to purified
      KDR and Flk-1 with nanomolar affinity. Three of the selected Fabs detected KDR
      expression on human endothelial cells as well as Flk-1 on murine endothelial
      cells. The availability of anti-VEGFR2 Fab with species cross-reactivity will
      help to decipher the functional role of KDR/Flk-1 in tumor biology as well as
      facilitate the preclinical evaluation of the suitability of KDR/Flk-1 for drug
      targeting. This report underscores our earlier finding that b9 rabbits are
      excellent sources for high-affinity cross-reactive antibodies with therapeutic
      potential.

PMID- 15183094
TI  - Monocyte activation test for pro-inflammatory and pyrogenic contaminants of
      parenteral drugs: test design and data analysis.
AB  - An optimised test designed for an in vitro monocyte activation test for pro
      inflammatory and pyrogenic contaminants of parenteral drugs is described,
      together with ways to address the inherent variability of such assays in which
      cells are cultured using 96-well plates. The test preparation is cultured with
      peripheral blood mononuclear cells (PBMNC) and the contaminants in the test
      article stimulate the release from the cells of the endogenous pyrogenic cytokine
      interleukin-6 (IL-6). The test system is in use within the pharmaceutical
      industry and at a national control authority for detecting pro-inflammatory and
      pyrogenic contaminants, including 'rabbit-negative' and 'LAL-negative' non
      endotoxin pyrogens. Products tested include small molecules, biologicals and
      vaccines. The PBMNC/IL-6 monocyte activation test has been approved by the US FDA
      as an 'end-product release test' and also is being used for in-process testing.

PMID- 15183096
TI  - Endothelin-1 distribution and basolateral secretion in the retinal pigment
      epithelium.
AB  - Endothelins are a family of conserved vasoactive peptides that are widely
      expressed in different biological systems including the eye. In the cell culture
      model of retinal pigment epithelium, ARPE-19, the synthesis and secretion of
      endothelin-1 (ET-1) is regulated by cholinergics and TNF-alpha. In the present
      study we investigated the expression of ET-1 in RPE in situ, in rat and human
      eyes. Additionally, we have employed the human retinal pigment epithelial (ARPE
      19) cells to delineate the apical and basolateral ET-1 expression and secretion
      by confocal microscopy and radioimmunoassay, respectively. Our results suggest a
      possible conservation of ET-1 expression predominantly in the mammalian RPE
      underlining its importance at this site. Additionally, our results suggest that
      constitutive ET-1 secretion is predominantly towards the basolateral side in
      cultured RPE possibly allowing ET-1 to activate its receptors located in the
      choroidal blood vessels and regulate retinal and choroidal blood flow.

PMID- 15183095
TI  - Molecular genetics of age-related cataract.
AB  - Advances in molecular biological and genetic technology have greatly accelerated
      elucidation of the genetic contribution to age-related cataract. Epidemiological
      studies have documented tendencies for cataracts to occur more frequently in
      relatives of cataract patients than in the general population, genetic studies
      have demonstrated contributory roles of some specific genes in age related
      cataract in small populations, and molecular studies have shown changes in
      expression of specific genes in cataractous lenses. Together, these studies are
      beginning to provide a conceptual framework for understanding age-related
      cataracts.

PMID- 15183097
TI  - Plasma and macular responses to lutein supplement in subjects with and without
      age-related maculopathy: a pilot study.
AB  - There is a growing body of evidence which suggests that macular pigment (MP),
      which is entirely of dietary origin, protects against age-related maculopathy. We
      evaluated the effect of a daily 20 mg lutein ester (equivalent of 10 mg/day free
      lutein) supplement in patients with early age-related maculopathy (ARM), in terms
      of macular pigment optical density (MPOD) and plasma concentrations of lutein.
      MPOD was measured using a flicker photometric technique in seven ARM sufferers
      and six age-matched controls over a period of supplementation which lasted 18-20
      weeks. Plasma lutein increased from a mean (SD) baseline concentration of 182
      (127)ng ml(-1) to a peak of 1077 (165)ng ml(-1) in ARM patients, and from 152
      (57) to 1110 (605)ng ml(-1) in control subjects. Mean MPOD had increased
      significantly from baseline of 0.24 to a peak of 0.31 in ARM sufferers. This mean
      increment of 0.07 was the same for the age-matched controls (baseline: 0.20;
      peak: 0.27). The augmentation of MP, and plasma concentrations of lutein,
      following supplementation in subjects with ARM provides the first evidence the
      disease is not associated with intestinal malabsorption of the relevant macular
      carotenoids, and that a diseased macula can accumulate and stabilise lutein
      and/or zeaxanthin. Furthermore, these results suggest that the beneficial effects
      of lutein supplementation, if any, may be extended to subjects with established
      ARM.

PMID- 15183098
TI  - Superior colliculus responses to light - preserved by transplantation in a slow
      degeneration rat model.
AB  - PURPOSE: To determine whether retinal transplantation can preserve visual
      responses in the superior colliculus (SC) of the S334ter-line-5 rat, a transgenic
      model for slow photoreceptor degeneration, which is more similar to human
      retinitis pigmentosa than the fast degeneration line 3 S334ter rat. METHODS:
      Visual responses to a light flash were recorded in the SC. Rats that had received
      embryonic day (E) 19-20 fetal retinal sheet transplants at the age of 26-30 days
      were tested at the ages of 200-254 days. Controls were age-matched rats without
      surgery and with sham surgery. As a baseline, in no-surgery line-5 rats, the
      temporal pattern of visual sensitivity loss was evaluated electrophysiologically
      in the SC from 60 days up to one year of age. RESULTS: In untreated S334ter-line
      5 rats, decline in visual sensitivity in the SC was parallel to the photoreceptor
      loss. At 109 day of age, a relative scotoma developed in the area of the SC
      corresponding to the nasal retinal region. At 200-254 days of age, the majority
      of the SC was devoid of any light-driven responses. In contrast, at this time
      point, transplanted rats with 'good' retinal grafts with normal lamination had
      visual responses in the caudal region of the SC, the area corresponding
      topographically to the transplant location in the retina. In these rats, the
      various parameters of SC responses such as the latency of the onset of the visual
      response, the response peak amplitude and the consistency of the visual response
      were significantly different from the control groups (no-surgery, sham surgery,
      'poor' transplants) and were more comparable to normal albino rats, however, with
      a slightly longer latency (70-90 vs. 30-50 msec). CONCLUSIONS: Fetal retinal
      sheet transplantation showed a long-term rescue effect on visual function in this
      animal model of slow photoreceptor degeneration.

PMID- 15183100
TI  - Epidermal growth factor stimulation of RPE cell survival: contribution of
      phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways.
AB  - Epidermal growth factor (EGF) previously has been shown to stimulate short-term
      survival in vitro of cells derived from the native amphibian retinal pigment
      epithelium (RPE). In the present experiments, we have examined intracellular
      signaling pathways responsible for mediating these survival-specific growth
      factor effects, distinct from proliferative effects, using the human epithelial
      cell line RPE D407. When maintained as single cells in suspension culture in the
      absence of serum and exogenous survival factors, RPE D407 cell viability
      gradually declined over a 3-4 day period as a result of apoptotic cell death, a
      pattern similar to that seen for eye-derived RPE cells. Exposure to EGF (50 ng
      ml(-1)) enhanced cell survival by nearly 40% and caused a parallel increase in
      the tyrosine phosphate content of the EGF receptor (EGFR), as determined by
      immunoprecipitation and Western blotting. Both effects were completely blocked by
      1 microm AG1478, an EGFR-selective tyrosine kinase inhibitor. EGF also stimulated
      phosphorylation of the phosphatidylinositol 3'-kinase (PI3K)-dependent effector
      kinase Akt, as well as that of the MEK-dependent mitogen-activated kinase (MAPK),
      extracellular signal-regulated kinase (ERK). Furthermore, EGF-induced protection
      was substantially reduced by either the PI3K inhibitor LY294002 (25 microm) or
      the MEK inhibitor U0126 (10 microm), under conditions in which phosphorylation of
      Akt and ERK1/2, respectively, was blocked. Our results indicate that EGF
      stimulated survival of RPE D407 cells takes place as a result of signaling
      through both PI3K and ERK/MAPK pathways. Further, residual anti-apoptotic
      activity stimulated by EGF in the presence of both blockers suggests that
      additional as yet unidentified growth factor-dependent survival pathways exist.

PMID- 15183099
TI  - Phenotypic characterization of human corneal epithelial cells expanded ex vivo
      from limbal explant and single cell cultures.
AB  - Cultivated human corneal epithelial cells have been successfully used for corneal
      reconstruction. Explant and single cell systems are currently used for human
      corneal epithelial cultivation. This study was conducted to characterize the
      phenotypes of human corneal epithelial cells expanded ex vivo by these two
      culture systems with regard to their growth potential, morphology and antigen
      expression patterns. Human corneal epithelial cells were expanded by limbal
      explant culture or limbal single cell suspension culture on a mitomycin C treated
      3T3 fibroblast feeder layer. The phenotypes of primary cultured cells were
      evaluated by morphology and immunohistochemical staining with antibodies for
      proposed keratinocyte stem cell markers (p63, EGFR, K19 and integrin beta1) and
      differentiation markers (K3, involucrin and gap junction protein connexin 43).
      BrdU labeling was performed to identify the label-retaining cells. Human corneal
      epithelial cells were grown from limbal tissues preserved as long as 16 days by
      both culture systems. The growth rate depended on the tissue freshness, the time
      from death to preservation and the time from death to culture, but not on the
      donor age. Cell growth was observed in 96.2% (n = 43) of single cell suspension
      cultures and in 90.8% (n = 213) of explant cultures. The cell expansion was
      confluent in 10-14 days in single cell suspension cultures and 14-21 days in
      explant cultures. The cell morphology in single cell suspension culture was
      smaller, more compact and uniform than that in explant culture. Immunostaining
      showed a greater number of the small cells expressing p63, EGFR, K19 and integrin
      beta1, while more larger cells stained positively for K3, involucrin and connexin
      43 in both culture systems. BrdU-label retaining cells were identified in 2.3+/
      0.7% of explant cultures and 3.73+/-1.5% of single cell cultures chased for 21
      days. In conclusion, the limbal rims are a great treasure for ex vivo expansion
      of human corneal epithelial cells. The phenotypes of corneal epithelial cells,
      ranging from basal cells to superficial differentiated cells, are well maintained
      in both culture systems. Slow-cycling BrdU-label retaining cells, that are
      characteristic of stem cells, were identified in the cultures.

PMID- 15183101
TI  - Distribution of syndecans 1-4 within the anterior segment of the human eye:
      expression of a variant syndecan-3 and matrix-associated syndecan-2.
AB  - Control of the actomyosin network plays a role in regulating the movement of
      aqueous humor through the anterior segment of the eye. Receptors that could
      control its activity are unknown. In this study, we show that all four members of
      the syndecan family, which can regulate the actomyosin network, are present
      within the anterior segment. In both sections of human anterior segments and
      cultures of human trabecular meshwork (HTM), Schlemm's canal (HSC) and the
      ciliary muscle (HCM) cells from the anterior segment, syndecans-3 and -4 were the
      predominant family members. They were widely distributed throughout the anterior
      segment. Syndecan-3 within the anterior segment was a novel, recently described
      variant 55 kDa form. Low levels of syndecans-1 and -2 were also observed in situ
      and in all three cultures. Their expression was weaker and more localized than
      that observed for syndecans-3 and -4. Staining for syndecan-1 in HCM cultures was
      variable. In HTM and HSC cultures, syndecan-2 also co-distributed with
      fibronectin, laminin and type IV collagen suggesting that it was shed and
      associated with the extracellular matrix. Western blots supported this idea and
      showed syndecan-2 ectodomains in lysates from anterior segments.

PMID- 15183102
TI  - Functional evaluation of retina and optic nerve in the rat model of chronic
      ocular hypertension.
AB  - PURPOSE: To functionally characterize the rat retina and optic nerve after
      chronic elevation of the intraocular pressure (IOP) using electroretinography
      (ERG) and computerized pupillometry. METHODS: Chronic elevation of the IOP was
      induced in Brown Norway rats by combined injection of indocyanine green dye (ICG)
      into the anterior chamber and diode laser treatment, followed by ERG and pupil
      light reflex (PLR) monitoring. RESULTS: Laser treatment induced significant
      elevation of the IOP in operated eyes for 6 weeks, with maximal values observed
      14 days postoperatively (ctrl=18.4+/-2.4 and operated=35+/-8.4 mmHg; mean+/-sd).
      Preoperative values for the PLR(ratio) were 68.5+/-4% (mean+/-sem; %). Three days
      postoperatively the PLR(ratio) decreased to 60.3+/-10.3%, but was not
      significantly different compared to preoperative values (p > 0.05 Kruskal-Wallis
      non-parametric test with Dunn's post-test). However, 7, 14 and 21 days
      postoperatively the PLR function dramatically decreased to 14.6+8.6, 11.5+/-6.7
      and 12.6+/-4%, respectively, and was significantly smaller compared to
      preoperative values (p < 0.01). At day 28 the PLR significantly recovered and was
      not significantly different compared to preoperative values (PLR(ratio)=38.5+/
      8.6, p > 0.05). However, 35 days after surgery the PLR started to decrease once
      again in the operated eyes (PLR(ratio)=17.2+/-7.4%) and was significantly smaller
      again compared to preoperative values (p < 0.05) The PLR values continued to
      decrease until the end of experiment (60 days postoperatively). ERG analysis of
      operated eyes revealed significantly decreased amplitudes of a- and b-waves 10d
      postoperatively, while oscillatory potentials (OPs) and flicker ERG (flERG)
      amplitudes were not detectable. However, 28 days postoperatively OPs
      significantly, but temporarily recovered, while a-wave, b-wave and flERG
      amplitudes did not significantly change compared to values observed 10d
      postoperatively. The ERG analysis of the operated eyes revealed significantly
      reduced amplitudes 60 days postoperatively. Histological analysis revealed
      degeneration of all retina layers and optic nerve axons. CONCLUSIONS: Chronic
      ocular hypertension in rats produces dramatic damage to all retinal layers and
      optic nerves observed by morphological and functional methods which significantly
      correlate with the IOP elevation. Outer retina of glaucomatous rats seems to be
      more susceptible to the damage due to chronic elevation of the IOP. Chronic
      hypertensive rat eyes have capacity to temporarily recover function of the inner
      retina and optic nerve.

PMID- 15183103
TI  - Investigations for retinopathy in an avian model for systemic sclerosis.
AB  - Systemic Sclerosis (SSc) is a connective tissue disease affecting the skin and
      internal organs. Retinopathy has been described in patients with SSc, but cannot
      be distinguished from secondary changes due to concomitant hypertension. UCD 200
      chickens, a well-established animal model for SSc, were used in this study to
      investigate the posterior ocular segment for manifestations of SSc. Terminal
      deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling was applied
      to detect endothelial cell (EC) apoptosis, a condition previously shown to
      represent the first step in SSc pathogenesis in humans and to be present in the
      skin and the involved internal organs of UCD 200 chickens in the acute stage. Our
      study showed a complete absence of EC apoptosis in the pecten and choroidal
      vessels of UCD 200 chickens in the acute stage. Ophthalmoscopy, biomicroscopy and
      histology revealed normal structures of the pecten, retina and choroid in the
      chronic stage. In summary, we showed that there is no primary involvement of the
      posterior ocular segment in avian SSc. SSc of UCD 200 chickens closely mimics
      human SSc, presenting all the clinical, serological and histological disease
      manifestations seen in the human counterpart. Therefore, our data raise serious
      doubts about primary posterior ocular involvement in human SSc. However, fundal
      examinations in patients with SSc may have their justification for assessment of
      hypertensive retinopathy.

PMID- 15183104
TI  - Intracellular [Na+], Na+ pathways, and fluid transport in cultured bovine corneal
      endothelial cells.
AB  - The mechanism of fluid transport across corneal endothelium remains unclear. We
      examine here the relative contributions of cellular mechanisms of Na+ transport
      and the homeostasis of intracellular [Na+] in cultured bovine corneal endothelial
      cells, and the influence of ambient Na+ and HCO3- on the deturgescence of rabbit
      cornea. Bovine corneal endothelial cells plated on glass coverslips were
      incubated for 60 min with 10 microm of the fluorescent Na+ indicator SBFI
      precursor in HCO3- HEPES (BH) Ringer's solution. After loading, cells were placed
      in a perfusion chamber. Indicator fluorescence (490 nm) was determined with a
      Chance-Legallais time-sharing fluorometer. Its voltage output was the ratio of
      the emissions excited at 340 and 380 nm. For calibration, cells were treated with
      gramicidin D. For fluid transport measurements, rabbit corneas were mounted in a
      Dikstein-Maurice chamber, and stromal thickness was measured with a specular
      microscope. The steady-state [Na+]i in BH was 14.36+/-0.38 mM (n = mean+/-s.e.).
      Upon exposure to Na+ -free BH solution (choline substituted), [Na+]i decreased to
      1.81+/-0.20mM (n = 19). When going from Na+ -free plus 100 microm ouabain to BH
      plus ouabain, [Na+]i increased to 46.17+/-2.50 (n = 6) with a half time of 1.26+/
      0.04 min; if 0.1 microm phenamil plus ouabain were present, it reached only
      21.78+/-1.50mm. The exponential time constants (min-1) were: 0.56+/-0.04 for the
      Na+ pump; 0.39+/-0.01 for the phenamil sensitive Na+ channel; and 0.17+/-0.02 for
      the ouabain-phenamil-insensitive pathways. In HCO3- free medium (gluconate
      substituted), [Na+]i was 14.03+/-0.11mM; upon changing to BH medium, it increased
      to 30.77+/-0.74 mm. This last [Na+]i increase was inhibited 66% by 100 microm
      DIDS. Using BH medium, corneal thickness remained nearly constant, increasing at
      a rate of only 2.9+/-0.9 microm hr-1 during 3 hr. However, stromal thickness
      increased drastically (swelling rate 36.1+/-2.6 microm hr-1) in corneas
      superfused with BH plus 100 microm ouabain. Na+ -free, HCO3- free solution and
      100 microm DIDS also led to increased corneal swelling rates (17.7+/-3.6, 14.4+/
      1.6 and 14.9+/-1.2 microm hr-1, respectively). The present results are explained
      by the presence of a DIDS-inhibitable Na+-HCO3- cotransporter and an epithelial
      Na+ channel, both previously found in these cells. On the other hand, the
      quantitative picture presented here appears a novelty. The changes we observe are
      consistent with pump-driven rapid exchange of intracellular Na+, and
      recirculation of fully 70% of the Na+ pump flux via apical Na+ channels.

PMID- 15183105
TI  - Revival of inactive glyceraldehyde 3-phosphate dehydrogenase in human cataract
      lenses by reduction.
AB  - In this study, endogenous as well as synthetic reducing systems were shown to
      reduce the disulphide bonds formed in glyceraldehyde 3-phosphate dehydrogenase,
      an important glycolytic enzyme previously reported to have lost its activity in
      human cataract lenses, resulting in reviving the activity of this enzyme.
      Disulphide bond formation is a non-specific posttranslational modification of
      proteins, which leads to a loss of function of the affected protein. When an
      enzyme is targeted, this harmful effect can be easily detected by monitoring the
      change of activity. Endogenous reducing systems are responsible for breaking
      these bonds and returning the protein (enzyme) to its natural state, when these
      mechanisms fail to do so, the loss of enzyme activity will be permanent.

PMID- 15183106
TI  - Role of chymase on growth of cultured canine Tenon's capsule fibroblasts and
      scarring in a canine conjunctival flap model.
AB  - Chymase is a chymotrypsin-like serine protease contained in the secretory
      granules of mast cells. Recently, we reported that chymase activity and the
      number of chymase-positive mast cells in conjunctival tissues were significantly
      increased during the wound healing process in a hamster model of glaucoma
      surgery. However, it has been unclear the role of chymase on conjunctival
      scarring. In the present study, we evaluated the effect of dog chymase on cell
      proliferation of fibroblasts established from canine Tenon's capsule and the
      effect of a chymase inhibitor on scarring in a canine conjunctival flap model.
      After a fibroblast cell culture was established from canine Tenon's capsules, the
      fibroblasts were incubated in the presence of dog chymase (5-20 ng ml(-1)). Cell
      proliferation was evaluated by bromodeoxyuridine incorporation. In a canine
      conjunctival flap model, a sponge treated with a chymase inhibitor, Suc-Val-Pro
      Phe(P)(OPh)(2), or placebo was placed in between the conjunctiva and sclera and
      the conjunctival incision was closed. One week after the surgery, adhesion degree
      was assessed, and chymase activities in the conjunctival lesion and in the areas
      of the conjunctiva and sclera were measured. In cultured canine Tenon's capsule
      fibroblasts, dog chymase significantly increased cell proliferation, and this
      chymase-dependent proliferation was completely suppressed by the chymase
      inhibitor. In the canine surgical model, chymase activity in placebo-treated eyes
      was significantly increased compared to control eyes, while it was significantly
      decreased by treatment with the chymase inhibitor. Scores for adhesion degree in
      the chymase inhibitor-treated eyes were significantly decreased in comparison
      with those in placebo-treated eyes. The conjunctival area in the chymase
      inhibitor-treated eyes was also suppressed to 52.6% compared with that in placebo
      treated treated eyes. In conclusion, chymase stimulates proliferation of
      fibroblasts derived from canine Tenon's capsule and chymase may play an important
      role in scarring after glaucoma surgery.

PMID- 15183107
TI  - Correlation between retinal ganglion cell death and chronically developing
      inherited glaucoma in a new rat mutant.
AB  - Glaucoma is a progressive optic neuropathy with characteristic optic disc
      changes, retinal ganglion cell loss and progressive visual field defects.
      Elevated intraocular pressure is considered to be a major risk factor in
      glaucomatous neuropathy. This study aimed to characterize and document a new
      chronic glaucoma model in the rat with respect to the effect of elevated
      intraocular pressure on overall retinal dysfunction and retinal ganglion cell
      loss, and to elucidate the possible mechanisms underlying this cell loss.
      Intraocular pressure (IOP) was measured in rats using a Tonopen. RGCs were
      retrogradely labeled with the fluorescent dye, 4-[didecylaminostyryl]-N-methyl
      pyridinium-iodide (4-Di-10 ASP) and quantified on retinal flat mounts using
      fluorescence microscopy. The optic nerve head was examined fundoscopically.
      Changes in the histological appearance of the whole eyes was studied in paraffin
      sections, and immunohistochemistry was carried out on cryostat sections. The
      levels of mRNA for several genes were compared between control and glaucomatous
      retinae using semi-quantitative RT-PCR. Mutant animals are affected with either a
      unilateral or bilateral enlargement of the globes having an IOP that ranged from
      25 to 45 mmHg, as compared to control values of 12-16 mmHg. The IOP of
      glaucomatous eyes increased significantly with age to attain a value of 35+/-7.3
      at 1.5 years. Concomitant with the rise in IOP, the number of labeled RGCs
      continued to decrease in number with age. A total of 1887+/-117RGC mm(-2) could
      be labeled in wild-type control and juvenile mutant pre-glaucomatous retinas,
      whereas this number dropped to 92+/-26RGC mm(-2) at 1.5 years. Ophthalmoscopy
      revealed atrophied optic nerve heads in the affected eyes. The pars plicata and
      the pars plana of the ciliary body of glaucomatous eyes were hypertrophied and
      elongated, respectively. The anterior chamber was narrow and the irido-corneal
      angle open in glaucoma eyes. The mRNA of glial-fibrillary-acidic protein,
      endothelin-1, STAT-3 and STAT-6 increased in the retinas correlating with the
      severity and duration of the disease. Changes in the expression of GFAP and
      endothelin-1 could be confirmed using immunohistochemistry. This model may help
      to address several fundamental issues in the pathogenesis of glaucoma and aid in
      the development of neuroprotective strategies.

PMID- 15183108
TI  - Quantitative ex vivo detection of rodent retinal ganglion cells by immunolabeling
      Brn-3b.
AB  - To evaluate the neuroprotective potential of drug candidates to treat human
      glaucoma, a short-term rodent model of retinal ganglion cell death was employed.
      Transient ischemia applied to the rodent retina, with subsequent reperfusion for
      1-4 weeks, produces an experimental retinal ganglion cell death that is
      quantifiable. A widely used method to detect viable retinal ganglion cells
      involves surgical injection of labeling compounds into the superior colliculus of
      the rodent brain, the retrograde transport of the compounds along the axons to
      the retina, and subsequent microscopic evaluation of the retina. In order to
      circumvent the labor intensive and invasive surgery of this method, we sought an
      alternative means of assessing retinal ganglion cell survival that would be more
      suitable for high-throughput analysis. We therefore developed a method of
      immunolabeling whole retinas ex vivo with an antibody to Brn-3b, an antigen
      expressed in a subpopulation of retinal ganglion cells, that allows for detection
      of a representative retinal ganglion cell population. Fluorescently tagged Brn-3b
      immunolabeled retinas were flat-mounted, digitally imaged, and assessed using
      image analysis software. We determined that 60 min of ischemia caused a 49% and a
      32% decrease in Brn-3b positive retinal ganglion cells in Lewis rats after 4
      weeks reperfusion, and Sprague-Dawley rats after 2 weeks reperfusion,
      respectively. In Swiss Webster ND4 mouse retinas subjected to 45 min ischemia and
      7 days reperfusion, we found a 70% decrease in Brn-3b positive cells. Thus, ex
      vivo immunolabeling of retinal ganglion cells using antibody to Brn-3b provides
      an alternative to other methods of quantifying retinal ganglion cells.

PMID- 15183109
TI  - Glutathione S-transferase M1 and its implications in glaucoma pathogenesis: a
      controversial matter.

PMID- 15183112
TI  - Oxidative stress response of tumor cells: microarray-based comparison between
      artemisinins and anthracyclines.
AB  - The antimalarial artemisinins also reveal profound cytotoxic activity against
      tumor cells. Artemisinins harbor an endoperoxide bridge whose cleavage results in
      the generation of reactive oxygen species (ROS) and/or artemisinin carbon
      centered free radicals. Established cancer drugs such as anthracyclines also form
      ROS and free radicals that are responsible for the cardiotoxicity of
      anthracyclines. In contrast, artemisinins do not reveal cardiotoxicity. In the
      present investigation, we compared the cytotoxic activities of different
      artemisinins (artemisinin, artesunate, arteether, artemether, artemisitene,
      dihydroartemisinylester stereoisomers) in 60 cell lines of the National Cancer
      Institute (NCI), USA, with those of anthracyclines (doxorubicin, daunorubicin, 4'
      epirubicin, idarubicin, deoxydoxorubicin, trifluoroacetyl-doxorubicin-14
      valerate). The inhibition concentration 50% (IC(50)) values of artemisinins and
      anthracyclines were correlated with the mRNA expression of 170 genes involved in
      oxygen stress response and metabolism as recently determined by microarray
      analysis and deposited in the NCI database (http://dtp.nci.nih.gov). The genes
      whose expression was significantly linked to cellular drug response in Kendall's
      tau tests were subjected to hierarchical cluster analysis and cluster image
      mapping. Mathematical correction for false-positive correlations was done by a
      false discovery rate algorithm. One cluster contained predominantly genes with a
      relationship to artemisinins and another one genes with a relationship to
      anthracyclines. In a third cluster, genes correlating to both drug classes were
      assembled. This indicates that different sets of genes involved in oxidative
      stress response and metabolism may contribute to the cytotoxic and differing
      toxic side effects of these drug classes.

PMID- 15183113
TI  - An in vitro model system that can differentiate the stages of DNA replication
      affected by anticancer agents.
AB  - We have previously reported on the potential use of a novel in vitro human cell
      derived model system to investigate the mechanism of action of anticancer agents
      that directly affect the process of DNA replication. Our cell-free system uses a
      multiprotein DNA replication complex (designated the DNA synthesome) that has
      been isolated, characterized, and extensively purified from a wide variety of
      mammalian cells and tissues. The DNA synthesome is competent to orchestrate
      simian virus 40 (SV40) origin-specific and large T antigen-dependent DNA
      replication in vitro. In this study, the synthesome-based cell-free system was
      tested to evaluate the mechanism of action of 1-beta-d-arabinofuranosylcytosine
      (ara-C), camptothecin (CPT), and doxorubicin (DOX). Using a novel synthesome
      based in vitro kinetic assay, we demonstrated that DNA replication mediated by
      the synthesome is initiated within the SV40 replication origin and proceeds
      bidirectionally in a manner analogous to that occurring within the cell. Ara-CTP,
      CPT, and DOX have been found to affect different stages of the in vitro DNA
      replication process mediated by the complex. Ara-CTP inhibited both the
      initiation and elongation stages, whereas CPT produced most of its effects by
      inhibiting the elongation phase of DNA replication. DOX inhibited the termination
      stage of DNA synthesis mediated by the synthesome. The data presented here
      support our contention that the DNA synthesome represents a highly effective in
      vitro model system for investigating the mechanism by which some anticancer
      agents can directly affect the process of DNA replication.

PMID- 15183114
TI  - Inactivation of protease-activated receptor-1 by proteolytic removal of the
      ligand region in vascular endothelial cells.
AB  - Proteolysis plays an important role in inactivating protease-activated receptor-1
      (PAR1). We aimed to determine the cleavage site(s) responsive for the proteolytic
      inactivation of PAR1 in human umbilical vein endothelial cells. Fura-2
      fluorometry revealed that the preceding stimulation with trypsin abolished the
      subsequent [Ca(2+)](i) response to thrombin, while the responses to PAR1
      activating peptides remained intact. On the other hand, thrombin had no effect on
      the subsequent response to trypsin. The immunostaining with antibodies against
      the residues 35-46 (SPAN12) and 51-64 (WEDE15) revealed the broad boundaries of
      cleavage. Trypsin removed both epitopes from the cell surface within 3 min, while
      thrombin removed the epitope of SPAN12. The longer incubation with thrombin
      removed the epitope of WEDE15. However, PAR1-activating peptides thereafter
      induced an attenuated but significant elevation of [Ca(2+)](i). Not only the
      receptor internalization as observed with a confocal microscope, but also an
      additional cleavage was thus suggested to contribute to the thrombin-induced
      removal of the epitope of WEDE15. The analyses of the PAR1 mutants identified
      three cleavage sites for trypsin; residues 41-42, 70-71 and 82-83. The cleavage
      at the latter two sites was suggested to dominate that at the former, and thus
      remove the ligand region (residues 42-47). The inactivation of PAR1 due to
      proteolytic removal of the ligand region may contribute not only to the
      inactivation of PAR1 by proteases such as trypsin, but also to the termination of
      the intracellular signaling initiated by thrombin in the vascular endothelial
      cells.

PMID- 15183115
TI  - Prior in vitro exposure to GLP-1 with or without GIP can influence the subsequent
      beta cell responsiveness.
AB  - Glucagon-like peptide-1 (7-36) amide (GLP-1) and glucose-dependent insulinotropic
      peptide (GIP) potentiate glucose-induced insulin release when present at the time
      of nutrient stimulation. This study examines whether they can also influence rat
      beta cell responsiveness to subsequent stimulations. When rat beta cells were
      cultured for 24 h with 1 nM GLP-1, they progressively desensitized to subsequent
      GLP-1 stimuli, as evidenced by cellular cAMP production. This GLP-1-induced
      desensitization did not occur when the incretin was only present during three
      periods of 1 h at 10 mM glucose that alternated with 6-9 h culture at 3 mM
      glucose. After these 24h, the beta cells exhibited the same secretory response to
      glucose (10 mM) and GLP-1 (10 nM at 10 mM glucose), whether GLP-1 was present
      during the pulses or not. Similarly the presence of 1 nM GIP during these one
      hour pulses did not influence subsequent secretory responses to glucose and GLP
      1. However, when both GLP-1 and GIP, each at 0.5 nM, were added to the one hour
      pulses, they not only amplified insulin release during the pulses, as was the
      case with their single addition, but also increased the secretory response to a
      subsequent stimulation by glucose and GLP-1. These data distinguish between a
      desensitization effect of a prolonged exposure to GLP-1 and a positive priming
      effect of a discontinuous exposure to a combination of GLP-1 plus GIP. They may
      have to be taken into account in drug treatment strategies aiming the mimicking
      of physiologic patterns in the regulation of insulin release.

PMID- 15183116
TI  - Selective inhibitors of type I receptor kinase block cellular transforming growth
      factor-beta signaling.
AB  - Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a
      key role in a variety of physiological processes and disease states. Blocking
      TGFbeta signaling represents a potentially powerful and conceptually novel
      approach to the treatment of disorders in which the signaling pathway is
      constitutively activated, such as cancer, chronic inflammation with fibrosis and
      select immune disorders. In this paper, we describe the biological properties of
      a novel series of quinazoline-derived inhibitors of the type I transforming
      growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and
      keep the kinase in its inactive conformation. These compounds effectively
      inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with
      an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block
      TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta
      mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and
      mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal
      transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the
      potential to be further developed as anti-cancer and -fibrosis agents. In
      addition, they represent valuable new tools for dissecting the biochemical
      mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta
      signaling pathways in different physiological and disease processes.

PMID- 15183117
TI  - Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation,
      development of cell-mediated cytotoxicity, and cytokine production in vitro.
AB  - Curcumin (diferuloylmethane), a major curcumanoid found in the spice turmeric,
      exhibits anti-inflammatory, anti-oxidant, and chemopreventive activities.
      However, the effect of curcumin on the development of T cell-mediated
      immunological responses largely remains unknown. In this study we have
      investigated the effect of curcumin on mitogen/antigen induced proliferation of
      splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs), lymphokine
      activated killer (LAK) cells, and the production of cytokines by T lymphocytes
      and macrophages. We found that mitogen, interleukin-2 (IL-2) or alloantigen
      induced proliferation of splenic lymphocytes, and development of cytotoxic T
      lymphocytes is significantly suppressed at 12.5-30 micromol/L curcumin. The
      generation of LAK cells at similar concentrations was less sensitive to the
      suppressive effect of curcumin compared to the generation of antigen specific
      CTLs. Curcumin irreversibly impaired the production of these immune functions,
      since lymphoid cells failed to respond to the activation signals following 8h
      pretreatment with curcumin. Curcumin also inhibited the expression/production of
      IL-2 and interferon-gamma (IFN-gamma) by splenic T lymphocytes and IL-12 and
      tumor necrosis factor-alpha (TNF-alpha) by peritoneal macrophages irreversibly.
      Curcumin inhibited the activation of the transcription factor nuclear factor
      kappaB (NF-kappaB) without affecting the levels of constitutively expressed NF
      kappaB. The latter result suggests that curcumin most likely inhibits cell
      proliferation, cell-mediated cytotoxicity (CMC), and cytokine production by
      inhibiting NF-kappaB target genes involved in induction of these immune
      responses.

PMID- 15183118
TI  - Phenylthiourea as a weak activator of aryl hydrocarbon receptor inhibiting
      2,3,7,8-tetrachlorodibenzo-p-dioxin-induced CYP1A1 transcription in zebrafish
      embryo.
AB  - The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor
      that can be activated by a diverse synthetic and naturally-occurring chemicals,
      such as the halogenated aromatic hydrocarbons (HAHs) and the non-halogenated
      polycyclic aromatic hydrocarbons (PAHs). The liganded AHR modulates the genetic
      activity of a variety of xenobiotic-responsive genes, including cytochrome
      P4501A1 (CYP1A1). The tyrosinase inhibitor 1-phenyl-2-thiourea (PTU) is widely
      used in zebrafish research to suppress pigmentation in developing embryos/fry.
      Here we showed that 0.2 mM PTU induced a basal level of CYP1A1 transcription in
      zebrafish embryonic integument as early as 24 h postfertilization (hpf) stage.
      Subsequently, PTU induced CYP1A1 transcription in blood vessels at 36 hpf. During
      larval stage, the liver and all pharyngeal arch vessels of PTU-treated embryos
      exhibited CYP1A1 transcription as well. Comparing to TCDD, PTU induces CYP1A1
      transcription with much lower efficacy in zebrafish embryos. Coincubating the
      embryos with PTU and TCDD led to repressing TCDD-induced CYP1A1 transcription.
      Mechanistic studies indicated that both of PTU- and TCDD-mediated CYP1A1
      transcriptions are modulated by the same AHR-ARNT signaling pathway.

PMID- 15183119
TI  - Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin
      containing monooxygenases (Fmos).
AB  - The cell-, tissue-, sex- and developmental stage-specific expression profiles of
      five members of the flavin-containing monooxygenase (FMO) family, FMO1, 2, 3, 4
      and 5, were investigated in 129/SV mice, using isoform-specific antisense RNA
      probes. In situ hybridization localized FMO1 and 5 mRNAs to the perivenous, and
      FMO 2, 3 and 4 mRNAs to the periportal, regions of the liver. In kidney, each FMO
      mRNA is localized to the distal and proximal tubules and collecting ducts; FMO1
      mRNA is present also in the glomerulus. In lung, FMO1 and 3 mRNAs are expressed
      in the terminal bronchiole, and FMO1 mRNA also in the alveoli. FMO1 mRNA is
      present in neurons of the cerebrum and in the choroid plexus. RNase protection
      assays showed that the most abundant isoform in newborn liver, lung, kidney and
      brain, and in adult lung and kidney is FMO1, but in adult liver FMO5 is present
      in greatest amounts. In liver, lung and kidney, expression of Fmo1, 3 and 5 peaks
      at 3 or 5 weeks of age, but in the brain, Fmo1 expression is greatest in
      newborns. In the kidney, FMO5 mRNA abundance is fourfold greater in males than in
      females, at all stages of development. Our results demonstrate that Fmo1, 2, 3, 4
      and 5 exhibit distinct cell-, tissue-, sex- and developmental stage-specific
      patterns of expression.

PMID- 15183120
TI  - In bcr-abl-positive myeloid cells resistant to conventional chemotherapeutic
      agents, expression of Par-4 increases sensitivity to imatinib (STI571) and
      histone deacetylase-inhibitors.
AB  - In a variety of malignant cells the prostate-apoptosis-response-gene-4 (Par-4)
      induces increased sensitivity towards chemotherapeutic agents by down-regulating
      anti-apoptotic B-cell lymphoma-gene 2 (Bcl-2). Hypothesizing that Par-4 also
      influences apoptosis in myeloid cell lines, we tested this hypothesis by stably
      transfecting bcr-abl transformed-K562 cells with a Par-4-expressing vector. Here
      we demonstrate that over-expression of Par-4 in K562 cells up-regulates
      expression levels of Bcl-2 and death-associated protein (Daxx). Upon treatment
      with different chemotherapeutic agents, Fas- or TRAIL agonistic antibodies, Par-4
      positive cells did not exhibit an increased rate of apoptosis as compared to Par
      4-negative control cells. However, incubation with histone deacetylase (HDAC)
      inhibitors Trichostatin A (TSA) and LAQ824 or the tyrosinkinase inhibitor
      Imatinib (STI571) increased the rate of apoptosis in Par-4-positive K562 cells.
      Assessing the underlying molecular mechanisms for the Par-4-induced response to
      HDAC-inhibitors and STI571 we provide evidence, that these effects are associated
      with a down-regulation of Daxx, enforced activation of caspases and enhanced
      cleavage of cellular inhibitor of apoptosis (cIAP)-1 and -2.

PMID- 15183121
TI  - Activation of deoxycytidine kinase by protein kinase inhibitors and okadaic acid
      in leukemic cells.
AB  - Deoxycytidine kinase (dCK) is a key enzyme in the deoxynucleoside salvage pathway
      and in the activation of numerous nucleoside analogues used in cancer and
      antiviral chemotherapy. Recent studies indicate that dCK activity might be
      regulated through reversible phosphorylation. Here, we report the effects of a
      large panel of protein kinase inhibitors on dCK activity in the B-leukemia cell
      line EHEB, both in basal conditions and in the presence of the nucleoside
      analogue 2-chloro-2'-deoxyadenosine (CdA) which induces activation of dCK. Except
      staurosporine and H-7 that significantly reduced the activation of dCK by CdA, no
      specific protein kinase inhibitor diminished basal dCK activity or its activation
      by CdA. In contrast, genistein, a general protein tyrosine kinase inhibitor, and
      AG-490, an inhibitor of JAK2 and JAK3, increased basal dCK activity more than two
      fold. Two specific inhibitors of the MAPK/ERK pathway, PD-98059 and U-0126, also
      enhanced dCK activity. These data suggest that the JAK/MAPK pathway could be
      involved in the regulation of dCK. Moreover, we show that the activity of dCK,
      raised by CdA, can return to its initial level by treatment with protein
      phosphatase-2A (PP2A). Accordingly, dCK activity in intact cells increased upon
      incubation with okadaic acid (OA) at concentrations that should inhibit PP2A, but
      not protein phosphatase-1. Activation of dCK by protein kinase inhibitors and OA
      was also observed in CCRF-CEM cells and in chronic lymphocytic leukemia B
      lymphocytes, suggesting a general mechanism of post-translational regulation of
      dCK, which could be exploited to enhance the activation of antileukemic
      nucleoside analogues.

PMID- 15183122
TI  - Rottlerin inhibits multiple steps involved in insulin-induced glucose uptake in
      3T3-L1 adipocytes.
AB  - Recently, it was shown that rottlerin inhibits insulin-stimulated glucose uptake
      and reduces intracellular adenosine triphosphate (ATP) levels in 3T3-L1
      adipocytes, suggesting that these two events are causally linked. However,
      several other reports show that ATP-depletion induces glucose uptake in both
      muscle cells and adipocytes. In the present study, the mechanism of inhibition by
      rottlerin was studied in detail, in order to resolve this apparent discrepancy.
      It was found that rottlerin strongly reduces insulin-stimulated 2-deoxyglucose (2
      DOG) uptake in 3T3-L1 adipocytes by a partial inhibition of the translocation of
      the insulin-responsive GLUT4 glucose transporter towards the plasma membrane
      (PM). Whereas the insulin-induced phosphatidyl-inositol-3' (PI-3') kinase
      signaling pathway is unaffected by rottlerin, Cbl tyrosine phosphorylation, which
      provides an essential, PI-3' kinase-independent signal towards GLUT4
      translocation, is markedly attenuated. Furthermore, we also observed a direct
      inhibitory effect of rottlerin on insulin-induced glucose uptake in 3T3-L1
      adipocytes. The direct inhibition of insulin-stimulated 2-DOG uptake by rottlerin
      displayed characteristics of uncompetitive inhibition: with the K(m(app)) of
      glucose uptake reduced from 1.6 to 0.9 mM and the V(max(app)) reduced from 5.2 to
      1.0 nmol/minmg in the presence of rottlerin. In conclusion, rottlerin inhibits
      multiple steps involved in insulin-stimulated 2-DOG uptake in 3T3-L1 adipocytes.
      The observed reduction in GLUT4 translocation towards the PM and the
      uncompetitive inhibition of the glucose transport process provide alternative
      explanations for the inhibitory effects of rottlerin aside from the effects of
      rottlerin on intracellular levels of ATP.

PMID- 15183123
TI  - Cloning, pharmacological characterisation and distribution of the rat G-protein
      coupled P2Y(13) receptor.
AB  - The human P2Y(13) receptor is a new receptor characterized by coupling to Gi,
      responsiveness to adenine di-phospho-nucleotides and blockade by the P2Y
      antagonist AR-C69931MX. The mouse P2Y(13) ortholog has also been reported. Here
      we report, for the first time, the cloning of rat P2Y(13) receptor, its
      pharmacological analysis and tissue distribution. Rat P2Y(13) is 79% and 87%
      identical to human and mouse P2Y(13) receptors, respectively. Expression of
      rP2Y(13) receptor in 1321N1 cells induced the appearance of responses to the
      typical P2Y(13) receptor agonists ADP and 2MeSADP, as detected by stimulation of
      [(35)S]GTPgammaS binding. Agonist activities were higher in cells transfected
      with rP2Y(13) receptor in the presence of the Galpha(16) subunit; in all cases
      agonist effects were abolished by pertussis toxin pre-treatment. At variance from
      both human and mouse receptors, ADP was more potent than 2MeSADP. Other
      nucleotides and sugar-nucleotides were ineffective. Both in the absence and
      presence of Galpha(16), activation of rP2Y(13) receptor by ADP and 2MeSADP was
      completely inhibited by nM concentrations of AR-C69931MX. In contrast, no
      inhibition of rP2Y(13) receptor was induced by the selective P2Y(1) receptor
      antagonist MRS2179. rP2Y(13) receptor showed highest expression levels in spleen,
      followed by liver and brain (with particularly high levels in cortex and striatum
      as reported in man), suggesting important roles in the nervous and immune
      systems. Expression levels comparable to those of the other cloned P2Y receptors
      were found in primary rat astrocytes, indicating a possible role in reactive
      astrogliosis. Hence, rat P2Y(13) receptor displays several similarities but also
      interesting differences with its human and mouse orthologs, that will have to be
      taken into account when characterizing the pathophysiological roles of this
      receptor in the rat animal models.

PMID- 15183124
TI  - Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential
      depolarization and apoptosis induction in rat C6 glioma cells.
AB  - The peripheral benzodiazepine receptor (PBR) is a component of a multiprotein
      complex, located at the contact site between the inner and outer mitochondrial
      membranes, which constitutes the mitochondrial permeability transition (MPT)
      pore. The opening of the MPT-pore, leading to the transmembrane mitochondrial
      potential (DeltaPsi(m)) dissipation, is a critical event in the mechanism of
      apoptosis. In the present work, we investigated the ability of the specific PBR
      ligands, PK 11195 or Ro5-4864, to affect mitochondrial potential and to induce
      apoptotic cell death in rat C6 glioma cells. Both specific ligands inhibited cell
      survival in a dose- and time-dependent manner, as assessed by MTS conversion
      assay, whereas the non-site selective ligand Diazepam or the low-affinity
      benzodiazepine Clonazepam showed no significant effects. After cell exposure to
      PK 11195 or Ro5-4864 we evidenced typical alterations of apoptotic cell death
      such as DNA fragmentation and chromatin condensation assessed by flow cytometric
      and transmission electron microscopy (TEM) analysis, respectively. Activation of
      the "effector" caspase-3 confirmed the ability of specific PBR ligands to induce
      apoptosis. Moreover, PK 11195 and Ro5-4864 induced a decrease of DeltaPsi(m), as
      evidenced by JC-1 flow cytometry analysis. Our data demonstrate the pro-apoptotic
      effects of specific PBR ligands on rat C6 glioma cells.

PMID- 15183125
TI  - The schedule-dependent enhanced cytotoxic activity of 7-ethyl-10-hydroxy
      camptothecin (SN-38) in combination with Gefitinib (Iressa, ZD1839).
AB  - The combination of the topoisomerase I (Topo I) inhibitor CPT-11 with the anti
      epidermal growth factor receptor (EGFR) agent Gefitinib (Iressa, ZD1839)
      represents a promising medical approach for colorectal cancer patients. In this
      report, we provide pre-clinical evidences for their optimal combination schedule
      in HT-29 and LoVo human colon cancer cell lines. We analyzed the different
      effects that three different combination schedules of SN-38 (the active CPT-11
      metabolite) and Gefitinib (Gefitinib before; Gefitinib simultaneously; Gefitinib
      after SN-38) have on cell growth, cell cycle, apoptosis, and
      expression/phosphorylation of EGFR, Topo I and some steps of the signal
      transduction pathway. We first determined the IC(50) of each drug choosing the 5
      days exposure for Gefitinib (0.6 and 3.8 microM for LoVo and HT-29 cells,
      respectively) and 1 day exposure for SN-38 (0.31 and 0.5 microM for LoVo and HT
      29 cells, respectively). The different drug combination schedules were tested in
      various concentrations by using equiactive concentrations of the two drugs. The
      cytotoxicity of Gefitinib and SN-38 combination was schedule- and concentration
      dependent but not cell line-specific. The most synergistic schedule was Gefitinib
      given after SN-38, with combination indexes (CI) of 0.007 and 0.454 in HT-29 and
      LoVo, respectively. Analysis of bio-molecular targets showed that Gefitinib was
      able to modulate SN-38 ability to inhibit Topo I, to accumulate cells in S-phase,
      and to induce apoptosis. Interestingly, SN-38 was able to activate EGFR and its
      signal transduction pathway. Confirming preliminary clinical experience of
      Gefitinib with other cytotoxic drugs, it seems that Gefitinib after SN-38
      represents the best cytotoxic combination schedule but the biomolecular basis for
      this synergism remain to be completely elucidated.

PMID- 15183126
TI  - Inhibition of insulin-like growth factor I receptor autophosphorylation by novel
      6-5 ring-fused compounds.
AB  - The insulin-like growth factor 1 receptor (IGF1R) plays an important role in cell
      transformation, and it has emerged as a target for anti-cancer drug design. IGF1R
      is activated by autophosphorylation at three sites in the enzyme activation loop.
      We describe here a group of 6-5 ring-fused compounds that are the first reported
      inhibitors selective for the unphosphorylated (0P) form of IGF1R. These compounds
      do not significantly inhibit the fully activated, triply phosphorylated (3P)
      form. IGF1R was produced from baculovirus-infected Spodoptera frugiperda (Sf9)
      cells, and the 0P and 3P forms were purified to homogeneity. We used a continuous
      spectrophotometric assay to measure inhibition of the 0P and 3P forms. Analysis
      by native gel electrophoresis confirmed that the step inhibited in the
      autoactivation process was the transition between the 0P and IP forms of IGF1R.
      The compounds were also active against IGF1R autophosphorylation in intact
      Chinese hamster ovary (CHO) cells. Most of the compounds also inhibited the
      closely related insulin receptor to varying degrees, although some compounds
      showed selectivity for IGF1R or insulin receptor. This class of compounds could
      form the basis of design efforts to selectively block the autoinhibited
      conformation of IGF1R.

PMID- 15183127
TI  - Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a
      combination of rosiglitazone and atorvastatin.
AB  - Rosiglitazone and atorvastatin combination therapy has beneficial effects on both
      glycemic control and plasma lipid levels in type 2 diabetic patients. In the
      present study, we sought to determine whether this combination can also exert
      direct antiatherosclerotic effects in macrophages. Our results show that 2 microM
      rosiglitazone, alone or combined with 5 microM atorvastatin, significantly
      upregulated the expression of the ATP-binding cassette transporter ABCA1 and of
      the class B scavenger receptor CLA-1 (CD36 and LIMPII analog), both involved in
      cholesterol efflux from macrophages. On the other hand, the combination with
      atorvastatin attenuated the inductive response elicited by rosiglitazone alone on
      CD36 mRNA (34%, P < 0.05) and protein (16%, P < 0.05), while the uptake of
      oxidized low density lipoprotein (LDL) remained unaffected. When we examined the
      effects of the drugs on acetyl-LDL-induced cholesterol accumulation, we found
      that only the combination of atorvastatin with rosiglitazone caused a net
      depletion in the cholesteryl ester content of macrophages (35%, P < 0.05). Our
      data suggest that this reduction was not mediated by effects on proteins that
      regulate cholesterol flux, but it may be related to the inhibition of cholesteryl
      ester formation elicited by the statin.

PMID- 15183128
TI  - Cloning and functional expression of a novel marmoset cytochrome P450 2D enzyme,
      CYP2D30: comparison with the known marmoset CYP2D19.
AB  - Using a primer set designed on the cDNA encoding the known marmoset cytochrome
      P450 2D19 (CYP2D19), a cDNA encoding a novel CYP2D enzyme (CYP2D30) was cloned
      from the liver of a female marmoset bred at Kyoto University (KYU). In addition,
      a cDNA encoding CYP2D19 was cloned from the liver of a female marmoset bred at
      Kagoshima University (KAU). CYP2D30 and CYP2D19 showed homologies of 93.6 and
      93.4% in their nucleotide and amino acid sequences, respectively. Reverse
      transcription polymerase chain reaction (RT-PCR) and digestion with NdeI
      demonstrated that the KYU-marmoset liver contained mainly mRNA for CYP2D30, while
      the KAU-marmoset liver contained mainly mRNA for CYP2D19. Marmoset CYP2D30, like
      human CYP2D6, exhibited high debrisoquine (DB) 4-hydroxylase activity and
      relatively low DB 5-, 6-, 7- and 8-hydroxylase activities, whereas CYP2D19 lacked
      DB 4-hydroxylase but exhibited marked 5-, 6-, 7- and 8-hydroxylase activities.
      The two marmoset recombinant enzymes showed enantioselective bufuralol (BF) 1"
      hydroxylase activities, similar to CYP2D6. BF 1"-hydroxylation by CYP2D30
      exhibited product-enantioselectivity of (1"R-OH-BF << 1"S-OH-BF), similar to that
      observed with human CYP2D6, whereas CYP2D19 showed a reversed selectivity of (1"R
      OH-BF > or = 1"S-OH-BF). BF 1"-hydroxylation in marmoset liver microsomes from
      both sources was inhibited by antibodies raised against rat CYP2D1 in a
      concentration-dependent manner. A known inhibitor of CYP2D6, quinidine,
      effectively inhibited the BF 1"-hydroxylation activities in liver microsomal
      fractions prepared from KYU- and KAU-marmosets. These results suggest that
      CYP2D19 and CYP2D30 proteins can be expressed as functional enzymes in marmoset
      livers, although it is unresolved whether both enzymes coexist in the same
      marmoset liver.

PMID- 15183129
TI  - Accumulation of [3H] glutamate in cultured rat calvarial osteoblasts.
AB  - In the present study, we have attempted to demonstrate constitutive and
      functional expression in bone of particular glutamate transporters (GluTs)
      required for signal termination in glutamatergic signaling process. Reverse
      transcription polymerase chain reaction revealed constitutive expression of mRNA
      for the neuronal GluT subtype excitatory amino acid carrier-1, in addition to
      glial subtypes such as glutamate aspartate transporter and glutamate transporter
      1, in rat calvarial osteoblasts cultured for 7-21 days in vitro (DIV). The
      accumulation of [3H]glutamate (Glu) occurred in a temperature- and sodium
      dependent manner with pharmacological profiles similar to those for brain GluTs
      in osteoblasts cultured for 7 DIV, while three different agonists at ionotropic
      Glu receptors significantly inhibited the accumulation of [3H]Glu in osteoblasts.
      Although [3H]Glu accumulation consisted of a single component with a K(m) value
      of 26.0 +/- 5.8 microM and a V(max) value of 960 +/- 122 nmol/(min mg protein),
      respectively, in osteoblasts cultured for 7 DIV, in vitro maturation led to a
      significant decrease in V(max) value to 290 +/- 33 nmol/(min mg protein) without
      significantly affecting K(m) values on 21 DIV. These results suggest that Glu
      could be incorporated into intracellular locations through glial and/or neuronal
      GluT subtypes expressed in cultured rat calvarial osteoblasts.

PMID- 15183130
TI  - Spin adducts of several N-2-(2-alkoxycarbonyl-propyl)-alpha-pyridylnitrone
      derivatives with superoxide, alkyl and lipid-derived radicals.
AB  - Several derivatives of N-t-butyl-alpha-phenylnitrone (PBN) such as N-2-(2
      ethoxycarbonyl-propyl)-alpha-phenylnitrone (EPPN) have recently been reported to
      form superoxide spin adducts (t(1/2) ca. 2-7 min at pH 7.0), which are
      considerably more stable than their respective PBN or DMPO adducts (t(1/2) ca. 10
      and 45 s, respectively). In continuation of our studies on structure optimization
      of EPPN derivatives, a series of 12 novel spin traps with 2-, 3- and 4-pyridinyl
      substituents was synthesized and fully characterized by 1H NMR, 13C NMR and IR
      spectroscopy. In addition to the replacement of the phenyl ring by a 2-, 3- or 4
      pyridinyl substituent, the ethoxy group of the parent compound EPPN was replaced
      by either a propoxy, iso-propoxy, or cyclopropylmethoxy moiety. Superoxide
      adducts of all PPyN derivatives were considerably more stable than those of the
      respective EPPN derivatives with half-lives ranging from about 6 to 11 min. In
      addition, alkoxyl radical adducts were also considerably more stable than those
      of the EPPN series. Hydroxyl radical adducts were not detected, on the other
      hand, very stable spin adducts were formed from a series of carbon centered
      radicals, e.g. from the methyl or hydroxymethyl radical. The novel spin traps are
      offering an alternative to PBN or POBN, especially where the higher stability of
      oxygen-centered radical adducts is of major importance. All of them can easily be
      synthesized from commercially available compounds in two or three steps.

PMID- 15183131
TI  - Hydroxytamoxifen protects against oxidative stress in brain mitochondria.
AB  - This study evaluated the effect of hydroxytamoxifen, the major active metabolite
      of tamoxifen (synthetic, nonsteroidal antiestrogen drug), on the function of
      brain mitochondria. We observed that only high concentrations of hydroxytamoxifen
      (60 nmol/mg protein) induced a significant decrease in RCR, while ADP/O ratio
      remained statistically unchanged. Similarly, only the highest concentration of
      hydroxytamoxifen (60 nmol/mg protein) affected the phosphorylative capacity of
      brain mitochondria, characterized by a decrease in the repolarization level and
      an increase in the repolarization lag phase. We observed that all the
      concentrations of hydroxytamoxifen tested (7.5, 15 and 30 nmol/mg protein)
      prevented lipid peroxidation induced by the oxidant pair ADP/Fe(2+). Furthermore,
      through the analyses of calcium fluxes and mitochondrial transmembrane potential
      parameters, we observed that hydroxytamoxifen (30 nmol/mg protein) exerted some
      protection against pore opening, although in a less extension than that promoted
      by cyclosporin A, the specific inhibitor of the mitochondrial permeability
      transition pore. However, in the presence of hydroxytamoxifen plus cyclosporin A,
      the protection observed was significantly higher when compared with that induced
      by both agents alone. These results support the idea that hydroxytamoxifen
      protects lipid peroxidation and inhibits the mitochondrial permeability
      transition pore in brain. Since numerous neurodegenerative diseases are
      intimately related with mitochondrial dysfunction resulting from lipid
      peroxidation and induction of mitochondrial permeability transition, among other
      factors, future therapeutical strategies could be designed taking in account this
      neuroprotective role of hydroxytamoxifen, which is pharmacologically much more
      potent and less toxic than its promoter tamoxifen.

PMID- 15183133
TI  - Reflections on the occurrence and significance of antepartum fetal asphyxia.
AB  - This chapter documents the growing evidence of the occurrence and significance of
      antepartum fetal asphyxia. Perinatal mortality studies demonstrate that the
      majority of fetal deaths, including those due to asphyxia, occur in the
      antepartum period. Epidemiological studies of cerebral palsy conclude that a
      minority of cases of cerebral palsy are due to intrapartum fetal asphyxia and
      implicate antenatal events, including asphyxia. Cordocentesis studies have
      confirmed that antepartum fetal asphyxia occurs in the growth-restricted fetus
      and might contribute to the increase of stillbirths and cerebral palsy in these
      children. Blood gas and acid-base studies in the immature fetus have demonstrated
      the increased prevalence of fetal asphyxia, and particularly of moderate or
      severe asphyxia, of which the majority might occur in the antepartum period. The
      ultimate determination of the prevalence and significance of antepartum fetal
      asphyxia requires the development of a non-invasive specific measure of fetal
      asphyxia.

PMID- 15183134
TI  - The role of uterine artery Doppler in predicting adverse pregnancy outcome.
AB  - The complications of placental insufficiency, pre-eclampsia and fetal growth
      restriction (FGR) are major causes of perinatal as well as maternal morbidity and
      mortality. In normal pregnancy, impedance to flow in the uterine arteries
      decreases with gestation, and histopathological studies suggest that this is due
      to trophoblastic invasion of the spiral arteries and their conversion into low
      resistance vessels. Failure of trophoblastic invasion is associated with
      complications of uteroplacental insufficiency. Several Doppler screening studies,
      both in the second and more recently in the first trimester of pregnancy, have
      demonstrated an association between increased impedance to flow in the uterine
      arteries and subsequent development of pre-eclampsia, FGR and perinatal death.

PMID- 15183135
TI  - Perinatal mortality and fetal growth restriction.
AB  - Stillbirths are the largest component of perinatal mortality. Most are currently
      classified as 'unexplained', which is not helpful for counselling and individual
      care or for setting priorities for maternity services. The new ReCoDe
      classification reduces the number of stillbirths categorized as 'unexplained'
      from 66 to 14%. Both stillbirths and neonatal deaths are strongly associated with
      fetal growth restriction, and increased awareness of intrauterine growth is
      essential for any strategies which seek to avoid adverse perinatal outcome.

PMID- 15183136
TI  - Assessing fetal health.
AB  - Fetal surveillance significantly reduces the incidence of fetal loss, perinatal
      morbidity and maternal distress. Obstetricians traditionally classify pregnancies
      as 'low' or 'high risk' and apply various methods of fetal surveillance in the
      latter group. However, the majority of stillbirths now occur in 'low-risk' women.
      This seemingly anomalous observation emphasises the need to develop more
      effective ways of identifying 'at-risk' fetuses in 'low-risk' women. This chapter
      describes and critically evaluates eleven currently available tools for fetal
      surveillance. It also reviews the criteria for ascribing risk status in pregnancy
      and suggests a pragmatic approach to health assessment in normally formed fetuses
      for each group. It does not address fetal surveillance during labour and
      delivery.

PMID- 15183137
TI  - Antenatal risk factors for cerebral palsy.
AB  - Two of every 1000 live-born children develop cerebral palsy (CP). The aetiology
      of CP is often unclear and because CP is a symptom complex rather than a disease,
      clinically defined at 4-5 years of age, it is not surprising that there are
      considerable problems associated with epidemiological studies of its aetiology.
      The only reason for the CP concept is that it emanates from an insult to a
      growing, developing brain and a dynamic clinical picture from static pathology.
      Evidence suggests that 70-80% of CP cases are due to prenatal factors and that
      birth asphyxia plays a relatively minor role (<10%). Some antenatal risk factors
      are repeatedly observed to be related to CP: low gestational age, male gender,
      multiple gestation, intrauterine viral infections and maternal thyroid
      abnormalities. Recently, intrauterine infection/inflammation with a maternal
      response (consisting of chorioamnionitis) and a fetal inflammatory response
      (consisting of funicitis or elevated interleukin-6 in fetal plasma) has been
      found to be related to white matter injury and CP. Some risk factors are
      associated with CP at all gestational ages whereas others mostly affect term or
      preterm infants, e.g. intrauterine growth restriction seems to be a risk factor
      in term infants. There also seems to be an association between autoimmune and
      coagulation disorders and CP.

PMID- 15183138
TI  - The CTG and the timing and mechanism of fetal neurological injuries.
AB  - Defining the relationship between the cardiotocograph (CTG) pattern and
      subsequent neurological injury is confounded by the requirement that certain
      clinical and biochemical perinatal findings are essential for relating
      intrapartum events to subsequent neurological injury. Similarly, the value of CTG
      analysis in these cases has been compromised by antiquated terminology focused on
      hypoxia but not neurological behavior. Strong evidence suggests that the
      evaluation of umbilical artery acidosis, low Apgar score and neonatal
      encephalopathy are limited in their ability to either include or exclude
      intrapartum injury. Proper evaluation of the CTG requires that trends and the
      rapidity of changes in patterns of decelerations are necessary to confidently
      define the normal-behaving fetus, the hypoxemic but uninjured fetus, the injured
      but non-hypoxic fetus, and finally to distinguish ischemic events from other
      forms of hypoxia. A newly defined CTG pattern, the 'conversion' pattern, appears
      to be a specific marker of ischemic injury and could help to redefine the role of
      CTG monitoring.

PMID- 15183139
TI  - Cardiotocography and medicolegal issues.
AB  - Obstetric litigation is on the increase. A review of litigation cases reveals
      that the majority of claims relating to the intrapartum period arise because the
      cardiotocograph- (CTG) was misinterpreted or because inappropriate action was
      taken in the presence of fetal heart rate abnormalities. Compulsory education and
      training in the interpretation of CTGs and in best practice are key factors in
      minimizing the threat of litigation. Newer methods, such as pulse oximetry or
      fetal electrocardiogram waveform analysis, can act as adjuncts to CTG and help to
      avoid birth asphyxia and hence litigation.

PMID- 15183140
TI  - Fetal scalp and cord blood lactate.
AB  - Lactate measurements have been evaluated in intrapartum fetal surveillance for
      some 30 years. However, it was not until reliable, handheld, microvolume devices
      were launched during the 1990s that lactate became a clinical option.
      Retrospective data suggest that lactate determinations in fetal scalp blood are
      better than pH for predicting severe neonatal morbidity. A randomised controlled
      trial comparing these two measurements found lactate to be more favourable in
      clinical practice in terms of less sampling failure and reduced time from the
      decision to do a fetal scalp blood sample to the clinician receiving the result.
      At present, a large multicenter randomised control trial is in progress in Sweden
      to compare lactate and pH measurement for the clinical management of suspected
      fetal compromise. Main end-points in the study are metabolic acidemia or pH <7.00
      in cord arterial blood at delivery. Results are likely to be available in 2-3
      years time.

PMID- 15183141
TI  - Fetal pulse oximetry: a critical appraisal.
AB  - Despite 40 years of cumulative clinical experience, and a number of randomized
      clinical trials, electronic fetal heart rate monitoring is perceived by many
      obstetrical caregivers as a suboptimal method of intrapartum fetal assessment.
      Fetal pulse oximetry emerged 15 years ago as a promising new technology intended
      to improve assessment of fetal condition during labor. A large amount of
      physiologic data and one large randomized clinical trial have brought this
      technology into clinical practice. We know that fetal acidemia is rare when the
      arterial oxygen saturation is >30% but fetal pulse oximetry as currently
      understood and applied does not reduce the overall cesarean rate. Thus, many
      clinicians remain unconvinced of the benefit of this technology and its
      utilization has stalled in the US and Europe. We need to further understand if
      there is a way to use fetal pulse oximetry in the setting of labor dystocia and a
      non-reassuring fetal heart rate pattern. Although hypoxemia is an accepted
      mechanism of fetal brain injury, other potential mechanisms should be explored.
      Current controversies and fertile areas of research are presented.

PMID- 15183142
TI  - Fetal ECG waveform analysis.
AB  - Fetal ECG waveform analysis as an adjunct to electronic fetal monitoring (EFM)
      has developed over the last 3 decades. From a multitude of potential parameters,
      ST waveform analysis has been documented to provide the information required to
      shift EFM from a screening device to a diagnostic tool that meets the standards
      of evidence-based medicine. This chapter details the experimental and clinical
      evolution of the STAN methodology for intrapartum fetal surveillance.
      Observational data formed the basis for cardiotocograph (CTG) and ST waveform
      analysis clinical guidelines. Data from two large, randomized controlled trials
      (6826 cases) are summarized together with the first analysis of the recently
      completed EU project of 7823 term fetuses monitored as part of the study to
      introduce ST analysis into clinical practice. The reduction in the incidence of
      newborns with marked neurological symptoms is supported by these findings. The
      detection of ST changes allowed earlier and more consistent intervention.

PMID- 15183143
TI  - Interferon alpha--a potential link in the pathogenesis of viral-induced type 1
      diabetes and autoimmunity.
AB  - The incidence of type 1 diabetes has been rapidly rising. Environmental factors
      such as viruses have been implicated as a possible agent accounting for this
      rise. Enteroviruses have recently been the focus in many research studies as a
      potential agent in the pathogenesis of type 1 diabetes. The mechanism of viral
      infection leading to beta cell destruction not only involves multiple pathways
      but also the cytokine-interferon alpha (IFN-alpha). Our hypothesis is that
      activation of toll receptors by double-stranded RNA or poly-IC (viral mimic)
      through induction of IFN-alpha may activate or accelerate immune-mediated beta
      cell destruction. Numerous clinical case reports have implicated that IFN-alpha
      therapy is associated with autoimmune diseases and that elevated serum IFN-alpha
      levels have been associated with type 1 diabetes. In multiple animal models,
      given specific genetic susceptibility, poly-IC can induce insulitis or diabetes.
      Therapeutic agents targeting IFN-alpha may potentially be beneficial in the
      prevention of type 1 diabetes and autoimmunity.

PMID- 15183144
TI  - Ubiquitin ligases in T cell activation and autoimmunity.
AB  - Ubiquitination-mediated protein modifications are increasingly recognized as key
      regulatory events in many basic cell biology processes. A key class of enzymes
      called ubiquitin ligases, which has been shown to play a crucial role in the
      ubiquitination process, can positively or negatively regulate T cell responses.
      This review summarizes the recent advances defining the roles of several
      ubiquitin ligases in T cell activation and autoimmunity.

PMID- 15183145
TI  - IgG reactivity with a 100-kDa tissue and endothelial cell antigen identified as
      topoisomerase 1 distinguishes between limited and diffuse systemic sclerosis
      patients.
AB  - We have analyzed antibody (Ab) reactivities of patients with limited systemic
      sclerosis (SSc) and anti-centromere Ab, patients with diffuse SSc and anti
      topoisomerase 1 (anti-topo 1) Ab, patients with diffuse SSc without anti-topo 1
      or anti-centromere Ab and age- and gender-matched healthy controls with normal
      human tissue and endothelial cell (EC) antigens. IgG reactivities with tissue
      antigens differed significantly between patients with anti-topo 1 Ab and patients
      with anti-centromere Ab. One 100-kDa band identified as topoisomerase 1 in
      macrovascular and microvascular EC extracts was recognized by IgG from patients
      with anti-topo 1 Ab and 50% of patients without specific Ab. IgG from patients
      with limited SSc and anti-centromere Ab, but not those of other patients or
      controls specifically recognized a 80-kDa band only in microvascular EC. Our
      results indicate that Ab from patients with limited or diffuse SSc with or
      without anti-topo 1 Ab exhibit specific and mutually exclusive reactivity
      patterns.

PMID- 15183146
TI  - Hydrolysis of the tumor-associated antigen epitope gp100(280-288) by membrane
      associated and soluble enzymes expressed by immature and mature dendritic cells.
AB  - The hydrolysis of the tumor-associated HLA-A2.1-restricted gp100(280-288) epitope
      by in vitro generated immature and mature dendritic cells (iDCs and mDCs) and by
      soluble supernatants prepared from these same cells, as well as the effect of the
      hydrolysis on in vitro immunorecognition, was studied by chromatographic and
      functional analyses. The results obtained indicate that exposure to iDCs induced
      a very rapid hydrolysis of the model peptide (half life, 62 s), resulting in
      complete loss of immunorecognition within 60 min. In the presence of mDCs, the
      hydrolysis kinetics were even faster (half life, 54 s), and the pattern of
      hydrolysis by-products was different from that observed for iDCs. Gp100(280-288)
      was also degraded in the presence of cell-free supernatants prepared both from
      iDCs and mDCS; in this case, degradation kinetics were slower, and the pattern of
      hydrolysis by-products was different from that observed in the presence of intact
      cells. The model epitope was degraded to non-immunogenic products by membrane and
      soluble enzymes expressed both by iDCs and by mDCs within periods of time that
      appear to be physiologically relevant. Development of antigenic formulations
      capable of protecting synthetic epitopes from these effects appears to represent
      a prerequisite for effective immunization procedures.

PMID- 15183147
TI  - Immune reconstitution following autologous transfers of CD3/CD28 stimulated
      CD4(+) T cells to HIV-infected persons.
AB  - We have previously shown that adoptive transfer of in vitro CD3/CD28 activated
      autologous CD4(+) T cells results in increased CD4 counts and CD4/CD8 ratios in
      HIV+ subjects. In this report, analysis of variable beta (Vbeta) chain T cell
      receptor (TCR) repertoire showed that CD3/CD28 stimulation was able to increase
      polyclonality within skewed spectra types in vitro. In vivo, two of eight
      subjects showed increase in TCR diversity and importantly, in no subject did a
      highly skewed in vivo repertoire emerge. Measurement of proliferative response to
      alloantigen showed increases following infusions. Response to pharmacological
      stimulus and lectin via Interferon-gamma ELISpot assay showed increases in a
      subset of subjects following infusions. However, interferon-gamma response to HIV
      antigens and peptides declined concurrent with stable or diminishing latent
      infectious viral load in CD4(+) T cells. These data provide further evidence that
      adoptive transfer of activated autologous CD4(+) T cells can augment the immune
      system.

PMID- 15183149
TI  - Identification of candidate microbial sequences from inflammatory lesion of giant
      cell arteritis.
AB  - Giant cell arteritis (GCA) is a granulomatous inflammatory disease of medium and
      large arteries which is prevalent in the elderly population. The etiology of GCA
      is unknown, although the immunologic features suggest the possible presence of a
      microorganism. Our group has examined whether microbial DNA fragments were
      present at GCA lesions and whether such microbial fragments could be associated
      with disease pathogenesis. Initial identification of microbial sequences was
      performed using genomic representational difference analysis (RDA). Laser
      dissecting microscopy was used to isolate cells from GCA lesions and adjacent
      uninvolved temporal artery. Using genomic RDA, we isolated 10 gene fragments;
      three of these sequences had high homology with prokaryotic genes and were
      considered high-priority candidates for further study. An examination of serum
      from GCA(+) individuals (in contrast to healthy age-matched controls) showed the
      presence of IgG which recognized in vitro translated proteins from these clones.

PMID- 15183148
TI  - HLA-DR, ICAM-1, CD40, CD40L, and CD86 are incorporated to a similar degree into
      clinical human immunodeficiency virus type 1 variants expanded in natural
      reservoirs such as peripheral blood mononuclear cells and human lymphoid tissue
      cultured ex vivo.
AB  - To provide additional information on the acquisition of host cell membrane
      proteins by human immunodeficiency virus type 1 (HIV-1) produced by natural
      cellular reservoirs, two different field isolates were used to infect ex vivo
      expanded peripheral blood mononuclear cells (PBMCs) and human lymphoid tissue
      histocultures. The insertion of host-derived HLA-DR, intercellular adhesion
      molecule-1 (ICAM-1), CD40, CD40L, and CD86 within HIV-1 particles was evaluated
      by using specific antibodies linked to a solid matrix to capture ultrafiltrated
      viral progeny. Overall, our data indicate that neither the HIV-1 co-receptor
      usage (i.e., T-tropic or macrophage-tropic) nor the cellular source of HIV-1 has
      an impact on the incorporation process but it was found to be under the influence
      of the donor source. Given that most viral replication is thought to occur in
      lymphoid tissues and previous works have shown that HIV-1 life cycle is affected
      by several virus-anchored host proteins, our results suggest that this phenomenon
      is likely to contribute to the pathogenesis of this retroviral infection.

PMID- 15183150
TI  - Cytokines modulate cilomilast response in lung fibroblasts.
AB  - Fibroblasts, as a major source of extracellular interstitial connective tissue
      matrix, play an important role in wound healing and the development of fibrosis.
      The phosphodiesterase (PDE) 4 inhibitor cilomilast inhibits fibroblast chemotaxis
      and fibroblast-mediated gel contraction. Using the Boyden blindwell chamber
      chemotaxis assay and the type I collagen gel contraction model, this study
      investigated whether specific cytokines modulate cilomilast's inhibitory effect
      through regulation of endogenous PGE(2) production. Human recombinant IL-1beta
      stimulated PGE(2) production and shifted the cilomilast concentration-dependence
      curve to the left in both assay systems, indicating increased sensitivity to
      cilomilast. In contrast, human recombinant IL-4 inhibited PGE(2) production and
      shifted the cilomilast concentration-dependence curve to the right in both
      systems. In summary, the inhibitory effect of cilomilast on fibroblast migration
      and collagen gel contraction is modulated by IL-1beta and IL-4 through regulation
      of PGE(2) production.

PMID- 15183151
TI  - A nonrandomized comparison of the clinical outcome of ocular involvement in
      patients with mucous membrane (cicatricial) pemphigoid between conventional
      immunosuppressive and intravenous immunoglobulin therapies.
AB  - The purpose of this study was to compare the clinical outcomes of intravenous
      immunoglobulin (IVIg) therapy to conventional immunosuppressive therapy in
      patients with mucous membrane pemphigoid (MMP), also known as cicatricial
      pemphigoid (CP), whose disease progressed to involve the eye. Before ocular
      involvement, all the patients in this study were diagnosed and treated with
      immunosuppressive agents, for biopsy-proven MMP, affecting the skin and/or mucous
      membranes, other than the conjunctiva. Eight patients in group A were treated
      with IVIg after the diagnosis of ocular cicatricial pemphigoid (OCP) was
      established. The efficacy and safety of IVIg therapy were compared to a
      clinically similar group of eight patients treated with conventional
      immunosuppressive therapy (group B). The inclusion criteria for both groups were:
      (1). presence of MMP at extraocular sites confirmed by biopsy before entry into
      the study; (2). entry into the study occurred when ocular involvement was noted
      and confirmed by biopsy; (3). presence of conventional immunosuppressive therapy
      at the time of ocular involvement; (4). a minimum of 18 months of follow-up after
      diagnosis of ocular involvement. The mean length of the therapy, after the onset
      of ocular involvement, was 24 months (range 16-30) in group A and 45 months
      (range 21-90) in group B. The median time between initiation of therapy and
      clinical remission in group A and group B was 4 and 8.5 months, respectively.
      This difference was statistically significant (P < 0.01). No recurrence of ocular
      inflammation was recorded in any of the patients in group A. On the contrary, at
      least one recurrence (median 1) was recorded in five patients in group B (range 0
      4). This difference was statistically significant (P < 0.05). All eight patients
      in group A and group B presented to the ophthalmologist in stage 2 of OCP at the
      time of the initial visit. At the last follow-up visit, no progression to
      advanced stages of OCP was recorded in all eight patients in group A. On the
      contrary, only four patients in group B remained in stage 2 of OCP at the last
      follow-up exam. The conjunctival scaring progressed from stage 2 to stage 3 in
      the remaining four patients of group B. At the last follow-up visit, both eyes of
      each patient in group A were free of inflammation. Some level of conjunctival
      inflammation at the last follow-up visit was noted in five patients in group B
      (range 0-1.5, P < 0.05). Both groups of patients were studied during the same
      time period. The results of this study suggest that ocular involvement in
      patients with MMP may be considered an indication for initiating IVIg therapy,
      since it was more effective in arresting progression of OCP, when compared to
      conventional immunosuppressive therapy. These data indicate that IVIg produced a
      faster control of the acute inflammation and that no recurrences were observed
      during the follow-up. This clinical difference could be because of the reduced
      production of pathogenic antibody, and/or restoration of the immunoregulation,
      which may have been disturbed.

PMID- 15183152
TI  - Differential effects of mercury, lead, and cadmium on IL-2 production by Jurkat T
      cells.
AB  - Mercury, lead, and cadmium are widespread and highly toxic pollutants. The aim of
      this study was to determine the effects of sublethal doses of CH(3)HgCl, CdCl(2),
      and PbCl(2) on IL-2 production by T lymphocytes. Jurkat T cells were stimulated
      by triggering CD3 and CD28 molecules before, in conjunction with, or following
      heavy metal exposure. Heavy metals, individually or mixed together at equimolar
      concentrations, were used. Results demonstrated that low, noncytotoxic doses of
      metals induce tyrosine phosphorylation. Mercury and lead (1 microM) inhibit IL-2
      production regardless of the state of T cell activation. Cadmium stimulated IL-2
      production only in preactivated T cells. Surprisingly, a mixture of these three
      metals had no effect. We subsequently determined the effects of heavy metals on
      NFAT (nuclear factors of activated T cells) activity. When cells were stimulated
      by potent stimulation involving the CD3 and CD28 molecules, an increased NFAT
      activation was noted when the cells were exposed to mercury and to the metal
      mixture. Activation with PMA/calcium ionophores indicated that the target of
      heavy metals is located downstream from PKC and calcium mobilization. These
      results suggest that the state and mode of T cell activation are important
      parameters to consider in heavy metal toxicity.

PMID- 15183153
TI  - Antigen synthesis opens the door to a broad-spectrum AIDS vaccine.

PMID- 15183154
TI  - Parkinson's disease in the PINK.

PMID- 15183155
TI  - Balancing US patent and FDA approval processes: strategically optimizing market
      exclusivity.

PMID- 15183156
TI  - Interfering with programmed cell death in neurodegenerative diseases: insights
      from experimental animal models.

PMID- 15183157
TI  - Multistage adaptive designs for clinical trials.

PMID- 15183158
TI  - Advances in high throughput screening.

PMID- 15183159
TI  - Evaluating the validity of animal models for research into therapies for immune
      based disorders.
AB  - The last few decades of the 20th century have shown an intensified search for
      safer and more effective medications against chronic diseases that burden ageing
      societies of the western world. The impressive development of biotechnological
      production techniques has greatly facilitated the pharmaceutical development of
      relatively non-toxic biological molecules. However, despite the huge investments,
      only a few effective therapies for immune-based diseases have reached the clinic.
      In this article we use examples from monoclonal antibody trials to discuss the
      validity and predictive strength of the animal models currently used for the
      development of effective therapies.

PMID- 15183160
TI  - Phage display-derived peptides as therapeutic alternatives to antibodies.
AB  - Peptide-based drugs are now viable alternatives to biopharmaceuticals, such as
      antibodies. Most of the past limitations of peptides have been removed by new
      technologies, so that peptides now face similar hurdles to antibodies. Phage
      display technology provides novel peptides that bind protein targets with high
      affinity and specificity. Most marketed peptide-based drugs are receptor agonists
      derived from natural peptides. To address the need for antagonists, novel
      strategies have been developed for inhibiting receptor-ligand interactions. We
      review results from phage display in finding peptide drug candidates and conclude
      with some business benefits of developing peptides.

PMID- 15183161
TI  - Compound lipophilicity for substrate binding to human P450s in drug metabolism.
AB  - Compound lipophilicity is of key importance to P450 binding affinity and enzyme
      selectivity. Here, lipophilicity is discussed with reference to the human drug
      metabolizing P450 enzymes of families CYP1, CYP2 and CYP3. From an extensive
      compilation of log P values for P450 substrates, and by analysis of relationships
      between partitioning energy and substrate-binding free energy, the relevance of
      lipophilicity and other factors pertaining to P450 binding affinity is explained,
      leading to the formulation of lipophilicity relationships within substrates of
      each human P450 enzyme involved in drug metabolism. Furthermore, log P values for
      P450 substrates appear to represent markers for enzyme selectivity. Together with
      the important roles of hydrogen bonding and pi-pi stacking interaction energies,
      the desolvation of the P450 active site makes a major contribution to the overall
      substrate-binding energy and, consequently, a good agreement with experimental
      information is reported based on this analysis.

PMID- 15183166
TI  - Comparison of the effects of entorhinal and retrosplenial cortical lesions on
      habituation, reaction to spatial and non-spatial changes during object
      exploration in the rat.
AB  - This study was aimed at comparing the effects of damage to the entorhinal cortex
      and retrosplenial cortex on exploration and reaction-to-change in rats. Following
      habituation to a configuration of objects, a familiar object was displaced
      therefore producing a spatial change. A non-spatial change was made by
      substituting a familiar object by a novel object. Both entorhinal cortex lesions
      and retrosplenial cortex lesions elicited a deficit in the rat's reaction to a
      spatial change. In addition, rats with entorhinal lesions showed hypoactive
      object exploration and exhibited a mild deficit in reaction to a non-spatial
      change. This may reflect the importance of temporal cortical input in object
      recognition. Overall, these results suggest that the entorhinal cortex and the
      retrosplenial cortex contribute to the processing of the geometric properties of
      the environment and have thus close functional links.

PMID- 15183167
TI  - Late-associativity, synaptic tagging, and the role of dopamine during LTP and
      LTD.
AB  - Protein synthesis-dependent, synapse input-specific late phases of long-term
      potentiation (LTP) and depression (LTD) may underlie memory formation at the
      cellular level. Recently, it was described that the induction of LTP can mark a
      specifically activated synapse by a synaptic tag to capture synapse non-specific
      plasticity-related proteins (PRPs) and thus maintaining input-specific LTP for
      prolonged periods. Here we show in rat hippocampal slices in vitro, that the
      induction of protein synthesis-dependent late-LTD is also characterized by
      synaptic tagging and that heterosynaptic induction of either LTD or LTP on two
      sets of independent synaptic inputs S1 and S2 can lead to late-associative
      interactions: early-LTD in S2 was transformed into a late-LTD, if late-LTP was
      induced in S1. The synthesis of process-independent PRPs by late-LTP in S1 was
      sufficient to transform early- into late-LTD in S2 when process-specific synaptic
      tags were set. We name this new associative property of cellular information
      processing 'cross-tagging.'

PMID- 15183168
TI  - On the delay-dependent involvement of the hippocampus in object recognition
      memory.
AB  - The role of the hippocampus in object recognition memory processes is unclear in
      the current literature. Conflicting results have been found in lesion studies of
      both primates and rodents. Procedural differences between studies, such as
      retention interval, may explain these discrepancies. In the present study, acute
      lidocaine administration was used to temporarily inactivate the hippocampus prior
      to training in the spontaneous object recognition task. Male C57BL/6J mice were
      administered bilateral lidocaine (4%, 0.5 microl/side) or aCSF (0.5 microl/side)
      directly into the CA1 region of the dorsal hippocampus 5 min prior to sample
      object training, and object recognition memory was tested after a short ( 5 min)
      or long (24 h) retention interval. There was no effect of intra-hippocampal
      lidocaine on the time needed for mice to accumulate sample object exploration,
      suggesting that inactivation of the hippocampus did not affect sample session
      activity or the motivation to explore objects. Lidocaine-treated mice exhibited
      impaired object recognition memory, measured as reduced novel object preference,
      after a 24 h but not a 5 min retention interval. These data support a delay
      dependent role for the hippocampus in object recognition memory, an effect
      consistent with the results of hippocampal lesion studies conducted in rats.
      However, these data are also consistent with the view that the hippocampus is
      involved in object recognition memory regardless of retention interval, and that
      object recognition processes of parahippocampal structures (e.g., perirhinal
      cortex) are sufficient to support object recognition memory over short retention
      intervals.

PMID- 15183169
TI  - Instrumental learning within the spinal cord: III. Prior exposure to
      noncontingent shock induces a behavioral deficit that is blocked by an opioid
      antagonist.
AB  - Spinally transected rats given legshock whenever one hindleg is extended learn to
      maintain a flexion response that decreases net shock exposure. Prior exposure to
      response-independent (noncontingent) shock prevents learning. This behavioral
      deficit was eliminated by systemic administration of the nonselective opioid
      antagonist naltrexone (Experiment 1). The deficit was also blocked by intrathecal
      (i.t.) naltrexone at a dose of 7 microg/microl (Experiment 2). Noncontingent
      shock undermined behavioral potential for 24 h (Experiment 3). The expression of
      the deficit was blocked by naltrexone (7 microg/microl, i.t.) given prior to
      testing. The same dose prior to initial shock exposure had no effect.
      Administration of an antagonist that acts on the kappa opioid receptor (nor-BNI)
      restored learning (Experiment 4). Equal molar concentrations of antagonists that
      act on the micro (CTOP) or delta (naltrindole) receptor had no effect.

PMID- 15183170
TI  - Different time course for the memory facilitating effect of bicuculline in
      hippocampus, entorhinal cortex, and posterior parietal cortex of rats.
AB  - Several lines of evidence indicate that gamma-aminobutyric acid (GABA) type A
      (GABA(A)) receptors regulate memory consolidation. Here we studied the effect on
      consolidation of the selective antagonist of GABA(A) receptors, bicuculline,
      given into several regions of the cortex at different times after one-trial step
      down inhibitory avoidance (0.5 mA, 2-s footshock). Rats were bilaterally
      implanted with cannulae aimed at the CA1 region of the dorsal hippocampus,
      entorhinal cortex or posterior parietal cortex, three areas known to be involved
      in the memory consolidation of this task. At different times after training,
      bicuculline (0.5 microg/side) was infused into the above mentioned structures.
      Bicuculline increased memory retention when administered either immediately or
      1.5h after training into CA1, and both immediately and 3h after training in the
      entorhinal or parietal cortex. Thus, in agreement with previous findings using
      other drugs, the response was biphasic in these latter structures. This suggests
      that GABAergic mechanisms normally downregulate, memory processing by inhibiting
      on-going activities necessary for consolidation at the times in which bicuculline
      was effective in each structure. Based on previous findings, in the hippocampus,
      such activity involves a number of receptors and signaling pathways in the first
      1.5h after training. In the entorhinal and parietal cortex memory-related
      activities include the participation of protein kinase A and extracellularly
      regulated kinase (ERK) twice, right after training and then again 3h later.

PMID- 15183172
TI  - Disruption of latent inhibition to a contextual stimulus with systemic
      amphetamine.
AB  - This experiment examined the effects of 0.5 and 1.5 mg/kg doses of amphetamine
      (AMP) in male Wistar rats, on conditioning to a contextual stimulus that for half
      the animals has been pre-exposed, in an appetitive conditioning procedure.
      Amphetamine was administered during both pre-exposure (3 days) and acquisition
      (15 days). Latent inhibition (LI, reduced conditioning in pre-exposed relative to
      non-pre-exposed rats) was seen in controls but not at either AMP dose. This
      abolition of LI was seen under AMP at two levels of responding in acquisition and
      confirmed in drug free extinction. It suggests that, like conditioning to
      discrete stimuli, conditioning to contextual stimuli is subject to LI and can be
      disrupted by AMP.

PMID- 15183171
TI  - Acute stress impairs trace eye blink conditioning in females without altering the
      unconditioned response.
AB  - Exposure to an acute stressor of inescapable swimming or intermittent tail shocks
      impairs classical eye blink conditioning 24h later in female rats. This effect is
      often attributed to a deficit in "learning," but since stress has been shown to
      induce analgesia, an alternative explanation is that stressor exposure reduces
      conditioning by lessening the perceived intensity of the unconditioned stimulus
      (US). To address this possibility we examined the amplitude of the unconditioned
      response (UR) during training and found that although exposure to the stressor
      impaired trace conditioning, there was no difference in the UR amplitude. We also
      found that eye blink responses to different US intensities (4-12 V) in the
      absence of training were unaffected by stressor exposure. Taken together, these
      experiments indicate that the stress-induced impairment of conditioning in
      females is not due to a decreased perception of US strength.

PMID- 15183173
TI  - Measurement of neuropeptide release and dense core granule fusion.

PMID- 15183174
TI  - Human growth hormone co-transfection assay to study molecular mechanisms of
      neurosecretion in PC12 cells.
AB  - The recent introduction of transient co-transfection assays, with human growth
      hormone (hGH) as a marker of transfection, has allowed us to study the function
      of transfected proteins in neurosecretion using intact PC12 cells and adrenal
      chromaffin cells [J. Biol Chem. 268 (1993) 10983]. Since this assay requires
      several non-trivial steps (transfection of the genes, triggering of secretion,
      and measurement of hGH), care should be taken before attributing any observed
      effect to the transfected proteins. In this article, we describe a detailed
      procedure for the hGH transfection assay and show that this approach can be used
      to study the molecular events involved in neurosecretion.

PMID- 15183175
TI  - Reverse hemolytic plaque assays: versatility in the study of secretion.
AB  - The reverse hemolytic plaque assay has been used for several years to study
      hormone release from various endocrine cell types. The basic method utilizes a
      monolayer (consisting of indicator erythrocytes and the cells under study) that
      is fixed to the floor of an incubation chamber. Antibody directed against a
      peptide or protein is added to the chamber. Peptides released from the cells
      under study complex with the antibody and bind to protein-A on the surface of the
      indicator erythrocytes. The addition of complement causes the indicator cells to
      lyse, forming a "plaque" or zone of hemolysis surrounding the secreting cells.
      The size or rate of formation of these plaques can be used as indices to monitor
      peptide or protein release. In addition to this standard procedure, the plaque
      assay can be modified by using loose or unattached indicator cells and is termed
      the loose plaque assay (LPA). The LPA for a particular peptide can be used alone,
      sequentially with an assay directed toward another peptide, or repeatedly on the
      same cells to monitor release over time. In light of the fact that plaque assays
      do not compromise the function of living cells, it is possible to combine these
      plaque assays with other procedures such as immunocytochemistry, in situ
      hybridization, fluorescent microscopy, electrophysiology, and electron microscopy
      to explore other facets of the secretory process in conjunction with release.
      When taken together, the plaque assay has been quite useful in the study of
      endocrine cell secretion. Moreover, with the many adaptations possible, it should
      be particularly valuable in the future for the study of peptide release in other
      cell types such as neurons.

PMID- 15183176
TI  - Using GFP to image peptide hormone and neuropeptide release in vitro and in vivo.
AB  - Traditionally, peptide secretion by endocrine cells and neurons was studied by
      measuring changes in release in response to experimental perturbations. Now it is
      possible to directly view dense core vesicles (DCVs), secretory apparatus
      proteins and individual exocytotic events by imaging fluorescent proteins in
      living cells. Fundamental insights into peptide release by cultured cells have
      been made with wide field, confocal and total internal reflection (also called
      evanescent wave) microscopes. Researchers have also used a variety of fluorescent
      protein constructs that vary in spectra, pH sensitivity, inducibility, and age
      dependence. Most recently, these approaches have been applied to transgenic
      animals so that hormone and neuropeptide release can be studied in vivo.

PMID- 15183177
TI  - Using FM1-43 to study neuropeptide granule dynamics and exocytosis.
AB  - In the study of neuropeptide secretion and membrane trafficking, the fluorescent
      dye FM1-43 provides the ability to label selectively those structures that are
      undergoing exocytosis and endocytosis in living cells in real time. This review
      describes the unique properties of the FM dyes that make them ideal for studying
      neuropeptide granule dynamics and discusses various techniques that take
      advantage of FM dyes.

PMID- 15183178
TI  - FMRFamide tagging--how an ionotropic receptor can be used to measure peptide
      secretion.
AB  - In this chapter, we describe a technique, FMRFamide tagging, that in principle
      can be used to measure the release of any sequenced neuropeptide. The method
      relies upon the addition of an "electrophysiologically active" tag to the
      prohormone that encodes the neuropeptide of interest. Secretion of the
      electrophysiological tag (and thus the peptide of interest) is detected by
      activation of the ionotropic "tag receptor." Both the tagged prohormone and the
      tag receptor are expressed in the cell type under investigation. Since the tag
      and the neuropeptide of interest are on the same prohormone they are co-secreted
      and thus secretion of the tag reflects the co-secretion of the neuropeptide of
      interest. This method can be used to detect neuropeptide secretion on a
      millisecond timescale.

PMID- 15183179
TI  - Large dense-core vesicle exocytosis in pancreatic beta-cells monitored by
      capacitance measurements.
AB  - This article discusses the currently used methodologies for monitoring exocytosis
      as changes in cell capacitance. Details are given on composition of solutions,
      experimental protocols, and how the observed responses can be interpreted
      physiologically. The concepts are illustrated by examples from our own work on
      insulin-releasing pancreatic beta-cells. Finally, we consider the feasibility of
      applying capacitance measurements to endocrine cells in intact pancreatic islets,
      where the cells are electrically coupled to each other.

PMID- 15183180
TI  - Detection of transmitter release with carbon fiber electrodes.
AB  - The use of constant voltage amperometry is described as an analytical technique
      for the detection of biogenic amines. This technique can be used to measure the
      amount of transmitter released from individual organelles and to determine the
      kinetic properties of transmitter discharge from the organelle providing unique
      insight into properties of signal transmission from secretory cells.

PMID- 15183181
TI  - In vivo monitoring of dopamine overflow in the central nervous system by
      amperometric techniques combined with carbon fibre electrodes.
AB  - Electrochemical techniques are extensively used to investigate in vivo and in
      vitro events associated with neurotransmission, particularly dopamine (DA)
      transmission. In vivo amperometric measurements only concern evoked extracellular
      neurochemical events over short time periods independently of changes in basal
      release. In this context, DA release is evoked either by brief and low electrical
      or by chemical stimulation, which, respectively, mimics or elicits the
      physiological discharge rates of DA neurones. The combination of
      electrochemically treated carbon fibre electrodes with differential pulse
      amperometry (DPA) has been extensively used to monitor DA overflow on a 1-s time
      scale. The more recent in vivo combination of untreated carbon fibre electrodes
      with continuous amperometry gives better temporal information allowing the
      precise description of the kinetic parameters of the mechanisms which regulate DA
      overflow. The results obtained in rats extended by the results obtained in mice
      lacking a protein involved in DA transmission demonstrate that DA autoregulation
      and DA uptake: (i) contributes to the operational properties of DA terminals in
      converting action potentials into DA release as a high pass filter which favours
      short bursts of action potentials and (ii) inhibits excessive DA release which
      might result from prolonged and large increases in the impulse flow.

PMID- 15183182
TI  - Cholesterol domains regulate the actin cytoskeleton at the leading edge of moving
      cells.

PMID- 15183183
TI  - Bromodomains in living cells participate in deciphering the histone code.

PMID- 15183184
TI  - The enigmatic TRPCs: multifunctional cation channels.

PMID- 15183185
TI  - Significant (re)location: how to use chromatin and/or abundant proteins as
      messages of life and death.

PMID- 15183186
TI  - Small is beautiful: what flies tell us about ERM protein function in development.
AB  - Actin dynamics is recognized as being a determinant in many developmental
      processes and pathologies, such as cell polarity, morphogenesis and tumour
      metastasis. However, how actin interacts with the plasma membrane is poorly
      understood. Although numerous studies in cell culture point to the crucial role
      of Ezrin, Radixin and Moesin (ERM) proteins in the actin-membrane link, genetic
      approaches in mice have not yet revealed their activity during development.
      Drosophila has recently become an alternative and promising system for the
      genetic study of ERM protein function. This article focuses on advances made in
      flies, providing evidence for the evolutionary conservation of functional
      properties of ERM proteins, in addition to shedding new light on their importance
      for development.

PMID- 15183187
TI  - Regulation of actin dynamics by WASP and WAVE family proteins.

PMID- 15183188
TI  - LKB1 tumor suppressor protein: PARtaker in cell polarity.
AB  - The LKB1 (also called serine/threonine kinase 11) tumor suppressor gene was
      cloned in 1998 by linkage analysis of Peutz-Jeghers cancer syndrome patients.
      Mammalian LKB1 has been implicated as a regulator of multiple biological
      processes and signaling pathways, including the control of cell-cycle arrest, p53
      mediated apoptosis, Wnt signaling, transforming growth factor (TGF)-beta
      signaling, ras-induced cell transformation, and energy metabolism. The
      Caenorhabditis elegans and Drosophila melanogaster LKB1 homologs, termed PAR4 and
      dLKB1, respectively, regulate cell polarity. Recently, mammalian LKB1 was found
      to be active only in a complex with two other proteins--STRAD and MO25--and to
      induce complete polarization of intestinal epithelial cells in a cell-autonomous
      fashion. In this article, we summarize the findings regarding LKB1 over the past
      six years. In addition, we discuss LKB1 in polarity in the context of both the
      other PAR proteins and its tumor suppressive activities.

PMID- 15183190
TI  - Preconditioning improves postischemic mitochondrial function and diminishes
      oxidation of mitochondrial proteins.
AB  - This study examines the hypothesis that ischemic or pharmacologic preconditioning
      improves postischemic mitochondrial function by attenuating oxidation of
      mitochondrial proteins. Isolated rat hearts were perfused for 38 min preischemia,
      followed by 25 min global ischemia and then 60 min reperfusion. Hearts were
      preconditioned by two episodes of 3 min global ischemia, followed by 2 min of
      reflow (IP), or by perfusion with 50 micromol/l nicorandil (Nic) for 10 min,
      followed by 10 min washout. IP and Nic significantly (p <.05) improved
      postischemic function, which was abolished by bracketing the protocols with 200
      micromol/l 5-hydroxydecoanate (5HD) or 300 micromol/l alpha
      mercaptopropionylglycine (MPG). After isolation of cardiac mitochondria, the
      respiratory control index (RCI) was calculated from State 3 and State 4
      respiration. Both IP and Nic significantly (p <.05) improved postischemic RCI,
      which was depressed 71% from preischemic values in control hearts. The protective
      effects of IP and Nic were partially abolished by bracketing with 5HD or MPG.
      Furthermore, mitochondria from ischemic hearts had significantly (p <.05) less
      ability to resist swelling on Ca2+ loading, which was improved by both IP and
      Nic. By use of an immunoblot technique, carbonyl content of multiple bands of
      mitochondrial proteins was observed to be elevated after 25 min ischemia, and
      still elevated by the end of 60 min reperfusion. Both IP and Nic attenuated the
      increased protein oxidation observed at the end of ischemia. The protective
      effect of IP was almost completely abolished by MPG and partially by 5HD, which
      also partially abolished the protective effect of Nic. These studies support the
      conclusion that one mechanism for enhanced postischemic function in the
      preconditioned heart is improved mitochondrial function as a result of decreased
      oxidation of mitochondrial proteins.

PMID- 15183189
TI  - Guiding neuronal growth cones using Ca2+ signals.
AB  - Pathfinding by growing axons in the developing or regenerating nervous system is
      guided by gradients of molecular guidance cues. The neuronal growth cone, located
      at the ends of axons, uses surface receptors to sense these cues and to transduce
      guidance information to cellular machinery that mediates growth and turning
      responses. Cytoplasmic Ca2+ signals have key roles in regulating this motility.
      Global growth cone Ca2+ signals can regulate cytoskeletal elements and membrane
      dynamics to control elongation, whereas Ca2+ signals localized to one side of the
      growth cone can cause asymmetric activation of effector enzymes to steer the
      growth cone. Modulating Ca2+ levels in the growth cone might overcome inhibitory
      signals that normally prevent regeneration in the central nervous system.

PMID- 15183192
TI  - Genome-wide transcriptional responses to a lipid hydroperoxide: adaptation occurs
      without induction of oxidant defenses.
AB  - Free radicals can initiate the oxidation of polyunsaturated fatty acids in cells
      through the process of lipid peroxidation. The genome-wide transcriptional
      changes in Saccharomyces cerevisiae after treatment with the toxic lipid
      peroxidation product linoleic acid hydroperoxide (LoaOOH) were identified. High
      dose treatment led to a switch in transcription from biosynthetic to protective
      functions. This response encompassed a set of genes stimulated predominantly by
      LoaOOH, and not by other oxidants or heat shock, which contained components of
      the pleiotropic drug resistance system. The dose dependence of the
      transcriptional response revealed that large and widespread changes occur only in
      response to higher doses. Pretreatment of cells with sublethal doses of LoaOOH
      induces resistance to an otherwise lethal dose through the process of adaptation.
      Adaptive doses elicited a more subtle transcriptional response affecting
      metabolic functions, including an increase in the capacity for detoxification and
      downregulation of the rate of protein synthesis. Surprisingly, the cellular
      response to adaptive doses did not include induction of oxidative-stress defense
      enzymes nor of transcripts involved in general cellular defense systems.

PMID- 15183191
TI  - Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide
      induced downregulation of nuclear receptor pregnane x receptor and its target
      gene CYP3a in mouse liver.
AB  - Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that
      regulates target gene transcription in a ligand-dependent manner. The in vivo
      effects of lipopolysaccharide (LPS) on expression of PXR and its target gene
      cytochrome P450 3A (CYP3A) in mouse liver were investigated in this study. Mice
      were injected intraperitoneally with different doses of LPS (0.1-5.0 mg/kg). PXR
      and CYP3A11 mRNA levels were measured using reverse transcription polymerase
      chain reaction. Results indicate that LPS significantly inhibits the expression
      of PXR mRNA in a dose-dependent manner, followed by suppression of CYP3A11 mRNA
      in mouse liver. LPS also represses the upregulation of CYP3A11 mRNA levels and
      erythromycin N-demethylase (ERND) catalytic activity in mice pretreated with PXR
      ligands dexamethasone, rifampicin, mifepristone, and phenobarbital. LPS-induced
      downregulation of PXR and CYP3A11 mRNA in liver was significantly attenuated in
      mice pretreated with gadolinium chloride, a selective Kupffer cell toxicant.
      Pretreatment with a single dose of gadolinium chloride (10 mg/kg) also
      significantly attenuated LPS-induced downregulation of dexamethasone-, rifampicim
      , mifepristone-, and phenobarbital-inducible, CYP3A11 mRNA expression and ERND
      activity in mouse liver. Furthermore, LPS-induced downregulation of PXR and
      CYP3A11 mRNA was significantly attenuated in mice pretreated with allopurinol, an
      inhibitor of xanthine oxidase, and diphenyleneiodonium chloride, an inhibitor of
      NADPH oxidase. Allopurinol and diphenyleneiodonium chloride pretreatment also
      attenuated the repressive effects of LPS on dexamethasone-, rifampicin-,
      mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND
      catalytic activity in mouse liver. However, aminoguanidine, a selective inhibitor
      of inducible nitric oxide synthase, has no effect on LPS-induced downregulation
      of PXR and CYP3A11 mRNA. Finally, LPS-induced downregulation of PXR and CYP3A11
      mRNA was prevented in mice pretreated with either N-acetylcysteine or ascorbic
      acid. These antioxidants also prevented the repressive effects of LPS on
      dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11
      mRNA expression and ERND catalytic activity in mouse liver. These results
      indicate that Kupffer cells contribute to LPS-induced downregulation of PXR and
      CYP3A in mouse liver. Reactive oxygen species, produced possibly by NADPH oxidase
      and perhaps by xanthine oxidase, are involved in LPS-induced downregulation of
      nuclear receptor PXR and its target gene CYP3A in mouse liver.

PMID- 15183193
TI  - Dissociation of oxidant production by peroxisome proliferator-activated receptor
      ligands from cell death in human cell lines.
AB  - Ligands of peroxisome proliferator-activated receptors (PPARs) come from a
      diverse group of chemicals that include pharmaceutical drugs, phthalate
      plasticizers, steroids, and pesticides. PPAR ligands exhibit a number of effects,
      including an ability to induce apoptosis in some systems. The mechanism(s)
      underlying the induction of apoptosis is not known. The current study examined
      the ability of Wy14643, a fibrate and PPARalpha agonist, and ciglitazone, a
      thiazolidinedione and PPARgamma agonist, to induce apoptosis as well as the
      production of oxidants in human Jurkat T cells that express all PPAR isoforms.
      Treatment with increasing doses of Wy14643 caused a substantial time-dependent
      increase in the overall oxidant status (as reflected by increased
      dichlorofluorescein fluorescence) of Jurkat cells without any change in viability
      except at the highest dose and longest time. Ciglitazone also caused a dose- and
      time-dependent increase in oxidant production. However, although the extent of
      this production was less than that seen with Wy14643, ciglitazone caused a dose-
      and time-dependent increase in apoptosis that could not be inhibited by
      antioxidants. Confocal micrographs of Jurkat cells loaded with
      dichlorofluorescein diacetate or dihydrorhodamine 123 and treated with Wy14643 or
      ciglitazone revealed a punctate pattern of fluorescence at early time points
      suggestive of a mitochondrial origin for these oxidants. Rotenone and antimycin A
      prevented Wy14643- but not ciglitazone-induced oxidant production. Other
      relatively specific PPARgamma agonists (15delta-PGJ2, and troglitazone), but not
      nonspecific agonists (bezafibrate and conjugated linoleic acid), were also able
      to induce oxidant production in Jurkat cells. These data, as well as the findings
      that oxidant production could be induced by Wy14643 in A549 cells that lack
      PPARalpha, and could not be blocked in Jurkat cells by the PPARalpha inhibitor
      MK886, indicate oxidant formation is unrelated to PPARalpha. These data also
      suggest that oxidant production induced by PPARalpha ligands originates in the
      mitochondria.

PMID- 15183195
TI  - Predominance of the 1,N2-propano 2'-deoxyguanosine adduct among 4-hydroxy-2
      nonenal-induced DNA lesions.
AB  - 4-Hydroxy-2-nonenal (HNE), one of the main aldehydic compounds released during
      lipid peroxidation, has been proposed to react with DNA bases in cells. Several
      classes of DNA lesions involving addition of either HNE or its 2,3-epoxide (epox
      HNE) have been identified. In the present work, HPLC associated with tandem mass
      spectrometry was used to determine the pattern of HNE-induced DNA lesions. First,
      adducts were quantified within isolated DNA treated with HNE under peroxidizing
      conditions. The 1,N2-propano-2'-deoxyguanosine adduct of HNE (HNE-dGuo) was found
      to be the major lesion under all conditions studied. 1,N6-Ethenoadenine and 1,N2
      ethenoguanine together with their (1,2-dihydroxyheptyl)-substituted derivatives,
      which all arise from the reaction of epox-HNE with DNA, were produced in
      significantly lower yields, even in the presence of 20 mM H2O2. The
      pyrimidopurinone malondialdehyde-2'-deoxyguanosine adduct was also found to be
      produced, although in very low yield. Similar results were obtained in cultured
      human monocytes incubated with HNE, because the HNE-dGuo adduct represented more
      than 95% of the overall adducts to DNA. In addition, the former lesion was poorly
      repaired, in contrast to 1,N2-ethenoguanine and, to a lesser extent, 1,N6
      ethenoadenine. Altogether, these results suggest than HNE-dGuo may represent the
      best biomarker of the genotoxic effects of HNE.

PMID- 15183194
TI  - Kaempferol blocks oxidative stress in cerebellar granule cells and reveals a key
      role for reactive oxygen species production at the plasma membrane in the
      commitment to apoptosis.
AB  - Micromolar concentrations of the flavonoid kaempferol were found to efficiently
      block cerebellar granule cell (CGC) death through low K+-induced apoptosis, as
      demonstrated by prevention of the activation of caspase-3, internucleosomal DNA
      fragmentation, and chromatin condensation, without a significant rise in
      intracellular free Ca2+ concentration. Half of the maximum protection against CGC
      apoptosis was attained with 8 +/- 2 microM kaempferol. Reactive oxygen species
      (ROS) were monitored with 2',7'-dichlorodihydrofluorescein diacetate.
      Quantitative analysis of intracellularly and extracellularly oriented ROS
      production up to 3 h from the onset of low K+-induced CGC apoptosis was carried
      out with acquired digital fluorescence microscopy images of CGC in culture plates
      using a CCD camera, and also with fluorescence measurements of resuspended CGCs.
      In both cases, nearly 90% of ROS production by CGCs during the early stages (up
      to 3 h) after induction of low-K+ apoptosis occurs at the plasma membrane.
      Kaempferol, at concentrations that blocked CGC apoptosis, has been found to be a
      particularly potent blocker of extracellularly oriented ROS production by CGCs,
      and to inhibit the ascorbate-dependent NADH oxidase and superoxide anion
      production activities of the neuronal plasma membrane redox chain.

PMID- 15183196
TI  - Thioredoxin reductase 1 is upregulated in atherosclerotic plaques: specific
      induction of the promoter in human macrophages by oxidized low-density
      lipoproteins.
AB  - Uptake of modified low-density lipoproteins (LDLs) by macrophages in the arterial
      wall is an important event in atherogenesis. Indeed, oxidatively modified LDLs
      (oxLDLs) are known to affect various cellular processes by modulating oxidation
      sensitive signaling pathways. Here we found that the ubiquitous 55 kDa
      selenoprotein thioredoxin reductase 1 (TrxR1), which is a key enzyme for cellular
      redox control and antioxidant defense, was upregulated in human atherosclerotic
      plaques and expressed in foam cells. Using reverse transcription polymerase chain
      reaction analysis, we also found that oxLDLs, but not native LDLs (nLDLs), dose
      dependently increased TrxR1 mRNA in human monocyte-derived macrophages (HMDMs).
      This stimulating effect was specific for oxLDLs, as pro-inflammatory factors,
      such as lipopolysaccharides (LPSs), interleukin-1beta (IL-1beta), interleukin-6
      (Il-6), and tumor necrosis factor alpha (TNFalpha), under the same conditions,
      failed to induce TrxR1 mRNA levels to the same extent. Moreover, phorbol ester
      differentiated THP-1 cells or HMDMs transiently transfected with TrxR1 promoter
      fragments linked to a luciferase reporter gene allowed identification of a
      defined promoter region as specifically responding to the phospholipid component
      of oxLDLs (p <.05 vs. phospholipid component of nLDLs). Gel mobility shift
      analyses identified a short 40-nucleotide stretch of the promoter carrying AP-1
      and HoxA5 consensus motifs that responded with an altered shift pattern in THP-1
      cells treated with oxLDLs, however, without evident involvement of either the
      Fos, Jun, Nrf2 or HoxA5 transcription factors.

PMID- 15183197
TI  - Impact of pulmonary arterial endothelial cells on duroquinone redox status.
AB  - The study objective was to use pulmonary arterial endothelial cells to examine
      kinetics and mechanisms contributing to the disposition of the quinone 2,3,5,6
      tetramethyl-1,4-benzoquinone (duroquinone, DQ) observed during passage through
      the pulmonary circulation. The approach was to add DQ, durohydroquinone (DQH2),
      or DQ with the cell membrane-impermeant oxidizing agent, ferricyanide (Fe(CN)6(3)
      ), to the cell medium, and to measure the medium concentrations of substrates and
      products over time. Studies were carried out under control conditions and with
      dicumarol, to inhibit NAD(P)H:quinone oxidoreductase 1 (NQO1), or cyanide, to
      inhibit mitochondrial electron transport. In control cells, DQH2 appears in the
      extracellular medium of cells incubated with DQ, and DQ appears when the cells
      are incubated with DQH2. Dicumarol blocked the appearance of DQH2 when DQ was
      added to the cell medium, and cyanide blocked the appearance of DQ when DQH2 was
      added to the cell medium, suggesting that the two electron reductase NQO1
      dominates DQ reduction and mitochondrial electron transport complex III is the
      predominant route of DQH2 oxidation. In the presence of cyanide, the addition of
      DQ also resulted in an increased rate of appearance of DQH2 and stimulation of
      cyanide-insensitive oxygen consumption. As DQH2 does not autoxidize
      comproportionate over the study time course, these observations suggest a cyanide
      stimulated one-electron DQ reduction and durosemiquinone (DQ*-) autoxidation. The
      latter processes are apparently confined to the cell interior, as the cell
      membrane impermeant oxidant, ferricyanide, did not inhibit the DQ-stimulated
      cyanide-insensitive oxygen consumption. Thus, regardless of whether DQ is reduced
      via a one- or two-electron reduction pathway, the net effect in the extracellular
      medium is the appearance of DQH2. These endothelial redox functions and their
      apposition to the vessel lumen are consistent with the pulmonary endothelium
      being an important site of DQ reduction to DQH2 observed in the lungs.

PMID- 15183198
TI  - Formation and hydrolysis of triacylglycerol and sterols epoxides: role of
      unsaturated triacylglycerol peroxyl radicals.
AB  - Epoxidation of unsaturated pure triacylglycerols (TAGs), cholesterol, and
      phytosterols was investigated using air and 18O2 oxidation experiments. Oxidized
      lipids were analyzed using both triple quadrupole mass spectrometry (MS), ion
      trap MS in the direct infusion mode, and triple quadrupole MS in tandem with a
      liquid chromatograph (LC-MS/MS). Pure 1,2-distearoyl-3-oleoyl-glycerol (SSO)
      samples were heated in sealed vials under air or 18O2 atmosphere at 160 degrees C
      for 1 h. LC-MS/MS analysis of 18O-labeled oxidized TAGs revealed that
      hydroperoxides and epoxide TAGs are formed mainly during this first step. Then,
      oxidized TAGs were incubated under an inert atmosphere, separately with 1,2
      dipalmitoyl-3-oleoyl-glycerol (PPO) at 160 degrees C for 90 min, and with
      cholesterol and stigmasterol at 100 degrees C for 10 min. Subsequent LC-MS/MS
      analysis revealed the occurrence of epoxidation products of PPO, cholesterol, and
      sitosterol. Therefore, we showed the epoxidation of unsaturated lipids proceeds
      readily in contact with hydroperoxide TAGs, in the absence of molecular oxygen.
      Dual oxidation experiments using both air and 18O2 allowed investigation of
      oxygen atom transfer during epoxidation of lipids. Moreover, the experimental
      oxidation design presented can be used to study fragmentation pathways, as
      illustrated for 5,6-epoxycholesterol (CE) on both triple quadrupole and ion-trap
      MS. We report for the first time the occurrence of 5,6;22,23-diepoxystigmasterol
      (StDE) and 5,6;22,23-diepoxybrassicasterol (BDE) in autoxidized vegetable oils.
      Additionally, acid-catalyzed hydrolysis of epoxidized lipids, with emphasis on
      phytosterol polyol formation, was investigated using a model gastric medium. For
      confirmation, almost all identified products were synthesized and characterized
      by MS.

PMID- 15183199
TI  - Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative
      stress in animal models of diabetes and obesity.
AB  - It is well established that oxidative stress is enhanced in diabetes. However,
      the major in vivo source of oxidative stress is not clear. Here we show that
      vascular NAD(P)H oxidase may be a major source of oxidative stress in diabetic
      and obese models. In vivo electron spin resonance (ESR)/spin probe was used to
      evaluate systemic oxidative stress in vivo. The signal decay rate of the spin
      probe (spin clearance rate; SpCR) significantly increased in streptozotocin
      induced diabetic rats 2 weeks after the onset of diabetes. This increase was
      completely normalized by treatment with the antioxidants alpha-tocopherol (40
      mg/kg) and superoxide dismutase (5000 units/kg), and was significantly inhibited
      by treatment with a PKC-specific inhibitor, CGP41251 (50 mg/kg), and a NAD(P)H
      oxidase inhibitor, apocynin (5 mg/kg). Both obese ob/ob mice (10 weeks old) with
      mild hyperglycemia and Zucker fatty rats (11 weeks old) with normoglycemia
      exhibited significantly increased SpCR as compared with controls. Again, this
      increase was inhibited by treatment with both CGP41251 and apocynin. Oral
      administration of insulin sensitizer, pioglitazone (10 mg/kg), for 7 days also
      completely normalized SpCR values. These results suggest that vascular NAD(P)H
      oxidase may be a major source of increased oxidative stress in diabetes and
      obesity.

PMID- 15183200
TI  - Polynitroxyl hemoglobin: a pharmacokinetic study of covalently bound nitroxides
      to hemoglobin platforms.
AB  - Adding antioxidant activities to hemoglobin-based oxygen carriers (HBOCs)
      represents a means of reducing cell-free hemoglobin-mediated oxidative cascades.
      We have covalently bound nitroxides, a class of antioxidant enzyme mimetics, to
      HBOCs. The objectives of this study were (1) to evaluate the pharmacokinetic (PK)
      effects of administering nitroxide covalently bound to HBOCs compared to those of
      free nitroxide coadministered with HBOCs and (2) to elucidate the effects of
      differing molecular weight HBOCs on the PK of bound nitroxide in a conscious
      guinea pig model of 25% blood exchange transfusion. Two HBOC platforms were used,
      intramolecular cross-linked hemoglobin (XLHb) and dextran polymerized/conjugated
      XLHb (PolyHb). Polynitroxylation was achieved by reacting 4-(2-bromoacetamido)
      2,2,6,6,-tetramethylpiperidine-1-oxyl with XLHb or PolyHb to form
      polynitroxylated XLHb and polynitroxylated PolyHb, respectively, whereas a
      physical mixture of XLHb or PolyHb with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1
      oxyl was prepared to reflect a molar equivalence to HBOC-bound nitroxide. Plasma
      concentrations of two redox states, nitroxide and hydroxylamine, were determined
      by electron paramagnetic resonance spectroscopy. Results are presented to
      illustrate the influence of covalent labeling and HBOC molecular weight on
      nitroxide PK. The therapeutic potential of polynitroxylation of HBOCs as it
      relates to observations from the current and previously reported studies is
      discussed.

PMID- 15183201
TI  - Differential loss of striatal projection systems in Huntington's disease: a
      quantitative immunohistochemical study.
AB  - Prior studies suggest differences exist among striatal projection neuron types in
      their vulnerability to Huntington's disease (HD). In the present study, we
      immunolabeled the fibers and terminals of the four main types of striatal
      projection neuron in their target areas for substance P, enkephalin, or glutamic
      acid decarboxylase (GAD), and used computer-assisted image analysis to quantify
      the abundance of immunolabeled terminals in a large sample of HD cases ranging
      from grade 0 to grade 4 [J. Neuropathol. Exp. Neurol. 44 (1985) 559], normalized
      to labeling in control human brains. Our goal was to characterize the relative
      rates of loss of the two striatopallidal projection systems (to the internal
      versus the external pallidal segments) and the two striatonigral projections
      systems (to pars compacta versus pars reticulata). The findings for GAD and the
      two neuropeptides were similar--the striatal projection to the external pallidal
      segment was the most vulnerable, showing substantial loss by grade 1. Loss of
      fibers in both subdivisions of the substantia nigra was also already great by
      grade 1. By contrast, the loss in the striatal projection system to the internal
      segment of globus pallidus proceeded more gradually. By grade 4 of HD, however,
      profound loss in all projection systems was apparent. These findings support the
      notion that the striatal neurons preferentially projecting to the internal
      pallidal segment are, in fact, less vulnerable in HD than are the other striatal
      projection neuron types.

PMID- 15183202
TI  - Comparison of hypocretin/orexin and melanin-concentrating hormone neurons and
      axonal projections in the embryonic and postnatal rat brain.
AB  - Hypocretin/orexin (H/O) and melanin-concentrating hormone (MCH) are peptide
      neuromodulators found in separate populations of neurons located within the
      lateral and perifornical hypothalamic regions. H/O has been linked to sleep
      wakefulness regulation and to the sleep disorder narcolepsy, and both systems
      have been implicated in energy homeostasis, including the regulation of food
      intake. In the present study we compared the development of H/O and MCH
      expressing neuronal populations with in situ hybridization and
      immunohistochemistry on adjacent sections in the embryonic and postnatal rat
      brain. We found that MCH mRNA and protein were present in developing neurons of
      the hypothalamus by embryonic day 16 (E16), whereas H/O mRNA and protein were not
      detected until E18. We also identified previously undescribed populations of MCH
      immunoreactive cells in the lateral septum, paraventricular hypothalamic nucleus,
      lateral zona incerta, and ventral lateral geniculate nucleus that may play a
      specific role in the development of these regions. MCH immunoreactive axonal
      processes were also evident earlier than H/O stained fibers and at the time H/O
      immunoreactive processes were first identified in the hypothalamus at E20,
      extensive MCH axonal fiber systems were already present in many brain regions.
      Interestingly, however, the density of axonal fibers immunoreactive for H/O in
      the locus coeruleus reached peak levels at the same developmental age (P21) as
      MCH immunoreactive axons in the diagonal band of Broca (DBB). The peak of axon
      density coincided with the developmental stage at which adult patterns of feeding
      and sleep-waking activity become established. The present results demonstrate
      developmental differences and similarities between the MCH and H/O systems that
      may relate to their respective roles in feeding and sleep regulation.

PMID- 15183203
TI  - Ontogeny of two calcium-binding proteins (calbindin D-28K and parvalbumin) in the
      human inferior olivary complex and their distribution in the adults.
AB  - The inferior olivary complex (IOC) is a prominent nuclear relay system of the
      medulla oblongata. Anatomically, it is connected to the cerebellum for
      coordination of motor activities. Calbindin D-28K (CALB) and parvalbumin (PV) are
      cytosolic calcium-binding proteins (CBP) that play a role in Ca2+ homeostasis. We
      examined their ontogeny and distribution in the fetal, postnatal and adult human
      IOC by immunohistochemistry. At 11-12 weeks of gestation (wg), calbindin
      immunoreactivity was present in the principal olive and the medial accessory
      olive, it was absent in the dorsal olive. Parvalbumin immunoreactivity developed
      at 16-17 wg in the ventral lamella and the lateral bulge of the principal olive
      only. Calbindin expression gradually increased from 20 to 37 wg, whilst by
      contrast, parvalbumin expression was moderate. By 37 wg, all three IOC subnuclei
      were immunopositive for both proteins. In a 3-month-old infant, parvalbumin was
      intensely developed in the olivary axons. In the adults (40- to 59-year-old),
      calbindin was distributed in most neurons, and olivocerebellar fibres, whereas
      parvalbumin was present in some neurons and few fibres. Parvalbumin expressed
      till 51 years, and disappeared by 59 years of age. Calbindin immunoreactivity in
      the olivary axons was declined at 70 years of age. The data suggest a
      differential distribution and requirement of these proteins in the human IOC
      maturation. It may be that the IOC utilizes mainly calbindin for Ca2+ buffering.
      The loss of parvalbumin with ageing might influence the excitability of the
      spared IOC neurons.

PMID- 15183204
TI  - Immunolocalisation of endothelin-1 in human brain.
AB  - The potent vasoconstrictor endothelin-1 (ET-1) may function as a neuropeptide and
      be a contributing factor in some neurological disorders, e.g. Alzheimer's
      dementia. The presence of ET-1 has been studied more extensively in the rat and
      porcine nervous systems than in the human brain. Also, the recent description of
      the extensive ET-1 mRNA localisation in human neural tissue supports expression
      in regions of human brain not previously investigated. Using specific anti-ET-1
      polyclonal antiserum, we immunolocalised ET-1 in 24 regions of human brain
      autopsy tissues, and correlated this with ET-1 mRNA distribution. ET-1
      immunoreactivity was observed within some cells of all the 24 areas examined.
      Neuronal staining for ET-1 was demonstrated within the diencephalon, brainstem,
      basal nuclei, cerebral cortex, cerebellar hemisphere, amygdala and hippocampus.
      In addition, ET-1 immunolabelling was visualised in the pituitary gland as well
      as in the choroid plexus. The primary sensory cortex and pineal gland also
      contained immunoreactive ET-1, although ET-1 mRNA had never been detected in
      these regions previously. The localisation of ET-1 and its subsequent correlation
      with ET-1 mRNA in most of the regions investigated suggest a more extensive
      distribution of the ET system in the human brain than was previously identified.

PMID- 15183205
TI  - Regional variations in the localization of insoluble kinase A regulatory isoforms
      during rodent brain development.
AB  - In eukaryothes, the second messenger cAMP regulates many cellular functions by
      binding to the regulatory subunits of cAMP-dependent protein kinases, and
      releasing the catalytic subunits. In the mammalian brain all four regulatory
      isoforms (RIalpha and beta, RIIalpha and beta) are present. Apparently, they are
      simple inhibitors of the catalytic subunits. It is still unclear why four
      isoforms are needed, but possibly they can target kinase activity at precise
      intracellular locations. Therefore, we examined the distribution of the insoluble
      regulatory isoforms in rat and mouse brains during prenatal (from embryonic day
      8) and postnatal development up to senescence (13 months), via
      immunohistochemistry. RIIalpha labelling is always restricted to the ventricular
      ependyma. Punctated RIIbeta labelling is observed in the embryo from early stages
      of development, and is mainly localized in the cortical plate. After birth,
      punctate RIIbeta labelling is present throughout almost the whole brain, often
      observed in proximity of neurofilaments. It shows different characteristics and
      relationships to the other isoforms: for example in the CA1 hippocampal field,
      RIIbeta is substituted by RIalpha 2 weeks after birth, while in CA2 it persists
      for life. In other regions, as in the reticular formation, RIIbeta and RIalpha
      aggregates are found in the same cell, although clearly segregated. The different
      regulatory isoforms show distinct patterns of distribution that change
      consistently during development. A careful characterization of second messenger
      systems may be as useful as the study of neurotransmitters to understand neuronal
      properties and their modifications during development, so as to relate
      biochemical to functional properties.

PMID- 15183206
TI  - Palliative care in the intensive care unit: barriers, advances, and unmet needs.
AB  - The concept that critical illness and terminal illness are necessarily distinct
      entities has given way to the understanding that they often exist on the same
      spectrum. Consequently, there is growing consensus that palliative treatment must
      coexist with attempts at restorative treatment in the intensive care unit (ICU).
      Palliative care in the ICU has evolved from a relatively one-dimensional
      construct of terminal sedation in dying patients to a multidisciplinary field
      addressing symptom control, physician-patient-family communication,spiritual
      needs, and the needs of health care providers. As ongoing research efforts yield
      new insights, our ability to practice evidence-based palliative care in the ICU
      will grow, and new avenues for improvement will become evident.

PMID- 15183207
TI  - Value and role of intensive care unit outcome prediction models in end-of-life
      decision making.
AB  - In the United States, intensive care unit (ICU) admission at the end of life is
      commonplace. What is the value and role of ICU mortality prediction models for
      informing the utility of ICU care?In this article, we review the history,
      statistical underpinnings,and current deployment of these models in clinical
      care. We conclude that the use of outcome prediction models to ration care that
      is unlikely to provide an expected benefit is hampered by imperfect performance,
      the lack of real-time availability, failure to consider functional outcomes
      beyond survival, and physician resistance to the use of probabilistic information
      when death is guaranteed by the decision it informs. Among these barriers, the
      most important technical deficiency is the lack of automated information systems
      to provide outcome predictions to decision makers, and the most important
      research and policy agenda is to understand and address our national ambivalence
      toward rationing care based on any criterion.

PMID- 15183208
TI  - Communicating about end-of-life care with patients and families in the intensive
      care unit.
AB  - Discussing end-of-life care and death with patients and their families is an
      extremely important part of providing a good quality care in the intensive care
      unit (ICU). Although there is little empiric research to guide ICU clinicians in
      the most effective way to have these conversations, there is a developing
      literature and experience and an increasing emphasis on making this an important
      part of the care we provide. Much like other ICU procedures or skills,providing
      sensitive and effective communication about end-of-life care requires training,
      practice, and supervision, as well as planning and preparation. Although
      different clinicians may have different approaches and should change their
      approach to match the needs of individual patients and their families, this
      article reviews some of the fundamental components to discussing end-of-life care
      in the ICU that should be part of the care of patients with life-threatening
      illnesses in the ICU.

PMID- 15183209
TI  - Pain management in the intensive care unit.
AB  - Pain management is an essential component of quality care delivery for the
      critically ill patient. Because outcomes are difficult to predict in the
      intensive care unit (ICU), high-quality pain management and palliative therapy
      should be a goal for every patient. For those patients actively dying, palliation
      may be among the main benefits offered by the health care team. Appropriate
      palliation of pain begins with the use of effective strategies for recognizing,
      evaluating,and monitoring pain. Skill in pain management requires knowledge of
      both pharmacologic and nonpharmacologic therapies. This article focuses on
      expertise in the use of opiates to facilitate confident and appropriate pain
      therapy. To optimize palliative therapy, symptoms are best addressed by
      interdisciplinary care teams guided by models that acknowledge a continuum of
      curative therapies and palliative care.

PMID- 15183210
TI  - Terminal dyspnea and respiratory distress.
AB  - Dyspnea is a subjective experience that can be reported by the patient.
      Respiratory distress is an observable corollary, and represents the physical or
      emotional suffering that results from the experience of dyspnea. Recognizing and
      understanding this subjective phenomenon poses a challenge to intensive care unit
      (ICU) clinicians when caring for the patient who is dying in the ICU. Dyspnea and
      cognitive impairment are highly prevalent in the terminally ill ICU patient. A
      Respiratory Distress Observation Model may provide a theoretical foundation for
      the assessment of this phenomenon that is grounded in emotional and autonomic
      domains of neurologic function. Treatment of dyspnea and respiratory distress
      relies on nonpharmacologic interventions and opioids and sedatives. As with pain,
      the treatment of dyspnea and respiratory distress relies on close evaluation of
      the patient and treatment to satisfactory effect. Empirical evidence suggests
      that quality care with control of distressing symptoms does not hasten death.
      Withholding opioids or sedatives in the face of unrelieved dyspnea or respiratory
      distress has no moral foundation.

PMID- 15183211
TI  - Delirium and sedation.
AB  - Critically ill patients nearing the end of life frequently present with needs for
      aggressive sedation and analgesia. Optimizing patient comfort while permitting
      effective communication are challenging goals in this patient population. This
      article discusses delirium and sedation as it applies to dying patients, and
      provides recommendations for effective management strategies to optimize the
      experience of such patients at the end of life.

PMID- 15183212
TI  - Principles and practice of withdrawing life-sustaining treatments.
AB  - The clinician's responsibility to the patient does not end with a decision to
      limit medical treatment, but continues through the dying process. Every effort
      should be made to ensure that withdrawing life support occurs with the same
      quality and attention to detail as is routinely provided when life support is
      initiated. Approaching the withdrawal of life support as a medical procedure
      provides clinicians with a recognizable framework for their actions. Key steps in
      this process are identifying and communicating explicit shared goals for the
      process, approaching withdrawal of life-sustaining treatments asa medical
      procedure, and preparing protocols and materials to assure consistent care. Our
      hope is that adopting a more formal approach to this common procedure will
      improve the care of patients dying in intensive care units.

PMID- 15183213
TI  - Caring for the family of the critically ill patient.
AB  - Family's needs and considerations are an essential component of intensive care
      unit (ICU) care. Family satisfaction is related to clinician communication and
      decision making. Indeed, timely, honest communication is vital to the
      psychosocial health and satisfaction of the family. Conflict often arises within
      the family and between the family and the clinicians, over decision making.
      Again, good communication skills are critical to family satisfaction with
      decision making and comfort with the care received. Family members have numerous
      psychosocial changes, and may experience depression,anxiety, or anticipatory
      grief while their family member is dying in the ICU. Awareness of these
      conditions, providing support to the families, and allowing family access to the
      dying individual can assist with meeting the family's desire to see their family
      member have a peaceful death.

PMID- 15183214
TI  - End-of-life care in the pediatric intensive care unit: research review and
      recommendations.
AB  - Improving the quality of end-of-life care has become a national health care
      priority. A necessary step in this process in the pediatric intensive care unit
      (ICU) is examining the knowledge, attitudes,and behaviors of pediatric critical
      care practitioners in this area. In addition, the perspectives of bereaved
      parents must be uncovered as well. In this article, the empirical data in the
      literature on end-of-life care in the pediatric ICU are reviewed, common ethical
      controversies in this environment are discussed, and promising interventions for
      the future are presented.

PMID- 15183215
TI  - Spirituality in health: the role of spirituality in critical care.
AB  - Caring for critically ill patients requires that physicians and other health care
      professionals recognize the potential importance of spirituality in the lives of
      patients, families, and loved ones and in their own lives. Patients and loved
      ones undergo tremendous stress and suffering in facing critical illness.
      Professional caregivers also face similar stress and sadness. Spirituality offers
      people away to understand suffering and illness. Spiritual beliefs can also
      impact how people cope with illness. By addressing spiritual issues of patients,
      loved ones, and ourselves, we can create more holistic and compassionate systems
      of care.

PMID- 15183216
TI  - Ethics and palliative care consultation in the intensive care unit.
AB  - It is clear that ethics and palliative care consultation have, in our view, much
      to offer intensivists as they attempt to work through the very complex and often
      tragic cases they face in their daily practice.Potential strengths include
      clarification of tangled normative issues, facilitation of shared decision
      making, conflict resolution,and expertise in the provision of comfort care.
      Despite this, it is an unfortunate fact that many intensivists remain reluctant
      to use ethics and palliative care services. There are, of course, many possible
      reasons for this, including the absence of quality services in certain
      institutions, issues, or power and control, and role misperceptions. It is our
      hope that we have helped to clarify appropriate roles for ethics and palliative
      care in the intensive care unit. We urge the continued development of quality
      ethics and palliative care services, and the use of those services by
      intensivists.

PMID- 15183217
TI  - The dying patient in the ICU: role of the interdisciplinary team.
AB  - Expert opinion supports the application of broad interdisciplinary team
      approaches to the care of the dying patient in the intensive care unit (ICU).
      Current literature contains many suggestions about how core team members
      physicians, nurses, and patients/family members-could systematically enhance
      interdisciplinary collaboration in the care of the dying patient. In the few
      studies of ICU interdisciplinary collaborative care of the dying patient,
      investigator shave demonstrated improvement in care. In addition, ethics
      consultants and interdisciplinary palliative care teams, working with the core
      team members, have improved care for the dying. Further studies are needed to
      document alternative interdisciplinary models for achieving improved and durable
      patient, family,and provider outcomes in the care of the dying ICU patient.

PMID- 15183218
TI  - Caring for the caregiver.
AB  - There are certainly many coping behaviors that may assist ICU caregivers in the
      process of caring for themselves. Staff support groups,regular interdisciplinary
      meetings to discuss difficult cases,and bringing trained personnel into the
      intensive care unit (ICU)environment to offer staff training in communication and
      conflict resolution skills have been suggested as methods for alleviating
      caregiver stress. Combining these as well as other tools with a deeper look at
      the caregiver-patient relationship are important building blocks for creating a
      sane, healthy environment in the ICU. Over the next years, as the population
      ages, and as technologic advances continue, the critical care units will play an
      even more prominent role in health care. Given the threat posed by the severe
      nursing shortage, it becomes apparent that, to prepare for this increased need
      for critical care services, efforts must be directed to identify the sources of
      distress for ICU caregivers and develop focused training programs that alleviate
      the inevitably strains and pressures that arise in the process of compassionate
      caring for the critically ill.

PMID- 15183220
TI  - Parotid tumors: differentiation of benign and malignant tumors with quantitative
      sonographic analyses.
AB  - We asked in this study if the quantitative sonographic analysis could diagnose
      effectively the benign and malignant tumors of the parotid gland. Sonographic
      analyses using mean grey values and SDs of echo levels were performed on the 21
      benign tumors and 22 malignant tumors of the parotid glands. Both the mean grey
      level and the SD of the echo levels were significantly and characteristically
      different among the different parotid tumor groups. Discrimination analysis
      showed that, compared with single uses, a combined use of these two criteria
      improved diagnostic accuracy to 81% (carcinoma vs. pleomorphic adenomas), 93%
      (malignant lymphomas vs. pleomorphic adenomas), 91% (carcinomas vs. malignant
      lymphomas), 100% (pleomorphic adenomas vs. Warthin's tumors), 100% (carcinomas
      vs. Warthin's tumors) and 100% (malignant lymphomas vs. Warthin's tumors). These
      findings suggest that quantitative sonographic analysis is effective in
      differentiating benign and malignant tumors of the parotid gland.

PMID- 15183221
TI  - Possible contribution of prostatic anterior fibromuscular stroma to age-related
      urinary disturbance in reference to pressure-flow study.
AB  - Recently, we reported that the anterior fibromuscular stroma (AFMS) of the
      prostate has significant different innervation compared with the other glandular
      regions of the prostate. In healthy volunteers (n = 12) using transrectal
      ultrasound (US), or TRUS, monitoring during voiding, we observed dynamic change
      (p < 0.0001) of the thickness of the AFMS during voiding. The aim of this study
      was to reveal the possible functional contribution of the AFMS to micturition, as
      well as the age-related voiding dysfunction. In the patients (n = 56) with
      voiding dysfunction who underwent both pressure-flow study (PFS) for determining
      obstruction and TRUS monitoring during voiding, we measured the ultrasonic
      dynamic change of the lower urinary tract during voiding. In old men with voiding
      dysfunction, ultrasonic measurements of dynamic change in the AFMS (p < 0.01) as
      well as the opening urethra (p < 0.05) could contribute to diagnosing of the
      anatomical localization of obstructive lesions. The poor movement of AFMS could
      account for the age-related urinary disturbance in the patients without benign
      prostatic enlargement and without bladder neck obstruction.

PMID- 15183222
TI  - Does 3-D sonography bring any advantage to noninvasive breast diagnostics?
AB  - The aim of this prospective trial was to evaluate if 3-D ultrasound (US) brings
      any advantage to breast diagnostics. A total of 65 women with breast lesions (42
      malignant, 23 benign) were examined preoperatively with 2-D and 3-D US. The
      impact of the use of the 3-D coronal plane for the visualization of the
      infiltrative zone in comparison to 2-D US was evaluated. Additionally, 3-D
      surface imaging and volumetry were performed. The coronal plane was of benefit
      when the infiltrative zone was unclear (6 of 8 cases) or not visible (17 of 39
      cases; 43.6%) using 2-D imaging. The surface mode was advantageous for imaging
      complex structures (e.g., a multinodular fibroadenoma). Volumetry yielded a
      highly significant correlation between 2-D and 3-D US. 3-D US of breast lesions
      as adjunct to 2-D sonography can offer a better assessment of the infiltrative
      zone. Moreover, it enables accurate documentation of data.

PMID- 15183223
TI  - Quantifying myocardial deformation throughout the cardiac cycle: a comparison of
      ultrasound strain rate, grey-scale M-mode and magnetic resonance imaging.
AB  - Strain rate imaging (SRI) is a new ultrasound (US) approach to the quantification
      of regional myocardial deformation. It previously has been validated in vitro and
      in vivo against other imaging techniques. However, in all such studies, only peak
      strain values were compared, and the temporal evolution of the strain curve was
      not studied. Yet, it is the temporal evolution of the strain curves that contains
      the more important clinical information (e.g., asynchrony, viability, etc). Thus,
      the aim of this study was to compare the evolution of strain during the complete
      cardiac cycle as measured by US SRI, US grey-scale M-mode and magnetic resonance
      imaging (MRI). In 10 healthy volunteers and 20 patients with chronic ischaemic
      heart disease, radial deformation of the inferolateral segment of the left
      ventricle was measured by US SRI, US M-mode and MRI. The correspondence of the
      temporal characteristics of these strain curves were compared by defining an
      intraclass correlation coefficient (ICC). In healthy volunteers, an overall good
      agreement (mean ICC: 0.75 and 0.63 for systole and diastole) was found between
      the different methods. However, in patients with abnormal segmental deformation
      and low peak strain values, the agreement was less (mean ICC: 0.42 and 0.32), but
      remained within acceptable limits for clinical decision making. Myocardial
      deformation measurements using SRI correlated well with MRI and US M-mode
      measurements throughout the complete cardiac cycle.

PMID- 15183224
TI  - Abnormally high resistive index of central retinal artery by ultrasound color
      Doppler in patients with viral chronic liver disease: correlation with worsening
      liver staging.
AB  - Retrobulbar-ocular circulation provides an opportunity to assess the terminal
      circulation of the arterial cerebral tree. To evaluate whether retrobulbar
      circulation in patients with chronic liver disease is affected by adaptive
      mechanisms, we assessed by echo color Doppler, 1. The resistive-index of the
      central retinal artery, a terminal branch of the ophthalmic artery, and 2. the
      potential interrelationships with both liver staging and the most important
      splanchnic Doppler-parameters used to assess portal hypertension. The resistance
      index (RI) of the central retinal artery was obtained and compared with other
      classical Doppler parameters known to be affected by portal hypertension. The RI
      of the central retinal artery (CRA) was higher in cirrhotic patients than in
      controls or subjects with chronic hepatitis; it correlated with all the Doppler
      parameters of portal hypertension considered, with plasma renin-activity, and
      norepinephrine concentrations. Similarly to renal and splanchnic hemodynamics,
      retinal arterial circulation assessed by duplex Doppler seems to be affected by
      the histology of liver disease and by the overactivity of vasoconstrictor
      systems.

PMID- 15183225
TI  - Evaluation of vertebral artery hypoplasia and asymmetry by color-coded duplex
      ultrasonography.
AB  - Distinguishing stenosis and hypoplasia of the extracranial vertebral artery (VA)
      is clinically important, but there is no agreement in defining VA hypoplasia. We
      endeavored to attain reference values for VA flow volume by color Doppler
      ultrasonography (CDU), analyze age and gender effects on VA flow volume and
      develop a definition of VA hypoplasia. CDU was performed in 447 subjects free of
      cerebrovascular diseases or carotid stenosis. The VA diameter, peak systolic
      velocity, end-diastolic velocity, time-averaged mean velocity, resistance index
      (RI) and flow volume were recorded bilaterally. We found significant asymmetries
      in diameter, flow velocities and flow volume with left-sided dominance. Diameters
      were different on left (0.297 +/- 0.052 cm) and right (0.323 +/- 0.057) sides (p
      < 0.001). Flow volume was different on right (83.0 +/- 36.9 mL/min) and left
      (96.6 +/- 42.4) sides (p < 0.001). Women had significantly smaller diameters,
      higher flow velocities and lower RIs than men. VA flow volume did not change with
      aging. We defined hypoplasia as a significant decrease in flow velocities and
      increase in RI for VA diameters < 0.22 cm. This definition is supported by
      findings of an increase in ipsilateral flow resistance (RI >/= 0.75),
      contralateral diameter (side-to-side diameter difference >/= 0.12 cm), and flow
      volume (side-to-side flow volume ratio >/= 5). This definition and these
      reference values may lead to better differentiation between congenital variation
      and steno-occlusion clinically.

PMID- 15183226
TI  - Carotid plaque spaces relate to symptoms and ultrasound scattering.
AB  - We have previously found that spectral analysis of ultrasound (US) can
      discriminate in vitro plaques from asymptomatic and symptomatic (transient
      ischemic attack within previous 4 weeks) patients. That study found no
      differences in percentages of lipid or thrombus between the two groups by optical
      microscopy/planimetry. The present study was to find out if another feature from
      the microscopy could show a difference. The number and size of spaces resulting
      from cell death or new blood vessels were measured to see if they related to
      symptoms or could help explain US differentiation. Twelve plaques from each group
      were examined by optical microscopy. The sizes and concentrations of two kinds of
      spaces, endothelial lined (vessel spaces) and unlined (tissue spaces), were
      correlated both with symptoms and also with the US tissue characterization scores
      from the previous study. Symptomatic vs. asymptomatic plaques showed a higher
      concentration and a larger size: 0.87 vs. 0.21 per mm(2) (p < 0.005) and 154 vs.
      110 microm (p < 0.02). A discriminant function of spaces with symptoms as
      dependent variables correctly identified 91.7% of the plaques (p < 0.001). The
      concentration in plaques previously designated by US as true positive plaques or
      true negative was 1.21 vs. 0.22 per mm(2) (p < 0.005). spaces were increased in
      plaques of symptomatic patients and were related to UTC scores. Both the lined
      and unlined spaces were useful as predictors.

PMID- 15183227
TI  - Enhancement of needle visibility in ultrasound-guided percutaneous procedures.
AB  - The visibility of a needle in ultrasound (US)-guided percutaneous procedures is
      often limited by dispersion of the needle's reflections away from the probe. A
      needle enhancement algorithm is developed that maximizes the received reflections
      by steering the US beam precisely perpendicular to the needle. The resulting
      image clearly depicts the needle as a bright line. The key is to automatically
      detect the needle in the image and maintain the appropriate beam steering angle
      during the procedure. The brightened needle in the steered image is then fused
      with the original image to produce an improved image. Implementation of the
      needle-enhancement algorithm was made possible by using the programmable
      ultrasound platform and interface library (PUPIL). PUPIL is capable of acquiring
      digital images, processing the images in real-time, controlling the beam angle,
      and displaying the fused image. The results demonstrate significantly improved
      needle visibility in both breast phantoms and turkey breast samples.

PMID- 15183228
TI  - Watershed segmentation for breast tumor in 2-D sonography.
AB  - Automatic contouring for breast tumors using medical ultrasound (US) imaging may
      assist physicians without relevant experience, in making correct diagnoses. This
      study integrates the advantages of neural network (NN) classification and
      morphological watershed segmentation to extract precise contours of breast tumors
      from US images. Textural analysis is employed to yield inputs to the NN to
      classify ultrasonic images. Autocovariance coefficients specify texture features
      to classify breasts imaged by US using a self-organizing map (SOM). After the
      texture features in sonography have been classified, an adaptive preprocessing
      procedure is selected by SOM output. Finally, watershed transformation
      automatically determines the contours of the tumor. In this study, the proposed
      method was trained and tested using images from 60 patients. The results of
      computer simulations reveal that the proposed method always identified similar
      contours and regions-of-interest (ROIs) to those obtained by manual contouring
      (by an experienced physician) of the breast tumor in ultrasonic images. As US
      imaging becomes more widespread, a functional automatic contouring method is
      essential and its clinical application is becoming urgent. Such a method provides
      robust and fast automatic contouring of US images. This study is not to emphasize
      that the automatic contouring technique is superior to the one undertaken
      manually. Both automatic and manual contours did not, after all, necessarily
      result in the same factual pathologic border. In computer-aided diagnosis (CAD)
      applications, automatic segmentation can save much of the time required to sketch
      a precise contour, with very high stability.

PMID- 15183229
TI  - A novel in vivo procedure for volumetric flow measurements.
AB  - We report on a novel procedure for invasive volumetric blood flow measurements
      using a commercially available Doppler flow wire system, which could, until now,
      only measure flow velocity. We here describe a method applicable in vivo to
      generate both velocity and cross-sectional area information from the same pulsed
      wave Doppler signal for volumetric flow assessment. We demonstrate its
      feasibility and validation in vivo in pig coronary arteries. Our Doppler-derived
      volumetric flow measurements were compared with the respective transit-time flow
      and showed an excellent correlation (r = 0.969; p < 0.0001). Agreement between
      transit-time and Doppler-derived flow measurements could be observed for flow
      conditions ranging from 30 to 180 mL/min. The mean values for the two methods
      were 71.4 +/- 43.7 mL/min and 71.3 +/- 42.2 mL/min, respectively. We conclude
      that this technique might possibly be introduced into future clinical practice as
      an invasive procedure of choice for the assessment of volumetric blood flow.

PMID- 15183230
TI  - Assessment of the effect of vessel curvature on Doppler measurements in steady
      flow.
AB  - Blood vessel curvature is responsible for the appearance of nonaxial velocity
      components and for minor changes in the pattern of the axial flow. All the
      velocity components are expected to contribute to the Doppler signal produced by
      the ultrasound (US) backscattered by the insonated blood cells, the axial
      velocity, contributing to the actual volumetric blood flow, and the transverse
      velocity, causing the recirculating vortices. A detailed, separate analysis of
      the velocity components is, therefore, mandatory to quantify how vessel curvature
      can affect results and clinical diagnosis. Both experimental in vitro measures
      and numerical simulations were performed on a curved tube and the Doppler power
      spectra so obtained were compared. The satisfactorily agreement of the above
      spectra shows that the nonaxial velocity components are easily detectable with
      clinical equipment and that their amplitude, as expected, is not negligible and
      can bias Doppler measurements and resulting clinical diagnosis.

PMID- 15183231
TI  - Online automated detection of cerebral embolic signals using a wavelet-based
      system.
AB  - Transcranial Doppler ultrasound (US) can be used to detect emboli in the cerebral
      circulation. We have implemented and evaluated the first online wavelet-based
      automatic embolic signal-detection system, based on a fast discrete wavelet
      transform algorithm using the Daubechies 8th order wavelet. It was evaluated
      using a group of middle cerebral artery recordings from 10 carotid stenosis
      patients, and a 1-h compilation tape from patients with particularly small
      embolic signals, and compared with the most sensitive commercially available
      software package (FS-1), which is based on a frequency-filtering approach using
      the Fourier transform. An optimal combination of a sensitivity of 78.4% with a
      specificity of 77.5% was obtained. Its overall performance was slightly below
      that of FS-1 (sensitivity 86.4% with specificity 85.2%), although it was superior
      to FS-1 for embolic signals of short duration or low energy (sensitivity 75.2%
      with specificity 50.5%, compared to a sensitivity of 55.6% and specificity of
      55.0% for FS-1). The study has demonstrated that the fast wavelet transform can
      be computed online using a standard personal computer (PC), and used in a
      practical system to detect embolic signals. It may be particularly good for
      detecting short-duration low-energy signals, although a frequency filtering-based
      approach currently offers a higher sensitivity on an unselected data set.

PMID- 15183232
TI  - Semiautomated thermal lesion segmentation for three-dimensional elastographic
      imaging.
AB  - Several studies have demonstrated that lesion volumes computed from multiple
      planar slices through the region-of-interest (ROI) are more accurate than volumes
      estimated assuming simple shapes and incorporating single or orthogonal diameter
      estimates. However, manual delineation of boundaries on multiple planar 2-D
      images is tedious and labor-intensive. Automatic extraction of lesion boundaries
      is, therefore, attractive and imperative to remove subjectivity and reduce
      assessment time. This paper presents a semiautomated segmentation algorithm for
      thermal lesions on 3-D elastographic data to obtain both area and volume
      information. The semiautomated segmentation algorithm is based on thresholding
      and morphologic opening of both 2-D and 3-D elastographic data. Results obtained
      on 44 thermal lesions imaged in vitro using elastography were compared to manual
      delineation of both elastographic and pathology images. Results obtained using
      semiautomated segmentation demonstrate a close correspondence with manual
      delineation results. However, area and volume estimates obtained using both
      manual and semiautomated segmentation of lesions seen on elastograms slightly
      underestimate areas and volumes measured from pathology.

PMID- 15183233
TI  - Thermal assessment of 40-MHz ultrasound at soft tissue-bone interfaces.
AB  - Tissue exposure to diagnostic ultrasound (US) can cause significant temperature
      rises. However, little has been reported on thermal effects of high-frequency US,
      and guidelines for the use of US do not necessarily apply to higher frequencies.
      Temperature rise induced by US biomicroscopy (UBM) was measured in phantoms
      containing mouse skulls and in anesthetized mice and mice post mortem, with a 50
      microm K-type thermocouple. The operating frequency was 40 MHz with a free field
      I(SPTA) of 2.6 mW/cm(2) (B-mode) and 11.9 W/cm(2) (Doppler). Peak negative
      pressures were 5.22 MPa (B mode) and 7.32 MPa (Doppler), resulting in a
      mechanical index (MI) of 0.83 (B-mode) and 1.05 (Doppler mode). In Doppler mode,
      mean temperature rises of 1.80 degrees C and 1.73 degrees C were measured for
      proximal and distal skull phantom surfaces after a 3-min insonation. In vivo, the
      proximal mouse skull surface showed a mean temperature rise of 2.1 degrees C,
      with no statistically significant differences post mortem. Our results indicate
      temperature rise from insonation of bone interfaces using similar exposure
      parameters should not cause adverse bioeffects.

PMID- 15183234
TI  - Reduction of tissue injury in shock-wave lithotripsy by using an acoustic diode.
AB  - An acoustic diode (AD) was constructed of two acoustic transparent membranes with
      good initial contact to allow the transmission of the positive pressure of
      lithotripter shock wave at an almost unaltered level, yet attenuate significantly
      its negative pressure, was fabricated. It was evaluated systematically on a
      Dornier HM-3 lithotripter to assess its application potential to reduce vascular
      injury without compromising stone fragmentation efficiency during shock-wave
      lithotripsy. By inserting the AD, the maximum compressive pressure, maximum
      tensile pressure and tensile duration of the lithotripter shock wave were formed
      to drop from 49.7 to 47.8 MPa, -7.5 to -7.0 MPa and 6.0 to 5.1 micros,
      respectively. Damage of a 0.2-mm inner diameter vessel phantom (cellulose hollow
      fiber) was reduced from rupture after 31 +/- 11 shocks to no rupture after 100
      shocks. Maximum bubble size in free-field, maximum dilation of the vessel phantom
      wall and bubble collapse time became smaller with the use of the AD. However,
      stone fragmentation showed similar results without a statistically significant
      difference between the case with and without the AD. All these evidences suggest
      that the use of an acoustic diode may be a feasible approach to reduce tissue
      injury without compromising stone comminution in shock-wave lithotripsy.

PMID- 15183236
TI  - Identification of hibernating myocardium by acoustic microscopy.
AB  - Hibernating myocardium is viable myocardium that recovers after
      revascularization. The observation of loss of contractile proteins (myofibrils)
      and accumulation of glycogen in hibernating cardiomyocytes provide the basis for
      diagnosing hibernating myocardium. In this pilot study, acoustic microscopy was
      used to identify the cellular structure of normal vs. hibernating myocardium.
      Sections cut at 5-microm of archival paraffin blocks on glass slides were used
      for this study. Acoustic microscopy of normal cardiomyocytes showed intracellular
      linear echoes suggestive of myofibrils, and cardiomyocytes of hibernating
      myocardium revealed absence of myofibrils and dense intracellular echoes that
      corresponded to glycogen accumulation on optical microscopy. This modality of
      visualization allows a definitive diagnosis of hibernating myocardium.

PMID- 15183235
TI  - Role of intracellular calcium ions and reactive oxygen species in apoptosis
      induced by ultrasound.
AB  - Recently, we have reported that ultrasound (US)-induced apoptosis is due to
      inertial cavitation and that extracellular reactive oxygen species (ROS)
      generated by inertial cavitation are not directly correlated with the apoptosis
      (Honda et al. 2002). The molecular mechanism of apoptosis induced by US is not
      yet sufficiently clear. Here, we examine the role of intracellular calcium ions
      and the intracellular ROS on apoptosis induced by US. Human myelomonocytic
      lymphoma U937 cells were exposed to continuous 1-MHz US at an intensity of 4.9
      W/cm(2) (I(SPTA)) in the presence of air, and changes of intracellular calcium
      ion concentration ([Ca(2+)]i) in individual cells by digital imaging, various
      flow cytometric analyses of endpoints of apoptosis (early apoptosis, secondary
      necrosis, loss of mitochondria membrane potential, superoxide formation, caspase
      3 activation) and DNA fragmentation were explored. Furthermore, the effects of an
      intracellular calcium ion chelator (BAPTA-AM), an antioxidant (N-acetyl-L
      cysteine, NAC), a calcium channel blocker (verapamil), Ca(2+)-free buffer and
      Levovist were also investigated. These results indicate that: 1. the mitochondria
      caspase pathway and the Ca(2+)-dependent pathway play cardinal roles in apoptosis
      induced by US because BAPTA-AM partially inhibited DNA fragmentation, loss of
      mitochondria membrane potential and caspase-3 activation; 2. intracellular ROS
      generated from mitochondria, rather than extracellular ROS (which were directly
      produced by inertial cavitation in the medium), are involved in the regulation of
      apoptosis induced by US because addition of NAC after sonication showed effective
      suppression of the apoptosis; and 3. increase of [Ca(2+)]i appears to be due to
      nonspecific influx from outside the cells because verapamil is not effective and
      no increase of [Ca(2+)]i due to sonication could be observed in the Ca(2+)-free
      buffer.

PMID- 15183237
TI  - An animal model for ultrasound lung imaging.
AB  - In the past decade, a number of clinical investigators have used ultrasound (US)
      to image the lung during video-assisted thoracoscopic surgery (VATS). In
      contrast, animal studies have shown prohibitively high attenuation levels in the
      lung, incompatible with the ability to image the lung. We hypothesized that the
      use of anesthesia during VATS augments lung collapse upon exposure to atmospheric
      pressure; thus, making US lung imaging possible. To test this hypothesis, we
      compared the effect of two commonly used anesthetic protocols on our ability to
      image 200 microL of US gel injected in rabbit lungs using a pulse echo transducer
      at 13 MHz. The anesthetic protocol, using acepromazine, ketamine and isoflurane,
      allowed US lung imaging in rabbits. It is concluded that US at 13 MHz can detect
      200 microL of US gel injected into the lung parenchyma in a rabbit model.

PMID- 15183238
TI  - Bacterial adaptation and resistance to antiseptics, disinfectants and
      preservatives is not a new phenomenon.

PMID- 15183239
TI  - Surveillance of multi-drug resistant Pseudomonas aeruginosa in an urban tertiary
      care teaching hospital.
AB  - Antimicrobial resistance in Pseudomonas aeruginosa is a serious clinical problem.
      To determine the incidence of multi-drug resistant P. aeruginosa, resistance
      rates of P. aeruginosa clinical isolates against commonly used antibiotics were
      evaluated for the period 1998 to 2002. Multi-drug resistance was defined as
      resistance to at least three of the four drugs, ceftazidime, imipenem,
      ciprofloxacin, and tobramycin. Resistance to most anti-pseudomonal agents has
      increased by >20% over the five-year period, with dramatic increases observed
      with fluoroquinolones, tobramycin, and imipenem (resistance increased by 34-37%).
      In 1998, 78% of isolates were susceptible to all four anti-pseudomonal agents and
      no isolate was considered multi-drug resistant. However, in 2002, only 27% of
      isolates were sensitive to all four of the drugs and 32% were considered multi
      drug resistant. Multi-drug resistance in individual institutions may be
      significantly higher than rates reported in nationwide surveillance studies and
      may more accurately reflect the true magnitude of local resistance problems. On
      going surveillance within individual institutions is critical for the selection
      of appropriate empiric antimicrobial therapy.

PMID- 15183240
TI  - Risk factors and clinical outcomes of nosocomial multi-drug resistant Pseudomonas
      aeruginosa infections.
AB  - Risk factors for multi-drug resistant Pseudomonas aeruginosa (MDRP) infections
      were investigated using a case-control study design involving MDRP patients (N =
      44) and controls (N = 68). A retrospective cohort study was performed to study
      the predictive factors of clinical outcome in MDRP patients. Multivariate
      analysis demonstrated that previous exposure to imipenem/meropenem [odds ratio
      (OR), 44.8] and mechanical ventilation (OR 8.2) were risk factors for nosocomial
      infections of MDRP. Of 44 cases of MDRP infections, 20 patients died directly
      from P. aeruginosa infections. Pulsed-field gel electrophoresis (PFGE) analysis
      on serial isolates from three patients showed that profiles of isolates from the
      same patient were closely related or indistinguishable. Multivariate analysis
      demonstrated that patients with adverse clinical outcomes were more likely to
      have been treated with mechanical ventilation (OR 12.8), and more likely to have
      MDRP resistance patterns that did not change during treatments (OR 26.5). We
      concluded that mechanical ventilation and previous exposure to imipenem/meropenem
      were independent risk factors for MDRP infections, while mechanical ventilation
      and antibiotic resistance switch were predictive factors of outcomes of MDRP
      infections.

PMID- 15183241
TI  - Emergence of Enterobacter cloacae as a common pathogen in neonatal units: pulsed
      field gel electrophoresis analysis.
AB  - In the first week of December 2002, three infants hospitalized in the neonatal
      department of our hospital had blood cultures positive with Enterobacter cloacae.
      Screening cultures and genotyping showed that 10 of 25 screened patients also
      carried E. cloacae and that nine isolates belonged to the same clone as that
      responsible for all three bacteraemias. This epidemic cluster was limited to one
      of the two units of the department. Surveillance of both units continued until
      the end of March 2003; 51 of 159 neonates screened were colonized with E.
      cloacae, 38 out of 80 (47.5%) in the premature unit (PU) and 13 out of 79 (16.4%)
      in the paediatric intensive care unit (PICU). Pulsed-field gel electrophoresis
      (PFGE) analysis of 130 available isolates revealed 30 different pulsotypes,
      including 24 unique pulsotypes from individual patients and six from multiple
      patients. Antibiotic (particularly beta-lactam) use did not significantly vary
      from 1999 to 2003. The consumption of alcohol-based hand rub (four-fold higher in
      the PICU than in the PU) and nurse-to-patient ratio (1:2 in the PICU and 1:4 in
      the PU) might explain the higher cross-transmission rate in the PU. Finally,
      despite an epidemiological survey, we failed to identify the causes of the
      emergence of E. cloacae in our neonatology units. However, improved hygiene
      practices combined with restriction of admission led to the progressive
      disappearance of the epidemic strain. The increasing importance of this type of
      unit and the dramatic consequences of infections emphasize the need for
      additional research on the constitution of the flora of newborns and the mode of
      acquisition Gram-negative multi-resistant bacteria.

PMID- 15183242
TI  - Development of a surveillance system for nosocomial infections: the component for
      neonatal intensive care units in Germany.
AB  - Neonates are at high risk of nosocomial infections and surveillance has been
      shown to be valuable for the reduction of nosocomial infections. The National
      Nosocomial Infections Surveillance (NNIS) system established in the US has a
      special surveillance component for neonatal intensive care units (NICUs) with
      some fairly specific methods. However, there are no specific definitions of
      nosocomial infections in this patient group. When creating a surveillance
      component for NICUs in Germany we therefore decided not to adopt merely all
      Centers for Disease Control and Prevention definitions and NNIS methods, but also
      to develop our own surveillance methods for this patient group. For this process
      four steps became necessary: (1)development of modified definitions for
      nosocomial infections and their evaluation; (2)testing the NNIS method in three
      NICUs with infection control nurses; (3)a pilot project for a surveillance
      component within the national surveillance system in Germany; and
      (4)establishment of a surveillance component within our national surveillance
      system. The system is now established in 33 hospital departments and 66 NICUs
      participate in the surveillance system. We have an overview of 3357 neonates in
      three birthweight groups. This article explains the reasons for the various
      steps, and the advantages and disadvantages of modification of the original NNIS
      methods and definitions.

PMID- 15183243
TI  - The importance of the day of the week and duration of data collection in
      prevalence surveys of nosocomial infections.
AB  - In a national prevalence survey setting, we studied whether the day of week
      selected for data collection, and the number of days needed to complete the
      survey, were associated with the prevalence of hospital-acquired infection (HAI).
      The EPINE (Estudio de Prevalencia de las Infecciones Nosocomiales en Espana)
      database (1990-2002) was analysed for the purposes of the study. Adjusting for
      the admission day in the week, the number of intrinsic risk factors, the number
      of extrinsic risk factors and the prevalence length of stay, a 'weekend effect'
      was confirmed in this study. The day of the week selected for data collection was
      related to the presence of infection in the surveyed patients, showing for the
      period of Saturday-Monday a higher prevalence of patients with HAI (adjusted OR
      1.08, 95%CI 1.05-1.10). There was a crude positive trend between number of weeks
      and prevalence, but the number of days involved in data collection was finally
      not associated with the prevalence of HAI, once adjustment for hospital size was
      made. The percentage of repeated records increased linearly with hospital size,
      and the frequency of infections was higher within this group (OR 2.8, 95%CI 2.6
      3.0). The results of this study highlight the need for encouraging hospitals to
      shorten the time spent in obtaining a prevalence survey. If it is impossible to
      carry out the survey within the limits of one day, data collection should then be
      limited to that period of the week, Tuesday to Friday.

PMID- 15183244
TI  - Surface fixation of dried blood by glutaraldehyde and peracetic acid.
AB  - The difficulties of successful prion inactivation by chemical agents has led to
      changes in recommendations regarding the reprocessing of instruments including
      flexible endoscopes. One of the changes is the preference for peracetic acid
      instead of glutaraldehyde in order to avoid fixation of organic material, but the
      surface fixation by various active agents has not been fully investigated. We
      used a standardized amount of dried blood soil on metal carriers (on average 22
      mg). One part of the carriers was exposed to different disinfectants (four based
      on peracetic acid, three based on glutaraldehyde, two based on quaternary
      ammonium compounds (QAC), one based on QAC and amines, one based on phenols and
      one cleaning agent) and air dried. The difference compared with the non-exposed
      soiled carrier was taken as the measure of blood removal by exposure to the
      disinfectants. In addition the other part of the carriers was exposed to a
      cleaning agent and air dried. The cleaning agent itself was capable of removing
      more than 99% of the dried blood and served as a control for non-fixation. The
      rate of fixation of dried blood was calculated as the ratio of the weight of
      residual soil on 'soiled, disinfected and cleaned' carriers and on 'soiled and
      disinfected' carriers. All experiments were repeated eight times. Blood removal
      varied between 90.3% +/- 1.5% (phenol-based disinfectant) and < 10%
      (glutaraldehyde-based preparations). Fixation of the remainder was between 76.9
      +/- 8.4% and 102.5 +/- 1.1% with glutaraldehyde and between 19.2% +/- 3.3% and
      78.1% +/- 2.4% with peracetic acid. No other preparations showed a potential for
      blood fixation (< 1.3%). Our findings underline the potential for blood fixation,
      not only by glutaraldehyde, but also by peracetic acid, and support the evidence
      that effective cleaning should precede the chemical disinfection.

PMID- 15183245
TI  - The effect of Perasafe and sodium dichloroisocyanurate (NaDCC) against spores of
      Clostridium difficile and Bacillus atrophaeus on stainless steel and polyvinyl
      chloride surfaces.
AB  - Clostridium difficile is an important cause of nosocomial diarrhoea. The aim of
      this study was to evaluate the potential for Perasafe, a recently introduced
      biocide, to contribute to control of C. difficile spores in the patient
      environment, in comparison with the chlorine-releasing agent sodium
      dichloroisocyanurate (NaDCC). These agents were evaluated against a water
      control, in a surface test on stainless steel and polyvinyl chloride (PVC) floor
      covering, materials commonly found in the hospital environment. The organisms
      studied were a toxigenic clinical isolate of C. difficile, and Bacillus
      atrophaeus (formerly B. subtilis var niger). The data indicate that in our in
      vitro system, Perasafe was significantly more active than NaDCC (1000 ppm
      available chlorine) against C. difficile spores dried on stainless steel
      surfaces, and against B. atrophaeus on PVC floor covering material, achieving
      mean log10 reduction factors in viable counts of 6 and 5.5, respectively, at 10
      min exposures. Perasafe appeared to be less lethal in 10 min exposures to C.
      difficile spores fixed on PVC floor covering material. In general, 1000 ppm
      chlorine generated from NaDCC showed lower log10 reduction factors in viable
      counts at 10 min, ranging from 0.7 to 1.5, than Perasafe which ranged from 2.7 to
      6.0. The potential efficacy of Perasafe in reducing the density of C. difficile
      spores in the patient environment in hospitals, nursing homes or other long-stay
      facilities should be evaluated in field studies.

PMID- 15183246
TI  - Environmental investigations and molecular typing of Aspergillus flavus during an
      outbreak of postoperative infections.
AB  - After an outbreak of sternal surgical-site infections (SSSI) with Aspergillus
      flavus following cardiac surgery, a mycological survey of air and surfaces (41
      and 149 samples, respectively) was performed throughout the surgical ward (SW)
      and in other areas of the hospital. Results showed massive contamination by A.
      flavus: more than 100 cfu per contact plate were frequently observed in some
      areas of the SW. The distribution of the A. flavus spores in the building, and
      especially in the SW, enabled the location of a possible source within the non
      medical part of the SW, but the true source could not be identified. Four other
      surveys were made to follow up the decontamination process; the contamination
      level did not fall rapidly, needing repetitive cleaning operations. Strains from
      patients and from the hospital environment selected all over the SW were typed by
      random amplification of polymorphic DNA (RAPD), using two different primers (ERIC
      1, BG-2). All these strains showed the same genotype, proving the clonal single
      source of the environmental contamination and the intra-operative acquisition of
      A. flavus in the SSSI outbreak.

PMID- 15183247
TI  - Detection of prion after decontamination procedures: comparative study of
      standard Western blot, filter retention and scrapie-cell assay.
AB  - Prion diseases such as Creutzfeldt-Jakob disease represent a unique infection
      control problem because the infectious agent exhibits an unusual resistance to
      conventional chemical and physical decontamination methods. We investigated the
      reliability and sensitivity of a filter retention assay and standard Western blot
      to detect the scrapie form of cellular prion protein (PrPSc), the most commonly
      used surrogate prion disease marker, on tissue infected samples, treated with
      five commercially available decontamination solutions currently used in
      hospitals. Major discrepancies were observed between the two immunoblot methods.
      By using Western blot, we observed that three decontamination solutions have a
      strong ability to reduce PrPSc levels, whereas in the filter assay, none have
      this effect and two even enhanced the detection of PrPSc. We used an original and
      rapid ex vivo approach called the scrapie-cell assay to analyse the persistence
      of infectivity on scrapie-treated tissues. We observed that tissues remained
      infectious after treatment with the decontaminant in concordance with in vivo
      data. This study suggests that conventional PrPSc detection methods are not
      adapted for the rapid study of a large number of prion decontaminants tested on
      infectious tissues, and that the scrapie-cell assay could be proposed as a
      relevant alternative method.

PMID- 15183248
TI  - Misuse of gloves: the foundation for poor compliance with hand hygiene and
      potential for microbial transmission?
AB  - Improvement in hand hygiene compliance is important for reducing cross-infection
      by micro-organisms. The objective of this prospective observational study was to
      measure how the improper use of gloves limits compliance to hand hygiene and
      exposes patient's to infection. The study was conducted in five wards (three
      intensive care units and two medical wards) in a French university hospital.
      Staff-patient and staff-environment contacts were observed in 120 healthcare
      workers caring for patients colonized or infected with pathogenic bacteria. Hand
      hygiene was not undertaken due to improper gloving in 64.4% (95%CI, 64.1% to
      65.1%) of instances. Possible microbial transmission might have occurred in 18.3%
      (95%CI, 17.8% to 18.8%) of all contacts because used gloves were not removed
      before performing care activities that necessitated strict aseptic precautions.
      Failure to change or remove contaminated gloves was a major component in the poor
      compliance with hand hygiene and carried a high-risk of microbial transmission.
      Improving hand hygiene compliance will require changing healthcare workers
      behaviour towards glove use.

PMID- 15183249
TI  - Antiseptic impregnated endotracheal tubes for the prevention of bacterial
      colonization.
AB  - The effect of endotracheal tubes (ETTs) impregnated with chlorhexidine (CHX) and
      silver carbonate (antiseptic ETTs) against Staphylococcus aureus, methicillin
      resistant S. aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumannii, and
      Enterobacter aerogenes [organisms associated with ventilator-associated pneumonia
      (VAP)], was evaluated in a laboratory airway model. Antiseptic ETTs and control
      ETTs (unimpregnated) were inserted in culture tubes half-filled with agar media
      (airway model) previously contaminated at the surface with 10(8) cfu/mL of the
      selected test organism. After five days of incubation, bacterial colony counts on
      all ETT segments were determined. Swabs of proximal and distal ends of the agar
      tract in antiseptic and control models were subcultured. The initial and residual
      CHX levels, (five days post-implantation in the model) were determined. Cultures
      of antiseptic ETTs revealed colonization by the tested pathogens ranging from 1
      100 cfu/tube, compared with approximately 10(6) cfu/tube for the control ETTs (P
      < 0.001). Subcultures from proximal and distal ends of the agar tract showed
      minimal or no growth in the antiseptic ETTs compared with the control ETTs (P <
      0.001). The amount of CHX retained in the antiseptic ETTs after five days of
      implantation was an average of 45% of the initial level. Antiseptic ETTs
      prevented bacterial colonization in the airway model and also retained
      significant amounts of the antiseptic. These results indicate that the
      effectiveness of antiseptic-impregnated ETTs in preventing the growth of
      bacterial pathogens associated with VAP may vary with different organisms.

PMID- 15183250
TI  - Effectiveness of detergent-disinfecting agents on Escherichia coli 54127 biofilm.
AB  - Detergent-disinfecting agents (dD) are used daily for cleaning reused medical
      devices. We have devised a simple method to test dD detergent activity (DA) using
      an E. coli 54127 biofilm prepared in haemolysis glass tubes, which are cleaned
      with test dD, according to supplier's recommendations. Crystal violet 0.05% is
      used to colour the residual biofilm after dD (or tap water control) application.
      The biofilm quantification was made indirectly by measuring the absorbance of
      crystal violet at 585 nm. A measure of the detergent effectiveness called DA was
      calculated as the percentage reduction of colour from a tap water control.
      Fifteen products including enzymatic and non-enzymatic dDs were evaluated. Most
      enzymatic dDs gave a high DA, as did some non-enzymatic products. Thus, the view
      that enzymatic dDs are more effective than non-enzymatic dDs, put forward by some
      manufacturers, should be regarded with caution. The DA determination should help
      infection control teams choose, within the wide range of products available on
      the market, the most effective dD based on both its detergent and disinfecting
      activity.

PMID- 15183252
TI  - Pre-incisional antibiotic infiltration for prevention of surgical-site infection.

PMID- 15183251
TI  - Benefits of a rapid HIV test for evaluation of the source patient after
      occupational exposure of healthcare workers.
AB  - Rapid human immunodeficiency virus (HIV) testing for the management of
      occupational exposure of healthcare workers significantly decreased the number of
      anti-retroviral post-exposure prophylaxis regimens started whilst awaiting HIV
      test results. The study confirmed an equivalent performance of the rapid test in
      comparison with HIV enzyme immunoassay, and suggests it is cost-effective. In
      addition, two other potential benefits emerged: reducing the number of source
      patients who remain untested and increasing the number of occupational exposures
      reported.

PMID- 15183253
TI  - Dental treatment of a patient in the new 'at-risk' category for CJD.

PMID- 15183254
TI  - Is the Escherichia coli 54127 biofilm model reliable for detergent activity
      assessment of detergent-disinfecting agents?

PMID- 15183255
TI  - Back to basics--optimizing the use of available resources during an outbreak of
      multi-drug resistant Acinetobacter spp.

PMID- 15183256
TI  - [Translation and construct validity of the Lequesne index for Arab speaking North
      African patients with osteoarthritis of the knee].
AB  - OBJECTIVE: To translate in Arabic and validate the Lequesne index for use in
      Tunisian. BACKGROUND: No instrument wording in Arabic language and validated in
      an Arab population to measure lower limb functional disability caused by OA.
      DESIGN: Arab translation was obtained using the "forward translation/backward
      translation" method. Adaptations were made after a pilot study. Patients with
      symptomatic knee osteoarthritis fulfilling the revised criteria of the American
      College of Rheumatology were included. Impairment outcome measures (VAS pain;
      knee mobility; Kellgren's radiological score); disability (the maximum distance
      walked; WOMAC index) and Beck depression scale were recorded. Inter rater
      reliability was assessed using the intra-class correlation coefficient (ICC) and
      the Bland and Altman method. Construct validity was investigated using the
      Spearman rank correlation coefficient (convergent and divergent validities) and a
      factor analysis was performed. Internal consistency of each factor was assessed
      by Crohnbach alpha coefficient. RESULTS: One hundred and three patients were
      included. All questions were acceptable and retained. Inter rater reliability was
      excellent with ICC = 0.91. The Bland and Altman method showed distribution of
      differences homogenous and no systematic trend. Expected divergent validity and
      convergent validity were observed, suggested good construct validity. Two main
      factors were extracted by factor analysis of the Lequesne, and explained more
      than 55% of the cumulative variance, the first factor represents disability and
      the second represents pain and stiffness. Crohnbach alpha coefficient was,
      respectively, 0.68 for factor 1 and 0.54 for factor 2. In conclusion, we
      translated and adapted the Lequesne index into Arabic to suit Tunisian people.
      Translated questionnaire is reliable and valid. Although the scale was validated
      in a Tunisian population, we expect that it can suit other Arab populations
      especially North Africans. Further studies are needed to confirm such hypothesis.

PMID- 15183257
TI  - [Influence of temperature changes on clinical symptoms in multiple sclerosis: an
      epidemiologic study].
AB  - The effects of the modifications of temperature are well known in patients
      affected by multiple sclerosis (MS). They are variable and can influence daily
      living. This sensibility can be used in the management of the disabilities.
      METHOD: An epidemiological study was realized on a cohort of 191 patients
      suffering from MS referred to the MS clinic of Rennes (France). All the patients
      were questioned about the influence of heat and cold on their clinical symptoms
      (fatigue spasticity, walking disorders, vision, em leader ). Correlations with
      the main clinical characteristics were studied. POPULATION: One hundred ninety
      one patients, 129 women and 62 men with an average age of 47.6 +/- 10 years were
      interviewed. Average score EDSS was of 5.2 +/- 1.5. The mean duration of MS was
      13.5 +/- 10 years. RESULTS: One hundred forty-seven patients (77%) reported a
      sensibility to the temperature. Heat deteriorated function in 104 cases and 82
      patients improved with cold. Paradoxically 20 patients reported to be
      deteriorated with cold and 19 improved with heat. Fatigue and walking were the
      most sensitive to temperature fluctuations. No particular clinical profile could
      be established. Fifty percent of the patients used this sensibility with
      therapeutic aim in everyday life. DISCUSSION: The clear influence of temperature
      fluctuations on the clinical symptom was confirmed in this study. However, there
      is a great variability from one patient to another. Different hypotheses have
      been evoked to explain this phenomenon. The most likely is an influence on the
      nervous specific conductivity. In routine practice cold physiotherapy will be
      proposed on case by case basis and still has an interesting place in the
      rehabilitation management.

PMID- 15183258
TI  - [Isokinetic assessment of muscular strength in subjects with acute inflammatory
      demyelinating polyradiculoneuropathy].
AB  - OBJECTIVE: To evaluate the feasibility and the interest of isokinetic measures
      tests in subjects with inflammatory demyelinating polyradiculoneuropathy or
      Guillain-Barre syndromes (GBS). METHODS: Nine patients with GBS are tested at the
      beginning and after 6 months of recovery stage. They benefit from (1) isokinetic
      assessment of muscular strength of knee, elbow, ankle: flexion/extension and
      shoulder abduction/adduction ranging 30 per s at 180 per s angular velocity; (2)
      isometric assessment of the same muscular groups; (3) manual muscle testing; (4)
      functional independence measure. RESULTS: Isokinetic tests were tolerated at 60
      and 120 per s. Fatigability appears since the third second of isometric test. The
      relationships between isokinetic, manual tests and isometric tests are variables
      (0.29 < r < 0.97). The evaluation after 6 months of recovery showed a good
      sensibility of isokinetic test. CONCLUSION: The continuation of this motor
      isokinetic evaluation, in a large population, will permit to establish
      longitudinal and evolutive profile of each patient and will facilitate to chose
      the rehabilitation program.

PMID- 15183259
TI  - [Quality assessment of information about female urinary incontinence from French
      speaking websites].
AB  - OBJECTIVES: An increasing number of patients look for medical information on
      Internet, and find hardly accurate answers to their questions. The objective of
      this study was to assess the quality of information about urinary incontinence on
      free access Web-sites. MATERIAL AND METHODS: A search using the most used search
      engines in French speaking countries and key words given by patients located 24
      Web-sites on female urinary incontinence to review. A general description of each
      site was done. Then a specially designed assessment scale, whose criteria were
      extracted from a literature review and from practice guidelines for the
      management of female urinary incontinence, was used by two reviewers to assess
      each Web-site content. RESULTS: Three key terms (urinary incontinence, urine
      loss, urine leak) were used on three search engine (Google, Yahoo, Voila) and the
      first 10 Web-sites located for each search were analyzed. The mean score was low
      (7.92 (+/-3.1) range 0-24, maximum 24) and only four sites received the "highly
      recommended" mention. CONCLUSIONS: This study using medical evidence-based
      criteria to assess the quality content of French speaking Web-sites about female
      urinary incontinence highlights the poor quality of information available for
      Internet "typical users". Doctors should play a greater role in evaluating these
      sites and/or developing their quality.

PMID- 15183261
TI  - [Evaluation of physiological properties of ankle braces based on a review of the
      literature].
AB  - INTRODUCTION: The objective of this work was to proceed to a review of the
      literature to assess the physiological basis of the ankle brace use. METHOD: An
      analysis of the international literature relating to the years 1980-2002 was
      carried out by questioning the Medline data bank. RESULTS: Three hundred and
      twenty-two articles were collected and 25 physiological studies were retained.
      Various changes can occur during brace use, first of all stability parameters and
      proprioceptive sense. Main changes affect position sense, stiffness, mobility and
      stability of ankle when standing. DISCUSSION: This review of the literature
      allows to specify the mechanisms involved by brace use in ankle stability. Some
      studies allow to compare the principal devices used to stabilize the ankle
      (taping, semi rigid braces) but, no physiological study was able to discriminate
      between different orthosis models. CONCLUSION: Many studies have been conducted
      in the field of the physiological evaluation of ankle orthosis. When these
      devices are widely used in current medical practice, physiological studies do not
      allow to characterize a better device with a specific test. These data point out
      the methodological difficulties in ankle brace evaluation.

PMID- 15183262
TI  - [Management of infectious risk associated with therapeutic pools].
AB  - There is no specific legislation concerning pools and others medical hydrotherapy
      equipments relating hygiene and security rules. For this reason, the hydrotherapy
      pools use the public swimming pools legislation. METHOD: This article is based on
      literature review (database Medline and Embase--manual research). RESULTS: This
      article offers a review of pool associated infections along with the description
      of the measures designed to minimise the possible transmission of infection
      during hydrotherapy activities such as: Technical measures: pool and premises
      conception, water treatments, feed tanks, air quality. Hygiene rules for patients
      and hospital staff and pathologies which are contra-indications to hydrotherapy
      activities. Microbiological and physico-chemical monitoring. DISCUSSION: The
      infectious risk remains low with therapeutic pools. However, the development of
      specific legislation and surveillance should be enhanced. CONCLUSION: All these
      measures are part of the quality assurance program that must be implemented to
      control the safety of these installations.

PMID- 15183263
TI  - An algorithm for real-time extraction of population EPSP and population spike
      amplitudes from hippocampal field potential recordings.
AB  - A new method is presented for extracting the amplitude of excitatory post
      synaptic potentials (EPSPs) and spikes in real time. It includes a low pass
      filter (LPF), a differentiator, a threshold function, and an intelligent
      integrator. It was applied to EPSP and population spike data recorded in the
      Dentate Gyrus and the CA1 hippocampus in vitro. The accuracy of the extraction
      algorithm was evaluated via the extraction normalized mean square error (eNMSE)
      and was found to be very high (eNMSE < 5%). The preservation of neuronal
      information was confirmed using the Volterra-Poisson modeling approach. Volterra
      Poisson kernels were computed using amplitudes extracted with both proposed and
      traditional methods. The accuracy of the computed kernels and the resulting model
      was evaluated via the prediction normalized mean square error (pNMSE) and was
      found to be very high (pNMSE < 5%). The similarity between the kernels computed
      when the proposed method was used to extract the field potential amplitude and
      their counterparts when the traditional method was used to extract the field
      potential amplitude confirms the preservation of the neuronal dynamics. The
      proposed method represents a new class of real time field potential amplitude
      extraction algorithms with complexity that can be included in hardware
      implementations.

PMID- 15183264
TI  - Quantitation of neurite growth parameters in explant cultures using a new image
      processing program.
AB  - An interactive image processing program was developed to quantify the effects of
      various biochemical and physical factors on cultured explants of nerve tissue. We
      used this method to obtain a growth curve of chick embryo dorsal root ganglia
      (DRG) in media containing various concentrations of nerve growth factor (NGF). In
      the past, neurite lengths and numbers were measured manually using collages of 35
      mm color photographs or made directly under the microscope. Our new program makes
      it possible to quantify the growth of whole live, unstained DRG's on photograph
      collages or digital images with respect to center area, neurite area, total
      explant area, and the number and length of neurites almost exclusive of
      background artifacts. After comparing the old and new methods, we conclude that
      our analysis algorithm correlates well with previously accepted protocols for
      assessing stimulation and inhibition of growth. It rapidly measures several
      biologically-relevant properties and provides a means to obtain information on
      six parameters (neurite area, neurite length, neurite number, center area, total
      area, neurite density) using a single quantitative method. Neurite area in the
      presence of 10 ng/ml or 20 ng/ml NGF was the most significantly increased
      parameter as was expected from previous studies since it includes both neurite
      length and number as well as any crossing fibers.

PMID- 15183265
TI  - Transient overexpression of kappa and mu opioid receptors using recombinant
      adenovirus vectors.
AB  - In order to study the trafficking and signal transduction mechanisms of the
      multiple opioid receptors, these receptors are expressed either transiently or
      stably in cell lines. Often, it is difficult to express receptors at a
      sufficiently high density to obtain reproducible results. To achieve a high
      density of receptors, replication-defective adenovirus (rAd5) vectors encoding
      the mu (MOR) and kappa (KOR) opioid receptors, both in their native form and as
      fusion proteins bearing the green fluorescent protein (GFP) at their C-terminus,
      were constructed. These vectors efficiently and reproducibly infected Chinese
      hamster ovary (CHO) cells that stably express the human coxsackie-adenovirus
      receptor (hCAR), with up to 90% of cells becoming infected at a low multiplicity
      of infection (MOI). Saturation receptor binding studies using mu- and kappa
      selective agonists, [3H][D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) and
      [3H](5alpha7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8
      yl)benzeneacetamide (U69,593), respectively, and a nonselective antagonist,
      [3H]diprenorphine, revealed that rAd5-transduced cells expressed MOR and KOR for
      at least 3 days, at levels which exceeded those present on widely-used CHO
      sublines that stably express MOR or KOR. Expression levels were highest for the
      vectors encoding native MOR or KOR, and slightly reduced for the GFP fusion
      proteins. These findings demonstrate the feasibility of using rAd5 vectors to
      express opioid receptors at high densities, which may facilitate opioid receptor
      studies.

PMID- 15183266
TI  - A device for investigating neuromuscular control in the human masticatory system.
AB  - A new apparatus has been developed to study the control of mastication in humans.
      The subject places his/her teeth on fixed upper and mobile lower bite plates; the
      device then enables opening and closing movements of the lower jaw against a
      controlled resistance. It is also possible to vary the number of teeth in contact
      with the device during an experiment from the entire dental arcade to a single
      tooth. The specially designed lower bite plate is dynamic and allows for both
      rotation and translation of the lower jaw during movement, thus, permitting the
      natural curvilinear trajectory of the jaw. The lower bite plate can follow
      chewing initiated by the subject without resisting the movement ('no force' mode)
      via a dedicated microprocessor controlled compensation mechanism. Another
      function of the device is to inject a constant predetermined load onto the lower
      bite plate so that the subject 'chews' against a fixed resistance simulating
      rapidly yielding food bolus ('fixed force' mode). The device can be programmed to
      increase or decrease the force during the closing or opening phase of chewing by
      feeding the position information into the force compensation system so both
      position and force change in parallel, hence, simulating a bite onto a non
      yielding, or sticky, food bolus ('normal chewing' mode). By use of a jaw position
      compensation mechanism, the device can actively move the lower jaw, following any
      imposed position pattern ('position controlled' mode). The chewing simulator also
      has a mode that holds the position at a fixed level and allows the force to
      change ('position hold' mode). Furthermore, the device can inject additional
      rapid or slow forces or displacements onto the lower bite plate in order to
      elicit reflexes so that the response of jaw muscles to such stimuli can be
      examined at various jaw positions, force levels, phases of motion and velocities.
      The different modes of the apparatus can be used to study the operation and
      feedback control of human mastication; in particular whether modulations in jaw
      muscle activity and reflexes are due to changes in force, velocity, position,
      chewing cycle phase or a combination of these factors.

PMID- 15183267
TI  - A fast flexible ink-jet printing method for patterning dissociated neurons in
      culture.
AB  - We present a new technique that uses a custom-built ink-jet printer to fabricate
      precise micropatterns of cell adhesion materials for neural cell culture. Other
      work in neural cell patterning has employed photolithography or "soft
      lithographic" techniques such as micro-stamping, but such approaches are limited
      by their use of an un-alterable master pattern such as a mask or stamp master and
      can be resource-intensive. In contrast, ink-jet printing, used in low-cost
      desktop printers, patterns material by depositing microscopic droplets under
      robotic control in a programmable and inexpensive manner. We report the use of
      ink-jet printing to fabricate neuron-adhesive patterns such as islands and other
      shapes using poly(ethylene) glycol as the cell-repulsive material and a
      collagen/poly-D-lysine (PDL) mixture as the cell-adhesive material. We show that
      dissociated rat hippocampal neurons and glia grown at low densities on such
      patterns retain strong pattern adherence for over 25 days. The patterned neurons
      are comparable to control, un-patterned cells in electrophysiological properties
      and in immunocytochemical measurements of synaptic density and inhibitory cell
      distributions. We suggest that an inexpensive desktop printer may be an
      accessible tool for making micro-island cultures and other basic patterns. We
      also suggest that ink-jet printing may be extended to a range of developmental
      neuroscience studies, given its ability to more easily layer materials, build
      substrate-bound gradients, construct out-of-plane structure, and deposit sources
      of diffusible factors.

PMID- 15183268
TI  - A new method for the extraction and classification of single motor unit action
      potentials from surface EMG signals.
AB  - It has been shown that multi-channel surface EMG allows assessment of anatomical
      and physiological single motor unit (MU) properties. To get this information, the
      action potentials of single MUs should be extracted from the interference EMG
      signals. This study describes an automatic system for the detection and
      classification of MU action potentials from multi-channel surface EMG signals.
      The methods for the identification and extraction of action potentials from the
      raw signals and for their clustering into the MUs to which they belong are
      described. The segmentation phase is based on the matched Continuous Wavelet
      Transform (CWT) while the classification is performed by a multi-channel neural
      network that is a modified version of the multi-channel Adaptive Resonance Theory
      networks. The neural network can adapt to slow changes in the shape of the MU
      action potentials. The method does not require any interaction of the operator.
      The technique proposed was validated on simulated signals, at different levels of
      force, generated by a structure based surface EMG model. The MUs identified from
      the simulated signals covered almost the entire recruitment curve. Thus, the
      proposed algorithm was able to identify a MU sample representative of the muscle.
      Results on experimental signals recorded from different muscles and conditions
      are reported, showing the possibility of investigating anatomical and
      physiological properties of the detected MUs in a variety of practical cases. The
      main limitation of the approach is that complete firing patterns can be obtained
      only in specific cases due to MU action potential superpositions.

PMID- 15183269
TI  - Rehabilitation strategy using enhanced housing environment during neural
      regeneration.
AB  - The influence of an enriched environment on the recovery of nerve function was
      studied after a sciatic nerve lesion and repair. A sciatic nerve gap of 15 mm was
      bridged in 12 rats using autologous nerve grafts. The rats were housed either in
      an enriched environment or in standard cages. In the enhanced housing
      environment, the rats were forced to move by dissociating food and water sources,
      including wire for foot gripping instead of flat plastic floors, and wooden play
      toys. Locomotor behavior was recorded on tape with a digital videorecorder and
      behavioral data were compared with those of a group of six unoperated rats. The
      video-recordings were analyzed for the stance factor (SF) as well as several
      other aspects of the rat's walking pattern. Walking was evaluated between 10 and
      21 weeks after the operation. Differences in walking behavior between rats raised
      in an enriched environment and rats raised in standard cages could not be
      demonstrated. Differences in walking behavior between male and female rats were
      not found either. But data differed significantly at all ages with rats of the
      control group. Automutilation of parts of the denervated foot revealed a
      significant difference in both experimental groups, occurring less often in the
      enriched environment group.

PMID- 15183270
TI  - Genotype identification of Math1/LacZ knockout mice based on real-time PCR with
      SYBR Green I dye.
AB  - Knockout mice are widely used in all fields of biomedical research. Determining
      the genotype of every newborn mouse is a tedious task, usually performed by
      Southern blot hybridization or Polymerase Chain Reaction (PCR). We describe here
      a quick and simple genotype identification assay based on real-time PCR and SYBR
      Green I dye, without using fluorescent primers. The discrimination between the
      wild type and targeted alleles is based on a PCR design that leads to a different
      melting temperature for each product. The identification of the genotype is
      obvious immediately after amplification, and no post-PCR manipulations are
      needed, reducing cost and time. Therefore, while the real-time PCR amplification
      increases the sensitivity, the fact that the reactions tubes are never opened
      after amplification, reduces the risk of contamination and eliminates errors,
      which are common during the repeated handling of dozens of samples from the same
      mouse line. The protocol we provide was tested on Math1 knockout mice, but is
      general, and may be utilized for any knockout line and real-time thermocycler,
      without any further modification, accessories or special reagents.

PMID- 15183272
TI  - Optimising coherence estimation to assess the functional correlation of tremor
      related activity between the subthalamic nucleus and the forearm muscles.
AB  - Application of coherence estimation needs not only to correctly estimate
      coherence values but also to efficiently test the statistical significance of the
      estimates. In the present report, we have explained the approach of optimising a
      coherence estimator by restricting its normalised bias error and random error. In
      addition to the commonly used independence threshold, two more tests based on the
      probability of detection and the exact confidence interval have been proposed for
      detecting the significance of the coherence estimates. All three methods have
      been used to evaluate the significant functional correlation between oscillatory
      field potentials (FPs) in the subthalamic nucleus (STN) and the surface
      electromyogram (EMG) of the forearm muscles during tremor in Parkinson's disease.

PMID- 15183271
TI  - The use of GAP-43 mRNA quantification in high throughput screening of putative
      neuroprotective agents in dorsal root ganglion cultures.
AB  - Large scale screening for neuroprotective drugs for peripheral neuropathies
      requires development of a high throughput system that is reliable and
      reproducible. Currently most accurate outcome measures of axonal degeneration are
      based on time-consuming, laborious measurement of morphological changes in
      neurites. In order to improve on the scalability of the screening procedure we
      developed a real-time RT-PCR based method of gene expression that correlates very
      well with morphological measures of neuritic degeneration. We examined the
      changes in GAP-43 expression in primary dorsal root ganglion (DRG) neurons in
      vitro with exposure to a zalcitabine (ddC), an antiretroviral drug that causes
      neuropathy in human immunodeficiency virus (HIV)-infected individuals, with and
      without FK506, an immunophilin ligand with neuroprotective and neuroregenerative
      properties. Similar to morphological measures of neuritic degeneration, in ddC
      treated cultures there was a reduction in the expression of GAP-43 mRNA. This was
      prevented, in a dose-dependent manner, by co-administration of FK506. This assay,
      performed in a 96-well format, can easily be scaled for high throughput screening
      (HTS) using robotic systems.

PMID- 15183273
TI  - A novel primary culture technique for adult retina allows for evaluation of CNS
      axon regeneration in rodents.
AB  - Unraveling the causes of regeneration failure in the adult injured CNS has
      remained a challenge in neurobiology. The notion that CNS neurons lose their
      regenerative potential during development has been challenged by the
      identification of several promoters of axon growth. Novel methods are required
      that allow to study and quantify interactions of molecular determinants, and to
      envisage future treatment applications. Here we report a novel, highly
      reproducible method for monitoring axonal regeneration of mature retinal ganglion
      cells (RGCs) in vitro. In contrast to earlier explantation methods, primary
      cultures derived from adult rodent retina are kept viable without growth factor
      supplements. Further, since intraretinal RGC axons remain unmyelinated,
      regeneration can be followed independently of non-permissive white matter
      compounds. Applying tracing techniques prior to retinal explantation, cell
      survival can be correlated to outgrowth activity on the single cell level.
      Following intervention with pharmacological, growth factor, or gene transfer
      treatments, retinal explants, and partially RGC neurites, can be processed for
      protein and gene expression analysis. This novel procedure will prove useful to
      get insight into complex cell survival and regeneration promoting cascades, and
      will complement in vivo strategies such as transgenic and knock out mouse models.

PMID- 15183274
TI  - An in vivo mouse spinal cord preparation for patch-clamp analysis of nociceptive
      processing.
AB  - The laboratory mouse is now considered the preferred mammalian species for
      molecular and genetic analysis in neurobiology. In part, this is due to the
      existence, in the mouse, of several well characterised naturally occurring
      mutations in ligand gated ion channels and recent knockout, knockin, and
      transgenic techniques, which facilitate the manipulation of key molecules. These
      techniques have recently been applied to pain research with in vitro
      electrophysiological and behavioural techniques traditionally developed for the
      rat, now being adapted for the mouse particularly at the level of the spinal
      cord. Here, we describe an in vivo preparation of the mouse spinal cord for patch
      clamp recording of nociceptive processing in the superficial dorsal horn (SDH)
      that permits analysis in the intact nervous system. We have recorded from SDH
      neurons and characterised their background synaptic activity, discharge
      properties, and evoked synaptic responses following controlled application of
      innocuous and noxious stimuli to the hind paw. Application of these techniques
      along with genetic, biomolecular, in vitro and behavioural approaches will allow
      future studies to comprehensively analyse the contributions of specific molecules
      involved in nociceptive processing in the spinal cord of a single species.

PMID- 15183275
TI  - Single-cell RT-PCR gene expression profiling of acutely dissociated and
      immunocytochemically identified central neurons.
AB  - Identification of neurons for single-cell mRNA profiling is difficult when cells
      of interest are located in heterogeneous brain regions. We developed a protocol
      in which acutely dissociated neurons are immunocytochemically labeled prior to
      single-cell reverse transcription-polymerase chain reaction (RT-PCR). We tested
      the protocol on hypothalamic melanin-concentrating hormone (MCH) and prepro
      orexin (PPO) neurons, which are similarly distributed but functionally different.
      Cells dissociated from the perifornical region of the posterior hypothalamus of
      juvenile or adult rats were incubated with anti-MCH or anti-PPO primary
      antibodies, followed by washout and incubation with fluorescein-tagged secondary
      antibodies. Individual labeled cells were subjected to RT-PCR with primers for
      PPO and MCH. MCH mRNA was detected in 26 out of the 38 successfully reverse
      transcribed cells identified as MCH-containing, and 28 cells out of the 42
      identified as PPO-containing expressed PPO mRNA. No cell expressed both mRNAs.
      Most MCH neurons tested (five out of six) expressed the adrenergic alpha2A
      receptor mRNA, whereas it was absent from all seven PPO neurons tested. Neither
      PPO (n = 11) nor MCH (n = 6) cells expressed the type 2 orexin receptor mRNA.
      Thus, the method allows, with at least 66% confidence, immunocytochemical cell
      identification prior to mRNA studies of single neurons located in heterogeneous
      brain regions.

PMID- 15183276
TI  - Drosophila gustatory receptors: from gene identification to functional
      expression.
AB  - Recent years have seen long-awaited progress in understanding of the molecular
      mechanisms of taste perception in insects. The breakthrough came in the early
      2000 with the identification of a novel family of candidate gustatory receptor
      (Gr) genes in the first release of the Drosophila melanogaster genome sequence.
      The 60 Gr genes are expressed in the subsets of gustatory neurons in the fly's
      taste organs and, without exception, encode heptahelical G protein-coupled
      receptors (GPCRs). Here I review our current knowledge about Gr genes and their
      products focusing on the newly emerging information regarding the function of the
      Gr-encoded proteins.

PMID- 15183277
TI  - Drosophila cryb mutation reveals two circadian clocks that drive locomotor rhythm
      and have different responsiveness to light.
AB  - Cryptochrome (CRY) is a blue-light-absorbing protein involved in the photic
      entrainment of the circadian clock in Drosophila melanogaster. We have
      investigated the locomotor activity rhythms of flies carrying cryb mutant and
      revealed that they have two separate circadian oscillators with different
      responsiveness to light. When kept in constant light conditions, wild-type flies
      became arrhythmic, while cryb mutant flies exhibited free-running rhythms with
      two rhythmic components, one with a shorter and the other with a longer free
      running period. The rhythm dissociation was dependent on the light intensities:
      the higher the light intensities, the greater the proportion of animals
      exhibiting the two oscillations. External photoreceptors including the compound
      eyes and the ocelli are the likely photoreceptors for the rhythm dissociation,
      since rhythm dissociation was prevented in so1;cryb and norpAP41;cryb double
      mutant flies. Immunohistochemical analysis demonstrated that the PERIOD
      expression rhythms in ventrally located lateral neurons (LNvs) occurred
      synchronously with the shorter period component, while those in the dorsally
      located per-expressing neurons showed PER expression most likely related to the
      longer period component, in addition to that synchronized to the LNvs. These
      results suggest that the Drosophila locomotor rhythms are driven by two separate
      per-dependent clocks, responding differentially to constant light.

PMID- 15183279
TI  - How the choice of method influence on the results in electrophysiological studies
      of insect olfaction.
AB  - In identifying the volatiles that insects use to locate suitable host plants,
      electrophysiological recordings of olfactory responses to plant volatiles may
      give important information. However, divergent results may be obtained with
      different recording techniques. To illustrate these differences, the results of a
      previous investigation using single cell recordings linked to a gas chromatograph
      (SCR-GC) are compared with the results obtained with an electroantennogram linked
      to a gas chromatograph (EAG-GC). Testing insects of the same species (Hylobius
      abietis) for the same test sample, 30 potent volatile compounds were identified
      by SCR-GC and 18 by EAG-GC. Of the 34 different compounds, 14 were identified by
      both techniques. Furthermore, when the same compound elicited detectable
      responses by both techniques, the response strength was usually not the same
      relative to the strongest response recorded by each technique. This shows that
      both EAG-GC and SCR-GC are important techniques in the identification of potent
      plant volatiles for insects. However, by using SCR-GC more information was
      obtained, information that can be crucial for understanding the insect-plant
      relationship.

PMID- 15183278
TI  - An entomopathogenic bacterium, Xenorhabdus nematophila, inhibits the expression
      of an antibacterial peptide, cecropin, of the beet armyworm, Spodoptera exigua.
AB  - An entomopathogenic bacterium, Xenorhabdus nematophila, is known to depress
      hemocyte nodule formation of target insects by inhibiting eicosanoid
      biosynthesis. This study analyzed the inhibitory effect of X. nematophila on the
      humoral immunity of the target insects and tested its association with the host
      eicosanoid pathway. Plasma collected from the fifth instar larvae of Spodoptera
      exigua, when they were injected with X. nematophila, did not show antibacterial
      activity against Escherichia coli by a growth inhibition zone assay. In
      comparison, heat-killed X. nematophila induced significant antibacterial activity
      in the plasma. The antibacterial humoral activity was further demonstrated by
      examining a specific potent antibacterial peptide, cecropin. Two cecropin genes
      ('A' and 'B') were partially cloned from the fifth instar larvae of S. exigua by
      conserved degenerate primers using nested reverse transcriptase-polymerase chain
      reaction (RT-PCR). They showed high homologies with known cecropins from other
      lepidopteran species. Northern analysis using the cecropin probe showed that the
      injection of the heat-killed X. nematophila induced significant expression of a
      cecropin mRNA transcript (approximately 1.1 kb), but the larvae injected with the
      live bacteria did not show the corresponding transcript. Injection of arachidonic
      acid did not rescue the inhibition of X. nematophila based on either
      antibacterial activity or cecropin gene expression. The addition of
      dexamethasone, a specific phospholipase A2 inhibitor, did not inhibit
      antibacterial activity or cecropin gene expression when the larvae were injected
      with heat-killed X. nematophila. These results suggest that X. nematophila
      inhibits the antibacterial humoral immune reaction as well as the cellular immune
      reaction in S. exigua and that the inhibition of X. nematophila on the expression
      of the antibacterial peptide is not associated with inhibition of the eicosanoid
      pathway.

PMID- 15183280
TI  - Effects of larval exposure to sublethal concentrations of the ecdysteroid
      agonists RH-5849 and tebufenozide (RH-5992) on male reproductive physiology in
      Spodoptera litura.
AB  - Sublethal concentrations of the bisacylhydrazine moulting hormone agonists, RH
      5849, and tebufenozide (RH-5992) were fed to sixth (final) instar larvae of
      Spodoptera litura. Both RH-5849 and tebufenozide adversely affected the mating
      success of S. litura when the surviving treated males were crossed with normal
      females. The ecdysone agonists decreased the longevity of treated males and of
      untreated females when crossed with treated males. The number of eggs laid by
      untreated females mated to treated males was decreased, and the fertility
      (percentage of hatching success) of the resulting eggs was reduced. These effects
      on male reproductive success were at least in part explained by a reduction in
      the number of sperm transferred during mating. The adverse effects of
      tebufenozide on male reproductive function were qualitatively the same as those
      of RH-5849, but tebufenozide was active at lower concentrations. To understand
      the reason for these adverse effects on male reproduction, we investigated the
      effects of the insecticides on male reproductive physiology. Male reproductive
      tract development and testicular volume of resulting adult moths were adversely
      affected by sublethal larval exposure to the ecdysone agonists. Dose-dependent
      reductions occurred in the production of eupyrene and apyrene spermatozoa in the
      adult testes, and in the number of spermatozoa released from the testes into the
      male reproductive tract. The descent into the male tract of both eupyrene and
      apyrene sperm was found to start at the normal stage of development in both
      normal and treated insects, but the daily rhythm of sperm descent was
      subsequently disturbed in the insecticide-treated moths. This affected the
      numbers of sperm in the upper vas deferens (UVD), seminal vesicle (SV), and
      duplex (duplex). Injections of RH-5849 given to pharate adult or newly emerged
      adult S. litura also caused drastic reduction in the number of sperm in the upper
      regions of the male tract, when measured 24 h after injection. The possible
      importance of pest population reduction through the sublethal anti-reproductive
      effects of insecticides is discussed.

PMID- 15183281
TI  - Effects of 20-hydroxyecdysone and other hormones on egg development, and
      identification of a vitellin-binding protein in the ovary of the tick, Amblyomma
      hebraeum.
AB  - Partially fed adult female Amblyomma hebraeum ticks were injected with 20
      hydroxyecdysone (20E; up to 43 microg/g body weight (bw)), juvenile hormone III
      (JH III; up to 100 microg/g bw), bovine insulin (up to 2000 mU/g bw), or
      triiodothyronine (up to 200 ng/g bw) in an attempt to stimulate vitellogenesis.
      Of these, only 20E stimulated synthesis and release of vitellogenin (Vg).
      Immunoblot analysis revealed that Vg-synthesis occurred in the fat body. However,
      consistent with earlier observations suggesting that a distinct signal may be
      required for Vg-uptake, there was no significant Vg-uptake by oocytes of
      partially fed, 20E-treated ticks. Because Vg-uptake commonly occurs via receptor
      mediated endocytosis (i.e., a specific Vg-receptor), we attempted to identify a
      vitellin (Vt)-binding protein in ovaries of engorged female ticks. A single 86
      kDa Vt-binding protein was identified, even under reducing conditions (2
      mercaptoethanol), by a ligand-blotting technique. Sodium salt of suramin (5 mM)
      inhibited binding of Vt to the 86 kDa protein. However, this protein was also
      detected in ovaries from small partially fed ticks (50-100 mg), suggesting that
      the inability of 20E to stimulate Vg-uptake in partially fed ticks may not have
      been due to the absence of a Vg-receptor.

PMID- 15183282
TI  - Increased juvenile hormone levels after long-duration flight in the grasshopper,
      Melanoplus sanguinipes.
AB  - Although, in many insects, migration imposes a cost in terms of timing or amount
      of reproduction, in the migratory grasshopper Melanoplus sanguinipes performance
      of long-duration flight to voluntary cessation or exhaustion accelerates the
      onset of first reproduction and enhances reproductive success over the entire
      lifetime of the insect. Since juvenile hormone (JH) is involved in the control of
      reproduction in most species, we examined JH titer after long flight using a
      chiral selective radioimmunoassay. JH levels increased on days 5 and 8 in animals
      flown to exhaustion on day 4 but not in 1-h or non-flier controls. No difference
      was seen in the diel pattern of JH titer, but hemolymph samples were taken
      between 5 and 7 h after lights on. Treatment of grasshoppers with JH-III mimicked
      the effect of long-duration flight in the induction of early reproduction. The
      increased JH titer induced by performance of long-duration flight is thus at
      least one component of flight-enhanced reproduction. To test the possibility that
      post-flight JH titer increases are caused by adipokinetic hormone (AKH) released
      during long flights, a series of injections of physiological doses of Lom-AKH I
      were given to unflown animals to simulate AKH release during long flight. This
      treatment had no effect on JH titers. Thus, although AKH is released during
      flight and controls lipid mobilization, it is not the factor responsible for
      increased JH titers after long-duration flight.

PMID- 15183283
TI  - Factors affecting post-flight behavior in primary reproductives of the Formosan
      subterranean termite, Coptotermes formosanus (Isoptera: Rhinotermitidae).
AB  - After swarming, reproductive dealates of the Formosan subterranean termite,
      Coptotermes formosanus, run together in tandem. The tandem running is an age
      related behavioral activity in C. formosanus. This behavior was not evoked in pre
      flight alates less than 6-d-old that were artificially dealated. Female age was
      more important than male age for evoking tandem behavior. Females and males,
      older than 35 days, did not exhibit this behavior. Mating status was not
      important for female and male dealates to form the tandem pairs. The titers of
      the major tergal gland component, trilinolein, did not decline significantly and
      remained high, not only in virgin females, but also in mated females for a period
      of time after swarming. On the other hand, increasing amounts of the female
      specific compound trilinolein were detected in male dealates 7, 14, and 42 days
      after pairing. This suggests that trilinolein in the females might be transferred
      to the males as a nuptial gift in C. formosanus. In addition, females have
      structurally different lateral setae that may constitute a morphological factor
      involved in the tandem behavior in this species. Covering the setae with dimethyl
      sulfoxide prevented the tandem behavior.

PMID- 15183285
TI  - PBAN stimulation of pheromone biosynthesis by inducing calcium influx in
      pheromone glands of Helicoverpa zea.
AB  - Isolated pheromone glands of Helicoverpa zea were utilized to investigate the
      physiological action of pheromone biosynthesis activating neuropeptide (PBAN)
      with regard to the role of calcium ions in stimulating pheromone biosynthesis
      under various incubation conditions. Incubation of glands with 1 microM or 1 nM
      PBAN produced a significant amount of pheromone after a 5 min incubation period
      and reached maximum pheromone production after 30 min. Glands incubated with PBAN
      for 1 min, and then without PBAN for 30 min, produced pheromone whether or not
      extracellular calcium was present during the first 1 min. The presence of
      lanthanum as a calcium channel blocker did not affect pheromone production if
      present during the first 1 min of incubation with PBAN. However, if calcium was
      absent or lanthanum ion was present during the 30 min of incubation, no pheromone
      was produced. A maximum amount of pheromone was reached when glands were
      incubated for 1 min with PBAN and for 10 min without PBAN, and repeated three
      times. The present results indicate that a time interval exists between PBAN
      binding to a receptor and opening of extracellular calcium channels. Calcium
      influx into the cytosol from extracellular stores is required for PBAN to
      stimulate pheromone production. This could be achieved by PBAN either binding
      periodically to the receptor or the plasma membrane calcium channel could remain
      activated for a period of time after the initial activation.

PMID- 15183284
TI  - The diapause hormone-pheromone biosynthesis activating neuropeptide gene of
      Helicoverpa armigera encodes multiple peptides that break, rather than induce,
      diapause.
AB  - FXPRLamide peptides encoded by the DH-PBAN (diapause hormone-pheromone
      biosynthesis activating neuropeptide) gene induce embryonic diapause in Bombyx
      mori, but terminate pupal diapause in Helicoverpa armigera (Har). Here, we
      explore the mechanisms of terminating pupal diapause by the FXPRLamide peptides.
      Using quantitative RT-PCR, we observed that expression of Har-DH-PBAN mRNA in the
      SG of nondiapause-type pupae was significantly higher than in diapause-type
      pupae. Immunocytochemical results indicated that the level of FXPRLamide peptides
      and axonal release are related to the diapause decision. Ecdysteroidogenesis in
      prothoracic glands (PGs) was stimulated by synthetic Har-DH in vivo and in vitro,
      and labeled Har-DH bound to the membrane of the PG, thus suggesting that DH
      breaks diapause by activating the PG to synthesize ecdysone. Furthermore, the
      response of DH in terminating diapause was temperature dependent. Decerebration
      experiments showed that the brain can control pupal development through the
      regulation of DH, and DH can terminate diapause and promote development without
      the brain. This result suggests a possible mechanism of response for the signals
      of DH and other FXPRLamide peptides in H. armigera.

PMID- 15183286
TI  - Juvenile hormone III titers and regulation of soldier caste in coptotermes
      formosanus (Isoptera: Rhinotermitidae).
AB  - Juvenile hormone (JH) is an important growth hormone in insects that has also
      been implicated in caste determination in termites. Gas chromatography-mass
      spectrometry was used to establish that the JH in the Formosan subterranean
      termite, Coptotermes formosanus Shiraki, is JH III. JH III titers were measured
      in workers, pre-soldiers, and soldiers from samples collected from the field. The
      average titers of JH III in workers and soldiers were about 13 and 25 pg mg(-1),
      respectively. However, pre-soldiers contained a significantly higher amount, 596
      pg mg(-1). As expected, treatment of workers with a JH-analogue, methoprene,
      triggered rapid formation of pre-soldiers. However, these pre-soldiers had a very
      low JH III titer (62 pg mg(-1)). It appears that the application of JHA, while
      inducing pre-soldier formation, does not increase the endogenous JH III titer.
      The titer, however, increased as the pre-soldiers aged and before transforming
      into soldiers.

PMID- 15183287
TI  - Nutritional suitability of corn pollen for the predator Coleomegilla maculata
      (Coleoptera: Coccinellidae).
AB  - The nutritional suitability of corn pollen for the facultatively phytophagous
      predator Coleomegilla maculata was studied in the laboratory. Dry matter, organic
      matter, ash, crude protein, amino acid, and quercetin contents of pollen from 10
      hybrids of field corn were determined. C. maculata were reared on pollen or
      aphids + artificial diet for their entire lives; larval duration, post-mortem
      adult dry weights, fecundity within 7 days of mating, and mortality rates were
      compared among the treatments. In another experiment, C. maculata larvae were
      reared on pollen; weight gained, pollen ingested, and frass produced were
      compared among instars. Also, consumption relative to increases in larval biomass
      and the efficiency with which larvae converted corn pollen into biomass were
      compared among instars. Beetles reared on aphids had greater weights and
      fecundity and a shorter larval duration relative to the pollen-fed beetles. The
      percentages of organic matter and ash in corn pollen were significantly
      correlated with C. maculata mortality, and we hypothesize that some micronutrient
      or phytochemical is at sub-optimal levels for C. maculata development in some of
      the pollens. We observed an increase in the conversion efficiency of pollen and a
      decrease in the consumption relative to biomass of C. maculata as the larvae
      aged, which suggests a physiological or behavioral alteration in the feeding
      behavior of C. maculata during the larval stage.

PMID- 15183288
TI  - Proceedings and abstracts of the IX International Congress on Pediatric
      Laboratory Medicine; International Association of Pediatric Laboratory Medicine &
      Italian Society of Clinical Biochemistry. Rome, Italy, September 13-16, 2003.

PMID- 15183289
TI  - Immunosuppressive drug monitoring of sirolimus and cyclosporine in pediatric
      patients.
AB  - Sirolimus is primarily used as a rescue agent in pediatric transplant recipients,
      particularly in cases of cyclosporine or tacrolimus toxicity. Preliminary data
      indicate a higher apparent oral clearance in younger children (4-10 years of
      age). Various drug interactions have been described between sirolimus and drugs
      that are substrates/inhibitors or inducers of CYP3A and the P-glycoprotein
      transporter. Close monitoring of trough sirolimus blood levels is therefore
      recommended for pediatric transplant recipients. In de novo adult kidney
      transplant recipients on triple therapy with cyclosporine, corticosteroids and
      sirolimus, a therapeutic window of 4-12 microg/l is recommended for sirolimus
      trough concentrations determined by HPLC or LC/MS-MS. In maintenance adult
      patients after conversion to a calcineurin inhibitor-free regimen, sirolimus
      trough concentrations of 5-10 microg/l are proposed in combination with
      mycophenolate mofetil. These therapeutic ranges may also serve as a guide for
      pediatric renal transplant recipients. The concept of C2 monitoring still needs
      to be critically evaluated in pediatric patients. The crucial importance of
      achieving an adequate cyclosporine exposure early after transplantation has been
      demonstrated for adult transplant recipients. A cyclosporine concentration taken
      2 h after dosing is a good surrogate marker of the AUC0-4h in adults. Various
      clinical studies have shown that in pediatric patients, the C2 concentration
      shows a substantially better correlation with cyclosporine exposure compared to
      the trough level (C0). In an outcome study with pediatric renal transplant
      recipients, it could be demonstrated that the AUC(0-4h) was a predictor of acute
      rejection in the first 3 weeks after transplantation, whereas C2 levels showed no
      significant association. Abbreviated AUC strategies may be preferable for
      optimization of CsA exposure in pediatric patients.

PMID- 15183290
TI  - Recent developments in meconium and hair testing methods for the confirmation of
      gestational exposures to alcohol and tobacco smoke.
AB  - The use of alcohol and tobacco is prevalent among pregnant women despite the well
      known adverse effects of these substances imposed on the developing fetus and
      immense public health education efforts. Confirmation of gestational exposures to
      these compounds have relied mostly on maternal self-reporting, which is often
      underestimated because of guilt, embarrassment, and fear of punitive action. The
      presence of fatty acid ethyl esters in various biological matrices as a result of
      alcohol consumption initiated the development of neonatal screening tests for
      these emerging biological markers in meconium and hair. The levels of nicotine
      and cotinine in hair have long been used as objective indices for the
      quantification of exposure to active and passive smoking. Maternal segmental hair
      analysis in the study of pharmacokinetic changes in nicotine metabolism in the
      obstetric population is a novel application of this traditional analytical
      method. The latest developments and novel applications of meconium and hair
      testing for the confirmation of prenatal alcohol and tobacco exposure are
      discussed in this review.

PMID- 15183291
TI  - Historical prospective of human cytogenetics: from microscope to microarray.
AB  - After the fundamental discovery in 1956 that normal human cells contain 46
      chromosomes, clinical cytogenetics was born and studies into the relation of
      chromosomal defects and disease could begin. Although many technical advances
      have been made over this long period, including the introduction of molecular
      techniques, until now, all cytogenetic studies have been performed through
      regular microscopes, which was throughout the years the most important equipment
      of a cytogenetic laboratory. However, recently a new technique has been
      introduced based on comparative genomic hybridization on an array of thousands of
      different probes (array-CGH). This technique enables an increase in the
      sensitivity of detecting chromosomal aberrations far beyond the detection limit
      of regular banding techniques. Furthermore, it gives us the possibility to detect
      genomic changes in malignant cells in cases where aberrations are too complex to
      study or when chromosomes are not available at all. Cytogenetic laboratories are
      now challenged to introduce and incorporate this new application next to the
      various well-established microscopical techniques to provide optimal diagnostic
      services.

PMID- 15183292
TI  - Maternal-fetal risk assessment.
AB  - In first-world countries, maternal and infant mortality has significantly
      decreased over the past 50 years due to factors such as skilled pregnancy care
      practitioners, aseptic hospital births, antibiotics, safe blood transfusions, and
      oxytocin. However, international maternal and infant mortality statistics from
      underdeveloped countries remain high. Pregnancy risk management requires
      implementation of risk-reduction strategies that have been proven to be
      effective. Marked physiological alterations in biochemical indices that occur in
      pregnancy require that laboratories participating in the evaluation of new
      interventions in pregnancy must ensure that tests are compared to appropriate
      gestation-specific reference intervals.

PMID- 15183293
TI  - Childhood tuberculosis and its early diagnosis.
AB  - Traditional methods for laboratory diagnosis of tuberculosis are unsatisfactory,
      especially for children, in whose specimens mycobacteria are usually sparse.
      Recent changes in tuberculosis epidemiology in developed countries, including a
      large increase in incidence in children from certain ethnic minorities, have
      prompted interest in newer diagnostic methods. Liquid-based culture detection
      systems offer improved sensitivity and speed of diagnosis, although the time
      taken for detection of growth is still upwards of 1 week. Nucleic acid
      amplification techniques offer more rapid results, but perform best on smear
      positive samples; sensitivities may be as low as 50% in smear-negative specimens.
      Although these newer techniques are widely used in some developed countries, in
      others, they are not perceived as offering sufficient benefit to justify their
      routine use. The diagnostic accuracy of mycobacteriophage and serologic methods
      is insufficient to justify their wide use even in developing countries. Despite
      recent developments, there is still no panacea for diagnosis of childhood
      tuberculosis.

PMID- 15183294
TI  - Point of care testing: improving pediatric outcomes.
AB  - OBJECTIVE: Goal-directed therapy (GDT) has been proven to reduce morbidly and
      mortality in critical illness. Point of care testing (POCT) allows rapid turn
      around time (TAT) of critical data, yet data suggesting improved outcomes are
      very limited. The impact of these two strategies on improving outcomes for
      patients after congenital heart surgery has never been evaluated. DESIGN:
      Beginning July 2001, POCT in the form of the i-STAT handheld analyzer was
      incorporated in the management of patients after congenital heart surgery at our
      institution. Blood lactate measurements were performed serially for 24 h after
      surgery. Based on a lactate value, medical therapy was escalated, diminished or
      left unchanged after surgery. Outcome data were collected prospectively for later
      review. Mortality at 30 days after surgery was compared for patients undergoing a
      GDT protocol to a group of historical cohorts. The operative risk for all
      operations was determined using the RACHS-1 scoring system. SETTING: A 16-bed
      Cardiac Intensive Care Unit (CICU) in a 268-bed free-standing pediatric hospital.
      PATIENTS: Outcomes of infants and neonates operated on from July 2001 through
      July 2003 (Group B) were compared to historical controls in our institution from
      June 1995 through June 2001 (Group A). There were 851 patients in Group A and 378
      patients in Group B. Patients in Group B were smaller and younger than those in
      group A (median weight 3.8 vs. 4.3 kg, P < 0.001; median age 42 vs. 76 days, P =
      0.02). MEASUREMENTS AND RESULTS: Overall mortality was lower for Group B as
      compared to Group A (2.4% vs. 6.2%, P < 0.007). Significant reduction in
      mortality between Group B and Group A was noted in neonates (4.3% vs. 12%, P =
      0.008) but did not reach significance in infants (0.9% vs. 2.6%, P = NS).
      Patients undergoing the highest-risk operations (RACHS-1 groups 5 + 6) had a 70%
      reduction in mortality when comparing Group B to Group A, (9% vs. 30%, P = 0.03),
      but no statistical difference in mortality was noted in those patients undergoing
      lower-risk operations (RACHS-1 groups 1 and 2, Group B 0.5% vs. Group A 1.5%, P =
      NS). CONCLUSIONS: The combination of goal-directed therapy and point of care
      testing significantly reduced mortality in patients undergoing congenital heart
      surgery. This improvement is greatest in the youngest patients and those
      undergoing higher-risk surgeries.

PMID- 15183295
TI  - An interfering component in cardiac troponin I immunoassays-Its nature and
      inhibiting effect on the binding of antibodies against different epitopes.
AB  - OBJECTIVES: We recently reported on the occurrence of a common interfering factor
      (IF) that negatively affects determinations of cardiac troponin I (cTnI). The aim
      of the present investigation was to extend our initial finding by a detailed
      epitope-based determination of the location of IF and to reveal the approximate
      size and characteristics of IF. DESIGN AND METHODS: Two-site immunoassays using
      combinations of 16 monoclonal and 2 polyclonal cTnI antibodies and 1 monoclonal
      troponin C (TnC) antibody were used to measure the analytical recovery of cTnI or
      cTnI-TnC in serum samples. Gel filtration of serum samples containing IF was
      performed and the analytical recovery of cTnI in the fractions was determined.
      EDTA-plasma samples to which cTnI had been added and serum samples containing
      endogenous cTnI were also separated by gel filtration. RESULTS: The mean
      analytical recoveries of cTnI were 28.3% (range 7.5-55.1%) and of cTnI-TnC were
      23.5% (range 8.7-51.8%) in samples containing IF when antibodies against
      midfragment epitopes of cTnI were used. The mean recovery of cTnI was 65.1% and
      73.3% for antibodies with N- and C-terminal epitopes. Gel filtration of samples
      with low recovery of cTnI showed that the approximate molecular mass of IF was 50
      200 kDa and that the cTnI elution profiles of samples containing IF were shifted
      towards higher molecular mass compared with samples with less IF. CONCLUSIONS:
      Antibodies against midfragment epitopes of cTnI are affected by IF to a
      considerable but variable extent, and the presence of IF can be demonstrated by
      gel filtration.

PMID- 15183297
TI  - Performance characteristics of five automated serum cortisol immunoassays.
AB  - BACKGROUND: Serum cortisol measurements are used to help diagnose conditions of
      cortisol deficiency and excess. Automated, nonisotopic immunoassays are used in
      most clinical laboratories. METHODS: Linearity, imprecision, and method
      comparison studies for serum cortisol assays were performed with the Access,
      Advia Centaur, AxSYM, Elecsys 2010, and IMMULITE 2000 analyzers. RESULTS: All
      methods demonstrated acceptable linearity with the AxSYM method showing the least
      deviation from target values. The Elecsys 2010 method was the most precise for
      all three levels of quality control material. Method comparison studies
      demonstrated good concordance among methods except for two patient samples that
      gave results on the Elecsys 2010 that were significantly higher than the other
      methods. Differences in assay calibration were observed. CONCLUSIONS: Overall,
      all methods performed well. Additional calibration standardization efforts are
      required to truly harmonize the results from each assay. The Elecsys 2010 method
      is less specific than other automated methods based on two discordant patient
      results.

PMID- 15183296
TI  - Electrophoretic measurement of lipoprotein(a) cholesterol in plasma with and
      without ultracentrifugation: comparison with an immunoturbidimetric
      lipoprotein(a) method.
AB  - OBJECTIVES: Elevated plasma lipoprotein(a) [Lp(a)] is a significant risk factor
      for vascular disease. Standardization of Lp(a) mass measurement is complicated by
      the heterogeneity of apolipoprotein(a) [apo(a)]. We investigated whether Lp(a)
      cholesterol measurement, which is not influenced by apo(a) size, is a viable
      alternative to measuring Lp(a) mass. DESIGN AND METHODS: Plasma Lp(a) cholesterol
      was measured electrophoretically, with and without ultracentrifugation, and
      results were compared to each other and to immunoturbidimetrically measured Lp(a)
      mass in 470 subjects. RESULTS: Ultracentrifuged and whole plasma Lp(a)
      cholesterol levels demonstrated high correlation (R = 0.964). All samples with
      detectable (>/=2.0 mg/dl) Lp(a) cholesterol had Lp(a) mass >30 mg/dl (the
      clinically relevant cutpoint), while 59 samples with Lp(a) mass >30 mg/dl did not
      have detectable Lp(a) cholesterol. CONCLUSIONS: Lp(a) cholesterol can be measured
      in whole plasma without interference from VLDL lipoproteins. The relative
      clinical merits of measuring Lp(a) cholesterol vs. Lp(a) mass or both in
      combination deserves investigation.

PMID- 15183298
TI  - Various forms of homocysteine and oxidative status in the plasma of ischemic
      stroke patients as compared to healthy controls.
AB  - OBJECTIVES: We compared various forms of plasma homocysteine (Hcy) including
      total Hcy (tHcy), free reduced Hcy (reHcy), free oxidized Hcy (oxHcy) and reHcy
      plus oxHcy between patients with acute/subacute-ischemic stroke and healthy
      controls. We also investigated whether the patients have increased oxidative
      stress. DESIGN AND METHODS: Using an in-tube derivatization method, we measured
      plasma levels of tHcy, reHcy and oxHcy in 55 ischemic-stroke patients (14 females
      and 41 males, median age 64) and 52 age-matched healthy subjects (15 females and
      37 males, median age 60). We also measured plasma malondialdehyde (MDA, as lipid
      peroxidation marker) and oxygen-radical absorbance capacity (ORAC, as total
      antioxidant activity). RESULTS: The plasma levels of reHcy and reHcy plus oxHcy
      and the ratio of reHcy to oxHcy were significantly higher in the patients than in
      the age-matched controls, whereas tHcy and oxHcy levels were not significantly
      different. The patients had a significantly higher level of MDA but a lower value
      of ORAC than that of controls. A significantly positive correlation was found in
      the levels of reHcy vs. MDA (r = 0.19, P < 0.03), whereas significant negative
      correlations were found for reHcy vs. ORAC (r = -0.30, P < 0.001) and free Hcy
      vs. ORAC (r = -0.30, P < 0.001). CONCLUSIONS: reHcy and reHcy plus oxHcy Hcy,
      rather than tHcy, are significantly elevated in patients with acute/subacute
      ischemic stroke. The elevated reHcy along with elevated MDA level and lowered
      ORAC value in the plasma of the stroke patients indicates an imbalance of
      antioxidant-prooxidant status in acute ischemic stroke.

PMID- 15183301
TI  - Autoimmune Rheumatic Diseases Days. Festschrift in honor of the 60th birthday of
      Professor Harry Moutsopoulos. Athens, Greece. June 24-26, 2004.

PMID- 15183299
TI  - Rebuttal to "Easy fix for clinical laboratories for the false positive defect
      with Abbott AxSYM Total BhCG test" by Dr. Laurence Cole, Clin Biochem, 37(5), 344
      349 (2004).

PMID- 15183302
TI  - Expression and mapping of duplicate neuropilin-1 and neuropilin-2 genes in
      developing zebrafish.
AB  - Previously, we described the isolation and characterization of the first
      zebrafish neuropilin gene, which we now call nrp1a, and found its protein to be a
      mediator of vascular endothelial growth factor (VEGF)-dependent angiogenesis
      [Proc. Natl Acad. Sci. USA 99 (2002) 10470]. Subsequently, we have isolated three
      other full-length neuropilin genes (nrp1b, nrp2a, and nrp2b) and find that they
      map to independent zebrafish linkage groups. The nrp1s and nrp2s had differential
      spatio-temporal gene expression profiles with nrp1a being most prominent in the
      gut, brain, retina, hypochord, motorneurons, fin bud and mandibular cartilage,
      nrp1b in the brain, dorsal aorta, melanophores, ventral fin, and heart, nrp2a in
      the brain, retina, heart, and caudal vessels, and nrp2b in the brain, retina,
      gut, fin bud, melanophores, heart, and caudal vessels. In addition, we have
      identified an alternatively-spliced transcript of the nrp1b gene (denoted as
      nrp1b(s)) which is predicted to encode a soluble form of Nrp1b, containing only
      the a, b, and c extracellular domains. Transcript expression of nrp1b(s) was
      different from full-length nrp1b transcript, with prominence in the brain,
      developing mouth, heart, and fin bud. The NRP1s were tested for VEGF-binding
      ability. Both 125 kDa Nrp1a and 145 kDa Nrp1b bound 125I-labelled VEGFA165. In
      summary, two nrp1 and two nrp2 genes, with expression patterns similar to higher
      vertebrates, have been isolated from zebrafish.

PMID- 15183303
TI  - Cloning and embryonic expression of zebrafish neuropilin genes.
AB  - Neuropilin (Nrp), a cell surface receptor for class 3 semaphorins and for certain
      heparin forms of vascular endothelial growth factors, functions in many
      biological processes including axon guidance, neural cell migration and
      angiogenesis in the development of the nervous system and the cardiovascular
      system. To understand the role of neuropilins in zebrafish embryogenesis, we have
      cloned three zebrafish neuropilin homologues, nrp1b, nrp2a and nrp2b. Based on
      synteny, zebrafish nrp1b and the previously cloned nrp1a are orthologous to human
      nrp1, and zebrafish nrp2a and 2b orthologous to human nrp2. We have characterized
      the expression patterns of these four zebrafish neuropilin genes in wild type
      embryos from the beginning of somitogenesis to 48 h post-fertilization. Zebrafish
      nrp1a is expressed in the neural tube including telencephalon, epithalamus, cells
      along the axonal trajectory of the posterior commissure and the medial
      longitudinal fascicle, hindbrain neurons, vagus motor neurons and spinal
      motoneurons. Zebrafish nrp1b is expressed in the nose, the cranial neural crest
      cell (NCC) derived tissue underlying the hypothalamus, endothelial precursors and
      the trunk and tail vasculature. Zebrafish nrp2a is expressed in telencephalon,
      anterior pituitary, oculomotor and trochlear motor neurons, cells along the supra
      optic and posterior commissures, hindbrain rhombomere 1, hindbrain neurons,
      cranial NCCs and sclerotome. Zebrafish nrp2b is expressed in telencephalon,
      thalamus, hypothalamus, epiphysis, cells along the anterior and posterior
      commissures, post-optic and supra-optic commissures and the olfactory axonal
      trajectory, hindbrain neurons, cranial NCCs, somites and spinal cord neurons.

PMID- 15183304
TI  - Differential expression of duplicated genes for brain-type fatty acid-binding
      proteins (fabp7a and fabp7b) during early development of the CNS in zebrafish
      (Danio rerio).
AB  - A gene for the zebrafish brain-type fatty acid-binding protein (fabp7b) was
      identified and its structure defined. The zebrafish fabp7b gene spans 1479 bp and
      consists of four exons encoding 24, 58, 34 and 16 amino acids, respectively,
      which is identical to the structure of the fabp7a gene previously described. The
      complete fabp7b cDNA was isolated by 5' and 3' RACE and its nucleotide sequence
      determined. The deduced amino acid sequence of FABP7B encoded by the zebrafish
      fabp7b gene shares 82% identity with that of FABP7A encoded by the zebrafish
      fabp7a gene. A single transcription start site for the fabp7b gene was mapped by
      5' RNA ligase-mediated RACE. Phylogenetic analysis indicated that the duplication
      of the fabp7 genes occurred in the fish lineage after their divergence from
      mammals. The zebrafish fabp7b gene was assigned to linkage group 20 by radiation
      hybrid mapping. Reverse transcription-polymerase chain reaction detected fabp7b
      transcripts in the same adult tissues as fabp7a transcripts. In the brain, levels
      of fabp7b transcripts were lower than fabp7a transcripts. Whole-mount in situ
      hybridization showed that the zebrafish fabp7a transcripts were distributed in
      the early developing central nervous system. In addition to being expressed in
      the developing brain and retina, zebrafish fabp7b mRNA was also detected in the
      swim bladder and pharynx during the embryonic to larval transitory phase.

PMID- 15183305
TI  - The proliferation associated nuclear element (PANE1) is conserved between mammals
      and fish and preferentially expressed in activated lymphoid cells.
AB  - The proliferation associated nuclear element (PANE1) had been identified in a
      screen for genes activated in mouse mammary epithelium transformed by stabilized
      beta-catenin. We have now cloned the human and zebrafish orthologs, analyzed
      their expression and expressed them ectopically in tissue culture cell lines.
      PANE1 consists of 180 amino acids and displays 38% conservation between man and
      zebrafish. Expression of the human PANE1 gene was detected preferentially in
      immune cells including leukemias and lymphomas, tumor tissues and tumor derived
      cell lines. In B- and T-cells PANE1 RNA was only detected after the respective
      cell types were activated either in vivo or in vitro.

PMID- 15183306
TI  - Lmx1b expression during joint and tendon formation: localization and evaluation
      of potential downstream targets.
AB  - The tetrapod limb exhibits distinct dorsoventral joint, tendon, and muscle
      asymmetry. The LIM-homeodomain transcription factor, Lmx1b, is required to
      achieve the dorsal character of these structures, but the mechanism by which
      Lmx1b orchestrates this asymmetrical development is unknown. To identify target
      tissues and genes regulated by Lmx1b, we examined Lmx1b expression during joint,
      tendon and muscle formation (9.5-16.5 dpc) and the expression of several genes
      spatially restricted to developing joints and associated tissues in normal and
      Lmx1b knockout (KO) mice including: Gdf-5, sFrp2, sFrp3, Six1 and Six2. Lmx1b was
      diffusely expressed in the undifferentiated dorsal mesoderm of the emerging limb
      bud (E9.5-E11.5). With progressive proximal to distal differentiation, Lmx1b
      expression localized to dorsal joint-forming regions, to developing tendons and
      ligaments, but not to migrating myocytes (E13.5-15.5). By E16.5, mature tendon
      and ligament associations were evident and Lmx1b expression had regressed. The
      expression patterns of Gdf-5 and sFrp3 at E15.5 were symmetrical along the
      dorsoventral axis in normal and Lmx1b KO mice. sFrp2, Six1 and Six2 exhibited
      asymmetrical dorsoventral expression and in Lmx1b KO mice, this asymmetry is
      lost; however, none were solely restricted to or excluded from dorsal Lmx1b
      expressing tissues.

PMID- 15183307
TI  - Developmental regulation of EVF-1, a novel non-coding RNA transcribed upstream of
      the mouse Dlx6 gene.
AB  - We previously reported that sonic hedgehog (Shh) induces the differentiation of
      rat ventral forebrain neurons expressing a novel marker, EVF-1 [Development 125
      (1998) 5079]. In this report, we show that EVF-1 is a novel, developmentally
      regulated, non-coding RNA, with no homology to other known non-coding RNA
      sequences. Sequence analysis, in vitro translation, and comparison of the rat and
      mouse EVF-1 sequences suggest that EVF-1 contains no protein coding regions.
      Chromosomal location indicates that EVF-1 maps adjacent to the Dlx6 gene on mouse
      chromosome 6. RNA in situ hybridization of the embryonic rat forebrain shows that
      EVF-1 is expressed by immature neurons in the subventricular zone and its
      expression decreases during forebrain development. Whole mount in situ
      hybridization shows that EVF-1 is expressed at high levels in the branchial
      arches, ventral forebrain, olfactory bulb, and limbs. EVF-1 expression is linked
      to Shh and the Dlx family of proteins, genes with a demonstrated importance to
      ventral forebrain and craniofacial development.

PMID- 15183308
TI  - A family of genes encoding zona pellucida (ZP) domain proteins is expressed in
      various epithelial tissues during Drosophila embryogenesis.
AB  - Zona pellucida (ZP) domain proteins have been identified in various species from
      worms to humans. Most of the characterized ZP family members are secreted or
      remain anchored to the plasma membrane where they play a structural role and/or
      act as receptors. In humans, several ZP proteins attracted attention because of
      their abundant expression in certain organs and their relation to various
      diseases. Here, we compare the molecular architecture and embryonic expression
      pattern of the 18 genes encoding ZP proteins in Drosophila melanogaster. Only
      five of these genes have been genetically characterized. All ZP genes are
      expressed in the embryo in epithelial tissues, such as the foregut, the hindgut,
      the Malpighian tubules, the salivary glands, the tracheal system, sensory organs
      and epidermis. Five genes are expressed during oogenesis; two of them are
      transcribed in the follicular epithelium, but not in the germ line cells.

PMID- 15183309
TI  - Expression pattern of the JAB1/CSN5 gene during murine embryogenesis:
      colocalization with NEDD8.
AB  - The COP9 signalosome (CSN) is a conserved multiprotein complex, with an important
      developmental role in several organisms, ranging from plants to mammalians. The
      influence of the CSN on several signaling and developmental processes has been
      ascribed to its ability to regulate degradation of a number of signaling proteins
      by the ubiquitin-proteasome system. The CSN controls the function of the SCF
      ubiquitin-ligase complex through an enzymatic activity that removes the small
      ubiquitin-like molecule NEDD8 from the cullin component of the SCF and that
      requires subunit 5 of the CSN (JAB1/CSN5). Mutants of the CSN display early
      embryonic lethality, a feature that has hindered further characterization of the
      role of the CSN at later stages of mammalian development. Here we report the
      analysis of JAB1/CSN5 expression pattern in the mouse embryo. At early stages of
      development, JAB1/CSN5 transcripts were present with low expression levels in all
      tissues. Preferential expression in selected tissues was detected starting at
      E11.5, with higher levels in dorsal root ganglia; at later stages, prominent
      expression of JAB1/CSN5 transcripts was observed in cranial nerve, spinal and
      sympathetic ganglia, as well as in selected epithelia, such as the oral and the
      olfactory epithelium. In the adult brain, additional areas of JAB1/CSN5
      expression were the hippocampus and the Purkinjie layer of the cerebellum. We
      also analyzed the temporal and spatial expression pattern of NEDD8, and found
      that it substantially overlapped JAB1/CSN5 expression at all stages analyzed,
      supporting the model of a functional interaction between the two proteins during
      developmental processes.

PMID- 15183310
TI  - Effect of ploidy and parental genome composition on expression of Oct-4 protein
      in mouse embryos.
AB  - The transcription factor Oct-4 is expressed in germ cells and also is considered
      as a marker for pluripotency of stem cells. We first examined dynamics of Oct-4
      protein expression during preimplantation development using both Western blot
      analysis, and immunofluorescence staining. We show that intact Oct-4 protein is
      not detected in either ovulated mature oocytes, or in zygotes and 2-4-cell
      embryos, which are the only known totipotent cell types in mammals. This finding
      is unexpected, since Oct-4 has been proposed to play a role in the control of
      totipotency. The results suggest that Oct-4 is not indispensable for
      fertilization and early cleavage. Rather, expression of Oct-4 protein is first
      detected in the nuclei of 8-16 cell morula, increases in early blastocysts, and
      declines in late blastocysts, in which most Oct-4 protein is confined to the
      inner cell mass (ICM) region, consistent with previous findings. We further
      compared Oct-4 protein expression in diploid and tetraploid blastocysts derived
      from normal fertilization or parthenogenesis, as well as expression in diploid
      androgenetic blastocysts. Expression levels and localization of Oct-4 protein are
      similar in both diploid and tetraploid early blastocysts, regardless of whether
      blastocysts are derived from fertilization or parthenogenesis. Androgenetic
      diploid blastocysts also express similar levels of Oct-4. Late blastocysts
      generated by both fertilization and parthenogenesis show a similar pattern of Oct
      4 expression, suggesting that paternal genome activation is not required for Oct
      4 expression. Expression of Oct-4 protein does not differ between diploid and
      tetraploid embryos, indicating that tetraploidy does not influence Oct-4
      expression. Thus, expression of Oct-4 protein is initiated at morula stage in
      preimplantation embryos and completely controlled by a mechanism activated in
      oocytes. Downregulation of Oct-4 expression coincides with differentiation of
      trophectoderm. Similar profiles of Oct-4 expression observed in embryos with
      different ploidy and genome composition, are suggestive of Oct-4 being necessary
      but not sufficient for developmental potency.

PMID- 15183311
TI  - Expression pattern of the homeobox gene Not in the basal metazoan Trichoplax
      adhaerens.
AB  - The homeobox gene Not is highly conserved in Xenopus, chicken and zebrafish with
      an apparent role in notochord formation, which inspired the name of this distinct
      subfamily. Interestingly, Not genes are also well conserved in animals without
      notochord such as sea urchins, Drosophila or even Hydra, but appear to be highly
      derived in mammals. A search for homeobox genes in the placozoan Trichoplax
      adhaerens, one of the simplest organisms available today, revealed only two
      homeobox genes: a Not homologue and the previously described gene Trox-2, which
      is most similar to the Gsx subfamily of the Hox/ParaHox cluster genes. Not has a
      unique expression profile in Trichoplax. It is highly expressed in folds of
      intact animals and in the wounds of regenerating animals. The dynamic expression
      pattern of Trichoplax Not is discussed in comparison with the invariable
      expression pattern of Trox-2 and the putative secreted protein Secp1. The high
      sequence conservation of Not from Trichoplax to lower vertebrates, but not to
      mammals, represents a rare example of an apparent gene decay in the lineage
      leading to humans.

PMID- 15183312
TI  - Expression patterns of four different regulatory genes that function during sea
      urchin development.
AB  - The spatial and temporal expression patterns of Strongylocentrotus purpuratus
      genes encoding four different transcription factors, viz. SpFoxb, SpHes, SpKrl,
      and SpNk1, have been examined, using a recently developed, highly sensitive whole
      mount in situ hybridization procedure, and quantitative real time PCR. Two of the
      genes studied, SpHes and SpNk1, are newly isolated. Their expression patterns
      suggest the existence of previously unknown ectodermal domains. Re-examination of
      the expression pattern of SpFoxb reveals domains of expression not previously
      reported for this gene, and we also provide a more detailed, temporal and spatial
      description of the expression pattern of SpKrl than heretofore available.

PMID- 15183313
TI  - Patterning and tissue movements in a novel explant preparation of the marginal
      zone of Xenopus laevis.
AB  - Development of the Xenopus embryo has provided an adaptable framework for the
      rapid evaluation of molecular factors that guide patterning and morphogenesis. We
      present and characterize a novel explant preparation that is useful for such
      studies. This preparation consists of 180 degrees of the marginal zone of the
      early Xenopus gastrula cultured on a fibronectin-coated substrate. In addition to
      a thorough description of its preparation, we analyze gene expression patterns at
      three stages of development. The stereotypic morphogenesis of this explant can be
      understood in the context of the intact embryo through a catalog of gene
      expression patterns providing definitive identities for epidermis, anterior and
      posterior neural, notochord, somitic mesoderm, and mesendoderm.

PMID- 15183314
TI  - Restricted expression of ETn-related sequences during post-implantation mouse
      development.
AB  - In a screen for potential targets of regulation by TWIST in mouse embryos we
      isolated a fragment with homology to type II early transposon (ETn) and type D
      endogenous provirus (MusD) elements. Whole-mount in situ hybridization to E7.5
      E13.5 mouse embryos reveals a tissue- and stage-specific expression pattern that
      contrasts with the previously reported lack of expression of ETn elements in
      mouse embryos beyond late gastrulation. Transcripts were detected in the epiblast
      at E7.5 and in the neural tube from E8.5 to E10.5. Later expression is
      predominantly confined to the mesodermal tissues of craniofacial structures, limb
      buds and somites. The tissue specificity of expression suggests tight regulation
      of the activity of this early transposon element during embryogenesis.

PMID- 15183315
TI  - Characterization and expression pattern of the novel MIA homolog TANGO.
AB  - A novel human gene, TANGO, encoding a MIA ('melanoma inhibitory activity')
      homologous protein was identified by a gene bank search. TANGO, together with the
      homologous genes MIA, OTOR (FPD, MIAL) and MIA2 define a novel gene family
      sharing important structural features, significant homology at both the
      nucleotide and protein level, and similar genomic organization. The four members
      share 34-45% amino acid identity and 47-59% cDNA sequence identity. TANGO encodes
      a mature protein of 103 amino acids in addition to a hydrophobic secretory signal
      sequence. Sequence homology confirms the highly conserved SH3 structure present
      also in MIA, OTOR and MIA2. Thus, it appears that there are a number of
      extracellular proteins with SH3-fold like structures. Interestingly, in situ
      hybridization, RT-PCR and Northern Blots revealed very broad TANGO expression
      patterns in contrast to the highly restricted expression patterns previously
      determined for the other members of the MIA gene family. The only cells lacking
      TANGO expression are cells belonging to the hematopoetic system. High levels of
      TANGO expression were observed both during embryogenesis and in adult tissues.

PMID- 15183318
TI  - Developments in peptide and amide synthesis.
AB  - The solid-phase methodology is key for an effective synthesis of peptides, from a
      milligram scale for research to a multi-kilo scale for drug production. Indeed,
      small peptides containing up to 20-30 amino acids are most readily synthesized by
      a solid-phase strategy. Larger peptides (up to 60 amino acids) should be
      synthesized by a convergent approach (i.e. synthesis of protected constituent
      peptides in solid-phase and combination of these units in solution). Larger
      peptides and proteins are prepared by chemical ligation, where unprotected
      segments have been prepared in solid-phase.

PMID- 15183316
TI  - Expression of sax1/nkx1.2 and sax2/nkx1.1 in zebrafish.
AB  - sax1/nkx1.2 and sax2/nkx1.1 are members of the evolutionally conserved NK-1
      homeobox gene family. sax1/nkx1.2 is reported to be expressed in the central
      nervous system during early and late neurogenesis in the chick and mouse, but the
      expression of sax2/nkx1.1 has not been reported. We isolated zebrafish cDNAs for
      sax1/nkx1.2 and sax2/nkx1.1 and examined their expression. In zebrafish, unlike
      chick and mouse, sax1/nkx1.2 was expressed in the prospective medial floor plate
      from the mid-gastrula period and was dependent on Nodal signaling. From the early
      segmentation period, sax1/nkx1.2 was also expressed in the posterior
      neuroectoderm. sax2/nkx1.1 was expressed in the prospective extraocular muscles,
      mesencephalic neurons residing along the tract of the posterior commissure,
      ventral neurons in the hindbrain, and interneurons in the spinal cord.

PMID- 15183319
TI  - Recent advances in the high-speed solid phase synthesis of RNA.
AB  - Development of rapid and reliable RNA synthesis strategies is fueled by the
      emergence of critical functional and regulatory roles for RNA, including RNA
      interference. Traditional methods are based on 5'-dimethoxytrityl-2'-silyl
      protection strategies which are derivatives of highly successful DNA synthesis
      methods. These approaches are limited in their ability to rapidly produce oligos
      of sufficient purity and length for genomic and pharmaceutical applications.
      Recently, new protection chemistries have been developed that circumvent the many
      limitations of 2'-silyl protection. The 5'-silyl-2'-bis(acetoxyethoxy)methyl
      strategy is the most notable, as it provides dramatic improvements--faster
      coupling rates, higher yields, greater product purity and superior post-synthetic
      ease-of-handling--affording a reliable high-speed chemical RNA synthesis
      technology.

PMID- 15183320
TI  - Traceless and multifunctional linkers for the generation of small molecules on
      solid supports.
AB  - Numerous developments in useful linkers are closely related with the advances in
      solid-phase organic synthesis. These linkers allow facile attachment
      functionalization and release molecules of interest. Designing a new anchoring
      group can be essential for synthesis success, especially for small molecules on
      solid supports. Many novel linkers have recently been developed. Traceless
      linkers can be excised efficiently and quantitatively when desired while leaving
      behind no trace of the solid-phase synthesis. However, multi-functional cleavage
      allows the introduction of new functionalities during cleavage from the resin.

PMID- 15183321
TI  - 'One bead two compound libraries' for detecting chemical and biochemical
      conversions.
AB  - When combinatorial chemistry was introduced 13 years ago, the expectations were
      high for the delivery of results, particularly in the pharmaceutical industry.
      However, combinatorial chemistry was implemented independently of the application
      for which the products were going to be used. Resins developed only for efficient
      solid-phase synthesis were used and products were employed in existing assays
      developed for traditional solution studies. There was almost no assay or
      technology development and the use of real combinatorial methods soon had to give
      way to high-throughput synthesis and traditional screening. However, during
      recent years more sophisticated resins and assay techniques have been developed
      that may result in a second and more successful implementation of real integrated
      combinatorial chemistry. The first in this line of new developments is the 'one
      bead two compound' assay, in which the resin bead in addition to a combinatorial
      library member contains a reporter compound that can act as a beacon to monitor
      the activity of the library member. This powerful concept can be generally
      applied in all fields of combinatorial chemistry including drug, catalysts and
      material development.

PMID- 15183322
TI  - Recent applications of olefin metathesis to combinatorial chemistry.
AB  - Olefin metathesis has emerged as a versatile technology for the synthesis of
      combinatorial libraries with regard to both scaffold creation and embellishment.
      The incessant pursuit of 'next-generation' catalysts continues to raise the bar
      in terms of efficiency, functional group tolerability, diminished reaction times
      and temperatures and has helped foster both diversity-oriented and target
      directed efforts. This report summarizes recent contributions in the area of
      olefin cross-metathesis and ring-closing metathesis as applied to combinatorial
      and parallel synthesis. These examples include generation of dimeric
      benzo[b]furans as novel probes for protein-protein interaction, a cross
      metathesis approach to 'traceless linkers' for azide-containing sugars, stereo
      diversified synthesis of 1,4- and 1,5-enediols, a novel mannitol derived
      combinatorial scaffold, parallel synthesis strategies for aza-sugars, as well as
      the synthesis of dehydro-Freidinger lactams.

PMID- 15183323
TI  - Pursuing the leadlikeness concept in pharmaceutical research.
AB  - Lipinski and others, through concepts such as drug-likeness, re-focussed drug
      discovery back to the principles of medicinal chemistry in the high-throughput
      era as key to reducing attrition. More recently, the need to go further in
      defining what makes a good lead has been recognised with the concept of
      leadlikeness. Leadlikeness implies cut-off values in the physico-chemical profile
      of chemical libraries such that they have reduced complexity (e.g. MW below <400)
      and other more restricted properties. We examine these concepts in the context of
      Virtual (theoretically possible), Tangible (chemically feasible) and Real
      (physically available) worlds of molecules. In a thought experiment, we take the
      HTS concept to the extreme: screening an estimated 60 million 'Global Collection'
      on 5000 targets and realising that perhaps millions of drug candidates might be
      found that could not possibly be handled in reality. Sampling of the Virtual and
      Tangible worlds is therefore a necessity. We show that the world of Reals is
      significantly under-sampled as the MW of compounds increases. This supports the
      design and screening of 'reduced complexity' (leadlike) compound libraries,
      preferably with synthetic handles available for rapid chemical iteration and
      detected as interesting by careful screening or biophysical assays.

PMID- 15183324
TI  - Applying data mining techniques to library design, lead generation and lead
      optimization.
AB  - Many data mining techniques have been applied to activity and ADMET datasets and
      the resulting models are being used to understand quantitative structure-activity
      relationships and design new libraries. This review summarizes data mining
      concepts and discuss their application to library design, lead generation
      (particularly for sequential screening) and lead optimization (specifically for
      generating and interpreting QSAR models). Also, this review discusses recent
      comparative studies between data mining techniques and draws some conclusions
      about the patterns emerging in the drug discovery data mining field.

PMID- 15183325
TI  - Natural products and combinatorial chemistry: back to the future.
AB  - The introduction of high-throughput synthesis and combinatorial chemistry has
      precipitated a global decline in the screening of natural products by the
      pharmaceutical industry. Some companies terminated their natural products
      program, despite the unproven success of the new technologies. This was a
      premature decision, as natural products have a long history of providing
      important medicinal agents. Furthermore, they occupy a complementary region of
      chemical space compared with the typical synthetic compound library. For these
      reasons, the interest in natural products has been rekindled. Various approaches
      have evolved that combine the power of natural products and organic chemistry,
      ranging from the combinatorial total synthesis of analogues to the exploration of
      natural product scaffolds and the design of completely unnatural molecules that
      resemble natural products in their molecular characteristics.

PMID- 15183326
TI  - Libraries from natural product-like scaffolds.
AB  - Natural products are an attractive source of varied structures that exhibit
      potent biological activities, and desirable pharmacological profiles. Since the
      relatively recent advent of high-throughput organic synthesis in the drug
      discovery process, several design approaches have been applied to the
      construction of screening libraries. Libraries of natural-product derivatives,
      natural-product-like compounds prepared by total synthesis, and libraries derived
      from natural-products are several types that have been reported.

PMID- 15183327
TI  - Ligand identification for G-protein-coupled receptors: a lead generation
      perspective.
AB  - This review addresses strategies for the generation of ligands for G-protein
      coupled receptors outside classical high-throughput screening and literature
      based approaches. These range from the chemical intuition-based strategies of
      endogenous ligand elaboration and privileged structure decoration to the in
      silico approaches of virtual screening and de novo design. Examples are cited
      where supporting pharmacological data has been presented.

PMID- 15183328
TI  - Process optimization using combinatorial design principles: parallel synthesis
      and design of experiment methods.
AB  - The use of parallel synthesis techniques with statistical design of experiment
      (DoE) methods is a powerful combination for the optimization of chemical
      processes. Advances in parallel synthesis equipment and easy to use software for
      statistical DoE have fueled a growing acceptance of these techniques in the
      pharmaceutical industry. As drug candidate structures become more complex at the
      same time that development timelines are compressed, these enabling technologies
      promise to become more important in the future.

PMID- 15183329
TI  - Combinatorial approaches to synthetic receptors.
AB  - Combinatorial chemistry can be efficiently used for the synthesis and evaluation
      of binding properties of libraries of synthetic receptors. This approach has been
      applied particularly to 'tweezer' and other 'multi-armed' receptors, and has been
      used for the identification of receptors for peptides in aqueous media, and for
      the development of new sensors and sensor arrays.

PMID- 15183330
TI  - Parallel and combinatorial approaches for synthesis of ligands.
AB  - Although new detection screening methods must still be developed, the actual main
      limitation in combinatorial chemistry seems to be the diversity of ligands that
      can be generated in terms of real structural and chemical diversity. Thus, there
      is a strong interest for the development of different strategies for the parallel
      or combinatorial synthesis of ligands. We report here a selection of recent
      attempts proposing 'open' approaches able to increase the diversity of molecular
      architecture truly accessible via parallel or combinatorial processes.

PMID- 15183331
TI  - Combinatorial chemistry and high-throughput screening for the discovery of
      organocatalysts.
AB  - In recent years, interest in organocatalysis, the catalysis with small organic
      molecules, has been revitalized. Independently, high-throughput-screening and
      combinatorial chemistry became practical methodologies in the discovery of novel
      catalytic entities. The logical extension of these methodologies to
      organocatalysis has led to several interesting results, which are highlighted in
      this review.

PMID- 15183332
TI  - Techniques for high-throughput characterization of peptides, oligonucleotides and
      catalysis efficiency.
AB  - Combinatorial processes have been widely applied to many disciplines in chemistry
      and biology. The vast numbers of unique entities generated by combinatorial
      synthesis have led to the development of high-throughput methods for
      characterizing samples, to avoid bottlenecks created by the application of
      conventional, serial-based analytical techniques. In recent years, high
      throughput and novel methods utilizing mass spectrometry, multiplexed capillary
      electrophoresis, various forms of optical detection, and even sound waves have
      been investigated for a variety of applications.

PMID- 15183333
TI  - Complex phenotypic assays in high-throughput screening.
AB  - High-throughput screening (HTS), systematically testing thousands of small
      molecules to find candidates for lead optimization, primarily involves exposure
      of purified proteins to arrayed collections of small molecules. More complex
      phenotypic assays, such as cell-based or whole-organism assays, traditionally
      have flanked HTS, preceding it to validate new therapeutic targets, and following
      it to characterize new lead compounds in cellular contexts. Recently, however,
      cell- and organism-based phenotypic assays have increasingly been adopted as a
      primary screening platform for annotating small molecules.

PMID- 15183334
TI  - Applications of high-throughput ADME in drug discovery.
AB  - Assessment of physicochemical and pharmacological properties is now conducted at
      very early stages of drug discovery for the purpose of accelerating the
      conversion of hits and leads into qualified development candidates. In
      particular, in vitro absorption, distribution, metabolism and elimination (ADME)
      assays and in vivo drug metabolism pharmacokinetic (DMPK) studies are being
      conducted throughout the discovery process, from hit generation through to lead
      optimization, with the goal of reducing the attrition rate of these potential
      drug candidates as they progress through development. Because the continuing
      trend in drug discovery has been to access ADME information earlier and earlier
      in the discovery process, the need has arisen within the analytical community to
      introduce faster and better analytical methods to enhance the 'developability' of
      drug leads. Strategies for streamlined ADME assessment of drug candidates in
      discovery and pre-clinical development are presented within.

PMID- 15183335
TI  - Special Issue on HIV.

PMID- 15183336
TI  - HIV/AIDS after twenty-five years.

PMID- 15183337
TI  - The chaperoning and assistance roles of the HIV-1 nucleocapsid protein in
      proviral DNA synthesis and maintenance.
AB  - In the following three sections, we will briefly review the seminal roles of the
      HIV-1 nucleocapsid protein p7 (NCp7) in the fate of the HIV-1 full length RNA
      from genomic RNA in a dimeric form to the proviral DNA. Emphasis will be given to
      the mechanisms of NC-directed assistance to the genomic RNA and reverse
      transcriptase (RT) in the course of proviral DNA synthesis and to DNA integrity
      at the end of the polymerization process, and to the NC-assisted repair and
      recombination reactions fueling the viability and variability of the virus.

PMID- 15183338
TI  - Primer unblocking by HIV-1 reverse transcriptase and resistance to nucleoside RT
      inhibitors (NRTIs).
AB  - During zidovudine and stavudine treatment, HIV-1 selects several mutations
      (thymidine-associated mutations, TAMs) in the reverse transcriptase gene that
      confer high- and moderate-levels of resistance, respectively, to these nucleoside
      reverse transcriptase inhibitors (NRTIs). The mechanism of the resistance
      provided by these mutations has long remained elusive. However, recent data
      showed that ATP-phosphorolysis, a reaction analogous to pyrophosphorolysis (the
      reverse of the nucleotide incorporation reaction) in which ATP is the
      pyrophosphate donor, is central to this mechanism by allowing repair of the chain
      terminated primer. A detailed structural and mechanistic model accounting for the
      specificity of the ATP-phosphorolysis and its inhibition by the next
      complementary nucleotide is now available. In the context of multiresistant
      viruses, the TAMs are also associated with resistance to abacavir, and to a
      lesser extent to didanisone, zalcitabine and tenofovir. When associated with the
      TAMs, a dipeptide insertion in the fingers of reverse transcriptase increases the
      ATP-phosphorolysis of most chain terminators, stressing the increasing importance
      of this mechanism. However, some non-nucleoside reverse transcriptase inhibitors
      (NNRTIs) inhibit this process. In addition, point mutations conferring resistance
      to NNRTIs (Y181C and L100I) or NRTIs (K65R, L74V, and M184V) partially
      resensitize the resistant viruses to AZT by inhibiting ATP-phosphorolysis. These
      findings allow rationalizing the beneficial effects of some drug combinations and
      should contribute to improve drug cocktails. The development of NRTIs that would
      not allow the ATP-mediated excision to take place should prove beneficial for
      future treatments, even though high-level resistance to multiple NRTIs can
      ultimately develop in the absence of any significant primer unblocking.

PMID- 15183339
TI  - Designing anti-AIDS drugs targeting the major mechanism of HIV-1 RT resistance to
      nucleoside analog drugs.
AB  - HIV reverse transcriptase (RT) is the target of a number of important anti-AIDS
      drugs. Drugs that inhibit RT are either nucleoside reverse transcriptase
      inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs).
      Combinations of various anti-AIDS drugs (highly active anti-retroviral therapies
      or HAART) can reduce the viral load to non-detectable levels. However, the
      development of drug resistance leads to the emergence of HIV strains that are
      resistant to multiple anti-AIDS drugs. The nucleotide analogs that are used as
      anti-HIV-1 drugs lack the normal 3'-OH and as a consequence act as chain
      terminators when incorporated into DNA. One mechanism of nucleoside analog
      resistance involves ATP-based excision to unblock chain-terminated primers and
      allow HIV replication to continue. There is an urgent need for new drugs and for
      new therapies that can overcome the excision mechanism of resistance. Compounds
      that disrupt the binding of the excision reaction substrate(s) (the blocked
      primer and/or ATP and/or pyrophosphate), or mimic the dinucleoside tetraphosphate
      product of the ATP-based excision reaction are potential inhibitors of excision.
      Detailed understanding of drug resistance mechanisms can reveal novel targets for
      anti-viral agents.

PMID- 15183340
TI  - Nucleoside-analog resistance mutations in HIV-1 reverse transcriptase and their
      influence on polymerase fidelity and viral mutation rates.
AB  - Nucleoside-analog inhibitors of human immunodeficiency virus type 1 (HIV-1)
      reverse transcriptase (RT) were the first drugs used against the virus. It is
      long known that monotherapy with these and other drugs leads to the rapid
      development of viral resistance and it is being increasingly appreciated that a
      significant percentage of individuals receiving highly active antiretroviral
      therapy (HAART) also develop resistance. Considering the fact that RT is
      responsible both for optimal rate of replication and an accurate copying of the
      viral genome, the consequence of drug-resistance mutations in RT to the
      biochemistry of this enzyme and to the biology of the virus are critically
      important. The biochemistry of HIV-1 reverse transcriptase variants harboring
      nucleoside-analog resistance mutations has been studied extensively. In this
      review, we describe a number of studies into the polymerase fidelity of
      nucleoside-analog resistant HIV-1 reverse transcriptase as well as the mutation
      rate of HIV-1 harboring these mutations.

PMID- 15183342
TI  - 'Binding, bending and bonding': polypurine tract-primed initiation of plus-strand
      DNA synthesis in human immunodeficiency virus.
AB  - During the course of reverse transcription, human immunodeficiency virus type 1
      reverse transcriptase (HIV-1 RT) initiates plus-strand DNA synthesis from two
      highly conserved, purine-rich RNA segments of the viral genome referred to as the
      3' and central polypurine tracts (3' and cPPTs). Processing of these elements
      occurs in several sequential steps including (1) minus-strand DNA synthesis over
      the PPT(s), (2) ribonuclease H (RNase H) mediated cleavage at the PPT 3'
      terminus, (3) plus-strand DNA synthesis from the nascent RNA primer(s), and (4)
      primer removal. Completing each of these steps precisely and specifically is
      essential, as failure to do so can result in reduced virus replication and/or
      impaired integration of viral DNA into the host cell genome. In this review, plus
      strand primer processing in HIV-1 is discussed from biochemical, structural, and
      historical perspectives. A comparative analysis of PPT-processing in different
      LTR-containing retroelements is also presented.

PMID- 15183341
TI  - Structural and biochemical effects of human immunodeficiency virus mutants
      resistant to non-nucleoside reverse transcriptase inhibitors.
AB  - Non-nucleoside reverse transcriptase inhibitors are potent, highly specific,
      noncompetitive inhibitors of the Human immunodeficiency virus type 1 (HIV-1)
      reverse transcriptase. They are used commonly as part of potent antiretroviral
      regimens for the treatment of HIV-1 infection, either in combination with
      nucleoside analogs, protease inhibitors, or both. A major limitation to the
      success of non-nucleoside inhibitors is the rapid emergence of HIV-1 variants
      resistant to these drugs. These drug-resistant variants contain one or more
      mutations in the non-nucleoside inhibitor binding pocket of reverse
      transcriptase. This review summarizes the effects that these mutations have on
      non-nucleoside inhibitor binding, reverse transcriptase structure, HIV-1
      replication, and the ability of reverse transcriptase to catalyze DNA
      polymerization and RNase H cleavage. In addition, studies are summarized
      evaluating important interactions between mutations conferring resistance to non
      nucleoside inhibitors and those conferring resistance to nucleoside analogs. The
      studies summarized in this review provide important insights into potentially
      useful approaches to minimize the development of HIV-1 resistant to non
      nucleoside inhibitors.

PMID- 15183343
TI  - HIV-1 infection and regulation of Tat function in macrophages.
AB  - The macrophage is an important cell type in the pathophysiology of human
      immunodeficiency virus type 1 (HIV-1) infection. Macrophages both support viral
      replication and are capable of attracting and activating lymphocytes, thus
      rendering CD4+ T lymphocytes highly permissive for infection. The viral Tat
      protein, whose function is mediated by the cellular cyclin T1 protein complexed
      with CDK9, is required for efficient transcription of the integrated HIV-1
      provirus by RNA polymerase II. Cyclin T1 expression is highly regulated during
      macrophage differentiation, and this has important implications for HIV-1
      replication. In monocytes isolated from healthy blood donors, cyclin T1 protein
      expression is low and is induced to high levels within the first few days of
      differentiation by a post-transcriptional mechanism. After 1-2 weeks of
      macrophage differentiation, however, cyclin T1 expression is shut off. Treatment
      of macrophages with lipopolysaccharide (LPS) can re-induce cyclin T1, indicating
      that the activation status of macrophages can regulate cyclin T1 expression.
      Recent results indicate that HIV-1 infection is able to induce cyclin T1
      expression in macrophages. Future studies of cyclin T1 regulation in macrophages
      may suggest means of manipulating expression of this crucial cellular co-factor
      for therapeutic benefit in HIV-1 infected individuals.

PMID- 15183344
TI  - The tRNALys packaging complex in HIV-1.
AB  - The major human tRNALys isoacceptors, tRNALys1,2 and tRNALys3, are selectively
      packaged into HIV-1 during assembly, where tRNALys3 acts as the primer for
      initiating reverse transcription. In this report, we shall review the evidence
      that supports a model for the formation of a tRNALys packaging complex, whose
      components include the precursor proteins Gag and Gag-Pol, viral genomic RNA,
      tRNALys, and lysyl-tRNA synthetase (LysRS). In the model proposed, the tRNALys
      packaging complex is formed when a Gag/Gag-Pol/viral RNA complex interacts with a
      tRNALys/LysRS complex, with Gag interacting with LysRS, and Gag-Pol interacting
      with tRNALys. The incorporation of Gag-Pol into HIV-1 requires its interaction
      with Gag multimers whose polymerization is promoted by RNA. Reverse transcriptase
      sequences within Gag-Pol also bind to tRNALys, and this binding is required for
      tRNALys packaging into viruses. LysRS, the enzyme that aminoacylates tRNALys, is
      also incorporated into HIV-1, and this protein is a strong candidate for being
      the signal that specifically targets tRNALys for viral incorporation. Newly
      synthesized LysRS is a main source of viral LysRS, and its incorporation into
      viruses occurs via its interaction with Gag and independently of tRNALys
      packaging. While tRNALys incorporation into viruses depends upon its interaction
      with LysRS, tRNALys aminoacylation is not a requirement for viral packaging.

PMID- 15183345
TI  - Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors
      with adaptability to mutations and high selectivity towards unwanted targets.
AB  - Protease inhibitors are key components in the chemotherapy of HIV-1 infection.
      However, the long term efficacy of antiretroviral therapies is hampered by issues
      of patient compliance often associated with the presence of severe side effects,
      and above all by the appearance of drug resistance. The development of new
      protease inhibitors with high potency, low susceptibility to mutations and
      minimal affinity for unwanted targets is an urgent goal. The engineering of these
      adaptive inhibitors requires identification of the critical determinants of
      affinity, adaptability, and selectivity. Analysis of the binding database for
      existing clinical and experimental inhibitors has allowed us to address the
      following questions in a quantitative fashion: (1) Is there an optimal binding
      affinity? Or, are the highest affinity inhibitors necessarily the best
      inhibitors? (2) What is the dependence of optimal affinity on adaptability and
      selectivity? (3) What are the determinants of adaptability to mutations
      associated with drug resistance? (4) How selectivity against unwanted targets can
      be improved? It is shown that the optimal affinity is a function of the effective
      target concentration and the desired adaptability and selectivity factors.
      Furthermore, knowledge of the enthalpic and entropic contributions to the binding
      affinity to the wild type provides a way of anticipating the response of an
      inhibitor to mutations associated with drug resistance, and therefore, a valuable
      guideline for optimization.

PMID- 15183346
TI  - HIV-chemotherapy and -prophylaxis: new drugs, leads and approaches.
AB  - In recent years, significant progress has been made towards the chemotherapy (and
      prophylaxis) of HIV infections. This progress is situated at three different
      levels. (i) New anti-HIV drugs have been approved for clinical use and have
      entered the market: the virus entry inhibitor enfuvirtide (Fuzeon), the
      nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (Emtriva), the
      nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate
      (Viread trade mark ) and the HIV protease inhibitor (PI) atazanavir (Reyataz
      trade mark ). (ii) Other compounds have proceeded through preclinical and/or
      clinical development: CXCR4 antagonists (i.e. AMD070), CCR5 antagonists (i.e. SCH
      C), NRTIs (such as amdoxovir), NNRTIs (such as etravirine), integrase inhibitors
      (such as S-1360) and PIs (such as tipranavir). (iii) Yet other compounds, acting
      by novel mechanisms, have recently been identified as anti-HIV agents that seem
      worthy of further (pre)clinical development: cell receptor CD4 down-modulators
      (i.e. cyclotriazadisulfonamides), viral envelope gp120-binding agents such as
      plant lectins and glycopeptide antibiotics, HIV integrase inhibitors such as the
      pyranodipyrimidine V-165, and two new classes of compounds (i.e. N
      aminoimidazoles and pyridine oxide derivatives) which seem to interfere with a
      post-integration, transcription transactivation event. Taken together, it is
      obvious that the approaches for the treatment of HIV infections in recent years
      have become both more diverse and more efficient.

PMID- 15183347
TI  - Impact of the translocational equilibrium of HIV-1 reverse transcriptase on the
      efficiency of mismatch extensions and the excision of mispaired nucleotides.
AB  - The reverse transcriptase of the human immunodeficiency virus type 1 (HIV-1 RT)
      does not possess an exonucleolytic proofreading activity; however, previous
      studies have shown that this enzyme can excise incorporated chain-terminators in
      the presence of pyrophosphate or ATP. This type of reaction provides a plausible
      mechanism for HIV-1 resistance to several nucleoside analogue inhibitors. Here we
      studied the efficiency of pyrophosphorolysis in the context of mismatched
      nucleotides, and found that the removal of dCMP and dTMP opposite T is literally
      blocked. Thus, pyrophosphorolysis may not provide an alternative, universal
      proofreading mechanism, although excision of dGMP and the correct dAMP opposite T
      can occur with considerable efficiency. Site-specific footprinting experiments
      revealed that the 3' end of C:T- and T:T-mispaired primer strands is
      predominantly found in a post-translocational configuration, which prevents the
      removal of terminal nucleotides. In contrast, complexes containing G:T and A:T
      base pairs can exist in both post- and pre-translocational stages. Excision can
      only occur in the latter, which helps to explain the observed selectivity of the
      reaction. The efficiency of mismatch extensions does not appear to depend on pre
      existing changes of the translocational equilibrium. However, footprints of
      complexes containing 3' penultimate mismatches suggest that the incorporation of
      the first nucleotide following the mispair can force the enzyme to slide
      backwards, which can inhibit ensuing polymerization events. The fact that
      misincorporated nucleotides can affect the precise positioning of RT provides a
      rational for the development of novel nucleoside analogue inhibitors that contain
      modifications in the base moiety.

PMID- 15183348
TI  - Proteolytic processing of an HIV-1 pol polyprotein precursor: insights into the
      mechanism of reverse transcriptase p66/p51 heterodimer formation.
AB  - HIV-1 reverse transcriptase (RT) is a heterodimer comprising a 66 kDa subunit
      (p66) and a p66-derived 51 kDa subunit (p51). RT is translated as part of a
      larger gag-pol polyprotein and subsequently processed to the p66/p51 heterodimer
      by HIV-1 protease (PR) during viral maturation. The processing events involved in
      the formation of the RT p66 and p51 subunits and the pathway(s) of RT dimer
      formation are poorly characterized. Attempts to study the kinetics of PR
      catalyzed formation of p66/p51 HIV-1 RT in isolated HIV virions produced in the
      presence of HIV PR inhibitors were unsuccessful due to difficulties in removal of
      the tight-binding inhibitor to initiate proteolytic processing. Accordingly, an
      inducible bacterial expression vector encoding a 90 kDa pol polyprotein fragment
      was constructed. Following expression in Escherichia coli, the pol polyprotein
      underwent time-dependent proteolytic processing to the RT p66/p51 heterodimer.
      This processing was catalyzed entirely by HIV-1 PR since mutations that
      inactivate PR prevented RT heterodimer formation. The kinetics of RT processing
      follow an ordered sequential pathway in which RT p66 is first excised from the
      pol polyprotein, followed by formation of the p51 subunit. Processing of the p66
      subunit to form p51 apparently proceeds through a p66/p66 RT homodimer
      intermediate since the L234A mutation in RT, a mutation that prevents RT
      dimerization, resulted in the formation of RT p66 only. These results provide the
      first experimental data defining the pathway for the HIV-1 PR catalyzed formation
      of the p66/p51 HIV-1 RT heterodimer.

PMID- 15183349
TI  - Obligatory involvement of CD26/dipeptidyl peptidase IV in the activation of the
      antiretroviral tripeptide glycylprolylglycinamide (GPG-NH(2)).
AB  - GPG-NH2 and G-NH2 are highly selective antiretroviral agents in cell culture, and
      both compounds inhibit HIV replication in CEM cell cultures to an equal extent
      (50% effective concentration: approximately 30 microM). The lymphocyte surface
      glycoprotein marker CD26, which is identical to dipeptidyl peptidase IV,
      efficiently converted GPG-NH2 to G-NH2 releasing the dipeptide GP-OH. The closely
      related QPG-NH2 derivative was also inhibitory to HIV, presumably by the
      dipeptidyl peptidase IV (DPP IV)-catalyzed release of G-NH2. In contrast, the
      cyclic pQPG-NH2 derivative in which the glutamine at the amino terminal position
      of QPG-NH2 was replaced by pyroglutamine and which is resistant to cleavage by
      purified CD26, was devoid of antiviral activity. CD26 is abundantly expressed on
      a variety of HIV target cells and is also present in serum of bovine, murine and
      human origin. The CD26/DPP IV enzymatic activity in serum and in cell suspensions
      could be efficiently inhibited by the CD26/DPP IV inhibitor L
      isoleucinepyrrolidine (IlePyr) with 50% inhibitory concentrations ranging between
      20 and 100 microM. When combined in HIV-1-infected cell cultures, IlePyr and
      Diprotin A (DP-A), another CD26/DPP IV inhibitor, abrogated the antiviral
      activity of GPG-NH2 but not of G-NH2. Therefore, it was concluded that the anti
      HIV drug GPG-NH2 is not active as such, but rather behaves as a prodrug that must
      be obligatorily cleaved by CD26/DPP IV to G-NH2 to exert its antiretroviral
      activity. This is the first demonstration of a lymphocyte
      activation/differentiation marker (i.e. CD26) that plays a direct regulatory and
      indispensable role in the eventual antiretroviral activity of small synthetic
      molecules such as the antiretroviral (pro)drug GPG-NH2.

PMID- 15183350
TI  - Sensitivity enhancement in pulse EPR distance measurements.
AB  - Established pulse EPR approaches to the measurement of small dipole-dipole
      couplings between electron spins rely on constant-time echo experiments to
      separate relaxational contributions from dipolar time evolution. This requires a
      compromise between sensitivity and resolution to be made prior to the
      measurement, so that optimum data are only obtained if the magnitude of the
      dipole-dipole coupling is known beforehand to a good approximation. Moreover, the
      whole dipolar evolution function is measured with relatively low sensitivity.
      These problems are overcome by a variable-time experiment that achieves
      suppression of the relaxation contribution by reference deconvolution.
      Theoretical and experimental results show that this approach leads to significant
      sensitivity improvements for typical systems and experimental conditions. Further
      sensitivity improvements or, equivalently, an extension of the accessible
      distance range can be obtained by matrix deuteration or digital long-pass
      filtering of the time-domain data. Advantages and limitations of the new variable
      time experiment are discussed by comparing it to the established analogous
      constant-time experiment for measurements of end-to-end distances of 5 and 7.5 nm
      on rod-like shape-persistent biradicals and for the measurement of a broadly
      distributed transmembrane distance in a doubly spin-labeled mutant of plant light
      harvesting complex II.

PMID- 15183351
TI  - High-resolution NMR of static samples by rotation of the magnetic field.
AB  - Mechanical rotation of a sample at 54.7 degrees with respect to the static
      magnetic field, so-called magic-angle spinning (MAS), is currently a routine
      procedure in nuclear magnetic resonance (NMR). The technique enhances the
      spectral resolution by averaging away anisotropic spin interactions thereby
      producing isotropic-like spectra with resolved chemical shifts and scalar
      couplings. It should be possible to induce similar effects in a static sample if
      the direction of the magnetic field is varied, e.g., magic-angle rotation of the
      B0 field (B0-MAS). Here, this principle is experimentally demonstrated in a
      static sample of solid hyperpolarized xenon at approximately 3.4 mT. By extension
      to moderately high fields, it is possible to foresee interesting applications in
      situations where physical manipulation of the sample is inconvenient or
      impossible. Such situations are expected to arise in many cases from materials to
      biomedicine and are particularly relevant to the novel approach of ex situ NMR
      spectroscopy and imaging.

PMID- 15183352
TI  - Enhanced sensitivity to residual dipolar couplings of elastomers by higher-order
      multiple-quantum NMR.
AB  - The homonuclear and heteronuclear residual dipolar couplings in elastomers
      reflect changes in the cross-link density, temperature, the uniaxial and biaxial
      extension or compression as well as the presence of penetrant molecules. It is
      shown theoretically that for an isolated methyl group the relative changes in the
      intensity of the homonuclear double-quantum buildup curves in the initial time
      regime due to variation of the residual dipolar coupling strength is less
      sensitive than the changes in the triple-quantum filtered NMR signal when
      considering the same excitation/reconversion time. For a quadrupolar nucleus with
      spin I=2 the sensitivity enhancement was simulated for four-quantum, triple
      quantum, and double-quantum buildup curves. In this case the four-quantum build
      up curve shows the highest sensitivity to changes of spin couplings. This
      enhanced sensitivity to the residual dipolar couplings was tested experimentally
      by measuring 1H double-quantum, triple-quantum, and four-quantum buildup curves
      of differently cross-linked natural rubber samples. In the initial
      excitation/reconversion time regime, where the residual dipolar couplings can be
      measured model free, the relative changes in the intensity of the four-quantum
      buildup curves are about five times higher than those of the double-quantum
      coherences. For the first time proton four-quantum coherences were recorded for
      cross-linked elastomers.

PMID- 15183353
TI  - Lineshapes of spin exchange broadened EPR spectra.
AB  - An unexplained residual in the fits of theoretical and experimental spectra of
      exchange broadened nitroxide spin probes reported by Robinson et al. [J. Magn.
      Reson. 138 (1999) 199] is shown to be understood by inclusion of theoretically
      predicted lineshape changes into the fitting routine. These lineshape changes
      provide an additional estimate of the spin exchange frequency that is independent
      of linewidth methods.

PMID- 15183354
TI  - The effect of rotational angle and experimental parameters on the diffraction
      patterns and micro-structural information obtained from q-space diffusion NMR:
      implication for diffusion in white matter fibers.
AB  - Diffusion NMR may provide, under certain experimental conditions, micro
      structural information about confined compartments totally non-invasively. The
      influence of the rotational angle, the pulse gradient length and the diffusion
      time on the diffusion diffraction patterns and q-space displacement distribution
      profiles was evaluated for ensembles of long cylinders having a diameter of 9 and
      20 microm. It was found that the diffraction patterns are sensitive to the
      rotational angle (alpha) and are observed only when diffusion is measured nearly
      perpendicular to the long axis of the cylinders i.e., when alpha= 90 degrees +/-
      5 degrees under our experimental conditions. More importantly, we also found that
      the structural information extracted from the displacement distribution profiles
      and from the diffraction patterns are very similar and in good agreement with the
      experimental values for cylinders of 20 microm or even 9 microm, when data is
      acquired with parameters that satisfy the short gradient pulse (SGP)
      approximation (i.e., delta -->0) and the long diffusion time limit. Since these
      experimental conditions are hardly met in in vitro diffusion MRI of excised
      organs, and cannot be met in clinical MRI scanners, we evaluated the effect of
      the pulse gradient duration and the diffusion time on the structural information
      extracted from q-space diffusion MR experiments. Indeed it was found that, as
      expected, accurate structural information, and diffraction patterns are observed
      when Delta is large enough so that the spins reach the cylinders' boundaries. In
      addition, it was found that large delta results in extraction of a compartment
      size, which is smaller than the real one. The relevance of these results to q
      space MRI of neuronal tissues and fiber tracking is discussed.

PMID- 15183355
TI  - Improvement of homonuclear dipolar decoupling sequences in solid-state nuclear
      magnetic resonance utilising radiofrequency imperfections.
AB  - The often annoying imperfections in the phases and pulses of typical
      radiofrequency multiple-pulse irradiation schemes for homonuclear dipolar
      decoupling are revisited and analysed here. The analysis is with respect to one
      such multiple-pulse sequence, namely, the windowed phase-modulated Lee-Goldburg
      sequence. The error terms in the Hamiltonian due to pulse imperfections may lead
      to effective rotation of the spins around the z-axis giving rise to image free
      and high-resolution 1H spectra. Certain precautions to be taken with regard to
      scale factor estimation are also detailed. The analysis also points out the range
      of off-set values where the best homonuclear dipolar decoupling performance of a
      particular pulse scheme may be obtained.

PMID- 15183356
TI  - Determining the relative sign and size of scalar and residual dipolar couplings
      in homonuclear two-spin systems.
AB  - Based on the sign and amplitude of TOCSY transfer functions, it is possible to
      determine the relative sign and size of scalar and residual dipolar couplings in
      homonuclear spin systems consisting of two spins 1/2. The efficiency of different
      mixing sequences and different transfer functions is examined both theoretically
      and experimentally.

PMID- 15183357
TI  - Combined relaxation and displacement experiment: a fast method to acquire T2,
      diffusion and velocity maps.
AB  - A fast method for quantitative imaging of T2 and displacement (flow and
      diffusion) is presented. The pulse sequence combines multi-PGSE NMR with multi
      echo acquisition and compensates for flow effects in the read gradient and
      diffusion during multi-echo trains. The impact of the gradient pulses in a multi
      echo train on the signal phase and amplitude is discussed. It is shown that
      separate T2 and displacement images with microscopic resolution can be obtained
      within minutes. The capability for 3D flow imaging is demonstrated. The sequence
      is then used to investigate forced detachment of a biofilm in a tube.

PMID- 15183358
TI  - Product operator descriptions of INEPT and RINEPT NMR spectroscopies for ISn
      (I=1/2, S=3/2) spin systems.
AB  - The product operator descriptions of INEPT and reverse INEPT (RINEPT) NMR
      experiments are introduced for weakly coupled ISn (I=1/2, S=3/2 with n=1,2,3)
      spin systems. Explicit expressions for polarization transfer from spin-3/2
      quadrupolar nuclei to spin-1/2 nuclei (and reversed polarization transfer) are
      given in detail by using the evolutions of product operators under the spin-spin
      coupling Hamiltonian. The results calculated for the intensities and positions of
      the observable signals are simulated in the molecules containing the 119Sn
      (I=1/2) and 35Cl (S=3/2) nuclei at the coupling constant of J(Sn-Cl)=375 Hz by
      using the Maple programme on computer.

PMID- 15183360
TI  - NMR diffusometry and the short gradient pulse limit approximation.
AB  - In NMR diffusometry, one often uses the short gradient pulse (SGP) limit
      approximation in the interpretation of data from systems with restricted
      diffusion. The SGP limit approximation means that the gradient pulse length,
      delta, is so short that the spins do not diffuse during the pulse duration, but
      this condition is rarely met. If the length scale of the pores corresponds to the
      molecular mean square displacement during the gradient pulse, the measured echo
      intensities become a function of the gradient pulse length. Here, we have studied
      highly concentrated emulsions to show how the length of the gradient pulse
      influences NMR diffusion experiments. We have focused on molecules confined to
      one pore and molecules that can migrate through the porous system. For the former
      the echo decays give smaller pores than the actual case and for the latter we
      show large changes in echo decay depending on the gradient pulse length,
      everything else being equal.

PMID- 15183359
TI  - A new adaptive subband decomposition approach for automatic analysis of NMR data.
AB  - This paper presents a non-iterative, fast, and almost automated time-data
      analysis method for NMR spectroscopy, based on a new adaptive implementation of
      high resolution methods used in spectral subbands. It is intended to avoid the
      choice of the decimation factor (or the width of the spectral windows) which, in
      the case of a uniform decomposition, strongly conditions the estimation results,
      and to diminish the computational burden. It is achieved through successive
      decimation/estimation stages each followed by a test procedure in order to decide
      whether or not the process should continue. The proposed test is based on a local
      spectral flatness measure of the estimation residuals. This stop-criterion
      involves an a posteriori validation of the estimation, thus the method proposed
      allows one to obtain a better detection rate at a lower complexity comparatively
      to other stopping rules, while preserving a reasonable estimation variance.
      Moreover, the reliability of the fitting algorithms considered is improved, by
      decreasing the influence of the model order and the number of false detections.
      Finally, the method is more efficient than Fourier transform (FT) at low signal
      to-noise ratio (SNR). The effectiveness of the method is demonstrated by
      analyzing a simulation signal and raw carbon-13 experimental data.

PMID- 15183361
TI  - Convection-compensating PGSE experiment incorporating excitation-sculpting water
      suppression (CONVEX).
AB  - We present a new diffusion experiment which provides simultaneous suppression of
      an on-resonance solvent peak and compensation for convection. The experiment,
      which we name CONVEX, exploits similarities between two functionally different
      pulse sequences to enable the same sequence to be used simultaneously for two
      different purposes. The CONVEX pulse sequence combines a double-echo PGSE with
      double excitation-sculpting water suppression, using unequal gradient pulse-pair
      amplitudes (g1 and g2) and unequal diffusion intervals (Delta1 and Delta2).
      Convection compensation is achieved by setting g1:g2 = Delta2:Delta1. The new
      experiment provides the spectral quality, flat baseline, and water-suppression
      power characteristic of excitation-sculpting experiments, combined with excellent
      compensation for convection. The resulting Stejskal-Tanner plots are linear over
      a greater range of signal attenuation than in the absence of water suppression.
      Possible applications include protein NMR; NMR of cellular or colloidal systems;
      and the monitoring of technological processes.

PMID- 15183362
TI  - Centric scan SPRITE magnetic resonance imaging: optimization of SNR, resolution,
      and relaxation time mapping.
AB  - Two strategies for the optimization of centric scan SPRITE (single point ramped
      imaging with T1 enhancement) magnetic resonance imaging techniques are presented.
      Point spread functions (PSF) for the centric scan SPRITE methodologies are
      numerically simulated, and the blurring manifested in a centric scan SPRITE image
      through PSF convolution is characterized. Optimal choices of imaging parameters
      and k-space sampling scheme are predicted to obtain maximum signal-to-noise ratio
      (SNR) while maintaining acceptable image resolution. The point spread function
      simulation predictions are verified experimentally. The acquisition of multiple
      FID points following each RF excitation is described and the use of the Chirp z
      Transform algorithm for the scaling of field of view (FOV) of the reconstructed
      images is illustrated. Effective recombination of the rescaled images for SNR
      improvement and T*2 mapping is demonstrated.

PMID- 15183363
TI  - Methods and limitations of NMR data inversion for fluid typing.
AB  - We introduce two NMR inversion methods within the framework of 1D NMR to extract
      fluid saturations by varying echo spacing and wait time. The first method
      connects the T2 distribution of each fluid with the overall apparent T2
      distribution using a shift matrix. Each fluid's saturation and T2 distribution
      are extracted by minimizing the difference between the model T2 distributions and
      measured apparent T2 distributions. The second method relates a model T2
      distribution of each fluid with CPMG echo trains using a global evolution matrix
      that governs the evolution of magnetization under T1, T2 relaxation, and
      diffusion. These methods will be useful whenever data are not sufficient for 2D
      NMR inversion. They are also much faster than 2D for fluid typing. We also point
      out an inherent limitation associated with NMR inversion methods for fluid
      typing. Whenever there is singularity in the inversion matrix caused by similar
      behavior of model function for different fluids, most inversion algorithms remove
      the solution space associated with the singularity and choose a solution vector
      of the minimum length. This results in equal proportions of different fluids in
      the final answer. If prior knowledge such as saturation or T2 shape of the oil is
      available, there are several methods to tailor the solution to our desired
      outcome. However, if there is no prior knowledge available, such ambiguity always
      exists irregardless of the inversion schemes.

PMID- 15183365
TI  - Microsecond time-scale dynamics from relaxation in the rotating frame:
      experiments using spin lock with alternating phase.
AB  - A spin lock comprised of radiofrequency pulses with alternating phase, (x) (
      x)(x) (-x) , is proposed as a new technique to probe microsecond time-scale
      dynamics. A series of R1rho measurements using different pulse duration tp allows
      one to determine exchange rate, kex, the product p(a)p(b)(Delta omega(ab))2
      involving populations of the exchanging species, p(a) and p(b), together with
      chemical shift difference, (Delta omega(ab)), and the strength of the spin-lock
      field, B1. The interpretation is based on simple analytical expression for R1rho
      derived on the basis of Redfield theory. The application of the method is
      demonstrated for partially deuterated molecule of cyclohexane undergoing chair-to
      chair interconversion at -9 degrees C.

PMID- 15183364
TI  - Comparing continuous wave progressive saturation EPR and time domain saturation
      recovery EPR over the entire motional range of nitroxide spin labels.
AB  - The measurement of spin-lattice relaxation rates from spin labels, such as
      nitroxides, in the presence and absence of spin relaxants provides information
      that is useful for determining biomolecular properties such as nucleic acid
      dynamics and the interaction of proteins with membranes. We compare X-band
      continuous wave (CW) and pulsed or time domain (TD) EPR methods for obtaining
      spin-lattice relaxation rates of spin labels across the entire range of
      rotational motion to which relaxation rates are sensitive. Model nitroxides and
      spin-labeled biological species are used to illustrate the potential
      complications that arise in extracting relaxation data under conditions typical
      to biological experiments. The effect of super hyperfine (SHF) structure is
      investigated for both CW and TD spectra. First and second harmonic absorption and
      dispersion CW spectra of the nitroxide spin label, TEMPOL, are all fit
      simultaneously to a model of SHF structure over a range of microwave amplitudes.
      The CW spectra are novel because all harmonics and microwave phases were acquired
      simultaneously using our homebuilt CW/TD spectrometer. The effect of the SHF
      structure on the pulsed free induction decay (FID) and pulsed saturation recovery
      spectrum is shown for both protonated and deuterated TEMPOL. We present novel
      pulsed saturation recovery measurements on biological molecules, including spin
      lattice relaxation rates of spin-labeled proteins and spin-labeled double
      stranded DNA. The impact of structure and dynamics on relaxation rates are
      discussed in the context of each of these examples. Collisional relaxation rates
      with oxygen and transition metal paramagnetic relaxants are extracted using both
      continuous wave and time domain methods. The extent of the errors inherent in the
      CW method and the advantages of pulsed methods for unambiguously measuring
      collisional relaxation rates are discussed. Spin-lattice relaxation rates,
      determined by both CW and pulsed methods, are used to determine the electrostatic
      potential on the surface of a protein.

PMID- 15183366
TI  - Thin film MRI-high resolution depth imaging with a local surface coil and spin
      echo SPI.
AB  - A multiple echo, single point imaging technique, employing a local surface coil
      probe, is presented for examination of thin film samples. Depth images with a
      nominal resolution of 5 microm were acquired with acquisition times on the order
      of 10 min. The method may be used to observe dynamic phenomenon such as
      polymerization, wetting, and drying in thin film samples. It is readily adapted
      to spatially resolved diffusion coefficient and T2 relaxation time mapping.

PMID- 15183367
TI  - Children and adolescents as sexual beings: a historical overview.
AB  - This article provides a historical overview of attitudes toward the sexual and
      erotic behavior of children and adolescents. It includes an examination of the
      conflicting attitudes of historians toward childhood and the living conditions
      and attitudes that influenced childhood sexual development. Attitudes have varied
      from an emphasis on childhood innocence to fears of childhood sinfulness, from
      children being regarded as asexual creatures to being extremely sexual, and from
      being little adults to regarding childhood as unique and different. Although
      there have always been observers of childhood sexuality, and much adult interest
      in it, research into the topic mainly is a twentieth century development. Sigmund
      Freud was a pioneer in recognizing children as sexual beings; however, research
      since his time has challenged and modified his assumptions. Whatever their
      discipline, however, there is general agreement that sexuality is part of
      childhood development.

PMID- 15183368
TI  - Children and adolescents as sexual beings: cross-cultural perspectives.
AB  - This article offers a broad perspective on child and adolescent behaviors, which
      are seen by different Western definitions as associated with sexual/erotic
      implications. This article also demonstrates that basic definitions or meanings
      that many modern Western societies consider important are viewed as unimportant
      in other societies. Topics such as masturbation, child-adult sexual activities or
      cross-generational marriages, same-sex activities, and sexual indoctrination are
      viewed differently among many groups.

PMID- 15183369
TI  - Biologic perspective on early erotic development.
AB  - Neurobiologic researchers can understand children's sexuality in less moral and
      more biologic terms. Genetically programmed levels of neurotransmitters and
      hormones establish a baseline trajectory of erotic interest and activity across
      the lifespan. Environmental influences also contribute. Intense early stimulation
      can affect the brain and create a condition of hyper eroticism, whereas too
      little stimulation can limit the ability to bond and impair the sexual response.
      Children who are erotically challenged or challenging are viewed correctly as
      having a brain imbalance, rather than as victims or as being morally deficient.
      This should pave the way for more humane, objective, and effective interventions.

PMID- 15183370
TI  - Typical adolescent sexual development.
AB  - This article addresses the typical components that contribute to the development
      of adolescent sexuality. It defines the important terms that are addressed in the
      article, explains the roots of human sexuality from birth and childhood, and
      details three components of adolescent sexuality: biologic, psychologic, and
      social cultural. The concluding sections on sexual education and sexual risk
      taking further explain key factors in the development of adolescent sexuality.

PMID- 15183371
TI  - Sex differences in childhood anger and aggression.
AB  - There are few differences in the frequency or intensity of men's and women's self
      reported or observed anger. Women are more likely to be angered by relationship
      conflicts than men. Men are more frequently the targets of anger than women.
      Typically, men see the expression of anger as exerting dominance, where as women
      view it as a loss of control. There are also sex differences in the mode of anger
      expression. At ages 8 and older, girls are more likely to engage in "relational"
      aggression (eg, deliberate social ostracism). The most consistent and salient
      difference in anger expression is women's tendency to cry when angry, whereas men
      are more likely to throw things or hit. The difference in physical aggression
      appears in children who are as young as 1 to 2 years of age. Despite an overall
      reduction in physical aggression after 2 to 3 years of age, the sex difference
      remains consistent into adulthood. In contrast to differences in physical
      aggression, differences in anger are few and inconsistent up to 4 or 5 years of
      age. By this age, girls tend to suppress the expression of anger consciously. By
      about 7 to 8 years of age, adult like differences become more consistent, with
      boys expressing more anger.

PMID- 15183372
TI  - Homoerotic development during childhood and adolescence.
AB  - To adequately understand the diversity of child and adolescent homoeroticism, a
      differential developmental trajectories perspective is proposed that integrates
      recent research about the development of sexual orientation, sexual behavior, and
      sexual identity. Only the latter two can be altered therapeutically. Biologic
      theories of homosexuality are reviewed. Homoerotic youth are shown to be similar
      and dissimilar to heterosexual youth; more variability occurs within than among
      sexual orientation groups. Contemporary homoerotic youth recognize their
      sexuality, self-label, and accept their sexuality at earlier ages than previous
      generations and many are rejecting traditional identity labels. Clinical
      recommendations offer ways to assess sexual orientation and help patients to
      achieve acceptance of their sexuality.

PMID- 15183373
TI  - Gender identity development and issues.
AB  - This article focuses on the psychosexual development of children and adolescents
      who have sex-typed behavioral patterns that correspond to the diagnosis of Gender
      Identity Disorder, as defined in the fourth edition of the Diagnostic and
      Statistical Manual of Mental Disorders. The author provides an update on
      phenomenology and diagnosis, associated behavior problems, developmental course,
      biologic and psychosocial influences, and treatment and ethical issues.

PMID- 15183374
TI  - Situating unusual child and adolescent sexual behavior in context.
AB  - There is a lack of scientific knowledge concerning what constitutes normal versus
      unusual sexual behaviors among minors. Clinical judgements in these cases often
      are clouded by unfounded sociocultural assumptions, personal biases, legal
      issues, and moral considerations. Current diagnostic nomenclature that is used
      commonly for adult sexual activities is inappropriately applied to minors.
      Considerations about unusual sexual interests (ie, frequency of sexual behaviors,
      difficulties controlling sexual expression,consent, nonheterosexual interests,
      much older or younger partners, atypical sexual stimuli, number of partners, and
      sexual abuse) are explored to provide perspective for evaluation.

PMID- 15183375
TI  - Sex, gender, and identity over the years: a changing perspective.
AB  - This article attempts to put changing terms, emphases, and views on the
      interrelated, but separate, concepts of sex, gender, and identity into
      perspective. Often, these facets of a person's life are intermingled and
      confused. To understand individuals whose lives are touched by any aspect of
      sexuality that is of interest to the medical community, knowledge of how these
      terms have developed and changed over the years seems of particular value. The
      article also tries to show the relevance of certain concepts in dealing with the
      specific issues of intersex. Here, medical management and ethical thinking about
      dealing with such conditions also have undergone change. It is probable that the
      terms and treatment modalities that are associated with sex- and gender-related
      conditions will continue to evolve as we learn more about them.

PMID- 15183376
TI  - Gender identity in XY intersexuality.
AB  - The following syndromes of XY intersexuality are reviewed: 5alpha-reductase-2
      deficiency, 17beta-hydroxysteroid dehydrogenase-3 deficiency, and complete and
      partial androgen insensitivity with attention focused on issues of gender
      identity. Each syndrome, with its unique presentation, provides an opportunity to
      explore the relative effects of nature (androgens) versus nurture (sex of
      rearing) in gender identity development. The phenomenon of gender role reversal
      in these conditions is described and theories on the determinants of gender
      identity formation are proposed. Issues of importance to psychiatrists in
      treating patients who have these conditions also are discussed.

PMID- 15183377
TI  - Androgen insensitivity syndrome and Klinefelter's syndrome: sex and gender
      considerations.
AB  - Two of the most common intersex conditions, androgen insensitivity and
      Klinefelter's syndrome, are described with an emphasis on aspects that are of
      relevance to psychiatrists. Attention is focused on commonalities and differences
      between these syndromes and particular attention is given to how persons who have
      these conditions manifest sexual and gender adjustments to their situations. Tips
      on counseling and medical management are offered.

PMID- 15183378
TI  - Psychosexual development in individuals who have female pseudohermaphroditism.
AB  - This article describes psychosexual outcomes and issues in syndromes of female
      pseudohermaphroditism, broadly defined. Congenital adrenal hyperplasia, the most
      common cause of intersex genitalia at birth, is covered as are Turner Syndrome
      and syndromes in which XY infants who are born with undervirilized genitalia are
      assigned and reared as girls (androgen insensitivity syndrome; cloacal
      exstrophy). The same hormonal abnormalities that cause most physical intersex
      conditions also influence brain development and behavior; individuals who have
      intersex conditions can show behavior that is in between that of the typical
      boy/man and the typical girl/woman. Changes in sex-typical play behavior in
      childhood are larger than in sexual orientation or core gender identity in
      adulthood. Most female pseudohermaphrodites, whether XX or XY, who are assigned
      and reared as girls evolve a feminine core gender identity and primarily are
      heterosexual. Implications for current debate about the treatment of infants who
      have ambiguous genitalia are discussed, as is the need for additional research
      and for consideration of psychologic counseling as part of the treatment program.

PMID- 15183379
TI  - Psychosexual development in genetic males assigned female: the cloacal exstrophy
      experience.
AB  - Genetic males who have cloacal exstrophy, a rare, severe pelvic field defect that
      leads to aphallia, traditionally have been socially, legally, and surgically sex
      assigned female at birth and reared female, despite a male karyotype and a
      typical male prenatal hormonal milieu. Psychosexual development in such children
      previously has been unknown. Studies of 29 children revealed that despite the
      absence of the typical postnatal and pubertal androgen surges and the presence of
      female genitalia, all female-assigned subjects displayed a marked male-typical
      shift in psychosocial and psychosexual development. Nearly half of them have
      declared themselves male. Psychosexual development, including gender identity, in
      genetic and hormonal male neonates seems to be influenced heavily by prenatal
      androgen exposure. The clinical practice of surgical sex assignment at birth
      requires re-evaluation.

PMID- 15183381
TI  - Gender, sex, and professional ethics in child and adolescent psychiatry.
AB  - Ethics in child and adolescent psychiatry can be understood as a collective
      effort to reconcile three potentially conflicting sets of duties toward the minor
      patient, the parents of the minor patient, and the community. Therapists have a
      primary duty to the medical needs and the emerging autonomy of the minor patient
      and must take into account the anticipated needs of the adult that the child will
      become. Therapists also have a duty to respect the authority of parents in
      medical decision-making and to respect the community's interest in preventing
      harm to children. Conflicts arise when parental demands or refusals are
      inconsistent with ethically weighty interests of the child and when a community
      mandates professional actions that serve families badly. Examples of these are
      examined.

PMID- 15183380
TI  - Legal implications surrounding adolescent health care decision-making in matters
      of sex, reproduction, and gender.
AB  - This article focuses on the thorny and evolving legal issues and implications of
      health care decision-making for children and adolescents in matters of gender,
      sexual identity, sexual conduct, and reproduction. In treating minors, health
      care professionals increasingly experience competing duties and responsibilities
      to their patient, the parents or guardians, and to the state. This article gives
      health care professionals a foundation for understanding the legal concepts of
      adolescent health care decision-making and provides an approach for balancing the
      potential competing interests of these stakeholders while complying with
      professional standards,the law, and their own ethical and moral convictions.

PMID- 15183384
TI  - The cortical organization of audio-visual sentence comprehension: an fMRI study
      at 4 Tesla.
AB  - Neuroimaging studies of written and spoken sentence processing report greater
      left hemisphere than right hemisphere activation. However, a large majority of
      our experience with language is face-to-face interaction, which is much richer in
      information. The current study examines the neural organization of audio-visual
      (AV) sentence processing using functional magnetic resonance imaging (fMRI) at 4
      Tesla. Participants viewed the face and upper body of a speaker via a video
      screen while listening to her produce, in alternating blocks, English sentences
      and sentences composed of pronounceable non-words. Audio-visual sentence
      processing was associated with activation in the left hemisphere in Broca's area,
      dorsolateral prefrontal cortex, the superior precentral sulcus, anterior and
      middle portions of the lateral sulcus, middle superior portions of the temporal
      sulcus, supramarginal gyrus and angular gyrus. Further, AV sentence processing
      elicited activation in the right anterior and middle lateral sulcus. Between
      hemisphere analyses revealed a left hemisphere dominant pattern of activation.
      The findings support the hypothesis that the left hemisphere may be biased to
      process language independently of the modality through which it is perceived.
      These results are discussed in the context of previous neuroimaging results using
      American Sign Language (ASL).

PMID- 15183385
TI  - Cerebral activation related to skills practice in a double serial reaction time
      task: striatal involvement in random-order sequence learning.
AB  - We used functional Magnetic Resonance Imaging (fMRI) to examine the distribution
      of cerebral activation related to prolonged skill practice. In a bimanual variant
      of the Serial Reaction Time Task (SRT), simultaneous finger movements of the two
      hands were made in response to randomly ordered pairs of visual stimuli (Double
      SRT, DoSRT). Extended practice by a week of daily performance resulted in gradual
      decrease of reaction times, associated with an increased involvement of the
      ventral putamen and globus pallidus, reaching statistical significance only on
      the left side (Statistical Parametric Mapping, SPM99). This increase was
      complementary to a decrease of cortical activations. The striatal activation
      after training on random order stimuli indicates that the striatum is not
      exclusively involved in sequence learning. This extended function implies a role
      in the acquisition of basic visuomotor skills that includes the specific
      selection of the appropriate muscles in response to independent stimuli.

PMID- 15183386
TI  - A topography of executive functions and their interactions revealed by functional
      magnetic resonance imaging.
AB  - We used fMRI to study the brain processes involved in the executive control of
      behavior. The Sustained Attention to Response Task (SART), which allows
      unpredictable and predictable NOGO events to be contrasted, was imaged using a
      mixed (block and event-related) fMRI design to examine tonic and phasic processes
      involved in response inhibition, error detection, conflict monitoring and
      sustained attention. A network of regions, including right ventral prefrontal
      cortex (PFC), left dorsolateral PFC (DLPFC) and right inferior parietal cortex,
      was activated for successful unpredictable inhibitions, while rostral anterior
      cingulate was implicated in error processing and the pre-SMA in conflict
      monitoring. Furthermore, the pattern of correlations between left dorsolateral
      PFC, implicated in task-set maintenance, and the pre-SMA were indicative of a
      tight coupling between prefrontally mediated control and conflict levels
      monitored more posteriorly. The results reveal that the executive control of
      behavior can be separated into distinct functions performed by discrete cortical
      regions.

PMID- 15183387
TI  - A ghost of retrieval past: a functional network of alpha EEG related to source
      memory in elderly humans.
AB  - The electrophysiological data from a study of source memory in young and older
      adults were analyzed in the frequency domain in order to find functional networks
      of alpha band activity related to source memory performance and cortical
      reorganization with age. Participants were instructed to remember noun pairs
      embedded in sentences, with sentences grouped into two temporally distinct lists.
      At test, in response to noun probes, participants made old/new, followed by
      source (i.e., list) judgments. Lower band alpha electroencephalography (EEG)
      recorded during recognition and source retrieval epochs was analyzed using
      spatial covariance analysis [Hum. Brain Mapp. 2 (1994) 79; J.R. Moeller, C. Ghez,
      A. Antonini, M.F. Ghilardi, V. Dhawan, K. Kazumata, D. Eidelberg, Brain networks
      of motor behavior assessed by principal component analysis, in: R.E. Carson, M.E.
      Daube-Witherspoon, P. Herscovitch (Eds.), Quantitative Functional Brain Imaging
      with Positron Emission Tomography, Academic, San Diego, 1998]: significant
      activation patterns were found in source retrieval epochs. For young subjects,
      the regional covariance pattern involved coactivation of right anterior and left
      posterior electrode sites. Source retrieval performance was predicted by the
      subject difference in pattern expression between epochs involving correct and
      incorrect source attribution. The older adults also exhibited significant
      coactivation of the right anterior and left posterior electrode sites. However,
      no compensatory activation sites were identified for these elders who performed
      near chance in source retrieval. In this regard, we replicated the main
      functional difference between good and poor performing elders reported in a
      recent O-15 PET study of source retrieval in young and older subjects [Neuroimage
      17 (2002) 1394]. These alpha band and O-15 PET findings complement the age group
      differences found in the time-domain (ERP) analysis of our EEG data [Psychol.
      Aging 14 (1999) 390]. We suggest that spatial covariance analyses of spectral EEG
      and MEG data will reveal new information about functional brain activity relevant
      to normal aging.

PMID- 15183388
TI  - fMRI evidence for the automatic phonological activation of briefly presented
      words.
AB  - Functional magnetic resonance imaging was used to investigate whether people
      generate the phonology of briefly presented words that they do not attend. This
      was done in Chinese by examining the effect of orthography-phonology regularity
      (i.e., how predictable the phonology of a word is from its components rather than
      whole-word form) with high- and low-frequency words, and by using a task that
      diverted participants' attention to a mask, rather than the words. The results
      showed that there was a significant interaction between regularity and word
      frequency in blood oxygen level-dependent (BOLD) signal, which mirrored the
      pattern found in behavioral data. Specifically, for low-frequency characters,
      bilateral fusiform gyri, the posterior superior temporal gyrus, and inferior
      parietal regions were more active when using irregular compared to regular
      characters. There were no significant differences when high-frequency characters
      were used. These results support the possibility that at least for low-frequency
      words, phonology is automatically generated when reading, even when people do not
      attend to the words and even in a language where the orthography-phonology
      mapping is extremely irregular.

PMID- 15183389
TI  - Neural correlates of working memory for sign language.
AB  - Eight, early bilingual, sign language interpreters participated in a PET study,
      which compared working memory for Swedish Sign Language (SSL) with working memory
      for audiovisual Swedish speech. The interaction between language modality and
      memory task was manipulated in a within-subjects design. Overall, the results
      show a previously undocumented, language modality-specific working memory neural
      architecture for SSL, which relies on a network of bilateral temporal, bilateral
      parietal and left premotor activation. In addition, differential activation in
      the right cerebellum was found for the two language modalities. Similarities
      across language modality are found in Broca's area for all tasks and in the
      anterior left inferior frontal lobe for semantic retrieval. The bilateral
      parietal activation pattern for sign language bears similarity to neural activity
      during, e.g., nonverbal visuospatial tasks, and it is argued that this may
      reflect generation of a virtual spatial array. Aspects of the data suggesting an
      age of acquisition effect are also considered. Furthermore, it is discussed why
      the pattern of parietal activation cannot be explained by factors relating to
      perception, production or recoding of signs, or to task difficulty. The results
      are generally compatible with Wilson's [Psychon. Bull. Rev. 8 (2001) 44] account
      of working memory.

PMID- 15183390
TI  - Facts, rules, and strategies in single-digit multiplication: evidence from event
      related brain potentials.
AB  - It has been hypothesized that zero vs. nonzero operands in single-digit
      multiplication problems invoke distinct solution strategies. We studied such
      problems in an implicit production task with event-related brain potentials
      (ERPs) recorded from 61 scalp positions in 18 participants. The topography of a
      slow negative wave, which accompanied the implicit production of the
      multiplication result, varied with problem type. In comparison to small problems,
      larger problems evoked a stronger negativity over fronto-central and right
      temporal sites, and zero problems evoked a left anterior negativity. These
      topographic differences indicate not only that zero and small nonzero problems
      are solved by means of distinct strategies-most likely rule application vs. fact
      retrieval-but also that larger, less practiced problems invoke other processes
      than pure fact retrieval. Moreover, ERPs showed a positive deflection around 450
      ms with a centro-parietal topography (P300), whose amplitude reflected
      differences in anticipated problem difficulty.

PMID- 15183391
TI  - The where and how of attention-based rehearsal in spatial working memory.
AB  - Rehearsal in human spatial working memory is accomplished, in part, via covert
      shifts of spatial selective attention to memorized locations ("attention-based
      rehearsal"). We addressed two outstanding questions about attention-based
      rehearsal: the topography of the attention-based rehearsal effect, and the
      mechanism by which it operates. Using event-related fMRI and a procedure that
      randomized the presentation of trials with delay epochs that were either filled
      with a flickering checkerboard or unfilled, we localized the effect to
      extrastriate areas 18 and 19, and confirmed its absence in striate cortex. Delay
      epoch activity in these extrastriate regions, as well as in superior parietal
      lobule and intraparietal sulcus, was also lateralized on unfilled trials,
      suggesting that attention-based rehearsal produces a baseline shift in areas
      representing the to-be-remembered location in space. No frontal regions
      (including frontal eye fields) demonstrated lateralized activity consistent with
      a role in attention-based rehearsal.

PMID- 15183392
TI  - Choosing sides: lateralization in line trisection and quadrisection as a function
      of reading direction and handedness.
AB  - It might be intuited that a person's reading direction will impact linguistic
      and/or oculomotor tasks. Whether it also influences nonlanguage tasks, and by
      what means, is less clear. A novel technique to probe this effect is introduced
      in this paper, and the affirmative results are presented. The line bisection task
      has been a standard bedside diagnostic technique for assessing hemifield spatial
      neglect for many years. In recent years, numerous studies have also examined how
      normal subjects perform on this task. A recent line of study has focused on the
      reading habits of the subjects and the effect it has on line bisection. Most
      European languages are read from left to right, and it is thus postulated that
      readers of those languages will scan a line from left to right. On the other
      hand, Hebrew is read from right to left. These previous studies have yielded
      intriguing results about the role that reading direction plays in nonlanguage
      tasks. The present study utilized two other line partition tasks, line trisection
      and line quadrisection, and subjects whose principal reading language was either
      right-to-left or left-to-right. These tasks are ambiguous when used without
      instructing the subject on which side to perform the line transection. It was
      found that principal language was correlated with the side on which the subject
      chose to trisect or quadrisect the line. However, there was no correlation
      between preferred side and writing hand and there was no significant difference
      in accuracy between the preferred side and the secondary side. Thus, the
      preferred side in this nonlanguage task does not seem to be influenced by writing
      hand or accuracy but rather would seem to depend exclusively upon the earliest
      legitimate point, as determined by reading direction.

PMID- 15183393
TI  - Intelligence and working memory systems: evidence of neural efficiency in alpha
      band ERD.
AB  - Starting from the well-established finding that brighter individuals display a
      more efficient brain function when performing cognitive tasks (i.e., neural
      efficiency), we investigated the relationship between intelligence and cortical
      activation in the context of working memory (WM) tasks. Fifty-five male (n=28)
      and female (n=27) participants worked on (1) a classical forward digit span task
      demanding only short-term memory (STM), (2) an attention-switching task drawing
      on the central executive (CE) of WM and (3) a WM task involving both STM storage
      and CE processes. During performance of these three types of tasks, cortical
      activation was quantified by the extent of Event-Related Desynchronization (ERD)
      in the alpha band of the human EEG. Correlational analyses revealed associations
      between the amount of ERD in the upper alpha band and intelligence in several
      brain regions. In all tasks, the males were more likely to display the negative
      intelligence-cortical activation relationship. Furthermore, stronger associations
      between ERD and intelligence were found for fluid rather than crystallized
      intelligence. Analyses also point to topographical differences in neural
      efficiency depending on sex, task type and the associated cognitive subsystems
      engaged during task performance.

PMID- 15183394
TI  - Brain areas underlying visual mental imagery and visual perception: an fMRI
      study.
AB  - We used functional magnetic resonance imaging (fMRI) to assess the maximal degree
      of shared neural processing in visual mental imagery and visual perception.
      Participants either visualized or saw faint drawings of simple objects, and then
      judged specific aspects of the drawings (which could only be evaluated properly
      if they used the correct stimulus). The results document that visual imagery and
      visual perception draw on most of the same neural machinery. However, although
      the vast majority of activated voxels were activated during both conditions, the
      spatial overlap was neither complete nor uniform; the overlap was much more
      pronounced in frontal and parietal regions than in temporal and occipital
      regions. This finding may indicate that cognitive control processes function
      comparably in both imagery and perception, whereas at least some sensory
      processes may be engaged differently by visual imagery and perception.

PMID- 15183395
TI  - Using visual advance information: an event-related functional MRI study.
AB  - Our event-related functional MRI (efMRI) study investigates whether visual
      advance information (AI) affects rather perceptual or central response-related
      processing areas. Twelve subjects were required to make a go/no-go decision to a
      conjunction of a specific color and motion direction. The stimuli were preceded
      by a cue, providing 100% valid advance information about motion direction.
      Partial and full advance information (PAI and FAI) predicted possible targets,
      respectively, certain nontargets, neutral cues (NAI) gave no prediction. The time
      between cue and stimulus (stimulus onset asynchrony, SOA) was varied. A response
      benefit was found after PAI as compared with NAI. The benefit was small with a
      short SOA (150 ms), increased with intermediate SOA (450 ms) and sustained with
      long SOA (750 ms). Perceptual and central processing areas were more active with
      increasing SOA, but only central response-related processing areas were
      selectively modulated by cue information. In particular, supplementary motor area
      and bilateral inferior parietal lobe were more active with PAI than with NAI. If
      comparing NAI with FAI, more errors were made and activity was larger in central
      processing areas. Our results suggest that, depending on the processing time,
      cues providing perceptual information modulate central response-related
      processes.

PMID- 15183396
TI  - Alpha power dependent light stimulation: dynamics of event-related
      (de)synchronization in human electroencephalogram.
AB  - The desynchronization and resynchronization of alpha oscillations was studied in
      10 normal subjects after visual stimulation of both eyes under two experimental
      conditions, "eyes opened" and "eyes closed". The electroencephalogram (EEG) was
      recorded bipolarly over the occipital area and sampled at 200 Hz. The data was
      processed in real time and evaluated online. In accordance with the alpha power
      in the 7 to 13 Hz band, short red light flashes of 10 ms duration were presented
      at intervals of at least 2 s. This stimulation resulted in an event-related
      desynchronization (ERD) followed by resynchronization. Trials were controlled for
      artifacts, averaged offline, and the amount of event-related (de)synchronization
      was calculated. The event-related desynchronization was significantly larger in
      the eyes open paradigm. In addition, the latencies of event-related
      desynchronization and resynchronization maxima were larger in the eyes open
      paradigm compared to the eyes closed one.

PMID- 15183397
TI  - Phonemic manipulation in Japanese: an fMRI study.
AB  - Phonological awareness is the ability to manipulate abstract phonological
      representations of language and is crucial to the process of learning to read.
      The neural substrates underlying this appear to be modality-independent at least
      in alphabetic languages. Japanese language has different orthographic "kana"
      system, in which each "kana" character strictly corresponds to a syllable. To
      investigate the neural substrates underlying phonological manipulation of the
      Japanese language, functional magnetic resonance imaging (fMRI) was used.
      Neuroimaging data were obtained from adult healthy volunteers during auditory and
      visual vowel exchange tasks, identical except for the modality of stimuli
      presentation: a voice and Japanese "kana" characters. Cerebellar vermis was
      activated by vowel exchange tasks of both modalities. The posterior parts of the
      superior temporal sulcus (STS) were active during the auditory tasks, suggesting
      that phonological representations of auditory stimuli are manipulated in this
      area. These findings are consistent with the previous studies with alphabetic
      languages. In contrast, the intraparietal sulci, which has been implicated for
      visuospatial tasks, was active during the visual tasks. This modality-dependent
      activation may indicate that the simple orthographic rule of the Japanese allows
      an alternate visual strategy to conduct the phonological awareness task,
      bypassing manipulation of phonological representation.

PMID- 15183398
TI  - Effects of motor imagery on finger force responses to transcranial magnetic
      stimulation.
AB  - The purpose of this study was to investigate whether characteristics of finger
      interaction seen in voluntary finger force production tasks could also be
      observed during motor imagery. Transcranial magnetic stimulation (TMS) was
      applied over the contralateral M1 hand area. Three conditions were tested in
      eight young healthy volunteers: At rest, during motor imagery of maximal force
      production by the index finger (ImIn), and during motor imagery of maximal force
      production by all four fingers simultaneously (ImAll). We obtained measures of
      motor threshold (MT), motor-evoked potentials (MEP) from the contralateral flexor
      digitorium superficialis, and TMS-induced forces from individual fingers.
      Increased MEP and decreased MT during motor imagery tasks suggested enhanced
      excitability of structures involved in the generation of TMS-induced responses.
      TMS-induced forces were larger during motor imagery tasks than at rest. This
      effect was present, albeit significantly smaller, in the middle, ring, and little
      fingers during ImIn as compared to ImAll. This finding has been interpreted as a
      correlate of the phenomenon of unintended finger force production (enslaving).
      The motor imagery effect on finger forces evoked by TMS was significantly larger
      during ImIn (4% MVC) than during ImAll (2.8% MVC) tasks, corresponding to the
      phenomenon of force deficit. These results provide direct evidence of the neural
      origin of the main phenomena of finger interaction. Furthermore, the similarities
      between characteristics of finger interaction during motor imagery and during
      voluntary movement suggest the involvement of similar neural structures
      (including M1).

PMID- 15183399
TI  - Evidence of partial response activation in a memory-search task.
AB  - Studies using the lateralized readiness potential (LRP; an index of hand-specific
      motor preparation), suggest that the motor system can be activated on the basis
      of partial information, providing support for a parallel view of the human
      information processing system. However, data to the contrary have been obtained
      in memory-search paradigms, leading Heil et al. [Psychological Research 62 (1999)
      289] to propose that hand-specific motor preparation cannot occur in parallel
      with memory scanning. To further investigate these findings we recorded the LRP
      in a fast-paced memory search task, in which the case of target letter and memory
      set size were manipulated and a choice-go/no-go procedure was used. The case of
      the test letter determined the response hand, whereas membership of the test
      stimulus in the memory set determined whether a response was required. We found
      different types of LRP effects as a function of time on task. Analyses based on
      the data from the first half of the experiment replicated those obtained by Heil
      et al. [Psychological Research 62 (1999) 289]. However, unlike Heil et al.
      [Psychological Research 62 (1999) 289], the second half of the data showed
      significant LRP activity on no-go trials and similar LRP onset latencies for go
      and no-go trials, as well as for different memory set size conditions in the
      stimulus-locked LRP waveforms. The response-related waveforms showed an earlier
      LRP onset in the set-size 4 than in the set-size 2 condition. These data suggest
      that motor preparation can occur simultaneously with memory search when
      participants are sufficiently practiced. Time-on-task and strategy differences
      between the two studies are discussed.

PMID- 15183400
TI  - Source localization (LORETA) of the error-related-negativity (ERN/Ne) and
      positivity (Pe).
AB  - We investigated error processing of 39 subjects engaging the Eriksen flanker
      task. In all 39 subjects a pronounced negative deflection (ERN/Ne) and a later
      positive component (Pe) were observed after incorrect as compared to correct
      responses. The neural sources of both components were analyzed using LORETA
      source localization. For the negative component (ERN/Ne) we found significantly
      higher brain electrical activity in medial prefrontal areas for incorrect
      responses, whereas the positive component (Pe) was localized nearby but more
      rostral within the anterior cingulate cortex (ACC). Thus, different neural
      generators were found for the ERN/Ne and the Pe, which further supports the
      notion that both error-related components represent different aspects of error
      processing.

PMID- 15183401
TI  - Pitch modulates lexical identification in spoken word recognition: ERP and
      behavioral evidence.
AB  - Event-related potentials (ERPs) were recorded in cross-modal word fragment
      priming (CMWP) to address the function of pitch for the identification of spoken
      words. In CMWP fragments of spoken words (e.g., re taken from Regal [Engl.
      shelves]) are immediately followed by visual targets. Together with reduced
      reaction times (RTs), an ERP deflection named P350 has been found to be reduced
      for targets, which match the primes (e.g., in the prime-target pair re-REGAL) as
      compared to unrelated targets (e.g., re-WIRBEL [Engl. burble]). The P350 has been
      related to facilitated lexical identification [Friedrich, Kotz, Friederici and
      Gunter (in press), ERPs reflect lexical identification in word fragment priming,
      JOCN]. In the present study, we presented syllable primes with different pitch
      contours. One version of each prime bore a stressed pitch contour (e.g., re_1),
      the other an unstressed pitch contour (e.g., re_2). Primes were combined with
      targets being either stressed on the first syllable (e.g., REgel [Engl. rule]) or
      on the second syllable (e.g., reGAL [Engl. shelves]). We found a reduced
      amplitude of the P350 and slightly faster reactions for targets with a stress
      pattern that matched the pitch of the primes (e.g., re_1-REgel) as compared to
      targets with a stress pattern that did not match the pitch of the primes (e.g.,
      re_1-reGAL). The present study replicates the P350 effect with different
      material, and indicates that pitch is used for lexical identification in spoken
      word recognition.

PMID- 15183402
TI  - Linguistic processing in visual and modality-nonspecific brain areas: PET
      recordings during selective attention.
AB  - Positron emission tomography (PET) was used to investigate the neural basis of
      selective processing of linguistic material during concurrent presentation of
      multiple stimulus streams ("cocktail-party effect"). Fifteen healthy right-handed
      adult males were to attend to one of three simultaneously presented messages: one
      presented visually, one to the left ear, and one to the right ear. During the
      control condition, subjects attended to visually presented consonant letter
      strings and ignored auditory messages. This paper reports the modality
      nonspecific language processing and visual word-form processing, whereas the
      auditory attention effects have been reported elsewhere [Cogn. Brain Res. 17
      (2003) 201]. The left-hemisphere areas activated by both the selective processing
      of text and speech were as follows: the inferior prefrontal (Brodmann's area, BA
      45, 47), anterior temporal (BA 38), posterior insular (BA 13), inferior (BA 20)
      and middle temporal (BA 21), occipital (BA 18/30) cortices, the caudate nucleus,
      and the amygdala. In addition, bilateral activations were observed in the medial
      occipito-temporal cortex and the cerebellum. Decreases of activation during both
      text and speech processing were found in the parietal (BA 7, 40), frontal (BA 6,
      8, 44) and occipito-temporal (BA 37) regions of the right hemisphere.
      Furthermore, the present data suggest that the left occipito-temporal cortex (BA
      18, 20, 37, 21) can be subdivided into three functionally distinct regions in the
      posterior-anterior direction on the basis of their activation during attentive
      processing of sublexical orthography, visual word form, and supramodal higher
      level aspects of language.

PMID- 15183403
TI  - Static motion aftereffect does not modulate positional representations in early
      visual areas.
AB  - A stationary stimulus is perceived to drift in the opposite direction after
      adaptation to a moving stimulus (static motion aftereffect (MAE)). It is commonly
      assumed that positional effects from the static motion aftereffect are mediated
      by early visual areas. Here we psychophysically showed that these positional
      effects did not modulate illusory line-tilt aftereffect (TAE). Since illusory
      contours seem to be represented at relatively early stages of visual hierarchy,
      we suggest that the neural substrates underlying the perception of static motion
      aftereffect and illusory contours are different.

PMID- 15183404
TI  - Epithelial malignancies of the salivary glands: clinical experience of a single
      institution-a review.
AB  - In this retrospective study we give a clinical review of our experience with
      different subtypes of salivary gland cancer. Between January 1983 and December
      2002, a total of 155 patients with carcinomas of the salivary glands received
      initial treatment at the Department of Oral and Maxillofacial Surgery, Hanover
      Medical School. There were 79 (51.0%) adenoid cystic carcinomas, 42 (27.1%)
      mucoepidermoid carcinomas, 12 (7.7%) adenocarcinomas, 10 (6.5%) polymorphous
      adenocarcinomas and 12 (7.7%) other tumor entities of smaller number. Complete
      resection was reached for 63.5% of patients with high grade carcinomas and for
      80.0% of patients with low grade carcinomas. 26.2% of patients with high grade
      carcinomas and 13.3% of patients with low grade carcinomas received postoperative
      radiation. Overall survival rates at 5, 10 and 15 years were 65.9, 48.0 and 39.8%
      with significant difference for patients with high grade and low grade
      carcinomas. Histopathologic subtype, tumor stage and margin status significantly
      influenced prognosis. Statistically, we were not able to demonstrate a positive
      effect for postoperative radiation. In the future, patients with salivary gland
      carcinomas should be randomised for prospective multicentric clinical trials,
      which could provide reliable information about adjuvant treatment modalities and
      their results even for rare subtypes of salivary gland cancer.

PMID- 15183405
TI  - Stabilisation of sagittal split advancement osteotomies with miniplates: a
      prospective, multicentre study with two-year follow-up. Part I. Clinical
      parameters.
AB  - The principal aim of this study was to assess the postoperative stability of
      bilateral sagittal split osteotomies (BSSO) using two miniplates. Part I reports
      on the clinical results including treatment characteristics, nerve functions, TMJ
      function, occlusional relapse and patient satisfaction. This prospective study
      evaluated a group of 222 patients who underwent a BSSO for mandibular
      advancement. The same treatment protocol was used at seven participating
      institutions at which the patients were treated. A stable occlusion without
      appreciable relapse was seen in 84% after 2 years of follow-up. A considerable
      minority (16%) had occlusal relapse. There were no clinical parameters that
      pointed towards a high risk for relapse except age. The mean operation age of the
      relapse group was 20.7 years (SD 6.7) and in the stable group 26.1 years (SD
      8.2). The function of the inferior alveolar nerve 2 years postoperatively was
      reported to be normal in approximately 88% of the patients, while 94% had no
      complaints about nerve dysaesthesia. In approximately 56% of the patients with
      pre-existing TMJ-dysfunction these signs and symptoms had disappeared. Another
      group of patients, however, without TMJ-dysfunction preoperatively (22%)
      developed signs or symptoms of TMJ-dysfunction postoperatively. The sagittal
      split osteotomy fixed with miniplates appeared to be a relatively safe and
      reliable procedure giving rise to a high degree of patient satisfaction, despite
      the fact that some occlusal relapse was seen.

PMID- 15183406
TI  - Transalveolar screws and the incidence of dental damage: a prospective study.
AB  - The incidence of screw/tooth contact in the placement of transalveolar screws was
      prospectively studied. The clinical significance of such contact when it occurred
      was assessed. Patients with fractures of the mandible requiring intra- or post
      operative control of their occlusion with transalveolar screws were entered into
      the study. Following screw removal, contact was assessed radiographically and all
      teeth adjacent to screws were tested for vitality. Any contacts were judged to be
      minor if less than 50% of the diameter of the screw hole impinged on a tooth root
      or major if this was more than 50%. Fifty-four male and one female patients
      completed the study. There were 232 screws placed in these patients adjacent to
      440 teeth. Twenty-six screws (11.2%) had major contacts and 37 (15.9%) had minor
      contacts. Seventeen teeth tested as non-vital with electronic pulp testing but of
      these only 6 showed any impingement by screws. Two screws were associated with
      complications in two patients. Screw/tooth contact does occur using transalveolar
      screws, however, the incidence of clinically significant damage appears to be
      very low.

PMID- 15183407
TI  - Relevance of positive margins in case of adjuvant therapy of oral cancer.
AB  - Positive or clean surgical margins are of great prognostic interest in the
      surgical treatment of oral and oropharyngeal cancer with poor survival of
      patients burdened with positive margins. The impact of postoperative treatment
      modalities on the survival of these patients is debated. The relevance of
      positive margins was investigated in three patient populations (a group treated
      by surgery only, a group with postoperative polychemotherapy, and a group with a
      multi-modality treatment comprising postoperative radiation with concurrent
      chemotherapy) which were compared retrospectively. Patients treated with adjuvant
      regimens following resection in healthy margins had a survival advantage as
      compared to the surgery only group possibly due to less local relapses and longer
      relapse latencies. Overall disease-free survival was better in the groups with
      adjuvant therapy irrespective of free or positive margins. Survival rates
      following positive surgical margins were worse in all three groups as compared to
      the respective subgroups with healthy margins. A second resection in patients
      with positive margins, executed in the group with postoperative radiation with
      concurrent chemotherapy, did not result in survival improvement. Therefore,
      radical resection at initial surgery in healthy and clear margins remains
      indispensable in multi-modality treatment strategies involving surgery. The
      combination of healthy margins and adjuvant treatment seems to be most favorable
      for patient survival.

PMID- 15183408
TI  - Mandibular invasion in oral squamous cell carcinoma: investigation by clinical
      examination and orthopantomogram.
AB  - Assessing the relationship of oral squamous carcinoma with the mandible prior to
      definitive therapy poses a perplexing problem for the head and neck oncologist.
      We carried out a prospective open study of 51 (21 female and 30 male; mean age of
      53.4 years) patients undergoing mandibular resections for oral squamous cell
      carcinoma to examine the incidence of mandibular bone invasion and to assess the
      predictive capabilities of clinical and radiological examination in detecting
      bone involvement. A detailed clinical examination was followed by radiographic
      evaluation of mandible for bone invasion. After resection, the mandible was
      sectioned serially at every cm to find the pathological bone involvement.
      Sensitivity, specificity, and positive and negative predictive values of clinical
      and radiological findings were calculated. Specimens from 25 patients (49%) (4
      segmental 21 hemi) demonstrated tumour invasion on histological examination.
      Clinical impression of mandibular invasion showed a sensitivity of 96% and
      specificity of 65%, whereas radiological examination had a sensitivity of 92% and
      specificity of 88%. When considered together, clinical and radiological
      examinations were able to detect all the cases of bone invasion, but specificity
      was only 58%. This study advocates careful correlation of clinical and
      radiological findings prior to definitive therapy, as clinical examination tends
      to over diagnose bone invasion in tumours adjacent to the mandible. The
      specificity of imaging was also found to be low pointing towards the need for
      more specific diagnostic tools in doubtful cases. Aggressive surgical therapy,
      namely segmental or hemi resection of mandible is warranted in case of tumours of
      the lower alveolus with definite bone invasion. In case of carcinomas of the
      buccal mucosa and tongue the mandibular resection can be limited to that required
      for clearance of margins provided the radiology is negative.

PMID- 15183409
TI  - Nevoid basal cell carcinoma syndrome: a retrospective analysis of 33 affected
      Korean individuals.
AB  - This article describes a pooled analysis of Korean individuals with nevoid basal
      cell carcinoma syndrome (NBCCS). The data upon which this review is based has
      been retrieved from published case reports in Korean dental and medical
      literature between the years 1981 to 2002. We found 33 subjects who met the
      diagnostic criteria for NBCCS. Relative frequencies of associated complications
      are presented and compared with those of the English literature. Odontogenic
      keratocyst (OKC) and palmar and/or plantar pits, and hypertelorism were the most
      frequently observed anomalies. OKCs are often the first signs of NBCCS and can be
      detected in patients younger than 20 years of age. However, the incidence and
      clinical manifestations of NBCCS in Korean individuals were found to be rather
      different from those of other countries. The relatively low frequency of basal
      cell carcinomas and falx calcification among the major criteria were two major
      differences. The frequencies of the minor criteria concur in general with the
      ranges given by some others. It is concluded that these differences may be
      attributed to genetic and geographic differences.

PMID- 15183410
TI  - Sclerotherapy of oral and facial venous malformations with use of pingyangmycin
      and/or sodium morrhuate.
AB  - Two hundred and sixty patients with oral and facial venous malformations received
      intralesional injections of either pingyangmycin, sodium morrhuate, or
      pingyangmycin alternating with sodium morrhuate. Results were rated excellent,
      good, fair, or poor, depending on clinical outcome. The prevalence of an
      "excellent" rating in the combined sclerotherapy group (82%) was higher than that
      in the pingyangmycin group (71%) and the sodium morrhuate group (61%). Swelling
      and pain following injection were commonly associated with the use of sodium
      morrhuate. Sclerotherapy with pingyangmycin or sodium morrhuate is an effective
      and safe treatment for oral and facial venous malformations. Alternate injection
      of pingyangmycin and sodium morrhuate appears to be more effective for venous
      malformations than using sclerosant alone.

PMID- 15183411
TI  - Effects of standardized acute normovolemic hemodilution on intraoperative
      allogeneic blood transfusion in patients undergoing major maxillofacial surgery.
AB  - The aim of the present study was to demonstrate the practicality and efficacy of
      acute normovolemic hemodilution (ANH) to reduce allogeneic red blood cell (RBC)
      transfusion in patients undergoing elective surgery with anticipated high
      intraoperative blood loss (BL). 124 patients (age 48 +/- 18 years, ASA classes I
      III) underwent major maxillofacial surgery in a university hospital (68% tumor
      surgery, 32% dysgnathia correction). After induction of general anesthesia, ANH
      was performed by standardized withdrawal of 900 ml (2 units) of whole blood and
      simultaneous infusion of 500 ml of hydroxyethyl starch solution (6% HES
      130,000/0.4) and 1500 ml of crystalloidal solution. Intraoperative BL was fluid
      compensated until physiologic parameters indicated the need for RBC transfusion.
      First, autologous ANH-blood was retransfused followed by, if necessary,
      allogeneic RBC. Total BL was referred to the patient's calculated blood volume
      (BV): fractional blood volume loss, BL(fract) = BL/BV. ANH took 16 +/- 2 min and
      was void of any adverse event. The costs for ANH was 24 per patient. 55 patients
      had a mean BL(fract) of 44 +/- 28% and required an intraoperative transfusion;
      49/55 patients with an average BL(fract) of 37 +/- 14% were transfused with only
      autologous ANH-blood; 6/55 patients with a mean BL(fract) of 100 +/- 47%
      underwent additional transfusion with allogeneic RBC. Standardized, 2 unit, ANH
      is a practicable, safe and economic blood conservation technique that allowed for
      the complete avoidance of allogeneic RBC transfusion in 89% of patients
      undergoing maxillofacial surgery that required an intraoperative RBC transfusion.

PMID- 15183413
TI  - Radiation-induced impairment of osseous healing with vascularized bone transfer:
      experimental model using a pedicled tibia flap in rat.
AB  - Aim of this study was to establish an appropriate animal model for investigating
      the healing of vascularized osseous transplants to irradiated recipient sites
      applying metabolic, vascular and immunologic experimental studies. In 20 Wistar
      rats (male, weight 300-500 g), a pedicled osseous tibia flap was raised and
      transferred to a subcutaneous pocket in the ipsilateral groin. The remaining
      tibia was stabilized with a monocortical titanium miniplate. To create a pre
      irradiated transplant bed, the donor-area including the adjacent bone of the
      tibia was irradiated with a total dose of 50Gy (5 x 10 Gy) in 10 animals. The
      interval between irradiation and retransfer of the non-irradiated pedicled tibia
      flap was 4 weeks. Ten animals received no radiation. Evaluation of osseous
      healing and the success of the transferred flap were based on a clinical and
      quantitative histomorphometric assessment. Testing for significant differences
      was performed using the non-parametric Mann-Whitney U-test. The rate of complete
      osseous healing in the non-irradiated animals was 90%. In contrast there was no
      significant bone union observed in the group of the pedicled flaps grafted to the
      pre-irradiated (50Gy) recipient site (P = 0.001). Similarly bone formation in the
      transitional zone between bone graft and recipient bone was significantly lower
      in the preirradiated group (P < 0.001) (16.9 +/- 3%) in contrast to the non
      irradiated transplant bed (47.9 +/- 6%).

PMID- 15183412
TI  - In vitro cultured autologous pre-confluent oral keratinocytes for experimental
      prefabrication of oral mucosa.
AB  - The reconstruction of large defects after head and neck cancer resection often
      requires composite tissue transfer to replace a combination of bone, muscle and
      mucosa. Thus, tissue engineering techniques may be useful for oral mucosal
      reconstructive surgery to prefabricate mucosal tissue on the muscle flap in vivo,
      instead of using conventional skin-bearing composite flaps. The aim of this study
      was to investigate whether autogenous pre-confluent oral keratinocytes (PCOK)
      cultured in vitro can create mucosal coverage on muscle in vivo, in a single
      grafting procedure. In 30 Wistar rats, with a small piece of oral mucosa (2 mm x
      5 mm), oral keratinocytes were isolated and then seeded on a hydrophilic PTFE
      membrane (n = 50) in serum-free culture condition. After 48 h, the membrane,
      together with the PCOK, was transplanted onto the gracilis muscle to fabricate a
      mucosal flap in vivo. The wound bed was closed primarily until the time of
      examination. Biopsies were carried out 1, 2, 3, and 4 weeks, respectively, after
      transplantation and were evaluated immunohistochemically (AE1/AE3 anti
      pancytokeratin, cytokeratin 5/6, collagen IV, laminin, lectin-specific labeling
      of N-acetylglucosamine oligomeres of endothelial cells) with relation to the
      following criteria: (1) graft acceptance; (2) inflammatory signs; (3) structural
      changes and keratinocyte lining; (4) expression of basement membrane components;
      and (5) vascularization. Ninety-one percent of the grafts showed uniform
      epithelial layers. The mean number of reconstructed epithelial cell layers was
      1.7, 2.0, 1.85 and 2.7 at 1, 2, 3 and 4 weeks, respectively after transplantation
      (P = 0.342). Collagen IV, laminin and lectin-specific capillaries developed
      between the neoepithelium and the underlying muscular layer. Only two specimens
      showed signs of infection 2 weeks after transplantation. In conclusion, this
      experiment demonstrated that PCOK grafts on muscle in vivo can achieve uniform
      multi-layered oral epithelial coverage in a short period of time. This technique
      may be a useful alternative tool for oropharyngeal reconstructive surgery and is
      also worth considering for further clinical studies.

PMID- 15183414
TI  - Expression of p63 (TA and deltaN isoforms) in human primary well differentiated
      buccal carcinomas.
AB  - Abnormalities in the p53 gene have been regarded as the most consistent genetic
      abnormalities detected in head and neck squamous cell carcinogenesis. Two new
      members of the p53 gene family, p73 and p63, have recently been identified. We
      investigated the expression of the two N-terminal p63 isoforms (TA and deltaN
      isoforms) in human primary well-differentiated buccal squamous cell carcinoma.
      Both TAp63 and deltaNp63 isoforms were detected in the basal/suprabasal layers of
      all of the five specimens of normal buccal mucosa. The deltaNp63 isoform was
      found in all of the 23 specimens of human primary well-differentiated buccal
      carcinoma whereas TAp63 isoform was absent in 18 (78.3%) of the 23 specimens. The
      immunostaining patterns of both TAp63 and deltaNp63 isoforms were similar in that
      the p63 positivity was noted mainly in the peripheral cells of tumor nests
      whereas negative staining was observed in the areas with keratin pearl formation.
      A higher number of T3-T4 patients and patients with recurrence showed negative
      staining of TAp63 than T1-T2 patients and patients without recurrence but the
      difference was not statistically significant. These results suggested that
      specific p63 isoforms were associated with human oral squamous cell
      carcinogenesis. The deltaNp63 isoforms might be involved in epithelial
      differentiation and proliferation in human oral carcinogenesis whereas there was
      evidence for a possible role of TAp63 under-expression in human oral
      tumorigenesis.

PMID- 15183415
TI  - Investigation of the GSalpha gene in the diagnosis of fibrous dysplasia.
AB  - Fibrous dysplasia is a benign fibro-osseous disease of bone and its etiology has
      been previously established. Activating mutations in the gene that encodes the
      alpha subunit of stimulatory G protein (G(S)alpha) has been described in
      monostotic and polyostotic fibrous dysplasia and in the McCune-Albright syndrome.
      The present report describes a patient with monostotic fibrous dysplasia which
      diagnosis was confirmed by sequencing of the G(S)alpha gene, demonstrating a
      heterozygous missense mutation on codon 201 (201C --> T). Due to the high
      prevalence of G(S)alpha gene mutations in fibrous dysplasia in contrast to other
      benign and malignant fibrous-osseous lesions, mutational analysis are an
      additional and helpful parameter for the diagnosis of fibrous dysplasia in
      selected cases.

PMID- 15183416
TI  - A new method for temporary maxillo-mandibular fixation.
AB  - We present a novel device which is an alternative to surgical wire for per
      operative maxillo-mandibular fixation prior to plate placement. It is easy to
      apply, causes minimal mucosal trauma and can be used in association with elastic
      chain.

PMID- 15183417
TI  - Eyebrow reconstruction using composite graft and microsurgical transplant.
AB  - The pivotal role that eyebrows play in facial expression and aesthetics is widely
      accepted, along with the difficulties faced by surgeons in reconstructing defects
      in this area. The case study presented demonstrates reconstruction of a traumatic
      eyebrow defect using a post-auricular composite graft in combination with a
      microfollicular hair transplant technique. The advantage of the combined approach
      is discussed with reference to the fine tuning of the adjoining areas between
      reconstructed and undamaged hair-bearing regions. The advantages of this
      technique in control of the direction of hair growth and preservation of hair
      density are emphasised.

PMID- 15183418
TI  - Primary meningioma of the scalp as a late complication of skull fracture: case
      report and literature review.
AB  - A case of primary meningioma of the scalp is presented in which the anatomical
      association with a previous skull fracture is demonstrated and pathogenesis
      discussed. The investigations and surgical treatment are briefly described.
      Review of the literature reveals a strong association between trauma of the
      central nervous system and intracranial meningioma. Occasional reports also exist
      of extra-cranial meningioma following trauma. This is, however, the first report
      of such an association in the scalp.

PMID- 15183419
TI  - Clear cell odontogenic carcinoma-a case report and review of literature.
AB  - The clear cell odontogenic carcinoma (CCOC) is a rare, locally infiltrative
      neoplasm with a marked tendency for local recurrence and regional lymph node
      metastasis. The first description in 1985 included three cases of destructive jaw
      lesions. The entity was described as a clear cell odontogenic tumour in the
      previous WHO classification due to the fact that rarity of the lesion restricting
      pathologists to understand the spectrum of the degree of malignancy. These
      tumours have a peak incidence in the 5th-7th decades. CCOC tends to occur more
      frequently in the mandible, with a female predilection. The most striking
      histological feature is of large islands and strands of uniform cells with round
      or ovoid nuclei and clear cytoplasm. Presently we describe a case of clear cell
      odontogenic carcinoma in a 52-year-old female who presented with a bony-hard lump
      in the left body of the mandible. The patient is free of any recurrence after 2
      years of follow-up.

PMID- 15183420
TI  - Oral cancer and cyclins.

PMID- 15183422
TI  - Transforming growth factor-beta1 induced alteration of skeletal morphogenesis in
      vivo.
AB  - Transforming growth factor beta (TGF-beta) is expressed in the growth plate and
      is an important regulator of chondrocyte maturation. Loss of function results in
      premature chondrocyte maturation both in vitro and in vivo. While TGF-beta
      inhibits chondrocyte maturation in cell cultures, the effect of increased TGF
      beta has not been well characterized in an in vivo development model. Addition of
      Affi-gel agarose beads loaded with TGF-beta1 (10 ng/microl) to developing stage
      24-25 chick limb buds resulted in limb shortening and altered morphology. In situ
      hybridization studies showed down regulation of Indian hedgehog (ihh), bone
      morphogenetic protein 6 (bmp6), and collagen type X (colX) expression, markers of
      chondrocyte maturation, in TGF-beta1 treated limbs. TGF-beta1 also decreased
      chondrocyte proliferation in the developing anlage. The findings confirm a
      critical role for TGF-beta during skeletal development. A more complete
      understanding of the role of TGF-beta and its down-stream signals will lead to
      improved understanding and treatment of cartilage diseases.

PMID- 15183424
TI  - Interactions of cisplatin with calcium phosphate nanoparticles: in vitro
      controlled adsorption and release.
AB  - A new system for the local delivery of chemotherapy to malignant solid tumors has
      been developed based on calcium phosphate (CaP) nanoparticles. The adsorption of
      the anti-neoplastic drug cis-diamminedichloroplatinum (cisplatin) was
      characterized on three types of apatitic CaP (poorly and well crystallized
      hydroxyapatite, and carbonated apatite). Adsorption isotherms obtained in
      chloride-free phosphate solutions at pH = 7.4 (24 and 37 degrees C) indicate that
      cisplatin adsorption increases with temperature and increases with decreasing
      crystallinity. Release studies in phosphate buffer saline (containing the
      chloride ion essential for release) showed that while the cumulative amount of
      released drug was the same for all apatites at 20 days (approximately 70% of the
      total bound), the least crystalline material released the drug more slowly. The
      drug release rate increased slightly with temperature. Cytotoxicity testing was
      conducted in a K8 clonal murine osteosarcoma cell line to verify that drug
      activity was retained after adsorption onto the apatite crystals. K8 cells were
      plated onto dried films of the apatite/cisplatin conjugates and after 24 h,
      viability was measured with tritiated uridine. The apatite/cisplatin formulations
      exhibited cytotoxic effects with a dose dependent diminishment of cell viability.

PMID- 15183423
TI  - Genetic marking with the DeltaLNGFR-gene for tracing goat cells in bone tissue
      engineering.
AB  - The use of bone marrow derived stromal cells (BMSC's) for bone tissue engineering
      has gained much attention as an alternative for autologous bone grafting. Little
      is known however, about the survival and differentiation of the cells, especially
      in the clinical application. The aim of this study was to develop a method to
      trace goat BMSC's in vivo. We investigated retroviral genetic marking, which
      allows stable expression of the label with cell division. Goat BMSC's were
      subjected to an amphotropic envelope containing a MoMuLV-based vector expressing
      the human low affinity nerve growth factor receptor (DeltaLNGFR). Labeling
      efficiency and effect on the cells were analyzed. Furthermore, transduced cells
      were seeded onto porous ceramic scaffolds, implanted subcutaneously in nude mice
      and examined after successive implantation periods. Flow cytometry indicated a
      transduction efficiency of 40-60%. Immunohistochemistry showed survival and
      subsequent bone formation of the gene-marked cells in vivo. Besides, marked cells
      were also found in cartilage and fibrous tissue. These findings indicate the
      maintenance of the precursor phenotype following gene transfer as well as the
      ability of the gene to be expressed following differentiation. We conclude that
      retroviral gene marking with DeltaLNGFR is applicable to trace goat BMSC's in
      bone tissue engineering research.

PMID- 15183425
TI  - The influence of cyclic compression and distraction on the healing of
      experimental tibial fractures.
AB  - Interfragmentary displacement has a main effect on callus formation in fracture
      healing. To test whether compressive or distractive displacements have a more
      pronounced effect on new bone formation, a sheep osteotomy model was created
      whereby the gap tissue was subjected to constant bending displacement. A
      diaphyseal osteotomy with a gap of 2 mm was created in 18 sheep tibiae and
      stabilized with a special unilateral actuator-driven external fixator. Two
      experimental groups with six sheep each received either 10 or 1000 cycles evenly
      distributed over 24 h. The third group of six sheep served as a control group
      without actively induced displacement. The amount and direction of cyclic
      displacement was kept constant throughout the observation period, resulting in
      50% compressive and 50% distractive displacement within the osteotomy gap. At
      sacrifice, six weeks after surgery, bending stiffness was measured and new bone
      formation was assessed radiologically and microradiographically. In all cycled
      groups, the amount of periosteal callus formation was up to 25 times greater on
      the compression compared to the distraction side (p < 0.001). The application of
      the higher number of daily cycles resulted in an up to 10-fold greater amount of
      periosteal new bone formation on the compression side (p < 0.012), while the
      difference on the distraction side was not significant. Ten cycles applied a day
      were sufficient to create an abundant periosteal callus on the compression side.
      In the 1000 cycle group, bending stiffness revealed slightly lower values but the
      difference was not significant. Solid periosteal bridging of the gap was observed
      in two sheep in the control group, whereas bridging in the cycled groups was
      observed exclusively at the medullary side. In conclusion, cyclic compressive
      displacements were found to be superior over distractive displacements. A higher
      number of enforced and maintained compressive displacements enhanced periosteal
      callus formation but did not allow bony bridging of the gap.

PMID- 15183426
TI  - Serum-free media for periosteal chondrogenesis in vitro.
AB  - Organ culture studies involving whole explants of periosteum have been useful for
      studying chondrogenesis, but to date the standard culture model for these
      explants has required the addition of fetal bovine serum to the media. Numerous
      investigators have succeeded in culturing chondrocytes and embryonic cells in
      serum-free conditions but there have been no studies focused on achieving a
      defined, serum-free media for culturing periosteal explants. The purpose of the
      present investigation was to determine if whole periosteal explants can be grown
      and produce cartilage in serum-free conditions, and to define the minimum media
      supplements that would be conducive to chondrogenesis. 321 periosteal explants
      were obtained from the medial proximal tibiae of 31 two month-old NZ white
      rabbits and cultured using a published agarose suspension organ culture model and
      DMEM for six weeks. The explants were cultured with and without fetal bovine
      serum or bovine serum albumin and exposed to transforming growth factor beta
      alone, a combination of growth factors we call ChondroMix (10 ng/ml transforming
      growth factor beta, 50 ng/ml basic fibroblast growth factor, and 5 microg/ml
      growth hormone), and/or ITS+ (2.08 microg/ml each of insulin, transferrin, and
      selenious acid, plus 1.78 microg/ml linoleic acid and 0.42 mg/ml BSA). Maximal
      chondrogenic stimulation in this study was observed with the combination of
      ChondroMix and ITS+. However, the minimal requirement to match or exceed the
      level of chondrogenic stimulation seen in the standard model (TGF-1 in 10% FBS)
      was achieved simply by the addition of 2.0 microg/ml insulin in 0.1% BSA
      containing medium (p < 0.05). Therefore, based on our results, it would be
      reasonable to assume that insulin is the component in ITS+ responsible for the
      observed increase in total cartilage growth. Lower concentrations of insulin were
      not effective, suggesting that the observed effect of insulin requires activation
      of the IGF-1 receptor.

PMID- 15183427
TI  - In vivo gene delivery to articular chondrocytes mediated by an adeno-associated
      virus vector.
AB  - PURPOSES: (1) To investigate the efficiency of direct in vivo adeno-associated
      virus (AAV) vector-mediated gene transduction to chondrocytes in relation to
      normal and injured articular cartilage. (2) To evaluate the effects of ultra
      violet light-activated gene transduction (LAGT) in chondrocytes in vivo. (3) To
      determine dissemination of active rAAV vector after intra-articular
      administration. METHODS: Rabbit knees with either normal or injured cartilage
      received an intra-articular injection with 1.5x10(12) infectious rAAV-eGFP
      particles. The right knees received rAAV-eGFP alone, whereas the left knees were
      given LAGT-treatment. The transduction efficiencies were determined at 1 and 3
      weeks after infection by fluorescence-activated cell scanning. The occurrence of
      active shedding was monitored in serum and various tissues. RESULTS: After 1
      week, 7% of the chondrocytes in normal cartilage were transduced by direct rAAV
      transduction technique. Chondrocytes in cartilage defects demonstrated higher
      transduction rates compared to chondrocytes in normal cartilage. LAGT increased
      the cellular eGFP expression in the internal zones to 12%, but did not have any
      effect in the external zones in defects. Finally, infectious particles were not
      detected in either serum or tissue samples. CONCLUSIONS: Direct rAAV-mediated
      gene transfer in vivo to articular chondrocytes is possible. LAGT improves rAAV
      transduction of chondrocytes in vivo but appears to have a very limited range of
      effect induction. Expression of eGFP was not determined in other tissues than
      synovium and cartilage in the treated joints.

PMID- 15183428
TI  - Targeted delivery of progenitor cells for cartilage repair.
AB  - An approach for promoting the adherence of chondrogenic progenitor cells to
      specific matrix molecules has been tested in a cartilage defect model. Culture
      expanded pre-chondrocytes fluorescently labeled with a vital dye were coated by a
      two-step method wherein lipidated protein G was first allowed to intercalate into
      cell membranes, and a second incubation in a solution of antibodies to cartilage
      matrix antigens allowed the binding of the antibodies to the protein G, on the
      external surface of the cell. The coating technique (termed "cell painting") does
      not effect cell viability or inhibit growth and chondrogenic potential. Painted
      cells were then added to rabbit cartilage explants that had a partial-thickness
      defect, washed, and prepared for histological examination and for confocal
      microscopy. The histological observations and the confocal observations and
      fluorescent intensity quantification consistently demonstrated that progenitor
      cells painted with multiple antibodies were capable of preferential binding to
      the exposed cartilage matrix within the defect. These results demonstrate that
      painting cell membranes with antibodies to matrix molecules is an effective
      method for promoting the adherence of stem or progenitor cells to a cartilage
      injury site.

PMID- 15183429
TI  - Suppression of early experimental osteoarthritis by gene transfer of interleukin
      1 receptor antagonist and interleukin-10.
AB  - Gene therapy offers a radically different approach to the treatment of arthritis.
      We demonstrated that cDNA coding for human interleukin-1 receptor-antagonist
      protein (IL-1Ra) and cDNA coding for human interleukin-10 (IL-10) can be
      delivered, by ex vivo techniques, to the synovial lining of joints, intra
      articular expression of gene significantly reduced cartilage matrix degradation
      and cartilage breakdown. To achieve this, lapine synoviocytes were first
      transduced in culture by retroviral infection. The genetically modified
      synoviocytes were then transplanted by intra-articular injection into the knee
      joints of OA rabbits, assay of joint lavages confirmed that the gene expression
      was not lost 14 days after transfer. Knees receiving the IL-1Ra gene had
      significantly reduced cartilage breakdown. Delivery of the IL-10 gene was less
      effective, having only a moderate effect on cartilage breakdown. When both genes
      were injected together, there was a greater inhibition of cartilage breakdown,
      suggesting that simultaneous gene delivery may be necessary to treat OA by
      targeting the activities of multiple inflammatory effectors.

PMID- 15183430
TI  - A silencer element in the cartilage oligomeric matrix protein gene regulates
      chondrocyte-specific expression.
AB  - The molecular mechanisms by which mesenchymal cells differentiate into
      chondrocytes are poorly understood. The cartilage oligomeric matrix protein gene
      (COMP) encodes a noncollagenous extracellular matrix protein whose expression
      pattern correlates with chondrocyte differentiation and arthritis. We have used
      the COMP promoter as a model to identify regulatory sequences necessary for
      chondrocyte-specific expression and to identify cell type-specific proteins that
      bind these sequences. We have previously cloned 1.9 kilobases of the 5(')
      flanking promoter sequence of the murine COMP gene and by deletion analysis have
      identified two spatially distant chondrocyte-specific regulatory regions. One
      element is situated proximally (-125 to -75), and a second region is located
      distally (-1925 to -592) relative to the transcription start site. In the present
      study, we performed a finer deletion analysis of the region of the COMP promoter
      from -1925 to -592 and identified a silencer region situated between -1775 and 
      1725. This silencer binds sequence-specific protein complexes; the intensity of
      these complexes is greater in two different fibroblast cell lines (NIH3T3 and
      10T1/2) than in chondrocytic RCS cells. Competition experiments localized the
      binding site of these protein complexes from -1775 to -1746; deletion of this 30
      bp site results in a selective increase in COMP promoter activity in fibroblasts.
      Four tandem repeats of this 30-bp site are sufficient to confer negative
      transcriptional regulation on a heterologous promoter (SV40) in NIH3T3
      fibroblasts. These results suggest that negative regulation of transcription is
      an important mechanism for chondrocyte-specific expression of the COMP gene.

PMID- 15183431
TI  - Chondrocyte cell death and intracellular distribution of COMP and type IX
      collagen in the pseudoachondroplasia growth plate.
AB  - Cartilage oligomeric matrix protein (COMP) is a large extracellular matrix
      protein expressed in cartilage, ligament and tendon. Mutations in the COMP gene
      cause two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH)
      and Multiple Epiphyseal Dysplasia (MED/EDM1). We report on a novel point mutation
      D511Y in the seventh calcium-binding repeat of the COMP gene and the resulting
      iliac crest growth plate pathology. The PSACH iliac crest growth plate is
      comprised of a large region of resting chondrocytes above a narrow region
      composed of clusters of disorganized proliferative and hypertrophic chondrocytes.
      Chondrocytes in all zones show massive intracellular retention of COMP and the
      surrounding extracellular matrix is deficient in COMP. Moreover, the 511Y COMP
      mutation selectively affects type IX collagen as little is found in the growth
      plate matrix whereas type II collagen and aggrecan are abundant in the matrix.
      Chondrocyte remnants are observed in the chondrocyte clusters and dead cells are
      found throughout the growth plate. Apoptosis studies demonstrate an unusual
      pattern of TUNEL staining in the PSACH chondrocytes compared to the control
      growth plate. These in vivo findings support our previous observation that
      retention of COMP leads to chondrocyte death. These results also add to the
      increasing evidence that PSACH and EDM1 are rER storage diseases and that
      impaired linear growth and joint erosion are caused by the disruptive effect of
      massive amounts of COMP within the chondrocytes.

PMID- 15183432
TI  - Neuromuscular quadriceps dysfunction prior to osteoarthritis of the knee.
AB  - Decreased maximal quadriceps strength and voluntary activation has been observed
      in patients with osteoarthritis in previous studies, but those results do not
      allow any conclusions to be drawn as to whether quadriceps dysfunction precedes
      or follows osteoarthritis. Thirty-two patients (group a) who underwent partial
      meniscectomy 48+/-9 month prior to the study were matched according to their
      weight and body mass index with a control group (group b). The twitch
      interpolation technique was used to determine maximal voluntary contraction (MVC)
      and voluntary activation (VA) of the quadriceps muscle of both legs. Subjective
      assessment of the knee was performed using the Lysholm-Score. AP and lateral X
      rays of the operated knee were obtained. None of the participants showed any
      evidence of characteristic radiological or clinical signs for osteoarthritis. A
      significantly lower MVC was noticed in both the affected and the contralateral
      knee of group a in comparison to group b (p < 0.01). The VA in group a yielded
      80.9+/-15.4% for the injured side and 83.1+/-11.5% for the contralateral side,
      with no statistical difference (p = 0.18). The VA in group b was 89.4+/-5.8% for
      the right side and 88+/-6.8% for the left side both being significantly higher in
      comparison to group a. This study has shown, that patients following meniscus
      resection present with bilateral quadriceps weakness as already described in
      patients with manifest osteoarthritis. The authors hypothesise that muscle
      dysfunction may be an etiologic factor underlying the pathologic changes of
      osteoarthritis. Whether muscle dysfunction occurs also at other sites, e.g. in
      the upper extremity, remains unclear but would be of interest in order to detect
      a generalized neuromuscular dysfunction.

PMID- 15183433
TI  - Expression of the CD44 variant isoform 5 in the human osteoarthritic knee joint:
      correlation with radiological, histomorphological, and biochemical parameters.
AB  - PURPOSE: The purpose of this study was to correlate expression of CD44v5 in
      osteoarthritic synovium, cartilage, and synovial fluid with radiographical,
      histomorphological, and biochemical data. METHODS: Cartilage and synovia
      specimens of 27 patients with osteoarthritis were histomorphologically assessed
      according to Mankin and Pelletier, respectively. Extended weight-bearing antero
      posterior radiographs were evaluated according to Kellgren and Ahlback.
      Expression of membrane-bound CD44v5 was analyzed by immunohistochemistry and
      levels of soluble CD44v5 were determined by ELISA. RESULTS: Expression of CD44v5
      in cartilage and synovia was detected in 67% and 59% of the patients,
      respectively. Immunohistochemical findings in cartilage correlated significantly
      with structural cartilage changes (p < 0.001), whereas no correlation was found
      between expression in synovia and inflammatory synovial changes. Additionally, no
      relationship was evident between CD44v5 expression and radiographical data, but
      expression in cartilage and synovium was significantly correlated with each other
      (p < 0.04). Surprisingly, expression of CD44v5 in both cartilage and synovia was
      negatively correlated with synovial fluid levels of TNFalpha (p < 0.03 and p <
      0.02, respectively), and no association was evident with levels of IL-1beta.
      CONCLUSIONS: The data demonstrate expression of CD44v5 in osteoarthritic
      cartilage and synovia, probably independent of joint inflammation. But more
      importantly, expression of this receptor variant in cartilage seems to be
      strongly related to the degree of cartilage destruction.

PMID- 15183434
TI  - Chondrocyte viability in press-fit cryopreserved osteochondral allografts.
AB  - The viability of chondrocytes in press-fit glycerol-preserved osteochondral
      allografts was compared to that in fresh autografts, after transplantation into
      load-bearing and non-load-bearing sites in mature sheep stifle joints. We used
      macroscopic grading, tonometer pen indentation testing, histology, sulfate uptake
      and viability as determined by confocal-microscopy to assess cartilage condition.
      Despite there being no statistical differences between macroscopic appearance and
      tonometer testing of all grafts, confocal microscopy and histology demonstrated a
      positive effect of load-bearing placement on cryopreserved osteochondral
      allografts. Allografts transplanted into load-bearing sites demonstrated superior
      confocal microscopy-measured chondrocyte viability (77%+/-17%SD) than those
      transplanted into non-load-bearing sites (25%+/-2%). Load-bearing effect was not
      seen in autografts (78%+/-15%), and was comparable in adjacent cartilage (83%+/
      9%). Similarly, load-bearing allografts demonstrated histological scoring closer
      to that of autografts and adjacent cartilage, all of which fared significantly
      better than non-load-bearing allografts. Load-bearing allografts had a greater
      amount of fibrocartilage than autografts or adjacent cartilage but less
      fibrocartilage than non-load-bearing allografts. Both autografts and allografts
      had non-significant increases in metabolism compared to adjacent cartilage as
      measured by sulfate-uptake. Load-bearing placement improved chondrocyte viability
      of glycerol cryopreserved osteochondral allograft following a press-fit
      implantation.

PMID- 15183435
TI  - Evaluation of a method to map tibiofemoral contact points in the normal knee
      using MRI.
AB  - A technique using magnetic resonance imaging (MRI) is proposed for analysis of
      knee motion that is practical in the clinical situation. T1 weighted fast spin
      echo (FSE) and spoiled gradient echo (GE) sequences were compared to image both
      knees at 15 degrees intervals from 0 degrees to 90 degrees flexion, while
      unloaded and loaded. The medial and lateral tibiofemoral contact points were
      mapped reliably using both FSE sequences and GE sequences with intra-class
      correlation((2,1)) of 0.96 (CI 99%=0.94-0.97) and 0.94 (CI 99%=0.91-0.97),
      respectively. Results were consistent with the current literature on knee motion:
      the medial and lateral tibiofemoral contact pathways were different (F(1,80) =
      253.9, p < 0.0001) reflecting the longitudinal rotation of the knee, the loaded
      and unloaded knees were not different in the healthy knee (F(1,80) = 0.007, p =
      0.935), and the left and right knee were consistent for each individual (F(1,80)
      = 0.005, p = 0.943). Therefore, right to left differences may be attributed to
      pathology. MRI analysis of knee kinematics as described by this technique of
      tibiofemoral contact point mapping provides a robust and reliable method of
      recording the tibiofemoral contact pattern of the knee.

PMID- 15183436
TI  - Secondary motions of the knee during weight bearing and non-weight bearing
      activities.
AB  - The objective of this study was to test the hypothesis that during a weight
      bearing activity such as walking, a dynamic range (envelope of motion) exists in
      the relationship between the secondary knee motions (anterior-posterior (AP)
      translation, internal-external (IE) rotation, and abduction-adduction (Ab
      Adduction)) and knee flexion angle. In addition differences in the envelope of
      motion between a weight bearing and non-weight bearing activity were tested. The
      hypothesis was evaluated by testing for differences (offsets) in secondary
      displacements at specific knee flexion angles during the walking cycle and seated
      leg extension (non-weight bearing). Kinematic measurements were obtained using a
      previously developed point cluster technique to analyze the six-degrees of
      freedom movement of the knee. During walking, phase plots of the IE rotation and
      AP translation versus knee flexion demonstrated significant offsets from one
      phase of the gait cycle to another at the same flexion angle. During the non
      weight bearing activity, no significant offset in the secondary movement was
      found; the knee followed the same pathway of motion during the flexion and
      extension phase of this activity. The characteristics of the secondary motions
      during walking indicated that secondary knee movements are caused by the external
      forces (muscle, inertial and gravitational) that act on the knee during the
      various phases of the walking cycle. The boundaries of the envelope appear to
      reflect the characteristics of the passive restraints. The weight bearing
      secondary motion AP and IE rotation seen during a walking activity demonstrated
      an envelope of dynamic laxity that could potentially be used to evaluate
      functional instabilities at the knee.

PMID- 15183437
TI  - The effect of tibiofemoral joint kinematics on patellofemoral contact pressures
      under simulated muscle loads.
AB  - Altered patellofemoral joint contact pressures are thought to contribute to
      patellofemoral joint symptoms. However, little is known about the relationship
      between tibiofemoral joint kinematics and patellofemoral joint contact pressures.
      The objective of this paper was to investigate the effect of tibiofemoral joint
      kinematics on patellofemoral joint pressures using an established in vitro
      robotic testing experimental setup. Eight cadaveric knee specimens were tested at
      0 degrees, 30 degrees, 60 degrees, 90 degrees, and 120 degrees of flexion under
      an isolated quadriceps load of 400 N and a combined quadriceps/hamstrings load of
      400 N/200 N. Tibiofemoral joint kinematics were measured by the robot and contact
      pressures by a TekScan pressure sensor. The isolated quadriceps loading caused
      anterior translation and internal rotation of the tibia up to 60 degrees of
      flexion and posterior translation and external rotation of the tibia beyond 60
      degrees. The co-contraction of the hamstring muscles caused a posterior
      translation and external rotation of the tibia relative to the motion of the
      tibia under the quadriceps load. Correspondingly, the contact pressures were
      elevated significantly at all flexion angles. For example, at 60 degrees of
      flexion, the hamstrings co-contraction increased the posterior tibial translation
      by approximately 2.8 mm and external tibial rotation by approximately 3.6
      degrees. The peak contact pressure increased from 1.4+/-0.8 to 1.7+/-1.0 MPa, a
      15% increase. The elevated contact pressures after hamstrings co-contraction
      indicates an intrinsic relation between the tibiofemoral joint kinematics and the
      patellofemoral joint biomechanics. An increase in posterior tibial translation
      and external rotation is accompanied by an increase in contact pressure in the
      patellofemoral joint. These results imply that excessive strength conditioning
      with the hamstring muscles might not be beneficial to the patellofemoral joint.
      Knee pathology that causes an increase in tibial posterior translation and
      external rotation might contribute to degeneration of the patellofemoral joint.
      These results suggest that conservative treatment of posterior cruciate ligament
      injury should be reconsidered.

PMID- 15183438
TI  - The sensitivity of tibiofemoral contact pressure to the size and shape of the
      lateral and medial menisci.
AB  - In an effort to prevent degeneration of articular cartilage associated with
      meniscectomies, both meniscal allografts and synthetic replacements have been
      studied. A number of biomechanical criteria may be important for a meniscal
      replacement to restore normal tibiofemoral contact pressure in the knee joint and
      hence be clinically successful. One of these criteria is geometric similarity.
      The objectives of the current study were to: determine the sensitivity of the
      contact variables of the tibial plateau to the transverse depth and width of both
      the lateral and medial menisci; determine the sensitivity of the contact
      variables of the tibial plateau to the cross-sectional width and height of the
      lateral and medial menisci; and determine the tolerances on each of the four
      parameters for both menisci. To satisfy these objectives, a previously developed
      finite element model of the tibiofemoral joint was used to compute the contact
      pressure distribution on the tibial plateau. The effect of the above-mentioned
      geometric parameters on the contact behavior was studied by perturbing the finite
      element model. Results showed that the contact variables are similarly sensitive
      to both the transverse and cross-sectional parameters of the menisci.
      Additionally the medial meniscal parameters have a greater effect on the contact
      variables than do the lateral meniscal parameters. Finally, less than a 0.5 mm
      change in the medial meniscal height and greater than a 1 mm change in the
      lateral meniscal height could be tolerated before the relative difference in the
      contact variables from those for the original geometry exceeded 10%. Thus in the
      design or selection of meniscal replacements, each of the four parameters should
      be measured when sizing a replacement tissue. Also tighter tolerances should be
      placed on the medial meniscal parameters compared to the lateral meniscal
      parameters.

PMID- 15183439
TI  - Compliant positioning of total hip components for optimal range of motion.
AB  - Impingement between femoral neck and endoprosthetic cup is one of the causes for
      dislocation in total hip arthroplasty (THA). Choosing a correct combined
      orientation of both components, the acetabular cup and femoral stem, in manual or
      computer-assisted implantation will yield a maximized, stable range of motion
      (ROM) and will reduce the risk for dislocation. A mathematical model of a THA was
      developed to determine the optimal combination of cup inclination, cup
      anteversion, and stem antetorsion for maximizing ROM and minimizing the risk for
      cup-neck impingement. Single and combined hip joint motions were tested. A
      radiographic definition was used for component orientation. Additional
      parameters, such as stem-neck (CCD) angle, head-neck ratio, and the design of the
      acetabular opening, were also considered. The model showed that a maximized and
      safe ROM requires compliant, well-defined combinations of cup inclination, cup
      anteversion, and stem antetorsion depending on the intended ROM. Radiographic cup
      anteversion and stem antetorsion were linearly correlated. Additional internal
      rotation reduced flexion, and additional external rotation reduced extension,
      abduction and adduction. The articulating hemispheric surface of acetabular cups
      should be oriented between 40 degrees and 45 degrees of radiographic inclination,
      between 20 degrees and 28 degrees of radiographic cup anteversion, and should be
      combined with stem antetorsion so that the sum of cup anteversion plus 0.7 times
      the stem antetorsion equals 37 degrees. Final component orientation must also
      consider cup containment, implant impingement with bone and soft tissue, and
      preoperative skeletal contractures or deformities to achieve the optimal
      compromise for each patient.

PMID- 15183440
TI  - Early cementing does not increase debond energy of grit blasted interfaces.
AB  - A fracture mechanics based approach was used to determine the debond energy or
      fracture toughness of the stem-cement interface for a variety of conditions. The
      goals of the study were to determine if early cementing of stems increased the
      debond energy of grit blasted stem-cement interfaces and if debond energy was
      dependent on mold type. Early (2 min) and late (6 min) times of cementation were
      considered for two different grit blasted surface finishes (16 and 60 grit,
      Ra=5.7 or 2.3 microm). Specimen fabrication was performed using a relatively
      simple, unconstrained rectangular mold and a mold that more closely simulated in
      vivo conditions. The rectangular mold was used with all components at room
      temperature whereas the in vivo simulated mold had a body that resembled the
      femoral canal in shape and was warmed to body temperature. Early cementing did
      not increase the debond energy using the in vivo simulated mold. Extensive
      porosity was found at the interface, and porosity had a strong negative effect on
      debond energy. When the simpler, rectangular mold was used, early cementing did
      result in higher debond energies, but few voids were found at the interface. It
      appears that porosity at the interface was the major factor affecting the debond
      energy. The results from this study do not support the concept that improved stem
      cement interface strength can be obtained by application of the cement while it
      is in a low viscosity state.

PMID- 15183441
TI  - Analysis of a retrieved UHMWPE acetabular cup crosslinked in air with 1000 kGy of
      gamma radiation.
AB  - The oxidation and degradation that accompany high dose gamma irradiation in air
      for crosslinking and sterilization are important because they could affect the
      clinical performance of polyethylene total joint implants. We report a clinical
      case of a 1000 kGy gamma-irradiated, highly crosslinked ultra-high molecular
      weight polyethylene acetabular cup retrieved 24 years postoperatively.
      Performance evaluations included absorbed radiation dose, total wear penetration,
      average wear rate, crystallinity, oxidation, and equibiaxial tensile properties.
      A retrieved acetabular cup of the same grade of polyethylene but gamma-sterilized
      using a conventional dose was used as control. The highly crosslinked and control
      cups took in about 1300 and 30 kGy of radiation, respectively, as measured using
      a trans-vinylene index. Direct dimensional measurements revealed average wear
      rates of the highly crosslinked and control cups were 0.04 and 0.06 mm/year,
      respectively. The oxidation index of the highly crosslinked cup was very high
      (0.679), but equivalent to that of a 1000 kGy irradiated reference cup. The
      retrieved highly crosslinked cup showed much higher equibiaxial ultimate tensile
      strength than the retrieved control cup. Based on these observations, the
      increased wear resistance and equibiaxial tensile properties that resulted from
      extensive crosslinking in the presence of air were partially offset by the
      adverse effects caused by immediate oxidation during the process.

PMID- 15183442
TI  - Comparison of the response of primary human blood monocytes and the U937 human
      monocytic cell line to two different sizes of alumina ceramic particles.
AB  - It is well recognized that wear particles derived from orthopaedic implants have
      the potential to induce inflammation, which may eventually lead to aseptic
      loosening of the artificial joint. We hypothesized that alumina ceramic particles
      of different sizes cause a differential cytokine response by human monocytes. To
      test this hypothesis a human monocytic cell line (U937) and primary human blood
      monocytes obtained from healthy volunteers were exposed to ceramic particles
      within the range known to be generated in vivo. Cellular responses were measured
      by quantifying the relative gene expression of 12 different cytokines using
      TAQman Real-Time Polymerase Chain Reaction (RT-PCR). Our results demonstrate that
      at a particle to cell ratio of 100:1, 0.5 microm ceramic particles consistently
      provoked higher amounts of Interleukin-1alpha (IL-1alpha), IL-1beta, IL-8, IL-10
      and Tumor necrosis factor-alpha (TNF-alpha) steady state mRNA by U937 cells. As
      expected, the variability of cytokine expression in primary blood monocytes was
      much higher compared to the cell line however, a similar trend was observed.
      These results show a differential response to ceramic particle size, which may
      imply that 0.5 microm particles are less biocompatible. New ceramic implants can
      be designed to generate a known particle size range in vivo. Implant materials of
      this type may induce relatively lower levels of production of inflammatory
      cytokines resulting in a reduced incidence of failure due to aseptic loosening.

PMID- 15183443
TI  - Lengthening of double-looped tendon graft constructs in three regions after
      cyclic loading: a study using Roentgen stereophotogrammetric analysis.
AB  - Lengthening of a double-looped tendon graft construct used to reconstruct the
      anterior cruciate ligament (ACL) can result in an increase in anterior knee
      laxity and affect the stability of the reconstructed knee. Three possible regions
      where lengthening of the construct can occur are (1) the region of the tibial
      fixation, (2) the region of the femoral fixation, and (3) the region of the graft
      between the fixations. One objective of this study was to demonstrate the
      feasibility of using Roentgen stereophotogrammetric analysis (RSA) to determine
      the lengthening in each region of a double-looped graft construct subjected to
      cyclic loading. A second objective was to determine which region(s) contributes
      most to an increase in length of this graft construct. Radio-opaque markers were
      attached to ten grafts to measure the lengthening in each of the three regions.
      Each graft was passed through a tibial tunnel in a bovine tibia, looped around a
      rigid cross-pin, and fixed to the tibia with a Washerloc fixation device. The
      grafts were cyclically loaded for 225,000 cycles from 20 to 170 N. Prior to and
      at intervals during the cyclic loading, simultaneous radiographs were taken of
      the tibia and graft. RSA was used to determine the 3-dimensional coordinates of
      the markers from which the lengthening in each region was computed at each
      interval. The regions of the tibial and femoral fixations were the largest
      contributors to the increase in length of the graft, with maximum average values
      of 0.91 and 0.76 mm respectively after 225,000 cycles. The region between the
      fixations contributed least to lengthening of the graft, with a maximum average
      value of 0.23 mm. More than 90% of the lengthening in each region occurred before
      100,000 cycles of loading. RSA proved to be a useful method for measuring
      lengthening in all three regions of the graft construct. Lengthening of the graft
      construct in both regions of fixation is sufficiently large that the combined
      contributions may cause a recurrence of instability in some knees.

PMID- 15183444
TI  - Cyclic strain influences the expression of the vascular endothelial growth factor
      (VEGF) and the hypoxia inducible factor 1 alpha (HIF-1alpha) in tendon
      fibroblasts.
AB  - Neovascularization is involved in beneficial and detrimental processes of tendon
      pathology. We investigated the influence of repetitive motion on the expression
      of the most important angiogenic factor, the vascular endothelial growth factor
      (VEGF) in the 3T3 NIH fibroblast cell line and in cultures of rat Achilles tendon
      fibroblasts. Monolayers of subconfluently grown cells were stretched in
      rectangular silicone dishes with cyclic uniaxial movement. Strain was applied
      over 24 h varying the frequency (0.5-1 Hz). Fibroblasts (3T3 fibroblasts and rat
      Achilles tendon cultures) cultivated without the application of cyclic strain
      released measurable VEGF amounts into their culture supernatants. Cyclic
      stretching of the cells with a frequency of 1 Hz resulted in an increased
      expression of VEGF. A low frequency (0.5 Hz) reduced VEGF expression to control
      levels. RT PCR revealed VEGF 121 and VEGF 165 as the only splice forms that were
      induced by cyclic stretching. Western blot experiments could further show that
      cyclic stretching induced activation of the transcription factor HIF-1alpha.
      These results demonstrate that mechanical factors are involved in the regulation
      of VEGF expression in tendon tissue.

PMID- 15183446
TI  - The role of cutaneous sensation in the motor function of the hand.
AB  - We studied the effect of abolishing cutaneous sensation (by infiltrating local
      anaesthetic around the median nerve at the wrist) on the ability of 10 healthy
      volunteers (a) to maintain a submaximal isometric pinch-grip force for 30 s
      without visual feedback, and (b) to perform a fine finger-manipulation
      'handwriting' task. Blocking cutaneous sensation had no effect on ability to
      maintain pinch force, suggesting that muscle afferents have the major role in
      force-control feedback. However, a near-linear fall in force, present with or
      without block (mean slope=-1.3+/-0.2% s(-1)), which cannot be attributed to motor
      fatigue, reveals a shortcoming of the afferent feedback system. Blocking
      cutaneous sensation did impair ability to perform the more demanding writing
      task, as judged by an 18+/-6% increase in the length of the path between target
      points, a 22+/-9% increase in the duration of the movement and a 63+/-24% in
      'normalised averaged rectified jerk', an averaged time-derivative of acceleration
      (all significantly nonzero, P < 0.04). These experiments demonstrate the relative
      importance of muscular and cutaneous afferent feedback on two aspects of hand
      performance, and provide a way to quantify the deficit resulting from the lack of
      cutaneous sensation.

PMID- 15183445
TI  - Extracorporeal shock waves promote healing of collagenase-induced Achilles
      tendinitis and increase TGF-beta1 and IGF-I expression.
AB  - Extracorporeal shock waves (ESW) have recently been used in resolving tendinitis.
      However, mechanisms by which ESW promote tendon repair is not fully understood.
      In this study, we reported that an optimal ESW treatment promoted healing of
      Achilles tendintis by inducing TGF-beta1 and IGF-I. Rats with the collagenease
      induced Achilles tendinitis were given a single ESW treatment (0.16 mJ/mm(2)
      energy flux density) with 0, 200, 500 and 1000 impulses. Achilles tendons were
      subjected to biomechanical (load to failure and stiffness), biochemical
      properties (DNA, glycosaminoglycan and hydroxyproline content) and histological
      assessment. ESW with 200 impulses restored biomechanical and biochemical
      characteristics of healing tendons 12 weeks after treatment. However, ESW
      treatments with 500 and 1000 impulses elicited inhibitory effects on tendinitis
      repair. Histological observation demonstrated that ESW treatment resolved edema,
      swelling, and inflammatory cell infiltration in injured tendons. Lesion site
      underwent intensive tenocyte proliferation, neovascularization and progressive
      tendon tissue regeneration. Tenocytes at the hypertrophied cellular tissue and
      newly developed tendon tissue expressed strong proliferating cell nuclear antigen
      (PCNA) after ESW treatment, suggesting that physical ESW could increase the
      mitogenic responses of tendons. Moreover, the proliferation of tenocytes adjunct
      to hypertrophied cell aggregate and newly formed tendon tissue coincided with
      intensive TGF-beta1 and IGF-I expression. Increasing TGF-beta1 expression was
      noted in the early stage of tendon repair, and elevated IGF-I expression was
      persisted throughout the healing period. Together, low-energy shock wave
      effectively promoted tendon healing. TGF-beta1 and IGF-I played important roles
      in mediating ESW-stimulated cell proliferation and tissue regeneration of tendon.

PMID- 15183447
TI  - Mechanical properties of the scapholunate ligament correlate with bone mineral
      density measurements of the hand.
AB  - The mechanical properties of the scapholunate ligament have been previously
      examined in small sample sizes, with ultimate load and occasionally stiffness
      reported. The present study examined 16 scapholunate ligaments in uniaxial
      extension at two rates and determined stiffness, ultimate load, and stress
      relaxation properties. Mean stiffness values of 66.4+/-28.6 N/mm at an elongation
      rate of 50 mm/min and 94.5+/-44.4 N/mm at an elongation rate of 100 mm/min were
      found. Relaxation behavior, determined by the percent load remaining after 100 s,
      was found to be 68.1+/-12%. Mean ligament ultimate loads were 357+/-110 N (n =
      8). In eight specimens, failure occurred in bone. Positive correlations were
      observed between bone mineral density of the hand and ligament stiffness,
      ligament ultimate load, and bone ultimate load. No correlation was observed
      between bone mineral density and ligament load relaxation behavior. The results
      provide a comprehensive understanding of scapholunate ligament biomechanics and
      demonstrate a relationship between bone and ligament properties.

PMID- 15183448
TI  - Measuring myoelectric fatigue of the serratus anterior in healthy subjects and
      patients with long thoracic nerve palsy.
AB  - Proper function of serratus anterior plays a vital role in the movement and
      stability of the scapula, and thus of the glenohumeral joint and the upper limb.
      The unique anatomy of this muscle makes direct measurements of its fatigue
      properties impossible. Here we describe for the first time indirect measurements
      of the myoelectric manifestations of fatigue in the serratus anterior. Eight
      healthy volunteers (29-35 years) were tested, four of them on two different
      occasions, using two exercise protocols (60 s isometric maximum upward force in
      120 degrees arm flexion, and 60 s maximum forward force at 90 degrees arm
      flexion) with simultaneous recording by surface and wire electrodes applied
      according to established methods. Signals were analysed to obtain the rate of
      fall of median EMG frequency and the rate of rise of amplitude. Both exercise
      protocols gave similar results. Frequency-slope measurements (mean rate of fall
      0.6+/-0.1% initial value per second (% s(-1)) with both surface and wire
      electrodes) were more precise than those of amplitude (mean rate of rise 2.6+/
      0.3% s(-1) with surface electrodes, only 1.3+/-0.2% s(-1) with wire electrodes).
      Surface electrodes gave much lower variation than fine wires, the coefficient of
      variation of slopes for surface electrodes being approximately 20-40% both
      between studies in a single subject and between subjects. In 5 patients (aged 22
      59 years) recovering from long thoracic nerve palsy studied using surface
      electrodes the frequency slopes was normal (0.6+/-0.1% s(-1)), while the
      amplitude slope was reduced (0.9+/-0.4% s(-1), P = 0.01). This shows abnormal
      fatigue properties of the reinnervated muscle and a dissociation between the
      frequency and amplitude manifestations of fatigue.

PMID- 15183449
TI  - Evaluation of muscle metabolic activity in the lower limb of a transfemoral
      amputee using a prosthesis by using (18)F-FDG PET imaging--an application of PET
      imaging to rehabilitation.
AB  - This study used FDG PET to evaluate the lower limb muscles metabolic activities
      of transfemoral amputees during walking with prostheses. As a preliminary study,
      FDG PET was applied for two normal adult volunteers to evaluate muscle activity
      in the lower extremities after gait exercise. This same method was applied for
      two amputee volunteers with prostheses. We found that FDG accumulated more in
      both gluteus medius muscles after gait exercise compared to other muscles in
      normal adult volunteers. In the skilled amputee volunteer, FDG uptake increased
      in the adductor and gluteus medius in the amputated side, while in the unskilled
      the adductor, gluteus maximus, and gluteus medius showed increased FDG uptake
      only in the normal side. This result suggests that basic metabolic changes such
      as an increase in oxidative metabolism and less reliance on glycolytic activity
      would occur as a result of skeletal muscle training in amputees.

PMID- 15183450
TI  - Predicting shoulder strength using allometry: implications for shoulder outcome
      assessments.
AB  - INTRODUCTION: Shoulder strength is an integral component of shoulder function. In
      assessing shoulder function many functional scales rely on direct or indirect
      measures of strength. Strength, and thus these scales, is often highly correlated
      with age. We propose an allometric method for assessing shoulder strength.
      Allometric modeling has provided accurate predictions of biologic growth and
      physiologic function in both human and animal studies. Allometry utilizes the
      relationship between the two homologous structures on the left and right sides of
      the body, providing in effect an internal control and thus eliminating many
      confounding effects, e.g. age and level of activity. METHODS: Twenty patients
      with unilateral shoulder dysfunction underwent strength testing of their affected
      and unaffected shoulder. Strength testing of the bilateral shoulders was also
      assessed in twenty people without shoulder pain in order to delineate the effect
      of hand dominance on strength in those without shoulder pain. Absolute and
      predicted strength deficits of the involved shoulder were calculated via
      regression analysis. Pearson's correlation coefficients were computed between age
      and strength. RESULTS: Utilizing the contralateral extremity as an internal
      control eliminates age as a confounding variable in predicting strength outcomes
      (r = 0.093). CONCLUSION: Allometric concepts, applied to shoulder strength
      assessment, eliminates age as a confounding variable. Strength testing of both
      shoulders should be considered in the development of future shoulder outcome
      scales in order to eliminate the strong influence of age.

PMID- 15183451
TI  - Multidirectional kinematics of the glenohumeral joint during simulated simple
      translation tests: impact on clinical diagnoses.
AB  - At the end ranges of motion, the glenohumeral capsule limits translation of the
      humeral head in multiple directions. Since the 6-degree of freedom kinematics of
      clinical tests are commonly utilized to diagnose shoulder injuries, the objective
      of this study was to determine the magnitude and repeatability of glenohumeral
      joint kinematics during a simulated simple anteroposterior translation test in
      the anterior and posterior directions. A magnetic tracking system was used to
      determine the kinematics of the humerus with respect to the scapula in eight
      cadaveric shoulders. At 60 degrees of glenohumeral abduction and 0 degrees of
      flexion/extension, a clinician applied anterior and posterior loads to the
      humerus at 0 degrees, 30 degrees, and 60 degrees of external rotation until a
      manual maximum (simulating a simple translation test) was achieved. Prior to each
      test, the reference position of the humerus shifted posteriorly 1.8+/-2.0 and
      4.1+/-3.8 mm at 30 degrees and 60 degrees of external rotation, respectively.
      Anterior translation decreased significantly (p < 0.05) from 18.2+/-5.3 mm at 0
      degrees of external rotation to 15.5+/-5.1 and 9.9+/-5.5 mm at 30 degrees and 60
      degrees, respectively. However, no significant differences were detected between
      the posterior translations of 13.4+/-6.4, 17.1+/-5.0, and 15.8+/-6.0 mm at 0
      degrees, 30 degrees, and 60 degrees of external rotation, respectively. Coupled
      translations (perpendicular to the direction of loading) at 0 degrees (6.1+/-4.0
      and 3.8+/-2.9 mm), 30 degrees (4.7+/-2.7 and 5.9+/-3.1 mm), and 60 degrees (2.3+/
      2.3 and 5.0+/-3.5 mm) of external rotation were in the inferior direction in both
      the anterior and posterior directions, respectively. Based on the data obtained,
      performing a simulated simple translation test should result in coupled inferior
      translations and anterior translations that are a function of external rotation.
      The low standard deviations demonstrate that the observed translations should be
      repeatable. Furthermore, capsular stretching or injury to the anterior-inferior
      region of the capsule should be detectable during clinical examination if
      excessive coupled translations exist or no posterior shift of the reference
      position with external rotation is noted.

PMID- 15183452
TI  - Sequential dynamics of inflammatory cytokine, angiogenesis inducing factor and
      matrix degrading enzymes during spontaneous resorption of the herniated disc.
AB  - Intervertebral disc herniation (HD) is one of the most common orthopaedic
      conditions. MRI analysis of HD has revealed a spontaneous resorption mechanism
      related with neo-vascularization. It appears that the interaction of activated
      macrophages with disc tissues leads to the generation of inflammatory cytokines.
      Moreover, inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha)
      is required for the induction of angiogenesis inducing factors such as vascular
      endothelial growth factor (VEGF) or matrix degrading enzymes such as MMP-3, MMP-7
      and plasmin. We hypothesized that these molecules play a crucial role during
      spontaneous HD resorption. In this study, we have examined the sequential
      expression of these molecules using a co-culture system which is composed of the
      interaction of activated macrophages and disc tissues as a model of the acute
      response of inflammation occurred in HD. We have also considered the mechanism of
      activating latent MMPs during HD resorption process. Current our results indicate
      that upregulation of both TNF-alpha mRNA and protein expressions occur first in
      the inflammation induced by HD. VEGF upregulation follows the increased level of
      TNF-alpha expression. Both plasmin and MMP-3 are upregulated at later time
      points. We also demonstrate that both TNF-alpha and VEGF induce upregulated
      expression of urokinase-type plasminogen activator (u-PA). Our previous work has
      demonstrated that TNF-alpha could upregulate the expression of VEGF, MMP-3 and
      MMP-7 in the co-culture system. It has been reported that plasmin could affect to
      activate latent MMPs. Based on these findings, we suggest that TNF-alpha acts as
      the initiator of inflammation following contact between macrophages and disc
      chondrocytes and that plasmin and u-PA play a crucial role in activation of MMPs.
      We propose a spontaneous HD resorption cascade. Further understanding of the
      resorption process may provide future novel therapies for HD.

PMID- 15183453
TI  - Theoretical model and experimental results for the nonlinear elastic behavior of
      human annulus fibrosus.
AB  - The physical properties of the annulus fibrosus are critical to the
      intervertebral disc's biomechanical function; alterations with degeneration and
      aging can contribute directly to joint dysfunction and pain. A constitutive model
      that links the mechanical structure of the annulus to its material properties is
      important for many bioengineering purposes. To this end, we developed a strain
      energy function with separate terms to represent the matrix, the fibers, and the
      interactions between the constituents. Additionally, we measured the tensile and
      compressive stress-strain response of the annulus in the circumferential
      direction. We simultaneously applied the strain energy function to these new data
      and to data from a wide range of experimental protocols reported in the
      literature. By choosing experimental protocols that use an unloaded reference
      configuration, we developed a comprehensive formulation for the multiaxial
      annular elastic behavior. As a partial validation, this formulation predicted
      experimental results that were not included in model parameter specification. We
      anticipate that this constitutive formulation will be useful for computational
      simulations of the disc's biomechanical response and for elucidating structure
      function relationships of the annulus fibrosus.

PMID- 15183454
TI  - Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of
      Ewing's sarcoma cells in vitro.
AB  - The defining cytogenetic abnormality of Ewing's sarcoma is the presence of a
      balanced t(11;22) translocation expressing the EWS/FLI-1 chimeric fusion protein.
      The effect of EWS/FLI-1 appears to be dominant negative since over-expression of
      EWS does not overcome the sarcoma phenotype. Previous studies have shown that
      EWS/FLI-1 as well as related sarcoma fusion proteins are necessary and sufficient
      to induce transformation both in vitro and in vivo. In this study we report that
      synthetic small interfering RNA (siRNA) specifically suppresses EWS/FLI-1 fusion
      gene expression in SK-ES Ewing's sarcoma cells. Knockdown of the EWS/FLI-1 fusion
      protein is correlated with decreased cell proliferation and increased apoptosis.
      We demonstrate that Ewing's sarcoma tumors as well as Ewing's sarcoma cell lines
      predominantly express the CXCR4 chemokine receptor. Using an in vitro invasion
      assay, the SDF-1 ligand of CXCR4 was shown to be a potent stimulus of invasion by
      SK-ES cells. Knockdown of EWS/FLI-1 by RNA interference abrogates the
      invasiveness of SK-ES cells. These experiments suggest that targeted silencing of
      the EWS/FLI-1 fusion gene by siRNA represents a promising strategy to study the
      loss of EWS/FLI-1 protein in Ewing's sarcoma cells of otherwise identical genetic
      background.

PMID- 15183455
TI  - Ischemic-preconditioning does not prevent neuromuscular dysfunction after
      ischemia-reperfusion injury.
AB  - The primary purpose of this study was to evaluate ischemic-preconditioning (IPC)
      as a means of improving tolerance to ischemia-reperfusion (IR) stress on
      neuromuscular function. A secondary objective was to isolate the area of injury
      within the neuromuscular unit responsible for contractile dysfunction after IR
      injury. Twenty-eight male rabbits were randomly assigned to four groups (sham,
      IPC only, sustained ischemia only, IPC and sustained ischemia). The IPC protocol
      consisted of three cycles of 10 min of tourniquet-induced ischemia (125 mmHg)
      followed by 10 min of reperfusion. Sustained ischemia was induced by 350 mmHg
      external compression for 2 h. Peak tetanic tension of the tibialis anterior (TA)
      muscle was evaluated 48 h after the tourniquet protocol by both peroneal nerve
      and direct muscle stimulation, with and without pharmacologic neuromuscular
      junction blockade. Animals subjected to combined IPC and sustained ischemia had
      an equivalent loss of contractile force to those undergoing sustained ischemia
      alone. Two hours of tourniquet-induced ischemia resulted in marked dysfunction of
      the TA neuromuscular unit when evaluated by peroneal nerve stimulation (p <
      0.0001). Isolation of the TA muscle from the peroneal nerve with direct muscle
      stimulation and neuromuscular junction blockade preserved muscle function after 3
      h of ischemia. In our model, these results clearly demonstrate that IPC provides
      no significant protective effect from IR injury to either nerve or muscle
      function in our model. In addition, nerve or neuromuscular junction injury,
      rather than muscle damage, is identified as primarily responsible for IR-related
      muscle dysfunction.

PMID- 15183456
TI  - The evaluation of the acute toxicity and long term safety of hydroalcoholic
      extract of Sapthaparna (Alstonia scholaris) in mice and rats.
AB  - The acute and sub-acute toxic effects of various doses of hydroalcoholic extract
      of Alstonia scholaris (ASE) was studied in mice and rats. The acute toxicity in
      mice depended on the season of collection of plant. The highest acute toxicity
      was observed in the ASE prepared from the summer collection followed by winter.
      The least toxicity was observed in the extract prepared from the bark of A.
      scholaris collected in the monsoon season. The administration of different doses
      of ASE showed a dose dependent increase in the toxicity in all species of mice.
      The Swiss albino mice were found to be the most sensitive followed by the DBA and
      C(57)BL. The crossbred mice were resistant when compared to the pure inbred
      strains. The oral administration of ASE was non-toxic up to a dose of 2000 mg/kg
      b. wt., while maximum number of animals succumbed to death after administration
      of 1100 mg/kg ASE by intraperitoneal route. The rats were more sensitive than the
      mice as the LD(50) dose of ASE was lesser for the former than the latter. The sub
      acute toxicity in the rats was carried out with 120 and 240 mg/kg b. wt. ASE
      (1/10th and 1/5th of the LD(50) dose of ASE). The 240 mg was observed to be more
      toxic than 120 mg/kg ASE since it caused mortality and deformity in various
      organs of the recipient animals. The various biochemical parameters like AST,
      ALT, ACP, ALP, CK, LDH, creatinine, urea, ammonia, glucose and LPx were higher at
      240 mg/kg ASE when compared with the 120 mg and the non-drug treated animals. In
      contrast, the total protein, albumin, DNA, RNA, cholesterol, glucose,
      glutathione, total thiols declined in the 240 mg/kg ASE treated animals when
      compared with non-drug treated controls. The hematological analysis showed a dose
      dependent decrease in the RBC, WBC, hemoglobin, neutrophils and monocytes, while
      a significant increase in the lymphocytes, eosinophils and basophils was
      observed. The observed toxic effect of ASE may be due to the presence of
      echitamine. Our studies shows that at high doses, A. scholaris exhibited marked
      damage to all the major organs of the body.

PMID- 15183457
TI  - A method for studies on milk excretion of chemicals in mice with 2,2',4,4',5
      pentabromodiphenyl ether (BDE-99) as a model.
AB  - A simple and rapid milking technique for mice is described by which multiple milk
      samples can be collected from anaesthetised dams after 1h separation from the
      litter. Three samples of milk were collected from each dam by aspiration via a
      flexible tubing fitted to the nipple and approximately 0.3-0.5 ml milk was
      obtained at each time point. The milking technique was tested with 14C-labelled
      2,2',4,4',5-pentabromodiphenyl ether (BDE-99) as a model substance. A rapid and
      efficient milk excretion of BDE-99, with a milk/plasma ratio of approximately 40,
      was demonstrated. During the studied 7 days most of the given dose was excreted
      in milk with peak levels already 4-10 h after an intravenous administration.
      Higher tissue concentrations of BDE-99 were found in suckling neonates than in
      dams, probably due to a high dose per kilogram body weight from milk and an
      efficient absorption via the gastrointestinal tract in the pups.

PMID- 15183458
TI  - The protective effect of taurine against cyclosporine A-induced oxidative stress
      and hepatotoxicity in rats.
AB  - Cyclosporine A (CsA) is the immunosuppressor which is most frequently used in
      transplant surgery and in the treatment of autoimmune diseases. Oxidative stress
      has been implicated as one of the possible mechanisms of CsA-induced
      hepatotoxicity. The present investigation examined the ability of taurine as an
      antioxidant to protect against CsA-induced oxidative stress and hepatotoxicity.
      CsA hepatotoxicity was induced by subcutaneous injection of CsA at a dose of
      20mg/kg body weight daily for 21 days. Hepatotoxicity was assessed by reduced
      serum total protein level and increased serum levels of gamma glutamyl
      transferase (GGT), alanine aminotransferase (ALT), and aspartate
      aminotransaminase (AST). CsA treatment increased lipid peroxidation measured as
      thiobarbituric acid reactive substances (TBARS) concentration and decreased
      reduced glutathione (GSH) content and activities of catalase and glutathione
      peroxidase (GSH-Px) in the rat liver. Taurine administration (1% in the drinking
      water) for 3 days before and concurrently during CsA injections improved liver
      functions, as indicated by decline of serum transaminases and GGT levels and
      elevation of serum total protein. Moreover, taurine significantly reduced hepatic
      TBARS and increased GSH content and catalase and GSH-Px activities in the hepatic
      tissue. These results indicate that taurine has a protective action against CsA
      hepatotoxicity and suggest that taurine may find clinical application against a
      variety of toxins where cellular damage is a consequence of reactive oxygen
      species.

PMID- 15183459
TI  - Benzo[a]pyrene diol epoxide up-regulates COX-2 expression through NF-kappaB in
      rat astrocytes.
AB  - Cyclooxygenase may be important in the pathogenesis of smoking-related cancer
      because it activates carcinogens and is highly inducible in inflammation.
      Benzo[a]pyrene (B[a]P) is one of the most common ingredients of cigarette smoke
      and benzo[a]pyrene diol epoxide (BPDE) is a metabolic product of B[a]P. Cigarette
      smoking-induced inflammation has been found in several tissues and in association
      with cyclooxygenase-2 (COX-2) expression. The contribution of COX-2 to peripheral
      inflammation is well documented, however, little is known about its role in brain
      inflammation. We studied COX-2 expression following treatment with BPDE in the
      cortical cells of Sprague-Dawley rats in vivo, as well as in DI TNC1 rat
      astrocytes and rat pheochromocytoma PC-12 cells (neurons) cultured in vitro. Our
      data showed that BPDE increases levels of COX-2 mRNA and protein in cortical
      cells of Sprague-Dawley rats. BPDE also increases levels of COX-2 mRNA in PC-12
      and DI TNC1 cells. Induction of COX-2 protein was only found in DI TNC1 cells.
      Gel shift assay and western blot revealed increased NF-kappaB binding activity
      and protein level after treatment with BPDE. Experiments were performed to define
      the signaling mechanism by which BPDE induces COX-2, and suggested that BPDE
      mediated COX-2 induction increases the risk of brain inflammation.

PMID- 15183460
TI  - Induction of oxidative stress by endosulfan and protective effect of lipid
      soluble antioxidants against endosulfan-induced oxidative damage.
AB  - The toxic mechanism of endosulfan, a widely used organochlorine pesticide, was
      investigated in Saccharomyces cerevisiae and human cell lines. A concentration
      dependent inhibition of cell growth was observed when S. cerevisiae was exposed
      to endosulfan, and its cytotoxicity (IC(50)) was found to be 49 microM and 86
      microM in HepG2 and HeLa human cell lines, respectively. The treatment of S.
      cerevisiae with endosulfan resulted in oxidative damage, as demonstrated by
      thiobarbituric acid-reactive substance (TBARS) production, in a dose-dependent
      manner, and the growth inhibition was recovered by treatment with lipid-soluble
      antioxidants, such as alpha-tocopherol or beta-carotene, suggesting that
      endosulfan toxicity may be closely associated with endosulfan-induced reactive
      oxygen species (ROS) generation. The inhibition of cellular respiration by
      endosulfan treatment and the recovery of respiration activity by antioxidant
      treatment confirmed that endosulfan induces oxidative stress and inhibits
      respiration via ROS generation. These results suggest that unicellular yeast
      might provide a useful system for elucidating the toxicity of endosulfan.

PMID- 15183461
TI  - Activation and up-regulation of nitric oxide synthase in human umbilical vein
      endothelial cells by polycyclic aromatic hydrocarbons.
AB  - PAHs, including naphthalene, fluoranthene and fluorene rapidly induced
      extracellular Ca(2+) influx and hence elevation of intracellular Ca(2+)
      concentration and NO production. The effect can be inhibited by Ca(2+) channel
      blocker but not by P450 inhibitor. In addition to the rapid effect, we have also
      found that the eNOS mRNA and protein expression were augmented in HUVECs treated
      with PAHs at concentration as low as 0.1 microM for 24 h. These effects were
      abolished when the HUVECs were pretreated with the BAPTA, NiCl(2) and SKF96365,
      as well as SKF525A. Our results revealed that, for the first time, PAHs induce
      the activation of eNOS and enhance eNOS protein expression in HUVECs both in a
      Ca(2+)-dependent manner.

PMID- 15183462
TI  - Involvement of cytochrome P450 1A in sanguinarine detoxication.
AB  - Sanguinarine (SA), a member of the benzo[c]phenanthridine alkaloids, is a potent
      anti-microbial agent with anti-inflammatory and anti-neoplastic properties.
      However, toxicity of the alkaloid severely limits its medical applications.
      Recent report by Williams et al. implicated rat hepatic cytochrome P450 (CYP) 1A2
      as a likely modulator of SA toxicity. Indeed, the in vitro toxicity of SA in
      primary culture of rat hepatocytes and human hepatic cell line HepG2,
      demonstrated as lactate dehydrogenase leakage and metabolic capability (MTT
      assay), was diminished following induction of CYP1A by 2,3,7,8-tetrachlorodibenzo
      p-dioxin, 3-methylcholanthrene, and beta-naphtoflavone. Using microsomes
      containing recombinant CYP1A1 or CYP1A2 we show that SA causes non-competitive
      inhibition of the former and competitive inhibition of the latter as assessed by
      ethoxyresorufin de-ethylation (EROD). In human hepatic microsomes SA exhibits
      competitive inhibition of EROD activity with apparent K(i) of 2 microM, a value
      identical to that observed for CYP1A2 inhibition in recombinant system. Pre
      incubation of SA with human liver microsomes resulted in time-dependent, but not
      dose-dependent decline in EROD activity suggesting CYP1A2 inhibition is not
      mechanism based. SA also inhibits activity of NADPH:CYP reductase, an enzyme
      required for CYP activity, with IC(50) very similar to that observed for EROD
      inhibition. Tentative mechanism for CYP1A involvement in decreased in vitro SA
      toxicity is discussed.

PMID- 15183463
TI  - Adjuvant effect of quaternary ammonium compounds in a murine model.
AB  - It has been suggested that occupational exposure to quaternary ammonium compounds
      (QACs) may promote the development of allergic airway diseases. In this study,
      hazard identifications of the adjuvant effect of cetylpyridinium chloride (CPC),
      dimethyldioctadecylammonium bromide (DDA), hexadecyltrimethylammonium bromide
      (HTA), and tetraethylammonium chloride (TEA) were performed in a screening
      bioassay. Female BALB/c mice were injected subcutaneously with the model allergen
      ovalbumin (OVA) alone or together with different quantities of one of the QAC
      test compounds. After one or two boosters, levels of OVA-specific IgE, IgG1 and
      IgG2a antibodies were measured in sera. CPC and DDA increased IgE and IgG1
      antibody production, respectively, compared to the OVA control group, whereas HTA
      and TEA showed no adjuvant effect. Nevertheless, when TEA was given in
      combination with DDA, the adjuvant effect was up to six-fold higher than the
      adjuvant effect of DDA alone. Only DDA had a statistically significant adjuvant
      effect on IgG2a antibody levels.

PMID- 15183464
TI  - ASTRO 45th annual meeting presidential address: Medicine's arrow, medicine's
      cycle: lessons for radiation oncology.

PMID- 15183465
TI  - Informed consent.

PMID- 15183466
TI  - Accurate diagnosis of regional metastasis from cervical cancer: is PET the
      answer?

PMID- 15183467
TI  - Melatonin as a radioprotective agent: a review.
AB  - Melatonin (N-acetyl-5-methoxytryptamine), the chief secretory product of the
      pineal gland in the brain, is well known for its functional versatility. In
      hundreds of investigations, melatonin has been documented as a direct free
      radical scavenger and an indirect antioxidant, as well as an important
      immunomodulatory agent. The radical scavenging ability of melatonin is believed
      to work via electron donation to detoxify a variety of reactive oxygen and
      nitrogen species, including the highly toxic hydroxyl radical. It has long been
      recognized that the damaging effects of ionizing radiation are brought about by
      both direct and indirect mechanisms. The direct action produces disruption of
      sensitive molecules in the cells, whereas the indirect effects ( approximately
      70%) result from its interaction with water molecules, which results in the
      production of highly reactive free radicals such as *OH, *H, and e(aq)- and their
      subsequent action on subcellular structures. The hydroxyl radical scavenging
      ability of melatonin was used as a rationale to determine its radioprotective
      efficiency. Indeed, the results from many in vitro and in vivo investigations
      have confirmed that melatonin protects mammalian cells from the toxic effects of
      ionizing radiation. Furthermore, several clinical reports indicate that melatonin
      administration, either alone or in combination with traditional radiotherapy,
      results in a favorable efficacy:toxicity ratio during the treatment of human
      cancers. This article reviews the literature from laboratory investigations that
      document the ability of melatonin to scavenge a variety of free radicals
      (including the hydroxyl radical induced by ionizing radiation) and summarizes the
      evidence that should be used to design larger translational research-based
      clinical trials using melatonin as a radioprotector and also in cancer
      radiotherapy. The potential use of melatonin for protecting individuals from
      radiation terrorism is also considered.

PMID- 15183468
TI  - Thymic carcinoma: state of the art review.
AB  - Thymic carcinoma is a rare neoplasm with distinct clinical and pathological
      characteristics. The prognosis is often poor with an aggressive course that
      belies its numerical rarity. Potentially prognostic factors for survival include
      histopathologic grade, clinical stage, and resectability of the tumor. Five-year
      survival rates for all patients are approximately 30-50%, with a significant
      survival time differential between low-grade and high-grade neoplasms. Owing to
      the paucity of cases, optimal management of thymic carcinoma has yet to be
      defined. At present, a multimodality approach involving aggressive surgical
      resection, platinum-based combination chemotherapeutic interventions, and
      radiotherapy represent the preferred therapeutic approach. Though our knowledge
      remains somewhat speculative at present, several scientific, technological and
      therapeutic innovations may have a potentially significant impact on the future
      of this disease.

PMID- 15183469
TI  - Time to metabolic atrophy after permanent prostate seed implantation based on
      magnetic resonance spectroscopic imaging.
AB  - PURPOSE: To characterize the time to metabolic atrophy (TMA) after permanent
      prostate implantation (PPI) using combined MRI and magnetic resonance
      spectroscopic imaging (MRSI) compared with the time to prostate-specific antigen
      (PSA) nadir. METHODS AND MATERIALS: This study was based on a posttreatment
      analysis comparing the MRI/MRSI findings with the PSA levels of 65 patients
      treated with PPI alone or combined with external beam radiotherapy and/or HT. The
      fraction of interpretable voxels demonstrating metabolic atrophy was used to
      compare the TMA with the time to PSA nadir. RESULTS: The fraction of patients
      with metabolic atrophy in >95% of usable voxels after PPI increased from
      approximately 46% to 100% at 6 and 48 months, respectively. The mean time for PSA
      nadir vs. TMA was 42.5 vs. 28.9 months (PPI), 32.8 vs. 25.6 months (external beam
      radiotherapy + PPI), and 25.3 vs. 28.0 months (external beam radiotherapy +
      hormonal therapy + PPI). CONCLUSION: Magnetic resonance spectroscopic imaging may
      provide an early tool for evaluating the treatment response for patients treated
      with PPI. If supported by longer follow-up, TMA may be a useful adjunct to PSA
      measurement for assessing local control after PPI and could be useful in
      evaluating the complex relationships between the quality of the implant and the
      time to indication of successful therapy.

PMID- 15183470
TI  - Role of postoperative radiotherapy after pelvic lymphadenectomy and radical
      retropubic prostatectomy: a single institute experience of 415 patients.
AB  - PURPOSE: To evaluate the clinical benefit deriving from early (within 6 months)
      radiotherapy (ERT) after pelvic lymphadenectomy and radical retropubic
      prostatectomy for localized/locally advanced adenocarcinoma of the prostate in a
      single-institution series. METHODS AND MATERIALS: We retrospectively analyzed 415
      patients who underwent pelvic lymphadenectomy and radical retropubic
      prostatectomy between 1986 and 1998 for pT2b-pT4, pN0-pN1 prostate carcinoma. Of
      the 415 patients, 237 underwent ERT for adverse pathologic findings and 178
      patients did not receive RT or underwent salvage RT < or =6 months (salvage or no
      RT [SNRT]). RESULTS: After a median follow-up of 62 months, the 8-year actuarial
      freedom from biochemical, local and systemic failure, and cause-specific survival
      rate was 69% vs. 31% (p <0.0001, log-rank), 93% vs. 63% (p <0.0001), 88% vs. 75%
      (p = 0.04), and 93% vs. 80% (p = 0.02) in the ERT and SNRT group, respectively. A
      subgroup analysis indicated that an improvement in 8-year actuarial cause
      specific survival was associated with ERT in patients with positive resection
      margins (91% vs. 67%, p = 0.007), extracapsular extension (92% vs. 75%, p =
      0.002), Gleason score > or =7 (88% vs. 72%, p = 0.02), and lymph node metastases
      (88% vs. 68%, p = 0.04). This strong association between ERT and cause-specific
      survival persisted at multivariate analysis in the whole group of patients
      examined (hazard ratio, 4.3) and in the subgroups of patients with extracapsular
      extension (hazard ratio, 4.9), positive resection margins (hazard ratio, 4.7),
      Gleason score > or =7 (hazard ratio, 4.4), and lymph node metastases (hazard
      ratio, 7.4). CONCLUSION: The results of this retrospective analysis indicate that
      ERT after pelvic lymphadenectomy and radical retropubic prostatectomy improved
      the 5-year and actuarial 8-year cause-specific survival of patients with adverse
      pathologic findings such as extracapsular extension, positive resection margins,
      Gleason score > or =7, and/or positive lymph nodes.

PMID- 15183471
TI  - Clinical results of combined treatment conformal high-dose-rate iridium-192
      brachytherapy and external beam radiotherapy using staging lymphadenectomy for
      localized prostate cancer.
AB  - PURPOSE: To report the first long-term biochemical control rate of patients
      treated with two protocols using a combination of external beam radiotherapy
      (EBRT) and high-dose-rate (HDR) brachytherapy for localized prostate cancer in
      Japan. METHODS AND MATERIALS: Between October 1997 and July 2001, 71 patients
      with localized prostatic adenocarcinoma were treated with a combination of EBRT
      and HDR brachytherapy. Patient age ranged from 58 to 81 years (mean 70.5). Of the
      71 patients, 12, 41, and 18 had Stage T1c, T2, and T3, respectively, according to
      the International Union Against Cancer classification system (1997). The mean
      initial prostate-specific antigen (PSA) level was 24.2 ng/mL (median, 11.9
      ng/mL); 30% of the patients had an initial PSA level >20 ng/mL. Of the 71
      patients, 31 had received neoadjuvant hormonal therapy. Hormonal therapy before
      treatment was stopped at the beginning of RT in all cases. Patients in this
      series were treated on two protocols. In the initial protocol, patients were
      treated with whole pelvis EBRT to 45.0 Gy in 25 fractions and three HDR fractions
      of 5.5 Gy each (35 patients). In the second protocol, patients were treated with
      prostatic EBRT to 41.8 Gy in 19 fractions, with an added staging lymphadenectomy
      to rule out lymph node metastasis for patients with high-risk factors, and four
      HDR fractions of 5.5 Gy each (36 patients). The American Society for Therapeutic
      Radiology and Oncology consensus definition for biochemical failure was used.
      Acute and chronic toxicities were scored using the Radiation Therapy Oncology
      Group guidelines. Follow-up ranged from 24 to 65 months (median, 44 months).
      RESULTS: Of the 71 patients, 69 were alive at the last follow-up. Two patients
      had died of hepatocellular carcinoma and gastric cancer at 3.5 and 4.0 years
      after treatment with no biochemical failure. Sixty-six patients (93%), including
      the two who had died of intercurrent disease, showed a tendency for a PSA decline
      after treatment and had no biochemical or clinical evidence of disease at the
      last follow-up visit. Sixty patients (85%) achieved PSA nadir levels of < or =1.0
      ng/mL. The biochemical/clinical failure-free control rate at 3 and at 5 years was
      93% and 93%, respectively. The bladder and rectal complications were minimal.
      CONCLUSION: Despite the high frequency of high-risk patients in the present
      patient population, the actuarial biochemical control rate was 93% at 5 years.
      Acute and chronic toxicity with this method was acceptable. Additional long-term
      follow-up is required to assess this treatment, because the median survival is
      not likely to be reached for several years.

PMID- 15183472
TI  - Prostate cancer brachytherapy: is real-time ultrasound-based dosimetry predictive
      of subsequent CT-based dose distribution calculation? A study of 450 patients by
      the Institut Curie/Hospital Cochin (Paris) Group.
AB  - PURPOSE: Real-time ultrasound (US)-based dosimetry performed during (125)I loose
      seed implantation provides the radiation oncologist with an estimation of the
      dose distribution at seed insertion. However, for a number of reasons, this
      distribution may not reflect the real (reference) dosimetry as determined by
      subsequent CT, usually performed 1-2 months after implantation. The present study
      compared the two dosimetry data sets (US and CT) to evaluate how predictive
      extemporaneous US-based dosimetry can be of the real dose distribution. METHODS
      AND MATERIALS: A total of 450 patients with prostate cancer were treated with
      loose (125)I seed implantation between June 1999 and October 2002 by the Institut
      Curie/Hospital Cochin (Paris) Group. The mean patient age was 65 years. Most
      patients (74%) had Stage T1c; the stage did not exceed T2b for the others. All
      patients had a prostate-specific antigen level of <15 ng/mL and was <10 ng/mL for
      72%; 84% had a Gleason score of < or =6 and did not exceed 7 for the others; and
      56% were treated with neoadjuvant hormonal therapy for a mean of 4.3 months. All
      patients were treated with loose seed implantation. Real-time US-based dosimetry
      was performed intraoperatively for all patients. CT-based dosimetry was performed
      2 months after implantation, using the VariSeed software. The minimal dose to 90%
      of the outlined volume (D(90)) and percentage of volume receiving at least 100%
      of the prescribed dose (V(100)) were calculated with the two methods and compared
      for all patients. RESULTS: On CT-based dosimetry, the D(90) was found to be > or
      =145 Gy (range, 115-240 Gy) in all patients except one. A large majority (86%) of
      patients showed a CT-based V(100) of >95%, and 48% had a V(100) of >98%. The mean
      CT-based D(90)/US-based D(90) ratio was 1.0 (range, 0.66-1.33). For 89% of the
      patients, the difference between the two values was <20% and for 62% was <10%.
      The mean CT-based V(100)/US-based V(100) ratio was 0.98 (range, 0-1.02), with 89%
      of patients showing a difference of <5%. CONCLUSION: Our results indicate that
      the D(90) and V(100) values obtained intraoperatively with our real-time US-based
      dosimetry are in reasonable agreement with the subsequent values obtained with CT
      based dosimetry performed 2 months after implantation. Recent innovations in our
      dose planning software allowed better control of the longitudinal seed position
      and could still improve the correlation between real-time US-based dosimetry and
      the subsequent CT-based dose distribution.

PMID- 15183473
TI  - Low-dose-rate brachytherapy is superior to high-dose-rate brachytherapy for
      bladder cancer.
AB  - PURPOSE: To determine the efficacy and safety of a high-dose-rate (HDR)
      brachytherapy schedule in the treatment of bladder cancer and to investigate the
      impact of different values of repair half-times and alpha/beta ratios on the
      design of the HDR schedule. METHODS AND MATERIALS: Between 2000 and 2002, 40
      patients with T1G3 and T2 bladder carcinoma were treated with 30 Gy external beam
      radiotherapy followed by interstitial HDR brachytherapy to a total dose of 32 Gy
      in 10 sessions of 3.2-Gy fractions in two fractions daily with a 6-h
      interfraction interval. The local control rate and toxicity were compared with a
      historical group of 108 patients treated with 30 Gy external beam radiotherapy
      followed by 40-Gy interstitial low-dose-rate (LDR) brachytherapy. The HDR
      schedule was designed to be biologically equivalent to the previously used LDR
      schedule with the linear-quadratic model, including incomplete mono-exponential
      repair. RESULTS: The local control rate at 2 years was 72% for HDR vs. 88% for
      LDR brachytherapy (p = 0.04). In the HDR group, 5 of 30 evaluable patients
      encountered serious late toxicity: 4 patients developed a contracted bladder with
      inadequate capacity (<100 mL), and 1 patient required cystectomy because of a
      painful ulcer at the implant site. In the LDR group, only 2 of 84 assessable
      patients developed serious late toxicity. One patient developed a persisting
      vesicocutaneous fistula and the other a urethral stricture due to fibrosis. The
      difference in observed late toxicity for HDR vs. LDR was statistically
      significant (p = 0.005). The increased late toxicity with the HDR schedule
      compared with the LDR schedule suggests a short repair half-time of 0.5-1 h for
      late-responding normal bladder tissue. CONCLUSION: Local control of HDR
      brachytherapy for bladder cancer was disappointing and late toxicity unexpectedly
      high. The increase in late toxicity suggested a short repair half-time of 0.5-1 h
      for late-responding normal bladder tissue, which would not support HDR
      brachytherapy in the treatment of bladder cancer. The analysis demonstrated that
      the calculation of equivalent HDR schedules on the basis of the LDR schedules
      used in clinical practice might be hazardous.

PMID- 15183475
TI  - Brachytherapy versus surgery in carcinoma of tonsillar fossa and/or soft palate:
      late adverse sequelae and performance status: can we be more selective and obtain
      better tissue sparing?
AB  - PURPOSE: To report on the tumor control, adverse late normal tissue sequelae, and
      functional performance in patients with tonsillar fossa and/or soft palate (SP)
      tumors. The aim of the study is to validate the use of a more selective clinical
      target volume in conjunction with highly conformal radiotherapy (RT) techniques
      to better spare the surrounding normal tissues. METHODS AND MATERIALS: Between
      1986 and 2001, T1-T3 tonsillar fossa/SP tumors were treated in the Erasmus
      Medical Center using external beam radiotherapy (EBRT) to 46 Gy in 2-Gy fractions
      to the primary tumor and neck, followed by brachytherapy (BT) to the primary.
      Neck dissection was performed for node-positive disease (BT group; 104 patients).
      If BT was not feasible, patients underwent surgery and postoperative RT (PORT) to
      a dose of 50-70 Gy in 2-Gy fractions (surgery group; 86 patients). Local control,
      regional control, disease-free survival, and overall survival were determined.
      Late side effects were scored using the Radiation Therapy Oncology Group
      criteria. Univariate and multivariate Cox regression analyses were performed for
      regional failure (RF), with the parameters gender, age, site, TN stage, modality,
      dose, and overall treatment time. Recurrences in the contralateral neck were also
      related to significant ipsilateral involvement of the base of tongue and/or
      involvement of the SP crossing the midline. To determine the performance status
      scale scores and degree of xerostomia, a survey was conducted among patients
      living with no evidence of disease and a minimum of 2 years of follow-up. For
      that purpose, a research nurse interviewed patients regarding eating in public,
      normalcy of diet, normalcy of speech, and xerostomia. RESULTS: The tumor control
      rates after BT vs. surgery at 5 years were 88% vs. 88% for local control; 93% vs.
      85% for regional control; 57% vs. 52% for disease-free survival; 67% vs. 57% for
      overall survival; and 5% vs. 6% for RF. No patient had RF in the contralateral
      untreated N0 neck (0 of 14 vs. 0 of 15). Multivariate Cox regression analysis for
      RF was statistically significant for Stage T2 vs. T3 (hazard ratio 0.09) and for
      the dose to the neck >46 Gy (hazard ratio, 8.7; 95% confidence interval, 1.3
      57.1). The significant late side effects in the BT group vs. surgery group were
      ulcer in 39% vs. 7% (p = 0.001) and trismus in 1% vs. 21% (p = 0.005). The
      performance status scale scores and response to questions regarding xerostomia
      for BT vs. surgery revealed no statistically significant differences for eating
      in public, normalcy of diet, normalcy of speech, and xerostomia. The mean visual
      analog score for xerostomia was 5.5 in the BT group vs. 6 in the surgery group.
      CONCLUSION: Excellent locoregional control was obtained in T1-T3 tonsillar fossa
      and/or SP tumors. The rate at 10 years was 84% (BT group) vs. 78% (surgery
      group). However, adverse late side effects were not negligible. In addition to
      modality-specific side effects (ulcer/trismus), both treatment groups were
      significantly affected by xerostomia. Only 6 recurrences (4%) were observed in
      the 149 electively treated contralateral necks, and no relapses were seen in the
      29 untreated contralateral necks. We, therefore, suggest that it is not necessary
      to treat the contralateral neck, unless the tumor extends beyond the midline of
      the soft palate (uvula) or beyond the lateral one-third of the ipsilateral base
      of the tongue. Moreover, with the currently available CT-based neck level
      definitions, more conformal contours (i.e., tighter boundaries) around the
      clinical target volume can be designed. In this way, critical structures such as
      the temporomandibular joint and part of the pterygoid muscles can be avoided more
      easily. Also, when using highly conformal treatment techniques (e.g., intensity
      modulated RT), one can further reduce the dose to the major salivary glands and
      oral mucosa. We believe these measures will lead to less trismus and less
      xerostomia.

PMID- 15183474
TI  - Lymph node control in cervical cancer.
AB  - PURPOSE: The aim was to evaluate pretreatment lymph node size, irradiation dose,
      and failure patterns. METHODS: Pretreatment PET and CT were performed in 208
      patients. Lymph nodes were scored as either positive or negative by PET and lymph
      node size was measured by CT. Lymph node irradiation dose and sites of failure
      were recorded. RESULTS: The mean pelvic lymph node doses were: PET negative
      nodes, < or =1 cm, 66.8 Gy, and 0/76 failures; PET positive nodes, < or =1 cm,
      66.8 Gy, and 3/89 failures; 1.1-< or =2 cm, 66.9 Gy, and 0/21 failures; 2.1-< or
      =3 cm, 69.4 Gy, and 2/15 failures; and 3.1 to < or =4 cm, 74.1 Gy, and 0/5
      failures. The mean paraaortic lymph node dose was 43.3 Gy and there were no
      paraaortic failures for 24 patients with PET positive < or =1 cm nodes, 0/5
      failures for 1.1 to < or =2 cm, and 0/4 failures for 2.1 to < or =3 cm. The most
      common site of failure was distant metastases. CONCLUSIONS: The irradiation doses
      given in this study were adequate to control most lymph node metastases. Positive
      lymph nodes of any size at diagnosis were the most significant predictor for
      developing distant metastases.

PMID- 15183476
TI  - Are neck nodal volumes drawn on CT slices covered by standard three-field
      technique?
AB  - PURPOSE: Several definitions have been proposed in the past few years on how to
      contour the various neck nodal levels on CT slices. However, whether the
      resulting nodal volumes would have been covered by standard techniques is
      unknown. The purpose of this study was to clarify this issue. METHODS AND
      MATERIALS: Eight patients (N0-N1) with head-and-neck cancer from various primary
      sites referred to us for definitive radiotherapy were included in this study. Two
      observers contoured the level Ib-V neck nodal volumes on planning CT according to
      seven reported definitions. Each observer also drew blocks on digitally
      reconstructed radiographs for the initial (on-cord) phase of a standard three
      field technique (parallel opposed lateral fields and AP supraclavicular field)
      for three different clinical settings: "medium" larynx (to cover upper, mid, and
      low jugular nodes), "big" larynx (same as for medium, plus posterior cervical
      nodes), and "tonsil" (same as for big plus retropharyngeal nodes). Fields blocks
      were concentrically reduced 5 mm in all directions as a surrogate for the
      clinical target volume to planning target volume expansion. A plan was created
      for each of the clinical settings, delivering 2 Gy to the International
      Commission on Radiation Units and Measurements reference point. The coverage of
      the nodal levels according to the various definitions was investigated throughout
      the analysis of the volume receiving 50%, 80%, and 95% of the prescribed dose
      (V(50), V(80), and V(95), respectively) and dose covering at least 95% of the
      volume (D(95)) values extracted from their cumulative dose-volume histograms in
      the three clinical settings. RESULTS: The V(50) coverage of levels III and IV was
      adequate for all definitions and trials. For level V, about 3-5% of the volume
      was outside the 50% isodose of those trials that targeted the posterior cervical
      chain. Coverage of level Ib was highly dependent on the definition, with up to
      21% of the volume outside the standard tonsillar fields. For level II, although
      the 50% isodose from the tonsillar fields seemed to encompass all definitions,
      this was not the case for the laryngeal trials. Overall, we found 20-30% of the
      volumes to be outside the 95% isodose, with larger percentages for levels II and
      V. Similarly the D(95) results showed all volumes to be underdosed; only about
      45% and 65% of levels II and V, on average, received 95% of the prescription
      dose. CONCLUSION: Within three different clinical settings, we showed that the
      current definitions provide nodal neck volumes that often fall outside the 50%
      and 95% isodose lines of the standard three-field technique. Because these
      volumes are routinely used to define nodal neck volumes for intensity-modulated
      radiotherapy, the dose-volume objectives of intensity-modulated radiotherapy may
      not be consistent with those traditionally achieved by the standard three-field
      technique.

PMID- 15183477
TI  - Radiation therapy for early-stage carcinoma of the oropharynx.
AB  - PURPOSE: To evaluate the outcomes of radiation therapy treatment of patients with
      Stage I and II squamous cell carcinoma (SCC) of the oropharynx and discover
      adverse prognostic factors that may help select a subgroup of patients for a
      different management approach. METHODS AND MATERIALS: A search of the database
      maintained by the Department of Radiation Oncology of The University of Texas M.
      D. Anderson Cancer Center for patients with Stage I or II SCC of the oropharynx
      was performed. This search identified 175 patients treated between 1970 and 1998
      who met the inclusion criteria for this retrospective study. Distribution of
      primary sites was: tonsillar fossa/pillar, 60 patients; soft palate, 55 patients;
      base of tongue, 40 patients; and pharyngeal wall, 20 patients. Twenty-five
      patients were stage T1, 124 were T2, and 26 were Tx. All patients were treated
      with fractionated radiation to a median dose of 66 Gy. Eighty-five patients were
      treated with conventionally fractionated radiation, 73 were treated with the
      concomitant boost fractionation schedule, and the remaining 17 were treated with
      other altered fractionation schedules or with intraoral or interstitial boosts.
      RESULTS: The median follow-up for all patients was 76 months (range, 2-302
      months). The actuarial 5-year local control (LC), regional control, locoregional
      control (LRC), and disease-free survival (DFS) rates were 85%, 93%, 81%, and 77%,
      respectively. Only 7 patients (5%) with LC developed nodal metastases, and 10
      patients (7%) with LRC developed distant metastases. Eleven patients (32%) with
      locoregional recurrence were rendered without evidence of disease after a
      surgical salvage procedure, resulting in a 5- year ultimate LRC rate of 87%. T
      stage classification was statistically significant (p = 0.03) in univariate
      analysis for actuarial 5-year LRC, 88% for Stage I vs. 72% for Stage II. The 5-
      and 10-year disease-specific survival rates were 85% and 79%, respectively, while
      the actuarial 5- and 10-year overall survival rates were 70% and 43%,
      respectively. Fifty-one patients (29%) developed second primary tumors, 86% of
      which were cancers of the upper aerodigestive tract (UADT). Heavy alcohol
      consumption was associated with both an increased risk of disease recurrence and
      development of a second cancer of the UADT. CONCLUSIONS: Patients with early
      stage oropharynx cancer have high rates of disease control when treated with
      radiation. Lymphatic and hematogenous metastases are uncommon. Surgical salvage
      of disease recurrence is successful in approximately one-third of patients. As
      the majority of recurrences occur within the first 2 years from treatment, close
      observation during this time period is important. The development of second
      primary tumors of the UADT adversely impacts survival in these patients to as
      great a degree as the index cancer.

PMID- 15183478
TI  - Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh.
AB  - PURPOSE: Fracture of the femur is one of the late complications of adjuvant
      radiotherapy for patients with soft tissue sarcomas of the thigh, who receive
      external beam irradiation after limb-sparing surgery. When the target volume
      approximates the femur, it is often inevitable that a large segment of the femur
      will receive full prescription dose with conventional radiation techniques. We
      report the dosimetric feasibility of intensity- modulated radiation therapy
      (IMRT) techniques to achieve adequate target coverage and bone sparing. METHODS
      AND MATERIALS: Treatment planning was performed using both three-dimensional
      conformal radiotherapy (3D-CRT) and IMRT techniques for 10 patients with soft
      tissue sarcoma of the thigh with tumor approaching the femur. None of the
      patients had bony involvement. For all patients, the gross total volume (GTV) and
      the femur were contoured. The clinical target volume (CTV) was defined as the GTV
      with a 1.5-cm margin axially, except at the bone interface where the bone
      interface was used as CTV if the 1.5-cm axial margin extended beyond the bone
      interface. In the superior-inferior direction, the CTV margin placed around the
      GTV varied from 5 to 10 cm. The planning target volume (PTV) was defined as the
      CTV with 5-mm margin all around. The 3D conformal technique consisted primarily
      of two to three beams with wedges or partial transmission blocks as compensators.
      For the IMRT technique, five coplanar beams were used, chosen so as to spare much
      of the surrounding soft tissue and to clear the other extremity or groin areas.
      IMRT plans were designed to adequately treat the planning target volume and spare
      the femur as much as possible. RESULTS: Dose distributions and dose-volume
      histograms were analyzed. PTV coverage was comparable with both IMRT and 3D-CRT
      plans. Dose distributions were more conformal with IMRT, however, especially for
      patients with large variations of contours. The volume of the femur receiving at
      least full prescription (63 Gy) V100 decreased on average by approximately 57%,
      from 44.7 +/- 16.8% with 3D-CRT to 18.6 +/- 9.2% with IMRT (p < 0.01). For 3
      patients with a GTV surrounding <50% of the circumference of the femur, the
      reduction in the V100 to the femur ranged from 61% to 79%. The hot spots in the
      femur, as measured by D05 (the dose encompassing 5% of volume), reduced on
      average from 67.2 +/- 1.8 Gy with 3D-CRT to 65.0 +/- 1.2 Gy with IMRT (p < 0.01).
      The mean dose to the femur was on average 38.5 +/- 11.5 Gy with IMRT, compared
      with 40.9 +/- 12.7 Gy with 3D-CRT. The volume of the surrounding soft tissues,
      defined as the ipsilateral limb excluding the PTV and the femur, receiving at
      least prescription dose (63 Gy) was reduced on average by about 78%, from 997 +/-
      660 cc with 3D-CRT to 201 +/- 144 cc with IMRT (p < 0.01). The D05 to the
      surrounding soft tissues was on average 58.7 +/- 4.7 Gy with IMRT, compared to
      67.8 +/- 1.3 Gy with 3D-CRT (p < 0.01), a reduction of approximately 13%. The
      mean dose to the surrounding soft tissues was comparable in both plans. The
      volume of the skin (from surface to 5 mm depth) receiving prescription dose (63
      Gy) declined by roughly 45%, from 115 +/- 40 cc with 3D-CRT to 61 +/- 20 cc with
      IMRT (p < 0.01), with IMRT providing full skin dose coverage to scars. The hot
      spots in the skin decreased from 68.0 +/- 1.7 Gy with 3D-CRT to 65.2 +/- 1.2 Gy
      with IMRT (p < 0.01). The mean dose to the skin lessened from 51.5 +/- 4.7 Gy
      with 3D- CRT to 44.0 +/- 4.2 Gy with IMRT (p < 0.01), a reduction of 14%.
      CONCLUSIONS: Intensity-modulated radiation therapy techniques can reduce the dose
      to the femur without compromising target coverage by achieving concave dose
      distributions around the interface of the PTV and the femur. At the same time,
      IMRT can reduce the hot spots significantly in the surrounding soft tissues and
      skin. Whether such dosimetric improvements can translate into reduction of
      complications and/or improving local control needs to be investigated.

PMID- 15183479
TI  - Primary non-Hodgkin's lymphoma of the bone: treatment and analysis of prognostic
      factors for Stage I and Stage II.
AB  - PURPOSE: Primary non-Hodgkin's lymphomas of the bone (PLB) are very rare diseases
      accounting for 3%-5% of primary bone tumors. The best treatment for PLB has not
      been found yet. We report on the experience of the Radiation Oncology Department
      of Bologna University, Italy, relative to the diagnosis and treatment of this
      disease. METHODS AND MATERIAL: Seventy-seven patients with newly diagnosed PLB
      were treated from June 1983 to October 2001. Fifty-six were male (72.7%) and 21
      were female (27.3%); the median age was 41.8 years, with a range of 16-84 years.
      The majority of patients had B-cell high-grade histology. The median follow-up
      was 149 months. Forty-four patients had a solitary bone lesion (Stage I); and in
      33 patients, the tumor was spread to locoregional lymphatic area (Stage II). All
      patients were treated with radiotherapy (RT) with a median dose of 40 Gy (range,
      36-54 Gy), and 67 received an additional anthracycline-based regimen of
      chemotherapy (combined modality therapy [CMT]). RESULTS: After therapy 73 of 77
      patients (94.8%) reached a complete remission. At a median time of 23 months, 14
      of 77 patients (18.2%) had a disease relapse. Four of them were treated with RT
      alone (in these cases tumor lesions were <3 cm and located at sites different
      from mandible); 10 patients were treated with combined RT and CMT. Actuarial
      disease-free survival (DFS) and overall survival (OS) at 15 years were,
      respectively, 76.6% and 88.3%. No local failures were seen. Prognostic factors
      such as age, sex, stage, and bulky lesions were analyzed. Age (<40 vs. >40 years)
      was the only significant factor for DFS (85.3% vs. 66.6%, p = 0.03). Bulky
      lesions apparently did not affect OS (90.9% vs. 72.7%). However, the difference
      has no statistical significance (p = 0.05). Acute and late toxicity related to
      the treatment was moderate. CONCLUSIONS: In PLB the CMT seems to produce a better
      outcome than RT alone; that still remains the best treatment for local disease
      control. Radiation therapy alone should be reserved for mandibular tumors, which
      are usually very small and earlier diagnosed.

PMID- 15183480
TI  - Combination chemotherapy plus low-dose involved-field radiotherapy for early
      clinical stage Hodgkin's lymphoma.
AB  - PURPOSE: To present our long-term experience regarding the use of chemotherapy
      plus low-dose involved-field radiotherapy (IFRT) for clinical Stage I-IIA
      Hodgkin's lymphoma. METHODS AND MATERIALS: We analyzed the data of 368 patients.
      Of these, 66 received mechlorethamine, vincristine, procarbazine, and prednisone
      (MOPP) and 302 received doxorubicin (or epirubicin), bleomycin, vinblastine, and
      dacarbazine [A(E)BVD]. Patients with complete remission or very good partial
      remission were scheduled for low-dose IFRT (< or =3200 cGy). RESULTS: The 10-year
      failure-free survival (FFS) and overall survival (OS) rate was 85% and 86%,
      respectively. A(E)BVD-treated patients had superior 10-year FFS and OS rates
      compared with MOPP-treated patients (87% vs. 75%, p = 0.009; and 93% vs. 71%, p =
      0.0004, respectively). Only 10 of 41 relapses had any infield (irradiated)
      component. Of the complete responders/very good partial responders treated with
      low-dose IFRT, those who received <2800 cGy had inferior FFS but similar OS as
      those who received 2800-3200 cGy. Adverse prognostic factors for FFS included age
      > or =45 years, leukocytosis > or =10 x 10(9)/L, and extranodal extension.
      Secondary acute leukemia developed after MOPP with or without salvage therapy (n
      = 6) or after ABVD plus salvage therapy (n = 2). None of the nine secondary solid
      tumors developed within the RT fields. CONCLUSION: IFRT at a dose of 2800-3000
      cGy is highly effective in clinical Stage I-IIA HL patients who achieved a
      complete response or very good partial response with A(E)BVD. The long-term
      toxicity with respect to secondary malignancies appears to be acceptable.

PMID- 15183481
TI  - In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients.
AB  - PURPOSE: To evaluate (99m)Tc-Annexin-V (TAV) scintigraphy in monitoring radiation
      induced apoptotic cell death in follicular lymphoma (FL) patients. PATIENTS AND
      METHODS: Eleven FL patients (7 female and 4 male; median age, 58 years; range, 42
      80 years) with recurrent disease underwent TAV imaging before and 24 hours after
      the last fraction of the 2 x 2 Gy involved field radiotherapy regimen. Fine
      needle aspiration cytology was performed on 5 consecutive days to determine the
      optimal time window for apoptosis detection and to confirm the apoptotic nature
      of the response. The TAV scintigraphy (total body studies and SPECT of the
      irradiated sites) was performed 4 hours after the administration of the
      radiopharmaceutical. Tumor uptake was scored in a semiquantitative manner as
      absent (-) weak (+/-), present (+), or intense (++) with corresponding categories
      for the cytologic slides. Response evaluation was performed after 1 week and 4
      weeks both in terms of completeness and speed of remission. RESULTS: Baseline TAV
      uptake was absent in 6 and weak in 5 patients. Sequential cytology indicated that
      the optimal time period for apoptosis assessment was between 24 and 48 hours
      after the last fraction of the 2 x 2 Gy regimen. Baseline cytology was concordant
      with baseline TAV in all patients. Apoptotic feature appearance (nuclear
      chromatin condensation, margination and apoptotic body formation) after low-dose
      irradiation matched the irradiation response in all patients. In all but 1
      patient the posttreatment TAV uptake matched the posttreatment cytology. In these
      10 patients the cytology and TAV results correlated with the type and onset of
      the clinical response. CONCLUSION: Tumor (99m)Tc-Annexin-V uptake can be
      increased after 2 x 2 Gy involved field radiotherapy. This increase was
      concordant with the appearance of apoptotic morphology as determined by cytology,
      and correlated with the clinical outcome. Apoptotic cell death can be observed on
      Day 4 of this regimen and if so predicts a complete remission within 1 week.

PMID- 15183482
TI  - Extranodal nonorbital indolent lymphomas of the head and neck: relationship
      between tumor control and radiotherapy.
AB  - PURPOSE: To review our experience managing extranodal nonorbital indolent
      lymphomas of the head and neck. PATIENTS AND METHODS: A retrospective review was
      made of 40 patients with indolent lymphomas of the head and neck evaluated at
      Stanford. The tumor head-and-neck location was Waldeyer's ring, 14; salivary
      glands, 16; thyroid, 4; and other sites, 6. Twenty-five were Stage I-IIE.
      Pathology was re-reviewed in 37. The most common histologies were marginal zone
      lymphoma and follicular grade 2. Patients received combinations of surgery,
      chemotherapy, and radiotherapy. Local therapy included surgery alone in 6
      patients, radiotherapy alone in 7, and surgery plus radiotherapy in 12. Median
      follow-up was 70.5 months. RESULTS: Freedom from local progression was 86%, and
      freedom from progression was 61% at 5 years. Patients with radiotherapy had
      significantly better freedom from local progression (5-year, 100% vs. 72% for
      patients without radiotherapy, p = 0.006) and freedom from progression (5-year,
      90% vs. 34% for patients without radiotherapy, p = 0.001). Improvement in freedom
      from progression with radiotherapy was statistically significant for Stage I-II
      patients (88% vs. 50%, p = 0.02) and of borderline significance in Stage III-IV
      patients (100% vs. 23%, p = 0.07). Overall survival at 10 years was 70%.
      Multivariate analysis revealed that significant prognostic factors for survival
      were tumor site (favoring salivary and thyroid, p = 0.02) and age (favoring
      younger, p = 0.04). CONCLUSION: Survival is excellent in patients with indolent
      lymphomas of the head and neck. Patients with salivary and thyroid primary tumors
      had better survival compared with others. Early use of radiotherapy resulted in
      significantly higher rates of freedom from progression and freedom from local
      progression in early-stage patients.

PMID- 15183483
TI  - Radiation-induced changes of brain tissue after radiosurgery in patients with
      arteriovenous malformations: correlation with dose distribution parameters.
AB  - PURPOSE: To investigate the correlation of radiation-induced changes of brain
      tissue after radiosurgery in patients with cerebral arteriovenous malformations
      (AVMs) with treatment planning and dose distribution parameters. METHODS AND
      MATERIALS: The data from 73 AVM patients with complete follow-up information who
      underwent stereotactic linear accelerator radiosurgery at our institution between
      1993 and 1998 were analyzed. Patients were treated with 11-14 noncoplanar fields
      shaped by a micromultileaf collimator. A median dose of 19 Gy (range, 13.3-22 Gy)
      was prescribed to the 80% isodose, which completely encompassed the target.
      Patients were followed at 3-month intervals the first year and then every 6
      months with MRI and neurologic examinations. No patient developed radiation
      necrosis. The end point of radiation-induced tissue changes on follow-up
      neuroimaging (i.e., edema, blood-brain barrier breakdown [BBBB], and edema and/or
      BBBB combined) was evaluated. Each end point was further differentiated into four
      levels with respect to the extent of the image change (i.e., small, intermediate,
      large, and very large). The correlation of each end point was investigated for
      several treatment planning parameters, including prescribed dose and the absolute
      size of the AVM target volume. In addition, a number of dose-volume variables
      were calculated from each patient's dose distribution in the brain, including the
      mean dose to a specified volume of 16 and 20 cm(3) that was given the highest
      dose (Dmean16 and Dmean20, respectively), and the absolute and percentage of
      brain volume (including the AVM target) receiving a dose of at least 8, 10, and
      12 Gy (V8-V12, and V8(rel)-V12(rel), respectively). These parameters were also
      determined excluding the AVM target volume from the considered volume (subscript
      "excl"). The correlation of all treatment planning and dose-volume parameters
      with outcome was assessed in univariate Cox proportional hazards models. The
      results were assessed by p values (statistical significance for p < or =0.05),
      residual deviance (ResDev) of the fits, and odds ratios. RESULTS: The prescribed
      dose was not predictive of outcome (p >0.05 for all end points). The AVM target
      volume correlated significantly with large edema, as well as large edema and/or
      BBBB. V12 and Dmean20 were significantly associated with all end points, except
      very large edema and large BBBB. Patients with V12 of 27.6 cm(3) (Dmean20 of 18.9
      Gy) had a 2.8-fold (fourfold) higher risk of developing edema and/or BBBB with
      large extent than those with V12 of 4.2 cm(3) (Dmean20 of 8.4 Gy). For all end
      points, V12(rel) correlated worse with outcome compared with V12 (e.g., end point
      of large edema and/or BBBB: ResDev = 85.8 and 86.5 for V12 and V12(rel),
      respectively). Excluding the AVM target volume from the considered irradiated
      volume led to only small changes in the resulting correlations (e.g., end point
      of small edema and/or BBBB: ResDev = 99.0 and 98.7 for V12 and V12(excl),
      respectively, and ResDev = 96.1 and 96.1 for Dmean20 and Dmean20(excl),
      respectively). Throughout the analysis, V8-V12, Dmean20, and Dmean16 yielded
      similar results and none of these parameters could be favored over the others.
      CONCLUSION: Radiation-induced changes of brain tissue after AVM radiosurgery can
      be well predicted by single dose distribution parameters that are a function of
      both dose and volume. These can be used to quantify dose-volume response
      relations. Studies of this nature will eventually help to improve our current
      understanding of the mechanisms leading to radiation-induced tissue changes after
      AVM radiosurgery and to optimize radiosurgery treatment planning.

PMID- 15183484
TI  - Silver leaf nylon dressing to prevent radiation dermatitis in patients undergoing
      chemotherapy and external beam radiotherapy to the perineum.
AB  - PURPOSE: Silver-leaf nylon dressing (SLND) has been shown to have effective
      antimicrobial activity and to enhance healing in burns and skin grafts. The
      purpose of this study was to evaluate the value of SLND in preventing radiation
      dermatitis in patients undergoing radiotherapy to target volumes that included
      the perineum and concurrent chemotherapy. METHODS AND MATERIALS: Fifteen
      consecutive patients with either anal canal or gynecologic cancer were offered
      the SLND as a preventive intervention. The evaluation was based on standardized
      photographs taken at the end of treatment. A historical control group of 15
      patients with the same neoplasms who received standard skin care was assessed in
      the same fashion. Ten observers unaware of the treatment intervention were
      enrolled in the evaluation of the skin changes. The Mann-Whitney U test was used
      to assess the statistical significance of the differences in the dermatitis
      scores between the two patient groups. RESULTS: The mean dermatitis score for
      controls was 2.62 (standard deviation, 0.48). The mean score for the SLND group
      was significantly lower at 1.16 (standard deviation, 0.40; p <0.0001).
      CONCLUSION: The results of this study suggest that SLND is effective in reducing
      radiation dermatitis, apparently because of its antibacterial properties.

PMID- 15183485
TI  - External beam radiotherapy fails to prevent restenosis after iliac or
      femoropopliteal percutaneous transluminal angioplasty: results of a prospective
      randomized double-blind study.
AB  - PURPOSE: Early restenosis is one of the major complications after successful
      percutaneous transluminal angioplasty (PTA), in main, as well as peripheral,
      arteries. The effectiveness of hypofractionated external beam radiotherapy (EBRT)
      as a prophylaxis for restenosis was examined in a prospective, randomized, double
      blind, clinical trial. METHODS AND MATERIALS: Forty-eight patients underwent sham
      RT and 47 were treated with daily RT in 3-Gy fractions, to a total dose of 21 Gy.
      The follow-up lasted for 12 months, and the examinations included pressure
      measurements and calculations of the ankle-brachial index or duplex sonography
      ("peak velocity ratio"). If restenosis was suspected, additional angiography was
      performed. RESULTS: No statistically significant difference was found between the
      treatment groups: sham RT 16 failures (33.3%) and EBRT group 21 failures (45.7%;
      p = 0.292). EBRT also showed no substantial effects on subgroups classified by
      the specific length of the lesion or in diabetic patients. CONCLUSION: External
      beam radiotherapy does not prevent restenosis. A reduction in the failure rate
      >8% using fractionated EBRT with doses aimed at keloid prevention can be ruled
      out with a probability of 97.5%. Endovascular brachytherapy remains the preferred
      therapeutic method for achieving restenosis prophylaxis through RT.

PMID- 15183486
TI  - Predicting the effect of temporal variations in PO2 on tumor radiosensitivity.
AB  - PURPOSE: Tumor hypoxia is associated with less effective radiation-mediated cell
      killing, increased metastatic potential, and poorer prognosis. Transient
      variations in hypoxia, with characteristic periodicity on the order of 1 to 10
      min, have been observed in animal models. This article explores the effect of
      these temporal variations in PO(2) on the oxygen enhancement ratio, effective
      radiation dose to the tumor, and tumor control probability. METHODS AND
      MATERIALS: PO(2) over a 50-60 min period was determined at multiple sites in rat
      fibrosarcomas, 9L gliomas, and R3230Ac mammary adenocarcinomas. Using a
      correlation derived from the data of Elkind et al. (1965), PO(2) data are
      converted into oxygen enhancement ratios (OERs.) A tumor is assumed to consist of
      10(3)-10(4) independent oxygenation subvolumes, each with a randomly chosen
      starting point on the OER-time curve. The effect of temporal variations in OER is
      examined for three cases: conventionally fractionated external beam radiotherapy
      (EBRT), stereotactic radiosurgery (SRS) and intraoperative radiotherapy (IORT).
      The oxygen effective dose (OED) for a subvolume is calculated from the dose to
      that subvolume modified by the OER. In turn, the distribution of OED for a tumor
      is analyzed for each treatment case and representative tumor control
      probabilities (TCPs) calculated. RESULTS: Oxygen enhancement ratio varied from 1
      to 3 over the range of PO(2) measured in this study. Mean OER ranged from 1.6 to
      2.6, and the variation in OER vs. time was greater with decreasing PO(2). In
      EBRT, the standard deviation in OED was small, <2%. In contrast, the standard
      deviation in OED was much higher for both SRS and IORT, typically ranging from 3
      to 6%, with the greatest variation at the lowest PO(2)s. Compared with a tumor
      with equal mean OED and uniform PO(2), TCP was minimally poorer for either EBRT
      or well-oxygenated tumors. However, for both SRS and IORT, temporal variations in
      more hypoxic tumors can produce a significant decrease in TCP. CONCLUSION:
      Temporal variations in tumor PO(2) can produce significant variations OER,
      particularly at low PO(2), resulting in decreased TCP for hypofractionated
      treatment regimens.

PMID- 15183487
TI  - Effect of RSR13, an allosteric hemoglobin modifier, on oxygenation in murine
      tumors: an in vivo electron paramagnetic resonance oximetry and bold MRI study.
AB  - PURPOSE: RSR13, an allosteric modifier of hemoglobin, reduces hemoglobin-oxygen
      binding affinity facilitating oxygen release from hemoglobin, resulting in
      increases in tissue pO(2). The purpose of this study was noninvasively to monitor
      the time course and effect of RSR13 on tumor oxygenation, directly using in vivo
      electron paramagnetic resonance (EPR oximetry), and indirectly using blood oxygen
      level dependent magnetic resonance imaging (BOLD MRI). METHODS AND MATERIALS: The
      study was performed in transplanted radiation-induced fibrosarcoma tumors (RIF-1)
      in 18 female C3H/HEJ mice, which had two lithium phthalocyanine (LiPc) deposits
      implanted in the tumor when the tumors reached about 200-600 mm(3). Baseline EPR
      measurements were made daily for 3 days. Then, for 6 consecutive days and after
      an initial baseline EPR measurement, RSR13 (150 mg/kg) or vehicle (same volume)
      was injected intraperitoneally, and measurements of intratumoral oxygen were made
      at 10-min intervals for the next 60 min. In each mouse, every third day, instead
      of EPR oximetry, BOLD MRI measurements were made for 60 min after administration
      of the RSR13. RESULTS: Based on EPR measurements, RSR13 produced statistically
      significant temporal increases in tumor pO(2) over the 60-min time course, which
      reached a maximum at 35-43 min postdose. The average time required to return to
      the baseline pO(2) was 70-85 min. The maximum increase in tumor tissue pO(2)
      values after RSR13 treatment from Day 1 to Day 5 (8.3-12.4 mm Hg) was greater
      than the maximum tumor tissue pO(2) value for Day 6 (4.7 mm Hg, p < 0.01). The
      maximum increase in pO(2) occurred on Day 2 (12.4 mm Hg) after RSR13 treatment.
      There was little change in R(2)*, indicating that the RSR13 had minimal
      detectable effects on total deoxyhemoglobin and hemoglobin-oxygen saturation.
      CONCLUSION: The extent of the increase in tumor pO(2) achieved by RSR13 would be
      expected to lead to a significant increase in the effectiveness of tumor
      radiotherapy. The lack of a change in the BOLD MRI signal suggests that the tumor
      physiology was largely unchanged by RSR13. These results illustrate a unique and
      useful capability of in vivo EPR oximetry and BOLD MRI to obtain repeated
      measurements of tumor oxygenation and physiology. The dynamics of tumor pO(2)
      after RSR13 administration may be useful for the design of clinical protocols
      using allosteric hemoglobin effectors.

PMID- 15183488
TI  - WR-1065, the active form of amifostine, protects HL-60 cells but not peripheral
      blood mononuclear cells from radiation and etoposide-induced apoptosis.
AB  - PURPOSE: Developing myeloid cells are particularly sensitive to chemotherapy and
      ionizing radiation. Mature cells of the hematopoietic lineages, such as are found
      in the peripheral blood mononuclear cells (PBMCs), are much less sensitive for
      reasons that are not yet understood. Protecting the myeloid precursors from
      radiation or chemotherapy is an important goal. METHODS: We have used
      fluorescence microscopy to assess the ability of WR-1065, the active metabolite
      of amifostine (Ethyol), to protect cultured myeloid leukemic HL-60 cells or
      freshly isolated PBMCs from the induction of apoptosis by ionizing radiation or
      etoposide. RESULTS: WR-1065 greatly reduced the percentage of radiation-induced
      apoptosis in the p53 negative HL-60 cells 24 h after exposure to 8 Gy. WR-1065
      also greatly reduced the percentage of HL-60 cells undergoing apoptosis 24 h
      after a 1-h exposure to 1 microM etoposide. The pan-caspase inhibitor ZVAD-fmk
      completely inhibited radiation-induced apoptosis in HL-60 cells when present for
      the first hour after exposure to radiation, but had no effect on cell survival.
      In contrast, neither WR-1065 nor ZVAD-fmk reduced the level of radiation-induced
      apoptosis in normal human PBMCs. CONCLUSION: These results suggest that pro
      apoptotic pathways are present in immature myeloid cells that can be selectively
      protected from radiation or chemotherapy-induced apoptosis.

PMID- 15183489
TI  - P53-independent thermosensitization by mitomycin C in human non-small-cell lung
      cancer cells.
AB  - PURPOSE: To elucidate the relationship between p53 functions and the interactive
      effects of the combined treatment with mild hyperthermia and mitomycin C. METHODS
      AND MATERIALS: p53-deficient human non-small-cell lung cancer H1299 cells were
      transfected with a vector carrying a neomycin-resistant gene (neo) or together
      with a wild-type or mutant p53 gene. Sensitivities of these transfectants to mild
      hyperthermia at 42 degrees C, mitomycin C (0.05 microg/mL) at 37 degrees C, or
      the combination treatment were determined by colony formation assay. After these
      treatments, the induction of apoptosis, the changes in cell cycle distribution,
      and the accumulation of Hsp72 were examined. RESULTS: The combined treatment
      resulted in an enhanced cell killing effect in H1299 cells in a p53-independent
      manner, which was partially the result of an enhancement of heat-induced
      apoptosis. The treatment also caused a marked G(2)/M arrest in the neo and the
      mutant p53 cells, but not in the wild-type p53 cells. The subsequent release of
      G(2)/M arrest was accompanied with an increase in the sub-G(1) fractions.
      Mitomycin C did not affect the accumulation of Hsp72 induced by hyperthermia in
      H1299 cells regardless of their p53 gene status. CONCLUSION: Our findings
      demonstrate a p53-independent mechanism for an interactively cytotoxic
      enhancement by combined treatment with mild hyperthermia and mitomycin C.

PMID- 15183491
TI  - Matching the dosimetry characteristics of a dual-field Stanford technique to a
      customized single-field Stanford technique for total skin electron therapy.
AB  - PURPOSE: To compare the dosimetry characteristics of a customized single-field
      and a matching dual-field electron beam for total skin electron therapy (TSET)
      within the framework of the Stanford technique. To examine and quantify its
      impact on patient dosimetry. METHODS AND MATERIALS: Two characteristically
      different electron beams were used for TSET employing the Stanford technique: a
      single-field beam created from a pencil beam of electrons passing through 7
      meters of air and a dual-field beam created from two heavily scattered electron
      beams directed at oblique angles to patients. The dosimetry characteristics of
      the two beams were measured by using ionization chambers, radiographic films, and
      thermal luminescent detectors. The impact of beam characteristic on patient
      dosimetry was quantified on both anthromorphic phantoms and on patients.
      Treatment protocols aimed at matching the patient dose between the two systems
      were established on the basis of these and other measurements. RESULTS: The dual
      field beam was matched to the single-field beam, resulting in approximately the
      same mean energy (approximately 4.0 MeV) and most probable energy (approximately
      4.5 MeV) at their respective treatment source-to-patient-surface distance (SSD).
      The depth dose curves on the beam axis were nearly identical for both beams. X
      ray contamination on the beam axis was 0.43% for the dual-field beam, slightly
      higher than that (0.4%) of the single-field beam. The beam uniformity, however,
      was quite different: the dual-field beam was more uniform in the vertical
      direction but was worse in the lateral direction compared to the single-field
      beam. For a TSET treatment using the Stanford technique, the composite depth dose
      curves were nearly identically at the level of beam axis: with an effective depth
      of maximum buildup (d(max)) at approximately 1 mm below the skin surface and the
      depth to 80% depth dose at around 6 mm. The overall X-ray contamination was
      approximately 1.0% and 1.2% for the single-field and dual-field system,
      respectively. Away from the beam axis level, treatment using either beam was able
      to deliver over 90% of prescription dose to the main body surfaces. For body
      surfaces tangential to the beam axis (e.g., top of head and shoulders), the dose
      was low especially when using the dual-field beam. By adding boost radiation to
      the tangential surfaces and by adjusting the planned shielding for critical
      structures, the total dose to the patient over a complete course of TSET
      treatment could be matched closely for the two systems. CONCLUSIONS: Although the
      depth doses can be matched at the level of the beam axis, there exist some
      characteristic differences in the angular distribution of the electrons between
      the large SSD single-field beam and the short SSD dual-field beam. These
      differences resulted in lower dose delivered to "tangential" body surfaces and to
      body structures that extended farther laterally when using the dual-field beam.
      However, by adjusting the treatment protocol regarding the boost irradiation and
      planned shielding, the total dose to patients from a complete course of TSET
      treatment using the dual-field beam can be matched to that given by the single
      field beam. Special attention should be paid to the dosimetry at the "tangential"
      body surfaces when commissioning a dual-field TSET system.

PMID- 15183490
TI  - Dosimetric effects within target and organs at risk of interfractional patient
      mispositioning in left breast cancer radiotherapy.
AB  - PURPOSE: To investigate the effects of interfraction setup uncertainties on the
      dose distribution within the clinical target volume (CTV) and the organs at risk
      (OAR) of left-sided breast cancer patients undergoing external radiotherapy.
      METHODS AND MATERIALS: Interfractional setup errors were assessed by measuring
      surface control points displacements during 89 irradiation sessions in 4
      patients, by means of opto-electronic localization. The measured position
      deviations were fed back to the treatment planning system for the evaluation of
      the corresponding dosimetric effects within CTV and OARs (lung, heart). RESULTS:
      Results revealed errors above 5 mm on some of the control points, but
      corresponding volumetric variations were on average below 2% for both the CTV
      within the 95-105% dose range and the OARs receiving more than 50% and 90% of the
      prescribed dose. A specific sensitivity to the setup errors was found as a
      function of the treatment plan design, leading to isolated cases exhibiting
      volumetric variations of CTV and OARs exceeding 2%. CONCLUSIONS: This study
      confirms the potential increase of treatment quality provided by the systematic
      patient position verification and highlights the role of opto-electronic position
      detection systems for the real-time check of patient setup errors and the
      evaluation of the corresponding dosimetric consequences, as a way to achieve
      consistent dose delivery.

PMID- 15183492
TI  - A study of planning dose constraints for treatment of nasopharyngeal carcinoma
      using a commercial inverse treatment planning system.
AB  - PURPOSE: The purpose of this study was to develop and test planning dose
      constraint templates for tumor and normal structures in the treatment of
      nasopharyngeal carcinoma (NPC) using a specific commercial inverse treatment
      planning system. METHODS AND MATERIALS: Planning dose constraint templates were
      developed based on the analyses of dose-volume histograms (DVHs) of tumor targets
      and adjacent sensitive structures by clinically approved treatment plans of 9 T1
      2 and 16 T3-4 NPC patients treated with inverse planned intensity-modulated
      radiation therapy (IP-IMRT). DVHs of sensitive structures were analyzed by
      examining multiple defined endpoints, based on the characteristics of each
      sensitive structure. For each subgroup of patients with T1-2 and T3-4 NPC, the
      resulting mean values of these defined endpoint doses were considered as
      templates for planning dose constraints and subsequently applied to a second
      group of patients, 5 with T1-2 NPC and 5 with T3-4 NPC. The 10 regenerated plans
      (called new plans) were compared to the original clinical plans that were used to
      treat the second group of patients, based on plan conformity index and DVHs.
      RESULTS: The conformity indices of the new plans were comparable to the original
      plans with no statistical difference (p = 0.85). Among the serial sensitive
      structures evaluated, there was a significant decrease with the new plans in the
      dose to the spinal cord when analyzed by the maximum dose (p = 0.001), doses
      encompassing 1 cc of the spinal cord volume (p = 0.001) and 3 cc of the spinal
      cord volume (p = 0.001). There was no significant difference in the mean maximum
      dose to the brainstem between the new plans and the original plans (p = 0.36).
      However, a significant difference in the mean maximum dose to the brainstem was
      seen among the different T-stages (p = 0.04). A decrease with the new plan to the
      brainstem in the doses encompassing 5% and 10% of the volume was of borderline
      statistical significance (p = 0.08 and p = 0.06, respectively). There were no
      statistical differences between the new plans and the original plans in the mean
      doses to the chiasm, optic nerve, or eye for each of the endpoints considered.
      For parallel sensitive structures in the new plans, there was a significant
      increase in the average mean dose to the parotid glands (p = 0.01), a decrease
      that was of borderline significance in the average mean dose to the
      temporomandibular joint (p = 0.07), but no difference in the average mean dose to
      the ear. CONCLUSIONS: The statistical analysis showed that new plans are
      comparable to the original plans for most of the sensitive structures except for
      a trade-off between a dose reduction to the spinal cord in the new plans and an
      increase in the mean dose to the parotid glands. These tested planning dose
      constraint templates can serve as good "starting points" for an inverse plan of
      NPC using a specific commercial inverse treatment planning system.

PMID- 15183493
TI  - Treatment of patients with cardiac pacemakers and implantable cardioverter
      defibrillators during radiotherapy.
AB  - PURPOSE: To define the practical clinical guidelines that can be implemented by
      busy radiation oncology departments to minimize the risk of harm to patients with
      implanted cardiac pacemaker (ICP) and implantable cardioverter-defibrillator
      (ICD) devices during radiotherapy. METHODS AND MATERIALS: A literature review was
      conducted to identify the mechanism of potential damage to ICPs and ICDs from
      exposure to electromagnetic interference and/or ionizing radiation and to assess
      the published evidence of such device malfunction or failure. Recommendations for
      patient management were obtained from three major manufacturers. Eighty-seven
      radiation oncology facilities across the United States and Canada were contacted
      to determine current practice patterns; 75 centers responded. RESULTS: The
      published documentation of potential life-threatening malfunction of ICP and ICD
      devices exposed to electromagnetic interference and ionizing radiation is
      considerable. However, major discrepancies exist among manufacturer
      recommendations and wide variations are present among radiation oncology
      facilities regarding patient management precautions. CONCLUSION: Precautions are
      necessary to minimize the risk to patients with ICP and ICD devices during
      radiotherapy. Practical management guidelines are presented that can be readily
      adopted by any busy clinical radiation oncology practice.

PMID- 15183494
TI  - Comparison of electron beam characteristics from multiple accelerators.
AB  - PURPOSE: To determine the relationships between electron beam depth dose
      characteristics, depth of maximum dose (d(max)), depth of 80% dose (d(80)), and
      depth of 50% dose (d(50)), and the nominal energy designation of electron beams
      from multiple linear accelerators for the purpose of electron beam treatment
      planning and quality assurance. METHODS: The Radiological Physics Center Staff,
      during its on-site dosimetry review visits to institutions participating in
      clinical trials, measured depth dose characteristics for more than 2000 electron
      beams. Measurements were performed on Varian, Siemens, and Elekta/Philips
      accelerators generating beams with nominal energy values ranging from 4-22 MeV.
      The depth dose data were determined at the nominal source-to-skin distance with
      the reference cone size in accordance with recommendation of the American
      Association of Physicists in Medicine Task Group 25 report. RESULTS: The
      important depth dose characteristics d(max), d(80), and d(50) varied in a
      predictable fashion when plotted against the true beam quality indicator, R(50).
      However, d(80) and d(50) values overlapped considerably when plotted against the
      manufacturers' nominal electron energy values. For a specific nominal electron
      energy value, the values of d(max), d(80), and d(50) varied by as little as 3 mm
      for low energy levels to nearly as much as 20 mm for high energies. CONCLUSIONS:
      The manufacturer's nominal electron energy value does not adequately describe the
      depth dose characteristics of an electron beam for treatment planning purposes.
      Clinicians and physicists should determine and use only the specific depth dose
      data for their clinical beams and not the manufacturer's nominal value.

PMID- 15183495
TI  - In regard to Anagnostopoulos et al.: In vivo thermoluminescence dosimetry dose
      verification of transperinal (192)Ir high dose rate brachytherapy using CT-based
      planning for the treatment of prostate cancer (Int J Radiat Oncol Biol Phys
      2003;57:1183-1191).

PMID- 15183497
TI  - In regard to Fiorino et al.: Rectal dose-volume constraints in high-dose
      radiotherapy of localized prostate cancer (Int J Radiat Oncol Biol Phys
      2003;57:953-962).

PMID- 15183499
TI  - In regard to Thomadsen et al.: Analysis of treatment delivery errors in
      brachytherapy using formal risk analysis techniques (Int J Radiat Oncol Biol Phys
      2003;57:1492-1508).

PMID- 15183501
TI  - Production and killing of second cancer precursor cells in radiation therapy: in
      regard to Hall and Wuu (Int J Radiat Oncol Biol Phys 2003;56:83-88).

PMID- 15183502
TI  - The effects of brain-derived neurotrophic factor (BDNF) administration on
      kindling induction, Trk expression and seizure-related morphological changes.
AB  - Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family
      that mediates synaptic plasticity and excitability in the CNS. Recent evidence
      has shown that increased BDNF levels can lead to hyperexcitability and
      epileptiform activities, while suppression of BDNF function in transgenic mice or
      by antagonist administration retards the development of seizures. However,
      several groups, including our own, have reported that increasing BDNF levels by
      continuous intrahippocampal infusion inhibits epileptogenesis. It is possible
      that the continuous administration of BDNF produces a down-regulation of its high
      affinity TrkB receptor, leading to a decrease of neuronal responsiveness to BDNF.
      If so, then animals should respond differently to bolus injections of BDNF, which
      presumably do not alter Trk expression, compared with continuous infusion. To
      test this hypothesis, we compared the effects of intrahippocampal BDNF continuous
      infusion and bolus injections on kindling induction. We showed that continuous
      infusion of BDNF inhibited the development of behavioral seizures and decreased
      the level of phosphorylated Trks or TrkB receptors. In contrast, multiple bolus
      microinjections of BDNF accelerated kindling development and did not affect the
      level of phosphorylated Trks or TrkB receptors. Our results indicate that
      different administration protocols yield opposite effects of BDNF on neuronal
      excitability, epileptogenesis and Trk expression. Unlike nerve growth factor and
      neurotrophin-3, which affect mossy fiber sprouting, we found that BDNF
      administration had no effect on the mossy fiber system in naive or kindled rats.
      Such results suggest that the effects of BDNF on epileptogenesis are not
      modulated by its effect on sprouting, but rather by its effects on excitability.

PMID- 15183503
TI  - Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and
      release by stress.
AB  - Neuropeptides modulate neuronal function in hippocampus, but the organization of
      hippocampal sites of peptide release and actions is not fully understood. The
      stress-associated neuropeptide corticotropin releasing hormone (CRH) is expressed
      in inhibitory interneurons of rodent hippocampus, yet physiological and
      pharmacological data indicate that it excites pyramidal cells. Here we aimed to
      delineate the structural elements underlying the actions of CRH, and determine
      whether stress influenced hippocampal principal cells also via actions of this
      endogenous peptide. In hippocampal pyramidal cell layers, CRH was located
      exclusively in a subset of GABAergic somata, axons and boutons, whereas the
      principal receptor mediating the peptide's actions, CRH receptor 1 (CRF1),
      resided mainly on dendritic spines of pyramidal cells. Acute 'psychological'
      stress led to activation of principal neurons that expressed CRH receptors, as
      measured by rapid phosphorylation of the transcription factor cyclic AMP
      responsive element binding protein. This neuronal activation was abolished by
      selectively blocking the CRF1 receptor, suggesting that stress-evoked endogenous
      CRH release was involved in the activation of hippocampal principal cells.

PMID- 15183504
TI  - Intraseptal muscarinic ligands and galanin: influence on hippocampal
      acetylcholine and cognition.
AB  - The cholinergic neurons in the septohippocampal projection are implicated in
      hippocampal functions such as spatial learning and memory. The aim of this study
      was to examine how septohippocampal cholinergic transmission is modulated by
      muscarinic inputs and by the neuropeptide galanin, co-localized with
      acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial
      learning assessed by the Morris water maze test is affected. Muscarinic inputs to
      the septal area are assumed to be excitatory, whereas galanin is hypothesized to
      inhibit septohippocampal cholinergic function. To test these hypotheses,
      compounds were microinjected into the medial septum and hippocampal ACh release
      was assessed by microdialysis probes in the ventral hippocampus of the rat.
      Blockade of septal muscarinic transmission by intraseptal scopolamine increased
      hippocampal ACh release suggesting that septal cholinergic neurons are under
      tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also
      increased hippocampal ACh release. Despite this increase, both scopolamine and
      carbachol tended to impair hippocampus-dependent spatial learning. This finding
      also suggests a revision of the simplistic notion that an increase in hippocampal
      ACh may be facilitatory for learning and memory. Galanin infused into the medial
      septum enhanced hippocampal ACh release and facilitated spatial learning,
      suggesting that septal galanin, contrary to earlier claims, does not inhibit but
      excites septohippocampal cholinergic neurons. Galanin receptor stimulation
      combined with muscarinic blockade in the septal area resulted in an excessive
      increase of hippocampal ACh release combined with an impairment of spatial
      learning. This finding suggests that the level of muscarinic activity within the
      septal area may determine the effects of galanin on hippocampal cognitive
      functions. In summary, a limited range of cholinergic muscarinic transmission may
      contribute to optimal hippocampal function, a finding that has important
      implications for therapeutic approaches in the treatment of disorders of memory
      function.

PMID- 15183505
TI  - Neuropeptide Y and N-methyl-D-aspartic acid interact within the suprachiasmatic
      nuclei to alter circadian phase.
AB  - Circadian rhythms are reset by exposure to photic stimuli and nonphotic stimuli.
      Glutamate appears to be the primary neurotransmitter that communicates photic
      stimuli to the circadian clock located in the suprachiasmatic nucleus. There is
      also substantial evidence that neuropeptide Y (NPY) mediates the effects of at
      least some nonphotic stimuli on the circadian clock. The purpose of this study
      was to investigate how NPY and glutamate receptor activation interact to reset
      the phase of the circadian clock. Microinjection of the glutamate agonist N
      methyl-D-aspartic acid (NMDA) during the subjective day significantly decreased
      NPY-induced phase advances. During the late subjective night, NMDA induced light
      like phase advances, which were significantly reduced by microinjection of NPY.
      Microinjection of NPY inhibited NMDA-induced phase advances during the late
      subjective night, even when sodium-dependent action potentials were inhibited by
      tetrodotoxin. These data support the hypothesis that, during the subjective
      night, NPY and NMDA act on the same clock cells or on cells that communicate with
      clock cells by mechanisms not requiring action potentials. Although NPY and NMDA
      appear to be mutually inhibitory during both the day and the night, the
      mechanisms of this inhibition appear to be different during the day versus the
      night.

PMID- 15183506
TI  - A neural network underlying individual differences in emotion and aggression in
      male golden hamsters.
AB  - In rodents, aggressive behavior can be altered by experimental manipulations of
      emotional responsiveness. The goal of this study was to identify characteristics
      of emotional reactivity associated with individual differences in aggressive
      behavior and their integration within a common neural network. Male golden
      hamsters were first screened for offensive aggression. Then, the animals were
      trained through immediate reinforcement and tested for their adaptation to a
      delayed reward. Similar protocols have been used to test behaviors associated
      with frustration. At first, all hamsters showed increased frequency of bar
      pressing per reward during delayed reinforcement. However, Low-Aggression animals
      were able to adapt to the delay and showed a decreased rate of bar pressing per
      reward within 5 days. In contrast, High-Aggression animals maintained a high rate
      of bar pressing per reward. In addition, brains were collected after immediate
      reward training or delayed reward testing, and labeled for pCREB-immunoreactivity
      as a marker of trans-synaptic activity. In High-Aggression individuals, elevated
      density of cyclic AMP response element binding protein, phosphorylated (pCREB)
      immunostaining was found within the anterior hypothalamus, an area critical to
      the control of aggression. Delayed reinforcement was associated with enhanced
      pCREB immunostaining within the central amygdala, medial amygdala and preoptic
      area/hypothalamus continuum. Further analysis of the data also showed a positive
      correlation in labeling density between the lateral septum and the anterior
      hypothalamus, specifically in Low-Aggression animals exposed to delayed reward.
      Therefore, as High-Aggression individuals lack control of their emotional
      reactivity, they are also characterized by a de-synchronization between the
      inhibitory output of the septum and the aggression areas of the hypothalamus.
      Finally, our data also show that frustration is associated with an extensive
      activation of the preoptic area/hypothalamus continuum and amygdala.

PMID- 15183507
TI  - Subfield-specific increase in brain growth protein in postmortem hippocampus of
      Alzheimer's patients.
AB  - The neuropathology of Alzheimer's disease (AD) reflects a precarious balance
      between neurodegenerative phenomena and reactive events of neuroplasticity. This
      latter aspect of AD neuropathology has received less attention than it deserves
      and its contribution to memory loss is therefore not well understood. To monitor
      neuroplastic-related events we studied the distribution of the plasticity
      associated, brain growth protein GAP-43 in AD subjects and age-matched controls.
      In tissue from AD patients, we observed a consistent elevation of GAP-43 in a
      subfield of the hippocampus, stratum lacunosum moleculare. This subfield contains
      inputs from multiple brain regions and is known to regulate declarative memory
      function. Levels of potentially aberrant sprouting, as marked by elevated growth
      protein, were positively correlated with the severity of AD suggesting that
      increased expression of GAP-43 leads to a miswiring of circuits critical for
      memory function. Our findings suggest a mechanism, aberrant neuroplasticity, that
      in concert with neurodegeneration may importantly contribute to the memory loss
      in AD.

PMID- 15183508
TI  - Morphological evidence for functional capsaicin receptor expression and
      calcitonin gene-related peptide exocytosis in isolated peripheral nerve axons of
      the mouse.
AB  - Rat sciatic nerve axons express capsaicin, proton and heat sensitivity and
      respond to stimulation with a Ca2+-dependent and graded calcitonin gene-related
      peptide (CGRP) release. In this study we demonstrate that similar functions,
      including capsaicin-induced CGRP release, are to be found in the desheathed
      sciatic nerve of the mouse. We have morphologically investigated the mechanisms
      of this axonal release in regions away from the active zones of synapses.
      Capsaicin receptor 1 (TRPV1) and CGRP immunostaining was performed using electron
      microscopic visualization. TRPV1 was identified in the axoplasm and inside
      vesicles--presumably on axonal transport--as well as in considerable quantity in
      the axonal plasma membrane of unmyelinated nerve fibers. Most of the unmyelinated
      axons were immunopositive for CGRP and in unstimulated nerves CGRP-containing
      vesicles almost entirely filled the axoplasm. After capsaicin stimulation (10(-6)
      M for 5 min), the fibers appeared depleted of CGRP with only few vesicles
      remaining as well as some residual staining of the axoplasm. In addition a large
      number of vesicles were fused with the axonal membrane, forming classical
      exocytotic figures--the omega structures--lined with CGRP immunoreactive product.
      These results present morphological evidence for the distribution of TRPV1 along
      unmyelinated axons in peripheral nerve and also provide the first demonstration
      of vesicular neuropeptide exocytosis along unmyelinated axons in peripheral
      nerve.

PMID- 15183509
TI  - Repeated application of ketamine to rats induces changes in the hippocampal
      expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to
      those found in human schizophrenia.
AB  - Treatment with the phencyclidine derivative ketamine, a non-competitive N-methyl
      D-aspartate receptor antagonist and a well known anesthetic, has recently been
      introduced to mimic schizophrenia in animals. Using rats repeatedly treated with
      sub-anesthetic doses we demonstrate in the hippocampal formation the cellular
      distribution patterns of proteins being relevant to the pathogenesis of
      schizophrenia. Compared with controls an increase in the density of reduced
      nicotinamide adenine dinucleotide phosphate diaphorase-, neuronal nitric oxide
      synthase- and cFOS-positive hippocampal interneurons was found, whereas the
      density of parvalbumin expressing cells was decreased. Our experiments show that
      repeated injections of sub-anesthetic doses of ketamine induce significant
      changes in the nitrergic and GABAergic system which, in part, resemble those
      described in postmortem brains of human schizophrenics indicating that sub
      chronic treatment with sub-anesthetic doses of ketamine might be a useful animal
      model to study schizophrenia.

PMID- 15183510
TI  - Modulation of septo-hippocampal Theta activity by GABAA receptors: an
      experimental and computational approach.
AB  - Theta frequency oscillation of the septo-hippocampal system has been considered
      as a prominent activity associated with cognitive function and affective
      processes. It is well documented that anxiolytic drugs diminish septo-hippocampal
      oscillatory Theta activity contributing to their either therapeutic or unwanted
      side effects. In the present experiments we applied a combination of
      computational and physiological techniques to explore the functional role of
      GABAA receptors in Theta oscillation. In electrophysiological experiments
      extracellular single unit recordings were performed from medial septum/diagonal
      band of Broca with simultaneous hippocampal (CA1) electroencephalogram (EEG)
      recordings from anesthetized rats. Neurotransmission at GABAA receptors were
      modulated by means of pharmacological tools: the actions of the GABAA receptor
      positive allosteric modulator diazepam and inverse agonist/negative allosteric
      modulator FG-7142 were evaluated on septo-hippocampal activity. Systemic
      administration of diazepam inhibited, whereas FG-7142 enhanced Theta oscillation
      of septal neurons and hippocampal EEG Theta activity. In parallel to these
      experimental observations, a computational model has been constructed by
      implementing a septal GABA neuron model with a CA1 hippocampal model containing
      three types of neurons (including oriens and basket interneurons and pyramidal
      cells; latter modeled by multicompartmental techniques; for detailed model
      description with network parameters see online addendum:
      http://geza.kzoo.edu/theta). This connectivity made the network capable of
      simulating the responses of the septo-hippocampal circuitry to the modulation of
      GABAA transmission, and the presently described computational model proved
      suitable to reveal several aspects of pharmacological modulation of GABAA
      receptors. In addition, computational findings indicated different roles of
      distinctively located GABAA receptors in theta generation.

PMID- 15183512
TI  - Fetal cortical allografts project massively through the adult cortex.
AB  - Allogeneic embryonic CNS tissue grafts placed in the mature brain are classically
      considered to lack significant long-range efferents. This problem was reexamined
      using 'green' cells from mice expressing ubiquitously an 'enhanced' green
      fluorescent protein as an alternative to classical tract tracing methods. The
      present study shows that fetal cortical neurons (E15; occipital origin) grafted
      in the occipitoparietal region of the adult cortex project massively throughout
      ipsilateral telencephalic structures. Two out of the nine grafted subjects had
      additional but sparse efferents in the visual thalamus, superior colliculus and
      pons.

PMID- 15183513
TI  - Effect of memantine on the levels of glial cells, neuropeptides, and peptide
      degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's
      disease model.
AB  - It has been implicated that glia activation plays a critical role in the
      progression of Alzheimer's disease (AD). However, the precise mechanism of glia
      activation is not clearly understood yet. In our present studies, we confirmed
      our previous results where change the levels of neuropeptides and peptidases in
      ibotenic acid (IBO) infusion into the rat nucleus basalis magnocellularis, an
      animal model of AD. Furthermore, we extended our study to investigate a possible
      protection effect of co-administration on the changes of neuropeptides, and
      neuronal and glial cells in IBO-infused rat brain by memantine treatment. The
      levels of substance P and somatostatin were decreased in the striatum and frontal
      cortex 1 week after IBO infusion, and recovered to the control level by memantine
      treatment, indicating the involvement of neuropeptides in AD pathology.
      Furthermore, the immunohistochemical and enzymatic studies of GFAP and CD 11b,
      and peptidylarginine deiminase, markers of glia, in the striatum and frontal
      cortex showed the increase in IBO-treated rat brain as compared with controls,
      while co-administration of memantine and IBO no increase of astrocytes and
      microglia activation was observed. The present biochemical and
      immunohistochemical results suggest that glia activation might play an important
      role to the pathology of AD, and correlate with the changes of neuropeptide
      levels in AD brain that is recovered by memantine treatment.

PMID- 15183511
TI  - Connexin47, connexin29 and connexin32 co-expression in oligodendrocytes and Cx47
      association with zonula occludens-1 (ZO-1) in mouse brain.
AB  - Gap junctions between glial cells in mammalian CNS are known to contain several
      connexins (Cx), including Cx26, Cx30 and Cx43 at astrocyte-to-astrocyte
      junctions, and Cx29 and Cx32 on the oligodendrocyte side of astrocyte-to
      oligodendrocyte junctions. Recent reports indicating that oligodendrocytes also
      express Cx47 prompted the present studies of Cx47 localization and relationships
      to other glial connexins in mouse CNS. In view of the increasing number of
      connexins reported to interact directly with the scaffolding protein zonula
      occludens-1 (ZO-1), we investigated ZO-1 expression and Cx47/ZO-1 interaction
      capabilities in brain, spinal cord and Cx47-transfected HeLa cells. From counts
      of over 9000 oligodendrocytes labeled by immunofluorescence in various brain
      regions, virtually all of these cells were found to express Cx29, Cx32 and Cx47.
      Oligodendrocyte somata displayed robust Cx47-immunopositive puncta that were co
      localized with punctate labeling for Cx32 and Cx43. By freeze-fracture replica
      immunogold labeling, Cx47 was abundant on the oligodendrocyte-side of
      oligodendrocyte/astrocyte gap junctions. By immunofluorescence, labeling for Cx47
      along myelinated fibers was sparse in most brain regions, whereas Cx29 and Cx32
      were previously found to be concentrated along these fibers. By immunogold
      labeling, Cx47 was found in numerous small gap junctions linking myelin to
      astrocytes, but not within deeper layers of myelin. Brain subcellular
      fractionation revealed a lack of Cx47 enrichment in myelin fractions, which
      nevertheless contained an enrichment of Cx32 and Cx29. Oligodendrocytes were
      immunopositive for ZO-1, and displayed almost total Cx47/ZO-1 co-localization. ZO
      1 was found to co-immunoprecipitate with Cx47, and pull-down assays indicated
      binding of Cx47 to the second PDZ domain of ZO-1. Our results indicate widespread
      expression of Cx47 by oligodendrocytes, but with a distribution pattern in
      relative levels inverse to the abundance of Cx29 in myelin and paucity of Cx29 in
      oligodendrocyte somata. Further, our findings suggest a scaffolding and/or
      regulatory role of ZO-1 at the oligodendrocyte side of astrocyte-to
      oligodendrocyte gap junctions.

PMID- 15183514
TI  - Participation of hippocampal nicotinic receptors in acquisition, consolidation
      and retrieval of memory for one trial inhibitory avoidance in rats.
AB  - One-trial step-down inhibitory avoidance in rats involves the activation of two
      separate memory types, a short-term system (STM) that lasts 3-6 h, and a long
      term system (LTM) that takes 3-6 h to be formed and lasts for many days or even
      months. Here we investigate the effect of nicotinic receptor (nAChR) ligands
      infused bilaterally in the hippocampus on STM and LTM formation and on LTM
      retrieval of this task. Rats were implanted with chronic cannulae in the CA1
      region of the dorsal hippocampus, trained using a 0.5 mA foot shock, and tested
      twice, first 1.5 h after training to measure STM, and again at 24 h to measure
      LTM. The drugs used were the nAChR antagonists, mecamylamine (1, 3 and 10
      microg/side) and dihydro-beta-erythroidine (DHbetaE; 2, 6 and 18 microg/side) and
      the agonist, nicotine (0.6, 1 and 3 microg/side). They were given either 15 min
      before training, immediately after training or 15 min prior to LTM retrieval.
      Mecamylamine and DHbetaE impaired and nicotine enhanced STM, LTM and retrieval
      similarly. The results indicate that nAChRs in CA1 participate in the regulation
      of both STM and LTM formation, and on the retrieval of LTM.

PMID- 15183515
TI  - Enlarged ventricles, astrogliosis and neurodegeneration in heat shock factor 1
      null mouse brain.
AB  - Heat shock transcription factors mediate the regulation of the organism
      physiological maintenance and adaptation. We investigated the morphology and
      cellular expression of selected genes in brains of transgenic mice lacking the
      heat shock transcription factor 1, HSF1, the main transactivator under stress
      conditions. All HSF1 null mice displayed major brain morphological alterations:
      the lateral ventricles were markedly enlarged and the white matter reduced, as in
      ventriculomegaly. Heterozygous mice for the HSF1 gene also had these
      abnormalities albeit to a lower extent in comparison to the wild type, indicating
      a gene dosage effect. Cell loss, vacuolisation, amorphous eosinophilic cytoplasm
      and pyknotic nucleus were evident in the white matter, especially in
      periventricular regions. These areas also exhibited astrogliosis and
      neurodegeneration. The expression of heat shock protein hsp 27 was up-regulated
      whereas alpha B-crystallin was down-regulated in different areas of HSF1 null
      mouse brain in comparison to control mice. These data implicate HSF1 in
      maintaining the postnatal mammalian brain under non-stress conditions.

PMID- 15183516
TI  - Differential expression of brain-derived neurotrophic factor transcripts after
      pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry.
AB  - Activity-dependent brain-derived neurotrophic factor (BDNF) expression is Ca2+
      dependent, yet little is known about the Ca2+ channel contributions that might
      direct selective expression of the multiple BDNF transcripts. Here, effects of
      pilocarpine-induced seizure activity on total BDNF expression and on the
      individual sensitivity of BDNF transcripts to glutamate receptor and Ca2+ channel
      blockers were evaluated using hippocampal slice cultures and in situ
      hybridization of transcript-specific cRNA probes directed against mRNAs for the
      four 5' exons (I-IV) of the BDNF gene. mRNAs for nerve growth factor (NGF) and
      tyrosine kinase B (trkB) also were studied. Pilocarpine (5 mM) induced a dose-
      and time-dependent increase in total BDNF (exon V) mRNA expression in the dentate
      granule cells and CA3-CA1 pyramidal cells with maximal effects at 6 and 24 h,
      respectively. Increases were blocked by co-treatment with the alpha-amino-3
      hydroxy-5-methylisoxazole-4-propionic acid/kainate 6-cyano-7-nitroquinoxaline-2,3
      dione (CNQX: 25 microM) and the N-methyl-d-aspartic acid receptor antagonist 2
      amino-5-phosphonovaleric acid (APV; 25 microM), whereas the L-type voltage
      sensitive Ca2+ channel blocker nifedipine (20 microM) was without detectable
      effect. Maximal NGF and trkB mRNA expression was induced by pilocarpine at 4 and
      12 h, respectively. For the individual BDNF transcripts, APV blocked pilocarpine
      induced increases in transcript II, whereas nifedipine blocked increases in
      transcripts I and III. Transcript IV levels were not altered by treatment. These
      results indicate that transcript II makes the greatest contribution to
      pilocarpine effects on total BDNF mRNA content in this model and provides
      evidence for regional and Ca2+ channel-specific differences in activity-dependent
      regulation of the different BDNF transcripts in hippocampus.

PMID- 15183518
TI  - Morphine-induced alterations in gene expression of calbindin immunopositive
      neurons in nucleus accumbens shell and core.
AB  - Chronic opiate administration induces a number of biochemical alterations within
      the mesolimbic dopamine system that may mediate various aspects of the addictive
      process. In the present study, rats were administered morphine (1.0 mg/infusion)
      for 20 days (17.6+/-3.0 infusions/day) based on infusion histories of self
      administering rats. Calbindin-D28K immunoreactive neurons were microdissected
      from the nucleus accumbens (NAc) shell and core subregions and gene expression
      was assessed using cDNA macroarrays. Comparison of gene expression between the
      shell and core subregions of vehicle-treated rats revealed significantly higher
      relative abundance of GABA-A alpha1, Galphai2 and post-synaptic density protein
      95 transcript (PSD-95) mRNA levels in the shell, whereas Ggamma2 and synuclein 1
      were more abundant in the core of the NAc. In the NAc shell, morphine
      administration resulted in upregulation of caspace 9, NF-kappaB, NF-H, tau, GABA
      A delta subunit, FGFR1, Ggamma2, synuclein 1, syntaxin 5 and 13, GRK5, and c-fos
      mRNAs. Caspace 1, D2 dopamine receptor, GABA-A alpha1 subunit, GRIA 1/3/4,
      Galphai2, PSD-95 and CREB were down-regulated in the NAc shell with morphine
      administration. In the core, neuronal apoptotic inhibitory protein (NAIP), GABA-A
      alpha1 subunit, GRIN2C, GRIA1, mGluR1, D4 dopamine receptor and PSD-95 were
      upregulated by morphine administration whereas bax, bcl-x, cox-1 and MAP2 were
      decreased. These data demonstrate that morphine administration alters gene
      expression differentially in NAc subregions. Specifically, GABA-A alpha1 subunit,
      GRIA1 subunit and PSD-95 mRNAs were decreased in the shell but increased in the
      core following morphine administration. In addition, these results provide
      potential targets for further evaluation in models of morphine reinforcement as
      well as novel mechanisms of action in morphine-induced pathophysiology.

PMID- 15183519
TI  - Stress potentiation of morphine-induced dopamine efflux in the nucleus accumbens
      shell is dependent upon stressor uncontrollability and is mediated by the dorsal
      raphe nucleus.
AB  - A single session of uncontrollable (inescapable tailshock, IS), but not
      controllable (escapable tailshock, ES), stress is known to selectively potentiate
      subsequent morphine-conditioned place preference in a dorsal raphe nucleus (DRN)
      serotonin (5-HT) dependent manner. Here, in vivo microdialysis is used to test
      the hypothesis that prior IS, but not ES, will potentiate morphine-induced
      dopamine (DA) efflux in the nucleus accumbens (NAc) shell and that this will
      occur by a pathway involving DRN 5-HT neurons. Male Sprague-Dawley rats were
      exposed to yoked IS, ES, or no stress. Twenty-four hours later, morphine (3 mg/kg
      s.c.) or saline was administered during microdialysis. As predicted, prior IS
      selectively potentiated morphine-induced DA, but not 5-HT, efflux in the NAc.
      This potentiation was due to morphine's action in the DRN because it was blocked
      by intra-DRN microinjection of the opioid antagonist naltrexone (10 microg). IS
      potentiation of morphine-induced DA efflux in the NAc was also dependent upon
      activation of 5-HT neurons in the DRN because it was blocked by intra-DRN
      microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-di-n-(propylamino)
      tetralin (1 microg). No effect of IS was found on morphine-induced 5-HT or DA
      efflux in the ventral tegmental area. These results suggest a neural substrate
      for stress potentiation of morphine reward involving 5-HT neurotransmission in
      the DRN.

PMID- 15183520
TI  - Mu but not delta and kappa opioid receptor involvement in ventrolateral orbital
      cortex opioid-evoked antinociception in formalin test rats.
AB  - The present study was designed to investigate the roles of different subtypes of
      opioid receptors in ventrolateral orbital cortex (VLO) opioid-evoked
      antinociception in formalin test by using an automatic detection system for
      recording the nociceptive behavior (agitation) and a manual method for detecting
      the duration of licking the injected paw in the conscious rat. Formalin (5%, 50
      microl) s.c. injected into the hindpaw produced a biphasic agitation response or
      lengthening duration of licking. Morphine (5 microg) microinjected unilaterally
      into VLO significantly inhibited the agitation response and the licking time, and
      these effects were blocked by pre-administration of the non-selective opioid
      receptor antagonist naloxone (1.0 microg) into the same site. Microinjection of
      endomorphin-1 (5 microg), a selective micro-receptor agonist, and [D-Ala2, D
      Leu5]-enkephalin (DADLE, 10 microg), a delta-/micro-receptor agonist also
      inhibited the nociceptive behaviors, and both the effects were blocked by
      selective mu-receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA;
      3.75 microg), but the DADLE-evoked inhibition was not influenced by the selective
      delta-receptor antagonist naltrindole (5 microg). Microinjection of selective
      kappa-receptor agonist (+/-)-trans-U-50488 methanesulfonate salt (1.5 microg)
      failed to alter the nociceptive behaviors induced by formalin injection. The beta
      FNA and naloxone applied into VLO and morphine into the adjacent regions ventral
      and dorsal to VLO had no effect on the formalin-evoked nociceptive behaviors.
      These results suggest that mu- but not delta- or kappa-opioid receptor is
      involved in the VLO opioid-evoked antinociception in formalin test rat.

PMID- 15183517
TI  - Sprouting and synaptic reorganization in the subiculum and CA1 region of the
      hippocampus in acute and chronic models of partial-onset epilepsy.
AB  - Repeated seizures induce permanent alterations in the hippocampal circuitry in
      experimental models and patients with intractable temporal lobe epilepsy (TLE).
      Most studies have concentrated their attention on seizure-induced reorganization
      of the mossy fiber pathway. The present study examined the projection pathway of
      the CA1 pyramidal neurons to the subiculum, which is the output of the
      hippocampal formation in five models of TLE. We examined the laminar pattern of
      Timm's histochemistry in the stratum lacunosum-moleculare of CA1 in three acute
      and two chronic models of TLE: intraventricular kainic acid (KA), systemic KA,
      systemic pilocarpine, chronic electric kindling and chronic i.p.
      pentylenetetrazol. The laminar pattern of Timm histochemistry in the stratum
      moleculare of CA1 was permanently remodeled in epileptic models suggesting
      sprouting of Timm containing terminals from the adjacent stratum lacunosum.
      Ultrastructural examination confirmed that Timm granules were localized in
      synaptic terminals. As the source of Timm-labeled terminals in this region was
      not known, sodium selenite, a selective retrograde tracer for zinc-containing
      terminals, was iontophoretically injected in vivo in rats exposed to systemic
      pilocarpine, systemic KA or chronic pentylenetetrazol. The normal projection of
      CA1 pyramidal neurons to the subiculum is topographically organized in a lamellar
      fashion. In normal rats, the extent of the injection site (terminals) and the
      retrogradely labeled pyramidal neurons (cell soma) corresponded to the same
      number of lamellas. In epileptic rats, the retrograde labeling extended 42-67%
      farther than the normal dorso-ventral extent including lamellas above and below
      the expected. This is direct evidence for sprouting of CA1 pyramidal axons into
      the subiculum and stratum lacunosum-moleculare of the CA1 region confirming the
      alterations of the laminar pattern of Timm's histochemistry. Sprouting of the CA1
      projection to subiculum across hippocampal lamellas might lead to translamellar
      hyperexcitability, and to amplification and synchronization of epileptic
      discharges in the output gate of the hippocampal formation.

PMID- 15183521
TI  - The central piriform cortex: anatomical connections and anticonvulsant effect of
      GABA elevation in the kindling model.
AB  - The piriform cortex (PC) is thought to be critically involved in the generation
      and propagation of forebrain (limbic type) seizures in the rat. The PC extends
      over a large area at the ventrolateral side of the rat brain with an anterior
      part highly sensitive for bicuculline-induced and a central part most sensitive
      for electrically induced seizures. Therefore, distinct parts of the PC might be
      differentially involved in the generation and spread of seizure activity. Since
      previous studies indicated that a loss of GABAergic inhibition in the PC is
      involved in the generation of epileptic activity, we microinjected the GABA
      transaminase blocker vigabatrin bilaterally in the anterior, central and
      posterior PC of previously amygdala-kindled rats and repeatedly tested its effect
      on kindled seizures. Vigabatrin was anticonvulsant in all groups for up to 13
      days with a maximal effect 24 h after injection. However, the anticonvulsant
      effect on seizure generalization was strongest after microinjection in the
      central PC suggesting that GABAergic synapses in this part are critically
      involved in the development of generalized seizures. Since differences in
      anatomical connections of the PC regions may be responsible for differences in
      seizure susceptibility, we addressed this question by injection of the
      anterograde tracer Phaseolus vulgaris leucoagglutinin in different PC subregions.
      Although there were similarities in the projections from different PC subregions,
      we also found differences between the PC subregions in their projections to
      structures known to be important in the limbic seizure network, such as the
      perirhinal cortex, nucleus accumbens, and striatum. These differences in
      anatomical connectivity between PC subregions may be involved in the differences
      in seizure susceptibility observed in the present and previous studies.

PMID- 15183522
TI  - Sensitization of dorsal root reflexes in vitro and hyperalgesia in neonatal rats
      produced by capsaicin.
AB  - The maturation of dorsal root reflexes (DRRs) in lumbar roots was characterized
      in neonatal rats at 1, 2 and 3 weeks after birth using an in vitro isolated
      spinal cord preparation with attached dorsal roots and dorsal root ganglia (DRG).
      Changes of DRRs in rats of increasing age were also tested by administration of
      capsaicin to the DRG and related to spinal mechanisms of hyperalgesia by defining
      the behavioral responses of neonatal rats to intradermal capsaicin. DRRs evoked
      by stimulating the adjacent root in 1 week old rats are characterized by highly
      desynchronized waveforms with power spectra concentrated at frequencies greater
      than 200 Hz. DRRs in 1 week old rats show very little change in amplitude or area
      with increasing afferent stimulation strength. In contrast DRRs in 2 and 3 weeks
      old rats are highly synchronized with power concentrated at frequencies less than
      100 Hz and show a graded increase in amplitude and area with increasing stimulus
      strength. The recovery of DRR amplitude in a paired pulse stimulus protocol is
      faster in 1 week rats than in 2 or 3 weeks old rats. Finally, DRRs in 2 and 3
      week old rats show increased amplitude and area following application of
      capsaicin to the DRG of the stimulating root whereas those in 1 week old rats do
      not. These changes parallel the behavioral responses of neonatal rats as 2 and 3
      weeks old rats show secondary mechanical hyperalgesia following intradermal
      capsaicin, but 1 week old rats do not. Our data indicate that the spinal
      circuitry for DRRs in the neonatal period undergoes rapidly dynamic development
      in the rat. This development is sufficiently rapid that mechanisms of spinal
      sensitization induced by capsaicin can be studied in rats 2 weeks old and older.

PMID- 15183523
TI  - Altered pain-related behaviors and spinal neuronal responses produced by s.c.
      injection of melittin in rats.
AB  - Recently, we have reported that following s.c. injection of a solution containing
      the whole bee-venom (BV; Apis mellifera), into one hind paw of a rat, the
      experimentally produced honeybee's sting, the animal shows altered pain-related
      behaviors and inflammation relevant to pathological pain state. To see whether
      melittin, the major (over 50%) toxic component of the BV, is responsible for the
      above abnormal pain behavioral changes, the present study was designed to
      investigate the effects of s.c. melittin on either nociceptive behaviors in
      conscious rats or spinal dorsal horn neuronal responses in anesthetized rats. In
      the behavioral surveys, s.c. injection of three doses of both melittin (5, 25 and
      50 microg) and BV (10, 50 and 100 microg) into the posterior surface of one hind
      paw of rats produced an immediate tonic nociceptive response displaying as
      persistent spontaneous paw flinching reflex. Similar to the BV test, the melittin
      response was also monophasic and dose-dependent in terms of both intensity and
      time course. As an accompanied consequence, both heat and mechanical
      hypersensitivity (hyperalgesia and allodynia) and inflammatory responses (paw
      swelling and plasma extravasation) were induced by s.c. melittin injections. In
      the electrophysiological recordings, s.c. injection of the same three doses of
      melittin into the cutaneous receptive field produced an immediate, dose-dependent
      increase in spontaneous spike discharges of spinal dorsal horn wide-dynamic-range
      (WDR) neurons which are believed to be responsible for the spinally-organized
      nociceptive flexion reflex. The melittin-induced ongoing spike responses are
      similar to the behavioral flinching reflex in terms of both duration and
      frequency. Furthermore, the responsiveness of the WDR neurons to both heat (42
      degrees C, 45 degrees C, 47 degrees C and 49 degrees C) and mechanical (brush,
      pressure and pinch) stimuli was significantly enhanced by s.c. injection of
      melittin shown as a leftward shift of the stimulus-response functional curves.
      Taken together, the present results suggest that melittin, the major toxin of the
      whole BV, is likely to be responsible for production of the long-term spinal
      neuronal changes as well as persistent spontaneous nociception, heat/mechanical
      hypersensitivity and inflammatory responses that are produced by experimental
      honeybee's sting.

PMID- 15183524
TI  - Noise exposure induces up-regulation of ecto-nucleoside triphosphate
      diphosphohydrolases 1 and 2 in rat cochlea.
AB  - Extracellular ATP acting via P2 receptors in the inner ear initiates a variety of
      signaling pathways that may be involved in noise-induced cochlear injury.
      Nucleoside triphosphate diphosphohydrolase (NTPDase)1/CD39 and NTPDase2/CD39L1
      are key elements for regulation of extracellular nucleotide concentrations and P2
      receptor signaling in the cochlea. This study characterized the effect of noise
      exposure on regulation of NTPDase1 and NTPDase2 expression in the cochlea using a
      combination of real-time RT-PCR, immunohistochemistry and functional studies.
      Adult Wistar rats were exposed to broad band noise at 90 dB and 110 dB sound
      pressure level (SPL) for 72 h. Exposure to 90 dB SPL induced a small and
      temporary change of auditory thresholds (temporary threshold shift), while
      exposure to 110 dB SPL induced a robust and permanent change of auditory
      thresholds (permanent threshold shift). NTPDase1 and NTPDase2 mRNA transcripts
      were upregulated in the cochlea exposed to 110 dB SPL, while mild noise (90 dB
      SPL) altered only NTPDase1 mRNA expression levels. Changes in NTPDases expression
      did not correlate with levels of circulating corticosterone, implying that the up
      regulation of NTPDases expression was not stress-related. Semi-quantitative
      immunohistochemistry in the cochlea exposed to 110 dB SPL localized the increased
      NTPDase1 and NTPDase2 immunostaining in the stria vascularis and up-regulation of
      NTPDase2 in the intraganglionic spiral bundle. In contrast, NTPDase1 was down
      regulated in the cell bodies of the spiral ganglion neurones. Distribution of
      NTPDases was not altered in the cochlea exposed to 90 dB SPL. Functional studies
      revealed increased ectonucleotidase activities in the cochlea after exposure to
      110 dB SPL, consistent with up-regulation of NTPDases. The changes in NTPDases
      expression may reflect adaptive response of cochlear tissues to limit ATP
      signaling during noise exposure.

PMID- 15183525
TI  - Electroretinogram changes associated with retinal upregulation of trophic
      factors: observations following optic nerve section.
AB  - The purpose of the present work was to assess whether upregulation of trophic
      factors and protection from damage induced in the retina by optic nerve section
      are associated with changes in the flash electroretinogram (ERG). We have
      examined the ERG in adult pigmented rat at different survival times over a period
      of 3 months following section of the optic nerve. The a-wave was analyzed using
      the Lamb-Pugh model and the parameters of best fit were estimated in control
      animals and at successive survival times. The amplitudes of the a- and b-waves
      were reduced over the first 7 days after nerve section. The a-wave recovered its
      relative amplitude by 21 days, but the b-wave remained depressed 5 weeks
      following nerve section. Analysis of the a-wave indicated a 20-30% reduction in
      the dark current of sectioned eyes at 7 days survival. A significant reduction of
      the amplification constant was observed in both nerve-sectioned and nerve-intact
      eyes, relative to normal and sham-operated controls. This reduction persisted to
      the longest survival time examined. The reduction of the a-wave at 7 days after
      nerve section coincides with a period of upregulation of ciliary nerve trophic
      factor. The amplification factor is influenced over a longer time course, which
      corresponds with a period of up-regulation of basic fibroblast growth factor.
      These changes in growth factor expression and ERG parameters are in turn
      associated with protection of photoreceptors against light damage. Present
      results suggest that the sensitivity of the retina to light may be regulated by
      mechanisms which protect photoreceptors against stress.

PMID- 15183526
TI  - Carotid baroreflex in the rat: role of glutamate receptors in the medial
      subnucleus of the solitary tract.
AB  - Experiments were done in urethane-anesthetized adult male Wistar rats to
      investigate the role of glutamate receptors in the medial subnucleus of the
      solitary tract (mNTS) in mediating the carotid sinus baroreflex responses. The
      carotid sinus on one side was isolated from the general circulation and perfused
      with a warm perfusion fluid (37 degrees C; pH 7.4) saturated with 100% oxygen.
      The carotid sinus was then connected to an apparatus that permitted application
      of pressure increments (20-100 mm Hg) to stimulate specifically baroreceptors.
      The mNTS ipsilateral to the isolated carotid sinus was identified by
      microinjections (100 nL) of L-glutamate (5 mM). The stereotaxic coordinates for
      mNTS were: 0.5-0.6 mm rostral to the calamus scriptorius, 0.5-0.6 mm lateral to
      the midline, and 0.5-0.6 mm deep from the dorsal medullary surface.
      Microinjections of either D(-)-2-amino-7-phosphono-heptanoic acid, which is an N
      methyl-D-aspartic acid (NMDA) receptor antagonist (5 mM) or 2,3-dioxo-6-nitro
      1,2,3,4-tetrahydro-benzo[f]quinoxaline-7-sulfonamide disodium (a non-NMDA
      receptor antagonist; 2 mM) significantly attenuated the depressor responses
      elicited by carotid baroreceptor stimulation. Simultaneous blockade of NMDA and
      non-NMDA receptors in the ipsilateral mNTS completely abolished the depressor
      responses to carotid baroceptor stimulation. Microinjections of either (RS)-1
      aminoindan-1,5-dicarboxylic acid (AIDA; 50 mM) or (RS)-alpha-cyclopropyl-4
      phosphono-phenyl-glycine (CPPG; 80 mM) did not alter baroreflex responses. AIDA
      blocked group I and III while CPPG blocked all three groups of metabotropic
      glutamate receptors (mGLURs). These results suggest that ionotropic glutamate
      receptors, but not mGLURs, in the mNTS mediate the reflex depressor responses to
      carotid baroreceptor stimulation in the rat.

PMID- 15183527
TI  - The anticonvulsant and proconvulsant effects of alpha2-adrenoreceptor agonists
      are mediated by distinct populations of alpha2A-adrenoreceptors.
AB  - The alpha2-adrenoreceptor (AR) is the most investigated noradrenergic receptor
      with regard to modulation of seizure activity. However, because of the complexity
      of multiple alpha2-AR subtypes and their distribution, the exact role of this
      receptor in modulating seizure activity is not clear. alpha2A- and alpha2C-ARs
      function as both autoreceptors (presynaptic) on noradrenergic neurons, where they
      regulate norepinephrine (NE) release, and as postsynaptic receptors on neurons
      that receive noradrenergic innervation, where they regulate the release of other
      neurotransmitters (heteroreceptor). The nonselective alpha2-AR agonist clonidine
      produced a proconvulsant effect on seizure susceptibility, while the selective
      alpha2A-AR agonist guanfacine was anticonvulsant. The effects of both alpha2-AR
      agonists were absent in alpha2a knockout mice, suggesting that the alpha2A-AR
      mediates the proconvulsant and anticonvulsant effect of alpha2-AR agonists on
      seizure susceptibility. To determine whether the alpha2-AR agonists were acting
      on inhibitory presynaptic autoreceptors to decrease NE release or on postsynaptic
      receptors on NE target neurons, the effects of clonidine and guanfacine were
      determined in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE. The
      anticonvulsant effect of guanfacine persisted in Dbh -/- mice, suggesting that
      guanfacine may act preferentially on alpha2A-postsynaptic receptors that regulate
      the action of NE on target neurons. In contrast, the proconvulsant effect of
      clonidine was lost in Dbh -/- mice, suggesting that clonidine may act on
      presynaptic autoreceptors to decrease NE release. We hypothesize that the alpha2A
      presynaptic autoreceptor is responsible for the proconvulsant effect of alpha2-AR
      agonists, while the alpha2A-postsynaptic receptor is responsible for the
      anticonvulsant effect of alpha2-AR agonists. These data help to clarify the
      inconsistent effects of alpha2-AR agonists on seizure activity.

PMID- 15183528
TI  - Lack of modifying effects of an estrogenic compound atrazine on 7,12
      dimethylbenz(a)anthracene-induced ovarian carcinogenesis in rats.
AB  - The modifying effects of dietary feeding of atrazine, which is one of the
      endocrine disrupting chemicals (EDCs), on 7,12-dimethylbenz(a)anthracene (DMBA)
      induced ovarian carcinogenesis were investigated in female Sprague-Dawley rats.
      We also assessed the effect of atrazine on proliferating cell nuclear antigen
      (PCNA)-index and the expression of estrogen receptor (ER)-alpha and -beta and
      androgen receptor (AR) in induced neoplasms. Rats were given a single injection
      of DMBA (0.01 ml of 0.5% DMBA suspended in olive oil) into their left ovary to
      induce ovarian neoplasms. They also received the experimental diet containing 5,
      50 or 500 ppm atrazine for 50 weeks, starting one week after the dosing of DMBA.
      The diets used were free of soy products. DMBA exposure produced left ovarian
      adenocarcinoma with an incidence of 45% at the end of the study (week 51).
      Dietary administration atrazine reduced the incidence of ovarian adenocarcinoma:
      22, 28, and 26% incidences in rats fed 5, 50, and 500 ppm atrazine containing
      diets after DMBA exposure, respectively, without statistical significance among
      the groups. The PCNA-index in adenocarcinomas was greater than that of surface
      ovarian epithelium. ER-alpha, beta and AR were expressed in a variable percentage
      of moderately and poorly differentiated adenocarcinoma cell nuclei, but their
      reactivity was extremely weak or negative in well differentiated adenocarcinoma
      cells. These results might suggest dietary feeding of a EDC atrazine did not
      affect DMBA-induced rat ovarian carcinogenesis.

PMID- 15183529
TI  - Positive correlation between overexpression of phospho-BAD with phosphorylated
      Akt at serine 473 but not threonine 308 in colorectal carcinoma.
AB  - The enhancement of cell proliferation and promotion of cell survival via the
      inhibition of apoptosis is thought to be the key to the initiation and
      progression of cancers. The phosphatidylinositol-3 kinase (PI3K)/Akt is an
      important survival signal pathway that has been shown to be crucial in the
      regulation of balance between pro-apoptotic and survival (anti-apoptotic) signal.
      In this study, the expression of phosphorylated Akt at Thr308 and Ser473, BCL-2
      antagonist of cell death (BAD) at Ser136 and glycogen synthase kinase-3beta (GSK
      3beta) at Ser9 in 47 paraffin-embedded human colorectal carcinoma (CRC) tissues
      were determined by immunohistochemical staining in order to dissect the
      alterations in the signal transduction pathways in CRC. Our results showed that
      there was a significant increase in the expression of these biomolecules in CRC
      tissues compared to the apparently normal adjacent tissues. The frequency of
      increased expression in tumor colonic mucosa were as follows: p-Akt1/2/3 (Thr308)
      = 16/47 (34%); p-Akt1 (Ser473) = 21/47 (44.7%); phospho-BAD (p-BAD) Ser136 =
      27/47 (57.4%) and phospho-GSK-3beta (p-GSK-3beta) = 21/47 (44.7%). Analysis of
      the total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD
      (Ser136) score found that there was a statistically significant relationship with
      each other. A statistically significant positive linear relationship was found
      between total p-Akt (Ser473) score and total p-GSK-3beta (Ser9) score as well as
      with total p-BAD (Ser136) score. On the other hand, total p-Akt1/2/3 (Thr308)
      scores had a statistically significant positive linear relationship with p-GSK
      3beta (Ser9) only. The Akt targets, p-GSK-3beta (Ser9) and p-BAD (Ser136) were
      positively correlated to each other. There was no significant correlation between
      clinico-pathological data with total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK
      3beta (Ser9) and p-BAD (Ser136) score except for age. The total scores of p-GSK
      3beta were found to be higher in patients in the age group of greater than 60.
      This is the first report of p-Akt1/2/3 (Thr308) and p-BAD (Ser136) expression in
      primary colorectal tumor tissue. Our data further supports the role of PI3K/Akt
      signaling pathways in the pathogenesis of CRC and contributes to the
      identification of target molecules in the signal transduction pathway for cancer
      therapy.

PMID- 15183530
TI  - Proline homozygosity in codon 72 of p53 is a factor of susceptibility for thyroid
      cancer.
AB  - A common germline polymorphism of p53 gene produces an Arginine to Proline change
      at aminoacid position 72. The resulting codon 72 variants have been reported
      associated with tumor susceptibility since they reduce p53 ability to activate
      apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to
      different carcinogens and might account for ethnic variations in cancer
      frequency. Using an allele-specific polymerase chain reaction (PCR), we tested
      peripheral blood samples from 98 patients with thyroid cancer, including 21
      follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign
      nodules, including 14 follicular adenomas and 30 goiters and 153 healthy
      individuals from the same geographical region. Data on lifetime occupational
      history, smoking history, general health conditions, previous diseases and other
      anamnestic data were obtained through interviews. Patients with FC (Pro/Pro =
      19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg =
      36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72
      variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%,
      Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender,
      age, tobacco and drugs, was associated with a markedly higher risk of FC
      (OR=9.714; CI: 2.334-40.436) and of PC (OR=5.299; CI: 2.334-40.436). These
      results provide evidence that p53 polymorphism is implicated in thyroid
      carcinogenesis and that individuals harboring the Pro/Pro genotype have an
      increased risk of developing thyroid cancer.

PMID- 15183532
TI  - Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine in
      patients with leukemia.
AB  - The nucleoside analog 2-chlorodeoxyadenosine (Cladribine, CdA) is used in the
      treatment of patients with several hematological malignancies. After
      administration of CdA, the major catabolite measured in plasma and urine is 2
      chloroadenine (CAde). This study was performed to determine the pharmacokinetics
      after oral and intravenous (iv) infusion of CdA in patients treated for chronic
      lymphocytic leukemia and to evaluate the toxicity of CAde to leukemia cells in
      vitro. CdA and CAde were also determined in plasma from 31 patients and in urine
      from 16 patients with reversed-phase high-performance liquid chromatographic. The
      toxicity of CdA and CAde was also determined in leukemic cells from 7 patients by
      fluorometric microculture cyotoxicity assay. Five times more CAde was quantified
      after oral treatment compared with an iv infusion of CdA. After iv infusion, the
      half-life was the same for CdA and CAde, but after oral administration the half
      life was doubled for CAde. Excreted amount of CAde in urine constituted about
      1.1% after iv infusion and 4.7% after oral CdA treatment. In vitro exposure of
      leukemia cells to CAde showed that it was eight times less toxic as compared to
      CdA. We conclude that CAde has a lower cytotoxic effect than CdA but may
      contribute significantly to the cytotoxicity after oral administration.

PMID- 15183531
TI  - Preventive effects of extract of leaves of ginkgo (Ginkgo biloba) and its
      component bilobalide on azoxymethane-induced colonic aberrant crypt foci in rats.
AB  - The modifying effects of dietary feeding of extract of leaves of ginkgo (Ginkgo
      biloba) (EGb) and bilobalide isolated from EGb on the development of azoxymethane
      (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344
      rats. We also assessed the effects of EGb and bilobalide on proliferating cell
      nuclear antigen (PCNA) index in 'normal-appearing' crypts and activities of
      detoxifying enzymes of cytochrome P450 (CYP), glutathione S-transferase (GST) and
      quinine reductase (QR) activity in the liver. To induce ACF, rats were given two
      weekly subcutaneous injections of AOM (20 mg/kg body wt). They also received the
      experimental diets containing EGb (50 or 500 ppm) and bilobalide (15 or 150 ppm)
      for 4 weeks, starting 1 week before the first dosing of AOM. AOM exposure
      produced a substantial number of ACF (106 +/- 10) at the end of the study (week
      4). Dietary administration of EGb and bilobalide caused significant reduction in
      the frequency of ACF: 50 ppm EGb, 73 +/- 17 (31% reduction, P < 0.001); 500 ppm
      EGb, 56 +/- 13 (47% reduction, P < 0.001); 15 ppm bilobalide, 79 +/- 17 (25%
      reduction, P < 0.001); and 150 ppm bilobalide, 71 +/- 30 (33% reduction, P <
      0.01). Immunohistochemically, EGb or bilobalide administration significantly
      lowered PCNA index in normal-appearing crypts. Feeding with EGb or bilobalide
      increased activities of CYP as well as GST and QR in the liver. These findings
      might suggest possible chemopreventive ability of EGb or bilobalide, through
      alterations in cryptal cell proliferation activity and drug metabolizing enzymes'
      activities, in colon tumorigenesis.

PMID- 15183533
TI  - Induction of cell differentiation in human leukemia U-937 cells by 5-oxygenated
      6,7-methylenedioxycoumarins from Pterocaulon polystachyum.
AB  - The present study focused on the effect of a series of extracts and two 5,6,7
      trioxygenated coumarins isolated from Pterocaulon polystachyum on the
      proliferation and differentiation of human promonocytic U-937 cells. The
      petroleum ether extract was the only extract that significantly reduced cell
      proliferation and induced cell differentiation. Treatment with pure 5-methoxy-6,7
      methylenedioxycoumarin (C1) and 5-(3-methyl-2-butenyloxy)-6,7
      methylenedioxycoumarin (C2), present in the petroleum ether extract, showed a
      time and concentration-dependent inhibition on cell proliferation. In addition,
      the coumarin derivatives were also able to induce CD88 functionality and NBT
      reduction, markers of monocytic cell differentiation. These results suggest that
      C1 and C2 might have a potential therapeutic role in the management of leukemia.

PMID- 15183534
TI  - Effect of intraperitoneal administration of docetaxel on peritoneal dissemination
      of gastric cancer.
AB  - The effect of intraperitoneal (i.p.) administration of docetaxel was evaluated
      for preclinical evidence of anticancer activity in athymic mice bearing a gastric
      cancer cell line, MKN-45-P that shows a high rate of metastasis to the peritoneal
      cavity of nude mice. Nude mice were inoculated i.p. with 10(7) MKN-45-P cells. On
      days 2, 5, 9, 12, 16 and 19 after tumor inoculation, mice were treated with i.p.
      injection of docetaxel. Treatment doses of docetaxel were 8 mg/kg (N = 7) 2 mg/kg
      (N = 7) and 0.5 mg/kg (N = 7). Intraperitoneal carcinoembryonic antigen (CEA)
      levels, animal body weight, mortality and survival were determined. All control
      mice developed ascites and died within 19-40 days. The median survival time in
      the control group was 32 days, while those of mice treated with 8, 2 and 0.5
      mg/kg were 90, 63 and 49.5 days, respectively. One of seven mice treated with 8
      mg/kg of docetaxel died of toxicity on day 12. Four mice were tumor-free on day
      90, but two had tumors in the abdomen when autopsied on day 90. One mouse treated
      with 2 mg/kg was ascertained to be tumor-free on day 90. All seven mice treated
      with 0.5 mg/kg of docetaxel died of peritoneal dissemination within 71 days. The
      results suggest the potential of intraperitoneal docetaxel administration for the
      treatment of peritoneal dissemination of gastric cancer.

PMID- 15183535
TI  - Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor
      positive breast cancer risk in Japanese women.
AB  - Since it is well established that inactivation of p53 is involved in pathogenesis
      of breast cancer, it seems to be reasonable to assume that p53 genetic
      polymorphism at codon 72 (p53Arg72Pro) which affects the function of p53 might
      have an influence on breast cancer risk. Thus, in the present study, we have
      studied the association of p53Arg72Pro polymorphism with breast cancer risk. A
      case-control study was conducted with 191 breast cancer patients and 218 healthy
      female controls. p53Arg72Pro polymorphism was examined in their association with
      breast cancer risk after adjustment for the epidemiological risk factors.
      Relationship between p53Arg72Pro polymorphism and clinicopathological
      characteristics of breast cancers was also studied. In addition, frequency of
      somatic p53 mutation was compared according to the genotype of p53Arg72Pro
      polymorphism. p5372Pro/Pro homozygotes showed a significant increase in the risk
      of estrogen receptor (ER) positive breast cancer (adjusted odds ratio (OR) =
      2.04, P = 0.04) as compared with p5372Arg/Arg homozygotes, whereas such an
      association was not found between p5372Pro/Pro homozygotes and ER negative breast
      cancer risk. Subset analysis according to menopausal status showed that
      p5372Pro/Pro homozygotes were significantly associated with ER positive breast
      cancer risk in postmenopausal women (adjusted OR = 3.42, P = 0.01) but not in
      premenopausal women. Frequency of ER positive tumors was significantly (p < 0.01)
      higher in breast cancer patients with p5372Pro/Pro genotype (82.8%) than those
      with p5372Arg/Arg genotype (54.5%). Mutational analysis of p53 in tumors showed
      that p5372Pro/Pro homozygotes had a lower frequency of p53 mutation (3.5%) than
      p5372Arg/Arg homozygotes (10.5%). It is suggested that p53Arg72Pro polymorphism
      is associated with ER positive breast cancer risk, especially, in postmenopausal
      women. The higher frequency of p53 somatic mutation in p5372Arg/Arg homozygotes
      than p5372Pro/Pro homozygotes is consistent with the thesis that the function of
      p5372Pro/Pro is impaired so that a further alteration of p53 gene is less
      required in p5372Pro/Pro homozygotes than p5372Arg/Arg homozygotes.

PMID- 15183536
TI  - Contribution of epigenetic risk factors but not p53 codon 72 polymorphism to the
      development of cervical cancer in Northeastern Thailand.
AB  - Relationships between cervical cancer and risk factors were investigated in
      Northeastern Thailand. Cases (n = 90) with squamous cell cervical cancer (SCCA)
      and age matched healthy controls (n = 100) were recruited. The p53 codon 72
      polymorphism, proline and arginine allele, was studied by the polymerase chain
      reaction-restriction fragment length polymorphism. There was no significant
      difference in the allele and the genotype distribution between the SCCA and the
      control groups (P > 0.05). Significant difference was observed in the number of
      sexual partners (P < 0.003) age at the first sexual intercourse (P < 0.03) and
      number of parities ( P< 0.006). After adjusted by age and p53 genotype,
      significant difference was still observed in the number of sexual partners (P =
      0.017) The partners' smoking increased the risk to develop SCCA. Increased odds
      ratios were observed when the partner had smoking history both at present (3.31;
      P < 0.003) and in the past (3.36; P < 0.003). The p53 polymorphism itself may not
      be a risk factor for cervical cancer in Northeastern Thailand. Much attention
      should be paid to the presence of other risk factors such as sexual behaviors and
      smoking habits in the prevention of cervical cancer in this region.

PMID- 15183537
TI  - p53 protein overexpression and p53 mutation analysis in patients with intestinal
      metaplasia of the cardia and Barrett's esophagus.
AB  - p53 mutation is a common genetic change in human cancers, but the clinical
      significance is controversial. We studied 68 patients and estimate the prevalence
      of intestinal metaplasia of cardia (IMC), Barrett's esophagus (BE), and p53
      protein overexpression, and described molecular alterations of p53 gene exons 5
      to 8. Immunohistochemical analysis showed positive p53 in 56.1-39.1% (IMC) and
      60.9% (BE). Molecular analysis showed 36.6% altered cases in exon 5 and 9.8% in
      exon 7. In conclusion, p53 protein overexpression is common in IMC and BE. The
      molecular alterations observed may be due to LOH, genomic instability or other
      unknown alteration.

PMID- 15183538
TI  - Protein levels of alpha1-tubulin, protein disulfide isomerase, tropomyosins and
      vimentin are regulated by the tuberous sclerosis gene products.
AB  - Tuberous sclerosis (TSC) is an autosomal dominant tumour suppressor gene syndrome
      affecting about 1 in 6000 individuals. It is characterized by mental retardation
      and epilepsy. A variety of tumours characteristically occur in different organs
      of TSC patients. Typically, highly epileptogenic dysplastic lesions (tubers)
      composed of abnormal shaped neurones can be detected in the cerebral cortex. Two
      tumour suppressor genes have been shown to be responsible for this disease: TSC1,
      encoding hamartin, and TSC2, encoding tuberin. In this study we performed a
      proteomic approach of two-dimensional gel electrophoresis with subsequent mass
      spectrometrical identification of protein spots after ectopic overexpression of
      human TSC1 or TSC2. We found the protein levels of alpha1-tubulin, protein
      disulfide isomerase, tropomyosin 3 and 5 and vimentin to be regulated by the two
      tuberous sclerosis gene products. The here presented findings suggest that
      deregulation of the control of these target proteins might contribute to the
      development of tumours in tuberous sclerosis patients. These data provide
      important new insights into the molecular development of this disease especially
      since alpha1-tubulin, protein disulfide isomerase and certain tropomyosins have
      also been implicated in the regulation of neuronal differentiation.

PMID- 15183539
TI  - Gene expression based classification of gastric carcinoma.
AB  - The aim of the present work is to identify molecular markers that allow
      classification of gastric carcinoma with respect to important clinicopathological
      parameters. Gastric adenocarcinomas were subjected to cDNA microarray analysis
      with a 2.504 gene probe set. Using the Rosetta rough-set based learning system,
      good classifiers were generated for gene-expression based prediction of
      intestinal or diffuse growth pattern according to Lauren's classification and
      presence of lymph node metastases. To our knowledge, this is the first study on
      gastric carcinoma in which molecular classification has been achieved for more
      than one clinicopathological parameter based on microarray gene expression
      profiles.

PMID- 15183540
TI  - Significant allelic loss of ANX7region (10q21) in hormone receptor negative
      breast carcinomas.
AB  - Loss of heterozygosity (LOH) in the 10q21 region that harbors the tumor
      suppressor gene ANX7-GTPase gene have been found in 35% of prostate tumors.
      Therefore, the rationale for this study is that this gene could also be
      implicated in breast pathogenesis as well. We investigated allelic losses in
      microsatellites of the 10q21 region, and their correlations with ANX7 status,
      estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 status
      and pathological phenotype in 30 breast carcinomas with matched control
      specimens. The LOH analysis was performed by amplifying DNA by PCR, using four
      markers of the 10q21 region (AFMa299ya5, AFM220xe5, AFM 063xc5, AFM200wf4). LOH
      in at least one marker of the 10q21 region (AFM220xe5 marker close to ANX7) was
      found in 66% of the first set of informative tumors containing 10 pairs of
      specimens. Subsequent comparison between 20 carcinomas using AFM220xe5, with and
      without LOH in terms of pathological parameters showed significant associations
      with differences in age (P = 0.04) ER (P = 0.05) Ki-67 (P = 0.04) and PR (P =
      0.01) a trend toward significance was found for tumor size (P = 0.06) and
      histological grade III (P = 0.06). These results suggest that the ANX7 gene, or
      other genes of the 10q21 region, could be functionally related to breast cancer,
      probably influencing the hormone receptor expression associated with poor
      prognosis during development.

PMID- 15183541
TI  - Proteomic phenotyping: metastatic and invasive breast cancer.
AB  - The adriamycin resistant breast cancer cell line (MCF-7/ADR) is a subject of
      ongoing debate concerning its origin and or source. Previous studies in our
      laboratory showed that MCF-7/ADR has a unique cytosolic protein expression
      pattern when compared to that of the parental MCF-7 cell line and other drug
      resistant MCF-7 cell lines. Protein expression patterns obtained using two
      dimensional gel electrophoresis and mass spectrometry indicated that this MCF
      7/ADR cell line shares some similarities with the metastatic breast cancer cell
      lines MDA-MB. Further comparisons with available two-dimensional gel
      electrophoresis maps in the literature indicate that MCF-7/ADR has a protein
      expression signature even closer to of the ductal infiltrating breast carcinoma
      cell line 8701. These observations suggest that MCF-7/ADR cells might have
      originated in a selection of ductal infiltrating carcinoma cells, which were
      present among the original MCF-7 cell population. These ductal infiltrating
      carcinoma cells may possess an intrinsic adriamycin resistance phenotype.

PMID- 15183542
TI  - EAU Guidelines on Penile Cancer.
AB  - OBJECTIVES: The European Association of Urology (EAU) consensus group on penile
      cancer has prepared these guidelines to help urologists assess the scientific
      evidence for the management of penile cancer and to incorporate recommendations
      into their clinical practice. METHOD: References used in the text have been
      assessed according to the level of scientific evidence involved and guideline
      recommendations have also been evaluated according to the Agency for Health Care
      Policy and Research [Clinical Practice Guidelines Development: Methodological
      Perspectives. Washington DC: US Department of Health and Human Services, Public
      Health Service; 1992, pp. 115-127]. RESULTS: The diagnosis, treatment and follow
      up of patients suspected of, or diagnosed with, penile cancer is listed as an
      easy reference text. CONCLUSION: A guidelines text is presented which aims at
      aiding medical specialists in determining the most optimal diagnostic and
      treatment options for this pathology.

PMID- 15183543
TI  - The impact of sildenafil on molecular science and sexual health.
AB  - OBJECTIVE: Sexual medicine has evolved greatly in the past several years, to a
      large extent because of the introduction of the phosphodiesterase-5 (PDE5)
      inhibitor, Viagra (sildenafil citrate), as a highly effective oral therapy for
      erectile dysfunction. METHODS: Recent literature pertaining to the development
      and clinical applications of sildenafil citrate was reviewed. RESULTS: The
      emergence of PDE5 inhibitor therapy for erectile dysfunction represents a major
      scientific and clinical breakthrough, and it has impacted on the field in such
      prominent areas as scientific discovery, clinical management, and public health
      awareness of sexual health disorders. CONCLUSION: The development of sildenafil
      citrate has had a major role in advancing the field of sexual medicine.

PMID- 15183544
TI  - Understanding the burden of stress urinary incontinence in Europe: a qualitative
      review of the literature.
AB  - OBJECTIVE: This study was undertaken to better define the prevalence, risk
      factors, as well as the economic and human burden of stress urinary incontinence
      (SUI) in Europe that will help health care providers better understand the impact
      of this condition. METHODS: A literature search was performed using MEDLINE,
      EMBASE, BIDS, HealthStar, HSRProj, and HSTAT databases to review the European
      literature (France, Germany, Italy, Spain, UK) on SUI between 1990 and 2001.
      Clinical experts on UI provided advice on this review. RESULTS: In all European
      countries studied SUI was identified as a distinct and highly prevalent form of
      urinary incontinence, and in some countries, as many as 80% of all incontinent
      women were diagnosed with SUI. However, epidemiological figures varied widely
      between studies, due to different definitions of diagnostic criteria and disease
      states and study designs used. Parity and vaginal birth were identified as major
      risk factors for developing SUI. Only a few studies have examined the economic
      burden of SUI, but have found it to be significant on patients and society. SUI
      also significantly affects the quality of women's lives. CONCLUSION: There is a
      clear need for harmonisation in defining SUI, standardising survey methods and
      validation criteria, and outcome measures, if results are to be compared with any
      validity. A better understanding of the burden of SUI is essential for future
      research.

PMID- 15183545
TI  - Comorbidity assessment in localized prostate cancer: a review of currently
      available techniques.
AB  - Pathological nomograms have allowed urologists to make accurate predictions about
      the behaviour of localized prostate cancers. However, predicting overall outcome
      and survival is not solely dependent on tumour characteristics; comorbidity is
      also a vital determinant of outcome The majority of prostate cancers are
      diagnosed in men over 65 years of age and many will have significant competing
      comorbid disease that will need to be accounted when considering eligibility for
      radical treatment. Most urologists currently make an educated guess about the
      risk posed by comorbid disease. Such an approach has the potential to allow
      personal bias to influence what should be an objective measure. This review
      describes the available methods for objectively assessing comorbid risk and
      assesses their potential utility to men with localized prostate cancer being
      considered for radical treatment.

PMID- 15183546
TI  - Is seminal vesicle ablation mandatory for all patients undergoing radical
      prostatectomy? A multivariate analysis on 1283 patients.
AB  - OBJECTIVE: With a shift in prostate cancer stage and a majority of patients
      operated nowadays with PSA levels <10 ng/ml, rates of seminal vesicle (SV)
      invasion found on radical prostatectomy specimens have decreased as compared to
      historical data. Since SV-sparing surgery may possibly have an influence on post
      operative erectile dysfunction and urinary recovery, we tried to determine which
      patients could be safely spared SV excision during radical prostatectomy.
      MATERIAL AND METHODS: We used preoperative data from 1283 patients operated by
      radical retropubic prostatectomy--777 with serum PSA <10.0 ng/ml--to predict SV
      invasion on final pathological examination. Variables analyzed included age,
      digital rectal examination, serum PSA, biopsy Gleason score and percentage of
      biopsy cores invaded by prostate cancer. Statistical analysis included
      univariate, multivariate logistic regression analysis and receiver operating
      characteristic (ROC) curves. RESULTS: Out of 1283 patients, 137 (10.6%) had SV
      involvement, 41/777 (5.2%) with PSA <10.0 ng/ml, 16.1% in the 10-20 ng/ml range
      and 26.2% when PSA was >20 ng/ml. Percentage of biopsies affected by prostate
      cancer and biopsy Gleason score were significant predictors of SV invasion in
      multivariate analysis, both in the entire population and in the subset of
      patients with PSA <10.0 ng/ml (p < 0.0001). Probability graphs created for
      patients with PSA <10 ng/ml indicate a risk of seminal invasion <5% when Gleason
      score on biopsy is <7 or when the percentage of biopsies affected by cancer is
      <50%. CONCLUSIONS: Resection of SV might not be "oncologically" necessary in all
      patients undergoing RP when PSA levels are below 10 ng/ml except when biopsy
      Gleason score is > or =7 or when more than 50% of prostate biopsy cores show
      cancer involvement. SV-sparing surgery could be prospectively compared to
      standard retropubic prostatectomy in selected individuals analyzing potential
      benefits on erectile function and urinary continence.

PMID- 15183547
TI  - Comparison of early oncologic results of laparoscopic radical prostatectomy by
      extraperitoneal versus transperitoneal approach.
AB  - PURPOSE: Compare the early oncological results of laparoscopic radical
      prostatectomy performed by either an extraperitoneal or a transperitoneal
      approach. METHODS: 330 consecutive men underwent laparoscopic radical
      prostatectomy for localized prostate cancer, the first 165 by transperitoneal
      approach, and the last 165 by extraperitoneal approach. Clinical stage, serum
      PSA, Gleason score of biopsy were recorded, as well as operating time, surgical
      and medical complications, blood loss, length of hospital stay and
      catheterization time. The weight of the specimen, pathological stage (1997 TNM
      classification) and status of the surgical margins were noted. The Fisher test as
      well as the chi2-test were used for statistical analysis. Differences were
      considered significant when p < 0.05. RESULTS: There were no significant
      differences between the two groups in terms of preoperative characteristics
      except for Gleason score of the biopsies which was higher in the extraperitoneal
      group (p < 0.0001). The operating time was longer with the transperitoneal
      approach (248.5 min vs. 220.0 min, p < 0.0001). There was no difference in
      transfusion rate (1.2% vs. 5.4%, transperitoneal vs. extraperitoneal,
      respectively, p = 0.6). There was no difference in hospital stay, medical and
      surgical complications. Respectively, in the transperitoneal and extraperitoneal
      groups, there were 108 and 88 pT2 tumors. There were no differences in terms of
      positive surgical margins between the two groups, 23% and 29.7% (p = 0.21)
      overall, 13.0% and 17.0% (p = 0.42) in pT2 tumors and 43.6% and 44.7% (p = 0.99)
      in pT3 tumors. CONCLUSIONS: Extraperitoneal approach offers the same early
      oncological results as transperitoneal approach with a shorter operative time.

PMID- 15183548
TI  - Can complexed prostate specific antigen enhance prostate cancer detection in
      Japanese men?
AB  - BACKGROUND: The aim of this study is to ascertain whether Bayer complexed PSA
      (cPSA) and volume referenced cPSA could enhance the detection of prostate cancer
      in Japanese men. METHODS: A total of 214 Japanese men whose serum total PSA
      (tPSA) values ranged from 1.2 ng/ml to 4600 ng/ml were enrolled from two
      institutions. Serum samples for tPSA, free PSA, PSA-alpha-1-antichymotripsin (PSA
      ACT) and cPSA (ADVIA-Centaur) were obtained in all cases. In addition, total
      gland (TGV) as well as transition zone volume (TZV) were determined in all cases
      who underwent untrasound guided prostate biopsy (sextant and two additional
      transition zone biopsies). Biopsy outcome was correlated to the following
      parameters: tPSA, cPSA, PSA-ACT, free to total (F/T) PSA ratio, 2 complex to
      total (C/T) PSA ratios and 6 volume referenced parameters. RESULTS: Prostate
      cancer was detected in 85 of 214 patients (40%). The area under the receiver
      operating characteristic curve in non-volume referenced variables was highest for
      cPSA (0.736), followed by PSA-ACT (0.735), tPSA (0.722), F/T PSA ratio (0.613)
      and C/T PSA ratio (0.591). Comparing tPSA with the cutoff value of 4.0 ng/ml, the
      cutoff value with a 2.8 ng/ml of cPSA detected one more positive biopsy patient,
      decreasing one more cancer missed case and 8 more false positive cases. At
      sensitivities of 85% to 95% in men with tPSA between 4.00 and 10.00 ng/ml (n =
      116), there were no significant differences in the corresponding specificities
      between tPSA and cPSA, or between cPSA and PSA-ACT. At sensitivities of 90% to
      95%, the corresponding specificities of PSA-ACT adjusted for transition zone
      volume revealed best performance. As for the performance in men with a tPSA less
      than 4.0 ng/ml, the specificities of cPSA performed best, and differed
      significantly from PSA-ACT and F/T PSA at sensitivities of 80% to 90%.
      CONCLUSION: Bayer cPSA could replace the first screening test by total PSA and
      can enhance cancer detection, compared with PSA-ACT. However, cPSA did not
      provide additional value in differentiating cancer from non-cancer cases in men
      with a tPSA between 4.00 and 10.00 ng/ml.

PMID- 15183549
TI  - Preliminary European results of local microwave hyperthermia and chemotherapy
      treatment in intermediate or high risk superficial transitional cell carcinoma of
      the bladder.
AB  - INTRODUCTION: Superficial bladder cancer can be treated by transurethral
      resection (TUR) and adjuvant intravesical therapy. Intravesical bacillus Calmette
      Guerin (BCG) has been proven to be more efficacious with respect to recurrence
      prevention than intravesical chemotherapy, although at the cost of more severe
      side effects. There is a need for a new treatment modality with higher efficacy
      and less toxicity. The subject of this study is the efficacy of local microwave
      hyperthermia and chemotherapy treatment in intermediate or high risk superficial
      transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Ninety
      eligible patients received adjuvant treatment with a combination of mitomycin-C
      (MMC) and local microwave hyperthermia. All patients had multiple or recurrent Ta
      or T1 TCC of the bladder and were classified as intermediate or high risk
      according to EAU criteria. In total, 41 patients were BCG failures. The treatment
      regimen included 6 to 8 weekly sessions followed by 4 to 6 monthly sessions.
      Follow-up consisted of video-cystoscopy and urine cytology every 3 months. All
      patients were observed for 2 years. RESULTS: Kaplan-Meier analyses of the total
      group (N = 90) indicated that 1 year after treatment only 14.3% (SE 4.5%) of all
      patients experienced a recurrence. After 2 years of follow-up the risk of
      recurrence was 24.6% (SE 5.9%). No progression in stage and grade was observed.
      CONCLUSION: Microwave induced hyperthermia combined with MMC has promising value
      in intermediate or high risk superficial bladder cancer patients compared to
      literature data of BCG and/or intravesical chemotherapy, particularly where other
      treatments, i.e. BCG, have failed.

PMID- 15183550
TI  - Efficacy of vardenafil in men with erectile dysfunction: a flexible-dose
      community practice study.
AB  - OBJECTIVE: To determine the efficacy and tolerability of flexible dosing with
      vardenafil in a broad population of men with erectile dysfunction (ED). METHODS:
      10-week, open-label, flexible-dose study starting with vardenafil 10 mg,
      titrating to 5 mg or 20 mg at weeks 2 and 6 based on efficacy and tolerability,
      set in 78 community practice centers in Germany and France. Participants
      comprised 398 men aged > or =18 years with ED. Main outcome measures were self
      reported improvement in erections according to a Global Assessment Question
      (GAQ), diary questions from the Sexual Encounter Profile (SEP2 and SEP3), and the
      erectile function domain score from the International Index of Erectile Function
      (IIEF) questionnaire. RESULTS: In a last observation carried forward (LOCF)
      analysis, a total of 92% (336/366) of men with ED reported an improvement of
      erections according to the GAQ. Per-patient success rates for penetration (SEP2)
      and maintenance (SEP3) of erection for intercourse were 89% (348/390) and 78%
      (303/390), respectively. Mean erectile function domain scores increased from 13.9
      at baseline to 25.9 at LOCF. Vardenafil was generally well tolerated; headache
      (6%, 25/398) and flushing (6%, 24/398) were the most frequent adverse events.
      CONCLUSIONS: In this community practice setting, vardenafil was shown to be a
      highly effective and generally well-tolerated treatment for men with ED when
      dosing was titrated by the physician to individual patient requirements.

PMID- 15183551
TI  - The Aging Males' Symptoms scale (AMS) as outcome measure for treatment of
      androgen deficiency.
AB  - INTRODUCTION: No clinical study data in which the AMS scale was applied as
      outcome measure has been reported until today. METHOD: An open post-marketing
      study was performed by office-based urologists in Germany in 2000/01. We analysed
      data of 1174 androgen-deficient males who were treated with testosterone
      enanthate. The AMS scale was applied prior to and after 12 weeks treatment.
      RESULTS: The improvement of complaints during treatment relative to the baseline
      score was 32% on average. Patients with little or no symptoms before therapy
      improved by 11%, those with mild complaints at entry by 24%, with moderate by
      31%, and with severe symptoms by 39% compared with the baseline score. We showed
      that the distribution of complaints of testosterone-deficient men before therapy
      almost returned to norm values after 12 weeks of testosterone treatment. We also
      demonstrated that the AMS results can predict the independent (physician's)
      opinion about the individual treatment effect. The positive predictive value was
      89%, the negative predictive value 59%, sensitivity (correct prediction of a
      positive assessment by the urologist) 96%, however, the specificity (correct
      prediction of a negative assessment by the physician) was only 30%. CONCLUSION:
      The AMS scale showed a convincing ability to measure treatment effects on quality
      of life across the full range of severity of complaints. In addition, results of
      the scale can predict the subjective clinical expert opinion on the treatment
      efficiency.

PMID- 15183552
TI  - Bladder C-fiber desensitization induces a long-lasting improvement of BPH
      associated storage LUTS: a pilot study.
AB  - OBJECTIVES: To evaluate the effect of bladder C-fiber desensitization on BPH
      associated storage LUTS. METHODS: Twelve patients with predominant BPH-associated
      storage LUTS gave written informed consent to enter the study. IPSS and QoL
      scores, micturition chart, uroflowmetry, cystometry and post-void residual (PVR)
      were obtained at baseline and at 1, 3 and 6 months after a single intravesical
      administration of 50 nM resiniferatoxin (RTX) solution. RESULTS: Mean IPSS score
      decreased from 20.1 +/- 6.0 to 10.5 +/- 4.4 at 1 month (p = 0.0001), to 10.3 +/-
      4.4 at 3 months (p = 0.00001) and to 9.8 +/- 5.7 at 6 months (p < 0.00001). Mean
      QoL score decreased from 4.5 +/- 1 to 2.5 +/- 1 at 1 month (p = 0.0001), to 2.3
      +/- 1 at 3 months (p = 0.0004) and to 2.6 +/- 1.2 at 6 months (p = 0.0003). Mean
      urinary frequency decreased from 15.2 +/- 8.5 to 10.8 +/- 7.3 at 1 month (p =
      0.0002), to 10.2 +/- 4.9 at 3 months (p = 0.002) and to 11.7 +/- 9.2 at 6 months
      (p = 0.005). Urge incontinence, which was present in six cases, disappeared in 4
      patients and decreased to less than half in the other two. Mean first desire to
      void and maximal cystometric capacity increased significantly after RTX whereas
      uroflowmetry and PVR were not altered. CONCLUSIONS: Intravesical desensitization
      of bladder C fibres with intravesical RTX might be useful in the treatment of
      patients with predominant BPH associated storage LUTS.

PMID- 15183553
TI  - The effect of a distance-learning programme on patient self-management of Lower
      Urinary Tract Symptoms (LUTS) in general practice: a randomised controlled trial.
AB  - OBJECTIVE: To determine whether a distance-learning programme on LUTS provided to
      the general practitioner affected patient self-management. METHODS: A randomised
      trial was performed to examine the effects of the distance-learning programme (an
      educational package for the GP and a patient information leaflet) compared with
      written guidelines on LUTS mailed to the GP. In 63 general practices (32
      intervention and 31 control) across the Netherlands all patients older than 50
      years presenting LUTS for the first time were invited to participate. Main
      outcome measures were patient evaluation of quality of care received and
      perceptions of enablement. RESULTS: A total of 151 patients was included. The
      intervention increased patient enablement regarding maintenance of independence
      (OR = 3.14) and coping with illness (OR = 2.21). Overall enablement scores were
      not changed. Patients in the intervention group had more positive evaluations of
      general practice care received (OR = 2.28 to 3.95). An explorative analysis
      suggested that the effects of the intervention were mediated in particular by
      handing out of patient information leaflets. CONCLUSIONS: A distance-learning
      programme on LUTS for general practitioners had positive effects on patient self
      management. Handing out leaflets appeared to be a crucial mediating factor.

PMID- 15183554
TI  - Surgical treatment of female stress urinary incontinence with a trans-obturator
      tape (T.O.T.) Uratape: short term results of a prospective multicentric study.
AB  - OBJECTIVE: The aim of the study was to assess the efficacy and safety of a new
      minimally invasive surgical procedure using the Trans-Obturator-Tape Uratape to
      treat female stress urinary incontinence. PATIENTS AND METHODS: 183 women with
      stress urinary incontinence (SUI) associated with urethral hypermobility,
      underwent the T.O.T. procedure (October 2001 to March 2003). 26 patients were
      previously operated for incontinence. 26 patients were operated at the same time
      for their genital prolapse. Mean age was 56 years (29-87). 50/183 patients were
      having mixed incontinence. A non-elastic, polypropylene tape (UraTape, Mentor
      Porges) with a silicon coated central part was placed under the mid-urethra. The
      surgical placement technique utilises a trans-obturator percutaneous approach.
      All patients underwent post-operative clinical examination, cough-stress test
      (full bladder), uroflowmetry, and post-voiding residual assessment. RESULTS: Mean
      follow-up was 7 months (1-21). At 1 year follow-up 80.5% of the patients were
      completely cured and 7.5% were improved. The overall peri-operative complication
      rate was 2.2% with no vascular, nerve or bowel injury. 6 patients (3.3%) had post
      operative urinary retention. CONCLUSION: The present multicentric study confirms
      the results obtained by the instigator of the technique, E. Delorme, and allows
      us to consider T.O.T. as an effective and safe technique for the treatment of
      female stress urinary incontinence, alone or in combination with prolapse repair.

PMID- 15183555
TI  - Hyperbaric oxygen for the treatment of interstitial cystitis: long-term results
      of a prospective pilot study.
AB  - OBJECTIVE: We conducted a prospective pilot study to assess the safety and
      efficacy of hyperbaric oxygen (HBO) for the treatment of interstitial cystitis
      (IC). METHODS: Six patients underwent 30 sessions of 100% oxygen inhalation in a
      hyperbaric chamber and were followed up over 15 months. The measures of efficacy
      were changes in pain and urgency (visual analog scales), alteration in the
      patient's assessment of overall change in his well-being (Patient Global
      Assessment Form), and changes in frequency and functional bladder capacity (48
      hours voiding log). Evaluation of symptom severity regarding pain and voiding
      problems was done using the O'Leary-Sant index. RESULTS: Four patients rated the
      therapeutic result as either excellent or good and assessed their well-being
      after HBO treatment as improved. Two patients showed only short-term amelioration
      of some of their symptoms. At 12 months follow-up the baseline functional bladder
      capacity increased from 37-161 ml (range) to 160-200 ml in the responder group.
      The 24-hour voiding frequency decreased from 15-27 to 6-11 voids per day, a pain
      scale improvement from 20-97 mm at baseline to 3-30 mm at 12 months follow-up and
      an urgency scale improvement from 53-92 mm to 3-40 mm, respectively was observed
      at 12 month follow-up. The symptom and pain index score decreased from 23-35 at
      baseline to 3-17 at 12 months follow-up. CONCLUSION: HBO appears to be effective
      to treat IC patients. Treatment was well tolerated and resulted in a sustained
      decrease of pelvic pain and urgency, improvement of voiding patterns and increase
      of functional bladder capacity for at least 12 months.

PMID- 15183556
TI  - Caecocystoplasty for intractable interstitial cystitis: long-term results.
AB  - OBJECTIVE: To evaluate the role of orthotopic substitution caecocystoplasty in
      intractable interstitial cystitis refractory to conservative measures by looking
      at long-term follow-up results. PATIENTS AND METHODS: We present a retrospective
      review of eleven patients who underwent a trigone-preserving orthotopic
      substitution caecocystoplasty for intractable classical interstitial cystitis.
      All patients received conservative treatment for a mean period of three years.
      They were followed up for a mean period of nine years (range 4-14 years) with
      evaluation of symptoms, biochemistry, ultrasound scan and flexible cystoscopy.
      RESULTS: Symptomatic relief was universal with an increase of bladder capacity to
      normal. There was no mortality and the postoperative morbidity was minimal.
      Intermittent self-catheterisation due to high residual volumes was necessary in
      two patients. There was no significant urinary reflux or metabolic complications
      noted. Two patients required a cystectomy after four and six years respectively
      due to recurrent trigonal disease in one and urethro-trigonal hypersensitivity
      following intermittent self-catheterisation in the other patient. One patient
      developed an advanced adenocarcinoma in the caecal segment seven years following
      the primary operation. CONCLUSION: A sustained relief of symptoms is noted after
      trigone-preserving orthotopic substitution caecocystoplasty in intractable
      classical interstitial cystitis. It may not be appropriate in patients with
      urethro-trigonal disease or hypersensitivity. There is low long-term morbidity
      due to the operation but is associated with malignancy in the augmentate. Long
      term follow-up is necessary to identify malignant change in the bladder.

PMID- 15183557
TI  - Ki-67-directed antisense therapy in an orthotopic renal cell carcinoma model.
AB  - PURPOSE: The Ki-67 antigen is only present in proliferating cells. We have shown
      previously that phosphorothioate-modified antisense oligonucleotides (ON) against
      this antigen are potent antitumoral agents in bladder and prostate cancer-derived
      cells. Since ON are known to accumulate in vivo in the kidney, high local
      effectivity may be expected. Here, we evaluated and characterized antitumoral
      effects in an orthotopic renal cell cancer (RENCA) model. MATERIAL AND METHODS:
      RENCA cells were incubated with antisense and control ON in the presence of a
      cationic lipid. Uptake studies were performed with FITC-labeled ON. Ki-67 protein
      analysis after ON treatment was performed by immunohistochemical staining. For
      animal studies, 1 x 10(5) RENCA cells were implanted under the renal capsule of
      Balb/c mice. Antisense and control ON were injected intraperitoneally daily for
      14 days. Tumor weights and status of metastasis were documented after sacrifice.
      Furthermore, vessel density in tumor tissues was determined by CD31
      immunolabeling. RESULTS: Antisense treatment of RENCA cells resulted in specific
      reduction of the Ki-67 protein and inhibition of cell growth. A substantial
      cellular uptake of labeled ON was noted in vitro and in vivo. The growth of
      orthotopically implantated syngeneic kidney tumors in immunocompetent mice was
      significantly inhibited in antisense-treated animals (p < 0.05). Furthermore,
      lung metastases were noted in 10% of antisense-treated animals compared to 30-40%
      in control groups. Immunohistochemical staining of the vessel density showed no
      significant difference among treatment groups. CONCLUSIONS: The results
      demonstrate that Ki-67-directed antisense oligonucleotides are potent inhibitors
      of target protein expression and proliferation of tumor cells in vitro, and of
      tumor growth and lung metastasis formation in murine renal cell carcinoma whereas
      tumor vascularization is not significantly affected.

PMID- 15183558
TI  - Engineered FGF-2 expression induces glandular epithelial hyperplasia in the
      murine prostatic dorsal lobe.
AB  - OBJECTIVE: It is known that androgens and stromal-epithelial interactions are
      required for the formation and growth of the prostate. FGF-2 is overexpressed in
      prostatic stromal cells in benign prostatic hypertrophy (BPH)/prostate cancer.
      This supports the paracrine/autocrine growth of prostatic epithelial/stromal
      cells in the pathogenesis of BPH and invasive prostate cancer. METHODS: We
      established transgenic mice expressing FGF-2 under the control of a short rat
      probasin promotor. FGF-2 transgenic founder mice expressing FGF-2 in the prostate
      were infertile. Thus, male founder mice were sacrificed for histological
      analysis. RESULTS: FGF-2 was expressed in epithelial cells in glands of the
      dorsal, lateral, and ventral prostatic lobes of two FGF-2 transgenic founder
      mice, but not in the anterior lobe of transgenic mice or in any lobe of non
      transgenic control littermates. Acinar epithelial glands in dorsal prostatic
      lobes of FGF-2 transgenic mice expressing FGF-2 were more dense and showed simple
      papillary hyperplasia of epithelial cells compared with those of control
      littermate mice. Glandular and luminal enlargement without epithelial growth was
      observed in the ventral lobe of FGF-2 transgenic mice compared with the controls.
      CONCLUSION: In conclusion, FGF-2 transgenic mice under the control of rat
      probasin promoter showed simple epithelial hyperplasia in glands of the prostatic
      dorsal lobe and glandular enlargement without epithelial growth in the prostatic
      ventral lobe.

PMID- 15183559
TI  - Re: Thompson IM, Klein EA, Lippman SM, Coltman CA, Djavan B. Prevention of
      prostate cancer with finasteride: US/European perspective. Eur Urol 2003;44:650
      5.

PMID- 15183561
TI  - Re: de Leval J. Novel surgical technique for the treatment of female stress
      urinary incontinence: transobturator vaginal tape inside-out. Eur Urol
      2003;44:724-30.

PMID- 15183563
TI  - Re: de Leval J. Novel surgical technique for the treatment of female stress
      urinary incontinence: transobturator vaginal tape inside-out. Eur Urol
      2003;44:724-30.

PMID- 15183565
TI  - The unique ethics of sports medicine.
AB  - The ethical code by which physicians traditionally conduct themselves is based on
      the relationship between the physician and the patient: both work toward the goal
      of improving or maintaining health. Constraints on this relationship may be
      behaviors of patient choice (tobacco use, excessive alcohol use, sedentary
      behavior, and so on). The athlete-physician relationship is ethically different.
      Influences such as the physician's employer, the athlete's desire to play with
      pain and injury, and the economic consequences of playing or not complicate
      medical decisions. This perspective suggests something different and even unique
      about the ethics of the sports medicine practitioner. This article explores the
      differences fostering the ethical tight ropes that sports physicians walk in
      their sports medicine practices.

PMID- 15183566
TI  - Informed consent in sports medicine.
AB  - Informed consent acknowledges the autonomy of a person to make choices consistent
      with personal goals and values. The virtuous physician will understand that the
      athlete's autonomy is severely diminished by internal and external forces beyond
      the control of medical personnel. Because of this, a truly informed consent in
      sports medicine is even more difficult to achieve than in other medical
      specialties. Awareness of these problems does not assure a genuine informed
      consent, but being unaware of them isa guarantee of its impossibility.

PMID- 15183567
TI  - The competing demands of sport and health: an essay on the history of ethics in
      sports medicine.
AB  - The history of ethics in sports medicine has been driven by the tension between
      the demands of sport and the demands of health.Historically, physicians have held
      that the demands of health place ethical limits upon the demands of sport. As
      external observers of the sports community, premodern sports physicians
      relentlessly criticized athletes and trainers who pursued victory even at the
      cost of the athlete's health. As integral members of the sports community,though,
      modern sports physicians have themselves sometimes placed the demands of sport
      ahead of the demands of health.

PMID- 15183568
TI  - Ethics and the athlete: why sports are more than a game but less than a war.
AB  - Are the ethics of athletes complex? Consider that an elite bicyclist might inject
      himself with hormones to increase his exercise capacity,but if his opponent
      falls, then that same hormone-abusing athlete will likely stop until his opponent
      has regained control. This article reviews key concepts from the philosophy of
      sport. Using six cases from the sports archives, it presents a practical
      framework for interpreting and assessing the moral status of an athlete's
      behavior. This work enables readers to appreciate more clearly both the
      contextual subtleties and the robust relationship between ethics and the athlete.

PMID- 15183569
TI  - Ethics and the professional team physician.
AB  - The professional team physician may face ethical questions that are unique to the
      practice of sports medicine. There are numerous pressures that potentially may
      affect or interfere with ethical medical decision-making. The purpose of this
      article is to highlight some of these issues and to increase awareness of them
      for the practicing team physician and trainers and others involved in
      professional sports.

PMID- 15183570
TI  - The role of the chief ethics officer in a physician's office.
AB  - The unique role of the chief ethics officer in a sports medicine office is
      described and guided by the four principles of ethics, as well as the principles
      and codes of ethics of the American Medical Association, the International Sports
      Medicine Federation, and the American Academy of Orthopaedic Surgeons. The chief
      ethics officer should understand and be conversant with these principles and
      these codes of medical ethics, and transmit this information in order to further
      patient goals, physician goals, and employee goals.

PMID- 15183571
TI  - Medical aspects of sports: epidemiology of injuries, preparticipation physical
      examination, and drugs in sports.
AB  - The epidemiology of sports injuries helps identify the necessity for medical
      event coverage, injury risk factors, and potential prevention strategies. The
      preparticipation examination provides an opportunity for the team physician to
      identify athletes at risk of injury, to teach injury prevention, and to address
      athlete wellness. Knowledge of performance-enhancing drugs, nutritional
      supplements,and banned and legal medications is critical in caring for athletes.

PMID- 15183572
TI  - Special concerns of the female athlete.
AB  - The majority of injuries sustained by female athletes are due to participation in
      sports rather than their sex. Anatomic, hormonal,and functional differences
      should be understood when treating the female athlete. Screening should be done
      for eating disorders and the female athlete triad. Female athletes have increased
      rates of injury to the anterior cruciate ligament and patellofemoral disorders
      compared with their male counterparts.

PMID- 15183573
TI  - Therapeutic modality: rehabilitation of the injured athlete.
AB  - Traditional therapeutic modalities include cryotherapy, sonotherapy, pulsed
      electrical stimulation, transcutaneous electrical nerve stimulation, high-volt
      pulsed current, and iotopheresis. Alternative modalities include acupuncture,
      magnetic field therapy, biofeedback,and massage. All therapeutic modalities
      should be considered adjuncts to progressive functional exercise. Controlled
      studies rarely reach consensus regarding the efficacy of therapeutic
      modalities,so their use should be individualized to the patient.

PMID- 15183576
TI  - The long-term speech outcome in Flemish young adults after two different types of
      palatoplasty.
AB  - OBJECTIVE: The success of cleft palate surgery is specifically determined by the
      subsequent speech characteristics. There are several types of surgical techniques
      to repair the palate. The surgeon chooses his or her own technique according to
      the principles (s)he have established based on experience. The main purpose of
      this study is to determine and to compare the long-term speech outcome (18 years
      after surgery) regarding overall intelligibility, articulation, resonance, and
      voice after one-stage Wardill-Kilner palatoplasty or two-stage Furlow
      palatoplasty. The authors hypothesized that a decreased overall intelligibility,
      more compensatory articulation disorders, higher nasalance values and more
      nasality disorders would occur in the two-stage Furlow palatoplasty. Moreover, an
      increased risk for dysphonic symptoms, caused by the more intensive vocal tract
      activities, were expected in subjects with higher nasalance scores. An additional
      objective of this study was to compare the speech and voice characteristics with
      the age related normative data. Significant differences between the resonance and
      voice characteristics of the two techniques of palatoplasty and the normative
      data were hypothesized. METHODS: Objective as well as subjective assessment
      techniques were used. The evaluation of the articulation included a phonetic
      inventory and a relational analysis in which the consonant and vowel productions
      were compared with target productions and analyzed for error types at the
      segmental level. The speech samples were perceptually judged for intelligibility
      and nasality. The Nasometer was used for the objective measurement of the
      nasalance values. The assessment of the voice included a perceptual evaluation
      and a determination of the Dysphonia Severity Index. RESULTS: The subjects who
      received a two-stage Furlow palatoplasty showed statistically more hypernasality
      and higher nasalance scores in comparison with the one-stage Wardill-Kilner
      palatoplasty. No major differences regarding articulation and voice
      characteristics were found. As expected, significant differences were found
      between the speech intelligibility and resonance characteristics in subjects who
      received a palatoplasty and the normative data. CONCLUSION: Since the subjects
      who received a one-stage Wardill-Kilner palatoplasty had a significantly better
      speech outcome it was decided in the craniofacial team of the University Hospital
      of Ghent that a two-stage palatoplasty would no longer be performed.

PMID- 15183577
TI  - The age dependent relationship between facial fractures and skull fractures.
AB  - OBJECTIVE: To provide clinical evidence to support the age dependent relationship
      between facial fractures and skull fractures. DESIGN: Retrospective chart review
      of all children and adults admitted with combined facial fractures and skull
      fractures and skull fractures alone between January 1991 and November 1997.
      SETTING: The Albany Medical Center Hospital, a tertiary level-one trauma center.
      PATIENTS: Two hundred and one children, ages 1 month to 17 years, with skull
      fractures (frontal, parietal, or temporal), and 41 children with concurrent
      facial fractures were included in this study. One hundred and thirty-nine adults,
      ages 18-90 years, with skull fractures, and 70 adults with concurrent facial
      fractures were also studied. OUTCOME MEASURES: The gender, age, skull fracture,
      facial fracture, Glasgow coma score (GCS), mechanism of injury, and outcome of
      all patients admitted with frontal, parietal, or temporal fractures with or
      without facial fractures. RESULTS: There are a significantly greater (P < 0.001)
      number of facial fractures associated with skull fractures among adults as
      compared to children. Moreover, there is an exponential rise in facial fractures
      associated with skull fractures between infancy and adolescence. The GCS of
      children with combined facial and skull fractures is significantly lower than in
      those with skull fractures only (P < 0.001). CONCLUSION: The spectrum of
      craniofacial injuries is related to the specific developmental stage of the
      craniofacial skeleton. This is demonstrated by the variable pattern of combined
      facial and skull fractures observed clinically in children and adults.

PMID- 15183578
TI  - Effects of otorhinolaryngological diseases and socioeconomic status on school
      performance: a survey study.
AB  - OBJECTIVE: The aim of the present study was to investigate the effects of
      otorhinolaryngological (ORL) diseases and socioeconomic status (SES) on school
      performance. METHODS: This study was conducted in three primary schools located
      in Duzce. Of three schools, two schools (group A) are located in the suburb area
      of the city and students had a low SES. The other one (group B) is in the center
      of the city and students had a high SES. A total of 1282 (urban 609 and rural
      673) students attending to these three schools were examined considering the ORL
      diseases. SES of the students were evaluated according to the mean monthly income
      within the family, educational level of parents and occupation, presence of
      conflict within the family, and smoking habits. School performance of the
      children is ranged between 1 and 5. School success of students were evaluated by
      asking their educators. RESULTS: The mean (S.D.) age was 9.15 (1.48) years
      (range, 7-12). The students in group B were observed as more successful than that
      of group A. A major finding in this study is that the incidence of ORL diseases
      in the rural school is high and it was found that when ORL diseases increased,
      the mean school success grade of the students decreased in group B. The
      otological diseases were found to have an effect on school performance more than
      the other ORL diseases independently of SES. When we analyzed the effect of SES
      on school performance, we found that the students' school grade level in group A
      was low. CONCLUSIONS: ORL diseases are more commonly detected in the primary
      schools with lower socioeconomic level than the other and we found that the
      effects of ORL diseases and SES on school performance in group B was low.

PMID- 15183579
TI  - The role of free oxygen radicals on the development of otitis media with
      effusion.
AB  - OBJECTIVE: The purpose of this study was to determine if free oxygen radicals
      (FORs) and antioxidant enzyme activities have some role in pathogenesis of otitis
      media with effusion (OME) in children with adenoid hyperplasia. METHODS: Seventy
      four patients were enrolled in three groups of this study. The study group (Group
      I) included 26 patients who had adenoidectomy with ventilation tube placement due
      to chronic OME. The control adenoid group (Group II) consisted of 28 age-matched
      patients who had adenoidectomy without ventilation tube insertion. Twenty
      children were included in the healthy control group (Group III). Erythrocyte
      malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT),
      glutathione peroxidase (GSH-Px) enzyme activities were investigated in the venous
      blood sample. RESULTS: Erythrocyte MDA level and GSH-Px enzyme activity in the
      blood samples of study group (Group I) were significantly higher than those of
      Group II and Group III (P < 0.05). SOD enzyme activity in the blood samples of
      Group I was significantly lower than Group II (P < 0.05), and were significantly
      higher than Group III (P < 0.05). CAT enzyme activity of Group I was
      significantly lower than that of Group III (P < 0.05). However, there was no
      statistically significant difference between Group I and Group II regarding CAT
      antioxidant enzyme activity (P < 0.05). CONCLUSIONS: The inflammation of the
      middle ear increases the level of FORs in erythrocyte. FOR level is normally
      maintained at a steady state by antioxidant enzymes. When the antioxidant defense
      system is weakened, the increased FORs may contribute to OME formation. We
      supposed that, antioxidant vitamins C and E, and scavenger enzymes such as CAT,
      SOD and GSH-Px may be added in the management of OME.

PMID- 15183580
TI  - Salivary gland tumors in children and adolescents: a clinicopathologic and
      immunohistochemical study of fifty-three cases.
AB  - OBJECTIVE: Salivary gland tumors in children and adolescents are rare. Most
      papers are case reports or short series of cases. The aim of this study was to
      analyze clinicopathological and immunohistochemical data from a large series of
      salivary gland tumors affecting youngsters from a single institution. METHODS:
      From 1953 to 1997, 53 patients 18 years old or less with epithelial salivary
      gland tumors from the Hospital do Cancer A.C. Camargo were studied. Clinical and
      treatment data were obtained from the medical records and histological features
      were reviewed. Paraffin-embedded tissues were immunohistochemically analyzed for
      p53, PCNA, Ki-67, bcl-2, c-erbB-2, and CEA. RESULTS: Twenty-seven tumors (51%)
      were benign and 26 (49%) malignant. Pleomorphic adenoma (PA) was the most common
      tumor type (49%), followed by mucoepidermoid carcinoma (MEC, 39.6%). The tumors
      were more common in female and 50.9% of the cases affected the parotid, followed
      by 26.4% of intraoral involvement. Immunohistochemical analysis did not show
      correlation with prognosis of the tumors. Twenty (74%) of the 27 patients with
      benign tumors were alive without evidence of disease after a mean of 16.5 years
      of follow up; 6 were lost of follow up and 1 died by causes not related to the
      disease. Nineteen (73%) of the 26 patients with malignant tumors did not show
      tumoral recurrence after a mean follow up of 14.3 years, and 3 (11.5%) patients
      died of the disease. CONCLUSIONS: In 53 cases of epithelial salivary gland tumors
      in youngsters, half were malignant, with favorable prognosis. On this series,
      immunohistochemical expression of p53, PCNA, Ki-67, c-erbB-2, bcl-2, and CEA,
      were not correlated with prognosis.

PMID- 15183581
TI  - Rhinovirus in adenoid tissue.
AB  - OBJECTIVE: Rhinovirus (RV) infection is the most common single cause of acute
      respiratory illness in children. The purpose of the study was to evaluate the
      prevalence of RV in adenoid tissue throughout the year. MATERIAL AND METHODS:
      Fifty-six samples of adenoid tissue removed either due to recurrent otitis media
      or adenoid hypertrophy were collected for in-situ hybridization (ISH) of RV. To
      confirm the specificity of the ISH probe, eight adenoid biopsies were
      investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) as well.
      RESULTS: ISH was positive for RV RNA in 45% of the specimens. There was a
      statistically significant difference (P = 0.002) in the prevalence of RV positive
      adenoid biopsies from late fall to spring (65%) in comparison to late spring to
      early fall (20%). Children with middle ear effusion were more often ISH positive
      than those with dry ears, but the number of past ear infections, signs of chronic
      nasal obstruction or recent runny nose did not correlate to the finding in ISH.
      There was a good concordance between the results obtained by ISH and by RT-PCR.
      CONCLUSION: Both epithelial and/or germinal cells of adenoid tissue are
      frequently loaded with RV during the cold months of the year, also known to have
      a high incidence of RV infections among population. Children with otitis media
      with effusion are more likely to harbor RV in adenoid tissue than those with dry
      ears. Further studies are, however, needed to show whether the effusion is due to
      RV or whether this association exists by coincidence.

PMID- 15183582
TI  - Cervical presentations of thymic anomalies in children.
AB  - OBJECTIVE: To better define the clinical manifestations, radiologic imaging and
      the surgical management of cervical thymic lesions in children. STUDY DESIGN:
      Multi-center retrospective case review. METHODS: The charts of all children with
      pathologically confirmed thymic lesions at six children's hospitals (1990-2002)
      were reviewed for demographics, physical findings, X-ray findings, operative
      outcomes and pathology. RESULTS: There were a total of 15 children, 2 of whom had
      ectopic cervical thymus and 13 who had thymic cysts. They ranged in age from 1
      month to 18 years. Thymic lesions were more common in males. Ectopic cervical
      thymus was best defined by MRI whereas thymic cyst had a more consistent
      appearance on CT. All children had successful surgical resection with no recorded
      complications or recurrences. CONCLUSIONS: Cervical thymic lesions are rare.
      Ectopic cervical thymus tends to be found primarily in infants whereas thymic
      cysts occur in a wider age range. Radiologic imaging is important but is not
      histologically specific. Definitive diagnosis and cure requires complete surgical
      excision.

PMID- 15183583
TI  - Objective assessment of frequency-specific hearing thresholds in babies.
AB  - OBJECTIVE: To report on clinical experience using dichotic multiple-stimulus
      auditory steady-state responses (ASSRs) as an objective technique to estimate
      frequency-specific hearing thresholds in hearing-impaired infants. METHODS: A
      comparison was made between the click-evoked auditory brainstem response (ABR),
      auditory steady-state responses and behavioral hearing thresholds (BHTs). Both
      ears of 10 infants between 3 and 14 months of age were tested. ABR and ASSRs were
      recorded during the same test session. ABR was evoked by 100 micros clicks. ASSRs
      were evoked by amplitude- and frequency-modulated tones with carrier frequencies
      of 0.5, 1, 2 and 4 kHz and modulation frequencies ranging from 82 to 110 Hz.
      Eight signals (four to each ear) were presented simultaneously. ASSR thresholds
      were derived after separate recordings of approximately 5, 7.5 and 10 min to
      compare the influence of test duration. BHTs were defined in later test sessions
      as soon as possible after the ASSR test, dependent on medical and developmental
      factors. RESULTS: For the subjects tested in this study 60% of ABR thresholds and
      95% of ASSR thresholds for 1, 2 and 4 kHz were found at an average age of 7
      months. Only 51% of frequency-specific BHTs could be obtained but on average 5
      months later. The correlation of ABR thresholds and ASSR thresholds at 2 kHz was
      0.77. The correlation of ASSRs and BHTs was 0.92. The mean differences and
      associated standard deviations were 4 +/- 14, 4 +/- 11, -2 +/- 14 and -1 +/- 13
      dB for 0.5, 1, 2 and 4 kHz, respectively. The average test duration was 45 min
      for ABR (one threshold in both ears) and 58 min for ASSR (four thresholds in both
      ears). By reducing the duration of the separate recordings of ASSR, the precision
      of the hearing threshold estimate decreased and the number of outlying and
      missing values increased. Correlation coefficients were 0.92, 0.89 and 0.83 for
      recordings of maximum 10, 7.5 and 5 min, respectively. A compromise between test
      duration and precision has to be sought. CONCLUSIONS: Multiple-frequency ASSRs
      offer the possibility to estimate frequency-specific hearing thresholds in babies
      in a time-efficient way.

PMID- 15183584
TI  - Comparison of currently available devices designed for newborn hearing screening
      using automated auditory brainstem and/or otoacoustic emission measurements.
AB  - OBJECTIVE: Suitability in clinical practise of three currently available devices
      designed for automated newborn hearing screening, one combining evoked
      otoacoustic emissions (EOAE) and automated auditory brain stem response (AABR),
      the Echoscreen-TDA from Fischer-Zoth, and two AABR screeners, the Algo 3 from
      Natus and the Beraphone MB11 from Maico, were tested prospectively. METHODS:
      Transiently evoked otoacoustic emissions (TEOAE) and distortion product
      otoacoustic emissions (DPOAE) were measured in one ear of 150 healthy newborns
      using the Echoscreen-TDA. Three groups of 50 subjects each were tested
      additionally for AABR recordings either with Echoscreen-TDA, Algo 3 or Beraphone
      MB11. Measurements were performed after the second day of life. The following
      aspects were evaluated: (a) subject-instrumentation interface (b) test time (c)
      costs (unit price and costs for disposable material) and (d) pass rates. RESULTS:
      Connecting the subjects to the device was the easiest for EOAE measurements with
      the Echoscreen-TDA, followed by AABR recordings with the Algo 3 and Echoscreen
      TDA and were most difficult with the Beraphone MB11. The median test time on one
      ear was less than 30 s for EOAE measurements and 4-5 min for AABR recordings.
      Costs for the equipment and for disposable material were lowest for the
      Echoscreen-TDA and Beraphone MB11, respectively and highest for the Algo 3. Pass
      rates were highest with 98% for AABR recordings using the Algo 3 and lowest with
      92% for AABR recordings using the Beraphone MB11, but differences were not
      statistically significant. CONCLUSIONS: All tested devices can be used for
      universal neonatal hearing screening. It was easier to connect the subject to the
      device and measurements were quicker for OAE than for AABR measurements.
      Echoscreen-TDA combines the two techniques and had the lowest costs for the AABR
      equipment. Algo 3 had the highest costs for the equipment and for disposable
      material, but it was highly reliable, and both ears can be tested simultaneously.
      Connecting the subject was the most difficult with the Beraphone MB11, but there
      were no disposable supply costs.

PMID- 15183585
TI  - Can we develop a protocol for the safe decannulation of tracheostomies in
      children less than 18 months old?
AB  - Expanding indications for airway and head and neck surgery have led to a number
      of children under 18 months of age being deemed suitable for decannulation of
      their tracheostomies. We present four cases to illustrate the particular problems
      encountered in this age group and suggest modifications to our previously
      published decannulation protocol.

PMID- 15183586
TI  - An update on choanal atresia surgery at Great Ormond Street Hospital for
      Children: preliminary results with Mitomycin C and the KTP laser.
AB  - We present the results of transnasal choanal atresia correction in 46 children,
      as an update to the published Great Ormond Street Hospital series. Females
      outnumbered males 2-1, and half the cases in our series were bilateral. Eight of
      the children with bilateral atresia had the CHARGE association. The median number
      of procedures required was three over a period of up to 3 years. Eighty-two
      percent of children with unilateral atresia and 78% of those with bilateral
      atresia were asymptomatic at the time of their last follow up. Four deaths
      occurred, all but one in children with CHARGE association. We were not able to
      demonstrate any benefit from the use of Mitomycin C, the KTP laser, betamethasone
      nasal drops or (in unilateral cases) stents.

PMID- 15183587
TI  - The negative effect of hyperbaric oxygen therapy at the acute phase of
      electrochemical esophageal burn induced by button battery ingestion.
AB  - OBJECTIVE: Ingestion of button battery, if lodges in esophagus, causes mucosal
      destruction in esophagus and may damage surrounding tissues due to
      electrochemical reactions which may lead to esophagus perforation,
      tracheosefageal fistula and other serious problems. We designed an experimental
      study to test the effect of hyperbaric oxygen therapy on battery induced
      electrochemical tissue damage in the esophagus of a rabbit model and possible
      change with duration of contact time. METHODS: Button batteries were inserted in
      esophagus of 40 rabbits which were divided into four groups. Groups 1 and 2 had
      15 min of duration of contact time of battery in esophagus, while Groups 3 and 4
      had 30 min. Groups 1 and 3 had hyperbaric oxygen therapy for 3 days; Groups 2 and
      4 did not. At the end of 3rd day all animals were sacrified and samples were
      taken from the esophagus for determination of malondialdehyde levels and for
      histopathological examination to compare: mucosal destruction, muscular layer
      involvement, perforation and tracheal involvement between groups. RESULTS:
      Malondialdehyde levels, mucosal destruction, muscular layer involvement,
      perforation and tracheal involvement were significantly higher in groups which
      had 30 min of contact time compared to groups which had 15 min. The same
      assessments were significantly higher in Group 1 (15 min of contact time with
      hyperbaric oxygen therapy) compared to Group 2 (15 min of contact time without
      hyperbaric oxygen therapy). However, the difference between Group 3 (30 min of
      contact time with hyperbaric oxygen therapy) and Group 4 (30 min of contact time,
      no hyperbaric oxygen therapy) was not significant. CONCLUSION: Our study
      demonstrated that if contact time is 15 min HBO had an additive adverse effect to
      electrochemically burned esophagus by increasing free radicals and eventually
      tissue damage. However, if the contact time is 30 min its adverse effect is
      shielded by huge electrochemical destruction due to long contact time.

PMID- 15183588
TI  - Endoscopic treatment of paranasal sinus mucoceles in children.
AB  - In this study, we have pointed out the effectiveness of the endoscopic approach
      for the treatment of three children affected by mucoceles. Two patients
      complained of visual disturbances while one complained of persistent bitemporal
      headache. None of these cases was affected by cystic fibrosis. The endoscopic
      treatment consisted mainly of drainage and marsupialization of the mucocele.
      These young patients were free of any recurrence and symptoms at 36, 30, and 16
      months of follow-up, respectively.

PMID- 15183589
TI  - Gastric heterotopia in the nasopharynx causing airway obstruction in the newborn.
AB  - We describe a newborn boy with a gastric heterotopia located in the nasopharynx,
      which caused airway obstruction soon after delivery. Gastric heterotopia is an
      uncommon lesion generally found throughout the alimentary tract, but nasopharynx
      is an exceptional location. To our knowledge, this is the second reported case of
      gastric heterotopia located in the nasopharynx, and the first one presenting in a
      newborn with symptoms at birth and with an associated central nervous system
      mass.

PMID- 15183590
TI  - Upper aerodigestive tract complications in a neonate with linear IgA bullous
      dermatosis.
AB  - Linear IgA bullous dermatosis (LABD) is a rare immunobullous condition known to
      affect the skin and mucous membranes of the eye and oral cavity in adults and
      young children. We describe a newborn with skin involvement who had life
      threatening respiratory compromise from disease affecting the larynx, subglottis,
      trachea, and esophagus. Management with both tracheostomy and gastrostomy tube
      placement was necessary. Treatment included systemic steroids, dapsone, and
      intravenous immunoglobulin. We compare our neonatal case to the only other report
      in the literature highlighting involvement of the mucous membranes of multiple
      levels of the aerodigestive tract leading to respiratory compromise.

PMID- 15183591
TI  - Pediatric Kikuchi-Fujimoto disease masquerading as a submandibular gland tumor.
AB  - Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis, is
      a rare disorder that typically affects the cervical lymph nodes. The disease
      usually occurs in women in their late 20s or early 30s. Reports in the pediatric
      literature are sparse. Most authors consider Kikuchi-Fujimoto disease as a self
      limiting disorder that requires no specific management but long-term follow-up.
      The clinical features of Kikuchi-Fujimoto disease are easily confused with other
      less-benign conditions. Thus, an early biopsy is instrumental in making definite
      diagnosis and preventing unnecessary investigations. We describe a case of
      Kikuchi-Fujimoto disease in an 8-year-old boy which presenting as a submandibular
      gland tumor. The case illustrates the clinical features of this unusual condition
      and emphasizes the potential confusion with other diagnoses.

PMID- 15183592
TI  - Otitis caused by Scedosporium apiospermum in an immunocompetent child.
AB  - Scedosporium apiospermum (Pseudallescheria boydii) is a ubiquitous saprophytic
      mold. It is considered an infrequent but important and emerging human pathogen,
      mostly in immunocompromised hosts. Otomycosis secondary to S. apiospermum is
      extremely rare. We report an 8-year-old immunocompetent male who developed otitis
      media and otitis externa from S. apiospermum, which was successful treated with
      combination of surgical debridement and topical clotrimazole therapy. A brief
      literature review of infections caused by S. apiospermum follows the case
      presentation.

PMID- 15183593
TI  - Course and therapy of intoxication with imidazoline derivate naphazoline.
AB  - OBJECTIVE: Imidazoline derivatives like naphazoline have a firm place in
      diagnostics and therapy of otorhinolaryngology because of their vasoconstrictive
      and decongestive properties. Their alpha-adrenergic potential could induce not
      only local but also systemic side effects like hypertension and tachycardia which
      can increase a life-threatening intoxication. Signs of imidazoline intoxication
      are excessive systolic and diastolic hypertension and hypotension, bradycardia
      with arrhythmia, respiratory depression, excitation or severe CNS depression.
      PATIENTS: The typical course of an intoxication and its sufficient therapy is
      reported by means of two cases of intraoperative application of naphazoline for
      hemostasis. RESULTS: In case of overdosage or intoxication, symptomatic drug
      therapy with intravenous administration of 5 mg phentolamine for adults and 1 mg
      phentolamine for infants has to be done. Phentolamine, an alpha-adrenoceptor
      antagonist, acting against peripheral and central side effects has to be used
      because no specific antidote is available. CONCLUSIONS: Especially pediatric
      otorhinolaryngologists have to know about symptoms and therapy of an intoxication
      after application of naphazoline. Particularly with children, a narrow
      therapeutic to toxic window can be observed in this frequently used drug.

PMID- 15183594
TI  - Geriatric depression and vascular diseases: what are the links?
AB  - BACKGROUND: The term "vascular depression" has been proposed to describe a subset
      of depressive disorders that occurs in old age as a consequence of
      cerebrovascular disease. However, depression has been shown to result from other
      cardiovascular diseases such as coronary heart diseases, as well as to
      precipitate, worsen or precede vascular diseases. Depression also increases the
      likelihood of the incidence of vascular risk factors such as diabetes. AIMS: To
      review clinical and epidemiological evidence linking geriatric depression and
      vascular diseases, and to discuss the potential mechanisms that could underlie
      this association. METHOD: Systematic review of the literature of the last 5 years
      through Medline database search. RESULTS: Papers report the following potential
      ways of association: (1) there is a direct influence of vascular disease, in
      particular, arteriosclerosis, on the incidence of depression; (2) depressive
      disorders have a direct impact on the cardiovascular system; (3) depression and
      vascular disease share either a common pathophysiological process or genetic
      determinants. DISCUSSION: Depression can be understood as the direct consequence
      of brain damage in neurodegenerative disorders such as Parkinson's or
      Huntington's diseases. Similarly, vascular depression is mostly considered to be
      the consequence of microvascular lesions on prefrontal and subcortical regions.
      However, this functional neuroanatomical model offers no explanation for cases
      where depression has been shown to precede vascular diseases. Since
      cardiovascular diseases develop in a context of acquired environmental factors
      together with genetically determined disease, it may be postulated that geriatric
      depression could both result from brain lesions of vascular origin and also share
      some pathogenic or genetic determinants.

PMID- 15183595
TI  - Autobiographical memory predicts cognitive but not somatic change in sleep apnea
      patients vulnerable for affective disorder.
AB  - BACKGROUND: Autobiographical memory style (AM) can serve as a marker for
      determining susceptibility for depression. Currently and formerly depressed
      persons show reduced specific memory for autobiographical events. AM also has
      proven to be a reliable predictor for the remissive course of depression.
      Recently the issue arose as to whether this predictive power depends on
      particular dimensions of depression (cognitive, somatic). METHODS: To replicate
      the predictability in vulnerable patients, we tested two groups of obstructive
      sleep apnea patients (OSAS) before and 2 months after initiation of nasal
      continuous positive airway pressure therapy (nCPAP). One group had a history of
      major depression (vulnerable persons; VUL), and the other group did not (NON
      VUL). Sensitivity of AM on the dimensions of depression was assessed through two
      published versions of the cognitive and somatic subscales of the Beck Depression
      Inventory (BDI). RESULTS: There was a significant interaction of Group by AM
      recall after presentation of positively valenced cues (AMpos) on the cognitive
      but not on the somatic dimension of the BDI. Only in the VUL did AMpos predict
      recovery. LIMITATIONS: Generalizability to other patient populations awaits
      further research. Reliability of the vulnerability assessment prior to the OSAS
      onset was not established. CONCLUSIONS: First, our findings further support the
      trait assumption of AM. Second, the AM methodology suggests sensitivity to only
      the cognitive dimensions of depression.

PMID- 15183596
TI  - How common is seasonal affective disorder in temperate Australia? A comparison of
      BDI and SPAQ estimates.
AB  - BACKGROUND: The frequency of winter Seasonal Affective Disorder (SAD) in
      temperate Australia is unknown. METHOD: A random community sample in Melbourne
      completed four waves of data collection (winter and summer across two years). The
      presence of winter SAD was estimated in three ways: (i) self-reports on the
      Seasonal Pattern Assessment Questionnaire (SPAQ), (ii) evidence of significant
      depression as assessed on the Beck Depression Inventory (BDI) in winters and not
      summers, and (iii) a combined definition based on both SPAQ and BDI estimates.
      RESULTS: Of 1080 questionnaires originally mailed, complete four-wave BDI data
      was obtained from 380 respondents, and complete SPAQ data from 297. The frequency
      of winter SAD as estimated from SPAQ data was 0.7% and from BDI data was 0.5%.
      One participant (1 of 297, 0.3%) met BDI criteria and approached caseness on SPAQ
      criteria. LIMITATIONS: A larger sample is necessary to definitively estimate
      prevalence. CONCLUSIONS: Winter SAD appears to be rare in temperate Australia.
      The best estimate from the current study (0.3%) is an advance on simple self
      report estimates and provides a necessary reference point for clinicians and
      researchers.

PMID- 15183597
TI  - Maternal touch and maternal child-directed speech: effects of depressed mood in
      the postnatal period.
AB  - BACKGROUND: Postnatal depression affects the emotional state of mothers and the
      quality of mother-infant interaction. METHOD: Touch behaviour and content of
      child-directed speech were analysed for 72 mothers and their infants during
      pleasurable play. Infants (18) of mothers with depressed mood and 18 controls
      were seen when they were 6 months old; and 18 infants of mothers with depressed
      mood and 18 controls were seen when they were 10 months old. RESULTS: Depressed
      mothers in comparison with non-depressed mothers lifted their infants more,
      restraining their behaviours. Infants of depressed mothers in contrast to infants
      of non-depressed mothers spent greater periods of time in touching self rather
      than mother or toy, compensating for the lack of positive touch from their
      mothers. Mothers with depressed mood of 6-month-old infants included fewer
      affective and informative features in their speech than their controls. Non
      depressed mothers of younger babies showed a higher use of affective features
      when compared with non-depressed mothers of older infants. In contrast, depressed
      mothers of 6- and 10-month-old babies showed similar frequencies of affect
      salient speech during interactions in spite of their infants' changing
      developmental demands. LIMITATIONS: Mothers in this study were only mildly
      depressed, as assessed by the Edinburgh Postnatal Depression Scale (EPDS).
      Nevertheless, the findings indicate that mothers with depressive symptoms differ
      from non-depressed mothers in relation to touch and content of speech when
      interacting with their infants. CONCLUSIONS: These results suggest that postnatal
      depression may influence touch behaviour as well as the affective and informative
      content of maternal speech. The effect is that mothers with depressed mood in
      comparison with non-depressed mothers touch their infants more negatively and
      their speech is less well adjusted concerning the amount of emotional vs.
      information-related content thereby preventing depressed mothers from responding
      effectively to their infants' developmental needs.

PMID- 15183598
TI  - Low CSF leptin in female suicide attempters with major depression.
AB  - BACKGROUND: Leptin is a hormone known to participate in the regulation of weight
      and appetite and is therefore of interest to examine in the context of major
      depressive disorder (MDD). Studies of circulating leptin have yielded variable
      results. We therefore decided to study leptin in cerebrospinal fluid (CSF).
      METHODS: We measured leptin in cerebrospinal fluid (CSF) in 72 patients admitted
      after a suicide attempt. They were divided in two groups: patients with major
      depressive disorder (MDD) and patients with other diagnoses (non-MDD). They were
      also subgrouped according to the number of suicide attempts (one or repeated) and
      whether the suicide attempt method was classified as violent or nonviolent. Since
      CSF leptin was considerably lower in men than in women, statistical calculations
      were made for men and women separately. RESULTS: We found that in spite of having
      similar body mass index (BMI) (P = 0.1), women in the MDD group had lower CSF
      leptin than those in the non-MDD group (P < 0.01). In contrast, no such
      difference was found among men. No significant differences were found between
      women with a first suicide attempt compared to those with a repeated one, or
      between women with a violent attempt compared to those with a nonviolent attempt.
      LIMITATIONS: The heterogeneity of the non-MDD group including patients with
      various diagnoses is the most important limitation of our study. CONCLUSIONS: CSF
      leptin is involved in the neuroendocrine dysfunction in women with suicide
      attempt and MDD. This finding contributes to the understanding of the metabolic
      symptoms in MDD.

PMID- 15183599
TI  - Treatment and response in refractory depression: results from a specialist
      affective disorders service.
AB  - BACKGROUND: The best treatment approaches for chronic severe refractory
      depression remain uncertain. This study aimed to identify short-term outcome and
      most successful somatic treatments of severe refractory depressives referred to
      an affective disorders service. METHODS: Patients with chronic refractory
      depression referred to a specialist affective disorders service over a 10-year
      period were studied. Using detailed case records of the index episode, courses of
      treatment and outcome were examined. RESULTS: Patients were predominantly middle
      aged females with few prior episodes but long index episodes. Patients received
      higher antidepressant doses and more combinations on the specialist service. Very
      high-dose antidepressants (tricyclics, velafaxine or tricyclic--MAOI
      combinations), usually augmented with lithium and often combined with ECT, were
      the most effective somatic treatments. Most subjects improved substantially, but
      few reached premorbid levels. LIMITATIONS: The study was retrospective. Treatment
      courses were sequential rather than random. CONCLUSIONS: Refractory depression is
      responsive to vigorous somatic therapy, although most patients continue with some
      symptoms.

PMID- 15183600
TI  - Urinary steroid metabolites and 11beta-hydroxysteroid dehydrogenase activity in
      patients with unipolar recurrent major depression.
AB  - BACKGROUND: The aim of the present study was to obtain comprehensive information
      on steroid metabolism in depressed patients. METHODS: 24-h urinary steroids were
      measured by gas chromatography in patients with unipolar recurrent major
      depression (URMD) compared to controls, and an index of relative activity of the
      11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzyme was calculated. RESULTS:
      The levels of etiocholanolone (E) (p < 0.05), beta-cortolone (beta-CL) (p < 0.01)
      were significantly decreased, while levels of allo-tetrahydrocorticosterone
      (aTHB) (p < 0.05) and cortisol (F) (p < 0.01) were elevated in depressed women.
      The levels of dehydroepiandrosterone (DHEA) (p < 0.01), tetrahydrocorticosterone
      (THB) (p < 0.01), beta-CL (p < 0.01), and aTHB (p < 0.05) were found
      significantly decreased in depressed men. The index of 11beta-HSD activity (p <
      0.01) was significantly decreased in patients in both sexes. LIMITATIONS: The
      sample is limited to only urine samples of patient with URMD; the correlation
      between the severity of depression and F and DHEA was not analyzed. CONCLUSION:
      Our investigations confirmed that URMD associated with altered steroid
      metabolism, which shows gender differences, pointing to the different stress
      sensibility of women. These differences may be the cause as well as the
      consequence of the major depression (MD).

PMID- 15183601
TI  - Measuring depression outcome with a brief self-report instrument: sensitivity to
      change of the Patient Health Questionnaire (PHQ-9).
AB  - BACKGROUND: The nine-item depression module from the Patient Health Questionnaire
      (PHQ-9) is well validated and widely used as a brief diagnostic and severity
      measure, but its validity as an outcome measure for depression has not yet been
      established. Therefore, we investigated the sensitivity to change of the PHQ-9 in
      three groups of patients whose depression status either improved, remained
      unchanged, or deteriorated over time. METHODS: From three cohorts of medical
      outpatients, with an equal distribution of major depressive disorder, other
      depressive disorders, or no depressive disorder, 167 patients (82.7%) were
      followed up after a mean of 12.3 +/- 3.0 months. The PHQ-9 and the Structured
      Clinical Interview for DSM-IV (SCID) were completed at both baseline and follow
      up. Depression diagnoses from the SCID were used as the criterion standard to
      divide patients into subgroups with (a) improved depression status, (b) unchanged
      depression status, and (c) deteriorated depression status. RESULTS: Effect sizes
      (ES) of PHQ-9 change scores were ES = -1.33 for the improved depression status
      subgroup (n = 52), ES = -0.21 for the unchanged status subgroup (n = 91), and ES
      = 0.47 for the deteriorated status subgroup (n = 24). PHQ-9 change scores
      differed significantly between the three depression outcome groups. LIMITATIONS:
      The PHQ-9 and the SCID were completed in person at baseline, whereas they were
      completed in a telephone interview at follow-up. CONCLUSIONS: This study
      demonstrates the ability of the PHQ-9 to detect depression outcome and changes
      over time. Data from treatment trials will help further establish the sensitivity
      to change of the PHQ-9 in comparison to other depression severity measures.

PMID- 15183602
TI  - Reboxetine adjunct for partial or nonresponders to antidepressant treatment.
AB  - BACKGROUND: To investigate the usefulness of the combination therapy with two
      antidepressants from different pharmacological families in treatment-resistant
      depressive patients. METHODS: In this prospective 6 weeks open-label study, we
      assessed the effectiveness of the addition of reboxetine to 61 depressive
      patients that had previously not responded, or had done so only in a partial way,
      to conventional treatment, in monotherapy, with selective serotonin reuptake
      inhibitors (SSRIs), venlafaxine or mirtazapine. Data were analyzed on an intent
      to-treat basis, using the last-observation-carried-forward (LOCF) method.
      RESULTS: Mean decrease on the 21-item Hamilton Depression Rating Scale (HDRS)
      score was 48.9% and on the Clinical Global Impressions Scale (CGI), 38.9%. At the
      end of the treatment, 62.3% of the patients were evaluated as improvement (CGI <
      4), 54.1% as responders (HDRS < or = 50%) and 45.9% in remission (HDRS < or =
      10). No serious side effects were observed during combination therapy, being more
      frequent increased sweating (8.2%) and dry mouth (6.6%). CONCLUSIONS: These
      findings suggest that the strategy of combination with reboxetine may be an
      effective and well-tolerated tool in treatment-resistant patients who have failed
      to adequately respond to monotherapy with SSRIs, venlafaxine or mirtazapine.

PMID- 15183603
TI  - Psychomotor retardation in elderly depressed patients.
AB  - BACKGROUND: The results of previous studies on psychomotor retardation (PR) in
      elderly depressed patients are inconsistent. The purpose of this study was (1) to
      try and establish whether elderly depressed patients show PR, and (2) if so,
      which process (cognitive/motor or both) is mainly slowed? METHODS: Twelve elderly
      depressed patients and healthy controls (age: 70) were compared on figure copying
      tasks in which the cognitive task difficulty was manipulated. RESULTS: Both
      initiation time (IT) and movement time (MT) were prolonged in the patient group.
      The effects of the cognitive manipulations were not larger in the patient group.
      LIMITATIONS: The sample size was small. Furthermore, patients were not medication
      free. CONCLUSIONS: A cognitive and a more pronounced motor retardation was found.
      Clinicians should be aware of this at least additive effect of aging and
      depression on PR in elderly patients.

PMID- 15183604
TI  - Sequence analysis of ADARB1 gene in patients with familial bipolar disorder.
AB  - BACKGROUND: The ADARB1 gene is located in 21q22.3 region, previously linked to
      familial bipolar disorder, and its product has a documented action in the editing
      of the pre-mRNA of glutamate receptor B subunit. Dysfunction of glutamatergic
      neurotransmission could play an important role in the pathophysiology of bipolar
      disorder (BD). Glutamate excitatory neurotransmission regulation is a possible
      mechanism of the initial effect of anticonvulsants in regulating mood. METHODS:
      To investigate the hypothesis of an involvement of ADARB1 gene in the BD, the
      ADARB1 cDNA has been cloned and sequenced in seven selected bipolar I disorder
      patients with evidence of familiarity of mood disorders. A detailed investigation
      of the gene nucleotide sequence in the open reading frame has been performed.
      RESULTS: No alteration in the sequence of the ADARB1 gene cDNA was found in any
      patient, except a common neutral polymorphism in three out of seven patients.
      CONCLUSIONS: Mutations in ADARB1 gene are not commonly associated with bipolar I
      disorder, therefore other genes in the 21q22 region could be associated with
      bipolar illness in some families, likely in the context of a multifactorial
      transmission model.

PMID- 15183605
TI  - Comparison of metal concentrations in rat tibia tissues with various metallic
      implants.
AB  - To compare metal concentrations in tibia tissues with various metallic implants,
      SUS316L stainless steel, Co-Cr-Mo casting alloy, and Ti-6Al-4V and V-free Ti-15Zr
      4Nb-4Ta alloys were implanted into the rat tibia for up to 48 weeks. After the
      implant was removed from the tibia by decalcification, the tibia tissues near the
      implant were lyophilized. Then the concentrations of metals in the tibia tissues
      by microwave acid digestion were determined by inductively coupled plasma-mass
      spectrometry. Fe concentrations were determined by graphite-furnace atomic
      absorption spectrometry. The Fe concentration in the tibia tissues with the
      SUS316L implant was relatively high, and it rapidly increased up to 12 weeks and
      then decreased thereafter. On the other hand, the Co concentration in the tibia
      tissues with the Co-Cr-Mo implant was lower, and it increased up to 24 weeks and
      slightly decreased at 48 weeks. The Ni concentration in the tibia tissues with
      the SUS316L implant increased up to 6 weeks and then gradually decreased
      thereafter. The Cr concentration tended to be higher than the Co concentration.
      This Cr concentration linearly increased up to 12 weeks and then decreased toward
      48 weeks in the tibia tissues with the SUS316L or Co-Cr-Mo implant. Minute
      quantities of Ti, Al and V in the tibia tissues with the Ti-6Al-4V implant were
      found. The Ti concentration in the tibia tissues with the Ti-15Zr-4Nb-4Ta implant
      was lower than that in the tibia tissues with the Ti-6Al-4V implant. The Zr, Nb
      and Ta concentrations were also very low. The Ti-15Zr-4Nb-4Ta alloy with its low
      metal release in vivo is considered advantageous for long-term implants.

PMID- 15183606
TI  - The effect of the physical characteristics of hydroxyapatite particles on human
      monocytes IL-18 production in vitro.
AB  - Hydroxyapatite (HA) is widely used to coat the metal parts of prosthetic implants
      in order to improve their biocompatibility and as a bone defect filling material.
      HA has been demonstrated to produce particles at the prosthetic interface that
      lead to an activation of phagocytic cells that induce a cascade reaction leading
      to bone resorption and aseptic loosening. Monocytes/macrophages are commonly
      observed in the interface tissue, and are among the first cells to colonize the
      inflammatory site where they play a key role in the immune response. IL-18 is a
      pro-inflammatory cytokine. Monocytes/macrophages were described as IL-18
      producing cells. IL-18 works antagonistically to IL-6, which activates
      osteoclastogenesis. In the present study, we investigated the ability of HA
      particles to induce the production of active IL-18 by human monocytes according
      to particle characteristics (size, sintering temperature and shape). Our study
      demonstrates, for the first time, that HA particles are capable of stimulating
      the production of the proinflammatory cytokine IL-18 in human monocytes according
      to their particle characteristics. The expression and the production of IL-18 was
      modified by the parameter studied. The difference observed between the expression
      and the production could be explain by the production of ICE. The needle shaped
      particles induced the larger production of IL-18.

PMID- 15183607
TI  - Chondrocyte phenotypes on different extracellular matrix monolayers.
AB  - Chondrocytes undergo a process of dedifferentiation in monolayer culture that is
      characterized by a transition to a fibroblast-like phenotype. This behavioral
      change poses a challenge for tissue-engineered cartilage constructs, as
      approaches using autologous cells require expansion in vitro. Because
      chondrocytes express a variety of integrin receptors specific to different
      adhesive proteins, we hypothesized that chondrocytes expanded on various
      underlying protein monolayers would have different phenotypic responses. Bovine
      articular chondrocytes were cultured for up to 2 weeks on tissue culture plastic,
      fibronectin, collagen type I or collagen type II substrate in the presence or
      absence of ascorbate. Contrary to our hypothesis, the extracellular matrix
      protein substrates used in this study did not significantly alter the changes in
      chondrocyte morphology, gene expression, matrix formation, or cytoskeletal
      organization. Cells on all substrates assembled equivalent matrices, which may
      have subsequently regulated cell behavior. In cultures with ascorbate,
      populations of round and spread cells emerged after 1 week, with round cells
      expressing collagen type II and the differentiated phenotype and spread cells
      dedifferentiating. In cultures without ascorbate, chondrocytes rapidly adhered
      and spread onto organized fibronectin matrices via the alpha5beta1 integrin,
      which has been associated with survival and proliferation of chondrocytes in
      vitro. These findings indicate that expanding chondrocytes on protein monolayers
      may not be an effective solution to preventing dedifferentiation and improving
      autologous chondrocyte transplantation.

PMID- 15183608
TI  - In vivo biocompatibilty and degradation behavior of elastic poly(L-lactide-co
      epsilon-caprolactone) scaffolds.
AB  - Tubular scaffolds were fabricated from very elastic poly(L-lactide-co-epsilon
      caprolactone) (PLCL, 50:50). The scaffolds were seeded with smooth muscle cells
      (SMCs) and implanted in nude mice to investigate the tissue compatibility and in
      vivo degradation behavior. Histological examination of all the implants with
      haematoxylin and eosin staining, masson trichrome staining, SM alpha-actin
      antibody, and CM-DiI labeling confirmed that the regular morphology and
      biofunction of the SMCs seeded and the expression of the vascular smooth muscle
      matrices in PLCL scaffolds. The implanted PLCL scaffolds displayed a slow
      degradation on time, where caprolactone units were faster degraded than lactide
      did. This could be explained by the fact that amorphous regions composed of
      mainly CL moieties degraded earlier than hard domains where most of the LA units
      were located. From these results, the scaffolds applied in this study were found
      to exhibit excellent tissue compatibility to SMCs and might be very useful for
      vascular tissue engineering.

PMID- 15183609
TI  - Surface chemistry modulates focal adhesion composition and signaling through
      changes in integrin binding.
AB  - Biomaterial surface properties influence protein adsorption and elicit diverse
      cellular responses in biomedical and biotechnological applications. However, the
      molecular mechanisms directing cellular activities remain poorly understood.
      Using a model system with well-defined chemistries (CH3, OH, COOH, NH2) and a
      fixed density of the single adhesive ligand fibronectin, we investigated the
      effects of surface chemistry on focal adhesion assembly and signaling. Surface
      chemistry strongly modulated integrin binding and specificity--alpha5beta1
      integrin binding affinity followed the pattern OH>NH2=COOH>CH3, while integrin
      alphaVbeta3 displayed the relationship COOH>NH2>>OH=CH3. Immunostaining and
      biochemical analyses revealed that surface chemistry modulates the structure and
      molecular composition of cell-matrix adhesions as well as focal adhesion kinase
      (FAK) signaling. The neutral hydrophilic OH functionality supported the highest
      levels of recruitment of talin, alpha-actinin, paxillin, and tyrosine
      phosphorylated proteins to adhesive structures. The positively charged NH2 and
      negatively charged COOH surfaces exhibited intermediate levels of recruitment of
      focal adhesion components, while the hydrophobic CH3 substrate displayed the
      lowest levels. These patterns in focal adhesion assembly correlated well with
      integrin alpha5beta1 binding. Phosphorylation of specific tyrosine residues in
      FAK also showed differential sensitivity to surface chemistry. Finally, surface
      chemistry-dependent differences in adhesive interactions modulated osteoblastic
      differentiation. These differences in focal adhesion assembly and signaling
      provide a potential mechanism for the diverse cellular responses elicited by
      different material properties.

PMID- 15183610
TI  - A novel hyaluronan-based biomaterial (Hyaff-11) as a scaffold for endothelial
      cells in tissue engineered vascular grafts.
AB  - Current prosthetic small diameter vascular grafts show poor long-term patency
      rates, leading to the pursuit of a biological alternative. Hyaff-11 is a
      hyaluronan-based biodegradable polymer developed for tissue-engineering
      applications. This study aimed to determine whether human vascular endothelial
      cells attach to Hyaff-11 scaffolds and produce a subendothelial matrix. Two forms
      of fibrous, non-woven Hyaff-11 scaffolds: unpressed and pressed felts, were
      analysed. Attachment of human venous endothelial cells was investigated after 1,
      5, 10 and 20 days in culture using SEM and confocal microscopy. The deposition of
      subendothelial matrix components was investigated by immunofluorescent staining.
      We demonstrate that endothelial cells adhere to the individual fibres of both
      unpressed and pressed scaffolds: with a seeding density of 1 x 10(6) cells/cm(2),
      94% of the cells attached to Hyaff-11 fibres after 24 h. The pressed material
      provided the best environment for cell growth, allowing the formation of a
      complete endothelial monolayer after 20 days. Furthermore, endothelial cells on
      Hyaff-11 pressed felts deposited an organised subendothelial matrix containing
      laminin, fibronectin, type IV and type VIII collagen. This work indicates Hyaff
      11 based biopolymers as suitable scaffolds to promote endothelialisation within
      the next generation of vascular grafts.

PMID- 15183611
TI  - Controlled preparation and properties of porous poly(L-lactide) obtained from a
      co-continuous blend of two biodegradable polymers.
AB  - This study prepares porous PLLA from a blend of two biodegradable polymers. This
      approach is based on a detailed and quantitative morphology control of the
      blends. Co-continuous blends comprised of poly(L-lactide)/poly(epsilon
      caprolactone) PLLA/PCL, were prepared via melt processing. Through a judicious
      combination of concentration control and a subsequent annealing step it is
      possible to generate a wide range of sizes for the co-continuous phases.
      Subsequent extraction of the PCL porogen phase generates a fully interconnected
      porous PLLA material with a void volume between 50% and 60%. The volume average
      pore diameter is controlled from 1.5 to 88 microm as measured by mercury
      intrusion porosimetry. Through static annealing it is also possible to generate
      porous structures well beyond that upper limit of pore size. The upper limit of
      pore size reported above is in the range required for scaffolds for tissue
      engineering. Micrographs of porous polyglycolide and PCL derived from co
      continuous blends of PLLA/polyglycolide and PCL/poly(ethylene oxide) are also
      shown and demonstrate the versatility and wide applicability of this preparation
      protocol. The porous structures produced from PLLA/PCL blends possess a high
      level of mechanical integrity and a degree of crystallinity between 25% and 38%.
      High values of both compressive modulus and strength at 10%-strain are obtained,
      greater than 190 and 11 MPa, respectively. The compressive modulus is found to be
      from 10% to 20% of that of the pure PLLA material. A series of loading studies
      were also carried out and it was shown that under a pressure of 40 atm applied
      for 1 h, the pores of a 1.5 microm porous PLLA structure were filled to
      approximately 80% by water. In addition, the loading of an aqueous solution of a
      model drug compound, bovine serum albumin (BSA), was carried out at 40 atm and
      the results indicate that large quantities of BSA (up to 25% of the weight of the
      original porous capsule) can be driven into the pores. These results indicate
      that the internal porous structure is accessible to aqueous solution and that
      this material also has potential as a substrate for controlled release
      applications.

PMID- 15183612
TI  - Development of guided bone regeneration membrane composed of beta-tricalcium
      phosphate and poly (L-lactide-co-glycolide-co-epsilon-caprolactone) composites.
AB  - To create biodegradable and thermoplastic materials for guided bone regeneration,
      GBR, and guided tissue regeneration, GTR, membranes, composites of beta
      tricalcium phosphate, TCP, and biodegradable polyesters, poly (L-lactide-co
      glycolide-co-epsilon-caprolactone), PLGC, and poly (L-lactide-co-epsilon
      caprolactone), PLCL, were prepared by a heat-kneading method. The composites
      maintained thermoplasticity and mechanical strength by formation of a chemical
      interaction between Ca on TCP and C=O on the lactide segment of PLGC or PLCL. The
      composites also indicated composite effects in pH auto-regulation property and
      elongation of biodegradation period, e.g., the composites maintained their
      mechanical strength up to 12 weeks after soaking in both physiological and
      phosphate-buffered saline, and the period was sufficient time to use for GBR and
      GTR membranes. Animal tests for GBR indicated that the present composite membrane
      successfully regenerated beagles' mandible defects 10 x 10 x 10 mm3 in size.
      These results suggested that the TCP/PLGC bioresorbable composites could be
      utilized for GBR and GTR therapy.

PMID- 15183613
TI  - Expression of fibrinolysis activators and their inhibitor in neointima of
      polyester vascular grafts.
AB  - The aim of the study was to evaluate dynamic changes in the expression of
      fibrinolytic system components in neointima forming in polyester vascular grafts.
      The study was carried out on 18 mongrel dogs divided into three groups, that
      underwent replacement of abdominal aorta with a polyester double velour
      prosthesis. Grafts were removed at 1, 4 and 12 months. The specimens were fixed
      according to AMeX method. Immunohistochemical labeling for von Willebrand factor
      (vWf), tissue plasminogen activator (t-PA), urokinase (u-PA), its receptor (u
      PAR), plasminogen activator inhibitor type 1 (PAI-1) and D-dimer (DD) was
      performed. Increasing intensity of vWf expression on the graft luminal surface
      was found in successive periods of the study. A light positive t-PA and u-PA
      staining was shown in neointima at 1 month and its intensity was significantly
      increased at 4 and 12 months. Expression of u-PAR appeared at 4 months. A light
      positive PAI-1 and DD staining was demonstrated in neointima in all periods of
      the study. The results demonstrated increasing expression of fibrinolysis
      activators in neointima of polyester vascular grafts. Intensive expression of
      plasminogen activators, when compared to their inhibitor may reduce thrombotic
      properties of graft neointima particularly in the late period after prosthesis
      implantation.

PMID- 15183614
TI  - Inorganic delivery vector for intravenous injection.
AB  - Uniform, small-sized (100-200 nm), layered double hydroxides (LDH) were prepared
      by a conventional, wet chemistry method using different aging times of 1 and 3
      days as an inorganic drug or gene delivery carrier. The samples prepared had a
      hexagonal thin, plate-like shape and TEM/SAD electron microscopy of LDH particles
      indicated that they were single crystals. In vivo testing of empty LDH
      administered to adult male Sprague Dawley rats was done to evaluate the
      possibility of using LDH as an injectable drug delivery vehicle.

PMID- 15183615
TI  - Bush vs Kerry: health is a critically decisive issue.

PMID- 15183616
TI  - Chlorproguanil-dapsone for malaria in Africa.

PMID- 15183618
TI  - Pain during prostate biopsy.

PMID- 15183619
TI  - Genetic counselling and prophylactic surgery in women from families with
      hereditary breast or ovarian cancer.

PMID- 15183620
TI  - Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the
      treatment of uncomplicated falciparum malaria in young African children: double
      blind randomised controlled trial.
AB  - BACKGROUND: Increasing resistance to sulfadoxine-pyrimethamine is leading to a
      decline in its effectiveness. We aimed to assess the safety profile of
      chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug
      with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated
      falciparum malaria. METHODS: We undertook a double-blind, randomised trial in
      1850 consecutively recruited children with uncomplicated falciparum malaria,
      pooling data from five African countries. Analyses were based on all randomised
      patients with available data. FINDINGS: CD was significantly more efficacious
      than SP (odds ratio 3.1 [95% CI 2.0-4.8]); 1313 patients (96%) given CD and 306
      (89%) given SP achieved acceptable clinical and parasitological response by day
      14. Adverse events were reported in 46% and 50% of patients randomised to CD and
      SP, respectively (treatment difference -4.4%, [95% CI -10.1 to 1.3]). Haemoglobin
      in the CD group was significantly lower than in the SP group at day 7, a
      difference of -4 g/L (95% CI -6 to -2). Mean day 14 haemoglobin (measured only
      for the small number of patients whose day 7 data caused concern) was 94 g/L (92
      96) and 97 g/L (92-102) after CD and SP, respectively. Glucose-6-phosphate
      dehydrogenase deficient patients on CD had greater odds than those on SP of
      having a fall of 20 g/dL or more in haemoglobin when baseline temperature was
      high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0.4% [95% CI 0.4
      0.4]) before treatment, 4.2% (95% CI 3.8-4.6) (n=301) at day 3, and 0.6% (0.6
      0.7) (n=300) at day 7). INTERPRETATION: CD had greater efficacy than SP in Africa
      and was well tolerated. Haematological adverse effects were more common with CD
      than with SP and were reversible. CD is a useful alternative where SP is failing
      due to resistance.

PMID- 15183621
TI  - Cervical cerclage for prevention of preterm delivery in women with short cervix:
      randomised controlled trial.
AB  - BACKGROUND: Cervical cerclage has been widely used in the past 50 years to
      prevent early preterm birth and its associated neonatal mortality and morbidity.
      Results of randomised trials have not generally lent support to this practice,
      but this absence of benefit may be due to suboptimum patient selection, which was
      essentially based on obstetric history. A more effective way of identifying the
      high-risk group for early preterm delivery might be by transvaginal sonographic
      measurement of cervical length. We undertook a multicentre randomised controlled
      trial to investigate whether, in women with a short cervix identified by routine
      transvaginal scanning at 22-24 weeks' gestation, the insertion of a Shirodkar
      suture reduces early preterm delivery. METHODS: Cervical length was measured in
      47?123 women. The cervix was 15 mm or less in 470, and 253 (54%) of these women
      participated in the study and were randomised to cervical cerclage (127) or to
      expectant management (126). Primary outcome was the frequency of delivery before
      33 completed weeks (231 days) of pregnancy. FINDINGS: The proportion of preterm
      delivery before 33 weeks was similar in both groups, 22% (28 of 127) in the
      cerclage group versus 26% (33 of 126) in the control group (relative risk=0.84,
      95% CI 0.54-1.31, p=0.44), with no significant differences in perinatal or
      maternal morbidity or mortality. INTERPRETATION: The insertion of a Shirodkar
      suture in women with a short cervix does not substantially reduce the risk of
      early preterm delivery. Routine sonographic measurement of cervical length at 22
      24 weeks identifies a group at high risk of early preterm birth.

PMID- 15183622
TI  - Pupil blown by a puffer.

PMID- 15183623
TI  - Comparison of surgery and compression with compression alone in chronic venous
      ulceration (ESCHAR study): randomised controlled trial.
AB  - BACKGROUND: Chronic venous leg ulceration can be managed by compression
      treatment, elevation of the leg, and exercise. The addition of ablative
      superficial venous surgery to this strategy has not been shown to affect ulcer
      healing, but does reduce ulcer recurrence. We aimed to assess healing and
      recurrence rates after treatment with compression with or without surgery in
      people with leg ulceration. METHODS: We did venous duplex imaging of ulcerated or
      recently healed legs in 500 consecutive patients from three centres. We randomly
      allocated those with isolated superficial venous reflux and mixed superficial and
      deep reflux either compression treatment alone or in combination with superficial
      venous surgery. Compression consisted of multilayer compression bandaging every
      week until healing then class 2 below-knee stockings. Primary endpoints were 24
      week healing rates and 12-month recurrence rates. Analysis was by intention to
      treat. FINDINGS: 40 patients were lost to follow-up and were censored. Overall 24
      week healing rates were similar in the compression and surgery and compression
      alone groups (65% vs 65%, hazard 0.84 [95% CI 0.77 to 1.24]; p=0.85) but 12-month
      ulcer recurrence rates were significantly reduced in the compression and surgery
      group (12% vs 28%, hazard -2.76 [95% CI -1.78 to -4.27]; p<0.0001). Adverse
      events were minimal and about equal in each group. INTERPRETATION: Surgical
      correction of superficial venous reflux reduces 12-month ulcer recurrence. Most
      patients with chronic venous ulceration will benefit from the addition of simple
      venous surgery.

PMID- 15183624
TI  - Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by
      HIV infection.
AB  - BACKGROUND: HIV infection increases the risk of malaria infection in pregnant
      women. Antibodies to variant surface antigens (VSA) on infected erythrocytes
      might protect against malaria in pregnancy. We postulated that HIV-induced
      impairment of humoral immunity to VSA mediates the increased susceptibility to
      malaria. METHODS: We compared serum concentrations of antibodies to VSA by flow
      cytometry or agglutination, and to merozoite proteins AMA-1 and MSP119 by ELISA,
      in 298 pregnant Malawian women, and related the findings to malaria and HIV
      infection, CD4-positive T-cell count, and HIV-1 viral load. FINDINGS:
      Concentrations of IgG to placental type VSA were lower in HIV-infected women than
      in HIV-uninfected women (median 8 units [IQR 4-23] vs 20 [12-30]; p<0.0001),
      among women with malaria (p=0.009) and those without malaria (p=0.0062). The
      impairment was greatest in first pregnancy. Agglutinating antibodies to placental
      VSA were present in a lower proportion of HIV-infected than HIV-uninfected women
      (58 [35.1%] of 165 vs 50 [53.8%] of 93, p<0.001). The degree of antibody binding
      by flow cytometry was correlated with CD4-positive T-cell count (r=0.16, p=0.019)
      and inversely with HIV-1 viral load (r=-0.16, p=0.030). Concentrations of
      antibodies to AMA-1 were lower in HIV infection (p<0.0001) but were not
      correlated with CD4-positive T-cell count or viral load. Responses to MSP119 were
      little affected by HIV infection. In multivariate analyses, HIV was negatively
      associated with amount of antibody to both VSA and AMA-1 (p<0.001 for each) but
      not MSP119. INTERPRETATION: HIV infection impairs antimalarial immunity,
      especially responses to placental type VSA. The impairment is greatest in the
      most immunosuppressed women and could explain the increased susceptibility to
      malaria seen in pregnant women with HIV infection.

PMID- 15183625
TI  - Fever, headache, and a stiff neck.

PMID- 15183626
TI  - Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection
      of annexin A1 (ANXA1).
AB  - A marker capable of distinguishing with certainty between hairy cell leukaemia
      and other B-cell malignant disease would be of great diagnostic value. Through
      gene expression profiling, annexin A1 (ANXA1) has been identified as a gene that
      is upregulated in hairy cell leukaemia. We did immunostaining of 500 B-cell
      tumours with a specific anti-ANXA1 monoclonal antibody and showed that ANXA1
      protein expression is specific to hairy cell leukaemia. Immunocytochemical
      detection of ANXA1 represents a simple, inexpensive, highly sensitive and
      specific (100%) assay for diagnosis of hairy cell leukaemia. This assay will be
      especially useful in distinguishing hairy cell leukaemia from splenic lymphoma
      with villous lymphocytes and variant hairy cell leukaemia, both of which usually
      respond poorly to treatments that are effective in hairy cell leukaemia.

PMID- 15183627
TI  - Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy
      children.
AB  - A trial with a 7-valent pneumococcal-conjugate vaccine in children with recurrent
      acute otitis media showed a shift in pneumococcal colonisation towards non
      vaccine serotypes and an increase in Staphylococcus aureus-related acute otitis
      media after vaccination. We investigated prevalence and determinants of
      nasopharyngeal carriage of Streptococcus pneumoniae and S aureus in 3198 healthy
      children aged 1-19 years. Nasopharyngeal carriage of S pneumoniae was detected in
      598 (19%) children, and was affected by age (peak incidence at 3 years) and day
      care attendance (odds ratio [OR] 2.14, 95% CI 1.44-3.18). S aureus carriage was
      affected by age (peak incidence at 10 years) and male sex (OR 1.46, 1.25-1.70).
      Serotyping showed 42% vaccine type pneumococci. We noted a negative correlation
      for co-colonisation of S aureus and vaccine-type pneumococci (OR 0.68, 0.48
      0.94), but not for S aureus and non-vaccine serotypes. These findings suggest a
      natural competition between colonisation with vaccine-type pneumococci and S
      aureus, which might explain the increase in S aureus-related otitis media after
      vaccination.

PMID- 15183628
TI  - Hypertrophic cardiomyopathy.
AB  - Hypertrophic cardiomyopathy is a common genetically transmitted disease, defined
      clinically by the presence of unexplained left ventricular hypertrophy. The
      disease has a varied clinical course and outcome; many patients have little or no
      discernible cardiovascular symptoms, whereas others have profound exercise
      limitation and recurrent arrhythmias. The overall risk of disease-related
      complications such as sudden death, endstage heart failure, and fatal stroke is
      roughly 1-2% per year, but the absolute risk in individuals varies as a function
      of underlying genetic abnormality, age, myocardial pathology, and other
      pathophysiological abnormalities such as impaired peripheral vascular responses.
      Genetic counselling and clinical risk stratification are relevant to all
      patients, but many therapeutic interventions, including septal alcohol ablation,
      septal myectomy, and implantable cardioverter defibrillators, are appropriate
      only in particular patient subsets. We review the management of patients with
      unexplained myocardial hypertrophy, considering the influence of underlying
      genetic and pathophysiological substrates on clinical decision-making.

PMID- 15183629
TI  - The nicotinic acid receptor--a new mechanism for an old drug.
AB  - CONTEXT: Non-esterified fatty acids in plasma originate from adipose tissue.
      Delivery of fatty acids to the liver provides the substrate for VLDL
      triglycerides. Insulin-sensitive organs, overburdened by high concentrations of
      non-esterified fatty acids, may develop resistance to insulin action. In
      addition, insulin secretion from pancreatic beta-cells may be impaired by long
      standing elevation of concentrations of non-esterified fatty acid in plasma.
      Normally, such concentrations fluctuate over the day depending on the transient
      suppression of lipolysis from adipose tissue by insulin released after meals.
      Diurnal concentrations of non-esterified fatty acid are often elevated in
      obesity, in particular in male-pattern upper-body fat accumulation. Nicotinic
      acid is the only drug that primarily lowers concentrations of non-esterified
      fatty acids and thereby lowers VLDL triglycerides. Nicotinic acid, or its
      analogues, seems to alleviate insulin resistance in the short-term whereas,
      paradoxically, the long-term effect is often the opposite. Suppression of
      lipolysis by nicotinic acid gives rise to a prominent rebound and the degree to
      which this occurs might explain this paradox. STARTING POINT: The exact cellular
      mechanism by which nicotinic acid exerts its antilipolytic effects has not been
      known until the recent discovery of a distinct G-protein coupled receptor.
      Nicotinic acid is a high affinity ligand, but the endogenous ligand is still
      unknown. Recently, Tina Rubic and colleagues (Biochem Pharmacol 2004; 67: 411-19)
      proposed a mechanism in which nicotinic acid stimulates cholesterol mobilisation
      from macrophages, thereby providing a potential link between regression of
      atherosclerosis and use of nicotinic acid. WHERE NEXT: Research on signalling
      through the nicotinic acid receptor might give rise to novel and more effective
      methods to interfere with fatty-acid metabolism, with insulin resistance,
      hyperlipidaemia, and atherosclerosis as target diseases.

PMID- 15183630
TI  - Support of the metabolic response to burn injury.
AB  - Severe burn causes metabolic disturbances that can last for a year after injury;
      persistent and profound catabolism hampers rehabilitative efforts and delays the
      meaningful return of individuals to society. The simplest, effective anabolic
      strategies for severe burn injuries are: early excision and grafting of the
      wound; prompt treatment of sepsis; maintenance of environmental temperature at 30
      32 degrees C; continuous feeding of a high carbohydrate, high protein diet,
      preferably by the enteral route; and early institution of vigorous and aerobic
      resistive exercise programmes. To further keep erosion of lean body mass to a
      minimum, administration of anabolic agents, recombinant human growth hormone,
      insulin, oxandrolone, or anticatabolic drugs such as propranolol are alternative
      approaches. Exogenous continuous low-dose insulin infusion, beta blockade with
      propranolol, and use of the synthetic testosterone analogue oxandrolone are the
      most cost effective and least toxic pharmacological treatments to date.

PMID- 15183631
TI  - Missed diagnosis and repeat procedures.

PMID- 15183632
TI  - Rabies and other lyssavirus diseases.

PMID- 15183633
TI  - Rabies and other lyssavirus diseases.

PMID- 15183634
TI  - Rabies and other lyssavirus diseases.

PMID- 15183636
TI  - Pergolide in Parkinson's disease: time for a change?

PMID- 15183637
TI  - Risk of cancer from diagnostic X-rays.

PMID- 15183638
TI  - Risk of cancer from diagnostic X-rays.

PMID- 15183639
TI  - Risk of cancer from diagnostic X-rays.

PMID- 15183640
TI  - Risk of cancer from diagnostic X-rays.

PMID- 15183641
TI  - Risk of cancer from diagnostic X-rays.

PMID- 15183642
TI  - Abortion and breast cancer.

PMID- 15183644
TI  - Does thalidomide have a role in leprosy?

PMID- 15183645
TI  - WHO policies for tuberculosis control.

PMID- 15183646
TI  - Colchicine for respiratory syncytial virus bronchiolitis.

PMID- 15183647
TI  - Use and misuse of outcome data.

PMID- 15183648
TI  - Polio-vaccination boycott in Nigeria.

PMID- 15183649
TI  - Inge Genefke.

PMID- 15183652
TI  - Evaluation and treatment of severe and prolonged thrombocytopenia in neonates.
AB  - Thrombocytopenia is one of the most common hematologic problems in the neonatal
      intensive care unit (NICU). Despite its prevalence,several basic pathophysiologic
      questions remain unanswered. For instance, there is a lack of evidence-based
      guidelines for treatment,and the kinetic mechanisms (decreased platelet
      production,increased platelet consumption, or sequestration) responsible for most
      varieties of neonatal thrombocytopenia are not well defined.Moreover, a clear
      correlation between degree of thrombocytopenia and the resulting bleeding risk
      has not been demonstrated, and no transfusion-trigger studies have been conducted
      in neonates. As a consequence of these deficiencies in knowledge, there is great
      variability in platelet transfusion practices among NICUs. This article presents
      an overview of the evaluation of a neonate with severe thrombocytopenia and a
      review of current and projected therapeutic options.

PMID- 15183653
TI  - Platelet function in term and preterm neonates.
AB  - Platelet dysfunction likely contributes to the pathophysiology of catastrophic
      hemorrhages in preterm neonates. In vitro studies have demonstrated that
      platelets of both term and preterm neonates are hyporesponsive to a variety of
      agonists. In contrast,template bleeding times of term neonates are shorter than
      those from adults. Very little is known about this and other tests of primary
      hemostasis in premature and sick neonates in the neonatal intensive care unit
      (NICU). This article covers the current knowledge of platelet function in preterm
      and term neonates and review show new agents (such as recombinant thrombopoietin
      and recombinant factor VIIa) may enhance neonatal platelet function.

PMID- 15183654
TI  - Congenital neutropenia.
AB  - The term "congenital neutropenia" signifies neutropenia that is present at birth.
      It includes a wide variety of disorders, some transient and others life long.
      Some varieties of congenital neutropenia are mild, with blood neutrophil
      concentrations below normal but not low enough to constitute a significant host
      defense deficiency. Other varieties of congenital neutropenia are characterized
      by low blood neutrophil concentrations and a predisposition to repeated
      infections.

PMID- 15183655
TI  - Neonatal neutrophils: the good, the bad, and the ugly.
AB  - Neonates are at considerable risk for bacterial and fungal infections,due in
      great part to a variety of age-related impairments in neutrophil function. In
      addition, evidence suggests that the tendency of the most immature neonates to
      develop chronic inflammatory disorders is also related to neutrophil dysfunction.
      This article provides an overview of specific functional deficiencies of
      neutrophils that have been reported in neonates.

PMID- 15183656
TI  - The role of molecular genetics in the pathogenesis and diagnosis of neonatal
      sepsis.
AB  - Polymorphisms within genes encoding endogenous mediators of inflammation are good
      candidates for the individual differences in systemic inflammatory responses of
      neonates to infection. Ina similar manner, polymorphisms in the genes encoding
      drug metabolizing enzymes, drug transporters, and drug receptors can influence a
      neonate's risk of an adverse drug reaction or can alter the efficacy of drug
      treatment. Additionally, molecular tools are proving valuable in the diagnosis of
      neonatal infection. This article gives an overview of the genetic susceptibility
      to sepsis, discusses the use of molecular genetics in diagnostic tests for
      infection, and reviews the potential for more effective and specific therapies
      for sepsis based on genetic variability.

PMID- 15183657
TI  - Immunoenhancement to prevent nosocomial coagulase-negative staphylococcal sepsis
      in very low-birth-weight infants.
AB  - Extremely low-birth-weight infants are susceptible to invasion by coagulase
      negative staphylococci (CONS). This article reviews the epidemiology, immunology,
      and microbiology of CONS and describes recent clinical trials of immunoenhancing
      agents such as intravenous immunoglobulin, granulocyte colony-stimulating factor,
      granulocyte macrophage colony-stimulating factor, and mouse humanized chimeric
      anti-lipoteichoic acid antibody. Potential avenues of research to reduce the
      incidence of nosocomial CONS sepsis in premature neonates are presented.

PMID- 15183658
TI  - Long-acting erythropoietin: clinical studies and potential uses in neonates.
AB  - Aranesp (darbepoietin alfa) is a biologically modified form of recombinant human
      erythropoietin (rHuEpo). Two additional carbohydrate-binding sites give Aranesp a
      half-life about three times that of rHuEpo. Extensive studies in adults and early
      studies in children indicate that Aranesp can be administered far less frequently
      than rHuEpo with an equivalent erythropoietic effect. This article reviews these
      studies and reports on the in vitro effects of Aranesp on human fetal and
      neonatal erythroid progenitors.

PMID- 15183659
TI  - Nuclear mechanisms of hypoxic cerebral injury in the newborn.
AB  - In early studies, we demonstrated that cerebral tissue hypoxia leads to N-methyl
      D-aspartate receptor modification and results in increased intracellular Ca2+.
      Our subsequent studies have demonstrated an alteration in nuclear Ca2+ influx
      mechanisms and an increase in the nuclear Ca2+ influx after hypoxia. The hypoxia
      induced nuclear Ca2+ influx increase correlated in a curvilinear function with
      the increase in the degree of cerebral tissue hypoxia. The activity of nuclear
      membrane high-affinity Ca2+-ATPase also increased with the increase in cerebral
      hypoxia. The expression of the proapototic protein Bax increased as an inverse
      function with cerebral tissue ATP and phosphocreatine concentrations. However,the
      expression of the antiapoptotic protein Bcl-2 did not increase after hypoxia.
      Cerebral tissue hypoxia also led to the activation of caspases 3, 8, and 9.
      Furthermore, our studies demonstrated that the fragmentation of neuronal genomic
      DNA increased with increase in degree of cerebral tissue hypoxia. Studies
      presented in this article elucidate nuclear Ca2+ influx and nuclear Ca2+-mediated
      mechanisms, including signal transduction, apoptotic gene transcription,caspase
      activation, and nuclear DNA fragmentation, that result in hypoxic neuronal injury
      in the newborn brain.

PMID- 15183660
TI  - Biomarkers of hypoxic brain injury in the neonate.
AB  - The specific pathologic processes preceding the onset of irreversible cerebral
      injury seem to be a combination of several complex mechanisms due to the severity
      and duration of the insult to the biochemical modifications in the brain. An
      early diagnosis of the newborn at high risk for brain damage is relevant for
      preventive programs. Neuroprotective strategies will benefit from the detection
      of biochemical markers with high reliability and predictability for brain injury.

PMID- 15183661
TI  - The role of complement in neonatal hypoxic-ischemic cerebral injury.
AB  - Complement activation participates in tissue injury after temporary loss of blood
      flow (ischemia-reperfusion injury). Recently reported evidence indicates that
      complement activation is a pathologic mechanism of injury in the post-hypoxic
      ischemic neonatal brain. Therefore, recently developed complement inhibitors may
      find a role in the amelioration of neonatal hypoxic-ischemic cerebral injury.
      Further research is needed to better define the role of complement in human
      neonatal cerebral injury and to determine the neuroprotective effect and safety
      of pharmacologic agents designed to inhibit complement.

PMID- 15183662
TI  - Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo
      models.
AB  - The biologic effects of erythropoietin in the central and peripheral nervous
      system involve the activation of its specific cell surface receptor and
      corresponding signal transduction pathways. This article reviews the
      neuroprotective effects of erythropoietin in brain, emphasizing the progress made
      using in vitro and in vivo research models.

PMID- 15183663
TI  - Role of cytokines in human intestinal villous development.
AB  - Villous development of the intestine is beginning to be understood in terms of
      the underlying molecular mechanisms. There is increasing information on the role
      of cytokines as extrinsic regulators in this process. This article summarizes
      information available on various cytokines that have been studied in this
      context.

PMID- 15183664
TI  - Necrotizing enterocolitis: preventative strategies.
AB  - Necrotizing enterocolitis (NEC) remains a major cause of morbidity and mortality
      in premature infants. Although the pathogenesis of NEC is unclear, prevention
      strategies have been developed based on clinical observations and epidemiologic
      and experimental data. Most current strategies have centered on feeding practices
      (eg, institution of feeds, advancement of feeds, composition of feeds, and
      standardization of feeding practices). Emerging strategies include amino acid
      supplementation, the use of platelet-activating factor(PAF) antagonists or PAF
      acetylhydrolase administration, polyunsaturated fatty acid administration,
      epidermal growth factor administration, and the use of pre- and probiotics.

PMID- 15183665
TI  - Hematopoietic growth factors in neonatal medicine: the use of enterally
      administered hematopoietic growth factors in the neonatal intensive care unit.
AB  - The practice of complete bowel rest in prematurely delivered neonates and those
      who have undergone surgery for congenital anomalies of the gastrointestinal (GI)
      tract is common in neonatal intensive care units (NICU). However, increased
      recognition of the critical role of growth factors in GI development suggests
      that this practice might be modified to include the administration of synthetic
      amniotic fluid-like solutions designed to bridge the neonate between their intra
      uterine environment and that of the NICU. This article reviews advances in
      administering synthetic amniotic fluid-like solutions in the NICU.

PMID- 15183666
TI  - Epidermal growth factor and necrotizing enterocolitis.
AB  - As the number of extremely low-birth-weight infants increases,necrotizing
      enterocolitis remains a critical eminent problem. Supplementation of enteral
      feeds with biologically active substances normally present in breast milk, such
      as epidermal growth factor, seems to be a logical and safe way to reduce the
      incidence of intestinal inflammation and necrotizing enterocolitis. Continuing
      basic research and clinical studies are essential before epidermal growth factor
      can be introduced as an efficient therapeutic approach in the treatment of
      neonatal necrotizing enterocolitis.

PMID- 15183668
TI  - Evidence of amelogenesis imperfecta in an early African Homo erectus.
AB  - The teeth of the Homo erectus child (Garba IV) recovered from Melka Kunture
      Ethiopia and dated to 1.5 Ma are characterized by generalized enamel dysplasia,
      reduced enamel radio-opacity, and severe attrition. This combination of features
      is found in a large group of hereditary, generalized enamel dysplasias known as
      amelogenesis imperfecta (AI). SEM studies carried out on epoxy replicas of teeth
      from the Garba IV child, confirmed that the defects noted were developmental and
      not due to diagenesis. The enamel prism arrangement is abnormal and there are
      deep vertical furrows lacking enamel on both buccal and lingual surfaces of all
      molars. The lesions differ from those characteristic of linear enamel hypoplasia
      that form discrete horizontal lesions or pits within otherwise normal enamel. We
      propose that the Garba IV child is the earliest example of AI and provides a link
      between palaeoanthropology and molecular biology in investigations of the
      evolutionary history of genetic disorders.

PMID- 15183669
TI  - Effects of food processing on masticatory strain and craniofacial growth in a
      retrognathic face.
AB  - Changes in the technology of food preparation over the last few thousand years
      (especially cooking, softening, and grinding) are hypothesized to have
      contributed to smaller facial size in humans because of less growth in response
      to strains generated by chewing softer, more processed food. While there is
      considerable comparative evidence to support this idea, most experimental tests
      of this hypothesis have been on non-human primates or other very prognathic
      mammals (rodents, swine) raised on hard versus very soft (nearly liquid) diets.
      Here, we examine facial growth and in vivo strains generated in response to
      raw/dried foods versus cooked foods in a retrognathic mammal, the rock hyrax
      (Procavia capensis). The results indicate that the hyrax cranium resembles the
      non-human primate cranium in having a steep gradient of strains from the occlusal
      to orbital regions, but differs from most non-anthropoids in being primarily
      twisted; the hyrax mandible is bent both vertically and laterally. In general,
      higher strains, as much as two-fold at some sites, are generated by masticating
      raw versus cooked food. Hyraxes raised on cooked food had significantly less
      growth (approximately 10%) in the ventral (inferior) and posterior portions of
      the face, where strains are highest, resembling many of the differences evident
      between humans raised on highly processed versus less processed diets. The
      results support the hypothesis that food processing techniques have led to
      decreased facial growth in the mandibular and maxillary arches in recent human
      populations.

PMID- 15183670
TI  - Comparison of cranial ontogenetic trajectories among great apes and humans.
AB  - Molecular data suggest that humans are more closely related to chimpanzees than
      either is to the gorillas, yet one finds the closest similarity in craniofacial
      morphology to be among the great apes to the exclusion of humans. To clarify how
      and when these differences arise in ontogeny, we studied ontogenetic trajectories
      for Homo sapiens, Pan paniscus, Pan troglodytes, Gorilla gorilla and Pongo
      pygmaeus. A total of 96 traditional three-dimensional landmarks and semilandmarks
      on the face and cranial base were collected on 268 adult and sub-adult crania for
      a geometric morphometric analysis. The ontogenetic trajectories are compared by
      various techniques, including a new method, relative warps in size-shape space.
      We find that adult Homo sapiens specimens are clearly separated from the great
      apes in shape space and size-shape space. Around birth, Homo sapiens infants are
      already markedly different from the great apes, which overlap at this age but
      diverge among themselves postnatally. The results suggest that the small genetic
      differences between Homo and Pan affect early human ontogeny to induce the
      distinct adult human craniofacial morphology. Pure heterochrony does not
      sufficiently explain the human craniofacial morphology nor the differences among
      the African apes.

PMID- 15183671
TI  - The deciduous lower dentition of Ouranopithecus macedoniensis (Primates,
      Hominoidea) from the late Miocene deposits of Macedonia, Greece.
AB  - Two mandibular fragments with associated milk teeth assigned to the late Miocene
      hominoid primate Ouranopithecus macedoniensis are analyzed. The fossils, which
      belong to a single individual, were found in the Vallesian locality of "Ravin de
      la Pluie" of the Axios Valley (Macedonia, Greece). The material is described here
      and compared with extant and extinct hominoids, allowing assessment of the
      evolutionary trends in the deciduous lower dentition within the Hominoidea.
      Hylobatids represent the more primitive pattern. Gorilla is slightly more derived
      than hylobatids, but less derived than Pongo and Pan, the latter being the most
      derived. With relatively smaller deciduous canines and more molarized deciduous
      premolars, Ouranopithecus is more derived than both Pan and Gorilla. Among the
      fossil hominoids, Proconsul, representing the primitive condition, has a very
      simple dp(3)and a dp(4)that has a trigonid that is taller than the talonid and
      which lacks a hypoconulid. Griphopithecus is more derived than Proconsul in
      having a dp(4) with a lower trigonid, a hypoconulid, and a less oblique cristid
      obliqua. Australopithecus and Paranthropus possess a similar morphology to that
      of Homo, while Ardipithecus appears to be more primitive than the latter genera.
      Ouranopithecus has a more derived lower milk dentition than Proconsul and
      Griphopithecus, but less derived than Australopithecus and Paranthropus. The
      comparison of the lower milk dentition of Ouranopithecus confirms our previous
      conclusions suggesting that this fossil hominoid shares derived characters with
      Australopithecus and Homo.

PMID- 15183672
TI  - Convergence of forelimb and hindlimb Natural Pendular Period in baboons (Papio
      cynocephalus) and its implication for the evolution of primate quadrupedalism.
AB  - The patterns of muscle mass distribution along the lengths of limbs may have
      important effects on the mechanics and energetics of quadrupedalism.
      Specifically, Myers and Steudel (J. Morphol. 234 (1997) 183) have shown that fore
      and hindlimb Natural Pendular Periods (NPPs) may affect quadrupedal kinematics
      and must converge to reduce locomotor energetic costs. This study quantifies
      patterns of limb mass distribution in a live sample of Papio cynocephalus using
      limb inertial properties (mass, center of mass, mass moment of inertia, and
      radius of gyration). These inertial properties are calculated using a geometric
      modeling technique similar to that of Crompton et al. (Am. J. phys. Anthrop. 99
      (1996) 547). The inertial properties in Papio are compared to those of Canis from
      Myers and Steudel (J. Morphol. 234 (1997) 183). The Papio sample has convergent
      fore- and hindlimb NPPs. Additionally, these limb NPPs are relatively large
      compared to those of Canis due to the relatively distally distributed limb mass
      in the Papio sample (relatively large limb masses, relatively distal centers of
      mass and radii of gyration, and relatively large limb mass moments of inertia).
      This relatively distal limb mass appears related to the grasping abilities of
      their hands and feet. Causal links are explored between limb shape adaptations
      for grasping hands and feet and the kinematics of primate quadrupedalism. In
      particular, if primates in general follow Papio's limb mass distribution pattern,
      then relatively large limb NPPs may lead to the relatively low stride frequencies
      already documented for primates. The kinematics of primate quadrupedalism appears
      to have been strongly influenced by both selection for grasping hands and feet
      and selection for reduced locomotor energetic costs.

PMID- 15183673
TI  - Do highly trained monkeys walk like humans? A kinematic study of bipedal
      locomotion in bipedally trained Japanese macaques.
AB  - In this study, we examined the kinematics of bipedal walking in macaque monkeys
      that have been highly trained to stand and walk bipedally, and compared them to
      the kinematics of bipedal walking in ordinary macaques. The results revealed that
      the trained macaques walked with longer and less frequent strides than ordinary
      subjects. In addition, they appear to have used inverted pendulum mechanics
      during bipedal walking, which resulted in an efficient exchange of potential and
      kinetic energy. These gait characteristics resulted from the relatively more
      extended hindlimb joints of the trained macaques. By contrast, the body of the
      ordinary macaques translated downward during the single-limb stance phase due to
      more flexed hindlimb joints. This resulted in almost in-phase fluctuations of
      potential and kinetic energy, which indicated that energy transformation was less
      efficient in the ordinary macaques. The findings provide two insights into the
      early stage of the evolution of human bipedalism. First, the finding that
      training considerably improved bipedal walking a posteriori may explain why the
      very first bipeds that might not yet have been morphologically adapted to bipedal
      walking continued to walk bipedally. The evolutionary transition from
      quadrupedalism to bipedalism might not be as difficult as has been envisioned. In
      addition, the finding that macaques, which are phylogenetically distant from
      humans and in which bipedal walking is unlike human walking, could develop
      humanlike gait characteristics with training, provides strong support for the
      commonly held but unproven idea that the characteristics of the human gait are
      advantageous to human bipedalism.

PMID- 15183674
TI  - The earliest human occupation of North Africa: a reply to Sahnouni et al. (2002).

PMID- 15183676
TI  - Tail loss in Proconsul heseloni.

PMID- 15183677
TI  - Good continuation with kinetic edges.
AB  - We examined the perceptual formation of extended contours from second-order
      kinetic-edges created by motion discontinuities. Paths were formed by spatially
      separate kinetic-edge elements, aligned along smooth paths, and embedded in
      randomly oriented noise elements. Path detection was severely degraded when the
      sign of motion contrast alternated along the path compared to when the same sign
      was used, or if random motion direction was assigned to each edge element, or if
      alternating opposite motion directions was used along the paths. Performance
      increased monotonically with the length of the path. Irrespectively of path
      curvature a fast temporal summation occurs within the first 200-400 ms and then
      levels off. Hence, the kinetic-edge grouping is relatively fast and a pure second
      order process that senses whether the motion is globally in the same phase and
      direction along extended contours.

PMID- 15183678
TI  - Differential latencies and the dynamics of the position computation process for
      moving targets, assessed with the flash-lag effect.
AB  - To investigate the dynamics of the position computation process for a moving
      object in human vision, we measured the response to a continuous change in
      position at a constant velocity (ramp-response) using the flash-lag illusion. In
      this illusion, flashed and moving objects appear spatially offset when their
      retinal images are physically aligned. The steady-state phase of the ramp
      response was probed using the "continuous-motion" (CM) paradigm, in which the
      motion of the moving object starts long before the occurrence of the flash. To
      probe the transient phase of the ramp-response, we used the "flash-initiated
      cycle" (FIC) paradigm, in which the motion of the moving object starts within a
      short time window around the presentation of the flash. The sampling instant of
      the ramp-response was varied systematically by changing the luminance or the
      presentation time of the flashed stimulus. We found that the perceived flash
      misalignments in the FIC and CM paradigms were approximately equal when sampling
      of the ramp-response occurred after a relatively long delay from the onset of
      motion and, were significantly different when sampling of the ramp-response
      occurred at a relatively short delay. The systematic variations in the perceived
      misalignment between the moving and flashed stimuli as a function of stimulus
      parameters are compared to the predictions of our differential latency and to
      alternative models of position computation.

PMID- 15183679
TI  - Compensation for longitudinal chromatic aberration in the eye of the firefly
      squid, Watasenia scintillans.
AB  - The camera eyes of fishes and cephalopods have come forth by convergent
      evolution. In a variety of vertebrates capable of color vision, longitudinal
      chromatic aberration (LCA) of the optical system is corrected for by the exactly
      tuned longitudinal spherical aberration (LSA) of the crystalline lens. The LSA
      leads to multiple focal lengths, such that several wavelengths can be focused on
      the retina. We investigated whether that is also the case in the firefly squid
      (Watasenia scintillans), a cephalopod species that is likely to have color
      vision. It was found that the lens of W. scintillans is virtually free of LSA and
      uncorrected for LCA. However, the eye does not suffer from LCA because of a
      banked retina. Photoreceptors sensitive to short and long wavelengths are located
      at appropriate distances from the lens, such that they receive well-focused
      images. Such a design is an excellent solution for the firefly squid because a
      large area of the retina is monochromatically organized and it allows for double
      use of the surface area in the dichromatically organized part of the retina.
      However, it is not a universal solution since compensation for LCA by a banked
      retina requires that eye size and/or spectral separation between photopigments is
      small.

PMID- 15183680
TI  - Perceptual biases in the interpretation of 3D shape from shading.
AB  - Two experiments are reported in which observers judged the sign and magnitude of
      surface curvature from shaded images of an indoor scene. The depicted surfaces
      were illuminated by an area light in the ceiling or floor, and the illumination
      was attenuated with distance in a physically correct manner. The displays were
      presented both with and without cast shadows, specular highlights and surface
      inter-reflections in all possible combinations. The overall pattern of results
      revealed a strong perceptual bias to interpret the images as convex rather than
      concave, and a weaker bias to prefer illumination from above rather than from
      below, though there were large individual differences in the relative strengths
      of these biases. For displays that did not contain cast shadows or specular
      highlights, the accuracy of observers' judgments about the sign of surface
      curvature was no greater than chance, but performance was significantly improved
      when those aspects of normal shading were included in the rendering model. An
      analysis of the apparent depth magnitudes revealed that convex surfaces produce
      much greater perceived depth than concave surfaces with comparable relief.

PMID- 15183681
TI  - A circadian clock regulates the process of ERG b- and d-wave dominance transition
      in dark-adapted zebrafish.
AB  - In zebrafish, during dark adaptation following bright light adaptation, the
      dominance of electroretinogram (ERG) b- and d-waves switches. In the early dark
      adaptation, when visual sensitivity is cone-dominant, both the b- and d-waves are
      readily recorded. In the late dark adaptation, along with the increase of rod
      sensitivity, the b-wave becomes dominant whereas the d-wave is gradually lost.
      The time for the ERG b- and d-wave dominance transition varies between the day
      and night. The transition requires a longer amount of time in the night and early
      morning than in the afternoon. This pattern of timing for ERG b- and d-wave
      dominance transition persists in constant light and can be reversed after
      exposure to a reversed light-dark cycle. The data suggest that the transition of
      the dominance of ERG b- and d-waves is regulated by an endogenous circadian
      clock.

PMID- 15183682
TI  - On the relation between the photoactivation energy and the absorbance spectrum of
      visual pigments.
AB  - We relate the collected experimental data on the minimum energy for
      photoactivation (E(a)) to the wavelengths of peak absorbance (lambda(max)) of 12
      visual pigments. The E(a) values have been determined from the temperature
      dependence of spectral sensitivity in the long-wavelength range. As shown
      previously, the simple physical idea E(a) =const. x (1/lambda(max)) (here termed
      the Stiles-Lewis-Barlow or SLB relation) does not hold strictly. Yet there is a
      significant correlation between E(a) and 1/lambda(max) (r(2)=0.73) and the
      regression slope obtained by an unbiased fit is 84% of the predicted value of the
      best SLB fit. The correlation can be decomposed into effects of A1 --> A2
      chromophore change and effects of opsin differences. For a chromophore change in
      the same opsin, studied in two A1/A2 pigment pairs, the SLB relation holds nearly
      perfectly. In seven pigments having different opsins but the same (A2)
      chromophore, the correlation of E(a) and 1/lambda(max) remained highly
      significant (r(2)=0.78), but the regression coefficient is only 72% of the best
      SLB fit. We conclude that (1) when the chromophore is exchanged in the same
      opsin, the lambda(max) shift directly reflects the difference in photoactivation
      energies, (2) when the opsin is modified by amino acid substitutions, lambda(max)
      and E(a) can be tuned partly independently, although there is a dominant tendency
      for inverse proportionality. In four (A1) rhodopsins with virtually the same
      lambda(max), E(a) varied over a 4.5 kcal/mol range, which may be taken as a
      measure of the freedom for independent tuning. Assuming that low E(a) correlates
      with high thermal noise, we suggest that the leeway in lambda(max) - E(a)
      coupling is used by natural selection to keep E(a) as high as possible in long
      wavelength-sensitive pigments, and that this is why the opsin-dependent E(a)
      (1/lambda(max))-relation is shallower than predicted.

PMID- 15183683
TI  - Monochromatic ocular wavefront aberrations in the awake-behaving cat.
AB  - Measurement of wavefront aberrations in human eyes has become a reliable,
      quantitative way of assessing the optical impact of experimental and corrective
      ocular manipulations. Wavefront measures have also been performed in several
      other species, but never in cats, an animal model of choice for many ocular
      studies. Our goal in this study was to measure wavefront aberrations reliably in
      live, awake-behaving cats in a manner that is directly comparable to that used in
      human subjects. Six adult cats (felis cattus) were trained to fixate small
      targets on a computer screen. A compact Shack-Hartmann wavefront sensor was
      aligned with each animal's pupil center and line of sight during fixation.
      Wavefront images were then collected from which the cats' ocular aberrations were
      measured up to tenth order Zernike polynomials over a 6 mm pupil. Results show
      that cat and human ocular wave aberrations were very similar. Second order
      Zernike modes accounted for more than 90% of the total wave aberration. In
      agreement with our observation that cat ocular optics were comparable with those
      of humans, the half height width of both the cat and human higher order point
      spread function was about 0.95 degrees. These results form a solid basis for
      future wavefront sensing studies aiming to quantify the effects of ocular
      manipulations in experimental animals.

PMID- 15183684
TI  - Factors affecting footsteps: contrast can change the apparent speed, amplitude
      and direction of motion.
AB  - Contrast can affect the apparent speed of a moving stimulus. Specifically, when a
      grey square drifts steadily across stationary black and white stripes, it appears
      to stop and start as its contrast changes--the so-called 'footsteps illusion'. We
      now show that what matters is the contrast of the leading and trailing edges, not
      of the lateral edges. The stripes act by altering the stimulus contrast, and are
      not merely stationary landmarks. Back and forth apparent motion appears smaller
      in amplitude at low contrasts, even on a spatially uniform (non-striped)
      surround, and this is a specific motion phenomenon, not a result of misjudging
      static position. Contrast also affects the perceived direction of a moving
      stimulus. A vertically jumping grey diamond on a surround of black and white
      quadrants appears to change its direction of movement depending on the relative
      contrast of its left-oblique versus right-oblique edges against the surround.
      Thus, the perceived direction, amplitude and speed of moving objects depend
      greatly on their luminance contrast against the surround. A model of motion
      coding is proposed to explain these results.

PMID- 15183685
TI  - Theory of texture discrimination of based on higher-order perturbations in
      individual texture samples.
AB  - This analysis addresses the issue that texture properties are defined on
      ensembles of possible textures, while psychophysical judgments of texture
      properties must be made on individual texture samples, or regions of uniform
      texture within a larger texture field. Since the basic discrimination task
      requires comparison of two sample images (or regions) specified by different
      ensemble rules, the viewer is thus required to compare the estimates of their
      ensemble statistics of single textures. This paper develops a theory of texture
      discrimination incorporating a roving local sampling window that allows the
      visual system to derive an estimate of the ensemble statistics over the window
      from any particular texture image, without the need to present multiple samples
      for evaluation. This approach to texture explains how we can have a clear sense
      that two patterns derive from different statistical generation rules even though
      we see only one example of each type. In providing the theoretical basis for
      texture discrimination of individual samples, this analysis goes beyond previous
      work to account for our intuitive sense that we can estimate the generation rule
      underlying particular textures. It also analyzes the decision process for
      discriminating texture boundaries in extended images, defining a novel "Gregorian
      attractor" that replaces and extends standard Bayesian decision rules.

PMID- 15183686
TI  - Beyond fourth-order texture discrimination: generation of extreme-order and
      statistically-balanced textures.
AB  - Julesz introduced the concept of statistically defined textures and their
      perceptual discrimination. Julesz showed that discrimination was possible with
      statistics equated to third-order, specifying fourth-order textures. Klein and
      Tyler offered a variety of paradigms suggesting that fourth order might be the
      limit on human texture processing. To go beyond this limit, new texture paradigms
      are now introduced to avoid contamination by luminance extrema, to control local
      and long-range texture properties, and to provide textures without global
      statistical structure. Local luminance contamination is avoided by novel
      orientation plaids, in which higher-order rules govern the orientation of local
      elements rather than their coloring. These textures allow evaluation of texture
      discrimination up to thirty-second order by cortical pattern elements. Long-range
      processing is studied by random strip rotation and by interlacing of independent
      textures. Each substantially degrades the visibility of the fourth-order
      textures, revealing that the fourth-order information is conveyed largely by
      local rather than long-range perturbations from random statistics. Finally,
      textures equated at all orders can be defined in terms of their global
      statistics, but may nevertheless readily be discriminated in human vision. The
      discrimination on the basis of local perturbations implies that human vision
      assesses textures through a local sampling window, and is largely insensitive to
      longer-range statistical properties.

PMID- 15183687
TI  - Dexamethasone, BMP-2, and 1,25-dihydroxyvitamin D enhance a more differentiated
      osteoblast phenotype: validation of an in vitro model for human bone marrow
      derived primary osteoblasts.
AB  - In vitro models of bone cells are important for the study of bone biology,
      including the regulation of bone formation and resorption. In this study, we have
      validated an in vitro model of human osteoblastic cells obtained from bone marrow
      biopsies from healthy, young volunteers, aged 20-31 years. Osteoblast phenotypes
      were induced by either dexamethasone (Dex) or bone morphogenetic protein-2 (BMP
      2). Bone marrow was obtained from biopsies at the posterior iliac spine. Cells
      were isolated by gradient centrifugation and grown to confluence. Cells were
      treated with 1 nM 1,25-dihydroxyvitamin D (vitamin D), 100 nM Dex, and/or 100
      ng/ml BMP-2. The osteoblast phenotype was assessed as alkaline phosphatase (AP)
      activity/staining, production of osteocalcin and procollagen type 1 (P1NP),
      parathyroid hormone (PTH)-induced cyclic adenosine mono-phosphate (cAMP)
      production, and in vitro mineralization. AP activity was increased by Dex, but
      not by BMP-2 treatment. P1NP production was decreased after Dex treatment, while
      BMP-2 had no effect on P1NP levels. Osteocalcin production was low in cultures
      not stimulated with vitamin D. Dex or BMP-2 treatment alone did not affect the
      basic osteocalcin levels, but in combination with vitamin D, BMP-2 increased the
      osteocalcin production, while Dex treatment completely suppressed osteocalcin
      production. Further, PTH-induced cAMP production was greatly enhanced by Dex
      treatment, whereas BMP-2 did not affect cAMP production. Finally, in vitro
      mineralization was greatly enhanced in cultures enriched with either BMP-2 or
      Dex. Cell proliferation was only increased significantly by Dex treatment. In
      conclusion, the model described produces cells with an osteoblastic phenotype,
      and both Dex and BMP-2 can be used as osteoblast inducers. However, the two
      treatments produce osteoblastic cells with different phenotypic characteristics,
      and a selective activation of some of the most important genes and functions of
      the mature osteoblast can thus be performed in vitro.

PMID- 15183688
TI  - Efficient routes to epimerically-pure side-chain derivatives of lanosterol.
AB  - A technically simple route is described to individual epimers of side-chain
      derivatives of lanosterol (3beta-hydroxy-5alpha-lanosta-8,24-diene). Epimerically
      pure 24,25-epoxy-, 24,25-dihydroxy- and 24-bromo-25-hydroxy-lanosterol have been
      prepared in good yield from commercial (50-60%) lanosterol. Hypophosphorous acid
      was used as a catalyst for the cohalogenation of the Delta24(25) bond and also
      for the efficient conversion of 24,25-epoxy- and 24-bromo-25-hydroxylanosterol to
      epimerically pure 24(R) or 24(S)-24,25-dihydroxylanosterols.

PMID- 15183689
TI  - Characterization of stable human aromatase expressed in E. coli.
AB  - Aromatase (P450arom, CYP19) catalyzes the aromatization reaction that converts
      androgens to estrogens. Although human P450arom has been readily purified from
      placenta, its hydrophobic properties and instability has hampered detailed
      characterization. Utilizing a N-terminal replacement (MARQSFGRGKL, derived from
      CYP2C11), we successfully modified this unstable enzyme into stable forms. Based
      on a known polymorphism, we created two constructs, NmA264C and NmA264R having
      cysteine or arginine at position 264. The recombinant P450arom NmA264R was
      expressed in Escherichia coli (350-400 nmol/L culture) primarily by coexpression
      with molecular chaperones GroES/GroEL while NmA264C was expressed (240 nmol/L
      culture) only in the presence of chloramphenicol. Although NmA264C was recovered
      only in the membrane fraction, approximately 14% of NmA264R was recovered in the
      cytosolic fraction, suggesting that NmA264R is more hydrophilic than NmA264C.
      NmA264R was highly purified to the specific content 13.6 nmol P450/mg protein.
      Purified P450arom NmA264R converted androstenedione to estrone with Vmax 12.4
      nmol/(min nmol) and Km) 0.26 microM, and testosterone to estradiol with Vmax 52.2
      nmol/(min nmol) and Km 10.9 microM. Because of the increased stability of
      NmA264R, we could unambiguously determine properties of human P450arom by optical
      and electron paramagnetic resonance spectroscopy. The purified protein was a
      typical low-spin form, which was converted to a high-spin form when
      androstenedione was added. The rhombicity of substrate-bound forms was higher
      than that reported for other P450s, an interesting characteristic of human
      P450arom. The highly stable and active P450arom NmA264R sets the stope for
      detailed structure/function analyses of this important member of the P450
      superfamily.

PMID- 15183690
TI  - A novel enzyme-linked immunosorbent assay for ethynylestradiol using a long-chain
      biotinylated EE2 derivative.
AB  - Ethynylestradiol (EE2) is one of the most potent endocrine disrupting compounds
      capable to induce estrogenic effects even at trace level concentrations in the
      aquatic environment. Methods for detecting EE2 in such concentrations are
      generally based on GC or HPLC coupled to at least one mass spectrometer. Another
      approach are immunoassays and sensor systems but for most designs, derivatives of
      EE2 are required (e.g. for coupling to carrier proteins, enzyme or fluorescent
      labels, etc.). Here we present the straightforward synthesis and complete
      characterization of a new long-chain biotinylated EE2 derivative. The new EE2
      derivative is used as tracer in a direct competitive enzyme-linked immunosorbent
      assay (ELISA) for the determination of EE2. With pure water, the limit of
      detection (LOD, signal-to-noise ratio, S/N = 3) and the test midpoint were found
      to be 14 and 136 ng l(-1), respectively. Cross reactivity (CR) was tested for 10
      endogenous steroids and the BSA-conjugate used for immunization, as well as a
      synthetic precursor of the conjugate. Among the naturally occurring compounds, CR
      was determined to be maximum for metabolites of EE2 conjugated at ring-position 3
      (17% and 37% for 3-glucuronide and 3-sulphate, respectively). Assay stability was
      tested against humic substances and organic solvents. Increasing amounts of
      organic solvents in the sample caused a clear decrease in sensitivity, presence
      of humic substances lead to an overestimation of EE2.

PMID- 15183691
TI  - A gas chromatography/mass spectrometry assay to measure estradiol,
      catecholestradiols, and methoxyestradiols in plasma.
AB  - We have developed a gas chromatography/mass spectrometry (GC/MS) assay to measure
      17beta-estradiol (E) and its biologically active metabolites 2-hydroxyestradiol
      (2OHE) and 4-hydroxyestradiol (4OHE), and 2-methoxyestradiol (2MEOE) and 4
      methoxyestradiol (4MEOE) in rat plasma. All analytes are well separated and show
      a linear relationship between concentration (0.25-5 pg/microl) and signal, and
      coefficients of variation (CVs) are low. Intra-assay CV for the lowest quality
      control samples (QCs) (0.375 pg/microl) were on average for 17beta-estradiol
      20.5%, for 2-hydroxyestradiol 15.6%, for 4-hydroxyestradiol 16.5%, for 2
      methoxyestradiol 16.5%, and for 4-methoxyestradiol 11.5%. The inter-assay CVs for
      the lowest QCs were for 17beta-estradiol 12.1%, for 2-hydroxyestradiol 7.1%, for
      4-hydroxyestradiol 15.5%, for 2-methoxyestradiol 16.7%, and for 4
      methoxyestradiol 9.7%. The highest sensitivity for this assay was observed for
      hydroxyestradiols followed by the methoxyestradiols and 17beta-estradiol. In
      summary, we describe a convenient, sensitive, and specific assay to measure
      17beta-estradiol and its biologically active metabolites.

PMID- 15183692
TI  - Effect of estradiol on expression and activation of Akt protein in rat
      hypothalamus exposed to chronic [D-Met2, Pro5]-enkephalinamide treatment.
AB  - Adult ovariectomized rats were implanted with [D-Met2, Pro5]-enkephalinamide
      (ENK)-containing osmotic minipumps. Two hours prior to sacrifice, some animals
      were treated with estradiol-17beta (E2) at a dose 10 microg/100 g bodyweight
      (BW). Expression and activation of Akt proteins, nuclear [3H]estradiol binding,
      and the expression of estrogen receptor alpha (ERalpha) and beta (ERbeta) and of
      progesterone receptor (PR) were investigated. Estradiol increased the level of
      activated Akt protein (pAkt473) in the hypothalamus by 52 +/- 11% in comparison
      to the vehicle-treated controls. No such effect of E2 was observed 24 and 48 h
      after ENK implantation. This effect of ENK was abolished by concomitant treatment
      with naloxone. Time-dependent changes in nuclear [3H]estradiol binding and the
      expression of estrogen and progesterone receptors were also detected in the
      hypothalamus of ENK-implanted and E2-treated rats. At 24-48 h following ENK
      implantation, expression of ERalpha and high affinity [3H]estradiol binding
      decreased. At this time point, the PR level was also reduced, while the ERbeta
      level was augmented. In conclusion, these results suggest that the stimulatory
      effects of E2 on the expression and activation of Akt protein and the expression
      of ERalpha and PR are negatively regulated in rat hypothalamus exposed to chronic
      ENK treatment.

PMID- 15183693
TI  - Selective ring-opening carbonylation of epoxy-steroids.
AB  - Ring-opening alkoxycarbonylation of epoxy-steroids has been carried out with a
      Co2(CO)8/3-hydroxypyridine catalytic system. High chemo- and regioselectivities
      were obtained under the reaction conditions applied. Structural analysis of the
      products proved their high stereochemical purity in each case, accompanied by
      inversion of the original configuration. No carbonylation took place for
      sterically hindered steranic epoxides.

PMID- 15183694
TI  - Dehydroepiandrosterone stimulates nitric oxide release in vascular endothelial
      cells: evidence for a cell surface receptor.
AB  - Dehydroepiandrosterone (DHEA) improves vascular function, but the mechanism of
      this effect is unclear. Since nitric oxide (NO) regulates vascular function, we
      hypothesized that DHEA affects the vasculature by increasing endothelial NO
      production. Physiological concentrations of DHEA stimulated NO release from
      intact bovine aortic endothelial cells (BAEC) within 5min. This effect was
      mediated by activation of endothelial nitric oxide synthase (eNOS) in BAEC and
      human umbilical vein endothelial cells (HUVEC). Dehydroepiandrosterone increased
      cyclic GMP (cGMP) levels in BAEC, consistent with its effect on NO production.
      Albumin-conjugated DHEA also stimulated NO release, suggesting that DHEA
      stimulates eNOS by a plasma membrane-initiated signal. Tamoxifen blocked estrogen
      stimulated NO release from BAEC, but did not inhibit the DHEA effect. Pertussis
      toxin abolished the acute effect of DHEA on NO release. Dehydroepiandrosterone
      had no effect on intracellular calcium fluxes. However, inhibition of tyrosine
      kinases or the mitogen-activated protein (MAP) kinase kinase (MEK) blocked NO
      release and cGMP production in response to DHEA. These findings demonstrate that
      physiological concentrations of DHEA acutely increase NO release from intact
      vascular endothelial cells, by a plasma membrane-initiated mechanism. This action
      of DHEA is mediated by a steroid-specific, G-protein coupled receptor, which
      activates eNOS in both bovine and human cells. The release of NO is independent
      of intracellular calcium mobilization, but depends on tyrosine- and MAP kinases.
      This cellular mechanism may underlie some of the cardiovascular protective
      effects proposed for DHEA.

PMID- 15183695
TI  - New polyoxygenated steroids from the Antarctic octocoral Dasystenella acanthina.
AB  - The chemical study of the Antarctic octocoral Dasystenella acanthina has led to
      the isolation of the new polyoxygenated steroids (24R,22E)-24-hydroxycholest-4,22
      dien-3-one (1), 23-acetoxy-24,25-epoxycholest-4-en-3-one (2), 12beta
      acetoxycholest-4-en-3,24-dione (3), 12beta-acetoxy-24,25-epoxycholest-4-en-3-one
      (4), (22E)-25-hydroxy-24-norcholest-4,22-dien-3-one (5), 3alpha-acetoxy-25
      hydroxycholest-4-en-6-one (6), and 3alpha,11alpha-diacetoxy-25-hydroxycholest-4
      en-6-one (7), whose structures have been established by spectroscopic analysis.
      The absolute stereochemistry at C-24 in compound 1 has been determined through
      the 1H NMR study of the corresponding (R)- and (S)-MPA esters. All the new
      compounds showed significant activities as growth inhibitors of several human
      tumor cell lines. In addition, cytostatic and cytotoxic effects were also
      observed on selected tumor cell lines.

PMID- 15183696
TI  - Computer aided orthopedic surgery (CAOS) -- a rapidly evolving technology.

PMID- 15183697
TI  - Letter of the reviewers--update on CAOS projects.

PMID- 15183698
TI  - Basic principles of CAOS.
AB  - The term computer aided orthopedic surgery (CAOS) stands for approaches that aim
      to improve visibility to the surgical field and increase application accuracy by
      means of so-called navigation systems alone or in combination with smart end
      effectors when carrying out surgical actions. These goals achieved by linking the
      bony anatomy being operated on with a virtual representation, such as an image
      dataset. This article introduces the basic principles of CAOS. Surgical
      navigation systems that use modern tracking technology are introduced and
      classified according to the chosen virtual representation of the surgical object,
      ie, image-free and image-based (preoperative and intraoperative) technology.
      Within the latter class in particular, CT-and fluoroscopy-based (2-D and 3-D)
      systems have successfully made their way into the operating room (OR). Challenges
      during the development of the underlying enabling technologies are presented and
      references to orthopedic applications in different anatomical areas are given.

PMID- 15183699
TI  - Potential pitfalls of computer aided orthopedic surgery.
AB  - Computer aided orthopedic surgery (CAOS) systems are becoming more and more
      frequently used in operating rooms all over the world. While their clinical
      benefit is no longer doubted, there is considerable potential for using these
      devices incorrectly At best, mishandling of a CAOS system may lead to prolonged
      operating times. In the worst case scenario, incorrect navigational feedback is
      provided, which carries the potential risk of endangering the patient or
      resulting in an unacceptable surgical outcome. From an economical point of view
      only the optimal performance of a navigation system will probably justify its
      significant investment costs. This article summarizes some of the major pitfalls
      that may occur during surgical navigation. It is structured to reflect different
      types of CAOS systems, and it presents guidelines on how to avoid most of the
      problems. In general, a surgeon who wants to apply this technology needs to be
      very familiar with the system that is used. It is essential to know the basics
      and the limitations of the underlying technical principles. Otherwise, the large
      potential that modern CAOS systems make available cannot be exploited effectively
      for the benefit of the patient.

PMID- 15183700
TI  - Modality-based navigation.
AB  - Modality-based navigation (MBN) means the interactive tracking of instruments in
      a co-ordinate system defined by an imaging modality, eg, CT, MR, or a
      fluoroscope. During the registration process, a transformation matrix between the
      two co-ordinate systems of the digitizer and imaging modality is calculated.
      Navigation can start immediately after collection of the images without an
      intraprocedural registration process. Since the imaging modality belongs to the
      OR or the intervention suite, image update can be performed at any time.
      Following a step-by-step procedure with navigation and image update in a
      reasonable sequence, the risk for a virtual-real mismatch is minimized. For CT
      MBN, we obtained a freehand absolute positioning accuracy of 1.9+/-1.1 mm in
      vitro. The in vivo freehand absolute positioning accuracy in pelvic fracture
      fixation was determined to be 3.1 mm (unpublished data). From our point of view,
      modality-based navigation is an efficient and safe alternative tool for computer
      aided interventions.

PMID- 15183701
TI  - Which navigation when?
AB  - If a surgeon is considering purchasing a navigation system, several factors have
      to be evaluated including, the planned applications, the equipment already
      installed, and the specific knowledge of the surgeon. For use in traumatology,
      fluoroscopy and more specifically 3-D fluoro-based computer guidance is
      preferable. These technologies are based on intraoperative acquired arbitrary
      images in contrast to CT-based techniques, which refer to preoperative acquired
      images that represent a so called "cannel reality". However, image quality has to
      be considered as fluoro-picture quality depending on the anatomical area (eg long
      bones, spine, pelvis) and body mass index. CT-based navigation provides better
      image quality and accuracy but is not able to visualize reduction processes.
      Therefore personal experience in courses or by on-site teaching is recommended
      prior taking the decision.

PMID- 15183702
TI  - Navigation at the spine.
AB  - Computer aided and computer navigated operative techniques have been used for the
      first time in neurosurgery and surgery of the spine. For computer aided surgery
      of the spine there are currently two different methods: CT-based and C-arm based
      techniques. The advantage of the CT-based technique is its accuracy especially in
      difficult anatomical regions like the cervical and upper thoracic spine, and the
      possibility of preoperative planning. The advantage of C-arm navigation is the
      broad intraoperative availability with the disadvantage of limited image quality
      in some regions of the spine eg, the upper thoracic spine. This last disadvantage
      has been dramatically improved by introducing 3-D C-arm navigation (ISO C 3-D,
      Siemens, GER). Generally, all methods enhance the precision of pedicle screw
      insertion. Clinical as well as experimental studies show an exact pedicle screw
      position using the computer navigated techniques in over 90% of cases. C-arm
      based navigational techniques are being constantly improved and the future will
      be CT-like images with instant intraoperative availability.

PMID- 15183703
TI  - Clinical applications--pelvis.
AB  - Navigation procedures based on CT data were introduced into spinal surgery in
      1994. Since then, the method has been used in other areas such as joint
      replacement, reconstructive surgery, and tumor surgery because of its high
      precision and reduced radiation exposure. The original CT-based spine module can
      be adjusted for pelvic surgery with the prerequisite that the positioning of the
      fragments is identical in CT and in the OR; otherwise a new dataset has to be
      acquired. Our experiences with CT-based navigation in pelvic surgery are
      explained on five percutaneous screw fixations and three tumor resections,
      including description of the technique. For modality-based navigation, the
      navigated procedure is performed in the CT suite with the advantage of immediate
      CT control of reduction quality and screw positioning. The technique is explained
      and illustrated on two cases. Fluoroscopy-based navigation has been used in
      trauma surgery since the late nineties. Since then, the method has been wide
      spread in the field of joint replacement and reconstructive surgery. Between June
      2000 and December 2002, we performed 36 percutaneous screw fixations in the
      pelvis with postoperative x-ray and CT control. 35 of the 36 screws were placed
      correctly. In one screw, an anterior cortex perforation of the sacrum was seen in
      the CT without any neurological consequences. The Iso C 3-D fluoroscope has
      recently been approved for pelvic surgery. With the ability to reconstruct
      images, visualization of the acetabulum and the posterior pelvic ring, there is
      marked an improvement compare to conventional 2-D fluoroscopy. Thus, the field
      for navigation is also enhanced. Based on our clinical experiences, the
      indications for navigated techniques in pelvic and acetabular surgery are defined
      and illustrated.

PMID- 15183704
TI  - Computer aided long bone fracture treatment.
AB  - Intraoperative fluoroscopy is the tool for intraoperative control of long bone
      fracture reduction and osteosynthesis. Limitations of this technology include:
      High radiation exposure to the patient and the surgical team, limited field of
      view, image distortion, limitation to 2-D representations, and cumbersome
      updating of verification images. Fluoroscopy based navigation systems partially
      address these limitations by allowing fluoroscopic images to be used for real
      time surgical localization and instrument tracking. In a clinical study on
      computer guidance by virtual fluoroscopy for distal locking, the capability to
      provide online guidance with significantly reduced fluoroscopy times is
      demonstrated. Virtual fluoroscopy applied for guidewire placement in a laboratory
      setup demonstrated the potential of the method to reduce procedure times, and the
      potential to increase precision of implant placement with decreased fluoroscopy
      times. By using virtual reality enhancement, starting from multiple registered
      fluoroscopy images, a virtual 3-D cylinder model for each principal bone fragment
      is reconstructed. This spatial cylinder model is not only used to supply a 3-D
      image of the fracture, but also allows effective fragment projection extraction
      from the fluoroscopic images and further achieves radiation-free updates of in
      situ surgical fluoroscopic images through a non-linear interpolation and warping
      algorithm. After primary image acquisition, the image intensifier was replaced by
      the virtual reality system. It was shown that all the steps of the procedure,
      including fracture reduction and LISS osteosynthesis can be performed completely
      in virtual reality.

PMID- 15183705
TI  - Computer aided ACL reconstruction.
AB  - The following article gives a clinical description of computer aided ACL
      reconstruction using the Praxim Medivision tool. The special feature of this
      navigation is the existence of the possibility to virtually graft the
      implantation without first having to attach anchoring channels, which allows
      potential risks to be recognized and thus avoided. This description meets with
      the current operating techniques of the 4-fold semitendinosus technique, and of
      extra-cortical anchoring with the endobutton/suture disc technique.

PMID- 15183706
TI  - Computer aided high tibial open wedge osteotomy.
AB  - High tibial osteotomy is a widely accepted treatment of medial compartment
      osteoarthritis as well as other lower extremity deformities. However, it is a
      technically demanding procedure. The lack of exact intraoperative real time
      control of the mechanical axis often results in postoperative malalignments,
      which is one reason for poor long term results. These problems can be addressed
      with the use of a surgical navigation system. Following exposure, dynamic
      reference bases (DRBs) are attached to the femur, and the proximal and the distal
      part of the tibia. After intraoperative measurement of the deformities and
      correction planning, the osteotomy is performed under navigational guidance. The
      wedge size, joint line orientation, and tibial plateau slope are monitored during
      correction. The in vitro evaluation with a plastic bone model suggests that the
      error of deformity correction is less than 1.7 degrees (95% confidence limits) in
      the frontal, and less than 2.3 degrees (95% confidence limits) in the sagittal
      plane, respectively. On a cadaver study of 13 legs, the mechanical axis
      intersected the Fujisawa line in 80.7% (range 77.5-85.8%). The preliminary
      clinical experience confirms these results. A novel computer tomography free
      navigation system for high tibial osteotomy has been developed that holds the
      promise of improving the accuracy, reliability, and safety of this kind of
      approach.

PMID- 15183707
TI  - Computer aided tumor resection in the pelvis.
AB  - Surgical treatment of malignant tumors within the pelvis is a complex problem due
      to the anatomy and biomechanics. There are standardized preoperative diagnostic
      tools like computed tomography (CT) or magnetic resonance imaging (MRI) that
      provide multidimensional information. However, this information cannot be
      transferred intraoperatively. Computer aided orthopedic surgery (CAOS) may be a
      solution for precise intraoperative accuracy for these indications. We report on
      two patients with tumors within the pelvis. In one patient, an infiltrating
      recurrent chordoma within the sacrum was resected with CAOS. The other patient
      presented with a periacetabular chondrosarcoma. Resection was done with
      navigation so precise that a custom-made hemipelvis prosthesis with a special
      coating fit. In both patients, a complete resection was achieved with tumor-free
      resection margins. Navigation may be helpful in tumor surgery within the pelvis.

PMID- 15183708
TI  - Joint replacement-total hip replacement with CT-based navigation.
AB  - Correct orientation of the cup optimizes the range of motion of total hip
      arthroplasty (THA) and reduces the risk of dislocation, wear, impingement,and
      pelvic osteolysis. Therefore, CT-based navigation is used to position the
      acetabular cup precisely in a planned orientation relative to predefined bony
      landmarks in order to increase the function and longevity of THA. METHODS:
      Fourteen patients were operated on using CT-based navigation for acetabular cup
      positioning. After scanning the patient's pelvis in a preoperative CT, a3-D plan
      was developed before surgery. Intraoperatively, the CT/3-D model is registered to
      coincide with the actual position of the patient on the operating table. RESULTS:
      Mean time for surgery increased by an average of 46 minutes and mean blood loss
      increased by 140 ml. Positioning of the cup was optimized, ie, it was close to
      the predefined target. There were no complications related to the use of CT-based
      navigation. Due to some technical failures at the beginning, two operations were
      completed manually. CONCLUSION: CT-based navigation greatly enhanced the
      precision of cup positioning,thus eliminating malpositioning. Although CT-based
      navigation does support the surgeon in controlling cup orientation, it increases
      time for surgery, blood loss, radiation of the patient, and total costs of the
      whole procedure. Furthermore,navigation of the acetabular cup alone is not
      sufficient for optimizing the range of motion in THA.

PMID- 15183709
TI  - C-arm based navigation in total hip arthroplasty-background and clinical
      experience.
AB  - After experimental and preclinical evaluation of a CT-free image guided surgical
      navigation system for acetabular cup placement, the system was introduced into
      clinical routine. The computation of the angular orientation of the cup is based
      on reference coordinates from the anterior pelvic plane concept. A hybrid
      strategy for pelvic landmark acquisition has been introduced, involving
      percutaneous pointer-based digitization with the noninvasive bi-planar landmark
      reconstruction using multiple registered fluoroscopy images. From January 2001 to
      October 2003, a total of 236 consecutive patients (mean age 66 years, 144 male,
      92 female, 124 left and 112 right hip joints) were operated on with the hybrid CT
      free navigation system. During each operation, the angular orientation of the
      inserted implant was recorded. To determine the placement accuracy of the
      acetabular components, the first 50 consecutive patients underwent a CT scan 7-10
      days postoperatively to analyze the cup position relative to the anterior pelvic
      plane. This procedure was done blinded and with commercial planning software.
      There was no significant learning curve observed for the use of the system. Mean
      values for postoperative inclination read 42 degrees (SD 3.6, range (37-49)) and
      anteversion 21 degrees (SD 3.9, range (10-28)). The resulting system accuracy,
      ie, the difference between intraoperatively calculated cup orientation and
      postoperatively measured implant position shows a maximum error of 5 degrees for
      the inclination (mean 1.5 degrees, SD 1.1) and 6 degrees for the anteversion
      (mean 2.4 degrees, SD 1.3). An accuracy of better than 5 degrees inclination and
      6 degrees anteversion was achieved under clinical conditions, which implies that
      there is no significant difference in performance from the established CT-based
      navigation methods. Image-guided CT-free cup navigation provides a reliable
      solution for future total hip arthroplasty (THA).

PMID- 15183710
TI  - Computer aided reduction and imaging.
AB  - Reduction is one of the key procedures in orthopedic trauma surgery and has been
      acknowledged as one of the conditions for a good outcome in intraarticular and
      extra-articular fractures. The information available to the surgeon during the
      reduction maneuver can be divided into visual and tactile information. The
      optimal implementation of these parameters, combined with the surgeon's
      individual experience, will significantly affect the results of the operation.
      Anatomical regions where a limited direct view through the approach is supported
      by intraoperative imaging are intra-articular fractures of the elbow, forearm,
      acetabulum, proximal tibia, pilon, and hindfoot, and extra-articular fractures of
      the spine, pelvis, femur, and tibial shaft. Surgery in these regions is demanding
      since the approaches limit the visual control of the axes and also the anatomical
      reduction within the joint. Computer aided orthopedic surgery (CAOS) was
      introduced to increase the accuracy of selected procedures in orthopedic surgery.
      One of the most frequently applied applications is pedicle screw insertion in
      posterior spinal surgery. The current working group has identified computer aided
      reduction and implant positioning as an unresolved area of CAOS that would be
      highly relevant to the operative treatment of fractures. The development of tools
      for computer aided reduction is of major importance and is much desired by the
      orthopedic community. Such a reduction tool would be a significant step forward
      in the development of orthopedic trauma care. It would facilitate new procedures
      and new operations and also help to attain a completely new level with regard to
      what we can achieve in terms of minimal invasiveness and increased precision. The
      synergies of the expert group are deployed to develop the required software
      modules and hardware. Other areas of computer aided orthopedic surgery will
      certainly benefit from the integration of this technology as well.

PMID- 15183711
TI  - New method to assess the registration of CT-MR images of the head.
AB  - Due to their complementary information content, both x-ray computed tomography
      (CT) and magnetic resonance (MR) imaging are employed in certain clinical cases
      to improve the understanding of pathology involved. o spatially relate the two
      datasets, image registration and image fusion are employed. However, registration
      errors, either global or local, are common and are nonuniform within the image
      volume. In this paper, we propose a new algorithm that assesses the quality of
      the registration locally within the CT-MR volume and provides visual, color-coded
      feedback to the user about the location and extent of good and bad correspondence
      between the two images. The proposed registration assessment algorithm is based
      on a correspondence analysis of bone structures in the CT and MR images. For that
      purpose, a custom segmentation algorithm for bone in MR images has been developed
      that is based on a stochastic threshold computation method. This segmentation
      method for MR images and the CT-MR registration assessment algorithm were
      validated on simulated MR datasets and real CT-MR image pairs of the head. Some
      partial-volume effects occur at the borders of the bone structures and at the
      bone interfaces with air, which cannot be separated from bone in the MR image.
      The presented assessment method of CT-MR image registration offers the user a new
      tool to evaluate the overall and local quality of the registration. With this
      information, the user does not have to blindly trust the fused CT-MR datasets but
      can easily identify areas of inaccurate correspondence. The application of the
      algorithm is so far limited to T1-weighted MR and CT images of the head area.

PMID- 15183712
TI  - Reduction of femoral shaft fractures in vitro by a new developed reduction robot
      system 'RepoRobo'.
AB  - Closed reduction of the long bones is associated with the use of considerable
      force. This force must be maintained for the reduction maneuver and fixation
      process. At present, apart from the extension table or the large AO distractor,
      only rather inadequate reduction aids are available. A solution to this problem
      is being sought in the form of a robotic system with which precision can be
      improved and the holding effort reduced. In the research project presented here,
      a synthetic femur with integrated tensioned mainspring and a 32-A3 type fracture
      served as a bone reduction model. The fracture was stabilized with a standard AO
      fixator. A Staubli robot (model RX130) was converted by appropriate modification
      so that it could be used for the reduction of femoral shaft fractures in vitro.
      The robot was equipped with a pneumatic 2-fingered gripper, on which the fingers
      have been modified so that they can grip the AO fixator clamp. A Force-Feedback
      Sensor was inserted between the gripper and the robot to obtain online recordings
      of the forces and moments in all three axes. With this setup it is possible to
      achieve precise reduction of the fracture in all planes under visual control.

PMID- 15183713
TI  - The MEPUC concept adapts the C-arm fluoroscope to image-guided surgery.
AB  - Image-guided surgery requires surgeons to be able to manipulate the imaging
      modality themselves and without delay. Intraoperative fluoroscopic imaging does
      not meet this requirement as the C-arm fluoroscope cannot be operated or
      positioned by the surgeons themselves. The Motorized Exact Positioning Unit for C
      arm (MEPUC) concept aims to optimize the workflow of positioning the C-arm
      fluoroscope. The hardware component of the MEPUC equips the fluoroscope with
      electric stepping motors. The software component allows the surgeon to control
      the fluoroscope's movements. The study presented here showed that translational
      movements within the x-y plane are most frequently performed when positioning the
      C-arm fluoroscope. Furthermore, reproducing a former projection was found to be a
      frequent task during image-guided procedures. In our opinion, the MEPUC concept
      adapts the fluoroscope to image-guided surgery. The most important improvement
      being definition of a bidirectional data exchange between the surgeon and the C
      arm fluoroscope: positioning data from the surgeon to the C-arm fluoroscope and
      subsequently-image information from C-arm fluoroscope to the surgeon.

PMID- 15183714
TI  - Aberrant endosperm development in interploidy crosses reveals a timer of
      differentiation.
AB  - The common assumption that the seed failure in interploidy crosses of flowering
      plants is due to parental genomic imprinting is based on vague interpretations
      and needs reevaluation since the general question is involved, how
      differentiation is timed so that cell progenies, while specializing, pass through
      proper numbers of amplification divisions before proliferation ceases. As
      recently confirmed, endosperm differentiation is accelerated or de-accelerated,
      depending upon whether polyploid females are crossed with diploid males, or vice
      versa. Unlike the zygote, the first cell of the endosperm is determined to
      produce a tissue that successively induces growth of maternal tissues, stimulates
      and nourishes the embryo, and finally ceases cell cycling. Altered timing of
      endosperm differentiation, thus, perturbs seed development. During fertilization,
      only the female genomes contribute cytoplasmic equivalents to endosperm
      development so that in interploidy crosses, the initial amount of cytoplasm per
      chromosome set is altered, and due to semi-autonomy of cytoplasmic growth,
      altered numbers of division cycles are needed to provide the amount of
      cytoplasmic organelles required for differentiation. Cytoplasmic semi-autonomy
      and dependence of differentiation on an increase in cytoplasm has been shown in
      other tissues of plants and animals, thus, revealing a common mechanism for
      intracellular timing of differentiation. As demonstrated, imprinted genes can
      alter the extent of cell proliferation by interfering with this mechanism.

PMID- 15183715
TI  - The Drosophila fragile X-related gene regulates axoneme differentiation during
      spermatogenesis.
AB  - Macroorchidism (i.e., enlarged testicles) and mental retardation are the two
      hallmark symptoms of Fragile X syndrome (FraX). The disease is caused by loss of
      fragile X mental retardation protein (FMRP), an RNA-binding translational
      regulator. We previously established a FraX model in Drosophila, showing that the
      fly FMRP homologue, dFXR, acts as a negative translational regulator of
      microtubule-associated Futsch to control stability of the microtubule
      cytoskeleton during nervous system development. Here, we investigate dFXR
      function in the testes. Male dfxr null mutants have the enlarged testes
      characteristic of the disease and are nearly sterile (>90% reduced male
      fecundity). dFXR protein is highly enriched in Drosophila testes, particularly in
      spermatogenic cells during the early stages of spermatogenesis. Cytological
      analyses reveal that spermatogenesis is arrested specifically in late-stage
      spermatid differentiation following individualization. Ultrastructurally, dfxr
      mutants lose specifically the central pair microtubules in the sperm tail
      axoneme. The frequency of central pair microtubule loss becomes progressively
      greater as spermatogenesis progresses, suggesting that dFXR regulates microtubule
      stability. Proteomic analyses reveal that chaperones Hsp60B-, Hsp68-, Hsp90
      related protein TRAP1, and other proteins have altered expression in dfxr mutant
      testes. Taken together with our previous nervous system results, these data
      suggest a common model in which dFXR regulates microtubule stability in both
      synaptogenesis in the nervous system and spermatogenesis in the testes. The
      characterization of dfxr function in the testes paves the way to genetic screens
      for modifiers of dfxr-induced male sterility, as a means to efficiently dissect
      FMRP-mediated mechanisms.

PMID- 15183716
TI  - Converse control of oligodendrocyte and astrocyte lineage development by Sonic
      hedgehog in the chick spinal cord.
AB  - In the developing spinal cord, oligodendrocyte progenitors (OLPs) originate from
      the ventral neuroepithelium and the specification of this lineage depends on the
      inductive activity of Sonic hedgehog (Shh) produced by ventral midline cells. On
      the other hand, it has been shown that OLP identity is acquired by the
      coexpression of the transcription factors olig2 and nkx2.2. Although initially
      expressed in adjacent nonoverlapping domains of the ventral neuroepithelium,
      these transcription factors become coexpressed in the pMN domain at the time of
      OLP specification through dorsal extension of the Nkx2.2 domain. Here we show
      that Shh is sufficient to promote the coexpression of Olig2 and Nkx2.2 in
      neuroepithelial cells. In addition, Shh activity is necessary for this
      coexpression since blocking Shh signalling totally abolishes Olig2 expression and
      impedes dorsal extension of Nkx2.2. Although Shh at these stages affects
      neuroepithelial cell proliferation, the dorsal extension of the Nkx2.2 domain is
      not due to progenitor proliferation but to repatterning of the ventral
      neuroepithelium. Finally, Shh not only stimulates OLP specification but also
      simultaneously restricts the ventral extension of the astrocyte progenitor (AP)
      domain and reduces astrocyte development. We propose that specification of
      distinct glial lineages is the result of a choice that depends on Shh signalling.

PMID- 15183717
TI  - NELL2 promotes motor and sensory neuron differentiation and stimulates
      mitogenesis in DRG in vivo.
AB  - We previously identified a secreted glycoprotein, neural epidermal growth factor
      like like 2 (NELL2), in a subtraction screen designed to identify molecules
      regulating sensory neurogenesis and differentiation in the chick dorsal root
      ganglion (DRG). Characterization of NELL2 expression during embryogenesis
      revealed that NELL2 was specifically expressed during the peak periods of both
      sensory and motor neuron differentiation, and within the neural crest was
      restricted to the sensory lineage. We now provide evidence for a function for
      NELL2 during neuronal development. We report here that NELL2 acts cell
      autonomously within CNS and PNS progenitors, in vivo, to promote their
      differentiation into neurons. Additionally, neuron-secreted NELL2 acts
      paracrinely to stimulate the mitogenesis of adjacent cells within the nascent
      DRG. These studies implicate dual functions for NELL2 in both the cell autonomous
      differentiation of neural progenitor cells while simultaneously exerting
      paracrine proliferative activity.

PMID- 15183718
TI  - Zebrafish rx3 and mab21l2 are required during eye morphogenesis.
AB  - Two alleles of an eyeless mutant, chokh (chk), were identified in ongoing
      zebrafish F(3) mutagenesis screens. Morphologically, chk mutants can be
      identified at 15 h post-fertilization by the failure of optic primordia to
      evaginate from the forebrain. The chk phenotype appears specific, as marker genes
      in the forebrain, midbrain, and pineal are expressed in normal temporal, spatial,
      and circadian patterns. Sequence analysis of the chk alleles revealed nonsense or
      missense mutations in the rx3 homeobox. Rx genes encode paired-type homeodomain
      transcription factors known to be key regulators of eye development in mouse,
      medaka, Xenopus, and zebrafish. To uncover novel Rx targets, we analyzed the
      expression of multiple eye development genes in chk. We find that expression of
      mab21l2, mab21l1 and rx2 are specifically absent in the eye field of chk embryos.
      Knockdown of Mab21l2 by antisense morpholino microinjections partially
      phenocopies the rx3 mutation, leading to microphthalmia, incomplete eye
      maturation, and dramatic increases in apoptotic eye progenitors. We propose that
      mab21l2 is an early downstream effector of rx3 and is critical for survival of
      eye progenitors.

PMID- 15183719
TI  - The role of DE-cadherin during cellularization, germ layer formation and early
      neurogenesis in the Drosophila embryo.
AB  - The Drosophila E-cadherin homolog, DE-cadherin, is expressed and required in all
      epithelial tissues throughout embryogenesis. Due to a strong maternal component
      of DE-cadherin, its early function during embryogenesis has remained elusive. The
      expression of a dominant negative DE-cadherin construct (UAS-DE-cad(ex)) using
      maternally active driver lines allowed us to analyze the requirements for DE
      cadherin during this early phase of development. Maternally expressed DE-cad(ex)
      result in phenotype with variable expressivity. Most severely affected embryos
      have abnormalities in epithelialization of the blastoderm, resulting in loss of
      the blastodermal cells' apico-basal polarity and monolayered structure. Another
      phenotypic class forms a rather normal blastoderm, but shows abnormalities in
      proliferation and morphogenetic movements during gastrulation and neurulation.
      Mitosis of the mesoderm occurs prematurely before invagination, and proliferation
      in the ectoderm, normally a highly ordered process, occurs in a random pattern.
      Mitotic spindles of ectodermal cells, normally aligned horizontally, frequently
      occurred vertically or at an oblique angle. This finding further supports recent
      findings indicating that, in the wild-type ectoderm, the zonula adherens is
      required for the horizontal orientation of mitotic spindles. Proliferation
      defects in DE-cad(ex)-expressing embryos are accompanied by the loss of
      epithelial structure of ectoderm and neuroectoderm. These germ layers form
      irregular double or triple layers of rounded cells that lack zonula adherens. In
      the multilayered neuroectoderm, epidermal precursors, neuroblasts and ganglion
      mother cells occurred intermingled, attesting to the pivotal role of DE-cadherin
      in delamination and polarized division of neuroblasts. By contrast, the overall
      number and spacing of neuroblasts was grossly normal, indicating that DE-cadherin
      mediated adhesion is less important for cell-cell interaction controlling the
      ratio of epidermal vs. neural progenitors.

PMID- 15183720
TI  - Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and
      modulates its activity during postnatal growth in mice.
AB  - Runx2-Cbfa1, a Runt transcription factor, plays important roles during skeletal
      development. It is required for differentiation and function of osteoblasts. In
      its absence, chondrocyte hypertrophy is severely impaired and there is no
      vascularization of cartilage templates during skeletal development. These tissue
      specific functions of Runx2 are likely to be dependent on its interaction with
      other proteins. We have therefore searched for proteins that may modulate the
      activity of Runx2. The yeast two-hybrid system was used to identify a groucho
      homologue, Grg5, as a Runx2-interacting protein. Grg5 enhances Runx2 activity in
      a cell culture-based assay and by analyses of postnatal growth in mice we
      demonstrate that Grg5 and Runx2 interact genetically. We also show that Runx2
      haploinsufficiency in the absence of Grg5 results in a more severe delay in
      ossification of cranial sutures and fontanels than occurs with Runx2
      haploinsufficiency on a wild-type background. Finally, we find shortening of the
      proliferative and hypertrophic zones, and expansion of the resting zone in the
      growth plates of Runx2(+/-) Grg5(-/-) mice that are associated with reduced Ihh
      expression and Indian hedgehog (Ihh) signaling. We therefore conclude that Grg5
      enhances Runx2 activity in vivo.

PMID- 15183721
TI  - Roof plate and dorsal spinal cord dl1 interneuron development in the dreher
      mutant mouse.
AB  - The establishment of neural circuits in the spinal cord depends on the
      differentiation of functionally distinct types of neurons in the embryonic neural
      tube. A number of genes have recently been shown to control the generation of
      dorsal interneurons through inductive signals provided by the roof plate. The
      roof plate is a transient signaling center on the dorsal midline of the neural
      tube that coordinates dorsal CNS development through the action of local peptide
      signals, primarily the bone morphogenic proteins (BMPs) and the Wingless-related
      genes (Wnts). The role of the roof plate has become evident through studies of
      mutations of genes in these gene families, and through several spontaneously
      occurring mouse mutants, including dreher(J) (dr(J)), all of which cause dorsal
      neural tube defects. We previously demonstrated that the roof plate is missing in
      the dreher mouse. Positional cloning of the dreher locus demonstrated that an
      inactivating point mutation in the LIM homeodomain (HD) transcription factor
      encoded by the Lmx1a gene, is responsible for the dreher(J) phenotype [Nature,
      403 (2000) 764]. Here we report that Lmx1a is first expressed at E8.5 in a small
      number of cells in the lateral neural plate. As the neural tube closes, Lmx1a
      expression is restricted to the roof plate. In dr(J)/dr(J), although non
      functional Lmx1a is correctly expressed at E8.5-E9.5, its expression is lost in
      the spinal cord roof plate by E10.5. Coincident with the loss of Lmx1a
      expression, Bmp expression fails, and the generation and differentiation of the
      dorsal-most spinal cord neurons, the dl1 interneurons, is abnormal. In
      dr(J)/dr(J) embryos, defects are evident in the number of dl1 progenitors, as
      well as in their migration to form the lateral and medial nuclei, and axon
      patterning, through mechanisms that apparently involve defects in early steps of
      neuronal polarity. Consistent with the general hypothesis that a failure of roof
      plate formation and function results in deficits in dorsal patterning of the
      neural tube, the dreher affects the generation and differentiation of the dl1
      interneuron population.

PMID- 15183722
TI  - Sonic hedgehog signaling is required for expansion of granule neuron precursors
      and patterning of the mouse cerebellum.
AB  - The signals that promote regional growth and development of the brain are not
      well understood. Sonic hedgehog (Shh) is produced by Purkinje cells of the
      cerebellum and is a potent inducer of granule cell proliferation. Here, we
      demonstrate that Shh protein is present in the murine cerebellum during late
      stages of embryogenesis and is associated with Purkinje cell bodies and their
      processes. To better determine the role of Shh during cerebellar development, we
      genetically removed Shh activity specifically from Purkinje cells and the
      cerebellar anlage of the mouse embryo. We show that Shh is required for expansion
      of the granule neuron precursor population, but not for the subsequent
      differentiation of these cells. In addition, the loss of Shh activity influences
      Purkinje cell development and the formation of folia in the cerebellum. A role
      for Shh in compartmentalization of the cerebellum is also suggested by the more
      severe rostral defects observed in the absence of Hedgehog signaling. Together,
      these findings provide additional evidence for Shh's key regulatory role in
      controlling growth of the cerebellar primordium.

PMID- 15183724
TI  - The mesenchymal alpha11beta1 integrin attenuates PDGF-BB-stimulated chemotaxis of
      embryonic fibroblasts on collagens.
AB  - alpha11beta1 constitutes the most recent addition to the integrin family and has
      been shown to display a binding preference for interstitial collagens found in
      mesenchymal tissues. We have previously observed that when alpha11beta1 integrin
      is expressed in cells lacking endogenous collagen receptors, it can mediate PDGF
      BB-dependent chemotaxis on collagen I in vitro. To determine in which cells PDGF
      and alpha11beta1 might cooperate in regulating cell migration in vivo, we studied
      in detail the expression and distribution of alpha11 integrin chain in mouse
      embryos and tested the ability of PDGF isoforms to stimulate the alpha11beta1
      mediated cell migration of embryonic fibroblasts. Full-length mouse alpha11 cDNA
      was sequenced and antibodies were raised to deduced alpha11 integrin amino acid
      sequence. In the embryonic mouse head, alpha11 protein and RNA were localized to
      ectomesenchymally derived cells. In the periodontal ligament, alpha11beta1 was
      expressed as the only detectable collagen-binding integrin, and alpha11beta1 is
      thus a major receptor for cell migration and matrix organization in this cell
      population. In the remainder of the embryo, the alpha11 chain was expressed in a
      subset of mesenchymal cells including tendon/ligament fibroblasts, perichondrial
      cells, and intestinal villi fibroblasts. Most of the alpha11-expressing cells
      also expressed the alpha2 integrin chain, but no detectable overlap was found
      with the alpha1 integrin chain. In cells expressing multiple collagen receptors,
      these might function to promote a more stable cell adhesion and render the cells
      more resistant to chemotactic stimuli. Wild-type embryonic fibroblasts activated
      mainly the PDGF beta receptor in response to PDGF-BB and migrated on collagens I,
      II, III, IV, V, and XI in response to PDGF-BB in vitro, whereas mutant
      fibroblasts that lacked alpha11beta1 in their collagen receptor repertoire showed
      a stronger chemotactic response on collagens when stimulated with PDGF-BB. In the
      cellular context of embryonic fibroblasts, alpha11beta1 is thus anti-migratory.
      We speculate that the PDGF BB-dependent cell migration of mesenchymal cells is
      tightly regulated by the collagen receptor repertoire, and disturbances of this
      repertoire might lead to unregulated cell migration that could affect normal
      embryonic development and tissue structure.

PMID- 15183723
TI  - Smad2 and Smad3 coordinately regulate craniofacial and endodermal development.
AB  - Ligands of the transforming growth factor-beta (TGF-beta) superfamily are
      involved in numerous developmental and disease processes. TGF-beta, activins, and
      nodal ligands operate through the highly homologous Smad2 and Smad3 intracellular
      mediators. Smad2 mutants exhibit early embryonic lethality, while Smad3 mutants
      are viable, but show a plethora of postnatal phenotypes, including immune
      dysfunction and skeletal abnormalities. Previously, we have shown that the Smad2
      and Smad3 genes function cooperatively during liver morphogenesis. Here we show
      that Smad2 and Smad3 are required at a full dosage for normal embryonic
      development. Animals lacking one allele of each gene exhibit a variably penetrant
      phenotype in which structures in the anterior and ventral midline are reduced or
      lost; additionally, we demonstrate that this craniofacial defect and the
      previously reported hepatic phenotypes are both due to defects in the definitive
      endoderm. A reduction of endodermal gene expression as well as a failure to
      displace the visceral endoderm occurs despite the formation of a normal foregut
      pocket. This precedes any defects in anterior patterning and likely causes the
      abnormalities observed in craniofacial and midline development, as well as
      hepatogenesis.

PMID- 15183725
TI  - Neurogenin 3-expressing progenitor cells in the gastrointestinal tract
      differentiate into both endocrine and non-endocrine cell types.
AB  - Mice deficient for the transcription factor neurogenin 3 (ngn3) fail to develop
      endocrine cells in the intestine and pancreas and show partial endocrine
      differentiation in the stomach. We expressed Cre recombinase under control of a
      ngn3 BAC to achieve high fidelity cell lineage tracing in vivo to determine
      whether endocrine cells in these organs differentiate from NGN3+ precursor cells.
      Our results indicate that all small intestinal enteroendocrine cells arise from
      ngn3-expressing cells and confirm that NGN3+ cells give rise to all pancreatic
      endocrine cells as noted previously. By examining mice at a developmental stage
      when all of the cell types in the stomach have differentiated, we have delineated
      region-associated differences in endocrine differentiation. A much smaller
      fraction of endocrine cells populating the acid-producing region of the stomach
      is derived from NGN3+ precursor in contrast to the antral-pyloric region.
      Unexpectedly, ngn3 is expressed in cells that adopt non-endocrine cell fates
      including significant fractions of goblet and Paneth cells in the intestine and a
      small number of duct and acinar cells in the pancreas. Rarely, ngn3 was expressed
      in pluripotent cells in intestinal crypts with resultant labeling of an entire
      crypt-villus unit. Thus, ngn3 expression occurs in mixed populations of immature
      cells that are not irreversibly committed to endocrine differentiation.

PMID- 15183726
TI  - Dynamics of neural crest-derived cell migration in the embryonic mouse gut.
AB  - Neural crest-derived cells that form the enteric nervous system undergo an
      extensive migration from the caudal hindbrain to colonize the entire
      gastrointestinal tract. Mice in which the expression of GFP is under the control
      of the Ret promoter were used to visualize neural crest-derived cell migration in
      the embryonic mouse gut in organ culture. Time-lapse imaging revealed that GFP(+)
      crest-derived cells formed chains that displayed complicated patterns of
      migration, with sudden and frequent changes in migratory speed and trajectories.
      Some of the leading cells and their processes formed a scaffold along which later
      cells migrated. To examine the effect of population size on migratory behavior, a
      small number of the most caudal GFP(+) cells were isolated from the remainder of
      the population. The isolated cells migrated slower than cells in large control
      populations, suggesting that migratory behavior is influenced by cell number and
      cell-cell contact. Previous studies have shown that neurons differentiate among
      the migrating cell population, but it is unclear whether they migrate. The
      phenotype of migrating cells was examined. Migrating cells expressed the neural
      crest cell marker, Sox10, but not neuronal markers, indicating that the majority
      of migratory cells observed did not have a neuronal phenotype.

PMID- 15183727
TI  - Differential requirement for ptf1a in endocrine and exocrine lineages of
      developing zebrafish pancreas.
AB  - Mammalian studies have implicated important roles for the basic helix-loop-helix
      transcription factor Ptf1a-p48 in the development of both exocrine and endocrine
      pancreas. We have cloned the Ptf1a-p48 ortholog in Danio rerio. Early zebrafish
      ptf1a expression is observed in developing hindbrain and in endodermal pancreatic
      precursors. Analysis of ptf1a and insulin expression reveals a population of
      exocrine precursors that, throughout early development, are temporally and
      spatially segregated from endocrine elements. Morpholino-mediated knockdown of
      ptf1a confirms early divergence of these endocrine and exocrine lineages. Ptf1a
      morphants lack differentiated exocrine pancreas, but maintain normal
      differentiation and organization of the principal islet. In addition to the
      exocrine phenotype, ptf1a knockdown also reduces the prevalence of a small
      population of anterior endocrine cells normally found outside the principal
      islet. Together, these findings suggest the presence of distinct ptf1a-dependent
      and ptf1a-independent precursor populations in developing zebrafish pancreas.

PMID- 15183728
TI  - Human embryonic stem cells express a unique set of microRNAs.
AB  - Human embryonic stem (hES) cells are pluripotent cell lines established from the
      explanted inner cell mass of human blastocysts. Despite their importance for
      human embryology and regenerative medicine, studies on hES cells, unlike those on
      mouse ES (mES) cells, have been hampered by difficulties in culture and by scant
      knowledge concerning the regulatory mechanism. Recent evidence from plants and
      animals indicates small RNAs of approximately 22 nucleotides (nt), collectively
      named microRNAs, play important roles in developmental regulation. Here we
      describe 36 miRNAs (from 32 stem-loops) identified by cDNA cloning in hES cells.
      Importantly, most of the newly cloned miRNAs are specifically expressed in hES
      cells and downregulated during development into embryoid bodies (EBs), while
      miRNAs previously reported from other human cell types are poorly expressed in
      hES cells. We further show that some of the ES-specific miRNA genes are highly
      related to each other, organized as clusters, and transcribed as polycistronic
      primary transcripts. These miRNA gene families have murine homologues that have
      similar genomic organizations and expression patterns, suggesting that they may
      operate key regulatory networks conserved in mammalian pluripotent stem cells.
      The newly identified hES-specific miRNAs may also serve as molecular markers for
      the early embryonic stage and for undifferentiated hES cells.

PMID- 15183729
TI  - Identification of C. elegans sensory ray genes using whole-genome expression
      profiling.
AB  - The three cells that comprise each C. elegans sensory ray (two sensory neurons
      and a structural cell) descend from a single neuroblast precursor cell. The
      atonal ortholog lin-32 and the E/daughterless ortholog hlh-2 act to confer neural
      competence during ray development, but additional regulatory factors that control
      specific aspects of cell fate are largely unknown. Here, we use full-genome DNA
      microarrays to compare gene expression profiles in adult males of two mutant
      strains to identify new components of the regulatory network that controls ray
      development and function. This approach identified a large set of candidate ray
      genes. Using reporter genes, we confirmed ray expression for 13 of these,
      including a beta-tubulin, a TWK-family channel, a putative chemoreceptor and four
      novel genes (the cwp genes) with a potential role in sensory signaling through
      the C. elegans polycystins lov-1 and pkd-2. Additionally, we have found several
      ray-expressed transcription factors, including the Zn-finger factor egl-46 and
      the bHLH gene hlh-10. The expression of many of these genes requires lin-32
      function, though this requirement may not reflect direct activation by lin-32.
      Our strategy provides a complementary foundation for modeling the genetic network
      that controls the development of a simple sensory organ.

PMID- 15183730
TI  - Transcriptional regulation of Msx2 in the AERs of developing limbs is dependent
      on multiple closely spaced regulatory elements.
AB  - In developing limb buds, Msx2 transcripts are expressed in the apical ectodermal
      ridge (AER) and in various regions of the limb mesenchyme. To identify DNA
      sequences responsible for Msx2 expression in the AER, we characterized the
      expression of LacZ reporter constructs driven by chicken Msx2 regulatory
      sequences in transgenic mice. We have identified a 55-bp enhancer that can direct
      AER-specific reporter gene expression. This 55-bp enhancer contains three
      elements that are evolutionary conserved among five vertebrate Msx2 genomic
      sequences. AER expression of reporter constructs in transgenic mice is lost or
      reduced when mutations are introduced into each of these three regions. Moreover,
      changing the relative orientation by reverse complementing one of the three
      elements also results in loss of expression, suggesting that the relative
      orientations of transcription factor binding is important. To identify the
      transcription factor(s) binding to these elements, we conducted one-hybrid
      screening and identified Dlx5 and Sox11. Both Dlx5 and Sox11 are expressed in the
      AER, and the proteins encoded by these genes bind to separate conserved elements,
      supporting their possible roles in regulating Msx2 expression.

PMID- 15183731
TI  - A conserved enhancer element that drives FGF4 gene expression in the embryonic
      myotomes is synergistically activated by GATA and bHLH proteins.
AB  - FGF4 is the earliest member of the fibroblast growth factor (FGF) family
      expressed during embryogenesis where it plays essential roles in post
      implantation development and limb growth and patterning. The expression of the
      Fgf4 gene in specific developmental stages, including the ICM of the blastocyst,
      the myotomes, and the limb bud AER, is regulated by distinct enhancer elements
      (Hom) in the 3' UTR. We previously identified the Hom3a region as the major DNA
      element responsible for Fgf4 expression in the myotomes and AER, and showed that
      a conserved E-box is a target for the myogenic bHLH transcription factors MYF5
      and MYOD. To further define the cis- and trans-acting elements that determine
      Hom3a activity, we conducted a mutational analysis of the ability of the Hom3a
      region to drive lacZ expression in the myotomes of transgenic mice. We identified
      a minimal enhancer of 226nt that contains four elements, including the E-box,
      necessary to drive gene expression in the myotomes. One of these elements is a
      binding site for the GATA family of transcription factors, and we show here that
      GATA 1-4 and 6 can synergize with MYF5 or MYOD to activate transcription of a
      reporter plasmid driven by a portion of the Hom3a enhancer including the GATA
      site and the E-box. In line with this finding, we could show a direct interaction
      between MYF5/MYOD and GATA-3 or GATA-4, mediated by the N-terminal and bHLH
      domains of MYF5/MYOD and the C-terminal zing finger domain of GATA-3/4. To
      further study the role of the Hom3a enhancer in directing Fgf4 expression and the
      function of FGF4 in limb and muscle development, we generated mutant mice in
      which the Fgf4 Hom3a region had been deleted (Delta3a). In situ hybridization
      analysis of sections from Delta3a/ Delta3a embryos at E11.5 showed a drastically
      reduced expression of Fgf4 mRNA in the myotomes and AER. However, these mice
      developed normally and show no limb or muscle defects, and the same was true of
      heterozygous mice in which one Fgf4 allele carried the Hom3a deletion and the
      other was a null allele (Delta3a/Fgf4(-)). Together, these results show that
      Hom3a is the major DNA enhancer element directing Fgf4 expression in myotomes and
      limb bud AER, and that its activity in the myotomes results at least in part from
      the synergistic action of GATA and bHLH myogenic factors that bind to
      evolutionary conserved sequences in the Hom3a enhancer. However, expression of
      Fgf4 in the myotomes or AER of murine embryos does not appear to be essential for
      muscle or limb development.

PMID- 15183732
TI  - Fluorinated cyclitols as useful biological probes of phosphatidylinositol
      metabolism.
AB  - A number of deoxyfluoro cyclitols have been synthesized and evaluated as probes
      of the phosphatidylinositol pathway (PtdIns pathway), most notably 5-deoxy-5
      fluoro-myo-inositol, which is incorporated into the pathway at about 25% the
      level of myo-inositol itself. Unfortunately, none of the cyclitols have proved
      effective in limiting cell proliferation, as the cells are able to 'synthesize
      around' the fraudulent cyclitols using natural myo-inositol as substrate.
      Inhibitors for 3-phosphatidylinositol kinase, which has importance in a number of
      pathological conditions, including cancer, have been intensively investigated. 3
      Deoxy-3-fluoro-myo-inositol is incorporated into the PtdIns pathway; however,
      only related phosphatidyl derivatives, for example, a methyl ether derivative of
      the 3-deoxy inositol, showed significant antiproliferative activity. Synthesis of
      the deoxyfluoro analogues most often has been accomplished by DAST fluoro-de
      hydroxylation of the appropriate cyclitol, generally leading to products of
      inversion.

PMID- 15183733
TI  - Sulfatase-catalyzed assembly of regioselectively O-sulfonated p-nitrophenyl alpha
      D-gluco- and alpha-D-mannopyranosides.
AB  - A chemoenzymic methodology is extended to the library synthesis of
      regioselectively O-sulfonated pNP D-gluco and D-mannopyranosides. The method
      involves the sequential reactions of chemical O-sulfonation and sulfatase
      catalyzed O-desulfonation. pNP 2,6-di-O-sulfo-alpha-D-glucopyranoside and pNP 3,6
      di-O-sulfo-alpha-D-mannopyranoside were obtained as sodium salts using chemical
      methods by way of dibutylstannylene acetals or tributylstannyl ethers. They were
      then applied to enzyme reactions using three molluscan enzymes (snail, limpet,
      and abalone). The sulfatase reactions cleaved a sulfate group at the secondary O
      2 or O-3 position to yield the corresponding pNP 6-O-sulfo sugars. Neither pNP 6
      O-sulfo-alpha-D-glucopyranoside nor 6-O-sulfo-alpha-D-mannopyranoside became the
      enzyme substrate. Evidently, the molluscan sulfatases have a tendency to cleave
      the secondary O-sulfo group with assistance from the 6-O-sulfo group.

PMID- 15183734
TI  - Enzymatic synthesis of a beta-D-galactopyranosyl cyclic tetrasaccharide by beta
      galactosidases.
AB  - The galactosyl transfer reaction to cyclo-[-->6)-alpha-D-Glcp-(1-->3)-alpha-D
      Glcp-(1-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->] (CTS) was examined using
      lactose as a donor and beta-galactosidases from Aspergillus oryzae and Bacillus
      circulans. The A. oryzae beta-galactosidase produced three galactosyl derivatives
      of CTS. The main galactosyl derivative produced by the A. oryzae enzyme was
      identified as 6-O-beta-D-galactopyranosyl-CTS, cyclo-[-->6)-alpha-D-Glcp-(1-->3)
      [beta-D-Galp-(1-->6)]-alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-
      >]. The B. circulans beta-galactosidase also synthesized three galactosyl
      transfer products to CTS. The structure of main transgalactosylation product was
      3-O-beta-D-galactopyranosyl-CTS, cyclo-[-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp
      (1-->6)-[beta-D-Galp-(1-->3)]-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->]. These
      results showed that beta-galactosidase transferred galactose directly to the ring
      glucose residue of CTS.

PMID- 15183735
TI  - Carbohydrate carbonyl mobility--the key process in the formation of alpha
      dicarbonyl intermediates.
AB  - Covalently cross-linked proteins are among the major modifications caused by the
      advanced Maillard reaction. In the present study, the formation pathway of the
      dideoxyosone N6-(2,3-dihydroxy-5,6-dioxohexyl)-L-lysine is shown. To elucidate
      the formation of this glucose-derived dideoxyosone D-lactose (O-beta-D-galp-(1-
      >4)-D-glcp) and D-glucose-6-phosphate were incubated with lysine in the presence
      of the trapping reagent o-phenylenediamine (OPD). Synthesis and unequivocal
      structural characterization were reported for the quinoxalines of the
      dideoxyosones N6-(5,6-dihydroxy-2,3-dioxohexyl)-L-lysine and N6-(2,3-dihydroxy
      4,5-dioxohexyl)-L-lysine, respectively. Additionally, dicarbonyl compounds
      derived from D-erythrose, D-glycero-D-mannoheptose, and D-gluco-L-talooctose were
      synthesized and structurally characterized.

PMID- 15183736
TI  - Desulfation of sulfated galactans with chlorotrimethylsilane. Characterization of
      beta-carrageenan by 1H NMR spectroscopy.
AB  - A desulfation method using chlorotrimethylsilane for treatment of pyridinium
      salts of sulfated galactans was developed. It proved to be appropriate for
      desulfation of polysaccharides of both agar and carrageenan families. In order to
      evaluate its efficiency in presence of the maximum content of 3,6
      anhydrogalactose, it was applied to commercial kappa-carrageenan, leading to
      obtention of a product mainly composed by beta-carrageenan. Best experimental
      conditions for achieving desulfation of kappa-carrageenan--in terms of low
      sulfate content, high recovery and low degradation of the product--were found. In
      addition, the complete assignment of the 1H NMR spectrum of beta-carrageenan was
      achieved by means of 1D and 2D NMR techniques.

PMID- 15183737
TI  - Chemical structure of aeromonas gum--extracellular polysaccharide from Aeromonas
      nichidenii 5797.
AB  - Aeromonas (A) gum, an extracellular heteropolysaccharide produced by the
      bacterium Aeromonas nichidenii strain 5797, was studied by 1H and 13C NMR
      spectroscopy including 2D COSY, TOCSY, 1H, 13C HMQC, HMBC and ROESY experiments
      after O-deacetylation and Smith degradation. These investigations revealed the
      presence of an O-acetylated pentasaccharide repeating unit composed of mannose,
      glucose, xylose and glucuronic acid, and it has the following structure: [Image:
      see text]

PMID- 15183738
TI  - The structure of the carbohydrate backbone of the lipopolysaccharide of
      Pectinatus frisingensis strain VTT E-79104.
AB  - The structure of the carbohydrate backbone of the lipopolysaccharide from
      Pectinatus frisingensis strain VTT E-79104 was analyzed using chemical
      degradations, NMR spectroscopy, mass spectrometry, and chemical methods. The LPS
      contains two major structural variants, differing in the presence or absence of
      an octasaccharide fragment. The largest structure of the carbohydrate backbone of
      the LPS, that could be deduced from experimental results, consists of 20
      monosaccharides arranged in a nonrepetitive sequence: [carbohydrate structure:
      see text] where R is H or 4-O-Me-alpha-L-Fuc-(1-2)-4-O-Me-beta-Hep-(1-3)-alpha
      GlcNAc-(1-2)-beta-Man-(1-3)-beta-ManNAc-(1-4)-alpha-Gal-(1-4)-beta-Hep-(1-3)-beta
      GalNAc-(1- where Hep is a residue of D-glycero-D-galacto-heptose; all
      monosaccharides have the D-configuration except for 4-O-Me-L-Fuc and L-Ara4N.
      This structure is architecturally similar to the oligosaccharide system reported
      previously in P. frisingensis VTT E-82164 LPS, but differs from the latter in
      composition and also in the size of the outer region.

PMID- 15183739
TI  - Characterisation of the core part of the lipopolysaccharide O-antigen of
      Francisella novicida (U112).
AB  - Francisella novicida (U112), a close relative of the highly virulent bacterium F.
      tularensis, is known to produce a lipopolysaccharide that is significantly
      different in biological properties from the LPS of F. tularensis. Here we present
      the results of the structural analysis of the F. novicida LPS core part, which is
      found to be similar to that of F. tularensis, differing only by one additional
      alpha-Glc residue:where R is an O-chain, linked via a beta-bacillosamine (2,4
      diamino-2,4,6-trideoxyglucose) residue. The lipid part of F. novicida LPS
      contains no phosphate substituent and apparently has a free reducing end, a
      feature also noted in F. tularensis LPS.

PMID- 15183740
TI  - Interaction between beta-cyclodextrin and 1,10-phenanthroline: uncommon 2:3
      inclusion complex in the solid state.
AB  - The crystallographic structure of the complex formed by beta-cyclodextrin with
      1,10-phenanthroline has been studied by X-ray diffraction. The result shows that
      the complex adopts an uncommon 2:3 stoichiometry in solid state, that is, every
      complex unit contains three 1,10-phenanthroline molecules and two beta
      cyclodextrin molecules, where two 1,10-phenanthroline molecules individually
      occupy two cyclodextrin cavities, and the third guest molecule is located in the
      interstitial space between two head-to-head cyclodextrin molecules. The
      intermolecular hydrogen bonds between the adjacent complex units further link
      these individual monomers to a channel-type assembly. Furthermore, 1H and 2D NMR
      spectroscopy has been employed to investigate the inclusion behavior between the
      host beta-cyclodextrin and guest 1,10-phenanthroline in aqueous solution.

PMID- 15183741
TI  - Structure of an acidic O-specific polysaccharide from marine bacterium Shewanella
      fidelis KMM 3582T containing Nepsilon-[(S)-1-carboxyethyl]-Nalpha-(D
      galacturonoyl)-L-lysine.
AB  - The O-specific polysaccharide was isolated by mild acid degradation of the
      lipopolysaccharide of the marine bacterium Shewanella fidelis type strain KMM
      3582T and studied by sugar analysis along with 1H and 13C NMR spectroscopy
      including one-dimensional NOE in difference mode and two-dimensional experiments.
      The polysaccharide was found to consist of linear tetrasaccharide repeating units
      containing Nepsilon-[(S)-1-carboxyethyl]-Nalpha-(D-galacturonoyl)-L-lysine and
      having the following structure: [See text.] The amide of D-galacturonic acid with
      Nepsilon-[(S)-1-carboxyethyl]-L-lysine ('alaninolysine', 2S,8S-AlaLys) was found
      for the first time in nature as a component of the O-specific polysaccharide of
      Providencia rustigianii O14 (Carbohydr. Res. 2003, 338, 1009-1016).

PMID- 15183742
TI  - Chromosome imbalances in oligodendroglial tumors detected by comparative genomic
      hybridization.
AB  - Seven well-differentiated oligodendrogliomas, 16 anaplastic oligodendrogliomas
      and two cases of oligoastrocytomas were investigated by comparative genomic
      hybridization (CGH) on frozen tissue samples. The most frequent losses found
      involved 1p and 19q in 32% of cases. Loss of 9p was observed during malignant
      progression in 25% of anaplastic oligodendrogliomas. In two anaplastic
      oligodendrogliomas gain of 1q was found. The frequent losses of chromosome 16 and
      22 have not been reported previously. These results underscore that CGH is a
      powerful tool for the classification of gliomas complementing the traditional
      histopathological approach.

PMID- 15183743
TI  - Meiotic studies of infertile men in case of non-obstructive azoospermia with
      normal karyotype and no microdeleted Y-chromosome precise the clinical couple
      management.
AB  - To identify meiotic criteria for infertility management in non-obstructive
      azoospermic men, a prospective and multicentric study was organized in
      Andrological Departments of Paris (France), Roma (Italy) and Budapest (Hungary).
      In 117 non-obstructive azoospermic men with normal karyotype and no Y-chromosome
      microdeletion, histology and meiotic studies on bilateral bipolar testicular
      biopsies were done. Histologically, 40 patients (34%) presented spermatocyte or
      spermatid arrest, 39 (33%) hypospermatogenesis whereas no meiotic cell could be
      observed in the remaining patients (33%). Cytogenetically, meiotic figures could
      only be obtained from the two first histological groups. Meiotic abnormalities
      were observed in a total of 44 patients (37.6%) including nine patients (7.7%)
      with severe class I and class IIB anomalies and 19 patients (16.2%) with class
      IIC environmentally linked meiotic abnormalities. These results provided
      essential clues for an accurate clinical management. For patients with no meiotic
      figures and patients with class I and class IIB anomalies, an hormonal
      stimulation is illusory and a sperm gift should be directly proposed. An hormonal
      stimulation should be proposed to all the other patients, either directly or
      following the treatment of the testicular microenvironment for the patients
      presenting class IIC anomalies. The genetic risk and possibility of prenatal
      chromosomal analysis in case of pregnancy should be clearly exposed to all the
      couples in all the cases where type IIA, III or IV anomalies are present. This
      therapeutical strategy has been applied to all the patients in our series.

PMID- 15183744
TI  - A novel promoter polymorphism (-71C>T) in KRTHB6 gene in Indian population.
AB  - We have screened the basal promoter region, of KRTHB6 gene involving CAAT and
      TATA boxes in randomly selected 125 individuals of Indian origin by PCR-SSCP and
      DNA sequencing. We observed a novel promoter polymorphism (-71C>T) which could be
      differentiated by using LweI restriction enzyme. The frequency of -71 C allele,
      allele A (Accession no AY203963), was observed to be higher ( 0.712) in
      comparison to -71 T allele, allele B (0.288) (Accession no. AY037552).

PMID- 15183746
TI  - Genealogical study of myotonic dystrophy in Istria (Croatia).
AB  - High prevalence of myotonic dystrophy (DM) of 18.1 per 100,000 has been found in
      Croatian region Istria, a region where a great mixture of nations occurred over
      the last three centuries. The objective of this study was to test the hypothesis
      of common ancestry in Istrian DM families. Pedigrees were constructed on the
      basis of extensive family history obtained from the patients in all Istrian DM
      families. Church records were consulted in order to improve genealogical
      reconstruction. Additionally, we performed haplotype analyses with two intragenic
      and three extragenic DNA polymorphic markers. A common ancestor couple for three
      of nine nucleus families was found eight generations backward, which was
      supported by haplotype analysis. In spite of finding an evidence of common
      ancestry in Croatian Istria we argue that the phenomenon of founder effect is not
      sufficient to explain the high DM prevalence in Istria.

PMID- 15183745
TI  - Consanguineous marriages in the province of Antalya, Turkey.
AB  - To assess the trends in the frequency and the medical effects of consanguinity in
      the south coast of Turkish population using local and national data in the last
      11 years. This cross-sectional study was carried out in Manavgat province, which
      is a major tourism center on the Mediterranean coast of Turkey. The authors
      studied consanguineous marriages in rural and urban population in the
      Mediterranean coast, Manavgat province, Turkey, via a 1500 random survey sample
      of married couples. There has been a significant increase in the incidence of
      consanguineous marriages in rural areas (40.7%) since 1989 in the southern
      population of Turkey. The results showed that the most frequent type of marriage
      was between the first cousins. It is found that there is no statistically
      significant difference between the consanguineous and non-consanguineous
      marriages in the different age groups. The results were discussed on the basis of
      educational status, reasons for having consanguineous marriages and the general
      medical effects as well as with the relation of congenital malformations. The
      custom of consanguineous unions in the Mediterranean population of Turkey is
      still extremely high, and preventive measures should be done to decrease its
      frequency and associated complications.

PMID- 15183747
TI  - Apolipoprotein E gene polymorphism effects triglycerides but not CAD risk in
      Caucasian women younger than 65 years.
AB  - The pathogenesis of CAD is similar in man and woman, yet some risk factors have a
      greater impact on the CAD risk in woman than in man. In this study we assessed
      the effect of the apoE gene polymorphism on lipid metabolism and risk for CAD in
      women younger than 65 years (premature CAD). In a cross-sectional case-control
      study, 147 female Caucasian patients with premature CAD (confirmed by
      coronarography) were compared with a control group of 114 healthy Caucasian
      women. The apoE allele frequencies of patients vs. controls were 5.1% vs. 5.7%
      for 2, 85.4% vs. 83.3% for 3, and 9.5% vs. 11% for epsilon4. The subjects with
      epsilon2/3 genotype had statistically significantly higher triglycerides levels
      than the subjects with epsilon3/3 genotype (2.23 +/- 2.13 mmol.L(-1) vs. 1.73 +/-
      0.84 mmol.L(-1); p<0.05). Logistic regression analysis revealed no association
      between risk genotypes (3/4 and 4/4) of the apoE gene polymorphism and CAD risk
      (OR 0.9; 95% CI 0. 5-1.7, P=0.7). We observed metabolic clustering of diabetes
      mellitus, arterial hypertension, higher BMI and triglycerides, and lower HDL
      cholesterol in the CAD group compared to the control group. Arterial
      hypertension, diabetes, HDL cholesterol level, and BMI were independent risk
      factors for premature CAD in female population, whereas, the risk genotype of the
      apoE gene polymorphism was not. In conclusion, in Slovene women risk genotypes of
      the apoE gene polymorphism are not associated with premature CAD; a metabolic
      clustering of diabetes, HDL, triglycerides and arterial hypertension is
      frequently present in Caucasian women with premature CAD.

PMID- 15183749
TI  - Cytogenetics and fluorescence in situ hybridization assessment of sex-chromosome
      mosaicism in Klinefelter's syndrome.
AB  - A retrospective study was carried out in 152 infertile men to determine the
      prevalence of sex chromosome abnormalities among non-obstructive azoospermic and
      severe oligospermic men (n = 51) and to evaluate the feasibility of fluorescence
      in situ hybridization (FISH) techniques to assess mosaicism in Klinefelter's
      patients in comparison with conventional cytogenetics. Cytogenetic analysis were
      performed for 51 infertile men and among 14 chromosomal abnormalities found, nine
      were compatible with Klinefelter's syndrome. FISH staining with a CEP X/CEP Y
      probes were performed for Klinefelter's patients and for five of them; testes
      were biopsied for histopathologic examination. Six Klinefelter's patients showed
      a non-mosaic 47,XXY and three showed a 47,XXY/46,XY mosaic by G or R banding
      analysis of 20 cells with a ratio of 17%, 20% and 33%, respectively. FISH
      analysis confirmed mosaicism in only one patient (the first) in whom a third
      cells population was found. There was no relationship between the ratios of
      mosaicism by banding and FISH analysis. Conventional histopathologic findings in
      five non-mosaic Klinefelter's patients confirm the diagnosis of Sertoli Only
      Cells syndrome. FISH is recommended in Klinefelter's syndrome to define exactly
      the cytogenetic statute as mosaic or non-mosaic and then discussing prognosis and
      decision regarding fertility counseling.

PMID- 15183748
TI  - Genotype and allele frequency of PAI-1 promoter polymorphism in healthy subjects
      from the west of Mexico. Association with biochemical and hematological
      parameters.
AB  - We investigated the genotype and allelic frequency of the -675 bp
      insertion/deletion polymorphism at the PAI-1 gene promoter, in healthy Mexican
      subjects. It was compared to the lipid profile and hematological parameters, and
      to other healthy worldwide populations. A Mexican population sample of 110
      individuals was studied. Demographic data and clinical characteristics of the
      subjects were registered. Fasting lipid profile, serum glucose, fibrinogen,
      hematological parameters and leukocyte genomic DNA isolation from peripheral
      blood were performed in all the participants. Screening of the PAI-1 genotype was
      done by PCR and restriction analysis. Genotype 4G/4G, 4G/5G, 5G/5G frequency in
      Mexican healthy subjects was: 14.55%, 39.09%, 46.36%, respectively, whereas the
      allelic frequency for 5G allele was 65.9%. A significant lesser frequency for 4G
      allele and related genotypes (4G/4G and 4G/5G) was established in healthy
      subjects from Mexico, respect to all the compared populations. A particular
      genotype and allelic frequency of this PAI-1 polymorphism was established in
      Mexico. The clinical parameters were not associated according to each genotype of
      PAI-1.

PMID- 15183750
TI  - Prenatal diagnosis of an interstitial 12q chromosome deletion.
AB  - Rearrangements involving long arm of chromosome 12 are rare events. To our
      knowledge, we present the first case of an interstitial deletion of the long arm
      of chromosome 12 in a prenatal diagnosis. A review of the literature is included
      in our report.

PMID- 15183751
TI  - Chromosome 22q11.2 microdeletion in a patient with hemophilia A.
AB  - We report a 6-year-old patient with hemophilia A, who also exhibited clinical
      features typical of 22q11.2 deletion syndrome (22qDS). The specific traits were
      mild mental retardation, speech delay, hypernasal speech, deficits in voice
      quality and articulation, narrow palpebral fissures, broad and depressed nasal
      root, high-arched palate, microstomia, and overfolded ears. The patient had no
      associated congenital cardiac or palatal malformations. It can be particularly
      difficult to identify this syndrome in newborns and infants without congenital
      heart defects. This case underlines that microdeletion of chromosome 22q11.2
      should be considered in any patient who exhibits typical clinical features of
      22qDS, regardless of whether they have another single-gene disorder.

PMID- 15183752
TI  - Description and molecular analysis of SRY and AR genes in a patient with 46,XY
      pure gonadal dysgenesis (Swyer syndrome).
AB  - 46,XY pure gonadal dysgenesis, first described in 1955 by Swyer, results from
      testicular tissue loss during the first 8 weeks of fetal life, a critical period
      for male differentiation. We describe a case of an 18 years old patient presented
      to us with a chief complain of primary amenorrhea. Chromosomal analysis revealed
      a 46,XY karyotype. A molecular investigation was undertaken in an attempt to
      determine mutations in SRY and AR genes through DNA sequencing. Mutations were
      shown to be absent. The molecular basis of Swyer syndrome is still unknown,
      although the presence of mutations in testicular organizing genes downstream of
      SRY is still to rule out. The patient, who is considered as female, was placed on
      estrogen replacement therapy, while bilateral prophylactic laparoscopic
      gonadectomy was programmed due to the high prevalence of gonadal tumors in this
      syndrome. No signs of malignance were detected in the gonadal tissue, which
      predicts that an intact SRY gene is usually, but not always, not related to the
      formation of malignancies like dysgeminomas or gonadoblastomas.

PMID- 15183753
TI  - Unbalanced translocation 8;Y (45,X,dic(Y;8)(q11.23;p23.1)): case report and
      review of terminal 8p deletions.
AB  - A boy with a rare unbalanced de novo Y/autosome translocation is presented. Main
      clinical features in the boy comprised a psychomotor delay, talipes planus, a
      dolichocephalus, low set and retroverted ears, supraorbital fullness of
      subcutaneous tissue and a bulbous nasal tip. Chromosomal analysis on amniocytes
      showed a single X chromosome and a derivative 8p (Karyotype: 45,X,der(8)GTG). The
      following DAPI staining revealed the inactivated centromere of the chromosome Y
      located on 8p and the absence of heterochromatic material Yq. Microsatellite
      analysis on fetal blood DNA using markers between SRY on Yp and DYS 240 on Yq
      proved presence of the spermatogenetic relevant factors. A terminal deletion of
      8p was confirmed by FISH postnatally. Molecular genetic reassessment revealed the
      monosomy 8p to be of maternal origin; the translocation can thus be proven to
      have occurred in the zygote. The breakpoint in 8p was localised distal to GATA4,
      a gene which is involved in heart development; the finding that our patient did
      not suffer from cardiac problems agrees with the disomic presence of GATA4. Only
      the application of FISH combined with microsatellite analysis allowed a precise
      correlation between clinical phenotype and a subtle deletion of terminal 8p;
      furthermore, a recurrence risk for the parents could be excluded.

PMID- 15183754
TI  - Characterization of an analphoid, neocentromere-positive inv dup 8p marker
      chromosome using multiplex whole chromosome and sub-telomere FISH analyses.
AB  - A 30-year-old male patient with mild mental retardation was found to have a small
      supernumerary marker chromosome (SMC) in 90% of his peripheral blood cells and in
      100% of his fibroblast cells. Multiplex whole chromosome and sub-telomere FISH
      analyses were used to determine that this SMC is an inverted duplicated distal
      chromosome 8p fragment. Although it was negative for alpha-DNA sequences, this
      marker had a functional kinetochore (neocentromere) demonstrated by a positive
      signal with a CENP-C antibody. Apparently intact 8p telomeres at the marker's
      ends were demonstrated by using a telomere repeat FISH probe. The patient's
      phenotypically normal mother on G-banding analysis had a small marker chromosome
      in 8% of her peripheral blood cells in two cultures of the first specimen
      studied. The marker was not seen in any subsequent maternal peripheral blood or
      fibroblast specimens. Although it was impossible to further characterize the
      maternal SMC, it was suggested that the mother had the same marker as the one
      seen in the proband. Inverted duplicated chromosomal fragments are the most
      frequent type of analphoid markers. Stable inverted duplicated 8p marker
      chromosomes were previously reported in three other patients. They all apparently
      occurred de novo and were found to be positive for kinetochore-associated
      proteins. Evidence for the possible inheritance of an inverted-duplicated,
      analphoid SMC was not shown to-date. This study also demonstrates a practical,
      straightforward approach for analphoid marker characterization in clinical
      laboratory settings, using whole chromosome multiplex and subtelomere-specific
      FISH analyses. FISH probes for all sub-telomere chromosomal regions are
      commercially available and the large majority of analphoid marker chromosomes
      involve telomere regions.

PMID- 15183755
TI  - A capillary electrophoretic method for monitoring the presence of alpha-tubulin
      in nuclear preparations.
AB  - A sensitive capillary electrophoretic method was developed to detect the presence
      of alpha-tubulin, a microtubular cytoskeletal component, in isolated nuclear
      preparations. These preparations are treated with anti-alpha-tubulin primary
      mouse antibodies and then stained with a fluorescently labeled anti-mouse IgG
      antibody. The stained preparation is then analyzed by capillary electrophoresis
      with laser-induced fluorescence detection, a technique that allows for sensitive
      detection of fluorescently labeled species. Using this method, it is feasible to
      count individual subcellular aggregates containing alpha-tubulin (SATs), estimate
      the number of alpha-tubulin molecules per SAT, determine the cumulative intensity
      of all SATs as an estimate of the relative level of alpha-tubulin in a
      preparation, and obtain their apparent electrophoretic mobility distribution. The
      method was validated by comparing SATs from untreated cells with those from
      colchicine-treated cells. Since colchicine is a microtubule-disrupting agent,
      treatment reduced the number of SATs per cell as well as the cumulative intensity
      of all SATs in a preparation. In contrast, the apparent electrophoretic mobility
      distribution was not influenced by colchicine treatment, suggesting that this
      parameter is not strongly dependent on the alpha-tubulin content. Given the
      zeptomolar sensitivity of laser-induced fluorescence detection and the widespread
      availability of antibodies, the approach used here represents an improvement in
      the detection of cytoskeletal impurities in subcellular fractions.

PMID- 15183756
TI  - Environmentally low-temperature kinetic and thermodynamic study of lactate
      dehydrogenase from Atlantic cod (G. morhua) using a 96-well microplate technique.
AB  - Analyses of temperature-dependent kinetic parameters in enzymes extracted from
      tissues of ectothermic animals are usually carried out within the range of
      physiological temperatures (0-40 degrees C). However, multisample
      spectrophotometers (so-called microplate readers) with efficient wide-range
      temperature control (including cooling) have previously been unavailable. This
      limits the statistical quality of the measurements. A temperature-controlled
      microplate was designed for a 96-well microplate reader to overcome this
      limitation. This so-called T-microplate is able to control assay temperature
      between the freezing point of a liquid sample and 60 degrees C with high
      stability and accuracy in any data acquisition mode. At 4 degrees C the accuracy
      of the temperature control was +/-0.1 degrees C and temperature homogeneity
      across the microplate was +/-0.3 degrees C. As examples, analyses of the
      temperature dependence of Michaelis-Menten (K'(PYR)(m) and substrate inhibition
      (K'(PYR)(si) constants for pyruvate, of the maximal rate of reaction (V'(max), of
      the apparent Arrhenius activation energy (E(A), and of the Gibbs free-energy
      change (deltaG) of lactate dehydrogenases from muscle of Atlantic cod Gadus
      morhua acclimated to 4 degrees C are described. The large dataset obtained
      allowed evaluation of a new mechanism of metabolic compensation in response to
      seasonal temperature change.

PMID- 15183757
TI  - A high-capacity assay for PPARgamma ligand regulation of endogenous aP2
      expression in 3T3-L1 cells.
AB  - A novel class of insulin-sensitizing agents, the thiazolidinedines (TZDs), has
      proven effective in the treatment of type 2 diabetes. These compounds, as well as
      a subclass of non-TZD insulin-sensitizing agents, have been shown to be
      peroxisome proliferator-activated receptor (PPAR) gamma agonists. PPARgamma plays
      a critical role in adipogenesis and PPARgamma agonists have been shown to induce
      adipocyte differentiation. Here, PPARgamma ligand activity has been assessed in
      murine 3T3-L1 cells, a commonly used in vitro model of adipogenesis, by measuring
      their ability to induce adipocyte fatty acid-binding protein (aP2) mRNA
      expression. In order to perform this task, we have developed a novel, multiwell
      assay for the direct detection of aP2 mRNA in cell lysates that is based on
      hybridization of mRNA to target-specific oligonucleotides. These oligonucleotide
      probes are conjugated to enzymes that efficiently process unique chemical
      substrates into robust fluorescent products. Ribosomal protein 36B4 mRNA, a gene
      whose expression is unaffected by adipogenesis, serves as the control in the
      assay. Two assay formats have been developed, a single analyte assay in which aP2
      and 36B4 mRNA expression are assayed in separate lysate aliquots and a dual
      analyte assay which can measure aP2 and 36B4 mRNA simultaneously. Both forms of
      the assay have been used to quantify attomole levels of aP2 and 36B4 mRNAs in
      differentiating 3T3-L1 preadipocytes treated with PPARgamma agonists. The
      potencies of PPARgamma agonists determined by this novel methodology showed good
      correlation with those derived from aP2 mRNA slot-blot analysis and PPARgamma
      transactivation assays. We conclude that the aP2 single and dual analyte assays
      both provide specific and sensitive measurements of endogenous aP2 mRNA levels
      that can be used to assess the activity of PPARgamma ligands in 3T3-L1 cells.
      Since the assay obviates the need for RNA isolation and is performed in an
      automatable multiwell format, it can serve as a high-throughput, cell-based
      screen for the identification and characterization of PPARgamma modulators.

PMID- 15183758
TI  - ARChip epoxy and ARChip UV for covalent on-chip immobilization of pmoA gene
      specific oligonucleotides.
AB  - ARChip Epoxy and ARChip UV are presented as novel chip platforms for
      oligonucleotide immobilization. ARChip Epoxy is made of reactive epoxy resin
      available commercially. ARChip UV consists of photoactivatable poly(styrene-co-4
      vinylbenzylthiocyanate). Both ARChip surfaces are tested in a model assay based
      on oligonucleotide probes from a real-life genotyping project and are evaluated
      in comparison with five commercial chip surfaces based on nitrocellulose, epoxy,
      and aldehyde polymer, and two different aminosilanes. Optimum print buffer,
      spotter compatibility, and data normalization are discussed.

PMID- 15183759
TI  - Protein analysis with tetra-substituted sulfonated cobalt phthalocyanine by the
      technique of Rayleigh light scattering.
AB  - This is the first report of cobalt-tetrasulfonatophthalocyanine (CoTSPc) as a
      probe of Rayleigh light scattering (RLS) to determine proteins at nanogram
      levels. A highly sensitive method has been developed for the determination of
      proteins by the light scattering technique on a common spectrofluorimeter, based
      on the fact that the weak RLS of CoTSPc can be greatly enhanced in the presence
      of proteins. Under optimum conditions, the linear ranges of the calibration
      curves were 0.10-34.3 microg x mL(-1) for both human serum albumin and bovine
      serum albumin, with detection limits of 15.5 and 13.9 ng x mL(-1), respectively.
      Moreover, there is almost no interference of any amino acids and metal ions. The
      method has been applied to the direct determination of total proteins in human
      serum samples, and the results were satisfactory with clinical data provided.

PMID- 15183760
TI  - Critical study of preanalytical and analytical phases of adenine and pyridine
      nucleotide assay in human whole blood.
AB  - Intracellular redox and energetic status play a crucial role in cardiovascular
      diseases and metabolic disorders. The physiological status of reducing agents,
      such as NADPH and NADH, and of high-energy molecules, such as ATP, is required
      for antioxidant system activity. For these reasons, an accurate measurement of
      adenine and pyridine nucleotides is fundamental. In this study we examined the
      preanalytical phase of reduced pyridine (RPN) and adenine and oxidized pyridine
      (AOPN) nucleotide assay in human whole blood. Different experimental conditions
      were applied to RPN alkaline and AOPN acid extracts to find the best analytical
      performance. Our results show that a good RPN and AOPN linearity (r from 0.994 to
      0.999), recovery (near to 100%), and precision (coefficient of variation < 5%)
      were obtained when supernatant from acid and ultrafiltrate from alkaline extracts
      were neutralized, frozen, and thawed just before HPLC injection. Since NADH
      decays rapidly at -80 degrees C, RPN levels must be assayed within 72 h while
      AOPN can be stored for 1 month at the same temperature. An accurate and
      quantitative method for nucleotide determination can be obtained by applying the
      preanalytical conditions proposed in this study.

PMID- 15183761
TI  - A cell-free biosensor for the detection of transcriptional inducers using firefly
      luciferase as a reporter.
AB  - A cell-free biosensor for the detection of transcription induction by specific
      small-molecule ligands is presented. As model systems, tetracycline and mercury
      inducible promoters were used containing firefly luciferase as reporter gene.
      Escherichia coli S30 extract was prepared and used for coupled transcription
      translation reactions. By using purified Tet repressor and MerR regulatory
      proteins, we could study repressor-operator interactions for optimizing the
      relative concentrations of each component. Previously, detection of tetracycline
      and mercury using similar transcriptional regulation in whole living cells has
      been carried out. As compared to whole-cell biosensors, our results showed better
      sensitivity for the detection of tetracycline and the toxic effect of mercury was
      avoided in the cell-free system. Also, as the system omits cell cultivation and
      bacterial membranes as molecule passage inhibitors, it is possible to carry out
      assays in much shorter times and without the use of genetically modified
      organisms.

PMID- 15183762
TI  - Uracil in DNA, determined by an improved assay, is increased when
      deoxynucleosides are added to folate-deficient cultured human lymphocytes.
AB  - Folate deficiency leads to increased dUMP/dTMP ratios and uracil misincorporation
      into DNA, which may increase cancer risk. We improved a previously described gas
      chromatography-mass spectrometry (GC-MS) assay for uracil in DNA and validated
      the assay by analyzing the DNA-uracil content of normal, primary human
      lymphocytes that were cultured in 0-3000 nM folic acid. In addition, the effects
      of nucleoside mixtures T or TdCA (T, thymidine; A, adenosine; dC, deoxycytidine)
      were investigated. Over 4 consecutive days, the inter- and intraassay
      coefficients of variation (CVs) were 2.3-3.9 and 0.6-2.2%. Mean recovery was
      99.4%. Oligonucleotides containing 100 pg of uracil yielded a mean uracil
      measurement of 110.1 pg (CV=2.7%). Cells grown in different concentrations of
      folate showed a bimodal response, with maximum DNA-uracil at 12 nM, and minima at
      0 and 3000 nM folate. Extremely folate-deficient cells may incorporate less
      uracil because DNA synthesis is reduced. A wide response to folate deficiency was
      seen in cells from different donors, suggesting that genetic background plays a
      critical role in individual susceptibility to DNA damage and cancer risk.
      Unexpectedly, TdCA supplementation caused increased DNA-uracil (vs 3000 nM folate
      for 10 days, P > 0.05), probably due to the conversion of deoxycytidine to
      deoxyuridine by cytidine deaminase, leading to elevated dUMP/dTMP ratios. This
      improved uracil assay could serve as a useful tool in the study of the mechanism
      of uracil misincorporation into DNA. The assay requires 3 microg of DNA per
      folate-deficient sample, but more may be required for baseline DNA-uracil
      detection in healthy humans.

PMID- 15183763
TI  - Lipase assay in soils by copper soap colorimetry.
AB  - A simple and sensitive method for the estimation of lipase activity in soils is
      reported. In this method, 50mg of soil is incubated with emulsified substrate,
      the fatty acids liberated are treated with cupric acetate-pyridine reagent, and
      the color developed is measured at 715 nm. Use of olive oil in this protocol
      leads to an estimation of true lipase activity in soils. The problem of released
      fatty acids getting adsorbed onto the soil colloids is obviated by the use of
      isooctane, and separate standards for different soils need not be developed.
      Among the various surfactants used for emulsification, polyvinyl alcohol is found
      to be the most effective. Incubation time of 20 min, soil concentration of 50 mg,
      pH 6.5, and incubation temperature of 37 degrees C were found to be the most
      suitable conditions for this assay. During the process of enrichment of the soils
      with oil, interference by the added oil is avoided by the maintenance of a
      suitable control, wherein 50 mg of soil is added after stopping the reaction.
      This assay is sensitive and it could be adopted to screen for lipase producers
      from enriched soils and oil-contaminated soils before resorting to isolation of
      the microbes by classical screening methods.

PMID- 15183764
TI  - A nonradioactive 96-well plate assay for the detection of hypoxia-inducible
      factor prolyl hydroxylase activity.
AB  - The transcriptional activation of hypoxia-inducible genes is essential for the
      adaptation of mammalian tissues to oxygen deficiency. The hypoxia-inducible
      transcription factor (HIF) is a cellular switch for the up-regulation of these
      genes during hypoxia. Under normoxia, HIFs are hydroxylated on conserved prolyl
      residues by a recently discovered family of HIF prolyl hydroxylases (HIF-PHD1-3).
      Hydroxylated HIF specifically interacts with the von Hippel-Lindau protein
      elongin B-elongin C complex (VBC) which leads to ubiquitination and subsequent
      proteasomal degradation of HIF. We developed a nonradioactive microtiter plate
      assay based on the interaction of hydroxylated HIF with VBC which enabled us to
      detect hydroxylated HIF in the nanomolar concentration range. A biotinylated HIF
      peptide substrate was bound to a streptavidin-coated microtiter plate and
      hydroxylated with the HIF-PHD3 isoenzyme. Recombinant VBC complex with a
      thioredoxin (Trx) tag was purified from Escherichia coli and bound to the
      hydroxylated HIF peptide. The interaction between VBC and hydroxylated HIF was
      detected by using an anti-thioredoxin antibody.

PMID- 15183765
TI  - Oligonucleotide-displaced organic monolayer-protected silver nanoparticles and
      enhanced luminescence of their salted aggregates.
AB  - N-(2-mercaptopropionyl)glycine (tiopronin) monolayer-protected silver particles
      were partially displaced by single-stranded oligonucleotides through ligand
      exchanges. The oligonucleotide-displaced particles could be hybridized with
      complementary fluorophore-labeled oligonucleotides. Both the oligonucleotide
      displaced and hybridized particles could be aggregated by electrostatic
      interactions with salt in buffer solution, and the aggregates displayed enhanced
      luminescence from fluorophores. This result suggests the possible application of
      surface-enhanced fluorescence from metallic nanoparticle aggregation for DNA
      detection.

PMID- 15183766
TI  - Efficacy and compatibility with mass spectrometry of methods for elution of
      proteins from sodium dodecyl sulfate-polyacrylamide gels and polyvinyldifluoride
      membranes.
AB  - The resolving power of sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      (SDS-PAGE) combined with isoelectric focusing in two-dimensional gel
      electrophoresis has made it one of the most important techniques for resolving
      complex mixtures, and it is of great importance for proteome mapping projects. As
      a result of this, methods for postelectrophoretic protein characterization are of
      great interest as exemplified by in situ protease digestion combined with mass
      spectrometry (MS), which is the method of choice for identification of proteins.
      In this study we have developed and compared methods for recovering intact
      proteins from polyacrylamide gels and electroblotting membranes to define
      efficient methods compatible with MS. These methods complement in situ digestion
      protocols and allow determination of the molecular mass of whole proteins
      separated by SDS-PAGE. Passive elution of proteins from SDS-PAGE gels was
      efficient only in the presence of SDS, whereas electroelution was achieved using
      buffers without SDS. Surface-enhanced laser desorption/ionization MS (SELDI-MS)
      analysis of proteins eluted in the presence of SDS was possible using ion
      exchange ProteinChip arrays for concentration of sample and removal of SDS.
      Comparison of different electroblotting methods verified that the different
      membranes and buffers were equally efficient for transfer of proteins in the
      range 20-100 kDa. Elution from polyvinyldifluoride membranes was most efficient
      using either concentrated solutions of trifluoroacetic acid (TFA) or combinations
      of 8M urea and 1% Triton X-100, 1% Tween 20, or 40% isopropanol. The same result
      was obtained using nitrocellulose membranes, except that these were incompatible
      with organic solvent and TFA. Elution by TFA was compatible with matrix-assisted
      laser desorption/ionization MS (MALDI-MS) but was complicated by a high degree of
      trifluoroacetylation of the proteins. Alternatively, elution by 8M urea+1% Triton
      X-100, 1% Tween 20, or 40% isopropanol was compatible with both SELDI-MS and
      MALDI-MS. Eluted proteins were identified in MS experiments by intact mass
      determination, by peptide mapping, and by MS/MS analysis.

PMID- 15183768
TI  - A high-throughput fluorescence polarization assay for signal transducer and
      activator of transcription 3.
AB  - Signal transducer and activator of transcription 3 (STAT3) is overactive in a
      wide variety of human tumors. Activity of STAT3 requires its own SH2-domain
      mediated binding to phosphotyrosine-containing sequences. We have developed a
      high-throughput binding assay, based on fluorescence polarization, which allows
      screening for small molecules that bind to the STAT3 SH2 domain and thereby
      inhibit its activity. The basis of this assay is the binding of a fluorescein
      labeled phosphotyrosine-peptide derived from the interleukin-6 receptor subunit
      gp130 to unphosphorylated STAT3 with a K(d) of 150 nM. The assay is stable with
      regard to salt concentration, dimethyl sulfoxide concentration, and time. It has
      been adapted to a 384-well format, with a Z' value of 0.87, and can be used to
      screen for small molecules that bind to the STAT3 SH2 domain.

PMID- 15183767
TI  - Comparative analyses of a small molecule/enzyme interaction by multiple users of
      Biacore technology.
AB  - To gauge the experimental variability associated with Biacore analysis, 36
      different investigators analyzed a small molecule/enzyme interaction under
      similar conditions. Acetazolamide (222 g/mol) binding to carbonic anhydrase II
      (CAII; 30000 Da) was chosen as a model system. Both reagents were stable and
      their interaction posed a challenge to measure because of the low molecular
      weight of the analyte and the fast association rate constant. Each investigator
      created three different density surfaces of CAII and analyzed an identical
      dilution series of acetazolamide (ranging from 4.1 to 1000 nM). The greatest
      variability in the results was observed during the enzyme immobilization step
      since each investigator provided their own surface activating reagents.
      Variability in the quality of the acetazolamide binding responses was likely a
      product of how well the investigators' instruments had been maintained. To
      determine the reaction kinetics, the responses from the different density
      surfaces were fit globally to a 1:1 interaction model that included a term for
      mass transport. The averaged association and dissociation rate constants were
      3.1+/-1.6 x 10(6)M(-1)s(-1) and 6.7+/-2.5 x 10(-2)s(-1), respectively, which
      corresponded to an average equilibrium dissociation constant (K(D) of 2.6+/-1.4 x
      10(-8)M. The results provide a benchmark of variability in interpreting binding
      constants from the biosensor and highlight keys areas that should be considered
      when analyzing small molecule interactions.

PMID- 15183769
TI  - High-performance liquid chromatography-mass selective detection assay for adenine
      released from a synthetic RNA substrate by ricin A chain.
AB  - High-performance liquid chromatography (HPLC) and selected ion monitoring mass
      spectrometry (MS) were used to develop a quantitative assay for adenine released
      from a synthetic RNA substrate by ricin A chain, which contains the toxin's N
      glycosidase activity. Because ricin and ricin A chain have potential applications
      as biotherapeutics and bioweapons, assays are needed to evaluate potency and
      potential inhibitors of activity. The detection limit for adenine was 0.02 microM
      (2.4 ng/ml), and the standard curve was linear up to 27.3 microM. The lower limit
      of quantitation was 0.27 microM and was reproducible throughout this range.
      Reaction characterization showed that most adenine was released by 5h and that
      the reaction could not be fully stopped with formic acid concentrations up to
      0.75 mM (the maximum typically used for HPLC-MS). Injections were made at 2-min
      intervals, 10 injections could be performed before the column was backflushed,
      and no ricin A chain was observed in the column effluent. This assay would also
      be useful for ricin since ricin A chain did not pass through the HPLC column.
      With minor modifications to this system, the assay should provide rapid,
      sensitive, selective, and quantitative assessment of the activity of most
      ribosome-inactivating proteins. In addition, further chromatographic and mass
      spectrometric improvements could reduce sample requirements and analysis times.

PMID- 15183770
TI  - A method for the non-covalent immobilization of heparin to surfaces.
AB  - The interaction of heparan sulfate (HS) with specific proteins facilitates a wide
      range of fundamental biological processes including cellular proliferation and
      differentiation, tissue homeostasis, and viral pathogenesis. This multiplicity of
      function arises through sequence diversity within the HS chain. Heparin, which is
      very similar in structure to the sulfated regions of HS, is an excellent model
      for studying HS-protein interactions. The development of high-throughput enzyme
      linked immunosorbent-like assays using surface-immobilized heparin has been
      hindered by the inability of this glycosaminoglycan to adhere to microtiter
      surfaces. Here we report the passive noncovalent adsorption of heparin onto
      microtiter wells following their treatment by plasma polymerization; there was no
      detectable binding of functional heparin onto untreated plates. Heparin
      immobilized in this way was able to interact with four different heparin-binding
      proteins tested, i.e., TSG-6, chemokines IL-8 and KC, and complement factor H.
      Heparin preparations ranging in size from high molecular weight to a defined
      decasaccharide could be adsorbed onto these plates in a functionally active form.
      Since plasma polymerization is possible for virtually any surface, this technique
      is likely to be of general use in the identification and characterization of
      heparin/HS-binding proteins in a wide range of applications.

PMID- 15183771
TI  - Neuronal-specific endoplasmic reticulum Mg(2+)/Ca(2+) ATPase Ca(2+) sequestration
      in mixed primary hippocampal culture homogenates.
AB  - Endoplasmic reticulum Mg(2+)/Ca(2+) ATPase Ca(2+) sequestration is crucial for
      maintenance of neuronal Ca(2+) homeostasis. The use of cell culture in
      conjunction with modern Ca(2+) imaging techniques has been invaluable in
      elucidating these mechanisms. While imaging protocols evaluate endoplasmic
      reticulum Ca(2+) loads, measurement of Mg(2+)/Ca(2+) ATPase activity is indirect,
      comparing cytosolic Ca(2+) levels in the presence or absence of the Mg(2+)/Ca(2+)
      ATPase inhibitor thapsigargin. Direct measurement of Mg(2+)/Ca(2+) ATPase by
      isolation of microsomes is impossible due to the minuscule amounts of protein
      yielded from cultures used for imaging. In the current study, endoplasmic
      reticulum Mg(2+)/Ca(2+) ATPase Ca(2+) sequestration was measured in mixed
      homogenates of neurons and glia from primary hippocampal cultures. It was
      demonstrated that Ca(2+) uptake was mediated by the endoplasmic reticulum
      Mg(2+)/Ca(2+) ATPase due to its dependence on ATP and Mg(2+), enhancement by
      oxalate, and inhibition by thapsigargin. It was also shown that neuronal Ca(2+)
      uptake, mediated by the type 2 sarco(endo)plasmic reticulum Ca(2+) ATPase
      isoform, could be distinguished from glial Ca(2+) uptake in homogenates composed
      of neurons and glia. Finally, it was revealed that Ca(2+) uptake was sensitive to
      incubation on ice, extremely labile in the absence of protease inhibitors, and
      significantly more stable under storage conditions at -80 degrees C.

PMID- 15183772
TI  - A rapid method for analyzing recombinant protein inclusion bodies by mass
      spectrometry.
AB  - The identification and characterization of a protein overexpressed in insoluble
      inclusion bodies in Escherichia coli are the first crucial and time-limiting
      steps in recombinant protein expression. Here, a straightforward approach to the
      analysis of recombinant proteins in inclusion bodies is presented. Inclusion
      bodies were dissolved in 8M urea and analyzed by matrix-assisted laser desorption
      ionization (MALDI)-time of flight mass spectrometry without prior desalting. Mass
      determination was achieved by direct spotting of the samples onto the MALDI
      target and serial dilution in the matrix. The masses of four different proteins,
      expressed in inclusion bodies, were determined with a mass accuracy better than
      0.1%. Furthermore, protein modifications, such as N-terminal processing of single
      amino acids or artificial cyanylation caused by incubation of the inclusion
      bodies with urea at elevated temperatures, could be detected. Similarly, tryptic
      digests were directly analyzed in 2M urea to obtain peptide mass fingerprints for
      identification and more detailed information on the primary protein structure and
      secondary modifications. Due to the presence of ammonia in the urea-containing
      buffers, no Na(+) adducts were observed in the peptide mass fingerprint analysis.
      Taken together, the rapid and robust procedures presented here greatly facilitate
      the analysis of recombinant proteins.

PMID- 15183773
TI  - Nanogold-plasmon-resonance-based glucose sensing.
AB  - Noble metal nanoparticles are well known for their strong interactions with light
      through the resonant excitations of the collective oscillations of the conduction
      electrons on the particles, the so-called surface plasmon resonances. The close
      proximity of two nanoparticles is known to result in a red-shifted resonance
      wavelength peak, due to near-field coupling. We have subsequently employed this
      phenomenon and developed a new approach to glucose sensing, which is based on the
      aggregation and disassociation of 20-nm gold particles and the changes in plasmon
      absorption induced by the presence of glucose. High-molecular-weight dextran
      coated nanoparticles are aggregated with concanavalin A (Con A), which results in
      a significant shift and broadening of the gold plasmon absorption. The addition
      of glucose competitively binds to Con A, reducing gold nanoparticle aggregation
      and therefore the plasmon absorption when monitored at a near-red arbitrary
      wavelength. We have optimized our plasmonic-type glucose nanosensors with regard
      to particle stability, pH effects, the dynamic range for glucose sensing, and the
      observation wavelength to be compatible with clinical glucose requirements and
      measurements. In addition, by modifying the amount of dextran or Con A used in
      nanoparticle fabrication, we can to some extent tune the glucose response range,
      which means that a single sensing platform could potentially be used to monitor
      microM --> mM glucose levels in many physiological fluids, such as tears, blood,
      and urine, where the glucose concentrations are significantly different.

PMID- 15183774
TI  - Fluorescence polarization assays for high-throughput screening of neuropeptide FF
      receptors.
AB  - We have developed the first fluorescence polarization assays of human
      neuropeptide FF2 receptors in 384-well microtiter plates. Assays are completed in
      a single well with no transfer, separation, or wash steps. The performance is
      suitable for high-throughput drug screening applications with regard to speed of
      analysis, magnitude of displaceable signal, precision, and sensitivity of various
      reagents. The rank order of potency of agonists and antagonists agrees well
      relative to the published radiometric filtration assays: DMe NPFF > NPFF > frog
      PP (Rana temporaria pancreatic polypeptide) > PQRFamide > BIBP 3226. The effect
      of highly colored compounds is very small on the polarization signal up to
      micromolar concentrations. The method serves as a simple and fast alternative to
      radioligand binding assays of antiobesity drug candidates related to NPFF
      receptors.

PMID- 15183775
TI  - An improved colorimetric assay for the measurement of transglutaminase (type II) 
      (gamma-glutamyl) lysine cross-linking activity.

PMID- 15183777
TI  - Peripheral blood mononuclear cell counting using a DNA-detection-based method.

PMID- 15183776
TI  - Analysis of enzymatically generated phosphoinositides by (31)P nuclear magnetic
      resonance spectroscopy.

PMID- 15183778
TI  - Characterization of GSTM3 polymorphism by real-time polymerase chain reaction
      with LightCycler.

PMID- 15183779
TI  - Countercurrent affinity electrophoresis of biotinylated proteins [correction for
      protiens].

PMID- 15183780
TI  - Surface calcification of silicone plate intraocular lenses in patients with
      asteroid hyalosis.
AB  - PURPOSE: To report three cases in which a silicone-plate lens was explanted
      because of whitish deposits on the posterior optic surface. DESIGN: Observational
      case series with clinicopathological correlation. PATIENTS AND METHODS: In the
      three instances, the deposits were observed at least 2 years after uneventful
      cataract surgery. All of the patients had unilateral mild asteroid hyalosis in
      the concerned eye. After explantation of the lenses, gross and light microscopic
      analyses were performed. The posterior optic surfaces of the lenses also
      underwent scanning electron microscopy coupled with energy dispersive x-ray
      spectroscopy for analysis of the elemental composition of the deposits. RESULTS:
      Gross and light microscopic analyses revealed well-demarcated areas of whitish
      deposits on the posterior optic surface of the lenses, as well as multiple pits
      caused by Neodymium:yttrium aluminum garnet laser treatments. The deposits formed
      an amorphous layer with a "crustlike" appearance, which was confirmed by scanning
      electron microscopy. X-ray spectroscopy analyses demonstrated the composition of
      the deposits to be similar to hydroxyapatite. CONCLUSIONS: The material
      opacifying the lenses was probably derived from the asteroid bodies or from a
      similar process that results in this vitreous condition. We were unaware of this
      association between asteroid hyalosis and late postoperative dystrophic
      calcification of silicone lenses.

PMID- 15183781
TI  - Age-related changes in corneal and ocular higher-order wavefront aberrations.
AB  - PURPOSE: To investigate age-related changes in ocular and corneal higher-order
      wavefront aberrations and elucidate relative contributions of the cornea and the
      lens in the age-related changes. DESIGN: Observational case series. METHODS:
      Corneal and ocular higher-order wavefront aberrations in the central 6 mm
      diameter were measured with videokeratography and the Hartmann-Shack wavefront
      aberrometer in 75 normal eyes of 75 patients with a mean age of 43.5 +/- 11.7
      years (range, 18-69 years). Higher-order wavefront aberrations were calculated
      with Zernike polynomials up to sixth order. From the Zernike coefficients, we
      calculated root mean square (RMS) of coma and spherical aberration. To examine
      age-related changes of the polarity of spherical aberration, the changes of the
      Zernike coefficient Z(4)(0) was also investigated. RESULTS: Both corneal (r
      =.307, P =.007) and ocular (r =.334, P =.0033) coma RMS showed positive
      correlations with age. There was a positive correlation between corneal and
      ocular coma RMS (r =.468, P <.0001). The RMS of corneal spherical aberration did
      not change with aging (r =.153, P =.1895), whereas the RMS of ocular spherical
      aberration had a positive correlation with aging (r =.308, P =.0068).
      CONCLUSIONS: These results suggest that the ocular coma increases with age,
      mainly because of the increase in the corneal coma, and the ocular spherical
      aberration increases with age, mainly because of the increase in the spherical
      aberration in the internal optics.

PMID- 15183782
TI  - A prospective multicenter clinical trial to evaluate the safety and effectiveness
      of the implantable miniature telescope.
AB  - PURPOSE: To evaluate the safety and preliminary efficacy of a novel visual
      prosthetic device, the Implantable Miniature Telescope, IMT (by Dr Isaac
      Lipshitz) (IMT), in a phase I trial in patients with significant bilateral
      central vision impairment from late-stage age-related macular degeneration (AMD).
      The IMT is designed to reduce the relative size of the scotoma by rendering
      enlarged (threefold) central visual field images over the central and peripheral
      retina. DESIGN: Prospective, multicenter, open-label clinical trial. METHODS: In
      this prospective, multicenter phase I trial, 14 patients aged 60 or older with
      bilateral geographic atrophy or disciform scar AMD, cataract, and best-corrected
      visual acuity (BCVA) between 20/80 and 20/400 had an IMT implanted in one eye.
      Distance and near BCVA, endothelial cell density, and quality of life, measured
      as activities of daily life (ADL), were evaluated preoperatively and
      postoperatively. RESULTS: At 12 months, 10 (77%) of 13 patients gained 2 more
      lines of either distance or near BCVA, and eight (62%) of 13 patients gained 3 or
      more lines in either distance or near BCVA. Mean endothelial cell density
      decreased by 13%. All adverse events resolved without sequelae. ADL scores
      improved in the majority of patients. CONCLUSION: The results of this phase I
      trial support further evaluation of the IMT in a larger study population with
      late-stage AMD. A phase II/III trial is in progress.

PMID- 15183784
TI  - Corneal thickness measurement by confocal microscopy, ultrasound, and scanning
      slit methods.
AB  - PURPOSE: To measure corneal thickness by using a calibrated confocal microscope
      and to compare this measurement to thickness determined by ultrasonic and
      noncontact scanning slit pachymetry. DESIGN: Comparison of corneal thickness
      measured by using four instruments in normal subjects. METHODS: Thickness
      measured by a clinical confocal microscope (Tandem Scanning) was calibrated from
      measurements of polymethylmethacrylate contact lenses with known thickness.
      Corneal thickness was measured in one eye of 24 normal subjects by using this
      instrument, two ultrasonic pachymeters (DHG-1000 and Sonogage), and a noncontact
      optical scanning slit pachymeter (Orbscan II). RESULTS: Mean corneal thickness
      measured by confocal microscopy was 516 +/- 30 microm (+/-SD). This was less than
      the mean thickness measured by both ultrasonic pachymeters, 554 +/- 28 microm by
      the DGH, and 555 +/- 28 microm by the Sonogage (P <.001). Thickness measured by
      the Orbscan II pachymeter was 540 +/- 35 microm (P <.001, compared with either
      confocal or ultrasound) after applying an "acoustic factor" of 0.92, a default
      correction of the software. CONCLUSION: Corneal thickness measured by calibrated
      confocal microscopy is approximately 39 microm (7.0%) less than thickness
      measured by two commonly used ultrasonic pachymeters and approximately 24 microm
      (4.4%) less than thickness measured by the corrected Orbscan II pachymeter. These
      differences are important for planning and measuring the effects of refractive
      and other surgical procedures. The precision of confocal microscopy is limited by
      corneal motion in an anterior-posterior direction. The difference between
      instruments suggests that verification of clinical ultrasonic pachymeters should
      be revisited.

PMID- 15183783
TI  - Survival after proton-beam irradiation of uveal melanomas.
AB  - PURPOSE: To evaluate the independent prognostic factors for survival, metastasis,
      local recurrence, and enucleation in patients who had undergone proton-beam
      therapy for posterior uveal melanomas. DESIGN: Interventional case series.
      METHODS: In this retrospective study, 224 consecutive incident cases were treated
      at the Biomedical Cyclotron Centre (Nice, France) from June 1991 to December
      1997. Overall, metastasis-free, local recurrence-free, and enucleation-free
      survival rates were calculated according to the Kaplan-Meier method using the log
      rank test. The multivariate prognostic analysis was performed using the Cox
      proportional hazards model. RESULTS: The 5-year overall survival rate was 78.1%
      (SE: 3.7%). A largest basal tumor diameter (LTD) below 10 mm and female sex were
      independently associated with a better prognosis. The 5-year metastasis-free
      survival rate was 75.6% (SE: 3.6%). Only an LTD above 10 mm and ciliary body
      involvement were independently associated with metastasis. Ten patients (4.5%)
      had a local recurrence, which was correlated with the risk of metastasis (P
      =.045). The 5-year enucleation-free survival rate was 69.6% (SE: 4.0%). Once
      again, an LTD below 10 mm and female sex were predictive of a better prognosis.
      CONCLUSION: Our results with proton-beam therapy correspond to those reported in
      the literature. This treatment strategy is safe and yields predictably good
      results. In addition to the two independent prognostic factors for survival and
      metastasis, namely LTD and ciliary body involvement, sex also had a significant
      impact in our case series, but the clinical relevance of this finding is unknown.

PMID- 15183785
TI  - Hard palate mucosal grafts in oculoplastic surgery: donor site lessons.
AB  - PURPOSE: Hard palate mucosal grafts have been used successfully in posterior
      lamellar reconstruction. Atypical surgical findings, techniques, and
      complications related to the hard palate donor site are reported herein. DESIGN:
      Interventional case series. METHODS: The medical records of five patients who
      were cared for in an institutional practice between 1987 and 2002 were
      retrospectively reviewed. All patients had unusual donor site findings discovered
      during or after hard palate mucosal grafting for eyelid or socket reconstruction.
      RESULTS: Seven eyelid reconstructions with hard palate grafts were performed on
      the five patients (three male, two female), with an age range of 14 to 73 years
      at surgery. Patients were followed for an average of 6 years (range: 9 months to
      11 years). Unusual hard palate findings during surgery or the postoperative
      period included hard palate and maxillary sinus malignancy, torus palatinus, and
      persistent donor site bleeding that provoked gastric variceal bleeding in a
      patient with preexisting liver disease. Atypical surgical techniques included
      both inadvertent and intentional harvesting of hard palate tissue over the
      midline palatine raphe. CONCLUSION: Hard palate grafting is a successful and
      commonly practiced approach to eyelid and socket reconstruction. An awareness of
      unusual anatomic findings or techniques associated with the hard palate donor
      site may improve surgical outcomes and decrease patient morbidity.

PMID- 15183786
TI  - Medial rectus pulley posterior fixation is as effective as scleral posterior
      fixation for acquired esotropia with a high AC/A ratio.
AB  - PURPOSE: To compare traditional medial rectus (MR) scleral posterior fixation
      versus MR pulley posterior fixation without scleral sutures for the treatment of
      acquired esotropia (ET) with a high accommodative convergence over accommodation
      (AC/A) ratio. DESIGN: Nonrandomized interventional case series. METHODS: Medical
      records were retrospectively reviewed for twenty-two patients who underwent
      bilateral MR posterior fixation for acquired ET with a high AC/A ratio, with or
      without associated MR recessions. The main outcome measure was the reduction in
      distance-near disparity created by MR scleral posterior fixation compared with MR
      pulley posterior fixation. RESULTS: Nine patients underwent MR scleral posterior
      fixation surgery, seven in combination with MR recessions for distance ET.
      Postoperatively, the distance-near disparity decreased an average of 11.8 prism
      diopters, stereoacuity improved in six patients, and eight patients no longer
      needed bifocals. Thirteen patients underwent MR pulley posterior fixation
      surgery, 10 in combination with MR recessions for distance ET. Postoperatively
      the distance-near disparity decreased an average of 14.4 prism diopters,
      stereoacuity improved in eight patients, and 12 patients no longer required
      bifocals. Statistically, the two procedures were equivalent. One patient in each
      group was undercorrected at near only, with the residual near ET controlled with
      bifocals. One patient who underwent MR pulley posterior fixation combined with
      large MR recessions was overcorrected at distance only. CONCLUSION: Traditional
      MR scleral posterior fixation and MR pulley posterior fixation are equally
      effective in treating acquired ET with a high AC/A ratio.

PMID- 15183787
TI  - Retinal changes after macular translocation with 360-degree retinotomy in monkey
      eyes.
AB  - PURPOSE: To determine the morphologic and functional changes of the fovea and
      retina of monkey eyes after macular translocation with 360-degree retinotomy.
      DESIGN: Experimental study. METHODS: The retinas of eight monkey eyes were
      surgically translocated with a 360-degree retinotomy with procedures similar to
      those used on human eyes. At 1, 2, and 3 months after the surgery, the six eyes
      that had successful surgery were studied by light and transmission electron
      microscopy, terminal deoxynucleotidyl transferase (TdT)-dNTP terminal nick-end
      labeling (TUNEL) assay, and immunohistochemistry with peanut agglutinin (PNA)
      lectin and glial fibrillary acidic protein (GFAP). Retinal physiology was
      assessed by scotopic and photopic electroretinograms (ERGs). RESULTS: The fovea
      was successfully translocated approximately 30 to 40 degrees superiorly in six
      eyes. The translocated macula and fovea had a normal layered architecture with no
      TUNEL-positive cells, minimal misalignment of the outer segments, and strong
      immunoreactivity to GFAP. The mean amplitudes of the scotopic and photopic b
      waves were significantly reduced at 1 month after the surgery, and there was only
      a slight recovery at 3 months. No significant changes were observed in the mean
      implicit times after the surgery. CONCLUSION: These findings indicate that
      macular translocation surgery with 360-degree retinotomy results in minimal
      morphologic alterations but significant depression of electrophysiologic
      function.

PMID- 15183788
TI  - Traumatic pediatric retinal detachment: a comparison between open and closed
      globe injuries.
AB  - PURPOSE: To compare retinal detachment as a result of open and closed globe
      trauma in a pediatric age group. DESIGN: Retrospective, comparative, consecutive,
      interventional case series study. SETTING: Tertiary referral medical center.
      PATIENTS AND METHODS: One-hundred thirty-eight (5.7%) of 2,408 retinal
      detachments that were treated at our facility between 1980 and 2000 occurred in
      children aged 18 years or younger. Of these, 37 eyes (26%, n = 36) had retinal
      detachment following open globe injury and 23 eyes (14%, n = 20) had retinal
      detachment following closed globe injury. Those were compared with regard to the
      retinal detachment characteristics, number, types and timing of surgeries, and
      the anatomic and functional surgical outcome. RESULTS: Similar incidence was
      found in the type of retinal detachment, number of tears, extent, macular
      attachment type, and timing of surgery. Anatomic surgical success was achieved in
      16 eyes (46%) with open globe injury and in 13 eyes (65%) with closed globe
      injury. The improvement in visual acuity was limited and comparable in both
      groups (23% to 25%), and lower than the expected according to the Ocular Trauma
      Score (OTS). The only predictor for favorable visual outcome of > or =20/200 was
      preoperative macular attachment (P =.003, Fisher exact test). CONCLUSION: The
      type, extent, and severity of the retinal detachment were similar in both open
      and closed globe injuries, suggesting that the detachment is caused by secondary
      indirect impact of globe deformation. The anatomic and functional surgical
      outcome was guarded and similar, suggesting that further surgical innovation is
      required to improve the visual outcome in this age group.

PMID- 15183789
TI  - Does refractive error influence the association of blood pressure and retinal
      vessel diameters? The Blue Mountains Eye Study.
AB  - PURPOSE: To determine if refractive errors influence the association of blood
      pressure and retinal vessel diameters. DESIGN: Population-based, cross-sectional
      study. METHODS: Retinal photographs from the right eyes of participants (n =
      3,654, aged 49+ years) in the Blue Mountains Eye Study taken during baseline
      examinations (1992 to 1994) were digitized. The diameter of all retinal vessels
      located half to one disk diameter from the disk margin was measured using a
      computer-assisted imaging program. These measurements were combined to provide
      the average diameters of retinal arterioles and venules of that eye, and the
      ratio of their diameters, the arteriole-to-venule ratio (AVR). The association of
      blood pressure and retinal vessel diameters was analyzed before and after
      correction for refraction using the Bengtsson formula. RESULTS: Before
      correction, each 10-mm Hg increase in mean arterial blood pressure was associated
      with a 3.7-microm (95% confidence interval [CI], 3.2-4.3) decrease in arteriolar
      diameter and a 0.9-microm (95% CI, 0.3-0.9) decrease in venular diameter. After
      correction for refraction, each 1-mm Hg increase in mean arterial blood pressure
      was associated with a 3.7-microm (95% CI, 3.2-4.2) decrease in arteriolar
      diameter and a 0.8-microm (95% CI, 0.3-0.9) decrease in venular diameter.
      Refraction was not associated with the AVR and had no effect on the association
      of blood pressure and AVR. CONCLUSION: Refraction had no appreciable effect on
      the association of blood pressure and retinal vessel diameters or on the AVR.
      Correction for refraction is important for quantifying absolute retinal vessel
      caliber, but may not be particularly important in epidemiologic studies
      investigating the association of generalized retinal arteriolar narrowing and
      hypertension.

PMID- 15183790
TI  - EDTA chelation for calcific band keratopathy: results and long-term follow-up.
AB  - PURPOSE: To determine the etiologies and management of calcific band keratopathy
      (CBK), and assess the results and long-term follow-up after ethylenediamine
      tetraacetic acid (EDTA) chelation. DESIGN: Retrospective interventional case
      series. METHODS: Two hundred thirty patients with clinically significant CBK were
      included from January 1996 to July 2002. Among these, 54 patients (65 eyes)
      underwent EDTA chelation. Outcome measures included symptomatic relief, visual
      improvement, and recurrences. The improvement or worsening of the number of lines
      of Snellen best-corrected visual acuity was determined at 1 month and at last
      follow-up visit. RESULTS: The most common causes of CBK were chronic corneal
      edema in 80 eyes (28%) and idiopathic in 74 eyes (25.9%). The mean follow-up time
      after EDTA chelation was 36.6 months (range, 1 month to 29.6 years). Forty-four
      of 45 patients (98%) reported partial or complete symptomatic relief. Seventeen
      eyes (33.3%) improved 2 or more lines at 1 month and 18 eyes (35.2%) at last
      follow-up visit (P =.0001). In patients with an initial visual acuity between
      20/50 and 20/400, 15 eyes (47%) improved 2 or more lines at 1 month and 16 eyes
      (50%) at last follow-up visit. Ten of 56 eyes (17.8%) had a recurrence at a mean
      time of 17.7 years (range, 1 month to 26 years). The highest number of
      recurrences was in three of five eyes with uveitis (60%; P =.03). CONCLUSION:
      Chelation with EDTA is an effective treatment of CBK. Visual acuity improves most
      in eyes with acuity between 20/50 and 20/400. This treatment can be used as the
      initial surgical intervention after conservative measures fail.

PMID- 15183791
TI  - Intraorbital and periorbital tumors in children--value of ultrasound and color
      Doppler imaging in the differential diagnosis.
AB  - PURPOSE: To evaluate the role of ultrasonography (US) and color Doppler imaging
      (CDI) in the diagnosis of orbital tumors in children. DESIGN: Retrospective
      nonrandomized interventional case series. METHODS: This study included 42
      children with intraorbital and periorbital tumors who were evaluated in our
      clinic. All children underwent a complete clinical evaluation as well as orbital
      US and CDI. The children then underwent operation or were followed up, based on
      the clinical diagnosis and the findings on the imaging modalities. RESULTS: The
      mean age of the patients at diagnosis was 22.5 months (range 2 weeks-14 years
      old). Eighteen patients (12 female and 6 male) were diagnosed with hemangioma
      based on the findings in US and CDI; 16 patients (9 female and 7 male) were
      diagnosed with dermoid, 5 patients (4 female and 1 male) with lymphangioma, 2
      patients with rhabdomyosarcoma, and 1 patient with a subperiostal abscess. Twenty
      two patients underwent operation, and the diagnosis was confirmed on pathology.
      Twenty patients did not undergo operation and continued to be followed up in the
      clinic (mean follow-up period 38.2 months). The disease course in all patients
      who did not undergo operation was consistent with the working diagnosis.
      CONCLUSION: Both US and CDI are useful modalities in the diagnosis of
      intraorbital and periorbital tumors in the pediatric age group.

PMID- 15183792
TI  - Chronic central serous chorioretinopathy: photodynamic therapy.
AB  - PURPOSE: To demonstrate, using optical coherence and fluorescien angiography, the
      efficacy of photodynamic therapy in treating chronic central serous
      chorioretinopathy. DESIGN: Interventional case series. METHODS: A retrospective
      study in a clinical practice setting of four patients (five eyes) with chronic
      central serous chorioretinopathy. The patients were treated with verteporfin
      photodynamic therapy and evaluated by optical coherence tomography and
      fluorescien angiography with average follow-ups of 10 months. RESULTS: Compared
      to pre-treatment optical coherence tomography, an acute reduction in subretinal
      fluid accumulation and serous detachment with stoppage of leakage was noted in
      the five eyes treated. Dramatic improvement in visual acuity was also noted,
      especially among patients with better vision initially. However, pigmentary
      changes persisted. CONCLUSION: Serial optical coherence tomography demonstrates
      that photodynamic therapy with verteporfin appears to have a beneficial effect in
      treating patients with chronic central serous chorioretinopathy by reducing fluid
      leakage, subretinal fluid accumulation, and serous detachment with resultant
      improvement in vision. Better visual results might be expected if photodynamic
      therapy is applied earlier in the course of the disease.

PMID- 15183793
TI  - A spectrum of clinical manifestations of gelatinous drop-like corneal dystrophy
      in japan.
AB  - PURPOSE: Typical manifestations of gelatinous drop-like corneal dystrophy (GDLD)
      have been documented in past studies. In practice, however, we see few typical
      cases and encounter many with atypical clinical manifestations. Moreover, there
      have been no detailed reports about the various clinical presentations. The
      purpose of this study is to describe a clinical subclassification for GDLD.
      DESIGN: Observational case series. METHODS: A retrospective, observational case
      series study was conducted at a single institution, Osaka University Hospital.
      Examined were 18 eyes of ten patients with GDLD with no prior surgery. All were
      found to have M1S1 mutations. Using slit-lamp examinations we performed a
      phenotypic classification. RESULTS: We classified GDLD patients into four groups.
      They included band keratopathy type (seven eyes of four patients), stromal
      opacity type (five eyes of three patients), kumquat-like type (four eyes of two
      patients), and typical mulberry type (two eyes of two patients). CONCLUSIONS:
      Gelatinous drop-like corneal dystrophy is thought to be the result of mutations
      in M1S1; however, it has various clinical manifestations. To our knowledge, this
      study is the first to report the range of clinical phenotypes of GDLD in a
      Japanese population. As most clinicians have no criteria for diagnosing GDLD,
      many cases are likely to be overlooked or be mistaken for other conditions. We
      believe that our present classification will be useful for the diagnosis of GDLD.

PMID- 15183794
TI  - The efficacy of delayed oxygen therapy in the treatment of experimental retinal
      detachment.
AB  - PURPOSE: To evaluate the ability of delayed hyperoxia to slow or prevent
      degenerative and gliotic changes initiated by retinal detachment. DESIGN: An
      experimental study. METHODS: Rhegmatogenous detachments were produced in the
      right eyes of eight cats. After 1 day in room air (21% O(2)), four cats were
      placed in chambers with the O(2) concentration regulated at 70%; the other four
      were left in room air. At 7 days the retinas were harvested and examined by light
      and confocal microscopy. Cell specific antibodies, TUNEL and proliferation
      assays, outer segment length, and photoreceptor counts, were used to assess the
      condition of the retina. The contralateral unoperated eyes were used as controls.
      RESULTS: Animals maintained in elevated O(2) showed a dramatic preservation of
      rod and cone outer segments as well as in the organization of the outer plexiform
      layer. The number of surviving photoreceptors was increased in the hyperoxia
      treated animals. Neurite sprouting, a characteristic of detached retina, was
      rarely observed in the experimental eyes. Proliferation of non-neuronal cells was
      reduced, but not halted, by hyperoxia. GFAP and vimentin expression was not
      effected by hyperoxia; these intermediate filament proteins increased in Muller
      cells similar to that observed in control detachments. CONCLUSIONS: Exposure to
      hyperoxia, delayed by 1 day after the onset of retinal detachment, was highly
      effective in preserving photoreceptor cells and in reducing proliferation within
      the retina. It did not, however, reduce the hypertrophy of Muller glia. There
      were no apparent detrimental effects of exposure to 70% O(2) for 6 days. These
      results suggest that human patients may benefit from breathing elevated oxygen
      levels while awaiting reattachment surgery, even if the hyperoxia is delayed
      relative to the time of detachment.

PMID- 15183795
TI  - An association between central serous chorioretinopathy and gastroesophageal
      reflux disease.
AB  - PURPOSE: To explore a clinically observed association between central serous
      chorioretinopathy (CSC) and gastroesophageal reflux disease (GERD) DESIGN: A
      retrospective case-control study. PARTICIPANTS AND CONTROLS: Sixty-nine
      consecutive patients diagnosed with CSC were compared with a control group of 55
      non-CSC patients. METHODS: The records of 69 patients with CSC were
      retrospectively reviewed and compared with the records of 55 controls. All
      patients and controls were examined in a referral setting. RESULTS: Patients with
      CSC were significantly more likely to have GERD compared with controls (odds
      ratio 6.05; 95% confidence interval 2.14-17.11; P =.0003). Central serous
      chorioretinopathy patients were also more likely than controls to have used oral
      corticosteroid medications (odds ratio 16.30; 95% confidence interval 2.09
      127.33; P =.0006) and antacid/antireflux medications (odds ratio 15.00; 95%
      confidence interval 1.91-117.58; P =.001). CONCLUSIONS: This study identifies an
      association between CSC and GERD. There are biochemical factors common to both
      diseases that support this association, giving further insight into the
      pathogenesis of CSC.

PMID- 15183796
TI  - The effect of off-the-visual-axis retinoscopy on objective refractive
      measurement.
AB  - PURPOSE: To determine the effect of off-axis retinoscopy on objective refractive
      measurement. DESIGN: Prospective experimental study. METHODS: Eight volunteers
      underwent cycloplegic retinoscopy of their right eye on-the-visual-axis, and 5,
      10, 15, and 20 degrees off-the-visual-axis in adduction. A single masked examiner
      performed all retinoscopy with random order of the patient and axis refracted.
      RESULTS: The average spherical retinoscopic value at 0, 5,10,15, and 20 degrees
      of off-axis alignment was -0.40, -0.90, -1.00, -1.38, and -1.80 diopters,
      respectively. The average spherical equivalent retinoscopic value obtained for
      each of the above positions of eye alignment was -0.02, -0.59, -0.45, -0.64, and 
      0.98 diopters, respectively. The induced cylinder power increased by an average
      of 3% for each degree of off-axis retinoscopy, though the axis of the cylinder
      was not predictable. CONCLUSION: Objective refractive measurement by retinoscopy
      is significantly altered by off-the visual-axis retinoscopy. The induced error
      may be clinically important even with small degrees of eccentricity.

PMID- 15183797
TI  - Prevalence and risk factors for proliferative vitreoretinopathy in eyes with
      rhegmatogenous retinal detachment but no previous vitreoretinal surgery.
AB  - PURPOSE: To determine the prevalence of and risk factors for proliferatative
      vitreoretinopathy (PVR) in eyes with rhegmatogenous retinal detachment but no
      previous vitreoretinal surgery. DESIGN: Observational case series. METHODS:
      Prospective study. SETTING: A private vitreoretinal clinic in Caracas, Venezuela.
      STUDY POPULATION: 119 eyes of 119 patients who presented with rhegmatogenous
      retinal detachment but no previous vitreoretinal surgery between 1995 and 1998.
      OBSERVATION PROCEDURES: Data from detailed preoperative and postoperative
      examinations of each eye were recorded prospectively and entered into an
      electronic database. MAIN OUTCOME MEASURES: Prevalence of PVR of any type and
      severe PVR, preoperative risk factors for PVR of any type and severe PVR, effect
      of PVR and retinal detachment duration on initial and final visual acuity, and
      surgical complexity. RESULTS: The prevalence of PVR of any type was 52.9% and of
      severe PVR was 26.9%. The mean retinal detachment duration (+/-SD) was 58.4 (+/
      129.1) days, and the mean time from initial examination to surgical treatment (+/
      SD) was 24.3 (81.2) days. By univariable analysis, long retinal detachment
      duration, poor initial visual acuity, and large retinal detachment extent were
      significantly associated with PVR prevalence and severity. The presence of
      vitreous hemorrhage was significantly associated with PVR prevalence, and
      cataract was significantly associated with PVR severity. By multivariable
      analysis, long retinal detachment duration and large retinal detachment extent
      were simultaneous risk factors for PVR prevalence, while long retinal detachment,
      large retinal detachment extent, and poor initial visual acuity were simultaneous
      risk factors for PVR severity. Eyes with longer retinal detachment duration, PVR
      of any type, and severe PVR had worse initial and final visual acuities than eyes
      with shorter retinal detachment duration or those without PVR, respectively. Eyes
      with PVR had more complex surgery than those without PVR. CONCLUSIONS: PVR
      occurred very frequently in this population and was associated with more complex
      surgery and worse visual outcomes than among eyes without PVR. We have identified
      preventable risk factors associated with PVR that suggest a specific and
      significant need for better access to ophthalmologic care and patient education
      in this group of patients.

PMID- 15183798
TI  - Interobserver variability in optical coherence tomography for macular edema.
AB  - PURPOSE: To assess the interobserver variability of optical coherence tomography
      (OCT) measurements in patients with macular edema. DESIGN: Noninterventional case
      series using a diagnostic instrument. METHODS: Ordinary least products analysis
      of OCT data obtained by two masked observers from a set of 20 eyes from 10
      patients. SETTING: Private retina practice. RESULTS: Foveal zone thickness
      measurements were operator dependent. Fixed and proportional bias was found
      between the two observers. Total macular volume measurements were independent of
      observers. CONCLUSION: Foveal zone thickness measurements are not directly
      comparable across different observers, but total macular volume measurements are
      directly comparable. Multicenter studies involving OCT measurements and clinical
      users of OCT data will need to factor interobserver variability into conclusions
      drawn from pooled OCT foveal zone thickness measurements.

PMID- 15183799
TI  - Clinical and immunologic aspects of cancer-associated retinopathy.
AB  - PURPOSE: To report clinical and immunologic aspects of cancer-associated
      retinopathy (CAR). DESIGN: Observational consecutive case series. METHODS: A
      retrospective review was made of 18 consecutive patients with cancer-associated
      retinopathy who had antiretinal antibody determination by Western blot testing.
      RESULTS: Clinically, a variety of ophthalmic observations including
      electroretinography impairment, retinal vessel narrowing, deterioration of visual
      acuity, visual field changes, and uveitis were frequently observed. As retinal
      autoantigens in the 18 cases, recoverin was found in all 18 cases (100%), heat
      shock cognate protein 70 (HSC70) was found in six cases (33%), and other proteins
      were found in four cases (20%). These antibodies were detected in only 60% of the
      patients at the initial examination, however, and then became increasingly
      apparent on the subsequent testing that was performed three times on serum
      samples obtained sequentially during the following months. CONCLUSION: For
      diagnosis of cancer-associated retinopathy, the presence of serum autoantibody
      toward recoverin is essentially required in addition to the characteristic
      clinical aspects noted above.

PMID- 15183800
TI  - Subconjunctival antibiotics for acute postcataract extraction endophthalmitis--is
      it necessary?
AB  - PURPOSE: To evaluate the efficacy of adjunctive subconjunctival antibiotic
      injection in the treatment of acute postcataract extraction endophthalmitis.
      DESIGN: Retrospective cohort study. METHODS: Patients who presented with hand
      motions or better vision and received subconjunctival antibiotics (SC+ group)
      were compared with those who did not (SC- group) in the treatment of acute
      postoperative endophthalmitis. RESULTS: The rate of obtaining a final vision of
      20/40 or better was 60% in the SC+ group (n = 25) compared with 72% in the SC-
      group (n = 18) (P =.69), and the mean change in logMAR was -1.36 (improvement)
      versus -1.34 (P =.93). Based on a linear regression model controlling for
      presenting vision, there was no statistical difference in the mean logMAR change
      between the two groups (P =.73). CONCLUSION: Subconjunctival antibiotic injection
      as an adjunct to intravitreal antibiotics was unassociated with treatment benefit
      in patients with acute postoperative endophthalmitis presenting with vision of
      hand motions or better.

PMID- 15183801
TI  - Transient homonymous hemianopia and positive visual phenomena in nonketotic
      hyperglycemic patients.
AB  - PURPOSE: To report a case of a transient homonymous hemianopia in a patient with
      nonketotic hyperglycemia with negative magnetic resonance imaging (MRI) scans.
      DESIGN: Case report. METHOD: A 72-year-old woman with diabetes mellitus was
      referred to the neuro-ophthalmology service with hyperglycemia and multiple
      visual complaints. RESULTS: The patient was found to have a dense left homonymous
      hemianopia on examination. An MRI scan of the brain was negative for a lesion
      affecting the visual pathways. Resolution of the homonymous hemianopia and the
      patient's symptoms came with normalization of her blood glucose levels.
      CONCLUSION: Nonketotic hyperglycemia is an important diagnostic consideration in
      patients who present with homonymous visual field defects but have negative
      neuroimaging studies.

PMID- 15183802
TI  - Anterior basement membrane corneal dystrophy and pseudo-unilateral lattice
      corneal dystrophy in a patient with recurrent corneal erosions.
AB  - PURPOSE: To report the utility of genetic testing in the diagnosis and management
      of patients with suspected corneal dystrophies. DESIGN: Case report. METHODS: A
      58-year-old man with a history of recurrent corneal erosions was diagnosed with
      bilateral anterior basement membrane dystrophy and unilateral lattice corneal
      dystrophy. All 17 exons of the TGFBI gene were screened for mutations previously
      associated with lattice corneal dystrophy as well as novel coding region changes.
      RESULTS: No mutations were found in the 17 exons of the TGFBI gene. A nucleotide
      change in exon 6 (651C>G) did not result in a change in the encoded amino acid
      (Leu217Leu). CONCLUSIONS: In cases of suspected TGFBI corneal dystrophies,
      genetic testing is a useful tool to confirm the clinical diagnosis. In this case
      of suspected unilateral lattice corneal dystrophy, screening of the TGFBI gene
      ruled out the diagnosis, raising the possibility that the corneal changes were
      related to the coexistent anterior basement membrane dystrophy.

PMID- 15183803
TI  - Optical coherence tomography under general anesthesia in a child with nystagmus.
AB  - PURPOSE: To describe a method that permits optical coherence tomography scanning
      to be performed under general anesthesia. DESIGN: Observational case report.
      METHODS: A 7-year-old child underwent optical coherence tomography scanning under
      general anesthesia. He was positioned prone, with the neck extended to enable
      vertical facial alignment on the scanner. An anti-Trendelenburg trend on the
      operating table minimized the degree of neck extension required. Intravenous
      fluids, modest ventilator airway pressures, and compression stockings were used
      to minimize perioperative hemodynamic disturbance and the potential for
      orthostatic hypotension associated with the anti-Trendelenburg trend. RESULTS:
      High-quality, diagnostically important optical coherence tomography scans were
      obtained. CONCLUSION: With appropriate patient positioning and anesthetic
      management, optical coherence tomography scanning can be performed on
      uncooperative adults and children under general anesthesia.

PMID- 15183804
TI  - Decreased levels of pigment epithelium-derived factor in eyes with neuroretinal
      dystrophic diseases.
AB  - PURPOSE: To determine the concentration of pigment epithelium-derived factor
      (PEDF) in the aqueous humor of eyes with neuroretinal dystrophy. DESIGN:
      Observational case series. METHODS: Aqueous humor was obtained from patients
      during cataract surgery, and the PEDF concentration in the aqueous humor was
      measured by enzyme-linked immunosorbent assay. The primary diagnosis was cataract
      in 162 eyes; of these there were five eyes with retinitis pigmentosa, nine eyes
      with advanced glaucoma, and 148 eyes with cataract alone. RESULTS: The mean
      levels of PEDF in eyes with retinitis pigmentosa (0.24 +/- 0.04 microg/ml, mean
      +/- SE, P =.0004) and advanced glaucoma (0.46 +/- 0.08 microg/ml, P =.003) were
      significantly lower than that in eyes with cataract alone (0.86 +/- 0.04
      microg/ml). CONCLUSION: The lower levels of PEDF in eyes with neuroretinal
      dystrophy may be related to the loss of the retinal ganglion cells or retinal
      pigment epithelium cells that synthesize PEDF.

PMID- 15183805
TI  - Buccal fat pad hemorrhage after retrobulbar injection.
AB  - PURPOSE: To enable ophthalmologists to recognize and manage buccal fat pad
      hemorrhage occurring after retrobulbar injection. DESIGN: Interventional case
      report. METHODS: A 52-year-old woman with proliferative diabetic retinopathy
      underwent left retrobulbar injection before panretinal photocoagulation (PRP).
      RESULTS: Immediately after PRP, the patient complained of left cheek swelling.
      Ocular examination was unremarkable. Computed tomographic imaging studies
      confirmed the clinical diagnosis of hemorrhage within the buccal fat pad. No
      hemorrhage was found within the retrobulbar space. The hemorrhage resolved
      spontaneously without sequelae. CONCLUSION: This case widens the known spectrum
      of hemorrhagic complications after retrobulbar injection.

PMID- 15183806
TI  - Macular burn after transpupillary thermotherapy for occult choroidal
      neovascularization.
AB  - PURPOSE: To report a case of severe macular burn as a complication of
      transpupillary thermotherapy treatment for occult choroidal neovascularization.
      DESIGN: Interventional case report. METHODS: A 65-year-old man developed a severe
      macular burn following transpupillary thermotherapy treatment. RESULTS: Before
      treatment, fluorescein angiography and indocyanine green angiography showed a
      progressive, ill-defined leakage corresponding to the presence of occult
      choroidal neovascularization. One month after treatment, fundus examination
      disclosed macular atrophy. The early phases of fluorescein angiography and
      indocyanine green angiography showed that the macular choroidal filling time had
      worsened dramatically. At the late phase of indocyanine green angiography, the
      initial hyperfluorescence of choroidal neovascularization was replaced by a
      persistent, markedly hypofluorescent area. CONCLUSION: Prolonged choroidal
      filling may be a risk factor for macular burn and choroidal occlusion after
      transpupillary thermotherapy. In such cases, we suggest that transpupillary
      thermotherapy should be considered with caution and, when applied, that its
      intensity should be reduced.

PMID- 15183807
TI  - Bull's-eye maculopathy secondary to herbal toxicity from uva ursi.
AB  - PURPOSE: To report a case of bilateral bull's-eye maculopathy in a patient who
      ingested uva ursi, a known inhibitor of melanin synthesis, for 3 years before the
      onset of symptoms. DESIGN: Observational case report. METHODS: Both eyes of a
      female patient were examined in the clinical practice setting. RESULTS: A 56-year
      old woman who ingested uva ursi for 3 years noted a decrease in visual acuity
      within the past year. Ocular examination including fluorescein angiography
      revealed a typical bull's-eye maculopathy bilaterally. CONCLUSIONS: Uva ursi is a
      known inhibitor of melanin synthesis. It is necessary to broaden the list of
      potential retinal toxic drugs to include herbal adjuvants such as Uva Ursi and to
      elicit a history of their use in patients with unexplained ocular findings.

PMID- 15183808
TI  - Novel 2336-2337delCT mutation in RP1 gene in a Japanese family with autosomal
      dominant retinitis pigmentosa.
AB  - PURPOSE: To determine the frequency and kinds of mutations in the RP1 gene, and
      to characterize the clinical features of a Japanese family with autosomal
      dominant retinitis pigmentosa (ADRP) with a novel 2336 to 2337delCT mutation in
      the RP1 gene. DESIGN: Case reports and results of DNA analysis. METHODS:
      Mutational screening by direct sequencing was performed on 96 unrelated patients
      with ADRP. The clinical features were determined by complete ophthalmologic
      examinations. RESULTS: A novel 2336 to 2337delCT mutation in the RP1 gene was
      identified in two patients from a Japanese family with ADRP. In addition, three
      families with ADRP carried a previously reported nonpathogenic Arg1933X mutation.
      The ophthalmic findings with a 2336 to 2337delCT mutation were similar to those
      of typical retinitis pigmentosa with rapid progression after age 40 years.
      CONCLUSIONS: The most common Arg677X mutation in the white population was not
      found in the Japanese population; instead a novel mutation was found.

PMID- 15183809
TI  - Optical coherence tomography findings in patients with late solar retinopathy.
AB  - PURPOSE: To investigate the morphologic appearance on optical coherence
      tomography (OCT) of the macula in patients with late solar retinopathy and its
      association with visual acuity. DESIGN: Observational case series. METHODS: All
      patients with solar retinopathy evaluated between 1998 and 2003 at one
      institution were invited to participate in an ophthalmic evaluation. RESULTS: In
      all four affected eyes of four patients, OCT demonstrated abnormal reflectivity
      at the outer foveal retina, such as fragmentation or interruption of the inner
      high reflective layer corresponding to the junction between the photoreceptor
      inner and outer segments. Involvement of the entire photoreceptor reflective
      layer at the fovea was observed in the patient with decreased visual acuity
      (20/60). CONCLUSIONS: Optical coherence tomography demonstrated abnormalities in
      the outer foveal retina. The OCT findings suggest that decreased visual acuity
      may be associated with full-thickness involvement of the photoreceptors.

PMID- 15183810
TI  - Serum levels of triamcinolone acetonide after intravitreal injection.
AB  - PURPOSE: To evaluate serum levels of triamcinolone acetonide after intravitreal
      high-dose injection. DESIGN: Prospective, interventional case series study.
      METHODS: For 20 consecutive patients, venous blood samples were taken before and
      13 +/- 19 days (range 4 to 92) after an intravitreal injection of 20 to 25 mg
      triamcinolone acetonide as treatment of edematous macular diseases. RESULTS:
      Serum levels of triamcinolone acetonide did not differ significantly (P =.174; t
      test for paired matches) preoperatively (0 microg/l) and postoperatively (0.065
      microg/l +/- 0.21 microg/l). In 18 eyes (90%), triamcinolone acetonide could not
      be detected in serum samples. For two patients (10%), serum samples taken 5 days
      and 7 days after the injection, respectively, contained 0.5 microg/l
      triamcinolone acetonide and 0.8 microg/l triamcinolone acetonide, respectively.
      CONCLUSION: After an intravitreal high-dose injection of 20 to 25 mg
      triamcinolone acetonide, triamcinolone acetonide is not, or only marginally,
      detectable in serum samples obtained within 4 to 92 days after the injection.

PMID- 15183811
TI  - Photodynamic therapy for choroidal metastasis from carcinoid tumor.
AB  - PURPOSE: To determine the efficacy of photodynamic therapy for the treatment of a
      choroidal metastasis unresponsive to chemotherapy and radiation therapy. DESIGN:
      Interventional case report. METHODS: Photodynamic therapy with verteporfin was
      performed. Visual acuity, local tumor control, and complications were assessed.
      RESULTS: A 72-year-old woman was diagnosed with bilateral, biopsy-proven
      choroidal metastasis from a pulmonary carcinoid tumor that was resistant to
      chemotherapy and radiotherapy. The tumor in the left eye caused a retinal
      detachment and vision loss to light perception. The smaller lesion in the right
      eye progressively enlarged toward the fovea despite therapy and was treated with
      photodynamic therapy with verteporfin. Within 2 months, the exudative detachment
      resolved, the visual acuity returned to baseline, and the tumor volume decreased
      by 50%. CONCLUSION: Photodynamic therapy may be an effective treatment option for
      selected patients with choroidal metastasis.

PMID- 15183812
TI  - Extraocular muscle enlargement with tendon involvement in thyroid-associated
      orbitopathy.
AB  - PURPOSE: To evaluate the configuration of extraocular muscle and tendon
      enlargement in patients with thyroid-associated orbitopathy (TAO). DESIGN:
      Retrospective, noncomparative case series. METHODS: We retrospectively evaluated
      the preoperative computed tomography (CT) or magnetic resonance imaging (MRI)
      scans, or both, of 125 consecutive patients with previously diagnosed TAO. Axial
      CT (n = 88) or MRI (n = 37) slices of the orbits were examined for tendon
      involvement of enlarged medial or lateral recti muscles. A ratio of tendon to
      muscle width greater than 0.5 was considered as tendon involvement. RESULTS:
      Eight patients (6.4%) with TAO demonstrated tendon involvement on axial CT or
      MRI. These patients had significantly greater diplopia in primary gaze than
      patients with no tendon involvement or patients with no muscle enlargement.
      CONCLUSION: The configuration of extraocular muscle enlargement on imaging
      studies has traditionally been used to differentiate TAO from other inflammatory
      processes because the tendon is typically spared (fusiform configuration) in TAO.
      However, we found that the configuration of tendon involvement (cylindrical
      configuration) can occasionally be noted in TAO and may be more frequently
      associated with primary gaze diplopia. Tendon involvement does not eliminate the
      diagnostic possibility of TAO.

PMID- 15183813
TI  - Conjunctival melanoma metastasis diagnosed by sentinel lymph node biopsy.
AB  - PURPOSE: Evaluate the use of sentinel lymph node biopsy (SLNB) in staging and
      directing treatment of patients with conjunctival malignancy. DESIGN:
      Retrospective, noncomparative, interventional case reports. METHODS: Two patients
      with conjunctival melanoma underwent SLNB, which consisted of lymphoscintigraphy
      with injection of sulfur colloid technetium-99m. Lymphazurin blue was injected
      intraoperatively into the area of prior excision. The combination of a signal
      through the sulfur colloid technetium-99m and blue staining identified SLNs.
      RESULTS: In both patients, the SLNs containing metastatic disease were identified
      and biopsies obtained, aiding staging and optimal therapy. CONCLUSION: Sentinel
      lymph node biopsy has been recently reported as an aid in evaluating patients
      with periocular malignancies. These reports of patients with tumor-positive SLNs
      arising from the lymphatic metastasis of conjunctival malignancies underscore the
      utility of this important technique in evaluating patients with periocular
      malignancies.

PMID- 15183814
TI  - Radiation-blocking glasses allow vision during ophthalmic plaque radiation
      therapy.
AB  - PURPOSE: To evaluate the use of leaded safety glasses to block radiation and
      allow for vision during ophthalmic plaque radiation therapy. DESIGN:
      Interventional case series. METHODS: Eight patients were treated with palladium
      103 ophthalmic plaque radiotherapy and measured for emitted radiation while
      wearing leaded glasses or a lead patch. Radiation emission was measured at 1 m so
      as to compare the glasses' ability to block radiation in vivo. RESULTS: In two
      patients the tumor was in the patients' only seeing eye, and the leaded radiation
      safety glasses allowed them to function (feed themselves and walk to the bathroom
      unassisted). In two additional patients, the glasses allowed binocularity and
      were preferred over the patch. Measurements revealed that both the lead patch and
      leaded radiation safety glasses reduced exposure to levels acceptable for
      discharge to home in New York City. CONCLUSIONS: Leaded radiation safety glasses
      improved patients' quality of life without sacrificing radiation safety.

PMID- 15183815
TI  - Intravitreal triamcinolone acetonide for the management of diabetic papillopathy.
AB  - PURPOSE: To present a case of severe drop in vision in both eyes caused by
      diabetic papillopathy that was treated with an intravitreal injection of
      triamcinolone acetonide. DESIGN: Interventional case report. METHODS: A diabetic
      patient with bilateral diabetic papillopathy and drop in vision received
      sequential intravitreal triamcinolone acetonide injections to both eyes. RESULTS:
      Within 2 weeks of intravitreal injection, vision improved from counting fingers
      at 1 m to 20/50 OS, and from counting fingers at 4 m to 20/40 OD. This
      improvement was accompanied by resolution of disk swelling and macular edema.
      Vision remained stable in both eyes at 20/40 for 8 months of follow-up. No
      elevation of intraocular pressure beyond 21 mm Hg was noted at any time.
      CONCLUSION: Diabetic papillopathy with severe drop in vision can be treated with
      intravitreal triamcinolone acetonide injection.

PMID- 15183816
TI  - Orbital cysticercosis-associated scleral indentation presenting with pseudo
      retinal detachment.
AB  - PURPOSE: To report a clinical picture similar to retinal detachment caused by
      orbital myocysticercosis-associated scleral indentation. DESIGN: Interventional
      case series. METHODS: Of the 49 cases of orbital myocysticercosis, four eyes of
      four patients had pseudoretinal detachment presentations that are detailed.
      RESULTS: Of the four patients with pseudoretinal detachment, three were found to
      have orbital myocysticerci in lateral and one in inferior recti muscles,
      mechanically indenting the eyeball, causing scleral indentation, evidenced by
      ultrasonography or computed tomography. Associated signs of myocysticercosis were
      orbital inflammation, restricted ocular motility or proptosis. In 2 to 10 days,
      the cysts traveled forward and came to lie in a sub-Tenon position. Three cysts
      were removed surgically and one extruded spontaneously. CONCLUSIONS: Patients
      presenting with a clinical picture similar to retinal detachment in the presence
      of symptoms and signs of orbital cysticercosis, with a history of exposure to an
      endemic area, should be considered to have orbital myocysticerci causing scleral
      indentation.

PMID- 15183817
TI  - Optical coherence tomographic findings of dissociated optic nerve fiber layer
      appearance.
AB  - PURPOSE: To examine the features of optical coherence tomographic (OCT) findings
      of dissociated optic nerve fiber layer (DONFL) appearance. DESIGN: Case-control
      study. METHODS: Twenty-four eyes undergoing vitrectomy for idiopathic epiretinal
      membrane or macular hole were examined postoperatively using OCT. RESULTS:
      Thirteen of the 24 eyes exhibited the DONFL appearance. In these 13 eyes, the OCT
      images indicated dimples in the retinal nerve fiber layer (RNFL) corresponding to
      each stria. The RNFL thickness (mean +/- SD) at the dimple site was 38.1 +/- 9.3
      microm. The depth of each dimple was 28.6 +/- 8.0 microm. The depths of all the
      dimples were limited to the RNFL thickness. In the other 11 eyes without the
      DONFL appearance, OCT images showed no distinct dimples. CONCLUSIONS: The DONFL
      appearance is caused by dimples the depths of which are limited to the RNFL
      thickness.

PMID- 15183818
TI  - The comparison of efficacies of topical corticosteroids and nonsteroidal anti
      inflammatory drops on dry eye patients: a clinical and immunocytochemical study.

PMID- 15183819
TI  - Optical coherence tomography findings in familiar foveal retinoschisis.

PMID- 15183822
TI  - Acute endophthalmitis following intravitreal triamcinolone acetonide injection.

PMID- 15183823
TI  - Vitreous wick syndrome--a potential cause of endophthalmitis after intravitreal
      injection of triamcinolone through the pars plana.

PMID- 15183826
TI  - Radial optic neurotomy as treatment for central retinal vein occlusion.

PMID- 15183827
TI  - Anatomical and visual outcome of macular hole surgery with infracyanine green
      assisted peeling of the internal limiting membrane, endodrainage, and silicone
      oil tamponade.

PMID- 15183829
TI  - Aqueous shunt devices compared with trabeculectomy with mitomycin-C for children
      in the first two years of life.

PMID- 15183831
TI  - Correlation between posterior capsule opacification and visual function before
      and after neodymium:YAG laser posterior capsulotomy.

PMID- 15183833
TI  - Acute endophthalmitis following intravitreal triamcinolone acetonide injection.

PMID- 15183835
TI  - Ciprofloxacin in endophthalmitis: an emerging alternative.

PMID- 15183837
TI  - Anterior chamber depth in plateau iris syndrome and pupillary block as measured
      by ultrasound biomicroscopy.

PMID- 15183839
TI  - Intraocular pressure, Goldmann applanation tension, corneal thickness, and
      corneal curvature in Caucasians, Asians, Hispanics, and African Americans.

PMID- 15183840
TI  - Erythroid differentiation regulator (EDR), a novel, highly conserved factor I.
      Induction of haemoglobin synthesis in erythroleukaemic cells.
AB  - In serum-free WEHI-3 supernatants an activity was detected inducing haemoglobin
      synthesis in human and murine erythroleukaemia cell lines. The absolute numbers
      of benzidine-positive cells induced with either DMSO or WEHI-3-conditioned medium
      were comparable. Terminal differentiation was not observed. An expression library
      from WEHI-3 RNA aided by PCR cloning revealed an open reading frame corresponding
      to a 209 amino acid protein. This was 100% identical to a sequence from human
      stimulated peripheral blood mononuclear cells. In contrast to human RNA, mouse
      RNA exhibited multiple bands of pre-mRNA in Northern blots. The gene was
      provisionally termed erythroid differentiation regulator (edr). In mammalian
      cells EDR is mostly expressed as a 56 kDa dimer showing higher activity than the
      recombinant monomer. The activity profile is bell-shaped. Expression was observed
      in many normal mouse tissues, yet in haematopoiesis it was largely confined to
      CD34+ cells. It was enhanced by a series of stimuli such as phorbol ester, and
      transformed cells generally showed a higher level of EDR expression than normal
      ones. The protein is localized at the inner side of the cytoplasmic membrane and
      is released in part via vesicles. In view of the broad range of EDR-expressing
      tissues the function obviously exceeds haemoglobin synthesis induction.
      Involvement in cell survival and growth control has been observed and will be
      dealt with in detail elsewhere.

PMID- 15183841
TI  - Heat stress decreases pulmonary MCP-1 production in endotoxemia.
AB  - An exaggerated pro-inflammatory response in endotoxemia may lead to multiple
      organ damage including acute lung injury. Heat stress prior to endotoxemia
      results in attenuation of inflammation possibly by decreasing cytokine
      production. Monocyte chemoattractant protein (MCP)-1, a pro-inflammatory
      cytokine, is responsible for monocyte recruitment into the lung in acute lung
      injury. The objective of this study is to determine if pretreatment with heat
      results in decreased MCP-1 production in the lungs of endotoxemic rats at a
      transcriptional or post-transcriptional level. Rats were assigned to one of four
      groups: control, heat alone, heat with or without endotoxin. Rats were made
      endotoxemic by injection of Escherichia coli lipopolysaccharide. MCP-1 was
      measured in lavage fluid and MCP-1 mRNA in the lung tissue. Endotoxemia resulted
      in production of MCP-1. Control and heat alone rats had 21+/-4 vs. 20+/-3 pg/ml,
      p=0.75. MCP-1 concentration was decreased in the lavage fluid of pre-heated when
      compared to non-heated endotoxemic rats (37+/-28 vs. 70+/-35 pg/ml, p <0.02 ).
      However, the MCP-1 mRNA was higher in the heated compared to non-heated
      endotoxemic rats (1.59+/-0.35 vs. 0.74+/-0.51, MCP-1/beta-actin mRNA, p <0.01).
      Control and heat alone rats had undetectable mRNA MCP-1 in the lungs. Heat stress
      prior to endotoxemia results in decreased production of MCP-1 by a post
      transcriptional mechanism.

PMID- 15183842
TI  - Functional analysis of the interleukin-5 receptor antagonist peptide, AF18748.
AB  - AF18748 is a dimeric peptide of 2 x 19 amino acids that specifically binds to the
      alpha-chain of the human IL-5 receptor (IL-5R), preventing binding of IL-5 and
      acting as a receptor antagonist. However, the peptide acts by inducing alpha
      chain dimerization, and we therefore set out to investigate whether this peptide
      would have any residual agonist activity. AF18748 was unable to induce activation
      of a number of signal transduction pathways, but was able to specifically block
      IL-5-dependent signal transduction. The peptide was unable to support the
      survival and proliferation of the cytokine dependent cell line, Ba/F3-IL-5R, and
      was unable to prime the respiratory burst, or induce adhesion, migration or
      survival of primary human eosinophils. In each case the AF18748 functioned as an
      antagonist. These data suggest that AF18748 may be useful to specifically
      modulate eosinophil function in vivo.

PMID- 15183843
TI  - Changes in cytokine production and impaired hematopoiesis in patients with
      anorexia nervosa: the effect of refeeding.
AB  - The changes in cytokines and hormones involved in hematopoiesis were studied in
      the serum of 7 girls with anorexia nervosa, 15-24 yr old, on admission and after
      5% and 10% weight gain. Hematopoiesis was studied by in-vitro culturing of
      circulating granulocyte-macrophage colony forming cells and erythroid burst
      forming cells. Nutritional status was studied by anthropometric measurements and
      resting energy expenditure. On admission, granulocyte-macrophage colony forming
      cells and erythroid burst forming cells were significantly lower than in age
      matched controls and increased significantly along weight gain. Blood leptin and
      erythropoietin levels increased significantly with weight gain. TNF-alpha levels
      tended to decrease while IL-1beta levels were lower than in the controls on
      admission (p <0.05) and did not change significantly during weight gain. IL-3, GM
      CSF and IL-6 were undetected on admission or along weight gain. The changes in
      granulocyte-macrophage colony forming cells and erythroid burst forming cells
      positively correlated with changes in resting energy expenditure and fat free
      mass. These results may suggest that undernutrition affects hematopoiesis as
      indicated by the reduction of hematopoietic progenitor cells before treatment and
      the significant increase with weight gain. The changes in the levels of hormones
      and cytokines known to be involved in hematopoiesis along refeeding may suggest a
      role for these factors in anorexia nervosa.

PMID- 15183844
TI  - Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory
      Smad7 by a negative feedback mechanism.
AB  - As a member of the TGF-beta superfamily, myostatin is a specific negative
      regulator of skeletal muscle mass. To identify the downstream components in the
      myostatin signal transduction pathway, we used a luciferase reporter assay to
      elucidate myostatin-induced activity. The myostatin-induced transcription
      requires the participation of regulatory Smads (Smad2/3) and Co-Smads (Smad4).
      Conversely, inhibitory Smad7, but not Smad6, dramatically reduces the myostatin
      induced transcription. This Smad7 inhibition is enhanced by co-expression of
      Smurf1. We have also shown that Smad7 expression is stimulated by myostatin via
      the interaction between Smad2, Smad3, Smad4 and the SBE (Smad binding element) in
      the Smad7 promoter. These results suggest that the myostatin signal transduction
      pathway is regulated by Smad7 through a negative feedback mechanism.

PMID- 15183845
TI  - Antitumor and antimetastatic effect of warfarin and heparins.
AB  - Experimental and clinical studies have shown an anticancer effect of
      anticoagulant drugs. The aim of this study is to review the mechanisms by which
      the common types of anticoagulants influence the primary tumor and metastatic
      processes of solid tumors. The review evaluates the interference of
      unfractionated heparin (UFH), low molecular weight heparin (LMWH) and warfarin on
      the growth of primary tumors and on the development of metastases. The first part
      of the review evaluates the effect on the growth and development of primary
      tumors. Attention is paid to the interference with proliferation of cancer cells,
      tumor angiogenesis and to the interference with the immune system. The second
      part of the review describes the metastatic process and the effect of
      anticoagulants on the cell motility and cancer cell adhesion. The third part
      refers to the outcomes of clinical studies with anticoagulant treatment in
      patients with cancer. The problem of thromboembolic disease in patients with
      advanced cancer is also mentioned. The anticoagulants are more effective in
      inhibition of stages of the metastatic cascade than in the influence on primary
      tumors. They can interfere with tumor angiogenesis, immunity system, cancer cell
      motility and adhesion. The first clinical trials showed an effect on the
      development of primary tumors and survival of patients namely with lung cancer.

PMID- 15183846
TI  - Mini review of high altitude health problems in Ladakh.
AB  - Ladakh is a sparsely populated area of Indian Himalaya lying at 3-4500 m altitude
      mainly consisting of arid desert. This paper will discuss high altitude health
      problems in Ladakh under the following headings. 1. Acute altitude illness: acute
      mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high altitude
      cerebral edema (HACE). 2. Effects of prolonged and permanent exposure to high
      altitude: (subacute and chronic mountain sickness). 3. Environmental dust and
      domestic fire pollution resulting in non-occupational pneumoconiosis and high
      prevalence of respiratory morbidity.

PMID- 15183847
TI  - Protein-bound polysaccharide K induced apoptosis of the human Burkitt lymphoma
      cell line, Namalwa.
AB  - Protein-bound polysaccharide K (PSK), which is derived from mushrooms belonging
      to the Basidiomycetes genus, has been clinically used as a biological response
      modifier (BRM) for the treatment of epithelial cancer patients in Japan and other
      Asian countries. There are a large number of studies on the biological activities
      of PSK as regards the activation of immunocompetent cells and the potential
      cytotoxic effects on epithelial cancer cells. However, only a few studies have
      been conducted to see the direct cytotoxic effects of PSK on hematological
      malignant cells. In this study, we investigated whether or not PSK was able to
      induce cellular apoptosis in hematological malignant cells. PSK was found to
      inhibit cell growth, and induced subsequent cellular apoptosis in the Burkkit
      lymphoma cell line (Namalwa), out of 33 hematological malignant cell lines
      tested. This PSK-induced apoptosis was neutralized by the addition of galactose
      to the culture medium, whereas apoptosis was augmented by treatment with beta
      galactosidase, indicating the inhibitory involvement of galactose in the
      mechanism of action. These results provide initial evidence of the direct
      cytotoxic activity of PSK in a hematological malignant cell line, thus
      encouraging further molecular-level study of PSK-mediated apoptosis in malignant
      hematological cells.

PMID- 15183848
TI  - Effect of cyclosporin A on human gingival fibroblast collagen turnover in
      relation to the development of gingival overgrowth: an in vitro study.
AB  - In a significant number of cases (25-81%) immunosuppressant treatment with
      cyclosporin A (CsA) is associated with gingival overgrowth, seriously interfering
      with the functions of mastication and speech. In CsA-induced gingival
      enlargement, quantitative modifications of the extracellular matrix components
      occur, and collagen (COL) metabolism and matrix metalloproteinases (MMPs) have
      been suggested as being the main targets. Since the mechanisms at the basis of
      CsA-induced gingival overgrowth are not yet completely understood, our aim was to
      analyze the effect of CsA on COL turnover in cultured human gingival fibroblasts.
      Cultured human gingival fibroblasts from four healthy volunteers were incubated
      with CsA (800 ng/ml) or with its vehicle (VH) for variable intervals of time (24,
      48, 72 h). Fibroblast morphology was studied by light and electron microscope.
      Collagen type I (COL-I), MMP-1, MMP-2, TIMP-1 and TGF-beta1 mRNA were determined
      by RT-PCR; COL-I and MMP-1 by dot blot, and MMP-2 by zymography. Our results
      evidenced an up-regulation of COL-I and TGF-beta1 gene expression 72 h after CsA
      treatment. MMP-1, MMP-2 and TIMP-1 mRNA levels are affected but not
      significantly. Protein analysis revealed COL-I increase at all the considered
      times and, 72 h after CsA treatment, reduced collagenolytic levels. Our data
      suggest that COL accumulation during CsA-induced gingival overgrowth may be
      mainly sustained by an altered COL-I degradation due to decreased MMP-1 activity.
      However, interindividual differences of collagenase levels after CsA treatment
      suggest that a genetic predisposition to develop gingival overgrowth may be
      relevant.

PMID- 15183849
TI  - Artificial neural network modeling to predict the plasma concentration of
      aminoglycosides in burn patients.
AB  - The goal was to use an artificial neural network model to predict the plasma
      concentration of aminoglycosides in burn patients and identify patients whose
      plasma antibiotic concentration would be sub-therapeutic based on the patients'
      physiological data and taking into account burn severity. Physiological data and
      some indicators of burn severity were collected from 30 burn patients who
      received arbekacin. A three-layer artificial neural network with five neurons in
      the hidden layer was used to predict the plasma concentration of arbekacin.
      Linear modeling for prediction of plasma concentration and logistic regression
      modeling for the classification of patients were also used and the predictive
      performance was compared to results from the artificial neural network model.
      Dose, body mass index, serum creatinine concentration and amount of parenteral
      fluid were selected as covariates for the plasma concentration of arbekacin. Area
      of burn after skin graft was a good covariate for indicating burn severity.
      Predictive performance of the artificial neural network model including burn
      severity was much better than linear modeling and logistic regression analysis.
      An artificial neural network model should be helpful for the prediction of plasma
      concentration using patients' physiological data, and burn severity should be
      included for improved prediction in burn patients. Because the relationship
      between burn severity and plasma concentration of aminoglycosides is thought to
      be nonlinear, it is not surprising that the artificial neural network model
      showed better predictive performance compared to the linear or logistic
      regression models.

PMID- 15183850
TI  - Essential oil of Australian lemon myrtle (Backhousia citriodora) in the treatment
      of molluscum contagiosum in children.
AB  - Molluscum contagiosum is a common viral illness of childhood and is increasingly
      found as a sexually transmitted disease in sexually active young adults. Current
      treatment options are invasive, requiring tissue destruction and attendant
      discomfort. Thirty-one children (mean age 4.6 +/- 2.1 years) with the diagnosis
      of molluscum contagiosum (mean length of time with condition 8.6 +/- 5.3 months)
      were treated with once daily topical application of a 10% solution (v/v) of
      essential oil of Australian lemon myrtle (Backhousia citriodora) or vehicle
      (olive oil). At the end of 21 days, there was greater than 90% reduction in the
      number of lesions in 9/16 children treated with lemon myrtle oil, while 0/16
      children met the same criteria for improvement in the vehicle group (P < 0.05).
      No adverse events were reported.

PMID- 15183851
TI  - Lidocaine has better antioxidant potential than ropivacaine and bupivacaine: in
      vitro comparison in a model of human erythrocytes submitted to an oxidative
      stress.
AB  - BACKGROUND: Local anesthetic agents may exert antioxidant properties in various
      models. The aim of this work was to compare the antioxidant properties of
      lidocaine, bupivacaine and ropivacaine using an in vitro model of human
      erythrocytes submitted to an oxidative stress. METHODS: Blood was obtained from
      healthy volunteers. After separation, erythrocytes were suspended in phosphate
      buffer. Oxidative stress was induced by incubation with 2,2'-azobis (2
      amidinopropane) hydrochloride (AAPH). (1) Effects of four different
      concentrations (50, 100, 300 and 600 microg ml(-1)) of lidocaine, bupivacaine and
      ropivacaine were studied in absence or presence of AAPH (20 mM). Potassium efflux
      was assessed by flame photometry. (2) Effects of 50 and 600 microg ml(-1) of
      lidocaine, bupivacaine and ropivacaine on AAPH (50 mM) induced hemolysis were
      also studied. (3) The oxygen radical absorbing capacity of lidocaine, bupivacaine
      and ropivacaine at the four concentrations was evaluated by the analysis of the
      allophycocyanin fluorescence. RESULTS: In absence of AAPH, neither extracellular
      potassium nor hemolysis was noted. AAPH (20 mM) induced a significant increase in
      extracellular potassium that was reduced by all local anesthetic agents, with
      greater effects for lidocaine. AAPH-induced hemolysis was significantly decreased
      by all the local anesthetic agents at higher concentration, but only by lidocaine
      at 50 microg ml(-1). Finally, none of the local anesthetic agents modified the
      allophycocyanin fluorescence. CONCLUSION: In this model, lidocaine was proved
      more effective than bupivacaine and ropivacaine in protecting human erythrocytes
      submitted to an oxidative challenge. This was not due to a free radical
      scavenging effect.

PMID- 15183852
TI  - The estrogen suppression after sequential treatment with formestane in advanced
      breast cancer patients.
AB  - In postmenopausal patients, estrogens have an important role in breast cancer
      growth and aromatase inhibitors (AI) suppress the aromatase enzyme system which
      converts androgens into estrogens. The aim of this study was to evaluate the
      effect on estrogen suppression of formestane 250 mg i.m. fortnightly, given
      immediately after the failure of a previous treatment with non-steroidal AI.
      Twenty-two advanced breast cancer patients progressing on letrozole, anastrozole
      and aminoglutethimide entered the study. At the beginning of the study, the serum
      estrogen levels were suppressed by the previous treatment with non-steroidal AI,
      and the following treatment with formestane moderately maintained this
      suppression; in four patients serum estrogen levels increased fivefold after 10
      weeks. Neither complete nor partial responses were observed; 11 patients (50%)
      showed a stable disease lasting > or = 6 months, and the median time to
      progression was 6 months (range 3-9 months). No correlation was observed between
      clinical responses and serum estrogen suppression. Tolerability was satisfactory,
      and no patient withdrew from the study due to adverse events. In conclusion,
      formestane has demonstrated a moderate activity in estrogen suppression, and
      there is evidence that, at the failure of a previous treatment with non-steroidal
      AI, the sequential use of steroidal AI is feasible. This approach can be used in
      clinical practice in order to offer a disease control with a satisfactory quality
      of life.

PMID- 15183853
TI  - Allergic contact dermatitis is accompanied by severe abnormal changes in
      antioxidativity of blood.
AB  - We investigated whether the oxidative stress (OS) caused by skin inflammation
      could reflect in the blood, in a 21-year-old female student sensitized to nickel,
      colophony and abitole with often relapsing allergic contact dermatitis (ACD). As
      glutathione redox ratio was increased in the blood not only during the relapse
      but also in the beginning of remission phase, we prescribed natural medical
      preparations of d-alpha-tocopherol (in the first week 100 mg three times a day
      followed by 100 mg/day) and ascorbic acid (200 mg/day) for 25 days to her. After
      using antioxidants in the remission period, one of the principal OS markers-the
      glutathione redox ratio reached the normal physiological level. In this report,
      we showed that during acute extensive ACD OS is expressed in the blood and
      simultaneous supplementation of d-alpha-tocopherol and ascorbic acid might reduce
      systemic OS.

PMID- 15183854
TI  - Chemopreventive effect of piperine on modulating lipid peroxidation and membrane
      bound enzymes in benzo(a)pyrene induced lung carcinogenesis.
AB  - The current study was designed to evaluate the effects of oral supplementation of
      the piperine on lung tumour initiation by orally applied benzo(a)pyrene (B(a)p).
      To evaluate the effects of orally supplemented piperine on lung tumour initiation
      by B(a)p, its effects on ATPase enzymes were first evaluated. Lung cancer bearing
      mice showed an increase in erythrocyte membrane and tissues ATPase enzymes
      (Na(+)/K(+)-ATPases, Mg(2+)-ATPases and Ca(2+)-ATPases). Na(+) K-ATPase and Mg
      ATPase enzyme activities were decreased and calcium ATPase increased (P < 0.05)
      in erythrocyte membrane and tissues of lung cancer bearing animals compared with
      control groups. The elevation of these enzyme activities in membrane and tissues
      were indicative of the persistent deteriorating effect of B(a)p in cancer bearing
      animals. These enzyme activities were reversed to near normal control values in
      animals treated with piperine (50 mg/kg body weight). It is apparent that the
      beneficial effect of piperine is primarily exerted on the during initiation phase
      and post-initiation stage of B(a)p induced lung carcinogenesis. Overall, these
      data indicative that piperine has chemopreventive effects when administered
      orally on lung cancer bearing animals.

PMID- 15183855
TI  - Endotipsitis: an emerging prosthetic-related infection in patients with portal
      hypertension.
AB  - The transjugular intrahepatic portosystemic shunt (TIPS) is an option for the
      treatment of portal hypertension. However, TIPS infection (endotipsitis) is
      distinctly uncommon. We report 3 new patients and review 23 published cases of
      endotipsitis. We calculate an incidence of 1.33% in patients undergoing the
      procedure. Twenty-three cases (88%) occurred more than a month after the
      procedure. The most common presentation included fever and primary bacteremia or
      fungemia. Gram-positive (18 cases), gram-negative microorganisms (10 cases), and
      fungi (3 cases) were the etiologic agents. Diagnosis may be difficult to
      establish, and new diagnostic criteria have been proposed. Twenty patients
      responded well to antibiotic treatment, and the 6 remaining patients died because
      of the infection. Endotipsitis is a new infectious disease to be considered in
      patients with a TIPS and bloodstream infection that is not clearly attributable
      to another source. Prolonged courses of antimicrobial agents can be curative, but
      liver transplantation is also an option to consider.

PMID- 15183856
TI  - Rapid and quantitative detection of mumps virus RNA by one-step real-time RT-PCR.
AB  - We developed a new TaqMan-based one-step real-time reverse transcription
      polymerase chain reaction (RT-PCR) assay for detection and quantification of
      mumps virus RNA. Oligos targeting the matrix protein gene of mumps virus were
      designed by using our oligo designing and analyzing software, Oligoware 1.0.
      Oligos's specificity was tested with 5 strains (4 laboratory isolated and 1 Jeryl
      Lynn strain) of mumps virus. The suggested TaqMan-based one-step real-time RT-PCR
      assay correctly detected the 4 laboratory-isolated strains and 1 Jeryl Lynn
      strain. To confirm the specificity of the TaqMan PCR assay, parainfluenza type 1,
      2, 3 strains, sendai virus, and measles virus (vaccine strain) were tested, and
      no cross-reactivity was observed between mumps and tested strains. In addition, a
      BLAST (NCBI) search showed no genomic cross-reactivity with other viruses or
      cells. Testing of the assay's reproducibility was repeated several times, and the
      same results were achieved. The new assay was able to quantify the concentrations
      of mumps virus gene ranging from 10(1) to 10(8) copies per reaction sensitively
      with generated plasmid standards. In addition, it was shown that a significant
      correlation (R2 = 0.9564) between genome number as determined by one-step real
      time RT-PCR and the corresponding number of plaque in paired samples was found
      with regression analysis. The results of one-step real-time RT-PCR assay also
      corresponded well to those of nested PCR. We conclude that our one-step real-time
      RT-PCR assay is a reliable, specific, and sensitive tool for the diagnosis of
      mumps virus. We consider that these results come from highly conserved primers
      and probe set that were designed with Oligoware 1.0.

PMID- 15183857
TI  - Accurate mapping of mutations of pyrazinamide-resistant Mycobacterium
      tuberculosis strains with a scanning-frame oligonucleotide microarray.
AB  - The increasing emergence of drug-resistant Mycobacterium tuberculosis poses
      significant threat to the treatment of tuberculosis. Conventional susceptibility
      testing for the front-line tuberculosis drug pyrazinamide (PZA) is difficult,
      because of the requirement for acid pH for the drug to show activity. Resistance
      to PZA in M. tuberculosis is caused by mutations in the pncA gene, and detection
      of pncA mutations can be an indicator of PZA resistance. In this study, we
      examined the feasibility of a microarray-based approach exploiting short
      overlapping oligonucleotides (sliding-frame array) to rapidly detect pncA
      mutations (substitutions, deletions, and insertions) in multiple strains of PZA
      resistant M. tuberculosis. The genetic mapping of these mutations is necessary to
      link the gene sequence to the protein function defined by mutant phenotype.
      Microarray analysis was performed in a blind manner using 57 isolates of M.
      tuberculosis for which the sequence of the pncA gene was previously determined.
      Our results showed that all mutations could be unambiguously detected, suggesting
      that microarray can be a routine and valuable tool for rapid identification of
      drug-resistant M. tuberculosis isolates. We expect that mutation mapping with a
      sliding-frame microarray will accelerate the molecular analysis of drug-resistant
      M. tuberculosis bacteria and the microorganism populations.

PMID- 15183858
TI  - A multiplex polymerase chain reaction assay for genus-, group- and species
      specific detection of mycobacteria.
AB  - We developed and evaluated a single-step, multiplex polymerase chain reaction
      (PCR) assay for distinguishing (1) between the Mycobacterium tuberculosis complex
      (MTBC) and mycobacteria other than tuberculosis (MOTT) and (2) between M.
      tuberculosis and M. bovis species. The assay targeted the 16S and the 23S rDNA to
      distinguish between MTBC and MOTT species, and the oxyR gene to distinguish
      between M. tuberculosis and M. bovis strains. Clinical samples and reference
      strains (N = 156) comprised 93 strains of M. tuberculosis, 44 of M. bovis, 1 M.
      africanum strain, and 18 strains representing 9 different species of MOTTs. MOTTs
      generated only a single PCR product of about 2.5 kilobase; however, all of the
      MTBC strains produced a 118 base pair (bp) fragment and an additional 270 bp
      fragment was obtained for M. tuberculosis and M. africanum when the primer pair
      oxyRTB-2.1/oxyRMT-1 was used. When oxyRTB-2.1/oxyRMB-1 primers were used, the 270
      bp fragment was obtained for only M. bovis. The assay needed as little as 1 pg of
      purified genomic DNA to make a positive identification.

PMID- 15183859
TI  - Review of the pharmacodynamics of antibiotic use in animal food production.
AB  - Much attention has been focused on food-producing animals as a potential source
      of antimicrobial-resistant bacteria in humans. These efforts, however, have been
      met with continued debate and disagreement within the medical, veterinary, and
      regulatory communities as to whether the veterinary use of antimicrobials is a
      significant risk factor for the development of antimicrobial-resistant pathogens.
      As such, it is the purpose of our paper to assess factors involved in the
      pharmacokinetics and pharmacodynamics of antibiotic use in animal food
      production. We conclude that, based on the number of variables involved and the
      lack of definitive studies, it is difficult to determine the AUC:MIC for
      antimicrobials. Unfortunately, we are left only with general principles that
      indicate that low doses of antibiotic tend to select for bacterial resistance,
      and high doses tend to kill the microorganism. In the case where animal
      associated pathogens cause human disease, those practices that target adequate
      exposures (AUC:MIC) of antimicrobials should continue, whereas those practices
      producing low exposures should be modified or halted to prevent the emergence and
      spread of resistant organisms.

PMID- 15183860
TI  - Pharmacodynamic comparisons of antimicrobials against nosocomial isolates of
      escherichia coli, klebsiella pneumoniae, acinetobacter baumannii and pseudomonas
      aeruginosa from the MYSTIC surveillance program: the OPTAMA Program, South
      America 2002.
AB  - The OPTAMA (Optimizing Pharmacodynamic Target Attainment using the MYSTIC
      [Meropenem Yearly Susceptibility Test Information Collection] Antibiogram)
      Program provides insight into the appropriate antibiotic options for empiric
      therapy for common nosocomial pathogens. In this report, South America is
      represented by Brazil, Colombia, Peru, and Venezuela. A 5000-subject Monte Carlo
      Simulation estimated pharmacodynamic target attainment for meropenem, imipenem,
      ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin against
      Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas
      aeruginosa. Pharmacokinetic parameter variability was derived from existing
      healthy volunteer data, and minimum inhibitory concentration (MIC) data came from
      the 2002 MYSTIC program. Piperacillin/tazobactam and ciprofloxacin displayed the
      lowest target attainment against all bacterial species (14% to 24% for A.
      baumannii, 26% to 37% for P. aeruginosa, and 48% to 66% for the
      Enterobacteriaceae). Overall, the carbapenems had the highest probabilities of
      attainment against the Enterobacteriaceae (98% to 100%) and A. baumannii (73% to
      74%), whereas cefepime obtained the greatest target attainment against P.
      aeruginosa (65%). Because no single regimen had high target attainment against A.
      baumannii and P. aeruginosa, the use of combination therapy to treat these
      pathogens in South America may be justified. Because of the lack of agreement
      with percent susceptibility for certain antimicrobial regimens, the use of
      pharmacodynamic target attainment may be a more accurate predictor of
      microbiologic success.

PMID- 15183861
TI  - Development and application of a rapid diagnostic method for invasive Candidiasis
      by the detection of D-/L-arabinitol using gas chromatography/mass spectrometry.
AB  - A rapid non-culture-based diagnostic method utilizing d-/l-arabinitol (DA/LA)
      ratios as a chemical marker of invasive candidiasis was developed and explored.
      The enantiomers-ratios detection was made possible by the use of gas
      chromatography coupled with mass spectrometry (GC/MS). The mean DA/LA ratios +/-
      standard deviation (range) in urine (n = 40) and serum (n = 20) were 2.08 +/-
      0.78 (0.57 to 3.55) and 1.79 +/- 0.75 (0.74 to 3.54), respectively, from patients
      without evidence of fungal infection or colonization; in patients (n = 7) with
      culture-proven invasive candida infections, the figures were 9.91 +/- 3.04 (7.24
      to 16.27) and 13.58 +/- 7.31 (5.57 to 25.88) in urine and serum, respectively.
      The differences in DA/LA ratios between the candidemic patients and the non
      candidemic patients were statistically significant (p < 0.01) in both serum and
      urine samples. The DA/LA ratios were not significantly affected in patients with
      oral or vaginal candidiasis and candiduria.

PMID- 15183862
TI  - Survey of CTX-M-3 extended-spectrum beta-lactamase (ESBL) among cefotaxime
      resistant Serratia marcescens at a medical center in middle Taiwan.
AB  - Thirty-four clinical isolates of Serratia marcescens nonsusceptible to cefotaxime
      were collected from a medical center in middle Taiwan. Confirmatory tests for
      extended-spectrum beta-lactamases (ESBLs) by cefotaxime and ceftazidime +/-
      clavulanic acid using Etest ESBL Screen identified only one ESBL producer; the
      remaining 33 isolates revealed nondeterminable results, because of off-scale
      minimum inhibitory concentration (MIC) levels for cefotaxime +/- clavulanic acid.
      Agar microdilution method using broader MIC ranges confirmed 21 ESBL-producers
      and one non-determinable result, achieving a highly predicting value compared to
      golden standard by PCR and DNA sequencing analysis, which identified 22 (65%)
      isolates containing blaCTX-M-3 genes. Only one strain carried concurrent CTX-M-3
      and SHV-5 conferring high-level MICs to both cefotaxime (128 microg/mL) and
      ceftazidime (64 microg/mL). Other enzymatic mechanisms, such as chromosome
      encoded AmpC including a novel SRT-2 enzyme, may confer resistance to cefotaxime
      on the remaining 12 isolates without ESBL bla genes. Thus, it is unreliable to
      predict the resistance mechanism by antibiogram, and current Etest ESBL Screen
      tests. Our study highlights expanding efforts to detect ESBLs in S. marcescens
      are urgently needed in Taiwan.

PMID- 15183863
TI  - How does susceptibility prevalence impact on the performance of disk diffusion
      susceptibility testing?
AB  - Antimicrobial disk diffusion susceptibility testing, devoted in a clinical
      context to predicting whether an antibiotic regimen will be effective, should be
      evaluated through predictive values. This approach implies that the
      susceptibility prevalence (frequency of susceptible, intermediate, and resistant
      isolates) affects the predictive value of a result. We quantified the influence
      of the susceptibility prevalence variation on the disk diffusion method
      performance through a modeling approach. Simulations based on a resampling
      procedure from two distinct minimum inhibitory concentration/diameter data sets
      were performed. Experimental variability on minimum inhibitory concentration and
      diameters was taken into account in the simulations. Results show that the
      susceptibility prevalence impact depends on the antibiotic and may be significant
      when prevalence variation is high enough. Consequences of these results on zone
      diameter breakpoint determination policy are discussed. This implies that the
      following should be done: (i) consider more rigorously the susceptibility
      prevalence in studies dealing with zone diameter breakpoint determination and
      performance evaluation, (ii) re-evaluate disk diffusion breakpoint consistency
      when the weight of prevalence variation is noteworthy, (iii) estimate
      consequences of a breakpoint international consensus on prediction quality and
      appropriate patient management.

PMID- 15183864
TI  - Are United States hospitals following national guidelines for the analysis and
      presentation of cumulative antimicrobial susceptibility data?
AB  - The National Committee for Clinical Laboratory Standards recently published
      guidelines for analysis and presentation of cumulative antimicrobial
      susceptibility test data (antibiograms). We sought to determine how well US
      hospitals already adhere to standards for antibiogram compilation, and to examine
      the relationship between hospital characteristics and guideline adherence. We
      surveyed laboratory directors at 670 hospitals and examined 3 guideline criteria:
      compilation of an antibiogram, annual updating, and distribution to infection
      control staff and medical staff yearly; 494 surveys were returned (74%). Almost
      all of the hospitals surveyed publish an antibiogram (95%, n = 481); however,
      only 60% (n = 296) met all three criteria. Hospital laboratories meeting criteria
      were more likely to serve as referral laboratories (OR = 1.82; 95% CI = 1.26
      2.63), perform susceptibility testing on site (OR = 4.47; 95% CI = 1.84-10.84),
      use confirmatory tests to detect extended-spectrum beta-lactamases (OR = 1.8; 95%
      CI = 1.2-2.6), and have more laboratory personnel per bed (3.0 vs. 2.0 FTEs/bed,
      p = 0.0031). Adherence to guidelines for preparation and dissemination of
      antibiograms could be improved. Institutional commitment to high quality, on-site
      microbiology laboratory services will improve adherence to these guidelines.

PMID- 15183865
TI  - Doxycycline use for community-acquired pneumonia: contemporary in vitro spectrum
      of activity against Streptococcus pneumoniae (1999-2002).
AB  - Because of the limited clinical testing of doxycycline, it has received guarded
      acceptance as an inexpensive, fluoroquinolone-sparing agent for treatment of
      community-acquired pneumonia. Examination of in vitro data from 3,902 recent
      Streptococcus pneumoniae isolates (SENTRY Program, USA) suggests that doxycycline
      has wider clinical application compared to macrolides, oral cephalosporins
      (directed by penicillin susceptibility), and trimethoprim-sulfamethoxazole.

PMID- 15183866
TI  - High phylogenetic diversity of transconjugants carrying plasmid pJP4 in an
      activated sludge-derived microbial community.
AB  - Transconjugants of plasmid pJP4, originating from an agar plate mating of a
      Pseudomonas putida donor with an activated sludge-derived microbial community,
      were isolated and identified by partial 16S rDNA sequencing. The transconjugant
      strains belonged to a variety of genera of the alpha-, beta-, gamabeta- and gamma
      classes of the Proteobacteria, mostly to the families Rhizobiaceae and
      Comamonadaceae and the genus Stenotrophomonas. Only P. putida and Delftia spp.
      strains were able to grow on 2,4-D as the sole carbon source.

PMID- 15183867
TI  - Macrofilamentous microbial communities in the metal-rich and acidic River Tinto,
      Spain.
AB  - A novel type of macroscopic microbial community consisting of large dendritic
      filaments (up to 1.5 m) in a pH 2.0 dam of the River Tinto (South-western Spain)
      is described. The combined use of 16S rRNA-gene surveys and fluorescent in situ
      hybridisation (FISH) suggested that gamma-proteobacteria and a relative large
      diversity of alpha-proteobacteria dominated these structures. beta
      Proteobacteria, Actinobacteria and Firmicutes were also detected. Whereas
      acidophilic bacteria of the genera Acidithiobacillus, Leptospirillum and
      Acidiphilium, and archaea belonging to the Thermoplasmatales dominate mine acid
      drainage waters and streamers (riverbed filamentous biofilms), none of the
      lineages identified in this study affiliate to typical acid mine drainage
      acidophilic bacteria. Bacteria of the Tinto macrofilaments might be
      heterotrophic, and could be feeding on the organic matter entrapped in the
      filamentous structure.

PMID- 15183868
TI  - Sequence divergence in type III secretion gene clusters of the Burkholderia
      cepacia complex.
AB  - The Burkholderia cepacia complex (BCC) comprises a group of bacteria associated
      with opportunistic infections, especially in cystic fibrosis patients. B.
      cenocepacia J2315, of the transmissible ET12 lineage, contains a type III
      secretion (TTS) gene cluster implicated in pathogenicity. PCR and hybridisation
      assays indicate that the TTS gene cluster is present in all members of the BCC
      except B. cepacia (formerly genomovar I). The TTS gene clusters of B. cenocepacia
      J2315 and B. multivorans are similar in organisation but have variable levels of
      gene identity. Nucleotide sequence data obtained for the equivalent region of the
      B. cepacia genome indicate the absence of TTS structural genes due to a
      rearrangement likely to involve more than one step.

PMID- 15183869
TI  - Epitope mapping of a single repetitive unit of the B13 Trypanosoma cruzi antigen
      as fusions to Escherichia coli LamB protein.
AB  - B13, one of the immunodominant antigens of Trypanosoma cruzi, is composed of
      repeats of a 12-amino-acid motif. Using synthetic peptides, the sequence
      FGQAAAGDK was previously shown to contain the B13 immunodominant epitope
      recognized by chagasic patients sera. To investigate the effects of neighboring
      sequences in the immunodominance, we tested serum recognition of two B13
      sequences fused to LamB. GDKPSPFGQAAA-LamB and FGQAAAGDKPSP-LamB were recognized,
      respectively, by 15% and 80% of 80 sera reactive to B13 antigen. Recognition of
      FGQAAAGDKPSP-LamB was inhibited by AAAGDK-containing synthetic peptides.
      FGQAAAGDKPSP-LamB competed with a B13 recombinant protein containing 16.6 repeats
      for binding to chagasic antibodies. These results strengthen previous conclusions
      on the immunodominant epitope of B13 and provide a comparison of two methods for
      epitope mapping.

PMID- 15183870
TI  - A plasmid-encoded class 1 integron carrying sat, a putative phosphoserine
      phosphatase gene and aadA2 from enterotoxigenic Escherichia coli O159 isolated in
      Japan.
AB  - A class 1 integron was detected in a single multidrug-resistant strain of
      enterotoxigenice Escherichia coli (ETEC) O159 after examination of 23 clinical E.
      coli isolates. This isolate was resistant to streptomycin, kanamycin, gentamicin,
      chloramphenicol and ampicillin. Sequencing of the class 1 integron identified
      three-gene cassettes. The first is the streptothricin acetyltransferase gene,
      sat, which confers resistance to streptothricin. The second is an ORF whose
      product is a putative phosphoserine phosphatase (PSP), and the last is an
      aminoglycoside adenyltransferase gene, aadA2, which confers resistance to
      streptomycin and spectinomycin. The putative PSP gene product was found to be
      39%, 38%, 28%, and 27% identical to PSP gene products of Vibrio vulnificus CMCP6,
      V. vulnificus YJ016, Pseudomonas syringae, and P. aeruginosa, respectively.
      Southern-blot hybridization showed that this integron is located on a 90 kb
      plasmid. This is the first report identifying a putative PSP gene in an integron.

PMID- 15183871
TI  - Comparative genomics identifies genes shared by distantly related insect
      transmitted plant pathogenic mollicutes.
AB  - Phytoplasmas and spiroplasmas are distantly related insect-transmitted plant
      pathogens within the class Mollicutes. Genome sequencing projects of phytoplasma
      strain Aster Yellows-Witches' Broom (AY-WB) and Spiroplasma kunkelii are near
      completion. Complete genome sequences of seven obligate animal and human
      pathogenic mollicutes (Mycoplasma and Ureaplasma spp.), and OY phytoplasma have
      been reported. Putative ORFs predicted from the genome sequences of AY-WB and S.
      kunkelii were compared to those of the completed genomes. This resulted in
      identification of at least three ORFs present in AY-WB, OY and S. kunkelii but
      not in the obligate animal and human pathogenic mollicutes. Moreover, we
      identified ORFs that seemed more closely related between AY-WB and S. kunkelii
      than to their mycoplasma counterparts. Phylogenetic analyses using parsimony were
      employed to study the origin of these genes, resulting in identification of one
      gene that may have undergone horizontal gene transfer. The possible involvement
      of these genes in plant pathogenicity is discussed.

PMID- 15183872
TI  - Molecular typing and phylogenetic analysis of enteroinvasive Escherichia coli
      using the fliC gene sequence.
AB  - Non-motile enteroinvasive Escherichia coli (EIEC) is serotyped based only on O
      antigen polymorphism, since H antigen epitopes, present on the flagellins, cannot
      be characterised in these bacteria. In this study, we demonstrate the presence of
      the flagellin-coding fliC gene in non-motile EIEC strains. Moreover, we were able
      to group the 11 most common non-motile EIEC serotypes into six different RFLP
      patterns of the fliC gene. Amplicons representing each RFLP pattern were
      sequenced. Sequencing data were used to construct a phylogenetic tree which
      showed two main clusters: one sharing similarity with Shigella dysenteriae and
      pathogenic E. coli, and the other being closer to non-pathogenic E. coli.

PMID- 15183873
TI  - The ypdI gene codes for a putative lipoprotein involved in the synthesis of
      colanic acid in Escherichia coli.
AB  - In Escherichia coli, the synthesis of colanic acid, an extracellular
      polysaccharide imminent in biofilm development, is a complicated process
      involving numerous genes and not yet wholly elucidated. Using a plasmid-borne E.
      coli K-12 gene library, we have identified a clone whose presence conferred
      mucoid colony phenotype onto E. coli CM2555 strain. Our results indicate that
      overexpression of a gene previously catalogued as ypdI, which encodes a putative
      lipoprotein, is responsible for this phenotype. We show that the mucoidy of ypdI 
      overexpressing bacteria is due to increased production of colanic acid. This
      phenotype depends on the function of the rcsA gene, but not on that of rcsF.
      These results suggest that the ypdI gene product might be an additional factor
      playing a role in colanic acid synthesis, indicating that this process can be
      even more complicated than supposed to date. However, no obvious phenotype was
      observed in the DeltaypdI::kan mutant cultivated under standard laboratory
      conditions.

PMID- 15183874
TI  - Characterization of bacterial diversity in pulque, a traditional Mexican
      alcoholic fermented beverage, as determined by 16S rDNA analysis.
AB  - The bacterial diversity in pulque, a traditional Mexican alcoholic fermented
      beverage, was studied in 16S rDNA clone libraries from three pulque samples.
      Sequenced clones identified as Lactobacillus acidophilus, Lactobacillus strain
      ASF360, L. kefir, L. acetotolerans, L. hilgardii, L. plantarum, Leuconostoc
      pseudomesenteroides, Microbacterium arborescens, Flavobacterium johnsoniae,
      Acetobacter pomorium, Gluconobacter oxydans, and Hafnia alvei, were detected for
      the first time in pulque. Identity of 16S rDNA sequenced clones showed that
      bacterial diversity present among pulque samples is dominated by Lactobacillus
      species (80.97%). Seventy-eight clones exhibited less than 95% of relatedness to
      NCBI database sequences, which may indicate the presence of new species in pulque
      samples.

PMID- 15183875
TI  - The pathogen Mycobacterium marinum, a faster growing close relative of
      Mycobacterium tuberculosis, has a single rRNA operon per genome.
AB  - Although Mycobacterium marinum and Mycobacterium tuberculosis are very closely
      related they differ significantly in their growth rates. The Type strain of M.
      marinum and one clinical isolate were investigated and, like M. tuberculosis,
      were found to have a single rRNA (rrn) operon per genome located downstream from
      murA gene and controlled by two promoters. No sequence differences were found
      that account for the difference in the growth rates of the two species. We infer
      that M. tuberculosis has the capacity to synthesize rRNA much faster than it
      actually does; and propose that the high number of insertion sequences in this
      species attenuate growth rate to lower values.

PMID- 15183876
TI  - Organization and transcriptional regulation of myo-inositol operon in Clostridium
      perfringens.
AB  - myo-Inositol operon of Clostridium perfringens strain 13 consists of 13 genes
      with an upstream divergent regulator, iolR. Transcriptional analysis showed three
      separate transcripts for the operon of 15.6, 4.6 and 2.0 kb in length. iolR
      mutation studies showed that IolR is a negative regulator of the operon at
      transcriptional level. All the transcripts were induced by myo-Inositol in dose-
      and time-dependent manner. Glucose repressed the expression of all the
      transcripts of myo-Inositol operon. We also found that the operon was positively
      regulated by the two-component VirR/VirS system both in the presence and absence
      of myo-Inositol. This study shows that the global regulatory VirR/VirS system
      controls the expression of genes related to energy production (e.g. myo-Inositol
      operon) in addition to the virulence genes of C. perfringens strain 13.

PMID- 15183877
TI  - Identification of an exoribonuclease homolog, CaKEM1/CaXRN1, in Candida albicans
      and its characterization in filamentous growth.
AB  - KEM1/XRN1 and RAT1 are two known exoribonuclease genes in Saccharomyces
      cereivsiae and encode a cytoplasmic and nuclear exoribonuclease, respectively.
      CaKEM1/CaXRN1 and CaRAT1, the Candida albicans homologs of 5'-->3'
      exoribonuclease genes, were identified by protein sequence comparisons and by
      functional complementation of the S. cerevisiae kem1/xrn1 null mutation. The
      deduced amino acid sequences of CaKEM1 and CaRAT1 show 51% and 55% identities to
      those of the S. cerevisiae KEM1 and RAT1, respectively. The exonuclease motifs
      were found to be highly conserved in CaKem1p and CaRat1p. We disrupted two
      chromosomal copies of CaKEM1 in a diploid C. albicans strain and demonstrate that
      C. albicans kem1/kem1 mutants are defective in filamentous growth on filamentous
      inducing media. These results imply that CaKEM1 is involved in filamentous growth
      of C. albicans.

PMID- 15183878
TI  - Low level of cross-resistance between triclosan and antibiotics in Escherichia
      coli K-12 and E. coli O55 compared to E. coli O157.
AB  - Misuse of biocides has encouraged the emergence of resistance and cross
      resistance in certain strains. This study investigated resistance of triclosan
      adapted Escherichia coli K-12 and E. coli O55 to antimicrobial agents and
      compared these to E. coli O157:H7. Cross-resistance in E. coli K-12 and E. coli
      O55 was observed however to a lesser extent than in E. coli O157:H7. Triclosan
      adapted E. coli K-12 demonstrated cross-resistance to chloramphenicol, whereas
      triclosan-adapted E. coli O55 exhibited resistance to trimethoprim. In
      comparison, E. coli O157:H7 was resistant to chloramphenicol, tetracycline,
      amoxicillin, amoxicillin/clavulanic acid, trimethoprim, benzalkonium chloride and
      chlorohexidine suggesting strain specific rather than general resistance
      mechanisms.

PMID- 15183879
TI  - Synthesis and immunogenicity of polysaccharide-protein conjugate composed of
      galactoglucoxylomannan of Cryptococcus laurentii.
AB  - Galactoglucoxylomannan (GalGXMan) antigen of Cryptococcus laurentii was
      conjugated to protein carrier by a simple one step reaction. The conjugate was
      immunogenic in rabbits and reinjection elicited booster response with significant
      increase of serum IgG (H+L) level. Induction of this Ig-isotype was confirmed in
      experiments with Protein A. Effectiveness of immune serum to inhibit the growth
      of C. laurentii was demonstrated. The results indicate that the prepared
      conjugate could be considered as effective immunogen with potential for
      incorporation in the vaccine.

PMID- 15183880
TI  - Enhanced expression of aconitase raises acetic acid resistance in Acetobacter
      aceti.
AB  - Acetobacter spp. are used for industrial vinegar production because of their high
      ability to oxidize ethanol to acetic acid and high resistance to acetic acid. Two
      dimensional gel electrophoretic analysis of a soluble fraction of Acetobacter
      aceti revealed the presence of several proteins whose production was enhanced, to
      various extents, in response to acetic acid in the medium. A protein with an
      apparent molecular mass of 100 kDa was significantly enhanced in amount by acetic
      acid and identified to be aconitase by NH2-terminal amino acid sequencing and
      subsequent gene cloning. Amplification of the aconitase gene by use of a
      multicopy plasmid in A. aceti enhanced the enzymatic activity and acetic acid
      resistance. These results showed that aconitase is concerned with acetic acid
      resistance. Enhancement of the aconitase activity turned out to be practically
      useful for acetic acid fermentation, because the A. aceti transformant harboring
      multiple copies of the aconitase gene produced a higher concentration of acetic
      acid with a reduced growth lag-time.

PMID- 15183881
TI  - Crude oil degradation efficiency of a recombinant Acinetobacter baumannii strain
      and its survival in crude oil-contaminated soil microcosm.
AB  - A hydrocarbon degrading Acinetobacter baumannii S30 strain, isolated from crude
      oil-contaminated soil, was inserted with the lux gene from the luciferase gene
      cassette luxCDABE. Soil microcosms were designed to study the degradation
      efficacy for total petroleum hydrocarbon (TPH) of crude oil by lux-tagged A.
      baumannii S30 pJES. Bioaugmentation of a TPH-contaminated microcosm with A
      baumannii S30 pJES showed that TPH levels were reduced from 89.3 to 53.9 g/kg
      soil in 90 days. Biodegradation of TPH by A baumannii S30 pJES was also monitored
      in shake flask conditions, which showed a reduction of initial TPH levels by over
      50% at the end of 120 h. A lux-PCR-based approach along with the standard
      dilution plating with selective antibiotics was successfully utilized to monitor
      the survivability of the lux-tagged strain A. baumannii S30 pJES in soil
      microcosms and stability of the lux insert in the host strain A. baumannii S30.
      The selective plating technique indicated the population of A. baumannii S30 pJES
      to be 6.5+/-0.13 x 10(8) CFU/g at day zero (just after bioaugmentation) and
      2.09+/-0.08 x 10(8) CFU/g of soil after 90 days of incubation. lux-PCR confirmed
      the stability of the insert in all the randomly selected colonies of A. baumannii
      strains from the antibiotic plates. The lux insert was stable after 50
      generations in Luria Bertini broth and storage at -70 degrees C as glycerol
      stocks for over a year. These results revealed that the lux insert was stable and
      lux-tagged A. baumannii S30 strain could survive in a TPH-contaminated soil
      microcosm and could degrade TPH in the soil microcosm conditions. It can be used
      as an effective marker to monitor the survival of augmented strains at a
      bioremediation site.

PMID- 15183882
TI  - Purification and characterization of a hemoglobin-binding outer membrane protein
      of Prevotella intermedia.
AB  - An outer membrane hemoglobin-binding protein of Prevotella intermedia was
      identified and purified in the present study. Hemoglobin-binding protein was
      purified via a series of column chromatographic methods. The molecular mass of
      the purified protein, which was approximately 60 kDa, was determined by SDS-PAGE.
      Hemoglobin binding of the protein was examined by Western blot and dot blot
      assays. Hemoglobin-binding activity was pH dependent; the strongest binding
      activity occurred at pH 5.0. Globin greatly decreased the binding activity,
      whereas transferrin, cytochrome C, and catalase exerted no effect. Dissociation
      constant between the 60-kDa protein and hemoglobin was 1.48 x 10(-8) M as
      measured by surface plasmon resonance. These results suggest that P. intermedia
      binds hemoglobin specifically through the 60-kDa outer membrane protein.

PMID- 15183883
TI  - The light-responsive promoter of cyanobacterial ORF76 gene overlaps with the htpG
      terminator.
AB  - A Synechococcus PCC7942 gene, encoding 76 amino acids of an unknown protein
      (designated ORF76), is located at the same orientation and downstream of the htpG
      gene. The processed site of ORF76 transcripts is located at position +39 with
      respect to the true transcription initiation site. The non-E. colisigma70-like
      basal promoter of ORF76 (-51 to -9) is controlled by three cis-acting elements:
      positively acting element (-160 to -86), negative regulatory element (-86 to -51)
      and light-responsive element (-51 to +63) that, together, respond to high light
      induction at transcriptional level. The ORF76 gene is expressed as monocistronic
      transcript. The promoter elements of ORF76 gene overlap with the coding sequence
      and 3' end formation signal of htpG gene.

PMID- 15183884
TI  - Sequence-based approach to finding functional lipases from microbial genome
      databases.
AB  - A sequence-based approach was used to retrieve functional lipases from microbial
      genome databases. Many novel genes assigned as putative lipases were tested using
      the criteria of the typical lipase sequence rule, based on a consensus sequence
      of a catalytic triad (Ser, Asp, His) and oxyanion hole sequence (HG). To obtain
      the lipase genes satisfying the sequence rule, PCR cloning was performed, while
      the lipase activities were tested using a tributyrin/tricaprylin plate and p
      nitrophenyl caproate. Among nine putative lipases from four strains, five
      functional lipolytic proteins were obtained from Archaeoglobus fulgidus,
      Deinococcus radiodurans, and Agrobacterium tumefaciens. All five lipases
      exhibited a relatively low sequence similarity (less than 26.7%) with known
      lipases and turned out to belong to different lipase families. Accordingly, the
      current results indicate that the proposed strategic approach based on the
      microbial genome is an efficient and rapid method for finding novel and
      functional lipases.

PMID- 15183885
TI  - Differences in biofilm and planktonic cell mediated reduction of metalloid
      oxyanions.
AB  - This study compares Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa
      ATCC 27853 biofilm and planktonic cell susceptibility to the selenium and
      tellurium oxyanions selenite (SeO3(2-)), tellurate (TeO4(2-)), and tellurite
      (TeO3(2-)). P. aeruginosa planktonic and biofilm cultures reduced the selenium
      and tellurium oxyanions to orange and black end-products (respectively) and were
      equally tolerant to killing by these metalloid compounds. S. aureus planktonic
      cell cultures processed these metalloid oxyanions in a similar way, but the
      corresponding biofilm cultures did not. S. aureus biofilms were approximately two
      and five times more susceptible to killing by tellurate and tellurite
      (respectively) than the corresponding planktonic cultures. Our data indicate that
      the means of reducing metalloid oxyanions may differ between the physiology
      displayed in biofilm and planktonic cultures of the same bacterial strain.

PMID- 15183887
TI  - Purification and characterization of a lysine aminopeptidase from Kluyveromyces
      marxianus.
AB  - A lysine aminopeptidase was purified from the yeast Kluyveromyces marxianus. This
      enzyme was purified 100-fold from a soluble extract obtained at 100,000g. The
      purification procedure consisted in fractionated precipitation with ammonium
      sulfate and five chromatography steps. The native enzyme had a molecular mass of
      46 kDa assessed through gel filtration. This aminopeptidase depicted an optimal
      pH of 7.0 and was stable at a pH range of 4-8, its optimal temperature was 45
      degrees C and the enzyme became unstable at temperatures above 55 degrees C. The
      isoelectric point of the purified enzyme was 4.4. Michaelis constant and Vmax for
      L-lysine-p-nitroanilide were 0.33 mM and 2.2 mM min(-1) per milligram of protein,
      respectively. The enzyme was strongly inhibited by bestatin, o-phenanthroline
      and, to a lesser extent, by EDTA, suggesting that this enzyme is a
      metalloprotease. Our results suggest that the lysine aminopeptidase from
      Kluyveromyces marxianus might be of biotechnological relevance.

PMID- 15183886
TI  - In vitro modeling of dental water line contamination and decontamination.
AB  - The contamination of dental unit water lines (DUWL) is an emerging concern in
      dentistry. The aim of this study was to use an in vitro DUWL to model microbial
      contamination and evaluate the decontamination efficacy of
      tetraacetylethylenediamine (TAED) solutions. A DUWL biofilm model used to
      simulate clinical conditions was used to generate a range of biofilms in DUWL.
      Three distinct biofilms were generated: (1) biofilm from water, (2) biofilm from
      a mix of water + contaminating human commensal bacteria, (3) biofilm from water
      with contaminating oral bacteria added after biofilm formed. The contaminating
      oral species used were Streptococcus oralis, Enterococcus faecalis and
      Staphylococcus aureus. Decontamination by simple water flushing or flushing with
      TAED was evaluated (2, 5 and 10 min intervals). The DUWL tubes were split and
      samples were plated onto a range of media, incubated and bacteria enumerated.
      Water flushing did not reduce the number of microorganisms detected. Bacteria
      were not detected from any of the TAED sampling points for any of the biofilm
      types tested. Interestingly, if contamination was introduced to new DUWL along
      with the waterborne species a biofilm was formed containing only the waterborne
      species. If however, an existing biofilm was present before the introduction of
      "contaminating" bacteria then these could be detected in the biofilm. This
      implies that if the DUWL are new or satisfactorily cleaned on a regular basis
      then the associated cross-contamination aspects are reduced. In conclusion, TAED
      provides effective control for DUWL biofilms.

PMID- 15183888
TI  - Transcriptional analysis of bacteriocin production by malt isolate Lactobacillus
      sakei 5.
AB  - Malt isolate Lactobacillus sakei 5 produces three bacteriocins, sakacin P,
      sakacin T and sakacin X. The structural and regulatory genes for sakacin T and
      sakacin X are part of the sakacin TX locus, which consists of two adjacent, but
      divergently oriented gene clusters. Primer extension transcriptional analysis
      pointed to the existence of three distinct promoters within the sakacin TX locus,
      indicating that the three-component regulatory system in this locus is atypical
      in the sense that it is divided into a pheromone-specifying operon and an operon
      containing the genes for the histidine protein kinase and response regulator.
      Quantitative real-time PCR analyses showed that a transient increase in the
      expression of these two regulatory operons precedes transcription of the
      bacteriocin genes and appearance of bacteriocins in the culture medium. The
      identified promoters of the sakacin TX locus contain putative regulatory
      sequences (direct repeats) at corresponding positions in front of their -10
      regions, which are likely to play a role in gene regulation.

PMID- 15183889
TI  - Conjugal transfer of aminoglycoside and macrolide resistance between Enterococcus
      faecium isolates in the intestine of streptomycin-treated mice.
AB  - The purpose was to study conjugal transfer of resistance genes between a multi
      resistant Enterococcus faecium isolate and a sensitive E. faecium isolate. Co
      transfer of erm(B)-Tn5405-like element and aac(6')-Ie-aph(2'')-Ia was obtained in
      both in vivo and in vitro. Plasmid profiles and Southern blots showed that both
      the erm(B)-Tn5405-like element and aac(6')-Ie-aph(2'')-Ia were placed on the same
      large plasmid (>147 kb). These data show to our knowledge the first co-transfer
      of the erm(B)-Tn5405-like element and aac(6')-Ie-aph(2'')-Ia. The in vivo study
      also indicates that transfer of resistance genes between enterococci might occur
      under natural conditions in the gut of animals.

PMID- 15183890
TI  - Cloning and characterization of the Halobacillus trueperi betH gene, encoding the
      transport system for the compatible solute glycine betaine.
AB  - Halobacillus trueperi accumulates glycine betaine under condition of high
      osmolarity. A fragment of the glycine betaine transporter betH gene was obtained
      from the genome of H. trueperi with degenerate primers. Through Southern blot
      hybridization and inverse PCR, a 5.1 kb EcoRI fragment containing the complete
      betH gene was identified and subsequently sequenced. The betH gene was predicted
      to encode a 55.2 kDa protein (504 amino acid residues) with 12 transmembrane
      regions. BetH showed 56% identity to the OpuD of Bacillus subtilis which belongs
      to the betaine/carnitine/choline transporter (BCCT) family. Its putative promoter
      region was highly homologous to sigmaB-dependent promoter of B. subtilis. A 2.6
      kb fragment containing the betH gene was cloned into pUC18 and transformed into
      the Escherichia coli MKH13. The accumulation of glycine betaine in transformed E.
      coli MKH13 bacteria was confirmed using 13C nuclear magnetic resonance
      spectroscopy.

PMID- 15183891
TI  - A phase space model of hemopoiesis and the concept of stem cell renewal.

PMID- 15183892
TI  - Human endogenous retrovirus (HERV-K) particles in megakaryocytes cultured from
      essential thrombocythemia peripheral blood stem cells.
AB  - OBJECTIVE: The aim of this study was to determine the extent of human endogenous
      retrovirus (HERV) gene translation in megakaryocytes cultured from peripheral
      blood stem cells of patients with essential thrombocythemia previously reported
      with platelet-associated HERV sequences and reverse transcriptase activity.
      MATERIALS AND METHODS: Terminally differentiated megakaryocytes derived from
      circulating stem cells in serum-free medium supplemented with stem cell factor
      and thrombopoietin were processed for electron microscopic immunostaining using a
      monoclonal antibody against the gag protein of HERV-K10 and an electron dense
      gold-labeled secondary antibody. RESULTS: We found that HERV-K gag protein was
      detected as clusters in the cytoplasm as well as associated with viral particles
      budding from the cell membrane and into intracellular vacuoles in megakaryocytes
      from two patients with essential thrombocythemia. None of these structures was
      observed in megakaryocytes from a normal control or from a patient with chronic
      myelocytic leukemia. CONCLUSION: This is the first evidence of HERV-K protein
      synthesis (gene translation) in human tissue other than seminomas, placenta, or
      fetal tissue. Translation of the HERV-K gag gene with subsequent packaging of the
      protein product into viral particles adds a new and important dimension to future
      studies on the role of HERVs in the myeloproliferative diseases.

PMID- 15183893
TI  - Vascular endothelial growth factor receptor-1 and receptor-2 initiate a
      phosphatidylinositide 3-kinase-dependent clonogenic response in acute myeloid
      leukemia cells.
AB  - OBJECTIVE: Vascular endothelial growth factor (VEGF) interacts with two high
      affinity receptor tyrosine kinases (RTK) on vascular endothelium to initiate
      complementary but disparate biologic responses. We previously reported that acute
      myeloid leukemia (AML) cells express VEGF and one or both VEGF-A receptors, Flt-1
      (VEGFR-1) and KDR (VEGFR-2). To evaluate receptor-selective trophic response to
      VEGF-A in AML cells, we investigated receptor-specific ligand activation
      responsible for VEGF-initiated clonogenic response. MATERIALS AND METHODS: Using
      KG1 (VEGFR-1+/VEGFR-2+) and HL60 (VEGFR-1+) cells with differential VEGF receptor
      display, we investigated ligand-induced clonogenic response and receptor
      initiated signaling after stimulation with VEGF-A, the VEGFR-1 selective ligand
      placental growth factor (PlGF), or receptor-specific antibody agonists. RESULTS:
      Recombinant human (rhu)-VEGF increased S-phase fraction and stimulated colony
      formation in both KG1 and HL60 cells. Ligation of VEGFR-1 or VEGFR-2 with
      receptor-specific antibody agonists triggered equivalent and concentration
      dependent stimulation of colony recovery in KG1 cells, whereas clonogenic
      response in HL60 cells was restricted to VEGFR-1 activation by antibody or PlGF.
      In serum-deprived KG1 and HL60 cells, rhu-VEGF stimulated rapid and sustained
      phosphorylation of Akt/PKB that was inhibited by the phosphatidyl inositol 3
      kinase (PI3-K) kinase inhibitor wortmannin. Preincubation with wortmannin
      inhibited VEGF-induced colony formation in a concentration-dependent fashion. rhu
      VEGF-induced clonogenic response and Akt phosphorylation was abolished by the
      VEGF-RTK inhibitor SU-5416 at concentrations greater than 10 microM, whereas MEK
      inhibition by PD98059 (1 and 10 microM) was ineffective. In vivo suppression of
      Akt phosphorylation was confirmed in myeloblast lysates from three patients with
      advanced myeloid malignancies treated with SU5416. CONCLUSION: These data
      indicate that VEGF interaction with either VEGFR-1 or VEGFR-2 initiates a
      clonogenic response in AML cells that is PI3-kinase dependent. RTK inhibitors
      with broad specificity for angiogenic receptors represent novel therapeutics that
      merit further clinical investigation in AML.

PMID- 15183894
TI  - Gene transfer into human T lymphocytes and natural killer cells by Ad5/F35
      chimeric adenoviral vectors.
AB  - OBJECTIVE: Genetic modification of effector lymphocytes, such as T cells and
      natural killer (NK) cells, is essential for many approaches to gene-based
      immunotherapy of cancer. However, transduction of lymphocytes has proven
      difficult by currently available gene transfer methods. Previous studies have
      shown that chimeric fiber-modified Ad5/F35 adenoviral vectors are able to
      efficiently transduce hematopoietic cells including immature progenitors. In this
      study, we examined the gene transfer into T lymphocytes and NK cells using
      Ad5/F35 compared with conventional Ad5 adenovectors. METHODS: Primary T and NK
      cells were isolated from healthy donors' peripheral blood leukocytes by
      immunomagnetic selection. Cell lines and primary lymphocytes were transduced with
      replication-defective Ad5/F35 and Ad5, both containing a GFP reporter gene under
      the control of a CMV promoter. Transduction efficiencies were monitored by flow
      cytometry. The function of transduced lymphocytes was assessed by analysis of
      proliferative responses to mitogenic agents and in mixed leukocyte reactions.
      RESULTS: Transgene expression was detected in up to 45% of primary CD3+ T
      lymphocytes and in up to 60% of primary NK cells using Ad5/F35. In contrast,
      conventional Ad5 transduced less than 8% and 5% of primary T cells and NK cells,
      respectively. Transduction efficiencies were similar in CD4+ and CD8+ T
      lymphocytes, and transgene expression could be detected for up to seven days.
      Activation of T cells significantly enhanced the efficiency of Ad5/F35-mediated
      gene transfer. Adenoviral transduction of lymphocytes did not result in any
      impairment of proliferative functions. CONCLUSION: The results of this study
      demonstrate that both T lymphocytes and NK cells can be transduced by chimeric
      Ad5/F35 adenoviral vectors.

PMID- 15183895
TI  - Linear polyamine copper chelator tetraethylenepentamine augments long-term ex
      vivo expansion of cord blood-derived CD34+ cells and increases their engraftment
      potential in NOD/SCID mice.
AB  - OBJECTIVE: We previously demonstrated that cellular copper is involved in the
      regulation of proliferation and differentiation of hematopoietic progenitor
      cells. Modulation of cellular copper was achieved by supplementing the culture
      with a copper chelator that reduces cell copper content, or copper salts, which
      elevate the level of cellular copper. In the present study, we evaluated the
      effect of short-term (3-week) treatment with the copper chelator
      tetraethylenepentamine (TEPA) on short- and long-term (up to 11 weeks) ex vivo
      expansion of hematopoietic progenitors, as well as on their SCID engraftment
      potential. MATERIALS AND METHODS: Cord blood-derived purified CD34+ cells were
      grown in liquid medium supplemented with the cytokines stem cell factor,
      thrombopoietin, Flt3 ligand, and IL-6, and the chelator TEPA for the first 3
      weeks and then for up to 11 weeks with cytokines alone. Control cultures were
      supplemented with cytokines alone for the entire culture duration. Cultured cells
      were characterized by immunophenotyping and cloning (CFUc). Transplantability was
      assayed by injection of repurified CD34+ cells into NOD/SCID mice. RESULTS: In
      the short term, TEPA supported increased percentages of early progenitors over
      control cultures incubated with cytokines alone (CD34(+)CD38-, p=0.001 and
      CD34(+)Lin-, p=0.016). In the long term, TEPA pretreated cultures showed
      prolonged expansion of CD34+ cells (p=0.01) and CFUc (p=0.002) compared with that
      of untreated cultures. The SCID engraftment potential of CD34+ cells repurified
      from the TEPA-treated cultures was higher compared with that of the control,
      i.e., only cytokine-treated cultures (p=0.03). CONCLUSION: TEPA enabled
      preferential proliferation of early progenitor cells with the phenotype
      CD34(+)CD38- and CD34(+)CD38- Lin- during the first weeks of culture, resulting
      in the observed increased long-term ex vivo expansion and engraftment
      capabilities.

PMID- 15183896
TI  - Functional evaluation of the role of inhibitor of apoptosis proteins in chronic
      lymphocytic leukemia.
AB  - OBJECTIVE: The slow accumulation of malignant cells in chronic lymphocytic
      leukemia (CLL) suggests a defect in the induction of apoptosis in these cells.
      Previous studies have found sporadic alterations in the apoptotic apparatus in
      CLL cells, but a widespread defect has not been detected until now. A crucial
      checkpoint in the progression of apoptosis is the activity of inhibitor of
      apoptosis proteins (IAP) that control the activity of caspases upon the release
      of cytochrome c from mitochondria. The aim of this study was to evaluate the role
      of IAP in the regulation of apoptosis in CLL cells. MATERIALS AND METHODS:
      Lysates from CLL cells were prepared, and the regular function of components of
      the cytochrome c-dependent caspase-activating machinery (the apoptosome) was
      investigated. The effect of IAP in caspase-inhibition was tested using a peptide
      derived from the mitochondrial IAP antagonist Smac/DIABLO. Regulation of
      expression as well as inhibitory function of the X-linked IAP (XIAP) by cytokines
      was analyzed. RESULTS: The apoptosome was found to be structurally and
      functionally competent in CLL. XIAP expression was enhanced by culture in the
      presence of cytokines. Smac/DIABLO was easily detectable in CLL cells and was
      released into the cytosol during apoptosis. No inhibitory effect of IAP was
      detected in CLL, irrespective of XIAP levels and culture conditions. CONCLUSION:
      Although XIAP is present in CLL cells and is up-regulated in conditions where
      apoptosis is prevented, no caspase-inhibiting anti-apoptotic effect of IAP is
      detectable. This is likely due to the high expression of Smac/DIABLO in CLL cells
      that is sufficient to overcome the caspase-inhibiting effect of IAP.

PMID- 15183897
TI  - Adhesion capacity and integrin expression by dendritic-like cells generated from
      acute myeloid leukemia blasts by calcium ionophore treatment.
AB  - OBJECTIVE: Dendritic cells (DC) play a key role in initiation of immune
      responses. In vitro modified acute myeloid leukemia (AML) blasts acquire certain
      specific features of DC and are suggested as a potential source of anti-leukemia
      vaccines. AML-DC have been characterized in terms of costimulatory molecule
      expression and cytokine production. In contrast, migratory capacity of AML-DC,
      which is a major attribute of DC required for their in vivo function, remains
      unknown. Here we present data on adhesion properties and profile of integrin
      expression of AML-DC. MATERIALS AND METHODS: Blasts from nine patients were used
      to generate AML-DC by calcium ionophore treatment. Adhesion of AML-DC to the
      major components of the extracellular matrix and the profile of integrin
      expression was studied using flow cytometry. RESULTS: Similar to their normal
      counterparts, calcium ionophore-induced AML-DC acquired the ability to bind to
      fibronectin and in 4 of 7 studied cases to bind to denatured collagen. Adhesion
      to native collagen remained unchanged during DC-type differentiation of AML
      blasts. AML-DC and DC obtained from monocytes of healthy donors expressed CD49d,
      CD49e, alphavbeta3, and alphavbeta5. However, AML-DC from 3 of 8 patients down
      regulated CD49d, which plays an important role in cell-to-cell and cell-to-matrix
      interactions and normally is coexpressed with CD83. CONCLUSION: The results
      provide further evidence that AML blasts can be induced to display functional
      properties characteristic for DC and may prove useful for in vivo delivery and
      presentation of tumor antigens to the immune system. Abnormal CD49d expression
      and variability in AML-DC adhesion to denatured collagen indicate that motility
      of AML-DC from individual patients may vary, and a customized approach is
      essential for evaluating leukemic cell feasibility for vaccine design.

PMID- 15183898
TI  - Polycomb group gene mel-18 modulates the self-renewal activity and cell cycle
      status of hematopoietic stem cells.
AB  - OBJECTIVE: Mel-18 is a member of the mammalian Polycomb group (PcG) genes. This
      family of genes regulates global gene expression in many biologic processes,
      including hematopoiesis and anterior-posterior axis formation by manipulating
      specific target genes, including members of the Hox family. Here, we demonstrate
      that mel-18 negatively regulates the self-renewal activity of hematopoietic stem
      cells (HSCs). MATERIALS AND METHODS: Long-term reconstitution activity was
      evaluated by competitive repopulating unit (CRU) and mean activity of the stem
      cells (MAS) assays in vivo in bone marrow cells (BMCs) derived from mel-18(-/-)
      and mel-18 tg mice. The expression levels of mel-18 and Hoxb4 were measured by
      quantitative real-time reverse transcription polymerase chain reaction. RESULTS:
      The Hoxb4 gene was highly expressed in HSCs derived from mel-18(-/-) mice. The
      observed CRUs were 3.21, 4.77, 3.32, and 1.64 CRU per 10(5) BMCs in mel-18(+/+),
      mel-18(-/-), C57BL/6, and mel-18 tg, respectively. MAS was 0.58, 0.18, 0.41, and
      5.89 in mel-18(+/+), mel-18(-/-), C57BL/6, and mel-18 tg, respectively. The
      percentage in G0 phase HSCs (lin(-)flk2(-)c-Kit(+)Sca1+ cells) was increased in
      mel-18(-/-) mice and decreased in mel-18 tg mice. CONCLUSION: Loss or knockdown
      of mel-18 leads to the expression of Hoxb4, an increase in the proportion of HSCs
      in G0 phase, and the subsequent promotion of HSC self-renewal. These findings
      will enable us to develop new approaches for controlling HSC activity for
      hematopoietic transplantations based on ex vivo expansion of HSCs.

PMID- 15183899
TI  - Prevention of diabetes in nonobese diabetic mice by nonmyeloablative allogeneic
      bone marrow transplantation.
AB  - OBJECTIVE: Autoimmune diabetes in nonobese diabetic (NOD) mice can be prevented
      by allogeneic bone marrow transplantation (BMT) from diabetes-resistant murine
      strains. Donor-specific tolerance can also be induced by BMT; however, clinical
      application of nonmyeloablative conditioning prior to BMT may be essential for
      reducing transplant-related toxicity and mortality. In this study, we have
      attempted to treat autoimmunity using a new nonmyeloablative regimen for BMT.
      MATERIALS AND METHODS: Naive NOD were irradiated with 650 cGy and injected
      intravenously (i.v.) with splenocytes from overtly diabetic NOD mice for
      induction of diabetes mellitus. Three days later, experimental mice received
      allogeneic C57BL/6 or (C57BL/6 x BALB/c) F1 bone marrow (BM) cells i.v. for
      intentional activation of donor-reactive cells, and 24 hours later
      intraperitoneal injection of cyclophosphamide (CY) for selective depletion of
      alloreactive cells. In order to induce chimerism, recipients were given a second
      IV inoculum of donor BM 1 day after CY. RESULTS: Our method of nonmyeloablative
      BMT converted recipients to full or to mixed chimeras and prevented development
      of diabetes. Although NOD mice treated with 200 mg/kg CY died of graft-vs-host
      disease (GVHD), we observed diabetes-free survival for >300 days in 90% of
      C57BL/6 --> NOD BM chimeras treated with 60 mg/kg CY. CONCLUSION: Our data show
      that allogeneic BMT after reduced-intensity conditioning based on deletion of
      activated donor-reactive host cells by means low-dose CY results in prevention of
      autoimmune diabetes by converting recipients to stable, GVHD-free BM chimeras.

PMID- 15183900
TI  - Optimizing platelet transfusion therapy.
AB  - Platelet transfusions are widely used. Prophylactic transfusions are employed in
      severely thrombocytopenic patients without evidence of bleeding, but no
      randomized trial data prove the safety or efficacy of this approach. Randomized
      trials have demonstrated the equivalence of transfusion triggers of 10,000 and
      20,000/microl for prophylactic transfusions. The former threshold is potentially
      safer for the patient, conservative of donor resources and leads to lower costs,
      with perhaps a slightly greater risk of minor hemorrhage. Randomized trials have
      demonstrated the equivalence of pheresis or whole blood-derived platelet
      transfusions. The former present a lower risk for infectious agents, and the
      latter are less expensive and a more efficient use of limited donor resources.
      Randomized trials prove that leukoreduced and ABO identical platelet transfusions
      reduce the risks of HLA alloimmunization and platelet transfusion refractoriness
      (both leukoreduction and ABO matching), transfusion reactions (leukoreduction)
      and CMV transmission (leukoreduction). Leukoreduction and ABO matching of
      platelet transfusions also have been associated in preliminary observational
      studies with reduced morbidity and mortality in surgical patients and reduced
      infections in patients with leukemia. These results require further
      investigation. Future challenges include (1) determining the best approach to
      bacterial contamination of platelets, whether by detection methods or pathogen
      inactivation and (2) determining the threshold for prophylactic platelet
      transfusions in thrombocytopenic patients undergoing surgery or invasive
      procedures.

PMID- 15183901
TI  - Umbilical cord blood transplantation--how, when and for whom?
AB  - In recent years, umbilical cord blood (UCB) has emerged as a feasible alternative
      source of hematopoietic progenitors (CD34+) for allogeneic stem cell
      transplantation, mainly in patients who lack HLA-matched marrow donors. Since the
      first case reported in 1998, more than 3500 patients have received UCB
      transplants for a variety of malignant and non-malignant diseases. The vast
      majority of recipients were children with an average weight of 20 kg; however,
      more than 500 UCB transplantations (UCBTs) have already been performed in adults.
      The "naive" nature of UCB lymphocytes also permits the use of HLA-mismatched
      grafts at 1-2 loci without higher risk for severe graft versus host disease
      (GvHD) relative to bone marrow transplantation (BMT) from a full matched
      unrelated donor. Furthermore, UCB is rich in primitive CD16(-)CD56++ NK cells,
      which possess impressive proliferative and cytotoxic capacities and can be
      induced to expand using IL-12 or IL-15, so as to mount a substantial graft versus
      leukemia (GvL) effect. The main disadvantage of UCB is the low stem cell yields,
      resulting in higher rates of graft failure as well as delayed time to engraftment
      compared to BMT. One rational approach to overcome this limitation involves ex
      vivo expansion of UCB derived hematopoietic precursors. In this review we tried
      to answer the question: UCBT how, when and for whom. This procedure is mostly
      applicable for children and especially those with indication for full allogeneic
      transplantation but who lack a matched sibling donor. Experimental approaches
      including ex vivo expansion of CB with cocktail of hematopoietic growth factors,
      with or without differentiation blocking agents, co-transplantation of
      haploidentical and CB cells or co-transfusion of CB and mesenchymal cells may
      enable successful UCBT in adults and probably will result in expanding the
      indication to solid tumors or autoimmune disorders.

PMID- 15183902
TI  - Haploidentical transplantation for acute lymphoblastic leukemia in childhood.
AB  - Haploidentical transplantation in childhood acute lymphoblastic leukemia (ALL) is
      a promising option for children lacking a suitable donor. We have updated our
      series of patients with ALL and report the results. Additionally, we reviewed the
      literature and try to embed our own experiences in the published results. We
      performed HLA-mismatched stem cell transplantations with megadoses of purified
      positively selected mobilized peripheral blood CD34+ progenitor cells (PBPC) from
      adult donors in 27 children with acute lymphoblastic leukemia (ALL) in first (CR1
      n = 7), second (CR2 n = 10), or third (CR3 n = 4) complete remission, and in
      refractory state (NR n = 6). The patients received a mean number of 19.1+/-11.3 x
      10(6)/kg purified CD34+ and a mean number of 15.5+/-24.2 x 10(3)/kg CD3+ T-cells.
      No additional graft-versus-host disease (GVHD) prophylaxis was used, except as
      short-term CSA in the first 3 patients. The myeloablative treatment was based on
      busulfan in 12 and on TBI in 14 patients. One patient was grafted with a non
      myeloablative approach. Engraftment was rapid in 26 patients, with two patients
      suffering from a rejection. These two and one patient with initial non
      engraftment had been successfully regrafted. The probability of survival of the
      total group is 0.34+/-0.09; the 12 patients transplanted in remission showed a
      probability of survival of 0.44+/-0.11. None of the patients transplanted in non
      remission survived. There was no statistical difference in survival for patients
      with a 1, 2 or 3 antigen mismatched donor (out of 6 HLA antigens) or for patients
      in 1st, 2nd or 3rd remission. Causes of death were relapses in 10 patients, veno
      occlusive disease (VOD) in 1, multi-organ failure (MOF) in 2 and infections in 4
      patients. 3/24 evaluable patients without any additional GVHD-prophylaxis
      developed grade 1 or 2 GVHD. Ten patients were treated with additional donor
      lymphocyte infusion (DLI), from which 4 developed a maximum grade 3 GVHD. We
      conclude that the HLA barrier can be overcome by transplantation of megadoses of
      highly purified CD34+ PBPC and GVHD can effectively be prevented. This approach
      offers a promising treatment option for patients with acute lymphoblastic
      leukemia needing urgently transplantation but lacking a suitable donor.

PMID- 15183903
TI  - Epstein-Barr virus-specific cytotoxic T-lymphocytes for adoptive immunotherapy of
      post-transplant lymphoproliferative disease.
AB  - Post-transplant lymphoproliferative disease (PTLD) refers to a collection of
      clinically and pathologically diverse tumours associated with iatrogenic
      immunosuppression following transplantation. In most cases, tumourigenesis
      results from a deficit in Epstein-Barr virus (EBV)-specific cytotoxic T
      lymphocyte (CTL) activity that leads to uncontrolled EBV-driven outgrowth of
      latently infected B-lymphocytes. Conventional treatment for PTLD typically
      involves a reduction in immunosuppression, but this approach is frequently
      unsuccessful and mortality remains high. An alternative, adoptive immunotherapy,
      involving the administration of EBV-specific CTLs cultured in vitro has been
      developed with the aim of selectively reconstituting EBV-directed immunity and
      effecting targeted tumour destruction. This approach has been the subject of
      several clinical studies, and these provide encouraging evidence of its clinical
      efficacy. This review presents an overview of the pathogenesis of PTLD and
      examines current progress in the use of adoptive immunotherapy for its treatment.

PMID- 15183904
TI  - Management of Jehovah's Witness patients with haematological problems.
AB  - The management of practising Jehovah's Witnesses who have haematological problems
      presents many different challenges both at the level of treatment strategy and
      ethics. This article focuses on the beliefs of Jehovah's Witnesses and addresses
      treatment modalities available for and acceptable to these individuals. Recent
      advances in the development of novel therapeutic agents have aided the management
      of Jehovah's Witnesses. Finally, the background to the ethical dilemmas raised by
      these issues is discussed.

PMID- 15183906
TI  - Dopamine/serotonin receptor ligands. Part VIII: the dopamine receptor antagonist
      LE300 - modelled and X-ray structure plus further pharmacological
      characterization, including serotonin receptor binding, biogenic amine
      transporter testing and in vivo testings.
AB  - -LE300, a benz[d]indolo[2,3-g]azecine with nanomolar affinities to the hD(1)
      receptor family, has been further pharmacologically characterized and its
      modelled structure was compared to its X-ray structure in order to explain NMR
      data, that was not in accordance to the X-ray structure. Moderate affinity at the
      hD(3) receptor was determined, nanomolar affinities were found at the 5-HT(2A)
      and 5-HT(2C) receptors, micromolar affinity at the 5-HT(1A) receptor using
      binding assays. Functional studies indicate moderate antagonist activity at the 5
      HT(2A) site. No activity was found at dopamine, serotonin and norepinephrine
      transporters. These results suggested the use of LE300 for cocaine addiction
      treatment. High activities were found using in vivo testing: LE300 suppressed
      spontaneous locomotor activity with an ID(50) of 1.24 mg/kg and attenuated
      locomotor activity induced by 20 mg/kg cocaine with an AD(50) of 1.50 mg/kg. It
      failed to substitute for the discriminative stimulus effects produced by cocaine.

PMID- 15183905
TI  - Structural requirements of the N-terminal region of GLP-1-[7-37]-NH2 for receptor
      interaction and cAMP production.
AB  - A series of GLP-1-[7-36]-NH(2) (tGLP-1) and GLP-1-[7-37] analogs modified in
      position 7, 8, 9 and 36, have been designed and evaluated on murine GLP-1
      receptors expressed in RIN T3 cells for both their affinity and activity. Ten of
      the synthesized peptides were found full agonists with activities superior or at
      least equal to that of the native hormone. Five of them were investigated for
      their plasmatic stability and the most stable, [a(8)-desR(36)]GLP-1-[7-37]- NH(2)
      (Compound 8), evaluated in vivo in a glucose tolerance test which confirmed a
      clearly longer activity than that of the native hormone. We also performed
      circular dichroism study and propose a hypothetical structural model explaining
      the most part of observed activities of GLP-1 analogs on RIN T3 cells.

PMID- 15183907
TI  - Synthesis and biological activity of novel substituted benzanilides as potassium
      channel activators. V.
AB  - As part of our program toward designing potassium channel openers, the synthesis
      of a novel series of substituted benzanilides and their vasodilating activity are
      presented. The facile synthetic pathway generally involves coupling between the
      appropriate benzoyl chloride and commercial available anilines, followed by the
      selective or non-selective cleavage of methyl ether substituent(s), affording the
      corresponding phenol or bisphenol derivatives. The pharmacological evaluation of
      these structurally novel potential BK-openers on vascular contractile activity
      was studied in vitro, using isolated rat aortic rings pre-contracted with KCl 20
      mM. Some derivatives were found to be potent smooth muscle relaxants and the
      vasodilation effects of these compounds were inhibited by tetraethylammonium
      (TEA) and iberiotoxin (IbTX), suggesting that the opening of BK channels is
      prevalent in the mechanism of action of these compounds. The best compound of the
      series was N-(2-hydroxy-5-phenyl)-(2-methoxy-5-chloro)-benzamide (16b) showing a
      full vasorelaxant efficacy and almost nanomolar potency index.

PMID- 15183908
TI  - Synthesis, characterization and cytotoxicity evaluation of some new platinum(II)
      complexes of tetrazolo[1,5-a]quinolines.
AB  - Several new platinum(II) complexes of the general formulae cis-[PtCl(2)(DMSO)L],
      where L is a Schiff base or hydrazone derived from tetrazolo[1,5-a]quinoline-4
      carboxaldehyde as carrier ligands, have been synthesized and characterized
      physicochemically and spectroscopically. These platinum complexes which are
      structurally analogues to what so called cisplatin [cis-[PtCl2(NH3)2]; the first
      generation anticancer agent] were evaluated for their cytotoxicity on HL-60
      (human promyelocytic leukemia) cells. Two of the platinum complexes were almost
      similar in their activity to cisplatin, while the remaining three complexes have
      demonstrated higher efficacy than that of cisplatin. Based on our findings, these
      novel platinum complexes appear to be valuable leading compounds with high
      efficacy.

PMID- 15183909
TI  - Synthesis and cytotoxic activity of substituted 7-aryliminomethyl derivatives of
      camptothecin.
AB  - A series of imines derived from camptothecin-7-aldehyde (CPT-CHO) and aromatic
      amines were synthesised and tested for their cytotoxicity against tumour cell
      line H460, that expresses a high level of topoisomerase I. In general ortho
      substituted compounds showed higher cytotoxic potency than the corresponding para
      substituted imines. This effect was dependent on the nature of the substituent.
      Structure-activity relationships were studied by calculation of docking energy
      with a model of the ternary complex camptothecin-DNA-topoisomerase I. The ability
      of selected compounds to stimulate the topoisomerase I-mediated DNA cleavage and
      the persistence of the cleavable complex were consistent with the cytotoxic
      activity.

PMID- 15183910
TI  - Preparation of 4-azaindole and 7-azaindole dimers with a bisalkoxyalkyl spacer in
      order to preferentially target melatonin MT1 receptors over melatonin MT2
      receptors.
AB  - Several 4-azaindole and 7-azaindole dimer analogues of melatonin with a
      bisalkoxyalkyl spacer between the position 5 of each heterocycle were
      synthetized. Our aim was to investigate the influence of the spacers length on
      the selectivity of such compounds for the MT(1) receptors over the MT(2)
      receptors. Our results suggest the distance between indole ring seems to be an
      important parameter in determining the potency of binding with melatonin receptor
      site.

PMID- 15183911
TI  - Synthesis and study of antibacterial and antifungal activities of novel 1-[2
      (benzoxazol-2-yl)ethoxy]- 2,6-diarylpiperidin-4-ones.
AB  - Some novel benzoxazolylethoxypiperidones have been synthesized and their
      antibacterial activity against streptococcus faecalis, bacillus subtilis,
      escherichia coli, staphylococcus aureus aand pseudomonas aeruginosa and
      antifungal activity against Candida-6, Candida albicans, Aspergillus niger,
      Candida-51 and Aspergillus flavus were evaluated. Compounds 37, 38 and 39 exerted
      potent in vitro antibacterial activity against Streptococcus faecalis while
      compounds 40 and 41 exhibited potent in vitro antifungal activity against Candida
      51.

PMID- 15183912
TI  - Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation
      activities of some new 2-[(2,6-dichloroanilino) phenyl]acetic acid derivatives.
AB  - The synthesis of a group of 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,3,4
      thiadiazoles and 1,2,4-triazine derived from 2-[(2,6-dichloroanilino) phenyl]
      acetic acid is described. The structures of new compounds are supported by IR,
      (1)H-NMR and Mass spectral data. These compounds were tested in vivo for their
      anti-inflammatory activity. The compounds, which showed activity comparable to
      the standard drug diclofenac, were screened for their analgesic, ulcerogenic and
      lipid peroxidation activities. Ten new compounds, out of 28 showed very good anti
      inflammatory activity in the carrageenin induced rat paw edema test, with
      significant analgesic activity in the acetic acid induced writhing test together
      with negligible ulcerogenic action. The compounds, which showed less ulcerogenic
      action, also showed reduced malondialdehyde content (MDA), which is one of the
      byproduct of lipid peroxidation. The study showed that the compounds inhibited
      the induction of gastric mucosal lesions and it can be suggested from our results
      that their protective effects may be related to inhibition of lipid peroxidation
      in the gastric mucosa.

PMID- 15183913
TI  - Piperazine-linked bisbenzamidines: a novel class of antileishmanial agents.
AB  - A series of 13 1,4-diarylpiperazines has been prepared, evaluated for
      antileishmanial activity and their binding affinity to DNA was measured. Among
      these compounds, 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl]piperazine (14) emerged
      as the most active compound with an IC(50) value of 0.41 microM which is about
      sevenfold more potent than pentamidine.

PMID- 15183914
TI  - Validity of dietary restraint among 5- to 9-year old girls.
AB  - Dietary restraint is defined as the cognitive tendency to restrict intake and is
      often accompanied by the breakdown of restraint, referred to as disinhibition,
      leading to overeating and overweight in adults. Given recent evidence suggesting
      that dietary restraint and disinhibition are emerging as early as middle
      childhood, this study examined the validity of the restraint construct as
      measured in girls between the ages of 5 and 9. Dietary restraint was assessed
      longitudinally by questionnaire and validity was established by correlating
      restraint with measures previously reported to be related to restraint including
      weight concerns, body esteem, self-reported dieting, and measures of dietary
      intake when girls were ages 5, 7, and 9. Participants were 153 girls from
      predominately middle class, and exclusively non-Hispanic white families living in
      central Pennsylvania. Correlational data were used to assess relationships
      between dietary restraint and weight concerns, body esteem, dietary intake, and
      dieting. Results from this study indicate that there is evidence for the validity
      of the dietary restraint construct among girls by age 9. Specifically, dietary
      restraint was highly and positively associated with body mass index, weight
      concerns and body dissatisfaction and negatively correlated with dietary intake,
      findings similar to those reported in the adult literature.

PMID- 15183916
TI  - Longitudinal dietary change from adolescence to adulthood: perceptions,
      attributions and evidence.
AB  - Dietary patterns and change in eating habits are influenced by multiple factors
      from an individual's internal and external environment. A longitudinal dietary
      survey study provided quantitative evidence of dietary change and investigated
      factors influencing dietary change from adolescence to adulthood, using
      sociodemographic data and participants' own perceptions of, and attributions for,
      their dietary change. Longitudinal dietary data were obtained in 1980 and 2000
      (average age 11.6 and 32.5 years, respectively). Two questionnaires (2000) and 2
      x 3-day food diaries (1980 and 2000) were collected from 198 participants. Foods
      consumed were assigned to one of the five food groups from The Balance of Good
      Health (a UK food guide). Questionnaire responses were used to examine how
      subjects perceived their own dietary change and the factors to which they
      attributed such change. Six key factors were identified from the questionnaire:
      parents, partners, children, nutritional awareness, employment and lack of time.
      Demographic and key factors were associated with degree of change in intake. The
      complex process of change in food consumption can be linked with an individual's
      attributions for change.

PMID- 15183915
TI  - Mothers misunderstand questions on a feeding questionnaire.
AB  - Feeding questionnaires have not consistently identified mothers' beliefs or
      behaviors associated with preschool children becoming overweight. One reason may
      be that mothers do not understand the constructs in the questions in the way
      intended by the developers of the questionnaire. This study assessed items on the
      Preschooler Feeding Questionnaire (PFQ)--a maternal questionnaire about feeding
      practices and beliefs relating to the weight status of preschoolers. Seven audio
      taped interviews were conducted with African American mothers of 24-59 month-old
      children in Chicago enrolled in the Special Supplemental Nutrition Program for
      Women, Infants, and Children. Questions in the PFQ were interpreted by
      respondents to mean something other than what was intended. In particular, the
      constructs difficulty in child feeding, pushing the child to eat more, and using
      food to calm the child were present among the mothers but not captured by items
      on the questionnaire. Thus, qualitative interviewing could help to match the
      intention in asking a question with its interpretation by respondents. A mismatch
      may contribute to our low level of understanding about the causes of early
      obesity.

PMID- 15183917
TI  - Food-related lifestyle and health attitudes of Dutch vegetarians, non-vegetarian
      consumers of meat substitutes, and meat consumers.
AB  - The aim was to investigate socio-demographic characteristics, and attitudes to
      food and health of vegetarians, non-vegetarian consumers of meat substitutes, and
      meat consumers in The Netherlands. The sample used for this study (participants >
      or =18 years) was taken from the Dutch National Food Consumption Survey,
      1997/1998. Vegetarians (n = 63) and consumers of meat substitutes (n = 39) had
      similar socio-demographic profiles: higher education levels, higher social
      economic status, smaller households, and more urbanised residential areas,
      compared to meat consumers (n = 4313). Attitudes to food were assessed by the
      food-related lifestyle instrument. We found that vegetarians (n = 32) had more
      positive attitudes towards importance of product information, speciality shops,
      health, novelty, ecological products, social event, and social relationships than
      meat consumers (n = 1638). The health consciousness scale, which was used to
      assess attitudes to health, supported earlier findings that vegetarians are more
      occupied by health. Food-related lifestyle and health attitudes of meat
      substitute consumers (n = 17) were predominantly in-between those from
      vegetarians and meat consumers. The outcome of this study suggests that in
      strategies to promote meat substitutes for non-vegetarian consumers, the focus
      should not only be on health and ecological aspects of foods.

PMID- 15183918
TI  - Good foods gone bad: 'infamous' nutrients diminish perceived vitamin and mineral
      content of foods.
AB  - The addition of disreputable ingredients (e.g. fat) can reduce the perceived
      health value of foods and cause the foods to take on negative qualities (e.g.
      promoters of obesity). However, are foods that contain disreputable ingredients
      perceived to lack positive components (e.g. vitamins and minerals)? In the
      present study, college students were asked to rate the vitamin and mineral levels
      of a group of primary foods (e.g. apple) as well as their counterparts, i.e. a
      second group of similar foods (e.g. caramel apple) that contained disreputable
      ingredients. The results strongly suggest that college students believe that fat,
      sugar, and salt deplete foods of vitamins and minerals. Perhaps as much as
      anything these results indicate that more care and caution should be used when
      disseminating nutritional information.

PMID- 15183919
TI  - An exploration of affective priming as an indirect measure of food attitudes.
AB  - During the last few years indirect measures of attitudes have been increasingly
      promoted. Because they are assumed to be less influenced by demand effects, these
      indirect measures would constitute a better basis to predict behaviour in some
      circumstances. In two studies, we examined the usefulness of the affective
      priming paradigm as an indirect measure of food likes and dislikes. Participants
      were asked to evaluatively categorize word targets, which were primed by
      individually selected positive and negative food pictures. The first experiment
      was a basic exploration of the usefulness of the affective priming paradigm to
      uncover food likes and dislikes, by making use of food stimuli that elicit strong
      evaluative reactions. The second experiment examined whether the paradigm can
      also be used in the context of weaker food (dis)likes. It could be demonstrated
      that both strongly (Experiments 1 and 2) and moderately (Experiment 2) evaluated
      food primes influenced the speed of responding to the positive and negative
      target words. No differential sensitivity for attitudes of moderate or extreme
      evaluative meaning could be demonstrated, however. The implications for future
      research and the applicability of this indirect index of food (dis)likes are
      discussed.

PMID- 15183920
TI  - Fructose-conditioned flavor preferences in male and female rats: effects of sweet
      taste and sugar concentration.
AB  - Previous studies indicate that fructose postingestive reward for flavor
      preference learning is weaker than that of glucose. The present experiments
      explored the effects of several variables that modulate the response to fructose.
      In Experiment 1, ad libitum fed male rats were trained in 22 h sessions with one
      flavor (the CS+) paired with intragastric infusions of 7.18% fructose and another
      flavor (the CS-) paired with intragastric water infusion. Subsequent preference
      for the CS+ relative to the CS- was 90% with saccharin-sweetened flavors and only
      67% with nonsweet flavors. Experiments 2 (males) and 3 (females) examined the
      effects of taste quality on conditioning with 16% fructose infusions. Males and
      females both preferred the sweet CS+ flavor (71-72%). In contrast, males avoided
      the nonsweet CS+ flavor (31%) and females were indifferent (47%). The different
      preference patterns were accompanied by differences in sweet and nonsweet
      training intakes and bout patterns, suggesting stimulation of intake with sweet
      flavor and 7.18% fructose, and satiating effects of 16% fructose. The sex
      difference in response to nonsweet flavors may reflect a greater sensitivity of
      male rats to fructose's postingestive satiating or aversive effects. Possible
      mechanisms for the sweet-taste enhancement of conditioning include increasing CS
      intakes in training, facilitating fructose metabolism and increasing flavor
      salience.

PMID- 15183921
TI  - Effects of ethanol consumption by adult female rats on subsequent consumption by
      adolescents.
AB  - We used a two-bottle choice test to measure voluntary ethanol consumption by
      adolescent rats that had lived with ethanol-consuming or water-consuming adult
      conspecifics. We found that housing weanlings with either a virgin or a lactating
      adult female rat that ingested ethanol increased the weanlings' subsequent
      voluntary intake of ethanol when they were fluid-deprived and provided with
      choices between 8% ethanol solution and water for 2 h/day. Rats housed with both
      an ethanol-consuming virgin female and their water-consuming dam drank more
      ethanol than did rats housed with a dam and virgin female, both consuming water.
      Rats housed with an ethanol-consuming dam and ethanol consuming adult virgin did
      not drink more ethanol than did rats housed with an ethanol-consuming dam and a
      water-consuming virgin female. In sum: (1) young rats learned socially to consume
      ethanol. (2) Exposure to ethanol in mother's milk was not necessary for such
      social learning to occur, and (3) living with an ethanol-consuming unfamiliar,
      virgin female conspecific resulted in enhanced ethanol intake by adolescent rats,
      even if a water-consuming dam was also present.

PMID- 15183922
TI  - Psycho-social influences on food choice in Southern France and Central England.
AB  - This study used attitudinal scales to investigate the nature of attitudes to diet
      and health in a northern European country (Central England) and a southern
      European country (Mediterranean France). Cross-sectional studies were conducted
      using self-administered postal questionnaires that were distributed
      simultaneously in April 2001 in Montpellier, France and Nottingham, England. A
      stratified random sample of 1000 males and 1000 females aged 18-65 years was
      generated from the electoral roll in each country. The final sample comprised
      England: n = 826 (58% male and 42% female; mean age=44 years) and France: n = 766
      (42% male and 58% female; mean age=42 years). This study has demonstrated that
      the pleasurable and social aspects of eating, certain food quality issues, as
      well as health as a value were regarded as priorities by French respondents. On
      the other hand, English respondents reported that organic and ethical issues and
      convenience were important factors influencing their food choices. In conclusion,
      the two populations can be differentiated overall in their attitudes and beliefs
      to food choice.

PMID- 15183923
TI  - Perceptions of meal convenience: the case of at-home evening meals.
AB  - Perceptions of a range of evening meal situations eaten in the home were explored
      in a female consumer population. The investigation was carried out using the
      repertory grid technique and using written scenarios as the research stimuli. The
      nine scenarios successfully manipulated perceived convenience, time and effort. A
      consumer-generated vocabulary pertaining to food-related convenience was derived
      and revealed that while elements of both time and effort contributed to perceived
      convenience, these two 'dimensions' were highly interdependent. The presence of
      terms related to planning, shopping, preparation, cooking and clean-up
      illustrated that all stages in the food provisioning process influenced perceived
      convenience. Some evidence was established of perceptual differences between
      individuals varying with respect to convenience orientation in meal preparation.

PMID- 15183924
TI  - Chewing gum differentially affects aspects of attention in healthy subjects.
AB  - In a study published previously in this journal (Wilkinson et al., 2002), the
      effect of chewing gum on cognitive functioning was examined. The results of this
      study indicated that chewing a piece of gum results in an improvement of working
      memory and of both immediate and delayed recall of words but not of attention. In
      the present study, memory and a variety of attentional functions of healthy adult
      participants were examined under four different conditions: no chewing, mimicking
      chewing movements, chewing a piece of tasteless chewing gum and chewing a piece
      of spearmint flavoured chewing gum. The sequence of conditions was randomised
      across participants. The results showed that the chewing of gum did not improve
      participants' memory functions. Furthermore, chewing may differentially affect
      specific aspects of attention. While sustained attention was improved by the
      chewing of gum, alertness and flexibility were adversely affected by chewing. In
      conclusion, claims that the chewing a gum improves cognition should be viewed
      with caution.

PMID- 15183925
TI  - A glucose-caffeine 'energy drink' ameliorates subjective and performance deficits
      during prolonged cognitive demand.
AB  - Effects of a combination of caffeine and glucose were assessed in two double
      blind, placebo-controlled, cross-over studies during extended performance of
      cognitively demanding tasks. In the first study, 30 participants received two
      drinks containing carbohydrate and caffeine (68 g/38 mg; 68 g/46 mg,
      respectively) and a placebo drink, in counter-balanced order, on separate days.
      In the second study 26 participants received a drink containing 60 g of
      carbohydrate and 33 mg of caffeine and a placebo drink. In both studies,
      participants completed a 10-min battery of tasks comprising 2-min versions of
      Serial 3s and Serial 7s subtraction tasks and a 5-min version of the Rapid Visual
      Information Processing task (RVIP), plus a rating of 'mental fatigue', once
      before the drink and six times in succession commencing 10 min after its
      consumption. In comparison to placebo, all three active drinks improved the
      accuracy of RVIP performance and both the drink with the higher level of caffeine
      in first study and the active drink in the second study resulted in lower ratings
      of mental fatigue. These results indicate that a combination of caffeine and
      glucose can ameliorate deficits in cognitive performance and subjective fatigue
      during extended periods of cognitive demand.

PMID- 15183926
TI  - The blocking activity of birch pollen-specific immunotherapy-induced IgG4 is not
      qualitatively superior to that of other IgG subclasses.
AB  - Allergen-specific IgG antibodies induced by specific immunotherapy (SIT)
      interfere with the allergen-IgE interaction, and act as blocking antibodies in
      vitro. It has been hypothesised that IgG4, as opposed to other IgG subclasses, is
      particularly important in this function, which may play a role for the clinical
      efficacy of SIT. In this study, fractionated serum samples from 14 SIT-treated
      birch pollen allergic individuals enabled determination of the inhibitory
      capacity of IgG4 alone versus non-IgG4 IgG. Allergen-binding activities of IgG
      and the IgG-mediated inhibition of allergen binding to autologous IgE were
      detected using 125I-labelled rBet v 1.2801, a recombinant variant of the major
      allergen of Betula verrucosa pollen. Results show that IgG4-depletion resulted in
      equivalent reductions in binding and blocking activities. In contrast, a
      significant but less than two-fold higher relative blocking activity was found in
      the purified IgG4 fraction. There was no significant difference in the binding
      avidities (1/K(d)) measured in the two IgG fractions. Thus, it appears that SIT
      induced specific IgG4 contributes to the IgG blocking of allergen binding to IgE
      in a simple quantitative manner and not by a particular intrinsic blocking
      activity.

PMID- 15183927
TI  - Responses to infection and possible recognition strategies in the innate immune
      system of Caenorhabditis elegans.
AB  - In recent years, researchers investigating innate immunity have begun to use C.
      elegans as a new model system. The worm has been found to mount protective
      responses to a variety of fungal and bacterial pathogens. Four signalling
      pathways involved in such responses have been identified so far: the p38 MAP
      kinase pathway, the programmed cell death pathway, the TGF-beta pathway and the
      DAF-2 insulin/IGF-I like signalling pathway. Activation of these pathways can
      lead to the production of immune effector molecules such as lysozymes, lipases
      and saposin-like proteins, which can act directly against the invading
      microorganisms. The signalling pathways used and the effectors produced depend on
      the nature of the infection, indicating that the worm can detect and discriminate
      between infecting microorganisms. However, the molecules involved in recognition
      of pathogens have yet to be identified. The worm genome encodes various proteins
      which might have this recognition function, such as numerous proteins containing
      C-type lectin domains. These and other candidates are discussed.

PMID- 15183928
TI  - Fine binding characteristics of human autoantibodies-partial molecular
      characterization.
AB  - The fine binding characteristics of three well-characterized human autoantibodies
      B3, RH14 (anti-DNA) and UK4 (anti-cardiolipin) in their IgG and cloned Fab
      formats, were investigated. Although in severe combined immunodeficiency (SCID)
      mice B3 and RH14 both induce proteinuria, only RH14 induces early features of
      lupus nephritis, whereas UK4 exhibits lupus anticoagulant activity. RH14
      exhibited up to 10 fold higher binding to DNA compared to that shown by B3 or UK4
      and involved significant electrostatic and phosphate group interactions. Only
      RH14 exhibited strong anti-Sm cross-reactivity residing on the C-terminus of the
      antigen as determined by the use of 76 overlapping 15mer peptides. Chain
      shuffling experiments indicate that anti-Sm/RNP and anti-Jo-1 activities of B3
      and UK4 co-exist on one of the two chains (light, B3; heavy, UK4). The present
      study provides evidence that a human anti-DNA antibody can also be an anti-ENA
      antibody. Furthermore, the anti-DNA antibodies also exhibited cross-reactivity
      against glutathione-S-transferase and DNA polymerase PolIV of bacterial origin.
      This is the first demonstration of the presence of such cross-reactivities on
      lupus anti-DNA antibodies. We now demonstrate that subsets of sera from the
      patients with lupus, recognise these antigens. This observation may in some cases
      provide a mechanism for the common expression of a variety of autoantibodies
      observed in systemic lupus erythematosus (SLE).

PMID- 15183929
TI  - A bispecific single-chain antibody fusion protein for targeted depletion of
      autoreactive B cells via unstimulated human T lymphocytes.
AB  - Autoantigen-specific B cells are culprits in the pathogenesis of many autoimmune
      diseases either through the production of autoreactive antibodies or as very
      effective antigen-presenting cells. A general depletion of B cells by a CD20
      specific monoclonal IgG1 antibody has recently been validated as an effective
      strategy for treating rheumatoid arthritis. However, general elimination of B
      cells can lead to immunosuppression and increased risk of infection. In search
      for a more specific approach, we have generated a fusion protein for the antigen
      specific targeting of autoreactive B cells for re-directed lysis by resting human
      T lymphocytes. We describe the design, purification and characterization of
      MOGxanti-CD3, a single-chain bispecific antibody fusion protein recognizing B
      cell receptors specific for the human myelin oligodendrocyte glycoprotein (MOG)
      and to CD3 on human T cells. MOGxAnti-CD3 induced selective and very efficient
      redirected lysis of MOG-reactive B cells through freshly isolated, unstimulated
      human T cells. Fusions between autoantigens and an anti-CD3 single-chain antibody
      may be suitable to develop very specific therapeutic approaches for the selective
      depletion of autoreactive B cells in autoimmune diseases.

PMID- 15183930
TI  - Human monoclonal antibodies produced in transgenic BABkappa,lambda mice
      recognising idiotypic immunoglobulins of human lymphoma cells.
AB  - Clonal idiotypic immunoglobulins of follicular lymphomas can be isolated by
      somatic fusion procedures. Idiotypic IgMs (Id-IgM) were isolated from two
      patients and used to immunise a strain of mice, deficient in mouse antibody
      production and engineered with yeast artificial chromosomes (YAC) containing
      fragments of the human immunoglobulin (Ig) micro/delta heavy chain and
      kappa/lambda light chain loci. Sequence analysis showed that hybridomas prepared
      from spleen cells of immunised mice expressed exclusively one of the six VH genes
      (VH1-2) present in the YAC transgene with different D/J rearrangements, and
      secrete fully human monoclonal antibodies (mAb) that recognised the tumour
      specific IgM proteins. Further studies of the reactivity of the monoclonal anti
      human Id-IgM antibodies revealed that they are specific for the individual
      protein of each patient and probably react with idiotypic determinants. In one
      case studied, the antibody recognised specifically the lymphoma cell expressing
      the corresponding idiotypic IgM and lysed those cells in the presence of
      complement. This is the first example of a human monoclonal antibody with such
      characteristics and may be of further use in the therapy of patients with B cell
      malignancies.

PMID- 15183932
TI  - A high-affinity macaque antibody Fab with human-like framework regions obtained
      from a small phage display immune library.
AB  - Tetanus toxoid was used as a model antigen for the immunization of Macaca
      fascicularis. Using peripheral blood as a template, specific Fab-encoding genes
      were amplified by PCR on the fourth day after the final boost, and cloned in a
      phagemidic vector (pComb3X) as a small immune library (5 x 10(5) clones). A high
      affinity Fab (Kd = 4 x 10(-10) M), 6-ATT, was isolated from this library by
      panning. The genes encoding 6-ATT were found to be similar to human
      immunoglobulin germline genes, and were assigned to subgroups of human V, (D) or
      J genes by IMGT/V-QUEST. Overall, the Fab variable domain framework regions were
      93% identical to the representative genes and alleles of the human subgroups,
      this level of identity being similar to that between genes of the same human
      subgroup. This strategy could be used for the isolation of high-affinity, human
      like Fab fragments directed against numerous antigens.

PMID- 15183931
TI  - Variable region domain exchange in human IgGs promotes antibody complex formation
      with accompanying structural changes and altered effector functions.
AB  - Variable region domain exchanged IgG, or "inside-out (io)," molecules, were
      produced to investigate the effects of domain interactions on antibody structure
      and function. Studies using ultracentrifugation and electron microscopy showed
      that variable region domain exchange induces non-covalent multimerization through
      Fab domains. Surprisingly, variable region exchange also affected Fc-associated
      functions such as serum half-life and binding to protein G and FcgammaRI. These
      alterations were not merely a consequence of IgG aggregation. Both the extent of
      multimerization and alterations in Fc-associated properties depended on the IgG
      isotype.

PMID- 15183933
TI  - Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are
      induced by TNF and responsible for elimination of ROS.
AB  - We recently showed that TNF induces accumulation of reactive oxygen species (ROS)
      that mediates necrosis in murine embryonic fibroblasts (MEFs) derived from TRAF2-
      and TRAF5-double deficient (DKO) mice. To elucidate the defects that subsequently
      cause accumulation of ROS in DKO MEFs, we compared gene expression profiles of
      wild-type and DKO MEFs before and after TNF stimulation using cDNA microarrays.
      Interestingly, many antioxidant enzymes are induced by TNF in wild-type MEFs,
      induction of these genes is impaired in DKO MEFs. Taken that TNF induces
      accumulation of ROS in DKO, but not wild-type MEFs, upregulation of antioxidant
      enzyme(s) might play a crucial role in elimination of ROS.

PMID- 15183934
TI  - Structure and organization of the T cell receptor alpha chain genes in Atlantic
      salmon.
AB  - A cDNA fragment of the T cell receptor (TCR) alpha chain mRNA in Atlantic salmon
      (Salmo salar) was amplified by PCR and used as a probe to isolate a full-length
      clone from a leukocyte cDNA library. Additionally, a genomic lambda clone
      comprising the TCR alpha chain constant region (Calpha) gene and flanking regions
      was isolated and partially sequenced. The Calpha gene consists of three exons
      corresponding to the immunoglobulin (Ig) domain, the hinge region and the
      transmembrane peptide/cytoplasmatic tail, and two exons corresponding to the
      untranslated tail of the mRNA. Remnants of a transposase gene and a partial
      duplication of the Calpha gene were found nearby the intact gene. One J segment
      was found 1.5kb upstream of the Calpha gene. Twenty-six other J elements were
      identified among cDNA fragments covering the V/J/Calpha junction. Representatives
      of five Valpha gene families were identified by PCR amplification of genomic DNA
      fragments. PCR amplification of Calpha fragments from another individual revealed
      a slightly different Calpha gene which most likely represents an allelic variant.

PMID- 15183935
TI  - LRRC8 extracellular domain is composed of 17 leucine-rich repeats.

PMID- 15183936
TI  - Value of urinary cytology in the diagnosis and management of urinary tract
      malignancies.

PMID- 15183937
TI  - Three-dimensional ultrasound guidance for percutaneous drainage of prostatic
      abscesses.
AB  - OBJECTIVES: To evaluate the feasibility and effectiveness of three-dimensional
      ultrasound-guided transperineal puncture and drainage of prostatic abscesses.
      METHODS: Between 1985 and 2003, a prostatic abscess was diagnosed in 22 patients.
      One of the therapeutic modalities used to drain the abscesses was transperineal
      puncture under three-dimensional ultrasound guidance. The postoperative results
      were compared with the outcomes of other modalities. RESULTS: The average patient
      age was 52 years. Predisposing factors were present in 12 patients. Transperineal
      puncture was performed in 7 patients under general anesthesia. In addition to
      antibiotic therapy, a nephrostomy tube was left in place in all cases for a mean
      period of 3 days to drain the abscess. All patients were treated effectively
      without additional therapy or complications. CONCLUSIONS: Three-dimensional
      ultrasound-guided transperineal puncture is a minimally invasive and effective
      technique for the treatment of prostatic abscesses.

PMID- 15183939
TI  - Cutaneous metastases from genitourinary malignancies.
AB  - OBJECTIVES: To review the world literature for reports of cutaneous metastases
      from primary genitourinary malignancies and compare them with our experience
      during a 10-year period. Cutaneous metastases from primary visceral malignancies
      are uncommon manifestations of advanced disease. Among patients with urologic
      malignancies, the incidence and appearance of cutaneous metastases are not well
      established and recognition is poor among practicing urologists. METHODS: A
      Medline search and manual bibliographic review was performed to identify peer
      reviewed reports pertaining to cutaneous metastases from all visceral
      malignancies. A comparative review of all pertinent cases arising from primary
      urologic malignancies was performed. A comprehensive search of our institution's
      tumor registry was performed to identify all analytic cases of urologic
      malignancy diagnosed, treated, and followed up between 1990 and 2000. Clinical
      and pathologic data were collated. RESULTS: We identified 2,369 reported cases of
      cutaneous metastases arising from 81,618 primary solid visceral malignancies, for
      an overall incidence of 2.9%. Dermatologic spread from primary urologic
      malignancies of the kidney, bladder, prostate, or testes was noted in 116 (1.3%)
      of 10,417. The incidence of cutaneous metastases from the kidney, bladder,
      prostate, and testes was 3.4%, 0.84%, 0.36%, and 0.4%, respectively. Overall, 436
      cases of cutaneous metastases from urologic organs were identified in the English
      language literature. We identified nine additional cases of pathologically
      confirmed cutaneous metastatic urologic tumors at our institution in the past 10
      years. The most common presentation was an infiltrated plaque or nodules. Most
      cases displayed clinical features that mimicked common skin disorders. The median
      disease-specific survival was less than 6 months from the presentation of
      cutaneous metastasis. CONCLUSIONS: Cutaneous metastases from urologic tumors are
      uncommon and occur in 1% of patients with advanced disease. Urologic skin
      metastases are most common from renal tumors, followed by those of the bladder
      and then prostate. Their clinical appearance may mimic other common dermatologic
      disorders affecting patients with advanced malignancies. Definitive diagnosis
      requires an index of suspicion and skin biopsy. Cutaneous metastases from
      urologic malignancies are associated with a poor prognosis.

PMID- 15183940
TI  - Two-year experience with the german-translated version of the NIH-CPSI in
      patients with CP/CPPS.
AB  - OBJECTIVES: To examine, after psychometric evaluation and validation of the
      translated National Institutes of Health Chronic Prostatitis Symptom Index (NIH
      CPSI), the practical value of this questionnaire in a routine diagnostic
      prostatitis setup for patients with chronic prostatitis/chronic pelvic pain
      syndrome (CP/CPPS). The NIH-CPSI is a well-accepted tool for the symptomatic
      evaluation of patients with CP/CPPS. The recently translated German version has
      not yet been validated in detail. METHODS: A total of 137 consecutive patients
      attending a prostatitis outpatient department were classified according to the
      internationally accepted NIH consensus classification into CP/CPPS NIH type IIIA
      (n = 53; mean age 43.2 years) and IIIB (n = 84; mean age 43.4 years). For
      psychometric analysis, the overall type III group was evaluated for reliability
      and validity of the German NIH-CPSI. The psychometric properties of the
      translated NIH-CPSI were compared with those of the original English version. In
      addition, the total scores of all men and separately for CP/CPPS NIH types IIIA
      and IIIB were evaluated. RESULTS: The German NIH-CPSI was reliable, with an alpha
      coefficient for the overall index and its subscales of between 0.60 and 0.74.
      However, the internal consistency of the pain subdomain was lower in our
      translated version (alpha 0.60) compared with the original English version (alpha
      0.86). In this cohort, men with NIH type IIIB CP/CPPS were significantly (P =
      0.03) more symptomatic in the total index compared with men with NIH type IIIA
      CP/CPPS. CONCLUSIONS: The German version of the NIH-CPSI has a relatively high
      reliability and face and construct validity overall. A validated translated NIH
      CPSI is suggested as a standardized tool to quantify chronic pelvic pain symptoms
      for different countries and languages.

PMID- 15183941
TI  - Healthcare use and costs of primary and secondary care patients with prostatitis.
AB  - OBJECTIVES: To examine and identify predictors of healthcare use and prostatitis
      related and total healthcare costs for primary and secondary care patients with
      new episodes of care for prostatitis. METHODS: We compared the use and costs for
      270 men with a new episode of care for prostatitis to those of randomly selected
      male health maintenance organization enrollees matched by age and primary care
      provider. We examined the episode of care (index visit and next 2 months) and the
      previous and subsequent years. Patients with prostatitis were interviewed 1 month
      after the index visit. RESULTS: Compared with controls, patients with prostatitis
      had significantly greater total healthcare use (P <0.001) and costs (P <0.05) in
      each period. The prostatitis costs were only a small proportion of the total
      costs of the patients with prostatitis and of the difference in costs between
      patients with prostatitis and controls. The 10% of patients with prostatitis with
      the greatest total costs accounted for about one half of all costs. White race (P
      = 0.04), less education (P = 0.02), greater disability (P = 0.003), and greater
      number of non-pelvic pain sites (P = 0.004) at baseline predicted greater total
      healthcare costs after the index visit. CONCLUSIONS: Health maintenance
      organization enrollees who seek care for prostatitis have greater total
      healthcare use and costs than do other enrollees of the same age and primary care
      provider. Most of the difference in costs reflects care for problems other than
      prostatitis. A small proportion of patients account for most of the costs.

PMID- 15183942
TI  - Tubeless percutaneous renal surgery in obese patients.
AB  - OBJECTIVES: To assess the outcome and safety of tubeless percutaneous renal
      surgery in overweight and obese patients. METHODS: A single urologist performed
      tubeless percutaneous renal surgery on a total of 138 renal units in 133 patients
      from March 1996 to January 2003. The tubeless procedures consisted of either
      nephrolithotripsy or endopyelotomy. We analyzed the clinical data of a subset of
      these patients who were of considered normal weight (body mass index [BMI] 18.5
      kg/m2 or greater but less than 25 kg/m2), overweight (BMI 25 kg/m2 or greater but
      less than 30 kg/m2), obese (BMI 30 kg/m2 or greater but less than 40 kg/m2), and
      morbidly obese (BMI 40 kg/m2 or greater). RESULTS: Of the 133 patients, 5 (3.8%)
      were considered morbidly obese, 28 (21.1%) were considered obese, 55 (41.4%) were
      considered overweight, and 45 (34%) were considered to be of normal weight. Of
      the 133 patients, 104 underwent percutaneous stone extraction and 29 underwent
      percutaneous antegrade endopyelotomy. Using unpaired t testing, BMI was compared
      with the transfusion rates, days of hospitalization, and stone-free outcome. The
      stone group did not demonstrate statistically significant relationships between
      BMI and transfusion rate, length of hospitalization, and stone-free outcome (P =
      0.423, P = 0.105, and P = 0.127, respectively). A stone-free rate of 94.5% was
      achieved. In the endopyelotomy group, 29 patients were analyzed. Follow-up showed
      24 patients (82.8%) had successful resolution of the ureteropelvic junction
      obstruction 1 year postoperatively. Two patients required readmission for gross
      hematuria and low hematocrit. One patient required selective angiographic
      embolization of a pseudoaneurysm. CONCLUSIONS: Tubeless percutaneous renal
      surgery is a safe and effective procedure in overweight, obese, and morbidly
      obese patients.

PMID- 15183944
TI  - Systematic evaluation of stone basket dimensions.
AB  - OBJECTIVES: To evaluate 17 commercial stone baskets for characteristics we
      believe are favorable for stone extraction. METHODS: The ACMI (Sur-Catch 3.0),
      Bard (Dimension 3.0), Boston Scientific (Zero-tip 2.4/3.0, Segura 2.4/3.0, Gemini
      3.0, Parachute 3.1), Cook (N-Circle 2.2/3.0/3.2, N-Force 3.2, Flatwire 2.0), and
      Sacred Heart (Halo 1.9, Vantage 2.4, Summit 3.0, Hercules 3.0) were tested in
      triplicate. The maximal basket width was measured with a digital caliper as the
      basket length was opened in 0.5 to 2-mm increments using a mechanical caliper
      under optical light microscope visualization. Baskets were rated for the
      linearity of opening and length at which the target basket width (5 mm) was
      reached. RESULTS: The only basket to exhibit linear opening was the N-Circle. All
      other baskets opened in an exponential fashion, with the initial excursion in
      length corresponding to little change in basket width, followed by a rapid
      increase in basket width as the basket extended further. The N-Circle 2.2F, 3.0F,
      and 3.2F baskets reached the target basket width at a basket length of 9.4, 9.7,
      and 9.6 mm, respectively. As a group, the tipless baskets opened more rapidly to
      the target basket width (9.4 to 14.8 mm) than did the flat-wire baskets (17.5 to
      22.7 mm) or helical baskets (18.6 to 24.8 mm). CONCLUSIONS: A basket that
      requires a shorter basket excursion to reach a 5-mm width will be easier to
      maintain in the field of view. Linear basket opening provides the operator with
      greater control to engage a stone. After closure of a basket on a 5-mm stone, the
      larger the basket length dimension, the greater the likelihood the calculus may
      escape.

PMID- 15183945
TI  - Prevalence of vesicoureteral reflux in patients with incidentally diagnosed adult
      hypertension.
AB  - OBJECTIVES: To evaluate the prevalence of vesicoureteral reflux (VUR) in
      hypertensive patients without any other evidence of renal involvement. Reflux
      nephropathy may be clinically latent and present in early adulthood as
      hypertension when superimposed confounding factors are added. METHODS: The
      medical records of 157 adult hypertensive patients with normal renal parameters
      and low-probability, captopril-enhanced renal dynamic scan findings who underwent
      direct radionuclide voiding cystoscintigraphy between June 1998 and May 2003 were
      retrospectively analyzed. RESULTS: VUR was documented in 30 patients (19.1%). In
      those 30 patients, VUR was mild in 8 (26.6%), moderate in 6 (20%), and severe in
      16 (53.3%) patients. Bilateral VUR was seen in 7 patients, graded as severe in
      all cases. The prevalence by age was 20% in the 18 to 30-year-old group, 16.6% in
      the 31 to 45-year-old group, and 20% in the older than 45-year-old group.
      CONCLUSIONS: The results of this study have shown that VUR is present in a
      significantly large proportion of adult patients with hypertension without any
      apparent renal parenchymal or renovascular involvement.

PMID- 15183948
TI  - Application of TNM, 2002 version, in localized renal cell carcinoma: is it able
      to predict different cancer-specific survival probability?
AB  - OBJECTIVES: To verify whether the latest version of the TNM staging system (2002)
      could predict different cancer-specific survival in patients with localized renal
      cell carcinoma (RCC; Stage T1-T2N0M0). METHODS: According to the 2002 TNM staging
      system, we reassigned the pathologic stage of 702 patients who had undergone
      surgical treatment for RCC from 1976 to 2000. We selected 491 patients with
      localized RCC (pT1-T2N0M0). In 334 patients (68.0%), we had performed radical
      nephrectomy; in 121 (24.6%), elective nephron-sparing surgery; and in 36 (7.3%),
      imperative nephron-sparing surgery. Cancer-specific survival was estimated
      according to the Kaplan-Meier method. The log-rank test and Cox's proportional
      hazard model was used for univariate and multivariate analysis, respectively.
      RESULTS: Of the 491 tumors, 249 (50.7%) were classified as pT1a, 155 (31.6%) as
      pT1b, and 87 (17.7%) as pT2. The median follow-up was 75 months. The 5-year and
      10-year cancer-specific survival probabilities were, respectively, 97.4% and
      95.6% in the pT1a patients, 92.5% and 89.8% in the pT1b patients, and 89.3% and
      78.5% in the pT2 patients. The survival curve comparison was statistically
      significant both between pT1a and pT1b (log-rank test, P = 0.01) and between pT1a
      and pT2 (log-rank test, P = 0.0007). No statistically significant difference was
      observed between the pT1b and pT2-specific survival probabilities (log-rank test,
      P = 0.42). CONCLUSIONS: The 2002 TNM staging system does not seem able to predict
      different cancer-specific survival between pT1b and pT2 RCC. These data highlight
      the need to define an optimal breakpoint to stratify patients with localized RCC.

PMID- 15183949
TI  - Prognostic value of uPA, PAI-1, and DNA content in adult renal cell carcinoma.
AB  - OBJECTIVES: To examine whether urokinase-type plasminogen activator (uPA) and
      type 1 plasminogen inhibitor (PAI-1), DNA ploidy, and S-phase fraction (SPF) add
      supplementary prognostic information relative to stage and Fuhrman's grade in
      renal cell carcinoma. METHODS: A total of 100 patients with primary renal
      adenocarcinoma treated by nephrectomy were followed up for a median of 42 months.
      Of the 100 patients, 78 with Stage M0N0-Nx tumors were studied by multivariate
      analysis. The study population was dichotomized on the basis of the median
      cytosolic uPA and PAI-1 concentrations (30 pg/mg protein and 12.7 ng/mg protein,
      respectively). DNA content was measured by flow cytometry (FCM) on multiple tumor
      samples from each patient. DNA aneuploidy was observed in 67% of cases. The SPF
      was calculated for aneuploid samples. RESULTS: An FCM classification based on a
      combination of DNA content and SPF was obtained. High-risk patients were those
      with aneuploid tumors and high SPF values (greater than 1.7%) and included 23% of
      patients with M0N0-Nx tumors. Cytosolic uPA and PAI-1 levels were not predictive
      of metastasis. The stage, grade, SPF, and FCM classification were statistically
      significant prognostic factors in the univariate analysis, in both the overall
      population and the M0N0-Nx subgroup. In multivariate analysis, tumor grade and
      the FCM classification were the only independent predictors of disease-free
      survival (P = 0.018 and P = 0.046, respectively). CONCLUSIONS: We defined a group
      of M0N0-Nx patients with aneuploid tumors and high SPF values who are at a high
      risk of metastasis and who may benefit from closer long-term follow-up.

PMID- 15183950
TI  - Phase II trial of combination interferon-alpha and thalidomide as first-line
      therapy in metastatic renal cell carcinoma.
AB  - OBJECTIVES: To present the results of a Phase II trial of thalidomide and
      interferon-alpha in renal cell carcinoma. METHODS: Patients with metastatic clear
      cell renal cell carcinoma and no prior systemic therapy were accrued. Interferon
      alpha was administered at 5 million units subcutaneously three times per week.
      Thalidomide was started at 100 mg/day for 2 weeks and then escalated 200 mg every
      2 weeks to 1000 mg or until grade 3-4 toxicity developed. Patients were assessed
      radiographically at baseline and after 12 weeks. Steady-state thalidomide plasma
      concentrations were determined. RESULTS: Thirty patients were enrolled. The
      median age was 62 years. Seventeen patients (57%) had undergone nephrectomy
      before therapy. One patient died during therapy. Of the 30 patients, 29 had at
      least grade 2 toxicity and 17 patients had at least grade 3. At 12 weeks, no
      patient had a complete response, 2 had a partial response (6.7%), 8 had stable
      disease (26.7%), and 11 (including 1 patient with an initial partial response)
      had disease progression (36.7%). Nine patients were removed from the study before
      12 weeks. The median follow-up was 49.6 weeks (range 2.4 to 123.7). The median
      time of participation in the study was 11.1 weeks (range 1.4 to 63.9). At last
      follow-up, 2 patients were receiving the study therapy, 1 with stable disease at
      64 weeks and 1 with a partial response at 53 weeks. The median survival was 68
      weeks. A linear relationship was found between the thalidomide plasma
      concentration and dose. No relationship was apparent between the concentration
      and either treatment-related toxicity or response. CONCLUSIONS: Interferon-alpha
      and thalidomide as front-line therapy for metastatic renal cell carcinoma showed
      limited activity. The objective response rate was 7%. One third of patients
      experienced toxicity that required discontinuation of thalidomide. Randomized
      controlled studies are needed to determine any objective benefit of this regimen
      over either drug alone.

PMID- 15183951
TI  - High rate of vaginal extrusion of silicone-coated polyester sling.
AB  - OBJECTIVES: To report the results of a pilot study evaluating the suitability of
      silicone-coated polyester as a suburethral sling material for female stress
      incontinence surgery. METHODS: Ten women with stress or mixed urinary
      incontinence were prospectively evaluated with history and physical examination,
      pad test, urodynamic studies, and the Incontinence-Quality of Life questionnaire.
      The 2 x 7-cm sling was secured with transvaginal bone anchors placed through an
      anterior vaginal wall incision. Patients were evaluated at 1, 6, and 12 months by
      history and physical examination, pad test, and the Incontinence-Quality of Life
      and Success Rate and Overall Patient Satisfaction questionnaires. RESULTS: Ten
      patients (mean age 62.3 years) underwent successful placement of the suburethral
      sling. The Incontinence-Quality of Life scores improved from a mean total score
      of 43.3 +/- 14.6 preoperatively to 97.7 +/- 14.4 at 1 year postoperatively (P
      <0.001). The Success Rate and Overall Patient Satisfaction questionnaires
      completed at 1 year demonstrated a mean satisfaction rating of 8.9 +/- 1.7 (scale
      1 to 10), and the mean reported improvement in incontinence was 90% +/- 16.3%.
      The mean pad weight decreased from 103.1 +/- 33.2 g preoperatively to 1.6 +/-
      1.01 g at 1 year (P <0.007). Two patients (20%) developed vaginal extrusion of
      the suburethral sling at 6 and 10 months. The slings were removed surgically.
      Both women healed without incident and reported continued continence at 1 year
      without additional surgical intervention. CONCLUSIONS: Placement of a suburethral
      sling using transvaginal bone anchors and silicone-coated polyester is an
      effective surgical treatment for stress urinary incontinence at 1 year. The high
      rate of vaginal extrusion in our series limits its utility.

PMID- 15183952
TI  - Use of botulinum-A toxin for the treatment of refractory overactive bladder
      symptoms: an initial experience.
AB  - OBJECTIVES: To define the role of botulinum toxin type A (botulinum-A)
      intradetrusor injections in the treatment of patients with symptoms of bladder
      overactivity in whom previous anticholinergic therapy has failed. METHODS: Thirty
      five patients (29 women and 6 men) with frequency, urgency, and/or urge
      incontinence received 300 U of botulinum-A toxin injected transurethrally at 30
      sites within the bladder. Patients were evaluated at 3 weeks and 6 months after
      treatment by completion of the short forms of the Incontinence Impact
      Questionnaire (IIQ-7) and the Urogenital Distress Inventory (UDI-6), as well as
      questions assessing global response to the treatment. RESULTS: After 3 weeks, the
      mean IIQ-7 score decreased from 19.4 to 13.9 (P = 0.0006) and the mean UDI-6
      score decreased from 16.8 to 12.8 (P = 0.0003). Overall, 21 (60%) of 35 patients
      reported slight to complete improvement of voiding symptoms after 3 weeks. Among
      the initial responders followed up for 6 months, the mean IIQ-7 score improved
      from 20.6 to 15.1 (P = 0.008) and the mean UDI-6 score improved from 16.9 to 13.5
      (P = 0.008). Mild hematuria, pelvic pain, and dysuria were seen in 7 patients,
      lasting for 3 days or less after the procedure. CONCLUSIONS: Botulinum-A toxin
      injections may provide improvement in symptoms associated with bladder
      overactivity in a subset of patients. Improvement may be seen for at least 6
      months after treatment. The procedure was well tolerated with minimal side
      effects. Additional study to define the role of injections in a broad group of
      patients with irritative voiding symptoms is warranted.

PMID- 15183953
TI  - International consultation on incontinence questionnaire short form: comparison
      of physician versus patient completion and immediate and delayed self
      administration.
AB  - OBJECTIVES: To compare the results of International Consultation on Incontinence
      Questionnaire Short Form (ICIQ-SF) with physician completion versus patient self
      administration. The ICIQ-SF is a new self-administered questionnaire that
      qualifies the symptoms and quality of life in both male and female adult patients
      with symptoms of urine loss. METHODS: Sixty-four women consulting for urinary
      incontinence completed the ICIQ-SF three times: twice during the same visit, by
      self-administration and physician interview, and once at home, approximately 1
      week later. RESULTS: All 64 patients completed the questionnaire the first two
      times, but only 59 of them sent back the questionnaire after 1 week. The mean
      patient age was 59 +/- 3.8 years. The distribution of the differences was similar
      among the three kinds of administration. The mean total symptom score for the
      self-administered, physician completed, and self-administered 1 week later ICIQ
      SF was 11.31 +/- 4.6, 11.98 +/- 4.4, and 11.4 +/- 4.7, respectively. The
      corresponding quality-of-life assessments were 5.2 +/- 2.9, 5.5 +/- 3, and 5.18
      +/- 2.9. No statistically significant differences were observed. CONCLUSIONS: The
      results of this study demonstrated that the information obtained by self
      administration of the ICIQ-SF at the office or at home or when completed by the
      physician during an interview is not different. These findings, showing the
      intraobserver and interobserver reliability of this new questionnaire, are
      extremely important for clinical use and research.

PMID- 15183954
TI  - Prognostic impact of p63 and p53 expression in upper urinary tract transitional
      cell carcinoma.
AB  - OBJECTIVES: To analyze p63 and p53 immunoreactivity of upper urinary tract
      transitional cell carcinoma with respect to prognosis. p63 is required for the
      differentiation of normal urothelium and is expressed in both non-neoplastic
      urothelium and transitional cell carcinoma of the bladder. METHODS: A total of 53
      upper urinary tract transitional cell carcinoma specimens were investigated
      immunohistochemically using a tissue microarray technique. p63 and p53
      immunoreactivity was analyzed digitally with respect to associations with pT
      stage and grade and impact on disease-free survival. RESULTS: p63 expression was
      detected in 51 (96.2%) of 53 cases. Normal expression (greater than 90% of tumor
      cell nuclei) was observed in 1 (4.5%) of 22 Stage pT3 compared with 13 (41.9%) of
      31 Stage pT1-T2 tumors (P = 0.003) and 4 (16%) of 25 G3 compared with 10 (35.7%)
      of 28 G2 tumors (P = 0.13). p53 overexpression (more than 10% of tumor cell
      nuclei) was found in 10 (18.9%) of 53 cases, including 2 (6.5%) of 31 Stage pT1
      T2 and 8 (36.4%) of 22 Stage pT3 (P = 0.011) and 0 of 28 G2 and 10 (40%) of 25 G3
      tumors (P <0.001). Metastatic disease was observed in 14 (26.4%) of 53 patients,
      including none of 14 with normal p63 expression compared with 14 (35.9%) of 39
      with decreased (less than 90% of tumor cell nuclei) p63 expression (P = 0.02) and
      5 (50%) of 10 patients with p53 overexpression compared with 9 (20.9%) of 43
      patients with p53-negative tumors (P = 0.01). Multivariate analysis proved Stage
      pT3 was the only independent prognostic factor. CONCLUSIONS: Decreased p63
      immunoreactivity and p53 overexpression were significantly associated with
      advanced tumor stages and poor prognosis. However, neither parameter was an
      independent prognostic factor in multivariate analysis.

PMID- 15183955
TI  - Long-term effects of bacille Calmette-Guerin perfusion therapy for treatment of
      transitional cell carcinoma in situ of upper urinary tract.
AB  - OBJECTIVES: To report our experience with bacille Calmette-Guerin (BCG) perfusion
      therapy for transitional cell carcinoma in situ of the upper urinary tract. BCG
      perfusion therapy is widely used to treat transitional cell carcinoma in situ of
      the upper urinary tract. However, it has not yet been established as a standard
      treatment. METHODS: Ten patients diagnosed with transitional cell carcinoma in
      situ of the upper urinary tract were treated with BCG perfusion therapy from
      January 1990 to May 2002. BCG was instilled weekly for 6 weeks, with a median
      dose of 65 mg at 1.17 mg/mL (Tokyo 172 strain, dissolved in normal saline).
      RESULTS: The mean follow-up period was 50.9 months (range 12 to 134). The initial
      response to therapy was excellent, and cytology became negative in all patients
      after one course of BCG perfusion. Five patients developed recurrence after 5,
      11, 24, 26, and 45 months, and all died after 46, 12, 41, 134, and 79 months,
      respectively. The mortality rate was 50% and was 100% in those with recurrence.
      The mean recurrence-free period was 22.2 months (range 5 to 45). Complications
      included bladder irritation-related symptoms in all patients, fever greater than
      38 degrees C (n = 9), hematuria (n = 2), hydronephrosis (n = 2), and lumbago (n =
      1) but all were transient and did not affect long-term prognosis. CONCLUSIONS:
      BCG perfusion therapy for carcinoma in situ of the upper urinary tract is safe,
      and the short-term response is excellent. However, the long-term results were not
      satisfactory. Therefore, this therapy should be considered experimental, although
      it may have potential benefits in delaying progression and possibly providing
      local control for patients in poor condition. Long-term studies are required for
      additional evaluation of BCG therapy.

PMID- 15183956
TI  - Expression of cathepsins B, H, and L and their inhibitors as markers of
      transitional cell carcinoma of the bladder.
AB  - OBJECTIVES: It has been shown that the expression of the lysosomal proteolytic
      enzymes cathepsin B, H, and L (CB, CH, and CL, respectively) correlate with tumor
      progression in various neoplasms. However, no data are available in cell lysates
      and supernatants of differently differentiated human bladder cell lines or in
      noncancerous and cancerous bladder tissue. METHODS: Using spectrofluorometric
      assays, catalytic activities of CB, CH, CL, and their inhibitor (CIP) were
      measured both in differently differentiated human bladder cell lines (HCV29,
      normal; RT4, well differentiated; J82, poorly differentiated) and in noncancerous
      and cancerous tissue samples (n = 20) of transitional cell carcinoma obtained
      from transurethral resections of the bladder or cystectomies. Enzyme activities
      were related to the protein content in tissue samples or to the cell count in
      cell lines. RESULTS: In comparison to the intracellular activities of CB, CH, and
      CL in the poorly differentiated cell line J82, the intracellular activities in
      the normal cell line HCV29 were significantly greater (P <0.05), independent of
      stage or grade. In contrast, the portion of cathepsins released from cell line
      J82 into the supernatant revealed higher values than that from cell line HCV29.
      In cancerous bladder tissue, CB and CH were significantly greater than in the
      matched normal tissue (P <0.05). CL and CIP did not show any statistically
      significant differences. CONCLUSIONS: Increased cathepsin concentrations in the
      supernatant of the poorly differentiated J82 carcinoma cell culture, as well as
      in cancerous bladder tissue, are indicative of a proteolytic imbalance and
      potential indicators of bladder cancer.

PMID- 15183957
TI  - Gender differences in radical cystectomy: complications and blood loss.
AB  - OBJECTIVES: To review the impact of gender on blood loss, transfusions, and
      complications. Radical cystectomy is technically different between men and women.
      Unique to women, dissection of the anterior vaginal wall can be associated with
      added blood loss. METHODS: We analyzed the records of 262 consecutive patients
      who underwent radical cystectomy for urothelial carcinoma from March 1993 to
      March 2003. The perioperative variables, amount of blood loss, transfusion
      requirements, need for intensive care, length of hospitalization, and 30-day
      complications were examined. RESULTS: Women accounted for 24% (n = 63) of this
      series and had a median operative blood loss of 1.4 L compared with 0.5 L in men
      (P = 0.001). The transfusion rate was 82% in women and 55% in men (P = 0.001),
      with the median number of units transfused greater in women (3 U versus 2 U, P =
      0.043). Also, 31% of women needed intensive care compared with 15% of men (P =
      0.004). The median postoperative stay was similar at 9 days for women and 8 days
      for men (P = 0.099). The incidence of complications was not significantly
      different statistically between the gender groups, occurring in 43% of women and
      33% of men (P = 0.161). Major complications occurred in 8% of women and 7.5% of
      men, and the most common minor complication was ileus, reported in 19% of women
      and 14% of men. CONCLUSIONS: Although the overall complications and length of
      hospital stay were similar between the gender groups, radical cystectomy in women
      was associated with greater blood loss, transfusion requirements, and intensive
      care needs.

PMID- 15183958
TI  - Comparison of several combinations of free, complexed, and total PSA in the
      diagnosis of prostate cancer in patients with urologic symptoms.
AB  - OBJECTIVES: To compare the diagnostic efficacy of prostate-specific antigen (PSA)
      and the PSA fractions (free PSA [fPSA] and complexed PSA [cPSA]) in the
      differential diagnosis between prostate cancer and benign prostatic hyperplasia.
      METHODS: We measured the serum levels of total PSA (tPSA; Hybritech and Bayer),
      fPSA (Hybritech), and cPSA (Bayer) in 72 patients with prostate cancer and 128
      patients with benign prostatic hyperplasia. RESULTS: Receiver operating
      characteristic curves were used for comparison of these tests. The greatest area
      under the curve was observed for the fPSA/cPSA ratio and the fPSA/tPSA ratio
      (0.757 and 0.754, respectively). The substitution of the fPSA/tPSA ratio with the
      fPSA/cPSA ratio in the diagnostic scheme of prostate cancer improved the
      diagnostic accuracy, with similar sensitivity and an increment in specificity
      (41% versus 45%). CONCLUSIONS: The fPSA/cPSA ratio ensures a reduction in
      negative biopsies in the PSA gray zone. We suggest substituting the fPSA/tPSA
      ratio with the fPSA/cPSA ratio for patients with a PSA level between 4 and 10
      ng/mL.

PMID- 15183961
TI  - Monofocal and plurifocal high-grade prostatic intraepithelial neoplasia on
      extended prostate biopsies: factors predicting cancer detection on extended
      repeat biopsy.
AB  - OBJECTIVES: To evaluate factors predicting cancer detection by extended repeat
      prostate biopsies in patients with an initial, isolated, monofocal or plurifocal,
      high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosis. METHODS: From
      1995 to 2002, after a first set of 10 to 12 systematic biopsy cores, 47 patients
      with an initial HGPIN diagnosis underwent repeat biopsy using the same technique
      (mean repeat biopsy cores 11.5) after a median follow-up of 11.4 months (range 3
      to 24). RESULTS: Cancer was detected at the second biopsy in 21 patients (44.6%).
      Cancer detection was significantly greater in patients with plurifocal HGPIN than
      in those with monofocal HGPIN (70% vs. 10%, respectively; P <0.005) and in
      patients who underwent repeat biopsy more than 6 months after the first biopsy
      set (65%) compared with patients who underwent repeat biopsy within 6 months
      (25%; P <0.01; mean follow-up 15.5 and 3.8 months, respectively). Multivariate
      analysis showed that prostate-specific antigen, prostate-specific antigen
      density, digital rectal examination, and transrectal ultrasound findings were not
      statistically significant predictors of prostate cancer, and HGPIN multifocality
      and interval between biopsies (more than a 6-month follow-up interval) were
      independent prognostic factors (odds ratio 4.65 and 2.65, respectively). After
      radical prostatectomy (14 patients), no statistically significant differences
      were found in the pathologic stage between patient groups stratified by repeat
      biopsy interval (within or after 6 months). CONCLUSIONS: After a 10 to 12-core
      biopsy, patients with initial, isolated monofocal or plurifocal HGPIN diagnoses
      had an overall cancer detection rate of 45% on repeat extended biopsies.
      Plurifocal HGPIN on the first biopsy set was the strongest independent predictive
      factor in cancer detection. A 12 to 18-month interval before repeat biopsy could
      permit a significantly greater cancer detection rate, with no apparent likelihood
      of clinical cancer progression.

PMID- 15183962
TI  - Accuracy and completeness in reporting family history of prostate cancer by
      unaffected men.
AB  - OBJECTIVES: To determine the accuracy of prostate cancer reports and completeness
      of the family history provided by unaffected men with a family history of
      prostate cancer. A positive family history is associated with increased prostate
      cancer risk and could influence surveillance recommendations and patient
      selection for genetic testing in the future. However, the accuracy of prostate
      cancer reports and completeness of the family history provided by unaffected men
      is poorly understood. METHODS: Eligible respondents were ascertained through
      participation in a population-based study of prostate cancer. The family history
      was collected by questionnaire and compared with the verified research pedigree.
      Information about the family history was also independently collected from
      spouses. A standard statistical method was used to determine the variables
      associated with accuracy and failure to report cases. RESULTS: A total of 154
      unaffected men (51%) responded. Most (82%) reports of prostate cancer cases were
      verified. Overall, 63% reported a family history that precisely matched the
      verified family history. The respondents' wives contributed little additional
      information. Age and degree of relationship to an affected person were associated
      with both accuracy and completeness of the family history. Verification altered
      the empirical risk category of 29% of the respondents; however, most (93%)
      remained at increased risk. CONCLUSIONS: Unaffected men with a family history of
      prostate cancer generally provide a reliable family history. We conclude that
      surveillance advice can be reasonably based on a man's reported family history.
      However, the identification of certain high-risk individuals, which may be
      relevant for selection for genetic testing in the future, requires more extensive
      ascertainment of the family history.

PMID- 15183963
TI  - Prognostic significance of obstructive uropathy in advanced prostate cancer.
AB  - OBJECTIVES: To report the incidence and prognostic implications of obstructive
      uropathy (OU) in patients with advanced prostate cancer receiving androgen
      deprivation therapy and to define the impact initial local therapy has on the
      development of OU in patients with prostate cancer who develop recurrence and
      begin androgen deprivation therapy. METHODS: From a population of 260 patients
      with advanced prostate cancer diagnosed between 1986 and 2003, OU was identified
      in 51 patients. The OU treatment options included ureteral stent, percutaneous
      nephrostomy, transurethral resection of the prostate, Foley catheter placement,
      and urinary diversion. Overall survival and the factors that influenced survival
      were calculated using standard statistical methods. RESULTS: OU was diagnosed in
      15 (16%) of 80 patients who received local therapy with curative intent and in
      whom local therapy subsequently failed and in 36 (19%) of 180 patients who had
      never received local therapy (P = 0.7, chi-square test). Of these 51 patients, 39
      had bladder neck obstruction and 16 had ureteral obstruction. Overall survival
      was significantly worse for the men with OU compared with those without OU (41
      versus 54 months). OU was associated with tumor stage and androgen-insensitive
      prostate cancer. CONCLUSIONS: OU results in significantly reduced survival in men
      with prostate cancer. In a select group of patients with prostate cancer with
      progression after local therapy (primarily radiotherapy), no statistically
      significant reduction in the development of OU was observed relative to patients
      matched for stage, grade, and pretreatment prostate-specific antigen level
      treated with androgen deprivation therapy alone. Aggressive advanced stage and
      hormone-insensitive disease are variables associated with OU.

PMID- 15183964
TI  - Impact of unilateral interposition sural nerve grafting on recovery of urinary
      function after radical prostatectomy.
AB  - OBJECTIVES: To test the hypothesis that unilateral sural nerve graft (SNG)
      interposition may improve the rate of urinary function (UF) recovery after
      radical retropubic prostatectomy (RRP) in patients undergoing unilateral nerve
      resection (UNR). METHODS: We studied 111 consecutive patients who underwent RRP
      with purposeful UNR performed by a single surgeon. Of the 111 patients, 53
      underwent unilateral SNG interposition. All patients were invited to complete a
      questionnaire that included the validated University of California, Los Angeles,
      Prostate Cancer Index. The time to UF recovery above the median value of the
      group and urinary control status were evaluated. RESULTS: The median follow-up
      was 26 and 12 months for the UNR and UNR+SNG patients, respectively. At 12 months
      after RRP, 94.7% of patients with UNR+SNG reported having complete urinary
      control or leakage of only a few drops of urine compared with 58.3% of patients
      with UNR alone (P = 0.012). In multivariate Cox regression models, UNR+SNG was
      associated with a 9.95 times greater rate of reaching a UF score above the median
      versus UNR alone (P <0.001). In multivariate logistic regression analyses, SNG
      status increased the odds of having complete urinary control or leakage of only a
      few drops of urine by 14.99 and 29.19 at 6 and 12 months after RRP, respectively
      (both P <0.05). CONCLUSIONS: In patients undergoing UNR surgery, SNG
      interposition is associated with a greater rate of UF recovery and a higher
      likelihood of urinary control after RRP. These findings need to be validated in
      larger, multicenter, prospective, randomized studies.

PMID- 15183965
TI  - Cancer control after low-dose-rate prostate brachytherapy performed by a
      multidisciplinary team with no previous prostate brachytherapy experience.
AB  - OBJECTIVES: To describe the biochemical disease-free survival observed in the
      first cohort men treated by a multidisciplinary team of clinicians with no
      previous experience in low-dose-rate prostate brachytherapy (LDRPB). METHODS: The
      information in this report concerns the first 63 men treated with LDRPB alone at
      our institution between September 1997 and September 1998. All men had
      histologically confirmed, clinically localized prostate cancer. All men were
      treated with iodine 125 according to published methods. The prescription dose was
      144 Gy according to the Task Group 43 formalism. LDRPB was performed jointly by a
      radiation oncologist and urologist. Three definitions of biochemical recurrence
      were used: the American Society for Therapeutic Radiology and Oncology consensus
      definition; prostate-specific antigen level greater than 0.4 ng/mL at last follow
      up; and prostate-specific antigen level greater than 0.2 ng/mL at last follow-up.
      Biochemical relapse-free survival was estimated using the product-limit method.
      Putative covariates for biochemical relapse-free survival were examined using the
      proportional hazards regression model. All P values are two-sided. RESULTS: The
      median follow-up for the entire cohort was 62 months. Of the 63 men, 45 (71%) had
      more than 60 months of follow-up. The median pretreatment prostate-specific
      antigen level was 6.68 ng/mL (range 1.1 to 23), and most men (44 of 63; 70%) had
      nonpalpable disease. The institutionally assigned Gleason score was less than 7
      in 54 men (86%). Nine men developed evidence of biochemical relapse at a median
      of 19 months (range 6 to 38). The 5-year estimate of biochemical relapse-free
      survival was 85% (95% confidence interval 80% to 90%), 80% (95% confidence
      interval 74% to 86%), and 70% (95% confidence interval 64% to 76%) according to
      the three definitions given above. CONCLUSIONS: The biochemical results achieved
      in the first cohort of men treated with LDRPB by a previously inexperienced
      multidisciplinary team of clinicians are similar to the results reported from
      centers with extensive LDRPB experience.

PMID- 15183966
TI  - Rise in serum PSA of 1.5 ng/mL above 24-month nadir after external beam
      radiotherapy is predictive of biochemical failure.
AB  - OBJECTIVES: To determine whether a rise in the serum prostate-specific antigen
      (PSA) concentration 24 months or later after completion of external beam
      radiotherapy (EBRT) for prostate cancer could predict for biochemical failure.
      METHODS: We evaluated the records of 1006 patients who had undergone full-dose
      EBRT alone as primary treatment for T1-T4NxM0 prostate cancer at our institution
      between April 1987 and January 1998. Patients who had biochemical failure--as
      determined by the American Society for Therapeutic Radiology and Oncology (ASTRO)
      definition--prior to 24 months after EBRT were excluded. PSA increases of four
      different magnitudes (0.5, 0.8, 1.0, and 1.5 ng/mL above the 24-month nadir) were
      evaluated for their ability to predict ASTRO-defined biochemical failure.
      RESULTS: A total of 745 patients met the analysis criteria. The rate of ASTRO
      defined biochemical failure in patients with a PSA increase of 0.5, 0.8, 1.0, and
      1.5 ng/mL above the 24-month nadir was 56%, 64%, 66%, and 71%, respectively. An
      increase of 1.5 ng/mL or more had a sensitivity of 80% and a specificity of 88%
      in the prediction of biochemical failure, with an accuracy of 86%. CONCLUSIONS: A
      PSA increase of 1.5 ng/mL or more above the 24-month nadir can be used to predict
      for ASTRO-defined failure after EBRT and may be used to identify patients at risk
      early-on.

PMID- 15183967
TI  - Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally
      advanced prostate cancer.
AB  - OBJECTIVES: To perform a Phase II trial of docetaxel administered on a weekly
      schedule for 6 weeks before radical prostatectomy (RP) in patients with locally
      advanced prostate cancer. METHODS: Treatment consisted of six doses of docetaxel
      40 mg/m(2) intravenously administered weekly for 6 weeks followed by RP.
      Eligibility criteria included clinical Stage T2b, prostate-specific antigen (PSA)
      level 15 ng/mL or greater or Gleason sum 8 or greater, and no evidence of
      metastatic disease. The primary endpoint was feasibility and drug-related and
      surgical-related toxicities. Secondary endpoints included pre-RP PSA level, local
      response, pathologic outcomes, and time to PSA failure. RESULTS: Twenty-nine
      patients were entered; 80% completed all 6 weeks of therapy and 97% underwent RP.
      The median PSA level was 12 ng/mL (range 2.5 to 43.3), the median Gleason sum was
      8 (range 6 to 9), and all had Stage T2b or greater disease. A statistically
      significant reduction in the prechemotherapy versus postchemotherapy mean PSA
      level was observed (12.00 +/- 1.86 ng/mL versus 8.42 +/- 1.63 ng/mL, P <0.03),
      with 79% of patients experiencing some reduction and 24% a more than 50%
      reduction in PSA level in response to docetaxel alone. No unexpected toxicities
      and no intraoperative complications occurred. Pathologic analysis demonstrated
      residual carcinoma in all cases. Three patients (11%) had organ-confined disease,
      and 26 (93%) had achieved an undetectable PSA postoperatively. At a median follow
      up of 23 months (range 1.5 to 36), 20 patients were disease free with no
      additional therapy. CONCLUSIONS: This trial establishes the baseline effect of
      short-course high-dose docetaxel alone on locally advanced prostate cancer.
      Additional study of this paradigm with other agents alone and in combination with
      docetaxel seems warranted.

PMID- 15183968
TI  - Does the gonadotropin-releasing hormone stimulation test predict clinical
      outcomes after microsurgical varicocelectomy?
AB  - OBJECTIVES: To examine the predictive value of the gonadotropin-releasing hormone
      (GnRH) stimulation test in a large cohort of infertile men undergoing
      varicocelectomy. METHODS: We examined the records of 144 consecutive infertile
      couples in whom the man underwent microsurgical varicocelectomy between September
      1998 and December 2002. All men underwent a GnRH stimulation test before surgery.
      Data on the preoperative and postoperative semen parameters, pregnancy outcome,
      and follicle-stimulating hormone (FSH) and luteinizing hormone increase after
      GnRH stimulation were recorded. RESULTS: The mean (+/-SE) sperm concentration and
      motility 6 months after varicocelectomy were significantly greater than the
      preoperative values (25.3 +/- 2.4 versus 19.7 +/- 2.1 x 10(6)/mL and 29.2% +/-
      1.4% versus 25.3% +/- 1.3%, respectively, P <0.05). Overall, 28% of the couples
      achieved a spontaneous pregnancy at a mean of 22 months of follow-up. The median
      elevation in the FSH and luteinizing hormone value 60 minutes after GnRH
      administration was 1.8 and 5.6 times the baseline level, respectively. No
      statistically significant relationship was found between the FSH or LH response
      to GnRH stimulation and improvement in the semen parameters or positive pregnancy
      outcome in our population. CONCLUSIONS: Our data showed that the FSH response to
      bolus GnRH stimulation does not predict improvement in semen parameters or
      unassisted pregnancy outcome in couples in whom the man undergoes varicocelectomy
      (for treatment of varicocele). The study was the largest of its type and
      sufficiently powered to validate these findings. The results indicate that the
      bolus GnRH stimulation test is of no clinical value in the treatment of infertile
      men with varicoceles.

PMID- 15183969
TI  - Obstructive lower urinary tract symptoms correlate with erectile dysfunction.
AB  - OBJECTIVES: To examine whether the severity of lower urinary tract symptoms
      (LUTS), when controlled for other factors, is related to erectile dysfunction
      (ED) in the male veteran population. Early evidence suggests that LUTS may be
      associated with ED in men. METHODS: A total of 181 male veterans were
      prospectively entered into the study. They completed the Sexual Health Inventory
      for Men (SHIM) and International Prostate Symptom Score (IPSS) questionnaires. Of
      the 181 men, 144 also underwent uroflowmetry, including determination of the
      postvoid residual urine volume. Demographic and medical history data were
      recorded. Pearson correlation coefficients and multiple linear regression
      analysis were used to examine the relationship between LUTS and ED, as well as
      the effects of age and comorbidities. RESULTS: The correlation coefficient (r)
      for the SHIM score with the total IPSS was -0.17 (P = 0.023); with the
      obstructive IPSS, it was -0.20 (P = 0.006); and with the irritative IPSS, -0.05
      (P = 0.492). Age was the only other factor with a statistically significant
      correlation with the SHIM score (r = -0.23, P = 0.002). Multiple linear
      regression modeling showed obstructive IPSS (P = 0.001) and depression (P =
      0.017) to be the only statistically significant predictors of the SHIM score. A
      consistent negative correlation was found between obstructive IPSS and the SHIM
      score across age groups, with the strongest effect for men aged 60 to 70 years (r
      = -0.412, P = 0.003). CONCLUSIONS: Obstructive LUTS correlated with, and were
      predictive of, ED, even after controlling for age and comorbidities. Although age
      correlated with ED, it did not add to the power of the multiple linear regression
      model composed of obstructive IPSS and depression.

PMID- 15183970
TI  - Female sexual dysfunction after radical cystectomy: a new outcome measure.
AB  - OBJECTIVES: To assess, in our contemporary radical cystectomy (RC) series, female
      sexual dysfunction and whether the type of diversion affected the occurrence of
      sexual dysfunction. Outcome data after RC with and without orthotopic diversion
      has focused primarily on cure, urethral recurrence, and continence. METHODS: The
      baseline and follow-up data from 27 sexually active female patients (mean age
      54.79 +/- 12.7 years) who underwent RC from 1997 to 2002 for transitional cell
      carcinoma of the bladder (16 with Stage T1-T2 and 11 with Stage T3-T4) were
      obtained. Thirteen patients were premenopausal before RC. Of the 27 patients, 10
      (37%) underwent Studor orthotopic diversion, 7 (26%) Indiana cutaneous diversion,
      and 10 (37%) ileal conduit diversion. A 10-item version of the self-administered
      Index of Female Sexual Function questionnaire was used to assess sexual
      dysfunction. The specific domains analyzed in the Index of Female Sexual Function
      include the degree of vaginal lubrication, ability to achieve orgasm, degree of
      pain during intercourse, overall sexual desire and interest, and overall sexual
      satisfaction, with responses graded on a scale of 1 (almost never, never) to 5
      (almost always, always). RESULTS: With a mean follow-up of 24.2 months (range 15
      to 65.1), the total mean baseline Index of Female Sexual Function score decreased
      from 17.4 +/- 7.23 to 10.6 +/- 6.62 after RC (P < or =0.05). The most common
      symptoms reported by the patients included diminished ability or inability to
      achieve orgasm in 12 (45%), decreased lubrication in 11 (41%), decreased sexual
      desire in 10 (37%), and dyspareunia in 6 patients (22%). Only 13 (48%) of the 27
      patients were able to have successful vaginal intercourse, with 14 (52%)
      reporting decreased satisfaction in overall sexual life after RC. Eight partners
      (30%) had a decrease in desire for sexual activity owing to apprehension after
      cancer diagnosis and treatment. Although the numbers were small, the preliminary
      data suggested no differences in sexual function between patients undergoing
      Studor orthotopic diversions and those undergoing Indiana cutaneous diversions.
      CONCLUSIONS: Sexual dysfunction is a prevalent problem after female RC. The
      nature of the dysfunction involves multiple domains, including decreased orgasm,
      decreased lubrication, lack of sexual desire, and dyspareunia. Our early results
      suggest that the type of continent diversion does not affect sexual function.
      Surgical modifications such as urethral and vaginal sparing, neurovascular
      preservation, and tubular vaginal reconstruction sparing may improve female
      sexual function after RC.

PMID- 15183971
TI  - Magnetic resonance imaging combined with artificial erection for local staging of
      penile cancer.
AB  - OBJECTIVES: To assess magnetic resonance imaging (MRI) combined with artificial
      erection for local staging of penile cancer. METHODS: We compared local clinical,
      MRI plus artificial erection, and pathologic staging in 9 cases of penile cancer.
      Erection was obtained by injecting 10 microg prostaglandin E1 into the corpora
      cavernosa. T1-weighted and T2-weighted MRI with and without contrast was obtained
      using a phased array coil. Local treatment was based on tumor location and
      extent, as defined by the clinical and MRI findings. RESULTS: The histologic
      diagnosis was squamous cell carcinoma in 8 patients and sarcoma in 1. The MRI and
      pathologic staging coincided in 8 of 9 patients. MRI, clinical, and pathologic
      staging coincided in 5 patients: 4 had Stage T2 and 1 had Stage T1 disease. In 2
      patients, the MRI and pathologic stage was T2, but the clinical stage differed.
      Another patient had Stage T2 clinically but T3 by MRI and pathologic staging. In
      the last patient, none of the stages coincided (clinical Stage T1, MRI Stage T0,
      and pathologic Stage Tis). The only complication during the procedure was that 1
      patient developed priapism after prostaglandin injection, which was relieved by
      evacuation of the corpora cavernosa. CONCLUSIONS: To our knowledge, this is the
      first study to use artificial erection with MRI to stage local penile cancer. The
      method appears promising for local staging of penile cancer, but additional
      studies are necessary to confirm its utility.

PMID- 15183972
TI  - Management of nonpalpable testicular tumors.
AB  - OBJECTIVES: To report our series of nonpalpable testicular tumors with a review
      of published studies. Radical orchiectomy remains the reference standard in the
      treatment of a solid testicular mass. Testis-sparing surgery has recently been
      advocated for a select group of patients with nonpalpable tumors. METHODS:
      Between 1998 and 2002, a nonpalpable testicular mass was discovered in 9
      patients. Ultrasonography was performed for infertility evaluation (5 patients),
      testicular pain (3 patients), and retroperitoneal lymphadenopathy (1 patient).
      RESULTS: Radical orchiectomy was performed in 7 of 9 patients and testis-sparing
      surgery with microsurgical excision of tumor in 1 patient. One patient decided
      against surgery. A benign testicular tumor was found in 6 and a malignant tumor
      in 2 of the 8 patients. CONCLUSIONS: A high incidence of benign nonpalpable tumor
      and an advanced microsurgical technique justifies organ-sparing surgery as an
      alternative for radical orchiectomy in a select group of patients. Testicular
      preservation in patients with a malignant nonpalpable testicular tumor is a
      feasible, but still controversial, approach.

PMID- 15183974
TI  - Percutaneous urethral catheter retraction of prostate during laparoscopic radical
      prostatectomy.
AB  - Laparoscopic radical prostatectomy is rapidly gaining popularity. Several
      techniques have been described to retract the prostate. We have developed a
      technique using a urethral catheter that is simple to reproduce and provides
      stationary anterior countertraction on the prostate that does not require an
      assistant.

PMID- 15183975
TI  - Novel technique to facilitate urethral stump exposure after radical retropubic
      prostatectomy.
AB  - A 12F Foley catheter is introduced retrogradely through the urethral stump and
      situated with the balloon partially inflated in the bulbous urethra after radical
      retropubic prostatectomy. This maneuver provides clear visualization of the
      urethral stump through gentle traction of the Foley catheter.

PMID- 15183976
TI  - Robotic laparoscopic radical prostatectomy with a single assistant.
AB  - INTRODUCTION: As experience with robot-assisted laparoscopic radical
      prostatectomy (rLRP) grows, the importance of the role of the assistant cannot be
      overstated. Key elements of the operation, dependent on the assistant, have not
      been reported. The focus of this report was to describe the key elements, which
      include positioning of the patient and assistant port sites, appropriate
      equipment, and the assistant-dependent steps of the procedure. TECHNICAL
      CONSIDERATIONS: During the course of the initial 100 cases, we reviewed the
      patient and port site positioning and reviewed the videotapes to identify key
      elements of the assistant's role that facilitate rLRP. We identified three
      important elements pertaining to patient positioning. In contrast to standard
      port site recommendations, we found that dominant and nondominant handedness
      dictate the assistant port site locations. Finally, we identified specific steps
      of the procedure that require the assistant to have laparoscopic skills necessary
      for the console surgeon to dissect the bladder neck, seminal vesicles, rectum,
      and neurovascular bundles. CONCLUSIONS: The assistant in rLRP is critical to the
      success of rLRP, especially in the learning phases. Right or left-handed
      dominance determines on which side the assistant should be positioned. In
      contrast to the console surgeon, the assistant should have intermediate to
      advanced laparoscopic skills.

PMID- 15183977
TI  - Laparoscopic nephrectomy for large renal arteriovenous malformation.

PMID- 15183978
TI  - Gas-forming infection from Clostridium perfringens in a renal cyst of a patient
      with autosomal dominant polycystic kidney disease.

PMID- 15183979
TI  - Extraordinary scrotal lymphedema after weight loss: resection and reconstruction
      of the giant end-stage scrotum.

PMID- 15183980
TI  - Eosinophilic cystitis after bladder instillation with dimethyl sulfoxide.
AB  - Eosinophilic cystitis is a rare and poorly understood disorder. We report the
      first case of an acute flare of eosinophilic cystitis in a 51-year-old woman
      after bladder instillation with dimethyl sulfoxide (DMSO) for presumed
      interstitial cystitis. The patient presented with severe bladder pain, fever, and
      eosinophilia several hours after instillation. These symptoms were unresponsive
      to conventional analgesic and antibiotic treatments. Cystoscopy revealed erythema
      and exudate at the bladder walls, along with edema of both ureteral orifices.
      Bladder biopsies demonstrated massive eosinophilic infiltration of the bladder,
      confirming the diagnosis of eosinophilic cystitis. Urologists should bear in mind
      this clinical entity, particularly when DMSO is administered to patients with
      multiple drug allergies.

PMID- 15183981
TI  - Idiopathic stuttering priapism: recovery of detumescence mechanism with temporal
      use of antiandrogen.
AB  - We report a case of idiopathic stuttering priapism in a 56-year-old Japanese man.
      We treated his recurrent priapism in stepwise fashion by withdrawal of the
      alpha/beta-blocker he used for hypertension, administration of low doses of an
      antiandrogen and baclofen, and finally by increasing the dose of antiandrogen,
      which lowered his testosterone to the castration level and was effective in
      preventing priapism. After 6 months of antiandrogen treatment, his erectile
      function gradually recovered to the baseline level, and he had no recurrence of
      priapism during the following 6 months without any medication.

PMID- 15183982
TI  - Laparoscopic-assisted upper pole ureterocalicostomy using renal inversion and
      autotransplantation.
AB  - Despite various described methods of reconstruction after upper ureteral injury,
      many cases are complex and remain a surgical challenge. Careful preoperative
      evaluation and planning are crucial in the selection of the appropriate
      procedure, particularly in patients in whom preservation of the renal mass is
      imperative. We report a case of severe upper ureteral injury and subsequent
      fibrosis, with no usable renal pelvis and focal upper pole dilation, that was
      managed with renal inversion and upper pole ureterocalicostomy. The option of
      autotransplantation was provided by laparoscopic nephrectomy and ex vivo
      reconstruction, minimizing patient morbidity and maximizing a successful outcome.
      This case illustrates the expansion of laparoscopy from the mere extirpative to a
      role in complex reconstruction. To our knowledge, this reconstructive strategy
      has never been previously reported and may be applicable in a limited number of
      situations.

PMID- 15183983
TI  - Ex vivo partial nephrectomy and autotransplantation for renal cell cancer after
      laparoscopic renal harvest.
AB  - Laparoscopic partial nephrectomy is an alternative to the open approach. For
      centrally located tumors, open extracorporeal partial nephrectomy has been used.
      We report 2 cases of laparoscopic nephrectomy for the purpose of extracorporeal
      partial nephrectomy and autotransplantation for renal cell cancer.

PMID- 15183984
TI  - Small bowel obstruction associated with tension-free vaginal tape.
AB  - A 73-year-old woman with stress urinary incontinence and uterine prolapse
      underwent vaginal hysterectomy followed by tension-free vaginal tape (TVT)
      placement. Postoperatively, she presented with low-grade fever and abdominal
      distension. Abdominal computed tomography revealed bowel distension and abrupt
      cutoff of the distended small bowel and normal bowel caliber. Transperitoneal
      laparotomy demonstrated perforation of the mesentery by the TVT without other
      injury. The tape was cut in its intraperitoneal portion. The patient resumed
      normal bowel function and, at last follow-up, remained continent. We advocate
      that when performing TVT placement in conjunction with vaginal hysterectomy, TVT
      placement should be performed at the beginning of the procedure.

PMID- 15183985
TI  - Ventriculoperitoneal shunt externalization during laparoscopic prostatectomy.
AB  - Ventriculoperitoneal shunt placement is the standard treatment for patients with
      hydrocephalus or increased cerebrospinal fluid pressure. Many patients with
      ventriculoperitoneal shunts require subsequent surgery. Increasingly, this
      surgery is performed laparoscopically. We describe externalizing the
      ventriculoperitoneal shunt outside the abdomen in a patient undergoing
      extraperitoneal laparoscopic radical prostatectomy.

PMID- 15183986
TI  - Removal of metal penile foreign body with a widely available emergency-medical
      services-provided air-driven grinder.
AB  - Penile incarceration with heavy metal objects can be a difficult problem,
      especially if the object cannot be removed by the standard equipment available in
      the hospital (eg, ring cutters, bolt cutters, motorized rotary tool). We report
      removal of heavy iron (barbell) and steel (sledgehammer head) items incarcerating
      the penis with a heavy-duty air grinder provided by the fire department. This is
      the first such report of which we are aware. Features of safe removal of these
      items are reviewed, including cooling the metal item with ice to prevent tissue
      heating, protecting the patient from sparks, and protecting the penis from the
      cutting blade.

PMID- 15183987
TI  - Expression of insulin-like growth factor binding protein-3 before and after
      neoadjuvant hormonal therapy in human prostate cancer tissues: correlation with
      histopathologic effects and biochemical recurrence.
AB  - OBJECTIVES: To determine the effects of neoadjuvant hormonal therapy (NHT) on
      insulin-like growth factor binding protein (IGFBP)-3 expression and whether IGFBP
      3 expression influences the pathologic effect of NHT and biochemical recurrence
      after radical prostatectomy in patients with prostate cancer. IGFBP-3 has pro
      apoptotic activity, and its expression correlates negatively with prostate cancer
      cell growth. Castration induces IGFBP-3 expression and apoptosis in the rat
      prostate. METHODS: We used tissue specimens from 42 patients who underwent NHT
      and radical prostatectomy. The pre-NHT and post-NHT specimens were examined for
      expression of IGFBP-3 using an immunohistochemical technique and for apoptosis
      using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end
      labeling method. The histopathologic effect was evaluated by the standardized
      rules for estimating the response of prostate cancer to NHT, determined by the
      percentage of remaining viable cancer cells, as advocated by the General Rule for
      Clinical and Pathological Study on Prostate Cancer published by the Japanese
      Urological Association. RESULTS: NHT resulted in a statistically significant
      increase in IGFBP-3 expression compared with baseline (P = 0.01). Such an
      increase in expression correlated significantly with the induction of apoptotic
      cells (r = 0.40 and P = 0.01). The post-NHT/pre-NHT IGFBP-3 ratio was
      significantly greater in the NHT-effective group than in the NHT-noneffective
      group (P = 0.02). Patients with high IGFBP-3 expression in the post-NHT specimens
      had a good prognosis (P = 0.03, log-rank test). CONCLUSIONS: Induction of IGFBP-3
      by NHT was associated with apoptosis and a histopathologic effect. IGFBP-3
      expression in post-NHT specimens is a potentially useful predictor of biochemical
      recurrence in patients with prostate cancer.

PMID- 15183988
TI  - Tissue expression of transforming growth factor-beta1 and its receptors:
      correlation with pathologic features and biochemical progression in patients
      undergoing radical prostatectomy.
AB  - OBJECTIVES: To determine whether the abnormal expression of transforming growth
      factor-beta1 (TGF-beta1) and/or its receptors (TGFbeta-RI and TGFbeta-RII) is
      associated with prostate cancer features and progression; and to investigate the
      relationship between tissue expression of TGFs and blood levels of TGF-beta1.
      METHODS: Immunohistochemical staining for TGF-beta1, TGFbeta-RI, and TGFbeta-RII
      was carried out on archival specimens from 118 consecutive patients who underwent
      radical prostatectomy for clinically localized disease (median follow-up 57.5
      months). Preoperative plasma TGF-beta1 levels were also measured. RESULTS: TGF
      beta1 was overexpressed in 71 (60%) of 118 patients, and TGFbeta-RI and TGFbeta
      RII expression was decreased in 34 (29%) and 39 (33%) of 118 patients,
      respectively. Of the 118 patients, 82 (70%) had abnormal expression of at least
      one of the three TGFs and 22 (19%) had abnormal expression of all three. The
      concordance rates between the expression of TGF-beta1 and its receptors were 54%
      and 62%. Abnormal expression of all three TGFs was significantly associated with
      extracapsular disease. However, only decreased expression of TGFbeta-RI and
      TGFbeta-RII was significantly associated with seminal vesicle involvement and
      greater pathologic Gleason score. Preoperative plasma TGF-beta1 levels were
      significantly elevated in patients with abnormal expression of TGFs. TGFbeta-RI
      expression and surgical margin status were independently associated with
      biochemical progression. CONCLUSIONS: Our results showed that abnormal expression
      of TGF-beta1 and its receptors is common in prostate cancer. TGF-beta1
      overexpression is moderately but significantly associated with a loss of
      expression of TGFbeta-RI and TGFbeta-RII. Loss of TGFbeta-RI expression is a
      prognostic marker in patients with prostate cancer.

PMID- 15183989
TI  - c-FLIP expression in bladder urothelial carcinomas: its role in resistance to Fas
      mediated apoptosis and clinicopathologic correlations.
AB  - OBJECTIVES: To investigate the incidence of Fas (exon 9) mutations and the
      expression of Fas, Fas-Fas ligand (FasL) system, and cellular FLICE-like
      inhibitory protein (c-FLIP) in relation to standard clinicopathologic parameters
      and patient outcome in bladder carcinoma. Disruption of apoptotic cell death has
      been implicated in tumor aggressiveness in bladder urothelial carcinomas. The
      FasL system is involved in the execution of apoptosis induced by the immune
      system. c-FLIP protein constitutes an important endogenous inhibitor of Fas and
      other death receptor-mediated apoptosis. METHODS: The expression of Fas, FasL,
      and c-FLIP was quantified immunohistochemically in paraffin-embedded tissues from
      53 patients for whom clinical information was available. DNA extracted from the
      same samples was screened for mutations in Fas exon 9 by single-strand
      conformation polymorphism and sequencing. The effect of Fas, FasL, and c-FLIP on
      clinical outcome was assessed by univariate and multivariate analyses. RESULTS:
      Positive immunostaining was detected for Fas, FasL, and c-FLIP in 72%, 66%, and
      81% of cases, respectively. Concurrent expression of Fas and FasL was seen in 27
      samples (51%), of which 22 (81.5%) also displayed c-FLIP positivity. FasL and c
      FLIP expression increased with advancing stage but was absent from normal
      urothelium. None of the 53 urothelial carcinoma samples analyzed showed evidence
      of mutations by polymerase chain reaction single-strand conformation polymorphism
      and direct sequencing. Survival analysis demonstrated that although both FasL and
      c-FLIP expression adversely affected survival, only c-FLIP remained statistically
      significant on multivariate analysis. CONCLUSIONS: The frequent expression and
      coexpression of Fas, FasL, and c-FLIP in urothelial carcinomas implicates c-FLIP
      as an inhibitor of the Fas-FasL-induced death pathway in these tumors. Moreover,
      c-FLIP conveys independent prognostic information in the presence of classical
      prognosticators.

PMID- 15183990
TI  - Methylene blue staining for nerve-sparing operative procedures: an animal model.
AB  - OBJECTIVES: To evaluate methylene blue fiber staining as a method of nerve fiber
      identification in an animal model, because the maintenance of organ function
      after surgery depends on exact intraoperative identification of the relevant
      nerve fibers. METHODS: Brindley electrodes were implanted bilaterally at S3 for
      sacral anterior root stimulation in six minipigs. For reference, stimulation
      induced detrusor contractions were recorded urodynamically. After exposure of the
      ureterovesical junction on both sides, a 2:8 methylene blue solution was applied
      to the right side; the left side remained untreated. Bilateral dissection of the
      ureter from the surrounding tissue for a distance of 4 cm proximal to the
      ureterovesical junction was performed. The methylene blue-stained nerve fibers on
      the right side were spared; no particular attention was paid to the nerves on the
      left. Again, sacral anterior root stimulation-induced detrusor contractions were
      monitored urodynamically on both sides. Then, the identified nerve fibers on the
      right were cut intentionally, and the detrusor pressure was recorded again under
      stimulation. Finally, the dissected nerve structures were evaluated
      histologically. RESULTS: The reference bladder pressures after unilateral
      stimulation on the left side before ureter dissection showed a mean detrusor
      pressure (Pdet) of 19 cm H2O. On the right side, the Pdet was 18 cm H2O. After
      preparation on both sides, a mean Pdet of 3 cm H2O was recorded after left side
      stimulation, and a Pdet of 17 cm H2O after right side stimulation. When the
      stained nerve fibers on the right side were cut, no bladder contractions could be
      induced. The histomorphology of the stained and dissected structures revealed
      multiple autonomous nerve fibers and small vessels in connective tissue.
      CONCLUSIONS: The identification of minute nerve bundles is a tedious and
      difficult task. The results from our animal model demonstrated that supravital
      staining of autonomous nerve fibers with methylene blue is a simple and reliable
      method of identification.

PMID- 15183991
TI  - Enhanced renal cryoablation with hilar clamping and intrarenal cooling in a
      porcine model.
AB  - OBJECTIVES: To evaluate the effects of renal vascular control and intrarenal
      cooling on the size of renal lesions attainable with a 3.4-mm cryoprobe. METHODS:
      Three groups of pigs underwent unilateral laparoscopic renal cryoablation with a
      3.4-mm cryoprobe inserted to a depth of 1 cm. An 8-minute double-freeze cycle was
      used. One week later, an acute contralateral cryolesion was created before
      killing the animal. In group 1 (n = 6), bilateral cryolesions were created
      without hilar clamping or intrarenal cooling. In group 2 (n = 6), the cryolesions
      were created after hilar clamping alone. In group 3 (n = 6), the cryolesions were
      created after both hilar clamping and application of intrarenal cooling with
      saline ice-slush infused into the renal pelvis. After nephrectomy, the gross
      diameters were determined for each cryolesion. The mean diameters of the zones of
      complete and partial necrosis were determined by histopathologic examination.
      RESULTS: In group 3, the cortex cooled from 36.9 degrees C to a mean of 24.8
      degrees C. Acutely, no statistically significant difference was found between the
      lesions produced with clamping alone (37.6 mm) and intrarenal cooling (40.4 mm);
      however, both were significantly larger than the control cryolesions (28.7 mm).
      At 1 week, the area of complete necrosis produced with intrarenal cooling (34.3
      mm) was significantly larger than the areas of necrosis produced by clamping
      alone (27.8 mm) or conventional cryoablation (23.9 mm; alpha = 0.05, Tukey's
      honestly significantly different [HSD] test). CONCLUSIONS: Enhanced cryolesion
      necrosis was achieved with intrarenal cooling with a 3.4-mm cryoprobe. Intrarenal
      cooling may be a valuable adjunct to cryoablation in selected cases.

PMID- 15183992
TI  - Effects of propanil, tebufenozide and mefenacet on growth of four freshwater
      species of phytoplankton: a microplate bioassay.
AB  - The Albufera Natural Park situated in Valencia (Spain), with a very rich flora
      and fauna is surrounded by rice fields in which pesticide spraying is a regular
      practice. With this in mind, the sensitivity of four algal species, Scenedesmus
      acutus, Scenedesmus subspicatus, Chlorella vulgaris and Chlorella saccharophila
      to pesticides propanil, tebufenozide and mefenacet was studied using single
      species toxicity tests. Organisms were exposed to different concentrations of
      these herbicides and the algal growth was measured in a microplate reader at 410
      nm, at 0, 24, 48 and 72 h. Tebufenozide appeared to be the most inhibitory to
      Scenedesmus and Chlorella species growth. 72 h EC50 of propanil, tebufenozide and
      mefenacet ranged from 0.29 to 5.98 mg/l, 0.12 to 0.15 mg/l and from 0.25 to 0.67
      mg/l, respectively for the four algal species. The two species of Chlorella were
      more tolerant than the two species of Scenedesmus.

PMID- 15183993
TI  - The aflatoxin contamination of some pepper types sold in Turkey.
AB  - In the present study, 44 red-scaled pepper and 26 red powder pepper samples
      obtained from various spice retailers in Erzurum, and 20 isot (red pepper
      produced in Sanliurfa) were investigated for aflatoxin contamination using thin
      layer chromatography. Aflatoxin (B + G) was found in 8 red pepper samples
      (18.2%), and 3 red powder peppers (10.7%), and 1 isot sample (5%). The aflatoxin
      amount ranged from 1.1 to 97.5 ppb in all samples investigated. The highest
      amount of aflatoxin was found in red-scaled pepper. Species of Aspergillus,
      Penicillium and Rhizopus were generally contaminants of all samples.

PMID- 15183994
TI  - Trichloroacetic acid in Norway spruce/soil-system. II. Distribution and
      degradation in the plant.
AB  - Independently from its origin, trichloroacetic acid (TCA) as a phytotoxic
      substance affects coniferous trees. Its uptake, distribution and degradation were
      thus investigated in the Norway spruce/soil-system using 14C labeling. TCA is
      distributed in the tree mainly by the transpiration stream. As in soil, TCA seems
      to be degraded microbially, presumably by phyllosphere microorganisms in spruce
      needles. Indication of TCA biodegradation in trees is shown using both
      antibiotics and axenic plants.

PMID- 15183995
TI  - Variation in sex steroids and phallus size in juvenile American alligators
      (Alligator mississippiensis) collected from 3 sites within the Kissimmee
      Everglades drainage in Florida (USA).
AB  - This 3-year study was designed to examine variation in plasma sex steroids,
      phallus size, and the standard error (S.E.) associated with these endpoints in
      juvenile alligators collected from 3 sites within the Kissimmee-Everglades
      drainage (Florida, USA) with varying concentrations of sediment organochlorine
      contaminants. We hypothesized that decreased plasma sex steroid concentrations
      and phallus size would be observed in the higher contaminant site when compared
      to the intermediate and lower contaminant sites. Furthermore, we hypothesized
      that greater S.E. associated with these endpoints would be observed for the
      populations from more contaminated sites. We found that differences existed with
      females from the higher contaminant site exhibiting lower plasma estradiol-17beta
      (E2) and testosterone (T) concentrations. Males from the higher contaminant site
      exhibited smaller phallus sizes than males from the intermediate and lower
      contaminant sites. Smaller phallus size in this case differed from that reported
      in Lake Apopka male alligators [Gen. Comp. Endocrinol. 116 (1999) 356] in that a
      significant positive relationship between body size and phallus size existed. No
      difference among sites was observed in plasma T for males. Lower S.E. was
      associated with E2 and T concentrations in females from the higher contaminant
      site and in phallus size in males from the higher contaminant site. This pattern
      was opposite to what we had hypothesized. We concluded that variation in plasma
      E2 and T concentrations, phallus size, and the S.E. associated with these
      endpoints exists among the 3 sites with the patterns matching the patterns of
      organochlorine contamination, although S.E. patterns were opposite to what was
      predicted.

PMID- 15183996
TI  - Response of Cyprinus carpio (Linn) to sublethal concentration of cypermethrin:
      alterations in protein metabolic profiles.
AB  - Freshwater fish, Cyprinus carpio were exposed to sublethal concentration (1.2
      microg l(-1)) of cypermethrin for 6, 12, 24 and 48 h to analyze various
      parameters of protein metabolism in functionally different tissues. Total,
      structural and soluble proteins showed decrement; where as free amino acids and
      the activities of protease, aspartate aminotransferase and alanine
      aminotransferase significantly increased in cypermethrin exposed fish.
      Interestingly, ammonia content decreased but urea and glutamine increased at all
      periods of exposure. It was also observed that alterations steadily increased
      with the period of exposure and exhibited tissue specificity. Thus variation in
      the protein metabolism of the fish exposed to cypermethrin indicates its toxic
      effect on the cellular metabolism thereby leading to impaired protein synthetic
      machinery.

PMID- 15183997
TI  - Toxicity of anti-fouling biocides to encysted metacercariae of Echinoparyphium
      recurvatum (Digenea: Echinostomatidae) and their snail hosts.
AB  - The toxicity of the anti-fouling biocides tributyltin (TBTO), copper, and Irgarol
      1051 (irgarol) at a nominal concentration of 10 microg/l over a 30 day period
      were investigated against the viability of metacercarial cysts of the digenean
      parasite Echinoparyphium recurvatum resident within the body of two common
      freshwater snails, Lymnaea peregra and Physa fontinalis. Reduced parasite
      viability was found under most exposures in both snail species. However a greater
      effect of toxicant exposure was found in cysts within P. fontinalis compared to
      those in L. peregra. This was associated with an increased mortality of the host
      snail. Among all tested biocides, TBTO exposures induced the highest mortality to
      both the parasite and their hosts. These results suggest that parasite viability
      is interlinked with survival of the host snail. The mechanisms of differing
      toxicity between host species and its relevance to successful parasite
      transmission to the next host are discussed.

PMID- 15183998
TI  - Comparison of RBCA and CalTOX for setting risk-based cleanup levels based on
      inhalation exposure.
AB  - Risk-based corrective action (RBCA) and CalTOX (California EPA) are often used to
      develop risk-based soil cleanup levels. The determination of the entry
      parameters, including slope factors, degradation assumption, methodologies, and
      dispersion models for these two approaches greatly affect the onsite/offsite
      cleanup levels, risk distribution, and ranking of the influential factors. The
      subsurface soil-to-ambient air was considered as the only significant exposure
      pathway in this study. RBCA and CalTOX apply analytical equations and multimedia
      fugacity model, respectively, to simulate the transport of contaminants from
      subsurface soil to ambient air. Nine carcinogenic organic contaminants were
      selected as the target compounds. Environmental monitoring data collected from a
      contaminated site in southern Taiwan was used as model inputs. In this study,
      degradation assumption had greater influence on CalTOX evaluation than slope
      factors. The cleanup soil levels of all target chemicals developed by both models
      were close under the same slope factors and degradation assumptions, except for
      vinyl chloride and hexachlorobenzene. Furthermore, RBCA generally had larger
      offsite dispersion ratios than CalTOX, especially for long distances. The risk
      distribution obtained by RBCA was much board than by CalTOX. When 95th percentile
      was considered as the starting point, the SSTLs derived by RBCA were much
      stricter than by CalTOX. The ranking of influential factors in the onsite risk
      assessment for these two models were completely different because of their
      distinct model methodologies.

PMID- 15183999
TI  - Comparative study on the susceptibility of freshwater species to copper-based
      pesticides.
AB  - Copper compounds have been intentionally introduced into water bodies as aquatic
      plant herbicides, algicides and molluscicides. Copper-based fertilizers and
      fungicides have been widely used in agriculture as well. Despite the fact that
      copper is an essential element for all biota, elevated concentrations of this
      metal have been shown to affect a variety of aquatic organisms. Nonetheless,
      comparative studies on the susceptibility of different freshwater species to
      copper compounds have seldom been performed. This study was conducted to compare
      toxicity of copper-based pesticides (copper oxychloride, cuprous oxide and copper
      sulfate) to different freshwater target (Raphidocelis subcapitata, a planktonic
      alga and Biomphalaria glabrata, a snail) and non-target (Daphnia similis, a
      planktonic crustacean and Danio rerio, a fish) organisms. Test water parameters
      were as follows: pH = 7.4 +/- 0.1; hardness 44 +/- 1 mg/l as CaCO3; DO 8-9 mg/l
      at the beginning and > 4 mg/l at the end; temperature, fish and snails 25 +/- 1
      degrees C, Daphnia 20 +/- 2 degrees C, algae 24 +/- 1 degrees C. D. similis
      (immobilization), 48-h EC50s (95% CLs) ranging from 0.013 (0.011-0.016) to 0.043
      (0.033-0.057) mg Cu/l, and R. subcapitata (growth inhibition), 96-h IC50s from
      0.071 (0.045-0.099) to 0.137 (0.090-0.174) mg Cu/l, were the most susceptible
      species. B. glabrata (lethality), 48-h LC50s from 0.179 (0.102-0.270) to 0.854
      (0.553-1.457) mg Cu/l, and D. rerio (lethality), 48-h LC50s 0.063 (0.045-0.089),
      0.192 (0.133-0.272) and 0.714 (0.494-1.016) mg Cu/l, were less susceptible than
      Daphnia to copper-based pesticides. Findings from the present study therefore
      suggest that increased levels of copper in water bodies is likely to adversely
      affect a variety of aquatic species.

PMID- 15184000
TI  - Investigation of acute toxicity and the effect of cadmium chloride (CdCl2 . H2O)
      metal salt on behavior of the guppy (Poecilia reticulata).
AB  - In this study 96-h LC50 value of cadmium chloride (CdCl2 . H2O), a metal salt
      widely used in industry, was determined for the guppy (Poecilia reticulata,
      Pallas, 1859). The experiments were planned in four series of a total of 440
      guppies employing the static test method of acute toxicity. 10 fish were placed
      in each replicate of each dose. The experiments were performed as four
      replicates, and behavioral changes in the guppy were determined for each cadmium
      chloride metal salt concentration. The data obtained were statistically evaluated
      by the use of EPA computer program based on Finney's Probit Analysis Method and a
      96-h LC50 value for P. reticulata was found to be 30.4 mg/l in a static bioassay
      test system. This value was estimated to be 30.6 mg/l with Behrens-Karber's
      method. The two methods were in good agreement. 95% lower and upper confidence
      limits for the LC50 were 29.3 and 31.7 mg/l, respectively. The water temperature
      was kept between 21 and 23 degrees C. The behavioral changes observed in fish
      were, swimming in imbalanced manner, capsizing, attaching to the surface,
      difficulty in breathing and gathering around the ventilation filter.

PMID- 15184001
TI  - Acute toxicity of alpha-cypermethrin to guppy (Poecilia reticulata, Pallas,
      1859).
AB  - Alpha-cypermethrin is a synthetic pyrethroid insecticide used to control pests in
      domestic, industrial and agricultural situations. Adult male guppy fish (Poecilia
      reticulata standard test species) were selected for the bioassay experiments. The
      experiments were performed in four series and the 96-h LC50 value was determined
      for guppies. The acute toxicity experiments were carried out by static method and
      behavioral changes in guppies were determined for each alpha-cypermethrin (98%
      technical grade) concentration. Data obtained from the alpha-cypermethrin
      investigation were evaluated by the use of probit analysis statistical method and
      the 96-h LC50 value for guppy was estimated as 9.43 microg/l.

PMID- 15184002
TI  - Photoinduced toxicity of fluoranthene on germination and early development of
      plant seedling.
AB  - The influence of light on phytotoxicity of increased concentration (2, 5, 10
      mg/l) of intact fluoranthene (FLT) and photomodified fluoranthene (phFLT) diluted
      in experimental solutions was investigated. The germination rate of lettuce
      (Lactuca sativa L.), onion (Allium cepa L.) and tomato (Lycopersicum esculentum
      L.) seeds and some parameters of seedlings primary growth of these plant species
      were used as laboratory indicators of phytotoxicity. Among them a length of root
      and shoot, their dry weight and a content of photosynthetic pigments in shoot
      were measured. The results demonstrated that the higher concentration (5 and 10
      mg/l) of FLT and especially of phFLT significantly inhibited the germination rate
      of seeds and the length of root and shoot seedlings of all plant species.
      Decreased production of biomass expressed by dry weight of root and shoot was
      found in lettuce seedlings under the inhibitory effect of FLT and phFLT. An
      increased concentration of FLT and phFLT did not exhibit an unambiguous effect on
      the content of photosynthetic pigments in shoot of experimental plants. Only the
      highest concentration (10 mg/l) of FLT significantly increased content of
      chlorophylls a and b in lettuce, onion and tomato plants and content of
      carotenoids in lettuce and onion. Light intensified a significant inhibitory
      effect of phFLT in the most testified parameters of germination and seedling
      growth.

PMID- 15184003
TI  - Adaptation to environmental stress in Daphnia magna simultaneously exposed to a
      xenobiotic.
AB  - In standardized ecotoxicological testing chemicals are investigated under optimal
      conditions for the test organisms despite the fact that environmental factors
      such as predation pressure and food availability are important parameters
      regulating natural populations. Food limitation and predator presence can induce
      shifts in life-history traits in various Daphnia species, especially trade-offs
      in reproductive biomass allocation. These adaptive responses are thought to
      ensure survival of the population in a highly variable environment. A xenobiotic
      dispersant (used in textile dyeing processes) also shifted the biomass allocation
      of Daphnia magna. To assess whether the dispersant could hinder D. magna
      adaptation to varying environmental conditions, we conducted experiments with
      food level and presence of Chaoborus larvae as environmental factors and
      simultaneous exposure to the dispersant. At low food level and in presence of the
      predator, D. magna produced fewer but larger sized neonates, regardless of
      dispersant exposure. The dispersant shifted biomass allocation towards more but
      smaller sized offspring in all experiments. However, the adaptive response to the
      environmental factors and the dispersant effect cancelled each other out in that
      they induced independently from each other opposite shifts in biomass allocation.
      In summary, the dispersant exposure resulted not in an inhibition of the adaptive
      response but in a reduction of the value of the response. Our study with this
      model substance demonstrates that xenobiotics can affect the adaptation of
      organisms to environmental stress which can result in effects likely to be
      overlooked in standardized testing.

PMID- 15184004
TI  - Retrospective analysis of the age at death in two heavily polluted and two
      unpolluted Russian towns.
AB  - Mean age at death during 1981-1999 was recorded in four small industrial towns
      located in the Kola Peninsula, north-western Russia. Two of these towns (Nikel
      and Monchegorsk) are heavily contaminated by sulphur dioxide and toxic metals
      (primarily Ni, Cu, Cd) emitted by large nickel-copper smelters; two other towns
      (Apatity and Polyarnye Zori) are nearly unpolluted. The results did not support
      the hypothesis that human life span is significantly shorter in the contaminated
      communities; moreover, mean age at death was lowest in Polyarnye Zori, the town
      not polluted by either sulfur dioxide or heavy metals but located close to the
      nuclear power plant. It seems that the impact of hazards other than pollution
      (both social and environmental), which are common for the populations of the
      investigated towns, shorten the life span so much that the contribution of
      pollutants to the decline in life expectancy cannot be detected. However, the
      relative importance of the life-shortening diseases associated with pollution may
      increase with the (expected) improvement of the quality of life.

PMID- 15184005
TI  - Sorghum phytochemicals and their potential impact on human health.
AB  - Sorghum is a rich source of various phytochemicals including tannins, phenolic
      acids, anthocyanins, phytosterols and policosanols. These phytochemicals have
      potential to significantly impact human health. Sorghum fractions possess high
      antioxidant activity in vitro relative to other cereals or fruits. These
      fractions may offer similar health benefits commonly associated with fruits.
      Available epidemiological evidence suggests that sorghum consumption reduces the
      risk of certain types of cancer in humans compared to other cereals. The high
      concentration of phytochemicals in sorghum may be partly responsible. Sorghums
      containing tannins are widely reported to reduce caloric availability and hence
      weight gain in animals. This property is potentially useful in helping reduce
      obesity in humans. Sorghum phytochemicals also promote cardiovascular health in
      animals. Such properties have not been reported in humans and require
      investigation, since cardiovascular disease is currently the leading killer in
      the developed world. This paper reviews available information on sorghum
      phytochemicals, how the information relates to current phytonutrient research and
      how it has potential to combat common nutrition-related diseases including
      cancer, cardiovascular disease and obesity.

PMID- 15184006
TI  - Identification of Vitis vinifera (-)-alpha-terpineol synthase by in silico
      screening of full-length cDNA ESTs and functional characterization of recombinant
      terpene synthase.
AB  - The flavour and aroma of certain Vitis vinifera grape varieties is dominated by
      volatile terpenes and small volatile aldehydes. Monoterpenes contribute to the
      final grape and wine aroma and flavour in form of free volatiles and as glycoside
      conjugates of monoterpene alcohols. Typical monoterpenol components of the
      cultivar Gewurztraminer and other aroma-rich grape varieties are linalool,
      geraniol, nerol, citronellol, and alpha-terpineol. In a functional genomics
      effort to identify genes for the formation of monoterpene alcohols in V.
      vinifera, a database of full-length cDNA sequences was screened in silico and
      yielded two clones for putative monoterpene synthases. The gene products were
      functionally characterized by expression in Escherichia coli, in vitro enzyme
      assay and gas chromatography-mass spectrometry (GC-MS) product identification as
      multi-product (-)-alpha-terpineol synthases.

PMID- 15184007
TI  - Analysis of the chlorophyll catabolism pathway in leaves of an introgression
      senescence mutant of Lolium temulentum.
AB  - Pigments, proteins and enzyme activity related to chlorophyll catabolism were
      analysed in senescing leaves of wild-type (WT) Lolium temulentum and compared
      with those of an introgression line carrying a mutant gene from stay-green (SG)
      Festuca pratensis. During senescence of WT leaves chlorophylls a and b were
      continuously catabolised to colourless products and no other derivatives were
      observed, whereas in SG leaves there was an accumulation of dephytylated and
      oxidised catabolites including chlorophyllide a, phaeophorbide a and 13(2) OH
      chlorophyllide a. Dephytylated products were absent from SG leaf tissue senescing
      under a light-dark cycle. Retention of pigments in SG was accompanied by
      significant stabilisation of light harvesting chlorophyll-proteins compared with
      WT, but soluble proteins such as Rubisco were degraded during senescence at a
      similar rate in the two genotypes. The activity of phaeophorbide a oxygenase
      measured in SG tissue at 3d was less than 12% of that in WT tissue at the same
      time-point during senescence and of the same order as that in young pre-senescent
      WT leaves, indicating that the metabolic lesion in SG concerns a deficiency at
      the ring-opening step of the catabolic pathway. In senescent L. temulentum tissue
      two terminal chlorophyll catabolites were identified with chromatographic
      characteristics that suggest they may represent hitherto undescribed catabolite
      structures. These data are discussed in relation to current understanding of the
      genetic and metabolic control of chlorophyll catabolism in leaf senescence.

PMID- 15184008
TI  - Lipids of the zygomycete Absidia corymbifera F-965.
AB  - The cell lipids of the zygomycete Absidia corymbifera F-965 extracted with
      isopropanol and CHCl3-MeOH mixtures at the exponential growth phase comprise 20+/
      2% of mycelium dry wt. The lipids consist of: triacylglycerols (51% of the total
      lipids extracted), diacylglycerols (9%), monoacylglycerols (3%), ergosterol (5%),
      ergosterol peroxide (5alpha,8alpha-epidioxyergosta-6,22-diene-3beta-ol) (3%),
      fatty-acid esters of ergosterol (less than 0.5%), free fatty acids (4%),
      glucocerebroside (3%), and glycerophospholipids (22%). The main phospholipids are
      phosphatidylethanolamine (39% of the total phospholipids), phosphatidyl-myo
      inositol (17%), diphosphatidylglycerol (12%), phosphatidic acid (7%),
      phosphatidylcholine (6%), phosphatidylglycerol (3%), and two unusual
      phospholipids reported earlier, N-acetylphosphatidylethanolamine (7%) and N
      ethoxycarbonyl phosphatidylethanolamine (9%). In addition, two unknown acidic
      phospholipids are present in traces. Saturated fatty acids of the lipids are
      dominated by n-hexadecanoic acid and unsaturated ones by octadecenoic acid;
      octadecadienoic and octadecatrienoic acids are present in lesser amounts.
      Ergosterol peroxide as well as the above glucocerebroside which contains 9
      methylsphinga-4(E),9(E)-dienine have first been revealed in zygomycetes.

PMID- 15184009
TI  - Glycosides of tricetin methyl ethers as chemosystematic markers in Stachys
      subgenus Betonica.
AB  - Nine species from the genus Stachys L. representing subgenera Stachys and
      Betonica were surveyed for flavonoid glycosides by means of HPLC coupled to diode
      array detection and LC-APCI-MS. Those species belonging to subgenus Betonica were
      characterised by the presence of glycosides of tricetin methyl ethers, including
      a new derivative, which was isolated from S. scardica Griseb. and identified as
      tricetin 3',4',5' -trimethyl ether 7-O-beta-glucopyranoside by spectroscopic
      methods. This type of flavonoid was absent from species belonging to subgenus
      Stachys and can be considered as a chemosystematic marker for subgenus Betonica.

PMID- 15184010
TI  - Essential oils from New Zealand manuka: triketone and other chemotypes of
      Leptospermum scoparium.
AB  - The triketone chemotype of manuka, Leptospermum scoparium (Myrtaceae), is
      commercially important because of its antimicrobial activity. Oils from 36
      individual plants on the East Cape of New Zealand all showed similar high
      triketone contents (>20% total triketones) with little seasonal variation.
      Analyses of oils from 261 individual manuka plants collected from 87 sites
      throughout New Zealand showed that the high triketone chemotype was localised on
      the East Cape, although oils with triketone levels up to 20% were found in the
      Marlborough Sounds area of the South Island. Cluster analysis revealed other
      chemotypes localised on other areas. Ten further chemotypes are described: alpha
      pinene; sesquiterpene-rich with high myrcene; sesquiterpene-rich with elevated
      caryophyllene and humulene; sesquiterpene-rich with an unidentified sesquiterpene
      hydrocarbon; high geranyl acetate; sesquiterpene-rich with high gamma-ylangene +
      alpha-copaene and elevated triketones; sesquiterpene-rich with no distinctive
      components; sesquiterpene-rich with high trans-methyl cinnamate; high linalol;
      and sesquiterpene-rich with elevated elemene and selinene. Some of the chemotypes
      contained aroma compounds at relatively high levels, with a geranyl acetate-rich
      oil being most notable. Possible origins for this complex array of chemotypes are
      proposed.

PMID- 15184011
TI  - Antitermitic quinones from Diospyros sylvatica.
AB  - Six quinones were isolated from the chloroform extract of the roots of Diospyros
      sylvatica and identified as 2-methyl-anthraquinone, plumbagin, diosindigo,
      diospyrin, isodiospyrin and microphyllone. The effect of the root extract on the
      orientation and survival of the subterranean termite, Odontotermes obesus was
      tested. In addition, four of these quinones were tested on the survival of the
      subterranean termite. In a direct-choice experiment, exposure to an extract
      treated filter disc had a significantly repellent effect over the solvent-treated
      filter disc. The no-choice experiment revealed the toxic property of the extract
      as well as the tested quinones and showed high mortality of the O. obesus workers
      after 48 h on forced exposure. The major termiticidal components identified were
      plumbagin, isodiospyrin and microphyllone while diospyrin was not toxic to
      termites at the concentration tested. All the quinones are reported for the first
      time from D. sylvatica.

PMID- 15184012
TI  - Heating decreases epithiospecifier protein activity and increases sulforaphane
      formation in broccoli.
AB  - Sulforaphane, an isothiocyanate from broccoli, is one of the most potent food
      derived anticarcinogens. This compound is not present in the intact vegetable,
      rather it is formed from its glucosinolate precursor, glucoraphanin, by the
      action of myrosinase, a thioglucosidase enzyme, when broccoli tissue is crushed
      or chewed. However, a number of studies have demonstrated that sulforaphane yield
      from glucoraphanin is low, and that a non-bioactive nitrile analog, sulforaphane
      nitrile, is the primary hydrolysis product when plant tissue is crushed at room
      temperature. Recent evidence suggests that in Arabidopsis, nitrile formation from
      glucosinolates is controlled by a heat-sensitive protein, epithiospecifier
      protein (ESP), a non-catalytic cofactor of myrosinase. Our objectives were to
      examine the effects of heating broccoli florets and sprouts on sulforaphane and
      sulforaphane nitrile formation, to determine if broccoli contains ESP activity,
      then to correlate heat-dependent changes in ESP activity, sulforaphane content
      and bioactivity, as measured by induction of the phase II detoxification enzyme
      quinone reductase (QR) in cell culture. Heating fresh broccoli florets or
      broccoli sprouts to 60 degrees C prior to homogenization simultaneously increased
      sulforaphane formation and decreased sulforaphane nitrile formation. A
      significant loss of ESP activity paralleled the decrease in sulforaphane nitrile
      formation. Heating to 70 degrees C and above decreased the formation of both
      products in broccoli florets, but not in broccoli sprouts. The induction of QR in
      cultured mouse hepatoma Hepa lclc7 cells paralleled increases in sulforaphane
      formation.

PMID- 15184013
TI  - Arudonine, an allelopathic steroidal glycoalkaloid from the root bark of Solanum
      arundo Mattei.
AB  - Bioassay-guided fractionation of the methanol extract of the root bark of Solanum
      arundo Mattei led to the isolation of a steroidal glycoalkaloid, designated
      arudonine, which was elucidated to be solasodine O-alpha-l-rhamnopyranosyl-(1-
      >2)-[beta-D-xylopyranosyl-(1-->3)], [alpha-l-rhamnopyranosyl-(1-->4)]-beta-D
      glucopyranoside. This steroidal glycoalkaloid inhibited the growth of lettuce
      seedlings (Lactuca sativa).

PMID- 15184014
TI  - Geranyl chalcone derivatives with antifungal and radical scavenging properties
      from the leaves of Artocarpus nobilis.
AB  - Antifungal activity guided fractionation of the n-butanol extract from the
      methanol extract of the leaves of Artocarpus nobilis furnished 2',4',4-trihydroxy
      3'-geranylchalcone (1), 2 ',4',4-trihydroxy-3'-[6-hydroxy-3,7-dimethyl-2(E),7
      octadienyl]chalcone (2), 2',4',4-trihydroxy-3'-[2-hydroxy-7-methyl-3-methylene-6
      octaenyl]chalcone (3), 2',3,4,4'-tetrahydroxy-3'-geranylchalcone (4), 2',3,4,4'
      tetrahydroxy-3'-[6-hydroxy-3,7-dimethyl-2(E),7-octadienyl]chalcone (5). The
      chalcones 3 and 5 are new natural products whereas 1 and 2 are reported first
      time from the family Moraceae. All these compounds showed good fungicidal
      activity against Cladosporium cladosporioides and high radical scavenging
      activity towards the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical in TLC bio
      autography method.

PMID- 15184015
TI  - Antibacterial diterpenes and their fatty acid conjugates from rice leaves.
AB  - Six structurally oryzalide-related compounds, oryzadione (1), 2, 3, 4, 5 and 6,
      were isolated from a neutral fraction of the extract of healthy leaves using a
      bacterial leaf blight-resistant cultivar of a rice plant, "Norin-27", as a group
      of antimicrobial substances. Their structures were determined by spectroscopic
      studies to be kaurane analogues and kaurane analogues conjugated with fatty
      acids, i.e., 1: ent-15,16-epoxy-kauran-2,3-dione (enol form: ent-15,16-epoxy-2
      hydroxy-kauran-1-en-3-one), 2: ent-15,16-epoxy-3beta-hydroxy-kauran-2-one, 3: ent
      15,16-epoxy-3-oxa-kauran-2-one, 4: ent-15,16-epoxy-3beta-myristoyloxy-kauran-2
      one, 5: ent-15,16-epoxy-3alpha-palmitoyloxy-kauran-2-one, and 6: ent-15,16-epoxy
      2beta-palmitoyloxy-kauran-2-one.

PMID- 15184016
TI  - Alkenone and alkenoic acid compositions of the membrane fractions of Emiliania
      huxleyi.
AB  - The lipid classes and unsaturation ratios of long-chain alkenones (nC37-C39),
      related alkyl alkenoate compounds (nC37-C38) and alkenoic acids (nC14-C22) were
      determined in isolated membrane and organelle fractions of Emiliania huxleyi. The
      percentage distribution of these compounds was predominantly high in the
      endoplasmic reticulum (ER) and coccolith-producing compartment (CPC)-rich
      membrane fraction, although alkenones and alkenoates could be detected in all
      membrane fractions. In particular, the alkenones were mainly located in CPC,
      since their distribution was closely correlated with that of uronic acids which
      are markers of CPC. In contrast, the alkenoic acids seemed to be mainly located
      in chloroplast (thylakoid)-rich fractions. The alkenone unsaturation ratio and
      the ratio of alkenoates to alkenones were similar in all fractions, while the
      unsaturation ratio of alkenoic acids in the thylakoid-rich and plasma membrane
      (PM)/Golgi body-rich fractions was overwhelmingly higher than that in the ER/CPC
      rich fractions. Thus, alkenoic acids seemed to be typical membrane-bound lipids,
      and could be closely related to photosynthesis and involved in regulating
      membrane fluidity and rigidity in E. huxleyi. It is presumed from these results
      that the alkenones and alkenoates were membrane-unbound lipids that might be
      associated with the function of CPC.

PMID- 15184017
TI  - Crystal structure of the schiff base intermediate prior to decarboxylation in the
      catalytic cycle of aspartate alpha-decarboxylase.
AB  - l-Aspartate alpha-decarboxylase (ADC), encoded by the panD gene, catalyzes the
      conversion of l-aspartate into beta-alanine. In the microorganisms, beta-alanine
      is required for the synthesis of pantothenate (vitamin B(5)), which is the
      precursor of 4'-phosphopantetheine and coenzyme A. We have determined the crystal
      structure of Helicobacter pylori ADC, a tetrameric enzyme, in two forms: the apo
      structure at 2.0 A resolution and the isoasparagine complex structure at 1.55 A
      resolution. All subunits of the tetramer are self-processed at the Gly24-Ser25
      linkage, producing the smaller beta chain (residues 1-24) and the larger alpha
      chain (residues 25-117). Each subunit contains nine beta-strands and three alpha
      helices; it is folded into the double-psi beta-barrel structure. In the apo
      structure, the new amino terminus of the alpha chain, Ser25, is converted into a
      pyruvoyl group. In the isoasparagine complex structure, the substrate analog is
      covalently attached to the pyruvoyl group. This structure represents the enzyme
      substrate Schiff base intermediate that was proposed to form prior to the
      decarboxylation step in the catalytic cycle of ADC. Thus our study provides
      direct structural evidence for the reaction mechanism of ADC.

PMID- 15184018
TI  - The stability of the intact envelope glycoproteins is a major determinant of
      sensitivity of HIV/SIV to peptidic fusion inhibitors.
AB  - C-peptides derived from the HIV envelope glycoprotein transmembrane subunit gp41
      C-terminal heptad repeat (C-HR) region are potent HIV fusion inhibitors. These
      peptides interact with the gp41 N-terminal heptad repeat (N-HR) region and block
      the gp41 six-helix bundle formation that is required for fusion. However, the
      parameters that govern this inhibition have yet to be elucidated. We address this
      issue by comparing the ability of C34, derived from HIV-1, HIV-2 and SIV gp41, to
      inhibit HIV-1, HIV-2 and SIV envelope-mediated fusion and the ability of these
      peptides to form stable six-helix bundles with N36 peptides derived from gp41 of
      these three viruses. The ability to form six-helix bundles was examined by
      circular dichroism spectroscopy, and HIV/SIV Env-mediated membrane fusion was
      monitored by a dye transfer assay. HIV-1 N36 formed stable helix bundles with HIV
      1, HIV-2 and SIV C34, which all inhibited HIV-1 Env-mediated fusion at
      IC(50)<10nM. The three C34 peptides were poor inhibitors of HIV-2 and SIV fusion
      (IC(50)>100nM), although HIV-2 and SIV N36 formed stable helix bundles with SIV
      C34. Priming experiments with sCD4 indicate that, in contrast to HIV-1, HIV-2 and
      SIV Env do not expose their N-HR region to SIV C34 following CD4 binding, but
      rapidly proceed to co-receptor engagement and six-helix bundle formation
      resulting in fusion. Our results suggest that several factors, including six
      helix bundle stability and the ability of CD4 to destabilize the envelope
      glycoprotein, serve as determinants of sensitivity to entry inhibitors.

PMID- 15184019
TI  - Complementation of yeast Arc1p by the p43 component of the human multisynthetase
      complex does not require its association with yeast MetRS and GluRS.
AB  - Yeast Arc1p, human p43 and plant methionyl-tRNA synthetase (MetRS) possess an
      EMAPII-like domain capable of non-specific interactions with tRNA. Arc1p
      interacts with MetRS (MES1) and GluRS and operates as a tRNA-interacting factor
      (tIF) in trans of these two synthetases. In plant MetRS, the EMAPII-like domain
      is fused to the catalytic core of the synthetase and acts as a cis-acting tIF for
      aminoacylation. We observed that the catalytic core of plant MetRS expressed from
      a centromeric plasmid cannot complement a yeast arc1(-) mes1(-) strain.
      Overexpression of the mutant enzyme from a high-copy number plasmid restored cell
      growth, suggesting that deletion of its C-terminal tIF domain was responsible for
      the poor aminoacylation efficiency of that enzyme in vivo. Accordingly,
      expression of full-size plant MetRS from a centromeric plasmid, but also of
      fusion proteins between its catalytic core and the EMAPII-like domains of yeast
      Arc1p or of human p43 restored cell viability. These data showed that homologous
      tIF domains from different origins are interchangeable and may act indifferently
      in trans or in cis of the catalytic domain of a synthetase. Unexpectedly, co
      expression of Arc1p with the catalytic core of plant MetRS restored cell
      viability as well, even though Arc1p did not associate with plant MetRS. Because
      Arc1p also interacts with yeast GluRS, restoration of cell growth could be due at
      least in part to its role of cofactor for that enzyme. However, co-expression of
      human p43, a tIF that did not associate with plant MetRS or with yeast GluRS and
      MetRS, also restored cell viability of a yeast strain that expressed the
      catalytic core of plant MetRS. These results show that p43 and Arc1p are able to
      facilitate tRNA aminoacylation in vivo even if they do not interact physically
      with the synthetases. We propose that p43/Arc1p may be involved in sequestering
      tRNAs in the cytoplasm of eukaryotic cells, thereby increasing their availability
      for protein synthesis.

PMID- 15184020
TI  - ADP-binding to origin recognition complex of Saccharomyces cerevisiae.
AB  - The origin recognition complex (ORC), a possible initiator of chromosomal DNA
      replication in eukaryotes, binds to ATP through its subunits Orc1p and Orc5p.
      Orc1p possesses ATPase activity. As for DnaA, the Escherichia coli initiator, the
      ATP-DnaA complex is active but the ADP-DnaA complex is inactive for DNA
      replication and, therefore, the ATPase activity of DnaA inactivates the ATP-DnaA
      complex to suppress the re-initiation of chromosomal DNA replication. We
      investigated ADP-binding to ORC by a filter-binding assay. The K(d) values for
      ADP-binding to wild-type ORC and to ORC-1A (ORC containing Orc1p with a defective
      Walker A motif) were less than 10nM, showing that Orc5p can bind to ADP with a
      high affinity, similar to ATP. ORC-5A (ORC containing Orc5p with a defective
      Walker A motif) did not bind to ADP, suggesting that the ADP-Orc1p complex is too
      unstable to be detected by the filter-binding assay. ADP dissociated more rapidly
      than ATP from wild-type ORC and ORC-1A. Origin DNA fragments did not stimulate
      ADP-binding to any type of ORC. In the presence of ADP, ORC could not bind to
      origin DNA in a sequence-specific manner. Thus, in eukaryotes, the ADP-ORC
      complex may be unable to initiate chromosomal DNA replication, and in this it
      resembles the ADP-DnaA complex in prokaryotes. However, overall control may be
      different. In eukaryotes, the ADP-ORC complex is unstable, suggesting that the
      ADP-ORC complex might rapidly become an ATP-ORC complex; whereas in prokaryotes,
      ADP remains bound to DnaA, keeping DnaA inactive, and preventing re-initiation
      for some periods.

PMID- 15184021
TI  - Transport-deficient Pit2 phosphate transporters still modify cell surface
      oligomers structure in response to inorganic phosphate.
AB  - Pit2 is a member of the Pit family of inorganic phosphate transporters and serves
      as a gamma-retrovirus receptor in mammals. Pit2 contains two copies of the
      protein homology domain PD001131, which defines the Pit family. These domains are
      presumably in opposite topology with respect to the plasma membrane plane. We
      have mutated a serine residue conserved in almost all of the 192 known PD001131
      sequences to alanine in each PD001131 domain of human Pit2. Expression in CHO
      cells showed that phosphate uptake was affected severely in mutants, whereas
      susceptibility to virus infection was conserved. We reported previously that the
      inorganic phosphate concentration affects both phosphate transport mediated by
      Pit2 and the conformation of cell-surface Pit2 oligomers. Cross-linking
      experiments in transport-incompetent Pit2 mutants indicated that structural
      changes induced by phosphate starvation or supply occur independently of the
      whole transport cycle. These results suggest that the structural reorganisation
      of cell-surface Pit2 occurred as a consequence of ion binding, a model consistent
      with the possible involvement of cell-surface Pit2 oligomers in inorganic
      phosphate sensing.

PMID- 15184022
TI  - Burkholderia cenocepacia phage BcepMu and a family of Mu-like phages encoding
      potential pathogenesis factors.
AB  - We have isolated BcepMu, a Mu-like bacteriophage whose host range includes human
      pathogenic Burkholderia cenocepacia (formally B. cepacia genomovar III) isolates,
      and determined its complete 36748 bp genomic sequence. Like enteric bacteriophage
      Mu, the BcepMu genomic DNA is flanked by variable host sequences, a result of
      transposon-mediated replication. The BcepMu genome encodes 53 proteins, including
      capsid assembly components related to those of Mu, and tail sheath and tube
      proteins related to those of bacteriophage P2. Seventeen of the BcepMu genes were
      demonstrated to encode homotypic interacting domains by using a cI fusion system.
      Most BcepMu genes have close homologs to prophage elements present in the two
      published Salmonella typhi genomes, and in the database sequences of Photorhabdus
      luminescens, and Chromobacterium violaceum. These prophage elements, designated
      SalMu, PhotoMu and ChromoMu, respectively, are collinear with BcepMu through
      nearly their entire lengths and show only limited mosaicism, despite the
      divergent characters of their hosts. The BcepMu family of Mu-like phages has a
      number of notable differences from Mu. Most significantly, the critical left end
      region of BcepMu is inverted with respect to Mu, and the BcepMu family of
      transposases is clearly of a distinct lineage with different molecular
      requirements at the transposon ends. Interestingly, a survey of 33 B.cepacia
      complex strains indicated that the BcepMu prophage is widespread in human
      pathogenic B.cenocepacia ET12 lineage isolates, but not in isolates from the PHDC
      or Midwest lineages. Identified members of the BcepMu family all contain a gene
      possibly involved in bacterial pathogenicity, a homolog of the type-two-secretion
      component exeA, but only BcepMu also carries a lipopolysaccharide modification
      acyltransferase which may also contribute a pathogenicity factor.

PMID- 15184023
TI  - The folding and dimerization of HIV-1 protease: evidence for a stable monomer
      from simulations.
AB  - HIV-1 protease (PR) is a major drug target in combating AIDS, as it plays a key
      role in maturation and replication of the virus. Six FDA-approved drugs are
      currently in clinical use, all designed to inhibit enzyme activity by blocking
      the active site, which exists only in the dimer. An alternative inhibition mode
      would be required to overcome the emergence of drug-resistance through the
      accumulation of mutations. This might involve inhibiting the formation of the
      dimer itself. Here, the folding of HIV-1 PR dimer is studied with several
      simulation models appropriate for folding mechanism studies. Simulations with an
      off-lattice Go-model, which corresponds to a perfectly funneled energy landscape,
      indicate that the enzyme is formed by association of structured monomers. All
      atom molecular dynamics simulations strongly support the stability of an isolated
      monomer. The conjunction of results from a model that focuses on the protein
      topology and a detailed all-atom force-field model suggests, in contradiction to
      some reported equilibrium denaturation experiments, that monomer folding and
      dimerization are decoupled. The simulation result is, however, in agreement with
      the recent NMR detection of folded monomers of HIV-1 PR mutants with a
      destabilized interface. Accordingly, the design of dimerization inhibitors should
      not focus only on the flexible N and C termini that constitute most of the dimer
      interface, but also on other structured regions of the monomer. In particular,
      the relatively high phi values for residues 23-35 and 79-87 in both the folding
      and binding transition states, together with their proximity to the interface,
      highlight them as good targets for inhibitor design.

PMID- 15184024
TI  - Directed evolution of soluble single-chain human class II MHC molecules.
AB  - Major histocompatibility complex (MHC) class II molecules are membrane-anchored
      heterodimers that present antigenic peptides to T cells. Expression of these
      molecules in soluble form has met limited success, presumably due to their large
      size, heterodimeric structure and the presence of multiple disulfide bonds. Here
      we have used directed evolution and yeast surface display to engineer soluble
      single-chain human lymphocyte antigen (HLA) class II MHC DR1 molecules without
      covalently attached peptides (scDR1alphabeta). Specifically, a library of mutant
      scDR1alphabeta molecules was generated by random mutagenesis and screened by
      fluorescence activated cell sorting (FACS) with DR-specific conformation
      sensitive antibodies, yielding three well-expressed and properly folded
      scDR1alphabeta variants displayed on the yeast cell surface. Detailed analysis of
      these evolved variants and a few site-directed mutants generated de novo
      indicated three amino acid residues in the beta1 domain are important for the
      improved protein folding yield. Further, molecular modeling studies suggested
      these mutations might increase the protein folding efficiency by improving the
      packing of a hydrophobic core in the alpha1beta1 domain of DR1. The
      scDR1alphabeta mutants displayed on the yeast cell surface are remarkably stable
      and bind specifically to DR-specific peptide HA(306-318) with high sensitivity
      and rapid kinetics in flow cytometric assays. Moreover, since the expression,
      stability and peptide-binding properties of these mutants can be directly assayed
      on the yeast cell surface using immuno-fluorescence labeling and flow cytometry,
      time-consuming purification and refolding steps of recombinant DR1 molecules are
      eliminated. Therefore, these scDR1alphabeta molecules will provide a powerful
      technology platform for further design of DR1 molecules with improved peptide
      binding specificity and affinity for therapeutic and diagnostic applications. The
      methods described here should be generally applicable to other class II MHC
      molecules and also class I MHC molecules for their functional expression,
      characterization and engineering.

PMID- 15184025
TI  - Molecular and biophysical characterization of assembly-starter units of human
      vimentin.
AB  - We have developed an assembly protocol for the intermediate filament (IF) protein
      vimentin based on a phosphate buffer system, which enables the dynamic formation
      of authentic IFs. The advantage of this physiological buffer is that analysis of
      the subunit interactions by chemical cross-linking of internal lysine residues
      becomes feasible. By this system, we have analyzed the potential interactions of
      the coiled-coil rod domains with one another, which are assumed to make a crucial
      contribution to IF formation and stability. We show that headless vimentin, which
      dimerizes under low salt conditions, associates into tetramers of the A(22)-type
      configuration under assembly conditions, indicating that one of the effects of
      increasing the ionic strength is to favor coil 2-coil 2 interactions.
      Furthermore, in order to obtain insight into the molecular interactions that
      occur during the first phase of assembly of full-length vimentin, we employed a
      temperature-sensitive variant of human vimentin, which is arrested at the "unit
      length filament" (ULF) state at room temperature, but starts to elongate upon
      raising the temperature to 37 degrees C. Most importantly, we demonstrate by
      cross-linking analysis that ULF formation predominantly involves A(11)-type dimer
      dimer interactions. The presence of A(22) and A(12) cross-linking products in
      mature IFs, however, indicates that major rearrangements do occur during the
      longitudinal annealing and radial compaction steps of IF assembly.

PMID- 15184026
TI  - Multiple probes reveal a native-like intermediate during low-temperature
      refolding of ubiquitin.
AB  - We investigate the refolding of ubiquitin Phe45Trp/Ile61Ala (Ub(*)I61A) in a low
      temperature, high-viscosity buffer, where folding is slowed so that apparent two
      state and three-state mechanisms are readily distinguishable. Ub(*)I61A forms a
      compact ensemble rapidly (as judged from stopped-flow, small-angle X-ray
      scattering) with a secondary structure signature similar to that of the native
      state (as judged from stopped-flow circular dichroism from 215 nm to 250 nm), but
      the fluorescence signature still resembles the guanidinium-denatured state. The
      compact ensemble forms over a range of solvent and temperature conditions. The
      native fluorescence signature, which requires the tryptophan residue to be packed
      tightly, is acquired at least 500 times more slowly. Molecular dynamics
      simulations at 495 K show no contraction of the backbone in ethylene glycol
      buffer compared to pure aqueous buffer, and no significant effect on the local
      backbone structure of the unfolded protein. Only at higher simulation temperature
      does a backbone contraction appear. Thus, it appears unlikely that the aqueous
      ethylene glycol buffer fundamentally changes the folding mechanism of ubiquitin.
      We suggest that ubiquitin forms a compact ensemble with native-like secondary
      structure, but without tight packing, long before the native state.

PMID- 15184027
TI  - Rapid self-assembly of alpha-synuclein observed by in situ atomic force
      microscopy.
AB  - Self-assembly of alpha-synuclein resulting in protein aggregates of diverse
      morphology has been implicated in the pathogenesis of Parkinson's disease and
      other neurodegenerative disorders known as synucleinopathies. Apart from its
      biomedical relevance, this aggregation process is representative of the
      interconversion of an unfolded protein into nanostructures with typical amyloid
      features. We have used in situ tapping mode atomic force microscopy to
      continuously monitor the self-assembly of wild-type alpha-synuclein, its disease
      related mutants A30P and A53T, and the C-terminally truncated variant alpha
      synuclein(1-108). Different aggregation modes were observed depending on
      experimental conditions, i.e. pH, protein concentration, polyamine concentration,
      temperature and the supporting substrate. At pH 7.5, in the absence of the
      biogenic polyamines spermidine or spermine, elongated sheets 1.1(+/-0.2)nm in
      height and presumably representing individual beta-sheet structures, were formed
      on mica substrates within a few minutes. Their orientation was directed by the
      crystalline substructure of the substrate. In contrast, sheet formation was not
      observed with hydrophobic highly oriented pyrolytic graphite substrates,
      suggesting that negatively charged surfaces promote alpha-synuclein self
      assembly. In the presence of spermidine or spermine 5.9(+/-1.0)nm high spheroidal
      structures were preferentially formed, sharing characteristics with similar
      structures previously reported for several amyloidogenic proteins and linked to
      neurotoxicity. alpha-Synuclein spheroid formation depended critically on
      polyamine binding to the C terminus, revealing a promoting effect of the C
      terminus on alpha-synuclein assembly in the bound state. In rare cases, fibril
      growth from spheroids or preformed aggregates was observed. At pH 5.0, fibrils
      were formed initially and incorporated into amorphous aggregates in the course of
      the aggregation process, providing evidence for the potential of amyloid fibril
      surfaces to act as nucleation sites in amorphous aggregation. This study provides
      a direct insight into different modes of alpha-synuclein self-assembly and
      identifies key factors modulating the aggregation process.

PMID- 15184028
TI  - The roles of ribosomal proteins in the structure assembly, and evolution of the
      large ribosomal subunit.
AB  - The structures of ribosomal proteins and their interactions with RNA have been
      examined in the refined crystal structure of the Haloarcula marismortui large
      ribosomal subunit. The protein structures fall into six groups based on their
      topology. The 50S subunit proteins function primarily to stabilize inter-domain
      interactions that are necessary to maintain the subunit's structural integrity.
      An extraordinary variety of protein-RNA interactions is observed. Electrostatic
      interactions between numerous arginine and lysine residues, particularly those in
      tail extensions, and the phosphate groups of the RNA backbone mediate many
      protein-RNA contacts. Base recognition occurs via both the minor groove and
      widened major groove of RNA helices, as well as through hydrophobic binding
      pockets that capture bulged nucleotides and through insertion of amino acid
      residues into hydrophobic crevices in the RNA. Primary binding sites on
      contiguous RNA are identified for 20 of the 50S ribosomal proteins, which along
      with few large protein-protein interfaces, suggest the order of assembly for some
      proteins and that the protein extensions fold cooperatively with RNA. The
      structure supports the hypothesis of co-transcriptional assembly, centered around
      L24 in domain I. Finally, comparing the structures and locations of the 50S
      ribosomal proteins from H.marismortui and D.radiodurans revealed striking
      examples of molecular mimicry. These comparisons illustrate that identical RNA
      structures can be stabilized by unrelated proteins.

PMID- 15184029
TI  - LGL: creating a map of protein function with an algorithm for visualizing very
      large biological networks.
AB  - Networks are proving to be central to the study of gene function, protein-protein
      interaction, and biochemical pathway data. Visualization of networks is important
      for their study, but visualization tools are often inadequate for working with
      very large biological networks. Here, we present an algorithm, called large graph
      layout (LGL), which can be used to dynamically visualize large networks on the
      order of hundreds of thousands of vertices and millions of edges. LGL applies a
      force-directed iterative layout guided by a minimal spanning tree of the network
      in order to generate coordinates for the vertices in two or three dimensions,
      which are subsequently visualized and interactively navigated with companion
      programs. We demonstrate the use of LGL in visualizing an extensive protein map
      summarizing the results of approximately 21 billion sequence comparisons between
      145579 proteins from 50 genomes. Proteins are positioned in the map according to
      sequence homology and gene fusions, with the map ultimately serving as a
      theoretical framework that integrates inferences about gene function derived from
      sequence homology, remote homology, gene fusions, and higher-order fusions. We
      confirm that protein neighbors in the resulting map are functionally related, and
      that distinct map regions correspond to distinct cellular systems, enabling a
      computational strategy for discovering proteins' functions on the basis of the
      proteins' map positions. Using the map produced by LGL, we infer general
      functions for 23 uncharacterized protein families.

PMID- 15184030
TI  - Microanatomy of dendritic spines: emerging principles of synaptic pathology in
      psychiatric and neurological disease.
AB  - Psychiatric and neurologic disorders ranging from mental retardation to addiction
      are accompanied by structural and functional alterations of synaptic connections
      in the brain. Such alterations include abnormal density and morphology of
      dendritic spines, synapse loss, and aberrant synaptic signaling and plasticity.
      Recent work is revealing an unexpectedly complex biochemical and subcellular
      organization of dendritic spines. In this review, we highlight the molecular
      interplay between functional domains of the spine, including the postsynaptic
      density, the actin cytoskeleton, and membrane trafficking domains. This research
      points to an emerging level of analysis--a microanatomical understanding of
      synaptic physiology--that will be critical for discerning how synapses operate in
      normal physiologic states and for identifying and reversing microscopic changes
      in psychiatric and neurologic disease.

PMID- 15184031
TI  - Pyramidal cell size reduction in schizophrenia: evidence for involvement of
      auditory feedforward circuits.
AB  - BACKGROUND: Subjects with schizophrenia have decreased gray matter volume of
      auditory cortex in structural imaging studies and exhibit deficits in auditory
      sensory processing that might reflect impairments of feedforward and/or feedback
      circuits within the auditory cortex. Recently, we reported that one component of
      these circuits, pyramidal cells in deep layer 3 of the auditory association
      cortex (area 42), has reduced mean somal volume in subjects with schizophrenia.
      To discriminate between involvement of feedforward and feedback circuit
      components, we examined pyramidal cell somal volume in layer 3 of primary
      auditory cortex (feedforward) and layer 5 of auditory association cortex
      (feedback). METHODS: We estimated somal volumes of pyramidal neurons in deep
      layer 3 of area 41 and layer 5 of area 42 in subjects with schizophrenia (area
      41, n = 16; area 42, n = 18), each of whom was matched to one normal comparison
      subject for gender, age, and postmortem interval. RESULTS: In deep layer 3 of
      area 41, mean pyramidal cell somal volume was significantly reduced, by 10.4%. No
      significant reduction was present in layer 5 of area 42. CONCLUSIONS: Pyramidal
      cell somal volume is reduced in layer 3 of area 41 and area 42, but not in layer
      5 of area 42, of subjects with schizophrenia. This pattern of abnormalities is
      consistent with impairments of auditory feedforward projection neurons.

PMID- 15184032
TI  - Reduced frontal white matter integrity in early-onset schizophrenia: a
      preliminary study.
AB  - BACKGROUND: Research suggests that brain frontal white matter (WM) might be
      qualitatively altered in adolescents with early onset schizophrenia (EOS).
      Diffusion tensor imaging provides a relatively new approach for quantifying
      possible connectivity of WM in vivo. METHODS: Diffusion tensor imaging was used
      to examine the WM integrity of frontal regions at seven levels from 25 mm above
      to 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. Three
      other regions were examined: the occipital region at the AC-PC plane and the genu
      and splenium of the corpus callosum. Fractional anisotropy was compared between
      12 adolescents (nine male, 3 female) with EOS (onset of psychotic symptoms by age
      18 years) and nine age-similar healthy comparison subjects (six male, 3 female).
      RESULTS: Adolescents with EOS had significantly reduced fractional anisotropy in
      the frontal WM at the AC-PC plane in both hemispheres and in the occipital WM at
      the AC-PC plane in the right hemisphere. CONCLUSIONS: These preliminary data
      support a hypothesis that alterations in brain WM integrity occur in adolescents
      with EOS. Abnormalities found in this study were similar to those reported in
      adults with chronic schizophrenia. Additional studies are needed to assess
      whether there is progression of WM abnormalities in schizophrenia.

PMID- 15184033
TI  - Cerebellar dysfunction in neuroleptic naive schizophrenia patients: clinical,
      cognitive, and neuroanatomic correlates of cerebellar neurologic signs.
AB  - BACKGROUND: There is increasing evidence that, aside from motor coordination, the
      cerebellum also plays an important role in cognition and psychiatric disorders.
      Our previous studies support the hypothesis that cerebellar dysfunction may
      disrupt the cortico-cerebellar-thalamic-cortical circuit and, in turn, lead to
      cognitive dysmetria in schizophrenia. The goal of this study was to investigate
      cerebellar dysfunction in schizophrenia by examining the clinical, cognitive, and
      neuroanatomic correlates of cerebellar neurologic signs in schizophrenia
      patients. METHODS: We compared the prevalence of cerebellar neurologic signs in
      155 neuroleptic-naive schizophrenia patients against 155 age- and gender-matched
      healthy control subjects. Differences in clinical characteristics, standardized
      neuropsychologic performance, and magnetic resonance imaging brain volumes
      between patients with and without cerebellar signs were also examined. RESULTS:
      Patients had significantly higher rates of cerebellar signs than control
      subjects, with coordination of gait and stance being the most common
      abnormalities. Patients with lifetime alcohol abuse or dependence were no more
      likely than those without alcoholism to have cerebellar signs. Presence of
      cerebellar signs in patients was associated with poorer premorbid adjustment,
      more severe negative symptoms, poorer cognitive performance, and smaller
      cerebellar tissue volumes. CONCLUSIONS: These findings lend further support for
      cerebellar dysfunction in schizophrenia.

PMID- 15184034
TI  - Regional brain gray matter volume differences in patients with bipolar disorder
      as assessed by optimized voxel-based morphometry.
AB  - BACKGROUND: Structural magnetic resonance imaging (MRI) studies of regions of
      interest in brain have been inconsistent in demonstrating volumetric differences
      in subjects with bipolar disorder (BD). Voxel-based morphometry (VBM) provides an
      unbiased survey of the brain, can identify novel brain areas, and validates
      previously hypothesized regions. We conducted both optimized VBM, comparing MRI
      gray matter volume, and traditional VBM, comparing MRI gray matter density, in 11
      BD subjects and 31 healthy volunteers. To our knowledge, these are the first VBM
      analyses of BD. METHODS: Segmented MRI gray matter images were normalized into
      standardized stereotactic space, modulated to allow volumetric analysis
      (optimized only), smoothed, and compared at the voxel level with statistical
      parametric mapping. RESULTS: Optimized VBM showed that BD subjects had smaller
      volume in left ventromedial temporal cortex and bilateral cingulate cortex and
      larger volume in left insular/frontoparietal operculum cortex and left ventral
      occipitotemporal cortex. Traditional VBM showed that BD subjects had less gray
      matter density in left ventromedial temporal cortex and greater gray matter
      density in left insular/frontoparietal operculum cortex and bilateral thalamic
      cortex. Exploratory analyses suggest that these abnormalities might differ
      according to gender. CONCLUSIONS: Bipolar disorder is associated with volumetric
      and gray matter density changes that involve brain regions hypothesized to
      influence mood.

PMID- 15184035
TI  - Abnormal ventral frontal response during performance of an affective go/no go
      task in patients with mania.
AB  - BACKGROUND: Patients with mania show a behavioral bias toward positive
      information in an emotional go/no go task. This is the converse of the bias
      toward negative information seen in unipolar depression that we have recently
      related to the abnormal function of ventral and medial prefrontal cortices
      (PFCs). The aim of this study was to investigate the neuronal basis of the bias
      toward positive information in manic patients. METHODS: During performance of an
      emotional go/no go task using functional magnetic resonance imaging, 8 manic
      patients and 11 healthy controls were scanned. The task allowed comparison
      between neural response to happy, sad, and neutral words in the context of these
      words being either targets or distracters. RESULTS: Manic patients showed
      attenuated orbitofrontal response when all the semantic conditions were compared
      with a control condition; however, they showed an enhanced response of the left
      ventrolateral PFC to emotional relative to neutral targets, as well as enhanced
      ventral and medial prefrontal response to emotional, particularly happy,
      distracters. CONCLUSIONS: These results suggest a critical role for ventral and
      medial dysfunction in the pathology of mania, which might underpin aspects of
      cognitive and clinical symptomatology.

PMID- 15184036
TI  - The selective serotonin reuptake inhibitor citalopram increases fear after acute
      treatment but reduces fear with chronic treatment: a comparison with tianeptine.
AB  - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are efficacious in
      the treatment of a variety of fear or anxiety disorders. Although they inhibit
      the reuptake of serotonin within hours of administration, therapeutic improvement
      only occurs after several weeks. In this study, we used fear conditioning to
      begin to understand how acute and chronic SSRI treatment might differentially
      affect well-characterized fear circuits. METHODS: We evaluated the effects of
      acute and chronic treatment with the SSRI citalopram on the acquisition of
      auditory fear conditioning. To further understand the role of serotonin in
      modulating fear circuits, we compared these effects with those of acute and
      chronic administration of the antidepressant tianeptine, a purported serotonin
      reuptake enhancer. RESULTS: We found that acute administration of the SSRI
      citalopram enhanced acquisition, whereas chronic treatment reduced the
      acquisition of auditory fear conditioning. In comparison, treatment with
      tianeptine had no effect acutely but also reduced the acquisition of tone
      conditioning when administered chronically. CONCLUSIONS: Our findings with
      citalopram are consistent with the clinical effects of SSRI treatment seen in
      patients with anxiety disorders, in which anxiety is often increased during early
      stages of treatment and decreased after several weeks of treatment. The findings
      also indicate that auditory fear conditioning can be a useful tool in
      understanding differences in the effects of short-term and long-term
      antidepressant treatment with serotonergic medications.

PMID- 15184037
TI  - Anterior cingulate activation in high trait anxious subjects is related to
      altered error processing during decision making.
AB  - BACKGROUND: Individuals with high trait anxiety (HTA) can be studied to examine
      the effect of elevated levels of anxiety on the processing of stimuli and the
      selection of actions. The anterior cingulate cortex has been implicated in the
      detection and processing of errors. This investigation examined the hypothesis
      that HTA subjects are more sensitive to errors than nonanxious comparison
      subjects during a simple decision-making task and show increased activation in
      the anterior cingulate, particularly at low error rates. METHODS: Thirteen HTA
      subjects were compared with 13 normal trait anxiety (NTA: 40th-60th percentile)
      subjects during functional magnetic resonance imaging while performing a two
      choice prediction task at three different error rates. RESULTS: Both HTA and NTA
      subjects performed similarly during a simple two-choice prediction task; however,
      during the low-error-rate condition, activation in the anterior cingulate and
      medial prefrontal cortex was significantly higher in HTA subjects and was
      correlated with trait but not state anxiety. CONCLUSIONS: These results support
      the idea that HTA subjects devote more processing resources to decision making
      than do NTA subjects during times in which there is little chance of incorrect
      responding (i.e., the low-error-rate condition). The extent to which this altered
      activation within the anterior cingulate contributes to anxiety-proneness remains
      to be determined.

PMID- 15184038
TI  - Amphetamine pretreatment induces a change in both D2-Receptor density and
      apparent affinity: a [11C]raclopride positron emission tomography study in cats.
AB  - BACKGROUND: Measuring changes in dopamine (DA) levels in humans using radioligand
      displacement studies and positron emission tomography (PET) has provided
      important empirical findings in disease and normal neurophysiology. These studies
      are based on the assumption that DA exerts a competitive inhibition on
      radioligand binding. To test this, we used PET and a Scatchard approach to
      investigate whether the decrease in [11C]raclopride binding following amphetamine
      results from competitive or noncompetitive interactions with DA. METHODS:
      Scatchard analyses of [11C]raclopride/PET data were used to quantify changes in
      apparent D2-receptor density (Bmax) and radioligand apparent affinity (K'D) at
      baseline and after amphetamine pretreatment (2 mg/kg; intravenous) in cats.
      RESULTS: Amphetamine induced a 46% decrease in [11C]raclopride binding in the
      striatum of five cats. Scatchard analyses revealed that this decrease in binding
      was due to a 28% decrease in Bmax and a concomitant 35% increase in K'D.
      CONCLUSIONS: Competition with DA is an insufficient explanation for the decrease
      in [11C]raclopride binding observed after amphetamine. Noncompetitive
      interactions, likely representing D2-receptor internalization, also play an
      important role in this phenomenon. This finding may have important implications
      for the interpretation of amphetamine-raclopride PET studies in schizophrenia
      because dysregulation of the agonist-induced internalization of D2 receptors was
      recently suggested in this disorder.

PMID- 15184039
TI  - Weak prepulses inhibit but do not elicit startle in rats and humans.
AB  - BACKGROUND: Inhibition of startle by weak prestimuli is called prepulse
      inhibition (PPI). It has recently been reported that 10- to 20-dB prepulses
      trigger eye-blink motor activity and PPI in normal human subjects. Motor activity
      after prepulses correlated negatively with PPI in four of nine possible
      conditions. We now report the relationship between prepulse-elicited startle
      (PPES) and PPI using weak prepulses. METHODS: We assessed PPI and PPES using 1-
      to 5-dB prepulses in humans and in rats after treatment with vehicle or
      apomorphine. RESULTS: Prepulses inhibited startle in an intensity-dependent
      fashion but elicited no startle activity in humans or rats. Apomorphine
      eliminated PPI in rats and produced a well-documented increase in stimulus
      independent motor activity but did not stimulate PPES. CONCLUSIONS: In humans and
      rats, PPES is not a necessary condition for either the elicitation or the
      disruption of PPI.

PMID- 15184040
TI  - Nuclear receptor coregulators: their modification codes and regulatory mechanism
      by translocation.

PMID- 15184041
TI  - Soluble expression of aggregating proteins by covalent coupling to the ribosome.
AB  - Ribosomes are extremely soluble ribonucleoprotein complexes. Heterologous target
      proteins were fused to ribosomal protein L23 (rpL23) and expressed in an rpL23
      deficient Escherichia coli strain. This enabled the isolation of 70S ribosomes
      with covalently bound target protein. Isolation of recombinant proteins from 70S
      ribosomes was achieved by specific proteolytic cleavage followed by efficient
      removal of ribosomes by centrifugation. By this procedure we isolated active
      green fluorescent protein, streptavidin (SA), and murine interleukin-6 (mIL-6).
      Approximately 500microg of each protein was isolated per gram cellular wet
      weight. By pull-down assays we demonstrate that SA covalently bound to the
      ribosome binds d-biotin. Ribosomal coupling is therefore suggested as a method
      for the investigation of protein interactions. The presented strategy is in
      particular efficient for the expression, purification, and investigation of
      proteins forming inclusion bodies in the E. coli cytoplasm.

PMID- 15184042
TI  - Evidence showing an intermolecular interaction between KChIP proteins and Taiwan
      cobra cardiotoxins.
AB  - Direct protein-protein interaction between Taiwan cobra cardiotoxin3 (CTX3) and
      potassium channel-interacting proteins (KChIPs) was investigated in the present
      study. It was found that KChIPs bound with CTX3, in which KChIP and CTX3 formed a
      1:1 complex as evidenced by the results of chemical cross-linking. Pull-down
      assay revealed that the intact EF-hands 3 and 4 of KChIP1 were critical for CTX3
      binding. Likewise, removal of EF-hands 3 and 4 distorted the ability of KChIP1 to
      bind with Kv4.2 N-terminal fragment (KvN) as well as fluorescent probe 8
      anilinonaphthalene-1-sulfonate (ANS). In contrast to the interaction between
      KChIP1 and KvN, the binding of CTX3 to KChIP1 showed a Ca(2+)-independent manner.
      Fluorescence measurement revealed that CTX3 affected the binding of ANS to Ca(2+)
      bound KChIP1, but not Ca(2+)-free KChIP1. Alternatively, KChIP1 simultaneously
      bound with KvN and CTX3, and the interaction between KChIP1 and KvN was enhanced
      by CTX3. In terms of the fact that KChIPs regulate the electrophysiological
      properties of Kv K(+) channel, the potentiality of CTX for this biomedical
      application could be considered.

PMID- 15184044
TI  - Development of Abeta terminal end-specific antibodies and sensitive ELISA for
      Abeta variant.
AB  - Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory
      dysfunction. Senile plaques are a pathological hallmark of AD, and amyloid beta
      (Abeta) peptides are a major component of these plaques. Abeta peptides are
      derived from proteolytic cleavage of the Abeta protein precursor (APP) by beta-
      and gamma-secretases to generate two principal species, Abeta1-40 and Abeta1-42.
      We have developed antibodies against the N- and C-termini of these peptides, and
      an ELISA for accurate and sensitive quantitative assessment. Sandwich ELISA
      composed of N-terminus (Abeta1) end-specific antibody, clone 82E1, and C-termini
      end-specific antibodies, and clones 1A10 and 1C3 for Abeta40 and Abeta42,
      respectively, detects full-length Abeta1-40 and 1-42 with a sensitivity in the
      sub single digit fmol/ml (equivalent to single digit pg/ml) range with no cross
      reactivity to APP. A combination of C-termini antibodies and an antibody against
      the middle region of Abeta detects mouse Abeta in non-transgenic mouse brains.

PMID- 15184043
TI  - Crystal structure of the regulatory subunit of archaeal initiation factor 2B
      (aIF2B) from hyperthermophilic archaeon Pyrococcus horikoshii OT3: a proposed
      structure of the regulatory subcomplex of eukaryotic IF2B.
AB  - Eukaryotic translation initiation factor 2B (eIF2B) is the guanine-nucleotide
      exchange factor for eukaryotic initiation factor 2 (eIF2). eIF2B is a
      heteropentameric protein composed of alpha- subunits. The alpha, beta, and delta
      subunits form a regulatory subcomplex, while the gamma and form a catalytic
      subcomplex. Archaea possess homologues of alpha, beta, and delta subunits of
      eIF2B. Here, we report the three-dimensional structure of an archaeal regulatory
      subunit (aIF2Balpha) from the hyperthermophilic archaeon Pyrococcus horikoshii
      OT3 determined by X-ray crystallography at 2.2A resolution. aIF2Balpha consists
      of two subdomains, an N-domain (residues 1-95) and a C-domain (residues 96-276),
      connected by a long alpha-helix (alpha5: 78-106). The N-domain contains a five
      helix bundle structure, while the C-domain folds into the alpha/beta structure,
      thus showing similarity to D-ribose-5-phosphate isomerase structure. The presence
      of two molecules in the crystallographic asymmetric unit and the gel filtration
      analysis suggest a dimeric structure of aIF2Balpha in solution, interacting with
      each other by C-domains. Furthermore, the crystallographic 3-fold symmetry
      generates a homohexameric structure of aIF2Balpha; the interaction is primarily
      mediated by the long alpha-helix at the N-domains. This structure suggests an
      architecture of the three subunits, alpha, beta, and delta, in the regulatory
      subcomplex within eIF2B.

PMID- 15184045
TI  - Subcellular localization and transcriptional repressor activity of HBx on
      p21(WAF1/Cip1) promoter is regulated by ERK-mediated phosphorylation.
AB  - The protein encoded by the hepatitis B viral X-gene, HBx, is essential for viral
      infection and has been shown to regulate gene transcription and the Ras signaling
      pathway including Raf, MEK, and ERK. To better understand regulatory mechanism of
      HBx functions, we investigated whether ERK1/2-induced phosphorylation of HBx
      regulates its transcriptional activity on p21(WAF1/Cip1) promoter. HBx-genotype A
      (WT1) and its modified HBx (WT2; (38)SSPSPS(43) in WT1 was substituted by
      (38)PPSSPS(43) in HBx-genotype F) were phosphorylated by ERK1/2 in vitro,
      although their Ser --> Ala constructs, SA1 (S(43) of WT1 to A) and SA2 (S(41) of
      WT2 to A), were not. HBx WT1 and WT2, but not SA2, repressed transcription from
      the p21(WAF1/Cip1) promoter. This repression was blocked by treatment with
      PD98059, an inhibitor of MEK, or by overexpression of dominant negative MEK1.
      Furthermore, WT1 and WT2 localized predominantly in the nucleus, whereas SA1 and
      SA2 localized to the cytoplasm, suggesting that the subcellular localization of
      HBx is controlled by its phosphorylation. Overall, our findings provide insight
      that ERK1/2-mediated phosphorylation of HBx regulates HBx function and
      localization, and may contribute to dysregulation of cell cycle progression
      leading to hepatocarcinogenesis in HBV-infected cells.

PMID- 15184047
TI  - Estrogen receptor expression in a human primitive neuroectodermal tumor cell line
      from the cerebral cortex: estrogen stimulates rapid ERK1/2 activation and
      receptor-dependent cell migration.
AB  - Primitive neuroectodermal tumors (PNETs) are the most common form of pediatric
      brain tumor. Most often these malignant childhood brain tumors arise from
      neuroepithelial precursor cells in the cerebellum, and less frequently in the
      cerebral cortex. Because the normal PNET precursor cells from the cerebrum and
      cerebellum transiently express high levels of estrogen receptors (ERs), we
      hypothesized that the PNET cells of the cerebrocortical-derived cell line PFSK1
      may also express ERs and would be responsive to estrogen. Results of immunoblot
      studies using ER-specific antiserum indicate that both ERalpha and ERbeta are
      expressed in PFSK1 cells. The ability of estrogen to rapidly activate MAPK
      signaling was tested; low physiological concentrations of E(2) stimulated ERK1/2
      phosphorylation and nuclear translocation within 15min of exposure. Exogenously
      added 17beta-estradiol (E(2)) could not stimulate PFSK1 growth, however E(2)
      significantly increased PFSK1 cell migration, suggesting that rapid actions of
      E(2) and ER-mediated processes might contribute to the metastatic phenotype of
      some PNETs.

PMID- 15184046
TI  - Suppression of SARS-CoV entry by peptides corresponding to heptad regions on
      spike glycoprotein.
AB  - Heptad repeat regions (HR1 and HR2) are highly conserved sequences located in the
      glycoproteins of enveloped viruses. They form a six-helix bundle structure and
      are important in the process of virus fusion. Peptides derived from the HR
      regions of some viruses have been shown to inhibit the entry of these viruses.
      SARS-CoV was also predicted to have HR1 and HR2 regions in the S2 protein. Based
      on this prediction, we designed 25 peptides and screened them using a HIV
      luc/SARS pseudotyped virus assay. Two peptides, HR1-1 and HR2-18, were identified
      as potential inhibitors, with EC(50) values of 0.14 and 1.19microM, respectively.
      The inhibitory effects of these peptides were validated by the wild-type SARS-CoV
      assay. HR1-1 and HR2-18 can serve as functional probes for dissecting the fusion
      mechanism of SARS-CoV and also provide the potential of further identifying
      potent inhibitors for SARS-CoV entry.

PMID- 15184048
TI  - Quadruplex to Watson-Crick duplex transition of the thrombin binding aptamer: a
      fluorescence resonance energy transfer study.
AB  - Thermodynamic parameters of closing up of guanine-rich thrombin binding element,
      upon binding to K(+) and Na(+) ions to form quadruplexes and opening up of these
      quadruplexes upon binding to its complementary strand, were investigated. For
      this purpose, 15mer deoxynucleotide, d(G(2)T(2)G(2)TGTG(2)T(2)G(2)), labeled with
      5'-fluorescein and 3'-tetramethylrhodamine was taken and fluorescence resonance
      energy transfer was monitored as a function of either metal ions or complementary
      strand concentrations. Equilibrium association constant obtained from FRET
      studies demonstrates that K(+) ions bind with higher affinity than the Na(+)
      ions. The enthalpy changes, DeltaH, obtained from temperature dependence of
      equilibrium association constant studies revealed that formation of quadruplex
      upon binding of metal ions is primarily enthalpy driven. Binding studies of
      complementary strand to the quadruplex suggest that opening of a quadruplex in
      NaCl buffer in presence of the complementary strand is enthalpic as well as
      entropic driven and can occur easily, whereas opening of the same quadruplex in
      KCl buffer suffers from enthalpic barrier. Comparison of overall thermodynamic
      parameters along with kinetics studies indicates that, although quadruplexes
      cannot efficiently compete with duplex formation at physiological pH, they delay
      the association of two strands.

PMID- 15184049
TI  - Selective depletion of the Type I, Type II, and Type III isozymes of hexokinase
      in mammalian cells using small interfering RNAs.
AB  - Constructs based on the pSUPER vector [Science 296 (2002) 550] and encoding small
      interfering RNAs specific for the Type I, Type II, or Type III isozymes of
      mammalian (rat) hexokinase were prepared. Transfection of Chinese hamster ovary
      and HeLa cells with these vectors resulted in selective depletion of the
      respective isozymes. A Zeocin marker was incorporated into the modified pSUPER
      vector, permitting isolation of stably transfected cell lines selectively
      depleted of the respective isozyme.

PMID- 15184050
TI  - Identification of two novel markers for alveolar epithelial type I and II cells.
AB  - Alveolar epithelial type I and type II cells (AEC I and II) are closely aligned
      in alveolar surface. There is much interest in the precise identification of AEC
      I and II in order to separate and evaluate functional and other properties of
      these two cells. This study aims to identify specific AEC I and AEC II cell
      markers by DNA microarray using the in vitro trans-differentiation of AEC II into
      AEC I-like cells as a model. Quantitative real-time PCR confirmed five AEC I
      genes: fibroblast growth factor receptor-activating protein 1, aquaporin 5,
      purinergic receptor P2X 7 (P2X7), interferon-induced protein, and Bcl2-associated
      protein, and one AEC II gene: gamma-aminobutyric acid receptor pi subunit
      (GABRP). Immunostaining on cultured cells and rat lung tissue indicated that
      GABRP and P2X7 proteins were specifically expressed in AEC II and AEC I,
      respectively. In situ hybridization of rat lung tissue confirmed the localization
      of GABRP mRNA in type II cells. P2X7 and GABRP identified in this study could be
      used as potential AEC I and AEC II markers for studying lung epithelial cell
      biology and monitoring lung injury.

PMID- 15184052
TI  - Crystal structure of the ribonuclease P protein Ph1877p from hyperthermophilic
      archaeon Pyrococcus horikoshii OT3.
AB  - Ribonuclease P (RNase P) is a ribonucleoprotein complex involved in the
      processing of pre-tRNA. Protein Ph1877p is one of essential components of the
      hyperthermophilic archaeon Pyrococcus horikoshii OT3 RNase P [Biochem. Biophys.
      Res. Commun. 306 (2003) 666]. The crystal structure of Ph1877p was determined at
      1.8A by X-ray crystallography and refined to a crystallographic R factor of
      22.96% (Rfree of 26.77%). Ph1877p forms a TIM barrel structure, consisting of ten
      alpha-helices and seven beta-strands, and has the closest similarity to the TIM
      barrel domain of Escherichia coli cytosine deaminase with a root-mean square
      deviation of 3.0A. The protein Ph1877p forms an oblate ellipsoid, approximate
      dimensions being 45Ax43Ax39A, and the electrostatic representation indicated the
      presence of several clusters of positively charged amino acids present on the
      molecular surface. We made use of site-directed mutagenesis to assess the role of
      twelve charged amino acids, Lys42, Arg68, Arg87, Arg90, Asp98, Arg107, His114,
      Lys123, Lys158, Arg176, Asp180, and Lys196 related to the RNase P activity.
      Individual mutations of Arg90, Arg107, Lys123, Arg176, and Lys196 by Ala resulted
      in reconstituted particles with reduced enzymatic activities (32-48%) as compared
      with that reconstituted RNase P by wild-type Ph1877p. The results presented here
      provide an initial step for definite understanding of how archaeal and eukaryotic
      RNase Ps mediate substrate recognition and process 5'-leader sequence of pre
      tRNA.

PMID- 15184051
TI  - HSV-1 amplicon-mediated transfer of 128-kb BMP-2 genomic locus stimulates
      osteoblast differentiation in vitro.
AB  - In previous studies, we developed mouse genetic models and discovered genetic
      components of quantitative trait loci on mouse chromosomes that contribute to
      phenotypes such as bone size, bone density, and fracture healing. However, these
      regions contain dozens of genes in several overlapping bacterial artificial
      chromosomes (BACs) and are difficult to clone by physical cloning strategies. A
      feasible and efficient approach of identifying candidate genes is to transfer the
      genomic loci in BAC clones into mammalian cells for functional studies. In this
      study, we retrofitted a BAC construct into herpes simplex virus-1 amplicon and
      packaged it into an infectious BAC (iBAC) to test gene function in a cell-based
      system, using a 128-kb clone containing the complete bone morphogenetic protein-2
      (BMP-2) gene. We transduced MC3T3-E1 cells with the iBAC bearing BMP-2 gene and
      examined transgene expression and function. Our results have demonstrated that an
      iBAC can efficiently deliver a BMP-2 genomic locus into preosteoblast cells and
      express functional BMP-2 protein, inducing a phenotype of cell differentiation,
      as indicated by an increase in alkaline phosphatase activity. Therefore, this
      experimental system provides a rapid, efficient cell-based model of high
      throughput phenotypic screening to identify the BAC clones from physically mapped
      regions that are important for osteoblast differentiation. It also illustrates
      the potential of iBAC technology in functional testing of single nucleotide
      polymorphisms located in the distal promoter or/and intron regions responsible
      for low bone density.

PMID- 15184053
TI  - 14-3-3sigma is down-regulated in human prostate cancer.
AB  - The 14-3-3sigma is a negative regulator of the cell cycle, which is induced by
      p53 in response to DNA damage. It has been characterized as an epithelium
      specific marker and down-regulation of the protein has been shown in breast
      cancers, suggesting its tumor-suppressive activity in epithelial cells. Here we
      demonstrate that 14-3-3sigma protein is down-regulated in human prostate cancer
      cell lines, LNCaP, PC3, and DU145 compared with normal prostate epithelial cells.
      Immunohistochemical analysis of primary prostate cells shows that the expression
      of 14-3-3sigma protein is epithelial cell-specific. Among prostate pathological
      specimens, > 95% of benign hyperplasia samples show significant and diffuse
      immunostaining of 14-3-3sigma in the cytoplasm whereas < 20% of carcinoma samples
      show positive staining. In terms of mechanisms for the down-regulation of 14-3
      3sigma in prostate cancer cells, hypermethylation of the gene promoter plays a
      causal role in LNCaP cells as 14-3-3sigma mRNA level was elevated by 5-aza-2'
      deoxycytidine demethylating treatment. Intriguingly, the proteasome-mediated
      proteolysis is responsible for 14-3-3sigma reduction in DU145 and PC3 cells, as
      14-3-3sigma protein expression was increased by treatment with a proteasome
      inhibitor MG132. Furthermore, tumor necrosis factor-related apoptosis-inducing
      ligand enhances 14-3-3sigma gene and protein expression in DU145 and PC3 cells.
      These data suggest that 14-3-3sigma expression is down-regulated during the
      neoplastic transition of prostate epithelial cells.

PMID- 15184054
TI  - Cellular and plasma levels of human glutaredoxin 1 and 2 detected by sensitive
      ELISA systems.
AB  - Glutaredoxins (Grx) catalyze glutathione-dependent thiol-disulfide oxidoreduction
      reactions. Mammalian cells contain at least two dithiol glutaredoxins, the well
      characterized cytoplasmic (12kDa) Grx1 and the recently identified (18kDa) Grx2
      with mitochondrial and nuclear isoforms. We have developed two sensitive and
      specific sandwich ELISAs to study the levels of human Grx1 and Grx2. Both Grx1
      and Grx2 were present in placenta extracts and in cell lysates prepared from
      various tumor cell lines. However, the levels of Grx1 were at least 20 times
      higher than those of Grx2. Plasma from healthy blood donors contained 13.4+/
      7.9ng/ml of Grx1, while Grx2 was not detected. Unstimulated peripheral blood
      mononuclear cells were shown to secrete Grx1, but upon 12-O-tetradecanoylphorbol
      13-acetate activation, the secretion of Grx1 was strongly suppressed. This effect
      was shown to occur at the transcriptional level. The secretion of Grx1 and its
      presence in plasma suggests extracellular functions as found for mammalian
      thioredoxin 1.

PMID- 15184055
TI  - Proteomic analysis reveals a role for protein kinase C-alpha in phagosome
      maturation.
AB  - Acquisition of microbicidal properties by phagosomes requires the action of
      molecules which regulate the interactions between phagosomes and endocytic
      organelles. Members of the protein kinase C (PKC) superfamily of serine/threonine
      kinases are recruited to phagosomes with various kinetics during phagolysosome
      biogenesis. To study the role of PKC-alpha in this process, we compared the
      composition of latex bead-containing phagosomes isolated from control and
      dominant-negative (DN) PKC-alpha-overexpressing RAW 264.7 macrophages. Western
      blot analysis indicated that the levels of both lysosomal-associated membrane
      protein-1 and flotillin-1, which are acquired through interactions with late
      endosomes and lysosomes, are reduced in phagosomes from DN PKC-alpha
      overexpressing macrophages. Proteomic characterization of latex bead-containing
      phagosomes revealed that recruitment of the small GTPase Rab7, cathepsin D, and
      cathepsin S is inhibited by DN PKC-alpha. Collectively, these data provide
      evidence that PKC-alpha plays a role in phagolysosome biogenesis, a critical
      process of the innate immune response against infections.

PMID- 15184056
TI  - T47D breast cancer cell growth is inhibited by expression of VACM-1, a cul-5
      gene.
AB  - Vasopressin-activated calcium-mobilizing (VACM-1), a cul-5 gene, is localized on
      chromosome 11q22-23 close to the gene for Ataxia Telangiectasia in a region
      associated with a loss of heterozygosity in breast cancer tumor samples. To
      examine the biological role of VACM-1, we studied the effect of VACM-1 expression
      on cellular growth and gene expression in T47D breast cancer cells.
      Immunocytochemistry studies demonstrated that VACM-1 was expressed in 0.6-6% of
      the T47D cells and localized to the nucleus of mitotic cells. Overexpressing VACM
      1 significantly attenuated cellular proliferation and MAPK phosphorylation when
      compared to the control cells. In addition, VACM-1 decreased egr-1 and increased
      Fas-L mRNA levels. Further, egr-1 protein levels were significantly lower in the
      nuclear fraction from VACM-1 transfected cells when compared to controls. These
      data indicate that VACM-1 is involved in the regulation of cellular growth.

PMID- 15184057
TI  - Charge-based separation of detergent-resistant membranes of mouse splenic B
      cells.
AB  - Current biochemical characterization for cholesterol- and glycolipid-rich
      membrane microdomains largely depends on analysis of detergent-resistant
      membranes (DRMs). In the present study, we succeeded in separation of DRMs of
      similar density-based on their electrical charge using free-flow electrophoresis
      (FFE). After crosslinking of B cell receptor (BCR), mouse splenic B cells were
      lysed with 1% Brij-58 and the resulting lysate was subjected to sucrose density
      gradient ultracentrifugation. The low-density fraction that recovered a part of
      DRMs containing IgM together with those enriched in GM1a, the Src family protein
      tyrosine kinase Lyn, and the alpha subunit of inhibitory heterotrimeric GTP
      binding protein was further resolved by FFE. FFE separated the former into more
      cathodally deflected fractions than the latter. In addition, FFE revealed an
      anodal shift of DRMs containing a transmembrane protein CD38 upon BCR
      crosslinking. The results demonstrate the effectiveness of FFE for the charge
      based separation of DRMs.

PMID- 15184058
TI  - Langerhans cells exhibit low responsiveness to double-stranded RNA.
AB  - Double-stranded RNA (dsRNA) is a viral product recognized by Toll-like receptor 3
      (TLR3), and it is a potent activator of dendritic cells (DC). We compared
      Langerhans cells (LC) and splenic CD11c(+) DC and investigated the responsiveness
      to dsRNA. We prepared highly purified LC (> 95%) using the panning method. TLR3
      mRNA was expressed in LC, splenic DC, and keratinocytes (KC). The expression of
      IFN-beta mRNA was enhanced in LC and splenic DC by Poly(I:C) stimulation.
      However, cytokine/chemokine production in response to Poly(I:C) by LC was much
      lower than that by splenic DC. In addition, Poly(I:C) induced further maturation
      in splenic DC, but not in LC. Finally, we found that the mouse KC cell line,
      PAM212, produced a great amount of IL-1alpha by Poly(I:C) stimulation, and that
      IL-1alpha promoted the maturation of LC. These data altogether indicate that LC
      exhibit low responsiveness to dsRNA. It is possible that KC may primarily trigger
      anti-viral immune responses in the skin via cytokine production such as IL
      1alpha.

PMID- 15184059
TI  - The yeast genes, ARL1 and CCZ1, interact to control membrane traffic and ion
      homeostasis.
AB  - The yeast ARL1 gene, encoding a guanine-nucleotide binding protein of the Arf
      like family, exhibits a synthetic genetic interaction with CCZ1. An arl1 Delta
      ccz1 Delta double mutant was viable but grew slowly, was more sensitive to
      caffeine, Ca(2+), Zn(2+), and hygromycin B than either single mutant, and had a
      more severe vacuolar protein sorting phenotype. Overexpression of ARL1 did not
      suppress ccz1 Delta mutant phenotypes, nor did overexpression of CCZ1 suppress
      arl1 Delta mutant phenotypes. We conclude that ARL1 and CCZ1 independently
      contribute to both ion homeostasis and protein sorting.

PMID- 15184060
TI  - An anti-inflammatory role for N-acetyl aspartate in stimulated human astroglial
      cells.
AB  - Although N-acetyl-L-aspartate (NAA) has been shown to be important to myelin
      synthesis and osmotic regulation, the biological rationale for the high levels of
      NAA found in the brain remains unknown. Here, a human astroglial cell line (STTG)
      was treated with NAA and stimulated with ionomycin, ionomycin/PMA, or IL-1beta.
      PGE(2) levels in ionomycin-stimulated STTG cells decreased by 76% and > 95% at
      NAA concentrations of 10 and 20mM, respectively. NAA also decreased the levels of
      COX-2 protein and activated NF-kappaB in IL-1beta-stimulated STTG cells but had
      little effect on unstimulated cells. Also, NAA significantly decreased
      intracellular calcium levels in ionomycin/PMA-stimulated cells. NAA had no effect
      on total COX-2 activity or COX-2 mRNA. Acetylation of IkappaBalpha kinase, an
      acetylation target of aspirin, was not observed when NAA was present. These
      results demonstrate that NAA appears to be important in the modulation of
      inflammation in the human STTG astroglial cell line. The results of these
      findings are discussed in relation to neuronal pathologies that exhibit abnormal
      NAA levels within the brain.

PMID- 15184061
TI  - Esterase activity as a novel parameter of spore germination in Bacillus
      anthracis.
AB  - Spores of Bacillus anthracis were shown to produce esterase activity about 4 min
      after exposure to conventional germinants such as combinations of amino acids and
      purine ribosides. Neither amino acids nor ribosides alone induce germination and
      esterase activity. Expression of esterase activity was chloramphenicol resistant,
      and correlated with loss of spore refractivity, a traditional parameter of early
      germination. Based on these observations, we hypothesized that esterase activity
      could be used as a novel parameter for quantifying early events during spore
      germination. To test this hypothesis, we measured expression of esterase activity
      under a variety of germinating conditions. Using diacetyl fluorescein as
      fluorogenic substrate of esterases, we demonstrated that esterase activity was
      invariably induced whenever spores were triggered by known germinants. Moreover,
      D-alanine, an inhibitor of L-alanine-mediated germination, was found to
      significantly inhibit expression of esterase activity. In terms of molecular
      mechanisms, esterase expression could represent activation of proteases at the
      onset of spore germination.

PMID- 15184062
TI  - A new compound from Micromonospora sp. SA246, 9-hydroxycrisamicin-A, activates
      hepatitis B virus replication.
AB  - A new compound from Micromonospora sp. SA246, 9-hydroxycrisamicin-A (9-HCA-A),
      showed potential for activating hepatitis B virus (HBV) replication. To define
      the mechanism of 9-HCA-A, we used HepG2 2.2.15 cells which support HBV
      replication. 9-HCA-A activated HBV replication, increased episomal and integrated
      HBV DNA content, and increased secretions of HBV antigens (HBsAg and HBeAg) into
      culture medium. 9-HCA-A also activated HBV transcription in Hep2 2.2.15 cell
      line. To examine transcriptional control mechanisms, we analyzed the effect of 9
      HCA-A on four different HBV promoters (Core, PreS1, PreS2, and X) in hepatoma
      cell line. 9-HCA-A responsive element was located at HBx promoter. By EMSA, we
      showed that 9-HCA-A activated the HBx promoter by detaching the 9-HCA-A
      responsive element binding protein (9H-REBP). Protein phosphatase (PP2A1)
      treatment detaches the 9H-REBP from the HBx promoter, similar to 9-HCA-A, while
      protein kinase A treatment does not detach the 9H-REBP from the HBx promoter. Our
      results showed that 9H- REBP functions as a repressor of HBV replication while 9
      HCA-A activated protein phosphatase released the BP on the HBx promoter, thus
      activating HBV replication.

PMID- 15184063
TI  - A case-control study provides evidence of association for a functional
      polymorphism -197C/G in XBP1 to schizophrenia and suggests a sex-dependent
      effect.
AB  - Schizophrenia and bipolar disorder are two major psychiatric illnesses that may
      share specific genetic risk factors to a certain extent. Increasing evidence
      suggests that the two disorders might be more closely related than previously
      considered. In order to test this hypothesis, we investigated a functional
      polymorphism -197C/G in XBP1, which was reported to increase the risk of bipolar
      disorder, in a case-control study (374 cases vs. 371 controls) to evaluate its
      genetic role in the pathogenesis of schizophrenia. In the present study, this
      polymorphism was found to be associated with schizophrenia both at allele
      (P=0.034; OR=1.26, 95% CI 1.02-1.55) and genotype levels (GG vs. CG+CC, 47.59%
      vs. 38.81%; P=0.016, df=1; OR=1.43, 95% CI 1.07-1.92). Our current data suggest
      that -197C/G in XBP1 is also a genetic risk factor for schizophrenia. In
      addition, it presents a sex-dependent genetic effect for the disorder.

PMID- 15184064
TI  - Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac
      fibroblasts.
AB  - The protein product of growth arrest specific gene 6 (Gas6), is the biological
      ligand for the Axl subfamily of receptor tyrosine kinases. We investigated the
      effects of exogenous Gas6 on growth of cardiac fibroblasts isolated from
      genetically Gas6-deficient mice. Recombinant Gas6, containing N terminal gamma
      carboxyglutamic acid residues formed from a vitamin K-dependent reaction,
      stimulated both DNA synthesis and proliferation of cardiac fibroblasts under
      serum-free conditions. Gas6 also markedly enhanced survival of cells during
      prolonged serum starvation. Gas6 stimulated tyrosine phosphorylation of Axl as
      well as phosphorylation of ERK kinase. The mitogenic effects of Gas6 were
      inhibited by neutralising anti-Gas6 antibodies and by a soluble Axl ectodomain
      fusion protein. In contrast, recombinant Gas6 from cells treated with warfarin,
      which prevents the gamma-carboxylation reaction, neither stimulated fibroblast
      proliferation nor activated Axl tyrosine phosphorylation. Gas6-induced cell
      proliferation was additive to the effects of epidermal growth factor, suggesting
      activation of discrete signalling pathways. In conclusion, Gas6 appears to be a
      unique growth factor for fibroblasts and post-translational gamma-carboxylation
      is necessary for its biological activity. These findings implicate vitamin K
      dependent biochemical reactions in growth processes in development and in
      disease.

PMID- 15184065
TI  - Stable and strictly controlled expression of LTR-flanked autoregulated expression
      cassettes upon adenoviral transfer.
AB  - An autoregulatory bidirectional expression cassette encoding all components
      necessary for regulated gene expression in a one-step gene transfer was evaluated
      for use in adenoviral vectors. Adenoviral vectors transducing this cassette
      provide about 1000-fold regulation. Regulation could be further improved by
      integrating the cassette as a retroviral vector into the adenoviral backbone.
      Moreover, with these adeno/retroviral hybrid vectors, the frequency of
      chromosomal integration is enhanced and about 1% of infected cells show stable
      chromosomal integration of the autoregulated cassette. In these stably transduced
      cells high regulation capacity is maintained. To elucidate the molecular
      mechanism underlying this unexpected observation we investigated the regulation
      capacity of these cassettes in a viral and non-viral vector background after
      stable integration into the host's DNA. While naked cassettes show regulated
      expression that is strongly influenced by the chromosomal surrounding sequences
      the regulatory capacity of LTR flanked cassettes is highly comparable amongst
      different cell clones. This strict regulation with little influence from the
      flanking sequences is obtained when LTR-flanked cassettes are transduced as DNA,
      by retroviral or by adenoviral infection.

PMID- 15184066
TI  - Regulation of the phosphorylation of the inositol 1,4,5-trisphosphate receptor by
      protein kinase C.
AB  - The various inositol 1,4,5-trisphosphate receptor (IP(3)R) isoforms are potential
      substrates for several protein kinases. We compared the in vitro phosphorylation
      of purified IP(3)R1 and IP(3)R3 by the catalytic subunit of protein kinase C
      (PKC). Phosphorylation of IP(3)R1 by PKC was about eight times stronger than that
      of IP(3)R3 under identical conditions. Protein kinase A strongly stimulated the
      PKC-induced phosphorylation of IP(3)R1. In contrast, Ca(2+) inhibited its
      phosphorylation (IC(50)<or=2microM) and this inhibition was further potentiated
      by calmodulin (CaM), while the Ca(2+)-independent CaM mutant CaM(1234) was
      ineffective. Ca(2+) and CaM, however, did not inhibit IP(3)R3 phosphorylation by
      PKC. Taken together, these findings show that Ca(2+) and CaM differentially
      regulate the PKC-mediated phosphorylation of IP(3)R1 and IP(3)R3 and are
      indicative for a role for the inhibition of IP(3)R1 phosphorylation by Ca(2+) and
      CaM in the negative slope of the bell-shaped effect of Ca(2+) on IP(3)R function.

PMID- 15184067
TI  - N-Acetyl-L-cysteine prevents exercise-induced intestinal lymphocyte apoptosis by
      maintaining intracellular glutathione levels and reducing mitochondrial membrane
      depolarization.
AB  - Intense exercise leads to post-exercise lymphocytopenia and immunosuppression,
      possibly by triggering lymphocyte apoptosis. To test the role of oxidative stress
      on exercise-induced lymphocyte apoptosis, we administered the antioxidant N
      acetyl--cysteine (NAC) and measured apoptosis in intestinal lymphocytes (IL) from
      exhaustively exercised animals. Eighty-seven female C57BL/6 mice were randomly
      assigned to receive NAC (1 g/kg) or saline 30 min prior to treadmill exercise for
      90 min at 2degrees slope (30 min at 22 m min(-1), 30 min at 25 m min(-1), and 30
      min at 28 m min(-1)) and sacrificed immediately (Imm) or 24 hours (24 h) after
      cessation of exercise. Control mice (nonexercised) were exposed to treadmill
      noise and vibration without running. Exercise increased IL phosphatidylserine
      externalization (p<0.001), mitochondrial membrane depolarization (p<0.05), and
      decreased intracellular glutathione concentrations (p<0.05) immediately following
      exercise in saline relative to nonexercised mice. At 24 h post-exercise, saline
      injected mice had fewer total (p<0.001) and CD3+ (p<0.005) IL compared to
      nonexercised animals. NAC injection in mice maintained intracellular glutathione
      levels, prevented phosphatidylserine externalization, mitochondrial membrane
      depolarization, and loss of IL immediately and 24 h after exercise. These data
      suggest that lymphocyte apoptosis precedes post-exercise lymphocytopenia and may
      be due to oxidative stress.

PMID- 15184068
TI  - Kinetic analysis of catechin oxidation by polyphenol oxidase at neutral pH.
AB  - Catechin oxidation by peach polyphenol oxidase was performed in a pH range of 3.5
      8.0. At acidic pH, maximal spectral changes were observed at 390nm and at pH 7.5,
      at 430nm. Catechin oxidation was studied at pH 7.5 to avoid the formation of free
      radicals. The results obtained allowed us to propose a pathway for the enzymatic
      oxidation of catechin, according to which enzymatic oxidation produces the
      corresponding catechin-o-quinone, which suffers the nucleophilic attack of
      another catechin unit, leading to the formation of a dimer. This dimer is then
      oxidized by the enzymatically generated o-quinone. The progress curves obtained
      for catechin oxidation by PPO showed a lag period, whose length changed with
      enzyme and substrate concentrations, and which must have been caused by the
      chemical reactions taking place after the enzymatic reaction. The results
      obtained by simulation of the model produced the same qualitative dependences as
      obtained experimentally.

PMID- 15184069
TI  - Molecular cloning and biochemical characterization of Candida albicans acyl
      CoA:sterol acyltransferase, a potential target of antifungal agents.
AB  - To determine whether Candida albicans acyl CoA:sterol acyltransferase (ASAT) can
      be a potential target enzyme for the protoberberine derivative (HWY-289), we have
      isolated a gene encoding Ca-ASAT and examined inhibitory effects of HWY-289 on
      the overexpressed Ca-ASAT. HWY-289 specifically inhibits Ca-ASAT in a non
      competitive manner in vitro (IC(50) [9.2microM], K(i) [5.15microM]). The cloned
      CaARE2 gene (1830 nucleotides [nt]) encodes active Ca-ASAT protein that exhibits
      a calculated molecular mass of 71.3kDa. The amino acid sequence of CaAre2p is
      33.4% and 35.1% identical to those of Saccharomyces cerevisiae ScAre1p and
      ScAre2p homologues, respectively. Recombinant and endogenous Ca-ASAT displayed
      identical patterns of inhibition upon exposure to HWY-289 and a preference for
      cholesterol and oleoyl-CoA as substrates. Northern blot analysis showed that
      CaARE2 was activated by HWY-289, but not by CI-976 (a human acyl-coenzyme
      A:cholesterol acyltransferase inhibitor), in a dose-dependent manner (up to
      5mg/L), suggesting different selectivities of action between HWY-289 and CI-976
      on Ca-ASAT activity.

PMID- 15184070
TI  - IgSF13, a novel human inhibitory receptor of the immunoglobulin superfamily, is
      preferentially expressed in dendritic cells and monocytes.
AB  - A novel inhibitory receptor of immunoglobin superfamily (IgSF), IgSF member 13
      (IgSF13), has been identified from human dendritic cells (DC). IgSF13 is a type I
      transmembrane protein containing an N-terminal signal peptide, a extracellular
      region with a single Ig V-like domain, a transmembrane region, and a cytoplasmic
      tail with two classical immunoreceptor tyrosine-based inhibitory motifs (ITIM),
      suggesting its inhibitory function. IgSF13 shows significant homology to human
      CMRF35 and pIgR. IgSF13 gene is mapped to chromosome 17q25.2, very close to that
      of CMRF35. IgSF13 is preferentially expressed in myelo-monocytic cells, including
      monocytes, monocyte-derived DC, and monocyte-related cell lines. Upon pervanadate
      treatment, IgSF13 was hyper-phosphorylated and associated with Src homology-2
      domain-containing phosphatases SHP-1 and SHIP, but not SHP-2. The identification
      of IgSF13 as a novel ITIM-bearing receptor selectively expressed by DC and
      monocytes suggests that it may be potentially involved in the negative regulation
      of specific leukocyte population.

PMID- 15184071
TI  - Identification of two antigenic epitopes on SARS-CoV spike protein.
AB  - The spike (S) protein of severe acute respiratory syndrome-coronavirus (SARS-CoV)
      is a major virion structural protein. It plays an important role in interaction
      with receptor and inducing neutralizing antibodies. In the study, six tentative
      antigenic epitopes (S1 S2 S3 S4 S5 S6) of the spike protein of SARS-CoV were
      predicted by bio-informatics analysis, and a multi-epitope chimeric gene of S1-S2
      S3-S4-S5-S6 was synthesized and fused to downstream GST gene in pGEX-6p-1. The
      Western blotting demonstrated that SARS patient convalescent serum could
      recognize the recombinant fusion protein. A number of monoclonal antibodies were
      developed against the fusion protein. In further, the six predicted epitope genes
      were individually fused to GST of pGEX-6p-1 and expressed in Escherichia coli
      BL21, respectively. Among six fusion peptides, S5 reacted with monoclonal
      antibody D3C5 and S2 reacted with monoclonal antibody D3D1 against spike protein
      of SARS-CoV. The epitopes recognized by monoclonal antibodies D3C5 and D3D1 are
      linear, and correspond to 447-458 and 789-799 amino acids of spike protein of
      SARS-CoV, respectively. Identification of antigenic epitope of spike protein of
      SARS-CoV could provide the basis for the development of immunity-based
      prophylactic, therapeutic, and diagnostic techniques for the control of severe
      acute respiratory syndrome.

PMID- 15184072
TI  - Identification and characterization of taxilin isoforms.
AB  - The syntaxin family is implicated in intracellular vesicle traffic. We have
      recently identified taxilin, a novel syntaxin-binding protein, which has a long
      coiled-coil region in its C-terminal half. A database search has revealed the
      presence of two other molecules having a long coiled-coil region homologous to
      that of taxilin in mammals. Then, we here attempted to isolate and characterize
      the two molecules. Both the two molecules stoichiometrically interacted with
      several syntaxin family members. Then, we renamed original taxilin alpha-taxilin
      and named the two molecules beta- and gamma-taxilins, respectively. Beta-taxilin
      was a human homologue of chicken MDP77. Gamma-taxilin was an uncharacterized
      protein and Northern blot analysis revealed that gamma-taxilin was ubiquitously
      expressed. Beta- and gamma-taxilins preferentially interacted with syntaxin-1a
      and -4, respectively. The taxilin family members mutually interacted with the
      syntaxin family members. These results indicate that there is the taxilin family
      composed of at least three members in mammals.

PMID- 15184073
TI  - Apo cytochrome c inhibits caspases by preventing apoptosome formation.
AB  - Caspases are cysteine proteases and potent inducers of apoptosis. Their
      activation and activity is therefore tightly regulated. There are several
      mechanisms by which caspases can be activated but one key pathway involves
      release of holo cytochrome c from mitochondria into the cytoplasm. Cytoplasmic
      holo cytochrome c binds to apoptotic protease activating factor-1 (Apaf-1),
      driving the formation of an Apaf-1 oligomer (the apoptosome) which in turn binds
      and activates caspase-9. Previously we showed that the apo form of cytochrome c
      (lacking heme) can bind Apaf-1 and block both holo-dependent caspase activation
      in cell extracts and Bax-induced apoptosis in cells. Here we tested the ability
      of apo cytochrome c to inhibit caspase-9 activation induced by recombinant Apaf
      1. Furthermore, using purified proteins and size exclusion chromatography we show
      that apo cytochrome c prevents holo cytochrome c-dependent apoptosome formation.

PMID- 15184074
TI  - Mechanical regulation of HB-GAM expression in bone cells.
AB  - Bone adaption upon mechanical stimulation is accompanied by changes in gene
      expression. In this context we investigated the influence of mechanical loading
      on heparin binding growth associated molecule (HB-GAM) expression, an
      extracellular matrix molecule which in cell culture has been shown to stimulate
      the differentiation of osteoblasts. We obtained information on the participating
      signal transduction pathways using a mitogenic loading regimen. Specific
      inhibitors of various signal transduction pathways were added to loaded cells and
      to unloaded controls. By semi-quantitative PCR studies we demonstrated a rapid
      decrease of HB-GAM expression in primary osteoblasts and SaOs-2 cells by 20-30%
      upon mechanical loading within 30min. We showed that the RGD-integrin interaction
      is involved in the regulation of HB-GAM expression. Furthermore, integrity of the
      cytoskeleton, stretch-activated, and voltage-sensitive Ca(2+) channels as well as
      gap junctional communication are necessary for the downregulation of HB-GAM
      expression by mechanical loading.

PMID- 15184075
TI  - Quantitative analysis of the interaction between the envelope protein domains and
      the core protein of human hepatitis B virus.
AB  - Interaction between preformed nucleocapsids and viral envelope proteins is
      critical for the assembly of virus particles in infected cells. The pre-S1 and
      pre-S2 and cytosolic regions of the human hepatitis B virus envelope protein had
      been implicated in the interaction with the core protein of nucleocapsids. The
      binding affinities of specific subdomains of the envelope protein to the core
      protein were quantitatively measured by both ELISA and BIAcore assay. While a
      marginal binding was detected with the pre-S1 or pre-S2, the core protein showed
      high affinities to pre-S with apparent dissociation constants (K(D)(app)) of
      7.3+/-0.9 and 8.2+/-0.4microM by ELISA and BIAcore assay, respectively. The
      circular dichroism analysis suggested that conformational change occurs in pre-S
      through interaction with core protein. These results substantiate the importance
      of specific envelope domains in virion assembly, and demonstrate that the
      interaction between viral proteins can be quantitatively measured in vitro.

PMID- 15184076
TI  - Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of
      synthetic PPAR-ligands: biochemical and pharmacological implications.
AB  - Peroxisome proliferator activated receptors (PPARs) are a class of nuclear
      receptors involved in lipid and glucidic metabolism, immune regulation, and cell
      differentiation. Many of their biological activities have been studied by using
      selective synthetic activators (mainly fibrates and thiazolidinediones) which
      have been already employed in therapeutic protocols. Both kinds of drugs,
      however, showed pharmacotoxicological profiles, which cannot be ascribed by any
      means to receptor activation. To better understand these non-receptorial or
      extrareceptorial aspects, the effect of different PPAR-ligands on the metabolic
      status of human HL-60 cell line has been investigated. At this regard, NMR
      analysis of cell culture supernatants was accomplished in order to monitor
      modifications at the level of cell metabolism. Cell growth and chemiluminescence
      assays were employed to verify cell differentiation. Results showed that all the
      considered PPAR-ligands, although with different potencies and independently from
      their PPAR binding specificity, induced a significant derangement of the
      mitochondrial respiratory chain consisting in a strong inhibition of NADH
      cytochrome c reductase activity. This derangement has been shown to be strictly
      correlated to the adaptive metabolic modifications, as evidenced by the increased
      formation of lactate and acetate, due to the stimulation of anaerobic glycolysis
      and fatty acid beta-oxidation. It is worthy noting that the mitochondrial
      dysfunction appeared also linked to the capacity of any given PPAR-ligand to
      induce cell differentiation. These data could afford an explanation of
      biochemical and toxicological aspects related to the therapeutic use of synthetic
      PPAR-ligands and suggest a revision of PPAR pathophysiologic mechanisms.

PMID- 15184077
TI  - Exocrine pancreatic secretion of phospholipid, menaquinone-4, and caveolin-1 in
      vivo.
AB  - The exocrine pancreas releases secretory products essential for nutrient
      assimilation. In addition to digestive enzymes, the release of lipoprotein-like
      particles containing the membrane trafficking protein caveolin-1 from isolated
      pancreatic explants has been reported. The present study examined: (1) if
      gastrointestinal hormones induce the apical secretion of phospholipid in vivo and
      (2) a potential association of caveolin-1 and the lipid-soluble vitamin K analog
      menaquinone-4 (MK-4) with these structures. Analysis of isolated acinar cells,
      purified zymogen granules, and pancreatic juice collected in vivo indicated the
      presence a caveolin-1 immunoreactive protein that was acutely released in
      response hormone stimulation. Chloroform-extracted fractions of pancreatic juice
      also contained high concentrations of MK-4 that was secreted in parallel to
      protein and phospholipid. The presence of caveolin-1 and MK-4 in the phospholipid
      fraction of pancreatic juice places these molecules in the secretory pathway of
      exocrine cells and suggests a physiological role in digestive enzyme synthesis
      and/or processing.

PMID- 15184078
TI  - Triptolide (PG-490) induces apoptosis of dendritic cells through sequential p38
      MAP kinase phosphorylation and caspase 3 activation.
AB  - Dendritic cells (DCs) are the most potent antigen-presenting cells that play
      crucial roles in the regulation of immune response. Triptolide, an active
      component purified from the medicinal plant Tripterygium wilfordii Hook F., has
      been demonstrated to act as a potent immunosuppressive drug capable of inhibiting
      T cell activation and proliferation. However, little is known about the effects
      of triptolide on DCs. The present study shows that triptolide does not affect
      phenotypic differentiation and LPS-induced maturation of murine DCs. But
      triptolide can dramatically reduce cell recovery by inducing apoptosis of DCs at
      concentration as low as 10ng/ml, as demonstrated by phosphatidylserine exposure,
      mitochondria potential decrease, and nuclear DNA condensation. Triptolide induces
      activation of p38 in DCs, which precedes the activation of caspase 3. SB203580, a
      specific kinase inhibitor for p38, can block the activation of caspase 3 and
      inhibit the resultant apoptosis of DCs. Our results suggest that the anti
      inflammatory and immunosuppressive activities of triptolide may be due, in part,
      to its apoptosis-inducing effects on DCs.

PMID- 15184079
TI  - The ribosome receptor, p180, interacts with kinesin heavy chain, KIF5B.
AB  - The conventional microtubule-dependent motor protein kinesin consists of heavy
      and light chains both of which have been documented to bind a variety of
      potential linker or cargo proteins. In this study we employed a yeast two-hybrid
      assay to identify additional binding partners of the kinesin heavy chain isoform
      KIF5B. A human brain cDNA library was screened with a bait corresponding to amino
      acid residues 814-963 of human KIF5B. This screen identified the ribosome
      receptor, p180, as a KIF5B-binding protein. The sites of interaction are residues
      1294-1413 of p180 and the C-terminal half of the cargo binding-domain of KIF5B
      (residues 867-907). The KIF5B-binding site in p180 is homologous to the
      previously determined KIF5B-binding site in kinectin. The interacting regions of
      p180 and KIF5B consist almost entirely of heptad repeats, suggesting the
      interaction is a coiled-coil. A role for the kinesin/p180 interaction may include
      mRNA localization and/or transport of endoplasmic reticulum-derived vesicles.

PMID- 15184080
TI  - The retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y
      cell line as a model for Alzheimer's disease-like tau phosphorylation.
AB  - The paired helical filaments of highly phosphorylated tau protein are the main
      components of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). Protein
      kinases including glycogen synthase kinase 3 beta (GSK3beta), cyclin-dependent
      kinase 5 (Cdk5), and c-Jun N-terminal kinase (JNK) have been implicated in NFT
      formation making the use of selective kinase inhibitors an attractive treatment
      possibility in AD. When sequentially treated with retinoic acid (RA) and brain
      derived neurotrophic factor (BDNF), the human neuroblastoma SH-SY5Y
      differentiates to neuron-like cells. We found that coincident with
      morphologically evident neurite outgrowth, both the content and phosphorylation
      state of tau increased in RA-BDNF differentiated SH-SY5Y cells. Tau
      phosphorylation increased at all the examined sites ser-199, ser-202, thr-205,
      ser-396, and ser-404, all of which are hyperphosphorylated in AD brain. We also
      investigated whether GSK3beta, Cdk5 or JNK was involved in tau phosphorylation in
      the differentiated SH-SY5Y cells. We found that GSK3beta contributed most and
      that Cdk5 made a minor contribution. JNK was not involved in tau phosphorylation
      in this system. The GSK3beta-inhibitor, lithium, inhibited tau phosphorylation in
      a concentration-dependent manner and with good reproducibility, which enables
      ranking of substances in this cell model. RA-BDNF differentiated SH-SY5Y cells
      could serve as a suitable model for studying the mechanisms of tau
      phosphorylation and for screening potential GSK3beta inhibitors.

PMID- 15184081
TI  - Cloning of IP15, a pancreatitis-induced gene whose expression inhibits cell
      growth.
AB  - We describe the cloning and expression of the mouse gene interferon-inducible
      protein 15 (IP15), whose activation is related to the acute phase of experimental
      pancreatitis. Analysis of its structure indicates that it encodes a putative
      transmembrane protein of 137 amino acids. This gene contains a predicted IFN
      stimulable-response element. In vivo studies showed that IP15 is strongly
      activated in pancreas early during caerulein-induced pancreatitis. In situ
      hybridization of IP15 mRNA showed that its expression is restricted to acinar
      cells. IP15 was also induced in pancreas under systemic-lipopolysaccharide
      treatment and in intestine under Salmonella infection. In vitro studies using
      NIH3T3 fibroblasts showed that IP15 is induced by IFN-alpha. Growth rate was
      significantly lower in cells transfected with pcDNA4/IP15 plasmid. In addition,
      cells expressing IP15 showed less capacity to develop colonies after antibiotic
      selection. In conclusion, we identified a new interferon-inducible gene that is
      activated early in pancreas with pancreatitis and whose expression inhibits cell
      growth.

PMID- 15184082
TI  - Sequence divergence of Entamoeba histolytica tubulin is responsible for its
      altered tertiary structure.
AB  - Atypical microtubular structures of the protozoan parasite Entamoeba histolytica
      (Eh) have been attributed to amino acid sequence divergence of Eh tubulin. To
      investigate if this sequence divergence leads to significant differences in the
      tertiary structure of the Eh alphabeta-tubulin heterodimer, we have modeled
      alphabeta-tubulin heterodimer of Eh based on the crystal structure of mammalian
      tubulin. The predicted 3D homology model exhibits an overall resemblance with the
      known crystal structure of mammalian tubulin except for the 16 residue long
      carboxy terminal region of Eh beta-tubulin. We propose that this C-terminal
      region may provide steric hindrance in the polymerization of Eh alphabeta-tubulin
      for microtubule formation. Using docking studies, we have identified the binding
      sites for different microtubule specific drugs on Eh beta-tubulin. Our model
      provides a rational framework, both for understanding the contribution of Eh beta
      tubulin C-terminal region to alphabeta-tubulin polymerization and design of new
      anti-protozoan drugs in order to control amoebiasis.

PMID- 15184083
TI  - Cloning and characterization of two thermostable xylanases from an alkaliphilic
      Bacillus firmus.
AB  - Two genes encoding thermostable xylanases, named xyn10A and xyn11A, from an
      alkaliphilic Bacillus firmus were cloned and expressed in Escherichia coli. The
      E. coli harboring either gene showed clear zone with Congo red clearance assay on
      xylan plate. The Xyn10A and Xyn11A have molecular weights of 45 and 23kDa,
      respectively, and both show activities on xylan-zymogram. The xyn10A encodes 396
      amino acid residues and is very similar to an alkaliphilic xylanase A from
      alkaliphilic Bacillus halodurans. The Xyn11A contains 210 amino acid residues and
      only one amino acid different from an endo-beta-1,4-xylanase from B. halodurans.
      From alignment of the amino acid sequences with other xylanases, Xyn10A and
      Xyn11A belong to family 10 and 11 glycosyl hydrolases, respectively. Both show
      activities over the pH range of 4-11 at 37 degrees C and over 80% activities at
      70 degrees C. Interestingly both still retain over 70% activities after 16h
      preincubation at 62 degrees C.

PMID- 15184084
TI  - A glutathione-S-transferase-FSHalpha subunit hybrid associates with FSHbeta,
      retains biological activity, and facilitates purification.
AB  - The glycoprotein hormones are heterodimeric proteins that share a common alpha
      subunit and have unique beta subunits that confer receptor selectivity. One
      member of this family, follicle-stimulating hormone (FSH), is secreted by the
      pituitary and is involved in the control of male and female reproduction. Herein,
      we describe the construction of baculoviruses for glutathione-S-transferase (GST)
      fusions of the human FSH (hFSH) subunits and their expression in insect cells,
      either alone or with the complementary non-fused FSH subunits (FSHalpha or
      FSHbeta). Only the GST-BV-hFSHalpha monomer and the GST-BV-hFSHalpha/BV-hFSHbeta
      (GST-BV-hFSH) heterodimer were efficiently secreted into the culture supernatant.
      The hybrid molecule, GST-BV-hFSH, was affinity purified in one step, and
      demonstrated activity in receptor-radioligand binding assays and in a cAMP
      accumulation assay. The use of GST-BV-hFSHalpha provides a novel and efficient
      method for purifying and studying members of the glycoprotein hormone family
      derived from the culture supernatant or subcellular fractions of the cell.

PMID- 15184085
TI  - NFI-C2 negatively regulates alpha-sarcoglycan promoter activity in C2C12
      myoblasts.
AB  - alpha-Sarcoglycan striated muscle-specific protein is a member of the sarcoglycan
      sarcospan complex. Positive and negative transcriptional regulation of
      sarcoglycan genes are important in sarcoglycan's intracellular localization and
      sarcolemmal stability. In the present work we assessed the function of NFI
      transcription factors in the regulation of alpha-sarcoglycan promoter through the
      C2C12 cell line differentiation. NFI factors act alternatively as activators and
      negative modulators of alpha-sarcoglycan promoter activity. In myoblasts NFI-A1.1
      and NFI-B2 are activators, whereas NFI-C2 and NFI-X2 are negative regulators. In
      myotubes, all NFI members are activators, being NFI-C2 the less potent. We
      identified the alpha-sarcoglycan promoter NFI-C2 response element by testing
      progressive deletion constructs and point mutations in C2C12 cells over
      expressing NFI-C2. Gel-shift and chromatin immunoprecipitation experiments
      demonstrated that NFI factors are indeed interacting in vitro and in vivo with
      the binding sequence. These results suggest a NFI role in C2C12 cell
      differentiation.

PMID- 15184086
TI  - Shared apical sorting of anion exchanger isoforms AE2a, AE2b1, and AE2b2 in
      primary hepatocytes.
AB  - AE2 (SLC4A2) is the member of the Na(+)-independent anion exchanger (AE) family
      putatively involved in the secretion of bicarbonate to bile. In humans, three
      variants of AE2 mRNA have been described: the full-length transcript AE2a
      (expressed from the upstream promoter in most tissues), and alternative
      transcripts AE2b(1) and AE2b(2) (driven from alternate promoter sequences in a
      tissue-restricted manner, mainly in liver and kidney). These transcripts would
      result in AE protein isoforms with short N-terminal differences. To ascertain
      their translation, functionality, and membrane sorting, we constructed expression
      vectors encoding each AE2 isoform fused to GFP at the C-terminus. Transfected
      HEK293 cells showed expression of functional GFP-tagged AE2 proteins, all three
      isoforms displaying comparable AE activities. Primary rat hepatocytes transfected
      with expression vectors and repolarized in a collagen-sandwich configuration
      showed a microtubule-dependent apical sorting of each AE2 isoform. This shared
      apical sorting is liver-cell specific, as sorting of AE2 isoforms was basolateral
      in control experiments on polarized kidney MDCK cells. Hepatocytic apical
      targeting of AE2 isoforms suggests that they all may participate in the
      canalicular secretion of bicarbonate to bile.

PMID- 15184087
TI  - Anti-inflammatory effects of tocopherol metabolites.
AB  - Our objective was to assess the anti-inflammatory effects of alpha-tocopherol,
      gamma-tocopherol, and their metabolites 2,5,7,8-tetramethyl-2-(beta-carboxyethyl)
      6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(beta-carboxyethyl)-6
      hydroxychroman (gamma-CEHC) in defined cell culture systems. Rat aortic
      endothelial cells and mouse microglial cultures were treated with tumor necrosis
      factor TNFalpha or bacterial lipopolysaccharide (LPS) and nitrite and
      prostaglandin E(2) (PGE(2)) were measured. alpha-CEHC suppressed TNFalpha
      stimulated nitrite production in both cell types, whereas both CEHC derivatives
      inhibited LPS-stimulated microglial nitrite efflux. Both alpha-CEHC and gamma
      CEHC inhibited microglial PGE(2) production, but neither alpha- nor gamma
      tocopherol was effective at inhibiting cytokine-stimulated inflammatory
      processes. These results show that the anti-inflammatory effects of tocopherols
      are highly cell type-, stimulus-, and endpoint-dependent.

PMID- 15184088
TI  - Kinetics of novel competitive inhibitors of urease enzymes by a focused library
      of oxadiazoles/thiadiazoles and triazoles.
AB  - Based on structure of the substrate of urease and for the purpose of designing
      pharmacophore models for urease inhibitors, which could be effective in
      physiological and pharmacological studies, a series of twenty-five 1,3,4-diazole
      2(3H)-thiones-2(3H)-thiones, 1,3,4-diazoles-2(3H)-thiones, and 1,2,4-tri-3
      thiones (OSNs) were designed, synthesized, and evaluated for various kinetic
      parameters of urease inhibition. OSNs inhibited the activity of urease(s) in a
      concentration dependent fashion. Dixon as well as Lineweaver-Burk plots and their
      secondary replots indicated that the nature of inhibition was of pure competitive
      type for all the 25 compounds. 5-[4-(hydroxy)phenyl]-1,3,4-thiadiazole-2(3H)
      thione was found to be the most active one with a Ki value of 2 microM. The Ki
      values were increased with an increase in substrate concentrations. Apparently,
      OSNs employ a homologous mechanism of action by exploiting a common transition
      catalysis state and acting as ligand chelators to form octahedral complexes with
      the urease enzymes in an orientation-specific mode. The inhibition was slightly
      potentiated by lower pH and not abolished in the presence of NH2OH (a scavenger
      of histidine residue). Because of their safe profile in the genotoxic assay, they
      may be pursued in the near future for human testing

PMID- 15184090
TI  - The relationship between marital quality and adherence to the diabetes care
      regimen.
AB  - BACKGROUND: Diabetes is a chronic illness that requires significant behavior
      change through adherence to, and maintenance of, a complex health care regimen.
      Social support has been found to be a factor that influences adherence. PURPOSE:
      This article reports a cross-sectional and prospective assessment of the
      relationship between marital quality (i.e., intimacy and adjustment) and self
      reported adherence to the diabetes care regimen. METHODS: Seventy-eight insulin
      treated adults with diabetes were assessed at Time 1 (T1) when they completed two
      marital quality measures and a measure of adherence to the diabetes care regimen.
      Sixty participants were contacted 2 years later (Time 2; T2), and the self-care
      measure was readministered. Blood glucose (sugar) control was assessed by
      hemoglobin A1c. Demographic data (age, gender, type and duration of diabetes,
      years married, other medical problems, family history of diabetes, years of
      education) were gathered from charts and questionnaires. Linear regression
      analyses were used to assess the ability of the two marital measures at T1 to
      predict adherence to self-care at T2, controlling for confounding baseline
      variables. RESULTS: Results showed that both of the marital quality measures
      predicted many aspects of self-care at T1. Dietary self-care related to marital
      intimacy and adjustment, as did adherence to exercise and to doctor's
      recommendations. Neither adherence to blood glucose testing nor blood glucose
      control was related to marital quality. Prospective analyses showed that neither
      marital quality measure at T1 was a prospective predictor of aspects of adherence
      to self-care at T2. CONCLUSIONS: Future efforts to improve self-care should
      explore the value of interventions that target the spouse and/or the couple's
      relationship.

PMID- 15184091
TI  - The role of perceived control and preference for control in adherence to a
      chronic medical regimen.
AB  - BACKGROUND: Poor patient adherence is a widespread problem among patients
      undergoing hemodialysis for end-stage renal disease. PURPOSE: The goal of this
      study was to examine the joint role of perceived restriction of control and
      individual differences in preference for control in predicting adherence to the
      hemodialysis regimen. METHODS: Participants were 49 patients recruited from five
      hemodialysis centers affiliated with the University of Iowa Hospitals and
      Clinics. Preference for control in the health care context was assessed using the
      Preference for Information and Preference for Behavioral Involvement subscales of
      the Krantz Health Opinion Survey, and perceived control was assessed using six
      items written for this study. Adherence was assessed by examining patients'
      interdialysis session weight gains (IWG). RESULTS: Hierarchical regression
      analysis indicated that the interaction between preference for information and
      perceived control over dialysis context explained a significant proportion of
      variance in IWG values, change in R2 =.09, F(1, 43) = 5.26, p <.05, standardized
      beta = -.32. Among patients with lower levels of perceived control in the
      dialysis setting, a higher preference for information concerning one's own health
      care was associated with increasingly poorer adherence. IWG levels in these
      individuals reflected clinically problematic nonadherence with fluid-intake
      restrictions. Among patients with a higher level of perceived control, preference
      for information had little effect on adherence. No main or interactive effects
      were found involving differences in patients' preference for behavioral
      involvement in their own health care or for the items reflecting perceived
      control outside the dialysis treatment setting. CONCLUSIONS: These data suggest
      that assessing and examining the interactive effects of patients' preferences for
      control and perceived control may, in some cases, be useful in identifying those
      individuals at risk for difficulty in adhering to the complex behavioral
      restrictions associated with chronic medical regimens.

PMID- 15184092
TI  - Social support and psychological adjustment among Latinas with arthritis: a test
      of a theoretical model.
AB  - BACKGROUND: Among people coping with chronic illness, tangible social support
      sometimes has unintended negative consequences on the recipient's psychological
      health. Identity processes may help explain these effects. Individuals derive
      self-worth and a sense of competence by enacting social roles that are central to
      the self-concept. PURPOSE: This study tested a model drawing from some of these
      theoretical propositions. The central hypothesis was that tangible support in
      fulfilling a highly valued role undermines self-esteem and a sense of self
      efficacy, which, in turn, affect psychological adjustment. METHODS: Structured
      interviews were conducted with 98 Latina women with arthritis who rated the
      homemaker identity as being of central importance to the self-concept. RESULTS: A
      path analysis indicated that, contrary to predictions, tangible housework support
      was related to less psychological distress. Emotional support predicted greater
      psychological well-being. These relationships were not mediated by self-esteem or
      self-efficacy. Qualitative data revealed that half of the sample expressed either
      ambivalent or negative feelings about receiving housework support. CONCLUSIONS:
      Results may reflect social and cultural norms concerning the types of support
      that are helpful and appropriate from specific support providers. Future research
      should consider the cultural meaning and normative context of the support
      transaction. This study contributes to scarce literatures on the mechanisms that
      mediate the relationship between social support and adjustment, as well as
      illness and psychosocial adaptation among Latina women with chronic illness.

PMID- 15184093
TI  - Developmentally appropriate sexual risk reduction interventions for adolescents:
      rationale, review of interventions, and recommendations for research and
      practice.
AB  - BACKGROUND: Despite awareness of the need to design developmentally appropriate
      sexual risk reduction interventions for adolescents, limited information exists
      to identify the aspects of intervention design or content that make an
      intervention developmentally appropriate. PURPOSE: (a) To clarify the rationale
      for designing developmentally appropriate interventions, (b) to review randomized
      controlled trials (RCTs) of adolescent sexual risk reduction interventions, (c)
      to identify developmentally appropriate strategies, (d) to examine the
      relationship between developmental appropriateness and sexual risk outcomes, and
      (e) to provide recommendations for research. METHODS: The authors examined
      studies (n = 24) published before 2003 that evaluated a risk reduction
      intervention, sampled adolescents, used an RCT study design, and evaluated sexual
      behavior outcomes. RESULTS: Content analysis indicated that the interventions
      tested were often tailored to the cognitive level of adolescents, as indicated by
      the use of exercises on decision making, goal setting and planning, and concrete
      explanation of abstract concepts. Interventions also addressed the social
      influences of risky sex such as peer norms and provided communication skills
      training. Overall, the interventions tested in RCTs were more effective in
      delaying the onset of sexual activity than in promoting abstinence among sexually
      active youth. Interventions with booster sessions were effective in reducing
      sexual risk behavior. The use of process measures, linked with developmental
      constructs, was rare. However, improvements in sexual communication skills and
      perceived norms for safer sex were associated with reductions in sexual risk
      outcomes. CONCLUSIONS: Developmental transitions during adolescence influence
      sexual behavior and should be considered when developing and evaluating risk
      reduction interventions for youth. Future research should assess process measures
      of key developmental constructs as well as risk behavior and biological outcomes.

PMID- 15184094
TI  - Catastrophizing and pain sensitivity among chronic pain patients: moderating
      effects of sensory and affect focus.
AB  - BACKGROUND: Pain catastrophizing is a particularly harmful cognitive factor among
      patients with chronic pain, but little is known of mechanisms linking this factor
      to pain and disability. PURPOSE: The study examined whether attentional focus on
      sensory versus affective information about pain constitutes a pathway by which
      catastrophizing affects responses to painful stimuli. METHODS: Participants were
      82 chronic pain patients assigned randomly to sensory focus, affect focus, or
      control conditions. They underwent cold pressors first prior to and then
      following an information focus manipulation, and they completed the Pain
      Catastrophizing Scale (PCS). RESULTS: Regressions produced significant Condition
      x PCS interaction effects on threshold and tolerance change from first to second
      cold pressor, such that PCS scores were significantly and negatively related to
      these changes in both sensory and affect focus conditions, but not in the control
      condition. Only a main effect for PCS scores emerged for self-reported pain
      changes. Solving regression equations for hypothetical PCS values (+- 1 SD from
      the mean) revealed that (a) high catastrophizers decreased threshold and
      tolerance in the affect focus condition and showed no appreciable changes in
      sensory focus and (b) low catastrophziers showed increases in threshold and
      tolerance in sensory focus, but no appreciable changes in affect focus. Further,
      the degree to which patients focused on emotions during pain partly mediated
      effects of PCS scores on threshold and tolerance changes. CONCLUSION:
      Catastrophizing about pain may affect pain severity and distress of chronic pain
      patients through a bias toward processing the most disturbing elements of a
      painful stimulus.

PMID- 15184095
TI  - Anger management style, blood pressure reactivity, and acute pain sensitivity:
      evidence for "Trait x Situation" models.
AB  - BACKGROUND: Anger management style is related to acute and chronic pain, but it
      is not clear whether anger arousal is needed for these associations to emerge or
      whether physiological mechanisms mediate these links. PURPOSE: "Trait x
      Situation" models were examined to determine whether relationships between anger
      out and pain and anger-in and pain depended on anger provocation's preceding pain
      induction and whether pain sensitivity variance explained by anger management
      style overlapped with variance in harassment-induced blood pressure reactivity.
      METHODS: Healthy individuals (N = 53) underwent either mental arithmetic with
      harassment and then a cold pressor (MA/CP) or vice versa (CP/MA). The Spielberger
      Anger Expression Inventory assessed anger-out using the Anger-Out subscale (AOS)
      and anger-in using the Anger-In subscale (AIS). RESULTS: AOS x Order and AIS x
      Order interactions for pain tolerance emerged, such that (a) AOS was related
      negatively to tolerance among MA/CP participants, whereas AOS and tolerance were
      not related in CP/MA; (b) AIS was related positively to tolerance in MA/CP,
      whereas AIS was related negatively to tolerance in CP/MA; and (c) tolerance
      variance accounted for by AOS in MA/CP overlapped substantially with tolerance
      variance accounted for by diastolic blood pressure reactivity. CONCLUSIONS:
      Findings support the notion that anger management style affects pain and are
      consistent with evidence that deficient endogenous opioid functioning may be one
      mechanism through which anger-out is linked to both pain sensitivity and
      cardiovascular stress reactivity, a connection that appears most reliably when
      anger is provoked.

PMID- 15184096
TI  - Odors and sounds as triggers for medically unexplained symptoms: a fixed-occasion
      diary study of Gulf War veterans.
AB  - BACKGROUND: Both laboratory studies on healthy volunteers and epidemiological
      evidence from patient samples indicate that odor can act as a trigger for the
      reporting of medically unexplained symptoms (MUSs). PURPOSE: The relationship
      between concurrent experiences of odor and MUSs has not been explored in a
      patient sample. METHODS: This study used an 8-day fixed-occasion diary study, in
      which 17 veterans of the Persian Gulf War completed diary assessments of (a) the
      intensity and duration of odor and sound and (b) MUS severity. RESULTS: The
      results showed that the intensity of odor was positively associated with the
      severity on the same day and subsequent days' symptoms, whereas the duration of
      odor was negatively related to the severity of MUS reporting on the same day.
      CONCLUSIONS: These results are consistent with an associative mechanism
      underlying symptom reporting in veterans. By contrast, the duration, but not the
      intensity, of sound was related to the severity of MUS reporting on the same day.

PMID- 15184100
TI  - Gene-environment interplay in schizopsychotic disorders.
AB  - Genetic studies have sought to identify subtypes or endophenotypes of
      schizophrenia in an effort to improve the reliability of findings. A number of
      chromosomal regions or genes have now been shown to have had replicated linkage
      to schizophrenia susceptibility. Molecules involved in neurodevelopment or
      neurotransmitter function are coded by many of the genes that have been
      implicated in schizophrenia. Studies of neurotransmitter function have
      identified, among others, a possible role for GABA, glutamate and dopamine in
      animal models of schizophrenia. GABA neurons that co-express the calcium binding
      protein parvalbumin have been implicated as have glutamatergic metabotropic
      receptors and dopamine D3 receptors. Stress influences glutamate and dopamine
      providing another environmental factor that may interact with the influence of
      genes on neurotransmitter function. Neurotransmitter interactions include
      influences on signaling molecules and these too have been implicated in forms of
      learning thought to be affected in schizophrenia. Results continue to unravel the
      interplay of genes and environment in the etiology of schizophrenia and other
      psychotic disorders.

PMID- 15184101
TI  - Genes and environment: nosology and psychiatry.
AB  - Psychiatric syndromal nosology is defined in terms of prototypical symptoms and
      course. Diagnosis does not depend on knowledge of etiology, pathophysiology or
      objective tests. Of what use is such a nosology? As formulated by Sydenham, and
      demonstrated by Kraepelin, certain concatenations of signs and symptoms afford
      improved prognostic ability. This is highly desirable, especially when treatment
      is ineffective. More recently, syndromes have provided some guidance for
      therapeutic choice. However, a syndrome has no claim for etiological homogeneity.
      Therefore, linkage studies are plagued by phenocopies that amount to false
      positives. An attempt to deal with the phenocopy problem in the area of
      depression is presented.

PMID- 15184102
TI  - Linkage studies of schizophrenia.
AB  - The study of schizophrenia genetics has revealed much about the disease but none
      of the essential secrets of its etiology, so far, for numerous reasons. First,
      schizophrenia is a complex trait, influenced by both genes and environment.
      Second, it appears to be a highly heterogeneous disease, with locus and allelic
      heterogeneity both between and within families likely. Third, since it is common,
      it is likely that the genetic liability variants are common, and so are found
      with relatively high frequency in the general population. Fourth, linkage
      methods, which deliver rapid coverage of the genome, have great power to identify
      single genes causing Mendelian disorders but are poorly suited to the genetic
      architecture of complex traits. Although association methods are undeniably more
      powerful in such situations, affordable technologies to deliver the much higher
      density whole genome coverage required are not yet available and candidate gene
      studies of schizophrenia have not produced robust and replicable results. In
      spite of these limitations, there are now sufficient data to support several
      conclusions. Numerous regions of the human genome give consistent, though by no
      means unanimous, support for linkage. The precise nature of these signals is not
      yet understood, and power to position the effects is poor, but metanalyses show
      the co-occurrence is unlikely to be due to chance. Combined approaches utilizing
      linkage for rapid genome coverage and association for fine-scale follow-up have
      identified several promising candidate genes. Although the definition of
      replication in a complex trait is itself complex, a number of these candidates
      have been supported by numerous studies. These converging lines of evidence
      suggest that the genetics of schizophrenia, long considered a most intractable
      problem, are at last beginning to be unraveled.

PMID- 15184103
TI  - Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia.
AB  - Genetic factors play an important part in the development of schizophrenia and
      bipolar disorder, and linkage analyses in families have successfully identified
      several chromosomal regions containing candidate genes. A single large pedigree
      has been described in which schizophrenia and depression segregate with a
      balanced chromosomal translocation involving the long arm of chromosome 1 and the
      short arm of chromosome 11. The gene named DISC1, disrupted at the chromosome 1
      breakpoint, is a novel candidate gene that may have a role in the pathogenesis of
      schizophrenia. The cellular location and function of the protein coded by DISC1
      is currently being investigated. The phenotype associated with DISC1 in the t
      (1;11) translocation family includes schizophrenia, schizoaffective disorder,
      recurrent major depression and bipolar disorder. Hence this locus is one of
      several now reported apparently showing linkage to both schizophrenia and bipolar
      disorder. The study of intermediate phenotypes or "endophenotypes" may clarify
      the relations between phenotype and genotype. Auditory event related potentials
      are EEG based physiological measures widely studied in schizophrenia. In
      particular the cognitive evoked potential, the P300 response generated during an
      "odd-ball" two-tone discrimination task consistently shows reduced amplitude in
      schizophrenia compared to controls. In members of the family with the t (1;11)
      translocation, P300 amplitude was reduced in relatives who carried the
      translocation compared to relatives with a normal karyotype. Furthermore the
      amplitude reduction was independent of the presence or absence of symptoms
      because asymptomatic translocation carriers showed similar P300 amplitude
      reduction as was found in translocation carriers who were diagnosed with
      schizophrenia, bipolar disorder or unipolar depression. The results confirm that
      subjects with schizophrenia who carry the t (1;11) translocation have similar
      phenotype to unrelated subjects with schizophrenia and a normal karyotype.
      Furthermore P300 amplitude may be a useful intermediate phenotype detecting the
      neuropathology of schizophrenia in "at risk" individuals even in the absence of
      clinical symptoms.

PMID- 15184104
TI  - The genetic relationship of personality to major depression and schizophrenia.
AB  - Since ancient times, dimensions of personality have been linked with the
      liability to psychiatric illness. In modern times, several research approaches
      suggest that personality and the liability to psychiatric illness such as
      schizophrenia and major depression (MD) are influenced by many of the same genes.
      If this is true, it could shed light on the genetic architecture of psychiatric
      illness. It could also validate the use of personality measures in unaffected
      relatives in linkage and association studies of psychiatric illness. This
      approach could potentially increase statistical power to detect genetic effects.
      The personality trait neuroticism (N) may be genetically related to MD, while
      schizotypal traits may be genetically related to schizophrenia. Twin studies have
      reported that most of the covariation between N and MD is due to shared additive
      genetic factors. Adoption studies have demonstrated that the biological offspring
      of schizophrenic mothers are more likely to have schizotypal personality disorder
      than are children of control mothers. At the current time, only one genome wide
      scan of N has been published, which does show some overlap in linkage results
      with genome scans of MD. However, this should be replicated and more rigorously
      studied. At the present time, there are no established susceptibility genes for
      MD. When these are established, it will be necessary to assess their relationship
      with N. Currently, no genome scans of schizotypy have been published.
      Furthermore, although several putative susceptibility genes for schizophrenia
      have been reported and replicated, only one--catechol-O-methyltransferase (COMT)-
      has been tested in schizotypy.

PMID- 15184105
TI  - Candidate gene studies of antipsychotic drug efficacy and drug-induced weight
      gain.
AB  - Converging data suggest that the identification of the molecular variants that
      influence antipsychotic drug response may soon be feasible. For the most part,
      these studies have focused on the new atypical antipsychotic agents, particularly
      clozapine. Although initial data in this regard has been inconclusive, recent
      studies have suggested that variation in the gene that codes for the dopamine D2
      receptor (DRD2) may significantly influence the clinical efficacy of a number of
      typical and atypical antipsychotic drugs, perhaps via a variant that influences
      messenger RNA (mRNA) stability and translation. Studies of antipsychotic-induced
      weight gain have been more consistent than studies of antipsychotic drug
      efficacy, perhaps because weight dysregulation represents a more powerful
      phenotype for genetic studies, with a specific single nucleotide polymorphism
      (SNP) in the 5- hydroxytryptamine 2C (5-HT2c) receptor being associated with
      weight gain across diverse samples. Larger, more comprehensive studies are needed
      to confirm these results, but taken together, they suggest that pharmacogenetic
      strategies may be critical towards gaining a more precise understanding of the
      mechanism of action of antipsychotic drugs in the treatment of schizophrenia.

PMID- 15184106
TI  - Calcium binding protein markers of GABA deficits in schizophrenia--postmortem
      studies and animal models.
AB  - As quantitative neuroimaging continues to elucidate the gross neuropathology of
      schizophrenia, neurochemical and histological studies have contributed to
      defining this pathology in terms of neurotransmitter dysfunction. Increasingly,
      there is evidence implicating neurons containing the major inhibitory
      neurotransmitter of the brain--gamma-aminobutyric acid (GABA). Benes was the
      first to demonstrate deficits in some morphological subtypes of interneurons in
      the frontal cortex in schizophrenia. We identified that this was specific to a
      subgroup of GABAergic interneurons containing parvalbumin (PV), which is found in
      the fast-firing cells providing inhibitory control of the cortico-fugal pyramidal
      cells. PV is notable in being expressed late in development; the late expression
      of this protective calcium binding protein (CBP) may impart an early
      vulnerability to these neurons, indicating a possible mechanism for the
      developmental origins of schizophrenia. Cortical GABAergic neurons expressing the
      CBP calretinin (CR) are unaffected in schizophrenia, although those containing
      calbindin (CB) are also diminished in number. These deficits in PV and CB are
      notable in also being observed in bipolar disorder, indicating how the close
      aetiological relationship of these two psychiatric disorders is reflected in
      their pathology. One of the most substantial abnormalities seen in post-mortem
      brain tissue is the hippocampal deficit of PV-containing neurons, again in the
      absence of effects on CR-positive cells. This deficit occurring in a structure
      implicated in cognitive symptomatology may well have functional relevance, and we
      find it can be induced by a model of the disease, sub-chronic phencyclidine (PCP)
      administration, that can also produce cognitive disturbances. This PCP model,
      like schizophrenia, demonstrates other neurochemical changes which include
      indicators of glutamatergic dysfunction. The temporal and aetiological
      relationships between glutamatergic and GABAergic deficits remains unclear, but
      may well relate to an initial loss/dysfunction of GABA/PV neurons that
      subsequently gives rise to a glutamatergic pathology.

PMID- 15184108
TI  - Effect of stress on prefrontal cortex function.
AB  - Stress is the major epigenetic factor that contributes to the etiology,
      pathophysiology, and treatment outcome of most psychiatric disorders.
      Understanding the mechanisms by which stress contributes to these processes can
      have important implications for improving therapeutic outcome. Considering that a
      dysfunctional prefrontal cortex has been implicated in many psychiatric
      disorders, such as schizophrenia and mood disorders, delineating mechanisms by
      which stress affects prefrontal cortex (PFC) function is critical to our
      understanding of the role of stress in influencing the disease process. This
      paper will review recent mechanistic information about the effects of stress on
      dopamine and glutamate neurotransmission in the PFC.

PMID- 15184107
TI  - Dopamine and glutamate dysfunctions in schizophrenia: role of the dopamine D3
      receptor.
AB  - Symptoms of schizophrenia are improved by dopamine antagonists and exacerbated by
      dopamine-releasing agents, suggesting hyperactivity of dopamine. However, chronic
      blockade of glutamate neurotransmission by antagonists at the N-methyl-D
      aspartate (NMDA) receptor subtype produces a pathophysiological state resembling
      schizophrenia. A link between cortical glutamate/NMDA deficiency and subcortical
      dopamine hyperactivity, particularly in the mesolimbic pathway, has been
      hypothesized in schizophrenia. Here we show that hyperactivity produced by NMDA
      receptor blockade is dependent upon stimulation of the dopamine D3 receptor
      subtype. Since D3 receptor antagonists and antipsychotics produced very similar
      effects, our results add to the growing evidence suggesting that D3 receptor
      blockade might produce antipsychotic effects.

PMID- 15184109
TI  - Interactions of the mGluR5 gene with breeding and maternal factors on startle and
      prepulse inhibition in mice.
AB  - Sensorimotor gating, measured by prepulse inhibition (PPI), is a fundamental form
      of information processing that is deficient in schizophrenia patients and mice
      lacking the gene for metabotropic glutamate receptor 5 (mGluR5). Both breeding
      strategies and mothering behaviors are capable of influencing the behavioral
      phenotype of knockout (KO) mice. Previous studies found a PPI deficit and
      increased startle magnitudes in mGluR5 KO mice derived from homozygous matings.
      Here we compared the PPI of mGluR5 wildtype (WT) and KO mice derived from
      heterozygous matings to that seen in mice derived from homozygous matings.
      Possible influences of postnatal mothering behaviors were examined using two
      different methods of cross-fostering. The potential developmental nature of the
      PPI deficit of the mGluR5 KO mice was also addressed via acute administration of
      the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to C57BL/6J
      mice. The mGluR5 KO mice exhibited reduced PPI independently of breeding strategy
      or postnatal mothering behavior. Startle magnitude, however, varied with breeding
      strategy. The PPI deficit seen in the mGluR5 KO mice is not mimicked by acute
      administration of an mGluR5 antagonist, and is therefore most likely due to
      compensatory alterations in neuronal circuitry occurring during development
      independent of maternal behaviors in the postnatal environment.

PMID- 15184110
TI  - The role of signaling molecules in reward-related incentive learning.
AB  - Reward-related incentive learning involves the acquisition by neutral stimuli of
      an enhanced ability to elicit approach and other responses. Previous studies have
      shown that both dopamine (DA) and glutamate (Glu) play critical roles in this
      type of learning. Signaling molecules are intracellular messengers that
      participate in the influence of transmitter-receptor events on intracellular
      function including transcription in the nucleus. In recent years studies have
      begun to implicate signaling molecules in incentive learning. Thus, inhibition of
      cyclic adenosine monophosphate-dependent protein kinase (PKA) in the nucleus
      accumbens (NAc), that is activated by DA acting at D1-like receptors, blocks the
      acquisition of conditioned approach responses, lever pressing for food,
      conditioned place preference (CPP) based on NAc injections of amphetamine or
      cocaine, and conditioned activity based on NAc injections of amphetamine. Similar
      effects have been observed with PKA inhibition in the basolateral amygdala or
      medial prefrontal cortex. If animals were trained prior to testing with PKA
      inhibitors in NAc, no effect was seen suggesting that PKA is more important for
      acquisition than expression of incentive learning. Inhibition of calcium
      dependent protein kinase or mitogen-activated protein kinases in NAc similarly
      has been shown to block the acquisition of incentive learning. Results support a
      model of DA-Glu synaptic interactions that form the basis of incentive learning.

PMID- 15184111
TI  - A special fondness for lactobacilli.

PMID- 15184113
TI  - In vivo immobilization of fusion proteins on bioplastics by the novel tag BioF.
AB  - A new protein immobilization and purification system has been developed based on
      the use of polyhydroxyalkanoates (PHAs, or bioplastics), which are biodegradable
      polymers accumulated as reserve granules in the cytoplasm of certain bacteria.
      The N-terminal domain of the PhaF phasin (a PHA-granule-associated protein) from
      Pseudomonas putida GPo1 was used as a polypeptide tag (BioF) to anchor fusion
      proteins to PHAs. This tag provides a novel way to immobilize proteins in vivo by
      using bioplastics as supports. The granules carrying the BioF fusion proteins can
      be isolated by a simple centrifugation step and used directly for some
      applications. Moreover, when required, a practically pure preparation of the
      soluble BioF fusion protein can be obtained by a mild detergent treatment of the
      granule. The efficiency of this system has been demonstrated by constructing two
      BioF fusion products, including a functional BioF-beta-galactosidase. This is the
      first example of an active bioplastic consisting of a biodegradable matrix
      carrying an active enzyme.

PMID- 15184112
TI  - Biology of the metabolically diverse genus Gordonia.

PMID- 15184114
TI  - Characterization and heterologous gene expression of a novel esterase from
      Lactobacillus casei CL96.
AB  - A novel esterase gene (estI) of Lactobacillus casei CL96 was localized on a 3.3
      kb BamHI DNA fragment containing an open reading frame (ORF) of 1,800 bp. The ORF
      of estI was isolated by PCR and expressed in Escherichia coli, the methylotrophic
      bacterium Methylobacterium extorquens, and the methylotrophic yeast Pichia
      pastoris under the control of T7, methanol dehydrogenase (P(mxaF)), and alcohol
      oxidase (AOX1) promoters, respectively. The amino acid sequence of EstI indicated
      that the esterase is a novel member of the GHSMG family of lipolytic enzymes and
      that the enzyme contains a lipase-like catalytic triad, consisting of Ser325,
      Asp516, and His558. E. coli BL21(DE3)/pLysS containing estI expressed a novel
      67.5-kDa protein corresponding to EstI in an N-terminal fusion with the S. tag
      peptide. The recombinant L. casei CL96 EstI protein was purified to
      electrophoretic homogeneity in a one-step affinity chromatography procedure on S
      protein agarose. The optimum pH and temperature of the purified enzyme were 7.0
      and 37 degrees C, respectively. Among the pNP (p-nitrophenyl) esters tested, the
      most selective substrate was pNP-caprylate (C(8)), with K(m) and k(cat) values of
      14 +/- 1.08 microM and 1,245 +/- 42.3 S(-1), respectively.

PMID- 15184115
TI  - Saturation mutagenesis of Burkholderia cepacia R34 2,4-dinitrotoluene dioxygenase
      at DntAc valine 350 for synthesizing nitrohydroquinone, methylhydroquinone, and
      methoxyhydroquinone.
AB  - Saturation mutagenesis of the 2,4-dinitrotoluene dioxygenase (DDO) of
      Burkholderia cepacia R34 at position valine 350 of the DntAc alpha-subunit
      generated mutant V350F with significantly increased activity towards o
      nitrophenol (47 times), m-nitrophenol (34 times), and o-methoxyphenol (174 times)
      as well as an expanded substrate range that now includes m-methoxyphenol, o
      cresol, and m-cresol (wild-type DDO had no detectable activity for these
      substrates). Another mutant, V350M, also displays increased activity towards o
      nitrophenol (20 times) and o-methoxyphenol (162 times) as well as novel activity
      towards o-cresol. Products were synthesized using whole Escherichia coli TG1
      cells expressing the recombinant R34 dntA loci from pBS(Kan)R34, and the initial
      rates of product formation were determined at 1 mM substrate by reverse-phase
      high-pressure liquid chromatography. V350F produced both nitrohydroquinone at a
      rate of 0.75 +/- 0.15 nmol/min/mg of protein and 3-nitrocatechol at a rate of
      0.069 +/- 0.001 nmol/min/mg of protein from o-nitrophenol, 4-nitrocatechol from m
      nitrophenol at 0.29 +/- 0.02 nmol/min/mg of protein, methoxyhydroquinone from o
      methoxyphenol at 2.5 +/- 0.6 nmol/min/mg of protein, methoxyhydroquinone from m
      methoxyphenol at 0.55 +/- 0.02 nmol/min/mg of protein, both methylhydroquinone at
      1.52 +/- 0.02 nmol/min/mg of protein and 2-hydroxybenzyl alcohol at 0.74 +/- 0.05
      nmol/min/mg of protein from o-cresol, and methylhydroquinone at 0.43 +/- 0.1
      nmol/min/mg of protein from m-cresol. V350M produced both nitrohydroquinone at a
      rate of 0.33 nmol/min/mg of protein and 3-nitrocatechol at 0.089 nmol/min/mg of
      protein from o-nitrophenol, methoxyhydroquinone from o-methoxyphenol at 2.4
      nmol/min/mg of protein, methylhydroquinone at 1.97 nmol/min/mg of protein and 2
      hydroxybenzyl alcohol at 0.11 nmol/min/mg of protein from o-cresol. The DDO
      variants V350F and V350M also exhibited 10-fold-enhanced activity towards
      naphthalene (8 +/- 2.6 nmol/min/mg of protein), forming (1R,2S)-cis-1,2-dihydro
      1,2-dihydroxynaphthalene. Hence, mutagenesis of wild-type DDO through active-site
      engineering generated variants with relatively high rates toward a previously
      uncharacterized class of substituted phenols for the nitroarene dioxygenases;
      seven previously uncharacterized substrates were evaluated for wild-type DDO, and
      four novel monooxygenase-like products were found for the DDO variants V350F and
      V350M (methoxyhydroquinone, methylhydroquinone, 2-hydroxybenzyl alcohol, and 3
      nitrocatechol).

PMID- 15184117
TI  - Metabolism of zearalenone by genetically modified organisms expressing the
      detoxification gene from Clonostachys rosea.
AB  - Zearalenone (ZEN) is converted to a nontoxic product by a lactonohydololase
      encoded by zhd101. An enhanced green fluorescent protein (EGFP) gene was fused to
      zhd101 (i.e., egfp::zhd101) and expressed in Escherichia coli. Both recombinant
      ZHD101 and EGFP::ZHD101 were purified to homogeneity and characterized. Maximal
      activity of ZHD101 toward ZEN was measured at approximately 37 to 45 degrees C
      and pH 10.5 (k(cat) at 30 degrees C, 0.51 s(-1)). The enzyme was irreversibly
      inactivated at pH values below 4.5 or by treatment with serine protease
      inhibitors. ZHD101 was also active against five ZEN cognates, although the
      efficiencies were generally low; e.g., the k(cat) was highest with zearalanone
      (1.5 s(-1)) and lowest with beta-zearalenol (0.075 s(-1)). EGFP::ZHD101 had
      properties similar to those of the individual proteins with regard to the EGFP
      fluorescence and lactonohydrolase activity. Fortuitously, EGFP::ZHD101 exhibited
      a good correlation between the fluorescence intensity and reaction velocity under
      various pH conditions. We therefore used egfp::zhd101 to visually monitor the
      lactonohydrolase activity in genetically modified organisms and evaluated the
      usefulness of zhd101 for in vivo detoxification of ZEN. While recombinant E. coli
      and transgenic rice calluses exhibited strong EGFP fluorescence and completely
      degraded ZEN in liquid media, recombinant Saccharomyces cerevisiae gave poor
      fluorescence and did not eliminate all the toxicity of the mycotoxin in the
      medium; i.e., the rest of ZEN was transformed into an unfavorable substrate, beta
      zearalenol, by an as-yet-unidentified reductase and remained in the medium. Even
      so, as much as 75% of ZEN was detoxified by the yeast transformant, which is
      better than the detoxification system in which food-grade Lactobacillus strains
      are used (H. El-Nezami, N. Polychronaki, S. Salminen, and H. Mykkuane, Appl.
      Environ. Microbiol. 68:3545-3549, 2002). An appropriate combination of a
      candidate host microbe and the codon-optimized synthetic gene may contribute
      significantly to establishing a mycotoxin detoxification system for food and
      feed.

PMID- 15184116
TI  - Biofilm development and cell death in the marine bacterium Pseudoalteromonas
      tunicata.
AB  - The newly described green-pigmented bacterium Pseudoalteromonas tunicata (D2)
      produces target-specific inhibitory compounds against bacteria, algae, fungi, and
      invertebrate larvae and is frequently found in association with living surfaces
      in the marine environment. As part of our studies on the ecology of P. tunicata
      and its interaction with marine surfaces, we examined the ability of P. tunicata
      to form biofilms under continuous culture conditions within the laboratory. P.
      tunicata biofilms exhibited a characteristic architecture consisting of
      differentiated microcolonies surrounded by water channels. Remarkably, we
      observed a repeatable pattern of cell death during biofilm development of P.
      tunicata, similar to that recently reported for biofilms of Pseudomonas
      aeruginosa (J. S. Webb et al., J. Bacteriol. 185:4585-4595, 2003). Killing and
      lysis occurred inside microcolonies, apparently resulting in the formation of
      voids within these structures. A subpopulation of viable cells was always
      observed within the regions of killing in the biofilm. Moreover, extensive
      killing in mature biofilms appeared to result in detachment of the biofilm from
      the substratum. A novel 190-kDa autotoxic protein produced by P. tunicata,
      designated AlpP, was found to be involved in this biofilm killing and detachment.
      A Delta alpP mutant derivative of P. tunicata was generated, and this mutant did
      not show cell death during biofilm development. We propose that AlpP-mediated
      cell death plays an important role in the multicellular biofilm development of P.
      tunicata and subsequent dispersal of surviving cells within the marine
      environment.

PMID- 15184118
TI  - Saturation mutagenesis of toluene ortho-monooxygenase of Burkholderia cepacia G4
      for Enhanced 1-naphthol synthesis and chloroform degradation.
AB  - Directed evolution of toluene ortho-monooxygenase (TOM) of Burkholderia cepacia
      G4 previously created the hydroxylase alpha-subunit (TomA3) V106A variant (TOM
      Green) with increased activity for both trichloroethylene degradation (twofold
      enhancement) and naphthalene oxidation (six-times-higher activity). In the
      present study, saturation mutagenesis was performed at position A106 with
      Escherichia coli TG1/pBS(Kan)TOMV106A to improve TOM activity for both chloroform
      degradation and naphthalene oxidation. Whole cells expressing the A106E variant
      had two times better naphthalene-to-1-naphthol activity than the wild-type cells
      (V(max) of 9.3 versus 4.5 nmol.min(-1).mg of protein(-1) and unchanged K(m)), and
      the regiospecificity of the A106E variant was unchanged, with 98% 1-naphthol
      formed, as was confirmed with high-pressure liquid chromatography. The A106E
      variant degrades its natural substrate toluene 63% faster than wild-type TOM does
      (2.12 +/- 0.07 versus 1.30 +/- 0.06 nmol.min(-1).mg of protein(-1) [mean +/-
      standard deviation]) at 91 microM and has a substantial decrease in
      regiospecificity, since o-cresol (50%), m-cresol (25%), and p-cresol (25%) are
      formed, in contrast to the 98% o-cresol formed by wild-type TOM. The A106E
      variant also has an elevated expression level compared to that of wild-type TOM,
      as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
      Another variant, the A106F variant, has 2.8-times-better chloroform degradation
      activity based on gas chromatography (V(max) of 2.61 versus 0.95 nmol.min(-1).mg
      of protein(-1) and unchanged K(m)) and chloride release (0.034 +/- 0.002 versus
      0.012 +/- 0.001 nmol.min(-1).mg of protein(-1)). The A106F variant also was
      expressed at levels similar to those of wild-type TOM and 62%-better toluene
      oxidation activity than wild-type TOM (2.11 +/- 0.3 versus 1.30 +/- 0.06
      nmol.min(-1).mg of protein(-1)). A shift in regiospecificity of toluene
      hydroxylation was also observed for the A106F variant, with o-cresol (28%), m
      cresol (18%), and p-cresol (54%) being formed. Statistical analysis was used to
      estimate that 292 colonies must be screened for a 99% probability that all 64
      codons were sampled during saturation mutagenesis.

PMID- 15184119
TI  - Protein engineering of toluene-o-xylene monooxygenase from Pseudomonas stutzeri
      OX1 for synthesizing 4-methylresorcinol, methylhydroquinone, and pyrogallol.
AB  - Toluene-o-xylene monooxygenase (ToMO) from Pseudomonas stutzeri OX1 oxidizes
      toluene to 3- and 4-methylcatechol and oxidizes benzene to form phenol; in this
      study ToMO was found to also form catechol and 1,2,3-trihydroxybenzene (1,2,3
      THB) from phenol. To synthesize novel dihydroxy and trihydroxy derivatives of
      benzene and toluene, DNA shuffling of the alpha-hydroxylase fragment of ToMO
      (TouA) and saturation mutagenesis of the TouA active site residues I100, Q141,
      T201, and F205 were used to generate random mutants. The mutants were initially
      identified by screening with a rapid agar plate assay and then were examined
      further by high-performance liquid chromatography and gas chromatography. Several
      regiospecific mutants with high rates of activity were identified; for example,
      Escherichia coli TG1/pBS(Kan)ToMO expressing the F205G TouA saturation
      mutagenesis variant formed 4-methylresorcinol (0.78 nmol/min/mg of protein), 3
      methylcatechol (0.25 nmol/min/mg of protein), and methylhydroquinone (0.088
      nmol/min/mg of protein) from o-cresol, whereas wild-type ToMO formed only 3
      methylcatechol (1.1 nmol/min/mg of protein). From o-cresol, the I100Q saturation
      mutagenesis mutant and the M180T/E284G DNA shuffling mutant formed
      methylhydroquinone (0.50 and 0.19 nmol/min/mg of protein, respectively) and 3
      methylcatechol (0.49 and 1.5 nmol/min/mg of protein, respectively). The F205G
      mutant formed catechol (0.52 nmol/min/mg of protein), resorcinol (0.090
      nmol/min/mg of protein), and hydroquinone (0.070 nmol/min/mg of protein) from
      phenol, whereas wild-type ToMO formed only catechol (1.5 nmol/min/mg of protein).
      Both the I100Q mutant and the M180T/E284G mutant formed hydroquinone (1.2 and
      0.040 nmol/min/mg of protein, respectively) and catechol (0.28 and 2.0
      nmol/min/mg of protein, respectively) from phenol. Dihydroxybenzenes were further
      oxidized to trihydroxybenzenes with different regiospecificities; for example,
      the I100Q mutant formed 1,2,4-THB from catechol, whereas wild-type ToMO formed
      1,2,3-THB (pyrogallol). Regiospecific oxidation of the natural substrate toluene
      was also checked; for example, the I100Q mutant formed 22% o-cresol, 44% m
      cresol, and 34% p-cresol, whereas wild-type ToMO formed 32% o-cresol, 21% m
      cresol, and 47% p-cresol.

PMID- 15184120
TI  - Localization and functional analysis of PepI, the immunity peptide of Pep5
      producing Staphylococcus epidermidis strain 5.
AB  - Pep5 is a cationic pore-forming lantibiotic produced by Staphylococcus
      epidermidis strain 5. The producer strain protects itself from the lethal action
      of its own bacteriocin through the 69-amino-acid immunity peptide PepI. The N
      terminal segment of PepI contains a 20-amino-acid stretch of apolar residues,
      whereas the C terminus is very hydrophilic, with a net positive charge. We used
      green fluorescent protein (GFP)-PepI fusions to obtain information on its
      localization in vivo. PepI was found to occur outside the cytoplasm and to
      accumulate at the membrane-cell wall interface. The extracellular localization
      appeared essential for conferring immunity. We analyzed the functional role of
      the specific segments by constructing various mutant peptides, which were also
      fused to GFP. When the hydrophobic N-terminal segment of PepI was disrupted by
      introducing charged amino acids, the export of PepI was blocked and clones
      expressing such mutant peptides were Pep5 sensitive. When PepI was successively
      shortened at the C terminus, in contrast, its export properties remained
      unchanged whereas its ability to confer immunity was gradually reduced. The
      results show that the N-terminal part is required for the transport of PepI and
      that the C-terminal part is important for conferring the immunity phenotype. A
      concept based on target shielding is proposed for the PepI immunity mechanism.

PMID- 15184121
TI  - Engineering the nifH promoter region and abolishing poly-beta-hydroxybutyrate
      accumulation in Rhizobium etli enhance nitrogen fixation in symbiosis with
      Phaseolus vulgaris.
AB  - Rhizobium etli, as well as some other rhizobia, presents nitrogenase reductase
      (nifH) gene reiterations. Several R. etli strains studied in this laboratory
      showed a unique organization and contained two complete nifHDK operons (copies a
      and b) and a truncated nifHD operon (copy c). Expression analysis of lacZ fusion
      demonstrated that copies a and b in strain CFN42 are transcribed at lower levels
      than copy c, although this copy has no discernible role during nitrogen fixation.
      To increase nitrogenase production, we constructed a chimeric nifHDK operon
      regulated by the strong nifHc promoter sequence and expressed it in symbiosis
      with the common bean plant (Phaseolus vulgaris), either cloned on a stably
      inherited plasmid or incorporated into the symbiotic plasmid (pSym). Compared
      with the wild-type strain, strains with the nitrogenase overexpression
      construction assayed in greenhouse experiments had, increased nitrogenase
      activity (58% on average), increased plant weight (32% on average), increased
      nitrogen content in plants (15% at 32 days postinoculation), and most
      importantly, higher seed yield (36% on average), higher nitrogen content (25%),
      and higher nitrogen yield (72% on average) in seeds. Additionally, expression of
      the chimeric nifHDK operon in a poly-beta-hydroxybutyrate-negative R. etli strain
      produced an additive effect in enhancing symbiosis. To our knowledge, this is the
      first report of increased seed yield and nutritional content in the common bean
      obtained by using only the genetic material already present in Rhizobium.

PMID- 15184122
TI  - In vivo production of artificial nonribosomal peptide products in the
      heterologous host Escherichia coli.
AB  - Nonribosomal peptide synthetases represent the enzymatic assembly lines for the
      biosynthesis of pharmacologically relevant natural peptides, e.g., cyclosporine,
      vancomycin, and penicillin. Due to their modular organization, in which every
      module accounts for the incorporation of a single amino acid, artificial assembly
      lines for the production of novel peptides can be constructed by biocombinatorial
      approaches. Once transferred into an appropriate host, these hybrid synthetases
      could facilitate the bioproduction of basically any peptide-based molecule. In
      the present study, we describe the fermentative production of the cyclic
      dipeptide D-Phe-Pro-diketopiperazine, as a prototype for the exploitation of the
      heterologous host Escherichia coli, and the use of artificial nonribosomal
      peptide synthetases. E. coli provides a tremendous potential for genetic
      engineering and was manipulated in our study by stable chromosomal integration of
      the 4'-phosphopantetheine transferase gene sfp to ensure heterologous production
      of fully active holoenzmyes. D-Phe-Pro-diketopiperazine is formed by the
      TycA/TycB1 system, whose components represent the first two modules for
      tyrocidine biosynthesis in Bacillus brevis. Coexpression of the corresponding
      genes in E. coli gave rise to the production of the expected diketopiperazine
      product, demonstrating the functional interaction of both modules in the
      heterologous environment. Furthermore, the cyclic dipeptide is stable and not
      toxic to E. coli and is secreted into the culture medium without the need for any
      additional factors. Parameters affecting the productivity were comprehensively
      investigated, including various genetic setups, as well as variation of medium
      composition and temperature. By these means, the overall productivity of the
      artificial system could be enhanced by over 400% to yield about 9 mg of D-Phe-Pro
      diketopiperazine/liter. As a general tool, this approach could allow the
      sustainable bioproduction of peptides, e.g., those used as pharmaceuticals or
      fine chemicals.

PMID- 15184123
TI  - Novel expression system for large-scale production and purification of
      recombinant class IIa bacteriocins and its application to piscicolin 126.
AB  - Piscicolin 126 is a class IIa bacteriocin isolated from Carnobacterium piscicola
      JG126 that exhibits strong activity against Listeria monocytogenes. The gene
      encoding mature piscicolin 126 (m-pisA) was cloned into an Escherichia coli
      expression system and expressed as a thioredoxin-piscicolin 126 fusion protein
      that was purified by affinity chromatography. Purified recombinant piscicolin 126
      was obtained after CNBr cleavage of the fusion protein followed by reversed-phase
      chromatography. Recombinant piscicolin 126 contained a single disulfide bond and
      had a mass identical to that of native piscicolin 126. This novel bacteriocin
      expression system generated approximately 26 mg of purified bacteriocin from 1
      liter of E. coli culture. The purified recombinant piscicolin 126 acted by
      disruption of the bacterial cell membrane.

PMID- 15184124
TI  - Cloning, nucleotide sequence, and overexpression of the L-rhamnose isomerase gene
      from Pseudomonas stutzeri in Escherichia coli.
AB  - The gene encoding L-rhamnose isomerase (L-RhI) from Pseudomonas stutzeri was
      cloned into Escherichia coli and sequenced. A sequence analysis of the DNA
      responsible for the L-RhI gene revealed an open reading frame of 1,290 bp coding
      for a protein of 430 amino acid residues with a predicted molecular mass of
      46,946 Da. A comparison of the deduced amino acid sequence with sequences in
      relevant databases indicated that no significant homology has previously been
      identified. An amino acid sequence alignment, however, suggested that the
      residues involved in the active site of L-RhI from E. coli are conserved in that
      from P. stutzeri. The L-RhI gene was then overexpressed in E. coli cells under
      the control of the T5 promoter. The recombinant clone, E. coli JM109, produced
      significant levels of L-RhI activity, with a specific activity of 140 U/mg and a
      volumetric yield of 20,000 U of soluble enzyme per liter of medium. This
      reflected a 20-fold increase in the volumetric yield compared to the value for
      the intrinsic yield. The recombinant L-RhI protein was purified to apparent
      homogeneity on the basis of three-step chromatography. The purified recombinant
      enzyme showed a single band with an estimated molecular weight of 42,000 in a
      sodium dodecyl sulfate-polyacrylamide gel. The overall enzymatic properties of
      the purified recombinant L-RhI protein were the same as those of the authentic
      one, as the optimal activity was measured at 60 degrees C within a broad pH range
      from 5.0 to 11.0, with an optimum at pH 9.0.

PMID- 15184125
TI  - Morphological, chemical, and genetic diversity of tropical marine cyanobacteria
      Lyngbya spp. and Symploca spp. (Oscillatoriales).
AB  - Although diverse natural products have been isolated from the benthic,
      filamentous cyanobacterium Lyngbya majuscula, it is unclear whether this chemical
      variation can be used to establish taxonomic relationships among disparate
      collections. We compared morphological characteristics, secondary-metabolite
      compositions, and partial 16S ribosomal DNA (rDNA) sequences among several
      collections of L. majuscula Gomont, Lyngbya spp., and Symploca spp. from Guam and
      the Republic of Palau. The morphological characteristics examined were cell
      length, cell width, and the presence or absence of a calyptra. Secondary
      metabolites were analyzed by two-dimensional thin-layer chromatography. Each
      collection possessed a distinct cellular morphology that readily distinguished
      Lyngbya spp. from Symploca spp. Each collection yielded a unique chemotype, but
      common chemical characteristics were shared among four collections of L.
      majuscula. A phylogeny based on secondary-metabolite composition supported the
      reciprocal monophyly of Lyngbya and Symploca but yielded a basal polytomy for
      Lyngbya. Pairwise sequence divergence among species ranged from 10 to 14% across
      605 bp of 16S rDNA, while collections of L. majuscula showed 0 to 1.3%
      divergence. Although the phylogeny of 16S rDNA sequences strongly supported the
      reciprocal monophyly of Lyngbya and Symploca as well as the monophyly of Lyngbya
      bouillonii and L. majuscula, genetic divergence was not correlated with chemical
      and morphological differences. These data suggest that 16S rDNA sequence analyses
      do not predict chemical variability among Lyngbya species. Other mechanisms,
      including higher rates of evolution for biosynthetic genes, horizontal gene
      transfer, and interactions between different genotypes and environmental
      conditions, may play important roles in generating qualitative and quantitative
      chemical variation within and among Lyngbya species.

PMID- 15184126
TI  - Evaluation of Nostoc strain ATCC 53789 as a potential source of natural
      pesticides.
AB  - The cyanobacterium Nostoc strain ATCC 53789, a known cryptophycin producer, was
      tested for its potential as a source of natural pesticides. The antibacterial,
      antifungal, insecticidal, nematocidal, and cytotoxic activities of methanolic
      extracts of the cyanobacterium were evaluated. Among the target organisms, nine
      fungi (Armillaria sp., Fusarium oxysporum f. sp. melonis, Penicillium expansum,
      Phytophthora cambivora, P. cinnamomi, Rhizoctonia solani, Rosellinia, sp.,
      Sclerotinia sclerotiorum, and Verticillium albo-atrum) were growth inhibited and
      one insect (Helicoverpa armigera) was killed by the extract, as well as the two
      model organisms for nematocidal (Caenorhabditis elegans) and cytotoxic (Artemia
      salina) activity. No antibacterial activity was detected. The antifungal activity
      against S. sclerotiorum was further studied with both extracts and biomass of the
      cyanobacterium in a system involving tomato as a host plant. Finally, the
      herbicidal activity of Nostoc strain ATCC 53789 was evaluated against a grass
      mixture. To fully exploit the potential of this cyanobacterium in agriculture as
      a source of pesticides, suitable application methods to overcome its toxicity
      toward plants and nontarget organisms must be developed.

PMID- 15184127
TI  - Purification, characterization, and sequencing of an extracellular cold-active
      aminopeptidase produced by marine psychrophile Colwellia psychrerythraea strain
      34H.
AB  - The limited database on cold-active extracellular proteases from marine bacteria
      was expanded by successful purification and initial biochemical and structural
      characterization of a family M1 aminopeptidase (designated ColAP) produced by the
      marine psychrophile Colwellia psychrerythraea strain 34H. The 71-kDa enzyme
      displayed a low optimum temperature (19 degrees C) and narrow pH range (pH 6 to
      8.5) for activity and greater thermolability than other extracellular proteases.
      Sequencing of the gene encoding ColAP revealed a predicted amino acid sequence
      with the highest levels of identity (45 to 55%) to M1 aminopeptidases from
      mesophilic members of the gamma subclass of the Proteobacteria and the next
      highest levels of identity (35 to 36%) to leukotriene A(4) hydrolases from
      mammalian sources. Compared to mesophilic homologs, ColAP had structural
      differences thought to increase the flexibility for activity in the cold; for
      example, it had fewer proline residues, fewer ion pairs, and a lower hydrophobic
      residue content. In addition to intrinsic properties that determine enzyme
      activity and stability, we also investigated effects of extracellular polymeric
      substances (EPS) from spent culture medium of strain 34H on ColAP activity at an
      environmentally relevant temperature (0 degrees C) and at 45 degrees C (the
      maximum temperature for activity). In both cases, ColAP stability increased
      significantly in the presence of EPS, indicating the importance of considering
      environmentally relevant extrinsic factors when enzyme structure and function are
      investigated.

PMID- 15184128
TI  - Enzyme production-based approach for determining the functions of microorganisms
      within a community.
AB  - The functions of specific microorganisms in a microbial community were
      investigated during the composting process. Cerasibacillus quisquiliarum strain
      BLx(T) and Bacillus thermoamylovorans strain BTa were isolated and characterized
      in our previous studies based on their dominance in the composting system. Strain
      BLx(T) degrades gelatin, while strain BTa degrades starch. We hypothesized that
      these strains play roles in gelatinase and amylase production, respectively. The
      relationship between changes in the abundance ratios of each strain and those of
      each enzyme activity during the composting process was examined to address this
      hypothesis. The increase in gelatinase activity in the compost followed a
      dramatic increase in the abundance ratio of strain BLx(T). Zymograph analysis
      demonstrated that the pattern of active gelatinase bands from strain BLx(T) was
      similar to that from the compost. Gelatinases from both BLx(T) and compost were
      partially purified and compared. Homologous N-terminal amino acid sequences were
      found in one of the gelatinases from strain BLx(T) and that of compost. These
      results indicate strain BLx(T) produces gelatinases during the composting
      process. Meanwhile, the increase in the abundance ratio of strain BTa was not
      concurrent with that of amylase activity in the compost. Moreover, the amylase
      activity pattern of strain BTa on the zymogram was different from that of the
      compost sample. These results imply that strain BTa may not produce amylases
      during the composting process. To our knowledge, this is the first report
      demonstrating that the function of a specific microorganism is directly linked to
      a function in the community, as determined by culture-independent and enzyme
      level approaches.

PMID- 15184129
TI  - Establishment of a pure culture of the hitherto uncultured unicellular
      cyanobacterium Aphanothece sacrum, and phylogenetic position of the organism.
AB  - Aphanothece sacrum, an edible freshwater unicellular cyanobacterium, was isolated
      by using novel synthetic media (designated AST and AST-5xNP). The media were
      designed on the basis of the ratio of inorganic elements contained in A. sacrum
      cells cultured in a natural pond. The isolated strain exhibits unicellular rod
      shaped cells approximately 6 microm in length that are scattered in an
      exopolysaccharide matrix, a feature similar to that of natural A. sacrum. DNA
      analysis of the isolated strain revealed that it carried two ferredoxin genes
      whose deduced amino acid sequences were almost identical to previously published
      sequences of ferredoxins from natural A. sacrum. Analysis of the 16S rRNA gene
      and ferredoxin genes revealed that A. sacrum occupies a phylogenetically unique
      position among the cyanobacteria.

PMID- 15184130
TI  - Evidence for the presence of Simkania negevensis in drinking water and in
      reclaimed wastewater in Israel.
AB  - Simkania negevensis is a recently discovered chlamydia-like intracellular
      microorganism which has been associated with bronchiolitis in infants and with
      community-acquired pneumonia in adults; a high seroprevalence of antibodies to
      the microorganism has been found in various population groups. S. negevensis can
      be grown in various cell lines as well as in free-living amoebae such as
      Acanthamoeba polyphaga. In this study, evidence for the existence of Simkania or
      Simkania-like microorganisms in drinking water and in reclaimed wastewater is
      presented for the first time. Detection of the microorganism was made possible by
      the development of a specific and sensitive filter membrane immunoassay and was
      confirmed by PCR detection of microbial DNA in the water samples. The common
      presence of S. negevensis in water sources together with the high seroprevalence
      of antibodies to it and early age of acquisition of infection may implicate water
      as a source of infection. The possible significance of this finding for public
      health and for municipal water testing and treatment needs to be further
      examined.

PMID- 15184131
TI  - Expression of functional recombinant mussel adhesive protein Mgfp-5 in
      Escherichia coli.
AB  - Mussel adhesive proteins have been suggested as a basis for environmentally
      friendly adhesives for use in aqueous conditions and in medicine. However,
      attempts to produce functional and economical recombinant mussel adhesive
      proteins (mainly foot protein type 1) in several systems have failed. Here, the
      cDNA coding for Mytilus galloprovincialis foot protein type 5 (Mgfp-5) was
      isolated for the first time. Using this cDNA, we produced a recombinant Mgfp-5
      fused with a hexahistidine affinity ligand, which was expressed in a soluble form
      in Escherichia coli and was highly purified using affinity chromatography. The
      adhesive properties of purified recombinant Mgfp-5 were compared with the
      commercial extracted mussel adhesive Cell-Tak by investigating adhesion force
      using atomic force microscopy, material surface coating, and quartz crystal
      microbalance. Even though further macroscale assays are needed, these microscale
      assays showed that recombinant Mgfp-5 has significant adhesive ability and may be
      useful as a bioadhesive in medical or underwater environments.

PMID- 15184132
TI  - Genome organization and localization of the pufLM genes of the photosynthesis
      reaction center in phylogenetically diverse marine Alphaproteobacteria.
AB  - Genome organization, plasmid content and localization of the pufLM genes of the
      photosynthesis reaction center were studied by pulsed-field gel electrophoresis
      (PFGE) in marine phototrophic Alphaproteobacteria. Both anaerobic phototrophs
      (Rhodobacter veldkampii and Rhodobacter sphaeroides) and strictly aerobic
      anoxygenic phototrophs from the Roseobacter-Sulfitobacter-Silicibacter clade
      (Roseivivax halodurans, Roseobacter litoralis, Staleya guttiformis, Roseovarius
      tolerans, and five new strains isolated from dinoflagellate cultures) were
      investigated. The complete genome size was estimated for R. litoralis DSM6996(T)
      to be 4,704 kb, including three linear plasmids. All strains contained
      extrachromosomal elements of various conformations (linear or circular) and
      lengths (between 4.35 and 368 kb). In strain DFL-12, a member of a putative new
      genus isolated from a culture of the toxic dinoflagellate Prorocentrum lima,
      seven linear plasmids were found, together comprising 860 kb of genetic
      information. Hybridization with probes against the pufLM genes of the
      photosynthesis gene cluster after Southern transfer of the genomic DNAs showed
      these genes to be located on a linear plasmid of 91 kb in R. litoralis and on a
      linear plasmid of 120 kb in S. guttiformis, theoretically allowing their
      horizontal transfer. In all other strains, the pufLM genes were detected on the
      bacterial chromosome. The large number and significant size of the linear
      plasmids found especially in isolates from dinoflagellates might account for the
      metabolic versatility and presumed symbiotic association with eukaryotic hosts in
      these bacteria.

PMID- 15184133
TI  - Increasing secretion of a bivalent anti-T-cell immunotoxin by Pichia pastoris.
AB  - The bivalent anti-T-cell immunotoxin A-dmDT390-bisFv(G(4)S) was developed for
      treatment of T-cell leukemia and autoimmune diseases and for tolerance induction
      for transplantation. This immunotoxin was produced extracellularly in toxin
      sensitive Pichia pastoris JW102 (Mut(+)) under control of the AOX1 promoter.
      There were two major barriers to efficient immunotoxin production, the toxicity
      of the immunotoxin for P. pastoris and the limited capacity of P. pastoris to
      secrete the immunotoxin. The immunotoxin toxicity resulted in a decrease in the
      methanol consumption rate, cessation of cell growth, and low immunotoxin
      productivity after the first 22 h of methanol induction. Continuous cell growth
      and continuous immunotoxin secretion after the first 22 h of methanol induction
      were obtained by adding glycerol to the methanol feed by using a 4:1 methanol
      glycerol mixed feed as an energy source and by continuously adding a yeast
      extract solution during methanol induction. The secretory capacity was increased
      from 22.5 to 37 mg/liter by lowering the induction temperature. A low temperature
      reduced the methanol consumption rate and protease activity in the supernatant
      but not cell growth. The effects of adding glycerol and yeast extract to the
      methanol feed were synergistic. Adding yeast extract primarily enhanced methanol
      utilization and cell growth, while adding glycerol primarily enhanced immunotoxin
      production. The synergy was further enhanced by decreasing the induction
      temperature from 23 to 15 degrees C, which resulted in a robust process with a
      yield of 37 mg/liter, which was sevenfold greater than the yield previously
      reported for a toxin-resistant CHO cell expression system. This methodology
      should be applicable to other toxin-related recombinant proteins in toxin
      sensitive P. pastoris.

PMID- 15184134
TI  - Aquaporin-mediated improvement of freeze tolerance of Saccharomyces cerevisiae is
      restricted to rapid freezing conditions.
AB  - Previous observations that aquaporin overexpression increases the freeze
      tolerance of baker's yeast (Saccharomyces cerevisiae) without negatively
      affecting the growth or fermentation characteristics held promise for the
      development of commercial baker's yeast strains used in frozen dough
      applications. In this study we found that overexpression of the aquaporin
      encoding genes AQY1-1 and AQY2-1 improves the freeze tolerance of industrial
      strain AT25, but only in small doughs under laboratory conditions and not in
      large doughs under industrial conditions. We found that the difference in the
      freezing rate is apparently responsible for the difference in the results. We
      tested six different cooling rates and found that at high cooling rates aquaporin
      overexpression significantly improved the survival of yeast cells, while at low
      cooling rates there was no significant effect. Differences in the cultivation
      conditions and in the thawing rate did not influence the freeze tolerance under
      the conditions tested. Survival after freezing is determined mainly by two
      factors, cellular dehydration and intracellular ice crystal formation, which
      depend in an inverse manner on the cooling velocity. In accordance with this so
      called two-factor hypothesis of freezing injury, we suggest that water
      permeability is limiting, and therefore that aquaporin function is advantageous,
      only under rapid freezing conditions. If this hypothesis is correct, then
      aquaporin overexpression is not expected to affect the leavening capacity of
      yeast cells in large, industrial frozen doughs, which do not freeze rapidly. Our
      results imply that aquaporin-overexpressing strains have less potential for use
      in frozen doughs than originally thought.

PMID- 15184135
TI  - Dimethylsulfoniopropionate metabolism by Pfiesteria-associated Roseobacter spp.
AB  - The Roseobacter clade of marine bacteria is often found associated with
      dinoflagellates, one of the major producers of dimethylsulfoniopropionate (DMSP).
      In this study, we tested the hypothesis that Roseobacter species have developed a
      physiological relationship with DMSP-producing dinoflagellates mediated by the
      metabolism of DMSP. DMSP was measured in Pfiesteria and Pfiesteria-like
      (Cryptoperidiniopsis) dinoflagellates, and the identities and metabolic
      potentials of the associated Roseobacter species to degrade DMSP were determined.
      Both Pfiesteria piscicida and Pfiesteria shumwayae produce DMSP with an average
      intracellular concentration of 3.8 microM. Cultures of P. piscicida or
      Cryptoperidiniopsis sp. that included both the dinoflagellates and their
      associated bacteria rapidly catabolized 200 microM DMSP (within 30 h), and the
      rate of catabolism was much higher for P. piscicida cultures than for P.
      shumwayae cultures. The community of bacteria from P. piscicida and
      Cryptoperidiniopsis cultures degraded DMSP with the production of dimethylsulfide
      (DMS) and acrylate, followed by 3-methylmercaptopropionate (MMPA) and
      methanethiol (MeSH). Four DMSP-degrading bacteria were isolated from the P.
      piscicida cultures and found to be taxonomically related to Roseobacter species.
      All four isolates produced MMPA from DMSP. Two of the strains also produced MeSH
      and DMS, indicating that they are capable of utilizing both the lyase and
      demethylation pathways. The diverse metabolism of DMSP by the dinoflagellate
      associated Roseobacter spp. offers evidence consistent with a hypothesis that
      these bacteria benefit from association with DMSP-producing dinoflagellates.

PMID- 15184136
TI  - Biomass content governs fermentation rate in nitrogen-deficient wine musts.
AB  - Problematic fermentations are common in the wine industry. Assimilable nitrogen
      deficiency is the most prevalent cause of sluggish fermentations and can reduce
      fermentation rates significantly. A lack of nitrogen diminishes a yeast's
      metabolic activity, as well as the biomass yield, although it has not been clear
      which of these two interdependent factors is more significant in sluggish
      fermentations. Under winemaking conditions with different initial nitrogen
      concentrations, metabolic flux analysis was used to isolate the effects. We
      quantified yeast physiology and identified key metabolic fluxes. We also
      performed cell concentration experiments to establish how biomass yield affects
      the fermentation rate. Intracellular analysis showed that trehalose accumulation,
      which is highly correlated with ethanol production, could be responsible for
      sustaining cell viability in nitrogen-poor musts independent of the initial
      assimilable nitrogen content. Other than the higher initial maintenance costs in
      sluggish fermentations, the main difference between normal and sluggish
      fermentations was that the metabolic flux distributions in nitrogen-deficient
      cultures revealed that the specific sugar uptake rate was substantially lower.
      The results of cell concentration experiments, however, showed that in spite of
      lower sugar uptake, adding biomass from sluggish cultures not only reduced the
      time to finish a problematic fermentation but also was less likely to affect the
      quality of the resulting wine as it did not alter the chemistry of the must.

PMID- 15184137
TI  - Evolutionary relationships of primary prokaryotic endosymbionts of whiteflies and
      their hosts.
AB  - Whiteflies (Hemiptera: Sternorrhyncha: Aleyrodidae) are plant sap-sucking insects
      that harbor prokaryotic primary endosymbionts (P-endosymbionts) within
      specialized cells located in their body cavity. Four-kilobase DNA fragments
      containing 16S-23S ribosomal DNA (rDNA) were amplified from the P-endosymbiont of
      24 whiteflies from 22 different species of 2 whitefly subfamilies. In addition, 3
      kb DNA fragments containing mitochondrial cytB, nd1, and large-subunit rDNA
      (LrDNA) were amplified from 17 whitefly species. Comparisons of the P
      endosymbiont (16S-23S rDNA) and host (cytB-nd1-LrDNA) phylogenetic trees
      indicated overall congruence consistent with a single infection of a whitefly
      ancestor with a bacterium and subsequent cospeciation (cocladogenesis) of the
      host and the P-endosymbiont. On the basis of both the P-endosymbiont and host
      trees, the whiteflies could be subdivided into at least five clusters. The major
      subdivision was between the subfamilies Aleyrodinae and Aleurodicinae. Unlike the
      P-endosymbionts of may other insects, the P-endosymbionts of whiteflies were
      related to Pseudomonas and possibly to the P-endosymbionts of psyllids. The
      lineage consisting of the P-endosymbionts of whiteflies is given the designation
      "Candidatus Portiera" gen. nov., with a single species, "Candidatus Portiera
      aleyrodidarum" sp. nov.

PMID- 15184138
TI  - Cloning, sequencing, and characterization of a heat- and alkali-stable type I
      pullulanase from Anaerobranca gottschalkii.
AB  - The gene encoding a type I pullulanase was identified from the genome sequence of
      the anaerobic thermoalkaliphilic bacterium Anaerobranca gottschalkii. In
      addition, the homologous gene was isolated from a gene library of Anaerobranca
      horikoshii and sequenced. The proteins encoded by these two genes showed 39%
      amino acid sequence identity to the pullulanases from the thermophilic anaerobic
      bacteria Fervidobacterium pennivorans and Thermotoga maritima. The pullulanase
      gene from A. gottschalkii (encoding 865 amino acids with a predicted molecular
      mass of 98 kDa) was cloned and expressed in Escherichia coli strain BL21(DE3) so
      that the protein did not have the signal peptide. Accordingly, the molecular mass
      of the purified recombinant pullulanase (rPulAg) was 96 kDa. Pullulan hydrolysis
      activity was optimal at pH 8.0 and 70 degrees C, and under these physicochemical
      conditions the half-life of rPulAg was 22 h. By using an alternative expression
      strategy in E. coli Tuner(DE3)(pLysS), the pullulanase gene from A. gottschalkii,
      including its signal peptide-encoding sequence, was cloned. In this case, the
      purified recombinant enzyme was a truncated 70-kDa form (rPulAg'). The N-terminal
      sequence of purified rPulAg' was found 252 amino acids downstream from the start
      site, presumably indicating that there was alternative translation initiation or
      N-terminal protease cleavage by E. coli. Interestingly, most of the
      physicochemical properties of rPulAg' were identical to those of rPulAg. Both
      enzymes degraded pullulan via an endo-type mechanism, yielding maltotriose as the
      final product, and hydrolytic activity was also detected with amylopectin,
      starch, beta-limited dextrins, and glycogen but not with amylose. This substrate
      specificity is typical of type I pullulanases. rPulAg was inhibited by
      cyclodextrins, whereas addition of mono- or bivalent cations did not have a
      stimulating effect. In addition, rPulAg' was stable in the presence of 0.5%
      sodium dodecyl sulfate, 20% Tween, and 50% Triton X-100. The pullulanase from A.
      gottschalkii is the first thermoalkalistable type I pullulanase that has been
      described.

PMID- 15184139
TI  - Evaluation of a cocktail of three bacteriophages for biocontrol of Escherichia
      coli O157:H7.
AB  - Escherichia coli O157:H7 is an endemic pathogen causing a variety of human
      diseases including mild diarrhea, hemorrhagic colitis, hemolytic-uremic syndrome,
      and thrombotic thrombocytopenic purpura. This study concerns the exploitation of
      bacteriophages as biocontrol agents to eliminate the pathogen E. coli O157:H7.
      Two distinct lytic phages (e11/2 and e4/1c) isolated against a human strain of E.
      coli O157:H7, a previously isolated lytic phage (pp01), and a cocktail of all
      three phages were evaluated for their ability to lyse the bacterium in vivo and
      in vitro. Phage e11/2, pp01, and the cocktail of all three virulent phages
      resulted in a 5-log-unit reduction of pathogen numbers in 1 h at 37 degrees C.
      However, bacteriophage-insensitive mutants (BIMs) emerged following the
      challenge. All tested BIMs had a growth rate which approximated that of the
      parental O157 strain, although many of these BIMs had a smaller, more coccoid
      cellular morphology. The frequency of BIM formation (10(-6) CFU) was similar for
      e11/2, pp01, and the phage cocktail, while BIMs insensitive to e4/1c occurred at
      the higher frequency (10(-4) CFU). In addition, BIMs commonly reverted to phage
      sensitivity within 50 generations. In an initial meat trial experiment, the phage
      cocktail completely eliminated E. coli O157:H7 from the beef meat surface in
      seven of nine cases. Given that the frequency of BIM formation is low (10(-6)
      CFU) for two of the phages, allied to the propensity of these mutants to revert
      to phage sensitivity, we expect that BIM formation should not hinder the use of
      these phages as biocontrol agents, particularly since low levels of the pathogen
      are typically encountered in the environment.

PMID- 15184140
TI  - Richness and diversity of bacterioplankton species along an estuarine gradient in
      Moreton Bay, Australia.
AB  - Bacterioplankton community diversity was investigated in the subtropical Brisbane
      River-Moreton Bay estuary, Australia (27 degrees 25 minutes S, 153 degrees 5
      minutes E). Bacterial communities were studied using automated rRNA intergenic
      spacer analysis (ARISA), which amplifies 16S-23S ribosomal DNA internally
      transcribed spacer regions from mixed-community DNA and detects the separated
      products on a fragment analyzer. Samples were collected from eight sites
      throughout the estuary and east to the East Australian Current (Coral Sea).
      Bacterioplankton communities had the highest operational taxonomic unit (OTU)
      richness, as measured by ARISA at eastern bay stations (S [total richness] = 84
      to 85 OTU) and the lowest richness in the Coral Sea (S = 39 to 59 OTU). Richness
      correlated positively with bacterial abundance; however, there were no strong
      correlations between diversity and salinity, NO(3)(-) and PO(4)(3-)
      concentrations, or chlorophyll a concentration. Bacterioplankton communities at
      the riverine stations were different from communities in the bay or Coral Sea.
      The main differences in OTU richness between stations were in taxa that each
      represented 0.1% (the detection limit) to 0.5% of the total amplified DNA, i.e.,
      the "tail" of the distribution. We found that some bacterioplankton taxa are
      specific to distinct environments while others have a ubiquitous distribution
      from river to sea. Bacterioplankton richness and diversity patterns in the
      estuary are potentially a consequence of greater niche availability, mixing of
      local and adjacent environment communities, or intermediate disturbance.
      Furthermore, these results contrast with previous reports of spatially
      homogeneous bacterioplankton communities in other coastal waters.

PMID- 15184141
TI  - Virus-binding proteins recovered from bacterial culture derived from activated
      sludge by affinity chromatography assay using a viral capsid peptide.
AB  - The contamination of water environments by pathogenic viruses has raised concerns
      about outbreaks of viral infectious diseases in our society. Because conventional
      water and wastewater treatment systems are not effective enough to inactivate or
      remove pathogenic viruses, a new technology for virus removal needs to be
      developed. In this study, the virus-binding proteins (VBPs) in a bacterial
      culture derived from activated sludge were successfully recovered. The recovery
      of VBPs was achieved by applying extracted crude proteins from a bacterial
      culture to an affinity column in which a custom-made peptide of capsid protein
      from the poliovirus type 1 (PV1) Mahoney strain (H(2)N-DNPASTTNKDKL-COOH) was
      immobilized as a ligand. VBPs exhibited the ability to adsorb infectious
      particles of PV1 Sabin 1 as determined by enzyme-linked immunosorbent assay. The
      evaluation of surface charges of VBPs with ion-exchange chromatography found that
      a majority of VBP molecules had a net negative charge under the conditions of
      affinity chromatography. On the other hand, a calculated isoelectric point
      implied that the viral peptide in the affinity column was also charged
      negatively. As a result, the adsorption of the VBPs to the viral peptide in the
      affinity column occurred with a strong attractive force that was able to overcome
      the electrostatic repulsive force. Two-dimensional electrophoresis revealed that
      the isolated VBPs include a number of proteins, and their molecular masses were
      widely distributed but smaller than 100 kDa. Amino acid sequences of N termini of
      five VBPs were determined. Homology searches for the N termini against all
      protein sequences in the National Center for Biotechnology Information (NCBI)
      database showed that the isolated VBPs in this study were newly discovered
      proteins. These VBPs that originated with bacteria in activated sludge might be
      stable, because they are existing in the environment of wastewater treatments.
      Therefore, a virus removal technology utilizing VBPs as viral adsorbents can be
      developed, since it is possible to replicate VBPs by protein cloning techniques.

PMID- 15184142
TI  - Distribution of RuBisCO genotypes along a redox gradient in Mono Lake,
      California.
AB  - Partial sequences of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)
      (EC 4.1.1.39) genes were retrieved from samples taken along a redox gradient in
      alkaline, hypersaline Mono Lake, Calif. The form I gene (cbbL) was found in all
      samples, whereas form II (cbbM) was not retrieved from any of the samples. None
      of the RuBisCO sequences we obtained were closely related (nucleotide similarity,
      <90%) to sequences in the database. Some could be attributed to organisms
      isolated from the lake (Cyanobium) or appearing in enrichment cultures. Most
      (52%) of the sequences fell into in one clade, containing sequences that were
      identical to sequences retrieved from an enrichment culture grown with nitrate
      and sulfide, and another clade contained sequences identical to those retrieved
      from an arsenate-reducing, sulfide-oxidizing enrichment.

PMID- 15184143
TI  - Effects of quaternary-ammonium-based formulations on bacterial community dynamics
      and antimicrobial susceptibility.
AB  - Quaternary ammonium compounds (QACs) are widely used as adjuncts to hygiene in
      domestic cleaning products. Current concern that the increased use of such
      biocides in consumer products might contribute to the emergence of antibiotic
      resistance has led us to examine the effects of a QAC-containing domestic
      cleaning fluid on the population dynamics and antimicrobial susceptibility of
      domestic sink drain biofilm communities. QAC susceptibilities of numerically
      dominant, culturable drain bacteria (15 genera, 17 species) were determined in
      vitro before and after repeated QAC exposure (14 passages). A fully characterized
      drain microcosm was then exposed to short-term (12 days) and long-term (3 months)
      dosing with a QAC-containing domestic detergent (QD). QAC exposure of isolated
      cultures caused both increases (three species) and circa twofold decreases (six
      species) in QAC susceptibility. The susceptibility of Ralstonia sp. was
      considerably decreased following 14 consecutive QAC passages. Control drain
      microcosm biofilms maintained dynamic stability, as evidenced by culture and
      denaturing gradient gel electrophoresis (DGGE) analysis. Bacterial population
      densities were largely unaffected during short-term exposure to use levels of QD,
      although 50% QD caused circa 10-fold viability reductions. DGGE analysis
      supported these observations; identified the major microcosm genera as
      Pseudomonas, Pseudoalteromonas, Erwinia, and Enterobacter, and showed that
      aeromonads increased in abundance under 10 to 50% QD. Long-term exposure of the
      microcosms to QD did not significantly alter the pattern of antimicrobial
      susceptibility. These data demonstrate the recalcitrance of domestic drain
      biofilms toward QAC and that although repeated QAC exposure of drain isolates in
      pure culture results in susceptibility change in some test bacteria, such changes
      do not necessarily occur within complex communities.

PMID- 15184144
TI  - Identification of sigma factor sigma B-controlled genes and their impact on acid
      stress, high hydrostatic pressure, and freeze survival in Listeria monocytogenes
      EGD-e.
AB  - The gene encoding the alternative sigma factor sigma(B) in Listeria monocytogenes
      is induced upon exposure of cells to several stresses. In this study, we
      investigated the impact of a sigB null mutation on the survival of L.
      monocytogenes EGD-e at low pH, during high-hydrostatic-pressure treatment, and
      during freezing. The survival of Delta sigB mutant exponential-phase cells at pH
      2.5 was 10,000-fold lower than the survival of EGD-e wild-type cells. Moreover,
      the Delta sigB mutant failed to show an acid tolerance response. Upon preexposure
      for 1 h to pH 4.5, the survival at pH 2.5 was 100,000-fold lower for the Delta
      sigB mutant than for the wild type. The glutamate decarboxylase (GAD) acid
      resistance system is important in survival and adaptation of L. monocytogenes in
      acidic conditions. The sigma(B) dependence of the gad genes (gadA, gadB, gadC,
      gadD, and gadE) was analyzed in silico. Putative sigma(B)-dependent promoter
      sites were found upstream of the gadCB operon (encoding a glutamate/gamma
      aminobutyrate antiporter and a glutamate decarboxylase, respectively) and the
      lmo2434 gene (gadD, encoding a putative glutamate decarboxylase). Reverse
      transcriptase PCR revealed that expression of the gadCB operon and expression of
      gadD are indeed sigma(B) dependent. In addition, a proteomics approach was used
      to analyze the protein expression profiles upon acid exposure. Although the GAD
      proteins were not recovered, nine proteins accumulated in the wild type but not
      in the Delta sigB strain. These proteins included Pfk, GalE, ClpP, and Lmo1580.
      Exposure to pH 4.5, in order to preload cells with active sigma(B) and
      consequently with sigma (B)-dependent general stress proteins, also provided
      considerable protection against high-hydrostatic-pressure treatment and freezing.
      The combined data argue that the expression of sigma(B)-dependent genes provides
      L. monocytogenes with nonspecific multiple-stress resistance that may be relevant
      for survival in the natural environment as well as during food processing.

PMID- 15184145
TI  - Extracellular iron reduction is mediated in part by neutral red and hydrogenase
      in Escherichia coli.
AB  - Both microbial iron reduction and microbial reduction of anodes in fuel cells can
      occur by way of soluble electron mediators. To test whether neutral red (NR)
      mediates iron reduction, as it does anode reduction, by Escherichia coli, ferrous
      iron levels were monitored in anaerobic cultures grown with amorphous iron oxide.
      Ferrous iron levels were 19.4 times higher in cultures fermenting pyruvate in the
      presence of NR than in the absence of NR. NR did not stimulate iron reduction in
      cultures respiring with nitrate. To explore the mechanism of NR-mediated iron
      reduction, cell extracts of E. coli were used. Cell extract-NADH-NR mixtures had
      an enzymatic iron reduction rate almost 15-fold higher than the chemical NR
      mediated iron reduction rate observed in controls with no cell extract. Hydrogen
      was consumed during stationary phase (in which iron reduction was detectable)
      especially in cultures containing both NR and iron oxide. An E. coli hypE mutant,
      with no hydrogenase activity, was also impaired in NR-mediated iron reduction
      activity. NR-mediated iron reduction rates by cell extracts were 1.5 to 2 times
      higher with hydrogen or formate as the electron source than with NADH. Our
      findings suggest that hydrogenase donates electrons to NR for extracellular iron
      reduction. This process appears to be analogous to those of iron reduction by
      bacteria that use soluble electron mediators (e.g., humic acids and 2,6
      anthraquinone disulfonate) and of anode reduction by bacteria using soluble
      mediators (e.g., NR and thionin) in microbial fuel cells.

PMID- 15184146
TI  - Syntrophic-methanogenic associations along a nutrient gradient in the Florida
      Everglades.
AB  - Nutrient runoff from the Everglades Agricultural Area resulted in a well
      documented gradient of phosphorus concentrations in soil and water, with
      concomitant ecosystem-level changes, in the northern Florida Everglades. It was
      recently reported that sulfate-reducing prokaryote assemblage composition,
      numbers, and activities are dependent on position along the gradient (H. Castro,
      K. R. Reddy, and A. Ogram, Appl. Environ. Microbiol. 68:6129-6137, 2002). The
      present study utilized a combination of culture- and non-culture-based approaches
      to study differences in composition of assemblages of syntrophic and methanogenic
      microbial communities in eutrophic, transition, and oligotrophic areas along the
      phosphorus gradient. Methanogenesis rates were much higher in eutrophic and
      transition regions, and sequence analysis of 16S rRNA gene clone libraries
      constructed from samples taken from these regions revealed differences in
      composition and activities of syntroph-methanogen consortia. Methanogens from
      eutrophic and transition regions were almost exclusively composed of
      hydrogenotrophic methanogens, with approximately 10,000-fold-greater most
      probable numbers of hydrogenotrophs than of acetotrophs. Most cultivable strains
      from eutrophic and transition regions clustered within novel lineages. In non
      culture-based studies to enrich syntrophs, most bacterial and archaeal clones
      were either members of novel lineages or closely related to uncultivated
      environmental clones. Novel cultivable Methanosaeta sp. and fatty acid-oxidizing
      bacteria related to the genera Syntrophomonas and Syntrophobacter were observed
      in microcosms containing soil from eutrophic regions, and different lines of
      evidence indicated the existence of novel syntrophic association in eutrophic
      regions.

PMID- 15184147
TI  - Effects of physical properties of feed on microbial ecology and survival of
      Salmonella enterica serovar Typhimurium in the pig gastrointestinal tract.
AB  - A two-by-two factorial experiment with pigs was conducted to study the effect of
      feed grinding (fine and coarse) and feed processing (pelleted and nonpelleted) on
      physicochemical properties, microbial populations, and survival of Salmonella
      enterica serovar Typhimurium DT12 in the gastrointestinal tracts of pigs. Results
      demonstrated a strong effect of diet on parameters measured in the stomachs of
      the pigs, whereas the effect was less in the other parts of the gastrointestinal
      tract. Pigs fed the coarse nonpelleted (C-NP) diet showed more solid gastric
      content with higher dry matter content than pigs fed the fine nonpelleted (F-NP),
      coarse pelleted (C-P), or fine pelleted (F-P) diet. Pigs fed the C-NP diet also
      showed significantly increased number of anaerobic bacteria (P < 0.05), increased
      concentrations of organic acids, and reduced pH in the stomach. In addition, pigs
      fed the C-NP diet showed increased in vitro death rate of S. enterica serovar
      Typhimurium DT12 in content from the stomach (P < 0.001). Pigs fed the C-NP diet
      had a significantly higher concentration of undissociated lactic acid in gastric
      content than pigs fed the other diets (P < 0.001). A strong correlation between
      the concentration of undissociated lactic acid and the death rate of S. enterica
      serovar Typhimurium DT12 was found. In the distal small intestine, cecum, and
      midcolon, significantly lower numbers of coliform bacteria were observed in pigs
      fed the coarse diets than in pigs fed the fine diets (P < 0.01). Pigs fed the C
      NP diet showed the lowest number of coliform bacteria in these segments of the
      gastrointestinal tract. Pigs fed the coarse diets showed increased concentration
      of butyric acid in the cecum (P < 0.05) and colon (P < 0.10) compared with pigs
      fed the fine diets. It was concluded that feeding a coarsely ground meal feed to
      pigs changes the physicochemical and microbial properties of content in the
      stomach, which decreases the survival of Salmonella during passage through the
      stomach. In this way the stomach acts as a barrier preventing harmful bacteria
      from entering and proliferating in the lower part of the gastrointestinal tract.

PMID- 15184148
TI  - Analysis of the peptidoglycan hydrolase complement of Lactococcus lactis:
      identification of a third N-acetylglucosaminidase, AcmC.
AB  - The peptidoglycan hydrolase (PGH) complement of Lactococcus lactis was identified
      by amino acid sequence similarity searching of the L. lactis IL-1403 complete
      genome sequence. Five PGHs that are not encoded by prophages were detected,
      including the previously characterized AcmA and AcmB proteins. Four of these
      PGHs, AcmA to AcmD, contain a catalytic domain homologous to that of enterococcal
      muramidase, but they have different domain structures. The fifth one (YjgB) has
      sequence similarity with the active-site domain of peptidoglycan-specific
      endopeptidases. The three new PGH-encoding genes identified in this study are all
      actively transcribed in L. lactis subsp. cremoris MG1363. The relative abundance
      of their transcripts varied during growth and was maximal during the early
      exponential growth phase. The three encoded proteins have peptidoglycan
      hydrolyzing activities which are detected only at acidic pHs by zymography. Like
      AcmA and AcmB, AcmC has N-acetylglucosaminidase activity rather than the N
      acetylmuramidase activity predicted by sequence similarity.

PMID- 15184149
TI  - Adaptation of Escherichia coli O157:H7 to pH alters membrane lipid composition,
      verotoxin secretion, and resistance to simulated gastric fluid acid.
AB  - The influence of adaptation to pH (from pH 5.0 to 9.0) on membrane lipid
      composition, verotoxin concentration, and resistance to acidic conditions in
      simulated gastric fluid (SGF) (pH 1.5, 37 degrees C) was determined for
      Escherichia coli O157:H7 (HEC, ATCC 43895), an rpoS-deficient mutant of ATCC
      43895 (HEC-RM, FRIK 816-3), and nonpathogenic E. coli (NPEC, ATCC 25922).
      Regardless of the strain, D values (in SGF) of acid-adapted cells were higher
      than those of non-acid-adapted cells, with HEC adapted at pH 5.0 having the
      greatest D value, i.e., 25.6 min. Acid adaptation increased the amounts of
      palmitic acid (C16:0) and decreased cis-vaccenic acid (C18:1 omega 7c) in the
      membrane lipids of all strains. The ratio of cis-vaccenic acid to palmitic acid
      increased at acidic pH, causing a decrease in membrane fluidity. HEC adapted to
      pH 8.3 and HEC-RM adapted to pH 7.3 exhibited the greatest verotoxin
      concentrations (2,470 and 1,460 ng/ml, respectively) at approximately 10(8)
      CFU/ml. In addition, the ratio of extracellular to intracellular verotoxin
      concentration decreased at acidic pH, possibly due to the decrease of membrane
      fluidity. These results suggest that while the rpoS gene does not influence acid
      resistance in acid-adapted cells it does confer decreased membrane fluidity,
      which may increase acid resistance and decrease verotoxin secretion.

PMID- 15184150
TI  - The weak acid preservative sorbic acid inhibits conidial germination and mycelial
      growth of Aspergillus niger through intracellular acidification.
AB  - The growth of the filamentous fungus Aspergillus niger, a common food spoilage
      organism, is inhibited by the weak acid preservative sorbic acid (trans-trans-2,4
      hexadienoic acid). Conidia inoculated at 10(5)/ml of medium showed a sorbic acid
      MIC of 4.5 mM at pH 4.0, whereas the MIC for the amount of mycelia at 24 h
      developed from the same spore inoculum was threefold lower. The MIC for conidia
      and, to a lesser extent, mycelia was shown to be dependent on the inoculum size.
      A. niger is capable of degrading sorbic acid, and this ability has consequences
      for food preservation strategies. The mechanism of action of sorbic acid was
      investigated using (31)P nuclear magnetic resonance (NMR) spectroscopy. We show
      that a rapid decline in cytosolic pH (pH(cyt)) by more than 1 pH unit and a
      depression of vacuolar pH (pH(vac)) in A. niger occurs in the presence of sorbic
      acid. The pH gradient over the vacuole completely collapsed as a result of the
      decline in pH(cyt). NMR spectra also revealed that sorbic acid (3.0 mM at pH 4.0)
      caused intracellular ATP pools and levels of sugar-phosphomonoesters and 
      phosphodiesters of A. niger mycelia to decrease dramatically, and they did not
      recover. The disruption of pH homeostasis by sorbic acid at concentrations below
      the MIC could account for the delay in spore germination and retardation of the
      onset of subsequent mycelial growth.

PMID- 15184151
TI  - Detection and quantification of airborne conidia of Fusarium circinatum, the
      causal agent of pine pitch canker, from two California sites by using a real-time
      PCR approach combined with a simple spore trapping method.
AB  - Pinus radiata (Monterey pine), a tree native to coastal California and Mexico, is
      widely planted worldwide for timber production. A major threat to Monterey pine
      plantations is the fungal disease pine pitch canker, caused by Fusarium
      circinatum (Hypocreales). We present a novel trapping approach using filter paper
      in combination with a rapid molecular method to detect the presence of inoculum
      in the air. The assay is also useful for diagnosing the presence of the pathogen
      on plants. The test is based on the F. circinatum specific primer pair CIRC1A
      CIRC4A, which amplifies a 360-bp DNA fragment in the intergenic spacer region of
      the nuclear ribosomal operon. Real-time PCR was used to calculate the number of
      fungal spores present in each reaction mixture by comparing the threshold cycle
      (Ct) of unknown spore samples to the Ct values of standards with known amounts of
      F. circinatum spores. The filter paper method allows prolonged and more sensitive
      spore sampling in the field compared to traditional traps using petri dishes
      filled with selective medium. A field test at two sites in coastal California
      infested with pine pitch canker was carried out during the summer and fall of
      2002. Spore counts were in the range of ca. 1 x 10(3) to ca. 7 x 10(5)/m(2), with
      the highest spore counts in the fall, suggesting a seasonal fluctuation.

PMID- 15184152
TI  - Specific 12 beta-hydroxylation of cinobufagin by filamentous fungi.
AB  - Biotransformation of natural products has great potential for producing new drugs
      and could provide in vitro models of mammalian metabolism. Microbial
      transformation of the cytotoxic steroid cinobufagin was investigated. Cinobufagin
      could be specifically hydroxylated at the 12 beta-position by the fungus
      Alternaria alternata. Six products from a scaled-up fermentation were obtained by
      silica gel column chromatography and reversed-phase liquid chromatography and
      were identified as 12 beta-hydroxyl cinobufagin, 12 beta-hydroxyl
      desacetylcinobufagin, 3-oxo-12 beta-hydroxyl cinobufagin, 3-oxo-12 beta-hydroxyl
      desacetylcinobufagin, 12-oxo-cinobufagin, and 3-oxo-12 alpha-hydroxyl
      cinobufagin. The last five products are new compounds. 12 beta-Hydroxylation of
      cinobufagin by A. alternata is a fast catalytic reaction and was complete within
      8 h of growth with the substrate. This reaction was followed by dehydrogenation
      of the 3-hydroxyl group and then deacetylation at C-16. Hydroxylation at C-12
      beta also was the first step in the metabolism of cinobufagin by a variety of
      fungal strains. In vitro cytotoxicity assays suggest that 12 beta-hydroxyl
      cinobufagin and 3-oxo-12 alpha-hydroxyl cinobufagin exhibit somewhat decreased
      but still significant cytotoxic activities. The 12 beta-hydroxylated
      bufadienolides produced by microbial transformation are difficult to obtain by
      chemical synthesis.

PMID- 15184153
TI  - Phylogenetic and ecological analysis of novel marine stramenopiles.
AB  - Culture-independent molecular analyses of open-sea microorganisms have revealed
      the existence and apparent abundance of novel eukaryotic lineages, opening new
      avenues for phylogenetic, evolutionary, and ecological research. Novel marine
      stramenopiles, identified by 18S ribosomal DNA sequences within the basal part of
      the stramenopile radiation but unrelated to any previously known group,
      constituted one of the most important novel lineages in these open-sea samples.
      Here we carry out a comparative analysis of novel stramenopiles, including new
      sequences from coastal genetic libraries presented here and sequences from recent
      reports from the open ocean and marine anoxic sites. Novel stramenopiles were
      found in all major habitats, generally accounting for a significant proportion of
      clones in genetic libraries. Phylogenetic analyses indicated the existence of 12
      independent clusters. Some of these were restricted to anoxic or deep-sea
      environments, but the majority were typical components of coastal and open-sea
      waters. We specifically identified four clusters that were well represented in
      most marine surface waters (together they accounted for 74% of the novel
      stramenopile clones) and are the obvious targets for future research. Many
      sequences were retrieved from geographically distant regions, indicating that
      some organisms were cosmopolitan. Our study expands our knowledge on the
      phylogenetic diversity and distribution of novel marine stramenopiles and
      confirms that they are fundamental members of the marine eukaryotic picoplankton.

PMID- 15184154
TI  - Prevalence of the stx2 gene in coliform populations from aquatic environments.
AB  - Shiga toxin-producing Escherichia coli strains are human pathogens linked to
      hemorrhagic colitis and hemolytic uremic syndrome. The major virulence factors of
      these strains are Shiga toxins Stx1 and Stx2. The majority of the genes coding
      for these toxins are borne by bacteriophages. Free Stx2-encoding bacteriophages
      have been found in aquatic environments, but there is limited information about
      the lysogenic strains and bacteria present in the environment that are
      susceptible to phage infection. The aim of this work was to study the prevalence
      and the distribution of the stx(2) gene in coliform bacteria in sewage samples of
      different origins. The presence of the stx(2) gene was monitored every 2 weeks
      over a 1-year period in a municipal sewage treatment plant. A mean value of 10(2)
      genes/ml was observed without significant variation during the study period. This
      concentration was of the same order of magnitude in raw municipal sewage of
      various origins and in animal wastewater from several slaughterhouses. A total of
      138 strains carrying the stx(2) gene were isolated by colony hybridization. This
      procedure detected approximately 1 gene-carrying colony per 1,000 fecal coliform
      colonies in municipal sewage and around 1 gene-carrying colony per 100 fecal
      coliform colonies in animal wastewaters. Most of the isolates belonged to E. coli
      serotypes other than E. coli O157, suggesting a low prevalence of strains of this
      serotype carrying the stx(2) gene in the wastewater studied.

PMID- 15184155
TI  - Molecular profiling of rhizosphere microbial communities associated with healthy
      and diseased black spruce (Picea mariana) seedlings grown in a nursery.
AB  - Bacterial and fungal populations associated with the rhizosphere of healthy black
      spruce (Picea mariana) seedlings and seedlings with symptoms of root rot were
      characterized by cloned rRNA gene sequence analysis. Triplicate bacterial and
      fungal rRNA gene libraries were constructed, and 600 clones were analyzed by
      amplified ribosomal DNA restriction analysis and grouped into operational
      taxonomical units (OTUs). A total of 84 different bacterial and 31 different
      fungal OTUs were obtained and sequenced. Phylogenetic analyses indicated that the
      different OTUs belonged to a wide range of bacterial and fungal taxa. For both
      groups, pairwise comparisons revealed that there was greater similarity between
      replicate libraries from each treatment than between libraries from different
      treatments. Significant differences between pooled triplicate samples from
      libraries of genes from healthy seedlings and pooled triplicate samples from
      libraries of genes from diseased seedlings were also obtained for both bacteria
      and fungi, clearly indicating that the rhizosphere-associated bacterial and
      fungal communities of healthy and diseased P. mariana seedlings were different.
      The communities associated with healthy and diseased seedlings also showed
      distinct ecological parameters as indicated by the calculated diversity,
      dominance, and evenness indices. Among the main differences observed at the
      community level, there was a higher proportion of Acidobacteria,
      Gammaproteobacteria, and Homobasidiomycetes clones associated with healthy
      seedlings, while the diseased-seedling rhizosphere harbored a higher proportion
      of Actinobacteria, Sordariomycetes, and environmental clones. The methodological
      approach described in this study appears promising for targeting potential
      rhizosphere-competent biological control agents against root rot diseases
      occurring in conifer nurseries.

PMID- 15184156
TI  - Spatial distribution of bacterial communities and phenanthrene degradation in the
      rhizosphere of Lolium perenne L.
AB  - Rhizodegradation of organic pollutants, such as polycyclic aromatic hydrocarbons,
      is based on the effect of root-produced compounds, known as exudates. These
      exudates constitute an important and constant carbon source that selects
      microbial populations in the plant rhizosphere, modifying global as well as
      specific microbial activities. We conducted an experiment in two-compartment
      devices to show the selection of bacterial communities by root exudates and
      phenanthrene as a function of distance to roots. Using direct DNA extraction, PCR
      amplification, and thermal gradient gel electrophoresis screening, bacterial
      population profiles were analyzed in parallel to bacterial counts and
      quantification of phenanthrene biodegradation in three layers (0 to 3, 3 to 6,
      and 6 to 9 mm from root mat) of unplanted-polluted (phenanthrene), planted
      polluted, and planted-unpolluted treatments. Bacterial community differed as a
      function of the distance to roots, in both the presence and the absence of
      phenanthrene. In the planted and polluted treatment, biodegradation rates showed
      a strong gradient with higher values near the roots. In the nonplanted treatment,
      bacterial communities were comparable in the three layers and phenanthrene
      biodegradation was high. Surprisingly, no biodegradation was detected in the
      section of planted polluted treatment farthest from the roots, where the
      bacterial community structure was similar to those of the nonplanted treatment.
      We conclude that root exudates and phenanthrene induce modifications of bacterial
      communities in polluted environments and spatially modify the activity of
      degrading bacteria.

PMID- 15184157
TI  - Modeling the rate of attachment of Listeria monocytogenes, Pantoea agglomerans,
      and Pseudomonas fluorescens to, and the probability of their detachment from,
      potato tissue at 10 degrees C.
AB  - The rate of attachment of bacteria to, and their subsequent detachment from, the
      cut surface of raw potato tissue was measured and modeled by using mathematical
      approaches that allowed detailed objective comparisons of adhesion processes
      under different conditions. Attachment was rapid and reached equilibrium after
      contact for 60 min. A new method to measure the probability of detachment was
      developed and modeled, revealing that the probability of detachment for
      Pseudomonas fluorescens remained unchanged for contact times between less than 5
      s and 60 min. Listeria monocytogenes, however, was more easily removed initially,
      with the probability of detachment decreasing over the first 2 min of contact but
      remaining constant and equivalent to that for Pseudomonas fluorescens thereafter.
      For all of the bacteria tested, the number of bacteria attached after 2 min of
      contact was proportional to the inoculum concentration raised to the power of
      0.79.

PMID- 15184158
TI  - Biotransformation of explosives by the old yellow enzyme family of flavoproteins.
AB  - Several independent studies of bacterial degradation of nitrate ester explosives
      have demonstrated the involvement of flavin-dependent oxidoreductases related to
      the old yellow enzyme (OYE) of yeast. Some of these enzymes also transform the
      nitroaromatic explosive 2,4,6-trinitrotoluene (TNT). In this work, catalytic
      capabilities of five members of the OYE family were compared, with a view to
      correlating structure and function. The activity profiles of the five enzymes
      differed substantially; no one compound proved to be a good substrate for all
      five enzymes. TNT is reduced, albeit slowly, by all five enzymes. The nature of
      the transformation products differed, with three of the five enzymes yielding
      products indicative of reduction of the aromatic ring. Our findings suggest two
      distinct pathways of TNT transformation, with the initial reduction of TNT being
      the key point of difference between the enzymes. Characterization of an active
      site mutant of one of the enzymes suggests a structural basis for this
      difference.

PMID- 15184159
TI  - Characterization of bacterial communities in feces from healthy elderly
      volunteers and hospitalized elderly patients by using real-time PCR and effects
      of antibiotic treatment on the fecal microbiota.
AB  - Fecal bacteria were studied in healthy elderly volunteers (age, 63 to 90 years; n
      = 35) living in the local community, elderly hospitalized patients (age, 66 to
      103; n = 38), and elderly hospitalized patients receiving antibiotic treatment
      (age, 65 to 100; n = 21). Group- and species-specific primer sets targeting 16S
      rRNA genes were used to quantitate intestinal bacteria by using DNA extracted
      from feces and real-time PCR. The principal difference between healthy elderly
      volunteers and both patient cohorts was a marked reduction in the Bacteroides
      Prevotella group following hospitalization. Reductions in bifidobacteria,
      Desulfovibrio spp., Clostridium clostridiiforme, and Faecalibacterium prausnitzii
      were also found in the hospitalized patients. However, total 16S rRNA gene copy
      numbers (per gram of wet weight of feces) were generally lower in the stool
      samples of the two groups of hospitalized patients compared to the number in the
      stool samples of elderly volunteers living in the community, so the relative
      abundance (percentage of the group- and species-specific rRNA gene copies in
      relation to total bacterial rRNA gene copies) of bifidobacteria, Desulfovibrio
      spp., C. clostridiiforme, and F. prausnitzii did not change. Antibiotic treatment
      resulted in further reductions in the numbers of bacteria and their prevalence
      and, in some patients, complete elimination of certain bacterial communities.
      Conversely, the numbers of enterobacteria increased in the hospitalized patients
      who did not receive antibiotics, and due to profound changes in fecal microbiotas
      during antibiotic treatment, the opportunistic species Enterococcus faecalis
      proliferated.

PMID- 15184160
TI  - Medium-chain fatty acids decrease colonization and invasion through hilA
      suppression shortly after infection of chickens with Salmonella enterica serovar
      Enteritidis.
AB  - The most common source of Salmonella infections in humans is food of poultry
      origin. Salmonella enterica serovar Enteritidis has a particular affinity for the
      contamination of the egg supply. In this study, the medium-chain fatty acids
      (MCFA), caproic, caprylic, and capric acid, were evaluated for the control of
      Salmonella serovar Enteritidis in chickens. All MCFA were growth inhibiting at
      low concentrations in vitro, with caproic acid being the most potent. Contact of
      Salmonella serovar Enteritidis with low concentrations of MCFA decreased invasion
      in the intestinal epithelial cell line T84. By using transcriptional fusions
      between the promoter of the regulatory gene of the Salmonella pathogenicity
      island I, hilA, and luxCDABE genes, it was shown that all MCFA decreased the
      expression of hilA, a key regulator related to the invasive capacity of
      Salmonella. The addition of caproic acid (3 g/kg of feed) to the feed of chicks
      led to a significant decrease in the level of colonization of ceca and internal
      organs by Salmonella serovar Enteritidis at 3 days after infection of 5-day-old
      chicks. These results suggest that MCFA have a synergistic ability to suppress
      the expression of the genes required for invasion and to reduce the numbers of
      bacteria in vivo. Thus, MCFA are potentially useful products for reducing the
      level of colonization of chicks and could ultimately aid in the reduction of the
      number of contaminated eggs in the food supply.

PMID- 15184161
TI  - Enrichment followed by quantitative PCR both for rapid detection and as a tool
      for quantitative risk assessment of food-borne thermotolerant campylobacters.
AB  - As part of a large international project for standardization of PCR (Food-PCR;
      www.pcr.dk), a multiplex, multiplatform, ready-to-go enrichment followed by a
      real-time PCR method, including an internal amplification control, was developed
      for detection of food-borne thermotolerant campylobacters in chickens. Chicken
      rinse samples were enriched in Bolton broth for 20 h, a simple and rapid (1-h)
      resin-based DNA extraction was performed, and DNA samples were then tested with
      two instrument platforms: ABI-PRISM 7700 and RotorGene 3000. The method was
      validated against an International Standard Organization (ISO)-based culture
      method by testing low, medium, and high levels of 12 spiked and 66 unspiked,
      presumably naturally contaminated, chicken rinse samples. In the RotorGene, a
      positive PCR response was detected in 40 samples of the 66. This was in complete
      agreement with the enriched ISO culture. The ABI-PRISM 7700 missed one culture
      positive sample. Positive samples contained 10(2) to 10(7) CFU/ml after
      enrichment in Bolton broth. In the enriched samples a detection probability of
      95% was obtained at levels of 1 x 10(3) and 2 x 10(3) CFU/ml in the RotorGene and
      ABI-PRISM, respectively. The amplification efficiency in both platforms was 90%,
      although the linear range of amplification of purified genomic DNA was 1.5 x
      10(1) to 1 x 10(7) (R(2) = 1.00) for the RotorGene and 10(3) to 10(7) (R(2) =
      0.99) for the ABI-PRISM. In RotorGene and ABI-PRISM the levels of precision of
      detection as determined by standard deviation (coefficients of variation) of 6
      carboxyfluorescein (FAM) threshold cycle (Ct) values were 0.184 to 0.417 (0.65 to
      2.57%) and 0.119 to 0.421 (0.59 to 1.82%), respectively. The results showed a
      correlation (R(2)) of 0.94 between the target FAM Ct values and CFU per
      milliliter of enriched naturally contaminated chicken samples, which indicates
      PCR's additional potential as a tool for quantitative risk assessment. Signal
      from the internal amplification control was detected in all culture-negative
      samples (VIC Ct: 23.1 to 28.1). The method will be taken further and validated in
      an international collaborative trial with regard to standardization.

PMID- 15184162
TI  - The Aspergillus parasiticus estA-encoded esterase converts versiconal hemiacetal
      acetate to versiconal and versiconol acetate to versiconol in aflatoxin
      biosynthesis.
AB  - In aflatoxin biosynthesis, the pathway for the conversion of 1
      hydroxyversicolorone to versiconal hemiacetal acetate (VHA) to versiconal (VHOH)
      is part of a metabolic grid. In the grid, the steps from VHA to VHOH and from
      versiconol acetate (VOAc) to versiconol (VOH) may be catalyzed by the same
      esterase. Several esterase activities are associated with the conversion of VHA
      to VHOH, but only one esterase gene (estA) is present in the complete aflatoxin
      gene cluster of Aspergillus parasiticus. We deleted the estA gene from A.
      parasiticus SRRC 2043, an O-methylsterigmatocystin (OMST)-accumulating strain.
      The estA-deleted mutants were pigmented and accumulated mainly VHA and
      versicolorin A (VA). A small amount of VOAc and other downstream aflatoxin
      intermediates, including VHOH, versicolorin B, and OMST, also were accumulated.
      In contrast, a VA-accumulating mutant, NIAH-9, accumulated VA exclusively and
      neither VHA nor VOAc were produced. Addition of the esterase inhibitor dichlorvos
      (dimethyl 2,2-dichlorovinylphosphate) to the transformation recipient strain
      RHN1, an estA-deleted mutant, or NIAH-9 resulted in the accumulation of only VHA
      and VOAc. In in vitro enzyme assays, the levels of the esterase activities
      catalyzing the conversion of VHA to VHOH in the cell extracts of two estA-deleted
      mutants were decreased to approximately 10% of that seen with RHN1. Similar
      decreases in the esterase activities catalyzing the conversion of VOAc to VOH
      were also obtained. Thus, the estA-encoded esterase catalyzes the conversion of
      both VHA to VHOH and VOAc to VOH during aflatoxin biosynthesis.

PMID- 15184163
TI  - Vertical transmission of endobacteria in the arbuscular mycorrhizal fungus
      Gigaspora margarita through generation of vegetative spores.
AB  - Arbuscular mycorrhizal (AM) fungi living in symbiotic association with the roots
      of vascular plants have also been shown to host endocellular rod-shaped bacteria.
      Based on their ribosomal sequences, these endobacteria have recently been
      identified as a new taxon, Candidatus Glomeribacter gigasporarum. In order to
      investigate the cytoplasmic stability of the endobacteria in their fungal host
      and their transmission during AM fungal reproduction (asexual), a system based on
      transformed carrot roots and single-spore inocula of Gigaspora margarita was
      used. Under these in vitro sterile conditions, with no risk of horizontal
      contamination, the propagation of endobacteria could be monitored, and it was
      shown, by using primers designed for both 16S and 23S ribosomal DNAs, to occur
      through several vegetative spore generations (SG0 to SG4). A method of confocal
      microscopy for quantifying the density of endobacteria in spore cytoplasm was
      designed and applied; endobacteria were consistently found in all of the spore
      generations, although their number rapidly decreased from SG0 to SG4. The study
      demonstrates that a vertical transmission of endobacteria takes place through the
      fungal vegetative generations (sporulation) of an AM fungus, indicating that
      active bacterial proliferation occurs in the coenocytic mycelium of the fungus,
      and suggests that these bacteria are obligate endocellular components of their AM
      fungal host.

PMID- 15184164
TI  - Unusual microbial xylanases from insect guts.
AB  - Recombinant DNA technologies enable the direct isolation and expression of novel
      genes from biotopes containing complex consortia of uncultured microorganisms. In
      this study, genomic libraries were constructed from microbial DNA isolated from
      insect intestinal tracts from the orders Isoptera (termites) and Lepidoptera
      (moths). Using a targeted functional assay, these environmental DNA libraries
      were screened for genes that encode proteins with xylanase activity. Several
      novel xylanase enzymes with unusual primary sequences and novel domains of
      unknown function were discovered. Phylogenetic analysis demonstrated remarkable
      distance between the sequences of these enzymes and other known xylanases.
      Biochemical analysis confirmed that these enzymes are true xylanases, which
      catalyze the hydrolysis of a variety of substituted beta-1,4-linked xylose
      oligomeric and polymeric substrates and produce unique hydrolysis products. From
      detailed polyacrylamide carbohydrate electrophoresis analysis of substrate
      cleavage patterns, the xylan polymer binding sites of these enzymes are proposed.

PMID- 15184165
TI  - Establishment of a real-time PCR-based approach for accurate quantification of
      bacterial RNA targets in water, using Salmonella as a model organism.
AB  - Quantitative PCR (Q-PCR) is a fast and efficient tool to quantify target genes.
      In eukaryotic cells, quantitative reverse transcription-PCR (Q-RT-PCR) is also
      used to quantify gene expression, with stably expressed housekeeping genes as
      standards. In bacteria, such stable expression of housekeeping genes does not
      occur, and the use of DNA standards leads to a broad underestimation. Therefore,
      an accurate quantification of RNA is feasible only by using appropriate RNA
      standards. We established and validated a Q-PCR method which enables the
      quantification of not only the number of copies of target genes (i.e., the number
      of bacterial cells) but also the number of RNA copies. The genes coding for InvA
      and the 16S rRNA of Salmonella enterica serovar Typhimurium were selected for the
      evaluation of the method. As DNA standards, amplified fragments of the target
      genes were used, whereas the same DNA standards were transcribed in vitro for the
      development of appropriate RNA standards. Salmonella cultures and environmental
      water samples inoculated with bacteria were then employed for the final testing.
      Both experimental approaches led to a sensitive, accurate, and reproducible
      quantification of the selected target genes and RNA molecules by Q-PCR and Q-RT
      PCR. It is the first time that RNA standards have been successfully used for a
      precise quantification of the number of RNA molecules in prokaryotes. This
      demonstrates the potential of this approach for determining the presence and
      metabolic activity of pathogenic bacteria in environmental samples.

PMID- 15184166
TI  - Inactivation of the flagellin gene flaA in Magnetospirillum gryphiswaldense
      results in nonmagnetotactic mutants lacking flagellar filaments.
AB  - Magnetotactic bacteria synthesize magnetosomes, which cause them to orient and
      migrate along magnetic field lines. The analysis of magnetotaxis and magnetosome
      biomineralization at the molecular level has been hindered by the unavailability
      of genetic methods, namely the lack of a means to introduce directed gene
      specific mutations. Here we report a method for knockout mutagenesis by
      homologous recombination in Magnetospirillum gryphiswaldense. Multiple flagellin
      genes, which are unlinked in the genome, were identified in M. gryphiswaldense.
      The targeted disruption of the flagellin gene flaA was shown to eliminate
      flagella formation, motility, and magnetotaxis. The techniques described in this
      paper will make it possible to take full advantage of the forthcoming genome
      sequences of M. gryphiswaldense and other magnetotactic bacteria.

PMID- 15184167
TI  - Comparison of total culturable virus assay and multiplex integrated cell culture
      PCR for reliability of waterborne virus detection.
AB  - The total culturable virus assay (TCVA) and an integrated cell culture-PCR (ICC
      PCR) were compared in parallel to evaluate their detection reliability. Source,
      finished, and tap water samples from three drinking water treatment plant systems
      were analyzed by TCVA, and every cell culture dish was subsequently examined by
      reverse transcription (RT) multiplex PCR using enterovirus- and adenovirus
      specific primers. Twenty-seven of 180 (15%) inoculated dishes exhibited
      cytopathic effects (CPE). Virus concentrations for source water ranged from 3.3
      to 21.0 most probable numbers of infectious units (MPN) per 100 liters. No
      finished or tap water samples were positive. On the other hand, 38 (21%) of the
      dishes were positive in multiplex ICC-PCR. Virus concentrations ranged from 4.5
      to 10.2 MPN/100 liters for source water and 0 to 0.9 MPN/100 liters for finished
      and tap water. In spite of its superior sensitivity, the ICC-PCR assay resulted
      in lower virus concentration values than the TCVA for two of the source water
      sites. Retest of the CPE-positive dishes using reovirus-specific RT-PCR revealed
      that 24 of the 27 (89%) dishes were also positive for reoviruses. These
      observations suggested that the detection reliability of ICC-PCR is restricted by
      the primer sets that are integrated in the reaction mixture. The observation of
      an uneven distribution of PCR-positive culture dishes in a given sample raises an
      additional caution that simple extrapolation of the ICC-PCR result from the
      analysis of a limited fraction of collected samples should be avoided to minimize
      possible over- and underestimation of the amount of virus.

PMID- 15184168
TI  - Biotransformation in double-phase systems: physiological responses of Pseudomonas
      putida DOT-T1E to a double phase made of aliphatic alcohols and biosynthesis of
      substituted catechols.
AB  - Pseudomonas putida strain DOT-T1E is highly tolerant to organic solvents, with a
      logP(ow) (the logarithm of the partition coefficient of a solvent in a two-phase
      water-octanol system of > or =2.5. Solvent tolerant microorganisms can be
      exploited to develop double-phase (organic solvent and water) biotransformation
      systems in which toxic substrates or products are kept in the organic phase. We
      tested P. putida DOT-T1E tolerance to different aliphatic alcohols with a
      logP(ow) value between 2 and 4, such as decanol, nonanol, and octanol, which are
      potentially useful in biotransformations in double-phase systems in which
      compounds with a logP(ow) around 1.5 are produced. P. putida DOT-T1E responds to
      aliphatic alcohols as the second phase through cis-to-trans isomerization of
      unsaturated cis fatty acids and through efflux of these aliphatic alcohols via a
      series of pumps that also extrude aromatic hydrocarbons. These defense mechanisms
      allow P. putida DOT-T1E to survive well in the presence of high concentrations of
      the aliphatic alcohols, and growth with nonanol or decanol occurred at a high
      rate, whereas in the presence of an octanol double-phase growth was compromised.
      Our results support that the logP(ow) of aliphatic alcohols correlates with their
      toxic effects, as octanol (logP(ow) = 2.9) has more negative effects in P. putida
      cells than 1-nonanol (logP(ow) = 3.4) or 1-decanol (logP(ow) = 4). A P. putida
      DOT-T1E derivative bearing plasmid pWW0-xylE::Km transforms m-xylene (logP(ow) =
      3.2) into 3-methylcatechol (logP(ow) = 1.8). The amount of 3-methylcatechol
      produced in an aliphatic alcohol/water bioreactor was 10- to 20-fold higher than
      in an aqueous medium, demonstrating the usefulness of double-phase systems for
      this particular biotransformation.

PMID- 15184169
TI  - Comparison of coliforms and coliphages as tools for assessment of viral
      contamination in river water.
AB  - The aim of the study was to evaluate the presence of pathogenic viruses in the
      Moselle River and to compare the usefulness of thermotolerant coliforms and
      somatic coliphages as tools for river water quality assessment in terms of viral
      contamination. Thermotolerant coliforms and somatic coliphages were enumerated by
      standardized methods in 170 samples of river water drawn from five sampling sites
      along the Moselle River (eastern France). BGM cell culture and integrated cell
      culture-reverse transcription-PCR DNA enzyme immunoassay were used to determine
      the presence of pathogenic viral genome (Enterovirus and Norovirus genogroup II
      [GGII]) and infectious Enterovirus spp. in 90 1-liter samples. No infectious
      Enterovirus spp. were isolated, but Enterovirus and Norovirus GGII genomes were
      detected in 38% of the samples. Norovirus GGII genome was mostly detected in
      winter, whereas Enterovirus genome was mostly detected in summer and fall.
      Somatic coliphages appeared to be less sensitive to higher river water
      temperature than thermotolerant coliforms. Furthermore, the number of river water
      samples positive for pathogenic viral genome increased with increasing
      concentration of somatic coliphages, whereas coliform concentration was unrelated
      to viral genome contamination. Consequently somatic coliphages, which are less
      sensitive to environmental factors than thermotolerant coliforms in river water,
      would provide a promising tool for assessment of river water quality in terms of
      fecal and viral pollution.

PMID- 15184170
TI  - Sequence-specific cleavage of small-subunit (SSU) rRNA with oligonucleotides and
      RNase H: a rapid and simple approach to SSU rRNA-based quantitative detection of
      microorganisms.
AB  - A rapid and simple approach to the small-subunit (SSU) rRNA-based quantitative
      detection of a specific group of microorganisms in complex ecosystems has been
      developed. The method employs sequence-specific cleavage of rRNA molecules with
      oligonucleotides and RNase H. Defined mixtures of SSU rRNAs were mixed with an
      oligonucleotide (referred to as a "scissor probe") that was specifically designed
      to hybridize with a particular site of targeted rRNA and were subsequently
      digested with RNase H to proceed to sequence-dependent rRNA scission at the
      hybridization site. Under appropriate reaction conditions, the targeted rRNAs
      were correctly cut into two fragments, whereas nontargeted rRNAs remained intact
      under the same conditions. The specificity of the cleavage could be properly
      adjusted by controlling the hybridization stringency between the rRNA and the
      oligonucleotides, i.e., by controlling either the temperature of the reaction or
      the formamide concentration in the hybridization-digestion buffer used for the
      reaction. This enabled the reliable discrimination of completely matched rRNA
      sequences from single-base mismatched sequences. For the detection of targeted
      rRNAs, the resulting RNA fragment patterns were analyzed by gel electrophoresis
      with nucleotide-staining fluorescent dyes in order to separate cleaved and intact
      rRNA molecules. The relative abundance of the targeted SSU rRNA fragments in the
      total SSU rRNA could easily be calculated without the use of an external standard
      by determining the signal intensity of individual SSU rRNA bands in the
      electropherogram. This approach provides a fast and easy means of identification,
      detection, and quantification of a particular group of microbes in clinical and
      environmental specimens based on rRNA.

PMID- 15184171
TI  - Isolation, characterization, and identification of bacterial contaminants in
      semifinal gelatin extracts.
AB  - Bacterial contamination of gelatin is of great concern. Indeed, this animal
      colloid has many industrial applications, mainly in food and pharmaceutical
      products. In a previous study (E. De Clerck and P. De Vos, Syst. Appl. Microbiol.
      25:611-618), contamination of a gelatin production process with a variety of gram
      positive and gram-negative bacteria was demonstrated. In this study, bacterial
      contamination of semifinal gelatin extracts from several production plants was
      examined. Since these extracts are subjected to harsh conditions during
      production and a final ultrahigh-temperature treatment, the bacterial load at
      this stage is expected to be greatly reduced. In total, 1,129 isolates were
      obtained from a total of 73 gelatin batches originating from six different
      production plants. Each of these batches was suspected of having bacterial
      contamination based on quality control testing at the production plant from which
      it originated. For characterization and identification of the 1,129 bacterial
      isolates, repetitive-element PCR was used to obtain manageable groups.
      Representative strains were identified by means of 16S rRNA gene sequencing,
      species-specific gyrB PCR, and gyrA and rpoB sequencing and were tested for
      gelatinase activity. The majority of isolates belonged to members of Bacillus or
      related endospore-forming genera. Representative strains were identified as
      Bacillus cereus, Bacillus coagulans, Bacillus fumarioli, Bacillus
      amyloliquefaciens, Bacillus licheniformis, Bacillus pumilus, Bacillus sonorensis,
      Bacillus subtilis, Bacillus gelatini, Bacillus thermoamylovorans, Anoxybacillus
      contaminans, Anoxybacillus flavithermus, Brevibacillus agri, Brevibacillus
      borstelensis, and Geobacillus stearothermophilus. The majority of these species
      include strains exhibiting gelatinase activity. Moreover, some of these species
      have known pathogenic properties. These findings are of great concern with regard
      to the safety and quality of gelatin and its applications.

PMID- 15184173
TI  - Endogenous xylose pathway in Saccharomyces cerevisiae.
AB  - The baker's yeast Saccharomyces cerevisiae is generally classified as a non
      xylose-utilizing organism. We found that S. cerevisiae can grow on D-xylose when
      only the endogenous genes GRE3 (YHR104w), coding for a nonspecific aldose
      reductase, and XYL2 (YLR070c, ScXYL2), coding for a xylitol dehydrogenase (XDH),
      are overexpressed under endogenous promoters. In nontransformed S. cerevisiae
      strains, XDH activity was significantly higher in the presence of xylose, but
      xylose reductase (XR) activity was not affected by the choice of carbon source.
      The expression of SOR1, encoding a sorbitol dehydrogenase, was elevated in the
      presence of xylose as were the genes encoding transketolase and transaldolase. An
      S. cerevisiae strain carrying the XR and XDH enzymes from the xylose-utilizing
      yeast Pichia stipitis grew more quickly and accumulated less xylitol than did the
      strain overexpressing the endogenous enzymes. Overexpression of the GRE3 and
      ScXYL2 genes in the S. cerevisiae CEN.PK2 strain resulted in a growth rate of
      0.01 g of cell dry mass liter(-1) h(-1) and a xylitol yield of 55% when xylose
      was the main carbon source.

PMID- 15184172
TI  - Identification and characterization of the novel LysM domain-containing surface
      protein Sep from Lactobacillus fermentum BR11 and its use as a peptide fusion
      partner in Lactobacillus and Lactococcus.
AB  - Examination of supernatant fractions from broth cultures of Lactobacillus
      fermentum BR11 revealed the presence of a number of proteins, including a 27-kDa
      protein termed Sep. The amino-terminal sequence of Sep was determined, and the
      gene encoding it was cloned and sequenced. Sep is a 205-amino-acid protein and
      contains a 30-amino-acid secretion signal and has overall homology (between 39
      and 92% identity) with similarly sized proteins of Lactobacillus reuteri,
      Enterococcus faecium, Streptococcus pneumoniae, Streptococcus agalactiae, and
      Lactobacillus plantarum. The carboxy-terminal 81 amino acids of Sep also have
      strong homology (86% identity) to the carboxy termini of the aggregation
      promoting factor (APF) surface proteins of Lactobacillus gasseri and
      Lactobacillus johnsonii. The mature amino terminus of Sep contains a putative
      peptidoglycan-binding LysM domain, thereby making it distinct from APF proteins.
      We have identified a common motif within LysM domains that is shared with
      carbohydrate binding YG motifs which are found in streptococcal glucan-binding
      proteins and glucosyltransferases. Sep was investigated as a heterologous peptide
      expression vector in L. fermentum, Lactobacillus rhamnosus GG and Lactococcus
      lactis MG1363. Modified Sep containing an amino-terminal six-histidine epitope
      was found associated with the cells but was largely present in the supernatant in
      the L. fermentum, L. rhamnosus, and L. lactis hosts. Sep as well as the
      previously described surface protein BspA were used to express and secrete in L.
      fermentum or L. rhamnosus a fragment of human E-cadherin, which contains the
      receptor region for Listeria monocytogenes. This study demonstrates that Sep has
      potential for heterologous protein expression and export in lactic acid bacteria.

PMID- 15184174
TI  - Identification of differential gene expression in bacteria associated with coral
      black band disease by using RNA-arbitrarily primed PCR.
AB  - RNA-arbitrarily primed PCR techniques have been applied for the first time to
      identify differential gene expression in black band disease (BBD), a virulent
      coral infection that affects reef ecosystems worldwide. The gene activity for the
      BBD mat on infected surfaces of the brain coral Diploria strigosa was compared
      with that for portions of the BBD mat that were removed from the coral and
      suspended nearby in the seawater column. The results obtained indicate that three
      genes (DD 95-2, DD 95-4, and DD 99-9) were up-regulated in the BBD bacterial mat
      on the coral surface compared to the transcript base levels observed in the BBD
      mat suspended in seawater. Clone DD 95-4 has homology with known amino acid ABC
      transporter systems in bacteria, while clone DD 99-9 exhibits homology with
      chlorophyll A apoprotein A1 in cyanobacteria. This protein is essential in the
      final conformation of photosystem I P700. DD 95-2, the only gene that was fully
      repressed in the BBD mat samples suspended in seawater, exhibited homology with
      the AraC-type DNA binding domain-containing proteins. These transcriptional
      activators coordinate the expression of genes essential for virulence in many
      species of gram-negative bacteria.

PMID- 15184175
TI  - Transformation of Leuconostoc carnosum 4010 and evidence for natural competence
      of the organism.
AB  - Plasmid transformation in Leuconostoc carnosum 4010 was analyzed. A successful
      transformation protocol for L. carnosum was established by modifying an existing
      protocol for Lactococcus lactis. Several parameters, including the number of
      generations that the cells had grown at the time of harvest, glycine
      concentration, the time of incubation for phenotypic expression, and the
      electrical field strength, were investigated and proved to have influence on the
      transformation frequency. Electrocompetence was found to be transient and to peak
      in the early exponential growth phase. Optimized conditions resulted in
      transformation frequencies of up to 6.7 x 10(5) transformants per microgram of
      plasmid DNA. A total of five plasmids in L. carnosum were successfully introduced
      and maintained. Interestingly, we discovered that DNA uptake was of a frequency
      of 3 x 10(-6) to 19 x 10(-6) transformants per CFU in the absence of an applied
      electrical field. We concluded that L. carnosum is naturally competent.

PMID- 15184176
TI  - Isolation and phylogenetic analysis of novel viruses infecting the phytoplankton
      Phaeocystis globosa (Prymnesiophyceae).
AB  - Viruses infecting the harmful bloom-causing alga Phaeocystis globosa
      (Prymnesiophyceae) were readily isolated from Dutch coastal waters (southern
      North Sea) in 2000 and 2001. Our data show a large increase in the abundance of
      putative P. globosa viruses during blooms of P. globosa, suggesting that viruses
      are an important source of mortality for this alga. In order to examine genetic
      relatedness among viruses infecting P. globosa and other phytoplankton, DNA
      polymerase gene (pol) fragments were amplified and the inferred amino acid
      sequences were phylogenetically analyzed. The results demonstrated that viruses
      infecting P. globosa formed a closely related monophyletic group within the
      family Phycodnaviridae, with at least 96.9% similarity to each other. The
      sequences grouped most closely with others from viruses that infect the
      prymnesiophyte algae Chrysochromulina brevifilum and Chrysochromulina strobilus.
      Whether the P. globosa viruses belong to the genus Prymnesiovirus or form a
      separate group needs further study. Our data suggest that, like their
      phytoplankton hosts, the Chrysochromulina and Phaeocystis viruses share a common
      ancestor and that these prymnesioviruses and their algal host have coevolved.

PMID- 15184177
TI  - Uptake and replication of Salmonella enterica in Acanthamoeba rhysodes.
AB  - The ability of salmonellae to become internalized and to survive and replicate in
      amoebae was evaluated by using three separate serovars of Salmonella enterica and
      five different isolates of axenic Acanthamoeba spp. In gentamicin protection
      assays, Salmonella enterica serovar Dublin was internalized more efficiently than
      Salmonella enterica serovar Enteritidis or Salmonella enterica serovar
      Typhimurium in all of the amoeba isolates tested. The bacteria appeared to be
      most efficiently internalized by Acanthamoeba rhysodes. Variations in bacterial
      growth conditions affected internalization efficiency, but this effect was not
      altered by inactivation of hilA, a key regulator in the expression of the
      invasion-associated Salmonella pathogenicity island 1. Microscopy of infected A.
      rhysodes revealed that S. enterica resided within vacuoles. Prolonged incubation
      resulted in a loss of intracellular bacteria associated with morphological
      changes and loss of amoebae. In part, these alterations were associated with hilA
      and the Salmonella virulence plasmid. The data show that Acanthamoeba spp. can
      differentiate between different serovars of salmonellae and that internalization
      is associated with cytotoxic effects mediated by defined Salmonella virulence
      loci.

PMID- 15184179
TI  - Discovery of the novel candidate phylum "Poribacteria" in marine sponges.
AB  - Marine sponges (Porifera) harbor large amounts of commensal microbial communities
      within the sponge mesohyl. We employed 16S rRNA gene library construction using
      specific PCR primers to provide insights into the phylogenetic identity of an
      abundant sponge-associated bacterium that is morphologically characterized by the
      presence of a membrane-bound nucleoid. In this study, we report the presence of a
      previously unrecognized evolutionary lineage branching deeply in the domain
      Bacteria that is moderately related to the Planctomycetes, Verrucomicrobia, and
      Chlamydia lines of decent. Because members of this lineage showed <75% 16S rRNA
      gene sequence similarity to known bacterial phyla, we suggest the status of a new
      candidate phylum, named "Poribacteria", to acknowledge the affiliation of the new
      bacterium with sponges. The affiliation of the morphologically conspicuous sponge
      bacterium with the novel phylogenetic lineage was confirmed by fluorescence in
      situ hybridization with newly designed probes targeting different sites of the
      poribacterial 16S rRNA. Consistent with electron microscopic observations of cell
      compartmentalization, the fluorescence signals appeared in a ring-shaped manner.
      PCR screening with "Poribacteria"-specific primers gave positive results for
      several other sponge species, while samples taken from the environment (seawater,
      sediments, and a filter-feeding tunicate) were PCR negative. In addition to a
      report for Planctomycetes, this is the second report of cell
      compartmentalization, a feature that was considered exclusive to the eukaryotic
      domain, in prokaryotes.

PMID- 15184178
TI  - Use of Sinorhizobium meliloti as an indicator for specific detection of long
      chain N-acyl homoserine lactones.
AB  - Population-density-dependent gene expression in gram-negative bacteria involves
      the production of signal molecules characterized as N-acyl homoserine lactones
      (AHLs). The synthesis of AHLs by numerous microorganisms has been identified by
      using biosensor strains based on the Agrobacterium tumefaciens and
      Chromobacterium violaceum quorum-sensing systems. The symbiotic nitrogen-fixing
      bacterium Sinorhizobium meliloti is rapidly becoming a model organism for the
      study of quorum sensing. This organism harbors at least three different quorum
      sensing systems (Sin, Mel, and Tra), which play a role in its symbiotic
      relationship with its host plant, alfalfa. The Sin system is distinguished among
      them for the production of long-chain AHLs, including C(18)-HL, the longest AHL
      reported so far. In this work, we show that construction of a sinI::lacZ
      transcriptional fusion results in a strain that detects long-chain AHLs with
      exquisite sensitivity. Overexpression of the SinR regulator protein from a vector
      promoter increases its sensitivity without loss of specificity. We also show that
      the resulting indicator strain can recognize long-chain AHLs produced by
      unrelated bacteria such as Paracoccus denitrificans and Rhodobacter capsulatus.
      This S. meliloti indicator strain should serve as a tool for the specific
      detection of long-chain AHLs in new systems.

PMID- 15184180
TI  - Methods for enhanced culture recovery of Francisella tularensis.
AB  - Francisella tularensis is found in a wide variety of hosts and extrahost
      environments, making culture recovery a diagnostic challenge. Here we demonstrate
      improved recovery times and good sensitivity (90%) when cultures were inoculated
      on the site of an investigation using fresh tissues. For contaminated specimens,
      antibiotic supplementation of enriched cysteine heart agar blood culture medium
      improved recovery of F. tularensis by 81.1%. For transport of tissues, immediate
      freezing yielded culture recovery rates as high as 94%.

PMID- 15184181
TI  - Protein expression by Streptococcus mutans during initial stage of biofilm
      formation.
AB  - Cells growing on surfaces in biofilms exhibit properties distinct from those of
      planktonic cells, such as increased resistance to biocides and antimicrobial
      agents. In spite of increased interest in biofilms, very little is known about
      alterations in cell physiology that occur upon attachment of cells to a surface.
      In this study we have investigated the changes induced in the protein synthesis
      by contact of Streptococcus mutans with a surface. Log-phase planktonic cells of
      S. mutans were allowed to adhere to a glass slide for 2 h in the presence of a
      (14)C-amino acid mixture. Nonadhered cells were washed away, and the adhered
      cells were removed by sonication. The proteins were extracted from the nonadhered
      planktonic and the adhered biofilm cells and separated by two-dimensional gel
      electrophoresis followed by autoradiography and image analysis. Image analysis
      revealed that the relative rate of synthesis of 25 proteins was enhanced and that
      of 8 proteins was diminished > or =1.3-fold in the biofilm cells. Proteins of
      interest were identified by mass spectrometry and computer-assisted protein
      sequence analysis. Of the 33 proteins associated with the adhesion response, all
      but 10 were identified by mass spectrometry and peptide mass fingerprinting. The
      most prominent change in adhered cells was the increase in relative synthesis of
      enzymes involved in carbohydrate catabolism indicating that a redirection in
      protein synthesis towards energy generation is an early response to contact with
      and adhesion to a surface.

PMID- 15184182
TI  - Cryptosporidium parvum and Giardia lamblia recovered from flies on a cattle farm
      and in a landfill.
AB  - Filth flies associated with a cattle barn and a municipal landfill were tested
      positive by combined immunofluorescent antibody and fluorescent in situ
      hybridization for Cryptosporidium parvum and Giardia lamblia on their
      exoskeletons and in their guts. More pathogens were carried by flies from the
      cattle barn than from the landfill; 81% of C. parvum and 84% of G. lamblia
      pathogens were presumptively viable.

PMID- 15184183
TI  - Noninvasive pigment identification in single cells from living phototrophic
      biofilms by confocal imaging spectrofluorometry.
AB  - A new imaging technique for the analysis of fluorescent pigments from a single
      cell is reported. It is based on confocal scanning laser microscopy coupled with
      spectrofluorometric methods. The setup allows simultaneous establishment of the
      relationships among pigment analysis in vivo, morphology, and three-dimensional
      localization inside thick intact microbial assemblages.

PMID- 15184184
TI  - Optimization of procedures for isolation of mycobacteria from soil and water
      samples obtained in northern India.
AB  - For isolation of environmental mycobacteria, a decontamination procedure has been
      standardized by which treatment with 3% sodium dodecyl sulfate plus 4% NaOH (15
      and 30 min for rapid and slow growers, respectively) is followed by incubation
      with 2% cetrimide (5 and 15 min for fast- and slow-growing mycobacteria,
      respectively); this procedure was found to completely eliminate contamination
      with other organisms and resulted in the isolation of only mycobacteria.

PMID- 15184185
TI  - Diverse tetracycline resistance genotypes of Megasphaera elsdenii strains
      selectively cultured from swine feces.
AB  - A total of 30 Megasphaera elsdenii strains, selectively isolated from the feces
      of organically raised swine by using Me109 M medium, and one bovine strain were
      analyzed for tetracycline resistance genotypic and phenotypic traits.
      Tetracycline-resistant strains carried tet(O), tet(W), or a tet gene mosaic of
      tet(O) and tet(W). M. elsdenii strains carrying tet(OWO) genes exhibited the
      highest tetracycline MICs (128 to >256 microg/ml), suggesting that tet(O)-tet(W)
      mosaic genes provide the selective advantage of greater tetracycline resistance
      for this species. Seven tet genotypes are now known for M. elsdenii, an archetype
      commensal anaerobe and model for tet gene evolution in the mammalian intestinal
      tract.

PMID- 15184186
TI  - Bacterial strains isolated from different niches can exhibit different patterns
      of adhesion to substrata.
AB  - Various mechanisms have been demonstrated to be operative in bacterial adhesion
      to surfaces, but whether bacterial adhesion to surfaces can ever be captured in
      one generally valid mechanism is open to question. Although many papers in the
      literature make an attempt to generalize their conclusions, the majority of
      studies of bacterial adhesion comprise only two or fewer strains. Here we
      demonstrate that three strains isolated from a medical environment have a
      decreasing affinity for substrata with increasing surface free energy, whereas
      three strains from a marine environment have an increasing affinity for substrata
      with increasing surface free energy. Furthermore, adhesion of the marine strains
      related positively with substratum elasticity, but such a relation was absent in
      the strains from the medical environment. This study makes it clear that strains
      isolated from a given niche, whether medical or marine, utilize different
      mechanisms in adherence, which hampers the development of a generalized theory
      for bacterial adhesion to surfaces.

PMID- 15184187
TI  - Molecular and biological characterization of a Cryptosporidium molnari-like
      isolate from a guppy (Poecilia reticulata).
AB  - Histological, morphological, genetic, and phylogenetic analyses of a
      Cryptosporidium molnari-like isolate from a guppy (Poecilia reticulata)
      identified stages consistent with those of C. molnari and revealed that C.
      molnari is genetically very distinct from all other species of Cryptosporidium.
      This study represents the first genetic characterization of C. molnari.

PMID- 15184188
TI  - Immobilization of Saccharomyces cerevisiae cystathionine gamma-lyase and
      application of the product to cystathionine synthesis.
AB  - Cystathionine gamma-lyase of Saccharomyces cerevisiae was immobilized to
      aminohexyl-Sepharose through the cofactor pyridoxal 5'-phosphate and was
      characterized with respect to its cystathionine gamma-synthase activity. The
      immobilized product was so stable that it repeatedly catalyzed as many as five
      cycles of the reaction without losing activity.

PMID- 15184189
TI  - Enhancement of Cry19Aa mosquitocidal activity against Aedes aegypti by mutations
      in the putative loop regions of domain II.
AB  - Improvements in the mosquitocidal activity of Bacillus thuringiensis Cry19Aa were
      achieved by protein engineering of putative surface loop residues in domain II
      through rational design. The improvement of Aedes toxicity in Cry19Aa was 42,000
      fold and did not affect its toxicity against Anopheles or Culex.

PMID- 15184190
TI  - Novel epibiotic thiothrix bacterium on a marine amphipod.
AB  - Comparative analysis of the 16S rRNA gene and fluorescent in situ hybridization
      (FISH) was used to identify epibiotic filamentous bacteria living on the marine
      amphipod crustacean Urothoe poseidonis. The epibionts belong to the gamma
      proteobacteria and represent a novel marine phylotype within the genus Thiothrix.
      FISH and denaturing gradient gel electrophoresis revealed that the Thiothrix
      filaments are present on the majority of the amphipods examined.

PMID- 15184192
TI  - Short-duration low-direct-current electrical field treatment is a practical tool
      for considerably reducing counts of gram-negative bacteria entrapped in gel
      beads.
AB  - Application of a direct-current electrical field for very short times can serve
      as a practical nonthermal procedure to reduce or modify the microbial
      distribution in gel beads. The viability of Escherichia coli and Serratia
      marcescens entrapped in alginate and agarose beads decreases as the field
      intensity and duration of electrical field increase.

PMID- 15184191
TI  - Distribution of Giardia duodenalis genotypes and subgenotypes in raw urban
      wastewater in Milwaukee, Wisconsin.
AB  - Giardia cysts in 131 raw wastewater samples from Milwaukee, Wis., were genotyped
      by sequence analysis of the triosephosphate isomerase gene which showed the
      presence of two distinct genotypes (assemblages A and B) of Giardia duodenalis.
      Of the 131 samples, 111 belonged to assemblage A, and the remaining samples
      belonged to assemblage B. A high degree of genetic polymorphism was evident
      within the assemblage B cluster, with 10 distinct subgenotypes identified, eight
      of which have not been reported before.

PMID- 15184193
TI  - Stable carbon isotopic fractionations associated with inorganic carbon fixation
      by anaerobic ammonium-oxidizing bacteria.
AB  - Isotopic analyses of Candidatus "Brocadia anammoxidans," a chemolithoautotrophic
      bacterium that anaerobically oxidizes ammonium (anammox), show that it strongly
      fractionates against (13)C; i.e., lipids are depleted by up to 47 per thousand
      versus CO(2). Similar results were obtained for the anammox bacterium Candidatus
      "Scalindua sorokinii," which thrives in the anoxic water column of the Black Sea,
      suggesting that different anammox bacteria use identical carbon fixation
      pathways, which may be either the Calvin cycle or the acetyl coenzyme A pathway.

PMID- 15184194
TI  - Differences between betaproteobacterial ammonia-oxidizing communities in marine
      sediments and those in overlying water.
AB  - To assess links between betaproteobacterial ammonia-oxidizing bacteria (AOB) in
      marine sediment and in overlying water, communities in Loch Duich, Scotland, were
      characterized by analysis of clone libraries and denaturant gradient gel
      electrophoresis of 16S rRNA gene fragments. Nitrosospira cluster 1-like sequences
      were isolated from both environments, but different sequence types dominated
      water and sediment samples. Detailed phylogenetic analysis of marine Nitrosospira
      cluster 1-like sequences in Loch Duich and surrounding regions suggests the
      existence of at least two different phylogenetic subgroups, potentially
      indicative of new lineages within the betaproteobacterial AOB, representing
      different marine ecotypes.

PMID- 15184195
TI  - Isolation and identification of actinobacteria from plant roots.

PMID- 15184196
TI  - Tumour necrosis factor alpha blocking agents in refractory adult Still's disease:
      an observational study of 20 cases.
AB  - BACKGROUND: Consensus is lacking on treatment for corticosteroid resistant adult
      onset Still's disease (ASD). OBJECTIVE: To assess anti-TNFalpha efficacy and
      tolerance in refractory ASD. METHODS: All departments of rheumatology and
      internal medicine in France were contacted by mail to identify cases of
      refractory ASD for which anti-TNFalpha had been used. Medical information was
      collected using a standardised questionnaire. RESULTS: Of 20 patients with mean
      age 40.7 years (range 18-74) at treatment start and mean disease duration 8.5
      years (range 2-21), the clinical expression of ASD was predominantly systemic in
      five patients and polyarticular in 15. Response to corticosteroids and
      methotrexate had been considered inadequate in all patients. Infliximab was used
      to treat 15 patients, and etanercept used for 10; five had received both drugs
      consecutively. Steroids were concurrently used in 18 patients and an
      immunosuppressant in 17. At a mean (SD) follow up of 13 (14) months, complete
      remission had occurred in five cases (of 25 treatment sequences): one receiving
      etanercept and four infliximab. Partial response was observed in 16 cases (seven
      etanercept and nine infliximab). Treatment failed in four cases (two with each
      anti-TNFalpha). At the last visit, anti-TNFalpha therapy was discontinued in 17
      cases, 11 times because of lack (or loss) of efficacy, four times because of a
      side effect, and twice for other reasons. CONCLUSION: Anti-TNFalpha therapy may
      be helpful for some patients with refractory ASD. However, most patients achieve
      only partial remission. Additional information is thus needed to evaluate more
      precisely the risk-benefit ratio of this treatment.

PMID- 15184197
TI  - Glutathione S-transferase variants and their interaction with smoking on lung
      function.
AB  - We studied glutathione S-transferase (GST) polymorphisms in 1,098 whites with the
      lowest (n = 544, FEV(1) % predicted mean +/- SEM = 62.6 +/- 0.1) and the highest
      (n = 554, FEV(1) % predicted mean +/- SEM = 91.8 +/- 0.1) lung function at the
      beginning of the Lung Health Study. Homozygosity for GSTP1 105Val was
      significantly more frequent in the low- than in the high-function group (13.2 vs.
      9.3%) (odds ratio = 1.69, 95% confidence interval [CI] = 1.11-2.61, p = 0.016),
      after adjustment for confounding variables. Subjects with 105Val homozygotes had
      higher rates of lung function decline in the high-function group (p = 0.017). The
      frequencies of GSTM1, GSTT1 null genotypes were similar between the high- and low
      function groups, but subjects with the GSTT1 null genotype had a faster decline
      of lung function in the low-function group (p = 0.032). In addition, there was a
      significant interaction of GSTT1 genotype and pack-years on lung function. When
      comparing individuals with GSTT1 null genotype with wild type, the adjusted odds
      ratio was 3.49 (95% CI, 1.48-8.39, p = 0.005) in mild smokers (< or = 25 pack
      years). We conclude that GST genotypes are risk factors for rapid decline or low
      lung function in smokers with mild to moderate airflow obstruction.

PMID- 15184198
TI  - Recurrence of pulmonary emphysema in an alpha-1 proteinase inhibitor-deficient
      lung transplant recipient.
AB  - Several types of primary disease may recur after lung transplantation, but
      recurrence of pulmonary emphysema has so far never been published. We report the
      case of a 49-year-old white male who underwent single lung transplantation for
      emphysema related to alpha-1 antitrypsin deficiency and to superimposed smoking.
      The postoperative course was complicated by several rejection episodes.
      Subsequently, the patient remained stable without evidence of graft dysfunction
      for more than 10 years, but he resumed light smoking at 8 years after transplant.
      At 11 years after transplant, although the patient was still asymptomatic and had
      a stable lung function, recurrence of emphysema on the grafted side was diagnosed
      on computerized tomography of the thorax. One year later, the patient began to
      experience a moderate decline in lung function. Two separate bronchoalveolar
      lavages performed after the onset of the recurrence disclosed a significant
      elastolytic activity related to neutrophil serine-elastase in lavage fluid. In
      summary, we describe a case of recurrence of pulmonary emphysema in a patient
      with alpha-1 antitrypsin deficiency. The resumption of smoking has probably
      played a central role in the presence of elastolytic activity in lavage fluid and
      in the recurrence of emphysema.

PMID- 15184199
TI  - Heme oxygenase-1 expression in human lungs with cystic fibrosis and
      cytoprotective effects against Pseudomonas aeruginosa in vitro.
AB  - Inflammation and oxidative stress play important roles in cystic fibrosis (CF)
      lung disease. Inflammatory/oxidant-mediated induction of heme oxygenase-1 (HO-1)
      is believed to be a cytoprotective response. This study examined HO-1 expression
      in lung samples from patients with CF using immunohistochemistry and quantitative
      reverse transcription-polymerase chain reaction. In addition, we evaluated
      myeloperoxidase staining as a marker of acute inflammation and potentially an
      increase in oxidant stress and Prussian blue and ferritin staining to assess iron
      status of the lung. Macrophage HO-1 staining was increased in diseased lungs as
      compared with normal control subjects and correlated with myeloperoxidase
      staining. Quantitative reverse transcription-polymerase chain reaction further
      supported an increase in HO-1 expression in CF lung disease. Although iron
      staining was minimal, ferritin staining was increased in diseased lungs in
      concert with HO-1 staining. To determine whether HO-1 induction was
      cytoprotective, we evaluated a CF airway epithelial cell line, IB3.1, in response
      to Pseudomonas aeruginosa-induced injury/apoptosis in cells overexpressing HO-1
      by either transient or stable transfection of pcDNA3.1/HO-1 construct.
      Overexpression of HO-1 resulted in protection against P. aeruginosa-induced
      injury/apoptosis. This suggests that the induction of HO-1 in patients with CF is
      a cytoprotective event and that augmenting its expression is a potential therapy
      against bacterial injury.

PMID- 15184201
TI  - Postnatal changes in response to norepinephrine in the normal and pulmonary
      hypertensive lung.
AB  - The effect of norepinephrine administration on pulmonary blood flow during the
      neonatal period is unclear. Therefore, norepinephrine responses were studied in
      isolated pulmonary arteries, pulmonary veins, and femoral arteries taken from
      normal pigs from birth to adulthood and from pigs subjected to chronic hypoxia
      either from birth for 3 days or from 3 to 14 days of age. Normally, the
      contractile response of pulmonary arteries and veins to norepinephrine decreased
      after birth (p < 0.01), and alpha2-adrenoceptor-mediated relaxation increased in
      pulmonary arteries and veins and in femoral arteries. Hypoxic exposure from birth
      prevented the normal postnatal reduction in pulmonary arterial contractile
      response, nor was there a postnatal increase in pulmonary arterial adrenoceptor
      mediated relaxation. When hypoxic exposure followed a period of normal
      adaptation, the pulmonary arterial contractile response was not enhanced, but
      relaxation was significantly impaired. The response of pulmonary veins and
      femoral arteries was not affected by hypoxic exposure. The contractile effect of
      norepinephrine was 15- to 60-fold greater in isolated systemic arteries than in
      pulmonary arteries taken from both normal and pulmonary hypertensive piglets at
      all ages. This suggests that use of norepinephrine to manage systemic hypotension
      in infants and children will not compromise the pulmonary vasculature.

PMID- 15184200
TI  - Combination antibiotic therapy lowers mortality among severely ill patients with
      pneumococcal bacteremia.
AB  - Retrospective studies have suggested that combination antibiotic therapy for
      severe bacteremic pneumococcal pneumonia may reduce mortality. We assessed this
      issue in a prospective, multicenter, international observational study of 844
      adult patients with bacteremia due to Streptococcus pneumoniae. The effect of
      combination antibiotic therapy versus monotherapy on mortality was examined by
      univariate analyses and by logistic regression models. The 14-day mortality was
      not significantly different for the two groups. However, among critically ill
      patients, combination antibiotic therapy was associated with lower 14-day
      mortality (23.4 versus 55.3%, p = 0.0015). This improvement in survival was
      independent of country of origin, intensive care unit support, class of
      antibiotics, or in vitro activity of the antibiotics prescribed. Combination
      antibiotic therapy improved survival among critically ill patients with
      bacteremic pneumococcal illness.

PMID- 15184202
TI  - Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in
      bronchopulmonary dysplasia.
AB  - Pulmonary hypertension contributes significantly to morbidity and mortality in
      bronchopulmonary dysplasia (BPD), but little is known about the relative
      contribution of arterial tone, structural remodeling, and vessel density to
      pulmonary hypertension, especially in older patients. To determine the role of
      high pulmonary vascular tone in pulmonary hypertension, we studied the acute
      effects of oxygen tension, inhaled nitric oxide (iNO), and calcium channel
      blockers (CCB) in 10 patients with BPD who underwent cardiac catheterization for
      evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary
      arterial pressure (PAP) and pulmonary to systemic vascular resistance ratio
      (PVR/SVR) were 34 +/- 3 mm Hg and 0.42 +/- 0.07, respectively. In response to
      hypoxia, PAP and PVR/SVR increased by 50 +/- 8% and 82 +/- 14%, respectively (p <
      0.01). Hyperoxia decreased PVR/SVR by 28 +/- 9% (p = 0.05). The addition of iNO
      treatment (20-40 ppm) to hyperoxia decreased PAP and PVR/SVR by 29 +/- 5% (p <
      0.01) and 45 +/- 6% (p < 0.05) from baseline values, respectively, achieving near
      normal values. CCB did not alter PAP or PVR/SVR from baseline values. We conclude
      that hyperoxia plus iNO causes marked pulmonary vasodilatation in older patients
      with BPD, suggesting that heightened pulmonary vascular tone contributes to
      pulmonary vascular disease in BPD.

PMID- 15184203
TI  - Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured
      pulmonary arteries.
AB  - We assessed the effects of dexamethasone (DEX) on hypoxia-induced dysfunction of
      the pulmonary endothelium using organ-cultured rabbit intrapulmonary arteries; 3
      microM DEX inhibited the 7-day hypoxia (5% oxygen)-induced impairments of
      endothelial-dependent relaxation, cGMP accumulation, and increase in
      intracellular Ca(2+) level under substance P-stimulated conditions. Treatment
      with DEX over the final 3 days of the 7-day hypoxic exposure period also restored
      the decreased endothelium-dependent relaxation. Although chronic hypoxia did not
      change the mRNA expression of endothelial nitric oxide synthase (eNOS), 3 microM
      of DEX increased eNOS mRNA expression in both the hypoxic and normoxic (20%
      oxygen) pulmonary endothelium. On the other hand, eNOS protein expression was not
      changed in any of the arteries. We next assessed the effects of DEX on the eNOS
      activation pathway. Chronic hypoxia impaired eNOS phosphorylation and Akt
      phosphorylation under both the nonstimulated and substance P-stimulated
      conditions, and 3-microM DEX restored these phosphorylations. Morphologic study
      revealed that 3-microM DEX inhibited chronic hypoxia-induced atrophy of
      endothelial cells and eNOS protein condensation into plasma membranes. These
      results suggest that DEX exerts beneficial effects on chronic hypoxia-induced
      impairments of nitric oxide-mediated arterial relaxation by increasing eNOS mRNA
      expression and inhibiting hypoxia-induced impairments in eNOS activation pathway
      with atrophy of endothelial cells.

PMID- 15184204
TI  - Glucocorticoid receptor isoforms alpha and beta in in vitro cytokine-induced
      glucocorticoid insensitivity.
AB  - We stimulated peripheral blood mononuclear cells from 14 healthy subjects, 14
      patients with stable asthma, and 13 patients with unstable asthma with
      interleukin (IL)-2 and IL-4 to induce glucocorticoid insensitivity and we
      examined the relationship between insensitivity and the expression of
      glucocorticoid receptor (GR) isoforms. Results are expressed as IC(50)
      (nanomolar) values (means +/- SD) in proliferation assays and as 10(3) cDNA
      molecules per microgram of total RNA (means +/- SD) in real-time polymerase chain
      reaction analysis. Cells from patients with unstable asthma were less sensitive
      (316 +/- 7 nM) to dexamethasone antiproliferative effects than those from healthy
      control subjects (102 +/- 4 nM, p < 0.05) and patients with stable asthma (107 +/
      2 nM, p < 0.05). Coincubation with IL-2 and IL-4 repressed the inhibitory effect
      of dexamethasone on proliferation in all groups (unstable: 851 +/- 47 nM, p <
      0.01; stable: 912 +/- 52 nM, p = 0.001; control subjects: 537 +/- 45 nM, p =
      0.001). GR-alpha mRNA baseline expression was higher in patients with unstable
      asthma [(1.95 +/- 0.40) x 10(3) cDNA molecules/microg total RNA, p < 0.05] than
      in patients with stable asthma [(1.46 +/- 0.35) x 10(3) cDNA molecules/microg
      total RNA] and healthy subjects [(1.35 +/- 0.25) x 10(3) cDNA molecules/microg
      total RNA]. GR-beta mRNA was 600 times lower than GR-alpha in the three groups.
      Coincubation with IL-2 and IL-4 significantly increased GR-alpha mRNA expression
      in the three groups (p < 0.01), but caused no significant change in GR-beta mRNA.
      GR-alpha, but not GR-beta, protein was detected at baseline and after cytokine
      exposure. Our data do not support the hypothesis that increased GR-beta
      expression can contribute to cytokine-induced glucocorticoid insensitivity.

PMID- 15184205
TI  - Peak flow monitoring for guided self-management in childhood asthma: a randomized
      controlled trial.
AB  - We asked whether the addition of PEF recordings to a symptom-based self
      management plan improved outcome in school children with asthma. In an open
      randomized, parallel-group, controlled trial, we studied children aged 7-14 years
      with moderate asthma. After a 4-week run-in, 90 children were randomized to
      receive either PEF plus symptom-based management or symptom-based management
      alone for 12 weeks. Thresholds for action based on PEF were 70% of best (for
      increasing inhaled steroids) and 50% of best (for commencing prednisolone).
      Children were asked to perform twice-daily spirometry at home (using an
      electronic recording spirometer that revealed only PEF to the study group alone)
      and to record a symptom diary. The mean daily symptom score was the main outcome.
      There were no differences between groups in mean symptom score or in spirometric
      lung function, PEF, quality of life score, or reported use of health services
      over 12 weeks. During acute episodes, children responded to changes in symptoms
      by increasing their inhaled steroids at a mean value of PEF of greater than 70%
      of best so that overall PEF did not contribute to this important self-management
      decision. Knowledge of PEF did not enhance self-management even during acute
      exacerbations.

PMID- 15184206
TI  - Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in
      the mouse.
AB  - Mice lacking tumor necrosis factor-alpha (TNF-alpha) receptors (TNFRKO mice) do
      not develop an inflammatory infiltrate or matrix breakdown after a single acute
      cigarette smoke exposure. To determine the role of TNF-alpha in the long-term
      development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice
      demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38%
      increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in
      lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13,
      and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but
      smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice.
      Lavage matrix breakdown products were elevated in wild-type mice and only
      partially reduced by anti-neutrophil antibody, implying both neutrophil- and non
      neutrophil-mediated matrix breakdown. We conclude that TNF-alpha-mediated
      processes, probably driving neutrophil influx, are responsible for approximately
      70% of airspace enlargement and the majority of inflammatory cell influx/matrix
      breakdown in the mouse model. TNF-alpha causes increased MMP production, but some
      increased MMP activity is present even in TNFRKO mice. These findings imply a
      second TNF-alpha-independent process, possibly related to direct MMP attack on
      matrix, that produces the remaining 30% of airspace enlargement.

PMID- 15184207
TI  - Adrenal suppression with dry powder formulations of fluticasone propionate and
      mometasone furoate.
AB  - Mometasone furoate (MF) and fluticasone propionate (FP) are high potency inhaled
      corticosteroids. The systemic bioavailability of MF is claimed to be negligible,
      leading to a minimal potential for systemic adverse effects. We assessed the
      overnight urinary cortisol/creatinine as the primary outcome of adrenal
      suppression in 21 patients with persistent asthma (mean FEV1 = 91%). Patients
      were randomized in a crossover fashion to receive 2 weekly consecutive doubling
      incremental doses of either FP Accuhaler (500, 1,000, and 2,000 microg/day) or MF
      Twisthaler (400, 800, and 1,600 microg/day). For the 21 per protocol completed
      patients, there was significant suppression of overnight urinary
      cortisol/creatinine with high and medium doses of both drugs-as geometric mean
      fold suppression (95% confidence interval) from baseline: FP 2,000 microg, 1.85
      (1.21-2.82, p = 0.002); FP 1,000 microg, 1.45 (1.07-1.96, p = 0.02); MF 1,600
      microg, 1.92 (1.26-2.93, p = 0.001); and MF 800 microg, 1.39 (1.04-1.88, p =
      0.02). For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin,
      and early morning urinary cortisol/creatinine, there was significant suppression
      with MF and FP at the highest dose. Our data refute the assertion that MF has
      negligible systemic bioavailability and a lower potential for systemic adverse
      effects compared with FP.

PMID- 15184208
TI  - Traffic-related air pollution near busy roads: the East Bay Children's
      Respiratory Health Study.
AB  - Recent studies, primarily in Europe, have reported associations between
      respiratory symptoms and residential proximity to traffic; however, few have
      measured traffic pollutants or provided information about local air quality. We
      conducted a school-based, cross-sectional study in the San Francisco Bay Area in
      2001. Information on current bronchitis symptoms and asthma, home environment,
      and demographics was obtained by parental questionnaire (n = 1,109).
      Concentrations of traffic pollutants (particulate matter, black carbon, total
      nitrogen oxides [NO(X)], and nitrogen dioxide [NO(2)]) were measured at 10 school
      sites during several seasons. Although pollutant concentrations were relatively
      low, we observed differences in concentrations between schools nearby versus
      those more distant (or upwind) from major roads. Using a two-stage multiple
      logistic regression model, we found associations between respiratory symptoms and
      traffic-related pollutants. Among those living at their current residence for at
      least 1 year, the adjusted odds ratio for asthma in relationship to an
      interquartile difference in NO(X) was 1.07 (95% confidence interval, 1.00-1.14).
      Thus, we found spatial variability in traffic pollutants and associated
      differences in respiratory symptoms in a region with good air quality. Our
      findings support the hypothesis that traffic-related pollution is associated with
      respiratory symptoms in children.

PMID- 15184210
TI  - Tuberculosis treatment outcomes: directly observed therapy compared with self
      administered therapy.
AB  - Effective treatment of tuberculosis requires adherence to a minimum of 6 months
      treatment with multiple drugs. To improve adherence and cure rates, directly
      observed therapy is recommended for the treatment of pulmonary tuberculosis. We
      compared treatment outcomes among all culture-positive patients treated for
      active pulmonary tuberculosis (n = 372) in San Francisco County, California from
      1998 through 2000. Patients treated by directly observed therapy at the start of
      therapy (n = 149) had a significantly higher cure rate compared with patients
      treated by self-administered therapy (n = 223) (the sum of bacteriologic cure and
      completion of treatment, 97.8% versus 88.6%, p < 0.002), and decreased
      tuberculosis-related mortality (0% vs. 5.5%, p = 0.002). Rates of treatment
      failure, relapse, and acquired drug resistance were similar between the two
      groups. Forty-four percent of patients who received self-administered therapy had
      risk factors for nonadherence and should have been assigned to directly observed
      therapy. We conclude that treatment plans that emphasize directly observed
      therapy from the start of therapy have the greatest success in improving
      tuberculosis treatment outcomes.

PMID- 15184211
TI  - Modification of the home environment for the reduction of injuries.

PMID- 15184212
TI  - Parents' assessment of quality of care and grief following a child's death.
AB  - BACKGROUND: Deaths among children are rare, but the effect on family members is
      profound. Compared with adult deaths, information about grief, recovery, and
      quality of care is sparse. OBJECTIVES: To describe aspects of bereavement for
      parents who had experienced the death of a child and to compare these aspects by
      parent sex, type of death, and overall experience. DESIGN: In-person interviews
      with families, primarily parents, a mean of 21.8 months after the child's death.
      SETTING: Academic, tertiary care, faith-based children's hospital. PARTICIPANTS:
      Fifty-nine child deaths and 79 parents or guardians. MAIN OUTCOME MEASURES: In
      person interviews, including standard instruments for bereavement and quality of
      care: the Texas Revised Inventory of Grief and the Comprehensive Assessment of
      Satisfaction With Care-Short Form. RESULTS: Fathers and mothers had similar
      levels of grief. Mothers who experienced the sudden death of their child had
      somewhat more intense grief reactions than those whose child died of a chronic
      condition. Grief scores did not vary according to satisfaction with treatment.
      Comprehensive Assessment of Satisfaction With Care-Short Form scores were high
      for parents and similar between mothers and fathers and between sudden and
      unexpected deaths. CONCLUSIONS: Although there were some differences in grief
      responses among parents, satisfaction-with-care scores were high. Further studies
      should examine the role of satisfaction with care in parental grief response and
      incorporate the reporting of experiences rather than simple ratings to measure
      satisfaction with care.

PMID- 15184213
TI  - Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or
      fever: a meta-analysis.
AB  - OBJECTIVE: To summarize studies testing the efficacy and safety of single-dose
      acetaminophen and ibuprofen for treating children's pain or fever. DATA SOURCES:
      Reports were gathered by searching computerized databases (from their inception
      through May 2002) and registries, relevant journals, and bibliographies of key
      articles. STUDY SELECTION: Seventeen blinded, randomized controlled trials with
      children (<18 years) receiving either drug to treat fever or moderate to severe
      pain. DATA EXTRACTION: Under a fixed-effects model, outcome measures for an
      initial single dose of ibuprofen vs acetaminophen were the risk ratio for
      achieving more than 50% of maximum pain relief, effect size for febrile
      temperature reduction, and risk ratio for minor and major harm. DATA SYNTHESIS:
      Ibuprofen (4-10 mg/kg) and acetaminophen (7-15 mg/kg) showed comparable efficacy
      (3 pain relief trials; 186 children). The risk ratio point estimates was 1.14
      (95%confidence interval [CI], 0.82-1.58) at 2 hours after receiving the dose, and
      1.11 (95% CI, 0.89-1.38) at 4 hours. Ibuprofen (5-10 mg/kg) reduced temperature
      more than acetaminophen (10-15 mg/kg) at 2, 4, and 6 hours after treatment
      (respective weighted-effect sizes: 0.19 [95% CI, 0.05-0.33], 0.31 [95% CI, 0.19
      0.44], and 0.33 [95% CI, 0.19-0.47]) (9 fever trials; 1078 children). For
      ibuprofen 10 mg/kg (acetaminophen, 10-15 mg/kg), corresponding effect sizes were
      0.34 (95% CI, 0.12-0.56), 0.81 (95% CI, 0.56-1.03), and 0.66 (95% CI, 0.44-0.87).
      There was no evidence the drugs differed from each other (or placebo) in
      incidence of minor or major harm (17 safety trials; 1820 children). CONCLUSIONS:
      In children, single doses of ibuprofen (4-10 mg/kg) and acetaminophen (7-15
      mg/kg) have similar efficacy for relieving moderate to severe pain, and similar
      safety as analgesics or antipyretics. Ibuprofen (5-10 mg/kg) was a more effective
      antipyretic than acetaminophen (10-15 mg/kg) at 2, 4, and 6 hours posttreatment.

PMID- 15184214
TI  - Impact of pulse oximetry and oxygen therapy on length of stay in bronchiolitis
      hospitalizations.
AB  - BACKGROUND: Infants hospitalized with bronchiolitis are frequently monitored with
      a pulse oximeter. However, there is little consensus on an acceptable lower limit
      of oxygenation. No previous studies have examined how the use of pulse oximetry
      and supplemental oxygen therapy affects length of stay. OBJECTIVE: To determine
      the extent to which bronchiolitis hospitalizations are prolonged by a perceived
      need for supplemental oxygen based on pulse oximetry readings. Design and
      Patients Retrospective case series of subjects younger than 2 years who were
      hospitalized with bronchiolitis at an academic medical center. Two investigators
      independently reviewed the hospitalization records of 73 infants and determined
      at what point an infant met all discharge criteria except oxygenation. We then
      calculated the extent to which hospitalizations were prolonged by a perceived
      need for supplemental oxygen therapy based on pulse oximetry readings alone.
      RESULTS: Sixty-two infants met inclusion criteria. There was high interrater
      reliability in determining whether hospitalizations were prolonged (kappa =
      0.75). In 16 (26%) of 62 patients (95% confidence interval, 15%-37%), the
      hospitalization was prolonged because of oxygenation concerns. Length of stay was
      prolonged an average of 1.6 days (range, 1.1-2.0 days) per hospitalization for
      these 16 patients, or 0.4 day (range, 0.2-0.6 day) per hospitalization for all 62
      patients. CONCLUSIONS: Hospitalizations of some infants with bronchiolitis are
      prolonged by a perceived need for supplemental oxygen therapy based on pulse
      oximetry readings. Further investigation into outcomes of different levels and
      durations of oxygen desaturation is needed and would have the potential to reduce
      practice variability and shorten the length of stay.

PMID- 15184215
TI  - Prevalence of vitamin D deficiency among healthy adolescents.
AB  - BACKGROUND: Although vitamin D deficiency has been documented as a frequent
      problem in studies of young adults, elderly persons, and children in other
      countries, there are limited data on the prevalence of this nutritional
      deficiency among healthy US teenagers. OBJECTIVE: To determine the prevalence of
      vitamin D deficiency in healthy adolescents presenting for primary care. DESIGN:
      A cross-sectional clinic-based sample. SETTING: An urban hospital in Boston.
      PARTICIPANTS: Three hundred seven adolescents recruited at an annual physical
      examination to undergo a blood test and nutritional and activity assessments.
      MAIN OUTCOME MEASURES: Serum levels of 25-hydroxyvitamin D (25OHD) and
      parathyroid hormone, anthropometric data, nutritional intake, and weekly physical
      activity and lifestyle variables that were potential risk factors for
      hypovitaminosis D. RESULTS: Seventy-four patients (24.1%) were vitamin D
      deficient (serum 25OHD level, </=15 ng/mL [</=37.5 nmol/L]), of whom 14 (4.6%)
      were severely vitamin D deficient (25OHD level, </=8 ng/mL [</=20 nmol/L]). By
      using a broader definition (25OHD level, </=20 ng/mL [</=50 nmol/L]), 129
      patients (42.0%) were vitamin D insufficient. Serum 25OHD levels were inversely
      correlated with parathyroid hormone levels (r = -0.29), and were 24% lower during
      winter compared with summer. In a final multivariate model, season, ethnicity,
      milk and juice consumption, body mass index, and physical activity were
      significant independent predictors of hypovitaminosis D. CONCLUSIONS: Vitamin D
      deficiency was present in many US adolescents in this urban clinic-based sample.
      The prevalence was highest in African American teenagers and during winter,
      although the problem seems to be common across sex, season, and ethnicity.

PMID- 15184216
TI  - A cross-national study of violence-related behaviors in adolescents.
AB  - BACKGROUND: Violent behavior among adolescents is a significant problem
      worldwide, and a cross-national comparison of adolescent violent behaviors can
      provide information about the development and pattern of physical violence in
      young adolescents. OBJECTIVES: To determine and compare frequencies of adolescent
      violence-related behaviors in 5 countries and to examine associations between
      violence-related behaviors and potential explanatory characteristics. DESIGN,
      SETTING, AND PARTICIPANTS: Cross-sectional, school-based nationally
      representative survey at ages 11.5, 13.5, and 15.5 years in 5 countries (Ireland,
      Israel, Portugal, Sweden, and the United States). MAIN OUTCOME MEASURES:
      Frequency of physical fighting, bullying, weapon carrying, and fighting injuries
      in relation to other risk behaviors and characteristics in home and school
      settings. RESULTS: Fighting frequency among US youth was similar to that of all 5
      countries (nonfighters: US, 60.2%; mean frequency of 5 countries, 60.2%), as were
      the frequencies of weapon carrying (noncarriers: US, 89.6%; mean frequency of 5
      countries, 89.6%) and fighting injury (noninjured: US, 84.5%; mean frequency of 5
      countries, 84.6%). Bullying frequency varied widely cross-nationally (nonbullies:
      from 57.0% for Israel to 85.2% for Sweden). Fighting was most highly associated
      with smoking, drinking, feeling irritable or bad tempered, and having been
      bullied. CONCLUSIONS: Adolescents in 5 countries behaved similarly in their
      expression of violence-related behaviors. Occasional fighting and bullying were
      common, whereas frequent fighting, frequent bullying, any weapon carrying, or any
      fighting injury were infrequent behaviors. These findings were consistent across
      countries, with little cross-national variation except for bullying rates.
      Traditional risk-taking behaviors (smoking and drinking) and being bullied were
      highly associated with the expression of violence-related behavior.

PMID- 15184217
TI  - Characterization of interpersonal violence events involving young adolescent
      girls vs events involving young adolescent boys.
AB  - BACKGROUND: Multiple studies have demonstrated that girls are engaging in
      interpersonal violence. However, little is known about the potentially unique
      aspects of violent events involving girls. OBJECTIVES: To describe
      characteristics of interpersonal violence events in preadolescents and young
      adolescents and to determine if events involving any girl are different than
      those involving only boys. DESIGN: A cross-sectional survey of 8- to 14-year-old
      patients who were being evaluated at an urban children's hospital emergency
      department for injuries caused by interpersonal violence was conducted between
      September 2000 and August 2001. The survey asked the patient to describe details
      about event circumstances, opponents, weapon use, and injury severity. RESULTS:
      We enrolled 190 patients into the study; 58 (31%) were girls. Seventy-four events
      (39%) had a girl involved, 156 (82%) occurred on a weekday, 127 (67%) were
      classified as fights, 140 (74%) were with a known opponent, and 93 (49%) occurred
      at school. Events involving girls were more likely than events involving all boys
      to occur at home (relative risk [RR], 1.6; 95% confidence interval [CI], 1.0
      2.5). Both boys and girls reported "being disrespected" and "teasing" as popular
      reasons for a fight. Events involving girls were more commonly related to a
      "recurrence of a previous fight" (RR, 6.4; 95% CI, 1.9-21.5), were more likely to
      end because of adult intervention (RR, 1.7; 95% CI, 1.1-2.6), and have a family
      member try to physically break up the fight (RR, 3.7; 95% CI, 1.5-9.1).
      CONCLUSION: Violent events involving preadolescent and early adolescent girls are
      more likely to be in response to a previous event and to involve the home
      environment and family member intervention. Health care professionals should
      screen violently injured girls for safety concerns and retaliation plans and
      consider engaging the family in efforts to prevent future events.

PMID- 15184218
TI  - Informed consent for genetic research.
AB  - BACKGROUND: Rapid technological advances in genetic research and public concern
      about genetic discrimination have led to anticipatory safeguards in the informed
      consent process in the absence of legal examples of proven discrimination.
      Despite federal and state regulations to restrict access to personal health
      information, including genetic information, institutional review boards have
      required the addition of language to informed consent documents that warns about
      the risks of discrimination with participation in genetic research. OBJECTIVE: To
      determine the reasons that families refused consent for their infant's
      participation in a study evaluating a genetic cause of respiratory distress
      syndrome. DESIGN: Survey conducted between February 1, 2002, and March 31, 2003.
      SETTING: Academic, tertiary free-standing children's hospital. PARTICIPANTS: A
      convenience sample of 465 families were approached for consent. The 135 families
      who refused consent were surveyed. MAIN OUTCOME MEASURES: Reasons for refusal.
      RESULTS: Of the nonconsenting families, 79% spontaneously and specifically
      identified institutionally required language in our consent form concerning the
      risk of denial of access to health insurance and employment as the primary reason
      for refusal; 97% indicated that their fears resulted directly from language in
      our consent form. Only 20% of families who refused consent cited inadequate time
      to consider the study. CONCLUSIONS: The institutionally required description of
      risk of genetic discrimination due solely to participation in genetic research
      was the primary reason for refusal to consent in this cohort. Information about
      federally and institutionally mandated protections for confidentiality of
      participants in genetic research should be included in the informed consent
      document to balance the description of hypothetical risks and more accurately
      inform subjects.

PMID- 15184219
TI  - Risk factors associated with ampicillin-resistant infection in newborns in the
      era of group B streptococcal prophylaxis.
AB  - OBJECTIVES: To document the trend of ampicillin-resistant infections in newborns
      weighing at least 1500 g and to determine factors associated with ampicillin
      resistant neonatal early-onset infection in the era of routine group B
      streptococcal prophylaxis. DESIGN: Case-control study. SETTING: Referral hospital
      with level I through level III nurseries.Patients Newborns aged 0 to 7 days with
      cultures positive for bacterial infection, born from January 1994 to August 2002
      (n = 53). Random controls were matched to admission year and nursery level (n =
      159). MAIN OUTCOME MEASURES: Trends of and factors associated with ampicillin
      resistant infections. RESULTS: Trends in our institution were the same as those
      found in some recent reports, a decrease in group B streptococcal early-onset
      infections without a concomitant increase in gram-negative early-onset
      infections. Specifically, when stratified by birth weight, newborns weighing at
      least 1500 g had no increase in gram-negative pathogens in the eras both before
      and after group B streptococcal prophylaxis (0.8 per 1000 live births to 0.3 per
      1000 live births; incidence ratio, 2.3 [95% confidence interval, 0.5-10.9]). No
      increase in ampicillin resistance was seen during the same 3 periods (50%, 60%,
      and 50%, respectively; P =.97). Independent risk factors associated with
      ampicillin-resistant early-onset infection were intrapartum antibiotics for a 24
      hour duration or longer (odds ratio, 4.8 [95% confidence interval, 1.0-23.3]) and
      clinical chorioamnionitis (odds ratio, 9.2 [95% confidence interval, 2.6-32.9]).
      CONCLUSIONS: No increase in early-onset infections with gram-negative or
      ampicillin-resistant pathogens was detected. Ampicillin-resistant early-onset
      infection was associated with intrapartum antibiotics given for 24 hours or
      longer prior to delivery and with clinical chorioamnionitis. Ampicillin sodium
      and gentamicin sulfate remain appropriate initial antibiotic therapies for early
      onset infection in newborns weighing at least 1500 g and without these risk
      factors.

PMID- 15184220
TI  - Association between television viewing and sleep problems during adolescence and
      early adulthood.
AB  - BACKGROUND: Although research has suggested that extensive television viewing may
      be associated with sleep problems, the direction of this association has not yet
      been determined. OBJECTIVE: To investigate directional hypotheses regarding the
      association between television viewing and sleep problems during adolescence and
      early adulthood. DESIGN: The Children in the Community Study, a prospective
      longitudinal investigation. PARTICIPANTS AND SETTING: A community-based sample of
      759 mothers from upstate New York and their offspring were interviewed during the
      early adolescence (mean age, 14 years), middle adolescence (mean age, 16 years),
      and early adulthood of the offspring (mean age, 22 years). MAIN OUTCOME MEASURES:
      Television viewing and sleep problems during adolescence and early adulthood
      measured using the Disorganizing Poverty Interview and the age-appropriate
      versions of the Diagnostic Interview Schedule for Children. RESULTS: Adolescents
      who watched 3 or more hours of television per day during adolescence were at a
      significantly elevated risk for frequent sleep problems by early adulthood. This
      elevation in risk remained significant after offspring age, sex, previous sleep
      problems, offspring psychiatric disorders, offspring neglect, parental
      educational level, parental annual income, and parental psychiatric symptoms were
      controlled statistically. Adolescents who reduced their television viewing from 1
      hour or longer to less than 1 hour per day experienced a significant reduction in
      risk for subsequent sleep problems. Sleep problems during adolescence were not
      independently associated with subsequent television viewing when prior television
      viewing was controlled. CONCLUSION: Extensive television viewing during
      adolescence may contribute to the development of sleep problems by early
      adulthood.

PMID- 15184221
TI  - Are parental vaccine safety concerns associated with receipt of measles-mumps
      rubella, diphtheria and tetanus toxoids with acellular pertussis, or hepatitis B
      vaccines by children?
AB  - OBJECTIVES: To identify parental perceptions regarding vaccine safety and assess
      their relationship with the immunization status of children. DESIGN, SETTING, AND
      PARTICIPANTS: Case-control study based on a survey of a sample of households
      participating in the 2000-2001 National Immunization Survey, a quarterly random
      digit-dialing sample of US children aged 19 to 35 months. Three groups of case
      children not up-to-date for 3 vaccines were compared with control children who
      were up-to-date for each respective vaccine. Main Outcome Measure Measles
      containing or measles-mumps-rubella, diphtheria and tetanus toxoids and pertussis
      or diphtheria and tetanus toxoids with acellular pertussis, and hepatitis B
      vaccination coverage. RESULTS: Among those sampled from the 2000-2001 National
      Immunization Survey, the household response rate was 2315 (52.1%) of 4440. Most
      respondents (>90%) in all groups believed vaccinations are important. In each
      case-control group, there was no significant difference between the percentage of
      case and control parents expressing general vaccine safety (range, 53.5%-64.1%).
      However, case parents were more likely to have asked that their child not be
      vaccinated for reasons other than illness (range, 10.2%-13.7% vs range, 2.9%
      5.3%, respectively) and to believe their children received too many vaccinations
      (range, 3.4%-7.6% vs range, 0.8%-1.0%, respectively). Among the case-control
      group receiving a measles-containing or measles-mumps-rubella vaccination, only a
      small percentage of parents knew about the alleged association between autism and
      measles-mumps-rubella vaccinations (8.2%), and case parents were more likely to
      believe it than control parents (4.4% vs 1.5%, respectively; chi(2) P =.04).
      CONCLUSIONS: Despite belief in the importance of immunization by a vast majority
      of parents, the majority of parents had concerns regarding vaccine safety.
      Strategies to address important misperceptions about vaccine safety as well as
      additional research assessing vaccine safety are needed to ensure public
      confidence.

PMID- 15184222
TI  - A randomized controlled trial to change antibiotic prescribing patterns in a
      community.
AB  - BACKGROUND: Excessive and inappropriate use of antibiotics has been identified as
      a leading cause of the emergence of multiply resistant strains of pneumococci.
      OBJECTIVE: To examine the effects of academic detailing and a parental education
      program on community pediatricians' prescription of antibiotics for young
      children. METHODS: Physician leaders in study practices prepared educational
      modules and presented the modules to their practices. The control groups received
      only practice-specific report cards. Using a time-series analysis, we collected
      data on office visits and antibiotic prescriptions filled between May 1, 2000,
      and April 30, 2001 (baseline period), and between May 1, 2001, and April 30, 2002
      (intervention period). Antibiotic prescription rate was defined as the ratio of
      antibiotic prescriptions filled to the number of office visits. RESULTS: The
      antibiotic prescription rate decreased to 0.82 (95% confidence interval, 0.71
      0.95) of the baseline rate for the study group (6 practices) and to 0.86 (95%
      confidence interval, 0.77-0.95) of the baseline for the control group (5
      practices). Similar patterns for antibiotic prescription rates were seen for
      study and control groups both before and after the intervention. Wide variations
      in prescription rates were observed among the practices, but, in general, the
      control practices had lower antibiotic prescribing rates during both the baseline
      and the intervention periods. Use of amoxicillin increased slightly in the study
      group and decreased slightly in the control group. The use of cephalosporins
      increased slightly in both groups. CONCLUSION: Overall, academic detailing
      appeared to be no more effective in reducing antibiotic use than the practice
      specific report cards alone.

PMID- 15184223
TI  - Diagnosing celiac disease: a comparison of human tissue transglutaminase
      antibodies with antigliadin and antiendomysium antibodies.
AB  - OBJECTIVE: To evaluate and compare the sensitivity and specificity of the new
      serologic marker human antitissue transglutaminase antibodies (IgA anti-tTG) with
      those of antiendomysium (IgA EMA) and antigliadin antibodies (IgA and IgG AGA)
      for the diagnosis of celiac disease (CD). METHODS: The level of IgA antibodies to
      tTG in serum was determined by an enzyme-linked immunosorbent assay (ELISA) test
      using recombinant human tTG as the antigen; IgA EMA, by indirect
      immunofluorescence; and IgA and IgG AGA, by ELISA. Sixty-eight serum samples from
      59 patients with CD were studied-30 patients had untreated CD, 22 were on gluten
      free diets, and 16 had been reintroduced to gluten-and compared with serum
      samples from 116 children examined for failure to thrive, short stature, various
      digestive diseases, or other non-CD conditions. RESULTS: Twenty-eight of 30
      patients with CD had anti-tTG (the 2 patients whose results were negative were 1
      patient with IgA deficiency and 1 infant); 27 of 30 patients had IgA EMA (1 child
      was IgA anti-tTG positive and IgA EMA negative); 18 of 30 had IgA AGA; and 28 of
      30 had IgG AGA. On gluten-free diets, 4 of 22 patients had anti-tTG but none had
      IgA EMA or IgA AGA. On normal diets, 15 of 15 children who had relapsed had anti
      tTG; 9, IgA EMA; 4, IgA AGA; and 8, IgG AGA (1 child did not relapse). In
      subjects without CD, 3 of 116 had anti-tTG; 12, IgG AGA; and 1, IgA AGA, but none
      had IgA EMA. In the 3 children who had anti-tTG, CD could be excluded. The
      positive predictive value of IgA anti-tTG was 90% and the negative predictive
      value, 98%. In comparison, results for IgA EMA were 100% and 97%, IgA AGA 94% and
      90%, and IgG AGA 70% and 98%, respectively. CONCLUSION: The presence of human
      anti-tTG is a reliable indicator for the diagnosis and follow-up of CD.

PMID- 15184224
TI  - Parental grief and palliative care require attention.

PMID- 15184225
TI  - Adolescent violence: is it the same everywhere?

PMID- 15184226
TI  - Pulse oximetry: good technology misapplied.

PMID- 15184227
TI  - Meta-analysis based on standardized effects is unreliable.

PMID- 15184228
TI  - Sleep difficulties in young people.

PMID- 15184229
TI  - Newborn babies: more pain than that.

PMID- 15184230
TI  - Evidence-based toilet training.

PMID- 15184231
TI  - Do you believe milk makes mucus?

PMID- 15184232
TI  - The 15-minute appointment: sacred cow?

PMID- 15184233
TI  - The Fairy Feller's Master-Stroke.

PMID- 15184234
TI  - Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic
      prefrontal cortex and midbrain.
AB  - CONTEXT: The schizophrenia-susceptibility gene dysbindin (DTNBP1 on 6p22.3)
      encodes a neuronal protein that binds to beta-dystrobrevin and may be part of the
      dystrophin protein complex. Little is known about dysbindin expression in normal
      or schizophrenic brain. OBJECTIVES: To determine whether brain regions implicated
      in schizophrenia express dysbindin and whether abnormal levels of dysbindin
      messenger RNA (mRNA) may be found in this disorder and to test whether sequence
      variations in the dysbindin gene in the promoter region, 5' and 3' untranslated
      regions, or introns would affect dysbindin mRNA levels. METHODS: In patients with
      schizophrenia and controls, we compared dysbindin, synaptophysin, spinophilin,
      and cyclophilin mRNA levels in the dorsolateral prefrontal cortex and dysbindin
      mRNA levels in the midbrain by in situ hybridization. We genotyped brain DNA at
      11 single nucleotide polymorphisms to determine whether genetic variation in the
      dysbindin gene affects cortical dysbindin mRNA levels. MAIN OUTCOME MEASURES:
      Quantitative assessment of dysbindin mRNA levels across various brain regions and
      comparative studies of dysbindin mRNA levels in brains of patients with
      schizophrenia compared with normal controls. RESULTS: Dysbindin mRNA was detected
      in the frontal cortex, temporal cortex, hippocampus, caudate, putamen, nucleus
      accumbens, amygdala, thalamus, and midbrain of the adult brain. Patients with
      schizophrenia had statistically significantly reduced dysbindin mRNA levels in
      multiple layers of the dorsolateral prefrontal cortex, whereas synaptophysin,
      spinophilin, and cyclophilin mRNA levels were unchanged. Dysbindin mRNA levels
      were quantitatively reduced in the midbrain of patients with schizophrenia, but
      not statistically significantly. Cortical dysbindin mRNA levels varied
      statistically significantly according to dysbindin genotype. CONCLUSIONS:
      Dysbindin mRNA is expressed widely in the brain, and its expression is reduced in
      schizophrenia. Variation in dysbindin mRNA levels may be determined in part by
      variation in the promoter and the 5' and 3' untranslated regions. These data add
      to the evidence that dysbindin is an etiologic factor in schizophrenia risk.

PMID- 15184235
TI  - Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a
      measure of serotonin synthesis in medication-free patients with major depression.
AB  - CONTEXT: The serotonin hypothesis of depression invokes a relative or absolute
      deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the
      brain pathways mediating the expression of mood (ie, the limbic cortex) is a
      plausible candidate mechanism. OBJECTIVES: To measure and compare, using the
      alpha-[(11)C]methyl-l-tryptophan/positron emission tomography method, the brain
      trapping constant of alpha-[(11)C]methyl-l-tryptophan (K*, milliliters per gram
      per minute), an index of serotonin synthesis, in brain areas involved in the
      regulation of mood in patients with major depression (MD) and age- and sex
      matched controls. DESIGN: Between-group comparison. SETTING: Department of
      Psychiatry and Montreal Neurological Institute, McGill University. PARTICIPANTS:
      Seventeen medication-free outpatients with a current episode of MD (9 women: mean
      +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17
      controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5
      +/- 9.9 years). Main Outcome Measure Normalized K*, normalized to the global
      mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial
      temporal cortices; the thalamus; and the caudate nucleus. RESULTS: Compared with
      age- and sex-matched controls, normalized K* was significantly decreased
      bilaterally in female patients with MD in the anterior cingulate cortex, in the
      left anterior cingulate cortex in male patients with MD, and in the left mesial
      temporal cortex in male and female patients with MD (P<.001 for all). Exploratory
      analyses identified additional patient-control differences for normalized K* (eg,
      inferior frontal gyrus and superior parietal lobule), most of which, once
      corrected for 38 multiple comparisons, lost their significance. Morphometric
      measurements of the cingulate cortex divisions confirmed that the reduction of
      normalized K* in depressed patients was not attributable to a reduction in gray
      matter volume. Normalized K* in the anterior cingulate cortex did not correlate
      with ratings of depression severity collected at the time of scan. CONCLUSIONS:
      Reduction of normalized K*, an index of serotonin synthesis, in parts of the
      limbic and paralimbic cortices may contribute to the biochemical alterations
      associated with MD.

PMID- 15184236
TI  - Distinct neural correlates of washing, checking, and hoarding symptom dimensions
      in obsessive-compulsive disorder.
AB  - CONTEXT: Obsessive-compulsive disorder (OCD) is clinically heterogeneous, yet
      most previous functional neuroimaging studies grouped together patients with
      mixed symptoms, thus potentially reducing the power and obscuring the findings of
      such studies. OBJECTIVE: To investigate the neural correlates of washing,
      checking, and hoarding symptom dimensions in OCD. DESIGN: Symptom provocation
      paradigm, functional magnetic resonance imaging, block design, and nonparametric
      brain mapping analyses. SETTING: University hospital. PARTICIPANTS: Sixteen
      patients with OCD (11 inpatients, 5 outpatients) with mixed symptoms and 17
      healthy volunteers of both sexes. Intervention All subjects participated in 4
      functional magnetic resonance imaging experiments. They were scanned while
      viewing alternating blocks of emotional (washing-related, checking-related,
      hoarding-related, or aversive, symptom-unrelated) and neutral pictures, and
      imagining scenarios related to the content of each picture type.Main Outcome
      Measure Blood oxygenation level-dependent response. RESULTS: Both patients and
      control subjects experienced increased subjective anxiety during symptom
      provocation (patients significantly more so) and activated neural regions
      previously linked to OCD. Analyses of covariance, controlling for depression,
      showed a distinct pattern of activation associated with each symptom dimension.
      Patients demonstrated significantly greater activation than controls in bilateral
      ventromedial prefrontal regions and right caudate nucleus (washing);
      putamen/globus pallidus, thalamus, and dorsal cortical areas (checking); left
      precentral gyrus and right orbitofrontal cortex (hoarding); and left
      occipitotemporal regions (aversive, symptom-unrelated). These results were
      further supported by correlation analyses within patients, which showed highly
      specific positive associations between subjective anxiety, questionnaire scores,
      and neural response in each experiment. There were no consistently significant
      differences between patients with (n = 9) and without (n = 7) comorbid diagnoses.
      CONCLUSIONS: The findings suggest that different obsessive-compulsive symptom
      dimensions are mediated by relatively distinct components of
      frontostriatothalamic circuits implicated in cognitive and emotion processing.
      Obsessive-compulsive disorder may be best conceptualized as a spectrum of
      multiple, potentially overlapping syndromes rather than a unitary nosologic
      entity.

PMID- 15184237
TI  - A randomized effectiveness trial of interpersonal psychotherapy for depressed
      adolescents.
AB  - CONTEXT: Adolescent depression is highly prevalent and has substantial morbidity,
      including suicide attempts, school dropout, and substance abuse, but many
      depressed adolescents are untreated. The school-based health clinic offers the
      potential for accessible and efficient treatment, although it is unknown whether
      school-based clinicians can be trained to implement evidence-based
      psychotherapies for depression in routine care. OBJECTIVE: To assess the
      effectiveness of interpersonal psychotherapy modified for depressed adolescents
      (IPT-A) compared with treatment as usual (TAU) in school-based mental health
      clinics. DESIGN: A 16-week randomized clinical trial was conducted from April 1,
      1999, through July 31, 2002. SETTING: Five school-based mental health clinics in
      New York City, NY. Patients Sixty-three adolescents referred for a mental health
      intake visit who met eligibility criteria. Eligible patients had a mean Hamilton
      Depression Rating Scale score of 18.6 (SD, 5.5) and a mean Children's Global
      Assessment Scale score of 52.6 (SD, 5.5) and met DSM-IV criteria for major
      depressive disorder, dysthymia, depression disorder not otherwise specified, or
      adjustment disorder with depressed mood. Mean age was 15.1 years (SD, 1.9 years).
      The sample was predominantly female (n = 53 [84%]), Hispanic (n = 45 [71%]), and
      of low socioeconomic status. Intervention Patients were randomly assigned to
      receive IPT-A (n = 34) or TAU (n = 29) from school-based health clinic
      clinicians. MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale, Beck
      Depression Inventory, Children's Global Assessment Scale, Clinical Global
      Impressions scale, and the Social Adjustment Scale-Self-Report. RESULTS:
      Adolescents treated with IPT-A compared with TAU showed greater symptom reduction
      and improvement in overall functioning. Analysis of covariance showed that
      compared with the TAU group, the IPT-A group showed significantly fewer clinician
      reported depression symptoms on the Hamilton Depression Rating Scale (P =.04),
      significantly better functioning on the Children's Global Assessment Scale (P
      =.04), significantly better overall social functioning on the Social Adjustment
      Scale-Self-Report (P =.01), significantly greater clinical improvement (P =.03),
      and significantly greater decrease in clinical severity (P =.03) on the Clinical
      Global Impressions scale. CONCLUSIONS: Interpersonal psychotherapy delivered in
      school-based health clinics is an effective therapy for adolescent depression.
      This effort is a significant step toward closing the gap between treatment
      conducted in the laboratory and community clinic.

PMID- 15184238
TI  - The nature and determinants of neuropsychological functioning in late-life
      depression.
AB  - CONTEXT: Cognitive impairment in late-life depression (LLD) is highly prevalent,
      disabling, poorly understood, and likely related to long-term outcome.
      OBJECTIVES: To determine the characteristics and determinants of
      neuropsychological functioning LLD. DESIGN: Cross-sectional study of groups of
      LLD patients and control subjects. SETTING: Outpatient, university-based
      depression research clinic. PARTICIPANTS: One hundred patients without dementia
      60 years and older who met DSM-IV criteria for current episode of unipolar major
      depression (nonpsychotic) and 40 nondepressed, age- and education-equated control
      subjects. MAIN OUTCOME MEASURES: A comprehensive neuropsychological battery.
      RESULTS: Relative to control subjects, LLD patients performed poorer in all
      cognitive domains. More than half exhibited significant impairment (performance
      below the 10th percentile of the control group). Information processing speed and
      visuospatial and executive abilities were the most broadly and frequently
      impaired. The neuropsychological impairments were mediated almost entirely by
      slowed information processing (beta =.45-.80). Education (beta =.32) and
      ventricular atrophy (beta =.28) made additional modest contributions to variance
      in measures of language ability. Medical and vascular disease burden,
      apolipoprotein E genotype, and serum anticholinergicity did not contribute to
      variance in any cognitive domain. CONCLUSIONS: Late-life depression is
      characterized by slowed information processing, which affects all realms of
      cognition. This supports the concept that frontostriatal dysfunction plays a key
      role in LLD. The putative role of some risk factors was validated (eg, advanced
      age, low education, depression severity), whereas others were not (eg, medical
      burden, age at onset of first depressive episode). Further studies of
      neuropsychological functioning in remitted LLD patients are needed to parse
      episode-related and persistent factors and to relate them to underlying neural
      dysfunction.

PMID- 15184239
TI  - Association of specific haplotypes of D2 dopamine receptor gene with
      vulnerability to heroin dependence in 2 distinct populations.
AB  - CONTEXT: Dopamine receptor-mediated pathways play critical roles in the mechanism
      of addiction. However, associations of the D(2) dopamine receptor gene (DRD2)
      with substance abuse are controversial. OBJECTIVE: To determine whether
      susceptibility sites resided at DRD2. DESIGN: Haplotype-based case-control
      analysis of 2 distinct populations using 10 single nucleotide polymorphisms
      (SNPs) with heroin dependence. SETTING: Universities of Mainz and Bonn, Germany,
      and 3 local hospitals in southwestern China. Patients Cases and control subjects
      recruited from China (486 cases, 313 controls) and Germany (471 cases, 192
      controls). INTERVENTIONS: Genotyping for 10 SNPs by 5'-exonuclease fluorescence
      assays. The D' value of linkage disequilibrium and haplotypes were generated by
      the expectation-maximization algorithm. MAIN OUTCOME MEASURES: Genotype, allele,
      and haplotype frequencies were compared between cases and controls by chi(2)
      tests constructed for each population. An additional 32 SNPs randomly distributed
      in the genome were genotyped for detecting population admixture in the 2
      populations. RESULTS: A haplotype block of 25.8 kilobases (kb) was defined by 8
      SNPs extending from SNP3 (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10
      kb distal to the 3' end of the gene. Within this block, specific haplotype
      cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin
      dependence in Chinese patients (P = 1.425 x 10(-22); odds ratio, 52.80; 95%
      confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination
      "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter
      haplotypes that were associated with a lower risk of heroin dependence in Germans
      (P = 1.94 x 10(-11) for 8-SNP analysis). There was no evidence of population
      stratification in either population. CONCLUSIONS: These results strongly support
      a role of DRD2 as a susceptibility gene with heroin dependence in Chinese
      patients and was associated with low risk of heroin dependence in Germans.

PMID- 15184240
TI  - Genetic and environmental contributions to the Child Behavior Checklist Obsessive
      Compulsive Scale: a cross-cultural twin study.
AB  - CONTEXT: We have reported elsewhere on the development of an 8-item Obsessive
      Compulsive Scale (OCS) contained in the Child Behavior Checklist (CBCL) to
      identify children who meet criteria for DSM-IV obsessive-compulsive disorder.
      Twin studies of obsessive-compulsive disorder have indicated a significant
      genetic component to its expression. OBJECTIVE: To determine the relative
      contributions of genetic and environmental influences on childhood obsessive
      compulsive behavior using the CBCL OCS in twin samples. DESIGN: The CBCL data
      were received by survey of twins in the Netherlands Twin Registry (NTR) and the
      Missouri Twin Study (USA/MOTWIN). SETTING: General community twin samples.
      PARTICIPANTS: Participants were 4246 twin pairs aged 7 years, 2841 aged 10 years,
      and 1562 aged 12 years (who also participated in the study at 7 and 10 years of
      age) from the NTR and 1461 mixed-age twin pairs (average age, approximately 9
      years) from the USA/MOTWIN. MAIN OUTCOME MEASURES: Model fitting to test for
      genetic and environmental influences, sex differences, and sibling
      interaction/rater contrast effects on the CBCL OCS. RESULTS: In each case, the
      best-fitting model was one that indicated significant additive genetic influences
      (range, 45%-58%; 95% confidence interval [CI], 45%-61%), and unique environmental
      influences (range, 42%-55%; 95% CI, 39%-55%), with shared environmental
      influences in the NTR sample aged 12 years (16%). Sex differences were seen in
      the mixed-age USA/MOTWIN model, but not in the NTR samples. No evidence of
      dominance, sibling interaction, or rater-contrast effects was seen. These data
      were relatively consistent across age and cultures. CONCLUSIONS: The CBCL OCS is
      influenced by genetic factors (approximately 55%) and unique environmental
      factors (approximately 45%) in the younger sample, with common environmental
      influences only at 12 years of age. These effects do not vary with differences in
      sex or sibling interaction/rater contrast effects. Our data reveal higher genetic
      influences for obsessive-compulsive behavior and do not demonstrate genetic
      differences across sex.

PMID- 15184242
TI  - Toward the last cohort.

PMID- 15184241
TI  - Perinatal factors and the development of autism: a population study.
AB  - BACKGROUND: Autism is considered to have a genetic basis, although exposure to
      certain stimuli in the prenatal period has been implicated to be causal in some
      cases. Some investigations have shown an association with obstetric complications
      but findings have been inconsistent owing to differences in sampling and methods.
      OBJECTIVE: To examine the association of obstetric factors with autism spectrum
      disorders for a cohort of children, using obstetric data contained in a statutory
      database collected at the time of birth. DESIGN: Subjects born in Western
      Australia between 1980 and 1995 and diagnosed with an autism spectrum disorder by
      1999 were included as cases (n = 465). Siblings of the cases (n = 481) and a
      random population-based control group (n = 1313) were compared with the cases on
      obstetric information contained in the Maternal and Child Health Research
      Database of Western Australia. RESULTS: Compared with control subjects, cases had
      significantly older parents and were more likely to be firstborn. Case mothers
      had greater frequencies of threatened abortion, epidural caudal anesthesia use,
      labor induction, and a labor duration of less than 1 hour. Cases were more likely
      to have experienced fetal distress, been delivered by an elective or emergency
      cesarean section, and had an Apgar score of less than 6 at 1 minute. Cases with a
      diagnosis of autism had more complications than those with pervasive
      developmental disorder not otherwise specified or Asperger syndrome. Nonaffected
      siblings of cases were more similar to cases than control subjects in their
      profile of complications. CONCLUSIONS: Autism is unlikely to be caused by a
      single obstetric factor. The increased prevalence of obstetric complications
      among autism cases is most likely due to the underlying genetic factors or an
      interaction of these factors with the environment.

PMID- 15184243
TI  - Measures for ascertaining use of colorectal cancer screening in behavioral,
      health services, and epidemiologic research.

PMID- 15184245
TI  - Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose
      on lung cancer risk in a Swedish population.
AB  - The major identified risk factor for lung cancer is tobacco smoking. We
      identified previously the possible modifying influence of CYP1A1 and GSTM1
      polymorphisms on lung cancer risk in a Swedish population. The present study,
      extended by several study subjects and with analyses for polymorphisms in GSTT1
      and NQO1, includes 524 lung cancer cases and 530 control subjects. No evidence
      for an influence of genetic polymorphisms in CYP1A1, GSTM1, GSTT1, and NQO1 on
      lung cancer risk overall was found. In smokers, there was, however, a suggestion
      that the variant CYP1A1 and NQO1 genotypes may confer an increased risk for
      squamous cell carcinoma. In ever smokers, the homozygously deleted GSTM1
      (GSTM1*O/*O) genotype was significantly associated with increased risk of small
      cell carcinoma (adjusted odds ratio 2.72, 95% confidence interval 1.32-5.90). The
      risks noted for the variant CYP1A1 genotypes and the GSTM1*O/*O genotype seemed
      to be restricted to light smokers. The GSTT1*O/*O genotype also appeared to be a
      possible risk factor in light smokers, whereas, in heavy smokers, this genotype
      was associated with decreased risk for lung cancer overall (odds ratio 0.36, 95%
      confidence interval 0.13-0.99). Due to the multiple comparisons made, we cannot
      exclude the possibility that some of these associations may represent chance
      findings.

PMID- 15184246
TI  - Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal
      cancer in men and women: a prospective analysis from the European prospective
      investigation into cancer-Norfolk study.
AB  - BACKGROUND: Increasing evidence suggests that abnormal glucose metabolism may be
      associated with increased risk of colorectal cancer. METHODS: We examined the
      relationship between known diabetes and glycated hemoglobin (HbA1c)
      concentrations measured in 1995 to 1997 and subsequent incident colorectal cancer
      after 6 years follow-up in 9,605 men and women ages 45 to 79 years in the
      European Prospective Investigation into Cancer-Norfolk Study. RESULTS: Among
      individuals not known to have cancer at the baseline survey, there were 67
      incident colorectal cancers. HbA1c concentration appeared continuously related to
      incident colorectal cancer risk, with lowest rates observed in those with HbA1c
      below 5%. Known diabetes was also associated with incident colorectal cancer,
      with relative risk (RR) 3.18 and 95% confidence interval (CI) 1.36-7.40 (P <
      0.01) adjusting for age and sex and RR 2.78 and 95% CI 1.10-7.00 (P = 0.03)
      adjusting for age, sex, body mass index, and smoking compared with those without
      known diabetes. The RR (95% CI) of incident colorectal cancer per 1% absolute
      increase in HbA1c was 1.34 (1.12-1.59; P < 0.001). HbA1c concentrations appeared
      to explain the increased colorectal cancer risk associated with diabetes in
      multivariate models. CONCLUSIONS: Known diabetes was associated with
      approximately 3-fold risk of colorectal cancer in this analysis; this increased
      risk was largely explained by HbA1c concentrations, which appears continuously
      related to colorectal cancer risk across the population distribution.

PMID- 15184247
TI  - Cell proliferation and apoptotic indices predict adenoma regression in a placebo
      controlled trial of celecoxib in familial adenomatous polyposis patients.
AB  - BACKGROUND: Celecoxib was shown to regress colorectal adenomas in familial
      adenomatous polyposis (FAP) patients relative to placebo. To address the
      mechanism of polyp regression, we determined whether celecoxib can modulate cell
      proliferation, apoptosis, and prostaglandin E(2) (PGE(2)) levels in colorectal
      epithelia from FAP trial participants and whether such alterations correlate with
      observed reductions in polyp number. MATERIALS AND METHODS: Colorectal mucosal
      biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg
      twice daily) or placebo administration (6 months). Residual paraffin-embedded
      adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone
      (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and
      apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling
      indices and their ratios were calculated in superficials (s) and nonsuperficial
      (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences
      were calculated. PGE(2) levels were analyzed by mass spectroscopy (normal, n =
      64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated
      with previously determined mean percentage reductions in colorectal polyp number.
      RESULTS: In adenomas, a reduction in the superficial proliferative activity i.e.,
      Ki-67(s) labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An
      increase in the apoptotic ratio [i.e., superficial apoptotic index
      (AI(s))/nonsuperficial apoptotic index (AI(ns))] was found to correlate with
      reduced polyp counts in that higher apoptotic ratios correlated with better
      response to celecoxib (r = 0.71, P = 0.004). Furthermore, the AI(s)/Ki-67(s)
      ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a
      trend toward increased AI(s) (r = 0.33, P = 0.053) and polyp regression was
      found. PGE(2) levels did not significantly correlate with polyp regression.
      Changes in biomarker levels (baseline to 6 months) were correlated in adenomas
      and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009;
      PGE(2), r = 0.50, P = 0.059) within individual patients. CONCLUSION: Suppression
      of cell proliferation and an increased apoptotic ratio, as well as the ratio of
      apoptosis to cell proliferation, accompany polyp regression in a chemoprevention
      trial in FAP patients. These findings suggest potential mechanisms for the
      efficacy of celecoxib and warrant further study of these biomarkers as
      intermediate endpoints in FAP patients.

PMID- 15184248
TI  - Variation in estradiol, estradiol precursors, and estrogen-related products in
      nipple aspirate fluid from normal premenopausal women.
AB  - The purpose of the study was to measure the concentrations of estradiol, its
      primary precursors, and factors with which it interacts in the breast, and
      determine their sources of variation. Nipple aspirate fluid (NAF) was collected
      from premenopausal women during the mid-luteal phase of the menstrual cycle. The
      fluid was diluted and unconjugated steroids were extracted. Estradiol was further
      purified by a solvent partition into aqueous NaOH. Androgens were measured in the
      non-phenolic fraction. Water-soluble, conjugated steroids and proteins were
      measured in the aqueous residue. All analytes were measured by immunoassays.
      Permutation methods were used to determine the correlations over multiple periods
      of time. The average concentration of estradiol in NAF was 435 pmol/L after
      purification but was many times higher when assayed without purification. Estrone
      and dehydroepiandrosterone (DHEA) sulfates were present in 3.7 and 75 micromol/L
      concentrations, respectively, while unconjugated androstenedione and DHEA were
      present in nanomole per liter concentrations. Lack of the steroid sulfates in NAF
      in 19% of subjects had no effect on NAF estradiol levels but was associated with
      a 77% lower concentration of unconjugated DHEA. Progesterone was present in
      concentrations that were 3- to 4-fold higher than normal serum concentrations
      (mean: 291 nmol/L). Cathepsin D, epidermal growth factor, and interleukin 6 had
      average values of 3.4 microg/mL, 424 ng/mL, and 1.7 ng/mL, respectively.
      Correlations between breasts were between 0.57 and 0.84 for the several analytes;
      correlations over time ranged from 0.64 and 0.93 with estrone sulfate highest in
      both categories. The lower correlation between breasts than within breasts
      indicates that local factors play an important role in determining the levels of
      many of these analytes in the breast. The high stability of the concentrations of
      several analytes over time indicates that fluctuations in environmental factors
      have little immediate effect on levels in the breast, and portends their utility
      as surrogate breast cancer risk markers.

PMID- 15184249
TI  - Epidemiology of urinary melatonin in women and its relation to other hormones and
      night work.
AB  - OBJECTIVE: Light exposure during night work suppresses melatonin production, and
      night work has been associated with an increased cancer risk. There is little
      information, however, about the interrelationships of night work, urinary
      melatonin levels, and levels of plasma steroid hormones in women. METHOD: We
      examined the reproducibility of morning urinary measurements of 6
      sulfatoxymelatonin over a 3-year period in 80 premenopausal women. We assessed
      correlations between average urinary melatonin and plasma steroid hormone levels
      and evaluated potential associations between night work and hormone levels, using
      current and long-term shift work information from two large, prospective cohorts,
      the Nurses' Health Study cohorts. RESULTS: The intraclass correlation for
      creatinine-adjusted 6-sulfatoxymelatonin was 0.72 (95% confidence interval, 0.65,
      0.82). We found significantly increased levels of estradiol after longer
      durations of night work (geometric mean levels of estradiol, 8.8 pg/mL for women
      who never worked night shifts versus 10.1 pg/mL for women who worked 15 or more
      years of night shifts; P for trend = 0.03). We observed a significant inverse
      association between increasing number of nights worked within the 2 weeks
      preceding urine collection and urinary melatonin levels (r = -0.30, P = 0.008),
      but no association of recent night work with estradiol (r = 0.10, P = 0.41).
      CONCLUSION: A single morning urinary melatonin measurement is a reasonable marker
      for long-term melatonin levels among premenopausal women. Women who work on
      rotating night shifts seem to experience changes in hormone levels that may be
      associated with the increased cancer risk observed among night-shift workers.

PMID- 15184250
TI  - Helicobacter pylori and malignant lymphoma in Spain.
AB  - Helicobacter pylori has been associated with gastric adenocarcinoma and gastric
      lymphoma. We report on the systematic evaluation of serologic detection of H.
      pylori in a lymphoma case-control study. METHODS: Cases (N = 536) were
      consecutive patients newly diagnosed with a lymphoid malignancy between 1998 and
      2002 in four centers in Spain. Lymphomas were diagnosed and classified using the
      WHO Classification. Controls (N = 603) were hospitalized patients frequency
      matched to the cases by 5-year age group, sex, and study center. Severe
      immunocompromised patients were excluded as controls. Patients underwent a
      personal interview and blood sampling. H. pylori infection was evaluated by the
      presence of IgG antibodies using the Premier enzyme immunoassay kit (Meridian
      Diagnostics Inc., Cincinnati, OH). Logistic regression analysis was used to
      estimate the odds ratios and 95% confidence intervals (OR, 95% CI) for lymphoma
      categories. RESULTS: Anti-H. pylori antibodies were detected in 68.5% of the
      cases and 71.3% of the controls (P = 0.29) H. pylori was associated with a 3-fold
      excess risk of splenic marginal B-cell lymphoma (OR = 3.97, 95% CI = 0.92-17.16).
      H. pylori was not associated with an overall increased risk of extranodal
      lymphomas (OR = 0.73, 95% CI = 0.44-1.22) but when specific sites were explored,
      the four mucosa-associated lymphoid tissue and the six diffuse large B-cell
      lymphomas primary localized in the stomach were all H. pylori seropositive.
      CONCLUSION: Persistent infection with H. pylori may be implicated in the
      development of lymphomas of the gastric mucosa and of the spleen. These results
      could have clinical implications in the management of splenic marginal zone
      lymphomas.

PMID- 15184251
TI  - Lung cancer mortality is related to age in addition to duration and intensity of
      cigarette smoking: an analysis of CPS-I data.
AB  - OBJECTIVES: Models previously developed for predicting lung cancer mortality from
      cigarette smoking intensity and duration based on aggregated prospective
      mortality data have employed a study of British doctors and have assumed a
      uniform age of initiation of smoking. We reexamined these models using the
      American Cancer Society's Cancer Prevention Study I data that include a range of
      ages of initiation to assess the importance of an additional term for age.
      METHODS: Model parameters were estimated by maximum likelihood, and model fit was
      assessed by residual analysis, likelihood ratio tests, and chi(2) goodness-of-fit
      tests. RESULTS: Examination of the residuals of a model proposed by Doll and Peto
      with the Cancer Prevention Study I data suggested that a better fitting model
      might be obtained by including an additional term specifying the ages when
      smoking exposure occurred. An extended model with terms for cigarettes smoked per
      day, duration of smoking, and attained age was found to fit statistically
      significantly better than the Doll and Peto model (P < 0.001) and to fit well in
      an absolute sense (goodness-of-fit; P = 0.34). Finally, a model proposed by
      Moolgavkar was examined and found not to fit as well as the extended model,
      although it included similar terms (goodness-of-fit; P = 0.007). CONCLUSIONS: The
      addition of age, or another measure of the timing of the exposure to smoking,
      improves the prediction of lung cancer mortality with Doll and Peto's
      multiplicative power model.

PMID- 15184252
TI  - Cancer prevention services and physician consensus in primary care group
      practices.
AB  - BACKGROUND: We conducted a randomized clinical trial of interventions to achieve
      physician consensus, practice changes, and patient activation designed to help
      primary care group practices enhance the delivery of cancer prevention and
      screening services. METHODS: In each of 42 primary care practices in 1991 to
      1994, we studied approximately 60 patients per physician who were between the
      ages 53 and 64. Data sources included patient and physician questionnaires,
      medical record audits of consenting patients for evidence of 11 cancer prevention
      services during the previous 3 years, and telephone interviews with key practice
      personnel. RESULTS: None of the interventions was associated with significant
      changes in frequency of services or procedures received or provided. Increased
      frequencies of services overall and of specific activities were associated with
      HMO membership or insurance coverage for six screening procedures. Patient
      reports of clinic staff recommendations to have each of six screening procedures
      were specifically associated with higher frequencies of services (P = 0.001).
      CONCLUSIONS: Demonstration of intervention impact may have been limited because
      the rates of prevention services were significantly higher in this study than
      have been reported elsewhere. These results might be explained by selection
      biases inherent in studying patients with a regular provider, overall practice
      trends for changes in provision of the studied services, and the study methods.

PMID- 15184254
TI  - Using nuclear morphometry to discriminate the tumorigenic potential of cells: a
      comparison of statistical methods.
AB  - Despite interest in the use of nuclear morphometry for cancer diagnosis and
      prognosis as well as to monitor changes in cancer risk, no generally accepted
      statistical method has emerged for the analysis of these data. To evaluate
      different statistical approaches, Feulgen-stained nuclei from a human lung
      epithelial cell line, BEAS-2B, and a human lung adenocarcinoma (non-small cell)
      cancer cell line, NCI-H522, were subjected to morphometric analysis using a CAS
      200 imaging system. The morphometric characteristics of these two cell lines
      differed significantly. Therefore, we proceeded to address the question of which
      statistical approach was most effective in classifying individual cells into the
      cell lines from which they were derived. The statistical techniques evaluated
      ranged from simple, traditional, parametric approaches to newer machine learning
      techniques. The multivariate techniques were compared based on a systematic cross
      validation approach using 10 fixed partitions of the data to compute the
      misclassification rate for each method. For comparisons across cell lines at the
      level of each morphometric feature, we found little to distinguish nonparametric
      from parametric approaches. Among the linear models applied, logistic regression
      had the highest percentage of correct classifications; among the nonlinear and
      nonparametric methods applied, the Classification and Regression Trees model
      provided the highest percentage of correct classifications. Classification and
      Regression Trees has appealing characteristics: there are no assumptions about
      the distribution of the variables to be used, there is no need to specify which
      interactions to test, and there is no difficulty in handling complex, high
      dimensional data sets containing mixed data types.

PMID- 15184253
TI  - O6-methylguanine-DNA methyltransferase gene: epigenetic silencing and prognostic
      value in head and neck squamous cell carcinoma.
AB  - BACKGROUND: Alkylating N-nitroso compounds can interact directly with DNA,
      forming O(6)-alkylguanine, a DNA adduct proved to be mutagenic and carcinogenic
      if not sufficiently repaired. A specific DNA repair enzyme, O(6)-methylguanine
      DNA methyltransferase (MGMT), can remove the alkyl group from the O(6)-position
      of the guanine, thereby preventing its mutagenic and carcinogenic effects.
      Inactivation of the MGMT gene in association with promoter hypermethylation
      results in persistence of O(6)-alkylguanine in DNA, leading to G:C to A:T
      transition mutation and these G:C to A:T transition mutations can inactivate p53
      tumor suppressor gene or activate ras proto-oncogene. METHODS: We analyzed MGMT
      promoter hypermethylation and protein expression patterns in 94 cases of primary
      head and neck squamous cell carcinoma (HNSCC) by methylation-specific PCR (MSP)
      and immunohistochemical staining. The results were then correlated with clinical
      follow-up data. RESULTS: MGMT promoter hypermethylation was present in 17 of 94
      patients (18.1%) and apparent loss of protein expression was seen in 19 of 93
      HNSCC patients (20.4%). The presence of MGMT promoter hypermethylation was
      significantly correlated with loss of MGMT protein expression in HNSCC. Both MGMT
      promoter hypermethylation and loss of protein expression were significantly
      correlated to increased tumor recurrences and decreased patient survival,
      independent of other risk factors, such as tumor site, tumor size, nodal status,
      age, and chemoradiation therapy. CONCLUSIONS: MGMT promoter hypermethylation and
      apparent loss of protein expression are reliable and independent prognostic
      factors in HNSCC. The above study may also provide guideline or basis for
      applying alkylating antitumor agents to patients with HNSCC that display MGMT
      promoter hypermethylation and/or loss of MGMT protein expression.

PMID- 15184255
TI  - Manganese superoxide dismutase polymorphism, plasma antioxidants, cigarette
      smoking, and risk of breast cancer.
AB  - Oxidative stress may be involved in the development of breast cancer. Manganese
      superoxide dismutase (MnSOD) is one of the primary enzymes that directly scavenge
      potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution
      at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD
      gene, has been associated with an increase in breast cancer risk. We conducted a
      nested case-control study within the Nurses' Health Study cohort to examine the
      role of this polymorphism and its interaction with environmental factors with
      breast cancer risk. MnSOD genotype data are available from 968 incident cases of
      breast cancer diagnosed after blood collection in 1989 and 1990, but before June
      1, 1998 and 1,205 matched controls. Compared with women homozygous for the Val
      allele, women homozygous for the Ala allele were not at an increased risk of
      breast cancer (multivariate odds ratio, 0.96; 95% confidence interval, 0.74
      1.24). We did not observe any significant interactions between MnSOD genotype
      with alcohol consumption, postmenopausal hormone use, plasma antioxidant levels,
      or dietary sources of antioxidants. We did observe evidence that the MnSOD Ala
      allele may modify the relation of cigarette smoking with breast cancer risk. A
      nonsignificant increased risk of breast cancer among current smokers was limited
      to women homozygous for the Ala alleles compared with Val/Val never smokers
      (multivariate odds ratio, 1.41; 95% confidence interval 0.77-2.60; P for
      interaction = 0.03). These data suggest that the Ala allele of MnSOD may modify
      breast cancer risk among current smokers, but is not an independent risk factor
      for breast cancer.

PMID- 15184256
TI  - Effects of cruciferous vegetable consumption on urinary metabolites of the
      tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
      in singapore chinese.
AB  - Vegetable consumption, including cruciferous vegetables, is protective against
      lung cancer, but the mechanisms are poorly understood. The purpose of this study
      was to investigate the effects of cruciferous vegetable consumption on the
      metabolism of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3
      pyridyl)-1-butanone (NNK) in smokers. The study was carried out in Singapore
      Chinese, whose mean daily intake of cruciferous vegetables is three times greater
      than that of people in the United States. Eighty-four smokers provided urine
      samples and were interviewed about dietary habits using a structured
      questionnaire, which included questions on consumption of nine commonly consumed
      cruciferous vegetables. Samples of these vegetables obtained in Singapore markets
      at three different times of year were analyzed for glucosinolates. Urine was
      analyzed for metabolites of NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
      (NNAL) and its glucuronides (NNAL-Glucs). Glucobrassicins, which release indole-3
      carbinols on chewing, were the major glucosinolates in seven of the nine
      cruciferous vegetables, accounting for 70.0% to 93.2% of all glucosinolates in
      these vegetables. There was a significant correlation (P = 0.01) between
      increased consumption of glucobrassicins and decreased levels of NNAL in urine
      after adjustment for number of cigarettes smoked per day; similar trends were
      observed for NNAL-Glucs (P = 0.08) and NNAL plus NNAL-Glucs (P = 0.03). These
      results are consistent with those of previous studies, which demonstrate that
      indole-3-carbinol decreases levels of urinary NNAL probably by inducing hepatic
      metabolism of NNK. The results are discussed with respect to the known
      chemopreventive activity of indole-3-carbinol against lung tumorigenesis by NNK
      in mice and the effects of isothiocyanates, which are also formed on consumption
      of cruciferous vegetables, on NNK metabolism. The results of this study
      demonstrate the complexities in assessing effects of cruciferous vegetables on
      carcinogen metabolism.

PMID- 15184257
TI  - Urinary biomarkers in charcoal workers exposed to wood smoke in Bahia State,
      Brazil.
AB  - Charcoal is an important source of energy for domestic and industrial use in many
      countries. Brazil is the largest producer of charcoal in the world, with
      approximately 350,000 workers linked to the production and transportation of
      charcoal. To evaluate the occupational exposure to wood smoke and potential
      genotoxic effects on workers in charcoal production, we studied urinary
      mutagenicity in Salmonella YG1041 +S9 and urinary levels of 2-naphthol and 1
      pyrenol in 154 workers of northeastern Bahia. Workers were classified into three
      categories according to their working location, and information about socio
      demographic data, diet, alcohol consumption, and smoking was obtained using a
      standard questionnaire. Spot urine samples were collected to evaluate urinary
      mutagenicity and urinary metabolites. Urinary mutagenicity increased
      significantly with exposure to wood smoke and was modified by smoking. The
      prevalence odds ratio was 5.31, and the 95% confidence interval was 1.85; 15.27
      for urinary mutagenicity in the highly exposed group relative to the nonexposed
      group. The levels of urinary metabolites increased monotonically with wood smoke
      exposure and were associated with the GSTM1 null genotype, which was determined
      previously. The prevalence odds ratio (95% confidence interval) for higher levels
      of 2-naphtol among the highly exposed was 17.13 (6.91; 42.44) and for 1
      hydroxyprene 11.55 (5.32; 25.08) when compared with nonexposed workers. Urinary 2
      naphthol was the most sensitive indicator of wood smoke exposure. This is the
      first reported measurement of internal exposure to wood smoke among charcoal
      workers, and the results showed that these workers receive a systemic exposure to
      genotoxic compounds.

PMID- 15184258
TI  - Using hierarchical modeling in genetic association studies with multiple markers:
      application to a case-control study of bladder cancer.
AB  - BACKGROUND: Genetic association studies are generating much information, usually
      in the form of single nucleotide polymorphisms in candidate genes. Analyzing such
      data is challenging, and raises issues of multiple comparisons and potential
      false-positive associations. Using data from a case-control study of bladder
      cancer, we showed how to use hierarchical modeling in genetic epidemiologic
      studies with multiple markers to control overestimation of effects and potential
      false-positive associations. METHODS: The data were first analyzed with the
      conventional approach of estimating each main effect individually. We
      subsequently employed hierarchical modeling by adding a second stage (prior)
      model that incorporated information on the potential function of the genes. We
      used an empirical-Bayes approach, estimating the residual effects of the genes
      from the data. When the residual effect was set to zero, we instead used a semi
      Bayes approach, in which they were pre-specified. We also explored the impact of
      using different second-stage design matrices. Finally, we used two approaches for
      assessing gene-environment interactions. The first approach added product terms
      into the first-stage model. The second approach used three indicators for
      subjects exposed to gene-only, environment-only, and both genetic and
      environmental factors. RESULTS: By pre-specifying the prior second-stage
      covariates, the estimates were shrunk to the mean of each pathway. The
      conventional model detected a number of positive associations, which were reduced
      with the hierarchical model. For example, the odds ratio for myeloperoxidase
      (G/G, G/A) genotype changed from 3.17 [95% confidence interval (CI), 1.32-7.59]
      to 1.64 (95% CI, 0.81-3.34). A similar phenomenon was observed for the gene
      environment interactions. The odds ratio for the gene-environment interaction
      between tobacco smoking and N-acetyltransferase 1 fast genotype was 2.74 (95% CI,
      0.68-11.0) from the conventional analysis and 1.24 (95% CI, 0.80-1.93) from the
      hierarchical model. CONCLUSION: Adding a second-stage hierarchical modeling can
      reduce the likelihood of false positive via shrinkage toward the prior mean,
      improve the risk estimation by increasing the precision, and, therefore,
      represents an alternative to conventional methods for genetic association
      studies.

PMID- 15184259
TI  - Longitudinal changes in lifestyle behaviors and health status in colon cancer
      survivors.
AB  - Lifestyle changes in persons diagnosed with cancer are important because they may
      impact prognosis, co-morbidities, and survival. This report describes
      longitudinal changes in lifestyle behaviors and health status among colon cancer
      survivors (n = 278) and population-based controls (n = 459) in North Carolina
      (39% African American), and examines demographic and psychosocial correlates of
      healthy lifestyle changes following a colon cancer diagnosis. Data are from
      surveys of a population-based cohort of colon cancer patients on diagnosis (the
      North Carolina Colon Cancer Study, NCCCS) and approximately 2 years post
      diagnosis [the North Carolina Strategies to Improve Diet, Exercise, and Screening
      Study (NC STRIDES)], and population-based controls. Both studies collected
      information on demographic/lifestyle characteristics and medical history. The
      NCCCS reflects pre-diagnosis or pre-interview patterns, whereas NC STRIDES
      queried on current practices. Between the NCCCS and NC STRIDES, colon cancer
      survivors reported significant increases in vegetable intake, physical activity,
      and supplement use (all P <0.01) and a non-statistically significant increase in
      fruit/juice consumption (0.1 serving), with larger fruit/vegetable changes in
      African Americans than Whites. Controls increased physical activity and
      supplement use and fewer reported arthritic symptoms (P < 0.05). Survivors who
      were older and female had an almost 3 times higher likelihood of having used at
      least one new dietary supplement post-diagnosis, whereas being retired correlated
      with increased vegetable intake, all P < 0.05. Having more barriers to increasing
      fruit/vegetable intake was inversely associated with taking a new supplement (P <
      0.05 only in controls). Colon cancer survivors reported making significant
      improvements in multiple health-related behaviors. Health care providers should
      communicate with persons diagnosed with colon cancer to ensure that they are
      making healthy lifestyle changes.

PMID- 15184260
TI  - Plasma adrenal androgens and risk of breast cancer in premenopausal women.
AB  - OBJECTIVES: Plasma DHEA and its sulfate (DHEA-S) are positively associated with
      breast cancer risk in postmenopausal women; but the relationships have not been
      studied in detail in premenopausal women. We prospectively evaluated
      relationships between plasma levels of DHEA and DHEA-S in blood samples provided
      by a group of primarily premenopausal women and subsequent breast cancer, by use
      of case-control sampling from the Nurses' Health Study cohort. METHOD: Blood
      samples were collected from 1989 to 1990. Among women who were not postmenopausal
      at blood collection, 302 were diagnosed with breast cancer between blood
      collection and June 1998. Two controls were selected per case and matched with
      respect to age, menopausal status, month and time of day of blood collection, and
      fasting status at blood collection. Statistical analyses using conditional
      logistic regression were done to adjust for potential confounders. RESULTS: At
      time of blood collection, the median age was 49 (10th to 90th percentiles 45 to
      53). In multivariable analyses, the highest quartile of DHEA was associated with
      an odds ratio of breast cancer of 0.92 (95% confidence interval, 0.59-1.43)
      relative to the lowest quartile (P value for log-linear trend 0.11). A similar
      analysis revealed an odds ratio of 1.08 (0.69-1.69) for DHEA-S (P value for log
      linear trend 0.83). No statistically significant interactions were noted
      according to certainty of menopausal status, age, or past oral contraceptive use.
      DISCUSSION: Our analysis did not reveal a relationship between DHEA or DHEA-S and
      subsequent breast cancer in middle-aged premenopausal women. In the future, this
      relationship should be studied in younger women.

PMID- 15184261
TI  - Missense mutations in the BRCT domain of BRCA-1 from high-risk women frequently
      perturb strongly hydrophobic amino acids conserved among mammals.
AB  - Inherited missense mutations in the tumor suppressor gene, BRCA-1, may predispose
      to breast or ovarian cancer, but the exact effects on the protein are generally
      unknown. The COOH-terminal region of BRCA-1 encodes two BRCT repeats, which are
      partially conserved in mammalian species (human, dog, rat, and mouse; 60% amino
      acid identity). A bioinformatic analysis was conducted to evaluate 246 BRCT
      missense mutations from high-risk breast and/or ovarian cancer patients (reported
      in the NIH Breast Cancer Information Core database). It was hypothesized that
      amino acids conserved in evolution would be disproportionately targeted by the
      mutations and that conserved amino acids with strongly hydrophobic side chains
      would be disproportionately perturbed. A statistical model was developed, and
      chi(2) tests were used to determine whether missense mutations are randomly
      distributed throughout the BRCT repeats or whether they disproportionately target
      certain amino acids. The results showed that missense mutations
      disproportionately target amino acids that are identical in all four mammals
      (chi(2) = 46.01, P < 0.001). In addition, missense mutations disproportionately
      perturb conserved amino acids with strongly hydrophobic side chains (chi(2) =
      68.57, P < 0.001) and alter the strongly hydrophobic property. The two most
      frequently observed known cancer-predisposing missense mutations in the BRCT
      repeats, M1775R and A1708E, conform to this pattern. These results suggest that
      missense mutations affecting highly conserved amino acids with strongly
      hydrophobic side chains can disturb important features of the BRCA-1 protein and
      may play a role in breast and ovarian cancer formation.

PMID- 15184262
TI  - Diet and melanoma in a case-control study.
AB  - BACKGROUND: Malignant melanoma has been one of the most rapidly increasing
      cancers within the United States with few modifiable risk factors. This study
      investigates risk related to dietary factors, which are potentially modifiable.
      METHODS: Newly diagnosed patients with melanoma (n = 502) were recruited from
      pigment lesion clinics and controls (n = 565) were recruited from outpatient
      clinics. To investigate the relationship between melanoma and dietary factors in
      this case-control study, study subjects were requested to complete a food
      frequency questionnaire, which assessed diet over the previous year. Using
      logistic regression, odds ratios (ORs) for melanoma were computed for nutrient
      and alcohol intake. RESULTS: Persons in high versus low quintiles of energy
      adjusted vitamin D, alpha-carotene, beta-carotene, cryptoxanthin, lutein, and
      lycopene had significantly reduced risk for melanoma (ORs < or = 0.67), which
      remained after adjustment for presence of dysplastic nevi, education, and skin
      response to repeated sun exposure. Addition of micronutrients from supplements
      did not add an additional reduction in risk. High alcohol consumption was
      associated with an increased risk for melanoma, which remained after adjustment
      for confounders [OR (95% confidence interval) in highest versus lowest quintiles,
      1.65 (1.09-2.49)]. CONCLUSIONS: Diets consisting of foods rich in vitamin D and
      carotenoids and low in alcohol may be associated with a reduction in risk for
      melanoma. These analyses should be repeated in large, prospective studies.

PMID- 15184263
TI  - WBC count and the risk of cancer mortality in a national sample of U.S. adults:
      results from the Second National Health and Nutrition Examination Survey
      mortality study.
AB  - Inflammation has been shown to be a risk factor for several chronic diseases. Few
      epidemiologic studies have examined the relationship between markers of
      inflammation and cancer. The current study included 7,674 Second National Health
      and Nutrition Examination Survey (NHANES II) participants, 30 to 74 years of age,
      between 1976 and 1980. Mortality follow-up through December 31, 1992 was assessed
      using the National Death Index and Social Security Administration Death Master
      File. A graded association between higher WBC and higher risk of total cancer
      mortality was observed [highest versus lowest quartile (relative risk [RR] 2.23;
      95% confidence interval [CI], 1.53-3.23)] after adjusting for age, sex, and race.
      After further adjustment for smoking, physical activity, body mass index, alcohol
      intake, education, hematocrit, and diabetes, WBC remained significantly
      associated (P trend = 0.03) with total cancer mortality [highest versus lowest
      quartile (RR 1.66; 95% CI, 1.08-2.56)]. In stratified analyses, increased WBC was
      associated with higher risk of non-lung cancer (P trend = 0.04), but not lung
      cancer (P trend = 0.18). Among never smokers, a 1 SD increase in WBC (2.2 x 10(9)
      cells/L) was associated with greater risk of total (RR 1.32; 95% CI, 1.05-1.67)
      and non-lung (RR 1.30; 95% CI, 1.03-1.63) cancer mortality. These findings
      support the hypothesis that inflammation is an independent risk factor for cancer
      mortality. Additional studies are needed to determine whether circulating levels
      of inflammatory markers are associated with increased risk of incident cancer.

PMID- 15184264
TI  - Birth weight and other risk factors for acute leukemia in the Jerusalem Perinatal
      Study cohort.
AB  - OBJECTIVES: To assess the effect of birth weight of children and their siblings
      and other perinatal/parental factors on the risk of acute leukemia. METHODS: We
      linked data from the Jerusalem Perinatal Study, a population-based research
      cohort (n = 88,829) of offspring born 1964 to 1976, with Israel's Cancer
      Registry. Risk factors for acute leukemia were assessed using univariate and
      multivariate proportional hazards models. RESULTS: Leukemias developed in 65
      individuals [24 acute myeloid leukemias (AML) and 41 acute lymphoblastic
      leukemias (ALL)]. A positive linear relation was found between gender-adjusted
      birth weight and all leukemias [hazard ratio (HR) 1.85, 95% confidence interval
      (95% CI) 1.1-3.0] and AML (HR 2.9, 95% CI 1.3-6.4). The association between birth
      weight and AML was especially notable among infants (HR 8.14, 95% CI 1.8-38.9 for
      age 0 to 1 year) but was also observed among subjects ages >14 years at
      diagnosis. The relation was particularly strong among females (P = 0.001). Other
      risk factors for AML risk on univariate analysis were maternal origin,
      socioeconomic status, birth weight of sibling > 3,500 g, and family size. On
      multivariate analysis, only birth weight retained borderline significance
      (adjusted HR 2.38 per kg, 95% CI 1.0-5.7). Significant predictors for ALL in both
      univariate and multivariate analyses were male sex (adjusted HR 1.92, 95% CI 1.0
      3.7) and birth weight categories > or = 3,000 g introduced into the model as
      nonlinear terms. CONCLUSION: Birth weight is associated with an increased risk of
      acute leukemia in infants, children, and young adults. Perinatal factors play a
      role in the development of childhood leukemias, but the patterns of association
      vary by leukemia type.

PMID- 15184265
TI  - The P2X7 receptor gene A1513C polymorphism does not contribute to risk of
      familial or sporadic chronic lymphocytic leukemia.
AB  - The P2X7 receptor, a plasma membrane ATP-gated ion channel that plays a role in
      lymphocyte apoptosis, has been suggested to be involved in the development of
      chronic lymphocytic leukemia (CLL). P2X7 is polymorphic with 1513A and 1513C
      alleles encoding fully active and nonfunctional proteins, respectively. We
      evaluated the significance of the P2X7-A1513C polymorphism on CLL risk by
      genotyping 424 patients and 428 healthy controls. To empower detection of an
      association, we included in our analysis 106 familial cases. Allele frequencies
      were identical in cases and controls irrespective of whether cases were familial
      or sporadic (frequency of the C allele was 0.17 and 0.17, respectively). The odds
      ratio of CLL associated with the C allele was 1.03 (95% confidence interval: 0.80
      1.31). A meta-analysis of this study and five other smaller published studies
      provides no evidence of relationship between this P2X7 polymorphism and risk of
      CLL (odds ratio = 0.99, 95% confidence interval: 0.74-1.32).

PMID- 15184267
TI  - Relationship between content and activity of cytochrome P450 and induction of
      heterocyclic amine DNA adducts in human liver samples in vivo and in vitro.
AB  - This study was designed to estimate a correlation between metabolic activation
      phenotypes and formation of DNA adducts by heterocyclic amines (HCA) in 15 liver
      samples from healthy donors. The correlation between the amount of endogenous DNA
      adducts and the content of cytochrome P450 in human liver samples in vivo was
      statistically significant at r(2) = 0.71 and P < 0.005. Furthermore, the isolated
      human liver microsomes were treated in vitro with two HCAs, 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-9H-pyrido[2,3-b]indole (A alpha
      C), which have been recognized to induce two DNA adducts: 3',5'-diphosphate-N-(2'
      deoxyguanosin-8-yl)-PhIP (3',5'-pdGp-C8-PhIP) and 3',5'-diphosphate-N-(2'
      deoxyguanosin-8-yl)-A alpha C (3',5'-pdGp-C8-A alpha C). The correlations between
      the amount of DNA adducts induced by both compounds in vitro and the content of
      cytochrome P450 in human microsomes are statistically significant at r(2) = 0.69
      and r(2) = 0.62 (P < 0.001), respectively. Furthermore, the level of DNA adducts
      after treatment with PhIP and A alpha C correlated with the activities of three
      isozymes of cytochrome P450: CYP1A1, CYP1A2, and CYP3A4. Therefore, three
      chemical inhibitors were used in the experiments: ellipticine against CYP1A1,
      furafylline against CYP1A2, and troleandomycin against CYP3A4. The highest
      inhibition levels in the formation of 3',5'-pdGp-C8-PhIP and 3',5'-pdGp-C8-A
      alpha C adducts were estimated to occur in the presence of furafylline at 56% and
      69%, respectively. Ellipticine was involved in the inhibition of 40% of 3',5'-pdG
      C8-PhIP adducts and in only 18% of the inhibition of 3',5'-pdGp-C8-A alpha C
      adducts. Troleandomycin did not significantly inhibit the formation of 3',5'-pdGp
      C8-PhIP adducts under these conditions, but it inhibited the formation of 31% of
      the 3',5'-pdGpC8-A alpha C adducts. We conclude that the formation of DNA adducts
      can be used as a relevant marker of interindividual variability in the metabolic
      activation of HCAs in humans.

PMID- 15184266
TI  - Reliability and validity of opiate use self-report in a population at high risk
      for esophageal cancer in Golestan, Iran.
AB  - OBJECTIVE: To assess the reliability and validity of self-reported opium use in a
      rural Iranian population at high risk for esophageal cancer in preparation for a
      large cohort study. METHOD: 1,057 subjects ages 33 to 84 years were recruited
      from Gonbad city and three surrounding villages in Golestan province of Iran and
      completed a questionnaire and provided biological samples. The history and
      duration of using opium, smoking tobacco, chewing nass, and drinking alcohol were
      measured by questionnaire in the entire cohort. A subgroup of 130 people was
      reinterviewed after 2 months to assess reliability. Validity of the opium
      question was assessed by comparing the questionnaire responses with the presence
      of codeine and morphine in the urine of 150 selected subjects. RESULTS: Self
      reported opiate use is reliable and valid in this population. The reliability of
      ever opium use and duration of opium use had kappa's of 0.96 and 0.74,
      respectively. The validity of self-reported opium use was also high. Using urine
      codeine or morphine as the gold standard for use of opium, self-report had a
      sensitivity of 0.93 and a specificity of 0.89. CONCLUSIONS: The self-reported use
      of opium can provide a reliable and valid measurement in this population and will
      be useful for studying associations between opium use and occurrence of
      esophageal cancer and other diseases.

PMID- 15184269
TI  - No Association between hOGG1 Ser326Cys polymorphism and risk of squamous cell
      carcinoma of the head and neck.

PMID- 15184268
TI  - No effect of beta-carotene supplementation on risk of nonmelanoma skin cancer
      among men with low baseline plasma beta-carotene.

PMID- 15184270
TI  - No association between the progesterone receptor gene +331G/A polymorphism and
      breast cancer.

PMID- 15184271
TI  - Effects of a low fat, high fiber-carbohydrate diet on components of the IGF axis
      measured in plasma: a controlled feeding study in men.

PMID- 15184272
TI  - No association between MTHFR 677 C->T or 1298 A->C polymorphisms and endometrial
      cancer risk.

PMID- 15184273
TI  - XRCC2 and XRCC3 polymorphisms are not associated with risk of colorectal adenoma.

PMID- 15184274
TI  - In situ measurements of crossbridge dynamics and lattice spacing in rat hearts by
      x-ray diffraction: sensitivity to regional ischemia.
AB  - BACKGROUND: Synchrotron radiation has been used to analyze crossbridge dynamics
      in isolated papillary muscle and excised perfused hearts with the use of x-ray
      diffraction techniques. We showed that these techniques can detect regional
      changes in rat left ventricle contractility and myosin lattice spacing in in situ
      ejecting hearts in real time. Furthermore, we examined the sensitivity of these
      indexes to regional ischemia. METHODS AND RESULTS: The left ventricular free wall
      of spontaneously beating rat hearts (heart rate, 290 to 404 bpm) was directly
      exposed to brief high-flux, low-emittance x-ray beams provided at SPring-8.
      Myosin mass transfer to actin filaments was determined as the decrease in
      reflection intensity ratio (intensity of 1,0 plane over the 1,1 plane) between
      end-diastole and end-systole. The distance between 1,0 reflections was converted
      to a lattice spacing between myosin filaments. We found that mass transfer (mean,
      1.71+/-0.09 SEM, n=13 hearts) preceded significant increases in lattice spacing
      (2 to 5 nm) during systole in nonischemic pericardium. Left coronary occlusion
      eliminated increases in lattice spacing and severely reduced mass transfer
      (P<0.01) in the ischemic region. CONCLUSIONS: Our results suggest that x-ray
      diffraction techniques permit real-time in situ analysis of regional crossbridge
      dynamics at molecular and fiber levels that might also facilitate investigations
      of ventricular output regulation by the Frank-Starling mechanism.

PMID- 15184275
TI  - Circulating CD34-positive cells provide an index of cerebrovascular function.
AB  - BACKGROUND: Increasing evidence points to a role for circulating endothelial
      progenitor cells, including populations of CD34- and CD133-positive cells present
      in peripheral blood, in maintenance of the vasculature and neovascularization.
      Immature populations, including CD34-positive cells, have been shown to
      contribute to vascular homeostasis, not only as a pool of endothelial progenitor
      cells but also as a source of growth/angiogenesis factors at ischemic loci. We
      hypothesized that diminished numbers of circulating immature cells might impair
      such physiological and reparative processes, potentially contributing to
      cerebrovascular dysfunction. METHODS AND RESULTS: The level of circulating
      immature cells, CD34-, CD133-, CD117-, and CD135-positive cells, in patients with
      a history of atherothrombotic cerebral ischemic events was analyzed to assess
      possible correlations with the degree of carotid atherosclerosis and number of
      cerebral infarctions. There was a strong inverse correlation between numbers of
      circulating CD34- and CD133-positive cells and cerebral infarction. In contrast,
      there was no correlation between the degree of atherosclerosis and populations of
      circulating immature cells. Analysis of patients with cerebral artery occlusion
      revealed a significant positive correlation between circulating CD34- and CD133
      positive cells and regional blood flow in areas of chronic hypoperfusion.
      CONCLUSIONS: These results suggest a possible contribution of circulating CD34-
      and CD133-positive cells in maintenance of the cerebral circulation in settings
      of ischemic stress. Our data demonstrate the utility of a simple and precise
      method to quantify circulating CD34-positive cells, the latter providing a marker
      of cerebrovascular function.

PMID- 15184276
TI  - Carvedilol but not metoprolol reduces beta-adrenergic responsiveness after
      complete elimination from plasma in vivo.
AB  - BACKGROUND: Carvedilol but not metoprolol exhibits persistent binding to beta
      adrenergic receptors (beta-ARs) even after washout in cell culture experiments.
      Here, we determined the significance of this phenomenon on human beta-ARs in
      vitro and in vivo. METHODS AND RESULTS: Experiments were conducted on human
      atrial trabeculae (n=8 to 10 per group). In the presence of metoprolol,
      isoproterenol potency was reduced compared with controls (P<0.001). In the
      presence of carvedilol, isoproterenol identified 2 distinct binding sites of high
      (36+/-6%; -8.8+/-0.4 log mol/L) and low affinity (-6.5+/-0.2 log mol/L). After
      beta-blocker washout, isoproterenol potency returned to control values in
      metoprolol-treated muscles, whereas in carvedilol-treated preparations,
      isoproterenol potency remained decreased (P<0.001 versus control). In vivo
      studies were performed in 9 individuals receiving metoprolol succinate (190 mg/d)
      or carvedilol (50 mg/d) for 11 days in a randomized crossover design. Dobutamine
      stress echocardiography (5 to 40 microg x kg(-1) x min(-1)) was performed before,
      during, and 44 hours after application of study medication. Beta-blocker
      medication reduced heart rate, heart rate-corrected velocity of circumferential
      fiber shortening, and cardiac output compared with baseline (P<0.02 to 0.0001).
      After withdrawal of metoprolol, all parameters returned to baseline values,
      whereas after carvedilol, all parameters remained reduced (P<0.05 to 0.001)
      despite complete plasma elimination of carvedilol. CONCLUSIONS: Carvedilol but
      not metoprolol inhibits the catecholamine response of the human heart beyond its
      plasma elimination. The persistent beta-blockade by carvedilol may be explained
      by binding of carvedilol to an allosteric site of beta-ARs.

PMID- 15184277
TI  - Lead, cadmium, smoking, and increased risk of peripheral arterial disease.
AB  - BACKGROUND: Lead and cadmium exposure may promote atherosclerosis, although the
      cardiovascular effects of chronic low-dose exposure are largely unknown. The
      objective of the present study was to evaluate the association between blood
      levels of lead and cadmium and peripheral arterial disease. METHODS AND RESULTS:
      We analyzed data from 2125 participants who were > or =40 years of age in the
      1999 to 2000 National Health and Nutrition Examination Survey (NHANES).
      Peripheral arterial disease was defined as an ankle brachial index <0.9 in at
      least 1 leg. Lead and cadmium levels were measured by atomic absorption
      spectrometry. After adjustment for demographic and cardiovascular risk factors,
      the ORs of peripheral arterial disease comparing quartiles 2 to 4 of lead with
      the lowest quartile were 1.63 (95% CI, 0.51 to 5.15), 1.92 (95% CI, 0.62 to
      9.47), and 2.88 (95% CI, 0.87 to 9.47), respectively (P for trend=0.02). The
      corresponding ORs for cadmium were 1.07 (95% CI, 0.44 to 2.60), 1.30 (95% CI,
      0.69 to 2.44), and 2.82 (95% CI, 1.36 to 5.85), respectively (P for trend=0.01).
      The OR of peripheral arterial disease for current smokers compared with never
      smokers was 4.13. Adjustment for lead reduced this OR to 3.38, and adjustment for
      cadmium reduced it to 1.84. CONCLUSIONS: Blood lead and cadmium, at levels well
      below current safety standards, were associated with an increased prevalence of
      peripheral arterial disease in the general US population. Cadmium may partially
      mediate the effect of smoking on peripheral arterial disease.

PMID- 15184278
TI  - Clinical assessment of norepinephrine transporter blockade through biochemical
      and pharmacological profiles.
AB  - BACKGROUND: To assess the sensitivity of biochemical, physiological, and
      pharmacological markers of peripheral norepinephrine (NE) transporter (NET)
      function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N
      methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE
      reuptake process. METHODS AND RESULTS: Duloxetine was administered in a
      randomized, placebo-controlled study in 15 healthy volunteers. Plasma from
      duloxetine-treated subjects (ex vivo effect) dose-dependently decreased
      radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose
      of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg
      (PD30) increased dose-dependently with duloxetine and was significant at the end
      of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE)
      ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine
      (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly
      increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour
      creatinine excretion) showed a dose-dependent change from the baseline urinary
      excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the
      DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was
      significantly raised after 2 weeks of treatment with 80 mg/d duloxetine
      (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest
      that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE
      ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more
      sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear
      relation, with NET inhibition commencing at a higher dose.

PMID- 15184279
TI  - Clopidogrel resistance is associated with increased risk of recurrent
      atherothrombotic events in patients with acute myocardial infarction.
AB  - BACKGROUND: Although clopidogrel reduces the risk of cardiovascular episodes
      after coronary events and stenting, a substantial number of incidents continue to
      occur. METHODS AND RESULTS: The antiplatelet effect of clopidogrel was studied
      prospectively in 60 consecutive patients who underwent primary angioplasty
      (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment
      elevation myocardial infarction (STEMI) to determine whether variability in
      response to clopidogrel affects clinical outcomes. Patients were stratified into
      4 quartiles according to the percentage reduction of ADP-induced platelet
      aggregation. Although patients in the first quartile were resistant to the
      effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103+/-8% of
      baseline), ADP-induced aggregation was reduced to 69+/-3%, 58+/-7%, and 33+/-12%
      of baseline, respectively, in patients in quartiles 2 through 4 (P<0.01 for all).
      In addition, epinephrine-induced platelet aggregation and platelet aggregation
      under flow conditions, assessed by the cone-and-plate(let) analyzer method, were
      reduced significantly less in the first quartile than in quartiles 2 through 4.
      Whereas 40% of patients in the first quartile sustained a recurrent
      cardiovascular event during a 6-month follow-up, only 1 patient (6.7%) in the
      second quartile and none in the third and fourth quartiles suffered a
      cardiovascular event (P=0.007). CONCLUSIONS: Up to 25% of STEMI patients
      undergoing primary PCI with stenting are resistant to clopidogrel and therefore
      may be at increased risk for recurrent cardiovascular events.

PMID- 15184280
TI  - Plasma brain natriuretic peptide to detect preclinical ventricular systolic or
      diastolic dysfunction: a community-based study.
AB  - BACKGROUND: Preclinical systolic or diastolic dysfunction is associated with
      increased morbidity and mortality. We postulated that plasma brain natriuretic
      peptide (BNP) might serve as a biomarker for preclinical ventricular dysfunction
      (PCVD) but that the discriminatory values for BNP may vary with age and sex.
      METHODS AND RESULTS: We measured BNP, systolic and diastolic ventricular
      function, and clinical parameters in 2042 randomly selected residents of Olmsted
      County, Minn, aged 45 years or older. For preclinical systolic dysfunction, the
      areas under the receiver operating characteristics curve were higher for those
      with more severe (0.82 to 0.92) than any (0.51 to 0.74) systolic dysfunction and
      were similar in men and women and in younger and older persons. For preclinical
      diastolic dysfunction, the areas under the receiver operating characteristics
      curve were higher for those with moderate-to-severe (0.74 to 0.79) than any (0.52
      to 0.68) diastolic dysfunction and were similar regardless of age or sex. Optimal
      discriminatory values of BNP varied with age and sex. Considering the prevalence
      of preclinical systolic or diastolic dysfunction and the predictive
      characteristics observed, using BNP to screen for PCVD would necessitate echo in
      10% to 40% of those screened, with most confirmatory echocardiograms being
      negative, and would miss 10% to 60% of those affected. CONCLUSIONS: BNP is a
      suboptimal screening test for PCVD in the population.

PMID- 15184281
TI  - Percutaneous coronary intervention results in acute increases in oxidized
      phospholipids and lipoprotein(a): short-term and long-term immunologic responses
      to oxidized low-density lipoprotein.
AB  - BACKGROUND: This study was performed to assess whether oxidized low-density
      lipoprotein (OxLDL) levels are elevated after percutaneous coronary intervention
      (PCI). METHODS AND RESULTS: Patients (n=141) with stable angina pectoris
      undergoing PCI had serial venous blood samples drawn before PCI, after PCI, and
      at 6 and 24 hours, 3 days, 1 week, and 1, 3, and 6 months. Plasma levels of OxLDL
      E06, a measure of oxidized phospholipid (OxPL) content on apolipoprotein B-100
      detected by antibody E06, lipoprotein(a) [Lp(a)], autoantibodies to
      malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL), and apolipoprotein
      B-100-immune complexes (apoB-IC) were measured. OxLDL-E06 and Lp(a) levels
      significantly increased immediately after PCI by 36% (P<0.0001) and 64%
      (P<0.0001), respectively, and returned to baseline by 6 hours. In vitro
      immunoprecipitation of Lp(a) from selected plasma samples showed that almost all
      of the OxPL detected by E06 was bound to Lp(a) at all time points, except in the
      post-PCI sample, suggesting independent release and subsequent reassociation of
      OxPL with Lp(a) by 6 hours. Strong correlations were noted between OxLDL-E06 and
      Lp(a) (r=0.68, P<0.0001). MDA-LDL and Cu-OxLDL autoantibodies decreased, whereas
      apoB-IC levels increased after PCI, but both returned to baseline by 6 hours.
      Subsequently, IgM autoantibodies increased and peaked at 1 month and then
      returned to baseline, whereas IgG autoantibodies increased steadily over 6
      months. CONCLUSIONS: PCI results in acute plasma increases of Lp(a) and OxPL and
      results in short-term and long-term immunologic responses to OxLDL. OxPL that are
      released or generated during PCI are transferred to Lp(a), suggesting that Lp(a)
      may contribute acutely to a protective innate immune response. In settings of
      enhanced oxidative stress and chronically elevated Lp(a) levels, the
      atherogenicity of Lp(a) may stem from its capacity as a carrier of
      proinflammatory oxidation byproducts.

PMID- 15184282
TI  - Inflammation as a possible link between coronary and carotid plaque instability.
AB  - BACKGROUND: Multiple complex stenoses, plaque fissures, and widespread coronary
      inflammation are common in acute coronary syndromes. A systemic cause of
      atherosclerotic plaque instability is also suggested by studies of ischemic
      cerebrovascular disease. We investigated the association between coronary and
      carotid plaque instability and the potential common causal role of inflammation.
      METHODS AND RESULTS: The ultrasound characteristics of carotid plaques were
      evaluated retrospectively in patients scheduled for coronary bypass surgery, 181
      with unstable and 92 with stable angina, and prospectively in a similar group of
      patients, 67 with unstable and 25 with stable angina, in whom serum C-reactive
      protein levels were also measured. The prevalence of carotid plaques was similar
      in the retrospective and prospective studies and >64% in both unstable and stable
      coronary patients. The prevalence of complex, presumably unstable carotid plaques
      was 23.2% in unstable versus 3.2% in stable patients (P<0.001) in the
      retrospective study and 41.8% versus 8.0% (P=0.002) in the prospective study. C
      reactive protein levels were higher in patients with complex (7.55 mg/L) than in
      those with simple (3.94 mg/L; P<0.05) plaques or without plaques (2.45 mg/L;
      P<0.05). On multivariate analysis, unstable angina and C-reactive protein levels
      >3 mg/L were independently associated with complex carotid plaques (OR, 6.09; 95%
      CI, 1.01 to 33.72; P=0.039, and OR, 5.80; 95% CI, 1.55 to 21.69; P=0.009,
      respectively). CONCLUSIONS: In unstable angina, plaque instability may not be
      confined to coronary arteries, and inflammation may be the common link with
      carotid plaque instability. These observations may have relevant implications for
      understanding the mechanisms of acute widespread atherothrombotic plaque
      inflammation.

PMID- 15184283
TI  - Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome.
AB  - BACKGROUND: The importance of germ-line mosaicism in genetic disease is probably
      underestimated, even though recent studies indicate that it may be involved in
      10% to 20% of apparently de novo cases of several dominantly inherited genetic
      diseases. METHODS AND RESULTS: We describe here a case of repeated germ-line
      transmission of a severe form of long-QT syndrome (LQTS) from an asymptomatic
      mother with mosaicism for a mutation in the cardiac sodium channel, SCN5A. A male
      infant was diagnosed with ventricular arrhythmias and cardiac decompensation in
      utero at 28 weeks and with LQTS after birth, ultimately requiring cardiac
      transplantation for control of ventricular tachycardia. The mother had no ECG
      abnormalities, but her only previous pregnancy had ended in stillbirth with
      evidence of cardiac decompensation at 7 months' gestation. A third pregnancy also
      ended in stillbirth at 7 months, again with nonimmune fetal hydrops. The
      surviving infant was found to have a heterozygous mutation in SCN5A (R1623Q),
      previously reported as a de novo mutation causing neonatal ventricular arrhythmia
      and LQTS. Initial studies of the mother detected no genetic abnormality, but a
      sensitive restriction enzyme-based assay identified a small (8% to 10%)
      percentage of cells harboring the mutation in her blood, skin, and buccal mucosa.
      Cord blood from the third fetus also harbored the mutant allele, suggesting that
      all 3 cases of late-term fetal distress resulted from germ-line transfer of the
      LQTS-associated mutation. CONCLUSIONS: Recurrent late-term fetal loss or sudden
      infant death can result from unsuspected parental mosaicism for LQTS-associated
      mutations, with important implications for genetic counseling.

PMID- 15184285
TI  - Nomogram to diagnose familial combined hyperlipidemia on the basis of results of
      a 5-year follow-up study.
AB  - BACKGROUND: Familial combined hyperlipidemia (FCH) is traditionally diagnosed by
      total plasma cholesterol and/or triglyceride levels above the 90th percentile
      adjusted for age and gender. In a recent study, we showed that the diagnosis of
      FCH on the basis of these diagnostic criteria was inconsistent in 26% of the
      subjects over a 5-year period. This result emphasizes the need for reevaluation
      of the diagnostic criteria for FCH. METHODS AND RESULTS: A total of 32 families
      (299 subjects) were studied in 1994 and 1999. A subject was defined "truly" FCH
      when diagnosed FCH in 1994 and/or 1999 on the basis of traditional plasma lipid
      criteria. Additional lipid and lipoprotein parameters, including apolipoprotein B
      (apoB) and small, dense LDL, were measured at both time points. In total, 121
      subjects (40%) were defined as truly FCH. Multivariate analysis revealed that
      absolute apoB values combined with triglyceride and total cholesterol levels
      adjusted for age and gender best predicted truly FCH. A nomogram including these
      parameters is provided to simply and accurately calculate the probability to be
      affected by FCH. Furthermore, it is shown that when percentiles of triglyceride
      and total cholesterol adjusted for age and gender are not available in a
      population, the definition of FCH can be established on the basis of
      hypertriglyceridemia (>1.5 mmol/L) and hyper-apoB (>1200 mg/L). CONCLUSIONS: The
      diagnosis of FCH is best predicted by absolute apoB levels combined with
      triglyceride and total cholesterol levels adjusted for age and gender and can
      accurately be calculated by a nomogram. This definition is also a good predictor
      of cardiovascular risk in FCH.

PMID- 15184284
TI  - Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic
      preconditioning.
AB  - BACKGROUND: The signaling pathways that control ischemia/reperfusion-induced
      cardiomyocyte apoptosis in heart have not been fully defined. In this study, we
      investigated whether Akt signaling has a role in the antiapoptotic pathways of
      preconditioning against hypoxia/reoxygenation (H/R). METHODS AND RESULTS: Primary
      cultures of adult rat ventricular myocytes (ARVMs) were subjected to
      preconditioning (PC) by exposing the cells to 10 minutes of hypoxia followed by
      30 minutes of reoxygenation. Non-PC and PC myocytes were subjected to 90 minutes
      of hypoxia followed by 120 minutes of reoxygenation. Hypoxic-PC protected the
      myocytes from subsequent H/R injury, as evidenced by decreased apoptosis and LDH
      release and increased cell viability. H/R-induced cytochrome c release and
      activation of caspase-3 and -9 were blocked by PC. This protective effect was
      inhibited by treating the cells with LY294002 (50 micromol/L), a PI3 kinase
      inhibitor, for 10 minutes before and during PC. PC also induced phosphorylation
      of Akt and BAD. Protein levels of Bcl-2 in mitochondria were maintained in PC.
      ARVMs were infected with either a control adenovirus (Adeno lac-Z), an adenovirus
      expressing dominant-negative Akt, or an adenovirus expressing constitutively
      active Akt. Ectopic overexpression of constitutively active Akt protected ARVMs
      from apoptosis induced by hypoxia/reoxygenation compared with Adeno lac-Z. In
      contrast, dominant negative Akt overexpression abolished the antiapoptotic effect
      of PC. CONCLUSIONS: Our data demonstrated that in adult cardiomyocytes, the
      antiapoptotic effect of PC against H/R requires Akt signaling leading to
      phosphorylation of BAD, inhibition of cytochrome c release, and prevention of
      caspase activation.

PMID- 15184286
TI  - Changes in atrial fibrillation cycle length and inducibility during catheter
      ablation and their relation to outcome.
AB  - BACKGROUND: The modification of atrial fibrillation cycle length (AFCL) during
      catheter ablation in humans has not been evaluated. METHODS AND RESULTS: Seventy
      patients undergoing ablation of prolonged episodes of AF were randomized to
      pulmonary vein (PV) isolation or additional ablation of the mitral isthmus. Mean
      AFCL was determined at a distance from the ablated area (coronary sinus) at the
      following intervals: before ablation, after 2- and 4-PV isolations, and after
      linear ablation. Inducibility of sustained AF (> or =10 minutes) was determined
      before and after ablation. Spontaneous sustained AF (715+/-845 minutes) was
      present in 30 patients and induced in 26 (AFCL, 186+/-19 ms). PV isolation
      terminated AF in 75%, with the number of PVs requiring isolation before
      termination increasing with AF duration (P=0.018). PV isolation resulted in
      progressive or abrupt AFCL prolongation to various extents, depending on the PV:
      to 214+/-24 ms (P<0.0001) when AF terminated and to 194+/-19 ms (P=0.002) when AF
      persisted. The increase in AFCL (30+/-17 versus 14+/-11 ms; P=0.005) and the
      decrease in fragmentation (30.0+/-26.8% to 10.3+/-14.5%; P<0.0001) were
      significantly greater in patients with AF termination. Linear ablation prolonged
      AFCL, with a greater prolongation in patients with AF termination (44+/-13 versus
      22+/-23 ms; P=0.08). Sustained AF was noninducible in 57% after PV isolation and
      in 77% after linear ablation. At 7+/-3 months, 74% with PV isolation and 83% with
      linear ablation were arrhythmia free without antiarrhythmics, which was
      significantly associated with noninducibility (P=0.03) with a recurrence rate of
      38% and 13% in patients with and without inducibility, respectively. CONCLUSIONS:
      AF ablation results in a decline in AF frequency, with a magnitude correlating
      with termination of AF and prevention of inducibility that is predictive of
      subsequent clinical outcome.

PMID- 15184287
TI  - Inhibition of mTOR signaling with rapamycin regresses established cardiac
      hypertrophy induced by pressure overload.
AB  - BACKGROUND: Rapamycin is a specific inhibitor of the mammalian target of
      rapamycin (mTOR). We recently reported that administration of rapamycin before
      exposure to ascending aortic constriction significantly attenuated the load
      induced increase in heart weight by approximately 70%. METHODS AND RESULTS: To
      examine whether rapamycin can regress established cardiac hypertrophy, mice were
      subjected to pressure overload (ascending aortic constriction) for 1 week,
      echocardiography was performed to verify an increase in ventricular wall
      thickness, and mice were given rapamycin (2 mg x kg(-1) x d(-1)) for 1 week.
      After 1 week of pressure overload (before treatment), 2 distinct groups of
      animals became apparent: (1) mice with compensated cardiac hypertrophy (normal
      function) and (2) mice with decompensated hypertrophy (dilated with depressed
      function). Rapamycin regressed the pressure overload-induced increase in heart
      weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and
      41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular
      end-systolic dimensions, fractional shortening, and ejection fraction in mice
      with decompensated cardiac hypertrophy. Rapamycin also altered the expression of
      some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and
      sarcoplasmic reticulum Ca2+ ATPase. CONCLUSIONS: Rapamycin may be a therapeutic
      tool to regress established cardiac hypertrophy and improve cardiac function.

PMID- 15184288
TI  - Obesity is an important determinant of baseline serum C-reactive protein
      concentration in monozygotic twins, independent of genetic influences.
AB  - BACKGROUND: C-reactive protein (CRP) values predict atherothrombotic
      cardiovascular disease and type 2 diabetes mellitus. Associations between CRP and
      obesity, predominantly assessed anthropometrically, may partly explain these
      observations. Previous studies have been unable to control for genetic influences
      on CRP and obesity. The aim of this study was to examine the relationship between
      CRP and accurately measured body fat, lipids, apolipoproteins, blood pressure,
      and environmental and behavioral factors, independent of genetic influences.
      METHODS AND RESULTS: One hundred ninety-four healthy female twins (age 57.2+/-7
      years) were studied after excluding pairs with CRP values >10 mg/L. Total body
      fat and central abdominal fat (CAF) were measured by dual-energy x-ray
      absorptiometry. CRP concentration was strongly related to surrogate and direct
      measures of body fat (r=0.31 to 0.54, P<0.001), diastolic blood pressure (r=0.20,
      P=0.003), and lipid and apolipoprotein levels (r=0.21 to 0.51, P<0.008). Light-to
      moderate alcohol consumers and nonusers of hormone replacement therapy (HRT) had
      lower CRP levels than abstainers and HRT users, respectively. In stepwise
      multiple regression analysis, CAF, triglycerides, apolipoprotein B, and HRT use
      explained 46% of the variance in circulating CRP. In analyses controlling for
      genetic influences in monozygotic twins, within-pair differences in CRP were
      associated with within-pair differences in total body fat (r=0.39, P<0.001), CAF
      (r=0.34, P=0.002), diastolic blood pressure (r=0.24, P=0.03), apolipoprotein AI
      (r=-0.33, P=0.01), HDL cholesterol (r=-0.42, P=0.001), and triglycerides (r=0.35,
      P=0.007). CONCLUSIONS: CRP was strongly related to total and central abdominal
      obesity, blood pressure, and lipid levels, independent of genetic influences.
      These relationships are likely to contribute significantly to prospective
      associations between CRP and type 2 diabetes and coronary events.

PMID- 15184289
TI  - Circulating humoral factors and endothelial progenitor cells in patients with
      differing coronary collateral support.
AB  - BACKGROUND: The mechanisms underlying the variation in collateral formation
      between patients, even with similar patterns of coronary artery disease, remain
      unclear. This study investigates whether circulating humoral or cellular factors
      can provide an insight into this variation. METHODS AND RESULTS: Thirty patients
      with isolated left anterior descending coronary artery disease underwent
      percutaneous coronary intervention with collateral flow index (CFI) determined
      using a pressure wire. Patients with inadequate (CFI <0.25) compared with those
      with adequate (CFI > or =0.25) collateral support had, or tended to have, lower
      concentrations of coronary sinus growth factors and plasma exerting a weaker
      effect on endothelial cell migration and angiogenesis in vitro. However, there
      was an inverse correlation between serum mitogenicity and CFI (r=-0.61, P<0.01).
      No significant differences were detected between the 2 groups in plasma levels of
      total vascular endothelial growth factor, vascular endothelial growth factor165,
      or placental growth factor. There was a strong positive correlation between
      numbers of CD34/CD133-positive circulating hemopoietic precursor cells and CFI
      (r=0.75, P<0.001). In patients with inadequate, compared with those with
      adequate, CFI, the numbers of differentiated endothelial progenitor cells (EPCs)
      appearing in the circulation and in culture were significantly reduced by 75%
      (P<0.05) and 70% (P<0.05), respectively. CONCLUSIONS: In this study, inadequate
      coronary collateral development is associated with reduced numbers of circulating
      EPCs and impaired chemotactic and proangiogenic but not mitogenic activity. These
      findings are consistent with current efforts to enhance collateral formation by
      augmentation of circulating EPCs.

PMID- 15184290
TI  - Lipid-rich atherosclerotic plaques detected by gadofluorine-enhanced in vivo
      magnetic resonance imaging.
AB  - BACKGROUND: MRI of specific components in atherosclerotic plaque may provide
      information on plaque stability and its potential to rupture. We evaluated
      gadofluorine in atherosclerotic rabbits using a new MR sequence that allows
      plaque detection within 1 hour after injection and assessed enhancement in lipid
      rich and non-lipid-rich plaques. METHODS AND RESULTS: Twelve rabbits with aortic
      plaque and 6 controls underwent MRI before and up to 24 hours after gadofluorine
      injection (50 micromol/kg). Two T1-weighted, segmented gradient-echo sequences
      (TFL) were compared to enhance vessel wall delineation after injection: (1) an
      inversion-recovery prepulse (IR-TFL) or (2) a combination of inversion-recovery
      and diffusion-based flow suppression prepulses (IR-DIFF-TFL). With the use of IR
      TFL at 1 hour after injection, the vessel wall was not delineated because of poor
      flow suppression; at 24 hours after injection, the enhancement was 37% (P<0.01).
      IR-DIFF-TFL showed significant enhancement after versus before contrast (1 hour:
      164% [P<0.005]; 24 hours: 207% [P<0.001]). At 1 hour and 24 hours after
      injection, the contrast-to-noise ratio was higher with the use of IR-DIFF-TFL
      than with IR-TFL (1 hour: 13.0+/-7.7 versus -19.8+/-10.3 [P<0.001]; 24 hours:
      15.2+/-5.9 versus 11.4+/-8.9, respectively [P=0.052]). There was no enhancement
      in the vessel wall after gadofluorine injection in the control group. A strong
      correlation was found (r2=0.87; P<0.001) between the lipid-rich areas in
      histological sections and signal intensity in corresponding MR images. This
      suggests a high affinity of gadofluorine for lipid-rich plaques. CONCLUSIONS:
      Gadofluorine-enhanced MRI improves atherosclerotic plaque detection. The IR-DIFF
      TFL method allows early detection of atherosclerotic plaque within 1 hour after
      gadofluorine injection.

PMID- 15184291
TI  - Does heparin cofactor II modulate atherosclerosis and restenosis?

PMID- 15184292
TI  - Implantable defibrillators and sudden cardiac death.

PMID- 15184293
TI  - Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell
      based therapies.

PMID- 15184294
TI  - Bidirectional relation between inflammation and coagulation.

PMID- 15184295
TI  - Accumulated evidence on fish consumption and coronary heart disease mortality: a
      meta-analysis of cohort studies.
AB  - BACKGROUND: Results from observational studies on fish consumption and coronary
      heart disease (CHD) mortality are inconsistent. METHODS AND RESULTS: A meta
      analysis of cohort studies was conducted to examine the association between fish
      intake and CHD mortality. Studies were included if they provided a relative risk
      (RR) and corresponding 95% CI for CHD mortality in relation to fish consumption
      and the frequency of fish intake. A database was developed on the basis of 11
      eligible studies and 13 cohorts, including 222 364 individuals with an average
      11.8 years of follow-up. Pooled RR and 95% CI for CHD mortality were calculated
      by using both fixed-effect and random-effect models. A linear regression analysis
      of the log RR weighted by the inverse of variance was performed to assess the
      possible dose-response relation. Compared with those who never consumed fish or
      ate fish less than once per month, individuals with a higher intake of fish had
      lower CHD mortality. The pooled multivariate RRs for CHD mortality were 0.89 (95%
      CI, 0.79 to 1.01) for fish intake 1 to 3 times per month, 0.85 (95% CI, 0.76 to
      0.96) for once per week, 0.77 (95% CI, 0.66 to 0.89) for 2 to 4 times per week,
      and 0.62 (95% CI, 0.46 to 0.82) for 5 or more times per week. Each 20-g/d
      increase in fish intake was related to a 7% lower risk of CHD mortality (P for
      trend=0.03). CONCLUSIONS: These results indicate that fish consumption is
      inversely associated with fatal CHD. Mortality from CHD may be reduced by eating
      fish once per week or more.

PMID- 15184296
TI  - Pulmonary embolism after coronary artery bypass grafting.

PMID- 15184297
TI  - Recommendations for physical activity and recreational sports participation for
      young patients with genetic cardiovascular diseases.
AB  - A group of relatively uncommon but important genetic cardiovascular diseases
      (GCVDs) are associated with increased risk for sudden cardiac death during
      exercise, including hypertrophic cardiomyopathy, long-QT syndrome, Marfan
      syndrome, and arrhythmogenic right ventricular cardiomyopathy. These conditions,
      characterized by diverse phenotypic expression and genetic substrates, account
      for a substantial proportion of unexpected and usually arrhythmia-based fatal
      events during adolescence and young adulthood. Guidelines are in place governing
      eligibility and disqualification criteria for competitive athletes with these
      GCVDs (eg, Bethesda Conference No. 26 and its update as Bethesda Conference No.
      36 in 2005). However, similar systematic recommendations for the much larger
      population of patients with GCVD who are not trained athletes, but nevertheless
      wish to participate in any of a variety of recreational physical activities and
      sports, have not been available. The practicing clinician is frequently
      confronted with the dilemma of designing noncompetitive exercise programs for
      athletes with GCVD after disqualification from competition, as well as for those
      patients with such conditions who do not aspire to organized sports. Indeed, many
      asymptomatic (or mildly symptomatic) patients with GCVD desire a physically
      active lifestyle with participation in recreational and leisure-time activities
      to take advantage of the many documented benefits of exercise. However, to date,
      no reference document has been available for ascertaining which types of physical
      activity could be regarded as either prudent or inadvisable in these subgroups of
      patients. Therefore, given this clear and present need, this American Heart
      Association consensus document was constituted, based largely on the experience
      and insights of the expert panel, to offer recommendations governing recreational
      exercise for patients with known GCVDs.

PMID- 15184298
TI  - Images in cardiovascular medicine. Dynamic assessment of tracheal stenosis due to
      double aortic arch using low-dose, 16-slice computed tomography.

PMID- 15184299
TI  - Fatigue as a prodromal symptom of myocardial infarct.

PMID- 15184300
TI  - Stents may be better after one year, but one year is not lifelong.

PMID- 15184301
TI  - Physical activity and the metabolic syndrome association with myocardial
      infarction and stroke.

PMID- 15184302
TI  - Lepirudin anaphylaxis and Kounis syndrome.

PMID- 15184303
TI  - Role of leptin in regulating nitric oxide production and membrane microviscosity.

PMID- 15184304
TI  - Percutaneous endovascular repair of aneurysm after previous coarctation surgery.

PMID- 15184306
TI  - From bench to bedside and back again?

PMID- 15184311
TI  - SSRI treatment for under-18s.

PMID- 15184312
TI  - The best type of trial.

PMID- 15184313
TI  - The best type of trial.

PMID- 15184319
TI  - Canada finally begins long journey to an HIV vaccine.

PMID- 15184320
TI  - Alcohol rivals tobacco for health impact: WHO.

PMID- 15184323
TI  - Actor teaches clinicians to communicate.

PMID- 15184325
TI  - Younger physicians, specialists use Internet more.

PMID- 15184326
TI  - WHO cares.

PMID- 15184327
TI  - Gene therapy: two steps forward, one step back.

PMID- 15184329
TI  - The headache of teenage acne.

PMID- 15184330
TI  - Developmental dysfluency: early intervention is key.

PMID- 15184331
TI  - A 32-year-old man with acute bilateral leg weakness following recreational
      diving.

PMID- 15184333
TI  - Family caregiver burden: results of a longitudinal study of breast cancer
      patients and their principal caregivers.
AB  - BACKGROUND: The vital role played by family caregivers in supporting dying cancer
      patients is well recognized, but the burden and economic impact on caregivers is
      poorly understood. We prospectively examined the psychosocial, occupational and
      economic impact of caring for a person with a terminal illness. METHODS: We
      studied 89 caregivers of women with advanced breast cancer receiving care at
      either the Ottawa or Hamilton regional cancer centres in Ontario. Patients were
      followed until their death or study completion at 3 years. Patients identified a
      principal caregiver to participate in the study. The Karnofsky Performance Status
      (KPS) index, the Medical Outcomes Study 36-item Short Form (SF-36), the Hospital
      Anxiety and Depression Scale, the Zarit Burden Inventory, FAMCARE and the Medical
      Outcomes Study Social Support Survey were administered during follow-up. Economic
      data were collected by means of a questionnaire administered by an interviewer.
      Assessments were conducted every 3 months during the palliative period (KPS score
      > 50) and every 2 weeks during the terminal period (KPS score < or = 50).
      RESULTS: Over half of the caregivers were male (55%) and the patient's spouse or
      partner (52%), with a mean age of 53 years. At the start of the palliative
      period, the caregivers' mean physical functioning score was better than the
      patients' (51.3 v. 35.1, 95% confidence interval [CI] 13.3-20.0); there were
      similar mean mental functioning scores (46.6 and 47.1 respectively); similar
      proportions were depressed (11% and 12%); and significantly more caregivers than
      patients were anxious (35% v. 19%, p = 0.009). More caregivers were depressed
      (30% v. 9%, p = 0.02) and had a higher level of perceived burden (26.2 v. 19.4, p
      = 0.02) at the start of the terminal period than at the start of the palliative
      period. Burden was the most important predictor of both anxiety and depression.
      Of employed caregivers, 69% reported some form of adverse impact on work. In the
      terminal period 77% reported missing work because of caregiving responsibilities.
      Prescription drugs were the most important component of financial burden.
      INTERPRETATION: Caregivers' depression and perceived burden increase as patients'
      functional status declines. Strategies are needed to help reduce the
      psychosocial, occupational and economic burden associated with caregiving.

PMID- 15184334
TI  - Safety and efficiency of emergency department assessment of chest discomfort.
AB  - BACKGROUND: Most Canadian emergency departments use an unstructured,
      individualized approach to patients with chest pain, without data to support the
      safety and efficiency of this practice. We sought to determine the proportions of
      patients with chest discomfort in emergency departments who either had acute
      coronary syndrome (ACS) and were inappropriately discharged from the emergency
      department or did not have ACS and were held for investigation. METHODS:
      Consecutive consenting patients aged 25 years or older presenting with chest
      discomfort to 2 urban tertiary care emergency departments between June 2000 and
      April 2001 were prospectively enrolled unless they had a terminal illness, an
      obvious traumatic cause, a radiographically identifiable cause, severe
      communication problems or no fixed address in British Columbia or they would not
      be available for follow-up by telephone. At 30 days we assigned predefined
      explicit outcome diagnoses: definite ACS (acute myocardial infarction [AMI] or
      definite unstable angina) or no ACS. RESULTS: Of 1819 patients, 241 (13.2%) were
      assigned a 30-day diagnosis of AMI and 157 (8.6%), definite unstable angina. Of
      these 398 patients, 21 (5.3%) were discharged from the emergency department
      without a diagnosis of ACS and without plans for further investigation. The
      clinical sensitivity for detecting ACS was 94.7% (95% confidence interval [CI]
      92.5%- 96.9%) and the specificity 73.8% (95% CI 71.5%- 76.0%). Of the patients
      without ACS or an adverse event, 71.1% were admitted to hospital or held in the
      emergency department for more than 3 hours. INTERPRETATION: The current
      individualized approach to evaluation and disposition of patients with chest
      discomfort in 2 Canadian tertiary care emergency departments misses 5.3% of cases
      of ACS while consuming considerable health care resources for patients without
      coronary disease. Opportunities exist to improve both safety and efficiency.

PMID- 15184335
TI  - Multiple myeloma in a patient with fever of unknown origin and cholestasis.
AB  - The differential diagnosis of fever of unknown origin includes infectious
      diseases, malignancies and connective tissue diseases. Multiple myeloma is not
      usually included in the differential diagnosis, nor is it considered a frequent
      cause of cholestasis in the absence of amyloidosis. We report a case of multiple
      myeloma in a patient presenting with a long-standing fever and cholestasis. The
      patient underwent a long and unfruitful series of diagnostic procedures,
      including liver biopsy. The clue to the diagnosis, established with a marrow
      biopsy, was the presence of a paraprotein in the serum.

PMID- 15184336
TI  - Family care and burden at the end of life.

PMID- 15184337
TI  - Charging the patient to save the system? Like bailing water with a sieve.

PMID- 15184338
TI  - The high costs of for-profit care.

PMID- 15184344
TI  - Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll
      like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization.
AB  - Toll-like receptor 4 (TLR4) and MD-2 recognizes lipid A, the active moiety of
      microbial lipopolysaccharide (LPS). Little is known about mechanisms for LPS
      recognition by TLR4-MD-2. Here we show ligand-induced TLR4 oligomerization,
      homotypic interaction of TLR4, which directly leads to TLR4 signaling. Since TLR4
      oligomerization normally occurred in the absence of the cytoplasmic portion of
      TLR4, TLR4 oligomerization works upstream of TLR4 signaling. Lipid IVa, a lipid A
      precursor, is agonistic on mouse TLR4-MD-2 but turns antagonistic on chimeric
      mouse TLR4-human MD-2, demonstrating that the antagonistic activity of lipid IVa
      is determined by human MD-2. Binding studies with radioactive lipid A and lipid
      IVa revealed that lipid IVa is similar to lipid A in dose-dependent and saturable
      binding to mouse TLR4-human MD-2. Lipid IVa, however, did not induce TLR4
      oligomerization, and inhibited lipid A-dependent oligomerization of mouse TLR4
      human MD-2. Thus, lipid IVa binds mouse TLR4-human MD-2 but does not trigger TLR4
      oligomerization. Binding study further revealed that the antagonistic activity of
      lipid IVa correlates with augmented maximal binding to mouse TLR4-human MD-2,
      which was approximately 2-fold higher than lipid A. Taken together, lipid A
      antagonist lipid IVa is distinct from lipid A in binding to TLR4-MD-2 and in
      subsequent triggering of TLR4 oligomerization. Given that the antagonistic
      activity of lipid IVa is determined by MD-2, MD-2 has an important role in a link
      between ligand interaction and TLR4 oligomerization.

PMID- 15184339
TI  - Payments for care at private for-profit and private not-for-profit hospitals: a
      systematic review and meta-analysis.
AB  - BACKGROUND: It has been shown that patients cared for at private for-profit
      hospitals have higher risk-adjusted mortality rates than those cared for at
      private not-for-profit hospitals. Uncertainty remains, however, about the
      economic implications of these forms of health care delivery. Since some policy
      makers might still consider for-profit health care if expenditure savings were
      sufficiently large, we undertook a systematic review and meta-analysis to compare
      payments for care at private for-profit and private not-for-profit hospitals.
      METHODS: We used 6 search strategies to identify published and unpublished
      observational studies that directly compared the payments for care at private for
      profit and private not-for-profit hospitals. We masked the study results before
      teams of 2 reviewers independently evaluated the eligibility of all studies. We
      confirmed data or obtained additional data from all but 1 author. For each study,
      we calculated the payments for care at private for-profit hospitals relative to
      private not-for-profit hospitals and pooled the results using a random effects
      model. RESULTS: Eight observational studies, involving more than 350 000 patients
      altogether and a median of 324 hospitals each, fulfilled our eligibility
      criteria. In 5 of 6 studies showing higher payments for care at private for
      profit hospitals, the difference was statistically significant; in 1 of 2 studies
      showing higher payments for care at private not-for-profit hospitals, the
      difference was statistically significant. The pooled estimate demonstrated that
      private for-profit hospitals were associated with higher payments for care
      (relative payments for care 1.19, 95% confidence interval 1.07-1.33, p = 0.001).
      INTERPRETATION: Private for-profit hospitals result in higher payments for care
      than private not-for-profit hospitals. Evidence strongly supports a policy of not
      for-profit health care delivery at the hospital level.

PMID- 15184345
TI  - Involvement of FcRgamma in signal transduction of osteoclast-associated receptor
      (OSCAR).
AB  - Osteoclasts regulate homeostasis of bone development. A defect in osteoclast
      development results in osteopetrosis. Recently, the involvement of several
      molecules in osteoclast development has been found. Osteoclast-associated
      receptor (OSCAR) is one of such molecules critical for osteoclast
      differentiation. However, it remains unclear how OSCAR transduces signals for
      osteoclast differentiation. Here, we found that the FcRgamma chain, a signal
      transducing adaptor molecule for Fc receptors, is associated with OSCAR and is
      involved in the cell surface expression of OSCAR. Furthermore, FcRgamma is
      required for signal transduction by OSCAR. These findings suggest that the
      FcRgamma-mediated signal transduction by OSCAR is involved in osteoclast
      differentiation.

PMID- 15184347
TI  - Dendritic cells generated in the presence of interferon-alpha stimulate
      allogeneic CD4+ T-cell proliferation: modulation by autocrine IL-10, enhanced T
      cell apoptosis and T regulatory type 1 cells.
AB  - Dendritic cells (DCs) generated in the presence of IFN-alpha (IFN-DCs) exhibit
      high expression of major histocompatibility and co-stimulatory molecules and a
      potent ability to stimulate CD8(+) T-cell responses. Here, we found that IFN-DCs
      were more potent stimulators of bulk and purified CD8(+) T-cell proliferation, as
      compared with IL-4-DCs. In contrast, IFN-DCs were less efficient than IL-4-DCs in
      stimulating allogeneic CD4(+) T-cell proliferation, due to a weak induction of
      naive CD4(+)CD45RO(-) T-cell proliferation by these DCs. However, both DC
      populations induced similar levels of proliferation of memory CD4(+)CD45RO(+) T
      cells. IFN-DCs and IL-4-DCs exhibited a similar phenotype and production of IL-10
      following maturation induced by CD40 ligation. In contrast, IFN-DCs produced
      higher levels of IL-10 during the first days of differentiation. In addition,
      neutralization of IL-10 during the differentiation of DCs increased the
      expression of DC-LAMP and MHC class II by IFN-DCs, and the ability of IFN-DCs to
      stimulate allogeneic CD4(+) T-cell proliferation at similar levels, than IL-4
      DCs. Independently of IL-10 production, IFN-DCs were found to induce higher
      levels of CD4(+)T-cell apoptosis, this effect being more sticking on naive T
      cells. Finally, we demonstrated that IFN-DCs induced a differentiation bias of
      naive CD4(+) T cells towards Th1 and Tr1 cells, compared to IL-4-DCs. Taken
      together, these results indicate that, despite the induction of Tr1 cells and
      enhanced apoptosis of naive CD4(+) T cells, IFN-DCs are potent stimulators of
      CD8(+) and memory CD4(+) T cells, and induce a strong polarization of naive
      CD4(+) T cells towards Th1 cells, further supporting their use in immune-based
      therapy.

PMID- 15184346
TI  - Tumor cells secreting IL-13 but not IL-13Ralpha2 fusion protein have reduced
      tumorigenicity in vivo.
AB  - IL-13 is a Th2 cytokine that plays crucial roles in the pathophysiology of
      allergy, asthma and helminth infection. The high affinity receptor for IL-13, IL
      13Ralpha2, may act as a decoy receptor for IL-13. The anti-tumor effect of IL-13
      and its soluble receptor IL-13Ralpha2 have been examined in different tumor
      systems. Previous studies have shown that IL-13 enhances anti-tumor responses in
      some model systems, whereas IL-13Ralpha2Fc prevents IL-13 mediated suppression of
      tumor immuno-surveillance in a different model system. In this study, we have
      used a cytokine (receptor) gene therapy approach and studied the immune responses
      mediated by IL-13 and IL-13Ralpha2Fc in poorly immunogenic B16F1 melanoma and
      immunogenic MethA fibrosarcoma tumor models. We find that IL-13 reduces the
      tumorigenicity of B16F1 melanoma and MethA fibrosarcoma cells in vivo, most
      likely through the recruitment of neutrophils and macrophages. IL-13 mediated
      anti-tumor responses do not lead to the generation of tumor-specific T cells.
      Neither IL-13Ralpha2Fc gene transduction nor in vivo treatment with soluble IL
      13Ralpha2Fc has a statistically significant effect of tumor growth. IL-13Ralpha2
      deficient host background does not alter tumor growth, suggesting that endogenous
      levels of IL-13 do not contribute to an anti-tumor response in these models. We
      conclude that IL-13, but not soluble IL-13Ralpha2, has anti-tumor activity in the
      models described here, possibly by enhancing innate anti-tumor immunity.

PMID- 15184348
TI  - Body mass index and blood pressure influences on left ventricular mass and
      geometry in African Americans: The Atherosclerotic Risk In Communities (ARIC)
      Study.
AB  - A unique interaction between the influences of body mass index and blood pressure
      on left ventricular mass index and geometry may contribute to the higher
      prevalence of left ventricular hypertrophy in African Americans. This cross
      sectional study assessed separate and joint influences of body mass index and
      blood pressure on left ventricular mass index and geometry in 1729 African
      American participants of the Atherosclerotic Risk in Communities Study. The
      association between both left ventricular mass index and relative wall thickness
      and body mass index in each blood pressure category and between these variables
      and blood pressure in each body mass index category was assessed adjusting for
      age, diabetes status, hypertension medication, and smoking status. We found that
      left ventricular hypertrophy and concentric geometry were highly prevalent and
      that body mass index and blood pressure were independently associated with left
      ventricular mass index. The adjusted association between blood pressure and left
      ventricular mass index was stronger with higher body mass index categories;
      however, there was no significant interaction suggesting merely an additive
      relationship (not synergistic/multiplicative as tested for in the interaction
      analysis). Although relative wall thickness was greater with higher categories of
      body mass index and blood pressure, the mean difference in relative wall
      thickness between body mass index and blood pressure categories was not
      statistically significant. The effect on left ventricular geometry as measured by
      relative wall thickness supports the theory that there is a pathophysiological
      component in the mechanism of hypertrophy.

PMID- 15184349
TI  - Effect of irbesartan versus atenolol on left ventricular mass and voltage:
      results of the CardioVascular Irbesartan Project.
AB  - Regression of hypertensive left ventricular hypertrophy (LVH) is associated with
      improved prognosis. The aim of this trial was to compare the effects of
      irbesartan versus atenolol on LVH in subjects with essential hypertension.
      Because electrocardiographic and echocardiographic parameters of LVH carry
      disparate prognostic information, both methods were applied in this trial. In the
      randomized, double-blind, multicenter trial CardioVascular Irbesartan Project,
      240 patients with essential hypertension were treated with irbesartan or atenolol
      for 18 months. Voltage criteria used for LVH were Sokolow index, Cornell index,
      Cornell voltage x QRS duration product and Lewis index. In parallel, left
      ventricular mass (LVM) was determined by 2-dimensional guided M-mode
      echocardiography. After 6 and 18 months, reductions of LVM and voltage criteria
      for LVH were only found in subjects treated with irbesartan. However, a reduction
      of LVM was only detectable in subjects within the highest quartile of baseline
      LVM but not overall. In contrast, reductions of voltage criteria for LVH were
      detectable after 6 and 18 months even within commonly used normal limits. In
      conclusion, treatment of hypertension with irbesartan resulted in a significant
      reduction in the voltage criteria for LVH, although an effect on LVM was only
      seen in subjects with high baseline LVM. In contrast, atenolol did not lead to
      reductions in electrocardiographic or echocardiographic parameters of LVH.
      Because voltage criteria for LVH have been shown to predict cardiovascular
      outcome independently from LVM, we suggest that both methods should be used to
      accurately assess the benefits of antihypertensive treatment.

PMID- 15184350
TI  - Perinatal L-arginine and antioxidant supplements reduce adult blood pressure in
      spontaneously hypertensive rats.
AB  - Embryo cross-transplantation and cross-fostering between spontaneously
      hypertensive rats (SHR) and normotensive rats (WKY) suggest that perinatal
      environment modulates the genetically determined phenotype. In SHR the balance
      between NO and reactive oxygen species (ROS) is disturbed. We hypothesized that
      increasing NO and diminishing ROS in perinatal life would ameliorate hypertension
      in adult SHR. Pregnant SHR and WKY and their offspring received l-arginine plus
      antioxidants (vitamin C, vitamin E, and taurine) during the last 2 weeks of
      pregnancy and then until either 4 or 8 weeks after birth. Systolic blood pressure
      (SBP) and urinary excretion of protein, nitrates (NO(x)), and thiobarbituric acid
      reactive substances (TBARS) were measured. At 48 weeks of age rats were
      euthanized for glomerular counts. Perinatal supplements reduced SBP persistently
      in SHR and prevented the SBP increase observed in aging WKY. Initially NO(x)
      excretion was lower and TBARS excretion higher in SHR than WKY. There was a
      direct effect on NO(x) excretion in supplemented pregnant SHR and their
      offspring, but no increase was observed after stopping the supplements. TBARS
      excretion was only depressed up to 14 weeks by the supplements despite persistent
      differences in SBP. Consistent effects on nephron number were absent. Mild
      proteinuria, present in control SHR at 48 weeks, was prevented in all
      supplemented rats. Perinatal supplementation of NO substrate and antioxidants
      results in persistent reduction of SBP and renal protection in SHR, although
      effects on NO(x) and TBARS were only transient. This suggests a critical role for
      perinatal pro- and antioxidant balance in programming BP later in life.

PMID- 15184352
TI  - Neural sympathetic activity in essential hypertension.

PMID- 15184351
TI  - Simvastatin combined with ramipril treatment in hypercholesterolemic patients.
AB  - Mechanisms underlying biological effects of statin and angiotensin-converting
      enzyme inhibitor therapies differ. Thus, we studied vascular responses to
      combination therapy in hypercholesterolemic patients. A randomized, double-blind,
      placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic
      patients with simvastatin and either placebo or ramipril (study I) and in 45
      hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo
      or simvastatin combined with ramipril (study II) for 2 months with 2 months
      washout. In study I simvastatin combined with ramipril significantly reduced
      blood pressure after 2 months. Simvastatin alone or combined with ramipril
      significantly changed lipoproteins, improved percent flow-mediated dilator
      response to hyperemia by 30+/-5% and 53+/-6%, respectively (P<0.001), and reduced
      plasma levels of malondialdehyde by 4+/-7% (P=0.026) and 25+/-4% (P<0.001),
      respectively. Monocyte chemoattractant protein-1 levels decreased by 3+/-3% and
      12+/-2%, respectively (P=0.049 and P=0.001, respectively), C-reactive protein
      levels changed by 0% and 18%, respectively (P=0.036 and P<0.001, respectively),
      and plasminogen activator inhibitor-1 antigen levels changed by -7+/-7% and 17+/
      5%, respectively (P=0.828 and P<0.001, respectively). In study II ramipril alone
      did not significantly change lipoproteins and C-reactive protein levels, however,
      simvastatin combined with ramipril significantly changed lipoproteins and C
      reactive protein levels more than ramipril alone (P<0.001 and P=0.048 by ANOVA,
      respectively). Ramipril alone or simvastatin combined with ramipril significantly
      improved the percent flow-mediated dilator response to hyperemia (both P<0.001),
      however, simvastatin combined with ramipril showed significantly more improvement
      than ramipril alone (P<0.001 by ANOVA). Simvastatin combined with ramipril
      significantly improved endothelium-dependent vasodilation and fibrinolysis
      potential and reduced plasma levels of oxidant stress and inflammation markers in
      hypercholesterolemic patients.

PMID- 15184354
TI  - Analysis of ex vivo left ventricular pressure-volume relations in the isolated
      murine ejecting heart.
AB  - The development of microconductance technology to study cardiac pressure-volume
      relations in mice in vivo has significantly advanced the haemodynamic assessment
      of gene-modified models of cardiovascular disease. In this study, we describe the
      application of microconductance analysis of cardiac function to the isolated
      murine ejecting heart. This ex vivo model is complementary to the previously
      described in vivo preparation, allows assessment without confounding effects of
      anaesthetic or neurohumoral influences and enables careful control of cardiac
      loading (particularly preload). Ex vivo pressure-volume relations in the isolated
      murine heart are sensitive to changes in myocardial contractility induced by beta
      adrenoceptor stimulation or beta-adrenoceptor blockade, as well as the effects of
      chronic pressure overload induced by aortic banding. We present data for both
      steady-state analyses of the Frank-Starling relation and for assessment of the
      left ventricular pressure-volume relation over variably loaded beats, which
      allows investigation of the end-systolic and end-diastolic pressure-volume
      relations. The measurement of ventricular volume in addition to pressure under
      carefully controlled loading conditions in the isolated ejecting heart allows a
      comprehensive analysis of cardiac contractile function, and provides a useful
      complementary model for the assessment of cardiac performance in murine models of
      heart disease.

PMID- 15184355
TI  - Orthostatic tolerance and blood volumes in Andean high altitude dwellers.
AB  - Orthostatic tolerance is a measure of the ability to prevent hypotension during
      gravitational stress. It is known to be dependent on the degree of
      vasoconstriction and the magnitude of plasma volume, but the possible influence
      of packed cell volume (PCV) is unknown. High altitude residents have high
      haematocrits and probably high packed cell volumes. However, it is not known
      whether plasma volume and blood volume are affected, or whether their orthostatic
      tolerance is different from low altitude residents. In this study we determined
      plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers
      (HA), including a subgroup of highland dwellers with chronic mountain sickness
      (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using
      Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was
      assessed as the time to presyncope in a test of head-up tilting and lower body
      suction. All studies were performed at 4338 m. Results showed that plasma volumes
      were not significantly different between CMS and HA, or in highland dwellers
      compared to those seen previously in lowlanders. PCV and haematocrit were greater
      in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although
      the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic
      tolerance was correlated with haematocrit (r= 0.57, P < 0.01) and PCV (r= 0.54, P
      < 0.01). This investigation has shown that although high altitude residents have
      large PCV, their plasma volumes were similar to lowland dwellers. The group with
      CMS have a particularly large PCV and also have a very high orthostatic
      tolerance, despite smaller heart rate responses. These results are compatible
      with the view that PCV is of importance in determining orthostatic tolerance.

PMID- 15184356
TI  - Stress-induced pressor and corticosterone responses in oxytocin-deficient mice.
AB  - We used oxytocin knockout (OTKO) mice to investigate the role of oxytocin in
      regulation of blood pressure, heart rate and stress reactivity (pressure
      reactivity and plasma corticosterone). Male OTKO and control wild-type mice with
      carotid arterial catheters were exposed to intermittent shaker stress for 7 days
      (2 min stressors, 45 times per day). Mean arterial pressure (MAP) and heart rate
      (HR) were recorded continuously (24 h) before stress (basal), on stress days 1, 3
      and 7 (S1, S3 and S7) and 1 day poststress (recovery). Plasma corticosterone
      (Cort) was measured before stress and 30 min after the last stress on day 7.
      Twenty-four hour averages of MAP and HR were lower in OTKO mice than in controls
      (P < 0.0001 and P < 0.005, respectively) with a significant diurnal rhythm.
      Chronic stress (S1 and S3) produced an increase in 24 h average MAP in OTKO mice,
      but not in controls. There were no stress-related changes in 24 h average HR
      values between control and OTKO mice. The immediate pressor responses were
      analysed during the dark and light periods (19.00 and 08.00 h). During the dark
      period, stress-induced pressor responses were observed only in OTKO mice (S1 and
      S3). In the light period, stress-induced MAP increases were seen on all days in
      OTKO mice and on days S1 and S3 in controls. There were no differences in
      baseline Cort between the groups; however, OTKO mice showed a reduced response to
      chronic stress (+298 versus+411%, OTKO mice versus controls, P < 0.005). In
      conclusion, oxytocin deficiency alters the endocrine and pressor responses to
      chronic stress, suggesting that the endogenous oxytocin system is important in
      regulating the stress-induced pressor response.

PMID- 15184357
TI  - Gut hormones in the control of appetite.
AB  - Obesity is one of the greatest threats to the health of the developed world. In
      order to design effective drugs to treat the alarming increase in obesity, it is
      essential to understand the physiology of normal appetite control and the
      pathophysiology of obesity. The hypothalamus interprets and integrates neural and
      humoral inputs to provide a coordinated feeding and energy expenditure response.
      Recent evidence suggests that certain gut hormones - ghrelin, polypeptide YY,
      pancreatic polypeptide, glucagon-like-peptide 1 and oxyntomodulin - have a
      physiological role in governing satiety via the hypothalamus. Gut hormone
      appetite-regulatory systems represent a potential target for the design of
      antiobesity drugs.

PMID- 15184358
TI  - Interaction of prolactin, ANPergic, oxytocinergic and adrenal systems in response
      to extracellular volume expansion in rats.
AB  - The present study evaluated the effect of acute extracellular volume expansion
      (EVE) induced by intravenous injection of isotonic (0.15 m NaCl) or hypertonic
      saline (0.3 m NaCl) on prolactin, corticosterone, vasopressin, oxytocin and
      atrial natriuretic peptide (ANP) secretion. Male Wistar rats were treated with
      bromocriptine, sulpiride or dexamethasone. After isotonic and hypertonic EVE, the
      control group showed a significant increase in the plasma concentrations of
      prolactin, corticosterone, ANP and oxytocin. The increase in ANP and oxytocin
      levels in response to hypertonic EVE was more pronounced than to isotonic EVE.
      Bromocriptine and sulpiride treatments did not modify corticosterone, ANP and
      oxytocin responses to either isotonic or hypertonic EVE. The increases in
      prolactin and oxytocin, but not ANP, were blocked in dexamethasone pretreated
      rats. In conclusion, isotonic or hypertonic EVE induced an increase in the plasma
      concentrations of prolactin, corticosterone, ANP and oxytocin. The increases in
      ANP and oxytocin were independent of plasma concentrations of prolactin. The
      increases in prolactin and oxytocin were blocked by the inhibition of the
      hypothalamo-pituitary-adrenal (HPA) axis by dexamethasone. However, dexamethasone
      did not alter the increase in ANP secretion induced by isotonic or hypertonic
      EVE. Therefore, prolactin might participate in regulation of the
      hydroelectrolytic balance in mammals; however, in the present study, there was no
      evidence for direct interaction with ANPergic and oxytocinergic systems. In
      addition, the responses of prolactin and oxytocin induced by isotonic or
      hypertonic EVE are modulated by the HPA axis.

PMID- 15184359
TI  - EDL and soleus muscles of the C57BL6J/dy2j laminin-alpha 2-deficient dystrophic
      mouse are not vulnerable to eccentric contractions.
AB  - Many muscular dystrophies arise as a consequence of mutations in a series of
      interconnected proteins associated with the sarcolemma. This group of proteins is
      collectively referred to as the 'dystrophin-associated complex'. We used the
      C57BL6J/dy(2j), dystrophia muscularis, dystrophic mouse, in which the laminin
      alpha(2) component of the dystrophin-associated complex is mutated, to test the
      hypothesis that the disruption of this complex will destabilize the lipid
      bilayer, rendering it more susceptible to damage during eccentric contractions.
      We demonstrated that neither slow- nor fast-twitch dystrophic muscles were more
      susceptible to eccentric contractions when compared with controls. Only fast
      twitch extensor digitorum longus (EDL) muscles (from both dystrophic and control
      mice) showed an irreversible loss of force with our eccentric contraction
      protocol, suggesting that it is the fast 11b fibres (not present in slow-twitch
      soleus) which are most susceptible to eccentric damage. We used the general
      anaesthetic halothane to increase the fluidity of the lipid bilayer to see if
      this would uncover any greater susceptibility of the dystrophic muscle to
      eccentric damage. This also did not reveal any greater fragility of fast- and
      slow-twitch dystrophic muscles. We did, however, demonstrate that halothane made
      both control and dystrophic fast- and slow-twitch muscles more susceptible to
      eccentric contraction damage. The C57BL6J/dy(2j) dystrophic laminopathy produced
      the pathophysiological and pathohistological characteristics associated with
      muscular dystrophy: the fast- and slow-twitch dystophic muscles produced only 55
      and 53%, respectively, of the force of control muscles and 34 and 40%,
      respectively, of the dystrophic muscle fibres were branched. The presence of the
      branched fibres in the dystrophic muscles did not make them more susceptible to
      eccentric damage but may have contributed to the reduction in maximal force in
      the dystrophic muscles. We conclude that our data do not support the structural
      hypothesis that the dystrophin-associated complex acts as a scaffolding to
      support the lipid bilayer, but are consistent with channel-based hypotheses put
      forward to explain the dystrophic process.

PMID- 15184360
TI  - Effect of short-term training on GLUT-4 mRNA and protein expression in human
      skeletal muscle.
AB  - Six untrained, male subjects (23 +/- 1 years old, 84 +/- 5 kg, (O(2)peak)= 3.7 +/
      0.8 l min(-1)) exercised for 60 min at 75 +/- 1%(O(2)peak) on 7 consecutive
      days. Muscle samples were obtained before the start of cycle exercise training
      and 24 h after the first and seventh exercise sessions and analysed for citrate
      synthase activity, glycogen and glucose transporter 4 (GLUT-4) mRNA and protein
      expression. Exercise training increased (P < 0.05) citrate synthase by
      approximately 20% and muscle glycogen concentration by approximately 40%. GLUT-4
      mRNA levels 24 h after the first and seventh exercise sessions were similar to
      those measured before the start of exercise training. In contrast, GLUT-4 protein
      expression was increased after 7 days of exercise training (12.4 +/- 1.5 versus
      3.4 +/- 1.0 arbitray units (a.u.), P < 0.05) and although it tended to be higher
      24 h after the first exercise session (6.0 +/- 3.0 versus 3.4 +/- 1.0 a.u.), this
      was not significantly different (P= 0.09). These results support the suggestion
      that the adaptive increase in skeletal muscle GLUT-4 protein expression with
      short-term exercise training arises from the repeated, transient increases in
      GLUT-gene transcription following each exercise bout leading to a gradual
      accumulation of GLUT-4 protein, despite GLUT-4 mRNA returning to basal levels
      between exercise stimuli.

PMID- 15184361
TI  - Mutation-induced quisqualic acid and ibotenic acid affinity at the metabotropic
      glutamate receptor subtype 4: ligand selectivity results from a synergy of
      several amino acid residues.
AB  - The metabotropic glutamate receptors (mGluRs) are key modulators of excitatory
      neurotransmission in the central nervous system. The eight mGluR subtypes are
      seven trans-membrane-spanning proteins that possess a large extracellular amino
      terminal domain in which the endogenous ligand binding pocket resides. In this
      study, we have identified four non-conserved amino acid residues that are
      essential for differentiating mGluR1 from mGluR4. Our approach has been to
      increase the affinity of the classic mGluR1 agonists, quisqualic acid and
      ibotenic acid, at mGluR4 by making various point mutations that mimicked mGluR1
      residues. Based on ligand docking to homology models, the non-conserved residues,
      Lys-74, Glu-287, Ser-313, and Lys-317, were chosen for the mutational studies and
      all of the mutations proved capable of partially or completely restoring the
      affinities of the ligands. In particular, the mutations K74Y and K317R induced
      dramatic triple-order-of-magnitude increases in the affinity of ibotenic acid at
      mGluR4, making the affinity equivalent to that of mGluR1. Furthermore, the
      affinity of quisqualic acid at mGluR4 was increased to the same level as mGluR1
      by the two double mutations, K74Y/K317R and K74Y/E287G. Advanced analysis of
      ligand conformation and docking procedures were used for the interpretation of
      these results. The study shows that mGluR subtype selectivity results from a
      complex interplay of residues shaping the binding pocket, rather than being
      attributable to a single specific ligand-receptor interaction.

PMID- 15184362
TI  - Stabilization of exocytosis by dynamic F-actin coating of zymogen granules in
      pancreatic acini.
AB  - Reorganization of F-actin in the apical region of mouse pancreatic acinar cells
      during Ca(2+)-dependent exocytosis of zymogen granules was investigated by two
      photon excitation microscopy with intact acini. Granules were rapidly coated with
      F-actin in response to either agonist stimulation or photolysis of a caged-Ca(2+)
      compound. Such F-actin coating occurred exclusively at the surface of granules
      undergoing exocytosis and was prevented either by latrunculin-A, which inhibits
      actin polymerization, or by Clostridium botulinum exoenzyme C3, which inhibits
      the small GTPase Rho. Latrunculin-A or exoenzyme C3 also triggered the formation
      of vacuoles in acinar cells, a characteristic of acute pancreatitis. Stimulation
      of acini with high concentrations of cholecystokinin, which cause acute
      pancreatitis in mice, also impaired the F-actin coating of granules and induced
      vacuole formation. Latrunculin-A reduced the latency to exocytosis but did not
      affect the total number of exocytic events, suggesting that F-actin slows and
      further stabilizes exocytosis by facilitating F-actin coating. Rho-dependent F
      actin coating of granule membranes thus stabilizes exocytic structures and is
      necessary for physiological progression of sequetial compound exocytosis in the
      exocrine pancreas and for prevention of acute pancreatitis.

PMID- 15184363
TI  - Identification of a novel family of ankyrin repeats containing cofactors for p160
      nuclear receptor coactivators.
AB  - Members of the p160 nuclear receptor coactivators interact with liganded nuclear
      receptors to enhance transcription of target genes. Here we identify a novel
      family of ankyrin repeats containing cofactors (ANCOs) that interact with the
      p160 coactivators. ANCO-1 binds to the conserved Per-Arnt-Sim (PAS) region of the
      p160 coactivators. It encodes a large nuclear protein with five ankyrin repeats,
      and parts of its sequences have been reported as nasopharyngeal carcinoma
      susceptibility protein and medulloblastoma antigen. Immunofluorescence staining
      reveals discrete nuclear foci of ANCO-1 that are distinct from known nuclear
      structures. Intriguingly, ANCO-1 also colocalizes and interacts with histone
      deacetylases. Transient reporter gene assay shows that ANCO-1 expression inhibits
      ligand-dependent transactivation by both steroid and nonsteroid nuclear
      receptors. Taken together, we have identified a novel family of ankyrin repeats
      containing cofactors that may recruit histone deacetylases to the p160
      coactivators/nuclear receptor complex to inhibit ligand-dependent
      transactivation.

PMID- 15184364
TI  - Protein 4.1R, a microtubule-associated protein involved in microtubule aster
      assembly in mammalian mitotic extract.
AB  - Non-erythroid protein 4.1R (4.1R) consists of a complex family of isoforms. We
      have shown that 4.1R isoforms localize at the mitotic spindle/spindle poles and
      associate in a complex with the mitotic-spindle organization proteins Nuclear
      Mitotic Apparatus protein (NuMA), dynein, and dynactin. We addressed the mitotic
      function of 4.1R by investigating its association with microtubules, the main
      component of the mitotic spindles, and its role in mitotic aster assembly in
      vitro. 4.1R appears to partially co-localize with microtubules throughout the
      mitotic stages of the cell cycle. In vitro sedimentation assays showed that 4.1R
      isoforms directly interact with microtubules. Glutathione S-transferase (GST)
      pull-down assays using GST-4.1R fusions and mitotic cell extracts further showed
      that the association of 4.1R with tubulin results from both the membrane-binding
      domain and C-terminal domain of 4.1R. Moreover, 4.1R, but not actin, is a mitotic
      microtubule-associated protein; 4.1R associates with microtubules in the
      microtubule pellet of the mitotic asters assembled in mammalian cell-free mitotic
      extract. The organization of microtubules into asters depends on 4.1R in that
      immunodepletion of 4.1R from the extract resulted in randomly dispersed
      microtubules. Furthermore, adding a 135-kDa recombinant 4.1R reconstituted the
      mitotic asters. Finally, we demonstrated that a mitotic 4.1R isoform appears to
      form a complex in vivo with tubulin and NuMA in highly synchronized mitotic HeLa
      extracts. Our results suggest that a 135-kDa non-erythroid 4.1R is important to
      cell division, because it participates in the formation of mitotic spindles and
      spindle poles through its interaction with mitotic microtubules.

PMID- 15184365
TI  - Effects of profilin and thymosin beta4 on the critical concentration of actin
      demonstrated in vitro and in cell extracts with a novel direct assay.
AB  - The free actin concentration at steady state, Ac, is a variable that determines
      how actin regulatory proteins influence the extent of actin polymerization. We
      describe a novel method employing fluorescence anisotropy to directly measure Ac
      in any sample after the addition of a trace amount of labeled thymosin beta4 or
      thymosin beta4 peptide. Using this assay, we confirm earlier theoretical work on
      the helical polymerization of actin and confirm the effects of actin filament
      stabilizing drugs and capping proteins on Ac, thereby validating the assay. We
      also confirm a controversial prior observation that profilin lowers the critical
      concentration of Mg2+-actin. A general mechanism is proposed to explain this
      effect, and the first quantitative dose-response curve for the effect of profilin
      on Ac facilitates its evaluation. This mechanism also predicts the effect of
      profilin on critical concentration in the presence of the limited amount of
      capping protein, which is the condition often found in cells, and the effect of
      profilin on critical concentration in cell extracts is demonstrated for the first
      time. Additionally, nonlinear effects of thymosin beta4 on the steady state
      amount of F-actin are explained by the observed changes in Ac. This assay has
      potential in vivo applications that complement those demonstrated in vitro.

PMID- 15184366
TI  - Two variable regions in carcinoembryonic antigen-related cell adhesion molecule1
      N-terminal domains located in or next to monoclonal antibody and adhesion
      epitopes show evidence of recombination in rat but not in human.
AB  - In this paper, we have characterized the structure, evolutionary origin, and
      function of rat and human carcinoembryonic antigen-related cell adhesion
      molecule1 (CEACAM1) multifunctional Ig-like cell adhesion proteins that are
      expressed by many epithelial tissues. Restriction enzyme digestion reverse
      transcriptase-PCR analysis identified three cDNAs encoding novel CEACAM1 N
      domains. Comparative sequence analysis showed that human and rat CEACAM1 N
      domains segregated into two groups differing in similarity to rat CEACAM1(a)-4L
      and human CEACAM1. Sequence variability analysis indicated that both human and
      rat N-domains possessed two variable regions, and one contained a major adhesive
      epitope. Recombination analysis showed that the group of rat but not human N
      domains with high sequence similarity was derived at least in part by
      recombination. Binding assays revealed that three monoclonal antibodies with
      strong reactivity for the CEACAM1(a)-4L N-domain showed no reactivity with
      CEACAM1(b)-4S, an allele with a different N-domain sequence. CEACAM1(b)-4S
      displayed adhesive activity efficiently blocked by a synthetic peptide
      corresponding to the adhesive epitope in CEACAM1(a)-4L. Blocking analysis also
      showed that the adhesive epitope for rat CEACAM1 was located downstream from the
      equivalent human and mouse epitopes. Glycosylation analysis demonstrated O-linked
      sugars on rat CEACAM1(b)-4S from COS-1 cells. However, this was not the
      alteration responsible for the lack of monoclonal antibody reactivity. When
      considered together with previous studies, our findings suggest an inverse
      relationship between functionality and amino acid sequence similarity to CEACAM1.
      Like IgG, the N-domain of CEACAM1 appears to tolerate 10-15% sequence
      diversification without loss of function but begins to show either altered
      specificity or diminished functionality at higher levels.

PMID- 15184367
TI  - Association of major histocompatibility complex II with cholesterol- and
      sphingolipid-rich membranes precedes peptide loading.
AB  - Major histocompatibility complex class II protein (MHC II) molecules present
      antigenic peptides to CD4-positive T-cells. Efficient T cell stimulation requires
      association of MHC II with membrane microdomains organized by cholesterol and
      glycosphingolipids or by tetraspanins. Using detergent extraction at 37 degrees C
      combined with a modified flotation assay, we investigated the sequence of events
      leading to the association of MHC II with cholesterol- and glycosphingolipid-rich
      membranes (DRMs) that are distinct from tetraspanins. We find two stages of
      association of MHC II with DRMs. In stage one, complexes of MHC II and invariant
      chain, a chaperone involved in MHC II transport, enter DRMs in the Golgi stack.
      In early endosomes, these complexes are almost quantitatively associated with
      DRMs. Upon transport to late endocytic compartments, MHC II-bound invariant chain
      is stepwise proteolyzed to the MHC class II-associated invariant chain peptide
      (CLIP) that remains MHC II-bound and retains a preference for DRMs. At the
      transition between the two stages, CLIP is exchanged against processed antigens,
      and the resulting MHC II-peptide complexes are transported to the cell surface.
      In the second stage, MHC II shows a lower overall association with DRMs. However,
      surface MHC II molecules occupied with peptides that induce resistance to
      denaturation by SDS are enriched in DRMs relative to SDS-sensitive MHC II-peptide
      complexes. Likewise, MHC II molecules loaded with long-lived processing products
      of hen-egg lysozyme containing the immunodominant epitope 48-61 show a very high
      preference for DRMs. Thus after an initial mainly intracellular stage of high DRM
      association, MHC II moves to a second stage in which its preference for DRMs is
      modulated by bound peptides.

PMID- 15184368
TI  - Bcl-2 is a key factor for cardiac fibroblast resistance to programmed cell death.
AB  - Cardiac fibroblasts play an essential role in the physiology of the heart. These
      produce extracellular matrix proteins and synthesize angiogenic and
      cardioprotective factors. Although fibroblasts of cardiac origin are known to be
      resistant to apoptosis and to remain metabolically active in situations
      compromising cell survival, the underlying mechanisms are unknown. Here, we
      report that cardiac fibroblasts were more resistant than dermal or pulmonary
      fibroblasts to mitochondria-dependent cell death. Cytochrome c release was
      blocked in cardiac fibroblasts but not in dermal fibroblasts treated with
      staurosporine, etoposide, serum deprivation, or simulated ischemia, precluding
      caspase-3 activation and DNA fragmentation. Resistance to apoptosis of cardiac
      fibroblasts correlated with the expression of the anti-apoptotic protein Bcl-2,
      whereas skin and lung fibroblasts did not express detectable levels of this
      protein. Bcl-x(L,) Bax, and Bak were expressed at similar levels in cardiac,
      dermal, and lung fibroblasts. In addition, the death of cardiac fibroblasts
      during hypoxia was not associated with the cleavage of Bid but rather with Bcl-2
      disappearance, suggesting the requirement of the mitochondrial apoptotic
      machinery to execute death receptor-induced programmed cell death. Knockdown of
      bcl-2 expression by siRNA in cardiac fibroblasts increased their apoptotic
      response to staurosporine, serum, and glucose deprivation and to simulated
      ischemia. Moreover, dermal fibroblasts overexpressing Bcl-2 achieved a similar
      level of resistance to these stimuli as cardiac fibroblasts. Thus, our data
      demonstrate that Bcl-2 is an important effector of heart fibroblast resistance to
      apoptosis and highlight a probable mechanism for promoting survival advantage in
      fibroblasts of cardiac origin.

PMID- 15184370
TI  - Nonreducing terminal modifications determine the chain length of polymannose O
      antigens of Escherichia coli and couple chain termination to polymer export via
      an ATP-binding cassette transporter.
AB  - The chain length of bacterial lipopolysaccharide O antigens is regulated to give
      a modal distribution that is critical for pathogenesis. This paper describes the
      process of chain length determination in the ATP-binding cassette (ABC)
      transporter-dependent pathway, a pathway that is widespread among Gram-negative
      bacteria. Escherichia coli O8 and O9/O9a polymannans are synthesized in the
      cytoplasm, and an ABC transporter exports the nascent polymer across the inner
      membrane prior to completion of the LPS molecule. The polymannan O antigens have
      nonreducing terminal methyl groups. The 3-O-methyl group in serotype O8 is
      transferred from S-adenosylmethionine by the WbdD(O8) enzyme, and this
      modification terminates polymerization. Methyl groups are added to the O9a
      polymannan in a reaction dependent on preceding phosphorylation. The bifunctional
      WbdD(O9a) catalyzes both reactions, but only the kinase activity controls chain
      length. Chain termination occurs in a mutant lacking the ABC transporter,
      indicating that it precedes export. An E. coli wbdD(O9a) mutant accumulated O9a
      polymannan in the cytoplasm, indicating that WbdD activity coordinates polymannan
      chain termination with export across the inner membrane.

PMID- 15184369
TI  - Ca2+ dependence of the Ca2+-selective TRPV6 channel.
AB  - Microfluorimetry and patch-clamp experiments were performed on TRPV6-expressing
      HEK cells to determine whether this Ca(2+)-sensing Ca(2+) channel is
      constitutively active. Intact cells loaded with fura-2 had an elevated
      intracellular free Ca(2+) concentration ([Ca(2+)](i)), which decreased to the
      same level such as in non-transfected cells if external Ca(2+) was chelated by
      EGTA. Whole cell recordings from non-transfected HEK cells and cells expressing
      human TRPV6 revealed the presence of a basal inward current in both types of
      cells when the internal solution contained 0.1 mm EGTA and 100 nm [Ca(2+)](i) or
      if the cytosolic Ca(2+) buffering remained undisturbed in perforated patch-clamp
      experiments. If recombinantly expressed TRPV6 forms open channels, one would
      expect Ca(2+)-induced current inhibition, because TRPV6 is negatively regulated
      by internal Ca(2+). However, dialyzing solutions with high [Ca(2+)] such as 1
      microm into TRPV6-expressing cells did not block the basal inward current, which
      was not different from the recordings from non-transfected cells. In contrast,
      dialyzing 0.5 mm EGTA into TRPV6-expressing cells readily activated Ca(2+) inward
      currents, which were undetectable in non-transfected cells. Interestingly,
      monovalent cations permeated the TRPV6 channels under conditions where no Ca(2+)
      permeation was detectable, indicating that divalent cations block TRPV6 channels
      from the extracellular side. Like human TRPV6, the truncated human TRPV6(Delta695
      725), which lacks the C-terminal domain required for Ca(2+)-calmodulin binding,
      does not form constitutive active channels, whereas the human TRPV6(D542A),
      carrying a point mutation in the presumed pore region, does not function as a
      channel. In summary, no constitutive open TRPV6 channels were detected in patch
      clamp experiments from transfected HEK cells. However, channel activity is highly
      regulated by intracellular and extracellular divalent cations.

PMID- 15184371
TI  - CbpA, a DnaJ homolog, is a DnaK co-chaperone, and its activity is modulated by
      CbpM.
AB  - The DnaK chaperone system, consisting of DnaK, DnaJ, and GrpE, remodels and
      refolds proteins during both normal growth and stress conditions. CbpA, one of
      several DnaJ analogs in Escherichia coli, is known to function as a multicopy
      suppressor for dnaJ mutations and to bind nonspecifically to DNA and
      preferentially to curved DNA. We found that CbpA functions as a DnaJ-like co
      chaperone in vitro. CbpA acted in an ATP-dependent reaction with DnaK and GrpE to
      remodel inactive dimers of plasmid P1 RepA into monomers active in P1 DNA
      binding. Additionally, CbpA participated with DnaK in an ATP-dependent reaction
      to prevent aggregation of denatured rhodanese. The cbpA gene is in an operon with
      an open reading frame, yccD, which encodes a protein that has some homology to
      DafA of Thermus thermophilus. DafA is a protein required for the assembly of ring
      like particles that contain trimers each of T. thermophilus DnaK, DnaJ, and DafA.
      The E. coli YccD was isolated because of its potential functional relationship to
      CbpA. Purified YccD specifically inhibited both the co-chaperone activity and the
      DNA binding activity of CbpA, suggesting that YccD modulates the activity of
      CbpA. We named the product of the yccD gene CbpM for "CbpA modulator."

PMID- 15184372
TI  - Molecular basis of the differences in binding properties of the highly related C
      type lectins DC-SIGN and L-SIGN to Lewis X trisaccharide and Schistosoma mansoni
      egg antigens.
AB  - The dendritic cell-specific C-type lectin DC-SIGN functions as a pathogen
      receptor that recognizes Schistosoma mansoni egg antigens through its major
      glycan epitope Galbeta1,4(Fucalpha1,3)GlcNAc (Lex). Here we report that L-SIGN, a
      highly related homologue of DC-SIGN found on liver sinusoidal endothelial cells,
      binds to S. mansoni egg antigens but not to the Lex epitope. L-SIGN does bind the
      Lewis antigens Lea, Leb, and Ley, similar as DC-SIGN. A specific mutation in the
      carbohydrate recognition domain of DC-SIGN (V351G) abrogates binding to all Lewis
      antigens. In L-SIGN Ser363 is present at the corresponding position of Val351 in
      DC-SIGN. Replacement of this Ser into Val resulted in a "gain of function" L-SIGN
      mutant that binds to Lex, and shows increased binding to the other Lewis
      antigens. These data indicate that Val351 is important for the fucose specificity
      of DC-SIGN. Molecular modeling and docking of the different Lewis antigens in the
      carbohydrate recognition domains of L-SIGN, DC-SIGN, and their mutant forms,
      demonstrate that Val351 in DC-SIGN creates a hydrophobic pocket that strongly
      interacts with the Fucalpha1,3/4-GlcNAc moiety of the Lewis antigens. The
      equivalent amino acid residue Ser363 in L-SIGN creates a hydrophilic pocket that
      prevents interaction with Fucalpha1,3-GlcNAc in Lex but supports interactions
      with the Fucalpha1,4-GlcNAc moiety in Lea and Leb antigens. These data
      demonstrate for the first time that DC-SIGN and L-SIGN differ in their
      carbohydrate binding profiles and will contribute to our understanding of the
      functional roles of these C-type lectin receptors, both in recognition of
      pathogen and self-glycan antigens.

PMID- 15184373
TI  - Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in
      invasive melanoma cells: role of BRAF mutation and fibroblast growth factor
      signaling.
AB  - Melanoma progresses as a multistep process where the thickness of the lesion and
      depth of tumor invasion are the best prognostic indicators of clinical outcome.
      Degradation of the interstitial collagens in the extracellular matrix is an
      integral component of tumor invasion and metastasis, and much of this degradation
      is mediated by collagenase-1 (MMP-1), a member of the matrix metalloproteinase
      (MMP) family. MMP-1 levels increase during melanoma progression where they are
      associated with shorter disease-free survival. The Ras/Raf/MEK/ERK mitogen
      activated protein kinase (MAPK) pathway is a major regulator of melanoma cell
      proliferation. Recently, BRAF has been identified as a common site of activating
      mutations, and, although many reports focus on its growth-promoting effects, this
      pathway has also been implicated in progression toward metastatic disease. In
      this study, we describe four melanoma cell lines that produce high levels of MMP
      1 constitutively. In each cell line the Ras/Raf/MEK/ERK pathway is constitutively
      active and is the dominant pathway driving the production of MMP-1. Activation of
      this pathway arises due to either an activating mutation in BRAF (three cell
      lines) or autocrine fibroblast growth factor signaling (one cell line).
      Furthermore, blocking MEK/ERK activity inhibits melanoma cell proliferation and
      abrogates collagen degradation, thus decreasing their metastatic potential.
      Importantly, this inhibition of invasive behavior can occur in the absence of any
      detectable changes in cell proliferation and survival. Thus, constitutive
      activation of this MAPK pathway not only promotes the increased proliferation of
      melanoma cells but is also important for the acquisition of an invasive
      phenotype.

PMID- 15184374
TI  - Crystal structure and functional characterization of yeast YLR011wp, an enzyme
      with NAD(P)H-FMN and ferric iron reductase activities.
AB  - Flavodoxins are involved in a variety of electron transfer reactions that are
      essential for life. Although FMN-binding proteins are well characterized in
      prokaryotic organisms, information is scarce for eukaryotic flavodoxins. We
      describe the 2.0-A resolution crystal structure of the Saccharomyces cerevisiae
      YLR011w gene product, a predicted flavoprotein. YLR011wp indeed adopts a
      flavodoxin fold, binds the FMN cofactor, and self-associates as a homodimer.
      Despite the absence of the flavodoxin key fingerprint motif involved in FMN
      binding, YLR011wp binds this cofactor in a manner very analogous to classical
      flavodoxins. YLR011wp closest structural homologue is the homodimeric Bacillus
      subtilis Yhda protein (25% sequence identity) whose homodimer perfectly
      superimposes onto the YLR011wp one. Yhda, whose function is not documented, has
      53% sequence identity with the Bacillus sp. OY1-2 azoreductase. We show that
      YLR011wp has an NAD(P)H-dependent FMN reductase and a strong ferricyanide
      reductase activity. We further demonstrate a weak but specific reductive activity
      on azo dyes and nitrocompounds.

PMID- 15184375
TI  - Cysteine oxidation of tau and microtubule-associated protein-2 by peroxynitrite:
      modulation of microtubule assembly kinetics by the thioredoxin reductase system.
AB  - Alterations in the redox status of proteins have been implicated in the pathology
      of several neurodegenerative conditions including Alzheimer and Parkinson
      diseases. We report that peroxynitrite- and hydrogen peroxide-induced disulfides
      in the neuron-specific microtubule-associated proteins tau and microtubule
      associated protein-2 are substrates for the ubiquitous thioredoxin reductase
      system composed of thioredoxin reductase, human or Escherichia coli thioredoxin,
      and NADPH. Tau and microtubule-associated protein-2 cysteine oxidation and
      reduction were quantitated by monitoring the incorporation of 5
      iodoacetamidofluorescein, a thiol-specific labeling reagent. Cysteine oxidation
      of tau and microtubule-associated protein-2 to disulfides altered the ability of
      the proteins to promote the assembly of microtubules from purified porcine
      tubulin. Treatment of tau and microtubule-associated protein-2 with either the
      thioredoxin reductase system or small molecule reductants fully restores the
      ability of the MAPs to promote microtubule assembly. Thus changes in the redox
      state of microtubule-associated proteins may regulate microtubule polymerization
      in vivo.

PMID- 15184376
TI  - Ultraviolet light activates NFkappaB through translational inhibition of
      IkappaBalpha synthesis.
AB  - UV light induces a delayed and prolonged (3-20 h) activation of NFkappaB when
      compared with the immediate and acute (10-90 min) activation of NFkappaB in
      response to tumor necrosis factor alpha treatment. In the early phase (3-12 h) of
      NFkappaB activation, UV light reduces inhibitor of NFkappaB (IkappaB) through an
      IkappaB kinase-independent, but polyubiquitin-dependent, pathway. However, the
      mechanism for the UV light-induced reduction of IkappaB and activation of
      NFkappaB is not known. In this report, we show that UV light down-regulates the
      total amount of IkappaB through decreasing IkappaB mRNA translation. Our data
      show that UV light inhibits translation of IkappaB in wild-type mouse embryo
      fibroblasts (MEF(S/S)) and that this inhibition is prevented in MEF(A/A) cells in
      which the phosphorylation site, Ser-51 in the eukaryotic translation initiation
      factor 2 alpha-subunit, is replaced with a non-phosphorylatable Ala (S51A). Our
      data also show that UV light-induced NFkappaB activation is delayed in MEF(A/A)
      cells and in an MCF-7 cell line that is stably transfected with a trans-dominant
      negative mutant protein kinase-like endoplasmic reticulum kinase (PERK). These
      results suggest that UV light-induced eukaryotic translation initiation factor 2
      alpha-subunit phosphorylation translationally inhibits new IkappaB synthesis.
      Without a continuous supply of newly synthesized IkappaB, the existing IkappaB is
      degraded through a polyubiquitin-dependent proteasomal pathway leading to
      NFkappaB activation. Based upon our results, we propose a novel mechanism by
      which UV light regulates early phase NFkappaB activation by means of an ER-stress
      induced translational inhibition pathway.

PMID- 15184377
TI  - Overactive bladder and incontinence in the absence of the BK large conductance
      Ca2+-activated K+ channel.
AB  - BK large conductance voltage- and calcium-activated potassium channels respond to
      elevations in intracellular calcium and membrane potential depolarization,
      braking excitability of smooth muscle. BK channels are thought to have a
      particularly prominent role in urinary bladder smooth muscle function and
      therefore are candidate targets for overactive bladder therapy. To address the
      role of the BK channel in urinary bladder function, the gene mSlo1 for the pore
      forming subunit of the BK channel was deleted. Slo(-/-) mice were viable but
      exhibited moderate ataxia. Urinary bladder smooth muscle cells of Slo(-/-) mice
      lacked calcium- and voltage-activated BK currents, whereas local calcium
      transients ("calcium sparks") and voltage-dependent potassium currents were
      unaffected. In the absence of BK channels, urinary bladder spontaneous and nerve
      evoked contractions were greatly enhanced. Consistent with increased urinary
      bladder contractility caused by the absence of BK currents, Slo(-/-) mice
      demonstrate a marked elevation in urination frequency. These results reveal a
      central role for BK channels in urinary bladder function and indicate that BK
      channel dysfunction leads to overactive bladder and urinary incontinence.

PMID- 15184378
TI  - Activation of protein kinase C epsilon inhibits the two-pore domain K+ channel,
      TASK-1, inducing repolarization abnormalities in cardiac ventricular myocytes.
AB  - Activation of the platelet-activating factor (PAF) receptor leads to a decrease
      in outward current in murine ventricular myocytes by inhibiting the TASK-1
      channel. TASK-1 carries a background or "leak" current and is a member of the two
      pore domain potassium channel family. Its inhibition is sufficient to delay
      repolarization, causing prolongation of the action potential duration, and in
      some cases, early after depolarizations. We set out to determine the cellular
      mechanisms that control regulation of TASK-1 by PAF. Inhibition of TASK-1 via
      activation of the PAF receptor is protein kinase C (PKC)-dependent. Using isoform
      specific PKC inhibitor or activator peptides in patch clamp experiments, we now
      demonstrate that activation of PKCepsilon is both necessary and sufficient to
      regulate murine TASK-1 current in a heterologous expression system and to induce
      repolarization abnormalities in isolated myocytes. Furthermore, site-directed
      mutagenesis studies have identified threonine 381, in the C-terminal tail of
      murine TASK-1, as a critical residue in this regulation.

PMID- 15184379
TI  - Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase.
AB  - The breast and ovarian tumor suppressor BRCA1 forms a heterodimeric RING-type
      ubiquitin ligase with BARD1 to catalyze untraditional Lys-6-linked polyubiquitin
      chains. It is not clear how the BRCA1-BARD1 ligase regulates various cellular
      processes such as DNA repair, cell-cycle progression, transcriptional regulation,
      and centrosome duplication. Here we report that BRCA1-BARD1 catalyzes the
      polyubiquitination of nucleolar phosphoprotein nucleophosmin/B23 (NPM). Two
      different mass spectrometry screens for protein ubiquitinated by BRCA1-BARD1 both
      identified NPM. NPM interacts with N-terminal fragments of BRCA1 and BARD1 in a
      manner dependent upon BRCA1-BARD1 heterodimer formation. NPM colocalizes with
      BRCA1 and BARD1 in mitotic cells suggesting the possibility of NPM regulation by
      BRCA1-BARD1 during mitosis. BRCA1-BARD1 catalyzes the ubiquitination of NPM in
      vitro and in vivo, and BRCA1-BARD1 co-expression in cells causes NPM
      stabilization rather than degradation. This is consistent with the notion that
      this ligase catalyzes untraditional polyubiquitin chains. Given the many
      overlapped functions between NPM and BRCA1, we propose that NPM is a strong
      candidate as a substrate of the BRCA1-BARD1 ubiquitin ligase.

PMID- 15184380
TI  - Hypophosphorylated ASF/SF2 binds TAP and is present in messenger
      ribonucleoproteins.
AB  - Serine/arginine-rich proteins (SR proteins) function in precursor mRNA (pre-mRNA)
      splicing and may also act as adaptors for mRNA export. SR proteins are
      dynamically phosphorylated in their RS domain, and differential phosphorylation
      modulates their splicing activity and subcellular localization. In this study, we
      investigated the influence of phosphorylation on the function of SR proteins in
      events occurring during mRNA maturation. Immunoprecipitation experiments showed
      that the mRNA export receptor TAP associates preferentially with the
      hypophosphorylated form of shuttling SR proteins, including ASF/SF2.
      Overexpression of ASF induced subnuclear relocalization of TAP to SR protein
      enriched nuclear speckles, suggesting their interaction in vivo. Moreover, the
      ASF found in a nucleoplasmic fraction rich in heterogeneous nuclear
      ribonucleoprotein (hnRNP) complexes is hyperphosphorylated, whereas mature
      messenger RNP (mRNP)-bound ASF is hypophosphorylated. Therefore,
      hypophosphorylation of ASF in mRNPs coincides with its higher affinity for TAP,
      suggesting that dephosphorylation of ASF promotes both its incorporation into
      mRNPs and recruitment of TAP for mRNA export. Thus, the phosphorylation state of
      RS domains may modulate the function of mammalian shuttling SR proteins during
      mRNA maturation or export.

PMID- 15184381
TI  - Cysteine protease cathepsin F is expressed in human atherosclerotic lesions, is
      secreted by cultured macrophages, and modifies low density lipoprotein particles
      in vitro.
AB  - During atherogenesis, low density lipoprotein (LDL) particles in the arterial
      intima become modified and fuse to form extracellular lipid droplets. Proteolytic
      modification of apolipoprotein (apo) B-100 may be one mechanism of droplet
      formation from LDL. Here we studied whether the newly described acid protease
      cathepsin F can generate LDL-derived lipid droplets in vitro. Treatment of LDL
      particles with human recombinant cathepsin F led to extensive degradation of apoB
      100, which, as determined by rate zonal flotation, electron microscopy, and NMR
      spectroscopy, triggered both aggregation and fusion of the LDL particles. Two
      other acid cysteine proteases, cathepsins S and K, which have been shown to be
      present in the arterial intima, were also capable of degrading apoB-100, albeit
      less efficiently. Cathepsin F treatment resulted also in enhanced retention of
      LDL to human arterial proteoglycans in vitro. Cultured monocyte-derived
      macrophages were found to secrete active cathepsin F. In addition, similarly with
      cathepsins S and K, cathepsin F was found to be localized mainly within the
      macrophage-rich areas of the human coronary atherosclerotic plaques. These
      results suggest that proteolytic modification of LDL by cathepsin F may be one
      mechanism leading to the extracellular accumulation of LDL-derived lipid droplets
      within the proteoglycan-rich extracellular matrix of the arterial intima during
      atherogenesis.

PMID- 15184382
TI  - Necessity of oligonucleotide aggregation for toll-like receptor 9 activation.
AB  - Toll-like receptor 9 (TLR9), a member of the interleukin-1 (IL-1) family of
      pathogen-associated molecular pattern receptors, is activated by unmethylated CpG
      containing sequences in bacterial DNA or synthetic oligonucleotides (ODNs) in the
      endosomal compartment. The stimulation of an IL-1 response is thought to require
      the aggregation of its receptor. By analogy, we postulated that the potency of a
      TLR9 ligand should depend first on its ability to enter cells and gain access to
      TLR9 and second on its capacity to form a multimeric complex capable of cross
      linking these receptors. Previously, we selected from a random library a series
      of phosphodiester ODNs with enhanced ability to permeate cells. Here, we studied
      the structural requirements for these penetrating ODNs to elicit a functional
      TLR9 response, as assessed by cytokine production from bone marrow-derived mouse
      mononuclear cells. The presence of a prototypic murine immunostimulatory DNA
      hexameric sequence (purine-purine-CG-pyrimidine-pyrimidine) in the ODNs was not
      sufficient for stimulation. In addition, the TLR9-activating ODNs had to have the
      ability to form aggregates and often to form secondary structures near the core
      CpG motifs. Multimerization was promoted by the presence of a guanine-rich 3'
      terminus. The phosphodiester ODNs with CpG motifs that did not aggregate
      antagonized the effects of the multimeric TLR9 activators. These findings suggest
      that an optimal TLR9 agonist needs to contain a spatially distinct
      multimerization domain and a receptor binding CpG domain. This concept may prove
      useful for the design of new TLR9-modulating agents.

PMID- 15184383
TI  - Tec kinases mediate sustained calcium influx via site-specific tyrosine
      phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker.
AB  - Tyrosine phosphorylation of phospholipase Cgamma2 (PLCgamma2) is a crucial
      activation switch that initiates and maintains intracellular calcium mobilization
      in response to B cell antigen receptor (BCR) engagement. Although members from
      three distinct families of non-receptor tyrosine kinases can phosphorylate
      PLCgamma in vitro, the specific kinase(s) controlling BCR-dependent PLCgamma
      activation in vivo remains unknown. Bruton's tyrosine kinase (Btk)-deficient
      human B cells exhibit diminished inositol 1,4,5-trisphosphate production and
      calcium signaling despite a normal inducible level of total PLCgamma2 tyrosine
      phosphorylation. This suggested that Btk might modify a critical subset of
      residues essential for PLCgamma2 activity. To evaluate this hypothesis, we
      generated site-specific phosphotyrosine antibodies recognizing four putative
      regulatory residues within PLCgamma2. Whereas all four sites were rapidly
      modified in response to BCR engagement in normal B cells, Btk-deficient B cells
      exhibited a marked reduction in phosphorylation of the Src homology 2 (SH2)-SH3
      linker region sites, Tyr(753) and Tyr(759). Phosphorylation of both sites was
      restored by expression of Tec, but not Syk, family kinases. In contrast,
      phosphorylation of the PLCgamma2 carboxyl-terminal sites, Tyr(1197) and
      Tyr(1217), was unaffected by the absence of functional Btk. Together, these data
      support a model whereby Btk/Tec kinases control sustained calcium signaling via
      site-specific phosphorylation of key residues within the PLCgamma2 SH2-SH3
      linker.

PMID- 15184384
TI  - The novel gene fad158, having a transmembrane domain and leucine-rich repeat,
      stimulates adipocyte differentiation.
AB  - Adipocyte differentiation is known to be regulated by a complex array of genes
      known as master regulators. Using a subtraction method, we previously isolated
      102 genes that are expressed in the early stage of adipocyte differentiation. One
      of these genes named fad158 (factor for adipocyte differentiation 158) seems to
      be a novel gene, since there is no significantly similar gene listed in
      databases. Both mouse and human fad158 encode 803 amino acids and contain 4
      transmembrane regions and 8 leucine-rich repeat motifs. Expression of fad158 was
      induced at an early stage in differentiating 3T3-L1 cells and was observed in the
      skeletal muscle. When the expression was knocked down with an antisense method in
      3T3-L1 cells, the accumulation of oil droplets was reduced. Moreover, on
      overexpression of fad158 in NIH-3T3 cells, which are fibroblasts and do not
      usually differentiate into adipocytes, stable transformants accumulated oil
      droplets and showed an elevated expression of adipocyte marker genes, indicating
      that these cells had differentiated into mature adipocytes. fad158 has the
      ability to regulate adipocyte differentiation positively, especially at an early
      stage.

PMID- 15184385
TI  - Identification of prodomain determinants involved in ADAMTS-1 biosynthesis.
AB  - The metalloprotease ADAMTS-1 (a disintegrin and metalloprotease with
      thrombospondin type I motif), similarly to other members of the ADAMTS family, is
      initially synthesized as a zymogen, proADAMTS-1, that undergoes proteolytic
      processing at the prodomain/catalytic domain junction by serine proteinases of
      the furin-like family of proprotein convertases. The goals of this study were to
      identify residues of the prodomain that play an essential role in ADAMTS-1
      processing and to determine the identity of the convertase required for zymogen
      processing. To gain insight into the putative roles of specific prodomain
      residues in ADAMTS-1 biosynthesis, we performed biosynthetic labeling experiments
      in transiently transfected human embryonic kidney 293 cells expressing wild-type
      and prodomain mutants of proADAMTS-1. Cells expressing wild-type ADAMTS-1
      initially produced a 110-kDa zymogen form that was later converted to an 87-kDa
      form, which was also detected in the media. Although convertases such as PACE4
      and PC6B processed proADAMTS-1, we found that furin was the most efficient enzyme
      at producing the mature ADAMTS-1 87-kDa moiety. Site-directed mutagenesis of the
      two putative furin recognition sequences found within the ADAMTS-1 prodomain
      (RRNR173 and RKKR235) revealed that Arg235 was the sole processing site. Use of
      the Golgi disturbing agent, Brefeldin A, and monensin suggests that the cleavage
      of proADAMTS-1 takes place in the Golgi apparatus prior to its secretion.
      Conserved residues within the prodomain of other ADAMTS members hinted that they
      might act as maturation determinants. Replacement with alanine of selected
      residues Cys106, Tyr108, Gly110, Cys125, and Cys181 and residues encompassing the
      137-144 sequence significantly affected the biosynthetic profile of the enzyme.
      Our results suggest that conserved residues other than the furin cleavage site in
      the prodomain of ADAMTS-1 are involved in its biosynthesis.

PMID- 15184386
TI  - Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice.
AB  - Members of the Foxo family, Foxo1 (Fkhr), Foxo3 (Fkhrl1), and Foxo4 (Afx), are
      mammalian homologs of daf-16, which influences life span and energy metabolism in
      Caenorhabditis elegans. Mammalian FOXO proteins also play important roles in cell
      cycle arrest, apoptosis, stress resistance, and energy metabolism. In this study,
      we generated Foxo1-deficient mice to investigate the physiological role of FOXO1.
      The Foxo1-deficient mice died around embryonic day 11 because of defects in the
      branchial arches and remarkably impaired vascular development of embryos and yolk
      sacs. In vitro differentiation of embryonic stem cells demonstrated that
      endothelial cells derived from wild-type and Foxo1-deficient embryonic stem cells
      were able to produce comparable numbers of colonies supported by a layer of OP9
      stromal cells. Although the morphology of the endothelial cell colonies was
      identical in both genotypes in the absence of exogenous vascular endothelial
      growth factor (VEGF), Foxo1-deficient endothelial cells showed a markedly
      different morphological response compared with wild-type endothelial cells in the
      presence of exogenous VEGF. These results suggest that Foxo1 is essential to the
      ability of endothelial cells to respond properly to a high dose of VEGF, thereby
      playing a critical role in normal vascular development.

PMID- 15184387
TI  - Effects of RNA interference-mediated silencing of gamma-secretase complex
      components on cell sensitivity to caspase-3 activation.
AB  - Familial Alzheimer's disease mutations in the presenilin 1 gene (PSEN1) have been
      previously shown to potentiate caspase activation and apoptosis in transfected
      cells and transgenic mice. However, the mechanism underlying this effect is not
      known. We set out to determine whether cellular sensitivity to caspase activation
      could be affected by modulating presenilin 1 (PS1) processing. PS1 processing was
      altered using RNA interference (RNAi) aimed at silencing the expression of the
      genes encoding the four components of the gamma-secretase complex, PSEN1, APH-1,
      PEN-2, and nicastrin. RNAi for these genes was carried out in naive H4 human
      neuroglioma cells, as well as H4 cell lines overexpressing either wild-type PSEN1
      or the Familial Alzheimer's disease mutant PSEN1-Delta9 (PS1-mutant), that were
      induced to undergo apoptosis. In wild-type PSEN1 cells, RNAi for PEN-2, as
      expected, increased levels of full-length PS1 (PS1-FL) and decreased PS1
      endoproteolysis. This was accompanied by potentiated caspase-3 activation in
      response to an apoptotic stimulus. In contrast, nicastrin RNAi, which only
      decreased levels of PS1-amino-terminal fragment and did not affect PS1-FL levels,
      had no effect on caspase-3 activation during apoptosis. Surprisingly, in the PS1
      mutant cells, RNAi for PEN-2 (and APH-1) did not increase but instead reduced the
      levels of PS1-FL deleted for exon 9. In turn, this was accompanied by attenuated
      caspase-3 activation in response to an apoptotic stimulus. Finally, in naive H4
      cells, PSEN1 RNAi also attenuated caspase-3 activation in response to an
      apoptotic stimulus. Collectively, these findings indicate that cellular
      sensitivity to caspase activation correlates with overall PS1 protein levels,
      particularly with levels of FL-PS1.

PMID- 15184388
TI  - Glucose up-regulates thrombospondin 1 gene transcription and transforming growth
      factor-beta activity through antagonism of cGMP-dependent protein kinase
      repression via upstream stimulatory factor 2.
AB  - Thrombospondin 1 (TSP1) transcription is stimulated by glucose, resulting in
      increased TGF-beta activation and matrix protein synthesis. We previously showed
      that inducible expression of the catalytic domain of cGMP-dependent protein
      kinase (PKG) inhibits glucose-regulated TSP1 transcription and transforming
      growth factor (TGF)-beta activity in stably transfected rat mesangial cells
      (RMCs(tr/cd)). However, the molecular mechanisms by which PKG represses glucose
      regulated TSP1 transcription are unknown. Using a luciferase-promoter deletion
      assay, we now identify a single region of the human TSP1 promoter (-1172 to -878,
      relative to the transcription start site) that is responsive to glucose. Further
      characterization of this region identified an 18-bp sequence that specifically
      binds nuclear proteins from mesangial cells. Moreover, binding is significantly
      enhanced by high glucose treatment and is reduced by increased PKG activity. Gel
      mobility shift and supershift assays show that the nuclear proteins binding to
      the 18-bp sequence are USF1 and -2. USF1 and USF2 bound to the endogenous TSP1
      promoter using a chromatin immunoprecipitation assay. Glucose stimulates nuclear
      USF2 protein accumulation through protein kinase C, p38 MAPK, and extracellular
      signal-regulated kinase pathways. Increased PKG activity down-regulates USF2
      protein levels and its DNA binding activity under high glucose conditions,
      resulting in inhibition of glucose-induced TSP1 transcription and TGF-beta
      activity. Overexpression of USF2 reversed the inhibitory effect of PKG on glucose
      induced TSP1 gene transcription and TGF-beta activity. Taken together these data
      present the first evidence that USF2 mediates glucose-induced TSP1 expression and
      TSP1-dependent TGF-beta bioactivity in mesangial cells, suggesting that USF2 is
      an important transcriptional regulator of diabetic complications.

PMID- 15184389
TI  - Group I metabotropic glutamate receptors mediate a dual role of glutamate in T
      cell activation.
AB  - Metabotropic glutamate receptors (mGluR) are present in cells of the nervous
      system, where they are activated by one of the main neurotransmitters, glutamate.
      They are also expressed in cells outside the nervous system. We identified and
      characterized two receptors belonging to group I mGluR, mGlu1R and mGlu5R, in
      human cell lines of lymphoid origin and in resting and activated lymphocytes from
      human peripheral blood. Both are highly expressed in the human Jurkat T cell
      line, whereas mGlu5R is expressed only in the human B cell line SKW6.4. In blood
      lymphocytes, mGlu5R is expressed constitutively, whereas mGlu1R is expressed only
      upon activation via the T cell receptor-CD3 complex. Group I receptors in the
      central nervous system are coupled to phospholipase C, whereas in blood
      lymphocytes, activation of mGlu5R does not trigger this signaling pathway, but
      instead activates adenylate cyclase. On the other hand, mGlu5R does not mediate
      ERK1/2 activation, whereas mGlu1R, which is coupled neither to phospholipase C
      nor to calcium channels and whose activation does not increase cAMP, activates
      the mitogen-activated protein kinase cascade. The differential expression of
      mGluR in resting and activated lymphocytes and the different signaling pathways
      that are triggered when mGlu1Rs or mGlu5Rs are activated point to a key role of
      glutamate in the regulation of T cell physiological function. The study of the
      signaling pathways (cAMP production and ERK1/2 phosphorylation) and the
      proliferative response obtained in the presence of glutamate analogs suggests
      that mGlu1R and mGlu5R have distinct functions. mGlu5R mediates the reported
      inhibition of cell proliferation evoked by glutamate, which is reverted by the
      activation of inducible mGlu1R. This is a novel non-inhibitory action mechanism
      for glutamate in lymphocyte activation. mGlu1R and mGlu5R thus mediate opposite
      glutamate effects in human lymphocytes.

PMID- 15184390
TI  - Physical and functional interaction of CARMA1 and CARMA3 with Ikappa kinase gamma
      NFkappaB essential modulator.
AB  - CARMA proteins are scaffold molecules that contain a caspase recruitment domain
      and a membrane-associated guanylate kinase-like domain. CARMA1 plays a critical
      role in mediating activation of the NFkappaB transcription factor following
      antigen receptor stimulation of both B and T lymphocytes. However, the
      biochemical mechanism by which CARMA1 regulates activation of NFkappaB remains to
      be determined. Here we have shown that CARMA1 and CARMA3 physically associate
      with Ikappa kinase gamma/NFkappaB essential modulator (IkappaKgamma-NEMO) in
      lymphoid and non-lymphoid cells. CARMA1 participates to an inducible large
      molecular complex that contains IkappaKgamma/NEMO, Bcl10, and IkappaKalpha/beta
      kinases. Expression of the NEMO-binding region of CARMA3 exerts a dominant
      negative effect on Bcl10-mediated activation of NFkappaB. Thus, our results
      provide direct evidence for physical and functional interaction between CARMA and
      the IkappaK complex and offer a biochemical framework to understand the molecular
      activities controlled by CARMA-1, -2, and -3 and Bcl10.

PMID- 15184391
TI  - Extracellular signal-regulated kinase activated by epidermal growth factor and
      cell adhesion interacts with and phosphorylates vinexin.
AB  - Extracellular signal-regulated kinase 1/2 (ERK1/2) is activated by various
      extracellular stimuli including growth factors and cytokines and plays a pivotal
      role in regulating cell proliferation and differentiation by phosphorylating
      nuclear transcription factors. Recently, it was reported that activated ERK1/2
      also concentrates at adhesion sites and regulates cell spreading and migration.
      Vinexin is a focal adhesion protein regulating both cell spreading and growth
      factor signaling. We show here that vinexin was directly phosphorylated by ERK1/2
      upon stimulation with growth factors. ERK1/2 phosphorylated the linker region of
      vinexin between the second and third SH3 domains. Site-directed mutagenesis
      revealed that ERK2 mainly phosphorylated the serine 189 residue of vinexin beta.
      Furthermore, vinexin beta interacted with ERK1/2 both in vitro and in vivo.
      Vinexin interacted with the active but not inactive form of ERK1/2. A putative
      DEF (docking for ERK FXFP) domain located in the linker region of vinexin was
      required for the interaction with ERK1/2 and efficient phosphorylation of vinexin
      beta by ERK2. Finally, we showed that cell adhesion to fibronectin also induced
      the association of vinexin beta with ERK2 and the phosphorylation of vinexin
      beta. Furthermore, vinexin and ERK were co-localized to the periphery of cells
      during cell spreading on fibronectin. Together, these results suggest that
      vinexin is a novel substrate of ERK2 and may play roles in ERK-dependent cell
      regulation during cell spreading as well as in growth factor-induced responses.

PMID- 15184392
TI  - Glutathione regulates telomerase activity in 3T3 fibroblasts.
AB  - Changes in telomerase activity have been associated either with cancer, when
      activity is increased, or with cell cycle arrest when it is decreased. We report
      that glutathione, a physiological antioxidant present at high intracellular
      concentrations, regulates telomerase activity in cells in culture. Telomerase
      activity increases in 3T3 fibroblasts before exponential cell growth. The peak of
      telomerase activity takes place 24 h after plating and coincides with the maximum
      levels of glutathione in the cells. When cells are treated with buthionine
      sulfoximine, which decreases glutathione levels in cells, telomerase activity
      decreases by 60%, and cell growth is delayed. Glutathione depletion inhibits
      expression of E2F4 and Id2, which regulate the cell cycle. When glutathione
      levels are restored after incubation with glutathione monoethylester, telomerase
      activity and the cell cycle-related proteins return to control values. To
      discover the effect of glutathione redox status on the telomerase multicomplex
      structure, we incubated protein extracts from fibroblasts with different
      glutathione redox buffers. Telomerase activity is maximal under reduced
      conditions i.e. when the reduced/oxidized glutathione ratio is high. Consequently
      glutathione concentration parallels telomerase activity. These results underscore
      the main role of glutathione in the control of telomerase activity and of the
      cell cycle.

PMID- 15184393
TI  - CLIC-5A functions as a chloride channel in vitro and associates with the cortical
      actin cytoskeleton in vitro and in vivo.
AB  - CLIC-5A is a member of the chloride intracellular channel protein family, which
      is comprised of six related human genes encoding putative chloride channels. In
      this study, we found that reconstitution of purified recombinant CLIC-5A into
      artificial liposomes resulted in a dose-dependent chloride efflux that was
      sensitive to the chloride channel blocker IAA-94. CLIC-5A was originally isolated
      as a component of an ezrin-containing cytoskeletal complex from human placental
      microvilli. Here we show that similar protein complexes can be isolated using
      either immobilized CLIC-5A or the C-terminal F-actin-binding domain of ezrin and
      that actin polymerization is required for de novo assembly of these complexes. To
      investigate the behavior of CLIC-5A in vivo, JEG-3 placental choriocarcinoma
      cells were stably transfected with epitope-tagged CLIC-5A. In fixed cells, CLIC
      5A displayed a polarized distribution and colocalized with ezrin in apical
      microvilli. Microvillar localization of CLIC-5A was retained after Triton X-100
      extraction and was disrupted by treatment with latrunculin B. In transient
      transfections assays, we mapped a region between residues 20 and 54 of CLIC-5A
      that is required for targeting of CLIC-5A to microvilli in JEG-3 cells.
      Interestingly, expression of CLIC-5A in JEG-3 cells did not enhance the rate of
      iodide efflux in intact cells, suggesting that if CLIC-5A is a chloride channel,
      its channel activity may be restricted to intracellular membrane compartments in
      these cells. Regardless of its role in ion transport, CLIC-5A, like ezrin, may
      play an important role in the assembly or maintenance of F-actin-based structures
      at the cell cortex.

PMID- 15184394
TI  - Bimodal effect of advanced glycation end products on mesangial cell proliferation
      is mediated by neutral ceramidase regulation and endogenous sphingolipids.
AB  - Advanced glycation end-products (AGE) are generated by chronic hyperglycaemia and
      may cause diabetic microvascular complications such as diabetic nephropathy. Many
      factors influence the development of diabetic nephropathy; however, dysregulation
      of mesangial cell (MC) proliferation appears to play an early and crucial role.
      In this study, we investigated the effects of AGE on rat MC proliferation and the
      involvement of sphingolipids in the AGE response. Results show a bimodal effect
      of AGE on MC proliferation. Thus, low AGE concentrations (<1 microm) induced a
      significant increase (+26%) of MC proliferation, whereas higher concentrations
      (10 microm) markedly reduced it (-24%). In parallel, AGE exerted biphasic effects
      on neutral ceramidase expression and activity. Low AGE concentrations increased
      neutral ceramidase activity and expression, whereas high AGE concentrations
      showed opposite effects. Surprisingly, neutral ceramidase modulation did not
      result in changes of ceramide levels. However, the AGE (10 microm)-inhibitory
      effect on MC proliferation was associated with accumulation of sphingosine and
      was specifically prevented by blocking glucosylceramide synthesis, suggesting
      that the high AGE concentration effects are mediated by sphingosine and/or
      glycolipids. On the other hand, treatment of cells with low AGE concentrations
      led to an increase of sphingosine kinase activity and sphingosine-1-phosphate
      production that drove the increase of MC proliferation. Interestingly, in
      glomeruli isolated from streptozotocin-diabetic rats, a time-dependent modulation
      of ceramidase activity was observed as compared with controls. These results
      suggest that AGE regulate MC growth by modulating neutral ceramidase and
      endogenous sphingolipids.

PMID- 15184395
TI  - Stretch of the vascular wall induces smooth muscle differentiation by promoting
      actin polymerization.
AB  - Stretch of the vascular wall by the intraluminal blood pressure stimulates
      protein synthesis and contributes to the maintenance of the smooth muscle
      contractile phenotype. The expression of most smooth muscle specific genes has
      been shown to be regulated by serum response factor and stimulated by increased
      actin polymerization. Hence we hypothesized that stretch-induced differentiation
      is promoted by actin polymerization. Intact mouse portal veins were cultured
      under longitudinal stress and compared with unstretched controls. In unstretched
      veins the rates of synthesis of several proteins associated with the
      contractile/cytoskeletal system (alpha-actin, calponin, SM22alpha, tropomyosin,
      and desmin) were dramatically lower than in stretched veins, whereas other
      proteins (beta-actin and heat shock proteins) were synthesized at similar rates.
      The cytoskeletal proteins gamma-actin and vimentin were weakly stretch-sensitive.
      Inhibition of Rho-associated kinase by culture of stretched veins with Y-27632
      produced similar but weaker effects compared with the absence of mechanical
      stress. Induction of actin polymerization by jasplakinolide increased SM22alpha
      synthesis in unstretched veins to the level in stretched veins. Stretch
      stimulated Rho activity and phosphorylation of the actin-severing protein cofilin
      2, although both effects were slow in onset (Rho-GTP, >15 min; cofilin-P, >1 h).
      Cofilin-2 phosphorylation of stretched veins was inhibited by Y-27632. The F/G
      actin ratio after 24 h of culture was significantly greater in stretched than in
      unstretched veins, as shown by both ultracentrifugation and confocal imaging with
      phalloidin/DNase I labeling. The results show that stretch of the vascular wall
      stimulates increased actin polymerization, activating synthesis of smooth muscle
      specific proteins. The effect is partially, but probably not completely, mediated
      via Rho-associated kinase and cofilin downstream of Rho.

PMID- 15184396
TI  - Triggering p53 after cytokinesis failure.
AB  - Cells that fail to divide during cytokinesis often arrest in the next G1 phase by
      a mysterious mechanism that depends upon p53. What triggers this arrest is
      unclear. New studies, including a report in this issue (Uetake and Sluder, 2004)
      suggest that this arrest does not occur because cells are polyploid, are
      binucleate, have multiple centrosome, or have failed cytokinesis, making this
      phenomenon even more puzzling.

PMID- 15184397
TI  - Cell cycle progression after cleavage failure: mammalian somatic cells do not
      possess a "tetraploidy checkpoint".
AB  - Failure of cells to cleave at the end of mitosis is dangerous to the organism
      because it immediately produces tetraploidy and centrosome amplification, which
      is thought to produce genetic imbalances. Using normal human and rat cells, we
      reexamined the basis for the attractive and increasingly accepted proposal that
      normal mammalian cells have a "tetraploidy checkpoint" that arrests binucleate
      cells in G1, thereby preventing their propagation. Using 10 microM cytochalasin
      to block cleavage, we confirm that most binucleate cells arrest in G1. However,
      when we use lower concentrations of cytochalasin, we find that binucleate cells
      undergo DNA synthesis and later proceed through mitosis in >80% of the cases for
      the hTERT-RPE1 human cell line, primary human fibroblasts, and the REF52 cell
      line. These observations provide a functional demonstration that the tetraploidy
      checkpoint does not exist in normal mammalian somatic cells.

PMID- 15184398
TI  - Cellular stresses induce the nuclear accumulation of importin alpha and cause a
      conventional nuclear import block.
AB  - We report here that importin alpha accumulates reversibly in the nucleus in
      response to cellular stresses including UV irradiation, oxidative stress, and
      heat shock. The nuclear accumulation of importin alpha appears to be triggered by
      a collapse in the Ran gradient, resulting in the suppression of the nuclear
      export of importin alpha. In addition, nuclear retention and the importin
      beta/Ran-independent import of importin alpha also facilitate its rapid nuclear
      accumulation. The findings herein show that the classical nuclear import pathway
      is down-regulated via the removal of importin alpha from the cytoplasm in
      response to stress. Moreover, whereas the nuclear accumulation of heat shock
      cognate 70 is more sensitive to heat shock than the other stresses, importin
      alpha is able to accumulate in the nucleus at all the stress conditions tested.
      These findings suggest that the stress-induced nuclear accumulation of importin
      alpha can be involved in a common physiological response to various stress
      conditions.

PMID- 15184399
TI  - Extracellular matrix mineralization is regulated locally; different roles of two
      gla-containing proteins.
AB  - Extracellular matrix mineralization (ECMM) is a physiologic process in the
      skeleton and in teeth and a pathologic one in other organs. The molecular
      mechanisms controlling ECMM are poorly understood. Inactivation of Matrix gla
      protein (Mgp) revealed that MGP is an inhibitor of ECMM. The fact that MGP is
      present in the general circulation raises the question of whether ECMM is
      regulated locally and/or systemically. Here, we show that restoration of Mgp
      expression in arteries rescues the arterial mineralization phenotype of Mgp-/-
      mice, whereas its expression in osteoblasts prevents bone mineralization. In
      contrast, raising the serum level of MGP does not affect mineralization of any
      ECM. In vivo mutagenesis experiments show that the anti-ECMM function of MGP
      requires four amino acids which are gamma-carboxylated (gla residues).
      Surprisingly, another gla protein specific to bone and teeth (osteocalcin) does
      not display the anti-ECMM function of MGP. These results indicate that ECMM is
      regulated locally in animals and uncover a striking disparity of function between
      proteins sharing identical structural motifs.

PMID- 15184400
TI  - The Drosophila pericentrin-like protein is essential for cilia/flagella function,
      but appears to be dispensable for mitosis.
AB  - Centrosomes consist of a pair of centrioles surrounded by an amorphous
      pericentriolar material (PCM). Proteins that contain a Pericentrin/AKAP450
      centrosomal targeting (PACT) domain have been implicated in recruiting several
      proteins to the PCM. We show that the only PACT domain protein in Drosophila (the
      Drosophila pericentrin-like protein [D-PLP]) is associated with both the
      centrioles and the PCM, and is essential for the efficient centrosomal
      recruitment of all six PCM components that we tested. Surprisingly, however, all
      six PCM components are eventually recruited to centrosomes during mitosis in d
      plp mutant cells, and mitosis is not dramatically perturbed. Although viable, d
      plp mutant flies are severely uncoordinated, a phenotype usually associated with
      defects in mechanosensory neuron function. We show that the sensory cilia of
      these neurons are malformed and the neurons are nonfunctional in d-plp mutants.
      Moreover, the flagella in mutant sperm are nonmotile. Thus, D-PLP is essential
      for the formation of functional cilia and flagella in flies.

PMID- 15184401
TI  - Myosin-II reorganization during mitosis is controlled temporally by its
      dephosphorylation and spatially by Mid1 in fission yeast.
AB  - Cytokinesis in many eukaryotes requires an actomyosin contractile ring. Here, we
      show that in fission yeast the myosin-II heavy chain Myo2 initially accumulates
      at the division site via its COOH-terminal 134 amino acids independently of F
      actin. The COOH-terminal region can access to the division site at early G2,
      whereas intact Myo2 does so at early mitosis. Ser1444 in the Myo2 COOH-terminal
      region is a phosphorylation site that is dephosphorylated during early mitosis.
      Myo2 S1444A prematurely accumulates at the future division site and promotes
      formation of an F-actin ring even during interphase. The accumulation of Myo2
      requires the anillin homologue Mid1 that functions in proper ring placement. Myo2
      interacts with Mid1 in cell lysates, and this interaction is inhibited by an
      S1444D mutation in Myo2. Our results suggest that dephosphorylation of Myo2
      liberates the COOH-terminal region from an intramolecular inhibition.
      Subsequently, dephosphorylated Myo2 is anchored by Mid1 at the medial cortex and
      promotes the ring assembly in cooperation with F-actin.

PMID- 15184402
TI  - Regulation of a formin complex by the microtubule plus end protein tea1p.
AB  - The plus ends of microtubules have been speculated to regulate the actin
      cytoskeleton for the proper positioning of sites of cell polarization and
      cytokinesis. In the fission yeast Schizosaccharomyces pombe, interphase
      microtubules and the kelch repeat protein tea1p regulate polarized cell growth.
      Here, we show that tea1p is directly deposited at cell tips by microtubule plus
      ends. Tea1p associates in large "polarisome" complexes with bud6p and for3p, a
      formin that assembles actin cables. Tea1p also interacts in a separate complex
      with the CLIP-170 protein tip1p, a microtubule plus end-binding protein that
      anchors tea1p to the microtubule plus end. Localization experiments suggest that
      tea1p and bud6p regulate formin distribution and actin cable assembly. Although
      single mutants still polarize, for3Deltabud6Deltatea1Delta triple-mutant cells
      lack polarity, indicating that these proteins contribute overlapping functions in
      cell polarization. Thus, these experiments begin to elucidate how microtubules
      contribute to the proper spatial regulation of actin assembly and polarized cell
      growth.

PMID- 15184405
TI  - Response of the clinical microbiology laboratory to emerging (new) and reemerging
      infectious diseases.

PMID- 15184404
TI  - American Society of Clinical Oncology recommendations for the initial hormonal
      management of androgen-sensitive metastatic, recurrent, or progressive prostate
      cancer.
AB  - PURPOSE: To develop a clinical practice guideline for the management of men with
      metastatic, recurrent, or progressive carcinoma of the prostate. The focus of
      this document is on the use, combinations, and timing of various forms of
      androgen deprivation therapy (ADT) for the palliation of men with androgen
      sensitive disease. METHODS: An expert panel and writing committee were formed.
      The questions to be addressed by the guideline were determined, and a systematic
      review of the literature was performed, which included a search of online
      databases, bibliographic review, and consultation with content experts. A priori
      criteria were used to select studies for analysis and study authors were
      contacted when necessary. RESULTS: There were 10 randomized controlled trials,
      six systematic reviews, and one Markov model available to inform the guidelines.
      CONCLUSION: A full discussion between practitioner and patient should occur to
      determine which therapy is best for the patient. Bilateral orchiectomy or
      luteinizing hormone releasing hormone agonists are the recommended initial
      treatments. Nonsteroidal antiandrogen therapy may be discussed as an alternative,
      but steroidal antiandrogens should not be offered as monotherapy. Patients
      willing to accept the increased toxicity of combined androgen blockage for a
      small benefit in survival should be offered nonsteroidal antiandrogen in addition
      to castrate therapy. Until data from studies using modern medical
      diagnostic/biochemical tests and standardized follow-up schedules become
      available, no specific recommendations can be issued regarding the question of
      early versus deferred ADT. A discussion about the pros and cons of early versus
      deferred ADT should occur.

PMID- 15184403
TI  - Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent
      TGF-beta binding protein-1.
AB  - Transforming growth factor-betas (TGF-beta) are secreted as inactive complexes
      containing the TGF-beta, the TGF-beta propeptide, also called the latency
      associated protein (LAP), and the latent TGF-beta binding protein (LTBP).
      Extracellular activation of this complex is a critical but incompletely
      understood step in TGF-beta regulation. We have investigated the role of LTBP in
      modulating TGF-beta generation by the integrin alphaVbeta6. We show that even
      though alphavbeta6 recognizes an RGD on LAP, LTBP-1 is required for alphaVbeta6
      mediated latent TGF-beta activation. The domains of LTBP-1 necessary for
      activation include the TGF-beta propeptide-binding domain and a basic amino acid
      sequence (hinge domain) with ECM targeting properties. Our results demonstrate an
      LTBP-1 isoform-specific function in alphaVbeta6-mediated latent TGF-beta
      activation; LTBP-3 is unable to substitute for LTBP-1 in this assay. The results
      reveal a functional role for LTBP-1 in latent TGF-beta activation and suggest
      that activation of specific latent complexes is regulated by distinct mechanisms
      that may be determined by the LTBP isoform and its potential interaction with the
      matrix.

PMID- 15184406
TI  - Nocardia arthritidis sp. nov., a new pathogen isolated from a patient with
      rheumatoid arthritis in Japan.
AB  - Two different bacterial strains with different drug susceptibilities were
      isolated from the sputum and an inflammatory discharge from a swelling in the
      left thigh of a patient with rheumatoid arthritis. Both bacterial strains were
      provisionally assigned to the genus Nocardia on the basis of their morphological
      and chemotaxonomic characteristics and were further studied in order to establish
      their taxonomic status. One strain (IFM 10034) was identified as Nocardia
      farcinica on the basis of its physiological characteristics. The other strain,
      which was designated Nocardia sp. strain IFM 10035(T), revealed a unique pattern
      of phenotypic properties that distinguished it from other representatives of
      established Nocardia species. Comparative 16S rRNA gene sequence studies of
      Nocardia sp. strain IFM 10035(T) also showed that the bacterium was closely
      related to the species Nocardia beijingensis. Determination of DNA-DNA
      relatedness, however, indicated that Nocardia sp. strain IFM 10035(T) could be
      delineated from N. beijingensis. The genotypic and phenotypic data combined
      indicated that the bacterium merits description as a new Nocardia species. The
      name proposed for the new species is Nocardia arthritidis sp. nov., the type
      strain being IFM 10035(T) (NBRC 100137(T), JCM 12120(T), DSM44731(T)). The
      present study suggests that Nocardia infections can be caused by multiple species
      of the bacterium.

PMID- 15184407
TI  - Implications of molecular genotyping of Helicobacter pylori isolates from
      different human populations by genomic fingerprinting of enterobacterial
      repetitive intergenic consensus regions for strain identification and geographic
      evolution.
AB  - Biogeographic partitioning of the genome is typical of the gastric pathogen
      Helicobacter pylori. Such population-specific evolution could serve as a model
      for understanding host-pathogen interaction and the impact of genetic drift and
      recombination on insular populations. With a total of 320 isolates from six
      geographic regions (Japan, India, England, Spain, Ireland, Africa, and Peru)
      analyzed by enterobacterial repetitive intergenic consensus (ERIC)-based
      genotyping, we examined genetic affinities among various H. pylori populations in
      the world. Several strain-specific and region-specific differences were observed
      by ERIC-based typing. Polymorphic ERIC patterns indicated that the ERIC sequences
      are in fact dispersed in the H. pylori chromosome at different locations
      separated by various distances. Phylogenetic analysis of 61 representative
      isolates revealed three distinct genetic clusters populated by isolates with
      shared ERIC types independent of the cag right-junction motif type and vacA
      allele status. Among the notable genetic relationships were the genotypic
      similarities between Irish and Japanese and between Peruvian and Japanese
      isolates. Insular genotypic characteristics of Irish isolates amid genetic
      similarity to East Asian, as well as North European, strains have been once again
      proved in this study. Peruvian genotypes were more similar to those of Japanese
      isolates than to those of Iberian or European isolates. Given the current debate
      on the origin and age of present-day H. pylori, this is a significant finding
      that supports the possibility of ancient colonization of Amerindians with East
      Asian strains. Genotypic data presented here will be additionally helpful in
      realizing the importance of H. pylori geographical genomics in the development of
      gastroduodenal pathology.

PMID- 15184408
TI  - Specific T-cell epitopes for immunoassay-based diagnosis of Mycobacterium
      tuberculosis infection.
AB  - The currently used method for immunological detection of tuberculosis infection,
      the tuberculin skin test, has low specificity. Antigens specific for
      Mycobacterium tuberculosis to replace purified protein derivative are therefore
      urgently needed. We have performed a rigorous assessment of the diagnostic
      potential of four recently identified antigens (Rv2653, Rv2654, Rv3873, and
      Rv3878) from genomic regions that are lacking from the Mycobacterium bovis
      bacillus Calmette-Guerin (BCG) vaccine strains as well as from the most common
      nontuberculous mycobacteria. The fine specificity of potential epitopes in these
      molecules was evaluated by sensitive testing of the T-cell responses of
      peripheral blood mononuclear cells derived from M. bovis BCG-vaccinated healthy
      individuals to synthesized overlapping peptides. Three of the four molecules
      contained regions with significant specificity problems (Rv2653, Rv3873, and
      Rv3878). We selected and combined the specific peptide stretches from the four
      proteins not recognized by M. bovis BCG-vaccinated individuals. These peptide
      stretches were tested with peripheral blood mononuclear cells obtained from
      patients with microscopy- or culture-confirmed tuberculosis and from healthy M.
      bovis BCG-vaccinated controls. The combination of the most promising stretches
      from this analysis showed a sensitivity level (57%) comparable to the level found
      with the two well-known M. tuberculosis-specific proteins ESAT-6 and CFP-10 (75
      and 66%, respectively). The combination of ESAT-6, CFP-10, and the novel specific
      peptide stretches gave an overall sensitivity of 84% at a specificity of 97%. In
      a validation experiment with new experimental groups, the sensitivities obtained
      were 57% for the combination of peptides and 90% for the combination of the
      peptides, ESAT-6, and CFP-10. This combination gave a specificity of 95%.

PMID- 15184409
TI  - Insertions, deletions, and single-nucleotide polymorphisms at rare restriction
      enzyme sites enhance discriminatory power of polymorphic amplified typing
      sequences, a novel strain typing system for Escherichia coli O157:H7.
AB  - Polymorphic amplified typing sequences (PATS) for Escherichia coli O157:H7 (O157)
      was previously based on indels containing XbaI restriction enzyme sites occurring
      in O-island sequences of the O157 genome. This strain-typing system, referred to
      as XbaI-based PATS, typed every O157 isolate tested in a reproducible, rapid,
      straightforward, and easy-to-interpret manner and had technical advantages over
      pulsed-field gel electrophoresis (PFGE). However, the system was less
      discriminatory than PFGE and was unable to differentiate fully between unrelated
      isolates. To overcome this drawback, we enhanced PATS by using another
      infrequently cutting restriction enzyme, AvrII (also known as BlnI), to identify
      additional polymorphic regions that could increase the discriminatory ability of
      PATS typing. Referred to as AvrII-based PATS, the system identified seven new
      polymorphic regions in the O157 genome. Unlike XbaI, polymorphisms involving
      AvrII sites were caused by both indels and single-nucleotide polymorphisms
      occurring in O-island and backbone sequences of the O157 genome. AvrII-based PATS
      by itself provided poor discrimination of the O157 isolates tested. However, when
      primer pairs amplifying the seven polymorphic AvrII sites were combined with
      those amplifying the eight polymorphic XbaI sites (combined PATS), the
      discriminatory power of PATS was enhanced. Combined PATS matched related O157
      isolates better than PFGE while differentiating between unrelated isolates. PATS
      typed every O157 isolate tested and directly targeted polymorphic sequences
      responsible for differences in the restriction digest patterns of O157 genomic
      DNA, utilizing PCR rather than relying on gel electrophoresis. This enabled PATS
      to resolve the ambiguity in PFGE typing, including that arising from the "more
      distantly related" and "untypeable" profiles.

PMID- 15184410
TI  - Relationship of MIC and bactericidal activity to efficacy of vancomycin for
      treatment of methicillin-resistant Staphylococcus aureus bacteremia.
AB  - We attempted to find a relationship between the microbiological properties of
      bloodstream isolates of methicillin-resistant Staphylococcus aureus (MRSA) and
      the efficacy of vancomycin in the treatment of bacteremia. Vancomycin
      susceptibility testing was performed, and bactericidal activity was determined
      for 30 isolates from 30 different patients with MRSA bacteremia for whom clinical
      and microbiological outcome data were available. The majority of these patients
      had been previously enrolled in multicenter prospective studies of MRSA
      bacteremia refractory to conventional vancomycin therapy. Logistic regression
      found a statistically significant relationship between treatment success with
      vancomycin and decreases in both vancomycin MICs (< or =0.5 microg/ml versus 1.0
      to 2.0 microg/ml; P = 0.02) and degree of killing (reduction in log(10)
      CFU/milliliter) by vancomycin over 72 h of incubation in vitro (P = 0.03). For
      MRSA isolates with vancomycin MICs < or = 0.5 microg/ml, vancomycin was 55.6%
      successful in the treatment of bacteremia whereas vancomycin was only 9.5%
      effective in cases in which vancomycin MICs for MRSA were 1 to 2 microg/ml.
      Patients with MRSA that was more effectively killed at 72 h by vancomycin in
      vitro had a higher clinical success rate with vancomycin therapy in the treatment
      of bacteremia (log(10) < 4.71 [n = 9], 0%; log(10) 4.71 to 6.26 [n = 13], 23.1%;
      log(10) > 6.27 [n = 8], 50%). We conclude that a significant risk for vancomycin
      treatment failure in MRSA bacteremia begins to emerge with increasing vancomycin
      MICs well within the susceptible range. Elucidating the mechanisms involved in
      intermediate-level glycopeptide resistance in S. aureus should begin by examining
      bacteria that begin to show changes in vancomycin susceptibility before the
      development of obvious resistance. Prognostic information for vancomycin
      treatment outcome in MRSA bacteremia may also be obtained by testing the in vitro
      bactericidal potency of vancomycin.

PMID- 15184412
TI  - Development of a species-specific probe for Pythium insidiosum and the diagnosis
      of pythiosis.
AB  - Pythium insidiosum, the only species in the genus that infects mammals, is the
      etiological agent of pythiosis, a granulomatous disease characterized by
      cutaneous and subcutaneous lesions and vascular diseases. Accurate diagnosis of
      pythiosis and identification of its causal agent are often inconsistent with
      current immunological diagnostic methods. A species-specific DNA probe was
      constructed by using a 530-bp HinfI fragment from the ribosomal DNA intergenic
      spacer of P. insidiosum. When the probe was incubated with dot blots of genomic
      DNA from 104 Pythium species, it hybridized only to the DNA of P. insidiosum and
      P. destruens-two species that have been considered conspecific. The probe also
      hybridized to DNA from 22 P. insidiosum isolates in this study, regardless of
      their geographic origin or animal host. When tested against genomic DNA from
      other pathogenic organisms (Aspergillus fumigatus, Basidiobolus ranarum,
      Conidiobolus coronatus, Lagenidium giganteum, Paracoccidioides brasiliensis, and
      Prototheca wickerhamii), no cross-hybridization of the probe was detected. The
      specificity of the probe to hybridize to genomic DNA from all isolates of P.
      insidiosum and not cross-react with DNA from other Pythium species or pathogens
      that cause symptoms similar to pythiosis in their hosts makes it a powerful tool
      for the accurate diagnosis of pythiosis. In addition, the probe has the potential
      for pathological and environmental diagnostic applications.

PMID- 15184411
TI  - Development of a multiplex PCR-ligase detection reaction assay for diagnosis of
      infection by the four parasite species causing malaria in humans.
AB  - The diagnosis of infections caused by Plasmodium species is critical for
      understanding the nature of malarial disease, treatment efficacy, malaria
      control, and public health. The demands of field-based epidemiological studies of
      malaria will require faster and more sensitive diagnostic methods as new
      antimalarial drugs and vaccines are explored. We have developed a multiplex PCR
      ligase detection reaction (LDR) assay that allows the simultaneous diagnosis of
      infection by all four parasite species causing malaria in humans. This assay
      exhibits sensitivity and specificity equal to those of other PCR-based assays,
      identifying all four human malaria parasite species at levels of parasitemias
      equal to 1 parasitized erythrocyte/microl of blood. The multiplex PCR-LDR assay
      goes beyond other PCR-based assays by reducing technical procedures and by
      detecting intraindividual differences in species-specific levels of parasitemia.
      Application of the multiplex PCR-LDR assay will provide the sensitivity and
      specificity expected of PCR-based diagnostic assays and will contribute new
      insight regarding relationships between the human malaria parasite species and
      the human host in future epidemiological studies.

PMID- 15184414
TI  - Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium
      tuberculosis strains isolated in Poland.
AB  - A total of 105 rifampin (RMP)- and/or isoniazid (INH)-resistant strains of
      Mycobacterium tuberculosis isolated from different parts of Poland in 2000 were
      screened for mutations associated with resistance to these drugs by two molecular
      methods, namely sequence analysis and real-time PCR technology. Three loci
      associated with drug resistance were selected for characterization: they were
      rpoB (RMP), katG, and the regulatory region of inhA (INH). Nineteen different
      mutations were identified in 64 RMP-resistant strains, and five new alleles were
      described. The most common point mutations were in codons 531 (41%), 516 (16%),
      and 526 (9%) of the rpoB gene. Mutations were not found in two (3%) of the
      isolates. In the case of resistance to INH, six different mutations in the katG
      gene of 83 resistant strains were detected. Fifty-seven (69%) isolates exhibited
      nucleotide substitutions at codon 315. One strain harbored a mutation affecting
      codon 279 (Gly279Thr). Twelve of 26 INH-resistant strains with the wild-type
      codon 315 (14.5% of all strains tested) had the mutation -15C-->T in the
      regulatory region of inhA. A full correlation between the DNA sequence analysis
      and real-time PCR data was obtained. We conclude that the real-time PCR method is
      fast and reliable for the detection of RMP and INH resistance-associated
      mutations in M. tuberculosis clinical isolates.

PMID- 15184413
TI  - Monitoring gp43 antigenemia in Paracoccidioidomycosis patients during therapy.
AB  - Paracoccidioidomycosis (PCM) is a systemic fungal disease that is particularly
      important among individuals living and working in rural areas of endemicity in
      Latin America. Detection of anti-Paracoccidioides brasiliensis antibodies is of
      limited value due to false-negative results. Detection of P. brasiliensis-gp43
      circulating antigen is a practical approach for a specific diagnosis of the
      disease. In a previous study we described an inhibition enzyme-linked
      immunosorbent assay able to detect the 43-kDa P. brasiliensis antigen in sera of
      100% of patients with the acute form of PCM and in 95.31 and 100% of patients
      with the chronic multifocal and unifocal forms of PCM. To investigate its
      potential application for the follow-up of PCM patients during treatment, antigen
      levels were monitored at regular intervals for up 8 to 12 months in serum samples
      from 23 patients. The results showed that treatment with itraconazole resulted in
      decreasing levels of circulating gp43 that were correlated with the reduction of
      anti-gp43 antibodies. It was also observed that by the end of 12 months of
      treatment gp43 levels were <5 microg/ml in all patients.

PMID- 15184415
TI  - SHV-12-like extended-spectrum-beta-lactamase-producing strains of Salmonella
      enterica serotypes Babelsberg and Enteritidis isolated in France among infants
      adopted from Mali.
AB  - From December 2002 to June 2003, 14 cultures of Salmonella enterica serotype
      Babelsberg and 6 cultures of serotype Enteritidis, isolated in France from
      internationally adopted children, were identified at the French National
      Reference Center for Salmonella. All serotype Babelsberg isolates were related,
      as determined by pulsed-field gel electrophoresis, and all serotype Enteritidis
      strains displayed the same phage type. All serotype Enteritidis and seven
      serotype Babelsberg isolates produced an SHV-12-like extended-spectrum beta
      lactamase as determined by sequencing of PCR products and by isoelectrofocusing.
      Some serotype Enteritidis isolates exhibited additional antimicrobial resistance
      (aminoglycosides, tetracycline, chloramphenicol, sulfonamides, and trimethoprim).
      Our investigation indicated that these Salmonella isolates were certainly
      acquired in the same orphanage in Bamako, Mali, before the children were adopted
      by French families. An inappropriate use of ceftriaxone was probably the cause of
      the emergence of such strains. There is an urgent need to determine the origin of
      the contamination and to introduce adequate antibiotic protocols into this
      orphanage to prevent further transmission and dissemination. Screening for
      infections and follow-up, adapted to the origin of the internationally adopted
      children, should be recommended.

PMID- 15184416
TI  - Analysis of the allelic diversity of the mycobacterial interspersed repetitive
      units in Mycobacterium tuberculosis strains of the Beijing family: practical
      implications and evolutionary considerations.
AB  - A study set comprised 44 Mycobacterium tuberculosis strains of the Beijing family
      selected for their representativeness among those previously characterized by
      IS6110-RFLP and spoligotyping (Northwest Russia, 1997 to 2003). In the present
      study, these strains were subjected to mycobacterial interspersed repetitive
      units (MIRU) typing to assess a discriminatory power of the 12-MIRU-loci scheme
      (P. Supply et al., J. Clin. Microbiol. 39:3563-3571, 2001). The 44 Russian
      Beijing strains were subdivided into 12 MIRU types with identical profiles: 10
      unique strains and two major types shared by 10 and 24 strains. Thus, basically,
      two distinct sublineages appear to shape the evolution of the Beijing strains in
      Russia. Most of the MIRU loci were found to be (almost) monomorphic in the
      Russian Beijing strains; the Hunter-Gaston discriminatory index (HGDI) for all 12
      loci taken together was 0.65, whereas MIRU26 (the most variable in our study)
      showed a moderate level of discrimination (0.49). The results were compared
      against all available published MIRU profiles of Beijing strains from Russia (3
      strains) and other geographic areas (51 strains in total), including South Africa
      (38 strains), East Asia (7 strains), and the United States (4 strains). A UPGMA
      (unweighted pair-group method with arithmetic averages)-based tree was
      constructed. Interestingly, no MIRU types were shared by Russian and South
      African strains (the two largest samples in this analysis), whereas both major
      Russian types included also isolates from other locations (United States and/or
      East Asia). This implies the evolution of the Beijing genotype to be generally
      strictly clonal, although a possibility of a convergent evolution of the MIRU
      loci cannot be excluded. We propose a dissemination of the prevailing local
      Beijing clones to have started earlier in South Africa rather than in Russia
      since more monomorphic loci were identified in Russian samples than in South
      African samples (mean HGDI scores, 0.08 versus 0.17). To conclude, we suggest to
      use a limited number of MIRUs for preliminary subdivision of Beijing strains in
      Russian (loci 26 + 31), South African (10 + 26 + 39), and global settings (10 +
      26 + 39).

PMID- 15184417
TI  - Rapid quantification of hepatitis B virus DNA by automated sample preparation and
      real-time PCR.
AB  - Monitoring of hepatitis B virus (HBV) DNA in serum by molecular methods has
      become the standard for assessment of the replicative activity of HBV. Several
      molecular assays for the detection and quantification of HBV DNA have been
      described. However, they usually lack automated sample preparation. Moreover,
      those assays, which are based on PCR, are limited by a short dynamic range (2 to
      3 log units). In the present study, the use of RealArt HBV LC PCR Reagents in
      conjunction with automated extraction on the COBAS AMPLIPREP analyzer was
      evaluated. Members of an HBV proficiency program panel were tested; linearity,
      interassay, and intra-assay variations were determined. The performance of the
      assay in a routine clinical laboratory was evaluated with a total of 117 clinical
      specimens. When members of the HBV proficiency program panel were tested by the
      new molecular assay, the results were found to be within +/-0.5 log unit of the
      results obtained by reference laboratories. Determination of linearity resulted
      in a quasilinear curve over more than 6 log units. The interassay variation of
      the RealArt HBV LC PCR Reagents by use of the automated sample preparation
      protocol ranged from 16 to 73%, and the intra-assay variation ranged from 9 to
      40%. When clinical samples were tested by the new assay with the automated sample
      preparation protocol and the results were compared with those obtained by the
      COBAS AMPLICOR HBV MONITOR Test with manual sample preparation, the results for
      76% of all samples with positive results by both tests were found to be within +/
      0.5 log unit and the results for another 18% were found to be within between 0.5
      and 1.0 log unit. In conclusion, the real-time PCR assay with automated sample
      preparation proved to be suitable for the routine molecular laboratory and
      required less hands-on time.

PMID- 15184418
TI  - Molecular and morphological identification of Colletotrichum species of clinical
      interest.
AB  - Colletotrichum species have caused human infections in recent years. Because of
      the difficulties in recognizing them in vitro, we have designed a quick and
      unambiguous molecular test, based on the amplification of a specific fragment of
      the internal transcribed spacer 1 region, to distinguish any Colletotrichum
      isolate from other fungi, including the common pathogenic species. Analysis of
      the sequences of the ribosomal DNA (rDNA) fragment showed sufficient variability
      to clearly separate the five species of Colletotrichum that are of clinical
      interest, i.e., Colletotrichum coccodes, C. crassipes, C. dematium, C.
      gloeosporioides, and C. graminicola. Sequencing of the D1-D2 region of the large
      subunit rDNA gene also supported these results. Additionally, we reviewed the
      most suitable morphological characteristics for the in vitro identification of
      these increasingly important opportunistic fungi.

PMID- 15184420
TI  - Transposition rates of Mycobacterium tuberculosis IS6110 restriction fragment
      length polymorphism patterns.
AB  - To determine the rate at which IS6110 restriction fragment length polymorphism
      (RFLP) patterns in Mycobacterium tuberculosis change over time, we applied a
      smooth nonparametric survival model to several data sets, including data from
      previous publications on the rate of change. The results strongly suggest a
      simple parametric model, with an instantaneous change at time zero and
      essentially a zero rate of change thereafter. Our interpretation of the results
      is that at the time of collection of the first isolate, more than one strain is
      present. We speculate that the selection of mutant strains is most likely during
      rapid growth, revival of the dormant bacteria, and/or adaptation to a new host.
      The parameter most accurately describing changing RFLP patterns is the proportion
      of isolates with band changes, rather than the half-life or the rate of change.

PMID- 15184419
TI  - Hepatitis B virus genotypes and precore and core mutants in Brazilian patients.
AB  - A method for genotyping hepatitis B virus by partial HBsAg gene sequencing with
      primers common to all known genotypes was developed. Mutations related to anti
      HBs resistance are also detected with this method. Samples from 103 Brazilian
      patients were analyzed. Precore and core region of these viruses were also
      sequenced in 101 patients. Genotypes A, B, C, D, and F were found with
      frequencies of 49.5, 2.9, 13.6, 24.3, and 9.7%, respectively. Genotypes B and C
      were found only in Asian patients, whereas genotypes A, D, and F were more common
      in patients without an Asian background. Precore mutants were found in 32 (31.7%)
      of 101 patients, with a higher frequency in those infected with genotype D (22 of
      25 [88.0%]). Analysis of nucleotide 1858 showed presence of thymine in all
      patients with genotypes B, C, and D and in a few patients with genotypes A
      (10.0%) and F (30.0%), who showed more frequently the presence of cytosine. This
      nucleotide was closely related to the presence of precore mutants. Mutations in
      the basal core promoter were found in 64 of 101 (63.4%) samples. These mutations
      were more frequent in patients infected with genotype F (90.0%) and less frequent
      in patients infected with genotype B (33.3%). Deletions in this region were found
      in two genotype C-infected patients.

PMID- 15184421
TI  - Molecular evidence of infections with Babesia gibsoni parasites in Japan and
      evaluation of the diagnostic potential of a loop-mediated isothermal
      amplification method.
AB  - Detection and analysis of Babesia gibsoni infection were performed with whole
      blood samples collected between July 2002 and July 2003 from 945 and 137 dogs
      from the Aomori and Okinawa Prefectures of Japan, respectively, by PCR and loop
      mediated isothermal amplification (LAMP). On the basis of the criterion for
      positivity by PCR, 3.9% (37 of 945) and 10.9% (15 of 137) of the dogs had B.
      gibsoni DNA. All 37 positive animals from Aomori Prefecture were male Tosa dogs
      (Japanese mastiff). The 15 dogs from Okinawa Prefecture with positive PCR assay
      results were of various breeds, ages, and sexes. The 18S ribosomal DNA (18S rDNA)
      sequences from all samples showed 100% homology to each other and to published B.
      gibsoni sequences. The limits of detection of B. gibsoni parasitemia by the PCR
      and LAMP methods with an 18S rDNA-based primer set were 0.0005% each. A
      comparison of the PCR and LAMP methods with microscopic examination for the
      detection of B. gibsoni infections in blood samples from 945 field dogs in Aomori
      Prefecture and 137 field dogs in Okinawa Prefecture showed that 37 and 15 dogs,
      respectively, were positive by the PCR and LAMP methods and that 16 and 12 dogs,
      respectively, were positive by light microscopic examination. All samples found
      to be positive by microscopic examination were also positive by the PCR and LAMP
      methods. The results of the PCR and LAMP methods agreed for samples with positive
      results by either method. Moreover, nonspecific reactions were not observed by
      the LAMP method. These results suggest that the LAMP method provides a useful
      tool for the detection of B. gibsoni infections in dogs.

PMID- 15184422
TI  - Human papillomavirus testing with the hybrid capture 2 assay and PCR as screening
      tools.
AB  - The recognition of high-risk human papillomaviruses (HPVs) as etiological agents
      of cervical cancer has increased the demands to use testing for HPV for the
      detection of abnormal cervical smears and for cervical cancer screening. The
      present study compared the performance of the Hybrid Capture 2 (HC2) assay with
      that of PCR for the detection of significant cervical lesions in 1,511 women with
      different risks for HPV infections in three New Independent States of the former
      Soviet Union. The results showed that the level of agreement between the HC2
      assay and PCR was substantial, with a kappa (Cohen) value of 0.669 (95%
      confidence interval [CI], 0.629 to 0.709). Of the 228 samples with discrepant
      results, 92 were positive by the HC2 assay but negative by PCR, whereas 136
      samples were PCR positive but HC2 assay negative. The positive predictive values
      (PPVs) of the HC2 assay and PCR in detecting high-grade intraepithelial lesions
      (HSILs) were 4.5% (95% CI, 3.5 to 5.5%) and 3.6% (95% CI, 2.7 to 4.5%),
      respectively, and the negative predictive values (NPVs) were 99.6% (95% CI, 99.3
      to 99.9%) and 99.3% (95% CI, 98.9 to 99.7%), respectively. The sensitivities of
      the HC2 assay and PCR for the detection of HSILs were 85.2 and 74.0%,
      respectively, and the specificities were 67.2 and 64.1%, respectively. In
      receiver operating characteristic (ROC) analysis, the performance of the HC2
      assay for the detection of HSILs was excellent (P = 0.0001); the area under the
      ROC analysis curve was 0.858 (95% CI, 0.811 to 0.905), and the optimal balance
      between sensitivity (86.5%) and specificity (80%) was obtained with an HC2 assay
      cutoff level of 15.6 relative light units/positive control. Use of this cutoff
      would increase the specificity of the HC2 assay to 80.0% without compromising
      sensitivity. In conclusion, the results of PCR and the HC2 assay were concordant
      for 85% of samples, resulting in substantial reproducibility. Both tests had low
      PPVs, equal specificities, and equal (almost 100%) NPVs for the detection of
      HSILs; but the sensitivity of the HC2 assay was slightly better.

PMID- 15184423
TI  - Comparison of quantitative and semiquantitative enzyme-linked immunosorbent
      assays for immunoglobulin G against Chlamydophila pneumoniae to a
      microimmunofluorescence test for use with patients with respiratory tract
      infections.
AB  - We previously reported a high degree of variation in the sensitivities of
      serodiagnostic kits for the detection of Chlamydophila pneumoniae in sera from
      healthy donors. Since a low predictive value of a test can impair its diagnostic
      value, we have extended our studies to samples from patients with pneumonia. We
      focused on the most promising enzyme-linked immunosorbent assays (ELISAs) (SeroCP
      and SeroCP Quant; Savyon) identified in our previous study and included a new
      ELISA (sELISA; Medac). The agreement between all ELISAs for immunoglobulin G
      (IgG) and a reference microimmunofluorescence (MIF) test for IgG (SeroFIA;
      Savyon) was > or = 90% for a collective of 80 patients. The positive predictive
      values were all > or = 93%. The negative predictive values ranged from 68 to 83%.
      False-negative results were obtained only for samples that had low titers in the
      MIF test. The correlation of the IgG antibody titers determined by the MIF and
      SeroCP Quant tests was high (r(sp) = 0.9). Since the semiquantitative SeroCP and
      quantitative SeroCP Quant ELISAs achieved the highest sensitivities, they were
      evaluated further by using a second batch of sera from 50 patients with
      predominantly medium and low antibody titers in the MIF test and a control
      collection of sera from 80 children with negative MIF results. Again, the tests
      showed a high concordance with the MIF results (96%), and the antibody titers in
      the SeroCP Quant and MIF tests correlated well (r(sp) = 0.8). The specificities
      determined with the negative sera were > or = 99% for the SeroCP Quant test and
      86% for the SeroCP test. These results show that ELISAs that are fast and
      objective deliver seroprevalence results, sensitivities, and specificities that
      are very similar to those of the MIF test.

PMID- 15184424
TI  - Multilocus sequence typing is a reliable alternative method to DNA fingerprinting
      for discriminating among strains of Candida albicans.
AB  - Multilocus sequence typing (MLST) has emerged as a powerful new DNA-typing tool
      for the evaluation of intraspecies genetic relatedness. This method relies on DNA
      sequence analysis of nucleotide polymorphisms in housekeeping genes and has shown
      a high degree of intraspecies discriminatory power for bacterial and fungal
      pathogens. However, the results of the MLST scheme for Candida albicans have
      heretofore never been formally compared to those of other established typing
      techniques. To assess the value of MLST relative to those of other DNA
      fingerprinting tools for discriminating among strains of C. albicans, we applied
      it to a previously well-characterized set of 29 C. albicans isolates evaluated by
      the random amplified polymorphic DNA (RAPD), multilocus enzyme electrophoresis
      (MLEE), and Ca3 Southern hybridization probe techniques. MLST identified three
      clusters of genetically related isolates, with 82.3% direct concordance with
      MLEE, 82.7% with RAPD analysis, and 86.2% with the Ca3 Southern hybridization
      technique. When MLST was applied to a subset of 22 isolates of unrelated origins,
      it identified 21 independent diploid sequence types (DSTs), resulting in a
      discriminatory power of 99.6%. These DSTs were 96.9, 99.6, and 99.6% concordant
      with the genotypes identified by RAPD analysis, MLEE, and Ca3 Southern
      hybridization, respectively. These results demonstrate that MLST is a highly
      effective technique that performs at least comparably to other established DNA
      fingerprinting techniques.

PMID- 15184425
TI  - Dengue virus serotyping based on envelope and membrane and nonstructural protein
      NS1 serotype-specific capture immunoglobulin M enzyme-linked immunosorbent
      assays.
AB  - Envelope and membrane (E/M) and nonstructural protein NS1 serotype-specific
      capture Immunoglobulin M (IgM) enzyme-linked immunosorbent assays (ELISAs) were
      developed to differentiate four dengue virus serotypes. A total of 93 anti-dengue
      virus IgM-positive serum samples collected between days 5 and 45 of illness from
      59 confirmed dengue patients were analyzed. The results showed that positive
      serotype specificity could be identified for 86.1 and 47.6% of serum samples
      tested for E/M-specific IgM antibodies versus 83.3 and 42.9% of serum samples
      tested for NS1-specific IgM antibodies from patients with primary and secondary
      dengue virus infections, respectively. Dual analyses with both E/M and NS1
      serotype-specific capture IgM ELISAs showed that positive serotype specificity
      could be correctly identified for 98.6 and 61.9% of all of the primary and
      secondary serum samples tested, respectively. These findings suggested that E/M
      and NS1 serotype-specific capture IgM ELISAs have the potential to be of use in
      dengue virus serotyping.

PMID- 15184426
TI  - Molecular epidemiologic evaluation of endocarditis due to Oerskovia turbata and
      CDC group A-3 associated with contaminated homograft valves.
AB  - Oerskovia turbata is an unusual bacterial cause of endocarditis and septicemia in
      immunocompromised patients. In this study, we compared 12 isolates from a 1975
      medical center cluster, 11 originally identified as O. turbata (four from the
      blood of a homograft aortic valve-associated endocarditis patient and seven from
      contaminated homograft valves) and one CDC group A-3 strain from the blood of a
      second endocarditis patient with fatal outcome, with eight control strains from
      unrelated locations. The control strains included type and reference strains of
      O. turbata, Cellulomonas hominis, and CDC group A-3. The four blood isolates from
      the first patient and six of the valve isolates shared identical biochemical,
      antimicrobial susceptibility, and BglI ribotype patterns that differed from the
      second patient's isolate and control strains. The blood isolate from the second
      patient and the remaining valve isolate shared a phenotypic and genotypic profile
      and were phenotypically identical to, but epidemiologically different from, the
      CDC group A-3 reference strain with the strain-specific enzyme. Also, these
      isolates differed from the type strain and the other reference strains of C.
      hominis and O. turbata. Our results indicate that the four blood isolates from
      the first patient and six of the homograft valve isolates represent a single
      clone of O. turbata associated with endocarditis. Additionally, our results
      indicate that the blood isolate from the second patient and one of the homograft
      valve isolates differ from O. turbata and C. hominis and represent a unique clone
      of CDC group A-3 associated with fatal endocarditis.

PMID- 15184427
TI  - Characterization of Chlamydia trachomatis omp1 genotypes detected in eye swab
      samples from remote Australian communities.
AB  - Chlamydia trachomatis conjunctival samples collected over a 6-month period from
      individuals with clinical signs of trachoma and located in remote communities in
      the Australian Northern Territory were differentially characterized according to
      serovar and variants. The rationale was to gain an understanding of the
      epidemiology of an apparent increased prevalence of acute trachoma in areas
      thought to be less conducive to this disease. Characterization was performed
      through sequencing of a region of the omp1 gene spanning the four variable
      domains and encoding the major outer membrane protein. Nucleotide and deduced
      amino acid sequences were genotyped by using a BLAST similarity search and were
      examined by phylogenetic analyses to illustrate evolutionary relationships
      between the clinical and GenBank reference strains. The predominant genotype
      identified corresponded to that of serovar C (87.1%), followed by the genotype
      corresponding to serovar Ba (12.9%). All nucleotide and amino acid sequences
      exhibited minor levels of variation with respect to GenBank reference sequences.
      The omp1 nucleotide sequences of the clinical samples best aligned with those of
      the conjunctival C. trachomatis reference strains C/TW-3/OT and Ba/Apache-2. All
      clinical samples (of serovar C) exhibited four or five nucleotide changes
      compared with C/TW-3/OT, while all serovar Ba samples had one or two nucleotide
      differences from Ba/Apache-2. Phylogenetic analyses revealed close relationships
      between these Northern Territory chlamydial samples and the respective reference
      strains, although the high proportion of sequence variants suggests an
      evolutionarily distinct C. trachomatis population causing eye infections in
      Australia. Given that such genotypic information has gone unreported, these
      findings provide knowledge and a foundation for trachoma-associated C.
      trachomatis variants circulating in the Northern Territory.

PMID- 15184428
TI  - Distinct diversity of the cag pathogenicity island among Helicobacter pylori
      strains in Japan.
AB  - The severity of Helicobacter pylori-related disease is correlated with the
      presence of a cag pathogenicity island (PAI). Genetic diversity within the cag
      PAI may have a modifying effect on the pathogenic potential of the infecting
      strain. We analyzed the complete cag PAI sequences of 11 representative Japanese
      strains according to their vacA genotypes and clinical effects and examined the
      relationship between the diversity of the cag PAI and clinical features. The cag
      PAI genes were divided into two major groups, a Western and a Japanese group, by
      phylogenetic analysis based on the entire cag PAI sequences. The predominant
      Japanese strains formed a Japanese cluster which was different from the cluster
      formed by Western strains. The diversity of the cag PAI was associated with the
      vacA and cagA genotypes. All strains with the s1c vacA genotype were in the
      Japanese cluster. In addition, all strains with the East Asian-type cagA genotype
      were also in the Japanese cluster. Patients infected with the Japanese-cluster
      strain had high-grade gastric mucosal atrophy. These results suggest that a
      distinct diversity of the cag PAI of H. pylori is present among Japanese strains
      and that this diversity may be involved in the development of atrophic gastritis
      and may increase the risk for gastric cancer.

PMID- 15184429
TI  - Simple, rapid latex agglutination test for serotyping of pneumococci (Pneumotest
      Latex).
AB  - The "gold standard" for epidemiological typing of Streptococcus pneumoniae
      (pneumococcus) is the capsular reaction test (Neufeld test) with antisera against
      the 90 pneumococcal polysaccharide capsules, i.e., serotyping. The method is
      labor intensive and requires a certain level of experience to be performed
      satisfactory, and thus it has been restricted for use in specialized reference or
      research laboratories. Surveillance of the serotype distribution of pneumococci
      that cause infections is important to secure an optimal composition of
      pneumococcal vaccines and to monitor antibiotic resistance in pneumococci. At
      Statens Serum Institut, a simple latex agglutination test for serotyping of
      pneumococci has been developed. The Pneumotest-Latex kit consists of 14 different
      pooled pneumococcus antisera (pools A to I and pools P to T) applied to latex
      particles. In a blind test of 352 isolates (with all 90 serotypes represented),
      336 (95.5%) were typed or grouped correctly by the Pneumotest-Latex; in addition,
      2 (7%) of 30 strains regarded as nontypeable or rough strains were serotyped, and
      the serotypes of these two isolates were confirmed by the capsular reaction test
      with type-specific antisera. The Pneumotest-Latex seems to be a sensitive method
      for serotyping or grouping of the majority of pneumococcal strains. By use of
      this ready-to-perform latex agglutination kit (Pneumotest-Latex), serotyping of
      pneumococci can gain more ground as a tool in prevention of pneumococcal
      diseases.

PMID- 15184430
TI  - Multifocal detection of multidrug-resistant Pseudomonas aeruginosa producing the
      PER-1 extended-spectrum beta-lactamase in Northern Italy.
AB  - Forty-four nonreplicate clinical isolates of Pseudomonas aeruginosa that were
      resistant to extended-spectrum cephalosporins (ceftazidime and cefepime) and
      aztreonam, that putatively produced an acquired extended- spectrum beta-lactamase
      (ESBL), according to the results of a double-disk synergy test, and that had been
      involved in nosocomial outbreaks were obtained from six different hospitals in
      northern Italy and screened for the presence of bla(PER) ESBL determinants.
      Twenty isolates, associated with nine independent outbreaks that occurred in five
      hospitals in the Milan area and its surroundings during 1995-2000, were found to
      carry an acquired bla(PER-1) gene. PER-1 producers representative of the nine
      outbreaks exhibited a multidrug resistance (MDR) phenotype, including resistance
      to extended-spectrum cephalosporins, aztreonam, meropenem, aminoglycosides, and
      in most cases, imipenem and ciprofloxacin. An analysis of macrorestriction
      profiles of their genomic DNAs by pulsed-field gel electrophoresis revealed an
      overall clonal diversity of the PER-1 producers, although interhospital clonal
      spread was also observed. The bla(PER-1) gene was not transferable and appeared
      to be chromosomally located. An analysis of the EcoRI and EcoRV restriction
      fragment length polymorphisms of the bla(PER-1) locus revealed identical patterns
      for all isolates, and the characterization of a 1.9-kb region containing bla(PER
      1) revealed a conserved structure in representatives of the various clonal
      lineages. The present findings indicate that MDR P. aeruginosa clones producing
      the PER-1 ESBL are endemic to this area of northern Italy, where they have been
      circulating since the mid-1990s and have been associated with several nosocomial
      outbreaks.

PMID- 15184431
TI  - Sequence-based identification of aerobic actinomycetes.
AB  - We investigated the utility of 500-bp 16S rRNA gene sequencing for identifying
      clinically significant species of aerobic actinomycetes. A total of 28 reference
      strains and 71 clinical isolates that included members of the genera
      Streptomyces, Gordonia, and Tsukamurella and 10 taxa of Nocardia were studied.
      Methods of nonsequencing analyses included growth and biochemical analysis, PCR
      restriction enzyme analysis of the 439-bp Telenti fragment of the 65 hsp gene,
      susceptibility testing, and, for selected isolates, high-performance liquid
      chromatography. Many of the isolates were included in prior taxonomic studies.
      Sequencing of Nocardia species revealed that members of the group were generally
      most closely related to the American Type Culture Collection (ATCC) type strains.
      However, the sequences of Nocardia transvalensis, N. otitidiscaviarum, and N.
      nova isolates were highly variable; and it is likely that each of these species
      contains multiple species. We propose that these three species be designated
      complexes until they are more taxonomically defined. The sequences of several
      taxa did not match any recognized species. Among other aerobic actinomycetes,
      each group most closely resembled the associated reference strain, but with some
      divergence. The study demonstrates the ability of partial 16S rRNA gene
      sequencing to identify members of the aerobic actinomycetes, but the study also
      shows that a high degree of sequence divergence exists within many species and
      that many taxa within the Nocardia spp. are unnamed at present. A major
      unresolved issue is the type strain of N. asteroides, as the present one (ATCC
      19247), chosen before the availability of molecular analysis, does not represent
      any of the common taxa associated with clinical nocardiosis.

PMID- 15184432
TI  - Characterization of G10P[11] rotaviruses causing acute gastroenteritis in
      neonates and infants in Vellore, India.
AB  - Rotavirus G10P[11] strains, which are commonly found in cattle, have frequently
      been associated with asymptomatic neonatal infections in India. We report the
      finding of G10P[11] strains associated with severe disease in neonates in
      Vellore, southern India. Rotavirus strains from 43 fecal samples collected from
      neonates with or without gastrointestinal symptoms between 1999 and 2000 were
      genotyped by reverse transcription-PCR. Forty-one neonates (95%) were infected
      with G10P[11] rotavirus strains, and 63% of the infections were in children who
      had gastrointestinal symptoms, including acute watery diarrhea. G10P[11] strains
      were also seen infecting older children with dehydrating gastroenteritis in
      Vellore. Characterization of the genes encoding VP7, VP4, VP6, and NSP4 of these
      strains revealed high sequence homology with the corresponding genes of the
      asymptomatic neonatal strain I321, which in turn is very closely related to
      bovine G10P[11] strains circulating in India. No significant differences were
      seen in the sequences obtained from strains infecting symptomatic neonates or
      children and asymptomatic neonates.

PMID- 15184433
TI  - Serological and genetic diversity of capsular polysaccharides in Enterococcus
      faecalis.
AB  - Enterococci possess capsular carbohydrate antigens that are targets of opsonic
      antibodies. These antigens may be used to develop alternative options for the
      treatment and prevention of enterococcal infections. The present study was done
      to analyze the diversity of capsular polysaccharides in Enterococcus faecalis.
      Four type-specific sera were used in an enzyme-linked immunosorbent assay format
      to detect polysaccharide antigen extracted from bacterial cell walls. A total of
      55% of a collection of 29 E. faecalis strains could be grouped into one of four
      serogroups. Additional analysis of the strains by opsonophagocytic assays
      revealed agreement between the results of the two methods for 72% of the
      isolates. An additional four strains could be assigned to a serogroup on the
      basis of opsonic killing by sera with antibodies against the four prototypes
      strains, provisionally named CPS-A to CPS-D. The results of the two methods
      disagreed for one strain (4%). When the results of both methods were combined,
      66% of the strains could be classified. One strain had to be assigned to two
      serogroups. The assignments to the four serogroups were confirmed by analysis of
      the genetic organization of the biosynthetic capsular polysaccharide (cps) locus.
      All strains grouped into serotypes CPS-A and CPS-B possessed only the cpsA and
      cpsB genes, while all strains grouped into serogroups CPS-C and CPS-D possessed
      an additional eight or nine genes. Our results suggest the existence of a limited
      number of E. faecalis capsule serotypes, and we provisionally propose four
      serotypes, named CPS-A to CPS-D, and the respective prototype strains for these
      families.

PMID- 15184434
TI  - Genotypic variation and stability of four variable-number tandem repeats and
      their suitability for discriminating strains of Mycobacterium leprae.
AB  - It has not been possible to distinguish different strains of Mycobacterium leprae
      according to their genetic sequence. However, the genome contains several
      variable-number tandem repeats (VNTR), which have been used effectively in strain
      typing of other bacteria. To determine their suitability for differentiating M.
      leprae, we developed PCR systems to amplify 5 different VNTR loci and examined a
      battery of 12 M. leprae strains derived from patients in different regions of the
      United States, Brazil, Mexico, and the Philippines, as well as from wild
      armadillos and a sooty mangabey monkey. We found diversity at four VNTR (D =
      0.74), but one system (C(16)G(8)) failed to yield reproducible results. Alleles
      for the GAA VNTR varied in length from 10 to 16 copies, those for AT(17) varied
      in length from 10 to 15 copies, those for GTA varied in length from 9 to 12
      copies, and those for TA(18) varied in length from 13 to 20 copies. Relatively
      little variation was seen with interspecies transfer of bacilli or during short
      term passage of strains in nude mice or armadillos. The TA(18) locus was more
      polymorphic than other VNTR, and genotypic variation was more common after long
      term expansion in armadillos. Most strain genotypes remained fairly stable in
      passage, but strain Thai-53 showed remarkable variability. Statistical cluster
      analysis segregated strains and passage samples appropriately but did not reveal
      any particular genotype associable with different regions or hosts of origin.
      VNTR polymorphisms can be used effectively to discriminate M. leprae strains.
      Inclusion of additional loci and other elements will likely lead to a robust
      typing system that can be used in community-based epidemiological studies and
      select clinical applications.

PMID- 15184435
TI  - Quantification of intestinal bacterial populations by real-time PCR with a
      universal primer set and minor groove binder probes: a global approach to the
      enteric flora.
AB  - The composition of the human intestinal flora is important for the health status
      of the host. The global composition and the presence of specific pathogens are
      relevant to the effects of the flora. Therefore, accurate quantification of all
      major bacterial populations of the enteric flora is needed. A TaqMan real-time
      PCR-based method for the quantification of 20 dominant bacterial species and
      groups of the intestinal flora has been established on the basis of 16S ribosomal
      DNA taxonomy. A PCR with conserved primers was used for all reactions. In each
      real-time PCR, a universal probe for quantification of total bacteria and a
      specific probe for the species in question were included. PCR with conserved
      primers and the universal probe for total bacteria allowed relative and absolute
      quantification. Minor groove binder probes increased the sensitivity of the
      assays 10- to 100-fold. The method was evaluated by cross-reaction experiments
      and quantification of bacteria in complex clinical samples from healthy patients.
      A sensitivity of 10(1) to 10(3) bacterial cells per sample was achieved. No
      significant cross-reaction was observed. The real-time PCR assays presented may
      facilitate understanding of the intestinal bacterial flora through a normalized
      global estimation of the major contributing species.

PMID- 15184436
TI  - Genomic characterization of an endemic Mycobacterium tuberculosis strain:
      evolutionary and epidemiologic implications.
AB  - In a study of 302 Mycobacterium tuberculosis clinical isolates from the low
      incidence Canadian-born population of Quebec, we characterized a large endemic
      strain family by using genomic deletions. The DS6(Quebec) deleted region (11.4
      kb) defined a strain family of 143 isolates encompassing two subgroups: one
      characterized by pyrazinamide (PZA) susceptibility and the other marked by a PZA
      monoresistant phenotype. A second deletion (8 bp) in the pncA gene was shared by
      all 76 isolates with the PZA resistance phenotype, whereas a third DRv0961
      deletion (970 bp) defined a further subset of 15 isolates. From their deletion
      profiles, we derived a most parsimonious evolutionary scenario and compared
      multiple standard genotyping modalities (using IS6110 restriction fragment length
      polymorphism [RFLP], spoligotyping, and mycobacterial interspersed repetitive
      units [MIRU]) across the deletion-based subgroups. The use of a single genotyping
      modality yielded an unexpectedly high proportion of clustered isolates for a high
      IS6110 copy strain (27% by IS6110 RFLP, 61% by MIRU, and 77% by spoligotyping).
      By combining all three modalities, only 14% were genotypically clustered overall,
      a result more congruent with the epidemiologic profile of reactivation
      tuberculosis, as suggested by the older age (mean age, 60 years), rural setting,
      and low proportion of epidemiologic links. These results provide insight into the
      evolution of genotypes in endemic strains and the potential for false clustering
      in molecular epidemiologic studies.

PMID- 15184437
TI  - Multiplex PCR for distinguishing the most common phase-1 flagellar antigens of
      Salmonella spp.
AB  - Most Salmonella serotypes alternatively express either phase-1 or phase-2
      flagellar antigens, encoded by the fliC and fljB genes, respectively. Flagellar
      phase reversal for the identification of both flagellar antigens is not necessary
      at the genetic level. Variable internal regions of the fliC genes encoding the
      H:i, H:r, H:l,v, H:e,h, H:z(10), H:b, and H:d antigens have been sequenced; and
      the specific sites for each antigen in selected Salmonella serotypes have been
      determined. These results, together with flagellar G-complex variable internal
      sequences obtained by the Foodborne and Diarrheal Diseases Branch at the Centers
      for Disease Control and Prevention in Atlanta, GA, have been used to design a
      multiplex PCR to identify the G-complex antigens as well as the H:i, H:r, H:l,v,
      H:e,h, Hz(10), H:b, and H:d first-phase antigens. These antigens are part of the
      most common Salmonella serotypes possessing first-phase flagellar antigens.
      Salmonella enterica serotype Enteritidis is identified by adding a specific
      primer pair published previously. This multiplex PCR includes 13 primers. A total
      of 161 Salmonella strains associated with 72 different serotypes were tested.
      Each strain generated one first-phase-specific antigen fragment ranging from 100
      to 500 bp; Salmonella serotype Enteritidis, however, generated two amplicons of
      500 bp that corresponded to the G complex and a 333-bp serotype-specific
      amplicon, respectively. Twenty-three strains representing 19 serotypes with
      flagellar genes different from those targeted in this work did not generate any
      fragments. The method is quick, specific, and reproducible and is independent of
      the phase expressed by the bacteria when they are tested.

PMID- 15184438
TI  - Evaluation and comparison of two commercial enzyme-linked immunosorbent assay
      kits for detection of antigenically diverse human noroviruses in stool samples.
AB  - Two recently commercialized enzyme-linked immunosorbent assay kits, the SRSV(II)
      AD (Denka Seiken Co. Ltd., Tokyo, Japan) and IDEIA NLV (DakoCytomation Ltd., Ely,
      United Kingdom) kits, that detect human norovirus (HuNV) antigens in stool
      samples were evaluated to assess whether they could be used instead of reverse
      transcription-PCR (RT-PCR) for routine diagnosis. The sensitivities and
      specificities of the two kits were tested with a panel of 103 stool samples
      containing HuNVs of 4 and 10 genetic subgroups within genogroups I and II (GI and
      GII), respectively, and 39 stool samples containing other enteric viruses. The
      Denka kit had a high sensitivity (>70% for 10 of the 14 subgroups) but a
      specificity of only 69%, and the Dako kit had a low sensitivity (<30% for 6 GII
      subgroups) but a high specificity of 100%. Statistical analysis suggests that
      HuNVs of four subgroups (subgroups GII/2, GII/5, GII/6, and GII/n) are likely to
      elude detection by the Dako kit. The two kits also demonstrated differences in
      reactivities. While the Dako kit discriminated between the GI and GII antigens of
      HuNVs, the Denka kit cross-reacted with samples containing all GI and GII
      subgroups of HuNVs. Moreover, the Denka kit also reacted with samples containing
      human sapovirus (HuSV). We demonstrate that the cross-reactivity of the Denka kit
      is not due to specific reactions with HuNV and HuSV antigens. These results
      indicate that neither the Denka kit nor the Dako kit has all the performance
      characteristics required to replace the RT-PCR methods used to detect HuNVs.

PMID- 15184439
TI  - Variability of the Chlamydia trachomatis omp1 gene detected in samples from men
      tested in male-only saunas in Melbourne, Australia.
AB  - A recent screening program in Melbourne, Victoria, Australia, has shown that
      Chlamydia trachomatis is an important infection among men who frequent male-only
      saunas. To evaluate the C. trachomatis isolates circulating in local saunas, the
      C. trachomatis-positive samples collected during the program underwent
      amplification and sequencing of the omp1 gene, and the corresponding serovars
      were deduced. Forty-seven C. trachomatis-positive samples collected (from October
      2001 to September 2002) from 39 men were evaluated. The deduced serovars found,
      in descending order of prevalence, were D, G, and J; and serovars B, E, F, and H
      were each found in single samples. The seven different serovars identified in the
      study sample indicate that local saunas are a reservoir of multiple C.
      trachomatis strains, possibly maintained by the introduction of new patrons or
      regular patrons who have been exposed to C. trachomatis elsewhere. No significant
      genetic variants were found, as most variable positions were silent and were
      detected only in single samples.

PMID- 15184440
TI  - Bovine tuberculosis (Mycobacterium bovis) in wildlife in Spain.
AB  - Mycobacterium bovis infection in wildlife and feral species is a potential source
      of infection for livestock and a threat to protected and endangered species. The
      aim of this study was to identify Spanish wild animal species infected with M.
      bovis through bacteriological culture and spacer oligonucleotide typing
      (spoligotyping) of isolates for epidemiological purposes. This study included
      samples from red deer (Cervus elaphus), fallow deer (Dama dama), wild boar (Sus
      scrofa), Iberian lynx (Lynx pardina), hare (Lepus europaeus), and cattle (Bos
      taurus). They were collected in several geographical areas that were selected for
      their unique ecological value and/or known relationships between wildlife and
      livestock. In the areas included in this survey, M. bovis strains with the same
      spoligotyping pattern were found infecting several wild species and livestock,
      which indicates an epidemiological link. A locally predominant spoligotype was
      found in these areas. Better understanding of the transmission and distribution
      of disease in these populations will permit more precise targeting of control
      measures.

PMID- 15184441
TI  - Multilocus sequence typing analysis of human and animal Clostridium difficile
      isolates of various toxigenic types.
AB  - A multilocus sequence typing (MLST) scheme was developed to study the genetic
      relationships and population structure of 72 Clostridium difficile isolates from
      various hosts, geographic sources, PCR ribotypes, and toxigenic types (determined
      by PCR targeting tcdA and tcdB genes). MLST was performed by DNA sequence
      analysis of seven housekeeping genes (aroE, ddl, dutA, tpi, recA, gmk, and sodA).
      The number of alleles ranged from five (dutA and ddl) to eleven (recA). Allelic
      profiles allowed the definition of 34 different sequence types (STs). These STs
      lacked correlation with geographic source but were well correlated to toxigenic
      type. The dendrogram generated from a matrix of pairwise genetic distances showed
      that animal isolates did not constitute a distinct lineage from human isolates
      and that there was no hypervirulent lineage within the population of toxigenic
      human isolates (isolates recovered from pseudomembranous colitis and antibiotic
      associated diarrhea did not cluster in distinct lineages). However, A(-) B(+)
      variant isolates shared the same ST that appeared as a divergent lineage in the
      population studied, indicating a single evolutionary origin. The population
      structure was further examined by analysis of allelic polymorphism. The
      dendrogram generated from composite sequence-based analysis revealed a
      homogeneous population associated with three divergent lineages, one of which was
      restricted to A(-) B(+) variant isolates. C. difficile exhibited a clonal
      population structure, as revealed by the estimation of linkage disequilibrium
      (Ia) between loci. The analysis of alleles within clonal complexes estimated that
      point mutation generated new alleles at a frequency eightfold higher than
      recombinational exchange, and the congruence of the dendrograms generated from
      separate housekeeping loci confirmed the mutational evolution of this species.

PMID- 15184442
TI  - Rapid and specific detection of Escherichia coli clonal group A by gene-specific
      PCR.
AB  - PCR primers specific for the recently described antimicrobial resistance
      associated Escherichia coli clonal group A (CGA), a widespread cause of drug
      resistant urinary tract infections in the United States, were devised on the
      basis of a novel single-nucleotide polymorphism identified within the
      housekeeping gene fumC, i.e., C288T. In comparison with two reference PCR-based
      fingerprinting methods, ERIC2 PCR and random amplified polymorphic DNA (RAPD)
      analysis, a PCR assay incorporating the new primers provided 100% sensitivity and
      100% specificity for the detection of CGA among 138 diverse clinical and
      reference E. coli isolates. E. coli reference (ECOR) strain 47 was shown to be a
      member or a close relative of CGA (by ERIC2 PCR and RAPD analysis, respectively)
      and yielded a positive assay result. The new CGA-specific PCR assay, which
      exhibited interlaboratory reproducibility and stability under various
      experimental conditions, should allow the rapid and specific detection of CGA by
      any laboratory equipped for diagnostic PCR.

PMID- 15184443
TI  - Performance characteristics of the immunoglobulin G-capture BED-enzyme
      immunoassay, an assay to detect recent human immunodeficiency virus type 1
      seroconversion.
AB  - Recently, we developed an immunoglobulin G (IgG)-capture BED-enzyme immunoassay
      (BED-CEIA) to identify recent human immunodeficiency virus (HIV) type 1 (HIV-1)
      seroconversion for use in incidence estimates. We have established an algorithm
      for its use; developed quality control reagents to monitor the assay; and
      evaluated its performance for interrun, intrarun, and operator variability.
      Analysis of 144 individual plates, which involved multiple plate lots and several
      operators over more than a year, indicated that the coefficients of variation
      (CVs) were between 10 and 15% for raw optical density (OD) values in the dynamic
      range between 0.5 and 2.0 OD units; the CVs decreased to 5 to 10% when the OD was
      normalized (OD-n; OD-n = specimen OD/calibrator OD). The intrarun CVs were
      generally in the range of 5 to 10% for specimens with ODs <0.5 and less than 5%
      for specimens with ODs >0.5. The level of concordance between multiple plate lots
      (n = 6) and multiple operators (n = 7) was quite high (R(2) > 0.9). Comparison of
      the results of the initial and the confirmatory tests with specimens with OD-n
      values </=1.5 demonstrated a high degree of correlation (R(2) = 0.92); 566 (92%)
      of 615 of specimens tested in the two modes retained the same classification
      (recent or long-term infection). The values for those specimens with changed
      classifications (n = 49) were close to the cutoff (OD-n = 1.0), as expected. The
      twofold difference in the HIV IgG contents between the controls and the
      calibrator reagents was exploited to monitor individual plate runs by using a
      control plot, which was incorporated into the spreadsheet for data entry and run
      monitoring. This information provides baseline data for the successful transfer
      of BED-CEIA to other laboratories and the use of BED-CEIA for the detection of
      recent HIV seroconversion and the calculation of incidence estimates worldwide.

PMID- 15184444
TI  - Sensitive and specific monoclonal antibody-based capture enzyme immunoassay for
      detection of nucleocapsid antigen in sera from patients with severe acute
      respiratory syndrome.
AB  - A rapid antigen test for the diagnosis of severe acute respiratory syndrome
      (SARS) is essential for control of this disease at the point of management. The
      nucleocapsid (N) protein of SARS-associated coronavirus (SARS-CoV) is abundantly
      expressed in infected-cell culture filtrate as demonstrable by Western blotting
      using convalescent-phase sera from patients with SARS. We used monoclonal
      antibodies specifically directed against N protein to establish a sensitive
      antigen capture sandwich enzyme-linked immunosorbent assay (ELISA) for the
      detection of SARS-CoV. The assay employed a mixture of three monoclonal
      antibodies for capture and rabbit polyclonal antibodies for detection of serum
      antigen in 32 cases of clinically probable SARS as defined by the World Health
      Organization during the epidemic in Guangzhou, China. Recombinant N protein was
      used as a standard to establish a detection sensitivity of approximated 50 pg/ml.
      The linear range of detection in clinical specimens was from 100 pg/ml to 3.2
      ng/ml. Using a panel of sera collected at different points in time, the amount of
      circulating N antigen was found to peak 6 to 10 days after the onset of symptoms.
      The sensitivity of the assay was 84.6% in 13 serologically confirmed SARS
      patients with blood taken during the first 10 days after the onset of symptoms
      (11 of 13). The specificity of the assay was 98.5% in 1,272 healthy individuals
      (1,253 of 1,272). There was no cross-reaction with other human and animal
      coronaviruses in this assay. In conclusion, a sensitive and quantitative antigen
      capture ELISA was established for the early diagnosis and disease monitoring of
      SARS-CoV infection.

PMID- 15184445
TI  - Comparison of the Roche LightCycler vanA/vanB detection assay and culture for
      detection of vancomycin-resistant enterococci from perianal swabs.
AB  - We compared the performance characteristics of a real-time PCR method, the
      LightCycler vanA/vanB detection assay (Roche Diagnostics Corporation,
      Indianapolis, Ind.) to that of Enterococcosel agar (BBL, Sparks, Md.) for direct
      detection of vancomycin-resistant enterococci (VRE) from 894 perianal stool
      swabs. For 421 of 894 swabs, the result for LightCycler PCR was compared to an
      Enterococcosel plate containing vancomycin at 6 microg/ml; for the remaining 473
      swabs, the result for LightCycler PCR was compared to an Enterococcosel plate
      containing 8 microg/ml vancomycin. The LightCycler method produced considerably
      more positive results than either the Enterococcosel plate containing vancomycin
      at 6 microg/ml (n = 25 versus n = 11; sensitivity, 100%; specificity, 97%;
      positive predictive value [PPV], 42%; negative predictive value [NPV], 100%) or
      the Enterococcosel plate containing vancomycin at 8 microg/ml (n = 31 versus n =
      10; sensitivity, 100%; specificity, 95%; PPV, 32%; NPV, 100%). When possible,
      additional testing, including culture, LightCycler PCR, and/or a conventional PCR
      method (PCR-restriction fragment length polymorphism assay), were performed on
      either the original specimens or original cultures or subsequent specimens for
      cases in which the original specimen was positive by LightCycler PCR but the
      Enterococcosel plate was negative. This additional testing demonstrated positive
      results for 7 of 14 (50%) evaluable discordant specimens which initially tested
      as LightCycler PCR positive but culture negative using the Enterococcosel plate
      containing vancomycin at 6 microg/ml and 12 of 17 (71%) evaluable discordant
      specimens which initially tested as LightCycler positive but culture negative
      using the Enterococcosel plate containing vancomycin at (8 microg/ml). These
      results demonstrate that the LightCycler VRE detection assay is considerably more
      sensitive than the standard culture method for detecting VRE directly from
      perianal swab specimens. The LightCycler assay also provides results much faster
      than culture (approximately 3.5 versus > or =72 h). The use of this test could
      have important implications for the effective control and prevention of
      nosocomial outbreaks of VRE.

PMID- 15184446
TI  - Real-time PCR assay using fine-needle aspirates and tissue biopsy specimens for
      rapid diagnosis of mycobacterial lymphadenitis in children.
AB  - A real-time PCR assay was developed to diagnose and identify the causative agents
      of suspected mycobacterial lymphadenitis. Primers and probes for the real-time
      PCR were designed on the basis of the internal transcribed spacer sequence,
      enabling the recognition of the genus Mycobacterium and the species Mycobacterium
      avium and M. tuberculosis. The detection limit for the assay was established at
      1,100 CFU/ml of pus, and the specificity tests showed no false-positive reaction
      with other mycobacterial species and other pathogens causing lymphadenitis. From
      67 children with suspected mycobacterial lymphadenitis based on a positive
      mycobacterial skin test, 102 samples (58 fine-needle aspirates [FNA] and 44
      tissue specimens) were obtained. The real-time PCR assay detected a mycobacterial
      infection in 48 patients (71.6%), whereas auramine staining and culturing were
      positive for 31 (46.3%) and 28 (41.8%) of the patients. The addition of the real
      time PCR assay to conventional diagnostic tests resulted in the recognition of 13
      more patients with mycobacterial disease. These results indicate that the real
      time PCR is more sensitive than conventional staining and culturing techniques (P
      = 0.006). The M. avium-specific real-time PCR was positive for 38 patients, and
      the M. tuberculosis-specific real-time PCR was positive for 1 patient. Analysis
      of 27 patients from whom FNA and tissue biopsy specimens were collected revealed
      significantly more positive real-time PCR results for FNA than for tissue biopsy
      specimens (P = 0.003). Samples from an age-matched control group of 50 patients
      with PCR-proven cat scratch disease were all found to be negative by the real
      time PCR. We conclude that this real-time PCR assay with a sensitivity of 72% for
      patients with lymphadenitis and a specificity of 100% for the detection of
      atypical mycobacteria can provide excellent support for clinical decision making
      in children with lymphadenitis.

PMID- 15184447
TI  - Identification of clinically relevant viridans group streptococci by sequence
      analysis of the 16S-23S ribosomal DNA spacer region.
AB  - The feasibility of sequence analysis of the 16S-23S ribosomal DNA (rDNA)
      intergenic spacer (ITS) for the identification of clinically relevant viridans
      group streptococci (VS) was evaluated. The ITS regions of 29 reference strains
      (11 species) of VS were amplified by PCR and sequenced. These 11 species were
      Streptococcus anginosus, S. constellatus, S. gordonii, S. intermedius, S. mitis,
      S. mutans, S. oralis, S. parasanguinis, S. salivarius, S. sanguinis, and S.
      uberis. The ITS lengths (246 to 391 bp) and sequences were highly conserved among
      strains within a species. The intraspecies similarity scores for the ITS
      sequences ranged from 0.98 to 1.0, except for the score for S. gordonii strains.
      The interspecies similarity scores for the ITS sequences varied from 0.31 to
      0.93. Phylogenetic analysis of the ITS regions revealed that evolution of the
      regions of some species of VS is not parallel to that of the 16S rRNA genes. One
      hundred six clinical isolates of VS were identified by the Rapid ID 32 STREP
      system (bioMerieux Vitek, Marcy l'Etoile, France) and by ITS sequencing, and the
      level of disagreement between the two methods was 18% (19 isolates). Most
      isolates producing discrepant results could be unambiguously assigned to a
      specific species by their ITS sequences. The accuracy of using ITS sequencing for
      identification of VS was verified by 16S rDNA sequencing for all strains except
      strains of S. oralis and S. mitis, which were difficult to differentiate by their
      16S rDNA sequences. In conclusion, identification of species of VS by ITS
      sequencing is reliable and could be used as an alternative accurate method for
      identification of VS.

PMID- 15184449
TI  - Comparative evaluation of three serological methods for detection of human
      herpesvirus 8-specific antibodies in Canadian allogeneic stem cell transplant
      recipients.
AB  - Human herpesvirus 8 (HHV-8) has been associated with all types of Kaposi's
      sarcoma (KS), including posttransplantation KS. However, little is known
      regarding HHV-8 infections in hematopoietic stem cell transplant (SCT)
      recipients. In this study, we used a variety of serological assays, including in
      house-developed enzyme immunoassays (EIAs) utilizing synthetic peptides
      corresponding to lytic viral antigens (ORFs 65 and K8.1) and a commercial EIA kit
      based on a whole virus lysate (Advanced Biotechnologies Inc.), as well as latent-
      and lytyc-antigen-based immunofluorescence assays (IFAs) to determine the
      seroprevalence of HHV-8 in 42 allogeneic SCT recipients from Canada. Using the
      two peptide-based EIA methods as for screening, HHV-8-specific antibodies were
      detected in five (12%) patients between days 21 and 91, although only one (2%)
      subject was positive for HHV-8-specific antibodies before transplantation. All
      positive results from these five patients were confirmed by at least one of the
      IFAs, with an additional patient showing seropositivity before transplantation.
      However, the commercial EIA was negative at all time points (days -7, 21, and 91)
      in those five patients. The episodes of seroconversion or reactivation were not
      associated with sustained viremia, since HHV-8 DNA was not detected by real-time
      PCR in the corresponding leukocytes and plasma of the seropositive patients. No
      clinical or laboratory abnormalities were clearly associated with HHV-8
      seropositivity. This study confirms the utility of simple peptide-based EIA
      methods to assess the presence of HHV-8-specific antibodies in immunocompromised
      patients and emphasizes the need of conducting prospective studies to determine
      the source of HHV-8 infection in SCT recipients.

PMID- 15184448
TI  - Generation and infectivity titration of an infectious stock of avian hepatitis E
      virus (HEV) in chickens and cross-species infection of turkeys with avian HEV.
AB  - Avian hepatitis E virus (HEV), a novel virus identified from chickens with
      hepatitis-splenomegaly syndrome in the United States, is genetically and
      antigenically related to human HEV. In order to further characterize avian HEV,
      an infectious viral stock with a known infectious titer must be generated, as HEV
      cannot be propagated in vitro. Bile and feces collected from specific-pathogen
      free (SPF) chickens experimentally infected with avian HEV were used to prepare
      an avian HEV infectious stock as a 10% suspension of positive fecal and bile
      samples in phosphate-buffered saline. The infectivity titer of this infectious
      stock was determined by inoculating 1-week-old SPF chickens intravenously with
      200 microl of each of serial 10-fold dilutions (10(-2) to 10(-6)) of the avian
      HEV stock (two chickens were inoculated with each dilution). All chickens
      inoculated with the 10(-2) to 10(-4) dilutions of the infectious stock and one of
      the two chickens inoculated with the 10(-5) dilution, but neither of the chickens
      inoculated with the 10(-6) dilution, became seropositive for anti-avian HEV
      antibody at 4 weeks postinoculation (wpi). Two serologically negative contact
      control chickens housed together with chickens inoculated with the 10(-2)
      dilution also seroconverted at 8 wpi. Viremia and shedding of virus in feces were
      variable in chickens inoculated with the 10(-2) to 10(-5) dilutions but were not
      detectable in those inoculated with the 10(-6) dilution. The infectivity titer of
      the infectious avian HEV stock was determined to be 5 x 10(5) 50% chicken
      infectious doses (CID(50)) per ml. Eight 1-week-old turkeys were intravenously
      inoculated with 10(5) CID(50) of avian HEV, and another group of nine turkeys
      were not inoculated and were used as controls. The inoculated turkeys
      seroconverted at 4 to 8 wpi. In the inoculated turkeys, viremia was detected at 2
      to 6 wpi and shedding of virus in feces was detected at 4 to 7 wpi. A
      serologically negative contact control turkey housed together with the inoculated
      ones also became infected through direct contact. This is the first demonstration
      of cross-species infection by avian HEV.

PMID- 15184450
TI  - Etiology of sporadic cases of pediatric acute gastroenteritis in asturias, Spain,
      and genotyping and characterization of norovirus strains involved.
AB  - From November 2000 to October 2001, a reverse transcription-PCR using primers
      directed to the norovirus RNA polymerase coding region was included in a viral
      and bacterial routine screening to diagnose sporadic cases of acute
      gastroenteritis among children in Asturias, Spain. The role of noroviruses (8.6%
      of the positively diagnosed cases) as the cause of sporadic pediatric
      gastroenteritis was evaluated with respect to the detection rates of other
      gastroenteritis-associated viruses and bacteria. The results indicated that
      noroviruses were less common than rotaviruses (36.9%), Campylobacter spp.
      (28.8%), and Salmonella spp. (18.4%) but more frequent than astroviruses (4.3%),
      adenoviruses (3.8%), and Yersinia spp. (2.2%). Mixed infections involving
      noroviruses were rarely observed (0.5%). The presence of a norovirus-associated
      pediatric gastroenteritis peak in summer, as well as the complete absence of
      norovirus-associated cases in colder months, challenges the view that norovirus
      infections exclusively have wintertime seasonality. On the other hand,
      phylogenetic analysis of the amplified fragments showed that the norovirus
      strains responsible were closely related. A further study using the full-length
      capsid region showed that these strains could be included into genogroup II,
      Bristol/Lorsdale cluster, and were closely related to the 1995 and 1996 U.S.
      subset of strains associated with outbreaks recorded worldwide between 1995 and
      1996.

PMID- 15184451
TI  - Characterization of novel coding sequences specific to Mycobacterium avium subsp.
      paratuberculosis: implications for diagnosis of Johne's Disease.
AB  - Mycobacterium avium subsp. paratuberculosis is the causative agent of Johne's
      Disease, an economically important intestinal ailment of ruminants. Due to the
      considerable genetic and serologic cross-reactivity with closely related and
      ubiquitous members of the M. avium complex, a species-specific method for the
      serological diagnosis of Johne's disease is unavailable. Computational and PCR
      based analysis of the complete genome sequence of M. avium subsp.
      paratuberculosis led to the identification of 13 open reading frames with no
      identifiable homologs. One of these sequences is a putative insertion element
      present in six copies on the M. avium subsp. paratuberculosis genome. These novel
      M. avium subsp. paratuberculosis genes were cloned into Escherichia coli
      expression vectors, and nine were successfully expressed as recombinant fusion
      proteins. Five of these proteins were purified in sufficient amounts to allow
      immunoblot analyses of their reactivity with sera from naturally infected cattle
      as well as mice and rabbits exposed to M. avium subsp. paratuberculosis. Fusion
      proteins representing MAP0862, MAP3732c, and MAP2963c were recognized by nearly
      all of the sera tested, including those from cattle in the clinical stages of
      disease. Notably, further analysis of the protein encoded by MAP0862 showed that
      it reacted with sera from additional infected cattle but not with sera from
      uninfected control animals. The fusion product of MAP0860c did not react with any
      of the sera tested, while the remaining four proteins were variably recognized by
      sera from M. avium subsp. paratuberculosis-infected cattle. Collectively, the
      results of this study demonstrate the utility of genomic data to identify
      potential diagnostic sequences.

PMID- 15184452
TI  - Prevalence of Helicobacter pylori vacA and cagA genotypes in Ethiopian dyspeptic
      patients.
AB  - A total of 300 gastric biopsy samples and 50 Helicobacter pylori isolates were
      collected from Ethiopian adult dyspeptic patients. The vacA and cagA genes were
      detected in 90 and 79% of biopsy specimens, respectively, and in 100 and 87% of
      clinical isolates, respectively. Both genes were detected in 84% of the gastric
      biopsy samples and in 87% of the clinical isolates. Among vacA genotypes, the
      s1/m1 genotype was the most common in gastric biopsy samples (48%). The vacA and
      cagA positive H. pylori strains were detected to a higher degree in patients with
      chronic active gastritis (71%) than patients with other histopathological
      findings (29%) (P < 0.05).

PMID- 15184453
TI  - Evaluation of a high-throughput repetitive-sequence-based PCR system for DNA
      fingerprinting of Mycobacterium tuberculosis and Mycobacterium avium complex
      strains.
AB  - Repetitive-sequence-based PCR (rep-PCR) is useful for generating DNA fingerprints
      of diverse bacterial and fungal species. Rep-PCR amplicon fingerprints represent
      genomic segments lying between repetitive sequences. A commercial system that
      electrophoretically separates rep-PCR amplicons on microfluidic chips, and
      provides computer-generated readouts of results has been adapted for use with
      Mycobacterium species. The ability of this system to type M. tuberculosis and M.
      avium complex (MAC) isolates was evaluated. M. tuberculosis strains (n = 56) were
      typed by spoligotyping with rep-PCR as a high-resolution adjunct. Results were
      compared with those generated by a standard approach of spoligotyping with IS6110
      targeted restriction fragment length polymorphism (IS6110-RFLP) as the high
      resolution adjunct. The sample included 11 epidemiologically and genotypically
      linked outbreak isolates and a population-based sample of 45 isolates from recent
      immigrants to Seattle, Wash., from the African Horn countries of Somalia,
      Eritrea, and Ethiopia. Twenty isolates exhibited unique spoligotypes and were not
      analyzed further. Of the 36 outbreak and African Horn isolates with nonunique
      spoligotypes, 23 fell into four clusters identified by IS6110-RFLP and rep-PCR,
      with 97% concordance observed between the two methods. Both approaches revealed
      extensive strain heterogeneity within the African Horn sample, consistent with a
      predominant pattern of reactivation of latent infections in this immigrant
      population. Rep-PCR exhibited 89% concordance with IS1245-RFLP typing of 28 M.
      avium subspecies avium strains. For M. tuberculosis as well as M. avium
      subspecies avium, the discriminative power of rep-PCR equaled or exceeded that of
      RFLP. Rep-PCR also generated DNA fingerprints from M. intracellulare (n = 8) and
      MAC(x) (n = 2) strains. It shows promise as a fast, unified method for high
      throughput genotypic fingerprinting of multiple Mycobacterium species.

PMID- 15184455
TI  - Detection and prevalence of active drug efflux mechanism in various multidrug
      resistant Klebsiella pneumoniae strains from Turkey.
AB  - The prevalence of active drug efflux pump and porin alterations was investigated
      in Turkish nosocomial strains of Klebsiella pneumoniae exhibiting a multidrug
      resistant phenotype. MICs of various antibiotics, including quinolones,
      chloramphenicol, tetracycline, and beta-lactams, for those strains were
      determined either with or without the efflux pump inhibitor phenylalanine
      arginine beta-naphthylamide (PAbetaN). Thirty-nine percent of the strains
      exhibited a PAbetaN-modulated resistance for quinolones, chloramphenicol, and
      tetracycline. In these strains, a significant increase of chloramphenicol
      accumulation was gained in the presence of the efflux pump inhibitor PAbetaN or
      with the energy uncoupler carbonyl cyanide m-chlorophenylhydrazone. Moreover,
      high-level expression of the membrane fusion protein AcrA, which was
      immunodetected in most of those isolates, suggests that the AcrAB/TolC efflux
      machinery contributed to their antibiotic resistance. Studies of K. pneumoniae
      porins indicated that the majority of the strains, including extended-spectrum
      beta-lactamase producers and efflux-positive ones, presented an alteration in
      their sorbitol-sensitive porin (OmpK35) expression. This is the first report
      showing the prominent role of active drug efflux in the antibiotic resistance of
      nosocomial K. pneumoniae strains from Turkey.

PMID- 15184454
TI  - Comparison of blood smear, antigen detection, and nested-PCR methods for
      screening refugees from regions where malaria is endemic after a malaria outbreak
      in Quebec, Canada.
AB  - The importation of malaria into a region where it is not endemic raises many
      concerns, including the timely delivery of appropriate care, safety of the blood
      supply, and the risk of autochthonous transmission. There is presently no
      consensus on the best way to screen mobile populations for malaria. Between
      August 2000 and March 2001, 535 refugees arrived in Quebec, Canada, from
      Tanzanian camps. Within 4 weeks of resettlement of the first group of 224, the
      McGill University Centre for Tropical Diseases noted an outbreak of malaria
      across the province (15 cases over a 3-week period). This group (group 1) was
      traced and screened for malaria between 3 and 4 months after arrival in Canada.
      Subsequent groups of 106 and 205 refugees were screened immediately upon arrival
      in Canada (group 2) and immediately prior to their departure from refugee camps
      (group 3), respectively. A single EDTA-blood sample was obtained from 521
      refugees for testing by thick and thin blood smears (groups 1 and 2), antigen
      detection (ICT Malaria Pf and OptiMAL; group 1 only), and nested PCR (all
      groups). Overall, 98 of 521 refugees were found to be infected (18.8%). The vast
      majority of infections (81 of 98) were caused by Plasmodium falciparum alone.
      Using PCR as the "gold standard," both microscopy (sensitivity, 50%; specificity,
      100%) and antigen detection (ICT sensitivity, 37.5%; ICT specificity, 100%;
      OptiMAL sensitivity, 29.1%; OptiMAL specificity, 95.6%) performed poorly. None of
      the PCR-positive subjects were symptomatic at the time of testing, and only two
      had recently had symptoms compatible with malaria (with or without diagnosis and
      treatment). Active surveillance of migrants from regions of intense malaria
      transmission can reduce the risk of morbidity in the migrant population and
      mitigate against transmission to the host population. Our data demonstrate that
      PCR is, by far, the most powerful tool for such surveillance.

PMID- 15184456
TI  - Prevalence of and risk factors for feline Tritrichomonas foetus and giardia
      infection.
AB  - Data were gathered for 117 cats from 89 catteries at an international cat show to
      examine prevalence and risk factors for feline Tritrichomonas foetus and Giardia
      infection. Prevalence of T. foetus was 31% among cats (36 out of 117) and
      catteries (28 out of 89) based on results of fecal smear examination (5 out of
      36), fecal culture in modified Diamond's medium (9 out of 36), fecal culture in
      In Pouch TF medium (20 out of 36), or PCR amplification of the ribosomal RNA gene
      from feces with T. foetus-specific primers (34 out of 36). Catteries in which T.
      foetus was identified were more likely to have had a recent history of diarrhea,
      historical diagnosis of coccidia infection in adult cats, and a decreased number
      of square feet of facility per cat. Evidence did not exist for the ongoing
      transmission of T. foetus by water, food, or contact with other species.

PMID- 15184457
TI  - Performance of the Celera Diagnostics ViroSeq HIV-1 Genotyping System for
      sequence-based analysis of diverse human immunodeficiency virus type 1 strains.
AB  - The Celera Diagnostics ViroSeq HIV-1 Genotyping System is a Food and Drug
      Administration-cleared, integrated system for sequence-based analysis of drug
      resistance mutations in subtype B human immunodeficiency virus type 1 (HIV-1)
      protease and reverse transcriptase (RT). We evaluated the performance of this
      system for the analysis of diverse HIV-1 strains. Plasma samples were obtained
      from 126 individuals from Uganda, Cameroon, South Africa, Argentina, Brazil, and
      Thailand with viral loads ranging from 2.92 to >6.0 log(10) copies/ml. HIV-1
      genotyping was performed with the ViroSeq system. HIV-1 subtyping was performed
      by using phylogenetic methods. PCR products suitable for sequencing were obtained
      for 125 (99%) of the 126 samples. Genotypes including protease (amino acids 1 to
      99) and RT (amino acids 1 to 321) were obtained for 124 (98%) of the samples.
      Full bidirectional sequence data were obtained for 95 of those samples. The
      sequences were categorized into the following subtypes: A1/A2 (16 samples), B (12
      samples), C (13 samples), D (11 samples), CRF01_AE (9 samples), F/F2 (9 samples),
      G (7 samples), CRF02_AG (32 samples), H (1 sample), and intersubtype recombinant
      (14 samples). The performances of the individual sequencing primers were
      examined. Genotyping of duplicate samples in a second laboratory was successful
      for 124 of the 126 samples. The identity level for the sequence data from two
      laboratories ranged from 98 to 100% (median, 99.8%). The ViroSeq system performs
      well for the analysis of plasma samples with diverse non-B subtypes. The
      availability of this genotyping system should facilitate studies of HIV-1 drug
      resistance in non-subtype B strains of HIV-1.

PMID- 15184458
TI  - DNA Sequence analysis of the PorB protein of nonserotypeable serogroup C ET-15
      meningococci suggests a potential mutational hot spot on their serotype antigens.
AB  - The nucleotide sequences of the PorB proteins from 28 nonserotypeable serogroup C
      ET-15 meningococci recovered from invasive meningococcal disease cases were
      determined. PCR amplification of the porB genes responsible for encoding the
      serotype antigen was used for DNA sequence determination and identification of
      the nature of the serotype antigen. DNA sequencing revealed that three strains
      were of serotype 2a, and of the remaining 25 strains, 20 were found to have an
      identical single point mutation in the region of the VR3 gene, which encodes
      surface-exposed loop VI, where the serotype 2a epitope resides. This
      nonsynonymous mutation was confirmed by synthetic peptide immunochemical analysis
      to confer new serospecificity to these serotype 2a mutants. This finding of a
      potential novel mutational hot spot on the PorB proteins of meningococci may have
      implications for pathogenesis and vaccine development.

PMID- 15184459
TI  - Use of the hupB gene encoding a histone-like protein of Mycobacterium
      tuberculosis as a target for detection and differentiation of M. tuberculosis and
      M. bovis.
AB  - The gene for histone-like protein (hupB [Rv2986c]) of Mycobacterium tuberculosis
      has been identified as a singular target which allows differentiation of two
      closely related mycobacterial species, namely, M. tuberculosis and M. bovis of
      the MTB complex, by a PCR assay. The N and S primer-generated PCR amplicons
      differed in M. tuberculosis and M. bovis; these amplicons were determined to be
      645 and 618 bp, respectively. This difference was localized to the C-terminal
      part of the gene by using primers M and S. The C-terminal PCR amplicons of M.
      tuberculosis and M. bovis were determined to be 318 and 291 bp, respectively. The
      differences in the C-terminal portion of the gene were confirmed by restriction
      fragment length polymorphism analysis and sequencing. Sequence analysis indicated
      that in M. bovis there was a deletion of 27 bp (9 amino acids) in frame after
      codon 128 in the C-terminal part of the hupB gene. In the present study 104
      mycobacterial strains and 11 nonmycobacterial species were analyzed for hupB gene
      sequences. Of the 104 mycobacterial strains included, 62 belonged to the MTB
      complex and 42 were non-MTB complex strains and species. Neither the hupB gene
      specific primers (N and S) nor the C-terminal primers (M and S) amplify DNA from
      any other mycobacteria, making the assay suitable for distinguishing members of
      the MTB complex from other mycobacterial species, as well as for differentiating
      between members of the MTB complex, namely, M. tuberculosis and M. bovis.

PMID- 15184460
TI  - Prospective comparison of the diagnostic potential of real-time PCR, double
      sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1-->3)-beta
      D-glucan test in weekly screening for invasive aspergillosis in patients with
      hematological disorders.
AB  - The establishment of an optimal noninvasive method for diagnosing invasive
      aspergillosis (IA) is needed to improve the management of this life-threatening
      infection in patients with hematological disorders, and a number of noninvasive
      tests for IA that target different fungal components, including galactomannan, (1
      ->3)-beta-d-glucan (BDG), and Aspergillus DNA, have been developed. In this
      study, we prospectively evaluated the diagnostic potential of three noninvasive
      tests for IA that were used in a weekly screening strategy: the double-sandwich
      enzyme-linked immunosorbent assay (ELISA) for galactomannan (Platelia
      Aspergillus), a real-time PCR assay for Aspergillus DNA (GeniQ-Asper), and an
      assay for BDG (beta-glucan Wako). We analyzed 149 consecutive treatment episodes
      in 96 patients with hematological disorders who were at high risk for IA and
      diagnosed 9 proven IA cases, 2 probable IA cases, and 13 possible invasive fugal
      infections. In a receiver-operating characteristic (ROC) analysis, the area under
      the ROC curve was greatest for ELISA, using two consecutive positive results
      (0.97; P = 0.036 for ELISA versus PCR, P = 0.055 for ELISA versus BDG). Based on
      the ROC curve, the cutoff for the ELISA could be reduced to an optical density
      index (O.D.I.) of 0.6. With the use of this cutoff for ELISA and cutoffs for PCR
      and BDG that give a comparable level of specificity, the
      sensitivity/specificity/positive predictive value/negative predictive value of
      the ELISA and the PCR and BDG tests were 1.00/0.93/0.55/1.00,
      0.55/0.93/0.40/0.96, and 0.55/0.93/0.40/0.96, respectively. In conclusion, among
      these weekly screening tests for IA, the double-sandwich ELISA test was the most
      sensitive at predicting the diagnosis of IA in high-risk patients with
      hematological disorders, using a reduced cutoff of 0.6 O.D.I.

PMID- 15184462
TI  - Ileocolitis associated with Anaerobiospirillum in cats.
AB  - Ileocolitis associated with spiral bacteria identified as an Anaerobiospirillum
      sp. was found in six cats. Two cats had acute onset of gastrointestinal signs
      characterized by vomiting and diarrhea in one cat and vomiting in another cat,
      one cat had chronic diarrhea that was refractory to medical therapy; one cat had
      acute onset of anorexia and lethargy, and two cats had clinical signs that were
      not related to the gastrointestinal tract. The presence of an Anaerobiospirillum
      sp. was demonstrated on the basis of ultrastructural morphology of spiral
      bacteria associated with intestinal lesions and PCR amplification of a genus
      specific 16S rRNA gene from affected tissues from each cat. The colons of three
      clinically healthy cats without lesions and one cat with mild colitis not
      associated with spiral bacteria were negative for Anaerobiospirillum spp. in the
      same assay. Comparative nucleotide sequence analysis of cloned PCR products from
      three affected cats further suggested that the spiral bacteria were closely
      related to Anaerobiospirillum succiniciproducens.

PMID- 15184461
TI  - Identification of subtype C human immunodeficiency virus type 1 by subtype
      specific PCR and its use in the characterization of viruses circulating in the
      southern parts of India.
AB  - Human immunodeficiency virus type 1 (HIV-1) subtype C viruses are associated with
      nearly half of worldwide HIV-1 infections and are most predominant in India and
      the southern and eastern parts of Africa. Earlier reports from India identified
      the preponderance of subtype C and a small proportion of subtype A viruses.
      Subsequent reports identifying multiple subtypes suggest new introductions and/or
      their detection due to extended screening. The southern parts of India constitute
      emerging areas of the epidemic, but it is not known whether HIV-1 infection in
      these areas is associated with subtype C viruses or is due to the potential new
      introduction of non-subtype C viruses. Here, we describe the development of a
      specific and sensitive PCR-based strategy to identify subtype C-viruses (C-PCR).
      The strategy is based on amplifying a region encompassing a long terminal repeat
      and gag in the first round, followed by two sets of nested primers; one amplifies
      multiple subtypes, while the other is specific to subtype C. The common HIV and
      subtype C-specific fragments are distinguishable by length differences in agarose
      gels and by the difference in the numbers of NF-kappaB sites encoded in the
      subtype C-specific fragment. We implemented this method to screen 256 HIV-1
      infected individuals from 35 towns and cities in four states in the south and a
      city in the east. With the exception of single samples of subtypes A and B and a
      B/C recombinant, we found all to be infected with subtype C viruses, and the
      subtype assignments were confirmed in a subset by using heteroduplex mobility
      assays and phylogenetic analysis of sequences. We propose the use of C-PCR to
      facilitate rapid molecular epidemiologic characterization to aid vaccine and
      therapeutic strategies.

PMID- 15184464
TI  - Identification of enterohepatic Helicobacter species in patients suffering from
      inflammatory bowel disease.
AB  - Using a group-specific PCR assay, we investigated the presence of enterohepatic
      Helicobacter species in gut specimens from patients with inflammatory bowel
      disease. Enterohepatic Helicobacter species were detected in 12% (3 of 25) of the
      patients with Crohn's disease, in 17% (3 of 18) of the ulcerative colitis
      samples, and in 4% (1 of 23) of the controls.

PMID- 15184463
TI  - Use of a recombinant envelope protein subunit antigen for specific serological
      diagnosis of West Nile virus infection.
AB  - Serological diagnosis of West Nile virus (WNV) infection is complicated by
      extensive antigenic cross-reactivity with other closely related flaviviruses,
      such as St. Louis encephalitis virus. Here we describe a recombinant, bacterially
      expressed antigen equivalent to structural domain III of the WNV envelope protein
      that has allowed clear discrimination of antibody responses to WNV from those
      against other related flaviviruses in indirect enzyme-linked immunosorbent assays
      using standardized control antisera and field-collected samples.

PMID- 15184465
TI  - Rapid immunochromatographic test for serodiagnosis of canine leishmaniasis.
AB  - An rK39 immunochromatographic test and immunofluorescent-antibody test (IFAT) for
      serodiagnosis of canine leishmaniasis were evaluated. The two tests showed
      correlation for all but one of the sera obtained from 68 dogs confirmed as
      leishmaniasis cases and 40 dogs (22 healthy dogs and 18 dogs with other diseases)
      from areas where the disease is not endemic. Specificity was 100% for both tests,
      while sensitivity was 97% for the rapid test and 99% for IFAT.

PMID- 15184466
TI  - High-efficiency detection of severe acute respiratory syndrome virus genetic
      material.
AB  - A Taqman amplicon targeting the nucleocapsid gene of severe acute respiratory
      syndrome coronavirus (SARS-CoV) is 5 log(10) times more sensitive for SARS-CoV
      target RNA extracted from infected cells and 2.79 log(10) times more sensitive
      for RNA extracted from patient material of the index case in Frankfurt than an
      amplicon targeting the polymerase gene.

PMID- 15184467
TI  - Comparison of versions 1.0 AND 1.5 of the UltraSensitive AMPLICOR HIV-1 MONITOR
      test for subjects with low viral load.
AB  - We compared the performance of two UltraSensitive AMPLICOR HIV-1 MONITOR kits
      (version 1.5 [v1.5] versus v1.0) by retesting 404 plasma samples with low viral
      loads (<3,000 copies/ml) with both kits. With 292 samples that initially had <50
      copies/ml by the v1.0 kit, the v1.5 assay was more sensitive than the v1.0 assay
      for samples with human immunodeficiency virus type 1 RNA near the 50-copy/ml
      cutoff (P = 0.0146). Median numbers of copies per milliliter were similar for 112
      samples with 50 to 3,000 copies/ml with no difference in sensitivity with a 200
      copy/ml cutoff.

PMID- 15184468
TI  - Incidence of constitutive and inducible clindamycin resistance in Staphylococcus
      aureus and coagulase-negative staphylococci in a community and a tertiary care
      hospital.
AB  - The incidences of inducible clindamycin resistance at two hospitals (an inner
      city hospital and a suburban community hospital) were 7 and 12% for methicillin
      resistant Staphylococcus aureus, 20 and 19% for methicillin-susceptible S.
      aureus, and 14 and 35% for coagulase-negative staphylococci, respectively. Given
      the variability of inducible resistance to clindamycin found in our two
      hospitals, we conclude that susceptibility testing of staphylococci should
      include the disk diffusion induction test (D-test).

PMID- 15184469
TI  - Evaluation of the methicillin-resistant Staphylococcus aureus (MRSA)-Screen latex
      agglutination test for detection of MRSA of animal origin.
AB  - Methicillin (oxacillin)-resistant staphylococci (MRS) have emerged as major
      clinical and epidemiological pathogens, and there have been frequent reports of
      MRS infections in the veterinary field. The MRSA-Screen latex agglutination test
      (Denka Seiken Co., Ltd., Tokyo, Japan) was compared with an oxacillin agar screen
      test, MIC determination, and mecA PCR assay, the "gold standard." In an analysis
      of 15 mecA-positive and 48 mecA-negative S. aureus animal isolates, as well as 9
      mecA-positive and 147 mecA-negative, coagulase-negative staphylococcal animal
      isolates, the latex agglutination test surpassed the widely used oxacillin agar
      screen method and MIC determination, with a sensitivity and a specificity of
      100%. The MRSA-Screen test is a reliable and rapid method of detecting MRS in the
      veterinary field.

PMID- 15184470
TI  - Clinical significance and mechanism of gas formation of pyogenic liver abscess
      due to Klebsiella pneumoniae.
AB  - We enrolled 22 patients with gas-forming pyogenic liver abscess in a study to
      assess the mechanism of gas formation. Klebsiella pneumoniae was cultured from
      specimens from all patients. Gas and pus samples from abscesses revealed four
      major components: nitrogen, oxygen, carbon dioxide, and hydrogen; this implicates
      mixed acid fermentation of glucose as the mechanism of gas formation.

PMID- 15184471
TI  - Immunoreactivity of cryptococcal antigen is not stable under prolonged
      incubations in human serum.
AB  - The stability of cryptococcal antigen from Cryptococcus neoformans serotype A and
      D strains at different temperatures in serum and other solvents was studied.
      Samples stored at -20 or 4 degrees C had equivalent stabilities as measured by
      the Premier Cryptococcal Antigen kit and the Cryptococcal Antigen Latex
      Agglutination System (CALAS) kit. However, using the Premier Cryptococcal Antigen
      kit, there was a 91% loss of reactivity in samples incubated in human serum for 4
      weeks at 37 degrees C. A loss of reactivity of more than 99% was observed after
      incubation at 45 degrees C for 4 weeks. The capsular antigen was not detected by
      the Premier Cryptococcal Antigen kit after 16 weeks at elevated temperatures.
      Antigen titers were also reduced in a latex agglutination assay (CALAS) after 4
      weeks at 37 and 45 degrees C. The loss of antigen reactivity was a function of pH
      and temperature.

PMID- 15184472
TI  - Multiple outbreaks of Yersinia pseudotuberculosis infections in Finland.
AB  - During 2001, 89 culture-confirmed cases of Yersinia pseudotuberculosis were
      reported in Finland; 55 (62%) were serotype O:1, and 34 (38%) were serotype O:3.
      Four major pulsed-field gel electrophoresis profiles were identified. A case
      control study of 25 case patients and 71 healthy controls identified eating
      outside the home as a risk factor for infection.

PMID- 15184473
TI  - A decline in mupirocin resistance in methicillin-resistant Staphylococcus aureus
      accompanied administrative control of prescriptions.
AB  - Susceptibility to mupirocin was assessed in methicillin-resistant Staphylococcus
      aureus isolates selected from eras corresponding to differences in usage rate and
      prescription policies at a Veterans Affairs medical center. The eras studied
      encompassed from the time of introduction of the drug to its widespread use,
      through recommended judicious use, and finally to subsequent stringent
      administrative control. Prescriptions declined from 3.0 to 0.1 per 1,000 patient
      days. Precipitous declines first in the numbers of isolates with high-level
      resistance (from 31% to 4%) and then in those with low-level resistance (from 26%
      to 10%) accompanied prescription control.

PMID- 15184474
TI  - Utility of reverse transcriptase PCR for rapid diagnosis of influenza a virus
      infection and detection of amantadine-resistant influenza a virus isolates.
AB  - A reverse transcriptase PCR was developed to detect 50 or 5,000 RNA copies of
      influenza A virus per ml in throat swab specimens. The assay was more sensitive
      than the Directigen Flu A test. The technique was also used to detect amantadine
      resistant isolates.

PMID- 15184475
TI  - Prevalence of Borrelia burgdorferi, Bartonella spp., Babesia microti, and
      Anaplasma phagocytophila in Ixodes scapularis ticks collected in Northern New
      Jersey.
AB  - PCR analysis of Ixodes scapularis ticks collected in New Jersey identified
      infections with Borrelia burgdorferi (33.6%), Babesia microti (8.4%), Anaplasma
      phagocytophila (1.9%), and Bartonella spp. (34.5%). The I. scapularis tick is a
      potential pathogen vector that can cause coinfection and contribute to the
      variety of clinical responses noted in some tick-borne disease patients.

PMID- 15184476
TI  - Molecular characterization and phylogenetic study of newcastle disease virus
      isolates from recent outbreaks in eastern Uganda.
AB  - Newcastle disease virus isolates from chickens in eastern Uganda in 2001 were
      found to be velogenic by fusion protein cleavage site sequence analysis and
      biological characterization; the intracerebral pathogenicity index was 1.8.
      Analysis of their hemagglutinin-neuraminidase protein gene sequences revealed a
      novel genotype unrelated to those that caused previous outbreaks.

PMID- 15184477
TI  - Survey of ferroxidase expression and siderophore production in clinical isolates
      of Pseudomonas aeruginosa.
AB  - Ferroxidase (encoded by the mco gene), a component of a ferrous iron uptake
      pathway in Pseudomonas aeruginosa, was detected in all of the 35 respiratory
      clinical isolates surveyed; in contrast, considerable variation in siderophore
      expression was observed. The ubiquitous expression of this periplasmic
      ferroxidase suggests that it plays a key role in iron uptake in this
      opportunistic pathogen.

PMID- 15184479
TI  - Hospital- and laboratory-based investigations of hospitalized children with
      central nervous system-related symptoms to assess Japanese encephalitis virus
      etiology in Cuddalore District, Tamil Nadu, India.
AB  - A collaborative investigation of hospitalized encephalitic children in south
      India, between July 2002 and February 2003, has indicated that Japanese
      encephalitis was confirmed in 27.3% of these children. In developing countries,
      assessment of actual Japanese encephalitis disease burden requires strengthening
      of diagnostic laboratory capacities at hospitals.

PMID- 15184478
TI  - Clonality of Streptococcus pneumoniae serotype 1 isolates from pediatric patients
      in the United States.
AB  - We compared Streptococcus pneumoniae serotype 1 isolates causing disease among
      children in six geographic regions of the United States to determine genetic
      relatedness. Genomic fingerprints were determined by repetitive element
      polymorphism PCR (Rep-PCR). Multilocus sequence type characterization was
      performed on selected isolates. Four different genomic banding patterns were
      identified by Rep-PCR. One profile (clone 1) was predominant and matched sequence
      type 227.

PMID- 15184481
TI  - Comparison of the sensitivities of the version 1.5 and version 1.0 ultrasensitive
      Roche AMPLICOR HIV-1 MONITOR kits at low concentrations of human immunodeficiency
      virus RNA.
AB  - The sensitivities of the version 1.5 and 1.0 Roche UltraSensitive AMPLICOR HIV-1
      MONITOR tests were compared using panels of coded samples of subtype B human
      immunodeficiency virus type 1 spiked into plasma at predetermined concentrations.
      Results indicate that the version 1.5 kit is more sensitive than the version 1.0
      kit.

PMID- 15184480
TI  - Sequencing and sequence analysis of VP7 and NSP5 genes reveal emergence of a new
      genotype of bovine group B rotaviruses in India.
AB  - Three bovine group B rotavirus strains were detected from diarrheic calves during
      a surveillance study of rotaviral diarrhea in West Bengal, India. The sequence
      analysis of VP7 and NSP5 genes of these strains demonstrates a high degree of
      sequence variation from other group B rotavirus strains, indicating the emergence
      of a new genotype.

PMID- 15184482
TI  - Multiplex PCR assay for rapid detection and genotyping of Helicobacter pylori
      directly from biopsy specimens.
AB  - We developed and evaluated a simple, novel multiplex PCR assay for rapid
      detection of Helicobacter pylori infection and for the determination of vacA and
      cagA genotypes directly from gastric biopsy specimens. This assay did not require
      culturing of strains or extraction of DNA from biopsy samples. This multiplex PCR
      assay would be of particularly great value for laboratories in developing
      countries.

PMID- 15184483
TI  - Outbreak of infection with hepatitis A virus (HAV) associated with a foodhandler
      and confirmed by sequence analysis reveals a new HAV genotype IB variant.
AB  - An outbreak of infection with hepatitis A virus associated with a foodhandler and
      involving 26 subjects occurred in Southern Italy. Sequence analysis of the VP3
      VP1 and VP1-P2A junctions confirmed that the outbreak was due to a point source
      and allowed the identification of a new genotype IB variant. This report confirms
      the usefulness of sequence-based molecular fingerprinting during outbreaks.

PMID- 15184484
TI  - Identification of a novel Brevibacterium species isolated from humans and
      description of Brevibacterium sanguinis sp. nov.
AB  - Six coryneforms isolated from blood and dialysate fluid were phenotypically
      similar to Brevibacterium casei, but 16S rRNA gene sequencing and DNA-DNA
      hybridization indicate that they belong to a new species for which the name
      Brevibacterium sanguinis is proposed.

PMID- 15184485
TI  - Evaluation of a new particle gel immunoassay for determination of antibodies
      against Treponema pallidum.
AB  - A new particle gel immunoassay (DiaMed AG, Cressier sur Morat, Switzerland) with
      three recombinant Treponema pallidum antigens was evaluated with serum samples
      from patients with syphilis (n = 124) and patients without syphilis (n = 490). It
      proved to be a simple, rapid (20 min), and useful test with sensitivity,
      specificity, and positive and negative predictive values of 91.9, 99.8, 99.2, and
      98%, respectively.

PMID- 15184486
TI  - Identification of Campylobacter jejuni multilocus sequence type ST-21 clonal
      complex by single-nucleotide polymorphism analysis.
AB  - Conserved single-nucleotide polymorphisms (SNPs) which characterize the allelic
      profile of the major epidemiological lineage ST-21 were identified from the
      alleles within the current Campylobacter jejuni multilocus sequence typing (MLST)
      database. Allelic discrimination assays were designed for the detection of SNPs,
      enabling rapid strain profiling for clonal complex ST-21. This method is suitable
      for epidemiological investigations and is complementary to full MLST.

PMID- 15184487
TI  - Use of paraffin-embedded tissue for identification of Saccharomyces cerevisiae in
      a baker's lung nodule by fungal PCR and nucleotide sequencing.
AB  - A 40-year-old healthy male employed in a bakery presented with a single lung
      nodule and underwent investigations to rule out pulmonary carcinoma. Biopsy was
      positive for yeast cells, which did not match common fungal pathogens. PCR assay
      of paraffin-embedded tissue and nucleotide sequencing with ribosomal ITS1-ITS2
      universal primers revealed the presence of Saccharomyces cerevisiae.

PMID- 15184488
TI  - First U.S. report of subcutaneous phaeohyphomycosis caused by Veronaea botryosa
      in a heart transplant recipient and review of the literature.
AB  - Veronaea botryosa is a rare agent of human phaeohyphomycosis. We describe the
      first case of subcutaneous disease occurring in the United States, alert
      clinicians to the second report of a transplant-associated mycosis in a heart
      transplant recipient, extend the previously defined area of endemicity, and
      review the literature.

PMID- 15184489
TI  - Subtype B human immunodeficiency virus (HIV) type 1 mutant that escapes detection
      in a fourth-generation immunoassay for HIV infection.
AB  - We report a case of human immunodeficiency virus (HIV) type 1 infection not
      detected by a highly sensitive combined antigen-antibody assay. The virus was a
      subtype B strain harboring a unique sequence within the immunodominant epitope of
      the transmembrane glycoprotein. Immunochemical analysis indicated that this
      sequence was probably responsible for the failure to detect HIV antibodies.

PMID- 15184490
TI  - A case of Epstein-Barr Virus (EBV)-associated thymic carcinoid and investigation
      of existence of EBV-infected cells in thymus and thymic tumors.
AB  - We describe the first case of Epstein-Barr virus (EBV)-associated thymic
      carcinoid tumor found by in situ hybridization (ISH) on paraffin-embedded
      sections. ISH revealed that both tumor cells and infiltrated lymphocytes were EBV
      positive, while a few EBV-infected lymphocytes were detected in 2 of 11 thymuses
      and 1 of 11 thymomas.

PMID- 15184491
TI  - First case report of catheter-related bacteremia due to "Mycobacterium
      lacticola".
AB  - This is the first report of infection caused by "Mycobacterium lacticola," a
      rapidly growing, scotochromogenic mycobacterium that was isolated from the blood
      of an immunosuppressed child. The organism was identified by sequence analysis of
      >1,400 bp of the 16S rRNA gene. The clinical relevance of this isolate, coupled
      with its unique 16S rRNA gene sequence, should prompt further investigation to
      establish this organism as a valid mycobacterial species.

PMID- 15184492
TI  - Hernia repair mesh-associated Mycobacterium goodii infection.
AB  - We report on a patient with an abdominal wall abscess that developed after an
      inguinal hernia repair that utilized synthetic mesh. Mycobacterium goodii, a
      recently recognized, rapidly growing mycobacterium related to M. smegmatis, was
      isolated both from the abdominal wall aspirate and from surgically drained
      material. Infection resolved following thorough debridement, mesh removal, and
      prolonged antimicrobial therapy. This case report extends our understanding of
      the spectrum of M. goodii infection.

PMID- 15184493
TI  - Hepatitis B surface antigen variant with multiple mutations in the a determinant
      in an agammaglobulinemic patient.
AB  - A patient with agammaglobulinemia developed acute hepatitis that progressed to
      chronic liver disease with high levels of hepatitis B virus (HBV) DNA in the
      absence of detectable HBsAg. Sequencing of the a determinant region of HBsAg
      revealed multiple amino acid substitutions that, unusually, also included a
      substitution at position 122 that defines subtype specificity. All of these
      mutations had a profound effect on the antigenicity of this region, which led to
      the complete failure of variant detection by commercially available routine
      diagnostic assays or laboratory-based monoclonal antibody assays.

PMID- 15184494
TI  - Fatal case of toxic shock-like syndrome due to group C streptococcus associated
      with superantigen exotoxin.
AB  - Group C streptococci have been reported to cause invasive disease similar to that
      classically associated with group A streptococcus (GAS). We describe a fatal case
      of toxic shock-like syndrome due to Streptococcus equi subsp. zooepidemicus. The
      causative organism did not possess any known GAS superantigen exotoxin genes but
      did show evidence of superantigen production.

PMID- 15184495
TI  - Bacteremia caused by Gordonia bronchialis in a patient with sequestrated lung.
AB  - Gordonia species have been recognized as pathogens in immunocompromised and
      immunocompetent patients. We report the first case of bacteremia due to Gordonia
      bronchialis in a diabetic patient with a sequestrated lung. Species
      identification was confirmed with mycolic acid analysis by high-performance
      liquid chromatography and sequencing of the 16S rRNA gene.

PMID- 15184496
TI  - Prosthetic joint infection due to "Helcococcus pyogenes" [corrected].
AB  - Helcococci have previously been associated with the colonization of ulcers and
      infections of the skin and soft tissues. We describe a case of prosthetic joint
      infection due to a previously undescribed organism that is genetically most
      closely related to Helcococcus.

PMID- 15184497
TI  - Reemergence of staphylococcal toxic shock syndrome in Minneapolis-St. Paul,
      Minnesota, during the 2000-2003 surveillance period.

PMID- 15184498
TI  - Isolation and characterization of a nonfluorescent strain of Legionella
      parisiensis.

PMID- 15184499
TI  - In vitro-expanded antigen-specific regulatory T cells suppress autoimmune
      diabetes.
AB  - The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype,
      and diverse antigen specificity present major challenges to harnessing this
      potent tolerogenic population to treat autoimmunity and transplant rejection. In
      this study, we describe a robust method to expand antigen-specific Tregs from
      autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded
      up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti
      CD28, and interleukin 2. The expanded Tregs express a classical cell surface
      phenotype and function both in vitro and in vivo to suppress effector T cell
      functions. Most significantly, small numbers of antigen-specific Tregs can
      reverse diabetes after disease onset, suggesting a novel approach to cellular
      immunotherapy for autoimmunity.

PMID- 15184500
TI  - CD25+ CD4+ T cells, expanded with dendritic cells presenting a single
      autoantigenic peptide, suppress autoimmune diabetes.
AB  - In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system
      recognizes many autoantigens expressed in pancreatic islet beta cells. To silence
      autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+
      suppressor T cells from BDC2.5 mice, which are specific for a single islet
      autoantigen. The expanded T cells were more suppressive in vitro than their
      freshly isolated counterparts, indicating that DCs from autoimmune mice can
      increase the number and function of antigen-specific, CD25+ CD4+ regulatory T
      cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block
      autoimmunity caused by diabetogenic T cells in NOD mice, whereas 10(5)
      polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were
      examined in treated mice, insulitis development was blocked at early (3 wk) but
      not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were
      effective even if administered 14 d after the diabetogenic T cells. Our data
      indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune
      disease in vivo. This might be harnessed as a new avenue for immunotherapy,
      especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen
      can inhibit diabetes mediated by reactivity to multiple antigens.

PMID- 15184501
TI  - CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector
      cells in the prediabetic lesion.
AB  - CD4+CD25+ T regulatory cells (Tregs) prevent autoimmune disease, yet little is
      known about precisely where they exert their influence naturally in a spontaneous
      autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs)
      coexist within the pancreatic lesion before type 1 diabetes onset. We find that
      BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3
      positive CD4+CD25+CD69- cells in the pancreas, actively turning over, expressing
      the clonotypic receptor, and containing functional regulatory activity. Gene
      expression profiling confirms that the CD4+CD25+CD69- cells in pancreatic tissue
      express transcripts diagnostic of regulatory cells, but with significantly higher
      levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node
      counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes,
      which disrupts the balance of Teffs and Tregs and promotes a very broad shift in
      the expression of the T regulatory-specific profile. Thus, CD4+CD25+69- Tregs
      operate directly in the autoimmune lesion and are dependent on ICOS to keep it in
      a nondestructive state.

PMID- 15184503
TI  - A multidomain adhesion protein family expressed in Plasmodium falciparum is
      essential for transmission to the mosquito.
AB  - The recent sequencing of several apicomplexan genomes has provided the
      opportunity to characterize novel antigens essential for the parasite life cycle
      that might lead to the development of new diagnostic and therapeutic markers.
      Here we have screened the Plasmodium falciparum genome sequence for genes
      encoding extracellular multidomain putative adhesive proteins. Three of these
      identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive
      modules including a common Limulus coagulation factor C domain also found in two
      additional Plasmodium genes. Orthologues were identified in the Cryptosporidium
      parvum genome sequence, indicating an evolutionary conserved function. Transcript
      and protein expression analysis shows sexual stage-specific expression of PfCCp1,
      PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane
      associated expression in mature gametocytes. During gametogenesis, PfCCps are
      released and localize surrounding complexes of newly emerged microgametes and
      macrogametes. PfCCp expression markedly decreased after formation of zygotes. To
      begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted
      by homologous recombination, resulting in parasites capable of forming oocyst
      sporozoites but blocked in the salivary gland transition. Our results describe
      members of a conserved apicomplexan protein family expressed in sexual stage
      Plasmodium parasites that may represent candidates for subunits of a transmission
      blocking vaccine.

PMID- 15184502
TI  - Nuclear factor of activated T cells balances angiogenesis activation and
      inhibition.
AB  - It has been demonstrated that vascular endothelial cell growth factor (VEGF)
      induction of angiogenesis requires activation of the nuclear factor of activated
      T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth
      factor and blocked by the inhibitor of angiogenesis pigment epithelial-derived
      factor (PEDF). This suggests a pivotal role for this transcription factor as a
      convergence point between stimulatory and inhibitory signals in the regulation of
      angiogenesis. We identified c-Jun NH2-terminal kinases (JNKs) as essential
      upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as
      responsible for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as
      mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target,
      caspase-8 inhibitor cellular Fas-associated death domain-like interleukin 1beta
      converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated
      by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of
      NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We
      propose that one possible mechanism of concerted angiogenesis regulation by
      activators and inhibitors may be modulation of the endothelial cell apoptosis via
      c-FLIP controlled by NFAT and its upstream regulator JNK.

PMID- 15184504
TI  - Ubiquitin-dependent degradation of p73 is inhibited by PML.
AB  - p73 has been identified recently as a structural and functional homologue of the
      tumor suppressor p53. Here, we report that p73 stability is directly regulated by
      the ubiquitin-proteasome pathway. Furthermore, we show that the promyelocytic
      leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a
      PML-nuclear body (NB)-dependent manner. p38 mitogen-activated protein kinase
      mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB
      and subsequent PML-dependent p73 stabilization. We find that p300-mediated
      acetylation of p73 protects it against ubiquitinylation and that PML regulates
      p73 stability by positively modulating its acetylation levels. As a result, PML
      potentiates p73 transcriptional and proapoptotic activities that are markedly
      impaired in Pml-/- primary cells. Our findings demonstrate that PML plays a
      crucial role in modulating p73 function, thus providing further insights on the
      molecular network for tumor suppression.

PMID- 15184505
TI  - Low dose Leishmania major promotes a transient T helper cell type 2 response that
      is down-regulated by interferon gamma-producing CD8+ T cells.
AB  - An unresolved issue in the field of T helper (Th) cell development relates to the
      findings that low doses of antigen promote Th2 cell development in vitro, whereas
      several classic in vivo studies suggest the opposite. Here we resolve this
      paradox by studying the early immune response in mice after infection with
      different doses of Leishmania major. We found that low parasite doses induced a
      Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response.
      However, the Th2 response in low dose-infected mice was transient and the animals
      healed. The appearance of a Th1 response after low dose infection was dependent
      upon the concomitant activation of interferon gamma-producing CD8+ T cells. In
      the absence of CD8+ T cells, the Th2 response was maintained. However, either
      neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1
      response after low dose infection of CD8-deficient mice, indicating that the
      required role for CD8+ T cells was limited to modulation of CD4+ T cell
      responses. Thus, the discrepant results seen between in vivo and in vitro studies
      on the effects of antigen dose on Th cell differentiation may depend upon whether
      CD8+ T cells participate in the immune response.

PMID- 15184506
TI  - Distinct time effects of vaccination on long-term proliferative and IFN-gamma
      producing T cell memory to smallpox in humans.
AB  - Residual immunity to the smallpox virus raises key questions about the
      persistence of long-term immune memory in the absence of antigen, since
      vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative
      memory T cells were compared in 79 vaccinees 13-25 yr after their last
      immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed
      both immediate IFN-gamma-producing effector-memory responses and proliferative
      memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had
      no detectable vaccinia-specific responses at all. Both responses were mediated by
      CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were
      composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their
      frequency was low but could be expanded in vitro within 7 d. Time since first
      immunization affected their persistence: they vanished 45 yr after priming, but
      proliferative responses remained detectable. The number of recalls did not affect
      the persistence of residual effector-memory T cells. Programmed revaccination
      boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in
      vaccinees with previously undetectable residual effector-memory cells. Such long
      term maintenance of vaccinia-specific immune memory in the absence of smallpox
      virus modifies our understanding of the mechanism of persistence of long-term
      memory to poxviruses and challenges vaccination strategies.

PMID- 15184508
TI  - The neural control of behavior in sea anemones. 1935.

PMID- 15184507
TI  - Tumor rejection induced by CD70-mediated quantitative and qualitative effects on
      effector CD8+ T cell formation.
AB  - In vivo priming of antigen-specific CD8+ T cells results in their expansion and
      differentiation into effector T cells followed by contraction into a memory T
      cell population that can be maintained for life. Recent evidence suggests that
      after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T
      cell response are programmed. However, it is unclear to what extent CD8+ T cell
      instruction in vivo is modulated by costimulatory signals. Here, we demonstrate
      that constitutive ligation of the tumor necrosis factor receptor family member
      CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to
      influenza virus infection and EL-4 tumor challenge in vivo by incrementing
      initial expansion and maintaining higher numbers of antigen-specific T cells in
      the memory phase. Concomitantly, the quality of antigen-specific T cells improved
      as evidenced by increased interferon (IFN)-gamma production and a greater
      cytotoxic potential on a per cell basis. As an apparent consequence, the superior
      effector T cell formation induced by CD70 protected against a lethal dose of
      poorly immunogenic EL4 tumor cells in a CD8+ T cell- and IFN-gamma-dependent
      manner. Thus, CD70 costimulation enhances both the expansion and per cell
      activity of antigen-specific CD8+ T cells.

PMID- 15184509
TI  - Colour vision in the glow-worm Lampyris noctiluca (L.) (Coleoptera: Lampyridae):
      evidence for a green-blue chromatic mechanism.
AB  - Male glow-worms Lampyris noctiluca find their bioluminescent mates at night by
      phototaxis. There is good evidence that location of mates by lampyrid beetles is
      achieved by a single spectral class of photoreceptor, whose spectral sensitivity
      is tuned to the bioluminescent spectrum emitted by conspecifics, and is
      achromatic. We ask whether glow-worm phototaxis involves interactions between two
      spectral classes of photoreceptor. Binary choice experiments were conducted in
      which males were presented with artificial light stimuli that differ in spectral
      composition. The normal preference for a green stimulus (lambdamax=555 nm),
      corresponding to the bioluminescence wavelength produced by signalling females,
      was significantly reduced by adding a blue (lambdamax=485 nm) component to the
      signal. This implies an antagonistic interaction between long- and short
      wavelength sensitive photoreceptors, suggesting colour vision based on chromatic
      opponency. Cryosections showed a band of yellow filter pigment in the fronto
      dorsal region of the male compound eye, which could severely constrain colour
      vision in the dim conditions in which the insects signal. This apparent paradox
      is discussed in the context of the distribution of the pigment within the eye and
      the photic niche of the species.

PMID- 15184510
TI  - Pineal organs of deep-sea fish: photopigments and structure.
AB  - We have examined the morphology and photopigments of the pineal organs from a
      number of mesopelagic fish, including representatives of the hatchet fish
      (Sternoptychidae), scaly dragon-fish (Chauliodontidae) and bristlemouths
      (Gonostomidae). Although these fish were caught at depths of between 500 and 1000
      m, the morphological organisation of their pineal organs is remarkably similar to
      that of surface-dwelling fish. Photoreceptor inner and outer segments protrude
      into the lumen of the pineal vesicle, and the outer segment is composed of a
      stack of up to 20 curved disks that form a cap-like cover over the inner segment.
      In all species, the pineal photopigment was spectrally distinct from the retinal
      rod pigment, with lambdamax displaced to longer wavelengths, between
      approximately 485 and 503 nm. We also investigated the pineal organ of the deep
      demersal eel, Synaphobranchus kaupi, caught at depths below 2000 m, which
      possesses a rod visual pigment with lambdamax at 478 nm, but the pineal pigment
      has lambdamax at approximately 515 nm. In one species of hatchet fish,
      Argyropelecus affinis, two spectral classes of pinealocyte were identified, both
      spectrally distinct from the retinal rod photopigment.

PMID- 15184511
TI  - Development and steroid regulation of RFamide immunoreactivity in antennal-lobe
      neurons of the sphinx moth Manduca sexta.
AB  - During metamorphosis, the insect nervous system undergoes considerable
      remodeling: new neurons are integrated while larval neurons are remodeled or
      eliminated. To understand further the mechanisms involved in transforming larval
      to adult tissue we have mapped the metamorphic changes in a particularly well
      established brain area, the antennal lobe of the sphinx moth Manduca sexta, using
      an antiserum recognizing RFamide-related neuropeptides. Five types of RFamide
      immunoreactive (ir) neurons could be distinguished in the antennal lobe, based on
      morphology and developmental appearance. Four cell types (types II-V, each
      consisting of one or two cells) showed RFamide immunostaining in the larva that
      persisted into metamorphosis. By contrast, the most prominent group (type I), a
      mixed population of local and projection neurons consisting of about 60 neurons
      in the adult antennal lobe, acquired immunostaining in a two-step process during
      metamorphosis. In a first step, from 5 to 7 days after pupal ecdysis, the number
      of labeled neurons reached about 25. In a second step, starting about 4 days
      later, the number of RFamide-ir neurons increased within 6 days to about 60. This
      two-step process parallels the rise and fall of the developmental hormone 20
      hydroxyecdysone (20E) in the hemolymph. Artificially shifting the 20E peak to an
      earlier developmental time point resulted in the precocious appearance of RFamide
      immunostaining and led to premature formation of glomeruli. Prolonging high 20E
      concentrations to stages when the hormone titer starts to decline had no effect
      on the second increase of immunostained cell numbers. These results support the
      idea that the rise in 20E, which occurs after pupal ecdysis, plays a role in the
      first phase of RFamide expression and in glomeruli formation in the developing
      antennal lobes. The role of 20E in the second phase of RFamide expression is less
      clear, but increased cell numbers showing RFamide-ir do not appear to be a
      consequence of the declining levels in 20E that occur during adult development.

PMID- 15184512
TI  - Switching destinations: memory change in wood ants.
AB  - We have studied the changing use of spatial memories in wood ants by charting how
      the ants' paths transform when ants are first trained to feed at one site and
      must then switch to another site. Because ants, which are trained to approach a
      single feeding site from a single starting point, are attracted directly to that
      goal when started from unfamiliar positions, we describe the ants' paths in terms
      of the use of two stored snapshots. Each snapshot consists of retinotopic views
      of the ants' surroundings acquired at one of the two feeding sites. When a
      snapshot is activated, it draws an ant to the related site from a wide range of
      directions. Here, we focus on routes that occur before ants have learnt to go
      directly from the start to the second site. The initial direction of the ant's
      path is then mostly aimed either at the first site or between the two sites. On
      62.2% of all recorded paths, this segment is followed by an abrupt turn, after
      which the ant often aims directly at the second feeding site. The details of this
      behaviour suggest that, after the turn, control of the path switches from the
      snapshot recorded at the first feeding site (or some combination of the two
      snapshots) to the snapshot recorded at the second feeding site. We discuss
      different ways in which control might be transferred from one snapshot to the
      other.

PMID- 15184513
TI  - Macrophage involvement for successful degeneration of apoptotic organs in the
      colonial urochordate Botryllus schlosseri.
AB  - Apoptosis is an important tool for shaping developing organs and for maintaining
      cellular homeostasis. In the colonial urochordate Botryllus schlosseri, apoptosis
      is also the hallmark end point in blastogenesis, a cyclical and weekly
      developmental phenomenon. Then the entire old generation of zooids are eliminated
      (resorbed) by a process that lasts 24-36 h. Administration of the antioxidant
      butylated hydroxytoluene (BHT) resulted in resorption being arrested by 1-8 days
      on average. At high doses (2.5-15.0 mg BHT l(-1)) resorption was completed only
      after removal of BHT. Colonies that were not removed in time, died. In treated
      colonies, although DNA fragmentation was high, tissues and organs that would
      normally have died, survived, and the general oxidative levels of lipids were
      reduced. Blood vessels were widened, containing aggregates of blood cells with a
      significantly increased proportion of empty macrophage-like cells without
      inclusion. In colonies rescued from BHT treatment, resorption of zooids started
      immediately and was completed within a few days. We propose three possible
      mechanisms as to how BHT may affect macrophage activity: (1) by interrupting
      signals that further promote apoptosis; (2) through the respiratory burst
      initiated following a phagocytic stimulus; and (3) by reducing lipid oxidation
      and changing cell surface markers of target cells. Our results point, for the
      first time, to the role of phagocytic cells in the coordination of death and
      clearance signals in blastogenesis.

PMID- 15184514
TI  - Mechanical energy in toddler gait. A trade-off between economy and stability?
AB  - Mechanical energy expenditure was investigated in children who are just learning
      to walk and compared with adult mechanical energy expenditure during walking.
      First, we determined whether the inverted pendulum (IP) mechanism of energy
      exchange was present in toddlers. It seems that new walkers partially make use of
      this energy saving mechanism, but it is less efficient than in adults. The
      reduced recovery values (R=40% at optimal speeds in toddlers compared to 70% in
      adults) can be explained by their low self-selected walking speed in combination
      with their tossing gait (large vertical oscillations of the body) and by the
      observation that during as much as 25-50% of the gait cycle kinetic and potential
      energy are oscillating in-phase. The second step was to calculate positive
      external mechanical work (Wext). Since the IP mechanism is less efficient in
      toddlers, more mass-specific positive work has to be performed to lift and
      accelerate the centre of mass than in adults walking at the same speed, even when
      differences in body size are taken into account. The amount of positive internal
      work (Wint,k) necessary to move the body segments relative to the centre of mass
      was the third parameter we calculated. In toddlers Wint,k is largely determined
      by the kinetic energy of the lower limb. Compared to adults, toddlers have to
      perform less mass-specific work per unit distance to accelerate the body segments
      since the upper body is kept relatively stiff during walking and there is no arm
      swing. Apart from work performed on the centre of mass and work performed to move
      the body segments relative to the centre of mass, when walking some work is also
      performed during double contact as both legs are pushing against each other. Two
      methods were used to calculate this amount of work, both leading to the same
      conclusions. Mass-specific work during double contact is small in toddlers
      compared to adults because of their low walking speed. Finally the total amount
      of mechanical work performed in toddlers was compared to the work production
      observed in adults. Wext seems to be the major determinant for total mechanical
      energy expenditure. At intermediate froude numbers work production is comparable
      between adults and toddlers, but at low and high froude numbers Wtot increases
      due to the steep increases in Wext. Despite the fact that mechanical work
      requirements in toddler gait are underestimated if work during double contact is
      not taken into account, it is not a major determinant of the energy cost of
      walking.

PMID- 15184515
TI  - Morphological and physiological specialization for digging in amphisbaenians, an
      ancient lineage of fossorial vertebrates.
AB  - Amphisbaenians are legless reptiles that differ significantly from other
      vertebrate lineages. Most species dig underground galleries of similar diameter
      to that of the animal. We studied the muscle physiology and morphological
      attributes of digging effort in the Brazilian amphisbaenid Leposternon
      microcephalum (Squamata; Amphisbaenia), which burrows by compressing soil against
      the upper wall of the tunnel by means of upward strokes of the head. The
      individuals tested (<72 g) exerted forces on the soil of up to 24 N. These forces
      were possible because the fibres of the longissimus dorsi, the main muscle
      associated with burrowing, are highly pennated, thus increasing effective muscle
      cross-sectional area. The muscle is characterized by a metabolic transition along
      its length: proximal, medial and distal fibres are fast contracting and
      moderately oxidative, but fibres closer to the head are richer in citrate
      synthase and more aerobic in nature. Distal fibres, then, might be active mainly
      at the final step of the compression stroke, which requires more power. For
      animals greater than a given diameter, the work required to compress soil
      increases exponentially with body diameter. Leposternon microcephalum, and
      probably some other highly specialized amphisbaenids, are most likely constrained
      to small diameters and can increase muscle mass and effective muscle cross
      sectional area by increasing body length, not body diameter.

PMID- 15184516
TI  - Pre-receptor profile of sensory images and primary afferent neuronal
      representation in the mormyrid electrosensory system.
AB  - Afferent responses to the fish's own electric organ discharge were explored in
      the electrosensory lobe of the mormyrid fish Gnathonemus petersii. In order to
      understand the neural encoding of natural sensory images, responses were examined
      while objects of different conductivities were placed at different positions
      along the skin of the fish, i.e. at different points within, and also outside,
      peripheral receptive fields. The presence of an object in the fish's self
      generated electric field produces local modulation of transcutaneous current
      density. Measurement of the local electric organ discharge shows that object
      images formed at the electroreceptive sensory surface have an opposing center
      surround, 'Mexican hat' profile. This is a pre-receptor phenomenon intrinsic to
      the physical nature of the sensory stimulus that takes place prior to neural
      lateral inhibition and is independent of such central inhibition. Stimulus
      intensity is encoded in the latency and number of action potentials in the
      response of primary afferent fibers. It is also reflected in changes in the
      amplitude and area of extracellular field potentials recorded in the deep
      granular layer of the electrosensory lobe. Since the object image consists of a
      redistribution of current density over the receptive surface, its presence is
      coded by change in the activity of receptors over an area much larger than the
      skin surface facing the object. We conclude that each receptor encodes
      information coming from the whole scene in a manner that may seem ambiguous when
      seen from a single point and that, in order to extract specific object features,
      the brain must process the electric image represented over the whole sensory
      surface.

PMID- 15184517
TI  - Cardiac-like behavior of an insect flight muscle.
AB  - The synchronous wing depressor muscles of the hawkmoth Manduca sexta undergo
      large amplitude motions at lengths that lie entirely on the ascending region of
      their twitch length-tension curve. Moreover, these muscles bear a striking
      functional resemblance to mammalian cardiac muscle in both the shape of their
      length-tension curve and in their working length range. Although operation on the
      ascending region of the twitch length-tension curve sacrifices maximal force, it
      does permit the generation of larger forces at greater strains. In the case of
      cardiac muscle, this mechanical behavior is critical for accommodating the
      increasing stresses associated with greater ventricular filling. Similar
      characteristics in moth flight muscle suggest an analogous regulatory mechanism
      for skeletal muscles performing repetitive oscillatory work; the strong length
      dependence of force over their working length range should give the wing
      depressors the capacity to generate larger forces as wing stroke amplitude
      increases. These results support the notion that the length-tension relationship
      of muscle can be tuned to function in locomotor muscles.

PMID- 15184518
TI  - Effect of polymorphic colour vision for fruit detection in the spider monkey
      Ateles geoffroyi, and its implications for the maintenance of polymorphic colour
      vision in platyrrhine monkeys.
AB  - Most platyrrhine monkeys have an X-linked tri-allelic polymorphism for medium and
      long wavelength (M/L) sensitive cone photopigments. These pigments' sensitivity
      maxima (lambdamax) range from 535 to 562 nm. All animals also have an autosomally
      coded short-wavelength-sensitive (S) cone pigment. In populations with three M/L
      alleles there are six different colour vision phenotypes. Heterozygous females
      have trichromatic colour vision, while males and homozygous females are
      dichromats. The selective basis for this polymorphism is not understood, but is
      probably affected by the costs and benefits of trichromatic compared to
      dichromatic colour vision. For example, it has been suggested that trichromats
      are better equipped than dichromats to detect fruit against a leaf background. To
      investigate this possibility, we modeled fruit detection by various colour vision
      phenotypes present in the frugivorous spider monkey, Ateles geoffroyi. Our study
      population is thought to have three M/L alleles with cone pigment lambdamax
      values close to 535, 550 and 562 nm. The model predicted that all trichromat
      phenotypes had an advantage over dichromats, and the 535/562 nm phenotype was
      best; however, the model predicted that dichromats could detect all of the fruit
      species consumed by spider monkeys. We conclude that the heterozygote advantage
      experienced by females may be the most plausible explanation for the maintenance
      of this polymorphism in A. geoffroyi. Nevertheless, more studies need to evaluate
      social foraging behaviour and the performance of different phenotypes of other
      New World monkeys to determine if this is a global explanation for this phenomena
      or more specific to A. geofforyi.

PMID- 15184519
TI  - Interspecific and intraspecific views of color signals in the strawberry poison
      frog Dendrobates pumilio.
AB  - Poison frogs in the anuran family Dendrobatidae use bright colors on their bodies
      to advertise toxicity. The species Dendrobates pumilio Schmidt 1858, the
      strawberry poison frog, shows extreme polymorphism in color and pattern in
      Panama. It is known that females of D. pumilio preferentially choose mates of
      their own color morph. Nevertheless, potential predators must clearly see and
      recognize all color morphs if the aposematic signaling system is to function
      effectively. We examined the ability of conspecifics and a model predator to
      discriminate a diverse selection of D. pumilio colors from each other and from
      background colors. Microspectrophotometry of isolated rod and cone photoreceptors
      of D. pumilio revealed the presence of a trichromatic photopic visual system. A
      typical tetrachromatic bird system was used for the model predator. Reflectance
      spectra of frog and background colors were obtained, and discrimination among
      spectra in natural illuminants was mathematically modeled. The results revealed
      that both D. pumilio and the model predator discriminate most colors quite well,
      both from each other and from typical backgrounds, with the predator generally
      performing somewhat better than the conspecifics. Each color morph displayed at
      least one color signal that is highly visible against backgrounds to both visual
      systems. Our results indicate that the colors displayed by the various color
      morphs of D. pumilio are effective signals both to conspecifics and to a model
      predator.

PMID- 15184520
TI  - Serotonin modifies the sensitivity of the male silkmoth to pheromone.
AB  - Serotonin is known to modulate the response of neuronal populations in the
      primary olfactory center of the moth olfactory system, the antennal lobe. Here,
      we analyzed the effects of serotonin on the behavior related to the restricted
      pheromone olfactory pathway of the male silkmoth, Bombyx mori. In order to
      understand the effects of serotonin at the behavioral level, we applied serotonin
      (10(-5) mol l(-1), 10(-4) mol l(-1) and 10(-3) mol l(-1)) to the brain and found
      that 10(-4) mol l(-1) serotonin increases the sensitivity to female pheromone
      whereas 10(-3) mol l(-1) serotonin had the opposite effect. Levels of serotonin
      in the brain were determined using HPLC with electrochemical detection.
      Inhibitory effects were observed after applying the serotonin antagonists
      mianserin (10(-4) mol l(-1)) and ketanserin (10(-3) mol l(-1)). Additionally, we
      quantified the circadian variation of serotonin in the brain using HPLC with
      electrochemical detection. Further, this variation correlated well with a
      circadian variation of the male sensitivity to pheromone. These results show that
      the serotonin-related enhancement of neuronal responses at the antennal lobe
      level is expressed at the behavioral level as a modulation of pheromone
      sensitivity and that the circadian variation of serotonin levels in the brain
      correlates with changes in the moth's pheromone sensitivity.

PMID- 15184521
TI  - Hypoxia tolerance and preconditioning are not additive in the trout (Oncorhynchus
      mykiss) heart.
AB  - Research has shown that the trout heart is normally hypoxia-sensitive, and that
      it can be preconditioned. However, we have identified a group of rainbow trout
      Oncorhynchus mykiss that shows a surprising degree of myocardial hypoxia
      tolerance. In this study, we used in situ hearts from these fish as a comparative
      model to examine whether the cardioprotective effects afforded by hypoxic
      adaptation and preconditioning are additive. In situ trout hearts were exposed to
      severe hypoxia (perfusate PO2 5-10 mmHg) in the absence and presence of a
      transient hypoxic pre-exposure (preconditioning). The four groups studied were:
      (1) control (no hypoxia); (2) 5 min of severe hypoxia; (3) 30 min of severe
      hypoxia; and (4) 5 min of severe hypoxia (hypoxic preconditioning) followed 20
      min later by 30 min of severe hypoxia. 30 min of severe hypoxia significantly
      decreased maximum cardiac output and stroke volume by 15-30%. However, hypoxic
      preconditioning failed to confer any protection against post-hypoxic myocardial
      dysfunction. This work shows that the protection afforded by inherent myocardial
      hypoxia tolerance and preconditioning are not additive in this population of
      trout, and strongly suggests that the relationship between hypoxic adaptation and
      preconditioning in fishes resembles that of the neonatal/immature, not adult,
      mammalian heart. Further, our results (1) indicate that stretch (volume loading)
      and chronic exposure to low levels of adrenaline (15 nmol l(-1)) do not confer
      any protection against hypoxia-related myocardial dysfunction in this population,
      and (2) validate the use of the in situ trout heart as a comparative model for
      studying aspects of myocardial hypoxia tolerance and preconditioning in
      vertebrates.

PMID- 15184522
TI  - Dopamine stimulates snail albumen gland glycoprotein secretion through the
      activation of a D1-like receptor.
AB  - The catecholamine dopamine is present in both the central nervous system and in
      the peripheral tissues of molluscs, where it is involved in regulating
      reproduction. Application of exogenous dopamine to the isolated albumen gland of
      the freshwater pulmonate snail Helisoma duryi (Wetherby) induces the secretion
      (release) of perivitelline fluid. The major protein component of the
      perivitelline fluid of Helisoma duryi is a native 288 kDa glycoprotein that is
      secreted around individual eggs and serves as an important source of nutrients
      for the developing embryos. The secretion of glycoprotein by the albumen gland is
      a highly regulated event that must be coordinated with the arrival of the
      fertilized ovum at the carrefour (the region where the eggs receive albumen gland
      secretory products). In order to elucidate the intracellular signalling
      pathway(s) mediating dopamine-induced glycoprotein secretion, albumen gland cAMP
      production and glycoprotein secretion were measured in the presence/absence of
      selected dopamine receptor agonists and antagonists. Dopamine D1-selective
      agonists dihydrexidine, 6,7-ADTN and SKF81297 stimulated cAMP production and
      glycoprotein secretion from isolated albumen glands whereas D1-selective
      antagonists SCH23390 and SKF83566 suppressed dopamine-stimulated cAMP production.
      Dopamine D2-selective agonists and antagonists generally had no effect on cAMP
      production or protein secretion. Based on the effects of these compounds, a
      pharmacological profile was obtained that strongly suggests the presence of a
      dopamine D1-like receptor in the albumen gland of Helisoma duryi. In addition,
      secretion of albumen gland glycoprotein was not inhibited by protein kinase A
      inhibitors, suggesting that dopamine-stimulated protein secretion might occur
      through a protein kinase A-independent pathway.

PMID- 15184523
TI  - Spectral properties of myoelectric signals from different motor units in the leg
      extensor muscles.
AB  - Myoelectric signals measured using intramuscular electromyograms (EMGs) in
      animals have shown that faster motor units generate higher frequencies in their
      power spectra. However, evidence to relate myoelectric frequency and motor unit
      type from the surface electromyograms typically measured from man have remained
      elusive. The purpose of this study was to determine if spectral properties from
      surface EMG could be related to the different motor units in the muscles of the
      leg extensors in man. Reflex experiments (both tendon tap and electrically
      stimulated) and graded isometric contractions were used to generate muscle
      contractions with different patterns of motor unit recruitment. EMG was recorded
      from the vastus lateralis and medialis, rectus femoris, medial and lateral
      gastrocnemius and soleus muscles. The EMGs were resolved into their intensities
      in time-frequency space using wavelet techniques. The intensity spectra were
      calculated for the reflex responses and for different contractile forces. The
      spectra were compared using principle component analyses and ANCOVA. Electrical
      stimulation can result in preferentially faster motor units being recruited, and
      in this study resulted in higher myoelectric frequencies than for the stretch
      reflex. During ramped contractions the motor units are recruited in an orderly
      fashion from slow to fast. As the faster motor units were recruited then higher
      frequency components appeared within the myoelectric intensity spectra. For all
      muscles tested there were significant correlations between the stage in
      contraction and the EMG frequency. Both approaches demonstrated higher frequency
      components in the myoelectric spectra when the faster motor units could be
      assumed to be active.

PMID- 15184524
TI  - Seasonality of energetic functioning and production of reactive oxygen species by
      lugworm (Arenicola marina) mitochondria exposed to acute temperature changes.
AB  - The influence of seasonal and acute temperature changes on mitochondrial
      functions were studied in isolated mitochondria of the eurythermal lugworm
      Arenicola marina (Polychaeta), with special emphasis on the interdependence of
      membrane potential and radical production. Acclimatisation of lugworms to pre
      spawning/summer conditions is associated with rising mitochondrial substrate
      oxidation rates, higher proton leakage rates, elevated membrane potentials, and
      increased production of reactive oxygen species (ROS) in isolated mitochondria,
      compared with mitochondria from winter animals. However, a high ROS production
      was compensated for by higher activities of the antioxidant enzymes catalase and
      superoxide dismutase, as well as lower mitochondrial densities in summer compared
      with winter animals. In summer animals, a higher sensitivity of the proton
      leakage rate to changes of membrane potential will confer better flexibility for
      metabolic regulation (mild uncoupling) in response to temperature change. These
      seasonal alterations in mitochondrial functions suggest modifications of energy
      metabolism in eurythermal and euryoxic organisms on intertidal mudflats during
      summer. In winter, low and less changeable temperatures in intertidal sedimentary
      environments permit higher respiratory efficiency at low aerobic metabolic rates
      and lower membrane potentials in A. marina mitochondria.

PMID- 15184526
TI  - Gonadotropin-releasing hormone (GnRH) receptor expression and membrane signaling
      in early embryonic GnRH neurons: role in pulsatile neurosecretion.
AB  - The characteristic pulsatile secretion of GnRH from hypothalamic neurons is
      dependent on an autocrine interaction between GnRH and its receptors expressed in
      GnRH-producing neurons. The ontogeny and function of this autoregulatory process
      were investigated in studies on the properties of GnRH neurons derived from the
      olfactory placode of the fetal rat. An analysis of immunocytochemically
      identified, laser-captured fetal rat hypothalamic GnRH neurons, and olfactory
      placode-derived GnRH neurons identified by differential interference contrast
      microscopy, demonstrated coexpression of mRNAs encoding GnRH and its type I
      receptor. Both placode-derived and immortalized GnRH neurons (GT1-7 cells)
      exhibited spontaneous electrical activity that was stimulated by GnRH agonist
      treatment. This evoked response, as well as basal neuronal firing, was abolished
      by treatment with a GnRH antagonist. GnRH stimulation elicited biphasic
      intracellular calcium ([Ca2+]i) responses, and both basal and GnRH-stimulated
      [Ca2+]i levels were reduced by antagonist treatment. Perifused cultures released
      GnRH in a pulsatile manner that was highly dependent on extracellular Ca2+. The
      amplitude of GnRH pulses was increased by GnRH agonist stimulation and was
      diminished during GnRH antagonist treatment. These findings demonstrate that
      expression of GnRH receptor, GnRH-dependent activation of Ca2+ signaling, and
      autocrine regulation of GnRH release are characteristics of early fetal GnRH
      neurons and could provide a mechanism for gene expression and regulated GnRH
      secretion during embryonic migration.

PMID- 15184525
TI  - Mitogen-activated protein kinase (MAPK) phosphatase-1 and -4 attenuate p38 MAPK
      during dexamethasone-induced insulin resistance in 3T3-L1 adipocytes.
AB  - Prolonged use of glucocorticoids induces pronounced insulin resistance in vivo.
      In vitro, treatment of 3T3-L1 adipocytes with dexamethasone for 48 h reduces the
      maximal level of insulin- and stress (arsenite)-induced glucose uptake by
      approximately 50%. Although phosphatidylinositol 3-kinase signaling was slightly
      attenuated, phosphorylation of its downstream effectors such as protein kinase B
      and protein kinase C-lambda remained intact. Nor was any effect of dexamethasone
      treatment observed on insulin- or arsenite-induced translocation of glucose
      transporter 4 (GLUT4) toward the plasma membrane. However, for a maximal response
      to either arsenite- or insulin-induced glucose uptake in these cells, functional
      p38 MAPK signaling is required. Dexamethasone treatment markedly attenuated p38
      MAPK phosphorylation coincident with an up-regulation of the MAPK phosphatases
      MKP-1 and MKP-4. Employing lentivirus-mediated ectopic expression in fully
      differentiated 3T3-L1 adipocytes demonstrated a differential effect of these
      phosphatases: whereas MKP-1 was a more potent inhibitor of insulin-induced
      glucose uptake, MKP-4 more efficiently inhibited arsenite-induced glucose uptake.
      This coincided with the effects of these phosphatases on p38 MAPK
      phosphorylation, i.e. MKP-1 and MKP-4 attenuated p38 MAPK phosphorylation by
      insulin and arsenite, respectively. Taken together, these data provide evidence
      that in 3T3-L1 adipocytes dexamethasone inhibits the activation of the GLUT4 in
      the plasma membrane by a p38 MAPK-dependent process, rather than in a defect in
      GLUT4 translocation per se.

PMID- 15184527
TI  - Switches, cross-talk and memory in Escherichia coli adherence.
AB  - Escherichia coli is a successful commensal and pathogen. Its pathogenic diversity
      stems from the acquisition and expression of multiple virulence-associated loci.
      Many of the key virulence factors are surface structures involved in adherence
      and motility. These are important antigens and their expression is limited by
      phase-variable genetic switches that are considered to act randomly. This review
      considers the possibility that such stochastic expression within a bacterial
      population belies sequential or co-ordinate control at the level of the
      individual bacterium. Co-ordinated expression or cross-talk between virulence
      loci can lead to a programmed set of events within a bacterium analogous to a
      simple form of electronic memory that is of benefit during infection.

PMID- 15184528
TI  - PCR-based assays for detection of Streptococcus pneumoniae serotypes 3, 14, 19F
      and 23F in respiratory specimens.
AB  - Current culture-based assays are insensitive for detection of simultaneous
      respiratory tract colonization by more than one pneumococcal serotype. Separate
      single-tube, nested PCR-based assays have been developed to detect Streptococcus
      pneumoniae serotypes 3, 14, 19F and 23F by amplifying unique DNA sequences in the
      capsular polysaccharide gene cluster of each serotype. Pairs of 27-32-base outer
      primers and 20-21-base inner primers and a 20-22-base probe were designed to
      amplify and detect a 200-221-base sequence by dot blotting using the labelled
      probe. Sensitivity of the assays was 0.01-10 fg using chromosomal DNA and < or =
      1 viable cell using DNA extracted from exponential-phase bacteria. Each serotype
      specific assay detected chromosomal DNA from all of five to ten clinical isolates
      of the homologous type and did not detect DNA sequences from any of 190-204
      strains from 51-52 different serotypes or 28 non-pneumococcal bacterial strains.
      Sixteen throat swabs from children that had been cultured for S. pneumoniae were
      tested in PCR assays following DNA extraction. All of six that grew S. pneumoniae
      serotype 3, 14, 19F or 23F were positive in the PCR assay for the homologous
      serotype (and in a PCR assay for sequences in lytA, present in all pneumococci)
      and were negative in assays for other serotypes. Of eight culture-negative
      specimens in children not receiving antimicrobials, three were positive for both
      the lytA assay and an assay for one of the four serotypes, suggesting true
      positive results; in three others all five PCR assays were negative and, in the
      remaining two, the lytA assay was positive but each of the four assays for
      individual serotypes was negative, suggesting either false-positive results or
      presence of DNA sequences from an S. pneumoniae serotype other than 3, 14, 19F or
      23F. These preliminary clinical data suggest that these PCR-based assays are
      sensitive and specific for detection of individual serotypes of pneumococci and
      may be used with respiratory tract specimens.

PMID- 15184529
TI  - Comparison between real-time PCR, conventional PCR and different staining
      techniques for diagnosing Pneumocystis jiroveci pneumonia from bronchoalveolar
      lavage specimens.
AB  - Between January 2002 and July 2003, 173 bronchoalveolar lavage (BAL) specimens
      from 150 patients (19 HIV-infected and 131 non-HIV-infected patients) were
      evaluated for identification of Pneumocystis jiroveci (formerly known as
      Pneumocystis carinii f. sp. hominis) using staining techniques, conventional PCR
      (mtLSUrRNA gene) and real-time PCR (MSG gene). Test results were compared to
      Pneumocystis pneumonia (PCP) confirmed by typical clinical findings and response
      to treatment. Sensitivity and specificity of the techniques were 60 and 100% for
      staining (where either one or both techniques were positive), 100 and 87.0% for
      conventional PCR and 100 and 84.9 % for real-time PCR, respectively. The use of a
      concentration of 10(3) copies of DNA per capillary of BAL as a cut-off
      (determined by real-time PCR) increased specificity from 84.9 to 98.6% without
      reducing the sensitivity of the technique. This technique is rapid (<3 h) and
      therefore of major interest in differentiating between asymptomatic carriage and
      PCP. A BAL specimen with <10(3) copies per capillary of Pneumocystis-specific DNA
      is more likely to indicate a chronic carrier state, but in such cases follow-up
      is required to ensure that the patient is not in the early stage of an active
      PCP.

PMID- 15184530
TI  - Identification and characterization of transmissible Pseudomonas aeruginosa
      strains in cystic fibrosis patients in England and Wales.
AB  - Most past studies of cross-infection with Pseudomonas aeruginosa among cystic
      fibrosis (CF) patients in the UK suggest that it is a rare occurrence. However,
      two recent reports of highly transmissible strains in patients in regional
      centres in England (Liverpool and Manchester) have raised questions as to the
      extent of the problem and prompted a nationwide survey to establish the
      distribution of P. aeruginosa strain genotypes among these patients. Isolates of
      P. aeruginosa were requested from over 120 hospitals in England and Wales and a
      sample size of approximately 20% of the CF patient population in each centre was
      recommended. In total, 1225 isolates were received from 31 centres (range 1 to
      330). Single patient isolates were typed by SpeI macrorestriction and PFGE. A
      panel of strains of the common genotypes including representatives of reported
      transmissible strains was assembled and further characterized by fluorescent
      amplified fragment length polymorphism (FAFLP) genotyping. At least 72% of all
      patients harboured strains with unique genotypes. Small clusters of related
      strains were evident in some centres, presumably indicating limited transmission
      of local strains. The most prevalent strain was indistinguishable from that
      previously described as the 'Liverpool' genotype, and accounted for approximately
      11% of patient isolates from 15 centres in England and Wales. The second most
      common genotype (termed Midlands 1) was recovered from 86 patients in nine
      centres and the third genotype, which matched closely the PFGE profile of Clone
      C, a genotype originally described in Germany, was found in eight centres and was
      isolated from 15 patients. A fourth genotype, identical to the published
      Manchester strain, was found in three centres. FAFLP analysis revealed some
      microheterogeneity among strains of the Liverpool genotype but all isolates of
      this genotype were positive by PCR for a strain-specific marker. These data
      suggest that cross-infection with P. aeruginosa has occurred both within and
      widely between CF centres in England and Wales. The two most common genotypes
      accounted for more than one-fifth of patients' isolates examined and
      transmissible genotypes were found in all but three centres studied. These
      results emphasize the need for continued surveillance of P. aeruginosa genotypes
      in CF patients to provide informed infection control policy in treatment centres.

PMID- 15184531
TI  - Improvement in the detection rate of diarrhoeagenic bacteria in human stool
      specimens by a rapid real-time PCR assay.
AB  - A rapid laboratory system has been developed and evaluated that can
      simultaneously identify major diarrhoeagenic bacteria, including Salmonella
      enterica, Vibrio parahaemolyticus, Campylobacter jejuni and Shiga toxin-producing
      Escherichia coli, in stool specimens by real-time PCR. Specific identification
      was achieved by using selective TaqMan probes, detecting two targets in each
      pathogen. A positive result was scored only when both targets of a pathogen were
      amplified and the difference between threshold cycles for detection was less than
      five. Diagnosis of enteric bacterial infections using this highly sensitive
      method, including DNA extraction and real-time PCR, requires only 3 h. Forty
      stool specimens related to suspected food poisoning outbreaks were analysed: 16
      (40%) of these samples were found to be positive for diarrhoeagenic bacteria
      using a conventional culture method; 28 (70%) were positive using the real-time
      PCR assay. Of the 12 PCR-positive but culture-negative cases, 11 patients had
      consumed pathogen-contaminated or high-risk food. Analysis of faecal samples from
      105 outpatients who complained of diarrhoea and/or abdominal pain identified 19
      (18%) patients as being positive for diarrhoeagenic bacteria using the culture
      method. An additional six (6%) patients were found to be positive by PCR
      analysis.

PMID- 15184532
TI  - Non-invasive diagnosis of Helicobacter pylori infection in adult dyspeptic
      patients by stool antigen detection: does the rapid immunochromatography test
      provide a reliable alternative to conventional ELISA kits?
AB  - Stool antigen-testing allows non-invasive detection of Helicobacter pylori that
      is indicative of active infection. Three commercial kits are currently marketed
      in the UK for stool antigen-testing. The aim of this study was to conduct a
      comparative evaluation of the performances of each of these tests, compared with
      culture and histological examination of gastric biopsies, for pre-treatment
      diagnosis of infection in an adult dyspeptic population in south-east England.
      Examination of 112 stool samples by the Premier Platinum HpSA ELISA (Meridian
      Diagnostics) and by the Amplified IDEIA HpStAR ELISA (DakoCytomation) kits
      demonstrated that the latter was more sensitive (81.3 versus 93.8%, respectively)
      and specific (91.7 versus 100.0%, respectively). Additionally, the IDEIA HpStAR
      was easier to interpret, with OD readings of positive and negative results being
      far from the recommended cut-off, whereas equivocal results that were generated
      by the HpSA kit were difficult to interpret. Additional testing of 87 of the 112
      stools by the ImmunoCard STAT! HpSA kit (Meridian Diagnostics) demonstrated that
      this test was easier to perform than ELISA and was more sensitive than the HpSA
      kit but, compared with the IDEIA HpStAR kit, the ImmunoCard test was less
      sensitive (87.8 versus 95.9%, respectively) and specific (89.4 versus 100.0%,
      respectively). Furthermore, the ImmunoCard test generated weakly positive
      results, correlating with lower OD readings for both ELISA kits, that were
      difficult to interpret. The Amplified IDEIA HpStAR kit is therefore the most
      sensitive and specific of the three tests that are available for pre-treatment,
      non-invasive detection of H. pylori in stool samples in an English adult
      dyspeptic population.

PMID- 15184533
TI  - Preliminary evaluation of one conventional nested and two real-time PCR assays
      for the detection of Toxoplasma gondii in immunocompromised patients.
AB  - Toxoplasma reactivation is a serious complication in patients receiving allogenic
      stem cell transplantation. Real-time PCR assays allow a rapid diagnosis of
      toxoplasma infection; however, no comparative data are available on the
      performance of real-time PCR protocols under routine conditions. Therefore, the
      aim of this study was to amplify Toxoplasma gondii DNA from routine samples of
      allogenic stem cell recipients using two real-time PCR assays on a LightCycler,
      and using conventional nested PCR. Conventional nested PCR revealed T. gondii DNA
      in 16 samples. Only 12 of the 16 samples yielded a positive result in both real
      time PCRs. The accuracy of the conventional PCR results was demonstrated by
      direct sequencing. Amplification and detection of the amplicon was completed in
      only 1 h using the real-time PCR assays. Thus, real-time PCR substantially
      accelerates the detection of T. gondii DNA in the majority of positive specimens;
      however, conventional nested PCR is required for detection of T. gondii DNA in
      some samples.

PMID- 15184534
TI  - Isolation and molecular identification of Candida dubliniensis from non-human
      immunodeficiency virus-infected patients in Kuwait.
AB  - Candida dubliniensis is an emerging pathogen capable of causing oropharyngeal,
      vaginal and bloodstream infections. Although C. dubliniensis is similar to
      Candida albicans in several phenotypic characteristics, it differs from it with
      respect to epidemiology, certain virulence factors and the ability to develop
      resistance to fluconazole rapidly. In this study, the first seven isolations of
      C. dubliniensis from Kuwait are described, all originating from non-human
      immunodeficiency virus (HIV)-infected patients. The isolates were initially
      identified by the Vitek 2 yeast identification system, positive germ tube test,
      production of rough colonies and chlamydospores on Staib agar and by their
      inability to assimilate xylose, trehalose or methyl alpha-D-glucoside. The
      species identity of the isolates was subsequently confirmed by specific
      amplification of rDNA targeting the internally transcribed spacer 2 (ITS2),
      restriction endonuclease digestion of the amplified DNA and direct DNA sequencing
      of the ITS2. Using the E-test method, the MICs of C. dubliniensis test isolates
      were in the range 0.125-0.75 microg ml(-1) for fluconazole, 0.002-0.75 microg ml(
      1) for itraconazole, 0.006-0.125 microg ml(-1) for ketoconazole, 0.002-0.5 microg
      ml(-1) for amphotericin B and 0.002-0.016 microg ml(-1) for voriconazole. Two of
      the isolates were resistant to 5-flucytosine (>32 microg ml(-1)), but none
      against fluconazole. The study reinforces the current view that C. dubliniensis
      has a much wider geographical and epidemiological distribution.

PMID- 15184535
TI  - Do procalcitonin and C-reactive protein levels have a place in the diagnosis and
      follow-up of Helicobacter pylori infections?
AB  - The aims of this study were to determine the levels of procalcitonin (PCT) and C
      reactive protein (CRP) in Helicobacter pylori-positive (HP+) patients diagnosed
      with duodenal and gastric ulcer and to evaluate the correlation of PCT and CRP
      levels with other invasive and non-invasive diagnostic methods for determination
      of H. pylori eradication in post-treatment follow-up. Thirty-five HP+ patients
      with dyspepsia were included in this study. Serum samples (5 ml) were collected
      at admission and after 24 h. Antimicrobial therapy (omeprazole, amoxycillin and
      clarithromycin) was given for 1 week to HP+ patients who were positive only by
      culture or by urease test plus pathology. After 1 month, serum samples (5 ml)
      were collected again and culture, urease and pathology investigations were
      performed on endoscopic samples. PCT and CRP levels were measured in the
      collected blood samples. Thirty-five H. pylori-negative (HP-) cases with
      dyspepsia, 38 cases with bacteraemia and 35 healthy blood donors were included in
      this study as control groups. The mean and minimum-maximum levels of PCT were
      1.39 (0.25-6.75), 0.35 (0.12-0.71), 7.45 (0.68-51.5) and 0.40 (0.12-0.71) ng ml(
      1) for the groups of HP+, HP- and bacteraemia patients and healthy donors,
      respectively. Mean CRP levels were 1.00 (<0.5-8.11), 0.62 (<0.5-3.2), 11.5 (3.2
      43.5) and 0.63 (<0.5-5.46) mg dl(-1) for the same groups. A statistically
      significant difference was found between HP+ patients and both HP- cases and
      healthy blood donors for PCT levels, and higher PCT levels were found on
      admission in cases of bacteraemia than in the other groups (P < 0.05). PCT levels
      of HP+ cases decreased significantly (from 1.39 to 0.86) between admission and
      the post-treatment period (30 days); however, PCT levels remained higher than the
      cut-off value (0.5 ng ml(-1)). Similar ranges of CRP levels were found over the
      same time-period. The sensitivity of PCT was found to be higher than that of CRP
      on admission, but the specificity of PCT was found to be lower than that of CRP
      on the day of admission (65 and 74%, respectively). The sensitivity of PCT was
      the same as that of CRP for the post-treatment period, but specificity of PCT was
      higher than that of CRP for the post-treatment period (83 and 76%, respectively).
      It was concluded that PCT and CRP are not very effective markers for H. pylori
      infection in primary diagnosis or in eradication follow-up after therapy when
      used in parallel with conventional diagnostic methods, even if there is a
      difference in PCT and CRP levels between HP+ and HP- cases on admission.

PMID- 15184536
TI  - Aetiology of acute pharyngitis: the role of atypical bacteria.
AB  - In order to establish the role of atypical bacteria and compare characteristics
      of different infectious agents in acute pharyngitis, 127 patients with acute
      pharyngitis (66 males; median age, 5.33 years; range, 6 months to 14 years) and
      130 healthy subjects of similar sex and age were studied. Serology with paired
      samples and PCR on nasopharyngeal aspirates and throat cultures were used to
      identify bacteria and viruses. Viruses were identified in 43 patients (33.8%) and
      five controls (3.8%; P < 0.0001), potential bacterial pathogens in 34 patients
      (26.8%) and 26 controls (20%; P = 0.256) and mixed viral/bacterial pathogens in
      26 patients (20.5%) and none of the controls (P < 0.0001). The main aetiological
      agents were adenovirus, respiratory syncytial virus (RSV), Mycoplasma pneumoniae,
      Streptococcus pyogenes and Chlamydia pneumoniae. M. pneumoniae was the agent
      found most frequently as a single pathogen. A history of recurrent pharyngitis,
      having older siblings and a negative outcome were significantly more common among
      patients with acute M. pneumoniae infection than among those with infections due
      to other pathogens or healthy controls. This study demonstrates that: (i)
      adenovirus and RSV have a prominent role in acute pharyngitis; (ii) S. pyogenes
      is found frequently, but it is not possible to distinguish simple carriers from
      patients with a true infection; (iii) M. pneumoniae appears to be able to cause
      acute pharyngitis per se; and (iv) C. pneumoniae seems to be mainly a co
      pathogen. To avoid the risk of an incorrect therapeutic approach, simple
      laboratory investigations that allow rapid identification of M. pneumoniae
      infections are urgently needed.

PMID- 15184537
TI  - Typing and characterization of carbapenem-resistant Acinetobacter calcoaceticus
      baumannii complex in a Chinese hospital.
AB  - This study was designed to investigate the prevalence of carbapenem-resistant
      Acinetobacter calcoaceticus-baumannii complex (Acb complex) and to type
      carbapenemases. The relatedness of 45 isolates of carbapenem-resistant Acb
      complex collected from a clinical setting was analysed by PFGE. The
      carbapenemases produced by these isolates were typed by IEF, a three-dimensional
      test, 2-mercaptopropanoic acid inhibition assay, PCR and DNA cloning and
      sequencing. Results showed that all 45 isolates were resistant to multiple
      antibiotics including meropenem. The resistance rates to cefoperazone/sulbactam
      and ampicillin/sulbactam were 2.2 and 6.5%, respectively. About 71.7-78.3% of
      these isolates were intermediately resistant to cefepime, ceftazidime and
      cefotaxime. Forty-five isolates were classified into type A (98%) and B (2%)
      based on their PFGE patterns. Most of type A isolates were from the ICU. Type A
      was the dominant isolate, including subtypes A1 (22%), A2 (71%), A3 (2%) and A4
      (2%). Only one isolate, from the haematology department, belonged to type B.
      Forty-three isolates (96%) were positive for carbapenemase. One isolate had two
      bands by IEF, the pIs of which were 6.64 and 7.17. The band with the pI of 6.64
      was OXA-23. The other 42 isolates produced two bands with pIs of 6.40 and 7.01
      which could not be inhibited by clavulanic acid, cloxacillin or 2
      mercaptopropanoic acid. It can be concluded that the prevalent carbapenem
      resistant Acb complex isolates from this hospital all had similar beta-lactamase
      patterns.

PMID- 15184538
TI  - Characterization of Neisseria meningitidis isolates collected from 1974 to 2003
      in Japan by multilocus sequence typing.
AB  - Analysis of 182 Neisseria meningitidis strains isolated over the past 30 years in
      Japan by serogroup typing and multilocus sequence typing (MLST) was performed.
      The serogroups of the 182 Japanese isolates were B (103 isolates), Y (39), W135
      (1) and non-groupable (39). By MLST analysis, 65 different sequence types (ST)
      were identified, 42 of which were not found in the MLST database as of January
      2004 and seemed to be unique to Japan. Statistical analysis of the MLST results
      revealed that, although the Japanese isolates seemed to be genetically divergent,
      they were classified into six major clonal complexes and other minor complexes.
      Among these isolates, well-documented ST complexes found worldwide were present,
      such as ST-23 complex (49 isolates), ST-44 complex (41 isolates) and ST-32
      complex (8 isolates). On the other hand, a new clonal complex designated ST-2046
      complex (28 isolates), which has not been identified in other countries, was also
      found, suggesting that this clone was indigenous to Japan. Taken together, it was
      speculated that meningococcal isolates in Japan comprised heterogeneous clones,
      which were derived both from clones identified in other countries and clones
      unique to Japan.

PMID- 15184539
TI  - Epidemiology of Burkholderia cepacia complex species recovered from cystic
      fibrosis patients: issues related to patient segregation.
AB  - Studies of the prevalence of Burkholderia cepacia complex species amongst cystic
      fibrosis (CF) patients in different geographical regions, and the association
      between cross-infection and putative transmissibility markers, will further our
      understanding of these organisms and help to address infection-control issues. In
      this study, B. cepacia complex isolates from CF patients in different regions of
      Europe were analysed. Isolates were examined for B. cepacia complex species and
      putative transmissibility markers [cable pilin subunit gene (cblA) and the B.
      cepacia epidemic strain marker (BCESM)]. Sporadic and cross-infective strains
      were identified by random amplification of polymorphic DNA (RAPD). In total, 79%
      of patients were infected with Burkholderia cenocepacia (genomovar III), 18% with
      Burkholderia multivorans (genomovar II) and less than 5% of patients with B.
      cepacia (genomovar I), Burkholderia stabilis (genomovar IV) or Burkholderia
      vietnamiensis (genomovar V). The cblA and BCESM transmissibility markers were
      only detected in strains of B. cenocepacia. The BCESM was a more sensitive marker
      for transmissible B. cenocepacia strains than cblA, although sporadic B.
      cenocepacia strains containing the BCESM, but lacking cblA, were also observed.
      Furthermore, clusters of cross-infection with transmissibility marker-negative
      strains of B. multivorans were identified. In conclusion, B. cenocepacia was the
      greatest cause of cross-infection, and the most widely distributed B. cepacia
      complex species, within these CF populations. However, cross-infection was not
      exclusive to B. cenocepacia and cblA and the BCESM were not absolute markers for
      transmissible B. cenocepacia, or other B. cepacia complex strains. It is
      therefore suggested that CF centres cohort patients based on the presence or
      absence of B. cepacia complex infection and not on the basis of transmissibility
      marker-positive B. cenocepacia as previously suggested.

PMID- 15184540
TI  - Microevolution between paired antral and paired antrum and corpus Helicobacter
      pylori isolates recovered from individual patients.
AB  - Sequence variations located at the signal sequence and mid-region within the vacA
      gene, the 3'-end of the cagA gene, the indel motifs at the 3'-end of the cag
      pathogenicity island and the regions upstream of the vacA and ribA genes were
      determined by PCR in 19 paired antral or antrum and corpus Helicobacter pylori
      isolates obtained at the same endoscopic session, and three antral pairs taken
      sequentially. Random amplification of polymorphic DNA (RAPD)-PCR and fluorescent
      amplified fragment length polymorphism (FAFLP)-PCR fingerprinting were applied to
      these paired clinical isolates. The FAFLP-PCR profiles generated were
      phylogenetically analysed. For the 22 paired isolates there were no differences
      within pairs at five of the genetic loci studied. However, six pairs of isolates
      (27%), of which four were antrum and corpus pairs, showed differences in the
      numbers of repeats located at the 3'-end of the cagA gene. RAPD-PCR
      fingerprinting showed that 16 (73%) pairs, nine of which were antrum and corpus
      pairs, possessed identical profiles, while six (27%) displayed distinctly
      different profiles, indicating mixed infections. Three of the six pairs showing
      differences at the 3'-end of the cagA gene yielded identical RAPD-PCR
      fingerprints. FAFLP-PCR fingerprinting and phylogenetic analysis revealed that
      all 16 pairs that displayed identical RAPD-PCR profiles had highly similar, but
      not identical, fingerprints, demonstrating that these pairs were ancestrally
      related but had undergone minor genomic alterations. Two antrum and corpus pairs
      of isolates, within the latter group, were isolates obtained from two siblings
      from the same family. This analysis demonstrated that each sibling was colonized
      by ancestrally related strains that exhibited differences in vacA genotype
      characteristics.

PMID- 15184541
TI  - Alginate production affects Pseudomonas aeruginosa biofilm development and
      architecture, but is not essential for biofilm formation.
AB  - Extracellular polymers can facilitate the non-specific attachment of bacteria to
      surfaces and hold together developing biofilms. This study was undertaken to
      qualitatively and quantitatively compare the architecture of biofilms produced by
      Pseudomonas aeruginosa strain PAO1 and its alginate-overproducing (mucA22) and
      alginate-defective (algD) variants in order to discern the role of alginate in
      biofilm formation. These strains, PAO1, Alg+ PAOmucA22 and Alg- PAOalgD, tagged
      with green fluorescent protein, were grown in a continuous flow cell system to
      characterize the developmental cycles of their biofilm formation using confocal
      laser scanning microscopy. Biofilm Image Processing (BIP) and Community
      Statistics (COMSTAT) software programs were used to provide quantitative
      measurements of the two-dimensional biofilm images. All three strains formed
      distinguishable biofilm architectures, indicating that the production of alginate
      is not critical for biofilm formation. Observation over a period of 5 days
      indicated a three-stage development pattern consisting of initiation,
      establishment and maturation. Furthermore, this study showed that phenotypically
      distinguishable biofilms can be quantitatively differentiated.

PMID- 15184542
TI  - Immunocytochemical studies of Salmonella Typhimurium invasion of porcine jejunal
      epithelial cells.
AB  - Although infection of pigs with Salmonella Typhimurium represents a serious
      problem, most studies on Salmonella infection have been carried out in other
      species. The purpose of the current study was to examine the route(s) of entry of
      Salmonella Typhimurium in pigs, using a jejunal loop model. The infection process
      was followed over 240 min using single to triple immunocytochemical detection of
      Salmonella and intestinal cell markers. Salmonella invasion was observed in both
      cytokeratin-18-positive and -negative cylindrical absorptive cells within 5-10
      min. Subepithelial invasion of ordinary villi was consistently less marked than
      invasion of the subepithelial layer of Peyer's patches. Our results show that
      several epithelial cell types were invaded by Salmonella, and that Peyer's
      patches represent the main portal of entry in early Salmonella infection.
      Additionally, infection was associated with alterations in the keratin and F
      actin cytoskeleton of intestinal epithelial cells, probably reflecting toxin
      mediated actions. Such changes were confined to the proximal region of the
      jejunum, demonstrating a regional heterogeneity of intestinal epithelial cell
      responses to Salmonella infection.

PMID- 15184543
TI  - Genotypic diversity and virulence traits of Streptococcus mutans in caries-free
      and caries-active individuals.
AB  - The present study evaluated the relationship between clonal diversity and some
      virulence traits of Streptococcus mutans isolated from eight caries-free and
      eight caries-active subjects. A total of 155 S. mutans isolates from caries-free
      subjects and 144 isolates from caries-active subjects were obtained from samples
      of saliva, dental plaque and tongue surface and identified by PCR. The isolates
      were submitted to arbitrarily primed (AP)-PCR (OPA-2 and OPA-13) and multilocus
      enzyme electrophoresis (MLEE) to establish the genotypic diversity. Production of
      water-insoluble glucan (WIG) (monitored by SDS-PAGE), final pH of cultures and
      the ability of bacterial cells to adhere to smooth glass in the presence of
      sucrose were measured. High and comparable abilities of MLEE and AP-PCR were
      found to distinguish S. mutans genotypes, using Simpson's index of discrimination
      (0.971 and 0.968, respectively). The results showed a significant difference (P <
      0.01) in the number of genotypes when caries-free and caries-active groups were
      compared by both fingerprinting methods used. Final pH (P = 0.32) and the
      percentage of adherence to a glass surface (P = 0.62) did not show differences
      between the two groups; however, the intensities of WIG bands from the caries
      active group were greater than those from the caries-free group (P < 0.01). In
      addition, WIG was positively correlated with the ability of S. mutans to adhere
      to a glass surface (r = 0.34, P = 0.02) from caries-active subjects. These data
      showed that AP-PCR analysis and MLEE are both effective methods for assessing the
      genetic relatedness of S. mutans. Using these techniques, it was found that there
      is a larger number of genotypes of S. mutans with increased ability to synthesize
      WIG in caries-active individuals.

PMID- 15184545
TI  - PeerGAD: a peer-review-based and community-centric web application for viewing
      and annotating prokaryotic genome sequences.
AB  - PeerGAD is a web-based database-driven application that allows community-wide
      peer-reviewed annotation of prokaryotic genome sequences. The application was
      developed to support the annotation of the Pseudomonas syringae pv. tomato strain
      DC3000 genome sequence and is easily portable to other genome sequence annotation
      projects. PeerGAD incorporates several innovative design and operation features
      and accepts annotations pertaining to gene naming, role classification, gene
      translation and annotation derivation. The annotator tool in PeerGAD is built
      around a genome browser that offers users the ability to search and navigate the
      genome sequence. Because the application encourages annotation of the genome
      sequence directly by researchers and relies on peer review, it circumvents the
      need for an annotation curator while providing added value to the annotation
      data. Support for the Gene Ontology vocabulary, a structured and controlled
      vocabulary used in classification of gene roles, is emphasized throughout the
      system. Here we present the underlying concepts integral to the functionality of
      PeerGAD.

PMID- 15184544
TI  - Protection in a mouse peritonitis model mediated by iron-regulated outer-membrane
      protein of Salmonella typhi coupled to its Vi antigen.
AB  - Vi polysaccharide and iron-regulated outer-membrane proteins (IROMPs) were
      extracted and purified from the standard strain of Salmonella typhi, Ty2. These
      were then conjugated by chemical coupling using the carbodimide method. Vi-IROMP
      conjugate was tested for its ability to protect against colonization by S. typhi
      in different organs. Mice immunized with 2.5 microg Vi-IROMP conjugate showed the
      most protection, as the least bacterial colonization of spleen, liver and Peyer's
      patches was observed. Peritoneal macrophages obtained from conjugate-treated mice
      phagocytosed bacteria efficiently. Circulating antibodies and the delayed type
      hypersensitivity response elucidated by mouse foot-pad swelling was significantly
      higher in conjugate-treated animals. These results clearly demonstrate that an
      IROMP and polysaccharide conjugate of S. typhi prepared from the same strain has
      the potential to protect animals against challenge.

PMID- 15184546
TI  - Genome update: tRNAs in sequenced microbial genomes.

PMID- 15184547
TI  - Methylotrophy versus heterotrophy: a misconception.

PMID- 15184548
TI  - The replication-related organization of bacterial genomes.
AB  - The replication of the chromosome is among the most essential functions of the
      bacterial cell and influences many other cellular mechanisms, from gene
      expression to cell division. Yet the way it impacts on the bacterial chromosome
      was not fully acknowledged until the availability of complete genomes allowed one
      to look upon genomes as more than bags of genes. Chromosomal replication includes
      a set of asymmetric mechanisms, among which are a division in a lagging and a
      leading strand and a gradient between early and late replicating regions. These
      differences are the causes of many of the organizational features observed in
      bacterial genomes, in terms of both gene distribution and sequence composition
      along the chromosome. When asymmetries or gradients increase in some genomes,
      e.g. due to a different composition of the DNA polymerase or to a higher growth
      rate, so do the corresponding biases. As some of the features of the chromosome
      structure seem to be under strong selection, understanding such biases is
      important for the understanding of chromosome organization and adaptation.
      Inversely, understanding chromosome organization may shed further light on
      questions relating to replication and cell division. Ultimately, the
      understanding of the interplay between these different elements will allow a
      better understanding of bacterial genetics and evolution.

PMID- 15184549
TI  - Substrate recognition by nonribosomal peptide synthetase multi-enzymes.
AB  - Nonribosomal peptide synthetases (NRPSs) are giant multi-domain enzymes that
      catalyse the biosynthesis of many commercially important peptides produced by
      bacteria and fungi. Several studies over the last decade have shown that many of
      the individual domains within NRPSs exhibit significant substrate selectivity,
      which impacts on our ability to engineer NRPSs to produce new bioactive microbial
      peptides. Adenylation domains appear to be the primary determinants of substrate
      selectivity in NRPSs. Much progress has been made towards an empirical
      understanding of substrate selection by these domains over the last 5 years, but
      the molecular basis of substrate selectivity in these domains is not yet well
      understood. Perhaps surprisingly, condensation domains have also been reported to
      exhibit moderate to high substrate selectivity, although the generality of this
      observation and its potential impact on engineered biosynthesis experiments has
      yet to be fully elucidated. The situation is less clear for the thioesterase
      domains, which seem in certain cases to be dedicated to the
      hydrolysis/cyclization of their natural substrate, whereas in other cases they
      are largely permissive.

PMID- 15184550
TI  - Specific growth rate and not cell density controls the general stress response in
      Escherichia coli.
AB  - In batch cultures of Escherichia coli, the intracellular concentration of the
      general stress response sigma factor RpoS typically increases during the
      transition from the exponential to the stationary growth phase. However, because
      this transition is accompanied by complex physico-chemical and biological
      changes, which signals predominantly elicit this induction is still the subject
      of debate. Careful design of the growth environment in chemostat and batch
      cultures allowed the separate study of individual factors affecting RpoS.
      Specific growth rate, and not cell density or the nature of the growth-limiting
      nutrient, controlled RpoS expression and RpoS-dependent hydroperoxidase activity.
      Furthermore, it was demonstrated that the standard E. coli minimal medium A (MMA)
      is not suitable for high-cell-density cultivation because it lacks trace
      elements. Previously reported cell-density effects in chemostat cultures of E.
      coli can be explained by a hidden, secondary nutrient limitation, which points to
      the importance of medium design and appropriate experimental set-up for studying
      cell-density effects.

PMID- 15184551
TI  - Oxidative stress response in Clostridium perfringens.
AB  - Clostridium perfringens, a strictly anaerobic bacterium, is able to survive when
      exposed to oxygen for short periods of time and exhibits a complex adaptive
      response to reactive oxygen species, both under aerobic and anaerobic conditions.
      However, this adaptive response is not completely understood. C. perfringens
      possesses specialized genes that might be involved in this adaptive process, such
      as those encoding superoxide dismutase (SOD), superoxide reductase and alkyl
      hydroperoxide reductase, but their contribution to the oxidative stress response
      and their control mechanisms are unknown. By a combination of functional
      complementation of Escherichia coli strains impaired in either SOD, alkyl
      hydroperoxide reductase (AhpC) or catalase activity (Cat), transcription analysis
      and characterization of mutants impaired in regulatory genes, it was concluded
      that: (i) the product of the sod gene is certainly essential to scavenge
      superoxide radicals, (ii) the ahpC gene, which is fully induced in all oxidative
      stress conditions, is probably involved in the scavenging of all intracellular
      peroxides, (iii) the three rubrerythrin (rbr) genes of C. perfringens do not
      encode proteins with in vivo H(2)O(2) reductase activity, and (iv) the two
      rubredoxin (rub) genes do not contribute to the hypothetical superoxide reductase
      activity, but are likely to belong to an electron transfer chain involved in
      energy metabolism.

PMID- 15184552
TI  - Characterization of Pseudomonas putida genes responsive to nutrient limitation.
AB  - The low bioavailability of nutrients and oxygen in the soil environment has
      hampered successful expression of biodegradation and biocontrol genes that are
      driven by promoters highly active during routine laboratory conditions of high
      availability of nutrients and oxygen. Hence, in the present study, expression of
      the gus-tagged genes in 12 Tn5-gus mutants of the soil microbe Pseudomonas putida
      PNL-MK25 were examined under various conditions chosen to mimic the soil
      environment: low carbon, phosphate, nitrate or oxygen, and in the rhizosphere.
      Based on their expression profiles, three nutrient-responsive mutant (NRM)
      strains, NRM5, NRM7 and NRM17, were selected for identification of the tagged
      genes. In strain NRM5, expression of the glutamate dehydrogenase (gdhA) gene was
      increased 4.9-26.4-fold under various low-nutrient conditions. In NRM7,
      expression of the novel NADPH : quinone oxidoreductase-like (nql) gene was
      consistently amongst the highest and was synergistically upregulated by low
      nutrient and anoxic conditions. The cyoD gene in NRM17, which encodes the fourth
      subunit of the cytochrome o ubiquinol oxidase complex, had decreased expression
      in low-nutrient conditions but its absolute expression level was still amongst
      the highest. Additionally, it was independent of oxygen availability, in contrast
      to that in Escherichia coli.

PMID- 15184553
TI  - FpvB, an alternative type I ferripyoverdine receptor of Pseudomonas aeruginosa.
AB  - Under conditions of iron limitation, Pseudomonas aeruginosa secretes a high
      affinity siderophore pyoverdine to scavenge Fe(III) in the extracellular
      environment and shuttle it into the cell. Uptake of the pyoverdine-Fe(III)
      complex is mediated by a specific outer-membrane receptor protein, FpvA
      (ferripyoverdine receptor). Three P. aeruginosa siderovars can be distinguished,
      each producing a different pyoverdine (type I-III) and a cognate FpvA receptor.
      Growth of an fpvA mutant of P. aeruginosa PAO1 (type I) under iron-limiting
      conditions can still be stimulated by its cognate pyoverdine, suggesting the
      presence of an alternative uptake route for type I ferripyoverdine. In silico
      analysis of the PAO1 genome revealed that the product of gene PA4168 has a high
      similarity with FpvA. Inactivation of PA4168 (termed fpvB) in an fpvA mutant
      totally abolished the capacity to utilize type I pyoverdine. The expression of
      fpvB is induced by iron limitation in Casamino acids (CAA) and in M9-glucose
      medium, but, unlike fpvA, not in a complex deferrated medium containing glycerol
      as carbon source. The fpvB gene was also detected in other P. aeruginosa
      isolates, including strains producing type II and type III pyoverdines.
      Inactivation of the fpvB homologues in these strains impaired their capacity to
      utilize type I ferripyoverdine as a source of iron. Accordingly, introduction of
      fpvB in trans restored the capacity to utilize type I ferripyoverdine.

PMID- 15184554
TI  - The Mycobacterium tuberculosis cysD and cysNC genes form a stress-induced operon
      that encodes a tri-functional sulfate-activating complex.
AB  - Sulfur metabolism has been implicated in the virulence, antibiotic resistance and
      anti-oxidant defence of Mycobacterium tuberculosis. Despite its human disease
      relevance, sulfur metabolism in mycobacteria has not yet been fully
      characterized. ATP sulfurylase catalyses the synthesis of activated sulfate
      (adenosine 5'-phosphosulfate, APS), the first step in the reductive assimilation
      of sulfate. Expression of the M. tuberculosis cysD gene, predicted to encode the
      adenylyl-transferase subunit of ATP sulfurylase, is upregulated by the bacilli
      inside its preferred host, the macrophage. This study demonstrates that cysD and
      cysNC orthologues exist in M. tuberculosis and constitute an operon whose
      expression is induced by sulfur limitation and repressed by the presence of
      cysteine, a major end-product of sulfur assimilation. The cysDNC genes are also
      induced upon exposure to oxidative stress, suggesting regulation of sulfur
      assimilation by M. tuberculosis in response to toxic oxidants. To ensure that the
      cysDNC operon encoded the activities predicted by its primary sequence, and to
      begin to characterize the products of the operon, they were expressed in
      Escherichia coli, purified to homogeneity, and tested for their catalytic
      activities. The CysD and CysNC proteins were shown to form a multifunctional
      enzyme complex that exhibits the three linked catalytic activities that
      constitute the sulfate activation pathway.

PMID- 15184555
TI  - Formation of 'non-culturable' cells of Mycobacterium smegmatis in stationary
      phase in response to growth under suboptimal conditions and their Rpf-mediated
      resuscitation.
AB  - Conditions were investigated that promote the formation of 'non-culturable' (NC)
      cells of Mycobacterium (Myc.) smegmatis in stationary phase. After cultivation in
      a rich medium, or under conditions that may be considered optimal for bacterial
      growth, or starvation for carbon, nitrogen or phosphorus, bacteria failed to
      enter a NC state. However, when grown under suboptimal conditions, resulting in a
      reduced growth rate or maximal cell concentration (e.g. in modified Hartman's-de
      Bont medium), bacteria adopted a stable NC state after 3-4 days incubation in
      stationary phase. Such conditions are not specific as purF and devR mutants of
      Myc. smegmatis also showed (transient) loss of culturability following growth to
      stationary phase in an optimized medium, but under oxygen-limited conditions. The
      behaviour of the same mutants in oxygen-sufficient but nutrient-inappropriate
      medium (modified Hartman's-de Bont medium) was similar to that of the wild-type
      (adoption of a stable NC state). It is hypothesized that adoption of a NC state
      may represent an adaptive response of the bacteria, grown under conditions when
      their metabolism is significantly compromised due to the simultaneous action of
      several factors, such as usage of inappropriate nutrients or low oxygen
      availability or impairment of a particular metabolic pathway. NC cells of wild
      type Myc. smegmatis resume growth when transferred to a suitable resuscitation
      medium. Significantly, resuscitation was observed when either recombinant Rpf
      protein or supernatant derived from a growing bacterial culture was incorporated
      into the resuscitation medium. Moreover, co-culture with Micrococcus (Mcc.)
      luteus cells (producing and secreting Rpf) also permitted resuscitation. Isogenic
      strains of Myc. smegmatis harbouring plasmids containing the Mcc. luteus rpf gene
      also adopt a similar NC state after growth to stationary phase in modified
      Hartman's-de Bont medium. However, in contrast to the behaviour noted above,
      these strains resuscitated spontaneously when transferred to the resuscitation
      medium, presumably because they are able to resume endogenous synthesis of Mcc.
      luteus Rpf. Resuscitation was not observed in the control strain harbouring a
      plasmid lacking Mcc. luteus rpf. In contrast to wild-type, the NC cells of purF
      and devR mutants obtained under oxygen-limited conditions resuscitate
      spontaneously, presumably because the heterogeneous population contains some
      residual viable cells that continue to make Rpf-like proteins.

PMID- 15184556
TI  - Phylogeny of Mycobacterium avium strains inferred from glycopeptidolipid
      biosynthesis pathway genes.
AB  - The Mycobacterium avium complex (MAC) encompasses two species, M. avium and
      Mycobacterium intracellulare, which are opportunistic pathogens of humans and
      animals. The standard method of MAC strain differentiation is serotyping based on
      a variation in the antigenic glycopeptidolipid (GPL) composition. To elucidate
      the relationships among M. avium serotypes a phylogenetic analysis of 13
      reference and clinical M. avium strains from 8 serotypes was performed using as
      markers two genomic regions (890 bp of the gtfB gene and 2150 bp spanning the
      rtfA-mtfC genes) which are associated with the strains' serological properties.
      Strains belonging to three other known M. avium serotypes were not included in
      the phylogeny inference due to apparent lack of the marker sequences in their
      genomes, as revealed by PCR and Southern blot analysis. These studies suggest
      that serotypes prevalent in AIDS patients have multiple origins. In trees
      inferred from both markers, serotype 1 strains, known to have the simplest and
      shortest GPLs among all other serotypes, were polyphyletic. Likewise, comparisons
      of the inferred phylogenies with the molecular typing results imply that the
      existing tools used in epidemiological studies may be poor estimators of M. avium
      strain relatedness. Additionally, trees inferred from each marker had
      significantly incongruent topologies due to a well supported alternative
      placement of strain 2151, suggesting a complex evolutionary history of this
      genomic region.

PMID- 15184557
TI  - Naturally occurring horizontal gene transfer and homologous recombination in
      Mycobacterium.
AB  - Acquisition of genetic information through horizontal gene transfer (HGT) is an
      important evolutionary process by which micro-organisms gain novel phenotypic
      characteristics. In pathogenic bacteria, for example, it facilitates maintenance
      and enhancement of virulence and spread of drug resistance. In the genus
      Mycobacterium, to which several primary human pathogens belong, HGT has not been
      clearly demonstrated. The few existing reports suggesting this process are based
      on circumstantial evidence of similarity of sequences found in distantly related
      species. Here, direct evidence of HGT between strains of Mycobacterium avium
      representing two different serotypes is presented. Conflicting evolutionary
      histories of genes encoding elements of the glycopeptidolipid (GPL) biosynthesis
      pathway led to an analysis of the GPL cluster genomic sequences from four
      Mycobacterium avium strains. The sequence of M. avium strain 2151 appeared to be
      a mosaic consisting of three regions having alternating identities to either M.
      avium strains 724 or 104. Maximum-likelihood estimation of two breakpoints
      allowed a approximately 4100 bp region horizontally transferred into the strain
      2151 genome to be pinpointed with confidence. The maintenance of sequence
      continuity at both breakpoints and the lack of insertional elements at these
      sites strongly suggest that the integration of foreign DNA occurred by homologous
      recombination. To our knowledge, this is the first report to demonstrate
      naturally occurring homologous recombination in Mycobacterium. This previously
      undiscovered mechanism of genetic exchange may have major implications for the
      understanding of Mycobacterium pathogenesis.

PMID- 15184558
TI  - DNA methyltransferases from Neisseria meningitidis and Neisseria gonorrhoeae
      FA1090 associated with mismatch nicking endonucleases.
AB  - The genes encoding the DNA methyltransferases M.NmeDI and M.NmeAI from Neisseria
      meningitidis associated with the genes encoding putative Vsr endonucleases were
      overexpressed in Escherichia coli. The enzymes were purified to apparent
      homogeneity on Ni-NTA agarose columns, yielding proteins of 49+/-1 kDa and 39.6+/
      1 kDa, respectively, under denaturing conditions. M.NmeDI recognizes the
      degenerate sequence 5'-RCCGGB-3'. It methylates the first 5' cytosine residue on
      both strands within the core sequence CCGG. The enzyme shows higher affinity with
      the hemimethylated degenerate sequence than with the unmethylated degenerate
      sequence. Comparison of the amino acid sequence of the target-recognizing domain
      of M.NmeDI with the closest neighbours recognizing the sequence 5'-RCCGGY-3'
      showed the presence of the homologous domain and an additional domain that may be
      responsible for recognizing the degenerate sequence. M.NmeAI recognizes the
      sequence 5'-CCGG-3' and methylates the second 5' cytosine residue on both DNA
      strands. In Neisseria gonorrhoeae strain FA1090 the homologues of these ORFs are
      truncated due to a variety of mutations.

PMID- 15184559
TI  - Molecular cloning of haemoglobin-binding protein HgbA in the outer membrane of
      Actinobacillus pleuropneumoniae.
AB  - From the porcine pathogen Actinobacillus pleuropneumoniae cultivated in iron
      deficient or haem-deficient media, haemoglobin (Hb)-agarose affinity purification
      was exploited to isolate an outer-membrane protein of approximately 105 kDa,
      designated HgbA. Internal peptide sequences of purified HgbA were used to design
      oligonucleotide primers for PCR amplification, yielding amplicons that showed
      partial sequences with homology to hgbA of Pasteurella multocida. Upon screening
      two genomic libraries of A. pleuropneumoniae serotype 1 strain 4074, positive
      clones were assembled into an ORF of 2838 bp. HgbA (946 aa) includes a signal
      peptide of 23 aa and the deduced HgbA sequence (104 890 Da) also demonstrated a
      possible Ton box. The promoter region of hgbA from A. pleuropneumoniae serotype 1
      showed consensus for -35 and -10 sequences and a putative Fur-binding site. RT
      PCR confirmed that hgbA of A. pleuropneumoniae is upregulated in response to
      diminished levels of iron in the culture medium. While an internally deleted hgbA
      mutant was unable to use pig Hb as sole source of iron for growth, flow cytometry
      confirmed its Hb binding; the internally deleted sequences may not be required
      for Hb binding, but appear necessary for the iron supply from Hb. HgbA is
      required for growth of A. pleuropneumoniae in the presence of Hb as sole iron
      source.

PMID- 15184560
TI  - Diversity analysis of commensal porcine Escherichia coli - associations between
      genotypes and habitat in the porcine gastrointestinal tract.
AB  - Diversity studies of enteric Escherichia coli have relied almost entirely on
      faecal isolations on the assumption that they are representative of flora found
      throughout the gastrointestinal tract. The authors have addressed this belief by
      analysing isolates obtained from the duodenum, ileum, colon and faeces of pigs.
      E. coli isolates were obtained from eight pigs and characterized using multi
      locus enzyme electrophoresis and PCR-based screening for a range of factors
      thought to be associated with intestinal and extra-intestinal disease. There are
      four main genetic groups of commensal E. coli (A, B1, B2, D). Group A strains
      represented 76 % of the isolates from the duodenum, ileum and colon compared to
      58 % of the strains isolated from faeces. A nested molecular analysis of variance
      based on the allozyme and virulence factor screening results showed that
      differences among individual pigs accounted for 6 % of the observed genetic
      diversity, whilst 27 % of the genetic variation could be explained by clonal
      composition differences among gut regions. Finally, the absence of virulence
      genes in these commensals indicates that they may be suitable as a probiotic
      consortium, particularly if they also display increased adherence to enterocytes
      and antagonistic activity against pathogenic strains of E. coli.

PMID- 15184561
TI  - Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents
      Borrelia burgdorferi in North America and Borrelia afzelii in Europe.
AB  - The genetic polymorphism of Borrelia burgdorferi and Borrelia afzelii, two
      species that cause Lyme borreliosis, was estimated by sequence typing of four
      loci: the rrs-rrlA intergenic spacer (IGS) and the outer-membrane-protein gene
      p66 on the chromosome, and the outer-membrane-protein genes ospA and ospC on
      plasmids. The major sources of DNA for PCR amplification and sequencing were
      samples of the B. burgdorferi tick vector Ixodes scapularis, collected at a field
      site in an endemic region of the north-eastern United States, and the B. afzelii
      vector Ixodes ricinus, collected at a similar site in southern Sweden. The
      sequences were compared with those of reference strains and skin biopsy isolates,
      as well as database sequences. For B. burgdorferi, 10-13 alleles for each of the
      4 loci, and a total of 9 distinct clonal lineages with linkage of all 4 loci,
      were found. For B. afzelii, 2 loci, ospC and IGS, were examined, and 11 IGS
      genotypes, 12 ospC alleles, and a total of 9 linkage groups were identified. The
      genetic variants of B. burgdorferi and B. afzelii among samples from the field
      sites accounted for the greater part of the genetic diversity previously reported
      from larger areas of the north-eastern United States and central and northern
      Europe. Although ospC alleles of both species had higher nucleotide diversity
      than other loci, the ospC locus showed evidence of intragenic recombination and
      was unsuitable for phylogenetic inference. In contrast, there was no detectable
      recombination at the IGS locus of B. burgdorferi. Moreover, beyond the signature
      nucleotides that specified 10 IGS genotypes, there were additional nucleotide
      polymorphisms that defined a total of 24 subtypes. Maximum-likelihood and
      parsimony cladograms of B. burgdorferi aligned IGS sequences revealed the subtype
      sequences to be terminal branches of clades, and the existence of at least three
      monophyletic lineages within B. burgdorferi. It is concluded that B. burgdorferi
      and B. afzelii have greater genetic diversity than had previously been estimated,
      and that the IGS locus alone is sufficient for strain typing and phylogenetic
      studies.

PMID- 15184563
TI  - Molecular identification of Vibrio harveyi-related isolates associated with
      diseased aquatic organisms.
AB  - Fifty strains belonging to Vibrio harveyi, Vibrio campbellii, and the recently
      described Vibrio rotiferianus, were analysed using phenotypic and genomic
      techniques with the aim of analysing the usefulness of the different techniques
      for the identification of V. harveyi-related species. The species V. harveyi and
      V. campbellii were phenotypically indistinguishable by more than 100 phenotypic
      features. Thirty-nine experimental strains were phenotypically identified as V.
      harveyi, but FAFLP, REP-PCR, IGS-PCR and DNA-DNA hybridization proved that they
      in fact belong to the species V. campbellii. Similar groupings were found among
      all fingerprinting methodologies (except IGS-PCR). Thirty-two experimental
      strains clustered with the V. campbellii type and one reference strain; seven
      strains clustered with the V. harveyi type and three reference strains; and the
      type and four reference strains of V. rotiferianus grouped together. The
      correlations between DNA-DNA hybridization and the genomic fingerprinting by
      FAFLP and (GTG)(5)-PCR were found to be above 0.68 and statistically significant,
      suggesting the value of the latter techniques for the reliable identification of
      V. harveyi-related species. The results presented indicate that strains
      phenotypically identified as V. harveyi are in fact V. campbellii; these findings
      position V. campbellii as an important species involved in diseases of reared
      aquatic organisms.

PMID- 15184562
TI  - Revised description and classification of atypical isolates of Pasteurella
      multocida from bovine lungs based on genotypic characterization to include
      variants previously classified as biovar 2 of Pasteurella canis and Pasteurella
      avium.
AB  - Strains deviating in key phenotypic characters, mainly isolated from cases of
      bovine pneumonia in five European countries, were genotyped in order to examine
      their genotypic relationship with Pasteurella multocida. Twenty-two strains of
      Pasteurella avium biovar 2, including variants in indole, xylose and mannitol, 18
      strains of Pasteurella canis biovar 2 and variants of this taxon, five strains of
      P. multocida subsp. septica showing variations in indole and ornithine
      decarboxylase, nine strains of P. multocida subsp. multocida showing variation in
      ornithine decarboxylase and mannitol, and type strains of the subspecies of P.
      multocida were included. Ribotyping was used to examine the relationship of the
      strains, and 13 types, each containing between one and 20 isolates, were
      observed. Identical ribotypes were observed in some cases for P. avium biovar 2
      and either P. canis biovar 2 or P. multocida subsp. septica. ITS (16S-23S rRNA
      internal transcribed spacer) fragment-length profiling showed identity of the
      majority of strains (47 of 52), representing all four taxa, with only five
      divergent strains. A 16S rRNA sequence comparison of 11 strains representing the
      main ribotype clusters showed 99.9 % similarity to the type strain of P.
      multocida subsp. multocida, but only 97.4 % similarity was obtained to P. canis
      (biovar 1) and 93.7 % to P. avium (biovar 1). A species-specific PCR test for P.
      multocida gave a positive result with biovar 2 variants of P. avium and P. canis.
      DNA-DNA hybridizations between strains of P. multocida, biovar 2 variants of P.
      avium and P. canis, and P. multocida subsp. septica confirmed similarity at the
      species level. It is proposed, on the basis of genotypic similarity, that P.
      multocida be reclassified to include the biovar 2 variants of P. avium and P.
      canis and that the existence of the biovar 2 variants of P. avium and P. canis is
      highly questionable. It is concluded that the redefined P. multocida is
      genotypically homogeneous, although phenotypically diverse lineages exist with
      respect to ornithine decarboxylase, indole and mannitol, characters that have
      been regarded as essential for identification to the species level. A formal
      reclassification of the species is not possible, however, since too few strains
      have been found to vary in these key characters. Considering the phenotypic
      diversity of P. multocida, identification will have to depend partly on genotypic
      methods and the source host also seems important for safe diagnosis.

PMID- 15184564
TI  - Multiple linear regression analysis of bacterial deposition to polyurethane
      coatings after conditioning film formation in the marine environment.
AB  - Many studies have shown relationships of substratum hydrophobicity, charge or
      roughness with bacterial adhesion, although bacterial adhesion is governed by
      interplay of different physico-chemical properties and multiple regression
      analysis would be more suitable to reveal mechanisms of bacterial adhesion. The
      formation of a conditioning film of organic compounds adsorbed from seawater
      affects the properties of substratum surfaces prior to bacterial adhesion, which
      is a complicating factor in studying the mechanism of bacterial adhesion. In this
      paper, the impact of conditioning films adsorbed from natural seawater to four
      polyurethane coatings with different hydrophobicity, elasticity and roughness was
      studied for three different marine bacterial strains in a multiple linear
      regression analysis. The water contact angle on hydrophobic coatings decreased on
      average by 8 degrees and increased on average by the same amount on hydrophilic
      coatings. These changes were accompanied by increased concentrations of oxygen
      and nitrogen on the surface as determined by X-ray photoelectron spectroscopy,
      indicative of adsorption of proteinaceous material. Furthermore, the mean surface
      roughness increased on average by 4 nm after conditioning film formation.
      Multiple linear regression analysis revealed that changes in deposition due to
      conditioning film formation of Marinobacter hydrocarbonoclasticus, Psychrobacter
      sp. SW5H and Halomonas pacifica in a stagnation-point flow chamber could be
      explained in a model comprising hydrophobicity and the prevalence of nitrogen
      rich components on the surface for the most hydrophobic strain. For the two more
      hydrophilic strains, deposition was governed by a combination of surface
      roughness and hydrophobicity. Elasticity was not a factor in bacterial adhesion
      to conditioning films.

PMID- 15184565
TI  - Diversity and distribution of Microcystis (Cyanobacteria) oligopeptide chemotypes
      from natural communities studied by single-colony mass spectrometry.
AB  - Microcystis sp. has been recognized in recent years as a producer of a high
      number of secondary metabolites. Among these, peptides that are produced by the
      non-ribosomal peptide synthetase pathway often show bioactivity or are toxic to
      humans. The production of particular peptides is specific for individual
      Microcystis clones, allowing their characterization as chemotypes by analysing
      the peptidome. The authors studied the in situ diversity of peptides and
      chemotypes in Microcystis communities from lakes in and around Berlin, Germany,
      by direct analysis of individual colonies by MALDI-TOF mass spectrometry. From
      165 colonies analysed a total of 46 individual peptides could be identified, 21
      of which have not been described previously. For six of the new peptides the
      structures could be elucidated from fragment patterns, while for others only a
      preliminary classification could be achieved. In most colonies, two to ten
      individual peptides were detected. In 19 colonies, 16 of which were identified as
      M. wesenbergii, no peptide metabolites could be detected. The peptide data of 146
      colonies were subjected to an ordination (principal components analysis). The
      principal components were clearly formed by the microcystin variants Mcyst-LR, 
      RR and -YR, anabaenopeptins B and E/F, a putative microviridin, and a new
      cyanopeptolin. In the resulting ordination plots most colonies were grouped into
      five distinct groups, while 40 colonies scattered widely outside these groups. In
      some cases colonies from different lakes clustered closely, indicating the
      presence of similar chemotypes in the respective samples. With respect to colony
      morphology no clear correlation between a chemotype and a morphospecies could be
      established, but M. aeruginosa, for example, was found to produce predominantly
      microcystins. In contrast, M. ichthyoblabe colonies were mostly negative for
      microcystins and instead produced anabaenopeptins. The number of peptides
      detected in a limited number of samples and the various combinations of peptides
      in individual Microcystis colonies highlights the immense metabolic potential and
      diversity of this genus.

PMID- 15184566
TI  - Evolution of compatible replicons of the related IncQ-like plasmids, pTC-F14 and
      pTF-FC2.
AB  - Two closely related but compatible plasmids of the IncQ-2alpha and IncQ-2beta
      groups, pTF-FC2 and pTC-F14, were discovered in two acidiphilic chemolithotrophic
      bacteria. Cross-complementation and cross-regulation experiments by the
      replication proteins were carried out to discover what changes were necessary
      when the plasmids evolved to produce two incompatibility groups. The requirement
      of a pTC-F14 oriV for a RepC DNA-binding protein was plasmid specific, whereas
      the requirement for the RepA helicase and RepB primase was less specific and
      could be complemented by the IncQ-2alpha plasmid pTC-FC2, and the IncQ-1beta
      plasmid pIE1108. None of the IncQ-1alpha plasmid replication proteins could
      complement the pTC-F14 oriV, and pTC-F14 and RSF1010 were incompatible. This
      incompatibility was associated with the RepC replication protein and was not due
      to iteron incompatibility. Replication of pTC-F14 took place from a 5.7 kb
      transcript that originated upstream of the mobB gene located within the region
      required for mobilization. A pTC-F14 mobB-lacZ fusion was regulated by the pTC
      F14 repB gene product and was plasmid specific, as it was not regulated by the
      RepB proteins of pTF-FC2 or the IncQ-1alpha and IncQ-1beta plasmids. Plasmid pTC
      F14 appears to have evolved independently functioning iterons and a plasmid
      specific RepC-binding protein; it also has a major replication transcript that is
      independently regulated from that of pTF-FC2. However, the RepA and RepB proteins
      have the ability to function with either replicon.

PMID- 15184568
TI  - Characterization of the Streptomyces lavendulae IMRU 3455 linear plasmid pSLV45.
AB  - Streptomyces lavendulae IMRU 3455 contains two large linear plasmids designated
      pSLV45 (45 kb) and pSLV195 (195 kb). A cosmid, pSPRX604, containing 42 kb from
      pSLV45 was cloned and sequenced. pSLV45 was tagged with a hygromycin-resistance
      marker by homologous recombination to generate the derivatives pSLV45.680 and
      pSLV45.681. An apramycin-resistance marker was introduced into S. lavendulae IMRU
      467 using the pSPR910 integration vector to yield the recipient strain SPW910.
      The self-transmissible nature of pSLV45 was determined by transfer of pSLV45.680
      and pSLV45.681 from the donor strains SPW680 and SPW681 into the recipient strain
      SPW910. Southern analysis indicated the presence of hygromycin- and pSLV45
      hybridizing sequences within SPW910 exconjugants. PFGE analysis confirmed
      pSLV45.680 and pSLV45.681 were transferred intact and formed freely replicating
      linear plasmids. Sequence analysis of pSPRX604 revealed genes predicted to be
      involved in plasmid transfer, partitioning and regulation. The transfer of the
      linear plasmid pSLV45 from S. lavendulae IMRU 3455 into S. lavendulae IMRU 467
      may allow the development of pSLV45 as an actinomycete-to-actinomycete
      conjugative shuttle vector.

PMID- 15184567
TI  - Sequence analysis of two plasmids from the phytoplasma beet leafhopper
      transmitted virescence agent.
AB  - The complete nucleotide sequences of the two plasmids from the phytoplasma beet
      leafhopper-transmitted virescence agent (BLTVA) have been determined. The larger
      plasmid, pBLTVA-1, was 10 785 nt in length and contained 11 putative ORFs, almost
      all of which were duplicated or triplicated on the plasmid due to the presence of
      large repeated regions. The sequence contained a series of tandem repeats, the
      largest of which was 338 nt long. The sequences of ORFs 4 and 11 showed homology
      with the replication genes of plasmids from other phytoplasmas and from
      geminiviruses. ORF9, the only ORF present as a single copy, showed homology with
      DNA primase genes from bacterial chromosomes and contained the conserved zinc
      finger and topoisomerase/primase domains. None of the other eight ORFs showed
      homology with known sequences in the GenBank database. pBLTVA-2 was 2587 nt in
      length, and all of its sequence was nearly identical to sequences from pBLTVA-1,
      most of which spanned ORFs 10 and 11, including the 338 nt tandem repeat.
      Analysis of 30 strains of BLTVA showed that most of the 11 putative ORFs were
      present, but the size of the plasmids varied in these strains.

PMID- 15184570
TI  - Branched swarming patterns on a synthetic medium formed by wild-type Bacillus
      subtilis strain 3610: detection of different cellular morphologies and
      constellations of cells as the complex architecture develops.
AB  - After optimizing the conditions, including nutrients and temperature, swarming of
      Bacillus subtilis 3610 was obtained on a synthetic, fully defined medium. The
      swarms formed highly branched (dendritic) patterns, generated by successive waves
      of moving cells. A detailed microscopic in situ analysis of swarms 1 and 2
      revealed varied cell morphologies and a remarkable series of events, with cells
      assembling into different 'structures', as the architecture of the swarm
      developed. Long filamentous cells begin to form before the onset of the first
      swarming (11 h) and are again observed at later stages in the interior of
      individual mature dendrites. Swarm 2, detected at 18-22 h, is accompanied by the
      rapid movement of a wave of dispersed (non-filamentous) cells. Subsequently at
      the forward edge of this swarm, individual cells begin to cluster together,
      gradually forming de novo the shape of a dendrite tip with progressive
      lengthening of this new structure 'backwards' towards the swarm centre. In both
      swarms 1 and 2, after the initial clustering of cells, there is the progressive
      appearance of a spreading monolayer of rafts (4-5 non-filamented cells, neatly
      aligned). The alternative possible roles of the rafts in the development of the
      swarm are discussed.

PMID- 15184569
TI  - GvpE- and GvpD-mediated transcription regulation of the p-gvp genes encoding gas
      vesicles in Halobacterium salinarum.
AB  - The transcription of the 14 p-gvp genes involved in gas vesicle formation of
      Halobacterium salinarum PHH1 is driven by the four promoters pA, pD, pF and pO.
      The regulation of these promoters was investigated in Haloferax volcanii
      transformants with respect to the endogenous regulatory proteins GvpE and GvpD.
      Northern analyses demonstrated that the transcription derived from the pA and pD
      promoters was enhanced by GvpE, whereas the activities of the pF and pO promoters
      were not affected. Similar results were obtained using promoter fusions with the
      bgaH reporter gene encoding an enzyme with beta-galactosidase activity. The
      largest amount of specific beta-galactosidase activity was determined for pA-bgaH
      transformants, followed by pF-bgaH and pD-bgaH transformants. The presence of
      GvpE resulted in a severalfold induction of the pA and pD promoter, whereas the
      pF promoter was not affected. A lower GvpE-induced pA promoter activity was seen
      in the presence of GvpD in the pA-bgaH/DE(ex) transformants, suggesting a
      function of GvpD in repression. To determine the DNA sequences involved in the
      GvpE-mediated activation, a 50-nucleotide region of the pA promoter was
      investigated by 4-nucleotide scanning mutagenesis. Some of these mutations
      affected the basal transcription, especially mutations in the region of the TATA
      box and the putative BRE sequence element, and also around position -10. Mutant
      E, harbouring a sequence with greater identity to the consensus BRE element,
      showed a significantly enhanced basal promoter activity compared to wild-type.
      Mutations not affecting basal transcription, but yielding a reduced GvpE-mediated
      activation, were located immediately upstream of BRE. These results suggested
      that the transcription activation by GvpE is in close contact with the core
      transcription machinery.

PMID- 15184571
TI  - AgmR controls transcription of a regulon with several operons essential for
      ethanol oxidation in Pseudomonas aeruginosa ATCC 17933.
AB  - The response regulator AgmR was identified to be involved in the regulation of
      the quinoprotein ethanol oxidation system of Pseudomonas aeruginosa ATCC 17933.
      Interruption of the agmR gene by insertion of a kanamycin-resistance cassette
      resulted in mutant NG3, unable to grow on ethanol. After complementation with the
      intact agmR gene, growth on ethanol was restored. Transcriptional lacZ fusions
      were used to identify four operons which are regulated by the AgmR protein: the
      exaA operon encodes the pyrroloquinoline quinone (PQQ)-dependent ethanol
      dehydrogenase, the exaBC operon encodes a soluble cytochrome c(550) and an
      aldehyde dehydrogenase, the pqqABCDE operon carries the PQQ biosynthetic genes,
      and operon exaDE encodes a two-component regulatory system which controls
      transcription of the exaA operon. Transcription of exaA was restored by
      transformation of NG3 with a pUCP20T derivative carrying the exaDE genes under
      lac-promoter control. These data indicate that the AgmR response regulator and
      the exaDE two-component regulatory system are organized in a hierarchical manner.
      Gene PA1977, which appears to form an operon with the agmR gene, was found to be
      non-essential for growth on ethanol.

PMID- 15184572
TI  - Rhodococcus opacus expresses the xsc gene to utilize taurine as a carbon source
      or as a nitrogen source but not as a sulfur source.
AB  - The Gram-positive bacteria Rhodococcus opacus ISO-5 and Rhodococcus sp. RHA1
      utilized taurine (2-aminoethanesulfonate) as the sole source of carbon or of
      nitrogen or of sulfur for growth. Different gene clusters and enzymes were active
      under these different metabolic situations. Under carbon- or nitrogen-limited
      conditions three enzymes were induced, though to different levels: taurine
      pyruvate aminotransferase (Tpa), alanine dehydrogenase (Ald) and
      sulfoacetaldehyde acetyltransferase (Xsc). The specific activities of these
      enzymes in R. opacus ISO-5 were sufficient to explain the growth rates under the
      different conditions. These three enzymes were purified and characterized, and
      the nature of each reaction was confirmed. Analyses of the genome of Rhodococcus
      sp. RHA1 revealed a gene cluster, tauR-ald-tpa, putatively encoding regulation
      and oxidation of taurine, located 20 kbp from the xsc gene and separate from two
      candidate phosphotransacetylase (pta) genes, as well as many candidate ABC
      transporters (tauBC). PCR primers allowed the amplification and sequencing of the
      tauR-ald-tpa gene cluster and the xsc gene in R. opacus ISO-5. The N-terminal
      sequences of the three tested proteins matched the derived amino acid sequences
      of the corresponding genes. The sequences of the four genes found in each
      Rhodococcus strain shared high degrees of identity (>95 % identical positions).
      RT-PCR studies proved transcription of the xsc gene when taurine was the source
      of carbon or of nitrogen. Under sulfur-limited conditions no xsc mRNA was
      generated and no Xsc was detected. Taurine dioxygenase (TauD), the enzyme
      catalysing the anticipated desulfonative reaction when taurine sulfur is
      assimilated, was presumed to be present because oxygen-dependent taurine
      disappearance was demonstrated with taurine-grown cells only. A putative tauD
      gene (with three other candidates) was detected in strain ISO-5. Regulation of
      the different forms of metabolism of taurine remains to be elucidated.

PMID- 15184573
TI  - The transcription of the cbb operon in Nitrosomonas europaea.
AB  - Nitrosomonas europaea is an aerobic ammonia-oxidizing bacterium that participates
      in the C and N cycles. N. europaea utilizes CO(2) as its predominant carbon
      source, and is an obligate chemolithotroph, deriving all the reductant required
      for energy and biosynthesis from the oxidation of ammonia (NH(3)) to nitrite ().
      This bacterium fixes carbon via the Calvin-Benson-Bassham (CBB) cycle via a type
      I ribulose bisphosphate carboxylase/oxygenase (RubisCO). The RubisCO operon is
      composed of five genes, cbbLSQON. This gene organization is similar to that of
      the operon for 'green-like' type I RubisCOs in other organisms. The cbbR gene
      encoding the putative regulatory protein for RubisCO transcription was identified
      upstream of cbbL. This study showed that transcription of cbb genes was
      upregulated when the carbon source was limited, while amo, hao and other energy
      harvesting-related genes were downregulated. N. europaea responds to carbon
      limitation by prioritizing resources towards key components for carbon
      assimilation. Unlike the situation for amo genes, NH(3) was not required for the
      transcription of the cbb genes. All five cbb genes were only transcribed when an
      external energy source was provided. In actively growing cells, mRNAs from the
      five genes in the RubisCO operon were present at different levels, probably due
      to premature termination of transcription, rapid mRNA processing and mRNA
      degradation.

PMID- 15184574
TI  - Phototrophic utilization of taurine by the purple nonsulfur bacteria
      Rhodopseudomonas palustris and Rhodobacter sphaeroides.
AB  - Taurine metabolism by two phototrophically grown purple nonsulfur bacteria
      enrichment isolates has been examined. Rhodopseudomonas palustris (strain Tau1)
      grows with taurine as a sole electron donor, sulfur and nitrogen source during
      photoautotrophic growth. Rhodobacter sphaeroides (strain Tau3) grows on the
      compound as sole electron donor, sulfur and nitrogen source, and partial carbon
      source, in the presence of CO(2) during photoheterotrophic growth. Both organisms
      utilize an inducible taurine-pyruvate aminotransferase and a sulfoacetaldehyde
      acetyltransferase. The products of this metabolism are bisulfite and acetyl
      phosphate. Bisulfite ultimately was oxidized to sulfate, but this was not an
      adequate source of electrons for photometabolism. Experiments using either [U
      (14)C]taurine or (14)CO(2) demonstrated that Rb. sphaeroides Tau3 assimilated the
      carbon from approximately equimolar amounts of taurine and exogenous CO(2). The
      taurine-carbon assimilation was not diminished by excess non-radioactive
      bicarbonate. Malate synthase (but not isocitrate lyase) was induced in these
      taurine-grown cells. It is concluded that assimilation of taurine carbon occurs
      through an intermediate other than CO(2). Similar labelling experiments with Rp.
      palustris Tau1 determined that taurine is utilized only as an electron donor for
      the reduction of CO(2), which contributes all the cell carbon. Photoautotrophic
      metabolism was confirmed in this organism by the absence of either malate
      synthase or isocitrate lyase in taurine+CO(2)-grown cells. Culture collection
      strains of these two bacteria did not utilize taurine in these fashions.

PMID- 15184576
TI  - luxS mutants of Serratia defective in autoinducer-2-dependent 'quorum sensing'
      show strain-dependent impacts on virulence and production of carbapenem and
      prodigiosin.
AB  - The enzyme LuxS is responsible for the production of autoinducer-2 (AI-2), a
      molecule that has been implicated in quorum sensing in many bacterial species.
      This study investigated whether there is a luxS-dependent signalling system in
      the Gram-negative bacteria Serratia spp. Serratia marcescens is a broad-host
      range pathogen and an important cause of nosocomial infections. Production of AI
      2 activity was detected in S. marcescens ATCC 274 and Serratia ATCC 39006 and
      their luxS genes were sequenced. luxS mutants were constructed in these strains
      and were analysed to determine which phenotypes are regulated by luxS and
      therefore, potentially, by AI-2. The phenotypes of the luxS mutants included
      decreased carbapenem antibiotic production in Serratia ATCC 39006 and decreased
      prodigiosin and secreted haemolysin production in S. marcescens ATCC 274. The
      luxS mutant of S. marcescens ATCC 274 was also found to exhibit modestly reduced
      virulence in a Caenorhabditis elegans model. Finally, it was shown that the
      culture supernatant of a wild-type strain contains a signal, presumably AI-2,
      capable of complementing the prodigiosin defect of the luxS mutant of another
      strain, even when substantially diluted. It is concluded that luxS modulates
      virulence and antibiotic production in Serratia, in a strain-dependent manner,
      and that, for at least one phenotype, this regulation is via extracellular
      signalling.

PMID- 15184575
TI  - The role of dor gene products in controlling the P2 promoter of the cytochrome c2
      gene, cycA, in Rhodobacter sphaeroides.
AB  - This study explores the regulatory networks controlling anaerobic energy
      production by the facultative phototroph Rhodobacter sphaeroides. The specific
      aim was to determine why activity of the P2 promoter for the gene (cycA) encoding
      the essential photosynthetic electron carrier, cytochrome c(2), is decreased when
      the alternative electron acceptor DMSO is added to photosynthetically grown
      cells. The presence of DMSO is believed to activate the DorR response regulator,
      which controls expression of proteins required to reduce DMSO. A DorR(-) strain
      showed no change in cycA P2 promoter activity when DMSO was added to
      photosynthetic cells, indicating that DorR was required for the decreased
      expression in wild-type cells. To test if DorR acted directly at this promoter to
      change gene expression, recombinant DorR was purified and studied in vitro.
      Preparations of DorR that were active at other target promoters showed no
      detectable interaction with cycA P2, suggesting that this protein is not a direct
      regulator of this promoter. We also found that cycA P2 activity in a DorA(-)
      strain was not decreased by the addition of DMSO to photosynthetic cells. A model
      is presented to explain why the presence of a functional DMSO reductase (DorA) is
      required for DMSO to decrease cycA P2 expression under photosynthetic conditions.

PMID- 15184577
TI  - Mutant alleles of the essential 14-3-3 gene in Candida albicans distinguish
      between growth and filamentation.
AB  - The opportunistic fungal pathogen Candida albicans has the ability to exploit
      diverse host environments and can either reside commensally or cause disease. In
      order to adapt to its new environment it must respond to new physical conditions,
      nutrient sources, and the host immune response. This requires the co-regulation
      of multiple signalling networks. The 14-3-3 family of proteins is highly
      conserved in all eukaryotic species. These proteins regulate signalling pathways
      involved in cell survival, the cell cycle, and differentiation, and effect their
      functions via interactions with phosphorylated serines/threonines. In C. albicans
      there is only one 14-3-3 protein, Bmh1p, and it is required for vegetative growth
      and optimal filamentation. In order to dissect separate functions of Bmh1p in C.
      albicans, site-directed nucleotide substitutions were made in the C. albicans
      BMH1 gene based on studies in other species. Putative temperature-sensitive,
      ligand-binding and dimerization mutants were constructed. In addition two mutant
      strains identified through random mutagenesis were analysed. All five mutant
      strains demonstrated varying defects in growth and filamentation. This paper
      begins to segregate functions of Bmh1p that are required for optimal growth and
      the different filamentation pathways. These mutant strains will allow the
      identification of 14-3-3 target interactions and correlate the individual
      functions of Bmh1p to cellular processes involved in pathogenesis.

PMID- 15184578
TI  - The RAM1 gene encoding a protein-farnesyltransferase beta-subunit homologue is
      essential in Cryptococcus neoformans.
AB  - Many small G proteins require post-translational modification to allow functional
      association to the cell membrane. This process often involves the enzymic
      addition of hydrophobic prenyl groups to a conserved cysteine residue near the C
      terminus of the protein. The enzymes that catalyse these reactions include
      protein farnesyltransferase and protein geranylgeranyltransferases. The human
      fungal pathogen Cryptococcus neoformans requires functional Ras and Rho proteins
      in order to undergo normal growth and differentiation. Since farnesylation and
      geranylgeranylation are likely required for the proper function of these small G
      proteins, we hypothesized that inhibition of these prenylation events would alter
      the growth and cellular morphogenesis of this fungus. We cloned the RAM1 gene
      encoding the single protein-farnesyltransferase beta-chain homologue in C.
      neoformans. Using a gene-disruption strategy in a diploid C. neoformans strain,
      we demonstrated that this gene encodes an essential function, in contrast to the
      case in Saccharomyces cerevisiae, in which the homologous RAM1 gene is not
      essential for growth. Pharmacological inhibition of farnesyltransferase activity
      resulted in dose-dependent cytostasis of C. neoformans, as well as prevention of
      hyphal differentiation. Simultaneous inhibition of farnesylation and calcineurin
      signalling results in a synthetic effect on growth. Protein farnesylation is
      required for the growth and cellular differentiation of C. neoformans and may
      provide novel targets for antifungal therapy.

PMID- 15184579
TI  - Oxidative and amphotericin B-mediated cell death in the opportunistic pathogen
      Aspergillus fumigatus is associated with an apoptotic-like phenotype.
AB  - When protoplasts of the opportunistic fungal pathogen Aspergillus fumigatus were
      treated with low but toxic levels of hydrogen peroxide (0.1 mM) or amphotericin B
      (0.5 microg ml(-1)), loss of cell viability and death were associated with a
      number of phenotypic changes characteristic of apoptosis. The percentage of
      protoplasts staining positive with annexin V-FITC, an indicator of the
      externalization of phosphatidylserine and an early marker of apoptosis, rose to
      approximately 55 % within 1 h. This was followed by a similar increase in
      apoptotic DNA fragmentation detected by the TUNEL assay, and led to a loss of
      cell permeability and death in approximately 90 % of protoplasts, as indicated by
      the uptake of propidium iodide. The development of an apoptotic phenotype was
      blocked when protoplasts were pre-treated with the protein synthesis inhibitor
      cycloheximide, indicating active participation of the cell in the process.
      However, no significant activity against synthetic caspase substrates was
      detected, and the inclusion of the cell-permeant broad-spectrum caspase inhibitor
      Z-VAD-fmk did not block the development of the apoptotic-like phenotype. Higher
      concentrations of H(2)O(2) (1.8 mM) and amphotericin B (1 microg ml(-1)) caused
      protoplasts to die without inducing an apoptotic phenotype. As predicted, the
      fungistatic antifungal agent itraconazole, which inhibits growth without causing
      immediate cell death, did not induce an apoptotic-like phenotype.

PMID- 15184580
TI  - A novel glucan-binding protein with lipase activity from the oral pathogen
      Streptococcus mutans.
AB  - Streptococcus mutans produces extracellular glucosyltransferases (GTFs) that
      synthesize glucans from sucrose. These glucans are important in determining the
      permeability properties and adhesiveness of dental plaque. GTFs and the GbpA
      glucan-binding protein are characterized by a binding domain containing a series
      of 33-amino-acid repeats, called 'A' repeats. The S. mutans genome sequence was
      searched for ORFs containing 'A' repeats, and one novel gene, gbpD, which appears
      to be unique to the mutans group of streptococci, was identified. The GbpD
      sequence revealed the presence of three 'A' repeats, in the middle of the
      protein, and a novel glucan-binding assay showed that GbpD binds to dextran with
      a K(D) of 2-3 nM. Construction of truncated derivatives of GbpD confirmed that
      the 'A' repeat region was essential for binding. Furthermore, a gbpD knockout
      mutant was modified in the extent of aggregation induced by polymers derived from
      sucrose. The N-terminus of GbpD has a signal sequence, followed by a region with
      no homologues in the public databases, while the C-terminus has homology to the
      alpha/beta hydrolase family (including lipases and carboxylesterases). GbpD
      contains the two regions typical of these enzymes: a GxSxG active site 'lipase
      box' and an 'oxyanion hole'. GbpD released free fatty acids (FFAs) from a range
      of triglycerides in the presence of calcium, indicating a lipase activity. The
      glucan binding/lipase bifunctionality suggested the natural substrate for the
      enzyme may be a surface macromolecule consisting of carbohydrate linked to lipid.
      The gbpD mutant was less hydrophobic than wild-type and pure recombinant GbpD
      reduced the hydrophobicity of S. mutans and another plaque bacterium,
      Streptococcus sanguinis. GbpD bound to and released FFA from lipoteichoic acid
      (LTA) of S. sanguinis, but had no effect on LTA from S. mutans. These results
      raise the intriguing possibility that GbpD may be involved in direct interspecies
      competition within the plaque biofilm.

PMID- 15184581
TI  - The Campylobacter jejuni general glycosylation system is important for attachment
      to human epithelial cells and in the colonization of chicks.
AB  - It has recently been shown that the enteropathogen Campylobacter jejuni has an N
      linked general protein glycosylation pathway (Pgl) that modifies many of the
      organism's proteins. To determine the role of the N-linked general glycosylation
      in C jejuni, the authors studied the pglH gene, which shows high similarity to a
      family of sugar transferases. pglH mutants were constructed in strains 81116 and
      11168H. Both mutants were shown to be deficient in their ability to glycosylate a
      number of C. jejuni proteins, but their lipooligosaccharide and capsule were
      unaffected. The pglH mutants had significantly reduced ability to adhere to and
      invade human epithelial Caco-2 cells. Additionally, the 81116 pglH mutant was
      severely affected in its ability to colonize chicks. These results suggest that
      glycosylation is important for the attachment of C. jejuni to human and chicken
      host cells and imply a role for glycoproteins in the pathogenesis of C. jejuni.

PMID- 15184582
TI  - Effects of high hydrostatic pressure on bacterial cytoskeleton FtsZ polymers in
      vivo and in vitro.
AB  - Some rod-shaped bacteria, including Escherichia coli, exhibit cell filamentation
      without septum formation under high-hydrostatic-pressure conditions, indicating
      that the cell-division process is affected by hydrostatic pressure. The effects
      of elevated pressure on FtsZ-ring formation in E. coli cells were examined using
      indirect immunofluorescence microscopy. Elevated pressure of 40 MPa completely
      inhibited colony formation of E. coli cells under the cultivation conditions
      used, and the cells exhibited obviously filamentous shapes. In the elongated
      cells, normal cell-division processes appeared to be inhibited, because no FtsZ
      rings were observed by indirect immunofluorescent staining. In addition, it was
      observed that hydrostatic pressure dissociated the E. coli FtsZ polymers in
      vitro. These results suggest that high hydrostatic pressure directly affects cell
      survival and morphology through the dissociation of the cytoskeletal frameworks.

PMID- 15184583
TI  - Molecular characterization of protein O-mannosyltransferase and its involvement
      in cell-wall synthesis in Aspergillus nidulans.
AB  - Protein O-glycosylation is essential for protein modification and plays important
      roles in eukaryotic cells. O-Mannosylation of proteins occurs in the filamentous
      fungus Aspergillus. The structure and function of the pmtA gene, encoding protein
      O-d-mannosyltransferase, which is responsible for the initial O-mannosylation
      reaction in Aspergillus nidulans, was characterized. Disruption of the pmtA gene
      resulted in the reduction of in vitro protein O-d-mannosyltransferase activity to
      6 % of that of the wild-type strain and led to underglycosylation of an
      extracellular glucoamylase. The pmtA disruptant exhibited abnormal cell
      morphology and alteration in carbohydrate composition, particularly reduction in
      the skeletal polysaccharides in the cell wall. The results indicate that PmtA is
      required for the formation of a normal cell wall in A. nidulans.

PMID- 15184584
TI  - Saccharomyces kluyveri FAD3 encodes an omega3 fatty acid desaturase.
AB  - Fungi, like plants, are capable of producing the 18-carbon polyunsaturated fatty
      acids linoleic acid and alpha-linolenic acid. These fatty acids are synthesized
      by catalytic reactions of Delta12 and omega3 fatty acid desaturases. This paper
      describes the first cloning and functional characterization of a yeast omega3
      fatty acid desaturase gene. The deduced protein encoded by the Saccharomyces
      kluyveri FAD3 gene (Sk-FAD3) consists of 419 amino acids, and shows 30-60 %
      identity with Delta12 fatty acid desaturases of several eukaryotic organisms and
      29-31 % identity with omega3 fatty acid desaturases of animals and plants. During
      Sk-FAD3 expression in Saccharomyces cerevisiae, alpha-linolenic acid accumulated
      only when linoleic acid was added to the culture medium. The disruption of Sk
      FAD3 led to the disappearance of alpha-linolenic acid in S. kluyveri. These
      findings suggest that Sk-FAD3 is the only omega3 fatty acid desaturase gene in
      this yeast. Furthermore, transcriptional expression of Sk-FAD3 appears to be
      regulated by low-temperature stress in a manner different from the other fatty
      acid desaturase genes in S. kluyveri.

PMID- 15184585
TI  - Dosage-dependent functions of fatty acid desaturase Ole1p in growth and
      morphogenesis of Candida albicans.
AB  - Conditions in the infected human host trigger virulence attributes of the fungal
      pathogen Candida albicans. Specific inducers and elevated temperatures lead to
      hyphal development or regulate chlamydospore development. To explore if these
      processes are affected by membrane lipids, an investigation of the functions of
      the Ole1 fatty acid desaturase (stearoyl-CoA desaturase) in C. albicans, which
      synthesizes oleic acid, was undertaken. A conditional strain expressing OLE1 from
      the regulatable MET3 promoter was unable to grow in repressing conditions,
      indicating that OLE1 is an essential gene. In contrast, a mutant lacking both
      alleles of OLE2, encoding a Ole1p homologue, was viable and had no apparent
      phenotypes. Partial repression of MET3p-OLE1 slightly lowered oleic acid levels
      and decreased membrane fluidity; these conditions permitted growth in the yeast
      form, but prevented hyphal development in aerobic conditions and blocked the
      formation of chlamydospores. In contrast, in hypoxic conditions, which trigger an
      alternative morphogenetic pathway, hyphal morphogenesis was unaffected. Because
      aerobic morphogenetic signalling and oleic acid biosynthesis require oxygen, it
      is proposed that oleic acid may function as a sensor activating specific
      morphogenetic pathways in normoxic conditions.

PMID- 15184586
TI  - The hyaluronate lyase of Staphylococcus aureus - a virulence factor?
AB  - The hyaluronate lyase (HL) gene of Staphylococcus aureus 8325-4 (hysA) was
      inactivated in vitro with the insertion of the erythromycin determinant, ermC,
      from plasmid pE194. The hysA : : ermC mutation was introduced into S. aureus via
      a temperature-sensitive shuttle vector, where it underwent homologous
      recombination with the wild-type (w.t.) allele. The insertion of ermC in the
      chromosomal hysA locus was confirmed by Southern blot hybridization and the loss
      of HL activity was demonstrated macroscopically by a plate assay. The importance
      of HL for pathogenicity was assessed by comparing the virulence of the HL(-)
      mutant strain to that of the w.t. in an established mouse abscess model of S.
      aureus infection. A significantly higher cell recovery was obtained from lesions
      infected with the w.t. strain compared to the lesions infected with the HL(-)
      strain (P =0.01). Although the lesion areas from both groups were not
      significantly different (P=0.9) they were of different morphology. A colorimetric
      assay was used to measure HL activity from culture supernatants of the S. aureus
      8325-4 strains w.t., WA250 (agr) and PC1839 (sar) grown in a chemically defined
      medium. HL activity reached a maximum in the w.t. strain during mid-exponential
      phase (t=5 h) and while it showed a 16-fold decrease in the agr mutant it
      increased 35-fold in the sar mutant background. These results strongly suggest
      that HL is a virulence factor which is important in the early stages of
      subcutaneous infections.

PMID- 15184587
TI  - Is "seronegative" MG explained by autoantibodies to MuSK?

PMID- 15184588
TI  - Anti-myelin oligodendrocyte glycoprotein antibodies in multiple sclerosis.

PMID- 15184589
TI  - Marijuana as a treatment for epilepsy and multiple sclerosis? A "grass roots"
      movement.

PMID- 15184590
TI  - Migraine practice patterns among neurologists.
AB  - OBJECTIVE: To assess the attitudes, knowledge, and practice patterns of US
      neurologists regarding migraine management relative to the US Headache Consortium
      Guidelines (the Guidelines). METHODS: Two samples of 600 neurologists each were
      selected from the American Academy of Neurology membership database. The first
      group received a Migraine Attitudes, Knowledge, and Practice Patterns (MKAPP)
      Survey. The second group received a Clinical Vignette (CV) Survey, presenting two
      patient histories and correspondent questions. RESULTS: The MKAPP Survey showed
      that most neurologists felt that migraine was primarily a disease of the brain
      with a well-established neurobiological basis (69%) and an important part of
      their practice (60%). Most (53%) indicated that they routinely used neuroimaging
      in evaluating severe headache, an approach not recommended by the Guidelines.
      Most favored acute treatment limits, but 36% did not agree with the Guidelines
      that acute treatment should be limited to 2 or 3 days/week. In the CV Survey, for
      vignette 1, most (91%) correctly diagnosed migraine, 31% requested neuroimaging
      in the absence of indications, 64% appropriately recommended a triptan, and 45%
      recommended a preventive medication in the absence of indications. For vignette
      2, 78% diagnosed migraine, 71% appropriately ordered neuroimaging, 80%
      appropriately recommended a preventive medication, and 38% prescribed a triptan
      in face of clear contraindication. CONCLUSIONS: Educational initiatives aiming to
      increase the awareness of the Guidelines among neurologists should highlight the
      full range of migraine symptoms that support the diagnosis, appropriate use of
      neuroimaging, indications for preventive treatments, issues of triptan
      cardiovascular safety, and preventing rebound headaches.

PMID- 15184591
TI  - Melvin David Yahr, MD (1917-2004).

PMID- 15184592
TI  - Calcific neurocysticercosis and epileptogenesis.
AB  - Neurocysticercosis is responsible for increased rates of seizures and epilepsy in
      endemic regions. The most common form of the disease, chronic calcific
      neurocysticercosis, is the end result of the host's inflammatory response to the
      larval cysticercus of Taenia solium. There is increasing evidence indicating that
      calcific cysticercosis is not clinically inactive but a cause of seizures or
      focal symptoms in this population. Perilesional edema is at times also present
      around implicated calcified foci. A better understanding of the natural history,
      frequency, epidemiology, and pathophysiology of calcific cysticercosis and
      associated disease manifestations is needed to define its importance, treatment,
      and prevention.

PMID- 15184593
TI  - Immunoglobulin improves a model of acute motor axonal neuropathy by preventing
      axonal degeneration.
AB  - BACKGROUND: The action mechanism of IV immunoglobulin (IVIg) for Guillain-Barre
      syndrome has yet to be clarified. OBJECTIVE: To evaluate clinical, histologic,
      and immunologic effects in a disease model of acute motor axonal neuropathy
      (AMAN) treated by IVIg. METHODS: Rabbits were sensitized with gangliosides
      including GM1 and divided randomly into two groups at disease onset. One group
      received IV homologous gamma-globulin (400 mg/kg/day) for 5 days (n = 15), and
      the other received saline (n = 15). Disease severity was scored (0 to 13 points)
      daily. Sixty days after onset, anti-GM1 antibodies were tested by ELISA, and the
      number of degenerative axons was counted in spinal anterior roots. RESULTS:
      Between both groups at onset, there was no difference in any characteristics
      including clinical score. The IVIg group had faster recovery than the saline
      group (p = 0.03). The percentage of rabbits that improved by a score of < or =4
      was higher in the IVIg (53%) than in the saline (13%) group 60 days after onset
      (p = 0.03). Anti-GM1 IgG titers 60 days after onset did not differ between the
      groups. The anterior roots of rabbits surviving 60 days after onset showed lower
      frequency of axonal degeneration in the IVIg-treated (n = 11; mean 4.5%) than in
      the saline-treated (n = 8; mean 11.1%) rabbits (p = 0.01). CONCLUSIONS: The
      therapeutic efficacy of IVIg in an AMAN model was confirmed. IVIg may not affect
      the production or catabolism of anti-GM1 IgG, but it may prevent axonal
      degeneration of motor nerves.

PMID- 15184594
TI  - Are MuSK antibodies the primary cause of myasthenic symptoms?
AB  - OBJECTIVE: To investigate the morphologic, electrophysiologic, and molecular
      correlates of muscle-specific tyrosine kinase-seropositive [MuSK(+)] myasthenia
      gravis (MG). BACKGROUND: Anti-MuSK antibodies are detected in some of
      acetylcholine receptor-seronegative [AChR(-)] patients with MG with prominent
      facial, bulbar, and respiratory muscle involvement. The morphologic and
      electrophysiologic correlates of MuSK(+) MG have not been investigated to date.
      METHODS: Immunohistochemistry, electron microscopy, and in vitro
      electrophysiology studies were performed on an intercostal muscle specimen of a
      patient with MuSK(+) MG and in control subjects. MUSK was directly sequenced, and
      the nucleotide changes were traced with allele-specific PCR in control subjects.
      RESULTS: A man aged 34 years has had facial weakness since childhood and
      progressive bulbar and respiratory muscle weakness and intermittent diplopia
      since age 21 years. He has thin temporalis and masseter muscles, a high-arched
      palate, and an atrophic tongue. EMG shows a 36% decrement in facial muscles. His
      mother has similar facial features. His endplates (EPs) show no AChR or MuSK
      deficiency, but the amplitudes of the miniature EP potentials and currents are
      reduced to 35% and 55% of normal, respectively. EP ultrastructure is well
      preserved, but some junctional folds immunostain faintly for immunoglobulin G.
      Mutation analysis of MUSK reveals one rare and two common DNA polymorphisms.
      CONCLUSIONS: 1) The circulating anti-muscle-specific tyrosine kinase antibodies
      caused neither muscle-specific tyrosine kinase nor acetylcholine receptor
      deficiency at the endplates; 2) the reduced intercostal miniature endplate
      potential and current amplitudes were not accounted for by acetylcholine receptor
      deficiency; 3) the faint immunoglobulin G deposits at the endplates may or may
      not represent anti-muscle-specific tyrosine kinase antibodies; and 4) the anti
      muscle-specific tyrosine kinase antibodies may not be the primary cause of
      myasthenic symptoms in this patient.

PMID- 15184595
TI  - Sensory regeneration following intraoperatively verified trigeminal nerve injury.
AB  - OBJECTIVE: To follow recovery of sensory function mediated by both myelinated and
      unmyelinated axons in relation to the type of inferior alveolar nerve (IAN)
      injury. METHODS: The authors assessed the function of afferent Abeta-, Adelta-,
      and C-fibers of the IAN using neurophysiologic (mental nerve blink reflex,
      sensory nerve conduction [NCS] of the IAN) and quantitative sensory tests (QST;
      cold, warm, heat pain, and tactile modalities). The tests were done 2 weeks, 1,
      3, 6, and 12 months postoperatively and compared to the preoperative baseline in
      20 patients undergoing mandibular bilateral sagittal split osteotomy. Nineteen
      patients underwent intraoperative monitoring. RESULTS: In primarily demyelinating
      injuries (21/40 nerves), the sensory alteration and all tests normalized on the
      group level within the first 3 months. After partial axonal lesions (15/40
      nerves), neurophysiologic and thermal QST results remained abnormal at 1-year
      control in a high proportion of the IAN distributions (up to 67%). At 1 year, the
      tactile QST was abnormal in 40%, but the NCS in 87% of the symptomatic IAN
      distributions. Neuropathic pain occurred in 5% of the patients, only after severe
      axonal damage. CONCLUSIONS: Sensory nerve conduction and thermal quantitative
      sensory testing showed incomplete sensory regeneration at 1 year after axonal
      trigeminal nerve damage. Clinical examination with tactile quantitative sensory
      testing was less reliable in the follow-up of sensory recovery. Sensory Abeta-,
      Adelta-, and C-fibers recovered function at similar rates. The trigeminal nerve
      does not differ from other peripheral nerves as regards susceptibility to
      neuropathic pain.

PMID- 15184596
TI  - Improving left hemispatial neglect using virtual reality.
AB  - BACKGROUND: In hemispatial neglect, space can be dissociated on the basis of
      "near" peripersonal vs "far" extrapersonal space. The clinical manifestations of
      neglect can be modified by having patients use a tool to explore "far"
      extrapersonal space. An explanation for this is that the use of a stick produced
      an extension of body space resulting in a remapping of "far" space as "near"
      space. OBJECTIVE: S: To determine whether the remapping of space can be
      generalized to the amelioration of the "affected" vs the "nonaffected" space,
      rather than being confined to the selective amelioration of "far" vs "near"
      neglect; and to determine whether tool use is a necessary condition for the
      remapping of space. METHODS: Using virtual reality, the authors asked six
      hemispatial neglect patients to reach and grasp a real object while
      simultaneously observing the grasping of a virtual object located within a
      virtual environment by a virtual hand. The virtual hand was commanded in real
      time by their real hand. RESULTS: After a period of adaptation, hemispatial
      neglect patients coded the visual stimuli within the neglected space in an
      identical fashion as those presented within the preserved portions of space.
      CONCLUSIONS: It is possible to re-create links between the affected and the
      nonaffected space. Wielding a tool is not a necessary condition in reopening
      neglected space.

PMID- 15184597
TI  - APOE influences on neuropsychological function after mild head injury: within
      person comparisons.
AB  - OBJECTIVE: To examine the relationship between neuropsychological outcome
      following mild head injury (MHI) and APOE genotype. METHODS: Data from a
      population-based longitudinal study (n = 3,500) were used to identify 34 adults
      who experienced MHI during the course of the study. Their pre- and postinjury
      performances on a battery of nine neuropsychological tests were compared within
      person, and the postinjury performance was compared with that of age- and gender
      matched control subjects. RESULTS: The within-person comparisons showed that
      participants with at least one APOE epsilon4 allele (n = 11) had a significantly
      decreased postinjury performance on three of the tests, whereas the postinjury
      performance for APOE epsilon4-negative participants (n = 23) was unchanged. There
      was no significant difference in postinjury performance between participants
      with/without the epsilon4 allele, and neither group was impaired relative to
      controls. CONCLUSIONS: APOE genotype may influence the outcome following an MHI.
      Pre/postinjury within-person comparisons seem more sensitive than control group
      comparisons for detecting injury-related effects.

PMID- 15184598
TI  - Low thyroid-stimulating hormone as an independent risk factor for Alzheimer
      disease.
AB  - OBJECTIVE: To assess a possible relationship between thyroid-stimulating hormone
      (TSH) levels, vascular risk factors, and Alzheimer disease (AD). METHODS: TSH
      levels were measured in 178 AD patients (35 confirmed post mortem) and 291
      cognitively screened control subjects who were all euthyroid (TSH: 0.5 to 6
      mU/L). The risk of AD was determined in participants with lower levels of TSH,
      several cerebrovascular risk factors, and other potential confounds. RESULTS: AD
      patients had significantly lower levels of TSH than control subjects. Lowered TSH
      was associated with a more than twofold increased risk of AD (odds ratio = 2.36,
      95% CI = 1.19 to 4.67), independent of other risk factors. CONCLUSION: Lowered
      TSH within the normal range is a risk factor for AD, independent of several
      cerebrovascular risk factors and confounding variables.

PMID- 15184599
TI  - Plasma homocysteine levels and risk of Alzheimer disease.
AB  - OBJECTIVE: To explore the association between high homocysteine levels and risk
      of Alzheimer disease (AD) in the Washington Heights-Inwood Columbia Aging Project
      (WHICAP). METHODS: The authors obtained fasting plasma samples in 909 elderly
      subjects chosen at random from a cohort of Medicare recipients; there was
      longitudinal data in 679 subjects without dementia at baseline who were followed
      for 3,206 person-years. Prevalent and incident dementia and its subtypes were
      diagnosed using standard methods. RESULTS: There were 128 persons with prevalent
      AD and 109 with incident AD in 3,206 person-years of follow-up. The adjusted OR
      of prevalent AD for the highest quartile of homocysteine compared to the lowest
      was 1.3 (95% CI = 0.7, 2.3; p for trend = 0.25). In longitudinal analyses, the
      authors found that the adjusted hazard ratio of AD for the highest quartile of
      homocysteine was 1.4 (95% CI = 0.8, 2.4; p for trend = 0.31). The authors also
      found that high homocysteine levels were not related to a decline in memory
      scores over time. Age was a significant confounder in all the analyses. The study
      had 80% power to detect a hazard ratio of 1.3 in the longitudinal analyses.
      CONCLUSION: High homocysteine levels were not associated with AD and were not
      related to a decrease in memory scores over time.

PMID- 15184600
TI  - Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer
      disease.
AB  - BACKGROUND: The APOE epsilon4 allele has emerged as a major genetic factor for
      Alzheimer disease (AD), and its presence has been associated with an increase in
      beta-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects
      neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains
      controversial. In contrast, the epsilon2 allele has been reported to decrease the
      risk for AD. However, its effect on neuropathologic and neurochemical markers of
      disease is unclear. OBJECTIVE: To investigate the relationship between APOE
      genotype and both pathologic severity and cholinergic dysfunction in AD. METHODS:
      In an autopsy series of 296 patients with AD, APOE genotype was determined in
      blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal
      (MF), inferior parietal (IP), and superior temporal (ST) cortices and the
      hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF,
      IP, and ST cortices. RESULTS: Compared with patients with no epsilon4 alleles,
      epsilon4 carriers (patients with either one or two epsilon4 alleles) did not
      differ significantly with regard to any pathologic or neurochemical measures,
      except for increased ST NPs. However, when cases were stratified into three
      groups according to the number of epsilon4 alleles, patients with two epsilon4
      alleles had significantly more NPs and NFTs in all neocortical regions than those
      with either one or no epsilon4 alleles. The association of the epsilon4/4
      genotype with neocortical pathologic severity remained significant even after
      adjusting for age at onset or age at death. In contrast, there were no
      significant group differences with regard to neocortical ChAT activity. When
      pathologic and neurochemical measures were compared between patients with the
      epsilon2 allele and those without, a strong relationship emerged between the
      epsilon2 allele and decreased NPs in all neocortical regions. CONCLUSIONS: The
      epsilon4 allele does not predict cholinergic decline in AD. Although the presence
      of a single epsilon4 allele appears to have no effect, the presence of two
      epsilon4 alleles is an important determinant of both NP and NFT accumulation. A
      putative protective role for the epsilon2 allele in AD may be mediated by reduced
      plaque burden.

PMID- 15184601
TI  - The importance of neuritic plaques and tangles to the development and evolution
      of AD.
AB  - OBJECTIVE: To determine the relation of neuritic plaques (NPs) and
      neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer
      disease (AD). METHODS: An autopsy series of 102 patients with dementia and
      pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD
      cases were stratified according to their last Mini-Mental State Examination
      (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were
      enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal
      (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations.
      RESULTS: Most (87%) of the NCs had allocortical NFTs, whereas only a minority
      (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In
      contrast, none of the NCs exhibited neocortical NFTs, except one case with a
      single ST tangle. However, neocortical NFTs were not detected in even 10% of the
      patients with AD and, in particular, were absent in nearly 50% of those with mild
      disease at death. Thus, their sensitivity as a marker of AD was lower than that
      of NPs, which, conversely, were found in all patients with AD. Comparing NCs and
      patients with mild AD, significant differences were found for numbers of NPs
      only. Across the AD groups, in contrast, although NP and NFT density increased
      with dementia severity, significant differences consistently emerged for NFTs
      alone. CONCLUSIONS: Deterioration in Alzheimer disease appears to be driven by
      neuritic plaques and neurofibrillary tangles at different stages of the disease.
      The significant increase in neuritic plaques, but not neurofibrillary tangles, in
      patients with even mild Alzheimer disease at death compared with normal control
      subjects suggests that only neuritic plaques are associated with the earliest
      symptoms of Alzheimer disease.

PMID- 15184602
TI  - Longitudinal changes in cognition and behavior in asymptomatic carriers of the
      APOE e4 allele.
AB  - OBJECTIVE: To determine whether memory loss is detectable before the symptomatic
      presentation of mild cognitive impairment (MCI) in those at greater genetic risk
      for Alzheimer disease (AD) based upon presence or absence of the e4 allele of
      APOE. METHODS: Participants were age 50 years or older who responded to newspaper
      advertisements. A total of 212 cognitively normal individuals of known APOE
      genotype were initially enrolled in a match paradigm that included e4
      homozygotes, e3/4 heterozygotes, and e4 noncarriers in a 1:1:2 ratio (53 sets).
      Of the original 212 individually matched participants, 180 completed at least two
      epochs of testing including 45 APOE e4/4 homozygotes, 42 APOE e3/4 heterozygotes,
      and 93 APOE e4 noncarriers, mean age 60 (+/-6.2) years. Of these, four developed
      MCI or AD during the follow-up period and were excluded from analysis.
      Longitudinal neuropsychological study included two verbal (Auditory Verbal
      Learning Test [AVLT], Selective Reminding Test [SRT]) and two visual (Complex
      Figure Test [CFT], Visual Retention Test) memory tests. RESULTS: Multiple
      measures on both verbal memory tests showed poorer performance over a mean
      interval of 33 months in e4 carriers than noncarriers: AVLT total learning, long
      term delayed recall; SRT free and cued recall. Among those age 50 to 59 years,
      AVLT long term delayed recall, SRT free and cued recall, and CFT recall declined
      more in APOE e4 carriers. No differences were found in the domains of language,
      spatial skills, or executive function. CONCLUSIONS: Memory declined in APOE e4
      carriers before the symptomatic presentation of MCI in a cohort whose mean age
      was 60 years over a median period of 33 months. The decline began prior to age
      60.

PMID- 15184603
TI  - Influence of the amyloid precursor protein locus on dementia in Down syndrome.
AB  - BACKGROUND: The amyloid precursor protein (APP) locus on chromosome 21 influences
      the development of Alzheimer disease. METHOD: The authors investigated the
      relationship between a tetranucleotide repeat on intron 7 of the APP gene and the
      age at onset of dementia in Down syndrome (DS). RESULTS: There was a 13-year
      difference in the age at onset of dementia in DS associated with the number of
      tetranucleotide repeat alleles in APP. CONCLUSION: APP is an important locus
      predicting the age at onset of dementia in people with Down syndrome.

PMID- 15184604
TI  - Prevalence of Parkinson disease in Singapore: Chinese vs Malays vs Indians.
AB  - OBJECTIVE: To investigate the prevalence of Parkinson disease (PD) in Singapore
      and compare the rates between Singaporean Chinese, Malays, and Indians. METHODS:
      A three-phase community-based survey among a disproportionate random sample of
      15,000 individuals (9,000 Chinese, 3,000 Malays, 3,000 Indians) aged 50 years and
      above who live in central Singapore was conducted. In phase 1, trained
      interviewers conducted a door-to-door survey using a validated 10-question
      questionnaire. In phase 2, medical specialists examined participants who screened
      positive to any of the questions. Participants suspected to have PD had their
      diagnosis confirmed in phase 3 by a movement disorders specialist. RESULTS: The
      participation rate was 67% among 22,279 eligible individuals. Forty-six
      participants with PD were identified of which 16 were newly diagnosed cases. The
      prevalence rate of PD for those aged 50 and above in Singapore was 0.30% (95% CI:
      0.22 to 0.41), age-adjusted to US 1970 census. The prevalence rates increased
      significantly with age. The age-adjusted prevalence rates among Chinese (0.33%,
      95% CI: 0.22 to 0.48), Malays (0.29%, 95% CI: 0.13 to 0.67), and Indians (0.28%,
      95% CI: 0.12 to 0.67) were the same (p = 1.0). CONCLUSIONS: The prevalence of PD
      in Singapore was comparable to that of Western countries. Race-specific rates
      were also similar to previously reported rates and similar among the three races.
      Environmental factors may be more important than racially determined genetic
      factors in the development of PD.

PMID- 15184605
TI  - Apolipoprotein E controls the risk and age at onset of Parkinson disease.
AB  - BACKGROUND: Similarities between Alzheimer disease (AD) and Parkinson disease
      (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous
      studies seeking to establish such a link used case-control datasets and results
      have been inconsistent. OBJECTIVE: To investigate APOE's role in PD using family
      based association analyses. METHODS: APOE functional polymorphisms were genotyped
      for 658 PD affected families, including 282 multiplex and 376 singleton families.
      The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the
      risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of
      APOE on age at onset of PD. RESULTS: APOE was significantly associated with risk
      of developing PD. Stratified analysis revealed that APOE was most strongly
      associated with families with a positive PD family history (global p = 0.003).
      Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele
      decreases risk. We detected a positive association of APOE-3 (p = 0.019) and a
      negative association of APOE-4 (p = 0.015) with age at onset in PD. CONCLUSIONS:
      The APOE-4 allele increases risk and decreases age at onset of PD, an association
      that may not be dependent upon cognitive impairment.

PMID- 15184606
TI  - Risk of Parkinson disease in women: effect of reproductive characteristics.
AB  - OBJECTIVE: To investigate the association between some fertile life
      characteristics and Parkinson disease (PD) in women. METHODS: Women affected by
      PD and control subjects were matched one to one by age (+/-2 years). One hundred
      thirty-one women with idiopathic PD and 131 matched control subjects were
      interviewed. Controls were randomly selected from the resident list of the same
      municipality of residence of cases. All subjects had a Mini-Mental State
      Examination score of > or =24. Cumulative length of pregnancies, age at menarche,
      age and type of menopause, and estrogen use before and after menopause were
      investigated in cases and controls through a structured questionnaire. Models of
      matched pair univariate analysis and conditional logistic regression analyses
      were used to calculate adjusted odds ratio (OR), 95% CI, and two-tailed p values
      for the investigated variables. RESULTS: PD was significantly associated with a
      fertile life length shorter than 36 years (OR 2.07; 95% CI 1.00 to 4.30) and a
      cumulative length of pregnancies longer than 30 months (OR 2.19; 95% CI 1.22 to
      3.91). An inverse association between PD and surgical menopause (adjusted OR
      0.30; 95% CI 0.13 to 0.77) was also found. CONCLUSIONS: An association between
      factors reducing estrogen stimulation during life and PD was found. These results
      support the hypothesis that endogenous estrogens play a role in the development
      of PD.

PMID- 15184607
TI  - The high risk of stroke immediately after transient ischemic attack: a population
      based study.
AB  - BACKGROUND: The risk of stroke is elevated in the first 48 hours after TIA.
      Previous prognostic models suggest that diabetes mellitus, age, and clinical
      symptomatology predict stroke. The authors evaluated the magnitude of risk of
      stroke and predictors of stroke after TIA in an entire population over time.
      METHODS: Administrative data from four different databases were used to define
      TIA and stroke for the entire province of Alberta for the fiscal year (April 1999
      March 2000). The age-adjusted incidence of TIA was estimated using direct
      standardization to the 1996 Canadian population. The risk of stroke after a
      diagnosis of TIA in an Alberta emergency room was defined using a Kaplan-Meier
      survival function. Cox proportional hazards modeling was used to develop adjusted
      risk estimates. Risk assessment began 24 hours after presentation and therefore
      the risk of stroke in the first few hours after TIA is not captured by our
      approach. RESULTS: TIA was reported among 2,285 patients for an emergency room
      diagnosed, age-adjusted incidence of 68.2 per 100,000 population (95% CI 65.3 to
      70.9). The risk of stroke after TIA was 9.5% (95% CI 8.3 to 10.7) at 90 days and
      14.5% (95% CI 12.8 to 16.2) at 1 year. The risk of combined stroke, myocardial
      infarction, or death was 21.8% (95% CI 20.0 to 23.6) at 1 year. Hypertension,
      diabetes mellitus, and older age predicted stroke at 1 year but not earlier.
      CONCLUSIONS: Although stroke is common after TIA, the early risk is not predicted
      by clinical and demographic factors. Validated models to identify which patients
      require urgent intervention are needed.

PMID- 15184608
TI  - Blood pressure and late-life cognitive function change: a biracial longitudinal
      population study.
AB  - OBJECTIVE: To examine the relation of blood pressure (BP) to subsequent decline
      in cognitive function among persons age 65 or over. METHODS: All persons age 65
      or over in a geographically defined community were invited to participate in a
      longitudinal study of problems of the elderly. Interviews were conducted in the
      participants' homes and included two BP measures and four tests of cognitive
      function. Follow-up interviews 3 and 6 years after baseline repeated the
      cognitive function tests. These analyses included 4,284 individuals who had
      baseline and at least one follow-up measure of cognitive function. The average of
      z scores of the individual cognitive function tests was used as a global measure
      of cognitive function. RESULTS: In random effects analyses controlling for age,
      sex, education, and race, there was no significant linear association of either
      systolic or diastolic BP with 6-year change in global cognitive function score.
      There was no significant curvilinear association with systolic BP. In tests for a
      curvilinear association with diastolic BP, there was a suggestion of increased
      decline among those with low or high diastolic BP (p = 0.03 for the quadratic
      diastolic term). At baseline, 50% of participants took some type of medication
      affecting BP. CONCLUSION: In this community population where BP treatment was
      common, there was no association of either high systolic or high diastolic BP at
      the beginning of the observation interval with 6-year cognitive decline.

PMID- 15184609
TI  - Stroke in patients with cancer: incidence and etiology.
AB  - OBJECTIVE: To assess the incidence and type of strokes in patients with cancer at
      Memorial Sloan-Kettering Cancer Center. METHODS: Retrospective review of all
      ischemic strokes diagnosed by a neurologist and confirmed by neuroimaging between
      February 1997 and April 2001 was conducted. Age, gender, cancer diagnosis and
      stage, and vascular risk factors were recorded. NIH Stroke Scale and modified
      Rankin Scale scores were calculated retrospectively. Stroke etiology was assigned
      independently by two neurologists using the Trial of Org 10172 in Acute Stroke
      Treatment (TOAST) criteria. RESULTS: Ninety-six patients with a confirmed stroke
      were identified. The median age was 67, and 61.5% were men. The distribution of
      vascular risk factors was comparable with that seen in large stroke trials. Lung
      cancer (30%) was the most common primary tumor followed by brain and prostate
      cancer (9% each). Strokes were embolic in 52 (54%) and nonembolic in 44 (46%).
      Eleven of 12 tested patients had an elevated D-dimer level, but in only 3
      patients could a definitive diagnosis of nonbacterial thrombotic endocarditis be
      made. The median survival was 4.5 months (95% CI 2.8 to 9.5) from the diagnosis
      of stroke; 25% of patients died within 30 days. Treatment had no effect on
      survival. CONCLUSIONS: Embolic strokes are the commonest cause of stroke in
      patients with cancer, due partially to hypercoagulability, whereas
      atherosclerosis accounted for only 22% of stroke in this population. Outcome was
      primarily determined by the underlying malignancy and the patient's neurologic
      condition.

PMID- 15184610
TI  - Neutralizing antibodies reduce the efficacy of betaIFN during treatment of
      multiple sclerosis.
AB  - OBJECTIVE: To analyze the impact of neutralizing antibodies (NAbs) on the
      clinical efficacy of IFNbeta. METHODS: This was an open-label study involving 78
      patients with multiple sclerosis treated with Betaferon 8 million IU (MIU)
      subcutaneously (SC) every other day (n = 20), Rebif 22 micro g SC 3 times weekly
      (n = 25), or Avonex 30 micro g IM once weekly (n = 33). Every 3 months, blood
      samples were collected and sera were analyzed for NAbs using an antiviral
      cytopathic effect assay. Patients were categorized according to their NAb status:
      NAb negative (NAb-); isolated NAb positive (NAb+), patients with > or =1 positive
      sample (titer > or = 20); and persistent NAb+, patients with > or =2 consecutive
      positive samples (titer > or = 20). Patients who were NAb- and persistent NAb+
      were compared for relapse rate, time between first and second relapse, percentage
      of relapse-free patients, and percentage of patients who had a sustained
      progression of > or =1 point on the Expanded Disability Status Scale (EDSS).
      RESULTS: The incidence of persistent NAb+ patients was 35% for Betaferon, 20% for
      Rebif, and 3% for Avonex. During IFNbeta treatment, both NAb+ and NAb- patients
      showed a reduction in relapse rate; this reduction (25%) was not significant in
      NAb+ patients but was significant (67%; p < 0.0001) in NAb- patients. In
      addition, the mean relapse rate was higher (p = 0.039), mean time between first
      and second relapse was shorter (13 vs 21 months; p = 0.0064), and there was a
      trend suggesting that NAbs affected the probability of remaining relapse free (p
      = 0.08). A higher percentage of NAb+ patients versus NAb- patients had worsening
      of EDSS scores during follow-up (p = 0.013). CONCLUSION: Persistent NAbs
      significantly reduce the clinical efficacy of IFNbeta.

PMID- 15184611
TI  - Randomized multicenter trial of natalizumab in acute MS relapses: clinical and
      MRI effects.
AB  - BACKGROUND: Relapses in multiple sclerosis (MS) can cause significant neurologic
      disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody
      that inhibits the trafficking of leukocytes across endothelium by blocking
      binding of alpha4beta1-integrin to vascular cell adhesion molecule-1. OBJECTIVE:
      To assess the effects of a single dose of IV natalizumab administered soon after
      the onset of MS relapses. METHODS: In this randomized, double-blind, multicenter
      trial, the effects of a single dose of IV natalizumab administered soon after the
      onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were
      randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo
      and were followed for 14 weeks. RESULTS: There was no difference in Expanded
      Disability Status Scale (EDSS) score change over time between treatment and
      placebo groups. In all three groups, approximately half of patients showed EDSS
      improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean
      value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in
      the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6
      points at week 4, and 1.6 points at week 8 in the placebo group. A significant
      decrease in Gd-enhancing lesion volume was seen in both active treatment groups
      at weeks 1 and 3 compared with placebo. CONCLUSIONS: A single dose of IV
      natalizumab did not hasten clinical recovery after relapse, although a
      significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks
      after treatment. These MRI findings are consistent with prior studies of
      natalizumab and support its further investigation as an agent for the treatment
      of MS.

PMID- 15184612
TI  - Enhanced brain motor activity in patients with MS after a single dose of 3,4
      diaminopyridine.
AB  - BACKGROUND: 3,4-diaminopyridine (3,4-DAP), a potassium (K+) channel blocker,
      improves fatigue and motor function in multiple sclerosis (MS). Although it was
      thought to do so by restoring conduction to demyelinated axons, recent
      experimental data show that aminopyridines administered at clinical doses
      potentiate synaptic transmission. OBJECTIVE: To investigate motor cerebral
      activity with fMRI and transcranial magnetic stimulation (TMS) after a single
      oral dose of 3,4-DAP in patients with MS. METHODS: Twelve right-handed women
      (mean +/- SD age 40.9 +/- 9.3 years) underwent fMRI on two separate occasions
      (under 3,4-DAP and under placebo) during a simple motor task with the right hand.
      FMRI data were analyzed with SPM99. After fMRI, patients underwent single-pulse
      TMS to test motor threshold, amplitude, and latency of motor evoked potentials,
      central conduction time, and the cortical silent period; paired-pulse TMS to
      investigate intracortical inhibition (ICI) and intracortical facilitation (ICF);
      and quantitative electromyography during maximal voluntary contraction. RESULTS:
      FMRI motor-evoked brain activation was greater under 3,4-DAP than under placebo
      in the ipsilateral sensorimotor cortex and supplementary motor area (p < 0.05).
      3,4-DAP decreased ICI and increased ICF; central motor conduction time and
      muscular fatigability did not change. CONCLUSION: 3,4-DAP may modulate brain
      motor activity in patients with MS, probably by enhancing excitatory synaptic
      transmission.

PMID- 15184614
TI  - Randomized controlled trial of yoga and exercise in multiple sclerosis.
AB  - OBJECTIVE: To determine the effect of yoga and of aerobic exercise on cognitive
      function, fatigue, mood, and quality of life in multiple sclerosis (MS). METHODS:
      Subjects with clinically definite MS and Expanded Disability Status Score less
      than or equal to 6.0 were randomly assigned to one of three groups lasting 6
      months: weekly Iyengar yoga class along with home practice, weekly exercise class
      using a stationary bicycle along with home exercise, or a waiting-list control
      group. Outcome assessments performed at baseline and at the end of the 6-month
      period included a battery of cognitive measures focused on attention, physiologic
      measures of alertness, Profile of Mood States, State-Trait Anxiety Inventory,
      Multi-Dimensional Fatigue Inventory (MFI), and Short Form (SF)-36 health-related
      quality of life. RESULTS: Sixty-nine subjects were recruited and randomized.
      Twelve subjects did not finish the 6-month intervention. There were no adverse
      events related to the intervention. There were no effects from either of the
      active interventions on either of the primary outcome measures of attention or
      alertness. Both active interventions produced improvement in secondary measures
      of fatigue compared to the control group: Energy and Fatigue (Vitality) on the SF
      36 and general fatigue on the MFI. There were no clear changes in mood related to
      yoga or exercise. CONCLUSION: Subjects with MS participating in either a 6-month
      yoga class or exercise class showed significant improvement in measures of
      fatigue compared to a waiting-list control group. There was no relative
      improvement of cognitive function in either of the intervention groups.

PMID- 15184613
TI  - Antiepileptic drug use increases rates of bone loss in older women: a prospective
      study.
AB  - OBJECTIVE: To test the hypothesis that older women with antiepileptic drug (AED)
      use have increased rates of bone loss. METHODS: AED use was ascertained and
      calcaneal and hip bone mineral density (BMD) measured in a cohort of 9,704
      elderly community-dwelling women enrolled in the Study of Osteoporotic Fractures,
      and they were followed prospectively for changes in BMD. Current use of AED was
      assessed by interview, with verification of use from medication containers at
      baseline and follow-up examinations. Women were classified as continuous users,
      partial (intermittent) users, or nonusers. Rates of change in BMD were measured
      at the total hip and two subregions (average 4.4 years between examinations) and
      at the calcaneus (average 5.7 years between examinations). RESULTS: After
      adjustment for confounders, the average rate of decline in total hip BMD steadily
      increased from -0.70%/year in nonusers to -0.87%/year in partial AED users to 
      1.16%/year in continuous AED users (p value for trend = 0.015). Higher rates of
      bone loss were also observed among continuous AED users at subregions of the hip
      and at the calcaneus. In particular, continuous phenytoin users had an adjusted
      1.8-fold greater mean rate of loss at the calcaneus compared with nonusers of AED
      (-2.68 vs -1.46%/year; p < 0.001) and an adjusted 1.7-fold greater mean rate of
      loss at the total hip compared with nonusers of AED (-1.16 vs -0.70%/year; p =
      0.069). CONCLUSIONS: Continuous AED use in elderly women is associated with
      increased rates of bone loss at the calcaneus and hip. If unabated, the rate of
      hip bone loss among continuous AED users is sufficient to increase the risk of
      hip fracture by 29% over 5 years among women age 65 years and older.

PMID- 15184615
TI  - The relative influence of environment and genes in episodic tension-type
      headache.
AB  - OBJECTIVE: To examine the relative importance of genetic and environmental
      influence for the development of tension-type headache by analyses of twins.
      METHODS: The authors screened by questionnaire a population of 5,360 twins born
      during 1953 to 1960 from the general population for migraine and headache
      symptoms. The response rate of the questionnaire was 87%. All twin pairs with at
      least one twin of the pair reporting migraine or headache symptoms were
      interviewed by telephone by a physician. Correlation of liability and structural
      equation modeling were applied on tension-type headache. RESULTS: A total of
      1,417 subjects had tension-type headache equivalent to a 1-year prevalence of
      62%. The male: female ratio was 1:1.24. Chronic tension-type headache was found
      in 49 twins corresponding to a prevalence of 2% with a male:female ratio of
      1:1.21. The prevalence, pain characteristics, frequency, and duration of tension
      type headache were similar to what has been found in the general Danish
      population. The correlation of liability of tension-type headache was low and not
      significantly different in monozygotic and dizygotic twin pairs: 0.21 (0.03 to
      0.39), 0.08 (0 to 0.24). The best fitting model of phenotypic variation consisted
      of 81% non-shared environmental effects and of 19% additive genetic effects.
      CONCLUSIONS: Environmental influence is of major importance for episodic tension
      type headache and a genetic factor, if it exits, is minor. In chronic tension
      type headache the genetic factor may be more important. These data clearly
      separate episodic tension-type headache from migraine without aura where the
      phenotypic variation consists of non-shared environmental effects of 39% and of
      61% additive genetic effects.

PMID- 15184616
TI  - Anomalous brain activation during face and gaze processing in Williams syndrome.
AB  - OBJECTIVE: To investigate the discrete neural systems that underlie relatively
      preserved face processing skills in Williams syndrome (WS). METHODS: The authors
      compared face and eye-gaze direction processing abilities in 11 clinically and
      genetically diagnosed WS subjects with 11 healthy age- and sex-matched controls,
      using functional MRI (fMRI). RESULTS: Compared to controls, WS subjects showed a
      strong trend toward being less accurate in determining the direction of gaze and
      had significantly longer response latencies. Significant increases in activation
      were observed in the right fusiform gyrus (FuG) and several frontal and temporal
      regions for the WS group. By comparison, controls showed activation in the
      bilateral FuG, occipital, and temporal lobes. Between-group analysis showed WS
      subjects to have more extensive activation in the right inferior, superior, and
      medial frontal gyri, anterior cingulate, and several subcortical regions
      encompassing the anterior thalamus and caudate. Conversely, controls had greater
      activation in the primary and secondary visual cortices. CONCLUSION: The observed
      patterns of activation in WS subjects suggest a preservation of neural
      functioning within frontal and temporal regions, presumably resulting from task
      difficulty or compensatory mechanisms. Persons with WS may possess impairments in
      visual cortical regions, possibly disrupting global-coherence and visuospatial
      aspects of face and gaze processing.

PMID- 15184618
TI  - The origins of scientific cinematography and early medical applications.
AB  - OBJECTIVE: To examine the neurologic cinematographic contributions of Gheorghe
      Marinescu. BACKGROUND: Near the end of the 19th century, cinematography developed
      and was immediately recognized as a new technique applicable to medical
      documentation. After studying with several prominent European neurologists and
      deeply influenced by Jean-Martin Charcot, Marinescu returned to Bucharest in 1897
      and applied moving picture techniques to the study of neurologic patients.
      METHODS: The Romanian State Archives were researched for original Marinescu
      films, and related publications were translated from Romanian and French.
      RESULTS: Between 1899 and 1902, Marinescu perfected the use of cinematography as
      a research method in neurosciences and published five articles based on
      cinematographic documents. He focused his studies particularly on organic gait
      disorders, locomotor ataxia, and hysteria. He adapted Charcot's method of lining
      up several patients with the same disorder and showing them together to permit
      appreciation of archetypes and formes frustes. He decomposed the moving pictures
      into sequential tracings for publication. He documented treatment results with
      cases filmed before and after therapy. Processed and digitized excerpts of these
      films accompany this manuscript. CONCLUSIONS: Marinescu's cinematographic studies
      led to several original contributions in clinical neurology. Remaining film
      archives include examples of many neurologic diseases, his examination
      techniques, and the working medical environment of the young founder of the
      Romanian school of neurology.

PMID- 15184617
TI  - Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome
      biogenesis disorder.
AB  - OBJECTIVE: To determine the enzymatic defect in a patient with ataxia, dysarthric
      speech, dry skin, hypotonia, and absent reflexes. The patient was previously
      diagnosed with a presumed deficiency of trihydroxycholestanoyl-CoA oxidase.
      BACKGROUND: Peroxisomes harbor a variety of metabolic functions, including fatty
      acid beta-oxidation, etherphospholipid biosynthesis, phytanic acid alpha
      oxidation, and L-pipecolic acid oxidation. This patient was previously described
      with an isolated peroxisomal beta-oxidation defect caused by a deficiency of the
      enzyme trihydroxycholestanoyl-CoA oxidase. This was based on the pattern of
      accumulating metabolites. METHODS: Measurement of beta-oxidation enzymes,
      peroxisomal biochemical analysis in body fluids and cultured skin fibroblasts,
      and DNA analysis of the PEX12 gene were performed. RESULTS: An isolated beta
      oxidation defect in this patient was excluded by measurement of the various beta
      oxidation enzymes. The authors found that the patient had a peroxisome biogenesis
      disorder caused by mutations in the PEX12 gene, although all peroxisomal
      functions in cultured skin fibroblasts were normal. CONCLUSIONS: The absence of
      clear peroxisomal abnormalities in the patient's fibroblasts, including a normal
      peroxisomal localization of catalase, implies that even when all peroxisomal
      functions in fibroblasts are normal, a peroxisome biogenesis disorder cannot be
      fully excluded, and further studies may be needed. In addition, the authors'
      findings imply that there is no longer evidence for the existence of
      trihydroxycholestanoyl-CoA oxidase deficiency as a distinct disease entity.

PMID- 15184619
TI  - Acute transverse myelitis in SLE.

PMID- 15184620
TI  - Perinatal stroke in term infants with neonatal encephalopathy.
AB  - In a prospective cohort of 124 encephalopathic term infants, six infants had an
      acute focal stroke. All six encephalopathic patients with strokes presented with
      seizures. Neurodevelopmental outcome at 30 months was abnormal in all six
      patients and significantly worse when compared with the entire cohort overall.
      These findings suggest that in newborns with encephalopathy, acute focal strokes
      are an uncommon but serious occurrence with substantial risk for abnormal
      neurodevelopmental outcome.

PMID- 15184621
TI  - Similar low frequency of anti-MOG IgG and IgM in MS patients and healthy
      subjects.
AB  - The authors used a liquid-phase radiobinding assay to measure serum anti-myelin
      oligodendrocyte protein (MOG) immunoglobulin (Ig) G in 87 patients with multiple
      sclerosis (MS), in 12 patients with encephalomyelitis, and in 47 healthy
      subjects. Anti-MOG IgM was determined in samples obtained at onset from 40 of 87
      patients with MS and in control subjects. The frequency of positive samples with
      low titers of anti-MOG IgG (< or =5.7%) and IgM (< or =8.3%) was similar in all
      the groups and subgroups. Binding competition experiments showed that these
      antibodies had low affinity. Anti-MOG antibodies are not disease specific.

PMID- 15184623
TI  - Patterns of cannabis use among patients with multiple sclerosis.
AB  - To estimate the patterns and prevalence of cannabis use among patients with
      multiple sclerosis (MS), 220 patients were surveyed in Halifax, Nova Scotia.
      Seventy-two subjects (36%) reported ever having used cannabis for any purpose; 29
      respondents (14%) reported continuing use of cannabis for symptom treatment.
      Medical cannabis use was associated with male gender, tobacco use, and
      recreational cannabis use. The symptoms reported by medical cannabis users to be
      most effectively relieved were stress, sleep, mood, stiffness/spasm, and pain.

PMID- 15184622
TI  - Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy
      center.
AB  - The authors sought to determine the prevalence of marijuana use in patients with
      epilepsy by performing a telephone survey in a tertiary care epilepsy center.
      Twenty-one percent of subjects had used marijuana in the past year with the
      majority of active users reporting beneficial effects on seizures. Twenty-four
      percent of all subjects believed marijuana was an effective therapy for epilepsy.
      Despite limited evidence of efficacy, many patients with epilepsy believe
      marijuana is an effective therapy for epilepsy and are actively using it.

PMID- 15184625
TI  - Confirming the validity and responsiveness of the Multiple Sclerosis Walking
      Scale-12 (MSWS-12).
AB  - The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a new, self-rated
      measure of walking ability. The scale has not been independently validated for
      use in differing MS populations. One hundred forty-nine patients in the community
      and 53 hospital outpatients with MS completed the MSWS-12 and other outcome
      measures. The psychometric properties of the MSWS-12 were excellent, and in
      particular the scale is responsive to change.

PMID- 15184624
TI  - Stiff person syndrome does not always occur with maternal passive transfer of
      GAD65 antibodies.
AB  - The authors report the presence of high titer antibodies to glutamic acid
      decarboxylase (anti-GAD65) until age 24 months in two asymptomatic newborns of a
      woman with stiff-person syndrome (SPS). No signs of SPS were detectable in the
      two children at ages 6 and 8 years. This observation indicates that other
      cofactors are involved in the pathogenesis of SPS.

PMID- 15184626
TI  - An open study of tacrolimus therapy in Rasmussen encephalitis.
AB  - Seven patients with Rasmussen encephalitis (RE) were treated with the
      immunosuppressant tacrolimus and followed for a median of 22.4 months. They were
      compared with 12 historical untreated RE patients (median follow-up 13.9 months).
      The tacrolimus-treated patients had a superior outcome regarding neurologic
      function and progression rate of cerebral hemiatrophy but no better seizure
      outcome. No treated patient, but 7 of 12 control patients, became eligible for
      hemispherectomy. Tacrolimus did not have any major side effects.

PMID- 15184627
TI  - The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain
      lesions.
AB  - To determine the effect of systemic thrombolysis with low-dose recombinant tissue
      plasminogen activator (rtPA) and the body-weight adjusted platelet GPIIb/IIIa
      receptor antagonist tirofiban, the authors performed lesion volumetry on magnetic
      resonance perfusion and diffusion images recorded before thrombolysis and on T2
      weighted magnetic resonance images on day 8. Treatment with rtPA and tirofiban (n
      = 13) resulted in a 50% lesion reduction (p < 0.03), while lesion reduction was
      less in rtPA treatment (n = 16) and absent in nontreated patients (n = 18).

PMID- 15184628
TI  - One week on/one week off: a novel active regimen of temozolomide for recurrent
      glioblastoma.
AB  - Twenty-one patients with recurrent or progressive glioblastoma were enrolled in a
      prospective phase II trial to determine the safety and efficacy of a 1-week on/1
      week off regimen of temozolomide administered at 150 mg/m2 on days 1 to 7 and
      days 15 to 21 of 28-day treatment cycles. Two patients achieved a partial
      response (10%), and 17 patients (81%) had stable disease. The median progression
      free survival was 5 months. The progression-free survival at 6 months was 48%.

PMID- 15184629
TI  - APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of
      Abeta42.
AB  - The epsilon4 allele of APOE is a risk factor for Alzheimer disease (AD). By
      analysis of a large cohort of AD patients (n = 563) and control subjects (n =
      118), it is shown that the epsilon4 allele is strongly associated with reduced
      CSF levels of beta-amyloid (1-42) (Abeta42) in both AD (p < 10(-9)) and control
      (p = 0.0012) populations. As no associations of APOE variants with other indexes
      of AD severity were observed, this effect may reflect a fundamental involvement
      of ApoE in Abeta metabolism.

PMID- 15184630
TI  - A novel mitochondrial tRNAPhe mutation causes MERRF syndrome.
AB  - A woman with typical features of myoclonic epilepsy with ragged red fibers
      (MERRF) had a novel heteroplasmic mutation (G611A) in the mitochondrial DNA tRNA
      phenylalanine gene. The mutation was heteroplasmic (91%) in muscle but
      undetectable in accessible tissues from the patient and her maternal relatives.
      Single-fiber PCR analysis showed that the proportion of mutant genomes was higher
      in cytochrome c oxidase (COX)-negative ragged red fibers (RRFs) than in COX
      positive non-RRFs. This report shows that typical MERRF syndrome is not always
      associated with tRNA lysine mutations.

PMID- 15184631
TI  - A novel MPZ gene mutation in congenital neuropathy with hypomyelination.
AB  - Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy
      with early infancy onset inherited as an autosomal dominant or recessive trait.
      Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly
      myelinated axons with basal lamina onion bulbs and lack of myelin breakdown
      products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been
      found in patients with CHN. The authors describe the clinical and morphologic
      features of a patient with CHN and the identification of a novel Thr124Lys
      mutation in the MPZ gene.

PMID- 15184632
TI  - Improved motor skill acquisition after selective stimulation of central
      norepinephrine.
AB  - It has been proposed that the beneficial effects of training on motor function
      can be enhanced by stimulation of alpha-adrenergic mechanisms. Consistent with
      this view, a single oral dose of the selective norepinephrine reuptake inhibitor
      reboxetine was found to enhance motor skill acquisition (rapid elbow flexion) and
      corticomotor excitability tested with transcranial magnetic stimulation in the
      absence of effects on basal motor performance. Therefore, alpha-adrenergic
      mechanisms could possibly be manipulated to magnify training effects in
      neurorehabilitation.

PMID- 15184633
TI  - Low levels of the vascular endothelial growth factor in CSF from early ALS
      patients.
AB  - Deletion of the hypoxia-response element in the vascular endothelial growth
      factor (VEGF) promoter causes motor neuron degeneration in a mouse model. "At
      risk" haplotypes with low circulating VEGF levels have been demonstrated in
      humans. Here the authors report low VEGF levels in the CSF of ALS patients during
      their first year of the disease, independently of VEGF promoter polymorphism.
      This finding early in ALS patients suggests a possible role for VEGF gene
      regulation in the pathogenesis of ALS.

PMID- 15184634
TI  - Crossed cerebellar diaschisis in stroke.

PMID- 15184635
TI  - Low frequency of MuSK antibody in generalized seronegative myasthenia gravis
      among Chinese.

PMID- 15184636
TI  - MuSK antibodies in AChR Ab-seropositive MG vs AChR Ab-seronegative MG.

PMID- 15184637
TI  - Absence of NR4A2 exon 1 mutations in 108 families with autosomal dominant
      Parkinson disease.

PMID- 15184638
TI  - Levetiracetam in the treatment of idiopathic hemifacial spasm.

PMID- 15184639
TI  - Cryptococcal meningitis mimicking vascular dementia.

PMID- 15184640
TI  - Doxifluridine-induced neurotoxicity with normal dihydropyrimidine dehydrogenase
      activity.

PMID- 15184641
TI  - A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1.

PMID- 15184642
TI  - Incomplete penetrance in an SPG3A-linked family with a new mutation in the
      atlastin gene.

PMID- 15184644
TI  - Mechanical compression of the extracranial vertebral artery during neck rotation.

PMID- 15184645
TI  - Botulinum toxin treatment of painful tonic spasms in multiple sclerosis.

PMID- 15184646
TI  - Repetitive TMS temporarily alters brain diffusion.

PMID- 15184647
TI  - Patient page. Antiseizure drugs and reduced bone density.

PMID- 15184648
TI  - Accumulation of mutant lamin A causes progressive changes in nuclear architecture
      in Hutchinson-Gilford progeria syndrome.
AB  - Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder,
      commonly caused by a point mutation in the lamin A gene that results in a protein
      lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and
      electron microscopy that HGPS is associated with significant changes in nuclear
      shape, including lobulation of the nuclear envelope, thickening of the nuclear
      lamina, loss of peripheral heterochromatin, and clustering of nuclear pores.
      These structural defects worsen as HGPS cells age in culture, and their severity
      correlates with an apparent increase in LADelta50. Introduction of LADelta50 into
      normal cells by transfection or protein injection induces the same changes. We
      hypothesize that these alterations in nuclear structure are due to a
      concentration-dependent dominant-negative effect of LADelta50, leading to the
      disruption of lamin-related functions ranging from the maintenance of nuclear
      shape to regulation of gene expression and DNA replication.

PMID- 15184649
TI  - Polarized type 1 cytokine response and cell-mediated immunity determine genetic
      resistance to mousepox.
AB  - Ectromelia virus (ECTV), a natural mouse pathogen and an orthopoxvirus, has been
      used to investigate the correlation between polarized type 1 or type 2 immune
      responses and resistance to disease in poxvirus infections by using well defined
      resistant and susceptible mouse strains. Our data show that distinct differences
      exist in the cytokine profiles expressed in resistant and susceptible mice
      infected with ECTV. Resistant C57BL/6 mice generate a type 1 cytokine response
      [IFN-gamma, IL-2, and tumor necrosis factor (TNF)], within the first few days of
      infection, which is associated with strong cytotoxic T lymphocyte response (CTL)
      and recovery from ECTV infection. Susceptible strains of mice (BALB/c and A/J) on
      the other hand generate a type 2 cytokine response (IL-4 but little or no IFN
      gamma and IL-2), which is associated with a weak or an absent CTL response,
      resulting in uncontrolled virus replication and death. Although deletion of IL-4
      function alone did not change the outcome of infection in susceptible mice, the
      loss of IFN-gamma function in resistant mice abrogated natural killer (NK) cell
      and CTL effector functions resulting in fulminant disease and 100% mortality.
      Therefore, a clear link exists between the early production of specific type 1
      cytokines, in particular, IFN-gamma, the nature of the cellular immune response,
      and disease outcome in this virus model. This finding in the mousepox model
      raises the possibility that inappropriate cytokine responses may result in
      increased susceptibility to smallpox in humans.

PMID- 15184652
TI  - Three-dimensional phase-encoded chemical shift MRI in the presence of
      inhomogeneous fields.
AB  - A pulse sequence consisting of an excitation pulse and two adiabatic full-passage
      pulses with scaled relative peak amplitudes is combined with phase encoding to
      recover chemical shift information within 3D images in a 1D inhomogeneous static
      magnetic field with a matched rf field gradient. The results are discussed in the
      context of ex situ magnetic resonance and imaging. The future directions of our
      research in implementing the ex situ technique in a real one-sided system are
      also discussed.

PMID- 15184651
TI  - Myosin subfragment 1 structures reveal a partially bound nucleotide and a complex
      salt bridge that helps couple nucleotide and actin binding.
AB  - Structural studies of myosin have indicated some of the conformational changes
      that occur in this protein during the contractile cycle, and we have now observed
      a conformational change in a bound nucleotide as well. The 3.1-A x-ray structure
      of the scallop myosin head domain (subfragment 1) in the ADP-bound near-rigor
      state (lever arm =45 degrees to the helical actin axis) shows the diphosphate
      moiety positioned on the surface of the nucleotide-binding pocket, rather than
      deep within it as had been observed previously. This conformation strongly
      suggests a specific mode of entry and exit of the nucleotide from the nucleotide
      binding pocket through the so-called "front door." In addition, using a variety
      of scallop structures, including a relatively high-resolution 2.75-A nucleotide
      free near-rigor structure, we have identified a conserved complex salt bridge
      connecting the 50-kDa upper and N-terminal subdomains. This salt bridge is
      present only in crystal structures of muscle myosin isoforms that exhibit a
      strong reciprocal relationship (also known as coupling) between actin and
      nucleotide affinity.

PMID- 15184650
TI  - Interplay between Drosophila Bloom's syndrome helicase and Ku autoantigen during
      nonhomologous end joining repair of P element-induced DNA breaks.
AB  - P transposable elements in Drosophila are mobilized via a cut-and-paste
      mechanism. The broken DNA ends generated during transposition can be repaired via
      the homology-directed synthesis-dependent strand annealing or by nonhomologous
      end joining (NHEJ). Genetic studies have demonstrated an interaction between the
      gene (mus309, for mutagen-sensitive) encoding the Drosophila Bloom's syndrome
      helicase homolog (DmBLM) and the Ku70 gene, which is involved in NHEJ. We have
      used RNA interference (RNAi) to knock down expression of DmBLM and one or both of
      the Drosophila Ku subunits, DmKu70 or DmKu80. Our results show that upon
      reduction of DmKu, an increase in small deletions (1-49 bp) and large deletions
      (>/=50 bp) flanking the site of P element-induced breaks is observed, and a
      reduction in large deletions at these sites is found upon reduction of DmBLM.
      Moreover, double RNAi of DmKu and DmBLM results in an increase in small deletions
      characteristic of the DmKu RNAi and also partially suppresses the reduction in
      repair efficiency observed with DmKu RNAi. These results suggest that there are
      DNA double-strand break recognition and/or processing events involving DmKu and
      DmBLM that, when eliminated by RNAi, lead to deletions. Finally, these results
      raise the possibility that, unlike the situation in mammals, where BLM appears to
      function exclusively in the homologous repair pathway, in Drosophila, DmBLM may
      be directly involved in, or at least influence the double-strand break
      recognition that leads to the NHEJ repair pathway.

PMID- 15184653
TI  - The crystal structure of activated protein C-inactivated bovine factor Va:
      Implications for cofactor function.
AB  - In vertebrate hemostasis, factor Va serves as the cofactor in the prothrombinase
      complex that results in a 300,000-fold increase in the rate of thrombin
      generation compared with factor Xa alone. Structurally, little is known about the
      mechanism by which factor Va alters catalysis within this complex. Here, we
      report a crystal structure of protein C inactivated factor Va (A1.A3-C1-C2) that
      depicts a previously uncharacterized domain arrangement. This orientation has
      implications for binding to membranes essential for function. A high-affinity
      calcium-binding site and a copper-binding site have both been identified.
      Surprisingly, neither shows a direct involvement in chain association. This
      structure represents the largest physiologically relevant fragment of factor Va
      solved to date and provides a new scaffold for the future generation of models of
      coagulation cofactors.

PMID- 15184654
TI  - Silencing of a gene adjacent to the breakpoint of a widespread Drosophila
      inversion by a transposon-induced antisense RNA.
AB  - Adaptive changes in nature occur by a variety of mechanisms, and Drosophila
      chromosomal inversions was one of the first studied examples. However, the
      precise genetic causes of the adaptive value of inversions remain uncertain. Here
      we investigate the impact of the widespread inversion 2j of Drosophila buzzatii
      on the expression of the CG13617 gene, whose coding region is located only 12 bp
      away from the inversion proximal breakpoint. This gene is transcribed into a 2.3
      kb mRNA present in all D. buzzatii developmental stages. More importantly, the
      expression level of CG13617 is reduced 5-fold in embryos of lines homozygous for
      the 2j inversion compared with lines without the inversion. An antisense RNA that
      originates in the Foldback-like transposon Kepler inserted at the breakpoint
      junction in all of the 2j lines and that forms duplexes with the CG13617 mRNA in
      2j embryos is most likely responsible for the near silencing of the gene. Few
      examples of RNA interference caused by transposable elements (TEs) have been
      previously described, but this mechanism might be prevalent in many organisms and
      illustrates the potential of TEs as a major source of genetic variation. In
      addition, because chromosomal rearrangements are usually induced by TEs, position
      effects might be more common than previously recognized and contribute
      significantly to the evolutionary success of inversions.

PMID- 15184655
TI  - Mutator genes for suppression of gross chromosomal rearrangements identified by a
      genome-wide screening in Saccharomyces cerevisiae.
AB  - Different types of gross chromosomal rearrangements (GCRs), including
      translocations, interstitial deletions, terminal deletions with de novo telomere
      additions, and chromosome fusions, are observed in many cancers. Multiple
      pathways, such as S-phase checkpoints, DNA replication, recombination, chromatin
      remodeling, and telomere maintenance that suppress GCRs have been identified. To
      experimentally expand our knowledge of other pathway(s) that suppress GCRs, we
      developed a generally applicable genome-wide screening method. In this screen, we
      identified 10 genes (ALO1, CDC50, CSM2, ELG1, ESC1, MMS4, RAD5, RAD18, TSA1, and
      UFO1) that encode proteins functioning in the suppression of GCRs. Moreover, the
      breakpoint junctions of GCRs from these GCR mutator mutants were determined with
      modified breakpoint-mapping methods. We also identified nine genes (AKR1, BFR1,
      HTZ1, IES6, NPL6, RPL13B, RPL27A, RPL35A, and SHU2) whose mutations generated
      growth defects with the pif1Delta mutation. In addition, we found that some of
      these mutations changed the telomere size.

PMID- 15184656
TI  - Caenorhabditis phylogeny predicts convergence of hermaphroditism and extensive
      intron loss.
AB  - Despite the prominence of Caenorhabditis elegans as a major developmental and
      genetic model system, its phylogenetic relationship to its closest relatives has
      not been resolved. Resolution of these relationships is necessary for studying
      the steps that underlie life history, genomic, and morphological evolution of
      this important system. By using data from five different nuclear genes from 10
      Caenorhabditis species currently in culture, we find a well resolved phylogeny
      that reveals three striking patterns in the evolution of this animal group: (i)
      Hermaphroditism has evolved independently in C. elegans and its close relative
      Caenorhabditis briggsae; (ii) there is a large degree of intron turnover within
      Caenorhabditis, and intron losses are much more frequent than intron gains; and
      (iii) despite the lack of marked morphological diversity, more genetic disparity
      is present within this one genus than has occurred within all vertebrates.

PMID- 15184657
TI  - Early events in speciation: polymorphism for hybrid male sterility in Drosophila.
AB  - Capturing the process of speciation early enough to determine the initial genetic
      causes of reproductive isolation remains a major challenge in evolutionary
      biology. We have found, to our knowledge, the first example of substantial
      intraspecific polymorphism for genetic factors contributing to hybrid male
      sterility. Specifically, we show that the occurrence of hybrid male sterility in
      crosses between Drosophila mojavensis and its sister species, Drosophila
      arizonae, is controlled by factors present at different frequencies in different
      populations of D. mojavensis. In addition, we show that hybrid male sterility is
      a complex phenotype; some hybrid males with motile sperm still cannot sire
      offspring. Because male sterility factors in hybrids between these species are
      not yet fixed within D. mojavensis, this system provides an invaluable
      opportunity to characterize the genetics of reproductive isolation at an early
      stage.

PMID- 15184658
TI  - Origins and dispersals of Pacific peoples: evidence from mtDNA phylogenies of the
      Pacific rat.
AB  - The human settlement of the Pacific in general, and the origin of the Polynesians
      in particular, have been topics of debate for over two centuries. Polynesian
      origins are most immediately traced to people who arrived in the Fiji, Tonga, and
      Samoa region approximately 3,000 B.P. and are clearly associated with the Lapita
      Cultural Complex. Although this scenario of the immediate origins of the
      Polynesians is generally accepted, the debate on the ultimate origin of the
      Polynesians and the Lapita cultural complex continues. Our previous research has
      shown that analyses of mtDNA variation in the Pacific rat (Rattus exulans), often
      transported as a food item in the colonizing canoes, are valuable for tracing
      prehistoric human migration within Polynesia. Here we present mtDNA phylogenies
      based on approximately 240 base pairs of the d-loop from both archaeological and
      modern samples collected from Island Southeast Asia and the Pacific. We identify
      three major haplogroups, two of which occur in the Pacific. Comparing our results
      with Lapita models of Oceanic settlement, we are able to reject two often cited
      but simplistic models, finding support instead for multifaceted models
      incorporating a more complex view of the Lapita intrusion. This study is unique
      and valuable in that R. exulans is the only organism associated with the Lapita
      dispersal for which there are sufficient ancient and extant populations available
      for genetic analysis. By tracking population changes through time, we can
      understand more fully the settlement process and population interactions in both
      Near and Remote Oceania.

PMID- 15184659
TI  - Human RAD9 checkpoint control/proapoptotic protein can activate transcription of
      p21.
AB  - When human cells incur DNA damage, two fundamental responses can follow, cell
      cycle arrest or apoptosis. Human RAD9 (hRAD9) and p53 function in both processes,
      but the mechanistic relationship between their activities is unknown. p53
      mediates checkpoint control at G(1) by transcriptional regulation of p21. In this
      report, we show that hRAD9, like p53, can also regulate p21 at the
      transcriptional level. We demonstrate that overexpression of hRAD9 leads to
      increased p21 RNA and encoded protein levels. The promoter region of p21 fused to
      a luciferase reporter can be transactivated by either hRAD9 or p53, indicating
      that hRAD9 regulates the p21 promoter for transcriptional control of expression.
      Using an electrophoretic mobility-shift assay, we show that hRAD9 specifically
      binds to a p53-consensus DNA-binding sequence in the p21 promoter. Microarray
      screening coupled with Northern analysis reveals that hRAD9 regulates the
      abundance of other messages in addition to p21. Our data reveal a previously
      undescribed mechanism for regulation of p21 and demonstrate that hRAD9 can
      control gene transcription. We suggest that hRAD9 and p53 co-regulate p21 to
      direct cell cycle progression by similar molecular mechanisms. Furthermore, hRAD9
      might regulate other cellular processes as well by modulating transcription of
      multiple down-stream target genes.

PMID- 15184660
TI  - Knock-in human rhodopsin-GFP fusions as mouse models for human disease and
      targets for gene therapy.
AB  - The human rhodopsin gene is the locus for numerous alleles linked to the
      neurodegenerative disease retinitis pigmentosa. To facilitate the study of
      retinal degeneration and to test reagents designed to alter the structure and
      function of this gene, we have developed strains of mice whose native rhodopsin
      gene has been replaced with the corresponding human DNA modified to encode an
      enhanced GFP fusion at the C terminus of rhodopsin. The human rhodopsin-GFP
      fusion faithfully mimics the expression and distribution of wild-type rhodopsin
      in heterozygotes and serves as a sensitive reporter of rod-cell structure and
      integrity. In homozygotes, however, the gene induces progressive retinal
      degeneration bearing many of the hallmarks of recessive retinitis pigmentosa.
      When the gene is flanked by recognition sites for Cre recombinase, protein
      expression is reduced approximately 5-fold despite undiminished mRNA levels,
      suggesting translation inhibition. GFP-tagged human rhodopsin provides a
      sensitive method to monitor the development of normal and diseased retinas in
      dissected samples, and it offers a noninvasive means to observe the progress of
      retinal degeneration and the efficacy of gene-based therapies in whole animals.

PMID- 15184661
TI  - Effective inhibition of Rta expression and lytic replication of Kaposi's sarcoma
      associated herpesvirus by human RNase P.
AB  - Ribonuclease P (RNase P) complexed with external guide sequence (EGS) represents
      a nucleic acid-based gene interference approach to knock-down gene expression.
      Unlike other strategies, such as antisense oligonucleotides, ribozymes, and RNA
      interference, the RNase P-based technology is unique because a custom-designed
      EGS molecule can bind to any complementary mRNA sequence and recruit
      intracellular RNase P for specific degradation of the target mRNA. In this study,
      we demonstrate that the RNase P-based strategy is effective in blocking gene
      expression and growth of Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), the
      causative agent of the leading AIDS-associated neoplasms, such as KS and primary
      effusion lymphoma. We constructed 2'-O-methyl-modified EGS molecules that target
      the mRNA encoding KSHV immediate-early transcription activator Rta, and we
      administered them directly to human primary-effusion lymphoma cells infected with
      KSHV. A reduction of 90% in Rta expression and a reduction of approximately 150
      fold in viral growth were observed in cells treated with a functional EGS. In
      contrast, a reduction of <10% in the Rta expression and viral growth was found in
      cells that were either not treated with an EGS or that were treated with a
      disabled EGS containing mutations that preclude recognition by RNase P. Our study
      provides direct evidence that EGSs are highly effective in inhibiting KSHV gene
      expression and growth. Exogenous administration of chemically modified EGSs in
      inducing RNase P-mediated cleavage represents an approach for inhibiting specific
      gene expression and for treating human diseases, including KSHV-associated
      tumors.

PMID- 15184662
TI  - Inhibition of nuclear import and cell-cycle progression by mutated forms of the
      dynamin-like GTPase MxB.
AB  - Mx proteins form a subfamily of the dynamin-like GTPases, which have well
      established roles in cellular trafficking. Some Mx proteins (e.g., human MxA)
      have antiviral activity and are tightly regulated by type I IFNs. Others (e.g.,
      human MxB) lack antiviral activity and are thought to have normal cellular
      functions that remain undefined. Consistent with this hypothesis, we report that
      MxB is expressed without IFN treatment. MxB seems to be exclusively extranuclear
      and is concentrated at the cytoplasmic face of nuclear pores, suggesting a role
      in their regulation. We find that expression of dominant negative (GTPase
      defective) MxB mutants efficiently blocks nuclear import and causes a delay in
      G(1)/S cell-cycle progression. MxB depletion using RNA interference (RNAi) leads
      to a similar cell-cycle defect but does not block nuclear import. MxB therefore
      seems not to be required for nuclear import per se but may instead regulate its
      efficiency and/or kinetics. These studies indicate an unexpected role for a
      dynamin-like protein in nucleocytoplasmic trafficking and suggest that a related
      function might be usurped by its antiviral relatives.

PMID- 15184663
TI  - Tumor-specific Ab-mediated targeting of MHC-peptide complexes induces regression
      of human tumor xenografts in vivo.
AB  - A cancer immunotherapy strategy is described herein that combines the advantage
      of the well established tumor targeting capabilities of high-affinity recombinant
      fragments of Abs with the known efficient, specific, and potent killing ability
      of CD8 T lymphocytes directed against highly antigenic MHC-peptide complexes.
      Structurally, it consists of a previously uncharacterized class of recombinant
      chimerical molecules created by the genetic fusion of single-chain (sc) Fv Ab
      fragments, specific for tumor cell surface antigens, to monomeric scHLA-A2
      complexes containing immunodominant tumor- or viral-specific peptides. The fusion
      protein can induce very efficiently tumor cell lysis, regardless of the
      expression of self peptide-MHC complexes. Moreover, these molecules exhibited
      very potent antitumor activity in vivo in nude mice bearing preestablished human
      tumor xenografts. These in vitro and in vivo results suggest that recombinant
      scFv-MHC-peptide fusion molecules could represent an approach to immunotherapy,
      bridging Ab and T lymphocyte attack on cancer cells.

PMID- 15184664
TI  - Biochemical crypsis in the avoidance of natural enemies by an insect herbivore.
AB  - Plant-herbivore interactions provide well studied examples of coevolution, but
      little is known about how such interactions are influenced by the third trophic
      level. Here we show that larvae of the specialized lepidopteran herbivore
      Heliothis subflexa reduce their vulnerability to natural enemies through
      adaptation to a remarkable and previously unknown feature of their host plant,
      Physalis angulata: The fruits of this plant lack linolenic acid (LA), which is
      required for the development of most insects. By overcoming this nutritional
      deficiency, H. subflexa larvae achieve numerous advantages. First, they gain near
      exclusive access to a food resource: we demonstrate that closely related
      Heliothis virescens larvae cannot develop on P. angulata fruit unless the fruit
      are treated with LA. Second, they reduce their vulnerability to enemies: LA is a
      key component of volicitin, an elicitor of plant-volatile-signaling defenses. We
      demonstrate that volicitin is absent in the oral secretions of fruit-feeding
      caterpillars, that the volatile profiles of plants induced by fruit feeding
      differ from those induced by leaf feeding or by feeding on LA-treated fruit, and
      that the former are far less attractive to female Cardiochiles nigriceps
      parasitoids. Finally, they render themselves nutritionally unsuitable as hosts
      for enemies that require LA for their own development: we show that C. nigriceps
      larvae fail to develop within the bodies of fruit-feeding caterpillars but do
      develop in caterpillars feeding on LA-treated fruit. Thus, H. subflexa larvae not
      only overcome a serious dietary deficiency but also reduce their vulnerability to
      natural enemies through a form of "biochemical crypsis."

PMID- 15184665
TI  - Carbon monoxide-induced suspended animation protects against hypoxic damage in
      Caenorhabditis elegans.
AB  - Oxygen deprivation is a major cause of cellular damage and death. Here we
      demonstrate that Caenorhabditis elegans embryos, which can survive both in anoxia
      (<0.001 kPa O(2)) by entering into suspended animation and in mild hypoxia (0.25
      1 kPa O(2)) through a hypoxia-inducible factor 1-mediated response, cannot
      survive in intermediate concentrations of oxygen, between 0.01 and 0.1 kPa O(2).
      Moreover, we show that carbon monoxide can protect C. elegans embryos against
      hypoxic damage in this sensitive range. Carbon monoxide can also rescue the
      hypoxia-sensitive mutant hif-1(ia04) from lethality in hypoxia. This work defines
      the oxygen tensions over which hypoxic damage occurs in C. elegans embryos and
      demonstrates that carbon monoxide can prevent this damage by inducing suspended
      animation.

PMID- 15184666
TI  - Genetic control of branching in foxtail millet.
AB  - Reduction in vegetative branching is commonplace when crops are domesticated from
      their wild progenitors. We have identified genetic loci responsible for these
      changes in foxtail millet (Setaria italica), a crop closely related to maize but
      whose genetics are little known. Quantitative trait locus (QTL) analysis and
      comparative genomics reveal that basal branching (tillering) and axillary
      branching are partially controlled by separate loci, and that the orthologue of
      teosinte branched1, the major gene controlling branching phenotype in maize, has
      only a minor and variable effect. We identify other candidate genes for control
      of branching, including a number of hormone biosynthesis pathway genes. These
      results suggest that similar phenotypic effects may not be produced by
      orthologous loci, even in closely related species, and that results from well
      characterized model systems such as maize must be reviewed critically before
      being applied to other species.

PMID- 15184667
TI  - Phosphoprotein inhibitor CPI-17 specificity depends on allosteric regulation of
      protein phosphatase-1 by regulatory subunits.
AB  - Inhibition of myosin phosphatase is critical for agonist-induced contractility of
      vascular smooth muscle. The protein CPI-17 is a phosphorylation-dependent
      inhibitor of myosin phosphatase and, in response to agonists, Thr-38 is
      phosphorylated by protein kinase C, producing a >1,000-fold increase in
      inhibitory potency. Here, we addressed how CPI-17 could selectively inhibit
      myosin phosphatase among other protein phosphatase-1 (PP1) holoenzymes. PP1 in
      cell lysates was separated by sequential affinity chromatography into at least
      two fractions, one bound specifically to thiophospho-CPI-17, and another bound
      specifically to inhibitor-2. The MYPT1 regulatory subunit of myosin phosphatase
      was concentrated only in the fraction bound to thiophospho-CPI-17. This binding
      was eliminated by addition of excess microcystin-LR to the lysate, showing that
      binding at the active site of PP1 is required. Phospho-CPI-17 failed to inhibit
      glycogen-bound PP1 from skeletal muscle, composed primarily of PP1 with the
      striated muscle glycogen-targeting subunit (G(M)) regulatory subunit. Phospho-CPI
      17 was dephosphorylated during assay of glycogen-bound PP1, not MYPT1-associated
      PP1, even though these two holoenzymes have the same PP1 catalytic subunit.
      Phosphorylation of CPI-17 in rabbit arteries was enhanced by calyculin A but not
      okadaic acid or fostriecin, consistent with PP1-mediated dephosphorylation. We
      propose that CPI-17 binds at the PP1 active site where it is dephosphorylated,
      but association of MYPT1 with PP1C allosterically retards this hydrolysis,
      resulting in formation of a complex of MYPT1.PP1C.P-CPI-17, leading to an
      increase in smooth muscle contraction.

PMID- 15184669
TI  - Using conservation of pattern to estimate spatial parameters from a single
      snapshot.
AB  - Rapid reaction in the face of an epidemic is a key element in effective and
      efficient control; this is especially important when the disease has severe
      public health or economic consequences. Determining an appropriate level of
      response requires rapid estimation of the rate of spread of infection from
      limited disease distribution data. Generally, the techniques used to estimate
      such spatial parameters require detailed spatial data at multiple time points;
      such data are often time-consuming and expensive to collect. Here we present an
      alternative approach that is computationally efficient and only requires spatial
      data from a single time point, hence saving valuable time at the start of the
      epidemic. By assuming that fundamental spatial statistics are near equilibrium,
      parameters can be estimated by minimizing the expected rate of change of these
      statistics, hence conserving the general spatial pattern. Although applicable to
      both ecological and epidemiological data, here we focus on disease data from
      computer simulations and real epidemics to show that this method produces
      reliable results that could be used in practical situations.

PMID- 15184668
TI  - Development of insulin resistance and obesity in mice overexpressing cellular
      glutathione peroxidase.
AB  - Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative
      stress. However, the role of reactive oxygen species or specific antioxidant
      enzymes in its development has not been tested under physiological conditions.
      The objective of our study was to investigate the impact of overexpression of
      glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces
      hydrogen peroxide (H(2)O(2)) in vivo, on glucose metabolism and insulin function.
      The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium
      adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE
      mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia
      (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of
      age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37%
      vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge,
      the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT
      mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05)
      in the insulin-stimulated phosphorylations of insulin receptor (beta-subunit) in
      liver and Akt (Ser(473) and Thr(308)) in liver and soleus muscle. Here we report
      the development of insulin resistance in mammals with elevated expression of an
      antioxidant enzyme and suggest that increased GPX1 activity may interfere with
      insulin function by overquenching intracellular reactive oxygen species required
      for insulin sensitizing.

PMID- 15184670
TI  - Functional organization of sensory input to the olfactory bulb glomerulus
      analyzed by two-photon calcium imaging.
AB  - Glomeruli in the olfactory bulb are anatomically discrete modules receiving input
      from idiotypic olfactory sensory neurons. To examine the functional organization
      of sensory inputs to individual glomeruli, we loaded olfactory sensory neurons
      with a Ca(2+) indicator and measured odorant-evoked presynaptic Ca(2+) signals
      within single glomeruli by using two-photon microscopy in anaesthetized mice.
      Odorants evoked patterns of discrete Ca(2+) signals throughout the neuropil of a
      glomerulus. Across glomeruli, Ca(2+) signals occurred with equal probability in
      all glomerular regions. Within single glomeruli, the pattern of intraglomerular
      Ca(2+) signals was indistinguishable for stimuli of different duration, identity,
      and concentration. Moreover, the response time course of the signals was similar
      throughout the glomerulus. Hence, sensory inputs to individual glomeruli are
      spatially heterogeneous but seem to be functionally indiscriminate. These results
      support the view of olfactory glomeruli as functional units in representing
      sensory information.

PMID- 15184671
TI  - RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a
      mechanism for diabetes-associated erectile dysfunction.
AB  - Significant impairment in endothelial-derived nitric oxide is present in the
      diabetic corpus cavernosum. RhoA/Rho-kinase may suppress endothelial nitric oxide
      synthase (eNOS). Here, we tested the hypothesis that RhoA/Rho-kinase contributes
      to diabetes-related erectile dysfunction and down-regulation of eNOS in the
      streptozotocin (STZ)-diabetic rat penis. Colocalization of Rho-kinase and eNOS
      protein was present in the endothelium of the corpus cavernosum. RhoA/Rho-kinase
      protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZ
      diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive
      NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess
      the functional role of RhoA/Rho-kinase in the penis, we evaluated the effects of
      an adeno-associated virus encoding the dominant-negative RhoA mutant
      (AAVTCMV19NRhoA) on RhoA/Rho-kinase and eNOS and erectile function in vivo in the
      STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a
      reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal
      eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels
      found in the control rats. There was a significant decrease in erectile response
      to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene
      transfer improved erectile responses in the STZ-diabetic rat to values similar to
      control. These data demonstrate a previously undescribed mechanism for the down
      regulation of penile eNOS in diabetes mediated by activation of the RhoA/Rho
      kinase pathway. Importantly, these data imply that inhibition of RhoA/Rho-kinase
      improves eNOS protein content and activity thus restoring erectile function in
      diabetes.

PMID- 15184672
TI  - Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation.
AB  - Nitric oxide (NO) possesses antiinflammatory effects, which may be exerted via
      its ability to inhibit the transcription factor, NF-kappaB. A commonly proposed
      mode of action for inhibition of NF-kappaBbyNO involves interference with NF
      kappaB binding to DNA. Because activation of inhibitory kappaB kinase (IKK), the
      prerequisite enzyme complex necessary to induce NF-kappaB, is subject to redox
      regulation, we assessed whether IKK could present a more proximal target for NO
      to inhibit NF-kappaB activation. We demonstrate here that S-nitrosothiols (SNO)
      caused a dose-dependent inhibition of the enzymatic activity of IKK, in lung
      epithelial cells and in Jurkat T cells, which was associated with S-nitrosylation
      of the IKK complex. Using biotin derivatization of SNO, we revealed that IKKbeta,
      the catalytic subunit required for NF-kappaB activation, was a direct target for
      S-nitrosylation. A mutant version of IKKbeta containing a Cys-179-to-Ala mutation
      was refractory to inhibition by SNO or to increases in S-nitrosylation, in
      contrast to wild-type IKKbeta, demonstrating that Cys-179 is the main target for
      attack by SNO. Importantly, inhibition of NO synthase activity in Jurkat T cells
      resulted in activation of IKK, in association with its denitrosylation. Moreover,
      NO synthase inhibition enhanced the ability of tumor necrosis factor alpha to
      activate IKK, illustrating the importance of endogenous NO in regulating the
      extent of NF-kappaB activation by cytokines. Collectively, our findings
      demonstrate that IKKbeta is an important target for the redox regulation of NF
      kappaB by endogenous or exogenous NO, providing an additional mechanism for its
      antiinflammatory properties.

PMID- 15184674
TI  - Genome sequence of Picrophilus torridus and its implications for life around pH
      0.
AB  - The euryarchaea Picrophilus torridus and Picrophilus oshimae are able to grow
      around pH 0 at up to 65 degrees C, thus they represent the most thermoacidophilic
      organisms known. Several features that may contribute to the thermoacidophilic
      survival strategy of P. torridus were deduced from analysis of its 1.55-megabase
      genome. P. torridus has the smallest genome among nonparasitic aerobic
      microorganisms growing on organic substrates and simultaneously the highest
      coding density among thermoacidophiles. An exceptionally high ratio of secondary
      over ATP-consuming primary transport systems demonstrates that the high proton
      concentration in the surrounding medium is extensively used for transport
      processes. Certain genes that may be particularly supportive for the extreme
      lifestyle of P. torridus appear to have been internalized into the genome of the
      Picrophilus lineage by horizontal gene transfer from crenarchaea and bacteria.
      Finally, it is noteworthy that the thermoacidophiles from phylogenetically
      distant branches of the Archaea apparently share an unexpectedly large pool of
      genes.

PMID- 15184673
TI  - AtNAP7 is a plastidic SufC-like ATP-binding cassette/ATPase essential for
      Arabidopsis embryogenesis.
AB  - In bacteria, yeast, and mammals, iron-sulfur (Fe-S) cluster-containing proteins
      are involved in numerous processes including electron transfer, metabolic
      reactions, sensing, signaling, and regulation of gene expression. In humans, iron
      storage diseases such as X-linked sideroblastic anemia and ataxia are caused by
      defects in Fe-S cluster availability. The biogenesis of Fe-S clusters involves
      several pathways, and in bacteria, the SufABCDSE operon has been shown to play a
      vital role in Fe-S biogenesis and repair during oxidative stress. Although Fe-S
      proteins play vital roles in plants, Fe-S cluster biogenesis and maintenance and
      physiological consequences of dysfunctional Fe-S cluster assembly remains
      obscure. Here we report that Arabidopsis plants deficient for the SufC homolog
      AtNAP7 show lethality at the globular stage of embryogenesis. AtNAP7 is expressed
      in developing embryos and in apical, root, and floral meristems and encodes an
      ATP-binding cassette/ATPase that can partially rescue growth defects in an
      Escherichia coli SufC mutant during oxidative stress. AtNAP7 is plastid
      localized, and mutant embryos contain abnormal developing plastids with
      disorganized thylakoid structures. We found that AtNAP7 can interact with AtNAP6,
      a plastidic Arabidopsis SufD homolog, and because Arabidopsis plastids also
      harbor SufA, SufB, SufS, and SufE homologs, plastids probably contain a complete
      SUF system. Our results imply that AtNAP7 represents a conserved SufC protein
      involved in the biogenesis and/or repair of oxidatively damaged Fe-S clusters and
      suggest an important role for plastidic Fe-S cluster maintenance and repair
      during Arabidopsis embryogenesis.

PMID- 15184675
TI  - Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen
      related receptor alpha (ERRalpha) ligand.
AB  - Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha
      (PGC-1alpha) is a transcriptional coactivator that is a key component in the
      regulation of energy production and utilization in metabolic tissues. Recent work
      has identified PGC-1alpha as a strong coactivator of the orphan nuclear receptor
      estrogen-related receptor alpha (ERRalpha), implicating ERRalpha as a potential
      mediator of PGC-1alpha action. To understand the role of ERRalpha in PGC-1alpha
      signaling, a parallel approach of high-throughput screening and gene-expression
      analysis was used to identify ERRalpha small-molecule regulators and target
      genes. We report here the identification of a potent and selective ERRalpha
      inverse agonist that interferes effectively with PGC-1alpha/ERRalpha-dependent
      signaling. This inverse agonist inhibits the constitutive activity of ERRalpha in
      both biochemical and cell-based assays. Also, we demonstrate that monoamine
      oxidase B is an ERRalpha target gene whose expression is regulated by PGC-1alpha
      and ERRalpha and inhibited by the ERRalpha inverse agonist. The discovery of
      potent and selective ERRalpha modulators and their effect on PGC-1alpha signaling
      provides mechanistic insight into gene regulation by PGC-1alpha. These findings
      validate ERRalpha as a promising therapeutic target in the treatment of metabolic
      disorders, including diabetes and obesity.

PMID- 15184676
TI  - Preferential states in soil moisture and climate dynamics.
AB  - Summer precipitation in continental midlatitude regions is significantly
      contributed by local recycling, i.e., by moisture returning to the atmosphere
      through evapotranspiration from the same region. On the other hand, reduced soil
      moisture availability may limit evapotranspiration rates with effects on the
      planetary boundary layer dynamics through the partitioning between sensible and
      latent heat fluxes. Thus, a dependence may exist between precipitation and
      antecedent soil moisture conditions. Here we provide theoretical and experimental
      evidence in support of the hypothesis that in continental regions summer soil
      moisture anomalies affect the probability of occurrence of subsequent
      precipitation. Owing to these feedbacks, two preferential states may arise in
      summer soil moisture dynamics, which thus tend to remain locked either in a "dry"
      or a "wet" state, whereas intermediate conditions have low probability of
      occurrence. In this manner, such land-atmosphere interactions would explain the
      possible persistence of summer droughts sustained by positive feedbacks in
      response to initial (spring) surface moisture anomalies.

PMID- 15184677
TI  - Large-scale meta-analysis of cancer microarray data identifies common
      transcriptional profiles of neoplastic transformation and progression.
AB  - Many studies have used DNA microarrays to identify the gene expression signatures
      of human cancer, yet the critical features of these often unmanageably large
      signatures remain elusive. To address this, we developed a statistical method,
      comparative metaprofiling, which identifies and assesses the intersection of
      multiple gene expression signatures from a diverse collection of microarray data
      sets. We collected and analyzed 40 published cancer microarray data sets,
      comprising 38 million gene expression measurements from >3,700 cancer samples.
      From this, we characterized a common transcriptional profile that is universally
      activated in most cancer types relative to the normal tissues from which they
      arose, likely reflecting essential transcriptional features of neoplastic
      transformation. In addition, we characterized a transcriptional profile that is
      commonly activated in various types of undifferentiated cancer, suggesting common
      molecular mechanisms by which cancer cells progress and avoid differentiation.
      Finally, we validated these transcriptional profiles on independent data sets.

PMID- 15184678
TI  - Critical roles of interferon regulatory factor 4 in CD11bhighCD8alpha- dendritic
      cell development.
AB  - IFN regulatory factors (IRFs) are a family of transcription factors that play an
      essential role in the homeostasis and function of immune systems. Recent studies
      indicated that IRF-8 is critical for the development of CD11b(low)CD8alpha(+)
      conventional dendritic cells (DCs) and plasmacytoid DCs. Here we show that IRF-4
      is important for CD11b(high)CD8alpha(-) conventional DCs. The development of
      CD11b(high) DCs from bone marrow of IRF-4(-/-) mice was severely impaired in two
      culture systems supplemented with either GM-CSF or Flt3-ligand. In the IRF-4(-/-)
      spleen, the number of CD4(+)CD8alpha(-) DCs, a major subset of CD11b(high) DCs,
      was severely reduced. IRF-4 and IRF-8 were expressed in the majority of
      CD11b(high)CD4(+)CD8alpha(-) DCs and CD11b(low)CD8alpha(+) DCs, respectively, in
      a mutually exclusive manner. These results imply that IRF-4 and IRF-8 selectively
      play critical roles in the development of the DC subsets that express them.

PMID- 15184679
TI  - Chemoattractant-induced phosphatidylinositol 3,4,5-trisphosphate accumulation is
      spatially amplified and adapts, independent of the actin cytoskeleton.
AB  - Experiments in amoebae and neutrophils have shown that local accumulations of
      phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P(3)] mediate the ability of
      cells to migrate during gradient sensing. To define the nature of this response,
      we subjected Dictyostelium discoideum cells to measurable temporal and spatial
      chemotactic inputs and analyzed the accumulation of PI(3,4,5)P(3) on the
      membrane, as well as the recruitment of the enzymes phosphoinositide 3-kinase and
      PTEN. In latrunculin-treated cells, spatial gradients elicited a PI(3,4,5)P(3)
      response only on the front portion of the cell where the response increased more
      steeply than the gradient and did not depend on its absolute concentration.
      Phosphoinositide 3-kinase bound to the membrane only at the front, although it
      was less sharply localized than PI(3,4,5)P(3). Membrane-bound PTEN was highest at
      the rear and varied inversely with receptor occupancy. The localization of
      PI(3,4,5)P(3) was enhanced further in untreated polarized cells containing an
      intact cytoskeleton. Interestingly, the treated cells could respond to two
      independent gradients simultaneously, demonstrating that a response at the front
      does not necessarily inhibit the back. Combinations of temporal and spatial
      stimuli provided evidence of an inhibitory process and showed that a gradient
      generates a persistent steady-state response independent of a previous history of
      exposure to chemoattractant. These results support a local excitation/global
      inhibition model and argue against other schemes proposed to explain directional
      sensing.

PMID- 15184681
TI  - Genetic diversity enhances the resistance of a seagrass ecosystem to disturbance.
AB  - Motivated by recent global reductions in biodiversity, empirical and theoretical
      research suggests that more species-rich systems exhibit enhanced productivity,
      nutrient cycling, or resistance to disturbance or invasion relative to systems
      with fewer species. In contrast, few data are available to assess the potential
      ecosystem-level importance of genetic diversity within species known to play a
      major functional role. Using a manipulative field experiment, we show that
      increasing genotypic diversity in a habitat-forming species (the seagrass Zostera
      marina) enhances community resistance to disturbance by grazing geese. The time
      required for recovery to near predisturbance densities also decreases with
      increasing eelgrass genotypic diversity. However, there is no effect of diversity
      on resilience, measured as the rate of shoot recovery after the disturbance,
      suggesting that more rapid recovery in diverse plots is due solely to differences
      in disturbance resistance. Genotypic diversity did not affect ecosystem processes
      in the absence of disturbance. Thus, our results suggest that genetic diversity,
      like species diversity, may be most important for enhancing the consistency and
      reliability of ecosystems by providing biological insurance against environmental
      change.

PMID- 15184680
TI  - Activation of NF-kappaB and inhibition of p53-mediated apoptosis by API2/mucosa
      associated lymphoid tissue 1 fusions promote oncogenesis.
AB  - Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common extranodal
      lymphoid cell neoplasia; it frequently follows chronic bacteria-induced
      inflammation in various tissues. MALT lymphomas are characterized genetically by
      the t(11;18)(q21;q21) translocation, which yields chimeric transcripts encoding
      structurally distinct API2/MALT1 fusion proteins. In this study, we provide
      functional evidence for the contribution of API2/MALT1 fusion proteins to
      transformation of cells in culture by activating the NF-kappaB pathway through a
      RelB/p50 dimer. Using microchip gene expression analysis, we demonstrate that
      different forms of the API2/MALT1 proteins activate both unique and overlapping
      gene programs in cells. In addition to this genome reprogramming, expression of
      distinct API2/MALT1 fusion products inhibits DNA damage-induced, p53-mediated
      apoptosis in an NF-kappaB-dependent manner. Collectively, these data reveal
      previously unknown functional diversity among API2/MALT1 fusion products and
      their function in NF-kappaB signaling as it connects to the apoptotic program, a
      pathway with strong relevance to cancer. Furthermore, they provide evidence
      underlying the emerging role of the NF-kappaB signaling pathway in the inhibition
      of apoptosis.

PMID- 15184682
TI  - Prediction of protein folding rates from the amino acid sequence-predicted
      secondary structure.
AB  - We present a method for predicting folding rates of proteins from their amino
      acid sequences only, or rather, from their chain lengths and their helicity
      predicted from their sequences. The method achieves 82% correlation with
      experiment over all 64 "two-state" and "multistate" proteins (including two
      artificial peptides) studied up to now.

PMID- 15184683
TI  - Crystal structures of the DsbG disulfide isomerase reveal an unstable disulfide.
AB  - Dsb proteins control the formation and rearrangement of disulfide bonds during
      the folding of secreted and membrane proteins in bacteria. DsbG, a member of this
      family, has disulfide bond isomerase and chaperone activity. Here, we present two
      crystal structures of DsbG at 1.7and 2.0-A resolution that are meant to represent
      the reduced and oxidized forms, respectively. The oxidized structure, however,
      reveals a mixture of both redox forms, suggesting that oxidized DsbG is less
      stable than the reduced form. This trait would contribute to DsbG isomerase
      activity, which requires that the active-site Cys residues are kept reduced,
      regardless of the highly oxidative environment of the periplasm. We propose that
      a Thr residue that is conserved in the cis-Pro loop of DsbG and DsbC but not
      found in other Dsb proteins could play a role in this process. Also, the
      structure of DsbG reveals an unanticipated and surprising feature that may help
      define its specific role in oxidative protein folding. Thus, the dimensions and
      surface features of DsbG show a very large and charged binding surface that is
      consistent with interaction with globular protein substrates having charged
      surfaces. This finding suggests that, rather than catalyzing disulfide
      rearrangement in unfolded substrates, DsbG may preferentially act later in the
      folding process to catalyze disulfide rearrangement in folded or partially folded
      proteins.

PMID- 15184684
TI  - Chemical genetics to identify NFAT inhibitors: potential of targeting calcium
      mobilization in immunosuppression.
AB  - The development of more selective immunosuppressive agents to mitigate transplant
      rejection and autoimmune diseases requires effective strategies of blocking
      signaling pathways in T cells. Current immunosuppressive strategies use
      cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and
      promotes the nuclear import of nuclear factor of activated T cells (NFAT)
      transcription factors. These nuclear NFATs then transactivate cytokine genes that
      regulate proliferative responses of T cells. Both CsA and FK506 have debilitating
      side effects, including nephrotoxicity, hypertension, diabetes, and seizures,
      that argue for the development of alternative or complementary agents. To this
      end, we developed cell-based assays for monitoring NFAT dynamics in nonlymphoid
      cells to identify small molecules that inhibit NFAT nuclear import.
      Interestingly, we found that the majority of these small molecules suppress NFAT
      signaling by interfering with "capacitative" or "store-operated" calcium
      mobilization, thus raising the possibility that such mobilization processes are
      relevant targets in immunosuppression therapy. Further, these small molecules
      also show dose-dependent suppression of cytokine gene expression in T cells.
      Significantly, the IC(50) of CsA in primary T cells was reduced by the addition
      of suboptimal concentrations of these compounds, suggesting the possibility that
      such small molecules, in combination with CsA, offer safer means of
      immunosuppression.

PMID- 15184685
TI  - Phylogenetic expression of Galalpha1-4Gal on avian glycoproteins: glycan
      differentiation inscribed in the early history of modern birds.
AB  - Glycoproteins containing Galalpha1-4Gal (galabiose) had been rarely found in
      vertebrates, except in a few species of birds and amphibians. We had previously
      reported that pigeon (Columba livia) egg white and serum glycoproteins are rich
      in N-glycans with Galalpha1-4Gal at nonreducing termini. To investigate the
      origin of Galalpha1-4Gal expression in avian evolution, we examined the presence
      of Galalpha1-4Gal glycoproteins in egg whites from 20 orders, 88 families, 163
      genera, and 181 species of birds, as probed by Western blot with Griffonia
      simplicifolia-I lectin (terminal alpha-Gal/GalNAc-specific) and anti-P(1) mAb
      (Galalpha1-4Galbeta1-4GlcNAcbeta1-specific). One of the significant observations
      is the total absence of Galalpha1-4Gal glycoproteins in Struthioniformes (four
      species), Tinamiformes (three species), Craciformes (two species), Galliformes
      (14 species), and Anseriformes (10 species), which are phylogenetically separated
      from other orders at earlier stage of modern bird diversification (100-65 million
      years ago). The presence or absence of Galalpha1-4Gal glycoproteins in other
      avian orders varied by the species (104 species positive, and 44 species
      negative), even though some of them belong to the same order or family. Our
      results revealed that the expression of Galalpha1-4Gal glycoproteins is not rare
      among avians, and is correlated with the phylogeny. The expression was most
      likely differentiated at earlier stage of diversification in modern birds, but
      some birds might have lost the facility for the expression relatively recently.

PMID- 15184686
TI  - The relationship between blood pressure and cognitive performance in the Third
      National Health and Nutrition Examination Survey (NHANES III).
AB  - OBJECTIVE: The present study examined the relationship between blood pressure and
      cognitive performance in 2727 healthy men and women between the ages of 20 and 59
      years who participated in the Third National Health and Nutrition Examination
      Survey (NHANES III). METHODS: Participants were selected from a subsample of 5662
      NHANES III respondents who completed an initial home interview, a medical
      examination, and a series of computerized cognitive tests of visuomotor reaction
      time, complex psychomotor speed (ie, symbol digit substitution), and verbal
      learning/attention (ie, serial digit learning). RESULTS: Hierarchical regressions
      tested the contribution of resting blood pressure to the prediction of
      performance on each of the cognitive tests. Results indicated that, after
      controlling for demographic variables (age, sex, race/ethnicity, education) and
      resting blood pressure, the interaction of systolic blood pressure by age was a
      significant predictor of performance on the test of verbal learning/attention.
      Follow-up analyses revealed that higher systolic blood pressure was associated
      with poorer performance in those younger than 40 years. CONCLUSIONS: Expanding on
      findings from previous epidemiological studies, the present study reports a small
      but significant relationship between resting blood pressure and cognitive
      performance that is particularly evident in younger healthy adults.

PMID- 15184687
TI  - Relationships between hostility, anger expression, and blood pressure dipping in
      an ethnically diverse sample.
AB  - OBJECTIVE: The purpose of this study was to examine relationships between
      hostility, anger expression, and blood pressure (BP) dipping. METHODS: A 24-hour
      ambulatory BP was obtained from 34 African Americans and 52 white Americans who
      were enrolled in a study of sleep, stress, and BP. Self-report measures were used
      to assess anger expression and hostility. RESULTS: After controlling for body
      mass index and BP status, African Americans were more likely to be classified as
      nondippers than white Americans. However, when hostility and anger expression
      were included in the model, there was no longer a significant relationship
      between ethnicity and BP dipping. Irrespective of race, high levels of hostility
      and anger were associated with less nocturnal dipping. CONCLUSIONS: These
      findings suggest that psychological factors may be important in understanding
      ethnic differences in nocturnal BP decline.

PMID- 15184689
TI  - Depression and the metabolic syndrome in young adults: findings from the Third
      National Health and Nutrition Examination Survey.
AB  - OBJECTIVE: Previous reports have suggested that depression may lead to the
      development of cardiovascular disease through its association with the metabolic
      syndrome; however, little is known about the relationship between depression and
      the metabolic syndrome. The aim of this study was to establish an association
      between depression and the metabolic syndrome in a nationally representative
      sample. METHODS: The Third National Health and Nutrition Examination Survey is a
      population-based health survey of noninstitutionalized US citizens completed
      between 1988 and 1994. Three thousand one hundred eighty-six men and 3003 women,
      age 17 to 39, free of coronary heart disease and diabetes, completed the
      depression module from the Diagnostic Interview Schedule and a medical
      examination that provided clinical data needed to establish the presence of the
      metabolic syndrome, as defined by the Third Report of the National Cholesterol
      Education Program Expert Panel on Detection, Evaluation, and Treatment of High
      Cholesterol in Adults. RESULTS: Women with a history of a major depressive
      episode were twice as likely to have the metabolic syndrome compared with those
      with no history of depression. The relationship between depression and metabolic
      syndrome remained after controlling for age, race, education, smoking, physical
      inactivity, carbohydrate consumption, and alcohol use. Men with a history of
      depression were not significantly more likely to have the metabolic syndrome.
      CONCLUSIONS: The prevalence of the metabolic syndrome is elevated among women
      with a history of depression. It is important to better understand the role
      depression may play in the effort to reduce the prevalence of the metabolic
      syndrome and its health consequences.

PMID- 15184688
TI  - Depression as a risk factor for coronary artery disease: evidence, mechanisms,
      and treatment.
AB  - OBJECTIVE: The present paper reviews the evidence that depression is a risk
      factor for the development and progression of coronary artery disease (CAD).
      METHODS: MEDLINE searches and reviews of bibliographies were used to identify
      relevant articles. Articles were clustered by theme: depression as a risk factor,
      biobehavioral mechanisms, and treatment outcome studies. RESULTS: Depression
      confers a relative risk between 1.5 and 2.0 for the onset of CAD in healthy
      individuals, whereas depression in patients with existing CAD confers a relative
      risk between 1.5 and 2.5 for cardiac morbidity and mortality. A number of
      plausible biobehavioral mechanisms linking depression and CAD have been
      identified, including treatment adherence, lifestyle factors, traditional risk
      factors, alterations in autonomic nervous system (ANS) and hypothalamic pituitary
      adrenal (HPA) axis functioning, platelet activation, and inflammation.
      CONCLUSION: There is substantial evidence for a relationship between depression
      and adverse clinical outcomes. However, despite the availability of effective
      therapies for depression, there is a paucity of data to support the efficacy of
      these interventions to improve clinical outcomes for depressed CAD patients.
      Randomized clinical trials are needed to further evaluate the value of treating
      depression in CAD patients to improve survival and reduce morbidity.

PMID- 15184690
TI  - Effort-reward imbalance, overcommitment, and measures of cortisol and blood
      pressure over the working day.
AB  - OBJECTIVE: To assess the biological correlates of effort-reward imbalance and
      overcommitment to work using measurements over the working day. METHODS:
      Participants were 197 working men and women aged 45 to 59 years, recruited from
      the Whitehall II epidemiological cohort. Salivary cortisol was sampled on waking,
      30 minutes later, and then at 2-hour intervals from 8:00 hours to 22:00 hours.
      Blood pressure was measured every 20 minutes using ambulatory methods. Effort
      reward imbalance and overcommitment to work were assessed with standard
      questionnaires. RESULTS: Cortisol responses to waking were positively associated
      with overcommitment in men, with mean increases between waking and 30 minutes of
      14.5 and 4.2 nmol/l in high and low overcommitment groups, after adjustment for
      age, socioeconomic position, smoking, time of waking up, and job demands.
      Cortisol averaged from 8 samples over the working day was also related to
      overcommitment in men, with an average difference of 22% between high and lower
      overcommitment groups. Overcommitment predicted systolic blood pressure over the
      day in men after adjustment for age, smoking, body mass index, physical activity,
      and job control, with adjusted means of 132.2 and 125.8 mm Hg in high and low
      overcommitment groups. There was a significant interaction between
      overcommitment, socioeconomic position, and time of day in men (p =.016), because
      systolic pressure was higher in lower status overcommitted men, and rose over the
      day. Neither effort-reward imbalance nor overcommitment predicted biological
      responses in women. CONCLUSIONS: Chronic neuroendocrine and cardiovascular
      activation may mediate in part the impact of overcommitment to work on
      cardiovascular disease risk in men.

PMID- 15184691
TI  - Temporal relations between unexplained fatigue and depression: longitudinal data
      from an international study in primary care.
AB  - OBJECTIVE: Unexplained fatigue syndromes, such as chronic fatigue syndrome and
      neurasthenia, are strongly associated with depression, but the temporal nature of
      this association is not clear. METHODS: The authors examined this issue by using
      data from the World Health Organization collaborative study of psychological
      problems in general health care. Three thousand two hundred one subjects from 15
      primary care centers in 14 countries were followed up for 12 months. The
      Composite International Diagnostic Interview was the main instrument used. Odds
      ratios and their 95% confidence intervals (CI) were calculated using logistic
      regression models adjusted for sociodemographic variables, physical morbidity and
      intercenter variability. RESULTS: Cases of depression were found to have an
      increased risk of developing a new episode of unexplained fatigue at follow-up
      with an adjusted odds ratio of 4.15 (95% CI = 2.64-6.54). Similarly, cases of
      unexplained fatigue were found to have an increased risk of developing a new
      episode of depression at follow-up with an adjusted odds ratio of 2.76 (95% CI =
      1.32-5.78). Further adjustment for subthreshold symptoms at baseline weakened the
      reported associations, especially between fatigue and development of a new
      episode of depression, but these remained significant. CONCLUSIONS: The findings
      support the view that unexplained fatigue and depression might act as independent
      risk factors for each other.

PMID- 15184692
TI  - Naturally occurring changes in physical activity are inversely related to
      depressive symptoms during early adolescence.
AB  - OBJECTIVE: We examined the relationship between naturally occurring changes in
      physical activity and depressive symptoms across a 2-year period among adolescent
      boys and girls. METHODS: Participants (N = 4594) reported their frequency of
      physical activity outside of school and completed the Center for Epidemiological
      Studies Depression scale in the Fall of 1998 (beginning of 7th grade; baseline
      data), Spring of 1999 (end of 7th grade; interim data), and Spring of 2000 (end
      of 8th grade; follow-up data). RESULTS: Latent growth modeling indicated that a 1
      SD unit change in the frequency of leisure-time physical activity was inversely
      related to a.25 SD unit change in depressive symptoms. This relationship was
      attenuated but remained statistically significant when simultaneously controlling
      for the confounding variables of sex, socioeconomic status, smoking, alcohol
      consumption, and the value participants placed on their health, appearance, and
      achievement. CONCLUSIONS: Naturally occurring changes in physical activity were
      negatively related with changes in depressive symptoms. The results encourage
      randomized controlled trials to experimentally determine whether an increase in
      physical activity reduces depression risk among adolescent boys and girls.

PMID- 15184693
TI  - Immigrant suicide rates as a function of ethnophaulisms: hate speech predicts
      death.
AB  - OBJECTIVE: The purpose of this study was to determine whether suicide rates among
      ethnic immigrant groups were predicted by the ethnophaulisms, or the hate speech,
      used to refer to those ethnic immigrant groups. METHODS: Data were obtained for
      10 European ethnic immigrant groups during the 1950s. These 10 European ethnic
      immigrant groups accounted for approximately 40% of all immigration into the
      United States during this time period. Both the suicide rates for these ethnic
      immigrant groups in the United States and suicide rates for those ethnic
      immigrant groups in their countries of origin were derived. The complexity and
      valence of ethnophaulisms used to refer to these ethnic immigrant groups were
      derived from the historical record of hate speech in the United States. RESULTS:
      Consistent with previous research, immigrant suicide rates were strongly
      correlated with origin suicide rates. As expected, the suicide rates for ethnic
      immigrant groups in the United States were significantly predicted by the
      negativity of the ethnophaulisms used to refer to those ethnic immigrant groups.
      This pattern was obtained even after taking into account the suicide rates for
      those ethnic immigrant groups in their countries of origin, and even after taking
      into account the size of those ethnic immigrant groups. CONCLUSIONS: This study
      found support for the expectation that suicide rates among ethnic immigrant
      groups would be predicted by the hate speech directed toward those ethnic
      immigrant groups.

PMID- 15184694
TI  - The relationship of asthma and anxiety disorders.
AB  - OBJECTIVE: This article reviewed the child and adult medical literature on the
      prevalence of comorbid anxiety disorders in patients with asthma. Theoretical
      ideas regarding the relatively high comorbidity rates are presented along with a
      model describing putative interactions between anxiety disorders and asthma.
      METHOD: A search of the literature from the last 2 decades using MEDLINE by
      pairing the word, "asthma," with the following words: "anxiety," "depression,"
      "panic," and "psychological disorders." We located additional research by
      screening the bibliographies of articles retrieved in the MEDLINE search.
      RESULTS: Both adult and child/adolescent populations with asthma appear to have a
      high prevalence of anxiety disorders. In child/adolescent populations with
      asthma, up to one third may meet criteria for comorbid anxiety disorders. In
      adult populations with asthma, the estimated rate of panic disorder ranges from
      6.5% to 24%. However, most studies are limited by small samples,
      nonrepresentative populations, self-reported asthma status, and lack of
      controlling for important potential confounders such as smoking and asthma
      medications. There are also limited data on the impact of anxiety comorbidity in
      patients with asthma on symptom burden, self-care regimens (such as monitoring
      peak expiratory flow, taking medication, and quitting smoking), functional
      status, and medical costs. CONCLUSIONS: There appears to be a high comorbidity of
      anxiety disorders in patients with asthma. The prevalence and longitudinal impact
      of anxiety comorbidity needs to be examined in a large population-based sample of
      children, adolescents, and adults with asthma. If a high prevalence of comorbid
      anxiety disorder is documented and if this comorbidity adversely affects the self
      efficacy and self-care, symptom burden, and functioning in persons with asthma,
      then it will be important to develop treatment trials.

PMID- 15184695
TI  - Androgens and mood dysfunction in women: comparison of women with polycystic
      ovarian syndrome to healthy controls.
AB  - OBJECTIVE: Our understanding of the organizational and activational effects of
      human gonadal hormones on behavior has depended on the study of endocrine
      disorders. Polycystic ovarian syndrome (PCOS) is a hormonal disorder that begins
      in puberty and is characterized by chronically augmented free testosterone (FT)
      levels. The purposes of this study were 1) to compare negative mood states of
      women with PCOS to those of women with normal hormonal levels and 2) to examine
      the relationship between negative moods and androgens. METHODS: Twenty-seven
      women with PCOS were case-matched to 27 normal menstruating women on body mass
      index since being overweight is a common symptom of PCOS and could affect mood
      states. Serum levels of FT, total testosterone, sex hormone binding globulin,
      estradiol, and progesterone were determined. Self-reported depression, anger,
      anxiety, and aggression were analyzed between groups, and individual scores were
      compared across groups to hormone values. RESULTS: Depression was significantly
      increased in the PCOS group and remained so after considering the variance
      related to physical symptomatology and other mood states. Furthermore, a
      curvilinear relationship between FT and negative affect across groups was
      suggested: the most elevated negative mood-scale scores were associated with FT
      values just beyond the upper limits of normal, while lower negative mood levels
      corresponded to both normal and extremely high values of FT. CONCLUSIONS: These
      results are consistent with a model of activational influences of testosterone on
      adult female behavior. Implications are discussed for future research and for
      treatment of PCOS and other menstrual-cycle mood disorders.

PMID- 15184696
TI  - Negative thoughts and health: associations among rumination, immunity, and health
      care utilization in a young and elderly sample.
AB  - OBJECTIVE: In the present study, it was tested whether rumination-negative,
      recurrent thoughts-would be associated with immune parameters and health care
      utilization. Because rumination has been associated with sadness and subjective
      sleep quality, it was tested whether these factors mediated the possible effects
      of rumination. A young sample and an elderly sample were included to test for age
      differences in the association between rumination and health-related measures.
      METHODS: A representative sample of 196 young subjects (20 to 35 years) and 314
      elderly subjects (70 to 85 years) completed questionnaire measures of rumination,
      sadness, and subjective sleep quality. Immune measures included leukocyte counts,
      lymphocyte subsets, natural killer cell activity, and T-cell proliferation.
      Contacts with primary care physicians were registered for 1 year through central
      registers. RESULTS: Rumination displayed a positive association with total
      leukocyte count, total lymphocyte count, and number of B cells among the elderly,
      and this was not mediated by sadness or subjective sleep quality. Rumination was
      also positively associated with number of telephone consultations during the
      follow-up for the elderly, and this was partly mediated by sadness and subjective
      sleep quality. Although total leukocyte counts correlated with number of
      telephone consultations at the follow-up, none of the immune parameters mediated
      the association between rumination and health care utilization. No significant
      associations were found for the young participants. CONCLUSION: The results
      suggest that rumination may be associated with health-related measures in the
      elderly. Thus, negative thoughts may be detrimental to health, independently of
      negative affect.

PMID- 15184698
TI  - Idler and Kasl's p values: a cautionary lesson.
AB  - Idler and Kasl's study of elderly New Haven residents indicated that some
      Christians and Jews postponed their deaths until after the celebration of
      religious holidays. However, the correct p values are larger than they report and
      make their conclusions less convincing, especially for Jews.

PMID- 15184700
TI  - Asian-American deaths near the Harvest Moon Festival.
AB  - OBJECTIVE: Reexamine the claim that elderly Chinese-American women are able to
      prolong their lives until after the celebration of the Harvest Moon Festival.
      METHODS: See if independent 1985 to 2000 data for Chinese-, Korean-, and
      Vietnamese-Americans replicate results that were reported using 1960 to 1984 data
      for Chinese-Americans. RESULTS: The original 1960 to 1984 data do not support the
      death-postponement theory unless deaths that occur on the festival day are
      classified as having occurred after the festival. The new data do not support the
      theory, no matter how deaths on the festival day are classified. CONCLUSIONS:
      These data do not support the hypothesis that elderly Chinese-, Korean-, or
      Vietnamese-American women are able to prolong their lives until after the
      celebration of the Harvest Moon Festival.

PMID- 15184701
TI  - Death takes a raincheck.
AB  - OBJECTIVE: To review the research literature on temporal variation in mortality
      rates around symbolically important occasions. METHODS: Qualitative literature
      review. RESULTS: Since the early 1970s, at least 18 studies have investigated
      whether death rates increase or decrease before, during, or after symbolically
      important occasions such as holidays and birthdays. Some studies but not others
      have found modest evidence of temporal effects. Methodological issues have raised
      questions about most of the positive findings. None of the studies provides any
      direct evidence that a psychophysiological mechanism enables people to postpone
      or hasten their own death. CONCLUSION: Research over the past 3 decades has
      failed to provide convincing evidence that psychological phenomena such as
      "giving up" or "holding on" can influence the timing of death.

PMID- 15184702
TI  - Mental disorders in obese children and adolescents.
AB  - OBJECTIVE: To evaluate the type and frequency of psychiatric disorders in obese
      children and adolescents; to assess the correlation between psychopathology and
      severity of obesity; to explore the relationship between psychiatric disorders in
      obese children and obesity and psychopathology in their parents. METHODS: One
      hundred fifty-five children referred and followed for obesity were evaluated (98
      girls and 57 boys; age, 5 to 17 years). Psychiatric disorders were assessed
      through a standardized diagnostic interview schedule (K-SADS R) and self-report
      questionnaires completed by the child (STAIC Trait-anxiety and CDI for
      depression) or his (her) parents (CBCL or GHQ). These obese children were
      compared with insulin-dependent diabetic (IDDM) outpatient children (N = 171) on
      questionnaire data. RESULTS: Eighty-eight obese children obtained a DSM-IV
      diagnosis, most often an anxiety disorder (N = 63). Psychological disorders were
      particularly pronounced in those obese children whose parents were disturbed.
      There was no correlation between severity of obesity in the child or his (her)
      parents and frequency of psychiatric disorders. Compared with diabetic children,
      they displayed significantly higher internalized and externalized questionnaire
      scores and poorer social skills. CONCLUSION: These results highlight the
      importance of including a child psychiatric component in the treatment of
      obesity, which must engage the whole family.

PMID- 15184703
TI  - Psychiatric comorbidity and work disability in patients with inflammatory
      rheumatic diseases.
AB  - OBJECTIVE: To determine the relative contribution of psychiatric comorbidity to
      work disability in patients with inflammatory rheumatic diseases (IRD). Parallel
      analyses were also performed in a matched control group with no diagnosis of IRD
      to investigate if predictors of work disability in medical patients are
      independent from the presence of IRD. METHOD: The patient group with IRD (73.9%
      female; mean age, 42.7 years) and the control group (73.9% female; mean age, 42.2
      years) consisted of 356 outpatients each. Psychiatric comorbidity was diagnosed
      using the Patient Health Questionnaire (PHQ), functional disability was measured
      with the 12-item Short-Form Health Survey (SF-12), and severity of illness was
      assessed by the treating physicians. Stepwise logistic regression analyses were
      performed to identify independent predictors of work disability controlling for
      psychiatric comorbidity, functional disability, severity of illness, additional
      clinical variables, and demographics. RESULTS: Psychiatric comorbidity increased
      work disability in patients with severe IRD from 25% to 50%, and from 5% to 17%
      in mild disease. Physical functioning (OR = 0.6; p <.0001), depression severity
      (OR = 1.6; p =.005), and illness severity (OR = 1.8; p =.006) were identified as
      independent predictors of work disability in patients with IRD. Similar
      predictors of work disability were identified in the control group, but
      depression severity did not meet statistical significance at the 5% level.
      CONCLUSIONS: This study provides evidence that depression is an independent risk
      factor of work disability in patients with IRD, but this result cannot be
      generalized to other medical conditions. Improved diagnosis and treatment of
      depressive disorders in patients with IRD may help avoid work disability.

PMID- 15184704
TI  - Historical sexual abuse and current thyroid axis profiles in women with
      premenstrual dysphoric disorder.
AB  - OBJECTIVE: This study investigated whether women with premenstrual dysphoric
      disorder (PMDD) who also had histories of sexual abuse differed from women with
      PMDD with no previous sexual abuse and from women without PMDD in hypothalamic
      pituitary-thyroid (axis measures). METHODS: Ten sexually abused women with PMDD
      were compared with 18 nonabused women with PMDD and 22 nonabused women without
      PMDD for hypothalamic-pituitary-thyroid axis hormone concentrations during the
      follicular and luteal phases of confirmed ovulatory cycles. RESULTS: Compared
      with the women without PMDD, only the group of women with PMDD with sexual abuse
      showed greater variance in both cycle phases in thyroid-stimulating hormone
      concentrations and greater luteal phase variance in free and total thyroxine (T4)
      and reverse tri-iodothyronine (T3). In the group of nonabused women with PMDD,
      there was greater variance in follicular phase thyroxine-binding globulin
      concentrations compared with the group without PMDD. Women with PMDD with abuse
      had greater mean concentrations of total T3 and thyroxine-binding globulin,
      greater total T3/free T4 and free T3/free T4 ratios, and lower ratios of free
      T3/total T3 and free T4/total T4 than either of the other 2 nonabused groups.
      Greater total T3 concentrations and histories of major depression independently
      predicted premenstrual symptoms in all women with PMDD, together accounting for
      31% to 38% of the variance in anxiety, anger, and depression ratings.
      CONCLUSIONS: These results suggest increased conversion of T4 to T3 and increased
      binding of thyroid hormones in women with PMDD with previous sexual abuse.
      Abnormal total T3 concentrations may have pathophysiological significance in
      PMDD.

PMID- 15184705
TI  - What you see may not be what you get: a brief, nontechnical introduction to
      overfitting in regression-type models.
AB  - OBJECTIVE: Statistical models, such as linear or logistic regression or survival
      analysis, are frequently used as a means to answer scientific questions in
      psychosomatic research. Many who use these techniques, however, apparently fail
      to appreciate fully the problem of overfitting, ie, capitalizing on the
      idiosyncrasies of the sample at hand. Overfitted models will fail to replicate in
      future samples, thus creating considerable uncertainty about the scientific merit
      of the finding. The present article is a nontechnical discussion of the concept
      of overfitting and is intended to be accessible to readers with varying levels of
      statistical expertise. The notion of overfitting is presented in terms of asking
      too much from the available data. Given a certain number of observations in a
      data set, there is an upper limit to the complexity of the model that can be
      derived with any acceptable degree of uncertainty. Complexity arises as a
      function of the number of degrees of freedom expended (the number of predictors
      including complex terms such as interactions and nonlinear terms) against the
      same data set during any stage of the data analysis. Theoretical and empirical
      evidence--with a special focus on the results of computer simulation studies--is
      presented to demonstrate the practical consequences of overfitting with respect
      to scientific inference. Three common practices--automated variable selection,
      pretesting of candidate predictors, and dichotomization of continuous variables-
      are shown to pose a considerable risk for spurious findings in models. The
      dilemma between overfitting and exploring candidate confounders is also
      discussed. Alternative means of guarding against overfitting are discussed,
      including variable aggregation and the fixing of coefficients a priori.
      Techniques that account and correct for complexity, including shrinkage and
      penalization, also are introduced.

PMID- 15184706
TI  - Patients with carcinoid syndrome exhibit symptoms of aggressive impulse
      dysregulation.
AB  - OBJECTIVE: Carcinoid tumors can produce excessive amounts of biogenic amines,
      notably serotonin. We assessed psychiatric symptoms in carcinoid patients and
      peripheral metabolism of tryptophan, the precursor of serotonin. METHODS: Twenty
      consecutive patients with carcinoid syndrome underwent a structured psychiatric
      interview applying DSM-IV (Diagnostical Statistical Manual) criteria. Tumor
      activity was measured by determination of 24-hour urine excretion of 5
      hydroxyindoleacetic acid (5-HIAA) and platelet serotonin levels. Plasma
      tryptophan levels were measured and compared with sex- and age-matched
      references. RESULTS: Fifteen patients (75%) fulfilled diagnostic DSM-IV criteria
      for a disorder of impulse control. Tryptophan plasma levels were lower in
      patients compared with controls (p =.031) and were correlated negatively with
      urinary 5-HIAA excretion (p =.001). CONCLUSIONS: Impulse control disorders are
      prevalent in patients with carcinoid syndrome. The serotonin production by the
      tumor possibly decreases the tryptophan pool in the cerebrospinal fluid, which is
      the essential substrate for the production of brain serotonin as a pivotal
      neurotransmitter.

PMID- 15184707
TI  - The effect of life stress on symptoms of heartburn.
AB  - OBJECTIVE: Psychosocial stressors have been associated with exacerbations of
      symptoms in functional and inflammatory disorders of the gastrointestinal tract.
      The present longitudinal study tests the general hypothesis that life stressors
      can exacerbate symptoms in patients with chronic heartburn. METHODS: Sixty
      subjects with current heartburn symptoms were recruited by community
      advertisement and assessed for presence of stressful life events retrospectively
      over the preceding 6 months and prospectively for 4 months. Symptom severity by
      daily diary, quality of life, and psychological symptoms of anxiety, depression,
      and vital exhaustion were also measured. RESULTS: The presence of a severe,
      sustained life stress during the previous 6 months significantly predicted
      increased heartburn symptoms during the following 4 months. In addition, symptoms
      showed a strong, independent correlation with vital exhaustion. Affective and
      subjective stress ratings were not strongly related to heartburn severity;
      however, anxiety showed the strongest relationship to impaired quality of life
      and depression to heartburn medication use. CONCLUSIONS: As with other chronic
      conditions such as irritable bowel syndrome (IBS), heartburn severity appears to
      be most responsive to major life events and not an accumulation of more minor
      stressors or fluctuations in mood. In addition, vital exhaustion, which may in
      part result from sustained stress, may represent the psychophysiological symptom
      complex most closely associated with heartburn exacerbation. Potential mechanisms
      for these results include increased level and frequency of esophageal acid
      exposure, inhibition of gastric emptying of acid, or stress-induced
      hypersensitivity.

PMID- 15184708
TI  - Depression and abdominal pain in IBS patients: the mediating role of
      catastrophizing.
AB  - OBJECTIVE: Depression has been linked to irritable bowel syndrome (IBS), but the
      mechanism underlying this relationship is unknown. This cross-sectional study
      explores the possibility that negatively skewed beliefs patients hold regarding
      abdominal pain (ie, catastrophizing) mediate the relationship between depression
      and pain severity. METHODS: The sample included 244 consecutively evaluated
      individuals who met Rome II diagnosis for IBS without comorbid gastrointestinal
      disease and completed measures of pain severity, trait anxiety, catastrophizing,
      maladaptive beliefs, and depression as part of baseline assessment of an National
      Institutes of Health-funded randomized controlled trial of 2 nondrug treatments.
      RESULTS: Using a mediational model involving a series of linear regressions,
      results indicated that pain catastrophizing partially mediated the link between
      depression and abdominal pain severity. Depression, catastrophizing, and control
      variables accounted for 21% of the variance in pain severity. The finding that
      patients with IBS with greater depression reported greater pain severity can be
      partially explained by their tendency to engage in more catastrophic thinking
      specific to pain. CONCLUSIONS: The relation between depression and pain is not,
      as psychogenic models predict, strictly a direct and linear one but works partly
      through patients' beliefs regarding their pain in general and pain
      catastrophizing in specific. Implications of the findings for understanding and
      investigating the depression-IBS link from a biopsychosocial perspective are
      discussed.

PMID- 15184709
TI  - Posttraumatic growth after breast cancer: patient, partner, and couple
      perspectives.
AB  - OBJECTIVE: The purpose of this study was to evaluate posttraumatic growth among
      breast cancer patients and their significant others over a 1(1/2)-year time span
      after diagnosis and to examine cognitive and emotional processes in posttraumatic
      growth. METHODS: One hundred sixty-two women with breast cancer and their
      partners completed surveys assessing posttraumatic growth, cognitive and
      emotional processing, and marital satisfaction at 3 time points spaced 9 months
      apart. RESULTS: Posttraumatic growth increased for both partners during this
      period. Patient posttraumatic growth was predicted by younger age, contemplating
      reasons for cancer, and more emotional expression at time 1. Partner
      posttraumatic growth was predicted by younger age, more intrusive thoughts, and
      greater use of positive reappraisal and emotional processing at time 1.
      CONCLUSION: Posttraumatic growth is reported by patients and by significant
      others. Cognitive and emotional processes predict growth. Patient growth is
      associated with the significant other's cognitive and emotional processing of
      breast cancer.

PMID- 15184710
TI  - Suicidal ideation in primary care: ask a vague question, get a confusing answer.

PMID- 15184711
TI  - Resistance and replication capacity assays: clinical utility and interpretation.
AB  - Resistance testing has emerged as an important tool for antiretroviral
      management. Research continues to refine phenotypic susceptibility cut-offs and
      genotypic interpretation schemes that relate resistance mutations with
      antiretroviral drug effectiveness. Highly sensitive phenotypic assays have
      allowed for the recognition of drug hypersusceptibility in HIV, and other studies
      have related hypersusceptibility to resistance mutations; efforts are ongoing to
      use what is known about hypersusceptibility to optimize the benefits of
      antiretroviral therapy. Resistance-associated mutations in several viral genes
      result in viruses that exhibit reduced replication capacity; assays to measure
      replication capacity are being developed that may, in the future, be useful in
      guiding therapy to improve treatment outcomes. This article summarizes a
      presentation given by Richard H. Haubrich, MD, at the International AIDS Society
      USA Sacramento course in November 2003.

PMID- 15184712
TI  - Sexually transmitted diseases in the HIV care setting: what's really going on
      down there?
AB  - Syphilis epidemics are occurring in a number of cities in the United States and
      worldwide. In New York City, the number of cases primary or secondary syphilis
      has increased from 130 in 1999 to 434 in 2002. The majority of new cases occur in
      men, with most of these occurring in men who have sex with men. The presentations
      of primary and secondary syphilis are varied and can be overlooked or confused
      with other diseases. Health care providers should be aware of atypical
      presentations of sexually transmitted diseases (STDs), screen for nonapparent
      STDs, and know how to treat such diseases once they are identified. Client
      centered counseling may be successful in reducing risky behaviors and the
      transmission of STDs. This article summarizes a presentation given by Jeanne
      Marrazzo, MD, MPH, at the October 2003 International AIDS Society-USA course in
      New York.

PMID- 15184713
TI  - Reproduction decision making for couples affected by HIV: a review of the
      literature.
AB  - Medical issues faced by HIV-affected couples include transmission risks between
      partners and between mother and child, as well as the technologies and procedures
      available to reduce those risks. Assisted reproductive techniques discussed are
      artificial insemination, in vitro fertilization, intracytoplasmic sperm
      injection, self-insemination, and timed intercourse. It is important that
      physicians be aware of reproductive options available to couples affected by HIV
      and be prepared to engage in nonjudgmental dialogue with patients. This review is
      the result of a literature search performed to identify useful information to
      counsel HIV-serodiscordant and HIV-seroconcordant couples facing decisions on
      reproduction.

PMID- 15184714
TI  - Continued needs for epidemiological studies of mental disorders in the community.

PMID- 15184715
TI  - Drug-induced depression: a systematic review to inform clinical practice.
AB  - BACKGROUND: Certain medications may contribute to the etiology of depressive
      symptoms and disorders. Research in this area, however, has been hampered by
      methodological and conceptual problems. This review had two objectives: to
      identify evidence linking medical drugs to depressive symptoms and disorders, and
      to summarize this evidence in a clinically meaningful way. METHODS: Electronic
      literature searches were performed and studies were reviewed with reference to
      critical methodological features. RESULTS: No medications causing the typical
      major depressive syndrome were identified. Evidence was found linking
      corticosteroids, interferon-alpha, interleukin-2, gonadotropin-releasing hormone
      agonists, mefloquine, progestin-releasing implanted contraceptives and
      propranolol to the etiology of atypical depressive syndromes. CONCLUSIONS: A
      small number of drugs have been shown capable of inducing depressive symptoms.
      Drug-induced depression appears to differ symptomatically from classical major
      depression.

PMID- 15184716
TI  - The Sesto Fiorentino study: background, methods and preliminary results. Lifetime
      prevalence of psychiatric disorders in an Italian community sample using clinical
      interviewers.
AB  - BACKGROUND: This paper presents lifetime prevalences and estimated risks of DSM
      IV psychiatric disorders from a community survey conducted in Sesto Fiorentino,
      Italy, using psychiatric interviewers with clinical experience and clinical
      instruments. METHODS: Two thousand five hundred subjects aged 14 or more were
      randomly selected from the lists of 15 general practitioners (GPs) regardless of
      whether or not they had consulted the GP. A three-phase design was adopted, with
      the GPs using the Mini International Neuropsychiatric Interview (MINI) for the
      first stage. All positive cases at the MINI and a probability sample of 123
      negative cases were re-interviewed by psychiatrists or trained residents in
      psychiatry using the Florence Psychiatric Interview (FPI) at the second stage.
      During phase III, the subjects were administered the rating scales specific to
      the pathology detected by the FPI. RESULTS: Two thousand three hundred and sixty
      three subjects were interviewed (response rate 94.5%) by their own GP; 623 were
      found positive for any psychiatric disorder. The psychiatrists could re-interview
      605 of these, along with a random sample of 123 negatives. Almost twenty-five
      percent (24.4%; 15.7% males, 31.7% females) of the population was found positive
      for any DSM-IV disorder during their lives. The most common diagnosis was major
      depressive episode, followed by anxiety not otherwise specified. Women had higher
      rates for most disorders. CONCLUSIONS: The prevalence rates for most of the
      disorders considered are generally comparable with the range identified by
      previous studies conducted in other Western countries, even though they were
      using different methodologies. Exceptions are represented by the high prevalence
      of residual categories and the lower prevalence of phobias.

PMID- 15184717
TI  - The Sesto Fiorentino study: point and one-year prevalences of psychiatric
      disorders in an Italian community sample using clinical interviewers.
AB  - BACKGROUND: It has been argued that lay interviewers' use of fully-structured
      interviews could lead to a diagnostic pattern different to that by treating
      physicians. Clinical interviewers in community samples should probably identify
      cases that are closer to those seen in clinical settings. The greatest advantage
      of using clinical interviewers consists of the immediate assessment of a possible
      psychopathology, i.e. the evaluation of current disorders. METHODS: Two thousand
      three hundred and sixty-three citizens from the community of Sesto Fiorentino,
      Italy, were interviewed by their own general practitioners using the Mini
      International Neuropsychiatric Interview (MINI). Positive cases for any lifetime
      psychiatric disorder as well as a random sample of the negative cases were re
      interviewed by psychiatrists or trained residents in psychiatry using the
      Florence Psychiatric Interview (FPI). RESULTS: The point prevalence for any
      current disorder was 8.7%; the two disorders with the highest prevalence were
      generalised anxiety disorder (2.9%) and major depressive episode (2.7%). The
      figures increase about 50% when the sub-threshold sequelae of previous disorders
      are considered. Current comorbidity was generally high. The one-year prevalence
      of any disorder was 10.6%. Ninety-two percent of the cases sought help, 82% were
      being treated at the moment of interview. Social impairment was considerable.
      CONCLUSIONS: The period prevalence rates for most of the disorders considered
      were generally comparable with the range defined by previous studies conducted in
      other Western countries, despite using different methodologies. Conversely, the
      use of health facilities, the treatment received and the social impairment were
      much higher than those reported by the other studies, suggesting a greater
      similarity with the clinical samples.

PMID- 15184718
TI  - Cancer and mental disorders in a national community sample: findings from the
      national comorbidity survey.
AB  - OBJECTIVE: To determine the association between cancer (past 12 months) and
      mental disorders (past 12 months) among community-dwelling adults. METHODS: Data
      were drawn from the National Comorbidity Survey (n = 5,877), a representative
      household sample of adults aged 15-54 years in the United States. Multiple
      logistic regression analyses were used to determine the association between
      cancer and mental disorders, adjusting for differences in sociodemographic
      characteristics. RESULTS: Cancer was significantly associated with increased
      rates of major depression [odds ratio (OR) = 3.6, 95% confidence interval (CI) =
      1.4-8.8], drug dependence (OR = 3.6, 95% CI = 1.3-9.8), simple phobia (OR = 2.5,
      95% CI = 1.0-6.2) and agoraphobia (OR = 3.3, 95% CI = 1.0-10.4). These
      associations persisted after adjusting for major sociodemographic factors, and
      sex plays a significant role in the association between cancer diagnosis and
      mental disorder, with cancer diagnosis having a stronger influence on major
      depression and drug dependence in men than in women. CONCLUSIONS: Clinicians and
      community health workers working with cancer survivors need to be not only alert
      for signs of clinical depression but also of co-occurring drug dependence and
      certain anxiety disorders so that appropriate referrals to mental health
      professionals can be made.

PMID- 15184719
TI  - Positive coping up- and down-regulates in vitro cytokine productions from T cells
      dependent on stress levels.
AB  - BACKGROUND: Specific coping styles have been shown to modulate stress-induced
      immune alterations and influence actual health outcomes. This study examined the
      effects of stressors and coping styles on human T-cell subpopulations and in
      vitro cytokine production using a cross-sectional design. METHODS: Seventy-one
      men (18-60 years old) were asked to complete a self-administered questionnaire
      that evaluates quantitative workload, mental demand and coping styles. The
      numbers of T-cell subpopulations and concentrations of interferon-gamma (IFN
      gamma) and interleukin-4 (IL-4) after stimulation with phytohemaglutinin were
      measured. RESULTS: Positive and negative coping were negatively related to IL-4
      and the number of CD4+ cells, respectively. Interactions between positive coping
      and mental demand significantly affected the number of CD8+ cells, IFN-gamma, IL
      4 and the IFN-gamma/IL-4 ratio. Among men reporting high mental demand, positive
      coping was related to increased IFN-gamma and IFN-gamma/IL-4. Among men reporting
      low mental demand, positive coping was related to a decreased number of CD8+
      cells and lower concentrations of IFN-gamma and IL-4. Analyses adjusting for the
      numbers of CD3+ and CD8+ cells revealed that the interactive effects of positive
      coping and mental demand on cytokine levels were attributable to the changes in T
      cell function rather than the number of T cells. No modulating effect of anxiety
      on the associations of stressors and coping with immune function was observed.
      Depressive symptoms slightly, though not significantly, modulated the association
      of negative coping and the number of CD4+ cells. CONCLUSIONS: From the
      perspective of immunology, optimal stress characteristics were determined by an
      individual's coping styles, with positive coping being associated with stress
      induced changes in the number of CD8+ cells and in vitro cytokine production from
      T cells. Our findings suggest that it is important to consider the interactive
      effects of the complexity of work and the individual coping style in stress
      management.

PMID- 15184720
TI  - Suitability of bupropion SR for nicotine-dependent smokers: problems in a
      practice setting.
AB  - BACKGROUND: Bupropion SR (Zyban) has been shown in randomized controlled trials
      to be an efficacious pharmacological aid for smoking cessation; however, recent
      reports have raised serious concerns about the breadth of its applicability
      without complications or contraindications. METHODS: We examined this issue in a
      well-documented medical population, i.e. veterans volunteering to participate in
      a smoking cessation treatment research program involving the use of bupropion SR.
      RESULTS: Overall, 22% of the 78 subjects who met the study criteria were
      appropriate for and completed the course of medication. CONCLUSIONS: Thus,
      bupropion SR in nicotine-dependent veterans may not be broadly applicable when
      conservative prescribing guidelines are carefully followed.

PMID- 15184721
TI  - Reintroduction of antidepressant therapy across pregnancy in women who previously
      discontinued treatment. A preliminary retrospective study.
AB  - BACKGROUND: Pregnancy has frequently been described as a time of emotional well
      being conferring 'protection' against psychiatric disorders. However, data to
      support this impression are sparse. METHODS: A retrospective review was
      undertaken in order to examine rates of reintroduction of antidepressants across
      pregnancy among a cohort of 54 euthymic pregnant women who had discontinued these
      medications around the time of conception. Reintroduction of antidepressants was
      used as a marker suggesting relapse of depression. RESULTS: Forty-two percent (n
      = 23) of these women reintroduced antidepressant therapy during pregnancy, with
      nearly half of these (n = 11) doing so in the first trimester. A greater time
      spent in episodes since depressive onset and a prior history of suicide attempts
      was associated with antidepressant reintroduction. CONCLUSIONS: Nearly half of
      the women who discontinued antidepressants during pregnancy to avoid fetal
      exposure appeared to experience symptoms severe enough to prompt reintroduction
      of treatment with these medications. The implications of these findings are
      discussed with respect to treatment planning for women who are maintained on
      antidepressants and who plan to conceive.

PMID- 15184722
TI  - SSRI and suicide.

PMID- 15184724
TI  - SSRI and suicide?

PMID- 15184726
TI  - Effect of bisoprolol on right ventricular function and brain natriuretic peptide
      in patients with heart failure.
AB  - Beta-blocker use improves left ventricular ejection fraction (LVEF) in patients
      with heart failure. A similar effect of b blockers on right ventricular function
      has been proposed, although the effect of bisoprolol, a highly selective b-1
      blocker, on right ventricular function has not been assessed. This study
      investigated the short-term effect of bisoprolol on right ventricular function in
      chronic heart failure patients. A cohort of 30 heart failure patients who were
      not taking b blockers at baseline was studied prospectively. Right ventricular
      ejection fraction (RVEF) and LVEF were measured at both baseline and 4 months by
      radionuclide angiography. Bisoprolol was up-titrated during four monthly visits
      by a preestablished protocol to a target dose of 10 mg/d. The dose of
      vasodilators was not changed. Quality of life and brain natriuretic peptide level
      were assessed. Mean age was 62.7+/-14.3 years. Baseline RVEF was 30.7%+/-6.3% and
      baseline LVEF was 21.7%+/-9.4%. Mean bisoprolol dose reached was 5.3+/-3.9 mg
      daily. At 4 months, RVEF significantly increased by 7.1% (95% confidence
      interval, 3.9-10.2; p=0.0001) and LVEF also increased significantly by 7.9% (95%
      confidence interval, 4.0%-11.9%; p=0.0003). Quality-of-life score improved from
      42.8 to 30.8 (p=0.047). No correlation was found between brain natriuretic
      peptide levels and RVEF. Bisoprolol treatment for 4 months resulted in a
      significant improvement of RVEF, which paralleled the improvement of LVEF.

PMID- 15184727
TI  - Potential of the right ventricular endomyocardial biopsy to diagnose and assist
      in the management of congestive heart failure: insights from recent clinical
      trials.
AB  - In the United States congestive heart failure is most commonly due to ischemic
      cardiomyopathy, but nonischemic causes of cardiomyopathy can also result in
      congestive heart failure. Indeed, nonischemic dilated cardiomyopathy affects
      approximately 100,000 persons in the United States and is responsible for 45% of
      heart transplants. Although these patients undergo thorough cardiovascular
      evaluation, a specific cause is usually not found. Endomyocardial biopsy may
      yield diagnostic and prognostic information in this setting, and there has been a
      renewed interest in the use of endomyocardial biopsy in the evaluation of
      specific subsets of patients with congestive heart failure to identify
      potentially treatable myocarditides. However, the role of endomyocardial biopsy
      in the evaluation of patients with nonischemic cardiomyopathy is ill defined. In
      this review, the authors discuss the latest data on the risks and the utility of
      endomyocardial biopsy in the management of heart failure in the setting of
      dilated cardiomyopathy and specific myocarditides. Gaps in present knowledge and
      the obstacles to research in this area are identified.

PMID- 15184728
TI  - B-type natriuretic peptide: practical diagnostic use for evaluating ventricular
      dysfunction.
AB  - Assessment of brain natriuretic peptide levels may provide important information
      that can be used in the evaluation of patients with dyspnea and follow-up of
      heart failure. Brain natriuretic peptide levels have been shown to be useful for
      evaluating patients in the emergency department and for evaluating patients
      complaining of dyspnea in the outpatient setting. Brain natriuretic peptide
      assessment also provides an adjunct to diagnosis of both systolic and diastolic
      dysfunction, has prognostic value for heart failure and in acute coronary
      syndromes, and may be a useful measure to guide therapy. Further work needs to be
      done to establish the best type of assay to use, to determine the optimal cutoff
      point for what is considered abnormal, and to determine how conditions other than
      ventricular dysfunction affect brain natriuretic peptide levels.

PMID- 15184729
TI  - Advanced glycation end product cross-linking: pathophysiologic role and
      therapeutic target in cardiovascular disease.
AB  - Advanced glycation end products (AGEs) form by a nonenzymatic reaction between
      reducing sugars and biological proteins. These stable compounds accumulate slowly
      throughout the life span and contribute to structural and physiologic changes in
      the cardiovascular system such as increased vascular and myocardial stiffness,
      endothelial dysfunction, altered vascular injury responses, and atherosclerotic
      plaque formation. Mechanisms underlying these alterations include AGE cross
      linking of collagen and AGE interactions with circulating proteins and AGE
      receptors. The clinical manifestations of AGE accrual-isolated systolic
      hypertension, endothelial and diastolic dysfunction, and atherosclerosis
      underscore their role in increased cardiovascular risk associated with aging as
      well as diabetes and hypertension, conditions that enhance AGE formation. New
      pharmacologic agents that prevent AGE, break cross-links, or block AGE receptors
      reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque
      formation, and improve endothelial function. These agents promise to reduce the
      risk of isolated systolic hypertension, diastolic dysfunction, and diabetes, and
      thus, heart failure.

PMID- 15184730
TI  - Right ventricular function: a stepchild in the management of congestive heart
      failure.

PMID- 15184731
TI  - Nesiritide for the treatment of diastolic dysfunction.
AB  - Despite advances in the treatment of left ventricular diastolic dysfunction,
      therapy is still primarily empiric and readmission rates remain high, with up to
      half of patients discharged with the diagnosis of congestive heart failure being
      rehospitalized within 6 months due to recurrent decompensation. Even with this
      high economic burden, no effective, long-term therapies have been developed. The
      authors present a patient with recurrent hospitalizations for decompensated
      congestive heart failure due to left ventricular diastolic dysfunction becoming
      refractory to parenteral diuretic therapy. The patient exhibited a dramatic
      response to a 96-hour intravenous infusion of nesiritide and experienced
      prolonged clinical benefit, remaining in New York Heart Association functional
      class I for more than 6 months after the infusion.

PMID- 15184734
TI  - ACE inhibitor intolerance and lessons learned from the candesartan in heart
      failure: assessment of reduction in mortality and morbidity (CHARM) trials.
AB  - The Candesartan in Heart Failure: Assessment of Reduction in Mortality and
      Morbidity (CHARM) trials looked at the effects of candesartan in addition to best
      possible treatment for heart failure in 7601 patients. CHARM encompassed three
      studies in discrete populations, including patients with left ventricular
      dysfunction taking angiotensin-converting enzyme (ACE) inhibitors (CHARM-Added),
      patients with maintained left ventricular function (CHARM-Preserved), and
      patients with left ventricular dysfunction and an intolerance to ACE inhibitors
      (CHARM-Alternative). CHARM-Alternative was considered a success in that its
      participants experienced a significant reduction in each component of the study's
      primary end point, which was a composite of cardiovascular death or
      hospitalization for heart failure, over a median follow-up of 34 months.
      Candesartan was by and large well tolerated in these ACE-inhibitor intolerant
      patients; thus, the findings of this study provide additional support for the
      effectiveness of angiotensin receptor blocker therapy in heart failure patients
      poorly tolerant of an ACE inhibitor; however, candesartan was not convincingly
      shown to improve the incidence/severity of hypotension, hyperkalemia, and
      glomerular filtration rate reductions that were the basis for ACE inhibitor
      intolerance in approximately 25% of the study population.

PMID- 15184735
TI  - Seeking more than satisfaction.

PMID- 15184738
TI  - The push and pull of staff accountability.
AB  - Motivate staff nurses to be accountable, even for duties beyond their job
      description.

PMID- 15184739
TI  - Who's minding our profession? Assessing the quality of nursing performance, part
      2.
AB  - IT plays a role in measuring performance quality, which is critical to nursing
      both in terms of fulfilling its caring mission and as a way to document the
      profession's contribution to positive outcomes.

PMID- 15184740
TI  - The ABCs of staffing decisions.

PMID- 15184741
TI  - Get to the root of sentinel events involving infection control.
AB  - Learn when it's necessary to perform a root cause analysis on a sentinel event,
      and why.

PMID- 15184742
TI  - Is family presence practical during emergency resuscitation?
AB  - When family members ask to be present during the resuscitation of their loved
      ones, should health care providers grant their requests?

PMID- 15184745
TI  - The code to safer transfusions.
AB  - A university hospital shares its experience using bedside bar-coding technology.

PMID- 15184743
TI  - Sharps injury prevention: select a safer needle.
AB  - Explore the clinical benefits of passive safety needles, including reduced
      exposure risk, ease of use, and minimal training requirements.

PMID- 15184746
TI  - Proactive management breaks the fall cycle.
AB  - Meet the challenge of keeping fall-prone and wandering patients safe.

PMID- 15184747
TI  - Reducing VAP with 6 Sigma.
AB  - An Illinois medical center integrates a new solution to reducing ventilator
      associated pneumonia.

PMID- 15184748
TI  - Mine data to discover infection control trends.
AB  - Progressive infection surveillance improves patient and financial outcomes.

PMID- 15184750
TI  - Evaluate employees with ease.
AB  - Learn the most effective method of completing performance evaluations for your
      staff members.

PMID- 15184751
TI  - Expert to novice: a nurse leader's evolution.
AB  - When transitioning from expert nurse to novice nurse manager, mentorship,
      communication, and constructive feedback prove invaluable.

PMID- 15184756
TI  - Acute and chronic hepatitis: Working Group report of the second World Congress of
      Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184757
TI  - Advances in endoscopy and other diagnostic techniques: Working Group report of
      the second World Congress of Pediatric Gastroenterology, Hepatology, and
      Nutrition.

PMID- 15184758
TI  - Biotherapeutic and nutraceutical agents: Working Group report of the second World
      Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184759
TI  - Celiac disease and other immunologically mediated disorders of the
      gastrointestinal tract: Working Group report of the second World Congress of
      Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184760
TI  - Cholestatic and metabolic liver diseases: Working Group report of the second
      World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184761
TI  - Functional gastrointestinal disorders, gastroesophageal reflux and
      neurogastroenterology: Working Group report of the second World Congress of
      Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184762
TI  - Helicobacter pylori and peptic ulcer: Working Group Report of the second World
      Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184763
TI  - Hepatic failure and liver transplant: Working Group report of the second World
      Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184764
TI  - HIV Infection: Working Group Report of the Second World Congress of Pediatric
      Gastroenterology, Hepatology, and Nutrition.

PMID- 15184765
TI  - Inflammatory bowel disease: Working Group report of the second World Congress of
      Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184766
TI  - Intestinal failure and small bowel transplantation, including clinical nutrition:
      Working Group report of the second World Congress of Pediatric Gastroenterology,
      Hepatology, and Nutrition.

PMID- 15184768
TI  - Malnutrition: Working Group report of the second World Congress of Pediatric
      Gastroenterology, Hepatology, and Nutrition.

PMID- 15184767
TI  - Intestinal infections and environmental enteropathy: Working Group report of the
      second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184769
TI  - Obesity in children and adolescents: Working Group report of the second World
      Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184770
TI  - Pancreatic disorders and cystic fibrosis: Working Group report of the second
      World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184771
TI  - Pediatric surgery of the digestive tract: Working Group report of the second
      World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184772
TI  - Perinatal nutrition and gastrointestinal disorders: Working Group report of the
      second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184773
TI  - Persistent and chronic diarrhea and malabsorption: Working Group report of the
      second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

PMID- 15184774
TI  - Be careful out there.

PMID- 15184776
TI  - Preventing and managing surgical wound dehiscence.
AB  - Most surgical wounds heal uneventfully--the dehisced surgical incision is
      definitely the exception to the rule. However, management of a dehisced incision
      is a fairly common home care challenge that must be understood. This month's
      column answers the questions: Why do some incisions dehisce, and what, if
      anything, can be done to prevent dehiscence? Are there early warning signs to
      look for? How should a dehisced wound be managed?

PMID- 15184777
TI  - What is a probe review?

PMID- 15184778
TI  - M0150--current payment sources for home care: including the impact of recent
      OASIS suspension for private pay patients.

PMID- 15184779
TI  - Understanding the impact of the new medicare law on home health patients: part
      II.

PMID- 15184780
TI  - Does depression predict falls among home health patients? Using a clinical
      research partnership to improve the quality of geriatric care.
AB  - This study found that patients with depressed mood or anhedonia identified on the
      OASIS were nearly three times more likely to fall. The authors describe the ways
      these findings are being used in a fall prevention program. The clinical-research
      partnership used in the study was found to help agencies develop clinically
      driven research, analyze clinical and administrative data for quality
      improvement, and provide a foundation for research consultation/collaboration in
      applied settings.

PMID- 15184782
TI  - An ICD-9-CM coding primer: incorporating changes made from October 1, 2003.

PMID- 15184785
TI  - Home Health Compare: Web site offers critical information to consumers and
      professionals.
AB  - The Centers for Medicare & Medicaid Services (CMS), a federal agency of the U.S.
      Department of Health and Human Services, has released new data about the quality
      of care provided by Medicare-certified home health agencies as part of an
      expanding initiative to continue to improve the home care services that are
      provided to millions of Americans. The initiative combines information about the
      quality of care provided by individual home health agencies-for use by consumers,
      their families, and health care professionals-with important resources to assist
      home health agencies working to improve quality of care. This article provides an
      overview of that initiative, and discusses information available on the Home
      Health Compare Web site that case managers and discharge planners will find
      useful for helping patients and their families select a home health agency.

PMID- 15184786
TI  - Better safe than sorry: one agency's successful safety and security strategies.
AB  - The Home Healthcare and Protective Services Departments of Cincinnati Children's
      Hospital Medical Center (CCHMC) pooled their expertise to develop a comprehensive
      safety and security program for the visiting clinical staff. This article
      describes the program, various training sessions and modules, and the escort
      program provided by the Protective Services officers.

PMID- 15184787
TI  - Home health overpayment.

PMID- 15184788
TI  - Anticholinergics: not such a dry topic anymore.

PMID- 15184789
TI  - Knock before you enter.
AB  - Early on Christmas morning I am suddenly awakened by the high-pitched sound of my
      pager. It screeches like a smoke alarm, piercing right through to my bones.
      Although I have become accustomed to the sound, I still feel disoriented when
      roused from my sleep, and for a moment, feel entirely disoriented.

PMID- 15184790
TI  - Anger and the use of nonviolent communication.

PMID- 15184791
TI  - The CMS Medicare and Medicaid Services Manual System goes paperless.

PMID- 15184792
TI  - [Imaging of the digestive tract and the peritoneum: greatness and servitude].

PMID- 15184793
TI  - [Esophageal disease: is cross sectional imaging contributive?].
AB  - For a long time, esophagography and endoscopy were the major diagnostic tests
      used for evaluation of the esophagus. Now, the development of computed
      tomography, endosonography and MR imaging has permitted more comprehensive
      evaluation of esophageal diseases. Cross sectional imaging is essential to
      evaluate the relationship between esophageal lesions and adjacent mediastinal
      structures and to evaluate the thickness of the esophageal wall.

PMID- 15184794
TI  - [Esophageal disease: is cross sectional imaging contributive?].

PMID- 15184795
TI  - [Imaging of the stomach and the duodenum].
AB  - Imaging of the stomach and duodenum provides an abundant semiology, which allows
      precise diagnosis. In this chapter we will review specific considerations related
      to CT, MRI and US imaging of the stomach and duodenum. Normal imaging features as
      well as the main gastric and duodenal diseases will be described and illustrated.

PMID- 15184796
TI  - [Imaging of the stomach and the duodenum].

PMID- 15184797
TI  - [Cross sectional imaging evaluation of the small bowel].
AB  - Recent advances of cross sectional imaging allow optimal evaluation of the small
      bowel. This chapter will detail technical considerations and emphasize the role
      of imaging in the evaluation of the most common diseases of the small bowel.

PMID- 15184798
TI  - [Cross sectional imaging evaluation of the small bowel].

PMID- 15184799
TI  - [Imaging of intestinal ischemia].
AB  - Ischemic bowel disease includes acute and chronic mesenteric ischemia, and colon
      ischemia. Cross-sectional imaging, and more particularly computed tomography, has
      an increasing role in the detection of acute and chronic mesenteric ischemia.
      Vascular obstructions or stenoses and changes in the bowel wall can be observed.
      Functional information can be added with MRI by using sequences that are
      sensitive to oxygen saturation in the superior mesenteric vein. Arteriography
      remains the reference examination in patients with acute mesenteric ischemia.

PMID- 15184800
TI  - [Imaging of intestinal ischemia].

PMID- 15184801
TI  - [Value of CT in small-bowel obstruction].
AB  - Small bowel obstruction is a leading cause of admission in surgical and emergency
      units. During the last two decades, the classical philosophy of "never let the
      sun set or rise on small-bowel obstruction" has been succeeded by a new
      management based especially on the cause and the severity of the obstruction. It
      most often allows a correct choice between medical therapy and surgery using
      laparotomy or laparoscopy. This changing attitude is still in progress and is
      mainly related to the high accuracy of computed tomography. This review will
      discuss the semiology and value of computed tomography compared with clinical
      examination and other imaging modalities.

PMID- 15184802
TI  - [Value of CT in small-bowel obstruction].

PMID- 15184803
TI  - [Secondary diseases of the peritoneum].
AB  - Most inflammatory, infectious or tumoral diseases of the bowel and abdominal
      organs may secondarily involve the peritoneum which acts as a mirror of the
      diseases. Multidetector CT allows breathhold acquisitions through the abdomen and
      pelvis providing high spatial and contrast resolution imaging at all phases of
      contrast distribution as well as MPR and 3D capabilities.

PMID- 15184804
TI  - [Secondary diseases of the peritoneum].

PMID- 15184806
TI  - [Disorders of the peritoneum].

PMID- 15184805
TI  - [Disorders of the peritoneum].
AB  - The peritoneum is an important actor in diseases of the abdomen: defects of the
      peritoneum or mesos may lead to internal hernias; developmental anomalies of the
      peritoneum may lead to volvulus and bowel obstruction; diffuse or localized
      primary or secondary tumors of the peritoneum may develop; infectious,
      inflammatory or ischemic primary diseases of the peritoneum may cause abdominal
      pain, sepsis or result in the formation of fluid collections. The purpose of this
      presentation is to illustrate the role of imaging in the diagnosis of these
      different diseases and to provide some guidelines allowing their detection and
      characterization.

PMID- 15184807
TI  - Prevention and treatment of sunburn.

PMID- 15184808
TI  - Two new drugs for colon cancer.

PMID- 15184810
TI  - Subtypes of constipation: sorting out the confusion.
AB  - In patients with chronic constipation, identifying subtypes based on underlying
      physiology guides subsequent therapeutic choices. Chronic constipation subtypes
      include slow-transit constipation, pelvic floor dyssynergia, functional
      constipation, and irritable bowel syndrome with constipation. Chronic
      constipation subtypes are defined by the result of colonic transit, pelvic floor
      function, and the presence or absence of significant abdominal pain. Although a
      variety of tests are available, the most straightforward approach uses the 5-day
      colonic marker test of transit and anorectal manometry with balloon expulsion
      testing to evaluate for pelvic floor dysfunction. Patients with normal
      physiologic tests have either irritable bowel syndrome with constipation or
      normal-transit constipation. Significant overlap exists between subtypes and a
      clear distinction is not always possible, with up to a 50% overlap between
      patients with slow-transit constipation and irritable bowel syndrome,
      approximately 10% of patients evaluated exhibiting both slow transit and pelvic
      floor dyssynergia, and 50% of patients with pelvic floor dyssynergia also found
      to have slow transit. Symptom severity assessment provides the rationale for
      pursuing further testing and directing the aggressiveness of treatment as
      patients with greater symptom severity have reduced quality of life and poor
      physical functioning scores. Few constipation-specific validated measures exist
      for measuring symptom severity in chronic constipation. In clinical practice
      severity may be defined as mild symptoms having minimal impact upon daily
      activities or moderate to severe symptoms that increasingly interfere with daily
      life.

PMID- 15184811
TI  - Diagnosis of constipation in primary and secondary care.
AB  - The evaluation of chronic constipation involves a careful delineation of its
      duration and characteristics as well as a physical examination including
      neurologic, anorectal, and perineal assessment. In patients who fail to respond
      to fiber supplements or simple laxatives, diagnostic studies such as barium
      radiography, rectal biopsy, and colonic transit studies may be warranted. Studies
      of defecation and anorectal function may be useful in those who complain of
      excessive straining or who use digital manipulation to facilitate evacuation.
      Most patients, however, do not require diagnostic studies beyond a careful
      history and physical examination, and are easily managed in the primary care
      setting.

PMID- 15184812
TI  - Current treatment options for chronic constipation.
AB  - Various agents are used for the medical management of chronic constipation but
      few have been carefully studied. This review examines available data concerning
      several bulk and fiber products, lubricating agents, stimulants, and osmotic
      laxatives, alone and in combination. Popular therapeutic options for initial
      treatment of chronic constipation are dietary fiber and medicinal bulk.
      Subsequent treatments if fiber is not successful or tolerated would include
      saline osmotic laxatives, lactulose, or stimulants like senna or bisacodyl.
      Recent data demonstrate polyethylene glycol laxative to be safe and effective as
      an initial or second-line agent for chronic constipation. Indications and use of
      surgery and biofeedback are also discussed.

PMID- 15184814
TI  - Definitions, epidemiology, and impact of chronic constipation.
AB  - Constipation, however it is defined, is a common problem in the community. The
      exact prevalence of constipation depends on the definition used; prevalence
      estimates range from 2% to 28%. The prevalence of constipation has been stable
      because the onset and disappearance rates over time are similar, but accurate
      data on the incidence of constipation are lacking. Approximately one third of
      those individuals with constipation seek health care; this is an expensive
      fraction due to investigational and medication costs. The evidence that life
      style factors are causally linked to constipation is weak, although nonsteroidal
      anti-inflammatory drug use and the use of other constipation-inducing medications
      are important risk factors. Constipation is not of clinical importance until it
      causes physical risks or impairs quality of life. There is accumulating evidence
      that self-reported constipation and functional constipation as defined by the
      Rome Criteria lead to significant impairment of quality of life, with the
      implication that this is a serious condition in the majority of people afflicted.
      Constipation may have other serious consequences; an increased risk of colon
      cancer has been reported but could be explained by confounding. Although
      hemorrhoids have been attributed to constipation, this association has been
      questioned. The costs of testing in patients presenting with constipation has
      been conservatively estimated to be 6.9 billion dollars annually in the United
      States; treatment costs add substantially to the health care burden.

PMID- 15184815
TI  - Pathogenesis of slow transit and pelvic floor dysfunction: from bench to bedside.
AB  - The colon and anorectum function together to provide intraluminal mixing,
      absorption of water, electrolytes, and short chain fatty acids, dehydration of
      fecal material, storage, and ultimately, elimination in a socially appropriate
      manner. Normal function and continence require accommodation of the colon and
      rectum to the entry of fecal materials, which includes receptive relaxation,
      perception, and discrimination of rectal contents, and voluntary and reflex motor
      function of the anorectum. Defecation, on the other hand, requires the reflex
      relaxation of the internal anal sphincter, voluntary and reflexive relaxation of
      the external anal sphincters and pelvic floor structures, and adequate
      rectosigmoid tone to allow funneling of contents through the anal canal. The
      sensation of urgency with rectal filling, and the motivation and prior learning
      of the appropriate responses are also required. Continence and defecation,
      therefore, involve complex sensory, structural, and motor mechanisms that involve
      both the colon and pelvic floor. These mechanisms and their relative importance
      to the pathogenesis of slow-transit constipation and pelvic floor dysfunction
      will be reviewed.

PMID- 15184816
TI  - New and emerging treatment options for chronic constipation.
AB  - Chronic constipation remains a therapeutic challenge for today's physicians.
      Traditional approaches include use of fiber, osmotic laxatives, stimulant
      laxatives, prokinetic agents, biofeedback training, and surgery. These often are
      tried sequentially and episodically and have little evidence of long-term
      efficacy. Patients often report inadequate relief of symptoms. There is room for
      improvement, therefore, in the therapy of chronic constipation. Future advances
      largely will be based on insights into the enteric nervous system (ENS), the
      structure and function of which is being revealed in great detail. Manipulating
      the ENS pharmacologically offers the opportunity to reprogram this key control
      system to improve bowel function. For example, interneurons in the ENS display 5
      HT4 receptors, activation of which enhances the peristaltic reflex. Prokinetic
      agents that stimulate those receptors, such as tegaserod and prucalopride, have
      demonstrated efficacy as investigational agents for the treatment of chronic
      constipation in large studies. Less well studied investigational drugs with
      presumed activity in the ENS include opiate antagonists and the nerve growth
      factor neurotrophin-3. Both of these types of agents have been shown to be
      effective in small groups of patients with constipation. Another approach under
      development is to stimulate colonic fluid secretion by opening chloride channels
      in the epithelium pharmacologically. Existing non-pharmacological treatments that
      can be improved include biofeedback training for pelvic floor dysfunction and
      surgery. Future developments include investigation of electrical stimulation of
      the colon and use of stem cells to repopulate degenerated populations of neurons,
      interstitial cells of Cajal, or smooth muscle cells.

PMID- 15184818
TI  - Host factors affecting the outcome of treatment of hepatitis C.
AB  - The development of peginterferon and ribavirin combination therapy has
      significantly improved the sustained virologic response (SVR) rates in patients
      with chronic hepatitis C. However, poor patient adherence to therapy negatively
      influences drug levels and drug exposure, often preventing the development of an
      inhibitory drug level. To optimize patient adherence, the clinician must
      recognize factors predicting low adherence and negotiate a treatment plan that
      the patient understands and to which he or she commits. If adverse effects become
      intolerable, continuing patients on a reduced dose rather than withdrawing
      treatment seems to confer considerable advantage in preserving the chance for
      attaining an SVR. Results of a head-to-head comparison have demonstrated the
      possibility that, in cases of dose reduction, levels of peginterferon alfa-2a
      could remain above the limit of detection, whereas those of peginterferon alfa-2b
      might not.

PMID- 15184819
TI  - Viral factors affecting the outcome of therapy for chronic hepatitis C.
AB  - The advent of sensitive virologic assays to quantify hepatitis C virus (HCV) RNA
      and to differentiate specific genotypes of HCV has greatly expanded our
      understanding of the pathogenesis of chronic hepatitis C. These molecular
      virologic techniques are regularly employed to assist with management decisions
      regarding antiviral therapy. Genotype is the strongest predictor of a sustained
      virologic response (SVR). The dynamic change of HCV RNA during treatment, defined
      at week 12 as early virologic response (EVR), is useful for identifying
      individuals who are unlikely to have an SVR. Discontinuation of therapy can be
      considered for those patients with genotype 1 when an EVR is not achieved.
      However, limitations exist regarding interpretation of EVR and treatment
      decisions must be individualized, particularly when other endpoints of therapy,
      such as histological response or treatment of extrahepatic manifestations are
      being considered.

PMID- 15184821
TI  - Management of patients with chronic hepatitis C virus infection and previous
      nonresponse.
AB  - The treatment of patients with chronic hepatitis C virus infection has improved
      dramatically over the past several years. Despite this, more than half of all
      patients with genotype 1 fail to achieve a sustained virologic response (SVR)
      following therapy. The decision to retreat a nonresponder should balance two
      major factors: the likelihood that the patient will achieve an SVR during
      retreatment and the likelihood that the patient will develop progressive fibrosis
      and cirrhosis within the next 5 to 10 years (before more effective therapy is
      developed). Recent data have demonstrated that about 18% of all patients with
      previous nonresponse to standard interferon therapy (with or without ribavirin)
      will achieve an SVR when retreated with peginterferon and ribavirin. However, no
      therapy has been shown to be effective for patients with nonresponse to
      peginterferon and ribavirin. The approach to such patients is based on correcting
      the factors that led to this nonresponse. Maintenance peginterferon therapy is
      currently being explored but is likely to be of benefit in only a select group of
      nonresponders. The management of patients who have failed to achieve SVR is,
      therefore, one of the most complicated issues in the spectrum of treating chronic
      hepatitis C. This article reviews the factors to consider when assessing
      nonresponders for additional therapy and options for patients with continued
      nonresponse.

PMID- 15184820
TI  - Epidemiology and treatment outcomes of patients with chronic hepatitis C and
      genotypes 4 to 9.
AB  - Pivotal clinical trials of antiviral therapy for chronic hepatitis C have been
      conducted predominantly in Europe and the United States, where most patients are
      infected with genotypes 1, 2, or 3. As a result, published data on the outcomes
      of therapy in patients infected with genotypes 4, 5, and 6 to 9 are limited.
      However, a major proportion of patients with chronic hepatitis C worldwide reside
      in geographic areas where genotypes 4 (Africa and the Middle East), 5 (South
      Africa), or 6 to 9 (southern China and Southeast Asia) are prevalent or even the
      most common genotypes. The epidemiology of hepatitis C virus genotypes 4 to 9 is
      reviewed, and the studies reporting the results of antiviral therapy of these
      genotypes are summarized. The limited data on antiviral therapy in patients with
      genotypes 4 to 9 highlight the need for further and controlled treatment trials
      in these populations.

PMID- 15184822
TI  - Current status of the use of growth factors and other adjuvant medications in
      patients receiving peginterferon and ribavirin.
AB  - Hepatitis C virus (HCV) is the most common chronic infection in the United
      States, affecting almost 3.9 million Americans. The most effective treatment for
      chronic HCV infection is combination antiviral therapy with peginterferon and
      ribavirin. However, combination therapy is also associated with significant
      adverse effects and is contraindicated in certain patient populations.
      Hematological adverse effects are common and are a frequent cause of dose
      reduction and interruption or discontinuation of therapy. Currently there are no
      approved treatments for the hematological adverse events associated with HCV
      therapy. However, emerging data suggest that utilization of hematopoietic growth
      factors can provide a useful adjunct to treatment and optimize sustained
      virologic response rates.

PMID- 15184823
TI  - Treatment of chronic hepatitis C in patients with decompensated cirrhosis.
AB  - Cirrhosis due to chronic hepatitis C is now the leading indication for liver
      transplantation in the United States. Current data from existing clinical trials
      suggest that 41% of patients with genotype 1 hepatitis C virus infection (HCV)
      and 73% with genotype 2 or 3 infection with advanced fibrosis or early
      compensated cirrhosis can achieve sustained virologic response (SVR) to antiviral
      therapy. However, response to therapy declines with severity of liver disease and
      nonresponse to prior interferon-based regimens. Although SVR rates are low in
      patients with decompensated cirrhosis, on-treatment clearance of HCV from blood
      occurs in about 30% of those with genotype 1 infection and 80% of those with
      genotype 2 or 3. In addition, recent reports suggest that pretransplantation
      clearance of HCV RNA from blood may reduce the risk of HCV recurrence after
      transplantation. In the absence of a virologic cure, maintenance therapy with
      peginterferon may slow disease progression and reduce the rate of clinical
      decompensation.

PMID- 15184824
TI  - Management of the patient with Barrett's esophagus: a continuing dilemma for the
      clinician.
AB  - The primary controversy regarding Barrett's esophagus (BE) relates to what form
      of therapy is "best" and, more importantly, whether any therapy results in the
      regression of abnormal epithelium or reduces the rate of progression to dysplasia
      and/or adenocarcinoma. The current standard of practice suggests that patients
      with BE should be treated in a similar fashion as patients with typical
      gastroesophageal reflux disease, that is, with antisecretory agents as needed to
      provide complete symptom relief. The most recent guidelines from the American
      College of Gastroenterology point out that there are no prospective studies that
      support any alternative approach to treatment (ie, neither high-dose acid
      suppression nor antireflux surgery has demonstrated reduced risk of dysplasia or
      esophageal adenocarcinoma). However, accumulating evidence suggests that simply
      controlling symptoms is inadequate.

PMID- 15184826
TI  - Emerging biologic therapies in inflammatory bowel disease.
AB  - Ulcerative colitis and Crohn's disease, the idiopathic inflammatory bowel
      diseases (IBD), are thought to represent genetically determined, dysregulated
      immune responses to otherwise innocuous luminal antigens. Although progress in
      research has advanced our understanding of the immunopathogenesis and begun to
      elucidate genetic contributions toward susceptibility, limitations of current
      medical approaches continue to drive the search for better therapeutic agents.
      Most recently, the introduction of infliximab has heralded a new era of evolving
      biologically targeted treatments for IBD. Infliximab is currently the only
      biologic agent approved for the treatment of inflammatory and fistulizing Crohn's
      disease, but ongoing research continues to generate new biologic agents targeted
      at specific pathogenic mechanisms involved in the inflammatory process.
      Undoubtedly, with the success of infliximab, the role of biologic therapy will
      continue to expand in the future treatment of IBD.

PMID- 15184827
TI  - Coronary artery restenosis: vision to the future. Introduction.

PMID- 15184825
TI  - Colorectal cancer in African Americans.
AB  - In the United States, African Americans have the highest incidence of colorectal
      cancer of any racial or ethnic group. Compared with whites, African Americans
      have a younger mean age at colorectal cancer diagnosis and a greater proportion
      have proximal cancers. Survival in African Americans with colorectal cancer is
      lower than in whites. Currently, there are no established biological explanations
      for these differences in colorectal cancer between African Americans and whites.
      As leaders in the prevention and early diagnosis of colorectal cancer in the
      United States, clinical gastroenterologists can play an important role in
      promoting colorectal cancer awareness and the need for screening in African
      Americans.

PMID- 15184828
TI  - Everolimus for stent-based intracoronary applications.
AB  - Everolimus, a novel proliferation signal inhibitor initially developed for the
      prevention of allograft rejection after organ transplantation, is a potent anti
      proliferative and immunosuppressive agent. Compared to sirolimus, everolimus
      absorbs to local tissue more rapidly and possesses longer cellular residence time
      and activity. The stent-based intracoronary elution of everolimus was first
      investigated by BioSensors International using a bioabsorbable-PLA-polymer-coated
      S-Stent for drug delivery. Following preclinical animal studies that demonstrated
      excellent safety and efficacy of this device, the clinical FUTURE trial program
      was initiated. FUTURE I and II were designed to demonstrate safety and
      feasibility of the everolimus-eluting stent in a small patient population with
      focal de novo coronary lesions. At follow-up, an acceptable safety profile
      without evidence of stent thrombosis or late stent malapposition was observed.
      Moreover, these studies revealed a remarkable reduction of neointimal
      proliferation with everolimus-eluting stent implantation versus procedures
      utilizing bare-metal stents. Guidant Corporation licensed the exclusive rights to
      both the S-Stent and the bioabsorbable drug delivery platform. Guidant will
      conduct two pivotal trials (FUTURE III and IV) in order to demonstrate the
      efficacy of this stent design. FUTURE IV will make a non-inferiority comparison
      between everolimus and the already-approved drug eluting stent systems. Given the
      pooled results of FUTURE I and II, there is already some evidence suggesting that
      the everolimus-eluting stent is as potent a suppressor of reactive neointimal
      ingrowth as the sirolimus-eluting CYPHERTM stent. The everolimus-eluting coronary
      stent might shortly be established as a new and promising contender in the field
      of drug eluting stents for treatment of coronary heart disease.

PMID- 15184829
TI  - Optimal stent design for drug delivery.
AB  - The efficacy and safety of drug-eluting coronary stents might differ depending on
      the pharmacologic agents and stent delivery systems used. Recent research has
      focused on the various constituents of drug-delivery stents, including the stent
      backbone, materials used as drug-delivery vehicles, and the physicochemical
      properties of the pharmacotherapeutic agents themselves. Metal stents coated with
      an outer layer of polymer (bioabsorbable or non-bioabsorbable) can be drug
      loaded, thus providing more controlled and sustained drug delivery and allowing
      more optimal drug-tissue interactions. Among the next generation of drug-eluting
      stents will be a stent that uses the non-bioabsorbable polymer phosphorylcholine
      to release the sirolimus analogue ABT-578; another stent will use a highly
      deliverable cobalt-chromium metal alloy stent platform and, for the first time, a
      bioabsorbable polymeric coating (thin-film polylactic acid) for drug
      encapsulation and release.

PMID- 15184830
TI  - Lesion preparation prior to stenting.
AB  - Lesion preparation before stent implantation remains an essential component of
      the contemporary practice of coronary stent implantation in patients with long
      lesions, ostial lesions, chronic total occlusions, bifurcations, and calcified or
      nondilatable lesions. The goal of lesion preparation in these patients is to
      facilitate stent delivery, reduce plaque shift, and allow optimal stent
      expansion. Several procedures and second-generation devices have been proposed to
      achieve this goal, such as directional coronary atherectomy, rotational
      atherectomy, the cutting balloon, and the FX miniRAIL catheter. Even with the
      advent of drug-eluting stents, theoretically there are several reasons that
      aggressive lesion preparation would still be beneficial in selected patient
      subsets.

PMID- 15184831
TI  - Identification and treatment of vulnerable plaque.
AB  - It is now well recognized that the rupture of vulnerable plaque, which consists
      of an atheromatous plaque core covered by a thin fibrous cap with ongoing
      inflammation, is a major cause of thrombus formation leading to the development
      of acute coronary syndrome. Several diagnostic techniques, including vascular
      imaging and serologic markers, are clinically available or currently under
      investigation for the detection of vulnerable plaque. A combination of several
      diagnostic modalities might allow effective screening of individuals at high risk
      for future cardiovascular events. Plaque stabilization with pharmacologic
      interventions--statins, beta-blockers, and angiotensin-converting enzyme
      inhibitors--might effectively prevent the development of acute coronary syndromes
      caused by plaque disruption.

PMID- 15184832
TI  - Coronary small-vessel stenting in the era of drug elution.
AB  - Stent therapy (versus balloon angioplasty alone) provides predictable outcomes
      following percutaneous coronary intervention (PCI), in both the immediate,
      periprocedural setting and in durable (6-12 month) follow-up, in patients with
      target vessel reference diameters greater than or equal to 3.0 mm. The rate of
      positive outcomes for stenting, versus balloon angioplasty, is less robust for
      smaller (< 3.0 mm) coronary vessels. Specific attributes of stent design,
      including strut thickness and metal alloy composition, influence stent
      performance characteristics, particularly in smaller coronary vessels. Polymer
      based drug elution from stents may reduce or eliminate the inflammatory
      neointimal proliferative response provoked by stent deployment but the drug
      delivery platform remains critically important. The best drug-eluting stent (DES)
      platform for small coronary vessel applications is one incorporating low profile,
      enhanced flexibility, and ease of deployment (balloon expandability), as well as
      providing adequate endoluminal surface coverage for scaffolding and uniform drug
      delivery. DES specifically designed for small-vessel application will become the
      standard for small vessel PCI.

PMID- 15184833
TI  - Chronic heart failure: applying new findings to optimize care and improve
      survival. Introduction.

PMID- 15184834
TI  - Management of chronic heart failure: what do recent clinical trials teach us?
AB  - Though understanding and development of new therapies for heart failure (HF) have
      increased dramatically in recent years, the condition still takes a huge toll in
      terms of both morbidity and mortality and it is essential to continue with the
      quest for more effective HF treatments. Clinical trials provide the most precise
      scientific data regarding efficacy of HF therapies. Over the past 2 decades,
      about 100 large-scale clinical trials have significantly impacted treatment
      practices with respect to HF patients. The latest have shown benefit in the use
      of certain beta-blockers, aldosterone-receptor blockers, and the implantation of
      biventricular pacing-cardioverter defibrillator devices, generally in conjunction
      with an aggressive medical therapy regimen. This information should be integrated
      into existing guidelines for HF patient treatment as the search for greater
      efficacy in controlling and reversing this disease state continues.

PMID- 15184835
TI  - Nonselective versus selective beta-blockers in the management of chronic heart
      failure: clinical implications of the carvedilol or Metoprolol European Trial.
AB  - The abundance of evidence supporting beta-blocker therapy has resulted in the
      widespread acceptance of these drugs in the treatment of heart-failure patients.
      However, beta-blockers are not a homogeneous class of drugs, and important
      differences in efficacy have been noted between different members of the class.
      Thus, practicing physicians are faced with a choice when selecting a particular
      beta-blocker for treating heart failure. One of the considerations is whether to
      choose a selective or a nonselective beta-blocker. The results of the Carvedilol
      or Metoprolol European Trial indicate that carvedilol, a third-generation,
      nonselective beta-blocker with additional a-blocking, antioxidant, and other
      properties, is clearly superior to a beta1-blocking drug, metoprolol tartrate.
      The choice between these drugs is therefore unambiguously in favor of carvedilol.

PMID- 15184836
TI  - Heart failure therapy in special populations: the same or different?
AB  - Traditional clinical trials of heart failure therapy have focused on fairly
      homogeneous patient populations. Therefore, a pressing question is raised
      regarding whether it is appropriate to extrapolate findings from these trials to
      other groups, such as the elderly, women, and African Americans. Based on current
      knowledge, the differences among these groups should be acknowledged as subtle
      and represent a need for heightened clinical awareness and more vigorous
      investigation. These special populations, however, should receive medical therapy
      for heart failure that is consistent with the results from the major trials and
      is in accordance with published heart failure guidelines.

PMID- 15184837
TI  - Practical considerations for switching beta-blockers in heart failure patients.
AB  - The use of beta-blocker therapy has proven extremely useful in a variety of
      clinical settings, including the management of hypertension, acute- and post
      myocardial infarction, and in congestive heart failure (HF). However, there are
      noticeable differences among individual beta-blockers in regard to efficacy of
      treatment and clinical outcomes in many of these conditions. These differences
      are particularly apparent in the treatment of HF, where effects on reverse
      remodeling and interactions on the periphery are potential factors that can
      differentiate between the efficacy of one drug versus another. In fact, beta
      blockers are not a singular, homogeneous group, but rather a class made up of a
      number of agents with individual differences in pharmacology, receptor biology,
      hemodynamic effects, and tolerability. In the event of ongoing disease
      progression, the onus of choosing the most appropriate beta-blocker falls on the
      clinician's shoulders. Given the baseline differences among medications of this
      class, the rationale and manner for transitioning to a different beta-blocker
      should take into account the specific receptor-blockade subtype of any given
      agent, as well as any other intrinsic effects attributed to a specific drug. This
      article includes 2 protocols for switching between carvedilol, a third generation
      non-selective agent with vasodilatory properties through a1-blockade, and a beta1
      selective agent (e.g., metoprolol, atenolol). The aim is to simplify and maximize
      the safety and tolerability of performing this exchange. With the increasing
      amount of clinical evidence supporting the use of one beta-blocker over another
      in the treatment of HF, it behooves physicians treating this patient population
      to utilize the adrenergic blocking agent that provides optimal therapy with
      minimal side effects and intolerability.

PMID- 15184838
TI  - Strategies to improve the use of evidence-based heart failure therapies: OPTIMIZE
      HF.
AB  - Patients with heart failure face a very high risk of hospitalizations and
      mortality. Despite the compelling scientific evidence that angiotensin-converting
      enzyme inhibitors, beta-blockers, and aldosterone antagonists reduce
      hospitalizations and mortality in patients with heart failure, these life-saving
      therapies continue to be underutilized. A number of studies in a variety of
      clinical settings have documented that a significant proportion of patients with
      heart failure are not receiving treatment with these guideline-recommended,
      evidence-based therapies when guided by conventional care. Treatment gaps in
      providing other components of heart failure patient care, including patient
      education, have also been documented. The demonstration that initiation of
      cardiovascular protective medications prior to hospital discharge results in a
      marked increase in treatment rates, improved long-term patient compliance, and
      better clinical outcomes has led to the revision of national guidelines to
      endorse this approach as the standard of care. Recent studies demonstrated that
      beta-blocker therapy can be safely and effectively initiated in heart failure
      patients prior to hospital discharge, resulting in improved treatment rates and
      clinical outcomes. The Organized Program to Initiate Lifesaving Treatment in
      Hospitalized Patients with Heart Failure (OPTIMIZE-HF) is a national
      collaborative designed to improve medical care and education of hospitalized
      heart failure patients and to accelerate initiation of evidence-based heart
      failure guideline-recommended therapies by administering them before hospital
      discharge. A registry focusing on hospital admission to discharge and 60-90 day
      follow-up is designed to evaluate the demographic, pathophysiologic, clinical,
      treatment, and outcome characteristics of patients hospitalized with heart
      failure. The aim of this program is to improve the standard of heart failure care
      in the hospital and outpatient settings and to increase the use of evidence-based
      therapeutic strategies to prolong life in the large number of heart failure
      patients hospitalized each year.

PMID- 15184840
TI  - Carvedilol: beta-blockade and beyond.
AB  - Carvedilol is an adrenergic antagonist with nonselective beta- and a1-receptor
      blocking properties that has demonstrated significant clinical benefit in the
      management of patients with heart failure and in the post-myocardial infarction
      setting. It also possesses unique ancillary properties that may account for
      positive results in a number of clinical trials. It appears to offer particular
      advantages in the treatment of comorbid conditions, including coronary artery
      disease, stroke, hypertension, renal failure, diabetes, and atrial fibrillation,
      that can independently contribute to the progression of heart failure.

PMID- 15184841
TI  - The role of aldosterone and aldosterone-receptor antagonists in heart failure.
AB  - Prolonged overactivation of neurohormonal mechanisms in heart failure produces
      deleterious effects on the cardiovascular system and leads to poor prognosis.
      Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers have been shown
      to interrupt this excessive overactivity and improve survival. Activation of the
      renin-angiotensin system leads to increased synthesis of aldosterone in heart
      failure. Some aldosterone production is independent of ACEs; therefore, ACE
      inhibition does not entirely suppress the excessive formation of aldosterone. An
      excess of aldosterone in heart failure leads to sodium retention and myocardial
      fibrosis. The use of aldosterone antagonists, combined with standard therapy for
      heart failure, improves morbidity and mortality.

PMID- 15184842
TI  - Stem cell transplantation in myocardial infarction.
AB  - Congestive heart failure, which is most commonly caused by myocardial infarction,
      is the most frequent cause of hospitalization in the United States in patients
      over the age of 65. Although current pharmacotherapy can inhibit neurohormonal
      activation, this falls short of preventing left ventricular remodeling and the
      development of congestive heart failure. Stem cells are undifferentiated
      pluripotent cells that have the potential to proliferate and differentiate into
      cardiomyocytes. Cellular cardiomyoplasty, which is the replacement or
      regeneration of cardiomyocytes through cell transplantation, is a potential
      therapeutic approach to prevent left ventricular remodeling after myocardial
      infarction. The majority of the data on stem cell transplantation comes from
      preclinical animal studies. Although the results are interesting and perhaps
      safe, early phase I clinical studies are small and very preliminary. Data from
      large, randomized controlled trials are needed to clarify the short- and long
      term effects of cellular cardiomyoplasty.

PMID- 15184843
TI  - Ximelagatran: a novel oral direct thrombin inhibitor for long-term
      anticoagulation.
AB  - The ideal anticoagulant agent would have a fixed oral dose without need for dose
      adjustment, a wider therapeutic window than that of warfarin, and acceptable
      bleeding risks without the need for routine coagulation monitoring. Ximelagatran
      is a new oral agent that, when converted to its active form, melagatran, directly
      inhibits thrombin, thus blocking its activity and modulating several of its key
      functions. For the prevention of venous thromboembolism after orthopedic surgery,
      treatment of venous thromboembolism, and prevention of stroke in patients with
      atrial fibrillation, clinical trials indicate that ximelagatran meets the
      criteria for a superior anticoagulant.

PMID- 15184844
TI  - Diabetes mellitus. The sulfonylurea controversy: friend or foe?

PMID- 15184845
TI  - Long-term management of venous thromboembolism.

PMID- 15184846
TI  - Training or education?

PMID- 15184847
TI  - Anterior buccal mucosal mass.

PMID- 15184848
TI  - Pregnancy and lactation.
AB  - Pregnancy results in physiologic changes in almost all organ systems in the body
      mediated mainly by female sex hormones. Physiologic changes of pregnancy
      influence the dental management of women during pregnancy. Understanding these
      normal changes is essential for providing quality care for pregnant women. This
      review article briefly discusses the cardiovascular, respiratory,
      gastrointestinal, urogenital, endocrine, and oral physiologic changes that occur
      during normal gestation. A summary of current scientific knowledge of ionizing
      radiation is presented. Information about the compatibility, complications, and
      excretion of the common drugs during pregnancy is provided. Drugs and their usage
      during breast-feeding are also discussed. Guidelines for the management of a
      pregnant patient in the dental office are summarized.

PMID- 15184849
TI  - Rehabilitation of the severely atrophied maxilla by horseshoe Le Fort I osteotomy
      (HLFO).
AB  - OBJECTIVE: The purpose of this study was to determine the long-term outcome of
      the horseshoe Le Fort I osteotomy (HLFO) as a preprosthetic operation technique
      for implant insertion in the extremely atrophied maxilla. STUDY DESIGN: 36
      patients (8 male, 28 female, average age 57.6 years) underwent HLFO combined with
      iliac crest bone grafting. They were divided into 2 groups: group A with 12
      patients who simultaneously received 100 implants; group B with 24 patients where
      176 implants were inserted in 18 patients in a second-stage procedure. Clinical
      and radiographic outcome with regard to implant osseointegration, alveolar bone
      height in the canine and molar regions, peri-implant bone loss and satisfaction
      of patients (esthetics, masticatory function, overall treatment) were
      investigated in all cases. RESULTS: The overall 2-year failure-free fraction of
      implants was 95.5%; the 5-year failure-free fraction was 89.3%. In the 1-step
      group the 2-year and 5-year failure-free fractions were 95.9% and 86.9%,
      respectively, in the 2-step group 95.0% and 91.3% (log rank test P=.57). A total
      of 27 implants were lost during the entire follow-up: 14 in 6 patients of the 1
      stage and 13 in 9 patients of the 2-stage group. The mean loss of alveolar bone
      after augmentation in the canine and molar regions was almost equal in both
      groups (overall means for the 2 regions 3.67 +/- 2.77 and 4.42 +/- 2.72 mm,
      respectively). The relationship between the jaws and thereby the esthetic profile
      could be improved in all cases. All patients were satisfied with the dental
      rehabilitation and the achieved new esthetic appearance. CONCLUSIONS: HLFO
      combined with iliac bone grafting is a feasible preprosthetic technique prior to
      implant insertion in cases of severe atrophy of the maxillary alveolar ridge,
      leading to satisfying implant survival and rehabilitation of function.

PMID- 15184851
TI  - An alternative approach to maxillofacial arteriovenous malformations with
      transosseous direct puncture embolization.
AB  - The management of arteriovenous (AVM) malformations of the jaws is complex and
      requires an integrated team approach. Subspecialists, such as maxillofacial
      surgeons, interventional radiologists, and critical care intensivists, are
      commonly involved in the management of these patients. The current treatment
      options for maxillofacial AVMs are surgical resection combined with endovascular
      embolization. Surgical treatment of arteriovenous malformations has been
      associated with significant morbidity and mortality due to potential for massive
      blood loss. In the pediatric population extensive resection of the craniofacial
      skeleton may be associated with growth disturbance, functional compromise, and
      cosmetic deformity. We report a novel technique using endovascular embolization
      via direct transosseous puncture for a high-flow vascular malformation, obviating
      the need for extensive surgical resection, and review the important clinical
      aspects of these life-threatening lesions.

PMID- 15184850
TI  - Enhancement of bone formation in rat calvarial bone defects using low-level laser
      therapy.
AB  - OBJECTIVE: To evaluate the effect of low-level laser therapy (LLLT), using a
      GaAlAs diode laser device, on bone healing and growth in rat calvarial bone
      defects. STUDY DESIGN: An animal trial of 4 weeks' duration was conducted using a
      randomized blind, placebo-controlled design. Standardized round osseous defects
      of 2.7 mm diameter were made in each parietal bone of 20 rats (n=40 defects). The
      animals were randomly divided into an experimental and a control group of 10
      animals each. In the experimental group, a GaAlAs diode laser was applied
      immediately after surgery and then daily for 6 consecutive days. The control
      group received the same handling and treatment, but with the laser turned off.
      Five rats from each group were killed on day 14 and the remainder on day 28
      postoperatively. From each animal, tissue samples from one defect were prepared
      for histochemistry and samples from the contralateral defect for histology.
      Levels of calcium, phosphorus, and protein were determined by using atomic
      absorption spectrometry, colorimetry, and photometry, respectively. Student t
      test and Mann-Whitney were used for statistical analyses. RESULTS: At both time
      points the tissue samples from the experimental animals contained significantly
      more calcium, phosphorus, and protein than the controls. Similarly, histological
      analyses disclosed more pronounced angiogenesis and connective tissue formation,
      and more advanced bone formation in the experimental group than in the controls.
      CONCLUSION: LLLT may enhance bone formation in rat calvarial bone defects.

PMID- 15184852
TI  - Factors associated with delay in presentation among younger patients with oral
      cancer.
AB  - Despite the reported increase in the incidence of oral squamous cell carcinoma
      (OSCC) in under 45-year-olds, little is known regarding the pattern and reasons
      for delay in presentation in this younger age group. The aim of this study was to
      investigate factors predictive of patient (primary) delay in a sample of 53 newly
      diagnosed patients under the age of 45 years. Multiple logistic regression was
      used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for
      primary delay (> or = 21 days between patient first noticing signs or symptoms
      and seeking professional advice). Self-reported delay ranged from less than 1
      week to 104 weeks, with a median of 5 weeks. A total of 33 patients (62%)
      reported a delay of at least 21 days. Three variables: lack of further education,
      perceptions of being under stress in the period prior to diagnosis, and lower
      amounts of tobacco smoked per day were included in the final model and together
      explained 43% of the variance in patient delay (R2 = 0.432). Although OSCC is
      relatively rare in this age group, the rise in incidence and the change in
      profile of risk factors may increase the odds of patient delay. This has
      important implications for increasing sign and symptom awareness among the public
      and primary health care professionals such as general medical practitioners and
      general dentists.

PMID- 15184853
TI  - Effect of antibacterial therapy and salivary secretion on the efficacy of
      Helicobacter pylori eradication in duodenal ulcer patients.
AB  - OBJECTIVE: Oral health status may play a role in Helicobacter pylori eradication.
      Because adequate secretion of saliva promotes oral health, the aim of the study
      was to assess the effect of salivary secretion on the efficacy of H pylori
      eradication from the stomach. STUDY DESIGN: The study involved 90 H pylori
      positive subjects with duodenal ulcer (68 men, 22 women, aged 20-70 years) in
      whom saliva was collected under basal conditions for 45 min before antibacterial
      treatment began. They received no drugs for at least 3 days prior to saliva
      collection. A 7-day course of either of 2 eradication regimens--omeprazole,
      amoxicillin, and tinidazole (OAT); or omeprazole, amoxicillin, and clarithromycin
      (OAC)--was used. The efficacy of eradication therapy was evaluated 30 days after
      its completion. RESULTS: The efficacy of H pylori eradication from the stomach
      (per protocol analysis) was 77.5% in the group of subjects treated with OAT and
      81.6% with OAC. Combined analysis of both groups (OAT+OAC) showed reduced
      salivary secretion in subjects with eradication failure (0.395 +/- 0.266 vs 0.25
      +/- 0.176 mL/min, P=.042). A similar outcome was obtained when the OAT group was
      analyzed separately (0.436 +/- 0.316 vs 0.211 +/- 0.216 mL/min, P=.022), but in
      the OAC group the difference was not significant. In the combined analysis, the
      efficacy of eradication therapy was lower in women than in men (52.9% vs 86.9%,
      P=.005). In women, it corresponded to salivary secretion (successful eradication
      0.337 +/- 0.133 mL/min, unsuccessful eradication 0.180 +/- 0.144 mL/min, P=.043);
      whereas in men, the difference was not significant (successful eradication 0.405
      +/- 0.282 mL/min, unsuccessful eradication 0.321 +/- 0.186 mL/min). CONCLUSION:
      Low salivary secretion may contribute to the decrease in efficacy of H pylori
      eradication from the stomach, at least in subjects treated with certain drug
      regimens.

PMID- 15184854
TI  - Oral mucosal pigmentation secondary to minocycline therapy: report of two cases
      and a review of the literature.
AB  - Minocycline is a semisynthetic broad-spectrum antimicrobial agent that was first
      introduced into clinical practice in 1967. The most common use of minocycline is
      for the long-term treatment of acne vulgaris. A well-recognized side effect of
      minocycline treatment is pigmentation, which has been reported in multiple
      tissues and fluids including thyroid, skin, nail beds, sclera, bone, and teeth.
      While there have been several reports of oral pigmentation following minocycline
      therapy, these have been, for the most part, pigmentation of the underlying bone
      with the overlying oral mucosa only appearing pigmented. We report two cases of
      actual pigmented oral mucosal lesions on the hard palate secondary to minocycline
      therapy with the accompanying histopathology, followed by a discussion of
      minocycline-induced oral pigmentation and a differential diagnosis of these
      lesions.

PMID- 15184855
TI  - Post-irradiation leiomyosarcoma of the maxilla: report of a case in a patient
      with prior radiation treatment for retinoblastoma.
AB  - Post-irradiation sarcoma is a well-defined complication of radiation therapy, yet
      few reports document such lesions in the head and neck. A 30-year-old man
      presented for evaluation of an expansile lesion of the left posterior maxilla.
      His medical history was significant for a childhood ocular malignancy -
      unilateral retinoblastoma - which was treated with a combination of surgical
      enucleation of the eye and external beam radiation therapy. Biopsy of his
      maxillary lesion revealed a spindle cell malignancy that was morphologically and
      immunohistochemically consistent with a diagnosis of leiomyosarcoma. Further
      investigation into the case revealed that the patient had three children, every
      one of whom developed unilateral retinoblastoma in infancy. Compared to the more
      frequent presentation of bilateral tumors in hereditary cases of retinoblastoma,
      such cases of heritable unilateral retinoblastoma are exceptional. Importantly,
      heritable forms of retinoblastoma confer a significant risk for development of
      second primary cancers, necessitating long-term clinical follow-up in these
      patients.

PMID- 15184856
TI  - Nager syndrome (preaxial acrofacial dysostosis): a case report.
AB  - The Nager syndrome is a rare condition associated with craniofacial malformations
      such as micrognathia, zygomatic hypoplasia, cleft palate, and preaxial limb
      deformities. This report features a case of the Nager syndrome occurring in a 4
      year-old boy showing microdontia, thumb duplication and radioulnar synostosis,
      and ventricular septum defect, characteristics not usually encountered in the
      published cases.

PMID- 15184857
TI  - Tooth-specific risk indicators for apical periodontitis.
AB  - The present study aimed at identifying tooth-specific risk indicators for apical
      periodontitis (AP) and to investigate their interrelations in order to identify
      those teeth that would benefit from a radiographic examination. The study
      included 311 males and 302 females who gave written informed consent and attended
      a full-mouth radiographic examination. All teeth were assessed individually. AP
      was scored by the periapical index (PAI); other variables were root fillings,
      coronal fillings and crowns, pulpal posts, and caries. A conditional logistic
      regression analysis was used to assess the effect of tooth-specific risk
      indicators on the presence of apical periodontitis. The dependent variable was
      presence of AP versus absence of AP in the tooth. A total of 536 teeth with AP
      were identified. A highly increased risk for AP was seen in teeth with root
      fillings, particularly for technically inadequate ones. Presence of coronal
      fillings also increased the risk for AP, and inadequate fillings were associated
      with a slightly higher risk than adequate fillings. A similar pattern was seen
      for crowns. Teeth with caries also had an increased risk of AP, but the
      difference was only statistically significant for primary caries. Compared to
      first incisors, second incisors and canines had a significantly reduced risk, and
      molars, especially first maxillary molars, had a significantly increased risk for
      having AP.

PMID- 15184858
TI  - Comparison of procedural errors resulting during root canal preparations
      completed by senior dental students in patients using an '8-step method' versus
      'serial step-back technique'.
AB  - OBJECTIVE: To compare procedural errors that occur in patients during root canal
      preparation by senior dental students using a new '8-step method' versus the
      traditional 'serial step-back technique.' STUDY DESIGN: Senior dental students
      treated 221 root canals of maxillary and mandibular teeth. Instrumentation
      included coronal flaring with Gates-Glidden reamers and standardized stainless
      steel K-files in all teeth. A new 8-step method was used to prepare 67 canals
      using standardized stainless steel hand instruments (8-step SS) and 69 canals
      using the rotary Nickel Titanium instruments (8-step NiTi). The traditional
      serial step-back technique (step-back) was used for 85 root canals. In the apical
      third, reaming or filing motions were used up to sizes 25 and only reaming motion
      in sizes larger than 25 with the new 8-step method. A filing motion was used in
      the step-back for all sizes. Root canals of all groups were obturated with gutta
      percha points and AH26 using a lateral condensation technique. Pre- and
      postoperative radiographs were taken of each tooth. Procedural errors were
      recorded and statistically analyzed using a binomic test for comparison of
      proportion. RESULTS: Procedural errors detected consisted of 2 canals with
      transportation (3%) with the 8-step SS, and 3 canals (4%) with transportation
      with 8-step NiTi. There were no canal obstructions or instrument separations.
      With the step-back, 20 canals were transported (24%), 7 canals had obstructions
      (8%), and in 1 canal instrument was separated (1%). CONCLUSIONS: The new 8-step
      method resulted in fewer procedural errors than the traditional serial step-back
      technique when senior students prepared root canals in patients either by hand
      with standardized K-files or by rotary NiTi instrumentation.

PMID- 15184859
TI  - Octacalcium phosphate-based cement as a pulp-capping agent in rats.
AB  - OBJECTIVE: The purpose of this study was to evaluate the pulpal response to an
      octacalcium phosphate (OCP)-based cement used as a pulp-capping material. STUDY
      DESIGN: The pulps of 60 maxillary first molars of male Sprague-Dawley rats were
      exposed and then capped directly by using either OCP-based cement or a calcium
      hydroxide slurry (control). Histologic examinations were performed at 1, 2, and 5
      weeks after the surgical procedure, and the results were analyzed statistically
      by using the Mann-Whitney U test (P<.05). RESULTS: One week after pulp capping,
      the initial formation of reparative dentin in the exposed areas was more notable
      in the calcium hydroxide group than in the OCP-based cement group. At 2 weeks,
      reparative dentin covered by a layer of odontoblast-like cells was observed in
      both groups. However, at 5 weeks, reparative dentin consisting of regular
      dentinal tubules was observed more frequently in the OCP-based cement group.
      CONCLUSION: OCP-based cement allowed favorable healing processes to occur in the
      dental pulp.

PMID- 15184860
TI  - Temporomandibular joint: a methodology of magnetic resonance imaging 3-D
      reconstruction.
AB  - OBJECTIVE: The aim of this study was to develop a new method for the 3
      dimensional reconstruction of the temporomandibular joint (TMJ) images by means
      of magnetic resonance imaging (MRI). In a preliminary study, this modality of 3-D
      representation was tested to evaluate the joint motion. STUDY DESIGN: Sagittal
      MRI slices were obtained from a healthy subject. Acquisitions were realized by a
      spin-echo sequence, with a proton-density weighting and a 2-mm slice thickness. A
      3-D reconstruction of the TMJ images was performed. RESULTS: Three-dimensional
      representations of the temporomandibular joint were obtained. The depiction of
      the principal anatomical elements of this joint was realized. A study of TMJ
      dynamics was also carried out. In this case, movements of the right and left
      disks and condyles were measured. CONCLUSION: This 3-D reconstruction methodology
      allowed a more understandable anatomical description than 2-D images of the TMJ
      and offered possibilities for joint functional analysis.

PMID- 15184861
TI  - Comparative investigation of subjective image quality of digital intraoral
      radiographs processed with 3 image-processing algorithms.
AB  - OBJECTIVE: To evaluate the subjective diagnostic image quality of clinical
      digital intraoral radiographs processed with 3 different image-processing
      algorithms. STUDY DESIGN: One hundred digital intraoral radiographs were
      collected and subsequently processed in 3 sets. In the first set the radiographs
      were processed for correction for attenuation and visual response. In the second
      set the radiographs were processed with the same algorithms but with an
      additional shift in gray levels so that the average brightness of a region of
      interest was displayed with the mean brightness of the computer monitor. In the
      third, the radiographs were processed with the default gamma-correction in the
      Dimaxis program (Planmeca Oy, Helsinki, Finland). The 3 radiographs that were
      differently processed from the same original were displayed simultaneously on the
      computer monitor. Ten observers evaluated subjectively all the radiographs
      according to the portrayal of normal structures under the same viewing
      conditions. Five of them performed repeated evaluations of 20 of the 100
      radiographs 2 months later. RESULTS: The best subjective diagnostic quality was
      found for the radiographs processed with the new algorithms plus an additional
      shift in gray levels. Radiographs processed with the new algorithms were
      preferred when compared with those processed with the default gamma-correction.
      The differences between the 3 types of radiographs were significant (P <.0001).
      No significant intraobserver differences were found (P=.5487). CONCLUSION:
      Radiographs processed for correction for attenuation and visual response might be
      beneficial in clinical work. Clinical radiographs processed with the new
      algorithms plus an additional shift in gray levels further improve the subjective
      impression of normal structures.

PMID- 15184862
TI  - T2-weighted MRI for the assessment of joint effusion: comparative study of
      conventional spin-echo and fast spin-echo sequences.
AB  - OBJECTIVE: This study aimed to evaluate the usefulness of suitable conventional
      spin-echo (CSE) and fast spin-echo (FSE) T2-weighted imaging parameters for the
      assessment of joint effusion in a phantom study and in a comparative study of CSE
      and FSE using clinical cases. STUDY DESIGN: In the phantom study, the signal
      ratios of water and oil signal fields were determined and studied comparatively.
      The shape and size of signals were evaluated separately. In the study of joint
      effusion images, 318 joints were evaluated. CSE T2-weighted imaging and FSE T2
      weighted imaging were carried out, and a comparative assessment was performed.
      RESULTS: In both CSE and FSE imaging, the ratios of mean MRI signal values showed
      divergence as TR/TE values increased. The evaluation of joint effusion with FSE
      TR/TE 8000/120 msec was significantly better than that in all other groups (P
      <.01). CONCLUSION: The use of FSE requires investigation of TR/TE values. When a
      0.5 T static field strength MRI apparatus is employed, TR/TE 8000/120 msec is
      recommended.

PMID- 15184863
TI  - Improved urinary continence after radical retropubic prostatectomy with
      preparation of a long, partially intraprostatic portion of the membraneous
      urethra: an analysis of 1013 consecutive cases.
AB  - PURPOSE: To improve the rate of full continence in our patients, we performed,
      since June 1997, a careful preparation of the distally intraprostatic part of the
      membranous urethra to obtain a long urethral stump for the vesicourethral
      anastomosis. PATIENTS AND METHODS: In all, 610 patients without (group 1) and 403
      patients with (group 2) a long intraprostatic stump of the urethra were asked by
      a self-administered questionnaire about their continence status. The rate of
      positive surgical margins were compared as a marker of local tumour control.
      RESULTS: Full continence (no pads) was achieved in 76.02% in group 1 and in
      88.84%, of all patients in group 2. Stress incontinence (SIC) I degrees was found
      in 12.46% and 7.44% respectively, SIC II degrees was noted in 8.69 and 3.72% and
      complete incontinence was seen in 2.79% in group 1 and in two patients (0.5%) in
      group 2. Also the time to reach the final continence status was statistically and
      highly significantly (P<0.001) shortened. The rate of positive margins decreased
      in group 2, despite intraprostatic preparation. CONCLUSIONS: The preparation of a
      long, partially intraprostatic portion of the membranous urethra for
      vesicourethral anastomosis in radical retropubic prostatectomy leads to a
      statistically highly significant improvement of full continence and earlier
      continence in prostate cancer patients without compromising local tumour control.

PMID- 15184864
TI  - Iodine seed prostate brachytherapy: an alternative first-line choice for early
      prostate cancer.
AB  - This article on permanent iodine-125 seed prostate brachytherapy reviews the
      techniques, results, and patient selection issues for early prostate cancer. The
      long-term 10 y results of brachytherapy from Seattle, and their reproducibility
      in other centres both in the USA and UK are reported. The use of hormone therapy
      in brachytherapy and the value of combining external beam radiotherapy with a
      brachytherapy implant are discussed. Reviewed comparative data show the
      similarity of biochemical survival in patients treated with brachytherapy,
      radical prostatectomy, and external beam radiotherapy. The role of brachytherapy
      as a first-line treatment option for patients with prostate cancer is
      demonstrated.

PMID- 15184865
TI  - Disease associated mutations at valine 804 in the RET receptor tyrosine kinase
      confer resistance to selective kinase inhibitors.
AB  - We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4
      anilinoquinazoline ZD6474 display a strong inhibitory activity (IC(50)< or =100
      nM) towards constitutively active oncogenic RET kinases. Here, we show that most
      oncogenic MEN2-associated RET kinase mutants are highly susceptible to PP1, PP2
      and ZD6474 inhibition. In contrast, MEN2-associated swap of bulky hydrophobic
      leucine or methionine residues for valine 804 in the RET kinase domain causes
      resistance to the three compounds. Substitution of valine 804 with the small
      amino- acid glycine renders the RET kinase even more susceptible to inhibition
      (ZD6474 IC(50): 20 nM) than the wild-type kinase. Our data identify valine 804 of
      RET as a structural determinant mediating resistance to pyrazolopyrimidines and 4
      anilinoquinazolines.

PMID- 15184866
TI  - Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors.
AB  - MKK4, located in close proximity to p53 gene, is thought to be a tumor suppressor
      and a metastasis suppressor gene. A low-rate MKK4 gene alteration has been found
      in a few tumor types, including breast and pancreatic. A suppressor activity for
      prostate and ovarian tumor metastasis has also been suggested. To understand the
      pathobiologic roles of MKK4 in tumorigenesis, we examined the phenotypic changes
      in response to perturbation of the MKK4 expression in breast and pancreatic
      cancer cell lines. Ectopic expression of MKK4 by adenoviral delivery in MKK4
      negative cancer lines stimulated the cell proliferation and invasion, whereas
      knockdown of MKK4 expression by small interference RNA in an MKK4-positive breast
      cancer cell line, MDA-MB-231, resulted in decreased anchorage-independent growth,
      suppressed tumor growth in mouse xenograft model, and increased cell
      susceptibility to apoptosis brought by stress signals such as serum deprivation.
      These results argue that MKK4 functions as a pro-oncogenic molecule instead of a
      suppressor in breast and pancreatic tumors.

PMID- 15184867
TI  - Transcription factor E2F3 overexpressed in prostate cancer independently predicts
      clinical outcome.
AB  - E2F transcription factors, including E2F3, directly modulate expression of EZH2.
      Recently, overexpression of the EZH2 gene has been implicated in the development
      of human prostate cancer. In tissue microrarray studies we now show that
      expression of high levels of nuclear E2F3 occurs in a high proportion (98/147,
      67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic
      epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis.
      Patients with prostate cancer exhibiting immunohistochemically detectable nuclear
      E2F3 expression have poorer overall survival (P=0.0022) and cause-specific
      survival (P=0.0047) than patients without detectable E2F3 expression. When
      patients are stratified according to the maximum percentage of E2F3-positive
      nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there
      is an increasingly significant association between E2F3 staining and risk of
      death both for overall survival (P=0.0014) and for cause-specific survival
      (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor
      predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and
      cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these
      results are considered together with published data on EZH2 and on the E2F3
      control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a
      critical role in modulating aggressiveness of individual human prostate cancer.

PMID- 15184869
TI  - The Ras-related protein AGS1/RASD1 suppresses cell growth.
AB  - AGS1/RASD1 is a Ras-related protein identified as a dexamethasone-inducible cDNA
      and as a signal regulator in various functional and protein-interaction screens.
      As an initial approach to define the role of AGS1/RASD1 as a Ras-family member,
      we determined its influence on cell growth/survival. In clonogenic assays with
      NIH-3T3 murine fibroblast cells, the MCF-7 human breast cancer cell line and the
      human lung adenocarcinoma cell line A549, AGS1/RASD1 markedly diminished the
      number of G418-resistant colonies, whereas the Ras subgroup member K-Ras was
      without effect. A549 cell infection with adenovirus engineered to express
      AGS1/RASD1 (Ad.AGS1) inhibited log phase growth in vitro and increased the
      percentage of cells undergoing apoptosis. The anti-growth action was also
      observed in vivo as the expression of AGS1/RASD1 inhibited the subcutaneous tumor
      growth of A549 cells in athymic nude mice. These data indicate that AGS1/RASD1, a
      member of the Ras superfamily of small G-proteins that often promotes cell growth
      and tumor expansion, plays an active role in preventing aberrant cell growth.

PMID- 15184868
TI  - Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC
      oncogenes and is a common event in human papillary thyroid carcinomas.
AB  - To identify genes involved in the transformation of thyroid follicular cells, we
      explored, using DNA oligonucleotide microarrays, the transcriptional response of
      PC Cl3 rat thyroid epithelial cells to the ectopic expression of the RET/PTC
      oncogenes. We found that RET/PTC was able to induce the expression of CXCR4, the
      receptor for the chemokine CXCL12/SDF-1alpha/beta. We observed that CXCR4
      expression correlated with the transforming ability of the oncoprotein and
      depended on the integrity of the RET/PTC-RAS/ERK signaling pathway. We found that
      CXCR4 was expressed in RET/PTC-positive human thyroid cancer cell lines, but not
      in normal thyroid cells. Furthermore, we found CXCR4 expression in human thyroid
      carcinomas, but not in normal thyroid samples by immunohistochemistry. Since
      CXCR4 has been recently implicated in tumor proliferation, motility and
      invasiveness, we asked whether treatment with SDF-1alpha was able to induce a
      biological response in thyroid cells. We observed that SDF-1alpha induced S-phase
      entry and survival of thyroid cells. Invasion through a reconstituted
      extracellular matrix was also supported by SDF-1alpha and inhibited by a blocking
      antibody to CXCR4. Taken together, these results suggest that human thyroid
      cancers bearing RET/PTC rearrangements may use the CXCR4/SDF-1alpha receptor
      ligand pathway to proliferate, survive and migrate.

PMID- 15184870
TI  - RBMY, a male germ cell-specific RNA-binding protein, activated in human liver
      cancers and transforms rodent fibroblasts.
AB  - The RNA-binding motif (RRM) gene on Y chromosome (RBMY), encoding a male germ
      cell-specific RNA-binding protein associated with spermatogenesis, was found
      inserted by hepatitis B virus (HBV) DNA in one childhood hepatocellular carcinoma
      (HCC). This study is aimed to explore the oncogenic potential of the RBMY
      protein. The RBMY transcripts, expressed exclusively in the testis of normal
      people, were detected by reverse transcription-polymerase chain reaction in 36%
      of HCCs from 90 males and in 67% of hepatoblastoma from six boys. The nontumor
      liver counter parts, cirrhotic liver tissues from children with biliary atresia,
      and other types of cancers, such as bile duct, colon, stomach, lung, prostate,
      and kidney, were all negative for RBMY expression. One to four types of RBMY
      transcripts, including wild type and variants with N-terminal RRM deletion, C
      terminal SRGY (serine-arginine-glycine-tyrosine) boxes deletion, or deletion of
      both domains, were found in the testis and liver cancer tissues. The wild-type
      RBMY protein was expressed in the nucleus and demonstrated its tumorigenicity by
      transformation of mouse fibroblast NIH3T3 cells and in vivo tumor formation. The
      RBMY variant protein with deletion of C-terminal exons 9-12 was trapped in the
      cytoplasm and showed decreased tumorigenicity. Our results suggest that RBMY is a
      new candidate oncogene specific for male liver cancer.

PMID- 15184871
TI  - Reduced DNA-dependent protein kinase activity in two cell lines derived from
      adult cancer patients with late radionecrosis.
AB  - Epstein-Barr virus-immortalized lymphoblastoid cell lines were derived from five
      patients with late radionecrosis. Two of these cell lines exhibited postradiation
      viability levels intermediate between normal cell lines and that from an
      individual with ataxia telangiectasia. Compared with controls, these two cell
      lines exhibited impaired ability to rejoin DNA double-strand breaks on pulsed
      field gel electrophoresis and 6-10-fold reduced DNA-dependent protein kinase (DNA
      PK) activity in vitro in cell-free extracts. Immunoblotting showed normal levels
      of Ku70, Ku80 and XRCC4 and the presence of DNA-PKcs in both cell lines. These
      findings suggest that DNA-PK might be an important factor affecting the
      predisposition of radiotherapy patients to late radionecrosis.

PMID- 15184873
TI  - Inverted signaling hierarchy between RAS and RAC in T-lymphocytes.
AB  - In order to generate coherent biological responses to extracellular stimuli,
      cells have established synergistic and antagonistic crosstalk between pathways
      with similar or opposing functions, respectively. Two routes cooperating in the
      generation of mitogenic and cytoskeletal functions are those induced by Ras and
      Rho/Rac GTPases. In these signaling interactions, Rho/Rac proteins have been
      always placed in a downstream position respect to Ras in all cell systems
      analysed so far. In this report, we describe that such signaling hierarchy does
      not apply to T-lymphocytes. Thus, we show that both Rac1 GDP/GTP exchange factors
      such as Vav and constitutively active versions of Rac1 can promote the effective
      stimulation of the Ras pathway in T-lymphocytes. The molecular link for this new
      type of pathway interconnectivity is RasGRP1, a diacylglycerol-dependent GDP/GTP
      exchange factor for Ras that translocates to the plasma membrane in a Vav- and
      Rac1-dependent manner. The effect of the Vav/Rac1 pathway on the Ras pathway is
      highly dependent on the activity of phospholipase C-gamma, the key cellular
      supplier of intracellular diacylglycerol. Signaling experiments suggest that this
      crosstalk represents a signaling strategy used by the T-cell receptor to promote
      robust biological responses of both the Rac/Rho and Ras pathways upon antigen
      engagement.

PMID- 15184872
TI  - A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-beta in
      pancreatic carcinogenesis.
AB  - MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic
      adenocarcinomas. The molecular mechanisms responsible for that altered pattern of
      expression are unknown. TGF-beta, a pleiotropic cytokine, regulates numerous
      genes involved in pancreatic carcinogenesis via activation of the Smads proteins
      and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether
      the regulation of MUC4 expression by TGF-beta in pancreatic cancer cells was
      strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1
      (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By
      RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4
      mRNA and apomucin expression are upregulated by TGF-beta, (ii) Smad2 positively
      cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by
      exogenous TGF-beta induces Smad4 binding to the promoter, (iv) Smad7 and c-ski
      both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-beta
      activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of
      expression in PANC-1 cells is due to histone deacetylation. Altogether, these
      results indicate that upregulation of MUC4 by TGF-beta is restricted to well
      differentiated pancreatic cancer cells, and point out a novel mechanism for TGF
      beta as a key molecule in targeting MUC4 overexpression in pancreatic
      adenocarcinomas.

PMID- 15184874
TI  - MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice
      lacking MMR.
AB  - Mbd4 (methyl-binding domain 4) has been shown to be mutated in a high percentage
      of mismatch repair (MMR)-deficient colorectal tumours that exhibit microsatellite
      instability (MSI). However, the significance of these mutations is still unclear
      as they are predominantly monoallelic and the majority occur at a poly-A tract.
      Apart from MMR-deficient tumours, no other reports of mutations of Mbd4 in human
      neoplasia are as yet published. To address the significance of loss of Mbd4 in
      the absence of MMR, we have crossed Mbd4-deficient mice to mice lacking DNA MMR.
      We show that, in the context of MMR deficiency, additional loss of Mbd4 does not
      alter spontaneous mutation frequency at the endogenous Dlb-1b locus, nor does it
      modify tumour onset, tumour spectrum or MSI compared to singly mutant Msh2 or
      Mlh1 mice. Taken together, these findings show that nullizygosity or
      heterozygosity for Mbd4 does not affect MMR-dependent tumorigenesis.

PMID- 15184875
TI  - Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell
      carcinoma.
AB  - Renal cell carcinoma of the clear cell type (ccRCC) is associated with loss of
      functional von Hippel-Lindau (VHL) protein and high, homogeneous expression of
      the G250MN protein, an isoenzyme of the carbonic anhydrase family. High
      expression of G250MN is found in all ccRCCs, but not in most normal tissues,
      including normal human kidney. We specifically studied the mechanism of
      transcriptional regulation of the CAIXG250 gene in RCC. Previous studies
      identified Sp1 and hypoxia-inducible factor (HIF) as main regulatory
      transcription factors of G250MN in various non-RCC backgrounds. However, G250MN
      regulation in RCC has not been studied and may be differently regulated in view
      of the HIF accumulation under normoxic conditions due to VHL mutations. Transient
      transfection of different G250MN promoter constructs revealed strong promoter
      activity in G250MN -positive RCC cell lines, but no activity in G250MN -negative
      cell lines. DNase-I footprint and band-shift analysis demonstrated that Sp1 and
      HIF-1alpha proteins in nuclear extracts of RCC cells bind to the CAIX promoter
      and mutations in the most proximal Sp1 binding element or HIF binding element
      completely abolished CAIX promoter activity, indicating their critical importance
      for the activation of G250 expression in RCC. A close correlation between HIF
      1alpha expression and G250MN expression was observed. In contrast, no
      relationship between HIF-2alpha expression and G250MN was seen. The participation
      of cofactor CBP/p300 in the regulation of G250 transcription was shown. In
      conclusion, HIF-1alpha and Sp1, in combination with CBP/p300, are crucial
      elements for G250MN expression in ccRCC, and CAIXG250 can be regarded as a unique
      HIF-1alpha target gene in ccRCC.

PMID- 15184876
TI  - Cloning of a soluble isoform of the SgIGSF adhesion molecule that binds the
      extracellular domain of the membrane-bound isoform.
AB  - SgIGSF (spermatogenic immunoglobulin superfamily) is a recently identified
      intercellular adhesion molecule of the immunoglobulin superfamily. In a mast-cell
      cDNA library, we found a clone that resulted from the retention of intron 7
      within the mature SgIGSF message. This clone was predicted to encode a soluble
      isoform of SgIGSF (sSgIGSF) with 336 amino-acid residues because its open reading
      frame ended just before the transmembrane domain. We constructed a plasmid
      expressing sSgIGSF fused to the human IgG Fc fragment at its C-terminus (sSgIGSF
      Fc), and transfected it into COS-7 cells. The fusion protein was readily
      detectable in the culture supernatant. Solid-phase binding assay showed that
      sSgIGSF interacted directly the extracellular domain of membrane-bound SgIGSF
      (mSgIGSF). We next examined whether this interaction inhibited homophilic binding
      of mSgIGSF by aggregation assays using L cells that did not express mSgIGSF. A
      stable L-cell clone that overexpressed mSgIGSF aggregated with each other but not
      with mock-transfected L cells, indicating that a homophilic interaction of
      mSgIGSF mediated the aggregation. Addition of sSgIGSF-Fc inhibited the
      aggregation of L cells overexpressing mSgIGSF in a dose-dependent manner.
      Moreover, FACScan analyses revealed the specific binding of sSgIGSF-Fc to mSgIGSF
      expressed in L cells. Binding of sSgIGSF-Fc to mSgIGSF appeared to inhibit
      homophilic interactions of mSgIGSF.

PMID- 15184877
TI  - The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho
      mediated actin reorganization.
AB  - Sprouty and the Sprouty-related protein, Spred (Sprouty-related Ena/vasodilator
      stimulated phosphoprotein homology-1 (EVH1) domain-containing protein), inhibit
      Ras-dependent extracellular signal-regulated kinase (ERK) signaling induced by a
      variety of growth factors. Since Sprouty proteins have been shown to inhibit not
      only ERK activation but also cell migration, we postulated that Spreds also
      inhibit cellular migration. Using stably highly metastatic LM8 cells infected
      with the Spred1-Sendai virus vector, we demonstrated that Spred1 inhibits the
      metastasis of LM8 cells in nude mice. Spred1 overexpression also inhibited
      migration of cells in vitro in response to chemokines, CCL19 and CCL21. We also
      found that Spred1 overexpression dissolved actin-stress fibers. Both EVH1 domain
      and C-terminal Sprouty-related domain were required for actin reassembly. Spred1
      and Spred2 suppressed constitutively activated RhoA (V14RhoA)-induced stress
      fiber formation and serum response factor activation. Spred1 bound to activated
      RhoA, but not cdc42 and Rac. Spred1 also inhibited chemokine-induced RhoA
      activation and active RhoA-induced Rho-kinase activation. These data suggest that
      Spreds are key regulators of RhoA-mediated cell motility and signal transduction.
      Furthermore, our study suggests that the induction of Spreds could be a novel
      strategy for preventing cancer cell metastasis.

PMID- 15184878
TI  - Re-expression of TSLC1 in a non-small-cell lung cancer cell line induces
      apoptosis and inhibits tumor growth.
AB  - The TSLC1 tumor-suppressor gene is silenced in a number of human cancer tissues
      and cell lines, including lung, prostate, liver, stomach, pancreatic, and breast
      cancers. Expression of TSLC1 in a non-small-cell lung cancer (NSCLC) cell line
      A549 suppresses tumorigenicity in nude mice. However, the molecular mechanism of
      TSLC1 action is not yet elucidated. In the present study, we show that the
      expression of TSLC1 from a recombinant adenovirus vector (Ad-TSLC1) inhibited
      cell proliferation and induced apoptosis in the NSCLC cell line A549. We also
      demonstrated that subcutaneous tumor growth in nude mice induced by A549 cells
      was suppressed to the extent of 70-80% by intratumoral injection of Ad-TSLC1. Re
      expression of TSLC1 also resulted in activation of the apoptotic protease caspase
      3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase
      (PARP). The antiproliferative and pro-apoptotic activity of TSLC1 required the
      presence of the FERM-binding and PDZ-interacting motifs located in the
      cytoplasmic domain. Our results demonstrate the pro-apoptotic and oncosuppressive
      activity of TSLC1 protein, and suggest the potential of TSLC1 for gene therapy.

PMID- 15184879
TI  - Molecular cloning, characterization and isolation of novel spliced variants of
      the human ortholog of a rat estrogen-regulated membrane-associated protein, UO
      44.
AB  - We have previously reported the characterization of an estrogen-regulated rat
      uterine-ovarian-specific complementary DNA (UO-44). To understand the involvement
      of this protein in the initiation and progression of human ovarian and uterine
      cancers, we now report the cloning and characterization of the human ortholog
      (HuUO-44). HuUO-44 is mapped to chromosome 10q26.13 and contains nine exons.
      Multiple tissue Northern blot detected two HuUO-44 transcripts of approximately 2
      and 3 kb in the pancreas. RT-PCR demonstrated that HuUO-44 undergoes a complex
      series of alternative splicing events between exons 2 and 6 that yielded four
      novel splice variants, HuUO-44A, HuUO-44B, HuUO-44C and HuUO-44D. Putative
      functional motifs identified in HuUO-44 are two CUB domains and a zona-pellucida
      domain. Transfection studies demonstrated the membrane-associated nature of HuUO
      44. By immunohistochemistry, HuUO-44 was located to the normal ovarian and
      ovarian tumor epithelial cells; in NIH-OVCAR3 ovarian cancer cells, HuUO-44 was
      detected only at the leading edge of the dividing cells. Most importantly, a
      marked loss in cell attachment and proliferation was observed in NIH-OVCAR3 cells
      cultured in the presence of a polyclonal HuUO-44 antiserum. These findings
      suggest the potential role of HuUO-44 in cell motility, cell-cell interactions
      and/or interactions with the extracellular matrices.

PMID- 15184880
TI  - Disruption of the Rad9/Rad1/Hus1 (9-1-1) complex leads to checkpoint signaling
      and replication defects.
AB  - The checkpoint sliding-clamp complex, Rad9/Rad1/Hus1, plays a critical role
      during initiation of checkpoint signals in response to DNA damage and replication
      disruption. We investigated the impact of loss of Rad1 on checkpoint function and
      on DNA replication in mammalian cells. We show that RAD1 is an essential gene for
      sustained cell proliferation and that loss of Rad1 causes destabilization of Rad9
      and Hus1 and consequently disintegration of the sliding-clamp complex. In Rad1
      depleted cells, Atr-dependent Chk1 activation was impaired whereas Atm-mediated
      Chk2 activation was unaffected, suggesting that the sliding clamp is required
      primarily in Atr-dependent signal activation. Disruption of sliding-clamp
      function also caused a major defect in S-phase control. Rad1-depleted cells
      exhibited an RDS phenotype, indicating that damage-induced S-phase arrest was
      compromised by Rad1 loss. Furthermore, lack of Rad1 also affected the efficiency
      of replication recovery from DNA synthesis blockage, resulting in a prolonged S
      phase. These deficiencies may perpetually generate DNA strand breakage as we have
      found chromosomal abnormalities in Rad1-depleted cells. We conclude that the
      Rad9/Rad1/Hus1 complex is essential for Atr-dependent checkpoint signaling, which
      may play critical roles in the facilitation of DNA replication and in the
      maintenance of genomic integrity.

PMID- 15184881
TI  - Identification of REPS2 as a putative modulator of NF-kappaB activity in prostate
      cancer cells.
AB  - The protein REPS2 is implicated in growth factor receptor-mediated endocytosis
      and signalling, and its expression is downregulated in androgen-independent
      prostate cancer cells. Herein, the NF-kappaB subunit p65 is identified as a human
      REPS2 protein partner, interacting with the EH domain of REPS2. Using crystal
      structure data from literature and experimental data from yeast and mammalian two
      hybrid analysis, the results indicate that the NPF-motif in p65 acts as binding
      site for the EH domain in REPS2. However, in cultured prostate cancer cells, the
      REPS2-p65 interaction is triggered upon stimulation with phorbol ester (PMA).
      This indicates that PMA-sensitive signalling pathways can affect the interaction
      between REPS2 and p65. During prostate cancer progression from androgen-dependent
      to androgen-independent growth, downregulation of REPS2 is accompanied by
      upregulation of NF-kappaB activity. This might involve loss of REPS2-p65
      interaction, which would lead to increased NF-kappaB activity. Androgen
      deprivation causes apoptosis of prostate cancer cells, and activated NF-kappaB is
      a known inhibitor of apoptosis. Hence, decreased expression of REPS2 might be a
      key factor, causing prostate cancer cells to become resistant to induction of
      apoptosis by androgen deprivation.

PMID- 15184882
TI  - Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c
      Jun N-terminal kinase and extracellular-signal regulated kinase-mediated
      phosphorylation of Bcl-2.
AB  - Garlic-derived organosulfides (OSCs) including diallyl trisulfide (DATS) are
      highly effective in affording protection against chemically induced cancer in
      animals. Evidence is also mounting to indicate that some naturally occurring OSCs
      can suppress proliferation of cancer cells by causing apoptosis, but the sequence
      of events leading to proapoptotic effect of OSCs is poorly defined. Using PC-3
      and DU145 human prostate cancer cells as a model, we now demonstrate that DATS is
      a significantly more potent apoptosis inducer than diallyl sulfide (DAS) or
      diallyl disulfide (DADS). DATS-induced apoptosis in PC-3 cells was associated
      with phosphorylation of Bcl-2, reduced Bcl-2 : Bax interaction, and cleavage of
      procaspase-9 and -3. Bcl-2 overexpressing PC-3 cells were significantly more
      resistant to apoptosis induction by DATS compared with vector-transfected control
      cells. DATS treatment resulted in activation of extracellular-signal regulated
      kinase 1/2 (ERK1/2) and c-jun N-terminal kinase 1 (JNK1) and/or JNK2, but not p38
      mitogen-activated protein kinase. Phosphorylation of Bcl-2 in DATS-treated PC-3
      cells was fully blocked in the presence of JNK-specific inhibitor SP600125.
      Moreover, JNK inhibitor afforded significant protection against DATS-induced
      apoptosis in both cells. DATS-induced Bcl-2 phosphorylation and apoptosis were
      partially attenuated by pharmacological inhibition of ERK1/2 using PD98059 or
      U0126. Overexpression of catalase inhibited DATS-mediated activation of JNK1/2,
      but not ERK1/2, and apoptosis induction in DU145 cells suggesting involvement of
      hydrogen peroxide as a second messenger in DATS-induced apoptosis. In conclusion,
      our data point towards important roles for Bcl-2, JNK and ERK in DATS-induced
      apoptosis in human prostate cancer cells.

PMID- 15184883
TI  - Molecular mechanisms of CD99-induced caspase-independent cell death and cell-cell
      adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular
      mediators.
AB  - CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but
      still poorly understood biological functions. In cancer cells, CD99 is highly
      expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast
      homotypic aggregation of ES cells and caspase-independent apoptosis. In this
      study, we analysed signal transduction after CD99 engagement on ES cells.
      Findings obtained with selective inhibitors indicated that only actin
      cytoskeleton integrity was essential for cell-cell adhesion and apoptosis of ES
      cells. Indeed, CD99 stimulation induced actin repolymerization, further
      supporting the role of cytoskeleton in CD99 signaling. Gene expression profiling
      of ES cells after CD99 engagement showed modulation in the expression of 32
      genes. Among the pool of upregulated genes reported to be involved in cell
      adhesion, we chose to analyse the role of zyxin, a cytoplasmic adherens junction
      protein found to play a role in the regulation of the actin cytoskeleton.
      Overexpression of zyxin after CD99 ligation was confirmed by real-time PCR and
      Western blot. Treatment of ES cells with zyxin antisense oligonucleotides
      inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional
      role for this protein. Therefore, our findings indicate that CD99 functions occur
      through reorganization of cytoskeleton and identify actin and zyxin as the early
      signaling events driven by CD99 engagement.

PMID- 15184884
TI  - Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high
      grade breast cancers.
AB  - Loss of genetic material from chromosome arm 8p occurs commonly in breast
      carcinomas, suggesting that this region is the site of one or more tumor
      suppressor genes (TSGs). Comparative genomic hybridization analysis showed that
      8p loss is more common in breast cancers from pre-menopausal compared with post
      menopausal patients, as well as in high-grade breast cancers, regardless of the
      menopausal status. Subsequent high-resolution gene expression profiling of genes
      mapped to chromosome arm 8p, on an extended cohort of clinical tumor samples,
      indicated a similar dichotomy of breast cancer clinicopathologic types. Some of
      these genes showed differential downregulation in early-onset and later-onset,
      high-grade cancers compared with lower-grade, later-onset cancers. Three such
      genes were analysed further by in situ technologies, performed on tissue
      microarrays representing breast tumor and normal tissue samples. PCM1, which
      encodes a centrosomal protein, and DUSP4/MKP-2, which encodes a MAP kinase
      phosphatase, both showed frequent gene and protein loss in carcinomas. In
      contrast, there was an excess of cases showing loss of expression in the absence
      of reduced gene copy number of SFRP1, which encodes a dominant-negative receptor
      for Wnt-family ligands. These candidate TSGs may constitute some of the molecular
      drivers of chromosome arm 8p loss in breast carcinogenesis.

PMID- 15184885
TI  - RACK1 regulates Src-mediated Sam68 and p190RhoGAP signaling.
AB  - RACK1 is the founding member of a family of receptors for activated C kinase
      collectively called RACKs. Upon activation of PKC, RACK1 co-localizes with the
      Src tyrosine kinase at the plasma membrane and functions as a substrate, binding
      partner and inhibitor of Src (as measured in vitro), and a growth inhibitor in
      NIH 3T3 cells. To further analyze the function of RACK1 in Src and PKC signaling,
      we utilized cell-permeable peptides that modulate the interaction of RACK1 and
      betaIIPKC, thereby affecting betaIIPKC translocation and function. We found that
      the association of betaIIPKC and RACK1 is necessary for Src phosphorylation of
      RACK1. Src activity is required for tyrosine phosphorylation of RACK1, and for
      RACK1 binding to Src, but not to betaIIPKC. Endogenous Src kinase activity, as
      measured by phosphorylation of Sam68 (a mitotic-specific Src substrate involved
      in cell cycle regulation and RNA splicing) or p190RhoGAP (a Src substrate and
      GTPase-activating protein involved in actin reorganization), increases with
      disruption of the Src-RACK1 complex, and decreases with enhanced complex
      formation. RACK1 inhibits Src-mediated p190RhoGAP signaling and actin
      cytoskeleton rearrangement. Thus, RACK1 functions as an endogenous inhibitor of
      the Src kinase in diverse signaling pathways that regulate distinct cellular
      functions. Our results demonstrate the potential for using peptide modulators of
      Src activity as a tool for uncovering the function of Src in cells.

PMID- 15184886
TI  - Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer
      progression.
AB  - The differentiation-related gene-1 (Drg-1) was first identified as a gene
      strongly upregulated by induction of differentiation in colon carcinoma cells in
      vitro, and later the same gene was shown to suppress tumorigenicity of human
      bladder cancer cells in vivo. On the other hand, we and others have demonstrated
      that the Drg-1 gene suppresses prostate and colon cancer metastases in mouse
      models. In the context of such potential organ-specific differential function of
      the Drg-1 gene, the present study was designed to clarify the expression status,
      regulation and function of Drg-1 in the case of human breast cancer. We found
      that the expression of the Drg-1 protein was significantly reduced in breast
      tumor cells, particularly in patients with lymph node or bone metastasis as
      compared to those with localized breast cancer. Drg-1 expression also exhibited
      significant inverse correlation with the disease-free survival rate of patients
      and emerged as an independent prognostic factor. The downregulation of the Drg-1
      gene appeared to be largely at the RNA level, and the DNA methylation inhibitor,
      5-Azacytidine, significantly elevated the Drg-1 gene expression in various breast
      tumor cell lines. Furthermore, we found that overexpression of the Drg-1 gene
      suppresses the invasiveness of breast cancer cells in vitro, and this suppression
      was also achieved by treatment of cells with 5-Azacytidine. Together, our results
      strongly suggest functional involvement of the Drg-1 gene in suppressing the
      metastatic advancement of human breast cancer.

PMID- 15184888
TI  - Interplay between scatter factor receptors and B plexins controls invasive
      growth.
AB  - Met and Ron tyrosine kinases are members of the Scatter Factor Receptor family.
      Met is the receptor for hepatocyte growth factor while Ron is that for macrophage
      stimulating protein. On ligand stimulation, activation of these receptors induces
      'invasive growth', a complex biological response involved in tissue morphogenesis
      and, when deregulated, in tumor progression and metastasis. Scatter Factor
      Receptors share structural homology with Plexins, transmembrane receptors for
      Semaphorins, a family of ligands originally identified as axon guidance
      molecules. A physical and functional association between Met and Plexin B1, the
      prototype of class B Plexin subfamily, has been previously demonstrated. Here, we
      show that both Met and Ron receptors can interact with each of the three members
      of class B Plexins, even in the absence of their ligands and that Plexin B1
      ligand, Sema 4D, can induce activation of Met and Ron receptors, promoting an
      invasive response. Furthermore, in some human neoplastic cell lines Plexin B1 is
      overexpressed, constitutively tyrosine phosphorylated, and associated with
      Scatter Factor Receptors. These data extend the crosstalk previously described
      between Met and Plexin B1 to the entire families of Scatter Factor Receptors and
      class B Plexins and show that interaction with multiple upstream activators can
      finely tune the invasive growth process both in physiological conditions and in
      tumor growth and metastatization.

PMID- 15184887
TI  - Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK
      positive anaplastic large cell lymphoma.
AB  - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene
      product expressed in a subset of cases of anaplastic large cell lymphoma (ALCL).
      It has been shown that NPM-ALK binds to and activates signal transducer and
      activator of transcription 3 (STAT3) in vitro, and that STAT3 is constitutively
      active in ALK(+) ALCL cell lines and tumors. In view of the oncogenic potential
      of STAT3, we further examined its biological significance in ALCL using two
      ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that
      carries dominant-negative STAT3 (AdSTAT3DN). Infection by AdSTAT3DN led to the
      expression of STAT3DN in both ALK(+) ALCL cell lines at a similar efficiency.
      Subcellular fractionation studies showed that a significant proportion of the
      expressed STAT3DN protein translocated to the nucleus, despite the fact that
      STAT3DN has a mutation at residue 705(tyrosine --> phenylalanine), a site that is
      believed to be crucial for STAT3 activation and nuclear translocation.
      Introduction of STAT3DN induced apoptosis and G(1) cell cycle arrest. Western
      blot studies showed that expression of STAT3DN resulted in caspase-3 cleavage,
      downregulation of Bcl-2, Bcl-xL, cyclin D3, survivin, Mcl-1, c-Myc and suppressor
      of cytokine signaling 3. These results support the concept that STAT3 activation
      is pathogenetically important in ALCL cells by deregulating the expression of
      multiple target proteins that are involved in the control of apoptosis and cell
      cycle progression.

PMID- 15184889
TI  - Versatile analysis of multiple macromolecular interactions by SPR imaging:
      application to p53 and DNA interaction.
AB  - The greatest challenge in the postgenomic era is the description of proteome
      interactions, such as protein-protein or protein-DNA interactions. Surface
      plasmon resonance (SPR) is an optical technique in which binding of an analyte to
      the surface changes the refractive index at the surface/solution interface.
      Molecular interactions are analysed in real time without a labeling step.
      Currently, the limit to SPR imaging is the small number of reactions that can be
      simultaneously analysed. Using a novel grafting technology and a new imaging
      system, we increased the throughput of SPR imaging. The interaction between p53
      and DNA was chosen as a paradigm for validation of this assay. Using a tagged DNA
      methodology, we simultaneously targeted multiple DNA sequences on a single chip.
      The interaction between p53 and these DNA sequences was monitored by SPR imaging.
      Qualitative and quantitative analysis provides results similar to those obtained
      with conventional technologies.

PMID- 15184890
TI  - Ligand-induced rearrangement of the dimeric metabotropic glutamate receptor
      1alpha.
AB  - The extracellular domain of the metabotropic glutamate receptor 1alpha
      (mGluR1alpha) forms a dimer and the ligand, glutamate, induces a structural
      rearrangement in this domain. However, the conformational change in the
      cytoplasmic domain, which is critical for mGluR1alpha's interaction with G
      proteins, remains unclear. Here we investigated the ligand-induced conformational
      changes in the cytoplasmic domain by fluorescence resonance energy transfer
      (FRET) analysis of mGluR1alpha labeled with fluorescent protein(s) under total
      internal reflection field microscopy. Upon ligand binding, the intersubunit FRET
      efficiency between the second loops increased, whereas that between first loops
      decreased. In contrast, the intrasubunit FRET did not change clearly. These
      results show that ligand binding does not change the structure of each subunit,
      but does change the dimeric allocation of the cytoplasmic regions, which may
      underlie downstream signaling.

PMID- 15184892
TI  - High-pressure synthesis of crystalline polyethylene using optical catalysis.
AB  - Polymerization processes are probably the most relevant example of a chemical
      reaction activated by catalysts or radical initiators. Among polymers,
      polyethylene is by far the most common and largely produced. Here we present a
      high-pressure synthesis of high-density crystalline polyethylene by using only
      physical tools such as pressure and light. Low-density polyethylene is obtained
      by compressing ethylene at room temperature above 3 GPa in the ordered crystal
      phase, and a highly crystalline polymer is produced in the fluid phase at
      pressures lower than 1 GPa by using continuous-wave laser lines (lambda < or =
      460 nm) as an optical catalyst. The photo-activation is based on a two-photon
      absorption process to pi* antibonding states, where the change in molecular
      geometry favours the polymeric chain formation. The high yield and crystallinity
      of the polymer recovered by the photoinduced reaction and the simplicity of the
      synthesis make this process appealing for large-scale applications.

PMID- 15184891
TI  - DNA transport into Bacillus subtilis requires proton motive force to generate
      large molecular forces.
AB  - Bacteria can acquire genetic diversity, including antibiotic resistance and
      virulence traits, by horizontal gene transfer. In particular, many bacteria are
      naturally competent for uptake of naked DNA from the environment in a process
      called transformation. Here, we used optical tweezers to demonstrate that the DNA
      transport machinery in Bacillus subtilis is a force-generating motor. Single DNA
      molecules were processively transported in a linear fashion without observable
      pausing events. Uncouplers inhibited DNA uptake immediately, suggesting that the
      transmembrane proton motive force is needed for DNA translocation. We found an
      uptake rate of 80 +/- 10 bp s(-1) that was force-independent at external forces
      <40 pN, indicating that a powerful molecular machine supports DNA transport.

PMID- 15184893
TI  - Controlling the morphology of polymer blends using periodic irradiation.
AB  - Morphology is the decisive factor controlling practical properties such as impact
      strength or transparency in multiphase polymeric materials. The co-continuous
      structure formed by polymers has been of great interest to material scientists
      because of their superiority over those with random morphology. Although a number
      of efforts--including forcibly freezing the spinodal structure of polymer blends-
      have been made to produce materials with co-continuous structures, an efficient
      method for controlling their regularity is still lacking. Here, we demonstrate a
      novel method using periodic photo-crosslinking to control the length-scale
      distribution of the spinodal structure in binary polymer blends. It was found
      that the period distribution of the resulting co-continuous structure became
      significantly narrow under this periodic forcing. Also, there exists a particular
      irradiation frequency at which the periodic structure exhibits a minimum,
      indicating the existence of an ordering process driven by the external modulation
      frequency. Our findings reveal an easy way to produce polymer materials that is
      not only useful for optical applications, but also promising for biological
      separation, such as hemodialysis.

PMID- 15184894
TI  - LARGE can functionally bypass alpha-dystroglycan glycosylation defects in
      distinct congenital muscular dystrophies.
AB  - Several congenital muscular dystrophies caused by defects in known or putative
      glycosyltransferases are commonly associated with hypoglycosylation of alpha
      dystroglycan (alpha-DG) and a marked reduction of its receptor function. We have
      investigated changes in the processing and function of alpha-DG resulting from
      genetic manipulation of LARGE, the putative glycosyltransferase mutated both in
      Large(myd) mice and in humans with congenital muscular dystrophy 1D (MDC1D). Here
      we show that overexpression of LARGE ameliorates the dystrophic phenotype of
      Large(myd) mice and induces the synthesis of glycan-enriched alpha-DG with high
      affinity for extracellular ligands. Notably, LARGE circumvents the alpha-DG
      glycosylation defect in cells from individuals with genetically distinct types of
      congenital muscular dystrophy. Gene transfer of LARGE into the cells of
      individuals with congenital muscular dystrophies restores alpha-DG receptor
      function, whereby glycan-enriched alpha-DG coordinates the organization of
      laminin on the cell surface. Our findings indicate that modulation of LARGE
      expression or activity is a viable therapeutic strategy for glycosyltransferase
      deficient congenital muscular dystrophies.

PMID- 15184895
TI  - Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic
      marginal zone.
AB  - The factors directing marginal zone B cells to the splenic marginal zone are not
      well understood. Here we report that FTY720, a drug that targets sphingosine 1
      phosphate (S1P) receptors, induced marginal zone B cell migration into follicles.
      Marginal zone B cells expressed S1P receptors 1 and 3 (S1P(1) and S1P(3),
      respectively). Using gene-targeted mice, we show that S1P(1) but not S1P(3) was
      required for localization in the marginal zone. In mice lacking the chemokine
      CXCL13, S1P(1)-deficient marginal zone B cells reacquired a marginal zone
      distribution. Exposure to lipopolysaccharide or antigen caused marginal zone B
      cells to downregulate S1P(1) and S1P(3) and to migrate into the splenic white
      pulp. These data suggest that marginal zone B cell localization to the marginal
      zone depends on responsiveness to the blood lysophospholipid S1P, with S1P(1)
      signaling overcoming the recruiting activity of CXCL13.

PMID- 15184897
TI  - Sequential targeting of the genes encoding immunoglobulin-mu and prion protein in
      cattle.
AB  - Gene targeting is accomplished using embryonic stem cells in the mouse but has
      been successful, only using primary somatic cells followed by embryonic cloning,
      in other species. Gene targeting in somatic cells versus embryonic stem cells is
      a challenge; consequently, there are few reported successes and none include the
      targeting of transcriptionally silent genes or double targeting to produce
      homozygotes. Here, we report a sequential gene targeting system for primary
      fibroblast cells that we used to knock out both alleles of a silent gene, the
      bovine gene encoding immunoglobulin-mu (IGHM), and produce both heterozygous and
      homozygous knockout calves. We also carried out sequential knockout targeting of
      both alleles of a gene that is active in fibroblasts, encoding the bovine prion
      protein (PRNP), in the same genetic line to produce doubly homozygous knockout
      fetuses. The sequential gene targeting system we used alleviates the need for
      germline transmission for complex genetic modifications and should be broadly
      applicable to gene functional analysis and to biomedical and agricultural
      applications.

PMID- 15184896
TI  - Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in
      mice.
AB  - T cell-derived cytokines are important in the development of an effective immune
      response, but when dysregulated they can promote disease. Here we identify a four
      helix bundle cytokine we have called interleukin 31 (IL-31), which is
      preferentially produced by T helper type 2 cells. IL-31 signals through a
      receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL
      31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes,
      whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice
      overexpressing IL-31 developed severe pruritus, alopecia and skin lesions.
      Furthermore, IL-31 receptor expression was increased in diseased tissues derived
      from an animal model of airway hypersensitivity. These data indicate that IL-31
      may be involved in promoting the dermatitis and epithelial responses that
      characterize allergic and non-allergic diseases.

PMID- 15184898
TI  - The MLH1 D132H variant is associated with susceptibility to sporadic colorectal
      cancer.
AB  - Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk
      factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC
      susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized
      that attenuated alleles might also underlie susceptibility to sporadic CRC. We
      looked for gene variants associated with HNPCC in Israeli probands with familial
      CRC unstratified with respect to the microsatellite instability (MSI) phenotype.
      Association studies identified a new MLH1 variant (415G-->C, resulting in the
      amino acid substitution D132H) in approximately 1.3% of Israeli individuals with
      CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically
      significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated
      with MLH1 415C usually do not have the MSI defect, which is important for
      clinical mutation screening. Structural and functional analyses showed that the
      normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1
      415G-->C mutation. The new MLH1 variant confers a high risk of CRC and identifies
      a previously unrecognized mechanism in microsatellite-stable tumors. These
      studies suggest that variants of mismatch repair proteins with attenuated
      function may account for a higher proportion of susceptibility to sporadic
      microsatellite-stable CRC than previously assumed.

PMID- 15184900
TI  - Evidence for substantial fine-scale variation in recombination rates across the
      human genome.
AB  - Characterizing fine-scale variation in human recombination rates is important,
      both to deepen understanding of the recombination process and to aid the design
      of disease association studies. Current genetic maps show that rates vary on a
      megabase scale, but studying finer-scale variation using pedigrees is difficult.
      Sperm-typing experiments have characterized regions where crossovers cluster into
      1-2-kb hot spots, but technical difficulties limit the number of studies. An
      alternative is to use population variation to infer fine-scale characteristics of
      the recombination process. Several surveys reported 'block-like' patterns of
      diversity, which may reflect fine-scale recombination rate variation, but
      limitations of available methods made this impossible to assess. Here, we applied
      a new statistical method, which overcomes these limitations, to infer patterns of
      fine-scale recombination rate variation in 74 genes. We found extensive rate
      variation both within and among genes. In particular, recombination hot spots are
      a common feature of the human genome: 47% (35 of 74) of genes showed substantive
      evidence for a hot spot, and many more showed evidence for some rate variation.
      No primary sequence characteristics are consistently associated with precise hot
      spot location, although G+C content and nucleotide diversity are correlated with
      local recombination rate.

PMID- 15184899
TI  - Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia.
AB  - Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs)
      distributed across the entire 1.5-Mb locus on chromosome 22q11 associated with
      susceptibilit to schizophrenia, we previously identified two subregions that were
      consistently associated with the disease. In the distal subregion, we detected an
      association signal with five neighboring SNPs distributed over a haplotypic block
      of 80 kb encompassing six known genes. One of these five SNPs, rs175174, had the
      strongest association of all 72 SNPs that we tested. Here we show that rs175174
      regulates the level of the fully functional transcript by modulating the
      retention of intron 4 of the gene ZDHHC8, which encodes a putative transmembrane
      palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in
      prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in
      a new environment and a decreased sensitivity to the locomotor stimulatory
      effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows
      differences in transmission distortion between sexes in individuals with
      schizophrenia. Our results indicate that there is an unexpected connection
      between impaired palmitate modification of neuronal proteins and the psychiatric
      phenotypes associated with microdeletions of chromosome 22q11.

PMID- 15184901
TI  - The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated
      demyelination.
AB  - Inhibitors associated with CNS myelin are thought to be important in the failure
      of axons to regenerate after spinal cord injury and in other neurodegenerative
      disorders. Here we show that targeting the CNS-specific inhibitor of neurite
      outgrowth Nogo A by active immunization blunts clinical signs, demyelination and
      axonal damage associated with experimental autoimmune encephalomyelitis (EAE), a
      model of multiple sclerosis (MS). Mice vaccinated against Nogo A produce Nogo
      specific antibodies that block the neurite outgrowth inhibitory activity
      associated with CNS myelin in vitro. Passive immunization with anti-Nogo IgGs
      also suppresses EAE. Our results identify Nogo A as an important determinant of
      the development of EAE and suggest that its blockade may help to maintain and/or
      to restore the neuronal integrity of the CNS after autoimmune insult in diseases
      such as MS. Our finding that Nogo A is involved in CNS autoimmune demyelination
      indicates that this molecule may have a far more complex role than has been
      previously anticipated.

PMID- 15184902
TI  - Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in
      hippocampus.
AB  - In hippocampal pyramidal cells, a rise in Ca(2+) releases endocannabinoids that
      activate the presynaptic cannabinoid receptor (CB1R) and transiently reduce
      GABAergic transmission-a process called depolarization-induced suppression of
      inhibition (DSI). The mechanism that limits the duration of endocannabinoid
      action in intact cells is unknown. Here we show that inhibition of cyclooxygenase
      2 (COX-2), not fatty acid amide hydrolase (FAAH), prolongs DSI, suggesting that
      COX-2 limits endocannabinoid action.

PMID- 15184903
TI  - Listening to speech activates motor areas involved in speech production.
AB  - To examine the role of motor areas in speech perception, we carried out a
      functional magnetic resonance imaging (fMRI) study in which subjects listened
      passively to monosyllables and produced the same speech sounds. Listening to
      speech activated bilaterally a superior portion of ventral premotor cortex that
      largely overlapped a speech production motor area centered just posteriorly on
      the border of Brodmann areas 4a and 6, which we distinguished from a more ventral
      speech production area centered in area 4p. Our findings support the view that
      the motor system is recruited in mapping acoustic inputs to a phonetic code.

PMID- 15184904
TI  - Para-position derivatives of fungal anthelmintic cyclodepsipeptides engineered
      with Streptomyces venezuelae antibiotic biosynthetic genes.
AB  - PF1022A, a cyclooctadepsipeptide possessing strong anthelmintic properties and
      produced by the filamentous fungus Rosellinia sp. PF1022, consists of four
      alternating residues of N-methyl-L-leucine and four residues of D-lactate or D
      phenyllactate. PF1022A derivatives obtained through modification of their benzene
      ring at the para-position with nitro or amino groups act as valuable starting
      materials for the synthesis of compounds with improved anthelmintic activities.
      Here we describe the production of such derivatives by fermentation through
      metabolic engineering of the PF1022A biosynthetic pathway in Rosellinia sp.
      PF1022. Three genes cloned from Streptomyces venezuelae, and required for the
      biosynthesis of p-aminophenylpyruvate from chorismate in the chloramphenicol
      biosynthetic pathway, were expressed in a chorismate mutase-deficient strain
      derived from Rosellinia sp. PF1022. Liquid chromatography-mass spectrometry and
      NMR analyses confirmed that this approach facilitated the production of PF1022A
      derivatives specifically modified at the para-position. This fermentation method
      is environmentally safe and can be used for the industrial scale production of
      PF1022A derivatives.

PMID- 15184905
TI  - Temperature-sensitive control of protein activity by conditionally splicing
      inteins.
AB  - Conditional or temperature-sensitive (TS) alleles represent useful tools with
      which to investigate gene function. Indeed, much of our understanding of yeast
      has relied on temperature-sensitive mutations which, when available, also provide
      important insights into other model systems. However, the rarity of temperature
      sensitive alleles and difficulty in identifying them has limited their use. Here
      we describe a system to generate temperature-sensitive alleles based on
      conditionally active inteins. We have identified temperature-sensitive splicing
      variants of the yeast Saccharomyces cerevisiae vacuolar ATPase subunit (VMA)
      intein inserted within Gal4 and transferred these into Gal80. We show that Gal80
      intein(TS) is able to efficiently provide temporal regulation of the
      Gal4/upstream activation sequence (UAS) system in a temperature-dependent manner
      in Drosophila melanogaster. Given the minimal host requirements necessary for
      temperature-sensitive intein splicing, this technique has the potential to allow
      the generation and use of conditionally active inteins in multiple host proteins
      and model systems, thereby widening the use of temperature-sensitive alleles for
      functional protein analysis.

PMID- 15184906
TI  - An engineered epigenetic transgene switch in mammalian cells.
AB  - In multicellular systems cell identity is imprinted by epigenetic regulation
      circuits, which determine the global transcriptome of adult cells in a cell
      phenotype-specific manner. By combining two repressors, which control each
      other's expression, we have developed a mammalian epigenetic circuitry able to
      switch between two stable transgene expression states after transient
      administration of two alternate drugs. Engineered Chinese hamster ovary cells
      (CHO-K1) showed toggle switch-specific expression profiles of a human
      glycoprotein in culture, as well as after microencapsulation and implantation
      into mice. Switch dynamics and expression stability could be predicted with
      mathematical models. Epigenetic transgene control through toggle switches is an
      important tool for engineering artificial gene networks in mammalian cells.

PMID- 15184907
TI  - Local sleep and learning.
AB  - Human sleep is a global state whose functions remain unclear. During much of
      sleep, cortical neurons undergo slow oscillations in membrane potential, which
      appear in electroencephalograms as slow wave activity (SWA) of <4 Hz. The amount
      of SWA is homeostatically regulated, increasing after wakefulness and returning
      to baseline during sleep. It has been suggested that SWA homeostasis may reflect
      synaptic changes underlying a cellular need for sleep. If this were so, inducing
      local synaptic changes should induce local SWA changes, and these should benefit
      neural function. Here we show that sleep homeostasis indeed has a local
      component, which can be triggered by a learning task involving specific brain
      regions. Furthermore, we show that the local increase in SWA after learning
      correlates with improved performance of the task after sleep. Thus, sleep
      homeostasis can be induced on a local level and can benefit performance.

PMID- 15184908
TI  - Neurotoxic effects of postnatal thimerosal are mouse strain dependent.
AB  - The developing brain is uniquely susceptible to the neurotoxic hazard posed by
      mercurials. Host differences in maturation, metabolism, nutrition, sex, and
      autoimmunity influence outcomes. How population-based variability affects the
      safety of the ethylmercury-containing vaccine preservative, thimerosal, is
      unknown. Reported increases in the prevalence of autism, a highly heritable
      neuropsychiatric condition, are intensifying public focus on environmental
      exposures such as thimerosal. Immune profiles and family history in autism are
      frequently consistent with autoimmunity. We hypothesized that autoimmune
      propensity influences outcomes in mice following thimerosal challenges that mimic
      routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed
      growth delay; reduced locomotion; exaggerated response to novelty; and densely
      packed, hyperchromic hippocampal neurons with altered glutamate receptors and
      transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not
      susceptible. These findings implicate genetic influences and provide a model for
      investigating thimerosal-related neurotoxicity.

PMID- 15184909
TI  - Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse
      gliomas.
AB  - Loss of phosphatase and tensin homolog (PTEN) and amplification of the epidermal
      growth factor receptor (EGFR) gene contribute to the progression of gliomas. As
      downstream targets of the PTEN and EGFR signaling pathways, Akt, NFkappaB, and
      signal transducer and activator of transcription-3 (Stat3) have been shown to
      play important roles in the control of cell proliferation, apoptosis, and
      oncogenesis. We examined the activation status of Akt, NFkappaB, and Stat3 in 259
      diffuse gliomas using tissue microarrays and immunohistochemistry, and evaluated
      their association with glioma grade. We observed significant positive
      correlations between the activation status of Akt and NFkappaB and glioma grade.
      In contrast, only focal immunoreactivity for phospho-Stat3 was observed in < 9%
      of high-grade gliomas. In addition, we observed a significant correlation between
      the activation of Akt and NFkappaB. Functional correlation between Akt activation
      and the activation of NFkappaB was confirmed in U251MG GBM cells in which
      inhibition of Akt activation either by stable expression of PTEN or by the PI3
      kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in
      NFkappaB-binding activity. Thus, our results demonstrate that constitutive
      activation of Akt and NFkappaB, but not Stat3, contributes significantly to the
      progression of diffuse gliomas, and activation of Akt may lead to NFkappaB
      activation in high-grade gliomas.

PMID- 15184910
TI  - Inducible short-term and stable long-term cell culture systems reveal that the
      PAX3-FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7 expression.
AB  - In the pediatric cancer alveolar rhabdomyosarcoma (ARMS), the 2;13 chromosomal
      translocation juxtaposes the PAX3 and FKHR genes to generate a chimeric
      transcription factor. To explore molecular pathways altered by this oncoprotein,
      we generated an inducible form by fusing PAX3-FKHR to a modified estrogen
      receptor ligand-binding domain and expressed this construct in the RD embryonal
      rhabdomyosarcoma cell line. This inducible system permits short-term evaluation
      of downstream expression targets of PAX3-FKHR and complements a panel of stable
      long-term RD subclones constitutively expressing PAX3-FKHR. Using these two sets
      of resources, we investigated several candidate PAX3-FKHR target genes. First, we
      demonstrated in both short-term and long-term systems that PAX3-FKHR upregulates
      expression of the gene encoding the chemokine receptor CXCR4. In addition, we
      found that expression of wild-type PAX3 is upregulated, whereas expression of
      wild-type PAX7 is downregulated by PAX3-FKHR. In the presence of cycloheximide,
      CXCR4 and PAX3 are still inducible, supporting the hypothesis that these genes
      are direct transcriptional targets of PAX3-FKHR. Finally, studies of ARMS tumors
      revealed CXCR4, PAX3, and PAX7 expression levels consistent with our cell culture
      results. These findings of genes regulated by PAX3-FKHR will direct future
      biological and clinical investigation to important pathways contributing to ARMS
      tumorigenesis and progression.

PMID- 15184911
TI  - Mast cells play a pivotal role in ischaemia reperfusion injury to skeletal
      muscles.
AB  - Ischaemia reperfusion (IR) injury is a serious complication of cardiovascular
      disease, transplantation and replantation surgery. Once established there is no
      effective method of treatment. Although studies using mast cell-depleted (Wf/Wf)
      mice implicate mast cells in this pathology, they do not exclude a contribution
      by other deficiencies expressed in Wf/Wf mice. In order to obtain conclusive
      evidence for the role of mast cells, we engrafted cultured bone marrow-derived
      mast cells (BMMC) from normal mice into their Wf/Wf littermates. After 12 weeks,
      the hind limbs of Wf/Wf, engrafted Wf/Wf and normal littermates were subjected to
      IR injury. Muscle viability was assessed by both morphology and by nitroblue
      tetrazolium histochemical assay. Here, we present conclusive evidence for a
      causal role of mast cells in IR injury. Our data show that muscles from Wf/Wf
      mice subjected to IR have a significantly greater proportion of viable fibres
      than normal littermates subjected to identical injury (78.9+/-5.2 vs 27.2+/-3.7%,
      respectively). When Wf/Wf IR-resistant mice were engrafted with BMMC from normal
      littermates and subjected to IR, the proportion of viable muscle fibres was
      significantly reduced (78.9+/-5.2 vs 37.0+/-6.5%). Thus, engraftment of BMMC into
      Wf/Wf mice restores the susceptibility of skeletal muscle to IR injury
      irrespective of other abnormalities in Wf/Wf mice. In this model, the numerical
      density of mast cells undergoes a significant decrease within 1 h of reperfusion,
      indicating extensive mast cell degranulation. We conclude that mast cells are
      pivotal effector cells in the pathogenesis of IR injury of murine skeletal
      muscle.

PMID- 15184912
TI  - The corporo-glans ligament: description and functional significance of a ligament
      connecting the corpora cavernosa to the glans penis.
AB  - The two corpora cavernosa (CC) end blindly under cover of the glans penis (GP).
      The method of attachment of the CC to the GP could not be traced in the
      literature. The current communication investigated the hypothesis of a
      ligamentous attachment existing between the two corporal ends and the GP. In all,
      18 male cadaveric specimens were studied by direct dissection and histologically.
      Six were neonates and 12 adults (mean age 32.3+/-10.6 s.d. y). After examining
      and photographing the connection between the CC and GP, sagittal, parasagittal,
      and coronal sections of the connection were stained and studied microscopically.
      A triangular fibrous tissue band connected the distal blind ends of the two CC
      with the GP. The base of this band was attached to the tunica albuginea of the
      two CC, while the apex was continuous with the fibrous septa between the
      sinusoids of the cavernous tissue of the GP. Microscopically, the ligament
      consisted of collagen and elastic fibers; in some sections, the collagen fibers
      of the tunica albuginea were continuous with those of the band. A band of
      collagen and elastic fibers could be identified connecting the two CC to the GP;
      we term it the 'corporo-glans ligament'. This ligament presumably affords the
      connection with rigidity, flexibility, and tissue strength. We suggest that it
      firmly connects the GP to the CC during penile thrusting. Further studies are
      required to assess the possible role of this ligament in erectile dysfunction.

PMID- 15184913
TI  - Effect of TCDD on corpus cavernosum histology and smooth muscle physiology.
AB  - A polyhalogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD), is one of the most potent toxic environmental pollutants. Decreases in
      spermatogenesis and the ability to conceive and carry a pregnancy to term are the
      most sensitive signs of reproductive toxicity by TCDD in the mammal, but no
      report of its effect on the erectile function exists. We performed this study to
      investigate the effect of TCDD on the erectile function. New Zealand white
      rabbits were treated intraperitoneally with 1 microg/kg of TCDD. At 4 (Gr I) and
      8 (Gr II) weeks after the administration of TCDD, cavernosal tissues were
      harvested for strip study in the organ bath and testes were prepared for
      histologic examination. Compared to the maximal amplitude of 17.1+/-4.12 mN in
      normal control (Gr III), the contractions to cumulative concentrations of NE (10(
      8)-10(-4) M) were significantly decreased to 6.57+/-1.34 and 5.45+/-1.01 mN in
      Groups I and II, respectively. Compared to 51.12+/-7.38% in Gr III, relaxation to
      cumulative concentration (10(-8)-10(-4) M) of acetylcholine was significantly
      decreased to 17.25+/-2.17% (Gr I) and 9.73+/-2.17% (Gr II) at a concentration of
      10(-4) M, respectively. Compared to 75.12+/-13.18% in Gr III, relaxation to
      cumulative concentration (10(-8)-10(-4) M) of SNP was significantly decreased to
      31.49+/-7.89% (Gr I) and 18.54+/-6.12% (Gr II) at a concentration of 10(-4) M,
      respectively. Histologically, intracavernosal fibrosis, abnormal subtunical
      deposition of fat and decreased sinusoidal space with consequent increase of
      trabecular smooth muscle contents were identified in TCDD-treated groups. In TCDD
      treated animals, seminiferous tubules showed a decrease of germ cells with
      vacuolar degeneration and apoptotic cells. Spermatids were hardly seen. These
      results suggest that TCDD inhibits spermatogenesis and has a potential harmful
      effect on erectile function via changes of corpus cavernosum histology and smooth
      muscle physiology.

PMID- 15184914
TI  - Prosthesis culture 6 months after implantation and the effect of haematogenous
      seeding in a rat model.
AB  - The aim of this study was to investigate the role of haematogenous seeding in
      late prosthesis infection. In all, 45 male Wistar albino rats were divided into
      three equal groups. A small piece of silicone prosthesis was implanted into the
      scrotum of all rats under sterile condition and antibiotic prophylaxis. In the
      first group, all silicones were removed after 6 months without any complication
      and were cultured for bacterial growth. In the second group, a disc, which was
      saturated with Staphylococcus epidermidis, was inoculated subcutaneously in the
      legs of the rats in the 6th month, revealing a nodule formation 4-5 days after
      the inoculation and treated with an appropriate antibiotic after the nodule
      formation. In the third group, the same disc was inoculated, but all rats were
      treated immediately from the inoculation time onwards. The silicones of the
      second and third group were also removed at the end of the 6th month and were
      cultured to observe the bacterial growth. There was no evidence of prosthesis
      infection in any of the three groups. In the first group, three cultures were
      positive and revealed approximately 10 000 colonies of S. epidermidis in two and
      Proteus mirabilis in the remaining. Three and four cultures were positive in the
      second and third group, respectively. Low colonies of four different organisms
      (Escherichia coli, S. aureus, S. epidermidis, Pseudomonas aeruginosa) were
      identified in these cultures. There was no statistical significance of positive
      cultures in the three groups. Based on our results, there does not appear to be a
      true significance of haematogenous seeding on late prosthesis infection.

PMID- 15184915
TI  - Correlation between penile duplex findings and stress electrocardiography in men
      with erectile dysfunction.
AB  - The aim of this work is to assess the association between vasculogenic erectile
      dysfunction (ED) and coronary artery disease in men above the age of 40 y. The
      study included 40 patients above 40 y of age with vasculogenic ED of more than 3
      months duration. A dynamic duplex study after intracavernosal injection of a
      bimix solution (60 mg papaverine + 2 mg phentolamine mesylate) was carried out
      using a color ultrasound machine. The patients underwent a stress ECG test,
      carried out on a motor-driven treadmill according to the 'Bruce Protocol'. A
      total of 12 patients were diagnosed with positive ischemic heart disease (IHD).
      Their mean peak systolic velocity (PSV) was PSV = 19.58 cm/s. In all, patients
      were diagnosed with negative IHD; their mean PSV was 36.21 cm/s. A statistically
      significant difference was observed between patients with positive IHD and
      patients with negative IHD regarding PSV (P = 0.003). The sensitivity of a PSV of
      less than 35 cm/s in predicting IHD was 50% with a specificity of 100%. Positive
      predictive value for abnormal stress ECG to predict a PSV of less than 35 cm/s
      was 100%. In conclusion, the PSV of cavernosal arteries is a reliable measure for
      predicting IHD in patients with vasculogenic ED. Patients with a PSV of less than
      35 cm/s should be referred for cardiologic assessment as they carry a real risk
      of having silent IHD.

PMID- 15184916
TI  - On categorization and quantification of women's sexual dysfunctions: an
      epidemiological approach.
AB  - The objectives of this study are to compare the two definitions of female sexual
      dysfunction, namely dysfunction per se (A category) and personal distress caused
      by dysfunction (B category), and to gauge their associations with some
      sociodemographic aspects and level of sexual well-being. The subjects were a
      nationally representative sample of sexually active Swedish women (n: 1056) aged
      18-65 y, who participated in a combined structured interview/questionnaire
      investigation. The functions analysed were: self-reported sexual desire,
      interest, lubrication, orgasm, genital pain and vaginism, which were
      subclassified for the A and B categories into no, mild (sporadically occurring)
      and manifest dysfunction. Sexual well-being was reported along a six-grade scale
      ranging from very satisfied to very dissatisfied. The sociodemographic items
      registered were: education, occupation, financial situation, social group,
      immigrant status, location of domicile and church-going. Aggregated mild and
      manifest dysfunction per se of sexual interest, orgasm and vaginal lubrication
      were reported by about 60-90%. More than one-third had dyspareunia, but few
      reported vaginism. Mild dysfunctions were clearly more common than manifest
      dysfunctions. Not fully 45% of those with manifest low interest and orgasm
      perceived these dysfunctions as manifestly distressing, while in 60-70%
      lubricational insufficiency of dyspareunia led to manifest distress. Age and the
      included sociodemographic variables had marginal or no influence on sexual
      functions. A four-factor sexual function pattern was identified, closely linking
      A and B categories in a pairwise manner. Three factors, labelled sexual desire,
      orgasm and genital function were powerful classifiers (discriminant analysis) of
      level of sexual well-being. Hence, it is a matter of taste whether to use the A
      or the B category. Together, they can explain the gross level of satisfaction
      with sexual life to an adequate extent.

PMID- 15184917
TI  - A case-control study of erectile dysfunction among men diagnosed with panic
      disorder.
AB  - The association between panic disorder and erectile dysfunction (ED) among men
      was examined in the Integrated Healthcare Information Services National Managed
      Care Benchmark Database (IHCIS). The IHCIS is a fully de-identified, HIPAA
      compliant database and includes complete medical history for more than 17 million
      managed care lives; data from more than 30 US health plans, covering seven census
      regions; and patient demographics, including morbidity, age and gender. A total
      of 60,949 ED cases and 243,796 controls were included for analysis. Unconditional
      logistic regression analyses were first performed to assess the crude risk of ED,
      and adjusted risks of ED that accounted for comorbid conditions and
      comedications. A second set of analyses measured the crude and adjusted risks
      after restricting the patient population to men who were diagnosed with panic
      disorder at least 1 month prior to an ED diagnosis. In the first set of analyses,
      men with panic disorder were observed to have more than a two-fold increase in
      risk for ED (OR=2.29, 95% CI=2.03, 2.58). After adjusting for comorbid
      conditions, a 52% increase in risk of ED was observed (OR=1.52, 95% CI=1.34,
      1.72). Following subsequent adjustment for comorbidities and comedications, a 33%
      increased risk of ED was detected (OR=1.33, 95% CI=1.17, 1.51). In the second set
      of analyses studying panic disorder that preceded ED, only a 13% higher risk was
      noted (OR=1.13, 95% CI=0.97, 1.31). However, after adjusting for comorbid
      conditions, a 25% reduction in risk was observed (OR=0.75, 95% CI=0.64, 0.88). A
      35% risk reduction was seen after adjusting for comorbidities and comedications
      (OR=0.65, 95% CI=0.56, 0.77).

PMID- 15184920
TI  - Amblyopia--Duke-Elder was right.

PMID- 15184919
TI  - Endophthalmitis.

PMID- 15184921
TI  - Phacoemulsification cataract extraction in diabetics from ethnic minorities.

PMID- 15184922
TI  - Efficacy of amblyopia therapy initiated after 9 years of age.
AB  - AIMS/PURPOSE: To evaluate the efficacy of occlusion therapy initiated after 9
      years of age. METHODS: A total of 16 amblyopes of 9 years or older (range, 9.0
      14.5 years; mean, 10.5 years) with a difference in visual acuity of over two
      lines between the eyes alter 4 weeks of first full-time spectacle wear were
      included. None of the children had undergone a previous ocular examination, had
      ever worn spectacles, received occlusion therapy, or had strabismus surgery.
      Initial worst visual acuity after 4 weeks of full-time spectacle wear was 20/100
      in three patients, between 20/80 and 20/40 in 11 patients, and 20/30 in two
      patients. Full-time occlusion was performed in 14 patients and part-time
      occlusion in two patients. RESULTS: The final visual acuity of 15 out of 16
      patients (94%) improved at least two lines. The final visual acuities ranged from
      20/30 to 20/20 in 14 patients, 20/40 in one patient, and 20/50 in one remaining
      patient who began amblyopia therapy at 14.5 years of age, with the poorest
      compliance among the patients. CONCLUSIONS: Occlusion therapy for anisometropic
      and strabismic amblyopia can be successful even if initiated after the age of 9
      years.

PMID- 15184923
TI  - Surveillance of endophthalmitis following cataract surgery in the UK.
AB  - AIMS: To estimate the incidence of acute-onset presumed infectious
      endophthalmitis (PIE) following cataract surgery in the UK and provide
      epidemiological data on the presentation, management, microbiology, and outcome
      of cases of endophthalmitis. METHODS: Cases were identified prospectively by
      active surveillance through the British Ophthalmological Surveillance Unit
      reporting card system, for the 12-month period October 1999 to September 2000
      inclusive. Questionnaire data were obtained from ophthalmologists throughout the
      UK at baseline and 6 months after diagnosis. Under-reporting was estimated by
      independently contacting units with infection databases. RESULTS: Data were
      available on 213 patients at baseline and 201 patients at follow-up. The minimum
      estimated incidence of PIE was 0.086 per 100 cataract extractions and the
      corrected incidence was 0.14 per 100 cataract extractions. For the management of
      PIE, 96% of patients received intravitreal, 30% subconjunctival, 65% oral, and
      17% intravenous antibiotics. In all, 17% of patients received intravitreal
      steroid. From the intraocular samples taken for microbiological analysis, 56%
      were culture positive. At follow-up, 48% of patients achieved visual acuity of
      6/12 or better and 66% achieved better than 6/60. 13% of patients were unable to
      perceive light or had evisceration of the globe. CONCLUSIONS: The incidence of
      PIE after cataract surgery in the UK is comparable to that of other studies.
      Approximately 50% of patients achieved a visual acuity close to the driving
      standard.

PMID- 15184924
TI  - The incidence and outcome of photodynamic therapy for macular degeneration in the
      Northern region of the UK.
AB  - PURPOSE: To assess the patients who have had photodynamic therapy (PDT) in the
      Northern region of the UK, in relation to the eligibility criteria found to
      benefit in the TAP study (treatment of age-related macular degeneration with
      photodynamic therapy study), so as to make an estimate of the number of patients
      who might benefit from this treatment and to present the outcome of the treatment
      so far. METHOD: The records and fluorescein angiograms (FFAs) of all patients who
      had had PDT in the Northern region between 2001 and 2002 were reviewed for
      compliance with the TAP criteria of >50% classic choroidal neovascularization and
      >34 letters on the 2 m logMAR Early Treatment Diabetic Retinopathy Study chart.
      NHS funding has been available in the Northern Region since January 2001 for
      'second eye' involvement. A review of all the angiograms performed for exudative
      macular degeneration in 1 year was also performed. The visual outcome of those
      patients 1 year from baseline was measured. RESULTS: A total of 82 'second eye'
      patients were treated between January 2001 and December 2002. This gives an
      incidence of 65 per 3 million and so about 1300 in the whole of the UK
      (population 60 million). In all, 238 FFAs were performed on exudative macular
      degeneration, with 21% being found eligible for PDT. As of February 2003, 54 TAP
      criteria, macular degeneration patients were 1 year from initial treatment. Of
      these, 12 had incomplete follow-up and 13 patients had lost more than 15 letters.
      The responder rate defined as losing <15 letters was 42-13/42=69%. Seven of those
      who did not make 1-year follow-up had lost more than 15 letters when last seen,
      giving a responder rate of 54-20/54=63%. CONCLUSION: There may not be as many
      patients eligible for PDT, using the TAP criteria, as previously hoped. The
      outcome of treatment appears similar to that found in the TAP study.

PMID- 15184925
TI  - Pulsatile ocular blood flow of choroidal neovascularization in asymmetric age
      related macular degeneration after transpupillary thermotherapy.
AB  - PURPOSE: A previous study has shown that the pulsatile ocular blood flow (POBF)
      in eyes with asymmetric age-related macular degeneration (AMD) differs. Whereas
      eyes with drusen have higher POBF than contralateral eyes with disciform
      scarring, the POBF of eyes with drusen is lower relative to contralateral eyes
      with choroidal neovascularization (CNV). This study was designed to assess
      whether the POBF of eyes with CNV changes after transpupillary thermotherapy
      (TTT), using the contralateral eyes with drusen or scarring without TTT as
      controls. METHODS: In total, 26 patients with CNV in one eye and drusen or
      scarring in the other were enrolled in this prospective case series. Eyes with
      CNV were treated with TTT. POBF was measured monthly in both eyes of each
      subject. RESULTS: Before TTT, the POBF of eyes with CNV was 1179+/-317
      microl/min. After TTT, the POBF of CNV eyes had decreased at 1 month (1015+/-273
      microl/min, P=0.002) and 2 months (945+/-398 microl/min, P=0.011) of follow-up,
      but had rebounded at 3 months (P=0.441) and 6 months (P=0.084). CONCLUSIONS:
      These findings suggest that TTT decreases the pulsatile choroidal blood flow in
      eyes with CNV in patients with asymmetric AMD and the effects persist for 2
      months. POBF may be used as a modality to monitor the therapeutic effects of CNV
      in asymmetric exudative AMD.

PMID- 15184926
TI  - The use of autologous serum tears in persistent corneal epithelial defects.
AB  - PURPOSE: Persistent corneal epithelial defects (PED) present a very challenging
      problem to anterior segment surgeons. Autologous serum tears had been
      demonstrated to be beneficial in the treatment of PED. The current study was
      conducted to review the local spectrum of indications and to examine the outcome
      of autologous serum tear usage. METHODS: All cases of PED treated with autologous
      serum tears at a tertiary referral centre for the period August 1999 - July 2001
      were identified and reviewed. RESULTS: A total of 10 eyes from 10 patients were
      identified (5OD : 5OS). The gender ratio was 7M : 3F and the mean age was 36.8
      (range 17-73) years old. The mean duration of PED before the usage of autologous
      serum tears was 22.4+/-69.6 days. Six eyes healed within 2 weeks, but two eyes
      failed to heal after 1 month of treatment and two patients defaulted follow-up.
      No adverse effects were observed with the addition of autoserum tears.
      CONCLUSIONS: The results of the current study correlated well with previous
      reported studies. Autologous serum tears may be considered as a valuable adjunct
      in the management of recalcitrant cases of PED.

PMID- 15184927
TI  - Calculated tumour volume as a prognostic parameter for survival in choroidal
      melanomas.
AB  - PURPOSE: Tumour diameter, tumour height, and tumour volume are considered
      important prognostic indicators of survival in choroidal melanomas. In this
      study, we investigated the prognostic impact on survival of the easily calculated
      volume estimate based on the assumption of a half-rotation ellipsoid. METHODS:
      The largest tumour diameter and tumour height were measured by ultrasound A- and
      B-scan in 93 patients with choroidal melanoma. Tumour volume was calculated by
      the half volume of a rotation ellipsoid formula, rotated around the y-axis, and
      compared to tumour diameter and tumour height. All parameters were correlated to
      the clinical outcome of the patients. RESULTS: At the time of diagnosis, the mean
      diameter was 10.4 mm (range 4.1-18.9 mm), and the mean height was 5.7 mm (range
      1.74-14.9 mm). The range of the calculated tumour volume was between 11 and 628
      mm(3) (mean volume 190 mm(3)). Among all patients, distant metastases occurred in
      10 patients (10.8%). In a univariate approach using Mantel-Haenszel log-rank
      test, the calculated tumour volume at the time of diagnosis was the best
      prognostic indicator of survival followed by tumour diameter and tumour height
      (P=0.028). When tumour volume, horizontal and vertical tumour diameter, age, sex,
      and primary tumour therapy were considered in a multivariate approach using Cox
      proportional Hazard model, only tumour volume turned out as a significant
      prognostic parameter (P=0.001). CONCLUSIONS: Calculated tumour volume is a better
      prognostic indicator of survival of patients with choroidal melanomas than the
      largest tumour diameter and tumour height, and might be established in daily
      routine.

PMID- 15184928
TI  - Management of Mersilene mesh chronic eyelid complications: a systematic approach.
AB  - BACKGROUND: Mersilene mesh (polyester fibre) is commonly used in ptosis surgery
      for frontalis suspension as it is readily available and cheap. Management of
      extrusion can be challenging. We report three cases of extrusion where extremely
      thick mesh or extremely thin tissue may have contributed to the extrusion.
      METHODS: Retrospective case note study of three adult patients who developed
      chronic mesh extrusion. RESULTS: Extrusion and chronic infection occurred 5-12
      months after surgery. Despite systemic antibiotics, all three patients required
      surgical excision of mesh from the eyelid up to the brow, which was curative.
      CONCLUSION: These cases illustrate the need for a systematic approach and the
      need in some cases to excise the mesh to prevent recurrent infection.

PMID- 15184929
TI  - Orbital cellulitis caused by Peptostreptococcus.

PMID- 15184930
TI  - Corneal crystalline deposits as the initial manifestation of IgA-kappa multiple
      myeloma.

PMID- 15184931
TI  - The varix of angular vein.

PMID- 15184932
TI  - Onset of Charles Bonnet syndrome (formed visual hallucinations) following
      bilateral laser peripheral iridotomies.

PMID- 15184933
TI  - Silicone oil endotamponade--is it safe?

PMID- 15184934
TI  - Acute angle closure glaucoma secondary to a luxated lens associated with
      retinitis pigmentosa.

PMID- 15184935
TI  - Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats
      and a sodium-iodate-induced model in rabbits.
AB  - PURPOSE: To investigate the in vivo effects of tissue factor pathway inhibitor 2
      (TFPI-2), which stimulates proliferation of retinal pigment epithelial cells, but
      not the proliferation of fibroblast and vascular endothelial cells in vitro, on
      retinal degeneration using a sodium-iodate (SI)-induced model in rabbits and
      Royal Collage of Surgeons (RCS) rats. METHODS: 79 microg of recombinant TFPI-2
      (rTFPI-2) or vehicle alone was injected intravitreously to 18 eyes of 12
      pigmented rabbits a day after 20 mg/kg of SI was intravenously administered.
      Retinal function was assessed 4, 7, 14, and 21 days after the injection by
      analysing amplitudes of the c-wave of a bright flash electroretinogram.
      Additionally, 10 microg of rTFPI-2 or vehicle alone was injected intravitreously
      to 11 eyes of RCS rats at both 3 and 4 weeks old, then the retina was examined
      histologically at 5 weeks old. RESULTS: The rTFPI-2-treated eyes in rabbits
      showed a significantly less decrease in the relative amplitude of the c-wave than
      control eyes on days 4 and 7. The thickness of the outer nuclear layer was
      significantly thicker and the vacuole in the photoreceptor layer was less
      frequently observed in the rTFPI-2-treated RCS rats than the controls.
      CONCLUSIONS: Intravitreal injection of TFPI-2 rescues SI-induced retinal
      degeneration in rabbits and naturally occurring retinal degeneration in RCS rats
      at least partly. These results may suggest that this compound can be utilized in
      the treatment of retinal degeneration.

PMID- 15184936
TI  - 'I took a gamble and I lost': unwarranted patient regrets about choice of
      treatment of uveal melanoma.

PMID- 15184937
TI  - Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular
      surface of Sjogren's syndrome patients.
AB  - AIM AND PURPOSE: To evaluate the effects of two NSAIDs on corneal sensitivity and
      ocular surface in Sjogren's syndrome (SS) patients. METHODS: In all, 20 SS
      patients with epithelial corneal defects, were randomly divided into two groups:
      group 1 (10 females, age 35-63 years), treated with 0.1% indomethacin, one drop
      three times a day; group 2 (nine females, one male, age 38-65 years) treated with
      0.1% diclofenac, at the same regimen. No systemic NSAIDs were allowed. Use of
      tear substitute was allowed. Corneal sensitivity, corneal staining, BUT, and
      ocular discomfort, were evaluated before and after 15, 30 days of treatment and 7
      days after NSAID discontinuation. For statistical analysis, the Student's t-test
      and Mann-Whitney U test were used. RESULTS: Both groups showed at day 30 a
      statistically significant reduction of corneal sensitivity (P<0.05), although the
      diclofenac-treated group showed a statistically significant lower sensitivity if
      compared to the indomethacin-treated group (P<0.05). Corneal fluorescein score
      showed a statistically significantly worst alteration in group 2, 7 days after
      the discontinuation of the therapy (P=0.02). The ocular discomfort score was
      statistically significantly reduced in both groups starting from day 15 (P<0.05).
      DISCUSSION: The results indicate that NSAIDs can be useful in resolving symptoms
      of ocular discomfort in SS patients. However, they should be used with caution
      and under close monitoring, and the treatment should be promptly discontinued if
      corneal epithelial defects develop or worsen during treatment.

PMID- 15184938
TI  - Spontaneous resolution of a choroidal mass.

PMID- 15184940
TI  - A hypopyon is a sign of post-trabeculectomy endophthalmitis or not?

PMID- 15184939
TI  - Vitreous and retinal amino acid concentrations in experimental central retinal
      artery occlusion in the primate.
AB  - PURPOSE: Vitreous and retinal amino-acid concentrations were evaluated in a
      primate model of central retinal artery occlusion (CRAO) to study the role of
      glutamate excitotoxicity in acute retinal ischaemia. METHODS: Unilateral, acute
      CRAO was produced by temporary clamping of the central retinal artery for 190 min
      in four elderly rhesus monkeys. Fundus photography, fluorescein angiography, and
      electroretinogram were performed before and during CRAO, and after unclamping the
      artery. Vitreous samples were obtained before and after CRAO in both eyes, and
      analysed for 13 amino-acid concentrations using high-pressure liquid
      chromatography. The animals were killed 350 min after retinal reperfusion, and
      the retinal tissue was submitted for amino-acid analysis. RESULTS: In all four
      eyes, the macula showed the 'cherry red spot'. The CRAO was confirmed by
      fluorescein angiography and decreased b-wave on electroretinogram. Retinal
      histology confirmed ischaemic changes in the inner retina. Changes in all 13
      vitreous amino-acid concentrations after CRAO (including glutamate) were not
      significantly different between study and control eyes (P = 0.09 to 0.82). All
      retinal amino-acid concentrations (including glutamate) were not significantly
      different between two eyes (P = 0.07-0.93). CONCLUSIONS: In the primate model of
      acute inner retinal ischaemia induced by transient CRAO, we were unable to detect
      significantly elevated concentrations of vitreous and retinal glutamate. Our
      primate model has the advantage of closely modelling the CRAO in humans. Further
      basic and clinical studies are needed to elucidate the role of glutamate
      excitotoxicity in retinal ischaemia.

PMID- 15184941
TI  - Time taken to do external and endoscopic endonasal dacryocystorhinostomy (DCR)
      surgery.

PMID- 15184943
TI  - Evaluation of TNF-alpha and IL-1beta polymorphisms in Taiwan Chinese patients
      with pterygium.
AB  - PURPOSE: Pterygium, a complex disease, is associated with ultraviolet radiation,
      immunoinflammatory process, genetic factors, and virus infection. Ultraviolet
      radiation induces secretion of proinflammatory cytokines by the ocular surface
      epithelium, inflammatory cells in the tear fluid, or both. Among these cytokines,
      tumour necrosis factor (TNF)alpha and interleukin (IL)-1beta activate pterygium
      body fibroblasts, resulting in a phenotype capable of expressing various
      proteinases associated with extracellular matrix remodelling, angiogenesis, and
      fibroblast proliferation, which are important for pterygium formation and
      recurrence. The genetic factor was proposed to play a role in pterygium
      formation, but there were few studies to clarify this proposition. For
      investigating genetic factors, the association between pterygium and TNF-alpha
      and IL-1beta polymorphisms is evaluated in this study. METHODS: A total of 128
      pterygium patients and 103 volunteers without pterygium were enrolled in this
      study. Polymerase chain reaction-based analysis was used to resolve the TNF-alpha
      308 promoter, IL-1beta-511 promoter, IL-1beta exon 5, and IL-1 receptor
      antagonist (IL-1 Ra) polymorphisms. RESULTS: There were no significant
      differences in the frequency of genotypes and alleles of TNF-alpha-308 promoter,
      IL-1beta-511 promoter, IL-1beta exon 5, and IL-1 Ra polymorphisms between both
      groups. CONCLUSIONS: The correlation between pterygium and TNF-alpha-308
      promoter, IL-1beta-511 promoter, IL-1beta exon 5, and IL-1 Ra polymorphisms does
      not exist and those polymorphisms are not useful genetic markers for pterygium
      susceptibility. Further studies on other polymorphisms or haplotypes of TNF-alpha
      and IL-1beta are necessary.

PMID- 15184944
TI  - Estimating visual acuity by character counting using the Snellen visual acuity
      chart.
AB  - PURPOSE: This study examines visual acuity estimation with character counting,
      which can be used in subjects with nonorganic visual loss. METHODS: The right
      eyes of 35 healthy subjects were fogged with plus lenses and tested with the
      Snellen visual acuity chart (Reichert 11180). Visual acuity and counting level
      were assessed under various degrees of fogging, up to a maximal fogged acuity of
      20/200. Counting level was defined as the smallest line that subjects could count
      the number of characters correctly. For each counting level, the visual acuity
      that 95% of subjects could see equal to or better than was determined. RESULTS: A
      counting level of 20/10 estimates (ie 95% chance) a visual acuity equal to or
      better than 20/30. Counting levels 20/15, 20/20, and 20/25 estimate visual
      acuities of at least 20/50, 20/80, and 20/80, respectively. Counting levels 20/30
      20/60 estimate a visual acuity of at least 20/200. CONCLUSIONS: Character
      counting appears to be a useful technique of obtaining a rough estimate of visual
      acuity in subjects unable to be tested by standard methods, such as those with
      non-organic visual loss.

PMID- 15184945
TI  - An evaluation of photographic screening for neovascular age-related macular
      degeneration.
AB  - BACKGROUND: Photographic screening for neovascular age-related macular
      degeneration (AMD) is not commonly employed because the prevalence of treatable
      disease is low and fluorescein angiography is considered necessary for the
      diagnosis of this form of AMD. However, there may be a role for colour retinal
      imaging in assisting with the diagnosis and triage of subjects with neovascular
      AMD. The purpose of this study was to evaluate the utility of colour fundus
      photographs for identifying subjects with potentially treatable neovascular AMD.
      METHODS: A total of 74 stereo pairs of Kodachrome colour slides of subjects with
      AMD were evaluated (i) nonstereoscopically, (ii) stereoscopically, and (iii)
      stereoscopically with visual acuity and visual symptom data. Two retina
      specialists read the images to identify active exudative lesions. RESULTS: The
      kappa statistic comparing the retinal specialists diagnosis of treatable
      neovascular AMD from color slides was excellent. The sensitivity and specificity
      of nonstereo images for the appropriate categorization of lesions was 0.95 and
      0.90 respectively. The evaluation of stereo pairs was more sensitive, but less
      specific, 0.98, 0.83, as was the evaluation of stereo-pairs with clinical
      histories and visual acuities, 1.00, 0.77. CONCLUSIONS: The evaluation of colour
      images for subjects with suspected exudative macular degeneration can be
      diagnostic for neovascular AMD and may expedite the appropriate referral of
      patients for more timely angiography and treatment. Incorporating more clinical
      information for the image evaluators ((i) stereo image pairs and/or (ii)
      presenting symptomatology and visual acuity data) led to a decrease in the false
      negative rate, but also decreased the screening specificity.

PMID- 15184947
TI  - Optical coherence tomography findings in benign concentric annular dystrophy.

PMID- 15184946
TI  - Ocular-hypertensive response and corneal endothelial changes after intravitreal
      triamcinolone injections in Chinese subjects: a 6-month follow-up study.
AB  - PURPOSE: To assess the intraocular pressure (IOP) and corneal endothelial
      changes, over a 6-month period, after a single injection of intravitreal
      triamcinolone (ivTA) in Chinese patients. METHODS: A total of 43 eyes of 43
      consecutive Chinese patients with various macular diseases received a single
      bolus injection of 4 mg ivTA, of which, 14 eyes with significant cataracts
      underwent simultaneous phacoemulsification and primary intraocular lens
      implantation. IOP was measured preoperatively and weekly in the first month, and
      then monthly until 6 months postinjection. Specular microscopy was performed on
      24 of the 29 eyes without simultaneous cataract surgery, preoperatively and at
      months 1, 3, and 6. RESULTS: All patients completed 6 months of follow-up. Nine
      out of 43 (20.9%) eyes had IOP >21 mmHg. Their mean maximum IOP was 29.2 mmHg
      (range 23.0-37.0), necessitating the use of 2.0 types of topical antiglaucomatous
      medications on average. The IOP elevation occurred at a mean of 5.2 weeks (range
      1-17) postinjection. All IOPs returned to normal, without additional
      antiglaucomatous medications, by 6 months. There was no statistically significant
      difference (paired t-test, P<0.05) in the corneal endothelial cell count and
      other specular microscopy parameters up to 6 months after the injections.
      CONCLUSION: A single 4 mg bolus injection of ivTA appeared to have no harmful
      effects on the corneal endothelium. IvTA caused transient IOP elevations in 20.9%
      of Chinese patients, similar to that observed in Caucasians. As the IOP rise can
      occur as early as 1 week after the injection, early monitoring will help its
      early detection and prevent optic nerve damage.

PMID- 15184948
TI  - Inferior oblique myectomy vs recession--its clinical significance.

PMID- 15184950
TI  - Use of the 60 D lens to view the fundus with the operating microscope after
      cataract surgery.

PMID- 15184951
TI  - An atypical case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis
      (IRVAN) syndrome.

PMID- 15184952
TI  - Evaluation of the outcome of amniotic membrane transplantation for ocular surface
      reconstruction in symblepharon.
AB  - AIMS: Symblepharon is a condition that can inflict serious morbidity on the
      affected patients. Our aim was to evaluate the efficacy of amniotic membrane
      transplantation in the surgical treatment of symblepharon by determining the rate
      of epithelization of the graft, the incidence of complications, and the rate of
      recurrence of cicatrization. METHODS: In all, 20 eyes of 18 patients with
      symblepharon due to various causes and with varied indications for surgery
      underwent symblepharon excision and amniotic membrane transplantation (AMT).
      RESULTS: We observed recurrence of symblepharon in eight out of the 20 eyes
      operated upon, but in two of these the cicatrization was focal in nature and did
      not afford any functional impairment to the patients. Four out of the six eyes
      that failed had preoperative severe dry eye, and four had undergone previous
      conjunctival surgery. CONCLUSIONS: AMT appears to be a safe and effective
      procedure for the surgical treatment of symblepharon. We observed a 100% rate of
      epithelization of the graft with no significant postoperative complications and a
      30% rate of cicatrization. Pre-existing dry eye and previous conjunctival surgery
      influence the success of the surgery and these eyes may need medical or surgical
      supplementation along with AMT to limit the amount of subconjunctival fibrosis
      for better surgical results.

PMID- 15184953
TI  - Peripheral retinal neovascularization in bullous central serous
      chorioretinopathy.

PMID- 15184954
TI  - CJD and intraocular surgery.

PMID- 15184955
TI  - Ocular pathology in congenital heart disease.
AB  - PURPOSE: To describe the ocular findings in subjects with congenital heart
      disease (CHD). METHODS: In a prospective study, the same observer examined 240
      consecutive patients with CHD admitted to the medical centre. Two independent
      geneticists performed identification of syndromes. RESULTS: The commonest
      anatomic cardiac anomalies were ventricular or atrial septal defects (62),
      tetralogy of Fallot (39), pulmonary stenosis (25), and transposition of the great
      arteries (24). The heart lesions were divided physiologically into volume
      overload (90), cyanotic (87), and obstructive (63). In all, 105 syndromic
      subjects included the velocardiofacial syndrome (18), Down's syndrome (17),
      CHARGE association (6), DiGeorge syndrome (5), Williams syndrome (3), Edwards
      syndrome (3), Noonan syndrome (3), VACTERL association (2), and Patau syndrome
      (trisomy 13) (2). The paediatric team recognized 51 patients as syndromic. Two
      independent geneticists recognized additional 54 patients as syndromic. Positive
      eye findings were present in 55% (132) and included retinal vascular tortuosity
      (46), optic disc hypoplasia (30), trichomegaly (15), congenital ptosis (12),
      strabismus (11), retinal haemorrhages (8), prominent eyes (7), and congenital
      cataract (6). There was a strong correlation between the retinal vascular
      tortuosity and both a low haematocrit (P=0.000) and a low arterial oxygen
      saturation (P=0.002). CONCLUSIONS: Patients with CHD are at a high risk for
      ocular pathology and need screening for various ocular abnormalities.

PMID- 15184956
TI  - A brief history of punctoplasty: the 3-snip revisited.
AB  - PURPOSE: To determine when and how to perform punctoplasty, review the history,
      and determine the efficacy of posterior ampullectomy. METHOD: Retrospective
      analysis of 53 cases of punctal stenosis, operated by a single surgeon by means
      of posterior ampullectomy via 3-snips. A review of the history of the procedure
      from papers found with a Medline search for 1-snip, 2-snip, 3-snip, and
      punctoplasty. RESULTS: In all, 102 sets of notes were reviewed. The age range was
      from 9 to 89 years with a mean age of 56 years. A total of 74% of patients were
      female. We excluded 22 patients who had additional surgery and 16 patients who
      elected not to have surgery. There was no comment as to success or failure in
      four sets of notes and seven notes could not be found; these cases were also
      excluded. Of the remaining 53 patients, success was documented in 49 cases, or
      92%. CONCLUSIONS: The historical review helps explain the debate about the
      procedure. The retrospective review confirms that posterior ampullectomy via 3
      snips is an effective procedure.

PMID- 15184957
TI  - Screening for visual impairment in elderly patients with hip fracture: validating
      a simple bedside test.
AB  - AIMS: 1. To assess the prevalence of visual impairment in those patients who
      sustain proximal hip fracture after a simple fall. 2. To test the validity of a
      simple screening test to identify patients with visual impairment. METHODS:
      Patients on the orthopaedic rehabilitation ward recuperating from proximal hip
      fracture were recruited. The nurse screener and examining Ophthalmologist
      independently assessed the patients' distance visual acuity and visual field to
      confrontation. In addition, the nurse screener assessed for the presence of
      cataract in the red reflex and the examining Ophthalmologist performed a dilated
      slit-lamp examination. On completion of the examination, the Ophthalmologist
      documented the cause(s) of any visual impairment found. RESULTS: A total of 89
      patients were assessed. In all, 29 patients (33%) could be classified as visually
      impaired using the United States criteria and 52 patients (58%) had a distance
      visual acuity of 6/18 or worse in at least one eye. The test reliably identified
      those patients with visual impairment (sensitivity 94% (+/-5%), specificity 92%
      (+/-6%)), but was less reliable at identifying those patients with potentially
      remedial visual impairment (sensitivity 70% (+/-10%), specificity 92% (+/-6%)).
      CONCLUSION: The level of visual impairment in this group of patients is high and
      screening for visual impairment in the elderly with a history of falls is
      justified. We have demonstrated that a suitably trained member of the
      rehabilitation team can identify over 94% of those patients with impaired vision.
      We believe this simple test should now be incorporated into the assessment of all
      patients requiring rehabilitation after a proximal hip fracture.

PMID- 15184958
TI  - Comparison of additional intraocular pressure-lowering effects of latanoprost vs
      brimonidine in primary open-angle glaucoma patients with intraocular pressure
      uncontrolled by timolol-dorzolamide combination.
AB  - PURPOSE: To compare the additive intraocular pressure (IOP)-lowering effects of
      latanoprost 0.005% and brimonidine 0.2% in primary open-angle glaucoma (POAG)
      patients uncontrolled on fixed combination of timolol 0.5% and dorzolamide 2%
      (TDC) alone. METHODS: In all, 80 eyes of 80 POAG patients with IOP inadequately
      controlled by TDC were randomly assigned to receive either latanoprost 0.005% or
      brimonidine 0.2%. IOP measurements were recorded at 1000 (peak effect) and 1600
      (trough effect) on day 0 (baseline) and at 1 and 3 months. At each stage and time
      point, the mean IOP reductions from baseline were evaluated for both groups, and
      success rates (minimum 15% reduction) were determined. RESULTS: At baseline, the
      mean peak/trough IOPs with TDC were 20.2/21.6 and 19.9/21.4 mmHg in latanoprost
      and brimonidine groups, respectively. Latanoprost+TDC reduced the mean
      peak/trough IOP by 4.4/3.4 and 5.2/3.5 mmHg at 1 and 3 months. The corresponding
      values for brimonidine+TDC were 3.9/2.9 and 4.6/2.9 mmHg. Each of these results
      represented a significant reduction from baseline (P<0.001 for all); however, the
      groups' peak/trough reductions from baseline did not differ at any time point
      (P>0.05 for all). With the latanoprost+TDC combination, the peak/trough success
      rates at 1 and 3 months were 76.3%/42.1% and 77.1%/40%. The corresponding values
      with the brimonidine+TDC combination were 71.8%/41% and 77.7%/41.7%. There were
      no significant differences in the groups' success rates at any time point (P>0.05
      for all). CONCLUSION: Addition of latanoprost 0.005% or brimonidine 0.2% to TDC
      reduces peak/trough IOPs significantly and the effects of these combinations are
      comparable.

PMID- 15184959
TI  - Comparison between fixed-angle and customised corneal-polarisation compensation
      methods in scanning laser polarimetric measurement of the retinal nerve fibre
      layer in glaucoma.
AB  - PURPOSE: To investigate the differences between the results of scanning laser
      polarimetric (SLP) measurements of the retinal nerve fibre layer thickness
      (RNFLT) made using two different corneal-polarisation techniques; customised (SLP
      C), and fixed-angle (SLP-F) compensations. METHODS: Both SLP-C and SLP-F were
      performed on 37 consecutive phakic patients with chronic open-angle glaucoma, and
      on 14 healthy control subjects. One randomly selected eye per subject was
      evaluated. RESULTS: Both SLP-C and SLP-F parameters were able to discriminate
      between the glaucoma group and the control group, except in the case of the
      ellipse modulation, which differed significantly between the two groups with SLP
      C (P=0.017), but not with SLP-F (P=0.056). When SLP-C and SLP-F values were
      compared, inferior maximum thickness and ellipse standard deviation were
      significantly lower with SLP-C in both groups (P<0.05 for each parameter).
      Superior maximum thickness was significantly lower in glaucoma with SLP-C than
      with SLP-F (P=0.006) and tended to be lower with SLP-C than with SLP-F in the
      control group (P=0.053). In the glaucoma group, it was only with SLP-C that a
      significant (positive) correlation between the superior maximum thickness and the
      inferior hemifield mean sensitivity (MS) (r=0.653, P<0.001), and between the
      inferior maximum thickness and the superior hemifield MS (r=0.420, P=0.023) was
      found. The other global and sectoral SLP parameters showed significant
      correlation with the corresponding visual field parameters with both techniques.
      CONCLUSION: Our findings suggest that SLP measurements with customised
      compensation provide more realistic results for RNFLT than those made with the
      conventional fixed-angle compensation.

PMID- 15184960
TI  - Influence of subfoveal choroidal neovascularisation on macular imaging with
      scanning laser polarimetry of the retinal nerve fibre layer.
AB  - PURPOSE: To investigate the influence of subfoveal choroidal neovascularisation
      (CNV) on macular imaging performed using scanning laser polarimetry (SLP) of the
      retinal nerve fibre layer. METHODS: SLP was performed on 22 consecutive patients
      with angiographically verified CNV, and on 23 healthy control subjects. One eye
      per subject was evaluated using the GDx Nerve Fibre Analyser. Regularity of the
      corneal retardation on the macular SLP images was assessed according to three
      criteria: (1) magnitude of the 'macular ratio', defined as the ratio of mean
      retardation values along two axes (the axis with the maximum retardation and the
      perpendicular one, corresponding in healthy eyes to minimum retardation); (2) the
      values of GDx parameters which are independent of quadrant position (ellipse
      modulation and ellipse average); and (3) the frequency of the regular 'bow-tie'
      polarisation pattern. RESULTS: 'Macular ratio' was significantly higher in the
      CNV group than in the control group (P<<0.001). Ellipse modulation did not differ
      between the groups, but ellipse average was higher in the CNV group (P=0.016).
      The variance for each of these two parameters was significantly higher for the
      CNV group (P<<0.001 for both comparisons). A 'bow-tie' pattern polarisation was
      seen in 23 of the 23 control eyes, but only in 7 of the 22 CNV eyes (P<<0.001).
      CONCLUSION: The results show that CNV influences the macular image obtained with
      SLP. This suggests that measurements with SLP may be disturbed for eyes with CNV
      when the customised corneal compensation method, which makes use of the macular
      retardation image, is employed.

PMID- 15184961
TI  - Scanning laser tomography of full thickness idiopathic macular holes.
AB  - AIM: We used a retinal tomographic analyser to study the profile of the retinal
      surface in patients with stage 3 and 4 idiopathic macular holes, to attempt to
      elucidate the direction of forces present. METHODS: The Heidelberg retina
      tomograph was used to acquire a three-dimensional tomographic image of the macula
      in each eye of 21 consecutive patients with full thickness macular hole. RESULTS:
      The surface profile showed an elevated rim around the 24 macular holes imaged,
      with a gently sloping outside edge and a steeply sloping inside edge. In
      addition, a ring of elevated tissue around the edge of the hole was observed in
      all the holes and also in two of the fellow 'normal' eyes. This ring of elevated
      tissue was presumed to represent a ring of persistent vitreo-retinal traction
      around the fovea in the presence of a perifoveal posterior vitreous detachment.
      This is consistent with antero-posterior traction persisting in stage 3 and 4
      full thickness macular holes. The mean ring diameter was 480 mum, when present in
      the fellow eye but was 950 microm in the presence of a macular hole, which we
      argue is suggestive of centrifugal displacement of retinal tissue on the
      formation of a stage 3 macular hole and provides evidence for tangential
      traction. CONCLUSION: We suggest that antero-posterior traction forces are the
      primary cause of full thickness macular holes, with these forces persisting in
      stage 3 and 4 macular holes, while tangential forces serve to enlarge the hole at
      this later stage.

PMID- 15184962
TI  - Alternate total ophthalmoplegia and optic neuropathy associated with ulcerative
      colitis.

PMID- 15184963
TI  - Acquired Brown's syndrome secondary to Ahmed valve implant for neovascular
      glaucoma.

PMID- 15184965
TI  - Buphthalmos in trisomy 13.

PMID- 15184964
TI  - Novel mutation in ABCC6 gene in a Japanese pedigree with pseudoxanthoma elasticum
      and retinitis pigmentosa.
AB  - PURPOSE: To report a novel mutation of the ABCC6 gene in a Japanese family that
      had a case of pseudoxanthoma elasticum (PXE) another with PXE and retinitis
      pigmentosa. METHODS: Ophthalmologic examinations were performed, and the ABCC6
      gene was analysed by direct genomic sequencing. RESULTS: Fundus examinations of
      the 48-year-old proband disclosed angioid streaks and a peud'orange appearance of
      the retina of the both eyes, whereas both of his 25- and 20-year-old daughters
      had pigmentary degeneration and angioid streaks. In the sibilings, the mixed cone
      rod ERG was almost nondetectable, whereas that of the proband was well-preserved.
      Molecular genetic analysis revealed that the proband has a homozygous nonsense
      mutation at the 595 bp in the ABCC6, and the siblings were heterozygous for the
      same mutation. This mutation was not detected in Japanese subjects in the JSNP
      database (http://snp.ims.u-tokyo.ac.jp/). CONCLUSIONS: Our results demonstrated
      an association between a novel mutation in the ABCC6 gene and PXE in a Japanese
      family.

PMID- 15184966
TI  - Minimising the risk of iatrogenic intraocular damage.

PMID- 15184967
TI  - Spontaneous inferior subconjunctival haemorrhages in association with
      circumferential drainage blebs.
AB  - AIM: To describe an association of spontaneous inferior subconjunctival
      haemorrhages in eyes with circumferential drainage blebs following
      trabeculectomy. METHODS: Observational case series. Patients with multiple
      episodes of spontaneous inferior subconjunctival haemorrhage following
      trabeculectomy (with or without antimetabolite) and circumferential blebs are
      presented. All patients described had multiple episodes. A possible mechanism is
      discussed. RESULTS: The number of spontaneous haemorrhages ranged from two to
      more than 10. All individual haemorrhages resolved spontaneously without adverse
      sequelae CONCLUSIONS: A new clinical presentation of inferior subconjunctival
      haemorrhage in association with circumferential blebs is described.

PMID- 15184969
TI  - Oliver Twist and Santa Claus.

PMID- 15184968
TI  - Oral fluorescein angiography with the scanning laser ophthalmoscope in diabetic
      retinopathy: a case controlled comparison with intravenous fluorescein
      angiography.
AB  - AIM: To compare the performance of oral fundus fluorescein angiography with a
      confocal scanning laser ophthalmoscope (SLO) with intravenous fundus fluorescein
      angiography (IVFFA) with a fundus camera in the assessment of sight-threatening
      diabetic retinopathy. PATIENTS AND METHODS: A total of 25 patients undergoing
      IVFFA to investigate their diabetic retinopathy were recruited. Participants
      returned 1 week later and an oral angiogram with the SLO was performed. Six
      facets of the oral and intravenous angiograms were scored and compared:
      visualization of the foveal avascular zone (FAZ); branch retinal identification;
      macular leakage; identification of microaneurysms in areas of macular leakage;
      peripheral nonperfusion, and leakage from neovascular complexes. RESULTS:
      Compared to IVFFA, the FAZ was unreliably visualized with oral angiography (Kappa
      0.1, 95% CI 0-0.3). In contrast, macular leakage (Kappa 0.78, 95%, CI 0.72-0.83),
      identification of microaneurysms in areas of macular leakage (Kappa 0.78, 95%, CI
      0.72-0.83), and neovascular complexes (Kappa 1.0) were reliably seen. Analysis of
      the visualization of peripheral nonperfusion was complicated by the finding that
      profuse dye leakage from neovascular complexes obscured the view of the
      peripheral retina. If the five angiograms in which this occurred were excluded,
      oral angiography identified 23 of the 24 eyes in which significant nonperfusion
      was found on IVFFA. CONCLUSION: Oral angiography with the SLO can provide high
      quality angiograms that allow judgments to be made about the presence of
      treatable diabetic maculopathy, proliferative diabetic retinopathy, and
      peripheral nonperfusion. In the presence of coexisting macular oedema, it proved
      to be an unreliable technique with which to investigate foveal ischaemia.

PMID- 15184970
TI  - GM food and crops: what went wrong in the UK? Many of the public's concerns have
      little to do with science.

PMID- 15184972
TI  - Basic research must come first. An interview with Zuoyan Zhu, Vice President of
      the National Natural Science Foundation of China and member of the Chinese
      Academy of Sciences. Interviewed by Holger Breithaupt and Caroline Hadley.

PMID- 15184971
TI  - Mastering science in the South. To develop much-needed research capacity,
      developing countries cannot rely on the industrialized world, but have to find
      their own specific solutions.

PMID- 15184973
TI  - Who did what? Uneasiness with the current authorship is prompting the scientific
      community to seek alternatives.

PMID- 15184974
TI  - Waiter, there's a nanobot in my martini! As nanotechnology gives birth to
      nanobiotechnology, definitions and perceptions are at risk of becoming mixed into
      an exotic cocktail.

PMID- 15184976
TI  - Structures of protein domains that create or recognize histone modifications.
AB  - DNA is packed together with histone proteins in cell nuclei to form a compact
      structure called chromatin. Chromatin represents a scaffold for many genetic
      events and shows varying degrees of condensation, including a relatively open
      form (euchromatin) and a highly condensed form (heterochromatin). Enzymes such as
      histone acetyltransferases (HATs) and methylases covalently label the amino
      termini of histones, thereby creating a 'histone code' of modifications that is
      interpreted by the recruitment of other proteins through recognition domains.
      Ultimately, this network of interacting proteins is thought to control the degree
      of chromatin condensation so that DNA is available when it is required for
      genomic processes. Reviewed here are the structures of HAT and SET domains, which
      mediate the acetylation and methylation of histones, respectively, and
      bromodomains and chromodomains, which recognize the modified histones. How these
      structures have increased our understanding of DNA regulation is also discussed.

PMID- 15184977
TI  - Multicellular microorganisms: laboratory versus nature.
AB  - Our present in-depth knowledge of the physiology and regulatory mechanisms of
      microorganisms has arisen from our ability to remove them from their natural,
      complex ecosystems into pure liquid cultures. These cultures are grown under
      optimized laboratory conditions and allow us to study microorganisms as
      individuals. However, microorganisms naturally grow in conditions that are far
      from optimal, which causes them to become organized into multicellular
      communities that are better protected against the harmful environment. Moreover,
      this multicellular existence allows individual cells to differentiate and acquire
      specific properties, such as forming resistant spores, which benefit the whole
      population. The relocation of natural microorganisms to the laboratory can result
      in their adaptation to these favourable conditions, which is accompanied by
      complex changes that include the repression of some protective mechanisms that
      are essential in nature. Laboratory microorganisms that have been cultured for
      long periods under optimized conditions might therefore differ markedly from
      those that exist in natural ecosystems.

PMID- 15184978
TI  - Early vitamin E supplementation attenuates diabetes-associated vascular
      dysfunction and the rise in protein kinase C-beta in mesenteric artery and
      ameliorates wall stiffness in femoral artery of Wistar rats.
AB  - AIMS/HYPOTHESIS: The impact of early vitamin E supplementation on vascular
      function in diabetes remains unresolved. Therefore, we examined the effects of
      vitamin E on functional and structural parameters and on chemical markers that
      are disturbed in diabetes in mesenteric and femoral arteries. METHODS: Segments
      of both arteries, taken from control and 8-week-old streptozotocin diabetic
      Wistar rats that were treated or not with vitamin E, were mounted on wire and
      pressure myographs, after which endothelium-dependent and -independent
      vasodilation was assessed. Passive mechanical wall properties and the
      localisation and levels of protein kinase C (PKC)-beta(2) and AGE were evaluated
      in these vessels. RESULTS: Vitamin E supplementation was associated with improved
      endothelium-dependent and -independent vasodilatation in mesenteric arteries from
      diabetic rats. Impaired endothelium-dependent vasodilatation in diabetic
      mesenteric vessels was associated with PKC-beta(2) up-regulation and this was
      prevented by vitamin E supplementation. Increased AGE accumulation and plasma
      isoprostane levels in diabetic rats were not changed by vitamin E. In the femoral
      artery, vitamin E supplementation had no effect on endothelium-dependent or 
      independent vasodilatation, but did prevent the wall stiffening associated with
      diabetes. CONCLUSIONS/INTERPRETATION: Early vitamin E supplementation has a
      beneficial effect on diabetes-induced endothelial dysfunction in resistance
      arteries. This benefit may arise from a direct effect on smooth muscle function,
      as a result of inhibition of the PKC-beta(2) isoform by vitamin E.

PMID- 15184979
TI  - Effects of metoprolol on QT interval and QT dispersion in Type 1 diabetic
      patients with abnormal albuminuria.
AB  - AIMS/HYPOTHESIS: The excess mortality in diabetes is mainly due to cardiovascular
      causes and almost confined to patients with abnormal albuminuria. Compared to
      healthy subjects, diabetic patients have a prolonged QT interval and increased QT
      dispersion. In non-diabetic subjects, as well as in Type 1 diabetic patients with
      overt nephropathy, a prolonged QT interval and increased QT dispersion are
      associated with cardiac morbidity and mortality. There is an increasing number of
      studies on effects of beta blocker treatment on QT interval and QT dispersion in
      non-diabetic subjects. In contrast, there are no studies on the effects of beta
      blocker treatment on QT interval and QT dispersion in patients with diabetes. The
      aim of our study was to describe the effects of metoprolol treatment on QT
      interval and QT dispersion in a group of well-characterised Type 1 diabetic
      patients with elevated urine albumin excretion. METHODS: We studied the effects
      of 6 weeks of treatment with metoprolol (100 mg once daily, zero order kinetics
      formulation) in a randomised, placebo-controlled, double blind, crossover trial
      including 20 Type 1 diabetic patients. Patients were simultaneously monitored
      under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood
      pressure recording and 24-h fractionated urine collections. On days of
      investigation 12-lead electrocardiograms were recorded and autonomic tests
      performed. RESULTS: We found strong associations between both daytime and night
      time blood pressure and heart-rate-corrected QT interval dispersion (QTc
      dispersion). Heart rate variability parameters indicating sympathetic and
      parasympathetic modulation showed strong correlations with heart-rate-corrected
      QT interval (QTc interval) and with QTc dispersion. Beta blocker treatment caused
      a decrease in QTc interval but no change in QTc dispersion.
      CONCLUSIONS/INTERPRETATION: This study is the first to address the QTc interval
      and QTc dispersion in Type 1 diabetic patients treated with metoprolol. Beta
      blocker treatment caused a decrease in QTc interval but no change in QTc
      dispersion. These results may in part explain the pronounced cardioprotective
      effect of beta blocker treatment in diabetic patients with cardiovascular
      disease.

PMID- 15184980
TI  - Nerve growth factor supplementation reverses the impairment, induced by Type 1
      diabetes, of hindlimb post-ischaemic recovery in mice.
AB  - AIMS/HYPOTHESIS: Type 1 diabetes increases the risk of peripheral ischaemia and
      impairs recovery once ischaemia occurs, probably because the healing process is
      hampered by diabetes-induced endothelial dysfunction. In normoglycaemic mice
      subjected to limb ischaemia, blockade of nerve growth factor (NGF) compromises
      reparative angiogenesis. In the present study, we evaluated if expressional
      alterations of endogenous NGF system components are associated with diabetes
      related impairment in neovascularisation. In addition, we tested whether the
      correction of NGF liabilities benefits post-ischaemic healing of Type 1 diabetic
      animals. METHODS: Unilateral hindlimb ischaemia was produced in streptozotocin
      induced Type 1 diabetic mice. Purified murine NGF (20 microg daily for 14 days)
      or PBS were injected into ischaemic adductors. Non-diabetic mice given PBS served
      as controls. Hindlimb blood flow was analysed sequentially for up to 14 days. At
      necroscopy, adductors were removed for quantification of microvessel density,
      endothelial cell apoptosis and NGF receptor expression. NGF content was
      determined by ELISA three days after ischaemia. In vitro, we tested whether NGF
      protects endothelial cells from apoptosis induced by high glucose and whether
      vascular endothelial growth factor-A (VEGF-A) is involved in this beneficial
      effect. RESULTS: Muscles removed from Type 1 diabetic mice showed reduced NGF
      content and up-regulation of the NGF p75 receptor. NGF supplementation promoted
      capillarisation and arteriogenesis, reduced apoptosis, and accelerated blood flow
      recovery. NGF stimulated VEGF-A production by human endothelial cells incubated
      in high-glucose medium and conferred resistance against high-glucose-induced
      apoptosis via a VEGF-A-mediated mechanism. CONCLUSIONS/INTERPRETATION: NGF
      protects endothelial cells from apoptosis induced by Type 1 diabetes and
      facilitates reparative neovascularisation. The findings may open up new
      therapeutic options for the treatment of diabetic complications.

PMID- 15184981
TI  - Human pancreatic duct cells can produce tumour necrosis factor-alpha that damages
      neighbouring beta cells and activates dendritic cells.
AB  - AIMS/HYPOTHESIS: In the human pancreas, a close topographic relationship exists
      between duct cells and beta cells. This explains the high proportion of duct
      cells in isolated human islet preparations. We investigated whether human duct
      cells are a source of TNFalpha-mediated interactions with beta cells and immune
      cells. This cytokine has been implicated in the development of autoimmune
      diabetes in mice. METHODS: Human duct cells were isolated from donor pancreases
      and examined for their ability to produce TNFalpha following a stress-signalling
      pathway. Duct-cell-released TNFalpha was tested for its in vitro effects on
      survival of human beta cells and on activation of human dendritic cells. RESULTS:
      Exposure of human pancreatic duct cells to interleukin-1beta (IL-1beta) induces
      TNFalpha gene expression, synthesis of the 26,000 M(r) TNFalpha precursor and
      conversion to the 17,000 M(r) mature form, which is rapidly released. This effect
      is NO-independent and involves p38 MAPK and NF-kappaB signalling. Duct-cell
      released TNFalpha contributed to cytokine-induced apoptosis of isolated human
      beta cells. It also induced activation of human dendritic cells.
      CONCLUSIONS/INTERPRETATION: Human pancreatic duct cells are a potential source of
      TNFalpha that can cause apoptosis of neighbouring beta cells and initiate an
      immune response through activation of dendritic cells. They may thus actively
      participate in inflammatory and immune processes that threaten beta cells during
      development of diabetes or after human islet cell grafts have been implanted.

PMID- 15184983
TI  - [Laser acupuncture as third-line therapy for primary nocturnal enuresis. First
      results of a prospective study].
AB  - Laser acupuncture is a painless, non-invasive, and cost effective treatment for
      children with therapy resistant monosymptomatic nocturnal enuresis. This kind of
      acupuncture is an alternative treatment with positive results. Currently, we are
      treating 24 children (22 males, 2 females) out of a planned 200 children aged
      between 5 and 12 years. These patients have had a classic monosymptomatic
      nocturnal enuresis. Up to now, school medicine therapy has been unsuccessful.
      Over 3 months, we treated the children once a week with acupuncture, inserting at
      the following points: medial Ren 3, bilateral Ma 36, bilateral Mi 6, bilateral Bl
      33, medial Ren 6, medial Ex B5.A better enuresis frequency was achieved in 21 out
      of the 24 children (87.5%). Before the end of the 12th treatment, six of the 24
      children (25%) were completely dry and 16 (66.6%) had an enuresis frequency
      reduced by more than half after the 12th treatment.

PMID- 15184982
TI  - Mapping 245 SSR markers on the Vitis vinifera genome: a tool for grape genetics.
AB  - The aim of the present work was to develop a microsatellite marker-based map of
      the Vitis vinifera genome (n=19), useful for genetic studies in this perennial
      heterozygous species, as SSR markers are highly transferable co-dominant markers.
      A total of 346 primer pairs were tested on the two parents (Syrah and Grenache)
      of a full sib population of 96 individuals (S x G population), successfully
      amplifying 310 markers. Of these, 88.4% markers were heterozygous for at least
      one of the two parents. A total of 292 primer pairs were then tested on Riesling,
      the parent of the RS1 population derived from selfing (96 individuals),
      successfully amplifying 299 markers among which 207 (62.9%) were heterozygous.
      Only 6.7% of the markers were homozygous in all three genotypes, stressing the
      interest of such markers in grape genetics. Four maps were constructed based on
      the segregation of 245 SSR markers in the two populations. The Syrah map was
      constructed from the segregations of 177 markers that could be ordered into 19
      linkage groups (total length 1,172.2 cM). The Grenache map was constructed with
      the segregations of 178 markers that could be ordered into 18 linkage groups
      (total length 1,360.6 cM). The consensus S x G map was constructed with the
      segregations of 220 markers that were ordered into 19 linkage groups (total
      length 1,406.1 cM). One hundred and eleven markers were scored on the RS1
      population, among them 27 that were not mapped using the S x G map. Out of these
      111 markers, 110 allowed to us to construct a map of a total length of 1,191.7
      cM. Using these four maps, the genome length of V. vinifera was estimated to be
      around 2,200 cM. The present work allowed us to map 123 new SSR markers on the V.
      vinifera genome that had not been ordered in a previous SSR-based map (Riaz et
      al. 2004), representing an average of 6.5 new markers per linkage group. Any new
      SSR marker mapped is of great potential usefulness for many applications such as
      the transfer of well-scattered markers to other maps for QTL detection, the use
      of markers in specific regions for the fine mapping of genes/QTL, or for the
      choice of markers for MAS.

PMID- 15184984
TI  - [Cortical representation of pain].
AB  - Contrary to the traditional view that the cerebral cortex is not involved in pain
      perception an extensive cortical network associated with pain processing has been
      revealed during the past decades. This network consistently includes the primary
      (S1) and secondary somatosensory cortices (S2), the insular cortex, and the
      anterior cingulate cortex (ACC). These cortical areas are organized in parallel
      and contribute to different dimensions of pain experience. The S1 cortex is
      mainly involved in discriminative aspects of pain, while the S2 cortex seems to
      have an important role in cognitive aspects of pain perception. The insula has
      been proposed to be involved in autonomic reactions to noxious stimuli and in
      pain-related learning and memory. The ACC is closely related to pain affect and
      may subserve the integration of general affect, cognition, and response
      selection. Furthermore, first pain appears to be particularly related to
      activation of S1 whereas second pain is closely related to ACC activation.

PMID- 15184985
TI  - SLC22A4 and RUNX1: identification of RA susceptible genes.
AB  - Recently we reported that SLC22A4 and RUNX1 are associated with rheumatoid
      arthritis (RA). SLC22A4 is an organic cation transporter with unknown
      physiological function, and RUNX1 is a hematological transcriptional regulator
      that has been shown to be responsible for acute myelogenic leukemia. It is
      suggested that the association of RUNX1 with RA is due to its regulation of
      expression of SLC22A4. Because the physiological function of SLC22A4 is still
      unclear, further investigation is needed into how SLC22A4 affects RA
      susceptibility. Although the association of RUNX1 with RA was identified as a
      regulatory factor of SLC22A4, it is possible that RUNX1 is a key molecule in
      autoimmunity, as it has been reported to be associated with systemic lupus
      erythematosus and psoriasis, two other autoimmune diseases.

PMID- 15184987
TI  - [Carcinogenic and co-carcinogenic effects of metals and ethanol on human salivary
      gland tissue].
AB  - BACKGROUND: The etiology of malignomas of human salivary glands is examined.
      MATERIAL AND METHODS: Macroscopic, healthy salivary gland tissue from 46 donors
      was harvested during surgery. Single cells were isolated by enzymatic digestion.
      These were then incubated for 60 min with Na(2)Cr(2)O(7), NiSO(4), CdSO(4),
      ZnCl(2) and ethanol. Additionally, incubation with Na(2)Cr(2)O(7) was combined
      with NiSO(4), CdSO(4), ZnCl(2) and ethanol. The influence of CdSO(4) was analyzed
      by altered combinations with Na(2)Cr(2)O(7) during incubation and by the DNA
      repair period. Evaluation was performed using fluorescent staining and digital
      analysis. RESULTS: Of all of the substances tested, only Na(2)Cr(2)O(7) showed
      genotoxic effects. NiSO(4), ZnCl(2) and ethanol had neither genotoxic nor
      cofactorial impacts. CdSO(4), however, caused additional genotoxic effects in
      combination with Na(2)Cr(2)O(7), although it lacked direct genotoxic potential. A
      reduction of DNA-repair of Na(2)Cr(2)O(7)-induced oxidative damage by CdSO(4)
      could be demonstrated. CONCLUSIONS: In this investigation, sodium dichromate was
      identified as genotoxic in association with human salivary gland tissue. These
      effects could be increased by CdSO(4), reinforcing DNA damage based on oxidative
      stress.

PMID- 15184986
TI  - Role of Id proteins in B lymphocyte activation: new insights from knockout mouse
      studies.
AB  - Id (inhibitor of differentiation) proteins play important roles in cell
      differentiation, cell cycle control, and apoptosis. They act as negative
      regulators of basic helix-loop-helix-type transcription factors, which positively
      regulate differentiation of various cell types. Id proteins work to block B
      lymphocyte (B cell) maturation at an early differentiation step, as demonstrated
      by gain-of-function studies. In recent years a series of gene-targeted mice
      lacking different Ids have been generated. Analyses of these gene-targeted mice
      provide information useful for understanding the physiological roles of Ids in B
      cell biology. Id3 is required for proper B cell functions and acts by controlling
      the cell cycle. Upon B cell activation, Id2 acts as a negative regulator to
      prevent potentially harmful effects brought about by excessive immunological
      reactions; one of its special roles is to maintain low serum concentrations of
      immunoglobulin E (IgE). The Id2 protein does this by antagonizing E2A and Pax5
      activities, both of which are required for proper B cell activation. This review
      presents several new insights into B cell differentiation and activation programs
      and the physiological role of Id proteins in B cell activation.

PMID- 15184988
TI  - [Influence of the head position in laryngoscopy].
AB  - INTRODUCTION: The aim of this study was to determine the optimal position of the
      head during larygoscopy. MATERIAL AND METHODS: During fiberoptic evaluation of
      the larynx, the head position of eight subjects (5 male, 3 female) was changed
      systematically. The influence of reclining and anteversion, tilting and rotation
      of the head on the quality of the endoscopic images was determined. RESULTS: The
      vocal tract became wider and the view onto the glottis could be improved by
      reclining the head and anteversion of the chin. On rotation of the head, the
      hypopharynx of the same side became narrower. This is well known and is used
      worldwide in the therapy of dysphagia. DISCUSSION: Positioning of the patient is
      important in laryngoscopy. Reclining the head and forward inclination of the
      trunk (horizontal axis of the mouth) seems to be the best position for obtaining
      an optimal view onto the glottis.

PMID- 15184989
TI  - [Is tracheotomy of angioedema associated with ACE-inhibitor therapy?].
AB  - Angioedema of the upper airways associated with angiotensin-converting enzyme
      inhibitors (ACEI) represent a rare but serious problem. We present two cases from
      our hospital in order to illustrate the therapeutic consequences resulting from
      angioedema associated with the intake of ACEIs. Surgical airway management should
      be considered early if medical treatment fails.

PMID- 15184991
TI  - [LipoRepair. Approach to correction of fat tissue deformities].
AB  - The increasing number of liposuction procedures has led to a growing number of
      iatrogenic fat tissue deformities, in addition to those of idiopathic, traumatic
      and disease-related nature. Correspondly the need for corrective procdures has
      incraesed. In recent years a number of methods have been developed with are
      minimally invasive and low-risk. LipoRepair is a treatment concept which combines
      several of these minimally invasive procedures in order to maximize results with
      maximum tissue sparing. LipoRepair is also suited to treat other fat tissue
      deformities. The following procedures can be employed alone or in combination:
      vibration-assisted liposuction, lipotransfer/liporecycling, liposhifting/
      internal lipomobilization, repeated hydrodissection training subcutaneous tissue
      and subcision.

PMID- 15184990
TI  - [Submandibular sialoliths. Stone removal with organ preservation].
AB  - BACKGROUND: Sialolithiasis as a cause of sialadenitis within Wharton's duct
      accounts for more than 80% of all cases. In the past extirpation of the gland was
      carried out in nearly all cases. Gland-preserving therapies such as transoral
      removal have so far been seldom examined. PATIENTS AND METHODS: In 683 patients
      suffering from submandibular lithiasis with a mean age of 45 years (8-87 years)
      transoral removal of the stones were carried out. The follow-up period was 1-7
      years. The stone location was distal to the edge of the mylohyoid muscle in 283
      cases and more proximal to the gland within the hilum in 296 patients (single
      concrements). Fifty-nine patients had two separate stones, one within the area of
      the hilum and other smaller ones proximal within the gland. RESULTS: All patients
      with distal stone location, 89% of patients with single stones of the perihilar
      region, and 63% of the patients with two separate stones in the hilum and
      parenchyma were free of stones. Another 8 and 23%, respectively, had small
      residual concrements without any complaints. Recurrence of lithiasis or damage of
      the lingual nerve remained below 1%. CONCLUSION: Transoral removal in palpable
      sialoliths should be considered as the treatment of choice in patients suffering
      from submandibular stones located within the floor of the mouth or within the
      perihilar region of the gland. Ultrasound imaging is important for exact location
      of the stones.

PMID- 15184992
TI  - [Gestational trophoblastic disease. Non-villous forms of gestational
      trophoblastic disease].
AB  - The non-villous forms of gestational trophoblastic disease (GTD) include a wide
      range of morphologic different lesions and cover a wide range of differential
      diagnosis. Choriocarcinomas (CCA) represent the most malignant form displaying a
      dimorphic pattern with proliferation of syncytio- and zytotrophoblast. An early
      start of chemotherapy is of great prognostic impact. Placental site nodule (PSN)
      and exaggerated placental site (EPS) are non-neoplastic lesions of the
      intermediate trophoblast without tumorous appearance, whereas placental site
      trophoblastic tumor (PSTT) and epitheloid trophoblastic tumor (ETT) represent
      tumorous neoplasms with a potential for local invasion and metastases. PSNs are
      incidental findings of highly polymorphic cells. In EPS chorionic villi are
      almost present, endometrial glands and spiral arteries are completely engulfed by
      intermediate trophoblastic cells without necroses. In PSTT the monomorphic,
      occasional multinucleated giant cells separating individual muscle fibers and
      charactersitically blood vessel walls are extensively replaced by trophoblastic
      cells and fibrinoid material. The ETT consists large necrotic areas with
      hyalinisation. Typically small blood vessels with preserved walls are located
      within the center of glycogen-rich monomorphous proliferation of trophoblastic
      cells.

PMID- 15184993
TI  - Urine mesna excretion after intravenous and oral dosing in ifosfamide-treated
      children.
AB  - PURPOSE: To describe mesna excretion in children. PATIENTS AND METHODS: We
      studied 14 children (aged 1-18 years) who received 1.8 g/m(2) of ifosfamide per
      day for 5 days. For uroprotection, the children were given intravenous mesna
      (equal to 20% of the ifosfamide dose) followed by two oral doses (each equal to
      40% of the ifosfamide dose). The concentrations of mesna and the metabolite
      dimesna were measured in urine samples collected on treatment days 1 and 5.
      RESULTS: Of 14 patients enrolled, 11 (aged 4-18 years) were evaluable. The
      profiles of mesna excretion rates were similar on days 1 and 5. Mesna excretion
      declined rapidly over 1-2 h after intravenous dosing. Increases in mesna
      excretion after oral dosing lagged by 2-4 h. About 21% of the mesna administered
      was excreted unchanged over 24 h on both days 1 and 5. The proportion excreted
      varied by severalfold between patients, but there was no association with age.
      CONCLUSION: The profile of mesna excretion after intravenous and oral dosing in
      these children was similar to that in reported studies of ifosfamide-treated
      adults.

PMID- 15184994
TI  - Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in
      combination with paclitaxel and carboplatin in patients with solid tumors.
AB  - PURPOSE: Preclinical studies have demonstrated a synergistic effect with the
      angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical
      trial with the combination of paclitaxel and TNP-470 has shown promising effects.
      The present study was designed to determine the toxicity and pharmacokinetics of
      carboplatin in combination with TNP-470 in comparison with the doublet regimen of
      paclitaxel and carboplatin in patients with solid tumors. EXPERIMENTAL DESIGN:
      Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2)
      and thymoma (1). The patients received intravenous paclitaxel and carboplatin on
      day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on
      Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The
      initial cohort of three patients received carboplatin at AUC 5 mg/ml x min. No
      dose-limiting toxic effects occurred, thus the subsequent cohort received
      carboplatin at AUC 6 mg/ml x min. In addition to toxicity, the pharmacokinetics
      of carboplatin were evaluated, and tumor response and patient survival rates were
      assessed. RESULTS: The administered regimen of paclitaxel (225 mg/m(2) i.v. over
      3 h) and carboplatin (AUC 6 mg/ml x min i.v. over 1 h) on day 1 followed by TNP
      470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday,
      and Friday) was defined as both the maximum tolerated and optimal dose.
      Hematological toxic effects were similar to those expected with the chemotherapy
      doublet. All neurocognitive impairments were graded as mild to moderate and
      reversed after discontinuation of TNP-470 administration. No alterations in the
      pharmacokinetic disposition of carboplatin were noted. Overall, the median
      survival duration was 297 days. Four patients (24%) had a partial response, and
      eight (47%) had stable disease. CONCLUSIONS: The combination of TNP-470,
      paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further
      randomized studies of TNP-470 with this doublet regimen are now warranted for non
      small-cell lung carcinoma and other solid tumors.

PMID- 15184995
TI  - Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant
      recurrent ovarian cancer.
AB  - PURPOSE: To determine the response rate to 26-h continuous infusion cyclosporine
      A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with
      recurrent ovarian cancer, and to determine the effect of CSA on the
      pharmacokinetics of CBDCA. EXPERIMENTAL DESIGN: To examine the effect of duration
      of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed
      in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every
      3 weeks was then administered to patients on this phase II study.
      Pharmacokinetics of CSA and CBDCA were determined in a subset of patients.
      RESULTS: Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA
      resistance in a concentration-dependent and time-dependent manner. A group of 23
      patients received 58 courses of CBDCA/CSA therapy. One partial response was
      observed. Eight patients achieved disease stabilization. Toxicity was similar to
      that observed in our previous phase I study and consisted of myelosuppression,
      nausea, vomiting, and headache. The mean +/- SD end-of-infusion CSA level (HPLC
      assay) was 1253 +/- 400 microg/ml. The pharmacokinetic studies suggest that CSA
      does not increase CBDCA AUC. CONCLUSIONS: Steady-state levels of >1 microg/ml CSA
      (HPLC assay) are achievable in vivo. Modest partial reversal of platinum
      resistance (in one patient with an objective response and in eight patients with
      stable disease noted) is achievable in vivo in patients pretreated with CSA. This
      phenomenon is not explained by alterations in CBDCA pharmacokinetics.

PMID- 15184996
TI  - Renal arteriovenous fistula with rapid blood flow successfully treated by
      transcatheter arterial embolization: application of interlocking detachable coil
      as coil anchor.
AB  - A 70-year-old woman presented to our outpatient clinic with a large idiopathic
      renal arteriovenous fistula (AVF). Transcatheter arterial embolization (TAE)
      using interlocking detachable coils (IDC) as an anchor was planned. However,
      because of markedly rapid blood flow and excessive coil flexibility, detaching an
      IDC carried a high risk of migration. Therefore, we first coiled multiple loops
      of a microcatheter and then loaded it with an IDC. In this way, the coil was well
      fitted to the arterial wall and could be detached by withdrawing the
      microcatheter during balloon occlusion ("pre-framing technique"). Complete
      occlusion of the afferent artery was achieved by additional coiling and absolute
      ethanol. This technique contributed to a safe embolization of a high-flow AVF,
      avoiding migration of the IDC.

PMID- 15184997
TI  - Percutaneous shunt creation for hemodialysis using uncovered metallic stents.

PMID- 15184998
TI  - Percutaneous endovascular treatment of chronic iliac artery occlusion.
AB  - PURPOSE: To evaluate the clinical and radiological long-term results of
      recanalization of chronic occluded iliac arteries with balloon angioplasty and
      stent placement. METHODS: Sixty-nine occluded iliac arteries (mean length 8.1 cm;
      range 4-16 cm) in 67 patients were treated by percutaneous transluminal
      angioplasty and stent placement. Evaluations included clinical assessment
      according to Fontaine stages, Doppler examinations with ankle-brachial index
      (ABI) and bilateral lower extremity arteriograms. Wallstent and Cragg vascular
      stents were inserted for iliac artery recanalization under local anesthesia.
      Follow-up lasted 1-83 months (mean 29.5 months). RESULTS: Technical success rate
      was 97.1% (67 of 69). The mean ABI increased from 0.46 to 0.85 within 30 days
      after treatment and was 0.83 at the most recent follow-up. Mean hospitalization
      time was 2 days and major complications included arterial thrombosis (3%),
      arterial rupture (3%) and distal embolization (1%). During follow-up 6% stenosis
      and 9% thrombosis of the stents were observed. Clinical improvement occurred in
      92% of patients. Primary and secondary patency rates were 75% and 95%,
      respectively. CONCLUSION: The long-term patency rates and clinical benefits
      suggest that percutaneous endovascular revascularization with metallic stents is
      a safe and effective treatment for patients with chronic iliac artery occlusion.

PMID- 15184999
TI  - Comparative effectiveness of several agents for preventing postoperative
      adhesions.
AB  - Postoperative adhesions (PAs) are usually clinically asymptomatic. Symptomatic
      cases, however, may present with chronic abdominal and pelvic pain, infertility,
      and intestinal obstruction; and they may require intensive, costly therapeutic
      modalities. Various agents have been used to prevent PAs, but the results
      indicate general suboptimal effectiveness. Our objective was to evaluate the
      comparative effectiveness of two pharmacologic agents for preventing PA:
      nadroparine calcium (low-molecular-weight heparin, or LMWH) and aprotinin, as
      well as a barrier agent, sodium hyaluronate/carboxymethycellulose (SCMC). Our
      subjects were 40 male Wistar-Albino rats divided into four groups, each
      consisting of 10 rats, which underwent standard cecal abrasion preceding midline
      laparotomy. In the control group (group 1) 1 ml of 0.9% NaCl was administered
      intraperitoneally before abdominal closure. In the three preventive groups, 100 U
      AXa (anti factor X activity) LMWH, 1800 IU aprotinin, and SCMC were administered
      intraperitoneally to groups 2, 3, and 4, respectively. Relaparotomy was performed
      on the 14th postoperative day. Visceral and abdominal wall adhesions were scored
      in a blinded fashion. The adhesion scores (mean +/- SD) for groups 1, 2, 3, and 4
      were 2.00 +/- 0.67, 0.6.00 +/- 0.84, 1.10 +/- 0.74, and 0.20 +/- 0.42,
      respectively. The differences in the adhesion scores among all three preventive
      groups (groups 2, 3, 4) were statistically significant when compared with the
      control group ( p < 0.001, p = 0.017, p < 0.001, respectively). Intraperitoneal
      SCMC and administration of LMWH were more effective than giving aprotinin.

PMID- 15185000
TI  - Positive status of alpha-fetoprotein and des-gamma-carboxy prothrombin: important
      prognostic factor for recurrent hepatocellular carcinoma.
AB  - The aim of this study was to evaluate prognostic factors after the recurrence of
      hepatocellular carcinoma (HCC) in patients who had undergone hepatic resection.
      We used univariate and multivariate retrospective analyses of 29
      clinicopathologic factors in 143 patients with recurrent HCC. Patients were
      classified into four groups according to the positivity of tumor markers at the
      time of recurrence. Survival rates and prognostic factors were then compared
      among the four groups. Multivariate analysis revealed four independent prognostic
      factors at recurrence: albumin level < 3.5 g/dl ( p = 0.0003), period until
      recurrence </= 1 year ( p = 0.0004), positive status of alpha-fetoprotein and des
      gamma-carboxy prothrombin (AFP+/DCP+) ( p < 0.0001), and portal vein invasion ( p
      < 0.0001). Among groups with varying status of AFP/DCP, the survival rate in
      patients with AFP+/DCP+ at recurrence was significantly lower than those in the
      other three groups (+/+ 15.9% vs. +/- 47.2%, -/+ 44.8%, or -/- 61.1% at 3 years:
      p < 0.05). The AFP+/DCP+ group also had significantly higher rates of the
      recurrence appearing </= 1 year after operation (+/+ 68.3% vs. +/- 45.2%, -/+
      41.9%, or -/- 32.5%: p = 0.0108), extrahepatic recurrence (29.3% vs. 6.5%, 9.7%,
      or 5.0%: p = 0.0026), and no treatment at recurrence (29.3% vs. 9.7%, 9.7%, or
      5.0%: p = 0.0115). These results indicate that the tumor markers AFP and DCP are
      significant prognostic factors for recurrent HCC, and their monitoring is
      essential for improving the prognosis after recurrence.

PMID- 15185001
TI  - Functional maps of metastases from breast cancers: proof of the principle that
      multidimensional scaling can summarize disease progression.
AB  - The mathematic technique of multidimensional scaling can create "functional maps"
      of metastases from breast cancer such that positions of organs in these maps are
      proportional to the probability of metastases. Areas that are likely to share
      disease are close together in a functional map, even though they may be
      physically distant, and vice versa. Two functional maps of breast cancers-one of
      local metastases to axillary levels I to III and another of distant metastases
      are statistically significant and clinically meaningful. The maps accurately
      reflect the clinical data ( r > 0.97, p < 0.01), and so the progression of
      disease is revealed in simple visual summaries. As an analogy, the metastatic
      sites are like buoys on a fluid surface, and cancer spreads from a primary tumor
      like waves emanating from a point of impact on that surface. Metastases are
      predicted when the waves swamp the buoys. Because breast cancers do not always
      spread to the next nearest site, these functional maps do not resemble anatomic
      maps. The maps are a view of the body as "seen" by the tumor. Several well known
      clinical features are seen in these maps: most local metastases are to axillary
      level I; upper-inner primaries spread equally to levels II and III; in-transit
      metastases in the lymph and blood vessels do not follow the pattern of other
      distant metastases. Future functional maps can expand these summary diagrams to
      include biologic parameters (gene-expression profiles or endocrine response) and
      give valuable insights into patterns of recurrence in different populations.

PMID- 15185002
TI  - Molecular detection of APC, K- ras, and p53 mutations in the serum of colorectal
      cancer patients as circulating biomarkers.
AB  - Early detection of tumor DNA in serum/plasma prior to the development of
      recurrence or metastases could help improve the outcome of patients with
      colorectal cancer (CRC) after tumor resection. Recent advances in the detection
      of tumor DNA in the serum/plasma has opened up numerous new areas for
      investigation and new possibilities for molecular diagnosis. APC and K- ras
      mutations are considered to be early-stage developments of CRCs, whereas p53
      mutations are thought to be relatively late events in the tumorigenesis of CRCs.
      The aim of this study was to search for the presence of genetic mutations in the
      DNA extracted from the serum of CRC patients and healthy subjects. We
      simultaneously evaluate the significance of APC, K- ras, and p53 gene mutations
      in cancer tissues and their paired serum samples of 104 CRC patients by
      polymerase chain reaction-single strand conformation polymorphism analysis (PCR
      SSCP) followed by direct sequencing. Additionally, analysis was carried out to
      detect the serum carcinoembryonic antigen (CEA) levels in CRC patients. Overall,
      we found at least one of the gene mutations in tumor tissues from 75% (78/104) of
      the CRC patients. Comparison of the three molecular markers showed that the
      detection rates in the serum were 30.4%, 34.0%, and 34.2% for APC, K- ras, and
      p53 genes, respectively. Of these patients, 46.2% (36/78) were identified as
      having positive serum results, whereas all healthy controls remained negative.
      The overall positive tumor DNA detection rates in the serum were 0% (0/7) for
      Dukes' A classification, 22.4% (11/49) for Dukes' B, 48.7% (19/39) for Dukes' C,
      and 66.7% (6/9) for Dukes' D. The detection rate increased as the tumor stage
      progressed ( p = 0.012). Concurrently, a significant difference was observed
      between lymph node metastases and positive serum tumor DNA detection ( p <
      0.001). A significantly higher postoperative metastasis/recurrence rate in
      patients harboring gene mutations with serum tumor DNA than those without serum
      tumor DNA was also demonstrated ( p < 0.001). However, no significant correlation
      between the postoperative metastasis/recurrence and serum CEA levels was observed
      ( p = 0.247). These data suggest that the identification of circulating tumor DNA
      using the molecular detection of APC, K- ras, and p53 gene mutations is a
      potential tool for early detection of postoperative recurrence/metastases.
      Moreover, these genes may be potential molecular markers of poor clinical outcome
      in CRC patients.

PMID- 15185003
TI  - Surgical workload and cost of postoperative adhesion-related intestinal
      obstruction: importance of previous surgery.
AB  - Postoperative intraabdominal adhesions cause morbidity of varying degree.
      Intestinal obstruction is the most severe complication of adhesions. This study
      examined the importance of previous surgery on clinical and economic workloads
      caused by intestinal obstruction due to postoperative intraabdominal adhesions.
      All emergency hospitalizations due to adhesion-related intestinal obstruction
      from January 1, 1999 to December 31, 1999 in a hospital district serving roughly
      450,000 inhabitants was reviewed retrospectively. The patient population was
      divided into six groups according to the site of previous surgery, and the total
      as well as group-related surgical workload and direct costs of inpatient care
      were analyzed. There were 123 hospitalizations due to postoperative adhesion
      related intestinal obstruction during the study period. A total of 101 patients
      had experienced 176 operations. The most prevalent operations were colorectal
      (with or without other operations), upper abdominal, and female reproductive
      system procedures. Colorectal surgery preceded 40% and 38% of inpatient episodes
      and inpatient days, respectively. Altogether, 40 operations were performed
      because of adhesion-related intestinal obstruction. No differences between groups
      were seen in terms of the mean operating or theater time. Total annual inpatient
      costs due to emergency hospitalizations for intestinal adhesion-related
      obstruction related to colorectal surgery in a hospital district serving roughly
      450,000 inhabitants was 72,520.60 (U.S. dollars) which accounted for 35.3% of all
      annual costs caused by postoperative adhesion-related intestinal obstructions.
      There were no significant differences between groups regarding the total mean
      inpatient episode costs. Intestinal obstruction due to postoperative adhesions
      poses substantial costs for the society. Colorectal operations are the most
      important procedures preceding adhesion-related intestinal obstruction,
      accounting for 35.3% to 46.8% of the total clinical workload or costs
      attributable to postoperative adhesion-related obstruction.

PMID- 15185004
TI  - Paranasal sinus cancer.

PMID- 15185005
TI  - Source control for surgical infections.
AB  - The concept of source control encompasses all of the physical interventions,
      surgical and otherwise, that are used to treat infection. Although source control
      is one of the most important aspects of the treatment of serious infection, it
      has received relatively little attention. It is the topic of this overview, which
      draws heavily on a book we edited recently: Source Control: A Guide to the
      Management of Surgical Infection (Springer-Verlag, 2002). The first section
      focuses on general considerations: historical perspective, scientific basis, and
      surgical principles of source control. The second section highlights specific
      considerations of source control in various situations.

PMID- 15185007
TI  - Dendritic cells can be rapidly expanded ex vivo and safely administered in
      patients with metastatic breast cancer.
AB  - PURPOSE: Immunotherapy using either dendritic cells (DCs) or expanded cytotoxic T
      cells (CTLs) has received increased interest in the treatment of specific
      malignancies including metastatic breast cancer (MBC). DCs can be generated ex
      vivo from monocytes or CD34+ precursors. The ability to expand and safely
      administer CD34-derived DCs in patients with MBC that have received prior
      cytotoxic chemotherapy has not been evaluated. METHODS: We enrolled ten patients
      with MBC that had received prior chemotherapy for the treatment of metastatic
      disease on a phase I/II trial designed to test the safety and feasibility of
      administering ex vivo expanded DCs from CD34+ progenitor cells. RESULTS: Using a
      cocktail of multiple different cytokines, we could expand DCs 19-fold compared to
      the initial CD34-selected product, which allowed the administration of as many as
      six vaccine treatments per patient. Patients received three to six injections
      i.v. of DCs pulsed with either the wild type GP2 epitope from the HER-2/neu
      protein or an altered peptide ligand, isoleucine to leucine (I2L). Toxicity was
      mild, with no patients demonstrating grade III toxicity during the treatment. Two
      patients with subcutaneous disease had a partial response to therapy, while IFN
      gamma-producing CD8+ T cells could be found in two other patients during
      treatment. CONCLUSIONS: This approach is safe and effective in generating a
      significant quantity of DCs from CD34-precursors.

PMID- 15185008
TI  - Tumour escape from the immune response.

PMID- 15185009
TI  - Correlation between interleukin 6 production and tumor proliferation in non-small
      cell lung cancer.
AB  - Interleukin 6 (IL-6) facilitates the differentiation of B cells to immunoglobulin
      secreting cells and is reported to be a proliferative factor in some tumors. In
      this study, we examined IL-6 production in non-small cell lung carcinoma (NSCLC)
      and the proliferation of tumor cells following IL-6 treatment in vitro and in
      vivo. We analyzed the expression of IL-6 mRNA and protein in a series of 15 human
      lung cancer cell lines (four adenocarcinomas, five squamous cell carcinomas, two
      large cell carcinomas, and four small cell carcinomas) by reverse transcriptase
      polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA).
      We established an IL-6-producing cell line (ABC-1#IL-6) by transfecting a human
      IL-6 cDNA into a human non-IL-6-producing NSCLC cell line (ABC-1). These two cell
      lines were used to determine tumor cell proliferation both in vivo and in vitro
      in order to clarify the effect of IL-6 on tumor growth and metastasis. Athymic
      nude mice, SCID mice, and BALB/c mice were subcutaneously inoculated with these
      two cell lines, and body weight, tumor growth, and tumor doubling time were
      measured. The presence of IL-6 and tumor-infiltrating lymphocytes (TILs) within
      tumor tissues was examined by immunohistochemical staining. RESULTS: Eight of 15
      (53%) lung cancer cell lines expressed both IL-6 mRNA and protein. Tumor lesions
      of both cell lines developed in nude and SCID mice, although no such lesions of
      either cell lines developed in BALB/c mice. The tumor doubling time in nude and
      SCID mice was 2.97+/-1.22 days and 2.45+/-1.32 days, respectively, in mice
      inoculated with the cell line ABC-1#IL-6. These doubling times were statistically
      significantly shorter than those evident in mice inoculated with the control
      original ABC-1 cell line (nude, p=0.0337; SCID, p=0.0119; unpaired t-test). The
      rates of cell proliferation in vitro of the ABC-1#IL-6 and original ABC-1 cells
      lines were comparable ( p=0.1441, unpaired t-test). Immunohistochemical staining
      revealed strong IL-6 expression in tumors derived from the IL-6-producing cell
      line but not in tumors derived from the original ABC-1 cell line (both in nude
      and SCID mice). CONCLUSION: 53% of lung cancer cell lines produce IL-6 mRNA and
      protein. Although IL-6 itself does not influence tumor cell proliferation in
      vitro, an association between IL-6 expression and tumor proliferation was found
      in vivo in nude and SCID mice. An anti-IL-6 reagent could provide a novel
      therapeutic strategy in patients with IL-6-producing lung tumors.

PMID- 15185010
TI  - Virosomes as new carrier system for cancer vaccines.
AB  - HER-2/neu, a tumor-associated antigen (TAAg), plays a critical role in
      oncogenesis of various tumor types, and its selective overexpression by malignant
      tumor cells makes it an ideal target for immunotherapy. A prerequisite for
      clinical vaccines is the construction of safe and highly immunogenic reagents
      able to generate efficient immune responses against TAAg. Previous protein
      vaccines, consisting of the extracellular domain of HER-2/neu (pNeuECD), were
      shown to elicit an immune response that did not provide protection from
      transplantable tumors expressing HER-2/neu. Here we showed that virosomes, which
      consist of reconstituted viral envelopes without viral genetic material, can act
      as a carrier and an adjuvant for a truncated protein pNeuECD. Mice vaccinated
      with pNeuECD either encapsulated in virosomes or bound to the virosomal membrane
      (Vir-pNeuECD), generated rNeu-specific humoral and cytotoxic immune responses. In
      addition, Vir-p(NeuECD) induced significant tumor rejection and additionally did
      not lead to delayed tumor formation when compared with free pNeuECD in complete
      Freund's adjuvant. There was no difference between the virosomal constructs.
      Taken together these results suggest that virosomes, as clinically approved safe
      vaccines, can be used to elicit both humoral and cell-mediated responses against
      TAAg and induce tumor rejection. Our model is providing important preclinical
      data to design human vaccination trials for patients with tumors overexpressing
      HER-2/neu, either as a primary vaccination or as a boost in combination with
      other vaccines in a context of an adjuvant treatment plan.

PMID- 15185011
TI  - Dendritic cell-tumor cell hybrid vaccination for metastatic cancer.
AB  - Dendritic cells are the most potent antigen-presenting cells, and the possibility
      of their use for cancer vaccination has renewed the interest in this therapeutic
      modality. Nevertheless, the ideal immunization protocol with these cells has not
      been described yet. In this paper we describe the preliminary results of a
      protocol using autologous tumor and allogeneic dendritic hybrid cell vaccination
      every 6 weeks, for metastatic melanoma and renal cell carcinoma (RCC) patients.
      Thirty-five patients were enrolled between March 2001 and March 2003. Though all
      patients included presented with large tumor burdens and progressive diseases,
      71% of them experienced stability after vaccination, with durations up to 19
      months. Among RCC patients 3/22 (14%) presented objective responses. The median
      time to progression was 4 months for melanoma and 5.7 months for RCC patients; no
      significant untoward effects were noted. Furthermore, immune function, as
      evaluated by cutaneous delayed-type hypersensitivity reactions to recall antigens
      and by peripheral blood proliferative responses to tumor-specific and nonspecific
      stimuli, presented a clear tendency to recover in vaccinated patients. These data
      indicate that dendritic cell-tumor cell hybrid vaccination affects the natural
      history of advanced cancer and provide support for its study in less advanced
      patients, who should, more likely, benefit even more from this approach.

PMID- 15185012
TI  - Both soluble and membrane-bound forms of Flt3 ligand enhance tumor immunity
      following "suicide" gene therapy in a murine colon carcinoma model.
AB  - In prodrug-activated ("suicide") gene therapy, tumor cells are transfected with
      the gene for an enzyme that converts an inactive prodrug, such as ganciclovir
      (GCV), to a toxic compound. Transfected cells are killed on administration of
      GCV, as also are untransfected "bystander" cells. The ability of the dendritic
      cell stimulatory cytokine Flt3 ligand (Flt3-L) to modulate prodrug-activated gene
      therapy has been investigated. Transfectants of the murine colon carcinoma MC26
      were generated expressing soluble (FLS) and membrane-bound forms of Flt3-L. They
      were inoculated together with wild-type MC26 cells and cells expressing herpes
      simplex virus-1 (HSV1) thymidine kinase into BALB/c mice, which were then
      administered GCV. Expression of Flt3-L or FLS prevented regrowth of tumor in most
      mice, which was comparable to the effect of granulocyte-macrophage colony
      stimulating factor (GM-CSF), while tumors recurred in all mice receiving
      "suicide" gene therapy alone. Recurring tumor cells were resistant to direct
      killing by GCV but sensitive to "bystander" killing in vitro. Mice without tumor
      recurrence were rechallenged with unmodified MC26 cells. Of those mice given
      transfectants expressing GM-CSF, Flt3-L, or FLS, approximately 50% were immune to
      rechallenge. These mice also showed cytotoxic and proliferative responses to MC26
      cells. These experiments show that both soluble and membrane-bound forms of Flt3
      L were able to induce a protective immune response to colon carcinoma cells in a
      fashion similar to GM-CSF.

PMID- 15185013
TI  - Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced
      killer cells derived from patients with pancreatic carcinoma.
AB  - AIM AND BACKGROUND: CD4+CD25+ cells are described as professional
      regulatory/suppressor T cells that are crucial for the prevention of spontaneous
      autoimmune diseases. They play an important role in maintaining a balanced
      peripheral immune system. On the other hand, it has been suggested that
      regulatory T cells (Treg) suppress antitumor immune responses after tumor
      specific vaccinations. Therefore, we determined the percentage of regulatory T
      cells in cytokine-induced killer (CIK) cells, an effector cell population with
      high impact for adoptive immunotherapeutic strategies. RESULTS: CIK cells showed
      strong induction of CD4+CD25+ cells with high secretion of interleukin 10 (IL-10)
      after unspecific stimulation of the TCR complex and stimulation with interleukin
      2. Depletion of CD25+ cells led to an increase in cytotoxic activity and a
      reduction of IL-10 release. A more pronounced reversal of suppression could be
      induced by coculture of CIK cells with dendritic cells (DCs). After coculture of
      CIK cells with DCs, the number of CD4+CD25+ cells as well as the IL-10
      concentration in the supernatant decreased, and the cytotoxic activity against
      pancreatic carcinoma cells increased. This was shown for cells from healthy
      donors as well as for cells from patients with pancreatic carcinoma. CONCLUSION:
      Our established effector cells possess some regulatory features induced by
      unspecific TCR-activation that could be prevented by coculture with DCs. CIK
      cells have desirable properties for immunotherapeutical approaches, especially
      after coculture with DCs, which could be used additionally for induction of a
      specific immune response.

PMID- 15185014
TI  - Evidence for immune defects in breast and lung cancer patients.
AB  - Immunosuppression is often identified in cancer patients. The aim of this study
      was to evaluate several immune parameters for patients with breast and lung
      cancer. Immunophenotyping analysis showed that the cancer patients investigated
      had significantly lower absolute numbers of peripheral blood lymphocytes than
      controls. The immunosuppression was more evident for the breast cancer subgroup.
      The most severe immune defect noticed was the marked impairment of IFN-gamma
      secretion. A shift toward the Th2 phenotype as revealed by assessment of
      intracellular level of IFN-gamma and IL-4 was also noticed. The secretion of
      proinflammatory cytokines IL-1beta and TNF-alpha in whole blood cultures was not
      impaired. Although the proportion of activated cells was slightly lower than in
      the control group, our results showed that both peripheral T lymphocytes and NK
      cells of cancer patients could be induced to express early activation marker CD69
      after ex vivo mitogen stimulation. In conclusion, our study revealed several
      immune defects in cancer patients. This suggests that an appropriate
      immunotherapeutical approach might be used to restore compromised immune
      functions with beneficial effects on both antitumor and general immunity.

PMID- 15185015
TI  - Analysis of the autoantibody repertoire in Burkitt's lymphoma patients: frequent
      response against the transcription factor ATF-2.
AB  - In the last few years, serological identification of tumour-associated antigens
      (TAAs) by recombinant cDNA expression cloning (SEREX) has enabled the mapping of
      humoral immune responses against TAAs in various types of cancer. The present
      paper describes the application of SEREX to Burkitt's lymphoma (BL), a malignancy
      not previously characterized by SEREX. By using a cDNA library from a BL cell
      line that does not express IgG, technical difficulties related to background
      immunoglobulin clones were overcome. Screening with sera from three BL patients
      revealed immunoreactivity against seven different gene products, six of which
      represent known human genes. Five proteins had previously been characterized by
      SEREX in other malignancies or identified as targets of autoantibodies in
      autoimmune disease. Seroreactivity against ATF-2, a member of the AP-1
      transcription factor family, was validated by enzyme-linked immunosorbent assay
      (ELISA) and Western blot analysis using recombinant ATF-2 protein. Autoantibody
      responses against ATF-2 were detected by ELISA in 6 of 8 BL patients, compared
      with 6 of 13 patients with T-cell non-Hodgkin's lymphoma (T-NHL), 5 of 23
      patients with follicular lymphoma and 2 of 27 diffuse large B-cell lymphoma
      patients. In contrast, reactivity was found in only 1 of 50 healthy volunteers.
      Next, we showed by immunohistochemistry that the activated form of ATF2 (ATF-2pp)
      was highly expressed in six different BL samples. We conclude that the SEREX
      approach with a B-cell cDNA source is applicable in NHL. Furthermore, we
      identified genes with possible involvement in the pathogenesis of BL using this
      technique.

PMID- 15185017
TI  - Milk of calcium in a pancreatic pseudocyst.
AB  - A 46-year-old man with a history of chronic alcohol use was found to have milk of
      calcium that had developed in a pancreatic pseudocyst. This was found
      incidentally on abdominal computed tomography during a workup for abnormal liver
      enzymes. Milk of calcium in the pancreas has been described only twice in the
      literature using plain abdominal radiographs and computed tomography. To our
      knowledge, this case report is the first to describe magnetic resonance findings
      of this entity.

PMID- 15185018
TI  - A huge intrahepatic portal vein aneurysm.
AB  - Portal vein aneurysm is an unusual vascular abnormality. We report a rare case of
      a huge intrahepatic portal vein aneurysm at the umbilical portion with hepatic
      encephalopathy. Abdominal contrast-enhanced dynamic computed tomography and
      angiography clearly showed a well-circumscribed, 50 x 40-mm portal vein aneurysm
      at the umbilical portion with portohepatic venous shunt. To our knowledge, this
      is the largest intrahepatic portal vein aneurysm ever reported.

PMID- 15185020
TI  - Fulminant herpes hepatitis in an immunocompetent pregnant woman: CT imaging
      features.
AB  - Fulminant hepatitis due to herpes simplex virus (HSV) is rare in immunocompetent
      adults. Most reported cases have clearly established pregnancy as a condition
      that can predispose to disseminated HSV infection. We report a case of a 25-year
      old previously healthy pregnant woman who presented with fatigue, fever, and
      anicteric hepatitis. Triphasic contrast-enhanced computed tomography demonstrated
      a miliary pattern of multiple, hypovascular, subcentimeter lesions scattered
      throughout the liver. Familiarity with the clinical findings and computed
      tomographic appearance may prompt early recognition of fulminant HSV hepatitis
      and allow differentiation from other hepatic disease during pregnancy.

PMID- 15185019
TI  - Bilateral ovarian leiomyomas: CT and MRI features.
AB  - We recently treated a 21-year-old woman with leiomyomas arising from the
      bilateral ovaries, a very rare condition. On magnetic resonance imaging, more
      than half of the left adnexal mass showed low signal intensity on T2-weighted
      images and good enhancement by gadolinium-DTPA, and the remaining part showed
      high signal intensity on T2-weighted images, so the lesions initially were
      diagnosed as ovarian fibromas or as thecomas with a certain degree of
      degeneration. Pathologic examination of the excised tumors proved that they were
      bilateral ovarian leiomyomas; in addition, the tumor from the left side showed
      hemorrhagic and myxoid changes with torsion of 180 degrees.

PMID- 15185021
TI  - Relation of cholangiocarcinomas to clonorchiasis and bile duct stones.

PMID- 15185022
TI  - Biliary intervention for cholangiocarcinoma.

PMID- 15185023
TI  - Imaging of extrahepatic cholangiocarcinoma.

PMID- 15185024
TI  - Intrahepatic intraductal cholangiocarcinoma.

PMID- 15185025
TI  - Imaging of intrahepatic and hilar cholangiocarcinoma.

PMID- 15185026
TI  - Cholangiocarcinoma: recent advances in imaging and intervention.

PMID- 15185027
TI  - Multiseptate gallbladder: diagnostic value of MR cholangiography and
      ultrasonography.
AB  - Multiseptate gallbladder is a rare congenital malformation. We present a case
      that emphasizes the importance of ultrasonography and magnetic resonance imaging.
      Ultrasound examination of the abdomen showed multiple linear internal echoes
      consistent with multiple septa crossing the entire gallbladder lumen, creating a
      honeycomb appearance. Magnetic resonance cholangiopancreatography showed a
      grapelike cluster of the whole gallbladder.

PMID- 15185028
TI  - Successful treatment of acute Budd-Chiari syndrome with percutaneous transluminal
      angioplasty.
AB  - A 26-year-old man developed progressive, massive ascites and hematemesis due to
      rupture of esophageal varices. Combination diagnostic modalities of color doppler
      ultrasonography, enhanced computed tomography, and magnetic resonance imaging led
      to the case being diagnosed as acute Budd-Chiari syndrome with severe stricture
      of the intrahepatic inferior vena cava. Percutaneous transluminal angioplasty
      this resulted in great improvement of the clinical manifestations.

PMID- 15185029
TI  - Laparoscopic Heller myotomy and fundoplication: findings and predictive value of
      early postoperative radiographic studies.
AB  - BACKGROUND: We describe the findings on esophagography, the frequency and
      appearance of leaks after laparoscopic Heller myotomy and fundoplication, and the
      utility of early postoperative studies for predicting clinical outcome. METHODS:
      Our study group consisted of 40 patients who underwent laparoscopic Heller
      myotomy and fundoplication in whom radiographic studies were performed during the
      early postoperative period. The radiographic reports and images were reviewed to
      determine the esophageal diameter, visualization or nonvisualization of the wrap,
      and the presence or absence of a leak. The esophageal diameter subsequently was
      correlated with the clinical findings to determine whether this was a useful
      parameter for predicting clinical outcome. RESULTS: Two patients (5%) had small,
      sealed-off leaks on radiographic studies, and four (10%) had pseudo-leaks
      resulting from trapping of contrast material alongside the fundoplication wrap.
      Twelve (60%) of 20 patients with a dilated esophagus had esophageal symptoms on
      short-term follow-up versus three (15%) of 20 with a normal-caliber esophagus (p
      = 0.008), and five (56%) of nine patients with a dilated esophagus had symptoms
      on long-term follow-up versus six (43%) of 14 with a normal-caliber esophagus (p
      = 0.68). CONCLUSION: Radiographic studies are useful for showing leaks after
      laparoscopic Heller myotomy and fundoplication, but radiologists should
      differentiate true leaks from trapping of contrast material alongside the
      fundoplication wrap. The caliber of the esophagus on early postoperative studies
      is also a useful parameter for predicting short-term clinical outcome in these
      patients.

PMID- 15185030
TI  - Extrarenal retroperitoneal angiomyolipoma: case report and review of the
      literature.
AB  - Angiomyolipomas are rare benign tumors that usually occur in the kidneys.
      Extrarenal angiomyolipomas are extremely uncommon. We describe a case of
      angiomyolipoma arising in the retroperitoneum that was successfully treated by
      arterial embolization and surgical excision. The literature on retroperitoneal
      extrarenal angiomyolipoma and its differential diagnoses is briefly reviewed.

PMID- 15185032
TI  - Liver metastases in cancer: detection with contrast-enhanced ultrasonography.
AB  - In patients with known or suspected malignancy, ultrasonography (US) is often the
      first choice for liver imaging because of its widespread availability and low
      cost. Compared with contrast-enhanced computed tomography (CT) and magnetic
      resonance imaging (MRI), the sensitivity of conventional US for detecting hepatic
      metastases is relatively poor. The advent of microbubble contrast agents changed
      this situation. Sensitivity and specificity increased substantially with the use
      of these contrast agents and contrast-specific imaging modes in recent years.
      Currently, numerous US imaging methods exist, based on Doppler techniques or
      harmonic imaging. They exploit the complex nonlinear behavior of microbubbles in
      a sound field to achieve marked augmentation of the US signal. Although
      microbubble contrast agents are essentially blood pool agents, some have a
      hepatosplenic specific late phase. Imaging during this late phase is particularly
      useful for improving the detection of malignant liver lesions and allows US to
      perform similarly to spiral CT as shown by recent studies. In addition, this late
      phase imaging is very helpful for lesion characterization. Low mechanical index
      imaging with the newer perfluor agents permits real-time imaging of the dynamic
      contrast behavior during the arterial, portal venous, and late phases and is
      particularly helpful for lesion characterization. The use of US for hemodynamic
      studies of the liver transit time may detect blood flow changes induced by
      micrometastases even before they become visible on imaging. In this field of
      functional imaging, further research is required to achieve conclusive results,
      which are not yet available.

PMID- 15185031
TI  - Coexistence of annular pancreas with carcinoma in the dorsal part of pancreas
      divisum: diagnostic value of magnetic resonance cholangiopancreatography.
AB  - We report on the incidental observation of a pancreas divisum coexistent with an
      annular pancreas in a 88-year-old woman presenting with jaundice due to a
      pancreatic carcinoma. This case report discusses the embryologic hypotheses
      underlying this peculiar association, highlights the capacities of imaging
      techniques to depict them, and enhances the performance of magnetic resonance
      imaging.

PMID- 15185033
TI  - Acute torsion of a wandering spleen: imaging findings.
AB  - Wandering spleen is a rare entity characterized by incomplete fixation of the
      spleen by lienorenal and gastrosplenic ligaments. It can migrate to the lower
      abdomen or pelvis and can be congenital or acquired. We report a case of torsion
      of a wandering spleen for which there was correlative imaging by ultrasonography,
      Doppler ultrasonography, computed tomography, magnetic resonance imaging, and
      angiography. To our knowledge, this is the first reported case in which all these
      modalities were used in the diagnostic evaluation.

PMID- 15185035
TI  - Role of CT-guided core needle biopsy in the diagnosis of a gossypiboma: case
      report.
AB  - A 66-year-old woman with previous hysterectomy had dysuria and vaginal spotting
      for 1 month. Computed tomography showed a heterogeneous presacral mass with
      eccentric calcification. Biopsies of the bladder and vagina and transrectal
      biopsy of the pelvic mass yielded only inflammation. T2-weighted magnetic
      resonance images revealed a heterogeneous mass with wavy hypointensities.
      Computed tomographically guided biopsy targeting at the calcified area disclosed
      thread-like materials, thus confirming the diagnosis of gossypiboma.

PMID- 15185034
TI  - Gallbladder wall thickening associated with infectious mononucleosis.
AB  - Acute infectious mononucleosis is a typical self-limited lymphoproliferative
      illness characterized by fever, tonsillar pharyngitis, and lymphadenopathy in
      adolescents and young adults. Thickening of the gallbladder wall is rarely
      observed. We report a case of infectious mononucleosis in which marked thickening
      of the gallbladder wall was detected by ultrasonography and computed tomography.

PMID- 15185036
TI  - Infected aortic aneurysms: CT features.

PMID- 15185037
TI  - Hepatic allograft salvage with early doppler ultrasound diagnosis of acute vena
      cava thrombosis.
AB  - Postoperative inferior vena cava obstruction is an uncommon complication after
      liver transplantation. Outflow obstruction, if not rapidly corrected, can lead to
      graft failure and the patient's death. We report a case in which Doppler
      ultrasound showed the thrombus inside the vessel, excluding extrahepatic causes
      of venous outflow obstruction, and permitted early surgical correction of the
      complication without graft loss.

PMID- 15185038
TI  - Proximal small bowel intussusceptions in adults: CT appearance and clinical
      significance.
AB  - BACKGROUND: According to the clinical literature, intestinal intussusception in
      adults is rare, is associated with a pathologic lead point, and is usually
      treated surgically. Nonobstructing small bowel intussusception has been reported
      as a transient finding on computed tomographic (CT) studies. METHODS: We
      evaluated the radiographic and clinical findings in 24 patients who were found to
      have 26 proximal small bowel intussusceptions on abdominal CT scans performed for
      a variety of indications. RESULTS: Twenty patients with intussusceptions had no
      evidence of small bowel obstruction. The transient and clinically insignificant
      nature of 22 intussusceptions in these 20 patients was proven radiologically (n =
      14), surgically (n = 1), or by clinical follow-up (n = 7). These patients
      demonstrated a bowel-within-bowel pattern on multiple contiguous images and
      absence of strangulation or intestinal dilatation. No lead points were
      demonstrated in these patients. Three other patients had symptoms of low-grade
      small bowel obstruction and were treated conservatively. Extensive follow-up
      investigations showed no recurrence of intussusception or a lead point. One
      patient had high-grade obstructive intussusception with intestinal ischemia and
      required surgical resection of necrotic bowel. CONCLUSIONS: Proximal small bowel
      intussusceptions are likely to be transient and nonobstructive and unlikely to
      have a significant lead point.

PMID- 15185039
TI  - Coprecipitation of Th(4+) and the purified extracellular polysaccharide produced
      by bacterium Bradyrhizobium (Chamaecytisus) BGA-1.
AB  - The soil bacterium Bradyrhizobium (Chamaecytisus) strain BGA-1 produces an
      extracellular polymeric substance (EPS) that, in the presence of Fe(3+), Al(3+)
      or Th(4+) solutions, forms a gel-like precipitate composed of polysaccharide,
      protein, lipopolysaccharide and the metal. Precipitation of the main component of
      the EPS, the extracellular polysaccharide, and thorium was studied. The
      precipitate was stable, but redissolved at pH values below 3.0 or in the presence
      of 10 mM EDTA. In the precipitate, the ratio thorium/basic repeating unit of the
      polysaccharide ranged from 0.4 to 0.8 mol/mol. Soluble polysaccharide-thorium
      complexes were not found, and larger polysaccharide molecules were precipitated
      in preference to smaller ones. Kinetic studies showed a non-linear dependence of
      the precipitate on the concentrations of both thorium and polysaccharide. The
      behaviors of the purified polysaccharide and of whole EPS with the thorium
      containing precipitate were compared. The results suggested that EPS components
      other than polysaccharide are able to modify the precipitating ability of the
      polysaccharide. Thus, whole EPS is a better substrate than the purified
      polysaccharide for the removal of thorium from its solutions.

PMID- 15185040
TI  - Enhanced production of lactococcin 972 in chemostat cultures.
AB  - Lactococcus lactis subsp. lactis IPLA972 is a wild lactococcal strain suitable as
      a single starter in the manufacture of dairy products. This strain synthesizes
      lactococcin 972 (Lcn972), a unique bacteriocin that blocks septum formation. In
      this work, we report on the conditions to optimize biomass and Lcn972 production.
      In batch cultures, pH 6.8 was found to be optimum for bacteriocin synthesis and
      both glucose and lactose supported Lcn972 production. The inhibitory activity
      improved up to eight-fold with increasing carbohydrate concentration. In
      chemostat cultures, steady states were achieved even at dilution rates higher
      than mu(max), due to the strong wall growth. Lcn972 behaved as a true primary
      metabolite, as it was maximally produced when the cells were actively growing.
      Bacteriocin yields were improved up to ten-fold in chemostat cultures compared
      with those achieved in batch.

PMID- 15185042
TI  - Resolution of calcific brown fat necrosis associated with prostaglandin therapy
      for cyanotic congenital heart disease in neonates: report of two cases.
AB  - Prostaglandin E1 (PGE1) administration for palliation of cyanotic congenital
      heart disease in neonates has been associated with radiographically visible
      necrosis of brown fat about the neck and shoulder girdles. However, the natural
      history of this process has not been described. We present two patients with
      cyanotic congenital heart disease, treated preoperatively with prostaglandin E2
      (PGE2), both of whom developed dramatic calcific brown fat necrosis. This process
      slowly resolved over time in both patients.

PMID- 15185041
TI  - SNP haplotypes and allele frequencies show evidence for disruptive and balancing
      selection in the human leukocyte receptor complex.
AB  - The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes
      polymorphic and highly homologous genes that are expressed by cells of the immune
      system and regulate their function. There is an enormous diversity at the LRC,
      most particularly the variable number of killer cell immunoglobulin-like receptor
      (KIR) genes. KIR have been associated with several disease processes due to their
      interaction with polymorphic human leukocyte antigen class I molecules. We have
      assessed haplotype compositions, linkage disequilibrium patterns and allele
      frequencies in two Caucasoid population samples (n=54, n=100), using a composite
      of single-nucleotide polymorphism (SNP) markers and high-resolution, allele
      specific molecular genotyping. Particular KIR loci segregated with SNP and other
      markers, forming two blocks that were separated by a region with a greater
      history of recombination. The KIR haplotype composition and allele frequency
      distributions were consistent with KIR having been subject to balancing selection
      (Watterson's F: P=0.001). In contrast, there was a high inter-population
      heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor
      A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32).
      An assessment of seven populations representative of African, Asian and Caucasoid
      ethnic groups (total n=593) provided little evidence for long-range LRC
      haplotypes. The different natural selection pressures acting on each locus may
      have contributed to a lack of linkage disequilibrium between them.

PMID- 15185043
TI  - Clinical presentations of mitochondrial cardiomyopathies.
AB  - To determine the clinical manifestations and interfamilial variability of
      patients diagnosed with a mitochondrial cardiomyopathy, we reviewed the charts of
      14 patients with cardiomyopathy out of 59 patients with mitochondrial disorders
      who attended the mitochondrial disease clinic at Wolfson Medical Center from 1996
      to 2001. All patients underwent a metabolic evaluation including blood lactate,
      pyruvate, carnitine, and amino acids and urine organic acids. Respiratory chain
      enzymes were assessed in 10 patients. The mitochondrial DNA (mtDNA) was assessed
      for mutations. The age at presentation ranged between 6 months and 24 years. Six
      of the patients died, 5 from heart failure. The cardiomyopathy was hypertrophic
      in 10 and dilated in 4. Conduction and rhythm abnormalities were present in 6.
      Eleven patients had family members with mitochondrial disorders. All the patients
      had additional involvement of one or more systems. Seven patients exhibited a
      deficiency of a respiratory chain enzyme in the muscle. The MELAS mtDNA point
      mutation (3243) was found in one patient. Blood lactic acid levels were increased
      in 5. Brain MRI abnormalities were observed in 4. CONCLUSIONS: Mitochondrial
      dysfunction frequently affects the heart and may cause both hypertrophic and
      dilated cardiomyopathy. The cardiomyopathy is usually a part of a multisystem
      involvement and may rarely be isolated. The course may be stable for many years,
      but rapid deterioration may occur. Understanding the biochemical and genetic
      features of these diseases will enable us to comprehend the clinical
      heterogeneity of these disorders.

PMID- 15185044
TI  - Rapid evolution of right ventricular cardiomyopathy after surgical closure of a
      secundum atrial septal defect.
AB  - Rapidly developing diffuse right ventricular cardiomyopathy presenting with right
      heart failure in a 9-year-old boy within 2 months after surgical closure of a
      secundum atrial septal defect is reported. The child was treated by palliative
      surgery with partial exclusion of the right ventricle by bidirectional Glenn
      shunt.

PMID- 15185045
TI  - Case report: fatal ventricular tachycardia exacerbated by fever in a child.
AB  - Primary ventricular tachycardia (VT) is rare in children. We report a child with
      VT exacerbated by fever which was ultimately fatal. His first episode occurred at
      5 months old and recurred with fever, occasionally causing syncope. Episodes were
      difficult to control with antiarrhythmic agents during fever but remitted with
      antipyretics. He was admitted to hospital 23 times because of VT and died
      suddenly with fever when he was 17 years old. At autopsy, severe fatty
      replacement of the bundle of His and interstitial fibrosis of the sinus node was
      found.

PMID- 15185046
TI  - Vasodilatory shock after surgery for aortic valve endocarditis: use of low-dose
      vasopressin.
AB  - This is the case report of a 13-year-old male who developed vasopressor-resistant
      hypotension after cardiac surgery for endocarditis. As norepinephrine resulted in
      aggravation of the preexisting ventricular arrhythmia, vasopressin was used to
      maintain blood pressure. The vasopressin continuous infusion was started at
      0.00002 units/kg/min and titrated up to 0.0003 U/kg/min. This low dose led to
      resolution of hypotension without causing side effects. As the appropriate
      indication and dose of vasopressin is not established, the cautious use of
      vasopressin in children is recommended.

PMID- 15185047
TI  - Doppler flow parameters of left ventricular filling in infants: how long does it
      take for the maturation of the diastolic function in a normal left ventricle to
      occur?
AB  - OBJECTIVE: To study the impact of the maturational process of diastolic left
      ventricular function on trans-mitral Doppler flow parameters. METHODS AND
      PARTICIPANTS: In a survey we examined pulsed-wave Doppler signals and diastolic
      time intervals from 238 healthy neonates and infants. Using multiple linear
      regression analysis, we evaluated the impact of physiological determinants on
      parameter expression. RESULTS: Early-filling and atrial-filling peak velocities,
      early-filling acceleration and deceleration rates, and the atrial-filling time
      velocity integral reached a climax within 2 months after birth, while early
      filling time velocity integral followed increasing throughout the study period.
      The isovolumic relaxation time was found to be significantly longer for neonates
      than for infants older than 2 months. The observed parameter movements could be
      attributed to changes of stroke volume and mitral valve area for early filling
      time velocity integral (R2 = 0.93), and of heart rate, stroke volume, and mitral
      valve area for early filling peak velocity (R2 = 0.84), and atrial-filling time
      velocity integral (R2 = 0.65). Isovolumic relaxation time and atrial-filling peak
      velocity became heart rate dependent not before 3 months after birth.
      CONCLUSIONS: The observed parameter changes are powerful indicators for the
      maturational process in diastolic function. This process is mainly completed by 3
      months of age.

PMID- 15185048
TI  - Severe transient left ventricular hypertrophy in an infant with acute myocarditis
      and heart failure.
AB  - A case of rare acute myocarditis with heart failure and transient left
      ventricular hypertrophy in a 4.5-month-old male infant is described. Initial
      echocardiogram demonstrated severe concentric left ventricular hypertrophy with
      depressed left ventricular systolic function and reduced left ventricular cavity.
      Left ventricular hypertrophy was transient; it decreased significantly within a
      couple of weeks concomitantly with the improvement of ejection fraction. The
      myocarditis resolved without sequelae. The natural course of this rare mode of
      presentation of myocarditis and its relationship to immunosuppressive and
      immunomodulatory treatment are discussed.

PMID- 15185049
TI  - Association of Children with Heart Disease in the World: 10-year experience.
AB  - Thousands of children live in developing countries with untreated but correctable
      congenital heart disease (CHD), and most of them will die simple because they
      live in poor countries that do not have suitable medical/surgical facilities. The
      aim of the Association of Children with Heart Disease in the World is to support
      the operatory and teaching activities of a group of voluntary doctors engaged in
      the management of children with CHD in developing countries. Since 1992, the
      association has obtained 160 grants for foreign doctors who have been trained in
      our hospitals; performed 75 missions abroad, with more than 2150 cases evaluated
      and 404 cardiac operations performed; obtained millions of dollars worth of
      donated medical equipment; and constructed two cardiac surgery departments in
      Syria and Cameroon. Many efforts have been made, but much more can be done as we
      attain more experience and develop better coordination and collaboration between
      the international groups engaged in this emerging social need.

PMID- 15185050
TI  - Dual-catheter balloon occlusion aortography in pulmonary atresia with ventricular
      septal defect and major aorto-pulmonary collaterals.
AB  - Angiography remains the gold standard in the preoperative evaluation of complex
      pulmonary blood supply in patients with pulmonary atresia, ventricular septal
      defect, and major aortopulmonary collateral arteries. In neonates, balloon
      occlusion aortography using a Berman balloon catheter is a very effective
      technique. However, in older patients this method is frequently limited due to
      failure to achieve distal balloon occlusion. A novel technique using a balloon
      valvuloplasty catheter and a standard angiographic catheter in combination is
      described. The technique allowed enhanced visualization of the complex anatomy in
      three patients scheduled for surgical intervention.

PMID- 15185051
TI  - Catecholaminergic polymorphic ventricular tachycardia detected by an insertable
      loop recorder in a pediatric patient with exercise syncopal episodes.
AB  - Syncope is a common clinical problem that occurs at all ages and is particularly
      prevalent in childhood and adolescence. The evaluation of syncope is best
      approached using the history and physical examination, electrocardiogram and risk
      stratification to guide further diagnostic tests. Syncope associated with
      exercise or exertion must be considered dangerous, it can be a predictor of
      sudden cardiac death and therefore it must be taken seriously. The insertable
      loop recorder has been proven to be useful in the diagnosis of recurrent syncope
      in adult patients in whom the cause of the syncope cannot be found by other
      noninvasive means. We report the first known case of cathecolaminergic
      polymorphic ventricular tachycardia detected by an insertable loop recorder in a
      5-year-old boy with a syncopal history and no structural heart disease.

PMID- 15185052
TI  - Double-lumen balloon microcatheter-assisted occlusion of cerebral vessels with
      coils: a technical note.
AB  - The purpose of this study was to describe a balloon-assisted double-lumen
      microcatheter technique to perform a controlled and tight coil packing of a
      vascular segment for vessel occlusion. This technique can be performed
      immediately after a test occlusion with the balloon kept in place and was, as
      illustrated in six cases, in our experience safe, straight forward to use and
      fast.

PMID- 15185053
TI  - Anatomical constraints on visualization of the human hippocampus using echo
      planar imaging.
AB  - Reliable visualization of the hippocampus on echo-planar imaging (EPI) is
      essential in analyzing memory function using functional magnetic resonance
      imaging. However, the hippocampal area is notoriously prone to susceptibility
      artifacts caused by structures at the skull base, and avoiding such artifacts by
      appropriately selecting the subjects for a study is of practical importance. To
      elucidate factors affecting the extent of the artifacts we obtained EPI in a
      total of 62 hippocampi from 31 healthy volunteers and evaluated various
      anatomical measurements possibly associated with the quality of the images. The
      hippocampal head was sufficiently well demonstrated on 40 of 62 images (65%), and
      there were two parameters that significantly differed between the good (n=40) and
      poor (n=22) imaging studies: The vertical diameter (DV) of the opening of the
      internal acoustic meatus (IAM) and the pneumatization rate of the sphenoid sinus
      (RP-SS). From logistic regression analysis with the stepwise method, in addition
      to these two factors, the distance between the hippocampal body and IAM (Dhippo
      IAM) and the distance between the hippocampal head and the middle cranial fossa
      at the skull base (Dhippo-base) were extracted. DV-IAM, RP-SS, and Dhippo-base
      were negatively correlated with the good imaging of the hippocampal head. On the
      other hand, Dhippo-IAM was positively correlated. These easily measurable
      parameters will be helpful in selecting subjects and in increasing the efficiency
      of hippocampal visualization in studies on human memory function.

PMID- 15185055
TI  - Fogging on T2-weighted MR after acute ischaemic stroke: how often might this
      occur and what are the implications?
AB  - "Fogging" is the temporary loss of visibility of an infarct on CT which occurs in
      the subacute phase at about 2 weeks after stroke. It occurs in up to 40% of
      medium to large infarcts on CT. It is unclear whether or how often fogging occurs
      on T2-weighted MR, but if it does occur, it can cause underestimation of true
      infarct size. This study examined the possible frequency and time scale of
      "fogging" on T2-weighted MR. We conducted a blinded, independent review of
      prospectively collected MR scans from patients with symptoms of cortical
      ischaemic stroke, scanned sequentially up to 7 weeks after stroke. On each scan
      maximum infarct area was measured, and the infarct extent and swelling were coded
      on a validated scale. "Fogging" was suggested by reduced infarct extent between
      initial and subsequent scans. In 30 patients (with 74 scans) there was some
      apparent "fogging" in 50% of patients between 6 and 36 days (median 10 days)
      after stroke. Reduction in infarct extent on T2-weighted MR which may be
      attributed to "fogging" occurs in a significant proportion of patients with
      cortical infarcts. This may lead to an underestimation of true final infarct
      extent. This suggests that true infarct extent on T2-weighted MR can probably
      only be assessed on scans obtained beyond 7 weeks after stroke.

PMID- 15185054
TI  - Abnormalities on magnetic resonance imaging seen acutely following mild traumatic
      brain injury: correlation with neuropsychological tests and delayed recovery.
AB  - Mild traumatic brain injury (MTBI) is a common reason for hospital attendance and
      is associated with significant delayed morbidity. We studied a series of 80
      persons with MTBI. Magnetic resonance imaging (MRI) and neuropsychological
      testing were used in the acute phase and a questionnaire for post-concussion
      syndrome (PCS) and return to work status at 6 months. In 26 subjects
      abnormalities were seen on MRI, of which 5 were definitely traumatic. There was
      weak correlation with abnormal neuropsychological tests for attention in the
      acute period. There was no significant correlation with a questionnaire for PCS
      and return to work status. Although non-specific abnormalities are frequently
      seen, standard MRI techniques are not helpful in identifying patients with MTBI
      who are likely to have delayed recovery.

PMID- 15185056
TI  - Action of estradiol on epiphyseal growth plate chondrocytes.
AB  - Estrogen plays an important role in the human growth plate by accelerating growth
      and promoting epiphyseal fusion in both sexes. Nevertheless, the precise
      mechanisms responsible for these effects are poorly understood. In the present
      study, we examined the role of 17beta-estradiol (E2) on cell proliferation and
      viability, type X collagen synthesis, alkaline phosphatase activity, and matrix
      calcification in primary cultures of resting, proliferating, and prehypertrophic
      chondrocytes derived from explants of the bovine fetal epiphyseal growth plate.
      Growth plate chondrocytes were isolated and separated into maturationally
      distinct subpopulations, which were cultured for 7-21 days to high density in
      either (1) serum-free medium, (2) 1 nM thyroid hormone (T3), (3) E2
      concentrations ranging from 10(-13) M to 10(-7) M, or (4) a combination of T3 and
      E2. To compare E2 effects in both sexes, chondrocytes were harvested from 8
      fetuses of both sexes. After hormone treatment, cell cultures were analyzed for
      cell number and viability, collagen type X, alkaline phosphatase (ALP), and
      matrix calcification. Neither DNA content nor cell viability were affected by the
      duration or type of hormone treatment. By itself, E2 stimulated maturation of all
      subpopulations only in pharmacologic doses (10(-7) M). Physiologic E2
      concentrations were no different than negative controls treated with ITS
      (insulin, transferrin, and selenite). Regardless of E2 concentrations, the
      addition of E2 to 1 nM T3 did not appreciably affect the response to T3 alone,
      which stimulates maturation of the phenotype. All effects were comparable in both
      male and female chondrocytes, in all cell subpopulations (maturation stages) and
      fetuses of varying gestational age. These findings indicate that at physiologic
      concentrations, the effects of E2 on fetal bovine growth plate chondrocyte appear
      to be indirect and independent of T3, suggesting that, in vivo, E2 acts in
      concert with other factors or hormones to induce fusion of the growth plate.

PMID- 15185057
TI  - Relationship between osteopenia and lumbar intervertebral disc degeneration in
      ovariectomized rats.
AB  - Ovariectomy (OVX) can cause bone loss in rats, but little is known about how it
      also induces lumbar intervertebral disc degeneration (LVD). This study
      investigated how estrogen deficiency affected intervertebral discs in OVX rats.
      Thirty 3-month-old female Sprague-Dawley rats were divided randomly into three
      equal groups. The baseline control group (BL) was killed at the beginning of the
      experiment. An ovariectomy was performed in 10 rats (OVX group) and another group
      of 10 rats was subjected to a sham surgery (Sham group). The OVX rats were
      untreated after the surgery to allow for the development of moderate osteopenia.
      Bone mineral density (BMD) measurement and bone histomorphometric analysis were
      applied to the segments of lumbar spines in all rats killed 6 months after
      surgery. The pathological changes of intervertebral discs were observed and the
      degree of LVD was scored by a histological scoring system. The BMD of the spines
      (L3-L5) in the OVX group decreased significantly compared with the Sham group.
      The bone volume indices in the OVX group were significantly lower, but the bone
      turnover rate parameters were significantly higher than those in the Sham group
      (P < 0.01). The histological scores for LVD in the OVX group were significantly
      higher than those in the Sham group (P < 0.01). There was a significant negative
      correlation between the BMD and Grade II discs in the OVX rats (P = 0.042). In
      conclusion, LVD occurs in the OVX rats and the degeneration of cartilage end
      plates may be a pathogenic factor in disc degeneration.

PMID- 15185058
TI  - Epidemiology of osteoporosis and fracture in men.

PMID- 15185060
TI  - Osteoporosis in men--consensus is premature.

PMID- 15185061
TI  - A radiofrequency glow-discharge-time-of-flight mass spectrometer for direct
      analysis of glasses.
AB  - A radiofrequency (rf) glow-discharge (GD) ion source coupled to a commercial on
      axis time-of-flight mass spectrometer (TOFMS) has been developed for the direct
      analysis of non-conducting samples. Different instrumental configurations of the
      rf-GD source, including the optional use of a sampler cone and the possibility of
      allowing electrical floating of the discharge, were evaluated first with a
      conducting sample. Higher ion signals were obtained when the GD was electrically
      floating and no sampler cone was used. A homogeneous glass was then analyzed
      using two different rf-GD configurations--with a sampler cone and discarding the
      use of the sampler cone. The atomic mass spectra obtained with the TOFMS using
      both configurations were compared. Analyte signals were systematically higher for
      the latest mode which avoids the sampler cone. The analytical capability of the
      proposed rf-GD-TOFMS system for the analysis of thick glasses, up to 6 mm, has
      been investigated in terms of sensitivity, isotopic ratio accuracy, and mass
      resolving power. Different homogeneous glasses (including glasses as thick as 6
      mm) have been analyzed and major and minor elements were detected. Isotope ratio
      accuracies of about +/-1% and mass resolving powers of about 700 were observed.

PMID- 15185062
TI  - Mercury-free sono-electroanalytical detection of lead in human blood by use of
      bismuth-film-modified boron-doped diamond electrodes.
AB  - We report the electroanalytical determination of lead by anodic stripping
      voltammetry at in-situ-formed, bismuth-film-modified, boron-doped diamond
      electrodes. Detection limits in 0.1 mol L(-1) nitric acid solution of 9.6 x 10(
      8) mol L(-1) (0.2 ppb) and 1.1 x 10(-8) mol L(-1) (2.3 ppb) were obtained after
      60 and 300 s deposition times, respectively. An acoustically assisted deposition
      procedure was also investigated and found to result in improved limits of
      detection of 2.6 x 10(-8) mol L(-1) (5.4 ppb) and 8.5 x 10(-10) mol L(-1) (0.18
      ppb) for 60 and 300 s accumulation times, respectively. Furthermore, the
      sensitivity obtained under quiescent and insonated conditions increased from 5.5
      (quiescent) to 76.7 A mol(-1) L (insonated) for 60 s accumulation and from 25.8
      (quiescent) to 317.6 A mol(-1) L (insonated) for 300 s accumulation.
      Investigation of the use of ultrasound with diluted blood revealed detection
      limits of the order of 10(-8) mol L(-1) were achievable with excellent inter- and
      intra-reproducibility and sensitivity of 411.9 A mol(-1) L. For the first time,
      electroanalytical detection of lead in diluted blood is shown to be possible by
      use of insonated in-situ-formed bismuth-film-modified boron-doped diamond
      electrodes. This method is a rapid, sensitive, and non-toxic means of clinical
      sensing of lead in whole human blood.

PMID- 15185064
TI  - Mandibular bone loss in an animal model of male osteoporosis (orchidectomized
      rat): a radiographic and densitometric study.
AB  - In humans, hypogonadism is associated with osteoporosis and can be studied by
      densitometry (DXA) on the vertebrae or long bones. There is some controversy
      about the relationships between bone loss in these sites and in the mandible.
      Osteoporosis has been suggested as a risk factor for dental problems. In the rat,
      orchidectomy (ORX) is associated with an increased bone resorption resulting in
      bone loss. We have studied the time effects of ORX on the alveolar bone in the
      rat. Forty-eight male Wistar rats were divided into four groups and studied over
      2, 4, 8 and 16 weeks. In each group, six rats were ORX and six sham-operated
      (SHAM) animals were used as control. The mandible of each rat was dissected.
      Numeric radiographs, centered on the molar region, were obtained. Bone loss was
      observed qualitatively at 16 weeks in ORX animals. Quantitative modifications
      were confirmed by texture analysis of numeric radiographs using the run-length
      technique. The bone mineral content (BMC) and density (BMD) of the hemimandible
      and in a region centered on the molars were measured by DXA. The coefficient of
      variation (CV) for BMC was poor on the whole bone and no differences could be
      observed even at 16 weeks. For BMC of the molar region, the CV was improved and
      significant bone loss occurred in the ORX group at 16 weeks ( P<0.016). This
      study confirms that in the male rat, the reduction of sex hormones induced by ORX
      is associated with a decrease in bone mass in the mandible.

PMID- 15185063
TI  - Involvement of 5-HT1B receptors in triptan-induced contractile responses in
      guinea-pig isolated iliac artery.
AB  - Using a series of triptans we characterized in vitro the 5-hydroxytryptamine (5
      HT) receptor that mediates the contraction in guinea-pig iliac arteries
      moderately precontracted by prostaglandin F2alpha (PGF2alpha). Additionally, we
      investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) which
      triptan-sensitive receptor is present in this tissue. Frovatriptan, zolmitriptan,
      rizatriptan, naratriptan, sumatriptan, and almotriptan contracted guinea-pig
      iliac arteries with pD2 values of 7.52+/-0.04, 6.72+/-0.03, 6.38+/-0.06, 6.22+/
      0.05, 5.86+/-0.05 and 5.26+/-0.04 respectively. For comparison, the pD2 values
      for 5-HT and 5-carboxamidotryptamine (5-CT) were 7.52+/-0.02 and 7.55+/-0.03
      respectively. In contrast to all other triptans tested, the concentration
      response curve for eletriptan was biphasic (first phase: 0.01-3 microM, pD2
      approximately 6.6; second phase: > or = 10 microM). Contractions to 5-HT, 5-CT,
      frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, almotriptan,
      and eletriptan (first phase) were antagonized by the 5-HT1B/1D receptor
      antagonist GR127935 (10 nM) and the 5-HT1B receptor antagonist SB216641 (10 nM).
      RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the 5-HT1B
      receptor while expression of 5-HT1D and 5-HT1F receptors was not detected in any
      sample. The present results demonstrate that triptan-induced contraction in
      guinea-pig iliac arteries is mediated by the 5-HT1B receptor. The guinea-pig
      iliac artery may be used as a convenient in vitro model to study the
      (cardio)vascular side-effect potential of anti-migraine drugs of the triptan
      family.

PMID- 15185065
TI  - Influence of weight and weight change on bone loss in perimenopausal and early
      postmenopausal Scottish women.
AB  - Weight is recognized as an important factor in determining an individual's risk
      of osteoporosis. However, little is known about whether weight or weight change
      influences bone loss around the time of the menopause, and the relationship with
      energy intake and physical activity level remains largely undefined. Healthy
      premenopausal women (1,064 selected from a random population of 5,119 women aged
      45-54 years at baseline) each had bone mineral density (BMD), weight and height
      measurements, and completed a food frequency and physical activity questionnaire.
      Of the original participants, 907 women (85.2%) returned 6.3 +/- 0.6 years later
      for repeat BMD measurements, and 896 women completed the questionnaires. Bone
      loss at the hip (FN) and spine (LS) occurred before the menopause. Weight change
      rather than weight was associated with FN BMD loss (r=0.102, p=0.002), but weight
      at follow-up was associated with LS BMD change (r=0.105, p=0.002). Although an
      increase in physical activity level (PAL) appeared to be beneficial for FN BMD in
      women who were heavy weight gainers, PAL was associated with increased LS BMD
      loss in women who lost weight. For current HRT users, neither weight nor weight
      change was associated with change in BMD. Postmenopausal women not taking HRT
      should be made aware that low body weight or losing weight during this
      particularly vulnerable period may worsen bone loss.

PMID- 15185066
TI  - Risk factors for hip fracture in women with high BMD: EPIDOS study.
AB  - Hip fractures are common among older women. At the present time, major efforts
      are being made to identify women with low bone mineral density (BMD). However,
      more than half of hip fractures occur in women who would not classically be
      considered osteoporotic by BMD. This study aimed to identify factors associated
      with hip fracture in women with high BMDs. A total of 7598 French women aged over
      74 participated in the EPIDOS study and had BMD measured by dual energy X-ray
      absorptiometry. Analysis was carried out comparing women with and without hip
      fractures over more than 3 years of follow-up. The participants were divided into
      three groups based on femoral neck BMD, so as to have equal numbers in each group
      (cut-off points=0.601 g/cm(2), and 0.683 g/cm(2)). Multiple risk factors thought
      to be associated with hip fracture were tested in the high and low BMD groups to
      search for those whose effect was stronger in the high BMD group. Age adjusted
      Cox regression was used. Results for continuous variables are reported per
      standard deviation change. Positive interaction between higher BMD, hip fracture
      and the following factors were found: age (P<0.01), ultrasound attenuation
      (P<0.05), urinary deoxypyridinoline (DPD) (P<0.05), left quadriceps strength
      (P<0.05) and right and left foot coordination (P<0.05). The following factors had
      a larger hazards ratio in those in the upper third of BMD than the low and were
      statistically significant: femoral neck BMD, nulliparity, age, ultrasound
      attenuation and speed, prior fracture, urinary deoxypyridinoline, left grip
      strength and foot coordination. Multiple factors appear to be more strongly
      associated with hip fractures in women with high BMD than low. They appear to
      cluster as factors that may relate to bone turnover and architecture and others
      which are more subtle measures of left-sided coordination.

PMID- 15185067
TI  - Acute respiratory distress syndrome (ARDS) and low tidal volume ventilation: the
      debate about weight.

PMID- 15185068
TI  - Can methadone prolong the QT interval?

PMID- 15185069
TI  - Combination enteral and parenteral nutrition in critically ill patients: harmful
      or beneficial? A systematic review of the evidence.
AB  - OBJECTIVE: A combination of enteral (EN) and parenteral nutrition (PN) is often
      used as a strategy to optimize nutritional intake in critically ill patients;
      however, the effects of this intervention on clinically important outcomes have
      not been widely studied. This paper systematically reviewed studies that compare
      EN + PN to enteral nutrition (EN) alone in critically ill patients. METHODS: We
      searched bibliographic databases, personal files, and relevant reference lists to
      identify randomized controlled trials that compared combination EN + PN to EN
      alone. RESULTS: Only five studies met the inclusion criteria. In all these
      studies PN was started at the same time as EN in the experimental group. When the
      results of these trials were aggregated, EN + PN had no significant effect on
      mortality. There was no difference between the two groups in rates of infectious
      complications, length of hospital stay, or ventilator days. CONCLUSIONS: In
      critically ill patients who are not malnourished and have an intact
      gastrointestinal tract, starting PN at the same time as EN provides no benefit in
      clinical outcomes over EN alone. More research is needed to determine the effects
      of combination EN + PN on clinical outcomes in critically ill patients who are
      poorly intolerant to EN.

PMID- 15185070
TI  - Noise exposure during noninvasive ventilation with a helmet, a nasal mask, and a
      facial mask.
AB  - OBJECTIVE: To assess noise exposure during noninvasive ventilation (NIV) with
      different types of interface (helmet, nasal, and facial masks). SUBJECTS AND
      METHODS: Ten "naive" healthy volunteers underwent NIV at pressure support levels
      of 10 and 15 cmH2O with: (a) helmet, (b) helmet equipped with HME filters at the
      junctions between the helmet and the inspiratory and expiratory branches of the
      respiratory circuit, (c) nasal mask, and (d) facial mask. Noise intensity was
      assessed with a sound level meter by placing a microphone near the right ear.
      Noise intensity and degree of discomfort were also assessed subjectively with a
      visual analogue scale. RESULTS: Inside the helmet noise exceeded 100 dB. Noise
      intensity was poorly affected by pressure support level and unaffected by the
      presence of HME filters. During NIV with nasal or facial masks the noise did not
      exceed 70 dB (i.e., noise was not louder than the usual noise background in ICU).
      Subjective evaluation of noise intensity mirrored objective measurements;
      however, the presence of HME filters was associated with the feeling of less
      noise inside the helmet. The discomfort associated with the helmet did not
      significantly differ from that associated with the masks. CONCLUSIONS: NIV helmet
      is associated with significantly greater noise than nasal and facial masks, but
      is as comfortable as masks, at least in the short term. Medium- and long-term
      exposure to loud noise may potentially impair ear function and increase the
      patient's discomfort.

PMID- 15185071
TI  - A novel approach for selective brain cooling: implications for hypercapnia and
      seizure activity.
AB  - OBJECTIVE: During selective brain cooling (SBC) the brain temperature (TB) is
      reduced while the core temperature (TC) remains unchanged. This animal study
      investigated changes in brain temperature induced by a novel approach of cooling
      the brain from the pharynx (pSBC) and whether these temperature changes are
      related to commonly encountered clinical situations (i.e., seizure activity and
      hypercapnia). DESIGN: Experimental animal study. SUBJECTS: Male Sprague-Dawley
      rats. INTERVENTIONS: pSBC was achieved by a heat exchanger placed in the pharynx;
      hypercapnia and seizure activity were induced by adding CO2 to the respiratory
      gases and by intravenous injection of bicuculline, respectively. MEASUREMENTS AND
      RESULTS: TB, TC, and pharynx (TP) were measured continuously with thermocouples.
      During pSBC TB declined significantly from 36.9+/-0.67 degrees C to 33.1+/-1.23
      degrees C. There was a trend towards lower TC during pSBC (from 36.9+/-0.70 to
      36.4+/-1.2 degrees C). TP during pSBC was 29.1+/-2.19 degrees C. From the lowest
      achieved pSBC temperature TB rose during CO2 challenge by 1.22+/-0.67 degrees C
      (vs. 0.85+/-0.34 degrees C in non-SBC controls). From the lowest pSBC temperature
      during seizure activity TB rose by 2.08+/-0.35 degrees C (vs. 1.15+/-0.55 degrees
      C in non-SBC controls). CONCLUSIONS: Significant cooling of the cortex can be
      achieved by pSBC in a rat rodent model. Marked increases in TB with hypercapnia
      and with seizure activity were observed. These results may have implications for
      cooling methods in clinical settings. For example, pSBC may offer distinct
      advantages over alternative methods such as whole-body cooling and externally
      implemented SBC.

PMID- 15185073
TI  - Three-dimensional reconstruction of vessel distribution in benign and malignant
      lesions of thyroid.
AB  - In order to better understand the spatial distribution of thyroid vessels, a
      series of benign and malignant thyroid lesions were studied with three
      dimensional (3D) histological stereomicroscopic reconstruction. Cases consisted
      of normal autoptic thyroids (n=6), colloid goitres (n=6), Basedow's disease
      (n=2), follicular adenoma (FA) (n=4) one of which with Hurthle cells (HC),
      minimally invasive, well-differentiated follicular carcinoma (FTC) (n=1), well
      differentiated FTC with HC (n=1), poorly differentiated FTC (n=13) with extensive
      angioinvasion, papillary carcinoma (PTC) (n=8) and medullary carcinoma (MTC)
      (n=1). From each selected nodule, parallel sections were obtained for 3D
      reconstruction and for histological and immunohistochemical studies. In normal
      thyroid, large vessels were located at the periphery of the gland with smaller
      branches present within the thyroid parenchyma that encircled follicles. The same
      pattern of vascularisation is maintained in lesions showing a follicular
      architecture as colloid goitre, Basedow's disease, FA, well-differentiated FTC
      and the follicular variant of PTC. Neoplastic lesions, at variance with non
      neoplastic lesions, contained rare anastomoses. Poorly differentiated FTC and MTC
      contained large intratumoural vessels surrounding avascular areas corresponding
      to solid neoplastic cellular sheets with necrosis. PTC were more vascularised and
      contained numerous vascular anastomoses. In conclusion, the present data indicate
      that the vascular distribution is related to the follicular, papillary or solid
      type of growth. Vascular anastomoses and intratumoural vessels surrounding solid
      avascular areas are signs of malignancy.

PMID- 15185072
TI  - [An update on thrombosis prophylaxis in orthopaedic and accident surgery].
AB  - The prevention of deep venous thrombosis has become a routine in orthopaedic
      surgery. While the necessity for prophylaxis is not questioned, its practice is
      still a matter of controversy. The development of new anticoagulants increases
      the variety of prophylactic methods but leads to a need for additional
      information. This review deals with the indications for thrombosis prophylaxis in
      relation to exposing and predisposing risk factors. The currently available
      modalities of prophylaxis, their pharmacological details and clinical
      significance are presented. Evidence based data, recommendations on the duration
      of prophylaxis derived from official guidelines, issues of the
      cost/effectiveness, and medico-judicial aspects are discussed.

PMID- 15185075
TI  - INK4a-ARF alterations in Barrett's epithelium, intraepithelial neoplasia and
      Barrett's adenocarcinoma.
AB  - INTRODUCTION: The INK4a-ARF [CDKN2A]- locus on chromosome 9p21 encodes for two
      tumour suppressor proteins, p16INK4a and p14ARF, which act as upstream regulators
      of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway to the
      carcinogenesis of Barrett's adenocarcinoma, we analysed the alterations of p14ARF
      and p16INK4a in preneoplastic and neoplastic lesions of this disease. MATERIALS
      AND METHODS: After microdissection, DNA of 15 Barrett's adenocarcinomas, 40
      Barrett's intraepithelial neoplasms (n=20 low- and n=20 high-grade) and 15
      Barrett's mucosa without neoplasia was analysed for INK4-ARF inactivation using
      DNA sequence and loss of heterozygosity (LOH) analysis, methylation-specific
      polymerase chain reaction, restriction-enzyme-related polymerase chain reaction
      and immunohistochemistry. RESULTS: We detected 9p21 LOH, p16INK4a methylation and
      p16INK4a mutations in Barrett's adenocarcinomas in 5 of 15 (33%), 8 of 15 (53%)
      and 1 of 15 (7%) patients, respectively. P14ARF was methylated in 3 of 15 (20%)
      adenocarcinomas. In Barrett's intraepithelial neoplasia, p16INK4a was altered in
      12 of 20 (60%) high-grade and in 4 of 20 (20%) low-grade intraepithelial
      neoplasms. In Barrett's mucosa without intraepithelial neoplasia p16(INK4a) was
      methylated in one case (7%). P14ARF was intact in Barrett's mucosa without
      intraepithelial neoplasia. CONCLUSIONS: We conclude that most Barrett's
      intraepithelial neoplasms contain genetic and/or epigenetic INK4a-ARF
      alterations. Methylation of p16INK4a appears to be the most frequent epigenetic
      defect in the neoplastic progression of Barrett's tumourigenesis.

PMID- 15185074
TI  - Handling and pathology reporting of specimens with carcinoma of the urinary
      bladder, ureter, and renal pelvis. A joint proposal of the European Society of
      Uropathology and the Uropathology Working Group.
AB  - Pathologists play a pivotal role in the diagnosis and in the report of the
      pathological features related to prognosis. To meet these endpoints, the
      following issues must be addressed: 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 evaluation of the prognostic variables, and standardized
      pathological reporting. In this review we discuss a proposal for standardization
      of sampling and reporting of the urothelial tissues achieved within uropathology.
      The urologists have a great role in assisting pathologists in the proper
      examination by providing them with clinical information.

PMID- 15185076
TI  - Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a
      review of 418 cases and a classification proposal.
AB  - Although cystic neoplasms and lesions of the pancreas are rare, they have
      attracted a great deal of attention because of their potential curability. Since,
      in recent years, several new entities have been identified, the relative
      frequency of the tumors and their classification need to be reevaluated. In a
      series of 1454 tumorous lesions of the pancreas collected between 1971 and 2003
      in our surgical pathology files and consultation files, all cystic pancreatic
      neoplasms and tumor-like lesions were identified and typed both histologically
      and immunohistochemically. There were 418 cases (29%) showing cysts with a
      diameter ranging between 0.5 cm and 27 cm. Most common were solid pseudopapillary
      neoplasms (21%) and intraductal papillary-mucinous neoplasms (18%). When only the
      cystic neoplasms and lesions that had been resected in a single institution were
      considered, intraductal papillary mucinous neoplasms were the most frequent
      cystic neoplasms, while solid pseudopapillary neoplasms took fifth place behind
      ductal adenocarcinomas with cystic features, serous cystic neoplasms and mucinous
      cystic neoplasms. The most frequent cystic tumor-like lesions were pancreatitis
      associated pseudocysts. New and rare entities that have recently been identified
      are mucinous nonneoplastic cysts, acinar cell cystadenomas and cystic hamartomas.
      Bearing in mind that figures from referral centers such as ours may be biased
      regarding the relative frequency of lesions, we concluded from our data that
      intraductal papillary-mucinous neoplasms are the most frequently occurring
      pancreatic cystic neoplasms, rather than solid pseudopapillary neoplasms. It was
      possible to classify all cystic lesions encountered in our files or described in
      the literature in a new system that distinguishes between neoplastic and
      nonneoplastic lesions, with further subdivisions into epithelial (adenomas,
      borderline neoplasms and carcinomas) and nonepithelial tumors. This
      classification is easy to handle and enables a distinction on the basis of
      clinical behavior and prognosis.

PMID- 15185077
TI  - Orthologous relationship of obscurin and Unc-89: phylogeny of a novel family of
      tandem myosin light chain kinases.
AB  - Myosin light chain kinases (MLCK) are a family of signaling proteins that are
      required for cytoskeletal remodeling in myocytes. Recently, two novel MLCK
      proteins, SPEG and obscurin-MLCK, were identified with the unique feature of two
      tandemly-arranged MLCK domains. In this study, the evolutionary origins of this
      MLCK subfamily were traced to a probable orthologue of obscurin-MLCK in
      Drosophila melanogaster, Drosophila Unc-89, and the MLCK kinase domains of
      zebrafish SPEG, zebrafish obscurin-MLCK, and human SPEG were characterized.
      Phylogenetic analysis of the MLCK domains indicates that the carboxy terminal
      kinase domains of obscurin-MLCK, SPEG and Unc-89 are more closely related to each
      other than to the amino terminal kinase domains or to other MLCKs, supporting the
      assertion that obscurin-MLCK is the vertebrate orthologue of Caenorhabditis
      elegans Unc-89, a giant multidomain protein that is required for normal myofibril
      assembly. The apparent lack of an invertebrate orthologue of SPEG and the
      conserved exon structure of the kinase domains between SPEG and obscurin-MLCK
      suggests that SPEG arose from obscurin-MLCK by a gene duplication event. The
      length of the primary amino acid sequence between the immunoglobulin (Ig) domains
      associated with the MLCK motifs is conserved in obscurin-MLCK, SPEG and C.
      elegans Unc-89, suggesting that these putative protein interaction domains may
      target the kinases to highly conserved intracellular sites. The conserved
      arrangement of the tandem MLCK domains and their relatively restricted expression
      in striated muscle indicates that further characterization of this novel MLCK
      subfamily may yield important insights into cardiac and skeletal muscle
      physiology.

PMID- 15185078
TI  - Molecular characterization of pepper germin-like protein as the novel PR-16
      family of pathogenesis-related proteins isolated during the resistance response
      to viral and bacterial infection.
AB  - To understand the molecular defense mechanism controlling the hypersensitive
      response (HR) better, we examined the hot pepper plant (Capsicum annuum L. cv.
      Bugang), which exhibits an HR in response to infection by Tobacco mosaic virus
      pathotype P0 (TMV-P0). A full-length cDNA clone was isolated by differential
      screening of a cDNA library that was constructed with mRNA extracted from hot
      pepper leaves during the resistance response to TMV-P0. The predicted amino acid
      sequence of the cDNA clone exhibited a high sequence similarity to germin-like
      protein (GLP). The CaGLP1 (Capsicum annuum GLP1) cDNA contains a single open
      reading frame of 660 bp encoding 220 amino acid residues. Upon inoculation with
      TMV or Xanthomonas, CaGLP1 transcripts were specifically accumulated in the
      incompatible interaction but not in the compatible interaction. In plants treated
      with salicylic acid (SA) or ethephon, which are signal molecules in the defense
      related signal transduction pathway, CaGLP1 transcripts were accumulated rapidly.
      As far as we know, this is the first report that plant GLPs can be specifically
      induced during a defense response against viral infection. These data suggest
      that in the hot pepper plant CaGLP1 may be involved in the defense response to
      viral pathogens, and thus be classified as a new family of PR proteins, 'PR-16'.

PMID- 15185079
TI  - Electron-microscopic structure of the V-ATPase from mung bean.
AB  - The vacuolar H(+)-ATPase from mung bean (Vigna radiata L. cv. Wilczek) was
      purified to homogeneity. The purified complex contained all the reported subunits
      from mung bean, but also included a 40-kDa subunit, corresponding to the membrane
      associated subunit d, which has not previously been observed. The structure of
      the V-ATPase from mung bean was studied by electron microscopy of negatively
      stained samples. An analysis of over 6,000 single-particle images obtained by
      electron microscopy of the purified complex revealed that the complex, similar to
      other V-ATPases, is organized into two major domains V1 and Vo with overall
      dimensions of 25 nm x 13.7 nm and a stalk region connecting the V1 and Vo
      domains. Several individual areas of protein density were observed in the stalk
      region, indicating its complexity. The projections clearly showed that the
      complex contained one central stalk and at least two peripheral stalks.
      Subcomplexes containing subunits A, B and E, dissociated from the tonoplast
      membrane by KI, were purified. The structure of the subcomplex was also studied
      by electron microscopy followed by single-molecule analysis of 13,000
      projections. Our preliminary results reveal an area of high protein density at
      the bottom of the subcomplex immediately below the cavity formed by the A and B
      subunits, indicating the position of subunit E.

PMID- 15185080
TI  - Assessment of the efficiency of warming devices during neonatal surgery.
AB  - This study assessed the relative efficiency of different warming devices
      (surgical sheets covering the body and a tubegauze on the head, forced-air
      warming, warming mattress) commonly used to prevent body hypothermia during
      neonatal surgery. Dry heat losses were measured from a thermal manikin, which
      simulated a low-birth-weight neonate of 1,800 g. The manikin's surface
      temperatures (35.8 degrees C) corresponded to those of neonates nursed in closed
      incubators. Experiments were performed in a climatic chamber at an ambient
      temperature of 30 degrees C, as commonly found in operating theatres. The supine
      manikin was naked or covered with operative sheets with a 5x5 cm aperture over
      the abdomen. Its head could be covered by a tube-gauze. Additional warming was
      provided by conduction through a warming mattress (surface temperature, 39
      degrees C) and/or by convection (Bair Hugger, forced-air temperature 38 degrees
      C). Covering the manikin with surgical sheets decreased the dry heat loss by 10.4
      W. Additional forced-air warming was more efficient than the warming mattress to
      reduce the total dry heat loss (6.8 W vs 2.1 W). Heat losses were reduced by 7.9
      W when combining the warming mattress and Bair Hugger. The heat loss from the
      head of the covered manikin was reduced from 4.5 W to 3.9 W when the head was
      covered with the tubegauze. Our data indicate that forced-air warming is more
      effective than conductive warming in preventing neonatal hypothermia during
      abdominal operations.

PMID- 15185081
TI  - Postmortem time estimation using body temperature and a finite-element computer
      model.
AB  - In the Netherlands most murder victims are found 2-24 h after the crime. During
      this period, body temperature decrease is the most reliable method to estimate
      the postmortem time (PMT). Recently, two murder cases were analysed in which
      currently available methods did not provide a sufficiently reliable estimate of
      the PMT. In both cases a study was performed to verify the statements of
      suspects. For this purpose a finite-element computer model was developed that
      simulates a human torso and its clothing. With this model, changes to the body
      and the environment can also be modelled; this was very relevant in one of the
      cases, as the body had been in the presence of a small fire. In both cases it was
      possible to falsify the statements of the suspects by improving the accuracy of
      the PMT estimate. The estimated PMT in both cases was within the range of
      Henssge's model. The standard deviation of the PMT estimate was 35 min in the
      first case and 45 min in the second case, compared to 168 min (2.8 h) in
      Henssge's model. In conclusion, the model as presented here can have additional
      value for improving the accuracy of the PMT estimate. In contrast to the simple
      model of Henssge, the current model allows for increased accuracy when more
      detailed information is available. Moreover, the sensitivity of the predicted PMT
      for uncertainty in the circumstances can be studied, which is crucial to the
      confidence of the judge in the results.

PMID- 15185082
TI  - Analysis of sensible heat exchanges from a thermal manikin.
AB  - The present work is dedicated to the analysis of dry heat exchanges as measured
      by a thermal manikin placed in still air. We believe that the understanding of
      some fundamental aspects governing fluid flow and heat transfer around three
      dimensional bodies such as human beings deserves appropriate attention. This
      should be of great significance for improving physiological models concerned with
      thermal exposures. The potential interest of such work can be directed towards
      quite distinct targets such as working conditions, sports, the military, or
      healthcare personnel and patients. In the present study, we made use of a climate
      chamber and an articulated thermal manikin of the Pernille type, with 16 body
      parts. The most common occidental postures (standing, sitting and lying) were
      studied. In order to separate heat losses due to radiation and convection, the
      radiative heat losses of the manikin were significantly reduced by means of a
      shiny aluminium coating, which was carefully applied to the artificial skin. The
      air temperature within the test chamber was varied between 13 degrees C and 29
      degrees C. The corresponding mean differences between the skin and the operative
      temperatures changed from 3.8 degrees C up to 15.8 degrees C. The whole-body heat
      transfer coefficients by radiation and convection for both standing and sitting
      postures are in good agreement with those in the published literature. The lying
      posture appears to be more efficient for losing heat by convection. This is
      confirmed when the heat losses of each individual part are considered. The
      proposed correlations for the whole body suggest that natural convection is
      mainly laminar.

PMID- 15185083
TI  - Thermal manikin history and applications.
AB  - Thermal manikins have served research and development purposes for more than 60
      years. They are widely used for analysing the thermal interface of the human body
      and its environment. Particular applications are found in the determination of
      thermal properties of clothing and in the evaluation of the local body-heat
      fluxes in complex environments such as in a vehicle cabin. Recent developments of
      sweating manikins as well as breathing manikins allow even more realistic
      simulations of the human thermal interaction with the environment.

PMID- 15185084
TI  - Design and manufacturing of two thermal observation manikins for automobile
      applications.
AB  - Two state-of-the-art thermal observation manikins were designed and built for use
      in automobile applications. These manikins not only apply the latest data
      acquisition and control technology but also incorporate new manufacturing and
      sensor technology for improved performance. The manikins are equipped with 26
      segments that can be easily removed for maintenance and replacement. Furthermore,
      their unique design offers an important and a major improvement over previous
      manikin designs by incorporating heat flux transducers (HFTs) to measure heat
      gain when exposed to external heating conditions. The HFTs provide these manikins
      the ability to measure heat flux to or from the environment, regardless of
      segment skin temperature. The end goal for these manikins is to incorporate a
      subjective model of thermal comfort along with a human thermal physiological
      model to produce a thermal sensation vote based on a combination of HFTs,
      temperature sensors, and heater power measurements. This paper discusses the need
      for two identical research quality thermal manikins and presents the details of
      the design and construction of two identical thermal manikins and the associated
      data acquisition and control software.

PMID- 15185085
TI  - Neuromuscular fatigue and potentiation following two successive high intensity
      resistance exercise sessions.
AB  - Resistance exercise can result in both potentiating and fatiguing responses.
      These responses can acutely affect performance, which may affect subsequent
      exercise sessions in the same day. The purpose of this investigation was to study
      the acute neuromuscular responses to two high intensity training sessions in the
      same day. Twelve recreationally trained males performed two training sessions,
      each involving ten sets of five repetitions in the speed squat exercise. For the
      initial session (HIT-1), the barbell load was constant at 70% one repetition
      maximum, whereas during the second session (HIT-2), barbell load decreased if
      movement velocity decreased. Neuromuscular performance testing consisted of
      unilateral isometric knee extensor actions performed prior to the training day
      (PRE) and following each testing session. Prior to the sessions, subjects
      provided a muscle biopsy for myosin heavy chain analysis. Peak force was impaired
      16.9 (9.5)% (P approximately 0.00; d=1.62) following HIT-1 and 19.9 (18.4)% (P
      approximately 0.00; d=1.94) following HIT-2. Initial rate of force development
      was depressed from PRE following HIT-1 (P approximately 0.00; d=1.74) and HIT-2
      (P approximately 0.00; d=2.18); however, this was dependent on muscle fiber
      composition. Significant correlations existed between the change score for
      initial rate of force development from HIT-1 to HIT-2 and myosin heavy chain I
      (r= -0.60; P=0.04) and IIa (r=0.69; P=0.01) expression. Impaired neuromuscular
      performance following HIT-1 may occur due to low frequency fatigue. For
      individuals with predominantly myosin heavy chain IIa, HIT-2 appeared to induce
      post-activation potentiation, resulting in restoration of the initial rate of
      force development.

PMID- 15185086
TI  - An innovative fixative for cytoskeletal components allows high resolution in
      colocalization studies using immunofluorescence techniques.
AB  - Using a new fixation solution, CytoSkelFix, it is now possible to obtain superior
      fixation and thus resolution of cytoskeletal components using immunofluorescence
      and fluorescence microscopy. This fixative combines rapid cell penetration and
      cellular crosslinking of proteins such that both preservation and resolution of
      cellular proteins can be detected. The cytoskeleton has proven very difficult to
      preserve, partly because of the lability of one of the filament systems
      (microtubules), and one single fixative is incapable of properly preserving
      microtubules, microfilaments, and intermediate filaments for localization in the
      same cell. Further, the motor proteins associated with the cytoskeletal elements
      are even more difficult to preserve, particularly simultaneously with the fiber
      system with which they associate. We present evidence that CytoSkelFix is a
      superior preservative and would be useful in fixation for all types of
      immunofluorescence colocalization studies where superior preservation is
      required.

PMID- 15185091
TI  - Improvement in near visual function after macular translocation surgery with 360
      degree peripheral retinectomy.
AB  - BACKGROUND: Information is limited on how specific near-vision skills are
      impacted by therapies such as macular translocation surgery with 360-degree
      retinectomy (MT360) for age-related macular degeneration (AMD). METHODS:
      Standardized tests of near vision were given to 25 consecutive patients with AMD
      who met entry criteria for this study, preoperatively and 6 and 12 months after
      MT360. Tests included: near acuity with the Lighthouse chart, timed reading speed
      using Sloan cards, contrast sensitivity, and color vision. Distance acuity was
      measured using Bailey-Lovey charts. Measures of preoperative visual function were
      analyzed to identify those predictive of visual outcomes. RESULTS: Distance
      acuity was 20/80 or better in 52% of patients at 12 months after surgery, and
      mean acuity improved from approximately 20/125 preoperatively to approximately
      20/100 at 12 months. Mean near acuity improved from 3.2+/-2.5 M before surgery to
      1.5+/-1.0 M at 12 months (significant change of -1.5+/-2 M, P<0.001). Gain of
      greater than five numbers in contrast sensitivity at 12 months was also
      significant ( P<0.001). Mean reading speed improved from 41+/-31 words per minute
      (wpm) before surgery to 67+/-44 wpm at 12 months (significant gain of 25+/-33
      wpm, P=0.001). Preoperative distance acuity, near acuity, and reading speed were
      each predictors of postoperative near visual function. CONCLUSION: Standardized
      testing of near visual function provides important predictive and functional
      outcome data for MT360. MT360 significantly improved near visual function
      (including near acuity, reading speed and contrast sensitivity) in patients with
      subfoveal lesions from AMD in the second eye.

PMID- 15185093
TI  - Genetic characteristics and population study of 4 X-chromosomal STRs in Koreans:
      evidence for a null allele at DXS9898.
AB  - The four X-chromosomal short tandem repeats (STRs), DXS9898, DXS6809, DXS7424 and
      DXS10011 were analyzed by single multiplex PCR in 150 male and 150 female
      Koreans. The loss of an allele at DXS9898 was observed in 13 out of 450
      chromosomes (2.9%) and the PCR analysis showed that the X-chromosome with a null
      allele at DXS9898 has more than 1 kb deletion at the DXS9898 locus. Statistical
      analyses for these four X-STRs showed that they are highly informative for
      forensic application in Koreans. No linkage disequilibrium was observed among
      these four STRs and the previously reported five polymorphic STRs, HumARA,
      DXS101, GATA172D05, HPRTB and DXS8377 in Koreans. The test of homogeneity between
      allele frequencies revealed that there are some discrepancies in allele
      distributions between Koreans and Germans.

PMID- 15185094
TI  - Molecular mapping of deletion breakpoints on chromosome 4 of Drosophila
      melanogaster.
AB  - As part of our effort to induce and identify mutations in all genes on chromosome
      4 of Drosophila melanogaster, we have mapped the breakpoints of eight chromosome
      4 deficiencies relative to the predicted genes along this chromosome. Although
      the approximate locations of Df(4)G, Df(4)C3, Df(4)M101-62f, Df(4)M101-63a,
      Df(4)J2, Df(4)O2, Df(4)C1-10AT, and Df(4)B2-2D are known (some from cytological
      observations and others predicted from P element locations), the extents of these
      deletions have not been mapped with respect to the predicted genes identified by
      the Drosophila Genome Project. Polymerase chain reaction primers were designed to
      amplify the predicted exons of all chromosome 4 genes, and homozygous embryos for
      each deficiency were identified and their DNA used to test for the presence or
      absence of these exons. By testing for the inability to amplify various exons
      along the length of the chromosome, we were able to determine which predicted
      genes are missing in each deficiency. The five deficiencies, Df(4)G, Df(4)C3,
      Df(4)C1-10AT, and Df(4)B2-20 (all terminal deletions), and Df(4)M101-62f (a
      proximal interstitial deletion), enabled us to partition the gene-containing,
      right arm of chromosome 4 into five regions. Region A [uncovered by Df(4)M101
      62f] contains the proximal-most 21 genes; region B [uncovered by Df(4)B2-2D]
      contains the next 12 genes; region C [uncovered by Df(4)B2-2D and Df(4)C1-10AT]
      contains the next 17 genes; region D [uncovered by Df(4)B2-2D, Df(4)C1-10AT, and
      Df(4)C3] contains the next 21 genes; and region E [uncovered by Df(4)B2-2D,
      Df(4)C1-10AT, Df(4)C3, and Df(4)G] contains the distal-most ten genes. By using
      Df(4)M101-62f, Df(4)B2-2D, Df(4)C1-10AT, Df(4)C3, and Df(4)G in complementation
      tests, we can assign newly induced recessive lethal mutations to one of the five
      regions on chromosome 4. This will substantially reduce the amount of DHPLC
      analysis required to match each mutation to a predicted transcript on chromosome
      4.

PMID- 15185096
TI  - Prenatal and postnatal findings of acrania.
AB  - INTRODUCTION: Acrania is a rare congenital anomaly in which the flat bones of the
      cranial vault are partial or complete absent with complete but abnormal
      development of the cerebral hemispheres. CASE REPORT: We report two cases,
      diagnosed prenatally by ultrasound and followed by medical pregnancy termination,
      one with isolated acrania and one with associated cleft lip and palate and spina
      bifida. DISCUSSION: The acrania pathogenesis is unknown and differential
      diagnosis should be made with other conditions like anencephaly and acalvaria.
      Genetic counselling is not easy because there is no evidence for a specific
      genetic origin, but the extreme rarity and sporadic nature suggests a low
      recurrence risk.

PMID- 15185097
TI  - Maternal height as a risk factor for Caesarean section.
AB  - BACKGROUND: Maternal height has been reported as an obstetric risk factor, since
      short maternal stature may be associated with an increased incidence of
      obstructed labour due to cephalopelvic disproportion. MATERIALS AND METHODS:
      There were 373 nulliparous women who were 150 cm or less in height (total
      n=5,650) and 367 women who were below 19 years old in the study group and 48 of
      these women were 150 cm or less in height. There were 37 patients who were 150 cm
      or less in height and over 39 years old. RESULTS: There was no statistically
      significant difference between the rates of Caesarean section in patients who
      were 150 cm or less in height and patients who were taller than 150 cm (P>0.05).
      However, the rate of Caesarean section was higher in patients who were 150 cm or
      less in height and below 19 years old (P<0.05) and over 39 years old (P<0.05).
      CONCLUSION: Short maternal height (<150 cm) was not associated with a greater
      likelihood of Caesarean section for cephalopelvic disproportion. However,
      patients who were below 19 years old and over 39 years old with a height of 150
      cm or smaller had a greater likelihood of undergoing Caesarean section.

PMID- 15185098
TI  - Prepregnancy body mass index as an important predictor of perinatal outcomes in
      Japanese.
AB  - OBJECTIVE: The influence of maternal body mass index (BMI) before pregnancy and
      weight gain during pregnancy on perinatal outcomes in the Japanese population
      remains to be elucidated. Therefore, we estimated the risk of perinatal morbidity
      of the mother and infant with respect to maternal prepregnancy BMI and weight
      gain during pregnancy in Japanese. RESULTS: In the obese before pregnancy group,
      the risks of cesarean delivery, preeclampsia, and gestational diabetes were
      significantly elevated compared with the normal group. In the underweight before
      pregnancy group, the risks of low birth weight infant and hospitalization of
      infant were elevated significantly. CONCLUSION: However, weight gain during
      pregnancy did not show any significant influence on the perinatal outcomes of the
      mother or infant.

PMID- 15185099
TI  - WITHDRAWN: Increased activity of lysosomal enzymes in the peritoneal fluid of
      patients with gynecological cancers.
AB  - This article has now been withdrawn and will not appear in print.

PMID- 15185101
TI  - Doppler ultrasound of the uterine artery in the prediction of severe
      complications during low-risk pregnancies.
AB  - AIM: The aim of this prospective study was to assess the role of uterine artery
      colour Doppler waveform analysis in the prediction of adverse pregnancy outcome
      such as preeclampsia, intrauterine growth retardation, placental abruption or a
      combination of outcome parameters. METHODS: Various uterine artery Doppler
      ultrasound parameters (RI>0.58, RI>0.7 and unilateral or bilateral notching) were
      tested. A second objective was to compare the predictive power of uterine artery
      Doppler ultrasound at 19-22 gestational weeks and 23-26 weeks' gestation for an
      adverse pregnancy outcome. RESULTS: The mean time of delivery was 39+0 weeks of
      gestation. Eight newborns (2%) were delivered before 34 weeks of gestation. The
      mean birth weight was 3,240 g. Dystrophic fetuses (<10% percentile) were
      registered in 35 cases (10%). In 31 of the 346 women (9%) a cesarean section was
      performed because of abnormal fetal heart recording. Preeclampsia was diagnosed
      in 17 cases (5%). In 5 cases (1.4%) a placental abruption and 2 (0.6%)
      intrauterine fetal deaths were diagnosed. The sensitivity of notching for the
      prediction of preeclampsia was 88% and for the prediction of a severe pregnancy
      complication (preeclampsia and/or intrauterine growth retardation and/or
      intrauterine fetal death and/or placental abruption) at any gestational age was
      62% with relative risks of 9.7 and 2.2, respectively. The sensitivity of notching
      for severe pregnancy complications requiring delivery before 34 weeks was 64%
      with a relative risk of 2.4. The sensitivity of notching in the uterine arteries
      for developing an IUGR was 56% with a relative risk of 1.7. CONCLUSION: The
      predictive value of uterine artery Doppler for adverse pregnancy outcome in a low
      risk population is of limited diagnostic value. Performing uterine artery Doppler
      studies at 23-26 weeks' gestation instead of 19-22 weeks' gestation increases the
      predictive value for adverse pregnancy outcomes.

PMID- 15185102
TI  - Pathological study of thyrotropin-secreting pituitary adenoma: plurihormonality
      and medical treatment.
AB  - Thyrotropin (TSH)-secreting adenomas are rare and, as most adenomas are large,
      invasive and difficult to cure by surgery only, many require additional medical
      treatment. Many TSH-secreting adenomas cosecrete growth hormone (GH) and/or
      prolactin (PRL). We evaluated the relationship between pathology and the effect
      of dopamine agonist bromocriptine and somatostatin analogue octreotide in 20
      operated patients with TSH-secreting adenomas. The four men and 16 women ranged
      in age from 23 to 62 years; three had clinically overt acromegaly; two manifested
      galactorrhea-amenorrhea. Endocrinologically, elevated serum GH, and/or IGF-1 were
      observed in six patients and elevated serum PRL was observed in eight.
      Immunohistochemically, 16 of the 20 adenomas were positive for GH and/or PRL (GH
      positive, n=13; PRL-positive, n=9). Pituitary-specific transcription factor Pit-1
      was demonstrated in the nuclei of all adenoma cells. Octreotide tests showed
      suppression of serum TSH (<50%) in ten of 14 patients. Preoperative octreotide
      treatment effectively reduced serum TSH and tumor size in two patients. Electron
      micrographs of octreotide-treated TSH-secreting adenomas showed shrinkage of the
      cytoplasm and diffuse distribution of secretory granules. Our study suggests that
      cosecretion of GH and/or PRL from TSH-secreting adenoma has no correlation with
      response of tumor cells to medical treatment.

PMID- 15185103
TI  - Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis.
AB  - Tuberous sclerosis (TSC) is an autosomal dominant disorder, caused by mutations
      of either the TSC1 or TSC2 gene. Characteristic brain pathologies (including
      cortical tubers and subependymal hamartomas/giant astrocytomas) are thought to
      cause epilepsy, as well as other neurological dysfunction. The Eker rat, which
      carries a spontaneous germline mutation of the TSC2 gene (TSC2+/-), provides a
      unique animal model in which to study the relationship between TSC cortical
      pathologies and epilepsy. In the present study, we have analyzed the seizure
      propensity and histopathological features of a modified Eker rat preparation, in
      which early postnatal irradiation was employed as a "second hit" stimulus in an
      attempt to exacerbate cortical malformations and increase seizure propensity.
      Irradiated Eker rats had a tendency toward lower seizure thresholds (latencies to
      flurothyl-induced seizures) than seen in non-irradiated Eker rats (significant
      difference) or irradiated wild-type rats (non-significant difference). The
      majority of irradiated Eker rats exhibited dysplastic cytomegalic neurons and
      giant astrocyte-like cells, similar to cytopathologies observed in TSC lesions of
      patients. The most prominent features in these brains were hamartoma-like lesions
      involving large eosinophilic cells, similar to giant tuber cells in human TSC. In
      some cells from these hamartomas, immunocytochemistry revealed features of both
      neuronal and glial phenotypes, suggesting an undifferentiated or immature cell
      population. Both normal-appearing and dysmorphic neurons, as well as cells in the
      hamartomas, exhibited immunopositivity for tuberin, the protein product of the
      TSC2 gene.

PMID- 15185104
TI  - Complete remission of primary colon cancer in a metastatic patient treated with
      CPT-11 plus capecitabine.
AB  - BACKGROUND AND AIMS: The best treatment of patients with advanced colorectal
      cancer at the time of diagnosis is not well known, and the medical treatment is
      still unsatisfactory. CASE PRESENTATION: We report the case of a patient showing
      a complete remission of primary tumor after medical therapy with CPT-11 plus
      capecitabine. DISCUSSION: The best management of advanced disease at first
      presentation is discussed.

PMID- 15185105
TI  - Pleuropulmonary blastoma in childhood. A malignant degeneration of pulmonary
      cysts.
AB  - Pleuropulmonary blastoma (PPB) is an extremely rare intrathoracic neoplasm of
      early childhood with an unfavorable outcome. In this article, two children with
      PPB associated with pre-existing pulmonary cysts are presented. It is emphasized
      that surgical excision is the treatment of choice for all pulmonary cysts.

PMID- 15185107
TI  - Sutureless circumcision: a prospective randomised controlled study.
AB  - Our aim was to study the advantages of glue versus sutures for circumcision in
      children. A randomised prospective controlled study was conducted with 152 boys;
      glue was used on 80 and sutures on 72. The procedures were quicker and the
      duration and severity of postoperative pain were significantly less (p < 0.001)
      in the cases in which glue was used. The tissue glue is a perfectly feasible
      alternative to sutures for circumcision in children and has potentially
      significant advantages.

PMID- 15185106
TI  - A novel approach for preventing esophageal stricture formation:
      sphingosylphosphorylcholine-enhanced tissue remodeling.
AB  - Using a new class of intracellular 2nd messengers to prevent stricture formation
      after caustic ingestion, sphingosylphosphorylcholine (SPC) has a wide spectrum of
      activity in cell growth regulation and signal transduction. Caustic esophageal
      burns were created with 15% NaOH in an experimental rat model. Control group
      animals (n = 10) had esophageal burns with no treatment, whereas the SPC group (n
      = 10) had esophageal burns gavaged with SPC for 7 days. Efficacy of treatment was
      assessed in 28 days by contrast esophagograms, histopathologic evaluation, and
      biochemically by tissue hydroxyproline (OHP) content. Contrast esophagograms
      demonstrated that SPC significantly prevented stricture formation. Obvious
      collagen deposition was present in submucosa, muscularis mucosa, and muscular
      layers in the control group compared with the SPC group. The damage to the
      esophageal wall on histopathologic examination was significantly lower in the SPC
      group (p < 0.05). Tissue OHP contents were significantly lower in the SPC-treated
      group (3.0 +/- 0.1 microg/mg) compared with the control group (4.3 +/- 0.2
      microg/mg) (p < 0.05). We conclude that SPC improves healing following caustic
      esophageal burns. Furthermore, SPC is effective in preventing caustic esophageal
      strictures. These effects of SPC occur through its proliferative and specifically
      its remodeling effects on wound healing.

PMID- 15185108
TI  - Diagnosis and outcome of Hirschsprung's disease: does age really matter?
AB  - Although Hirschsprung's disease (HD) typically presents in the newborn period, it
      is often diagnosed in older children, in whom the presentation and management
      remain poorly defined. We hypothesized that older patients with HD have a milder
      variant of the disease with an improved prognosis compared with those diagnosed
      earlier. Children with HD (1995-2001) were divided into Group I (diagnosis before
      30 days) and Group II (after 30 days). Patients with total colonic disease were
      excluded. There were 66 patients; 47 in Group I and 19 in group II. Mean age at
      diagnosis was 7.1+/-1.3 days (range 1-30 days) versus 27+/-10 months (1.3 months
      19 years). Older children differed mainly in the symptoms at presentation and the
      length of the involved segment of aganglionosis. Surgical strategies were applied
      equally in both groups. Complications, including postoperative enterocolitis,
      occurred equally, but the length of stay and costs were lower in Group II. The
      delayed diagnosis of HD does not worsen outcomes of older children with HD. This
      finding implies that these children have a milder form of the disease, perhaps
      because of adaptation to the aganglionic state.

PMID- 15185109
TI  - Intrapleural fibrinolytic treatment of multiloculated pediatric empyemas.
AB  - Our objective was to compare the efficacy of adjunctive intrapleural fibrinolytic
      agents (IPFA) (streptokinase, urokinase) on fibrinopurulent stage empyema and
      chronic stage empyema in children. IPFA were used in 78 pediatric patients with
      empyema (36 fibrinopurulent stage empyemas, 42 chronic stage empyemas) between
      December 1994 and September 2002. Pleural biopsy was done for staging in all
      cases. Streptokinase 250,000 units in 100 ml normal saline (62 patients) or
      100,000 units urokinase in 100 ml normal saline (16 patients) was instilled daily
      into the patient's chest tube, and the tube was clamped for 4 h, followed by
      suction. This treatment was continued daily for 2-8 days until resolution was
      demonstrated by chest radiographs and/or computed chest tomography. Success of
      treatment was 97.2% (complete response 24/36, partial response 11/36) in the
      fibrinopurulent stage and 9.4% (complete response 2/42, partial response 2/42) in
      chronic empyema cases. In one patient with fibrinopurulent empyema, the treatment
      was stopped due to allergic reaction and pleural hemorrhage; this patient died 1
      day later in a septic condition. Although an invasive method, the pleural biopsy
      technique may be an alternative way of more properly staging thoracic empyema in
      selected children in whom staging based on radiographic and biochemical findings
      is doubtful. Intrapleural fibrinolytic treatment is an effective and safe therapy
      of choice and may have significant benefit in most children with fibrinopurulent
      phase empyema, except for those with bronchopleural fistula. IPFA do not seem to
      be effective in children with chronic phase empyema.

PMID- 15185110
TI  - Congenital cystic adenomatoid malformation of the lung: indications and timing of
      surgery.
AB  - We review a single surgeon and surgical centre's experience with congenital
      cystic adenomatoid malformation of the lung (CCAML) in relation to clinical
      spectrum, operative experience, and postoperative course. A retrospective
      hospital record review was done on surgically treated cases of CCAML over a 10
      year period, focusing on number with antenatal diagnosis, spectrum of postnatal
      presentation, type of surgery performed, and outcome. Forty-seven patients from
      birth to 14 years of age underwent surgery for CCAML. Antenatal diagnosis (ante)
      was made in 30 cases. Of these, 10 became symptomatic before surgery. Six of the
      17 postnatally-diagnosed (pnd) cases were an asymptomatic incidental finding.
      Overall, 16 were symptomatic in the 1st year of life, and five were symptomatic
      beyond 1 year of age. Symptoms varied from respiratory distress (seven ante, six
      pnd) to chronic cough (three, and recurrent chest infection (three ante, two
      pnd). All preoperative diagnoses were confirmed with chest CT. Most patients (25)
      were operated on before 3 months of age. Eleven were operated on in the first 2
      weeks of life as emergency surgery for respiratory distress. The most common lobe
      involved was the right upper lobe (16), and lobectomy was performed in 42 cases,
      segmentectomy in four, and pneumonectomy in one. Seventeen cases were extubated
      immediately postoperatively; 29 required postoperative ventilation overnight, and
      nine needed more prolonged ventilation. Early postoperative complications
      included pneumothorax (two), pleural effusion (one), and chylous effusion (one).
      Late complications included recurrence in three cases (all segmentectomy), who
      then subsequently underwent lobectomy. There was one death from respiratory
      failure. Because there is an increasing trend in the detection of asymptomatic
      antenatally-diagnosed CCAML, consideration of early surgical excision to prevent
      complications is suggested by our series. CT scanning is mandatory for postnatal
      evaluation because chest x-ray could be normal. Safe elective excision after 3
      months is supported by our low morbidity and less need for postoperative
      ventilation. Lobectomy is the procedure of choice to prevent recurrence.

PMID- 15185111
TI  - Endoscope-controlled microneurosurgery for the treatment of intracranial fluid
      cysts.
AB  - OBJECTIVE: This study assessed the role of endoscope-controlled microneurosurgery
      (ECM) in the treatment of intracranial cerebrospinal fluid (CSF) cysts. METHODS:
      Twelve patients affected by symptomatic arachnoid cysts (11 in the sylvian
      fissure and 1 in the cerebellopontine angle) underwent ECM, in which the
      endoscope is used to view the operating field while microsurgical instruments can
      be passed alongside the endoscope for surgical maneuvers. All the cysts were
      superficially located and could be reached directly through a burr hole on their
      surface, so that the endoscope was inserted into the cyst without passing through
      the brain parenchyma. We used a rigid endoscope, performing a wide fenestration
      of the cyst in the basal cisterns (cystocisternostomy). The excellent endoscopic
      vision facilitated the surgical procedure with safe maneuvers through a minimally
      invasive approach. In 11 patients, we observed the resolution of symptoms. A
      radiological reduction in the cyst was observed in 7 cases. No mortality or major
      complications were observed. CONCLUSIONS: Endoscope-controlled microsurgery is a
      valid minimally invasive procedure for treating superficially located
      intracranial arachnoid cysts.

PMID- 15185112
TI  - Endoscopic approach for the treatment of relapses in cystic craniopharyngiomas.
AB  - INTRODUCTION: Craniopharyngiomas are tumours of the central nervous system of
      dysontogenetic origin. They are most commonly localized in the sellar region and
      appear to originate from an embryogenetic defect of the Rathke cleft. It is
      universally accepted that radical surgery should be performed as first surgery
      because surgery after relapses usually causes more difficulty due to tighter
      adhesion to surrounding structures. It is essential when relapses occur to
      evaluate which technique to use for treatment. For this reason, any new approach
      is welcomed in order to have as many alternatives as possible. MATERIAL AND
      METHODS: In this paper we present the treatment, with a minimum follow-up of 4
      years, of 5 paediatric patients affected by cystic craniopharyngiomas who went
      through first traditional surgery in other institutions and suffered relapses in
      various anatomical structures. One had a second successful endoscopic attempt at
      total gross resection. In 3 cases we endoscopically implanted a stent in the
      cystic cavity draining the cystic liquid out from the cystic cavity of the
      craniopharyngioma to the sphenoid sinus in order to form an accessory sinus. In 1
      case a multiphase treatment has been undertaken. RESULTS: All patients treated
      using a transsphenoidal endoscopic approach are still living, without relapses
      and no postoperative complications. In particular, there where no episodes of
      vasospasm (a common complication reported in the literature when the "motor oil"
      comes into contact with the subarachnoid space) or infections. The patient
      treated using the multiphase approach recovered but suffered a recurrence 2 years
      later due to hypothalamic infiltration. DISCUSSION AND CONCLUSIONS:
      Craniopharyngioma relapse needs different treatments. Many alternative approaches
      have been reported but none of them is the first choice alternative. We believe
      endoscopic stent placement in the cystic cavity is an alternative method for the
      treatment of cystic relapses.

PMID- 15185113
TI  - Incidence of complications in neuroendoscopic surgery.
AB  - OBJECTIVE: This study was undertaken to determine the complication rate in
      intracranial endoscopic neurosurgery. RESULTS: The complications in our series of
      endoscopic intracranial procedures for the treatment of hydrocephalus, colloid
      and arachnoid cysts, as well as intraventricular tumors, were analyzed.
      CONCLUSION: Although the complication rate in endoscopic neurosurgery is low,
      severe, rarely even life-threatening, complications may occur. The complication
      rate decreases markedly with surgical experience, indicating a steep learning
      curve.

PMID- 15185114
TI  - Mild trigonocephaly and intracranial pressure: report of 56 patients.
AB  - INTRODUCTION: We report the surgical results in patients with mild trigonocephaly
      and clinical symptoms. Since high intracranial pressure (ICP) was noted during
      surgery in our previous patient series, we began to record intraoperative ICP.
      The importance of treating mild trigonocephaly with clinical symptoms is
      stressed. PATIENTS AND METHODS: Fifty-six children (44 boys, 12 girls) in whom
      ICP was measured were diagnosed with mild trigonocephaly (nonsyndromic type) with
      symptoms such as language delay, hyperactivity, autistic tendencies, self
      mutilation, motor delay, etc. Their ages ranged from 2 to 8 (mean 5.1) years. ICP
      was measured after a burr hole was made under endotracheal general anesthesia and
      a sensor was inserted in the right frontal lobe epidurally immediately in front
      of the right coronal suture. The first recordings were made at around 30 mmHg of
      PCO(2) as for neuroanesthesia, and the second were at around 40 mmHg of PCO(2) as
      during natural breathing. We also investigated which factors accounted for the
      improvement of clinical symptoms. RESULTS: The first ICP records at 29.1 mmHg of
      PCO(2) indicated a mean ICP of 13.3 mmHg. The second changed to a mean 38.2 mmHg
      of PCO(2) for an increased mean ICP of 19.8 mmHg. The pulse pressures were a mean
      7.1 mmHg in the first recordings and 8.5 mmHg in the second. The mean ICP and
      pulse pressure were thus high in these children. Clinically, 30 out of 56
      patients improved markedly and 22 improved slightly, while 4 did not exhibit any
      change. Factors contributing to improvement were younger age, relatively higher
      development quotient, marked digital impressions on skull X-rays, abnormal
      findings on SPECT, and moderate degree of trigonocephaly. CONCLUSION: Although
      our patients had mild trigonocephaly, their ICP and pulse pressure were high.
      Decompressive cranioplasty in cases of mild trigonocephaly is feasible.

PMID- 15185115
TI  - Interindividual variation of isolated muscle performance and fibre-type
      composition in the toad Bufo viridus.
AB  - Interindividual analyses of physiological performance represent one of the most
      powerful tools for identifying functional positive and negative linkages between
      various performance traits. In this study we investigated functional linkages in
      the whole-gastrocnemius performance of juvenile Bufo viridis by examining
      interindividual variation in in vitro muscle performance and muscle fibre-type
      composition. We used the work-loop technique to investigate the maximum in vitro
      power output and fatigue resistance of the gastrocnemius muscle during repeated
      sets of three cycles at the cycle frequency of 5 Hz, simulating an intermittent
      style of locomotion. We found several significant correlations between different
      measures of in vitro muscle performance, including a negative correlation between
      maximum net power output and fatigue resistance of power, indicating functional
      trade-offs between these performance traits. We also investigated the extent of
      individual variation in the proportions of different fibre types, and tested for
      correlations between individual variation in muscle fibre-type composition and
      the previously measured isolated muscle performance. Fast glycolytic fibres
      represented 84.0 +/- 3.4% of the muscle, while the combined slow oxidative and
      fast oxidative-glycolytic fibres represented 16 +/- 3.4%. We found no significant
      correlations between measures of in vitro muscle performance and the proportion
      of different fibre types in the gastrocnemius muscle. However, despite this lack
      of correlation between whole-muscle performance and muscle fibre-type composition
      data, we suggest the functional linkages detected between different measures of
      in vitro muscular performance have important ecological and evolutionary
      consequences.

PMID- 15185116
TI  - Cross-talk of phosphoinositide- and cyclic nucleotide-dependent signaling
      pathways in differentiating avian nasal gland cells.
AB  - In many bird species, the nasal glands secrete excess salt ingested with drinking
      water or food. In ducks ( Anas platyrhynchos), osmotic stress results in adaptive
      cell proliferation and differentiation in the gland. Using 'naive' nasal gland
      cells isolated from animals that had never ingested excess salt or
      'differentiated' cells from animals fed with a 1% NaCl solution for 48 h, we
      investigated the allocation of metabolic energy to salt excretory processes and
      to other cellular activities. Activation of muscarinic acetylcholine receptors
      (carbachol) or beta-adrenergic receptors (isoproterenol) in nasal gland cells
      resulted in a transient peak in metabolic rate followed by an elevated plateau
      level that was maintained throughout the activation period. Activation of cells
      using vasoactive intestinal peptide, however, had only marginal effects on
      metabolic rate. In differentiated cells, sequential stimulation with carbachol
      and isoproterenol resulted in additive changes in metabolic rate during the
      plateau phase. Naive cells, however, developed supra-additive plateau levels in
      metabolic rates indicating cross-talk of both signaling pathways. Using
      bumetanide, TEA or barium ions to block different components of the ion transport
      machinery necessary for salt secretion, the relative proportion of energy needed
      for processes related to ion transport or other cellular processes was
      determined. While differentiated cells in the activated state allocated virtually
      all metabolic energy to processes related to salt secretion, naive cells reserved
      a significant amount of energy for other processes, possibly sustaining cellular
      signaling and regulating biosynthetic mechanisms related to adaptive growth and
      differentiation.

PMID- 15185117
TI  - Responsiveness to sucrose and habituation of the proboscis extension response in
      honey bees.
AB  - In honey bees, complex behaviours such as associative learning correlate with
      responsiveness to sucrose. In these behaviours, the subjective evaluation of a
      sucrose stimulus influences the behavioural performance. Habituation is a well
      known form of non-associative learning. In bees, the proboscis extension response
      can be habituated by repeatedly stimulating the antennae with a low sucrose
      concentration. A high sucrose concentration can dishabituate the response. This
      study tests whether habituation correlates with responsiveness to sucrose in bees
      of different behavioural states and in bees which are habituated with different
      sucrose concentrations. Habituation and dishabituation in newly emerged bees, 5
      day-old bees and foragers strongly correlated with responsiveness to sucrose.
      Bees with high responsiveness to sucrose displayed a lower degree of habituation
      and showed greater dishabituation than bees with low responsiveness. The degree
      of habituation and dishabituation also depended on the concentration of the
      habituation stimulus. These experiments demonstrate for the first time in a non
      associative learning paradigm that the subjective strength of a sucrose stimulus
      determines the behavioural performance. Non-associative learning shares this
      property with associative learning, which suggests that the two processes might
      rely on similar neural mechanisms.

PMID- 15185118
TI  - [Carboxyamido-triazole inhibits substeps of choroidal neovascularization on
      retinal pigment epithelial cells and choroidal endothelial cells in vitro].
AB  - BACKGROUND: Retinal pigment epithelial cells (RPE cells) and choroidal
      endothelial cells (CECs) are important cell types in the process of choroidal
      neovascularization in exudative age-related macular degeneration (AMD). In this
      study, we evaluated the antiproliferative and antimigratory abilities of
      carboxyamido-triazole (CAI), a drug modulating calcium-dependent signal
      transduction on RPE cells and CECs. METHODS: Human fetal RPE cells and bovine
      CECs were exposed to CAI in a concentration range of 0.1 to 10 microM. Cell
      proliferation was stimulated with 10% serum or 10 ng/ml bFGF. The effect of CAIs
      on cell proliferation was estimated. Furthermore, we evaluated CAI's effects on
      CEC and RPE cell migration induced by fibronectin. RESULTS: CAI had a stronger
      inhibitory effect on serum-induced CEC proliferation than on RPE cell
      proliferation. A much stronger effect was seen on the proliferation of bFGF
      stimulated RPE cells and CECs. Furthermore, the fibronectin-stimulated migration
      of RPE cells and CECs was inhibited by CAI. In this assay, a stronger inhibitory
      effect was seen on RPE cells than on CECs. CONCLUSION; CAI inhibits important
      substeps of choroidal neovascularization on RPR cells and CECs. Therefore, CAI
      may be of value for the treatment of choroidal neovascularization in exudative
      AMD.

PMID- 15185120
TI  - [White planar deposits on the retina].

PMID- 15185119
TI  - [Association of malignant tumors of the conjunctiva and HIV infection in Kinshasa
      (D. R. Congo). First results].
AB  - BACKGROUND: Conjunctival carcinomas are tumors especially of the 6th/7th decades.
      They occur in Germany with a frequency of 1/20,000. For years it has been well
      known that in Africa the number of malignant tumors of the conjunctiva has been
      increasing. The reasons for that are not well known. HIV is a possible
      pathogenetic cofactor. METHOD: A histological examination of 34 specimens was
      performed in Rostock on conjunctival tumors removed at the Ophthalmologic
      Department of the University of Kinshasa in 2001. The study included 23 female
      and 11 male patients aged 20-75 years (mean 42). All patients underwent
      serological investigation for HIV infection. RESULTS: Of 34 patients 18 were HIV
      positive. Of the HIV-positive patients, six had a squamous cell carcinoma, seven
      a CIN (conjunctival intraepithelial neoplasia) I-III, and five a pinguecula. Of
      the HIV-negative patients, five showed a squamous cell carcinoma, eight a CIN I
      III, one a pinguecula, one a sebaceous gland carcinoma, and one a papilloma. The
      average age of the HIV-positive patients with a squamous cell carcinoma was 41
      years compared to the HIV-negative patients with 58 years. CONCLUSIONS: There was
      no difference in frequency of conjunctival intraepithelial neoplasia between HIV
      positive or HIV-negative patients. HIV-positive patients with a squamous cell
      carcinoma were on average 17 years younger. UV radiation is the main risk factor
      and HIV infection is a possible carcinogenic cofactor. Investigations on
      additional viral infections as possible pathogenetic factors and on changed tumor
      suppressor genes are needed.

PMID- 15185121
TI  - Renal MRI findings and their clinical associations in nephropathia epidemica:
      analysis of quantitative findings.
AB  - Morphologic renal magnetic resonance imaging (MRI) findings in patients with
      nephropathia epidemica (NE) were evaluated, and these findings were correlated
      with the clinical course of NE. Renal MRI was performed in 20 hospitalized NE
      patients during the acute phase of their disease. A repeat MRI study was made 5-8
      months later. Renal parenchymal volume, renal length and parenchymal thickness
      were decreased in all patients in the repeat study. Edema/fluid collections were
      found bilaterally in 16 patients in the primary MRI study. Greater change in
      parenchymal volume, renal length and parenchymal thickness between the primary
      and the repeat MRI study as well as the presence of edema/fluid collections in
      the primary study evinced mild association with clinical fluid volume overload,
      high blood pressure level, inflammation, thrombocytopenia and severe clinical
      renal insufficiency. Change in parenchymal volume was associated with a severe
      clinical course more markedly than the other MRI findings. Measurable renal MRI
      changes occurred in every NE patient. The severity of the findings in MRI evinced
      mild association with clinical fluid volume overload, high blood pressure level,
      inflammation, thrombocytopenia and severe clinical renal insufficiency. Based on
      this study and our previous ultrasound (US) findings, we prefer US as the primary
      examination mode in NE patients.

PMID- 15185123
TI  - Somatic embryogenesis in Solanum tuberosum L.: a histological examination of key
      developmental stages.
AB  - A potential novel method of producing high-quality potato ( Solanum tuberosum L.)
      nuclear seeds is through the process of somatic embryogenesis (SE). Somatic
      embryo formation has been successfully reported in many plant species, but in
      potato, reliable SE systems are still at the experimental stage. A key factor in
      the success of any SE system is the ability to discriminate SE-specific cellular
      structures from those emerging through an organogenic route. In the investigation
      reported here we attempted to discriminate the progression of specific stages of
      potato SE by histological means. Internodal segment (INS) explants from 4- to 6
      week-old cv. Desiree in vitro cultures were successively cultured on SE induction
      (for 2 weeks) and expression/regeneration media (for 3 weeks) with and without
      2,4-dichlorophenoxyacetic acid (5 microM). Microscopic examination of
      histological slides prepared using INS explants at different stages revealed the
      presence of characteristic globular, heart and torpedo stages in the potato SE
      system along with other associated unique features such as protoderm development
      and discrete vascular connections. These results confirm the occurrence of potato
      SE as per the accepted definition of the term.

PMID- 15185122
TI  - Genetic transformation of selected mature cork oak (Quercus suber L.) trees.
AB  - A transformation system for selected mature cork oak (Quercus suber L.) trees
      using Agrobacterium tumefaciens has been established. Embryos obtained from
      recurrent proliferating embryogenic masses were inoculated with A. tumefaciens
      strains EHA105, LBA4404 or AGL1 harbouring the plasmid pBINUbiGUSint [carrying
      the neomycin phosphotransferase II (nptII) and beta-glucuronidase (uidA) genes].
      The highest transformation efficiency (4%) was obtained when freshly isolated
      explants were inoculated with A. tumefaciens strain AGL1. Evidence of stable
      transgene integration was obtained by PCR for the nptII and uidA genes, Southern
      blotting and expression of the uidA gene. The transgenic embryos were germinated
      and successfully transferred to soil.

PMID- 15185124
TI  - WR-2721 (Amifostine) ameliorates cisplatin-induced hearing loss but causes
      neurotoxicity in hamsters: dose-dependent effects.
AB  - Chemoprotective agents reduce the toxic side effects of chemotherapy agents such
      as cisplatin. The conventional belief is that the chemoprotective agent WR-2721
      (Amifostine), while protecting against most cisplatin-induced side effects, does
      not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is
      no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in
      possibly protecting against cisplatin-induced ototoxicity. Thus, the dose
      dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity
      were investigated. Hamsters were given a series of 5 cisplatin injections (3
      mg/kg/injection once every other day, i.p.) either alone or in combination with
      18, 40, 80, or 400 mg/kg/injection of the rescue agent WR ( n = 5 or 10/group).
      Other groups received either 80 mg/kg/injection WR alone ( n = 5) or were
      untreated ( n = 14). Ototoxicity was assessed by auditory brain stem responses
      (ABR). WR provided dose-dependent rescue from cisplatin's ototoxicity with no
      protection at the low dose of 18 mg/kg, moderate protection at 40 mg/kg, and
      nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or
      higher caused neurotoxicity as evidenced by prolongations in the ABR's interpeak
      latencies. Thus, high doses of WR provided the beneficial effect of protecting
      against cisplatin-induced ototoxicity, but had the harmful side effect of
      neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced
      ototoxicity were likely due to the use of WR doses that were too small. The
      clinical implications of the beneficial and harmful effects of high doses of WR
      are discussed.

PMID- 15185125
TI  - Along with GREPA towards EHS, meeting AHS.
AB  - The popular proverb that says "Happy people have no history" is not true. This
      short chronicle, from experience inside GREPA-EHS, by one of its founding
      members, tells the contrary to the reader. It suggests that, by meeting together,
      hernia surgeons got much welfare through scientific assessment, a more efficient
      practice, and increased recognition of their art.

PMID- 15185127
TI  - The evaluation of the peak flow velocity and cross-sectional area of the femoral
      artery and vein following totally extraperitoneal vs preperitoneal open repair of
      inguinal hernias.
AB  - BACKGROUND: Both totally extraperitoneal (TEP) and preperitoneal (PPOR)
      approaches involve the placement of prosthetic material preperitoneally. As the
      prosthetic material overlies the femoral artery and vein, we aimed to assess its
      effect on the velocity and the diameter of the artery and vein, using colour
      Doppler ultrasonography in both approaches. METHODS: Eighty patients with
      unilateral groin hernia were prospectively randomised to have either TEP repair
      (n = 40) or PPOR (n = 40). All patients underwent colour Doppler ultrasound study
      6 months after the procedure, and all patients were followed up for 5 years to
      evaluate real recurrence rates. RESULTS: Our study revealed that neither mean
      diameter nor mean flow velocity is changed by the insertion of the mesh
      preperitoneally. Change was only observed in the peak systolic femoral arterial
      blood velocity, which was significantly decreased in the PPOR group. We also
      found that no patient in this study developed a clinically significant deep-vein
      thrombosis during 6 months of follow-up. CONCLUSIONS: It is concluded that the
      insertion of a prosthetic mesh during TEP or PPOR does not influence the mean
      peak flow velocity and the cross-sectional area of the vessels in the inguinal
      region and can be used safely for open and laparoscopic preperitoneal approaches.

PMID- 15185128
TI  - Primary omental liposarcoma presenting as an incarcerated inguinal hernia.
AB  - Herein, we present a case of primary liposarcoma of the omentum found in an
      incarcerated inguinal hernia in a 52-year-old male patient. The patient was
      admitted to our hospital in June 2000 with sudden onset of left-sided abdominal
      and groin pain of 12 hours' duration with a large, irreducible inguinal hernia.
      This was not associated with nausea or vomiting. An emergency operation was
      performed, and in the hernia sac the tumor, arising from the greater omentum, was
      found. After we opened the transversal fascia and peritoneum, the tumor was
      resected with a block of the greater omentum, and hernioplasty was performed
      using Shouldice's method. The histopathological diagnosis of resected tumor
      showed myxoid type liposarcoma. In the English medical literature, omental
      liposarcoma has never before been reported as the content of a hernia sac.

PMID- 15185126
TI  - Pitfalls in retromuscular mesh repair for incisional hernia: the importance of
      the "fatty triangle".
AB  - Open retromuscular mesh repair has become a standard procedure in incisional
      hernia repair. This technique led to a significant decrease of recurrences.
      Recurrences after this technique typically occur at the upper mesh border and are
      a result of the technical complexity of reaching the postulated underlay of 5 cm
      in the region of the linea alba. We performed an anatomical study in human
      corpses to investigate the abdominal wall with its different structures, with
      emphasis on the overlap of the mesh under the linea alba. The overlap can be
      achieved by incision of the posterior lamina of the rectus sheath, on both sides
      close to the linea alba. The incision opens the preperitoneal space and appears
      in the shape of a "fatty triangle". The anterior lamina of the rectus sheath
      above the hernia defect remains intact and facilitates a sufficient thrust
      bearing for a retromuscular mesh implantation. Knowledge of the anatomy and
      preparation of the "fatty triangle" enables a mesh positioning according to the
      principles of retromuscular mesh repair.

PMID- 15185130
TI  - The preperitoneal approach to the groin and the inferior epigastric vessels.
AB  - Preperitoneal, a word coined by Nyhus in the 1960s, has been applied not only to
      posterior approaches that he, Stoppa, and Wantz popularized but to anterior
      exposures of the groin, which divide the transversalis fascia. This assumes that
      all give similar views of the easily cleaved space of Bogros. However,
      accumulated anatomical observations reveal the transversalis fascia as having not
      one but two layers. The inferior epigastric vessels run between rather than in
      the preperitoneal space, which is avascular and has its own fascia lining the
      peritoneum. Historical evidence shows that both the midline Cheatle-Henry and
      lateral Ugahary-Kugel approaches, which transect the abdominal wall, provide
      excellent exposure of the avascular preperitoneal space. However, neither the
      unilateral posterior McEvedy approach nor the anterior approach does, as only
      part of the musculature and fasciae are retracted. The inferior epigastric
      vasculature and posterior lamina transversalis fascia, which remain in situ,
      block the view. Unless they are disrupted or circumvented, neither of the latter
      approaches or subsequent repairs should be labeled preperitoneal.

PMID- 15185129
TI  - Combined anterior and posterior inguinal hernia repair: intermediate recurrence
      rates with three groups of surgeons.
AB  - BACKGROUND: Use of a bilayer polypropylene mesh device (BPMD) for inguinal hernia
      repair began in 1998. Intermediate follow-up is now available for patients
      undergoing repair by three groups of surgeons. METHODS: Surgeons whose practice
      is dedicated to hernia repair trained preceptors who, in turn, assisted in the
      training of other surgeons in this new technique. All three groups provided
      information regarding their recurrence rates with this technique. RESULTS:
      Recurrence rates were similar for all three groups. Hernia specialists reported
      three recurrences out of 4,801 repairs. Preceptors reported one recurrence in
      3,780 repairs. Other surgeons reported one failure in 3,369 repairs. CONCLUSIONS:
      Use of the BPMD (Prolene Hernia System) provides reliable results in the hands of
      hernia specialists, as well as general surgeons whose practices are not
      concentrated on the management of hernias.

PMID- 15185131
TI  - Ventral hernia repair using allogenic acellular dermal matrix in a swine model.
AB  - BACKGROUND: This study was designed to assess the long-term efficacy of allogenic
      acellular dermal matrix (ADM) used as an interpositional graft for ventral hernia
      repair in a swine model. METHODS: We created 12x4-cm full-thickness abdominal
      wall defects in 22 Yucatan miniature pigs. The defect was repaired with either
      two 6x4-cm pieces of AlloDerm (acellular dermal matrix processed from pig skin in
      order to avoid a xenogenic response, LifeCell Corporation, Branchburg, NJ USA) (n
      = 12), or expanded polytetrafluoroethylene mesh (ePTFE) (Gore-Tex, W.L. Gore &
      Associates, Inc., Newark, DE USA) (n = 10). In six pigs, a separate 3-cm fascial
      incision was made, which was then suture repaired as a control for tensiometry
      testing. The surgical sites were evaluated at either 3 months or 9 months for the
      presence of a hernia, stretching of the implant, adhesions, vascularity, and
      biomechanical strength. RESULTS: Two hernias occurred in both the ADM and the
      ePTFE groups. There was minimal stretching of the implants and minimal adhesions
      in both groups. Fluorescein testing and histology indicated vascular ingrowth
      into the ADM. There was no statistical difference between the mean breaking
      strengths of the ADM-fascial interface (106.5 N +/- SD 40.1), the interface
      between two pieces of ADM (149.1 N +/- SD 76.7), and the primary fascial repair
      (108.1 N +/- SD 20.9) at 9 months. The ADM-fascial interface had a significantly
      higher breaking strength than that of the ePTFE-fascia interface (66.1 N +/- SD
      30.1) (P = 0.017, t-test, P = 0.043 Wilcoxon rank sum test). CONCLUSIONS: In this
      study, we were unable to demonstrate a difference between ADM and ePTFE in their
      ability to repair ventral hernias at 9 months in a swine model. The ADM
      additionally supports vascular ingrowth and exhibits increased breaking strength
      at the fascia-implant interface.

PMID- 15185132
TI  - Preperitoneal gridiron hernia repair for inguinal hernia: single-center
      experience with 2 years of follow-up.
AB  - The optimal operation technique for groin hernia repair has not been established.
      This study evaluates the long-term recurrence rate and perioperative
      complications after posterior inguinal mesh hernia repair using a gridiron
      incision described by Frans Ugahary. A retrospective analysis was performed of
      the medical records of 366 patients who underwent Ugahary hernia repair.
      Operative results and perioperative morbidity were evaluated retrospectively.
      Follow-up was done by clinical examination. The main outcome measure was
      recurrence rate at a mean follow-up of 2 years. Of the 386 groin hernia repairs,
      263 hernia repairs were examinated in the outpatient clinic. The overall
      recurrence rate was 6.5% with a mean follow-up of 2 years, and 10.1% of the
      patients had minor complications. This retrospective study demonstrates that the
      repair according to Ugahary is a safe technique for operating on groin hernia.
      However, the procedure is difficult to reproduce in nonexpert hands. This
      technique must be compared to other inguinal hernia operation techniques in the
      near future.

PMID- 15185133
TI  - The catalytic cycle of catechol oxidase.
AB  - Hybrid density functional theory with the B3LYP functional has been used to
      investigate the catalytic mechanism of catechol oxidase. Catechol oxidase belongs
      to a class of enzymes that has a copper dimer with histidine ligands at the
      active site. Another member of this class is tyrosinase, which has been studied
      by similar methods previously. An important advantage for the present study
      compared to the one for tyrosinase is that X-ray crystal structures exist for
      catechol oxidase. The most critical step in the mechanism for catechol oxidase is
      where the peroxide O-O bond is cleaved. In the suggested mechanism this cleavage
      occurs in concert with a proton transfer from the substrate. Shortly after the
      transition state is passed there is another proton transfer from the substrate,
      which completes the formation of a water molecule. An important feature of the
      mechanism, like the one for tyrosinase, is that no proton transfers to or from
      residues outside the metal complex are needed. The calculated energetics is in
      reasonable agreement with experiments. Comparisons are made to other similar
      enzymes studied previously.

PMID- 15185134
TI  - Outcomes of treatment pathways in outpatient treatment of low risk febrile
      neutropenic cancer patients.
AB  - BACKGROUND: We treated low-risk febrile neutropenic cancer patients utilizing two
      standard outpatient antibiotic pathways: oral ampicillin/clavulanate (500 mg) and
      ciprofloxacin (500 mg) or intravenous ceftazidime (2 g) and clindamycin (600 mg)
      every 8 h. The objectives were to determine the success of outpatient treatment
      of low-risk febrile neutropenia, to identify factors predicting outpatient
      failure, and to determine mortality related to the febrile episode. METHODS:
      Eligibility criteria included solid tumor diagnosis, stable vital signs,
      temperature > or =38.0 degrees C, absolute neutrophil count (ANC) of <1000/ml,
      patient compliance, no significant organ dysfunction, ability to tolerate oral
      medication and fluids for oral pathway, residence within 30 miles of the
      institution, 24-h caregiver, and telephone and transportation access. RESULTS:
      There were 257 febrile episodes in 191 patients meeting the criteria. Patients
      were treated during March 1998 through February 2000. Median age was 48 (range,
      17-77) years, and 60% (n = 153) had an entry ANC of <100/ml; 205 (80%) febrile
      episodes successfully responded to outpatient treatment, and 52 (20%) were
      hospitalized. Logistic regression analysis showed the following were related to
      hospitalization: mucositis >grade 2 (p < 0.002); Zubrod performance status > or
      =2 (p = 0.029); ANC <100/ml (p = 0.039), and age > or =70 years (p = 0.048).
      CONCLUSIONS: Outpatient treatment of low-risk febrile neutropenic cancer patients
      utilizing standard treatment pathways is associated with minimal morbidity and
      mortality and should be considered an acceptable standard of care with
      appropriate infrastructure available to provide strict and careful follow-up
      while on treatment. Certain factors are associated with higher risk of
      hospitalization and should be further examined in eligible patients with low-risk
      febrile neutropenia.

PMID- 15185135
TI  - Oncology professionals and patient requests for cancer support services.
AB  - OBJECTIVE: To examine the kinds of psychosocial support services that cancer
      patients most often request across a multidisciplinary sample of currently
      practicing U.S. oncological health care professionals (OHCPs) representative of a
      typical cancer care team. PARTICIPANTS: Primary data collection. A randomly
      selected sample of 1,180 OHCPs (44% physicians, 24% nurses, 32% social workers)
      who were active members of their respective oncological associations completed a
      brief four-page mailed survey during the spring of 2001. METHODS: Cross
      sectional, descriptive study. Descriptive statistics were computed for all study
      variables. ANOVA procedures were used to examine demographic difference between
      respondents and non-respondents. Frequencies were calculated for patient inquires
      for cancer support services inquiries, and logistic regression was used to
      evaluate professional group differences on inquiries. Chi-square statistics were
      used to test for significant differences between professional groups. RESULTS:
      Approximately 94% of OHCPs were asked about cancer-related support services by
      their patients. Quantitative data indicated that information and education about
      cancer (72%), support groups (65%), and hospice referral (52%) were paramount
      among patient concerns. Qualitatively, comments about transportation, lodging
      during treatment, and alternative medicine reflected the general sentiment that
      basic needs and opportunities for options may still be unmet. Patient inquiries
      for services varied significantly by professional group (p<.001). CONCLUSION:
      This information reflects the need for a multidisciplinary perspective and will
      be useful for planning patient-based cancer education and support initiatives,
      refining existing programs, and targeting materials to specific oncological
      professionals.

PMID- 15185136
TI  - Isolated abducens nerve palsy in hemolytic uremic syndrome.
AB  - Isolated abducens nerve (VI cranial nerve) palsies are reported in a dialyzed
      child with Escherichia coli 0157:H7-associated hemolytic uremic syndrome (HUS).
      There were no other neurological manifestations and he made a complete recovery,
      suggesting that isolated abducens nerve palsy in HUS may represent a minor
      neurological complication.

PMID- 15185137
TI  - Deuterium stable isotope ratios as tracers of water resource use: an experimental
      test with rock doves.
AB  - Naturally-occurring deuterium stable isotope ratios can potentially be used to
      trace water resource use by animals, but estimating the contribution of
      isotopically distinct water sources requires the accurate prediction of isotopic
      discrimination factors between water inputs and an animal's body water pool. We
      examined the feasibility of using estimates of water fluxes between a bird and
      its environment with a mass-balance model for the deuterium stable isotope ratio
      of avian body water (deltaDbody) to predict isotopic discrimination factors.
      Apparent fractionation and thus discrimination factors were predicted to vary
      with the proportion of an animal's total water losses than could be attributed to
      evaporative processes. To test our ability to predict isotopic discrimination, we
      manipulated water intake and evaporative water loss in rock doves (Columba livia)
      by providing them with fresh water or 0.15 M NaCl solution in thermoneutral or
      hot environments. After we switched the birds from drinking water with deltaD=-95
      per thousand VSMOW (Vienna Standard Mean Ocean Water) to enriched drinking water
      with deltaD=+52 per thousand VSMOW, steady-state deltaDbody was approached
      asymptotically. The equilibrium deltaDbody was enriched by 10-50 per thousand
      relative to water inputs. After isotopic equilibrium was reached, the degree of
      enrichment was positively related (r2=0.34) to the fraction of total water loss
      that occurred by evaporation (revap/rH2O)supporting the major prediction of the
      model. The variation we observed in discrimination factors suggests that the
      apparent fractionation of deuterium will be difficult to predict accurately under
      natural conditions. Our results show that accurate estimates of the contribution
      of different water sources to a bird's body water pool require large deuterium
      isotopic differences between the sources.

PMID- 15185138
TI  - Rodents balancing a variety of risks: invasive fire ants and indirect and direct
      indicators of predation risk.
AB  - We used foraging trays to compare how oldfield mice, Peromyscus polionotus,
      altered foraging in response to the presence of fire ants, Solenopsis invicta,
      and in the presence of direct (predator urine) and indirect (sheltered or exposed
      microhabitat, moonlight, and precipitation) indicators of predation risk.
      Foraging reductions elicited by S. invicta were greater than reductions in
      response to well-documented indicators of risk (i.e., moonlit nights) and the
      presence of predator urine. The presence of S. invicta always led to reduced
      foraging, but the overall impact of S. invicta was dependent upon microhabitat
      and precipitation. When S. invicta was not present, foraging was greater in
      sheltered microhabitats compared to exposed microhabitats. S. invicta made
      sheltered microhabitats equivalent to more risky exposed microhabitats, and this
      effect was especially pronounced on nights without precipitation. The effect of
      S. invicta suggests that interactions with S. invicta may entail a potentially
      heavy cost or that presence of S. invicta may represent a more reliable indicator
      of imminent competition or predation compared to indirect cues of risk and
      predator urine. The presence of S. invicta led to reduced foraging under
      situations when foraging activity would otherwise be greatest (i.show $132#e.,
      under vegetative cover), potentially reducing habitat quality for P. polionotus
      and the distribution of seeds consumed by rodents.

PMID- 15185139
TI  - Development of the caput epididymidis studied by expressed proteins (a glutamate
      transporter, a lipocalin and beta-galactosidase) in the c-ros knockout and wild
      type mice with prepubertally ligated efferent ducts.
AB  - Expression of a glutamate transporter (EAAC1), a lipocalin (MEP17) and beta
      galactosidase (beta-Gal) in histological sections was used to monitor post-natal
      development of the murine epididymis. Three epithelia in the adult caput of wild
      type mice were distinguished: I, the initial segment; II, the proximal caput; and
      III, the distal caput. The regions in which epithelia I, II and III were situated
      were called regions I, II and III, respectively. Regions I, II and III developed
      from a precursor epithelium present on day 14; from day 16, a presumptive region
      I epithelium was evident and, by day 21, epithelia characteristic of future
      regions II and III appeared. The relationship between the c-ros gene and the
      initial segment was studied by investigating the development of the caput
      epididymidis in transgenic homozygous c-ros knockout (-/-) mice that lack the
      initial segment, heterozygous (+/-) males and wild-type males in which the
      efferent ducts had been ligated prepubertally so that the initial segment failed
      to develop. In mice with prepubertally ligated efferent ducts, regions II and III
      developed normally but region I was missing in the adult and expression of c-ros
      was partially decreased. In (-/-) mice, the precursor epithelium was present,
      differentiation of epithelium II was delayed until day 32 and epithelium I never
      developed. Thus, caput region I develops before c-ros expression, high
      testosterone secretion and differentiation of regions II and III but not if the
      organ is deprived of the oncogene c-ros or testicular exocrine secretions. The
      caput of the knockout male lacks solely the initial segment so that the efferent
      ducts are in continuity with the post-initial segment, proximal caput region. The
      ligand for c-ros may be present in testicular fluid and both ligand and receptor
      may be necessary for differentiation of epithelia I and II.

PMID- 15185140
TI  - Serum-free cryopreservation of porcine hepatocytes.
AB  - The use of porcine hepatocytes in xenotransplantation, bioartificial liver
      support or pharmacological approaches demands serum-free cryopreservation
      protocols yielding high quality, viable, functional hepatocytes. Here, primary
      porcine hepatocytes were frozen without serum in liquid nitrogen by the use of a
      computer-assisted freezing device. After thawing, more than 90% of the initial
      hepatocytes were lost, in part because of damage to genomic DNA. When
      cryoprotectants were used, the loss was lowered to 70% of the initial cell
      number; 90% of the remaining cells excluded trypan blue indicating a high degree
      of viability. Cells were seeded serum-free onto collagen-coated plastic dishes to
      determine proliferation and retainment of specific functions representing
      prominent features of hepatocytes in vivo. Whereas no cells adhered to the
      substratum effectively in conventional culture medium, the addition of
      conditioned medium derived from hepatic non-parenchymal cells improved
      attachment. Cells proliferated, retained hepatocyte-specific functions, such as
      urea production and cytochrome P450 activity, and expressed liver-specific genes
      to levels observed in non-cryopreserved hepatocytes. Thus, serum-free
      cryopreserved primary porcine hepatocytes may serve as a valid source of cells
      for downstream applications. The cells seem to function adequately when an
      appropriate environment is chosen for recovery after cryopreservation, an
      ultimate demand for the clinical application of human hepatocytes.

PMID- 15185141
TI  - Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer
      linkage.
AB  - The tumor suppressor functions of PTEN and CDKN1B have been extensively
      characterized. Recent data from mouse models suggest that, for some organs, the
      combined action of both PTEN and CDKN1B has a stronger tumor suppressor function
      than each alone; for the prostate, heterozygous knockout of both genes leads to
      100% penetrance for prostate cancer. To assess whether such an interaction
      contributes to an increased risk of prostate cancer in humans, we performed a
      series of epistatic PTEN and CDKN1B interaction analyses in a collection of 188
      high-risk hereditary prostate cancer families. Two different analytical
      approaches were performed; a nonparametric linkage (NPL) regression analysis that
      simultaneously models allele sharing at these two regions in all families, and an
      ordered subset analysis (OSA) that assesses linkage evidence at a target region
      in a subset of families based on the magnitude of allele sharing at the reference
      region. The strongest evidence of interaction effect was observed at 10q23-24 and
      12p11-13 from both the NPL regression analysis (P = 0.0002) in all families and
      the OSA analyses in subsets of families. A LOD-delta of 3.15 (P = 0.01) was
      observed at 10q23-24 among 54 families with the highest NPL scores at 12p11-13,
      and a LOD-delta of 2.63 (P = 0.02) was observed at 12p11-13 among 34 families
      with the highest NPL scores at 10q23-24. The evidence for the interaction was
      stronger when using additional fine-mapping markers in the PTEN (10q23) and
      CDKN1B (12p13) regions. Our data are consistent with epistatic interactions
      between the PTEN and CDKN1B genes affecting risk for prostate cancer and
      demonstrate the utility of modeling epistatic effects in linkage analysis to
      detect susceptibility genes of complex diseases.

PMID- 15185142
TI  - Use of in vitro cytoadherence assays in the comparative study of the virulence of
      isolates of Trichomonas vaginalis.
AB  - This study describes the use of bromo-deoxiuridine, a non-radioactive analogue of
      thymidine, to determine the adhesion of 40 T. vaginalis isolates, as compared
      with the clinical manifestations found in patients. Parasite-labeling was
      optimized and label detection by immunoassay was carried out. Bromo-deoxiuridine
      at 10 microM for 16 h produced the highest sensitivity. Once optimized, the assay
      was able to detect between 3.12 x 10(3) and 4 x 10(5) parasites, with a detection
      limit of 9.14 x 10(2), which is lower than with the use of [3H]-thymidine. The
      variation coefficients were 2.65% for repeatability and 3.8% for reproducibility.
      A correlation coefficient of 0.97 was found between the pattern curves obtained
      by both labeling procedures. The level of adhesion to HeLa cells was directly
      proportional to the severity of the clinical manifestations (P < 0.05).

PMID- 15185143
TI  - Use of ITS rDNA for discriminating of larval stages of two microphallid (Digenea)
      species using Hydrobia ulvae (Pennant, 1777) and Corophium volutator (Pallas,
      1766) as intermediate hosts.
AB  - Digenean trematodes encompass several species with little morphological
      differentiation in the larval stages and, as a result, uncertainty prevails
      regarding species identification. The microphallid trematode Maritrema subdolum
      occurs widespread geographically in mud snail and crustacean hosts in European
      marine shallow-water ecosystems. Larval stages of this and other congeneric
      species are, however, difficult to separate morphologically. To verify the
      species status and to secure identification of two co-occurring microphallids, M.
      subdolum and microphallid sp. no. 15 (Deblock, 1980), we examined the nucleotide
      sequences of the internal transcribed spacer regions (ITS1, ITS2). From fragments
      consisting of both ITS regions and the 5.8S gene (nearly 1,200 bp), a sequence
      divergence of 2.9% between the two types was recorded. In accordance with the
      morphological traits of the cercariae (stylet shape, length), the results support
      the view that the two types actually represent different species. Species
      specific primers were prepared for each species. They proved to be efficient
      diagnostic tools for identifying single larval-stage individuals. Using these
      primers, infections in host organisms were also verified without performing a
      dissection of the host individuals.

PMID- 15185144
TI  - No change in parasite genotype during single episodes of Plasmodium falciparum
      malaria in Gabonese children.
AB  - Patients living in endemic areas can carry a mixture of Plasmodium falciparum
      genotypes. To investigate the genetic composition of parasite genotypes in
      malaria patients during the acute phase of the infection, we performed close
      follow-ups of 17 Gabonese pediatric patients aged 2-7 years. Capillary blood
      samples were taken on admission and every 4-6 h after the start of quinine
      therapy. Merozoite surface protein 2 (MSP2) genotypes were used to assess the
      parasites' genetic characteristics in each sample. We found that each patient
      carried parasites with the same genotypic pattern throughout the infection.

PMID- 15185145
TI  - Subcellular localization of an extracellular serine protease in Leishmania
      (Leishmania) amazonensis.
AB  - Extracellular proteolytic activity was detected in a Leishmania ( L.) amazonensis
      culture supernatant and a 56-kDa protein was purified using (NH4)2SO4
      precipitation followed by affinity chromatography on aprotinin-agarose. A rabbit
      serum obtained against the 56-kDa extracellular serine protease was used in order
      to analyze its location in L. ( L.) amazonensis parasites. Immunocytochemistry
      studies revealed that the enzyme is mainly found in the flagellar pocket and
      cytoplasmic vesicles of promastigote forms, whereas in amastigotes, it is located
      in electron-dense structures resembling megasomes. These results indicate that
      the 56-kDa serine protease is released into the extracellular environment through
      the flagellar pocket; and its intracellular location suggests either a correlated
      enzymatic activity or intracellular trafficking.

PMID- 15185146
TI  - Differential expression of S100 gene family in human esophageal squamous cell
      carcinoma.
AB  - PURPOSE: To study the differential expression of the S100 gene family at the RNA
      level in human esophageal squamous cell carcinoma (ESCC), and to find the
      relationship of the S100 gene family with ESCC. METHODS: Firstly, the specific
      primers were designed for the different S100 genes with Software Primer 3, which
      required that both primer sequences of each S100 gene were from two different
      exons respectively. Then, the differential expression of 16 S100 genes was
      examined by semiquantitative reverse transcription-polymerase chain reaction (RT
      PCR) in 62 cases of ESCC versus the corresponding normal esophageal mucosa. All
      RT-PCR products were analyzed by 1.5% agarose gel. With Fluor-S MultiImager and
      Multi-Analyst software, the electrophoresis images were evaluated with statistics
      analysis using SAS 8.1 software. RESULTS: Eleven out of 16 S100 genes were
      significantly downregulated ( p<0.05) in ESCC versus the normal counterparts such
      as S100A1, S100A2, S100A4, S100A8, S100A9, S100A10, S100A11, S100A12, S100A14,
      S100B, and S100P genes. Only the S100A7 gene in the S100 family was markedly
      upregulated ( p<0.05). Moreover, the S100B gene was significantly correlated with
      histological differentiation of ESCC ( p=0.0247), and the deregulation of some
      S100 genes was closely correlated ( p<0.05), such as S100A10/S100A11,
      S100A2/S100A8, S100A2/S100A14, S100A8/S100A14, and S100A2/S100P etc. CONCLUSIONS:
      The S100 gene family is closely associated with ESCC.

PMID- 15185147
TI  - Cerebral palsy in triplet pregnancies with and without iatrogenic reduction.
AB  - Iatrogenic fetal reduction is undertaken to try and improve the outcome of
      multiple pregnancies by reducing the rate of severe preterm delivery. In twin
      pregnancies, however, spontaneous death of one of the fetuses is associated with
      increased risk of cerebral palsy (CP) in the survivor. The aim of this study was
      to determine whether iatrogenic fetal reduction might also increase the
      prevalence of CP. The database of a tertiary fetal medicine unit was interrogated
      to identify women with trichorionic triplet pregnancies who had either given
      birth to three live infants or two live infants following selective fetal
      reduction. A questionnaire was sent to the women's general practitioners asking
      them to report whether any of the children had CP. The results of the
      questionnaire revealed that the CP prevalence (13.8 per 1000) of 72 children from
      trichorionic triplet pregnancies reduced to twins by selective termination was
      similar to that of 111 children from trichorionic triplet pregnancies with no
      loss (18 per 1000), but the pregnancies with selective termination delivered at a
      later gestation (P = 0.004). CONCLUSION: a lower cerebral palsy rate might have
      been expected in the pregnancies with selective termination given that they were
      delivered at a later gestational age; these data, therefore, emphasise the
      importance of further investigating the impact of selective reduction on the
      prevalence of cerebral palsy.

PMID- 15185148
TI  - Evaluation of surfactant function at birth determined by the stable microbubble
      test in term and near term infants with respiratory distress.
AB  - Surfactant function using the stable microbubble test (SMT) was investigated in
      term or near term infants with respiratory distress. Newborn infants > or = 34
      weeks gestation with an initial clinical hypothesis of transient tachypnoea of
      the newborn (TTN) needing supplemental oxygen and controls were included. Gastric
      aspirates were collected immediately after birth for SMT. The first chest X-ray
      films were examined by three independent radiologists and according to their
      interpretation the babies were divided into a TTN, a respiratory distress
      syndrome of the newborn (RDS), or a poorly-defined X-ray group. A total of 32
      infants with respiratory distress and 32 controls with similar gestational age
      and birth weight were studied. The median and interquartile range (IQR) of the
      stable microbubble (SMB) count was significantly lower (P < 0.001) for the
      respiratory distress group than for the control group (17; range 6-33 versus 120;
      range 79-275). The proportion of babies with less than 35 stable microbubbles/mm2
      (SMB/mm2) was significantly different for the whole respiratory distress group
      (24/32-75%) and for the TTN (9/13-69%), the RDS (5/5-100%), and the poorly
      defined (10/12-83%) groups as compared with the controls (2/32-6%; P < 0.05). A
      total of 24/26 babies (92%) who needed oxygen for > or = 24 h but only 1/6 (17%)
      of them who needed < 24 h had a bubble count of less than 35 SMB/mm2 (P < 0.05).
      CONCLUSION: the results suggest that deficiency or dysfunction of the surfactant
      system is involved in the majority of cases of respiratory distress in near term
      and possibly term babies. The stable microbubble test can enable clinicians to
      take an earlier decision to give surfactant to term or near term infants with
      more severe and progressive respiratory distress.

PMID- 15185150
TI  - Evolving experience in the management of pleural empyema.
AB  - The objective of this study was to determine treatment strategies for children
      admitted with pleural empyema. We reviewed the medical records of 93 consecutive
      patients with pleural empyema who presented in the last three years. Mean age was
      3.8 years (range 3.5 months to 14 years) and the male to female ratio was 52 :
      41. The left side was involved in 51 (54.8 %) cases and there was only one case
      with bilateral effusion. After the chest X-ray and analysis of pus obtained by
      thoracocentesis, the initial treatment modality was chest tube drainage in 81 (87
      %) patients. Children required chest tube drainage for an average of 11.9 +/- 4.8
      days. Out of the 81 children, 6 needed thoracotomy due to organized pleural fluid
      and another 4, who developed loculated pleural effusions, were treated with
      intrapleural urokinase (UK) administration. Twelve children, who had a delayed
      presentation with organized loculated pleural fluid and pleural thickening,
      underwent decortication and one, who was found to have a foreign body, found
      during surgery, needed an upper lobe resection. Medical management with adequate
      chest tube drainage and appropriate antibiotics has resulted in full resolution
      in the majority of patients with empyema. In cases of loculated pleural effusions
      identified at the early stages of the chest tube drainage, intrapleural UK
      administration was found to be a safe and efficient treatment modality.
      Thoracotomy should be reserved for late and organized empyema cases.

PMID- 15185149
TI  - Severe hypertriglyceridaemia in a Greek infant: a clinical, biochemical and
      genetic study.
AB  - A 32-day-old girl with massive hypertriglyceridaemia and clinical signs of
      chylomicronaemia syndrome is described. Genetic study of the patient revealed
      compound heterozygosity for a common lipoprotein lipase gene mutation (G188E) and
      a novel missense mutation (M301R), consistent with reduced post-heparin plasma
      lipoprotein lipase immunoreactive mass observed. CONCLUSION: to the best of our
      knowledge, this is the first description of a patient with a M301R mutation in
      the lipoprotein lipase gene. In addition, dietary therapy with medium-chain
      triglycerides was successful supporting the effectiveness of this therapeutic
      approach in familial chylomicronaemia syndrome.

PMID- 15185151
TI  - Alimentary tract duplications in children: high incidence of associated
      anomalies.
AB  - BACKGROUND: Alimentary tract duplications (ATDs) are rare congenital anomalies
      affecting about 1 in 4500 newborns with a male/female ratio of 1.2 : 1. The
      presence of associated, sometimes complex congenital anomalies can pose a
      challenge to surgeons treating patients with ATDs. The aim of this work was to
      study the characteristics of ATDs and associated anomalies in our patients.
      METHODS: Retrospective study. Medical charts of 24 patients (7 males, 17 females)
      diagnosed with ATD during the years 1990 - 2001 at the Department of Paediatric
      Surgery, Motol Children's Hospital in Prague, Czech Republic were reviewed.
      RESULTS: Sixteen patients (67 %) were diagnosed at ages younger than 3 years.
      Eight cases were foregut duplications, 9 were midgut, and 7 hindgut anomalies. In
      13 patients (54 %) associated malformations were documented. Eight patients (33
      %) developed postoperative complications, 1 patient died. Complications were more
      frequent in the group of patients with associated anomalies (53 % vs. 9 %).
      CONCLUSIONS: Associated congenital malformations are frequently present in
      patients with ATDs. The complexity of the surgical repair of these anomalies may
      contribute to higher morbidity and mortality rates. A thorough examination to
      identify and characterise the presence of ATDs and associated congenital defects
      would provide appropriate diagnostic and surgical approaches for these patients.

PMID- 15185152
TI  - Peritoneal needle suction for intestinal perforation in the preterm neonate.
AB  - A few years ago, most intestinal perforations in the premature newborn appeared
      within the clinical context of necrotising enterocolitis (NEC). Since then, we
      have observed an increase in the number of isolated perforations appearing
      outside typical NEC. The fact that the perforations are more often isolated, and
      the healing capabilities of the premature intestine, led us to propose peritoneal
      needle suction (PNS) alone as first treatment for intestinal perforations in the
      premature neonate. MATERIALS AND METHOD: The charts of 6 consecutive premature
      infants presenting with intestinal perforations treated initially by PNS alone
      were reviewed. RESULTS: The patients' median birth weight was 1030 g, with a
      median gestational age of 27 weeks. In 5 out of 6 infants (83 %), PNS achieved
      complete exsufflation without recurrence of the pneumoperitoneum and complete
      intestinal healing, allowing complete enteral feeding 30 to 71 days after
      perforation. One infant with recurrent pneumoperitoneum after 3 PNS and
      peritoneal drainage was operated. All infants survived. CONCLUSION: We believe
      that for early perforations of the premature neonate, the poor diffusion of the
      infection and the frequent capacity of the perforation to close and subsequently
      heal without scars, favour a minimally invasive management using PNS.

PMID- 15185153
TI  - Laparoscopic fundoplication in neurologically impaired children with percutaneous
      endoscopic gastrostomy.
AB  - TOPIC: Laparoscopic fundoplication is the preferred surgical procedure for
      children with gastro-oesophageal reflux. Little data exist on the feasibility of
      laparoscopic fundoplication after placement of a percutaneous endoscopic
      gastrostomy (PEG). PATIENTS AND METHODS: Thirty-nine children aged 4 months to 18
      years (median 3.6 years) presented for an antireflux procedure between November
      2000 and July 2003. The surgical technique used was the Thal (270 degrees )
      fundoplication. Clinical data, technical aspects of the operation, and the
      postoperative course were collected prospectively. RESULTS: Twenty-two children
      (56 %), all of them neurologically impaired, already had a PEG in place due to
      feeding problems irrespective of gastro-oesophageal reflux symptoms. In all
      cases, laparoscopic fundoplication was performed immediately after gastroscopic
      removal of the PEG tube. In two cases, conversion to an open procedure became
      necessary, due to reasons unrelated to the PEG. In one case conversion was
      necessary because of adhesions of an intrathoracic stomach and in the other case
      because of circulatory problems due to congenital cardiomyopathy. In one patient,
      the gastrostomy was moved at the end of the procedure because it was too close to
      the antrum. In two further cases, the gastrostomy detached during fundoplication.
      In this case, the gastrostomy catheter was replaced and secured laparoscopically
      with a purse-string suture. All other cases were without any complications and a
      balloon tube or a button was placed into the existing gastrostomy channel at the
      end of surgery. CONCLUSION: No adverse effects are associated with PEG placement
      prior to a consecutive laparoscopic antireflux procedure. Possible detachment of
      the pre-existing gastrostomy must be excluded at the end of the procedure.

PMID- 15185154
TI  - Evaluation of pelvic contractility in ureteropelvic junction obstruction: an
      experimental study.
AB  - BACKGROUND/PURPOSE: Ureteropelvic junction (UPJ) obstruction causes adaptive
      and/or compensatory alterations in renal pelvic contractility. As these
      alterations directly affect the outcome after renal damage, definition of these
      alterations is of the utmost importance from a clinical point of view. Thus, an
      experimental study was designed to determine the alterations of renal pelvic
      contractility in response to partial and complete UPJ obstruction. METHODS:
      Fifteen adult female New Zealand white rabbits were randomly assigned into three
      groups (each containing 5 rabbits) according to the degree of unilateral UPJ
      obstruction. Group I: sham operation was performed and served as the control
      group; group II: partial UPJ obstruction was made; group III: complete UPJ
      obstruction was made. The animals in groups I and II were sacrificed after three
      weeks and the rabbits in group III were sacrificed after two weeks. Muscle strips
      from the renal pelvis were prepared. Spontaneous mechanical activity and
      contractile responses to phenylephrine (PE), serotonin (5-HT), and KCl were
      recorded isometrically and compared in all groups. RESULTS: Both the frequency
      and amplitude of spontaneous mechanical contractions were significantly (p <
      0.05) increased in partial (group II) and complete UPJ obstruction (group III)
      groups. PE and 5-HT-induced tonic contractions, which were more prominent in the
      complete and partial obstruction groups when compared with the control group (p <
      0.05). PE and 5-HT also increased the frequency of spontaneous contractions in
      both partial and complete obstruction groups. KCl induced long lasting tonic
      contractions in the control muscles. The duration of contraction to reach the
      maximum amplitude was shortened in the obstruction groups and the amplitudes of
      the contractions were significantly augmented when compared to control
      preparations. CONCLUSION: UPJ obstruction alters the contractile properties of
      renal pelvis smooth muscle. Increased frequency of spontaneous mechanical
      activity suggests that pacemaker cells of the renal pelvis change their
      activities in response to UPJ obstruction. Increase in tonic contraction
      amplitudes in response to PE and 5-HT suggests an increased sensitivity of smooth
      muscle cells to these agents. Potentiation of the contractile response to KCl
      suggests that adaptive changes take place at the level of excitation-contraction
      coupling in the smooth muscle of the renal pelvis following UPJ obstruction.

PMID- 15185155
TI  - Injection sclerotherapy of rectal prolapse in children with 15 percent saline
      solution.
AB  - PURPOSE: A wide variety of sclerosing agents have been used in the treatment of
      rectal prolapse (RP) in children. We have used 15 % saline solution for the first
      time in the treatment. The aim of this study is to review the results of a 15 %
      saline solution and other sclerosing agents. PATIENTS AND METHODS: A total of 16
      children with RP were treated by injection of 15 % saline solution. Under general
      anesthesia, the patient was placed in the lithotomy position. The left index
      finger was inserted into the rectum to control the position of the needle, a 20
      gauge spinal needle was introduced through the perianal skin and was advanced.
      The saline was slowly injected, the needle was then withdrawn slightly, and the
      injection was continued until 2 - 3 ml of 15 % saline were injected. The
      injection was made into the submucosal tissue, the right perirectal area, the
      left perirectal area, and posterior to the rectum at 5 points. RESULTS:
      Conservative treatment had previously failed in all patients. Prolapse ceased in
      15 (93.7 %) of the 16 children after the first injection. Only one patient
      required a second injection. There were no complications. CONCLUSIONS: The
      success rates and complications of the treatment reported in the literature
      differ for each sclerosing agent. 15 % saline is preferable because of the high
      cure rate, the safety of the procedure, the easy injection, and the lack of
      complications.

PMID- 15185156
TI  - Electromyographic studies on the external anal sphincter in children with
      operated anorectal malformations.
AB  - Fecal incontinence is a common problem after surgical repair in patients with
      anorectal malformations. A normally functioning external anal sphincter (EAS)
      mechanism is a major factor for continence. The aim of this study was to assess
      the function of the EAS in children with operated anorectal malformations by
      electromyography (EMG) and to refine the sphincter function further. The study
      group consisted of 8 patients with incontinence problems who were operated for
      anorectal malformations. The electrical activity of EAS was evaluated by EMG
      using concentric needle electrodes in all subjects. The presence, localization,
      integrity and activity of the sphincter were assessed. Seven of 8 patients showed
      electrical activity of the EAS. Sphincter localization was found to be
      appropriate in six children. Five children showed a well preserved sphincter
      integrity and 2 of them disclosed normal EMG activity. In cases of localization
      or integrity abnormalities, secondary corrective surgery was planned, while in
      patients showing only abnormal EMG activity, biofeedback treatment was given. In
      cases of fecal incontinence in patients with operated anorectal malformations,
      electromyographic study shows the type of sphincter abnormality and further helps
      to make a decision whether to improve the EAS function with conservative
      treatment or surgically.

PMID- 15185157
TI  - Iron deficiency anemia in children with exstrophy of the cloaca.
AB  - The clinical records of twenty-five children with exstrophy of the cloaca (EC)
      were retrospectively reviewed to evaluate the prevalence and the clinical
      characteristics of iron deficiency anemia (IDA). Five of the 25 children with EC
      (20 %) exhibited IDA at some point. Their ages at the time of diagnosis were
      between 1.9 and 13.0 years. In the four cases where IDA was thought to be related
      to iron malabsorption secondary to short-bowel syndrome, its treatment required
      longer periods of iron supplementation to correct the anemia and to restore the
      total body iron stores. Physicians caring for children with EC should monitor for
      and treat IDA as part of a comprehensive management plan.

PMID- 15185158
TI  - Familial syndromic duodenal atresia: Feingold syndrome.
AB  - Familial duodenal atresia occurs as part of Feingold syndrome. Other features of
      this variable autosomal dominant condition include tracheo-oesophageal fistula
      and oesophageal atresia, microcephaly, hand and foot anomalies, facial
      dysmorphism, and developmental delay. We report a father and two sons with
      Feingold syndrome. One has bilateral dysplastic kidneys which have not been
      reported previously.

PMID- 15185159
TI  - Thymic teratoma or thymic remnant attached to mediastinal teratoma? The cellular
      origin of mediastinal teratomas revisited.
AB  - Thymic tissue can be encountered in about 20 % of mediastinal teratomas. It is
      found located at the periphery of the teratoma mass. Although rare, mediastinal
      teratoma arising within the thymus can be seen. It has not been defined yet
      whether the thymus is an organ simply attached to the teratoma or whether the
      teratoma arises from the thymus. The authors present here two illustrative cases
      of mediastinal teratoma, one raised within the thymus and the other closely
      attached to the thymic remnant, to discuss the cellular origin of mediastinal
      teratomas.

PMID- 15185160
TI  - Duodenal atresia and gastric antral web. A significant lesson to learn.
AB  - We report the case of a child who had a duodenal atresia and also a gastric
      antral web. The two conditions are not known to be associated. The child had a
      duodenoduodenostomy for the duodenal atresia that had been diagnosed on a "double
      bubble" appearance at antenatal ultrasound scan. She eventually had a second
      laparotomy due to persistent gastric outlet obstruction, at which a pyloroplasty
      was performed and an antral web excised. The child remains well four months after
      discharge. This case has taught us several salutary lessons, which we consider
      relevant to share with colleagues.

PMID- 15185161
TI  - TAR syndrome with annular pancreas and anal atresia - a case report.
AB  - TAR syndrome is manifested by the presence of hypomegakaryocytic thrombocytopenia
      and the bilateral absence of radii. An 8-day-old female newborn was referred to
      our clinic with diagnosis of TAR syndrome and symptoms of intestinal obstruction.
      On perineal examination she also had anal atresia with rectovestibular fistula.
      Because of persistent bile-stained drainage from the nasogastric tube, an upper
      gastrointestinal contrast study was performed and partial duodenal obstruction
      was detected. At operation, an annular pancreas was encountered and side-to-side
      duodenoduodenostomy was performed. A small number of gastrointestinal system
      malformations associated with TAR syndrome has been reported. Our case is unique;
      the association with annular pancreas and anal atresia with rectovestibular
      fistula has never been previously reported.

PMID- 15185162
TI  - Large supraumbilical pseudocystic tumour due to ectopic pancreatic tissue located
      in a rest of the omphaloenteric duct.
AB  - Ectopic umbilical pancreatic tissue is extremely rare. We report on a case of a
      two-year-old boy who suffered from a large recurrent supraumbilical tumour with
      central cystic degeneration. Ectopic pancreatic tissue was located within the
      submucosal layer of an umbilical rest of the omphaloenteric duct. Peptic erosion
      and inflammatory alteration of tissue surrounding the umbilical vein caused
      recurrent bleeding and formation of a pseudocyst as well as chronical
      inflammatory granulations within the abdominal wall.

PMID- 15185163
TI  - Interventional radiology cases from the royal hospital for sick children,
      glasgow: percutaneous metal biliary stent placement for palliation of intra
      abdominal desmoplastic small round-cell tumour in a child.
AB  - Percutaneous placement of metal biliary stents for palliation of malignant
      processes affecting the porta hepatis is a well established technique in adults.
      We describe a case where the technique has been used successfully to treat
      obstructive jaundice in a ten-year-old boy suffering from intra-abdominal
      desmoplastic small round-cell tumour.

PMID- 15185164
TI  - Handlebar hernia in children: two cases and review of the literature.
AB  - Localised traumatic abdominal hernias are rare. Most such hernias are due to the
      direct impact of the handlebars of a bicycle or motorcycle, with 20 cases
      reported to date in the English language literature, 12 in children. We report
      two new cases of handlebar hernia, in children aged 6 and 10 years. In both
      cases, physical examination revealed an area of contusion and bruising in the
      lower abdomen. However, the muscle defect was detected during the first
      examination in only one of the patients, and not until several days later in the
      other patient. Abdominal ultrasonography proved useful for diagnosis in both
      patients. Early surgical correction is necessary to prevent possible
      complications. This type of hernia should be borne in mind when evaluating
      children who have suffered abdominal trauma in a bicycle accident.

PMID- 15185165
TI  - A case of virilised female with urethral duplication and valve formation.
AB  - We report the case of a female (chromosomal 46 XX) with a complex congenital
      urogenital malformation. Caesarian section was performed at the 30th gestational
      week due to hydrops fetalis and polyhydramnion. Clinical and radiological
      evaluation demonstrated a complex urogenital malformation with an enlarged
      penoclitoral organ, urethral duplication, and concomitant malformations. The girl
      presented with a female urethra with a vaginal orificium as well as a male
      urethra culminating in a microphallus. Additionally, a urethral valve formation
      just cranial to the bifurcation of the male and female urethra was also present.
      Due to concomitant diseases, a complicated clinical course and recurrent urinary
      tract infections, the final operative correction resulting in a female phenotype,
      was performed at the age of 2 (1/2) years as a single-stage procedure.

PMID- 15185166
TI  - Non-operative management of isolated solid organ injuries due to blunt abdominal
      trauma in children.

PMID- 15185173
TI  - Basics of magnetic resonance imaging.
AB  - In clinical diagnostic imaging there has been a rapid evolution of nuclear
      magnetic resonance techniques. A subset of these has proven particularly powerful
      when applied to the arena of noninvasive vascular imaging. This article will
      serve as a primer for practitioners with little prior background in magnetic
      resonance angiography (MRA). It will develop the first principles of magnetic
      resonance image creation, and establish familiarity with current imaging
      applications of the thoracic, abdominal, and peripheral vasculature.

PMID- 15185171
TI  - Intergenerational instability of the expanded CTG repeat in the DMPK gene:
      studies in human gametes and preimplantation embryos.
AB  - The CTG repeat at the 3' untranslated region of the dystrophia myotonica protein
      kinase (DMPK) gene shows marked intergenerational and somatic instability in
      patients with myotonic dystrophy (DM1), when the repeat is expanded to more than
      approximately 55 repeats. Intensive research has yielded some insights into the
      timing and mechanism of these intergenerational changes: (1) increases in
      expansion sizes occur during gametogenesis but probably not during meiosis, (2)
      the marked somatic mosaicism becomes apparent from the 2nd trimester of
      development onward and increases during adult life, and (3) DNA repair mechanisms
      are involved. We have performed preimplantation genetic diagnosis for DM1 since
      1995, which has given us the unique opportunity to study the expanded CTG repeat
      in affected embryos and in gametes from affected patients. We were able to
      demonstrate significant increases in the number of repeats in embryos from female
      patients with DM1 and in their immature and mature oocytes, whereas, in
      spermatozoa and embryos from male patients with DM1, smaller increases were
      detected. These data are in concordance with data on other tissues from adults
      and fetuses and fill a gap in our knowledge of the behavior of CTG triplet
      expansions in DM1.

PMID- 15185169
TI  - Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.
AB  - We have identified truncating mutations in the human DLG3 (neuroendocrine dlg)
      gene in 4 of 329 families with moderate to severe X-linked mental retardation.
      DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane
      associated guanylate kinase protein family. Neuronal SAP102 is expressed during
      early brain development and is localized to the postsynaptic density of
      excitatory synapses. It is composed of three amino-terminal PDZ domains, an src
      homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains
      interact directly with the NR2 subunits of the NMDA glutamate receptor and with
      other proteins responsible for NMDA receptor localization, immobilization, and
      signaling. The mutations identified in this study all introduce premature stop
      codons within or before the third PDZ domain, and it is likely that this impairs
      the ability of SAP102 to interact with the NMDA receptor and/or other proteins
      involved in downstream NMDA receptor signaling pathways. NMDA receptors have been
      implicated in the induction of certain forms of synaptic plasticity, such as long
      term potentiation and long-term depression, and these changes in synaptic
      efficacy have been proposed as neural mechanisms underlying memory and learning.
      The disruption of NMDA receptor targeting or signaling, as a result of the loss
      of SAP102, may lead to altered synaptic plasticity and may explain the
      intellectual impairment observed in individuals with DLG3 mutations.

PMID- 15185174
TI  - Magnetic resonance angiography.
AB  - MRA and MRI have become increasingly important diagnostic modalities in vascular
      surgery. The ability to obtain cross-sectional and angiographic images by these
      noninvasive and non-nephrotoxic modalities represents one of the most significant
      advances in vascular surgery over the past decade. We review the current status
      of MRI and MRA in vascular surgical practice.

PMID- 15185175
TI  - Basics of computed tomography angiography of the lower extremity vessels.
AB  - Complete noninvasive, angiographic evaluation of the abdominal aorta and lower
      extremity vessels using the latest generation of multidetector row computed
      tomography (CT) scanners can now be accomplished in a single scan lasting less
      than a minute. The high spatial resolution of these new scanners and their more
      efficient use of contrast permit accurate depiction of disease in the smaller
      tibial and pedal vessels, as well as the larger diameter iliac and femoral
      arteries; nevertheless, many challenges and obstacles remain to its more
      widespread acceptance. Foremost among these, is the difficulty in accurately
      reconstructing the smaller leg and pedal vessels from individual CT slices, a
      process that must to a very great extent be done manually, and the potential
      nephrotoxicity of iodinated contrast material. Future advances in imaging
      software that could more fully automate accurate three-dimensional
      reconstructions of the lower extremity vasculature, and detector technology to
      allow for even finer resolution of the vasculature will further enhance an
      already powerful and clinically useful tool.

PMID- 15185170
TI  - Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with
      novel loci on 9q21 and 2q32-35.
AB  - Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a
      common birth defect with a complex etiology. A 10-cM genome scan of 388 extended
      multiplex families with CL/P from seven diverse populations (2,551 genotyped
      individuals) revealed CL/P genes in six chromosomal regions, including a novel
      region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses
      with the addition of results from 186 more families (six populations; 1,033
      genotyped individuals) showed genomewide significance for 10 more regions,
      including another novel region at 2q32-35 (P=.0004). These are the first
      genomewide significant linkage results ever reported for CL/P, and they represent
      an unprecedented demonstration of the power of linkage analysis to detect
      multiple genes simultaneously for a complex disorder.

PMID- 15185176
TI  - Basics of intravascular ultrasound: an essential tool for the endovascular
      surgeon.
AB  - The concept of catheter-based ultrasound imaging was first introduced in the
      early 1970s. Since its inception, intravascular ultrasound (IVUS) technology has
      become more user-friendly because of improvements in both the catheters and
      computer-driven imaging platforms. IVUS catheters enable luminal and transmural
      cross-sectional imaging of coronary and peripheral blood vessels with high
      dimensional accuracy and detailed information about lesion morphology. With the
      advent of endovascular techniques in both the coronary and peripheral
      vasculature, IVUS has emerged as a useful and necessary adjunct. In addition to
      providing diagnostic information, IVUS enables optimal choice of appropriate
      angioplasty technique, endovascular device guidance, and controlled assessment of
      the efficacy of interventions. In this review we discuss the design and function
      of available IVUS catheters, imaging techniques and interpretation, and the
      present and future clinical utility in peripheral endovascular interventions.

PMID- 15185177
TI  - Peripheral application of intravascular ultrasound virtual histology.
AB  - Intravascular ultrasound (IVUS) provides direct depiction of coronary artery
      anatomy. Traditional use of this tomographic imaging modality has been in
      determination of geometric measurements of an artery, such as lumen or plaque
      size. However, by analyzing the backscattered or radiofrequency (RF) data it is
      possible to glean information on the composition of plaques. This chapter
      describes the theory of spectral analysis and its application clinical practice.

PMID- 15185178
TI  - Computed tomography scanning for endograft planning: evolving toward three
      dimensional, single source imaging.
AB  - One of the most fundamental differences between open surgical repair of aortic
      aneurysms and treatment by endograft exclusion is the dependency on imaging for
      all critically important aspects of the endovascular approach. Patient selection
      and preprocedure planning for device selection and sizing depend on imaging.
      Computed tomography (CT) scanning for endograft planning is capable of providing
      accurate and complete measurement data. There are problems with diameter, length,
      and angulation measurement when using conventional two-dimensional (2D) axial CT
      images that can be partly overcome by expert interpretation. However, when
      computerized 3D programs that include easy-to-use measurement tools process CT
      data, the problems of 2D CT scan data are relieved. In addition, virtual
      simulation of various endograft choices can be modeled within computerized
      renderings of patient-specific anatomy that allow testing of alternatives and
      provide an intuitive understanding during the planning phase.

PMID- 15185179
TI  - Magnetic resonance imaging for planning aortic endograft procedures.
AB  - Patients with aortic aneurysms and renal insufficiency are at an increased risk
      when conventional imaging modalities (contrast enhancing computed tomography and
      arteriography) are used for aortic endograft design. Magnetic resonance imaging
      (MRI) provides a nonionizing, noninvasive alternative to standard measurement
      techniques. Reliable diameter and length measurements can be obtained with MRI at
      a computer workstation without the use of iodinated radiologic contrast agents.
      The authors describe their experience with the use of magnetic resonance
      angiography as the sole imaging modality for aortic endograft design. Although
      not without limitations, MRI can be an effective measurement tool, particularly
      in patients who are at high risk of complications related to conventional
      imaging.

PMID- 15185180
TI  - Contribution of PET scanning to the evaluation of abdominal aortic aneurysm.
AB  - The size of abdominal aortic aneurysms (AAA) is the most usual predictor of the
      risk for rupture. Because chronic metalloproteinases production and activation by
      inflammatory cells causes degradation of elastin and collagen in the aneurysmal
      wall, the detection of an increased metabolic process preceding fissuration and
      rupture could be a more sensitive predictor of rupture risk. We investigated the
      metabolic activity of the aneurysmal wall by whole-body positron emission
      tomography (PET) in 26 patients with a documented AAA (mean diameter 63 mm,
      extremes 45 mm and 78 mm). A positive (18)F-fluorodeoxyglucose ((18)F-FDG) uptake
      at the level of the AAA was observed in 38% of the cases (10 of 26 patients).
      Nine of these 10 patients required emergent or urgent aneurysmectomy for ruptured
      (n = 1), leaking (n = 1), rapidly expanding (n = 2), or painful (n = 5)
      aneurysms; the negative (18)F-FDG uptake patients had a more benign course. This
      preliminary study suggests a possible correlation between (18)F-FDG uptake by the
      aneurysm wall and the triggering of processes leading to rupture. The (18)F-FDG
      uptake in the aneurysm wall may correspond to the accumulation of inflammatory
      cells responsible for the production and activation of degrading enzymes. PET
      scan seems useful in high-risk patients. Positive PET imaging in these cases
      would help us to decide to proceed with surgery, despite factors favoring a
      surveillance strategy.

PMID- 15185181
TI  - Imaging modalities for the detection and management of endoleaks.
AB  - Although endovascular aneurysm repair (EVAR) has shown promising initial results,
      there are unique complications to this procedure. Endoleaks, which do not occur
      after traditional surgical repair of abdominal aortic aneurysms, are detected in
      patients undergoing EVAR and are thought by some to be one of the limitations of
      this procedure. Endoleaks may continue to perfuse and pressurize the aneurysm
      sac, thereby conferring an ongoing risk of aneurysm enlargement and/or rupture.
      Because of this, accurate endoleak detection and classification is essential
      following EVAR. Surveillance of patients is critical to determine the long-term
      performance of the stent grafts. Although this is usually accomplished with
      contrast-enhanced spiral computed tomography scans performed at regular
      intervals, duplex ultrasonography exams; magnetic resonance angiography; and
      digital subtraction angiography all have a role in endoleak detection and
      classification. This article will cover imaging modalities used to detect
      endoleaks. In addition, we will cover which imaging exams should be performed to
      help with endoleak management.

PMID- 15185182
TI  - Duplex scanning after endovascular aneurysm repair: an alternative to computed
      tomography.
AB  - Late complications following endovascular aneurysm repair indicate the need for
      long-term surveillance. Clinical trials involving endoluminal stent grafts have
      typically used computed tomography angiography as the main imaging modality for
      surveillance. However, computed tomography angiography exposes the patient to
      higher levels of ionizing radiation, nephrotoxic agents, and increased cost
      compared to duplex ultrasound. Duplex ultrasound scanning has been widely used
      for surveillance of abdominal aortic aneurysms for many years. It is well
      established and the procedure of choice for noninvasive imaging of the aorta. It
      offers the advantages of easy access, decreased cost, no radiation exposure, and
      no nephrotoxicity. There is little controversy about duplex scanning for
      preoperative patient evaluation or surveillance of patients with small aneurysms.
      However, the use and reliability of duplex scanning in the evaluation and
      surveillance of patients following endovascular repair is controversial. This
      article will discuss the benefits, techniques, and limitation of duplex
      ultrasound in the long-term surveillance of endografts following endovascular
      abdominal aortic aneurysm repair.

PMID- 15185183
TI  - Computed tomography assessment of thoracic aortic pathology.
AB  - Computed tomography technology has improved dramatically in the past decade and
      now constitutes the backbone of preoperative evaluation for aortic disease. Image
      acquisition is accomplished with multi-row detectors, and coupled with new
      reconstruction algorithms provide clinicians with high-resolution images that can
      be visualized in synch with the cardiac cycle, or as complex three-dimensional
      renditions of in vivo anatomy. Knowledge regarding the means of data acquisition,
      reconstruction algorithms, and modes of interpretation are critical for the
      optimal assessment of aortic disease. These issues are increasingly important as
      endovascular therapy becomes more commonplace for the treatment of thoracic
      aortic lesions.

PMID- 15185184
TI  - Diagnosis of pulmonary embolism with various imaging modalities.
AB  - Pulmonary embolism (PE) is a major health concern that affects approximately
      600,000 new patients annually. The diagnosis of PE can be difficult to make, and
      several imaging studies have been developed to aid in this process. Initial
      evaluation involves the acquisition of a chest radiograph. Findings on
      radiography, however, are often non-specific. The gold-standard study
      historically has been pulmonary angiography, with increasing diagnostic yield
      since the implementation of digital subtraction technology. This is an invasive
      procedure, however, but the incidence of major complications is low. Less
      invasive modalities have been developed and include ventilation-perfusion lung
      scans. These are used as one of the initial screening tests in evaluation of
      patients with suspected PE. The presence of a high-probability scan usually
      indicates the presence of a PE, although few patients have high probability
      scans. The test is significantly affected by underlying pulmonary disease or
      previous PE. Given this, ventilation-perfusion lung scans are limited as a
      primary diagnostic tool in the evaluation of suspected PE. Helical computed
      tomography (CT) is currently under much scrutiny as a diagnostic tool for PE.
      Currently a prospective, multicenter trial evaluating its efficacy (PIOPED II)
      has been initiated, but the results are pending. Preliminary reports suggest the
      helical CT and venous phase CT may become a first line study in patient
      evaluation. The diagnosis of PE is challenging and several imaging modalities are
      currently used to assist the clinician. Currently, multiple modalities are often
      required to make the diagnosis. With the advent of new technology and improved
      imaging techniques, the diagnosis of PE will become easier.

PMID- 15185185
TI  - Imaging of acute stroke: state of the art.
AB  - The high incidence of stroke, plus its fatal or debilitating outcome, has
      prompted tremendous advances over the last two decades on both diagnostic and
      therapeutic fronts. Multiple randomized trials have proven the utility of
      thrombolytic agents with rejuvenation of the role of diagnostic imaging. State of
      the art imaging (mainly computed tomography and magnetic resonance imaging) is
      crucial for patient selection (eg, excluding intracranial hemorrhage), diagnosis
      of stroke and prediction of prognosis. Here, we discuss the anatomic and
      physiologic changes due to an ischemic insult as manifested by modern imaging
      techniques, including diffusion and perfusion imaging, as well as demonstration
      of vascular disease by cross sectional angiography supplemented by three
      dimensional postprocessing. The main target of management is "Penumbra", or
      salvageable tissue, which is primarily dependent upon the expediency of the whole
      process, better expressed by the phrase "Time is Brain".

PMID- 15185187
TI  - Introduction. Special issues in pediatric antimicrobial resistance.

PMID- 15185188
TI  - Clinically silent infection in a premature infant.

PMID- 15185189
TI  - Antimicrobial resistance among enteric pathogens.
AB  - Diarrhea is a major cause of morbidity and mortality in infants and children
      worldwide. Use of antimicrobial therapy in children with bacterial diarrhea
      involves consideration of advantages and limitations of use of appropriate agents
      in the general population and in specific hosts. Antimicrobial agents for
      bacterial diarrhea should be prescribed with an appreciation of limitations
      including antimicrobial resistance. Studies from many countries have reported
      resistance to Campylobacter jejuni, Campylobacter coli, Shigella species,
      Salmonella species, and shiga toxin producing Escherichia coli. In many
      geographic areas of the world including the United States, resistance patterns
      have demonstrated a consistent increase over the course of time, with resistance
      occurring to several classes of antimicrobial agents. Resistance patterns are
      influenced by geographic location, year isolates were obtained, classes of
      antimicrobial agents, pressure exerted by antimicrobial use, and source of the
      isolate. Because antimicrobial resistance among enteric pathogens is a common
      finding, has increased over time, and varies by geographic location, constant
      monitoring of susceptibility patterns is necessary for selection of appropriate
      antimicrobial agents for therapy when indicated.

PMID- 15185190
TI  - Antimicrobial use in agriculture: controlling the transfer of antimicrobial
      resistance to humans.
AB  - Salmonella and Campylobacter infections occur commonly in children. Some of these
      infections are severe, requiring treatment with antimicrobial agents. Many
      classes of antimicrobial agents that are used in humans also are used in food
      animals for growth promotion, disease prevention, and therapy. The use of such
      antimicrobial agents in food animals increases the likelihood that human
      bacterial pathogens that have food animal reservoirs, such as Salmonella or
      Campylobacter, will develop cross-resistance to drugs approved for use in human
      medicine. Resistance determinants also may be transmitted from food animals to
      humans through the food supply with bacteria that usually are commensal, such as
      Escherichia coli and enterococci. Clinicians should be aware that antimicrobial
      resistance is increasing in food-borne pathogens and that patients who are taking
      antimicrobial agents for any reason are at increased risk for acquiring
      antimicrobial-resistant food-borne infections. Several European countries have
      demonstrated that restricting the use of antimicrobial agents in food animals can
      be followed by a decrease in antimicrobial resistance in humans without
      compromising animal health or significantly increasing the cost of production.
      Appropriate use of antimicrobial agents in humans and food animals is an
      important factor in maintaining their effectiveness.

PMID- 15185191
TI  - Vaccines as tools against resistance: the example of pneumococcal conjugate
      vaccine.
AB  - Pneumococcal conjugate vaccine not only reduces the incidence of invasive
      antibiotic-resistant pneumococcal infections in young children receiving the
      vaccine, but it also reduces transmission of these strains to their younger
      siblings and to adults. Evidence from the United States indicates that the burden
      of resistant pneumococcal invasive disease in adults is reduced by immunization
      of children with these vaccines. Data from Israel and California suggest that
      antibiotic use is reduced in immunized children, and this reduction in use may
      further reduce the selection of antibiotic-resistant strains in immunized
      communities. Surveillance is needed to monitor the spread of antimicrobial
      resistance into nonvaccine serotypes, which may lead to a resurgence of
      resistance.

PMID- 15185192
TI  - Antimicrobial resistance in countries with limited resources: unique challenges
      and limited alternatives.
AB  - The haphazard use of antimicrobial agents has caused these essential drugs to
      lose their effectiveness. In the resource-poor parts of the world, the problem is
      complex, involving inadequate access to antimicrobial agents in the poorest
      countries along with an excessive variety of drugs in middle-income countries
      that have inadequate capability to use them well or to control the unnecessary
      emergence of resistant microbes. Both circumstances may result in the rapid
      dissemination of antimicrobial resistance. Resistant organisms, which in wealthy
      countries would result in the increased expense or inconvenience of alternative
      agents, in poor countries may cause infections that for practical purposes are
      untreatable. The basic requirements for controlling drug-resistant problems in
      resource-poor and wealthy countries alike include first-line prevention of
      infectious diseases, laboratory support for etiologic diagnosis, adequate
      surveillance and epidemiological information, appropriate drug selection, locally
      appropriate guidelines for treatment, and proper education about infectious
      diseases in all levels. These requirements generally are lacking in resource-poor
      countries. The most important key to success in these countries is a strong
      central commitment and governmental support for minimizing drug-resistance
      problems while maintaining the highest effectiveness of health care within the
      limits of available resources.

PMID- 15185193
TI  - Antimicrobial resistance: is it really that bad?
AB  - Antimicrobial resistance has been the subject of this and numerous other special
      issues of pediatric and infectious disease journals during the past several
      years. Pediatricians may be forgiven for expressing skepticism occasionally about
      dour scenarios predicting the advent of untreatable infections or a return to the
      preantibiotic era. Certainly, some benefits may accrue to pharmaceutical
      companies, academic and public health experts, and managed care systems from
      promoting concern about antimicrobial resistance. In fact, the response to the
      spread of resistance has been forceful, and in some cases successful, with
      reductions achieved in unnecessary prescribing, treatment regimens modified, and
      some new antimicrobial agents made available during the past several years. The
      problem, however, remains substantial, as several clear examples of dangerous and
      nearly untreatable multiply resistant organisms exist and the costs associated
      with treating resistant organisms continue to skyrocket. In many instances in the
      developing world, antimicrobial resistance can mean that a formerly treatable
      infection has become untreatable, and for pediatricians in the United States,
      resistance has, at the least, complicated therapy and limited options in everyday
      practice.

PMID- 15185194
TI  - Who defines resistance? The clinical and economic impact of antimicrobial
      susceptibility testing breakpoints.
AB  - Antimicrobial susceptibility test breakpoints are necessary for the correct
      clinical interpretation of quantitative or qualitative susceptibility test values
      of antibacterial agents. Breakpoints are selected by regulatory bodies or
      professional groups (eg, the National Committee for Clinical Laboratory
      Standards) based on an extensive review of the microbiological, pharmacokinetic,
      and clinical data applicable to each drug. No precise formula for selection of
      optimal breakpoints has been established. Instead, the process involves a review
      of all existing data and is influenced by the perspectives of the individuals
      charged with selecting the breakpoints. The interpretive breakpoints may differ
      somewhat by country with some antibiotics because of regional or national
      decisions on dosing regimens. Breakpoints also influence the selection of empiric
      therapy and development of local, regional, or national treatment guidelines by
      classifying the percentage of previously tested organisms that were susceptible
      to various antibiotics. Thus, antibiotic breakpoints affect the care of
      individual patients and provide epidemiologists and policy makers with data
      regarding trends in antibiotic resistance.

PMID- 15185195
TI  - Sir Howard Walter Florey--the force behind the development of penicillin.
AB  - The development of penicillin was a watershed in the battle against infectious
      diseases. The primary individuals responsible for its discovery and development
      were Sir Alexander Fleming, Sir Howard Walter Florey, and Ernst B. Chain, now
      primary figures in the annals of medical history. The individual who
      serendipitously "discovered" penicillin was Sir Alexander Fleming. Despite the
      determination displayed by Fleming, little notice was given to his discovery for
      more than a decade, and the active substance was not isolated. Finally, in 1939,
      Florey, along with Chain, led a team of British scientists who successfully
      manufactured the drug from the liquid broth in which penicillin grows. They,
      along with Fleming, were given the 1945 Nobel Prize in Physiology or Medicine for
      their roles in the discovery and development of this agent. This biography
      focuses on the life and work of Sir Howard Walter Florey.

PMID- 15185199
TI  - Biliary atresia--a fifteen-year review of clinical and pathologic factors
      associated with liver transplantation.
AB  - PURPOSE: The aim of this study was to identify clinical and pathologic factors
      associated with liver transplantation in infants with biliary atresia initially
      treated with Kasai hepatic portoenterostomy (KHPE). METHODS: Institutional Review
      Board approval was obtained. Records of patients with biliary atresia diagnosed
      between January 1986 and December 2000 were reviewed. Patients were divided into
      those who never required transplantation, those who underwent transplant in the
      first year after KHPE, and those who required transplantation later in childhood.
      Analysis of variance (ANOVA) compared multiple factors among the 3 groups.
      Proportional analysis compared those who required transplantation against those
      who did not. Statistical significance was considered achieved if P was less
      than.05. RESULTS: Forty-five patients were identified. Survival after KHPE was
      96% (43 of 45). Sixteen (37%) never required transplantation, 13 (30%) underwent
      transplant within 1 year after KHPE, and 14 (33%) underwent transplant more than
      1 year after KHPE. ANOVA comparison showed that the duration of jaundice before
      KHPE as a predictor for liver transplantation approached significance (P =.082).
      Proportional analysis found that a longer initial duration of jaundice before
      KHPE (P =.016) and failure to establish biliary flow (P =.033) were also
      significant predictive factors. An initial requirement for phototherapy (P =.057)
      and ductules less than 200 microm in diameter (P =.060) showed a trend toward
      predictor of liver transplantation. CONCLUSIONS: A longer duration of jaundice
      before KHPE, failure to establish bile flow, requirement for phototherapy in the
      neonatal period, and ductules smaller than 200 microm are associated with liver
      transplant after KHPE.

PMID- 15185198
TI  - Chronic constipation: no longer stuck! Characterization of colonic dysmotility as
      a new disorder in children.

PMID- 15185200
TI  - Initial experience with complex laparoscopic biliary surgery in children: biliary
      atresia and choledochal cyst.
AB  - BACKGROUND: Laparoscopic approaches are possible for many pediatric surgical
      diseases, including complex biliary disorders. The authors describe their early
      experience with laparoscopic procedures for biliary atresia and choledochal
      cysts. METHODS: A retrospective review was performed with Institutional Review
      Board (IRB) approval of children undergoing laparoscopic Kasai portoenterostomy
      (n = 2) or laparoscopic excision of a choledochal cyst with Roux-en-y biliary
      reconstruction (n = 3). The authors report the operative technique for these
      procedures and present their initial results. RESULTS: All procedures were
      performed with 4 to 5 trocars using 3- and 5-mm ports. Excision of the fibrous
      biliary remnant (biliary atresia) or of the cyst (choledochal cysts) was
      performed laparoscopically in all cases. The Roux-en-y limb was created through a
      1-cm extension of the umbilical port site. Laparoscopic biliary reconstruction
      was performed successfully in 4 of 5 patients. In one child, the proximal extent
      of the choledochal cyst was at the bifurcation of the hepatic duct, and the
      biliary reconstruction was performed via an open incision with separate
      anastomoses of the right and left ducts. The gallbladder was used as a handle for
      retraction of the liver for portal visualization, as in a cholecystectomy, and
      was resected at the end of the procedure. All children with choledochal cysts
      have normal bilirubin values. One of 2 children who underwent laparoscopic Kasai
      has a normal postoperative bilirubin level, whereas the other child did not drain
      bile and underwent a successful liver transplantation. Mean length of surgery was
      338 minutes; mean length of stay was 5.5 days. There were no significant
      postoperative complications. Cosmesis was excellent in all cases. CONCLUSIONS:
      Laparoscopic approaches for children with biliary atresia and choledochal cysts
      are possible. Excellent visualization of the portal structures can be achieved
      laparoscopically with adequate retraction of the liver. Further follow-up is
      needed to determine broader application.

PMID- 15185201
TI  - Management of suspected common bile duct stones in children: role of selective
      intraoperative cholangiogram and endoscopic retrograde cholangiopancreatography.
AB  - BACKGROUND: Evidence for diagnostic accuracy and clinical efficacy of
      intraoperative cholangiogram (IOC) and endoscopic retrograde
      cholangiopancreatography (ERCP) in the management of common bile duct (CBD)
      stones in children is sparse and unclear. METHODS: Retrospective analysis of 202
      children who underwent laparoscopic cholecystectomy (LC) between 1996 and 2002
      was performed. Forty-eight children had suspected CBD stones on clinical,
      biochemical, and radiologic grounds. Two clinical pathways, LC followed by ERCP
      (L-->E) versus ERCP followed by LC (E-->L) were compared. RESULTS: From the
      cohort of 202 patients, 154 did not have suspected CBD stones. Of the 48 patients
      that did have suspected stones, 2 management pathways were followed: (1) ERCP
      first: 14 of 48 patients (including 1 failed examination). Three yielded positive
      findings on ERCP. Ten had negative findings on ERCP, 3 of which went on to have a
      subsequent IOC. All 3 had negative IOC examination findings. (2) LC +/- IOC
      first: 34 of 48 patients. Twenty-eight had negative findings on IOC and had no
      further investigations. Three patients had positive IOC examination findings and
      went on to have postoperative ERCP. Two of these 3 patients were positive for CBD
      stones. The remaining 3 of 34 patients had LC with no IOC followed by ERCP. Only
      1 of 3 patients yielded a positive examination finding on ERCP. Therefore, of the
      168 patients that did not have IOC, only 1 stone (0.6%) would have been missed
      using the selective criteria. Of those that did meet the criteria for IOC, only 2
      of 31 (6.5%) had positive examination findings. There were no adverse effects of
      a retained or passed stone during our study, nor where there complications in
      those who had a concomitant sphincterotomy (12 of 20 ERCP patients, mean follow
      up of 4.2 years). IOC and ERCP findings correlated in all 6 of the patients in
      which both procedures were performed. CONCLUSIONS: Selective IOC with LC is an
      acceptable and safe initial approach in suspected CBD. Most CBD stones in
      children pass spontaneously. Endoscopic sphincterotomy appears to be safe with no
      long-term sequelae.

PMID- 15185202
TI  - Predictors of successful outcome after cholecystectomy for biliary dyskinesia.
AB  - PURPOSE: Laparoscopic cholecystectomy is accepted therapy for children with ill
      defined abdominal pain and impaired gallbladder emptying (biliary dyskinesia).
      Follow-up shows poor clinical response in many of these patients. The purpose of
      this report is to identify clinical and radiographic predictors of successful
      outcome after cholecystectomy for biliary dyskinesia. METHODS: The authors
      retrospectively reviewed records of 51 children after laparoscopic
      cholecystectomy for biliary dyskinesia (1990 to 2003). Clinical symptoms,
      radiographic findings, and pathology were evaluated. Subjective clinical
      improvement is stratified using an established patient satisfaction score.
      Logistic regression analysis determines statistically independent predictors of
      successful outcome. RESULTS: Thirty-eight of 51 (75%) patients were available for
      follow-up. Twenty-seven of 38 (71%) patients reported complete resolution of
      symptoms. Nausea was the only symptom predictive of successful outcome by
      univariate analysis (odds ratio, 5.00). A cholecystokinin-stimulated, gallbladder
      ejection fraction less than 15% also predicts successful outcome (odds ratio,
      8.00). Children with an ejection fraction greater than 15% did not have
      predictable resolution of symptoms. When present with pain and nausea,
      gallbladder emptying less than 15% has a positive predictive value of 93% and a
      negative predictive value of 81%. CONCLUSIONS: Together, nausea, pain, and
      decreased gallbladder emptying (<15%) most reliably predict which children will
      benefit from cholecystectomy for biliary dyskinesia.

PMID- 15185203
TI  - Frey procedure for surgical management of chronic pancreatitis in children.
AB  - BACKGROUND: The authors adopted the Frey procedure for the surgical management of
      chronic pancreatitis after one of their patients had recurrent disease in the
      head of the gland after a longitudinal pancreaticojejunostomy (LPJ or modified
      Puestow procedure). This is the first description of its use in children.
      METHODS: A retrospective chart review was performed of all children undergoing a
      drainage or resection procedure for chronic pancreatitis from 1995 to 2002.
      RESULTS: Eleven children (6 boys, 5 girls, ages 8 to 18 years) underwent either
      the LPJ (3) or Frey (8) procedure. Etiologies included: idiopathic (5), familial
      (2), congenital anomaly of the major papilla (1), pancreatic head mass (1), short
      bowel syndrome (1), and pancreatic divisum (1). Before surgical therapy, patients
      had been symptomatic 2.3 years (range, 1 month to 6 years) and had been
      hospitalized for pancreatitis 4 times (range, 1 to 10). Four patients did not
      respond to endoscopic stenting, and 5 had a pancreatic pseudocyst. Patients were
      followed up in clinic an average of 2.5 years, with total time elapsed since
      surgery averaging 4.6 years. Eight of 11 patients experienced excellent or good
      results subsequent to surgical intervention. CONCLUSIONS: The Frey procedure is
      effective for children who have not responded to conservative management of
      chronic pancreatitis and may prevent recurrent disease in the head of the gland.

PMID- 15185204
TI  - Factors influencing survival in newborns with congenital diaphragmatic hernia:
      the relative role of timing of surgery.
AB  - PURPOSE: Controversy persists regarding the factors influencing survival in
      patients with congenital diaphragmatic hernia (CDH), in particular, the role of
      timing of surgery. The authors therefore sought to determine such factors and to
      assess the relative role of timing of surgery on outcome. METHODS: All CDH
      newborns 1991 through 2002 (n = 111) were divided into those undergoing repair
      before ("early" n = 35), or after ("late" n = 76) 48 hours. A multivariate
      analysis was performed to determine the relative impact of various factors on
      survival rate. RESULTS: Overall survival rate was 64%. There was no effect on
      survival of heart rate, temperature, systolic blood pressure, age, extracorporeal
      membrane oxygenation use, mesh use, infections, or intracranial hemorrhage, and
      there was no difference between early (68%) or late (62%) repair (P =.2). Initial
      pCO2 greater than 50, pO2 less than 40, cardiac defects, or renal failure
      significantly decreased survival rate. CONCLUSIONS: Significant factors
      influencing survival rate in patients with CDH include cardiac defects, renal
      failure, and the initial blood gases and not the timing of surgery. CDH repair
      should be based on the optimization of clinical parameters as opposed to a
      specific time period to improve outcome.

PMID- 15185205
TI  - VEGF expression is downregulated in nitrofen-induced congenital diaphragmatic
      hernia.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) is upregulated in pulmonary
      alveolarization. However, developmental expression of pulmonary VEGF and its
      possible role in the pathogenesis of CDH are not well described. METHODS: Timed
      pregnant VEGF-LacZ mice, possessing a beta-galactosidase reporter introduced into
      the 3' region of the VEGF gene, were used to examine fetal lung gene expression
      in a model of nitrofen-induced CDH. RESULTS: VEGF gene expression increased from
      embryonic day 13 until its peak at embryonic day 16 and then decreased until term
      in all groups. This pattern was most apparent in the periphery with smaller
      differences noted in central lung locations. Expression of VEGF/beta-gal in the
      lungs of nitrofen-treated mice was less than controls at all time-points (P
      <.0001) The type-II pneumocyte population did not significantly differ between
      the groups. Study concentrations of nitrofen showed no effect on vascular
      endothelial proliferation in vitro. CONCLUSIONS: Nitrofen downregulates the
      production of VEGF during gestation and attenuates the peak seen at the onset of
      the canalicular stage, despite preservation of type-II pneumocytes. This effect
      was most pronounced in peripheral lung tissue. The authors speculate that altered
      VEGF expression may have a pivotal role in the pathogenesis of nitrofen-induced
      CDH.

PMID- 15185206
TI  - Surfactant does not improve survival rate in preterm infants with congenital
      diaphragmatic hernia.
AB  - BACKGROUND: Use of exogenous surfactant in congenital diaphragmatic hernia (CDH)
      patients is routine in many centers. The authors sought to determine the impact
      of surfactant use in the premature infant with CDH. METHODS: Data on liveborn
      infants with CDH from participating institutions were collected prospectively.
      Surfactant use and timing and outcome data were analyzed retrospectively. The
      authors evaluated the prenatal diagnosis patients as well. The outcome variable
      was survival to discharge. Odds ratios with confidence intervals were calculated.
      RESULTS: Five hundred ten infants less than 37 weeks' gestation were entered in
      the CDH registry. Infants with severe anomalies (n = 80) were excluded.
      Information on surfactant use was available for 424 patients. Infants receiving
      surfactant (n = 209) had a greater odds of death than infants not receiving
      surfactant (n = 215, odds ratio, 2.17, 95% CI: 1.5 to 3.2; P <.01). In prenatally
      diagnosed infants with immediate distress, there was a trend toward worse
      survival rates among those receiving surfactant at 1 hour (52 patients) versus
      those that did not (93 patients; odds ratio, 1.93, 95% CI: 0.96 to 3.9; P <.07).
      CONCLUSIONS: Surfactant, as currently used, is associated with a lower survival
      rate in preterm infants with CDH. The use of surfactant replacement in premature
      infants with CDH can be recommended only within the context of a randomized
      clinical trial.

PMID- 15185207
TI  - Diaphragmatic reconstruction with autologous tendon engineered from mesenchymal
      amniocytes.
AB  - PURPOSE: This study examined the effects of amniocyte-based engineered tendons on
      partial diaphragmatic replacement. METHODS: Ovine mesenchymal amniocytes were
      labeled with green fluorescent protein (GFP), expanded, and seeded into a
      collagen hydrogel. Composite grafts (20 to 25 cm2) based on acellular dermis
      (group I), or acellular small intestinal submucosa (group II) received either a
      cell-seeded or an acellular hydrogel within their layers. Newborn lambs (n = 20)
      underwent partial diaphragmatic replacement with either an acellular or a
      cellular autologous construct from either group. At 3 to 12 months'
      postoperatively, implants were subjected to multiple analyses. RESULTS:
      Diaphragmatic hernia recurrence was significantly higher in animals with
      acellular grafts (5 of 5) then in animals with cellular ones (1 of 4) in group I
      (P <.05) but not in group II (3 of 6 and 4 of 5, respectively). Cellular grafts
      had higher modular (5.27 +/- 1.98 v. 1.27 +/- 0.38 MPa) and ultimate (1.94 +/-
      0.70 v. 0.29 +/- 0.05 MPa) tensile strength than acellular implants in group I (P
      <.05), but not in group II. Quantitative analyses showed no differences in
      extracellular matrix components between cellular and acellular implants in either
      group. All cellular implants showed GFP-positive cells. CONCLUSIONS:
      Diaphragmatic repair with an autologous tendon engineered from mesenchymal
      amniocytes leads to improved mechanical and functional outcomes when compared
      with an equivalent acellular bioprosthetic repair, depending on scaffold
      composition. The amniotic fluid may be a preferred cell source for engineered
      diaphragmatic reconstruction.

PMID- 15185209
TI  - How low can you go? Effectiveness and safety of extracorporeal membrane
      oxygenation in low-birth-weight neonates.
AB  - PURPOSE: Controversy exists regarding the criteria for placement of infants on
      extracorporeal membrane oxygenation (ECMO) at low birth weights. The authors
      hypothesized that ECMO is effective and safe in babies under 2 kg and sought to
      examine outcome and survival rate in these infants. METHODS: All patients less
      than 30 days old in the Extracorporeal Life Support Organization (ELSO) registry
      (n = 14,305) were divided into those less than 2 kg (n = 663) and more than 2 kg
      (n = 13,642). Multiple regression analysis determined factors that predicted
      survival rate and the lowest safe weight for ECMO. RESULTS: Overall survival rate
      was 76% and was lower in infants less than 2 kg (> or =2 kg, 77% v <2 kg, 53%, P
      <.0001). Survival rate was significantly lower for patients with diaphragmatic
      hernia (CDH), bleeding, and intracranial hemorrhage (ICH) by regression. The
      incidence of ICH in babies less than 2.0 kg was 6% versus 4% in those more than
      2.0 kg (P <.05). Regression analysis determined that the lowest weight at which a
      survival rate of 40% could be achieved was 1.6 kg. CONCLUSIONS: Cannulation for
      ECMO may be safe and effective in babies under 2.0 kg and potentially as low as
      1.6 kg. Judicious anticoagulation might limit bleeding, which occurred in a
      minority of these patients.

PMID- 15185208
TI  - Intravenous insulin decreases protein breakdown in infants on extracorporeal
      membrane oxygenation.
AB  - BACKGROUND/PURPOSE: Infants requiring extracorporeal membrane oxygenation (ECMO)
      have the highest rates of protein catabolism ever reported. Recent investigations
      have found that such extreme protein breakdown is refractory to conventional
      nutritional management. In this pilot study, the authors sought to use the
      anabolic hormone insulin to reduce the profound protein degradation in this
      cohort. METHODS: Four parenterally fed infants on ECMO were enrolled in a
      prospective, randomized, crossover trial. Subjects were administered an insulin
      infusion using a 4-hour hyperinsulinemic euglycemic clamp followed by a control
      saline infusion on consecutive days in random order. Whole-body protein flux and
      breakdown were quantified using a primed continuous infusion of the stable
      isotope L-[1-13C]leucine. Statistical analyses were performed using paired t
      tests. RESULTS: Serum insulin levels were increased 15-fold during the insulin
      clamp compared with the saline control (407 +/- 103 v 26 +/- 12 microU/mL; P
      <.05). During the insulin infusion, infants had decreased rates of total leucine
      flux (214 +/- 25 v 298 +/- 38 micromol/kg/h; P <.05) and leucine flux derived
      from protein breakdown (156 +/- 40 v 227 +/- 54 micromol/kg/h; P <.05) when
      compared with saline control. Overall, insulin administration produced a 32%
      reduction in protein breakdown (P <.05). CONCLUSIONS: In this pilot study, the
      anabolic hormone insulin markedly reduced protein breakdown in critically ill
      infants on ECMO. Because elevated protein breakdown correlates with mortality and
      morbidity, the administration of intravenous insulin may ultimately have broad
      applicability to the metabolic management of critically ill infants.

PMID- 15185211
TI  - Feasibility of thoracoscopic U-clip esophageal anastomosis: an alternative for
      esophageal atresia reconstruction.
AB  - BACKGROUND: The authors propose that U-Clips can significantly decrease the
      technical difficulty of performing thoracoscopic esophageal reconstruction, thus,
      reducing operating time, the incidence of postoperative leak, and stricture rate.
      METHODS: After obtaining Institutional Animal Care and Use Committee approval, 3
      4-kg female piglets underwent complete thoracoscopic esophageal transections. The
      esophagus was reconstructed thoracoscopically using S50 and S60 U-Clips over an
      8F transanastomotic tube. Esophagrams were performed on postoperative day (POD)
      7, 21, 44, and 77. RESULTS: Mean operating time was 57 minutes (45 to 75 min).
      Two of 3 piglets had no evidence of leak on POD 7 esophagrams. One animal had a
      small leak that resolved spontaneously on antibiotics. All 3 piglets tolerated a
      formula diet orally by POD 8. Over a 77-day survival period all 3 piglets had
      steady weight gain on an oral diet. CONCLUSIONS: U-Clips are a feasible
      alternative to sutures for esophageal reconstruction in thoracoscopic surgery.
      Further study is warranted to investigate the full potential of U-Clips in
      minimally invasive pediatric surgery.

PMID- 15185210
TI  - Risk factors for acute chest syndrome in children with sickle cell disease
      undergoing abdominal surgery.
AB  - BACKGROUND/PURPOSE: The reported incidence of acute chest syndrome (ACS) in
      children with sickle cell disease (SCD) is 15% to 20%. Our current objective was
      to assess risk factors and morbidity associated with ACS. METHODS: The authors
      reviewed the outcome of children with SCD undergoing abdominal surgery over a 10
      year period. RESULTS: From 1991 to 2003, 60 children underwent laparoscopic
      cholecystectomy (LC; n = 29), laparoscopic splenectomy (LS; n = 28), or both (LB;
      n = 3). Mean age was 8.6 (0.7 to 20) years, and 35 (58%) were boys. Fifty-four
      (90%) had a preoperative hemoglobin greater than 10 g/dL, but only 22 (37%)
      received routine oxygen after surgery. No surgery was converted to an open
      procedure. Four children (6.6%), all of whom underwent either LS or LB, had ACS
      associated with an increased length of stay (7.4 +/- 2.4 days) but no mortality.
      Factors associated with the development of ACS were age (3.0 +/- 1.7 v 9.4 +/-
      5.7 years; P =.03), weight (12.1 +/- 3.0 v 32.6 +/- 18.2 kg; P =.04), operative
      blood loss (3.2 +/- 0.5 v 1.4 +/- 1.2 mL/kg; P =.03), and final temperature in
      the operating room (OR; 36.2 +/- 0.4 v 37.6 +/- 0.4 degrees C; P =.01). ACS was
      not significantly related to duration of surgery, OR fluids, or oxygen usage.
      CONCLUSIONS: Younger children with greater blood and heat loss during surgery
      appear more prone to ACS. Splenectomy also seems to increase the risk of ACS. The
      authors' current incidence (6.6%) of ACS in children with SCD undergoing
      abdominal surgery is much lower than previously reported. This may be explained
      by the aggressive use of preoperative blood transfusion or more routine use of
      laparoscopy.

PMID- 15185212
TI  - Minimal access extrapleural esophagoesophagostomy.
AB  - BACKGROUND/PURPOSE: Minimal access repair of esophageal atresia is gaining
      acceptance but usually requires a transpleural approach. An extrapleural approach
      using a 2-cm incision has been described. The purpose of this study was to
      develop a less-invasive approach to extrapleural esophagoesophagostomy. METHODS:
      A 5-8 kg nonsurvivor piglet model was used to develop this technique. The
      extrapleural dissection was performed under direct vision utilizing transpleural
      thoracoscopy. A 16-gauge needle and a spatula were used to create an extrapleural
      space that allowed insertion of a 3-mm trocar. An 8F catheter with a 3-mL balloon
      was inserted through the trocar and inflated to create enough space to exchange
      it for a 5-mm trocar. A 12F catheter with a 5-mL balloon was inserted through the
      5-mm trocar and inflated to enlarge the space. These steps were repeated at each
      of the 3 extrapleural port sites until one confluent extrapleural space was
      created that did not communicate with the transpleural port site.
      Esophagoesophagostomy was then completed within the extrapleural space. RESULTS:
      Thoracoscopic guidance and balloon dissection facilitated creation of an adequate
      extrapleural working space. CONCLUSIONS: This new minimal access extrapleural
      approach offers an attractive alternative to the currently described minimal
      access approaches to esophagoesophagostomy.

PMID- 15185213
TI  - Adriamycin induces notochord hypertrophy with conservation of sonic hedgehog
      expression in abnormal ectopic notochord in the adriamycin rat model.
AB  - BACKGROUND/PURPOSE: The Adriamycin rat model (ARM) is a well-established model of
      the Vertebral, Anorectal, Cardiac, Tracheoesophageal, Renal, Limb (VACTERL)
      association. The notochord, which expresses Sonic Hedgehog (Shh), has been found
      to be grossly malformed with ventral ectopic branches in the foregut region of
      embryos in the ARM. The authors designed this study to test the hypothesis that
      Shh-expressing ectopic notochord could contribute to an increased volume of
      notochord relative to total embryo volume, resulting in an increased
      concentration of Shh in the notochord of affected embryos. METHODS: Adriamycin
      was administered intraperitoneally to rats on days 7 (E7), E8, and E9 of
      gestation and saline to control animals. Embryos recovered at E12 and E14 were
      examined immunohistochemically for Shh expression. Quantitative morphology using
      the Cavalieri technique was performed to determine embryo and notochord volume.
      RESULTS: Embryos in both Adriamycin and control groups at E12 and E14 showed
      comparable levels of Shh expression in notochord at all locations. The percentage
      of notochord per embryo was significantly increased in Adriamycin embryos at E12
      and E14 compared with equivalent controls. CONCLUSIONS: These data suggest that
      Adriamycin induces notochord hypertrophy. With all regions of the notochord
      secreting Shh, this could result in a higher concentration gradient of Shh in
      close abnormal proximity to the foregut, possibly contributing to the
      malformations found in the VACTERL association.

PMID- 15185214
TI  - Computer-assisted robot-enhanced laparoscopic fundoplication in children.
AB  - BACKGROUND/PURPOSE: Robotic surgery improves laparoscopic surgery through a more
      natural interface, tremor filtration, motion scaling, and additional degrees of
      freedom of the instruments. Here, the authors report that experience with robot
      assisted fundoplication in children. METHODS: The authors have performed 15
      laparoscopic fundoplications with the Zeus Robotic Surgery System and
      retrospectively reviewed prospectively collected data on set-up time, operating
      time, and outcome. RESULTS: All cases were completed successfully: one Heller
      myotomy with Dor fundoplication and 14 Nissen fundoplications. Patients ranged
      from 2 months to 18 years old (mean, 4.3 years) and from 3.4 kg to 37.7 kg (mean,
      13.0 kg). There were no technical errors, equipment errors, or conversions. There
      were no complications in the first 30 days after surgery. The operating time
      declined from 323 minutes for the first case to 180 minutes for the last (mean,
      195 minutes). The 14th case was the shortest at 123 minutes. Setting up the
      robotic surgery system took an average of 11 minutes. The surgeons perceived
      benefits of greater ease and confidence in suture placement and knot tying.
      CONCLUSIONS: The authors have successfully used surgical robots for gastric
      fundoplication at a pediatric teaching hospital. Our experience with this
      operation has shown the additional dexterity that the robot provides and will
      pave the way to more complex procedures.

PMID- 15185215
TI  - Duodenal atresia and stenosis: long-term follow-up over 30 years.
AB  - BACKGROUND: Duodenal atresia and stenosis is a frequent cause of congenital,
      intestinal obstruction. Current operative techniques and contemporary neonatal
      critical care result in a 5% morbidity and mortality rate, with late
      complications not uncommon, but unknown to short-term follow-up. METHODS: A
      retrospective review of patients with duodenal anomalies was performed from 1972
      to 2001 at a tertiary, children's hospital to identify late morbidity and
      mortality. RESULTS: Duodenal atresia or stenosis was identified in 169 patients.
      Twenty children required additional abdominal operations after their initial
      repair with average follow-up of 6 years (range, 1 month to 18 years) including
      fundoplication (13), operation for complicated peptic ulcer disease (4), and
      adhesiolysis (4). Sixteen children underwent revision of their initial repair:
      tapering duodenoplasty or duodenal plication (7), conversion of
      duodenojejunostomy to duodenoduodenostomy (3), redo duodenojejunostomy (3), redo
      duodenoduodenostomy (2), and conversion of gastrojejunostomy to
      duodenoduodenostomy (1). There were 10 late deaths (range, 3 months to 14 years)
      attributable to complex cardiac malformations (5), central nervous system
      bleeding (1), pneumonia (1), anastomotic leak (1), and multisystem organ failure
      (2). CONCLUSIONS: Late complications occur in 12% of patients with congenital
      duodenal anomalies, and the associated late mortality rate is 6%, which is low
      but not negligible. Follow-up of these patients into adulthood is recommended to
      identify and address these late occurrences.

PMID- 15185216
TI  - Fibroblast growth factor receptor 2 IIIb invalidation--a potential cause of
      familial duodenal atresia.
AB  - BACKGROUND/PURPOSE: Duodenal atresia (DA) occurs in 1 in every 6,000 live births
      and represents a significant surgically correctable cause of intestinal
      obstruction in the neonate. Familial or congenital DA has been reported, implying
      that at least some cases of DA are the result of genetic, heritable
      abnormalities. The genes controlling duodenal development are incompletely
      understood. Fibroblast growth factor receptor 2IIIb (Fgfr2b) is known to play a
      critical role in the development of multiple organ systems including other
      gastrointestinal tract (GIT) structures. This study shows the key role of Fgfr2b
      in normal duodenal development and the pathogenesis of DA. METHODS: Wild type
      (Wt) and Fgfr2b-/- embryos were harvested from timed pregnant mothers at stage
      E18.5 and were analyzed for duodenal phenotype. RESULTS: Inactivation of Fgfr2b
      results in DA. DA is present in the Fgf2b-/- mutants with a 35% penetrance. The
      duodenal phenotype of the Fgf2b-/- mutants ranges from normal to a mucosal web,
      type I, and type III atresia. CONCLUSIONS: Fgfr2b is a critical regulatory gene
      in the development of the duodenum. Fgfr2b invalidation (Fgfr2b-/- mutant)
      results in a reproducible, autosomal recessive duodenal atresia phenotype with
      incomplete penetrance and a variable phenotype.

PMID- 15185217
TI  - The management of pediatric appendicitis: a survey of North American Pediatric
      Surgeons.
AB  - BACKGROUND/PURPOSE: Variation exists among pediatric surgeons in the management
      of pediatric appendicitis. The goal of this study was to determine current
      practice patterns and provide a foundation for evidence-based outcome studies
      that would standardize patient care. METHODS: Members of the American Pediatric
      Surgical Association (APSA) were surveyed. Data included preference of imaging,
      timing of operation, and opinions on interval appendectomy. Intraoperative
      principles surveyed included use of cultures, antibiotic irrigation,
      transperitoneal drains, and method of wound closure. Spectrum and duration of
      antibiotic coverage were assessed, as were discharge criteria. RESULTS: Survey
      response was 70%. A majority prefers computerized tomographic (CT) imaging and
      favors interval appendectomy in appropriate candidates. Seventy percent indicate
      a stable child with suspected appendicitis would be operated on in a semiurgent
      manner rather than emergently in their practice. Discrepancy exists in the type
      and duration of antibiotic coverage, impact of clinical parameters on antibiotic
      use, and utility of discharge criteria. CONCLUSIONS: This study consolidates
      current opinions on appropriate management of pediatric appendicitis, providing a
      foundation for evidence-based outcome studies capable of bringing conformity to
      the management of this surgical disease. Such studies would establish clinical
      practice guidelines that optimize resource utilization while maintaining quality
      care.

PMID- 15185218
TI  - The optimal initial management of children with suspected appendicitis: a
      decision analysis.
AB  - BACKGROUND/PURPOSE: As abdominal imaging has improved, the use of computed
      tomography (CT) and ultrasonography (US) for evaluating children with suspected
      appendicitis has increased. The purpose of this study was to determine the
      optimal management strategy for evaluating children with suspected appendicitis
      given the current accuracy of abdominal imaging. METHODS: Decision analysis was
      used to evaluate 5 management strategies: discharge, observation, CT, US, and
      appendectomy. Probabilities and time variables were obtained from publications
      and a chart review. Each approach was evaluated for its impact on length of stay,
      hospital charges, cost effectiveness and its capacity to minimize perforation and
      avoid negative appendectomy (risk-benefit). RESULTS: Discharge was preferred when
      the probability of appendicitis was low (<0.09 to <0.47), imaging when in an
      intermediate range and surgery when high (>0.61 to >0.91). A role for observation
      was found only when the anticipated time of inpatient observation was brief (<9
      hours). Although CT was more expensive than US, CT was more cost effective for
      preventing negative appendectomy and perforation and achieved a better risk
      benefit. CONCLUSIONS: CT has an important role in the management of suspected
      appendicitis. Among children with a low or high likelihood of appendicitis, the
      cost of imaging tests required to prevent the complications of appendicitis is
      high.

PMID- 15185219
TI  - CT scans may not reduce the negative appendectomy rate in children.
AB  - BACKGROUND/PURPOSE: Concern about an increased lifetime risk of cancer in
      children who have undergone a single computed tomography (CT) scan prompted us to
      review utilization of this diagnostic test in our appendicitis population.
      METHODS: From 1998 to 2001, the records of 720 children admitted to our hospital
      with a diagnosis of appendicitis were reviewed for adjunct diagnostic modalities,
      including ultrasonography (USG) and CT scanning. Negative appendectomy rates were
      determined by the final pathologic report. Statistical comparisons were made
      using the chi(2) test, and significance was assigned at P <.05. RESULTS: The use
      of ultrasound scan for diagnosing appendicitis decreased from 20.0% in 1998 to
      7.0% in 2001 (P <.01). Conversely, the use of CT scans increased from 17.6% in
      1998 to 51.3% in 2001 (P <.001). During this time period the difference in the
      negative appendectomy rate was not statistically significant (P < 0.20). Of the
      negative appendectomies, 11 of these patients had a USG interpreted as positive
      for appendicitis (22.0%), and 9 had a CT scan interpreted as positive (18.0%).
      CONCLUSIONS: Liberal use of CT scans in diagnosing appendicitis in children has
      not resulted in a decreased negative appendectomy rate. Potentially harmful
      radiation exposure should prompt pediatric surgeons to reevaluate the role of CT
      scanning in the management of children with suspected appendicitis.

PMID- 15185220
TI  - Effect of epidermal growth factor infusion on fetal rabbit intrauterine growth
      retardation and small intestinal development.
AB  - BACKGROUND/PURPOSE: Intrauterine growth retardation (IUGR) infants have impaired
      gastrointestinal function with resultant feeding difficulties and predisposition
      to necrotizing enterocolitis. Supplemented amniotic fluid swallowed by the
      developing fetus is a potential prenatal treatment for IUGR. Rabbits have
      naturally occurring IUGR fetuses based on uterine position. To determine
      intestinal response to epidermal growth factor (EGF) infusion, this rabbit model
      of IUGR was studied. METHODS: Eight pregnant rabbits underwent placement of
      intraamniotic catheters into 2 normal and 2 IUGR fetuses per mother on
      gestational day 24 of a 31-day gestation. Miniosmotic pumps infused either EGF
      (about 300 microg/kg/d) or control solution forming 4 study groups (EGF-Favored
      [Fav] v. Cont-Fav; EGF-IUGR v. Cont-IUGR). On gestational day 31, the fetal
      gastrointestinal tracts were harvested for analysis. Intestinal epithelial cell
      proliferation was studied by 5-bromo-2-deoxyuridine (BrdU) incorporation, villus
      heights were measured, and EGF mRNA was measured by reverse transcriptase
      polymerase chain reaction (RT-PCR). Statistical analysis was performed using
      Students' t test. RESULTS: Fetal survival rate was 87%. EGF-IUGR fetal weights
      were increased compared with Cont-IUGR fetuses. EGF infusion significantly
      increased IUGR fetal small intestinal villus height and BrdU-positive small
      intestinal (SI) crypt cells, all approaching Cont-Fav levels. EGF mRNA was
      expressed throughout the gastrointestinal tract. CONCLUSIONS: Supplemental
      amniotic EGF normalizes fetal weight and intestinal proliferation in the IUGR
      fetal rabbit. The inclusion of EGF in supplemental amniotic feeding solutions is
      supported.

PMID- 15185221
TI  - Hyperglycemia is associated with increased morbidity and mortality rates in
      neonates with necrotizing enterocolitis.
AB  - BACKGROUND PURPOSE: An association between hyperglycaemia and poor outcome has
      been reported in critically ill adults and children. The authors investigated the
      incidence of hyperglycemia in infants with necrotizing enterocolitis (NEC) and
      the relationship between glucose levels and outcome in these infants. METHODS:
      All glucose measurements (n = 6508) in 95 neonates with confirmed NEC admitted to
      the surgical intensive care unit (ICU) were reviewed. Maximum glucose
      concentration during admission (Gmax) was determined for each infant and
      correlated with outcome. Eleven infants in whom treatment was withdrawn within 24
      hours owing to unsalvageable panintestinal NEC were excluded from the analysis.
      RESULTS: Glucose levels ranged from 0.5 to 35.0 mmol/L and 69% of infants became
      hyperglycemic (>8 mmol/L) during their admission. Thirty-two infants died.
      Mortality rate tended to be higher in infants with Gmax greater than 11.9 mmol/L
      compared with those with Gmax less than 11.9 mmol/L, and late (>10 days
      admission) mortality rate was significantly higher in these infants (29% v, 2%; P
      =.0009). Median length of stay was 9.3 days. Linear regression analysis indicated
      that Gmax was significantly related to length of stay (P <.0001). CONCLUSIONS:
      Hyperglycemia is common in infants with NEC admitted to the ICU and is associated
      with an increase in late mortality and longer intensive care stay. Aggressive
      glycemic control may improve outcome in this group of infants.

PMID- 15185222
TI  - Laparoscopy assists surgical decision making in infants with necrotizing
      enterocolitis.
AB  - BACKGROUND: Lack of specific indications for surgical intervention is not
      uncommon in critically ill infants with necrotizing enterocolitis (NEC). The
      authors hypothesized that knowledge of the extent of intestinal disease would
      assist in deciding the operative treatment of choice. The authors report that
      initial experience with laparoscopy in infants with NEC. METHODS: Prospective
      evaluation was done of 11 infants with a clinical diagnosis of NEC who were
      deteriorating despite maximal medical therapy. All underwent laparoscopy on the
      intensive care unit (ICU). RESULTS: Median gestational age at birth was 29 weeks
      (range, 24 to 34) and median weight at the time of laparoscopy was 1.2 kg (range,
      0.6 to 2.9). Laparoscopy was tolerated well in all cases. NEC was excluded
      because of the normal intestinal appearance in 2 infants and confirmed in the
      remaining 9. Urgent laparotomy was avoided in 8 infants, in one of whom a
      laparoscopically guided ileostomy was performed. In 5 infants, a Penrose drain
      was inserted at laparoscopy; 3 of these did not require further surgery, and the
      remaining 2 underwent delayed laparotomy. Three infants, all with intestinal
      gangrene, died. CONCLUSIONS: Laparoscopy performed in the ICU can provide
      information regarding intestinal viability which can guide further surgical
      management. It is feasible and tolerated well even in critically ill neonates
      less than 1,000 g.

PMID- 15185223
TI  - Preventing enterocyte apoptosis after massive small bowel resection does not
      enhance adaptation of the intestinal mucosa.
AB  - BACKGROUND: After massive small bowel resection (SBR), increased rates of
      enterocyte apoptosis are observed in the remnant bowel via a mechanism requiring
      bax gene expression. This study tested the hypothesis that adaptive mucosal
      growth could be enhanced by the novel strategy of preventing postresection
      enterocyte apoptosis. METHODS: Male bax-null and corresponding wild-type (WT)
      mice underwent a 50% proximal SBR or sham operation (bowel transaction with
      reanastomosis alone). Mice were killed after a full adaptation interval of 1
      month. Adaptation was measured in the remnant ileum as alterations in villus
      height, crypt depth, and wet weight. Rates of enterocyte proliferation were
      derived by immunostaining of crypt enterocytes for Ki-67 and apoptosis by the
      presence of apoptosis bodies. RESULTS: The expected increase in enterocyte
      apoptosis after SBR occurred in the WT mice but was unchanged in the bax-null
      mice. Despite the prevention of postresection apoptosis in the bax-null mice, all
      parameters of adaptation and proliferation increased equally after SBR in both
      groups of mice. CONCLUSIONS: Bax deficiency prevents the increase in enterocyte
      apoptosis that occurs after massive SBR throughout the entire adaptation period.
      Attenuation of postresection enterocyte apoptosis does not augment mucosal
      adaptation to massive intestinal loss.

PMID- 15185224
TI  - Endotoxin induces an exaggerated interleukin-10 response in peritoneal
      macrophages of children compared with adults.
AB  - BACKGROUND: Children have a lower incidence of postinjury multiple organ failure
      (MOF) compared with adults with equivalent injury severity. Because MOF appears
      to be the end result of systemic hyperinflammation, children may have either an
      attenuated proinflammatory response or an augmented antiinflammatory response
      compared with adults. The purpose of this study was to determine the
      lipopolysaccharide (LPS)-induced pro- and antiinflammatory cytokine response of
      pediatric versus adult peritoneal macrophages (PM). The authors hypothesized that
      pediatric PMs would have an enhanced antiinflammatory response compared with
      adults. METHODS: Human PMs were collected during elective laparoscopic procedures
      and stimulated with LPS. (Pediatric cohort: n = 9 [mean, 5.4 years], adult
      cohort: n = 8 [mean, 41.6 years]). P less than.05 was accepted as significant.
      RESULTS: LPS-induced a 50-fold increase in interleukin-10 (IL-10)
      antiinflammatory cytokine production in pediatric versus adult PMs. LPS-induced
      tumor necrosis factor-alpha (TNF-alpha) production was also increased in
      pediatric versus adult PMs. The anti-proinflammatory cytokine ratio (IL-10 to TNF
      alpha) was 20-fold higher in pediatric versus adult PMs. CONCLUSIONS: LPS-induced
      macrophage production of both IL-10 and TNF-alpha was increased in children. The
      anti-proinflammatory cytokine ratio (IL-10 to TNF-alpha) was strikingly higher in
      pediatric versus adult PMs. These data suggest that the age-related balance of
      anti- and proinflammatory cytokines in resident macrophages is different in
      children compared with adults.

PMID- 15185225
TI  - Cecal volvulus: a report of two cases occurring after the antegrade colonic enema
      procedure.
AB  - BACKGROUND: Many children with chronic constipation and fecal incontinence have
      benefited from the antegrade colonic enema (ACE) procedure. Routine antegrade
      colonic lavage often allows such children to avoid daytime soiling. This report
      describes 2 children in whom the ACE procedure was complicated by a cecal
      volvulus. METHODS: A retrospective review of 164 children with an ACE procedure
      was conducted. Two instances of cecal volvulus were identified. RESULTS: The
      first child presented with abdominal pain and difficulty intubating the ACE site.
      Over the subsequent day, his pain worsened, and radiographs depicted a colonic
      obstruction. At laparotomy, a cecal volvulus resulting in bowel necrosis was
      observed, and resection of the affected bowel and appendix (in the right lower
      quadrant) and end ileostomy was required. He subsequently had the stoma closed
      and a new ACE constructed with a colon flap. The second child presented with
      shock and evidence of an acute abdomen. At laparotomy, a cecal volvulus was
      noted, and ileocolic resection including the ACE stoma (located at the umbilicus)
      and an ileostomy and Hartmann pouch was performed. He had a protracted hospital
      course requiring ventilator and inotropic support. He currently is well and still
      has an ileostomy stoma. CONCLUSIONS: A high index of suspicion for a potentially
      life-threatening cecal volvulus should be maintained in children undergoing an
      ACE procedure who present with abdominal pain, evidence of bowel obstruction, or
      difficulty in advancing the ACE irrigation catheter.

PMID- 15185226
TI  - Posterior myotomy/myectomy for persistent stooling problems in Hirschsprung's
      disease.
AB  - BACKGROUND: Hirschsprung's disease (HD) patients after pull-through (PT) may have
      recalcitrant constipation or recurrent enterocolitis (EC). Posterior
      myotomy/myectomy (POMM) are possible options for these problems. This study
      analyzed the outcome of POMM in HD patients post-PT. METHODS: Records of 348 HD
      patients were reviewed, and 32 were found to have undergone a POMM post-PT (1981
      to 2002). Outcomes after this procedure were assessed. Statistics used linear and
      logistic regression. RESULTS: Of the 32 patients, 29 had complete records for
      analysis. Of those with pure constipation (12), 6 had aganglionosis post-PT. Of
      those with recurrent EC (17) only 1 had aganglionosis post-PT. POMM was performed
      at a mean of 3.1 years post-PT (11 myotomy, 18 myectomy). Average follow-up was
      8.6 years (range, 0.7 to 21). Type of POMM had no correlation with overall
      functional outcome (P =.44). Of those with chronic constipation, 60% had good
      results after POMM; the remainder required a redo-PT or colostomy. Interestingly,
      most patients with retained aganglionosis and chronic constipation did not
      respond after POMM (83%). Of those with recurrent EC, 75% became free of
      symptoms; none of the patients not responding have required redo-PT. CONCLUSIONS:
      POMM to treat chronic constipation or recurrent EC in patients with HD post-PT is
      moderately successful. Because of the unsuccessful outcome with POMM in patients
      with a combination of constipation and aganglionosis, one should defer to a redo
      PT in this group.

PMID- 15185228
TI  - Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer
      Group study.
AB  - BACKGROUND/PURPOSE: Previous reports indicate that complete resection of high
      risk neuroblastoma improves outcome but may entail high surgical complication
      rates. The authors evaluated the effect of complete primary site resection on
      event-free survival (EFS), overall survival (OS), and complication rates in
      patients entered on a high-risk neuroblastoma treatment protocol. METHODS: A
      total of 539 eligible patients with high-risk neuroblastoma were entered on
      protocol CCG-3891. Patients were assigned randomly to continuation chemotherapy
      or autologous bone marrow transplantation. Surgical resection was performed at
      diagnosis or after induction chemotherapy. Surgeons assessed resection as
      complete (CR), minimal residual (<5%, MR), or partial (PR). Incomplete resections
      received secondary resection or 10 Gy of external beam radiation. Patients were
      evaluated for EFS, OS, and complications of surgery based on completeness of
      overall best resection. RESULTS: The proportion of patients resectable at
      diagnosis was 27% for CR and 14% for MR. This improved after chemotherapy to 45%
      and 25%. Complication rates based on completeness of resection were 29%, 38%, and
      36% for CR, MR, and PR, respectively. Estimated 5-year EFS rate was 30% +/- 3%
      for patients who achieved CR (n = 210) compared with 25% +/- 3% (P =.1010) for
      those with less than CR (n = 258). CONCLUSIONS: Resectability improved after
      neoadjuvant chemotherapy. Complete resection did not increase complications.
      There was a small survival benefit for complete resection. This study suggests
      that complete resection may still be important in the current era of intense
      chemotherapy and transplant.

PMID- 15185227
TI  - Acetylcholine-related bowel dysmotility in homozygous mutant NCX/HOX11L.1
      deficient (NCX-/-) mice-evidence that acetylcholine is implicated in causing
      intestinal neuronal dysplasia.
AB  - BACKGROUND/PURPOSE: Homozygous mutant Ncx/Hox11L.1-deficient (Ncx-/-) mice
      develop mega-ileo-ceco-colon (mega-ICC) with a caliber change in the proximal
      colon. The authors investigated the mechanism of intestinal dysmotility in these
      mice. METHODS: Five-week-old Ncx-/- mice with mega ICC were compared with age
      matched BDF1 control mice. Jejunum, ileum, and colon were excised from all mice
      and 1.0-cm-long strips of each organ, each with a resting tension of 0.5g, were
      suspended in an organ bath filled with Tyrode's solution at 37 degrees C and
      bubbled with a mixture of 95% oxygen and 5% carbon dioxide. Contractile responses
      to acetylcholine chloride (ACh), histamine, serotonin, and barium chloride
      (BaCl2) were recorded isometrically. RESULTS: For ACh, Ncx-/- mice had decreased
      distal colon circular muscle contraction only at lower doses and decreased distal
      colon longitudinal muscle contraction for all doses compared with controls (P
      <.05 or P <.01). In the proximal colon, Ncx-/- mice had increased circular muscle
      contraction only at higher doses and decreased longitudinal muscle contraction
      only at lower doses compared with controls (P <.01 or P <.05). ACh did not affect
      jejunum, and there were no significant effects on ileum. There was no response to
      histamine and serotonin by any part of the bowel, and the response to BaCl2 was
      the same for both Ncx-/- mice and controls. CONCLUSIONS: Only ACh differentially
      affected muscle contraction in Ncx-/- mice in the proximal and distal colon.
      Thus, ACh is implicated in causing the bowel dysmotility seen in Ncx-/- mice and
      human IND.

PMID- 15185229
TI  - Preferential proliferation of attenuated Salmonella typhimurium within
      neuroblastoma.
AB  - BACKGROUND/PURPOSE: Attenuated Salmonella typhimurium, a facultative
      intracellular parasite that colonizes the liver, has been shown to accumulate
      within extrahepatic malignancies. The authors sought to define a mechanism for
      attenuated Salmonella accumulation within cancer cells compared with hepatocytes.
      METHODS: Invasion and intracellular proliferation of attenuated Salmonella was
      assessed through an in vitro assay performed on neuroblasoma, osteosarcoma,
      hepatoma, and colon adenocarcinoma cell lines and compared with freshly isolated
      mouse hepatocytes. RESULTS: The efficiency of attenuated S typhimurium invasion
      into hepatocytes was greater than any malignant cell line (3.8 v 0.46; P <.04).
      However, the intracellular proliferation of the bacteria was most abundant within
      neuroblastoma, exceeding the proliferation within hepatocytes (14.3 v 6.2; P
      <.01). CONCLUSIONS: Attenuated S typhimurium may prove to be an effective in vivo
      immunotherapy for the local delivery of therapeutic proteins to neuroblastoma.

PMID- 15185230
TI  - Restored immune response to an MHC-II-Restricted antigen in tumor-bearing hosts
      after elimination of regulatory T cells.
AB  - BACKGROUND/PURPOSE: Pediatric sarcomas have a poor prognosis, recur frequently,
      and are not effectively treated by currently available therapy. Immunotherapy is
      a promising treatment modality; however, to be successful, immune tolerance must
      be overcome. CD4+CD25+ T cells are immunosuppressive. The authors hypothesize
      that immune tolerance may be overcome by eliminating the regulatory CD4+CD25+ T
      cells, which are induced by tumor. METHODS: A murine fibrosarcoma (MF), which
      expresses an MHC-II-restricted tumor antigen (mL26), was injected subcutaneously.
      CD4+ T cells were isolated and CD25+ population examined. Monoclonal antibody was
      used to deplete CD25+ T cells. Proliferation to mL26 was used to determine CD4+ T
      cell response to tumor-associated antigen (TAA). RESULTS: Depletion of CD25+
      cells prevented tumor establishment. Tumor-infiltrating CD25+ T cells, which made
      up 48% of CD4+ T cells in tumors, suppressed proliferation in allogeneic mixed
      lymphocyte reactions. Draining lymph node cells from tumor-bearing (TB) mice did
      not proliferate in response to mL26, whereas those from naive mice responded
      vigorously. Depletion of CD25+ cells before immunization restored response to
      mL26 in TB mice. CONCLUSIONS: CD4+CD25+ T cells induced by MF facilitate tumor
      establishment and maintain immune tolerance. Depletion of CD4+CD25+ T cells may
      be an effective means for reversing tumor tolerance and enhancing cancer
      vaccines.

PMID- 15185231
TI  - Gait analysis in patients operated on for sacrococcygeal teratoma.
AB  - BACKGROUND: Long-term follow-up of sacrococcygeal teratoma (SCT) is well
      established; however, little is known about the effects of extensive surgery in
      the pelvic and perineal region, which involves disruption of muscles providing
      maximal support in normal walking. METHODS: Thirteen patients operated on at
      birth for SCT with extensive muscle dissection underwent gait studies with a
      Vicon 3-D motion analysis system with 6 cameras. Results were compared with 15
      age-matched controls. Statistical analysis was performed with Mann-Whitney test;
      correlations were sought with Spearman's correlation coefficient. RESULTS: All
      subjects were independent ambulators, and no statistically significant
      differences were seen in walking velocity and stride length. However, in all
      patients, toe-off occurred earlier (at 58% +/- 1.82% of stride length) than
      controls (at 65.5% +/- 0.52%; P <.05). On kinetics, all patients exhibited, on
      both limbs, a significant reduction of hip extensory moment (-0.11 +/- 0.11 left;
      -0.16 +/- 0.15 right v 1.19 +/- 0.08 Newtonmeter/kg; P <.05) and of ankle
      dorsi/plantar moment (-0.07 +/- 0.09 right; -0.08 +/- 0.16 v -0.15 +/- 0.05
      Nm/kg, p < 0.05). Knee power was also significantly reduced (0.44 +/- 0.55 right,
      0.63 +/- 0.45 left v 0.04 +/- 0.05 W/kg), whereas ankle power was increased (3 +/
      1.5 right; 2.8 +/- 0.9 left v 1.97 +/- 0.2 W/kg; P <.05). No statistically
      significant correlation was found between tumor size and either muscle power
      generation or flexory/extensory moments. CONCLUSIONS: Patients operated on for
      SCT exhibit nearly normal gait patterns. However, this normal pattern is
      accompanied by abnormal kinetics of some ambulatory muscles, and the extent of
      these abnormalities appears to be independent of tumor size. A careful follow-up
      is warranted to verify if such modifications are stable or progress over the
      years, thereby impairing ambulatory potential or leading to early arthrosis.

PMID- 15185232
TI  - Raman spectroscopy for neoplastic tissue differentiation: a pilot study.
AB  - BACKGROUND: Several changes occur during the transformation of normal tissue to
      neoplastic tissue. Such changes in molecular composition can be detected by Raman
      spectroscopy. Raman spectroscopy is a nondestructive method of measuring these
      changes, which suggests the possibility of real-time diagnosis during medical
      procedures. METHODS: This study seeks to evaluate the ability of Raman spectra to
      distinguish tissues. The Raman signatures of normal kidney, lung, and liver
      tissue samples from pigs and rats were characterized in vitro. Further, a human
      neuroblastoma and a hepatoblastoma, obtained at resection were also studied.
      RESULTS: The Raman spectra of the animal samples of kidney, liver, and lung are
      distinctly different in the intensity distribution of the Raman peaks. Further,
      the spectra of a given organ from pigs and rats, although similar, were different
      enough to distinguish between the 2 animals. In the patient tissues, the Raman
      spectra of normal liver, viable tumor, and fibrotic hepatoblastoma were very
      different. Fibrotic tissue showed a greater concentration of carotenoids, whereas
      viable tissue was rich in proteins and nucleic acids. The normal tissue showed
      both components. Similar differences were also seen in the neuroblastoma tissue.
      CONCLUSIONS: The results of this study show the potential use of Raman
      spectroscopy in clinical diagnosis.

PMID- 15185233
TI  - Evolving treatment in a decade of pediatric burn care.
AB  - BACKGROUND: Over the last decade, an ambulatory burn care (ABC) and procedural
      sedation (PS) program was instituted at St Louis Children's Hospital (SLCH). This
      study assessed the effect of these interventions on resource utilization.
      METHODS: The authors reviewed the hospital experience comparing 1993 with 2002
      data regarding gender, age, burn depth, patient admissions, inpatient days, and
      ABC visits. Outcome measures included length of stay (LOS), incidence of
      infection, and hospital charges. RESULTS: Gender, age, and burn depth were
      similar; 192 patients were admitted in 1993. In 2002, there were 167 admissions
      and 118 patients treated solely on an ABC basis resulting in a total of 285 burn
      patients treated (+48%). Hospital days decreased from 2,041 (1993) to 963 (2002 [
      53%]). LOS declined from 10.4 +/- 8.3 days (1993) to 5.8 +/- 14.2 days (2002 [
      44%; P <.05]). PS was used sporadically in 1993, and increased to 71% in patients
      in 2002. There were no ABC visits in 1993 and 501 visits in 2002. The incidence
      of infection was 5.2% in 1993 versus 3.0% in 2002 (P <.05) Average charge per
      patient fell 45% from 13,286 dollars (1993) to 7,372 dollars (2002), adjusted to
      1993 dollars using medical care price index. CONCLUSIONS: Over a 10-year period,
      the program achieved a significant reduction in resource utilization while
      increasing the number of patients treated and maintaining a low incidence of
      infection. This was due in large part to a shift to ABC and the use of PS.

PMID- 15185234
TI  - The pediatric burn unit: a profit center.
AB  - BACKGROUND: Establishment of a pediatric burn center represents a major
      commitment of resources. The impact of a Pediatric Burn Unit on the finances of a
      children's hospital has never been reported and was the purpose of this study.
      METHODS: Burn registry data for patients discharged from our Pediatric Burn Unit
      from 2000 to 2002 were integrated with financial and administrative data.
      Reimbursement was determined by calculating expected payments for each patient.
      The relationship between percent total body surface area (TBSA) burned and
      profit/loss margin was evaluated using regression analysis. RESULTS: During the
      study period, 264 pediatric burn patients were admitted to our burn service. One
      hundred forty-three (54%) had less than 10% TBSA burned, and their average loss
      margin was -179.03 dollars per patient. The 121 patients (46%) who had greater
      than 10% TBSA burned had an average profit margin of +349.68 dollars per patient
      (P =.22, SE+ 605.03) Patients treated operatively (49; 18%) had a profit margin
      of +2237.77 dollars per patient, whereas patients treated nonoperatively (215;
      81%) had a profit margin of -432.30 dollars per patient (P =.0007, SE +249.65)
      The overall profit margin was +63.88 dollars per patient. CONCLUSIONS: Our
      pediatric burn service covered all hospital fixed costs and made a small profit.
      Pediatric burn care can be a profit center for children's hospitals. Investment
      in a Pediatric Burn Program provides adequate financial return for the hospital.

PMID- 15185235
TI  - Management of duodenal injuries in children.
AB  - BACKGROUND/PURPOSE: The natural history and management of pediatric duodenal
      injuries are incompletely described. This study sought to review injury
      mechanism, surgical management, and outcomes from a collected series of pediatric
      duodenal injuries. METHODS: A retrospective chart review was conducted for a 10
      year period of all children less than 18 years old treated for duodenal injuries
      at 2 pediatric trauma centers. RESULTS: Forty-two children were treated for
      duodenal injuries. There were 33 blunt and 9 penetrating injuries. Injuries were
      classified using the Organ Injury Scale for the Duodenum. Twenty-four patients
      underwent operative management by primary repair (18), duodenal resection and
      gastrojejunostomy (4), or pyloric exclusion (2). Duodenal hematomas were treated
      nonoperatively in 94% of cases. The average ISS for operative versus nonoperative
      cases was 23 and 10, respectively. Delay in diagnosis or operative intervention
      (>24 hours) was associated with increased complication rate (43% v 29%) and
      hospitalization (32 v 20 days). Nine children requiring surgery experienced
      delays and were most highly associated with foreign body, child abuse, and
      bicycle injuries. There were no deaths caused by duodenal injuries. CONCLUSIONS:
      Duodenal injuries in children were predominantly blunt and had a low mortality
      rate. When surgery was required, primary repair was usually feasible.

PMID- 15185237
TI  - Incidence and clinical significance of abdominal wall bruising in restrained
      children involved in motor vehicle crashes.
AB  - BACKGROUND: Children involved in motor vehicle crashes (MVC) can sustain bruising
      of the abdominal wall associated with seat belt restraint. The incidence of
      bruising and its relationship with significant intraabdominal injuries are not
      known. METHODS: An analysis of children involved in MVC between December 1998 and
      November 2002 was performed, using the crash surveillance database from the
      Partners for Child Passenger Safety (PCPS) project. Optimally (OR) or
      suboptimally (S-OR) restrained children aged 4 to 15 years were selected. The
      incidence of abdominal wall bruising was calculated then correlated with the type
      of restraint as well as any intraabdominal injury with an Abbreviated Injury
      Scale score > or =2. RESULTS: A total of 147,985 children in 102,548 crashes met
      study criteria. An abdominal bruise was noted in 1.33% of the children (n =
      1,967; 881 OR and 1,086 S-OR). Significant intraabdominal injury was present in
      309 children (0.21%, 95% CI 0.13 to 0.33), including 69 OR and 240 S-OR. The
      sensitivity, specificity, and positive and negative predictive values of
      abdominal wall bruising for a significant intraabdominal injury were 73.5%,
      98.8%, 11.5%, and 99.9%, respectively. Children with a bruise were substantially
      more likely to have an intraabdominal injury than children without a bruise.
      (Odds Ratio 232.1, 95% CI, 75.9 to 710.3) Among those children with an abdominal
      bruise, 1% required an abdominal operation (n = 20). CONCLUSIONS: Abdominal wall
      bruising was relatively uncommon in both OR and S-OR children. Among restrained
      children involved in MVC, those with a bruise were 232 times more likely to have
      a significant intraabdominal injury when compared with those without a bruise. It
      is imperative to pursue intraabdominal injury in children with a bruise of the
      abdominal wall after MVC.

PMID- 15185236
TI  - Pediatric splenic injuries with a contrast blush: successful nonoperative
      management without angiography and embolization.
AB  - BACKGROUND: The presence of a contrast blush on computed tomography (CT) in adult
      splenic trauma is a risk factor for failure of nonoperative management. Arterial
      embolization is believed to reduce this failure rate. The significance of a blush
      in pediatric trauma is unknown. The authors evaluated the outcome of children
      with blunt splenic trauma and contrast extravasation. METHODS: The trauma
      registry was queried for all pediatric patients with blunt splenic injuries.
      Admission CT was reviewed for injury grade and presence of an arterial blush by a
      radiologist blinded to patient outcome. Hospital and office charts were reviewed
      for success of nonoperative management, late splenic rupture, and other
      complications. RESULTS: One hundred seven children with blunt splenic trauma were
      identified over a 6-year period. Mean injury grade was 2.9. Six patients required
      emergency splenectomy. An additional 7 patients met hemodynamic criteria for
      surgical intervention (3 splenectomies, 4 splenorrhaphies). Admission CT was
      available in 63 patients. An arterial blush was identified in 5 (9.7%). Four
      remained stable and were treated conservatively. One underwent splenectomy for
      hemodynamic instability. There were no cases of delayed splenic rupture, failed
      nonoperative treatment, or long-term complications. CONCLUSIONS: Contrast blush
      in children with blunt splenic trauma is rare, and its presence alone does not
      appear to predict delayed rupture or failure of nonoperative treatment. Based on
      this limited series, splenic artery embolization does not have a place in the
      management of splenic injuries in children.

PMID- 15185238
TI  - Determination of national pediatric injury prevention priorities using the Injury
      Prevention Priority Score.
AB  - PURPOSE: Previous studies have found that the Injury Prevention Priority Score
      (IPPS) provides a reliable and valid method to gauge the relative importance of
      different injury causal mechanisms at individual trauma centers. This study
      examines its applicability to prioritizing injury mechanisms on a national level
      and within defined pediatric age groups. METHODS: A total of 47,158 patients (age
      <17) in the National Pediatric Trauma Registry were grouped into common injury
      mechanisms based on ICD-9 E-Codes. Patients also were stratified by age group.
      IPPS was calculated for each mechanism and within each age group. RESULTS: Falls
      of all types account for the greatest number of injuries (n = 15,042; 32%),
      whereas child abuse results in the most severe injuries (mean Injury Severity
      Score, 13.3) However, the most significant mechanisms of injury, according to
      IPPS, were motor vehicle crashes followed by pedestrian struck by motor vehicles.
      Certain age groups had specific injury problems including child abuse in infants
      and assault and gun injuries in adolescents. CONCLUSIONS: IPPS provides an
      objective, quantitative method for determining injury prevention priorities based
      on both frequency and severity at the national level. It also is sensitive to age
      related changes in different mechanisms of injury.

PMID- 15185239
TI  - Assessment of pain after injury in the pediatric patient: child and parent
      perceptions.
AB  - BACKGROUND/PURPOSE: Pain is an inevitable consequence of injury. Accurate
      assessment and treatment of a child's pain after injury is essential. This study
      sought to describe children's pain with injury and to elucidate the concordance
      of parental and self-reported pain in a pediatric traffic-injured population.
      METHODS: Children (5 to 17 years) admitted for traffic-related injuries and 1
      parent were invited to participate in the study. Consented participants were
      interviewed within 1 month of injury. Participants were asked to rate current and
      worst pain on 2 validated pediatric pain assessment scales (Bieri Faces Pain
      Scale and Color Analogue Scale). Demographic, crash, and injury data were
      abstracted from the medical record. RESULTS: Data from 276 child-parent dyads
      show that most children reported clinically significant pain initially after
      injury. Greater "worst pain" ratings did not correlate with injury severity but
      were associated with loss of consciousness and extremity fracture. Generally,
      parent-report of child's pain was concordant with child self-report. CONCLUSIONS:
      This study shows the feasibility of pain assessment for pediatric injury using 2
      validated scales and the appropriateness of parental report when the child is not
      able to provide self-report. Because pain was not correlated with injury
      severity, pain assessment and intervention for all children with traumatic
      injuries is strongly recommended.

PMID- 15185240
TI  - Keys to career satisfaction: insights from a survey of women pediatric surgeons.
AB  - BACKGROUND/PURPOSE: Declining interest in the field of surgery is attributed to
      lifestyle issues, more women per class, high debt, and long residency. To
      maintain surgery as a premier career choice, female students must find surgery to
      be professionally and personally rewarding. METHODS: A 35-item questionnaire was
      mailed to 95 women pediatric surgeons (WPS), assessing multiple professional and
      personal factors. Responses were entered into a confidential database and
      analyzed by chi2 or t tests. RESULTS: Seventy-nine percent of surveys were
      returned; practice was identified as academic (60%) and private (40%).
      Respondents were grouped by age: A, less than 44 years (41%); B, 45 to 54 years
      (37%); and C, greater than 55 years (22%). For academic WPS, 81% are on timeline
      for promotion. Insufficient protected time was a significant obstacle for a
      successful academic career in groups A and B (P =.001). Clinical load, on-call
      responsibilities, lack of mentorship, and departmental support were major
      obstacles in all groups (P =.05). Seventy-three percent of WPS in private
      practice were satisfied with their role in practice management; poor practice
      conditions were cited as the most frequent reason for job relocation. Sixty-one
      percent of WPS are married, and 46% are raising children. WPS had statistically
      significant more responsibilities for child care and household tasks in
      comparison with their partners. Eighty-three percent report career satisfaction
      but desire more time with family and for personal interests. Part-time and
      flexible work schedules were identified as attractive ways to achieve career
      family balance. Eighty-four percent believe that quality-of-life issues are the
      dominant reason that fewer medical students choose surgical fields. CONCLUSIONS:
      WPS express career satisfaction but share the concerns of their female colleagues
      in other surgical disciplines. Quality of life is viewed as central to career
      choice for the current generation of medical students; female role models are key
      to recruiting women into pediatric surgery.

PMID- 15185241
TI  - Billing and reimbursement for pediatric surgical services: a unique assessment of
      a complex process.
AB  - BACKGROUND/PURPOSE: Billing and reimbursement for pediatric surgical services is
      a complicated process that has not been rigorously evaluated. This study
      evaluates pediatric surgery billing and reimbursement and compares the process
      between third party payors. METHODS: The authors tracked all noncapitated bills
      from submission to final payment for all cases performed during 1 month. Data
      included operation, insurance type, amount billed, and amount collected. If
      payments were denied, the reasons were ascertained and the appropriateness
      verified. Chi-square and Student's t tests were used for comparisons. RESULTS:
      The billing process for all noncapitated pediatric surgical cases during May
      2000, was reviewed (n = 136). The majority of bills (79%) were paid outright. Of
      the rejected bills, 76% were denied inappropriately. Inappropriate denial of
      payment was most frequent among patients insured by Medicaid. Mean time to
      complete payment was longest among patients insured by managed care groups.
      Percent of total charges reimbursed for surgical services was significantly lower
      for patients insured by Medicaid and Health Maintenance Organizations (HMO).
      CONCLUSIONS: A significant number of bills for pediatric surgical services are
      rejected inappropriately. Careful analysis of one's rejected bills can recoup up
      to 20% of revenue. HMO's and Medicaid are more likely to deny payment
      inappropriately, take longer to make payments, and reimburse less for pediatric
      surgical services.

PMID- 15185244
TI  - Extending the reach of pediatric nursing practice.

PMID- 15185245
TI  - Gender, ethnicity, and the interactions of prematurely born children and their
      mothers.
AB  - This study examined the relationship of child gender and maternal ethnicity to
      the interactive behaviors of 53 3-year-old prematurely born children and their
      mothers. Boys and Non-White children had more developmental sequelae. Although
      most interactive behaviors did not differ by gender or ethnicity, mothers
      expressed more positive affect to girls than boys, and girls looked at their
      mothers more often and expressed more positive affect. White mothers expressed
      more positive affect, touched more, and had better scores on three Home
      Observation for Measurement of the Environment (HOME) Inventory subscales and the
      total HOME score than Non-White mothers. Child behaviors did not differ by
      ethnicity. Gender and ethnic group differences were affected by maternal
      education and child illness severity. Thus, although the interactive behaviors of
      mothers and prematurely born children are related to both child gender and
      ethnicity, some of these effects are better explained by maternal education and
      child illness severity. The systems view of the mother-child relationship is used
      to interpret these findings.

PMID- 15185246
TI  - Nurses' attitudes, knowledge, and beliefs related to the promotion of
      breastfeeding among women who bear children during adolescence.
AB  - This descriptive study examined the attitudes, knowledge, and beliefs of maternal
      child nurses related to the promotion of breastfeeding among adolescent mothers.
      Nurses (N = 151) employed by three nonprofit hospitals and city and county public
      health departments located in the southeastern part of the United States were
      surveyed. Overall, the findings revealed that participants were generally
      knowledgeable about and supportive of breastfeeding by adolescent mothers.
      However, some of the nurses did not know that there are nutritional differences
      between breast milk and infant formula, continued the practice of imposing time
      limits for feedings at the breast, and indicated that they were skeptical about
      young mothers' potential for success with breastfeeding because of immaturity and
      lack of commitment. Statistically significant differences were noted in mean
      attitude and knowledge scores based on the participant's specialty; knowledge and
      attitude were positively correlated with the nurse's level of education.
      Implications for nursing practice and future research are discussed.

PMID- 15185247
TI  - Health care barriers for Latino children and provision of culturally competent
      care.
AB  - The demography of the United States is rapidly changing. The impressive growth
      rate of Latino populations within the United States has great impact on health
      care. This article includes discussion of a significant increase from 1988 to
      2000 in Latino utilization of emergency department and inpatient services at a
      pediatric medical center in Salt Lake City, Utah, information on health care
      barriers for Latinos, and suggestions for providing culturally competent care.

PMID- 15185248
TI  - The social ecology of changing pain management: do I have to cry?
AB  - OBJECTIVE: To improve acute pain management for children with systematic
      assessment and appropriate analgesia. DESIGN: An action research design was used;
      pre-post data were collected during a four-phase intervention. The intervention
      was a social ecological approach to changing pain assessment and prescription
      practices. SETTING: A university-affiliated public hospital in the greater Los
      Angeles area. PARTICIPANTS: An interdisciplinary team of clinicians and hospital
      administrators were engaged in implementing new pain management procedures for
      children with postoperative and procedural pain. INTERVENTIONS: We implemented
      the Poker Chip Tool as a standard pain assessment tool, changed policy to make
      morphine drug of choice for acute postoperative pain, provided extensive
      educational activities, and conducted weekly rounds with
      anesthesiologist/intensivist, nurses, pharmacist, and child life specialist. Role
      modeling by leaders was used to build skill in interdisciplinary collaboration
      for staff. We promoted the initiative as an activity of the medical center
      strategic plan. Efforts were linked to national shifts in pain management through
      guideline review and use of a visiting expert. OUTCOME MEASURES: Charts were
      audited for assessment of pain intensity. Doses dispensed by pharmacy were used
      as a proxy measure of analgesia administered to children to establish change in
      pattern of analgesic use. RESULTS: In Phase I: 54% of charts audited had
      documentation of pain intensity. This rate climbed to Phase II, 93% of the
      audited charts at full implementation and stabilized at 84% at the project
      conclusion. Record of doses of analgesia dispensed demonstrated a shift from
      reliance on meperidine to morphine and acetaminophen with codeine. The relative
      rates demonstrated a 100% increase in acetaminophen with codeine distributed from
      the beginning of the study to full implementation of the project (chi(2) = 9.01,
      df = 1, p < 0.002). The relative rate for meperidine demonstrated a 250% decrease
      (chi(2) = 12.26, df = 1, p < 0.0004), and the relative rate for morphine
      exhibited a 455% increase (chi(2) = 209.20, df = 1, p < 0.0001). By the final
      phase (IV: Evaluation), meperidine was only 1% of the analgesia dispensed.
      Morphine doses that were initially 35% climbed to 62% at the close of the study.
      Acetaminophen with codeine shifted correspondingly from 24% to 36%. Anecdotal
      reports suggested that skills in assessment and building collaboration
      generalized to other patient care situations. CONCLUSIONS: Using a social ecology
      approach that focused simultaneously on the environment (ward, medical center,
      and national scene) and relationships among the clinical team improved pain
      management practices. These changes took place over 2 years and were sustained 2
      years after the intense intervention.

PMID- 15185249
TI  - Temperament and pain in 3 to 7-year-old children undergoing tonsillectomy.
AB  - The purpose of this study was to examine the relationships among temperament,
      self-reported pain, parent's report of children's pain behavior and pain
      intensity, amount of pain medication received, and parents' attitudes toward use
      of analgesics in 3- to 7-year-old children undergoing tonsillectomy. Sixty-eight
      child/parent dyads participated in the study. Correlations were found between
      some temperamental factors and child's self-reported pain intensity in the
      hospital and at home as well as parents' report of pain behavior at home. There
      was a significant positive relationship between the child's self-reported pain
      intensity and analgesic administration in the hospital and at home.

PMID- 15185250
TI  - Adopting children.

PMID- 15185252
TI  - A study of parental involvement in pediatric hospital care: implications for
      clinical practice.
AB  - BACKGROUND: Although it has become common practice for parents to stay with their
      sick child in hospital, most hospitals lack routines and staff guidelines for
      involving parents in care processes and decisions. AIM: To gain a deeper
      understanding of factors that influence parental involvement and to clarify the
      parental role in the hospital care of chronically ill children. METHODS:
      Semistructured interviews with 14 parents of chronically ill children. RESULTS:
      Four themes were identified: support, professionalism, work environment, and
      responsibility. These themes describe the experience and perceptions of parents
      who regularly spend time in the hospital with their children. CONCLUSIONS:
      Clinical practices regarding parental involvement need to be established to
      optimize the hospital care of chronically ill children.

PMID- 15185254
TI  - Incorporating Florence Nightingale's theory of nursing into teaching a group of
      preadolescent children about negative peer pressure.
AB  - Clinically based nurses often question the value of nursing theory, ultimately
      resulting in the reluctance to implement nursing theory into practice. This
      clinical practicum project successfully used Nightingale's primary tenets, such
      as building trust, self-assessment, and group leadership, as a theoretical
      framework in a nursing practice group for the purpose of teaching a group of
      preadolescent children about negative peer pressure. Preadolescent children are
      particularly vulnerable to peer group culture. Proactive strategies, as
      demonstrated through this project, can be used to positively influence children's
      behavior toward each other during the formative middle years. Group sessions
      addressed such topics as moral beliefs and values, bullying, and saying "no" to
      peer pressure and were structured using a variety of contemporary resources to
      develop interactive exercises that engaged the children and enhanced group
      communication. The children and their parents reported positive outcomes from the
      nurse-led group sessions.

PMID- 15185256
TI  - Nodular histiocytic/mesothelial hyperplasia: a potential pitfall.
AB  - We present five cases of nodular histiocytic/mesothelial hyperplasia (two
      peritoneal, two pulmonary, and one pericardial) with identical microscopic
      features. All the lesions were biphasic and composed of cohesive monotonous
      epithelioid clusters of polygonal or oval cells with round or deeply grooved
      nuclei in association with darker cuboidal cells. Because of the increased
      cellularity and monotonous histologic pattern with some degree of cytologic
      atypia, neoplastic processes were seriously considered in the differential
      diagnoses. The majority of the cells marked as histiocytes by immunostain. A few
      scattered individual cells or small epithelial cell clusters were confirmed by
      calretinin stain to be mesothelial cells. The histologic patterns of the current
      lesions, irrespective of the location, were identical to nodular
      histiocytic/mesothelial hyperplasia. Histiocytic proliferations can be
      erroneously confused with primary mesothelial lesions or neoplasms such as
      granulosa cell tumor, eosinophilic granuloma, chronic myelogenous leukemia, and
      carcinoma. The purpose of this article is to describe the clinicopathologic
      features of nodular histiocytic/mesothelial hyperplasia and help familiarize
      pathologists with this lesion to prevent an erroneous diagnosis, particularly
      when it occurs in locations where mesothelial cells are not normally present.

PMID- 15185257
TI  - Solitary fibrous tumor of the mammary gland: a potential pitfall in breast
      pathology.
AB  - We report three cases of solitary fibrous tumor of the breast. The patients were
      adult to elderly women and complained of a slowly but relentless growing lump.
      The tumors were fairly circumscribed and cured by means of lumpectomy or, in one
      case, simple mastectomy. Histologically, they featured the customary "patternless
      pattern" of short spindle cells haphazardly arranged in fascicles within a
      collagenized or myxoid ground substance. In two cases, a prominent
      hemangiopericytic arrangement of tumor cells around a rich vascular framework
      could be noticed. Cellular areas were often present and showed nuclear
      overlapping, clumping of chromatin, and a brisk mitotic activity. No atypical
      mitosis was recognized. Tumor cells were immunoreactive for CD34, bcl2, and
      vimentin only. On follow-up there was no evidence of either local recurrence or
      distant metastases. Solitary fibrous tumors of the breast may represent a
      significant diagnostic problem because of the close mimicry to numerous benign
      and malignant mammary lesions composed of spindle cells; diagnostic clues may be
      further obscured in cellular and actively proliferating tumors. A brief overview
      of mammary solitary fibrous tumor taxonomy along with the principal differential
      diagnoses within the breast is presented.

PMID- 15185258
TI  - Pleomorphic solid and cystic papillary carcinoma of the breast: two cases
      occurring in young women.
AB  - Solid and cystic papillary carcinoma is typically a localized indolent, low
      nuclear-grade form of intraductal carcinoma of the breast that occurs in a
      cystically dilated duct and predominantly affects elderly women in the sixth to
      the eighth decade of life (mean age, 57 to 75 years). We describe two such
      lesions, both of high nuclear grade, of larger than average size, that occurred
      in women in their second decade, one of whom was pregnant.

PMID- 15185259
TI  - Pilomatrixoma: a diagnostic pitfall in fine-needle aspiration biopsies. A review
      from a small county hospital.
AB  - A 10-year-old Hispanic girl presented with a 3-cm mass over her right parotid
      region. A fine-needle aspiration (FNA) was performed and the preliminary and
      final diagnoses were "suspicious for carcinoma, possible mucoepidermoid
      carcinoma." A subsequent computed tomography demonstrated an extra-parotid lesion
      attached to the skin. The FNA smears were reviewed and the diagnosis of a
      pilomatrixoma (PMT) was reached. The lesion was excised and the diagnosis of
      benign PMT confirmed. Pilomatrixomas are uncommon skin adnexal tumors most
      commonly found in the head and neck area of young adults and children. In 10
      years there were 16 PMTs among 60,280 surgical pathology specimens in the
      pathology files of our 300-bed general county hospital. Pilomatrixoma is
      recognized as a diagnostic pitfall not only clinically but also on FNA cytology.
      On the physical examination, the bluish skin discoloration over the lesion so
      typical of PMT was overlooked. On FNA, the basaloid cells of PMT were mistaken
      for intermediate cells of mucoepidermoid carcinoma. The presence of anucleated
      squames was not properly recognized. These are usually absent in mucoepidermoid
      carcinoma and represent a hallmark of PMT. This case illustrates well the risk of
      misdiagnosing a pre-auricular PMT as a malignant tumor of the parotid gland.

PMID- 15185261
TI  - Intrasellar and parasellar cellular schwannoma.
AB  - The complexity of the anatomy of the sella turcica and its surroundings accounts
      for the large number of pathologic entities that may involve this critical area.
      Intrasellar and parasellar schwannomas are exceedingly rare; only a handful of
      true sellar tumors of this nature have been reported in the English literature.
      These lesions may simulate nonsecretory pituitary adenomas clinically and
      neuroradiologically. Although benign, complete surgical resection of these tumors
      is usually difficult because of their size, invasiveness, and rich vascularity.
      From the histopathologic stand point, those cases lacking typical schwannoma
      histomorphologic features may pose a diagnostic challenge to the pathologist,
      especially at the time of frozen section examination, because they may resemble
      other spindle cell neoplasms more common to that location, such as fibrous
      meningothelial tumors. We report a case of intrasellar and parasellar cellular
      schwannoma lacking common and reliable neurilemmomatous features, such as the
      coexistence of cellular Antoni A and loose Antoni B areas, Verocay bodies, and
      hyalinized thickened vessels. In addition, features infrequently seen in
      schwannomas were identified in the specimen, including the presence of psammoma
      bodies, nuclear optically clear pseudoinclusions, and fine intracytoplasmic
      melanin-like pigment. Ultimately, the use of immunohistochemistry was necessary
      to achieve a definitive pathologic diagnosis. Cellular schwannoma expands the
      pathologic differential diagnosis of spindle cell neoplasms of sellar location
      that the pathologist should have in mind, especially at the time of frozen
      section examination. The clinical, histopathologic, and neurosurgical aspects of
      primary cellular schwannomas of the sella turcica are reviewed.

PMID- 15185260
TI  - Hepatoid adenocarcinoma of the stomach.
AB  - A 54-year-old man presented to his doctor with hematemesis and was found at
      endoscopy to have an ulcerated lesion in his stomach. A computed tomography scan
      was performed and revealed a mass in the fundus of the stomach. Multiple other
      lesions were identified in the liver, lungs, retroperitoneal space, and
      mesentery. Gross examination showed two separate gastric lesions containing nests
      and single cells with mucin intermixed with sheets of tumor cells with abundant
      eosinophilic cytoplasm invading throughout the wall of the stomach.
      Immunohistochemical studies were performed and the cells were positive for
      hepatocyte, MOC 31, cytokeratin A1/A3, and CK 7, and were negative for CK 20,
      alpha-fetoprotein, and thyroid transcription factor. The histologic features
      together with the immunohistochemical findings were diagnostic of a hepatoid
      adenocarcinoma of the stomach. Hepatoid adenocarcinoma is a rare tumor associated
      with a very poor prognosis. Immunohistochemical studies may help to identify the
      characteristic features of hepatoid differentiation and prevent mistaking this
      tumor for other types of carcinoma.

PMID- 15185262
TI  - Borderline mucinous cystic tumor in jejunal pancreatic heterotopia.
AB  - Heterotopic pancreas is a relatively common congenital anomaly, usually found
      incidentally during laparotomies. The jejunum is an uncommon site; stomach and
      duodenum are the most frequent reported locations. Every pathologic change that
      occurs in the pancreas can occur in its heterotopic counterpart, but neoplastic
      transformation is rare. Most reported cases of neoplastic transformation are
      ductal adenocarcinomas, and there are only a few reported cases of mucinous
      neoplasms arising in heterotopic pancreas. We report a mucinous neoplasm arising
      in a heterotopic pancreatic tissue in the jejunum of an 86-year-old woman found
      during a laparotomy for bowel ischemia. Because of the presence of focal
      papillary architecture and cytologic atypia, the tumor was classified as a
      borderline neoplasm. To the best of our knowledge, is the first reported case of
      a borderline mucinous neoplasm occurring in heterotopic pancreatic tissue.

PMID- 15185263
TI  - Malignant rhabdoid tumor arising from a pleomorphic adenoma.
AB  - Malignant transformation of pleomorphic adenomas often occurs in long-standing
      tumors or tumors with multiple local recurrences. The malignant component is
      usually a carcinoma. The case reported herein concerns a 60-year-old man who had
      a malignant rhabdoid tumor arising in a painless parotid mass that remained
      untreated for 25 years. Malignant rhabdoid tumors are clinically aggressive
      neoplasms with phenotypic features that resemble rhabdomyomatous differentiation
      but lack genuine skeletal muscle differentiation. The salient features of
      rhabdoid tumor cell include large, pleomorphic, and eccentric nucleus and a
      solitary and prominent intracytoplasmic inclusion that is strongly immunoreactive
      for vimentin. It is our understanding that this is the first reported case of
      malignant rhabdoid tumor arising in the parotid gland in the English literature.
      The pathologic features of our case will be discussed in context with malignant
      rhabdoid tumors from other parts of the body.

PMID- 15185264
TI  - Spiradenocarcinoma of the breast arising in a long-standing spiradenoma.
AB  - The embryologic origin of the breast is related to salivary and sweats glands.
      Thus, breast neoplasms may show differentiation toward these tissues, although
      this is a rare event in humans. We report the clinicopathologic and
      immunohistochemical features of a 57-year-old woman presenting with a spiradenoma
      that originated in breast tissue and became malignant 40 years later. Some
      histogenetic concepts relevant to this case are discussed, along with a brief
      review of this neoplasm.

PMID- 15185265
TI  - Malignant and benign lymphoid lesions of the lung.
AB  - Lymphoid lesions of the lung produce a complex of problems for the practicing
      pathologist. Although these lesions are eventually referred to
      hematopathologists, it is still the general surgical pathologist who first
      encounters them and confronts the problem of formulating an initial diagnosis.
      Over the last 20 years there has been a revolution in our knowledge of the
      classification and natural history of the pulmonary lesions, a plethora of
      information which warrants a thorough review. The purpose of this discussion is
      to report the clinical features and courses, pathologic features and, when known,
      etiologies or pathogenesis of the major "primary" pulmonary lymphoid lesions and
      present a brief approach to differential diagnosis. I will divide the lesions
      into malignant and benign, discussing each in turn.

PMID- 15185267
TI  - Patterns of weight change after treatment for bulimia nervosa.
AB  - OBJECTIVE: The current study examined changes in weight and body mass index (BMI)
      at 5-year follow-up among women treated for bulimia nervosa. METHOD: The study
      comprised 80 women who had participated in a randomized clinical trial evaluating
      cognitive-behavior therapy for bulimia nervosa. The women had attended
      assessments at posttreatment and at 5-year follow-up while not pregnant. RESULTS:
      Changes in mean weight and BMI between posttreatment and 5-year follow-up were
      small in absolute terms and were not statistically significant. However, by the 5
      year follow-up, approximately one half of the participants had either lost (31%)
      or gained (18%) 5 or more kilograms or were underweight (31%) or overweight (24%)
      as defined by BMI. Univariate analyses suggest that it is the patients who gain
      weight over the follow-up that are distinctive. Patients who gained weight over
      the follow-up were more likely to have commenced menstruation at a younger age,
      to have a lifetime history of being heavier, and to have been heavier and more
      dissatisfied with their body at pretreatment, posttreatment, and at 5-year follow
      up. CONCLUSION: Five years after treatment for bulimia nervosa, approximately one
      half of the participants had changed substantially in weight. For those who had
      changed, weight loss was more common than weight gain.

PMID- 15185266
TI  - Evaluation of a school-based program designed to improve body image satisfaction,
      global self-esteem, and eating attitudes and behaviors: a replication study.
AB  - OBJECTIVE: The purpose of the current study was to evaluate the effectiveness of
      a life-skills promotion program designed to improve body image satisfaction and
      global self-esteem, while reducing negative eating attitudes and behaviors and
      feelings of perfectionism, all of which have been identified as predisposing
      factors to disordered eating. METHOD: A total of 258 girls with a mean age of
      11.8 years (intervention group = 182 and control group = 76) completed
      questionnaires before, and 1 week after, the six-session school-based program,
      and again 6 and 12 months later. RESULTS: The intervention was successful in
      improving body image satisfaction and global self-esteem and in reducing dieting
      attitude scores at post intervention only. The gains were not maintained at the
      12-month follow-up. DISCUSSION: The need to assess the influence of health
      promotion programs on predisposing risk factors, compared with problem-based
      outcome measures, is discussed.

PMID- 15185268
TI  - Predictors of rehospitalization after total weight recovery in adolescents with
      anorexia nervosa.
AB  - OBJECTIVE: The current study analyzed the variables related to rehospitalization
      after total weight recovery in adolescents with anorexia nervosa. METHOD: One
      hundred and one patients first admitted for inpatient treatment, aged 11-19
      years, were followed up for 12 months after discharge. RESULTS: Twenty-five
      subjects (24.8%) required readmission after complete weight recovery and 76
      (75.2%) did not. Duration of disorder, weight loss, body mass index at first
      admission, and global body image distortion were similar in the two groups.
      Patients needing readmission had a lower rate of weight gain (p < .001), a lower
      mean age (p = . 007), a higher mean score on the Eating Attitudes Test (EAT; p =
      .009), and a higher percentage of hips overestimation (p = .049). In a stepwise
      logistic regression analysis, these three variables predicted readmission and
      correctly classified 77.6% of patients. Taken as discrete variables, age younger
      than 15 years old, EAT score above 55, and a rate of weight gain lower than 150
      grams per day were associated with a higher percentage of readmissions.
      DISCUSSION: The variables most clearly related to readmission were young age,
      abnormal eating attitudes, and a low rate of weight gain.

PMID- 15185269
TI  - Reduction of food cravings through concurrent visuospatial processing.
AB  - OBJECTIVE: Two experiments adopted a working memory approach to evaluate the
      effectiveness of visuospatial tasks as a technique for reducing food cravings.
      METHOD: Dieting and non-dieting women were asked to form images of both food
      related and nonfood items, induced by either pictures (Experiment 1) or verbal
      cues (Experiment 2). They were required to concurrently perform one of three
      tasks that load on the visuospatial sketch pad of working memory: saccadic eye
      movements, dynamic visual noise, or spatial tapping. RESULTS: In support of the
      working memory model of limited visuospatial capacity, concurrent visuospatial
      activity reduced the vividness of food-related images which, in turn, reduced the
      intensity of the associated craving. The same pattern of results was observed
      across dieters and non-dieters and for all stimulus types. DISCUSSION:
      Visuospatial tasks may provide a useful technique for the treatment of food
      craving episodes in both nonclinical and clinical populations.

PMID- 15185270
TI  - Perfectionism, body dissatisfaction, and self-esteem in predicting bulimic
      symptomatology: lack of replication.
AB  - OBJECTIVE: Few prospective studies have tested multivariate models of bulimic
      pathology development, but two studies have found support for a Perfectionism x
      Body Dissatisfaction x Self-Esteem etiologic model (Vohs, K.D., Bardone, A.M.,
      Joiner, T.E., Abramson, L.Y., & Heatherton, T.F., 1999;108:695-700; Vohs et al.,
      2001;20:476-497). The current study sought to provide an independent replication
      of these promising findings. METHOD: Data from 496 adolescent girls that were
      followed prospectively over a 1-year period were used to test this predictive
      model. RESULTS: Although our study should have provided a more sensitive test of
      this model because we used a sample at higher risk for bulimic symptom increases,
      more sensitive diagnostic interviews, a longer follow-up period, and a larger
      sample, the three-way interaction did not predict subsequent increases in bulimic
      symptoms. DISCUSSION: Results suggest that the predictive power of this
      interactive model may not be as robust as previously believed.

PMID- 15185271
TI  - Efficacy of sertraline for bulimia nervosa.
AB  - OBJECTIVE: The current study examined the efficacy of sertraline in the treatment
      of individuals diagnosed with bulimia nervosa. METHOD: Eighteen women enrolled in
      an 8-week open trial of sertraline. Eating disorder psychopathology and
      depressive symptoms were assessed at baseline and at the end of the trial using
      both semistructured interviews and self-report questionnaires. RESULTS: Findings
      indicated significant reductions in eating disorder psychopathology, including
      the number of binges and purges per week, as well as significant reductions in
      depressive symptoms. In addition, participants did not experience significant
      weight gain or any other sertraline side effect assessed at the end of the trial
      compared with baseline. DISCUSSION: Findings from the current study indicate that
      sertraline is efficacious in the treatment of bulimia nervosa. A double-blind
      controlled trial of sertraline is recommended for future research.

PMID- 15185272
TI  - Is major depressive disorder or dysthymia more strongly associated with bulimia
      nervosa?
AB  - OBJECTIVE: Research on adult samples has found that the comorbidity between
      depression and eating disorders exceeds the comorbidity of any other Axis I
      disorder and eating disorders. Few studies have investigated the specific
      associations of major depression versus dysthymia with eating disorders. METHOD:
      This sample consisted of 937 adolescents who were repeatedly assessed until the
      age of 24. RESULTS: Analyses revealed that dysthymia was a stronger correlate
      with bulimia than major depression, even while controlling for other mood
      disorders and a history of depression and dysthymia. CONCLUSIONS: The presence of
      dysthymia in adolescence might be a possible risk factor for the development of
      bulimia nervosa.

PMID- 15185273
TI  - Beliefs of the public concerning the helpfulness of interventions for bulimia
      nervosa.
AB  - OBJECTIVE: To examine the beliefs of women concerning the helpfulness of various
      possible interventions for bulimia nervosa. METHOD: Face-to-face interviews were
      conducted with a community sample of 208 women aged 18-45 years. Respondents were
      presented with a vignette describing a fictional person meeting diagnostic
      criteria for bulimia nervosa and were asked to indicate whether various persons,
      treatments, medications, and self-help activities would be helpful, harmful, or
      neither helpful nor harmful for the person described. RESULTS: Respondents
      indicated that seeing a general practitioner (GP), counselor, or dietitian was
      more likely to be helpful than seeing either a psychologist or a psychiatrist.
      GPs were perceived as the individuals likely to be most helpful for the problem
      described, and most likely to be approached first, whereas counseling was
      regarded as the most helpful treatment. Self-help interventions, including the
      use of vitamins and minerals, were also highly regarded, while a minority of
      participants believed that anti-depressant medication would be helpful.
      CONCLUSIONS: Information concerning treatments that are effective for eating
      disorders should be included in prevention programs. Collaborations between
      mental health specialists and primary health providers are vital to ensure the
      optimal treatment of eating-disordered behavior.

PMID- 15185274
TI  - Accuracy in the estimation of body weight: an alternate test of the motivated
      distortion hypothesis.
AB  - OBJECTIVE: Inaccuracies in self-reported weight are believed to represent a
      motivated distortion, but cognitive or perceptual biases have not been excluded.
      We examined the ability of participants to estimate the weight of a target person
      as a means of distinguishing between motivated distortions and perceptual biases.
      METHOD: Participants (restrained eaters and unrestrained eaters; women and men)
      estimated the weight of a target individual, which was compared with the actual
      weight of the target individual. RESULTS: Restrained and unrestrained eaters did
      not differ in their estimates of the target's weight, and men underestimated the
      target's weight to a greater extent than did women. DISCUSSION: The pattern of
      inaccuracies observed does not parallel those found in research on self-reported
      weight. This observation suggests that perceptual biases do not explain
      inaccuracies in self-reported weight and that such inaccuracies may be the result
      of motivated distortions. Issues regarding data analysis and presentation are
      also discussed.

PMID- 15185275
TI  - Predictors of the accuracy of self-reported height and weight in adolescent
      female school students.
AB  - OBJECTIVE: The authors investigated predictors of the accuracy of self-reported
      values of body weight and height in adolescent females. METHOD: Self-reported and
      measured weight and height values were obtained for 683 school students aged 11
      18 years. Predictors of accuracy were determined for self-reported weight,
      height, and body mass index (BMI; based on self-reported values). RESULTS: Self
      reported weight was underestimated. This was most likely for students with higher
      BMI values and actual weight. Younger, early pubertal and premenarcheal students
      were most likely to underestimate their height whereas older, postmenarcheal
      (more than 3 years) students were most likely to overestimate their height. The
      more exercise reported, the more accurate the height estimation. This translates
      to a greater underestimation of BMI as adolescents become older, have a longer
      duration since menarche, and exercise more. DISCUSSION: When accurate information
      is required, clinicians should measure height and weight, particularly if the
      adolescent female is perimenarcheal or appears to differ from population averages
      for height and weight.

PMID- 15185276
TI  - Comparing two measures of eating restraint in bulimic women treated with
      cognitive-behavioral therapy.
AB  - OBJECTIVE: To examine changes in dietary restraint patterns revealed by the
      Eating Disorders Examination Restraint subscale (EDE-R) and the Three-Factor
      Eating Questionnaire Cognitive Restraint scale (TFEQ-CR) in a large sample of
      women with bulimia nervosa (BN) who completed 18 weeks of cognitive-behavioral
      therapy (CBT). METHOD: Data from 134 subjects were obtained from a larger study
      and analyzed using repeated-measures analysis of variance (ANOVA). RESULTS: The
      EDE-R showed statistically and clinically significant decreases post-CBT, whereas
      the TFEQ-CR did not change significantly. DISCUSSION: This is the first study to
      directly compare the EDE-R and TFEQ-CR before and after CBT in the same
      population. The contrasting results suggest the two measures tap different
      aspects of the dietary restraint construct. The EDE-R may primarily reflect
      dieting to lose weight whereas the TFEQ-CR may reflect dieting to avoid weight
      gain. In assessing changes in dietary restraint targeted by CBT for BN, the TFEQ
      CR appears less useful.

PMID- 15185277
TI  - Nonresponse bias in a general population survey of eating-disordered behavior.
AB  - OBJECTIVE: To investigate nonresponse bias in a two-phase epidemiologic study of
      eating-disordered behavior. METHOD: Self-report questionnaires were delivered to
      a community sample of women aged 18-45 drawn from the electoral roll. Follow-up
      interviews were completed with a subgroup of respondents. Eating disorder
      psychopathology, general physical and mental health, and sociodemographic
      characteristics were compared among early (n = 259) and late (n = 71) respondents
      at the first phase of the study and among individuals with whom interviews were
      completed (n = 208) and individuals declining to be interviewed (n = 63) at the
      second phase. RESULTS: With respect to levels of eating disorder psychopathology,
      and on all other measures, individuals who responded at the first phase of the
      study only after repeated reminders did not differ from those who responded to
      the initial mailout, and individuals who declined to be interviewed did not
      differ from individuals with whom interviews were completed. CONCLUSIONS:
      Nonresponse bias among individuals declining to be interviewed is unlikely to
      pose a problem in two-phase epidemiologic studies of eating disorders. Further
      research is needed to examine the characteristics of nonrespondents at the first
      phase of such studies.

PMID- 15185278
TI  - Suicide in anorexia nervosa: a meta-analysis.
AB  - OBJECTIVE: Suicide is a major cause of death among subjects with anorexia
      nervosa, but the rate of suicide among this population is very often
      underestimated. We conducted a meta-analysis to compare data reported in
      representative studies of suicide in anorexia nervosa with data for the general
      population. METHOD: We searched the Index Medicus until 2002 through MedLine. We
      also searched the World Health Statistics Annual to ascertain the suicide rate in
      the age group 14-25 for specific years and country. RESULTS: We selected nine
      studies comprising 1,536 patients. Of these patients, 36 committed suicide.
      Results obtained for each study were processed together to calculate the mean
      figure for each year of suicides for 100,000 individuals suffering from anorexia
      nervosa. DISCUSSION: Our meta-analysis shows that suicide among patients with
      anorexia nervosa is more frequent when compared with the general population. All
      study analyses, except one, reported that the patients with anorexia nervosa
      committed suicide more often than their counterparts in the general population.

PMID- 15185279
TI  - Osteoporosis in Chinese patients with anorexia nervosa.
AB  - OBJECTIVE: A case-control study was conducted to determine whether bone mass is
      reduced in Chinese patients with anorexia nervosa (AN) and to study the risk
      factors for low bone mass in the same population. METHOD: Bone mineral density
      (BMD) of the lumbar spine and hip was measured by dual-energy X-ray
      absorptiometry in 42 AN patients and 221 controls. RESULTS: Patients with AN had
      a significantly lower BMD in the total hip and spine compared with controls (p
      <.001). In AN patients, linear regression showed that lowest body mass index
      (BMI) was positively associated with BMD in the hip (p = .04) whereas duration of
      illness was negatively associated with BMD in the hip (p = .05). DISCUSSION:
      Chinese patients with AN are at risk of low BMD. Duration of illness and lowest
      BMI were significant predictors of reduced BMD in Chinese patients with AN.

PMID- 15185280
TI  - Anorexia nervosa and gender identity disorder in biologic males: a report of two
      cases.
AB  - Gender identity disorder is a rare disorder of uncertain etiology. The emphasis
      on body shape in this disorder suggests that there may be an association with
      anorexia nervosa. METHOD: We report two cases of anorexia nervosa and gender
      identity disorder in biologic males who presented to an eating disorders service.
      RESULTS: One was treated successfully as an outpatient and subsequently underwent
      gender reassignment surgery. The other patient required admission and prolonged
      psychotherapy. DISCUSSION: Differences between the two cases are discussed.
      Issues of gender identity should be considered in the assessment of male patients
      presenting with anorexia nervosa.

PMID- 15185281
TI  - Acute liver damage in anorexia nervosa.
AB  - We report a case of a 26-year-old White woman with a history of anorexia nervosa
      who developed severe liver damage and multiorgan dysfunction. At admission to our
      medical unit, her body mass index (BMI) was 10.8. Biochemical evaluation showed a
      marked increase in serum levels of aspartate aminotransferases (AST = 9,980
      IU/L), alanine aminotransferase (ALT = 3,930 IU/L), amylase (1,002 IU/L), lipase
      (1,437 IU/L), creatine phosphokinase (CPK; 783 IU/L), and lactate dehydrogenase
      (LDH = 6,830 IU/L). Glomerular filtration rate was reduced (35 ml/min),
      reflecting dehydration and prerenal azotemia. No other cause of acute liver
      damage except malnutrition was evidenced. Hydration and nutritional support were
      the unique medical treatment. A rapid recovery occurred in few days and all
      laboratory data were normal at discharge after a 37-day hospitalization.

PMID- 15185282
TI  - Incidence of severe anorexia nervosa in Switzerland: 40 years of development.

PMID- 15185284
TI  - A critical role for the chimpanzee model in the study of hepatitis C.
AB  - Chimpanzees remain the only recognized animal model for the study of hepatitis C
      virus (HCV). Studies performed in chimpanzees played a critical role in the
      discovery of HCV and are continuing to play an essential role in defining the
      natural history of this important human pathogen. In the absence of a
      reproducible cell culture system, the infectivity titer of HCV challenge pools
      can be determined only in chimpanzees. Recent studies in chimpanzees have
      provided new insight into the nature of host immune responses-particularly the
      intrahepatic responses-following primary and secondary experimental HCV
      infections. The immunogenicity and efficacy of vaccine candidates against HCV can
      be tested only in chimpanzees. Finally, it would not have been possible to
      demonstrate the infectivity of infectious clones of HCV without chimpanzees.
      Chimpanzees became infected when RNA transcripts from molecular clones were
      inoculated directly into the liver. The infection generated by such transfection
      did not differ significantly from that observed in animals infected intravenously
      with wild-type HCV. The RNA inoculated into chimpanzees originated from a single
      sequence, and the animals therefore had a monoclonal HCV infection. Monoclonal
      infection simplifies studies of HCV, because virus interaction with the host is
      not confounded by the quasispecies invariably present in a natural infection. It
      furthermore permits true homologous challenge in studies of protective immunity
      and in testing the efficacy of vaccine candidates. Finally, this in vivo
      transfection system has made it possible to test for the first time the
      importance of genetic elements for HCV infectivity.

PMID- 15185285
TI  - Hepatobiliary pathophysiology study section.

PMID- 15185286
TI  - Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells.

PMID- 15185287
TI  - Infliximab and prednisolone: too much of a good thing?

PMID- 15185289
TI  - Liver transplantation: an "in vivo" model for the pathophysiology of
      hemochromatosis?

PMID- 15185290
TI  - Plasticity in the adult rat pancreas: transdifferentiation of exocrine to
      hepatocyte-like cells in primary culture.
AB  - Under certain experimental conditions, hepatocytes can arise in the pancreas. It
      has been suggested that the pancreas retains a source of hepatocyte progenitor
      cells. However, such cells have not been yet identified in the adult pancreas. We
      describe here the transdifferentiation of primary rat pancreatic exocrine cells
      into hepatocyte-like cells during 5 days of tissue culture in the presence of
      dexamethasone (DX). Using reverse-transcription polymerase chain reaction and
      immunocytochemistry, it was observed that DX treatment induced albumin RNA and
      protein expression in the cells. Coexpression of albumin and amylase, and the
      absence of cell proliferation, demonstrated a direct transdifferentiation of
      acinar cells to hepatocytic cells. CCAAT enhancer-binding protein-ss protein, a
      liver-enriched transcription factor that is considered to be the master switch in
      pancreatohepatic transdifferentiation, and alpha-fetoprotein were markedly
      upregulated in the cells after treatment with DX. We compared transcriptional
      profiles of freshly isolated exocrine cells and DX-treated cells using
      oligonucleotide microarrays and found that multiple liver-specific genes are
      induced along with albumin, and that certain pancreatic genes are downregulated
      in the DX-treated cells. In conclusion, these observations support the notion of
      plasticity in the adult pancreas and that exocrine cells can be reprogrammed to
      transdifferentiate into other cell types such as hepatocytes.

PMID- 15185288
TI  - Vascular interference: a blockade to tumor epithelial growth.

PMID- 15185291
TI  - Murine hepatocyte cell lines promote expansion and differentiation of NK cells
      from stem cell precursors.
AB  - While fetal liver is a major hematopoietic organ, normal adult liver provides a
      suitable microenvironment for a variety of immune cells and, in several
      pathological conditions, may become a site of extramedullary hematopoiesis. The
      direct influence of hepatocytes on hematopoietic cell differentiation is poorly
      understood. We have previously reported that the Met murine hepatocyte (MMH)
      untransformed hepatocytic lines retain several morphological and functional
      features of hepatocytes in vivo and are able to support the survival, self
      renewal, and differentiation of hematopoietic precursors in a cell-cell contact
      system. Here we report the effects of soluble factors released by MMH lines on
      bone marrow-derived cells. Lymphohematopoietic cells were cultured in two
      different cell contact-free systems: transwell inserts on MMH feeder layers, and
      MMH conditioned medium (MMH-CM). Both culture systems were able to promote a
      substantial expansion of bone marrow-derived cells and their differentiation to
      natural killer (NK) cells that express the NK1.1 and U5A2-13 markers. Purified
      hematopoietic stem cells (Sca-1+Lin-), either plated as a bulk population or as
      single cells, were also able to differentiate into NK cells, when cultured in MMH
      CM; thus, soluble factors secreted by MMH lines promote the expansion and
      differentiation of NK precursor cells. MMH-CM-derived NK cells are functionally
      active; stimulation by interleukin (IL)-12 together with IL-18 was required to
      induce interferon-gamma (IFNgamma) expression and to enhance their cytotoxic
      activity. In conclusion, our findings may imply a direct role of hepatocytes in
      NK cell development, and the system we have used may provide a tool for studying
      the molecular mechanisms of NK cell differentiation.

PMID- 15185292
TI  - Halting the interaction between vascular endothelial growth factor and its
      receptors attenuates liver carcinogenesis in mice.
AB  - It has been shown that angiogenesis plays an important role not only in tumor
      growth, but also in early carcinogenesis. The expression of a potent angiogenic
      factor, vascular endothelial growth factor (VEGF), increased during the early
      stage of carcinogenesis. In this study, the effects of the neutralizing
      monoclonal antibodies R1 mAb and R2 mAb of the VEGF receptors Flt-1 (VEGFR-1) and
      KDR/Flk-1 (VEGFR-2), respectively, on murine hepatocarcinogenesis induced by
      diethylnitrosamine (DEN) were examined. The effects of R1 mAb and R2 mAb on
      spontaneous lung metastasis from hepatocellular carcinoma (HCC) were also
      investigated. VEGF expression and neovascularization in the tumor increased
      stepwise during hepatocarcinogenesis. Treatment with both R1 mAb and R2 mAb
      markedly inhibited the development of HCC and adenoma in the liver. The
      inhibitory effect of R2 mAb was more potent than that of R1 mAb, and the
      combination treatment with both mAbs almost completely attenuated
      hepatocarcinogenesis. Both R1 mAb and R2 mAb treatment significantly suppressed
      the development of angiogenesis in HCC. The suppressive effects against
      angiogenesis R1 mAb and R2 mAb were similar in magnitude to their inhibitory
      effects against hepatocarcinogenesis. Furthermore, spontaneous lung metastasis
      from HCC was also significantly suppressed by R1 mAb and R2 mAb treatment. In
      conclusion, these results suggest that VEGF and receptor interaction plays an
      important role in hepatocarcinogenesis and in spontaneous lung metastasis from
      HCC.

PMID- 15185293
TI  - Effect of murine liver cell proliferation on herpes viral behavior: implications
      for oncolytic viral therapy.
AB  - Replication-competent herpes simplex oncolytic viruses are promising anticancer
      agents that partly target increased DNA synthesis in tumor cells. Investigators
      have proposed that these DNA viruses may be combined with liver resection to
      enhance killing of liver malignancies. Whether or not the cellular alterations
      associated with hepatic regeneration affect the efficacy and toxicity of these
      promising anticancer agents is unknown. This study examined the behavior of two
      oncolytic viruses, NV1020 and G207, during liver regeneration. When delivered
      during the peak of liver regeneration, replication and appearance of both G207
      and NV1020 in hepatic tissue are enhanced as demonstrated by histochemical
      staining for the marker gene lac Z, immunohistochemical staining, and
      quantitative polymerase chain reaction. This increased appearance of virus in
      liver tissue correlates with increases in cellular ribonucleotide reductase
      activity and DNA synthesis and is also associated with increased viral binding.
      However, increased viral presence is transient, and viral detection declines to
      baseline within 7 days. When these viruses were delivered to animals even as
      early as 7 days after hepatectomy, there proved to be no measurable viral
      replication in any organ and no increased morbidity or mortality. In conclusion,
      the early stages of hepatic regeneration after resection provide an environment
      suitable for viral replication. Administration of replication-competent herpes
      simplex virus during the peak of hepatocyte regeneration (24-48 hours) permits
      viral productivity in tissue that otherwise does not support viral growth. The
      increase in hepatotoxicity after hepatectomy is short-lived and can be predicted
      by peak hepatocyte DNA synthesis.

PMID- 15185294
TI  - Nitric oxide protects rat hepatocytes against reperfusion injury mediated by the
      mitochondrial permeability transition.
AB  - We investigated the effects of nitric oxide (NO) on hepatocellular killing after
      simulated ischemia/reperfusion and characterized signaling factors triggering
      cytoprotection by NO. Cultured rat hepatocytes were incubated in anoxic Krebs
      Ringer-HEPES buffer at pH 6.2 for 4 hours and reoxygenated at pH 7.4 for 2 hours.
      During reoxygenation, some hepatocytes were exposed to combinations of NO donors
      (S-nitroso-N-acetylpenicillamine [SNAP] and others), a cGMP analogue (8
      bromoguanosine-3,5-cGMP [8-Br-cGMP]), and a cGMP-dependent protein kinase
      inhibitor (KT5823). Cell viability was determined by way of propidium iodide
      fluorometry. Inner membrane permeabilization and mitochondrial depolarization
      were monitored by confocal microscopy. SNAP, but not oxidized SNAP, increased
      cGMP during reperfusion and decreased cell killing. Other NO donors and 8-Br-cGMP
      also prevented cell killing. Both guanylyl cyclase and cGMP-dependent kinase
      inhibition blocked the cytoprotection of NO. However, 5-hydroxydecanoate and
      diazoxide- mitochondrial K(ATP) channel modulators-did not affect NO-dependent
      cytoprotection or reperfusion injury. During reoxygenation, confocal microscopy
      showed mitochondrial repolarization, followed by depolarization, inner membrane
      permeabilization, and cell death. In the presence of either SNAP or 8-Br-cGMP,
      mitochondrial repolarization was sustained after reperfusion preventing inner
      membrane permeabilization and cell death. In isolated rat liver mitochondria, a
      cGMP analogue in the presence of a cytosolic extract and adenosine triphosphate
      blocked the Ca(2+)-induced mitochondrial permeability transition (MPT), an effect
      that was reversed by KT5823. In conclusion, NO prevents MPT-dependent necrotic
      killing of ischemic hepatocytes after reperfusion through a guanylyl cyclase and
      cGMP-dependent kinase signaling pathway, events that may represent the target of
      NO cytoprotection in preconditioning.

PMID- 15185295
TI  - Susceptibility of murine periportal hepatocytes to hypoxia-reoxygenation: role
      for NO and Kupffer cell-derived oxidants.
AB  - Ischemia/reperfusion (I/R) is an important problem in liver resection and
      transplantation that is associated with hepatocellular dysfunction and injury.
      This study was designed to investigate whether a difference in hepatocyte
      susceptibility occurs in the periportal (PP) and/or perivenous (PV) zones in
      response to hypoxia/reoxygenation (H/R), and to delineate the mechanisms
      underlying this susceptibility. H/R was induced in an in situ perfused mouse
      liver model with deoxygenated Krebs-Henseleit buffer followed by oxygenated
      buffer. Selective destruction of PP or PV sites was achieved by digitonin
      perfusion into the portal or inferior vena cava, and was confirmed by
      histological evaluations and zone-specific enzymes. Hepatocellular injury was
      assessed by alanine aminotransferase (ALT) release. In whole liver, H/R
      significantly increased perfusate ALT. H/R of PP-enriched zones caused ALT
      release that was similar to that of whole liver (80 + 10 vs. 70 + 12 U/mg
      protein), consistent with significant PP hepatocyte injury. Minimal ALT release
      occurred in PV zones (10 + 5 U/mg protein). Administration of N-acetyl L-cysteine
      or a chimeric superoxide dismutase (SOD)-SOD2/3, a genetically engineered SOD
      abrogated ALT release in H/R-perfused PP zones, implicating a role for superoxide
      (O(2) (-)). This elevated ALT release was attenuated by gadolinium chloride
      pretreatment, indicating that Kupffer cells are the O(2) (-) source. Enzymatic
      inhibition of cellular nitric oxide synthase (NOS) or genetic depletion of
      endothelial nitric oxide synthase (eNOS) aggravated hypoxia injury while
      exogenous NO and inducible nitric oxide synthase (iNOS) deficiency abolished
      reoxygenation injury. In conclusion, PP hepatocytes are more vulnerable to H/R;
      this injury is mediated directly or indirectly by Kupffer cell derived O(2) (-)
      and is limited by eNOS-derived NO.

PMID- 15185296
TI  - Improvement of rat liver graft quality by pifithrin-alpha-mediated inhibition of
      hepatocyte necrapoptosis.
AB  - Early graft dysfunction due to ischemia reperfusion injury remains a major
      clinical challenge in liver transplantation. Because apoptosis may contribute to
      graft dysfunction, we studied whether transient inhibition of p53 is capable of
      improving graft quality by reducing apoptotic cell death. Rat livers were
      harvested and stored for 24 hours or 48 hours in a 4 degrees C solution
      containing either pifithrin-alpha (PFT-alpha), a specific p53-inhibitor, or the
      vehicle dimethyl-sulfoxide. Storage was followed by 2-hour reperfusion with 37
      degrees C Krebs-Henseleit buffer in an isolated liver perfusion system. Besides
      caspase-3 activation, apoptosis was quantified using fluorescence microscopy and
      hematoxylin-eosin histology. Trypan blue allowed for assessment of cell membrane
      damage, indicating both secondary apoptosis and primary necrosis. Bile flow,
      oxygen consumption, K(+)-excretion and enzyme release served as indicators of
      overall graft quality. Upon 2-hour reperfusion, livers developed procaspase
      activation as well as a mixture of apoptotic and necrotic cell death,
      representing necrapoptosis. In livers that had been stored for 48 hours,
      necrapoptotic injury was more pronounced compared with that after 24-hour
      storage. PFT-alpha effectively attenuated caspase activation as well as
      hepatocellular apoptosis and necrosis. Attenuation of both modes of cell death by
      PFT-alpha was associated with improved liver function, metabolism, and integrity.
      Experiments with the caspase inhibitor z-VAD-fmk confirmed that apoptosis is one
      mode of cell death in cold ischemia reperfusion. In conclusion, inhibition of p53
      dependent apoptosis by PFT-alpha reduces hepatic preservation-reperfusion injury
      and improves primary organ function and metabolism. Fortification of the
      preservation solution with PFT-alpha may represent a promising and easily
      applicable approach to mitigate reperfusion injury in liver transplants.

PMID- 15185297
TI  - Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced
      apoptosis via activation of survival pathways.
AB  - Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver
      diseases, but its mechanism of action is not yet well defined. The aim of this
      study was to explore the protective mechanisms of the taurine-conjugate of UDCA
      (tauroursodeoxycholic acid [TUDCA]) against glycochenodeoxycholic acid (GCDCA)
      induced apoptosis in primary cultures of rat hepatocytes. Hepatocytes were
      exposed to GCDCA, TUDCA, the glyco-conjugate of UDCA (GUDCA), and TCDCA. The
      phosphatidylinositol-3 kinase pathway (PI3K) and nuclear factor-kappaB were
      inhibited using LY 294002 and adenoviral overexpression of dominant-negative
      IkappaB, respectively. The role of p38 and extracellular signal-regulated protein
      kinase mitogen-activated protein kinase (MAPK) pathways were investigated using
      the inhibitors SB 203580 and U0 126 and Western blot analysis. Transcription was
      blocked by actinomycin-D. Apoptosis was determined by measuring caspase-3, -9,
      and -8 activity using fluorimetric enzyme detection, Western blot analysis,
      immunocytochemistry, and nuclear morphological analysis. Our results demonstrated
      that uptake of GCDCA is needed for apoptosis induction. TUDCA, but not TCDCA and
      GUDCA, rapidly inhibited, but did not delay, apoptosis at all time points tested.
      However, the protective effect of TUDCA was independent of its inhibition of
      caspase-8. Up to 6 hours of preincubation with TUDCA before addition of GCDCA
      clearly decreased GCDCA-induced apoptosis. At up to 1.5 hours after exposure with
      GCDCA, the addition of TUDCA was still protective. This protection was dependent
      on activation of p38, ERK MAPK, and PI3K pathways, but independent of competition
      on the cell membrane, NF-kappaB activation, and transcription. In conclusion,
      TUDCA contributes to the protection against GCDCA-induced mitochondria-controlled
      apoptosis by activating survival pathways.

PMID- 15185298
TI  - Interleukin-1beta represses MRP2 gene expression through inactivation of
      interferon regulatory factor 3 in HepG2 cells.
AB  - The human multidrug resistance protein 2 (MRP2/ABCC2), expressed on the bile
      canalicular membrane, mediates the multispecific efflux of several organic
      anions, including conjugates of glucuronate, sulfate, and glutathione. Expression
      of MRP2 can be altered in response to environmental stimuli such as cholestasis
      and jaundice. We previously reported that MRP2 mRNA expression levels are
      decreased in the nontumorous part of hepatitis C virus-infected human liver
      tissues, and that inflammatory cytokines inhibit MRP2 expression in human hepatic
      (HepG2) cells. We investigated the molecular mechanisms by which inflammatory
      cytokines modulate MRP2 gene expression in hepatic cells. Treatment of human
      hepatic cells with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha
      resulted in a decrease in the protein and mRNA levels of MRP2. IL-1beta inhibited
      the transcriptional activity of MRP2 promoter constructs by 40%, and this
      inhibition of MRP2 promoter activity was mediated through the interferon
      stimulatory response element (ISRE). Electrophoretic mobility shift assays with
      IL-1beta-treated nuclear extracts showed a decrease in the formation of DNA
      protein complexes, specifically those including interferon regulatory factor 3
      (IRF3). Expression of recombinant human IRF3 increased MRP2 promoter activity.
      Treatment with a specific extracellular signal-regulated kinase inhibitor
      relieved IL-1beta-induced MRP2 mRNA downregulation and abrogated the binding of
      IRF3 to the ISRE element. In conclusion, IL-1beta induces downregulation of the
      MRP2 gene by inactivating IRF3 binding to ISRE on the MRP2 promoter in human
      hepatic cells; this inactivation is accomplished via interference with the
      extracellular signal-regulated kinase pathway.

PMID- 15185299
TI  - Covalent modification as a mechanism for the breakdown of immune tolerance to
      pyruvate dehydrogenase complex in the mouse.
AB  - The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by
      the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex
      (PDC). How tolerance is broken to such a central and highly conserved self
      antigen in the initiation of autoimmunity remains unclear. One postulated
      mechanism is that reactivity arises to an altered form of self antigen with
      subsequent cross-reactivity to native self. In this murine study, we set out to
      examine whether sensitization with a covalently modified form of self PDC can
      give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC
      seen in PBC patients. The notion that altered self can lead to tolerance
      breakdown was studied by sensitizing SJL/J mice with a covalently modified
      (biotinylated) preparation of self murine PDC (mP/O-B). Subsequently, antibody
      and T-cell reactivities to unmodified self mP/O were studied. Sensitization with
      mP/O-B elicited high-titre, high-affinity antibody responses reactive with both
      the mP/O-B immunogen and, importantly, native mP/O. In addition, significant MHC
      class II restricted splenic T-cell responses to native mP/O (i.e., true
      autoimmune responses) were seen in mP/O-B sensitized animals. The breakdown of T
      cell self tolerance to mP/O was not seen in animals sensitized with irrelevant
      biotinylated antigens. In conclusion, this study provides evidence to support the
      concept that exposure to covalently modified self PDC can, in the correct
      proimmune environment, replicate the full breakdown of B-cell and T-cell immune
      tolerance to PDC seen in PBC. One potential etiological pathway in PBC therefore
      could be the breakdown of tolerance to self PDC occurring after exposure to self
      antigen covalently modified in the metabolically active environment of the liver.

PMID- 15185300
TI  - The role of endothelin-1 and the endothelin B receptor in the pathogenesis of
      hepatopulmonary syndrome in the rat.
AB  - Endothelin-1 (ET-1) stimulation of endothelial nitric oxide synthase (eNOS) via
      pulmonary endothelial endothelin B (ET(B)) receptors and pulmonary intravascular
      macrophage accumulation with expression of inducible nitric oxide synthase (iNOS)
      and heme oxygenase-1 (HO-1) are implicated in experimental hepatopulmonary
      syndrome (HPS) after common bile duct ligation (CBDL). Our aim was to evaluate
      the role of ET-1 in the development of experimental HPS. The time course of
      molecular and physiological changes of HPS and the effects of selective
      endothelin receptor antagonists in vivo were assessed after CBDL. Effects of ET-1
      on intralobar pulmonary vascular segment reactivity and on eNOS expression and
      activity in rat pulmonary microvascular endothelial cells (RPMVECs) were also
      evaluated. Hepatic and plasma ET-1 levels increased 1 week after CBDL in
      association with a subsequent increase in pulmonary microvascular eNOS and ET(B)
      receptor levels and the onset of HPS. Selective ET(B) receptor inhibition in vivo
      significantly decreased pulmonary eNOS and ET(B) receptor levels and ameliorated
      HPS. CBDL pulmonary artery segments had markedly increased ET(B) receptor
      mediated, nitric oxide dependent vasodilatory responses to ET-1 compared with
      controls and ET-1 triggered an ET(B) receptor dependent stimulation of eNOS in
      RPMVECs. Pulmonary intravascular macrophages also accumulated after CBDL and
      expressed HO-1 and iNOS at 3 weeks. Selective ET(B) receptor blockade also
      decreased macrophage accumulation and iNOS production. In conclusion, ET-1 plays
      a central role in modulating pulmonary micovascular tone in experimental HPS.

PMID- 15185301
TI  - HLA class II genotype influences the type of liver injury in drug-induced
      idiosyncratic liver disease.
AB  - Drug-induced idiosyncratic liver disease (DIILD) depends largely on host
      susceptibility factors. Small studies support the genetic influence of human
      leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We
      sought associations between HLA-DRB and -DQB alleles and DIILD considered
      collectively or according to the biochemical expression of liver damage. We
      studied a total of 140 patients with a definitive or probable diagnosis of DIILD,
      as assessed with the Council for International Organizations of Medical Sciences
      scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA
      DRB1* and -DQB1* genotyping was performed by hybridization with sequence-specific
      oligonucleotides after genomic amplification. The group with DIILD did not differ
      from control subjects with regard to the distribution of HLA-DRB and -DQB
      antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P
      =.002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P =.001; OR 2.32) were
      significantly increased in patients with the cholestatic/mixed type of liver
      damage in comparison to healthy subjects. By contrast, frequencies of alleles
      DRB1*07 (16.9% vs. 35.4%; P =.003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P
      =.0003; OR 0.39) were significantly decreased. In conclusion, there is no
      association between any specific HLA allele and the propensity to develop DIILD.
      However, the genetic influence associated with HLA class II alleles appears to
      play a role in the biochemical expression of liver injury in cholestatic/mixed
      hepatotoxicity and may explain why a given drug may cause different patterns of
      liver damage.

PMID- 15185302
TI  - Effects of dilutional hyponatremia on brain organic osmolytes and water content
      in patients with cirrhosis.
AB  - In advanced cirrhosis there is a reduction in the brain concentration of many
      organic osmolytes, particularly myo-inositol (MI). Hyponatremia could
      theoretically aggravate these changes as a result of hypo-osmolality of the
      extracellular fluid. The aim of this study was to determine the effects of
      hyponatremia on brain organic osmolytes and brain water content in cirrhosis.
      Brain organic osmolytes, measured by (1)H-magnetic resonance spectroscopy, and
      brain water content, as estimated by magnetization transfer ratio (MTR) and
      measurement of brain volume were determined in 14 patients with dilutional
      hyponatremia, 10 patients without hyponatremia, and eight healthy subjects.
      Patients with hyponatremia had remarkable lower levels of MI compared with values
      in nonhyponatremic patients and healthy subjects. Brain MI levels correlated
      directly with serum sodium and osmolality. Serum sodium was the only independent
      predictor of low brain MI levels. Serum sodium also correlated directly with
      other brain organic osmolytes, such as choline-containing compounds,
      creatine/phosphocreatine, and N-acetyl-aspartate. By contrast, brain
      glutamine/glutamate levels were higher in patients with cirrhosis compared with
      values in healthy subjects and correlated with plasma ammonia levels but not with
      serum sodium or osmolality. No significant differences were found in MTR values
      and cerebral volumes between patients with and without hyponatremia. In
      conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable
      reductions in brain organic osmolytes that probably reflect compensatory
      osmoregulatory mechanisms against cell swelling triggered by a combination of
      high intracellular glutamine and low extracellular osmolality. These findings may
      be relevant to the pathogenesis of encephalopathy in hyponatremic patients.

PMID- 15185303
TI  - Sustained rise of portal pressure after sclerotherapy, but not band ligation, in
      acute variceal bleeding in cirrhosis.
AB  - During variceal bleeding, several factors may increase portal pressure, which in
      turn may precipitate further bleeding. This study investigates the early effects
      of endoscopic injection sclerotherapy (EIS) and endoscopic band ligation (EBL) on
      hepatic venous pressure gradient (HVPG) during acute bleeding and the possible
      influence in outcome. In 50 cirrhotic patients with bleeding esophageal varices
      treated with EIS (n = 25) or EBL (n = 25), we performed repeated HVPG
      measurements before and immediately after endoscopic treatment (time 0) and every
      24 hours for a 5-day period. Endotherapy was continued until the varices were too
      small for further treatment. Both groups were comparable with regard to age,
      gender, Child-Turcotte-Pugh grade, and HVPG. In the EBL and EIS groups, a
      significant (P <.0001) increase was observed in mean portal pressure (20.7 mm Hg
      +/- 4.4 SD and 21.5 mm Hg +/- 4.5 SD, respectively) immediately after treatment
      (time 0) as compared with pretreatment (18.1 +/- 4.5 and 18.1 +/- 4.0). However,
      HVPG in the EBL group returned to baseline values within 48 hours after
      treatment, while in the EIS group it remained high during the 120-hour study
      period (P <.0001). Bleeding stopped in all patients after endotherapy. During the
      42-day follow-up period, the rebleeding rate over time was lower in the EBL group
      compared with the EIS group (P =.024). Patients with an initial HVPG greater than
      16 mm Hg had, despite endoscopic treatment, a significantly higher likelihood of
      death (P =.024) and overall failure (P =.037) [correction]. In conclusion, during
      acute variceal bleeding EIS, but not EBL, causes a sustained increase in HVPG,
      which is followed by a higher rebleeding rate.

PMID- 15185304
TI  - Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis.
AB  - Hepatic fibrosis and cirrhosis are possible consequences of corticosteroid
      treated autoimmune hepatitis. Our aims were to determine the frequency of
      progressive fibrosis and the factors associated with this progression. Two
      hundred seventy-seven liver tissue specimens that had been obtained from 73
      patients were interpreted in batch under code by a single pathologist. Fibrosis
      scores and histological activity indices were determined using the Ishak scoring
      system, and worsening fibrosis scores were correlated with clinical features,
      laboratory findings, and treatment responses. Fibrosis scores increased (2.3 +/-
      0.4 points to 4.2 +/- 0.4 points; P <.0001) in 18 patients (25%) during 79 +/- 13
      months. Only five patients (7%) developed cirrhosis, and 55 patients (75%) had
      stable (16 patients) or decreased (39 patients) fibrosis scores. Human leukocyte
      antigen (HLA) DR3/DR4 occurred more frequently in patients with progressive
      fibrosis than others (23% vs. 2%; P =.03). Patients with progressive fibrosis had
      higher histological activity indices at last follow-up than patients with stable
      or reduced fibrosis (3.2 +/- 0.7 vs. 1.7 +/- 0.2; P =.01), and these indices
      worsened more commonly during therapy (17% vs. 2%, P =.04). Relapse, treatment
      failure, and incomplete response did not affect progression of fibrosis. In
      conclusion, fibrosis progresses in only a minority of patients during
      corticosteroid therapy. Progression is associated with HLA DR3/DR4 and worsening
      histological activity. Exacerbations or persistence of disease activity does not
      increase disease progression after treatment has been instituted.

PMID- 15185305
TI  - Prediction of liver fibrosis in patients with features of the metabolic syndrome
      regardless of alcohol consumption.
AB  - The aim of this study was to determine noninvasive predictive factors of
      significant liver fibrosis in patients with increased serum aminotransferases
      associated with features of metabolic syndrome (abdominal obesity, systemic
      hypertension, fasting hyperglycemia, and dyslipidemia). One hundred seventy-three
      patients were prospectively examined, regardless of alcohol consumption.
      Biometric, metabolic, and hepatic biochemical variables were tested for
      association with fibrosis assessed on liver biopsy according to the Metavir score
      system. Significant fibrosis, defined as Metavir scores F2, F3, or F4, was
      observed in 42 of 173 patients (24%). A logistic regression model and receiver
      operating characteristic curve were used to construct a simple index predictive
      of significant fibrosis. None of the patients with serum hyaluronate levels of 35
      microg/L or less had significant fibrosis. In patients with serum hyaluronate
      levels >35 microg/L, no case of fibrosis stage F3 or F4 was found when serum
      carbohydrate-deficient transferrin/transferrin ratio was less than 0.9. In
      conclusion, in patients with increased serum aminotransferases associated with
      features of metabolic syndrome, a simple algorithm, including serum hyaluronate
      and serum carbohydrate-deficient transferrin/transferrin ratio, allows the
      exclusion of clinically relevant hepatic fibrosis, regardless of current or past
      alcohol consumption.

PMID- 15185306
TI  - Nonalcoholic fatty liver disease: Improvement in liver histological analysis with
      weight loss.
AB  - The effect of significant weight loss on nonalcoholic fatty liver disease remains
      unclear. In this case series of 36 selected obese patients, we examined the
      effect of weight loss on nonalcoholic fatty liver disease, including nonalcoholic
      steatohepatitis (NASH) and hepatic fibrosis. These 36 patients (11 males, 25
      females) had paired liver biopsies, the first at the time of laparoscopic
      adjustable gastric band placement and the second after weight loss. Second
      biopsies were obtained from two groups: those requiring a subsequent laparoscopic
      procedure (n = 19) and those with index biopsy score of 2 or greater for zone 3
      centric hepatic fibrosis (n = 17). All biopsies were scored, blinded to the
      patient's identity and clinical condition, for individual histological features
      and for NASH stage and grade. Initial biopsies demonstrated NASH in 23 patients
      and steatosis in 12 patients. Repeat biopsies were taken at 25.6 +/- 10 months
      (range, 9-51 months) after band placement. Mean weight loss was 34.0 +/- 17 kg,
      and percentage of excess weight loss was 52 +/- 17%. There were major
      improvements in lobular steatosis, necroinflammatory changes, and fibrosis at the
      second biopsy (P <.001 for all). Portal abnormalities remained unchanged. Only
      four of the repeat biopsies fulfilled the criteria for NASH. There were 18
      patients with an initial fibrosis score of 2 or more compared with 3 patients at
      follow-up (P <.001). Those with the metabolic syndrome (n = 23) had more
      extensive changes before surgery and greater improvement with weight loss. In
      conclusion, weight loss after surgery provides major improvement or resolution of
      obesity and metabolic syndrome-associated abnormal liver histological features in
      severely obese subjects.

PMID- 15185307
TI  - Patient and graft survival after liver transplantation for hereditary
      hemochromatosis: Implications for pathogenesis.
AB  - The clinical outcome of patients who have undergone liver transplantation for
      hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is
      unclear. We reviewed 3,600 adult primary orthotopic liver transplants and
      assessed the outcomes in 22 patients with HH. We also evaluated graft function
      and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22
      subjects who received liver transplants for HH were male; 13 had other risk
      factors for liver disease. HH patients had comparatively poor outcomes following
      transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%,
      and 55%, respectively. Recurrent hepatocellular cancer was the most common cause
      of death. There was no convincing evidence of reaccumulation of iron in the
      grafted liver in HH; however, 1 subject demonstrated increased serum ferritin
      concentration and grade 2 hepatic siderosis. Liver iron stores were slow to
      mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had
      appropriate early graft function, but 2 patients with heavy iron loading and
      increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an
      uncommon indication for liver transplantation, and the majority of patients
      requiring transplantation had other risk factors for chronic liver disease; (2)
      reaccumulation of liver iron in HH patients is very unusual, but increased iron
      stores may be slow to mobilize in normal recipients of iron-loaded grafts,
      potentially compromising late graft function; (3) post-liver transplant survival
      is reduced in HH, and affected patients require careful clinical evaluation of
      perioperative and postoperative risk factors. Our data suggest that iron excess
      in HH does not wholly depend on intestinal iron absorption but is also influenced
      by liver factors that moderate iron metabolism.

PMID- 15185308
TI  - Oxidative damage is increased in human liver tissue adjacent to hepatocellular
      carcinoma.
AB  - Accumulation of genetic alterations in hepatocarcinogenesis is closely associated
      with chronic inflammatory liver disease. 8-oxo-2'-deoxyguanosine (8-oxo-dG), the
      major promutagenic DNA adduct caused by reactive oxygen species (ROS), leads to
      G:C --> T:A transversions. These lesions can be enzymatically repaired mainly by
      human MutT homolog 1 (hMTH1), human 8-oxo-guanine DNA glycosylase (hOGG1) and
      human MutY homolog (hMYH). The aim of this study was to evaluate the extent of
      oxidative damage and its dependence on the cellular antioxidative capacity and
      the expression of specific DNA repair enzymes in tumor (tu) and corresponding
      adjacent nontumor (ntu) liver tissue of 23 patients with histologically confirmed
      hepatocellular carcinoma. 8-oxo-dG levels, as detected by high-pressure liquid
      chromatography with electrochemical detection, were significantly (P =.003)
      elevated in ntu tissue (median, 129 fmol/microg DNA) as compared to tu tissue
      (median, 52 fmol/microg DNA), and were closely associated with inflammatory
      infiltration. In ntu tissue, the hepatic iron concentration and malondialdehyde
      levels were significantly (P =.001) higher as compared to tu tissue. Glutathione
      content, glutathione peroxidase activity and manganese superoxide dismutase
      messenger RNA (mRNA) expression did not show statistical differences between ntu
      and tu tissue. Real-time reverse transcription polymerase chain reaction revealed
      in tu tissue significantly (P =.014) higher hMTH1 mRNA expression compared to ntu
      tissue. In contrast, hMYH mRNA expression was significantly (P <.05) higher in
      ntu tissue. No difference in hOGG1 mRNA expression was seen between tu and ntu.
      In conclusion, these data suggest that ROS generated by chronic inflammation
      contribute to human hepatocarcinogenesis. The role of DNA repair enzymes appears
      to be of reactive rather than causative manner.

PMID- 15185309
TI  - Endogenous ursodeoxycholic acid and cholic acid in liver disease due to cystic
      fibrosis.
AB  - Focal biliary cirrhosis causes significant morbidity and mortality in cystic
      fibrosis (CF). Although the mechanisms of pathogenesis remain unclear, bile acids
      have been proposed as potential mediators of liver injury. This study examined
      bile acid composition in CF and assessed altered bile acid profiles to determine
      if they are associated with incidence and progression of liver injury in CF
      associated liver disease (CFLD). Bile acid composition was determined by gas
      liquid chromatography/mass spectrometry in bile, urine, and serum samples from 30
      children with CFLD, 15 children with CF but without liver disease (CFnoLD), and
      43 controls. Liver biopsies from 29 CFLD subjects were assessed histologically by
      grading for fibrosis stage, inflammation, and disruption of the limiting plate. A
      significantly greater proportion of endogenous biliary ursodeoxycholic acid
      (UDCA) was demonstrated in CFnoLD subjects vs. both CFLD subjects and controls
      (2.4- and 2.2-fold, respectively; ANOVA, P =.04), and a 3-4 fold elevation in
      endogenous serum UDCA concentration was observed in both CFLD subjects and CFnoLD
      subjects vs. controls (ANOVA, P <.05). In CFLD, there were significant
      correlations between serum cholic acid and hepatic fibrosis, inflammation, and
      limiting plate disruption as well as the ratio of serum cholic
      acid/chenodeoxycholic acid to hepatic fibrosis, inflammation, and limiting plate
      disruption. In conclusion, elevated endogenous UDCA in CFnoLD suggests a possible
      protective role against liver injury in these patients. The correlation between
      both cholic acid and cholic acid/chenodeoxycholic acid levels with histological
      liver injury and fibrosis progression suggests a potential monitoring role for
      these bile acids in CFLD.

PMID- 15185310
TI  - Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin
      signaling in hepatoma cells.
AB  - Wnt/beta-catenin signaling contributes to diverse cellular functions, such as
      Drosophila wing development and colon carcinogenesis. Recently, stabilizing
      mutations of beta-catenin, a hallmark of Wnt signaling, were documented in
      significant numbers of primary hepatocellular carcinomas (HCC). However, whether
      the beta-catenin mutation leads to the activation of Wnt/beta-catenin signaling
      in hepatoma cells has not been established. We found that Wnt/beta-catenin
      signaling could be activated by ectopic expression of Wnt-1 in some hepatoma
      cells, such as Hep3B and PLC/PRF/5 cells, but not in others, such as Huh7 and
      Chang cells. Importantly, we noted that the former were derived from hepatitis B
      virus (HBV)-infected livers, whereas the latter were derived from HBV-negative
      livers. It was then speculated that HBx, a viral regulatory protein of HBV, is
      involved in activating Wnt/beta-catenin signaling in hepatoma cells. In agreement
      with this notion, ectopic expression of HBx along with Wnt-1 activated Wnt/beta
      catenin signaling in Huh7 cells by stabilizing cytoplasmic beta-catenin. Further,
      we showed that such stabilization of beta-catenin by HBx was achieved by
      suppressing glycogen synthase kinase 3 activity via the activation of Src kinase.
      In conclusion, the data suggest that Wnt-1 is necessary but insufficient to
      activate Wnt/beta-catenin signaling in hepatoma cells and the enhanced
      stabilization of beta-catenin by HBx, in addition to Wnt-1, is essential for the
      activation of Wnt/beta-catenin signaling in hepatoma cells.

PMID- 15185311
TI  - HBsAg seroclearance in chronic hepatitis B in the Chinese: virological,
      histological, and clinical aspects.
AB  - Few studies have examined Chinese patients with chronic hepatitis B who exhibit
      hepatitis B surface antigen (HBsAg) seroclearance. We comprehensively studied the
      biochemical, virological, histological, and clinical aspects of 92 patients with
      HBsAg seroclearance (median follow-up, 126 months). Ninety-two HBsAg-positive
      controls matched for age, sex, and duration of follow-up were also recruited.
      Liver biochemistry, serum hepatitis B virus (HBV) DNA levels, and development of
      clinical complications were monitored. Intrahepatic total and covalently closed
      circular (ccc) HBV DNA were measured quantitatively in 16 patients. HBV genotype
      was determined in 30 patients. The mean age at HBsAg seroclearance was 48.8 (+
      13.81) years. There was a significant improvement in serum alanine
      aminotransferase levels after HBsAg seroclearance (p<0.0001). Patients with
      genotype B had a higher chance of HBsAg seroclearance than those with genotype C
      (P =.014). Ninety-eight percent of patients had undetectable serum HBV DNA.
      Thirty-seven percent of patients had low titer of intrahepatic HBV DNA, mainly in
      the form of cccDNA (71%-100%). All 14 patients with liver biopsies had near
      normal histology. There was no difference in the risk of development of
      hepatocellular carcinoma (HCC) between patients with and without HBsAg
      seroclearance. However, the mean age of HBsAg seroclearance was significantly
      older in patients with HCC than in patients without HCC (P =.016). In conclusion,
      patients with HBsAg seroclearance had favorable biochemical, virological, and
      histological parameters. Intrahepatic HBV DNA level was low and predominantly in
      the form of cccDNA. However, HCC could still develop, particularly in patients
      with cirrhosis who had HBsAg seroclearance at an older age.

PMID- 15185312
TI  - Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with
      chronic HCV genotype 1.
AB  - Black Americans (blacks) have a high prevalence of chronic hepatitis C virus
      (HCV) infection and respond poorly to therapy with interferon alfa-based
      regimens, but they have been underrepresented in clinical trials. The aim of this
      study was to assess the rate of sustained virological response (SVR) to
      peginterferon alfa-2a (40 kd) in combination with ribavirin in black patients
      chronically infected with HCV genotype 1. In a prospective, multicenter, open
      label trial, 78 black and 28 white American interferon-naive patients were
      enrolled to receive once weekly subcutaneous injections of 180 microg
      peginterferon alfa-2a plus oral ribavirin (1000 mg/d for patients weighing less
      than 75 kg and 1200 mg/d for patients weighing 75 kg or more) for 48 weeks. Pre-
      and post-treatment liver biopsies were evaluated for necroinflammation and
      fibrosis. SVR, defined as undetectable (<50 IU/mL) HCV RNA, was 26% in the black
      group and 39% in the white group. Although the SVR rate was lower in blacks than
      in whites, the SVR of 26% represents an improvement over previously reported SVR
      rates from smaller, retrospective studies of black patients. We also observed
      improvement in fibrosis in 25% of the black patients. No unexpected adverse
      events occurred. In conclusion, this prospective study evaluating responses of
      black patients with chronic hepatitis C to peginterferon alfa-2a/ribavirin has
      demonstrated that treatment can be safely offered to such individuals with
      reasonable antiviral and histological benefit.

PMID- 15185313
TI  - Hepatitis C virus kinetics and host responses associated with disease and outcome
      of infection in chimpanzees.
AB  - To study determinants of clinical outcome following HCV infection, viral
      kinetics, immune events, and intrahepatic cytokine markers were compared in 10
      naive chimpanzees. Four of the animals cleared HCV; 6 developed persistent
      infections. All animals developed similar acute infections with increasing
      viremia from 1 to 2 weeks, followed by alanine aminotransferase (ALT) elevations
      and seroconversion. This viremia pattern consisted of a biphasic increase, a
      rapid slope (mean doubling time [t(2)] = 0.5 days) followed by a slower slope
      after the second week (t(2) = 7.5 days). This slowing of virus replication
      correlated in all animals with increased intrahepatic 2'5' oligoadenylate
      synthetase 1 (2OAS-1) messenger RNA (mRNA) levels and was independent of disease
      outcome. An effective control of virus replication was observed following
      increases in intrahepatic interferon gamma (IFN-gamma) mRNA and ALT levels.
      Although this control was associated in all animals with a 2-log decrease in
      virus titer, the timing occurred approximately 2 weeks later in the chronic group
      (P <.05). Additionally, while cleared infections were characterized by a
      continual decrease in virus titer, the titers in the persistent infections
      reached a steady state level of 10(4) to 10(5) RNA copies/mL. This inability of
      the immune response to sustain viral clearance in the persistent infections was
      associated with a reduced intrahepatic CD3e and monocyte-induced protein 1alpha
      (MIP-1alpha) mRNA induction. In conclusion, these data indicate that, regardless
      of outcome, chimpanzees generate responses that control HCV replication during
      the early and late acute phase. However, the pathogenesis of HCV may be
      determined by a more rapid onset of the induced response and the cell population
      that migrates to the liver.

PMID- 15185314
TI  - Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C
      virus-specific T cell response kinetics.
AB  - Pegylated interferon alpha (PEG IFN-alpha) improves sustained virological
      response rates in chronic hepatitis C, but neither its role in acute hepatitis C
      nor the biologic basis for its action has been defined. This prospective study
      assessed the efficacy of PEG IFN-alpha treatment in acute hepatitis C in relation
      to the kinetics of hepatitis C virus (HCV)-specific CD4(+) T cell responses
      during therapy and follow-up. Forty subjects with proven acute hepatitis C who
      received either PEG IFN-alpha plus ribavirin (n = 20) or PEG IFN-alpha
      monotherapy (n = 20) for 24 weeks in addition to 14 untreated subjects with acute
      hepatitis C were prospectively followed. Serum HCV RNA, HCV-specific CD4(+) T
      cell responses, and cytokine production were measured before and during therapy
      and at follow-up and correlated to the outcome. The sustained virological
      response rate was 85% with PEG IFN-alpha/ribavirin combination and 80% with PEG
      IFN-alpha monotherapy. Five untreated subjects had spontaneous recovery. The
      frequency, magnitude, and breadth of HCV-specific CD4(+) T helper 1 responses
      were significantly higher in treated subjects compared with untreated subjects
      with self-limited disease or subjects with chronic evolution. The CD4(+) T cell
      responses were maintained in subjects with sustained virological responses and
      self-limited disease but fluctuated in those who developed chronic infection. In
      conclusion, PEG IFN-alpha therapy in acute hepatitis induces high rates of
      sustained virological response and prevents choronicity, probably through
      efficient early stimulation of multispecific HCV-specific CD4(+) T helper 1
      responses.

PMID- 15185315
TI  - DDB treatment of patients with chronic hepatitis.
AB  - We report 13 patients (10 with chronic hepatitis C, 1 with chronic hepatitis B, 2
      with nonalcoholic steatohepatitis) with persistently elevated alanine
      aminotransferase (ALT) levels who were treated with dimethyl-4,4'-dimethoxy
      5,6,5',6-dimethylenedioxybiphenyl-2,2' dicarboxylate (DDB). ALT rapidly
      normalized in 12/13 patients and remained normal during treatment. Unlike ALT
      levels, aspartate aminotransferase, gamma-glutamyl transferase and glutamate
      dehydrogenase levels were not affected. Furthermore, there was no beneficial
      effect on the histological grade and stage of liver disease. In vitro experiments
      with hepatocytes resulted in a significant decrease of hepatocellular ALT levels
      in the DDB treated cells, suggesting, that DDB affects the synthesis and/or
      degradation of ALT in liver cells. In conclusion, the normalization of ALT during
      DDB treatment does not indicate therapeutic efficacy. In view of the wide use of
      DDB in patients with chronic liver diseases who participate in clinical studies
      DDB use should be excluded.

PMID- 15185316
TI  - Overdependence on the host-an Achilles' heel of HCV?

PMID- 15185317
TI  - Tracking cccDNA in chronic HBV infection.

PMID- 15185318
TI  - Nomenclature of the finer branches of the biliary tree: canals, ductules, and
      ductular reactions in human livers.
AB  - The work of liver stem cell biologists, largely carried out in rodent models, has
      now started to manifest in human investigations and applications. We can now
      recognize complex regenerative processes in tissue specimens that had only been
      suspected for decades, but we also struggle to describe what we see in human
      tissues in a way that takes into account the findings from the animal
      investigations, using a language derived from species not, in fact, so much like
      our own. This international group of liver pathologists and hepatologists, most
      of whom are actively engaged in both clinical work and scientific research, seeks
      to arrive at a consensus on nomenclature for normal human livers and human
      reactive lesions that can facilitate more rapid advancement of our field.

PMID- 15185319
TI  - Monitoring of HVPG during pharmacological therapy: evidence in favor of the
      prognostic value of a 20% reduction.

PMID- 15185321
TI  - Relative contribution of iron burden, HFE mutations, and insulin resistance to
      fibrosis in nonalcoholic fatty liver.

PMID- 15185323
TI  - Try, try, try again . . . and again.

PMID- 15185324
TI  - Development of the force field parameters for phosphoimidazole and
      phosphohistidine.
AB  - Phosphorylation of histidine-containing proteins is a key step in the mechanism
      of many phosphate transfer enzymes (kinases, phosphatases) and is the first stage
      in a wide variety of signal transduction cascades in bacteria, yeast, higher
      plants, and mammals. Studies of structural and dynamical aspects of such enzymes
      in the phosphorylated intermediate states are important for understanding the
      intimate molecular mechanisms of their functioning. Such information may be
      obtained via molecular dynamics and/or docking simulations, but in this case
      appropriate force field parameters for phosphohistidine should be explicitly
      defined. In the present article we describe development of the GROMOS96 force
      field parameters for phosphoimidazole molecule--a realistic model of the
      phosphohistidine side chain. The parameterization is based on the results of ab
      initio quantum chemical calculations with subsequent refinement and testing using
      molecular mechanics and molecular dynamics simulations. The set of force
      constants and equilibrium geometry is employed to derive force field for the
      phosphohistidine moiety. Resulting parameters and topology are incorporated into
      the molecular modeling package GROMACS and used in molecular dynamics simulations
      of a phosphohistidine-containing protein in explicit solvent.

PMID- 15185325
TI  - Accuracy of free energies of hydration using CM1 and CM3 atomic charges.
AB  - Absolute free energies of hydration (DeltaGhyd) have been computed for 25 diverse
      organic molecules using partial atomic charges derived from AM1 and PM3 wave
      functions via the CM1 and CM3 procedures of Cramer, Truhlar, and coworkers.
      Comparisons are made with results using charges fit to the electrostatic
      potential surface (EPS) from ab initio 6-31G* wave functions and from the OPLS-AA
      force field. OPLS Lennard-Jones parameters for the organic molecules were used
      together with the TIP4P water model in Monte Carlo simulations with free energy
      perturbation theory. Absolute free energies of hydration were computed for OPLS
      united-atom and all-atom methane by annihilating the solutes in water and in the
      gas phase, and absolute DeltaGhyd values for all other molecules were computed
      via transformation to one of these references. Optimal charge scaling factors
      were determined by minimizing the unsigned average error between experimental and
      calculated hydration free energies. The PM3-based charge models do not lead to
      lower average errors than obtained with the EPS charges for the subset of 13
      molecules in the original study. However, improvement is obtained by scaling the
      CM1A partial charges by 1.14 and the CM3A charges by 1.15, which leads to average
      errors of 1.0 and 1.1 kcal/mol for the full set of 25 molecules. The scaled CM1A
      charges also yield the best results for the hydration of amides including the E/Z
      free-energy difference for N-methylacetamide in water.

PMID- 15185326
TI  - Assessing the reliability of density functional methods in the conformational
      study of polypeptides: the treatment of intraresidue nonbonding interactions.
AB  - The role of intraresidue interactions in determining the conformational behavior
      of polypeptides is analyzed by means of density functional and post-Hartree-Fock
      computations on the alanine dipeptide analog and other model compounds. Our
      computations show that the accuracy of current density functionals is sufficient
      for H-bond, electrostatic, inductive, and short-range repulsive interactions,
      whereas medium-range attractions between electron-rich atoms and/or bonds are
      underestimated. This leads, in turn, to an underestimation of the stability of
      helical structures w.r.t. extended or folded conformers involving H-bonds. Those
      results could pave the route for devising local ad hoc corrections able to
      significantly improve structural and dynamic predictions for polypeptides issuing
      from DFT computations.

PMID- 15185327
TI  - Basis set effects on calculated geometries: 6-311++G** vs. aug-cc-pVDZ.
AB  - The effect of basis sets on MP2 and CCSD calculated geometries has been
      investigated for a series of small organic molecules with two to four nonhydrogen
      atoms. Whereas 6-311++G** usually leads to satisfactory structures, this was not
      true with aug-cc-pVDZ, although it uses more basis functions than the former set.
      In addition, the smaller 6-311++G** invariably leads to lower calculated energies
      than aug-cc-pVDZ. With a given basis set, CCSD gives more satisfactory calculated
      geometries than MP2, but with a much greater computation time. For the compounds
      in this report, B3LYP/6-311++G** is quite effective in giving satisfactory
      calculated geometries at a relatively small computational cost.

PMID- 15185328
TI  - Electrostatic potentials and fields from density expansions of deformed atoms in
      molecules.
AB  - The exact representation of the molecular density by means of atomic expansions,
      consisting in spherical harmonics times analytical radial factors, is employed
      for the calculation of electrostatic potentials, fields, and forces. The
      resulting procedure is equivalent to an atomic multipolar expansion in the long
      range regions, but works with similar efficiency and accuracy in the short-range
      region, where multipolar expansions are not valid. The performances of this
      procedure are tested on the calculation of the electrostatic potential contour
      maps and electrostatic field flux lines of water and nitrobenzene, computed from
      high-quality molecular electron densities obtained with Slater basis sets.

PMID- 15185329
TI  - Analytical method for the representation of atoms-in-molecules densities.
AB  - We present analytic refinements and applications of the deformed atomic densities
      method [Fernandez Rico, J.; Lopez, R.; Ramirez, G. J Chem Phys 1999, 110, 4213
      4220]. In this method the molecular electron density is partitioned into atomic
      contributions, using a minimal deformation criterion for every two-center
      distributions, and the atomic contributions are expanded in spherical harmonics
      times radial factors. Recurrence relations are introduced for the partition of
      the two-center distributions, and the final radial factors are expressed in terms
      of exponential functions multiplied by polynomials. Algorithms for the practical
      implementation are developed and tested, showing excellent performances. The
      usefulness of the present approach is illustrated by examining its ability to
      describe the deformation of atoms in different molecular environments and the
      relationship between these atomic densities and some chemical properties of
      molecules.

PMID- 15185330
TI  - New 2D graphical representation of DNA sequences.
AB  - We consider a 2D graphical representations of DNA sequences, which avoids loss of
      information associated with crossing and overlapping of the corresponding curve.
      We outline an approach, which is based on the construction of a three-component
      vector whose components are the normalized leading eigenvalues of the L/L
      matrices associated with DNA. The examination of similarities/dissimilarities
      among the coding sequences of the first exon of beta-globin gene of different
      species illustrates the utility of the approach.

PMID- 15185331
TI  - Wavelet algorithm for solving integral equations of molecular liquids. A test for
      the reference interaction site model.
AB  - A new efficient method is developed for solving integral equations based on the
      reference interaction site model (RISM) of molecular liquids. The method proposes
      the expansion of site-site correlation functions into the wavelet series and
      further calculations of the approximating coefficients. To solve the integral
      equations we have applied the hybrid scheme in which the coarse part of the
      solution is calculated by wavelets with the use of the Newton-Raphson procedure,
      while the fine part is evaluated by the direct iterations. The Coifman 2 basis
      set is employed for the wavelet treatment of the coarse solution. This wavelet
      basis set provides compact and accurate approximation of site-site correlation
      functions so that the number of basis functions and the amplitude of the fine
      part of solution decrease sufficiently with respect to those obtained by the
      conventional scheme. The efficiency of the method is tested by calculations of
      SPC/E model of water. The results indicated that the total CPU time to obtain
      solution by the proposed procedure reduces to 20% of that required for the
      conventional hybrid method.

PMID- 15185332
TI  - An evaluation of the radial part of numerical integration commonly used in DFT.
AB  - Recently, Gill and Chien introduced a new radial quadrature for multiexponential
      integrands (MultiExp grid) to deal with the radial part of the numerical
      integration. In this article, the MultiExp grid is studied and used to integrate
      the charge density. The MultiExp grid, along with an optimal pruning scheme,
      performed very well both in terms of accuracy and efficiency compared to other
      radial mappings commonly used in Density Functional Theory.

PMID- 15185333
TI  - A comparative molecular field analysis (CoMFA) study using semiempirical, density
      functional, ab initio methods and pharmacophore derivation using DISCOtech on
      sigma 1 ligands.
AB  - The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a
      three-dimensional quantitative structure activity relationship (3D-QSAR) model of
      ligands for the sigma 1 receptor. The starting geometry of sigma-1 receptor
      ligands was obtained from the Tripos force field minimizations and conformations
      were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48
      molecules were fully optimized at the ab initio HF/3-21G* and semiempirical AM1
      calculations using GAUSSIAN 98. The electrostatic charges were calculated using
      several methods such as semiempirical AM1, density functional B3LYP/3-21G*, and
      ab initio HF/3-21G*, MP2/3-21G* calculations within GAUSSIAN 98. Using the
      optimized geometries, the CoMFA results derived from the HF/3-21G method were
      better than those from AM1. The best CoMFA was obtained from HF/3-21G* optimized
      geometry and charges (R2 = 0.977). Using the optimized geometries, the CoMFA
      results derived from the HF/3-21G methods were better than those from AM1
      calculations. The training set of 43 molecules gave higher R2 (0.989-0.977) from
      HF/3-21G* optimized geometries than R2 (0.966-0.911) values from AM1 optimized
      geometries. The test set of five molecules also suggested that HF/3-21G*
      optimized geometries produced good CoMFA models to predict bioactivity of sigma 1
      receptor ligands but AM1 optimized geometries failed to predict reasonable
      bioactivity of sigma 1 receptor ligands using different calculations for atomic
      charges.

PMID- 15185334
TI  - Extending the treatment of backbone energetics in protein force fields:
      limitations of gas-phase quantum mechanics in reproducing protein conformational
      distributions in molecular dynamics simulations.
AB  - Computational studies of proteins based on empirical force fields represent a
      powerful tool to obtain structure-function relationships at an atomic level, and
      are central in current efforts to solve the protein folding problem. The results
      from studies applying these tools are, however, dependent on the quality of the
      force fields used. In particular, accurate treatment of the peptide backbone is
      crucial to achieve representative conformational distributions in simulation
      studies. To improve the treatment of the peptide backbone, quantum mechanical
      (QM) and molecular mechanical (MM) calculations were undertaken on the alanine,
      glycine, and proline dipeptides, and the results from these calculations were
      combined with molecular dynamics (MD) simulations of proteins in crystal and
      aqueous environments. QM potential energy maps of the alanine and glycine
      dipeptides at the LMP2/cc-pVxZ//MP2/6-31G* levels, where x = D, T, and Q, were
      determined, and are compared to available QM studies on these molecules. The
      LMP2/cc-pVQZ//MP2/6-31G* energy surfaces for all three dipeptides were then used
      to improve the MM treatment of the dipeptides. These improvements included
      additional parameter optimization via Monte Carlo simulated annealing and
      extension of the potential energy function to contain peptide backbone phi, psi
      dihedral crossterms or a phi, psi grid-based energy correction term.
      Simultaneously, MD simulations of up to seven proteins in their crystalline
      environments were used to validate the force field enhancements. Comparison with
      QM and crystallographic data showed that an additional optimization of the phi,
      psi dihedral parameters along with the grid-based energy correction were required
      to yield significant improvements over the CHARMM22 force field. However,
      systematic deviations in the treatment of phi and psi in the helical and sheet
      regions were evident. Accordingly, empirical adjustments were made to the grid
      based energy correction for alanine and glycine to account for these systematic
      differences. These adjustments lead to greater deviations from QM data for the
      two dipeptides but also yielded improved agreement with experimental
      crystallographic data. These improvements enhance the quality of the CHARMM force
      field in treating proteins. This extension of the potential energy function is
      anticipated to facilitate improved treatment of biological macromolecules via MM
      approaches in general.

PMID- 15185335
TI  - Charge optimization of the interface between protein kinases and their ligands.
AB  - Examining the potential for electrostatic complementarity between a ligand and a
      receptor is a useful technique for rational drug design, and can demonstrate how
      a system prioritizes interactions when allowed to optimize its charge
      distribution. In this computational study, we implemented the previously
      developed, continuum solvent-based charge optimization theory with a simple,
      quadratic programming algorithm and the UHBD Poisson-Boltzmann solver. This
      method allows one to compute the best set of point charges for a ligand or ligand
      region based on the ligand and receptor shape, and the receptor partial charges,
      by optimizing the binding free energy obtained from a continuum-solvent model. We
      applied charge optimization to a fragment of the heat-stable protein kinase
      inhibitor (PKI) of protein kinase A (PKA), to three flavopiridol inhibitors of
      CDK2, and to cyclin A which interacts with CDK2 to regulate the cell cycle. We
      found that a combination of global (involving every charge) and local (involving
      only charges in a local region) optimization can give useful hints for designing
      better inhibitors. Although some parts of an inhibitor may already contribute
      significantly to binding, we found that they could still be the most important
      targets for modifications to obtain stronger binders. In studying the binding of
      flavopiridol inhibitors to CDK2, comparable binding affinity could be obtained
      regardless of whether the net charges of the inhibitors were constrained to -2, 
      1, 0, 1, or 2 during the optimization. This provides flexibility in inhibitor
      design when a certain net charge of the inhibitor is desired in addition to
      strong binding affinity. For the study of the PKA-PKI and CDK2-cyclin A
      interfaces, we identified residues whose charge distributions are already close
      to optimal and those whose charge distributions could be refined to further
      improve binding.

PMID- 15185336
TI  - B-cell non-Hodgkin's lymphoma and hepatitis C virus infection: a systematic
      review.
AB  - A high prevalence of hepatitis C virus (HCV) infection in patients with B-cell
      non-Hodgkin's lymphoma (B-NHL) has been reported in some, but not all, studies,
      and the association showed a strong regional variation. We conducted a systematic
      review of the prevalence of HCV infection in case series of B-NHL and, when an
      appropriate control group was available, of the odds ratio of B-NHL associated
      with HCV infection. A high HCV prevalence in B-NHL was found in southern and
      eastern Europe, Japan and the southern United States, but not in central and
      northern Europe, Canada, northern United States, or a few Asian countries.
      Possible sources of heterogeneity and bias are discussed. The odds ratio of B-NHL
      for HCV infection was relatively weak, ranging from 2 to 4 in most studies. Thus,
      even if the observed association were causal, the percentage of cases of B-NHL
      attributable to HCV infection would be relatively low (10%) also in countries
      with a high prevalence of HCV infection in the general population, and extremely
      low in other countries. This may explain apparent inconsistencies between
      studies. Potential mechanisms of action are also discussed.

PMID- 15185337
TI  - Polygenic control of hepatocarcinogenesis in Copenhagen x F344 rats.
AB  - Cop and CFF1 rats exhibit resistance to hepatocarcinogenesis, associated with
      high rates of remodeling of neoplastic lesions. We have mapped
      hepatocarcinogenesis susceptibility, resistance and remodeling loci affecting the
      number, volume and volume fraction of neoplastic nodules induced by the
      "resistant hepatocyte" model in male CFF2 rats. Three loci in significant linkage
      with the number or volume of nonremodeling lesions were identified on chromosomes
      1, 4 and 18. Suggestive linkage with number or volume fraction of total,
      nonremodeling or remodeling lesions was found for 7 loci on chromosomes 1, 2, 13,
      14 and 15. All of these loci showed significant allele-specific effects on the
      phenotypic traits. We also detected by analysis of variance 19 2-way interactions
      inducing phenotypic effects not predictable on the basis of the sum of separate
      effects. These novel epistatic loci were in significant linkage with the number
      and/or volume of total, nonremodeling or remodeling nodules. These data indicate
      that susceptibility to hepatocarcinogenesis in Cop rats is controlled by a
      complex array of genes with several gene-gene interactions and that different
      genetic mechanisms control remodeling and nonremodeling liver nodules. Frequent
      deregulation in human liver cancer of genes positioned in chromosomal segments
      syntenic to rat susceptibility/resistance loci suggests some similarities between
      the genetic mechanisms involved in hepatocarcinogenesis in rats and humans.

PMID- 15185338
TI  - Loss of cyclin E requirement in cell growth of an oral squamous cell carcinoma
      cell line implies deregulation of its downstream pathway.
AB  - Cyclin E and Cdk2 have been shown to play an important role in G1/S transition of
      the cell cycle. Two E-type cyclins (E1 and E2) have been identified to date and
      share functionally similarities. Upregulation of these cyclins has been observed
      frequently in human cancers. We examined the expression profile of cyclin E1 and
      E2 in cell lines derived from human oral squamous cell carcinoma (SCC), and found
      that the expression of cyclin E1 protein was hardly detected in HSC-2 cells.
      Although cyclin E2 was abundantly expressed, histone H1 kinase activities of both
      E-type cyclins were virtually undetectable in this cell line. Inhibition of
      cyclin E1, but not that of E2, by using vectors expressing antisense-oriented
      their cDNAs induced drastic growth suppression on HOC313 cells that express both
      E-type cyclins. Inhibition of neither cyclin E1 nor E2 suppressed the growth of
      HSC-2 cells, and compensatory elevation of cyclin E1 was not evident in cyclin E2
      inhibited HSC-2 cells. In contrast, HSC-2 cells expressed cyclin D1 and
      hyperphosphorylated forms of Rb family proteins, and were arrested in G1 by
      overexpression of p16(INK4), a specific inhibitor against D-type cyclin activity.
      These results indicate that HSC-2 cells lost proper growth control specifically
      mediated by cyclin E and suggest that deregulation of its downstream pathway may
      contribute to tumorigenesis of oral SCC.

PMID- 15185340
TI  - Interferon receptor expression regulates the antiproliferative effects of
      interferons on cancer cells and solid tumors.
AB  - In addition to antiviral effects, Type I interferons (IFN) have potent
      antiproliferative and immunomodulatory activities. Because of these properties
      IFNs have been evaluated as therapeutics for the treatment of a number of human
      diseases, including cancer. Currently, IFNs have been shown to be efficacious for
      the treatment of only a select number of cancers. The reason for this is unclear.
      Recent evidence has demonstrated that some cancer cell types seem to be defective
      in their ability to respond to IFN. It has been suggested that defects in IFN
      signaling is one mechanism by which cancer cells escape responsiveness to Type I
      IFNs and growth control in general. We report that transfection and enhanced
      expression of the Type I IFN receptor chain (IFNAR2c) in 3 different human cancer
      cell lines markedly increases the sensitivity of these cells to the
      antiproliferative effects of IFNs. In cancer cells transfected with IFNAR2c, dose
      response curves demonstrate a significant decrease in the concentrations of IFN
      required to achieve maximum cell death. Furthermore, in these transfected cells,
      we observe a significant increase in the number of cells undergoing apoptosis, as
      measured by DNA fragmentation and Caspase 3 activation. In addition, using an in
      vivo xenograft tumor model we show an increase in the effectiveness of
      systemically delivered Betaseron in decreasing tumor burden in animals in which
      solid tumors were generated from IFNAR2c transfected cells. These data show that
      specific regulation of IFN receptor expression can play a major role in
      determining the clinical outcome of IFN-based cancer therapeutics by regulating
      the relative sensitivity of cancer cells to IFN-dependent growth control.

PMID- 15185341
TI  - Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to
      growth factor, protease and apoptosis pathways.
AB  - Hypoxia-inducible factor (HIF)-1 alpha is the regulatory subunit of HIF-1 that is
      stabilized under hypoxic conditions. Under different circumstances, HIF-1 alpha
      may promote both tumorigenesis and apoptosis. There is conflicting data on the
      importance of HIF-1 alpha as a prognostic factor. This study evaluated HIF-1
      alpha expression in 172 consecutive patients with stage I-IIIA non small cell
      lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of
      HIF-1 alpha nuclear immunostaining was determined using light microscopy and the
      results were analyzed using the median (5%) as a low cut-point and 60% as a high
      positive cut-point. Using the low cut-point, positive associations were found
      with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase
      (MMP)-9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic
      anhydrase (CA) IX, p53 (p = 0.008), T-stage (p = 0.042), tumor necrosis (TN; p <
      0.001) and squamous histology (p < 0.001). No significant association was found
      with Bcl-2 or either N- or overall TMN stage or prognosis. When the high positive
      cut-point was used, HIF-1 alpha was associated with a poor prognosis (p = 0.034).
      In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that
      these factors may either regulate or be regulated by HIF-1 alpha. The association
      with TN and squamous-type histology, which is relatively more necrotic than other
      NSCLC types, reflects the role of hypoxia in the regulation of HIF-1 alpha. The
      prognostic data may reflect a change in the behavior of HIF-1 alpha in
      increasingly hypoxic environments.

PMID- 15185339
TI  - Glycine-extended gastrin induces matrix metalloproteinase-1- and -3-mediated
      invasion of human colon cancer cells through type I collagen gel and Matrigel.
AB  - The effects of glycine-extended gastrin (G-Gly) on the invasion by colon cancer
      cells through stromal extracellular matrix and the role of metalloproteinases
      (MMPs) in this invasion were investigated. We found that 10(-9)-10(-6) M G-Gly
      significantly increased the invasiveness of 2 human colon cancer cell lines, LoVo
      and HT-29, both expressing the G-Gly-specific binding site but little gastrin/CCK
      B receptor (gastrin receptor). LoVo cells expressed MMP-1, -2, -3 and -9. An
      amount of 10(-7) M G-Gly enhanced collagenase MMP-1 expression. Overexpression of
      enhanced green fluorescent protein (EGFP)-fused MMP-1 in LoVo cells, by cDNA
      transfection, enhanced invasiveness through type I collagen gel.
      Immunofluorescence study revealed that G-Gly increased the number of cytoplasmic
      vesicles containing MMP-1, some vesicles being released from the cells. The MMP-1
      vesicles contained one of the ubiquitous coat proteins, Golgi-localized, gamma
      adaptin ear-containing, ARF-binding proteins-2 (GGA-2). MMP-1 also colocalized
      with CD147 (EMMPRIN, an extracellular matrix metalloproteinase inducer in
      adjacent stromal cells). It was suggested that G-Gly increased the number of
      vesicles containing MMP-1 and that MMP-1 interacted with CD147 to increase
      invasion. G-Gly significantly enhanced the production of MMP-3, an activator of
      MMP-1 and -9, as well as gelatinase MMP-9 activity. The G-Gly-mediated MMP-9
      increase was inhibited by treatment with anti-MMP-3 IgG and MMP-3 siRNA.
      Furthermore, G-Gly increased the proMMP-2 level, although no activated MMP-2 was
      found in conditioned medium in either the presence or the absence of G-Gly. By
      contrast, gastrin (10(-7) M) had no effect on the levels of these MMPs or the
      invasiveness of colon cancer cells in type I collagen gel and Matrigel. These
      effects of G-Gly on the activity and expression of MMPs and the invasiveness of
      colon cancer cells were inhibited by treating the cells with a broad-spectrum
      metalloproteinase inhibitor (CGS27023A) and nonselective gastrin/CCK receptor
      antagonists (proglumide and benzotript). But a gastrin/CCK-B receptor antagonist
      (YM022) did not inhibit the increased invasion by G-Gly. Together, these results
      demonstrate that G-Gly renders colon cancer cells more invasive by increasing MMP
      1 and MMP-3 expressions via the putative G-Gly receptor and would thus be a good
      molecular target in a clinical setting.

PMID- 15185342
TI  - Inhibition of human vascular endothelial cells proliferation by terbinafine.
AB  - We have demonstrated previously that terbinafine (TB), an oral antifungal agent
      used in the treatment of superficial mycosis, suppresses proliferation of various
      cultured human cancer cells in vitro and in vivo by inhibiting DNA synthesis and
      activating apoptosis. In our study, we further demonstrated that TB at a range of
      concentrations (0-120 microM) dose-dependently decreased cell number in cultured
      human umbilical vascular endothelial cells (HUVEC). Terbinafine was not cytotoxic
      at a concentration of 120 microM, indicating that it may have an inhibitory
      effect on the cell proliferation in HUVEC. The TB-induced inhibition of cell
      growth rate is reversible. [(3)H]thymidine incorporation revealed that TB reduced
      the [(3)H]thymidine incorporation into HUVEC during the S-phase of the cell
      cycle. Western blot analysis demonstrated that the protein levels of cyclin A,
      but not cyclins B, D1, D3, E, CDK2 and CDK4, decreased after TB treatment. The TB
      induced cell-cycle arrest in HUVEC occurred when the cyclin-dependent kinase 2
      (CDK2) activity was inhibited just as the protein level of p21 was increased and
      cyclin A was decreased. Pretreatment of HUVEC with a p21 specific antisense
      oligonucleotide reversed the TB-induced inhibition of [(3)H]thymidine
      incorporation. Taken together, these results suggest an involvement of the p21
      associated signaling pathway in the TB-induced antiproliferation in HUVEC.
      Capillary-like tube formation and chick embryo chorioallantoic membrane (CAM)
      assays further demonstrated the anti-angiogenic effect of TB. These findings
      demonstrate for the first time that TB can inhibit the angiogenesis.

PMID- 15185343
TI  - Altered mode of allelic replication accompanied by aneuploidy in peripheral blood
      lymphocytes of prostate cancer patients.
AB  - Replication timing of the genetic material is a highly programmed process
      correlated with expression, stability and methylation capacity. An important
      aspect of that timing is the temporal order of allelic replication: a synchronous
      mode for biallelically expressed genes and an asynchronous for monoallelically
      expressed genes. Previous studies showed that malignancy is associated with
      changes in the inherent mode of allelic replication, and even normal cells of
      cancer patients display alterations in the replication of various genes. Using
      fluorescence in situ hybridization (FISH), we checked whether allelic-replication
      mode differentiates cancer patients from healthy individuals. We focused on
      prostate cancer (CAP), the most common diagnosed cancer and the second leading
      cause of cancer death in men over 50 years old. Five nonrelated genes and a
      nontranscribed DNA sequence associated with chromosomal segregation were used in
      our study. All 6 tested loci displayed in peripheral blood lymphocytes stimulated
      with phytohemagglutinin (PHA) of CAP patients loss of their inherent temporal
      order of allelic replication, coupled with aneuploidy, the outcome of chromosome
      malsegregation. The replication-timing modification is a reversible epigenetic
      alteration, evidenced by our ability to resurrect the normal pattern in all 6
      tested loci by introducing an inhibitor of methyl transferase. On the other hand,
      the methylation-blocking agent failed to obliterate aneuploidy. The replication
      alteration accompanied by aneuploidy, detected in peripheral blood cells,
      distinguishes between CAP patients and individuals with benign prostate
      hyperplasia (BPH; a common disorder in elderly men) better than the routinely
      used blood marker, the prostate-specific antigen (PSA).

PMID- 15185344
TI  - Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland.
AB  - It has been suggested based on familial data that Nijmegen breakage syndrome
      (NBS) heterozygotes have an increased risk of malignant tumors. We found 15
      carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of
      the NBS1 gene among 1,289 consecutive patients from Central Poland with various
      cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from
      this region. Most of the 657del5 mutation carriers were found among patients with
      melanoma (4/105), non-Hodgkin lymphoma (2/42) and breast cancer (4/224) and of
      the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3
      others the R215W molecular variant. The frequencies of 657del5 mutation carriers
      among patients with melanoma and non-Hodgkin lymphoma and of R215W carriers in
      patients with colorectal cancer were significantly higher than in controls (p <
      0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and
      R215W mutations in all cancer patients were also significantly higher than in
      controls (p < 0.05). Two carriers of the 657del5 mutation had second primary
      tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers
      (14/77) were twice more frequent than in population controls. Three carriers of
      this mutation (2 probands with melanoma) reported melanoma in relatives. These
      results suggest strongly that NBS1 heterozygosity may be associated with elevated
      risk of some cancers. Larger studies are needed to evaluate the impact of the
      high frequency of germline NBS1 mutations on the cancer burden in the Slav
      populations.

PMID- 15185345
TI  - C8orf4 is a transforming growth factor B induced transcript downregulated in
      metastatic colon cancer.
AB  - Transforming growth factor (TGF) beta mediates a tumor suppressor pathway in
      human colon epithelial cells. We were interested in identifying and
      characterizing novel genes regulated by the TGF beta pathway in the colon. We
      employed expression microarrays to identify transcripts induced by TGF beta in
      Vaco 330, a colon adenoma cell line. We then used expression microarrays to
      determine which of these TGF beta induced transcripts are down-regulated in
      metastatic colon cancer. Northern analysis and real-time reverse transcription
      PCR confirmed and quantified our findings from the microarrays. These analyses
      highlighted C8orf4 as induced by TGF beta in colon cells. Moreover, C8orf4 is
      expressed in most normal colon mucosa samples, and is not expressed in most colon
      cancer metastases or colon cancer cell lines. Colon cancer primary tumors showed
      reduced expression of C8orf4 relative to normal mucosa, possibly reflecting
      contributions of C8orf4 expression in stromal cells. C8orf4 is a gene regulated
      by TGF beta signaling and loss in advanced colon cancer suggests C8orf4 may play
      a role in colon cell differentiation or growth regulation.

PMID- 15185346
TI  - Hepatitis C virus infection and non-Hodgkin lymphoma: results of the NCI-SEER
      multi-center case-control study.
AB  - Several studies have noted elevated hepatitis C virus (HCV) prevalence among
      patients with non-Hodgkin lymphoma (NHL), suggesting that HCV infection increases
      NHL risk through chronic immune stimulation. Population-based data from the U.S.
      are lacking. In a population-based case-control study of NHL in the United
      States, we identified HCV infection using an enzyme immunoassay, confirmed by
      recombinant immunoblot assay or HCV RNA detection. The association between HCV
      and NHL was assessed using logistic regression, adjusting for demographic
      factors, illicit drug use or medical history. Thirty-two of 813 (3.9%) NHL cases
      and 14 of 684 (2.1%) controls were HCV-infected [odds ratio (OR) 1.96, 95%CI 1.07
      4.03]. For separate NHL subtypes, numbers were limited. Nonetheless, positive
      associations were noted for follicular (OR 2.46, 95%CI 1.01-5.81), marginal zone
      (3.99, 0-13.6) and mucosa-associated lymphoid tissue (2.04, 0-7.20) NHLs. For all
      NHLs combined, the HCV-NHL association changed little after adjustment for sex,
      age, race and study center (OR 1.89, 95%CI 1.00-4.00). HCV was common in controls
      who had injected drugs (40%) or used other illicit drugs (6.5%), but adjustment
      for drug use did not affect the HCV-NHL association (OR 1.87, 95%CI 0.95-4.10).
      Transfusion history was unrelated to HCV status, and adjustment for this exposure
      did not attenuate the HCV-NHL association (OR 2.15, 95%CI 1.12-4.76). Excluding 4
      subjects with a history of hemodialysis or 3 subjects with organ transplants also
      did not affect the results. Our study demonstrates an association between HCV
      infection and NHL in the United States. HCV infection may be a cause of NHL.

PMID- 15185347
TI  - Role of hepatitis C virus infection in malignant lymphoma in Spain.
AB  - Hepatitis C virus (HCV) has been implicated in the etiology of malignant
      lymphomas. We estimated the risk of lymphoma associated with detection of HCV
      infection. Cases (n = 529) were consecutive patients newly diagnosed with a
      lymphoid malignancy between 1998 and 2002 in 4 centers in Spain. Lymphomas were
      diagnosed and classified using the WHO Classification. Controls (n = 600) were
      hospitalized patients matched to the cases by 5-year age group, gender and study
      center. Several medical conditions associated with severe immunosuppression
      precluded the eligibility of controls. Patients underwent a personal interview
      and blood sampling. HCV positive subjects were considered those with antibody
      response to third generation ELISA or detection of HCV RNA with Amplicor 2.0.
      Cases were systematically tested for HIV antibodies. We used the chi(2) test and
      unconditional logistic regression to estimate the odds ratio (OR) and 95%
      confidence interval (95% CI) for lymphoma associated with HCV. HCV infection was
      detected in 40 cases (7.5%) and 23 (3.8%) control subjects. Six of 16 patients
      with HIV-related lymphomas and 4 of 8 organ-recipient-related lymphomas were HCV
      positive. The analysis, excluding HIV-infected subjects and organ recipients, led
      to a prevalence of HCV of 5.9% among cases and 3.8% among controls. The age-,
      gender- and center-adjusted OR for all lymphomas was 1.58 (95% CI = 0.89-2.79).
      Among all lymphoma categories, HCV was associated with an increased risk of low
      grade B-cell lymphomas not otherwise specified (NOS) (OR = 35.98, 95% CI = 4.70
      275.4). A 2-fold excess risk associated to HCV was observed for marginal B-cell
      lymphomas, diffuse large B-cell lymphoma and lymphoma B NOS but the associations
      were not statistically significant. HCV infection is associated with an increased
      risk of a broad spectrum of lymphoid neoplasms among non severely
      immunocompromised subjects in Spain.

PMID- 15185348
TI  - Enhanced efficacy of DNA vaccination against Her-2/neu tumor antigen by genetic
      adjuvants.
AB  - Certain types of malignant tumors overexpress Her-2/neu, a transmembrane
      glycoprotein of the class I receptor tyrosine kinase erbB family. To develop an
      effective Her-2/neu vaccine for selective immunotherapy of these malignancies, we
      prepared Her-2/neu DNA plasmid encoding the transmembrane and extracellular
      domain (pHM) and tested the ability of this construct to induce antitumor
      immunity in animal models. In addition, we investigated the effects of cytokine
      used as a genetic adjuvant. Modulation by factors that affect T-cell function or
      hematopoiesis, including interleukin-12, interleukin-15, interleukin-18,
      interleukin-23, Eta-1, Flt3L and GM-CSF, was studied in the forms of
      monocistronic and bicistronic plasmid. Our results demonstrated that vaccination
      of pHM could induce successful antitumor immunity against Her-2/neu-expressing
      murine tumor cells in BALB/c mice. We also showed that the antitumor activity of
      pHM was augmented by coadministration and coexpression of different cytokines.
      Despite the similar levels of gene expression, the antitumor effects of
      bicistronic plasmids coexpressing Her-2/neu antigen and cytokine were improved in
      comparison with coadministration of separate monocistronic plasmid. In
      particular, coexpression of interleukin-18 or GM-CSF with Her-2/neu increased
      antitumor activity in both preventive and therapeutic experiments. These findings
      can help in the decision concerning which of the various cytokine adjuvants
      should be used for the development of a Her-2/neu DNA vaccine. In addition, our
      results from a large panel of cytokine adjuvants in the various tumor models may
      provide an insight into the important immune components of antitumor immunity.

PMID- 15185349
TI  - Microsatellite analysis of serum DNA in patients with head and neck cancer.
AB  - We have shown previously that microsatellite alterations in serum DNA was
      predictive of distant metastasis in a study with 21 primary head and neck
      squamous cell carcinoma patients. To further investigate serum microsatellite
      alterations as a prognostic tool, we carried out microsatellite analysis of serum
      DNA with 10 markers on 152 patients with head and neck cancer. Forty-five percent
      (68/152) of patients had microsatellite alterations of serum DNA identical to
      corresponding tumor DNA. In 16 patients that had distant metastasis, 11 patients
      had a positive serum test (microsatellite alterations detectable in their serum
      DNA with one or more markers). The difference in distant metastasis rates between
      the negative and positive serum tests (6.0% [5/84] vs. 16.2% [11/68], RR = 2.7)
      was clinically significant and almost reached statistical significance (p =
      0.06). When the analysis was restricted to patients with recurrent disease, a
      positive serum test correlated with those who developed distant metastasis (p =
      0.04). Other parameters, such as development of recurrence, stage of the cancer,
      disease-free survival and overall survival, were not associated with a positive
      serum test. Detecting tumor DNA in serum by microsatellite analysis may help
      identify patients at risk for distant metastasis. Therefore, circulating tumor
      cells may contribute to the presence of tumor DNA in the serum. In the future if
      a serum test is positive, therapeutic approaches may by intensified, such as
      platinum-based chemoradiation, to reduce distant failures.

PMID- 15185350
TI  - Detection of occult tumour cells in lymph nodes of colorectal cancer patients
      using real-time quantitative RT-PCR for CEA and CK20 mRNAS.
AB  - The purpose of our study was to develop specific, sensitive, objective assays for
      early detection of disseminated tumour cells in patients with colorectal cancer
      (CRC). Carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) were chosen as
      markers because they are selectively expressed in epithelial cells with
      maintained expression in CRC. Real-time quantitative RT-PCR assays with RNA copy
      standards were constructed. Regional lymph nodes were collected from patients
      with CRC (n = 51) and benign intestinal disease (n = 10). Results were compared
      to routine histopathology and anti-CEA immunohistochemistry. Lymph node levels of
      CEA and CK20 mRNA correlated strongly (p < 0.0001, r = 0.8). Lymph nodes from non
      CRC patients had <0.01 CEA and <0.001 CK20 mRNA copies/18S rRNA unit. Lymph nodes
      from 3/6 Dukes' A, 17/26 Dukes' B, 10/10 Dukes' C and 7/9 Dukes' D patients had
      CEA mRNA levels above cut-off. Corresponding figures for CK20 mRNA were 3/6,
      10/26, 9/10 and 5/9, respectively. CEA mRNA levels varied from 0.001 to 100
      copies/18S rRNA unit in Dukes' A and B, and 50% of the Dukes' B patients had CEA
      mRNA levels within the range of Dukes' C patients. Three Dukes' B patients have
      died from CRC or developed distant metastases. All 3 had high CEA and CK20 mRNA
      levels. Determination of mRNA was superior to immunohistochemistry in showing CEA
      expression in lymph nodes. The present qRT-PCR assay for CEA mRNA seems to be a
      superior tool to identify individuals with disseminated tumour cells. Future
      extended studies will establish the clinically most relevant cut-off level.

PMID- 15185351
TI  - Bovine lactoferrin inhibits tumor-induced angiogenesis.
AB  - Recent studies have demonstrated that bovine lactoferrin (bLF) suppresses tumor
      growth and metastasis in the mouse and rat and moreover may inhibit angiogenesis.
      To determine whether angiogenesis inhibition might contribute to antitumor
      activity, we examined the influence of bLF on tumor-induced angiogenesis and
      endothelial cell functions as well as angiogenesis-related cytokine production.
      Bovine LF exhibited dose-dependent inhibition of angiogenesis on 4-6-day-old
      chick embryo chorioallantoic membranes (CAMs) that lack a mature immune response.
      This inhibition was reversed when bLF was simultaneously treated with basic
      fibroblast growth factor (bFGF). It also inhibited in vitro formation of tube
      like structures of mouse endothelial KOP2.16 cells. Moreover, it potently
      suppressed bFGF- or VEGF-induced proliferation of mouse endothelial KOP2.16
      cells, but not of mouse fibroblast A31 cells and Lewis lung carcinoma (3LL)
      cells. In mice, both orally and intraperitoneally administered bLF significantly
      and dose-dependently suppressed 3LL cell-induced angiogenesis in a dorsal air sac
      assay. As orally administered bLF was reported to exhibit antitumor activity
      through production of interferon (IFN)-gamma and interleukin (IL)-18 in
      intestinal mucosa (Kuhara T et al., Nutr Cancer 2000;38:192-9), production of
      these cytokines in mouse serum and peritoneal macrophages by bLF was examined.
      IFN-gamma was not detected in serum by bLF administration. However, bLF markedly
      elevated IL-18 concentration in serum by oral administration, but not by
      intraperitoneal administration. It also induced IL-18 in peritoneal macrophages
      in vitro. These results suggest that bLF participates as a regulator of
      angiogenesis, possibly explained by blocking endothelial function and inducing IL
      18 production. Antitumor activity of bLF may thus be partly mediated by
      angiogenesis inhibition.

PMID- 15185352
TI  - Epstein-Barr virus seroreactivity among unaffected individuals within high-risk
      nasopharyngeal carcinoma families in Taiwan.
AB  - Most adults have been infected with EBV. Many studies have indicated that
      antibodies against specific EBV antigens, particularly IgA antibodies, can be
      predictive or prognostic of EBV-associated malignancies, such as NPC. We
      hypothesized that healthy individuals from families with a history of multiple
      members affected with NPC (who therefore might be genetically susceptible to NPC
      themselves) might have an EBV antibody profile that is distinct from that seen in
      healthy individuals from the community at large. To explore this possibility and
      examine determinants of anti-EBV antibody levels in healthy, high-risk
      individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which
      included 1,229 healthy members of families in which 2 or more individuals were
      affected with NPC and 320 controls from the community at large. Blood collected
      from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and
      for neutralizing antibodies against EBV DNase using standard assays. We observed
      evidence of familial aggregation of EBV seroreactivity among individuals from
      high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody
      seroprevalence in unaffected family members of NPC cases was 5-6 times higher
      than in members of the community (p < 0.01). This elevated seroprevalence among
      unaffected individuals from high-risk families was observed regardless of the
      relationship of the unaffected individual to the closest affected relative
      (siblings, parents, children or spouses). No sociodemographic or environmental
      factors examined were found to strongly and consistently correlate with elevated
      seroprevalence, but patterns emerged of increasing seroprevalence among older
      individuals and among females. Unaffected individuals from high-risk NPC families
      have elevated anti-EBV IgA antibody titers. The etiologic and clinical
      implications of this finding remain to be established.

PMID- 15185353
TI  - Association of cigarette smoking with the risk of ovarian cancer.
AB  - Cigarette smoking may be associated with ovarian cancer risk. This association
      may differ by histological type. The authors conducted a population-based case
      control study in Canada of 442 incident cases of ovarian cancer and 2,135
      controls 20-76 years of age during 1994-1997 to examine this association, overall
      and by histological type. Compared to women who never smoked, those who smoked
      had higher odds (odds ratio [OR] = 1.22; 95% confidence interval [CI] = 0.98
      1.53) of having ovarian cancer, and the OR was larger for ex-smokers (1.30; 95%
      CI = 1.01-1.67) than for current smokers (1.10; 95% CI = 0.81-1.49). The
      association with cigarette smoking was stronger for mucinous tumors (OR = 1.77;
      95% CI = 1.06-2.96) than for nonmucinous tumors (OR = 1.13; 95% CI = 0.89-1.44).
      In addition, the odds of smokers having mucinous tumors increased with years of
      smoking (OR = 1.36, 1.88, 1.19, 4.89 for <20, 21-30, 31-40 and >40 years,
      respectively; p for trend = 0.002), number of cigarettes smoked per day (OR =
      1.55, 1.89, 2.28 for <10, 11-20 and >20 cigarettes/day, respectively; p for trend
      = 0.014) and smoking pack-years (OR = 1.13, 2.65, 1.77 and 2.39 for <10, 11-20,
      21-30 and >30 pack-years, respectively; p for trend = 0.004). Our data suggest
      that cigarette smoking is associated with an increased risk of ovarian cancer,
      especially for mucinous types.

PMID- 15185354
TI  - Low urine osmolarity as a determinant of cisplatin-induced nephrotoxicity.
AB  - Cisplatin is widely used in the treatment of human tumors, but it is a
      nephrotoxic drug. Early pragmatic clinical trials have shown that cisplatin
      induced renal toxicity is greatly reduced through the use of high hydration, a
      large NaCl supply and mannitol infusion, but the precise mechanisms of these
      nephroprotective measures are not fully understood. We show here an increase in
      the cisplatin uptake and cytotoxicity on 56/10 A1 human glomerular and HK-2 human
      tubular cells when the drug incubation was performed in a hypotonic phosphate
      buffered saline solution or in human urine ("drag in" transport hypothesis). When
      4 mg/kg cisplatin was intraperitoneally injected in rats in 20 ml of a hypotonic
      4 g/l NaCl solution, the platinum accumulation increased in both the cortex and
      papilla but not in the subcutaneously grafted colon tumors when compared to rats
      injected with cisplatin in normal or hyperosmotic solutions (9 and 14 g/l NaCl,
      respectively). The urea and creatinine blood levels were significantly increased,
      and more apoptotic cells were detected by the caspase-3 cleavage and TUNEL assays
      in the tubular cells of rats treated with cisplatin in a hypotonic solution
      compared to animals that received normal or hypertonic solutions. Osmolarity was
      sometimes low in urine from patients receiving an intravenous hydration for a
      cisplatin treatment or from healthy volunteers who were given an oral hydration
      with a 50 g/l glucose solution. Our results show that low urine osmolarity could
      be a major determinant in the increase of cisplatin-induced nephrotoxicity and
      justify the widely used concurrent infusion of osmotically active substances
      during intravenous hydration.

PMID- 15185355
TI  - mTHPC-mediated photodynamic therapy for early oral squamous cell carcinoma.
AB  - Surgery and radiotherapy are standard treatments for early oral squamous cell
      carcinoma, both resulting in good tumour control. However, neither of these
      modalities is without consequent functional or cosmetic impairment, and there are
      patients in whom both are contraindicated. Furthermore, there is a significant
      risk of metachronous tumours developing in the oral cavity, and salvage or
      retreatment with either surgery or radiotherapy poses difficulties. Photodynamic
      therapy (PDT) offers the potential for improved functional and cosmetic outcomes,
      while achieving comparable tumour control. We conducted an open-label,
      multicentre study to assess the efficacy and safety of meta
      tetrahydroxyphenylchlorin (mTHPC) in patients with early oral cancer. One hundred
      twenty-one patients received intravenously administered mTHPC, followed 96 hr
      later by illumination of the tumour surface with 652 nm laser light. Of these
      patients, 114 were protocol compliant. A complete tumour response was achieved in
      85% of protocol-compliant patients (97 of 114 patients). A complete response was
      maintained in 85% of responders at 1 year and in 77% at 2 years. One- and 2-year
      actuarial survival rates were 89% and 75%, respectively. In the opinion of the
      investigators, tumour clearance was accompanied by excellent cosmetic and
      functional results, without impact on the patients' performance status. Mild-to
      moderate pain at the treatment site, a recognised side effect of PDT in the oral
      cavity, was reported by 82% of patients but was manageable with appropriate
      analgesia. Mild-to-moderate skin photosensitivity reactions were reported for 13%
      of patients. mTHPC offers an effective alternative treatment for early oral
      squamous cell carcinoma. It is associated with excellent functional and cosmetic
      results and can be used in conjunction with other standard therapies.

PMID- 15185356
TI  - Colorectal cancer risk in adenoma patients: a nation-wide study.
AB  - Colorectal cancer incidence after adenoma removal has been studied in selected
      populations of adenoma patients. Our study estimates the trend in colorectal
      cancer incidence after adenoma removal in actual clinical practice. From PALGA, a
      nationwide network and registry of histo- and cytopathology in the Netherlands,
      we extracted data of all patients diagnosed with colorectal adenomas between 1
      January 1988 and 1 October 1998. The data were used to calculate population-based
      colorectal cancer incidence rates after adenoma removal. A total of 78,473
      adenoma patients were followed for a mean of 4.5 years after the first adenoma
      removal. The colorectal cancer incidence ratio compared with the general
      population matched by age and gender was 38.4 (37.3-39.5) in the first year after
      adenoma removal and 1.5 (95% confidence interval (CI): 1.4-1.6) after Year 1. The
      incidence ratio decreased from 2.8 (2.5-3.1) in Year 2 to 0.9 (0.6-1.2) in Years
      9-11. This time trend is the opposite of the upward time trend that was expected
      after adenoma removal. Adenoma patients in the Netherlands are at increased risk
      for colorectal cancer compared to the general population. The high cancer
      incidence in Years 1-5 after polypectomy can be explained by a colonoscopic
      sensitivity for cancer of approximately 90%.

PMID- 15185357
TI  - Bone metastasis: Osteoblasts affect growth and adhesion regulons in prostate
      tumor cells and provoke osteomimicry.
AB  - Bone metastasis is the primary cause of death in human prostate cancer.
      Disseminated from primary tumor and distributed via the bloodstream, a proportion
      of prostate carcinoma cells eventually reach the skeleton and develop into
      metastases, requiring adhesion to inner bone surfaces lined by osteoblasts. The
      crosstalk of tumor cells with osteoblasts is a critical but poorly characterized
      step in the metastatic process. Using an in vitro metastasis model system, we
      have been examining effects of osteoblast-released factors on gene expression of
      prostate carcinoma cells. Here, we show by large-scale transcript profiling and
      quantitative RT-PCR that osteoblast-released factors target in particular the
      proliferation and adhesion regulons of tumor cells. Genes encoding components of
      the cell-cycle control machinery and connected pathways are predominantly
      repressed and cell proliferation is slowed down, resembling in vivo observations
      assumed to render commonly used chemotherapeutic measures ineffective. Genes
      encoding anchoring junction components are predominantly elevated, and the
      adhesion properties of tumor cells are altered. Moreover, prostate carcinoma
      cells are provoked to undergo osteomimicry, i.e., to express bone cell-related
      genes. The data indicate that the crosstalk with osteoblasts induces expressional
      changes in prostate carcinoma cells favoring the bone colonization process.

PMID- 15185358
TI  - Is a once-in-a-lifetime pap smear the best option for low-resourced settings?

PMID- 15185362
TI  - Neem--an omnipotent plant: a retrospection.
AB  - Neem (Azadirachta indica A. Juss.) has universally been accepted as a wonder tree
      because of its diverse utility. Multidirectional therapeutic uses of neem have
      been known in India since the Vedic times. Besides its therapeutic efficacies,
      neem has already established its potential as a source of naturally occurring
      insecticide, pesticide and agrochemicals. Safe and economically cheaper uses of
      different parts of neem in the treatment of various diseases and in agriculture
      are discussed in this article. It further deals with the active chemical
      constituents of various neem formulations. Commercially available neem products
      are also mentioned along with their respective applications. Furthermore,
      evaluation of safety aspects of different parts of neem and neem compounds along
      with commercial formulations are also taken into consideration. Systematic
      scientific knowledge on neem reported so far is thus very useful for the wider
      interests of the world community.

PMID- 15185363
TI  - French swimwear for membrane proteins.

PMID- 15185364
TI  - Plant "polyphenolic" small molecules can induce a calorie restriction-mimetic
      life-span extension by activating sirtuins: will "polyphenols" someday be used as
      chemotherapeutic drugs in Western medicine?

PMID- 15185365
TI  - The molecular mechanism of membrane proteins probed by evanescent infrared waves.
AB  - The catalytic action of membrane proteins is vital to many cellular processes.
      Yet the molecular mechanisms remain poorly understood. We describe here the
      technique of evanescent infrared difference spectroscopy as a tool to decipher
      the structural changes associated with the enzymatic action of membrane proteins.
      Functional changes as minute as the protonation state of individual amino acid
      side chains can be observed and linked to interactions with a ligand, agonist,
      effector, or redox partner.

PMID- 15185366
TI  - Loading of the antigen-presenting protein CD1d with synthetic glycolipids.
AB  - CD1 proteins present mammalian and microbial lipid and glycolipid antigens to
      different subsets of T cells. Few such antigens have been identified and the
      binding of these to CD1 molecules has mainly been studied by using responding T
      cells in cellular assays or recombinant solid-phase CD1 proteins. In the present
      study we use four different glycolipids, some of which contain tumor-associated
      carbohydrate antigens, to develop a procedure to easily detect binding of
      glycolipids to CD1 proteins on viable cells. Two of these glycolipids are novel
      glycoconjugates containing alpha-D-N-acetylgalactosamine (alpha-GalNAc) that were
      prepared by a combined solution and solid-phase approach. The key step, a Fischer
      glycosylation of 9-fluorenylmethoxycarbonylaminoethanol with GalNAc, furnished
      the alpha-glycoside 4 in 34% yield. Cells were incubated with glycolipids and
      stained with monoclonal antibodies specific for the carbohydrate part. The level
      of glycolipid bound to cells was then determined by flow cytometry with a
      secondary antibody labeled with fluorescein isothiocyanate. All four glycolipids
      were found to bind to CD1d but with different selectivity. The loading was dose
      dependent and could be inhibited by an established CD1d ligand, alpha
      galactosylceramide. Through use of this procedure, glycolipids were selectively
      loaded onto CD1d expressed on professional antigen-presenting cells for future
      use as cellular vaccines. Moreover, the glycolipids described in this study
      represent novel CD1d-binding ligands that will be useful derivatives in the study
      of CD1d-dependent immune responses, for example, against tumors.

PMID- 15185367
TI  - Fluorescent labelled thiourea-bridged glycodendrons.
AB  - GlcNAc-coated glycodendrimers, which are polyvalent glycomimetics, display strong
      in vitro affinity for the rat natural killer cell protein-1A (NKR-P1A), a C-type
      lectin-like receptor of natural killer (NK) cells in rats, humans and some
      strains of mice. Administration of these compounds in vivo results in a
      substantial increase in the antitumour activity with involvement of the natural
      cell immunity. To clarify the in vitro and in vivo fate of these molecules, we
      synthesized labelled glycodendron analogues of the previously studied
      glycodendrimers. Labelling with fluorescent tags enabled the localization of the
      glycodendrons in white blood cells, tumours and other tissues by using different
      imaging techniques such as fluorescence and confocal microscopy. These studies
      are useful for probing the mechanism of action and fate of artificial ligands and
      the cell receptors involved.

PMID- 15185368
TI  - DDI-microFIA--A readily configurable microarray-fluorescence immunoassay based on
      DNA-directed immobilization of proteins.
AB  - We describe a chip-based immunoassay for multiplex antigen detection, based on
      the self-assembly of semi-synthetic DNA-protein conjugates to generate an easily
      configurable protein microarray. The general principle of this microarray
      fluorescence immunoassay (microFIA) is similar to that of a two-sided (sandwich)
      immunoassay. However, covalent single-stranded DNA-streptavidin conjugates are
      employed for the efficient immobilization of biotinylated capture antibodies
      through hybridization to complementary surface-bound DNA oligomers. In a model
      system, we use the DNA-directed immobilization (DDI) of antibodies to generate an
      antibody microarray for the parallel detection of the tumor marker human
      carcinoembryonic antigen (CEA), recombinant mistletoe lectin rViscumin (rVis),
      ceruloplasmin (CEP), and complement-1-inactivator (C1A) in human blood serum
      samples. Detection limits down to 400 pg mL(-1) are reached. In addition, we
      describe a method for the internal standardization of protein microarray
      analyses, based on the simultaneous measurement of constant amounts of the blood
      proteins CEP and C1 A, intrinsically present in human serum, to compensate for
      interexperimental variations usually occurring in microarray analyses. The
      standardization leads to a significantly higher data reliability and
      reproducibility in intra- and interassay measurements. We further demonstrate
      that the DDI-microFIA can also be carried out in a single step by tagging of the
      analyte simultaneously with both capture and detection antibody and subsequent
      immobilization of the immunocomplex formed, on the DNA microarray capture matrix.
      This protocol significantly reduces handling time and costs of analysis.

PMID- 15185369
TI  - Immunological optimization of a generic hydrophobic pocket for high affinity
      hapten binding and Diels-Alder activity.
AB  - Antibody 1E9, which binds a tetrachloronorbornene derivative with subnanomolar
      affinity and catalyzes the Diels-Alder reaction between tetrachlorothiophene
      dioxide and N-ethylmaleimide with high efficiency, arose from a family of highly
      restricted germ-line immunoglobulins that bind diverse hydrophobic ligands. Two
      somatic mutations, one at position L89 in the light chain (SerL89Phe) and another
      at position H47 in the heavy chain (TrpH47Leu), have been postulated to be
      responsible for the unusually high degree of shape and chemical complementarity
      observed in the crystal structure of 1E9 complexed with its hapten. To test this
      hypothesis, the germ-line sequence at these two positions was restored by site
      directed mutagenesis. The ensuing 160 to 3900-fold decrease in hapten affinity
      and the complete loss of catalytic activity support the hypothesis that these
      somatic mutations substantially remodel the antibody binding pocket. Mutation of
      the highly conserved hydrogen-bond donor AsnH35, which sits at the bottom of the
      active site and is a hallmark of this family of antibodies, is also catastrophic
      with respect to hapten binding and catalysis. In contrast, residues in the CDR H3
      loop, which contributes a significant fraction of the hapten-contacting protein
      surface, have a more subtle influence on the properties of 1E9. Interestingly,
      while most changes in this loop have neutral or modestly deleterious effects,
      replacement of MetH100b at the floor of the pocket with phenylalanine leads to a
      significant sevenfold increase in catalytic activity. The latter result is
      surprising given the unusually close fit of the parent antibody to the transition
      state analogue. Further fine-tuning of the interactions between 1E9 and its
      ligands by introducing mutations outside the active site could conceivably yield
      substantially more active catalysts.

PMID- 15185370
TI  - Membrane protein-lipid interactions in mixed micelles studied by NMR spectroscopy
      with the use of paramagnetic reagents.
AB  - For solution NMR studies of the structure and function of membrane proteins,
      these macromolecules have to be reconstituted and solubilized in detergent
      micelles. Detailed characterization of the mixed detergent/protein micelles is
      then of key importance to validate the results from such studies, and to evaluate
      how faithfully the natural environment of the protein in the biological membrane
      is mimicked by the micelle. In this paper, a selection of paramagnetic probes
      with different physicochemical properties are used to characterize the 60 kDa
      mixed micelles consisting of about 90 molecules of the detergent
      dihexanoylphosphatidylcholine (DHPC) and one molecule of the Escherichia coli
      outer-membrane protein X (OmpX), which had previously been extensively studied by
      solution NMR techniques. The observation of highly selective relaxation effects
      on the NMR spectra of OmpX and DHPC from a water-soluble relaxation agent and
      from nitroxide spin labels attached to lipophilic molecules, confirmed data
      obtained previously with more complex NMR studies of the diamagnetic OmpX/DHPC
      system, and yielded additional novel insights into the protein-detergent
      interactions in the mixed micelles. The application of paramagnetic probes to the
      well-characterized OmpX/DHPC system indicates that such probes should be widely
      applicable as an efficient support of NMR studies of the topology of mixed
      membrane protein-detergent micelles.

PMID- 15185371
TI  - Synthesis of new boron-rich building blocks for boron neutron capture therapy or
      energy-filtering transmission electron microscopy.
AB  - The synthesis of a new ortho-carborane derivative, tetracarboranylketone 4, is
      reported here. Ketone 4 was prepared from a tetraalkynylated ketone by the
      addition of decaborane. The keto group was then easily modified to yield the
      glycosides 17alpha and 18beta, which contain glucose or galactose, respectively,
      and the nucleotide 13b. In addition to ketone 4, which is acyclic, cyclic ketone
      8 was also synthesised. X-ray diffraction analysis of compound 4 indicated the
      presence of two toluene guest molecules per molecule of the host compound.
      Furthermore, compound 4 displays a rather low cytotoxicity. These novel products
      can be used as building blocks to create a new class of biomolecules containing
      high-density carborane clusters. Such molecules may constitute powerful tools for
      applications like Boron Neutron Capture Therapy or Energy-Filtering Transmission
      Electron Microscopy.

PMID- 15185372
TI  - Design, synthesis, and biological evaluation of aminoboronic acids as growth
      factor receptor inhibitors of EGFR and VEGFR-1 tyrosine kinases.
AB  - A series of aminoboronic acids was synthesized based on the structure of
      lavendustin pharmacophore 1. Their inhibitory activities against the epidermal
      growth-factor receptor (EGFR) and vascular endothelial growth-factor receptor-1
      (VEGFR-1, Flt-1) protein tyrosine kinases, and various protein kinases, PKA, PKC,
      PTK, and eEF2K were evaluated. Selective inhibition activities were observed in a
      series of aminoboronic acids. 4-Methoxy-3-((2-
      methoxyphenylamino)methyl)phenylboronic acid 10 inhibited EGFR tyrosine kinase,
      whereas 4-(2,5-dihydroxybenzylamino)phenylboronic acid 12 inhibited Flt-1 protein
      kinase, although lavendustin pharmacophore 1 inhibited both EGFR and Flt-1
      kinases at a compound concentration of 1.0 microg mL(-1). The selective
      inhibition of EGFR by 10 is considered to be due to the substitution of the
      dihydroxy groups on the benzyl moiety for a boronic acid group at the para
      position, whereas the selective inhibition of Flt-1 by 12 is due to the
      substitution of the carboxyl group on the aniline moiety in the lavendustin
      pharmacophore 1 for a boronic acid group.

PMID- 15185373
TI  - Autodisplay of active sorbitol dehydrogenase (SDH) yields a whole cell
      biocatalyst for the synthesis of rare sugars.
AB  - Whole cell biocatalysts are attractive technological tools for the regio- and
      enantioselective synthesis of products, especially from substrates with several
      identical reactive groups. In the present study, a whole cell biocatalyst for the
      synthesis of rare sugars from polyalcohols was constructed. For this purpose,
      sorbitol dehydrogenase (SDH) from Rhodobacter sphaeroides, a member of the short
      chain dehydrogenase/reductase (SDR) family, was expressed on the surface of
      Escherichia coli using Autodisplay. Autodisplay is an efficient surface display
      system for Gram-negative bacteria and is based on the autotransporter secretion
      pathway. Transport of SDH to the outer membrane was monitored by SDS-PAGE and
      Western blotting of different cell fractions. The surface exposure of the enzyme
      could be verified by immunofluorescence microscopy and fluorescence activated
      cell sorting (FACS). The activity of whole cells displaying SDH at the surface
      was determined in an optical test. Specific activities were found to be 12 mU per
      3.3 x 10(8) cells for the conversion of D-glucitol (sorbitol) to D-fructose, 7 mU
      for the conversion D-galactitol to D-tagatose, and 17 mU for the conversion of L
      arabitol to L-ribulose. The whole cell biocatalyst obtained by surface display of
      SDH could also produce D-glucitol from D-fructose (29 mU per 3.3 x 10(8) cells).

PMID- 15185374
TI  - Exploring recombinant flavonoid biosynthesis in metabolically engineered
      Escherichia coli.
AB  - Flavonoids are important plant-specific secondary metabolites synthesized from 4
      coumaroyl coenzyme A (CoA), derived from the general phenylpropanoid pathway, and
      three malonyl-CoAs. The synthesis involves a plant type III polyketide synthase,
      chalcone synthase. We report the cloning and coexpression in Escherichia coli of
      phenylalanine ammonia lyase, cinnamate-4-hydroxylase, 4-coumarate:CoA ligase, and
      chalcone synthase from the model plant Arabidopsis thaliana. Simultaneous
      expression of all four genes resulted in a blockage after the first enzymatic
      step caused by the presence of nonfunctional cinnamate-4-hydroxylase. To overcome
      this problem we fed exogenous 4-coumaric acid to induced cultures. We observed
      high-level production of the flavanone naringenin as a result. We were also able
      to produce phloretin by feeding cultures with 3-(4-hydroxyphenyl)propionic acid.
      Feeding with ferulic or caffeic acid did not yield the corresponding flavanones.
      We have also cloned and partially characterized a new tyrosine ammonia lyase from
      Rhodobacter sphaeroides. Tyrosine ammonia lyase was substituted for phenylalanine
      ammonia lyase and cinnamate-4-hydroxylase in our E. coli clones and three
      different growth media were tested. After 48 h induction, high-level production
      (20.8 mg L(-1)) of naringenin in metabolically engineered E. coli was observed
      for the first time.

PMID- 15185375
TI  - Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely
      related compounds as potent and selective dopamine D3 receptor ligands.
AB  - Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are
      structurally related to the partial agonist BP 897, a series of novel, selective
      dopamine D3 receptor antagonists has been synthesised. Derivatisation included
      changes in the arylamide moiety and the tetrahydroisoquinoline substructure
      leading to compounds with markedly improved selectivities and affinities in the
      low nanomolar concentration range. From the 55 structures presented here, (E)-3
      (4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has
      high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor
      relative to the D2 receptor subtype. Its pharmacological profile offers the
      prospect of a novel radioligand as a tool for various dopamine D3-receptor
      related in vitro and in vivo investigations.

PMID- 15185376
TI  - Synthesis of metal-carbonyl-dendrimer-antibody immunoconjugates: towards a new
      format for carbonyl metallo immunoassay.
AB  - We report the preparation of metal-carbonyl-dendrimer-antibody conjugates. These
      metal-carbonyl-multilabeled antibodies are designed to be used in a new solid
      phase-format carbonyl metallo immunoassay (CMIA). A fourth-generation
      polyamidoamine dendrimer was labeled with 10-25 (eta5-cyclopentadienyl)iron
      dicarbonyl (eta1-N-succinimidyl) entities. An antibody was chemically modified at
      its carbohydrate chains by a site-directed process used to preserve the antigen
      antibody binding site. The antibody was then coupled with the dendrimer labeled
      with 10 metal carbonyl groups. An average of 1.4 labeled dendrimers were grafted
      per antibody molecule. These metal-carbonyl-dendrimer-antibody conjugates were
      used as new universal detection reagents that recognize their specific antigens.
      The antigens were spotted onto nitrocellulose membranes and detected by using the
      conjugates in combination with Fourier transform infrared spectroscopy. A
      detection level in the range 5-200 pmol per membrane was achieved. This approach
      opens the way to a new CMIA format.

PMID- 15185377
TI  - Selective inhibition of HIV-1 reverse transcriptase (HIV-1 RT) RNase H by small
      RNA hairpins and dumbbells.
AB  - We present here the design of a novel class of RNA inhibitors of the RNase H
      domain of HIV-1 RT, a ribonuclease activity that is essential for viral
      replication in vivo. Specifically, we show that small RNA hairpins and dumbbells
      can selectively inhibit the RNase H activity of HIV-1 RT without affecting other
      cellular RNases H (e.g., E. coli and human RNase H). These results suggest that
      the inhibitors do not interact with the nucleic acid binding site of RT RNase H,
      as this region should be well conserved among the various enzymes. The most
      potent inhibitors displayed IC50 values in the 3-8 microM range. Remarkably, the
      DNA polymerase activity, an intrinsic property of HIV RT, was not inhibited by
      the hairpin and dumbbell aptamers, a property not previously observed for any
      nucleic acid aptamer directed against RT RNase H. The results described here
      suggest a noncompetitive binding mechanism, as outlined in the differential
      inhibitory characteristics of each of the nucleic acid aptamers against the
      bacterial, human, and viral RNase H homologues.

PMID- 15185378
TI  - New rapamycin derivatives by precursor-directed biosynthesis.

PMID- 15185379
TI  - Evaluation of distance metrics for ligand-based similarity searching.

PMID- 15185380
TI  - Benzophenone photophore flexibility and proximity: molecular and crystal-state
      structure of a Bpa-containing trichogin dodecapeptide analogue.

PMID- 15185383
TI  - Should physicians' dual practice be limited? An incentive approach.
AB  - We develop a principal-agent model to analyze how the behavior of a physician in
      the public sector is affected by his activities in the private sector. We show
      that the physician will have incentives to over-provide medical services when he
      uses his public activity as a way of increasing his prestige as a private doctor.
      The health authority only benefits from the physician's dual practice when it is
      interested in ensuring a very accurate treatment for the patient. Our analysis
      provides a theoretical framework in which some actual policies implemented to
      regulate physicians' dual practice can be addressed. In particular, we focus on
      the possibility that the health authority offers exclusive contracts to
      physicians and on the implications of limiting physicians' private earnings.

PMID- 15185384
TI  - Decomposing the effects of children's health on mother's labor supply: is it time
      or money?
AB  - In this paper, I explore how children's health influences the wages and work
      hours of their mother. Some children have illnesses that require expensive
      medicine or treatment, but demand little parental time. Others require
      extraordinary amounts of time; and still others require care at unpredictable
      times of the day. I construct a theoretical model of mother's labor supply that
      explicitly incorporates the financial and time costs associated with the presence
      of unhealthy children. The model predicts that children with time-intensive
      illnesses and those with unpredictable illnesses negatively influence mother's
      labor supply, whereas children with illnesses with a strong financial component
      have a positive effect on mother's labor supply. In order to empirically test
      this, I organize a focus group of doctors to categorize illnesses and
      disabilities by the type of resources they require. Using the 1997 PSID Child
      Development Supplement, I estimate the effects of these requirements on mother's
      decision to work and work hours. After controlling for the financial burden of
      the illness, single mothers work fewer hours if their child has a time-intensive
      illness and married mothers are less likely to work and work fewer hours if their
      child has a severe condition with an unpredictable time component. These findings
      are consistent with the theoretical model and highlight the need to decompose the
      effects of child health on mother's work status. Model specifications that
      aggregate across illnesses are incapable of disentangling these effects and may
      therefore underestimate the welfare costs of having a sick child in the family.

PMID- 15185385
TI  - Aging and aggregate costs of medical care: conceptual and policy issues.
AB  - The conventional wisdom says that because the cost of health care for the aged is
      more than that of the young at any time, there is a positive relationship between
      the aging or higher life expectancy of the population and aggregate health care
      spending. It is difficult, however, to find evidence to support this argument. We
      present a simple framework that shows how aging of the population may not
      necessarily increase the total cost of medical care over time or be observed
      across nations. This follows because numerous other factors that change with
      aging affect cost of care in ways that are not age-neutral. Such factors include
      age-specific shifts in morbidity and mortality, growth in income and insurance
      coverage, rising levels of education and changing technology. Consequently, the
      relative medical costs of the aged may indeed increase, at least for demographic
      reasons. Simultaneously, however, the costs of the young may decrease for the
      same reasons. The Israeli experience, used as a basis for a cursory empirical
      discussion of the issues, supports the line of reasoning presented in the paper.

PMID- 15185386
TI  - Using stated preference and revealed preference modeling to evaluate prescribing
      decisions.
AB  - The use of stated preference analyses to evaluate choice of health care products
      has been growing in recent years. This paper shows how revealed preference data
      can be enriched with stated preference data and highlights the relative
      advantages of revealed and stated preference data. The techniques were applied to
      a study of determinants of physicians' prescriptions of alcoholism medications.
      Analyses were conducted on the relationship between physicians' perceptions of
      existing alcoholism medication attributes and their prescribing rates of those
      medications. Analyses were also conducted on physicians' decisions to prescribe
      hypothetical alcoholism medications with varying attributes such as efficacy,
      side effects, compliance, mode of action, and price. Finally, analyses were
      conducted on the combined stated and revealed preference data. Joint estimation
      suggests that parameters from the revealed and stated preference data are equal,
      up to scale. Joint analyses highlight how stated preference data can be used to
      estimate parameters for attributes that are not observed in the marketplace, that
      do not vary in the marketplace, or that are highly collinear with other
      attributes in actual markets.

PMID- 15185387
TI  - How property rights and patents affect antibiotic resistance.
AB  - Antibiotic resistance tends to increase when a patent on an antibiotic expires.
      Since other companies can now sell the antibiotic, more of the antibiotic is
      produced and prices fall. Because the benefits of reducing current production go
      to other firms, pharmaceutical companies will have little concern about future
      resistance. This 'open-access' problem causes excessive antibiotic use and
      resistance problems in the future. Extending patents is one solution. However, a
      pharmaceutical company that has patent protection on a drug that is cross
      resistant may have little concern about future resistance. This is because when
      people use completely different antibiotics which cause bacteria to become
      resistant to the original antibiotic, then the benefits of reducing current
      production go to other companies. A single buyer such as national health
      insurance or private health insurance may also have an incentive to reduce
      antibiotic resistance since they bear the future cost of future resistance.
      However, insurance coverage reduces the price that patients pay at the margin and
      thus the patients are likely to use more antibiotics. National health insurance
      policies may even set the price of antibiotics so low that resistance problems
      are created even when the patent is in effect.

PMID- 15185388
TI  - Resistance-induced antibiotic substitution.
AB  - In many cases, physicians prescribe antibiotics without knowing whether an
      individual patient is infected with a susceptible or resistant pathogen. As the
      proportion of resistant organisms in a community increases, physicians substitute
      away from older-inexpensive drugs to newer, more expensive agents as first line
      therapy. This paper explores the implications of resistance-induced antibiotic
      substitution for epidemiological models to predict future resistance levels,
      efforts to measure the health care costs associated with resistance, and policies
      to improve physicians' antibiotic prescribing decisions. The extent of resistance
      induced substitution in outpatient settings is documented using a data set
      consisting of observations on initial physician office visits for otitis media in
      the US controlling for new product introductions and price increases, per
      prescription antibiotic spending increased by 22% between 1980 and 1996,
      corresponding to a steep increase in resistance levels over the same period.

PMID- 15185389
TI  - Price discrimination in obstetric services--a case study in Bangladesh.
AB  - This article examines the existence of price discrimination for obstetric
      services in two private hospitals in Bangladesh, and considers the welfare
      consequences of such discrimination, i.e. whether or not price discrimination
      benefited the poorer users. Data on 1212 normal and caesarean section patients
      discharged from the two hospitals were obtained. Obstetric services were chosen
      because they are relatively standardised and the patient population is relatively
      homogeneous, so minimising the scope and scale of product differentiation due to
      procedure and case-mix differences. The differences between the hospital list
      price for delivery and actual prices paid by patients were calculated to
      determine the average rate of discount. The welfare consequences of price
      discrimination were assessed by testing the differences in mean prices paid by
      patients from three income groups: low, middle and high. The results suggest that
      two different forms of price discrimination for obstetric services occurred in
      both these hospitals. First, there was price discrimination according to income,
      with the poorer users benefiting from a higher discount rate than richer ones;
      and second, there was price discrimination according to social status, with three
      high status occupational groups (doctors, senior government officials, and large
      businessmen) having the highest probability of receiving some level of discount.

PMID- 15185390
TI  - Muller cell response to laser-induced increase in intraocular pressure in rats.
AB  - The goal of this study was to investigate the reaction of the Muller cells to
      elevated intraocular pressure (IOP). Elevated IOP is one of the risk factors in
      glaucomatous retinal ganglion cell (RGC) degeneration. Muller cells play an
      important role in retinal homeostasis. The reaction of Muller cells was examined
      by evaluating temporal changes in glutamate aspartate transporter (GLAST),
      glutamine synthase (GS), glial fibrillary acidic protein (GFAP), and the B-cell
      lymphoma (Bcl-2) using immunoblotting and immunohistochemical techniques. After
      IOP was elevated for 4-60 days, there was a time-related decrease in RGC ranging
      from 6% to 44%. There was also a time-related increase in GLAST protein reaching
      maximum after 3 weeks of elevated IOP. On the other hand, there was very little
      change in the expression of GS during the first 2 weeks followed by some increase
      between 21 and 60 days. An increase in Bcl-2 was biphasic with maximum increase
      after 4 days followed by decline after 15 and 21 days. GFAP, which is usually not
      expressed in normal Muller cells, was present at all time points. In all cases,
      the increase was most intense in the vicinity of the ganglion cells where the
      astrocytes and endfeet of the Muller cells are located. These results indicate
      that Muller cells react to the insult of elevated IOP by expressing GFAP and Bcl
      2, proteins that are expressed in reactive gliosis and other pathological
      conditions. The increase in GLAST along with minimum change in GS indicates a
      disturbance in glutamate homeostasis.

PMID- 15185391
TI  - FK506 enhances regeneration of axons across long peripheral nerve gaps repaired
      with collagen guides seeded with allogeneic Schwann cells.
AB  - We assessed the effects of FK506 administration on regeneration after a 6-mm gap
      repair with a collagen guide seeded with allogeneic Schwann cells (SCs) in the
      mouse sciatic nerve. SCs were isolated from predegenerated adult sciatic nerves
      and expanded in culture using a defined medium, before being seeded in the
      collagen guide embedded in Matrigel. Functional reinnervation was evaluated by
      noninvasive methods to determine recovery of motor, sensory, and autonomic
      functions in the hindpaw over 4 months postoperation. Histological analysis of
      the regenerated nerves was performed at the end of the study. Using simple
      collagen guides for tubulization repair, treatment with an immunosuppressant dose
      of FK506 (5 mg/kg/day) resulted in significant improvement of the onset and the
      degree of reinnervation. While the introduction of allogeneic SCs did not improve
      regeneration versus a collagen guide filled only with Matrigel, treatment with
      FK506 allowed for successful regeneration in all the mice and for significant
      improvement in the levels of functional recovery. Compared with the untreated
      group, there was greater survival of transplanted pre-labeled SCs in the FK506
      treated animals. Morphologically, the best nerve regeneration (in terms of nerve
      caliber and numbers of myelinated axons) was obtained with SC-seeded guides from
      FK506-treated animals. Thus, FK506 should be considered as adjunct therapy for
      various types of tubulization repair.

PMID- 15185392
TI  - Ensheathing cell cultures from the olfactory bulb and mucosa.
AB  - Transplantation of cells cultured from the nerve layers of the adult rat
      olfactory bulb has been shown to repair CNS tract injuries. The precise cellular
      composition of the culture appears to be important for this effect. Comparison
      was made of tissue cultured from the adult rat olfactory mucosa with that from
      the olfactory bulb. Both yielded mixtures of p75 immunoreactive cells and
      fibronectin immunoreactive cells. In sequential observations over 21 days in
      culture, the population of p75-expressing cells was maintained and continued to
      proliferate for longer in the samples from the olfactory mucosa. For derivation
      of cells for transplantation, the mucosa can be accessed without the need for
      intracranial surgery.

PMID- 15185393
TI  - Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4.1,
      and the water-permeable channel, AQP4, via a dystroglycan-containing complex in
      astrocytes.
AB  - Dystroglycan (DG) is part of a multiprotein complex that links the extracellular
      matrix to the actin cytoskeleton of muscle fibers and that is involved in
      aggregating acetylcholine receptors at the neuromuscular junction. This complex
      is also expressed in regions of the central nervous system where it is localized
      to both neuronal and glial cells. DG and the inwardly rectifying potassium
      channels, Kir4.1, are concentrated at the interface of astroglia and small blood
      vessels. These channels are involved in siphoning potassium released into the
      extracellular space after neuronal excitation. This raises the possibility that
      DG may be involved in targeting Kir4.1 channels to specific domains of astroglia.
      To address this question, we used mixed hippocampal cultures to investigate the
      distribution of DG, syntrophin, dystrobrevin, and Kir4.1 channels, as well as
      aquaporin-permeable water channels, AQP4. These proteins exhibit a similar
      distribution pattern and form aggregates in astrocytes cultured on laminin. Both
      DG and syntrophin colocalize with Kir4.1 channel aggregates in astrocytes.
      Similarly, DG colocalizes with AQP4 channel aggregates. Quantitative studies show
      a significant increase of Kir4.1 and AQP4 channel aggregates in astrocytes
      cultured in the presence of laminin when compared with those in the absence of
      laminin. These findings show that laminin has a role in Kir4.1 and AQP4 channel
      aggregation and suggest that this may be mediated via a dystroglycan-containing
      complex. This study reveals a novel functional role for DG in brain including K+
      buffering and water homeostasis.

PMID- 15185394
TI  - Olfactory ensheathing cell grafts have minimal influence on regeneration at the
      dorsal root entry zone following rhizotomy.
AB  - The effectiveness of grafts of olfactory ensheathing cells (OECs) as a means of
      promoting functional reconnection of regenerating primary afferent fibers was
      investigated following dorsal root injury. Adult rats were subjected to dorsal
      root section and reanastomosis and at the same operation a suspension of purified
      OECs was injected at the dorsal root entry zone and/or into the sectioned dorsal
      root. Regeneration of dorsal root fibers was then assessed after a survival
      period ranging from 1 to 6 months. In 11 animals, electrophysiology was used to
      look for evidence of functional reconnection of regenerating dorsal root fibers.
      However, electrical stimulation of lesioned dorsal roots failed to evoke
      detectable cord dorsum or field potentials within the spinal cord of any of the
      animals examined, indicating that reconnection of regenerating fibers with spinal
      cord neurones had not occurred. In a further 11 rats, immunocytochemical labeling
      and biotin dextran tracing of afferent fibers in the lesioned roots was used to
      determine whether regenerating fibers were able to grow into the spinal cord in
      the presence of an OEC graft. Although a few afferent fibers could be seen to
      extend for a limited distance into the spinal cord, similar minimal in-growth was
      seen in control animals that had not been injected with OECs. We therefore
      conclude that OEC grafts are of little or no advantage in promoting the in-growth
      of regenerating afferent fibers at the dorsal root entry zone following
      rhizotomy.

PMID- 15185395
TI  - Astrocyte-induced regulatory T cells mitigate CNS autoimmunity.
AB  - Although astrocytes presumably participate in maintaining the immune privilege of
      the central nervous system (CNS), the mechanisms behind their immunoregulatory
      properties are still largely undefined. In this study, we describe the
      development of regulatory T cells upon contact with astrocytes. Rat T cells pre
      incubated with astrocytes completely lost the ability to proliferate in response
      to mitogenic stimuli. The cells were blocked in G0/G1 phase of the cell cycle,
      expressed less IL-2R, and produced significantly lower amounts of interferon
      gamma (IFN-gamma), but not interleukin-2 (IL-2), IL-10, or tumor necrosis factor
      (TNF). These anergic cells completely prevented mitogen-induced growth of normal
      T lymphocytes, as well as CNS antigen-driven proliferation of autoreactive T
      cells. The suppressive activity resided in both CD4+ and CD8+ T-cell
      compartments. Heat-sensitive soluble T-cell factors, not including transforming
      growth factor-beta (TGF-beta) or IL-10, were solely responsible for the observed
      suppression, as well as for the transfer of suppressive activity to normal T
      cells. The administration of astrocyte-induced regulatory T cells markedly
      alleviated CNS inflammation and clinical symptoms of CNS autoimmunity in rats
      with experimental allergic encephalomyelitis. Finally, the cells with suppressive
      properties were readily generated from human lymphocytes after contact with
      astrocytes. Taken together, these data indicate that astrocyte-induced regulatory
      T cells might represent an important mechanism for self-limitation of excessive
      inflammation in the brain.

PMID- 15185396
TI  - Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased
      Rheb/S6K pathway signaling important for astrocyte cell size regulation.
AB  - Individuals with tuberous sclerosis complex (TSC) develop central nervous system
      abnormalities that may reflect astrocyte dysfunction. In an effort to model
      astrocyte dysfunction in TSC, we generated mice lacking Tsc1 (hamartin)
      expression in astrocytes and demonstrated that Tsc1-null astrocytes exhibit
      abnormalities in contact inhibition growth arrest. In this study, we demonstrate
      that hamartin-deficient astrocytes are also defective in cell size regulation. We
      show that the increase in Tsc1-null astrocyte size is associated with increased
      activation of the S6-kinase pathway. In keeping with recent reports that the
      hamartin/tuberin complex may regulate Rheb and downstream S6K activation, we
      demonstrate that expression of either Rheb or S6K in primary astrocytes results
      in increased S6 pathway activation, and that inhibition of Rheb activity in Tsc1
      deficient astrocytes using either pharmacologic or genetic strategies markedly
      reduces S6 activation. Collectively, these observations suggest that TSC
      inactivation in astrocytes results in defective cell size regulation associated
      with dysregulated Rheb/mTOR/S6K pathway activity.

PMID- 15185398
TI  - Case-control association studies with matching and genomic controlling.
AB  - Family-based association studies have gained in popularity for mapping disease
      susceptibility gene(s) of complex diseases. However, recruiting family controls
      is often more difficult than recruiting unrelated controls. The author proposes a
      case-control study, where the possible biases due to population stratification
      are controlled by matching in the design stage and by genomic controlling in the
      data-analytic stage. The matching is based on a set of "stratum-delineating
      variables," such as, race, ethnicity, nationality, ancestry, and birthplace; and
      the genomic controlling is based on typing a number of null markers across the
      genome and applying the principle of multiplicative scaling of chi-square
      distribution. It pays to match carefully to have a higher proportion of correctly
      matched sets, as computer simulation showed that this would increase the power of
      the study. If matching is crude, one loses power but still has the correct type I
      error rate after genomic controlling. Power studies showed that the numbers of
      affected subjects required for the pair-matched study are comparable to those
      required by the case-parents design, if the study was conducted in a homogeneous
      population. As the (control-to-case) matching ratio increases, the number of
      affected subjects required decreases. With matching ratio tending toward
      infinity, the number required shrinks roughly by half. The case-control study
      with matching and genomic controlling frees us from family bondage, and the
      genetic problem as complicated as mapping genes can now be studied using simple
      epidemiologic methods.

PMID- 15185397
TI  - Peripherally-derived olfactory ensheathing cells do not promote primary afferent
      regeneration following dorsal root injury.
AB  - Olfactory ensheathing cells (OECs) may support axonal regrowth, and thus might be
      a viable treatment for spinal cord injury (SCI); however, peripherally-derived
      OECs remain untested in most animal models of SCI. We have transplanted OECs from
      the lamina propria (LP) of mice expressing green fluorescent protein (GFP) in all
      cell types into immunosuppressed rats with cervical or lumbar dorsal root
      injuries. LP-OECs were deposited into either the dorsal root ganglion (DRG),
      intact or injured dorsal roots, or the dorsal columns via the dorsal root entry
      zone (DREZ). LP-OECs injected into the DRG or dorsal root migrated centripetally,
      and migration was more extensive in the injured root than in the intact root.
      These peripherally deposited OECs migrated within the PNS but did not cross the
      DREZ; similarly, large- or small-caliber primary afferents were not seen to
      regenerate across the DREZ. LP-OEC deposition into the dorsal columns via the
      DREZ resulted in a laminin-rich injection track: due to the pipette trajectory,
      this track pierced the glia limitans at the DREZ. OECs migrated centrifugally
      through this track, but did not traverse the DREZ; axons entered the spinal cord
      via this track, but were not seen to reenter CNS tissue. We found a preferential
      association between CGRP-positive small- to medium-diameter afferents and OEC
      deposits in injured dorsal roots as well as within the spinal cord. In the cord,
      OEC deposition resulted in increased angiogenesis and altered astrocyte
      alignment. These data are the first to demonstrate interactions between sensory
      axons and peripherally-derived OECs following dorsal root injury.

PMID- 15185399
TI  - Evaluating bias due to population stratification in case-control association
      studies of admixed populations.
AB  - The potential for bias from population stratification (PS) has raised concerns
      about case-control studies involving admixed ethnicities. We evaluated the
      potential bias due to PS in relating a binary outcome with a candidate gene under
      simulated settings where study populations consist of multiple ethnicities.
      Disease risks were assigned within the range of prostate cancer rates of African
      Americans reported in SEER registries assuming k=2, 5, or 10 admixed ethnicities.
      Genotype frequencies were considered in the range of 5-95%. Under a model
      assuming no genotype effect on disease (odds ratio (OR)=1), the range of observed
      OR estimates ignoring ethnicity was 0.64-1.55 for k=2, 0.72-1.33 for k=5, and
      0.81-1.22 for k=10. When genotype effect on disease was modeled to be OR=2, the
      ranges of observed OR estimates were 1.28-3.09, 1.43-2.65, and 1.62-2.42 for k=2,
      5, and 10 ethnicities, respectively. Our results indicate that the magnitude of
      bias is small unless extreme differences exist in genotype frequency. Bias due to
      PS decreases as the number of admixed ethnicities increases. The biases are
      bounded by the minimum and maximum of all pairwise baseline disease odds ratios
      across ethnicities. Therefore, bias due to PS alone may be small when baseline
      risk differences are small within major categories of admixed ethnicity, such as
      African Americans.

PMID- 15185400
TI  - Maximum-likelihood estimation of haplotype frequencies in nuclear families.
AB  - The importance of haplotype analysis in the context of association fine mapping
      of disease genes has grown steadily over the last years. Since experimental
      methods to determine haplotypes on a large scale are not available, phase has to
      be inferred statistically. For individual genotype data, several reconstruction
      techniques and many implementations of the expectation-maximization (EM)
      algorithm for haplotype frequency estimation exist. Recent research work has
      shown that incorporating available genotype information of related individuals
      largely increases the precision of haplotype frequency estimates. We, therefore,
      implemented a highly flexible program written in C, called FAMHAP, which
      calculates maximum likelihood estimates (MLEs) of haplotype frequencies from
      general nuclear families with an arbitrary number of children via the EM
      algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative
      mode of the EM-algorithm, which gives reliable approximations of the MLEs for up
      to 63 SNP loci, or less when multi-allelic markers are incorporated into the
      analysis. Missing genotypes can be handled as well. The program is able to
      distinguish cases (haplotypes transmitted to the first affected child of a
      family) from pseudo-controls (non-transmitted haplotypes with respect to the
      child). We tested the performance of FAMHAP and the accuracy of the obtained
      haplotype frequencies on a variety of simulated data sets. The implementation
      proved to work well when many markers were considered and no significant
      differences between the estimates obtained with the usual EM-algorithm and those
      obtained in its locus-iterative mode were observed. We conclude from the
      simulations that the accuracy of haplotype frequency estimation and
      reconstruction in nuclear families is very reliable in general and robust against
      missing genotypes.

PMID- 15185401
TI  - Method for using complete and incomplete trios to identify genes related to a
      quantitative trait.
AB  - A number of tests for linkage and association with qualitative traits have been
      developed, with the most well-known being the transmission/disequilibrium test
      (TDT). For quantitative traits, varying extensions of the TDT have been
      suggested. The quantitative trait approach we propose is based on extending the
      log-linear model for case-parent trio data (Weinberg et al. [1998] Am. J. Hum.
      Genet. 62:969-978). Like the log-linear approach for qualitative traits, our
      proposed polytomous logistic approach for quantitative traits allows for
      population admixture by conditioning on parental genotypes. Compared to other
      methods, simulations demonstrate good power and robustness of the proposed test
      under various scenarios of the genotype effect, distribution of the quantitative
      trait, and population stratification. In addition, missing parental genotype data
      can be accommodated through an expectation-maximization (EM) algorithm approach.
      The EM approach allows recovery of most of the lost power due to incomplete
      trios.

PMID- 15185402
TI  - Haplotype sharing correlation analysis using family data: a comparison with
      family-based association test in the presence of allelic heterogeneity.
AB  - The haplotype-sharing correlation (HSC) method for association analysis using
      family data is revisited by introducing a permutation procedure for estimating
      region-wise significance at each marker on a study segment. In simulation
      studies, the HSC method has a correct type 1 error rate in both unstructured and
      structured populations. The HSC signals on disease segments occur in the vicinity
      of a true disease locus on a restricted region without recombination hotspots.
      However, the peak signal may not pinpoint the true disease location in a small
      region with dense markers. The HSC method is shown to have higher power than
      single- and multilocus family-based association test (FBAT) methods when the true
      disease locus is unobserved among the study markers, and especially under
      conditions of weak linkage disequilibrium and multiple ancestral disease alleles.
      These simulation results suggest that the HSC method has the capacity to identify
      true disease-associated segments under allelic heterogeneity that go undetected
      by the FBAT method that compares allelic or haplotypic frequencies.

PMID- 15185403
TI  - Ordered subset analysis in genetic linkage mapping of complex traits.
AB  - Etiologic heterogeneity is a fundamental feature of complex disease etiology;
      genetic linkage analysis methods to map genes for complex traits that acknowledge
      the presence of genetic heterogeneity are likely to have greater power to
      identify subtle changes in complex biologic systems. We investigate the use of
      trait-related covariates to examine evidence for linkage in the presence of
      heterogeneity. Ordered-subset analysis (OSA) identifies subsets of families
      defined by the level of a trait-related covariate that provide maximal evidence
      for linkage, without requiring a priori specification of the subset. We propose
      that examining evidence for linkage in the subset directly may result in a more
      etiologically homogeneous sample. In turn, the reduced impact of heterogeneity
      will result in increased overall evidence for linkage to a specific region and a
      more distinct lod score peak. In addition, identification of a subset defined by
      a specific trait-related covariate showing increased evidence for linkage may
      help refine the list of candidate genes in a given region and suggest a useful
      sample in which to begin searching for trait-associated polymorphisms. This
      method provides a means to begin to bridge the gap between initial identification
      of linkage and identification of the disease predisposing variant(s) within a
      region when mapping genes for complex diseases. We illustrate this method by
      analyzing data on breast cancer age of onset and chromosome 17q [Hall et al.,
      1990, Science 250:1684-1689]. We evaluate OSA using simulation studies under a
      variety of genetic models.

PMID- 15185404
TI  - Multivariate linkage analysis of blood pressure and body mass index.
AB  - Multivariate linkage analyses of correlated traits provide greater statistical
      power to identify genetic loci with effects too small to be detected in single
      trait analyses. We conducted genomewide multivariate analyses of systolic BP,
      diastolic BP, and body mass index (BMI) in 1,848 non-Hispanic white subjects (968
      females, 880 males) from 279 multigenerational pedigrees from Rochester,
      Minnesota. Blood pressure was measured by random zero sphygmomanometer; body mass
      index was calculated from measurements of height and weight; and genotypes were
      measured at 520 microsatellite marker loci distributed across the 22 autosomes.
      Univariate linkage analyses demonstrated tentative evidence of linkage (defined
      by univariate LOD scores of 1.30-1.99) for diastolic BP on chromosome 18 and for
      BMI on chromosomes 3, 10, and 18. Bivariate linkage analyses showed tentative
      evidence of linkage (defined by bivariate LOD scores of 2.06-2.86) for systolic
      and diastolic BP on chromosome 14 and for either measure of BP and BMI on
      chromosomes 2, 3, 10, and 18; and suggestive evidence of linkage (defined by
      bivariate LOD scores of 2.87-3.99) for either measure of BP and BMI on
      chromosomes 10 and chromosome 15. Trivariate linkage analyses of systolic and
      diastolic BP and BMI provided evidence of a region influencing all three traits
      on chromosome 10, where the trivariate LOD score rose to a maximum value of 4.09
      (at 144 cM, P=0.0007), and possibly on chromosome 2, where it rose to a maximum
      value of 2.80 (at 77 cM, P=0.0075). For genomewide linkage analyses to succeed in
      localizing genes influencing BP, it may be advantageous to exploit the greater
      statistical power of multivariate linkage analyses to identify loci with
      pleiotropic effects on correlated traits.

PMID- 15185405
TI  - Consanguinity and endogamy in Northern Tunisia and its impact on non-syndromic
      deafness.
AB  - Deafness is an important health problem in the Tunisian population, especially in
      isolates where the prevalence ranges from 2 to 8%. To evaluate the effect of
      inbred unions on deafness, a study was conducted on 5,020 individuals (160 are
      deaf) between 2000 and 2002 in the North of Tunisia. The coefficient of
      inbreeding for all individuals and the levels of inbreeding in ten districts were
      computed. The higher levels were obtained in the rural districts. Our study
      revealed that geographic isolation, social traditions, and parental involvement
      in mode selection all contribute to increase consanguinity in these regions. The
      mean inbreeding seems to be similar to those estimated in highly inbred isolates
      in the world. The relative risk of the 35delG mutation, the single most frequent
      allele for non-syndromic recessive deafness in Tunisia, was estimated from the
      observed inbreeding coefficient and found to be 10.76 (SD 7.74) for first-cousin
      marriages, which are the most common form of consanguineous marriage encountered.
      Our knowledge of the risk rate of deafness and our understanding of consanguinity
      is required for the prevention of genetic deafness in the Tunisian population.

PMID- 15185406
TI  - Is haplotype block identification useful for association mapping studies?

PMID- 15185407
TI  - The campaign to revitalize academic medicine kicks off: we need a deep and broad
      international debate to begin.

PMID- 15185408
TI  - Academic medicine: one job or three?
AB  - Academic medicine consists of three vocations: clinical care, research, and
      teaching. Many argue that academic medicine is undergoing a crisis. In response
      to the crisis a debate has been initiated to discuss how to revitalize academic
      medicine. The debate is to examine "the fundamental nature of academic medicine."
      The present editorial seeks to explore one problematic feature of academic
      medicine: the fact that it consists of three vocations. This problematic feature
      is fundamental to academic medicine.

PMID- 15185409
TI  - Academic approach to academic medicine.
AB  - Scientific approach to academic medicine crisis would require research to provide
      evidence for the present state of academic medicine and future actions. The
      prerequisites for such a research would be clear definitions, appropriate
      indicators, and measuring instruments. The approach should be holistic, covering
      tripartite academic medicine activity: education, research, and health care.

PMID- 15185410
TI  - Academic medicine--experiences from Finland and suggestions for the future.
AB  - This article presents the basic facts about education, health care system, and
      academic medicine in Finland. The issue of the academic medicine in the world is
      discussed and Finnish models compared with those of the rest of the world.
      Possible solutions for the recovery of academic medicine, education, and research
      are proposed.

PMID- 15185411
TI  - Academic medicine: what does an outsider have to offer?
AB  - One of the many problems of academic medicine is its detachment from actual
      health problems of the population. Family medicine has a potential of bridging
      this gap. The paper describes the positive experience from introducing family
      medicine as a new academic discipline to the medical school in Slovenia. Its
      introduction was of benefit to family medicine, which has received recognition
      and has experienced a rapid academic growth. Medical academic establishment has
      benefited by being exposed to new ideas in research and education. The key to
      success was the fact that the academic world accepted a newcomer to its midst and
      that the newcomer managed to integrate its principles into the rules of the
      academic environment. The next step in this process is to apply some of the
      positive experiences of the family medicine department to the curriculum reform
      of the entire faculty.

PMID- 15185412
TI  - Academic medicine and quality of medical care.
AB  - Academic medicine comprises education, research, and medical care, respectively
      provided by medical schools, research institutions, and teaching hospitals. Thus
      far, academic medicine has been unsuccessful in establishing, protecting,
      promoting, and improving the quality of care. Its role in that area should
      therefore be reconsidered. Quality improvement activities require constant
      planning and perseverance, explicit standards of good practice, quantitative
      measurement, and comparison with previous performance or the performance of
      others. Preparedness and willingness to change attitude, approach, and behavior
      are pivotal to the success of such activities. Early exposure of medical students
      to the principles and practices of quality of care improvement would be a
      starting point for a life long process of experience-based learning that allows
      physicians to change and improve practice through the application of relevant
      knowledge and skills. It is essential that changes in graduate and postgraduate
      education and training be introduced, to improve an understanding of the
      importance of focusing on the care process from the patient's perspective as well
      as on the need for interdisciplinary cooperation and team performance as
      prerequisites for good medical care. Their education should also emphasize the
      measurement of the quality of delivered care, provide an understanding of the
      demand of society for accountability and how to meet it, as well as competence in
      using the principles and practice of quality improvement to provide, document,
      and improve the quality of care in institutions of academic medicine.

PMID- 15185413
TI  - Balancing traditional values in academic medicine with advances in science and
      technology.
AB  - Scientific discovery, population growth, and world commerce are converging to
      reshape medicine in unforeseen ways. Instead of responding passively to change we
      must embrace each challenge as an opportunity. Critical issues facing academic
      medicine today include a revolution in molecular biology and biotechnology,
      spiraling costs of health care, lack of consensus on a frame of reference for
      strategic planning (global versus local), and lack of appropriate methods of
      assessment (outcome analysis). These issues are complex and broad. Thus, it may
      be that the best that can emerge from our discussion is to identify the major
      dimensions along which progress may be expected and to predict ways in which
      change can be directed to serve the needs of health care institutions and medical
      professionals around the world. Solutions will require innovation in medical
      education, leadership, and international collaboration.

PMID- 15185414
TI  - Caring for academic ophthalmology in Croatia.
AB  - Like any other area of academic medicine in Croatia, academic ophthalmology has
      always been limited by or has depended on the factors outside the profession
      itself: during the communist regime, it was mostly political and ideological
      correctness of academic ophthalmologists, and today during the social and
      economic transition, it is the lack of finances, planning, and sophisticated
      technology. The four university eye clinics, which are the pillars of academic
      ophthalmology in Croatia, provide health care to most difficult cases, educate
      students, residents, and specialists, and do research. On the other hand, they
      lack equipment, room, and financial recognition. This ever growing imbalance
      between requirements imposed on academic ophthalmology today and its
      possibilities make it less and less attractive, especially in comparison with
      private practice. The possible solution lies in increasing the independence of
      ophthalmology from pharmaceutical industry and politics, especially in research
      and financial aspects.

PMID- 15185415
TI  - Open globe injuries: epidemiological study of two eye clinics in Germany, 1981
      1999.
AB  - AIM: To analyze the epidemiology of open eye globe injuries and their treatment
      outcomes in patients treated at two university eye clinics in Germany in the past
      two decades. METHODS: Retrospective analysis was performed of medical records of
      1,026 patients with open globe injuries primarily treated at the Universities of
      Freiburg and Wurzburg between January 1981 and December 1999. Final visual
      function was determined as a parameter of age, extent of injury, sex, cause of
      injury, and activity at the time of injury. Relative risk was calculated.
      RESULTS: After correction for the demographic distribution, the risk for open
      globe injury was 1.7 times the average for young adults and 0.6 for seniors. In
      the recent years, the risk for severe eye injury has been more equally
      distributed and is increasing for old people. The proportion of injuries at work
      decreased over the studied period from 42% to 32% for all open globe injuries,
      and the proportion of injuries in traffic accidents decreased from 30% to 4%. The
      number of eye injuries related to hobby activities increased. The proportion of
      enucleations and blindness decreased. Social life and income was moderately or
      severely impaired in 27% of patients after severe unilateral eye trauma. The
      median follow up of patients was 7 months. CONCLUSION: The prevalence and types
      of open globe injuries changed over the years, especially in relation to the law
      requiring seat belt use in traffic. The progress in surgical techniques led to a
      significant reduction in the number of blind eyes after injury. The proportion of
      enucleations and blindness decreased partly due to better surgical techniques,
      but mostly due to the decrease in injuries with usually poor outcome, such as
      gunshots, ruptures, and windscreen injuries.

PMID- 15185416
TI  - Fornix vs limbus based flap in phacotrabeculetomy with mitomycin C: prospective
      study.
AB  - AIM: To compare the efficacy and safety of fornix-based and limbus-based
      conjunctival flaps of phacotrabeculectomy with mitomycin C in patients with
      primary open angle glaucoma and cataract. METHODS: The study included 16 patients
      (6 men and 10 women) with primary open angle glaucoma and bilateral cataract. In
      each patient, phacotrabeculectomy with mitomycin C was performed on both eyes:
      the eye first operated received a fornix-based conjunctival flap, whereas the
      fellow eye was assigned to the limbus-based group. We compared preoperative and
      postoperative visual acuity, intraocular pressure, number of antiglaucoma
      medications, and postoperative complications between flap-based and limbus-based
      groups. RESULTS: There was no difference in the decrease in the mean intraocular
      pressure between the fornix-based and limbus-based groups after
      phacotrabeculectomy: from 22.1+/-4.4 mm Hg to 16.2+/-3.4 mm Hg in the fornix
      based group, and from 22.4+/-4.5 mm Hg to 15.9+/-3.2 mm Hg in the limbus-based
      group. The two groups also did not differ in the number of medications received
      either before or after the surgery. Early bleb leak was observed only in the
      fornix-based group (2 eyes). CONCLUSIONS: Phacotrabeculectomy with intraoperative
      mitomycin C was successful in regard to both reduction of intraocular pressure
      and glaucoma medications. There was no difference in the safety or efficacy of
      the procedure between groups receiving either fornix- or limbus-based flap,
      except for the early bleb leak, which was observed only in the fornix flap group.

PMID- 15185417
TI  - Incidence of acute angle-closure glaucoma in Dalmatia, southern Croatia.
AB  - AIM: To investigate the incidence of acute angle-closure glaucoma among residents
      of Dalmatia, southern part of Croatia. METHODS: We reviewed hospital records of
      176 patients with acute angle-closure glaucoma treated between January 1995 and
      December 2001 at the Departments of Ophthalmology at four hospitals in Dalmatia.
      There were 122 women, aged between 29 and 89 years (median age; 68 years), and 54
      men, aged between 33 and 88 years (median age, 70 years). RESULTS: The unadjusted
      crude incidence was 2.9/100,000 (95% confidence interval [CI], 1.6-4.5). The
      unadjusted crude incidence among men and women was 1.9 (95% CI, 0.3-3.8) and 3.9
      (95% CI, 1.7-6.1) cases/100,000 per year, respectively. The relative risk (RR) of
      developing acute angle-closure glaucoma was 2.1 (95% CI, 1.5-2.9) times higher
      for women as compared to men. The RR of acute angle-closure glaucoma was 1.9 (95%
      CI, 0.6-6.2) in the 40-49 years group, 6.5 (95% CI, 2.3-18.8) in the 50-59 years
      group, 17 (95% CI, 6.3-47.8) in the 60-69 years group, and 28 (95% CI, 10.4-77.3)
      in the over 69 years group. The median time from the onset of symptoms to
      presentation at the hospital was 2 days (range, 1-15 days). In 87 (48%) patients
      intraocular pressure control was achieved by medical treatment, 41 (23%) patients
      underwent peripheral iridectomy, and 48 (27%) patients required a trabeculectomy.
      In 35 (73%) out of 48 patients managed by filtering surgery, the delay in
      treatment was 3 or more days. In 34 (19%) eyes with final visual acuity 0.1 or
      worse, the delay in presentation was 3 days or more. No statistically significant
      association was found between acute angle-closure glaucoma and seasonal variation
      (chi-square=0.85; p=0.8). CONCLUSION: Earlier recognition of the patients with
      acute angle-closure glaucoma and a shorter time of delay in presentation could
      have saved many patients from surgery and vision loss each decade.

PMID- 15185418
TI  - Novel approach in the treatment of intravitreal foreign body and traumatic
      cataract: three case reports.
AB  - We present a novel surgical technique of simultaneous traumatic cataract
      extraction, internal magnet removal of the intraocular foreign body, and
      implantation of a posterior chamber intraocular lens in the eyes of three
      patients with traumatic cataract and ferrous intraocular foreign body retained in
      the anterior part of the vitreous body. Primary corneal wound repair, cataract
      extraction, anterior vitrectomy, removal of the intraocular foreign body through
      the corneoscleral limbal incision by using intraocular magnet, and intraocular
      lens implantation were performed. All intraocular foreign bodies and corneal
      entry sites were not larger than 3 mm. After a median follow-up of 13.6 months
      (range, 9-21 months), visual acuity ranged from 0.6 to 1.0. There were no early
      or late postoperative complications. According to our experience, an anterior
      approach in the surgical technique of simultaneous cataract extraction,
      intraocular foreign body extraction and implantation of a intraocular lens in the
      capsular bag is possible in selected patients with intraocular foreign bodies
      positioned in the anterior vitreous, behind the lens, with no associated retinal
      pathology.

PMID- 15185419
TI  - Surgical technique and postoperative complications in pediatric cataract surgery:
      retrospective analysis of 21 cases.
AB  - AIM: To evaluate postoperative complications of different surgical techniques for
      cataract treatment in children. METHODS: We reviewed clinical records of 21
      children (33 eyes) who underwent cataract surgery between January 1998 and
      December 2002. The median age of children at the time of cataract surgery was 39
      months (range, 4-115 months). The median follow up was 26 months (range, 6-58
      months). A posterior continuous curvilinear capsulorhexis with anterior
      vitrectomy was performed in 24 eyes, and posterior continuous curvilinear
      capsulorhexis without anterior vitrectomy in 9 eyes (children older than 7
      years). Nine eyes were left aphakic and intraocular lens was implanted in 24
      eyes. RESULTS: Opacification of the visual axis was the most frequent
      complication. One of nine eyes in the group of children undergoing posterior
      continuous curvilinear capsulorhexis developed posterior capsule opacification.
      This also occurred in 6 out of 24 eyes with posterior continuous curvilinear
      capsulorhexis and anterior vitrectomy. In 5 eyes with secondary opacification
      Nd:YAG laser capsulotomy was performed as a secondary procedure. In uncooperative
      children (2 eyes) more extensive anterior vitrectomy was repeated. Other
      postoperative complications included aphakic glaucoma (n=1), synechia formation
      (n=4), intraocular lens deposits (n=2), and pupil capture (n=1). CONCLUSIONS: The
      main complication in the pediatric cataract surgery was posterior capsule
      opacification, and the management of posterior capsule seems to be a very
      important factor. In younger children, cataract surgery with posterior
      capsulorhexis and anterior vitrectomy was advantageous, whereas in older children
      a clear visual axis was achieved without vitrectomy.

PMID- 15185420
TI  - Trauma of the lacrimal drainage system: retrospective study of 32 patients.
AB  - AIM: To assess retrospectively the results and complications of surgical
      techniques applied in the treatment of patients with trauma of the lacrimal
      drainage system. METHODS: Out of 32 patients with lacrimal drainage system trauma
      included in the study, 25 were treated at the University Eye Clinic, Ljubljana
      Medical Center, Ljubljana, Slovenia, from 1999 to 2003, and 7 were referred for
      secondary repair from other health care institutions in the same time period. All
      patients with fresh injuries underwent surgery within 48 h. The patients were
      followed up to a year after surgery. We evaluated the function of the lacrimal
      drainage system by irrigation at the last follow-up visit. RESULTS: Patent
      lacrimal drainage system was achieved in all 25 patients with primary
      reconstruction of the injury. Restenosis of the canaliculus occurred in 4 out of
      7 patients after secondary reconstruction. CONCLUSIONS: Early repair of the
      lacrimal drainage system eliminates complications in comparison with secondary
      repair. Repair of the lacrimal drainage system may be delayed for up to 48 h, if
      an experienced operating team is available.

PMID- 15185421
TI  - Combined clear cornea phacoemulsification, vitrectomy, foreign body extraction,
      and intraocular lens implantation.
AB  - AIM: To analyze the outcome of combined clear cornea phacoemulsification,
      vitrectomy, foreign body extraction, and intraocular lens implantation in
      patients with traumatic cataract and intraocular foreign body. METHODS:
      Retrospective analysis included the results of combined cataract and
      vitreoretinal surgery in 16 patients. All patients had a penetrating eye injury,
      traumatic cataract, and intraocular foreign body. Twelve patients had a corneal
      entry site and in 4 patients intraocular foreign body entered through the sclera.
      RESULTS: After a mean follow-up of 25.2 months, 10 out of 16 patients had a
      visual acuity of 0.1 or better. Postoperative complications were encountered in 4
      patients: 2 patients had retinal detachment, one had a massive retinal fibrosis,
      and one developed postoperative endophthalmitis. CONCLUSION: Simultaneous
      posterior chamber intraocular lens implantation with vitreoretinal surgery is
      safe in certain cases of severe ocular trauma due to intraocular foreign body.
      Visual outcome was mainly related to the underlying posterior segment pathology.

PMID- 15185422
TI  - Prognostic factors in open eye injury managed with vitrectomy: retrospective
      study.
AB  - AIM: To evaluate surgery results and establish prognostic factors that predicted
      final functional (good or poor vision) and anatomic (final retinal detachment)
      outcome in open eye injury involving the posterior segment managed with pars
      plana vitrectomy. METHODS: Medical records of 52 consecutive patients with open
      eye injury involving the posterior segment were retrospectively reviewed.
      Specific variables of a system for classifying mechanical injuries of the eye
      were analyzed: the type of injury (defined by the mechanism of injury), grade of
      injury (defined by initial visual acuity), zone of injury (defined by the
      location of the wound), and relative afferent pupillary defect. Additional
      variables, such as wound length, retinal detachment, endophthalmitis, and timing
      of vitrectomy, were also included in the analysis. Final visual outcome and
      retinal attachment rate were recorded. Data were analyzed with chi-square test,
      univariate analysis for predictors, and multivariate logistic regression
      analysis. RESULTS: After a mean follow up of 20.0+/-10.5 months, 50% of eyes
      achieved visual acuity 0.5 or better, 27% of eyes achieved visual acuity 0.1 or
      worse, and 10% of eyes had final retinal detachment. According to univariate
      analysis results, the following parameters were predictors of good vision (visual
      acuity > or =0.5 in comparison with visual acuity <0.5): grade of injury
      (p=0.008), zone of injury (p=0.01), afferent pupillary response (p<0.001), wound
      length (p=0.002), and initial retinal detachment (p=0.009). The predictors of
      poor vision (visual acuity < or =0.1 in comparison with visual acuity >0.1) were
      zone of injury (p<0.001), relative afferent pupillary defect (p<0.001), wound
      length (p=0.002), and initial retinal detachment (p<0.001). Relative afferent
      pupillary defect (p=0.003) and initial retinal detachment (p<0.001) were
      predictors of final retinal detachment with proliferative vitreoretinopathy.
      However, multivariate logistic regression analyses revealed that relative
      afferent pupillary defect was the only significant factor for poor visual acuity
      (odds ratio, 10.3; 95% confidence interval, 1.1-92; p=0.04). On the other hand,
      none of the variables was a significant independent predictor for either good
      visual acuity or final retinal detachment. CONCLUSION: Half of the eyes with a
      good final visual outcome in our study were successfully managed with pars plana
      vitrectomy for open eye injury after trauma. The classification system may become
      useful prognostic tool for visual outcome in posterior segment ocular injuries
      managed with vitrectomy. Relative afferent pupillary defect as a functional test
      is a good predictor for visual outcome.

PMID- 15185423
TI  - Epidemiology of adult eye injuries in Split-Dalmatian county.
AB  - AIM: To determine the incidence of eye injuries, population groups at risk,
      circumstances and activities at the time of accident, causes, mechanism, type and
      severity of injury, therapeutic procedures, final outcome, and the incidence of
      blindness in patients over 18 years of age. METHODS: We retrospectively analyzed
      data on 383 patients with eye injuries (397 eyes) hospitalized at Split
      University Hospital, Department of Ophthalmology, between January 1998 and
      December 2002. Standardized international classification of ocular trauma
      (Birmingham Eye Trauma Terminology) and eye injury score were used for eye injury
      categorization. RESULTS: The incidence of ocular injuries requiring
      hospitalization in Split-Dalmatian County was 23.9 per 100,000 population and the
      incidence of monocular blindness caused by injuries was 4.1 per 100,000
      population. The male to female ratio was 5.4 to 1. Forty-one percent of injuries
      occurred at home, 27.7% at work, 13.8% in agriculture, 7.0% during assault or
      scuffle, 5.2% in traffic, 3.7% during sports activities, and 1.6% at school.
      Among 397 injuries, 86.4% were mechanical and 13.6% chemical. Out of 343
      mechanical injuries, 67.3% were closed globe and 32.7% were open globe injuries.
      The most frequent objects causing mechanical injuries were tree branch or wood
      (15.9%) causing 26.3% of ruptures and 21.4% of contusions; pieces of metal or
      stone (13.9%) causing 80.8% of intraocular foreign body lacerations; and nails,
      wire, or scissors (8.8%) causing 26.7% of lamellar and 23.9% of penetrating
      lacerations. Closed globe injuries were less severe and had better final visual
      outcome than open globe injuries. Final visual acuity was 0.4 or better in 91.4%
      of mild vs 13.9% of severe injuries. Injuries resulted in monocular blindness
      (visual acuity <0.1) in 71 (17.9%) patients: 35.2% were due to penetrating
      lacerations, 23.9% to ruptures, 21.1% to contusions, 16.9% to intraocular foreign
      body lacerations, and 1.4% due to burns as well as lamellar lacerations.
      CONCLUSION: There was a high incidence of ocular trauma and consequent blindness
      in Split-Dalmatian County. For the prevention of serious eye injuries, health
      education and safety strategies should be applied both at home and place of work,
      where blinding injuries most often occur.

PMID- 15185424
TI  - Surgical treatment, clinical outcomes, and complications of traumatic cataract:
      retrospective study.
AB  - AIM: To analyze clinical outcomes and complications after traumatic cataract
      extractions because of post-traumatic lens opacification. METHODS: We performed a
      retrospective analysis of 24 eyes with traumatic cataract surgically treated
      between May 2000 and June 2003. Preoperative visual acuity, postoperative best
      corrected visual acuity, and preoperative, intraoperative, and postoperative
      complications were analyzed for all eyes. RESULTS: Most patients were young men,
      with preoperative visual acuity of 0.05-0.1, who underwent surgery between one
      and six months after the trauma. We found corneal scar in 5 eyes, rupture of the
      anterior capsule in 4 eyes, sphincter damage in 2 eyes, anterior synechiae in 3
      eyes, iridodialysis in one eye, zonullar loss in one eye, and macular scar in one
      eye. Mild or moderate postoperative complications occurred in 9 out of 24 cases.
      Visual acuity improved in 17 eyes. Seven out of 24 patients did not benefit from
      cataract surgery because of traumatic involvement of the retina and opacification
      of posterior capsule. CONCLUSION: The majority of the eyes with traumatic
      cataract were safely rehabilitated with intraocular lens implantation.

PMID- 15185425
TI  - Cost of treating preventable minor ocular injuries in Rijeka, Croatia.
AB  - AIM: To determine the cost of medical services for the treatment of preventable
      minor ocular injuries in Rijeka, Croatia. METHODS: We analyzed data on 3,755
      outpatients (3,363 men and 392 women) treated for eye injuries at the Department
      of Ophthalmology, Rijeka University Hospital, from April 2002 to March 2003.
      Median age of patients was 37 years (range, 26-47 years). Data were collected
      with a questionnaire designed for the study, which included sociodemographic
      data, type of injury, time and place of injury, and preventability. We carried
      out cost analysis of the procedures and determined the length of hospital stay.
      RESULTS: Out of 5,143 emergencies, minor eye injuries comprised 3,755 cases
      (73%). Minor injuries were potentially preventable in 90% of cases, as they
      resulted from nonuse or misuse of obligatory protection devices. Total one-year
      cost of preventable eye injuries was 135,529.55 Euros. CONCLUSION: Preventable
      minor eye injuries in Rijeka, Croatia, cause a serious medical and economic
      burden. Stricter adherence to the use of protection devices should be promoted.

PMID- 15185426
TI  - Endonasal endoscopic orbital decompression in patients with Graves'
      ophthalmopathy.
AB  - AIM: To present the results of endonasal endoscopic orbital decompression in
      patients with Graves' ophthalmopathy. METHODS: Endonasal endoscopic orbital
      decompression was performed in 32 orbits of 21 patients with Graves'
      ophthalmopathy. In 17 patients the surgery was performed because of active
      ophthalmopathy non-responsive to conservative treatment, and in 4 patients for
      esthetic reasons. Preoperative and postoperative examination included visual
      acuity, examination of the eyelids and cornea, ocular motility, cover testing,
      Hertel exophthalmometry, and applanation tonometry. RESULTS: Visual acuity
      improved from preoperative 0.81+/-0.28 (mean +/- standard deviation) to
      postoperative 0.92+/-0.21 (p=0.0032, Student t-test). Retraction of upper and
      lower eyelids, as well as exposure keratitis, was reduced after operation
      (p<0.001). Mean proptosis reduction in all orbits was 4.6+/-1.7 mm (p<0.001). An
      average reduction of intraocular pressure was 3.4+/-3.0 mmHg (p<0.001). New-onset
      diplopia developed in 8 patients. Diplopia persisted in 9 out of 11 patients who
      had preoperative diplopia. Two patients experienced postoperative relief of
      diplopia. Ocular motility was subsequently corrected by eye muscle surgery in 13
      eyes, whereas prisms were used in other 5 manifestly strabic eyes. CONCLUSIONS:
      Endonasal endoscopic orbital decompression procedure improved visual acuity,
      decreased proptosis and intraocular pressure, and also had favorable cosmetic
      results in most patients. Post decompression diplopia and strabismus were
      successfully managed by either eye muscle surgery or application of prisms.

PMID- 15185427
TI  - Visual evoked potentials in multiple sclerosis patients treated with interferon
      beta-1a.
AB  - AIM: To study pattern-reversal visual evoked potentials (VEP) in patients with
      relapsing-remitting multiple sclerosis on interferon beta-1a treatment. METHODS:
      In a randomized, prospective, non-blinded, placebo-uncontrolled study, VEP were
      studied in 9 patients (18 eyes) with relapsing-remitting multiple sclerosis
      treated with interferon. Three of them have had an episode of unilateral optic
      neuritis. VEP were first recorded before interferon treatment and then followed
      up for 12 months, at 3-month intervals, in the time when patients were receiving
      interferon, 11 microg twice weekly. All patients did not appear regularly at 3
      months intervals follow-up, except for 6-month follow-up. P100 latency and P100
      amplitude in responses to full field, right and left half-field stimulation were
      evaluated. RESULTS: For the group of 18 eyes, there was no statistically
      significant difference in P100 latency and P100 amplitude before and after 6
      months of treatment. In individual cases P100 latency was delayed in 3 eyes of 3
      patients with a history of optic neuritis before treatment. At follow-up, P100
      latency remained delayed in 3 eyes with a history of optic neuritis. Further, in
      3 eyes of two patients who have had normal P100 latency before treatment, P100
      latency became delayed. Overall, P100 latency was at follow-up delayed in 6 eyes
      of 5 patients. CONCLUSION: Interferon beta-1a therapy (22 microg per week)
      administered for 12 months during 1998/99 in Croatia showed no statistically
      significant VEP changes in the group of relapsing-remitting multiple sclerosis
      patients. However, VEP may reveal evidence for asymptomatic deterioration.

PMID- 15185428
TI  - Outcome and prognostic factors in ocular adnexal lymphoma.
AB  - AIM: To classify ocular lymphomas in patients treated at the Zagreb University
      Hospital Center according to the new classification of the World Health
      Organization (WHO) and to determine factors with prognostic significance.
      METHODS: From 1986 to 2003, histological diagnosis of ocular lymphoma was made in
      24 patients. The median age of patients was 62 years, with 2:1 female
      predominance. The patients underwent staging procedures and clinical evaluations
      prior to the date of the initial therapy. Histopathologic slides were reviewed
      and tumors were classified according to the new WHO classification. Additional
      immunohistochemical studies were performed on 35 available specimens. The
      antibodies used were CD3, CD5, CD10, CD20, CD43, and bcl-6; and in a few cases
      cyclin D1, bcl-2, CD23, CD79a, and CD138. The main outcome measures were
      development of distant recurrence after new presentation with solely ocular
      adnexal disease, and death attributable to widespread lymphoma. RESULTS: Ocular
      adnexal lymphomas were found in orbit in 20 patients, in eyelid in two, and
      conjunctiva in two patients. Twenty patients had lymphoma stage IE, one had IIE,
      and three had stage IV. Three patients had prior or concurrent systemic disease
      and 21 patients had primary lymphoma. The main subtypes of non-Hodgkin lymphoma
      according to the WHO classification were extranodal marginal zone B-cell lymphoma
      (n=20), diffuse large cell B-cell lymphoma (n=2), mantle cell lymphoma (n=1), and
      plasmacytoma (n=1). Six lymphomas were CD43 positive and five of them were
      extranodal marginal zone B-cell lymphomas. Radiotherapy was given to 11 patients,
      chemotherapy in 8 patients, whereas radiotherapy and chemotherapy were
      implemented in three patients. Two patients underwent only surgical excision of
      the tumor. Local relapse was found in three and distant recurrence in four
      patients. Distant recurrence was found in four patients with stage IE (two of
      them also had a local relapse). In the group of patients with extranodal marginal
      zone B-cell lymphoma of mucosa-associated lymphoid tissue (B-EMZL), the estimated
      5-year overall survival was 92.9+/-6.6% (mean+/-standard deviation) and the 5
      year failure-free survival was 80.1+/-10.3%. Age, sex, side of involvement,
      anatomic localization of the lesion, clinical stage of disease, and mode of
      therapy did not have any prognostic significance during the follow-up period
      (median, 53; range, 9-131 months). Immunohistochemical marker CD43 was the only
      parameter of prognostic significance (p=0.035). Patients with B-EMZL had almost
      14 times higher chance for an unfavorable outcome if the tumor cells expressed
      CD43 on their surface, than the CD43-negative cases. CONCLUSION: Most ocular
      adnexal lymphomas usually have a B-cell immunophenotype, the morphologic and
      immunohistochemical features of extranodal marginal zone B-cell lymphoma, and a
      favorable prognosis. Our data suggest that CD43 could be useful to separate the
      group of patients with extranodal marginal zone B-cell lymphomas with unfavorable
      prognosis from those that have a good prognosis. CD43 positive ocular lymphomas
      are associated with a higher rate of subsequent distant recurrence and the rate
      of lymphoma-related death.

PMID- 15185429
TI  - Atherosclerosis of retinal arteries in men: role of serum lipoproteins and
      apoproteins.
AB  - AIM: To explore the relationship between retinal vessel atherosclerosis and serum
      concentrations of total cholesterol, triglycerides, low density lipoprotein (LDL)
      cholesterol, high density lipoprotein (HDL) cholesterol, HDL(2) cholesterol,
      HDL(3) cholesterol, apoprotein B, apoprotein A-I, and apoprotein A-II. METHODS:
      Lipids and lipoproteins were measured in 101 male patients aged between 26 and 69
      years (median, 48 years), and the degree of their retinal vessels atherosclerosis
      (stage 1-4 according to Scheie) was determined. Diabetics, alcoholics,
      hypertensive, extremely obese patients, and patients with thyroid, liver, or
      kidney diseases were excluded from the analysis. The results were compared with
      those in 47 apparently healthy men aged between 22 and 65 years (median, 47
      years) with no retinal vessel changes. Direct ophthalmoscopy for the fundus
      examination was carried out by a single ophthalmologist unaware of the patients'
      group. RESULTS: Retinal vessel atherosclerosis strongly correlated with total
      serum cholesterol, LDL cholesterol, triglycerides, and apoprotein B
      concentrations. The higher these lipid and apoprotein values, the more advanced
      the stage of the disease. No significant association between HDL cholesterol as
      well as HDL(2) and HDL(3) cholesterol and atherosclerosis of retinal arteries
      could be proved but an inverse association, although a very weak one, between the
      low serum concentration of HDL cholesterol and the stage of the retinal artery
      atherosclerosis was found. CONCLUSION: Changes in lipoproteins and apoproteins
      associated with atherosclerosis of the retinal arteries correspond well to those
      associated with coronary artery atherosclerosis.

PMID- 15185430
TI  - Susac syndrome: retinocochleocerebral vasculopathy.
AB  - Susac syndrome is a rare microangiopathy of cochlea, retina, and brain. We report
      a case of a 30-year-old man with Susac syndrome. The patient initially suffered
      from unilateral hearing loss associated with peripheral vestibular syndrome, and
      followed with recurrent arterial retinal occlusions and encephalopathy. The
      patient underwent clinical, laboratory, and neuroradiological examination.
      Laboratory tests were negative for systemic inflammatory or infectious disease.
      Signs of encephalopathy and vestibular syndrome regressed after 6 weeks, retinal
      obstructions were partially improved, and deafness remained unchanged. Two
      unexplained epileptic seizures had been documented 7 years before the development
      of typical clinical course. The etiology is still unknown and diagnosis was
      suggested by the clinical triad of bilateral sensorineural hearing loss on low
      frequency on audiology, recurrent bilateral retinal branch artery occlusions, and
      small multiple areas of signal hyperintensity in the white and gray matter on
      brain magnetic resonance T2-weighted images. The clinical course is self-limited
      and treatment options are not codified. Epileptic seizures, as those in our
      patient, may extend the clinical spectrum of Susac syndrome. This case also
      documents the possibility of multiphasic disease course.

PMID- 15185431
TI  - What should a doctor do?

PMID- 15185432
TI  - "Peace Works"--birth of an innovative group.

PMID- 15185433
TI  - Quality of care in ophthalmology.

PMID- 15185434
TI  - ['Sitting on air' in infants: a sign of simple delay in the gross motor
      milestones].
AB  - A delay in motor maturation of infants usually presents as late mastery of gross
      motor milestones, such as rolling over, sitting, crawling, standing up and
      walking. Because this can be a symptom of serious neuromuscular disease or
      cerebral palsy, parents' and doctors' concern is understandable. Three children,
      a girl aged 17 months, and two boys aged 20 and 18 months respectively, were
      referred to the paediatric outpatient department because of delayed motor
      development. Physical examination revealed no pathological disorder; fine motor
      development, social-adaptive and language behaviour were age-appropriate. All
      three patients showed the characteristic 'sitting on air' posture while lifted
      vertically. With this information the diagnosis was 'dissociation of maturation',
      which can be managed by watchful waiting and has an excellent prognosis. All
      three patients recovered spontaneously.

PMID- 15185435
TI  - [Bile duct injury after cholecystectomy: risk of mortality substantially higher].
AB  - Previous studies showed that bile duct injury after cholecystectomy is associated
      with substantial morbidity and a negative effect on Quality of Life. In a recent
      study, patients with a bile duct injury after cholecystectomy exhibited a 3-fold
      increase in mortality during a follow-up period of nine years compared to
      patients without injury. This is the first study to demonstrate a negative impact
      of bile duct injury on survival. Repair by a less experienced surgeon leads to an
      11% higher mortality during follow-up. Cholangiography should probably be
      performed routinely during cholecystectomy. A bile duct lesion should be
      suspected when the patient has not recovered within 48 hours. Endoscopic or
      percutaneous treatment of stenoses or leakage is usually successful, even after
      several weeks.

PMID- 15185436
TI  - [Sixty years of autism].
AB  - The concept of autism has been broadened the last few years from 'early infantile
      autism' to 'an autistic spectrum'. Autism and related contact disorders are
      grouped together under 'pervasive developmental disorders' or 'autistic spectrum
      disorders'. The autistic disorder, Asperger's syndrome, pervasive developmental
      disorder not otherwise specified (PDD-NOS), Rett's disorder and the childhood
      disintegrative disorder all belong to this group. People with an autistic
      spectrum disorder have severe difficulties in the integration of perceived
      stimuli into a meaningful entity. More than two-thirds of the people with the
      autistic disorder (classical autism) are also mentally retarded. Although autism
      can still only be diagnosed at the behavioural level, there is considerable
      consensus regarding an underlying organic aetiology. Autism is clearly a
      multifactorial condition. Autism cannot be cured, but adequate intervention can
      significantly improve the quality of life of people with this disorder. Diagnosis
      and intervention are highly interrelated. In the intervention, a distinction is
      made between family-oriented and child-oriented strategies. Augmentative
      communication plays a key role in the treatment. People with autism need a lot of
      structure, clarity and predictability, also when they have become adults.

PMID- 15185437
TI  - [A model code of practice in accordance with the Dutch Embryo act].
AB  - Under the terms of the Dutch Embryo Act, institutions that perform in vitro
      fertilisation must work in accordance with a legally prescribed procedure. A
      model protocol has been drawn up under the auspices of the Dutch Institute for
      Healthcare Improvement that can serve as a guideline and that may be amplified in
      details with regard to local circumstances. In vitro fertilisation is reserved to
      licensed centres with expert and experienced personnel. These centres must fulfil
      specific standards for both the clinical part and the laboratory part of the
      treatment. The decision in favour of ovarian stimulation depends on the wish to
      be able to select from multiple embryos and must be weighed against the burden on
      the patient, her age and the risk of developing an ovarian hyperstimulation
      syndrome. Placing more than two embryos at a time is discouraged. In the contract
      between the depositors and the depository concerning the storage of embryos
      (cryopreservation), the points of departure are that the parties involved must
      agree on the use of the embryos and that each involved person may withdraw his or
      her permission at any time. In the Netherlands, oocyte donation is performed
      predominantly in women with premature ovarian failure. The maximum age of the
      acceptor is 45 years. Legally, the minimum age of a donor is 18 years, but the
      Committee recommends caution with donors under the age of 30 years; from the
      point of view of treatment efficacy, the maximum age is 40 years. For each
      individual oocyte donation procedure, permission is required from the medical
      ethical assessment committee of the hospital in question. Often, a written report
      to the committee from the treating gynaecologist and a psychosocial counsellor
      will suffice. Because of the increased risk of pregnancy complications after
      oocyte donation, control and delivery in hospital are recommended. Post-mortem
      use of gametes or embryos is permitted, provided that the parties involved have
      given written permission.

PMID- 15185438
TI  - [Diagnostic image (190). A man with melaena. Enteral varices due to portal
      hypertension].
AB  - A 58-year-old man was seen because of anaemia and melaena, due to bleeding from
      colonic varices resulting from thrombosis of the V. portae hepatis and the V.
      lienalis.

PMID- 15185439
TI  - [From gene to diseases; hypokalemic periodic paralysis].
AB  - Hypokalaemic periodic paralysis is an autosomal, dominantly inherited disorder,
      characterised by attacks of partial or total muscle weakness and serum
      hypokalaemia. the mutations responsible are located in the CACNA1S gene (type 1)
      and in the SCN4A gene (type 2), and are all missense mutations where arginine is
      mostly replaced by histidine or sometimes glycine. The mutation has been
      localised in the voltage sensor of the transmembrane segment of calcium channel
      (type 1) and sodium channel (type 2) respectively. How muscle weakness develops
      is not known. Oral or intravenous administration of potassium is helpful in
      treating partial or complete attacks. Acetazolamide can reduce the frequency of
      attacks in type-1 hypokalaemic periodic paralysis.

PMID- 15185440
TI  - [Outbreak of methicillin-resistant Staphylococcus aureus (MRSA) in the Rijnmond
      region: the largest outbreak in the Netherlands].
AB  - EPIDEMIC: The annual number of new MRSA isolates in the Netherlands tripled in
      2002 compared with previous years. This increase was in part due to a MRSA
      outbreak in the Rijnmond region. The outbreak occurred in two merged hospitals
      and is the largest ever to occur in the Netherlands. From November 2001 till June
      2003 MRSA was isolated from 381 patients and 113 hospital employees. The worst
      affected departments were Surgery and Internal Medicine. One MRSA strain (pulsed
      field gel electroforesis (PFGE) type 16) remained initially unrecognised and was
      therefore able to spread unnoticed. Soon two additional epidemic MRSA strains
      (types 37 and 38) were discovered. DISCUSSION: Multiple factors played a role in
      the extent and duration of the outbreak. Because of the delayed detection and
      rapid spread of MRSA type 16, the outbreak grew too large once recognised to be
      resolved within the available infrastructure. Investments were needed at various
      fields, including the infection-control service and the microbiology laboratory.
      Employees had to be informed and motivated, and a separate MRSA ward and OPD were
      provided. New MRSA outbreaks occurred, despite extensive MRSA (contact) screening
      among patients and employees. The numbers of isolates began falling as from the
      beginning of 2003.

PMID- 15185441
TI  - [Widely divergent clinical phenotype of x-linked agammaglobulinemia in two
      cousins].
AB  - X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency caused by a
      mutation in the gene encoding Bruton's tyrosine kinase (BTK). The classical
      presentation of XLA consists of the almost complete absence of B-lymphocytes and
      immunoglobulins in the peripheral blood leading to severe, mainly bacterial,
      upper and lower respiratory-tract infections already in early childhood.
      Irrespective of the kind of BTK-gene mutation the phenotype of XLA can be very
      diverse. Two 9-year-old cousins with the same BTK-gene mutation illustrate this
      phenotypical diversity. One boy had a classical presentation and was on
      maintenance treatment with intravenous immunoglobulins and prophylactic
      antibiotics to control his infections. Without any prophylactic treatment, his
      cousin had no abnormal infectious course despite very low B-lymphocyte counts and
      immunoglobulin levels in the blood. The mechanisms underlying the phenotypical
      diversity of XLA have not been clarified. Gene polymorphisms affecting the innate
      immune system may play a role.

PMID- 15185442
TI  - [Paraneoplastic syndromes in three patients with renal cell carcinoma].

PMID- 15185443
TI  - [A teenager presenting with vomiting, general malaise and weight loss].

PMID- 15185444
TI  - [Pregnancy and chemotherapy; an apparent contradiction].

PMID- 15185445
TI  - [Intraocular pressure in rabbits after administration of 10% L-arginine HCl in 2%
      Trusopt].
AB  - In this contribution publish the observation that addition of 10% L-arginin.HCl
      to the 2% Trusopt eye drops intensifies activity of antiglaucomatics with an
      important reduction of the normal intraocular pressure (IOP) in rabbits New
      Zealand white namely from 15 up to 240 minutes, compared with application of both
      substance alone. Size of the pupil was not affected. Based on our experimental
      results we assume that this increasing activity of Trusopt mixture with amino
      acid L-arginin.HCl created a new metabolite. According to our observations this
      metabolite caused reduction of the humor aqueous production and together with the
      increased of the uveo-scleral outflow leads to the striking reduction of the IOP.

PMID- 15185446
TI  - [Transpupillary thermotherapy in age-related serous detachment of retinal
      pigmented epithelium].
AB  - The goal of this prospective study was to evaluate results of the transpupillary
      thermotherapy (TTT) in the age related macular degeneration (ARMD) where the
      serous detachment of the pigment epithelium (SDPE) was the dominant sign.
      MATERIAL AND METHODS: Thirty eyes of 29 patients were treated by TTT. All
      patients were examined before and 3, 6, 9, 12, 18, and 24 months after TTT in
      terms of visual acuity (VA), indirect binocular ophthalmoscopy, and indirect
      slitlamp biomicroscopy, fluorescein angiography, and optic coherent tomography
      (OCT) of the macular region. In 25 eyes (83,3%) signs of choroidal
      neovascularization (CNV) were present (vascular SDPE). TTT was performed with a
      standard technique by diode laser (wavelength 810 nm). In 14 eyes (46.7%) the TTT
      procedure was repeated after 3 to 38 weeks. The follow-up period was 7 to 28
      month (mean 15.2 months). RESULTS: After TTT, VA improved in 6 eyes (20.0%),
      remained stable in 8 eyes (26.7%), and deteriorated in 16 eyes (53.3%). Indirect
      slitlamp biomicroscopy revealed, that the SDPE re-attached in 13 eyes (43.3%),
      decreased in size in 12 eyes (40.0%); fluorescein leakage disappeared in 16 eyes
      (53.3%) and was reduced in 10 eyes (33.3%). By OCT, the re-attachment of SDPE was
      confirmed in 14 eyes (46.7%) and it's reduction in 13 eyes (43.3%). The leading
      cause of the same or worse VA after diminishing of SDPE was chorioretinal
      atrophy, with or without subretinal fibrosis. CONCLUSION: In the long term, the
      TTT led to the decline of SDPE in the majority of eyes and improved or stabilized
      VA in nearly on half of eyes. In most cases, signs of neovascularization were
      present. After the SDPE regression, the chorioretinal atrophy prevented the
      better functional results. TTT is not economically expensive and widens treatment
      possibilities in exsudative form of ARMD including SDPE.

PMID- 15185447
TI  - [The frosted retinal vascular branch syndrome].
AB  - In January 2002, thirty-eight years old healthy man with unusual clinical signs
      of vasculitis was examined in the Center for Diagnosis and Treatment of Uveitis
      in our Department of Ophthalmology. The patient had a flu-like disease one month
      before the signs of the eye disease started. In the beginning of the disease, the
      visual acuity (VA) was 6/12 (20/40 or 0.5) for distance and Jaeger 8 for near and
      6/6 (20/20 or 1.0) and Jaeger 1 respectively. The clinical appearance was similar
      to this of frosted branch angiitis. The thorough medical examination did not
      discover link between vasculitis and any systemic disease. Serologic examination
      discovered positivity of IgG immunoglobulin antibody against cytomegalovirus
      (CMV) only. The intraocular fluid sampling to confirm CMV antibody presence was
      denied by the patient. After starting the treatment with gancyclovirus and
      corticosteroids, the considerable improvement of clinical signs of the frosted
      branch angiitis was noticed. VA improved after five days of treatment. During one
      year follow-up, neither recurrence of vasculitis nor the decline of VA of both
      eyes was marked. In Czech ophthalmologic literature, we did not find any article
      referring to frosted branch angiitis, so we took the liberty of offering the
      Czech term "syndrom omrzlych vetvi retinalnich cev".

PMID- 15185448
TI  - [Optimal combined therapy in retinoblastoma].
AB  - Eighteen patients suffering of retinoblastoma during three years period (1999
      2001) were treated in two departments of ophthalmology in the Czech Republic. In
      four cases, the involvement was bilateral. In six eyes, because of very late
      stage of the disease at the time of diagnosis, the initial treatment was the
      enucleation. The rest, (sixteen eyes) was treated by chemoreduction
      (chemotherapy) and different combinations of local therapeutic methods according
      to their respective findings. Nine eyes from this cohort were enucleated in
      different period of time after the beginning of the treatment because of the
      relapse of the disease, its continuing or complications of the treatment. In the
      remaining seven eyes there are no sings of tumor activity. The fractioned
      radiotherapy was used in the treatment in one eye only and this eye was
      enucleated subsequently. So the maintaining therapy was successful in seven eyes
      of sixteen involved, or in 43.75% of cases.

PMID- 15185449
TI  - [Personal experience in treatment of diabetic maculopathy].
AB  - The authors evaluate group of 111 eyes with diabetic macular edema treated by
      laser photocoagulation. The criterion to start laser therapy was
      biomicroscopically evident clinical significant macular edema. The visual acuity
      (VA) is evaluated during 1-5 years after the photocoagulation was started. The
      group with stabilized VA includes eyes with change of VA up to one line of
      Snellen optotypes. The groups with improved or worsened VA include eyes with
      change of 2 or more lines of Snellen optotypes. In the first year after the
      beginning of photocoagulation, VA in 87 eyes (78%) was stabilized, in 20 eyes
      (18%) improved, and in 4 eyes (4%) worsened. In the second year after the
      beginning of photocoagulation, VA in 85 eyes (77%) was stabilized, in 19 eyes
      (17%) improved, and in 7 eyes (6%) worsened. In the fifth year, VA in 82 eyes
      (74%) was stabilized, in 12 eyes (11%) improved, and in 17 eyes (15%) worsened
      comparing to the findings of first examination. It is evident from the study, the
      group with stable VA during the 5 years period changes a little bit, in the group
      with improved VA it is a perceptible decline from 18% to 11%. The most evident
      change is seen in the group with worsened VA--here we can notice an interesting
      conspicuous tendency of doubling the number of worsened eyes during each two
      years. Whereas 1 year after the beginning of the photocoagulation it consists of
      4 eyes (4%) only, two years later, this is in the third year, it is 9 eyes (8%),
      and another two years later, thus 5 years after the beginning of photocoagulation
      it is already 17 eyes (15%). Very important finding is the low number of eyes in
      the group with worsened VA--together 7 (6%) at the examination performed 2 years
      after of the photocoagulation has been started because it is confirmed that in
      groups without treatment the number of eyes with worsened VA exceeds 50%. The
      photocoagulation near the center of the macula has to be performed with
      considerable caution--the authors have the experience that during several years
      after the photocoagulation the atrophic lesion enlarges up to twice its size to
      the original one, especially in older patients.

PMID- 15185450
TI  - [Is it possible to sucessfully treat severe penetrating injuries?].
AB  - The number of serious devastating eye injuries caused by violent crimes or
      transport accidents is growing. The patients are mostly young men and the
      preserving of the eye, especially its function is often difficult. From June 2000
      to March 2003, 4 eyes of 3 men (aged 16-23 years) with extraordinary serious
      devastating penetrating injuries were treated in the Department of Ophthalmology
      in Pilsen. One eye was enucleated because of serious laceration of the whole
      globe and eyelids at the initial treatment. In three eyes, a pars plana
      vitrectomy (PPV) with inner silicone tamponade was performed after the initial
      treatment of the penetrating and eventually exiting site. In all vitrectomized
      eyes a pars plana lensectomy (PPL) was performed, at the time of PPV in one eye,
      and in two eyes subsequently. When the eyes were stabilized, and the retina was
      attached, the silicone oil was removed in two eyes. The visual acuity before the
      surgery decreased to uncertain light projection, and in two eyes of one patient,
      we were not able to detect the visual acuity because of the unconsciousness of
      the patient. The follow-up period was 3 months to 2 years; all three eyes are
      aphakic, and the central visual acuity improved in two eyes to 6/6-9 (20/20-30 or
      1.0-0.66) with the aphakic correction or with the contact lens, in one eye with
      the silicone eye remained the visual acuity is 6/60 (20/200 or 0.1). Even as the
      prognosis in such patients is unfavorable, in some cases good functional results
      may be obtained. The basic precondition for successful reconstruction of the
      seriously injured eye is meticulous primary treatment. For salvage of visual
      functions, there are often necessary repeated surgeries on the anterior as well
      as posterior segment of the eye. Their good timing and adequate technique may
      rapidly decrease the risk of complications after the injury and/or after the
      surgery respectively.

PMID- 15185451
TI  - [Effect of adjustment of corneal running sutures on cylindrical refraction after
      perforating keratoplasty].
AB  - Authors refer about the effect of adjusting (adjustment of the suture tension) of
      the running corneal suture on the final cylindrical refraction in patients who
      underwent penetrating keratoplasty due to keratoconus. In our article we evaluate
      two groups of patients. The group I consists 76 patients (76 eyes) who regularly
      visited our department of ophthalmology. There were 52.6% of females and 47.4% of
      males. The average age at the time of surgery was 33.5 +/- 5.2 years (range, 18
      52 years). In this group of patients, the adjusting was performed during the
      surgery. In the group II 35 patients (40 eyes) underwent the adjusting procedure
      of the running corneal suture in the early postoperative period. There were 19
      (54.0%) women and 16 (46.0%) men. The average age of the whole group at the time
      of surgery was 34.6 +/- 3.8 years (range, 18-50 years). The indication to carry
      out the adjusting was topographically verified astigmatism of more then 3.5
      cylindrical diopters (D cyl). The purpose of this study was to find the ultimate
      surgery technique to get not only the clearness and good healing of the corneal
      graft, but first of all to prevent extensive ametropia already during the
      surgery. In the early stage after the surgery we are trying to reduce emerged
      refractive error and to get faster recovery of good visual acuity of the operated
      eye. In the sense of the least final postoperative astigmatism, the best results
      we have reached in cases where the donor corneal graft was 0.25 mm larger in
      diameter and the suture was adjusted during the surgery using light circles
      according to Serdarevic. In this group of patients the average final cylindrical
      refractive error after the surgery was 2.00 +/- 0.81 D cyl. When adjusting the
      corneal suture in postoperative period, the mean final refractive error decreased
      of about 3.09 +/- 1.62 D cyl.

PMID- 15185452
TI  - [Treatment of uveal effusion syndrome after filtering surgery (2 case reports)].
AB  - The purpose of this article is to report the surgical treatment of two patients.
      After the filtering surgery a dehiscence of the conjunctiva emerged and was
      followed by an extreme hypotony of the eyeball and an extensive uveal effusion.
      The first patient, 82 years old lady, was treated with the diagnosis of chronic
      open angle glaucoma for 25 years. The right eye with an absolute glaucoma, the
      left eye had normal intraocular pressure (IOP) and was after a combined filtering
      surgical procedure with phacoemulsification and posterior chamber intraocular
      lens (PC IOL) implantation in 1998. In autumn 2000, the patient suffered
      conjunctivitis, and the prominent filtering bleb was damaged due to frequent
      rubbing of the eye because of itching. Severe hypotony of the eyeball with
      secondary uveal effusion followed. Considering the age of the patient and the
      only functional eye, an extreme surgery was indicated: PC IOL explantation
      (removal), pars plana vitrectomy (ppV) with silicone oil implantation. After the
      surgery the eyeball was anatomically stabilized and the VA (visual acuity)
      improved from initial uncertain light perception to 0.08 (1/12 or 3/36) and
      certain light perception. The second patient, 35 years old man suffered in 1995 a
      serious penetrating injury with an intraocular foreign body of the right globe.
      During the following five years the patient underwent in altogether six
      intraocular surgeries due to posttraumatic cataract and rhegmatogenous and
      tractional detachment of the retina. In the year 2000, trabeculectomy due to
      secondary glaucoma was indicated and 8 months later, on patients demand an
      anterior chamber intraocular lens (AC IOL) was implanted. During the first week
      after the surgery severe hypotonia of the globe and secondary uveal effusion
      caused by conjunctival dehiscence in the upper nasal quadrant of the eyeball
      developed. Because of complicated ocular history of the patient who underwent on
      the whole eight eye surgeries a relative minimal procedure was indicated: AC IOL
      removal and insufflation of 1 ml of 100% hexafluorosulfide (SF6) expansive gas
      into the anterior chamber and vitreous cavity. The globe was stabilized and the
      VA (visual acuity) improved from initial uncertain light perception to 0.25 (6/24
      or 20/80) with certain light perception.

PMID- 15185453
TI  - [Phacoemulsification of cataracts after pars plana vitrectomy (comparison of
      phacoemulsification with pars plana infusion and without pars plana infusion)].
AB  - PURPOSE: To compare peroperative complications of standard phaco technique and
      phaco with pars plana infusion performed for cataract after pars plana
      vitrectomy. METHOD: This prospective study randomly divided group of 64 patients
      with cataract after PPV into group A (standard phaco, 38 patients) and group B
      (phaco with par olana infusion, 26 patients).  The study verifies the rate of
      peroperative complications such as deep anterior chamber, diaphragma movement
      miosis, and zonular dehiscention in these two groups. RESULTS: Peroperative
      complications had slightly higher rate in group B (with infusion).  No specific
      complication in group A (standard phaco) was found. CONCLUSION: Standard phaco
      technic without par plana infusion has at least the same level of safety as phaco
      with pars plana infusion.

PMID- 15185454
TI  - [Evaluation of subjective complaints of patients with a visual acuity of 20/30 to
      20/20 before and after cataract surgery].
AB  - PURPOSE: To quantify patient's functional visual complaints in early cataract and
      after cataract surgery. PATIENTS AND METHODS: Forty-nine patients scheduled for
      cataract surgery with a visual acuity of 20/30 or better on Snellen optotypes at
      the time of patient selection and no other ocular pathology were evaluated
      subjectively for visual functions preoperatively and 12 months postoperatively. 
      Subjective visual functions were evaluated using a questionnaire that evaluated
      patient's visual functions by assessing the degree of difficulty they experience
      in performing tasks involving distance vision, near vision, mesopic vision and
      glare conditions. RESULTS: The questionnaire scores were correlated with visual
      performance both before cataract surgery and thereafter.  Significant improvement
      of subjective visual performance was described postoperatively. CONCLUSION:
      Questionnaire should be considered as adjuncts to visual acuity and constrast
      sensitivity testing in evaluation of early cataract.

PMID- 15185455
TI  - [Rhegmatogenous retinal detachment and its treatment].
AB  - We have analyzed the surgery results of rhegmatogenous retinal detachment (RD) on
      73 patients (76 eyes) operated on in 2000.  Retinal reattachment was achieved on
      59 eyes (77.6%) without silicone oil tamponade (SO)  and on 17 eyes (22.4%) with
      the use of permanent silicone oil tamponade.  Visual acuity following the
      operation was improved on 47 eyes (61.8%).     Visual acuity 20/20-20/40 was
      reached on 16 eyes (21.1%), 20/60-20/120 on 35 eyes (46.0%), 20/200-4/200 on 19
      eyes (25.0%), worse than 4/200 on 6 eyes (7.9%).   Based on contemporary surgical
      technique the most important criterion of anatomical and functional success with
      the retinal detachment treatment is the time between RD onset and the time of the
      surgery, as well as the presence and extent of proliferative vitreoretinopathy.

PMID- 15185456
TI  - [Methods of evaluating posterior capsular opacification after cataract surgery].

PMID- 15185457
TI  - [Will anthropology help in detecting refraction errors in a long-deceased
      individual?].

PMID- 15185458
TI  - [Body condition and frequency of ovarian cysts in Brown Swiss cows during the
      first 40 days of lactation].
AB  - For this investigation 50 Brown Swiss cows from 21 different farms were used.
      Twenty-five peripartal overconditioned cows (back fat thickness > 38 mm) were
      compared with 25 peripartal not overconditioned animals (back fat thickness < 38
      mm). On days 20, 30 and 40 post partum the ovaries were examined sonographically
      and 10, 15, 20, 30 and 40 days after calving plasma concentrations of
      progesterone and 17-beta estradiol were determined. In peripartal overconditioned
      animals 12 ovarian cysts were found while only one cyst was present in not
      overconditioned cows (P < 0.05). At first examination all ovarian cysts were
      classified by ultrasound as follicle theca cysts (progesterone < 0.5 ng/ml
      plasma). Follow examinations resulted in 3 cysts which persisted as theca cysts
      while 8 cysts became luteinized and 2 cysts completely regressed. There was no
      indication of increased plasma progesterone and/or estradiol concentrations in
      overconditioned cows with higher fat deposit before of ovarian cysts had
      occurred.

PMID- 15185460
TI  - [Sacral osteochondrosis dissecans in a Bernese Mountain Dog: diagnosis and
      treatment].
AB  - A 18-month-old female Bernese Mountain Dog with chronic pain at jumping,
      extension of the right hind leg and paresis of the tail was referred to the
      Neurological Service of the Veterinary Hospital of the University of Zurich. Upon
      radiological examination a mineralised fragment at the dorsal aspect of the
      endplate of S1 was detected. The diagnosis of Osteochondrosis dissecans was
      confirmed by linear and computed tomography as well as histologic examination of
      the fragment, which was surgically removed. Preoperative imaging allowed a
      minimal surgical approach using a unilateral, modified dorsal laminectomy.
      Outcome was evaluated by neurological reevaluation and a CT scan performed 6
      months after surgery.

PMID- 15185459
TI  - [Demographic characteristics of dog population in Switzerland].
AB  - Dog Registration data from three Cantons, patient data of 13 veterinary practices
      and registrations in the Swiss Dog Pedigree Book were collected, analysed and
      compared to results of a commercial household survey, to assess demographic
      characteristics of dog population in Switzerland. The proportion of "pure-bred"
      dogs was different depending on how the term was used, varying from 24% regarding
      registrations in the Swiss Dog Pedigree Book, to 75% regarding dogs with only one
      breed recorded in Veterinarian's patient-history-management systems. Most popular
      breeds were dogs called "German Shepherd/Shepherd", followed by the Labrador and
      Golden Retriever. Comparison of different data sources suggested regional
      differences in popularity of breeds. The average life expectancy was estimated on
      10.5 and 11 years. Sex distribution was equal. One third of all male dogs and
      half of the female dogs were neutered. Regardless sex, neutering was more common
      in cross-bred dogs than in "pure-bred" dogs (OR = 1.9). Some bias in all sources
      had to be considered and there was a major concern regarding definition of
      breeds. However, the study was able to add different parameters out of different
      sources to a homogenous picture of demographic data of dog population in
      Switzerland.

PMID- 15185461
TI  - [Sustained animal health and consumer product safety in organic agriculture-
      Report from the first workshop SAFO-Netzwerks].

PMID- 15185462
TI  - [Damage and prevention in professional liability insurance].

PMID- 15185463
TI  - [How the natural history of dilated cardiomyopathy has changed. Review of the
      Registry of Myocardial Diseases of Trieste].
AB  - Dilated cardiomyopathy (DCM), a heart muscle disease characterized by ventricular
      dilation and dysfunction, is a leading cause of mortality and morbidity. In the
      present paper we will consider the main results of studies on the natural history
      of DCM in 581 consecutive patients prospectively enrolled and systematically
      followed in the Heart Muscle Disease Registry of Trieste in the last 25 years. In
      the last decades prognosis of DCM significantly improved over time, mainly as a
      consequence of optimized treatment with ACE-inhibitors and beta-blockers.
      However, a strong heterogeneity of prognosis was observed among patients both in
      familial and sporadic cases. Early diagnosis and treatment allowed to recognize
      two distinct subgroups, one with a rapidly progressive downhill course, high
      mortality and urgent indication to heart transplantation, another with a more
      favorable outcome. Long-term optimized treatment with ACE-inhibitors (in 90% of
      cases) and beta-blockers (in 87% of cases) was associated with a remarkable
      clinical improvement in 50% of patients and apparent "healing" in 16% of cases. A
      systematic and accurate echocardiographic follow-up showed in these cases a
      significant improvement of the left ventricular ejection fraction (LVEF) with
      "reverse remodeling", frequently associated with a decrease of severity of
      functional mitral regurgitation and regression of the restrictive filling
      pattern. The response to optimal treatment showed a strong relation to long-term
      outcome. The 8-year transplant-free survival, starting from the evaluation at 2
      years, was 31% in patients with persistent NYHA class III-IV, 64% in NYHA class I
      II and LVEF < or = 40%, 83% in NYHA class I-II and LVEF > 40% and 94% in patients
      with apparent "healing" (p < 0.0001). Long-term follow-up showed a significant
      clinical progression of the disease in 33% of cases, independently of the initial
      clinical response to treatment. Predictive factors of a favorable response to
      beta-blocker treatment associated with ACE-inhibitors were a history of mild
      hypertension, an early diagnosis and treatment and the presence of sinus
      tachycardia. The risk of sudden death was increased particularly in patients with
      long-term persistent or progressive left ventricular dilation and dysfunction. A
      rigorous pharmacological approach (optimization of beta-blockers, withdrawal or
      decrease of dosage of digitalis), and selective non-pharmacological strategy
      (automated implantable cardioverter-defibrillators for primary prevention in high
      risk patients) are potentially effective to decrease the incidence of sudden
      death during long-term follow-up. In conclusion, the Heart Muscle Disease
      Registry of Trieste gave us in the last 25 years new insights into the natural
      history of DCM, underlying the importance of a rigorous and systematic approach
      both at clinical presentation and during long-term follow-up on optimized medical
      treatment.

PMID- 15185464
TI  - [Studies of equivalence in cardiovascular diseases].
AB  - An increasing number of equivalence and non-inferiority trials appeared in recent
      years among randomized clinical trials, particularly for the evaluation of
      efficacy of treatments in cardiovascular medicine. These studies are
      characterized by remarkable methodological issues and important ethical
      implications. The aim of this review was to underscore some topic methodological
      problems: setting the equivalence boundary, the special logic used to establish
      equivalence, and the determinants of sample size. A Medline search was performed
      in order to identify the main problems in study design and in the interpretation
      of results of the equivalence and non-inferiority trials in cardiovascular
      diseases.

PMID- 15185465
TI  - [Myocardial revascularization without extracorporeal circulation in patients with
      multivessel coronary disease].
AB  - BACKGROUND: Some criticisms have been addressed to off-pump coronary surgery
      technique concerning the possibility of its systematic use with the respect of
      the completeness of revascularization. We report our experience with off-pump
      revascularization in patients with multivessel coronary disease. METHODS: Between
      September 1997 and April 2003, 868 patients with multivessel coronary disease
      were scheduled for off-pump surgical revascularization. From September 2000, the
      percentage of patients operated on without cardiopulmonary bypass has been stably
      > 90%. Fifteen patients (1.7%) had a conversion to cardiopulmonary bypass for
      anatomical reasons (n = 6) or clinical instability (n = 9). RESULTS: An average
      of 2.5 +/- 0.8 (range 1-5) anastomoses per patient were completed. Bilateral
      mammary artery was used in 573 patients (66%); totally arterial revascularization
      was accomplished in 479 patients (55.2%). In-hospital mortality rate was 0.6% (5
      patients). Total incidence of non-fatal postoperative complications (bleeding
      requiring re-exploration, perioperative myocardial infarction, stroke, new onset
      of acute renal failure) was 3.5%. Mean postoperative hospital stay was 4.8 +/-
      3.8 days. At a mean follow-up of 21.6 +/- 15.6 months (range 1-65 months), the
      postoperative actuarial survival rates were 97.3, 93.7 and 86.7% at 1, 3 and 5
      years postoperatively. Actuarial freedom rates from new revascularization were
      98.7, 96.6 and 96.6% at 1, 3 and 5 years postoperatively. CONCLUSIONS: Early- and
      intermediate-term results of this study demonstrate the feasibility of off-pump
      revascularization in all patients with multivessel coronary disease, respecting
      the criterion of complete myocardial revascularization.

PMID- 15185466
TI  - [Proposed protocol for the ambulatory management of patients discharged with
      heart failure diagnosis: collaborative project Venice-HF].
AB  - BACKGROUND: Hospital admissions for heart failure are common and readmission
      rates are high. Many admissions and readmissions may be avoidable, so that
      alternative strategies are needed to improve long-term management. METHODS: We
      conducted a randomized trial of the effect of a guideline-based intervention on
      rates of readmission within 90 days of hospital discharge and costs of care for
      patients who were hospitalized due to decompensated heart failure. The
      intervention consisted of comprehensive education of the patient and family, a
      prescribed diet and intensive application of guidelines' recommendations on
      pharmacological therapy. The intervention started before discharge and continued
      thereafter with follow-up visits for up to 3 months. Two hundred and nine
      guideline-managed patients were compared to 209 concurrent normally-discharged
      patients. RESULTS: Patients in the study group were more prescribed beta
      blockers, ACE-inhibitors, angiotensin receptor blockers, and spironolactone.
      Sixteen patients (8%) in the intervention group and 31 (15%) among controls were
      readmitted for DRG 127, within 3 months of discharge (Fisher's exact test, p <
      0.01), while the 6-month mortality rate was similar between groups (9 and 11.5%
      respectively). Quality of life significantly improved from 5.6 +/- 1.0 to 6.1 +/-
      1.9 (Mann-Whitney U-test, p < 0.05). The overall costs of care were lower for
      guideline-managed patients (110 vs 150 Euro per patient per month), due to the
      lower readmission rates. CONCLUSIONS: Our study showed that a guideline-based
      management program for patients with heart failure at discharge improves quality
      of life and reduces readmission for DRG 127 and total bed days, allowing relevant
      cost savings.

PMID- 15185467
TI  - [Repair technique of post-infarction ventricular free wall rupture with
      pericardial patch].
AB  - The development of a left ventricular rupture after myocardial infarction is not
      a rare complication. We report a case of 70-year-old male patient with clinical
      and instrumental signs of cardiac tamponade after left ventricular rupture. We
      repaired this lesion with pericardial patch and biological Glue without
      extracorporeal circulation and sutureless.

PMID- 15185468
TI  - [Biventricular heart failure in patient treated with anthracycline in childhood:
      myocardial dysfunction is not always the cause].
AB  - Anthracyclines, found to be efficacious in the treatment of a broad spectrum of
      pediatric malignancies, are cardiotoxic and may lead to heart failure even a long
      time after successful treatment of cancer. It is thought that subtle
      abnormalities can progress to the more permanent myocardial disease, resulting in
      cardiomyopathy which may progress to congestive heart failure. There are some
      precipitating factors leading to the sudden onset of cardiac symptoms such as
      increase in afterload or preload. We describe a young patient with congestive
      heart failure treated with doxorubicin (cumulative mean dose 420 mg/m2) in
      infancy because of pelvic sarcoma in whom the appearance of symptoms was related
      to pulmonary embolism. Four years before hospital admission, the patient
      presented echocardiographic abnormalities such as left ventricular fractional
      shortening and thickness reduction and he was treated with ACE-inhibitors. The
      myocardial ischemia, which is present in pulmonary embolism, probably worsened
      the left ventricular systolic function and caused congestive heart failure.

PMID- 15185469
TI  - [Task force on thoracic pain management].

PMID- 15185470
TI  - [The heart and diabetes. Introduction].

PMID- 15185471
TI  - [Pathogenesis of atherosclerosis in diabetes mellitus].

PMID- 15185472
TI  - [Diagnosis and classification of diabetes mellitus and of prediabetic states].

PMID- 15185473
TI  - [To cure diabetes and secondary prevention?].

PMID- 15185474
TI  - [Metabolic syndrome: a cluster of risk factors].

PMID- 15185475
TI  - [Aggressive control of cardiovascular risk factors].

PMID- 15185476
TI  - [Treatment of acute phase ischemic cardiopathy: therapeutic options in the
      diabetic patient].

PMID- 15185477
TI  - [Optimal coronary revascularization in type 2 diabetes mellitus].

PMID- 15185478
TI  - [Specificity of ischemic cardiopathy in the diabetic patient: prognosis].

PMID- 15185479
TI  - [The diabetic and coronary patient: how to treat hyperglycemia?].

PMID- 15185480
TI  - [Approach to the diabetic patient: compliance and change strategy].

PMID- 15185481
TI  - [Prevention of alveolar ridge resorption after tooth extraction--a review].
AB  - Alveolar bone resorption is frequently observed after tooth extraction. Atrophy
      of the alveolar ridge may cause esthetic and surgical problems in prosthetic
      dentistry. Augmentative measures may thus be required to guarantee optimal
      prosthetic replacement of the lost tissues. Augmentative bone treatment may
      result in extensive surgical interventions and increased treatment costs.
      Alveolar ridge prophylaxis immediately upon tooth extraction may reduce such
      sequelae for both, the treating dentist and the patient. Attempts to reduce
      alveolar bone resorption have included the placement of natural roots, root
      analogues, and immediate implants into the extraction socket, sometimes in
      combination with membrane or graft techniques. In the current review of the
      literature, techniques for alveolar ridge preservation are discussed.

PMID- 15185482
TI  - [Bacterial contamination of bony particles from the bone collection trap].
AB  - Intraoral bony defects can be filled with bony particles that are collected in a
      titanium filter while drilling. The rinsing liquid is contaminated with blood and
      saliva which implies that the bony particles are also contaminated with bacteria.
      The aim of this study was to determine quantitatively and qualitatively the
      degree of this contamination. Over a period of three months bony particles were
      collected from 50 patients undergoing surgery. The bony particles were scraped
      off the filter, resuspended and incubated aerobically and anaerobically on human
      blood agar media. Colony forming units (CFU) were determined as well as the most
      common species of bacteria. All samples showed anaerobic and aerobic growth.
      After anaerobic incubation in 44 samples the number of bacteria was higher (38)
      or equal (six) to that after aerobic incubation. On average 435,000 CFU (aerobic)
      and 1,013,000 CFU (anaerobic) per sample were found. The most frequently
      identified bacteria belonged to Veillonella spp. in the anaerobic and to
      Streptococcus oralis in the aerobic cultures. In 43 samples black pigmented
      colonies were detected. There were only bacteria identified which are common in
      the oral cavity.

PMID- 15185483
TI  - [Treatment of intraoral hemangiomas with the CO2 laser].
AB  - Intra-oral haemangiomas can lead to intra-operative bleeding while being excised
      conventionally with a scalpel. Therefore excision with CO2-Laser using
      coagulating effects and vaporisation of soft-tissues has been introduced. 52
      intra-oral haemangiomas were excised minimal invasively and without relapse. With
      CO2-Laser no complications were seen postoperatively but the healing period was
      prolonged.

PMID- 15185484
TI  - [Piezoelectric surgery. An alternative method of minimally invasive surgery].
AB  - The piezoelectric surgery is an ultrasonic surgery which represents a novel and
      alternative method to the conventional hard and soft tissue management with
      rotating instruments in the oral district. The innovation of this technique is
      mainly due to three major characteristics: a) a micrometric cut of 60 mu to 200
      mu, b) a selective cut which works on hard tissues but not on soft tissues, c) a
      relative blood free surgical field due to the air-water cavitation effect of the
      ultrasonic device. The final result of these characteristics is a definite
      clinical advantage with regard to the cut precision, the sparing of vital nervous
      soft tissues, the better visualisation of the surgical area. The present work
      shows through a series of case reports the possible use of the piezoelectric
      surgery in the oral district, presenting observed advantages and disadvantages
      over a time lag of 18 months. The entire clinical work was performed with the
      Piezosurgery device Mectron (Mectron Medical Technology, I-16042 Carasco).

PMID- 15185485
TI  - [What is your diagnosis? Primary eosinophilic esophagitis].

PMID- 15185486
TI  - [Withdrawal of a drug from the market for safety reasons: process and
      communication].
AB  - Each year, drugs must be withdrawn from the market following the identification
      of serious adverse reactions. We report here on an enquiry addressed to persons
      involved in the recent withdrawal of nefazodone, and a survey of physicians and
      pharmacists. Our results show the complexities of such withdrawal decisions and
      the difficulty in communicating them through the network of health professionals
      down to the patients.

PMID- 15185487
TI  - [Atrila fibrillation: a review].
AB  - Atrial fibrillation (AF) is the most common sustained arrhythmia and increases
      exponentially with age. The physiologic basis are certain triggers initiating
      multiple micro-reentry circuits, which require a certain amount of "myocardial
      mass" to be sustained. There are numerous predisposing factors for AF, mostly
      leading to dilatation or hypertrophy of the atrial myocardium. Lone AF, however,
      occurs in structurally normal hearts. In the management of AF it is mandatory to
      decide between medical or electrical cardioversion in persistent AF and rate
      control in permanent AF. Medical cardioversion or prophylaxis of recurrence can
      be performed with Class IA, IC or Class III antiarrhythmic drugs. The choice of
      drugs depends on the underlying cardiac pathology of the individual patient.
      Patients with long duration of poor rate control during AF are at risk for
      tachycardia-induced cardiomyopathy. Cardioversion is safe to be performed within
      48 hours after the onset of AF without prior and--if there is no risk of
      recurrence--without consecutive anticoagulation. When AF persists longer than 48
      hours, anticoagulation for three weeks is mandatory prior to attempted
      cardioversion, or alternatively, transesophageal echocardiography can be
      performed to exclude the presence of an intraatrial thrombus. Anticoagulation has
      to be maintained for a minimum of four weeks after the restoration of sinus
      rhythm. Anticoagulation is required for paroxysmal, persistent and permanent AF.
      Lone atrial fibrillation in patients under the age of 60 years is an exception to
      these rules and does not require anticoagulation. In case of refractory AF with
      poor rate control, catheter ablation of the AV node with pacemaker implantation
      is the treatment of last choice. Early attempts to provide a cure for AF included
      the surgical "Maze" procedure, followed by linear catheter ablation with the goal
      of reducing the atrial mass. Catheter ablation of the triggers of AF, which
      mainly originate at the pulmonary veins and the "substrate modification" have
      been introduced in the last couple of years and is performed increasingly in
      specialized EP centers.

PMID- 15185488
TI  - [Fever, malaise and new onset mitral valve insufficiency. Subacute Streptococcus
      bovis mitral valve endocarditis ].
AB  - A 62-year-old patient with low grade fever, fatigue, arthralgia and newly
      discovered mitral regurgitation was diagnosed with subacute endocarditis.
      Streptococcus bovis grew from all six blood culture bottles. Streptococcus bovis
      is known to be associated with gastrointestinal neoplasias. Therefore a
      colonoscopy was performed and two polyps were removed. Histological analysis
      revealed a tubulovillous adenoma and a serrated adenoma. Colonoscopy is mandatory
      for all patients with Streptococcus bovis endocarditis even without any symptoms
      for colorectal neoplasia. The significance of Streptococcus bovis for the
      carcinogenesis of colorectal neoplasias and the possible alternative pathway for
      colorectal carcinomas through serrated adenomas will be discussed.

PMID- 15185489
TI  - Wisconsin Supreme Court decides hospital's interpretation of "legal counsel" in
      bylaws is reasonable.

PMID- 15185490
TI  - Hospital held liable on nondelegable duty theory.

PMID- 15185491
TI  - ERISA at 30: the decline of private-sector defined benefit promises and annuity
      payments? What will it mean?

PMID- 15185492
TI  - Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin
      variants.
AB  - Most transthyretin (TTR) mutations lead to TTR amyloid depositions in patients
      with familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy.
      However, though an amyloidogenic protein itself, TTR inhibits aggregation of
      Alzheimer's amyloid beta protein (A beta) in vitro and in vivo. The pathogenic
      relationship between two amyloidogenic processes remains unclear. To understand
      how TTR mutations influence the ability of TTR to inhibit A beta amyloidosis,
      forty-seven recombinant TTR variants were produced and analyzed. We showed that
      all recombinant proteins formed tetramers and were functional in thyroxine
      binding. Acid denaturation at pH 3.8 resulted in aggregation and fibril formation
      of all TTR variants. However, only TTR G42 and TTR P55 formed fibrils at pH 6.8.
      Most TTR variants bound to A beta and inhibited A beta aggregation in vitro. TTR
      variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to A beta
      and decreased inhibition of A beta aggregation. Only TTR G42 and TTR P55
      completely failed to bind A beta and to inhibit A beta aggregation. We suggest
      that TTR variants characterized by decreased binding to A beta or by decreased
      inhibition of A beta aggregation in vitro may contribute to A beta amyloid
      formation in vivo. These TTR variants might be important targets for
      epidemiological studies in Alzheimer's disease.

PMID- 15185493
TI  - ABri peptide associated with familial British dementia forms annular and ring
      like protofibrillar structures.
AB  - Amyloid plaque deposition involves the aggregation of normally soluble proteins
      into insoluble amyloid fibrils (fibrillization) and proceeds through
      intermediates with distinct morphologies, including spherical aggregates,
      protofibrils, and mature fibrils. Recently, a novel annular protofibril-like
      intermediate with unique pore-like properties was produced by alpha-synuclein, A
      beta-Arctic and amylin, which are proteins associated with Parkinson's disease,
      Alzheimer's disease, and type-II diabetes. The observation of annular structures
      coupled with size selective channel-like activity by these proteins suggests that
      these structures may be responsible for vesicle permeability by ion-channel
      formation. Using atomic force spectroscopy, we report here that the ABri peptide
      associated with familial British dementia produces similar annular and ring-like
      protofibril structures during the following sequence of events: spherical
      aggregates (0.4-1.5 nm height)-->chain-like protofibrils (1.5-2.3 nm height)-
      >ring-like protofibrils and annular protofibrils (1.5-2.3 nm height). This
      suggests that ABri fibrillization occurs in a similar fashion to other
      amyloidogenic proteins and that the annular protofibrillar structures may
      represent a common amyloid intermediate.

PMID- 15185494
TI  - Non-glycosylphosphatidylinositol (GPI)-anchored recombinant prion protein with
      dominant-negative mutation inhibits PrPSc replication in vitro.
AB  - Dominant-negative mouse prion protein (PrP) with a lysine mutation at codon 218
      (Q218K) is known to inhibit prion replication. In order to gain further
      mechanistic insight into such dominant negative inhibition, non
      glycosylphosphatidylinositol (GPI)-anchored recombinant PrP with Q218K (rPrP
      Q218K) was investigated. When applied into scrapie-infected mouse neuroblastoma
      (ScN2a) cells, rPrP-Q218K but not wild-type rPrP (rPrP-WT) exclusively inhibited
      abnormal protease-resistant pathogenic isoform (PrPSc) replication without
      reducing the viability of the cells. It was even more efficient than quinacrine,
      which has already been prescribed for sporadic Creutzfeldt-Jakob disease (CJD)
      patients; 50% effective concentration (EC50) = 0.20 microM, 99% effective
      concentration (EC99) = 0.86 microM vs. EC50 = 0.45 microM, EC99 = 1.5 microM.
      Besides, no apparent cell damage was observed at the concentration of up to 4.3
      microM (100 micrograms/ml). In combination treatment with 0.43 microM (10
      micrograms/ml) of rPrP-Q218K, EC99 of quinacrine was decreased from 1.5 microM to
      0.5 microM, and the cell viability was recovered from 50% to over 90% as
      inversely proportional to the concentration of quinacrine. Such combination could
      alleviate the side effects of quinacrine by reducing its effective concentration
      without changing or even acceleration the inhibition efficacy. Since homogeneous,
      high-quality rPrPs could be easily prepared from Escherichia coli in large
      quantities, rPrP-Q218K is a good candidate for a prion replication antagonist.

PMID- 15185495
TI  - Amyloidogenesis is neither accelerated nor enhanced by injections of preformed
      fibrils in mice transgenic for wild-type human transthyretin: the question of
      infectivity.
AB  - It is possible to accelerate amyloid formation in both the Senescence Accelerated
      Mouse, where ApoAIIC is the precursor, and in murine Amyloid A (AA) by the
      injection of preformed fibrils in the former and amyloid enhancing factor, which
      appears to consist of AA fibril fragments, in the latter. These two observations
      have raised the question of whether murine amyloids, like scrapie, are
      infectious. Injection of preformed fibrils into mice transgenic for many copies
      of the human wild-type transthyretin gene do not result in acceleration or
      enhancement of the process of deposition or the conversion of non-Congophilic
      deposits to fibrils.

PMID- 15185496
TI  - End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M:
      presentation, survival and prognostic factors.
AB  - Classical familial amyloid polyneuropathy may have a course with progressive
      renal impairment. We studied 62 patients (24 males, 38 females) with FAP,
      transthyretin variant V30M, and end-stage renal disease (ESRD) treated with
      hemodialysis, all referred to a single center over a period of 11 years. Clinical
      course, morbidity and survival after dialysis were analyzed. Patient's mean age
      at first dialysis was 51.5 +/- 10.7 years, and mean duration of neuropathy was
      10.2 +/- 3.8 years. The most frequent form of presentation of FAP nephropathy was
      nephrotic proteinuria with renal dysfunction. In the year prior to dialysis,
      renal function declined rapidly, and fluid overload was the main indication to
      initiate treatment. The presence of decubitus ulcers, significant disability,
      venous catheter for definitive vascular access for long-term treatment, and
      permanent bladder catheter, were related to death during the first year of
      dialysis. The mean duration of renal replacement therapy was 21 months, with a
      54.5% one year, and 38.4% two year treatment survival. However, when the duration
      of neurological symptoms at first dialysis exceeded 10 years, survival was
      significantly lower. Infections, (41% were decubitus ulcers with sepsis) were the
      cause of early, as well as late mortality. Early creation of vascular access for
      hemodialysis, surveillance of skin wounds, and intervention on neurogenic bladder
      are essential to improve the prognosis of ESRD in FAP.

PMID- 15185497
TI  - Analysis of cDNA sequences of feline SAAs.
AB  - Feline amyloidosis is an uncommon disorder caused by deposits of amyloid in a
      variety of organs. Most frequently encountered types are amyloid derived of
      pancreatic islet amyloid polypeptide (AIAPP) in older cats and of the
      apolipoprotein, apo-serum amyloid A (AA) in Abyssinian/Somali (Aby) and
      Siamese/Oriental (Siam) cats occurring at a relatively young age. For the AA
      protein of the Aby, Siam and domestic shorthair cat (DSH) breed different amino
      acid sequences have been described. It is not yet clear, however, whether the
      tendency to develop AA amyloidosis in Aby and Siam is associated with specific
      apoSAA protein sequences and whether this is breed specific. In this study, DNA
      from one Siam and two DSH cats revealed on Southern blot three bands suggesting
      at least three genes or gene clusters. The SAA cDNAs of hepatic mRNA from three
      Abys, five Siams and five DSHs were amplified by RT-PCR, cloned and sequenced.
      Siams and Abys had limited SAA sequence variability. All five Siams, three of
      which were positive for amyloid, had the amyloidogenic Siam SAA and the
      amyloidogenic Aby SAA sequence. Two of the Abys, both with amyloid, had the
      amyloidogenic Aby SAA sequence. The third Aby, without amyloid, missed its
      amyloidogenic sequence. The SAA sequences of the DSHs found in the present
      preliminary survey, suggested a possible tendency for more variability, whereas
      the amyloidogenic Siam as well as the amyloidogenic Aby sequence were found once.
      Up to five different sequences were found in a single animal. All five DSHs,
      moreover, had a specific sequence lacking in the Siams and Abys. The present
      results, especially those of the Siams, favor that in addition to the occurrence
      of amyloid associated SAA genes other factors such as infections and inflammatory
      processes are involved in the development of phenotypical amyloidosis.

PMID- 15185498
TI  - Familial amyloidotic polyneuropathy with severe renal involvement in association
      with transthyretin Gly47Glu in Dutch, British and American-Finnish families.
AB  - Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder
      associated with more than 80 different transthyretin (TTR) mutations. The
      clinical features of FAP are broad and variable, but knowledge of the pattern and
      natural history of disease associated with particular mutations nevertheless
      offers the best guidance for management of individual patients, including the
      role and timming of treatment by orthotopic liver transplantation. FAP in
      association with TTR Gly47Glu has been described previously in an Italian
      kindred, and we report here its phenotype in 7 additional patients from Dutch,
      British, and American (Finnish) families. Characteristic clinical features
      included amyloid cardiomyopathy and autonomic failure but, unusually, moderate to
      severe renal failure was present in more than half of the cases. Only four
      patients were deemed to be sufficiently fit to undergo orthotopic liver
      transplantation, and clinical deterioration was generally rapid. These
      observations support early intervention with orthotopic liver transplantation in
      patients with FAP associated with TTR Gly47Glu.

PMID- 15185499
TI  - Chemical characterization of a lambda I amyloid protein isolated from formalin
      fixed and paraffin-embedded tissue sections.
AB  - Amyloid protein was isolated from formalin-fixed paraffin-embedded heart tissue
      sections from a patient with primary (AL) amyloidosis by extraction with 6 M
      guanidine HCl. SDS-PAGE analysis of extracted material showed a major band at 16
      kDa and a minor band at 18 kDa. Edman degradation analysis before and after
      pyroglutamate aminopeptidase treatment showed that the amyloid protein contained
      N-terminal pyroglutamic acid and was derived from an immunoglobulin lambda light
      chain. Analysis of tryptic peptides from the extract identified the amyloid
      protein as a lambda I. Of particular interest is that almost the entire amyloid
      protein amino acid sequence could be obtained from the cardiac sections. These
      results demonstrate that formalin-fixed paraffin-embedded tissue sections can be
      used for extensive biochemical characterization of amyloid proteins and will
      become a valuable source for isolation and extensive biochemical characterization
      of amyloid proteins as they are now a valuable source for isolation of DNA for
      genetic analysis.

PMID- 15185500
TI  - Postmortem findings in a familial amyloid polyneuropathy patient with
      homozygosity of the mutant Val30Met transthyretin gene.
AB  - Autopsy findings in a 68-year-old FAP patient with a homozygous mutation of the
      Val30Met TTR gene were described. In addition to amyloid deposits on the visceral
      organs, peripheral nerves and the vitreous body, severe deposition of amyloid in
      the leptomeninges and subarachnoid vessels in the brain and spinal cord was
      present. A double dose of the mutant gene may accelerate amyloid deposition on
      the ocular and meningeal tissues.

PMID- 15185501
TI  - A rare transthyretin mutation (Asp18Glu) associated with cardiomyopathy.
AB  - The identification of a rare transthyretin (TTR) gene mutation (Asp18Glu) in a
      middle-aged male with biopsy proven amyloid disease featuring cardiomyopathy is
      described. The more commonly occurring light chain amyloidosis (AL) was initially
      considered, but negative hematologic testing prompted screening for a pathologic
      TTR mutation. A differential diagnosis of familial transthyretin type amyloidosis
      (ATTR) was established using a combination of molecular genetic and biochemical
      techniques. Single-strand conformation polymorphism (SSCP) screening of exons 2,
      3 and 4 of the TTR gene indicated the presence of atypical DNA. SSCP testing was
      performed using a new non-radioactive, silver stained minigel technique. The
      genetic abnormality was identified by direct DNA sequence analysis as a T to A
      transversion at the third base position in codon 18. This result was confirmed by
      restriction fragment length polymorphism (RFLP) testing. The presence of the
      variant protein, TTR Asp18Glu, in serum from the proband was confirmed by mass
      spectrometric analysis.

PMID- 15185502
TI  - [Is there a risk to discontinue statin treatment? Statins are advantageous also
      to the elderly].

PMID- 15185503
TI  - [Ethics in the physician's every day life. The ethical forum overviews in the
      doctor's database are intended to provide supports for doctors in every day
      tasks].

PMID- 15185504
TI  - [On the way to the diagnosis. Diagnosis belongs to the doctor's basic skills,
      which can be improved].

PMID- 15185505
TI  - [Biotechnology in food production].

PMID- 15185507
TI  - [Self-mutilating adolescents].

PMID- 15185508
TI  - [Neurobiology behind opioid dependence].

PMID- 15185506
TI  - [Using characteristic numbers to estimate the usefulness of laboratory tests for
      diagnosis].

PMID- 15185509
TI  - [Inhalation stridor of children].

PMID- 15185510
TI  - [History and current situation of medical schools in Finland].

PMID- 15185511
TI  - [The rupture of both Achilles tendons as a complication from fluoroquinolone
      treatment].

PMID- 15185512
TI  - [Oral drugs for diabetes--update of current use and availability].

PMID- 15185513
TI  - [Myocardial thickening in a patient with rheumatoid arthritis].

PMID- 15185514
TI  - [Treatment of migraine].

PMID- 15185515
TI  - [Dizziness after surgery of the ear].

PMID- 15185516
TI  - [Blockage of deep arteries and pulmonary embolism].

PMID- 15185517
TI  - S. Manzoor Abidi, MD, sets goals. New MSNJ president desires negotiation, not
      confrontation, sees adversaries, not enemies. Interview by Bernard A. Rineberg,
      Patricia A. Costante, Paul J. Hirsch.

PMID- 15185518
TI  - Communication. A matter of life and death.

PMID- 15185519
TI  - More than just caps are needed to solve New Jersey's professional liability
      crisis.

PMID- 15185520
TI  - Challenges and strategies for proper pediatric nutrition and weight control.
AB  - Pediatric and adolescent obesity are a growing problem in New Jersey and
      throughout the United States. The long-term health consequences may produce a
      generation of children with a shorter life expectancy than their parents have. A
      coordinated effort by parents, teachers, physicians, public health organizations,
      schools, and peers is essential in encouraging children who are currently
      overweight to lose weight and attain a normal body mass index and to prevent
      other children from becoming overweight.

PMID- 15185521
TI  - Opinion reflections on my presidency of UMDNJ.

PMID- 15185523
TI  - [Immunostimulation as a part of urologic infection therapy in pregnancy].
AB  - Twenty-six pregnant women (group I) with uroinfection were treated with Urostim
      and antibiotic. The effect of treatment was compared to that of 20 pregnant women
      (group II) treated with antibiotic only. In group I recurrence of infections was
      found out in 15.3%, while in group II in 55%. We would like to offer it as part
      of the treatment of uroinfections with pregnant women, because it will reduce the
      usage of antibiotics and the recurrence of the uroinfections in postpartum
      period.

PMID- 15185522
TI  - [Effect of intravenous gamma-globulin therapy on lymphocyte population in
      pregnant women with antiphospholipid antibodies].
AB  - The aim of the study was to establish the distribution of the lymphocyte
      populations in peripheral blood in pregnant women with antiphospholipid
      antibodies (aPL) and a history of recurrent pregnancy loss as well as to make a
      study on the influence of the intravenous IgG-treatment (IVIg) on the levels of
      antibodies and peripheral lymphocytes. MATERIALS AND METHODS: 14 pregnant women
      were investigated. The latter had two or more recurrent abortions and positive
      aPL--anticardiolipin (aCL) and/or anti-beta 2-Glycoprotein I (anti-beta 2-GPI).
      The lymphocyte populations were examined, using a flowcytometric method in
      peripheral blood before 6-7th gestational week and on the 10-14 day after the
      second IVIg infusion. 10 pregnant women wer used as controls who had no aPL
      antibodies and no pregnancy loss. RESULTS: 13 out of 14 pregnancies were
      successful Lymphocyte populations of the examined patients before the first
      infusion compared to the controls showed statistically significant differences
      for: T-lymphocyted Th(reduced) and CD3-CD56 + NK (increased) Significant increase
      after therapy was noticed for the levels of T-lymphocytes, and Th while the NK
      cell populations were significantly reduced. CONCLUSIONS: aPL-positive
      pregnancies most probably were associated with elevated and activated peripheral
      NK-cell subpopulations. The low doses of IVIg successfully reduce the levels of
      aPL, as well as peripheral CD3-CD56 + NK cells.

PMID- 15185524
TI  - [Study of women preference regarding mode of delivery].
AB  - The aim of this inquiry study is to assess the women's preference for abdominal
      or vaginal delivery in 113 women, divided in tree subgroups: 38 nonpregnant, 38
      pregnant with one more births and 37 puerperas. All women are with high education
      and 49.6% of them had past at least one university exam of obstetrics and
      gynecology. 42.1% of nonporous women and 40.9% from parous would like to deliver
      CS. With the time from vaginal delivery the preference for vaginal deliver again
      decreases from 84.2% to 60.9% of cases. All women delivered by CS prefer CS
      again. Complications of vaginal delivery are factor for increasing CS rate. The
      pain relief of vaginal delivery does not increase the preference for vaginal
      deliver again. In 40% of women there is steady desire for vaginal delivery
      despite previous complications or full medical information for the concrete
      conditions. 88.5% of inquired women agree with "CS on request".

PMID- 15185526
TI  - [Respiratory and hemodynamic monitoring during laparoscopy and two computer
      controlled TCI anesthesiologic technique].
AB  - Forty women under general anaesthesia (computer-controlled TCI-infusion) in two
      groups were subjected to non-invasive haemodynamic monitoring together with
      arterial gasometry and capnography. Simultaneous continuous monitoring of aortic
      blood flow and PetCO2 allows an undelayed recognition of major circulatory
      disturbances, before significant changes in heart rate and arterial pressure
      occur.

PMID- 15185525
TI  - [Active screening for genetic pathology in newborns. I. Registration of
      congenital abnormalities].
AB  - Active screening for genetic pathology over a period of 12 years (1990-2001)
      involved examination of 29,629 newborns at the Clinic of Obstetrics and
      Gynaecology. Congenital anomalies were detected in 1244 cases (live-, stillbirths
      and terminated pregnancies) which gives an average incidence rate of 42.0 per
      1000 among the studied population. Congenital cardiac anomalies and CA of the
      central nervous system were the most common types of isolated CA. They provided
      frequencies of 7.76 per 1000 and 6.85 per 1000 cases respectively. The incidence
      of the neural tube defects (NTD), particularly, varied throughout the years (t =
      2.69; p < 0.01) but stated high--on average 2.12 per 1000 with the highest rate
      of 3.89 per 1000 in 1993. A reduction in the incidence of NTD is possible with a
      recommendation of periconceptional folic acid supplementation. Registration of CA
      is a strategy for identifying families at risk to give births of child with CA.
      This approach enabled us to provide more accurate genetic counselling and
      prenatal diagnosis for genetic pathology. Active screening of newborn population
      is likely to be an effective and necessary service.

PMID- 15185527
TI  - [Histological analysis of endometrial polyps in breast cancer patients treated
      with tamoxifen (nolvadex)].
AB  - Endometrial polyps are the most common endometrial pathology described in
      association with Tamoxifen exposure. The aim of this study was to evaluate the
      malignant potential of endometrial polyps in breast cancer patients receiving
      Tamoxifen. We analyzed 140 endometrial polyps divided into two groups: 1) 73
      endometrial polyps from 57 breast cancer patients receiving Tamoxifen (Nolvadex):
      T+ endometrial polyps; 2) 67 control endometrial polyps received for analysis in
      the period January-December 2000. The analysis was performed on archival H&E
      sections. We found that the rates of endometrial carcinoma and atypical
      hyperplasia were high in patients treated with Tamoxifen (7.02% vs 2.99% and
      17.54% vs 11.94%), but the results did not reach statistical significance (p >
      0.05).

PMID- 15185528
TI  - [Determination of epidermal growth factor receptor expression in malignant
      ovarian tumors using radioligand assay].
AB  - The objective of the authors was to determine in a prospective study EGFR level
      of expression in ovarian cancer. For a period of 2 years EGFR expression was
      studied in 23 patients having malignant ovarian tumors by 125I-labelled human
      epidermal growth factor and recombinant human epidermal growth factor. EGFR
      expression was observed in 56.5% of the cases. Insignificant mucinous and clear
      cell cancers prevailed in the EGFR/+/ group. All patients having wider metastasis
      were EGFR/+/, as this dependency was statistically significant (p = 0.017).
      Radioligand binding assays enabled exact quantitative determination of EGFR
      expression in malignant ovarian tumors. Statistically significant relation
      existed between the ovarian cancer metastatic potential and EGFR expression
      level.

PMID- 15185529
TI  - [Study of neovascularisation in endometrial cancer and hyperplasia using angio
      Doppler technique].
AB  - The aim of our research work was to evaluate the neovascularisation in
      endometrial cancer and hyperplasia of the endometrium using "power" angio-Doppler
      technique. Two hundred and fifty patients /200 bulgarian and 50 patients from
      Greece/ with irregular bleeding, as well as women without bleeding in menopause
      were estimated. Age of the patients ranged between 44 and 80 years. There was not
      found any neovascularisation in the control group patients with normal
      histopathological results. The sensitivity of our method was 15% for the
      endometrial hyperplasia and 84% for the endometrial cancer. The specificity and
      the positive predictive value was for both 100%. For the endometrial cancer p <
      0.06/pulsative index--PI--0.95 +/- 14, resistance index--RI--0.45 +/- 0.09, while
      for the endometrial hyperplasia--PI--1.40 +/- 0.25 and RI--0.65 +/- 0.20. If we
      summarize our results using "power" angio-Doppler technique the irregular
      vascularisation of the endometrium in patients with hyperplasia was found in 14%,
      while for the women with endometrial cancer was 85%. The analysis of the values
      of blood flow in the neovascularisation areas of the endometrium for level of
      significance PI < or = 1.0; RI < or = 5 and time-averaged maximum velocity/TAMV/
      > 18 cm, may be a very important element in differentiation of benign from
      malignant lesions. The transvaginal ultrasonography with "power" angio-Doppler
      technique may serve as an important diagnostic method for differentiation of
      endometrial hyperplasia from endometrial cancer especially in the early stages of
      this malignant disease.

PMID- 15185530
TI  - [Endometriosis--a disease of the archimetra?].
AB  - This article reveals one of the newest theories on the pathogenesis of
      endometriosis. The research was carried out in the last two years and the
      suggested conclusions give much more convenient explanations on the way
      endometriosis develops.

PMID- 15185531
TI  - [Aromatase inhibitors--is it a new opportunity in the treatment of infertility?].
AB  - Aromatase P-450 is a key enzyme in the production of estrogens, that is, the
      conversion of androstenedione and testosterone to estrone and estradiol.
      Aromatase is a good target for selective inhibition. New aromatase inhibitors
      provide a good opportunity for successful treatment during infertility
      management. They have a potential to replace clomiphene citrate (CC) as the first
      line treatment for ovulation induction. Applying aromatase inhibitors during
      assisted reproduction followed: reducing the FSH dose needed to achieve optimum
      controlled ovarian hyperstimulation (COH); improving ovarian response to FSH in
      poor responders; terminating positive feedback loop and improving ovarian
      response to COH in infertile case with endometriosis; improving implantation
      rates in assisted reproduction technology (ART); reducing estrogen levels to
      reduce the risk of OHSS during COH.

PMID- 15185532
TI  - [Giant leiomyoma of the ovary].
AB  - Most of benign and malignant mesenchimal tumors may develop in the ovary. A case
      of 58 years old female, operated for ovary tumor is presented. A large soft mase
      10-7-5 cm with in semilucent capsule is resected. Different (small and large)
      nodules with in edematous stroma constitute the tumor and imitate a large ovarian
      cancer. After histologic examination the nodules are composed of criss-crossing
      and whirling bundles of smooth muscle cells. Immunohistochemically they express
      Desmin diffusely and don't express Vimentin and S100 protein. Smooth muscle cells
      bundles in large amount of edematous, colagenous stroma look like islands.
      Stromal cells are Vimentin positive. Operation in this case is just limited to
      the tumor.

PMID- 15185533
TI  - [Effect of low-dose oral contraceptive regulon-Gedeon Richter on some hemostatic
      variables].
AB  - The authors have investigated the changes of some haemostatic variables at 33
      women, who used low-dosed oral contraceptive REGULON--Gedeon Richter in the
      duration of six months. Statistically significant decrease is found in the
      activity of Protein S and Protein C, but plasminogen level is increased. The
      levels of the other variables remained in referential ranges. The use of REGULON
      doesn't influence the coagulation system.

PMID- 15185534
TI  - [Plant preparations administration to children is not without risks!].

PMID- 15185536
TI  - [Positive tuberculin reaction in children: from a life insurance to a ticking
      bomb. Latent tuberculosis should be treated to reduce the risk of active
      disease].

PMID- 15185535
TI  - [Hypertension--a hot topic for writers of Lakartidningen's articles. From
      observations and diet to surgery and extensive clinical trials].

PMID- 15185537
TI  - [The Pediatric Association recommends: Oats can be implemented in the gluten-free
      diet].

PMID- 15185538
TI  - [Few alternatives to estrogen replacement therapy for vegetative symptoms after
      menopause].
AB  - Vasomotor symptoms with hot flushes and sweating are reported by about 75 percent
      of women around menopause. Hormone replacement therapy (HRT) is the treatment of
      choice but some women have medical contraindications or side effects. There is,
      therefore, a need of alternative therapies. Progestagens may decrease hot
      flushes, as will clonidin and selective serotonin reuptake inhibitors.
      Phytoestrogens, which exist in some dietary products and complementary and
      alternative medicines have estrogen-like effects and may decrease hot flushes,
      although there are contradictory scientific reports. Acupuncture, exercise and
      behavioral therapy may also decrease vasomotor symptoms. No alternative therapy
      is as effective as HRT.

PMID- 15185539
TI  - [Combination of serotonergic agents resulted in severe adverse effects].
AB  - A 52 year old woman on buspirone was prescribed paroxetine for depressive
      symptoms. She also got papaverine. Within a month she experienced high fever,
      shivering, tremor, hyper-reflexia, tachycardia (120 bpm), and tracheal cramps,
      symptoms of the serotonin syndrome. Since both paroxetine and buspirone have
      serotonergic effects it is probable that the symptoms were caused by the drug
      combination. She also had ecchymoses on her thighs, probably due to serotonergic
      effects. The symptoms rapidly decreased after withdrawing paroxetine. Paroxetine,
      papaverine, and possibly also buspirone interact with cytochrome P450 CYP2D6.
      They can probably inhibit the metabolism of each other. We recommend observance
      of serotonergic syndrome symptoms and restricted combination of serotoninergic
      drugs.

PMID- 15185540
TI  - [Appendicitis--after the diagnostics. Focusing on the diagnostics has pushed the
      disease management into the background].

PMID- 15185541
TI  - [The sick Sweden--a challenge for the medical profession!].

PMID- 15185542
TI  - [Mental health as a stabilization factor in the Southeastern Europe].

PMID- 15185543
TI  - [New union reference interval within clinical chemistry--nonsense in, nonsense
      out!].

PMID- 15185544
TI  - [Results of psychotherapy depend on both the method and the relation!].

PMID- 15185545
TI  - [Driving lessons in the back seat or putting a student on the right track?].

PMID- 15185546
TI  - [A network for psychiatry for asylum seekers has been established within child
      and adolescent psychiatry].

PMID- 15185547
TI  - [Primary health care--an answer to health care needs, not a duty coming from the
      top!].

PMID- 15185548
TI  - [Bleeding ulcer--more important to improve the primary treatment than the
      secondary therapy].

PMID- 15185549
TI  - [Chronicles, sick listing and sour reactions].

PMID- 15185550
TI  - [Serious concept confusion coming from the insurance authority to the
      Lakartidningen].

PMID- 15185551
TI  - [Adverse effects of lithium treatment are not to be neglected].

PMID- 15185552
TI  - [Adequate dialysis, efficient dialysis: the "Holy Grail" of nephrology].

PMID- 15185553
TI  - [Dependent elderly and dialysis].

PMID- 15185554
TI  - [The peritoneal dialysis and hemodialysis studies--will they revolutionize our
      ways of prescribing and evaluating dialysis?].

PMID- 15185555
TI  - [Concerning: aging, the beginning of dialysis, the beginning of dependence:
      repercussions on the psychopathology of the very old dialysis patient].
AB  - The incidence of psychopathology, particularly depression, is high in dialysed
      elderly patients whereas their perceived level of health in the mental domain is
      similar to that of a non-dialysed and, even younger, population. Although the
      losses associated with advancing years, chronic disease and then entry into
      dialysis renders the psyche of elderly people frail, they do not strictly add in
      negative terms: their psychological reserve or resignation helps very elderly
      people to tolerate dialysis and its constraints. However, maintaining functional
      autonomy (ability to provide for one's fundamental needs and preserve leisure
      activities) while remaining independent to take decisions (particularly in
      controlling ways of receiving assistance) and preserving close relationships
      emerge as major determinant factors of the quality of life of very elderly
      dialysed patients. Added to the dependency due to dialysis, losses in these
      domains very often represent a turning point by changing the patient's identity,
      predisposing to the development of relationship problems, leading the patient to
      question his self-esteem or even resulting in psychological dependency, which
      itself adversely affects the quality of life. These mechanisms of psychopathology
      may not hide the possibility of an underlying dementia.

PMID- 15185556
TI  - [Symptoms and quality of life of hemodialysis patients aged 75 and over].
AB  - BACKGROUND: The population of dialysed patients includes an increasing percentage
      of very elderly patients. Although their life expectancy continues to increase,
      there are few currently available data about their quality of life. OBJECTIVES:
      descriptive analysis of the determinants of quality of life, perceptual level of
      health and quality of life, and estimation of symptomatic complaints in a
      population of very elderly haemodialysed patients. METHOD: Study of 35
      haemodialysed patients aged 75 years old and older, who answered a questionnaire
      divided into 7 parts, defining: the determinants of their quality of life by open
      ended questions, the prevalence of complaints amongst 35 pre-determined symptoms,
      Folstein MMSE performance, scores on Katz (ADL) and Lawton (IADL) independence
      scales, SF-36 perceptual health scale, and score subjectively allocated by the
      patients to their quality of life. RESULTS: Maintenance of functional autonomy,
      independence in the decision-making process and maintaining good relationships
      with friends and family were major determinants of quality of life. Asthenia, the
      major complaint, was well reflected the reduced physical capabilities of the
      patients (mean SF-36 physical score: -1.1 SD). Despite the high prevalence of
      incapacitating painful symptoms (42%) and psychological symptoms (23%), autonomy
      remained satisfactory (mean ADL score: 5.6 out of 6 and IADL: 58%). The levels of
      perceptual health and of quality of life remained satisfactory for the majority
      of patients (mean mental SF-36 score: -0.06 SD, and 84% of the patients scored
      their quality of life > 5 out of 10). CONCLUSION: These figures indicate the
      considerable resources that these patients could mobilise. It also emerges as an
      additional argument against the exclusion, based only on the criteria of age and
      multiple pathologies, of the oldest patients from the access to dialysis.

PMID- 15185557
TI  - [Stomatitis and ageusia induced by candesartan].
AB  - Cases of dysgeusia or ageusia have been reported in patients treated with
      angiotensin II receptor antagonist such as losartan (5 cases), valsartan (1
      case), eprosartan (1 case). This is the first case-report of ageusia following
      candesartan. A 46-year-old-male patient, with a medical history of renal chronic
      reject allograft disease, started candesartan 4 mg once daily to treat high blood
      pressure. Six months later, a progressive ageusia occurred with a burning mouth
      syndrome. He also developed aphthous ulcers of the mouth, stomatitis and
      perleche, which led him to lose 8 kilos within 13 months. Thirteen months after
      the beginning of the treatment candesartan was stopped. The symptoms and lesions
      required 2 to 3 weeks to disappear. Subsequently, appetite was found again as
      well as the sense of taste. The temporal sequence of events suggests a causal
      relationship between ageusia and candesartan.

PMID- 15185558
TI  - [Response to the article in Nephrologie 2004; Volume 25 No. 1, with the title
      "Disparities of access to kidney transplantations for diseases in Departments and
      Territories Overseas"].

PMID- 15185560
TI  - Cytochrome P450 1A1 (CYP1A1) T6325C polymorphism might modulate essential
      hypertension-associated stroke risk.
AB  - Stroke is a serious complication associated with hypertension. Because cytochrome
      P450 1A1 (CYP1A1) is involved in the production of arachidonic acid-derived
      vasoactive substances, we hypothesized that CYP1A1 functional polymorphisms
      (linked to changes in enzyme activity) might be related to pathological
      conditions associated with essential hypertension. We genotyped 32 patients with
      hypertension for three CYP1A1 polymorphisms, and individuals with or without
      history of previous stroke were compared. These results were also compared with a
      control population sample of 152. The distributions of T6235C (m1) CYP1A1
      genotypes in patients with (TT: 44.4%; TC/CC: 55.6%; n = 9) and without stroke
      (TT: 82.6%; TC/CC: 17.4%; n = 23) indicate that the C allele is associated with
      stroke (OR = 5.94; 95% C = 1.46 - 24.23). No association was found between the
      polymorphism studied and essential hypertension. Our results suggest a
      relationship between CYP1A1 activity and incidence of stroke in patients with
      essential hypertension, but no conclusion can be drawn regarding an association
      with essential hypertension.

PMID- 15185559
TI  - Low birth weight and cardiovascular risk factors at school age.
AB  - BACKGROUND: Many epidemiological studies show a strong association between
      nutritional status at birth and later chronic diseases, particularly
      cardiovascular diseases. These results seem to confirm fetal programming
      regarding risk factors and future diseases such as diabetes, hypertension,
      cardiovascular disease and kidney dysfunction. The aim of the present study is to
      evaluate, in a group of low-birth-weight (LBW) newborns, the influence of
      nutritional status at birth on blood pressure and lipid profile at school age.
      METHODS: A group of low birth weight newborns (n = 30) and a group with
      appropriate gestational age (AGA) (n = 26) were prospectively evaluated from
      birth up to 84 months of age. Nutritional status was evaluated at every
      observation and blood pressure and lipid profile were measured at 84 months
      according to international recommendations. RESULTS: A catch-up growth was
      observed in the LBW group during the first two years of life, stature at 84
      months being similar in both groups (AGA = -0.3 +/- 0.8 Z-score; LBW = -0.4 +/-
      1.1 Z-score). When results are grouped according to weight gain between birth and
      84 months of life, and taking account of breast-feeding duration, the LBW
      children show higher values, with significant differences in diastolic blood
      pressure between groups in those with greater weight gain (AGA = 88.8 +/- 5.8% of
      50th percentile; LBW = 101.2 +/- 5.8% of 50th percentile; p < or = 0.01).
      Regarding lipid profile, no differences were found except for apolipoprotein A,
      with lower values in the LBW group (LBW = 125.6 +/- 4.1 mg/dl; AGA = 143.4 +/-
      24.6 mg/dl; p < or = 0.05). CONCLUSIONS: Low birth weight newborns are at higher
      risk of future cardiovascular disease as they show higher blood pressure values
      compared to those with appropriate nutritional status at birth. These results are
      more evident in those individuals with greater weight gain, irrespective of
      breastfeeding duration. All efforts should be directed towards environmental
      factors that can negatively influence the health and nutritional status of
      pregnant women in order to reduce the prevalence of LBW newborns.

PMID- 15185561
TI  - Genetic polymorphisms and stroke risk.

PMID- 15185562
TI  - Transesophageal echocardiography-guided cardioversion of atrial fibrillation.
      Selection of a low-risk group for immediate cardioversion.
AB  - INTRODUCTION: In patients (pts) with atrial fibrillation (AF) of more than 48
      hours' duration, electrical cardioversion (ECV) should only be performed after 3
      weeks of effective anticoagulation. Transesophageal echocardiography (TEE) allows
      earlier ECV; however, despite exclusion of thrombi in the atrium and left atrial
      appendage (LAA), cases of thromboembolism related to ECV have been documented in
      AF. To define a low-risk group for cardioversion without previous
      anticoagulation, pts were selected for immediate ECV if no thrombi or dynamic
      spontaneous echo contrast (auto-contrast) were found after TEE and if LAA
      velocity was more than 0.25 m/sec. METHODS AND RESULTS: We performed TEE in 31
      consecutive pts referred for ECV for AF of more than 48 hours' duration and
      without previous anticoagulation. After TEE the pts eligible for immediate ECV
      began anticoagulation with low molecular weight heparin (enoxaparin),
      subcutaneously in therapeutic doses, together with warfarin immediately before
      cardioversion. Enoxaparin was continued until an INR of over 2 was reached. Based
      on the TEE findings, the pts were divided in 2 groups: immediate ECV, group A, 20
      pts with a mean age of 62 +/- 13 years, 6 female; and conventional therapy with
      warfarin before ECV, group B, 11 pts, mean age of 67 +/- 10 years (p < 0.05), 2
      female. None of the pts in either group had mitral stenosis or previous episodes
      of thromboembolism. The mean transverse diameter of the left atrium in the 31 pts
      was 47 +/- 4.5 mm, without statistically significant differences between the 2
      groups. Of the 11 pts in group B, 3 had a thrombus in the LAA, 6 dynamic
      spontaneous echo contrast and the remainder LAA velocities of less than 0.25
      m/sec. ECV was achieved in all the pts, with no complications. Oral
      anticoagulation was maintained for at least a month. At one month, sinus rhythm
      was maintained in 75% of group A and 45% of group B (p < 0.01). CONCLUSION: In
      pts with AF of more than 48 hours' duration and no previous history of
      thromboembolism, the use of our exclusion criteria during TEE enabled
      stratification of a low-risk population for immediate ECV, which was accomplished
      effectively and safely in 2/3 of the pts. This strategy is associated with early
      symptomatic improvement, and may contribute to maintenance of sinus rhythm after
      one month, which was significantly better than in the pts who had prolonged
      therapy with warfarin before ECV, despite the differences found in age and left
      ventricular function.

PMID- 15185563
TI  - Coronary spasm in acute myocardial infarction.
AB  - The authors present a clinical case of coronary spasm in acute myocardial
      infarction in a 22-year-old patient, admitted to the emergency department with
      chest pain. Angiography revealed normal coronary arteries and during the
      procedure a coronary spasm occurred.

PMID- 15185564
TI  - Coronary artery spasm during dobutamine stress echocardiography in a patient with
      angiographically normal coronary arteries.
AB  - Dobutamine stress echocardiography (DSE) has been extensively used for diagnostic
      and prognostic purposes in patients with suspected or known coronary artery
      disease. During DSE transitory alterations of myocardial wall mobility can occur
      in the absence of electrocardiographic alterations, or they can be associated
      with ST segment depression or even elevation on the electrocardiogram. ST segment
      elevation during DSE has been reported as an infrequent event, generally
      associated with previous myocardial infarction or coronary artery disease with
      critical lesions, since the positive inotropic and chronotropic effects of
      dobutamine produce an increase in myocardial oxygen demand, causing ischemia and
      segmental contractility abnormalities in patients with significant coronary
      stenosis. The present case relates to a patient referred for DSE after an
      ischemic treadmill exercise test. During DSE she presented ST segment elevation
      associated with chest pain. Subsequent coronary arteriography showed normal
      coronary arteries. We speculate that coronary spasm may have occurred in this
      patient, as a paradoxical response to the dobutamine-induced increase in coronary
      flow.

PMID- 15185565
TI  - Pulmonary embolism.
AB  - Pulmonary embolism (PE) is an important health problem and often a major clinical
      challenge, not only because of the low specificity of its clinical manifestations
      but also because of the increasing number of medical circumstances that are risk
      factors for this illness and the importance of early identification, since prompt
      and appropriate treatment can decrease mortality from this disease by about 25%.
      In recent years research on PE has been extensive, directed mainly at trying to
      determine and characterize its risk factors, establish new clinical probability
      algorithms, develop new diagnostic methods and put existing ones into
      perspective, seek new therapeutic approaches (pharmacological and non
      pharmacological), and above all establish protocols that can guide the clinician
      from the stage of clinical suspicion to measures to prevent recurrence. It was
      the authors' aim to review the most significant literature on this subject, in
      order to produce a text that reflects the state of the art concerning PE and that
      can be used as a guide in the clinical approach to this pathology.

PMID- 15185566
TI  - Methodological appraisal of guidelines. The AGREE instrument.
AB  - The increasingly important role of clinical practice guidelines as a support tool
      for clinical decision-making is shown by a growing number of publications in the
      literature. In fact, it is almost impossible to open a medical journal without
      coming across one or more guidelines on various subjects. Guidelines serve
      several objectives: 1) improvement in health care (increasing good and decreasing
      bad practices); 2) greater availability of and access to medical knowledge; and
      3) promotion of cost-effective strategies. The recommended methodology for
      guideline design and development requires that the recommendations should be
      evidence-based, i.e., based on selected and critically appraised data, with the
      final inclusion of evidence that is valid, important and applicable, based on
      explicit pre-defined criteria. The methodological quality of guidelines varies
      substantially, raising credibility issues, with subsequent lack of results (in
      terms of changing medical practice). This has given rise to a series of recent
      publications on methodological rules for the design and writing of guidelines.
      This paper presents the first international instrument that can be used as a
      quality assurance tool for evidence-based clinical guidelines: the Appraisal of
      Guidelines Research and Evaluation (AGREE) instrument.

PMID- 15185567
TI  - How important is a cardiac echogenic focus in a routine fetal examination?
AB  - Intracardiac echogenic foci are very frequent findings during routine fetal
      ultrasound examination and sometimes a reason for referral of patients for fetal
      echocardiography. OBJECTIVE: To assess the incidence of echogenic intracardiac
      foci in a mixed population of fetuses at high and low risk for congenital heart
      defects, and to determine whether the association between echogenic foci and
      congenital heart disease is stronger than in the general fetal population.
      DESIGN: Retrospective evaluation of clinical files at two fetal cardiology
      referral centers, during the last two years. All cases that had at least one
      echogenic focus were selected for our study. Maternal age, gestational age,
      reason for referral, location and number of echogenic foci, chromosomal
      abnormalities and cardiac defects were analyzed. As previous studies suggest
      increased risk of trisomy associated with echogenic foci and considering that
      congenital heart defects are more frequent in fetuses with trisomy 21, we
      excluded all fetuses with aneuploidy from our study. RESULTS: Thus, 753 clinical
      files were reviewed, of which 61 (8.1%) had a fetus with at least one echogenic
      focus. Mean maternal age was 29.0 years (minimum--19 years, maximum--43 years).
      Mean gestational age at the time of the examination was 23.4 weeks (minimum--19
      weeks, maximum--31 weeks). In 48.0% the reason for referral for fetal
      echocardiography was the existence of echogenic foci previously seen during a
      routine maternal examination. Increased nuchal translucency in 13.0% of pregnant
      women, maternal age in 10.0%, family history of congenital heart defects in 8.4%,
      suspicion of cardiac malformation in the obstetric scan in 4.2%, twinning in
      4.0%, history of miscarriage in 2.1% and maternal pathology in 10.3% were other
      referral reasons. In 53 cases a single echogenic focus was found, 44 of them
      inside the left ventricle and 9 in the right ventricle. Multiple echogenic foci
      were found in the different heart chambers in the eight remaining cases. Fifty
      six fetuses had a structurally normal heart and in five (8.1%) a cardiac defect
      was found. CONCLUSION: Echogenic foci are commonly seen inside heart chambers
      during routine fetal heart scanning, the left ventricle being the most frequent
      location. Although they probably represent a normal variant of papillary muscle
      development their presence should be interpreted as a possible risk for
      congenital heart defects.

PMID- 15185568
TI  - Left ventricular pseudoaneurysm with a double oriffice after myocardial
      infarction.

PMID- 15185569
TI  - Limitation of the spread and impact of infectious coryza through the use of a
      continuous disinfection programme.
AB  - The effect of a continuous disinfection programme, using the non-toxic
      disinfectant Virukill, in layers, on the spread and impact of infectious coryza,
      caused by Haemophilus paragallinarum was evaluated. In this experiment, both
      unvaccinated layers and layers vaccinated against infectious coryza were used.
      Duplicate smaller groups of vaccinated and unvaccinated chickens were challenged
      with different serovars of both NAD-dependent as well as NAD-independent isolates
      of Haemophilus paragallinarum. One group of chickens challenged with each of the
      different becterial serovars was treated with the continuous disinfection
      programme, while the other group remained as the untreated controls. The clinical
      signs of infectious coryza were evaluated over a period of 20 days in each group.
      The egg production over this period was also evaluated. It was found in all
      experimental challenges, that the severity of the symptoms was reduced in the
      birds receiving the continuous disinfection programme. The drop in egg production
      was also found to be less severe in the treated groups when compared to the
      untreated control groups. The duration of infection was found to be either
      unchanged, or shorter in the birds treated with the continuous disinfection
      programme. In none of the experimental challenges was the duration or expression
      of clinical signs of IC increased due to the continuous disinfection programme.

PMID- 15185570
TI  - Parasites of domestic and wild animals in South Africa. XLIV. Fleas (Insecta:
      Siphonaptera: Pulicidae) collected from 15 carnivore species.
AB  - Fleas were collected from 61 wild carnivores belonging to 13 species in various
      nature reserves and on farms, two feral domestic cats in a nature reserve and a
      domestic dog in the city of Johannesburg. Eleven flea species, including two
      subspecies of one of these, belonging to six genera were recovered. Amongst these
      only Ctenocephalides felis felis and Ctenocephalides felis strongylus are
      considered specific parasites of carnivores. The remaining ten species normally
      infest the prey animals of the various carnivores.

PMID- 15185571
TI  - A laboratory comparison of the life cycles of the dog ticks Haemaphysalis leachi
      and Rhipicephalus sanguineus.
AB  - Engorged female Haemaphysalis leachi and Rhipicephalus sanguineus as well as
      their eggs, flat and engorged larvae and nymphs were incubated at combinations of
      five temperatures and three relative humidities. Mean pre-oviposition periods for
      H. leachi varied between 4.3 days and 12.1 days and for R. sanguineus between 4.8
      days and 21.0 days. Haemaphysalis leachi converted up to 65.7% of their body mass
      into eggs and produced up to 16.3 eggs/mg body mass, with 4801 eggs the maximum
      number deposited by a single female. Peak egg production of 520 eggs/day was
      recorded 3 days after the commencement of oviposition. Rhipicephalus sanguineus
      converted up to 68.1% of their body mass into eggs and produced up to 17.2
      eggs/mg body mass, with a maximum of 3,232 eggs, and peak egg production of 400
      eggs/day 4 days after the commencement of oviposition. Mean incubation periods
      for eggs of H. leachi varied between 15.5 days and 66.7 days, and for R.
      sanguineus between 19.0 days and 72.0 days. Mean pre-moult periods for engorged
      larvae and nymphs of H. leachi varied between 14.0 days and 192.0 days, and 13.0
      days and 41.0 days respectively, and for R. sanguineus between 9.5 days and 36.5
      days, and 15.0 days and 44.5 days respectively. Allowing 7 days for female
      engorgement and 7 days for hardening of the exoskeletons and mouthparts of each
      of the three parasitic stages before they attach to a host, the life cycle of H.
      leachi would require 97-190 days and that of R. sanguineus 99-236 days to
      complete at the various regimes of temperature and relative humidity. The
      greatest proportion of H. leachi larvae engorging on mice detached between 18:00
      and 19:00 on the first day of detachment and between 06:00 and 08:00 in the
      morning and 14:00 and 18:00 in the afternoon of the following day, while the
      greatest proportion of nymphs engorging on dogs detached around 19:00 on the
      first day of detachment and between 13:00 and 17:00 on the following day. The
      greatest proportion of R. sanguineus larvae engorging on dogs detached between
      11:00 and 21:00 on the second day of detachment, and the greatest proportion of
      nymphs detached between 03:00 and 5:00 on the second and third days of
      detachment.

PMID- 15185572
TI  - Psittacine beak and feather disease virus in budgerigars and ring-neck parakeets
      in South Africa.
AB  - Psittacine beak and feather disease (PBFD) is a common disease of the psittacine
      species and is caused by the psittacine beak and feather disease virus (PBFDV).
      In this study the occurrence of the disease in ring-neck parakeets and
      budgerigars in South Africa suffering from feathering problems, using polymerase
      chain reaction as a diagnostic test was investigated. The genetic variation
      between viral isolates was also studied. Results indicate that PBFDV can be
      attributed to being the cause of feathering problems in some of the ring-neck
      parakeets and budgerigars in South Africa. Genetic variation of isolates occurs
      between species and individuals. A cheap and easy to use method of blood sample
      collection on filter paper for diagnostic purposes was also evaluated. It proved
      to be less stressful to the birds and did not inhibit further processes.

PMID- 15185573
TI  - The occurrence of Contracaecum sp. larvae (Nematoda: Anisakidae) in the catfish
      Clarias gariepinus (Burchell) from Lake Chivero, Zimbabwe.
AB  - Clarias gariepinus were collected from Lake Chivero, Zimbabwe, and examined for
      nematode parasites from November 2000 to May 2002. Of the 202 specimens
      collected, 42.6% were infected with third-stage larvae of Contracaecum sp. in the
      body cavity. The intensity of the infection was 1-7 worms per fish (mean
      intensity = 2.2). Seasonal variation in the prevalence of the parasite was not
      obvious and there was no significant difference in the prevalence of infection
      between males and females (chi 2 = 2.228; P > 0.05). No significant relationship
      between host size and prevalence was established. There was also no significant
      relationship between intensity and the body condition factor (r = 0.11; P >
      0.05). The low parasite prevalence may have been caused by the disruption of the
      infection cycle since piscivorous birds, which are the final hosts of the
      parasite, do not feed on C. garieplnus in Lake Chivero.

PMID- 15185574
TI  - Development of a novel self-medicating applicator for control of internal and
      external parasites of wild and domestic animals.
AB  - Four trials, three in the United States and one in South Africa, were conducted
      to evaluate the potential value of a novel self-medicating applicator in the
      passive control of gastrointestinal nematodes in cattle and deer, and of files
      and ticks on cattle using oil-based treatments. The results of the trials
      demonstrated that this applicator is an effective and practical device for the
      passive treatment of both deer and cattle for trichostrongyle infections using
      the endectocide, moxidectin (Cydectin. Fort Dodge Animal Health, USA), of cattle
      for hom fly (Haemotobia irritans) infestations using the insecticide, cyfluthrin
      (CyLence, Bayer AG, Germany) and of cattle for tick infestations (in particular
      Amblyomma hebraeum and Rhipicephalus appendiculatus) using the acaricides
      deltamethrin and amitraz (Delete All, Intervet, South Africa).

PMID- 15185576
TI  - Linognathus weisseri n. sp. (Phthiraptera: Linognathidae) of impalas, Aepyceros
      melampus: description and biology.
AB  - The adult male and female and first instar nymph of the sucking louse Linognathus
      weisseri n. sp. are described. This louse was collected from impalas, Aepyceros
      melampus, at three localities in Limpopo Province, and at three in Mpumalanga
      Province, South Africa. Although it usually accounted for only a small proportion
      of the total louse burden, its overall prevalence exceeded 27%. Its prevalence on
      adult male impalas (9%) was significantly lower (P = 0.004) than that on adult
      females (39%), but did not differ among age classes. However, the intensity of L.
      weisseri infestation was higher on lambs than on yearlings and adults, and peaked
      on impalas in late winter to early summer. Five species of lice are now known to
      parasitize impalas and a key for distinguishing adults of these species is
      included.

PMID- 15185575
TI  - Evidence of possible evasion of protective immunity by NAD-independent isolates
      of Haemophilus paragallinarum in poultry.
AB  - An indication of the ability of NAD-independent variants of Haemophilus
      paragallinarum to evade the immune system has been obtained from data obtained
      from several experiments. Firstly, it was noted that there was a difference in
      the serovar distribution between the NAD-dependent isolates in the 1990s and the
      NAD-independent isolates, as there was a significant decrease in the incidence of
      serogroup A NAD-dependent isolates. This can possibly be attributed to the
      extensive use of vaccines. On the other hand, most of the earlier NAD-independent
      isolates were serovar A. This is a possible indication of evasion of the
      protective immunity by the NAD-independent isolates. Further evidence of possible
      evasion of the protective immunity was obtained from results obtained when
      different isolates, both NAD dependent and NAD independent, were tested with a
      panel of monocional antibodies (Mabs). The V1 Mab reaction pattern was only seen
      in the reference strain 0083 among all of the NAD-dependent isolates tested in
      South Africa. This Mab was, however, found to react with some of the NAD
      independent isolates. Furthermore, the isolation of NAD-dependent isolates in
      Australia which react with the V1 Mab also suggest possible evasion of the
      protective immunity by the NAD-independent isolates as no vaccines containing
      strain 0083 are used in Australia. In order to investigate the hypothesis of
      immune-evasion by NAD-independent H. paragallinarum, vaccinated and unvaccinated
      chickens were challenged with a NAD-independent serogroup C isolate. As a
      control, chickens were also challenged with NAD-dependent H. paragallinarum of
      the same serogroup. The results obtained indicate that there is no significnat
      difference in the disease profiles obtained in vaccinated and unvaccinated
      chickens challenged with the NAD-independent isolate, thus providing further
      evidence of evasion of the productivity immunity by the NAD-independent isolates.
      The ability of the NAD-independent isolates to evade the immune system suggests
      that a different vaccination strategy, or alternative control methods may be
      needed for the control of IC caused by these isolates.

PMID- 15185577
TI  - A sero-epidemiological survey of blood parasites in cattle in the north-eastern
      Free State, South Africa.
AB  - A survey to determine the incidence of parasites in cattle (n = 386) was
      conducted in the north eastern Free State between August 1999 and July 2000.
      Giemsa-stained blood smears were negative for blood parasites. A total of 94% of
      the cattle were sero-positive for Babesia bigemina by indirect fluorescent
      antibody test while 87% were sero-positive for Anaplasma by enzyme-linked
      immunosorbent assay. The observation of negative blood smears but high incidence
      of positive serological results for Anaplasma and Babesia for the same group of
      cattle indicates that this area is endemic for these diseases but with a stable
      disease situation. All the animals were sero-negative for B. bovis and this is
      probably because the tick vector (Boophilus microplus) which transmits the
      disease is not present in the Free State Province. Two tick species belonging to
      the family ixodidae were found on cattle, namely Boophilus decoloratus and
      Rhipicephalus evertsi evertsi. In the present study significant differences in
      seasonal burdens of B. decoloratus occurred, with the highest infestations
      recorded from February to June. The presence of R. evertsi evertsi throughout the
      year without any or with small fluctuations in winter months was observed, with a
      peak from February to May.

PMID- 15185578
TI  - Reference serum protein and lipoprotein fractions of ostriches (Struthio camelus)
      in Turkey.
AB  - The aim of this study was to determine for reference purposes the values of serum
      albumin, alpha 1-globulin, alpha 2-globulin, beta-globulin, gamma-globulin, and
      alpha-lipoprotein (high density lipoprotein), pre-beta-lipoprotein (very low
      density lipoprotein) and beta-lipoprotein (low density lipoprotein) fractions of
      normal ostriches (Struthio camelus) in Turkey. Five male and five female
      ostriches, 18 months old, were used. All the ostriches were fed on a diet that
      contained 15.14% crude protein and 2,950 Kcal/kg of metabolizable energy. The
      serum protein and lipoprotein fractions were measured using agarose gel
      electrophoresis. The fractions were found to be 60.96% albumin, 0.24% alpha 1
      globulin, 15.91% alpha 2-globulin, 13.34% beta-globulin, 9.55% gamma-globulin,
      53.77% HDL, 0.60% VLDL and 48.09% LDL.

PMID- 15185579
TI  - [Public health and current social reform].

PMID- 15185580
TI  - [Should health promotion enter into resistance?].

PMID- 15185581
TI  - [False evidence and real dilemmas in public health: breast cancer radiologic
      screening].

PMID- 15185582
TI  - [Breast cancer: dangers of alleged certainties].
AB  - The artificial increase of breast cancer incidence is estimated as amounting to
      30,000 new cases in the year 2000 in France. This increase would be attributable
      to a 1.2% lack of specificity for the whole range of diagnostic procedures.
      Sociologically, it appears that the Hippocratic devise "primum nil nocere"
      ("first don't harm") has been replaced today by "primum agere" ("act first").
      Professionals should give information about both limitations and risks of
      screening. From an ethical point of view, screening programs justify themselves
      arguing that "there can't be harm in doing good". Absence of alternative
      strategies is not a sufficient argument for justifying screening with its
      uncertain consequences.

PMID- 15185583
TI  - [Poor management of diarrhea in children in France].
AB  - Every year in France infant diarrhoea is responsible for the death of 50-80
      children under the age of 5 and the hospitalization of approximately 50,000
      children principally related to the deshydration which it causes. A significant
      number of these deaths and hospitalizations could be avoided by simple measures
      aimed at preventing dehydration, measures which have been codified and
      internationally promoted by the WHO for the past 25 years. In France, a large
      number of physicians do not yet apply them; they do not prescribe oral
      rehydration salts in case of infant diarrhoea, but prescriable antidiarrhoeal
      drugs which are ineffective on dehydration and are formally rejected by the WHO
      in these cases. Looking through the prism of this collective failure, one can
      identify the various causes which put into question the entire French health
      system: Lack of epidemiological observation; Lack of targeting health actions and
      initiatives towards children; Insufficient medical culture; Very ambiguous
      relationships between the state and the pharmaceutical industry; System of
      continuing medical education strongly linked to the pharmaceutical industry and
      incapable, to date, of raising up the challenge of a change in practice, which is
      nevertheless necessary.

PMID- 15185584
TI  - [Twelve years after the Bamako initiative: facts and political implications for
      equity in health services accessibility for indigent Africans].
AB  - Launched in 1988, the Bamako Initiative was considered as a policy aimed at
      revitalizing the primary health care strategy while strengthening equity in
      access to health care. A decade later, two research initiatives conducted in Mali
      and Uganda, and later in Burkina Faso, concluded that a) this policy did very
      little to improve or increase access to health care among the most deprived and
      excluded vulnerable population groups, b) this policy only served to marginalize
      certain population groups already disenfranchised due to the emphasis on
      financial sustainability and viability of health care organisations, and c) the
      exemption mechanisms for alleviating the burden of payment and financial barriers
      for the poorest represent a technically feasible solution, while one not socially
      advocated. The current state of affairs requires that in order to give impetus to
      the principles of equity and the initial goals of the Bamako Initiative, African
      states should implement incentives, NGOs should consider planning as a tool for
      social change and donors need to ensure investments which are centred upon and
      prioritize principles of equity.

PMID- 15185585
TI  - [SARS epidemic in the world, from March to July 2003: what lessons can be learned
      from press coverage?].
AB  - In the period from March to July 2003, the French and international press
      published a great deal of information and news about the first occurrence of the
      global SARS epidemic, due to its threat on numerous developed or lesser developed
      countries. The author collected all of the available French daily newspapers,
      dating from March 17 to July 31, 2003, and in particular every edition of the
      five national papers relaying any information on the epidemic covered on the
      front page. The review and study of these papers' headlines highlight the intense
      media coverage given in the French press primarily from April to May 2003,
      accompanied by an evolution of the themes being tackled above all which concerned
      the world-wide alert from WHO which originally comprised the countries of the
      East (mainly China) as well as Canada, European countries (including France) and
      finally whose scale reached that of global proportions. Due to this situation,
      certain countries adopted more drastic protective measures.

PMID- 15185586
TI  - [Attitude and behavior of health services users in the face of real or perceived
      emergencies].
AB  - OBJECTIVES: To perform an opinion poll of users of normal health care, excluding
      emergency care, and also to identify populations which have required emergency
      care and to clarify the parameters which influence user decisions. METHODS: A
      transversal descriptive survey of users of Primary Medical Assurance Centres
      (Caisse Primaire d'Assurance Maladie) in the catchment area of the Hopital Nord
      in Marseilles, France, on a given day (7 days in total). Data were gathered using
      a standardised questionnaire based on the following topics: socio-demographic
      profile of interviewed participants, patient attitude toward general
      practitioners' care, the reaction to a situation felt to be urgent and for which
      they resorted to emergency services. RESULTS: Interpretation of the results from
      253 completed questionnaires demonstrated that users are mainly young,
      underprivileged, females, but who are not excluded from the health care system
      (good social security cover and marked presence of a family doctor). User
      behaviour differs according to the moment at which the problem arises (working
      hours, outside working hours) and depending on the degree of urgency perceived.
      ARISE OF DEMAND: In the most of cases, the patient consults emergency services
      for himself/herself. He/She takes the decision without prior consultation with a
      physician, within one hour of the problem arising, whether the problem is
      perceived as urgent or life-threatening, and arrived there under his/her own
      means. The main reason given is the access to emergency services without
      appointment and the principal medical reasons were for injuries and pain.
      CONCLUSION: This study demonstrates that users have a coherent approach depending
      on physician's consulting hours and according to user's perception of the
      emergency. On the other hand it is clear that users lack information concerning
      available after-hours care and the physicians night-duty organisation.

PMID- 15185587
TI  - [Analysis of regional health policy for children: an example from Lorraine].
AB  - Whereas today we have good, solid knowledge of the perception of health and its
      objectives from the perspective of youth, the recommendations of the High
      Commission on Public Health are geared towards the implementation of an overall
      health policy focusing on adolescent health. How is this policy implemented on a
      regional level? Is there coherence between actions undertaken within the same
      region? How do the various actors, elected officials, professionals, young people
      and families work together? A survey was conducted in the Lorraine region
      involving 217 people with a framework utilising both individual and group
      interviews. All categories of actors and stakeholders were represented. The
      results of this work demonstrate an often negative representation settings, and a
      partition of different approaches. Given that a variety of activities and actions
      exist, they are most often thematic. There undoubtedly remains a need to create
      links and build bridges between all of the projects carried out and to define in
      a more precise manner the common objectives focused on the health of young
      people.

PMID- 15185589
TI  - [Analysis of pregnant women's narratives].
AB  - Due to the fact that numerous social situations are directed by the provision of
      medical care and guide individuals to conform to general norms which are to the
      detriment of the individuality of specific cases, care remains embedded in logic
      intrinsically linked to machines and reflecting these norms, and finally
      eliminates them from the relational dimension of these situations. Nevertheless,
      human beings tend to maintain their individuality and humanity, by inscribing
      these situations within a general anthropological model of giving and counter
      giving. The analysis of narratives of pregnant women allows us to highlight a
      sort of normative conditioning towards medical norms and to demonstrate their
      escape from standardization. It depicts a picture of how women try to overcome
      the problems created by modern medical care solely obeying the rationale of
      public health management at a crossroads where knowledge development and social
      progress should have been able to bring about greater welfare.

PMID- 15185588
TI  - [Female general practitioners in Maine-et-Loire: "1990-2000"].
AB  - In 1990, there were approximately 60 female general practitioners in the Maine-et
      Loire region, 58 of which participated in the survey that year. By the year 2000,
      the number had risen to 137. A new study was conducted involving 70 women who had
      opened practices over that decade. Analyses of the responses to the questionnaire
      and a comparison with the results of the previous survey demonstrate distinct
      changes and a real evolution in the working conditions of this new generation of
      female general practitioners and in their relationships with their colleagues and
      families. More involved in their work and professional lives, they are now more
      accepted by other physicians and enjoy real family support. They are fulfilled
      and appear to succeed fully in all of their roles--those of physician, mother and
      wife. More active participation in social and political life would enable these
      professionals to achieve greater self-fulfillment and satisfaction; it is perhaps
      still too early to comprehend the true specificity, if any, of the private
      general practice of medicine by women. A new survey is planned to be conducted in
      ten years.

PMID- 15185590
TI  - [Diagnostic value of tegument pallor in anemia in pregnant women in Benin].
AB  - Anemia in pregnant women is a common and severe public health problem encountered
      in developing countries. Its detection is most often based upon clinical
      examination and observation of conjunctive pallor; however, little is known or
      documented on the performance indicators of this clinical method in Africa. This
      work aims assess the value of performance indicators in detecting moderate and
      severe anemia by means of tegument pallor examination in a maternity ward in
      rural Benin. To this end, 480 pregnant women were recruited at random during
      their prenatal visits to a rural maternity clinic. Two independent observers had
      noted conjunctive or other forms of teguments in all of the women selected, and a
      concentration of hemoglobin was confirmed by a blood test. An analysis of the
      results indicated that 67.4% of pregnant women were biologically anemic (Hb <
      11.0 g/dl) while only 49% among them were clinically anemic. The sensitivity of
      the clinical observation method for conjunctive pallor is 87.5% for severe anemia
      and 74% for moderate anemia. Its positive predictive value is 62.5% for moderate
      anemia and very weak for light cases of anemia, at only 3%. The accuracy of this
      clinical method varies from 51-71%, when the likelihood is determined as 1.8 to
      2.3. Its reproducibility appears equally weak and clinical observer variability
      seems to be poor to fair agreement at k = 0.34 (p = 0.00). For practical reasons,
      the authors suggest the strengthening of the teaching of this method to
      obstetrics' care providers and medical students in training in order to improve
      its more effective use and practice in rural maternity units without
      laboratories.

PMID- 15185591
TI  - [Development of health care networks: ethical and political contexts].
AB  - The operation of our health care system is in the midst of a major crisis. There
      is a significantly unacceptable level of health inequities and access to care,
      high premature mortality rates, lack of a coherent health policy, a weakness in
      the professional demographic projections, increasing financial deficits, quasi
      revolt of professionals, complete disregard for the law (Parliament's vote on the
      National Insurance's budget)--these are just a few of the symptoms of chaos which
      have embedded themselves right before our very eyes. This article aims to offer a
      glimmer of light on this gloomy horizon. It is the first outcome of a new working
      group which was originally referred to as "les Vignerons d'Uzes", a title which
      could be seen as lacking substance and has therefore become "The
      Transdisciplinary Working Group on the Organisation of Health and Care". The
      group's purpose and objective is to reflect upon the values, practices,
      regulations, evaluation and what is at stake in the context of our health care
      system.

PMID- 15185592
TI  - [Factors associated with the late management of HIV-infected patients: literature
      review].
AB  - In the United States, Australia and Europe, many HIV infected individuals are
      still diagnosed and/or treated late in the course of the disease. This literature
      review of studies published over a ten year period between 1993 and 2003 has
      identified the following principle factors associated with the late diagnosis of
      HIV: male gender, aged older than 45 years, heterosexual intercourse, the lack of
      previous screening. It also identified the factors linked to the delay in
      beginning anti-retroviral treatment as being male gender, the lack of awareness
      or denial of the possibility of HIV infection, intravenous drug use, lack of post
      screening follow-up or counseling, lack of social protection, and the lack of
      regular medical visits and care. Early detection and suitable early treatment of
      the HIV virus are the main determining factors which will effectively contribute
      to the control and maintenance of the virus in as much as they are focused upon
      these particular at-risk populations.

PMID- 15185593
TI  - [Inflammatory bowel diseases and lymphoma].
AB  - The aims of this review are to precise the incidence of non-Hodgkin's lymphoma
      and Hodgkin's disease in inflammatory bowel disease and to assess the
      relationship between immunosuppressive therapy and lymphoma in inflammatory bowel
      disease. Population-based data show that incidence of lymphoma is not increased
      in patients with Crohn's disease or ulcerative colitis. There is an increased
      incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on
      immunosuppressive therapy but overall risk is low in all cohort studies.
      Relationship between immunosuppression and lymphoma in inflammatory bowel disease
      is confirmed by frequency of cerebral lymphoma and association with Epstein-Barr
      virus.

PMID- 15185594
TI  - [Modalities and interest in followup of colorectal cancers after curative
      surgery].
AB  - Recurrence is found in 24 to 50% in patients undergoing surgery for colorectal
      cancer. The main purpose of follow-up is the screening of local or metastatic
      recurrence. Actually, the follow-up can not be justified only if there is a real
      advantage for the patient. Optimal modalities of surveillance of colorectal
      cancers resected have not been determined. The search of liver or lung metastases
      is actually preferred. The same pattern is used for searching colorectal lesions
      after a resection of colorectal cancer and after a polypectomy. The
      cost/effectiveness deontological value must be considered in the choice of
      further exams. However, the contribution of a cancerology follow-up is always
      controversial. Only prospective and randomized trials with a sufficient number of
      patients would prove the usefulness of a follow-up. In order to minimize the
      cost's problem, it is interesting to propose follow-up for a target population
      with a greater individual risk for recurrence.

PMID- 15185595
TI  - [Maternal mortality trends in the Sfax region from 1979 to 2000].
AB  - We report a retrospective study about maternal mortality in Sfax (Tunisia)
      between 1979 and 2000. Maternal mortality rate has fallen strikingly from 76.8
      per 100,000 mortality cases in 1979 to 40.1 per 100,000 mortality cases in
      20,000. However deaths from unavoidable causes have fallen much more slowly than
      avoidable causes.

PMID- 15185596
TI  - [Interest in prolactin levels in galactorrhea].
AB  - The action of prolactin (PRL) in supra-physiological levels on the ovaries or on
      the hypothalamic-pituitary axis for the release of gonadotropins leads to a
      reversible inhibition of the cyclic functioning of the pituitary gland and of the
      ovaries. The consequences are either the production of immature follicles marked
      by anovulatory or dysovulatory cycles, or the absence of follicle production
      marked by amenorrhea. Thus, prolactin plays a major role in the productive system
      by its lactotropic and antigonadotropic effects. Through this study we intend to
      try to determine the diagnostic value of the association of the cyclic
      dysfunctions with galactorrhea by measuring the prolactin levels in 2236 patients
      complaining of galactorrhea. Measurements of FSH and LH levels were also
      performed in 236 women among those consulting for infertility associated with
      galactorrhea. The results obtained showed that galactorrhea was associated with
      prolactenemia in only 17% of cases and of the ovaries was proportional to the
      prolactin in blood.

PMID- 15185597
TI  - [Obstructive sleep apnea syndrome. Analytical study of 63 cases].
AB  - Obstructive sleep apnoea (OSA) is a relatively common disorder, in developed
      country with prevalence estimated to lie between 2 and 4% in adult population.
      The diagnosis of this syndrome is made on the basis of characteristic clinical
      features and the results of nocturnal polysomnography. There is no data
      concerning the OSA in developing country. It is therefore of interest to
      determine the clinic and polysomnographic profile of this disease and to landmark
      factors correlated with severity in our country. This was achieved by studying a
      set of 63 OSA. The mean of age was 53 + 13 years with sex ratio 1. The means of
      Epworth sleepiness scale score, BMI and Apnoea/Hypopnoea index (AHI) were
      respectively 16 + 4, 38.8 + 7 kg/m2 and 51.7 + 28.6. 44% of patients have OSA
      severe with IAH > 50/h. Arousal index and desaturation index were respectively
      36.4 + 21.7 and 49 + 26. Trial of continuous positive airway pressure (CPAP)
      therapy was proposed first to 40 patients, 17 were able to use CPAP.

PMID- 15185598
TI  - [Diabetes following kidney transplantation. Report of 35 cases].
AB  - Post-transplant diabetes mellitus (PTDM) is a frequent complication of renal
      transplantation. It has a prevalence rate ranging from 3 to 46%. We undertook a
      retrospective study of 175 nondiabetic renal transplant recipients to determine
      the prevalence rate, clinical characteristics, and risk factors of PTDM in kidney
      transplant recipients in our region. Thirty five patients (20%) developed PTDM,
      50% were diagnosed by 3 months post transplantation. Eight patients (22.8%) were
      insulin recurrent. PTDM was independent of kidney source, family history of
      diabetes, age, sex, incidence of acute rejection, body weight gain, steroid or
      cyclosporine dose, use of beta-blockers and cytomegalovirus infection. Acturial 5
      years survival was 79.4% in the diabetic compared to 80.5% in the control group.
      Patient survival was similar in the two groups. We conclude that PTDM is frequent
      in our patients. No significant risk factors of PTDM were identified in this
      study.

PMID- 15185599
TI  - [Exploring the effect of aspirin on primary hemostasis through bleeding time.
      Study of 16 volunteers].
AB  - Strong anti-binding platelets, aspirin is used in the treatment or the prevention
      of many thrombotic pathologies. We wanted to study the effect of aspirin over the
      bleeding time of a group of volunteers. It consisted of 16 volunteers aged from
      20 to 25 years and having no haemorrhagic or thrombotic antecedent. For each of
      them, we have carried out a blood count by means of an automaton Sysmex K800,
      followed by a measure of the bleeding time (BT). Immediately after, each
      volunteer has ingested 250 mg of Aspegic; then, the BT has been measured every 24
      hours and up to the fifth day. The BT has been carried out by means of IVY
      technique 3 points, that besides the time, allows to measure the volume of
      bleeding (microliter). All the check-ups were normal, however, the time and
      volumes of bleeding were respective by short and weak. After having taken
      aspirin, the bleeding time has significantly become longer to day 1 and day 2
      (respectively 48% and 31.5% with regard to day 0) and the volume has increased to
      day 1, day 2 and day 3 (respectively 122.6%, 74.7% and 38.1% with regard to day
      0).

PMID- 15185600
TI  - [Uterine leiomyosarcoma: report of seven cases and review of the literature].
AB  - We report 7 cases of leiomyosarcoma of the uterus observed in the obstetrical and
      gynaecological department of Sfax (Tunisia). It's a rare tumour with difficult
      diagnosis and poor prognosis. It requires mainly a surgical treatment and
      radiotherapy.

PMID- 15185601
TI  - [Acute pancreatitis due to lupus].
AB  - Among digestive clinical presentations of systemic lupus erythematosus, acute
      pancreatitis remains a serious affection with very poor prognosis. To date,
      pathogenesis is still unclear. We report two cases of fatal acute pancreatitis
      related to systemic lupus erythematosus.

PMID- 15185602
TI  - [Efficacy of doxycycline in thoracic actinomycosis: a case report].
AB  - The authors present a case of thoracic actinomycosis in a 32 year-old man with a
      history of cervico-facial actinomycosis. Diagnosis was made by bacterial
      examination of purulent drainage from sternal wound showing typical sulfures
      granules. One year course of doxycycline gives clinical and radiological
      improvement.

PMID- 15185603
TI  - [Primitive adenocarcinoma of the fallopian tube: a case report].
AB  - Tubal carcinoma is rare and its prognosis is poor. His diagnosis before
      intervention is not easy because clinic is poor and complementary exams not
      specifics. His treatment is radical surgery by laparoscopy associated with
      chemotherapy. The prognosis is correlated with cancer stage and residual tumoral
      volume after surgery. We report a 55 years case who underwent coelioscpic
      annexectomy for left pyosalpinx. Definitive histology answered tubal cancer.
      Patient dead after three months because disseminated and parietal metastasis.

PMID- 15185604
TI  - Lymphadenopathic form of alveolar rhabdomyosarcoma: A case report.
AB  - We report the case of a special form of rhabdomyosarcoma called
      "lymphadenopathic" which was reported only two times in the literature. This
      lymphadenopathic alveolar RMS shows lymph nodes as clinical manifestation
      mimicking lymphoma with an unknown primary neoplasm. In the case we report,
      clinical examination, and radiological studies revealed superficial and deep
      located lymph nodes in association with bilateral pleural effusion. Conventional
      histological examination showed lymph node infiltration by a metastatic tumour
      having alveolar pattern. Some of tumour cells were round with multilobed off
      centred nucleus and eosinophilic cytoplasm containing fibril material with
      longitudinal and transverse striation indicating a muscle nature of the tumour
      proliferation. The immunohistochemical study showed intense and diffuse
      immunoreactivity of tumour cells for vimentin and a discreet immunostaining by
      desmin. These findings were compatible with the diagnosis of lymph node
      metastasis by alveolar rhabdomyosarcoma.

PMID- 15185605
TI  - [True aneurysm of the common hepatic artery: a case report].
AB  - We report a case of hepatic artery aneurysm suggested by the appearance of
      epigastric mass. The diagnosis was confirmed by doppler sonography and helical
      CT. Surgical excision of the aneurysm without vascular reconstruction was carried
      out.

PMID- 15185607
TI  - [Cervical metastases of melanoma. A case report and review of literature].
AB  - We are reporting the clinical case of a 56 years-old female who was diagnosed and
      operated of a stage V Clark melanoma in temporal zone that showed, 21 months
      after the surgery, several left cervical lymph nodes. The F.N.A.B. informed as
      melanoma metastases, result that was confirmed by AP study then a functional neck
      dissection. Later she has followed treatment by Oncology-Radiotherapy. Melanoma
      can isolate between a 5%-10% from all the cases of cervical lymph node metastases
      but in most of the patients it is not possible to find the primary lesion. Its
      vital prognosis is bad and the role of adjuvant irradiation remains
      controversial.

PMID- 15185606
TI  - [Latero-pharyngeal phlegmons and abscesses in adults. Reports of 6 cases and
      literature review].
AB  - Lateropharyngeal phlegmons and abscesses are an uncommon complication actually
      but they are requiring an adequate knowledge to get later an adequate treatment.
      We are reporting a clinical review of 6 cases corresponding to adults admitted by
      our ENT service in 11 years period. Four were men and two women with ages between
      21 and 92 years old. In most of them it was found a pharyngotonsillar focus and
      after the diagnosis they were treated by endovenous antibiotic therapy, corticoid
      and, in one case, surgery by incision and drainage. All the patients had a
      satisfactory evolution standing between 6-12 days in the hospital. We have
      performed a bibliographic review on this subject.

PMID- 15185608
TI  - [Epidemiological notes on nasal bleeding].
AB  - The incidence of epistaxis is difficult to calculate because only a 10% of them
      look for medical attention. In this study the nasal bleeding means the 13.3% of
      the ENT emergencies (279 patients). Its incidence was 6 cases/10,000/year. The
      majority were over 50 years old (57.3%). There was season variations. The
      anterior epistaxis were more frequent but he posterior ones increased over the
      40. An 18% had rebleeding more significatively with age and localization. We
      discuss the mechanisms that can explain the male dominance, the season incidence,
      and the old ages of the patients with hospital epistaxis.

PMID- 15185609
TI  - [Pleomorphic adenoma of the tongue base. A new case of big size].
AB  - The pleomorphe adenomas (PA) of the tongue base are rare (there are only 6 cases
      published until now) We present one case of a male 42 years old with a PA of the
      tongue base very big but with few symptoms. The FNAB and MRI were the key for the
      diagnosis and therapy. The treatment was surgical with a trans oral resection.
      The patient is free of tumor after seven years.

PMID- 15185610
TI  - [Cerebellar and pulmonary metastases from papillary thyroid carcinoma. Report of
      a case].
AB  - We are reporting the clinical case of a male who was diagnosed as papillary
      thyroid carcinoma with cervical, cerebellar and lung metastases. Although in
      theory it was a well differentiated tumour and slow progression with a good
      prognosis, there was a very aggressive spread in our patient up to his death. We
      decided not to operate him and send him to the Oncology Service for chemotherapy
      that was unsuccessful. The intracranial metastases due to papillary thyroid
      carcinoma are very uncommon (about 1%) on the contrary of cervical ones, but
      their behaviour is more aggressive and frequently associated to other metastases
      on bone or lung.

PMID- 15185611
TI  - [Monostotic fibrous dysplasia. Three cases and literature review].
AB  - The fibrous dysplagia is a rare benign osseous pathology of unknown aetiology. It
      presents an incidence of craniofacial affectation of a 10% in its monostotic
      variety and a 100% in the poliostotic. The temporal bone implication is very
      rare, being usually referred in the monostotic variety. The diagnosis is based on
      radiology (CT) and histology. The majority of the authors agree in a conservative
      treatment. We present three clinical cases of monostotic fibrous dysplagia with
      craniofacial affectation, two of them in the temporal bone and another one in the
      frontal bone.

PMID- 15185612
TI  - [Current aspects of laryngeal tuberculosis].
AB  - In the preantibiotic era laryngeal tuberculosis was the most frequent pathology
      of the larynx. In the last decades some changes in the presentation and evolution
      of the pathology have occurred due to the new chemiotherapy and the improvement
      of the nutrition. Actually it presents less incidence and infectivity and less
      evidence of pulmonary disease. In this article we analyse, on occasion of a
      clinical case and with a revision of the literature, the actual patterns of the
      laryngeal tuberculosis.

PMID- 15185613
TI  - [Hereditary angioneurotic edema (Quincke's edema). Report of a case and
      literature review].
AB  - Familiar angioneurotic edema or Quincke's edema is an uncommon variant of
      urticaria, associated or not, that involves the subcutanean cell tissue and
      mucous of the face and upper airdigestive tract. It can produce an acute dyspnea
      and risk of suffocation with intubation or tracheostomy up to a 20% of the cases.
      The disease is a result of deficit in C esterasa inhibitor which autosomal
      dominant inheritance. We are reporting one clinical case confirmed as such
      corresponding to a 81 years-old male whom was operated by tracheotomy after
      sending from UCI with an emergency coniotomy and failure for orotracheal
      intubation.

PMID- 15185614
TI  - Early diagnosis of endolymphatic hydrops with distortion. Product otoacoustic
      emissions.
AB  - The present investigation was specifically designed to evaluate the ability of
      the glycerol test combined with pure-tone audiometry, distortion-product
      otoacoustic emissions (DPOAEs) to diagnose endolymphatic hydrops early and to
      identify patients who may evolve toward Meniere's disease. This investigation
      consisted of 43 consecutive patients with daily episodes of tinnitus with
      duration exceeding few hours or with continuous tinnitus who received no
      treatment. These were the unique symptoms reported by the patients. Each patient
      underwent glycerol testing measured with conventional pure tone audiometry and
      with distortion product otoacoustic emissions (DPOAEs). For the traditional pure
      tone glycerol test a hearing improvement of at least 10 dB, at the lower two or
      three frequencies (125,250 and 500 Hz) was judged as positive result. For the
      DPOAEs glycerol testing, a smaller positive difference (5 dB) for at least three
      frequencies was interpreted as a significant fluctuation. Twenty four patients
      showed negative glycerol test both with pure tone audiometry and DPOAEs. In 7
      cases the improvement was concurrently observed. In 9 patients post-glycerol
      changes appeared only in the DPOAEs outcomes. Finally the remaining three
      patients had two different patterns. Two had different ameliorations of the
      DPOAEs and pure-audiometry on the left and right sides respectively, and in the
      last one only post-glycerol, audiograms recovered. The present study re-confirms
      the potentiality of DPOAEs associated with glycerol test in diagnosing
      endolymphatic hydrops precociously. The possibility of these patients
      degenerating into Meniere's disease should not be underestimated.

PMID- 15185615
TI  - A serological survey for pathogens in old fancy chicken breeds in central and
      eastern part of The Netherlands.
AB  - To get an impression of the presence of pathogens in multi-aged flocks of old
      fancy chicken breeds in the Netherlands, plasma samples originating from 24
      flocks were examined for antibodies against 17 chicken pathogens. These flocks
      were housed mainly in the centre and east of the Netherlands, regions with a high
      poultry density. The owners of the tested flocks showed their chicken at national
      and international poultry exhibitions. Antibodies against Avian Influenza, Egg
      Drop Syndrome '76 virus, Pox virus, Salmonella pullorum/gallinarum, Salmonella
      Enteritidis or Salmonella Typhimurium were not detected. However, antibodies
      against other Salmonella species, Mycoplasma gallisepticum, infectious bursal
      disease virus, infectious bronchitis virus, avian encephalomyelitis virus,
      chicken anaemia virus, infectious laryngotracheitis virus, and avian leukosis
      virus, subgroups A and B, and subgroup J were detected in a varying proportion of
      the flocks. This study shows that antibodies against many chicken pathogens are
      present among the flocks of old fancy chicken breeds that are exhibited at
      international poultry exhibitions.

PMID- 15185616
TI  - [Hip luxation].

PMID- 15185617
TI  - [Antibiotic resistance in agriculture].

PMID- 15185618
TI  - [Campylobacter and Salmonella control in chickens and the role of fermented
      food].
AB  - Salmonella and Campylobacter are undesirable pathogens on poultry. Therefore the
      effect of fermented feed on the colonization in the gastro-intestinal tract of
      the chicken, the introduction of both bacteria in a chicken flocks, and the
      transmission between chickens was studied. Broilers that were fed with fermented
      feed were significantly less susceptible for Salmonella and Campylobacter than
      chickens on a standard chicken feed. The spread of Salmonella between broiler
      chickens was reduced. However, the results also showed, like for other known
      control measures, that this feed can not absolutely guarantee the absence of
      Salmonella and Campylobacter. Therefore fermented feed must be seen as one of the
      hurdles in a so called multiple hurdle strategy. The combination of different
      hurdles should prevent the introduction and transmission. The effect of fermented
      feed on Campylobacter and Salmonella is partially caused by the presence of high
      concentrations of organic acids. In chickens fed with liquid feed the acidic
      barrier in the first part of the GI-tract was clearly improved. Besides organic
      acids there are other changes in the GI-tract. Changes in colonization levels of
      indicator organisms, changes in levels of organic acids and an increased pH in
      ileum and ceacum. These changes indicate a stabilised GI-flora in fermented feed
      fed poultry. The research confirmed that by changes in the composition of the
      feed (carbohydrates, acids, or micro-organisms) the GI-health can be promoted and
      therewith can contribute to the control of food pathogens in farmed animals.

PMID- 15185619
TI  - ['Petting dogs can cause blindness': a critical analysis].

PMID- 15185620
TI  - [Reinstatement of the distribution and administration system of veterinary drugs
      in the Netherlands].

PMID- 15185621
TI  - [Unique privilege position of homeopathy within KNMvD].

PMID- 15185622
TI  - [Remarkable verdict of the Veterinary Tuchtcollege about homeopathic treatment of
      pets].

PMID- 15185623
TI  - [Alienation from the society].

PMID- 15185624
TI  - Disruptive technology: new medical advances are troublesome for even the most
      successful health systems and innovator health companies.
AB  - An independent expert panel conducted a multi-year research/education/advocacy
      initiative on the impact of the new drug-eluting stent technology. They conclude
      that this technology represents a "tipping point" in a series of transformative
      drugs and medical devices, often used in combination, and recommend that
      healthcare decision makers develop careful, data-based strategies to avoid the
      disruptiveness of these medical advances.

PMID- 15185625
TI  - Translational barriers and their effect upon cardiovascular revenues and
      reimbursement.
AB  - During the past 2 decades in health care environments, particularly hospitals,
      attempts to centralize operational processes have inadvertently bred barriers to
      interdepartmental communication, resulting in the creation of informational silos
      and, ultimately, decreases in revenues reported and reimbursement obtained.
      Overall, operational centralization has reaped process improvement. However,
      these efficiencies have come at the cost of measurable accuracies that directly
      affect the bottom line. Cardiovascular managers and administrators should not
      assume that all the benefits from reviewing claims and information processes
      within symbiotic departments have already been obtained. Key long-standing
      services provided to the managers and administrators by departments such as
      Hospital or Health Information Management/Systems (HIM/HIS), the Business Office
      (Patient Financial/Account Services), and Information Systems should be
      periodically reviewed, fine tuned, and overhauled if necessary. The consequence
      of such reviews and maintenance will be tangible gains in operational efficiency
      as well as increased financial productivity.

PMID- 15185626
TI  - Building a cardiology practice.
AB  - This study was designed to quantify the clinical and marketing effectiveness of
      the Pocket EKG Clinical Based Marketing Program by measuring its impact on new
      patient visits, patient satisfaction, payor negotiations, and patient management
      at Pikes Peak Cardiology (PPC), Colorado Springs, Colorado. New patient visits
      were found to increase by 22% for 6.5 consecutive years. Ninety-two percent of
      patients surveyed found that the Pocket EKG Card promoted loyalty to the
      cardiology practice. The Pocket EKG Patient Satisfaction Survey was proven to
      satisfy Health Plan Employer Data and Information Set (HEDIS) guidelines as
      required in payor contracting. Finally, access to a baseline electrocardiogram
      contributed to a 54% reduction in unnecessary hospitalization. The Pocket EKG
      Clinical Based Marketing Program proved to successfully market PPC to its three
      customers: patients, payors, and primary care physicians.

PMID- 15185627
TI  - A six sigma approach to maximizing productivity in the cardiac cath lab.
AB  - Cardiac catheterization laboratories represent one of the most significant
      capital investments for hospitals. Historically, hospitals could achieve an
      economic return fairly rapidly on this capital investment because of the
      relatively high contribution margin on many of the procedures performed in the
      department. However, recent changes in DRG assignments, declines in Medicare
      reimbursement, and the advent of new technologies, such as drug-coated stents,
      pose a threat to achieving planned economic return. In response, many hospitals
      are pursuing strategies to improve throughput in the cardiac cath lab and
      maximize the number of procedures performed. The case example in this article
      describes how a busy cardiac catheterization lab in the southeastern United
      States successfully applied the Six Sigma methodology to improving productivity
      and increasing available capacity.

PMID- 15185628
TI  - [Viral hepatitis in users of addictive drugs in the Czech Republic].
AB  - INTRODUCTION: Prevalence of viral hepatitis A-C markers in problematic drug users
      was studied. MATERIAL AND METHODS: Two groups of drug users, i.e. addicts
      enrolled in a mid-term drug withdrawal community program (group 1) and
      penitentiary prisoners (group 2), were tested for the presence of viral hepatitis
      A-C markers. Group 1 of 546 addicts (335 males and 211 females) included 163 male
      and 91 female injection drug users (IDUs) and 172 male and 120 female mostly
      alcohol abusers. Group 2 of 197 male prisoners included 150 injection drug users
      and 47 mostly alcohol abusers. Serological markers of viral hepatitis were
      detected by EIA within the entry check-up; RT PCR was used for detection of HCV
      nucleic acid. RESULTS: The prevalence rates of anti-HAV antibodies among group 1
      addicts were 33.6% for IDUs and 39.5% for the remaining mostly alcohol abusers.
      HBsAg was found in 4.2% of IDUs and 0.0% in the remaining addicts. Two IDUs also
      tested positive for HBeAg. Anti-HCV positivity was recorded in 22.4% of IDUs and
      5.6% of the remaining addicts. The prevalence rates of anti-HAV antibodies among
      group 2 penitentiary prisoners were 40.7% for IDUs and 28.6% for the remaining
      mostly alcohol abusers. Anti-HAV IgM antibodies were detected in 4.2% prisoner
      IDUs. HBsAg was found in 3.4% of IDUs and 6.5% in the remaining addicts. Anti-HCV
      positivity was recorded in 18.1% of IDUs and 16.3% of the remaining addicts.
      CONCLUSION: The prevalence rates of the markers studied in the addicts are
      several times as high as in the general population; therefore, the population of
      addicts is a potential source of the spread of viral hepatitis.

PMID- 15185629
TI  - [Hepatitis B virus (HBV) genotypes in the Czech Republic].
AB  - Hepatitis B virus (HBV) was genotyped based on sequencing and analysis of
      nucleotide sequences of HBV S gene in sera samples from 176 patients with viral
      hepatitis B from all over the Czech Republic. The most frequent genotype A was
      detected in 118 (67.1%) of the patients, followed by genotype D found in 50
      (28.4%) of the patients. Genotypes B and C were identified in 6 (3.4%) and 2
      (1.1%) of the patients, respectively. The incidence of genotype A statistically
      significantly increases with age. There is no statistically significant
      correlation between genotypes A and D and gender or locality (region). Genotypes
      B and C, found mainly in South East Asia, were first detected in the Czech
      Republic. Detection of these genotypes in both foreigners and Czech population is
      suggestive not only of import but also of transmission of these genotypes in the
      Czech Republic. Fylogenetic analysis documents dissimilarity levels between HBV
      isolates. Based on the amino sequence derived, the percentages of HBV subtype
      determinants d (68.6%) and y (31.4%) were established. The gene S sequencing
      analysis proved suitable for HBV genotyping.

PMID- 15185630
TI  - [Detection of MRSA in a group of 752 strains of S. aureus using a cefoxitin
      disk].
AB  - A set of 752 S. aureus strains including 665 fresh clinical isolates, 82
      collection strains from the NRL for staphylococci and three control strains for
      external quality assessment were tested for susceptibility to oxacillin by three
      routine phenotypic methods with oxacillin (agar screening method, dilution
      micromethod and disk diffusion method) and a new method with a 30 micrograms
      cefoxitin disk. Gene mecA coding for oxacillin resistance was detected by PCR,
      PBP2a gene product was detected by latex agglutination. All of 218 oxacillin
      resistant strains--MRSA (methicillin resistant S. aureus)--gave inhibition zones
      of 6-19 mm around the cefoxitin disk, i.e. zones within the range set up for
      oxacillin resistant strains, eight out of these strains showing false oxacillin
      susceptibility in one or more phenotypic tests. It can be stated that the
      presence of an inhibition zone of < 20 mm around the 30 micrograms cefoxitin disk
      allows for reliable differentiation between MRSA and oxacillin susceptible S.
      aureus.

PMID- 15185631
TI  - [Differences in antibiotic sensitivity in biofilm-positive and biofilm-negative
      strains of Staphylococcus epidermidis isolated from blood cultures].
AB  - The adhering capability and biofilm growth facilitate staphylococcal colonization
      of surfaces of damaged tissues and foreign bodies. Biofilm-forming bacteria are
      more resistant to immune system activities, mechanical effects of blood flow and
      other adverse effects, e.g. those due to antibiotics. Minimal inhibitory
      concentrations (MICs) were compared for two groups of Staphylococcus epidermidis
      strains isolated from blood cultures. Group 1 included biofilm positive strains
      whose biofilm-forming potential was revealed by both phenotypic and genotypic
      methods. Group 2 included strains without biofilm-forming potential. The
      comparison of MICs for selected antibiotics showed higher resistance of biofilm
      positive compared to biofilm negative strains. The difference was evident
      particularly for oxacillin, tetracycline, co-trimoxazole and gentamicin.

PMID- 15185633
TI  - [Characterization of Haemophilus influenzae strains using multilocus sequencing].
AB  - First results of multilocus sequence typing (MLST) of Haemophilus influenzae
      strains are presented. MLST of 28 H. influenzae strains isolated from patients
      with invasive diseases in the Czech Republic is indicative of clonal homogeneity
      of these strains: 22 out of 26 H. influenzae b strains tested were of the same
      sequence type, ST-6. Four strains were of two sequence types newly described in
      this study: ST-83 (3 strains) and ST-84 (1 strain). Two nontypeable H. influenzae
      strains were assigned to sequence types other than ST-6: ST-3 and ST-85 newly
      described in this study. First MLST results show ST-6 to be typical of H.
      influenzae b isolated from patients with invasive diseases in the Czech Republic.
      The sequence types newly described in this study, i.e. ST-83, ST-84 and ST-85,
      were submitted to the worldwide H. influenzae MLST database
      (http://haemophilus.mlst.net).

PMID- 15185632
TI  - [Occurrence of phage types of non-typhoid Salmonella serovar in the Slovak
      Republic 2000-2003].
AB  - Salmonellae of non-typhoidal serovars are the most important pathogens involved
      in foodborne diseases in humans all over the world. The incidence rates of two
      major Salmonella serovars, i.e. S. enterica serovar Enteritidis (S. Enteritidis)
      and S. enterica serovar Typhimurium (S. Typhimurium), in the Slovak Republic in
      2000-2003 are given. Over the period studied, 829 S. Enteritidis strains and 258
      S. Typhimurium strains isolated from patients with salmonellosis were
      investigated in the National Reference Centre for Salmonella Phage Typing. The S.
      Enteritidis strains were differentiated into 16 phage types, with phage type 8
      being dominant since found in 73.6%, 53.8%, 62.8% and 45.6% of strains in 2000,
      2001, 2002 and 2003, respectively. The following most frequent phage types were 4
      and 13a. New phage types, i.e. 15, 5, 25 and 14b, were identified from
      salmonellosis outbreaks in 2003. The S. Typhimurium strains were also
      differentiated into 16 phage types with phage type DT104 strains being prevalent
      and showing an increase from 7.4% in 2000 to 44.6% in 2003; 54.2% of them were
      resistant and of R type ACSSut. The second most frequent phage type in 2000-2001
      was 2b in 2003 DT41. The frequency of the other phage types was not
      epidemiologically significant.

PMID- 15185634
TI  - [Detection of anti-microsporidial antibodies in patients with secondary
      immunodeficiency].
AB  - Microsporidia are a group of eukaryotic obligate intracellular parasites that
      infect most invertebrates and all classes of vertebrates, including man. In human
      population, microsporidia are emerging as opportunistic pathogens in
      immunocompromised patients. Two groups of human sera (318 serum samples) were
      tested by ELISA for the presence of specific antimicrosporidial (anti
      Encephalitozoon intestinalis) antibodies. Group 1 included 120 patients with
      secondary immunodeficiency, group 2 consisted of 198 immunocompetent controls.
      Anti-Encephalitozoon intestinalis antibodies were detected in 29 (24.16%)
      patients and 20 (10.1%) immunocompetent controls. The difference in prevalence of
      antibodies against Encephalitozoon intestinalis between the groups was
      statistically significant (P < 0.05%).

PMID- 15185635
TI  - [Type III bacterial secretion systems and their relation to virulence].
AB  - Newer data on type III secretion systems (SST systems) associated with virulence
      in gramnegative bacteria are summarized. The focus is on substrates of SST
      systems (effector proteins), recognition of type III secretion signals,
      structural components of SST systems and their genetic determination.

PMID- 15185637
TI  - [Why should neurovascular units be developed in France?].

PMID- 15185638
TI  - [Functional insulin therapy].
AB  - This concept has been developed since 1983 in Germany and Austria. It is of
      greatest interest with regard to a pedagogical approach of insulin therapy in
      type 1 diabetic patients. The goal of functional insulin therapy is to separate
      basal and prandial insulin requirements. The patients perform the following
      experimental sessions in order to establish their own insulin requirements: 24 h
      fasting to assess the basic insulin requirement, ingestion of test meals
      containing different amounts of carbohydrates to determine the individual
      carbohydrate-intake/insulin requirement relationship, determination of an
      individual correction algorithm to decrease an elevated blood glucose level (1.60
      g/L). It involves patient's therapeutic education, frequent self monitoring blood
      glucose (6 to 8 daily controls), multiple daily insulin injections. This concept
      has to be adapted to patient's desire of self responsibility and autonomy.
      Functional insulin therapy improves metabolic control, decreases the frequency of
      mild and severe hypoglycaemia, it enhances self-esteem in diabetic patients.

PMID- 15185639
TI  - [Treatment of hepatitis C. Different modalities based on viral genotype].

PMID- 15185640
TI  - [Emergency psychiatry. Suicidal tendency obsessions].

PMID- 15185641
TI  - [Emergency situations in psychiatry].
AB  - Emergencies in psychiatry depend both on the diagnosis of the pathology (past
      diagnosis or that revealed by the emergency), and on the situations that caused
      the crisis, of which their reactional nature demands specific treatment.  There
      is an emergency when this  is felt by any of the protagonists: the patient, the
      doctor or the entourage.  The response in the environment can be indifferent,
      aggravating or pacifying.  The behavioural outbursts in the agitated and
      aggressive situations necessitate a symptomatic treatment of the agitation,
      investigation of the underlying somatic or psychiatric pathology, and an
      evaluation of the milleu often at the origin of the aggravation or agitation. 
      New types of emergency psychiatric  consultations are currently being observed,
      underlaid by outbursts of anxieties and anguish, and this occuring across the
      board.  Patients with diverse pathological  anxieties arrive in the emergency
      department with an imperative demand to be relieved.  Thus psychiatirc emergency
      go from behavioural to more intra-psychi situations, and necessitate an
      evaluation and an immediate response.

PMID- 15185642
TI  - [Suicide risk evaluation].
AB  - Assessing suicidal potential in the setting of psychiatric emergencies is triple.
      First the risk factors predisposing to the acting out are to be taken into
      account (depression, addictive disorders, psychotic disorders, personality
      disorders, previous history of suicide attempts). Secondly emergency factors
      immediately preceding the suicidal act (presence of active suicidal ideas and
      suicidal scenario) and thirdly dangerousness factors (lethality and accessibility
      of the means) are important to be detected. This assessment has to enable a
      better estimation of the intervention to be set up.

PMID- 15185643
TI  - [Psychiatric emergencies in adolescents].
AB  - Psychiatric emergencies in adolescents, apart from difficulties also found in
      adults, present specific difficulties linked to psychological characteristics of
      this period of life and to importance of familial interactions. "Real"
      emergencies or situations felt to be emergencies, they all need that we take time
      for serious assessment. Drugs and hospitalization are possible responses but must
      be challenged with much care. After some general aspects of these emergencies, we
      detail the most frequent clinical situations.

PMID- 15185644
TI  - [Psychiatric emergencies in the elderly].
AB  - If it is common place to claim that old age is not a disease, however the losses
      and mournings related to that stage of life generate the production of acute
      psychopathological disorders. A few of them will be approached and treated as
      emergencies and required from the physician a good command of their existence and
      of specificities: atypical depressive disorders stressed by the risk of suicide,
      sits of delusions some themes of which are typical of senesence, excitement and
      aggressiveness inherent to dementia. As to the ill-treatment of the elderly often
      under-diagnosed, it requires urgent interventions both clinical and even
      juridical.

PMID- 15185645
TI  - [Psychiatric emergencies in drug addiction].
AB  - The practitioner is very frequently confronted by emergencies in drug-addicted
      patients also having psychiatric symptomatology. In this article the authors will
      address emergencies related to alcohol (notably intoxication, pre-DTs and the
      encephalopathies); emergencies related to cannabis (notably intoxication,
      psychotic states and panic attacks); and emergencies related to other psycho
      active substances (overdoses, drug-withdrawal, psychiatric complications related
      to cocaine or amphetamines). In the domain of drug addiction, as in psychiatry,
      the practitioner must give as much importance to the organisation of the long
      term healthcare plan for the drug addict, ulterior to the management of the
      immediate emergency. For example, whereas 90% of subjects presenting to the
      emergency department for acute alcoholic intoxication have a pathological
      consumption of alcohol (abuse or dependance), management of the alcoholism is
      proposed in only 2% of them.

PMID- 15185646
TI  - [Prescriptions in psychiatric emergencies].
AB  - The two missions of an emergency psychiatric intervention are firstly diagnostic,
      and then if possible, therapeutic. The therapeutic aims are thus dominated by two
      potential cases, one not exclusive of the other: hospitalisation and/or the
      obtainment of anxiolysis, if not sedation. In a psychiatric emergency, everything
      comes together in such a way that can induce serious errors, in terms of
      prescription, for the outcome for the patient: 1) not to appreciate the situation
      of the crisis, and above all, 2) to "over-estimate" the intensity of the
      problems, in confusing the gravity of the clinical picture with the intensity of
      the psychomotor agitation. A sedative and anxiolytic molecule proves to be
      necessary when faced with a patient in whom the agitation doesn't settle, who
      remains threatening and oppositional, or in whom the anxious character of the
      life-like delirium is manifest. Physical containment may be necessary and is then
      considered a prescribed therapeutic act that necessitates the surveillance of the
      subject. Therapeutic prescriptions are led by two cases which are not
      reciprocally exclusive non exclusive.

PMID- 15185648
TI  - [Predictive signs of suicide].

PMID- 15185647
TI  - [Rules for psychiatric emergency hospitalization].
AB  - The author describe how psychiatric emergencies are dealt with in France.
      Emergency rooms can admit these patients 24 hours a day particularly somato
      psychiatric emergencies as well as situations of existential crisis.  Many
      psychiatric hospitals have also designed a 24 hours a day response to emergencies
      but with a great diversity depending on local situations.  Free-will
      hospitalization is the most common response but some situations can require
      commitment to a psychiatric hospital.  The author describes in details the
      enforcement of the law in the case of hospitalization without patients's consent.

PMID- 15185649
TI  - [Medical professionalism: three rules and ten commitments].

PMID- 15185650
TI  - [Followup of the normal newborn, child and adolescent. 3rd Part: Screening for
      hearing disorders].

PMID- 15185651
TI  - [Acute fever in an immunocompromised patient].

PMID- 15185652
TI  - [Quincke's edema and anaphylaxis].

PMID- 15185653
TI  - [Premarital certification].

PMID- 15185654
TI  - [Chronic respiratory insufficiency].

PMID- 15185655
TI  - [Buy Patin. A physician in Moliere's time].

PMID- 15185656
TI  - [Continuous EEG video recording. A better approach to epilepsy].

PMID- 15185657
TI  - [Psychiatric care in emergency victims].
AB  - Immediate psychiatric care are realised either in the frame of acute traumatic
      crisis centres or on specific psychotraumatic consultations. They are indicated
      for victims of disasters, collective accidents, and hostages taken as well as for
      rescuers themselves, so frequently exposed to extreme situations. They are also
      indicated for victims of numerous individual aggressions who are seen in medico
      judiciary emergencies. Their purpose is to reduce clinical manifestations of
      stress (adapted or complicated) by a quick intervention and to prevent the risk
      of installation of a chronic psychotraumatic syndrome, which is the principal
      psychiatric complication linked to these situations. These immediate psychiatric
      care allow the organisation of rapid psychotherapeutic interventions, i.e.
      psychological debriefing.

PMID- 15185658
TI  - [Better prescribing of antibiotics. Preventing the risk of ineffective treatment
      in current infection].

PMID- 15185659
TI  - [Antibiotic use: excesses and consequences].
AB  - Antibiotic use in France is excessive. This statement is regularly expressed. The
      comparison with usage in other European countries, the frequency of use in viral
      infections, the misuse, specifically in the duration of treatment is easy proof
      of this. However, does this excessive use really have negative consequences in
      terms of public health? Yes, through the development of antibiotic resistance in
      hospital bacteria and also in the community. The phenomenon of selection has been
      amplified as much in the hospital as in the community due to the increase in
      antibiotic use. It has been a problem that has been neglected for a long time due
      to the regular release of new antibiotics with better performance onto the
      market. More than ever, as with any side effect, it has to be taken into account
      with each prescription of an antibiotic. It encourages the development of a
      reservoir of resistant bacteria and creates a collective medical risk of the
      appearance of infections for which the choice of treatment is at best restricted
      and costly, and at worst inexistent.

PMID- 15185660
TI  - [The keys to antibiotic therapy decision making in daily practice].
AB  - Current daily good antimicrobial practice is a key point for controlling the
      spread of bacterial antibiotic resistance. In addition one should give every
      patient an optimal therapy. A pragmatic classification of antibiotics would be
      useful if made according to diagnosis, mainly community-acquired infections, when
      known to benefit from antibiotic therapy, and according to responsible bacterial
      species. On the basis of these bacterial species and updated knowledge of
      antibacterial activity of current antibiotics, a selection of several antibiotic
      drugs can be made for prescribers, according to their known clinical efficacy and
      their limitations, if any, and according to well-established therapeutic
      guidelines. A simple armentarium can be proposed, with the most useful and well
      adapted drugs for current clinical practice of infectious diseases.

PMID- 15185661
TI  - [What must one know about microbiology for prescribing antibiotics?].
AB  - Antibiotics are usually prescribed for serious bacterial infections. The
      knowledge of ecological niche of each bacterium, mechanisms of action and
      resistance to antibiotics and the correct interpretation of a direct exam of
      microbiological samples are essential to improve the use of antibiotics. Finally,
      the update of the epidemiology of resistance is necessary to interpret the
      susceptibility tests and for the optimal use of empirical antibiotherapy.

PMID- 15185662
TI  - [Antibiotic therapy: from pharmacology to decision making].
AB  - The decision of an antibiotic treatment depends first on clinical and
      bacteriological data. Then PK/PD (pharmacodynamics/pharmacokinetics) of
      antibiotics must be taken into account in order to optimise the dosing regimen,
      and to reach the targeted serum concentrations. The good oral bioavailability of
      some drugs allows the use of the oral route, at the beginning of the treatment,
      or shortly after an initial successful i.v. administration, even in severe
      infections.

PMID- 15185665
TI  - [Emergency antibiotic therapy in the adult].
AB  - Few studies have shown a direct relationship between the timing of antibiotic
      therapy and the outcome. In severe infections, the outcome is mainly dependent of
      virulence of the pathogen, and host susceptibility. Indeed, in some individuals,
      an enhanced inflammatory response may lead to multiple organ failure despite
      early and appropriate use of antibiotics. In critically-ill patients, antibiotic
      treatment should be associated with optimisation of oxygen delivery and with
      source control. Before deciding to administer antibiotics, the physician should
      try to classify the patient according to the degree of urgency to start the
      treatment. True emergencies are limited to fulminant meningococcemia and to
      infection in splenectomized patients. In other cases, careful analysis of
      patient's history and clinical examination are important steps to decide if
      antibiotic treatment should be given rapidly or may be delayed. The initial
      antibiotic regimen should be re-evaluated on day 3.

PMID- 15185663
TI  - [How to prescribe fewer antibiotics in children?].
AB  - During the last years, there has been an alarming worldwide increase in
      antibiotic resistance among bacterial pathogens of the respiratory tract, and
      particularly pneumococcus. This is generally attributed to extensive use of
      antibiotics prescribed for respiratory tract infection and the selection pressure
      they exert on bacterial strains of nasopharyngeal flora. In our opinion, five
      actions have to be coordinated in order to control this phenomenon. To improve
      the continuing education of practitioners and the diagnosis between viral and
      bacterial respiratory infections, to restrict the use for the situations where
      antibiotics are really necessary, to prescribe in these situations at the right
      dosage and duration the more potent antibiotics, to plan straight-a-way an
      alternative treatment in case of failures, finally achieve a prompt
      implementation of the pneumococcal conjugate vaccine.

PMID- 15185664
TI  - [Antibiotic therapy in the elderly].
AB  - The management of antibiotherapy in elderly patients is a unique and challenging
      problem. Old patients often suffer more serious complications of infection, more
      serious adverse events and drug interaction with drug therapy. The choice of
      antibiotherapy must also take into account the evolution of bacterial ecology.
      About one third of persons older than 80 and a higher proportion of elderly
      disabled patients reside in long term care facilities. And now, bacterial flora
      in institutions remains intermediate between that of community acquired
      infections and the more antibiotic resistant hospital flora.

PMID- 15185666
TI  - [New role for patients?].

PMID- 15185667
TI  - [Nutritional needs and food supplements in the adult. Evaluation of nutritional
      status--Malnutrition].

PMID- 15185668
TI  - [Atheroma. Epidemiology and physiopathology of multiple atheromatosis].

PMID- 15185670
TI  - [Acute respiratory distress in the newborn, child and the adult. Foreign bodies
      of the upper respiratory tract. 1st part: in the adult].

PMID- 15185669
TI  - [Vaccinations. Immunologic basis, indications, efficacy, complications].

PMID- 15185672
TI  - Abstracts of papers presented at the 49th Annual Meeting of the Health Physics
      Society. Washington, DC, USA, 11-15 July 2004.

PMID- 15185671
TI  - [1803: administrative organization of the medical profession. A forgotten
      celebration].

PMID- 15185674
TI  - Abstracts of the Hong Kong-Shanghai International Liver Congress 2004. Liver
      Diseases in Functional-Genomic Era. 14-17 February 2004, Hong Kong.

PMID- 15185673
TI  - PEACH 4 with ABINIT-MP: a general platform for classical and quantum simulations
      of biological molecules.
AB  - A program package for molecular simulations of biological molecules was
      developed. The package, "PEACH version 4 with ABINIT-MP version 20021029," was
      constructed by incorporating ABINIT-MP, a program for the fragment molecular
      orbital (FMO) method [Chem.Phys. Lett. 313 (1999) 701], into PEACH, a program
      package for classical molecular dynamics simulations (MD). A few capabilities of
      the package were demonstrated. First, high parallel efficiency of FMO was
      demonstrated in a single point calculation of a protein. Second,FMO-MD
      simulations [Chem. Phys. Lett. 372 (2003) 342] of a peptide were performed with
      and without explicit solvent, and the simulations showed the influence of the
      solvent on the electronic state of the peptide.

PMID- 15185675
TI  - Public health achievements. I: Diversity.

PMID- 15185676
TI  - Abstracts of the 57th Annual Meeting of the Japan Society for Cell Biology.
      Osaka, Japan, May 26-28, 2004.

PMID- 15185678
TI  - Abstracts of the 51st Annual Meeting of the Japanese Association for Laboratory
      Animal Science. May 20-22, 2004, Nagasaki, Japan.

PMID- 15185677
TI  - Neurobiological evidence for abstract phonological representations in the mental
      lexicon during speech recognition.
AB  - A central issue in speech recognition is how contrastive phonemic information is
      stored in the mental lexicon. The conventional view assumes that this information
      is closely related to acoustic properties of speech. Considering that no world is
      ever pronounced alike twice and that the brain has limited capacities to manage
      information, an opposing view proposes abstract underspecified representations
      where not all phonemic features are stored. We examined this propos.al using
      event-related brain potentials, in particular mismatch negativity (MMN), an
      automatic change detection response in the brain that is sensitive to language
      specific phoneme representations. In the current study, vowel pairs were
      presented to subjects, reversed as standard and deviant. Models not assuming
      underspecification predict equal MMNsfor vowel pairs regardless of the reversal.
      In contrast, enhanced and earlier MMNs were observed for those conditions where
      the standard is not phonologically underspecified in the mental representation.
      This provides the first neuro-biological evidence for a featurally underspecified
      mental lexicon.

PMID- 15185679
TI  - [XX National Congress of the Spanish Society of Parenteral and Enteral Nutrition.
      Salamanca, Spain, 5-7 May 2004].

PMID- 15185681
TI  - Abstracts of the 88th Meeting of the German Society of Pathology. 2-5 June 2004,
      Rostock, Germany.

PMID- 15185680
TI  - Abstracts of the 21st Annual Meeting of the German Parasitology Association. 17
      20 March 2004, Wurzburg, Germany.

PMID- 15185682
TI  - Abstracts of the 74th Congress of the European Atherosclerosis Society. 17-20
      April 2004, Seville, Spain.

PMID- 15185683
TI  - Abstracts of the American Society for Cell Biology 43rd Annual Meeting. December
      13-17 2003, San Francisco, California, USA.

PMID- 15185684
TI  - Abstracts of the 27th Annual Meeting of the Research Society on Alcoholism. June
      26-30, 2004. Vancouver, Canada.

PMID- 15185685
TI  - Abstracts of the European Society of Gastrointestinal and Abdominal Radiology
      15th Annual Meeting and Postgraduate Course. June 15-18, 2004, Geneva,
      Switzerland.

PMID- 15185686
TI  - Abstracts of the 17th International Conference on Antiviral Research. Tucson,
      Arizona, USA. May 2-6, 2004.

PMID- 15185687
TI  - Torture continues for death-sentence medics in Libya.

PMID- 15185688
TI  - Mandatory condom use urged for adult film industry.

PMID- 15185689
TI  - Can PPPs wash their hands of ethical dilemmas?

PMID- 15185690
TI  - Bush's AIDS funding branded scarce.

PMID- 15185691
TI  - Thar desert: sitting on the tip of a malarial iceberg.

PMID- 15185692
TI  - ASPH/American Legacy Foundation STEP UP Program: An innovative partnership for
      tobacco studies in the schools of public health.

PMID- 15185693
TI  - A message from a mentor.

PMID- 15185694
TI  - From the electrodiagnostics lab... When quantitative sudomotor axon reflex
      testing helps differentiate central versus peripheral nervous system as the
      source of sensory symptoms in an extremity.

PMID- 15185695
TI  - From the infectious disease service... When a septic patient develops increasing
      general weakness.

PMID- 15185696
TI  - Italian doctors face charges over GSK incentive scheme. Over 4000 doctors are
      alleged to have received cash, gifts, and prizes to encourage them to prescribe
      GSK products.

PMID- 15185697
TI  - Cuban doctors provide care in Venezuela's barrios. But critics say the scheme
      allows poorly trained immigrants to practise medicine illegally.

PMID- 15185698
TI  - Nigerian state promises to end polio vaccine boycott.

PMID- 15185699
TI  - Health care dominates run-up to Canadian election.

PMID- 15185700
TI  - Oregon court upholds assisted-suicide law.

PMID- 15185701
TI  - South African pharmacists to fight drug laws in court.

PMID- 15185702
TI  - Court case sparks outcry over secret HIV test.

PMID- 15185703
TI  - Holding hands.

PMID- 15185704
TI  - Preventing HIV in newborns.

PMID- 15185705
TI  - Flood-hit Haiti struggles to manage health disaster. International aid agencies
      are helping clean up, but health workers warn of long-term disease risks.

PMID- 15185706
TI  - Night-float memories.

PMID- 15185707
TI  - Doctors' involvement in human rights abuses of men who have sex with men in
      Egypt.

PMID- 15185708
TI  - Asylum seekers: an ethical response to their plight.

PMID- 15185709
TI  - Legal abortion in Nepal and women in prison.

PMID- 15185711
TI  - [Proceedings of the XIIth Annual Paris Obstetrics-Pediatrics Round Tables. 5-6
      February 2004, Paris, France].

PMID- 15185710
TI  - Abstracts of the 58th Annual Meeting of the American Academy of Oral Medicine.

PMID- 15185712
TI  - International Conference on Harmonisation; evaluation of stability data;
      availability. Notice.
AB  - The Food and Drug Administration (FDA) is announcing the availability of a
      guidance entitled "Q1E Evaluation of Stability Data." The guidance was prepared
      under the auspices of the International Conference on Harmonisation of Technical
      Requirements for Registration of Pharmaceuticals for Human Use (ICH). This
      guidance is a supplement to an ICH guidance entitled "Q1A(R2) Stability Testing
      of New Drug Substances and Products," which was revised from Q1A(R) and published
      in the Federal Register of November 21, 2003 (68 FR 65717). It is intended to
      provide guidance on how to use stability data, generated in accordance with the
      principles outlined in Q1A(R2), to propose a retest period for the drug substance
      and a shelf life for the drug product.

PMID- 15185713
TI  - A case for reinvigorating your capabilities: the increasing importance of
      certification.

PMID- 15185715
TI  - Proceedings of the 1st SIVIM Forum. Viral hepatitis: from the laboratory to the
      clinic. January 31, 2003, Milan, Italy.

PMID- 15185714
TI  - Molecular Basis of Neurological Disease and New Therapeutic Strategies. Warszawa,
      Poland, 28029 November 2003. Proceedings and abstracts.

PMID- 15185716
TI  - Mapping the SF-12 to the EuroQol EQ-5D Index in a national US sample.
AB  - BACKGROUND: Preference scores for the Medical Outcomes Study (MOS) SF-12 would
      enable its use in cost-effectiveness analyses. Previous mapping studies of MOS
      instruments top reference-based instruments have not examined performance in
      national samples. PARTICIPANTS: 15,000 adults in the 2000 Medical Expenditure
      Panel Survey annual survey including the SF-12 and EQ-5D Index. METHODS:
      Regression of the EQ-5D Index scores onto the physical and mental component
      summary scores of the SF-12, testing 2nd-4th degree polynomial and spline models,
      including and excluding sociodemographics. RESULTS: A 2nd degree polynomial model
      explained 63% of the variance in EQ-5D scores, with robust internal and external
      validation. More complex mod-els explained minimally additional variance.
      Compared with EQ-5D valuations, prediction models overestimated the lowest health
      states (6% of the population). CONCLUSIONS: The mapped SF-12 yields usable
      preference-scaled scores, with some caution for the lowest health states.

PMID- 15185717
TI  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and long term immunologic memory.
AB  - The highlighted article by B. Paige Lawrence and Beth Vorderstrasse addresses an
      oft forgotten aspect of immunotoxicity, the effects of environmental toxins on
      immunologic memory. Here, the authors take a step towards filling that
      information gap by evaluating the effects of a prototypic environmental toxin,
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on memory responses to a real-world
      pathogen, influenza A virus, presented to an animal model in a physiologically
      relevant manner. Multiple outcomes are evaluated, the vast majority of which
      suggest important and long-term TCDD-induced changes in the immune system after
      both primary and secondary exposure to this pathogen. The implications of these
      studies with regard to the immuno-competence of TCDD-exposed individuals are far
      reaching.

PMID- 15185718
TI  - HCV and HIV: a tale of two viruses.
AB  - Liver disease has emerged as a major cause of morbidity and mortality in patients
      infected with the human immunodeficiency virus. Hepatic injury is highly
      associated with hepatitis C virus (HCV) infection, though hepatitis B virus and
      drug-induced hepatotoxicity are also important cofactors. HCV coinfection is
      linked to increased hepatic fibrosis progression, leading to development of
      cirrhosis and liver failure earlier than in HCV monoinfected patients. Initiation
      of highly active antiretroviral treatment regimens may paradoxically increase HCV
      loads. Some data suggest that HCV coinfection may hasten progression of AIDS, but
      this remains controversial. Three major randomized clinical trials demonstrate
      improved efficacy of peginterferon with ribavirin for treatment of HCV in
      coinfected subjects compared to those with HCV alone. However, response rates are
      lower than those observed in patients with HCV monoinfection. Sustained virologic
      response rates of 27% to 40% are reported.

PMID- 15185719
TI  - The short- and long-term safety of 5-aminosalicylate products in the treatment of
      ulcerative colitis.
AB  - 5-aminosalicylic acid agents are effective in the treatment of ulcerative
      colitis. Balsalazide, mesalamine, and olsalazine are alternative formulations to
      sulfasalazine for the delivery of 5-aminosalicylic acid. The newer compounds
      might be better tolerated than sulfasalazine in some patients, as long as the
      intolerance is not due to hypersensitivity to 5-aminosalicylic acid. Adverse
      events requiring the withdrawal of therapy seem to occur less frequently with
      balsalazide, mesalamine, and olsalazine compared with sulfasalazine. If patients
      are unable to tolerate any one of these three 5-aminosalicylic acid-releasing
      preparations, they might be able to tolerate one of the others, as long as the
      intolerance is not due to hypersensitivity to 5-aminosalicylic acid.

PMID- 15185720
TI  - Immunoregulation in periodontal disease.

PMID- 15185721
TI  - Measuring outcomes of dual sphincterotomy.

PMID- 15185722
TI  - The potential dangers of test-and-treat strategies directed at H. pylori.

PMID- 15185723
TI  - No mercy from MRSA.

PMID- 15185724
TI  - Gene silencing of HIV-1 by RNA interference.
AB  - Short interfering RNAs (siRNAs) are as effective at targeting and silencing genes
      by RNA interference (RNAi) as long double-stranded RNAs (dsRNAs). siRNAs are
      widely used for assessing gene function in cultured mammalian cells or early
      developing vertebrate embryos. siRNAs are also promising reagents for developing
      gene-specific therapeutics. Specifically, the inhibition of HIV-1 replication is
      particularly well-suited to RNAi, as several stages of the viral life cycle and
      many viral and cellular genes can be targeted. The future success of this
      approach will depend on recent advances in siRNA-based silencing technologies.

PMID- 15185725
TI  - Design and synthesis of novel dihydroxyindole-2-carboxylic acids as HIV-1
      integrase inhibitors.
AB  - In a search for new HIV-1 integrase (IN) inhibitors, we synthesized and evaluated
      the biological activity of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and a
      series of its derivatives. These compounds were designed as conformationally
      constrained analogues of the acrylate moiety of caffeic acid phenethyl ester
      (CAPE). DHICA, an intermediate in the biosynthesis of melanins, was prepared as a
      monomeric unit by a novel synthetic route. In order to perform coherent SAR
      studies, two series of DHICA amides were synthesized. First, to validate the
      utility of a previously identified three-point pharmacophore based on CAPE in
      inhibitor design, we prepared a series of benzyl- or phenylethylamine substituted
      derivatives lacking and containing hydroxyl groups. Second, dimers of DHICA
      containing various aminoalkylamine linkers were also prepared with a goal to
      increase potency. All compounds were tested against purified IN and the C65S
      mutant in enzyme-based assays. They were also tested for cytotoxicity in an
      ovarian carcinoma cell line and antiviral activity in HIV-1-infected CEM cells.
      Seven compounds inhibited catalytic activities of purified IN with IC50 values
      below 10 microM. Further computational docking studies were performed to
      determine the title compounds' mode of interaction with the IN active site. The
      residues K156, K159 and D64 were the most important for potency against purified
      IN.

PMID- 15185726
TI  - New synthetic glutathione derivatives with increased antiviral activities.
AB  - A series of glutathione (GSH) derivatives with aliphatic chains of different
      lengths, coupled by peptides bound to the alpha-NH2 group of Glu, were
      synthesized. When added to several cell lines, the C6 (n-hexanoyl), C8 (n
      octanoyl) and C12 (n-dodecanoyl) derivatives were toxic while the C2 (nethanoyl)
      and C4 (n-butanoyl) derivatives were not. Preliminary experiments were performed
      to investigate the potential antiviral activity of the C2 and C4 derivatives
      compared to GSH. The C4 derivative was the most potent and fully characterized.
      GSH-C4 is a poor substrate of GSH metabolizing enzymes; once oxidized by
      disulphide-bound formation, C4 is slowly reduced by GSH-reductase. GSH-C4
      completely abrogated Sendai virus replication at 7.5 mM with an EC50 of 3.6 mM,
      compared to 7.5 mM for GSH. GSH-C4 completely inhibited herpes simplex virus (HSV
      1) virus production in Vero cells at 10 mM, while the same dose of GSH caused
      only a 2.5 log10 reduction. Furthermore, the GSH-C4 treatment (7.5 mM) was able
      to markedly reduce the cytopathic effect of HSV-1 in Vero cells. Thus, GSH
      derivatives with increased hydrophobic properties are more effective antiviral
      agents against Sendai and HSV-1 viruses than GSH, suggesting their usefulness in
      antiviral therapy.

PMID- 15185727
TI  - In vitro and in vivo transport and delivery of phosphorothioate oligonucleotides
      with cationic liposomes.
AB  - A recent strategy in gene therapy has been using antiviral genes that are
      delivered to uninfected cells, either as RNA or DNA, to provide intracellular
      protection from human immunodeficiency virus type-1 (HIV-1) infection. Antisense
      oligonucleotides that are complementary to specific target genes suppress gene
      expression. A variety of techniques are available to enhance the cellular uptake
      and pharmacological effectiveness of antisense oligonucleotides, both in vitro
      and in vivo. We investigated the intracellular and tissue uptake of an
      oligonucleotide/cationic lipid complex, using a fluorescently labeled
      oligonucleotide. The antisense oligonucleotide was designed against the HIV-1 gag
      gene sequence. A T-cell line (MT-4) and PHA-stimulated peripheral blood
      mononuclear cells (PBMCs) were both infected with HIV-1(NL432) at an MOI of 0.01.
      One h later, both cultures were washed and treated with medium containing 1
      microM antisense oligonucleotide. After a 3-day interval, the HIV-1 antigen
      expression was monitored by an indirect immunofluorescence assay. At 3 days post
      infection, we confirmed that p24 antigen production was inhibited by the
      antisense oligonucleotide/cationic lipid complex at a 1/10 ratio in the PBMCs,
      using enzyme-linked immunosorbent assay (ELISA). We also confirmed the
      intracellular existence of the complex by fluorescent microscopy. We investigated
      different means of transporting the antisense oligonucleotide/cationic lipid
      complex to mouse tissues by intravenous, intraperitoneal and subcutaneous
      injections. We observed that the anti-HIV-1 activity of the antisense
      oligonucleotide/cationic lipid complex was the result of enhanced cellular
      uptake, both in vitro and in vivo. Therefore, the antisense
      oligonucleotide/cationic lipid complex is an excellent system for the transport
      and delivery of genes to target cells, as it is effective both in vitro and in
      vivo.

PMID- 15185728
TI  - Effect of interferon-alpha and interferon-inducers on West Nile virus in mouse
      and hamster animal models.
AB  - The recent West Nile virus (WNV) outbreak in the United States has increased the
      need to identify effective therapies. Studies were conducted in cell culture and
      in rodent animal models to determine the efficacy of interferon-alpha (IFN
      alpha), interferon (IFN) inducers and ribavirin, alone or in combination with
      IFN, in treating WNV. Intraperitoneal injection of IFN-alpha B/D (qd for 7 days),
      polyI-polyC(12)U [Ampligen (every other day for 7 days)] and topically applied
      imiquimod (qd for 7 days), administered from 1 day before viral challenge, were
      effective in protecting, respectively, 100%, 100% and 70% of BALB/c mice from
      mortality induced by subcutaneous injection of WNV. When IFN-alpha B/D or
      Ampligen treatments were delayed to 4-6 h before viral challenge in mice,
      efficacy was greatly diminished. Infected Syrian golden hamsters treated with
      interferon alphacon-1 (Infergen) and Ampligen 4-6 h before viral challenge gained
      more weight and had a greater survival than saline-treated animals. A combination
      study of subcutaneously administered Infergen (5 to 0.05 microg/kg/day) and
      ribavirin (75 to 7.5 mg/kg/day) in >7 week old hamsters demonstrated that
      Infergen was slightly efficacious in reducing mortality and disease signs;
      however, it was not synergistic in its antiviral effects when combined with
      ribavirin. Ribavirin treatment alone increased mortality of infected hamsters.
      The reduced mortality correlated with reduced plasma viraemia. Since WNV-infected
      patients have already been treated with IFN and ribavirin and future clinical
      trials have been suggested, this first report of IFN alone or in combination with
      ribavirin in WNV-infected animal models might provide useful information for
      subsequent treatment of patients.

PMID- 15185729
TI  - Alternative advice to "clean your plate".

PMID- 15185730
TI  - The importance of postural control for feeding.
AB  - Children with cerebral palsy and other neurodisabilities often have decreased
      postural control that exacerbates their feeding/swallowing disorders. Correct
      postural alignment is important in the normal feeding/swallowing process. In the
      child with cerebral palsy, the alignment and stability of the oral structures for
      feeding/swallowing may be compromised by abnormal muscle tone and movement
      patterns. Effective oral functioning for feeding begins with attaining better
      head stability to improve jaw control. Head control is influenced by trunk
      alignment, which depends upon the stability of the pelvic area. Techniques such
      as therapeutic seating and oral control can enhance postural alignment and
      improve oral functioning for the safe intake of food.

PMID- 15185731
TI  - Picky eating: a toddler's continuing approach to mealtime.
AB  - Research indicates that three primary components play a role in the picky eating
      phenomenon: development, personal preferences, and the family. Picky eating is an
      aspect of child development. Children will develop their own preferences when
      given the appropriate tools to do so. Parents are their children's greatest role
      models. An understanding of these concepts can help guide the primary care
      provider in making appropriate recommendations to parents to improve their
      toddlers' eating behaviors.

PMID- 15185733
TI  - A follow-up case study on teenage pregnancy: "havin' a baby isn't a nightmare,
      but it's really hard".
AB  - Two adolescent mothers who participated in a previously published study on
      teenage pregnancy agreed to participate in follow-up interviews in their homes
      about 1 1/2 years after giving birth. A naturalistic, qualitative case study
      approach was used to examine the participants' views and perceptions related to
      adolescent pregnancy and childbearing. Both mothers reported general satisfaction
      with their lives as young mothers, but indicated that their attitudes about early
      maternity changed once they experienced the day-to-day realities of motherhood.
      Overall, the participants adequately managed single motherhood with support from
      family. Regrets and hopes for a better future, mended and broken relationships,
      and thinking about and avoiding or engaging in fighting behavior were themes that
      emerged from the data. In addition, some of the findings of this case study were
      compared and contrasted with the initial study (Spear, 2001), and implications
      for practice and research are discussed.

PMID- 15185732
TI  - Duration of breast milk expression among working mothers enrolled in an employer
      sponsored lactation program.
AB  - BACKGROUND: Maternal employment has been one of the greatest barriers to
      breastfeeding. Women are increasingly solving this problem by expressing milk at
      work and taking it home to their infants. PURPOSE: The objective was to determine
      duration of breast milk expression among working mothers enrolled in an employer
      sponsored lactation program. DESIGN AND METHODS: Retrospective reviews were
      conducted on the lactation records of 462 women employed by 5 corporations in
      order to describe and characterize their experiences. The lactation program
      included the employees' choice of (a) a class on the benefits of breastfeeding;
      (b) services of a certified lactation consultant (CLC); and (c) private room in
      the workplace with equipment for pumping. RESULTS: Breastfeeding was initiated by
      97.5% of the participants, with 57.8% continuing for at least 6 months. Of the
      435 (94.2%) who returned to work after giving birth, 343 (78.9%) attempted
      pumping milk at work, and 336 (98%) were successful. They expressed milk in the
      workplace for a mean of 6.3 months (SD = 3.9, range 2 weeks to 21 months). The
      mean age of infants when the mothers stopped pumping at work was 9.1 months (SD =
      4.1, range 1.9 to 25 months). Most of the women who pumped their milk at work
      were working full time (84.2%). The mean postnatal maternity leave was 2.8
      months. The proportion of women who chose to pump at work was higher among women
      who were salaried than among those who were paid hourly wages (p < 0.01).
      CONCLUSIONS: Company-sponsored lactation programs can enable employed mothers to
      provide breast milk for their infants as long as they wish, thus helping the
      nation attain the Healthy People 2010 goals of 50% of mothers breastfeeding until
      their infants are 6-months-old.

PMID- 15185734
TI  - Parental presence during resuscitation: help or hindrance?

PMID- 15185736
TI  - Responding to depression in parents.
AB  - Pediatric professionals may naturally view themselves as gatekeepers or
      facilitators of access to mental health services for children, but may not see
      themselves as the first line of "defense" for parents with mental health issues.
      However, about two thirds of women who meet criteria for affective disorders, and
      slightly more than half of the men who do, are parents. Given that the average
      age of onset for affective disorders is several years after the birth of first
      children, parental depression may initially come to the attention of pediatric
      providers, the most likely professionals with whom parents have contact prior to
      children starting school. The health and well-being of parents and children are
      intimately intertwined. Simple screening, education, and support strategies for
      parents and referral to specialty services, when appropriate, have the potential
      for positive impact on all family members.

PMID- 15185735
TI  - Leaves of three, let them be: if it were only that easy!

PMID- 15185737
TI  - The effectiveness of parent-focused interventions in improving coping/mental
      health outcomes of critically ill children and their parents: an evidence base to
      guide clinical practice.

PMID- 15185738
TI  - Mercury, 101.
AB  - October 3, 2003, The Washington Post--Students steal a 250-milliliter container
      of mercury from a science lab and spread it around the school and grounds. As of
      October 28, 2003, the school has been shut down and decontaminated, five people
      showed some type of mercury exposure, more than 100 homes were tested and found
      contaminated, families were told to leave with the clothes on their backs, city
      buses were cleaned due to mercury contamination, 1,300 students were displaced
      and in temporary classrooms, and the cleanup and investigation costs are in the
      millions and still climbing. As the community nurse, would you know the health
      risks and could you assist students, parents, and educators?

PMID- 15185739
TI  - Perfectly poised: a unique nursing position. Interview by Elizabeth Ahmann.

PMID- 15185740
TI  - Immunization schedule 2004.

PMID- 15185741
TI  - Pediatric management problems. Positive pregnancy test.

PMID- 15185742
TI  - Community-based strategies for pediatric nurses to combat the escalating
      childhood obesity epidemic.

PMID- 15185743
TI  - Using structural genomics to understand Mycobacterium tuberculosis.

PMID- 15185744
TI  - The role of protein misfolding in the pathogenesis of human diseases.
AB  - The ability of proteins to fold into complex three-dimensional shapes is truly
      amazing. Given the difficulty of the reaction it is perhaps unsurprising that
      many proteins in vivo are unable to fold correctly. These misfolded proteins are
      generally recognized by the cell's quality control machinery and dealt with
      through degradation. However in an increasing number of diseases, such as
      Huntington's, Alzheimer's and alpha1-antitrypsin deficiency, misfolded protein
      accumulates both within and outside the cell. This aggregated protein is able to
      evade the normal cellular responses and in some cases even disable it. In this
      review we present an overview of protein misfolding and examine recent data which
      is beginning to reveal the mechanisms by which protein aggregates are toxic to
      cells.

PMID- 15185745
TI  - Symmetry preservation in the evolution of the genetic code.
AB  - The standard genetic code is found to exhibit an exact symmetry under a finite
      group of order 4 known in mathematics as the Klein group. The same symmetry is
      also present in almost all non-standard codes, mitochondrial as well as nuclear.
      Analysis of the phylogenetic tree for the evolution of the mitochondrial codes
      reveals that all changes along the main line of evolution preserve this symmetry,
      with a tendency towards symmetry enhancement. In the side branches of the
      evolutionary tree, the majority of changes also respect the symmetry. The few
      exceptional cases where it is broken correspond to reassignments that appear to
      be unstable or incomplete. Since the Klein group emerges naturally from the
      symplectic model for the prebiotic evolution that has led to the standard code,
      we interpret these results as lending support to the hypothesis that this
      symmetry has been selected during the evolution of the genetic code, not only
      before but also after establishment of the standard code.

PMID- 15185746
TI  - Differential expression of mycothiol pathway genes: are they affected by
      antituberculosis drugs?
AB  - Mycothiol (MSH) is the major cellular thiol in Mycobacterium tuberculosis (M.tb).
      We hypothesize that the mycothiol-dependent detoxification pathway may serve an
      important role during oxygen stress management in M. tuberculosis, derived from
      normal aerobic metabolism, the macrophage environment and through the action of
      anti-tubercular antibiotics, such as Isoniazid (INH). Total mRNA and DNA were
      isolated from M. bovis BCG at different stages of growth in 7H9 mycobacterial
      medium. Three genes involved in mycothiol metabolism and encoding the enzymes
      mycothiol S-conjugate amidase (Mca, Rv1082), NADPH dependent mycothiol reductase
      (mtr, Rv2855), and N-Acetyl-1-D-myo-Inosityl-2-Amino-2-Deoxy-alpha-D
      Glucopyranoside Deacetylase (GlcNAc-Ins deacetylase, Rv1170 or mshB) were
      investigated for genomic rearrangements and expression. The results show that the
      genomic domains of the genes remain conserved in evolutionary diverse and
      unrelated M. tuberculosis isolates. The genes encoding enzymes implicated in
      mycothiol reduction, mtr (Rv2855) and the mycothiol-dependant detoxification of
      electrophilic agents, Mca (Rv1082), are shown to be actively transcribed during
      logarithmic M. bovis BCG growth. The gene encoding GlcNAc-Ins deacetylase (the
      rate limiting mycothiol biosynthesis step) shows induction in the presence of
      INH. Antisense oligonucleotides to both GlcNAc-Ins deacetylase (Rv1170) and mtr
      (Rv2855) mRNA affect mycobacterial growth. In conclusion the results presented
      here suggest that these enzymes are sensitive to free radical generating
      antituberculosis drugs and may be useful targets for new drug development.

PMID- 15185747
TI  - Detection of glycosylase, endonuclease and methyltransferase enzyme activities
      using immobilized oligonucleotides.
AB  - A novel rapid assay for detection of DNA glycosylase, restriction endonuclease,
      and DNA methyltransferase enzyme activities is presented. The assay is based on
      enzyme-dependent label release (in case of glycosylase and endonuclease), or non
      release (in case of methyltransferase) into solution from end-labeled DNA
      immobilized on solid support (CPG or Tenta Gel S-NH2). The assay has been
      validated for monitoring activity of repair enzyme uracil-DNA glycosylase,
      restriction endonucleases SsoII, MvaI and EcoRII and (cytosine-5)-DNA
      methyltransferase SsoII. Two types of labels have been tested and found
      compatible with the assay: radioactive (32P) and fluorescent (rhodamine B and
      fluorescein). The enzyme activity is estimated as a ratio of the label released
      into solution to the total amount of the label. Use of fluorescent labeling
      facilitates detection while use of solid phase-immobilized substrates facilitates
      product separation, improved assay sensitivity, and increases throughput of
      assay. Proposed technique provides an estimate of enzyme activity but not its
      specific activity. Thus, the assay will most valuable in the applications where
      rapid estimation of enzyme activity is necessary.

PMID- 15185748
TI  - Nutritional flavonoids modulate estrogen receptor alpha signaling.
AB  - Estrogen receptor alpha (ERalpha) mediates 17beta-estradiol (E2) actions through
      the transcription of E2-sensitive target genes. In addition, rapid non-genomic
      signaling (e.g., MAPK/ERK) occurs. It is now well accepted that these rapid
      membrane-initiated responses account for E2-related cancer. Beside many
      beneficial effects on human health, nutritional flavonoids exert protective and
      anticarcinogenic effects on E2-related cancer. The mechanism underlying these
      effects seems to be related to flavonoids antioxidant properties and/or to their
      ability to alter signal transduction protein kinases. In addition, an
      antiestrogenic activity has been proposed but not yet defined. However, the
      identification and characterization of the responsible mechanisms for flavonoid
      antitumoral effects is poorly understood. Here, we investigated the possibility
      that the antimitogenic effects of flavonoids are transduced by modulating ERalpha
      mediated rapid signaling. The ability of two flavonoids, the flavanone naringenin
      and the flavanol quercetin, with respect of E2, to induce ERalpha activities has
      been studied in the human cervix epitheloid carcinoma cell line (HeLa) devoid of
      any estrogen receptors and rendered E2-sensitive by transient transfection with a
      human ERalpha expression vector. Our results indicate that flavonoids act as E2
      mimetic on ERalpha transcriptional activity, whereas they impair the activation
      of rapid signaling pathways committed to E2-induced proliferation. The resulting
      decoupling of ERalpha signal transduction could be proposed as a new mechanism in
      the protective effects of flavonoids against E2-related cancer.

PMID- 15185749
TI  - Src kinase-dependent epidermal growth factor receptor transactivation in
      PPARgamma ligand-induced suppression of Porphyromonas gingivalis interference
      with salivary mucin synthesis.
AB  - Peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged recently
      as an important participant in the resolution of inflammation by conveying
      signals that lead to mitogen-activated protein kinase (MAPK) cascade activation.
      In this study, we report that PPARgamma activation leading to the impedance of P.
      gingivalis lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis
      requires epidermal growth factor receptor (EGFR) participation. We show that
      activation of PPARgamma with a specific agonist, ciglitazone, prevents the LPS
      induced reduction in mucin synthesis, and the effect is reflected in a marked
      decrease in apoptosis, caspase-3 activity and NO generation. The impedance by
      ciglitazone of the LPS-induced reduction in mucin synthesis was countered (up to
      68.9%) in a dose-dependent fashion by a specific inhibitor of EGFR kinase,
      PD153035, as well as wortmannin, an inhibitor of phosphatidylinositol 3-kinase
      (PI3K). Moreover, the inhibitory effect of ciglitazone on the LPS-induced
      reduction in mucin synthesis and upregulation in apoptosis, caspase-3 activity,
      and NO generation was blunted by a selective inhibitor of tyrosine kinase Src,
      PP2, responsible for ligand-independent EGFR transactivation. These findings
      indicate that PPARgamma activation leading to the suppression of P. gingivalis
      LPS inhibition of salivary mucin synthesis involves Src kinase-dependent EGFR
      transactivation.

PMID- 15185751
TI  - Question: What is the biological function of the polyamines?

PMID- 15185752
TI  - How I became a biochemist.

PMID- 15185750
TI  - Characterization of COBRA1 in human breast cancer cell lines using a new
      polyclonal antibody against COBRA1.
AB  - Mutations in the breast cancer susceptibility gene BRCA1 predispose individuals
      to breast and ovarian cancers. Cofactor of BRCA1 (COBRA1), a novel protein, was
      isolated as a BRCA1-interacting protein. However, the role of COBRA1 in breast
      cancer is poorly understood. In this study, we demonstrate that COBRA1 mRNA was
      differentially expressed in breast cancer cell lines by semi-quantitative reverse
      transcription-polymerase chain PCR (RT-PCR). We developed a highly specific
      rabbit polyclonal anti-COBRA1 antibody using GST-COBRA1 fusion protein. In most
      cases, the levels of COBRA1 protein in breast cancer cell lines detected by
      Western blotting with the anti-COBRA1 antibody correlated with those of COBRA1
      mRNA. Immunofluorescence analysis indicated that COBRA1 was a nuclear protein.
      Endogenously expressed COBRA1 interacted with the nuclear protein BRCA1 in human
      breast cancer cells. These data suggest that the COBRA1 antibody may be a useful
      tool to investigate functions of COBRA1 in cancers and that, like BRCA1, COBRA1
      may regulate various nuclear events in breast cancer cells.

PMID- 15185753
TI  - Surgical treatment of unruptured intracranial aneurysms over the past 22 years.
AB  - The medical records of 312 patients who underwent surgical intervention for
      unruptured intracranial aneurysm by the same neurosurgeon between April 1979 and
      December 2000 were analyzed retrospectively to clarify the complexities of this
      treatment. Patients were divided into Groups I (earlier) to IV (later) according
      to the date of surgery. Outcome was evaluated as no change after surgery,
      transient postoperative deterioration (TD), or permanent deterioration (PD).
      Operative period, background disease, age, aneurysm location and size,
      postoperative results, and affecting factors were investigated. The overall rate
      of PD was 5%, including one death (0.3%), and the overall rate of TD was 11%.
      Cases of middle cerebral artery aneurysm and small aneurysm with diameters less
      than 10 mm in all locations showed favorable outcomes. There were no significant
      differences in operative results and period except the lower incidence of TD in
      Group IV. Surgical outcome was significantly correlated with aneurysm size.
      Vertebrobasilar artery aneurysm was associated with worse operative results. Most
      of the causes of PD were related to operative procedures, mainly perforator
      injury and general complications. Unruptured aneurysm can be treated safely,
      especially in cases of middle cerebral artery aneurysm and small aneurysm of less
      than 10 mm diameter in all locations. Larger aneurysms and vertebrobasilar artery
      aneurysm should be treated by experienced neurosurgeons.

PMID- 15185754
TI  - Aneurysms of the posterior cerebral artery: retrospective review of surgical
      treatment.
AB  - A series of 10 cases of posterior cerebral artery (PCA) aneurysms were
      retrospectively reviewed. There were five men and five women aged 38 to 68 years
      (mean 57.5 years). Seven patients presented with subarachnoid hemorrhage. Two
      aneurysms were found incidentally during clinical examination for stroke. One
      aneurysm was associated with moyamoya disease. All aneurysms were saccular. The
      aneurysms arose from the P1 segment in three patients, the P1/P2 junction in
      three patients, the P2 segment in three patients, and the P3 segment in one
      patient. Two patients died before operation and one patient refused surgery.
      Aneurysmal clipping was performed for seven patients. All aneurysms except the P2
      and the P3 aneurysms were treated via the pterional approach. Four patients had
      excellent outcome, but one patient with a P3 aneurysm developed homonymous
      hemianopsia due to thrombosis of the parent vessel and another patient with a P2
      aneurysm had moderate disability from the initial insult. Coil embolization has
      been indicated as the first choice of therapy, but PCA aneurysms are good
      candidates for direct clipping.

PMID- 15185755
TI  - Intraoperative monitoring of the corticospinal motor evoked potential (D-wave):
      clinical index for postoperative motor function and functional recovery.
AB  - The corticospinal motor evoked potential was investigated as a monitoring index
      of motor function to perform maximal resection of brain tumors located around the
      motor cortex in 37 patients with glioma. Tumor resections were performed under
      general anesthesia with muscle relaxant and completely controlled ventilation. No
      special arrangements for anesthesia were required. Direct cortical stimulation
      revealed that if one electrode was placed on the posterior half of the precentral
      gyrus, the D-wave could be recorded even when using an electrode separation of 10
      mm, and the amplitude was larger with anodic rather than cathodic stimulation.
      Monitoring of the D-wave enabled the function of the corticospinal tract to be
      evaluated selectively. Postoperative persistent motor disturbance remained in six
      patients who had a decrease of over 30% in amplitude of the D-wave during tumor
      resection. A decrease of less than 30% may indicate postoperative preservation of
      motor function, including transient motor disturbance with subsequent complete
      recovery. Intraoperative monitoring of the D-wave is suitable for open cranial
      surgery with general anesthesia, can detect the primary motor cortex, and allow
      maximal resection of brain tumors located around the motor cortex.

PMID- 15185756
TI  - Magnetic resonance angiography demonstrating adult moyamoya disease progressing
      from unilateral to bilateral involvement--case report.
AB  - A 21-year-old woman presented with moyamoya disease manifesting as speech
      disturbance and right quadrant hemianopsia on October 22, 1994. Magnetic
      resonance (MR) angiography showed occlusion of the left internal carotid artery
      (ICA) with the normal right ICA. The diagnosis was "unilateral" moyamoya disease
      by conventional angiography. Follow-up MR angiography revealed further occlusive
      changes of the right middle cerebral artery (MCA) trunk on July 30, 1995, which
      progressed to occlusion of the MCA on March 25, 1997. Conventional angiography
      confirmed occlusion of the right terminal ICA to MCA with basal moyamoya vessels.
      The diagnosis was "bilateral" moyamoya disease. She was successfully treated by
      bilateral superficial temporal artery-MCA anastomosis. Follow-up MR angiography
      should be performed in relatively young patients with "unilateral" moyamoya
      disease to detect any progression to bilateral moyamoya disease.

PMID- 15185757
TI  - Spontaneous regression of a primary cerebral tumor following vasospasm caused by
      subarachnoid hemorrhage due to rupture of an intracranial aneurysm--case report.
AB  - A 40-year-old man demonstrated spontaneous regression of a malignant glioma
      following vasospasm caused by subarachnoid hemorrhage due to rupture of an
      intracranial aneurysm. The patient had been treated under a diagnosis of
      malignant glioma for 5 years. He presented with a ruptured aneurysm manifesting
      as subarachnoid hemorrhage. Single photon emission computed tomography with N
      isopropyl-p-123I-iodoamphetamine and diffusion-weighted magnetic resonance (MR)
      imaging revealed severe flow reduction due to vasospasm in the bilateral
      temporoparietal cortical regions, including the tumor. MR imaging performed 5
      months later showed marked tumor regression. The present case suggests that
      treatment targeting angiogenesis of malignant gliomas may be effective as a part
      of multimodality treatment.

PMID- 15185758
TI  - Olfactory groove schwannoma--case report.
AB  - A 30-year-old man presented with a 2-year history of intermittent headache. No
      neurological deficit was detected. Computed tomography (CT) and magnetic
      resonance imaging showed a tumor with a diameter of 2.5 cm in the left anterior
      skull base associated with bone scalloping on three-dimensional CT. Angiography
      showed a hypovascular tumor. Craniotomy demonstrated a tumor in the region of the
      left olfactory groove attached to the anterior part of the cribriform plate. The
      histological diagnosis was schwannoma. Schwannoma arising from near the olfactory
      groove is rare, with only 13 other cases reported. The precise origin of these
      tumors is not well understood, but the tumor in this case probably arose from the
      fila olfactoria, because the olfactory bulb was involved in the tumor, whereas
      the olfactory tract remained intact.

PMID- 15185759
TI  - Solitary plasmacytoma of the skull: immunohistochemical study of angiogenic
      factors and syndecan-1--two case reports.
AB  - Two cases of solitary plasmacytomas of the skull are presented, and some
      biological aspects of the tumor examined. A 75-year-old woman presented with a
      tumor in the right parietal region. The serum level of immunoglobulin G (IgG) was
      high and a urine test for Bence Jones protein was negative. A reddish vascular
      mass was totally removed at surgery. The serum level of IgG was within normal
      limits after the operation. Postoperative radiotherapy was not performed. A 58
      year-old woman presented with a tumor in the occipital region. Serum levels of
      Igs were within normal limits. A urine test for Bence Jones protein was positive
      for Ig kappa chain. Bone marrow aspiration revealed no evidence of systemic
      myelomatosis. The tumor mass was totally removed at surgery and she received
      local radiation therapy (total 50 Gy). Three months after the surgery, Bence
      Jones protein (kappa chain) was detected in both the urine and serum and bone
      scintigraphy showed a weak hot spot in the iliac bone, suggesting development to
      multiple myeloma. Immunohistochemical studies showed that most tumor cells were
      positive for vascular endothelial growth factor and syndecan-1, and some tumor
      cells were strongly positive for basic fibroblast growth factor in both cases.
      The Ki-67 staining indices were 11.3% and 15.6%. Tumor tissues were negative for
      p53. These results suggest that solitary plasmacytoma of the skull expresses the
      angiogenic factors, vascular endothelial growth factor, and basic fibroblast
      growth factor, in accordance with the high vascularity of the tumors, and
      syndecan-1 may be an immunohistochemical marker of solitary plasmacytoma of the
      skull.

PMID- 15185760
TI  - Association of paranasal sinus osteoma and intracranial mucocele--two case
      reports.
AB  - Two young adult males presented with paranasal sinus osteoma associated with
      mucocele. A 20-year-old man presented with headache and seizure, and another 20
      year-old man presented with headache, frontal deformity, and visual disturbances.
      Both patients underwent surgery and satisfactory results were obtained. Isolated
      paranasal sinus osteomas are benign and slow-growing tumors, but may become more
      aggressive in association with mucoceles. The higher aggressiveness of the
      lesions may be due to the presence of the mucocele. Calcification and
      ossification of the mucocele probably contributes to the unexpected enlargement
      of the osteoma.

PMID- 15185761
TI  - Tension pneumocephalus after a neuroendoscopic procedure--case report.
AB  - A 60-year-old female presented with gait disturbance, urinary incontinence, and
      recent memory disturbance. Computed tomography and magnetic resonance imaging
      revealed a partially calcified mass lesion without enhancement in the left
      caudate head and mild ventriculomegaly. She underwent endoscopic tumor biopsy.
      The histological diagnosis was astrocytoma grade 2. After the endoscopic
      procedure she presented with prolonged consciousness disturbance caused by
      tension pneumocephalus. Tension pneumocephalus is one of the potential
      complications of neuroendoscopic procedures.

PMID- 15185762
TI  - Stereotactically inserted tube-guided brain biopsy using positron emission
      tomography and magnetic resonance coregistered images--case report.
AB  - A 53-year-old man presented with malignant lymphoma manifesting as disturbances
      of walking and standing. Magnetic resonance (MR) imaging showed multifocal
      bifrontal lesions which were enhanced by gadolinium-diethylenetriaminepenta
      acetic acid. Positron emission tomography (PET) with [18F]fluorodeoxyglucose
      showed high uptake of tracer in the lesion. The PET-MR coregistered image was
      used to determine the biopsy target. After right frontal craniotomy, a sterilized
      probe controlled by a neuronavigation system was directly passed into the tumor,
      and a guide tube was inserted along the same track. After dura opening, a small
      corticotomy was performed along the guide tube track and the tumor was biopsied.
      Histological examination revealed malignant lymphoma. The stereotactically
      inserted tube-guided brain biopsy was less invasive and provided an accurate
      diagnosis. The PET-MR coregistered image was helpful for determining the most
      active lesion of the brain tumor.

PMID- 15185763
TI  - Small unruptured aneurysm verification (SUAVe Study, Japan)--interim report.
AB  - A prospective study (SUAVe Study, Japan) is in progress at 13 national hospitals
      to determine the surgical indications for small unruptured intracranial aneurysm.
      These hospitals are observing the natural history of small unruptured aneurysms
      (under 5 mm diameter) without surgical treatment. Since October 2000, 455
      aneurysms (393 patients) with 75 aneurysms excluded by film judgment committees
      have been registered, of which 380 aneurysms (329 cases) have been followed up
      for a mean of 13.8 months (5 aneurysms for 36 months, 68 for 24 months, 164 for
      12 months, and 64 for 6 months). Four aneurysms have already ruptured (3 multiple
      and 1 single). The annual rupture rate was 0.8% (95% confidence interval 0.2-3%).
      Another 18 aneurysms have enlarged including seven aneurysms treated for
      enlargement over 2 mm in size. Considering this finding, the annual rupture rate
      might rise slightly. The important factors for rupture and enlargement were
      multiplicity of aneurysm, female, patient aged over 70 years old, and location of
      aneurysm (anterior communicating artery, basilar artery). The growth rate may be
      faster in multiple aneurysms than in single aneurysms.

PMID- 15185764
TI  - Japan Carotid Atherosclerosis Study: JCAS.
AB  - The recent randomized trials, North American Symptomatic Carotid Endarterectomy
      Trial, European Carotid Surgery Trial, and Asymptomatic Carotid Atherosclerosis
      Study, have demonstrated the effectiveness of carotid endarterectomy to reduce
      the incidence of cerebral infarction in patients with symptomatic and
      asymptomatic high-grade carotid artery stenosis. However, no studies on Japanese
      patients have been done until now, and recent progress in endovascular stent
      treatment has been made. The present prospective, multicenter (not randomized)
      trial, the Japan Carotid Atherosclerosis Study, has started to analyze present
      practice and propose treatment guidelines for Japanese patients. Here, the
      protocol and early results of 565 patients registered until the end of January
      2004 are presented.

PMID- 15185765
TI  - Study design for a prospective randomized trial of extracranial-intracranial
      bypass surgery for adults with moyamoya disease and hemorrhagic onset--the Japan
      Adult Moyamoya Trial Group.
AB  - This article summarizes the study design and organization of a multicenter,
      prospective randomized trial of extracranial-intracranial (EC-IC) bypass for
      treating adult patients with moyamoya disease who suffered episodes of
      intracranial bleeding. The Japan Adult Moyamoya Trial will determine whether the
      combination of EC-IC bypass with risk factor modifications affects the prognosis
      and the incidence of recurrent bleeding attacks. Direct bypass such as
      superficial temporal artery-middle cerebral artery anastomosis is essential and
      indirect bypass procedures alone such as encephalo-duro-arterio-synangiosis or
      encephalo-myo-synangiosis are not dealt with in this trial. Power calculations
      are based on an assumption of alpha=0.05 with an annual event rate of 8%
      significant morbidity and mortality per year in the non-surgical group and 4% in
      the surgical group. The study has an 80% rate of accuracy for detection of a 20%
      difference between the two groups in events in a 5-year follow up.

PMID- 15185766
TI  - Randomized controlled trial on malignant brain tumors--activities of the Japan
      Clinical Oncology Group-Brain Tumor Study Group.
AB  - The Japan Clinical Oncology Group (JCOG)-Brain Tumor Study Group was organized
      with the support of the Health and Labour Sciences Research Grants of the
      Ministry of Health, Labour and Welfare. The group is now preparing a multi
      institutional randomized controlled phase II/III study of chemoradiotherapy using
      ACNU versus procarbazine and ACNU for astrocytoma grades 3 and 4. The overall
      survival and response rates will be compared between the patients treated with
      ACNU and those treated with ACNU plus procarbazine. This study, under the
      surveillance of the JCOG, aims to set a standard protocol for treating patients
      with malignant glioma. Moreover, the study will establish a proper methodology
      for performing randomized studies in the field of neuro-oncology.

PMID- 15185767
TI  - Clinical guidelines for idiopathic normal pressure hydrocephalus.
AB  - Idiopathic normal pressure hydrocephalus (iNPH) is a syndrome characterized by
      gait disturbance, dementia, and/or urinary incontinence without causative
      disorders, and ventricular enlargement due to disturbance of the cerebrospinal
      fluid (SF) circulation. The number of patients with iNPH will increase with the
      aging of the population in Japan. However, iNPH is often difficult to
      differentiate from other senile disorders such as lumbar canal stenosis,
      parkinsonism, and so on. Clinical guidelines for iNPH are required to improve
      understanding and provide for patients' quality of life and social care. These
      guidelines propose three levels of iNPH: possible, probable, and definite.
      Possible iNPH includes one or more of the classical triad and ventricular
      dilation in middle aged and elderly patients with closing of the CSF space at
      high convexity on magnetic resonance imaging. Probable iNPH shows improvement of
      the symptoms after CSF removal in patients with possible iNPH. Definite iNPH
      shows clinical improvement after CSF shunt operation. The CSF tap test is a major
      diagnostic measure because of the simplicity and less invasiveness. Use of the
      programmable valve is recommended to decrease CSF overdrainage. These guidelines
      are helpful for the diagnosis and treatment of iNPH.

PMID- 15185768
TI  - Management of renal osteodystrophy in peritoneal dialysis patients.
AB  - The term "renal osteodystrophy" encompasses all forms of metabolic bone disease
      found in dialysis patients. The primary approach to the treatment of renal
      osteodystrophy in peritoneal dialysis (PD) patients is similar to that in
      hemodialysis patients. However, the increased prevalence of adynamic bone
      histology, together with the difficulty in judging calcium balance, the inability
      to practicably give intravenous vitamin D, and the clearance of vitamin D and
      parathyroid hormone via dialysate require a different therapeutic approach in PD
      compared to hemodialysis patients. Clearly, more comparative studies of new
      agents are needed to find the optimal approach to achieving the K/DOQI guidelines
      in PD patients. The unique aspects of the approach to renal osteodystrophy in PD
      patients are the focus of this review.

PMID- 15185769
TI  - Comparing the incomparable: hemodialysis versus peritoneal dialysis in
      observational studies.
AB  - A randomized trial comparing survival in hemodialysis and peritoneal dialysis
      remains a utopian aspiration. Dialysis is still relatively rare on a population
      basis, and a natural tension exists between desirability and feasibility in terms
      of quality of evidence. In practice, it is very difficult to perform prospective
      comparisons with large groups of contemporary representative subjects, and much
      of the literature comes from retrospective national registries. This article
      considers several questions to address when trying to compare the outcomes of
      peritoneal dialysis and hemodialysis. Prognostic similarity at baseline is a
      fundamental issue. Traditionally, adjustment for known prognostic factors has
      been used in an attempt to minimize the bias caused by nonrandom treatment
      assignment. Propensity scores have been suggested to be superior, and matched
      case analysis may also be a useful method for comparison. Other questions
      include, when, in relation to starting dialysis, to start the observation clock;
      the definition and handling of switches of dialysis therapy; and the decision to
      censor at transplantation. Finally, comparisons are complicated by hazards ratios
      that vary over time, and time-segmented analysis is obligatory. Many types of
      analytical approaches are needed to begin to appreciate outcome disparities
      between dialysis therapies.

PMID- 15185770
TI  - A randomized clinical trial with a 0.6% amino acid/ 1.4% glycerol peritoneal
      dialysis solution.
AB  - BACKGROUND: Glucose is an accepted osmotic agent for peritoneal dialysis (PD)
      although it has several drawbacks. Some of these drawbacks have been addressed by
      the introduction of solutions with low glucose degradation products and
      physiological pH in dual-chambered bags. Despite this achievement, there is a
      need for alternative osmotic agents.This randomized clinical trial analyzes 3
      month's clinical experience with a mixture of 0.6% amino acids and 1.4% glycerol.
      METHODS: The study was performed at the renal units of the University Hospitals
      Ghent, Belgium, and Utrecht, The Netherlands. Stable PD patients were randomized
      for either protocol A (test solution, n = 5) or protocol B (control regimen, n =
      5). In both protocols, there was a run-in phase of 1 month with a dialysis
      regimen of 2 x 2 L 2.27% glucose solution (Dianeal; Baxter, Nivelles, Belgium), 1
      x 2 L Extraneal (Baxter), and 1 x 2 L glucose solution (Dianeal). After this
      month-long run-in period, patients in group A received during 3 months 2 x 2 L
      amino acid/glycerol solution, 1 x 2 L Extraneal, and at least 1 x 2 L of a
      classic glucose solution. RESULTS: Glucose absorption decreased in the test group
      during the test phase (from 84.2 +/- 8.7 to 11.7 +/- 11.6 g/24 hours, p = 0.001).
      Dialysate levels of cancer antigen 125 (CA125) increased in the test group, from
      17.5 +/- 11.0 to 32.4 +/- 4.6 units/L (p = 0.04), whereas, in the control group,
      the levels remained stable (15.5 +/- 8.7 and 14.9 +/- 9.8 units/L respectively, p
      = 0.4). There were no differences in serum urea, serum bicarbonate, serum
      osmolarity, serum albumin, or parameters related to skin-fold thickness or serum
      glycerol levels between control and test solutions. No differences were observed
      in obtained ultrafiltration after a 4-hour dwell with 2.27% glucose or the test
      solution, both measured at week 4 of the run-in period and week 12 of the test
      period. CONCLUSION: This study demonstrated that the use of a new 0.6% amino
      acid/1.4% glycerol-containing dialysis solution is safe and well tolerated.
      Glucose load was reduced significantly and dialysate CA125 levels improved
      significantly. Ultrafiltration was comparable with that of a 2.27% glucose
      solution. All these factors, in combination with the potential nutritional
      benefits, can contribute to a beneficial impact on the success of the PD
      technique. Further long-term studies in larger patient groups are warranted to
      explore the potential of this promising new solution.

PMID- 15185771
TI  - Relationship of demographic, dietary, and clinical factors to the hydration
      status of patients on peritoneal dialysis.
AB  - OBJECTIVES: To establish which clinical factors are associated with an increased
      proportion of extracellular fluid (ECF) in peritoneal dialysis (PD) patients.
      DESIGN: A single-center, cross-sectional analysis of 68 stable PD patients.
      METHOD: Bioelectrical impedance measurements (RJL, single frequency; RJL Systems,
      Clinton, Michigan, USA) of resistance and reactance were used to determine the
      proportion of ECF comprising total body water (TBW) in 68 stable PD patients
      attending for routine clearance and membrane studies. All patients underwent
      detailed dietetic, adequacy, and membrane function tests. Blood pressure and
      antihypertensive requirements were also documented. RESULTS: Significant gender
      differences in body composition were observed, such that women had lower absolute
      TBW and fat-free mass per kilogram body weight, but proportionately more ECF for
      a given TBW, mean ECF:TBW 0.5 +/- 0.03 versus 0.44 +/- 0.05, p < 0.005. In view
      of this, patients were split into two groups, defined as "over-" or "normally"
      hydrated, either by using the single discriminator (median ECF:TBW = 0.47) for
      the whole population, which resulted in groups distorted by gender, or by using
      different discriminators according to gender (women: 0.49, men 0.45). In both
      analyses, overhydrated patients were older, had significantly lower plasma
      albumin, less total fluid removal per kilogram body weight, and higher peritoneal
      solute transport. When split by a single discriminator, the overhydrated patients
      had lower sodium removal and significantly less intracellular fluid volume due to
      an excess of women in this group who also had less residual function and had been
      on dialysis longer. Using gender-specific discrimination, overhydrated patients
      were heavier due to expansion of the ECF volume: 20 +/- 4.1 L versus 16 +/- 3.3
      L, p < 0.001. Stepwise multivariate analysis found age (p = 0.001), albumin (p =
      0.009), and fluid losses per kilogram body weight (p = 0.025) to be independent
      predictors of gender-adjusted hydration status. Sodium intake did not vary
      according to hydration status. CONCLUSION: Gender influences the assessment of
      hydration status of PD patients when employing bioimpedance, such that women tend
      to have more ECF. Taking this into account, age, albumin, and achieved fluid
      removal appear to be independently associated with hydration status, whereas
      peritoneal solute transport is not. Advice on dietary sodium should take account
      of hydration status and achievable losses.

PMID- 15185772
TI  - Peritoneal fluid transport in CAPD patients with different transport rates of
      small solutes.
AB  - BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) patients with high
      peritoneal solute transport rate often have inadequate peritoneal fluid
      transport. It is not known whether this inadequate fluid transport is due solely
      to a too rapid fall of osmotic pressure, or if the decreased effectiveness of
      fluid transport is also a contributing factor. OBJECTIVE: To analyze fluid
      transport parameters and the effectiveness of dialysis fluid osmotic pressure in
      the induction of fluid flow in CAPD patients with different small solute
      transport rates. PATIENTS: 44 CAPD patients were placed in low (n = 6), low
      average (n = 13), high-average (n = 19), and high (n = 6) transport groups
      according to a modified peritoneal equilibration test (PET). METHODS: The study
      involved a 6-hour peritoneal dialysis dwell with 2 L 3.86% glucose dialysis fluid
      for each patient. Radioisotopically labeled serum albumin was added as a volume
      marker.The fluid transport parameters (osmotic conductance and fluid absorption
      rate) were estimated using three mathematical models of fluid transport: (1) Pyle
      model (model P), which describes ultrafiltration rate as an exponential function
      of time; (2) model OS, which is based on the linear relationship of
      ultrafiltration rate and overall osmolality gradient between dialysis fluid and
      blood; and (3) model G, which is based on the linear relationship between
      ultrafiltration rate and glucose concentration gradient between dialysis fluid
      and blood. Diffusive mass transport coefficients (K(BD)) for glucose, urea,
      creatinine, potassium, and sodium were estimated using the modified Babb
      Randerson-Farrell model. RESULTS: The high transport group had significantly
      lower dialysate volume and glucose and osmolality gradients between dialysate and
      blood, but significantly higher K(BD) for small solutes compared with the other
      transport groups. Osmotic conductance, fluid absorption rate, and initial
      ultrafiltration rate did not differ among the transport groups for model OS and
      model P. Model G yielded unrealistic values of fluid transport parameters that
      differed from those estimated by models OS and P. The K(BD) values for small
      solutes were significantly different among the groups, and did not correlate with
      fluid transport parameters for model OS. CONCLUSION: The difference in fluid
      transport between the different transport groups was due only to the differences
      in the rate of disappearance of the overall osmotic pressure of the dialysate,
      which was a combined result of the transport rate of glucose and other small
      solutes. Although the glucose gradient is the major factor influencing
      ultrafiltration rate, other solutes, such as urea, are also of importance. The
      counteractive effect of plasma small solutes on transcapillary ultrafiltration
      was found to be especially notable in low transport patients. Thus, glucose
      gradient alone should not be considered the only force that shapes the
      ultrafiltration profile during peritoneal dialysis. We did not find any
      correlations between diffusive mass transport coefficients for small solutes and
      fluid transport parameters such as osmotic conductance or fluid and volume marker
      absorption. We may thus conclude that the pathway(s) for fluid transport appears
      to be partly independent from the pathway(s) for small solute transport, which
      supports the hypothesis of different pore types for fluid and solute transport.

PMID- 15185773
TI  - Laparoscopic placement of Oreopoulos-Zellerman catheters in CAPD patients.
AB  - BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) is widely accepted
      for the management of end-stage renal disease. Various techniques have been
      described for the insertion of peritoneal dialysis catheters. Lately, with the
      evolution of laparoscopic surgery, different laparoscopic techniques have also
      been presented, suggesting the technique is preferable to the open and
      percutaneous methods. OBJECTIVE: To introduce and evaluate a new laparoscopic
      technique for insertion of Oreopoulos-Zellerman catheters in CAPD patients.
      SETTING: The study was carried out in the First Department of Propaedeutic
      Surgery, Athens University Medical School, Hippokration Hospital. PATIENTS AND
      METHODS: Between November 2000 and March 2002, the technique was applied in 20
      consecutive patients (mean age 62 years, range 54 - 70 years) with end-stage
      renal disease. During this technique, a 10-mm trocar is placed just below the
      umbilicus for the optics and a 5-mm trocar is placed in the right lower quadrant.
      With the help of a 10-mm trocar, a tunnel is formed in the standard paramedian
      position on the left side, 2 - 3 cm below the plane of the umbilicus, for the
      insertion of the peritoneal catheter. A laparoscopic needle (GraNee needle; R
      Med, Oregon, Ohio, USA) is used for the closure of the 10-mm trocar-induced
      peritoneal and fascia defect using a purse-string suture. The catheter is
      advanced into the abdomen under direct vision and guided toward the Douglas
      pouch. The subcutaneous tunnel and the patency test of the catheter are performed
      as the last main steps in our procedure. One surgeon undertook all procedures.
      RESULTS: All procedures were completed laparoscopically. The mean operative time
      was 30 minutes (range 25 - 40 minutes). There was no intraoperative complication
      or surgical mortality. One patient developed leakage at the catheter exit site 3
      days after surgery; it was corrected under local anesthesia. During a mean follow
      up time of 17 months (range 12 - 28 months), 1 patient required catheter removal
      due to fungal peritonitis. CONCLUSION: Laparoscopic insertion of the Oreopoulos
      Zellerman catheter is a simple, quick, and safe method. We believe future
      experience will encourage the laparoscopic technique as the method of choice.

PMID- 15185774
TI  - The effect of depressive symptoms on survival in peritoneal dialysis patients.
AB  - OBJECTIVE: There is little information on the relationship between depressive
      symptoms and survival in peritoneal dialysis (PD) patients. We examined whether a
      single measurement of depressive symptoms using a simple self-administered tool
      predicts survival. DESIGN: Screening test of depressive symptoms as a predictor
      of outcome. SETTING: Three dialysis centers in Southwestern Pennsylvania.
      PARTICIPANTS: 66 adult PD subjects were screened in 1997-1998 for depression
      using the Zung scale. MAIN OUTCOME MEASURES: Baseline data collection included
      assessments of comorbidity, residual renal function, total Kt/V, nPNA, previous
      renal transplant, and serum albumin. Outcomes were collected prospectively after
      completion of the depression survey to 12/01. Cox regression analysis of patient
      survival was performed using all cofactors with p < 0.05 on univariate analysis.
      RESULTS: One third of patients had depressive symptoms. Compared to nondepressed
      patients, depressive symptom patients were older (62.5 vs 52.5 years, p = 0.012),
      had borderline lower serum albumin levels (3.47 vs 3.70 g/dL, p = 0.058), and
      were more disabled (Karnofsky score 70 vs 90, p< 0.001), but had similar Kt/V,
      residual renal function, and previous time on PD at the point of the testing.
      Using multivariate analysis and controlling for comorbidity (using a measurement
      that includes diabetes mellitus and age) and serum albumin, the survival of
      patients with depressive symptoms was significantly reduced compared to
      nondepressed patients. CONCLUSION: A single measurement of depressive symptoms
      using a simple self-administered test was an independent predictor of death in a
      cohort of PD patients, which extends observations in hemodialysis patients.
      Screening for depressive symptoms should be routine for dialysis patients, and
      those depressed should have thorough assessment and treatment. Whether treating
      depression will have an impact on survival is unclear and needs to be studied.

PMID- 15185775
TI  - Protein adsorption on ex vivo catheters and polymers exposed to peritoneal
      dialysis effluent.
AB  - BACKGROUND: Deposition of proteins on surfaces of medical devices has been
      recognized to putatively relate to the process of regulation of biomaterial
      associated complications by attachment of fibrin clots, eukaryotic cells, and
      microbes. The molecules adsorb to a varying extent, depending not only on the
      physicochemical properties of the biomaterial, but also on the composition of the
      host fluid. OBJECTIVE: Adsorption of proteins on catheters exposed both ex vivo
      and in vitro to dialysate of patients on peritoneal dialysis (PD) was studied.
      METHODS: Peritoneal dialysis effluent was collected from 5 patients with end
      stage renal disease on continuous ambulatory PD. Tenckhoff catheters were
      obtained from 16 patients. Deposition of proteins on excised Tenckhoff catheters
      and tubing of different materials exposed to PD effluent in vitro was studied
      using 125iodine-labeled antibodies. Adhesion of Staphylococcus aureus and
      Staphylococcus epidermidis strains was quantified on tubing exposed to PD
      effluent in vitro. RESULTS: The presence of albumin, transferrin, immunoglobulin
      G, fibrinogen, fibronectin, von Willebrand factor, vitronectin, and
      thrombospondin was determined at various concentrations in PD effluent. All
      proteins analyzed were detected on PD catheters removed from patients. The extent
      of protein deposition on Tenckhoff catheters exposed to PD effluent, in vitro,
      rapidly reached a plateau and remained constant, as it did on polyvinyl chloride
      and polyethylene tubing. Adhesion of staphylococci was enhanced on Tenckhoff
      catheters exposed to PD effluent compared to unused PD solution. CONCLUSIONS: The
      data identify surface exposed proteins that may serve as adhesion sites for
      microbes on peritoneal catheters indwelled in patients undergoing PD.

PMID- 15185776
TI  - Exercise capacity in pediatric patients with end-stage renal disease.
AB  - OBJECTIVE: To evaluate the correlation between exercise capacity and hemoglobin
      in pediatric patients with end-stage renal disease (ESRD) treated with automated
      peritoneal dialysis (APD) and hemodialysis. DESIGN: Prospective case-control
      study and retrospective review. SETTING: Dialysis summer camp and Children's
      Mercy Hospital exercise laboratory. PARTICIPANTS: Prospective evaluation
      conducted with 14 patients (9 males, mean age 14.5 +/- 2.5 years) who received
      either home APD (5 patients) or in-center hemodialysis (9 patients), and 8
      healthy age-matched controls. Retrospective data derived from 10 children (7
      males, mean age 12.3 +/- 3.3 years), all of whom received APD. INTERVENTION:
      Maximal treadmill evaluation conducted with each patient and control. The
      hemoglobin value of each patient was also assessed. MAIN OUTCOME MEASURES:
      Comparison of the following data generated during treadmill protocol: peak heart
      rate, blood pressure, oxygen saturation, treadmill time, oxygen consumption
      (VO2), ventilation (Ve), oxygen consumption at anaerobic threshold (VO2AT), and
      respiratory exchange ratio. RESULTS: The hemoglobin value of the current patient
      group (12.8 +/- 1.6 g/dL) was significantly greater than the previously studied
      patients (10.5 +/- 1.1 g/dL) (p = 0.001). Treadmill time, VO2, and VO2AT were
      significantly lower in both groups of dialysis patients compared to the control
      subjects (p < 0.05). No differences were noted in any of these variables when
      comparing these two groups of dialysis patients only. CONCLUSION: The exercise
      capacity of pediatric dialysis patients is significantly poorer than that of
      healthy children, an outcome apparently related to factors other than
      normalization of the hemoglobin value.

PMID- 15185777
TI  - Cholesterol ester transfer protein in children on peritoneal dialysis.
AB  - OBJECTIVES: To examine whether cholesterol ester transfer protein (CETP) activity
      and mass contribute to dyslipidemia in children on peritoneal dialysis (PD), and
      to determine whether CETP activity or mass is responsible for severer
      hyperlipidemia in smaller (younger) patients. STUDY DESIGN: 27 patients (18
      males, 9 females; mean age 11.8 +/- 6.1 years) were enrolled. Each patient had
      been receiving PD for more than 6 months. Fasting blood samples were drawn and
      CETP activity, CETP mass, total cholesterol, triglyceride, beta-lipoprotein
      profiles, lipoprotein lipid profiles (cholesterol and triglyceride in
      lipoproteins), apoprotein profile, and serum albumin levels were measured. The
      results were then compared, using Student's t-test, with those for a control
      group. In the patient group, the relationships between CETP activity and each
      factor were examined using simple and multiple regression analyses. RESULTS:
      Total cholesterol, triglyceride, low-density lipoprotein (LDL), very low-density
      lipoprotein (VLDL), chylomicron, and ApoB levels were significantly higher in the
      patient group. Mean CETP activity levels were 106% +/- 24% in the patient group
      and 111% +/- 21% in the control group. No significant difference in CETP activity
      was seen between the two groups, but CETP mass was lower in the patient group
      than in the control group (2.2 +/- 0.6 microL/dL for the patient group vs 2.8 +/-
      0.9 microL/dL for the control group, p = 0.01). As a result, specific CETP
      activity (activity/protein mass ratio) was significantly higher in the patient
      group (p < 0.0001). CETP activity was positively related to LDL and other
      atherogenic factors and negatively related to serum albumin level. No
      relationship between CETP activity and patient body weight was seen. CONCLUSION:
      Specific CETP activity was higher in the patient group compared with that in the
      control group, and strong correlations were found between CETP activity and
      atherogenic factors in the patient group. Therefore, CETP seems to be associated
      with lipid abnormalities in children on PD but is not responsible for the severer
      hyperlipidemia seen in smaller children.

PMID- 15185778
TI  - Fibrin glue used successfully in peritoneal dialysis catheter leakage in
      children.
AB  - BACKGROUND: Acute renal failure in infants and small children is generally
      treated with peritoneal dialysis (PD). Dialysis has to be started immediately
      after catheter implantation. Early dialysate leakage can complicate the
      effectiveness of dialysis. Fibrin glue applied to the external part of the tunnel
      may stop dialysate leakage and eliminate the need for surgical intervention. The
      use of fibrin glue in the treatment of PD catheter leakage in children was
      studied. METHODS: Fibrin glue was used in 8 children (age 0.8 - 57 months) on PD
      in whom dialysate leakage was seen during the first 24 to 48 hours after catheter
      insertion. The dialysis volume initially administered was 20 mL/kg body weight.
      Fibrin glue (1 mL) was applied to the external part of the subcutaneous catheter
      tunnel through the exit site, as close to the cuff as possible. The occurrence of
      dialysate leakage and complications such as exit-site or tunnel infection and
      peritonitis were evaluated. RESULTS: Nine single-cuff straight Tenckhoff
      catheters were implanted in 8 children. In 5 cases, no subcutaneous tunnel was
      created. One child had catheter replacement due to obstruction of the catheter;
      on both occasions, catheter leakage was seen and treated with fibrin glue. In all
      8 patients, no relapse of dialysate leakage was seen after application of the
      fibrin glue. During the time of PD, exit-site infections, tunnel infections, and
      peritonitis did not occur. CONCLUSION: Fibrin glue is a successful, simple, and
      safe substance for the treatment of peritoneal dialysate leakage in infants and
      small children with acute renal failure treated with PD.

PMID- 15185779
TI  - Assessment of peritoneal fibrosis by conventional light microscopy and
      hydroxyproline measurements.

PMID- 15185780
TI  - Extended peritoneal dialysis catheters for upper abdominal wall exit sites.

PMID- 15185781
TI  - Small volume APD as alternative treatment for peritoneal leaks.

PMID- 15185782
TI  - Glucose monitoring for diabetic patients using icodextrin.

PMID- 15185783
TI  - Perforation of the transverse colon caused by a permanent peritoneal dialysis
      catheter.

PMID- 15185784
TI  - Wrong-site eye surgery.

PMID- 15185785
TI  - Perioperative treatment of patients with diabetes having eye surgery with local
      anesthesia in an ambulatory facility.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the incidence of hyperglycemia and
      hypoglycemia in diabetic patients on the morning of eye surgery scheduled under
      local anesthesia in an ambulatory surgery facility. PATIENTS AND METHODS: A
      retrospective analysis of fasting blood glucose levels in 216 diabetic patients
      on 326 admissions. RESULTS: The fasting blood glucose level was 80 mg/dL or lower
      in 10 patient admissions (3%). Hyperglycemia (fasting blood glucose level of
      greater than 300 mg/dL) was present on 8 admissions (2.4%). CONCLUSIONS: Blood
      glucose levels need to be monitored in diabetic patients undergoing even short
      surgical procedures. The dosage of long-acting insulins or oral hypoglycemics
      given the night prior to surgery may have to be reduced to prevent hypoglycemia
      on the morning of surgery.

PMID- 15185786
TI  - Intermediate-term results of Baerveldt tube shunt surgery with mitomycin C use.
AB  - BACKGROUND AND OBJECTIVE: To study the intermediate-term results of the Baerveldt
      glaucoma drainage device with adjunctive use of intraoperative mitomycin C.
      PATIENTS AND METHODS: Charts of 243 consecutive patients with advanced glaucoma
      who had undergone tube shunt surgery between 1992 and 1999 were retrospectively
      analyzed. A total of 64 patients were eligible for the study. Patients were
      observed for a mean of 34.3 +/- 21 months. Kaplan-Meier survival analysis was
      used to determine intermediate-term success. RESULTS: The mean preoperative
      intraocular pressure (IOP) was 34.4 mm Hg and the 1-year postoperative IOP was
      16.6 mm Hg. The mean percent IOP reduction after surgery was 51.7%, 53.2%, and
      51.4% at 1, 2, and 5 years, respectively. Kaplan-Meier analysis showed a 77%
      success rate at 1 year, 66% at 2 years, and 59% at 5 years. The most common
      complication was choroidal detachment (18.8%). CONCLUSION: The use of mitomycin C
      with Baerveldt implantation showed IOP control equivalent to that without
      mitomycin C at intermediate follow-up.

PMID- 15185787
TI  - Indocyanine green dye-enhanced transpupillary thermotherapy of classic subfoveal
      choroidal neovascularization.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the efficacy of indocyanine green dye
      enhanced transpupillary thermotherapy for the treatment of classic subfoveal
      choroidal neovascular membrane (CNVM) with differing etiologies. PATIENTS AND
      METHODS: Nine eyes of 9 patients with classic subfoveal CNVM with different
      etiologies that was treated with indocyanine green dye-enhanced transpupillary
      thermotherapy were prospectively studied. All patients underwent pretreatment
      fluorescein angiography. Three minutes after dye injection (25 mg of indocyanine
      green), transpupillary thermotherapy was delivered using a modified diode laser
      at 810 nm, with a variable spot size of 0.8 to 2 mm depending on the size of the
      CNVM. A power range between 100 and 800 mW was used and treatment was initiated
      in one spot for 60 seconds; the end point was a barely detectable light gray
      appearance of the lesion. The outcome measures were assessed by Snellen visual
      acuity chart and obliteration of the CNVM by fluorescein angiography. Mean follow
      up was 16 months. RESULTS: Obliteration of the CNVM was seen in all patients
      during the last visit. Visual acuity improved in one eye and remained stable (+/
      2 line change on Snellen chart) in three eyes. Three eyes revealed a moderate
      visual loss of 3 to 4 lines and two eyes had a severe decline (> 5 lines) in
      vision. None of the eyes exhibited recurrence of the CNVM during follow-up.
      CONCLUSIONS: Indocyanine green dye-enhanced transpupillary thermotherapy was
      highly effective in closing classic CNVM in all cases without any recurrence.
      Visual acuity was either stabilized or improved in 4 of 9 eyes (44.5%).

PMID- 15185788
TI  - Predictors of success in macular hole surgery with emphasis on the internal
      limiting membrane (ILM) and ILM peeling.
AB  - BACKGROUND AND OBJECTIVE: To study the predictors of success in macular hole
      surgery. PATIENTS AND METHODS: Twenty-two eyes of 21 patients underwent macular
      hole surgery. The hole closure rate and the visual improvement were studied based
      on the preoperative visual acuity, stage and duration of the macular hole, the
      type of intravitreal tamponade used, and internal limiting membrane peeling. The
      internal limiting membrane was peeled only when it was clinically prominent.
      RESULTS: Macular holes were closed in 19 of the 22 eyes and visual improvement of
      2 lines or more was achieved in 17 eyes. Preoperative visual acuity, duration of
      the macular hole, type of intraocular tamponade used, and internal limiting
      membrane peeling did not affect the outcome. A final visual acuity of 20/70 or
      better was more common after surgery for stage 2 holes (P = .019). CONCLUSION:
      The best predictor of outcome was the stage of the hole, with best results
      obtained in stage 2 holes.

PMID- 15185789
TI  - Phacoemulsification cataract extraction and intraocular lens implantation in
      patients with Behcet's disease.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the outcomes of phacoemulsification
      cataract extraction and intraocular lens implantation in patients with Behcet's
      disease. PATIENTS AND METHODS: This prospective study was based on 40 eyes of 34
      patients with Behcet's disease who underwent phacoemulsification cataract
      extraction and intraocular lens implantation between May 2000 and February 2003.
      Their postoperative ocular complications and visual outcomes were observed during
      a mean follow-up period of 18.35 +/- 6.17 months (range, 6 to 32 months).
      RESULTS: Postoperative visual acuity increased in 29 eyes (72.5%) and was 20/40
      or better in 18 eyes (45%). It decreased in 7 eyes (17.5%), resulting in a visual
      acuity of 20/400 or worse. The most frequent postoperative complication was
      posterior capsular opacification, which developed in 15 eyes (37.5%). Other
      complications were posterior synechiae formation in 7 eyes (17.5%), severe
      inflammation in 5 eyes (12.5%), cystoid macular edema in 5 eyes (12.5%),
      epiretinal membrane in 3 eyes (7.5%), and optic atrophy in 2 eyes (5%).
      CONCLUSION: With appropriate preoperative and postoperative suppression of
      inflammation, phacoemulsification and intraocular lens implantation are safe
      procedures leading to visual improvement in patients with Behcet's disease
      without preexisting fundus lesions.

PMID- 15185790
TI  - Visual results and complications of posterior chamber intraocular lens
      implantation after capsular tear during phacoemulsification.
AB  - BACKGROUND AND OBJECTIVE: To determine the visual outcome and complications of
      posterior chamber intraocular lens implantation after capsular tear in patients
      undergoing phacoemulsification at Istanbul University, Istanbul Faculty of
      Medicine, Department of Ophthalmology, Istanbul, Turkey. PATIENTS AND METHODS:
      The medical records of patients who underwent phacoemulsification surgery for
      senile cataract from January 1, 1996, to December 31, 1998, were reviewed.
      Patient inclusion criteria were implantation of a posterior chamber intraocular
      lens after phacoemulsification, being operated on by one of two surgeons, and a
      follow-up of at least 1 year. There were 58 eyes in the group with capsular tear
      and 159 eyes in the group with intact capsule. RESULTS: A final visual acuity of
      0.8 or more was more common in eyes with uncomplicated phacoemulsification
      surgery (chi-square = 16.25, P = .03). Refraction stabilized most commonly at 2
      to 6 months postoperatively in patients with capsular tear and 1 to 21 days
      postoperatively in patients with uncomplicated phacoemulsification (chi-square =
      22.61, P < .001). Complications such as retinal detachment (odds ratio = 11.70, P
      < .05), cystoid macular edema (odds ratio = 26.33, P < .01), increased
      intraocular pressure (odds ratio = 14.54, P < .05), and decentration of the
      intraocular lens (odds ratio = 32.79, P = .001) were more frequently observed in
      eyes with capsular tear. CONCLUSIONS: It takes longer for the refraction to
      stabilize in eyes with posterior chamber intraocular lens implantation after
      capsular tear during phacoemulsification. Complications such as retinal
      detachment, cystoid macular edema, increased intraocular pressure, and
      decentration of the intraocular lens are more common in these patients, and
      therefore they should be observed for a longer period of time.

PMID- 15185791
TI  - Discrimination between normal and glaucomatous eyes with the Topographic Scanning
      System: a preliminary report.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the ability of the Topographic Scanning
      System (TopSS; Laser Diagnostic Technologies, San Diego, CA) to differentiate
      individuals with glaucoma from normal subjects. PATIENTS AND METHODS: The
      subjects were divided into two groups: primary open-angle glaucoma and normal.
      All individuals underwent a complete ophthalmic evaluation, a 24-2 full threshold
      Humphrey visual field evaluation, and a TopSS examination. Cut-off points were
      selected, receiver operator characteristic (ROC) curves were created, and
      sensitivity and specificity were calculated for individual TopSS parameters and
      combinations of variables using multivariate analysis. RESULTS: One hundred
      twelve patients with glaucoma and 88 normal individuals were enrolled in the
      study. The best TopSS individual parameters were: average disc diameter
      (sensitivity: 64%, specificity: 89%, area under ROC curve: 0.824), total disc
      area (sensitivity: 85%, specificity: 66%, area under ROC curve: 0.802), and cup
      area (sensitivity: 69%, specificity: 85%, area under ROC curve: 0.797). The
      multivariate analysis resulted in an area under the ROC curve of 0.91
      (sensitivity: 90%, specificity: 81%). CONCLUSIONS: This preliminary report
      suggests that the use of a multivariate discriminant formula may enhance the
      ability to differentiate individuals with glaucoma from normal subjects with the
      TopSS, with high sensitivity and specificity. Further studies investigating a
      random population are needed to test the validity of this formula.

PMID- 15185792
TI  - Enhanced documentation of slit-lamp images of the human vitreous stained with
      fluorescein sodium.
AB  - BACKGROUND AND OBJECTIVE: To develop a new method to document the slit-lamp image
      of the vitreous body as stained with fluorescein sodium. PATIENTS AND METHODS:
      The system consists of a Goldmann-type slit-lamp biomicroscope, a highly
      sensitive monochromatic charge-coupled device camera, and a video attachment for
      real-time observation and recording. As a standard procedure, observation of the
      vitreous was conducted 60 minutes after intravenous administration of 500 mg of
      fluorescein sodium. This method was applied to 19 eyes with various eye diseases.
      RESULTS: Fine details of the vitreous were observed in all of the eyes. Posterior
      vitreous detachment could be recorded in 5 of the 19 eyes examined. Vitreoschisis
      and large lacunae were documented in 11 eyes. CONCLUSION: This method promises to
      be of value in detecting early age-related and pathological changes of the
      vitreous such as posterior vitreous detachment and vitreoschisis in clinics.

PMID- 15185793
TI  - Tomographic features of serous retinal detachment in Vogt-Koyanagi-Harada
      syndrome.
AB  - To clarify the nature of serous retinal detachment in Vogt-Koyanagi-Harada (VKH)
      syndrome, 42 consecutive eyes of 21 patients with acute phase VKH syndrome were
      examined using optical coherence tomography (OCT). OCT revealed two patterns of
      serous retinal detachment. Twenty-nine eyes (69%) had a true retinal detachment,
      17 eyes (40%) had intraretinal fluid accumulation in the outer retina, and 4 eyes
      had both. Intraretinal fluid accumulation appeared as an oval space in the outer
      retina. On fluorescein angiography, the eyes with intraretinal fluid accumulation
      showed more severe dye leakage from the retinal pigment epithelium.

PMID- 15185794
TI  - Pars plana vitrectomy and lamina cribrosa puncture in absolute glaucoma.
AB  - Two patients with refractory end-stage glaucoma who had no light perception
      underwent pars plana vitrectomy and lamina cribrosa puncture to relieve pain and
      decrease intraocular pressure. The patients presented with blind, painful eyes
      and high intraocular pressure (> 40 mm Hg). After the procedure, the pain was
      relieved and the intraocular pressure was lowered in both cases. The patients
      remained asymptomatic. Pars plana vitrectomy and lamina cribrosa puncture might
      be related to the decrease of intraocular pressure, probably by facilitating
      drainage of aqueous humor through the optic nerve.

PMID- 15185795
TI  - Malignant glaucoma as a complication of Nd:YAG laser posterior capsulotomy.
AB  - A 79-year-old woman with pseudophakia who underwent Nd:YAG posterior capsulotomy
      for posterior capsular opacification in her right eye had increased intraocular
      pressure associated with a flat anterior chamber. Full-thickness patent iridotomy
      performed with an Nd:YAG laser did not reduce the intraocular pressure. B-scan
      ultrasonography showed aqueous pockets in the vitreous, leading to a diagnosis of
      malignant glaucoma. Medical and surgical therapy normalized the intraocular
      pressure and resolved the symptoms of malignant glaucoma.

PMID- 15185796
TI  - Necrotizing scleritis following diode laser transscleral cyclophotocoagulation.
AB  - A 23-year-old Chinese woman presented with necrotizing scleritis 10 months after
      diode laser cyclophotocoagulation for the treatment of her neovascular glaucoma.
      There were areas of scleral thinning with uveal prolapse in the superior
      quadrant. The inflammation and progression of the staphyloma were controlled with
      systemic steroids. Diode laser cyclophotocoagulation may not be safe in patients
      suspected to have underlying systemic vasculitic diseases.

PMID- 15185797
TI  - Post-surgical scleritis associated with the ganciclovir implant.
AB  - Although the ganciclovir implant is an effective and well-tolerated treatment for
      cytomegalovirus retinitis in patients with human immunodeficiency virus
      infection, complications that may occur include retinal detachment, implant
      extrusion, and endophthalmitis. A 22-year-old woman with human immunodeficiency
      virus infection presented with a painful left eye with scleritis overlying
      previous ganciclovir implant sclerotomy sites. The inflammation progressed 360
      degrees around the pars plana with progressive thinning at the implant sites.
      Post-surgical necrotizing scleritis is another complication that can occur in
      patients with ganciclovir implants.

PMID- 15185798
TI  - Walker-Warburg syndrome: congenital neurodysplasia and bilateral retinal folds.
AB  - A 2-month-old girl with a history of congenital hydrocephalus presented due to
      "wandering eyes." Initial eye examination at age 2 months showed response to
      light and a prominent retinal fold that extended through the macula and made
      contact with the posterior and inferior temporal lens capsule in each eye.
      Combined with the patient's neurologic findings, the results of the ocular
      examination led to the diagnosis of Walker-Warburg syndrome. During 5 years of
      follow-up, the patient developed progressive cataracts in both eyes but
      maintained ambulatory vision in the left eye. Walker-Warburg syndrome should be
      included in the differential diagnosis for pediatric patients with a history of
      prominent retinal folds.

PMID- 15185799
TI  - A curved vitrectomy probe.
AB  - A curved vitrectomy probe for better accessibility of the peripheral retina in
      phakic eyes is described. The specially designed curved vitrectomy probe has a 20
      gauge pneumatic cutter. The radius of curvature at the shaft is 19.4 mm and it is
      25 mm long. The ora serrata is accessed through a 3.0- or 4.0-mm sclerotomy in
      phakic eyes without touching the crystalline lens. Use of this instrument avoids
      inadvertent trauma to the clear lens in phakic eyes requiring vitreous base
      excision. This curved vitrectomy instrument complements wide-angle viewing
      systems and endoscopes for safe surgical treatment of peripheral retinal
      pathology in phakic eyes.

PMID- 15185800
TI  - A conjunctival retractor for glaucoma filtering surgery.
AB  - A new conjunctival retractor provides the desired exposure of the scleral bed
      during filtering surgery. It elevates the conjunctiva without causing crush
      injury and allows excellent exposure of the scleral bed with a smaller incision
      than is required when non-toothed forceps or Weck cell sponges are used. The
      surgeon or assistant holding the retractor can move it in various directions to
      provide a good view of any particular site for which exposure is needed.

PMID- 15185801
TI  - Caries control and other variables associated with success of primary molar vital
      pulp therapy.
AB  - PURPOSE: This research evaluated initial treatment of deep dental caries with
      caries control (CC) procedure and the effect of other factors on the success of
      indirect pulp therapy (IPT) and formocresol pulpotomy (FP). METHODS:
      Retrospective chart audits were performed on 226 primary molars with deep caries
      approaching the pulp that were treated using IPT and FP. Mean follow-up was 3.4
      years. CC with glass ionomer cement (GIC) was performed on 50 of the 226 teeth 1
      to 3 months before pulp therapy. RESULTS: IPT therapy was successful 94% of the
      time, whereas FP was successful 70% of the time. The initial use of CC increased
      the IPT/FP success rate to 92% vs a 79% success rate in teeth without CC. Primary
      molar FP success on primary first molars was 61% vs 83% in second molars. IPT
      therapy was successful 92% of the time for first molars vs 98% of the time for
      second molars. Thirty-six percent of the FP-treated teeth exfoliated early vs 2%
      of the IPT-treated teeth. Primary first molars with reversible pulpitis had a
      higher success with IPT (85%) vs FP (53%). The type of final restoration did not
      affect IPT or FP success, except that FPs restored with an immediate IRM
      (Dentsply/Caulk, Milford, Del) restoration decreased success to 39%. CONCLUSIONS:
      IPT for the treatment of deep dental caries lesions produced greater long-term
      success than FP. FP success in primary first molars was lower compared to IPT
      success, especially in teeth with reversible pulpitis. Also FP-treated teeth
      showed significantly earlier exfoliation patterns. The prior treatment of deep
      dental caries lesions with CC procedures improved the subsequent IPT or FP
      success.

PMID- 15185802
TI  - Do pediatric dentists practice the orthodontics they are taught?
AB  - PURPOSE: The purpose of this study was to determine whether the orthodontic
      treatment provided by pediatric dentists reflects the orthodontic training
      received in pediatric dental residency programs. METHODS: Five questions from a
      survey of the American Academy of Pediatric Dentistry (AAPD) diplomates in August
      2002 and a survey of pediatric dental residency program directors in June 2002
      were statistically analyzed to compare the orthodontic treatment provided by
      diplomates to that provided within pediatric dental residency programs. RESULTS:
      Patient populations differed financially between pediatric dental residencies and
      diplomates of the AAPD. Residents treated significantly more public assistance
      patients. The residents were more likely than diplomates to use most orthodontic
      appliances and treat most stages of dental development and most
      conditions/malocclusions with orthodontics. Diplomates anticipated a decrease in
      the amount of orthodontic treatment provided in the next 5 years, while program
      directors anticipated an increase. CONCLUSIONS: The majority of the orthodontic
      treatment provided by pediatric dental residents and diplomates was similar,
      although the residents were exposed to more diverse orthodontic treatment
      modalities than those used by diplomates. The residencies were also more likely
      than the diplomates to increase the amount of orthodontic treatment provided in
      the next 5 years.

PMID- 15185803
TI  - Comparison of powered and manual toothbrushes for plaque removal by 4- to 5-year
      old children.
AB  - PURPOSE: This study compared the small head Oralgiene 60 Second Time Machine
      powered toothbrush, used for 60 seconds, with the Braun Oral-B Mickey Mouse
      powered toothbrush and a manual toothbrush (Oral-B Rugrats 20), each used for 2
      minutes, for efficacy in plaque removal and reduction of gingival inflammation in
      young children. METHODS: Fifty-eight children, ages 4 to 5 years old, were
      randomly assigned to one of the 3 toothbrush groups. At visit 1, plaque and
      gingival indices were recorded for all subjects. Then, the children did not brush
      for 24 hours. At visit 2, 24 hours later, plaque indices were recorded, the
      children brushed with their assigned toothbrush, and plaque indices were recorded
      again. Six weeks later, plaque and gingival indices were recorded again. The data
      was analyzed to detect plaque reduction after a one-time use (visit 2,
      prebrushing and postbrushing) as well as plaque and gingival inflammation
      reduction after 6 weeks of use. RESULTS: The Oralgiene toothbrush removed
      significantly more plaque during the one-time trial and reduced significantly
      more gingival inflammation during the 6-week trial. The Braun Oral B powered
      toothbrush removed significantly more plaque than the other toothbrushes during
      the 6-week trial. However, no clinically meaningful differences were found
      between any of the toothbrushes with regard to plaque removal or gingival scores.
      CONCLUSIONS: There were no clinically meaningful differences found between any of
      the toothbrushes tested during either of the trials with regard to plaque removal
      or improvement in gingival health.

PMID- 15185804
TI  - Microbiological screening for cariogenic bacteria in children 9 to 36 months of
      age.
AB  - PURPOSE: The objective of this study was to evaluate sampling methods for
      recovery of mutans streptococci (MS) and lactobacilli (LB) in children 9 to 36
      months of age. METHODS: Tongue and plaque specimens collected on cotton swabs and
      stimulated saliva were diluted and plated on selective and nonselective media.
      Tongue specimens on a swab and mouth mirror were inoculated directly on selective
      agar media (MS only). Sampling methods were compared by frequency of recovery of
      MS or LB, correlation of microbial counts with dmfs scores, and potential of
      specific microbial counts to predict caries presence or absence. RESULTS: The
      mean dmfs score of 87 subjects was 6.3; 48 subjects were caries free. Levels of
      MS and LB were consistently higher in plaque than in other sampling techniques
      (P<.001), and frequencies of recovery of MS were highest in plaque (P<.041) and
      tongue (P<.006). Frequency of LB recovery did not differ significantly between
      sampling methods. Counts of MS or LB in total subjects and subjects aged 9 to 24
      months correlated positively with dmfs scores (P<.028). Threshold levels of MS
      which were predictive of presence of caries were: (1) plaque=>2x10(5); (2)
      tongue=>10(4); (3) saliva=>10(5); (4) mirror=>50; and (5) swab=>50. Comparable
      levels of LB were: plaque, >10(3); tongue, >10(2) and saliva, >10(3).
      Specificities associated with these predictions were higher than sensitivities
      for all sampling methods. CONCLUSIONS: (1) All sampling methods were adequate for
      microbial risk assessment tests in children under 3 years of age; (2) MS was a
      stronger indicator of caries status than LB.

PMID- 15185805
TI  - Bond strength of a sealant to primary and permanent enamel: phosphoric acid
      versus self-etching adhesive.
AB  - PURPOSE: The objective of this study was to compare the effect of phosphoric acid
      and a self-etching adhesive on the short and long-term bond strength of a light
      curing sealant to unground primary and permanent enamel. METHODS: A light-curing
      resin sealant (Delton Light Curing Pit & Fissure Sealant-CLEAR) was bonded to the
      flattest, peripheral surface of 40 primary and 40 permanent molars following
      conditioning of the cleaned enamel with 38% phosphoric acid or with the self
      etching adhesive Prompt L-Pop (N=10/group). After either 1 week or 1 year in
      water, shear bond strengths were measured. Failure mode was determined in a
      stereo microscope. RESULTS: There was no significant difference in bond strengths
      between the phosphoric acid-etch and the self-etching adhesive groups, nor
      between the 1-week and 1-year results (P>.05). However, the bond strengths to
      primary enamel were lower than those to permanent enamel (P=.0021). The number of
      pure adhesive failures in each of the 8 groups varied between 0 and 3 (0-30%),
      and the remaining teeth displayed mixed adhesive-cohesive failures. CONCLUSIONS:
      The self-etching adhesive studied seems an attractive alternative to the acid
      etch technique for sealant application in young children where simplifications in
      the clinical procedure are warranted.

PMID- 15185806
TI  - Clinical evaluation of a compomer and an amalgam primary teeth class II
      restorations: a 2-year comparative study.
AB  - PURPOSE: This study was performed to compare the clinical performance between the
      compomer F2000 and amalgam Dispersalloy in Class II restorations in primary
      molars over a 2-year period. METHODS: Seventy-five amalgam and 75 compomer
      restorations were placed in 75 children based on a split-mouth design. The
      restorations were evaluated after 1 week and after 6, 12, 18, and 24 months of
      oral function. The evaluation consisted of a clinical assessment according to
      modified Ryge criteria, a radiographic examination using bite-wing radiographs,
      and an observation of epoxy casts under scanning electron microscopy. RESULTS:
      The results showed statistically significant differences in the marginal
      adaptation and anatomic form between amalgam and compomer restorations. A higher
      number of compomer restorations were rated as Bravo, while a higher number of
      amalgam restorations were rated as Alpha at 24 months. Significant differences in
      the failure of the restoration and development of secondary caries were not found
      between the materials. CONCLUSIONS: The use of compomer F2000 in Class II
      resorations in primary molars, although it presents a significantly higher number
      of restorations rated as Bravo regarding the marginal adaptation and anatomic
      form vs the amalgam, does not increase the risks of developing secondary caries
      and failure of the restoration over a period of 2 years.

PMID- 15185807
TI  - Therapeutic protocols for avulsed permanent teeth: review and clinical update.
AB  - Traumatic injuries to permanent teeth include coronal and root fractures,
      subluxations, luxations, and avulsions. The most common complications after
      avulsions are necrosis of the pulp and root resorption. Treatment is often
      complex, time consuming, and expensive and requires multidisciplinary approaches
      such as endodontic and periodontal treatments, surgery, orthodontic movements, as
      well as esthetic coronal restoration. This review describes new clinical
      modalities for the treatment of avulsed teeth and discusses the rationale for
      their use.

PMID- 15185808
TI  - Bispectral Index System (BIS) monitoring reduces time to discharge in children
      requiring intramuscular sedation and general anesthesia for outpatient dental
      rehabilitation.
AB  - PURPOSE: Pediatric patients who receive both intramuscular (i.m.) sedation and
      general anesthesia (GA) for oral rehabilitation occasionally experience prolonged
      sedation and delayed discharge. The Bispectral Index System (BIS) is an EEG
      monitor that measures the level of sedation. The authors compared discharge times
      of patients who had BIS monitoring to those who did not to determine if the use
      of BIS speeded discharge. METHODS: After IRB approval, 20 children were enrolled.
      BIS was monitored continuously from admission until discharge. Each child
      received ketamine, midazolam, and glycopyrrolate i.m. Once sedated, the patient
      was transferred to the operating room, monitored, and i.v. access was
      established. GA proceeded with sevoflurane, rocuronium, and fentanyl. Randomly,
      in half the patients, the anesthesiologist knew and maintained the BIS at GA
      level of sedation by adjusting sevoflurane. In the rest, the anesthesiologist did
      not know BIS. Time from turning of sevoflurane to discharge was noted and
      compared. RESULTS: Patients where the BIS was known and used were discharged 60+/
      13 minutes after the end of GA. Patients where BIS was unknown were discharged
      90+/-11 minutes after the end of GA (P<.001). CONCLUSIONS: Based on the data, the
      authors recommend the use of BIS to facilitate faster discharge of pediatric
      patients who require i.m. sedation and GA for oral rehabilitation.

PMID- 15185809
TI  - Aberrant root formation: review of root genesis and three case reports.
AB  - The mechanism of root formation and tooth eruption is a complex process which is
      not fully understood. Prior to a tooth emerging into the oral cavity, root
      genesis is initiated by derivatives of the enamel organ. The dental follicle
      mediates an eruption pathway allowing for movement of the developing tooth in a
      coronal direction. As the tooth moves towards the oral cavity, root formation
      occurs passively in the resulting space. Failure of the enamel organ and dental
      follicle to properly coordinate may result in complications in the eruption
      process. This clinical report presents 3 cases of isolated, unerupted teeth with
      dysmorphology of the roots. The process of root development and tooth eruption is
      also briefly reviewed.

PMID- 15185810
TI  - Correction of posterior crossbites: diagnosis and treatment.
AB  - The correction of posterior crossbites is more complex than it appears. To
      develop an appropriate treatment plan, it is first necessary to determine if: (1)
      there is a functional jaw shift on closing; (2) the crossbite is unilateral or
      bilateral; (3) it is dental, skeletal, or a combination of both; and (4) it is
      related only to the maxilla or both jaws. Once the problem's apparent cause has
      been defined, it is then necessary to select the appropriate modality of
      treatment, which, in the maxilla, is: (1) usually a removable acrylic-based
      appliance with 1 or more transverse screws; or (2) a fixed Hyrax-type or Hass
      type appliance. In the mandible, if dental expansion is required, the appliances
      most frequently used are the lip bumper or a removable acrylic-based appliance
      with a single screw lingual to the incisors. Once the appliance has been placed,
      it must be determined when adequate expansion has been achieved and how best to
      retain it.

PMID- 15185811
TI  - Multi-colored dual-cured compomer.
AB  - A new polyacid-modified resin-based composite (compomer) restorative material has
      been introduced. Unlike other compomers, this material undergoes both chemical
      polymerization and photocuring hardening reactions. The new compomer is called
      MagicFil, and its chief attraction to children is that it is manufactured in 4
      different colors, all with glitter inclusions.

PMID- 15185812
TI  - Oral manifestations in Ellis-van Creveld syndrome: report of five cases.
AB  - Ellis-van Creveld syndrome, or chondroectodermal dysplasia, is an autosomal
      recessive disorder with characteristic clinical manifestations. Its incidence in
      the general population is low. The oral manifestations of Ellis-van Creveld are
      found in soft tissues and teeth, but the dental literature on the subject is
      scarce. In the last 20 years, 5 cases of Ellis-van Creveld syndrome have been
      followed at the Pediatric Dentistry Service of the Hospital Sant Joan de Deu,
      Barcelona. The present study describes the constant and variable oral findings in
      these patients, which play an important role in the diagnosis criteria for the
      syndrome. The presence of a great variety of oral manifestations such as fusion
      of the upper lip to the gingival margin, presence of multiple frenula, abnormally
      shaped and microdontic teeth, and congenitally missing teeth requires
      multidisciplinary dental treatment, with consideration for the high incidence of
      cardiac defects in these patients.

PMID- 15185813
TI  - Comparison of oral findings in special needs children with and without
      gastrostomy.
AB  - PURPOSE: The objective of this study was to compare aspiration pneumonia (AP)
      associated microflora, calculus, and oral hygiene/care seeking behaviors in
      special health care needs children (SC) with gastrostomy (GT) and without.
      METHODS: Twenty-seven GT SC, ages 3 to 12 years old and matched for age and
      gender with 27 non-GT SC, were examined by 2 trained investigators who recorded
      calculus and gingival inflammation and reconciled differences. Plaque was
      obtained using preweighed dry paper points and saliva sampled using sterile
      pipettes and cultured using standard bioassay procedures in a hospital
      laboratory. Parent/caretakers completed a medical and oral health questionnaire.
      RESULTS: No significant differences were noted for age, gender, weight, primary
      diagnosis, vomiting, constipation, or swallowing disorder, but GT children
      received 4 medications vs 1 for non-GT and were significantly more likely to have
      had AP, need special feeding, and drool (P < or = .05). Oral health measures were
      not significantly different for brushing frequency, dentifrice use, brushing
      problems, frequency of dental care, or gingival inflammation, but GT patients had
      significantly more plaque and calculus. GT patients had significantly more
      Haemophilus influenzae, with trends toward more gram negative enteric rods,
      pseudomonas, and Streptococcus pneumoniae and higher concentrations in several GT
      patients and little or none in non-GT patients. GT SC had significantly less beta
      streptococci than non-GT patients (P < or = .05). CONCLUSIONS: GT SC had
      significantly more of 1 AP-associated organism than non-GT SC and significantly
      more calculus and plaque, in spite of similar care seeking and hygiene behaviors.

PMID- 15185814
TI  - Laparoscopic radical prostatectomy: oncological evaluation in the early phase of
      the learning curve comparing to retropubic approach.
AB  - OBJECTIVES: Radical prostatectomy is actually the gold-standard treatment for
      organ-confined prostate cancer. Since Schuessler et al. performed the first
      laparoscopical radical prostatectomy (LRP) in 1992 this surgical approach for
      prostate cancer treatment has been widely diffused among european urologists. In
      this study we report our initial experience with laparoscopic surgery focusing on
      the oncological assessments and comparing these results to those of the
      retropubic approach. MATERIAL AND METHODS: Between March 2002 and November 2003,
      50 laparoscopic radical prostatectomy were performed at our Institute. We
      reviewed the operative times, intraoperative complications, mean catheterization
      and postoperative hospital stay of these first 50 cases. Moreover during the same
      period a group of 50 consecutive patients underwent retropubic radical
      prostatectomy (RRP) and data were analyzed and compared to laparoscopic issues.
      The laparoscopic approach was performed according to the Montsouris technique.
      Patient age, Gleason score at biopsy, PSA and clinical stage of the two groups
      were compared. Positive margins of the two groups were compared in relation to
      their location and pathological stage. RESULTS: No significative statistical
      differences of age, preoperatory PSA, Gleason score at biopsy and clinical stage
      were observed between the two groups (p > 0.05). Also in post-operative data no
      significative statistical differences regarding the pathological stage (p = 0.54)
      and the Gleason score (p = 0.714) were noted between the two groups. In RRP group
      the pathological stage was pT2 in 28 patients and pT3 in 22 patients; in LRP
      group was pT2 in 31 patients and pT3 in 19 patients. The mean Gleason score
      resulted 6.16 in RRP group and 6.10 in LRP group. The number of positive surgical
      margins was low in both groups and the location was similar in retropubic and
      laparoscopic specimens. We reported 13 positive surgical margins in RRP group and
      12 in LRP (p = 0.8). CONCLUSIONS: Basing on our initial experience with 50
      patients we can affirm that laparoscopic radical prostatectomy can be performed
      with a lower morbidity and oncological results similar to the retropubic approach
      even in the early phase of the learning curve. Our experience could be useful to
      encourage all the urologists approaching laparoscopy.

PMID- 15185815
TI  - Patients with bladder outlet obstruction who refuse treatment show no clinical
      and urodynamic change after long-term follow-up.
AB  - OBJECTIVE: To evaluate in patients with mild bladder outlet obstruction (BOO) who
      refused the proposed treatment and were on watchful waiting (WW), the symptomatic
      and urodynamic changes after 1-5 years of follow-up. METHODS: 102 patients with
      lower urinary tract symptoms (LUTS) and BOO (Schafer class: 2-6, median 3) were
      clinically and urodinamically re-evaluated after 1-5 years of follow-up. Of
      these, 82 were submitted to medical (alfuzosin or finasteride) or surgical
      treatment (prostatectomy or TUIP) and 20, who refused the proposed treatment,
      were on WW. A retrospective study was made on these 20 patients who underwent a
      second International Prostatic Symptom Score and pressure-flow evaluation after 1
      5 years (median: 22 months) of watchful waiting. Wilcoxon matched-pairs signed
      ranks test and Kruskal Wallis as appropriate were used for statistical analysis.
      RESULTS: In the group of patients who refused the proposed treatment, no
      statistically significant differences between the two evaluations were observed
      for any of the parameters investigated: International Prostatic Symptom Score
      (15.1 +/- 6.8; 14.7 +/- 7.5); maximum flow (11.5 +/- 4.2; 12.1 +/- 4.3); residual
      urine (90.2 +/- 154.5; 113.3 +/- 158.4); Schafer class (2.9 +/- 0.9; 2.8 +/-
      1.2); Urethral Resistance Algorithm (37.1 +/- 14.4; 37.3 +/- 16.3); Projected
      Isometric Pressure (113.7 +/- 26.5; 112.7 +/- 21.8). CONCLUSIONS: Patients with
      mild BOO may remain clinically and urodynamically stable for a long time.

PMID- 15185816
TI  - Transurethral resection versus minimally invasive treatments of benign prostatic
      hyperplasia: results of treatments. Our experience.
AB  - OBJECTIVE: In this non-randomized prospective study the results of standard TURP
      (Transurethral Resection of the Prostate) versus other minimally invasive
      treatments were compared. MATERIALS AND METHODS: Among all the patients treated
      at our Institution for bladder outlet obstruction due to BPH (Benign Prostatic
      Hyperplasia) from January 1995 to June 1998, 212 patients have been evaluated; 90
      patients underwent to TURP, 13 patients to TVP (Transurethral
      ElectroVaporization), 24 patients to TUNA (TransUrethral Needle Ablation), 71
      patients to ILC (Interstitial Laser Coagulation), and 13 patients to WIT (Water
      Induced Thermotherapy). RESULTS: TURP achieves the highest decrease of prostate
      volume (48.8%), the best increase of maximum flow rate (75.3%) and the highest
      decrease of residual volume (89.8%) in comparison to other methods; these results
      are substantially stable 24 months after treatment; on the other hand, after WIT
      a reduction of prostatic volume of 5.2%, an increase of maximum flow rate of
      16.7% and a decrease of residual volume of 25.2% can be observed. The relief of
      bladder outlet obstruction is indicated by the decrease of detrusor pressure at
      maximum flow rate in comparison to baseline values; it decreases of 27.5% for
      WIT, of 34.8% for TUNA, of 38.3% for ILC, of 48.4% for TUR, and of 53.3% for T.P
      The recorded results are substantially stable 24 months after treatment. A marked
      decrease of IPSS and QL score can be observed for all the procedures after 6
      months, ranging from 40.2% for WIT to 76.7% for TUNA; however, these parameters
      undergo to a slight worsening 24 months after treatment for TURP, TVP and TUNA,
      while remain substantially stable for ILC and WIT. CONCLUSION: From the analysis
      of our results, it appears that TURP is still the golden standard treatment for
      BPH; TURP remains the most effective and definitive way of treatment, but it
      could be less attractive from the patients' perspective, especially after
      minimally invasive treatments with good tolerability have become available. It is
      therefore evident that the choice of each method should be performed in
      consideration of patients' general performance status, of symptoms and of
      indications and contraindications of each method.

PMID- 15185817
TI  - Uro-gramma: the importance of updating the predictive model.
AB  - OBJECTIVES: Uro-gramma is a probabilistic predictive model of pathological
      staging of prostate cancer (Pca) from preoperative parameters (PSA, clinical Gs,
      clinical stage) published in 2000. Aim of this study is to improve Uro-gramma,
      updating it, to take into account the continuous evolution of the population.
      MATERIALS AND METHODS: From 1998 to 2000, 991 Pca patients have undergone radical
      prostatectomy in several Italian urological centers. Inclusion criteria were:
      preoperative PSA < 50 ng/ml, clinical stage < or = T3c, availability of a bioptic
      Gs and pathological staging. A predictive model has been estimated for each year
      and its behaviour on the following years tested, using Hosmer and Lemeshow tests,
      which compare the expected rate with the observed one. RESULTS: The mean age was
      66.3 years. Pca familiarity was present in 3.2% of the patients in 1998, 2.6% in
      1999 and 7.4% in 2000. PSA values < 10 have increased (from 41% to 47%) and those
      > 10 decreased (from 59% to 53%). The mean number of bioptic samples per patient
      has increased from 4.9 to 6, while clinical and pathologic Gs have remained
      stable. An increase in the rate of organ confined Pca has been noticed, either
      clinically (87.4% in 1998, 92% in 2000) or pathologically (55.2% in '98, 57% in
      2000). Staging lymphadenectomy has been performed in 88% of the pts in 1998,
      94.2% in 1999 and 94.5% in 2000, whereas the % of N+ patients has moved from
      11.3% in 1998 to 9.8% in 2000. CONCLUSIONS: Uro-gramma update results show that
      the mean estimate error has fallen from 6.4% to 1.2%. The new model strengthens
      the previous one and confirms its validity, but it also underlines the need of a
      constant update to take into account the continuous evolution of the population
      and of the methods of diagnosis and staging.

PMID- 15185818
TI  - The influence of Genoa G8 events on people sexuality.
AB  - OBJECTIVES: Aim of the study is to verify if a stress reaction due to G8 meeting,
      held in Genoa on July 2001, can produce a mass stress reaction and influence
      negatively people sexuality and so the birth rate. MATERIALS AND METHODS: 402
      citizens (221 men and 181 women ranging in age from 25 to 52 years, mean 39) have
      been invited to answer two questionnaires concerning their sexual activity and
      their feelings before, during and after the G8 meeting. After 9,10 and 11 months
      we have valued the birth rate in Genoa. RESULTS: 30 people (7%) did not answer
      the two questionnaires. 12 people (3%) answered the questionnaire wrongly and
      were excluded from the study. 228 people (63%) didn't report changes about their
      sexual activity, during G8 meeting. 120 people (33%) reported a decrease of
      sexual intercourses and of sexual desire; 12 people (4%) reported an increase of
      these parameters. 54% of our population reported a definite anxiety. We want to
      emphasize the high number of people that had anxiety even in the group that
      didn't report changes in sexual activity (105/228 = 46%). After 9, 10 and 11
      months we have recorded a significant decrease of the birth rate respectively of
      29%, 23%, 20%. (P < 0.05). CONCLUSIONS: Violent demonstrations during G8 meeting
      have negatively influenced people sexual activity and people behaviour. Besides,
      we have recorded a decrease of birth rate in Genoa, nine, ten and eleven months
      after G8. This decrease rate was respectively 29%-23%-20% as regards the same
      months during the three years before (P < 0.05). We cannot determine the real
      cause of this decrease. Violent G8 demonstrations could be responsible for a
      stress reaction with negative consequences on human reproductive functions.

PMID- 15185819
TI  - Evolution in varicocele sclerosing treatment: the ante/retrograde (A/R) approach.
AB  - OBJECTIVE: To evaluate diagnostic and therapeutic efficacy of simultaneous
      ante/retrograde (A/R), trans-scrotal and trans-brachial approach in sclerotherapy
      of varicocele. MATERIALS AND METHODS: Between June 2000 and June 2002, 99
      patients with varicocele were submitted to simultaneous A/R sclerotherapy of
      internal spermatic venous plexus. All presented grade III left varicocele, 39
      also had right varicocele. Recurrent left varicocele was present in 25 following
      surgical ligations, in 1 following retrograde sclerosis, in 3 following both
      surgical and sclerosing techniques. Simultaneous A/R approach was performed using
      transbrachial percutaneous access for retrograde catheterization which does not
      obstruct trans-scrotal surgical field. The procedure is performed without need
      for general anaesthesia. RESULTS: Sclerotherapy of spermatic veins was always
      completed. At minimum 12 months follow-up (mean 18 months), only 1 failure was
      observed. CONCLUSION: Trans-scrotal access allowed to guide, by means of
      antegrade venography, retrograde selective cannulation of spermatic vein. A/R
      procedure allows a complete diagnostic evaluation of collateral circulation, with
      possibility to occlude all vessels draining varicocele. Results at long-term
      follow-up show very low incidence of recurrence.

PMID- 15185820
TI  - Mucosal fold as a mechanical cause of obstruction in orthotopic ileal neobladder.
AB  - Studer's ortothopic neobladder after radical cistectomy has become a good
      alternative and has improved the patients' quality of life. Voiding dysfunction
      after surgery is one of the possible late complications with incomplete emptying
      of the neobladder and chronical urinary retention. The mechanical obstruction may
      be due to recurrence of the tumor, anterior vaginal wall prolapse,
      urethrointestinal anastomosis stricture, mucose plug, stone and mucosal fold. We
      present a clinical case of voiding dysfunction after radical cystectomy with
      Studer's neobladder. One year after surgery the patient developed obstructive
      symptoms due to a mucosal fold of the neobladder. An endoscopic incision resolved
      the obstructive symptoms.

PMID- 15185821
TI  - Renal metastasis from pancreatic adenocarcinoma.
AB  - The Authors describe a case of a man (68 years) affected by renal metastasis from
      pancreatic adenocarcinoma. Additional metastases had been detected in the liver,
      in the spleen and in the small intestine. The man underwent radical nephrectomy
      (to prevent hematuria), splenectomy and biopsies in liver and small intestine.
      After surgery the patient refused adjuvant chemotherapy.

PMID- 15185822
TI  - Multilocular cystic nephroma in adults.
AB  - Predominantly cystic neoplasms of the kidney may cause diagnostic difficulties.
      We describe a case of cystic nephroma, a rare renal tumour characterized by a
      mixture of epithelial and stromal elements, in an elderly man, uncommonly located
      close to the renal pelvis.

PMID- 15185823
TI  - Parasitic manifestation of testicular pain.
AB  - Genital filariasis is common in endemic areas of the world. However, filariasis
      cannot be eliminated from the differential diagnosis of scrotal swellings, as
      international travel is more frequent. We report a case in a patient in London,
      UK.

PMID- 15185824
TI  - Clinical evaluation of urinary incontinence and pelvic prolapse: ICI flow-chart.
AB  - The 2nd International Consultation on Urinary Incontinence met from July 1-3,
      2001 in Paris, in order to develop recommendations for the diagnostic evaluation
      and treatment of urinary incontinence and pelvic prolapse. Basic tests and
      assessments (patient history, urinary diary, symptom score, quality of life
      impact, physical assessment) are important to depict the type of incontinence.
      Specialized evaluation is necessary in women with complex history, large residual
      urine or prior to invasive treatment. A brief explanation of the recommended
      algorithms is reported.

PMID- 15185826
TI  - ReMeEx device (External Mechanical Regulator) for incontinence: implantation and
      regulation procedure, complications and results at 3 years follow-up.
AB  - A new sling technique that allows a postoperative adjustment of the sling tension
      is presented with encouraging results in the treatment of female stress urinary
      incontinence. The readjustment prevents the need of a reoperation in case of
      relapse with great compliance of the patients. Indications for surgical treatment
      of female stress urinary incontinence by ReMeEx included patients with: fixed
      urethra, urethral hypermobility, intrinsic sphyncteric deficiency and previous
      incontinence surgical interventions. Out of 32 patients treated, 31 were cured
      with transitory urge in 2 and readjustment in 3. In one case the device was
      removed for infection. IN CONCLUSION: the ReMeEx system offers the possibility to
      modify the sling support level whenever needed during patient's life. Wiyh the
      ReMeEx system we can and should improve the outcome of these patients leaving
      them completely dry, without any urine leakage.

PMID- 15185825
TI  - Pubo-vaginal sling.
AB  - The Authors discuss their experience in the use of pubo-vaginal sling in the
      treatment of female urinary stress incontinence. In the last 5 years (1997-2002)
      35 patients with type 3 incontinence underwent pubo-vaginal sling with rectus
      fascia or porcine skin. Healing was obtained in 74.2%, de novo urgency in 5.7%,
      obstruction in 8.5% and persisting incontinence in 11.4% of cases. The
      developments of the technique have recently turned pubo-vaginal sling into a
      minimally invasive procedure with low morbidity. Its indications have therefore
      been extended to the point that it is now considered by many authors as the
      treatment of choice in any type of incontinence, whether associated with genital
      prolapse or not.

PMID- 15185827
TI  - Family functioning in adolescent anorexia nervosa: a comparison of family
      members' perceptions.
AB  - Abnormal patterns of family functioning have often been reported in anorexia
      nervosa. Moreover, members of families with an adult with eating disorders have
      different family functioning perspectives. This study investigated whether
      differences in family members' perspectives, similar to the ones found in
      families of adults with eating disorders, can be found in families of adolescents
      with anorexia nervosa. Perceived family functioning, measured with the Family
      Assessment Device, was compared between 49 control and 34 clinical families, and
      across family members. Differences were found between the two groups on a number
      of aspects of family functioning, with the clinical families showing most
      disturbances. There was a general agreement across family members in their
      perceptions of family functioning, with one notable exception. Clinical daughters
      disagreed with both their parents about the family level of communication,
      whereas control daughters disagreed only with their fathers. Disagreements
      between clinical adolescents and their mothers about the family communication
      style appear to be important in anorexia nervosa in this age group, although it
      is not possible to reach conclusions about the direction of causality. These
      findings support the use of family-oriented therapies that aim to identify and
      work with difficulties in communication within the family.

PMID- 15185828
TI  - Antecedents and consequences of binge eating episodes in women with an eating
      disorder.
AB  - The aim of this study was to explore antecedents and sequelae of binge eating
      episodes. A sample of eating disorders (n = 154 women) was selected from a total
      of 1849 female respondents (out of 2500) recruited as part of a general
      population-based survey. Included participants met DSM-III-R criteria for
      anorexia nervosa (AN), bulimia nervosa (BN) or eating disorder not otherwise
      specified (EDNOS) based on the Survey for Eating Disorders (SEDs). Preliminary
      criteria for binge eating disorder (BED) were added. Results indicated that the
      most frequently reported antecedents and consequences of binge eating were
      emotional and physiological factors. There were significant differences between
      the different ED subgroups in their frequency of binge eating episodes. Regarding
      antecedents of a binge eating episode, the SEDs-defined ED subgroups had overall
      differences in frequency on "stomach feeling". In particular, the BN-group
      reported "euphoria" more frequently than the BED and EDNOS-groups. Concerning
      consequences of a binge eating episode, there were overall differences between
      the ED subgroups on "fall asleep", and in addition a borderline significance was
      found for "disturbed by others" (p = 0.059). None of the eight women in the AN
      group reported "euphoria" as a factor that terminated a binge eating episode. The
      findings may have important implications with regard to prevention and treatment
      of ED.

PMID- 15185830
TI  - Digital photography: a new method for estimating food intake in cafeteria
      settings.
AB  - OBJECTIVE: The primary objective of this study was to test the comparability of
      digital photography and visual estimation procedures for estimating food intake.
      RESEARCH METHODS AND PROCEDURES: The study sample included 71 breakfast meals and
      59 lunch meals eaten in a university cafeteria during a single day. A total of 66
      different foods were employed as test foods that could be selected by the
      students. Food selections and plate waste, as estimated by digital photography
      and visual estimation, were compared. For digital photography, three observers
      independently estimated portion sizes of each food item based upon digital
      photographs. One observer estimated portion sizes in the cafeteria setting, using
      visual estimation, a method that has been validated in other studies. RESULTS: To
      test the accuracy of the two procedures for measuring food intake, the estimates
      of food weights derived from both procedures were compared using Bland-Altman
      regression. In comparison to visual estimation, the digital photography method
      yielded comparable estimates of food selections, plate waste, and total food
      intake for seven of nine comparisons. The two methods of estimating food portions
      yielded comparable results for most (78%) types of foods. The two methods also
      yielded similar variability. DISCUSSION: These findings suggest that the digital
      photography method is an alternative to the traditional method of estimating food
      intake via direct observation.

PMID- 15185829
TI  - Eating attitudes across age and gender groups: a Canadian study.
AB  - OBJECTIVE: The purpose was to examine the eating attitudes across gender and age
      groups. METHOD: The study included 343 individuals over 18 years of age (range:
      18 to 94 years; mean 48 +/- 22), who were divided into 3 age categories: 18 to 34
      years, 35 to 64 years and 65 years and above with a distribution of 35% (119),
      37% (128) and 28% (97) respectively. The participants completed a background
      questionnaire and the Eating Attitudes Test (EAT-26). RESULTS: A total of 30
      participants (8.7%) scored above the cut-off point on the EAT-26 which is
      indicative of potential eating disturbances. Only statistically significant
      gender differences were observed in the total EAT-26 scores. Factor analysis
      revealed three subscales of EAT-26, food preoccupation, image preoccupation, and
      external focus or social pressure, with acceptable level of reliability and these
      were used for age and gender comparison. Age and gender differences were observed
      in the food and image preoccupation subscales only. DISCUSSION: Although EAT-26
      is widely used in clinical and non-clinical population, age and gender
      comparisons have not been made in a population-based sample. Use of the subscales
      of eating attitudes should help health professionals better identify those at
      risk for eating disturbances and provide the opportunity for intervention.

PMID- 15185831
TI  - New interdisciplinary cognitive-behavioural-nutritional approach to obesity
      treatment: a 5-year follow-up study.
AB  - OBJECTIVE: The aim of this prospective case-control study was to assess the long
      term effectiveness of interdisciplinary cognitive-behavioural-nutritional
      therapy, combined with daily physical exercise and relaxation sessions, on weight
      and psychosocial issues during a 6-week in-hospital stay. SETTING: Five years (60
      +/- 1 months) later, the patients were readmitted for a one-day medical
      evaluation including a physical examination and laboratory work-up, and the
      completion of a detailed questionnaire focusing on dietary and psychosocial
      factors that may affect weight loss/regain. SUBJECTS: The follow-up population
      consisted of 55 morbidly obese subjects aged 49.5 +/- 2 years (45 females and 10
      males; BMI: 40 +/- 0.7 kg/m2). During their initial 6-week in-hospital stay, they
      lost an average of 7.6 +/- 0.4 kg. RESULTS: Five years later, 25.5% of the
      patients had lost a further 11.9 +/- 1.8 kg, 20% maintained their initial weight
      loss (0.6 +/- 0.4 kg), and 54.5% regained weight (10.4 +/- 1 kg). The weight
      changes significant correlated with the degree of psychosocial difficulties (p <
      0.001), eating behaviour problems (p < 0.001), dietary fat intake (p < 0.005) and
      total energy intake (p < 0.05). Fasting plasma insulin and blood glucose
      concentrations were significantly higher in the patients who regained weight
      after five years, and significantly lower in those who had lost more weight.
      CONCLUSION: As a whole, these results show the efficacy of an interdisciplinary
      approach to the long-term treatment of morbidly obese patients. It is likely that
      an outpatient psychological follow-up would have improved this therapeutic
      success.

PMID- 15185832
TI  - Degree of body weight in obesity and Rorschach personality aspects of mental
      distress.
AB  - OBJECTIVE: To study the relationship between degree of obesity and personality
      measures of mental distress. METHOD: The Rorschach method (Comprehensive System)
      and the Beck Depression Inventory. General descriptors were also included.
      Participants were 120 obese patients with a mean body mass index (BMI) of 41 (+/-
      SD 6) kg/m2. RESULTS: Depression, stress or psychopathology such as distortions
      in perception and cognitions were not related to the degree of obesity. Body
      concern and body-related anxiety (An+Xy) were more common in relatively lower
      degrees of obesity. According to general descriptors heavier patients had lower
      educational and socio-economic level, and more bodily pain problems. DISCUSSION:
      Depression was not related to body weight, in spite of findings of more
      depression in obesity compared to normal weights. Other factors than severity of
      obesity would account for the mental distress in obese patients. The differences
      in body concern and anxiety in varying degrees of obesity could be related to the
      social and educational context, where attitudes toward obesity differ. Less
      Rorschach signs of body concern in the morbidly obese contrasted with more self
      reported bodily pain problems.

PMID- 15185833
TI  - Predictive factors of binge eating disorder in women searching to lose weight.
AB  - METHODS: The aim of this study was to detect predictive factors of binge eating
      disorder (BED) in an out-patient obesity clinic. Eating behaviour, weight history
      and body composition were assessed in 138 consecutive patients. BED was diagnosed
      according to the criteria of appendix B of the Diagnostic and Statistical Manual
      of Mental Disorders. RESULTS: The body mass index (BMI; p < 0.005) and the waist
      circumference (p < 0.05) were significantly higher in binge patients than in
      patients without eating disorders. Similar differences were observed between
      patients who regularly went through weight loss programmes and patients who
      consulted for the first time. The prevalence of BED increases with the degree of
      obesity and especially with the number of previous intentional weight loss
      programmes. A positive and significant correlation was found between the weight
      cycling syndrome and BMI (p < 0.0001), waist circumference (p < 0.0001) and body
      fat (p < 0.001). DISCUSSION: The patients with BED present a specific
      anthropometric profile and a typical behavioural pattern characterized by a
      higher degree of central obesity and a weight history with a higher number of
      attempts of weight loss.

PMID- 15185834
TI  - Unreported sauna use in anorexia nervosa: evidence from the world-wide-web.
AB  - Weight loss methods employed in anorexia nervosa (AN) are vomiting, laxatives,
      diuretics, enemas, suppositories, ipecac, weight loss medications and inadequate
      insulin in diabetics. Some methods result in weight loss from fluid depletion and
      not a reduction in body fat. Sauna use causes rapid fluid loss, but has not been
      reported in the medical literature as a weight loss strategy used in AN. We found
      reports of sauna use in AN on the world-wide-web are rare. We hypothesize that
      the warming caused by the use of sauna, may result in physical improvement in AN
      and thereby reduce its acceptability as a weight loss strategy.

PMID- 15185835
TI  - The Sociocultural Internalization of Appearance Questionnaire - Adolescents (SIAQ
      A): psychometric analysis and normative data for three countries.
AB  - A brief measure of internalization of societal norms regarding appearance was
      developed and validated on six early adolescent female samples (mean ages 11.7
      13.3) from three countries (US, Australia, India; total n = 2210). Internal
      consistency levels were uniformly high in all samples, ranging from 0.83 to 0.92.
      Convergent validity estimates were high in all samples. Level of internalization
      was significantly positively correlated with levels of body dissatisfaction and
      restriction for all samples. Internalization was also significantly positively
      correlated with bulimic behaviors and negatively correlated with levels of self
      esteem for the four samples that included these variables. The findings indicate
      that the Sociocultural Internalization of Appearance Questionnaire - Adolescents
      (SIAQ-A) may be used to further explore a media influence cross-culturally,
      allowing for the investigation of the role of internalization as a potential risk
      factor for body image problems and eating disturbances in different contexts.

PMID- 15185836
TI  - Short-term follow-up of adults with long standing anorexia nervosa or non
      specified eating disorder after inpatient treatment.
AB  - OBJECTIVE: There are few follow-up studies on outcome for patients with long
      standing anorexia nervosa (AN) or non-specified eating disorder with several
      comorbid psychiatric disorders. Inpatient treatment is one option for these
      patients. The aim of this prospective study was to report one-year follow-up for
      a consecutive sample of these patients after an inpatient treatment program.
      METHOD: All 24 patients with a mean age of 28 years and mean duration of an
      eating disorder of 11 years were treated in a 23-week inpatient group treatment
      program for AN. Patients were assessed using Eating Disorder Examination
      interview (EDE), Eating Disorder Inventory (EDI) and Symptom Check List (SCL-90
      R) at pre-treatment, post-treatment and at one year after start of treatment. At
      the follow-up 24 patients were personally interviewed. On admission 12 (50%) had
      AN, 8 (33%) non-specified eating disorder (EDNOS) and 4 (17%) bulimia nervosa
      (BN). All had previously suffered from AN and were clinically evaluated to have
      mostly anorectic psychopathology. RESULTS: Ten (42%) patients had improved at
      follow-up and 14 (58%) had a poor outcome. There was a moderate but significant
      improvement on the EDE, EDI and GSI from pre-treatment to follow-up. The
      improvement occurred during inpatient treatment, and no significant differences
      from post-treatment to follow-up were found. Patients with low weight on
      admission showed a significant mean weight increase of about 4 kg at the follow
      up. CONCLUSIONS: At one-year follow-up there was a moderate reduction of eating
      disorder symptoms and general psychiatric symptoms for patients with long
      standing anorexic symptoms. The improvement occurred during inpatient treatment.
      Inpatient treatment may be a treatment option in long-time rehabilitation for
      some of these patients.

PMID- 15185837
TI  - Cognitive-behavioural guided self-help for obesity: a preliminary research.
AB  - This study examined the effectiveness of the manual for obesity Perdere peso
      senza perdere la testa (Losing weight without losing your mind) used in form of
      guided self-help on 161 patients. Three levels of treatments were compared: (a)
      guided self-help treatment (GSH); (b) minimal guided self-help treatment (M-GSH);
      (c) control condition (CC). At the end of the treatment, a significant reduction
      in body weight was observed in GSH and M-GSH, but not in the CC. At six-month
      follow-up 32.7% of GSH subjects and 15.1% of M-GSH subjects were able to maintain
      at least a 5% weight loss. The findings show that GSH is more effective than M
      GSH in determining a significant short-term reduction of body weight.

PMID- 15185838
TI  - Microstructure of sleep in eating disorders: preliminary results.
AB  - Attempts to analyse the sleep structure of patients with eating disorders have so
      far led to conflicting results. Polygraphic findings suggest that patients with
      bulimia nervosa are not easily distinguishable from age-matched controls, whereas
      anorexic patients show some abnormalities in sleep efficiency and sleep
      architecture. Nevertheless, both bulimic and anorexic patients complain of poor
      quality sleep. The aim of this study was to evaluate the microstructure of sleep
      in anorexia and bulimia by analysing arousal (following the rules of the American
      Sleep Disorders Association) and the cyclic alternating pattern (CAP). The
      results confirmed the presence of sleep disturbances in eating disordered
      patients: an increase in arousal length and the CAP rate. They also seem to
      confirm the findings of previous studies suggesting that altered sleep in eating
      disordered patients may be related to their body mass index (BMI) and
      psychopathological status.

PMID- 15185839
TI  - Flavonoids from Radix Scutellariae as potential stroke therapeutic agents by
      targeting the second postsynaptic density 95 (PSD-95)/disc large/zonula occludens
      1 (PDZ) domain of PSD-95.
AB  - Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and subsequent
      production of nitric oxide by neuronal nitric oxide synthase (nNOS) contribute to
      neuronal damage resulting from hypoxic and ischemic insults. NMDARs and nNOS are
      coupled together at the postsynaptic membrane through their interaction with
      postsynaptic density protein (PSD) 95 via PSD-95/disc large/zonula occludens-1
      (PDZ) domains. We used NMR (nuclear magnetic resonance) spectroscopy to screen
      medicinal herbs used in traditional Chinese medicine (TCM) stroke therapy for
      compounds binding to the second PDZ domain (PDZ2) of PSD-95, the domain linking
      nNOS and PSD-95. Aqueous extract of Huangqin, the root of Scutellaria baicalensis
      Georgi (Labiatae), showed significant binding to PDZ2 of PSD-95. The binding site
      of the active components in the extract overlapped with the nNOS/NR2B-binding
      pocket of PDZ2 of PSD-95. Four flavones, baicalin, norwogonoside, oroxylin A
      glucuronide (oroxyloside), and wogonoside were isolated and found to account for
      the PDZ-binding activity of the extract. NMR titration experiments showed that
      baicalin and norwogonoside displayed the highest PDZ2 binding affinity, while
      oroxylin A-glucuronide and wogonoside showed 4-5 fold less potency in binding to
      the PDZ domain. Identification of the PDZ binding activity of these compounds
      will allow investigating whether or not it contributes to the observed clinical
      effects of Radix Scutellariae. Furthermore, these molecules might provide leads
      for the development of drugs targeting the signaling pathways mediated by PDZ
      domains.

PMID- 15185840
TI  - Effects of kava (Kava-kava, 'Awa, Yaqona, Piper methysticum) on c-DNA-expressed
      cytochrome P450 enzymes and human cryopreserved hepatocytes.
AB  - The effects of the herbal product kava (Kava kava, 'Awa, Yaqona, Piper
      methysticum) on human P450 isoforms were studied in vitro using both cDNA
      expressed human enzymes and cryopreserved human hepatocytes. Increasing
      concentrations of an ethanolic extract of dried kava root and three purified kava
      lactones (methysticin, desmethoxyyangonin, and yangonin) were tested for their
      ability to inhibit the catalytic activity of a panel of P450 isoforms (1A2, 2A6,
      2C9, C2C19, 2D6, 2E1, and 3A4) present as c-DNA expressed-enzymes and in
      previously cryopreserved human hepatocytes. In addition, the test compounds'
      effect on hepatocyte viability was evaluated by measuring cellular ATP content.
      In both models, the kava extract and the three kava lactones were found to be
      potent inhibitors of CYPs 1A2, 2C9, 2C19, 2E1, and 3A4 with IC50 values of
      approximately 10 microM. The test compounds were also moderately cytotoxic to
      human hepatocytes (EC50 values of approximately 50 microM). Methysticin was the
      most potent enzyme inhibitor as well as the most cytotoxic, followed by (in order
      of potency:) the kava root extract, desmethoxyyangonin, and yangonin. Our results
      suggest that the drug interaction and hepatotoxic potential of kava should be
      further investigated.

PMID- 15185841
TI  - Involvement of NF-kappaB and c-myc signaling pathways in the apoptosis of HL-60
      cells induced by alkaloids of Tripterygium hypoglaucum (levl.) Hutch.
AB  - Tripterygium hypoglaucum (levl.) Hutch (Celastraceae) (THH) root is a Chinese
      medicinal herb commonly used for treating autoimmune diseases. In the present
      study, alkaloids of THH were prepared and their cytotoxicity against the HL-60
      cell was investigated. THH-induced apoptosis was observed using flow cytometry,
      confocal fluorescence microscope, and DNA laddering and caspase assays. The
      molecular mechanism involved in the induction of HL-60 cell apoptosis by THH
      alkaloids was examined using cDNA microarrays containing 3000 human genes derived
      from a leukocyte cDNA library. Sixteen genes were identified to be differentially
      expressed in HL-60 cells upon THH treatment. Several genes related to the NF
      kappaB signaling pathway and cell apoptosis (such as NFKBIB, PRG1 and B2M) were
      up-regulated. In addition, c-myc binding protein and apoptosis-related cysteine
      proteases caspase-3 and caspase-8 were also regulated. The changes in c-Myc RNA
      expression and c-myc protein level were further confirmed by RT-PCR and Western
      blot analysis. The results demonstrated that THH alkaloids induced apoptosis of
      HL-60 cells though c-myc and NF-kappaB signaling pathways.

PMID- 15185842
TI  - Soy isoflavones prevent the ovarian hormone deficiency-associated rise in
      leukocytes in rats.
AB  - Recent reports indicate that ovariectomy (ovx) increases lymphopoiesis.
      Ipriflavone, a synthetic isoflavone, has been reported to reduce lymphocytes in
      postmenopausal women. The aim of this study was to investigate whether naturally
      occurring isoflavones also affect lymphopoiesis in ovarian hormone deficiency.
      The present study was carried out using an ovariectomized (ovx) rat model. To
      mimic early menopause, forty-eight 12-month-old Sprague-Dawley rats were either
      sham-operated (sham; 1 group) or ovx (3 groups) and were fed a standard semi
      purified diet for 120 days. Thereafter, the ovx groups received one of the three
      doses of isoflavones: 0 (ovx), 500 (ISO500), or 1000 (ISO1000) mg/kg diet for 100
      days. Ovariectomy increased total leukocyte counts significantly (p < 0.05) as a
      result of increased (p < 0.05) lymphocyte, monocyte, eosinophil, and basophil
      differential counts. Isoflavones at 500 and 1000 mg/kg diet returned the total
      leukocyte counts, as well as leukocyte subpopulations, to levels comparable to
      that of sham-operated rats. No other hematological parameters, e.g., red blood
      cell counts or red cell indices, were affected by ovariectomy or isoflavones. We
      conclude that soy isoflavones restore normal leukocyte counts elevated in ovarian
      hormone deficiency.

PMID- 15185843
TI  - Protective role of Apigenin on the status of lipid peroxidation and antioxidant
      defense against hepatocarcinogenesis in Wistar albino rats.
AB  - Apigenin, a dietary plant derived flavone subclass of flavonoid is expected to
      play a role in cancer chemoprevention and cancer chemotherapy. Here we designed
      our experiment to establish whether treatment of apigenin (25 mg/kg body weight)
      for 14 consecutive days to (N-nitrosodiethylamine) DEN induced (200 mg/kg body
      weight; by single ip. injection) and phenobarbital promoted (0.05% through
      drinking water for 14 successive weeks) rats provide protection against the
      oxidative stress caused by the carcinogen. The level of lipid peroxidation (LPO)
      markedly increased in carcinogen administered animals, which was brought back to
      near normal by apigenin treatment. In contrast the activities/levels of the
      antioxidant status both in liver and kidney were decreased in carcinogen
      administered animals, which was recouped back to near normal upon apigenin
      administration. From our findings we concluded that apigenin prevents LPO and
      protects antioxidant system in DEN induced and phenobarbital promoted
      hepatocellular carcinogenesis.

PMID- 15185845
TI  - Evaluation of antipyretic potential of Clitoria ternatea L. extract in rats.
AB  - The methanol extract of Clitoria ternatea L. root (MECTR) blue flowered variety
      (Family: Fabaceae), was evaluated for its anti-pyretic potential on normal body
      temperature and yeast-induced pyrexia in albino rats. Yeast suspension (10 ml/kg
      body wt.) increased rectal temperature after 19 hours of subcutaneous injection.
      The extract, at doses of 200, 300 and 400 mg/kg body wt., p.o., produced
      significant reduction in normal body temperature and yeast-provoked elevated
      temperature in a dose-dependent manner. The effect extended up to 5 hours after
      the drug administration. The anti-pyretic effect of the extract was comparable to
      that of paracetamol (150 mg/kg body wt., p.o.), a standard anti-pyretic agent.

PMID- 15185844
TI  - Analgesic and anti-inflammatory activities of a fraction rich in oncocalyxone A
      isolated from Auxemma oncocalyx.
AB  - In the present work we studied the antinociceptive and antiedematogenic effects
      of a quinone fraction (QF) isolated from the heartwood of Auxemma oncocalyx Taub.
      The major constituent of QF, which represented around 80% of this fraction, was a
      terpenoid quinone named oncocalyxone A (1). Results show that QF (10 and 30 mg/kg
      body wt., i.p.) significantly inhibited paw edema induced by carrageenan at the
      second, third, and fourth hours. The effect was dose-dependent and long lasting,
      and QF was less effective orally. An antiedematogenic effect was also
      demonstrated in the dextran-induced paw edema. In this model, however, QF was
      somewhat less potent. QF (1 and 5 mg/kg body wt., i.p.) inhibited acetic acid
      induced abdominal contractions in mice in a dose-dependent manner. In addition,
      QF (5 and 10 mg/kg body wt., i.p.) inhibited only the second phase (inflammatory)
      in the formalin test, and showed no effect in the hot-plate test in mice. The
      antinociceptive activity of QF was predominantly peripheral and independent of
      the opioid system. The observed effects of QF are, at least in part, probably due
      to the presence of oncocalyxone A (1).

PMID- 15185846
TI  - Effect of Calotropis procera latex on isoproterenol induced myocardial infarction
      in albino rats.
AB  - The alcoholic extract of the latex obtained from Calotropis procera
      (Asclepidaceae) was evaluated for protection against isoproterenol (20 mg/100 g
      body wt., s.c.)-induced myocardial infarction in albino rats. The heart damage
      induced by isoproterenol was indicated by elevated levels of the marker enzymes
      such as Creatine Kinase-isoenzyme (CK-MB), Lactate dehydrogenase (LDH), Serum
      Glutamate Oxaloacetic Transaminase (SGOT) and Serum Glutamate Pyruvate
      Transaminase (SGPT) in serum with increased lipid peroxide and reduced
      glutathione content in heart homogenates. Microscopical examination
      (histopathology) was also performed on the myocardial tissue. Pretreatment with
      an ethanolic latex extract of Calotropis procera at a dose of 300 mg/kg body wt.,
      administered orally thrice a day for 30 days, reduced significantly (p < 0.01)
      the elevated marker enzyme levels in serum and heart homogenates in isoproterenol
      induced myocardial infarction. Histopathological observation revealed a marked
      protection by the extract in myocardial necrotic damage.

PMID- 15185847
TI  - Antibacterial properties of a new isoflavonoid from Erythrina poeppigiana against
      methicillin-resistant Staphylococcus aureus.
AB  - A new isoflavonoid, together with four known isoflavonoids, was isolated from the
      roots of Erythrina poeppigiana. The chemical structure was determined by
      extensive spectroscopic studies, and then its antibacterial activity against
      methicillin-resistant Staphylococcus aureus (MRSA) was investigated. The new
      isoflavonoid was identified as 3,9-dihyroxy-10-gamma,gamma-dimethylallyl-6a,11a
      dehydropterocarpan (compound 1). Compound 1 inhibited bacterial growth most
      potently of the five isolates, and had a minimum inhibitory concentration (MIC)
      of 125 microg/ml against thirteen MRSA strains. Inhibitory activity was based on
      bactericidal action and viable cell number reduced by approximately 1/10,000
      after 4 h incubation with compound 1. Despite intense bactericidal action against
      MRSA, compound 1 never resulted in leakage of 260 nm-absorbing substances from
      bacterial cells. Compound 1 (12.5 microg/ml) completely inhibited incorporation
      of radio-labeled thymidine, uridine and leucine into MRSA cells. Although glucose
      incorporation was also markedly inhibited by the compound, the amount of glucose
      incorporated by bacterial cells increased gradually with incubation time. These
      findings suggest that compound 1 exhibits anti-MRSA activity by interfering with
      incorporation of metabolites and nutrients into bacterial cells or by affecting
      the nucleic acids of MRSA cells. Furthermore, this new compound could be a potent
      phytotherapeutic agent for treating MRSA infections.

PMID- 15185848
TI  - Studies on medicinal plants of Ivory Coast: investigation of Sida acuta for in
      vitro antiplasmodial activities and identification of an active constituent.
AB  - Sida acuta Burm. (Malvaceae) originating from Ivory Coast was selected after an
      ethnobotanical survey: traditional healers of malaria commonly used this plant
      for the treatment. Extracts were tested on two strains of Plasmodium falciparum:
      FcM29-Cameroon (chloroquine-resistant strain) and a Nigerian chloroquine
      sensitive strain. Extracts were obtained by preparing decoction in water of the
      powdered plant, the technique used by most of the traditional healers. An ethanol
      extract was then made and tested. The IC50 values obtained for these extracts
      ranged from 3.9 to -5.4 microg/ml. Purification of this active fraction led to
      the identification of cryptolepine as the active antiplasmodial constituent of
      the plant.

PMID- 15185849
TI  - A 13-week subchronic intravaginal toxicity study of pokeweed antiviral protein in
      mice.
AB  - Pokeweed antiviral protein (PAP), a 29-kDa plant-derived protein isolated from
      Phytolacca americana, is a broad-spectrum antiviral agent. PAP shows unique
      clinical potential to become the active ingredient of a non-spermicidal
      microbicide because of its potent in vivo anti-HIV activity, non-interference
      with in vivo sperm functions, and lack of cytotoxicity to genital tract
      epithelial cells. Over 13 weeks the subchronic and reproductive toxicity
      potential of an intravaginally administered gel formulation of PAP was studied in
      mice to support its further development as a vaginal microbicide. Female B6C3F1
      and CD-1 mice in subgroups of 20, were exposed intravaginally to a gel
      formulation containing 0, 0.025, 0.05, or 0.1% PAP, 5 days/week for 13
      consecutive weeks. On a molar basis, these concentrations are 500- to 2000-times
      higher than the in vitro anti-HIV IC50 value. After 13 weeks of intravaginal
      treatment, B6C3F1 mice were evaluated for survival, body weight gain, and
      absolute and relative organ weights. Blood was analyzed for hematology and
      clinical chemistry profiles. Microscopic examination was performed on hematoxylin
      and eosin-stained tissue sections from each study animal. Placebo-control and PAP
      dosed female CD-1 mice were mated with untreated males in order to evaluate if
      PAP has any deleterious effects on reproductive performance. There were no
      treatment-related mortalities. Mean body weight gain was not reduced by PAP
      treatment during the dosing period. The hemogram and blood chemistry profiles
      revealed lack of systemic toxicity following daily intravaginal instillation of
      PAP for 13 weeks. No clinically significant changes in absolute and relative
      organ weights were noted in the PAP dose groups. Extensive histopathological
      examination of tissues showed no increase in treatment-related microscopic
      lesions in any of the three PAP dose groups. Repeated intravaginal exposure of CD
      1 mice to increasing concentrations of PAP for 13 weeks showed no adverse effect
      on their subsequent reproductive capability (100% fertile), neonatal survival
      (>90%) or pup development. Collectively, these findings demonstrate that
      repetitive intravaginal administration of PAP at concentrations as high as 2000
      times its in vitro anti-HIV IC50 value was not associated with local or systemic
      toxicity and did not adversely affect the reproductive performance of mice. PAP
      may be useful as an active ingredient of a safe vaginal microbicide for
      prevention of the sexual transmission of viruses, particularly of HIV-1.

PMID- 15185850
TI  - Is Berlina grandiflora (Leguminosae) toxic in rats?
AB  - The toxicity profile of the aqueous methanolic extract of Berlina grandiflora
      (BG) stem bark was studied in rats. The rats were administered graded doses (125
      500 mg/kg p.o) of the extract daily for 21 days and the effects on body weight,
      organ weight, clinical signs, gross pathology, hematology, histology and serum
      biochemical parameters were measured. The relative weights of the heart, liver,
      kidneys and lungs of treated rats were unaffected but there were significant
      changes in the relative weights of the spleen and testes. The packed cell volume
      and hemoglobin concentrations were slightly reduced whereas total leucocytes
      counts were increased remarkably. Alkaline phosphatase and Creatine Kinase levels
      were reduced in all the groups but Glutamate oxaloacetate was significantly
      elevated. Total proteins and albumin levels remained normal. BG elicited a
      significant increase in gamma glutamyl transferase concentrations at 250 mg/kg.
      No significant changes occurred in urea, uric acid and BUN concentrations but
      calcium levels shot up remarkably. Histological findings did not reveal any
      treatment-related effects. The acute toxicity LD50 was estimated to be >2000
      mg/kg but dose-related mortality rates of 16.7, 33.4 and 50% were observed during
      the sub-acute toxicity studies. These findings have once more highlighted the
      limitations of acute toxicity LD50 testing and suggest that BG may exert varied
      toxicological effects when administered orally in rats.

PMID- 15185851
TI  - Preliminary immunomodulatory activities of methanol extracts of Eclipta alba and
      Centella asiatica.
AB  - An attempt has been made to assess the immunomodulatory activity of methanol
      extracts of whole plant of E. alba (1.6% wedelolactone) and C. asiatica (0.18% of
      asiaticoside) at five dose levels (dose-response relationship) ranging from 100
      to 500 mg/kg body wt. using carbon clearance, antibody titer and cyclophosphamide
      immunosuppression parameters. In the case of E. alba, the phagocytic index and
      antibody titer increased significantly and the F ratios of the phagocytic index
      and WBC count were also significant. Regression analysis showed linearity in
      patterns of the dose-response relationship, greatest in the case of the
      phagocytic index, moderate in the WBC count and lowest in the antibody titer. For
      C. asiatica, significant increases in the phagocytic index and total WBC count
      were observed and the F ratio of the phagocytic index was also significant.
      Regressed values revealed maximum linearity in the case of the phagocytic index,
      moderate linearity in the total WBC count and lowest linearity in the antibody
      response.

PMID- 15185852
TI  - Flavonoids from Achyrocline satureioides with relaxant effects on the smooth
      muscle of Guinea pig corpus cavernosum.
AB  - Ethanol extract of the aerial parts of Achyrocline satureioides (Lam.) DC.
      (Asteraceae) showed a significant, dose dependent, relaxant effect on the smooth
      muscle of corpus cavernosum strips, obtained from Guinea pig (65.5 +/- 4.1% of
      relaxation at the dose of 25.0 mg/ml). Bioassay guided fractionation of this
      extract furnished two flavonoids, quercetin and quercetin 3-methyl ether, with
      important vasorelaxing effects on the corpus cavernosum strips (79.8 +/- 8.4 and
      66.0 +/- 4.8% of relaxation respectively at the dose of 0.075 mg/ml). Two methyl
      derivatives of quercetin obtained by synthesis, quercetin 3,7,3',4'
      tetramethylether and quercetin 3,5,7,3',4'-pentamethylether, showed similar
      relaxant effects at the dose of 0.075 mg/ml (86.4 +/- 8.5 and 67.31 +/- 1.4% of
      relaxation respectively). The results show that the ethanol extract of A.
      satureioides and the assayed compounds exhibit significant vasorelaxing
      properties. Additionally, it is shown that the number of methyl groups in the
      quercetin nucleus has no significant influence on the effectiveness of these
      compounds.

PMID- 15185853
TI  - Quantification the bioactivity of plant extracts during screening and bioassay
      guided fractionation.

PMID- 15185854
TI  - Adult celiac disease and the severe "flat" small bowel biopsy lesion.
AB  - Classification of architectural changes in the small intestinal biopsy may be
      clinically useful to define the cause of diarrhea or suspected malabsorption,
      especially in adults. Pathologic changes may include severe (flat) or variably
      severe (mild or moderate) abnormalities. For some disorders, small bowel biopsy
      findings may be very distinctive and lead to a specific diagnosis. For others,
      like adult celiac disease, biopsy changes are less specific. Indeed, it is
      becoming increasingly appreciated that several conditions can produce similar
      histopathologic changes. Serological assays, including endomysial antibodies and
      tissue transglutaminase antibodies, may be very useful tools for screening and
      case finding in clinical practice. However, demonstration of characteristic
      changes in the small intestinal biopsy is critical, along with a gluten-free diet
      response.

PMID- 15185855
TI  - Seronegative celiac disease: increased prevalence with lesser degrees of villous
      atrophy.
AB  - Our aim was to assess differences in the sensitivities of serologic tests used
      for the diagnosis of celiac disease among patients with varying degrees of
      villous atrophy. Among 115 adults with biopsy-proven celiac disease who fulfilled
      strict criteria, including serologic testing at the time of diagnosis and
      response to a gluten-free diet, 71% had total villous atrophy and 29% partial
      villous atrophy. Endomysial antibody was positive in 77% of those with total
      villous atrophy, compared to 33% with partial villous atrophy (P < 0.001). There
      was no difference in sensitivity when the type of presentation (classical vs.
      silent) was compared. Endomysial antibody-positive and negative patients did not
      differ with respect to age at diagnosis, duration of symptoms, mode of
      presentation, or family history of celiac disease. All anti-tissue
      transglutaminase-positive patients had TVA on biopsy. Seronegative celiac disease
      occurs. Endomysial antibody positivity correlates with more severe villous
      atrophy and not mode of presentation of celiac disease. Serologic tests, in
      clinical practice, lack the sensitivity reported in the literature.

PMID- 15185856
TI  - CD4+ T-cell lymphoproliferative disorder of the gut clinically mimicking celiac
      sprue.

PMID- 15185857
TI  - Impact of dextran sulfate sodium load on the severity of inflammation in
      experimental colitis.
AB  - In dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice the
      relationship between the amount of ingested DSS and the severity of colitis has
      not been systematically investigated. We examined whether (1) the severity of
      colitis is DSS load-dependent, and (2) there is a critical DSS load required to
      reliably induce colitis. DSS load was calculated as: (drinking volume (ml) x [DSS
      (g)/100 ml])/body weight (g). A minimum DSS load > or = 30 mg/g body weight over
      7 days resulted in a significantly elevated colonic myeloperoxidase (MPO)
      activity, compared to mice receiving less DSS and controls (P < 0.05).
      Histomorphologic data correlated with MPO activity and revealed significantly
      higher damage scores once the DSS load was > or = 30 mg/g body weight. Our
      findings demonstrate the importance of monitoring DSS load in this model of
      experimental colitis.

PMID- 15185858
TI  - Selective granulocyte and monocyte adsorptive apheresis as a first-line treatment
      for steroid naive patients with active ulcerative colitis: a prospective
      uncontrolled study.
AB  - Corticosteroid therapy of ulcerative colitis (UC) is associated with frequent
      adverse side effects and poor quality of life. Recently, adsorptive granulocyte
      and monocyte/macrophage apheresis has shown efficacy in patients with severe
      steroid refractory UC. The objective of this study was to investigate if, instead
      of corticosteroids, adsorptive leukocytapheresis has efficacy as the first-line
      therapy for steroid-naive patients with active UC. Twenty patients, aged 15-49
      years, with a mean clinical activity index (CAI) of 8.6 were recruited.
      Adsorptive leukocytapheresis was done with Adacolumn, which contains cellulose
      acetate beads as adsorptive carriers for granulocytes and monocytes (FcgammaR and
      complement receptors expressing leukocytes). Each patient received 6 to 10
      leukocytapheresis sessions of 60-min duration, at 2 sessions/week. Efficacy was
      assessed 1 week after the last session. Post treatment, the mean CAI was 3.0 (P =
      0001), and 17 of 20 patients (85%) were in remission. There were significant
      falls in C-reactive protein (P = 0.0003), total white cell counts (P = 0.003),
      neutrophils (P = 0.0029), and monocytes (P = 0.0038), an increase in lymphocytes
      (P = 0.001), and increases in the blood levels of soluble TNF-alpha receptors I
      (P = 0.0007) and II (P = 0.0045) in the column outflow (blood return to the
      patients). Further, at 8 months, 60% of patients had maintained their remission.
      No severe side effects were reported. In conclusion, adsorptive leukocytapheresis
      should reduce corticosteroid therapy in patients with moderate UC; cases with
      early-stage active disease may benefit most.

PMID- 15185859
TI  - Durability of the diagnosis of irritable bowel syndrome based on clinical
      criteria.
AB  - Our purpose was to evaluate the durability of the diagnosis of irritable bowel
      syndrome (IBS) based on clinical criteria. The study population consisted of a
      cohort of previously published study patients evaluated for IBS between 1989 and
      1992, who met the International Congress of Gastroenterology criteria for IBS.
      Patients were reinterviewed for cardinal features of IBS, Rome I, Rome II, and
      Manning criteria 10-13 years after the initial diagnosis. During the
      observational follow-up period, there were 75 patients, 14 males and 61 females,
      with a mean age of 47.5 +/- 11.3 years (SD; range, 20 to 75 years). Mean time of
      reinterview after initial diagnosis was 11.8 +/- 0.9 years (range, 10 to 13
      years). None of the 75 patients had an abdominal condition which could have been
      mistaken for IBS. Other abdominal conditions diagnosed during this period
      included diverticulitis (five), uterine fibromyoma (three), and gallbladder
      disease (three). Sixty-nine patients (92%) did not consider their symptoms as
      resolved. Thirty-five (46.7%) had repeat structural evaluation of the colon for
      similar symptoms without any new diagnoses made. Twenty-six (34.7%) and 32
      (42.7%) presently meet the Rome II and Rome I criteria for IBS, respectively.
      Clinicians are advised to use clinical criteria for a specific and durable
      diagnosis of IBS.

PMID- 15185860
TI  - What does pain or discomfort in irritable bowel syndrome mean?
AB  - Despite many studies on pain of functional gastrointestinal disorders (FGID), the
      pain mechanism of FGID is not well understood, and pain treatment of FGID is not
      established. Following our former functional dyspepsia (FD) study, we proposed
      two subgroups of patients with irritable bowel syndrome (IBS), pain and
      discomfort (not pain). The duration of disease of discomfort IBS patients was
      longer than that of pain IBS patients (P < 0.05) The rate of anxiety disorder of
      pain IBS patients tended to be higher than that of discomfort IBS patients (P =
      0.07172). Fifteen (15.2%) of 99 pain IBS patients and 1 (3.4%) of 29 discomfort
      IBS patients overlapped FD (P < 0.1). We expected that a common psychosocial
      mechanism would influence both pain dyspepsia patients and pain IBS patients,
      however, there were some differences between these FGID patients with pain.
      Anxiety in IBS patients with lower gastrointestinal pain seems to be important in
      their treatment.

PMID- 15185862
TI  - A patient with a polyglandular autoimmune syndrome involving the salivary glands,
      thyroid, intestine, and pancreas.

PMID- 15185861
TI  - In vivo effects of bifidobacteria and lactoferrin on gut endotoxin concentration
      and mucosal immunity in Balb/c mice.
AB  - The aim of the present study was to examine the effects of oral supplementation
      of newborn Balb/c mice with bifidobacteria (B. infantis, B. bifidum) and iron
      free apo-lactoferrin (bovine, human) on gut endotoxin concentration and mucosal
      immunity. Endotoxin concentration was measured in ileocecal filtrates at 7, 14,
      21, and 28 days postdelivery by a quantitative limulus amebocyte lysate test.
      While endotoxin levels in bifidobacteria-fed mice showed a steady rise over time,
      they were consistently lower than that observed in control animals. Results of
      lactoferrin supplementation varied depending on the specific time point, but
      overall by day 28, all treatment groups showed lower intestinal endotoxin
      concentrations compared to saline fed animals. Neither bifidobacteria nor
      lactoferrin stimulated an increase in B or T cells, or in cytokine production (IL
      6, TNF-alpha, INF-gamma), in Peyer's patches as measured by flow cytometry.
      Bifidobacteria and lactoferrin were well tolerated as dietary supplements and
      showed promising potential to reduce gut endotoxin levels.

PMID- 15185863
TI  - Multichannel electrogastrography (EGG) in normal subjects: a multicenter study.
AB  - The aim of this study was to record gastric myoelectric activity using
      multichannel electrogastrography (EGG) and to determine if there are differences
      due to age, gender, body mass, and study location. In 61 normal subjects from
      four centers, fasting multichannel EGG was recorded for 1 h, followed by two 1-h
      postprandial recordings after a test meal. Variables assessed included dominant
      frequency (DF) and its power, percentage time in 2- to 4-cpm frequency, and
      percentage slow-wave coupling (%SWC). There were no significant differences in
      EGG parameters with respect to gender or age. Subjects with a BMI > 25 had a
      decrease in the absolute DF power but a similar increase in the postprandial DF
      power. Subjects with a BMI > 25 had a postprandial decrease in the %SWC compared
      to those with a BMI < 25. There was a decrease in postprandial %SWC in
      European/Asian centers compared to American centers. In conclusion, multichannel
      EGG provides assessment of electrical slow-wave coupling in addition to
      determining dominant frequency, power, and percentage normal rhythm. This
      multicenter study of normal subjects shows similar multichannel EGG values among
      different genders and ages. Body mass and ethnicity may impact on some of the EGG
      values.

PMID- 15185864
TI  - A comparative study of the effects of electroacupuncture and moxibustion in the
      gastrointestinal motility of the rat.
AB  - We compared the outcomes of the stimulation of specific sets of acupoints with
      either acupuncture or moxibustion over peristalsis. Twenty-five plastic beads
      were orally administered in the stomach of the rats and 90 min later animals were
      sacrificed, the stomach and small intestine were opened, and the number of beads
      remaining in each segment was counted. Forty rats were immobilized for 20 min and
      stimulated at either abdominal or hindlimbs acupoints, with either
      electroacupuncture or moxibustion. Under this restraint (stress) condition
      electroacupuncture at hindlimb points or moxibustion at abdominal points
      significantly enhanced gastric emptying (P < 0.02) as well as intestinal motility
      compared with animals subjected only to immobilization and not stimulated with
      electroacupuncture or moxibustion. We conclude that the effects of different
      acupoints and modes of stimulation (electrical vs. moxibustion) over
      gastrointestinal motility in rats subjected to restraint-induced stress is not
      uniform and discuss the different neural pathways underlying these differences.

PMID- 15185865
TI  - Frequency and significance of antibodies to Saccharomyces cerevisiae in
      autoimmune hepatitis.
AB  - Our aims were to determine the frequency of antibodies to Saccharomyces
      cerevisiae in autoimmune hepatitis and assess associations with concurrent
      mucosal diseases, genetic factors, and corticosteroid response. Seropositivity
      was determined by enzyme immunoassay in 385 samples obtained from 178 patients.
      Antibodies to Saccharomyces cerevisiae were detected in 49 patients (28%), and
      serum levels of immunoglobulin A were higher in seropositive patients (410 +/- 35
      versus 321 +/- 20 mg/dL; P = 0.02). Individuals with and without antibodies were
      not otherwise distinguished by concurrent mucosal diseases, laboratory findings,
      or outcomes. Antibodies to tissue transglutaminase occurred more commonly in
      seropositive patients (16 versus 4%; P = 0.008), but this association was lost
      when corroborating serological criteria for celiac disease were sought. We
      conclude that antibodies to Saccharomyces cerevisiae are common in autoimmune
      hepatitis. They may be associated with non-disease-specific immune responses, but
      they do not define individuals with a distinctive clinical phenotype, associated
      mucosal diseases, or treatment outcome.

PMID- 15185866
TI  - Bell's palsy: a rare complication of interferon therapy for hepatitis C.

PMID- 15185867
TI  - Assessment of intestinal permeability and absorption in cirrhotic patients with
      ascites using combined sugar probes.
AB  - Gastrointestinal dysfunction in patients with cirrhosis may contribute to
      complications such as malnutrition and spontaneous bacterial peritonitis. To
      determine whether cirrhotic patients with ascites have altered intestinal
      function, we compared intestinal permeability and absorption in patients with
      liver disease and normal subjects. Intestinal permeability and absorption were
      investigated in 66 cirrhotic patients (48 with ascites, 18 without ascites) and
      74 healthy control subjects. Timed recovery of 3-O-methyl-D-glucose, D-xylose, L
      rhamnose, and lactulose in urine following oral administration was measured in
      order to assess active and passive carrier-mediated, and nonmediated, absorptive
      capacity, as well as intestinal large-pore/small-pore (lactulose/rhamnose)
      permeability. Test sugars were measured by quantitative thin-layer chromatography
      and results are expressed as a percentage of test dose recovered in a 5-h urine
      collection. Sugar excretion ratios relating to small intestinal permeability
      (lactulose/rhamnose) and absorption (rhamnose/3-O-methyl-D-glucose) were
      calculated to avoid the effects of nonmucosal factors such as renal clearance,
      portal hypertension, and ascites on the recovery of sugar probes in urine.
      Compared with normal subjects, the mean lactulose/rhamnose permeability ratio in
      cirrhotic patients with ascites was significantly higher (0.058 vs. 0.037, P <
      0.001) but not in cirrhotic patients without ascites (0.041 vs. 0.037). Cirrhotic
      patients with ascites had significantly lower mean recoveries of 3-O-methyl-D
      glucose (23.0 vs. 49.1%; P < 0.001), D-xylose (18.8 vs. 34.5%; P < 0.001), L
      rhamnose (4.0 vs. 9.1%; P < 0.001), and lactulose (0.202 vs. 0.337%; P < 0.001)
      than normal subjects. However, the mean rhamnose/3-O-methyl-D-glucose ratio was
      the same in cirrhotic patients with ascites as normal subjects (0.189 vs. 0.189),
      indicating that the reduction in probe recovery was due to nonmucosal factors.
      Compared with normal subjects, cirrhotic patients with ascites have abnormal
      intestinal permeability, measured by urinary lactulose/rhamnose excretion, and
      normal small intestinal absorption, assessed by the urinary rhamnose/3-O-methyl-D
      glucose ratio. Low urine recovery of sugar probes found in cirrhotic patients
      appears to be the result of nonintestinal factors affecting clearance rather than
      reduced intestinal absorption.

PMID- 15185868
TI  - Pseudo-angiocholitis revealing adult-onset Still's disease.

PMID- 15185869
TI  - Renal insufficiency may partly explain chronic anemia in patients awaiting liver
      transplantation.
AB  - In patients with cirrhosis, anemia is common and is likely to be multifactorial,
      including decreased erythrocyte production, sequestration due to hypersplenism,
      hemolysis, and increased blood loss from gastrointestinal bleeding. Renal
      dysfunction is also common in liver disease and this may also cause anemia.
      However, an association between anemia and renal dysfunction has not been
      reported in patients with cirrhosis. Our objective was to determine whether
      anemia in cirrhotic patients is independently related to renal dysfunction. We
      conducted a retrospective chart review of patients in our institution listed for
      liver transplantation. We collected simultaneous data on age, hemoglobin,
      creatinine, albumin, liver enzymes, prothrombin time, and bilirubin. We excluded
      patients who were hospitalized or deceased to avoid confounding variables. Two
      hundred eighty-six (female n = 130) patients with a mean age of 52.8 +/- 9.7
      (range, 18-73) years were studied. Renal dysfunction (creatinine > 1.2 mg/dL) was
      present in 55 (19%) patients, and anemia (hemoglobin < 12 g/dL) was seen in 115
      (40%) patients. Anemia was more common in patients with renal dysfunction (64
      versus 34%; P < 0.001) compared to those with normal renal function. Creatinine,
      prothrombin time, and bilirubin showed an inverse relationship (all P's < 0.001)
      with hemoglobin, and albumin showed a positive correlation with hemoglobin (P <
      0.001). Multivariate analysis showed that creatinine (OR, 2.4; 95% CI, 1.05-5.3;
      P = 0.038), prothrombin time (P = 0.026), bilirubin (P = 0.035), and albumin (P =
      0.001) were independent predictors of anemia. Renal dysfunction is an important
      cause of anemia in patients with cirrhosis. The role of erythropoietin in the
      management of anemia in patients with cirrhosis and renal dysfunction should be
      explored in prospective studies.

PMID- 15185870
TI  - Experimental studies to estimate the intestinal viability in a rat strangulated
      ileus model using a dielectric parameter.
AB  - This study aimed at establishment of adequate evaluation of intestinal viability
      before release of the strangulated intestine by measuring electrical properties.
      In rats a 20-cm segment of the distal ileum and mesentery was strangulated. The
      intestine was strangulated for 0, 2, 15, 45, 90, and 120 min. The conductance and
      capacitance obtained by impedance analyzer were used to calculate tan(delta)m in
      the strangulated intestine. ATP was measured as well. In another experiment,
      after various periods of strangulation, tan(delta)m was measured just before
      release of the strangulation. Rats were divided into Group A (survived for 7
      days) and Group D (died within 7 days). There was a positive correlation between
      tan(delta)m and ATP levels (P < 0.01). And tan(delta)m was significantly greater
      in Group A than in Group D (P < 0.05). There were no deaths at a tan(delta)m
      value of 2.36 or more and no survivors at a tan(delta)m of less than 2.20 except
      for one rat. These results suggested that tan(delta)m may be a useful index of
      the viability of the strangulated intestine before reperfusion.

PMID- 15185871
TI  - Metastatic carcinoid tumor discovered by capsule endoscopy and not detected by
      esophagogastroduodenoscopy.

PMID- 15185872
TI  - The importance of interleukin 18, glutathione peroxidase, and selenium
      concentration changes in acute pancreatitis.
AB  - Cytokinemia and oxidative stress are important factors responsible for an
      inadequate immune response in the early course of acute pancreatitis (AP). The
      aim of the study was to evaluate the profiles of interleukin 18 (IL-18),
      glutathione peroxidase (GPx), and selenium concentrations in serum with respect
      to AP severity and to study the relationships between these parameters and
      recognized prognostic indicators of AP severity. Prospective clinical analyses
      were performed on 61 patients with mild and severe forms of AP and for 15 healthy
      volunteers. In both forms of AP severity, the IL-18 concentration in the serum
      was significantly higher than in healthy controls. In the severe form of AP, the
      IL-18 concentration was the highest and exceeded significantly the values
      recorded on the 1st, 2nd, 3rd, 5th, and 10th days of mild AP. A significantly
      lower GPx concentration in the serum was recorded in severe AP compared to the
      mild form and in the control group. There was a significantly lower selenium
      concentration in the severe form of AP. Significant correlations between GPx and
      selenium, between IL-18 and GPx, and between IL-18 and selenium were recorded.
      The ROC analysis shows a high prognostic accuracy of IL-18 and GPx concentrations
      in the determination of AP severity. IL-18 is released early in the course of AP
      and may be a key immunomodulator of the inflammatory response in the severe form
      of this disease. Low GPx and selenium concentrations in severe AP reflect the
      lower antioxidative ability in this form of AP. IL-18 and GPx may represent new
      indicators of AP severity.

PMID- 15185873
TI  - Initial presentation of hepatocellular carcinoma as a subcutaneous mass on the
      anterior chest wall.

PMID- 15185874
TI  - Differential expression of three matrix metalloproteinases, MMP-19, MMP-26, and
      MMP-28, in normal and inflamed intestine and colon cancer.
AB  - Several matrix metalloproteinases (MMPs) have been implicated in intestinal
      inflammation, mucosal wound healing, and cancer progression. The purpose of this
      study was to examine the cellular location and putative function of MMP-19, MMP
      26 (matrilysin-2), and MMP-28 (epilysin), in normal, inflammatory, and malignant
      conditions of the intestine. Peroperative tissue specimens from patients with
      ulcerative colitis (UC) (n = 16) and archival tissue samples of ischemic colitis
      (n = 9), Crohn's disease (n = 7), UC (n = 8), colon cancer (n = 20), and healthy
      intestine (n = 5) were examined using immunohistochemical analyses with
      polyclonal antibodies. Unlike many classical MMPs, MMP-19, MMP-26, and MMP-28
      were all expressed in normal intestine. In inflammatory bowel disease (IBD), MMP-
      19 was expressed in nonmigrating enterocytes and shedding epithelium. MMP-26 was
      detected in migrating enterocytes, unlike MMP-28. In colon carcinomas, MMP-19 and
      MMP-28 expression was downregulated in tumor epithelium. Staining for MMP-26
      revealed a meshwork-like pattern between cancer islets, which was absent from
      most dedifferentiated areas. Our results suggest that MMP-19 is involved in
      epithelial proliferation and MMP-26 in enterocyte migration, while MMP-28
      expression is not associated with inflammatory and destructive changes seen in
      IBD. In contrast to many previously characterized MMPs, MMP-19 and MMP-28 are
      downregulated during malignant transformation of the colon and may play a
      prominent role in tissue homeostasis.

PMID- 15185875
TI  - High prevalence of hyperplastic colonic polyps in acromegalic subjects.
AB  - We evaluated the prevalence and features of colonic polyps in a population of
      acromegalic subjects, compared to a control group of patients with irritable
      bowel syndrome (IBS). Colonic polyps were found in 30 acromegalic subjects (40%)
      and in 10 controls (13%) (P < 0.0001). Among the acromegalic patients, polyps
      were of the hyperplastic type in 27 subjects (90%) and adenomatous in 3 (10%). In
      the control group, polyps were hyperplastic in nine subjects (90%) and
      adenomatous in one (10%). We also observed a significant association (P < 0.0001)
      between the presence of hyperplastic polyps and the older age in both the
      acromegalic and the control groups. There were no differences between the two
      groups regarding sex, site, size, or macroscopic and histological types of
      polyps. Acromegalic patients have a higher prevalence of colonic hyperplastic
      polyps than IBS subjects, while the prevalence of adenomatous polyps is similar
      in the two groups.

PMID- 15185876
TI  - Gastrointestinal stromal tumor of jejunum with angiodysplasia.

PMID- 15185877
TI  - Clinical presentation and personality factors are predictors of the response to
      treatment in patients with functional dyspepsia; a randomized, double-blind
      placebo-controlled crossover study.
AB  - The role of psychological factors or symptom pattern for the response to
      treatment in patients with unexplained (functional) dyspepsia is unknown. We
      hypothesized that patients with reflux- and ulcer-like symptoms would be more
      likely to respond to acid-lowering therapy, while psychological disturbances
      would be associated with a less favorable response to treatment. Seventy-eight
      patients with a diagnosis of functional dyspepsia were recruited and 75 completed
      the trial. Patients were treated for 4 weeks in a double-blind, placebo
      controlled crossover trial starting in random order with either active drug
      (ranitidine, 150 mg b.d.) or placebo. Every 7 days, medication was switched from
      active drug to placebo, or vice versa. At entry, patient characteristics were
      assessed utilizing a semistructured standardized interview and standardized
      questionnaires, and weekly intensity of symptoms was assessed utilizing a visual
      analogue scale. Patients with a greater reduction of the symptom score during
      active treatment and an overall reduction of the global symptom score by more
      than 50% at the end of the study period were categorized as responders. Logistic
      regression analysis was utilized to assess the influence of symptom type and
      presence of psychological disturbances on the treatment response. During
      treatment the symptom score decreased significantly, from 32.1 +/- 1.44 (SD) to
      21.3 +/- 1.9 at the end of the trial (P < 0.001). Twenty of 75 were responders.
      High scores for somatization (OR, 3.6; 95% Cl, 1.2-11.4), anxiety (OR, 3.3; 95%
      Cl, 0.9-11.8), and reflux-like symptoms (OR, 5.3; 95% Cl, 1.7-16.7) were
      associated with response to treatment, while dysmotility-like symptoms were
      associated with an unfavorable response (OR, 0.3; 95% Cl, 0.1-0.9). Symptom
      pattern and psychological disturbances are independent predictors of treatment
      response. Patients with reflux-like symptoms and greater psychological
      disturbances are more likely to respond to an acid-lowering compound.

PMID- 15185878
TI  - Quality of life in patients with subjective food hypersensitivity: applicability
      of the 10-item short form of the Nepean Dyspepsia Index.
AB  - The aim of this study was to investigate quality of life and applicability of the
      10-item short form of the Nepean Dyspepsia Index (SF-NDI) in patients with
      subjective food hypersensitivity. Fifty-two adult patients and 120 controls were
      examined using three questionnaires: Quality of life Nepean Dyspepsia Index
      (NDI), Gastrointestinal Symptom Rating Scale (GSRS), and Ulcer Esophagitis
      Subjective Symptoms Scale (UESS). To document psychometric properties, 20 of the
      patients filled in the SF-NDI questionnaire once more 4 weeks later. Patients had
      poor quality of life compared with controls from health care workers or general
      population (P < 0.001). Scores on SF-NDI were significantly correlated with
      scores on the GSRS (r = 0.34, P = 0.02) and UESS (r = 0.41, P = 0.003). The SF
      NDI performed very satisfactorily, with a high reliability, construct validity,
      and responsiveness. Patients with subjective food hypersensitivity have
      considerably reduced quality of life. The SF-NDI provides reliable, responsive,
      and clinically valid measures of quality of life in these patients.

PMID- 15185879
TI  - Post-test calibration of single-use, antimony, 24-hour ambulatory esophageal pH
      probes is necessary.
AB  - Twenty-four-hour pH monitoring is considered the "gold standard" for detection of
      gastroesophageal reflux disease (GERD). However, reference pH can drift during
      studies using antimony pH electrodes. Posttest calibration of antimony probes to
      assess a "drift" has been advocated but is not routinely preformed in clinical
      practice. We undertook this study to determine the frequency and degree of drift
      that occurs during pH studies using single-use antimony pH electrodes. One
      hundred consecutive 24-hr ambulatory esophageal pH studies were reviewed for
      presence and degree of pH drift. Separately, 10 in vitro studies using antimony
      electrodes exposed to solution of constant pH and temperature were recorded to
      determine timing of drift. Drift of at least 0.1 pH unit occurred in 88 (P <
      0.001). Drift of 0.1, 0.2, 0.3, 0.4, and > 0.4 pH unit occurred in 38, 28, 15, 4,
      and 5 of the 100 studies, respectively. In six studies the adjustment for the
      poststudy calibration drift changed the overall interpretation of the test. Small
      degrees of drift occurred at various times during the 10 in vitro studies. Drift
      in pH during 24-hr pH studies using antimony is common, but large degrees of
      drift are not. When the threshold of pH 4.0 was adjusted to reflect the drift, a
      small but significant number of interpretations changed. Drift artifact may
      impact the results of the pH study, and calibration should be repeated after all
      studies.

PMID- 15185880
TI  - Reflux laryngitis in a patient with Zollinger Ellison syndrome and the role of
      epidermal growth factor.

PMID- 15185881
TI  - Patient localization of esophageal dysphagia.
AB  - The accuracy of patients' symptom localization in dysphagia is not clear. This
      study aims to determine the accuracy of patient localization and to determine the
      correlation of localization with motility disorders. We reviewed 100 patients
      after completion of EGD, manometry, and a dysphagia questionnaire. Proximal and
      midesophageal localization were rarely associated with a proximal cause of
      dysphagia. Distal localization correlated in 80% of cases. Fifty-seven percent of
      patients reporting diffuse symptoms had manometric abnormalities, but only 9% of
      patients with manometric abnormalities reported diffuse symptoms. In conclusion,
      patient localization in esophageal dysphagia is not accurate. The data suggest
      that proximal localization is especially inaccurate, whereas distal localization
      may be more accurate. Finally, there is no correlation between diffuse
      localization and diagnosis of motility disorders.

PMID- 15185882
TI  - New trends in the epidemiological and clinical features of infective
      endocarditis: results of a multicenter prospective study.
AB  - BACKGROUND: The clinical and epidemiological profiles of infective endocarditis
      (IE) are continuously evolving. We report the results of a 2-year multicenter
      prospective survey that investigated new trends in the epidemiology,
      microbiological and clinical features and the prognosis of IE. METHODS: From
      January 2000 through December 2001, a prospective multicenter survey on IE was
      conducted in the region of Piedmont, Italy (4.2 million inhabitants). RESULTS: A
      total of 267 patients with suspected IE were enrolled, of whom 147 received a
      definite diagnosis of IE, as confirmed by pathology or follow-up data. The annual
      estimated incidence of IE was 36 cases per 1 million inhabitants in urban Turin
      and 30 cases per 1 million inhabitants in the province of Turin. A predisposing
      heart disease was detected in 70.8% of cases, with prosthetic valve involvement
      in 27 (18%). The incidence of injection drug use was 10%. Twenty-two cases (15%)
      were related to invasive procedures. Causative microorganisms included:
      streptococci 37.4% (oral streptococci 17.7%, group D streptococci 9.5%, pyogenic
      streptococci 3.4%, enterococci 6.8%), staphylococci 34%, other pathogens 28.5%.
      Blood cultures were negative in 25% of cases. The mean time between symptom onset
      and hospital admission was 39.7 days; this interval was shorter and associated
      with a poorer prognosis in cases of IE due to Staphylococcus aureus infection (p
      < 0.001). The delay in carrying out echocardiographic and blood culture
      evaluation often led to a late diagnosis as defined by the Duke criteria (8.2 +/-
      7.4 days after admission). Valve surgery was performed in 31% of patients. The in
      hospital mortality was 14% and that at 3 months 18%. CONCLUSIONS: In Piedmont,
      the incidence of IE is similar to the rates reported in other recent series.
      Still, the diagnosis and management of IE remain a challenge. The variegated
      clinical manifestations of IE and its changing epidemiology require constant
      surveillance.

PMID- 15185883
TI  - Usefulness of pulsed tissue Doppler for the assessment of left ventricular
      myocardial function in overt hypothyroidism.
AB  - BACKGROUND: The aim of this study was to assess the role of tissue Doppler (TD)
      in the identification of left ventricular (LV) myocardial regionl abnormalities
      in overt hypothyroidism. METHODS: Fourteen women with newly diagnosed, never
      treated overt hypothyroidism and 14 healthy women, matched for age, underwent
      standard echocardiography and pulsed TD, by placing the sample volume at the
      basal posterior septum and lateral mitral annulus, in the apical 4-chamber view.
      The myocardial systolic (SM) and diastolic velocities (Em, Am and their ratio)
      and time intervals (relaxation time [RTm], pre-contraction time [PCTm],
      contraction time) were measured. RESULTS: The two groups were comparable for body
      surface area, blood pressure and heart rate. At standard echocardiography,
      patients with overt hypothyroidism had a significantly greater septal thickness
      and LV mass index, a longer LV pre-ejection period (PEP), deceleration time and
      isovolumic relaxation time (IVRT) and a lower E peak velocity and E/A ratio. TD
      showed a significantly longer PCTm and RTm and a lower Em and Em/Am ratio of both
      the septum and mitral annulus in overt hypothyroidism. The ratio of the standard
      Doppler E to Em of the mitral annulus was 5.5 +/- 1.2 in controls and 5.3 +/- 1.7
      in overt hypothyroidism (p = NS). In the overall population, PEP, IVRT, PCTm and
      RTm were correlated negatively with FT3 and FT4, and positively with thyroid
      stimulating hormone. After adjusting for age, body surface area and heart rate in
      separate multivariate analyses, the associations of TD PCTm with the thyroid
      hormones and thyroid-stimulating hormone were greater than the homologous
      associations of standard Doppler PEP. CONCLUSIONS: Standard echocardiography
      confirms itself as a satisfactory diagnostic technique for the identification of
      LV global dysfunction in overt hypothyroidism. Pulsed TD may be useful to
      determine the severity of LV myocardial dysfunction in relation to the degree of
      hormonal impairment.

PMID- 15185884
TI  - Aortic valve-sparing surgery for aortic root aneurysm.
AB  - BACKGROUND: Replacement of the aortic valve and ascending aorta with a composite
      graft is the most common surgical treatment for aortic root aneurysms with or
      without aortic regurgitation (AR). In the early 90's reconstructive procedures of
      the aortic root have been described with encouraging results. This paper presents
      our experience with this technique. METHODS: Between January 2001 and May 2003,
      28 patients (25 males, 3 females, mean age 60 years) with aortic root aneurysm
      were treated with reimplantation of the aortic valve. Twenty-two patients had AR
      > 2+, 5 had Marfan syndrome, 5 had an aortic arch aneurysm, 4 had type A aortic
      dissection, 2 patients had associated coronary artery disease, and one had mitral
      valve insufficiency. The only contraindication was primitive disease of the
      aortic leaflets. RESULTS: There was one perioperative death (type A aortic
      dissection) and 1 patient was discharged with mild to moderate AR requiring
      aortic valve replacement. The cardiopulmonary bypass and aortic cross-clamping
      times were 230 and 184 min respectively. No neurological events were recorded.
      During follow-up (mean 16.7 months, range 3-32 months) 1 patient died and one had
      mild AR. Freedom from reoperation and from AR at 24 months was 94 and 89%
      respectively. At multivariate analyses we did not find any correlation between
      Marfan syndrome, type A aortic dissection, grade of preoperative AR, and
      recurrence of AR. CONCLUSIONS: In our experience, valve-sparing surgery was
      feasible with a low mortality and morbidity and with good early results. It
      should be applied to all patients requiring aortic root surgery for aortic root
      aneurysm, a diseased aortic valve being the only contraindication.

PMID- 15185885
TI  - Randomized trial of conventional balloon angioplasty versus cutting balloon for
      in-stent restenosis. Acute and 24-hour angiographic and intravascular ultrasound
      changes and long-term follow-up.
AB  - BACKGROUND: The aim of this study was to investigate the angiographic and
      intravascular ultrasound (IVUS) changes following cutting balloon (CB) and
      percutaneous transluminal coronary angioplasty (PTCA) treatment in in-stent
      restenosis. METHODS: Fifty consecutive patients with in-stent restenosis were
      randomized to treatment with CB (n = 25) or PTCA (n = 25). The size of the device
      was selected using IVUS according to a 1:1 device-to-stent ratio and balloons
      were inflated to a maximal pressure of 8 atm. Quantitative coronary angiography
      (QCA) and IVUS (both planar and volumetric) evaluations were carried out before
      and after treatment and 24 hours later. In case of suboptimal results at 24 hours
      (> or = 50% diameter stenosis at QCA and/or < or = 4.7 mm2 minimal lumen area
      [MLA] at IVUS), the patients were re-randomized to receive additional treatment
      (CB for PTCA and vice versa) or to follow-up. Measurements included the minimal
      lumen diameter and diameter stenosis for QCA and the external elastic membrane
      area (EEMA), stent area (SA), MLA, restenosis area (RA = SA - MLA) and plaque +
      media area (PMA = EEMA - SA) for IVUS. RESULTS: A similar minimal lumen diameter
      increase (1.19 +/- 0.44 vs 1.37 +/- 0.55 mm) and diameter stenosis decrease (-37
      +/- 14 vs -45 +/- 13%) was found after PTCA and CB. No significant difference was
      found in MLA increase (4.81 +/- 1.9 vs 5.45 +/- 2.0 mm2) and RA decrease (-3.8 +/
      1.3 vs -4.2 +/- 1.7 mm2) in PTCA and CB. SA, EEMA and PMA did not significantly
      change after treatment in either group. Of the total mean lumen enlargement after
      PTCA and CB, 20% was due to additional stent expansion and 80% was due to RA
      decrease. At 24 hours, a greater minimal lumen diameter increase (-0.23 +/- 0.34
      vs -0.06 +/- 0.23 mm, p = 0.03) and MLA loss (-1.9 +/- 1.4 vs 0.37 +/- 0.8 mm2, p
      = 0.000) and RA increase (1.74 +/- 1.3 vs 0.37 +/- 0.52 mm2, p = 0.000) were
      detected in PTCA vs CB. Volumetric changes paralleled planar IVUS variations. A
      suboptimal result was more frequently found in PTCA as compared to CB (36 vs 4%,
      p < 0.01). At follow-up, PTCA had a higher target lesion revascularization as
      compared to CB (40 vs 12.5%, p < 0.05). CONCLUSIONS: In in-stent restenosis, PTCA
      and CB share similar effects and mechanisms of lumen enlargement. In-stent tissue
      is mainly redistributed along a larger stent rather than being extruded out of
      the stent struts. At 24 hours, a significant lumen loss (instant restenosis)
      occurred more frequently in PTCA as compared to CB and may account for a higher
      target lesion revascularization in this group.

PMID- 15185886
TI  - Cutting balloon and the search for an optimal treatment for in-stent restenosis.

PMID- 15185887
TI  - Survival after stentless and stented xenograft aortic valve replacement: a
      concurrent, case-match trial.
AB  - BACKGROUND: In order to compare the long-term outcome of stented vs stentless
      aortic xenografts, a non-randomized, concurrent case-match trial was conducted on
      all consecutive patients operated between January 1992 and April 2000. METHODS:
      Two hundred and ninety-two patients had stented (group 1) and 376 stentless
      (group 2) xenograft aortic valve replacement (AVR). Group 1 patients were older
      (75.0 +/- 4.1 vs 70.4 +/- 6.7 years, p = 0.01), while male gender and aortic
      stenosis were equally prevalent. NYHA functional class III-IV (85 vs 78%, p =
      0.03) and associated procedures (53 vs 41%, p = 0.01) were more common in group
      1. The aortic cross-clamping (79.7 +/- 27.8 vs 96.1 +/- 23.3, p = 0.001) and
      bypass (91.4 +/- 57.5 vs 128.5 +/- 34.0, p = 0.002) times were shorter in group
      1. A case-match analysis identified 113 identical patient pairs, on the basis of
      age, gender, diagnosis, NYHA class, associated cardiac disease, and valve size.
      RESULTS: The early mortality was higher in group 1 (5.3 vs 2.7%, p = 0.3), though
      not significantly. During follow-up (37 +/- 30 vs 43 +/- 35 months, p = 0.6), 26
      late deaths were recorded (10.3 vs 13.6%, p = 0.4). The 8-year survival was
      comparable (76 +/- 7 vs 75 +/- 5%, p = 0.2), but freedom from cardiac (77 +/- 7
      vs 90 +/- 4%, p = 0.02) and from valve-related death (78 +/- 7 vs 91 +/- 4%, p =
      0.02) was higher in group 2. Freedom from structural deterioration (99 +/- 1 vs
      98 +/- 2%, p = 0.7) and from reoperation (99 +/- 1 vs 95 +/- 3%, p = 0.2) at 8
      years was similar. The late functional status was equally satisfactory (NYHA
      class I-II 92.7 vs 94.7%, p = 0.06). CONCLUSIONS: The survival free from cardiac
      and valve-related mortality when stentless xenografts for AVR are used is
      superior to that achieved with stented grafts. Stentless AVR has the potential of
      conferring selective survival advantages late after operation.

PMID- 15185888
TI  - Analysis of Y-graft blood flow and flow reserve in conditions of increased
      myocardial oxygen consumption.
AB  - BACKGROUND: It is not well established whether early following surgery the blood
      flow of arterial composite Y-grafts may efficiently meet the flow demand of the
      coronary system. The aim of this study was to evaluate whether early after
      surgery arterial composite Y-grafts may increase the blood flow in response to an
      increase in myocardial oxygen consumption (MVO2). METHODS: Twenty-seven patients
      who received complete arterial myocardial revascularization using the left
      internal thoracic artery (LITA) and the radial artery (RA) as composite Y-graft
      gave their consent to a pre-discharge coronary angiography and intravascular flow
      velocity measurements using a Doppler guidewire. Flow measurements were performed
      in the LITA main stem, the distal LITA and the RA, both at rest and during atrial
      pacing at 85% of the patient age-predicted maximum heart rate. The heart rate
      systolic blood pressure product was considered as an indirect index of MVO2.
      Hyperemic flow was determined after injection of adenosine. The flow reserve was
      defined as the ratio of blood flow during maximal hyperemia (Qmax) to baseline
      flow (Qbasal). RESULTS: Atrial pacing significantly increased MVO2 (p < 0.000).
      None of the patients developed ischemic ST-segment modifications or complained of
      chest pain. Qbasal increased significantly in the LITA main stem (p = 0.001),
      distal LITA (p = 0.041) and RA (p = 0.004) while Qmax did not change
      significantly. As a consequence the flow reserve decreased in the LITA main stem
      (p = 0.002), distal LITA (p = 0.000) and RA (p = 0.000) but was not completely
      exhausted. CONCLUSIONS: Early after surgery arterial composite Y-grafts may
      significantly increase blood flow in response to conditions of increased MVO2 and
      maintain a normal myocardial oxygen supply-to-demand ratio.

PMID- 15185889
TI  - The rationale for facilitated percutaneous coronary intervention: philosophical
      speculation, methodological problem or practical need?

PMID- 15185890
TI  - Left atrial cardiac hemangioma: a report of two cases.
AB  - Cardiac hemangiomas are exceptionally rare tumors with an incidence of 1 to 3% of
      all detected benign heart neoplasms. We report 2 cases of left atrial hemangioma
      of which only one associated with clinical symptoms such as dyspnea and
      palpitations. Two years following surgical excision of the tumors, there was no
      echocardiographic evidence of recurrence.

PMID- 15185891
TI  - Asymptomatic cardiac lymphoma in a hepatitis C virus-positive thalassemic
      patient.
AB  - Primary cardiac non-Hodgkin lymphomas are fast-growing intracavitary and/or
      intramyocardial nodular masses, while secondary lymphomas most commonly
      infiltrate the cardiac tissue. By any definition, cardiac non-Hodgkin lymphomas
      usually manifest through arrhythmias, refractory heart failure, pericardial
      effusion, and embolic stroke. We here describe a case of a cardiac non-Hodgkin
      lymphoma in which the following, previously undescribed features manifest
      simultaneously. It occurred in a polytransfused hepatitis C virus-positive
      splenectomized thalassemic patient; it rapidly grew, giving rise to an enormous
      right atrial mass and, this notwithstanding, it was completely asymptomatic. This
      cardiac lymphoma was discovered during staging for a CD20+ large B-cell lymphoma
      of the tonsils. In particular, transesophageal echocardiography, showing that
      this prolapsing mass had a wide base on the atrial wall, led us to strongly
      suspect the lymphomatous origin of the mass itself. Notwithstanding anti-CD20
      antibody therapy, urgent surgery was unavoidable and histology revealed that the
      mass consisted of lymphoma proliferation infiltrating even the right atrial wall
      and the pericardium. During the postoperative course the patient presented with a
      massive, fatal hemopericardium consequent to intravascular disseminated
      coagulation. This very unusual case, occurring in a hepatitis C virus-positive
      thalassemic patient, suggests that a case control study on the incidence of non
      Hodgkin lymphoma in such patients may be interesting.

PMID- 15185892
TI  - Isolated distal coronary dissection in Marfan syndrome.

PMID- 15185893
TI  - Intracardiac proliferation of a very aggressive primary lung cancer.

PMID- 15185894
TI  - Italian Society of Cardiovascular Echography (SIEC) Consensus Conference on the
      state of the art of contrast echocardiography.
AB  - Part 1: Technical and methodological issues. Contrast echocardiography is based
      on the use of gas microbubbles. The size, gas composition and shell structure of
      the microbubbles modify their stability, resistance to pressure and scattering
      behavior. A proposed classification of contrast agents is based on the modalities
      of production of microbubbles (galenic or industrial); the industrial agents are
      divided into three generations depending on their characteristics. Following
      venous administration, the industrial microbubbles behave as intravascular free
      flowing tracers and this is fundamental for their use in perfusion studies. When
      insonated at a low acoustic pressure, microbubbles show a linear behavior and can
      be used for signal amplification. At intermediate acoustic pressures microbubbles
      resonate and produce a harmonic signal that is detectable by new scanners. Higher
      acoustic pressures cause microbubble disruption with emission of a transient
      acoustic signal. The available contrast agents behave differently in an
      ultrasound field. Part 2: Safety of contrast echocardiography. Galenic contrast
      agents were tested in many studies for intracoronary and intravenous injection
      and no clinically relevant side effects were detected. The intravenous injection
      of industrial contrast agents is safe in all conditions, even in acute coronary
      syndromes. The interaction between ultrasound and microbubbles produces energy
      with potential effects on tissue for inertial cavitation and acoustic current
      production. These effects seem particularly interesting for the therapeutic
      applications of contrast echocardiography, but they do not appear to have
      clinically relevant effects. Part 3: Experimental studies. Experimental studies
      in contrast echocardiography are designed to induce, in animal models, acute
      myocardial infarction and coronary artery stenosis and to evaluate the
      differences in blood flow. The risk area and infarct area are well visualized
      with serial contrast agent infusion. No-reflow after coronary occlusion is a well
      known phenomenon and is detectable at contrast echocardiography. Different
      degrees of induced coronary stenosis cause differences in the regional flow rate.
      The results of contrast echocardiographic studies are comparable with those of
      other invasive flow measurements. Caution must be used to transfer the knowledge
      acquired from animal studies to the clinical arena, owing to both methodological
      and anatomical differences. Part 4: Enhancement of Doppler signal and coronary
      flow study. The anterior descending coronary artery flow is detectable in almost
      all patients, and the posterior descending coronary artery in about 70%. The
      coronary flow reserve can be measured by injection of a vasodilator agent
      (dipyridamole or preferably adenosine) with a success rate of almost 100 % for
      the anterior descending but only 50 % for the posterior descending coronary
      artery. Data from transthoracic studies are comparable with those of Doppler flow
      wire. The fields of application presently include the evaluation of acute
      myocardial infarction, the short- and long-term results of percutaneous coronary
      interventions and coronary grafts, and the study of the microcirculation in
      several clinical conditions where the coronary flow reserve may be reduced, such
      as in syndrome X, hypertension, hypercholesterolemia or diabetes. Part 5:
      Endocardial border enhancement. Opacification of the left ventricle is the main
      indication to contrast echocardiography that, in this setting, is principally
      used to improve endocardial border delineation. This allows accurate evaluation
      of left ventricular volumes and function, increasing the role of echocardiography
      for the quantitative study of the left ventricle. Other indications for left
      ventricular opacification are the identification of intraventricular thrombosis,
      non-compaction of the left ventricle and heart rupture. In this respect,
      industrial second-generation contrast agents are more useful. The most
      appropriate patients for contrast echocardiography are those with a poor or
      suboptimal acoustic window, in whom a predictable diagnostic and prognostic
      usefulness of the procedure is expected. If appropriately used, contrast
      echocardiography is a cost-effective technique, although lack of reimbursement
      presently limits its use. Part 6: Use of contrast agents during stress
      echocardiography. Contrast agents during stress echocardiography may be used to
      improve the diagnostic accuracy of the test and to study myocardial perfusion.
      The diagnosis of ischemia in stress echo relies on the operator's visual
      assessment of changes in contractility during stress. Contrast agents must be
      considered an important tool that improve image quality especially in patients
      with an intermediate or poor acoustic window and their use has been reported to
      be cost-effective in the few studies designed to this end. The evaluation of
      myocardial perfusion during stress is certainly one of the most important goals
      of contrast echocardiography. Preliminary data are interesting but there is still
      a number of methodological problems that currently hamper clinical application.
      Part 7: Myocardial perfusion. Echocardiography has the potential of visualizing
      microbubbles in the microcirculation by detecting stimulated acoustic emission,
      produced by high-energy applied ultrasound, or by detecting the harmonic signal
      produced by resonance of the microbubbles in a low-energy ultrasound field. In
      the first case images are triggered at increasing end-systolic intervals
      (intermittent imaging), whereas in the second case entire cardiac cycles are
      analyzed (real-time imaging). Continuous infusion is the preferred method of
      maintaining a large and constant microbubble concentration inside the
      microcirculation. Analysis of the perfusion signal may be made in the
      qualitative, semi-quantitative or quantitative mode. Quantitative analysis is
      based on the construction of videointensity-time curves to study the refilling
      phase after complete microbubble destruction. There are not enough data in the
      literature showing the additional role of quantitative analysis for clinical
      purposes. Thus, at present, quantitative softwares should be considered as
      research tools. Conversely, there is a general consensus based on experimental
      and clinical studies on the use of myocardial contrast echo in patients with
      acute myocardial infarction by means of qualitative or semi-quantitative
      analysis. Important information on the infarct area extension, on the efficacy of
      reperfusion therapy, on the presence and extension of the no-reflow phenomenon
      and on the extent of residual tissue viability may be derived from the routine
      use of myocardial contrast echo. The reference technique still remains myocardial
      scintigraphy even though many theoretical problems are being discussed. Part 8:
      Implementing ultrasound contrast in the echocardiography laboratory. Contrast
      echocardiography should be considered an extension of the existing
      echocardiographic examination. Standard laboratory equipment is sufficient to run
      a contrast echocardiography program. However, cultural and technological
      upgrading is mandatory to obtain good results in contrast echocardiography.
      Intravenous infusion is easier during stress echocardiography than during rest
      study, because the time and cost for the venous line are comprised. In this
      setting, the cost-effectiveness for the addition of contrast agent is optimal,
      but patient selection is a critical point. The economic issue (contrast agent and
      personnel costs, and time needed) of contrast echocardiography determines the
      fact that without adequate reimbursement there is no incentive to perform the
      procedure.

PMID- 15185895
TI  - A promising advance in anticoagulant therapy for patients with atrial
      fibrillation.

PMID- 15185896
TI  - Stem cell transplantation for ischemic myocardium.

PMID- 15185897
TI  - Sexual activity with and without the use of sildenafil: risk of cardiovascular
      events in patients with heart disease.
AB  - The data in the literature on the relationship between sexual activity, with and
      without the use of sildenafil, and the occurrence of cardiovascular events
      (ventricular arrhythmias, nonfatal myocardial infarction, stroke and death) have
      been reviewed in patients with heart disease. To date, only patients with
      ischemic heart disease (IHD) have been investigated. The prevalence of premature
      ventricular beats during sexual intercourse is similar to that observed during
      other daily activities. Therefore, sexual activity does not seem to have a
      relevant arrhythmogenic effect. The incidence of sustained ventricular
      tachycardia during sexual intercourse in unknown. The relative risk of nonfatal
      myocardial infarction is 2.7 in males and 1.3 in females; however, the absolute
      risk appears extremely low and is similar in normal subjects and in patients with
      and without IHD. The risk appears to be restricted to the 2-hour time period
      after sexual intercourse. The incidence of stroke during sexual intercourse
      appears very low, but clear data are lacking. The incidence of death during
      sexual activity is unknown; the few available data suggest that it is very low.
      Extramarital sexual intercourse seems to increase the risk of death. The
      incidence of cardiovascular events after sildenafil administration has been
      investigated in placebo-controlled studies in patients with IHD. The incidence of
      nonfatal myocardial infarction, stroke and death did not significantly differ
      between sildenafil-treated and placebo-treated patients; therefore, sildenafil
      does not appear contraindicated in subjects with IHD. However, the drug should be
      administered with caution in patients with recent myocardial infarction or
      stroke, in those with active coronary ischemia and in patients with episodes of
      heart failure. The drug is absolutely contraindicated in patients using nitrates.

PMID- 15185898
TI  - Infectious agents and atherosclerosis: current perspectives and unsolved issues.
AB  - The large amount of data accumulated in recent years has reinforced the idea that
      infectious agents may play a significant role in the pathogenesis of
      atherosclerosis and in the clinical manifestations of vascular disease.
      Seroepidemiological and experimental data linking Herpesviridae and Chlamydia
      pneumoniae to atherosclerosis appear to be confirmed by a number of studies,
      while the available evidence regarding Helicobacter pylori is more conflicting,
      partly due to the fact that the interest in this agent is more recent. Infectious
      agents may influence atherogenesis through a number of mechanisms, ranging from
      cell lysis to the stimulation of adhesion molecule expression and cytokine
      production by infected cells. The development of atherosclerosis after an acute
      infection seems unlikely. Rather, it appears that a chronic, persistent form of
      infection, especially with Chlamydia pneumoniae, may favor those structural and
      proinflammatory changes in the vascular wall which are necessary for the
      formation of an atheroma. A persistent chlamydial infection is accompanied by an
      increased production of microbial heat shock protein 60, which may induce
      antigenic mimicry and a chronic inflammatory reaction in the vascular wall.
      Pharmacological trials have yielded conflicting indications regarding the
      hypothesis that treatment with macrolide antibiotics may limit the progression of
      vascular disease and the recurrence of cardiovascular events, although in a
      limited number of cases. However, antimicrobial drugs do not act specifically
      against a single infectious agent and more specific therapeutic agents would be
      needed in order to test a causative link between a single infectious agent and
      vascular disease.

PMID- 15185899
TI  - Has anything changed in multivessel coronary artery revascularization in diabetes
      since BARI?
AB  - Diabetic patients have an increased risk of coronary disease partly due to a
      higher frequency of associated risk factors including hypertension and
      hyperlipidemia but also from specific risks largely resulting from insulin
      resistance, hyperinsulinemia and hyperglycemia. This has resulted in a greater
      need for revascularization. Despite this there are few randomized data comparing
      surgery and angioplasty in patients with diabetes. The evidence to define the
      best operative strategy is limited, mainly confined to a subanalysis of the BARI
      trial suggesting the superiority of surgery in patients with multivessel disease.
      However there has been in Europe a wide increase in multivessel angioplasty, even
      in diabetic patients. This article discusses the higher risk of patients with
      diabetes, the data comparing surgery and angioplasty and outlines the advances in
      angioplasty since BARI.

PMID- 15185900
TI  - Effects of cardiac resynchronization therapy on disease progression in patients
      with congestive heart failure.
AB  - BACKGROUND: Cardiac resynchronization therapy (CRT) represents a new therapeutic
      modality of proven efficacy for selected patients with heart failure and
      ventricular asynchrony. The aim of this study was to assess the effects of CRT on
      clinical variables and cardiac remodeling in patients with moderate-to-severe
      congestive heart failure and inter/intraventricular conduction delays. METHODS:
      Thirty-seven patients (32 males, 5 females, mean age 73 +/- 7 years), in NYHA
      functional class III-IV, with left ventricular ejection fraction (LVEF) < or =
      35%, QRS > or = 150 ms, and left ventricular end-diastolic diameter (LVEDD) > or
      = 55 mm, underwent CRT by biventricular pacing (InSync, InSync III, InSync ICD;
      Medtronic Inc.). Fourteen (37.8%) had a previous pacemaker, and 11 (29.7%) were
      in permanent atrial fibrillation. The QRS width, NYHA functional class, LVEDD,
      left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic
      volume (LVEDV), left ventricular endsystolic volume (LVESV), and LVEF were
      retrospectively evaluated in the period before CRT. For the purposes of the
      present study, the pre-CRT period was divided in two: T(-2) (from 6 to 3 years)
      and T(-1) (from 3 years to CRT). Moreover, these parameters were measured at the
      time of CRT (T0) and prospectively in the post-CRT follow-up (Tp). RESULTS:
      Before CRT, a progressive worsening of the parameters was observed. The QRS
      duration steadily increased from T(-2) to T(-1) and T0 (both p = 0.000). The NYHA
      functional class increased from T(-2) to T(-1) and T0 (both p = 0.000). LVEDD and
      LVESD also increased and were higher at T(-1) (p = 0.001 and p = 0.000,
      respectively) and at T0 (both p = 0.000) compared to T(-2). Similar results were
      observed for LVEDV and LVESV. Finally, LVEF was higher at T(-2) than T(-1) and T0
      (both p = 0.000). After CRT, there was a reduction in the QRS duration and an
      improvement in the NYHA functional class compared to T0 (both p = 0.000). LVEDD
      and LVESD were also reduced (p = 0.005 and p = 0.016, respectively), LVEDV and
      LVESV decreased (both p = 0.000), and LVEF increased (p = 0.000) with respect to
      T0. A highly significant correlation was found between LVEDD and LVESD both in
      the pre- and post-CRT time intervals, with a non-significant difference between
      the two linear regression lines. Similar results were obtained for the
      correlations between LVEDV and LVESV. CONCLUSIONS: Congestive heart failure is
      associated with a progressive widening of the QRS complex and a worsening of the
      clinical status and results in anatomic remodeling with deterioration of the left
      ventricular function. CRT induces opposite changes in QRS duration, clinical
      status, and left ventricular remodelling.

PMID- 15185902
TI  - Myocardial revascularization with and without cardiopulmonary bypass in
      multivessel disease patients.
AB  - BACKGROUND: Off-pump coronary artery bypass surgery is widely performed because
      of its proved safety, but its effectiveness remains controversial. The aim of
      this retrospective study was to compare early and late results in patients with
      multivessel disease, operated on off-pump and on-pump. METHODS: From November
      1994 to December 2001, 2957 patients with multivessel disease underwent isolated
      coronary revascularization, on-pump (n = 1924) and off-pump (n = 1033). Sixty
      five patients (2.2%) who were converted from off-pump to on-pump were considered
      as part of the off-pump group. RESULTS: Stepwise logistic regression analysis
      showed that the use of cardiopulmonary bypass was an independent predictor for
      early death, early negative primary endpoints, and early major events. Conversion
      to on-pump was an independent risk factor for a higher incidence of death due to
      any cause and cardiac death, early negative primary endpoints, and early major
      events. Conversion, however, did not affect late clinical outcome. The 6-year
      freedom from death (any cause, cardiac cause), myocardial infarction,
      redo/coronary angioplasty and any events was similar in the two groups.
      CONCLUSIONS: These results suggest that off-pump surgery reduces early mortality
      and morbidity. These benefits are not at the expense of the long-term clinical
      outcome which seems to be similar in the two groups. Patients who require
      conversion from off-pump to on-pump have a much higher mortality and morbidity
      although this does not seem to influence their long-term clinical outcome.

PMID- 15185901
TI  - Endothelial dysfunction in patients with kidney failure and vascular risk
      factors: acute effects of hemodialysis.
AB  - BACKGROUND: Patients with kidney failure present endothelial dysfunction, which
      was shown to be partly corrected by hemodialysis. No data exist on the effects of
      hemodialysis on endothelial dysfunction in kidney failure patients with
      associated vascular risk factors. The aim of this study was to evaluate the acute
      effects of hemodialysis on endothelial dysfunction in patients with kidney
      failure and associated vascular risk factors and to assess the role of
      endothelium-toxic substances. METHODS: We assessed endothelial dysfunction in 13
      patients with chronic renal failure and other vascular risk factors before and
      after hemodialysis and in 13 healthy controls and simultaneously measured nitric
      oxide (NO) synthesis and activity. Endothelial dysfunction was studied using an
      echographic method as flow-mediated dilation (FMD) of the brachial artery; plasma
      NO2- and NO3-, cyclic guanosine-5-monophosphate (cGMP), plasma homocysteine
      levels and low molecular mass-advanced glycation end-products (LMM-AGEs) were
      simultaneously measured. RESULTS: As compared with healthy controls, patients
      with renal failure showed a reduced FMD (2.89 +/- 1.43 vs. 7.81 +/- 1.54%, p <
      0.01) which was not corrected by dialysis (after dialysis 2.40 +/- 1.65%, p = NS
      vs. pre). Plasma NO2- and NO3- were normal or slightly increased and remained
      unchanged after dialysis. Plasma cGMP levels were reduced and remained unchanged
      after dialysis. Homocysteine and LMM-AGE plasma levels were raised and, although
      significantly reduced by dialysis, remained higher than in controls. CONCLUSIONS:
      Patients with kidney failure and associated vascular risk factors show an
      endothelial dysfunction related to defective NO activity, which is not corrected
      by hemodialysis despite the reduction, though not to normal, in homocysteine and
      LMM-AGE levels. Endothelial dysfunction may contribute to the progression of
      atherosclerosis in patients with kidney failure and vascular risk factors.

PMID- 15185903
TI  - Cardiac precursors in human bone marrow and cord blood: in vitro cell
      cardiogenesis.
AB  - BACKGROUND: Cell transplantation has come of age but numerous questions still
      remain. Which type of cell should be used? Cardiac precursors are present in
      mouse bone marrow and used to repair the infarcted myocardium in mice. We
      searched for these precursors in human bone marrow and analyzed gene expression
      patterns in cells induced to differentiate in vitro. METHODS: Cells from human
      bone marrow were isolated and cultured in medium supplemented with autologous
      serum and 5% CO2. Cell characterization was performed by immunocytochemical
      analysis. mRNA was isolated and retrotranscribed. The active genes were detected
      with polymerase chain reaction by using specific oligonucleotides. RESULTS: Some
      inducers pushed the cell through different stages of cardiogenesis, with
      expression of cardiac transcriptional activators and structural proteins. Some
      combinations of stimuli were able to drive cells to advanced stages of
      cardiogenesis. CONCLUSIONS: These studies lead to an exact description of in
      vitro cardiogenesis in humans. Our aim was also to assess the residual
      proliferative capacity of cells and to enhance the differentiation efficiency,
      thus maximizing their repair capacity and the likelihood that they functionally
      integrate with the surrounding cardiac tissue.

PMID- 15185904
TI  - Late concomitant repair of tetralogy of Fallot and aortic valve replacement
      following successful pregnancy.
AB  - The importance of patient follow-up after repair of tetralogy of Fallot, with
      special attention to the development of arrhythmias, has been widely studied. It
      is only recently that postoperative problems relating to the aortic root of these
      individuals have been looked into. The present case report refers to a patient
      with tetralogy of Fallot who underwent complete correction, together with aortic
      valve replacement at 33 years of age following a successful pregnancy. To our
      knowledge, this is the third report of primary repair of tetralogy of Fallot with
      simultaneous aortic valve replacement for severe aortic regurgitation. Our
      patient is unique in that she had uncorrected and unpalliated tetralogy of Fallot
      and severe aortic regurgitation and still went through an uneventful pregnancy
      and delivery. There is only one report of successful pregnancy and delivery in
      uncorrected tetralogy, but this was not associated with aortic regurgitation.

PMID- 15185905
TI  - Intracardiac echocardiography using the AcuNav ultrasound catheter during
      percutaneous closure of multiple atrial septal defects.
AB  - Transesophageal echocardiography is routinely used in catheterization
      laboratories to guide the percutaneous closure of ostium secundum atrial septal
      defects. The patient is under general anesthesia, and the interatrial septum
      anatomy is usually well defined. Multiple atrial septal defects are, in some
      cases, a challenge for both the interventional echocardiographer and the
      interventional cardiologist, when trying to evaluate the anatomy of the defects,
      the strategy of closure and the correct choice of the device. We describe the
      usefulness of a new phased-array ultrasound-tipped catheter for intracardiac
      echocardiography in a case of percutaneous closure of multiple ostium secundum
      atrial septal defects.

PMID- 15185906
TI  - Neurocardiogenic syncope: a case of prolonged asystole.
AB  - We report the case of a 48-year-old woman with frequent episodes of loss of
      consciousness. The patient was submitted to head-up tilt testing that evoked a
      prolonged asystole associated with sphincteric incontinence and loss of urine.
      The patient was treated with dual-chamber pacemaker implantation; at a follow-up
      of 18 months no other episodes of syncope had occurred.

PMID- 15185907
TI  - Twiddler's syndrome and pectoral stimulation in a patient with dual-site unipolar
      atrial pacing.
AB  - Twiddler's syndrome is a rare condition of pacemaker rotation; when associated
      with unipolar pacing it could provoke extracardiac muscular stimulation. We
      report a case of an obese woman who unintentionally reversed her triple-chamber,
      dual-site unipolar atrial pacemaker, implanted for the prevention of paroxysmal
      atrial fibrillation. The extracardiac pectoral stimulation was due to unipolar
      atrial stimulation. The polarity mode was not programmable and output reduction
      was unsuccessful. Thus, the problem was resolved noninvasively by means of
      external manual rotation of the pacer. At 24 months of follow-up, the patient was
      still free of symptoms.

PMID- 15185909
TI  - Sirolimus-eluting stent implantation in a heart transplant recipient.

PMID- 15185908
TI  - Acute myocardial infarction after radiofrequency catheter ablation of typical
      atrial flutter: histopathological findings and etiopathogenetic hypothesis.
AB  - The right atrial inferior cavotricuspid isthmus represents the targeting site for
      radiofrequency (RF) current application during ablation treatment of typical
      atrial flutter. Despite the vicinity of the right coronary artery (RCA) to the RF
      application site and the long energy exposure needed to achieve
      electrophysiological success, reports about direct thermal damage of the coronary
      vessel during ablation of the cavotricuspid isthmus are rare and anecdotal. The
      present is the first case report describing the cardiac macroscopic and
      histological examination in a patient who died of cardiac rupture, as a
      complication of a myocardial infarction occurring after a standard procedure of
      RF ablation of typical atrial flutter. In consideration of the proximity we found
      between the RF energy-dependent tissue damage and the RCA, thermal-related damage
      of RCA during ablation of typical atrial flutter should always be considered as a
      potentially harmful risk of the procedure.

PMID- 15185910
TI  - Prevention of cardiovascular disease: challenges and opportunities.

PMID- 15185911
TI  - The redefinition of acute myocardial infarction.
AB  - In the year 2000 a consensus document of the Joint European Society of
      Cardiology/American College of Cardiology Committee proposed new diagnostic
      criteria for acute myocardial infarction (MI), emphasizing the role of more
      sensitive and specific serologic biomarkers of myocardial necrosis. Although
      several criticisms soon followed this redefinition of acute MI, it was expected
      that these new criteria would substantially impact the clinical management and
      prognosis of patients with coronary artery disease. Important consequences on the
      health care system and government policies were supposed as well. However, 4
      years later a substantial proportion of patients with acute MI are still
      diagnosed according to the old World Health Organization criteria, irrespective
      of the results of biomarker assays. This finding indicates that the redefinition
      of acute MI is far from being universally adopted. Thus, the reasons that
      hampered a widespread diffusion of such criteria, mainly a mixture of technical,
      logistic and cultural points, and the main, still controversial issues are
      discussed and commented on.

PMID- 15185912
TI  - New cardiovascular risk factors: homocysteine and vitamins involved in
      homocysteine metabolism.
AB  - Among various cardiovascular risk factors, hyperhomocysteinemia has recently
      emerged as an important one. While there are currently no doubts on the
      relationship between severe hyperhomocysteinemia and vascular disease, some
      uncertainty still persists on the relationship between mild hyperhomocysteinemia
      and vascular disease. Several group B vitamins, namely vitamin B6, vitamin B12,
      and folate, influence homocysteine metabolism, being cofactors of the main
      metabolic pathways which allow the disposal of this amino acid. There are also,
      however, suggestions from the literature that group B vitamins, and in particular
      vitamin B6 (pyridoxine/pyridoxal-phosphate), are modulators of cardiovascular
      risk independent of homocysteine. The results of a recent study of ours, with a
      long follow-up, indeed suggest that homocysteine and vitamin B6 are independent
      and additive cardiovascular risk factors.

PMID- 15185913
TI  - New echocardiographic technologies in the study of acute myocardial infarction.
AB  - Echocardiography has a key role in the diagnostic and prognostic evaluation of
      patients in the different phases of acute myocardial infarction. Despite this
      important role of the conventional echocardiographic technologies, novel
      echocardiographic applications are under development or already used in the
      clinical practice. It is very difficult to distinguish which of these techniques
      will play a consistent role and will cover important diagnostic, prognostic and
      therapeutic use. The wise cardiologist will be the one who will choose the
      appropriate technology for the right subset of patients. In this review paper we
      try to assign to each novel echocardiographic technique its actual clinical
      weight in every pathophysiological condition: myocardial contrast
      echocardiography, contrast opacification of the left ventricle, coronary flow
      reserve study, integrated backscatter, tissue Doppler and strain rate imaging.
      For the best treatment choice, each patient has to be perfectly diagnosed and
      characterized in order to have a tailored therapy. A correct diagnosis of the
      extension of myocardial necrosis cannot ignore the transmural wavefront
      development, the amount of viable myocardium or the presence of microvascular
      damage. Also the simple echocardiographic wall motion akinesia can be caused by a
      variable extension of non-contracting, scarred myocardium. The different anatomic
      and functional intramyocardial patterns represent the basis for different
      functional outcome of regional and hence global left ventricular function. The
      greatest understanding of the pathology always leads to the best treatment.

PMID- 15185914
TI  - Echocardiography in left ventricular dysfunction.
AB  - Left ventricular (LV) function is an important predictor of cardiac morbidity and
      mortality. The role of echocardiography in the assessment of LV function is well
      established and has been expanded over the last few years with the development of
      new methodologies. Echocardiography can assess LV global and regional function,
      as well as systolic and diastolic function. It has the ability to measure
      volumes, including cardiac output, pressures, LV mass, dP/dt. It can also assess
      regional dysfunction using the wall motion score. However quantitation by
      standard echo can be limited, due to poor endocardial definition, time-consuming,
      and reproducibility, lack of accuracy, particularly considering it takes a lot of
      geometric assumptions. Therefore, new methodologies have been recently developed
      to increase echo accuracy. These include the introduction of second harmonics,
      which is becoming a standard in most equipments; the use of contrast echo to
      improve LV opacification and endocardial border definition; color kinesis, which
      allows automated segmental motion analysis; tissue Doppler imaging, which can
      help in the assessment of regional and diastolic function; and more recently the
      ability to assess strain and strain rate. This last technology has the ability to
      quantify local myocardial deformation and it has shown to be a potential strong
      marker of ischemia, as well as a predictor of LV myocardial recovery
      postrevascularization. In conclusion, echocardiography is widely used to assess
      LV function. The recent developments of new ultrasound-related technologies have
      further increased the interest and importance of echocardiography in the
      assessment of LV function.

PMID- 15185915
TI  - Diastolic heart failure.
AB  - Diastolic heart failure is characterized by the presence of heart failure with
      preserved left ventricular ejection fraction (LVEF): documentation of diastolic
      dysfunction, usually by Doppler echocardiography, is strongly recommended. Heart
      failure with preserved LVEF is a heterogeneous and common condition, especially
      in the elderly, among whom represents up to 50% of all heart failure patients.
      Mortality is generally lower than in patients with heart failure and low LVEF,
      and depends on etiology, patient conditions, and comorbidities. Anyway, morbidity
      is very high. So far, treatment of diastolic heart failure is empirical, and is
      aimed to maintain cardiac output, reduce filling pressure, control heart rate and
      rhythm, and antagonize disease progression with diuretics, inhibitors of the
      renin-angiotensin-aldosterone system, nitrates, and digoxin.

PMID- 15185916
TI  - Hospitalization for worsening chronic heart failure.
AB  - The total number of admissions for heart failure (HF) in the United States is
      approaching 1 million/year. HF is the number one volume diagnosis in the Medicare
      health system. Readmission rates are as high as 30 to 60% within 3 to 6 months
      after discharge even in patients without renal failure, low blood pressure or
      significant arrhythmias. Patients admitted with HF can be classified into three
      categories: new-onset HF (5% of total admissions), end-stage or refractory HF
      (5%), and worsening chronic HF (90%). This review will focus on the epidemiology,
      prognosis, pathophysiology and pharmacological treatment of patients hospitalized
      for worsening chronic HF.

PMID- 15185917
TI  - New positive inotropic agents in the treatment of left ventricular dysfunction.
AB  - Three major classes of inotropic agents have been clinically evaluated in
      patients with left ventricular dysfunction: a) agents that increase the
      intracellular concentration of cyclic adenosine monophosphate by stimulating the
      beta-adrenergic receptor or inhibiting phosphodiesterase; b) drugs that increase
      the intracellular sodium concentration; c) the new calcium-sensitizing drugs.
      This review will focus on the newest drug for each of the above-mentioned classes
      of inotropic agents. Moreover, we present a new protocol which provides the use
      of levosimendan in patients with post-ischemic left ventricular dysfunction.

PMID- 15185918
TI  - Cardiac contractility modulation by non-excitatory electrical currents. The new
      frontier for electrical therapy of heart failure.
AB  - Heart failure (HF) may complicate ischemic heart disease in both its acute and
      chronic manifestations, representing a prevalent health problem throughout the
      world. Development of therapies to improve heart function, relieve symptoms,
      reduce hospitalizations and improve survival is a high priority in cardiovascular
      medicine. The available pharmacological strategies, including angiotensin
      converting enzyme inhibitors, angiotensin receptor antagonists, beta-blockers,
      and aldosterone receptor antagonists have recently been complemented by new
      electrical therapy, including implantable cardioverter-defibrillators for "MADIT
      II" patients and cardiac resynchronization for the 30% of HF patients with
      concomitant intraventricular conduction delay. The wide variety of available HF
      medications provides ample evidence that we have not yet succeeded in this
      effort. Safe and effective inotropic electrical therapy could be a useful
      addition to our therapeutic armamentarium in an attempt to correct Ca2+ fluxes
      abnormalities during the cardiac action potential. Cardiac contractility
      modulation (CCM) by means of non-excitatory electrical currents delivered during
      the action potential plateau has been shown to acutely enhance systolic function
      in humans with HF. Herewith, we report on our preliminary experience with CCM
      therapy for patients with HF, providing fundamental notions to characterize the
      rationale of this novel form of therapy. Briefly, CCM therapy appears to be safe
      and feasible. Proarrhythmic effects of this novel therapy seem unlikely.
      Preliminary data indicate that CCM gradually and significantly improves systolic
      performance, symptoms and functional status. The technique would appear to be
      attractive as an additive treatment for severe HF. Controlled randomized studies
      are needed to validate this novel concept.

PMID- 15185919
TI  - Primary coronary intervention in acute myocardial infarction.
AB  - Percutaneous coronary intervention (PCI) with stent implantation has become the
      standard of care for acute myocardial infarction <12 hours from symptom onset.
      This has led to decreased morbidity and mortality both short and long term
      compared to thrombolytic therapy. Stent implantation has been demonstrated to be
      superior to balloon PCI for mechanical reperfusion of acute myocardial
      infarction. Intravenous antiplatelet glycoprotein IIb/IIIa inhibitors may have a
      role in improving TIMI flow prior to PCI and decreasing morbidity and mortality.
      The role of thrombolytics vs. IIb/IIIa inhibitors in "facilitated reperfusion" is
      unclear at this time and further research is needed to define the indication of
      adjunctive pharmacology.

PMID- 15185920
TI  - Which is the best reperfusion strategy for patients with high-risk myocardial
      infarction?
AB  - Systemic thrombolysis and primary percutaneous coronary intervention (PCI) are
      both effective treatments for acute ST-elevation myocardial infarction. Several
      randomized trials have shown that primary PCI is superior to thrombolytic therapy
      in acute myocardial infarction (AMI). Despite these findings, thrombolytic
      therapy remains an acceptable alternative for most patients, yet it may not be
      ideal for higher-risk AMI patients. Advanced age, diabetes mellitus, anterior
      infarction, severe tachycardia, shock and comorbidities are associated with early
      mortality rates ranging from 10 to 58% in patients treated with thrombolytic
      agents. This review will examine the data comparing primary PCI and systemic
      thrombolysis in the different clinical conditions which identify patients at high
      risk in the setting of AMI.

PMID- 15185921
TI  - Surgical treatment of acute myocardial infarction.
AB  - BACKGROUND: The role of surgical revascularization in the treatment of acute
      myocardial infarction (AMI) has changed considerably over the last 30 years along
      with improvement in intraoperative management and techniques of myocardial
      protection. The aim of this work was to analyze the long-term results of our
      experience of emergency myocardial surgical revascularization for AMI. METHODS:
      Between January 1986 and October 2003, 237 patients (85.3% males; mean age 59.6
      +/- 9.6 years) underwent emergency coronary artery bypass graft for severe AMI.
      At admission 82 patients (34.6%) were in cardiogenic shock, while 124 patients
      (52.3%) presented major preoperative complications (acute pulmonary edema,
      mechanical ventilation, intra-aortic counterpulsation, cardiac arrest).
      Preoperative intra-aortic counterpulsation was performed in 125 patients (52.7%).
      The mean time interval between symptom onset and surgery was 9.4 hours. Three
      vessel disease was detected in 107 patients (45%), with main left stenosis in
      12.9%. RESULTS: There were overall 50 hospital deaths (21.1%). Amongst patients
      with major preoperative complications, mortality was 36.2% (45 cases out of 124);
      mortality for cardiogenic shock was 40.2% (33 patients out of 82). Survival of
      the first 140 patients undergoing operation and then discharged was 97.8% at 1
      year and 79.6% at 5 years. The survival rate of the first 60 patients in
      cardiogenic shock operated on and then discharged is 98.8% at 1 year and 81.2% at
      5 years. The ejection fraction in 102 echocardiographically controlled patients
      was 37.2 +/- 8.5% preoperatively and 44.0 +/- 10.1% at pre-discharge (p =
      0.0001). CONCLUSIONS: Surgical revascularization for AMI, especially if
      complicated by cardiogenic shock, is a valid therapeutic option that carries a
      high periprocedural risk but that is balanced by a satisfactory late survival. A
      more precise patient's risk assessment at admission, improvement of surgical and
      myocardial protection techniques, extensive use of intra-aortic counterpulsation,
      and new circulatory support when needed, can improve outcomes and late survival.

PMID- 15185922
TI  - Surgical options in ischemic cardiomyopathy.
AB  - The prevalence of ischemic dilated cardiomyopathy in western countries is
      increasing despite improvements in prevention, diagnosis, and treatment of
      cardiovascular disease. The management of patients with coronary artery disease
      and severe left ventricular dysfunction continues to be challenging and the
      mortality rate with medical therapy alone in this setting remains very high.
      Since heart transplantation represents a realistic option just for a very small
      number of patients, in recent years a variety of classic surgical interventions
      have been improved or optimized to address the complex and multifactorial
      pathophysiology of the ischemic heart failure picture. Myocardial
      revascularization, left ventricular restoration, mitral valve repair, passive
      containment device implantation, and surgical ablation of atrial fibrillation
      represent some of the "conventional" procedures which are currently in use or
      under development for the surgical treatment of ischemic cardiomyopathy. For
      several of them, the exact indications and results are not yet established and
      significant changes and improvements should reasonably be waited over the next
      few years. As techniques are refined and more data become available, the optimum
      surgical strategy for patients with advanced ischemic heart failure is likely to
      become clearer and more effective.

PMID- 15185923
TI  - Cell transplantation: a novel perspective in the treatment of heart failure.
AB  - Stem cell transplantation has been proposed as a novel experimental strategy to
      treat heart diseases, such as acute myocardial infarction and heart failure. The
      beneficial effects of transplanted cells may include active contribution to
      contractile function, passive improvement of cardiac mechanics, induction of
      neoangiogenesis or other indirect influences on the biology of the heart. Several
      cell types have been used for cardiac transplantation. These include embryonic
      stem cells, bone marrow stem cells, and skeletal myoblasts. Encouraging results
      have been obtained in experimental ischemic and non-ischemic heart disease that
      show sustained cell survival after transplantation, integration into the host
      myocardium, and functional improvement of diseased hearts. Furthermore,
      preliminary data, obtained in patients with acute myocardial infarction, suggest
      that the observation obtained in the experimental animal may be transferred to
      the clinical arena in the near future. These observations fueled an exciting
      period of discovery and high expectations followed by controversies that need to
      be addressed before this strategy can be added to the therapeutic options for
      patients with heart disease.

PMID- 15185924
TI  - Identification of a third Boophilus microplus (Acari: Ixodidae) cDNA
      presumptively encoding an acetylcholinesterase.
AB  - Oligodeoxynucleotide primers, based on amino acid sequences conserved in known
      acetylcholinesterases (AChEs), were used in reverse-transcription polymerase
      chain reaction (RT-PCR) with mRNA from Boophilus microplus (Canestrini) as the
      template. Primer walking and rapid amplification of cDNA ends (RACE) techniques
      were used to complete the cDNA sequence identified by RT-PCR. The complete B.
      microplus cDNA sequence contained an open reading frame encoding a 620 amino acid
      protein with a 20 amino acid signal peptide at the N-terminus targeting the
      protein for the secretion pathway. BLAST searches of GenBank using the
      presumptively encoded protein revealed highest sequence similarity to AChEs. The
      presumptively encoded protein was of similar size and structural properties to
      other identified AChEs, including the presence of the catalytic triad (Ser, Glu,
      His) and appropriate placement of internal cysteines to yield three internal
      disulfide bonds corresponding to those of known AChEs. Putative conserved domains
      identified the sequence as a member of the carboxylesterase family, pfam00135.8,
      of which AChE is a member. This cDNA therefore presumptively encodes a third
      transcribed AChE (AChE3) cDNA of B. microplus. Comparison of the three AChE eDNA
      sequences expressed in B. microplus demonstrated no discernible nucleotide
      sequence homology and relatively low amino acid sequence homology, strongly
      suggesting that they are not alleles of one another. The potential presence of
      multiple expressed AChEs in B. microplus suggests alternative mechanisms for
      development of resistance to pesticides that target AChE. The homology-based
      identification of a third expressed AChE in B. microplus is a surprising result
      and strongly implies the need for confirmation of gene identity for presumptive
      AChEs.

PMID- 15185925
TI  - Analysis on the dispersal pattern of newly introduced Latrodectus hasseltii
      (Araneae: Theridiadae) in Japan by spider diagram.
AB  - The dispersal pattern of the widow spider Latrodectus hasseltii (Araneae:
      Theridiadae), in Osaka Prefecture, Japan, was analyzed from accumulated survey
      data of spider distribution. All confirmed infested points from 1996 to 2002 were
      plotted on a map, and infested points in each survey year were connected with the
      nearest previously confirmed points. Expansion patterns of the confirmed habitats
      were analyzed by year and dispersion distances were classified by using spider
      diagram, one of method of geographical information system spatial analysis. L.
      hasseltii moves by walking step by step on the ground, mainly in coastal areas
      during early stages of infestation, and also can be conveyed over distances by
      various vehicles, mainly in inland areas. These analyses show L. hasseltii does
      not move by ballooning.

PMID- 15185926
TI  - Phylogenetic analysis of the Francisella-like endosymbionts of Dermacentor ticks.
AB  - Bacterial endosymbionts with significant homology to Francisella tularensis
      (gamma-proteobacteria) have been described from at least five species of ticks in
      three different genera, including two North American Dermacentor species [D.
      andersoni Stiles and D. variabilis (Say)]. The evolutionary relationships among
      the Francisella-like endosymbionts (FLE) from different hosts and between FLE and
      the arthropod-borne pathogen F. tularensis are not known. A 1,169-base fragment
      of the 16s rDNA and a 713-base fragment of the F. tularensis 17-kDa lipoprotein
      gene homolog of the FLE of six North American Dermacentor tick species [D.
      anderson, D. variabilis, D. albipictus (Packard), D. occidentalis Marx, D.
      hunteri Bishopp, and D. (Anocentor) nitens Neumann] and of Amblyomma maculatum
      Koch and Ornithodoros porcinus (Murry 1877, sensu Walton 1979) as outgroups, were
      subjected to phylogenetic analysis. These gene phylogenies were compared with a
      phylogeny of the same tick species constructed from a 435-base fragment of the
      tick mitochondrial 16s rDNA. Although the phylogenies of the FLE and their tick
      hosts are parallel at the genus level, the Dermacentor FLE are unresolved at the
      species level. The FLE and the Dermacentor ticks show little sign of co
      speciation, possibly indicating that the association between these endosymbiont
      and the Dermacentor ticks is of a relatively recent origin. Several ticks were co
      infected, either with two FLE with divergent 17-kDa lipoprotein gene sequences or
      with FLE and an unidentified species of spotted fever group rickettsia (alpha
      proteobacteria). Infection with FLE does not seem to have precluded infection
      with either a second closely related gamma-proteobacterial symbiont or with a
      second less closely related alpha-proteobacterial symbiont.

PMID- 15185927
TI  - Molecular evidence of speciation between island and continental populations of
      Anopheles (Cellia) sundaicus (Diptera: Culicidae), a principal malaria vector
      taxon in Southeast Asia.
AB  - Anopheles sundaicus s.l. is a principal malaria vector taxon on islands and along
      the coastal areas of Southeast Asia. It has a wide geographical distribution and
      exhibits a high level of ecological and behavioral variability. Study of this
      taxon is crucial for understanding its biology and implementing effectise vector
      control measures. We compared populations of An. sundaicus from Vietnam,
      Thailand, and Malaysian Borneo by using two mitochondrial DNA markers: cytochrome
      oxidase I and cytochrome b. Genetic divergence, geographic separation, and
      cladistic analysis of relationships revealed the presence of two cryptic species:
      Anopheles sundaicus s.s. on Malaysian Borneo and An. sundaicus species A in
      coastal areas of Thailand and Vietnam. A polymerase chain reaction (PCR) assay
      was developed to easily identify these two species throughout their geographic
      distributions. The assay was based on sequence characterized amplified region
      derived from random amplified polymorphic DNA. This PCR identification method
      needs to be validated and adapted for the recognition of other possible species
      in the Sundaicus Complex.

PMID- 15185928
TI  - Metric variation among geographic populations of the Chagas vector Triatoma
      dimidiata (Hemiptera: Reduviidae: Triatominae) and related species.
AB  - Eight Triatoma dimidiata populations from different geographic regions were
      compared along with related species using traditional morphometry of head
      characters. A method for removing allometric change was used for the
      intraspecific comparisons, and scaling for the isometric change of size was used
      for the interspecific comparisons. The intraspecific comparison showed
      significant head shape differences between T. dimidiata populations correlating
      with geography, showing a separation between the northern, intermediate, and
      southern collections (more evident in females), and supporting the idea that this
      species includes several evolutionarily divergent populations. The positioning of
      one sylvatic group from Guatemala did not correlate with geography, because it
      was more closely related to a distinct population of Colombia. This sylvatic
      group was found in caves, while the Colombian specimens, although collected in
      houses, may have migrated from nearby caves. Evolutionary and/or ecological
      influences could be responsible for the head shape similarities between these two
      groups: a common ancestral origin of both populations or a morphological
      convergence caused by similar environmental pressures. The interspecific
      comparisons included four other regional species of the same genus, three of them
      belonging to the phyllosoma complex (T. pallidipennis, T. mexicana, and T.
      ryckmani, the latter provisionally) and the fourth one classified in the
      protracta complex (T. nitida). Both complexes were readily separated by their
      head dimensions, even after size adjustment, and our data support inclusion of T.
      dimidiata within the phyllosoma complex.

PMID- 15185929
TI  - Malaria vector anopheles (Nyssorhynchus) nuneztovari comprises one genetic
      species in colombia based on homogeneity of nuclear ITS2 rDNA.
AB  - Previous studies indicated that two distinct chromosomal forms of Anopheles
      nuneztovari Gabaldon, cytotypes B and C, occurred on the west and east of the
      Latin American Andes Mountains, respectively. To determine the taxonomic status
      ofAnopheles (Nyssorhynchus) nuneztovari in Colombia, link-reared specimens were
      collected from four sites: in the departments of Choco (La Pacurita) and Valle
      (Sitronella) in the west, and Norte de Santander (Guaramito andl Tibu) in the
      east. Nuclear ITS2 sequences were generated for 46 individuals. Only two
      specimens (4.4%) showed divergent haplotypes, varying from the consensus by a
      single-base polymorphism (0.18%). These results suggest that populations of An.
      nuneztovari corresponding to cytotypes (B and C) are conspecific.

PMID- 15185930
TI  - Systematics of the genus Sciurocheyla (Acari: Cheyletidae), parasites of tropical
      squirrels (Rodentia: Sciuridae).
AB  - Two genera of parasitic cheyletid mites, Smileycheles Fain, 1979 (monotypic) and
      Thryonomycheyla Fain, 1972 (two species), are synonymized with the genus
      Sciurocheyla Volgin, 1969. An emended diagnosis of the genus Sciurocheyla is
      provided. Sciurocheyla squamosa (Domrow & Baker, 1963), type species of the
      genus, and Sciurocheyla camerounensis (Fain, 1979), new combination, are
      redescribed. Females, males, teleo- and protonymphs of Sciurocheyla funisciurus,
      new species, collected from Funisciurus pyrrohopus F. Cuvier in tropical Africa
      are described and illustrated.

PMID- 15185931
TI  - Triatoma ryckmani (Hemiptera: Reduviidae) in the epiphyte Tillandsia xerographica
      (Bromeliaceae) in the semiarid region of Guatemala.
AB  - For the first time, the reduviid bug Triatoma ryckmani Zeledon and Ponce
      (Hemiptera; Reduviidae) was recorded to inhabit the epiphyte Tillandsia
      xerographica Rohweder (Bromeliaceae) in the semiarid region of Guatemala. These
      bromeliads grow mainly in drought-resistant trees with rough bark such as
      Pereskia lychnidiflora (Cactaceae). In our study site, we investigated 30 T.
      xerographica, and 53 specimens of T. ryckmani were found. Most T. ryckmani
      (68.5%) were unfed. Ants (Formicidae) were the predominant (92.2%) insect taxon
      in T. xerographica. Other insects such as Blattidae (3.0%), Reduviidae (T.
      ryckmani: 2.5%), Blaberidae (2.2%), Gryllidae (0.1%), and Acrididae (0.1%) were
      recorded in the bromeliads. T. xerographica is illegally commercialized without
      previous inspection. This may cause accidental introduction of T. ryckmani to
      houses and to other countries.

PMID- 15185932
TI  - Study of the seasonal dynamics, life cycle, and host specificity of Amblyomma
      aureolatum (Acari: Ixodidae).
AB  - In the first part of this study, monthly infestation by ticks was evaluated on
      dogs from December 2000 to November 2002 in the rural area of Taiacupeba, Sao
      Paulo. Adults of Amblyomma aureolatum (Pallas) were found on dogs in all months,
      with a mean prevalence per month of 46.9 +/- 15.7% (range, 25-80%). The mean tick
      relative abundance per month was 2.4 +/- 2.7 ticks (range, 0.5-14 ticks), and the
      mean tick mean intensity per month was 4.7 +/- 4.2 ticks (range, 1.5-23.3 ticks).
      No A. aureolatum immature ticks were found on dogs. In the second part of this
      study, we studied the life cycle of A. aureolatum in the laboratory. We tested
      the suitability of six host species for the immature stages and dogs for the
      adult stage. Tick developmental periods were observed at different temperatures
      (23, 25, or 27 degrees C), always with RH >95%, which were satisfactory for all
      free-living developmental stages of the tick life cycle. Chickens and guinea pigs
      were the most suitable hosts for larvae and nymphs (recovery rates, 18.4-52.2%).
      Dogs were highly suitable for adult ticks (all females exposed to them were
      recovered and laid eggs) but were unsuitable for the immature ticks (recovery
      rates, 0-10%). Based on published host records for A. aureolatum, our results
      indicate that dogs and birds are primary hosts for adult and immature stages,
      respectively, of A. aureolatum in nature. In addition, wild guinea pigs are
      indicated as another potential primary host for immature ticks.

PMID- 15185933
TI  - Survivorship and distribution of immature Anopheles gambiae s.l. (Diptera:
      Culicidae) in Banambani village, Mali.
AB  - We observed the survivorship and distribution of larvae and pupae of Anopheles
      gambiae s.l. Giles immature stages in three habitats (rock pools, swamp, and
      puddles) in Banambani village. Mali, West Africa, during the mid-rainy season of
      2000. Horizontal life tables were constructed for immatures in the laboratory.
      Times spent in the various immature stages were determined, and laboratory
      survival was measured. Vertical life tables were obtained from each habitat. We
      found large day-to-day variation for age class composition within habitats across
      days. The swamp samples had small but statistically significant different
      distributions in some instar stages compared with rock pools and puddles as
      affected by precipitation history. There were obviously unstable age
      distributions in the swamp and puddles and to some extent in rock pools. There
      were more individuals in some later age classes than in earlier ones. The daily
      survival estimates using an exponential decay model were 0.807 in rock pools,
      0.899 in the swamp, 0.818 in puddles, and 0.863 in the overall village. Possible
      reasons for the departure from stable age distribution were cannibalism,
      predation and other complex interactions, rainfall effects, sampling bias, and
      differences in physicochemical properties of the water in the habitats.

PMID- 15185934
TI  - Culture-independent analysis of midgut microbiota in the arbovirus vector
      Culicoides sonorensis (Diptera: Ceratopogonidae).
AB  - Differences in midgut microbial communities inhabiting Culicoides spp., insect
      vectors of virus pathogens, may affect the variation observed in the ability of
      these biting midges to propagate arthropod-borne viruses. As a first step toward
      addressing this hypothesis, midgut bacterial communities were compared between
      Culicoides species expected to be efficient and inefficient vectors of virus
      pathogens. We used 16S rDNA sequence and restriction fragment information to
      provisionally identify 36 bacterial genera from guts of wild adult female biting
      midges, Culicoides sonorensis Wirth and Jones and Culicoides variipennis
      (Coquillet), from two geographical locations. Bacterial identification was made
      by sequence analysis of 16S rDNA fragments and by terminal restriction fragment
      length polymorphism analysis of polymerase chain reaction-amplified 16S rDNA
      fragments from adult guts. Of 36 bacterial genera identified, 12 had been
      previously identified in other insects: Comomonas, Enterobacter, Klebsiella,
      Acinetobacter, Pseudomonas, Stenotrophomonas, Staphylococcus, Chryseobacterium,
      Moraxella, Acholeplasma, Flavobacterium, and Rickettsia, Significant differences
      in bacterial community composition were found between all three groups of wild
      adult females analyzed: live-trapped C. sonorensis, laboratory-emerged C.
      sonorensis, and laboratory-emerged C. variipennis.

PMID- 15185935
TI  - Seasonal distribution, biology, and human attraction patterns of culicine
      mosquitoes (Diptera: Culicidae) in a forest near Puerto Almendras, Iquitos, Peru.
AB  - This study was conducted as part of a field ecology study of arboviral activity
      in the Amazon Basin, Peru, to determine the taxonomy, frequency, seasonal, and
      vertical distributions of potential mosquito vectors. In addition, the relative
      efficiency of human-landing collections and dry ice-baited Centers for Disease
      Control (CDC)-type light traps was determined for collecting mosquitoes. A total
      of 70 species of mosquitoes from 14 genera were collected from June 1996 through
      December 1997 at a forested site near Puerto Almendras, approximately 20 km west
      southwest of Iquitos, Peru. Three species [Psorophora (Janthinosoma) albigenu
      (Peryassu), Ochlerotatus (Ochlerotatus) fulvus (Wiedemann), and Ochlerotatus
      (Ochlerotatus) serratus (Theobald)] accounted for 70% of all mosquitoes captured
      in human-landing collections. Overall, biting activity occurred throughout the 24
      h cycle but was higher during the daytime, primarily because of large populations
      of two day-biting species, Ps. albigenu and Oc. serratus. Oc. fulvus was active
      throughout the 24-h cycle but was more frequently collected during the evening.
      Oc. fulvus, Ps. albigenu, Culex (Melanoconion) pedroi Sirivanakarn & Belkin, and
      a mixture of Culex (Melaonoconion) vomerifer Komp, and Culex (Melanoconion)
      gnomatos Sallum, Huchings & Ferreira, accounted for 73% of the mosquitoes
      captured during darkness) by human collectors. In general, Ochlerotatus spp. and
      Psorophora spp. were more commonly captured in human-landing collections, whereas
      most Culex spp. were more frequently collected in the dry ice-baited CDC-type
      light traps. In general, mosquito populations were lowest from June through
      August when river levels were at their lowest. Two large population peaks
      occurred in November-December and in February-March as a result of "flood water"
      mosquito populations (e.g., Ps. albigenu). These data provide a better
      understanding of the taxonomy, population density, and seasonal distribution of
      potential mosquito vectors within the Amazon Basin region and allow for the
      development of appropriate vector and disease prevention strategies.

PMID- 15185936
TI  - Influence of climate on the proportion of Ixodes ricinus nymphs and adults
      questing in a tick population.
AB  - We studied the relationship between climate and Ixodes ricinus L. tick behavior
      by following every day the proportion of ticks questing in a tick population
      placed in polyamide mesh-delimited arenas in the field. Simultaneously, the
      phenology of the questing density of nymphs and adults was studied by sampling
      ticks in a close location. At any time during the year, the proportion of
      questing adults was significantly higher (mean 24%) than the proportion of
      questing nymphs (mean 12%). The proportion of questing nymphs and adults
      decreased stepwise with time. The proportion of questing adults partially
      recovered after each decrease. In contrast, the proportion of questing nymphs was
      strongly reduced during a single short period in June and did not recover even
      partially. Decrease in the proportion of questing ticks was strongly related
      either to a peak in saturation deficit or to a drop in maximal relative humidity.
      No increase in the proportion of questing nymphs was observed in the arenas
      during autumn, although an autumn peak of nymphs was observed at the sampling
      location close to the arenas. This suggests that the autumn peak of nymphs
      observed in nature was due to newly emerged spring-fed larvae and not to
      reactivated spring active nymphs.

PMID- 15185937
TI  - Eco-ethological heterogeneity of the members of the Anopheles minimus complex
      (Diptera: Culicidae) in Southeast Asia and its consequences for vector control.
AB  - The presence of cryptic species within Anopheles minimus s.l. Theobald, one of
      the most widespread malaria vectors in Southeast Asia, was suggested on the basis
      of behavioral heterogeneities observed within this taxon. Subsequently, two
      species, A and C, were recognized. However, the existence of these cryptic
      species did not explain all observed behavioral heterogeneities within this
      complex. Besides, data on the behavior of vectors are essential to understand the
      dynamics of disease transmission and thus evaluate the appropriateness of vector
      control measures. Different collection methods were used to collect Anopheles
      species from several localities in Southeast Asia to assess the inter- and
      intraspecific behavioral divergences of An. minimus A and C. Collection results
      were subjected to a correspondence analysis. The members of the An. minimus
      complex were identified by use of the octanol dehydrogenase allozyme profiles or
      the polymerase chain reaction-restriction fragment length polymorphism assay.
      Large intraspecific behavioral differences were observed among populations of An.
      minimus A. These populations belong to the same species on the basis of the
      applied genetic markers. In northern Vietnam, species A tended to be more
      zoophilic, whereas in the study sites of south central Vietnam, Cambodia, and
      Laos it showed marked antropophilic behavior when cattle were scarce. In the most
      northern study site, An. minimus A showed noteworthy endophilic behavior. An.
      minimus C was primarily zoophilic and based on this behavior, its role in malaria
      transmission is questionable. However, it was only found in one locality, so that
      intraspecific behavioral variation could not be assessed. An. minimus A is able
      to change its host preference in function of local situations in host
      availability. Hence, its role in malaria transmission can differ from region to
      region. Similarly, the impact of vector control on this species may differ
      between localities. In conclusion, intraspecific behavioral differences in
      Anopheles species can occur and these behavioral heterogeneities, albeit
      important for disease transmission and control, are not a priori indicative for
      the presence of cryptic species.

PMID- 15185938
TI  - The "wingbeat hypothesis" of reproductive isolation between members of the
      Anopheles gambiae complex (Diptera: Culicidae) does not fly.
AB  - Recent advances have demonstrated that, in the absence of postmating barriers to
      hybridization, reproductive isolation between different forms of Anopheles
      gambiae sensu stricto is maintained by strong assortative mating. The forms of
      An. gambiae s.s. and the sister species An. arabiensis commonly form mixed swarms
      in which they mate. This raises the question as to how individuals recognize
      mates of their own species or form within swarms. It has been proposed that
      wingbeat frequency is used as a cue to discriminate potential mates. This has
      important implications for prospective genetic control programs. We used a
      photosensor to record the transient waveforms generated by individuals An.
      arabiensis and from the M and S molecular forms of An. gambiae s.s. as they flew
      through a beam of light. We found no significant between-species or between-form
      differences in the fundamental harmonic--equivalent to wingbeat frequency--either
      in males or females collected from sympatric populations in Mali, West Africa.
      However, there were significant differences in the amplitude of the first and
      third harmonics in females and of the first and second harmonics in males.
      Whereas these results suggest some morphological or behavioral differences
      between species and forms, the extensive overlap in the distributions of harmonic
      amplitudes does not point to them as reliable cues for assortative mating.
      Combining all waveforms parameters into a discriminant analysis did not yield
      characteristic scores either for males or females. Thus, our results do not
      support the wingbeat hypothesis of premating isolation in the An. gambiae
      complex.

PMID- 15185939
TI  - Crimson: a novel sex-linked eye color mutant of Culex pipiens L. (Diptera:
      Culicidae).
AB  - Xanthommatin is the primary ommochrome eye pigment in mosquitoes. The terminal
      step in xanthommatin biosynthesis, involving oxidation of 3-hydroxykynurenine
      (3HK), can proceed enzymatically by phenoxazinone synthase or by nonenzymatic
      auto-oxidation of 3HK. The relative contributions of these pathways, however, are
      unclear. We isolated a novel Culex pipiens mutant (crimson) that could be used to
      address this question. Homozygous crimson embryos exhibit no visible eyespot;
      first-instar larval ocelli are colorless. Eyes gradually turn red through
      immature development. Teneral crimson adults possess red eyes that darken to wild
      type approximately 5 d after emergence. Crosses indicate that crimson is sex
      linked and fully recessive. Addition of xanthommatin precursors to rearing water
      did not rescue wild-type phenotype and suggested that the mutation is in the
      terminal step of ommochrome biosynthesis. Crimson expression was not temperature
      sensitive. Thin-layer chromatography demonstrated teneral crimson adults lacked
      xanthommatin. Teneral and aged wild-type adults exhibited low-mobility black
      ommochrome spots; aged crimson adults exhibited low-mobility brown-red ommochrome
      spots. Absorbance spectroscopy of eye extracts indicated teneral adult crimson
      eyes lacked xanthommatin but had abnormally high levels of 3HK, whereas extracts
      of 10-d-old crimson adults had depleted levels of 3HK and detectable levels of
      xanthommatin. Light microscopy indicated that eyes of young (3 d old) wild-type
      adults had a high concentration of pigment granules. Eyes of teneral crimson
      adults had no pigment granules. Eyes of 20-d-old crimson adults had low levels of
      pigment granules. We suggest two possible mechanisms for the crimson mutation:
      (1) transport of 3HK into the pigment cells and/or pigment granules is slow, with
      normal oxidation of 3HK into xanthommatin, or (2) 3HK is transported normally
      into pigment cells/granules but is not immediately oxidized to xanthommatin,
      resulting in 3HK hyper-accumulation and slow nonenzymatic production of
      xanthommatin after adult emergence.

PMID- 15185940
TI  - Ribosomal DNA ITS2 sequences differentiate six species in the Anopheles crucians
      complex (Diptera: Culicidae).
AB  - Anopheles crucians Wiedemann (sensu lato) was investigated for the presence of
      cryptic species using rDNA ITS2 sequences. This complex of species presently
      contains the named species An. crucians, An. bradleyi King, and An. georgianus
      King. Adult female mosquitoes were collected at 28 sites in Alabama, Florida,
      Georgia, North Carolina, Mississippi, and Louisiana, resulting in 245 progeny
      broods. Species were identified using preliminary morphological characters, and
      the internal transcribed spacer two (ITS2) was amplified from all broods. The
      result was five distinct sizes of amplification product, and based on
      morphological characters, one of the size classes was suspected to consist of two
      species. All six putative species were then sequenced: five directly, and the
      sixth, because of extreme intragenomic (each individual with many variants) size
      variability, cloned. The ITS2 sequences were markedly distinct for all six
      species. Species designations and ITS2 sequence lengths (base pairs in
      parentheses) were A (461), B (1,000+), C (204), D (293), E (195), and An.
      bradleyi (208). Species B showed both large intraspecific and intragenomic
      sequence variability and is distinguished by having the longest ITS2 found so far
      in an Anopheles. Based on these data, we found that all species could be
      identified with polymerase chain reaction (PCR) using a mixture of four primers
      in a single reaction. Members of this complex were often found in sympatry, with
      the adults of five species collected at a single site in central Florida.

PMID- 15185941
TI  - Therapeutic and persistent efficacy of a single application of doramectin applied
      either as a pour-on or injection to cattle infested with Boophilus microplus
      (Acari: Ixodidae).
AB  - The efficacy of a single treatment with a pour-on application or a subcutaneous
      injection of the macrocyclic lactone endectocide, doramectin, was evaluated in
      separate trials on Hereford heifers infested with Boophilus microplus
      (Canestrini). Significantly fewer ticks per calf were recovered from both groups
      of treated animals than from the complimentary untreated calves. The mean weights
      of engorged females and egg masses from both pour-on-treated and injectable
      treated calves were also significantly smaller than the complimentary variables
      for the two groups of untreated calves. Among the treated groups, the mean weight
      of females from calves treated with the subcutaneous injection was 55% less than
      females from cattle that received the pour-on treatment and the weights of egg
      masses were 71% lighter than those from the pour-on-treated group. The estimates
      of percentage control for the two treatments were 88.6 for the pour-on
      formulation and a notably higher 99.8 for the injectable formulation. To obtain
      estimates of the effect of the treatments on the parasitic stages of the tick,
      cattle were infested with B. microplus larvae at three weekly intervals beginning
      18 d pretreatment to ensure that, on the day of treatment, ticks in all three
      parasitic stages (adult, nymph, larva) would be on the cattle. The effect of the
      treatments on each parasitic stage was estimated by partitioning detached females
      into three groups by noting in which of the three 7-d intervals after detachment
      of engorged females began that detachment occurred. There was no difference for
      either the pour-on or injectable in the effect of the specific treatment on each
      parasitic stage. The persistent efficacy of the pour-on treatment against larvae
      placed on the hosts 1 wk after treatment was zero. The persistent efficacy of the
      injectable treatment ranged from 100 to 82.1% (mean, 93.7%) against the larvae
      placed on calves the first 3 wk after treatment and was still 44% against the
      fourth weekly posttreatment infestation. The injectable doramectin is a potential
      alternative to the coumaphos product now used as a precautionary treatment at
      USDA, Veterinary Services, Livestock Import Stations, for cattle exported from
      Mexico.

PMID- 15185942
TI  - Insecticide resistance and cross-resistance in Alabama and Florida strains of
      Culex quinquefasciatus [correction].
AB  - Insecticide resistance and cross-resistance was determined for three strains of
      Culex quinquefasciatus Say in the southeastern United States. HAmCq and MAmCq
      strains were collected in 2002 from Huntsville and Mobile, AL. The VBFmCq strain
      was collected in 1998 from Vero Beach, FL. VBFmCq, HAmCq, and MAmCq larvae showed
      resistance to permethrin with resistance ratios of 13, 100, and 940,
      respectively, compared with the susceptible S-Lab strain. Levels of resistance in
      HAmCq and MAmCq larvae were 200- and 830-fold to resmethrin and 4- and 70-fold to
      malathion, respectively. VBFmCq, HAmCq, and MAmCq strains all demonstrated a
      great ability to develop tolerance and/or cross-resistance to different
      insecticides, including deltamethrin (50-, 100-, and 300-fold), chlorpyrifos (150
      , 33-, and 720-fold), fipronil (10-, 5-, and 15-fold), and imidacloprid (7.5-, 5-
      and 10-fold, respectively). Comparison of resistance ratios for pyrethroids,
      organophosphates, and imidacloprid at LC50 and LC90 and gradual slopes of dose
      response curves indicated that VBFmCq, HAmCq, and MAmCq were heterozygous in
      response to these insecticides. All three strains showed high levels of
      susceptibility to Bacillus thuringiensis variety israelensis (Bti) and spinosad,
      although these mosquitoes had been extensively exposed to Bti. Thus, we conclude
      that Bti and spinosad may be valuable for the management of Cx. quinquefasciatus,
      especially in situations where local strains are highly resistant to other
      insecticides.

PMID- 15185943
TI  - Field evaluation of repellent formulations containing deet and picaridin against
      mosquitoes in Northern Territory, Australia.
AB  - Field efficacy of repellent formulations containing picaridin (1-methyl-propyl 2
      (2-hydroxyethyl)-1-piperidinecarboxylate) or deet (N,N,-diethyl-3
      methylbenzamide) against mosquitoes in Northern Territory, Australia, was
      evaluated. The following repellent treatments were evaluated: 19.2% picaridin
      (Autan Repel Army 20), a solution of 20% deet in ethanol, and 35% deet in a gel
      (Australian Defense Force [ADF]). The predominant mosquito species were Culex
      annulirostris Skuse (57.8%), Anopheles merankensis Venhuis (15.4%), and Anopheles
      bancroftii Giles (13.2%). The protection provided by repellents against Anopheles
      spp. was relatively poor, with 19.2% picaridin and ADF deet providing >95%
      protection for only 1 h, whereas 20% deet provided <95% protection at 1 h after
      repellent application. In contrast, the repellents provided good protection
      against Cx. annulirostris, with 19.2% picaridin providing >95% protection for 5 h
      and both deet formulations providing >95% protection for 7 h when collections
      ceased. This study provides additional field data showing tolerance of Anopheles
      spp. for repellents. The response of field populations of Cx. annulirostris, an
      important vector of arboviruses in Australia, to repellents containing deet and
      picaridin is reported for the first time.

PMID- 15185944
TI  - Comparative resistance of Anopheles albimanus and Aedes aegypti to N,N-diethyl-3
      methylbenzamide (Deet) and 2-methylpiperidinyl-3-cyclohexen-1-carboxamide (AI3
      37220) in laboratory human-volunteer repellent assays.
AB  - The insect repellents N,N-diethyl-3-methylbenzamide (Deet) and the racemate and
      1S,2'S stereoisomer of 2-methylpiperidinyl-3-cyclohexene-1-carboxamide (AI3
      37220) were tested against Anopheles albimanus Wiedemann and Aedes aegypti (L.)
      in laboratory human-volunteer assays. Estimated skin doses of Deet or racemic AI3
      37220 required to reduce biting by 95% in Ae. aegypti were 2.3 and 3.5 x 10(-2)
      micromol/cm2 skin, respectively, whereas estimated doses for 95% bite reduction
      of An. albimanus in an approximately 40-yr-old laboratory colony established from
      El Salvador were 5 times higher at 12 x 10(-2) micromol Deet/cm2 skin and >20 x
      10(-2) micromol/cm2 skin for AI3-37220. In tests with the 1S,2'S stereoisomer of
      AI3-37220, a newly established colony of An. albimanus from Belize bit less
      aggressively than El Salvador An. albimanus. However, the Belize-derived
      mosquitoes were as resistant as the old El Salvador colony to repellent effects
      of 1S,2'S stereoisomer of 2-methylpiperidinyl-3-cyclohexene-1-carboxamide.
      Earlier workers surmised that usual skin doses of Deet would offer only limited
      protection against An. albimanus in the field. Our findings support this
      speculation, but they also indicate that doses of Deet higher than those needed
      for protection against Ae. aegypti might offer reasonable protection against An.
      albimanus. Results indicate that neither racemate nor 1S,2'S stereoisomer of 2
      methylpiperidinyl-3-cyclohexene-1-carboxamide offer as much protection as Deet
      against An. Albimanus, despite being highly effective against Ae. aegypti.

PMID- 15185945
TI  - Laboratory and simulated field evaluation of a new recombinant of Bacillus
      thuringiensis ssp. israelensis and Bacillus sphaericus against Culex mosquito
      larvae (Diptera: Culicidae).
AB  - In the laboratory, three microbial mosquito larvicidal products consisting of
      Bacillus thuringiensis ssp. israelensis de Barjac (Bti), Bacillus sphaericus
      (Neide) (Bsph) (strain 2362), and the University of California Riverside (UCR)
      recombinant (producing toxins of both Bacillus sphaericus and Bacillus
      thuringiensis ssp. israelensis) were bioassayed against larvae of Culex
      quinequefasciatus Say (susceptible and resistant to Bsph 2362), and Aedes aegypti
      (L.). Bti proved highly effective against Cx. Quinequefasciatus susceptible and
      resistant strains, with LC50 values of 0.009 and 0.011 ppm and LC90 values of
      0.057 and 0.026 ppm for Bsph-susceptible and -resistant strains, respectively.
      Bti was also highly active against Ae. eagypti with LC50 and LC90 values of 0.014
      and 0.055 ppm, respectively. The UCR recombinant was equally active against both
      Bsph-susceptible and -resistant strains of Cx. Quinquefasciatus; LC50 values were
      0.005 and 0.009 and LC90 values were 0.030 and 0.043 ppm, respectively. Bti and
      the UCR recombinant essentially showed similar activity against Bsph-susceptible
      and -resistant strains. UCR recombinant showed high toxicity against Ae. eagypti
      with LC50 and LC90 values of 0.023 and 0.064 ppm, respectively. Bsph was highly
      active against susceptible strain of Cx. quinequefasciatus with LC50 and LC9o
      values of 0.006 and 0.024 ppm, respectively. Bsph exhibited little toxicity
      against Ae. eagypti larvae and also no toxicity to Bsph resistance. In the field,
      we evaluated four experimental corn grit formulations of Bti (VBC 60021), Bsph
      (VBC 60022), UCR recombinants VBC 60023 (7.89%), and VBC 60024 (1.87%) in
      simulated field (microcosms) against Bsph-susceptible Culex mosquitoes. Bti and
      low-concentrate UCR recombinant showed similar initial activity as well as
      persistence. Both materials provided high-to-moderate level of control for 2-7 d
      posttreatment at low treatment rates. At low dosages, residual activity of Bti
      and UCR recombinant lasted for <7 d. Bsph and high-concentrate UCR recombinant
      (VBC 60023), however, were more effective against natural populations of Cullex
      and achieved longer control (7-21 d) than the other two materials.

PMID- 15185946
TI  - In vitro repellency of N,N-diethyl-3-methylbenzamide and N,N
      diethylphenylacetamide analogs against Aedes aegypti and Anopheles stephensi
      (Diptera: Culicidae).
AB  - Seventeen analogs of the repellent compounds N,N-diethyl-3-methylbenzamide (DEET)
      and N,N-diethylphenylacetamide (DEPA) were evaluated in vitro for repellency
      against laboratory-reared Aedes aegypti (L.) and Anopheles stephensi Liston
      mosquitoes by using a modified membrane blood feeding test system. The system was
      a valuable tool for comparing the effective concentrations of the repellent
      analogs. Additionally, this method used easily controlled test conditions,
      allowing completion of the many test replications necessary to evaluate all of
      the repellent analogs over a period of several years. One compound, N,N-diethyl-2
      [3-(triflouromethyl)phenyl] acetamide, provided significantly better repellency
      than DEET against Ae. aegypti and slightly improved efficacy against An.
      stephensi. Eight of the analogs were as effective as or slightly more repellent
      than DEET against both species. Seven analogs were less effective than DEET and
      one compound, N,N-diethyl-3-hydroxybenzamide, was as a poor repellent. Overall,
      two DEPA analogs and a single DEET analog provided better repellency than DEET
      against both mosquito species and warrant future laboratory and field evaluation.

PMID- 15185947
TI  - Laboratory selection for resistance to Bacillus thuringiensis subsp. jegathesan
      or a component toxin, Cry11B, in Culex quinquefasciatus (Diptera: Culicidae).
AB  - The bacteria Bacillus thuringiensis subsp. israelensis and Bacillus sphaericus
      produce insecticidal toxins used to control mosquito larvae throughout the world.
      Unfortunately, there are few alternative insecticides with similar activity and
      environmental safety, which may limit the long-term success of these
      insecticides. Bacillus thuringiensis subsp. jegathesan is another bacterium with
      toxins that are active against mosquitoes and has potential for development as a
      commercial product. B. t. subsp. jegathesan would be ineffective if cross
      resistance was detected or if treated mosquito populations evolved resistance. B.
      t. subsp. jegathesan was evaluated for its potential for selecting insecticide
      resistance in Culex quinquefasciatus Say. Susceptibility changes in mosquitoes
      selected with the wild-type strain were compared with susceptibility changes in
      mosquitoes selected with Cry11B, a component toxin of B. t. subsp. jegathesan.
      Resistance was detected in generation 18 in the Cry11B-selected colony, reached a
      maximum of 38-fold, and was present through generation 40. The B. t. subsp.
      jegathesan-selected colony evolved 13-fold resistance in generation 22, but
      resistance declined to 2.3-fold in generation 26 and remained low throughout the
      study. Cry11B-selected mosquitoes showed no significant resistance to the wild
      type bacterium, whereas B. t. subsp. jegathesan-selected mosquitoes expressed
      significant resistance to Cry11B. Both colonies displayed cross-resistance to
      component toxins of B. t. subsp. israelensis, but they lacked cross-resistance to
      that wild-type strain. The patterns of resistance and cross-resistance in this
      study are consistent with the patterns previously observed in mosquitoes selected
      with B. t. subsp. israelensis and suggest that B. t. subsp. jegathesan might also
      be at low risk for resistance.

PMID- 15185949
TI  - Ectopic expression of a cecropin transgene in the human malaria vector mosquito
      Anopheles gambiae (Diptera: Culicidae): effects on susceptibility to Plasmodium.
AB  - Genetically altering the disease vector status of insects using recombinant DNA
      technologies is being considered as an alternative to eradication efforts.
      Manipulating the endogenous immune response of mosquitoes such as the temporal
      and special expression of antimicrobial peptides like cecropin may result in a
      refractory phenotype. Using transgenic technology a unique pattern of expression
      of cecropin A (cecA) in Anopheles gambiae was created such that cecA was
      expressed beginning 24 h after a blood meal in the posterior midgut. Two
      independent lines of transgenic An. gambiae were created using a piggyBac gene
      vector containing the An. gambiae cecA cDNA under the regulatory control of the
      Aedes aegypti carboxypeptidase promoter. Infection with Plasmodium berghei
      resulted in a 60% reduction in the number of oocysts in transgenic mosquitoes
      compared with nontransgenic mosquitoes. Manipulating the innate immune system of
      mosquitoes can negatively affect their capacity to serve as hosts for the
      development of disease-causing microbes.

PMID- 15185948
TI  - Host-feeding pattern of Culex quinquefasciatus Say and Mansonia annulifera
      (Theobald) (Diptera: Culicidae), the major vectors of filariasis in a rural area
      of south India.
AB  - Culex quinquefasciatus and Mansonia annulifera are abundant in the rural areas of
      Kuttanadu, Kerala, India. Bloodmeal identification for individuals of these
      species collected in this region was determined by the agar-gel precipitin test.
      A total of 2,328 blood smears from Cx. quinquefasciatus (1,148) and Ma.
      annulifera (1,180) was tested. Results showed that Cx. quinquefasciatus and Ma.
      annulifera were highly anthropophilic and that human feeding accounted for 74 and
      66% of the total bloodmeals tested. Feeding on cattle accounted for only 1.5 and
      2.1% of Cx. quinquefasciatus and Ma. annulifera bloodmeals, respectively. This
      study showed the high anthropophilic feeding rates of Cx. quinquefasciatus and
      Ma. annulifera collected from an endemic belt of Malayan filariasis, where
      epidemiological studies revealed the coexistence of Bancroftian and Malayan
      filariasis.

PMID- 15185950
TI  - Japanese encephalitis in Kerala, south India: can Mansonia (Diptera: Culicidae)
      play a supplemental role in transmission?
AB  - A 2-yr entomological study was carried out in Kerala, south India, to identify
      the mosquito vectors of Japanese encephalitis (JE) virus and to determine their
      seasonal abundance and infection. In total, 150,454 mosquitoes belonging to five
      genera and 18 species were collected from vegetation surrounding cattle sheds and
      pigsties in villages at dusk. Culex tritaeniorhynchus Giles (66.7%) was the most
      abundant species, with increases in numbers associated with rice cultivation. JE
      virus isolations were made from Cx. tritaeniorhynchus and Mansonia indiana
      Edwards. Based on high abundance and frequent JE virus infection, Cx.
      tritaeniorhynchus seems to be the most important vector, whereas Ma. indiana is
      probably a secondary vector.

PMID- 15185951
TI  - Encephalitis virus persistence in California birds: experimental infections in
      mourning doves (Zenaidura macroura).
AB  - After-hatching and hatching year, mourning doves were infected by inoculation
      with either western equine encephalomyelitis (WEE) or St. Louis encephalitis
      (SLE) viruses; some birds in each group also were treated with the
      immunosuppressant cyclophosphamide before and during infection. Cyclophosphamide
      treatment significantly increased the WEE viremia but did not alterthe antibody
      response. In contrast, cyclophosphamide-treated and -untreated doves did not
      develop a detectable SLE viremia but became antibody positive. Antibody peaked at
      10 wk after inoculation for both viruses and remained detectable in most birds
      throughout the 26-wk study. When treated with cyclophosphamide the following
      spring, birds did not relapse and develop a detectable viremia. Previously
      infected birds were protected when challenged with conspecific virus (i.e., none
      produced a detectable viremia), but there was no anamnestic antibody response to
      reinfection. In agreement with our failure to detect relapses, all birds were
      negative for viral RNA when sera, spleen, lung, and kidney tissues were tested by
      reverse transcriptase-polymerase chain reaction after necropsy. Our results
      indicated that adult mourning doves were an incompetent host for SLE virus and
      probably do not serve as a suitable overwintering or dispersal host for either
      WEE and SLE viruses.

PMID- 15185952
TI  - Evidence for arbovirus dissemination conduits from the mosquito (Diptera:
      Culicidae) midgut.
AB  - The mechanism by which arboviruses bypass the basal lamina of mosquito midgut
      cells and enter the body cavity has been unclear. Experiments using Venezuelan
      equine encephalitis viral replicon particles, which express the green fluorescent
      protein gene in cells, indicate the operation of tissue conduits, possibly
      involving tracheae and visceral muscles, that facilitate virus movement through
      the basal lamina. Ultrastructural studies of the midgut reveal evidence for
      possible complete penetration of the basal lamina by tracheal cells and regions
      of modified basal lamina associated with visceral muscle. The modified basal
      lamina closely resembles proventricular matrix material known to allow virus
      passage.

PMID- 15185953
TI  - Effects of Anaplasma phagocytophilum infection on the molting success of Ixodes
      scapularis (Acari: Ixodidae) larvae.
AB  - We assessed the effects of sympatric (occupying the same or overlapping
      geographic areas) and allopatric (occurring in separate geographic areas)
      isolates of Anaplasma phagocytophilum on the survival of Ixodes scapularis Say
      larvae that were derived from ticks collected in Bridgeport, CT. Seven isolates
      of A. phagocytophilum, originating from different geographic regions of the
      United States, were tested: four isolates from the northeast (Bridgeport, Dawson,
      Gaillard, and NY-8), two from the Midwest (Webster and Sp-Is), and one from
      California (MRK). BALB/c mice were infected with each of the seven isolates via
      exposure to infected I. scapularis nymphs, whereas uninfected nymphs fed upon
      control mice. Both infected and control mice were infested with uninfected larvae
      at 1, 2, 3, 4, 6, and 9 wk after nymphal infestation. The molting success in
      cohorts of infected and uninfected ticks was calculated as the percentage of
      larvae successfully molting into nymphal stage, and the prevalence of infection
      in molted nymphs was determined by polymerase chain reaction. In ticks that
      became infected with the Bridgeport or Sp-Is isolates, the molting success
      decreased with an increase in the prevalence of infection. Ticks that fed upon
      mice infected with six allopatric isolates (Dawson, Gaillard, NY-8, Sp-Is,
      Webster, and MRK) showed significantly lower levels of survival than those fed
      upon control mice, regardless of the prevalence of infection, whereas in ticks
      fed upon mice infected with a sympatric isolate (Bridgeport), the overall molting
      success was similar to the control. Thus, some but not all of the A.
      phagocytophilum isolates have adverse effects on ticks. Ticks exposed to harmful
      isolates may experience higher levels of bacterial metabolism, and/or reduced
      quality of their blood meal, thereby reducing their survival. Noted differences
      between isolates may be due to the origin of a particular isolate and/or the
      degree of coadaptation between the pathogen and its vector on the population
      level.

PMID- 15185954
TI  - Colonization of rock pile boundary walls in fields by sylvatic triatomines
      (Hemiptera: Reduviidae) in Jalisco State, Mexico.
AB  - Granite rocks is a very abundant material in Mexico because they are used
      habitually as borders for fields. The current work established the significance
      of this ecotype as a colonization site for triatomines of the Phyllosoma complex.
      Seven sites, arbitrary selected, in San Martin de Hidalgo municipality (Mexico)
      were investigated in April 2002 by using 210 mouse bait-traps left during the
      night in wall hollows. One hundred and seventy-two triatomines of all life stages
      were collected from the seven sites. Triatomines adhered to the tape that covered
      the traps or were found near them, and 36.6% of the traps collected triatomines.
      The principal species was Triatomia longipennis Usinger (1939) and low numbers of
      Triatoma picturata Usinger (1939) were found. The nymphal population was very
      young, probably corresponding to the reproductive period in April (end of the dry
      season). The infection rate of the triatomines for Trypanosoma cruzi was 49%.
      Because collecting triatomines in the field is laborious and time-consuming, the
      mouse bait-trap method found to be practical to assess the population of
      triatomines within a sylvatic habitat.

PMID- 15185955
TI  - Natural Plasmodium infections in Anopheles darlingi and Anopheles benarrochi
      (Diptera: Culicidae) from eastern Peru.
AB  - Malaria, both Plasmodium falciparum (Welch) and Plasmodium vivax (Grassi &
      Feletti), has reemerged as a significant public health disease issue in Peru,
      especially in forested areas in the eastern part of the country. The spread of
      Anopheles darlingi Root, the principal South American malaria vector, into new
      areas of Peru is thought to be a factor in this resurgence. However,
      epidemiological evidence suggests that in malaria endemic areas of eastern Peru
      where An. darlingi does not occur, other species are involved in malaria
      transmission. The objective of this study was to analyze Anopheles species
      collected from 11 provinces within four departments in eastern Peru during 2001
      and 2002 for infections with P. falciparum and P. vivax. More than 84,000
      Anopheles mosquitoes representing 13 species were tested by enzyme-linked
      immunosorbent assay for the presence of Plasmodium circumsporozoite (CS)
      proteins. Of these, only An. darlingi and Anopheles benarrochi Gabaldon, Cova
      Garcia & Lopez were found positive. In total, 14 (0.98%) of 1,432 pools of An.
      darlingi were positive for Plasmodium species; specifically 10 (0.70%) pools were
      positive for P. falciparum, two (0.14%) were positive for P. vivax VK210, and two
      (0.14%) were positive for P. vivax VK247 proteins. Nine (0.14%) of 6,323 pools of
      An. benarrochi were positive for Plasmodium; five (0.08%) of 6,323 pools were
      positive for P. falciparum, two (0.03%) were positive for P. vivax VK247, one
      (0.02%) was positive for mixed P. vivax VK210/VK247 infections, and one (0.02%)
      was positive for mixed P. falciparum and P. vivax VK210 CS-proteins. Although
      infection rates in An. benarrochi were significantly lower (0.14%) than rates
      found for An. darlingi (0.98%), our data suggest that An. benarrochi may play a
      role in transmitting and maintaining Plasmodium species in various malaria
      endemic areas of eastern Peru.

PMID- 15185956
TI  - Mosquito and arbovirus activity during 1997-2002 in a wetland in northeastern
      Mississippi.
AB  - The species composition and population dynamics of adult mosquitoes in a wetland
      near Iuka, MS, were analyzed over a 6-yr period (1997-2002) and reverse
      transcription-polymerase chain reaction (PCR) detection rates of arboviruses
      determined during five of those years. Blood meals of three likely vector species
      were identified using a PCR-based method that allows identification of the host
      to species. Culex erraticus (Dyar & Knab) composed 51.9% of the population during
      the 6-yr period with 295 females collected per trap night. Eastern equine
      encephalomyelitis (EEE) virus was detected in six genera of mosquitoes
      [Coquillettidia perturbans (Walker), Culex restuans Theobald, Culex salinarius
      Coquillett, Culex erraticus (Dyar & Knab), Anopheles crucians Wiedemann,
      Anopheles quadrimaculatus Say, Aedes vexans (Meigen), Ochlerotatus triseriatus
      Say, and Psorophora ferox Humboldt) with positive pools occurring in 1998, 1999,
      and 2002. Culiseta melanura Coquillett occurred at a low level (< 1%) and was not
      infected. Saint Louis encephalitis virus was detected once in a single pool of
      Cx. erraticus in 1998. Neither West Nile virus nor LaCrosse virus was found.
      Minimum infection rates per 1000 females tested of competent vectors of EEE virus
      were variable and ranged from 0.14 for Cx. erraticus to 40.0 for Oc. triseriatus.
      Thirty-nine species of birds were identified in the focus with blood-engorged
      mosquitoes found to contain meals (n = 29) from eight avian species. The majority
      of meals was from the great blue heron, Ardea herodias L. (n = 55%), but when
      bird abundance data were adjusted for avian mass, the brown-headed cowbird,
      Molothrus ater (Boddaert); blue jay, Cyanocitta cristata (L.); and northern
      mockingbird, Mimus polyglottos (L.), were overrepresented as hosts.

PMID- 15185957
TI  - Evaluation of a sampling methodology for rapid assessment of Aedes aegypti
      infestation levels in Iquitos, Peru.
AB  - An epidemic of dengue during 2001 in Northwestern Peru reemphasized the need for
      efficient, accurate, and economical vector surveillance. Between November 1998
      and January 1999, we carried out extensive entomological surveys in two
      neighborhoods of approximately 600 contiguous houses located in the Amazonian
      city of Iquitos, providing a unique opportunity to evaluate the Aedes aegypti
      (L.) rapid assessment survey strategy. Based on Pan American Health Organization
      recommendations, this strategy is used by the Peruvian Ministry of Health (MOH).
      In our analysis all household locations, including closed and unoccupied houses,
      were georeferenced and displayed in a geographic information system, which
      facilitated simulations of MOH surveys based on hypothetical systematic sampling
      transects. Larval, pupal, and adult mosquito indices were calculated for each
      simulation (n = 10) and compared with the indices calculated from the complete
      data set (n = 4). The range of indices calculated from simulations was moderately
      high, but included actual indices. For example, simulation ranges for house
      indices (HI, percentage of infested houses from complete survey) were 38-56%
      (45%), 36-42% (38%), 21-34% (30%), and 13-33% (27%) in four surveys. HI, Breteau
      index, pupae per hectare, adult index, and adults per hectare were more robust
      entomological indicators (coefficient of variation [CV]/mean = 0.1-2.9) than the
      container index, pupae per person, pupae per house, adults per person, and adults
      per house (CV/mean >20). Our results demonstrate that the MOH's Ae. aegypti risk
      assessment program provides reasonable estimates of indices based on samples from
      every house. However, it is critical that future studies investigate the
      association of these indices with rates of virus transmission to determine
      whether sampling variability will negatively impact the application of indices in
      a public health context.

PMID- 15185958
TI  - Initial study of arthropod succession on pig carrion in a central European urban
      habitat.
AB  - We conducted a carrion succession study within a restricted urban backyard in the
      city of Vienna, Austria (16 degrees 22'E, 48 degrees 12'N) from May to November
      2001 to analyze sequence and composition of the local carrion visiting fauna. Two
      medium sized clothed domestic pig carcasses (Sus scrofa Linnaeus), were used as
      surrogate human models. In total, 42 arthropod species from the families
      Calliphoridae, Sarcophagidae, Sepsidae, Piophilidae, Muscidae, Fanniidae,
      Sphaeroceridae, Phoridae, Drosophilidae, Anthomyiidae, and Lauxaniidae (Diptera),
      Formicidae, Braconidae, Pteromalidae, and Vespidae (Hymenoptera), Silphidae,
      Staphylinidae, Histeridae, Cleridae, and Dermestidae (Coleoptera), as well as
      species from the orders Isopoda and Acari were collected during the decomposition
      of these carcasses. A significant feature in this study was the high abundance of
      Calliphora vomitoria (L.) and Chrysomya albiceps (Wiedemann). In the experiment
      conducted May to June, larvae and adults of C. vomitoria outnumbered all other
      blow fly species, followed by Protophormia terraenovae (Robineau-Desvoidy), C.
      vicina Robineau-Desvoidy, and Lucilia sericata (Meigen). C. vomitoria is
      generally considered to be rural in distribution, where it prefers shaded
      locations. The presence of this species in rural as well as in urban habitats in
      Austria precludes this species as biogeographic indicator. In the study beginning
      in August large numbers of female adults of the nonindigeous blow fly C. albiceps
      began oviposition at day 3 after placement of the cadaver. The predatory second
      and third instars of C. albiceps larvae subsequently almost monopolized the
      cadaver. C. albiceps is generally described as tropical and subtropical species.
      The observed northward expansion of its range beyond southern Europe obviously
      decreases the value of C. albiceps in estimating place of death, in that it is no
      longer exclusive to southern regions. Our results clearly show, that caution must
      be used when drawing conclusions from succession data generated in different
      geographic areas. Moreover, this study demonstrates, that arthropod mediated
      decomposition of a 44 kg exposed pig carcass in a central European urban habitat
      can be completed within 3 wk.

PMID- 15185959
TI  - Control of an organophosphate-resistant strain of Boophilus microplus (Acari:
      Ixodidae) infested on cattle after a series of dips in coumaphos applied at
      different treatment intervals.
AB  - Efficacy of multiple dip treatments (one to three) at 0.3% active ingredient (AI)
      coumpahos applied at 7- or 10-d intervals was determined against organophosphate
      (OP)-resistant Boophilus microplus (Canestrini). None of the treatments totally
      prevented repletion of all females. In the 7 d after one treatment, the
      percentage of reduction of female ticks was 24.8%, whereas in the 10 d after one
      treatment, the reduction of female numbers was 47.1%. Application of two or three
      dips at either interval provided substantially higher reductions in female
      numbers than either single treatment (range 80.2-88.8%). Percentage reduction of
      the index of fecundity of females (designated as percentage of control) in the 7
      d after one dip provided 46.8% control, whereas control in the 10 d after one
      treatment was 65.6%. Again, application of two or three dips at either interval
      provided substantially higher control (range 92.9 to >99.9%). Although control
      levels after two or three dips were similar, only application of three dips at
      either interval provided a high enough level of control (>99.5%) to ensure that
      the U.S. Boophilus eradication program would not be at risk of inadvertently
      dispersing viable ticks. Thus, although no treatment regime prevented repletion
      of all treated females, application of three dips at either interval virtually
      eliminated production of reproductively active females, thereby eliminating the
      possibility that ticks would become established. It should be noted that ticks
      possessing different OP resistance mechanisms than ticks in this study could have
      higher reproductive capabilities than were observed against these treatment
      regimes.

PMID- 15185960
TI  - Eliminating Dermatophagoides farinae spp. (Acari: Pyroglyphidae) and their
      allergens through high temperature treatment of textiles.
AB  - House dust mite allergens cause allergy and asthma in sensitized individuals. The
      allergens they produce are known to resist decay under natural household
      conditions and are thought to accumulate until removed. We sought to evaluate the
      effects of high temperature (96 degrees C) generated by a hard surface cleaner on
      live mite populations of American house dust mites, Dermatophagoides farinae
      Hughes and their allergens in carpet and mattresses. Statistically significant (P
      < 0.05) mite mortality (100%) was observed in response to treatment in both
      textile surfaces. Similar effects were observed on Der f1 fecal allergen.
      Allergen reductions in carpet with two or five pass treatment regimes were 61.4
      and 100%, respectively. These results demonstrate the potential of employing a
      hard surface steam cleaner as a novel method to eliminate house dust mite
      populations and their allergens in a residential setting and appeal particularly
      promising as an environmental control strategy.

PMID- 15185961
TI  - Molecular evidence for a spotted fever group Rickettsia species in the tick
      Amblyomma longirostre in Brazil.
AB  - Two Amblyomma longirostre adult male ticks were collected from a Brazilian
      porcupine Coendou prehensilis L. in the state of Rondonia, Western Amazon,
      Brazil. The two ticks were pooled for DNA extraction and tested for the presence
      of rickettsial DNA by amplifying portions of the gltA, 17-kDa, ompA, and ompB
      rickettsial genes by polymerase chain reaction (PCR). Portions of the four genes
      were amplified from the sample and subsequently sequenced. These results
      indicated the presence of a Rickettsia strain infecting A. longirostre, which was
      designated as strain Aranha. Compared with homologous ompA rickettsial sequences,
      "Rickettsia amblyommii" ompA seemed to be the closest relative to Aranha
      (similarity values: 99.0-99.3%). Phylogenetic analyses of more conserved genes
      including 17-kDa and gtlA partial sequences indicated that this Rickettsia sp. is
      a spotted fever group rickettsia. The partial ompB sequence of strain Aranha was
      distinct from all homologous sequences available in GenBank. Although our ompA
      analysis suggested a very close molecular phylogenetic relationship of Aranha
      with "R. amblyommii," we cannot at this time determine if Aranha is a new strain
      of "R. amblyommii" or a new Rickettsia species in South America.

PMID- 15185962
TI  - Rapid purification and crystal structure analysis of a small protein carrying two
      terminal affinity tags.
AB  - Small peptide tags are often fused to proteins to allow their affinity
      purification in high-throughput structure analysis schemes. To assess the
      compatibility of small peptide tags with protein crystallization and to examine
      if the tags alter the three-dimensional structure, the N-terminus of the chicken
      alpha-spectrin SH3 domain was labeled with a His6 tag and the C-terminus with a
      StrepII tag. The resulting protein, His6-SH3-StrepII, consists of 83 amino-acid
      residues, 23 of which originate from the tags. His6-SH3-StrepII is readily
      purified by dual affinity chromatography, has very similar biophysical
      characteristics as the untagged protein domain and crystallizes readily from a
      number of sparse-matrix screen conditions. The crystal structure analysis at 2.3
      A resolution proves native-like structure of His6-SH3-StrepII and shows the
      entire His6 tag and part of the StrepII tag to be disordered in the crystal.
      Obviously, the fused affinity tags did not interfere with crystallization and
      structure analysis and did not change the protein structure. From the extreme
      case of His6-SH3-StrepII, where affinity tags represent 27% of the total fusion
      protein mass, we extrapolate that protein constructs with N- and C-terminal
      peptide tags may lend themselves to biophysical and structural investigations in
      high-throughput regimes.

PMID- 15185963
TI  - Solution structure of a PAN module from the apicomplexan parasite Eimeria
      tenella.
AB  - Micronemes, specialised organelles found in all apicomplexan parasites, secrete
      molecules that are essential for parasite attachment and invasion of host cells.
      EtMIC5 is one such microneme protein that contains eleven tandemly repeating
      modules. These modules have homology with the PAN module superfamily. Members of
      this family are found in blood clotting proteins, some growth factors and some
      nematode proteins. This paper presents the structure of the 9th PAN module in
      EtMIC5, determined using high resolution NMR. The structure shows similarities to
      and some differences from the N-terminal module of hepatocyte growth factor
      (HGF), the only previous member of the PAN family with known structure.

PMID- 15185964
TI  - Solution structure of a putative ribosome binding protein from Mycoplasma
      pneumoniae and comparison to a distant homolog.
AB  - The solution structure of MPN156, a ribosome-binding factor A (RBFA) protein
      family member from Mycoplasma pneumoniae, is presented. The structure, solved by
      nuclear magnetic resonance, has a type II KH fold typical of RNA binding
      proteins. Despite only approximately 20% sequence identity between MPN156 and
      another family member from Escherichia coli, the two proteins have high
      structural similarity. The comparison demonstrates that many of the conserved
      residues correspond to conserved elements in the structures. Compared to a
      structure based alignment, standard alignment methods based on sequence alone
      mispair a majority of amino acids in the two proteins. Implications of these
      discrepancies for sequence based structural modeling are discussed.

PMID- 15185966
TI  - Elimination of intraluminal colonization by antibiotic lock in catheters.
AB  - Antibiotic lock (AL) technique for catheter related infection encompasses the
      filling of a catheter lumen with high concentrations of antibiotics for hours.
      The goal of AL therapy is to decontaminate the intraluminal surface of the
      catheter. However the duration of antibiotic therapy is not established. An in
      vitro model was designed to establish the time needed to eliminate intraluminal
      microbial colonization and to evaluate the efficacy of vancomycin in comparison
      with teicoplanin by using laboratory AL model. Human plasma was instilled into
      the catheters to allow deposition of fibrin and other products on the catheter
      wall. After 48 hours, the catheters were drained and inoculated with bacteria in
      tryptic soy broth. The catheters were then drained and filled with either (a)
      vancomycin saline solution (VSS) lock (b) teicoplanin saline solution (TSS) lock
      or (c) saline solution (SS) as the control and then incubated for 12 hours. After
      12 hours incubation all the catheter were drained and filled with human plasma.
      Instillation of human plasma and AL was alternated every 12 hours to simulate
      clinical conditions. For each day three catheters, locked with VSS, TSS and SS
      were cultured for colony count. Microbial counts were expressed as total colony
      forming units per longitudinal centimeters of catheter surface. A significant
      decrease in intraluminal catheter colonization started as early as day 1. At the
      end of 7th day catheters treated with VSS and TSS lock were completely sterile.
      The decrease of intraluminal colonization was similar in catheters treated with
      VSS and TSS lock. Also the decrease of intraluminal colonization were similar in
      catheter colonized with slime forming S. epidermidis and nonslime-forming S.
      epidermidis.

PMID- 15185967
TI  - Nutritional effects of supplementing liquid-formula diet with dietary fiber on
      elderly bed-ridden patients.
AB  - In the past few decades, the number of bed-ridden elderly patients has been
      increasing. This group of patients is frequently fed with a liquid formula diet.
      The aim of this study was to evaluate the usefulness of a liquid formula diet
      containing dietary fiber (DF) for elderly bed-ridden patients. Eighteen elderly,
      bed-ridden patients were given L-3 Fiber, a DF-containing liquid formula diet (DF
      LFD), for 4 weeks, while a number of parameters were monitored, including serum
      levels of total cholesterol, triglyceride, total protein, creatinine, uric acid,
      glucose, sodium, potassium, and calcium, urine protein/sugar, and defecation
      frequency. Total protein, albumin and total cholesterol significantly increased
      following the administration of the DF-LFD, associated with an average increase
      in body weight of 1.94 kg (5.0%). Defecation frequency significantly increased
      one week after DF-LFD administration was started, but this effect was transient.
      Although a few patients complained of nausea, vomiting or abdominal pain, no
      severe side effects were seen. In conclusion, DF-LFD supplementation appears to
      be beneficial for elderly bed-ridden patients, and can increase nutritional
      related parameters, such as body weight, total protein, albumin and total
      cholesterol, without severe side effects.

PMID- 15185968
TI  - Beat-to-beat evaluation of systolic time intervals during bicycle exercise using
      impedance cardiography.
AB  - In order to elucidate the beat-to-beat changes of the systolic time intervals
      (STI) during exercise, we proposed new techniques relating to an adaptive filter
      and detection algorithms for B- and X-points in the impedance cardiograph (ICG).
      Six male subjects underwent a ramp bicycle exercise up to maximum intensity
      during which an ECG, ICG and phonocardiogram (PCG) were continuously measured.
      Following the application of an adaptive filter, the scaled Fourier linear
      combiner (SFLC), to the first derivative (dZ/dt) of the base impedance (deltaZ)
      and PCG waveforms, the B- and X-points were automatically determined. For the B
      point detection we used three criteria: the zero-crossing point (B(zero)), the
      15% response point (B15%) of the negative peak of the dZ/dt (dZ/dt(min)) and a
      new algorithm (B(new)). The X-point was separately determined by using the ICG
      and PCG waveforms. It was found that the shape of the dZ/dt waveform directly
      affected the determination of the B- and X-points. The B-points determined using
      B(zero) and B15%, criteria were sometimes unstable caused by the location of a
      notch preceding the dZ/dt(min) compared to the B(new). The time difference
      between the X-points measured by the ICG and PCG was mostly within +/- 20
      milliseconds but statistically significant. Although a wide variation was seen in
      R-R intervals, the STI were more stable. The relationships between HR and STI
      from rest to maximal exercise showed a gentle curvilinear relationship. It is
      suggested that the STI can be obtained precisely on a beat-to-beat basis by using
      the adaptive filter and detection algorithms for the inflection points of the ICG
      even during maximum exercise.

PMID- 15185969
TI  - Incidence of bladder cancer discovered by urethrocystoscopy at prostate biopsy:
      extraordinary high incidence of tiny bladder cancer in elderly males.
AB  - In order to clarify the incidence of bladder cancer with and without prostate
      cancer, we investigated bladder cancer discovered incidentally by
      urethrocystoscopy at prostate biopsy. Between April 1997 and December 2003, 498
      patients who were suspected prostate cancer were performed prostate biopsy and
      urethrocystoscopy simultaneously. We investigate possible invasion of prostate
      cancer into the urethra or bladder mucosa as well as bladder cancer, including
      other benign lesions of the bladder by urethrocystoscopy. Prostate cancer was
      confirmed in 175 (35.1%) of the 498 patients histologically, and bladder cancer
      was discovered incidentally in 12 patients (2.4 %). The incidence of bladder
      cancer in patients with prostate cancer of 2.3% (4/175) was not significantly
      different from that in patients without prostate cancer, which was 2.5% (8/323).
      Superficial and those with a size less than 1 cm were noted in 11 patients (92%)
      and 10 patients (83%) respectively. High incidence rate of bladder cancer with
      prostate cancer was reported previously, however, there was no study to compare
      the incidence rate of bladder cancer between cases with and without prostate
      cancer. The present study suggests that asymptomatic tiny bladder cancer may be
      present at an unexpectedly high incidence rate in elderly males.

PMID- 15185965
TI  - Computational approaches to protein-protein interaction.
AB  - The interactions between proteins allow the cell's life. A number of
      experimental, genome-wide, high-throughput studies have been devoted to the
      determination of protein-protein interactions and the consequent interaction
      networks. Here, the bioinformatics methods dealing with protein-protein
      interactions and interaction network are overviewed. 1. Interaction databases
      developed to collect and annotate this immense amount of data; 2. Automated data
      mining techniques developed to extract information about interactions from the
      published literature; 3. Computational methods to assess the experimental results
      developed as a consequence of the finding that the results of high-throughput
      methods are rather inaccurate; 4. Exploitation of the information provided by
      protein interaction networks in order to predict functional features of the
      proteins; and 5. Prediction of protein-protein interactions.

PMID- 15185970
TI  - Reliability and validity of the Multidimensional Health Locus of Control Scale in
      Japan: relationship with demographic factors and health-related behavior.
AB  - We assessed the reliability and validity of the Multidimensional Health Locus of
      Control Scale (MHLC scale) in a rural Japanese community. The study subjects were
      2388 men and 2454 women aged 40-79 years, who completed a questionnaire regarding
      socio-demographics, health-related behavior, such as smoking and drinking, and
      the MHLC. The Cronbach alpha of the MHLC scale, which is an indicator of the
      internal consistency of the scale, was within the range 0.62-0.76. Elderly
      subjects, women, and subjects with fewer years of education showed more
      "external" belief, which is generally consistent with previous reports from
      overseas. Subjects with adverse health behavior, such as smoking and excess
      drinking, also had more "external" belief. These results indicate that the MHLC
      scale has sufficient reliability and validity among the Japanese population. Use
      of the MHLC scale should help to provide a better understanding of health belief
      among Japanese, and development of health education programs to prevent lifestyle
      related disease.

PMID- 15185971
TI  - Phenoxazine compounds produced by the reactions with bovine hemoglobin show
      antimicrobial activity against non-tuberculosis mycobacteria.
AB  - We studied the anti-microbial effects of phenoxazines produced by the reaction of
      o-aminophenol or its derivatives with bovine hemoglobin, on seven species of
      mycobacteria such as Mycobacterium tuberculosis, Mycobacterium marinum,
      Mycobacterium intracellulare, Mycobacterium scrofulaceum, Mycobacterium
      fortuitum, Mycobacterium kansasii and Mycobacterium smegmatis and some bacteria
      such as Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica serovar
      Typhimurium, Staphylococcus aureus, Listeria monocytogeneses. These phenoxazines,
      including 2-amino-4, 4alpha-dihydro-4alpha, 7-dimethyl-3H-phenoxzine-3-one (Phx
      1), 3-amino-1, 4alpha-dihydro-4alpha, 8-dimethyl-2H-phenoxazine-2-one (Phx-2),
      and 2-aminophenoxazine-3-one (Phx-3), prevented the proliferation of four non
      tuberculosis mycobacteria including M. scrofulaceum, M. kansasii, M. marinum, and
      M. intracellulare dose-dependently, though the inhibitory effects of these
      phenoxazines differed according to the species of mycobacteria. However these
      phenoxazines failed to prevent the proliferation of M. tuberculosis, M.
      fortuitum, and M. smegmatis, and the concerned bacteria other than mycobacteria.
      The present results may contribute to development of novel antibiotics against
      non-tuberculolsis mycobacteria.

PMID- 15185972
TI  - The role of beta2 microglobulin levels in monitoring chronic hepatitis B.
AB  - Beta2 microglobulin is one of the domains of the histocompatibility class I human
      leukocyte antigen (HLA) antigen. In hepatitis infection the presentation of the
      viral antigen on the hepatocyte in the presence of class I HLA antigens plays a
      significant role in the elimination of the virus. The aim of the study was to
      estimate the serum beta2 microglobulin levels in cases of chronic hepatitis B
      infection. Serum beta2 microglobulin levels were assessed in 65 cases with
      chronic hepatitis B infection including 29 pediatric and 36 adult patients as the
      study group and in 30 cases as seronegative control group. Beta2 microglobulin
      level was found significantly higher in chronic active Hepatitis B virus (HBV)
      patients compared to the asymptomatic HBV carriers and also in the chronic active
      HBV patients compared to control group. We are of the opinion that beta2
      microglobulin concentration is an indicator for monitoring chronic active HBV
      infections at the asymptomatic hepatitis B virus carrier patients, thus would
      lead to early initiation of Interferon (IFN) treatment and to monitor the
      effectiveness of the therapy.

PMID- 15185973
TI  - Warfarin-intractable, intraatrial thrombogenesis in a 52-year-old woman with
      mitral stenosis and chronic atrial fibrillation.
AB  - Thromboembolic events are serious complications of atrial fibrillation (AF). We
      histologically investigated intraatrial thrombogenesis in a 52-year-old woman
      with mitral stenosis and chronic AF who had recurrent attacks of cerebral
      infarction despite continuous warfarin therapy. She underwent cardiac surgery for
      mitral valve replacement and maze procedure including left atrial thrombectomy.
      Macroscopic thrombi were found on the endocardium and their surfaces appeared
      rough and dark red in most areas. Histological examination showed that a single
      thrombus mass was composed of several tissue layers or blocks on the endocardium.
      Immunohistochemistry revealed stratum-like accumulations of small platelet
      aggregate/fibrin clot complexes in the superficial, fresh thrombus layers and
      multiple neovessel formation in the basal organized tissue layers. This case
      study suggests that intraatrial thrombi may develop in a stepwise fashion on the
      endocardium involving platelet aggregate/fibrin clot complex formation.

PMID- 15185974
TI  - Sudden infant death syndrome is not associated with the mutation of PHOX2B gene,
      a major causative gene of congenital central hypoventilation syndrome.
AB  - Sudden infant death syndrome (SIDS) is a major cause of infant death, but its
      etiology is unknown. There are several independent risk factors for SIDS, and
      prone sleeping is a major risk factor. SIDS is probably based on a compromise in
      arousal response to breathing or blood pressure during sleep. Congenital central
      hypoventilation syndrome (CCHS or Ondine's curse) is a disorder characterized by
      an idiopathic failure of the autonomic control of breathing and has been regarded
      as one of the compromised conditions in SIDS. Recently, mutations of the PHOX2B
      gene have been detected in half to two-thirds of CCHS patients. We therefore
      analyzed the PHOX2B gene in 23 cases of SIDS and did not find any mutations,
      except for three polymorphic nucleotidic substitutions. The mutation of PHOX2B is
      thus not likely associated with SIDS.

PMID- 15185975
TI  - Tuberculina-Thanatophytum/Rhizoctonia crocorum-Helicobasidium: a unique
      mycoparasitic-phytoparasitic life strategy.
AB  - Tuberculina species are mitosporic parasites of rust fungi. Phylogenetically they
      belong to the Urediniomycetidae, therefore being closely related to their rust
      fungal hosts. We reveal by means of molecular analyses, ultrastructural and
      morphological features, observations in the field, and infection experiments that
      species of the genus Tuberculina and the violet root rot
      (Helicobasidium/Rhizoctonia crocorum) are stages of the life-cycle of one
      holomorph. This opens up new perspectives on parasitic life strategies as the
      resulting life-cycle is based on interkingdom host jumping between rusts and
      spermatophytes. In addition, we point at the consequences for any practical
      application dealing with Helicobasidium as an economically important plant
      pathogen and Tuberculina as a biological agent in rust control.

PMID- 15185976
TI  - Chemotaxonomy of Entonaema, Rhopalostroma and other Xylariaceae.
AB  - Entonaema, Pulveria, Phylacia, Rhopalostroma, Sarcoxylon and Thamnomyces are
      relatively small and poorly studied genera of Xylariaceae. Their affinities to
      the mainstream of the family largely remain to be evaluated. Secondary metabolite
      profiles of type materials, recently collected specimens, and cultures, were
      generated to address this problem from a chemotaxonomic point of view. Micro
      scale extraction and subsequent analytical HPLC with uv/visual (diode array) and
      ms detection in the positive and negative Electrospray mode were carried out,
      employing spectral libraries and standardised gradients that had been optimised
      to detect characteristic pure compounds in species of allied genera.
      Surprisingly, the characteristic metabolites had frequently remained stable even
      in specimens collected up to 190 years ago. Hence, this methodology not only
      proved valuable to establish the conspecificity of type materials with recent
      records, but also revealed some interesting correlations: (1) Stromatal pigments
      of Entonaema cinnabarina, E. globosum and E. liquescens are mitorubrins and other
      characteristic compounds also prevailing in particular species of Hypoxylon; (2)
      Rhopalostroma, Phylacia, Pulveria and Thamnomyces contain binapththalenes and
      other compounds typical of Daldinia and Hypoxylon; (3) Sarcoxylon, as well as E.
      dengii, E. moluccanum and E. pallida, contained none of these pigments, but
      characteristic yet unknown lipophilic metabolites were detected in their
      stromatal extracts; (4) Cultures of E. cinnabarina and Rhopalostroma indicum,
      obtained for the first time, produced essentially the same secondary metabolites
      that are also typical of Daldinia, but absent in Biscogniauxia, Hypoxylon and
      other xylariaceous genera. Hence, chemotaxonomic characters reflected the
      adaptive radiation of this family. Correlations between the evolution of
      morphological/anatomical characters are discussed.

PMID- 15185977
TI  - Cryptic species related to Daldinia concentrica and D. eschscholzii, with notes
      on D. bakeri.
AB  - Daldinia macaronesica (from the Canary Islands and Madeira), D. palmensis (from
      the Canary Islands), D. martinii and D. raimundi (from Sicily), and D.
      vanderguchtiae (from Jersey, Channel Islands) spp. nov., are described, based on
      new combinations of teleomorphic and anamorphic characters. They all resemble the
      pantropical D. eschscholzii and/or the European D. concentrica with regard to
      teleomorphic characters and secondary metabolite profiles generated by analytical
      HPLC. The status of the newly described taxa was established by SEM of ascospores
      and microscopic studies of their anamorphs in comparison with various materials
      of the aforementioned known species. HPLC and SEM studies on the holotype of D.
      bakeri confirmed its relationships to D. fissa and D. loculata. Yellowish
      pigments contained in the type specimen of D. bakeri are probably artificial.

PMID- 15185978
TI  - Preservation methodology for Rosellinia species.
AB  - Many small (temporary) collections of fungi maintained by plant pathologists
      during their research receive inadequate attention to ensure stability.
      Maintaining collections of fungi in pure and viable conditions, minimising
      physiological and morphological changes is, however, a necessity. The objective
      of this study was to find preservation techniques for three Rosellinia isolates
      used in our plant pathogenic research. Various inert and nutritious carriers,
      solid as well as liquid, were used to test their suitability for conserving these
      Rosellinia isolates. Different cryoprotectants, cooling rates and thawing rates
      were tested to optimise liquid nitrogen storage procedures. Survival and/or
      growth rate were assessed over time. Rosellinia bunodes was the most difficult to
      store with survival not exceeding six to nine months using traditional storage
      methods in mineral oil and silica gel. Storage of Rosellinia necatrix and
      Rosellinia pepo was successful for periods up to at least 16 months in several
      carriers and for up to two years for R. necatrix in silica gel. Storage in liquid
      nitrogen proved no problem for R. necatrix or R. pepo with a 100% survival in all
      cases, although radial growth rates after recuperation were affected by
      cryoprotectant and thawing rates. Storage of R. bunodes was more difficult and
      survival as well as growth rates were affected by cryoprotectant and thawing
      rates. Cooling rates did not affect radial growth in any of the isolates. The
      results showed that development of a generalised procedure for storage of our
      Rosellinia species was not possible and successful storage protocols had to be
      developed for individual isolates.

PMID- 15185979
TI  - Systematic reappraisal of Coniella and Pilidiella, with specific reference to
      species occurring on Eucalyptus and Vitis in South Africa.
AB  - The genus Pilidiella, including its teleomorphs in Schizoparme, has a
      cosmopolitan distribution and is associated with disease symptoms on many plants.
      In the past, conidial pigmentation has been used as a character to separate
      Pilidiella (hyaline to pale brown conidia) from Coniella (dark brown conidia). In
      recent years, however, the two genera have been regarded as synonymous, the older
      name Coniella having priority. To address the generic question, sequences of the
      internal transcribed spacer region (ITS1, ITS2), 5.8S gene, large subunit (LSU)
      and elongation factor 1-alpha gene (EF 1-alpha) were analysed to compare the type
      species of Pilidiella and Coniella. All three gene regions supported the
      separation of Coniella from Pilidiella, with the majority of taxa residing in
      Pilidiella. Pilidiella is characterised by having species with hyaline to pale
      brown conidia (avg. length:width > 1.5), in contrast to the dark brown conidia of
      Coniella (avg. length:width < or = 1.5). Pilidiella diplodiella, which is a
      pathogen associated with white rot of grapevines, was shown to be an older name
      for C. petrakii. To delineate species in the P. diplodiella species complex,
      isolates were also compared based on histone (H3) gene sequences. Analyses
      derived from these sequence data separated P. diplodiella from a newly described
      species, P. diplodiopsis. The new species P. eucalyptorum sp. nov. is proposed
      for isolates formerly treated as C. fragariae and associated with leaf spots of
      Eucalyptus spp. This species clustered basal to Pilidiella, and may represent yet
      a third genus within this complex. Pilidiella destruens sp. nov. is newly
      described as anamorph of Schizoparme destruens, which is associated with twig
      dieback of Eucalyptus spp. in Hawaii. A key based on morphological
      characteristics is provided to separate the taxa treated in this study.

PMID- 15185980
TI  - Tuber aestivum (syn. T. uncinatum) biotopes and their history on Gotland, Sweden.
AB  - This study aimed at testing the hypothesis that the genetically distinct Tuber
      aestivum population on the island of Gotland, Sweden, is adapted to habitats
      different from French T. aestivum populations. The soil structure, soil
      chemistry, bedrock, climate, vegetation and host tree continuity of 18 T.
      aestivum sites on Gotland were analysed and compared with data from France. We
      conclude that T. aestivum can grow in soils with a broad soil structure range and
      that no striking differences in soil chemistry were found. No T. aestivum
      indicator plants other than the host trees were found, but the host tree
      continuity on the T. aestivum sites on Gotland was more than 300 yr. If the T.
      aestivum population on Gotland constitutes an ecotype it is rather an adaptation
      to the colder and drier climate on Gotland. Selecting local T. aestivum inoculum
      for truffle orchards in northern Europe could be important for successful truffle
      production.

PMID- 15185981
TI  - Phylogenetic analysis of multiple loci reveal the population structure within
      Letharia in the Caucasus and Morocco.
AB  - The sequence variation within the genus Letharia in the Caucasus and Morocco was
      investigated. Twelve thalli from each area were sequenced at eight different
      loci. Phylogenetic analysis of the multiple loci data revealed the cryptic
      species Letharia 'lupina' in Morocco, previously known only from western North
      America. The two cryptic species L. vulpina and L. 'lupina' locally share the
      same ecology but are genetically isolated from each other. In the Caucasus, five
      different haplotypes of L. vulpina were detected, and in Morocco four L. vulpina
      haplotypes and six L. 'lupina' haplotypes were found. For L. vulpina, allelic
      differences were detected at five of the eight loci in the Caucasus and Morocco.
      The populations of L. vulpina in both the Caucasus and Morocco contain more
      genetic variation than those previously investigated in Europe, which indicates
      that the Caucasus and Morocco acted as refugia during quaternary glaciations, and
      that central and northern Europe may have been recolonised from one or both of
      these areas.

PMID- 15185982
TI  - Genetic variation between Phytophthora cactorum isolates differing in their
      ability to cause crown rot in strawberry.
AB  - Analysis of 44 isolates of Phytophthora cactorum, isolated from strawberry and
      other hosts, by AFLP showed that the crown rot pathotype is different from
      leather rot isolates and from P. cactorum isolated from other hosts. 16 of 23
      crown rot isolates, including isolates from Europe, Japan, Australia, and New
      Zealand, were identical in an analysis based on 96 polymorphic bands from seven
      primer combinations. Leather rot isolates of strawberry could not be
      distinguished from isolates from other hosts. The pathogenicity test of all 44
      isolates on strawberry plants mostly gave unambiguous results, except for three
      American isolates, which seemed to have reduced aggressiveness compared to the
      crown rot isolates. These isolates also differed in the AFLP analysis. Comparing
      information on the origin of the isolates with results from the pathogenicity
      test, showed that isolates from strawberry fruits or petioles could be either
      leather rot or crown rot pathotypes. None of the isolates from hosts other than
      strawberry caused crown rot symptoms in strawberry.

PMID- 15185983
TI  - Comparative studies on microfungi in tropical ecosystems in Ivory Coast forest
      litter: behaviour on different substrata.
AB  - Fungal colonies sporulating on 71 kinds of leaves that fell during the dry season
      in the Tai National Park (Ivory Coast) were analysed. A consistent connection
      between certain fungal species and their substrata was detected among the 184
      fungal species that were identified. Each fungal species was characterized
      according to morphological and ecological features. Multidimensional scaling
      showed that certain ubiquitous and common species have morphological characters
      distinguishing them from specialised species.

PMID- 15185984
TI  - Medication and treatment--more questions than answers?

PMID- 15185985
TI  - Responses of jawbone to pressure.
AB  - OBJECTIVE: To provide a literature review of bone resorption of edentulous jaws
      focusing on responses to pressure. BACKGROUND: After the extraction of all teeth
      in a jaw there is a continuous reduction of the residual ridge. The individual
      variation of bone resorption is great, and the aetiology is complex and not yet
      well understood. MATERIALS AND METHODS: A search of the literature published up
      to May 2003 on bone resorption and pressure was performed using PubMed/Medline.
      RESULTS: Animal studies have demonstrated that excessive and constant pressure
      induces bone resorption. Recent experimental research has indicated that bone
      resorption is a pressure-regulated phenomenon with a lower threshold for
      continuous than for intermittent pressure. Clinical studies have suggested that
      residual ridge resorption is due more to the effects of denture wearing than to
      disuse atrophy. However, the results of leaving out dentures at night are not
      conclusive. Nor does the literature offer any strong evidence for the so-called
      combination syndrome, which has been described as a result of unfavourable
      loading. Clinical studies using multivariate analyses indicate that female gender
      and systemic factors may be of greater importance than oral and denture factors.
      Implant-supported prostheses have a bone preserving effect rather than the
      continuing resorption under complete dentures. CONCLUSIONS: The best way to
      reduce bone resorption is to avoid total extraction, preserve a few teeth and
      fabricate overdentures. In edentulous jaws, placement of implant-supported
      prostheses will lead to less bone loss and may even promote bone growth. To
      increase our knowledge of residual ridge resorption extended experimental,
      clinical and statistical methods will be needed, preferably including
      collaboration between dental and medical researchers.

PMID- 15185986
TI  - Functional behaviour of bone around dental implants.
AB  - Achieving a long-term stable implant interface is a significant clinical issue
      when there is insufficient cortical bone stabilisation at implant placement.
      Clinical outcomes studies suggest that the higher risk implants are those placed
      in compromised cortical bone (thin, porous, etc.) in anatomical sites with
      minimal existing trabecular bone (characterised as type IV bone). In establishing
      and maintaining an implant interface in such an environment, one needs to
      consider the impact of masticatory forces, the response of bone to these forces
      and the impact of age on the adaptive capacity of bone. These forces, in turn,
      have the potential to create localised changes in interfacial stiffness through
      viscoelastic changes at the interface. Changes in bone as a function of age (e.g.
      localised hypermineralised osteopetrosis and localised areas of osteopenia) will
      alter the communication between osteocytes and osteoblasts creating the potential
      for differences in response of osteoblastic cells in the older population. A key
      to understanding the biomechanical and functional behaviour of implants in the
      older population is to control the anticipated modelling and remodelling
      behaviour through implant design that takes into account how tissues respond to
      the mechanically active environment.

PMID- 15185988
TI  - Remineralisation study of artificial root caries lesions after fluoride
      treatment. An in vitro study using electric caries monitor and transversal micro
      radiography.
AB  - AIMS: To evaluate and compare remineralisation of root caries lesions after in
      vitro treatment with various fluoride (F) agents using an Electric Caries Monitor
      (ECM) and Transversal Micro-Radiography (TMR). MATERIALS: Permanent human teeth
      were extracted and root surface specimens were sectioned, prepared (n = 35), and
      randomly allocated into seven different experimental groups (groups 1-7).
      METHODS: Root surfaces were demineralised in an acidified gel (pH = 5.0) for 3
      weeks followed by various F treatments and stored in a standardised
      remineralising solution at 37 degrees C for 6 weeks. The root surfaces were
      treated twice daily with different dentifrice slurries for 2 min, either with a
      neutral placebo dentifrice without F (group 5); or a neutral sodium fluoride
      (NaF) 1400 p.p.m. F dentifrice (group 1); or a neutral 1250 p.p.m. F dentifrice
      (group 6); or an acid dentifrice (pH 4.7) with 1400 p.p.m. F containing amine
      fluoride (AmF) (groups 3 and 4) or a 1250 p.p.m. (pH 4.7) AmF dentifrice (group
      6). In groups 1, 2, 5, 6, and 7, the root surfaces were additionally rinsed for 2
      min with a neutral non-F placebo solution. In groups 3 and 4, rinsing were
      performed for 2 min with an acid (pH 4.7) 250 p.p.m. F solution, containing 125
      p.p.m. F as AmF and 125 p.p.m. F as potassium fluoride (KF), once or twice per
      day respectively. ECM was used to measure electrical resistance on root surfaces
      at baseline and after 3 and 6 weeks respectively. TMR technique was used to
      measure and compare root surface lesion depths and mineral loss. RESULTS: Six
      weeks daily treatment with a dentifrice slurry containing AmF followed by rinsing
      with a combination of equal amounts of AmF and KF solution twice a day showed a
      statistical significant higher ECM values compared with the other groups. TMR
      data measuring lesion depths and mineral loss reduction supported the results of
      the ECM findings. CONCLUSIONS: Daily application of a dentifrice slurry
      containing 1400 p.p.m. F as AmF combined with twice daily rinsing with a 250
      p.p.m. F solution containing equal amount of AmF and KF significantly
      remineralise primary root caries lesions in vitro. ECM and TMR are valuable
      complementary methods in order to analyse the remineralisation processes.

PMID- 15185987
TI  - Oral mucosal and osseous disorders in frail elders.
AB  - OBJECTIVE: This paper reviews the implications of frailty for oral health in old
      age due to the incidence of oral pathoses following on mucosal atrophy, tooth
      loss, trauma from dentures, polypharmacy, malnutrition, salivary disorders,
      degeneration of jawbone and cancer. BACKGROUND: Frailty as a condition of old age
      occurs when elders have energy levels below a critical threshold, or when the
      social or cultural environment is limited. RESULTS: Frail elders are particularly
      vulnerable to pathoses, but not simply because of old age per se. Oral diseases
      accompanying frailty are due to a complicated mixture of biopsychosocial changes
      that accompany old age. CONCLUSIONS: Management of oral mucosal and osseous
      disorders in frail elders requires an understanding of the changes that occur
      with advancing age.

PMID- 15185989
TI  - Oral health and treatment needs of the long-term hospitalised elderly.
AB  - OBJECTIVES: To determine the oral health and treatment needs of the long-term
      hospitalised elderly. SETTING: The Laakso long-term hospital, Helsinki, Finland.
      DESIGN: A cross-sectional study with clinical oral examinations. SUBJECTS: All
      long-term patients (n = 260) aged 60 and older. MAIN OUTCOME MEASURES:
      Edentulousness, presence and hygiene of dentures, mucosal findings, number of
      teeth, functioning teeth and tooth remnants, level of dental hygiene, and need
      for operative treatment. RESULTS: Subjects' mean age was 83.3 years (SD = 8.1);
      42% were edentulous, 45% of women and 33% of men (p = 0.12). With no gender
      difference, 41% had removable dentures, but one in four were considered to be in
      need of repair or replacement. Denture hygiene was good in 19%, moderate in 44%,
      and poor in 37%, and for men worse than for women (p = 0.02). Stomatitis was
      found in 25%, and angular cheilitis in 28% of the denture wearers. The dentate
      subjects had on average 12.4 (SD = 8.6) teeth with a clear difference by age (p =
      0.03), but no difference by gender. Dental hygiene was considered poor. Of the
      dentate subjects, 37% were in need of restorations, 51% of periodontal therapy
      and 42% of extractions. CONCLUSIONS: Oral cleanliness should be improved with
      regards to dentures and teeth. More attention should be focused on dental care of
      the long-term hospitalised elderly.

PMID- 15185990
TI  - Use of a mandibular advancement device in patients with congestive heart failure
      and sleep apnoea.
AB  - OBJECTIVE: To evaluate the practical use of the mandibular advancement device
      (MAD) for treatment of sleep apnoea (SA) in patients with congestive heart
      failure (CHF) over 1 year. SUBJECTS: Twenty-five patients aged 66 +/- 8 years
      (mean +/- SD) met the inclusion criteria and were included in the study. DESIGN:
      In a prospective, clinical trial, the apnoea-hypopnoea index (AHI), a measure of
      SA, was determined with a portable device. Failure to enter treatment and
      compliance, adverse events and signs and symptoms of temporomandibular disorders
      (TMD) were examined before intervention and 4-6 weeks, 6 months, and 1 year after
      intervention. RESULTS: Six patients had removable dentures of whom four had
      complete dentures. Before treatment, eight patients reported minor symptoms of
      TMD. The AHI fell from 19.3 +/- 12.1 to 11.8 +/- 9.5 (p = 0.004) with use of the
      device. In most patients, use of the MAD had no severe effects on the signs and
      symptoms of TMD. Adverse events such as pain in the temporomandibular joints,
      soreness in the teeth, and tiredness in the jaws were reported by 10 patients.
      Dental complications were observed in two patients. Sixty-four per cent of the
      patients were still using the MAD at the 1-year follow-up. CONCLUSIONS: Both the
      general and oral health of CHF patients were important in treatment with a MAD.
      The MAD therapy had no severe effect on the masticatory system and edentulous
      patients could be treated.

PMID- 15185991
TI  - Effects of functional training of dysphagia to prevent pneumonia for patients on
      tube feeding.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of functional
      training on outbreak frequency of pneumonia for the elderly dysphagia patients
      who were being tube fed. METHODS: Subjects were divided into two groups; one
      group (n = 10) received oral care (i.e. non-training group) and the other group
      (n = 11) received functional training of dysphagia in addition to oral care (i.e.
      training group). The dental health team treated subjects once a week for 3 years
      (1999-2001). The frequency of pneumonia outbreaks and changes in activities of
      daily living scale (ADL) were evaluated for each year. RESULT: It was recognised
      that the frequency of pneumonia in the training group decreased year by year (p <
      0.05). Cognitive items in ADL improved in two subjects of the training group. No
      statistical differences were recognised in the non-training group. CONCLUSION: It
      was suggested that once-a-week functional training of dysphagia with professional
      oral care might be effective in preventing pneumonia for elderly people who were
      being tube fed.

PMID- 15185992
TI  - Masticatory performance in 80-year-old individuals.
AB  - OBJECTIVE: To evaluate the masticatory performance of elderly people at the age
      of 80 years. SUBJECTS: A total of 283 individuals of 80 years of age took part in
      a general and dental health survey. MAIN OUTCOME MEASURES: A dental examination
      including the number of remaining teeth, occlusion, prostheses, bite force
      recording, and a questionnaire regarding masticatory performance were recorded.
      SETTING: Five municipalities (Okazaki city, Tokoname city, Tahara town, Atsumi
      town and Minami-chita town) in Aichi prefecture, Japan. RESULTS: There were 20 or
      more teeth in 7.4% subjects, and 44.5% were edentulous. Subjects with no
      occlusion accounted for 77.4% of the total. Subjects with prostheses accounted
      for 90.8%. Maximum bite force and masticatory ability score for patients with 20
      or more teeth or not wearing prostheses were higher than other groups. The non
      wearing prostheses group had a low masticatory ability score. CONCLUSION: Most of
      the 80-year-old individuals recovered their masticatory ability with the
      assistance of prostheses. Several individuals with 20 or more remaining teeth or
      without removable dentures present in both jaws had a high score for bite forces
      and masticatory abilities.

PMID- 15185993
TI  - Sleep-disordered breathing in a military population.

PMID- 15185994
TI  - Interview with Army Specialist Billie Grimes. Interview by Captain Melvin
      Lessing.

PMID- 15185995
TI  - Military medical education: nuclear, biological, and chemical medical defense
      training as a model for planners.

PMID- 15185996
TI  - Airway and ventilatory equipment in field anesthesia: what's new?
AB  - Advances in medical technology provide the modern day field anesthetist with the
      extra edge to meet the challenges faced in the harsh environment of the
      battlefield and enhance the survivability of casualties. The tasks of triage,
      resuscitation, and administration of anesthesia can be facilitated with the use
      of new airway devices, portable ventilators, and monitoring devices. Before such
      equipment is used in the field, the anesthetist must carefully weigh the
      advantages and disadvantages and must be cognizant of the limitations of
      individual devices in different environmental settings. These devices should
      ideally be portable, lightweight, rugged in construction, durable, easy to use
      (requiring minimal training and supervision), readily replaceable, and cost
      effective.

PMID- 15185997
TI  - Dental emergency rates at an expeditionary medical support facility supporting
      Operation Enduring Freedom.
AB  - The purpose of this study was to report the dental emergency rate and the
      distribution of cause of dental emergencies at an Expeditionary Medical Support
      +25 medical facility during a 6-month deployment in support of Operation Enduring
      Freedom. A retrospective cohort analysis of 1,972 soldiers stationed at Seeb Air
      Base, Sultanate of Oman, was accomplished from a phased deployment from March to
      September 2002. Procedures were divided into 11 categories: endodontic,
      extraction of teeth other than third molars, extraction of third molar teeth,
      restoration of teeth (caries), restoration of broken teeth (not caries),
      orthodontic bracket/wire problem, sensitive teeth, temperomandibular pain,
      periodontal, oral pathology, and prosthodontic. One hundred thirty-five dental
      emergency visits were recorded, corresponding to a rate of 137 dental emergencies
      per 1,000 soldiers per year. Most of the emergencies (34.8%) were due to caries.
      Pain from third molars was the second most common reason for visiting the dental
      clinic (19.3%).

PMID- 15185999
TI  - Humanitarian service and recruitment and retention of uniformed services medical
      personnel.
AB  - A recent voluntary survey of 410 personnel from the U.S. Armed Forces Medical
      Departments and the Public Health Service indicated that humanitarian service
      experience has positive effects on recruitment and retention: 48% of respondents
      indicated that the opportunity to provide humanitarian service was a factor in
      their decision to join a uniformed service and 62% indicated that humanitarian
      service opportunities positively influenced their decision to remain in uniform.
      Humanitarian service requirements were a disincentive to remain in uniform for
      25%. Pending further study, these preliminary implications can be applied to
      personnel policies and programs to recruit and retain uniformed health care
      professionals.

PMID- 15185998
TI  - Use of complementary and alternative therapies among active duty soldiers,
      military retirees, and family members at a military hospital.
AB  - OBJECTIVE: To survey soldiers, retirees, and spouses about their use and interest
      in complementary and alternative medicine (CAM) therapies. METHODS: We used an
      anonymous, self-administered survey. RESULTS: Of 291 completed surveys, 81% used
      one or more CAM therapy. The most commonly used were massage and herbal/food
      supplements. The most common reasons were pain, stress, and anxiety. In addition,
      69% wanted CAM therapies offered at the medical treatment facility (MTF), whereas
      24% would pay for the services, and 44% were undecided. CONCLUSION: A high
      percentage of soldiers, retirees, and dependents are using CAM therapies and most
      would prefer that they be made available at the MTF. The implications of such
      high CAM usage within the military suggests a need for nurses and providers to
      become educated in CAM therapies to better assist patients in making appropriate
      choices between two very different forms of medical treatment options and for
      consideration to provide these services within the MTF.

PMID- 15186000
TI  - Breast imaging in a military setting: a comparison with civilian breast imaging.
AB  - A retrospective study was performed to evaluate breast imaging in the Wilford
      Hall Medical Center, the largest medical facility in the U.S. Air Force, from the
      time period of October 1997 to October 2000, in comparison with its civilian
      counterparts. The results demonstrate that although Wilford Hall Medical Center
      breast imaging is faced with unique difficulties in having a relatively mobile
      patient and physician population, military breast imaging corresponds with
      civilian breast imaging in the following aspects: screening the eligible
      population according to age and risk factors, cancer and precancerous abnormality
      detection rate, and biopsy techniques, including stereotactic-guided vacuum
      assisted, automated gun biopsy, ultrasound-guided biopsy, and needle localization
      assisted excision biopsy. Positive predictive value based on biopsy
      recommendations are lower than in civilian practice, likely because military
      radiologists are keenly aware of the mobile status of their population and are
      more aggressive in recommending biopsy for a definitive diagnosis rather than
      mammographic follow up. In our practice, cancer diagnosed at stage 0 or 1 is 85%,
      4.3% of patients have positive lymph nodes, the overall cancer detection rate per
      1,000 population is 3.97, the recall rate is 8.8%, sensitivity is 100%, and
      specificity is 98.1%. All of these aspects are comparable with those of civilian
      practice.

PMID- 15186001
TI  - Validity of using a panoramic radiograph for initial dental classification of
      Army recruits.
AB  - OBJECTIVE: The objective of this study was to examine the validity of classifying
      Initial Entry Training (IET) soldiers into dental fitness classification 2 or 3
      based solely on examining panoramic radiographs. MATERIALS AND METHODS: The
      dental readiness classification, derived from a clinical screening examination
      versus a panoramic radiological examination, was compared for 1,050 Fort Sill
      Basic Training recruits during a 1-month period. The dentist who reviewed the
      panoramic radiograph and determined a dental classification was blinded to the
      earlier dental classification from the clinical examination. The Spearman's rank
      order correlation test was used to determine if a statistically significant
      correlation existed between classifications based on the clinical examination
      versus classification by review of the panoramic radiograph alone. RESULTS: The
      project identified that 18% (n = 186) and 23.7% (n = 249) of the sample
      population had at least one class 3 condition identified from the clinical
      screening examination and the panoramic radiograph review, respectively. Of the
      186 dental fitness category 3 conditions identified from the routine dental
      screening, 81.7% (152) of them were also identified from the review of the
      panoramic radiograph. Spearman's rank order correlation test statistic was 0.633
      for a p < 0.001, indicating a statistically significant correlation in the
      identification of IET soldiers with class 3 conditions using a screening
      examination with a review of the panoramic radiograph. CONCLUSIONS: The findings
      of this study suggest that panoramic radiograph review can identify IET soldiers
      with dental fitness category 3 conditions and implies that a policy change may be
      prudent to allow this type of initial classification.

PMID- 15186002
TI  - A case series of group A Streptococcus necrotizing fasciitis in military
      trainees.
AB  - We describe a case series of group A Streptococcus (GAS) necrotizing fasciitis
      occurring over a 10-week period in military recruits undergoing intense physical
      training. These cases highlight that GAS may cause life-threatening infections in
      addition to mild diseases such as pharyngitis. This series suggests that the
      incidence of severe GAS infections may be increasing in certain populations and
      it emphasizes the importance of considering prophylactic measures against GAS in
      high-risk populations.

PMID- 15186003
TI  - A benign soft tissue mass simulating a glenoid labral cyst on unenhanced magnetic
      resonance imaging.
AB  - A 72-year-old Caucasian man initially presented with a vibratory sensation
      progressing to pain in his left scapular region. After failed conservative
      therapy, a left shoulder unenhanced magnetic resonance (MR) imaging study was
      performed. Initial interpretation suggested a glenoid labral tear with an
      associated paralabral cyst. Further review of the images identified heterogeneous
      increased T2-weighted signal intensity, which led to repeat MR imaging with
      intravenous contrast and the diagnosis of a solid tumor in the suprascapular
      notch. The MR appearance of the mass is illustrated and the usefulness of
      intravenous contrast administration in differentiating between a solid and cystic
      mass on MR imaging is discussed.

PMID- 15186004
TI  - Outsourcing of primary care: satisfaction level in the Israeli Defense Forces.
AB  - OBJECTIVE: To examine the effect of outsourcing primary care services on
      satisfaction levels among career soldiers in the Israeli Defense Forces (IDF).
      METHODS: Data were acquired via self-administered satisfaction questionnaires
      during the visits of soldiers and civilians to primary care clinics in military
      bases, hospitals, and HMO settings. Multivariable analyses (GLM) used the SAS
      statistical program. RESULTS: Two hundred thirty civilians and 618 soldiers (200
      in hospital clinics, 277 in military clinics, and 141 in HMO clinics) completed
      848 questionnaires. Gender did not influence satisfaction level (alpha < 0.05).
      Age and rank influenced two parameters: surroundings (p = 0.0277) and
      availability of the medical service (p = 0.0368). Location (hospital clinic, HMO
      clinic, and military clinic) was the primary variable influencing and predicting
      satisfaction level (11.6%). "Quality of medical care" predicts only 4% of
      satisfaction level. Soldiers in HMO settings expressed a higher degree of
      satisfaction particularly in availability of service, quality of service, general
      satisfaction, and courtesy. CONCLUSIONS: Career soldiers in Israel value all
      aspects of primary care given by a civilian HMO and are willing to accept a
      change (outsourcing primary care to a civilian provider). As a result, decision
      makers should expand the provision of these services to all career soldiers in
      Israel. Outsourcing of medical services can serve as a model to military corps
      worldwide.

PMID- 15186005
TI  - Army personnel satisfaction in different settings of primary health care clinics.
AB  - PURPOSE: To analyze patient satisfaction in Israeli Defense Forces primary care
      clinics (PCCs), and to compare different satisfaction indices that best correlate
      with general satisfaction index. METHODS: Large-scale patient satisfaction survey
      throughout all PCCs, classified as active front clinics, training schools
      clinics, and home front clinics. RESULTS: Participants (5,103) filled out
      standardized questionnaires. Patients in active front clinics were more satisfied
      with their PCCs than in the other two settings. Patients showed the highest
      satisfaction level in the environment questions and the lowest satisfaction level
      in the accessibility questions. In training school clinics and home front
      clinics, accessibility questions were most important, whereas in active front
      clinics, health outcome questions prevailed. CONCLUSIONS: Overall patient
      satisfaction is the highest in active front clinics, lower in training school
      clinics, and lowest in home front clinics. Accessibility is the most important
      factor in patient satisfaction in training school and home front units, and is
      less important in active front units.

PMID- 15186006
TI  - Military implications of atropine hypersensitivity.
AB  - Atropine hypersensitivity is a rarely reported condition. However, in the
      military environment, such reactions are of significant concern given the threat
      of chemical warfare and the use of atropine as a nerve agent antidote. Upon
      deployment to regions where chemical attacks are a threat, each service member is
      issued three 2-mg intramuscular autoinjectors of atropine for self-treatment. In
      the case presented here, an active duty service member presented to his Aid
      Station to request red dog tags for a previously identified allergy to atropine.
      Sensitivity testing revealed a significant reaction to <0.03 mg of intradermal
      atropine. This rarely reported reaction, in the military environment, poses a
      unique question regarding the suitability of deploying military members to areas
      where exposure to chemical warfare agents is possible.

PMID- 15186007
TI  - Prevalence of in-service and post-service sexual assault among combat and
      noncombat veterans applying for Department of Veterans Affairs posttraumatic
      stress disorder disability benefits.
AB  - OBJECTIVE: To describe the prevalence of in-service and post-service sexual
      assault among combat and noncombat veterans seeking Veteran's Affairs disability
      benefits for posttraumatic stress disorder (PTSD). METHODS: Cross-sectional
      survey of 4,918 veterans. RESULTS: Surveys were returned by 3,337 veterans
      (effective response rate, 68%). Among men, 6.5% of combat veterans and 16.5% of
      noncombat veterans reported in-service or post-service sexual assault. Among
      women, 69% of combat veterans and 86.6% of noncombat veterans reported in-service
      or post-service sexual assault. CONCLUSIONS: Reported rates of sexual assault
      were considerably higher among veterans seeking Veteran's Affairs disability
      benefits for PTSD than historically reported rates for men and women in the
      general population. In this population, male gender and veterans' combat status
      should not dissuade clinicians from screening for sexual traumas.

PMID- 15186008
TI  - Profile of psychiatric disorders in the Sri Lanka Air Force and the outcome at 6
      months.
AB  - The epidemiology of mental disorders in the Sri Lanka Air Force is not known,
      although they have been engaged in front line military service in a civil war for
      the past two decades. This study aims to identify the mental health needs of
      military personnel as a means to resource development. Referrals to a specialist
      psychiatry outpatient service were studied to assess the profile of diagnoses and
      outcome after 6 months. Fifty percent suffered from adjustment disorder or a
      stress reaction. In a majority, the onset of the mental health problem was not
      caused by direct exposure to the war situation. There was a high rate of return
      to work at 6 months. However, a disproportionately high loss of personnel was
      seen in the new recruits and trainee soldiers. These data are useful in
      developing services and resources for mental health care for the workforce.

PMID- 15186009
TI  - Deaths in Turkish military services, 1998-2000.
AB  - The aim of this study was to evaluate the causes of death in the military in
      Turkey and to evaluate the previously obtained data relating to the
      characteristics peculiar to the army in those cases of death that have acquired a
      juridical attribute. In this study, the cases presented in the years 1998 and
      2000 have been investigated retrospectively. Seventy military cases investigated
      within a period of 3 years were all men. Except for the 20 cases in which the
      cause of death could not be determined, 30 of 50 cases in our study are included
      in the group of "natural deaths" and 20 are included in the group of "forced
      deaths." In conclusion, natural causes are still the leading cause of death in
      Turkey, and regarding this, it can be suggested that these deaths could be
      preventable by better health care and more careful premilitary health
      examinations.

PMID- 15186010
TI  - Improvised chest tube drain for decompression of an acute tension pneumothorax.
AB  - A case of a woman presenting with an acute tension pneumothorax during a Navy
      humanitarian mission in East Timor is presented. The patient was treated at a
      local rural clinic run by our medical team. Prompt insertion of a chest tube
      saved the woman's life; however, there were no chest tube drains available. A
      field chest tube drain constructed out of an IV bag, a sterile water bottle, and
      tubing provided an adequate underwater seal and drain. Because of the remote
      location and limited resources, standard prehospital chest tube management had to
      be modified. A brief review of simple and tension pneumothoraces and management
      along with a description of the field chest tube drain is presented.

PMID- 15186011
TI  - Forty-two-year-old active duty Marine presents with hematemesis.
AB  - A 42-year-old active duty marine presented to the emergency room with
      hematemesis. This article describes the appropriate step-by-step management for
      this individual with an upper gastrointestinal bleed, and we discuss potential
      differential diagnoses and update readers on the current aspects of managing his
      final diagnosis. Through questions and discussions, we will cover various
      diagnostic modalities and management strategies related to this case and provide
      some insight on the military relevance of his final condition.

PMID- 15186012
TI  - Me, and Walter Reed.

PMID- 15186013
TI  - Prevalence of chlamydial and gonorrheal infections among females in a juvenile
      detention facility, Honolulu, Hawaii.
AB  - Limited studies have shown high rates of gonorrheal and chlamydial infections
      among incarcerated adolescents, however, this population has not been routinely
      targeted for sexually transmitted disease (STD) screening. This study was done to
      ascertain the feasibility of screening females for STDs at a juvenile detention
      facility in Honolulu, Hawaii, and to determine the prevalence of chlamydial and
      gonorrheal infections in this population. Between January 2000 and December 2001,
      pelvic examination-based STD screening was offered to all female detainees, on
      selected dates. Specimens from multiple anatomical sites were cultured for
      Neisseria gonorrhoeae. Endocervical swabs were tested for Chlamydia trachomatis
      using a DNA probe (GenProbe). One-hundred one of 204 (50%) eligible females were
      screened. Fourteen of 101 (13.9%) females were screen positive for chlamydial
      infection, while six of 101 (5.9%) were culture positive for infection with N.
      gonorrhoeae. Three females were co-infected with both organisms. The high STD
      rates justify the institution of a routine screening program for this high risk
      and previously underserved group.

PMID- 15186014
TI  - Factors associated with state variations in homicide, suicide, and unintentional
      firearm deaths.
AB  - This study examined the relationship of 16 variables with homicide, suicide, and
      unintentional firearm deaths. This cross-sectional analysis, using adjusted
      partial correlation coefficients, found that state-level firearm homicide rates
      significantly varied by the prevalence of firearms and by percent of the
      population which was African American. Whereas, state-level variations in firearm
      suicide mortality significantly varied by firearm prevalence, per capita alcohol
      consumption, percent of the population which was African American, and level of
      urbanization. None of the variables were significantly (p < or = .05) related to
      state-level variations in unintentional firearm mortality. Furthermore, state gun
      laws had only a limited effect on firearm-related homicide deaths. Although the
      current study cannot determine causation, firearm mortality in its various forms
      is most commonly related to the prevalence of firearms and the percent of the
      population that is African American.

PMID- 15186015
TI  - Home deliveries in Indonesia: who provides assistance?
AB  - Indonesia has set an ambitious target of reducing its maternal mortality rate to
      125 maternal deaths per 100,000 live births by the year 2010. This poses
      formidable challenges in a geographically diverse country where the majority of
      births occur at home. One option for the Indonesian government in order to reduce
      its maternal mortality would be to increase rates of skilled assistance for home
      deliveries. In order to design appropriate policies to achieve this, it is
      imperative to understand the determinants of use of birth attendants by mothers
      delivering at home. We use the Andersen Behavioral Model as a theoretical
      framework to understand the determinants of the use of a trained provider,
      traditional birth attendant, or no trained assistance during home deliveries in
      Indonesia. The 1997 Indonesia Demographic and Health Survey (IDHS) was used, and
      data from the most recent home delivery was abstracted for analysis. Out of a
      total sample of 10,692 home deliveries, a majority (53%) used the services of a
      TBA, 40% had a doctor, nurse or midwife in attendance, and only 7% delivered with
      the help of family and/or friends. A multinomial logit model was used to predict
      determinants of use. Our results indicate that maternal education, religion,
      asset index quartile and number of antenatal visits are significant determinants
      among all choice sets.

PMID- 15186016
TI  - Baseline assessment of the health status and health behaviors of African
      Americans participating in the activities-for-life program: a community-based
      health intervention program.
AB  - Obesity is a serious problem in the United States and is associated with
      hypertension, diabetes, and other health problems such as heart disease and some
      forms of cancer. There is a higher prevalence of being overweight among African
      American adults than among their Caucasian counterparts. The objective of this
      study was to assess baseline health behaviors and health status (hypertension,
      body mass indices, cholesterol and blood sugar levels) of African Americans
      participating in a community-based health education and physical fitness program.
      The sample consisted of 1.34 African American adults (30% males) from a low
      income urban area in the Midwest. A health survey was administered to assess
      their health behaviors and previously diagnosed health problems. Additional data
      was obtained from health screenings to obtain current information on height,
      weight, and blood sugar, blood pressure and cholesterol levels. In addition to
      the sample being markedly overweight and obese (30% and 60% respectively), the
      results of the health screenings indicated a disproportionate number of
      participants (62%) with hypertension; 74% of the male participants had high blood
      pressure. Moreover, the self-reported data suggested that the participants had
      poor eating habits, sedentary lifestyles, and previously diagnosed health
      conditions (hypertension, diabetes, and high cholesterol levels) that were
      comparable to the results of their health screenings. These findings suggest that
      culturally-relevant, community-based programs that incorporate both nutritionl
      education and physical fitness are needed in order to educate and motivate
      participants to decrease behaviors that put them at risk for obesity and other
      health related problems.

PMID- 15186017
TI  - HIV prevention in Africa: programs and populations served by non-governmental
      organizations.
AB  - The AIDS epidemic in Africa remains an urgent health crisis. Non-governmental
      organizations (NGOs) in Africa play a critical role in the delivery of HIV
      prevention services and assistance to persons living with AIDS. African NGOs are
      conducting numerous HIV prevention programs with several at-risk populations, yet
      their efforts have only rarely been systematically documented. To address this
      gap in the literature, the authors surveyed one NGO in each of 29 African
      countries regarding their HIV prevention activities and populations served. This
      report provides details concerning HIV prevention activities across the continent
      and describes in detail innovative programs from Togo and South Africa. NGOs in
      the present sample operate with modest budgets and small staff sizes, yet conduct
      programs that reach large segments of their communities. NGOs were most likely to
      report community-level interventions such as peer-education or community
      outreach. Faced with an epidemic where the main transmission occurs via
      heterosexual activity, African NGOs were most likely to direct their attention to
      the general public and to youth. NGOs in Africa are struggling to implement
      sustainable, cost-effective programs with few resources. Strengthening the
      infrastructure and capacity of these key agencies is crucial to fighting the AIDS
      epidemic in Africa.

PMID- 15186018
TI  - Ooplasmic transplantation.

PMID- 15186019
TI  - The difficult MESA: findings from tubuli recti sperm aspiration.
AB  - PURPOSE: To investigate sperm quality aspirated from the tubuli recti compared to
      that obtained from microsurgical epididymal sperm aspiration (MESA). METHODS:
      Sixteen patients with congenital bilateral absence of the vas deferens (CBAVD)
      underwent MESA. Six MESA procedures were difficult, and therefore sperm were
      retrieved from the tubuli recti ductules. Intraoperative sperm parameters,
      recovery after freeze-thaw, and ICSI outcomes were analyzed and compared between
      tubuli recti and MESA sperm. RESULTS: Mean initial sperm concentration was
      similar in both groups (18 vs. 16 million sperm/mL). Initial sperm motility was
      significantly higher in the tubuli recti group (35%) than the MESA group (25%).
      However, post thaw motility was higher with MESA compared to tubuli recti sperm
      (8.7 vs. 1.5%). ICSI fertilization rates after sperm freeze-thaw were 66% for
      tubuli recti sperm and 71% for MESA sperm. CONCLUSIONS: Tubuli recti sperm may
      provide an attractive alternative to testis sperm extraction. Poor sperm recovery
      after freeze-thaw should be expected.

PMID- 15186020
TI  - Comparison of basal and clomiphene citrate induced FSH and inhibin B, ovarian
      volume and antral follicle counts as ovarian reserve tests and predictors of poor
      ovarian response in IVF.
AB  - PURPOSE: To compare basal and clomiphene citrate (CC) induced follicle
      stimulating hormone (FSH), estradiol (E2), and inhibin B levels with ultrasound
      indices of ovarian reserve in infertile women and to test the prognostic value of
      these tests on response to ovarian stimulation in in vitro fertilization (IVF).
      METHODS: Fifty-six patients had basal and CC induced serum hormone levels and
      ultrasound measured mean ovarian volume (MOV) and mean antral follicle counts
      (MFC). Thirty-two patients were then appropriately selected to have a total of 41
      cycles of IVF/ICSI treatment. RESULTS: Women with diminished ovarian reserve had
      lower MOV, MFC, day 3 and day 10 inhibin B levels (p < 0.001). Only basal and CC
      induced FSH and inhibin B correlated with MOV and MFC. Poor responders in
      IVF/ICSI had higher basal FSH (p < 0.05), lower basal and induced inhibin B
      levels (p < 0.05), and lower MOV and MFC (p < 0.01) than normal responders.
      Ovarian volume alone was better than age and basal hormones in predicting poor
      ovarian response, while abnormal CC test was the only independent significant
      factor in predicting ovarian response. However, age was the only independent
      predictor of pregnancy in IVF as compared to hormonal and ultrasound indices of
      ovarian reserve. CONCLUSION: CC test and ovarian volume are better than other
      hormonal and sonographic tests in predicting the response to ovarian stimulation
      in IVF cycles.

PMID- 15186021
TI  - Cumulative embryo score, not endometrial thickness, is best for pregnancy
      prediction in IVF.
AB  - PURPOSE: To assess the combined effect of endometrial thickness and cumulative
      embryo score (CES) on pregnancy rates in assisted reproduction cycles compared to
      the effect of each of these factors considered individually. METHODS:
      Retrospective review of 2001 IVF pregnancy outcomes with respect to endometrial
      thickness and CES. RESULTS: One hundred fifty-five IVF cycles were reviewed.
      Endometrial thickness ranged from 6.4 to 22 mm. CES ranged from 16 to 194. CES
      scores above 50 correlated with improved pregnancy rates (31%) over those less
      than 50 (12.5%). CES scores above 150 were correlated with a further doubling in
      pregnancy rates (66%). Endometrial thickness alone or in combination with
      cumulative embryo score did not improve the prediction of pregnancy. CONCLUSIONS:
      CES alone, and not combined with endometrial thickness, is a statistically
      significant factor in pregnancy rates that may be clinically useful in decisions
      regarding number of embryos transferred to ensure a better pregnancy rate.

PMID- 15186022
TI  - Longevity of donor serum.
AB  - PURPOSE: To determine the viability of long-term, stored serum, which is used in
      human in vitro production as a source of energy substrates, amino acids,
      vitamins, growth factors, and other nutrients. METHOD: Two-cell mouse embryos
      were used in this prospective, cohort study. Serum stored for 1-, 5-, 10-, and 12
      year intervals was subjected to four replications of mouse-embryo testing.
      RESULT(S): There were no significant differences in blastocyst rates between any
      of the replicates by year (80-100% blastocyst rate; P > 00.1) or between pooled
      replicate means by time period. CONCLUSION(S): Serum may be frozen up to 12
      years.

PMID- 15186023
TI  - Embryonic chromosomal abnormalities obtained after rescue intracytoplasmic sperm
      injection of 1-day-old unfertilized oocytes.
AB  - PURPOSE: To study if second day intracytoplasmic sperm injection (ICSI) results
      in chromosomal abnormalities in the embryos. METHODS: Rescue ICSI was performed
      on 14 metaphase II (MII) oocytes after unsuccessful conventional IVF, four were
      fertilized. Fluorescent in situ hybridization (FISH) was performed on these four
      embryos and was informative for three. RESULTS: There were two tetraploid
      embryos, one mosaic embryo with trisomy 21, tetrasomy 18, and tetrasomy for sex
      chromosomes in one cell and trisomy 22 in another cell. CONCLUSIONS: We
      discourage the use of second day ICSI due to the observed increase in chromosomal
      abnormalities in these embryos.

PMID- 15186024
TI  - Successful spouse pregnancy of male patients with severe aplastic anemia and
      chronic myelogenous leukemia using spermatozoa banked prior to bone marrow
      transplantation and using the ICSI procedure: case reports.
AB  - PURPOSE: To report two cases of successful spouse pregnancies which were
      conceived with long-term cryopreserved spermatozoa that had been collected prior
      to the male patients receiving a bone marrow transplant. METHODS: The first case
      is the pregnant wife of a 25-year-old man with chronic myelogenous leukemia,
      whose semen was collected before bone marrow transplant and then cryopreserved,
      thawed, and then injected into the wife's eggs via ICSI. The second case is a 28
      year-old man with severe aplastic anemia who became a father after his wife's
      eggs were fertilized via ICSI with thawed spermatozoa. RESULTS: These two cases
      were achieved pregnancies. CONCLUSIONS: These cases support research that men
      with malignancy have the chance of fathering their own genetic children.
      Therefore, it is important to increase the awareness of clinicians, oncologists,
      and patients to the new developments in preserving fertility for cancer patients.

PMID- 15186025
TI  - Bacterial degradation of chlorophenols: pathways, biochemica, and genetic
      aspects.
AB  - Chlorophenols belong to the group of toxic and persistent to microbial attack
      xenobiotics. Nevertheless, due to the adaptation microorganisms acquire the
      ability to use chlorophenols as the sole source of carbon and energy. The present
      review describes the diversity of aerobic pathways for the utilization of
      halogenated phenols by bacteria with the emphasis on the main reactions and
      intermediates formed, enzymes responsible for these reactions and their genetic
      basis. Taking into account (i) the fact that enzymes degrading chlorophenols are
      similar to the ones involved in the conversion of other (chloro)aromatic
      compounds and (ii) that present numerous publications describing the properties
      of separated enzymes or encoding their genes are published, this review was
      planned as the attempt to present both, the most general and specific aspects in
      chlorophenols degradation with the emphasis on the literature of the last ten
      years.

PMID- 15186026
TI  - Sample purification for analysis of organochlorine pesticides in sediment and
      fish muscle.
AB  - The methods of sample purification for determinations of organochlorine
      pesticides (OCPs) in sediment and fish muscle were investigated in this study. A
      two-step procedure with preliminary cleanup and florisil column fraction was
      adopted. The working conditions of florisil column were firstly optimized. As to
      preliminary cleanup, liquid-liquid extraction by mixture of dimethyl formamide
      (DMF) and hexane and sulphonation by concentrated sulfuric acid were applied
      respectively and compared for the studied samples. The results indicated that
      liquid-liquid distribution could effectively separate lipids from fish muscle
      extracts, while failed in elimination of chlorophyll extracted from the relicts
      of hydrophytes in the sediment sample. In view of the sample appearance and
      clarity of gas chromatogram, sulphonation was more suitable to purify the
      sediment sample, however, the recoveries of the spiked standards were poor. The
      use of eluting solvent with stronger polarity could improve the corresponding
      recoveries significantly. Due to complete loss of Dieldrin, Endrin, and Endrin
      aldehyde after sulphonation, this pretreatment was improper to the three
      components. Sulfur, as the particular disturbing element in sediment, could be
      removed sufficiently by addition of activated copper powder. The relevant
      detection limits of the selected methods for OCPs in the studied substrates were
      also provided.

PMID- 15186027
TI  - Factors influencing 2,4-D sorption and mineralization in soil.
AB  - This study quantified 2,4-D [(2,4-dichlorophenoxy)acetic acid] sorption and
      mineralization rates in five soils as influenced by soil characteristics and
      nutrient contents. Results indicated that 2.4-D was weakly sorbed by soil, with
      Freundlich distribution coefficients ranging from 0.81 to 2.89 microg(1 - 1/n) g(
      1) mL(1/n). First-order mineralization rate constants varied from 0.03 to 0.26,
      corresponding to calculated mineralization half-lives of 3 and 22 days,
      respectively. Herbicide sorption generally increased with increasing soil organic
      carbon content, but the extent of 2,4-D sorption per unit organic carbon varied
      among the soils due to differences in soil pH, clay content and/or organic matter
      quality. Herbicide mineralization rates were greater in soils that sorbed more
      2,4-D per unit organic carbon, and that had greater soil nitrogen contents. We
      conclude that the effect of sorption on herbicide degradation cannot be
      generalized without a better understanding of the effects of soil characteristics
      and nutrient content on herbicide behavior in soil.

PMID- 15186028
TI  - Behavior of Chlorpyrifos-methyl in soil and sediment.
AB  - This research was carried out with the aim of obtaining information regarding the
      possible environmental impact of Chlorpyrifos-methyl, an organophosphoric
      insecticide used in agriculture for its phytoiatric action against Hemiptera,
      Lepidoptera, Coleoptera, and Diptera. Studies relating to the degradation
      kinetics of the insecticide in two soils and one sediment have shown a rapid
      degradation process in all three. The prevalent form of degradation would appear
      to be the chemical type, because the degradation kinetics in a sterile soil have
      not demonstrated that micro-organisms play a significant part. The adsorption
      isotherms showed that the insecticide has a greater affinity for the sediment
      (Kf=143) as opposed to the soils (Kf=65) and that the adsorption process is
      practically irreversible. Moreover, hydrolysis tests in buffered solutions at pH
      4, 7, and 9 revealed that the molecule is particularly unstable with a basic pH.

PMID- 15186029
TI  - Oxidation of MCPA and 2,4-D by UV radiation, ozone, and the combinations UV/H2O2
      and O3/H2O2.
AB  - The phenoxyalkyl acid derivative herbicides MCPA (4-chloro 2-methylphenoxyacetic
      acid) and 2,4-D (2,4-dichlorophenoxyacetic acid) were oxidized in ultrapure water
      by means of a monochromatic UV irradiation and by ozone, as well as by the
      combinations UV/H2O2 and O3/H2O2. In the direct photolysis of MCPA, the quantum
      yield at 20 degrees C was directly evaluated and a value of 0.150 mol Eins(-1)
      was obtained in the pH range 5-9, while a lower value of 0.41 x 10(-2) mol Eins(
      1) was determined at pH=3. Similarly, for 2,4-D a value of 0.81 x 10(-2) mol
      Eins(-1) was deduced, independent of the pH of work. The influence of the
      additional presence of hydrogen peroxide was established in the combined process
      UV/H2O2, and the specific contribution of the radical pathway to the global photo
      degradation was evaluated. The oxidation by ozone and by the combination O3/H2O2
      was also studied, with the determination of the rate constants for the reactions
      of both herbicides with ozone and hydroxyl radicals at 20 degrees C. These rate
      constants for the direct reactions with ozone were 47.7 and 21.9 M(-1) s(-1) for
      MCPA and 2,4-D respectively, while the found values for the rate constants
      corresponding to the radical reactions were 6.6 x 10(9) and 5.1 x 10(9) M(-1) s(
      1).

PMID- 15186030
TI  - Determination of endosulfan residues in eggplant (Solanum melongena) by ELISA.
AB  - Eggplant samples were analyzed for endosulfan residues using ELISA, a technique
      recognized as a promising tool for screening environmental contaminants.
      Calibration curve for endosulfan was standardized using kits developed by CFTRI
      Mysore. Farm gate samples of eggplant from 12 different locations were analyzed.
      The matrix effect was removed by charcoal clean-up. The results were compared
      with gas chromatographic (GC) analysis. The residues in different samples were in
      the range of 5-226 ppb. Correlation coefficient between the two methods was found
      to be 0.98.

PMID- 15186031
TI  - Adsorption, desorption, and mobility of permethrin in Malaysian soils.
AB  - The adsorption, desorption, and mobility of permethrin in six tropical soils was
      determined under laboratory and greenhouse conditions. The six soils were
      selected from vegetable growing areas in Malaysia. Soil organic matter (OM) was
      positively correlated (r2 = 0.97) with the adsorption of permethrin. The two
      soils, namely, Teringkap 1 and Lating series with the highest OM (3.2 and 2.9%)
      released 32.5 and 30.8% of the adsorbed permethrin after four consecutive
      repetitions of the desorption process, respectively, compared to approximately
      75.4% of the Gunung Berinchang soil with the lowest OM (1.0%) under the same
      conditions. The mobility of permethrin down the soil column was inversely
      correlated to the organic matter content of the soil. Permethrin residue
      penetrated only to the 10-15 cm zone in the Teringkap 1 soil with 3.2% OM but
      penetrated to a depth of more than 20 cm in the other soils. The Berinchang
      series soil with the lowest OM (1.0%) yielded leachate with 14.8% permethrin, the
      highest level in leachates from all the soils tested. Therefore, the possibility
      for permethrin to contaminate underground water may be greater in the presence of
      low organic matter content, which subsequently allows a higher percentage of
      permethrin to move downwards through the soil column.

PMID- 15186032
TI  - The response of Escherichia coli, Bacillus subtilis, and Burkholderia cepacia WZ1
      to oxidative stress of exposure to quinclorac.
AB  - The activity response of the antioxidant enzymes superoxide dismutase, catalase,
      ATP enzyme activities of Escherichia coli (G-), Bacillus subtilis (G+), and
      Burkholderia cepacia WZ1 (G-) following exposure to quinclorac was investigated.
      The bacterial strains were treated with the different concentrations of
      quinclorac (1.65, 16.5, 33.0, 165.0, 330.0, and 500.0 microg L(-1)). Results
      obtained indicated that SOD and CAT activities of these bacteria were induced
      positively and obviously by quinclorac, especially to gram-positive (G+) bacteria
      treated by lower than 330 microg L(-1) of quinclorac. The inhibition of ATPase in
      E. coli K12, B. subtilis, and B. cepacia WZ1 appeared stronger with the increase
      of quinclorac concentration, showing a striking dose response relationship, which
      can, therefore, be used as an available bioindicator for quinclorac pollution.
      The concentration of quinclorac applied in this research had significant effects
      on these three bacteria at the early stage of incubation, but none of which was
      persistent. Native polyacrylamide gel electrophoresis and activity staining of
      SOD revealed that quinclorac had effects on isoforms of E. coli and B. subtilis,
      and on the staining intensities of the isoforms of B. cepacia WZ1. When E. coli
      K12 was incubated with 330 microg L(-1) of quinclorac, the upper band of the
      isoforms of SOD tended to become slightly more apparent at 1 h after the
      quinclorac treatment, but the staining activity was slightly reduced after the
      prolonged treatment of quinclorac. No such changes of the isoforms of B. cepacia
      WZ1 was observed.

PMID- 15186033
TI  - Role of alpha-tocopherol and beta-carotene in ameliorating the fenvalerate
      induced changes in oxidative stress, hemato-biochemical parameters, and semen
      quality of male rats.
AB  - Role of alpha-tocopherol (vitamin E), beta-carotene and/or their combination as
      antioxidants against the toxicity of fenvalerate on blood hematology, free
      radicals, biochemical parameters, and semen quality were studied in male rats.
      Fenvalerate (20 mg/kg BW), vitamin E (100 mg/kg BW), beta-carotene (10 mg/kg BW),
      and vitamin E plus beta-carotene (100 + 10 mg/kg BW, respectively) were given
      alone or in combination with fenvalerate. The tested doses were given to rats
      every other day for 30 days. Results obtained showed that fenvalerate
      significantly (P < 0.05) induced free radicals in plasma and brain and
      insignificantly in liver and testes. While, vitamin E, beta-carotene alone and/or
      in combination decreased the levels of free radicals in plasma, liver, testes,
      and brain. The activities of glutathione S-transferase (liver), alkaline
      phosphatase (plasma and liver), aspartate aminotransferase (plasma, liver, and
      testes) and alanine aminotransferase (plasma and liver) were significantly (P <
      0.05) increased due to fenvalerate administration. The activity of
      acetylcholinesterase was significantly (P < 0.05) decreased in brain and plasma,
      while plasma glucose, urea, creatinine, and bilirubin concentrations were
      significantly (P < 0.05) increased in rats treated with fenvalerate. Also,
      results showed a significant (P < 0.05) alterations in plasma proteins,
      hematological parameters, body weight, and relative weights of organs. Sperm
      concentration and motility (%) were significantly (P < 0.05) decreased, while
      dead and abnormal sperm increased in rats exposed to fenvalerate. Vitamin E, beta
      carotene alone and/or in combination did not cause any changes in the
      investigated parameters, but improved semen quality and minimized the toxic
      effect of fenvalerate. The obtained results demonstrated the beneficial
      influences of vitamin E, beta-carotene alone and/or in combination in reducing
      the harmful effects of fenvalerate.

PMID- 15186034
TI  - Environmental and potential health effects of growing leafy vegetables on soil
      irrigated using sewage sludge and effluent: a case of Zn and Cu.
AB  - The use of sewage sludge and effluent as a source of nutrients and water for crop
      production is increasing worldwide. A study was conducted in 2001 at Pension farm
      (near Harare) to determine the effect of long term (>30 yrs) application of
      sewage sludge and effluent on Zn and Cu accumulation in top soil, uptake of these
      metals by lettuce (Lactuca sativa L.) and mustard rape (Brassica juncea L.), and
      dry matter yield. Application of sewage sludge/effluent significantly (p<0.001)
      increased total Zn (13.7-1563.9 mg kg(-1)) and Cu (2.5-133.3 mg kg(-1)) in the
      top soil (0-20 cm depth) compared to the control. Sewage sludge/effluent addition
      significantly (p<0.001) increased Zn uptake by both test crops, while Cu uptake
      was significant in the first crop of lettuce and the second crop of mustard rape.
      Based on the dietary patterns of poor urban households in Zimbabwe, the maximum
      possible intake of Cu will only constitute 40% the Maximum Daily Intake (MDI).
      The toxicological implications for Zn will however be more severe, exceeding the
      MDI by 77% through exposure by lettuce consumption and by 251% consumption of
      mustard rape. It was concluded that long-term addition of sewage sludge/effluent
      to soil at Pension farm had increased the concentration of Zn and Cu in top soil
      to levels that pose environmental concern. The consumption of leafy vegetables
      produced on these soils pose a health risk to poor communities that reside around
      the study site, especially children, through possible Zn toxicity.

PMID- 15186035
TI  - Heavy metal uptake by spinach leaves grown on contaminated soils with lead,
      mercury, cadmium, and nickel.
AB  - Spinach plants were grown in soil pots contaminated with increasing mixtures of
      lead, mercury, cadmium, and nickel salts. Plants in the control soil were grown
      in the absence of the heavy metals mixture. The elemental distribution of Cd, Ni,
      Pb, and Hg in the roots and leaves of Spinach (Spinacia Oleracea) was determined
      in two stages, Stage 1, after five weeks of plant growth and Stage 2, after 10
      weeks with full growth. Under the influence of contamination of soil with the
      heavy metal mixtures, Hg was the most accumulated element in the root of the
      spinach plant with a concentration of 283 ppm recorded in the highest
      contaminated soil, followed by Cd at 148 ppm.

PMID- 15186036
TI  - A comparison of swine wastewater treatment using real-time and fixed-time two
      stage sequencing batch reactors.
AB  - This study compared the swine wastewater treatment of two identical lab-scale two
      stage sequencing batch reactors (TSSBR) under similar conditions except that one
      was operated on a fixed-time mode and the other on a real-time mode. While both
      TSSBR systems performed very well, the real-time TSSBR performed far better then
      the fixed-time TSSBR, in every aspect of carbon, nitrogen, and phosphorous
      removal. The removals of COD, TOC, were at 97% and for BOD5 even at 99.7%. In
      terms of NH4-N and TKN removals, the real-time TSSBR achieved removal of over
      98%. For phosphorus removals (Ortho-P and total P) the results from the real-time
      TSSBR was quite remarkable at 97.7%.

PMID- 15186037
TI  - Xenoestrogen modulation of the immune system: effects of
      dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD).
AB  - Dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD) are complex organic compounds that are frequently found in the environment
      as a result of agricultural and industrial activities. Both compounds have
      substantial immune system and endocrine system disrupting activity, acting as
      estrogen agonists or antagonists (xenoestrogens). Research has demonstrated that
      exposure to xenoestrogens can result in body weight loss, developmental
      abnormalities, thymic atrophy, carcinogenesis, and tissue-specific hypoplastic
      and hyperplastic responses. Although several studies have reported significant
      adverse effects of these compounds on the endocrine system, very few
      investigations have focused on the specific mechanisms of action on the immune
      system. This paper reviews the cellular and molecular mechanisms of DDT- and TCDD
      induced toxicity on the endocrine and immune systems, and explores their
      potential impact on the pathogenesis of immune disease.

PMID- 15186038
TI  - Genetic polymorphisms and environmental risk of lung cancer: a review.
AB  - Lung cancer results from man-made and natural environmental exposures acting in
      concert with both genetic and acquired characteristics. Chronic inhalation of
      cigarette smoke is a major risk factor, and environmental tobacco exposure can
      cause lung cancer in life-long neversmokers. Air pollution, indoor-radon
      exposure, occupational exposures, dietary, physical activity, and reproductive
      history have been identified as independent or contributing risk factors for lung
      cancer. Because only a small portion of smokers develops the disease, genetic
      susceptibility can contribute to the risk. Developments in molecular biology have
      led to the discovery of biological markers that increase predisposition to lung
      carcinogenesis. Therefore, the high-risk genotype of an individual can be
      determined easily. Because of the great number of carcinogen-activating and 
      detoxifying enzymes, the variation in their expression, the complexity of
      exposures to tobacco carcinogens, and the existence of multiple alleles at loci
      of those enzymes results in differential susceptibilities of individuals. As lung
      cancer is a multifactorial disease, an improved understanding of the interplay of
      environmental and genetic polymorphisms at multiple loci can help identify
      individuals who are at increased risk for lung cancer. Hopefully, in the future
      we will be able to screen for lung cancer susceptibility by using specific
      biomarkers.

PMID- 15186040
TI  - Phytoremediation: biological cleaning of a polluted environment.
AB  - Phytoremediation is the direct use of living green plants to degrade, contain, or
      render harmless various environmental contaminants, including recalcitrant
      organic compounds or heavy metals. The methods involved include phytoextraction,
      direct phytodegradation, rhizofiltration, phytovolatilization or formation of
      artificial wetlands, and lagoon systems. More research background and the
      development of plants tailored for remediation purposes, using genetic
      engineering and deeper understanding of plant cooperation with microorganisms is
      needed. This approach is illustrated by our studies of heavy metal uptake
      improvement or studies of the PCB conversion, which include in-vitro screening of
      plant species, analysis of the products, evaluation of their toxicity and field
      plots, and also studies of enzymes and cloning of foreign genes into plants.

PMID- 15186039
TI  - Lung cancer and mesothelioma among male automobile mechanics: a review.
AB  - BACKGROUND: Extensive, overt asbestos exposure clearly causes lung cancer and
      mesothelioma. Elevated cancer risk has also been documented for short term or low
      levels of asbestos exposure. Automobile mechanics are potentially exposed to
      asbestos through brake repair work. Few studies have specifically examined the
      risk of lung cancer and mesothelioma associated with exposure to asbestos in
      brakes, but automobile mechanics are included in many studies of occupation and
      cancer. METHODS: We critically reviewed all epidemiologic studies of lung cancer
      and mesothelioma risk among male automobile mechanics identified through a
      broadly based Medline search and scrutiny of references in primary and review
      articles. We discuss the studies grouped by study design and control for smoking,
      the major risk factor for lung cancer. RESULTS/CONCLUSIONS: We reviewed all
      individual analytical studies meeting our criteria, plus all available case
      series and case reports. When examined in aggregate, the evidence did not support
      an increase in risk of either lung cancer or mesothelioma among male automobile
      mechanics occupationally exposed to asbestos from brake repair.

PMID- 15186041
TI  - An antidote for prevaricating physicians in matters medicolegal: Coalition and
      Center for Ethical Medical Testimony.

PMID- 15186042
TI  - What's eating you? Schistosoma japonicum.

PMID- 15186043
TI  - Photo Quiz. What is your diagnosis? Eczema herpeticum superinfection in a patient
      with pemphigus vulgaris.

PMID- 15186044
TI  - Treatment of palmoplantar keratoderma with continuous infusion 5-fluorouracil.
AB  - A 49-year-old man electively chose to undergo a trial of intravenous chemotherapy
      with 5-fluorouracil (5-FU) for his inherited punctate palmoplantar keratoderma
      (PPK). His father also had this skin disorder, which coincidentally cleared after
      2 courses of chemotherapy consisting of 5-FU and cisplatin to treat his lung
      cancer, prompting the patient to undergo this trial of therapy. After the
      patient's first course of a 5-day continuous infusion (CI) of 5-FU (1000 mg/m2
      per day), the lesions on his hands and feet regressed by approximately 80%.
      However, after completion of each course, the lesions seemed to reappear to some
      degree. The patient desired to pursue further therapy; therefore, CI 5-FU at a
      dose of 250 mg/m2 per day (500 mg/d) was instituted, while pyridoxine was avoided
      in the hope of causing a hand-foot syndrome that may provide some long-term
      benefit. After receiving a 12-week course of therapy of CI 5-FU at 250 mg/m2 per
      day, his lesions were approximately 95% improved, with only a few minute punctate
      keratoses remaining. At follow-up nearly 4 years later, the lesions remain 90%
      cleared.

PMID- 15186045
TI  - Large solitary cafe au lait spots: a report of 5 cases and review of the
      literature.
AB  - The presence of multiple cafe au lait spots (CALSs) has been well described and
      associated with several neurocutaneous and genetic syndromes including, most
      commonly, neurofibromatosis. However, scant literature exists regarding the
      clinical significance of the large solitary CALS. We describe 5 patients with
      congenital large solitary CALSs without associated abnormalities. Our cases and
      review of the literature suggest that large solitary CALSs are uncommon benign
      lesions that most likely are not associated with any neurocutaneous syndromes or
      developmental anomalies.

PMID- 15186046
TI  - Recurrent, localized urticaria and erythema multiforme: a review and management
      of cutaneous anthrax vaccine-related events.
AB  - The October 2001 domestic anthrax attacks affected 22 people, resulting in 5
      fatalities. The added global terrorist threats have created an increasing need
      for homeland protection, as well as protection of our widely deployed forces
      battling terrorism. It is now relevant for physicians to be familiar with both
      clinical anthrax and adverse vaccine-related events associated with the
      resumption of the anthrax vaccine program. Dermatologists played a lead role in
      the initial response to the anthrax attack. We must be the lead providers most
      familiar with the cutaneous reactions that may be seen with the preventive
      vaccination. This article reviews the latest recommended evaluation and
      management of anthrax vaccine adverse events.

PMID- 15186047
TI  - Pemphigus, pregnancy, and plasmapheresis.
AB  - Pemphigus vulgaris (PV) is an autoimmune blistering disorder that usually occurs
      in the fifth and sixth decades of life but may occur at younger ages and during
      pregnancy. Circulating intercellular antibodies directed at desmosomal proteins
      may cross the placenta and place children at risk for neonatal pemphigus (NP). We
      describe the case of a pregnant woman with PV treated successfully with a
      combination of systemic corticosteroids and plasmapheresis. The possibility of PV
      should be considered in any pregnant woman with a worsening, widespread,
      mucocutaneous, blistering disease. Plasmapheresis offers a useful alternative to
      immunosuppressive therapy in the setting of pregnancy.

PMID- 15186048
TI  - Should coal tar products carry cancer warnings?
AB  - This article addresses the controversy whether over-the-counter products that
      contain coal tar concentrations greater than 0.5% must carry cancer warnings.
      Evidence that topical coal tar is carcinogenic in laboratory animals and humans
      is reviewed. In addition, the potential risk of internal malignancies arising
      from the topical use of coal tar is discussed. The view is expressed that the
      California court decision that such products should carry cancer warnings is
      correct.

PMID- 15186049
TI  - Piloleiomyoma mistaken for postacne scarring.
AB  - Piloleiomyomas are benign, smooth muscle neoplasms arising from the arrectores
      pilorum muscles in the skin. They differ in size and number and are often cold
      and painful or sensitive to touch. Piloleiomyomas, though not exceedingly rare,
      may not be expected in the differential diagnosis for multiple skin nodules. We
      present a case of a piloleiomyoma that was initially diagnosed as postacne
      scarring.

PMID- 15186051
TI  - Parry-Romberg syndrome and sympathectomy--a coincidence?
AB  - Parry-Romberg syndrome is a clinical entity consisting of progressive hemifacial
      atrophy appearing at a young age. Animal studies indicate that sympathectomy can
      produce hemifacial atrophy. To our knowledge, this is the first report of a
      patient with a possible association between Parry-Romberg syndrome and
      thoracoscopic sympathectomy.

PMID- 15186050
TI  - A nonsurgical approach to painful piezogenic pedal papules.
AB  - For more than 3 decades, piezogenic pedal papules have been described in the
      literature. While many individuals with these papules are asymptomatic, patients
      with trauma or connective tissue diseases can experience pain. In our case study,
      we describe a unique, nonsurgical approach that abates the pain of painful
      piezogenic pedal papule (PPPP). Three injections of a solution of equal parts
      betamethasone (Celestone) and bupivacaine (Marcaine) were curative in a male
      patient with Ehlers-Danlos syndrome type III with PPPP. In addition, combination
      steroid/anesthetic injection provides another method of treatment in the
      management of PPPP.

PMID- 15186052
TI  - Multifocal papillary apocrine adenoma arising in a systematized linear epidermal
      nevus.
AB  - Previous reports indicate that a linear epidermal nevus (LEN) may serve as a
      source of development for additional skin tumors. We report an unusual case of
      multifocal papillary apocrine adenoma (PAA) arising in an LEN. This is the first
      case of its kind documented in the literature.

PMID- 15186053
TI  - The use of 40% urea cream in the treatment of moccasin tinea pedis.
AB  - Moccasin tinea pedis is a chronic dermatophyte infection of the foot that is
      recalcitrant to topical antifungal therapy. Furthermore, most patients with
      moccasin tinea pedis also have onychomycosis, thus adding to the recalcitrant
      nature of the infection. The topical antifungals used as sole therapy are
      generally ineffective because the scale on the plantar surface impedes or limits
      the absorption of the antifungal agent. The aim of this study was to evaluate the
      efficacy of 40% urea cream as an adjunct to topical antifungals in the treatment
      of moccasin tinea pedis. Patients with untreated moccasin tinea pedis were
      selected from the general dermatology clinic. The diagnosis of moccasin tinea
      pedis was made clinically and confirmed with a potassium hydroxide test or a
      positive fungal culture. A total of 12 patients with moccasin tinea pedis were
      treated with 40% urea cream once daily and ciclopirox cream twice daily. Patients
      then were evaluated after 2 to 3 weeks of treatment for the presence of erythema,
      scaling, and pruritus. After 2 to 3 weeks, a 100% cure rate was achieved in the
      12 patients treated with topical 40% urea cream and ciclopirox cream
      concomitantly.

PMID- 15186054
TI  - Organization seeks public comment on plan for underserved communities.

PMID- 15186055
TI  - Evidence-based dentistry, part II. Interview.

PMID- 15186056
TI  - Blood test may correlate to oral health.

PMID- 15186057
TI  - A health issue that affects us all.

PMID- 15186058
TI  - Child abuse: dentists' recognition and involvement.
AB  - Children in our society are too often maltreated by adults in their lives. These
      adults may be their parents, caretakers, youth leaders, coaches or perhaps even a
      health care provider. Children become missing daily in the United States, perhaps
      running away or being abducted. Occasionally, abductions lead to tragic
      conclusions. This paper will cover the dental staff's involvement with a
      physically abused child including documenting suspected injuries, the dentist's
      responsibility in maintaining good records in case a young patient should go
      missing, and the role of the forensic dentist with patterned injuries of abusive
      origin.

PMID- 15186059
TI  - What is this red mark?

PMID- 15186060
TI  - Mandated reporting of child abuse: answers for dentists.
AB  - As mandated reporters, dentists play an important role in recognizing child
      abuse. This article covers many of the key issues involved in making a suspected
      child abuse report and what happens after a report is made.

PMID- 15186061
TI  - Do I make the call? A first-person account.

PMID- 15186062
TI  - How are children impacted by adult partner violence?

PMID- 15186063
TI  - Abuse and neglect of elderly individuals: guidelines for oral health
      professionals.
AB  - The number of elderly individuals in our society is growing rapidly. This
      demographic change presents a number of challenges to our society and our health
      care systems. One of these is elder abuse and neglect, a serious and growing
      problem. In California, there are a number of state agencies responsible for
      oversight of care provided to elderly individuals and several systems for
      reporting suspected abuse and neglect depending on where the suspected abuse or
      neglect is occurring. Dental professionals are mandated reporters and therefore
      must understand how to recognize and--where possible prevent--abuse and neglect
      in their older patients and know how to report these suspicions.

PMID- 15186064
TI  - Forensic odontology and elder abuse--a case study.

PMID- 15186065
TI  - Statisticians have it all figured out.

PMID- 15186066
TI  - Dental students are often invited to participate in health-related research.

PMID- 15186067
TI  - Addressing health disparities through dental-medical collaborations, Part III:
      Leadership for the public good.
AB  - This is the third in a series of articles featuring dental-medical collaborations
      to reduce oral health disparities. Previous articles have targeted disparities
      among children, the elderly, and those with mental retardation and developmental
      disabilities and the importance of cultural factors in health disparities.
      Articles in this third group describe projects that originated in the public
      health sector or utilize public health approaches. They include training of non
      dental providers and Head Start/Early Head Start workers in children's oral
      health promotion; case management to ensure early preventive medical, dental, and
      developmental services for children; and a dental school-led outreach, training,
      and research effort to address oral cancer disparities. In this introductory
      article, we review lessons learned from the entire series of projects reported in
      these articles. The primary take-home message is that educational changes are
      needed in dental and medical training to better address oral health disparities.
      Other important lessons include the value of local or state-specific data, the
      need for partnerships with key stakeholders, and the role of financial incentives
      in leveraging change. We recommend more attention to outcome assessments in
      educational initiatives, greater partnering with families and patients, and
      utilization of change-management methodologies with systems, providers, and
      patients. We also advocate increased collaboration with the public health sector
      and bold leadership in dental education.

PMID- 15186068
TI  - OPENWIDE: an innovative oral health program for non-dental health and human
      services providers.
AB  - Emerging awareness of the nature and severity of oral diseases and disorders and
      their serious impact on overall health and well-being, combined with a nationwide
      crisis in access to oral health care for populations with the most and worst
      disease, makes it imperative that non-dental health and childcare professionals
      engage more fully in oral health promotion and disease prevention. OPENWIDE is a
      comprehensive training program designed to help achieve this goal. The
      Connecticut Department of Public Health has trained more than 2,000 individuals
      during the first year of the OPENWIDE program. This article reports on successes
      and impediments to training and implementation encountered in the early stages of
      OPENWIDE and makes recommendations to improve the curriculum and its delivery to
      families and children.

PMID- 15186069
TI  - Kids get care: integrating preventive dental and medical care using a public
      health case management model.
AB  - Kids Get Care is a public health-based program in the Seattle area designed to
      ensure that low-income children, regardless of insurance status, receive early
      integrated preventive medical, dental, and developmental health services through
      attachment to medical and dental homes (the usual sources of medical or dental
      care). The oral health component of the program focuses on cross-training medical
      and dental providers, providing partner medical clinics with a case manager, and
      educating staff in nearby community-based organizations about how to identify
      incipient dental disease and possible early childhood developmental delays. The
      program identifies a local, well-respected dentist to champion the delivery of
      oral health screening within a medical clinic and to provide oral health training
      to medical clinic staff. The program works with community agencies to educate
      families on the importance of healthy baby teeth, routine dental care beginning
      at age one, and general prevention. In its first year, the program trained 355
      community staff and 184 primary care providers on how to conduct an oral health
      assessment. These staff and providers screened more than 5,500 children for oral
      health problems. One medical clinic more than doubled the number of fluoride
      varnishes it provided, increasing from 80 to 167 during a nine-month pilot phase.
      Other outcome studies are in progress.

PMID- 15186071
TI  - Enrichment and recruitment programs at dental schools: impact on enrollment of
      underrepresented minority students.
AB  - Dental schools have created summer enrichment and recruitment programs to
      increase enrollment of underrepresented and disadvantaged students. Enrichment
      programs strengthen students' academic skills in the areas of basic medical
      sciences, communications, test taking, and other learning strategies. The purpose
      of this study was to identify program characteristics of summer enrichment and
      recruitment programs and to determine which characteristics predicted participant
      enrollment in dental school. Twenty-three schools received a survey, and
      seventeen responded for a response rate of 74 percent. The majority of program
      participants were underrepresented minority (URM) students (program median=99
      percent). The leading program goals were to increase minority enrollment (47
      percent) and URM competitiveness (35 percent). The median program length was
      seven weeks and forty hours per week. Programs offered the following components:
      basic sciences (thirty-two median hours). DAT review/preparation (thirty median
      hours), introduction to dentistry (sixteen median hours), preclinical laboratory
      activities (sixteen median hours), and learning strategies (nine median hours).
      The length of program time in existence was a significant predictor of
      participant enrollment into dental school (R square=.320; p=.035). The overall
      median percentage for dental school enrollment in the study was 52.3 percent. The
      directors of six programs who place more than 60 percent of their students in
      dental school were interviewed. They reported that mentorship, institutional
      support, program structure, and admission policies were key factors contributing
      to success. It is concluded that recruitment and enrichment programs are a viable
      option to increase URM dental school enrollment.

PMID- 15186070
TI  - An academic dental center grapples with oral cancer disparities: current
      collaboration and future opportunities.
AB  - This article reviews the epidemiology of oral cancer in the United States,
      explores the complex reasons for its disproportionate burden in minority groups,
      and describes the efforts of New York University's College of Dentistry to
      address these oral cancer disparities. These efforts include the development of
      state and regional consortia and networks, public education and community
      screening efforts, undergraduate dental curriculum development, professional
      education, intensive research efforts, and significant dental-medical
      collaborations. Future directions include the need to develop and assess oral
      cancer education/awareness programs, specifically customized to the various
      dental-medical professionals/trainees and to populations at risk. Improving the
      quality of life of patients during and following treatment for oral cancer is
      another important area that has great opportunity for dental-medical
      collaboration.

PMID- 15186072
TI  - An exploratory study of orthodontic resident communication by patient race and
      ethnicity.
AB  - Race has been shown to affect the quality of physician-patient relations. In view
      of this, dentistry must consider whether race also affects dentist-patient
      relations. The purpose of this study was to explore whether orthodontic residents
      showed more social connection and concern for European ancestry patients, were
      more negative to minority patients, and appropriately used interventions designed
      to overcome cultural differences. Communications in sixty-eight dentist-patient
      encounters were analyzed using the Roter Interaction Analysis System (RIAS). The
      frequencies of each type of utterance were examined according to the patient's
      race/ethnicity. The race/ethnic groups were European (nineteen), African American
      (eleven), Latino (thirty-four), and Asian (four). In 90 percent of the sessions,
      the resident and the patient were of different ethnicity. Residents used social
      connection utterances more with European ancestry patients, but used personal
      utterances more with Latino patients. Residents did not use open-ended questions
      or probes for patient understanding more with minority patients. The
      communication patterns observed in this study were similar to those reported in
      the literature. This study has limitations, but additional research may confirm
      that residents communicate differently with patients by race and could use more
      appropriate methods of dealing with cross-cultural situations. More research on
      cross-cultural communication is needed.

PMID- 15186073
TI  - Attitudes of incoming dental students toward tobacco cessation promotion in the
      dental setting.
AB  - Dentists can play an important role in helping patients quit using tobacco. The
      aim of this study was to investigate incoming dental students' attitudes toward
      tobacco cessation promotion in the dental setting. Such attitudes can impact
      students' receptivity to training and subsequent involvement in tobacco cessation
      promotion. A twenty-six-item written survey was administered to freshman students
      at a midwestern dental school during orientation weeks 2002 and 2003. Questions
      focused on students' attitudes toward the dental professional's responsibilities
      and scope of practice in promotion of tobacco cessation. Response rate was 99
      percent (139/140). Respondents were 75 percent male, 25 percent female. Mean age
      was 24.8 +/- 3.0 years. Ninety-nine percent agreed that it is the dental
      professional's responsibility to educate patients about the oral health risks of
      tobacco use. Eighty-five percent agreed that it is within the scope of dental
      practice to advise patients to quit using tobacco, but fewer agreed that it is
      within the scope of practice to discuss specific strategies for stopping (70
      percent) or to prescribe nicotine gum (45 percent). Sixty-nine percent agreed
      that tobacco cessation counseling in the dental office could impact patients'
      quitting. Seventy-one percent anticipated that patient resistance could be a
      barrier to tobacco cessation promotion. Nearly one quarter (23 percent) were only
      slightly or not interested in receiving tobacco cessation training. Attitudes of
      incoming dental students appear to be positive regarding the dental
      professional's responsibility to educate patients about the risks of tobacco use.
      However, some students may have reservations about the extent to which tobacco
      cessation services fit within the scope of dental practice, the efficacy of such
      services, and patient receptiveness. These reservations should be addressed if
      dental school curricula in tobacco cessation are to be effective.

PMID- 15186074
TI  - How to word effective messages about smoking and oral health: emphasize the
      benefits of quitting.
AB  - This project examined whether smokers differentially responded to messages about
      oral health that emphasized either the benefits of quitting smoking or the risks
      of continued smoking. Messages concerning oral health and smoking were developed
      to emphasize the benefits of quitting smoking (gain-framed) or the costs of
      continued smoking (loss-framed). These messages were embedded in recruitment
      brochures for smoking cessation trials, which were placed in twenty dental office
      waiting rooms for a six-month period. The number of brochures taken from the
      waiting rooms was tracked, as well as calls to inquire about smoking cessation
      studies. As hypothesized, dental patients were more likely to acquire gain-framed
      brochures. Out of 271 brochures taken from the dental office waiting rooms,
      significantly more brochures contained gain-framed messages compared to loss
      framed messages (59 percent vs. 41 percent, p<.05). There was an equal number of
      calls to inquire about smoking cessation studies for each message type. Overall,
      individuals in dental office waiting rooms were more likely to take brochures
      about smoking cessation trials that contained gain-framed messages concerning
      oral health and smoking. Information about oral health and smoking typically
      emphasizes the dangers of continued smoking. This study found that smokers are
      more receptive to information that emphasizes the benefits of quitting.

PMID- 15186075
TI  - Dental school vacant budgeted faculty positions, academic year 2002-03.
AB  - The number of vacant budgeted full-time faculty positions has changed little over
      the last three years, standing in 2002-03 at 280. The number of part-time
      vacancies, though, has continued to decline to twenty-seven. The average number
      of vacancies per school was 5.7, down from 6.4 of the past several years. The
      average number of vacancies reported to be usual and normal at any one time was
      3.6. Forty-three percent of the schools reported four or fewer vacant budgeted
      faculty positions in 2002-03. Overall, the order of primary disciplines by their
      number of vacancies varies from year to year; however, with no particular trend
      by discipline. Also there does not appear to be any significant correlation
      between discipline and the length of time a position has been vacant. Fifty-five
      percent of the vacant positions had been vacant less than seven months.
      Salary/budget limitations and lack of response to position announcements were the
      most frequently reported factors influencing the ability to fill a position.
      There were 921 reported faculty separations in 2002-03. Forty-six percent were a
      result of faculty leaving for private practice. The number of new faculty
      reported in 2002-03 was 1,231. Fifty-one percent of the new faculty came from
      private practice. The total number of faculty reported in 2002-03 was 357 more
      than reported in 2001-02. Rather than a perceived pending shortage of faculty, it
      may be more of an endemic number of vacancies due to the amount of time needed to
      fill a position. While there is no indication expressed in the survey that
      current vacancies are adversely affecting the quality of dental education,
      foresight, planning, and necessary steps need to continue to ensure the
      preparation and continuity of a dental workforce sufficient in size and expertise
      to meet the teaching, research, patient care, and administrative needs of the
      dental education community.

PMID- 15186076
TI  - The Human Fertilisation and Embryology Authority: evidence based policy formation
      in a contested context.
AB  - This article briefly reviews the various papers contained in this volume. They
      were originally presented at a research work shop held at Keele University in the
      UK in February 2003. It is suggested that the different papers raise a series of
      related legal, social and ethical issues and can be collectively seen to
      demonstrate the fact that policy formation in relation to reproductive matters is
      highly contested. It is concluded that ethical policy formation in this area
      needs to be based on actual evidence of harm rather than assumed harm and that
      this therefore entails more empirical research into reproductive matters.

PMID- 15186077
TI  - Ethics, economics and the exotic: the early career of the HFEA.
AB  - The Human Fertilisation & Embryology Authority (HFEA) is the UK's statutory
      regulator of licensed assisted conception treatments. The past 10 years have,
      inevitably, drawn it further and deeper into this area of legal, moral and
      political controversy. It is opportune to consider how it has fared in the new
      climate of public accountability and critical scrutiny, and whether reform or
      revision of its role, mandate or operation may be called for. Through a close
      analysis of its published Annual Reports, it is possible to form a picture of a
      development of the HFEA which has not been consistent, coherent or comfortable.

PMID- 15186079
TI  - Assisted reproduction: managing an unruly technology.
AB  - Technology is "unruly" because it operates in a social context where it is shaped
      by institutions, organisations and individuals in ways not envisaged when it was
      first developed. In the UK assisted reproductive technology has developed from
      strictly circumscribed beginnings as a treatment for infertility within the NHS,
      to a service which is more often offered by commercial clinics and purchased by
      clients who are not necessarily infertile. The article considers the process by
      which assisted reproductive technology has been created and developed, a process
      which is ideological rather than technical, and the social implications of its
      ever expanding use. In a society where the discourse around reproduction and
      family life, is one of choice and acceptance of diversity of life styles, the
      conditions are set for further "uruliness" supported by clinicians and commercial
      interests. The HFEA, public consultations and media coverage tend to subscribe to
      the way ethical issues are framed by those interested parties, an approach that
      favours increased liberalisation.

PMID- 15186078
TI  - Like a frog in boiling water: the public, the HFEA and sex selection.
AB  - This paper analyses the British Human Fertilisation and Embryology Authority's
      2002 public consultation on sex selection, a consultation that was mainly
      concerned with sex selection for non-medical reasons. Based on a close reading of
      the consultation document and questionnaire it is argued that the consultation is
      biased towards certain outcomes and can most plausibly be construed as an attempt
      not to investigate but to influence public opinion.

PMID- 15186080
TI  - Preimplantation genetic diagnosis: choosing the "good enough" child.
AB  - Preimplantation genetic diagnosis (PGD) raises serious moral questions concerning
      the parent-child relationship. Good parents accept their children
      unconditionally: they do not reject/attack them because they do not have the
      features they want. There is nothing wrong with treating a child as someone who
      can help promote some other worthwhile end, providing the child is also respected
      as an end in him or herself. However, if the child's presence is not valued in
      itself, regardless of any further benefits it brings, the child is not being
      treated as an end in the full sense of the term, in this paper, I argue that
      these principles apply to human embryos, as well as to born human offspring: the
      human moral subject is a bodily being, whose interests and rights begin with the
      onset of his or her bodily life. The rights of the living, bodily human
      individual include a righ not to be attacked/abandoned because of his or her
      genetic profile. PGD is harmful to the parent-child relationship, and we give
      mixed messages to parents by expecting them to show unconditional commitment to
      offspring after birth, while inviting them to take a very different approach at
      the prenatal stage.

PMID- 15186081
TI  - Sex selection, child welfare and risk: a critique of the HFEA's recommendations
      on sex selection.
AB  - This paper will examine the recent Human Fertilisation and Embryology Authority
      public consultation on sex selection. It will review the current regulation on
      sex selection in the United Kingdom and critically examine the outcomes of the
      HFEA consultation. The paper will argue that the current ban on embryo sex
      selection for social reasons and a proposed ban on sperm selection are not
      justified. There is no evidence for sex selection causing an increase in sex
      discrimination; creating a slippery slope towards selection for other non-disease
      characteristics; or promoting a consunmerist attitude towards children. The HFEA
      recommendations to prohibit social sex selection techniques rely upon an
      unwarranted concern about the risk of the procedures used. Reproductive
      technologies should be made available to peoptle unless a substantial risk of
      harm--to the child, the parents or to society--can be identified. There is no
      such evidence of harm in this case.

PMID- 15186082
TI  - Separation and characterization of phenolic compounds in fennel (Foeniculum
      vulgare) using liquid chromatography-negative electrospray ionization tandem mass
      spectrometry.
AB  - Liquid chromatography (LC) diode array detection (DAD) coupled to negative
      electrospray ionization (ESI) tandem mass spectrometry (MS/MS) was used for the
      rapid and sensitive identification of water-soluble phenolic compounds in fennel
      waste. The plant material was first extracted and then chromatographed on
      Sephadex LH-20 to afford seven fractions, each of them being subjected to LC-MS
      analysis. Identification of the compounds was carried out by interpretation of
      UV, MS, and MS/MS spectra. Forty-two phenolic substances were identified, 27 of
      which had not previously been reported in fennel, including hydroxycinnamic acid
      derivatives, flavonoid glycosides, and flavonoid aglycons.

PMID- 15186083
TI  - Sensitive determination of sulfate in drinks and vegetables digests by Rayleigh
      light scattering technique.
AB  - In this paper, a novel and sensitive method based on Rayleigh light scattering
      technique (RLS) was proposed for the determination of sulfate using a
      conventional spectrofluorometer. Sulfate was transformed to BaSO4 particles,
      which displayed intense light scattering in aqueous solutions. The effects of
      factors such as wavelength, acidity, stabilizers and interferents were studied in
      detail. The RLS intensity of the BaSO4 suspension was obtained in 0.1 mol L(-1)
      of [H+] and the addition of 2 mL of cationic polyacrylamide (CPAM) with 7.05 x
      10(-3) mmol mL(-1) charged cations and 1.0 mL of BaCl2.2H2O (5.0%) at 510 nm. In
      the range of 8-400 microg mL(-1), RLS intensity was linear to the concentration
      of BaSO4, and the detection limit was 0.3 microg mL(-1). To determine the
      feasibility of the proposed method, some samples of water, drinks, and vegetables
      digests were analyzed, and the results were in agreement with the standard
      turbidimetric method. Good recovery results were also obtained in the range of 94
      105%. Although this method was limited in stability, it was characterized with
      simplicity, sensitivity, reliability, and little interference.

PMID- 15186084
TI  - Comparison of accelerator mass spectrometry with gas chromatography for the
      determination of pesticide residues in individual items in the diets of wild
      birds and mammals.
AB  - Methods to refine the assessment of exposure of wild birds and mammals to
      pesticides required measurement of pesticide residues in very small samples of
      their diets. Sample sizes were in the 1-100 mg range, and the target residue for
      measurement was 0.01 mg/kg. Gas chromatography-mass spectrometry (GC-MS) with
      large volume injection was compared with the use of an accelerator mass
      spectrometer (AMS) to measure residues of pesticide labeled at near-background
      levels with carbon-14. The GC-MS method was able to detect residues down to 0.1
      ng per item of diet, and the AMS detected the radiolabel down to 1 mBq (0.06
      disintegration per minute, 1 ng of pesticide at the specific activity used) per
      sample. The target residue level was achieved by the GC-MS method for samples
      down to 10 mg. The GC method appeared to be best suited to monitoring residues in
      field studies, and the AMS shows great potential for use in laboratory
      experiments concerning pesticide degradation.

PMID- 15186085
TI  - New methodology for the determination of phthalate esters, bisphenol A, bisphenol
      A diglycidyl ether, and nonylphenol in commercial whole milk samples.
AB  - This paper reports a new methodology aimed at determining dimethyl phthalate,
      diethyl phthalate, di-n-butyl phthalate, butylbenzyl phthalate, bis(2-ethylhexyl)
      phthalate, nonylphenol, bisphenol A, and bisphenol A diglycidyl ether in
      commercial whole milk. These compounds are used as plastic additives, lacquers,
      resins, or surfactants and can be found in milk due to contact with plastic
      materials during food processing and storage. They are all suspected endocrine
      disrupters or mutagens. A multiresidue method based in solid-phase extraction
      with C-18 cartridges followed by a cleanup step using disposable cartridges was
      developed. Detection and quantification were performed by gas chromatography
      coupled to mass spectrometric (GC-MS) detection using an appropriate surrogate (4
      n-nonylphenol) and internal standard [deuterated bis(2-ethylhexyl) phthalate].
      Limits of detection were from 0.06 to 0.36 microg/kg and intraday variation from
      3 and 27%, with recoveries between 73 and 119%. Five brands of commercial whole
      milk processed and packed in different ways were analyzed. All samples contained
      target compounds at concentrations between 0.28 and 85.3 microg/kg, and the total
      concentration ranged between 79.3 and 187.4 microg/kg, the levels being higher in
      sterilized milks. Nonylphenol, diethyl phthalate, dibutyl phthalate, and bis(2
      ethylhexyl) phthalate were the major contributors.

PMID- 15186086
TI  - Identification of puerarin and its metabolites in rats by liquid chromatography
      tandem mass spectrometry.
AB  - Puerarin (daidzein-8-C-glucoside) is the major bioactive isoflavone of kudzu root
      (the root of Pueraria lobata). Its metabolic fate, however, is not well-known. In
      this study, a sensitive and specific LC-ESI-MS/MS method for the determination of
      puerarin and its metabolites daidzein, dihydrodaidzein, and equol was developed
      for their analysis in biological samples. Two new metabolites of puerarin, mono-
      and dihydroxylated derivatives, were detected in the urine and feces of rats
      after oral administration. The persistence of puerarin in blood and urine as the
      principal metabolic form for the period of 4-72 h after oral administration
      suggested that puerarin is rapidly absorbed from the intestine without
      metabolism. Its presence in organs such as the brain suggests that this glucoside
      may enter tissues by specific transport pathways. Study of these metabolites may
      provide further understanding of the health beneficial effects of puerarin in
      kudzu dietary supplements.

PMID- 15186087
TI  - Comparison of the acetyl bromide spectrophotometric method with other analytical
      lignin methods for determining lignin concentration in forage samples.
AB  - Present analytical methods to quantify lignin in herbaceous plants are not
      totally satisfactory. A spectrophotometric method, acetyl bromide soluble lignin
      (ABSL), has been employed to determine lignin concentration in a range of plant
      materials. In this work, lignin extracted with acidic dioxane was used to develop
      standard curves and to calculate the derived linear regression equation (slope
      equals absorptivity value or extinction coefficient) for determining the lignin
      concentration of respective cell wall samples. This procedure yielded lignin
      values that were different from those obtained with Klason lignin, acid detergent
      acid insoluble lignin, or permanganate lignin procedures. Correlations with in
      vitro dry matter or cell wall digestibility of samples were highest with data
      from the spectrophotometric technique. The ABSL method employing as standard
      lignin extracted with acidic dioxane has the potential to be employed as an
      analytical method to determine lignin concentration in a range of forage
      materials. It may be useful in developing a quick and easy method to predict in
      vitro digestibility on the basis of the total lignin content of a sample.

PMID- 15186088
TI  - Efficient 1H nuclear magnetic resonance method for improved quality control
      analyses of Ginkgo constituents.
AB  - We developed an analytical method using 1H nuclear magnetic resonance (NMR)
      spectrometry to resolve analytical problems with Ginkgo. After a simple
      hydrolysis step, an NMR analysis of the terpene trilactone H-12 signals and the
      flavonol aglycone H-2' (or H-2'/6' for kaempferol) signals was performed. By
      comparing the solvent effects on the resolution of these signals, methanol-d4
      benzene-d6 (65:35) was selected as the optimal 1H NMR solvent. The amounts of
      terpene lactones and flavonol aglycones in various commercial Ginkgo products and
      Ginkgo leaves were determined. This newly developed 1H NMR method enables the
      simultaneous analysis of terpene trilactones and flavonols and allows simple,
      rapid quantification of these compounds in pharmaceutical Ginkgo preparations.

PMID- 15186089
TI  - Principal component analysis applied to Fourier transform infrared spectroscopy
      for the design of calibration sets for glycerol prediction models in wine and for
      the detection and classification of outlier samples.
AB  - Principal component analysis (PCA) was used to identify the main sources of
      variation in the Fourier transform infrared (FT-IR) spectra of 329 wines of
      various styles. The FT-IR spectra were gathered using a specialized WineScan
      instrument. The main sources of variation included the reducing sugar and alcohol
      content of the samples, as well as the stage of fermentation and the maturation
      period of the wines. The implications of the variation between the different wine
      styles for the design of calibration models with accurate predictive abilities
      were investigated using glycerol calibration in wine as a model system. PCA
      enabled the identification and interpretation of samples that were poorly
      predicted by the calibration models, as well as the detection of individual
      samples in the sample set that had atypical spectra (i.e., outlier samples). The
      Soft Independent Modeling of Class Analogy (SIMCA) approach was used to establish
      a model for the classification of the outlier samples. A glycerol calibration for
      wine was developed (reducing sugar content < 30 g/L, alcohol > 8% v/v) with
      satisfactory predictive ability (SEP = 0.40 g/L). The RPD value (ratio of the
      standard deviation of the data to the standard error of prediction) was 5.6,
      indicating that the calibration is suitable for quantification purposes. A
      calibration for glycerol in special late harvest and noble late harvest wines (RS
      31-147 g/L, alcohol > 11.6% v/v) with a prediction error SECV = 0.65 g/L, was
      also established. This study yielded an analytical strategy that combined the
      careful design of calibration sets with measures that facilitated the early
      detection and interpretation of poorly predicted samples and outlier samples in a
      sample set. The strategy provided a powerful means of quality control, which is
      necessary for the generation of accurate prediction data and therefore for the
      successful implementation of FT-IR in the routine analytical laboratory.

PMID- 15186090
TI  - High-resolution NMR and diffusion-ordered spectroscopy of port wine.
AB  - The use of high-resolution NMR and high-resolution diffusion-ordered spectroscopy
      (DOSY) for the characterization of selected Port wine samples of different ages
      with the aim of identifying changes in composition is described. Conventional 1D
      and 2D NMR methods enabled the identification of about 35 compounds, including
      minor components such as some medium-chain alcohols, amino acids, and organic
      acids. High-resolution (HR) DOSY extended sample characterization, increasing the
      number of compounds identified and NMR assignments made, by providing information
      on the relative molecular sizes of the metabolites present. Port wines of
      different ages were found to differ mainly in their content of (a) organic acids
      and some amino acids, (b) an unidentified possible disaccharide, and (c) large
      aromatic species. The relative amount of these last high Mw aromatics is seen to
      decrease significantly in the oldest wine, as expected from the known formation
      and precipitation of anthocyanin-based polymers during red wine aging.

PMID- 15186091
TI  - Silylation of acrylamide for analysis by solid-phase microextraction/gas
      chromatography/ion-trap mass spectrometry.
AB  - A method for quantitative analysis of acrylamide has been developed for use with
      headspace solid-phase microextraction (SPME). In the method, acrylamide undergoes
      silylation with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to form the
      volatile N,O-bis(trimethylsilyl)acrylamide (BTMSA). Once formed, BTMSA is readily
      extracted from the headspace over the silylation reaction using a 100 microm
      poly(dimethylsiloxane) SPME fiber. A series of experiments was undertaken to
      optimize the amount of BSTFA, the silylation reaction temperature, the silylation
      reaction duration, and SPME sampling duration to maximize the analytical
      sensitivity for BTMSA. Acrylamide levels were quantified relative to a [13C3]
      acrylamide internal standard using gas chromatography/ion-trap mass spectrometry
      (GC/MS) in the single ion monitoring mode. An analytical working curve was
      constructed and found to be linear over the 4 to 6700 ppb acrylamide range
      investigated with a limit of detection of 0.9 ppb. The native acrylamide levels
      of three commercial cereals were measured using the optimized analytical method.
      Quantitative standard additions of acrylamide to the cereal matrixes demonstrated
      complete recovery of the spiked acrylamide.

PMID- 15186092
TI  - Comparison of three colorimetric reagents in the determination of methanol with
      alcohol oxidase. Application to the assay of pectin methylesterase.
AB  - Three colorimetric reagents for the determination of formaldehyde, the Nash
      reagent (ammonia plus acetylacetone), Purpald (4-amino-3-hydrazino-5-mercapto
      1,2,4-triazole), and N-methylbenzothiazolinone-2-hydrazone (MBTH), were compared
      for the determination of methanol when used in conjunction with alcohol oxidase.
      The combination of alcohol oxidase plus the commonly used Nash reagent was
      specific for methanol versus ethanol, but had the lowest sensitivity of the three
      reagents tested. Substituting Purpald for the Nash reagent increased the
      sensitivity 3-fold while still maintaining a high (59-fold) selectivity for
      methanol versus ethanol. Using MBTH increased the sensitivity still further, but
      with a loss of the selectivity toward methanol. Since MBTH reacted with aldehydes
      under neutral conditions, it could be included along with the alcohol oxidase to
      act as an aldehyde trap. This prevented further oxidation reactions by alcohol
      oxidase and allowed for extended incubations. A procedure for assaying low levels
      of pectin methylesterase activity that relies on this trapping ability is
      described. In addition, alcohol oxidase plus Purpald is shown to be a simple and
      sensitive way to measure the methanol released from plant material following the
      thermal activation of endogenous pectin methylesterase.

PMID- 15186093
TI  - Development of a real-time PCR and a sandwich ELISA for detection of potentially
      allergenic trace amounts of peanut (Arachis hypogaea) in processed foods.
AB  - Hidden allergens in food products are, especially for peanut-allergic consumers,
      a serious problem because even low amounts (approximately 200 microg) of peanut
      can elicit allergic reactions. Undeclared peanut traces can be found in processed
      food products, because contaminations with peanut during production processes are
      frequent. To minimize the risk of such cross-contaminations, it is necessary to
      develop sensitive analytical methods for the detection of hidden allergens in
      foods. For this approach we developed two peanut-specific assays based on the
      detection of peanut protein by specific antibodies (sandwich ELISA) and by the
      detection of peanut-specific DNA (part of the coding region of Ara h 2) by a real
      time PCR. Both tests did not show any cross-reactivity with 22 common food
      ingredients (cereals, nuts, legumes), and the limit of detection is <10 ppm
      peanut in processed foods. Thirty-three random samples of food products were
      tested for the presence of peanut to compare both assay types with each other and
      to evaluate the percentage of foods on the German market that are contaminated
      with peanut traces. We found that four products (13.3%) without peanut in the
      list of ingredients contained peanut protein in a range from 1 to 74 ppm peanut
      protein and that the results of both tests correlated well. The real-time PCR was
      able to detect one more positive sample than the sandwich ELISA. In conclusion,
      both assays are sensitive and specific tools for the detection of hidden
      allergens in processed foods.

PMID- 15186094
TI  - Identification and synthesis of a novel selenium-sulfur amino acid found in
      selenized yeast: Rapid indirect detection NMR methods for characterizing low
      level organoselenium compounds in complex matrices.
AB  - After proteolytic digestion, aqueous extraction, and derivatization with diethyl
      pyrocarbonate or ethyl chloroformate, HPLC-inductively coupled plasma (ICP)-MS,
      GC-atomic emission detection (AED), and GC-MS analysis of high-selenium yeast
      stored at room temperature for more than 10 years showed selenomethionine as the
      major Se product along with substantial amounts of selenomethionine selenoxide
      hydrate and the previously unreported selenoamino acid having a Se-S bond, S
      (methylseleno)cysteine. The identity of the latter compound was confirmed by
      synthesis. The natural product was shown to be different from a synthetic sample
      of the isomeric compound Se-(methylthio)selenocysteine. Selenium-specific NMR
      spectroscopic methods were developed to directly analyze the aqueous extracts of
      the hydrolyzed selenized yeast without derivatization or separation.
      Selenomethionine and S-(methylseleno)cysteine were identified by 77Se-1H HMQC
      TOCSY experiments.

PMID- 15186095
TI  - Determination of limonin D-ring lactone hydrolase activity by solid phase
      extraction with indirect fluorescence detection.
AB  - A method for the evaluation of limonin D-ring lactone hydrolase activity is
      described. The method utilizes solid phase extraction (SPE) for the isolation of
      limonin A-ring limonoate (LARL), which is subsequently converted to limonin and
      quantitated by fluorescence. The fluorescence method is capable of quantifying
      the formation of LARL in concentrations as low as 75 ng and is applicable to both
      purified and crude enzyme preparations. The coupling of SPE with fluorescence
      detection allows for the simple and rapid analysis of samples.

PMID- 15186096
TI  - Water plasticization of extruded material made from meat and bone meal and sodium
      caseinate.
AB  - Meat and bone meal (MBM) is a high protein agricultural commodity that currently
      has few applications other than as an animal feed. Unmodified MBM has poor
      functional properties, due to its low solubility. Our results from pilot plant
      trials demonstrate that MBM can be extrusion-processed along with sodium
      caseinate to produce a useful plastic material. We developed this material for
      use as a dog chew toy. For this application, elastic modulus (stiffness) is a key
      characteristic. Our results detail the relationship between ambient relative
      humidity and equilibrium moisture content (MC) in the material. The influence of
      MC on the glass transition temperature and elastic modulus reflects the
      plasticization of this material by water. On the basis of a comparison to a
      commercially available dog chew, the range of stiffness achievable with our
      material, 0.25-2.50 GPa, encompasses the values appropriate for a dog chew. Our
      results show that a particular desired stiffness can be maintained by applying an
      edible moisture barrier to the surface of the material.

PMID- 15186097
TI  - Enrichment of higher molecular weight fractions in inulin.
AB  - Inulin (general formulas GFn and Fm, with G = anhydroglucose and F =
      anhydrofructose) naturally occurs as a homologous series of oligo- and
      polysaccharides with different chain lengths. For reasons of growing interest in
      the food and pet food industries, the short chain inulins have to be separated
      from their long chain analogues because their properties (digestibility,
      prebiotic activity and health promoting potential, caloric value, sweetening
      power, water binding capacity, etc.) differ substantially. To study these
      properties in relation to the number average degree of polymerization (DPn),
      ultrafiltration, specific crystallization from aqueous solution, and
      precipitation from solvent/water mixtures were used to enrich native chicory and
      dahlia inulin in the higher molecular weight fractions. Depending on the membrane
      module used, the DPn of chicory inulin (DPn = 8.1) and dahlia inulin (DPn = 29)
      could be increased by ultrafiltration to a maximum value of, respectively, 22 and
      43. With crystallization from aqueous solutions (25 degrees C), similar results
      were obtained but at a much higher yield. Finally, long chain inulin could be
      precipitated from aqueous solutions in the presence of high concentrations of
      methanol, ethanol, and acetone. Acetone demonstrated to be the best solvent
      system to increase the DPn, followed by ethanol and methanol. However, for safety
      reasons and food purposes, ethanol was evaluated to be the best choice. With
      ethanol, the DPn could be raised to 25 for chicory inulin and up to 40 for dahlia
      inulin.

PMID- 15186098
TI  - Identification and quantification of polyphenols in carob fruits (Ceratonia
      siliqua L.) and derived products by HPLC-UV-ESI/MSn.
AB  - The polyphenolic patterns of carob pods (Ceratonia siliqua L.) and derived
      products were identified and quantified using high-performance liquid
      chromatography-UV absorption-electrospray ion trap mass spectrometry after
      pressurized liquid extraction and solid-phase extraction. In carob fiber, 41
      individual phenolic compounds could be identified. In addition,
      spectrophotometric quantification using the Folin-Ciocalteu and vanillin assays
      was performed, and the antioxidative activity was determined as the 1,1-diphenyl
      2-picrylhydrazyl radical scavenging activity. Carob pods contain 448 mg/kg
      extractable polyphenols comprising gallic acid, hydrolyzable and condensed
      tannins, flavonol-glycosides, and traces of isoflavonoids. Among the products
      investigated, carob fiber, a carob pod preparation rich in insoluble dietary
      fiber (total polyphenol content = 4142 mg/kg), shows the highest concentrations
      in flavonol-glycosides and hydrolyzable tannins, whereas roasted carob products
      contain the highest levels of gallic acid. The production process seems to have
      an important influence on the polyphenolic patterns and quantities in carob
      products.

PMID- 15186099
TI  - Structural characteristics of purified glycinin from soybeans stored under
      various conditions.
AB  - Soybeans were stored in 84% relative humidity at 30 degrees C (adverse
      conditions) for 9 months and in 57% relative humidity at 20 degrees C, cold (4
      degrees C), and an uncontrolled ambient garage for 18 months. Glycinin was
      isolated and purified; its structural properties were characterized. The purified
      glycinin from soybean in the adverse conditions was associated with a significant
      amount of sugar and showed reductions in hydrophobic interactions after 3 months;
      the total free sulfhydryl content in glycinin decreased, but the intramolecular
      disulfide bonds increased; the alpha-helix content of secondary structure
      slightly increased, but the beta-sheet content decreased. The structure of
      glycinin purified from the other three conditions showed no significant changes
      for 18 months of storage when compared to the control. The molecular mass of
      glycinin remained in the range of 313-340 kDa during the whole storage period for
      the four conditions.

PMID- 15186100
TI  - Acrylamide in French fries: influence of free amino acids and sugars.
AB  - The free amino acid profile and sugar (fructose, glucose, and sucrose)
      composition were determined in potato samples selected to give a large range of
      variation (a total of 66 samples). From these samples French fries were produced
      in a laboratory-scale simulation of an industrial process followed by a finish
      fry at 180 degrees C for 3.5 min using a restaurant fryer. The final product was
      blast frozen and analyzed for acrylamide. Acrylamide was detected in all samples,
      but its concentration varied significantly from 50 to 1800 ng/g. For isotope
      dilution (13C3) acrylamide analysis, samples were extracted with water, cleaned
      up on HLB Oasis polymeric and Accucat mixed mode anion and cation exchange SPE
      columns, and analyzed by LC-MS/MS. Statistical analysis of the data indicates
      that the effect of sugars and asparagine on the concentration of acrylamide in
      French fries is positive and significant (p < 0.001). It appears that one of the
      ways acrylamide formation in French fries can be effectively controlled is by the
      use of raw products with low sugar (and to a lesser degree, asparagine) content.

PMID- 15186101
TI  - Effect of storage temperature on the stability of anthocyanins of a fermented
      black carrot (Daucus carota var. L.) beverage: shalgam.
AB  - The effect of temperature on the stability of shalgam anthocyanins stored at 4,
      25, and 40 degrees C for 90 days was investigated. The effect of pasteurization
      and sorbate addition on the anthocyanin stability as compared to control was also
      studied. The monomeric anthocyanin content and color density decreased with
      increasing time as a function of storage temperature whereas the percent
      polymeric color and browning increased. The same trends were observed in control,
      pasteurized, and sorbate-added shalgam samples. Shalgam anthocyanins consisted of
      two nonacylated and three acylated cyanidin derivatives. Acylated anthocyanins
      were more stable when compared to nonacylated ones at all storage temperatures.
      The activation energies, 11.11-11.64 kcal/mol, were calculated from the reaction
      rate constants evaluated taking first-order reaction kinetics. The highest
      anthocyanin retention was observed at 4 degrees C storage temperature with a half
      life between 231 and 239 days.

PMID- 15186102
TI  - Quantitative relationship between trimethylamine oxide aldolase activity and
      formaldehyde accumulation in white muscle from gadiform fish during frozen
      storage.
AB  - The accumulation of formaldehyde and the resulting deterioration of seafood
      products during frozen storage are primarily caused by the enzymatic activity of
      trimethylamine oxide aldolase (TMAOase). A screening of muscle samples from 24
      species showed TMAOase activity in only the nine gadiform species that were
      analyzed. Enzyme activities in the major white muscle of gadiform fish showed
      large variations between species as well as between individuals. A frozen storage
      experiment showed a similarly large variation in the rate of formaldehyde
      accumulation, which could be accounted for by the endogenous white muscle in situ
      TMAOase activity. This TMAOase activity also correlated with the rate of
      insolubilization of otherwise high ionic strength soluble protein. A simple model
      describing the accumulation of free formaldehyde during frozen storage of
      gadiform fish is proposed. The model is based on a storage time-dependent decay
      of substrate-saturated white muscle TMAOase activity.

PMID- 15186103
TI  - Stability of whey-protein-stabilized oil-in-water emulsions during chilled
      storage and temperature cycling.
AB  - The stability of heat-treated and/or acidified, partly-crystalline-fat-based,
      whey-protein-stabilized oil-in-water (o/w) emulsions against partial coalescence
      was investigated during chilled storage (at 5 degrees C) and repeated temperature
      cycling (three times between 5 and 25 degrees C). Experiments focused on the
      evolution of firmness and droplet size (using pulsed field gradient NMR and
      scanning electron microscopy). Besides the effects of denaturation and/or
      acidification, the influence of the droplet size of the dispersed phase on
      emulsion stability was investigated also. It was found that heat treatment or
      acidification before emulsification led to unstable emulsions during temperature
      cycling, whereas heat treatment after acidification resulted in stable emulsions.

PMID- 15186104
TI  - Physicochemical changes in the hull of corn grains during their alkaline cooking.
AB  - The alkaline cooking of corn in a solution of Ca(OH)2 to produce corn-based foods
      is oriented to make corn proteins available, to incorporate Ca to the cooked
      grains, and also to remove the corn hull. This process (nixtamalization) is known
      in Mexico and Guatemala from prehispanic times; however, the effect of the
      alkaline cooking on the corn hull remains poorly documented. In this work, the
      physicochemical changes that take place in the corn hull during its cooking in a
      saturated solution of Ca(OH)2 were studied using infrared, X-ray diffraction, 13C
      cross-polarization/magic-angle spinning (CP/MAS) NMR, confocal imaging
      microscopy, differential scanning calorimetry, and thermogravimetry techniques.
      The main effect of this treatment on the hull is the removal of hemicelluloses
      and lignin, increasing the hull permeability and, as a consequence, facilitating
      the entry of the alkaline solution into the corn kernel. No significant changes
      were observed in the cellulose fiber network, which remains as native cellulose
      I, with a crystalline index, according to 13C CP/MAS NMR spectra, of 0.60. The
      alkaline treatment does not allow the cellulose fibers to swell and their
      regeneration in the form of cellulose(II). It seems any attempt to make use of
      the Ca binding capacity of the hull to increase the Ca availability in
      nixtamalized corn-based foods requires a separated treatment for the hull and
      kernel. On alkaline cooking, the hull hemicellulose fraction dissolves, losing
      its ability to bind Ca as a way to incorporate this element into foods elaborated
      from nixtamalized corn.

PMID- 15186105
TI  - Germplasm characterization of Zolfino landraces (Phaseolus vulgaris L.) by
      flavonoid content.
AB  - The flavonoid composition of three phenotypes of "Zolfino" landraces, a typical
      bean grown in Tuscany, has been elucidated by means of HPLC-DAD and HPLC-MS
      analysis. Flavonols, isoflavones, and anthocyanins have been separated and
      determined in the different samples chosen on the basis of their seed coat color.
      A flavonol that has not been previously found in Phaseolus vulgaris L. seeds has
      been characterized. The quantitative data show the presence of flavonols (ranging
      from 709 to 118 mg/kg of fresh weight), isoflavones (ranging from 14 to 2 mg/kg
      of fresh weight), and anthocyanins, in black beans only. These results show that
      this genotype could be very interesting from a nutritional point of view.

PMID- 15186106
TI  - Chemical and sensory characterization of DOC red wines from Marche (Italy)
      related to vintage and grape cultivars.
AB  - Monomeric phenols, color and copigmentation parameters, pigments with different
      chemical structure, tannin, glucose, fructose, glycerol, ethanol, and organic
      acids were determined in DOC red wines from Marche (Italy), obtained during three
      different vintages ranging from 1996 to 2000. The intensity of the bitter and
      astringent tastes of the wines was determined with panel tastings. Lacrima di
      Morro and Vernaccia di Serrapetrona (obtained from local cultivars) were
      different from Rosso Piceno, Rosso Piceno Superiore, and Rosso Conero (produced
      from different percentages of Sangiovese and Montepulciano). Vernaccia, a red,
      sweet, "spumante" wine, was an outlier. Lacrima showed a low tannin content, a
      high content of small pigments and phenols, and a high ratio of copigmented
      color, which persisted after 3 years of aging. The chemical determinations
      accounted for a high percentage of variability of measured panel astringency,
      copigmented color, and measured wine absorbance at 520 nm. It was not possible to
      create a predictive model for bitterness.

PMID- 15186107
TI  - Cluster analysis for the systematic grouping of genuine cocoa butter and cocoa
      butter equivalent samples based on triglyceride patterns.
AB  - The triglyceride profile of cocoa butters (CBs) from different geographical
      origins, varieties, growing seasons, and a number of cocoa butter equivalents
      (CBEs) was determined by capillary gas liquid chromatography. Hierarchical
      cluster analysis was applied to the five main triglycerides of the samples for
      the ability to find natural groupings among (a) CBs of various provenance and (b)
      CBE samples of different types. The samples were clustered using Ward's method,
      and the similarity values of the linkages were represented by dendrograms. The
      five triglycerides contained adequate information to obtain a meaningful sample
      differentiation. This information can be used to assess the purity and the origin
      of the CB sample examined.

PMID- 15186108
TI  - Characterization and quantitation of antioxidant constituents of sweet pepper
      (Capsicum annuum L.).
AB  - Sweet peppers (Capsicum annuum L.) cv. Vergasa have been studied at four maturity
      stages (immature green, green, immature red, and red). The individual phenolics
      (hydroxycinnamic acids and flavonoids), vitamin C (ascorbic acid and
      dehydroascorbic acid), and individual carotenoids were characterized and
      quantified. Five hydroxycinnamic derivatives and 23 flavonoids were characterized
      and quantified from the pericarp of sweet pepper by high-performance liquid
      chromatography-diode array detection-electrospray ionization-mass spectrometry.
      Identification was carried out by their UV spectra, chromatographic comparisons
      with authentic markers, identification of hydrolysis products, and tandem mass
      spectrometry analysis. Hydroxycinnamic derivatives, O-glycosides of quercetin,
      luteolin, and chrysoeriol, and a large number of C-glycosyl flavones have been
      characterized. Some of these compounds were found for the first time in nature.
      Clear differences in the individual and total phenolic content were detected
      between the different maturity stages. Immature green pepper had a very high
      phenolic content while green, immature red, and red ripe peppers showed a 4-5
      fold reduction. Ascorbic acid was the main form of vitamin C, and its content
      increased as the pepper reached maturity. The red ripe stage had a relevant
      impact on the carotenoids content. Thus, immature green peppers showed the
      highest content of polyphenols, while red ripe fruits had the highest content of
      vitamin C and provitamin A.

PMID- 15186109
TI  - Identification and quantification of astaxanthin esters in shrimp (Pandalus
      borealis) and in a microalga (Haematococcus pluvialis) by liquid chromatography
      mass spectrometry using negative ion atmospheric pressure chemical ionization.
AB  - Negative ion liquid chromatography-atmospheric pressure chemical ionization mass
      spectrometry [negative ion LC-(APCI)MS] was used for the identification of
      astaxanthin esters in extracts of commercial shrimp (Pandalus borealis) and dried
      microalga (Haematococcus pluvialis) samples. A cleanup step using a normal phase
      solid phase extraction (SPE) cartridge was applied prior to analysis. Recovery
      experiments with astaxanthin oleate as model compound proved the applicability of
      this step (98.5 +/- 7.6%; n = 4). The assignment of astaxanthin esters in
      negative ion LC-(APCI)MS was based on the detection of the molecular ion (M*-)
      and the formation of characteristic fragment ions, resulting from the loss of one
      or two fatty acids. Quantification of individual astaxanthin esters was performed
      using an astaxanthin calibration curve, which was found to be linear over the
      required range (1-51 micromol/L; r2 = 0.9996). Detection limits, based on the
      intensity of M*-, a signal-to-noise ratio of 3:1, and an injection volume of 20
      microL, were estimated to be 0.05 microg/mL (free astaxanthin), 0.28 microg/mL
      (astaxanthin-C16:0), and 0.78 microg/mL (astaxanthin-C16:0/C16:0), respectively.
      This LC-(APCI)MS method allows for the first time the characterization of native
      astaxanthin esters in P. borealis and H. pluvialis without using time-consuming
      isolation steps with subsequent gas chromatographic analyses of fatty acid methyl
      esters. The results suggest that the pattern of astaxanthin-bound polyunsaturated
      fatty acids of P. borealis does not reflect the respective fatty acid pattern
      found in triacylglycerides. Application of the presented LC-(APCI)MS technique in
      common astaxanthin ester analysis will forestall erroneous xanthophyll ester
      assignment in natural sources.

PMID- 15186110
TI  - Comparative ultrastructure of Ilpumbyeo, a high-quality japonica rice, and its
      mutant, Suweon 464: scanning and transmission electron microscopy studies.
AB  - A new rice mutant Suweon 464 (S-464), which has extreme contrast in cooking
      quality and physicochemical properties from those of its mother variety Ilpumbyeo
      (IP), revealed striking differences in ultrastructure in in situ, fractured whole
      grain, and isolated starch preparation. In scanning electron microscopy (SEM),
      compound starch granules (CSG) in whole grains of IP were readily split during
      fracturing, whereas those in S-464 were structurally intact and were enclosed
      within a sac-like structure tolerant of fracturing. In isolated preparation, IP
      starch consisted entirely of individual starch granules, whereas S-464 starch
      consisted of mostly large CSG enclosed within the sac, preventing the release of
      the individuals. In transmission electron microscopy (TEM), S-464 starch granules
      were smaller, solidly "condensed", and highly contrasted, whereas those of IP
      were larger, loosely "diffused", and less contrasted. The boundaries of
      amyloplasts and starch granules in S-464 were coated with a thin proteinaceous
      layer, presumed to be the counterpart of the sac that enclosed the CSG observed
      in SEM.

PMID- 15186111
TI  - Receptor assay-guided isolation of anti-GABAergic insecticidal alkaloids from a
      fungal culture.
AB  - The gamma-aminobutyric acid (GABA) receptor bears sites of action for
      insecticides. To discover GABA receptor-directed insecticides in natural
      products, fungal culture extracts were screened for their ability to inhibit
      specific binding of the radiolabeled noncompetitive antagonist [3H]1-(4
      ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane to housefly head
      membranes. The screening efforts led to the isolation of two alkaloids from
      Aspergillus terreus: PF1198A (alantrypinone) and PF1198B (serantrypinone), which
      had IC50 values of 0.34 and 2.1 microM, respectively, in this assay. These
      compounds were ca. 47-61-fold selective for housefly vs rat GABA receptors. Both
      compounds showed insecticidal activity against Myzus persicae in the range of 100
      500 ppm. Binding assay-guided screening should provide significant opportunities
      for the identification of novel and selective insecticides.

PMID- 15186112
TI  - Use of activated bentonites in controlled-release formulations of atrazine.
AB  - The herbicide atrazine (6-chloro-N2-ethyl-N4-isopropyl-1,3,5-triazine-2,4
      diamine) was incorporated in alginate-based granules to obtain controlled-release
      (CR) properties. The basic formulation [sodium alginate (1.40%)-atrazine (0.60%)
      water] was modified by the addition of sorbents. The effect on atrazine release
      rate caused by the incorporation of acid-treated bentonite (0.5 and 2.5 M H2SO4)
      in alginate formulation was studied by immersion of the granules in water under
      static conditions. The water uptake, sorption capacity of the sorbent,
      permeability, and time taken for 50% of the active ingredient to be released into
      water, t50, were calculated for the comparison of the preparations. t50 values
      were longer for those formulations containing acid-treated bentonite (36.78 and
      29.01 days for 0.5 and 2.5 M H2SO4 treatments, respectively) than for the
      preparation without bentonite (9.69 days). On the basis of a parameter of an
      empirical equation used to fit the herbicide release data, it appears that the
      release of atrazine from the various formulations into water is controlled by
      diffusion mechanism. The sorption capacity of the sorbents and the permeability
      of the formulations (ranging from 4.99 to 20.83 mg day(-1) mm(-1)) were the most
      important factors affecting herbicide release.

PMID- 15186114
TI  - Procedure to measure the level of polycyclic aromatic hydrocarbons in wood ashes
      used as fertilizer in agroforestry soils and their transfer from ashes to water.
AB  - Before wood ash can be safely used as a fertilizer in soils, possible negative
      effects such as input of organic contaminants or remobilization of contaminants
      already stored in the soil must be investigated. The objective of this study was
      to optimize and characterize extraction methods to isolate and quantitatively
      measure polycyclic aromatic hydrocarbons (PAHs) concentrations in wood ash that
      can be used as amendment of soils. It will be then possible to examine the
      effects of wood ash application on PAHs concentrations in the washing waters with
      the aim of evaluating their distribution by storage in the different compartments
      and what influences their stability and persistence. Simple, rapid and
      inexpensive methods have been set up for the determination of seven polycyclic
      aromatic hydrocarbons (PAHs) in wood ashes and ash aqueous extracts without
      interferences from other chemical contaminants using organic solvent extraction
      and/or SPE techniques and analyzed by an optimized RP-HPLC-FLD method. The
      feasibility of extraction for the determination of PAHs in wood ashes has been
      evaluated because PAHs are strongly sorbed to such a matrix, which explains why
      the PAHs content in ash was seldom studied. The method resulted to be of
      recoveries ranging from 81 to 97% for the different PAHs, with repeatabilities
      (RSDs%) better than 6%. Detection levels were from 0.2 to 2.2 microg/kg, while
      quantification limits were from 0.7 to 5.6 microg/kg, low enough to evaluate the
      presence of PAHs in wood ashes.

PMID- 15186113
TI  - Bioavailability of cadmium-organic complexes to soil alga--an exception to the
      free ion model.
AB  - It is generally considered that cadmium bioavailability shows a considerable
      dependence on chemical speciation of Cd in solution, correlates best with the
      activity of free metal ion (Cd2+) in solution, and is largely indifferent to
      soluble metal complexes. The role of soluble organic matter (DOM) and soluble
      metal-organic complexes in metal bioavailability and toxicity, however, is not
      clear. Growth studies with a soil alga (Chlorococcum sp.) were conducted on a
      growth medium and pore water of Cookes Plain soil (Paleuxeralf), spiked with Cd
      as Cd(NO3)2. Speciation of the Cd in pore water, and in growth medium with and
      without citrate, was performed using the MINTEQA2 computer model incorporating
      updated values of the stability constants of Cd-DOM complexes, as well as using
      anode stripping voltammetry. Analysis of the toxicity data showed that Cd
      citrate, as well as the Cd-DOM complexes, is bioavailable and contributes toward
      the toxicity to alga. These data contradict the long-held notion that Cd-DOM
      complexes are not bioavailable to soil biota although they may increase the
      mobility of Cd.

PMID- 15186115
TI  - Off-vine grape drying effect on volatile compounds and aromatic series in must
      from Pedro Ximenez grape variety.
AB  - Changes in 36 volatile compounds of must from ripe grapes dried by direct
      exposure to sun and must from ripe grapes were studied. Compounds not dependent
      on sampling site in both musts were selected, and their concentration/Brix degree
      ratio values, were subjected to variance analysis. Only butan-1-ol and isoamyl
      alcohols showed no differences, while (E)-hex-3-en-1-ol, (Z)-hex-3-en-1-ol, (E)
      hex-2-en-1-ol, (E)-hex-2-enal, hexanoic acid, isobutanol, benzyl alcohol, 2
      phenylethanol, gamma-butyrolactone, gamma-hexalactone, and 5-methylfurfural,
      showed significant differences between the two must types, which may be ascribed
      to the drying process. An approach to describe must odor has been carried out by
      grouping volatile compounds in aromatic series, increasing their values in the
      fruity, solvent, sweet, and roasted series and diminishing the herbaceous as a
      consequence of the drying process.

PMID- 15186116
TI  - Chemical composition and antimicrobial activity of the essential oils from the
      gum of Turkish pistachio (Pistacia vera L.).
AB  - The essential oil from the gum of Pistachio (Pistacia vera L. (Anacardiaceae))
      grown in Turkey was obtained by the hydro-distillation method, and its chemical
      composition was analyzed by GC and GC-MS. Moreover, the antimicrobial activities
      of the oil against the growth of 13 bacteria and 3 pathogenic yeasts were
      evaluated using the agar-disk diffusion and minimum inhibitory concentration
      (MIC) methods. The results showed that the essential oil contained about 89.67%
      monoterpenes, 8.1% oxygenated monoterpenes and 1.2% diterpenes. alpha-Pinene
      (75.6%), beta-pinene (9.5%), trans-verbenol (3.0%), camphene (1.4%), trans
      pinocarveol (about 1.20%), and limonene (1.0%) were the major components. The
      antimicrobial results showed that the oil inhibited nine bacteria and all the
      yeasts studied, and the activities were considerably dependent upon concentration
      and its bioactive compounds such as carvacrol, camphene, and limonene. Moreover,
      the essential oil of the gum was found to be more effective yeastcide than
      Nystatin, synthetic yeastcide. Furthermore, the antibacterial activities of the
      oil were lower than those of standard antibiotics, ampicillin sodium, and
      streptomycine sulfate under the conditions studied.

PMID- 15186117
TI  - Essential oil of Valeriana officinalis L. cultivars and their antimicrobial
      activity as influenced by harvesting time under commercial organic cultivation.
AB  - The essential oil content and the composition of subterranean parts of two
      valerian (Valeriana officinalis, L.) cultivars Select and Anthose, from certified
      commercial organic fields, were determined by hydrodistillation, followed by gas
      chromatography (GC) and GC/mass spectrometry analysis. Eight and fourteen month
      old cv. Select had 0.67 and 0.87% essential oil, while similar aged cv. Anthose
      contained 0.97 and 1.1% essential oil. Forty-three and fifty-three components
      from cv. Select and cv. Anthose oils were detected, respectively. The oil
      composition significantly varied due to the cultivar type, plant age, and/or
      harvesting time. The major components for cv. Select were valerenal, bornyl
      acetate, 15-acetoxy valeranone, valerenic acid, and camphene, while cv. Anthose
      had valerenal, (-)-bornyl acetate, alpha-humulene, camphene, 15-acetoxy
      valeranone, and valerenic acid. With further aging of the plants, the valerenal,
      valerenic acid, and alpha-humulene contents increased. The oil of cv. Select had
      a strong antimicrobial effect against Aspergillus niger, Escherichia coli,
      Staphylococcus aureus, and Saccharomyces cerevisiae, while cv. Anthose showed low
      or no activity against all test microbes, including Pseudomonas aeruginosa,
      suggesting that the inhibitory activity of valerian oil depends on the cultivar
      and its developmental stage. The oil profile of our cultivars did not match the
      literature proposed chemotype profiles.

PMID- 15186118
TI  - Monitoring of denaturation processes in aged beef loin by Fourier transform
      infrared microspectroscopy.
AB  - We present the results of a Fourier transform infrared (FT-IR) microspectroscopic
      study using conventional FT-IR microscopy and FT-IR imaging to detect the
      denaturation process during four different heating temperatures (raw, 45, 60, and
      70 degrees C) spatially resolved in bovine cryosections from longissimus dorsi
      muscle. FT-IR imaging, employing a focal plane array detector, which allowed the
      simultaneous collection of spectra at 4096 pixels, enabled the investigation of
      the heat-induced changes in the two major meat constituents, i.e., myofibrillar
      and connective tissue proteins, spatially resolved. The infrared spectra of both
      compounds revealed that the major spectral changes involved an increase in beta
      sheet and a decrease in alpha-helical structures, which appeared to be much more
      pronounced for the myofibers than for the connective tissue. These conformational
      changes could be correlated to the denaturation of the major meat proteins, such
      as myosin, actin, and collagen.

PMID- 15186119
TI  - Rheology of mixed beta-casein/beta-lactoglobulin films at the air-water
      interface.
AB  - The adsorption of dilute mixtures of beta-casein/beta-lactoglobulin to the air
      water interface was investigated using surface dilatation and surface shear
      rheology. The data were fitted to simple rheological models to try to gain
      further information regarding the composition and nature of the interface. The
      dilatational measurements suggested that the composition of the interface could
      be determined using these models and that the surface concentration was dominated
      by the beta-casein in the early stages of adsorption but that high levels of beta
      lactoglobulin were present in the final stages. Surface shear rheological
      measurements showed a similar trend. However, the shear measurements appeared to
      be more sensitive to the strength of the network than to the composition of the
      interface. Fluorescence microscopy supported the findings and demonstrated that
      any "phase separation" capable of affecting the surface rheological measurements
      occurred at the sub-micrometer scale. The results also demonstrated that the
      heterogeneity of the interface, once formed, is kinetically trapped, and no
      further phase separation occurs over the time span of the experiments.

PMID- 15186120
TI  - Effect of technological processing on the allergenicity of mangoes (Mangifera
      indica L.).
AB  - In parallel with the rising popularity of exotic fruits in Europe, allergy
      against mango is of increasing importance. Because mangoes are also consumed as
      processed products such as chutneys or beverages, the influences of different
      process conditions on their allergenicity were investigated. Mango purees and
      nectars were manufactured at small pilot-plant scale, and the allergenic
      potencies of the resulting intermediate and final products were determined by
      means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE),
      immunoblotting and inhibitive enzyme allergosorbent tests (EAST-inhibition),
      using a pool serum of 9 individuals with manifest mango allergy. The mango
      allergens were shown to be very stable during technological processing.
      Irrespective of enzymatic matrix decomposition, mechanical tissue disintegration
      and heating during peeling, mash treatment, and pasteurization, significant loss
      of allergenicity could not be observed in the extracts of mango purees and
      nectars derived thereof. These results were confirmed by analogous investigation
      of commercial mango drinks and nectars. Hence, conventional mango processing into
      pulp-containing products typical for this species obviously does not allow
      complete elimination of the allergenic potency.

PMID- 15186121
TI  - Analysis and modeling of the ferulic acid oxidation by a glucose oxidase
      peroxidase association. Comparison with a hexose oxidase-peroxidase association.
AB  - A commercial glucose oxidase (GOX) from Aspergillus niger was partially
      characterized. The enzyme exhibited a two-step transfer mechanism, and the
      kinetic constants toward glucose and oxygen were determined. Under conditions
      similar to dough making (glucose concentration and pH), GOX does not exhibit
      maximum activity. A hexose oxidase (HOX) from Chondrus crispus was partially
      characterized as well. The HOX activity is not far from the optimum in the
      kneading conditions (pH and glucose concentration). A peroxidase (POD) purified
      from wheat germ was used to oxidize ferulic acid in the presence of GOX or HOX.
      Hydrogen peroxide produced during the glucose oxidation activates the wheat germ
      POD. Ferulic acid oxidation in solutions containing different ratios of POD + GOX
      or HOX + POD was followed by UV spectrophotometry. For the same dosage, the HOX
      POD system is the most efficient for peroxidase activation. Using absorbance data
      and kinetic constants of GOX and POD, a mathematical model describing the release
      or consumption of the different reactants (hydrogen peroxide, oxygen, and ferulic
      acid) in the medium was developed, and experimental data correlated well with
      calculated values. The results obtained will be applied to investigate the effect
      of GOX and HOX activities on the rheological properties of dough.

PMID- 15186122
TI  - Selenium distribution in a Se-enriched mushroom species of the genus Ganoderma.
AB  - Data reported here show that Ganoderma lucidum could biotransform inorganic
      selenite in the substrate into organic forms by intergrating Se into proteins (56
      61%) and polysaccharides (11-18%) and other components. Furthermore, water- and
      alkaline-soluble protein components were mainly responsible for the storage of
      organic Se, and Se-Met accounts for only a minor (8.2-18.3%) amount of the
      selenocompounds present in proteins. The molecular mass of most proteins or
      protein subunits containing Se was no more than 16 kDa. A low concentration of Se
      (<100 microg/g) in the substrate facilitated the synthesis of total protein and
      amino acids in G. lucidum, but a high concentration of Se (>150 microg/g) played
      a reverse role. Additionally, Se concentration in the culture had no significant
      effect on the distribution of the amino acids and proteins.

PMID- 15186123
TI  - Effect of long-term dietary supplementation of high-gamma-linolenic canola oil
      versus borage oil on growth, hematology, serum biochemistry, and N-6 fatty acid
      metabolism in rats.
AB  - Dietary supplementation of a high-gamma-linolenic acid canola oil (HGCO)
      containing approximately 36% (w/w) of gamma-linolenic acid (GLA, 18:3n-6) from
      the seeds of a genetically transformed canola strain, was assessed for its long
      term biological effects. Growing Sprague-Dawley rats (n = 30) were fed a purified
      AIN93G diet containing 5, 10, or 15% (w/w) of HGCO as the fat source. For
      comparison, a separate group of rats (n = 10) was given the diet containing 15%
      (w/w) of borage oil (BO), which contained 22% (w/w) of GLA. After 12 weeks of
      feeding, the growth, relative organ weights, hematology, and serum biochemistry
      were found to be similar among rats fed the 5, 10, and 15% HGCO diets. The GLA
      levels in plasma and liver phospholipids (PL) were also similar. However, the
      levels of GLA in peripheral tissues (muscle PL and adipose triacylglycerols) were
      significantly higher in rats fed the 10 and 15% HGCO diets than those fed the 5%
      HGCO diet. When the above biologic parameters were compared between the 15% HGCO
      and 15% BO dietary groups, there were no significant differences except for lower
      final body weights and higher tissue levels of GLA, dihomo-gamma-linolenic acid
      (20:3n-6) and arachidonic acid (20:4n-6) in the 15% HGCO dietary group as
      compared with the 15% BO dietary group. This is due to a higher GLA content and
      possibly a more favorable stereospecific distribution of GLA in HGCO. Overall,
      long-term (12-week) feeding with diets containing up to 15% HGCO resulted in no
      adverse effects on growth, organ weight, hematology and serum biochemistry as
      compared to the diet containing 15% BO, suggesting that HGCO may be a safe
      alternative source of GLA.

PMID- 15186124
TI  - Identification of specific oxidatively modified proteins in chicken muscles using
      a combined immunologic and proteomic approach.
AB  - Muscle proteins are generally believed to be key players in free radical
      processes that eventually lead to oxidative deterioration or modifications of
      meat proteins resulting in alterations in functionality, for example, gel-forming
      ability, emulsification properties, and water-binding capacity. This study
      addresses protein oxidation in chicken muscles using a combined immunologic and
      proteomic approach and identifies specific proteins that contain carbonyls and/or
      3-nitrotyrosine (3-NT). Whereas alpha-enolase was the predominant carbonyl
      reactive species among the water-soluble muscle proteins, several other proteins
      (actin, heat shock protein 70, and creatine kinase) contained carbonyls and/or 3
      nitrotyrosine. Finally, this approach was used to demonstrate differential
      susceptibility of water-soluble muscle proteins toward oxidation in chickens fed
      a low-antioxidant diet compared with chickens fed a diet supplemented with
      antioxidant-rich fruits/vegetables.

PMID- 15186125
TI  - Effect of sulfated polysaccharides on heat-induced structural changes in beta
      lactoglobulin.
AB  - The mechanism that leads to a decreased aggregation of beta-lactoglobulin in the
      presence of dextran sulfate and lambda-carrageenan was investigated by assessing
      changes in the denaturation thermodynamics and protein structure. Differential
      scanning calorimetry results showed that the denaturation temperature (Tp) was
      about 4.6 degrees C higher in the presence of dextran sulfate, as compared with
      beta-lactoglobulin alone, whereas in the presence of lambda-carrageenan the
      difference in Tp was about 1.2 degrees C. Changes in protein structure studies
      using near-UV circular dichroism (CD) provided support for the calorimetric
      results. The transition midpoint (Tm) for denaturation of beta-lactoglobulin was
      about 5 degrees C higher in the presence of dextran sulfate than that found with
      beta-lactoglobulin alone and about 2 degrees C in the presence of lambda
      carrageenan. Thermal modifications of the tertiary structure of beta
      lactoglobulin were irreversible at temperatures above 67 degrees C; the addition
      of dextran sulfate reduced the extent of such modifications. Far-UV CD studies
      indicated that the addition of dextran sulfate or lambda-carrageenan did not
      affect secondary structure changes of beta-lactoglobulin upon heating. These
      studies indicate that dextran sulfate and lambda-carrageenan can enhance the
      stability of beta-lactoglobulin and thereby inhibit heat denaturation and
      aggregation.

PMID- 15186126
TI  - Constitution of stable artificial oil bodies with triacylglycerol, phospholipid,
      and caleosin.
AB  - Seed oil bodies are lipid storage organelles of 0.5-2 microm in diameter and
      comprise a triacylglycerol matrix shielded by a monolayer of phospholipids and
      proteins. These proteins include abundant structural proteins, oleosins, and at
      least two minor proteins termed caleosin and steroleosin. This study examined if
      artificial oil bodies (AOBs) composed of triacylglycerol and phospholipid could
      be stabilized by oleosin, caleosin, or steroleosin. Our results showed that
      stabilization effects could be realized by oleosin or caleosin but not by
      steroleosin. The sizes of the AOBs constituted with oleosin (0.5-2 microm) or
      caleosin (50-200 nm) were similar to or 10 times smaller than those of the native
      oil bodies. Recombinant caleosin expressed in Escherichia coli also encapsulated
      AOBs with a size, topology, and stability comparable to those encapsulated with
      native caleosin. A proteinase K digestion indicated that caleosin anchored the
      AOBs via its central hydrophobic domain of approximately 4 kDa.
      Isoelectrofocusing revealed that the isoelectric point of the caleosin-stabilized
      AOBs was pH 4.0. Aggregation of AOBs was observed at a pH lower than 4.5; thus,
      their stability and integrity were presumably contributed by surface caleosin via
      electronegative repulsion and steric hindrance. The caleosin-stabilized AOBs were
      thermostable up to 70 degrees C and potentially useful for biotechnological
      applications.

PMID- 15186127
TI  - Effects of casein and fat content on water self-diffusion coefficients in casein
      systems: a pulsed field gradient nuclear magnetic resonance study.
AB  - The water self-diffusion coefficients in casein matrixes were measured using a
      pulsed field gradient spin-echo nuclear magnetic resonance technique (PFG-SE
      NMR). The dependence of the water self-diffusion coefficient on the casein
      concentration and the aqueous phase composition is reported in both a rehydrated
      native phosphocaseinate dispersion and a concentrated casein retentate. A model
      has been proposed to explain the different behavior of the water self-diffusion
      coefficient in the two casein systems. This model demonstrates that the water
      self-diffusion cannot be simply explained by the water content only. So, taking
      into account the specific effect of each constituent of the aqueous dispersing
      phase, the water self-diffusion reduction induced by the casein micelle can be
      modeled. The effect of fat on the water self-diffusion coefficients was
      investigated. Anhydrous milk fat-reconstituted retentate samples were used in
      order to estimate the obstruction effect of fat globules in the modeling process.
      The dependence of the self-diffusion coefficient of water on the fat and casein
      content is reported. A general model included the effect of the aqueous phase
      composition, and the obstruction effects of casein micelles and fat globules were
      proposed. This model was validated for water self-diffusion coefficients in
      industrial fatty retentates.

PMID- 15186128
TI  - Stabilization of oil-in-water emulsions by cod protein extracts.
AB  - The ability of two protein fractions extracted from cod to form and stabilize oil
      in-water emulsions was examined: a high salt extracted fraction (HSE protein) and
      a pH 3 acid extracted fraction (AE protein). Both fractions consisted of a
      complex mixture of different proteins, with the predominant one being myosin (200
      kDa). The two protein fractions were used to prepare 5 wt % corn oil-in-water
      emulsions at ambient temperature (pH 3.0, 10 mM citrate-imidazole buffer).
      Emulsions with relatively small mean droplet diameters (d(3,2) < 1 microm) and
      good creaming stability (> 9 days) could be produced at protein concentrations >
      or =0.2 wt % for both fractions. The isoelectric point of droplets stabilized by
      both protein fractions was pH approximately 5. The emulsions were stable to
      droplet flocculation and creaming at relatively low pH (< or =4) and NaCl
      concentrations (< or =150 mM) when stored at room temperature. In the absence of
      salt, the emulsions were also stable to thermal treatment (30-90 degrees C for 30
      min), but in the presence of 100 mM NaCl droplet flocculation and creaming were
      observed in some of the emulsions, particularly those stabilized by the AE
      fraction. The results suggest that protein fractions extracted from cod can be
      used as emulsifiers to form and stabilize food emulsions.

PMID- 15186129
TI  - Maillard reaction and enzymatic browning affect the allergenicity of Pru av 1,
      the major allergen from cherry (Prunus avium).
AB  - The influence of thermal processing and nonenymatic as well as polyphenoloxidase
      catalyzed browning reaction on the allergenicity of the major cherry allergen Pru
      av 1 was investigated. After thermal treatment of the recombinant protein rPru av
      1 in the absence or presence of carbohydrates, SDS-PAGE, enzyme allergosorbent
      tests, and inhibition assays revealed that thermal treatment of rPru av 1 alone
      did not show any influence on the IgE-binding activity of the protein at least
      for 30 min, thus correlating well with the refolding of the allergen in buffer
      solution as demonstrated by CD spectroscopic experiments. Incubation of the
      protein with starch and maltose also showed no effect on IgE-binding activity,
      whereas reaction with glucose and ribose and, even more pronounced, with the
      carbohydrate breakdown products glyceraldehyde and glyoxal induced a strong
      decrease of the IgE-binding capacity of rPru av 1. In the second part of the
      study, the effect of polyphenoloxidase-catalyzed oxidation of polyphenols on food
      allergen activity was investigated. Incubation of rPru av 1 with epicatechin in
      the presence of tyrosinase led to a drastic decrease in IgE-binding activity of
      the protein. Variations of the phenolic compound revealed caffeic acid and
      epicatechin as the most active inhibitors of the IgE-binding activity of rPru av
      1, followed by catechin and gallic acid, and, finally, by quercetin and rutin,
      showing significantly lower activity. On the basis of these data, reactive
      intermediates formed during thermal carbohydrate degradation as well as during
      enzymatic polyphenol oxidation are suggested as the active chemical species
      responsible for modifying nucleophilic amino acid side chains of proteins, thus
      inducing an irreversible change in the tertiary structure of the protein and
      resulting in a loss of conformational epitopes of the allergen.

PMID- 15186130
TI  - Characterization of soluble non-covalent complexes between bovine serum albumin
      and beta-1,2,3,4,6-penta-O-galloyl-D-glucopyranose by MALDI-TOF MS.
AB  - Beta-1,2,3,4,6-penta-O-galloyl-D-glucopyranose (PGG) and soluble complexes of PGG
      with bovine serum albumin (BSA) were characterized by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). PGG was
      also characterized by electrospray ionization mass spectrometry (ESI-MS). Similar
      fragmentation patterns of PGG were found in ESI-MS and MALDI-TOF MS. The apparent
      stoichiometries of non-covalent BSA-PGG complexes were determined by MALDI-TOF
      MS.

PMID- 15186131
TI  - Comprehensive phytochemical profile of soy protein isolate.
AB  - Although an FDA health claim for soy protein has been issued, the potential
      health benefits of soy foods remain controversial among scientists, especially
      with regard to soy infant formula. The UV detectable isoflavones have been the
      focus of the majority of studies concerning health-related effects of soy protein
      isolate (SPI). However, the chemical identities and health effects of other SPI
      phytochemicals without UV absorption properties are less well-studied. In the
      current study, we employed liquid chromatography-tandem mass spectrometry methods
      to reveal a complicated phytochemical profile for SPI consisting of 136
      phytochemicals. Also, we have quantitated many of these SPI phytochemicals so
      that dietary intakes can be estimated for foods containing SPI. On a
      weight/weight basis, fatty acids are the largest group of phytochemicals in the
      extract (64.13% total fat), followed by saponins (21.48%), and then isoflavones
      at 6.82%. Of the 56 lysophospholipids identified in SPI, 0.50% was
      lysophosphatidylcholines and 0.23% was lysophosphatidylethanolamines.

PMID- 15186132
TI  - Reduction of acrylamide uptake by dietary proteins in a caco-2 gut model.
AB  - The report of elevated acrylamide levels in some foods raised an international
      health alarm, because acrylamide probably has carcinogenic, neurotoxic, and
      genotoxic properties. However, data on the bioavailability of acrylamide from
      food matrices in humans are limited. In particular, only little is known about
      the interactions of acrylamide with food ingredients. Using a human intestine
      model (Caco-2 cells), this study shows that acrylamide monomers are highly
      bioavailable and pass the cell monolayer via passive diffusion. Furthermore,
      acrylamide binds to dietary proteins such as chicken egg albumin under intestinal
      and cooking conditions. This binding reduces the concentration of acrylamide
      monomers and leads to a reduced uptake by Caco-2 cells. Hence, it is concluded
      that a protein-rich diet may reduce acrylamide uptake.

PMID- 15186135
TI  - One-directional crystal growth in charged colloidal silica dispersions driven by
      diffusion of base.
AB  - Aqueous dispersions of charged colloidal silica particles showed a novel one
      directional crystal growth by diffusion of a weak base, pyridine. The colloidal
      crystal consisted of pillar-shaped crystal grains whose height and width were in
      the order of centimeter and subcentimeter, respectively. The growth process was
      explainable in terms of (i) the diffusion of pyridine with neutralization
      reactions between weakly acidic silica surfaces, (ii) charging up of the silica
      particles, and (iii) the charge-induced crystallization of the dispersions.

PMID- 15186133
TI  - Lipophilic and hydrophilic antioxidant capacities of common foods in the United
      States.
AB  - Both lipophilic and hydrophilic antioxidant capacities were determined using the
      oxygen radical absorbance capacity (ORAC(FL)) assay with fluorescein as the
      fluorescent probe and 2,2'-azobis(2-amidinopropane) dihydrochloride as a peroxyl
      radical generator on over 100 different kinds of foods, including fruits,
      vegetables, nuts, dried fruits, spices, cereals, infant, and other foods. Most of
      the foods were collected from four different regions and during two different
      seasons in U.S. markets. Total phenolics of each sample were also measured using
      the Folin-Ciocalteu reagent. Hydrophilic ORAC(FL) values (H-ORAC(FL)) ranged from
      0.87 to 2641 micromol of Trolox equivalents (TE)/g among all of the foods,
      whereas lipophilic ORAC(FL) values (L-ORAC(FL)) ranged from 0.07 to 1611 micromol
      of TE/g. Generally, L-ORAC(FL) values were <10% of the H-ORAC(FL) values except
      for a very few samples. Total antioxidant capacity was calculated by combining L
      ORAC(FL) and H-ORAC(FL). Differences of ORAC(FL) values in fruits and vegetables
      from different seasons and regions were relatively large for some foods but could
      not be analyzed in detail because of the sampling scheme. Two different
      processing methods, cooking and peeling, were used on selected foods to evaluate
      the impact of processing on ORAC(FL). The data demonstrated that processing can
      have significant effects on ORAC(FL). Considering all of the foods analyzed, the
      relationship between TP and H-ORAC(FL) showed a very weak correlation. Total
      hydrophilic and lipophilic antioxidant capacity intakes were calculated to be
      5558 and 166 micromol of TE/day, respectively, on the basis of data from the USDA
      Continuing Survey of Food Intakes by Individuals (1994-1996).

PMID- 15186136
TI  - Single-cell detection of trans-splicing ribozyme in vivo activity.
AB  - The Tetrahymena trans-splicing ribozyme can edit RNA in a sequence-specific
      manner, but its efficiency needs to be improved for any functional rescues. This
      communication describes a simple method that uses a bacterial enzyme beta
      lactamase to report trans-splicing activity of Tetrahymena ribozyme in single
      living mammalian cells by fluorescence microscopy and flow cytometry. This enzyme
      based single-cell detection method is highly sensitive and compatible with living
      cell flow cytometry, and should allow a cell-based systematic screening of a vast
      library of ribozymes for better trans-spliced ribozyme variants.

PMID- 15186137
TI  - Real time differentiation of G-protein coupled receptor (GPCR) agonist and
      antagonist by two photon fluorescence laser microscopy.
AB  - Receptor-based signaling mechanisms are the primary source of cellular
      regulation. The superfamily of G protein-coupled receptors (GPCR) is the largest
      and most ubiquitous of the receptor-mediated processes. Desensitization of G
      protein-coupled receptors is a fundamental mechanism regulating the cellular
      response to agonists. We have recently studied the agonist and antagonist of the
      human melanocortin receptors (hMC1, hMC3, hMC4, and hMC5 receptors), the human
      delta opioid receptor, and the human gluacagon receptor with the help of
      synthetic fluorescent labeled ligands and fluorescent protein-labeled beta
      arrestin-receptors that shed new insight on cellular signaling and rapid
      screening of drugs in real time. It was demonstrated that stimulation of these
      receptors by the cognate agonist triggers the rapid internalization of ligand
      receptor complexes, while the interaction of the receptor with antagonists does
      not follow this pathway. Furthermore, receptor internalization is dependent upon
      beta-arrestin, which has been shown to be responsible for the rapid
      desensitization of cAMP-signaling processes.

PMID- 15186138
TI  - Spontaneous formation of cadmium hydroxide nanostrands in water.
AB  - Cadmium hydroxide nanostrands with a diameter of 1.9 nm were spontaneously formed
      by raising the pH of a dilute Cd(NO3)2 solution. The length reaches a few
      micrometers and the aspect ratio exceeds 1000. The crystallographic structure was
      successfully elucidated by high-resolution electron microscopy. The surface of
      the nanostrands was remarkably positively charged and adsorbed an astonishing
      number of negatively charged dye molecules.

PMID- 15186139
TI  - A solvent-free, SeCN-/(SeCN)3- based ionic liquid electrolyte for high-efficiency
      dye-sensitized nanocrystalline solar cells.
AB  - A solvent-free ionic liquid electrolyte based on the SeCN-/(SeCN)3- redox couple
      has been employed for high-efficiency dye-sensitized nanocrystalline solar cells.
      For the first time an alternative redox couple has been identified to rival and
      even exceed the performance of the iodide/triiodide couple even at full sunlight.
      Unprecedented 7.5-8.3% power conversion efficiencies under AM 1.5 sunlight have
      been achieved for photovoltaic devices with solvent-free ionic liquid
      electrolytes.

PMID- 15186140
TI  - Sweeping capillary electrophoresis: a non-stopped-flow method for measuring
      bimolecular rate constant of complex formation between protein and DNA.
AB  - We introduce sweeping capillary electrophoresis (SweepCE), a non-stopped-flow
      method for directly measuring the bimolecular rate constant of complex formation,
      and demonstrate its use for studying protein-DNA interaction. The capillary is
      prefilled with a solution of DNA, and electrophoresis is then carried out from a
      solution of the protein in a continuous mode. Because the electrophoretic
      mobility of the protein is greater than that of DNA, the protein continuously
      mixes with DNA and forms the protein-DNA complex. The complex migrates with a
      velocity higher than that of DNA and causes sweeping of DNA, which gave the name
      to the method. The bimolecular rate constant, kon, of complex formation can be
      determined from the time profile of DNA concentration using a simple mathematical
      model of the sweeping process. In this proof-of-principle work, we used SweepCE
      to directly measure kon = (3.4 +/- 0.6) x 106 M-1 s-1 for the interaction between
      single-stranded DNA-binding protein and a 15-mer DNA oligonucleotide. Along with
      nonequilibrium capillary electrophoresis of equilibrium mixtures (NECEEM),
      SweepCE establishes a universal and comprehensive platform for studying kinetic
      and equilibrium parameters of complex formation between biopolymers.

PMID- 15186141
TI  - Reductive desorption of thiolate from monolayer protected gold clusters.
AB  - The "electrochemical potential window" of monolayer-protected gold cluster (MPC)
      nanoelectrodes is probed where the electrified liquid-liquid interface is used as
      the detector. The first observation of the reductive desorption of thiolate at
      negative MPC core charge is reported.

PMID- 15186143
TI  - Zirconocene-mediated intermolecular coupling of one molecule of Si-tethered diyne
      with three molecules of organonitriles: one-pot formation of pyrrolo[3,2
      c]pyridine derivatives via cleavage of CN triple bonds of organonitriles.
AB  - One Si-tethered diyne is coupled in one pot with three molecules of
      organonitriles promoted by a low-valent zirconocene species. Cleavage of one of
      the three CN triple bonds and cleavage of the two Si-C bonds take place to afford
      pyrrolo[3,2-c]pyridine derivatives after hydrolysis.

PMID- 15186142
TI  - Simultaneous triggering of protein activity and fluorescence.
AB  - Many areas of biology can benefit greatly from methods to spatially and
      temporally control protein activity. Here, we describe an approach that allows
      the simultaneous photo-triggering of the activity and the fluorescence of a
      protein. Smad2, a protein central to the transforming growth factor-beta (TGF
      beta) signal transduction pathway, was modified with a fluorophore and a
      photocleavable moiety that acted as both a caging and a fluorescence quenching
      group. In its caged state, the protein formed a non-fluorescent heterodimer with
      the protein SARA. Irradiation with UV light and photocleavage of the caging group
      produced a fluorescent homotrimer. These in vitro experiments demonstrated that a
      photochemical trigger mimicking the critical biochemical event of serine
      phosphorylation involved in the TGF-beta signaling pathway could be obtained and
      that fluorescence could be used as a read-out of protein activity. This approach
      should prove particularly useful for the monitoring of a protein's activity and
      location inside of living cells.

PMID- 15186144
TI  - Isotope effects in photochemistry. 1. o-nitrobenzyl alcohol derivatives.
AB  - The photolysis of o-nitrobenzyl alcohol derivatives shows a strong kinetic
      isotope effect (KIE up to 8.3) at the benzylic center. For some derivatives, the
      KIE is wavelength dependent, suggesting the involvement of higher excited states.
      In addition to the important mechanistic consequences, isotopic substitution is a
      convenient way to alter the quantum yield without changing the absorbance, as
      would the introduction of substituents. This paves the way for a subtle tuning of
      the reaction rates in photochemical reactions. We illustrated this feature in the
      sequential deprotection of a diester protected at both termini with photolabile
      groups.

PMID- 15186145
TI  - Stabilization and size control of gold nanoparticles during laser ablation in
      aqueous cyclodextrins.
AB  - Femtosecond laser radiation has been used to ablate a gold target in aqueous beta
      cyclodextrin (CD) solutions to produce stable gold nanoparticle colloids with
      extremely small size (2 to 2.4 nm) and size dispersion (1 to 1.5 nm). On the
      basis of XPS and zeta-potential measurements, we propose a model involving
      chemical interactions between the gold and the CDs. The model includes both the
      hydrophobic interaction of the Au0 with the interior cavity of the CD and the
      hydrogen bonding of O- groups on the partially oxidized gold surface with -OH
      groups of the CDs.

PMID- 15186146
TI  - Tuning porphyrin/DNA supramolecular assemblies by competitive binding.
AB  - Addition of an intercalating but nonaggregating porphyrin, AuT4, to a preformed
      adduct between DNA and a strongly aggregating porphyrin, t-H2Pagg, permits
      control of the extent of aggregation of the latter. The size and the intensity of
      the ICD and RLS signals depend linearly on the concentration of the intercalating
      dye and decrease markedly on increasing the concentration of the available
      binding sites on the biopolymer template.

PMID- 15186147
TI  - Single- and double-linkage isomerism in a six-coordinate iron porphyrin
      containing nitrosyl and nitro ligands.
AB  - Density Functional theoretical calculations confirm the experimental observation
      that the low-temperature photolysis of (TPP)Fe(NO)(NO2) (as a KBr pellet) results
      in the generation of linkage isomers involving the axial NO and NO2 groups and
      suggest the possible formation of the double linkage isomer (TPP)Fe(ON)(ONO). The
      energy difference between the ground state (porphine)Fe(NO)(NO2) and the double
      linkage isomer (porphine)Fe(ON)(ONO) is 1.57 eV, which is comparable to the 1.59
      eV calculated previously for the nitrosyl-to-isonitrosyl linkage isomerism in the
      five-coordinate (porphine)Fe(NO) analogue.

PMID- 15186148
TI  - alpha-Aminoallylation of aldehydes with ammonia: stereoselective synthesis of
      homoallylic primary amines.
AB  - Three-component reactions of aldehydes, ammonia, and allylboronates were found to
      provide homoallylic primary amines in high yields with high chemo- and
      stereoselectivities. A two-step, one-pot, stereoselective synthesis of an
      uncommon alpha-amino acid, alloisoleucine, was achieved utilizing this reaction.

PMID- 15186149
TI  - Spatial encoding and the acquisition of high-resolution NMR spectra in
      inhomogeneous magnetic fields.
AB  - A scheme enabling the acquisition of high-resolution nuclear magnetic resonance
      (NMR) spectra within inhomogeneous magnetic fields is introduced and exemplified.
      The scheme is based on the spatial encoding protocol recently introduced for
      collecting multidimensional NMR data within a single scan, which retrieves
      spectral information via interference phenomena between spin packets located at
      distinct positions within the sample. This in turn enables compensating for field
      inhomogeneities over the sample as a whole by shifting the phases of the radio
      frequency pulses involved in the spatial encoding, rather than by demanding an
      extreme uniformity in the employed magnetic field. The upper tolerable field
      inhomogeneity limit thus becomes orders of magnitude higher than that in
      conventional time-domain acquisitions. No particular spatial dependencies are
      demanded by the new scheme, which can yield its high-resolution results on a
      single-scan basis.

PMID- 15186150
TI  - Indium-catalyzed direct chlorination of alcohols using chlorodimethylsilane
      benzil as a selective and mild system.
AB  - The InCl3-catalyzed reaction of alcohols with chlorodimethylsilane (HSiMe2Cl) in
      the presence of benzil gave the corresponding organic chlorides under mild
      conditions. Benzil significantly changes the reaction course because the reducing
      product through dehydroxyhydration was obtained in the absence of benzil. The
      secondary or tertiary alcohols were effectively chlorinated. The substrates
      bearing acid-sensitive functional groups were also applied to this system. The
      highly selective chlorination of the tertiary site was observed in the
      competitive reaction between tertiary and primary alcohols. The highly
      coordinated hydrosilane generated from benzil and HSiMe2Cl is an important
      intermediate.

PMID- 15186151
TI  - Evolution of function in the crotonase superfamily: the stereochemical course of
      the reaction catalyzed by 2-ketocyclohexanecarboxyl-CoA hydrolase.
AB  - Members of the mechanistically diverse enoyl-CoA hydratase (crotonase)
      superfamily catalyze reactions that involve stabilization of an enolate anion
      derived from an acyl thioester of coenzyme A. 2-Ketocyclohexanecarboxyl-CoA
      hydrolase (BadI), found in a pathway for anaerobic degradation of benzoate by
      Rhodopseudomonas palustris, is a member of the crotonase superfamily that
      catalyzes a reverse Dieckmann reaction in which the substrate is hydrolyzed to
      pimelyl-CoA. The substrate is the configurationally labile 2S
      ketocyclohexanecarboxyl-CoA, and in 2H2O solvent hydrogen is incorporated into
      the 2-proS position of the pimelyl-CoA product. Therefore, the stereochemical
      course of the BadI-catalyzed reaction is inversion. This information is important
      for understanding the roles of active-site functional groups in the active site
      of BadI as well as in the active sites of the homologous 1,4-dihydroxynaphthoyl
      CoA synthases that catalyze a forward Dieckmann reaction.

PMID- 15186152
TI  - SmCP-networked films obtained by in situ photopolymerization of neat reactive
      banana-shaped liquid crystals.
AB  - The synthesis and characterization of reactive banana-shaped compounds have been
      carried out, and their ability to be photopolymerized in their SmCP mesophase has
      been assessed. The presence of a SmCP liquid crystalline phase in these compounds
      has been confirmed by X-ray studies. The polymerization of these molecules has
      been demonstrated by calorimetric techniques as well as by the preparation and
      characterization of SmCP-ordered free films that are mechanically stable at room
      temperature. Furthermore, polymerized films exhibit second harmonic generation
      activity at room temperature in the absence of an electric field.

PMID- 15186153
TI  - Highly efficient and enantioselective cyclization of aromatic imines via directed
      C-H bond activation.
AB  - The first highly enantioselective catalytic reaction involving aromatic C-H bond
      activation is communicated. Enantioselective cyclization of aromatic ketimines
      containing alkenyl groups tethered at the meta position of an imine directing
      group has been achieved using 5 mol % [RhCl(coe)2]2 and 15 mol % of an (S)-binol
      derived phosphoramidite ligand. Selectivities of up to 96% ee and up to
      quantitative yields were obtained. Moreover, the identified catalyst system
      enables the intramolecular alkylation reaction to be performed at temperatures 75
      degrees C lower than our previously reported achiral system. The reaction can
      even be performed at room temperature for one of the optimal substrates.

PMID- 15186154
TI  - Changing catalytic activity during colloidal platinum nanocatalysis due to shape
      changes: electron-transfer reaction.
AB  - The shape distribution of the catalytic nanoparticles and the activation energy
      of the electron-transfer reaction between hexacyanoferrate (III) and thiosulfate
      ions were determined at different times during the course of the reaction. The
      activation energy is found to increase during the reaction when dominantly
      tetrahedral nanoparticles are used, decreases slightly when dominantly cubic
      nanoparticles are used, and remains almost unchanged when spherical nanoparticles
      are used. Corresponding changes in the shape of the tetrahedral and cubic, but
      not spherical, shape is observed. This is consistent with the changes in the
      activation energy that are observed. The shape distribution and activation energy
      of dominantly spherical nanoparticles is found to remain stable during the course
      of the reaction.

PMID- 15186155
TI  - Diluting abundant spins by isotope edited radio frequency field assisted
      diffusion.
AB  - A new solid-state NMR method is described for obtaining long-range distance
      constraints in nanocrystalline samples of 13C-, 15N-, and 2H-enriched protein.
      The method selects only those 13C or 15N nuclei close to 1Hs for dipolar
      recoupling. When used with extensive deuteration, the bath of abundant 13C spins
      is made to appear dilute. Contacts over 4.5 A are readily observed in human
      ubiquitin.

PMID- 15186156
TI  - Acetylcholinesterase: enhanced fluctuations and alternative routes to the active
      site in the complex with fasciculin-2.
AB  - A 15 ns molecular dynamics simulation is reported for the complex of mouse
      acetylcholinesterase (mAChE) and the protein neurotoxin fasciculin-2. As compared
      to a 15 ns simulation of apo-mAChE, the structural fluctuations of the enzyme are
      substantially increased in magnitude for the enzyme in the complex. Fluctuations
      of part of the long omega loop (residues 69-96) are particularly enhanced. This
      loop forms one wall of the active site, and the enhanced fluctuations lead to
      additional routes of access to the active site.

PMID- 15186157
TI  - A bifunctional poly(ethylene glycol) silane immobilized on metallic oxide-based
      nanoparticles for conjugation with cell targeting agents.
AB  - A trifluoroethylester-terminal poly(ethylene glycol) (PEG) silane was synthesized
      and self-assembled on iron oxide nanoparticles. The nanoparticle system thus
      prepared has the flexibility to conjugate with cell targeting agents via either
      carboxylic or amine terminal groups for a number of biomedical applications,
      including magnetic resonance imaging (MRI) and controlled drug delivery. The
      trifluoroethylester silane was synthesized by modifying a PEG diacid to form the
      corresponding bistrifluoroethylester (TFEE), followed by a reaction with 3
      aminopropyltriethoxysilane (APS). The APS coupled with PEG chains confers the
      stability of PEG self-assembled monolayers (SAMs) and increases the PEG packing
      density on nanoparticles by establishing hydrogen bonding between the carbonyl
      and amine groups present within the monolayer structure. The success of the
      synthesis of the PEG TEFE silane was confirmed with (1)H NMR and Fourier
      transform infrared spectroscopy (FTIR). The conjugating flexibility of the PEG
      TEFE was demonstrated with folic acid that had carboxylic acid groups and amine
      terminal groups, respectively, and was confirmed by FTIR. TEM analysis showed the
      well-dispersed nanoparticles before and after they were coated with PEG and folic
      acid.

PMID- 15186158
TI  - Aristolochene synthase: mechanistic analysis of active site residues by site
      directed mutagenesis.
AB  - Incubation of farnesyl diphosphate (1) with Penicillium roqueforti aristolochene
      synthase yielded (+)-aristolochene (4), accompanied by minor quantities of the
      proposed intermediate (S)-(-)germacrene A (2) and the side-product (-)-valencene
      (5) in a 94:4:2 ratio. By contrast, the closely related aristolochene synthase
      from Aspergillus terreus cyclized farnesyl diphosphate only to (+)-aristolochene
      (4). Site-directed mutagenesis of amino acid residues in two highly conserved
      Mg(2+)-binding domains led in most cases to reductions in both k(cat) and
      k(cat)/K(m) as well as increases in the proportion of (S)-(-)germacrene A (2),
      with the E252Q mutant of the P. roqueforti aristolochene synthase producing only
      (-)-2. The P. roqueforti D115N, N244L, and S248A/E252D mutants were inactive, as
      was the A. terreus mutant E227Q. The P. roqueforti mutant Y92F displayed a 100
      fold reduction in k(cat) that was offset by a 50-fold decrease in K(m), resulting
      in a relatively minor 2-fold decrease in catalytic efficiency, k(cat)/K(m). The
      finding that Y92F produced (+)-aristolochene (4) as 81% of the product,
      accompanied by 7% 5 and 12% 2, rules out Tyr-92 as the active site Lewis acid
      that is responsible for protonation of the germacrene A intermediate in the
      formation of aristolochene (4).

PMID- 15186159
TI  - Preparation and characterization of individual peptide-wrapped single-walled
      carbon nanotubes.
AB  - Two challenges for effectively exploiting the remarkable properties of single
      walled carbon nanotubes (SWNTs) are the isolation of intact individual nanotubes
      from the raw material and the assembly of these isolated SWNTs into useful
      structures. In this study, we present atomic force microscopy (AFM) evidence that
      we can isolate individual peptide-wrapped SWNTs, possibly connected end-to-end
      into long fibrillar structures, using an amphiphilic alpha-helical peptide,
      termed nano-1. Transmission electron microscopy (TEM) and well-resolved
      absorption spectral features further corroborate nano-1's ability to debundle
      SWNTs in aqueous solution. Peptide-assisted assembly of SWNT structures,
      specifically in the form of Y-, X-, and intraloop junctions, was observed in the
      AFM and TEM images.

PMID- 15186160
TI  - Investigation of the calcium-binding site of the oxygen evolving complex of
      photosystem II using 87Sr ESEEM spectroscopy.
AB  - The proximity of the calcium/strontium binding site of the oxygen evolving
      complex (OEC) of photosystem II (PSII) to the paramagnetic Mn cluster is explored
      with (87)Sr three-pulse electron spin-echo envelope modulation (ESEEM)
      spectroscopy. CW-EPR spectra of Sr(2+)-substituted Ca(2+)-depleted PSII membranes
      show the modified g = 2 multiline EPR signal as previously reported. We performed
      three-pulse ESEEM on this modified multiline signal of the Mn cluster using
      natural abundance Sr and (87)Sr, respectively. Three-pulse ESEEM of the natural
      abundance Sr sample exhibits no detectable modulation by the 7% abundance (87)Sr.
      On the other hand, that of the (87)Sr enriched (93%) sample clearly reveals
      modulation arising from the I = (9)/(2) (87)Sr nucleus weakly magnetically
      coupled to the Mn cluster. Using a simple point dipole approximation for the
      electron spin, analysis of the (87)Sr ESEEM modulation depth via an analytic
      expression suggests a Mn-Ca (Sr) distance of 4.5 A. Simulation of three-pulse
      ESEEM with a numerical matrix diagonalization procedure gave good agreement with
      this analytical result. A more appropriate tetranuclear magnetic/structural model
      for the Mn cluster converts the 4.5 A point dipole distance to a 3.8-5.0 A range
      of distances. DFT calculations of (43)Ca and (87)Sr quadrupolar interactions on
      Ca (and Sr substituted) binding sites in various proteins suggest that the lack
      of the nuclear quadrupole induced splitting in the ESEEM spectrum of (87)Sr
      enriched PSII samples is related to a very high degree of symmetry of the ligands
      surrounding the Sr(2+) ion in the substituted Ca site. Numerical simulations show
      that moderate (87)Sr quadrupolar couplings decrease the envelope modulation
      relative to the zero quadrupole case, and therefore we consider that the 3.8-5.0
      A range obtained without quadrupolar coupling included in the simulation
      represents an upper limit to the actual manganese-calcium distance. This (87)Sr
      pulsed EPR spectroscopy provides independent direct evidence that the
      calcium/strontium binding site is close to the Mn cluster in the OEC of PSII.

PMID- 15186161
TI  - Enhanced hairpin stability through loop design: the case of the protein G B1
      domain hairpin.
AB  - A mutational study of the peptide corresponding to the second hairpin of the
      protein G B1 domain (GB1p) provided a series of mutants with significantly
      increased fold stability. Mutations focused on improvement of the direction
      reversing loop and the addition of favorable Coulombic interactions at the
      sequence termini. The loop optimization was based on a database search for
      residues that occur with the greatest probability in similar hairpin loops in
      proteins. This search suggested replacing the native DDATKT sequence with NPATGK,
      which resulted in a 4.5 kJ/mol stabilization of the hairpin fold. The
      introduction of positively charged lysines at the N-terminus provided an
      additional 2.4 kJ/mol of stabilization, affording a GB1p mutant that is 86 +/- 3%
      folded at 25 degrees C with a melting temperature of 60 +/- 2 degrees C. The
      trpzip version of this peptide, in which three of the hydrophobic core residues
      were mutated to tryptophan, yielded a sequence that melted at 85 degrees C.
      Throughout, fold populations and melting temperatures were derived from the
      mutation and temperature dependence of proton chemical shifts and were
      corroborated by circular dichroism (CD) melts. The study also suggests that the
      wild-type GB1p sequence is significantly less stable than reported in some other
      studies: only 30% folded in water at 25 degrees C.

PMID- 15186163
TI  - Design, synthesis, and photophysical studies of a porphyrin-fullerene dyad with
      parachute topology; charge recombination in the marcus inverted region.
AB  - As part of a continuing investigation of the topological control of
      intramolecular electron transfer (ET) in donor-acceptor systems, a symmetrical
      parachute-shaped octaethylporphyrin-fullerene dyad has been synthesized. A
      symmetrical strap, attached to ortho positions of phenyl groups at opposing meso
      positions of the porphyrin, was linked to [60]-fullerene in the final step of the
      synthesis. The dyad structures were confirmed by (1)H, (13)C, and (3)He NMR, and
      MALDI-TOF mass spectra. The free-base and Zn-containing dyads were subjected to
      extensive spectroscopic, electrochemical and photophysical studies. UV-vis
      spectra of the dyads are superimposable on the sum of the spectra of appropriate
      model systems, indicating that there is no significant ground-state electronic
      interaction between the component chromophores. Molecular modeling studies reveal
      that the lowest energy conformation of the dyad is not the C(2)(v)() symmetrical
      structure, but rather one in which the porphyrin moves over to the side of the
      fullerene sphere, bringing the two pi-systems into close proximity, which
      enhances van der Waals attractive forces. To account for the NMR data, it is
      proposed that the dyad is conformationally mobile at room temperature, with the
      porphyrin swinging back and forth from one side of the fullerene to the other.
      The extensive fluorescence quenching in both the free base and Zn dyads is
      associated with an extremely rapid photoinduced electron-transfer process, k(ET)
      approximately 10(11) s(-)(1), generating porphyrin radical cations and C(60)
      radical anions, detected by transient absorption spectroscopy. Back electron
      transfer (BET) is slower than charge separation by up to 2 orders of magnitude in
      these systems. The BET rate is slower in nonpolar than in polar solvents,
      indicating that BET occurs in the Marcus inverted region, where the rate
      decreases as the thermodynamic driving force for BET increases. Transient
      absorption and singlet molecular oxygen sensitization data show that fullerene
      triplets are formed only with the free base dyad in toluene, where triplet
      formation from the charge-separated state is competitive with decay to the ground
      state. The photophysical properties of the P-C(60) dyads with parachute topology
      are very similar to those of structurally related rigid pi-stacked P-C(60) dyads,
      with the exception that there is no detectable charge-transfer absorption in the
      parachute systems, attributed to their conformational flexibility. It is
      concluded that charge separation in these hybrid systems occurs through space in
      unsymmetrical conformations, where the center-to-center distance between the
      component pi-systems is minimized. Analysis of the BET data using Marcus theory
      gives reorganization energies for these systems between 0.6 and 0.8 eV and
      electronic coupling matrix elements between 4.8 and 5.6 cm(-)(1).

PMID- 15186162
TI  - The selenocysteine-substituted blue copper center: spectroscopic investigations
      of Cys112SeCys Pseudomonas aeruginosa azurin.
AB  - Azurin is a small electron-transfer protein belonging to the cupredoxin family.
      The Cu atom is located within a trigonal plane coordinated by two histidines
      (His46 and His117) and a cysteine (Cys112) with two more distant ligands (Gly45
      and Met121) providing axial interactions. A Cys112SeCys derivative has been
      prepared by expressed protein ligation, and detailed UV/vis, EPR and EXAFS
      studies at the Cu and Se K-edges have been carried out. Marked changes are
      observed between the EPR parameters of the Cys112SeCys and WT azurin derivatives,
      which include a 2-fold increase in A(||), a decrease in g-values, and a large
      increase in rhombicity of the g-tensor. The Cu-Se and Se-Cu bond lengths obtained
      from analysis of the Cu and Se K-EXAFS of the oxidized protein were found to be
      2.30 and 2.31 A, respectively, 0.14 A longer than the Cu-S distance of the WT
      protein. Unexpectedly, the Cu-Se bond lengths were found to undergo only minor
      changes during reduction, suggesting a very similar structure in both redox
      states and extending the "rack" hypothesis to the Se-substituted protein.

PMID- 15186164
TI  - Reaction pathway and stereoselectivity of asymmetric synthesis of chrysanthemate
      with the aratani C1-symmetric salicylaldimine-copper catalyst.
AB  - The reaction pathway and the mechanism of asymmetric induction in the synthesis
      of (+)-trans-(1R,3R)-chrysanthemic acid methyl ester from methyl diazoacetate and
      2,5-dimethyl-2,4-hexadiene in the presence of a C(1)-chiral salicylaldimine Cu(I)
      complex has been probed with the aid of hybrid density functional calculations.
      The key finding is that the alkoxycarbonyl carbene complex intermediate is
      intrinsically chiral and that the intramolecular hydrogen bonding in the carbene
      complex transmits the chirality information from the side chain to the carbene
      complex. Molecular orbital backgrounds of the structure of the carbene complex
      and the transition state of the cyclopropanation have been elucidated.

PMID- 15186165
TI  - An empirical backbone-backbone hydrogen-bonding potential in proteins and its
      applications to NMR structure refinement and validation.
AB  - A new multidimensional potential is described that encodes for the relative
      spatial arrangement of the peptidyl backbone units as observed within a large
      database of high-resolution X-ray structures. The detailed description afforded
      by such an analysis provides an opportunity to study the atomic details of
      hydrogen bonding in proteins. The specification of the corresponding potential of
      mean force (PMF) is based on a defined set of physical principles and optimized
      to yield the maximum advantage when applied to protein structure refinement. The
      observed intricate differences between hydrogen-bonding geometries within various
      patterns of secondary structure allow application of the PMF to both validation
      of protein structures and their refinement. A pronounced improvement of several
      aspects of structural quality is observed following the application of such a
      potential to a variety of NMR-derived models, including a noticeable decrease in
      backbone coordinate root-mean-square deviation relative to the X-ray structures
      and a considerable improvement in the Ramachandran map statistics.

PMID- 15186166
TI  - A simple approach to sensor discovery and fabrication on self-assembled
      monolayers on glass.
AB  - Self-assembled monolayers (SAMs) on glass were used as a platform to sequentially
      deposit fluorophores and small molecules for ion sensing. The preorganization
      provided by the surface avoids the need for complex receptor design, allowing for
      a combinatorial approach to sensing systems based on small molecules. The
      resulting libraries are easily measured and show varied responses to a series of
      both cations and anions. This technology is transferable from the macro- to the
      microscale both via microcontact printing (microCP), where the fluorophore is
      printed onto a glass surface, and via direct attachment of the fluorophore to
      microchannel walls. The ease of miniaturization of this technology may make the
      generation of a wide variety of simple yet efficient microarrays possible.

PMID- 15186167
TI  - Synthesis, photophysics, electrochemistry, theoretical, and transient absorption
      studies of luminescent copper(I) and silver(I) diynyl complexes. X-ray crystal
      structures of [Cu3(micro-dppm)3(micro3-eta1-C triple bond CC triple bond
      CPh)2]PF6 and [Cu3(micro-dppm)3(micro3-eta1-C triple bond CC triple bond
      CH)2]PF6.
AB  - A series of soluble trinuclear copper(I) and silver(I) complexes containing
      bicapped diynyl ligands, [M(3)(micro-dppm)(3)(micro(3)-eta(1)-C triple bond CC
      triple bond CR)(2)]PF(6) (M = Cu, R = Ph, C(6)H(4)-CH(3)-p, C(6)H(4)-OCH(3)-p,
      (n)C(6)H(13), H; M = Ag, R = Ph, C(6)H(4)-OCH(3)-p), has been synthesized and
      their electronic, photophysical, and electrochemical properties studied. The X
      ray crystal structures of [Cu(3)(micro-dppm)(3)(micro(3)-eta(1)-C triple bond CC
      triple bond CPh)(2)]PF(6) and [Cu(3)(micro-dppm)(3)(micro(3)-eta(1)-C triple bond
      CC triple bond CH)(2)]PF(6) have been determined.

PMID- 15186168
TI  - Theoretical study of the relative stability of rotational conformers of alpha and
      beta-D-glucopyranose in gas phase and aqueous solution.
AB  - The alpha-beta anomer energy difference and the stability of 10 rotamers of
      counterclockwise D-glucopyranose were studied in vacuo and in aqueous solution at
      the B3LYP/6-31+G(d,p) level. To obtain the solute charge distribution and the
      solvent structure around it, we used the averaged solvent electrostatic potential
      from molecular dynamics method, ASEP/MD, which alternates molecular dynamics and
      quantum mechanics calculations in an iterative procedure. The main
      characteristics of the anomeric equilibrium, both in vacuo and in solution, are
      well reproduced. The relative stability of the different anomers is related to
      the availability of the free pairs of electrons in the anomeric oxygen to
      interact with the water molecules. The influence of solvation in the conformer
      equilibrium is also analyzed.

PMID- 15186169
TI  - Multiple-quantum relaxation dispersion NMR spectroscopy probing millisecond time
      scale dynamics in proteins: theory and application.
AB  - New relaxation dispersion experiments are presented that probe millisecond time
      scale dynamical processes in proteins. The experiments measure the relaxation of
      (1)H-(15)N multiple-quantum coherence as a function of the rate of application of
      either (1)H or (15)N refocusing pulses during a constant time relaxation
      interval. In contrast to the dispersion profiles generated from more conventional
      (15)N((1)H) single-quantum relaxation experiments that depend on changes in
      (15)N((1)H) chemical shifts between exchanging states, (1)H-(15)N multiple
      quantum dispersions are sensitive to changes in the chemical environments of both
      (1)H and (15)N spins. The resulting multiple-quantum relaxation dispersion
      profiles can, therefore, be quite different from those generated by single
      quantum experiments, so that an analysis of both single- and multiple-quantum
      profiles together provides a powerful approach for obtaining robust measures of
      exchange parameters. This is particularly the case in applications to protonated
      proteins where other methods for studying exchange involving amide proton spins
      are negatively influenced by contributions from neighboring protons. The
      methodology is demonstrated on protonated and perdeuterated samples of a G48M
      mutant of the Fyn SH3 domain that exchanges between folded and unfolded states in
      solution.

PMID- 15186170
TI  - Capture and release of proteins on the nanoscale by stimuli-responsive elastin
      like polypeptide "switches".
AB  - This article describes the fabrication and characterization of stimulus
      responsive elastin-like polypeptide (ELP) nanostructures grafted onto omega
      substituted thiolates that were patterned onto gold surfaces by dip-pen
      nanolithography (DPN). In response to external stimuli such as changes in
      temperature or ionic strength, ELPs undergo a switchable and reversible,
      hydrophilic-hydrophobic phase transition at a lower critical solution temperature
      (LCST). We exploited this phase transition behavior to reversibly immobilize a
      thioredoxin-ELP (Trx-ELP) fusion protein onto the ELP nanopattern above the LCST.
      Subsequent binding of an anti-thioredoxin monoclonal antibody (anti-Trx) to the
      surface-captured thioredoxin showed the presentation of the immobilized protein
      in a sterically accessible orientation in the nanoarray. We also showed that the
      resulting Trx-ELP/anti-Trx complex formed above the LCST could be reversibly
      dissociated below the LCST. These results demonstrate the intriguing potential of
      ELP nanostructures as generic, reversible, biomolecular switches for on-chip
      capture and release of a small number (order 100-200) of protein molecules in
      integrated, nanoscale bioanalytical devices. We also investigated the molecular
      mechanism underlying this switch by measuring the height changes that accompany
      the binding and desorption steps and by adhesion force spectroscopy using atomic
      force microscopy.

PMID- 15186171
TI  - Why is silver catalytically active for NO reduction? A unique pathway via an
      inverted (NO)2 dimer.
AB  - NO reduction on the noble metal Ag has been studied using density functional
      theory calculations. It was found that monomeric NO dissociation is subject to
      prohibitive barriers on Ag metal and is thus unlikely to account for the
      experimental observations for NO reduction over Ag-based catalysts. For the first
      time, a mechanism via an inverted (NO)(2) dimer is identified, which can explain
      both the high activity and the selectivity of this catalytic system. N(2)O is the
      major reduction product of the inverted (NO)(2) dimer, in accord with experiment.
      The physical origin of the Ag metallic state as a good catalyst is furthermore
      identified: Ag surfaces, including small clusters, have little or no covalent
      bonding ability but can bond ionically with adsorbates. We conclude that the
      variation of the ionic bonding strength of Ag toward different reactants
      determines its catalytic selectivity.

PMID- 15186172
TI  - One-electron oxidation of DNA: the effect of replacement of cytosine with 5
      methylcytosine on long-distance radical cation transport and reaction.
AB  - One-electron oxidation of duplex DNA generates a radical cation that migrates
      through the nucleobases until it is trapped by an irreversible reaction with
      water or oxygen. The trapping site is often a GG step, because this site has a
      relatively low ionization potential and this causes the radical cation to pause
      there momentarily. Modifications to guanine that lower its ionization potential
      convert it to a better trap for the radical cation. One such modification is the
      formation of the Watson-Crick base pair with cytosine, which is reported to very
      significantly decrease its ionization potential. Methylation of cytosine to form
      5-methylcytosine (5-MeC) is a naturally occurring reaction in genomic DNA that
      may be associated with regions of enhanced oxidative damage. The G.5-MeC base
      pair is reported to be more rapidly oxidized than normal G.C base pairs. We
      examined the oxidation of DNA oligomers that were substituted in part with 5-MeC.
      Irradiation of a covalently linked anthraquinone group injects a radical cation
      into the DNA and results in strand cleavage after piperidine treatment. For the
      sequences examined, substitution of 5-MeC for C has no measurable effect on the
      reactions. Cytosine methylation is not a general cause of enhanced oxidative
      damage in DNA.

PMID- 15186173
TI  - Dimer-of-dimers model for the oxygen-evolving complex of photosystem II.
      Synthesis and properties of [MnIV4O5(terpy)4(H2O)2](ClO4)6.
AB  - A dimer-of-dimers model compound for the oxygen-evolving complex of photosystem
      II, [[(H(2)O)(terpy)Mn(IV)(micro-O)(2)Mn(IV)(terpy)](2)(micro-O)](ClO(4))(6)
      (terpy = 2,2':6',2' '-terpyridine), has been prepared and characterized by X-ray
      crystallography and ESI-MS. Low pH was found to promote the disproportionation of
      [Mn(III/IV)(2)O(2)(terpy)(2)(OH(2))(2)](3+) to Mn(2+) and a
      Mn(IV/IV)(2)O(2)(terpy)(2) species; the latter complex slowly dimerizes to form
      the title complex. Protonation of a micro-oxo bridge is proposed to initiate the
      disproportionation, based on analogy with the [Mn(III/)(IV)(2)O(2)(bpy)(4)](3+)
      system.

PMID- 15186174
TI  - Reversible dimerization of [5,6]-C60O.
AB  - The recently discovered [5,6]-open isomer of C(60)O has been found to undergo
      facile dimerization to form a new C(2) symmetry isomer of C(120)O(2), which can
      be photodissociated with relatively high efficiency to regenerate monomeric [5,6]
      C(60)O. High yield dimerization of [5,6]-C(60)O proceeds spontaneously in toluene
      solution near room temperature. On the basis of (13)C NMR spectroscopy, ab initio
      quantum computations, and HPLC retention patterns, the resulting C(120)O(2)
      product has been deduced to be a nonpolar dimer of C(2) symmetry in which the
      C(60)O moieties are linked by two single bonds between sp(3)-hybridized carbon
      atoms adjacent to oxygen atoms. Photophysical properties of this dimer have also
      been measured and compared to those of C(120), the [2 + 2]-dimer of C(60). The
      ground-state absorption spectrum of C(120)O(2) in toluene is slightly red-shifted
      relative to that of C(120), with a distinctive peak at 329 nm and an S(1)-S(0)
      origin band at 704 nm. Its fluorescence spectrum shows two major peaks at 718 and
      793 nm. In room-temperature toluene, the measured triplet state intrinsic
      lifetime of this C(120)O(2) isomer is 34 +/- 2 micros, a value somewhat shorter
      than that of C(120) (44 micros). C(120)O(2) undergoes photodissociation from its
      triplet state to regenerate monomeric [5,6]-C(60)O with quantum yields of 2.5% at
      24 degrees C and 43% at 70 degrees C. It can therefore serve as a stable reactant
      for photolytic production of [5,6]-C(60)O. As a simple fullerene adduct that
      reacts under mild conditions, [5,6]-C(60)O may prove useful in special synthetic
      applications. Solutions of [5,6]-C(60)O are also unique because they can provide
      mixtures of a fullerene monomer and its dimer in a dynamic balance controllable
      by adjustment of concentration, temperature, and optical irradiation.

PMID- 15186175
TI  - Efficient methods for the preparation of alkyl-aryl and symmetrical or
      unsymmetrical dialkyl ethers between alcohols and phenols or two alcohols by
      oxidation-reduction condensation.
AB  - Oxidation-reduction condensation via alkoxydiphenylphosphines
      (diphenylphosphinite esters) (1), generated in situ from chlorodiphenylphosphine
      (2) and alcohols, 2,6-dimethyl-1,4-benzoquinone (3), and phenols proceeds
      smoothly to afford alkyl-aryl ethers in good to high yields under neutral
      conditions. In a similar fashion, a new and efficient method for the preparation
      of symmetrical or unsymmetrical dialkyl ethers in good to high yields is
      established via tetrafluoro-1,4-benzoquinone (fluoranil) (4), alcohols, and 1
      formed in situ from (n)BuLi-treated alcohols and 2. This method is applicable
      also to the etherification of chiral secondary or tertiary alcohols with
      retention or inversion of configurations. The inverted ethers are afforded by
      treating chiral alkoxydiphenylphosphines and achiral alcohols, while the reaction
      of achiral alkoxydiphenylphosphines and chiral alcohols forms retained ethers.

PMID- 15186176
TI  - Continuous chemoselective methylation of functionalized amines and diols with
      supercritical methanol over solid acid and acid-base bifunctional catalysts.
AB  - The selective N-methylation of bifunctionalized amines with supercritical
      methanol (scCH(3)OH) promoted by the conventional solid acids (H-mordenite, beta
      zeolite, amorphous silica-alumina) and acid-base bifunctional catalysts (Cs-P-Si
      mixed oxide and gamma-alumina) was investigated in a continuous-flow, fixed-bed
      reactor. The use of scCH(3)OH in the reaction of 2-aminoethanol with methanol
      (amine/CH(3)OH = 1/10.8) over the solid catalysts led to a significant
      improvement in the chemoselectivity of the N-methylation. Among the catalysts
      examined, the Cs-P-Si mixed oxide provided the most efficient catalyst
      performance in terms of selectivity and reactivity at 300 degrees C and 8.2 MPa;
      the N-methylation selectivity in the products reaching up to 94% at 86%
      conversion. The present selective methylation was successfully applied to the
      synthesis of N-methylated amino alcohols and diamines as well as O-methylated
      ethylene glycol. Noticeably, ethoxyethylamine was less reactive, suggesting that
      the hydroxy group of the amino alcohols is a crucial structural factor in
      determining high reactivity and selectivity, possibly because of the tethering
      effect of another terminus, a hydroxo group, to the catalyst surface. The magic
      angle-spinning NMR spectroscopy and X-ray diffraction analysis of the Cs-P-Si
      mixed oxide catalyst revealed that the acidic and basic sites originate from
      P(2)O(5)/SiO(2) and Cs/SiO(2), respectively, and the weak acid-base paired sites
      are attributed to three kinds of cesium phosphates on SiO(2). The weak acid-base
      sites on the catalyst surface might be responsible for the selective dehydrative
      methylation.

PMID- 15186177
TI  - Reactivity of the indole ring in palladium(II) complexes of 2N1O-donor ligands:
      cyclopalladation and pi-cation radical formation.
AB  - The Pd(II) complexes of new 2N1O-donor ligands containing a pendent indole, 3-[N
      2-pyridylmethyl-N-2-hydroxy-3,5-di(tert-butyl)benzylamino]ethylindole (Htbu
      iepp), 1-methyl-3-[N-2-pyridylmethyl-N-2-hydroxy-3,5-di(tert
      butyl)benzylamino]ethylindole (Htbu-miepp), 3-[N-2-pyridylmethyl-N-2-hydroxy-3,5
      di(tert-butyl)benzylamino]methylindole (Htbu-impp), and 3-(N-2-pyridylmethyl-N-4
      hydroxybenzylamino)ethylindole (Hp-iepp) (H denotes a dissociable proton), were
      synthesized, and the structures of [Pd(tbu-iepp)Cl] (1a), [Pd(tbu-iepp-c)Cl]
      (1b), [Pd(tbu-miepp)Cl] (3), and [Pd(p-iepp-c)Cl] (4) (tbu-iepp-c and p-iepp-c
      denote tbu-iepp and p-iepp bound to Pd(II) through a carbon atom, respectively)
      were determined by X-ray analysis. Complexes 1a prepared in CH(2)Cl(2)/CH(3)CN
      and 3 prepared in CH(3)CN have a pyridine nitrogen, an amine nitrogen, a
      phenolate oxygen, and a chloride ion in the coordination plane. Complex 1b
      prepared in CH(3)CN has the same composition as 1a and was revealed to have the
      C2 atom of the indole ring bound to Pd(II) with the Pd(II)-C2 distance of
      1.973(2) A. The same Pd(II)-indole C2 bonding was revealed for 4. Interconversion
      between 1a and 1b was observed for their solutions, the equilibrium being
      dependent on the solvent used. Reaction of 1b and 4 with 1 equiv of Ce(IV) in DMF
      gave the corresponding one-electron-oxidized species, which exhibited an ESR
      signal at g = 2.004 and an absorption peak at approximately 550 nm, indicating
      the formation of the Pd(II)-indole pi-cation radical species. The half-life,
      t(1/2), of the indole radical species at room temperature was calculated to be 20
      s (k(obs) = 3.5 x 10(-)(2) s(-)(1)) for 1b. The cyclic voltammogram for 1b in DMF
      gave two irreversible oxidation peaks at E(pa) = 0.68 and 0.80 V (vs Ag/AgCl),
      which were ascribed to the oxidation processes of the coordinated indole and
      phenolate moieties, respectively.

PMID- 15186178
TI  - A catalytic synthesis of thiosilanes and silthianes: palladium nanoparticle
      mediated cross-coupling of silanes with thio phenyl and thio vinyl ethers through
      selective carbon-sulfur bond activation.
AB  - Palladium nanoparticles generated in situ from N,N-dimethyl-acetamide (DMA)
      solutions of PdX(2) (X = Cl(-), OAc(-), OCOCF(3)(-)) or Pd(2)(dba)(3) by
      reduction with alkyl silanes R(3)SiH (R = Me, Et, i-Pr, t-Bu) are selective
      catalysts for the cross-coupling of the silanes R(3)SiH with phenyl and vinyl
      thioethers forming the corresponding thiosilanes and silthianes in high yields
      and under mild conditions. The method is applicable to phenyl thioglycosides,
      giving access to thiosilyl glycosides a new class of sugar derivatives.

PMID- 15186179
TI  - Observation of molecules adsorbed on III-V semiconductor quantum dots by surface
      enhanced Raman scattering.
AB  - I report for the first time surface-enhanced Raman scattering (SERS) from
      molecules adsorbed on InAs/GaAs quantum dots. This result is very interesting
      because previous SERS experiments have been essentially restricted to molecules
      adsorbed on metallic surfaces. Raman scattering from pyridine molecules adsorbed
      on these III-V quantum dots structures is strongly enhanced relative to the same
      molecules in solution. The most interesting feature in the SERS spectrum is the
      appearance of a new vibrational band. I suggest that this line should be
      attributed to the chemisorbed pyridine that is formed by coordination of its lone
      pair electrons of the N atom to the semiconductor surface. This work provides
      unambiguous experimental evidence for SERS on III-V semiconductor quantum dots.
      Nanostructures are currently considered as potential building blocks for
      nanodevices. The performance and reliability of these devices strongly depend on
      the surface and interfacial properties of the constituent nanomaterials.
      Therefore, this work illustrates the considerable potential of SERS spectroscopy
      as a powerful new tool in nanoscience.

PMID- 15186180
TI  - On the nature of the low-lying singlet states of 4-(Dimethyl-amino)benzonitrile.
AB  - 4-(N,N-Dimethyl-amino)benzonitrile (DMABN) is a prototype molecule for dual
      fluorescence. The anomalous emission has been attributed to an intramolecular
      charge-transfer (ICT) state, and the structure of the latter is still subject to
      some controversy. We applied a recently developed analytical gradient code for
      the approximate coupled-cluster singles-and-doubles method CC2 in combination
      with accurate basis sets to address this problem. Fully optimized excited state
      structures are presented for the ICT state and the so-called locally excited
      state, and recent transient IR and Raman measurements on the excited states are
      interpreted by means of calculated harmonic frequencies. Strong evidence is found
      for an electronic decoupling of the phenyl and the dimethyl-amino moiety,
      resulting in a minimum structure for the ICT state with a twisted geometry. In
      contrast to previous findings, the structure of this state is, at least in the
      gas phase, not C(2v) symmetric but distorted towards C(s) symmetry. The
      distortion coordinate is a pyramidalization of the phenyl carbon atom carrying
      the dimethyl-amino group. The results from the CC2 model are supported by single
      point calculations using more elaborate coupled-cluster models (CCSD, CCSDR(3))
      and by CASSCF calculations.

PMID- 15186181
TI  - Reactions and kinetics of unsaturated C2 hydrocarbon radicals.

PMID- 15186182
TI  - Probes of structural and electronic environments of phosphor activators:
      Mossbauer and Raman spectroscopy.

PMID- 15186183
TI  - Naturally occurring cyclohexane epoxides: sources, biological activities, and
      synthesis.

PMID- 15186184
TI  - Bolaamphiphiles.

PMID- 15186185
TI  - Claisen rearrangement over the past nine decades.

PMID- 15186186
TI  - Electrochemiluminescence (ECL).

PMID- 15186187
TI  - Oxidation of alcohols with molecular oxygen on solid catalysts.

PMID- 15186188
TI  - Coumarins in polymers: from light harvesting to photo-cross-linkable tissue
      scaffolds.

PMID- 15186189
TI  - Transition-metal-catalyzed addition of heteroatom-hydrogen bonds to alkynes.

PMID- 15186190
TI  - Allosteric supramolecular receptors and catalysts.

PMID- 15186191
TI  - Ligands derived from carbohydrates for asymmetric catalysis.

PMID- 15186192
TI  - Quantifying actinic keratosis: assessing the evidence.
AB  - Actinic keratoses are pre-malignant lesions, and it is standard practice to
      destroy them. Optimal management of actinic keratoses requires data on the
      efficacy of the numerous techniques employed in their treatment. Evaluating
      treatment efficacy requires before and after treatment quantification of actinic
      keratoses. Studies on the therapy and natural history of actinic keratoses have
      quantified these lesions by counting them. Counting actinic keratoses is
      unreliable because this technique lacks interobserver reproducibility.
      Consequently, studies based on counting actinic keratoses are fatally flawed and
      their conclusions of doubtful accuracy. Counting actinic keratoses should be
      abandoned as a technique for evaluating the therapy of actinic keratoses and the
      issue of spontaneous regression of actinic keratoses. A technique for reliably
      quantifying actinic keratoses is sorely needed.

PMID- 15186194
TI  - Efficacy and safety of intravenous immunoglobulin for immune-mediated skin
      disease: current view.
AB  - Intravenous immunoglobulins (IVIgs) exert a variety of immunomodulating
      activities and are, therefore, increasingly being used for the treatment of
      immune-mediated as well as autoimmune diseases. There is also accumulating
      evidence that high-dose IVIg (hdIVIg) is highly efficacious in the treatment of
      skin diseases, despite the lack of evidence from randomized, double-blind,
      placebo-controlled trials. A major advantage of hdIVIg in comparison with other
      commonly used immunomodulating therapeutic strategies is the excellent safety
      profile. Accordingly, IVIgs have been used successfully for the treatment of
      bullous autoimmune diseases such as pemphigus and bullous pemphigoid,
      dermatomyositis, scleroderma, cutaneous lupus erythematosus, toxic epidermal
      necrolysis, and erythema exudativum multiforme. In most cases, hdIVIg is
      effective only in combination with other immunomodulating strategies and allows
      for the reduction of adjuvants. Adverse effects of hdIVIg are generally mild and
      self-limiting. These include headache, myalgia, flush, fever, nausea or vomiting,
      chills, lower backache, changes in blood pressure, and tachycardia. To avoid
      infusion-related rigors, headaches, and other adverse events, pre-treatment with
      analgesics, NSAIDs, antihistamines, or low-dose intravenous corticosteroids may
      be beneficial. Controlled, double-blind, long-term clinical trials and a better
      understanding of the complex immunomodulating mechanism of IVIg are required to
      ultimately optimize dose, frequency, duration, and mode of IVIg administration.

PMID- 15186193
TI  - Assessing treatment outcomes in toenail onychomycosis clinical trials.
AB  - Several oral and topical medications are available for the treatment of
      onychomycosis, a widespread fungal infection of the nail. Since efficacy criteria
      vary greatly among clinical trials for onychomycosis treatment, it is difficult
      for physicians to compare outcomes and determine the appropriate therapy for a
      given patient. The present analysis evaluates the efficacy criteria used in
      intention-to-treat clinical trials of itraconazole, terbinafine, and 8%
      ciclopirox nail lacquer, drugs approved by the US FDA for the treatment of
      onychomycosis. Efficacy parameters often appear to use subjective assessment
      tools and may not include the actual size measurement of the affected target nail
      as an efficacy variable. Parameters, which assess both mycologic and clinical
      cure, are frequently omitted from clinical trials. Not surprisingly, clinical
      trials with stringent efficacy criteria, which assess both mycologic and clinical
      response/cure without use of subjective methods, appear to have the lowest rates
      for both therapeutic response and complete cure. Thus, an evaluation of treatment
      options for onychomycosis cannot solely compare success/failure rates in clinical
      trials, but requires a critical appraisal of the efficacy criteria utilized in
      those trials.

PMID- 15186195
TI  - Optimal management of recalcitrant disorders of hyperpigmentation in dark-skinned
      patients.
AB  - Alterations in skin pigmentation may often have a dramatic expression in
      individuals with a dark skin complexion and can be a source of significant
      emotional distress in these individuals. Hyperpigmented disorders such as
      melanosis (melasma), post-inflammatory hyperpigmentation, drug-induced
      hyperpigmentation, and erythema dyschromicum perstans tend to have a prolonged
      course and, in many cases, are refractory to treatment, further contributing to
      the psychological impairment of the affected patients. Melanosis, is a common
      form of facial pigmentation attributable to sunlight and hormonal factors. A
      range of treatment modalities, such as depigmenting agents, topical retinoids,
      and chemical peels in conjunction with rigorous sun protection, can improve the
      melanosis but the condition usually recurs. Combination regimens, including
      frequent applications of superficial- and medium-depth chemical peels, appear to
      be particularly effective and well tolerated in dark-skinned patients with
      melanosis. Post-inflammatory hyperpigmentation is the result of excess pigment
      deposition following an inflammatory skin disorder. Topical tretinoin,
      hydroquinone, azelaic acid, kojic acid, and glycolic acid peels have been
      employed with variable degrees of success. Drug-induced pigmentation is a
      frequent cause of acquired hypermelanosis, its clinical expression depending on
      the triggering molecule and the underlying pathogenetic mechanism. Identifying
      and discontinuing the offending agent is the main approach in this condition,
      although, recent reports have demonstrated the efficacy of Q-switched lasers in
      accelerating the pigment removal. Erythema dischromicum perstans is a
      characteristic dermal pigmentation occurring mainly in dark-skinned individuals.
      Immunomodulating agents, such as clofazimine and dapsone have been shown to
      lighten this disorder, although, the exact mode of action is not clear.

PMID- 15186196
TI  - Managing head lice in an era of increasing resistance to insecticides.
AB  - Head lice are present in all age groups, however, the peak age for infestation is
      7-8 years and the incidence varies throughout the year with higher incidence
      during the winter. Different insecticides have been used over the past 60 years
      to manage this condition. There is now strong evidence of insecticide resistance
      established in many countries to such an extent that some of these chemicals have
      become obsolete. Resistance to some pediculicides can vary from country to
      country and region to region within a country. The lack of a local monitoring
      system of resistance patterns means that parents and pupils are hampered in
      making an informed decision regarding how to treat head lice. One should no
      longer assume that treatment failure is due to poor treatment compliance or re
      infestation. Clear treatment guidelines drawn up by healthcare professionals with
      an interest in head lice and taking into account regional/national resistance
      patterns should be implemented. These guidelines should combine chemical and non
      chemical approaches to treatment and be coordinated and regularly reviewed by
      local public health departments. Drug companies should be made to provide up-to
      date efficacy of their products.

PMID- 15186197
TI  - Chemical peels: their place within the range of resurfacing techniques.
AB  - The photoaging index has been developed to determine the level of skin
      rejuvenation required to reduce the visible signs of aging. Minor photoaging is
      reversed with free-radical avoidance and peeling with a topical skin care regimen
      consisting of buffing grains, alpha-hydroxy acid normalizing tonics and vitamin A
      conditioning lotions. The reversal of moderate photoaging requires the addition
      of light-to-moderate peels using alpha-hydroxy acids combined with
      microdermabrasion. For the more advanced case the Jessner/trichloroacetic acid
      (TCA) combination peel (Monheit peel) is used which can be repeated once to twice
      a year. Laser resurfacing is especially useful to shrink the collagen and produce
      a 'face-lift bypass'. The phenol peel remains the standard to reverse heavy
      lines. A new modified formula (Hetter) is used which contains less phenol and
      less croton oil. Dermabrasion is helpful for removing multiple actinic keratosis.
      With this combination of skin care, chemical peels, and dermabrasion it is
      possible to reverse the photoaging index.

PMID- 15186198
TI  - Eosinophilic pustular folliculitis: a comprehensive review of treatment options.
AB  - Eosinophilic pustular folliculitis (EPF), also known as Ofuji disease, is a
      disease that manifests with follicular papules or pustules. Its variants include
      a classic type that occurs most commonly in Japan, an HIV-associated type, an
      infantile type, a type that occurs on the palms and soles, a rare medication
      associated variant, and a rare neoplasia-associated variant.A wide range of
      medications has been used to treat EPF. Topical corticosteroids are the first
      line treatment option for EPF. Topical tacrolimus seems to be useful initial
      therapy as well. Oral indometacin (50-75 mg/day) is an effective treatment of
      classic EPF although it can induce peptic ulcers. For treatment of HIV-associated
      EPF when topical corticosteroids and indometacin do not work, various other
      treatments should be considered. These treatment options include cetirizine 20-40
      mg/day, metronidazole 250 mg three times a day, itraconazole starting at a dosage
      of 200 mg/day and increasing to 300-400 mg/day, and topical permethrin. If these
      treatments do not work phototherapy with UVB is the 'gold standard' of treatment
      and is often curative. Treatments with less certain risk-benefit ratios but with
      some efficacy include PUVA (psoralen + UVA) photochemotherapy, oral
      corticosteroids, synthetic retinoids (i.e. isotretinoin 1 mg/kg/day), and
      acitretin (0.5 mg/kg/day), oral cyclosporine (ciclosporine) 5 mg/kg/day,
      interferon (IFN)-alpha-2b, and IFNgamma. Minocycline 100mg twice daily and
      dapsone 50-100mg twice daily have been used with some effect. The use of highly
      active antiretroviral therapy for HIV has resulted in the amelioration of EPF as
      CD4 cell counts rise above 250/mm(3). The diversity of clinical presentations and
      affected populations make it seem that EPF is a reaction pattern as much as a
      disease and that therapy should be tailored to the variant of EPF and the
      underlying etiology.

PMID- 15186199
TI  - Acanthosis nigricans associated with insulin resistance : pathophysiology and
      management.
AB  - The association of acanthosis nigricans, skin tags, diabetes mellitus due to
      insulin resistance, and obesity in adolescents and young adults represents a well
      defined syndrome. Hyperandrogenism may also be present. The endocrine origin of
      this condition is beyond doubt. Insulin and insulin-like growth factor-1, and
      their receptors on keratinocytes are obviously involved in the complex
      regulations leading to the peculiar epidermal hyperplasia. This condition is
      unrelated to other types of acanthosis nigricans, including the congenital and
      the paraneoplastic types. Control of obesity contributes largely to reverse the
      whole process, essentially by reducing both insulin resistance and compensatory
      hyperinsulinemia. Several drugs including metformin, octreotide, retinoids and
      topical colecalciferol (vitamin D(3)) analogs are also beneficial in clearing
      acanthosis nigricans.

PMID- 15186200
TI  - Videodermatoscopy enhances diagnostic capability in some forms of hair loss.
AB  - BACKGROUND: Videodermatoscopy is a non-invasive technique that allows in vivo
      skin observation at high magnifications. OBJECTIVE: The goal of this study was to
      determine if videodermatoscopy enhances diagnostic capability beyond standard
      clinical observation in three series of patients: one group of patients with
      overt alopecia areata (AA), one with overt androgenetic alopecia (AGA), and one
      with hair loss with no apparent diagnostic features. METHODS: The first group
      consisted of 200 patients affected by acute (140 patients) and chronic (60
      patients) AA, and the second group of 100 patients affected by AGA. In both
      groups, the clinical diagnosis was confirmed by pull tests and trichograms. The
      third group consisted of 50 patients with clinically undifferentiated hair loss.
      In all groups, videodermatoscopy was performed at magnifications ranging from 20x
      to 600x. RESULTS: In acute AA (n = 140), three videodermatoscopy patterns were
      identified, characterized by: (i). 'exclamation point' and/or 'cadaveric' hairs
      (n = 62); (ii). 'vellus' hairs, in some cases with increased proximal shaft
      thickness and pigmentation (n = 38); and (iii). coexistence of all the features
      from (i). and (ii). [n = 40]. In chronic AA (n = 60), in those cases who were
      recently converted to chronic form from acute AA (n = 35), videodermatoscopy
      showed a scalp skin that appeared smooth and thin, with evident follicular
      openings. In cases of long-standing chronic AA (n = 25), hair follicle openings
      appeared to be obstructed by keratotic plugs. However, whether the two follicular
      patterns were related to disease duration or to some unknown factors is unclear.
      In some patients with chronic AA, videodermatoscopy also revealed hair regrowth,
      which appeared either as homogeneous, indicating early disease remission (upright
      'vellus' hairs), or as sparse, thin, and twisted vellus hairs that were usually
      lost in a few weeks time. In AGA patients, videodermatoscopy observation allowed
      an accurate assessment of the ratios of miniaturized to normal hairs, a finding
      that was interpreted as a prognostic feature. Interestingly, videodermatoscopy
      clearly demonstrated the hair abnormalities corresponding to both diseases in
      those patients with concomitant causes of hair loss, as we observed in five
      patients simultaneously affected by AA and AGA. In the third group,
      videodermatoscopy allowed identification of early or minimal forms of AA (n =
      20), AGA with mild hair loss of the centro-parietal area of the scalp (n = 20),
      and scarring alopecia (n = 10). CONCLUSION: The results indicate that
      videodermatoscopy represents a very useful tool in the evaluation of hair loss,
      both for differential diagnosis (especially in early, transitional and mild
      forms) and for prognostic evaluation. It allows rapid, detailed, and non-invasive
      observation of the scalp skin and hair, and it provides high-resolution quality
      imaging.

PMID- 15186201
TI  - Penile involvement with hand-foot syndrome.
AB  - Hand-foot syndrome, or palmar plantar erythrodysesthesia, is a chemotherapy
      induced cutaneous reaction typically characterized by painful erythema of the
      palms and soles followed by desquamation and exfoliation in those areas. This
      report represents the first case of hand-foot syndrome associated with penile
      erythema, pain, and desquamation in addition to the classic hand and sole
      findings.

PMID- 15186202
TI  - Will wavefront aberrometry become a part of routine optometric practice?

PMID- 15186203
TI  - Australasian rivalry.

PMID- 15186204
TI  - Recent advances in representation of monochromatic aberrations of human eyes.
AB  - The field of aberrations of the human eye is moving rapidly, being driven by the
      desire to monitor and optimise vision following refractive surgery. In this
      paper, I discuss the different ways of representing aberrations of the human eye,
      the terminology used, how wave aberrations are used to determine refractions, the
      influence of pupil size on aberrations, how to compare right and left eye
      aberrations, how aberrations can be manipulated into different forms, how to make
      corrections for changes in wavelength, the appropriate ocular axis, and corneal
      and lenticular components of the aberrations.

PMID- 15186205
TI  - Rehabilitation in Charles Bonnet syndrome: a review of treatment options.
AB  - People with vision loss sometimes experience visual hallucinations associated
      with Charles Bonnet syndrome. The appearance of these hallucinations often causes
      anxiety for the sufferer and can be difficult for the attending eye care
      professional to manage. A review of the literature highlighted a range of visual,
      pharmacological and social management regimes that may alleviate these
      hallucinations, albeit using small samples in uncontrolled trials. Eye care
      practitioners should be aware of methods of rehabilitation in Charles Bonnet
      syndrome that may lead to resolution of the visual hallucinations.

PMID- 15186206
TI  - Contradictory influence of context on predominance during binocular rivalry.
AB  - BACKGROUND: Binocular rivalry is a complex process characterised by alternations
      in perceptual suppression and dominance that result when two different images are
      presented simultaneously to the left and right eyes. It has been reported
      recently that the addition of contextual cues will promote the predominance of
      the context consistent rivalry target. In contrast to Levelt's second proposition
      (1965), this effect has been found to result exclusively from an increase in the
      dominance phase duration, while the suppression phase duration remains
      unaffected. METHODS: Human subjects were simultaneously presented with a small (2
      degrees ) disc consisting of gratings (four cycles per degree) of different
      orientations to the two eyes. Four experiments were conducted to ascertain the
      effects of background gratings and contextual colour information on target
      predominance and phase duration. For each of the four experimental conditions,
      the orientation and colour of the target gratings and surrounding contextual
      background were systematically manipulated. RESULTS: In this study, we report an
      effect opposite to that of Levelt. Contradictory contextual information increases
      target predominance and phase duration during binocular rivalry. Our results
      demonstrate that it is possible to promote the dominance of the context
      contradictory percept with co-linearity, co-chromaticity and orientation cues. In
      line with previous studies involving context, we find that this effect on
      predominance is due to an increase in the duration of the dominance rather than
      the suppression phase. DISCUSSION: We discuss our findings in respect to those
      from previous studies and consider high- and low-level processes that may be
      responsible for these apparently 'contradictory' roles of context on binocular
      rivalry. In addition, we discuss how the apparent 'anti-Levelt' effect of context
      can be reinterpreted in a manner that brings it back in line with Levelt's second
      proposition and raises the question of whether 'suppressability' plays a
      disproportionately large role in determining the duration of perceptual phases in
      binocular rivalry.

PMID- 15186207
TI  - Clinical application of the multifocal visual evoked potential.
AB  - BACKGROUND: Measures of visual function thresholds such as visual acuity and
      visual fields are generally dependent on subjective responses and assume
      maintenance of fixation, attention and motivation. In the young, elderly,
      cognitively impaired or malingering populations, such measures may be inaccurate
      or difficult to obtain. The Visual Evoked Response Imaging System (VERIS) has
      been claimed to give more objective topographic recordings of retinal and
      cortical function. This paper aims to explore the adequacy of this technique in
      four unusual, unrelated, clinically difficult cases. METHODS: Multifocal visual
      evoked potentials (mfVEPs) recorded on the VERIS System 3.01 are used to assess
      visual function in four cases with contradictory clinical findings or unreliable
      subjective responses. RESULTS: Patient 1 had sustained a head injury and had
      normal ocular and pupil examination but light perception in the right eye and 6/5
      acuity in the left. Multifocal VEPs showed a marked depression of the right
      visual field with little macular response. Patient 2 had sustained a head injury,
      had a left field hemianopia, possible macular sparing and loss of much of the
      right field, reduced but variable visual acuities, good near vision and normal
      ocular fundi. Multifocal VEPs showed a severe depression in both visual fields (L
      more than R) with little macular response. Patient 3 had a left optic nerve
      meningioma and experienced great difficulty with visual field assessment. mfVEPs
      showed a bilateral depression in the superior field particularly the left field,
      with a larger deficit in the left eye. Patient 4 had unexplained visual acuity
      and peripheral field deficits. mfVEP results were inconclusive in this case.
      DISCUSSION: Where there is difficulty performing traditional techniques or
      conflicting clinical findings, mfVEPs may provide additional objective
      information to aid in the assessment of patients.

PMID- 15186208
TI  - Effects of vitamin E and pinoline on retinal lipid peroxidation.
AB  - BACKGROUND: Pinoline is a pineal indoleamine naturally found in the retina. This
      study compared the effects of pinoline and vitamin E on the copper (I)-induced
      retinal lipid peroxidation (LPO). METHODS: Porcine retinal homogenates were mixed
      with 120 micro M copper (I) solution. The mixtures were co-incubated with various
      concentrations of pinoline or trolox (water-soluble vitamin E analogue) at 37
      degrees Centigrade for 60 minutes. The amounts of malondialdehyde (MDA) and
      protein were assayed to quantify the LPO. RESULTS: Copper (I) ions significantly
      increased the MDA concentration in the retinal homogenates (p < 0.0007). Both
      pinoline and trolox significantly suppressed MDA in a dose-dependent manner (p <
      0.0001) and their effects were significantly different (p = 0.004). The
      concentrations that inhibited 50 per cent of LPO were 0.24 mM and 0.68 mM for
      pinoline and trolox, respectively. DISCUSSION: Pinoline suppressed the LPO at a
      potency of 2.8 times compared with trolox. The results support an anti-oxidative
      role for pinoline in the retina. Further study is required to characterise the
      pharmacological potency of pinoline in vivo.

PMID- 15186209
TI  - Spectacle use and reduced unaided vision in third grade students: a comparative
      study in different educational settings.
AB  - BACKGROUND: The development of myopia is influenced by hereditary factors,
      environmental factors and gene-environment interaction. Reading and near-work
      activity are associated with myopia and myopic progression. This study sought to
      determine and compare the prevalence of reduced unaided vision and spectacle use
      among third grade Israeli students from three different educational settings.
      METHOD: A sample of 917 students (mean age 8.5 years, range seven to 10 years)
      was drawn from the three Israeli educational streams: secular, Orthodox and ultra
      Orthodox. Children in the ultra-Orthodox education pathway begin studying at the
      age of three years and their daily reading involves sustained near work with
      increased accommodative effort accompanied by head-rocking movements. Reduced
      distance vision was used to indicate the likely development of or an increase in
      the amount of myopia. Spectacle lenses were measured to determine the prevalence
      of myopia. RESULTS: Of the 917 students studied, 103 (11.2 per cent) wore
      spectacles (14.2 per cent of the males and eight per cent of the females); 82.5
      per cent of those who wore spectacles were myopic. Males from ultra-Orthodox
      schools had the highest rate of reduced unaided vision (72.5 per cent) compared
      with males from secular schools (27.3 per cent), males from Orthodox schools
      (59.3 per cent) or with females from all three groups (average of 34.8 per cent,
      p < 0.0001, chi squared). Males had a higher rate of reduced unaided vision,
      especially in the Orthodox and ultra-Orthodox schools. CONCLUSIONS: Our study
      suggests that Jewish ultra-Orthodox males have a higher prevalence and degree of
      myopia. The study habits of young children, including exposure to prolonged near
      tasks, high accommodative demands and possibly optical defocus induced by body
      sway, may contribute to the development of myopia.

PMID- 15186210
TI  - Pellucid marginal degeneration and scleroderma.
AB  - Systemic scleroderma is a progressive multi-system connective tissue disease.
      Ocular involvement includes keratoconjunctivitis sicca, progressive shallowing of
      conjunctival fornices, peripheral ulcerative keratitis and eyelid tightness. No
      association has been reported between scleroderma and pellucid marginal
      degeneration, which is a rare bilateral corneal ectasia. Pellucid marginal
      degeneration is characterised by non-inflammatory and progressive peripheral
      corneal thinning inferiorly, often with high against-the-rule astigmatism. We
      report a case of a 55-year-old woman with systemic scleroderma who presented with
      rapidly progressing against-the-rule astigmatism. The differential diagnosis of
      peripheral corneal thinning and the challenge of the surgical management of
      pellucid marginal degeneration are briefly discussed.

PMID- 15186211
TI  - Effects of corneal thickness on IOP measurement.

PMID- 15186212
TI  - Donald Herbert Schultz.

PMID- 15186213
TI  - Complementary medicine.

PMID- 15186215
TI  - Plasma from women with severe pre-eclampsia increases microvascular permeability
      in an animal model in vivo.
AB  - Pre-eclampsia results in oedema, hypertension and proteinuria, and is associated
      with increased vascular permeability. A number of studies have pointed to the
      existence of a circulating macromolecule that induces this endothelial
      dysfunction. To test whether this circulating factor could increase vascular
      permeability, we have measured the effect of dialysed human plasma from pregnant
      women with mild or severe pre-eclampsia (pre-eclamptic toxaemia). Plasma was
      collected from patients with mild or severe pre-eclampsia and from normotensive
      women. Plasma was dialysed against frog Ringer's solution using a 12-14 kDa
      molecular-mass cut-off dialysis tubing. pi c (colloid osmotic pressure) was
      measured with a modified Hansen oncometer. Lp (hydraulic conductivity) and sigma
      (oncotic reflection coefficient) were measured in individually perfused frog
      mesenteric microvessels using the Landis-Michel technique during perfusion with
      dialysed plasma. Perfusion of vessels with normal plasma or plasma from patients
      with mild pre-eclampsia did not alter either Lp or sigma. However, plasma from
      patients with severe pre-eclampsia resulted in a 3.8+/-0.3-fold increase in Lp
      and a reduction in sigma from 0.96+/-0.03 to 0.80+/-0.11. There was a significant
      correlation between the change in sigma and the change in Lp, suggesting that the
      increase in permeability was due to an increase in pore size in these vessels. A
      circulating macromolecule in human plasma in severe pre-eclampsia is therefore
      able to increase vascular permeability in an animal model. The nature of the
      circulating macromolecule is not known, except that it is, or is bound to, a
      molecule greater than 12 kDa.

PMID- 15186218
TI  - Melanoma epidemic: true or false?
AB  - Melanoma incidence has increased dramatically over the last decades in most
      industrial countries, mainly as a result of the large numbers of early melanomas
      being diagnosed. Simultaneously, a lack of commensurate change in mortality has
      been reported, raising the possibility that skin melanoma may have modified its
      aggressiveness as a result of the increased diagnosis of biologically benign
      lesions. The main data and controversies arising from the melanoma epidemic are
      reviewed.

PMID- 15186219
TI  - Immunohistochemical study of serotonin in lesions of psoriasis.
AB  - OBJECTIVE: To study the role of serotonin in the pathogenesis of psoriasis.
      METHODS: Immunohistochemical techniques were used to study the expression of
      serotonin in the lesions of patients with psoriasis. RESULTS: Expression of
      serotonin was significantly stronger in the prickle cells, sweat gland cells,
      sebaceous gland cells, and hair roots of the lesions in the progressive stage of
      psoriasis than in the static stage. There was no difference in serotonin
      expression between the vulgaris type and the pustular type. No expression of
      serotonin occurred in the specimens of normal skin. CONCLUSION: Serotonin
      probably plays an important role in the pathogenesis and activity of psoriasis.

PMID- 15186216
TI  - Cortactin signalling and dynamic actin networks.
AB  - Cortactin was first identified over a decade ago, and its initial
      characterization as both an F-actin binding protein and v-Src substrate suggested
      that it was likely to be a key regulator of actin rearrangements in response to
      tyrosine kinase signalling. The recent discovery that cortactin binds and
      activates the actin related protein (Arp)2/3 complex, and thus regulates the
      formation of branched actin networks, together with the identification of
      multiple protein targets of the cortactin SH3 domain, have revealed diverse
      cellular roles for this protein. This article reviews current knowledge regarding
      the role of cortactin in signalling to the actin cytoskeleton in the context of
      these developments.

PMID- 15186217
TI  - The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell
      cytotoxicity.
AB  - Hallmarks of the inflammatory process in Type I diabetes are macrophage
      activation, local release of beta-cell-toxic cytokines and infiltration of
      cytotoxic T lymphocytes. We have observed recently that mice overexpressing
      active FRK (fyn-related kinase)/RAK (previously named GTK/Bsk/IYK, where GTK
      stands for gut tyrosine kinase, Bsk for beta-cell Src-homology kinase and IYK for
      intestinal tyrosine kinase) in beta-cells exhibit increased susceptibility to
      beta-cell-toxic events, and therefore, we now attempt to find a more precise role
      for FRK/RAK in these processes. Phosphopeptide mapping of baculovirus-produced
      mouse FRK/RAK revealed an autophosphorylation pattern compatible with Tyr-394
      being the main site. No evidence for in vitro phosphorylation of the C-terminal
      regulatory sites Tyr-497 and Tyr-504 was obtained, nor was there any indication
      of in vitro regulation of FRK/RAK kinase activity. Screening a panel of known
      tyrosine kinase inhibitors for their ability to inhibit FRK/RAK revealed several
      compounds that inhibited FRK/RAK, with a potency similar to that reported for
      their ability to inhibit other tyrosine kinases. Cytokine-induced islet toxicity
      was reduced in islets isolated from FRK/RAK knockout mice and this occurred
      without effects on the production of nitric oxide. Addition of the nitric oxide
      inhibitor nitroarginine to FRK/RAK knockout islets exposed to cytokines decreased
      cell death to a basal level. In normal islets, cytokine-induced cell death was
      inhibited by the addition of two FRK/RAK inhibitors, SU4984 and D-65495, or by
      transfection with short interfering RNA against FRK/RAK. It is concluded that
      FRK/RAK contributes to cytokine-induced beta-cell death, and inhibition of this
      kinase could provide means to suppress beta-cell destruction in Type I diabetes.

PMID- 15186220
TI  - Methicillin-resistant Staphylococcus aureus in community-acquired pyoderma.
AB  - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is an important
      nosocomial pathogen. It can also cause community-acquired infections. Indian
      reports about MRSA in community-acquired infections are rare. AIM: To evaluate
      the rate of MRSA in community-acquired pyoderma and the nasal colonisation with
      S. aureus in such patients. METHODS: Two hundred and fifty patients with
      community-acquired pyoderma, who attended outreach camps around Mangalore, south
      India between January 2000 and July 2001, were studied. Swabs collected from the
      skin lesions and anterior nares were inoculated onto blood agar and MacConkey's
      agar. Antimicrobial sensitivity testing was performed using Kirby-Bauer disk
      diffusion, agar dilution, and agar screen. RESULTS: Of 250 pyoderma cases, S.
      aureus was isolated from 202 (80.8%) patients. Twenty-two (10.9%) S. aureus
      isolates were methicillin resistant, 179 (88.6%) were resistant to penicillin,
      and 114 (56.4%) were resistant to erythromycin. S. aureus colonization in the
      anterior nares was observed in 136 (54.4%) cases, 11.8% of which were MRSA.
      Antibiograms of clinical isolates of S. aureus matched with nasal isolates in 99
      (49%) cases. CONCLUSION: The emergence of MRSA in the community is a warning. A
      high nasal carriage rate may contribute to recurrent pyoderma. A correct
      antimicrobial policy and the avoidance of inappropriate antimicrobial usage are
      mandatory to reduce the spread of MRSA in the community.

PMID- 15186222
TI  - The study of the participation of basement membrane zone antibodies in the
      formation of the lupus band in systemic lupus erythematosus.
AB  - BACKGROUND: The lupus band test (LBT) is an important auxiliary method in the
      diagnosis of systemic lupus erythematosus (SLE), but the mechanism of its
      formation is still unknown. There are many kinds of autoantibodies, such as
      basement membrane zone autoantibodies (BMZ-Abs), in patients with SLE. AIM: To
      detect whether skin BMZ-Abs participated in the formation of the lupus band in
      SLE. Methods Immunoglobulin G (IgG)-type BMZ-Abs in 15 SLE patients were detected
      by means of immunofluorescence (IF), immunoblotting (IB), and immunoelectron
      microscopy (IEM). RESULTS: Direct immunofluorescence (DIF) on salt-split skin
      showed epidermal fluorescence in 12 of the 15 SLE patients. Two of the 12
      patients also showed dermal fluorescence. Indirect immunofluorescence (IIF) on
      salt-split skin revealed that, in 12 of the 15 (80%) sera, antibodies were bound
      to the epidermal roof of the salt-split skin. IB showed that, in 14 SLE sera,
      autoantibodies reacted to 230, 200, 180, 130, and 97 kDa epidermal extracts and
      75 kDa dermal extracts. Direct (DIEM) and indirect (IIEM) immunoelectron
      microscopy showed that gold particles were directed to every region of the BMZ,
      including hemidesmosomes, lamina lucida, lamina densa, and sublamina densa.
      CONCLUSIONS: BMZ-Abs in SLE sera may participate in the formation of the lupus
      band.

PMID- 15186221
TI  - Primary hereditary ichthyoses in the Eastern Province of Saudi Arabia.
AB  - BACKGROUND: Of 10,455 new dermatology patients seen at the Dermatology Clinic of
      King Fahad Hospital of the University, Al-Khobar, Saudi Arabia, between January
      1990 and December 1995, the epidemiologic and demographic features of 71
      patients, each with a histopathologically confirmed diagnosis of one specific
      type of primary hereditary ichthyosis (PHI), have been reviewed. OBJECTIVE: To
      study and document the epidemiologic and demographic profiles of patients with
      PHI in the Eastern Province of Saudi Arabia. METHODS: From the outpatient
      department dermatology logbooks, 71 patients with PHI, from 10,455 new cases with
      different dermatologic problems seen during the 5-year period, were included in
      this study. Using specially designed protocol forms, epidemiologic and
      demographic data were extracted from the medical records of the patients, entered
      into a computer, and analyzed using the SPSS program. RESULTS: Seventy-one
      patients with PHI, 44 males and 27 females (ratio, 1.63 : 1), were seen at our
      Dermatology Clinic between January 1990 and December 1995. The occurrence rate of
      PHI in our clinic is 0.67%, i.e. approximately 7 per 1000 new cases. The clinical
      pattern of PHI was as follows: 31 patients (44.7%) with ichthyosis vulgaris (IV),
      12 (16.9%) with X-linked recessive ichthyosis (XLRI), four (5.6%) with lamellar
      ichthyosis (LI), three (4.2%) with bullous ichthyosiform erythroderma (BIE), and
      21 (29.6%) with nonbullous ichthyosiform erythroderma (NBIE). IV was most common,
      followed by NBIE. Parental consanguinity was high (approximately 85%), and the
      family history was positive in 53 of the 71 cases (75%). CONCLUSIONS: This
      preliminary study has attempted to document the epidemiologic patterns of PHI
      patients in Saudi Arabia and, to our knowledge, this is the first report of its
      kind in this country. We found a high rate of parental consanguinity, a high
      percentage of patients with a positive family history, and many siblings affected
      by the severest forms of PHI, namely NBIE, BIE, and LI, which accounted for 39.4%
      of all cases of PHI.

PMID- 15186223
TI  - Lupoid plaque--a new morphologic variant of post-kala-azar dermal leishmaniasis.

PMID- 15186224
TI  - Bedbug bites: a review.

PMID- 15186225
TI  - Extensive inflammatory nevus comedonicus involving half of the body.
AB  - Nevus comedonicus is an uncommon variant of adnexal hamartoma without known
      cause. It usually occurs on the face, neck and chest and appears as groups of
      closely arranged dilated follicular openings with keratin plugs. We report
      extensive inflammatory nevus comedonicus in a 14-year-old boy involving half of
      his body, limited by the midline, with suppuration and residual scarring. The
      lesions first appeared at 3 years of age and worsened at the start of puberty.
      The clinical features, etiopathology, histopathology and treatment options of
      nevus comedonicus are briefly reviewed in the light of the literature.

PMID- 15186226
TI  - Tinea faciei, an often deceptive facial eruption.
AB  - Tinea faciei is a relatively uncommon superficial dermatophyte infection limited
      to the glabrous skin of the face. It is usually seen in pediatric patients. This
      fungus can be found worldwide, but has a predilection for tropical humid
      climates. Although the infecting organisms and treatments are the same as for
      other superficial fungal infections, it is frequently misdiagnosed clinically and
      histologically.

PMID- 15186227
TI  - Granuloma multiforme.
AB  - CASE 1: A 51-year-old woman presented with skin-colored annular lesions on the
      upper chest, neck, and dorsa of the hands of 1-year duration. The lesions
      initially started as small papular lesions, which gradually evolved to form large
      annular and polycyclic lesions. Initially, the lesions were associated with a
      burning sensation and pruritus. She had no other systemic complaints. Examination
      revealed 5-6 annular, polycyclic lesions distributed over the upper chest, neck,
      and dorsa of both hands, varying in size from 1 to 5 cm. All the lesions had a
      prominent erythematous to skin-colored, irregular, papular border which was firm
      in consistency (Figs 1 and 2). Central clearing and minimal atrophy were evident
      in larger lesions. There was no sensory loss or peripheral nerve thickening.
      Clinical possibilities entertained were granuloma annulare, granuloma multiforme,
      and annular sarcoid. Routine investigations, including hemogram, renal and liver
      functions, blood sugar levels, chest X-ray, and urine examination, were within
      normal limits. A skin biopsy taken from the edge of a lesion revealed foci of
      collagen degeneration surrounded by an inflammatory infiltrate composed of many
      histiocytes and multinucleated giant cells. In addition, there were perivascular
      and periadnexal lymphocytic aggregates. No acid-fast bacilli (AFB) were detected.
      These findings were consistent with a diagnosis of granuloma multiforme (Fig. 3).
      CASE 2: A 47-year-old man presented with annular skin-colored lesions associated
      with a mild burning sensation of 8 months' duration. On examination, 2-3 annular,
      arciform lesions were distributed over the upper chest and neck. The lesions
      ranged in size from 2 to 7 cm in diameter, were irregular in shape, and were
      rimmed by a well-defined raised papular border. Again, there was no sensory loss
      or peripheral nerve thickening. Histopathology of the skin from the edge of the
      lesion showed multiple areas of histiocytic granulomas with focal necrobiosis and
      prominent multinucleated giant cells, findings consistent with granuloma
      multiforme.

PMID- 15186228
TI  - Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous
      pemphigoid antigen (BP180): evidence for a distinct subtype.
AB  - BACKGROUND: Autoantibodies in linear immunoglobulin A (IgA) disease (LAD) are
      reported to be of IgA class and directed against a 97-120 kDa epidermal antigen.
      METHODS: We report a 39-year-old woman with clinical features of LAD and with
      circulating IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen
      (BP180). RESULTS: Histopathology of lesional skin revealed a subepidermal blister
      with mixed inflammatory cell infiltrate. Direct immunofluorescence of
      perilesional skin showed linear deposits of IgA along the dermal-epidermal
      junction. The antigen specificity of the patient's circulating antibodies was
      determined by Western blotting and enzyme-linked immunoabsorbent assay (ELISA)
      using various antigen sources, including cultured human keratinocytes, dermal
      protein lysates, and purified laminin-5, as well as proteins corresponding to
      BP180, the 230 kDa bullous pemphigoid antigen (BP230), laminin-5 subunits, and
      collagen IV alpha1-alpha6 chains. IgA and IgG antibodies in the patient's serum
      were directed against BP180, and no IgA or IgG reactivity was found against the
      other skin antigens. CONCLUSIONS: These data provide evidence for the presence of
      a subtype of LAD with dual IgA and IgG autoimmune response to BP180.

PMID- 15186230
TI  - Solitary neurofibroma: an uncommon location.

PMID- 15186229
TI  - Cardio-facio-cutaneous syndrome: report of a case with a review of the
      literature.
AB  - A sporadic case of cardio-facio-cutaneous syndrome occurring in an 18-year-old
      girl is reported, with a brief review of pertinent literature, for its rarity and
      clinical interest. She had a characteristic cranio-facial appearance, a wide
      range of ectodermal defects, dystrophic nails and teeth, palmo-plantar
      keratoderma, typical short, coarse, unruly hair, pulmonic stenosis and mild
      mental retardation. She had no history of consanguinity and genetic studies did
      not reveal any abnormality.

PMID- 15186231
TI  - Cranial fasciitis treated with intralesional corticosteroids.

PMID- 15186232
TI  - Residual skin cancer after preoperative biopsy: evaluation by Mohs micrographic
      surgery.
AB  - BACKGROUND: Some patients are referred for Mohs surgery with no or minimal
      clinical evidence of skin cancer at the biopsy site. OBJECTIVE: To determine the
      incidence of residual skin cancer at biopsy sites during Mohs micrographic
      surgery. METHODS: We evaluated all patients that underwent Mohs surgery for basal
      cell and squamous cell carcinomata in one year. The study was carried out
      prospectively. Debulking was done using a no. 15 blade at the clinical borders of
      the tumor or biopsy site. All specimens were sectioned at the middle and cut to
      the periphery at 20- microm intervals. RESULTS: Seven hundred and forty-one
      patients underwent operations. In 390 patients, a biopsy was performed prior to
      surgery. A total of 351 patients were biopsied as prestaged (chemocheck) during
      surgery. Ninety-nine (25%) of the preoperatively biopsied patients showed no
      residual tumor in the debulking specimen or the first layer. Of these 99
      patients, 84 had basal cell carcinoma and 15 had superficial or in situ squamous
      carcinoma. CONCLUSIONS: In this study, preoperative biopsy for diagnosis of skin
      cancer of the face was curative in 25% of patients, despite pathologic diagnosis
      of incompletely excised tumor. However, as the majority of preoperatively
      biopsied patients showed residual tumor, Mohs micrographic surgery is indicated
      in all patients with incomplete removal of skin cancer of the head and neck.

PMID- 15186233
TI  - Celecoxib-induced photoallergic drug eruption.
AB  - Photoallergic dermatitis is caused by a photosensitizing substance plus sunlight
      exposure in a sensitized person. If the photosensitizer is delivered internally,
      it is called a photoallergic drug reaction. Celecoxib is a new generation non
      steroidal anti-inflammatory drug and sulfonamide derivative. We report a
      photoallergic drug eruption associated with the introduction of celecoxib. To our
      knowledge, this is the first report of photoallergic drug reaction associated
      with celecoxib.

PMID- 15186234
TI  - Broad-band UVB fiber-optic comb for the treatment of scalp psoriasis: a pilot
      study.
AB  - Abstract Background Scalp psoriasis is a frustrating condition with limited
      treatment options. Our objective was to test a new fiber-optic broad-band UVB
      comb device for the treatment of this condition. Methods Scalp psoriasis on adult
      subjects was treated three times a week for up to 12 weeks with a fiber-optic UVB
      comb. A minimum 50-cm(2) scalp area served as the control. Starting doses were
      based on the standard minimal erythema dose (MED) with increments up to 20% for
      subsequent treatments. Results Fourteen subjects completed the study without
      sunburn reactions or blisters. Treated sites showed a mean improvement in the
      modified PASI score of 3.6. The difference in the mean modified PASI scores
      between the control and treated sites was 3.9 (< 0.0001). Conclusions This fiber
      optic broad-band UVB comb can safely and effectively treat scalp psoriasis.

PMID- 15186236
TI  - Bullous skin eruption associated with entacapone.

PMID- 15186235
TI  - Dermatologists, beacons of epidemics; past, present and future!

PMID- 15186237
TI  - Eccrine poroma associated with Bowen's disease.

PMID- 15186240
TI  - Morphometric analysis of shank-to-flute ratio in rotary nickel-titanium files.
AB  - AIM: To evaluate the shank-to-flute ratio in rotary nickel-titanium (Ni-Ti)
      instruments. METHODOLOGY: The cutting portion of 15 size 30 Ni-Ti rotary
      instruments, ProFile.04, ProFile.06, Pow R.02, Pow R.04 and Quantec series 2000,
      were examined. The handles of the instruments were fixed to a bench and supported
      by a removable resin base. The cutting portion was then manually abraded with
      abrasive strips along one aspect of their length. All instruments were fixed in a
      stub that permitted the adaptation and inspection of six instruments at the same
      time. A scanning electron microscope (SEM; Phillips model XL 20; Eindhmoven, the
      Netherlands) at x60 magnification was used to collect cross-sectional
      measurements of the shank and the flutes at the first, third and fifth flutes
      from the tip. The software autocad 2000 was used to measure these areas. RESULTS:
      The shank percentage value was, on average, equal to or greater than the flute
      percentage value at the sites analyzed. A regular and proportional pattern of
      increase of shank and flute measurements, as well as the ratio between them, was
      preserved. There was no significant difference between instruments and between
      flute sites on the same instrument (P > 0.05). However, the Quantec instruments
      had a flute area twice the flute area of the other instruments. CONCLUSIONS: The
      instruments had a shank percentage measurement value equal to or greater than the
      flute percentage value; the cross-sectional shank-to-flute ratio was preserved.
      The instruments had similar shank areas, but the flute area of the Quantec
      instruments was twice their shank area; i.e. the design of the Quantec files
      provides longitudinal reinforcement by means of a gain in flute area.

PMID- 15186241
TI  - Comparison of apical transportation between ProFile and ProTaper NiTi rotary
      instruments.
AB  - AIM: To use a newly developed radiographic technique to compare apical
      transportation and loss of working length (WL) between.06 taper ProFile Series 29
      and ProTaper nickel-titanium (NiTi) rotary instruments in vitro. METHODOLOGY:
      Mesio-buccal canals of 40 extracted mandibular molars were randomly divided into
      two groups. Group 1 was instrumented with ProFile and group 2 with ProTaper
      instruments according to the manufacturers' directions. A specially constructed
      radiographic jig with a Schick digital radiographic system (Schick Technologies
      Inc., Long Island City, NY, USA) was used to take pre- and postoperative
      radiographs of the samples at predetermined angulations. Using AutoCAD 2000
      (Autodesk Inc., San Rafael, CA, USA), the central axes of initial and final
      instruments were radiographically superimposed to determine the loss of WL and
      degree of transportation at D(0), D(1), D(2) and D(4) from the WL. Data were
      analysed using repeated-measures anova. RESULTS: A statistically significant
      difference in apical transportation was found at the D(4) level between the two
      groups (P = 0.05). There was no statistical significance regarding
      postinstrumentation change in WL between groups. Spearman's Bivariate Correlation
      analysis indicated no statistically significant relationship between the radius
      of curvature and transportation. CONCLUSION: The results indicate that both
      ProTaper and ProFile instruments are comparable to each other in regards to their
      ability to optimally enlarge root canal with minimal transportation and loss of
      WL in vitro.

PMID- 15186242
TI  - Decalcification of root canal dentine by citric acid, EDTA and sodium citrate.
AB  - AIM: To measure the demineralization capability of 1 and 10% citric acid, 10%
      sodium citrate and 17% EDTA during immersions of 5, 10 and 15 min on root canal
      dentine. METHODOLOGY: Crowns were sectioned from eight maxillary canines. The
      cementum was removed from the cervical third of the roots to expose the dentine.
      Canals were prepared using a handpiece-mounted Largo Peeso reamer. A 3-mm thick
      cross-sectional slice was obtained from the cervical third of each root. Each
      slice was sectioned into four equal parts. These specimens were assigned to one
      of four groups (n = 8) for the application of 1% citric acid, 10% citric acid,
      10% sodium citrate or 17% EDTA. Each specimen underwent three successive 5-min
      immersions in each solution at room temperature. The solutions were not renewed
      between immersions. Two millimetres of solution were collected from the extracts
      and lanthanum oxide was added for the calcium reading by spectrophotometry. To
      compare the amounts of calcium removed by each solution, the Friedman test was
      used for the global comparison and the Wilcoxon test for paired comparisons.
      Differences between groups were evaluated using the Kruskal-Wallis test for the
      global comparison and Mann-Whitney test for paired comparisons. RESULTS: Overall,
      1 and 10% citric acid were more effective than EDTA or sodium citrate at the
      three immersion times (P < 0.001); 10% citric acid was more effective than 1%
      citric acid (P < 0.001). EDTA and 1 and 10% citric acid showed decreasing
      effectiveness with time, and the decrease was significant for citric acid at both
      concentrations (P < 0.001). Although sodium citrate removed little calcium during
      the three time periods, the small increase recorded was significant (P < 0.01).
      CONCLUSIONS: Citric acid at 10% was the most effective decalcifying agent,
      followed by 1% citric acid, 17% EDTA and 10% sodium citrate.

PMID- 15186243
TI  - Torsional fatigue and endurance limit of a size 30.06 ProFile rotary instrument.
AB  - AIM: To evaluate the torsional cyclic fatigue characteristics and specifically
      the endurance limit (EL) of a nickel-titanium rotary instrument. METHODOLOGY:
      Size 30.06 taper ProFile instruments were evaluated. The equipment was assembled
      according to the ANSI/ADA Specification No. 28. The motor was programmed to
      repeatedly rotate to a selected deflection angle (DA) and then return to zero
      (cycle). Testing started at 200 degrees and was continued at decreasing angles
      until 10(6) cycles were reached without instrument fracture. Ten instruments were
      tested at each DA. The mean log number of cycles to fracture and standard
      deviation were determined for each DA at which fracture occurred. The DA at which
      10(6) cycles were reached without instrument fracture corresponded by definition
      to the EL. Analysis of variance and pairwise comparisons using Duncan's multiple
      range test were performed to detect significant differences among the mean log
      number of cycles of the different DA. Significance was determined at the 95%
      confidence level. RESULTS: Instruments cycled at larger DA consistently
      demonstrated fewer cycles to fracture than those cycled at smaller DA. The
      differences among the mean log number of cycles of the different DA were
      statistically significant (P < 0.001). Cycles of 10(6) were completed without
      instrument fracture at 2.5 degrees. CONCLUSIONS: A torsional fatigue profile was
      generated for a specific NiTi rotary instrument. The EL was 2.5 degrees.

PMID- 15186244
TI  - An evaluation of the use of tooth temperature to assess human pulp vitality.
AB  - AIM: To evaluate change in tooth surface temperature following a thermal stimulus
      as a simple and reliable method to assess the presence and the extent of blood
      flow through teeth. METHODOLOGY: Miniature thermometers were used to measure the
      relationship between surface temperature of teeth and internal flow of 37 degrees
      C water (in vitro) or blood (in vivo). In addition, thermal stimuli were applied
      to the external surface of the teeth, and the rate of temperature recovery was
      related to internal flow. RESULTS: Under in vitro conditions, the surface
      temperature of teeth and rate of temperature recovery were related to the rate of
      internal water flow. However, in vivo neither standing surface temperature (P =
      0.47) nor rate of temperature recovery (P = 0.19) were significantly related to
      evidential pulp vitality. CONCLUSION: Change in the surface temperature of teeth
      is not suitable as a simple clinical means to assess pulp vitality.

PMID- 15186245
TI  - Prevalence of and factors affecting post-obturation pain in patients undergoing
      root canal treatment.
AB  - AIM: This longitudinal, prospective study (1) investigated the prevalence of post
      obturation pain after root canal treatment and (2) evaluated the influence of
      factors affecting the pain experience. METHODOLOGY: Twenty practitioners,
      comprising general dental practitioners, MSc graduates and Endodontists,
      participated in this study. The patient sample (n = 415) was derived from
      consecutive patients attending the practitioners' surgeries for root canal
      treatment on a single tooth. Demographic, medical history, preoperative and intra
      operative data as well as pain experience on day 1 and day 2 after root canal
      obturation were recorded. Intensity of pain experienced was recorded on a visual
      analogue scale (VAS) of 0-5. The data were analysed using logistic regression
      models. RESULTS: The prevalence of post-obturation pain within 48 h after
      treatment was 40.2% (n = 167) but less than 12% of patients experienced severe
      pain (VAS 4 or 5) on either day 1 or day 2. The factors that significantly
      influenced post-obturation pain experience were: gender (OR = 0.434, P < 0.001),
      tooth type (OR = 1.733, P = 0.007), size of periapical lesion (OR = 0.493, P =
      0.004), history of post-preparation pain (OR = 4.110, P = <0.001) or generalized
      swelling (OR = 3.435, P = 0.005) and number of treatment visits (OR = 2.604, P <
      0.001). CONCLUSIONS: The prevalence of post-obturation pain was high (40.2%). The
      important prognostic determinants of post-obturation pain were female, molar
      tooth, size of periapical lesion smaller than 3 mm, history of post-preparation
      pain or generalized swelling and single-visit treatment.

PMID- 15186246
TI  - Percentage of canals filled in apical cross sections - an in vitro study of seven
      obturation techniques.
AB  - AIM: To compare the apical density of several obturation techniques when used in
      palatal roots of extracted maxillary molars. METHODOLOGY: Seventy extracted
      molars were randomly divided into seven groups with 10 teeth each. The palatal
      root canals were instrumented to size 60 MAF, coated with Kerr's Pulp Canal
      Sealer, and obturated using one of seven techniques. The palatal roots were
      separated from the crowns, decalcified, and sectioned horizontally at 2 and 4 mm
      from the apex. The cross-sections were photographed through a microscope, the
      photos were analysed, and the amount of area in the canal that was obturated with
      gutta-percha was measured. The means for the 20 sections per group were
      calculated and the means were compared using mixed analysis of variance test.
      RESULTS: Simplifill used in accordance with the manufacturer's directions and
      Thermafil had the greatest mean obturated area, but neither were statistically
      better than mechanical lateral or warm vertical compaction (WVC; Schilder
      Technique). Simplifill as recommended and Thermafil were statistically better
      than cold lateral (P = 0.0210 and 0.0433, respectively), WVC (continuous wave) (P
      = 0.0006 and 0.0015), and the modified Simplifill group (P = 0.0010 and 0.0012).
      In addition, mechanical lateral and WVC (Schilder) had statistically more
      obturated area than WVC (continuous wave) (P = 0.0054 and 0.0073) and modified
      Simplifill (P = 0.0015 and 0.0016). Cold lateral and WVC (continuous wave) had
      significantly more obturated area than modified Simplifill (P = 0.0040 and
      0.0087). CONCLUSIONS: Simplifill as recommended, Thermafil, mechanical lateral
      and WVC (Schilder) obturation techniques created more complete obturation using
      gutta-percha at the 2 and 4 mm levels than cold lateral, WVC (continuous wave),
      and Simplifill not used as directed.

PMID- 15186247
TI  - Accuracy of the DTC torque control motor for nickel-titanium rotary instruments.
AB  - AIM: To determine the torque output and examine the accuracy of five identical
      DTC torque control (DTC) motors. METHODOLOGY: Torque settings on the DTC motors
      for the.04 ISO ProFile nickel-titanium (NiTi) rotary instruments were evaluated
      at 350 r.p.m. A modification of the ANSI/ADA Specification No. 28 setup for the
      evaluation of torsional properties of endodontic instruments was used. A
      handpiece was attached to the motor and gripped with a vice. An.07 Orifice
      Shaper, size 50, was inserted in the handpiece. The instrument tip was clamped in
      a chuck connected to a torque sensor. The motor was then activated to rotate the
      instrument in a clockwise direction until reversal of the rotation occurred. The
      actual torque generated at the reversal of the rotation was recorded. Ten tests
      were carried out at each torque setting. A new Orifice Shaper was used for each
      test. The means of the actual torque values generated by the motors at the
      different torque settings were compared with the torque values claimed by the
      manufacturer and analysed using analysis of variance and the Student's t-test
      (alpha = 0.05). RESULTS: The actual torque values were significantly higher than
      the torque preset on the motors (P < 0.0001) and did not differ significantly
      among the motors (P > 0.05). CONCLUSIONS: The actual torque deviated from the
      preset torque and was higher than the reported torque at fracture of several NiTi
      rotary instruments. The usefulness of these motors is questionable.

PMID- 15186248
TI  - The influence of root-end resection and root-end cavity preparation on
      microleakage of root filled teeth in vitro.
AB  - AIM: To investigate in vitro the influence of root-end resection and root-end
      cavity preparation on leakage of root filled teeth. METHODOLOGY: The root canals
      of 48 roots, 16 mandibular premolars (G1), 16 mandibular incisors (G2) and 16
      maxillary incisors (G3), 12 mm in length, were enlarged using a modified
      'balanced force' technique and filled with gutta-percha and sealer using lateral
      compaction. After setting, leakage along the canal was measured using a fluid
      transport model. Root-end resection and root-end cavity preparation were then
      performed, leaving roots 10 mm in length with root fillings of 7 mm (groups R1,
      R2 and R3, respectively). Fluid transport was measured again along the remaining
      root fillings of all groups using the same experimental conditions. Results of
      leakage before and after root-end resection were analysed statistically using the
      Kruskal-Wallis and Wilcoxon tests. RESULTS: A total of 31% of the roots leaked
      before and 54% after root-end preparation; the difference was significantly
      different (P < 0.001). No significant differences were found either among groups
      G1, G2, G3 (P = 0.565) or among groups R1, R2, R3 (P =0.2628). Significant
      differences, however, were shown between groups G1-R1 (P = 0.0053), G2-R2 (P
      =0.0089) and G3-R3 (P = 0.0461). CONCLUSIONS: Root-end resection and root-end
      cavity preparation compromised the seal of 7 mm root fillings in all tooth
      groups. Increased leakage was recorded in the following order: mandibular
      incisors > mandibular premolars > maxillary incisors.

PMID- 15186249
TI  - Prognosis of large cyst-like periapical lesions following nonsurgical root canal
      treatment: a clinical review.
AB  - AIM: To evaluate clinically and radiographically the long-term clinical outcome
      of nonsurgical root canal treatment using calcium hydroxide in teeth with large
      cyst-like periapical lesions. SUMMARY: A total of 42 mature anterior teeth with
      large periapical lesions ranging in size from 7 to 18 mm in diameter were
      included in this study. Fluid samples from the lesions contained cholesterol
      crystals, which were identified by light microscopy. After adequate draining, the
      teeth were treated endodontically using calcium hydroxide as the intracanal
      medicament. All cases were followed up for a period of 2-10 years. Complete
      healing was observed in 73.8% and incomplete healing in a further 9.5% of cases.
      KEY LEARNING POINTS: Root canal treatment using calcium hydroxide as an
      antibacterial dressing was successful in healing large cyst-like periapical
      lesions. This study suggests that the size of a periapical lesion is not a major
      determining factor in the decision to perform conventional root canal treatment
      or surgical removal of the lesion. Even large cyst-like periapical lesions
      containing cholesterol crystals can heal following nonsurgical root canal
      treatment.

PMID- 15186252
TI  - Proinflammatory effects of copper deficiency on neutrophils and lung endothelial
      cells.
AB  - Dietary copper deficiency increases the accumulation of circulating neutrophils
      in the rat lung microcirculation. This process includes neutrophil adhesion to,
      migration along, and emigration though the vascular endothelium. The current
      study was designed to examine the role of copper in each of these steps.
      Neutrophils were isolated from rats fed either a copper-adequate (CuA, 6.1 microg
      Cu/g diet) or copper-deficient diet (CuD, 0.3 microg Cu/g diet) for 4 weeks.
      First, transient and firm adhesion of neutrophils to P-selectin in a flow chamber
      showed there were more adhered CuD neutrophils than CuA ones. This effect is
      probably caused by the increased expression of CD11b that was observed in the
      current study. Second, the evaluation of neutrophil migration under agarose
      showed that the CuD neutrophils moved farther than the CuA group in response to
      IL-8 but not fMLP; this suggests an increased sensitivity to a CD11/CD18
      independent signalling pathway. Third, the contractile mechanism of endothelial
      cells was studied. Elevated F-actin formation in Cu-chelated lung microvascular
      endothelial cells suggests that neutrophil emigration may be promoted by enhanced
      cytoskeletal reorganization of the endothelium during copper deficiency.
      Combined, these results support the theory that dietary copper deficiency has
      proinflammatory effects on both neutrophils and the microvascular endothelium
      that promote neutrophil-endothelial interactions.

PMID- 15186253
TI  - Rapid downregulation of antigen processing enzymes in ex vivo generated human
      monocyte derived dendritic cells occur endogenously in extended cultures.
AB  - Dendritic cells, the most potent antigen presenting cells, have been shown in
      murine models to induce immune responses against many antigens. Their role in the
      initiation of antitumour immunity has received enormous attention. Their ability
      to process and present antigen is dependent on their state of maturation. This
      study examines the activity of human monocyte-derived dendritic cells at two
      different time points and the corresponding changes in the proteolytic enzyme
      activity. Dendritic cells were produced from peripheral blood mononuclear cells
      of normal volunteers. Plastic adherent cells were cultured for 5 or 7 days with
      recombinant human (rh)GM-CSF and rhIL-4. Flow cytometry showed that day 5
      dendritic cells (DC) were less mature than day 7 DC as indicated by the
      expression of CD1a, CD11c, CD14, CD80, CD83, CD86 and MHC-II. Proteolytic
      activity of the enzymes cathepsin C and cathepsin G and phagocytosis of
      particulate antigens also showed significant differences between d5 dendritic
      cells and d7 dendritic cells. Allogeneic costimulatory activity of d7 dendritic
      cells was also significantly increased. Induction of immunity requires active
      presentation of antigens by antigen processing cells on their MHC-I and/or MHC-II
      molecules. Study of peptide carriers and peptide precursor molecules showed a
      significant decrease in CLIP levels in the day 7 DC, suggesting their decreased
      ability to process antigens but no difference in their ability to load MHC-II
      molecules. These findings indicate that the length of time in culture, in the
      absence of exogenous maturation - inducing stimuli affects dendritic cell
      maturation. Intracellular enzymatic activities of dendritic cells also changed
      rapidly with small changes in phenotype.

PMID- 15186255
TI  - Normal levels of immunocompetence in possums (Trichosurus vulpecula) exposed to
      different laboratory housing conditions post capture.
AB  - Specific and non-specific immunological tests were used to monitor aspects of the
      immune response in captive possums. The tests included total and differential
      white blood cell counts, lymphocyte transformation assay, and enzyme linked
      immunosorbant assay. The level of free cortisol present in possum plasma samples
      was evaluated as an endocrine marker for stress. Four different housing
      conditions were used to test whether stress could be managed or avoided in
      captive animals. Animals were caged individually or as groups in pens. Bacille
      Calmette-Gurein (BCG) and tetanus toxoid immunization was used to evoke primary
      cell mediated and antibody responses in test animals. The results indicated that
      there was no significant difference in immunological responses or endocrine
      parameters in animals held under any of the housing conditions. The results infer
      that wild possums adapt quickly post-capture to novel housing conditions and
      produce representative patterns of immunity when held in housing conditions and
      fed ad libitum.

PMID- 15186254
TI  - Systemic NKT cell deficiency in NOD mice is not detected in peripheral blood:
      implications for human studies.
AB  - In the diabetes-prone NOD mouse, there is a proven association between a systemic
      deficiency of NKT cells and the onset of type 1 diabetes. Numerous reports of
      similar defects within the NKT cell compartment of human type 1 diabetes patients
      suggested NKT cell levels might be a valuable predictor of susceptibility and
      could provide a target for therapeutic intervention. Two recent studies, however,
      found no association between type 1 diabetes and blood NKT cell levels in humans
      and consequently rejected a link between the onset of diabetes and NKT cell
      deficiency. This cast considerable doubts on the potential for NKT cell-based
      clinical applications and challenged the validity of the NOD mouse as a model of
      human type 1 diabetes. We now report that NKT cell levels in blood are a poor
      representation of those in other organs. Strikingly, systemic NKT cell
      deficiencies were identified in NOD mice with normal, or even raised, blood
      levels. This re-establishes the correlation between NKT cell deficiency and type
      1 diabetes and raises important questions regarding the assaying of NKT cell
      levels in humans.

PMID- 15186256
TI  - A web application to manage a database for liquid nitrogen tanks.
AB  - Summary We have developed a software, Cell Database, for archiving records about
      cells stored in liquid nitrogen tanks. Once installed on a web server, the
      database is accessed through a standard web browser. This user-friendly and self
      explanatory application is independent of computer platform and periodic upgrades
      of a commercial software. Our web application allows import of data from other
      database programs and adaptation to different tank formats, types of samples, and
      archiving needs.

PMID- 15186257
TI  - T cell activation: in vivo veritas.
AB  - Phenotypic changes in CD4(+) T cells undergoing antigen-dependent activation were
      compared in vivo and in vitro. The most obvious difference was in expression of
      CD25, the alpha chain of the high affinity receptor for IL-2. High level
      expression of CD25 in vivo is restricted to a small fraction of the cells at the
      leading edge of the cell division profile, whereas all activated cells express
      high levels of CD25 in cultures responding to antigen. Because IL-2 is known to
      upregulate expression of CD25 in preactivated T cells, this suggests a difference
      in IL-2 exposure in the two responses. A number of other markers, including CD54,
      show a similar difference in the pattern of expression in vivo and in vitro.
      Using 6-colour flow cytometry, it was demonstrated that the small percentage of
      cells expressing CD25 in vivo coexpresses a very high level of a number of other
      activation markers, including CD38, CD44 and Ly-6A/E, suggesting that these may
      also be upregulated by autocrine IL-2.

PMID- 15186258
TI  - Parallels and distinctions between T and NKT cell development in the thymus.
AB  - NKT cells are emerging as an extremely influential regulatory subset of T
      lymphocytes that are functionally and developmentally distinct from their
      mainstream counterparts. Like other T cells, NKT cells are thymus-dependent but
      their apparently unique pathway of differentiation is poorly characterized. Given
      the strong association between NKT cell deficiency and increased incidences of
      autoimmunity and cancer it is imperative that the mechanisms by which NKT cells
      are generated becomes better understood. This review examines what is known about
      NKT cell development in the thymus and highlights elements of the pathway that
      differ significantly from mainstream T-cell development. It is here that NKT cell
      specific disorders may originate and may best be addressed.

PMID- 15186259
TI  - Genetic control of NKT cell numbers.
AB  - NKT cells play a critical role in shaping the character and strength of a wide
      range of immune responses, including those against pathogens, tumours, allografts
      and autologous tissues. Because numbers of NKT cells affect clinical outcomes in
      a wide range of disease models, and this characteristic demonstrates allelic
      variation, the mapping of the locations and identification of the coding
      sequences of these genes has become a matter of significant importance. Here, we
      review the results to date that examine the effects of targeted deletion of a
      number of candidate genes, as well as the congenic and genetic linkage analyses
      that have attempted to localize allelic loci that affect NKT cell numbers.
      Although a number of candidate genes have been examined, there is no evidence
      that any of these contribute to variation in NKT cell numbers in natural
      populations. Two of the most important genetic regions controlling NKT cell
      numbers are Nkt1 on chromosome 1, which may contribute to lupus susceptibility,
      and Nkt2 on chromosome 2, which appears to contribute to diabetes susceptibility.
      Of great interest is a third locus on chromosome 18, identified in a novel
      congenic line, which can confer an absolute deficiency in this important
      immunoregulatory lymphocyte population.

PMID- 15186260
TI  - Antigen specificity of semi-invariant CD1d-restricted T cell receptors: the best
      of both worlds?
AB  - T lymphocytes are characterized by the use of structurally diverse TCR. The
      discovery of subsets of canonical T cells that have structurally homogeneous TCR
      presents an enigma: What antigens do these T cells recognize, and how does their
      antigen specificity relate to their functions? One subset of canonical T cells is
      restricted by CD1d, a non-classical antigen presenting molecule that presents
      lipids and glycolipids. Canonical CD1d-restricted T cells have semi-invariant TCR
      consisting of an invariantly rearranged TCR alpha chain, paired with diversely
      rearranged TCR beta chains. Most respond strongly to the unusual glycolipid alpha
      galactosylceramide (alpha-GalCer), and can also respond to cellular antigens
      presented by CD1d. Mounting evidence indicates that alpha-GalCer responsive T
      cells are heterogeneous in their reactivities to cellular antigens, suggesting
      that an individual semi-invariant TCR may be capable of recognizing more than one
      ligand. Recent crystal structures of CD1b molecules with three different bound
      lipids indicate that the antigenic features of lipids may be localized over a
      smaller area than those of peptides, and that the positioning of the polar head
      group can vary substantially. A model that explains how CD1d-restricted T cells
      could possess both conserved and heterogeneous antigen specificities, is that
      different lipid antigens may interact with distinct areas of a TCR due to
      differences in the positioning of the polar head group. Hence, canonical CD1d
      restricted TCR could recognize conserved antigens via the invariant TCR alpha
      chain, and have diverse antigen specificities that are conferred by their
      individual TCR beta chains.

PMID- 15186261
TI  - The Third Way: Progress on pathways of antigen processing and presentation by
      CD1.
AB  - CD1 proteins are a third family of antigen presenting molecules that bind
      bacterial and autologous lipid antigens for presentation to T cells. With the
      solution of the crystal structures of several complexes of CD1 molecules with
      lipids, a greater appreciation has been gained of the adaptability of CD1 in
      binding lipid antigens with diverse structural features. Biochemical studies of
      the interactions between the TCR and CD1-lipid complexes have revealed striking
      contrasts with TCR that bind to peptides presented by MHC-encoded class I and
      class II molecules. The sphingolipid activating proteins (SAP) have recently been
      found to facilitate the transfer of lipid antigens onto CD1 molecules. This helps
      to provide an explanation as to how the thermodynamic barrier, caused by loading
      hydrophobic lipid antigens in a hydrophilic environment, can be overcome.
      Mechanisms of CD1 endosomal trafficking are being delineated, including the means
      by which adaptor proteins induce the localization of some types of CD1 molecules
      to lysosomes, where they bind antigens. Unlike MHC class I and class II proteins,
      specialized molecules that function solely in chaperoning CD1 molecules, or in
      facilitating their antigen loading, have not been found. This suggests that the
      CD1 antigen presenting system, which diverged early in vertebrate evolution from
      MHC antigen presenting molecules, is a simpler system with a character closer to
      the primordial antigen presenting function.

PMID- 15186262
TI  - CD1d-restricted T-cell subsets and dendritic cell function in autoimmunity.
AB  - CD1-restricted T cells have been shown to play a critical role in host defence,
      tumour surveillance, and maintenance of tolerance. However, immunologic outcomes
      resulting from activation of CD1d-restricted T cells can be either beneficial or
      deleterious. A major mechanism by which CD1d-restricted T cells are thought to
      exert immunoregulatory control is via effects on dendritic cell (DC)
      differentiation and migration. Important functional subsets of CD1d-restricted T
      cells are also known to exist and the potential implications for preferential
      subset activations are discussed.

PMID- 15186263
TI  - Natural killer T cells as targets for immunotherapy of autoimmune diseases.
AB  - CD1d-restricted natural killer T (NKT) cells are innate lymphocytes that play a
      regulatory role during an immune response. The identification of alpha
      galactosylceramide (alpha-GalCer), a marine sponge-derived glycosphingolipid, as
      a potent stimulator of NKT cells led many laboratories to investigate the effects
      of NKT cell activation on the regulation of immune responses. These studies
      revealed that alpha-GalCer induces rapid and robust cytokine production by NKT
      cells, secondary activation of a variety of innate and adaptive immune cells, and
      modulation of Th cell responses. Further, alpha-GalCer influences disease
      progression in a variety of experimental models of autoimmunity and inflammation
      in mice, including models for type 1 diabetes, multiple sclerosis, rheumatoid
      arthritis, systemic lupus erythematosus, inflammatory bowel disease, and
      atherosclerosis. While these studies have raised significant enthusiasm for
      manipulation of NKT cells as a means of preventing autoimmunity in the clinical
      setting, there are significant concerns regarding the safety of repeated alpha
      GalCer injections in human subjects.

PMID- 15186264
TI  - Regulation of antitumour immunity by CD1d-restricted NKT cells.
AB  - An understanding of the complex interactions occurring between tumours and the
      immune system is a prerequisite for the rational design of effective cancer
      immunotherapies. To date, attention has focused mainly on the role the adaptive
      immune system plays in controlling tumourigenesis, with conventional T cells,
      which recognize peptide antigens presented by classical MHC molecules, coming
      under close scrutiny. Accumulating reports now suggest that an additional T-cell
      subset, known as CD1d-restricted natural killer T (NKT) cells, also plays a
      pivotal role in modulating antitumour responses. Found in both humans and mice,
      CD1d-restricted NKT cells are a highly specialized cell type that, in contrast to
      conventional T cells, recognize lipid/glycolipid antigens presented by the non
      classical MHC molecule CD1d. Several features of NKT cells, including their
      ability to rapidly produce large quantities of cytokines upon primary
      stimulation, make them ideal targets for developing anticancer immunotherapies.
      This intriguing cell type is the focus of this review.

PMID- 15186265
TI  - NKT cells and viral immunity.
AB  - Over the past 10 years a new population of cells has been the focus of much
      attention. The functions of these unique lymphocytes, characterized by the
      concomitant expression of T- and NK-cell markers and thus termed NKT cells, have
      been implicated in many diverse aspects of immunity, including regulation of
      autoimmune disorders, control of tumour growth and spread, and defence against a
      number of pathogens. Although much debate still remains as to the natural role of
      NKT cells, it is clear that these cells have the capacity, either constitutively
      or postactivation, to promote an amazing array of immunoregulatory responses. The
      involvement of NKT cells in viral immune-surveillance and their ability to induce
      protection against pathogens once activated make them an attractive clinical
      target.

PMID- 15186267
TI  - Immunohistochemistry in melanocytic proliferative lesions.
AB  - Melanoma incidence is rising worldwide. Early diagnosis is very important, as the
      most effective treatment for melanoma still consists of excision of the tumour
      before onset of the metastatic growth phase. Immunohistochemistry is a valuable
      tool for (dermato)pathologists to aid establishing diagnosis. Melanoma markers
      can be classified into two main categories: melanocytic differentiation markers
      and melanoma progression markers. Melanocytic differentiation markers are mostly
      used to distinguish poorly differentiated melanomas from non-melanocytic tumours
      and for staging of melanocytic proliferative lesions. Melanoma progression
      markers are most suitable to determine the level of malignancy and/or
      aggressiveness of tumour cells. This review describes the classification of
      melanoma markers, including commonly used and recently identified antigens with
      potential marker function. We characterize their expression profile in
      melanocytic proliferative lesions and their potential usefulness for diagnosis,
      prognosis, microstaging, immunotherapeutic purposes and evaluation of therapies.

PMID- 15186268
TI  - Microsatellite allelotyping differentiates chromophobe renal cell carcinomas from
      renal oncocytomas and identifies new genetic changes.
AB  - AIMS: The diagnosis of renal oncocytomas (ROs) and chromophobe renal cell
      carcinomas (RCCs) based on histological features is often uncertain. To assess
      the value of genetic analysis in their differential diagnosis we analysed 27 ROs
      and 21 chromophobe RCCs by microsatellite allelotyping. METHODS AND RESULTS:
      Markers at the short and long arms of chromosomes specifically involved in the
      genetic changes of the four main types of renal cancers were selected. Allelic
      changes were identified by automated sequencing. Allelic changes at chromosome 1p
      occurred in 8/26 (31%) and at chromosome 14q in 4/27 (15%) ROs. Loss of
      heterozygosity (LOH) at chromosomes 1, 2, 6, 10, 13, 17 and 21 were seen in 90%,
      90%, 96%, 86%, 85%, 90% and 72% of the chromophobe RCCs, respectively.
      Alterations of at least three of these chromosomal sites were detected in each
      chromophobe RCC. In addition, we found recurrent LOH at chromosomes 9p23 (43%),
      18q22 (30%), 5q22 (28%) and 8p (28%) in chromophobe RCCs. CONCLUSIONS:
      Chromophobe RCCs can be differentiated from ROs by analysing specific chromosomal
      regions with microsatellites.

PMID- 15186269
TI  - Microinvasive germ cell tumour (MGCT) adjacent to testicular germ cell tumours.
AB  - AIMS: To examine the occurrence and prognostic significance of intratubular germ
      cell neoplasia (IGCN) and microinvasive germ cell tumour (MGCT) in tissue
      adjacent to testicular germ cell tumours (TGCT) in adults. METHODS AND RESULTS:
      The study was based on two Danish studies of adult patients with stage I TGCT and
      included 255 patients. Of 106 patients with seminoma, 75 [71%, 95% confidence
      interval (CI) 61, 79] had IGCN without MGCT and nine (8%, CI 4, 15) had both IGCN
      and MGCT. Of 149 patients with non-seminoma, 62 (42%, CI 34, 50) had IGCN without
      MGCT, and 32 (22%, CI 15, 29) had both IGCN and MGCT. Non-seminomas with a
      seminoma component were more often associated with MGCT (23 of 54 testes, 43%, CI
      29, 57) than were non-seminomas without this component (nine of 95 testes, 10%,
      CI 4, 17) (P < 0.000 05, Fisher's exact test). Relapse-free survival was not
      influenced by the concomitant presence of the two precursor stages in the testes
      (P = 0.36, and P = 0.19, log rank test, respectively). CONCLUSIONS: MGCT was a
      relatively frequent finding in testes adjacent to a macroscopic TGCT. However,
      neither IGCN nor MGCT predicted relapse for patients with stage I TGCT.

PMID- 15186270
TI  - Histological indicators of prognosis in glioblastomas: retinoblastoma protein
      expression and oligodendroglial differentiation indicate improved survival.
AB  - AIM: To assess the potential prognostic significance of a range of molecular and
      morphological parameters in glioblastomas that can be applied in the setting of a
      routine diagnostic neuropathology laboratory. METHODS AND RESULTS: A consecutive
      series of 107 adult glioblastomas were studied. Retinoblastoma and deleted-in
      colon cancer (DCC) protein expression were assessed using immunocytochemistry and
      chromosome 10 loss by in-situ hybridization. Loss of retinoblastoma expression
      was associated with a worse outcome, which appeared to be independent of age.
      There was no significant association between chromosome 10 loss or DCC protein
      expression and survival. Survival was significantly increased in the 5% of
      patients whose tumours had focal morphological features suggesting
      oligodendroglial differentiation. CONCLUSIONS: Glioblastomas containing areas of
      oligodendroglial differentiation or showing widespread immunocytochemical
      expression of retinoblastoma protein have a better prognosis than those without
      these features.

PMID- 15186271
TI  - The activation profile of tumour-associated reactive T-cells differs in the
      nodular and diffuse patterns of lymphocyte predominant Hodgkin's disease.
AB  - AIMS: To compare the activation profile of T-cells in reactive lymphoid follicles
      with that of tumour-associated T-cells in lymphocyte predominant Hodgkin's
      disease (LPHD) with a nodular pattern (n = 21), LPHD with partial diffuse growth
      pattern (n = 11) and T-cell-rich large B-cell lymphoma (TCRLBCL, n = 8). METHODS
      AND RESULTS: Reactive germinal centres showed sparse numbers of T-cells positive
      for CD134, a transient/early T-cell activation marker, and only scattered T-cells
      in the interfollicular areas positive for CD38, a marker of persistent
      activation. Lymphoid follicles showing progressive transformation of germinal
      centres (PTGC) had more numerous CD134+ T-cells which were negative for CD38.
      Tumour-associated T-cells in nodular LPHD were frequently positive for CD134 (15
      of 16 cases, 94%), but negative or only focally positive for CD38 (three of 21
      cases, 14%). LPHD with diffuse areas, however, showed increased CD38+ T-cells in
      the diffuse component in 10 of 11 (90%) cases, with CD134+ T-cells being more
      prominent in the nodular tumour component. TCRLBCL showed strong, uniform CD38
      expression in T-cells and histiocytes in eight cases. CONCLUSIONS: T-cells in
      nodular LPHD express markers of transient/early T-cell activation. By contrast, T
      cells in the diffuse form of LPHD, similar to those in TCRLBCL, have an
      immunostaining profile consistent with persistent cellular activation. T-cell
      activation may precede or accompany histological progression in nodular LPHD and
      immunostaining for these markers, in small samples or in difficult cases, may be
      useful in highlighting those cases of LPHD undergoing histological progression.

PMID- 15186272
TI  - Adenosquamous carcinoma of the head and neck: criteria for diagnosis in a study
      of 12 cases.
AB  - AIMS: Adenosquamous carcinoma (ASC) of the head and neck is an unusual neoplasm
      in which a general consensus with regard to diagnostic criteria has not yet been
      reached. In this study we report the clinicopathological results of 12 ASCs, with
      special attention to their histological and immunohistochemical characteristics
      in order to define this neoplasm more precisely. METHODS AND RESULTS: All the
      patients were male with a peak incidence in the sixth decade of life. The tumours
      were located most frequently in the larynx and oral cavity, followed by the nasal
      cavity and pharynx. ASCs had two distinct histological components. The most
      extensive one was an usual keratinizing squamous cell carcinoma, arising from the
      surface epithelium, where characteristically severe dysplasia or carcinoma in
      situ was found in all cases. The second component was an adenocarcinoma, usually
      displayed in the deepest areas of the tumour. Evidence of origin from salivary or
      seromucinous glands was not found. Immunohistochemical studies demonstrated in
      most cases positivity of glandular differentiated areas for carcinoembryonic
      antigen (CEA) (11/12), CK7 (9/12) and CAM5.2 (7/12), whereas the squamous cell
      component was unreactive or reacted only focally for these markers. High
      molecular-weight cytokeratin 34BE12 was positive in both components and CK20 was
      always negative. All cases showed high expression of Ki67 antigen. Most of them
      had overexpression of p53 (8/12) and DNA aneuploidy (10/12). Fifty percent of
      patients with ASC died of disease after a mean period of 23 months (range 12-35
      months). CONCLUSIONS: ASC of the head and neck is an aggressive neoplasm that
      originates in the surface epithelium of the upper respiratory tract. Severe
      dysplasia or carcinoma in situ is usually found and its recognition helps to make
      the diagnosis. In addition to mucin stains, positive immunoreactivity for CEA,
      CK7 and CAM5.2 helps to identify the glandular component.

PMID- 15186273
TI  - High-grade carcinomas of the breast showing patterns of mixed ductal and
      myoepithelial differentiation (including myoepithelial cell-rich carcinoma of the
      breast).
AB  - AIMS: To assess the clinical, morphological and immunophenotypic characteristics
      of breast carcinomas showing patterns of mixed epithelial and myoepithelial
      differentiation. METHODS AND RESULTS: Included in the study were four carcinomas
      containing a mixed population of epithelial and myoepithelial cells identified
      using morphological features at the light microscopic level which were found
      amongst a review of 500 archival cases and two recently accessioned cases. The
      carcinomas varied in size from 20 to 38 mm and all were grade 3 ductal
      carcinomas. Most showed nodular and sheet-like cellular aggregates, although one
      case showed small solid cell aggregates with duct formation. The cells were
      large, round, polygonal or spindle-shaped and had areas of clear or eosinophilic
      cytoplasm in variable proportions. Foci of metaplasic carcinoma were present in
      three cases. All cases showed strong, patchy positivity for cytokeratin (CK)14,
      calponin, smooth actin and muscle specific actin. Epithelial membrane antigen and
      CK8 were positive in a similar proportion of cells. One patient died 23 months
      following diagnosis with metastatic carcinoma, another patient died of unrelated
      disease and four patients are alive with follow-up ranging from 18 months to 25
      years. CONCLUSIONS: High-grade carcinomas of the breast showing patterns of mixed
      ductal and myoepithelial differentiation may show additional morphological
      features such as foci of metaplasia and appear to have a good prognosis similar
      to myoepithelial cell-rich carcinomas. However, young age and lymph node
      metastasis may portend a worse prognosis.

PMID- 15186274
TI  - Variations in histological patterns of interstitial pneumonia between connective
      tissue disorders and their relationship to prognosis.
AB  - AIMS AND METHODS: Pulmonary parenchymal disease is common in patients with
      connective tissue disorders (CTDs). However, most reports precede recognition of
      non-specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung
      biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13),
      Sjogren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus
      erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of
      patterns of interstitial pneumonia and their impact on prognosis. RESULTS AND
      CONCLUSIONS: NSIP was the most common pattern with an overall biopsy prevalence
      of 39% and patient prevalence of 41%. There was variation in prevalence between
      individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5),
      rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjogren's
      syndrome showing chronic bronchiolitis (n = 4). These patterns presented either
      separately or in association with NSIP, occasionally with different patterns in
      biopsies from separate lobes. Only four patients showed a pattern of usual
      interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with
      PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern
      being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the
      systemic manifestation of the CTDs. When patients with CTDs present with chronic
      interstitial lung disease, the most common pattern is NSIP, although there is
      variation in pattern prevalence between individual disorders and patterns of
      interstitial pneumonia frequently overlap. These data suggest a different biology
      for intestitial pneumonias in CTDs when compared with the idiopathic interstitial
      pneumonias where UIP is the most common pattern. Mortality is similar to that
      seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior
      to the systemic manifestation of disease, this may have a bearing on the origin
      of some cases of putative idiopathic NSIP.

PMID- 15186276
TI  - DNA ploidy analysis in histopathology. Morphometry and DNA cytometry
      reproducibility conditions and clinical applications.

PMID- 15186275
TI  - Intraosseous benign notochordal cell tumours: overlooked precursors of classic
      chordomas?
AB  - AIMS: Intraosseous benign notochordal cell tumour is a recently recognized
      condition that may undergo malignant transformation to classic chordoma. The aim
      of this study was to describe its clinicopathological characteristics. METHODS
      AND RESULTS: One hundred vertebral columns from atlas to coccyx and 61 pieces of
      the clival portion of the skull base, which were dissected from 100 autopsy
      cases, were examined microscopically. Twenty-six intraosseous benign notochordal
      cell tumours were found in 20 cases. The patient group consisted of 15 males and
      five females with a mean age of 63 years. The results, according to anatomical
      segments, showed that 11.5% of the clivus, 5.0% of the cervical vertebrae, 0% of
      the thoracic vertebrae, 2.0% of the lumbar vertebrae, and 12.0% of the sacro
      coccygeal vertebrae were affected. Microscopic examination revealed well
      demarcated but unencapsulated sheets of bland physaliphorous cells mimicking
      adipocytes. The lesions lacked any intercellular myxoid matrix. The affected bone
      trabeculae were characteristically sclerotic. CONCLUSIONS: The study indicated a
      surprisingly high incidence of intraosseous benign notochordal cell tumours. The
      anatomical distribution of the tumours was identical to that of classic
      chordomas. The results support other evidence that classic chordomas develop from
      intraosseous benign notochordal cell tumours.

PMID- 15186277
TI  - Squamous metaplasia of the peritoneum: a potential diagnostic pitfall.

PMID- 15186278
TI  - Assignment of more than one gene to the same chromosome band on metaphase
      cytogenetics.

PMID- 15186279
TI  - Extramedullary haematopoietic tumour of the breast: a case report in a woman with
      secondary myelofibrosis following essential thrombocythaemia.

PMID- 15186281
TI  - Leiomyoma of the nipple, and normal subareolar muscle fibres, are oestrogen and
      progesterone receptor positive.

PMID- 15186282
TI  - Merkel cell carcinoma associated with a paraneoplastic neurological syndrome.

PMID- 15186283
TI  - Cytoplasmic birefringent needle-like inclusions in hepatocytes in a patient with
      hepatoerythropoietic porphyria.

PMID- 15186286
TI  - How to create successful partnerships-a review of the literature.
AB  - This literature review covers a wide range of publications (articles, books,
      reports and government publications) that provide an overview of the wider topic
      of partnership working. It is not a systematic review, but the authors' personal
      review, drawing largely on the resources available in the King's Fund Library.
      Partnership working is a key component of the UK government's modernization
      agenda, particularly in the health field. However, the principles of achieving
      successful partnership are generally applicable. The review therefore
      concentrates on literature that can provide guidance for people planning to set
      up a partnership, or re-evaluating an existing partnership. The sections of this
      review comprise: definition of partnership working; types of partnership;
      partnership initiatives; drivers; critical success factors; barriers; benefits;
      the process of partnership working; evaluation and assessment tools; demolishing
      the Berlin Wall: government policy on partnership working; exemplars of library
      information service partnerships.

PMID- 15186287
TI  - Community partnerships for health information training: medical librarians
      working with health-care professionals and consumers in Tennessee.
AB  - In Tennessee, several medical library outreach projects have involved
      collaborative work with health-care professionals, public librarians, consumers,
      faith-based organizations and community service agencies. The authors are medical
      librarians who worked as consultants, trainers and project directors to promote
      health literacy using PubMed medline and other health information resources in
      the several funding projects described here. We explain the programmes briefly,
      focusing on lessons learned and suggestions for those who follow us.

PMID- 15186288
TI  - Helping the public 'Discover Health' in their local library. Providing health
      information in public libraries: a partnership approach in Scotland.
AB  - A partnership between the Specialist Health Promotion Service of NHS Tayside and
      Dundee City Council developed a project, 'Discover Health', to bring health
      information to the public. The two main formats used were traditional leaflets
      and Internet access via the People's Network, both available in public libraries.
      The steering group for the project was made up of staff from both organisations.
      The NHS side secured the funding; the Council side provided the accommodation and
      information and communication technologies. The partnership worked well, and the
      project is continuing, with expansion in the pipeline for other areas within
      Tayside. The various aspects of the functioning of the partnership are discussed.
      A literature review of similar initiatives is included.

PMID- 15186289
TI  - Creation and development of an All-Wales Health Library Catalogue.
AB  - This article focuses on the collaboration between the University of Wales College
      of Medicine (UWCM) libraries and the Welsh National Health Service (NHS)
      libraries to create a joint library catalogue. The goal was to create an all
      Wales resource that gave users one access point to search for the location and
      availability of health-related material in any Welsh medical library. This
      venture grew out of the existing collaborative scheme, the All-Wales Health
      Information and Library Extension Services (AWHILES). Currently, all seven UWCM
      libraries and 17 NHS libraries contribute to the catalogue. Four more libraries
      are due to join in late 2003 or early 2004. All UWCM and AWHILES libraries would
      then be contributing members of the joint catalogue. The article discusses the
      background and motivation to the creation of the database. It explores the
      positives and negatives of the project plus what was learnt as the venture
      progressed. It reviews the establishment and operations of the Welsh Health
      Voyager User Group (WHVUG) created to involve all contributing members in the
      running and future development of the library catalogue.

PMID- 15186290
TI  - All for one, one for all: collaboration between NHS and Higher Education in
      establishing provision of a multi-disciplinary, hospital-based library and
      information services.
AB  - Developing multi-disciplinary library and information services is high on the
      agenda for many NHS trusts and this brings with it a climate of change for both
      those who manage and work in services today. The development of such new services
      needs to be carefully managed and developed, and this presents a challenge for
      librarians and service managers. In the UK during 1999 and 2000, Aintree Hospital
      Trust, in conjunction with Edge Hill College of Higher Education, established a
      truly multi-disciplinary service based at its hospital site and managed by Edge
      Hill. This paper outlines the key stages in the development of the Library and
      Information Service with the focus on the management of change, collaboration and
      the development of a unique partnership between Higher Education and an NHS
      trust. The case study example will provide an outline of strategic and project
      planning, with insights into staff management and development, delivering user
      expectations and developing stakeholder relationships in the health library
      setting.

PMID- 15186291
TI  - Partnership working in the production of clinical guidelines.
AB  - This article describes a working partnership between the Cairns Clinical
      Librarian Service, Health Care Libraries, University of Oxford and the Emergency
      Department (ED) at the John Radcliffe Hospital, Oxford. This collaboration
      resulted in the establishment of a guideline development group in June 2002. The
      aim of the group is to produce a set of easily accessible, user-orientated,
      evidence-based guidelines for the use of clinicians in the Emergency Department,
      within a realistic timescale. The Cairns Clinical Librarian Project was built on
      previous models of clinical librarianship and incorporated an evaluation of
      previous programmes. The objective was to provide information to clinicians at
      the time and point of need. Consultation with the ED from the outset determined
      the approach adopted by the Cairns team. Clinical guidelines have been shown to
      improve clinical practice. Pending the introduction of nationally available
      protocols, we have begun to establish a collection of evidence-based guidelines
      using web-based architecture in conjunction with the Oxford Radcliffe Hospitals
      NHS Trust's IT department. A piece of diagnostic analysis was undertaken to
      ensure a coherent strategy was developed for the guideline project. An
      'intermediate approach' was adopted, where existing valid guidelines were
      modified to fit local circumstances. We strove to be transparent at all times
      about all aspects of the guideline development process. Formative evaluation has
      shown how the application of evidence-based health care needs adequate resources
      and requires people with appropriate knowledge and skills. This article charts
      the progress of the project and highlights how the partnership between the
      clinical team and the Clinical Librarian has been deemed to be essential to the
      success of the project.

PMID- 15186292
TI  - Developing integrated knowledge services for NHS Scotland: managing continuity
      and transition within a new collaborative dynamic.

PMID- 15186293
TI  - A joined-up approach: how England's National electronic Library for Health (NeLH)
      is working with librarians.

PMID- 15186294
TI  - An unlikely grouping? The vision of CHILL. Co-operation between independent
      health libraries in London.

PMID- 15186295
TI  - Information partnerships building a health gateway-HealthInsite.

PMID- 15186298
TI  - Relaxation treatment administered by school nurses to adolescents with recurrent
      headaches.
AB  - OBJECTIVE: To study the outcome of two different forms of relaxation training
      administered by school nurses to adolescents suffering from recurrent headaches
      in an effectiveness study. METHODS: A total of 11 school nurses were randomized
      to administer one of the two treatments to 63 adolescents. A post hoc group with
      42 untreated subjects, matched for headache diagnosis, sex, and age were included
      as a control group. RESULTS: The results showed no pre-post differences in
      headache reduction between the treatment groups, however, subjects treated with
      either of the two relaxation approaches were significantly more improved than
      those in the post hoc group on total headache activity and headache-free days.
      Clinical improvement (at least 50% improvement) was attained among 19% of the
      treated subjects as compared to 7% for those in the post hoc group, a
      nonsignificant difference. Higher functional disability predicted a worse
      outcome, and positive self-statements predicted better outcome. Altogether, these
      variables accounted for 29% of the outcome variance in the total headache
      activity. CONCLUSIONS: In the present study, outcomes of relaxation training as
      administered by school nurses were not found to be as powerful as similar
      treatments provided for adolescents with migraine or tension-type headache in the
      previous controlled studies of clinic as well as school samples. It is likely
      that the school nurses need to be more thoroughly trained and informed to achieve
      cost-effective improvement. Presently, it is suggested that the relaxation
      training should not be used as a part of regular treatment in the school health
      care for adolescents with recurrent headaches until further evidence is provided.

PMID- 15186299
TI  - Self-reported headache frequency and features associated with frequent headaches
      in Canadian young adolescents.
AB  - OBJECTIVE: To explore the associated factors for frequent headache among young
      adolescent Canadians. METHODS: We analyzed the self-administered questionnaire
      microdata files of the National Longitudinal Survey of Children and Youth (NLSCY:
      1996 to 1997). Two thousand and ninety respondents representing 793,100 Canadian
      youth aged 12 to 13 years were asked how often they had headaches in the previous
      6 months. RESULTS: Of the 2090 adolescents, 1998 (96%) responded. Frequent
      headaches of "about once a week" or more often were reported by 26.6% of them
      aged 12 to 13 years (95% CI: 24.2, 28.6). Frequent headaches appear to be
      associated with a plethora of risk factors germane to the life experience of
      these young adolescents. All factors were significant at P <.0001 by chi-square
      analysis and can be loosely categorized as school-related, lifestyle-related, or
      involving mental health. A multivariate Classification and Regression Tree (CART)
      analysis models frequent headaches on a depression scale, a self-esteem scale,
      and ever having smoked, with 60% sensitivity, and 65% specificity. CONCLUSIONS:
      The NLSCY reveals a remarkable insight into headache frequency and the life
      experience of Canada's young adolescents with frequent headaches.

PMID- 15186300
TI  - The medical costs of migraine and comorbid anxiety and depression.
AB  - OBJECTIVE: To examine the direct medical costs associated with migraine, when
      diagnosed alone and in conjunction with anxiety and/or depression in adults and
      children. BACKGROUND: Migraine is a common disorder that can often be accompanied
      by comorbid anxiety and/or depression. Given the prevalence of migraine and the
      likelihood for comorbid conditions, it is not surprising that migraine is
      extremely costly for society. METHODS: Migraine cohorts were identified in a 1999
      2000 database capturing inpatient, outpatient, and prescription drug services
      from approximately 45 large employers. Four cohorts of adults (migraine only,
      migraine and anxiety, migraine and depression, migraine and both conditions), and
      two cohorts of children (migraine only, migraine and anxiety and/or depression),
      were compared to respective "healthy" cohorts. t-statistics were used to capture
      differences in costs between the migraine cohorts and the healthy cohorts whereas
      ANOVA was used to test for differences in costs between subgroups of migraine
      sufferers. RESULTS: Compared to nonmigraineurs, adults and children with migraine
      had significantly higher total direct medical costs in all examined categories (P
      < .0001) (7,089 US Dollars vs US Dollars adults; 4,272 US Dollars vs 1,400 US
      Dollars children). For adults, the presence of depression and/or anxiety along
      with migraine equated to significantly greater total direct medical costs when
      compared to their matched healthy cohorts (P < .0001) (12,642 US Dollars vs 5,179
      US Dollars anxiety; 11,290 US Dollars vs 3,135 US Dollars depression). Children
      with migraine and either anxiety or depression (or both) incurred an average of
      9,875 US Dollars in total direct medical costs as compared with only 1,165 US
      Dollars for healthy comparators. For children and adults, the presence of
      comorbid anxiety or depression was associated with significantly higher medical
      costs when compared to migraine alone (P < .0001). CONCLUSIONS: This analysis
      quantifies the economic impact of a migraine diagnosis for both adults and
      children. The results of this analysis demonstrate that individuals identified as
      migraineurs have significantly higher medical costs than healthy comparators,
      with or without comorbid anxiety and/or depression. This study also suggests that
      clinicians should be aware that while proper treatment of migraine with effective
      acute and prophylactic therapy is important, attention must also be directed to
      comorbid conditions.

PMID- 15186301
TI  - Impact of headache on quality of life in a general population survey in France
      (GRIM2000 Study).
AB  - OBJECTIVES: The objectives of this study were to determine the impact of headache
      on health-related quality of life in a nationwide sample of the French general
      population using a disease-specific measure, the Qualite de Vie et Migraine
      (QVM), to compare quality of life in subjects reporting different headache to
      types, and to evaluate the relationship between quality of life and severity,
      frequency, associated disability, and treatment responsiveness of headaches.
      METHODS: The QVM questionnaire was included within a large epidemiological survey
      of 1486 headache sufferers. Diagnosis was assigned retrospectively using an
      algorithm based on the International Headache Society classification. Headache
      severity was assessed with the MIGSEV scale and disability with the MIDAS scale.
      RESULTS: The mean global QVM score in the sample was 80.2. Quality of life was
      poorer in subjects with chronic daily headache (QVM score: 66.2) than in those
      with migraine (QVM score: 76.7), while those with other forms of episodic
      headache had the best quality of life (QVM score: 91.7). Quality-of-life scores
      were correlated with frequency, severity, disability, and treatment resistance of
      headaches (P <.001). CONCLUSION: The QVM scale is a sensitive tool to measure
      health-related quality of life in headache sufferers in the general population.

PMID- 15186302
TI  - Montelukast for migraine prophylaxis: a randomized, double-blind, placebo
      controlled study.
AB  - OBJECTIVE: To evaluate the efficacy and tolerability of montelukast 20 mg in the
      prophylactic treatment of migraine. BACKGROUND: A previous small open-label study
      in migraine patients suggested prophylactic efficacy for montelukast, an
      antagonist of the cysteinyl leukotriene receptor that is used in the treatment of
      asthma. We sought to confirm these findings in a randomized controlled trial.
      METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel
      groups study enrolled adult migraine outpatients who experienced > or =3 and < or
      =8 migraine attacks per month for the last 6 months. Patients were entered into a
      2-month, single-blind, placebo run-in phase. Only patients who experienced > or
      =3 migraine attacks in the second month were eligible to enter the subsequent 3
      month, double-blind treatment phase of the study. The primary efficacy endpoint
      was the percentage of patients reporting at least a 50% decrease in migraine
      attack frequency per month during the double-blind treatment period (months 3-5)
      compared to baseline (run-in month 2). RESULTS: A total of 93 patients were
      randomized to montelukast 20 mg and 84 patients to placebo at the end of the
      placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo
      completed the double-blind treatment period. Over 3 months of treatment, there
      was no significant difference between the two groups in the percentage of
      patients who reported at least a 50% decrease in migraine attack frequency per
      month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition,
      montelukast 20 mg was not significantly superior to placebo on any of the
      secondary endpoints. There were no differences between treatment groups for
      adverse events. CONCLUSION: Montelukast 20 mg was well tolerated in migraine
      patients but was not an effective prophylactic for prevention of migraine.

PMID- 15186303
TI  - Evidence-based diagnosis of nontraumatic headache in the emergency department: a
      consensus statement on four clinical scenarios.
AB  - OBJECTIVE: To provide to emergency department (ED) physicians with guidelines for
      diagnosis of patients with nontraumatic headaches. BACKGROUND: Many patients
      present to an ED with the chief complaint of headache. Causes of nontraumatic
      headache include life-threatening illnesses, and distinguishing patients with
      such ominous headaches from those with a primary headache disorder can be
      challenging for the ED physician. CONCLUSION: We present a consensus statement
      aimed to be a useful tool for ED doctors in making evidence-based diagnostic
      decisions in the management of adult patients with nontraumatic headache.
      METHODS: A multidisciplinary work performed an extensive review of the medical
      literature and applied the information obtained to commonly encountered scenarios
      in the ED.

PMID- 15186304
TI  - The effect of weather on headache.
AB  - OBJECTIVES: To assess headache patients' beliefs about how strongly weather
      affects their headaches; To objectively investigate the influence of multiple
      weather variables on headache. DESIGN AND METHODS: Our sample consisted of 77
      migraineurs seen in a headache clinic, who provided headache calendars for a
      period ranging from 2 to 24 months. Our study was divided into two phases. First,
      each patient was given a questionnaire assessing their beliefs about how strongly
      (if so) weather affected their headaches. Second, weather data were collected
      from the National Weather Service, from three reporting stations central to the
      residences of the study participants. Analysis was performed on 43 variables to
      generate three meteorological factors. Linear regression was used to assess the
      relationship between headache and these three factors. Factor 1 represents a
      function of absolute temperature and humidity. Factor 2 represents a changing
      weather pattern. Factor 3 represents barometric pressure. RESULTS: Of the 77
      subjects in the study, 39 (50.6%), were found to be sensitive to weather, but 48
      (62.3%) thought they were sensitive to weather conditions (P < 0.05). Thirty
      (38.9%) were sensitive to one weather factor and 9 (11.7%) to two factors. Twenty
      six (33.7%) were sensitive to factor 1; 11 (14.3%) to factor 2; 10 (12.9%) to
      factor 3. CONCLUSIONS: Our study supports the influence of weather variables on
      headache. We showed that patients are susceptible to multiple weather variables
      and that more patients thought weather was a trigger than was the case.

PMID- 15186305
TI  - Headache in sleep apnea syndrome.
AB  - OBJECTIVE: To find out whether there is a relationship between the headache
      characteristics and polysomnographic findings in patients with prediagnosis of
      the sleep apnea syndrome (SAS) and, if there is, to search for its possible
      cause. BACKGROUND: Chronic morning headache is considered by many to be an
      important part of the SAS. Some reports support this relationship, and some do
      not. METHODS: We questioned 75 patients with SAS about headache. Headaches were
      classified according to the International Headache Society (IHS-88) system. We
      evaluated the relationship between headache and polysomnographic findings.
      RESULTS: There was no statistically significant relationship between headache and
      apnea hypopnea index (AHI) or minimal oxygen saturation (P >.05). CONCLUSIONS: We
      could not demonstrate a statistically significant relationship between headache,
      AHI, and minimal oxygen saturation in our patients with SAS.

PMID- 15186306
TI  - Obstructive sleep apnea and cluster headache.
AB  - A patient with cluster headache often wakes from sleep. The relationship to sleep
      apnea has been described. This study sought to confirm the relationship cluster
      may have with sleep apnea. METHODS: Thirty-nine consecutive patients diagnosed
      with episodic cluster headache according to the International Headache Society
      (IHS) criteria were sent for polysomnographic studies. All patients were in an
      active phase when they were in the study. Patients were told of the proposed
      relationship and were allowed to choose a sleep laboratory close to their home.
      RESULTS: Thirty-one patients with episodic cluster headache completed an
      overnight polysomnographic study. Twenty-three were male and eight female. The
      average age was 51 years (range 33 to 78 years). The average weight was 173
      pounds (range 117 to 260 pounds). A total of 80.64% had sleep apnea (25/31).
      Average respiratory depression index (RDI) was 19.0 (SD 14.6) with 6 patients
      having no apnea, 10 having mild, 11 having moderate, and 4 having severe apnea
      (RDI < 5 = none; RDI 5 to 20 mild; RDI 20 to 40 moderate; RDI > 40 severe).
      Oxygen saturation decreased on average to 88.4% SD 4.5. Sleep efficiency was
      76.2% (SD 13.4). CONCLUSIONS: The data closely approximate those of Chervin et
      al, where 80% had RDI > 5. The relationship sleep apnea has in the perpetuation
      or precipitation of cluster headache is still to be determined. There are some
      reports that treatment stops the cluster but there is no prospective study. The
      high incidence (80.64%) seen in this population suggests the cluster patient
      should receive a sleep evaluation and perhaps intervention with continuous
      positive airway pressure (CPAP) or an appropriate dental device.

PMID- 15186307
TI  - Nummular headache: a prospective series of 14 new cases.
AB  - OBJECTIVE: To study the clinical features of nummular headache (NH) and get an
      approach to its epidemiology. BACKGROUND: NH has been recently described as a
      primary disorder characterized by head pain exclusively felt in a small rounded
      area typically 2-6 cm in diameter. METHODS: Through a 1-year period we have
      studied all patients referred to our neurologic clinic because of head pain
      exclusively felt in a small-circumscribed area, and not attributed to another
      disorder. All the patients had normal neurological, analytical, and neuroimaging
      examinations. All the patients belonged within the same regional care system
      comprising 220,000 inhabitants. RESULTS: A total of 11 females and 3 males were
      studied. Based in our hospital series, the incidence was 6.4/100,000/year. The
      mean age at the onset was 38 years (range: 13-72). Only three patients had
      another concurrent headache: migraine (n = 2), and trigeminal neuralgia (n = 1)
      which proved to have an independent course. All the patients reported head pain
      exclusively felt in either a rounded (n = 12) of 1-6 cm diameter, or an oval area
      (n = 2) of 5 x 3 cm, and 2 x 3 cm, respectively. Both size and shape of the
      painful area remained constant since the onset of symptoms. The location of the
      symptomatic area was mostly parietal (n = 7) or temporal (n = 5), but also
      frontal (n = 1) and in occiput (n = 1). The background pain was mostly mild-to
      moderate, but also moderate-to-severe pain was reported. Exacerbations-either
      spontaneous or precipitated by combing hair or touching the symptomatic area-were
      reported by 8 patients. The temporal pattern was chronic-continuous (n = 7) and
      episodic (n = 7). Ten patients reported a variable combination of sensory
      disturbance (tenderness, hypoesthesia, hyperalgesia, and allodynia) in the
      symptomatic area. There were no autonomic accompaniments. Treatment was generally
      not necessary. When needed, standard oral doses of paracetamol usually sufficed.
      CONCLUSIONS: NH emerges as a clear-cut clinical picture. It is a noninfrequent
      primary headache. The particular topography suggests the pain has a probable
      epicranial source conveyed by, or originated in, one/a few terminal branch(es) of
      the cutaneous nerves of the scalp.

PMID- 15186308
TI  - Spontaneous intracranial hypotension syndrome: report of twelve cases.
AB  - PURPOSE: To investigate clinical, MRI, and radioisotope findings and therapeutic
      outcome of the syndrome of spontaneous intracranial hypotension (SIH).
      BACKGROUND: Spontaneous intracranial hypotension is characterized by orthostatic
      headache, low CSF pressure, and MRI findings of diffuse pachymeningeal gadolinium
      enhancement without previous history of head trauma or lumbar puncture.
      Spontaneous CSF leakage from a spinal dural tear has been suggested as the
      underlying pathogenic mechanism of SIH. Most patients recover without sequelae,
      but subdural collections have been described in a few. METHODS: Twelve
      consecutive patients (10 females, 2 males, mean age 39 years) with headache
      related to the syndrome of spontaneous intracranial hypotension were
      investigated. RESULTS: Eleven patients presented orthostatic headache, one
      patient had continuous nonpostural headache. Additional clinical symptoms
      included nausea, vomiting, tinnitus, diplopia, and back pain. All the patients
      had low CSF opening pressure, seven had increased CSF albumin, and four had
      pleocytosis. Brain MRI showed diffuse pachymeningeal gadolinium enhancement.
      Other features included subdural fluid collections (hematoma/hygroma) in four
      patients, downward displacement of the brain in four patients, and enlargement of
      the pituitary gland in one patient. Radioisotope cisternography results
      indicated, in two patients, a CSF leakage site in the cervico-thoracic region,
      and in one patient showed limited ascent of the tracer to the cerebral convexity
      and early appearance of radioisotope in the bladder. All the patients had
      complete resolution of headache with conservative treatment. CONCLUSIONS:
      Patients with SIH have distinct MRI and sometimes radioisotope cisternographic
      abnormalities and generally respond favorably to conservative management.

PMID- 15186309
TI  - Headache from chronic subdural hematoma: negative CT, positive MRI.

PMID- 15186310
TI  - The Alice in Wonderland Syndrome.

PMID- 15186311
TI  - Toward better characterization of the migraine patient: "complex migraine
      comorbidity disorder".

PMID- 15186318
TI  - Statins: novel additions to the dermatologic arsenal?
AB  - The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
      (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and
      simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is
      growing evidence that statins have immunomodulatory activities. Statins
      downregulate the expression of adhesion molecules, intercellular adhesion
      molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte
      function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and,
      through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is
      crucial for activation of lymphocytes by antigen-presenting cells, ingress of
      leucocytes into the inflammation sites and immunologic cytotoxicity. Statins
      inhibit the inducible expression of major histocompatibility complex class II in
      several cell types including macrophages and downregulate the expression of T
      helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of
      activation of lymphocytes and their infiltration into the inflammation sites.
      Statins block the induction of inducible nitric oxide synthase and the expression
      of several proinflammatory cytokines such as tumour necrosis factor-alpha and
      interferon-gamma in macrophages and possess antioxidant effects. These agents
      inhibit the proliferation of immunocytes and the activation of natural killer
      cells. Regarding the above facts and in view of their safety and inexpensiveness,
      statins may prove invaluable in the treatment of a multiplicity of dermatologic
      disorders, especially those characterized by ingress of activated leucocytes into
      the skin, such as alopecia areata, vitiligo, lichen planus, subacute cutaneous
      lupus erythematosus, erythema multiforme, psoriasis, bullous pemphigoid, systemic
      sclerosis, mycosis fungoides, toxic epidermal necrolysis and Behcet's disease.

PMID- 15186320
TI  - Suprabasal expression of human amphiregulin in the epidermis of transgenic mice
      induces a severe, early-onset, psoriasis-like skin pathology: expression of
      amphiregulin in the basal epidermis is also associated with synovitis.
AB  - The expression of amphiregulin (AR) in the basal epidermis of transgenic mice
      [keratin 14 promoter AR gene (K14-ARGE)] has been previously shown to induce an
      early-onset and severe skin pathology, with many similarities to psoriasis. In
      this study, it is demonstrated that involucrin enhancer/promoter-dependent
      expression of human AR (INV-AR) in the suprabasal epidermis of transgenic mice
      also produces a cutaneous psoriasis-like phenotype. INV-AR mice possess a limited
      lifespan and scaling, papillomatous, erythematous skin with partial alopecia. INV
      AR mouse histopathology also revealed epidermal hyperkeratosis, parakeratosis,
      acanthosis, and an exaggerated dermal vasculature. A dermal and epidermal
      infiltrate was also evident and consisted of both neutrophils and CD3(+) T
      lymphocytes. The histology of synovial joints in both the INV-AR mice and the K14
      ARGE mice of our previous investigation was examined. The histologic examination
      revealed that 3-week-old INV-AR transgenic mice displayed normal knee joint
      histology, while 2- to 3-week-old K14-ARGE transgenic mice frequently displayed
      synovitis, as exemplified by the presence of a mixed leukocytic infiltration,
      increased vascularization, and enhanced deposition of fibrous matrix in the knee
      synovium. These results demonstrate that AR overexpression in both the basal and
      suprabasal epidermis of transgenic mice induces a phenotype that mimics cutaneous
      psoriasis, while basal AR expression is also associated with synovial
      inflammation, a precursor to the psoriasis-associated arthropathy, psoriatic
      arthritis. Collectively, the results implicate epidermal AR expression as a
      possible mediator of innate cutaneous immunity and epidermal proliferation and
      also as a potential trigger of both cutaneous psoriasis and psoriatic arthritis.

PMID- 15186319
TI  - Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis resembles
      psoriasis with regard to abnormal cytokine expression and epidermal activation.
AB  - Psoriasis is a chronic inflammatory skin disorder characterized by accumulation
      of Th1-type T cells and neutrophils, regenerative keratinocyte proliferation and
      differentiation, and enhanced epidermal production of antimicrobial peptides. The
      underlying cause is unknown, but there are some similarities with the immunologic
      defense program against bacteria. Development of psoriasiform skin lesions has
      been reported after administration of granulocyte colony-stimulating factor (G
      CSF), a cytokine induced in monocytes by bacterial antigens. To further
      investigate the relation between this type of cytokine-induced dermatitis and
      psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor
      alpha (TNF-alpha), interferon-gamma, transforming growth factor-beta1 (TGF
      beta1), interleukin-10 (IL-10), IL-12p35 and p40, and IL-8] and expression of
      markers of epidermal activation [Ki-67, cytokeratin-16, major histocompatibility
      complex (MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a patient
      who developed G-CSF-induced psoriasiform dermatitis by using quantitative real
      time reverse transcriptase-polymerase chain reaction and immunohistology. The
      histologic picture resembled psoriasis with regard to epidermal
      hyperparakeratosis and the accumulation of lymphocytes in the upper corium.
      CD8(+) T cells were found to infiltrate the epidermis which was associated with
      an aberrant expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on
      adjacent keratinocytes. As compared to normal skin (n = 7), there was an
      increased expression of TNF-alpha, IL-12p40, and IL-8, a decreased expression of
      TGF-beta1, and a lack of IL-10, similar to the findings in active psoriasis (n =
      8). Therefore, G-CSF may cause a lymphocytic dermatitis that, similar to
      psoriasis, is characterized by a pro-inflammatory Th1-type cytokine milieu and an
      epidermal phenotype indicative of aberrant maturation and acquisition of non
      professional immune functions.

PMID- 15186321
TI  - Serum levels of manganese superoxide dismutase in patients with localized
      scleroderma.
AB  - The objective was to determine the serum levels of manganese superoxide dismutase
      (Mn SOD) in patients with localized scleroderma and investigate their clinical
      significance in this disease. Serum samples from 15 patients with localized
      scleroderma and 20 healthy volunteers were examined by a specific enzyme-linked
      immunosorbent assay. Serum levels of Mn SOD were significantly higher in patients
      with generalized morphea than those in healthy individuals. And the patients with
      elevated serum Mn SOD levels had significantly larger number of sclerotic lesions
      and significantly higher serum levels of soluble interleukin-2 receptor than
      those without it. These results suggested that the serum levels of this enzyme
      may be a serological marker for the disease activity and the extent of skin
      involvement in this disease.

PMID- 15186322
TI  - Lipid raft-enriched stem cell-like keratinocytes in the epidermis, hair follicles
      and sinus tracts in hidradenitis suppurativa.
AB  - Hidradenitis suppurativa (HS) is a disease, that causes considerable morbidity in
      patients. A histological hallmark of the disorder is the formation of sinus
      tracts in the dermis and the subcutis. Biologically, they represent a poorly
      understood phenomenon involving the infiltrative growth of proliferating non
      malignant keratinocytes. Lipid domains in plasma membranes (lipid rafts) play a
      role in the function of growth factors and are suspected of having a pathogenic
      role in cell migration and invasive growth. Using HS as a model, the presence of
      lipid rafts was studied using cholera toxin conjugated with FITC (CTx-FITC) and
      antibeta1 integrin (CD29)-CyChrome conjugate fluorescence staining of unfixed and
      acetone-fixed cryostat sections of lesional and paralesional skin samples. The
      double-labeled skin samples were observed in the confocal laser-scanning
      fluorescence microscope. Samples were obtained from five patients with HS. The
      lesional epidermis of HS contained three populations of keratinocytes:
      CD29(bright)CTx(dim), CD29(dim)CTx(bright) and a third hitherto unseen population
      containing double-positive CD29(bright)CTx(bright) cells. The
      CD29(bright)CTx(dim) population resembles the earlier described epidermal stem
      like cells, while the CD29(dim)CTx(bright) basal keratinocytes overlap with the
      transit-amplifying cell pool. The new population of double-positive
      CD29(bright)CTx(bright) cells was localized on the slopes of the papillas,
      focally in the suprabasal epidermal layers, in some hair follicles and in the
      majority of sinus tracts. Such double-positive cells have not previously been
      encountered by us in normal epidermis and hair follicles. Using HS as a model, it
      is suggested that the keratinocytes involved in sinus tract formation are
      CD29(bright)CTx(bright) cells. Owing to the physical proximity of the cells, it
      is hypothesised that the described CD29(bright)CTx(bright) cells result from an
      increased expression of CD29 on the CTx(bright) cells. It is likely that the
      double-positive CD29(bright)CTx(bright) cells emerge due to the influence of
      local inflammatory cytokines. Sinus tract formation may represent an aberrant
      epidermal repair response executed by the activated CD29(bright)CTx(bright)
      keratinocytes capable of non-malignant infiltrative growth in the dermis and
      subcutis.

PMID- 15186323
TI  - The production of collagen and the activity of mast-cell chymase increase in
      human skin after irradiation therapy.
AB  - Fibrosis is a common complication of radiotherapy. The pathogenesis of radiation
      induced fibrosis is not known in detail. There is increasing evidence to suggest
      that mast cells contribute to various fibrotic conditions. Several mast-cell
      mediators have been proposed to have a role in fibrogenesis. Tryptase and
      chymase, the predominant proteins in mast cells, have been shown to induce
      fibroblast proliferation and collagen synthesis in vitro. In order to explore the
      role of mast cells in irradiation-induced fibrosis, we analyzed skin biopsies and
      suction blister fluid (SBF) samples from the lesional and healthy-looking skin of
      10 patients who had been treated for breast cancer with surgery and radiotherapy.
      The biopsies were analyzed histochemically for mast-cell tryptase, chymase, kit
      receptor, and tumor necrosis factor-alpha. Skin collagen synthesis was assessed
      by determining the levels of type I and III procollagen amino-terminal
      propeptides (PINP and PIIINP) in SBF and using immunohistochemical staining for
      PINP. Immunohistochemical stainings for prolyl-4-hydroxylase reflecting collagen
      synthesis and chymase immunoreactivity in irradiated and control skin were also
      performed. The mean level of procollagen propeptides in SBF, which reflects
      actual skin collagen synthesis in vivo, was markedly increased in irradiated skin
      compared to corresponding healthy control skin areas. The mean number of PINP
      positive fibroblasts was also significantly increased in the upper dermis of
      radiotherapy-treated skin. The number of cells positive for tryptase, chymase and
      kit receptor was markedly increased in irradiated skin. In addition, using double
      staining techniques, it was possible to demonstrate that in some areas of the
      dermis, tryptase-positive mast cells and fibroblasts are closely associated.
      These findings suggest a possible role of mast cells in enhanced skin collagen
      synthesis and fibrosis induced by radiotherapy.

PMID- 15186324
TI  - The molecular basis of porphyria cutanea tarda in Chile: identification and
      functional characterization of mutations in the uroporphyrinogen decarboxylase
      gene.
AB  - The porphyrias are heterogeneous disorders arising from predominantly inherited
      catalytic deficiencies of specific enzymes in heme biosynthesis. Porphyria
      cutanea tarda (PCT) results from a decreased activity of uroporphyrinogen
      decarboxylase, the fifth enzyme in heme biosynthesis. The disorder represents the
      only porphyria that is not exclusively inherited monogenetically. In PCT, at
      least two different types can be distinguished: acquired/sporadic (type I) PCT,
      in which the enzymatic deficiency is limited to the liver and inherited/familial
      (type II) PCT, which is inherited as an autosomal dominant trait with a decrease
      of enzymatic activity in all tissues. In an effort to characterize the molecular
      basis of PCT in Chile, we identified eight mutations in 18 previously
      unclassified PCT families by polymerase chain reaction, heteroduplex analysis,
      and automated sequencing. To study the role of these mutations in disease
      causality, in vitro expression of all novel missense mutations was studied. Our
      results indicate that the frequency of familial PCT in Chile is approximately
      50%, thus, to our knowledge, representing the highest incidence of familial PCT
      reported to date. The data further emphasize the molecular heterogeneity in type
      II PCT and demonstrate the advantages of molecular genetic techniques as a
      diagnostic tool and in the detection of clinically asymptomatic mutation
      carriers.

PMID- 15186326
TI  - Near-infrared Fourier transform Raman spectroscopic analysis of proteins, water
      and lipids in intact normal stratum corneum and psoriasis scales.
AB  - Previous biochemical studies demonstrated differences in the structure of lipids
      in normal skin and psoriatic lesions. Raman spectroscopy provides a unique
      possibility of studying the molecular structure of proteins, lipids and water in
      intact skin. Near-infrared Fourier transform Raman spectroscopy was used to study
      changes in molecular structure and conformation of proteins and lipids of stratum
      corneum in healthy persons and patients with psoriasis. In vitro Raman spectra
      were obtained from intact psoriatic scales in 11 patients and from normal stratum
      corneum of forearm, elbow and heel in a group of age-matched healthy persons. The
      spectra of stratum corneum differed between psoriasis and normal skin but not
      between investigated regions. No major changes of lipid band positions in Raman
      spectra were found, but the crystalline lipid structure was disrupted in
      psoriatic scales (assessed as the ratio of the symmetric methylene C-H stretching
      mode intensities, S(lat)). Major spectral differences were seen in the molecular
      structure of the proteins. In the spectra of psoriatic scales, the peak position
      of the amide I band, in comparison with the normal skin, was shifted to higher
      wavenumbers, suggesting unfolding of proteins. Moreover, alterations in the
      disulfide stretch bonds of proteins were found in psoriasis scales, resulting in
      a less energetically favourable gauche-gauche-trans conformation (band around 520
      cm(-1)). Psoriatic scales and normal stratum corneum did not statistically differ
      in their water content. The findings further define the molecular abnormalities
      in the stratum corneum in psoriasis.

PMID- 15186325
TI  - IP-10-encoding plasmid DNA therapy exhibits anti-tumor and anti-metastatic
      efficiency.
AB  - We report here that the interferon-induced protein of 10 kDa (IP-10 or CXCL10)
      elicits strong anti-tumor and anti-metastatic responses in mice when administered
      by plasmid DNA. Intratumoral but not intramuscular IP-10 DNA inoculation resulted
      in reduced tumor formation of malignant melanoma (B16F10) and Lewis lung
      carcinoma (LL/2) in C57BL/6 mice. In addition, plasmid DNA-encoding IP-10
      substantially reduced the establishment of metastases when injected systemically
      by the intramuscular route. In contrast to the primary tumor model, the anti
      metastatic effect of DNA-encoding IP-10 was primarily mediated by NK cells.
      Compared to DNA-encoding interleukin-12 (IL-12), therapy with DNA-encoding IP-10
      exhibits lower efficacy against primary melanoma tumors but equivalent efficacy
      against primary Lewis lung tumors and against B16F10 lung metastasis formation.
      Co-administration of DNA-encoding IP-10 and IL-12 enhanced the anti-tumor
      activity of IL-12 in the lung metastasis model but had little effect in the local
      treatment of established subcutaneous tumors. Interestingly, treatment of nude
      mice lacking T lymphocytes with DNA-encoding IP-10 or IL-12 still resulted in a
      pronounced reduction of tumor growth or metastasis formation.

PMID- 15186327
TI  - Identification of mutations in the ATP2A2 gene in patients with Darier's disease
      from Hungary.
AB  - Mutation analysis in the ATP2A2 gene had been performed in eight Hungarian
      patients with Darier's disease (DD), to get more information about phenotype
      genotype relations. All patients had moderate to severe skin symptoms. Polymerase
      chain reaction (PCR) amplification of the entire coding region of ATP2A2 was
      performed. Mutation detection strategies included heteroduplex scanning by
      conformation-sensitive gel electrophoresis (CSGE) and direct nucleotide
      sequencing. We found distinct, heterozygous mutations (five missense, one
      nonsense, one deletion, and one insertion), six of which were novel. In a 31-year
      old DD woman with learning difficulties we disclosed a previously described
      missense mutation (D702N) in exon 15. A 44-year-old DD woman had a novel T
      insertion at nucleotide 559 in exon 7 of the ATP2A2 gene, which resulted in a
      premature termination codon (PTC) at codon 192. A woman, whose skin symptoms
      developed unusually late, at the age 50, had a new T deletion (1320delT) in exon
      11 resulting in a PTC at codon 448. Our most severe case had a known missense
      mutation N39T, resulting in a non-conservative amino acid change at the upstream
      stalk region. Three new missense mutations (A161D, R164S, and Q790P) affected
      conservative regions of the SERCA2 protein within the activation (A)-domain and
      the M6 transmembrane region. A further new nonsense mutation (C909X) was detected
      in the M8 transmembrane domain. Our data suggest that differences in DD
      phenotypes are probably also related to factors different from the type of
      causative mutation.

PMID- 15186339
TI  - Neurobiology of seizures and behavioral abnormalities.
AB  - Seizures are both caused by and induce a complex set of neurobiological
      alterations and adaptations. The animal model of amygdala kindling provides
      insight into the spatiotemporal evolution of these changes as a function of
      seizure development and progression. Intracellular, synaptic, and microstructural
      changes are revealed as related to both the primary pathophysiology of kindled
      seizure evolution and compensatory secondary, or endogenous anticonvulsant
      adaptations. At the level of gene expression, the balance of these pathological
      and adaptive processes (as augmented by exogenous medications) probably
      determines whether seizures will be manifest or suppressed and could account for
      aspects of their intermittency. As anxiety and emotion modulation are subserved
      by many of the same neuroanatomic substrates involved in the evolution of complex
      partial seizures, particularly those of the medial temporal lobe, it is readily
      conceptualized how vulnerability to a range of psychiatric disorders could be
      related to the primary or secondary neurochemical alterations associated with
      seizure disorders. The discrete and methodologically controlled elucidation of
      the cascades and spatiotemporal distributions of neurobiological alterations that
      accompany seizure evolution in the kindling model may help resolve some of the
      difficulty and complexity of elucidating these biobehavioral relationships in the
      clinic.

PMID- 15186340
TI  - The treatment of nonepileptic seizures: historical perspectives and future
      directions.
AB  - Nonepileptic seizures (NES) are neuropsychiatric disorders presenting with a
      combination of neurologic signs and underlying psychological conflicts. For more
      than a century, the medical community has accumulated data and insights about the
      phenomenology, epidemiology, risks, comorbidities, and prognosis of NES. However,
      we have not progressed much beyond anecdotal reports of treatments for NES, and
      no randomized, controlled trials of treatment for the disorder have been
      conducted. We review the diagnosis and treatment of NES and suggest directions
      for future research in these areas.

PMID- 15186341
TI  - Recognition of the various expressions of anxiety, psychosis, and aggression in
      epilepsy.
AB  - Anxiety, psychosis, and aggressive behavior are among the frequent comorbid
      psychiatric disorders identified in patients with epilepsy. Often the clinical
      manifestations of these disorders vary according to their temporal relation
      relative to seizure occurrence. Thus, postictal symptoms of anxiety or psychosis
      differ in severity, duration, and response to treatment with interictal
      symptomatology. Psychiatric symptomatology in epilepsy can appear concurrently
      with the seizure disorder and improve or remit on the abolition of epileptic
      activity. We refer to these as paraictal psychiatric phenomena. Such is the case
      of aggressive disturbances associated with gelastic seizures caused by
      hypothalamic hamartomas. In this article, three case studies are presented to
      illustrate the importance of distinguishing psychiatric symptoms of anxiety,
      psychosis, and aggression, with respect to their temporal relation with seizure
      occurrence.

PMID- 15186343
TI  - Therapy for neurobehavioral disorders in epilepsy.
AB  - Neurobehavioral disorders commonly affect patients with epilepsy. In addition to
      the behavioral changes during and immediately after seizures, the epileptogenic
      disorder of function often extends further into the postictal and interictal
      period. Cognitive impairments commonly affect attention, memory, mental speed,
      and language, as well as executive and social functions. Reducing seizure
      frequency and the antiepileptic drug burden can reduce these problems.
      Attentional deficits may respond to therapies for attention-deficit/hyperactivity
      disorder, but apart from patients with this comorbid disorder, their efficacy is
      unproven in other epilepsy patients. No effective therapies are established for
      other cognitive problems, but pragmatic, compensatory strategies can be helpful.
      Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of
      these disorders usually respond well to pharmacotherapy, which can be
      supplemented by psychotherapy. Cognitive and behavioral disorders can be the
      greatest cause of morbidity and impaired quality of life, often overshadowing
      seizures. Yet these problems often go unrecognized and, even when identified, are
      often undertreated or untreated.

PMID- 15186342
TI  - Depression in epilepsy: ignoring clinical expression of neuronal network
      dysfunction?
AB  - Epilepsy is a chronic disorder that adversely affects social, vocational, and
      psychological functioning. Despite the variety and complexity of the negative
      clinical associations with epilepsy, depression is remarkable in prevalence and
      related adverse effects on health status. An estimated 30-50% of persons with
      refractory epilepsy have major depression, and depression has a stronger
      correlation than seizure rate with quality of life. Suicide is one of the leading
      causes of death in epilepsy. Available data indicate that depression may result
      from underlying brain dysfunction rather than social and vocational disability.
      Most patients with depression are not screened systematically for the diagnosis,
      and are subsequently not treated. Although the density of serotonin receptors is
      greatest in limbic brain regions commonly involved in human epilepsy, such as the
      mesial temporal and prefrontal areas, no prior randomized controlled trials have
      evaluated the efficacy of serotonin reuptake inhibitors for depression in
      epilepsy.

PMID- 15186344
TI  - Genetic organization of the catabolic plasmid pJP4 from Ralstonia eutropha JMP134
      (pJP4) reveals mechanisms of adaptation to chloroaromatic pollutants and
      evolution of specialized chloroaromatic degradation pathways.
AB  - Ralstonia eutropha JMP134 (pJP4) is a useful model for the study of bacterial
      degradation of substituted aromatic pollutants. Several key degrading
      capabilities, encoded by tfd genes, are located in the 88 kb, self-transmissible,
      IncP-1 beta plasmid pJP4. The complete sequence of the 87,688 nucleotides of
      pJP4, encoding 83 open reading frames (ORFs), is reported. Most of the coding
      sequence corresponds to a well-conserved IncP-1 beta backbone and the previously
      reported tfd genes. In addition, we found hypothetical proteins putatively
      involved in the transport of aromatic compounds and short-chain fatty acid
      oxidation. ORFs related to mobile elements, including the Tn501-encoded mercury
      resistance determinants, an IS1071-based composite transposon and a cryptic class
      II transposon, are also present in pJP4. These mobile elements are inefficient in
      transposition and are located in two regions of pJP4 that are rich in remnants of
      lateral gene transfer events. pJP4 plasmid was able to capture chromosomal genes
      and form hybrid plasmids with the IncP-1 alpha plasmid RP4. These observations
      are integrated into a model for the evolution of pJP4, which reveals mechanisms
      of bacterial adaptation to degrade pollutants.

PMID- 15186345
TI  - Adaptation of sympatric Achromatium spp. to different redox conditions as a
      mechanism for coexistence of functionally similar sulphur bacteria.
AB  - Changes in the abundance of sympatric Achromatium spp. in response to the
      artificial manipulation of redox conditions in sediment microcosms was determined
      by fluorescence in situ hybridization (FISH). Adaptation to different redox
      conditions was shown to be one mechanism that supported the coexistence of
      functionally similar Achromatium spp. In sediment microcosms, in which the
      overlying water was oxygenated, Achromatium community size and composition
      remained unchanged over time. However, imposition of anoxic conditions induced
      changes in community structure. Anoxia caused a reduction in the relative
      abundance of Achromatium sp. RY8 (72 +/- 4% to 49 +/- 2%) and an increase in
      Achromatium sp. RY5 (19 +/- 5% to 32 +/- 3%) and a newly identified Achromatium
      sp., RYKS (14 +/- 4% to 27 +/- 2%). In anoxic microcosms supplemented with a
      single addition of nitrate at different initial concentrations the relative
      decline in Achromatium sp. RY8 was dependent on the initial nitrate
      concentration. In these experiments nitrate was rapidly removed. In contrast,
      when high levels of nitrate were maintained by periodic replacement of the
      overlying water with nitrate supplemented anoxic water, the composition of the
      Achromatium community remained stable over time. This suggested that all of the
      coexisting Achromatium spp. are obligate or facultative anaerobes, but,
      Achromatium sp. RY8 was more sensitive to sediment redox conditions than the
      other Achromatium species. Given the heterogeneous nature of sedimentary
      environments, redox-related niche differentiation may promote coexistence of
      sympatric Achromatium spp.

PMID- 15186346
TI  - Design and application of two oligonucleotide probes for the identification of
      Geodermatophilaceae strains using fluorescence in situ hybridization (FISH).
AB  - Bacteria of the family of Geodermatophilaceae are actively involved in the decay
      processes [Urzi, C. and Realini, M. (1998) Int Biodeterior Biodegrad 42: 45-54;
      Urzi, C., Salamone, P., Schumann, P., and Stackebrandt, E. (2000) Int J Syst Evol
      Microbiol 50: 529-536] of stone monuments. Characterization of isolates includes
      phenotypic, chemotaxonomic and genetic analysis often requiring long-term
      procedures. The use of specific probes for members of Geodermatophilaceae family
      could be useful for the easy detection of those strains colonizing rock surfaces
      and involved in the biodeterioration. Two 16S rRNA-targeted oligonucleotide
      probes were designed for the specific detection of members of the family
      Geodermatophilaceae using fluorescence in situ hybridization (FISH); one probe
      specific for members of the two genera Geodermatophilus/Blastococcus and the
      second for members of the genus Modestobacter.

PMID- 15186348
TI  - Occurrence and distribution of Vibrio cholerae in the coastal environment of
      Peru.
AB  - The occurrence and distribution of Vibrio cholerae in sea water and plankton
      along the coast of Peru were studied from October 1997 to June 2000, and included
      the 1997-98 El Nino event. Samples were collected at four sites in coastal waters
      off Peru at monthly intervals. Of 178 samples collected and tested, V. cholerae
      O1 was cultured from 10 (5.6%) samples, and V. cholerae O1 was detected by direct
      fluorescent antibody assay in 26 out of 159 samples tested (16.4%). Based on the
      number of cholera cases reported in Peru from 1997 to 2000, a significant
      correlation was observed between cholera incidence and elevated sea surface
      temperature (SST) along the coast of Peru (P < 0.001). From the results of this
      study, coastal sea water and zooplankton are concluded to be a reservoir for V.
      cholerae in Peru. The climate-cholera relationship observed for the 1997-98 El
      Nino year suggests that an early warning system for cholera risk can be
      established for Peru and neighbouring Latin American countries.

PMID- 15186347
TI  - High overall diversity and dominance of microdiverse relationships in salt marsh
      sulphate-reducing bacteria.
AB  - The biogeochemistry of North Atlantic salt marshes is characterized by the
      interplay between the marsh grass Spartina and sulphate-reducing bacteria (SRB),
      which mineralize the diverse carbon substrates provided by the plants. It was
      hypothesized that SRB populations display high diversity within the sediment as a
      result of the rich spatial and chemical structuring provided by Spartina roots. A
      2000-member 16S rRNA gene library, prepared with delta-proteobacterial SRB
      selective primers, was analysed for diversity patterns and phylogenetic
      relationships. Sequence clustering detected 348 16S rRNA sequence types
      (ribotypes) related to delta-proteobacterial SRB, and it was estimated that a
      total of 623 ribotypes were present in the library. Similarity clustering showed
      that approximately 46% of these sequences fell into groups with < 1% divergence;
      thus, microheterogeneity accounts for a large portion of the observable genetic
      diversity. Phylogenetic comparison revealed that sequences most frequently
      recovered were associated with the Desulfobacteriaceae and Desulfobulbaceae
      families. Sequences from the Desulfovibrionaceae family were also observed, but
      were infrequent. Over 80% of the delta-proteobacterial ribotypes clustered with
      cultured representatives of Desulfosarcina, Desulfococcus and Desulfobacterium
      genera, suggesting that complete oxidizers with high substrate versatility
      dominate. The large-scale approach demonstrates the co-existence of numerous SRB
      like sequences and reveals an unexpected amount of microdiversity.

PMID- 15186349
TI  - Bacteria and viruses in the water column of tropical freshwater reservoirs.
AB  - In tropical freshwater reservoirs of Sri Lanka, which are linked in an aquatic
      network, bacterial abundance and production as well as virus abundance, frequency
      of viral infection and virus production were investigated together with a set of
      nutrient species (Kjeldahl-N, NO3-N, total P, soluble P, PO4-P). At two
      characteristic seasons (wet season, dry season), samples were taken from two
      types of reservoirs (new upland impoundment and ancient, shallow lowland
      reservoir), each during 4 days at various depths of the entire water columns.
      Kjeldahl-N and total P were greatly elevated in the wind-mixed water body of the
      shallow impoundment during the dry season, whereas the deeper reservoir type
      exhibited no obvious seasonality. In SYBR green trade mark -stained samples,
      bacterial abundance showed no seasonal pattern in either reservoir type.
      Bacterial secondary production, however, was significantly elevated in the entire
      water column of the shallow impoundment under wind-mixed conditions in the dry
      season. Highest abundance of virus particles and elevated frequency of bacteria
      containing mature phages were also observed in the shallow reservoir during the
      dry season indicating favourable conditions for virus propagation. Data from this
      aquatic network show that most virus parameters, such as abundance or frequency
      of visibly infected cells, were positively linked to bacterial abundance and
      production, but also to organic nitrogen or some phosphorus species. We
      calculated that between 13.2% and 46.1% of the bacterial standing stocks would be
      subjected to virus-mediated mortality. Estimates of bacteriophage production
      revealed that from 10 x 10(9) up to 98 x 10(9) phages were produced per litre and
      day. Bacteria and viruses in the studied tropical freshwater system appear to be
      linked to various environmental conditions and may affect processes at the
      ecosystem scale.

PMID- 15186350
TI  - Free Shiga toxin bacteriophages isolated from sewage showed diversity although
      the stx genes appeared conserved.
AB  - Phages carrying the stx2 gene were detected in a range of sewage samples using a
      plaque hybridization-based method. After detection, phages were isolated and
      propagated with a laboratory strain of Escherichia coli as host for
      characterization purposes. Although it was not possible to conduct propagation or
      transduction experiments on most of the phages, 11 reached a sufficiently high
      titre for studies of host infectivity, electron microscopy and sequencing of the
      stx2 flanking regions to be performed. These phages showed a wide range of host
      infectivity and morphology. The genetic structure of the 5' stx flanking region
      appeared conserved whereas the 3' region differed from that of previously
      described phages. This is the first description of infectious stx-phages isolated
      as free particles in the environment, and as such constitutes a new contribution
      to the study of the ecology of these phages.

PMID- 15186351
TI  - Mini-Tn7 transposons for site-specific tagging of bacteria with fluorescent
      proteins.
AB  - The mini-Tn7 transposon system is a convenient tool for site-specific tagging of
      bacteria in which the tagging DNA is inserted at a unique and neutral chromosomal
      site. We have expanded the panel of mini-Tn7 delivery plasmids expressing
      different fluorescent proteins (stable and unstable) from the Escherichia coli
      lac derived promoter, P(A1/04/03), or from the growth-rate-dependent Escherichia
      coli promoter PrrnB P1. The mini-Tn7 transposons were inserted and tested in the
      soil bacterium, Pseudomonas putida KT2440. Successful and site-specific tagging
      was verified by Southern blots as well as by PCR. Furthermore, the effect of
      fluorescent protein expression on the cellular growth rate was tested by growth
      competition assays.

PMID- 15186352
TI  - Top-down impact of bacterivorous nematodes on the bacterial community structure:
      a microcosm study.
AB  - The influence of bacterivorous nematodes (Diplolaimelloides meyli,
      Diplolaimelloides oschei, Diplolaimella dievengatensis, Panagrolaimus paetzoldi)
      on the development of a bacterial community growing on decaying cordgrass
      detritus was studied in laboratory microcosm experiments. Cordgrass leaves were
      incubated on a sediment surface with a natural bacterial mixture containing
      bacteria from sediment, cordgrass detritus and habitat water. The four nematode
      species were applied separately to the microcosms; controls remained without
      nematodes. Samples were taken seven times over a 65-day period. The bacterial
      community structure was analysed by means of DGGE of the 16S rRNA genes. Multi
      Dimensional Scaling showed grouping of the samples per treatment. Analysis of
      Similarities indicated that the differences between treatments were significantly
      larger than differences within treatments. Our results suggest that nematodes can
      have a significant structuring top-down influence on the 'pool' of bacteria
      growing on the detritus, even at low densities. Dissimilarities were similar
      between all treatments. Differences in bacterial community composition within the
      treatments with monhysterids (D. meyli, D. oschei and D. dievengatensis) can be
      explained by species-specific food preferences. Panagrolaimus paetzoldi on the
      other hand feeds unselectively, and thus affects the bacterial community
      differently. A top-down effect of the nematodes on the diversity of the bacterial
      community was only evident under high grazing pressure, i.e. in the presence of
      P. paetzoldi.

PMID- 15186354
TI  - Identification and phylogenetic sorting of bacterial lineages with universally
      conserved genes and proteins.
AB  - Molecular characterizations of bacteria often employ ribosomal DNA (rDNA) to
      establish the identity and relationships among organisms, but the use of rRNA
      sequences can be problematic as the result of alignment ambiguities caused by
      indels, the lack of informative characters, and varying functional constraints
      over the molecule. Although protein-coding regions have been used as an
      alternative to rRNA, there is neither consensus among the genes examined nor ways
      to rapidly obtain sequence information for such genes from uncharacterized
      bacterial species. To standardize the set of protein-coding loci assayed in
      bacterial genomes, we examined over 100 widely distributed genes to identify sets
      of universal primers for use in the PCR amplification of protein coding regions
      that are common to virtually all bacteria. From this set, we developed primer
      sets that each target of 10 genes spanning an array of genomic locations and
      functional categories. Although many of the primers contain sequence degeneracies
      that aid in targeting genes across diverse taxa, most are adequate for direct
      sequencing of amplification products, thereby eliminating intermediate cloning
      before sequence determination. We foresee the analysis of these protein-coding
      regions as being complementary to ribosomal DNA for answering questions
      pertaining to bacterial identification, classification, phylogenetics and
      evolution.

PMID- 15186353
TI  - Bacterial diversity in deep Mediterranean sediments: relationship with the active
      bacterial fraction and substrate availability.
AB  - We investigated vertical distribution and depth-related patterns (from 670 to
      2,570 metres) of bacterial diversity in sediment samples collected along a
      transect in the warm deep Mediterranean sea. Analyses of bacterial diversity were
      compared with the abundance of benthic bacteria, their metabolically active
      fraction and the substrates potentially available for their growth. The number of
      active bacteria was dependent upon the availability of organic substrate in the
      sediment deriving from phytopigment inputs from the photic layer. The T-RFLP
      analysis revealed that the surface layers of all sediments analysed were
      dominated by the same ribotypes, but clear shifts in bacterial community
      structure were observed in deeper sediment layers. High values of bacterial
      diversity (expressed as D, H') and evenness (as J) were observed at all stations
      (a total of 61 ribotypes was identified), and as a result of the large fraction
      of rare ribotypes (c. 35%), the overall bacterial diversity in the deep sea
      region investigated was among the highest reported so far in literature.
      Biodiversity parameters did not display any relationship with water depth, but
      ribotype richness was related with the number and percentage of active bacteria,
      suggesting a coupling between organic inputs stimulating bacterial growth and
      deep-sea bacterial diversity.

PMID- 15186355
TI  - Polylysogeny and prophage induction by secondary infection in Vibrio cholerae.
AB  - Strains of Vibrio cholerae O1, biotypes El Tor and classical, were infected with
      a known temperate phage (PhiP15) and monitored over a 15-day period for prophage
      induction. Over the course of the experiment two morphologically and three
      genomically distinct virus-like particles were observed from the phage-infected
      El Tor strain by transmission electron microscopy and field inversion gel
      electrophoresis, respectively, whereas only one phage, PhiP15, was observed from
      the infected classical strain. In the uninfected El Tor culture one prophage was
      spontaneously induced after 6 days. No induction in either strain was observed
      after treatment with mitomycin C. Data indicate that El Tor biotypes of V.
      cholerae may be polylysogenic and that secondary infection can promote multiple
      prophage induction. These traits may be important in the transfer of genetic
      material among V. cholerae by providing an environmentally relevant route for
      multiple prophage propagation and transmission.

PMID- 15186358
TI  - Birthing Sphere.
AB  - This paper tells the story of the initiation and first year of Sphere. It traces
      the history of how the project was started and its relationship to other major
      events of that time, principally the multi-donor Rwanda evaluation. The paper
      describes how the basic structure of the Sphere standards was agreed upon and
      discusses why some sectors were eventually left out of the standards. Tensions
      and public disagreements between the agencies that created Sphere are discussed,
      along with the manner in which the chosen working processes contributed to the
      successful publication of the Sphere standards. We show how the process of policy
      formulation, which led up to the publication of the first edition of the Sphere
      standards, was as dependent upon the ability of the project team to work
      opportunistically as it was upon the application of agency principles. Finally
      the paper reflects upon the success of Sphere and lessons that can be learned
      from this early Sphere process.

PMID- 15186359
TI  - Locating responsibility: the Sphere Humanitarian Charter and its rationale.
AB  - Criticised by some as a technical initiative that neglects core principles,
      Sphere was seen by its originators precisely as an articulation of principle. The
      Humanitarian Charter was the main vehicle through which this was expressed, but
      its relationship to the Minimum Standards has remained a matter of uncertainty.
      Specifically, it was unclear in the original (1999) edition of Sphere how the
      concept of rights informed the Minimum Standards. The revised (2004) edition goes
      some way to clarifying this in the way the standards are framed, yet the link
      between the standards and the charter remains unclear. The concern with the
      quality and accountability of humanitarian assistance, which motivated the
      attempt to establish system-wide standards through the Sphere Project, was
      accompanied by a desire to establish such actions in a wider framework of legal
      and political responsibility. In part, this reflects the conditional nature of
      the undertaking that agencies make when they adopt Sphere. This aspect of the
      charter has been neglected, but it is fundamental to an understanding of the
      standards and their application. This paper considers the rationale of the Sphere
      Humanitarian Charter and the conceptual model that underpins it. It discusses the
      relationship between the charter and the Minimum Standards, and the sense in
      which the latter are properly called "rights-based" (explored further in a
      related paper herein by Young and Taylor). The author was closely involved in the
      conception and drafting of the charter, and this paper attempts to convey some of
      the thinking that lay behind it.

PMID- 15186360
TI  - Rights, standards and quality in a complex humanitarian space: is Sphere the
      right tool?
AB  - The Sphere Project (consisting of both the Humanitarian Charter and Minimum
      Standards for Disaster Response) has made prominent contributions to the debates,
      thinking and work on the quality of assistance and accountability of aid
      agencies. However, since its inception in 1997, several agencies expressed
      concerns regarding Sphere's approach, many of which were confirmed by the Sphere
      evaluation (2002/3). The present article restates these concerns, and addresses
      more fundamental issues regarding Sphere's cornerstone. It questions the validity
      of Sphere's rights-based approach, which consists of a tenuous link between the
      rights of affected populations and standards for technical interventions. Sphere
      is founded on "the right to assistance", although this right does not exist in
      international law. Its elaboration would entail solving several complex legal and
      political issues, which Sphere fails to address. This article also questions the
      validity and usefulness of universal standards for technical performance in
      helping relief agencies provide adapted assistance to disaster-affected
      populations, in line with their mandates and principles. It suggests that
      Sphere's approach and content largely reflect the concerns, priorities and values
      of technical professionals in Northern agencies, leaving limited space to genuine
      "participation" by affected populations and partners from the South.

PMID- 15186362
TI  - Dilemmas and challenges for the shelter sector: lessons learned from the Sphere
      revision process.
AB  - Key dilemmas and challenges for those involved in the shelter sector are
      described, based on issues that emerged from the extensive global consultative
      process undertaken to inform the revision of the Sphere handbook. The range of
      perspectives on the major themes is presented, with suggestions as to how these
      issues could be progressed. Themes include the poor definition of the sector and
      the lack of a consistent approach among the leading shelter actors; the absence
      of a common terminology; the conflict between "temporary" versus "durable"
      solutions; the disconnect between technical advisers and the field; the need for
      greater recognition of local coping strategies and the local context; the
      involvement of recipients and host governments in policy development; the need
      for better "how-to" guidance; and the limited incorporation of the emerging
      themes of livelihoods etc. to date.

PMID- 15186363
TI  - Questionable accountability: MSF and Sphere in 2003.
AB  - This article examines the relationship between Medecins Sans Frontieres (MSF) and
      the Sphere Project. Prior to revisiting the concerns MSF had with the project, it
      looks at factors that give rise to differences between NGOs and cites some
      reasons for why an organisation such as MSF would not embrace such a project and
      clarifies some key elements of MSF-style humanitarianism. The author revisits the
      original concerns and arguments presented by MSF when it decided not to
      participate beyond assisting with the establishment of technical standards and
      key indicators for the handbook. This is followed by a critical discussion
      examining these concerns and counter-criticism with reference to experiences a
      few years after the inception of Sphere. It concludes with MSF's perceptions and
      stance regarding Sphere and accountability in 2003.

PMID- 15186361
TI  - Linking rights and standards: the process of developing "rights-based" minimum
      standards on food security, nutrition and food aid.
AB  - This article examines the recent revision of the Sphere Minimum Standards in
      disaster response relating to food security, nutrition and food aid. It describes
      how the revision attempted to incorporate the principles of the Humanitarian
      Charter, as well as relevant human rights principles and values into the Sphere
      Minimum Standards. The initial aim of the revision was to ensure that the Sphere
      Minimum Standards better reflected the principles embodied in the Humanitarian
      Charter. This was later broadened to ensure that key legal standards and
      principles from human rights and humanitarian law were considered and also
      incorporated, in part to fill the "protection gap" within the existing standards.
      In relation to the food security, nutrition and food aid standards, it was agreed
      by participants in the process that the human right to adequate food and freedom
      from hunger should be incorporated. In relation to more general principles
      underlying the Humanitarian Charter, itself drawn largely from human rights and
      humanitarian law, it was agreed that there was a need to strengthen "protection"
      elements within the standards and a need to incorporate the basic principles of
      the right to life with dignity, non-discrimination, impartiality and
      participation, as well as to explore the relevance of the concept of the
      progressive realisation of the right to food. The questions raised in linking
      rights to operational standards required thought, on the one hand, about whether
      the technical standards reflected a deep understanding of the values expressed
      within the legal instruments, and whether the existing standards were adequate in
      relation to those legal rights. On the other hand, it also required reflection on
      how operational standards like Sphere could give concrete content to human
      rights, such as the right to food and the right to be free from hunger. However,
      there remain challenges in examining what a rights-based approach will mean in
      terms of the role of humanitarian agencies as duty-bearers of rights, given that
      the primary responsibility rests with state governments. It will also require
      reflection on the modes and mechanisms of accountability that are brought to bear
      in ensuring the implementation of the Minimum Standards.

PMID- 15186364
TI  - The future of humanitarian action: mapping the implications of Iraq and other
      recent crises.
AB  - In late 2003 the Feinstein International Famine Center, in partnership with
      institutions in London, Geneva and Washington, organised a series of
      consultations on the future of humanitarian action post-Iraq. This article is
      based on those discussions. A number of recurring concerns are elaborated,
      ranging from the perception of humanitarianism as a Northern-driven and Northern
      controlled enterprise, through the politicisation of security and the devaluation
      of the protective power of emblems, to the very nature of how the crisis in Iraq
      is perceived. The article explores the implications of such issues for
      humanitarian workers and their institutions. It concludes by framing an agenda
      for action by the humanitarian sector.

PMID- 15186365
TI  - Humanitarian action and military intervention: temptations and possibilities.
AB  - Although the war in Liberia in July 2003 claimed hundreds of lives, the
      international community was reluctant to intervene. In this article, the author
      debates the question: does international military intervention equal protection
      of populations? The role of humanitarian organisations in military intervention
      is considered. Aid organisations cannot call for deployment of a protection force
      without renouncing their autonomy or appealing to references outside their own
      practices. Such organisations provide victims with vital assistance and
      contribute to ensuring that their fate becomes a stake in political debate by
      exposing the violence that engulfs them, without substituting their own voices
      for those of the victims. The political content of humanitarian action is also
      outlined and military intervention in the context of genocide is discussed. The
      author concludes that the latter is one of the rare situations in which
      humanitarian actors can consider calling for an armed intervention without
      renouncing their own logic.

PMID- 15186366
TI  - The United Nations' humanitarian pillar: refocusing the UN's disaster and
      emergency roles and responsibilities.
AB  - Changes in the nature of humanitarian crises and in the ways that the
      international community responds to such crises demand a radically overhauled
      role for the United Nations system. At a time when the UN and its member states
      are pursuing reform of some of that institution's most fundamental peace and
      security functions, this paper suggests that reform, too, is required to meet
      humanitarian crises of the future. This paper proposes a new type of operational
      role for the UN, while at the same time arguing that the UN has to place itself
      in the vanguard of humanitarian assistance as "the standard-bearer". The article
      draws many of its conclusions and recommendations from a recently completed
      study, requested by the Inter-Agency Standing Committee, concerning the effect
      for the UN system of changes in humanitarian financing.

PMID- 15186367
TI  - Allergic contact dermatitis: pathophysiology applied to future therapy.
AB  - Contact dermatitis is a common reason for patient visits to primary-care clinics
      and represents up to 7% of all dermatologic consultations in the US. Substantial
      progress has been made in elucidating the pathophysiology of contact dermatitis,
      particularly the allergic form. A better understanding of pathologic mechanisms
      has led to improved management of cases and will continue to advance treatment
      modalities. The present paper reviews the pathogenesis and current treatment of
      allergic contact dermatitis and speculates on the prospects for improved future
      therapy.

PMID- 15186368
TI  - Clues to an accurate diagnosis of contact dermatitis.
AB  - An accurate diagnosis of allergic contact dermatitis can be achieved by a
      combination of historical, morphologic, and diagnostic steps. Clues in the
      history and physical examination can point to an irritant as the source of
      contact dermatitis. While irritants and allergens share many common features both
      immunologically and clinically, there are grounds for the distinction. Knowledge
      of occupational factors is necessary to assess the source of contact dermatitis.
      A common pitfall is the failure to appreciate the role of endogenous factors in
      the clinical presentation and overall care of the dermatitis patient. A
      comprehensive assessment of the patient's environment will lead to appropriate
      patch tests being applied and a correct diagnosis being reached.

PMID- 15186369
TI  - Patch testing with a standard allergen ("screening") tray: rewards and risks.
AB  - The TRUE Test panels, which are the only patch testing devices approved by the
      Food and Drug Administration in the US, consist of 24 patches, one of which is a
      negative control. The remaining 23 patches contain 42 unique allergens and four
      complex mixtures. Although these panels contain approximately 1.4% of the > 3700
      known allergens, they perform robustly in detecting allergic contact dermatitis
      (ACD). Twenty-eight percent of patients are fully evaluated by application of
      TRUE Test((R)). The present paper reviews the appropriate use of the TRUE Test
      panels. The need to determine relevance of any positive reaction is stressed. The
      common causes of false-positive and false-negative reactions are outlined. Those
      product types where the TRUE Test panels detect the majority of relevant allergic
      reactions are reviewed, as are the other sources of exposure to the allergens on
      these panels. The impact of ACD on quality of life is significant. Only by patch
      testing can the diagnosis be made.

PMID- 15186370
TI  - Therapeutic options for chronic hand dermatitis.
AB  - Hand dermatitis is a common skin condition that often has a chronic and/or
      relapsing clinical course. Several clinical forms of hand dermatitis have been
      described, including contact (i.e., allergic and irritant), hyperkeratotic (i.e.,
      psoriasiform or tylotic), frictional, nummular, atopic, pompholyx (i.e.,
      dyshidrosis), and chronic vesicular hand dermatitis. In the present review,
      therapeutic options for these types of hand dermatitis are discussed in detail,
      focusing on treatments for recalcitrant hand dermatitis.

PMID- 15186371
TI  - Hypersensitivity to preservatives.
AB  - Preservatives are biocidal chemicals added to cosmetics, topical medicaments,
      consumer goods, foods, and industrial products to protect them against microbial
      spoilage and to protect the consumer against infection. The ideal preservative,
      both effective and devoid of irritant or sensitizing potential, is still to be
      discovered. The present paper reviews the most important classes of
      preservatives, namely parabens, formaldehyde-releasers, and isothiazolinones. The
      author also discusses newer agents such as Euxyl K 400 and isopropynyl
      butylcarbamate. Each preservative is described in terms of chemical and physical
      characteristics, antimicrobial efficacy, exposure, cutaneous adverse reactions,
      patch testing concentrations, patterns of cross-reactions, and reported rates of
      sensitization. The history of preservatives goes back to the 1930s, and
      ironically, the parabens, which the industry has sought to replace with "safer"
      alternatives, are still the most frequently used biocides in cosmetics and appear
      to be far less sensitizing than most of the newer agents.

PMID- 15186372
TI  - Contact dermatitis to cosmetics, fragrances, and botanicals.
AB  - Cosmetics, fragrances, and botanicals are important causes of allergic contact
      dermatitis. Identifying and avoiding the causative allergens can pose a challenge
      to both the patient and the dermatologist. The site of involvement can give the
      investigator clues to the cause of the eruption in many cases. Fragrances and
      preservatives are the two most clinically relevant allergens in cosmetics.
      Botanicals are being added to cosmetics because of consumer demand and are now
      being recognized as sources of allergy as well. Patch testing allows for the
      detection of allergens that are potentially relevant in the genesis of the
      patient's eczema. Common skin-care product allergens, including fragrances and
      botanicals as well as those found in sunscreen, nail, and hair-care products, are
      reviewed. Practical methods of allergen avoidance are also discussed.

PMID- 15186373
TI  - Occupational contact dermatitis.
AB  - The dermatologist should be aware of the many facets of occupational skin
      diseases, which can be caused by physical, chemical, and biological insults. The
      most common manifestation of occupational skin diseases is contact dermatitis
      (both irritant and allergic). Three factors point out the importance of
      occupational skin diseases as diseases that have a public health impact: 1)
      occupational skin diseases are common; 2) they often have a poor prognosis; and
      3) they result in a noteworthy economic impact for society and for an individual.
      They are also diseases amenable to public health interventions. Specific
      industries and exposures may put a worker at risk of occupational contact
      dermatitis. The accuracy of the diagnosis of occupational contact dermatitis is
      related to the skill level, experience, and knowledge of the medical professional
      who makes the diagnosis and confirms the relationship with a workplace exposure.
      Prevention of occupational contact dermatitis is important, and a variety of
      prevention strategies are available.

PMID- 15186375
TI  - Strong irritants masquerading as skin allergens: the case of benzalkonium
      chloride.
AB  - Chemicals may possess a number of hazards to human health including the ability
      to cause skin irritation and contact allergy. Identification and characterization
      of these properties should fall within predictive toxicology, but information
      derived from human exposure, including clinical experience, is also of
      importance. In this context, it is of interest to review the case of benzalkonium
      chloride, a cationic surfactant. This chemical is a well-known skin irritant, but
      on occasions it has also been reported to have allergenic properties, typically
      on the basis of positive diagnostic patch test data. Because the accumulated
      knowledge concerning the properties of a chemical is employed as the basis for
      its regulatory classification (e.g. in Europe), as well as for informing the
      clinical community with respect to the diagnosis of irritant versus allergic
      contact dermatitis (ACD), it is important to distinguish properly which chemicals
      are simply irritants from those which are both irritant and allergenic on skin. A
      review of the information on benzalkonium chloride confirms that it is a
      significant skin irritant. However, both predictive test results and clinical
      data lead to the conclusion that benzalkonium chloride is, at most, an extremely
      rare allergen, except perhaps in the eye, but with many supposed cases of ACD
      being likely to arise from the misinterpretation of patch test data. As a
      consequence, this substance should not normally be regarded as, or classified as,
      a significant skin sensitizer.

PMID- 15186376
TI  - Single doses of local betamethasone do not suppress allergic patch test reactions
      to nickel sulfate.
AB  - Topical corticosteroids are usually banned on test areas prior to patch testing.
      The previous literature on the effect of topical corticosteroids is conflicting.
      Patients allergic to nickel sulfate were patch tested on 4 sites with nickel on
      day (D) 0. Intracutaneous betamethasone was injected to test sites on D-1, D0 and
      D1. NaCl injection on D-1 was control. The patch test reactions were evaluated
      clinically and with laser Doppler. There were no differences in patch test
      reaction intensities on sites treated with intracutaneous betamethasone as
      compared to control. A single local dose of potent corticosteroid does not
      suppress allergic patch reactions to nickel. The current practice of avoiding
      topical corticosteroid use prior to patch testing should be re-evaluated.

PMID- 15186377
TI  - Allergic contact urticaria from natural rubber latex in healthcare and non
      healthcare workers.
AB  - To compare the prevalence of natural rubber latex (NRL) sensitization and
      allergic contact urticaria from NRL in healthcare and non-healthcare workers, we
      studied all 1171 patients who attended our clinic during 2001 and 2002. Prick
      testing for NRL and patch testing with European standard series were performed in
      all patients and an additional rubber series in those who had contact with
      rubber. Specific immunoglobulin E (IgE) levels against NRL and tropical fruits
      were measured when prick testing was positive. Sensitization to NRL (positive
      prick test and specific IgE levels) was much more common in healthcare workers
      than that in non-healthcare workers, 16.7 versus 2.3%. Among the non-healthcare
      workers, sensitization to NRL was more common in food handlers (17.1%),
      construction workers (6.6%), painters (6.2%), hairdressers (5.1%) and cleaners
      (3.8%). The difference in the prevalence of specific IgE to tropical fruits was
      not significant. Allergic contact urticaria from NRL was also much more frequent
      in healthcare workers, 71.4 versus 28.6%. In conclusion, sensitization to NRL and
      allergic contact urticaria from NRL are more common in healthcare workers, but
      this is a growing problem in non-healthcare workers and should be investigated in
      all workers with a history of NRL intolerance or who have contact with NRL.

PMID- 15186378
TI  - Exposure of the hands to wet work in nurses.
AB  - Prevention of hand dermatitis among nurses can be achieved by reduction of wet
      work exposure. A preventive programme should be based on knowledge of exposure
      levels. An accurate method to assess such exposure levels is needed. Duration and
      frequency of wet-work activities were assessed by a questionnaire, in various
      parts of the health care sector. In addition, a randomly chosen sample from this
      population was observed for the duration and frequency of wet work. In contrast
      to the questionnaire, the observation method showed less than half the duration
      of wet work. Observation detected almost double the frequency that was reported
      with the questionnaire. Gloves were observed to be used daily in special care
      units for short time periods. A questionnaire does not accurately assess the
      quantity of wet-work activities. On regular wards, the exposure to irritants is
      mainly associated with the frequency of wet hands, rather than the duration of
      wet hands. We assume that the short-term use of gloves on special care units does
      not cause an increased risk of hand dermatitis. Preventive programmes can focus
      on decreasing the frequency of wet hands by encouraging the use of gloves; the
      use of gloves should not only be advised to prevent infections but also to
      protect against hand dermatitis.

PMID- 15186379
TI  - Comparison of patch test contact sensitivity to acetone and aqueous extracts of
      Parthenium hysterophorus in patients with airborne contact dermatitis.
AB  - Our aim was to compare the degree of patch test positivity to acetone and aqueous
      extracts of Parthenium hysterophorus in patients with airborne contact
      dermatitis. We performed patch testing with the Indian standard series (which
      includes aqueous extracts of parthenium, xanthium and chrysanthemum), and with 1
      : 100 and 1 : 200 dilutions of an acetone extract of parthenium in 72 patients
      with airborne contact dermatitis. All patients showed contact sensitivity to the
      1 : 100 dilution and 67 patients had positive allergic reactions to the 1 : 200
      dilution of the acetone extract, whereas only 45 patients showed a positive
      reaction to the aqueous extract of P. hysterophorus. Our results confirm that
      parthenium allergens are more soluble in acetone than in water, and that the
      acetone extract is significantly better in detecting contact sensitivity to
      parthenium in patients with suspected plant dermatitis. Hence, the acetone
      extract is recommended for routine patch testing.

PMID- 15186380
TI  - Methacrylates in dental restorative materials.
AB  - Commercial dental restorative materials were analysed in order to obtain
      information about the occurrence of sensitizing acrylates. Acetone-soluble
      methacrylates of 7 bonding materials, 8 composite resins and 2 glass ionomers
      were identified by gas chromatography with mass-selective detection and
      quantified by liquid chromatography with ultraviolet detection. The most
      frequently occurring methacrylates in the bonding materials were 2-hydroxyethyl
      methacrylate (2-HEMA) and 2,2-bis-[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]
      propane (bis-GMA). Bis-GMA and triethyleneglycol dimethacrylate were the most
      frequently occurring methacrylates in composite resins. The main methacrylate of
      the 2 glass ionomers was 2-HEMA or trimethylolpropane trimethacrylate.
      Information about methacrylates was given in the safety data sheets (SDSs) for
      about half of the products that according to the analysis results contained
      methacrylates. SDSs need to be improved so that the health risks for dental
      personnel can be reliably assessed and controlled.

PMID- 15186381
TI  - Contact and photocontact allergy to ketoprofen. The Belgian experience.
AB  - Topical ketoprofen (KP) is widely used because of its anti-inflammatory effect.
      However, photocontact dermatitis is a side-effect. Between May 2001 and June
      2002, the Belgian Contact & Environmental Dermatitis Group conducted a
      prospective, open patch and photopatch test study in 20 patients suspected of KP
      dermatitis. Severe skin symptoms requiring systemic corticotherapy occurred in
      47%. 5 patients were hospitalized. 1 patient showed prolonged photosensitivity.
      All patients were tested with KP and the other constituents of KP gel.
      Attribution to KP was demonstrated in all cases. Patch and photopatch tests with
      KP 2% in petrolatum showed contact photoallergy in 17 patients, contact allergy
      in 1 patient and photoaggravated contact allergy in 2 patients. 5 patients also
      reacted to the fragrance components lavender (Lavandula augustifolia) oil and/or
      neroli (Citrus aurantium dulcis) oil 5% in alcohol. However, in 4 of these,
      irritant reactions to the ethanolic dilutions could not be ruled out. Additional
      tests with 3 non-steroidal anti-inflammatory drugs without benzophenone structure
      ibuprofen, naproxen and diclofenac identified only 1 contact allergic reaction to
      diclofenac. Cross-reactivity to the substituted benzophenones, oxybenzone and
      sulisobenzone occurred only to the first in less than 30% of the patients. A high
      frequency (69%) of contact allergy to fragrance mix was found. Dermatologists
      should be aware of the severity of photoallergic reactions to KP and the risk of
      cross-sensitization.

PMID- 15186382
TI  - Isopropyl myristate recommended for aimed rather than routine patch testing.
AB  - Isopropyl myristate (IPM) is considered a very weak sensitizer. Patch test
      results with 20% IPM in petrolatum (pet.) in 8117 patients and 10% IPM in pet. in
      4554 patients between January 1992 and December 2001 by the IVDK are presented.
      While irritant and questionable reactions were frequently observed, especially
      with 20% test concentration and 2-day patch test exposure, respectively, and a
      decrescendo pattern was common, morphologically positive reactions at day 3 were
      seen in only 16 patients, i.e. altogether 0.13%. In line with previous clinical
      and experimental evidence, our results indicate that IPM is an extremely weak
      sensitizer or possibly, in our material, not a sensitizer at all. IPM should thus
      not be tested routinely, but only in the case of suspected exposure as a possible
      source of allergic contact dermatitis, e.g. to cosmetics and perfumes, to avoid
      an unacceptable reduction of the positive predictive value of the test.

PMID- 15186383
TI  - Irritant hand dermatitis: severity of disease, occupational exposure to skin
      irritants and preventive measures 5 years after initial diagnosis.
AB  - Irritant contact dermatitis (ICD) is often chronic; its aetiology frequently
      being related to occupational exposure. Management of ICD involves persistent
      reduction in exposure to skin irritants such as water, detergents and prolonged
      occlusion by gloves. The aim of this study was to determine the severity of hand
      dermatitis 5 years after initial diagnosis and to find out what factors were
      related to this outcome. A questionnaire survey was carried out on severity of
      hand dermatitis, exposure to skin irritants and preventive measures, 5 years
      after initial ICD diagnosis. Of a cohort of 201 patients with ICD, 172 received
      the questionnaire and 124 (72%) responded. 5 years after initial diagnosis, 50%
      still had medium and 32% severe hand dermatitis. Patients with severe ICD and
      high exposure showed low levels of prevention and difficulty in changing their
      occupational exposure. Use of emollients was predominantly therapeutic rather
      than preventive. Occupation was changed in 57% of cases, of which 46% was
      permanent. In this population, ICD is a chronic disease; implementation of
      secondary preventive measures appears to fail. In occupations with high exposure
      to skin irritants, implementation of permanent exposure reduction is more
      difficult, compared to occupations with a medium level of exposure. High
      exposures might have led to change of occupation; medium exposures could have
      been reduced to low levels. In occupations with high exposure, women were
      overrepresented.

PMID- 15186384
TI  - Dermatological problems in dental health personnel.

PMID- 15186385
TI  - Allergic contact dermatitis from cosmetics applied by the patient's girlfriend.

PMID- 15186386
TI  - Allergic contact dermatitis from cinnamon as an odour-neutralizing agent in shoe
      insoles.

PMID- 15186387
TI  - A medicolegal controversy due to a hidden allergen in cutting oils.

PMID- 15186388
TI  - Phototoxic and photoallergic dermatitis caused by hydroxychloroquine.

PMID- 15186390
TI  - Widespread eczema from triflusal confirmed by patch testing.

PMID- 15186389
TI  - Allergic contact dermatitis from isohexadecane and isopropyl myristate.

PMID- 15186391
TI  - Black rubber tyremaker's tattoo.

PMID- 15186392
TI  - Allergic contact dermatitis from colophonium, turpentine and ebony in a violinist
      presenting as fiddler's neck.

PMID- 15186393
TI  - Role of patch testing in antimicrobial drug eruptions.

PMID- 15186394
TI  - Allergic contact dermatitis from VP/eicosene copolymer (Ganex V-220) in an
      emollient cream.

PMID- 15186395
TI  - Allergic contact dermatitis from direct dyes for hair colouration in
      hairdressers' clients.

PMID- 15186397
TI  - Apoptosis paves the detour path for CD8 T cell activation against intracellular
      bacteria.
AB  - Intracellular bacteria such as Mycobacterium tuberculosis primarily infect
      macrophages. Within these host cells, the pathogens are confined to phagosomes
      and their antigens are secluded from the classical MHC I presentation pathway.
      Moreover, macrophages fail to express certain antigen presenting molecules like
      CD1 proteins. As a result of this intracellular lifestyle, the pathways for the
      induction of MHC I- and CD1-restricted CD8 T cells by such microorganisms remain
      elusive. Based on recent findings in tuberculosis and salmonellosis, we propose a
      new detour pathway for CD8 T cell activation against intracellular bacteria
      through apoptotic blebs from infected macrophages. Pathogen-derived antigens
      including proteins and lipids are delivered from infected cells to non-infected
      dendritic cells. Subsequently, these professional antigen presenting cells
      display microbial antigens through MHC I and CD1 to T cells. Thus, cross-priming
      mediated by apoptotic vesicles is not just a matter of antigen distribution, but
      an intrinsic immunological function due to the nature of phagosomally located
      intracellular bacteria. We consider infection-induced apoptosis the conditio sine
      qua non for antigen-specific CD8 T cell activation by phagosome-enclosed
      pathogens. This important new function of cell death in antibacterial immunity
      requires consideration for rational vaccine design.

PMID- 15186396
TI  - Piroxicam-induced erythema multiforme.

PMID- 15186398
TI  - Whole-body autoradiography reveals that the Peptostreptococcus magnus
      immunoglobulin-binding domains of protein L preferentially target B lymphocytes
      in the spleen and lymph nodes in vivo.
AB  - Protein L is an immunoglobulin (Ig)-binding protein produced by the Gram-positive
      bacterium Peptostreptococcus magnus that interacts with the variable region of Ig
      kappa light chains. The Ig light chain-binding capacity of protein L gives it the
      potential to interact with cells expressing surface Ig such as B cells. The
      present study was performed to address the in vivo trafficking of protein L at
      both the organ and the cellular level. Using the powerful technique of whole-body
      autoradiography in a murine model system, we demonstrate specific targeting of
      protein L to secondary lymphoid tissues in whole-animal analysis. The observed
      targeting depends on the capacity to interact with murine Ig, as tissue targeting
      was not apparent in mice given protein H, an Ig-binding protein produced by
      Streptococcus pyogenes with affinity for human but not murine Ig. Tissue
      targeting data were combined with flow cytometry analysis, which demonstrated the
      capacity of protein L to target and activate B lymphocytes in vivo. B cells
      targeted by protein L had increased surface expression of CD86 and MHC-II, and
      protein L was present in vacuolar compartments of B cells. Protein L did not bind
      T cells or natural killer cells but had some capacity to target dendritic cells
      and macrophages. The data show that protein L preferentially targets secondary
      lymphoid organs, and activates and is internalized by B cells in vivo.
      Furthermore, the observed tissue and cell targeting properties require an
      affinity for murine Ig. These data support the potential use of this Ig-binding
      protein as a targeting approach to deliver agents to defined cell populations in
      vivo.

PMID- 15186399
TI  - Human dendritic cell activation by Neisseria meningitidis: phagocytosis depends
      on expression of lipooligosaccharide (LOS) by the bacteria and is required for
      optimal cytokine production.
AB  - Group B Neisseria meningitidis is a human pathogen, for which a universally
      effective vaccine is still not available. Immune responses to bacteria are
      initiated by dendritic cells (DC), which internalize and process bacterial
      antigens for presentation to T cells. We show here that optimal IL-12 and TNF
      alpha production by human monocyte derived DC in response to killed serogroup B
      N. meningitidis depends on physical contact and internalization of the bacteria
      by DC. The majority of DC producing cytokines had internalized N. meningitidis
      while inhibition of bacterial internalization markedly impaired IL-12 and TNF
      alpha, but not IL-6 production. Internalization of N. meningitidis was shown to
      depend on lipooligosaccharide (LOS) expressed by the bacteria with poor
      internalization of LOS deficient bacteria compared to wild-type bacteria.
      Restoration of LOS biosynthesis in a LOS regulatory strain also restored both
      internalization and cytokine production and was enhanced in the presence of LPS
      binding protein (LBP). These results suggest that DC phagocytosis depends on
      expression of LOS within the bacteria and that optimal cytokine production,
      particularly IL-12, requires internalization of the bacteria. These findings have
      important implications for designing vaccines that will induce protective immune
      responses to group B N. meningitidis.

PMID- 15186400
TI  - Differential post-transcriptional activation of human phagocytes by different
      Pseudomonas aeruginosa isolates.
AB  - Pseudomonas aeruginosa is a pulmonary pathogen in individuals with impaired
      mucociliary clearance such as cystic fibrosis or mechanical ventilation. Non
      opsonic phagocytosis of P. aeruginosa can be mediated by either CR3 or CD14 and
      different strains appear to have a bias towards one or the other receptor. Strain
      Fc808 is ingested through CD14 whereas P1 (Fc194) uses CR3. In an in vitro
      culture system, the inflammatory response of macrophages to these two different
      strains of P. aeruginosa was divergent at the protein level, with higher IL-6 and
      tumour necrosis factor (TNF)-alpha production generated in response to strain P1
      and higher IL-1 beta production in response to strain Fc808. Interaction of
      macrophages with these two bacterial strains induced distinct gene expression
      patterns as detected by gene array analysis, with prominence of genes encoding
      pro-inflammatory cytokines, surface receptors, transcription factors and proteins
      involved in phagocytosis. However, comparison of gene expression data and
      cytokine response data with the two bacterial strains indicated that production
      of IL-1 beta, IL-6 and TNF-alpha was under differential post-transcriptional
      control. Interestingly, this effect did not correlate with receptor bias but
      instead was related to the different LPSs of the two strains. The use of specific
      mitogen-activated protein kinase (MAPK) inhibitors suggested a role for
      extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in
      the differential cytokine production by strains P1 and Fc808. These results
      indicate that strains of the same species of bacteria may induce differential
      macrophage phagocytic and inflammatory responses with likely consequence for
      bacterial clearance and host injury.

PMID- 15186401
TI  - Activation of human dendritic cells by the PorA protein of Neisseria
      meningitidis.
AB  - The major porin proteins present in the outer membrane of Neisseria meningitidis,
      the causative agent of life-threatening meningitis and septicaemia, are believed
      to have potent immunostimulatory effects. In this study, the interactions between
      human monocyte-derived dendritic cells (mo-DC) and the PorA porin were
      investigated, in order to reveal the role of this protein in promoting innate and
      adaptive immune responses. Recombinant (r)PorA induced mo-DC maturation, as
      reflected by reduced receptor-mediated endocytosis, increased production of the
      chemokines IL-8, RANTES, MIP-1 alpha and MIP-1 beta and augmented expression of
      the surface markers CD40, CD54, CD80, CD86 and major histocompatibility complex
      class II molecules. However, rPorA induced either low level or no significant
      secretion of pro-inflammatory cytokines from mo-DC. The protein potently
      augmented the capacity of mo-DC to activate both allogeneic CD4(+) memory T-cells
      and CD4(+)RA(+) naive T-cells. In addition, rPorA appeared to inhibit the
      production of IL-12p70 that follows from the interaction between CD40 on the mo
      DC and CD40-ligand on T-cells, thereby directing T-cell differentiation towards a
      Th2 type response. These data demonstrate that PorA is involved in DC activation
      and in influencing the nature of the T-helper immune response, which are
      important properties for generating antibody responses required for protective
      immunity against meningococci and for determining the immuno-adjuvant effects of
      this protein.

PMID- 15186402
TI  - Epithelial cell responses induced upon adherence of pathogenic Neisseria.
AB  - Neisseria meningitidis and Neisseria gonorrhoeae colonize human mucosal surfaces
      and cause sepsis/meningitis and gonorrhoea respectively. The first step in the
      infection process is pilus-mediated adhesion of the bacteria to epithelial cells,
      followed by host cell invasion. Adhesion of pathogenic Neisseria elicits multiple
      responses in host cells, including cellular signalling events, cytokine
      production and modulation of the eukaryotic cell surface. We used microarrays to
      assess the respective involvement of 375 human cytokine and adhesion related
      genes during adhesion of piliated and non-piliated N. gonorrhoeae, and piliated
      encapsulated N. meningitidis to the epithelial cell line ME-180. We identified 29
      differentially regulated genes not previously reported to respond to neisserial
      infections, many of which encode membrane proteins. Selected genes were further
      analysed by semiquantitative RT-PCR, and protein expression was examined by flow
      cytometry. We found that N. gonorrhoeae elicited a different inflammatory
      response than N. meningitidis and we also demonstrated that early adhesion events
      are responsible for the induction of specific genes. Our data create a new
      platform for elucidating the interaction between pathogenic Neisseria and target
      cells.

PMID- 15186403
TI  - Real-time, in vivo analysis of malaria ookinete locomotion and mosquito midgut
      invasion.
AB  - Invasion of the Anopheles mosquito midgut by the Plasmodium ookinete is a
      critical step in the malaria transmission cycle. We have generated a fluorescent
      P. berghei transgenic line that expresses GFP in the ookinete and oocyst stages,
      and used it to perform the first real-time analysis of midgut invasion in the
      living mosquito as well as in explanted intact midguts whose basolateral plasma
      membranes were vitally stained. These studies permitted detailed analysis of
      parasite motile behaviour in the midgut and cell biological analysis of the
      invasion process. Throughout its journey, the ookinete displays distinct modes of
      motility: stationary rotation, translocational spiralling and straight-segment
      motility. Spiralling is based on rotational motility combined with translocation
      steps and changes in direction, which are achieved by transient attachments of
      the ookinete's trailing end. As it moves from the apical to the basal side of the
      midgut epithelium, the ookinete uses a predominant intracellular route and
      appears to glide on the membrane in foldings of the basolateral domain. However,
      it traverses serially the cytoplasm of several midgut cells before entering and
      migrating through the basolateral intercellular space to access the basal lamina.
      The invaded cells commit apoptosis, and their expulsion from the epithelium
      invokes wound repair mechanisms including extensive lamellipodia crawling. A
      'hood' of lamellipodial origin, provided by the invaded cell, covers the ookinete
      during its egress from the epithelium. The flexible ookinete undergoes shape
      changes and temporary constrictions associated with passage through the plasma
      membranes. Similar observations were made in both A. gambiae and A. stephensi,
      demonstrating the conservation of P. berghei interactions with these vectors.

PMID- 15186404
TI  - Imaging movement of malaria parasites during transmission by Anopheles
      mosquitoes.
AB  - Malaria is contracted when Plasmodium sporozoites are inoculated into the
      vertebrate host during the blood meal of a mosquito. In infected mosquitoes,
      sporozoites are present in large numbers in the secretory cavities of the
      salivary glands at the most distal site of the salivary system. However, how
      sporozoites move through the salivary system of the mosquito, both in resting and
      feeding mosquitoes, is unknown. Here, we observed fluorescent Plasmodium berghei
      sporozoites within live Anopheles stephensi mosquitoes and their salivary glands
      and ducts. We show that sporozoites move in the mosquito by gliding, a type of
      motility associated with their capacity to invade host cells. Unlike in vitro,
      sporozoite gliding inside salivary cavities and ducts is modulated in speed and
      motion pattern. Imaging of sporozoite discharge through the proboscis of
      salivating mosquitoes indicates that sporozoites need to locomote from cavities
      into ducts to be ejected and that their progression inside ducts favours their
      early ejection. These observations suggest that sporozoite gliding allows not
      only for cell invasion but also for parasite locomotion in host tissues, and that
      it may control parasite transmission.

PMID- 15186406
TI  - Are rhoptries in Apicomplexan parasites secretory granules or secretory lysosomal
      granules?
AB  - The club-shaped rhoptries in Apicomplexan parasites are one of the most unusual
      secretory organelles among the eukaryotes, containing unusual lipid and protein
      cargo that is specialized for intracellular parasitism. Rhoptries have
      traditionally been viewed strictly as regulated secretory granules. We discuss in
      this article recent data on the cargo, function and biogenesis of rhoptries in
      two parasitic model systems, Toxoplasma and Plasmodium. Current findings suggest
      that rhoptries receive products from both biosynthetic and endocytic pathways
      and, therefore, they are most analogous to secretory lysosomal granules found in
      mammalian cells.

PMID- 15186407
TI  - Lipoprotein processing is required for virulence of Mycobacterium tuberculosis.
AB  - Lipoproteins are a subgroup of secreted bacterial proteins characterized by a
      lipidated N-terminus, processing of which is mediated by the consecutive activity
      of prolipoprotein diacylglyceryl transferase (Lgt) and lipoprotein signal
      peptidase (LspA). The study of LspA function has been limited mainly to non
      pathogenic microorganisms. To study a potential role for LspA in the pathogenesis
      of bacterial infections, we have disrupted lspA by allelic replacement in
      Mycobacterium tuberculosis, one of the world's most devastating pathogens.
      Despite the presence of an impermeable lipid outer layer, it was found that LspA
      was dispensable for growth under in vitro culture conditions. In contrast, the
      mutant was markedly attenuated in virulence models of tuberculosis. Our findings
      establish lipoprotein metabolism as a major virulence determinant of tuberculosis
      and define a role for lipoprotein processing in bacterial pathogenesis. In
      addition, these results hint at a promising new target for therapeutic
      intervention, as a highly specific inhibitor of bacterial lipoprotein signal
      peptidases is available.

PMID- 15186408
TI  - New Listeria monocytogenes prfA* mutants, transcriptional properties of PrfA*
      proteins and structure-function of the virulence regulator PrfA.
AB  - PrfA, a transcription factor structurally related to Crp/Fnr, activates Listeria
      monocytogenes virulence genes during intracellular infection. We report two new
      PrfA* mutations causing the constitutive overexpression of the PrfA regulon. Leu
      140Phe lies in alphaD adjacent to the DNA-binding motif in the C-terminal domain,
      like a previously characterized PrfA* mutation (Gly-145Ser). Ile-45Ser, in
      contrast, maps to the N-terminal beta-roll, a structure similar to that of the
      Crp cAMP binding site. The in vitro transcriptional properties of recombinant
      PrfA*(I45S) and PrfA*(G145S) were compared to those of PrfA(WT) at two
      differentially regulated PrfA-dependent promoters, PplcA and PactA. The two PrfA*
      mutations increased the affinity for the target DNA to a different extent, and
      the differences in DNA binding (PrfA*(G145S) > PrfA*(I45S) >>> PrfA(WT))
      correlated with proportional differences in transcriptional activity. The use of
      the PrfA* proteins revealed that PplcA had a greater affinity for, and was more
      sensitive to, PrfA than PactA. RNA polymerase (RNAP) initiated transcription
      independently of PrfA at PplcA, but not at PactA, consistent with bandshift
      experiments suggesting that PplcA has a greater affinity for RNAP than PactA.
      Thus, differences in affinity for both PrfA and RNAP appear to determine the
      different expression pattern of PrfA-regulated promoters. Modelling of the PrfA*
      mutations in the crystal structure of PrfA and comparison with structure-function
      analyses of Crp, in which similar mutations lead to constitutively active (cAMP
      independent) Crp* proteins, suggested that PrfA shares with Crp an analogous
      mechanism of cofactor-mediated allosteric shift. Our data support a regulatory
      model in which changes in PrfA-dependent gene expression are primarily accounted
      for by changes in PrfA activity.

PMID- 15186409
TI  - Anucleate and titan cell phenotypes caused by insertional inactivation of the
      structural maintenance of chromosomes (smc) gene in the archaeon Methanococcus
      voltae.
AB  - SMC (structural maintenance of chromosomes) proteins are highly conserved and
      present in eukaryotes, bacteria and archaea. They function in chromosome
      condensation and segregation and in DNA repair. Using an insertion vector
      containing the pac gene for resistance to puromycin, we have created an insertion
      in the smc gene of Methanococcus voltae. We used epifluorescence microscopy to
      examine the cell and nucleoid morphology, DNA content and metabolic activity.
      This insertion causes gross defects in chromosome segregation and cell
      morphology. Approximately 20% of mutant cells contain little or no DNA, and a
      subset of cells ( approximately 2%) IS abnormally large (three to four times
      their normal diameter) titan cells. We believe that these titan cells indicate
      cell division arrest at a cell cycle checkpoint. The results confirm that SMC in
      archaea is an important player in chromosome dynamics (as it is in bacteria and
      eukaryotes).

PMID- 15186410
TI  - Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of
      Treponema pallidum during infection.
AB  - The tprK gene sequence of Treponema pallidum subspecies pallidum (T. pallidum) is
      heterogeneous within and among isolates. Heterogeneity in the tprK open reading
      frame is localized in seven discrete variable (V) regions, and variability
      results from apparent base changes, insertions or deletions. The TprK V regions
      are the focus of anti-TprK antibodies arising during infection. To test our
      hypothesis that V region sequences change during infection and passage, we
      developed a clonal isolate from the Chicago strain of T. pallidum and confirmed V
      region diversification during passage of this isolate. We describe the sequence
      anatomy of the seven V regions of tprK and the identification of putative donor
      sites for new V region sequences, and we propose a model for generation of new V
      regions by segmental gene conversion. These findings suggest that antigenic
      variation of TprK occurs in T. pallidum and may be important in immune evasion
      and persistence.

PMID- 15186411
TI  - Replication fork and SeqA focus distributions in Escherichia coli suggest a
      replication hyperstructure dependent on nucleotide metabolism.
AB  - Replication from the origin of Escherichia coli has traditionally been visualized
      as two replisomes moving away from each other, each containing a leading and a
      lagging strand polymerase. Fluorescence microscopy studies of tagged polymerases
      or forks have, however, indicated that the polymerases may be confined to a
      single location (or a few locations in cells with overlapping replication
      cycles). Here, we have analysed the exact replication patterns of cells growing
      with four different growth and replication rates, and compared these with the
      distributions of SeqA foci. The SeqA foci represent replication forks because the
      SeqA protein binds to the newly formed hemimethylated DNA immediately following
      the forks. The results show that pairs of forks originating from the same origin
      stay coupled for most of the cell cycle and thus support the replication factory
      model. They also suggest that the factories consisting of four polymerases are,
      at the time immediately after initiation, organized into higher order structures
      consisting of eight or 12 polymerases. The organization into replication
      factories was lost when replication forks experienced a limitation in the supply
      of nucleotides or when the thymidylate synthetase gene was mutated. These results
      support the idea that the nucleotide synthesis apparatus co-localizes with the
      replisomes forming a 'hyperstructure' and further suggest that the integrity of
      the replication factories and hyperstructures is dependent on nucleotide
      metabolism.

PMID- 15186412
TI  - SepL, a protein required for enteropathogenic Escherichia coli type III
      translocation, interacts with secretion component SepD.
AB  - Enteropathogenic Escherichia coli (EPEC), an important cause of infantile
      diarrhoea in the developing world, disrupts host cell microvilli, causes actin
      rearrangements and attaches intimately to the host cell surface. This
      characteristic phenotype, referred to as the attaching and effacing (A/E) effect,
      is encoded on a 36 kb pathogenicity island called the locus of enterocyte
      effacement (LEE). The LEE includes genes involved in type III secretion and
      translocation, the eae gene encoding an outer membrane adhesin known as intimin,
      the tir gene for the translocated intimin receptor, a regulator and various genes
      of unknown function. Among this last group is sepL. To determine the role of SepL
      in EPEC pathogenesis, we constructed and tested a non-polar sepL mutant. We found
      that this sepL mutant is deficient for A/E and that it secretes markedly reduced
      quantities of those proteins involved in translocation (EspA, EspB and EspD), but
      normal levels of those proteins presumed to be effectors (Tir, EspF and EspG).
      Despite normal levels of secretion, the mutant strain was unable to translocate
      EspF and Tir into host cells and formed no EspA filaments. Fractionation studies
      revealed that SepL is a soluble cytoplasmic protein. Yeast two-hybrid and
      affinity purification studies indicated that SepL interacts with the LEE-encoded
      protein SepD. In contrast to SepL, we found that SepD is required for type III
      secretion of both translocation and effector proteins. Together, these results
      demonstrate that SepL has a unique role in type III secretion as a functional
      component of the translocation system that interacts with an essential element of
      the secretion machinery.

PMID- 15186414
TI  - Quorum-sensing antiactivator TraM forms a dimer that dissociates to inhibit TraR.
AB  - The quorum-sensing transcriptional activator TraR of Agrobacterium tumefaciens,
      which controls the replication and conjugal transfer of the tumour-inducing (Ti)
      virulence plasmid, is inhibited by the TraM antiactivator. The crystal structure
      of TraM reveals this protein to form a homodimer in which the monomer primarily
      consists of two long coiled alpha-helices, and one of the helices from each
      monomer also bundles to form the dimeric interface. The importance of
      dimerization is addressed by mutational studies in which disruption of the
      hydrophobic dimer interface leads to aggregation of TraM. Biochemical studies
      confirm that TraM exists as a homodimer in solution in equilibrium with the
      monomeric form, and also establish that the TraM-TraR complex is a heterodimer.
      Thus, the TraM homodimer undergoes dissociation in forming the antiactivation
      complex. Combined with the structure of TraR (Zhang et al., 2002, Nature 417: 971
      974; Vannini et al., 2002, EMBO J 21: 4393-4401), our structural analysis
      suggests overlapping interactive surfaces in homodimeric TraM with those in the
      TraM-TraR complex and a mechanism for TraM inhibition on TraR.

PMID- 15186413
TI  - Visualization of DNA double-strand break repair in live bacteria reveals dynamic
      recruitment of Bacillus subtilis RecF, RecO and RecN proteins to distinct sites
      on the nucleoids.
AB  - We have found that SMC-like RecN protein, RecF and RecO proteins that are
      involved in DNA recombination play an important role in DNA double-strand break
      (DSB) repair in Bacillus subtilis. Upon induction of DNA DSBs, RecN, RecO and
      RecF localized as a discrete focus on the nucleoids in a majority of cells,
      whereas two or three foci were rarely observed. RecN, RecO and RecF co-localized
      to the induced foci, with RecN localizing first, while RecO localized later,
      followed by RecF. Thus, three repair proteins were differentially recruited to
      distinct sites on the nucleoids, potentially constituting active DSB repair
      centres (RCs). RecF did not form regular foci in the absence of RecN and failed
      to form any foci in recO cells, demonstrating a central role for RecN and RecO in
      initializing the formation of RCs. RecN/O/F foci were detected in recA, recG or
      recU mutant cells, indicating that the proteins act upstream of proteins involved
      in synapsis or post-synapsis. In the absence of exogenous DNA damage, RCs were
      rare, but they accumulated in recA and recU cells, suggesting that DSBs occur
      frequently in the absence of RecA or RecU. The results suggest a model in which
      RecN that forms multimers in solution and high-molecular-weight complexes in
      cells containing DSBs initiates the formation of RCs that mediate DSB repair with
      the homologous sister chromosome, which presents a novel concept for DSB repair
      in prokaryotes.

PMID- 15186415
TI  - In UV-irradiated Saccharomyces cerevisiae, overexpression of Swi2/Snf2 family
      member Rad26 increases transcription-coupled repair and repair of the non
      transcribed strand.
AB  - Nucleotide excision repair (NER) in eukaryotes is a pathway conserved from yeast
      to humans that removes many bulky chemical adducts and UV-induced photoproducts
      from DNA in a relatively error-free manner. In addition to the recognition and
      excision of DNA damage throughout the genome (GGR), there exists a mechanism,
      transcription-coupled nucleotide excision repair (TCR), for recognizing some
      types of DNA damage in the transcribed strand of genes in Escherichia coli, yeast
      and mammalian cells. An obstacle in the repair of the transcribed strand of
      active genes is the RNA polymerase complex stalled at sites of DNA damage. The
      stalled RNA polymerase complex may then mediate recruitment of repair proteins to
      damage in the transcribed strand. Proteins enabling TCR are the Cockayne syndrome
      B (CSB) protein in humans and its yeast homologue Rad26. Both CSB and Rad26
      belong to the Swi2/Snf2 family of DNA-dependent ATPases, which change DNA
      accessibility to proteins by altering chromatin structure. To address how Rad26
      functions in yeast repair, we used the genetic approach of overexpressing Rad26
      and examined phenotypic changes, i.e. changes in NER. We found that repair of
      both the transcribed and the non-transcribed strands is increased. In addition,
      overexpression of Rad26 partially bypasses the requirement for Rad7 in GGR,
      specifically in the repair of non-transcribed sequences. As TCR takes place in
      very localized regions of DNA (i.e. within genes) in wild-type cells, we propose
      that overexpression of recombinant Rad26 increases accessibility of the damaged
      DNA in chromatin for interaction with repair proteins.

PMID- 15186416
TI  - Specificity of streptolysin O in cytolysin-mediated translocation.
AB  - Cytolysin-mediated translocation (CMT) is a recently described process in the
      Gram-positive pathogen Streptococcus pyogenes that translocates an effector
      protein of streptococcal origin into the cytoplasm of a host cell. At least two
      proteins participate in CMT, the pore-forming molecule streptolysin O (SLO) and
      an effector protein with the characteristics of a signal transduction protein,
      the Streptococcus pyogenes NAD-glycohydrolase (SPN). In order to begin to
      elucidate the molecular details of the translocation process, we examined whether
      perfringolysin O (PFO), a pore-forming protein related to SLO, could substitute
      for SLO in the translocation of SPN. When expressed by S. pyogenes, PFO, like
      SLO, had the ability to form functional pores in keratinocyte membranes. However,
      unlike SLO, PFO was not competent for translocation of SPN across the host cell
      membrane. Thus, pore formation by itself was not sufficient to promote CMT,
      suggesting that an additional feature of SLO was required. This conclusion was
      supported by the construction of a series of mutations in SLO that uncoupled pore
      formation and competence for CMT. These mutations defined a domain in SLO that
      was dispensable for pore formation, but was essential for CMT. However,
      introduction of this domain into PFO did not render PFO competent for CMT,
      implying that an additional domain of SLO is also critical for translocation.
      Taken together, these data indicate that SLO plays an active role in the
      translocation process that extends beyond that of a passive pore.

PMID- 15186417
TI  - A distinctive dual-channel quorum-sensing system operates in Vibrio anguillarum.
AB  - Many bacterial cells communicate using diffusible signal molecules to monitor
      cell population density via a process termed quorum sensing. In marine Vibrio
      species, the Vibrio harveyi-type LuxR protein is a key player in a quorum-sensing
      phosphorelay cascade, which controls the expression of virulence, symbiotic and
      survival genes. Previously, we characterized Vibrio anguillarum homologues of
      LuxR (VanT) and LuxMN (VanMN) and, in this study, we have identified homologues
      of LuxPQ (VanPQ) and LuxOU (VanOU). In contrast to other Vibrio species, vanT was
      expressed at low cell density and showed no significant induction as the cell
      number increased. In addition, although the loss of VanO increased vanT
      expression, the loss of VanU, unexpectedly, decreased it. Both VanN and VanQ were
      required for repression of vanT even in a vanU mutant, suggesting an alternative
      route for VanNQ signal transduction other than via VanU. VanT negatively
      regulated its own expression by binding and repressing the vanT promoter and by
      binding and activating the vanOU promoter. The signal relay results in a cellular
      response as expression of the metalloprotease, empA, was altered similar to that
      of vanT in all the mutants. Consequently, the V. anguillarum quorum-sensing
      phosphorelay systems work differently from those of V. harveyi and may be used to
      limit rather than induce vanT expression.

PMID- 15186418
TI  - The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to
      cellular glutamate/glutamine levels and is important for growth in vivo.
AB  - The function of the Mycobacterium tuberculosis eukaryotic-like protein
      serine/threonine kinase PknG was investigated by gene knock-out and by expression
      and biochemical analysis. The pknG gene (Rv0410c), when cloned and expressed in
      Escherichia coli, encodes a functional kinase. An in vitro kinase assay of the
      recombinant protein demonstrated that PknG can autophosphorylate its kinase
      domain as well as its 30 kDa C-terminal portion, which contains a
      tetratricopeptide (TPR) structural signalling motif. Western analysis revealed
      that PknG is located in the cytosol as well as in mycobacterial membrane. The
      pknG gene was inactivated by allelic exchange in M. tuberculosis. The resulting
      mutant strain causes delayed mortality in SCID mice and displays decreased
      viability both in vitro and upon infection of BALB/c mice. The reduced growth of
      the mutant was more pronounced in the stationary phase of the mycobacterial
      growth cycle and when grown in nutrient-depleted media. The PknG-deficient mutant
      accumulates glutamate and glutamine. The cellular levels of these two amino acids
      reached approximately threefold of their parental strain levels. Higher cellular
      levels of the amine sugar-containing molecules, GlcN-Ins and mycothiol, which are
      derived from glutamate, were detected in the DeltapknG mutant. De novo glutamine
      synthesis was shown to be reduced by 50%. This is consistent with current
      knowledge suggesting that glutamine synthesis is regulated by glutamate and
      glutamine levels. These data support our hypothesis that PknG mediates the
      transfer of signals sensing nutritional stress in M. tuberculosis and translates
      them into metabolic adaptation.

PMID- 15186419
TI  - The Mycoplasma fermentans prophage phiMFV1: genome organization, mobility and
      variable expression of an encoded surface protein.
AB  - The approximately 16 kb genome of the Mycoplasma fermentans phiMFV1 prophage is
      described, and its mobility, replication and effect on the mycoplasma surface
      phenotype are demonstrated. In various M. fermentans strains, phiMFV1 was either
      absent or integrated at diverse (and sometimes multiple) chromosomal sites, each
      marked by a conserved TTTTTA target sequence that is duplicated upon integration.
      Precise excision, replication of an extrachromosomal form and loss of phiMFV1
      from the mycoplasmal genome were documented in a series of clonal derivatives of
      M. fermentans propagated in culture. Of 18 open reading frames (ORFs) encoded by
      phiMFV1, most can be ascribed functions related to phage biology, whereas one
      encodes a unique coiled-coil membrane surface protein, Mem, that was confirmed to
      be expressed in propagating populations of M. fermentans. With the exception of
      Mem and other minor ORFs, the striking similarity between the deduced proteomes
      of phiMFV1 and the recently described phiMAV1 of arthritogenic strains of
      Mycoplasma arthritidis, along with the prominent gene synteny between these
      elements, provides the taxonomic basis for a new family of prophage. Their coding
      features are consistent with long-term residence in mycoplasma genomes and the
      divergence of species within a phylogenetic clade of mycoplasmas. The unique Mem
      protein expressed from phiMFV1 and the unique hypothetical surface lipoproteins
      encoded by phiMAV1 and phiMFV1 also suggest that prophage-associated genes may
      provide specific, selectable phenotypic traits during co-evolution of mycoplasma
      species with their respective mammalian hosts. Retention of these labile prophage
      elements in organisms with such drastically reduced genome sizes implies a
      significant role in adaptation and survival.

PMID- 15186420
TI  - Involvement of multiple DNA elements in iron-inducible transcription of the ap65
      1 gene in the protozoan parasite Trichomonas vaginalis.
AB  - A reputed iron-responsive region, which contains multiple nuclear protein-binding
      DNA sequences, was shown previously to regulate iron-inducible transcription of
      the ap65-1 gene in the protozoan pathogen, Trichomonas vaginalis. These DNA
      sequences include two overlapping MYB recognition elements (MRE-1/MRE-2r) and
      three abutted T-tract elements. Additional nuclear protein-binding DNA sequences
      flanking the 5' (AGTGAAGTGA) and 3' (MRE-2f) of the iron-responsive region were
      identified in the present study. A stable promoter assay and primer extension
      revealed that transcriptional activity of the ap65-1 promoter is iron inducible
      as well as growth related, being lowest in the early logarithmic phase and
      highest in the mid-logarithmic phase. Subsequent mutational analysis of
      individual DNA elements of the ap65-1 promoter suggests that closely spaced T
      tract elements together with an intervening GAAGGAAG sequence within the iron
      responsive region are most critical for regulation of overall transcriptional
      activity, whereas an additional AGTGAAGTGA and MRE-2f together with an upstream T
      rich region are required for optimal iron-inducible activity, and the MRE-1/MRE
      2r overlap is only involved in growth-related activity. These observations
      suggest that expression of the ap65-1 gene is dynamically regulated under various
      growth conditions via interactions among multiple DNA regulatory elements.

PMID- 15186421
TI  - Role of the amino-terminal GAF domain of the NifA activator in controlling the
      response to the antiactivator protein NifL.
AB  - The NifA protein from Azotobacter vinelandii belongs to a family of enhancer
      binding proteins (EBPs) that activate transcription by RNA polymerase containing
      the sigma factor sigma(54). These proteins have conserved AAA+ domains that
      catalyse ATP hydrolysis to drive conformational changes necessary for open
      complex formation by sigma(54)-RNA polymerase. The activity of the NifA protein
      is highly regulated in response to redox and fixed nitrogen through interaction
      with the antiactivator protein NifL. Binding of NifL to NifA inhibits the ATPase
      activity of NifA, and this interaction is controlled by the amino-terminal GAF
      domain of NifA that binds 2-oxoglutarate. Mutations conferring resistance to NifL
      are located in both the GAF and the AAA+ domains of NifA. To investigate the
      mechanism by which the GAF domain regulates the activity of the AAA+ domain, we
      screened for second-site mutations that suppress the NifL-resistant phenotype of
      mutations in the AAA+ domain. One suppressor mutation, F119S, in the GAF domain
      restores inhibition by NifL to an AAA+ domain mutation, E356K, in response to
      fixed nitrogen but not in response to oxygen. The biochemical properties of this
      mutant protein are consistent with the in vivo phenotype and demonstrate that
      interdomain suppression results in sensitivity to inhibition by NifL in the
      presence of the signal transduction protein GlnK, but not to the oxidized form of
      NifL. In the absence of an AAA+ domain mutation, the F119S mutation confers
      hypersensitivity to repression by NifL. Isothermal titration calorimetry
      demonstrates that this mutation prevents binding of 2-oxoglutarate to the GAF
      domain. Our data support a model in which the GAF domain plays an essential role
      in preventing inhibition by NifL under conditions appropriate for nitrogen
      fixation. These observations are of general significance in considering how the
      activities of EBPs are controlled in response to environmental signals.

PMID- 15186422
TI  - Biosynthesis of the angiogenesis inhibitor borrelidin by Streptomyces parvulus
      Tu4055: insights into nitrile formation.
AB  - The 18-membered polyketide macrolide borrelidin exhibits a number of important
      biological activities, including potent angiogenesis inhibition. This has
      prompted two recent total syntheses as well as the cloning of the biosynthetic
      gene cluster from Streptomyces parvulus Tu4055. Borrelidin possesses some unusual
      structural characteristics, including a cyclopentane carboxylic acid moiety at
      C17 and a nitrile moiety at C12 of the macrocyclic ring. Nitrile groups are
      relatively rare in nature, and little is known of their biosynthesis during
      secondary metabolism. The nitrile group of borrelidin is shown here to arise from
      the methyl group of a methylmalonyl-CoA extender unit incorporated during
      polyketide chain extension. Insertional inactivation of two genes in the
      borrelidin gene cluster, borI (coding for a cytochrome P450 monooxygenase) and
      borJ (coding for an aminotransferase), generated borrelidin non-producing
      mutants. These mutants accumulated different compounds lacking the C12 nitrile
      moiety, with the product of the borI-minus mutant (12-desnitrile-12-methyl
      borrelidin) possessing a methyl group and that of the borJ-minus mutant (12
      desnitrile-12-carboxyl-borrelidin) a carboxyl group at C12. The former but not
      the latter was converted into borrelidin when biotransformed by an S. parvulus
      mutant that is deficient in the biosynthesis of the borrelidin starter unit. This
      suggests that 12-desnitrile-12-methyl-borrelidin is a competent biosynthetic
      intermediate, whereas the carboxylated derivative is a shunt metabolite.
      Bioconversion of 12-desnitrile-12-methyl-borrelidin into borrelidin was also
      achieved in a heterologous system co-expressing borI and borJ in Streptomyces
      albus J1074. This bioconversion was more efficient when borK, which is believed
      to encode a dehydrogenase, was simultaneously expressed with borI and borJ. On
      the basis of these findings, a pathway is proposed for the formation of the
      nitrile moiety during borrelidin biosynthesis.

PMID- 15186423
TI  - Control of DNA replication initiation by recruitment of an essential initiation
      protein to the membrane of Bacillus subtilis.
AB  - The Bacillus subtilis proteins DnaD and DnaB are essential for replication
      initiation and are conserved in low G+C content Gram-positive bacteria. Previous
      work indicated that DnaD and DnaB are involved in helicase loading during the
      process of restarting stalled replication forks. We have investigated the roles
      of DnaD and DnaB in replication initiation at oriC in vivo. Using chromatin
      immunoprecipitation (ChIP), we found that DnaD and DnaB functions are needed to
      load the replicative helicase at oriC. To investigate further the functions of
      DnaD and DnaB in replication initiation, we isolated and characterized
      suppressors of the temperature sensitivity of dnaD and dnaB mutant cells. In both
      cases, we isolated the identical missense mutation in dnaB, dnaBS371P. Using
      yeast two-hybrid analysis, we found that dnaBS371P uncovers a previously
      undetected physical interaction between DnaD and DnaB. We also found that
      DnaBS371P constitutively recruits DnaD to the membrane fraction of cells, where
      DnaB and oriC are enriched. Phenotypes of cells expressing DnaBS371P are
      consistent with aberrant replication control. We hypothesize that B. subtilis
      regulates replication initiation by regulating a physical interaction between two
      proteins essential for helicase loading at chromosomal origins.

PMID- 15186424
TI  - Effects of RNA polymerase modifications on transcription-induced negative
      supercoiling and associated R-loop formation.
AB  - Transcription in the absence of topoisomerase I, but in the presence of DNA
      gyrase, can result in the formation of hypernegatively supercoiled DNA and
      associated R-loops. In this paper, we have used several strategies to study the
      effects of elongation/termination properties of RNA polymerase on such
      transcription-induced supercoiling. Effects on R-loop formation were exacerbated
      when cells were exposed to translation inhibitors, a condition that stimulated
      the accumulation of R-loop-dependent hypernegative supercoiling. Translation
      inhibitors were not acting by decreasing (p)ppGpp levels as the absence of
      (p)ppGpp in spoT relA mutant strains had little effect on hypernegative
      supercoiling. However, an rpoB mutation leading to the accumulation of truncated
      RNAs considerably reduced R-loop-dependent hypernegative supercoiling.
      Transcription of an rrnB fragment preceded by a mutated and inactive boxA
      sequence to abolish the rrnB antitermination system also considerably reduced R
      loop-dependent supercoiling. Taken together, our results indicate that RNA
      polymerase elongation/termination properties can have a major impact on R-loop
      dependent supercoiling. We discuss different possibilities by which RNA
      polymerase directly or indirectly participates in R-loop formation in Escherichia
      coli. Finally, our results also indicate that what determines the steady-state
      level of hypernegatively supercoiled DNA in topA null mutants is likely to be
      complex and involves a multitude of factors, including the status of RNA
      polymerase, transcription-translation coupling, the cellular level of RNase HI,
      the status of DNA gyrase and the rate of relaxation of supercoiled DNA.

PMID- 15186425
TI  - A pheromone receptor gene, pre-1, is essential for mating type-specific
      directional growth and fusion of trichogynes and female fertility in Neurospora
      crassa.
AB  - Neurospora crassa is a heterothallic filamentous fungus with two mating types,
      mat a and mat A. Its mating involves differentiation of female reproductive
      structures (protoperithecia) and chemotropic growth of female-specific hyphae
      (trichogynes) towards a cell of the opposite mating type in a pheromone-mediated
      process. In this study, we characterize the pre-1 gene, encoding a predicted G
      protein-coupled receptor with sequence similarity to fungal pheromone receptors.
      pre-1 is most highly expressed in mat A strains under mating conditions, but low
      levels can also be detected in mat a strains. Analysis of pre-1 deletion mutants
      showed that loss of pre-1 does not greatly affect vegetative growth, heterokaryon
      formation or male fertility in either mating type. Protoperithecia from Deltapre
      1 mat A mutants do not undergo fertilization; this defect largely stems from an
      inability of their trichogynes to recognize and fuse with mat a cells. Previous
      work has demonstrated that the Galpha subunit, GNA-1, and the Gbeta protein, GNB
      1, are essential for female fertility in N. crassa. Trichogynes of Deltagna-1 and
      Deltagnb-1 mutants displayed severe defects in growth towards and fusion with
      male cells, similar to that of Deltapre-1 mat A strains. However, the female
      sterility defect of the Deltapre-1 mat A mutant could not be complemented by
      constitutive activation of gna-1, suggesting additional layers of regulation. We
      propose that PRE-1 is a pheromone receptor coupled to GNA-1 that is essential for
      the mating of mat A strains as females, consistent with a role in launching the
      pheromone response pathway in N. crassa.

PMID- 15186426
TI  - The Che4 pathway of Myxococcus xanthus regulates type IV pilus-mediated motility.
AB  - Myxococcus xanthus co-ordinates cell movement during its complex life cycle using
      multiple chemotaxis-like signal transduction pathways. These pathways regulate
      both type IV pilus-mediated social (S) motility and adventurous (A) motility.
      During a search for new chemoreceptors, we identified the che4 operon, which
      encodes homologues to a MCP (methyl-accepting chemotaxis protein), two CheWs, a
      hybrid CheA-CheY, a response regulator and a CheR. Deletion of the che4 operon
      did not cause swarming or developmental defects in either the wild-type
      (A(+)S(+)) strain or in a strain sustaining only A motility (A(+)S(-)). However,
      in a strain displaying only S motility (A(-)S(+)), deletion of the che4 operon or
      the gene encoding the response regulator, cheY4, caused enhanced vegetative
      swarming and prevented aggregation and sporulation. In contrast, deletion of mcp4
      caused reduced vegetative swarming and enhanced development compared with the
      parent strain. Single-cell analysis of the motility of the A(-)S(+) parent strain
      revealed a previously unknown inverse correlation between velocity and reversal
      frequency. Thus, cells that moved at higher velocities showed a reduced reversal
      frequency. This co-ordination of reversal frequency and velocity was lost in the
      mcp4 and cheY4 mutants. The structural components of the S motility apparatus
      were unaffected in the che4 mutants, suggesting that the Che4 system affects
      reversal frequency of cells by modulating the function of the type IV pilus.

PMID- 15186427
TI  - HrpA, a DEAH-box RNA helicase, is involved in mRNA processing of a fimbrial
      operon in Escherichia coli.
AB  - Endonucleolytic cleavage of mRNA in the daa operon of Escherichia coli is
      responsible for co-ordinate regulation of genes involved in F1845 fimbrial
      biogenesis. Cleavage occurs by an unidentified endoribonuclease, is translation
      dependent and involves a unique recognition mechanism. Here, we present the
      results of a genetic strategy used to identify factors involved in daa mRNA
      processing. We used a reporter construct consisting of the daa mRNA processing
      region fused to the gene encoding green fluorescent protein (GFP). A mutant
      defective in daa mRNA processing and expressing high levels of GFP was isolated
      by flow cytometry. To determine the location of mutations, two different genetic
      approaches, Hfr crosses and P1 transductions, were used. The mutation responsible
      for the processing defect was subsequently mapped to the 32 min region of the E.
      coli chromosome. A putative DEAH-box RNA helicase-encoding gene at this position,
      hrpA, was able to restore the ability of the mutant to cleave daa mRNA. Site
      directed mutagenesis of the hrpA regions predicted to encode nucleotide
      triphosphate binding and hydrolysis functions abolished the ability of the gene
      to restore the processing defect in the mutant. We propose that HrpA is a novel
      enzyme involved in mRNA processing in E. coli.

PMID- 15186428
TI  - The bacterial signal molecule, ppGpp, regulates Salmonella virulence gene
      expression.
AB  - Numerous, overlapping global regulatory systems mediate the environmental
      signalling controlling the virulence of Salmonella typhimurium. With both extra-
      and intracellular lifestyles, unravelling the mechanisms involved in regulating
      Salmonella pathogenesis has been complex. Here, we report a factor co-ordinating
      environmental signals with global regulators involved in pathogenesis. An S.
      typhimuriumDeltarelADeltaspoT strain deficient in guanosine tetraphosphate
      (ppGpp) synthesis was found to be highly attenuated in vivo and non-invasive in
      vitro. The DeltarelADeltaspoT strain exhibited severely reduced expression of
      hilA and invF, encoding major transcriptional activators required for Salmonella
      pathogenicity island 1 (SPI-1) gene expression and at least two other
      pathogenicity islands. None of the growth conditions intended to mimic the
      intestinal milieu was capable of inducing hilA expression in the absence of
      ppGpp. However, the expression of global regulators of Salmonella virulence, RpoS
      and PhoP/Q, and RpoS- and PhoP/Q-dependent, non-virulence-related genes was not
      significantly different from the wild-type strain. The results indicate that
      ppGpp plays a central role as a regulator of virulence gene expression in S.
      typhimurium and implicates ppGpp as a major factor in the environmental and host
      dependent regulation of Salmonella pathogenesis.

PMID- 15186429
TI  - Collagenolytic (necrobiotic) granulomas: part II--the 'red' granulomas.
AB  - A collagenolytic or necrobiotic non-infectious granuloma is one in which a
      granulomatous infiltrate develops around a central area of altered collagen and
      elastic fibers. The altered fibers lose their distinct boundaries and exhibit new
      staining patterns, becoming either more basophilic or eosinophilic. Within the
      area of altered collagen, there may be deposition of acellular substances such as
      mucin (blue) or fibrin (red), or there may be neutrophils with nuclear dust
      (blue), eosinophils (red), or flame figures (red). These color distinctions can
      be used as a simple algorithm for the diagnosis of collagenolytic granulomas,
      i.e. 'blue' granulomas vs. 'red' granulomas. Eight diagnoses are included within
      these two groupings, which are discussed in this two-part article. In the
      previously published first part, the clinical presentation, pathogenesis and
      histologic features of the 'blue' collagenolytic granulomas were discussed. These
      are the lesions of granuloma annulare, Wegener's granulomatosis, and rheumatoid
      vasculitis. In this second half of the series, the 'red' collagenolytic
      granulomas are discussed; these are the lesions of necrobiosis lipoidica,
      necrobiotic xanthogranuloma, rheumatoid nodules, Churg-Strauss syndrome, and
      eosinophilic cellulitis (Well's Syndrome).

PMID- 15186430
TI  - Cutaneous metastasis: a clinical, pathological, and immunohistochemical
      appraisal.
AB  - BACKGROUND: Cutaneous tumor metastasis may be the first manifestation of cancer,
      but more often is a harbinger of advanced disease that portends an ominous
      prognosis. All skin accessions over the past 10 years from a large Veterans
      Administration (VA) hospital were reviewed. METHODS: Archived histories, glass
      slides, and the immunohistochemical battery (IHC), were assessed to determine
      diagnostic accuracy. RESULTS: Of the 100,453 cases reviewed, there were a total
      of 77 cases (75 males and 2 females) of cutaneous metastasis from the lungs
      (28.6%), metastatic melanoma (18.2%), gastrointestinal tract (14.2%),
      genitourinary tract (10.4%), head and neck (9.1%), hematologic (5.2%), breast
      (5.2%), and miscellaneous (<2%). Metastasis represented the first indication of
      an internal malignancy in 7.8% of cases. The cutaneous sites of involvement
      included the head and neck (28%), the trunk (40%), the extremities (18%), and
      multiple sites (14%). The age range was 38-83 years, with a mean of 62 years. The
      average time interval between diagnosis of internal malignancy and cutaneous
      presentation was 33 months (range: <1 month-22 years), and the average survival
      following diagnosis was 7.5 months (range: <1 month-8 years). In a cohort of
      subjects, a truncated immunohistochemical battery consisting of CK-7, CK-20, and
      S-100 was consistent with the expected staining pattern of the primary source of
      cutaneous metastasis in 83.33% of the patients. CONCLUSIONS: Excluding the
      potential for age and gender bias in this study conducted in a VA setting,
      cutaneous metastases represent an uncommon, deadly, and late-developing
      occurrence in many patients. Compared with previous studies, lung carcinoma
      remains the most common of the cutaneous metastases, with a relative rise in the
      incidence of metastatic melanoma. The immunohistochemical battery of CK-7, CK-20,
      and S-100 is a helpful adjunct in narrowing the differential diagnosis of the
      primary site of a large proportion of cutaneous metastases, particularly tumors
      with an epithelioid appearance such as carcinomas and melanomas.

PMID- 15186432
TI  - Perilesional vs. lesional skin changes in senile lentigo.
AB  - BACKGROUND: Senile lentigo (SL) is a common component of photoaged skin. It is
      characterized by hyperpigmented macules which affect chronically irradiated skin
      mostly after 50 years of age. This study was undertaken to assess the basic
      morphology of SL on dorsum of hands. METHODS: A systematic comparison between
      lesional vs. perilesional skin using immunohistochemistry and electron microscopy
      was done to detect precursor lesions of SL and to determine whether melanocytes
      or keratinocytes were first affected in the evolution of lesions. RESULTS: In 12
      cases studied, the main findings show that clusters of perilesional keratinocytes
      accumulate melanin in large melanosomial complexes, and that melanocytes counts
      are increased respective to total length of section in lesional skin, but the
      increment is probably due to the development of characteristic epidermal rete
      ridges. Melanocytes had overall a normal ultrastructure, with mostly quiescent
      features in perilesional skin and melanosomial transport seeming more active in
      lesional skin. CONCLUSIONS: Our data indicate that SL may represent a loss of
      epidermal melanin unit homeostasis due to chronic irradiation, where
      keratinocytic changes predominate over melanocytic changes. We hypothesize that
      abnormal pigment retention in keratinocytes is the primary defect in SL, which
      may partly explain the therapeutic effect of retinoids.

PMID- 15186431
TI  - Hyperplasia of dermal microvascular pericytes in scleroderma.
AB  - BACKGROUND: Pericytes (PCs) are smooth muscle-like mural cells of capillaries and
      venules, which can synthesize matrix components and fibroblast-activating
      cytokines, and are thus potential mediators of pathological changes in
      scleroderma. In this study, alterations in microvessels were quantitatively
      imaged, taking PC into account for the first time. METHODS: Skin biopsies from
      systemic (12) and localized (14) scleroderma forms as well as age-, sex-, and
      body location-matched controls were examined with respect to capillary and
      venular densities as well as endothelial cell (EC) and PC counts using a newly
      developed (in respect of PC and EC) indirect collagen IV immunostaining-based
      method. RESULTS: Hyperplasia of the PC that doubled the microvascular PC density
      was the most conspicuous characteristic. In the capillaries of the upper dermal
      plexus of the periphery of the sclerotic zones, median ratios of PC : EC were
      0.23 (controls 0.10) or 0.18 (controls 0.11) in systemic or localized
      scleroderma, respectively. Furthermore, an increase in capillary density in the
      upper dermal plexus could be demonstrated in the marginal zones of both types of
      disease. CONCLUSIONS: The observed PC increase in the peripheral zones of active
      disease supports the hypothesis of a vascular pathogenesis of scleroderma and
      directs the focus to microvascular PC.

PMID- 15186433
TI  - Multicentric plasma cell variant of Castleman's disease with cutaneous
      involvement.
AB  - BACKGROUND: Castleman's disease (CD) is a rare low-grade B-cell
      lymphoproliferative disorder that can be associated with a variety of antibody
      mediated paraneoplastic syndromes. The disease is classified clinically by two
      forms and three histologic variants. METHODS: We describe the clinical and
      pathological features of a 44-year-old woman who presented with an autoimmune
      hemolytic anemia, thrombocytosis, polyclonal gammopathy, axillary
      lymphadenopathy, hepatosplenomegaly, and several erythematous and violaceous
      nodules and plaques without scaling involving the trunk and extremities. RESULTS:
      Histologic examination of the skin lesions revealed a deep dermal and
      subcutaneous nodular mononuclear infiltrate composed primarily of polyclonal
      plasmacytoid cells without atypia and an increased vascular proliferation.
      Additional studies including a bone marrow and lymph node biopsy, serum and urine
      protein electrophoresis, and computed tomography scans supported the diagnosis of
      multicentric plasma cell variant of CD with an associated autoimmune
      paraneoplastic hemolytic anemia. CONCLUSION: Cutaneous involvement in CD is part
      of the multicentric nature and should be considered in the differential diagnosis
      of a polyclonal plasma cell-rich lymphoproliferative disorder associated with
      paraneoplastic autoimmune disease.

PMID- 15186434
TI  - Post-transplant lymphoproliferative disorder limited to the skin.
AB  - BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a condition
      affecting immunosuppressed transplant patients and has a variety of clinical
      presentations. It is rarely found in the skin, and cases of PTLD in the skin are
      usually linked with lymph node or other organ involvement. METHODS: We report a
      case of plasmacytoid PTLD that is limited to the skin. A 63-year-old man with a
      history of cardiac transplant presented with exophytic tumors involving the lower
      extremity. The diagnosis and classification of the various forms of PTLD are
      discussed. RESULTS: Histology, immunohistochemical stains, and in situ
      hybridization revealed an aggressive plasmacytoid tumor that was Epstein-Barr
      virus positive. The patient's tumors resolved with decreased immunosuppression
      and localized radiation. CONCLUSION: This case is unusual for several reasons
      including involvement limited to the skin, presentation 15 years following
      transplant, and plasmacytoid phenotype of the tumor. This disorder will likely be
      seen by dermatologists and dermatopathologists with the increasing use of
      immunosuppressive medications in the dermatologist's patient population.

PMID- 15186435
TI  - Primary cutaneous CD30 anaplastic large cell lymphoma with keratoacanthoma-like
      pseudocarcinomatous hyperplasia and marked eosinophilia and neutrophilia.
AB  - BACKGROUND: Pseudocarcinomatous hyperplasia (PCH) and marked tissue neutrophilia
      have been observed in cutaneous CD30(+) anaplastic large cell lymphoma (ALCL)
      occasionally and may cause misdiagnosis. METHODS: An unusual case of CD30(+) ALCL
      of the skin resembling keratoacanthoma (KA) both clinically and pathologically
      was described. Histologic examination and immunostaining were performed. RESULTS:
      A 55-year-old woman presented with a 3-month history of an enlarging
      hyperkeratotic tumor on the forehead with a central keratinous plug. Microscopic
      examination showed epithelial hyperplasia resembling KA and a diffuse background
      infiltrate of large atypical lymphoid cells in the dermis. The atypical cells
      resembled epithelial cells and were obscured by a massive infiltrate of
      eosinophils and neutrophils. Immunostaining confirmed the presence of a diffuse
      infiltrate of CD30(+) cells; these cells were negative for CD45RO, CD20, CD15,
      epithelial membrane antigen, anaplastic lymphoma kinase-1, and cytokeratin. There
      was no evidence of extracutaneous involvement. The findings were consistent with
      primary cutaneous CD30(+) ALCL of null cell phenotype with KA-like epithelial
      hyperplasia and marked eosinophilia and neutrophilia. CONCLUSIONS: Our case
      illustrates that primary cutaneous ALCL may be associated with KA-like PCH and
      concurrent marked tissue eosinophilia and neutrophilia. Diagnosis in such cases
      is challenging both clinically and histologically because the large atypical
      lymphoid cells may easily be obscured by the massive infiltrates of eosinophils
      and neutrophils or confused with invasive squamous cell carcinoma.

PMID- 15186437
TI  - Adhesion of Staphylococcus aureus and Staphylococcus epidermidis to the Episkin
      reconstructed epidermis model and to an inert 304 stainless steel substrate.
AB  - AIMS: The aim of this study was to evaluate the respective influence of the
      physicochemical interactions and the roughness involved in the first part of the
      biological substrate biocontamination. METHODS AND RESULTS: Therefore we compared
      the bioadhesion results obtained on the biological model substrate (Episkin) and
      on a commonly employed inert substrate (AISI 304 stainless steel), frequently
      used either in dermatology or in development of medical devices. The two studied
      strains presented different characteristics, both physicochemical and
      microbiological. Staphylococcus epidermidis, a relatively hydrophobic bacteria
      capable of exchanging interactions which are principally of the van der Waals
      type, adhered more to 304 steel than to the surface of reconstituted skin. As for
      S. aureus, an essentially basic, hydrophilic bacteria, was more adherent to
      Episkin (a bipolar, hydrophilic substrate) than to stainless steel (a unipolar,
      basic, hydrophilic substrate). CONCLUSIONS: In the absence of electrostatic
      interactions, the adhesion of substrate-dependent bacteria to the surface of
      reconstituted skin was dependent upon the balance between gamma(LW), gamma(+) and
      gamma(-). SIGNIFICANCE AND IMPACT OF THE STUDY: Consequently, so as to restrict
      microbial adhesion and reduce adhesive binding between micro-organisms and the
      surface of the skin, it would be preferable to render this substrate hydrophobic
      and apolar through the use of appropriate surface treatment.

PMID- 15186438
TI  - PCR detection of pathogenic viruses in southern California urban rivers.
AB  - AIMS: To investigate human viral contamination in urban rivers and its impact on
      coastal waters of southern California, USA. METHODS AND RESULTS: Three types of
      human viruses (adeno, entero and hepatitis A) were detected using nested- and RT
      PCR from 11 rivers and creeks. Faecal indicator bacteria as well as somatic and F
      specific coliphage were also tested. Approximately 50% of the sites were positive
      for human adenoviruses. However, there was no clear relationship between
      detection of human viruses and the concentration of indicator bacteria and
      coliphage. Both faecal indicator bacteria and human viral input at beaches near
      river mouths were associated with storm events. The first storm of the wet season
      seemed to have the greatest impact on the quality of coastal water than following
      storm events. CONCLUSIONS: This study provides the first direct evidence that
      human viruses are prevalent in southern California urban rivers. Urban run-off
      impacts coastal water quality most significantly during the storm season.
      SIGNIFICANCE AND IMPACT OF THE STUDY: To protect human health during water
      recreational activities, it is necessary to develop effective strategies to
      manage urban run-off during storm events.

PMID- 15186439
TI  - Effect of Bifidobacterium longum ingestion on experimental salmonellosis in mice.
AB  - AIMS: The effect of lactic acid bacteria on the immune system is well established
      under normal conditions and generally by in vivo determinations, but few data are
      available, in vivo, during an infectious challenge. The objective of this study
      was to obtain data on the putative protective role of bifidobacteria upon
      challenge with an intestinal pathogen. METHODS AND RESULTS: The effect of oral
      treatment with Bifidobacterium longum Bb46 on intragastric challenge with
      Salmonella Typhimurium was studied. Faecal bacterial levels were determined in
      gnotobiotic (GN) mice and mortality, histopathology (intestines, liver),
      immunoglobulin levels (IgM, IgG, IgG1, IgG2a) and cytokine production (IFN-gamma,
      IL-10) were determined in conventional (CV) mice. Conventional mice received 0.1
      ml probiotic milk (10(8) CFU) daily, 10 days before the oral pathogenic challenge
      (10(2) CFU). Then, probiotic treatment was continued until the end of the
      experiment. Probiotic treatment in germ-free mice consisted of a single dose at
      the beginning of the experiment. Control groups were treated with sterile skim
      milk and submitted to the same procedure. A higher survival (40%) was observed
      for probiotic-treated animals when compared with the control group (0%). This
      protective effect was confirmed by the histopathological and morphometric data.
      However, S. Typhimurium population levels in the faeces were similar among
      control and probiotic-treated groups. During the challenge with S. Typhimurium, a
      decrease in IFN-gamma and IgG2a productions was observed in probiotic-treated
      mice. CONCLUSIONS: The protective effect against the pathogenic challenge may be
      due to a reduced inflammatory response, mediated by the probiotic treatment, but
      not to a population antagonism. SIGNIFICANCE AND IMPACT OF THE STUDY: Results
      suggest that dietary supplementation with B. longum could provide benefits
      against enteric infection.

PMID- 15186440
TI  - PCR detection and 16S rRNA sequence-based phylogeny of a novel Propionibacterium
      acidipropionici applicable for enhanced fermentation of high moisture corn.
AB  - AIMS: The aims of this study were to develop a sensitive and more rapid detection
      of Propionibacterium acidipropionici DH42 in silage and rumen fluid samples, and
      to explore its 16S rRNA sequence-based phylogeny. METHODS AND RESULTS: Nested
      polymerase chain reaction (PCR) was used with DH42-specific primers dhb1 and dhb2
      for the secondary amplification of a 1267-bp fragment of 16S rRNA encoding gene.
      Using the established protocols for PCR amplification, as low as 10(2) and 10(3)
      CFU ml(-1) of strain DH42 in silage extracts and rumen fluid, respectively, were
      detected. To determine phylogenetic relationships between DH42 and other
      representatives of Propionibacterineae, a 1529-bp fragment of its 16S rRNA was
      amplified by PCR and sequenced. The propionibacterium DH42 formed a cluster with
      Eubacterium combesii, P. acidipropionici and P. microaerophilus. CONCLUSIONS: 16S
      rRNA-based PCR detection technique was developed for DH42 in silage and rumen
      fluid samples. The 16S rRNA sequence confirmed the earlier identification of
      strain DH42 as P. acidipropionici. However, variable nucleotide positions were
      revealed. SIGNIFICANCE AND IMPACT OF THE STUDY: Variability of 16S rRNA sequence
      within the species P. acidipropionici, determined in this study, poses the need
      of re-sequencing for some species of the suborder Propionibacterineae for a more
      reliable classification.

PMID- 15186441
TI  - Effect of combined physico-chemical preservatives on enterocin AS-48 activity
      against the enterotoxigenic Staphylococcus aureus CECT 976 strain.
AB  - AIMS: Control of the enterotoxigenic Staphylococcus aureus CECT 976 strain by
      enterocin AS-48 in laboratory cultures, and behaviour of the AS-48 activity in
      the presence of food preservatives. METHODS AND RESULTS: Enterocin AS-48 shows
      inhibitory activity on the majority of the Staphylococcus species tested. This
      enterocin has a bactericidal and bacteriolytic mode of action on S. aureus CECT
      976, a strain selected for this study by its enterotoxigenic character (SEA
      production). The inhibitory effect of AS-48 was pH and temperature dependent, and
      enterocin activity was higher at pH 5. The minimum bactericidal concentration
      (MBC) of AS-48, decreased from 15 microg ml(-1) at 37 degrees C to 10 microg ml(
      1) at 15 degrees C. Sublethally injured cells showed an increased sensitivity
      with a MBC of 5 microg ml(-1). In this way, the highest effectiveness of Ent AS
      48 against S. aureus CECT 976 was obtained at 4 degrees C in combination with
      high concentrations of NaCl (6 and 7%). Interestingly, enterotoxin SEA production
      by strain CECT 976 was markedly inhibited by subinhibitory concentrations of Ent
      AS-48. These low concentrations also provoked a delay of bacterial growth.
      CONCLUSION: The results presented indicated that Ent AS-48 has a potential for
      application as a protective agent against S. aureus in foods. SIGNIFICANCE AND
      IMPACT OF THE STUDY: In this study, we have established the conditions for an
      efficient inhibition of growth and enterotoxin production by S. aureus CECT 976
      in culture media by a combination of environmental factors and Ent AS-48.

PMID- 15186442
TI  - Comprehensive gene expression analysis of the response to straight-chain alcohols
      in Saccharomyces cerevisiae using cDNA microarray.
AB  - AIMS: The purpose of this study was to examine the gene expression profiles of
      yeast Saccharomyces cerevisiae subjected to straight-chain alcohols. METHODS AND
      RESULTS: Lipophilic alcohols with high log Pow values were more toxic to yeast
      than those with low log Pow values. Morphological changes after exposure to
      ethanol, 1-pentanol, 1-octanol were observed, whereas n-pentane as a model
      hydrocarbon affected the surface of the outer membrane, with little change in
      organelles. Using cDNA microarrays, quite a few up-regulated gene categories were
      classified into the category 'cell rescue, defence and virulence' by ethanol, and
      the category 'energy' and 'metabolism' by 1-pentanol. Meanwhile, the
      characteristic genes up-regulated by n-pentane were not observed, and the
      expression profile was distantly related to ethanol, 1-pentanol and 1-octanol.
      CONCLUSIONS: This study suggests that gene expression profiles at the whole
      genome level were intimately associated with the cell growth inhibition and
      morphological changes by straight-chain alcohols with differing log Pow values.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The study of comprehensive gene expression
      profiles by cDNA microarrays elucidates the straight-chain alcohol adaptation
      mechanisms.

PMID- 15186443
TI  - The microbial ecology of high-risk, chilled food factories; evidence for
      persistent Listeria spp. and Escherichia coli strains.
AB  - AIMS: The intention of this study was to provide evidence of any Listeria spp. or
      Escherichia coli strain persistence, and to identify whether strains of these
      organisms adapt to specific environmental or product niches in food factories.
      METHODS AND RESULTS: A 3-year assessment of the microbial ecology of four, ready
      to-eat food-processing factories was undertaken in which approx. 196 000 and 75
      000 product and environmental samples were examined for Escherichia coli and
      Listeria spp. respectively. A total of 152 E. coli isolates (44 environmental and
      108 product in 62 ribogroups) and 260 Listeria spp. isolates (174 environmental
      and 86 product in 30 ribogroups) were identified and ribotyped. The overall
      prevalence of E. coli (0.08%), all Listeria spp. (0.35%) and L. monocytogenes
      (0.23%) was very low. Some 10 E. coli ribogroups and 14 Listeria spp. ribogroups
      showed evidence for persistence, defined as the isolation of the same strain,
      from the same site, over a prolonged time period. The majority of E. coli strains
      were product niche oriented whilst the majority of Listeria spp. strains were
      environmental niche oriented. CONCLUSION: Current UK high-risk food factory
      designs, personnel hygiene and cleaning and disinfection regimes are sufficient
      to control Listeria spp. and E. coli to very low levels. SIGNIFICANCE AND IMPACT
      OF THE STUDY: Persistent strains of these organisms, however, can remain within
      factory high-risk production areas over considerable time periods, warranting an
      examination of the strain persistence mechanisms and alternative hygiene
      controls.

PMID- 15186444
TI  - Genotypic analysis of Escherichia coli recovered from product and equipment at a
      beef-packing plant.
AB  - AIMS: To identify sources of Escherichia coli on beef by characterizing strains
      of the organism on animals, equipment and product at beef-packing plant. METHODS
      AND RESULTS: Generic E. coli were recovered from hides, carcasses, beef
      trimmings, conveyers and ground beef during the summer of 2001 (750 isolates) and
      winter of 2002 (500 isolates). The isolates were characterized by Random
      Amplification of Polymorphic DNA (RAPD). The numbers of E. coli recovered from
      dressed carcasses were less than the numbers recovered from hides. The numbers
      recovered from chilled carcasses were too few for meaningful analysis of the
      strains present on them but the numbers recovered from trimmings and ground beef
      were larger. The RAPD patterns showed that the majority of isolates from hides,
      carcasses, beef trimmings, conveyers and ground beef were of similar RAPD types,
      but a few unique RAPD types were recovered from only one of those sources. The E.
      coli populations present on the hides of incoming animals and in the beef
      processing environment were highly diverse. Randomly selected E. coli isolates
      from each of the five sources were further characterized by pulsed-field gel
      electrophoresis (PFGE). Most genotypes of E. coli defined by PFGE corresponded to
      the E. coli types defined by RAPD. CONCLUSIONS: The hides of the incoming animals
      appeared to be only one of the sources of the E. coli on trimmings and in ground
      beef, as additional sources were apparently present in equipment used for carcass
      breaking. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates that
      hazardous microbiological contamination of meat may occur after the dressing of
      carcasses at commercial beef-packing plants, which suggests that attention should
      be given to the control of the contamination of meat during carcass breaking as
      well as during the dressing of carcasses.

PMID- 15186445
TI  - In vitro inhibitory effect of gossypol from gossypol-acetic acid, and (+)- and (
      )-isomers of gossypol on the growth of Edwardsiella ictaluri.
AB  - AIM: This study was conducted to evaluate the toxic effect of gossypol from
      gossypol-acetic acid, and (+)- and (-)-isomers of gossypol on the growth of
      Edwardsiella ictaluri. METHODS AND RESULTS: Inhibitory effect of various
      concentrations of gossypol on the growth of E. ictaluri was determined. Bacterial
      recovery was performed by preincubation of bacteria in medium containing various
      concentrations of gossypol and subsequent activation of bacteria by inoculating
      on gossypol-free plates. Concentrations of racemic gossypol, (+)-gossypol and (-)
      gossypol of 1.5 microg ml(-1) or higher significantly reduced the number of
      bacterial colonies compared with that of the control. The growth of E. ictaluri
      was completely inhibited on agar plates supplemented with 3 microg ml(-1),
      regardless of the forms of gossypol. The inhibitory effect of (+)-gossypol was
      higher than that of (-)-gossypol or gossypol-acetic acid. Recovery of E. ictaluri
      was <50% for all three forms of gossypol at concentrations of 5 microg ml(-1).
      Bacterial recovery remained relatively constant (6.5%) at gossypol concentrations
      from 10 to 100 microg ml(-1). Complete killing of E. ictaluri was not reached at
      gossypol levels up to 100 microg ml(-1). CONCLUSION: Gossypol-acetic acid, and
      (+)- and (-)-optical isomers have anti-bacterial effect against E. ictaluri. The
      results suggest the action is bacteriostatic rather than bactericidal.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The therapeutic effect of gossypol against
      E. ictaluri may be useful in controlling enteric septicaemia of catfish.

PMID- 15186446
TI  - Characterization of Pantoea dispersa UQ68J: producer of a highly efficient
      sucrose isomerase for isomaltulose biosynthesis.
AB  - AIMS: Isolation, identification and characterization of a highly efficient
      isomaltulose producer. METHODS AND RESULTS: After an enrichment procedure for
      bacteria likely to metabolize isomaltulose in sucrose-rich environments, 578
      isolates were screened for efficient isomaltulose biosynthesis using an
      aniline/diphenylamine assay and capillary electrophoresis. An isolate designated
      UQ68J was exceptionally efficient in sucrose isomerase activity. Conversion of
      sucrose into isomaltulose by UQ68J (enzyme activity of 90-100 U mg(-1) DW) was
      much faster than the current industrial strain Protaminobacter rubrum CBS574.77
      (41-66 U mg(-1) DW) or a reference strain of Erwinia rhapontici (0.3-0.9 U mg(-1)
      DW). Maximum yield of isomaltulose at 78-80% of supplied sucrose was achieved in
      less than half the reaction time needed by CBS574.77, and the amount of
      contaminating trehalulose (4%) was the lowest recorded from an isomaltulose
      producing microbe. UQ68J is a Gram negative, facultatively anaerobic, motile,
      noncapsulate, straight rod-shaped bacterium producing acid but no gas from
      glucose. Based on 16S rDNA analysis UQ68J is closest to Klebsiella oxytoca, but
      it differs from Klebsiella in defining characteristics and most closely resembles
      Pantoea dispersa in phenotype. SIGNIFICANCE AND IMPACT OF STUDY: This organism is
      likely to have substantial advantage over previously characterized sucrose
      isomerase producers for the industrial production of isomaltulose.

PMID- 15186447
TI  - Mode of antimicrobial action of vanillin against Escherichia coli, Lactobacillus
      plantarum and Listeria innocua.
AB  - AIMS: To investigate the mode of action of vanillin, the principle flavour
      component of vanilla, with regard to its antimicrobial activity against
      Escherichia coli, Lactobacillus plantarum and Listeria innocua. METHODS AND
      RESULTS: In laboratory media, MICs of 15, 75 and 35 mmol l(-1) vanillin were
      established for E. coli, Lact. plantarum and L. innocua, respectively. The
      observed inhibition was found to be bacteriostatic. Exposure to 10-40 mmol l(-1)
      vanillin inhibited respiration of E. coli and L. innocua. Addition of 50-70 mmol
      l(-1) vanillin to bacterial cell suspensions of the three organisms led to an
      increase in the uptake of the nucleic acid stain propidium iodide; however a
      significant proportion of cells still remained unstained indicating their
      cytoplasmic membranes were largely intact. Exposure to 50 mmol l(-1) vanillin
      completely dissipated potassium ion gradients in cultures of Lact. plantarum
      within 40 min, while partial potassium gradients remained in cultures of E. coli
      and L. innocua. Furthermore, the addition of 100 mmol l(-1) vanillin to cultures
      of Lact. plantarum resulted in the loss of pH homeostasis. However, intracellular
      ATP pools were largely unaffected in E. coli and L. innocua cultures upon
      exposure to 50 mmol l(-1) vanillin, while ATP production was stimulated in Lact.
      plantarum cultures. In contrast to the more potent activity of carvacrol, a well
      studied phenolic flavour compound, the extent of membrane damage caused by
      vanillin is less severe. CONCLUSIONS: Vanillin is primarily a membrane-active
      compound, resulting in the dissipation of ion gradients and the inhibition of
      respiration, the extent to which is species-specific. These effects initially do
      not halt the production of ATP. SIGNIFICANCE AND IMPACT OF THE STUDY:
      Understanding the mode of action of natural antimicrobials may facilitate their
      application as natural food preservatives, particularly for their potential use
      in preservation systems employing multiple hurdles.

PMID- 15186448
TI  - Isolation of Bacillus pumilus from in vitro grapes as a long-term alcohol
      surviving and rhizogenesis inducing covert endophyte.
AB  - AIMS: To isolate and characterize the alcohol-surviving covert bacterium
      associated with grape tissue culture. METHODS AND RESULTS: Single colony was
      isolated by plating the spent rectified spirit used during grape culturing and
      the organism was identified as Bacillus pumilus using partial 16S rDNA sequence
      data. Spotting tests (1 microl) using 3-day-old broth culture having a spore
      content of 20-30% showed similar bacterial survival in 25-90% (v/v) aqueous
      ethanol for 14 days. Survival in 90% ethanol and 90% rectified spirit appeared
      affected thereafter with no colony growth from 1 microl samples after 4 months.
      Plating the samples at this stage gave similar CFU ml(-1) for 25, 50 and 70%
      ethanol, a significant reduction in 80% ethanol and very few colonies in 90%
      ethanol and rectified spirit. B. pumilus-inoculated grape microcuttings showed
      substantial endophytic colonization of original cuttings (7.4 x 10(6) CFU g(-1))
      followed by the sprout (5.9 x 10(5)) and roots (2.0 x 10(4)). The bacterium
      although a poor root colonizer, induced early rooting and more roots in vitro.
      Inoculation at ex vitro planting resulted in significantly more roots, root
      weight and shoot growth. CONCLUSIONS: Bacillus pumilus could remain as a covert
      endophyte in grape tissue cultures and survive in aqueous ethanol for extended
      periods. 90% ethanol was the most effective bactericidal concentration. The
      bacterium showed endophytic colonization and root and shoot growth promotion.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The revelation that general recommendation
      of 70-80% ethanol may not be the most effective bactericidal concentration for
      all bacteria, elucidation of the possibility of covert bacterial survival in
      vitro plant cultures and isolation of a potential plant growth promoting
      endophyte in grape.

PMID- 15186449
TI  - Source of tryptone in growth medium affects oxidative stress resistance in
      Escherichia coli.
AB  - AIMS: To investigate the influence of the source of tryptone in the growth medium
      on the resistance of Escherichia coli to various types of oxidative stress.
      METHODS AND RESULTS: Cultures of Escherichia coli MG1655 were grown in Luria
      Bertani (LB) medium at 37 degrees C to stationary phase, harvested, and
      subsequently subjected to various types of oxidative stress. A marked difference
      in oxidative stress sensitivity was observed depending on the origin of the
      tryptone in the LB medium used to grow the cultures. Cells harvested from LB
      containing tryptone from source x (LBx) were more sensitive to inactivation by
      the superoxide generating compound plumbagin and by t-butyl peroxide, and to
      growth inhibition by the lactoperoxidase enzyme system, than cells harvested from
      LB containing tryptone from source y (LBy). By monitoring expression of a panel
      of stress gene promotors linked to the gfp (green fluorescent protein) gene, and
      using Delta2-22 alkaline phosphatase as a probe for disulphide bridge formation
      from protein sulphydryl groups, it was demonstrated that a greater cytoplasmic
      oxidative stress existed in cells during growth in LBy than in LBx. CONCLUSIONS:
      Depending on the source of tryptone, bacteria may experience different levels of
      oxidative stress in tryptone-containing nonselective growth media. Although these
      levels of oxidative stress are subinhibitory, they may trigger a stress response
      that makes the bacteria more resistant to a subsequent exposure to a lethal or
      inhibitory level of oxidative stress. SIGNIFICANCE AND IMPACT OF THE STUDY: This
      work highlights the importance of controlling very subtle differences in
      composition of nonselective growth media in studies on bacterial physiology.

PMID- 15186450
TI  - Evidence for natural horizontal transfer of tetO gene between Campylobacter
      jejuni strains in chickens.
AB  - AIMS: The transfer of tetO gene conferring resistance to tetracycline was studied
      between Campylobacter jejuni strains, in the digestive tract of chickens. METHODS
      AND RESULTS: In vitro conjugation experiments were first performed in order to
      select donor/recipient couples for further in vivo assay. Then, chickens were
      inoculated with a donor/recipient couple of C. jejuni strains displaying
      spontaneous in vitro tetracycline resistance gene transfer. The donor was a
      tetracycline-resistant ampicillin-susceptible strain, and the recipient was a
      tetracycline-susceptible ampicillin-resistant strain. Chicken droppings were
      streaked on antimicrobial selective media and bi-resistant Campylobacter isolates
      were further characterized according to their donor or recipient flaA gene RFLP
      profile. The acquisition of tetracycline-resistance gene by the recipient C.
      jejuni strain from the donor C. jejuni strain was confirmed by tetO PCR.
      CONCLUSIONS: The study showed that transfer of tetO gene occurs rapidly and
      without antimicrobial selection pressure between C. jejuni strains in the
      digestive tract of chickens. SIGNIFICANCE AND IMPACT OF THE STUDY: The rapid and
      spontaneous transfer of tetO gene may explain the high prevalence of tetracycline
      resistance in chicken Campylobacter strains.

PMID- 15186451
TI  - Characterization of erythromycin resistance in Campylobacter coli and
      Campylobacter jejuni isolated from pig offal in New Zealand.
AB  - AIMS: To determine the level and mechanism(s) of antimicrobial resistance in
      Campylobacter isolates obtained from human and environmental sources from South
      Canterbury, New Zealand. METHODS AND RESULTS: A total of 251 Campylobacter
      isolates were tested for susceptibility to ciprofloxacin, erythromycin, nalidixic
      acid and tetracycline using disc diffusion assays. Five pig offal isolates were
      observed to be highly erythromycin resistant, with minimal inhibitory
      concentrations determined to be >/=256 microg ml(-1). Nucleotide sequencing of
      the 23S ribosomal DNA (rDNA) in these resistant isolates identified an A --> G
      change at Escherichia coli position 2059 that has been previously implicated in
      erythromycin resistance in Campylobacter coli. Macrorestriction profiling using
      pulsed-field gel electrophoresis showed these isolates were nonclonal.
      CONCLUSIONS: The majority of Campylobacter isolates from South Canterbury remain
      sensitive to the most clinically relevant antimicrobial agents. Our results
      support other reports showing that specific variations in the 23S rDNA contribute
      to erythromycin resistance. SIGNIFICANCE AND IMPACTS OF THE STUDY: This study
      defines the baseline frequency of antimicrobial resistance associated with
      Campylobacter isolates from South Canterbury, and discusses the likely molecular
      mechanisms conferring erythromycin resistance in this organism. Resistance to
      erythromycin in these isolates is not linked to a dominant Campylobacter clone
      and has likely arisen independently in different genetic lines exposed to
      selective antimicrobial pressure.

PMID- 15186452
TI  - Localization of MtuA, an LraI homologue in Streptococcus uberis.
AB  - AIMS: To determine the localization of MtuA, an LraI lipoprotein within
      Streptococcus uberis and assess whether the protein was able to induce an
      antibody response capable of growth inhibition. METHODS AND RESULTS: Immunoblots
      and ELISAs were performed on S. uberis cell fractions to localize the protein.
      The strongest reactivity was within the membrane-enriched fraction. Electron
      micrographs also showed labelling consistent with a location within the membrane.
      Specific antibodies from both rabbits and calves were unable to inhibit the
      growth of S. uberis in milk. In addition, MtuA was not detectable in a whole-cell
      ELISA and whole bacterial cells were unable to adsorb specific antibodies from
      antiserum raised against MtuA. CONCLUSIONS: The MtuA protein appears to be
      located within the cell membrane and is not on the bacterial surface and thus not
      available for interaction with potentially growth-inhibiting antibodies.
      SIGNIFICANCE AND IMPACT OF THE STUDY: Unlike PsaA of S. pneumoniae and MtsA of S.
      pyogenes, MtuA of S. uberis does not appear to be located at the cell surface.
      Therefore, in contrast to studies with other similar proteins, MtuA is unlikely
      to be a good vaccine candidate.

PMID- 15186453
TI  - The autolytic phenotype of Bacillus thuringiensis.
AB  - AIMS: To evaluate the autolytic phenotype of Bacillus thuringiensis. METHODS AND
      RESULTS: The autolytic rate of 87 strains belonging to different subsp. of B.
      thuringiensis was examined at pH 6, 6.5 and 8.5 in different buffers under
      starvation conditions. At pH 6 the extent of autolysis (average in the strain
      collection 38.3 +/- 21.1) was strain-dependent with wide variability, while at pH
      6.5 and 8.5 (averages 72.0 +/- 9.0 and 63.1 +/- 8.2, respectively) it was much
      more uniform with only a few strains showing low autolytic rates. Forty-one per
      cent of the strains showed high resistance (>/=80%) to mutanolysin, a commercial
      muramidase from Streptomyces. The peptidoglycan hydrolase pattern was evaluated
      by renaturing SDS-PAGE using cells of B. thuringiensis subsp. tolworthi HD125 as
      indicator. The strain collection showed seven major lytic bands of about 90, 63,
      46, 38, 32, 28 and 25 kDa, and in the stationary growth phase (72 h) there was a
      more intense 25 kDa band in the autolytic pattern. Using Micrococcus
      lysodeicticus and Listeria monocytogenes as the indicators lytic activity was
      retained, as seen by the bands of 63, 46, 38, 32 and 25 kDa. Growth in the
      different media did not affect the autolytic pattern. NaCl abolished the activity
      of all the peptidoglycan hydrolases in the gel, but in the presence of KCl,
      MgCl(2), MnCl(2) and EDTA some activity was retained. At basic pH the lytic
      activity increased. CONCLUSIONS: The autolytic phenotype of B. thuringiensis was
      found to be strain-dependent, and different proteins exibited peptidoglycan
      hydrolase activity, particularly at alkaline pH. Several of these proteins
      retained lytic activity against other bacterial species. SIGNIFICANCE AND IMPACT
      OF THE STUDY: The characterisation of the autolytic phenotype of B. thuringiensis
      should expand the prospects of using this species in bacterial bio-control and
      field applications.

PMID- 15186454
TI  - Characterization of antimicrobial peptides against a US strain of the rice
      pathogen Rhizoctonia solani.
AB  - AIM: To identify antimicrobial peptides with high lytic activity against
      Rhizoctonia solani strain LR172, causal agent of rice sheath blight and aerial
      blight of soyabeans in the US. METHODS AND RESULTS: Among 12 natural and
      synthetic antimicrobial peptides tested in vitro, the wheat-seed peptide,
      purothionin, showed the strongest inhibitory activity that was similar to the
      antifungal antibiotics, nystatin and nikkomycin Z. Cecropin B, a natural peptide
      from cecropia moth, and synthetic peptide D4E1 produced the highest inhibitory
      activity against R. solani among linear peptides. Membrane permeabilization
      levels strongly correlated with antifungal activity of the peptides. Noticeable
      changes in membrane integrity were observed at concentrations of >/=0.5 micromol
      l(-1) for purothionin, 2 micromol l(-1) for cecropin B, D4E1, D2A21, melittin,
      and phor21, and 8 micromol l(-1) for magainin II and phor14. An increase of
      nuclear membrane permeabilization was observed in fungal cells treated with
      cecropin B, but not with purothionin. Diffusion of nuclear content was observed
      by fluorescent microscopy 10 min after adding a lethal concentration of cecropin
      B. Evaluation by electron microscopy confirmed severe cytoplasmic degradation and
      plasma membrane vesiculation. Purothionin and cecropin B were the most stable
      against proteolytic degradation when added to liquid cultures of R. solani.
      CONCLUSIONS: Purothionin, cecropin B, D4E1 and phor21 were shown to exhibit high
      in vitro lytic activity against R. solani strain LR172 for rice and soyabean.
      These peptides are greater than 16 amino acids long and rapidly increase fungal
      membrane permeabilization. Resistance to proteolysis is important for sufficient
      antifungal activity of antimicrobial peptides. SIGNIFICANCE AND IMPACT OF THE
      STUDY: Selected antimicrobial peptides offer an attractive alternative to
      traditional chemicals that could be utilized in molecular breeding to develop
      crops resistant to rice sheath blight and aerial blight of soyabean.

PMID- 15186455
TI  - Identification of Escherichia coli O172 O-antigen gene cluster and development of
      a serogroup-specific PCR assay.
AB  - AIM: To characterize the locus for O-antigen biosynthesis from Escherichia coli
      O172 type strain and to develop a rapid, specific and sensitive PCR-based method
      for identification and detection of E. coli O172. METHODS AND RESULTS: DNA of O
      antigen gene cluster of E. coli O172 was amplified by long-range PCR method using
      primers based on housekeeping genes galF and gnd Shot gun bank was constructed
      and high quality sequencing was performed. The putative genes for synthesis of
      UDP-FucNAc, O-unit flippase, O-antigen polymerase and glycosyltransferases were
      assigned by the homology search. The evolutionary relationship between O-antigen
      gene clusters of E. coli O172 and E. coli O26 is shown by sequence comparison.
      Genes specific to E. coli O172 strains were identified by PCR assays using
      primers based on genes for O-unit flippase, O-antigen polymerase and
      glycosyltransferases. The specificity of PCR assays was tested using all E. coli
      and Shigella O-antigen type strains, as well as 24 clinical E. coli isolates. The
      sensitivity of PCR assays was determined, and the detection limits were 1 pg
      microl(-1) chromosomal DNA, 0.2 CFU g(-1) pork and 0.2 CFU ml(-1) water. The
      total time required from beginning to end of the procedure was within 16 h.
      CONCLUSION: The O-antigen gene cluster of E. coli O172 was identified and PCR
      assays based on O-antigen specific genes showed high specificity and sensitivity.
      SIGNIFICANCE AND IMPACT OF THE STUDY: An O-antigen gene cluster was identified by
      sequencing. The specific genes were determined for E. coli O172. The sensitivity
      of O-antigen specific PCR assay was tested. Although Shiga toxin-producing O172
      strains were not yet isolated from clinical specimens, they may emerge as
      pathogens.

PMID- 15186456
TI  - Identification of waterborne bacteria by the analysis of 16S-23S rRNA intergenic
      spacer region.
AB  - AIM: In this study, we evaluated, the use of universal primers, specific for the
      16S-23S rRNA intergenic region, to detect and identify nine species that are of
      high interest for the microbiological control of water. METHODS AND RESULTS: The
      analysis of the fragments was carried out using a High Resolution
      acrylamide/bisacrylamide gels in a fluorescent automated DNA sequencer. The
      results showed specific profiles for each of the nine species but this technique
      failed to detect simultaneously micro-organisms in samples containing a mixed
      population. CONCLUSION: Nevertheless, the electrophoretic profiles obtained
      provided a very useful tool for the rapid and specific identification of water
      isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: A possible new methodology for a
      rapid identification of pathogens in water.

PMID- 15186457
TI  - Genetic diversity of the species Debaryomyces hansenii and the use of chromosome
      polymorphism for typing of strains isolated from surface-ripened cheeses.
AB  - AIMS: To investigate the genetic diversity among strains of Debaryomyces hansenii
      and further to evaluate chromosome polymorphism determined by pulse-field gel
      electrophoresis (PFGE) as a tool for strain typing. METHODS AND RESULTS: In total
      56 isolates of D. hansenii were analysed by PFGE. The isolates included type
      strains and other strains obtained from culture collections as well as strains
      collected during production of Danish surface-ripened cheeses. By use of the PFGE
      technique the number and size of the chromosomal bands were calculated and the
      total genome size estimated. The number of chromosomal bands observed was found
      to vary from five to 10. The most common chromosome number was found to be six
      and for strains with six chromosomes the total genome size was found to vary from
      9.4 to 12.6 Mb. The chromosome numbers for the type strain of each variety of D.
      hansenii (D. hansenii var. hansenii and D. hansenii var. fabryi) appeared to be
      six and seven respectively. By use of the PFGE technique it was possible to
      differentiate between all the investigated CBS strains and the vast majority of
      the dairy isolates. The dairy isolates that were found to have identical profiles
      (three of 56 isolates) were all isolated during production of one batch of
      surface-ripened cheeses and are likely to be the same strain isolated several
      times during cheese production. Further it was shown that the PFGE analysis did
      not result in a division of the two D. hansenii varieties, i.e. D. hansenii var.
      fabryi and D. hansenii var. hansenii into separate groups. CONCLUSION: The
      present study shows that the chromosomal arrangement of D. hansenii strains is
      heterogenic and does have a distinct chromosome polymorphism. Further the PFGE
      technique was proved to have a high discriminative power for strain typing of D.
      hansenii. SIGNIFICANCE AND IMPACT OF THE STUDY: The results obtained add to the
      first knowledge on the genetic diversity of the species D. hansenii. Further the
      distinct chromosome polymorphism of D. hansenii strains as shown in this study
      makes the PFGE technique a useful tool for strain typing of D. hansenii, e.g.
      during cheese production.

PMID- 15186458
TI  - Survival of Bacillus cereus spores and vegetative cells in acid media simulating
      human stomach.
AB  - AIMS: To determine the fate of Bacillus cereus spores or vegetative cells in
      simulated gastric medium. METHODS AND RESULTS: The effects of acidity on the
      survival of B. cereus in a medium simulating human stomach content was followed
      on spores at pH 1.0-5.2, and on vegetative cells at pH 2.5-5.7. Gastric media
      (GM) were prepared by mixing equal volumes of a gastric electrolyte solution with
      J broth (JB), half-skim milk, pea soup and chicken. At pH 1.0 and 1.4, the number
      of spores slightly decreased in GM-JB and GM-pea soup and remained stable in GM
      milk and GM-chicken. A rapid marked decrease (always higher than 2.0 log CFU ml(
      1) in 2 h) in vegetative cell counts was observed at pH below 4.2, 4.0, 3.6 and
      3.5 in GM-chicken, GM-JB, GM-milk and GM-pea soup, respectively. Between pH 5.0
      and 5.3, B. cereus growth was observed in GM-JB (1.2 log CFU ml(-1) increase
      after 4 h) and in GM-pea soup (1.8 log CFU ml(-1) increase after 4 h).
      CONCLUSIONS: Bacillus cereus spores are very much more resistant to gastric
      acidity than vegetative cells. This resistance strongly depends on the type of
      food present in the GM. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results suggest
      that the probability that viable B. cereus cells enter the small intestine, where
      they can cause diarrhoea, strongly depends on the form of the ingested cells
      (spores or vegetative cells), on what food they are ingested with, and on the
      level of stomach acidity.

PMID- 15186459
TI  - The detection of non-O157 E. coli in food by immunomagnetic separation.
AB  - AIMS: To compare immunomagnetic separation (IMS) protocols (enrichment media and
      temperature) for the isolation of Escherichia coli serotypes O26 and O111 from
      four different foods. METHODS AND RESULTS: Foods (minced beef, cheese, apple
      juice and pepperoni) spiked with low numbers (<100 g(-1)) of stressed nalidixic
      mutant E. coli serotypes O26 and O111 were enriched in media based on buffered
      peptone water (BPW), tryptone soya and EC broths incubated at temperatures of 37
      and 42 degrees C to optimize the IMS technique. BPW enrichments gave increased
      recoveries of both serotypes compared with tryptone soya and EC broths. Elevated
      temperatures of incubation at 42 degrees C were superior to 37 degrees C.
      CONCLUSIONS: Positive detection of low numbers of stressed target pathogens in
      all replicate tests was only possible using BPW enrichments. The majority of
      tests from alternative enrichments resulted in zero or single colonies recovered
      post-IMS. SIGNIFICANCE AND IMPACT OF THE STUDY: The optimum IMS protocol would
      improve isolation rates of E. coli O26 and O111 from foods and lead to increased
      safety for the consumer. Sub-optimal IMS protocols could lead to foods being
      incorrectly labelled free from these pathogens.

PMID- 15186460
TI  - Effect of point-of-use disinfection, flocculation and combined flocculation
      disinfection on drinking water quality in western Kenya.
AB  - AIMS: Point-of-use drinking water disinfection with sodium hypochlorite has been
      shown to improve water quality and reduce diarrhoeal disease. However, the
      chlorine demand of highly turbid water may render sodium hypochlorite less
      effective. METHODS AND RESULTS: We evaluated a novel combined flocculant
      disinfectant point-of-use water treatment product and compared its effect on
      drinking water quality with existing technologies in western Kenya. In water from
      30 sources, combined flocculant-disinfectant reduced Escherichia coli
      concentrations to <1 CFU100 ml(-1) for 29 (97%) and reduced turbidity to <5
      nephelometric turbidity units (NTU) for 26 (87%). By contrast, water from 30
      sources treated with sodium hypochlorite reduced E. coli concentrations to <1 CFU
      100 ml(-1) for 25 (83%) and turbidity to <5 NTU for 5 (17%). CONCLUSIONS: For
      source waters over a range of turbidities in western Kenya, combined flocculant
      disinfectant product effectively reduces turbidity to <5 NTU and reduces E. coli
      concentrations to <1 CFU 100 ml(-1). SIGNIFICANCE AND IMPACT OF THE STUDY: The
      novel flocculant-disinfectant product may be acceptable to consumers and may be
      effective in reducing diarrhoeal disease in settings where source water is highly
      turbid.

PMID- 15186462
TI  - Promoting participation in cardiac rehabilitation: patient choices and
      experiences.
AB  - BACKGROUND: Cardiac rehabilitation can be an effective means for the secondary
      prevention of coronary heart disease, but a majority of eligible individuals fail
      to attend or drop out prematurely. Little research has examined patients'
      decisions about attendance. AIMS: This paper reports a study examining patients'
      beliefs and decision-making about cardiac rehabilitation attendance. METHODS: A
      purposive sample of patients from a mixed urban-rural region of Scotland was
      studied in 2001 using focus groups. Those who were eligible for a standardized 12
      week cardiac rehabilitation programme were compared, with separate focus groups
      held for individuals with high attendance (>60% attendance; n = 27), high rates
      of attrition (<60% attendance; n = 9) and non-attendance (0% attendance; n = 8).
      A total of 44 patients (33 men; 11 women) took part in eight focus groups.
      RESULTS: Participants from all groups held sophisticated and cohesive frameworks
      of beliefs that influenced their attendance decisions. These beliefs related to
      the self, coronary heart disease, cardiac rehabilitation, other attending
      patients, and health professionals' knowledge base. An enduring embarrassment
      about group or public exercise also influenced attendance. Those who attended
      reported increased faith in their bodies, a heightened sense of fitness and a
      willingness to support new patients who attended. CONCLUSIONS: Reassurance to
      ease exercise embarrassment should be given before and during the early stages of
      programmes, and this could be provided by existing patients. Strategies to
      promote inclusion should address the inhibiting factors identified in the study,
      and should present cardiac rehabilitation as a comprehensive programme of
      activities likely to be of benefit to the individual irrespective of personal
      characteristics, such as age, sex or exercise capacity.

PMID- 15186463
TI  - A preventative health education programme for osteoporosis.
AB  - BACKGROUND: Osteoporosis is a preventable disease that is usually not managed
      until the disease becomes evident, although it places huge economic and social
      burdens on societies worldwide. It is predicted that this burden will grow if
      left unchecked. Despite this, evidence suggests that osteoporosis prevention
      activity is given a low priority, and services often only provide biomedically
      based programmes, in which resources are predominantly allocated to screening and
      pharmacological treatments. Referral to these services mostly occurs when a
      client is already known to have osteoporosis or to be at risk, rather than as an
      early preventative intervention. AIM: This paper reports an action research
      project with one hospital osteoporosis service. The aim of the project was to
      assess the current service, identify areas where change was needed, and evaluate
      the implementation of such changes. METHOD: Participatory action research was
      used, with group meetings and reflective journals to collect data for analysis.
      The process involved assessment of a preventative osteoporosis service, and
      determination of clinical issues and problems, and it aided decisions on an
      appropriate course of organizational reform and evaluated any change processes as
      they occurred. It also encouraged participants to reflect on and evaluate their
      experiences of using a participatory framework. CONCLUSION: A change programme
      was implemented that focused on preventative health education activity in a range
      of clinical settings. Over the two and a half years of the project, the
      osteoporosis service expanded its programme to include a wide range of
      preventative activities, running alongside other organizational reforms.

PMID- 15186464
TI  - Nursing care at night: an evaluation using the Night Nursing Care Instrument.
AB  - INTRODUCTION: Night nurses carry overall nursing responsibility for approximately
      half the time that patients spend in hospital. However, there is a paucity of
      literature that focuses on nursing care provided at night. AIM: The aim of this
      study was to evaluate nursing care provided at night from the perspective of both
      nurses and patients. METHODS: The study, which had an evaluative and a
      comparative design, was carried out using the Night Nursing Care Instrument at a
      hospital in southern Sweden. Nurses (n = 178) on night duty were consecutively
      selected, while the patients (n = 356) were selected by convenience sampling.
      RESULTS: The results showed a statistically significant difference between
      nurses' assessments and patients' perceptions of the nursing care provided at
      night in nursing interventions (P < 0.0001). In the areas of medical
      interventions and evaluation, no statistically significant differences were found
      between nurses and patients. For eight of 11 items, patients reported that they
      were satisfied (> or =80%) with the nursing care provided at night. CONCLUSIONS:
      These findings suggest that night nurses need to improve their ability to assess
      patients' needs for nursing care at night. A first step in this direction is for
      them to become aware of how patients perceive night nursing. As a second step,
      nurses need to increase their knowledge of which nursing actions promote
      patients' rest at night.

PMID- 15186465
TI  - Staff and patient perceptions of seclusion: has anything changed?
AB  - BACKGROUND: Seclusion continues to be widely used in the management of disturbed
      behaviour in hospitalized patients. While early research on the topic highlighted
      significant differences in staff and patient perceptions, there are few recent
      data to indicate if these differences still exist. AIM: This paper reports a
      study exploring the perceptions of both nursing staff and patients towards the
      reasons for seclusion; its effects; patients' feelings during seclusion; and
      possible changes to the practice. METHODS: Sixty nursing staff and 29 patients
      who had experienced seclusion at three inpatient units in Queensland, Australia
      completed Heyman's Attitudes to Seclusion Survey. RESULTS: The findings indicate
      that the two groups differed significantly on a number of the dimensions
      assessed. Nurses believed seclusion to be very necessary, not very punitive and a
      highly therapeutic practice that assisted patients to calm down and feel better.
      Patients, on the other hand, believed that seclusion was used frequently for
      minor disturbances and as a means of staff exerting power and control. Patients
      also believed that seclusion resulted in them feeling punished, and had little
      therapeutic value. CONCLUSION: The disagreement between staff and patients
      highlights the need for greater dialogue between these groups. While nursing
      staff require greater understanding of how patients feel about seclusion,
      patients require information on why and how seclusion is implemented.

PMID- 15186466
TI  - Evaluating a nurse-led model for providing neonatal care.
AB  - AIMS: The paper presents an overview of a multi-dimensional, prospective,
      comparative 5-year audit of the quality of the neonatal care provided by a
      maternity unit in the UK delivering 2000 babies a year, where all neonatal care
      after 1995 was provided by advanced neonatal nurse practitioners, in relation to
      that provided by a range of other medically staffed comparator units. METHODS:
      The audit includes 11 separate comparative studies supervised by a panel of
      independent external advisors. Data on intrapartum and neonatal mortality is
      reported. A review of resuscitation at birth, and a two-tier confidential inquiry
      into sentinel events in six units were carried out. The reliability of the
      routine predischarge neonatal examination was studied and, in particular, the
      recognition of congenital heart disease. A review of the quality of postdischarge
      letters was undertaken alongside an interview survey to elicit parental views on
      care provision. An audit of all hospital readmissions within 28 days of birth is
      reported. Other areas of study include management of staff stress, perceived
      adequacy of the training of nurse practitioners coming into post, and an
      assessment of unit costs. RESULTS: Intrapartum and neonatal death among women
      with a singleton pregnancy originally booked for delivery in Ashington fell 39%
      between 1991-1995 and 1996-2000 (5.12 vs. 3.11 deaths per 1000 births); the
      decline for the whole region was 27% (4.10 vs. 2.99). By all other indicators the
      quality of care in the nurse-managed unit was as good as, or better than, that in
      the medically staffed comparator units. CONCLUSION: An appropriately trained,
      stable team with a store of experience can deliver cot-side care of a higher
      quality than staff rostered to this task for a few months to gain experience, and
      this is probably more important than their medical or nursing background. Factors
      limiting the on-site availability of medical staff with paediatric expertise do
      not need to dictate the future disposition of maternity services.

PMID- 15186467
TI  - Midlife experiences of Thai women.
AB  - BACKGROUND: Midlife is not a universal notion because the conception of midlife
      arises from specific historical and social conditions. This can be a challenging
      time for women; however, the study of Thai women in the middle years has received
      relatively little attention. AIM: This paper reports a study exploring the
      meaning of midlife to Thai women currently residing in Bangkok. METHOD: The
      integration of Heideggerian phenomenology and feminist theory guided data
      collection. Experiential understanding of midlife phenomena was obtained through
      interviewing 32 Thai women with diverse educational and socioeconomic
      backgrounds. Each description was analysed to identify themes pertinent to the
      individual midlife experience. Emergent themes were extracted from the
      similarities and differences across descriptions to depict the broad points of
      view of women's midlife experiences. FINDINGS: Five collective themes were
      identified: being stereotyped, transforming, being vulnerable to poor health,
      adapting, and thinking ahead. CONCLUSION: The findings reflected the fact that
      these women's midlife experiences were the product of the interrelationship of
      biological, psychological, and sociocultural factors. Awareness of these
      interrelationships in mind could enrich understanding of midlife experience in
      women, guide family members and friends in supporting midlife women, including
      helping to uphold their dignity, and raise the consciousness of health planners
      and health care professionals for developing effective programmes and
      interventions to promote wellness for Thai midlife women. The findings could help
      nurses to build their practice on a significant philosophical foundation and
      increase their sensitivity with regard to holistic care for midlife women.

PMID- 15186468
TI  - Groningen Orthopaedic Social Support Scale: validity and reliability.
AB  - BACKGROUND: Social support is an important factor in the rehabilitation process,
      as it has a positive influence on patients' health, functioning and recovery. In
      particular, perceived social support and instrumental support are important after
      total hip or knee arthroplasty. However, nursing staff often appear to estimate
      the amount of support available to patients by number of visitors. Until now, no
      suitable Dutch-language scale was available to measure social support in
      orthopaedic patients. AIM: The aim of this paper is to describe the development
      and initial validity and reliability testing of the Groningen Orthopaedic Social
      Support Scale, a self-report questionnaire to measure social support in patients
      after total hip or knee arthroplasty. METHODS: A total of 119 people who had had
      arthroplasty completed the Groningen Orthopaedic Social Support Scale and a
      control scale. The reliability and validity of the questionnaire were analysed.
      RESULTS: Reliability of the Groningen Orthopaedic Social Support Scale can be
      considered satisfactory, with a Cronbach's alpha of 0.89. Analysis of construct
      validity by means of factor analysis yielded two factors: perceived social
      support and instrumental support. A Pearson's correlation between these subscales
      was moderate (r = 0.61 and statistically significant). Concurrent validity can be
      considered satisfactory, with a Pearson correlation of 0.72 (P < 0.001) between
      the Groningen Orthopaedic Social Support Scale and the control list. CONCLUSIONS:
      The Groningen Orthopaedic Social Support Scale can be considered suitable for
      measuring social support. It can be used to help nursing staff determine if a
      patient's need for social support is fulfilled, and to advise family and friends
      on the basis of the results. The questionnaire can also be used to establish the
      role of social support as a factor in supportive interventions during and after
      hospital stay.

PMID- 15186469
TI  - The intensive care experience: development of the ICE questionnaire.
AB  - BACKGROUND: Previous research has shown that patients' reported memories of
      intensive care are often of unpleasant events which are described as frightening
      and persecutory in nature. Currently, there is no standardized way of assessing
      perceptions of such an experience or relating it to long-term outcome. AIMS: This
      paper describes the development of an intensive care experience questionnaire
      which aims to (a) identify the domains of such an experience, (b) assess and
      quantify that experience, and (c) explore its impact on short- and long-term
      emotional outcome. METHODS: Data from two studies are reported. Participants were
      non-elective patients and > or =18 years of age with an ICU stay > or =24 hours.
      Study 1 (n = 34) generated and developed items. Study 2 (n = 109) allowed
      evaluation of the factor analytic structure and psychometrics of the
      questionnaire. RESULTS: From a set of 31 items, exploratory factor analysis
      identified four components of the intensive care experience: 'awareness of
      surroundings' (nine items), 'frightening experiences' (six items), 'recall of
      experience' (five items), and 'satisfaction with care' (four items). Cronbach's
      alpha statistics were acceptable for each component (0.71-0.93). Correlational
      analysis with the subscales of the Hospital Anxiety and Depression Scale and
      Impact of Event Scale demonstrated concurrent and univariate predictive validity.
      The intensive care experience was associated with adverse emotional outcome in
      both the short- and long-term. DISCUSSION: The intensive care experience
      questionnaire identified four dimensions of experience and performed
      satisfactorily in these developmental analyses. Further study of an independent
      intensive care unit data set is necessary to confirm these findings, including
      the four-component structure. Development of a standardized measure provides the
      opportunity to increase our understanding of the intensive care experience. The
      questionnaire may be useful to inform the development of effective interventions
      to improve subsequent outcomes for these patients.

PMID- 15186470
TI  - Evaluation of the Rhodes Index of Nausea and Vomiting for ambulatory surgery
      patients.
AB  - BACKGROUND: The Index of Nausea and Vomiting (INV), developed by Rhodes and
      others in 1984, measures three dimensions of upper gastrointestinal distress:
      nausea, vomiting and retching (NVR). While the revised version has been tested
      with a variety of high-risk populations, there are no data suggesting that it can
      be used to assess upper gastrointestinal distress among the growing numbers of
      ambulatory or day surgery patients. AIM: The aim of this study was to evaluate a
      modified version of the INV for use with ambulatory surgery patients. METHODS: A
      secondary analysis was conducted using data obtained from a descriptive study
      designed to identify risk factors for postdischarge nausea and vomiting (PDNV)
      among adult ambulatory surgery patients. Patients who reported PDNV (n = 190)
      participated via phone interview 24 hours after discharge by completing a
      modified Rhodes INV. FINDINGS: Reliability analysis (alpha = 0.897) indicated
      that the modified Rhodes INV measured upper gastrointestinal distress as a single
      concept in the postdischarge ambulatory surgical sample. One item of the 8-item
      scale was dropped. Principal component analysis extracted one factor that
      accounted for 67% of the variance with all items loading. CONCLUSIONS: Upper
      gastrointestinal distress following ambulatory surgery discharge comprises a
      different symptom mix than during other high-risk events such as pregnancy or
      chemotherapy. Further research on the differences in assessing NVR among
      different populations is indicated.

PMID- 15186471
TI  - What counts as evidence in evidence-based practice?
AB  - BACKGROUND: Considerable financial and philosophical effort has been expended on
      the evidence-based practice agenda. Whilst few would disagree with the notion of
      delivering care based on information about what works, there remain significant
      challenges about what evidence is, and thus how practitioners use it in decision
      making in the reality of clinical practice. AIM: This paper continues the debate
      about the nature of evidence and argues for the use of a broader evidence base in
      the implementation of patient-centred care. DISCUSSION: Against a background of
      financial constraints, risk reduction, increased managerialism research evidence,
      and more specifically research about effectiveness, have assumed pre-eminence.
      However, the practice of effective nursing, which is mediated through the contact
      and relationship between individual practitioner and patient, can only be
      achieved by using several sources of evidence. This paper outlines the potential
      contribution of four types of evidence in the delivery of care, namely research,
      clinical experience, patient experience and information from the local context.
      Fundamentally, drawing on these four sources of evidence will require the
      bringing together of two approaches to care: the external, scientific and the
      internal, intuitive. CONCLUSION: Having described the characteristics of a
      broader evidence base for practice, the challenge remains to ensure that each is
      as robust as possible, and that they are melded coherently and sensibly in the
      real time of practice. Some of the ideas presented in this paper challenge more
      traditional approaches to evidence-based practice. The delivery of effective,
      evidence-based patient-centred care will only be realized when a broader
      definition of what counts as evidence is embraced.

PMID- 15186472
TI  - Workplace breastfeeding support for hospital employees.
AB  - BACKGROUND: Breastfeeding initiation rates have been steadily rising in Hong
      Kong, but most employed women wean prior to returning to work. While health care
      providers promote breastfeeding, women receive little support from employers. A
      few health care facilities offer some workplace breastfeeding support, but little
      is known about the specific types and amount of support that are offered. AIMS:
      This paper reports a study whose aim was to describe workplace supports available
      to breastfeeding women employed by hospitals that provide maternity services in
      Hong Kong, and to determine if differences in workplace supports exist based on
      the hospitals' numbers of employees or funding source. METHODS: In late 2001, a
      cross-sectional survey was completed by nurse managers or lactation consultants
      most knowledgeable about supports to breastfeeding employees in 19 hospitals.
      FINDINGS: The number of workplace breastfeeding supports or Breastfeeding Support
      Score (M = 7.47; sd = 3.37) varied considerably. Mean Breastfeeding Support Score
      for government-funded hospitals was significantly higher (t = 2.31; P = 0.03)
      than for private hospitals. Of the 14 hospitals that had a designated space for
      using a breast pump, only five (26.3%) had a private room with a door that
      locked. Only two hospitals (11.1%) allowed employees to take breaks as needed to
      use a pump; employees in 10 (55.6%) had to use their meal and regular break
      times. Hospitals having a hospital-wide committee that addressed workplace
      breastfeeding issues had a more supportive environment for breastfeeding
      employees. Although all surveyed hospitals returned the questionnaire, the sample
      size was small. It was difficult to ensure accuracy and to differentiate subtle
      variations in the services provided using a self-report survey. CONCLUSIONS:
      Facilitating continued breastfeeding after employees' return to work requires
      that employers understand the needs of breastfeeding employees. Policy at the
      level of the employer and government is an essential component of creating a
      supportive environment.

PMID- 15186473
TI  - Emotional intelligence in nursing work.
AB  - BACKGROUND: Emotional labour has been widely accepted in the literature as part
      of nursing work, however the contribution of emotional intelligence in the
      nursing context requires further study. AIM: This paper aims to present an
      analysis of the literature on emotional intelligence and emotional labour, and
      consider the value of emotional intelligence to nursing. METHOD: A literature
      search was undertaken using the CINAHL and MEDLINE databases. Search terms used
      were 'emotions', 'intelligence', 'emotions and intelligence' and 'emotional
      labour'. A hand-search of relevant journals and significant references added to
      the data. RESULTS: Emotional intelligence plays an important part in forming
      successful human relationships. Emotional labour is important in establishing
      therapeutic nurse-patient relationships but carries the risk of 'burnout' if
      prolonged or intense. To prevent this, nurses need to adopt strategies to protect
      their health. The potential value of emotional intelligence in this emotional
      work is an issue that still needs to be explored. CONCLUSIONS: Analysis of the
      literature suggests that the modern demands of nursing draw on the skills of
      emotional intelligence to meet the needs of direct patient care and co-operative
      negotiations with the multidisciplinary team. The significance of this needs to
      be recognized in nurse education. The link between emotional intelligence and
      emotional labour is a fruitful area for further research. The potential benefits
      of gaining a better understanding of how these concepts interact is largely
      conjecture until we have more evidence. The prospect that there may be advantages
      to both nurses and patients is a motivating factor for future researchers.

PMID- 15186474
TI  - A response to "The effectiveness of public health nursing: the problems and
      solutions in carrying out a review of systematic reviews" by L. Elliott, I.K.
      Crombie, L. Irvine, J. Cantrell & J. Taylor (2003) Journal of Advanced Nursing
      45(2), 117-125.

PMID- 15186479
TI  - Intestine in the lung.
AB  - The phenomenon of metaplasia, in which one tissue type is converted into another,
      is beginning to be explained in molecular terms. The transformation of lung to
      intestinal tissue has not previously been described, but it is now reported that
      it can be brought about by prolonged Wnt signaling in late development.

PMID- 15186481
TI  - Pharmacogenomics arrives.

PMID- 15186480
TI  - Hyperactive Wnt signaling changes the developmental potential of embryonic lung
      endoderm.
AB  - BACKGROUND: Studies in many model systems have shown that canonical signaling
      through the pathway downstream of ligands of the Wnt family can regulate multiple
      steps in organogenesis, including cell proliferation, differentiation, and
      lineage specification. In addition, misexpression of the Wnt-family member
      Wingless in Drosophila imaginal disc cells can lead to transdetermination of
      progenitors from one lineage to another. Conditional deletion of the beta-catenin
      component of the Wnt signaling pathway has indicated a role for Wnt signaling in
      mouse lung endoderm development. The full range of effects of this pathway, which
      includes the transcription factor Lef1, has not been explored, however. RESULTS:
      To explore this issue, we expressed a constitutively active beta-catenin-Lef1
      fusion protein in transgenic embryos using a lung-endoderm-specific promoter from
      the surfactant protein C gene. Transgenic lungs appeared grossly normal, but
      internally they contained highly proliferative, cuboidal epithelium lacking fully
      differentiated lung cell types. Unexpectedly, microarray analysis and in situ
      hybridization revealed a mosaic of cells expressing marker genes characteristic
      of intestinal Paneth and goblet cells and other non-lung secretory cell types. In
      addition, there was strong ectopic expression of genes such as Cdx1 and Atoh1
      that normally regulate gut development and early allocation of cells to
      intestinal secretory lineages. CONCLUSIONS: Our results show that hyperactive Wnt
      signaling in lung progenitors expressing a lung-specific gene can induce a
      dramatic switch in lineage commitment and the generation of intestinal cell
      types. We discuss the relevance of our findings to the poorly understood
      pathological condition of intestinal metaplasia in humans.

PMID- 15186482
TI  - Metabolite profiling in plant biology: platforms and destinations.
AB  - Optimal use of genome sequences and gene-expression resources requires powerful
      phenotyping platforms, including those for systematic analysis of metabolite
      composition. The most used technologies for metabolite profiling, including mass
      spectral, nuclear magnetic resonance and enzyme-based approaches, have various
      advantages and disadvantages, and problems can arise with reliability and the
      interpretation of the huge datasets produced. These techniques will be useful for
      answering important biological questions in the future.

PMID- 15186483
TI  - The diversity of LTR retrotransposons.
AB  - Eukaryotic genomes are full of long terminal repeat (LTR) retrotransposons.
      Although most LTR retrotransposons have common structural features and encode
      similar genes, there is nonetheless considerable diversity in their genomic
      organization, reflecting the different strategies they use to proliferate within
      the genomes of their hosts.

PMID- 15186484
TI  - An overview of the basic helix-loop-helix proteins.
AB  - The basic helix-loop-helix proteins are dimeric transcription factors that are
      found in almost all eukaryotes. In animals, they are important regulators of
      embryonic development, particularly in neurogenesis, myogenesis, heart
      development and hematopoiesis.

PMID- 15186485
TI  - Root genomics: towards digital in situ hybridization.
AB  - Separation of cell types and developmental stages in the Arabidopsis root and
      subsequent expression profiling have yielded a valuable dataset that can be used
      to select candidate genes for detailed study and to start probing the
      complexities of gene regulation in plant development.

PMID- 15186486
TI  - Common ground in the transcriptional profiles of wounds and tumors.
AB  - Healing wounds and developing tumors are both sites of dynamic interactions
      between a variety of cell types. Recent microarray studies comparing wounds and
      tumors have identified characteristic similarities in gene expression that may
      prove to be useful for assessing cancer prognosis and for choosing subsequent
      treatment.

PMID- 15186487
TI  - A burst of energy in metabolic disease research.

PMID- 15186488
TI  - Genomic, chromosomal and allelic assessment of the amazing diversity of maize.

PMID- 15186489
TI  - Bacterial alpha2-macroglobulins: colonization factors acquired by horizontal gene
      transfer from the metazoan genome?
AB  - BACKGROUND: Invasive bacteria are known to have captured and adapted eukaryotic
      host genes. They also readily acquire colonizing genes from other bacteria by
      horizontal gene transfer. Closely related species such as Helicobacter pylori and
      Helicobacter hepaticus, which exploit different host tissues, share almost none
      of their colonization genes. The protease inhibitor alpha2-macroglobulin provides
      a major metazoan defense against invasive bacteria, trapping attacking proteases
      required by parasites for successful invasion. RESULTS: Database searches with
      metazoan alpha2-macroglobulin sequences revealed homologous sequences in
      bacterial proteomes. The bacterial alpha2-macroglobulin phylogenetic distribution
      is patchy and violates the vertical descent model. Bacterial alpha2-macroglobulin
      genes are found in diverse clades, including purple bacteria (proteobacteria),
      fusobacteria, spirochetes, bacteroidetes, deinococcids, cyanobacteria,
      planctomycetes and thermotogae. Most bacterial species with bacterial alpha2
      macroglobulin genes exploit higher eukaryotes (multicellular plants and animals)
      as hosts. Both pathogenically invasive and saprophytically colonizing species
      possess bacterial alpha2-macroglobulins, indicating that bacterial alpha2
      macroglobulin is a colonization rather than a virulence factor. CONCLUSIONS:
      Metazoan alpha2-macroglobulins inhibit proteases of pathogens. The bacterial
      homologs may function in reverse to block host antimicrobial defenses. Alpha2
      macroglobulin was probably acquired one or more times from metazoan hosts and has
      then spread widely through other colonizing bacterial species by more than 10
      independent horizontal gene transfers. yfhM-like bacterial alpha2-macroglobulin
      genes are often found tightly linked with pbpC, encoding an atypical
      peptidoglycan transglycosylase, PBP1C, that does not function in vegetative
      peptidoglycan synthesis. We suggest that YfhM and PBP1C are coupled together as a
      periplasmic defense and repair system. Bacterial alpha2-macroglobulins might
      provide useful targets for enhancing vaccine efficacy in combating infections.

PMID- 15186490
TI  - Signal sequence analysis of expressed sequence tags from the nematode
      Nippostrongylus brasiliensis and the evolution of secreted proteins in parasites.
AB  - BACKGROUND: Parasitism is a highly successful mode of life and one that requires
      suites of gene adaptations to permit survival within a potentially hostile host.
      Among such adaptations is the secretion of proteins capable of modifying or
      manipulating the host environment. Nippostrongylus brasiliensis is a well-studied
      model nematode parasite of rodents, which secretes products known to modulate
      host immunity. RESULTS: Taking a genomic approach to characterize potential
      secreted products, we analyzed expressed sequence tag (EST) sequences for
      putative amino-terminal secretory signals. We sequenced ESTs from a cDNA library
      constructed by oligo-capping to select full-length cDNAs, as well as from
      conventional cDNA libraries. SignalP analysis was applied to predicted open
      reading frames, to identify potential signal peptides and anchors. Among 1,234
      ESTs, 197 (~16%) contain predicted 5' signal sequences, with 176 classified as
      conventional signal peptides and 21 as signal anchors. ESTs cluster into 742
      distinct genes, of which 135 (18%) bear predicted signal-sequence coding regions.
      Comparisons of clusters with homologs from Caenorhabditis elegans and more
      distantly related organisms reveal that the majority (65% at P < e-10) of signal
      peptide-bearing sequences from N. brasiliensis show no similarity to previously
      reported genes, and less than 10% align to conserved genes recorded outside the
      phylum Nematoda. Of all novel sequences identified, 32% contained predicted
      signal peptides, whereas this was the case for only 3.4% of conserved genes with
      sequence homologies beyond the Nematoda. CONCLUSIONS: These results indicate that
      secreted proteins may be undergoing accelerated evolution, either because of
      relaxed functional constraints, or in response to stronger selective pressure
      from host immunity.

PMID- 15186491
TI  - A survey of ovary-, testis-, and soma-biased gene expression in Drosophila
      melanogaster adults.
AB  - BACKGROUND: Sexual dimorphism results in the formation of two types of
      individuals with specialized reproductive roles and is most evident in the germ
      cells and gonads. RESULTS: We have undertaken a global analysis of transcription
      between the sexes using a 31,464 element FlyGEM microarray to determine what
      fraction of the genome shows sex-biased expression, what tissues express these
      genes, the predicted functions of these genes, and where these genes map onto the
      genome. Females and males (both with and without gonads), dissected testis and
      ovary, females and males with genetically ablated germlines, and sex-transformed
      flies were sampled. CONCLUSIONS: Using any of a number of criteria, we find
      extensive sex-biased expression in adults. The majority of cases of sex
      differential gene expression are attributable to the germ cells. There is also a
      large class of genes with soma-biased expression. There is little germline-biased
      expression indicating that nearly all genes with germline expression also show
      sex-bias. Monte Carlo simulations show that some genes with sex-biased expression
      are non-randomly distributed in the genome.

PMID- 15186492
TI  - START lipid/sterol-binding domains are amplified in plants and are predominantly
      associated with homeodomain transcription factors.
AB  - BACKGROUND: In animals, steroid hormones regulate gene expression by binding to
      nuclear receptors. Plants lack genes for nuclear receptors, yet genetic evidence
      from Arabidopsis suggests developmental roles for lipids/sterols analogous to
      those in animals. In contrast to nuclear receptors, the lipid/sterol-binding StAR
      related lipid transfer (START) protein domains are conserved, making them
      candidates for involvement in both animal and plant lipid/sterol signal
      transduction. RESULTS: We surveyed putative START domains from the genomes of
      Arabidopsis, rice, animals, protists and bacteria. START domains are more common
      in plants than in animals and in plants are primarily found within homeodomain
      (HD) transcription factors. The largest subfamily of HD-START proteins is
      characterized by an HD amino-terminal to a plant-specific leucine zipper with an
      internal loop, whereas in a smaller subfamily the HD precedes a classic leucine
      zipper. The START domains in plant HD-START proteins are not closely related to
      those of animals, implying collateral evolution to accommodate organism-specific
      lipids/sterols. Using crystal structures of mammalian START proteins, we show
      structural conservation of the mammalian phosphatidylcholine transfer protein
      (PCTP) START domain in plants, consistent with a common role in lipid transport
      and metabolism. We also describe putative START-domain proteins from bacteria and
      unicellular protists. CONCLUSIONS: The majority of START domains in plants belong
      to a novel class of putative lipid/sterol-binding transcription factors, the HD
      START family, which is conserved across the plant kingdom. HD-START proteins are
      confined to plants, suggesting a mechanism by which lipid/sterol ligands can
      directly modulate transcription in plants.

PMID- 15186494
TI  - TXTGate: profiling gene groups with text-based information.
AB  - We implemented a framework called TXTGate that combines literature indices of
      selected public biological resources in a flexible text-mining system designed
      towards the analysis of groups of genes. By means of tailored vocabularies, term-
      as well as gene-centric views are offered on selected textual fields and MEDLINE
      abstracts used in LocusLink and the Saccharomyces Genome Database. Subclustering
      and links to external resources allow for in-depth analysis of the resulting term
      profiles.

PMID- 15186493
TI  - Microarray-based genomic surveying of gene polymorphisms in Chlamydia
      trachomatis.
AB  - By comparing two fully sequenced genomes of Chlamydia trachomatis using
      competitive hybridization on DNA microarrays, a logarithmic correlation was
      demonstrated between the signal ratio of the arrays and the 75-99% range of
      nucleotide identities of the genes. Variable genes within 14 uncharacterized
      strains of C. trachomatis were identified by array analysis and verified by DNA
      sequencing. These genes may be crucial for understanding chlamydial virulence and
      pathogenesis.

PMID- 15186495
TI  - Nadroparine calcium or enoxaparine in acute coronary syndrome patients suffering
      renal insufficiency: The nadroparin versus enoxaparin (NaVe) study design.
AB  - In the general population, mild renal impairment is associated with increases
      risk for coronary artery disease and stroke, suggesting that cardiovascular
      disease begins to develop early in the natural history of renal dysfunction.
      Patients with renal failure are known to be at increased risk of death following
      acute myocardial infarction or congestive heart failure.In such sense,
      anticoagulation in addition to antiplatelet inhibitor drugs became the standard
      of care, particularly, among high risk unstable angina patients associated with a
      scarce side effects.The Nadroparin calcium Versus Enoxaparin (NaVe) Study will
      evaluate in a head to head basis the anti Xa activity reached by nadroparine or
      enoxaparine, both low molecular weight heparins, in patients at high risk for
      ischemic episodes, and renal insufficiency to eventually be undergone to
      angiographic diagnosis studies, and in consequence proposing the best
      anticoagulant strategies for these patients before being invasively
      treated.Patients will be randomly assigned to one of the two groups: Group 1:
      thirty patients will be given with subcutaneous enoxaparine injections into the
      abdominal wall in a dose of 0,85 mg/kg every 12 hours for a maximum of 48 hours.
      A saline infusion dose will be given in between. Total number of injections: 6.
      Group 2:Thirty patients will be receiving subcutaneous injections into the
      abdominal wall in a doses of 30% less in relationship with his / her body weight
      every 8 hours for a maximum of 48 hours.In order to achieve the goal of the
      study, the antiXa activity will be measure using venous blood samples taken as
      follows: Group 1:*Within 3rd and 4 hour of the second doses of HBPM for
      enoxaparine.*Within 11 th and 12 th hour next to fourth doses of enoxaparine.
      Group 2: *Within 3rd and 4 th hour next to 3rd doses of HBPM for the
      nadroparine.*Within 7th and 8th hour next to 4th doses HBPM for the
      nadroparine.The primary end point is to analyze during the in-hospital stay phase
      the stability of the anti Xa activity within the therapeutic ranges which will be
      estimated between 0.5 to 1.0 IU during the first 48 hours.

PMID- 15186496
TI  - Strong science challenges conventional wisdom: new perspectives on ovarian
      biology.

PMID- 15186498
TI  - Carcinoma of sigmoid colon following urinary diversion: a case report and review
      of literature.
AB  - BACKGROUND: The association of ureterosigmoidostomy with colonic cancer is well
      established. A 100-fold increased risk of malignancy has been proposed in
      association with ureterosigmoidostomy. Characteristically there is a latent
      period of around 20-30 years before the occurrence of cancer. CASE PRESENTATION:
      An unusual case of adenocarcinoma of the colon in a 36-year-old patient is
      presented. The patient underwent three operations in his infancy for exstrophy
      but after failure to close bladder, ureterosigmoidostomy was attempted at the age
      of 5 years and was converted to an ileal conduit after 8 months. At the age of 36
      years, 30 years following ileal conduit urinary diversion for exstrophy, he
      presented in emergency with large bowel obstruction due to adenocarcinoma of the
      sigmoid colon. CONCLUSION: Patients who undergo urinary diversion for exstrophy
      may be kept on a regular follow-up surveillance colonoscopy as most of these
      young adults may later present with vague abdominal symptoms which may not be
      taken seriously until they increase to an extent as to present with intestinal
      obstruction as in the present case.

PMID- 15186499
TI  - Malarone treatment failure not associated with previously described mutations in
      the cytochrome b gene.
AB  - Malarone (atovaquone-proguanil) is an effective drug for the treatment and
      prophylaxis of multidrug-resistant falciparum malaria. However, first cases of
      resistance have been reported, which are associated with mutations at codon 268
      of the parasite's cytochrome b gene. We report the first case of Malarone
      treatment failure from Central Africa.Drug concentration was well within curative
      range. Pre- and post-treatment Plasmodium falciparum isolates revealed codon 268
      wild-type alleles, and no other mutations of the putative atovaquone-binding
      domain.These findings illustrate the spread of atovaquone-proguanil-resistance in
      Africa and question the usefulness of codon 268 as the only target for the
      surveillance of its emergence.

PMID- 15186500
TI  - Evaluation of toxicity after one-months treatment with Bauhinia forficata
      decoction in streptozotocin-induced diabetic rats.
AB  - BACKGROUND: Previous experiments have shown that a decoction of Bauhinia
      forficata leaves reduces the changes in carbohydrate and protein metabolism that
      occur in rats with streptozotocin-induced diabetes. In the present investigation,
      the serum activities of enzymes known to be reliable toxicity markers were
      monitored in normal and streptozotocin-diabetic rats to discover whether the use
      of B. forficata decoction has toxic effects on liver, muscle or pancreas tissue
      or on renal microcirculation. METHODS: An experimental group of normal and
      streptozotocin-diabetic rats received an aqueous decoction of fresh B. forficata
      leaves (150 g/L) by mouth for 33 days while a control group of normal and
      diabetic rats received water for the same length of time. The serum activity of
      the toxicity markers lactate dehydrogenase, creatine kinase, amylase, angiotensin
      converting enzyme and bilirubin were assayed before receiving B. forficata
      decoction and on day 19 and 33 of treatment. RESULTS: The toxicity markers in
      normal and diabetic rats were not altered by the diabetes itself nor by treatment
      with decoction. Whether or not they received B. forficata decoction the normal
      rats showed a significant increase in serum amylase activity during the
      experimental period while there was a tendency for the diabetic rats, both
      treated and untreated with decoction, to have lower serum amylase activities than
      the normal rats. CONCLUSIONS: Administration of an aqueous decoction of B.
      forficata is a potential treatment for diabetes and does not produce toxic
      effects measurable with the enzyme markers used in our study.

PMID- 15186501
TI  - Comparisons of mortality and pre-discharge respiratory outcomes in small-for
      gestational-age and appropriate-for-gestational-age premature infants.
AB  - BACKGROUND: There are differences in the literature regarding outcomes of
      premature small-for-gestational-age (SGA) and appropriate-for gestational-age
      (AGA) infants, possibly due to failure to take into account gestational age at
      birth. OBJECTIVE: To compare mortality and respiratory morbidity of SGA and AGA
      premature newborn infants. DESIGN/METHODS: A retrospective study was done of the
      2,487 infants born without congenital anomalies at </=36 weeks of gestation and
      admitted to the neonatal intensive care unit (NICU) at John Dempsey Hospital,
      between Jan. 1992 and Dec. 1999. Recent (1994-96) U.S. birth weight percentiles
      for gestational age (GA), race and gender were used to classify neonates as SGA
      (<10th percentile for GA) or AGA (10th-90th percentile for GA). Using
      multivariate logistic regression and survival analyses to control for GA, SGA and
      AGA infants were compared for mortality and respiratory morbidity. RESULTS:
      Controlling for GA, premature SGA infants were at a higher risk for mortality
      (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome
      (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression
      modeling found that the odds of having respiratory distress syndrome (RDS) varied
      between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants
      at GA </= 32 wk (OR = 1.27, 95% CI 0.32 - 1.98) but significantly decreased risk
      for RDS at GA > 32 wk (OR = 0.41, 95% CI 0.27 - 0.63; p < 0.01). After
      controlling for GA, SGA infants were observed to be at a significantly higher
      risk for developing chronic lung disease as compared to AGA infants (OR = 2.2,
      95% CI = 1.2 - 3.9, P = 0.01). There was no significant difference between SGA
      and AGA infants in total days on ventilator. Among infants who survived, mean
      length of hospital stay was significantly higher in SGA infants born between 26
      36 wks GA than AGA infants. CONCLUSIONS: Premature SGA infants have significantly
      higher mortality, significantly higher risk of developing chronic lung disease
      and longer hospital stay as compared to premature AGA infants. Even the reduced
      risk of RDS in infants born at >/=32 wk GA, (conferred possibly by intra-uterine
      stress leading to accelerated lung maturation) appears to be of transient effect
      and is counterbalanced by adverse effects of poor intrauterine growth on long
      term pulmonary outcomes such as chronic lung disease.

PMID- 15186502
TI  - Fast detection of Noroviruses using a real-time PCR assay and automated sample
      preparation.
AB  - BACKGROUND: Noroviruses (NoV) have become one of the most commonly reported
      causative agents of large outbreaks of non-bacterial acute gastroenteritis
      worldwide as well as sporadic gastroenteritis in the community. Currently,
      reverse transcriptase polymerase chain reaction (RT-PCR) assays have been
      implemented in NoV diagnosis, but improvements that simplify and standardize
      sample preparation, amplification, and detection will be further needed. The
      combination of automated sample preparation and real-time PCR offers such
      refinements. METHODS: We have designed a new real-time RT-PCR assay on the
      LightCycler (LC) with SYBR Green detection and melting curve analysis (Tm) to
      detect NoV RNA in patient stool samples. The performance of the real-time PCR
      assay was compared with that obtained in parallel with a commercially available
      enzyme immunoassay (ELISA) for antigen detection by testing a panel of 52 stool
      samples. Additionally, in a collaborative study with the Baden-Wuerttemberg State
      Health office, Stuttgart (Germany) the real-time PCR results were blindly
      assessed using a previously well-established nested PCR (nPCR) as the reference
      method, since PCR-based techniques are now considered as the "gold standard" for
      NoV detection in stool specimens. RESULTS: Analysis of 52 clinical stool samples
      by real-time PCR yielded results that were consistent with reference nPCR
      results, while marked differences between the two PCR-based methods and antigen
      ELISA were observed. Our results indicate that PCR-based procedures are more
      sensitive and specific than antigen ELISA for detecting NoV in stool specimens.
      CONCLUSIONS: The combination of automated sample preparation and real-time PCR
      provided reliable diagnostic results in less time than conventional RT-PCR
      assays. These benefits make it a valuable tool for routine laboratory practice
      especially in terms of rapid and appropriate outbreak-control measures in health
      care facilities and other settings.

PMID- 15186503
TI  - Complete hepatitis B virus genome analysis in HBsAg positive mothers and their
      infants with fulminant hepatitis B.
AB  - BACKGROUND: After perinatal transmission of hepatitis B virus, infants of anti
      HBe positive HBsAg carrier mothers may develop fulminant hepatitis B. Previously
      it has been suggested, that fulminant hepatitis B in adults was associated with
      specific mutations in the HBV-genome. The aim of this study was to investigate,
      whether specific viral variants are associated with fulminant hepatitis B in
      young infants. METHODS: The complete HBV-genomes of five mothers and their
      infants with fulminant hepatitis were isolated from the sera, amplified and
      directly sequenced. RESULTS: Between 6 and 43 base pair exchanges between the HBV
      genomes of the infants and their mothers were identified. The mutations spread
      over the entire virus genome. Nucleotide exchanges in the basic core promotor and
      precore region were identified in all cases. A heterogeneous virus population was
      detected in four mothers. CONCLUSIONS: Many new mutations were proved to emerge
      during fulminant hepatitis B in infants, who had been perinatally infected. HBeAg
      negative variants were the predominant population in all children, whereas these
      mutants could only be detected as subpopulations in four mothers. The data
      suggest that the selection of a specific HBeAg negative viral strain may be
      associated with the development of fulminant hepatitis B in children.

PMID- 15186504
TI  - Non-invasive evaluation of ventricular refractoriness and its dispersion during
      ventricular fibrillation in patients with implantable cardioverter defibrillator.
AB  - BACKGROUND: Local ventricular refractoriness and its dispersion during
      ventricular fibrillation (VF) have not been well evaluated, due to methodological
      difficulties. METHODS: In this study, a non-invasive method was used in
      evaluation of local ventricular refractoriness and its dispersion during induced
      VF in 11 patients with VF and/or polymorphic ventricular tachycardia (VT) who
      have implanted an implantable cardioverter defibrillator (ICD). Bipolar
      electrograms were simultaneously recorded from the lower oesophagus behind the
      posterior left ventricle (LV) via an oesophageal electrode and from the right
      ventricular (RV) apex via telemetry from the implanted ICD. VF intervals were
      used as an estimate of the ventricular effective refractory period (VERP). In 6
      patients, VERP was also measured during sinus rhythm at the RV apex and outflow
      tract (RVOT) using conventional extra stimulus technique. RESULTS: Electrograms
      recorded from the RV apex and the lower esophagus behind the posterior LV
      manifested distinct differences of the local ventricular activities. The
      estimated VERPs during induced VF in the RV apex were significantly shorter than
      that measured during sinus rhythm using extra stimulus technique. The maximal
      dispersion of the estimated VERPs during induced VF between the RV apex and
      posterior LV was that of 10 percentile VF interval (40 +/- 27 ms), that is
      markedly greater than the previously reported dispersion of ventricular
      repolarization without malignant ventricular arrhythmias (30-36 ms). CONCLUSIONS:
      This study verified the feasibility of recording local ventricular activities via
      oesophageal electrode and via telemetry from an implanted ICD and the usefulness
      of VF intervals obtained using this non-invasive technique in evaluation of the
      dispersion of refractoriness in patients with ICD implantation.

PMID- 15186505
TI  - Overcoming antigen masking of anti-amyloidbeta antibodies reveals breaking of B
      cell tolerance by virus-like particles in amyloidbeta immunized amyloid precursor
      protein transgenic mice.
AB  - BACKGROUND: In prior work we detected reduced anti-Abeta antibody titers in Abeta
      vaccinated transgenic mice expressing the human amyloid precursor protein (APP)
      compared to nontransgenic littermates. We investigated this observation further
      by vaccinating APP and nontransgenic mice with either the wild-type human Abeta
      peptide, an Abeta peptide containing the "Dutch Mutation", E22Q, or a wild-type
      Abeta peptide conjugated to papillomavirus virus-like particles (VLPs). RESULTS:
      Anti-Abeta antibody titers were lower in vaccinated APP than nontransgenic mice
      even when vaccinated with the highly immunogenic Abeta E22Q. One concern was that
      human Abeta derived from the APP transgene might mask anti-Abeta antibodies in
      APP mice. To test this possibility, we dissociated antigen-antibody complexes by
      incubation at low pH. The low pH incubation increased the anti-Abeta antibody
      titers 20-40 fold in APP mice but had no effect in sera from nontransgenic mice.
      However, even after dissociation, the anti-Abeta titers were still lower in
      transgenic mice vaccinated with wild-type Abeta or E22Q Abeta relative to non
      transgenic mice. Importantly, the dissociated anti-Abeta titers were equivalent
      in nontransgenic and APP mice after VLP-based vaccination. Control experiments
      demonstrated that after acid-dissociation, the increased antibody titer did not
      cross react with bovine serum albumin nor alpha-synuclein, and addition of Abeta
      back to the dissociated serum blocked the increase in antibody titers.
      CONCLUSIONS: Circulating human Abeta can interfere with ELISA assay measurements
      of anti-Abeta titers. The E22Q Abeta peptide vaccine is more immunogenic than the
      wild-type peptide. Unlike peptide vaccines, VLP-based vaccines against Abeta
      abrogate the effects of Abeta self-tolerance.

PMID- 15186506
TI  - Tandem repeats analysis for the high resolution phylogenetic analysis of Yersinia
      pestis.
AB  - BACKGROUND: Yersinia pestis, the agent of plague, is a young and highly
      monomorphic species. Three biovars, each one thought to be associated with the
      last three Y. pestis pandemics, have been defined based on biochemical assays.
      More recently, DNA based assays, including DNA sequencing, IS typing, DNA arrays,
      have significantly improved current knowledge on the origin and phylogenetic
      evolution of Y. pestis. However, these methods suffer either from a lack of
      resolution or from the difficulty to compare data. Variable number of tandem
      repeats (VNTRs) provides valuable polymorphic markers for genotyping and
      performing phylogenetic analyses in a growing number of pathogens and have given
      promising results for Y. pestis as well. RESULTS: In this study we have genotyped
      180 Y. pestis isolates by multiple locus VNTR analysis (MLVA) using 25 markers.
      Sixty-one different genotypes were observed. The three biovars were distributed
      into three main branches, with some exceptions. In particular, the Medievalis
      phenotype is clearly heterogeneous, resulting from different mutation events in
      the napA gene. Antiqua strains from Asia appear to hold a central position
      compared to Antiqua strains from Africa. A subset of 7 markers is proposed for
      the quick comparison of a new strain with the collection typed here. This can be
      easily achieved using a Web-based facility, specifically set-up for running such
      identifications. CONCLUSION: Tandem-repeat typing may prove to be a powerful
      complement to the existing phylogenetic tools for Y. pestis. Typing can be
      achieved quickly at a low cost in terms of consumables, technical expertise and
      equipment. The resulting data can be easily compared between different
      laboratories. The number and selection of markers will eventually depend upon the
      type and aim of investigations.

PMID- 15186507
TI  - Section-level relationships of North American Agalinis (Orobanchaceae) based on
      DNA sequence analysis of three chloroplast gene regions.
AB  - BACKGROUND: The North American Agalinis are representatives of a taxonomically
      difficult group that has been subject to extensive taxonomic revision from
      species level through higher sub-generic designations (e.g., subsections and
      sections). Previous presentations of relationships have been ambiguous and have
      not conformed to modern phylogenetic standards (e.g., were not presented as
      phylogenetic trees). Agalinis contains a large number of putatively rare taxa
      that have some degree of taxonomic uncertainty. We used DNA sequence data from
      three chloroplast genes to examine phylogenetic relationships among sections
      within the genus Agalinis Raf. (=Gerardia), and between Agalinis and closely
      related genera within Orobanchaceae. RESULTS: Maximum likelihood analysis of
      sequences data from rbcL, ndhF, and matK gene regions (total aligned length 7323
      bp) yielded a phylogenetic tree with high bootstrap values for most branches.
      Likelihood ratio tests showed that all but a few branch lengths were
      significantly greater than zero, and an additional likelihood ratio test rejected
      the molecular clock hypothesis. Comparisons of substitution rates between gene
      regions based on linear models of pairwise distance estimates between taxa show
      both ndhF and matK evolve more rapidly than rbcL, although the there is
      substantial rate heterogeneity within gene regions due in part to rate
      differences among codon positions. CONCLUSIONS: Phylogenetic analysis supports
      the monophyly of Agalinis, including species formerly in Tomanthera, and this
      group is sister to a group formed by the genera Aureolaria, Brachystigma,
      Dasistoma, and Seymeria. Many of the previously described sections within
      Agalinis are polyphyletic, although many of the subsections appear to form
      natural groups. The analysis reveals a single evolutionary event leading to a
      reduction in chromosome number from n = 14 to n = 13 based on the sister group
      relationship of section Erectae and section Purpureae subsection Pedunculares.
      Our results establish the evolutionary distinctiveness of A. tenella from the
      more widespread and common A. obtusifolia. However, further data are required to
      clearly resolve the relationship between A. acuta and A. tenella.

PMID- 15186510
TI  - Expanded school mental health: exploring program details and developing the
      research base.
AB  - Expanded school mental health (ESMH) programs, the focus of this special issue,
      provide comprehensive mental health care to youth in general and special
      education through partnerships between schools and community mental health
      agencies and programs. As these programs progressively develop in the United
      States, there is a critical need to build the research and evidence base for
      them. This article presents background to the national movement toward ESMH and
      provides an overview of articles contained in this special issue, which provide
      in-depth details and early research findings on diverse aspects of mental health
      programs in schools. Advantages of greater involvement of behavioral
      professionals in ESMH are discussed.

PMID- 15186509
TI  - Correction: Benchmarking tools for the alignment of functional noncoding DNA.

PMID- 15186508
TI  - The XMAP215-family protein DdCP224 is required for cortical interactions of
      microtubules.
AB  - BACKGROUND: Interactions of peripheral microtubule tips with the cell cortex are
      of crucial importance for nuclear migration, spindle orientation, centrosome
      positioning and directional cell movement. Microtubule plus end binding proteins
      are thought to mediate interactions of microtubule tips with cortical actin and
      membrane proteins in a dynein-dependent manner. XMAP215-family proteins are main
      regulators of microtubule plus end dynamics but so far they have not been
      implicated in the interactions of microtubule tips with the cell cortex. RESULTS:
      Here we show that overexpression of an N-terminal fragment of DdCP224, the
      Dictyostelium XMAP215 homologue, caused a collapse of the radial microtubule
      cytoskeleton, whereby microtubules lost contact with the cell cortex and were
      dragged behind like a comet tail of an unusually motile centrosome. This
      phenotype was indistinguishable from mutants overexpressing fragments of the
      dynein heavy chain or intermediate chain. Moreover, it was accompanied by
      dispersal of the Golgi apparatus and reduced cortical localization of the dynein
      heavy chain indicating a disrupted dynein/dynactin interaction. The interference
      of DdCP224 with cortical dynein function is strongly supported by the
      observations that DdCP224 and its N-terminal fragment colocalize with dynein and
      coimmunoprecipitate with dynein and dynactin. CONCLUSIONS: Our data show that
      XMAP215-like proteins are required for the interaction of microtubule plus ends
      with the cell cortex in interphase cells and strongly suggest that this function
      is mediated by dynein.

PMID- 15186511
TI  - Understanding expanded school mental health services in Baltimore City.
AB  - This article explores the nature of expanded school mental health (ESMH) services
      in Baltimore City, which at the time of the study were incorporated into 40% of
      the city's public schools. A provider survey was distributed to ESMH clinicians
      to gather information on the characteristics of service providers and recipients,
      types of services being provided, and their proposed outcomes. Provider reports
      indicated an impressive service capacity, augmentation of traditional school
      based services, and the continual need for increased mental health service hours
      in their buildings. In addition, the most frequently voiced benefits of the ESMH
      programs were increased mental health awareness and improved school climate.
      Implications of the findings for future programming development and research are
      discussed.

PMID- 15186512
TI  - School-based mental health services in Baltimore: association with school climate
      and special education referrals.
AB  - This study investigated the association between school-based mental health
      services and two proposed but untested outcomes of these services: (a) school
      climate and (b) patterns of referrals to special education. Results from a
      climate survey found that teachers and staff in eight elementary schools with
      expanded school mental health (ESMH) services gave higher ratings on the survey's
      mental health climate subscale than respondents from schools in a matched
      comparison group. No differences were found for the General Climate subscale of
      the survey. Results also indicated that teachers in ESMH schools referred fewer
      students to the special education eligibility process because of emotional and
      behavioral issues and that fewer students in ESMH schools were found eligible for
      special education for emotional and behavioral disabilities. Results of this
      study provide beginning evidence for the positive impact of ESMH programs on
      these two schoolwide indicators of functioning.

PMID- 15186513
TI  - A drop-out prevention program for high-risk inner-city youth.
AB  - Inner-city youth are at high risk for dropping out of high school. Within this
      article, risk factors associated with dropout and strategies for effective
      prevention and intervention are reviewed. An example of a school-based drop-out
      prevention program is highlighted. The FUTURES Program is a school-based drop-out
      prevention program designed to address the needs of high-risk youth through
      smaller classes, character development, career preparation, case
      management/mentoring, positive incentives, and access to mental health services.
      Components of the program are described in detail and data evaluating the
      effectiveness of the program are presented. Directions for the future development
      of programs and conducting research to prevent dropout by inner-city youth are
      discussed.

PMID- 15186514
TI  - Efficacy of a school-based treatment program for middle school youth with ADHD:
      pilot data.
AB  - The effects of a set of behavioral and educational interventions provided in a
      middle-school-based mental health program on the behavior and academic
      performance of 7 students diagnosed with attention-deficit/hyperactivity disorder
      (ADHD) were studied. The treatments included educational, social skills and
      family interventions designed to target school functioning, peer relations, and
      family functioning. Dependent measures included parent and teacher ratings of
      ADHD symptoms, daily functioning, and academic grades. Large effect sizes were
      found on measures of inattention and school functioning. Grades and measures of
      family functioning and peer relations yielded small to moderate effect sizes.
      Description of the procedures is provided and implications for advancing school
      based mental health care for adolescents with a diagnosis of ADHD are discussed.

PMID- 15186515
TI  - Associations between youth risk behavior and exposure to violence: implications
      for the provision of mental health services in urban schools.
AB  - This article assesses the relation between health risk behaviors and varying
      levels of exposure to violence in an effort to inform assessment and intervention
      efforts of a school-based mental health program serving inner-city youth. Health
      risk behaviors such as involvement in violence, risky sexual behavior, and
      substance use are clearly associated, both with each other and with violence
      exposure. However, differential relationships were observed depending on the
      nature of violence exposure. Knowledge of violence was associated with substance
      use and sexual behavior variables. Witnessing violence was associated with
      violence involvement, substance use, and exercise variables. Finally, violent
      victimization was associated with violence involvement and sexual behavior
      variables. A more complete understanding of the associations among health risk
      factors and violence exposure variables has the potential to improve
      implementation of school mental health services for urban youth.

PMID- 15186516
TI  - Assessment, prevention, and intervention activities in a school-based program for
      children experiencing homelessness.
AB  - Children who experience homelessness are at increased risk for a range of health
      and mental health problems. In spite of this increased risk, they are often less
      likely to receive appropriate services. School-based programs offer considerable
      potential to reduce the gap between needs and appropriate services for these
      youth; however, there are few examples of such programs in the published
      literature. This article provides information from a mental and physical health
      prevention program and needs assessment for at-risk children, who were
      experiencing homelessness or were from very low-income families, which was
      piloted during a summer camp program in an urban school. Results of the needs
      assessment indicated that children residing in homeless shelters reported less
      consistent access to medical and dental care than children residing with their
      families. It is interesting that children experiencing homelessness were more
      likely to report that they had participated in counseling than did children from
      low-income families. Satisfaction ratings of prevention activities conducted in
      the program were positive for students and teachers.

PMID- 15186517
TI  - Assessing the psychosocial and academic needs of Latino youth to inform the
      development of school-based programs.
AB  - A survey was made of the leaders in the Latino community from four East coast
      cities on the mental health, academic, and behavioral needs of Latino youth,
      services available to them, and recommendations to better address their needs. Of
      the 112 Latino leaders recruited, 46 responded to the survey, expressing their
      views that Latino youth experience significant stress in the United States,
      present behavioral and academic adjustment problems, and generally have
      difficulty accessing appropriate services and resources. Programs for these youth
      were presented as limited in number and lacking in cultural sensitivity.
      Community leaders endorsed the development of comprehensive and culturally
      sensitive programs for Latino youth in schools that address their psychosocial
      and academic needs.

PMID- 15186519
TI  - Development of a novel human immunodeficiency virus type 1 subtyping tool,
      Subtype Analyzer (STAR): analysis of subtype distribution in London.
AB  - We have developed a high throughput computational tool for assigning subtype to
      HIV-1, based solely on protease and reverse transcriptase (PR-RT) amino acid
      sequence, generated routinely for clinical assessment of genotypic drug
      resistance. Subtype-specific profiles were created by generation of position
      specific scoring matrices (PSSMs) from multiple amino acids alignments of HIV-1
      sequence data from GenBank, phylogenetically divided into subtypes A, AG, B, C,
      D, F/K, G, H, and J and the separate groups N and O. Query sequences of unknown
      subtype are aligned with these profiles and a score is derived by comparing each
      amino acid position in the unknown sequence to the normalized frequency
      distribution of amino acids at the corresponding positions in the subtype
      alignments. The highest score is used to assign subtype to the query sequence.
      Leave one out cross-validation analysis showed the Subtype Analyzer (STAR) was
      99% accurate in subtype assignation. STAR can be updated with additional subtype
      specific sequence data from sequence databases. STAR was used to classify HIV-1
      PR-RT sequences from 843 HIV-1 clinical isolates submitted for drug resistance
      profiling in London. Within this dataset 26.9% of sequences were classified by
      STAR as non-B subtypes.

PMID- 15186518
TI  - Quality improvement activities and expanded school mental health services.
AB  - Quality improvement (QI) activities, designed to enhance program evaluation
      efforts and to improve quality of care, have become increasingly important in
      children's services research. QI activities examine outcomes and provide
      accountability data that can be very useful for telling the story of the
      development, implementation, and effectiveness of expanded school mental health
      (ESMH) programs. This article discusses the implementation and results of QI
      activities for two ESMH programs, one relatively new program, and one with 10
      years of experience. When presenting each case example, the authors review key QI
      activities such as developing new measures and interventions, evaluating costs of
      care, and disseminating results to clinicians, program administrators, and
      funders. The article concludes with a discussion of the importance of QI in
      school-based mental health and reviews directions for future research and program
      development.

PMID- 15186520
TI  - The changing molecular epidemiology of HIV type 1 among northern Thai drug users,
      1999 to 2002.
AB  - CRF01_AE and subtype B have dominated the HIV-1 epidemic in Thailand since 1989.
      We reported a new circulating recombinant form of HIV-1, CRF15_01B, as well as
      other unique CRF01_AE/B recombinants among prevalent HIV infections in Thailand.
      We sought to study this challenging molecular picture through assessment of
      subtypes among recent HIV-1 seroconverters in northern Thai drug users. A total
      of 847 HIV-1 seronegative drug users (342 IDU and 505 non-IDU) were enrolled,
      from 1999 to 2002, in a prospective study; 39 HIV-1 incident cases were
      identified and characteristics were collected. The overall HIV-1 incidence rate
      was 2.54/100PY, but it was 10.0/100PY among male IDU. HIV was strongly associated
      with injection history; 38 of 39 seroconverters gave a history of IDU. A near
      full-length genome of HIV-1 was recovered by PCR amplification and sequenced from
      peripheral mononuclear cell extracted DNA of 38 seroconverters. Phylogenetic
      analysis revealed that 33 (86.8%) were CRF01_AE and 5 (13.2%) were CRF01_AE/B
      recombinants. These recombinants had different structure but shared some common
      breakpoints, indicating an ongoing recombination process. Recombinant infection
      increased with year of sampling (0 to 57.1%). The molecular epidemiology of HIV-1
      among drug users in northern Thailand has thus entered a new era. CRF01_AE
      remains predominant while pure subtype B is becoming rare, and now a substantial
      component of the epidemic. These findings support the need for CRF01_AE and
      subtype B components in clade-matched vaccine strategies for Thai phase III
      trials. Ongoing molecular surveillance of circulating HIV-1 strains is imperative
      for the evaluation of HIV vaccine efficacy.

PMID- 15186521
TI  - Sensitivity of HIV type 1 subtype C isolates to the entry inhibitor T-20.
AB  - T-20 is the first in a new class of antiretroviral drugs targeting the entry
      stage of the virus life cycle. It is a 36 amino acid peptide that binds to the
      HR1 region of gp41 preventing gp41-mediated fusion with the host cell membrane. T
      20 was designed based on the HR2 sequence of HIV-1 subtype B gp41, a region that
      shows significant genetic variation with HIV-1 subtype C sequences. In order to
      assess the efficacy of T-20 to inhibit subtype C isolates, a total of 23 isolates
      were tested for their ability to replicate in the presence of T-20. This included
      15 isolates that used CCR5, five that used both CCR5 and CXCR4, and three that
      used CXCR4. Five of these were from patients failing other antiretroviral
      therapies. Sequence analysis of the HR2 region indicated that there were 10-16
      amino acid changes in the region corresponding to T-20. However, all isolates
      were effectively inhibited by T-20 at 1 microg/ml. There were no significant
      differences between viruses that used CCR5 or CXCR4 to enter cells. All isolates,
      except one, had GIV at positions 36-38 in the HR1 region. One isolate had a GVV
      motif but this did not affect its sensitivity to T-20. Therefore, T-20 inhibited
      subtype C viruses despite significant genetic differences in the HR2 region and
      there was no evidence for baseline resistance to T-20. These data suggest that T
      20 would be highly effective in patients with HIV-1 subtype C infection,
      including those failing existing antiretroviral drug regimens.

PMID- 15186522
TI  - Prevention of AIDS dementia by HAART does not depend on cerebrospinal fluid drug
      penetrance.
AB  - The impact of the cerebrospinal fluid (CSF) penetrance properties of different
      highly active antiretroviral therapy (HAART) regimes on cognitive processing in
      AIDS dementia is still undetermined. We therefore designed a retrospective cross
      sectional and prospective longitudinal analysis of event-related potentials in
      HIV-infected patients with different combinations of HAART or without
      antiretroviral treatment. A total of 353 consecutive patients without secondary
      CNS manifestation of HIV infection were enrolled in the cross-sectional study and
      135 consecutive patients without secondary CNS manifestations of HIV infection
      were enrolled in the longitudinal study. HAART in different combinations (n =
      306) or no antiretroviral treatment (n = 47) was given for at least 6 months in
      the retrospective cross-sectional study. HAART in different combinations (n =
      110) or no antiretroviral treatment (n = 25) was given for 1 year in the
      prospective longitudinal study. We evaluated the latency and amplitude of the P3
      component of visually evoked event-related potentials and mean choice reaction
      time as measures of cognitive processing. Patients receiving HAART had decreased
      P3 latencies as compared to those patients not receiving HAART but P3 latency and
      P3 amplitude were not correlated with the amount of CSF penetrance of the
      different HAART combinations in either statistical analysis. However, mean choice
      reaction time was significantly correlated with the amount of CSF penetrance. In
      HIV-infected patients, the CSF penetrance properties of HAART do not have any
      significant influence on cognitive processing as measured by event-related
      potentials.

PMID- 15186523
TI  - Haemophilus influenzae type b immunization in adults infected with the human
      immunodeficiency virus.
AB  - The purpose of this study was to assess the influence of Haemophilus influenzae
      type b conjugate vaccine on HIV-1 RNA level, CD4 count, and anti-Hib
      polysaccharide (PRP) antibody concentration. Eighty HIV-infected adults were
      randomized to receive Hib conjugate vaccine or not. Twenty HIV-seronegative
      controls were also vaccinated. Blood samples were taken before and after
      vaccination, with a follow-up period of 6 months. HIV infection markers and anti
      PRP antibodies were monitored. There was no change in either HIV-1 viremia or CD4
      count after vaccination. Immunization immunogenicity was superior in HIV
      uninfected than in HIV-infected individuals (p < 0.01). Hib vaccination was safe
      but induced suboptimal antibody response in HIV-infected adults.

PMID- 15186524
TI  - Expression of latent HAART-persistent HIV type 1 induced by novel cellular
      activating agents.
AB  - The novel antitumor-promoting phorbol ester, prostratin, was evaluated for its
      ability to induce the expression of latent, highly active antiretroviral therapy
      (HAART)-persistent human immunodeficiency virus type I (HIV-1) from specific
      subsets of patients' peripheral blood cells. This evaluation was performed
      relative to the use of other cellular activating agents, such as OKT3, a
      monoclonal antibody against the human T cell receptor, interleukin-2 (IL-2),
      phytohemagglutinin (PHA), p24 antigen (HIV-1-specific capsid protein), and a
      molecular relative of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP).
      Prostratin performed as efficiently as the other cellular activators at inducing
      the expression of latent HIV-1 from cells of patients on virally suppressive
      HAART. Of interest was the induction of a novel species of latent virus from the
      cells of an individual after exposure to the HIV-1-specific capsid protein, p24,
      relative to virus expression induced by several other cell activators. This
      suggests that a variety of agents may be available for animal model studies of
      lentiviral latency and clinical use to broadly induce the expression of latent,
      HAART-persistent HIV-1 in vivo with the goal of potential HIV-1 reservoir
      depletion or eradication.

PMID- 15186525
TI  - HIV type 2 primary isolates induce a lower degree of apoptosis "in vitro"
      compared with HIV type 1 primary isolates.
AB  - To determine whether subtypes of HIV-1 and HIV-2 vary in their ability to induce
      T cell apoptosis in vitro, human peripheral blood mononuclear cells (PBMC) from
      healthy donors and CEM.NKR-CCR5 cells were infected with a variety of HIV-1 and
      HIV-2 isolates in vitro. Apoptotic cell levels and chemokine and cytokine
      production were analyzed. Significant variations in cytopathic effects following
      in vitro infection with primary isolates of HIV-1 or HIV-2 subtypes were observed
      in PBMCs. The percent of apoptotic cells from each individual ranged from 2 to
      78% after HIV-1 infection and from 0 to 28% after HIV-2 infection (p < 0.01). We
      did not observe significant differences in the degree of apoptosis induced among
      cells infected with different HIV-1 group M subtypes or group O virus, nor among
      cells infected with different HIV-2 isolates. However, HIV-2 induced
      significantly lower degree of apoptosis overall in PBMC and CEM.NKR-CC5 cells
      when compared with HIV-1 subtypes (p < 0.0001). No significant differences were
      observed in the production of chemokines, such as RANTES, MIP-1alpha, and MIP
      1beta, and cytokines, such as TNF-alpha and TNF-beta when PBMC cultures were
      infected with different HIV-1 subtype viruses, or HIV-2 isolates. In conclusion,
      HIV-2 isolates induced significantly lower levels of T cell apoptosis in both
      PBMC and CEM.NKR-CCR5 cells than HIV-1 isolates. No differences in T cell
      apoptosis levels were seen between different subtypes of HIV-1 group M or group O
      isolates. This is consistent with the mild clinical course of infection with HIV
      2 that has been reported relative to that observed with HIV-1.

PMID- 15186526
TI  - Alcohol enhances HIV type 1 infection in normal human oral keratinocytes by up
      regulating cell-surface CXCR4 coreceptor.
AB  - Recent studies suggest that normal human oral keratinocytes (NHOKs) can be
      infected by HIV-1, and alcohol can enhance HIV infection and replication in
      lymphocytes. In this study, we examined the possibility that alcohol might
      facilitate HIV-1 infection of NHOKs by up-regulating cell surface expression of
      the coreceptor, CXCR4. Alcohol enhanced in vitro infection of NHOKs by CXCR4
      tropic strains of HIV-1 as indicated by synthesis of viral reverse transcripts
      and production of p24gag protein. Alcohol had no effect on CXCR4 gene expression
      or on total cellular complements of CXCR4 protein. However, alcohol did enhance
      the fraction of total CXCR4 expressed on the cell surface relative to
      intracellular stores. Alcohol-induced up-regulation of cell surface CXCR4
      expression and HIV-1 infectivity could be blocked by SDF-1alpha-mediated
      internalization. These data suggest that alcohol may influence oral HIV
      transmission by altering the cellular compartmentalization of CXCR4 in cells of
      the oral cavity.

PMID- 15186528
TI  - Conserved neutralizing epitopes of HIV type 1 CRF01_AE against primary isolates
      in long-term nonprogressors.
AB  - Linear conserved B cell epitopes in envelope glycoprotein of long-term
      nonprogressors (LTNPs) HIV-1 CRF01_AE were determined. The envelope sequences of
      HIV-1 subtype E from Thailand were aligned to define consensus sequences. Then
      the peptides corresponding to these predicted regions were synthesized as
      peptides represent C1, C2, C3, C5, V2, V3, and gp41 regions. After that, the
      neutralizing B cell epitopes were determined by neutralized competitive assay
      with pool sera of typical progressor and LTNP HIV-1 CRF01_AE patients against HIV
      1 CRF01_AE 24 primary isolates (PI) and laboratory strains (TCLA). We found that
      the strength and breadth of neutralization were greater for sera from LTNPs
      compared with sera from typical progressors. Peptides C1E and C2E could inhibit
      primary isolates but not the TCLA strain in LTNP sera. The new B cell epitopes,
      which were located in the C1 and C2 regions of CRF01_AE against primary HIV-1
      isolates, were identified in HIV-1 CRF01_AE LTNPs. This may be important in HIV-1
      vaccine development and trial.

PMID- 15186527
TI  - Development and application of a high-throughput HIV type 1 genotyping assay to
      identify CRF02_AG in West/West Central Africa.
AB  - In West/West Central Africa, CRF02_AG is the most prevalent HIV-1 strain and
      circulates in the milieu of rare subtypes, circulating recombinant forms (CRFs),
      and unique recombinant forms (URFs). The molecular complexity of HIV-1 epidemics
      in this region and the need to extensively sample large populations, such as in
      the case of vaccine trials, pose seemingly conflicting requirements between full
      genome sequencing and high-throughput low-resolution assays. Here we describe the
      development and evaluation of a multiregion hybridization assay (MHAcrf02) for
      the efficient genotyping of CRF02_AG in West/West Central Africa. Subtype A, G,
      and CRF02_AG-specific fluorescent probes were designed flanking five
      recombination breakpoints in CRF02_AG and were used in real-time PCRs. A panel
      representing West/West Central African HIV-1 genetic diversity was evaluated by
      MHAcrf02. The sample set, previously characterized by full-genome sequencing,
      included CRF02_AG and CRF02_AG-containing recombinants (n = 28), other subtypes,
      CRFs, and URFs (n = 34). DNA from peripheral blood mononuclear cells, cocultures,
      and plasmids was used as template. When the patterns of probe reactivity were
      evaluated. CRF02_AG was identified with a 100% specificity and sensitivity. In
      conclusion, MHAcrf02 will permit more efficient characterization of HIV-1 in
      West/West Central Africa, where CRF02_AG is an important strain. Together with
      other regional genotyping assays MHAcrf02 will contribute to the development of a
      global picture of HIV-1 diversity and geographic distribution, providing a strong
      foundation for intervention, including vaccine development.

PMID- 15186529
TI  - Implications of blood contamination for assessment of local cellular immunity in
      the endocervix.
AB  - Cervical cytobrushes provide a tool to sample endocervical T cells for assessment
      of local immunity. However, most previous studies in HIV-seropositive women have
      excluded samples containing blood and hence have analyzed selected populations of
      patients. As determined by multiple-parameter flow cytometric analysis of T
      lymphocytes from two sequential cytobrushes and concurrently collected blood
      samples, this study found a minimal effect of blood contamination on cervical T
      cell phenotypic parameters in normal women. The consequences of blood in
      endocervical samples will ultimately depend on the design and objective of each
      study, but these data suggest studies could be more inclusive and should not
      automatically discard samples that contain red blood cells.

PMID- 15186530
TI  - HIV type 1 Nef increases the association of T cell receptor (TCR)-signaling
      molecules with T cell rafts and promotes activation-induced raft fusion.
AB  - HIV-1 Nef (Nef) is a myristoylated protein that contributes to HIV disease
      pathogenesis. Nef has a modulatory effect on T cell receptor (TCR) signaling,
      resulting in up-regulation of interleukin-2 (IL-2) production in stimulated T
      cells. Recent studies have shown that efficient TCR signaling requires enhanced
      association of TCR-signaling molecules with plasma membrane microdomains (lipid
      rafts) and fusion of rafts into larger structures. We utilized Jurkat T cell
      lines expressing wild-type Nef (Nef(wt)) and a myristoylation-deficient form of
      Nef (Nef(G)2(A)), from an inducible promoter, to determine the effects of Nef on
      the association of TCR-signaling molecules with rafts in nonstimulated T cells.
      In addition, the effect of Nef on raft size, before and after TCR activation by
      CD3 cross-linking, was also examined. Following induction, Nef(wt) was associated
      with both rafts and nonrafts, while Nef(G)2(A) was almost exclusively cytosolic.
      Induction of Nef(wt), but not Nef(G)2(A), coincided with an increased association
      of the src family tyrosine kinase, Lck, and TCRzeta with rafts, but not with
      nonrafts. Further, rafts were found to be significantly larger in CD3-activated T
      cells in the presence of Nef(wt) when compared to nonexpressing cells. We propose
      that myristoylated, raft-localized Nef primes resting T cells for activation by
      increasing the levels of signaling molecules within rafts, and that TCR
      activation is enhanced by the capacity of Nef to promote raft fusion.

PMID- 15186531
TI  - Differences in the expressed HLA class I alleles effect the differential
      clustering of HIV type 1-specific T cell responses in infected Chinese and
      caucasians.
AB  - China is a region of the world with a rapidly spreading HIV-1 epidemic. Studies
      providing insights into HIV-1 pathogenesis in infected Chinese are urgently
      needed to support the design and testing of an effective HIV-1 vaccine for this
      population. HIV-1-specific T cell responses were characterized in 32 HIV-1
      infected individuals of Chinese origin and compared to 34 infected caucasians
      using 410 overlapping peptides spanning the entire HIV-1 clade B consensus
      sequence in an IFN-gamma ELISpot assay. All HIV-1 proteins were targeted with
      similar frequency in both populations and all study subjects recognized at least
      one overlapping peptide. HIV-1-specific T cell responses clustered in seven
      different regions of the HIV-1 genome in the Chinese cohort and in nine different
      regions in the caucasian cohort. The dominant HLA class I alleles expressed in
      the two populations differed significantly, and differences in epitope clustering
      pattern were shown to be influenced by differences in class I alleles that
      restrict immunodominant epitopes. These studies demonstrate that the clustering
      of HIV-1-specific T cell responses is influenced by the genetic HLA class I
      background in the study populations. The design and testing of candidate vaccines
      to fight the rapidly growing HIV-1 epidemic must therefore take the HLA genetics
      of the population into account as specific regions of the virus can be expected
      to be differentially targeted in ethnically diverse populations.

PMID- 15186534
TI  - Phoning logistics in a longitudinal follow-up of batterers and their partners.
AB  - More needs to be known about the phoning logistics of interviewing subjects for
      longitudinal follow-up studies in the domestic violence field. Using phoning logs
      from a 4-year follow-up of batterer intervention, the authors calculated the
      number, results, and costs of phone calls from a subsample of 100 men and 138
      women. The number of calls is high (5.5 per man and 7.1 per woman), locators play
      a substantial role (for 25% of the men and women), and mailed questionnaires are
      a useful supplement (increasing response rate 5% for men and 11% for women). On
      average, about half of the subjects were interviewed at each interval. The main
      obstacle is not refusals but no response and not being able to locate a subject.
      Strategies to address "no response" are considered.

PMID- 15186535
TI  - Perceptions of help resources for victims of intimate partner violence.
AB  - Intimate partner violence (IPV) constitutes a major public health problem in the
      United States. This cross-sectional survey of 108 emergency department (ED) care
      providers and 146 ED visitors at three metropolitan EDs compared the beliefs of
      ED health care providers with those of community members about the relative
      benefits of the helpfulness of resources for IPV victims using hypothetical case
      scenarios. Although providers generally indicated that help resources were
      helpful in all scenarios, visitors were more discriminating, showing less support
      for resources in the lower-risk scenario. Regarding differences between groups,
      visitors selected police and attorneys more frequently than providers as a
      helpful resource, whereas providers selected shelters and counselors more
      frequently than visitors. Adjustment for previous experience with IPV did not
      change these results. Understanding the differences between health care
      providers' and community members' perceptions of resources for victims of IPV may
      improve the effectiveness of referral to IPV resources.

PMID- 15186536
TI  - Battered women's perceptions of risk versus risk factors and instruments in
      predicting repeat reassault.
AB  - This study partially replicates and expands on a previous study that showed
      women's perceptions of risk to be a strong predictor of reassault among
      batterers. The current study employed a larger and multisite sample, a longer
      follow-up period of 15 months, and multiple outcomes including "repeated
      reassault" (n = 499). According to the multinomial logistic regressions, women's
      perceptions of risk improved prediction with risk factors (ROC area under the
      curve improved by.04 and sensitivity of repeated reassault increased 12
      percentage points). In comparison to simulated risk instruments, women's
      perceptions by themselves were better predictors than the K-SID, similar in
      predictive ability to the SARA, and almost as strong as the DAS. The best
      prediction of repeated reassault was obtained using risk markers, including
      women's perceptions (ROC AUC =.83; 70% sensitivity) or by using the DAS and
      women's perceptions together (ROC AUC =.73; 64% sensitivity).

PMID- 15186537
TI  - Prevalence of trauma, PTSD, and dissociation in court-referred adolescents.
AB  - This study examines the prevalence of trauma, posttraumatic stress disorder
      (PTSD), and dissociative symptoms in adolescents. The sample consisted of 76
      females and 76 males, between the ages of 12 and 18, referred to the Child
      Guidance Clinic of the Superior Court of the District of Columbia for a
      psychological evaluation. Two sets of analyses were conducted. One set included
      the entire sample; the second set excluded those individuals whose listed
      referral problem included only being a victim of abuse. Results of the study
      suggest a high prevalence of trauma in both genders; however, females had
      significantly higher rates than those reported in males. Similarly, female
      adolescents demonstrated significantly higher prevalence rates of PTSD symptoms
      compared with their male counterparts in the entire sample and showed a trend
      toward significance in the analysis of the subsample. There was a low prevalence
      of dissociative symptoms across both genders.

PMID- 15186538
TI  - Effectiveness of hotline, advocacy, counseling, and shelter services for victims
      of domestic violence: a statewide evaluation.
AB  - The authors report the results of an evaluation of services provided by 54
      Illinois domestic violence agencies. In collaboration with the University of
      Illinois at Chicago evaluation team, domestic violence advocates identified
      services to be evaluated, specified desired outcomes of those services, and
      participated in developing measures of those outcomes in both English and
      Spanish. With in the limitations of the study, outcomes were positive in all four
      program areas: hotline, counseling, advocacy, and shelter. The authors then
      discuss implications for evaluation of domestic violence programs that maintain
      victim safety as a guiding principle.

PMID- 15186539
TI  - The adolescent health gap in developing countries.

PMID- 15186532
TI  - Genetic diversity and high proportion of intersubtype recombinants among HIV type
      1-infected pregnant women in Kisumu, western Kenya.
AB  - The high genetic diversity of HIV-1 continues to complicate effective vaccine
      development. To better understand the extent of genetic diversity, intersubtype
      recombinants and their relative contribution to the HIV epidemic in Kenya, we
      undertook a detailed molecular epidemiological investigation on HIV-1-infected
      women attending an antenatal clinic in Kisumu, Kenya. Analysis of gag-p24 region
      from 460 specimens indicated that 310 (67.4%) were A, 94 (20.4%) were D, 28
      (6.1%) were C, 9 (2.0%) were A2, 8 (1.7%) were G, and 11 (2.4%) were
      unclassifiable. Analysis of the env -gp41 region revealed that 326 (70.9%) were
      A, 85 (18.5%) D, 26 (5.7%) C, 9 (2.0%) each of A2 and G, 4(0.9%) unclassifiable,
      and 1 (0.2%) CRF02_AG. Parallel analyses of the gag-p24 and env-gp41 regions
      indicated that 344 (74.8%) were concordant subtypes, while the remaining 116
      (25.2%) were discordant subtypes. The most common discordant subtypes were D/A
      (40, 8.7%), A/D (27, 5.9%), C/A (11, 2.4%), and A/C (8, 1.7%). Further analysis
      of a 2.1-kb fragment spanning the gag-pol region from 38 selected specimens
      revealed that 19 were intersubtype recombinants and majority of them were unique
      recombinant forms. Distribution of concordant and discordant subtypes remained
      fairly stable over the 4-year period (1996-2000) studied. Comparison of amino
      acid sequences of gag-p24 and env-gp41 regions with the subtype A consensus
      sequence or Kenyan candidate vaccine antigen (HIVA) revealed minor variations in
      the immunodominant epitopes. These data provide further evidence of high genetic
      diversity, with subtype A as the predominant subtype and a high proportion of
      intersubtype recombinants in Kenya.

PMID- 15186541
TI  - Intensive care needs of children with acute bacterial meningitis: a developing
      country perspective.
AB  - In view of very limited availability of paediatric intensive care (PIC)
      facilities in developing countries, it is important to define priorities and
      recognise children who might benefit most from PIC. The objective of this
      retrospective, descriptive analysis was to identify the clinical indicators for
      intensive care in children with acute bacterial meningitis (ABM). The study
      included 220 children aged between 1 month and 12 years with ABM admitted to the
      paediatric services of an urban, tertiary-care, teaching hospital in northern
      India from July 1993 to December 1996. Of these, 88 were transferred to the PICU
      by the primary physician, 59% were comatose (Glasgow coma score <8), 44% had
      raised intracranial pressure (ICP), 24% were in shock and 42% had respiratory
      distress/failure. Seizures occurred during their illness in 64 children, 34 of
      whom had refractory status epilepticus. Endotracheal intubation was needed in 29
      and ventilatory support in 19 children. Most of the life support measures were
      required during the initial 48 hours. Nineteen (22%) children died, 16 of whom
      were comatose on admission. Multiple system involvement was associated with
      higher mortality. There were no deaths among the children who were not
      transferred to the PICU. Children with ABM who have a Glasgow coma score <8,
      clinical signs of raised ICP, refractory status epilepticus, shock and/or
      respiratory compromise should be prioritised to receive PIC.

PMID- 15186540
TI  - Towards an integrated approach to lung health in adolescents in developing
      countries.
AB  - The World Health Organization strategies, Integrated Management of Childhood
      Illness and Practical Approach to Lung health provide assessment and management
      guidelines for health workers in developing countries. We reviewed issues
      important to lung health in adolescents to highlight whether differences in
      factors such as adolescent behaviour have consequences for the development of
      case management guidelines, to form a bridge between guidelines for younger
      children and for adults and to make suggestions for further study. Pneumonia,
      asthma and tuberculosis are the leading lung health problems in adolescents. As
      countries industrialise, the importance of asthma mortality and morbidity
      increases as that of pneumonia and pulmonary tuberculosis decreases. Guidelines
      for managing pneumonia and asthma in children and adults in developing and
      developed countries should be adaptable for use in adolescents in developing
      countries, although more information is needed on predictors of severity such as
      respiratory rate cut-offs, level of fever, hypotension, malnutrition and level of
      consciousness. The effectiveness of low-cost treatment for asthma should be
      explored further. HIV and the global resurgence of tuberculosis pose significant
      challenges for improving adolescent lung health, and prevention of smoking
      initiation during adolescence is a priority goal of any integrated approach to
      improving lung health.

PMID- 15186542
TI  - Acute disseminated encephalomyelitis associated with hepatitis A virus infection.
AB  - We describe the case of a 30-month-old boy who developed acute disseminated
      encephalomyelitis (ADEM) after hepatitis A virus (HAV) infection and ultimately
      died. As far as we know, this is only the second case of HAV-associated ADEM to
      be reported in the literature. The child was brought to hospital with fever,
      lethargy and weakness of 2 days duration. He had developed jaundice, abdominal
      pain and malaise 2 weeks beforehand and these problems had resolved within 2
      days. Neurological examination revealed lethargy, generalised weakness and
      positive Babinski's signs bilaterally. Cerebrospinal fluid examination showed
      mild lymphocytic pleocytosis, increased protein and elevated anti-HAV IgM and IgG
      titres. Serum HAV IgM and IgG titres were also elevated. Despite aggressive
      treatment with ceftriaxone, acyclovir and anti-oedema measures, he developed
      papilloedema and coma within 24 hours of admission. Magnetic resonance imaging of
      the brain revealed diffuse cerebral oedema and multifocal hyperintensities on T2
      weighted images, with most lesions in the white matter of both cerebral
      hemispheres. The diagnosis of ADEM was established and high-dose steroids and
      intravenous immunoglobulin were added to the treatment regimen. However, his
      clinical condition continued to deteriorate and he died on the 20th day in
      hospital. This case shows that HAV infection can be linked with ADEM. Patients
      with HAV infection should be examined carefully for central nervous system
      symptoms during follow-up. Likewise, the possibility of HAV infection should be
      investigated in cases of ADEM.

PMID- 15186543
TI  - Morbidity in neonates of mothers who have ingested aflatoxins.
AB  - This study was undertaken to assess whether aflatoxin M(1) concentrations in
      newborn infants correlated with those of their mothers and to determine whether
      the presence of aflatoxin M(1) in cord blood was associated with an increase in
      morbidity in the newborn. There was a strong correlation (r =0.797, p <0.0001)
      between mothers' and cord blood levels of aflatoxin. There was also a strong
      negative correlation between aflatoxin levels and birthweight (r =-0.565, p
      <0.001) but there was no association between aflatoxin M(1) concentration in
      maternal or cord blood and rates of jaundice or infection.

PMID- 15186544
TI  - Cardiac manifestations in HIV-infected Thai children.
AB  - Cardiac complications contribute significantly to morbidity and mortality in HIV
      infected children. There have been few reports of cardiac manifestations in HIV
      infected children in developing countries. The aims of this study were to
      evaluate the clinical manifestations and echocardiographic findings in Thai
      children with HIV infection and determine the clinical predictors of left
      ventricular dysfunction and pulmonary hypertension. We retrospectively reviewed
      the medical records of 27 infants infected with HIV perinatally who presented
      with cardiovascular problems at a tertiary care hospital between 1995 and 2000.
      The mean age at initial cardiac evaluation was 36 months (range 8-65). Signs and
      symptoms included dyspnoea in all cases, oedema in 12 (44%), finger clubbing in
      11 (41%), cyanosis in 6 (22%) and S(3) gallop in 8 (30%). Echocardiographic
      abnormalities included pericardial effusion in 12 (44 %), right ventricular
      dilatation in 12 (44%), pulmonary hypertension in 11 (41%), diminished left
      ventricular fractional shortening in 10 (37%), left ventricular dilatation in 9
      (33%) and combined ventricular dilatation in 2 (7%). Left ventricular dysfunction
      did not correlate with HIV CDC classification, age, nutritional status or
      clinical signs and symptoms.

PMID- 15186545
TI  - Post-neonatal infant mortality in Malawi: the importance of maternal health.
AB  - In a cohort study of mothers and their infants, information was collected from
      women attending the antenatal services of two hospitals in a rural area of Malawi
      and 561 of their babies were enrolled in a follow-up study. There were 128 with a
      low birthweight (LBW, <2500 g), 138 with fetal anaemia (FA, cord haemoglobin
      <12.5 g/dl), 42 with both and 228 with a normal birthweight and no FA. Infants
      were seen monthly for 1 year. Risk factors for post-neonatal infant mortality
      (PNIM) were calculated using Cox regression analysis adjusting for LBW and FA.
      PNIM was 9.3%. Respiratory infections and diarrhoeal disease were the principal
      attributable causes of death. PNIM increased with LBW (RR 3.08, 95% CI 1.51-6.23)
      but not significantly so with FA (RR 1.60, 95% CI 0.78-3.27). An additional
      effect on PNIM was observed with maternal HIV (RR 3.44, 95% CI 1.63-7.26) and
      malaria at the first antenatal visit (RR 2.26, 95% CI 1.09-4.73). Illiteracy was
      not associated with mortality. Placental malaria in HIV-seronegative mothers was
      significantly associated with increased PNIM. Improving birthweight through
      effective antimalarial control in pregnancy will lead to a reduction in PNIM.
      Reduction of HIV prevalence and prevention of mother-to-child transmission of HIV
      must be a main target for government health policy.

PMID- 15186546
TI  - Integrated care pathways: a tool to improve infant monitoring in a neonatal unit.
AB  - An integrated care pathway (ICP) is a structured chart that prompts for key
      observations and interventions in patients to be recorded at set times by medical
      and nursing staff. ICPs were introduced into the neonatal department of the Queen
      Elizabeth Central Hospital in Blantyre, Malawi. The number of observations of
      babies recorded in the year before and 2 years after the introduction of ICPs
      were compared. When ICPs were in use, 9-96% of the 18 possible daily observations
      were recorded as having been carried out, compared with 0-33% before their
      introduction. In the 2nd of the 3 years, there was a fall-off in some
      observations made, probably because of staff shortages. The ICPs proved effective
      and easy to use. When adapted to local needs they play an important role in
      delivering neonatal care.

PMID- 15186547
TI  - Health status of working and non-working school children in Ibadan, Nigeria.
AB  - Child labour continues to pose a challenge to national and international
      agencies. This study compares the health status of working and non-working school
      children in Ibadan, Nigeria. Altogether, 223 working and 230 non-working children
      were interviewed. Their ages ranged between 8 and 15 years. Fifty-nine (13%)
      reported fever, 36 (8%) visual problems, 28 (6%) skin lesions, 17 (4%) muscular
      and joint pains and 5 (1%) diarrhoea. Schistosoma ova were observed in 25 (6%)
      children. There was no difference in the occurrence of diseases between working
      and non-working children. Twenty-seven per cent of the children were underweight
      and 30% were stunted. Malnutrition was more prevalent among working children as
      74 (33%) were underweight (p =0.001) and 76 (34%) were stunted. Public
      enlightenment about the effect of child labour might discourage parents from
      engaging their school-age children in work. Governments should address the socio
      economic factors that promote child labour.

PMID- 15186548
TI  - Gross motor skills of premature, very low-birthweight Chinese children.
AB  - We investigated whether premature, very low-birthweight (VLBW) Asian children
      without major handicap had poor motor skills compared with their normal
      birthweight counterparts. We compared a cohort of 42 preterm babies with
      birthweights <1500 g who participated in a developmental stimulation programme
      with 69 children of normal birthweight matched for age, gender and paternal
      education. VLBW children participated in the programme for 3 years and were
      followed to the age of 5-7 years. The VLBW cohort had significantly lower scores
      in B- and C-rated skills of the Peabody Developmental Motor Scales. Their total
      score was also significantly lower. This is in agreement with studies in other
      populations that found that VLBW children had lower motor scores and that early
      interventions failed to ameliorate this motor disadvantage.

PMID- 15186549
TI  - Hypernatraemic dehydration in exclusively breastfed neonates.

PMID- 15186550
TI  - Breastfeeding malnutrition and hypernatraemia: three severe cases that featured
      hyperglycaemia.

PMID- 15186551
TI  - Group B Streptococcus colonisation in obstetric cases in a tertiary care hospital
      in Delhi, India.

PMID- 15186552
TI  - Visceral leishmaniasis accompanied by subacute Epstein-Barr virus infection in a
      Turkish adolescent girl.

PMID- 15186553
TI  - Acute T-cell lymphoblastic leukaemia as a presenting finding of ataxia
      telangiectasia.

PMID- 15186554
TI  - Screening audiometry in a private primary school in Ilorin, Nigeria.

PMID- 15186557
TI  - Learning from abroad or policy tourism?

PMID- 15186558
TI  - Inequalities in access to care for patients with ischaemic heart disease.

PMID- 15186559
TI  - Hayfever--practical management issues.

PMID- 15186560
TI  - Questioning the claims from Kaiser.
AB  - BACKGROUND: The article by Feachem et al, published in the BMJ in 2002, claimed
      to show that, compared with the United Kingdom (UK) National Health Service
      (NHS), the Kaiser Permanente healthcare system in the United States (US) has
      similar healthcare costs per capita, and performance that is considerably better
      in certain respects. AIM: To assess the accuracy of Feachem et al's comparison
      and conclusions. METHOD: Detailed re-examination of the data and methods used and
      consideration of the 82 letters responding to the article. RESULTS: Analyses
      revealed four main areas in which Feachem et al's methodology was flawed.
      Firstly, the populations of patients served by Kaiser Permanente and by the NHS
      are fundamentally different. Kaiser's patients are mainly employed, significantly
      younger, and significantly less socially deprived and so are healthier. Feachem
      et al fail to adjust adequately for these factors. Secondly, Feachem et al have
      wrongly inflated NHS costs by omitting substantial user charges payable by Kaiser
      members for care, excluding the costs of marketing and administration, and
      deducting the surplus from Kaiser's costs while underestimating the capital
      charge element of the NHS budget and other costs. They also used two methods of
      converting currency, the currency rate and a health purchasing power parity
      conversion. This is double counting. Feachem et al reported that NHS costs were
      10% less per head than Kaiser. Correcting for the double currency conversion
      gives the NHS a 40% cost advantage such that per capita costs are 1161 dollars
      and 1951 dollars for the NHS and Kaiser, respectively. Thirdly, Feachem et al use
      non-standardised data for NHS bed days from the Organisation for Economic
      Cooperation and Development, rather than official Department of Health bed
      availability and activity statistics for England. Leaving aside the non
      comparability of the population and lack of standardisation of the data, the
      result is to inflate NHS acute bed use and underestimate the efficiency of
      performance by at least 10%. Similar criticisms apply to their selective use of
      performance measures. Finally, Feachem et al claim that Kaiser is a more
      integrated system than the NHS. The NHS provides health care to around 60 million
      people free at the point of delivery, long-term and psychiatric care, and
      continuing care after 100 days whereas Kaiser provides care to 6 million people,
      mainly employed and privately insured. Important functions, such as health
      protection, education and training of healthcare professionals, and research and
      development are not included or properly costed in Feachem et al's integrated
      model. CONCLUSION: We have re-examined the statements made by Feachem et al and
      show that the claims are unsupported by the evidence. The NHS is not similar to
      Kaiser in coverage, costs or performance.

PMID- 15186562
TI  - Influence of practices' ethnicity and deprivation on access to angiography: an
      ecological study.
AB  - BACKGROUND: Coronary heart disease is more common among some ethnic minority
      groups (particularly people from the Indian sub-continent living in Europe and
      North America) and in socially deprived populations. Hospital studies in the
      United Kingdom (UK) suggest that these groups have less access to treatment for
      coronary heart disease. Studies from primary care have found reduced access to
      angiography for lower social class groups, but there are no studies on the
      ethnicity of primary care populations in relation to angiography. AIMS: To
      determine the influence of ethnicity and social deprivation in primary care on
      access to coronary angiography. DESIGN OF STUDY: Ecological study measuring
      general practices' ethnicity, socioeconomic status, and nitrate prescribing rates
      with angiography rates. SETTING: General practices (n = 143) in East London, UK.
      METHOD: Ecological study measuring the proportion of general practice populations
      with South Asian ethnicity and high social deprivation score (Carstairs). Nitrate
      prescriptions and admissions for myocardial infarction per 1000 population per
      year were used as measures of need. Distance from the tertiary centre was used as
      a measure of supply. The outcome measure was coronary angiography procedures data
      (n = 869) collected in the context of the appropriateness of coronary
      revascularisation study. RESULTS: Practices with a higher proportion of South
      Asian patients had higher rates of angiography after adjustment for age,
      distance, deprivation, nitrate prescribing and myocardial infarction admissions
      (regression coefficient B = 0.02, 95% confidence interval [CI] = 0.01 to 0.03,
      P<0.001). There was no association between deprivation and angiography
      (regression coefficient B = -0.41, 95% CI = -0.13 to 0.05, P = 0.393).
      CONCLUSION: General practices with a higher proportion of South Asian patients
      had higher rates of angiography, challenging the widely held belief that access
      may be inequitable. Deprivation shows no relationship with angiography in this
      study.

PMID- 15186563
TI  - Management of patients with suspected angina, but without known myocardial
      infarction: a cross-sectional survey.
AB  - BACKGROUND: Although several studies describing the diagnostic and therapeutic
      management of patients with myocardial infarction (MI) by general practitioners
      have recently been published, little information exists about patients with
      angina without MI. AIM: To describe the management of patients with angina
      without known MI in general practice. DESIGN: A cross-sectional survey. SETTING:
      Italian general practitioners providing data to the Health Search Database.
      METHOD: Prevalent cases of angina, using the prescription of nitrates as a
      'proxy' for disease status, in patients without known MI were selected from the
      Health Search Database. Data on patient demographics, clinical information,
      established therapies and cardiology visits were collected. A binomial logistic
      regression analysis was performed to test which variable made prescription more
      or less likely. RESULTS: There were 10 455 patients with angina. Blood pressure
      readings were available for 73.8% of patients; in this group 58.9% had inadequate
      (> or = 140/90 mmHg) blood pressure control. Total cholesterol was recorded in
      61.6% of cases (mean value = 5.5 mmol/L). Antiplatelet or oral anticoagulant
      agents were used by 67.8% of the patients, while 24.1% of patients received lipid
      lowering agents, 61% received ACE-inhibitors or angiotensin-II receptor
      antagonists, and 25.2% received beta-blockers. CONCLUSIONS: In patients treated
      with nitrates the monitoring of modifiable risk factors and the use of preventive
      drugs is lower than expected. New strategies aimed at improving secondary
      cardiovascular prevention among these easily identifiable high-risk subjects are
      needed.

PMID- 15186564
TI  - An absence of evidence linking perceived memory problems to the menopause.
AB  - BACKGROUND: Little is known about the prevalence of subjective or perceived
      memory difficulties in the general population. This is of particular interest in
      the field of menopause as self-reported memory difficulties make up a large
      proportion of complaints by women presenting at specialist menopause clinics.
      There is also a general assumption that memory problems increase with age. AIM:
      To investigate the prevalence of perceived memory difficulties in women to
      establish whether there are variations with menopausal status and age. DESIGN OF
      STUDY: Cross-sectional questionnaire study. SETTING: Sheffield, United Kingdom.
      METHOD: Standardised questionnaires assessing subjective memory, mood and
      menopausal symptoms were sent to a random sample of 400 women, aged 25-64 years,
      identified from a general practice list. Menopausal status and demographic
      details were also recorded. Two hundred and two women responded, giving a
      response rate of 50.5%. RESULTS: The prevalence of perceived memory difficulties
      was low, and did not differ on the basis of menopausal status or age. Anxiety and
      depressive symptoms were the main significant predictors of perceived memory
      difficulties. CONCLUSION: Perceived memory difficulties are not specific to
      particular stages of the life cycle or age, but are experienced to a greater
      degree by those with high levels of depressive or anxiety symptoms.

PMID- 15186565
TI  - Co-ingestion of herbal medicines and warfarin.
AB  - BACKGROUND: A large proportion of patients use herbal remedies with a potential
      to interact with prescribed drugs. Such interactions can be dangerous,
      particularly if the therapeutic window of the prescribed drug is small, as with
      warfarin. AIMS: Our aim was to estimate the prevalence of the use of herbal
      medicines by patients taking warfarin (co-ingestion). DESIGN OF STUDY: Postal
      questionnaire. SETTING: General practices in the South West of England. METHOD:
      Thirty-five general practices in Devon and Somerset identified 2600 patients
      taking warfarin and sent postal questionnaires to them. RESULTS: One thousand,
      three hundred and sixty usable responses were received (response rate = 54.2%).
      One or more of the specified herbal remedies thought to interact with warfarin
      were taken by 8.8% of all patients. Complementary or homeopathic treatments not
      specified in the survey questionnaire were taken by 14.3% of responders. Overall,
      19.2% of responders were taking one or more such medicines. The use of herbal
      medicines had not been discussed with a conventional healthcare professional by
      92.2% of patients. Twenty-eight point three per cent of responders thought that
      herbal medicines might or definitely could interfere with other drugs prescribed
      by their doctor, however, patients taking any non-prescribed medication were less
      likely to believe this (chi2 = 20, degrees of freedom = 1, P<0.001). CONCLUSION:
      A substantial proportion of patients taking warfarin in southwest England self
      medicate with both herbal medicines that are thought to interact with warfarin
      and with others of unknown effect, usually without informing their healthcare
      team. Patients have a responsibility to mention such non-prescribed medication to
      their general practitioners, and general practitioners also have a responsibility
      to ask whether such co-ingestion is occurring.

PMID- 15186566
TI  - The use of lipid-lowering drugs across ethnic groups in the secondary prevention
      of ischaemic heart disease: analysis of cross-sectional surveys in England.
AB  - A secondary analysis of the Health Surveys for England data was performed to
      explore the use of lipid-lowering drug therapy in people with ischaemic heart
      disease (IHD) across ethnic groups. There were significant associations with age
      group, type of IHD, and housing tenure and the taking of lipid-lowering drugs.
      There was no significant association with ethnic group.

PMID- 15186567
TI  - Hepatitis B vaccination and injecting drug users.
AB  - This study seeks to test the feasibility of vaccinating injecting drug users for
      hepatitis B in primary care and to identify predictors of poor immune response.
      Two hundred and seventy-five injecting drug users were identified from the case
      notes of a large general practice in an area of high multiple deprivation in
      northwest Edinburgh and, where appropriate, offered hepatitis B vaccination
      followed by a post-vaccination serological test. We concluded that hepatitis B
      vaccination of drug users in primary care is both feasible and effective. This
      study was unable to identify a group at risk of vaccine failure, however, it
      found post-vaccination serological testing to be problematic and potentially
      misleading. Therefore, we would not recommend its routine use in a primary care
      setting. Significantly, prolonged primary courses were not associated with
      reduced efficacy. The findings indicate that an appropriate vaccination schedule
      for primary care should be flexible to maximise compliance.

PMID- 15186568
TI  - The use of infrared thermometry for the detection of fever.
AB  - The use of tympanic thermometry is attractive in primary care, but a recent
      systematic review highlighted the paucity of data comparing tympanic thermometry
      with conventional methods. We report a study of 94 preschool children presenting
      to primary care in the United Kingdom (UK) with acute cough in whom tympanic
      infrared and axillary mercury thermometry are compared. Infrared thermometry
      showed poor agreement, poor sensitivity and high specificity. Infrared
      thermometry is too insensitive to be used as a screening test for fever, but when
      fever is already suspected, for example by touch, it may be useful as a 'rule in'
      test.

PMID- 15186569
TI  - Topical treatments for seasonal allergic conjunctivitis: systematic review and
      meta-analysis of efficacy and effectiveness.
AB  - BACKGROUND: Evidence for the effectiveness of topical treatments, in providing
      symptomatic relief from ocular allergy, remains uncertain. AIMS: To assess the
      effectiveness and relative efficacy of topical treatments for the management of
      seasonal allergic conjunctivitis. DESIGN OF STUDY: A systematic review and meta
      analysis. SETTING: A literature search of the Cochrane Library, Medline, and
      EMBASE bibliographic databases. METHOD: Double-masked randomised controlled
      trials were identified, that compared the use of topical mast cell stabilisers
      (sodium cromoglycate, nedocromil, lodoxamide) with placebo, topical
      antihistamines with placebo, and topical mast cell stabilisers with topical
      antihistamines. RESULTS: A meta-analysis of six trials showed that patients using
      sodium cromoglycate were 17 times (95% confidence interval [CI] = 4 to 78) more
      likely to perceive benefit compared with those using a placebo, although this
      estimate may be partially influenced by publication bias. Five trials indicated
      that those patients using nedocromil were 1.8 times (95% CI = 1.3 to 2.6) more
      likely to perceive their allergy to be moderately or totally controlled than
      those using a placebo. Four trials showed that those using antihistamines were
      1.3 times (95% CI = 0.8 to 2.2) more likely to perceive a 'good' treatment effect
      than those using mast cell stabilisers, although this beneficial effect was not
      statistically significant. Limited evidence suggests that antihistamines might
      have a faster therapeutic effect compared to mast cell stabilisers. CONCLUSION:
      Overall, these findings confirm the benefit of topical mast cell stabilisers and
      antihistamines over placebo for the treatment of allergic conjunctivitis. There
      is, however, insufficient evidence to recommend the use of one type of medication
      over another. Treatment preferences should therefore be based on convenience of
      use (with reduced frequency of instillation for some preparations), patient
      preference, and costs, especially as important side effects were not reported
      with any medication.

PMID- 15186571
TI  - Non-urgent breast referrals subsequently diagnosed with cancer.

PMID- 15186572
TI  - Training threatened by its own success.

PMID- 15186570
TI  - Rheumatology and musculoskeletal medicine.
AB  - Musculoskeletal disease accounts for a large proportion of a general
      practitioner's (GP's) workload. Proper management can not only improve quality of
      care, but also increase job satisfaction and reap rewards under the new contract.
      Osteoporosis creates a huge socioeconomic burden of disease and disability.
      Identifying high-risk groups in primary care and using preventative treatment can
      result in a substantial reduction in morbidity and mortality. GPs can help by
      presenting a unified lifestyle message, advising on fall prevention, and
      providing effective treatment; in particular, calcium and vitamin D for female
      nursing home residents. Osteoarthritis is eminently treatable in primary care
      with a number of management options for GPs, in addition to drug therapy.
      Glucosamine and chondroitin have few side effects and are worth recommending to
      patients with mild knee osteoarthritis. Rheumatoid arthritis can cause
      significant disability, which can be limited by early diagnosis, referral, and
      treatment. Severe refractory rheumatoid arthritis may warrant referral for
      consideration of biologic therapy. Assessment of the cardiovascular risk and
      possible use of statins in rheumatoid patients may reduce their cardiovascular
      mortality. GPs should aim to help patients to achieve optimum quality of life by
      using a holistic approach and by allowing maximum choice and control over their
      disease.

PMID- 15186574
TI  - Through a glass darkly.

PMID- 15186575
TI  - Evidence-based management?

PMID- 15186577
TI  - Critical appraisal of commonly used treatment for genital warts.
AB  - Genital warts are one of the most commonly reported sexually transmitted diseases
      worldwide. A variety of treatment options are available but few have been
      assessed in large-scale, randomized, placebo-controlled trials. Provider-applied
      surgical and non-surgical treatments have traditionally been the therapies of
      choice. Surgical therapies, including cryotherapy, electrotherapy, laser surgery
      and surgical excision, are generally equivalent in terms of wart clearance rates,
      but are associated with high rates of wart recurrence. Trichloroacetic acid is a
      widely used non-surgical therapy, but little is known about its efficacy, and it
      is associated with unpleasant side-effects. The patient-applied treatments
      imiquimod and podophyllotoxin are newer therapy choices which are more acceptable
      to both patients and practitioners. The wart clearance rates for these two
      treatments are similar, although imiquimod is associated with lower recurrence
      rates. In the face of increasing pressures on genitourinary clinic services,
      patient-applied home therapy represents an attractive option for the treatment of
      genital warts.

PMID- 15186579
TI  - Genital syndromes and syndromic management of vaginal discharge in a community
      setting.
AB  - The objective of the study was to determine the community prevalence of genital
      syndromes in women and evaluate the syndromic management of vaginal discharge in
      this setting. A representative sample for the state of Tamilnadu was chosen using
      probability proportional to size cluster technique. Thirty clusters were selected
      from three districts. Demographic, sexual behaviour, risk factors, clinical and
      laboratory data were collected from the selected population using a structured
      questionnaire. Direct smear examination for Trichomonas vaginalis, culture for
      Neisseria gonorrhoeae and Haemophilus ducreyi, serological tests for syphilis
      (RPR and TPHA), hepatitis B (Hbs Ag ELISA), IgM and IgG antibodies to HSV2 (Novum
      diagnostics, Germany) and PCR test for detection of C. trachomatis from urine
      were done. There were 1157 women in the selected population. On examination,
      vaginal discharge was the most common genital syndrome (38.4%). The sensitivity,
      specificity, positive and negative predictive value of vaginal discharge as a
      marker for STD in women was found to be 43.3%, 61.6%, 10.7% and 91.1%,
      respectively. We concluded that treatment on the basis of syndromic management
      would result in over-treatment of 90% of women with vaginal discharge.

PMID- 15186580
TI  - Marginal validity of syndromic management for reproductive tract infections among
      pregnant women in Jamaica.
AB  - We assessed the validity of a syndromic case management approach for reproductive
      tract infections (RTIs) among 371 pregnant women attending antenatal care
      facilities in Kingston, Jamaica, using an algorithm previously validated in high
      risk Jamaican women. For our antenatal attenders, the algorithm had low
      sensitivities for all RTIs (66.7% for cervicitis, 35.4% for trichomoniasis, 11.1%
      for bacterial vaginosis (BV) and 24% for candidiasis). Specificities for BV
      (88.9%) and candidiasis (81.1%) were higher than for cervicitis (62.8%) and
      trichomoniasis (68.5%). The positive predictive values were lower than 36% for
      all diagnoses, especially BV (6.9%). Syndromic management of RTIs in pregnant
      women was problematic using a clinical algorithm that had worked well for high
      risk women. Syndromic management for RTIs in Jamaican antenatal clinics is only a
      temporary solution until more simple and affordable diagnostic tests for RTIs are
      developed and/or until laboratory support and clinical care can be upgraded at
      antenatal clinics.

PMID- 15186581
TI  - Is telephone follow-up as good as traditional clinic follow-up in achieving the
      proposed national outcome standards for chlamydia management?
AB  - A retrospective review of 400 cases of genital chlamydia managed with a
      traditional clinic follow-up was compared to 400 cases with a telephone follow-up
      appointment. We satisfactorily treated more patients with the telephone follow-up
      appointment than with a traditional clinic follow-up (204 [51%] vs 121 [30%]; P
      <0.0001). We also satisfactorily treated more partners with the telephone follow
      up system than a traditional clinic appointment system (0.57 vs 0.45 contacts per
      case; P =0.0006). The introduction of the telephone follow-up appointment system
      in the clinic increased the number of patients and contacts of patients
      successfully managed for genital chlamydial infection. Our findings should lead
      to increased research and adoption of different methods of follow-up and help
      develop proper outcome standards.

PMID- 15186582
TI  - Client perspectives on sexual health service provision.
AB  - Development of integrated genitourinary medicine (GUM) and family planning (FP)
      services must take into account the views and requirements of service users. As
      we strive to modernize sexual health services, various changes are being
      introduced, such as a policy of no microscopy for selected patients attending GUM
      clinics. In order to determine the views of our clients prior to implementation
      of change, we performed a qualitative study in our UK centre, which houses both
      FP and GUM. One hundred women presenting to FP and 100 to GUM were interviewed.
      In addition, we collected details of their characteristics to identify any
      significant differences in users attending each clinic. A summary of their views
      and characteristics is presented. Although near-patient testing results in a
      longer time spent in clinic, 99% of participants expressed a preference for
      immediate microscopy results and treatment. GUM and FP clients exhibited many
      similar characteristics.

PMID- 15186583
TI  - Genotypic resistance testing in HIV-infected pregnant women in an urban setting.
AB  - This study examines the utility of HIV genotypic resistance testing (GT) in
      pregnant women at their initial pregnancy evaluation. A retrospective medical
      record review of 50 consecutive HIV-infected pregnant women in whom GT was
      obtained in the Bronx, New York was conducted. Twenty-eight (56%) were
      antiretroviral experienced, including 12 on antiretroviral therapy (ART) at time
      of GT. Major mutations were found in 11 (24%) of 45 amplifiable GTs. Major
      resistance mutations were identified against nucleoside reverse transcriptase
      inhibitors (NRTIs) in six (13%) patients; against non-nucleoside reverse
      transcriptase inhibitors (NNRTIs) in eight (18%) patients, and against protease
      inhibitors in two (4%) patients. Duration of ART exposure was significantly
      associated with identification of resistance mutations by GT for NRTIs and NNRTIs
      (P < or =0.05). Results of this study indicate that GT at presentation may have
      implications on the initial choice of ART in up to one-quarter of HIV-infected
      pregnant women, especially with current or prior antiretroviral use.

PMID- 15186584
TI  - Quality of primary care for sexually transmitted diseases in Durban, South
      Africa: influences of patient, nurse, organizational and socioeconomic
      characteristics.
AB  - Quality of sexually transmitted disease (STD) primary care in South Africa varies
      widely but reasons for this are poorly understood. We investigated 37 randomly
      sampled clinics providing STD care, with simulated patients, and staff interviews
      and record review. Census data provided local socioeconomic indicators. Multiple
      regression identified independent predictors of quality. Of 271 simulated patient
      visits, 79% were correctly treated and 39% were correctly managed. Women received
      worse care, and care tended to be poorer in mainly African and mainly coloured
      (mixed race) areas. African and Indian nurses were more likely to provide correct
      treatment. Previous STD training was marginally associated with correct
      treatment. Quality assessments using simulated patients were not generally
      associated with assessments using staff interviews and record review. There were
      frequent missed opportunities for STD prevention and treatment, and evidence of
      racial but not socioeconomic inequalities.

PMID- 15186585
TI  - Epidemiology of HIV infection in urban Burkina Faso.
AB  - We conducted a cross-sectional study of sexually transmitted disease and HIV
      infections among a random sample of the 2364 adult population in 2000 in Bobo
      Dioulasso, the second largest town in Burkina Faso. The prevalence of HIV
      infection was 5.2%. Risk factor analysis was conducted among sexually active men
      20 to 34 years old and women 15 to 24 years old. Factors independently associated
      with HIV infection among men were having been married (adjusted odds ratio
      (aOR)=8.19 [1.70-39]), reporting more than two non-marital partners in the last
      12 months (aOR=6.07 [1.14-32.4]), reporting a past urban residence other than
      Bobo-Dioulasso (aOR =6.37 [1.96-20.7] and having a positive serology for HSV-2
      infection (aOR=12.0 [3.49-40.9]). Among women the factors were being Christian
      (aOR=3.73 [1.20-11.6]), having had a first sexual partner more than 24 years old
      (aOR =4.30 [1.35-13.6]) and having a positive serology for HSV-2 infection (aOR
      =4.40 [1.32-14.6]). HIV infection in Bobo-Dioulasso therefore depends on both
      exposure factors (sexual behaviours) and transmissibility cofactors (HSV-2).

PMID- 15186586
TI  - Condom use in multi-partnered females.
AB  - Many women attending sexual health clinics have multiple partners, and
      determining factors associated with condom use may provide useful information for
      health promotion strategies. Demographic and sexual data were obtained from
      computerized records at the Sydney Sexual Health Centre from 1991 to 1999.
      Females with >2 partners were categorized according to their condom use in the
      last three months and compared using chi-squared (chi2) tests and logistic
      regression. Of the 2198 women identified, 22% did not use condoms, 28% reported
      consistent condom use and 50% inconsistent use. Variables independently
      associated with failure to use condoms included older age and being in a regular
      relationship. Women with more partners were more likely to use condoms. Students
      [odds ratio (OR)=0.7 (95% confidence interval (CI) 0.5-0.9)] and those in
      employment [OR=0.7 (95% CI 0.5-0.9)] were more likely to use condoms than the
      unemployed. Focusing health promotion on multi-partnered women who fail to use
      condoms consistently may help in reducing sexually transmitted infections.

PMID- 15186587
TI  - Prevalence and risk factors of asymptomatic chlamydial infection among students
      in Japan.
AB  - The objective was to determine the prevalence of asymptomatic Chlamydia
      trachomatis infection (CTI) among students in Japan, and to examine risk factors
      and methods of prevention. A total of 1004 students were analysed. Urine samples
      were checked for chlamydial DNA using polymerase chain reaction techniques.
      Prevalence of CTI was 8.3%. Risk factors were age and a history of four or more
      sexual partners for females, and history of CTI and contact with new sexual
      partners for males. Age did not represent a risk factor for male students. A
      correlation was identified between history of genital infection and experience
      with commercial sex workers for male students. Sex education programmes should be
      implemented encouraging use of condoms not only by students over 18 years, but
      also by senior high school students. Development of efficient and practical
      screening systems tailored to the current status of school health management in
      Japan is also needed.

PMID- 15186588
TI  - Partner notification: preferences of Melbourne clients and the estimated
      proportion of sexual partners they can contact.
AB  - This study was conducted to determine the estimated proportion of contactable
      sexual partners, the most common types of contact information available and the
      most acceptable contact tracing strategies for our clients. Five hundred 'walk
      in' clients completed a questionnaire about their total number of sexual
      partners, the proportion of contactable partners and available contact
      information. Women had the highest estimated number of contactable partners (89
      94%), men who have sex with men had the lowest (51-73%). The preferred contact
      tracing strategy was to give partners a website address (76%) and the least
      preferred was provider referral (33%). There was a difference in the type of
      information available for contacting sexual partners (P <0.001); most commonly
      clients reported partners contactable by phone or face to face and least commonly
      through a third person. The currently used method (doctor's letter) is not the
      preferred choice of these clients and more innovative methods using recent
      technology may prove more effective.

PMID- 15186589
TI  - HIV-1 cord-blood seroprevalence of parturient women in Sihanoukville, Cambodia.
AB  - Facing a 1.2% HIV-1 seroprevalence amongst its adult female population, Cambodia
      recently established national guidelines for the expansion of services to prevent
      mother-to-child transmission. Anticipating this expansion, Sihanoukville Hospital
      performed an anonymous HIV-1 cord-blood serosurvey of 600 consecutive deliveries
      from May 2001 through June 2002. Laboratory analysis utilizing ELISA and Western
      blot techniques yielded a 4.2% seroprevalence; a value resembling previous
      reports from other Sihanoukville antenatal clinics (3.9%) but exceeding the
      national ANC clinic average of 2.3%. Demographic information was confidentially
      collected and analysed for co-variation to HIV-1 status. One hundred percent of
      HIV positive mothers (P =0.013) self-reported the occupation of housewife,
      consistent with previous documentations suggesting the shift in infection burden
      from high-risk groups into the general female population. A substantial
      proportion received no prenatal care, suggesting that interventions addressing
      mother-to-child transmission will need to prepare for the management of pregnant
      women presenting at or near the time of delivery.

PMID- 15186590
TI  - Impact of information leaflets on HIV test uptake amongst GUM clinic attendees:
      an update.
AB  - In the Sexual Health Strategy, the targets of HIV testing uptake in genitourinary
      medicine clinics (GUM) are set at 40% by year 2004 and 60% by 2007. We assessed
      the uptake of HIV test amongst GUM clinic attendees, more than six months after
      introducing an information leaflet in place of verbal pre-test counselling (PTC).
      The uptake rate was significantly higher than in a previous audit conducted in
      the same year, two weeks after introduction of the leaflets (62% vs 50%, P
      =0.001).

PMID- 15186591
TI  - Cocaine-induced penile necrosis.

PMID- 15186592
TI  - HIV test, counselling and gypsies!

PMID- 15186593
TI  - Radioimmunotherapy of human colon carcinoma xenografts using a 213Bi-labeled
      domain-deleted humanized monoclonal antibody.
AB  - The data presented within this paper is the first report of a humanized domain
      deleted monoclonal antibody (HuCC49DeltaCH2) to be utilized in a
      radioimmunotherapeutic (RIT) application with 213Bi. An initial study indicated
      that 111In-HuCC49DeltaCH2 targets the subcutaneously implanted human colon
      carcinoma xenograft, LS-174T, when injected via a peritoneal route. The
      HuCC49DeltaCH2 was then radiolabeled with 213Bi, an alpha-emitting radionuclide
      with a half-life of 45.6 minutes, and evaluated for therapeutic efficacy. Dose
      titration studies indicated that a single dose of 500-1000 microCi, when injected
      by an intraperitoneal route, resulted in the growth inhibition or regression of
      the tumor xenograft. The radioimmunotherapeutic effect was found to be dose
      dependent. Specificity of the therapeutic efficacy was confirmed in a subsequent
      experiment with athymic mice bearing TAG-72 negative MIP (human colorectal)
      xenografts. A preliminary study was also performed to assess a multiple-dose
      administration of 213Bi-HuCC49DeltaCH2. Doses (500 microCi) were administered at
      14-day intervals after tumor implantation. A reduction in volume and/or delay in
      tumor growth was evident following the second and third injections of 213Bi
      HuCC49DeltaCH2. As further validation of the use of 213Bi-HuCC49DeltaCH2 for RIT,
      a study using 131I was conducted. The overall survival of mice receiving 213Bi
      HuCC49DeltaCH2 was greater than those that received 131I-HuCC49DeltaCH2.

PMID- 15186594
TI  - Role of 18F-FDG PET for evaluating malignant pleural mesothelioma.
AB  - Malignant Pleural Mesothelioma (MPM) is a relatively rare neoplasia characterized
      by a poor prognosis. Recent studies show that new therapeutic approaches can lead
      to an improvement in life quality and to a prolonged survival; therefore, proper
      evaluation of MPM before, as well as after, therapy, is needed. The aim of this
      study was to evaluate the impact of 18F-FDG photon emission tomography (PET) scan
      compared to computed tomography (CT) findings in patients affected by MPM,
      whether untreated or already treated. We studied 15 consecutive patients (13 male
      and 2 female) with a histological diagnosis of MPM, with a mean age of 69.9 years
      (range: 38-78 years old) and a recent total-body CT scan. Five (5) patients were
      studied for staging, while 10 patients were studied after therapy. An FDG PET
      scan was carried out 60 minutes after an intravenous (i.v.) injection of 370 MBq
      of 18F-FDG. For each patient, we compared the PET stage to the CT stage, and
      evaluated the role of PET in choosing a therapeutic approach. In 9 of 15 (60%)
      patients, there was no difference between the PET and the CT stage. In 2 of 15
      (13%) patients, PET upstaged the disease, while in 4 of 15 (27%) patients PET
      downstaged MPM. According to these results, patient management was changed in 3
      cases. Specifically, 1 patient was excluded from surgery, and 2 patients had
      different chemotherapy. These data suggest that PET is useful in the evaluation
      of MPM, giving additional data that can clarify doubtful CT findings, especially
      regarding lymph node involvement and distant lesions. In conclusion, FDG PET was
      found to play a worth-while role in patient management.

PMID- 15186595
TI  - PET radioimmunoscintigraphy of renal cell cancer using 89Zr-labeled cG250
      monoclonal antibody in nude rats.
AB  - INTRODUCTION: With the introduction of positron-emitting radionuclides with half
      lifes in days, such as 89Zr and 124I, radioimmunoscintigraphy (RIS) with positron
      emitter-labeled monoclonal antibodies (moAbs) becomes feasible. RIS, using
      positron emission tomography (immuno-PET), combines the specific localization of
      an antibody with the high resolution of a PET camera. In the present study,
      scintigraphic tumor imaging using chimeric moAb G250 labeled with 89Zr (immuno
      PET) or 111In (RIS), and [18F]FDG-(PET) was explored in rats with s.c. renal cell
      carcinoma (RCC) tumors. METHODS: Nude rats (6-8 rats per group) with s.c. SK-RC
      52 tumors were i.v. injected with 4 MBq 111InDTPA-cG250, 20 MBq 89Zr-Df-cG250 or
      4 MBq [18F]FDG. Planar 111In-DTPA-cG250 images were obtained 5 minutes, and 24,
      48, and 72 hours postinjection (p.i.). 3D PET imaging was performed 5 minutes,
      and 24, 48, and 72 hours after a 89Zr-Df-cG250 injection and 1 hour after a
      [18F]FDG injection using a Siemens ECAT EXACT PET camera. Rats were killed after
      the last imaging session, and the uptake of the radiolabel in the dissected
      tissues was determined. RESULTS: Both radiolabeled antibody preparations were
      stable during 4 days of incubation in serum at 37 degrees C, and the
      immunoreactivity was preserved. Two (2) days after injection, s.c. tumors (100
      mg) were clearly visualized, both with 89Zr-Df-cG250 and 111In-DTPA-cG250. Tumors
      were not visualized with [18F]FDG (uptake in tumor of 0.5 +/- 0.1 %ID/g, 1 hour
      p.i.). The biodistribution experiments showed an identical uptake in the tumor
      for both 89Zr-Df-cG250 and 111In-DTPA-cG250 at 3 days p.i. (5.0 +/- 2.4 and 4.9
      +/- 2.9 %ID/g, respectively). Blood levels at 3 days p.i. were also identical
      (1.4 +/- 0.4 versus 1.7 +/- 0.7 %ID/g), and no significant differences were found
      in the biodistribution of normal tissues between the two radiolabeled cG250
      preparations. CONCLUSION: The cG250 antibody can be stably labeled with the
      positron-emitter 89Zr, while preserving the immunoreactivity of the moAb. In this
      rat model, the in vivo biodistribution of 89Zr-Df-cG250 was identical to that of
      111In-DTPA-cG250. Immuno-PET of RCC is feasible with 89Zr-cG250, and relatively
      small tumors could be visualized, even without a dedicated PET camera for small
      animals.

PMID- 15186596
TI  - Functional imaging of multidrug resistant phenotype by 99mTc-MIBI scan in
      patients with multiple myeloma.
AB  - Overexpression of P-glycoprotein (Pgp) is one of the primary mechanisms of
      multidrug resistance (MDR) in several diseases, including multiple myeloma. The
      aim of this study was to investigate whether the washout of 99mTc-MIBI, a
      transport substrate of Pgp, is enhanced in the bone marrow of patients with
      multiple myeloma overexpressing Pgp. Seventeen (17) patients were i.v. injected
      with 555 MBq of 99mTc-MIBI, and whole-body scans were performed at 10 and 60
      minutes. A region of interest (ROI) was drawn over the thoracic spine of each
      scan, and the washout of 99mTc-MIBI was calculated, after decay correction, as:
      (10-minute counts/pixel minus 60-minute counts/pixel) divided by 10-minute
      counts/pixel. Pgp expression was determined in 17 bone marrow samples obtained
      from the same patients immediately before the 99mTc-MIBI scan. Following
      centrifugation over the Ficoll-Hypaque gradient, cytospins were obtained and
      immunostained with C219 monoclonal antibody. The immunostaining of Pgp was graded
      as 1, 2, or 3 when a faint, moderate, or intense reaction, respectively, was
      observed in infiltrating plasma cells. Washout of 99mTc-MIBI ranged between 5%
      and 26%. A statistically significant direct correlation was found between the
      washout of the tracer and Pgp expression (Spearman rank correlation coefficient r
      = 0.74, p < 0.001). A partial overlap of washout values was observed in different
      classes of Pgp expression, thus preventing the discrimination of individual
      patients. Washout of 99mTc-MIBI, expressed as the percentage of radioactivity
      cleared from the bone marrow over a 1-hour period, may be used as a noninvasive
      tool for in vivo whole-body imaging of Pgp expression and function in multiple
      myeloma patients.

PMID- 15186597
TI  - Radiolabeled RGD-DTPA-Tyr3-octreotate for receptor-targeted radionuclide therapy.
AB  - The aim of this study was to develop and investigate a radiopeptide for the
      treatment of cancers which overexpress cell surface somatostatin receptors. The
      new radiopharmaceutical is composed of a somatostatin receptor-targeting peptide,
      a chelator (DTPA) to enable radiolabeling, and an apoptosis-inducing RGD
      (arginine-glycine-aspartate) peptide moiety. The receptor-targeting peptide
      portion of the molecule, Tyr3-octreotate, is specific for the somatostatin
      subtype-2 cell surface receptor (sst2), which is overexpressed on many tumor
      cells. Because of the rapid endocytosis of the somatostatin receptor, the entire
      molecule can thus be internalized, allowing the RGD portion to activate
      intracellular caspases, which in turn promotes apoptosis. In this paper, we
      present the synthesis and the in vitro and in vivo tumor binding and
      internalization characteristics of this hybrid peptide. In vitro internalization
      into sst2-positive tumor cells of the radiolabeled hybrid peptide appeared to be
      a rapid process and could be blocked by an excess of unlabeled octreotide,
      indicating an sst2-specific process. Tumor uptake in vivo in rats of radiolabeled
      RGD-DTPA-Tyr3-octreotate was in agreein vitro data and similar to that of
      radiolabeled DOTA-Tyr3-octreotate. The combined molecule is expected to
      significantly enhance the therapeutic efficacy of the somatostatin-based agent.

PMID- 15186598
TI  - Improving the tumor uptake of 99mTc-labeled neuropeptides using stabilized
      peptide analogues.
AB  - Two neuropeptides, bombesin (BBS) and neurotensin (NT) and their radiolabeled
      analogues, have great potential for tumour targeting, either for diagnosis (e.g.,
      with 99mTc) or therapy (e.g., with 90Y or 188Re). In this study, we investigated
      NT(8-13) and BBS(7-14) analogues with Nalpha-histidinyl acetate linked to the N
      terminus of the peptide. This His-derivative forms a stable and inert tridentate
      complex with the 99mTc(CO)3 and the 188Re(CO)3 moieties. The stability of 99mTc
      labeled neurotensin and bombesin analogues was tested in human plasma samples and
      in tumour cell cultures in the presence and absence of specific enzyme
      inhibitors. The inhibitor of ACE (angiotensin converting enzyme) was the most
      effective in inhibiting the peptide cleavage of both NT(8-13) and BBS(7-14). In
      agreement with this finding, the replacement of Ile12 by tert-leucine (NT) and
      Leu13 by cyclohexylalanin (BBS) brought about a better stability. With NT(8-13)
      analogues, higher tumour to nontarget (t/nt) ratios and the same affinity to the
      receptor was observed, but with BBS(7-14) derivatives the affinity was lower and
      the t/nt ratio was not significantly improved. Toxicity tests showed no effect in
      mice of up to a five-hundred-fold higher dose than planned for patient
      application, which started successfully with NT(8-13) analogues.

PMID- 15186599
TI  - Radiolabeled annexin-V for monitoring treatment response in oncology.
AB  - Because of its potential to allow for noninvasive, repetitive, and selective in
      vivo identification of the site and extent of apoptotic cell death and for
      monitoring cell death kinetics without the need for invasive biopsy, radiolabeled
      annexin-V is of major clinical relevance. This paper reviews available
      preclinical and clinical data on radiolabeled annexin-V pertaining to the domain
      of monitoring response to radiotherapy and chemotherapy, focusing especially on
      advantages and drawbacks of the different labeling procedures for the
      radiolabeling of annexin-V.

PMID- 15186600
TI  - [177Lu]Bz-DTPA-EGF: Preclinical characterization of a potential radionuclide
      targeting agent against glioma.
AB  - Patients with glioblastoma multiforme have a poor prognosis due to recurrences
      originating from spread cells. The use of radionuclide targeting might increase
      the chance of inactivating single tumor cells with minimal damage to surrounding
      healthy tissue. As a target, overexpressed epidermal growth factor receptors
      (EGFR) may be used. A natural ligand to EGFR, the epidermal growth factor (EGF)
      is an attractive targeting agent due to its low molecular weight (6 kDa) and high
      affinity for EGFR. 177Lu (T(1/2) = 6.7 days) is a radionuclide well suited for
      treatment of small tumor cell clusters, since it emits relatively low-energy beta
      particles. The goal of this study was to prepare and preclinically evaluate both
      in vitro and in vivo the [177Lu]Bz-DTPA-EGF conjugate. The conjugate was
      characterized in vitro for its cell-binding properties, and in vivo for its
      pharmacokinetics and ability to target EGFR. [177Lu]Bz-DTPA-EGF bound to cultured
      U343 glioblastoma cells with an affinity of 1.9 nM. Interaction with EGFR led to
      rapid internalization, and more than 70% of the cell-associated radioactivity was
      internalized after 30 minutes of incubation. The retention of radioactivity was
      good, with more than 65% of the 177Lu still cell-associated after 2 days.
      Biodistribution studies of i.v. injected [177Lu]Bz-DTPA-EGF in NMRI mice
      demonstrated a rapid blood clearance. Most of the radioactivity was found in the
      liver and kidneys. The liver uptake was receptor-mediated, since it could be
      significantly reduced by preinjection of unlabeled EGF. In conclusion, [177Lu]Bz
      DTPA-EGF seems to be a promising candidate for locoregional treatment of
      glioblastoma due to its high binding affinity, low molecular weight, and ability
      to target EGFR in vivo.

PMID- 15186601
TI  - Intraobserver, interobserver, and day-to-day reproducibility of quantitative
      99mTc-HYNIC annexin-V imaging in head and neck carcinoma.
AB  - RATIONALE: For clinical application, a sufficient reproducibility of 99mTc-HYNIC
      annexin-V quantitative uptake measurements must be demonstrated to allow a study
      of cell-death changes induced by chemotherapy over time and intersubject. Thus,
      the aim of this study was to estimate the intra-, inter-, and day-to-day
      reproducibility of quantitative 99mTc-HYNIC annexin-V tumor uptake values in
      patients suffering from head and neck carcinomas. METHODS: Thirteen (13) patients
      suffering from clinically suspected, histologically confirmed squamous head and
      neck carcinomas were prospectively included in the study. All patients were
      scheduled to undergo a spiral computed tomography scan and two 99mTc-HYNIC
      annexin-V scintigraphies within 3-5 days from each other, referred to as day 1
      and day 2 of scintigraphy. The percentage of uptake of the injected dose of 99mTc
      HYNIC annexin-V in tumor lesions on scintigrams divided by the tumor volume, as
      derived from CT, was determined twice within an interval of 2 weeks by observer 1
      and once by observer 2 on day 1 of scintigraphy and once on day 2 of scintigraphy
      by observer 1. RESULTS: The mean of the difference for the intra-, inter-, and
      day-to-day measurements were -3.4%, 2.4%, and -6%, respectively. No systematic
      bias was observed for the mean of the differences for the intra-, inter-, and day
      to-day measurements. The respective confidence intervals for the mean of the
      differences of intra-, inter-, and day-to-day variability were -8.2%-1.4%, -2.9%
      7.8%, and -14.7%-2.7%. CONCLUSION: The reproducibility of quantitative 99mTc
      HYNIC annexin-V tumor uptake measurements using a manual method appears to be
      acceptable for clinical use.

PMID- 15186602
TI  - 99mTc-EDDA/HYNIC-TOC in the management of medullary thyroid carcinoma.
AB  - An early diagnosis of distant metastases or local recurrences of medullary
      thyroid carcinoma (MTC) can be achieved by several conventional radiological
      modalities (e.g., ultrasonography, computed tomography [CT], and magnetic
      resonance imaging [MRI] as well as by radioisotopic procedures, such as positron
      emission tomography (PET), scintigraphy with different types of
      radiopharmaceuticals, and radiolabeled receptor-ligands in particular. The aim of
      this study was to evaluate the clinical utility of 99mTc-EDDA/HYNIC-TOC, a new
      octreotide derivative, to detect recurrences of disease or distant metastases in
      MTC. Images obtained of 5 patients with high levels of serum calcitonin were
      compared to findings obtained with other diagnostic procedures: 111In-octreotide,
      99mTc-DMSA-V, 18F-flouro-D-deoxyglucose-PET, and CT/MRI. 99mTc-EDDA/HYNIC-TOC was
      positive in all patients and showed 15 areas of pathological uptake in the
      cervical and mediastinal regions. 111In-octreotide was positive in 3 of 3
      patients and showed 4 areas, compared to 8 of 99mTc-EDDA/HYNIC-TOC. 99mTc-V-DMSA
      was positive in 3 of 4 patients but showed 6 pathological areas, compared to 13
      of 99mTc-EDDA/HYNIC-TOC. 18F-FDG-PET was positive in 5 of 5 patients but showed
      only 11 areas, compared to 15 of 99mTc-EDDA/HYNIC-TOC. The CT scan was positive
      in only 2 patients. In conclusion, 99mTc-EDDA/HYNIC-TOC detected more sites of
      pathological uptake than other modalities, showed better imaging properties than
      111In-octreotide, and might be the radiopharmaceutical of choice for providing a
      rationale for radioisotopic therapy.

PMID- 15186603
TI  - Gastrin-releasing peptide (GRP) analogues for cancer imaging.
AB  - Small neuropeptides, labeled with gamma- and/or beta-emitting radionuclides, are
      currently being investigated for their ability to bind to cell-surface receptors,
      overexpressed in a wide variety of malignant tissues being, thus, potentially
      useful for radionuclide detection and/or therapy for tumors. Particular attention
      has been focused on the amphibian peptide, bombesin (BN), and the molecularly
      related gastrin-releasing peptide (GRP). These peptides act as neurotransmitters
      and endocrine cancer cell-growth factors on normal tissues as well as on
      neoplastic cells of various origin. In recent investigations, modification of the
      native peptide structure has been attempted in order to obtain derivatives, which
      might easily be labeled with radionuclides. Thus, iodinated (I-125) BN
      derivatives, as well as Indium (In-111) labeled BN analogs are currently being
      investigated, presenting satisfactory tumor localization. Also, some new BN
      analogs containing a 6-carbon linker have been prepared and labeled with Rhenium
      188, resulting in positive in vitro binding to prostate cancer cells. More recent
      studies refer to the Technetium-99m labeling of BN, performed either directly,
      after attaching proper technetium-chelating groups onto the BN sequence, or
      indirectly, by coupling BN to a preformed 99mTc-tagging ligand. Both types of
      conjugates were found to have a high in vitro affinity for cells with BN
      receptors, also presenting satisfactory in vivo uptake in experimental tumor
      models. Pilot clinical studies of a new BN-derived, 99mTc-labeled
      pentadecapeptide indicated significant uptake by breast cancer and invaded lymph
      nodes, as well as by prostate cancer, small-cell lung carcinoma, gastro-entero
      pancreatic tumors, and others, Further studies of this new GRP derivative, as
      well as of other new BN-like peptides, are intensively performed internationally
      today.

PMID- 15186604
TI  - Radiolabeled carbohydrated somatostatin analogs: a review of the current status.
AB  - During the last decade, peptide radiopharmaceuticals have become an important
      class of tracers for the detection and localization of malignant neoplasms by
      peptide receptor imaging (PRI) and for therapeutic intervention by peptide
      receptor radiotherapy (PRRT). Various radiometalated peptides have entered
      detailed clinical studies or found broad application for peptide receptor
      radiotherapy. In contrast, radiohalogenated peptides could not benefit from this
      development. Especially with respect to the growing number of peptidic structures
      with high receptor affinity and the increasing demand for means of corresponding
      receptor status quantification for therapy planning and control, the development
      of methods for the improved availability of 18F-labeled peptides for positron
      emission tomography imaging is still a very important objective in
      radiopharmaceutical research. Consequently, as part of our ongoing efforts in
      this field, we investigated the potential of carbohydration as a valuable tool to
      modify pharmacokinetics of peptides and evaluated the influence of this
      modification on the in vitro and in vivo behavior of octreotide analogs.
      Furthermore, a new methodology is presented allowing for the fast and
      straightforward labeling of peptides in a chemoselective manner. This combined
      approach to the chemoselective conjugation of unprotected, carbohydrated peptides
      seems to have the potential for a redirection and reevaluation of the future of
      radiohalogenated peptides in nuclear medicine.

PMID- 15186605
TI  - Detection of colon cancer with 99mTc-labeled bombesin derivative (99mTc-leu13
      BN1).
AB  - Breast, prostate, and lung cancer have been successfully detected with 99mTc
      bombesin (99mTc-leu13-BN1), the radiopharmaceutical that our group developed from
      synthesis to diagnostic trials. Overexpression of bombesin receptors (BNRs) in
      colon cancer is well known: the aim of this study was to assess whether or not
      colon cancer can be detected with a 99mTc-leu13-BN1 scan. Thirteen (13) patients,
      7 of whom with known rectal cancer and 6 scheduled to undergo endoscopic removal
      of polyps for suspicion of colon cancer, were studied with a 99mTc-leu13-BN1
      scan. Dynamic, single photon emission computed tomography, and whole-body scans
      were performed within 1 hour, before discharge of radioactivity from the liver
      into the duodenum. Sixteen (16) of 17 colorectal cancer locations were detected
      with a 99mTc-leu13-BN1 scan with 94.1% sensitivity. Six (6) lesions were benign:
      1 Crohn's disease, 1 polyp with mild dysplasia, 4 polyps with simple hyperplasia;
      99mTc-leu13-BN1 scans were positive in two nontumoral lesions, Crohn's disease,
      and mild dysplasia and true negative in 4: specificity was 67%. Of the 7 patients
      with known rectal cancer, 5, who underwent operations instead of radiation
      therapy, showed lymph-node invasion on 99mTc-leu13-BN1 scans. Operations
      confirmed the scintigraphic staging. 99mTc-leu13-BN1 is taken up by colon cancer.
      Scans are sensitive, although scarcely specific. 99mTc-leu13-BN1 allows for node
      invasion detection.

PMID- 15186606
TI  - 99mTc-depreotide scintigraphy in the evaluation of indeterminate pulmonary
      lesions: clinical experience.
AB  - Indeterminate lung nodules (LN) constitute a clinical problem of increasing
      frequency that requires an effective diagnostic approach. This study evaluates
      the contribution of 99mTc-depreotide scintigraphy in the management of such
      patients. Forty (40) patients (27 males/13 females) 29 to 82 years old (61 +/-
      12) with lung nodules/masses of indeterminate origin on computed tomography (CT)
      images were injected with 99mTc-depreotide and underwent thoracic tomography
      (single photon emission computed tomography) 2 and 4-4.5 hours later. All
      parenchymal lesions (50) identified by CT were scored as negative or positive as
      to the uptake of 99mTc-depreotide. Positive images were also evaluated
      semiquantitatively. Thirty (30) of 31 malignant lesions were positive (97%
      sensitivity) and 12 out of 19 benign lesions were negative (63% specificity),
      with positive images obtained in benign processes such as inflammation/infection
      and bronchiectasis. Semiquantitative analysis showed a statistically significant
      difference between benign and malignant positive lesions on the late images, and
      may play a complementary role in interpretation. 99mTc-depreotide was a useful
      noninvasive tool in the evaluation of patients with LN, allowing for the
      exclusion of malignancy with great confidence, due to its high sensitivity.
      Because of moderate specificity, a positive test is best valued together with
      clinical and radiological features.

PMID- 15186607
TI  - Clinical usefulness of 99mTc-EDDA/HYNIC-TOC scintigraphy in oncological
      diagnostics: a pilot study.
AB  - The clinical usefulness of a new 99mTc-labeled somatostatin analogue has been
      studied from the standpoint of oncological diagnostics. The group of patients
      studied included 40 individuals with diagnosed malignant neoplasms (32 primary
      and 8 metastatic). Among the primary tumors were 7 pituitary adenomas (5
      hormonally active and 2 inactive), 1 liposarcoma, 2 carcinoids, 1 breast
      carcinoma, and 21 cases of lung cancer (2 small cell and 19 non-small cell) were
      represented. The metastatic tumors consisted of: 3 malignant melanomas, 1
      pheochromocytoma, 1 prostatic cancer, 1 leiomyosarcoma, 1 pancreatic carcinoma
      ectopically secreting ACTH, and 1 carcinoid of the thymus. The
      radiopharmaceutical, 99mTc-EDDA/HYNIC-octreotide, was i.v. administered at the
      activity of 740-925 MBq. The imaging was comprized of a whole-body scan and
      single photon emission computed tomography. Positive scintigrams were obtained in
      4 of 5 hormonally active pituitary adenomas, in 1 of 2 cases of carcinoid, in
      liposarcoma, breast cancer, and all cases of small cell (SCLC) and non-small cell
      lung cancer (NSCLC). The neoplastic metastases were visualized in 2 of 3 cases of
      melanoma and in patients with pheochromocytoma, pancreatic carcinoma secreting
      ACTH, and thymic carcinoid. Scintigrams were negative in both hormonally inactive
      pituitary adenomas, in one case of metastatic malignant melanoma, leiomyosarcoma,
      and in cases of metastasis from the prostatic carcinomas. The results of this
      pilot study indicated that 99mTc-EDDA/HYNIC-TOC is a potentially useful
      radiopharmaceutical for the imaging of a wide range of primary and metastatic
      tumors. More detailed indications for the clinical usefulness of the new tracer
      for the imaging of selected tumor types require studies on much larger groups of
      patients. Special attention should be paid to the successful imaging of all cases
      of NSCLC.

PMID- 15186608
TI  - Thyroid cancer in thyroglossal duct remnants: a diagnostic and therapeutic
      dilemma.

PMID- 15186609
TI  - Differences in thyroid-infiltrating B lymphocytes in patients with Graves'
      disease: relationship to autoantibody detection.
AB  - OBJECTIVE: Thyroid-infiltrating B (Thyr-B) lymphocytes are thought to play an
      important role in the pathogenic mechanisms underlying Graves' disease. DESIGN
      AND METHODS: In this study, a broad phenotypic analysis of these cells has been
      performed in 15 consecutive patients who underwent thyroidectomy. RESULTS: Data
      reveal the occurrence of two distinct types of Thyr-B cell infiltrates. Type 1
      was present in most of the cases (10/15) and consisted of a combination of IgM+
      IgD(low to-) B lymphocytes showing features of marginal zone B cells, and IgG+
      classic memory B cells. In contrast, in 5 of the 15 cases, a second type of Thyr
      B cell infiltrate occurred, exhibiting the profile IgM- IgD- CD44(low to-) CD38++
      CD71+ CD95+. This phenotype is highly suggestive of germinal center (GC) B cells,
      a finding not always anticipated from routine histologic examination. The
      presence of these ectopic GC was closely associated with the elevated serum level
      of anti-thyroid peroxidase (TPO), but not with anti-thyrotropin receptor (TSHR),
      autoantibodies. Moreover, local active anti-thyroglobulin (Tg) antibody secretion
      was only detected in cultures of type 2 Thyr-B cells. CONCLUSION: These findings
      indicate that high titers of anti-TPO, but not anti-TSHR antibody, might be
      associated with intrathyroidal GC development.

PMID- 15186610
TI  - A thyroid hormone analogue, triiodothyroacetic acid, corrects corticosteroid
      downregulated collagen synthesis.
AB  - The aim of this study was to compare the change in collagen synthesis between
      topical treatments with two doses of triiodothyroacetic acid (TRIAC), a thyroid
      hormone analogue, and placebo, after pretreatment with topical betamethasone 17
      valerate (BM). Eighteen healthy volunteers were pretreated with BM on abdominal
      skin for 3 days, and were then treated for 14 days with a cream containing TRIAC
      (0.03% or 0.1%) or a placebo cream. Collagen production was assessed by
      quantifying the amino terminal propeptides of human type I and type III
      procollagen (PINP and PIIINP) in fluids from suction-induced blisters on the
      treated skin. Three days of treatment with BM led to an average reduction of PINP
      of 70% and of PIIINP of 50%. Seven days after treatment, the median increase in
      PINP was 230% (p = 0.03) in the Triac 0.03% group, 148% (p = 0.2) in the TRIAC
      0.1% and 5% in the placebo group. The median increase in PINP in the skin area
      from the start of treatment to the end of treatment was 521% (p = 0.06) in the
      TRIAC 0.03% group, 339% (p = 0.2) in the TRIAC 0.1% group, and 55% in the placebo
      group (the p values are related to baseline). Seven days after treatment, the
      median increase in PIIINP was 24% (p = 0.6) in the Triac 0.03% group, 23% (p =
      0.6) in the TRIAC 0.1% group, and -12% in the placebo group. The median increase
      in PIIINP in the skin area from the start of treatment to the end of treatment
      was 137% (p = 0.7) in the TRIAC 0.03% group, 230% (p = 0.9) in the TRIAC 0.1%
      group and 58% in the placebo group (the p values are related to baseline).
      Histologic examinations of sections from punch biopsies taken at the end of the
      treatment showed more thickened collagen fibers and increased density of PINP
      producing dermal fibroblasts in the TRIAC groups compared to the placebo group.
      The result suggests a potential role for TRIAC-containing cream concomitant with
      anti-inflammatory topical treatment with potent glucocorticoids to prevent their
      suppressive activity on dermal collagen production.

PMID- 15186611
TI  - Search for genetic variants in the retinoid X receptor-gamma-gene by polymerase
      chain reaction-single-strand conformation polymorphism in patients with
      resistance to thyroid hormone without mutations in thyroid hormone receptor beta
      gene.
AB  - Resistance to thyroid hormone (RTH) is an inherited disease characterized by
      reduced tissue sensitivity to thyroid hormone. Approximately 90% of subjects with
      RTH have mutation in the thyroid hormone receptor beta (TRbeta) gene.
      Approximately 10% of subjects diagnosed as having RTH do not carry mutation in
      the TRbeta gene. A possible linkage was reported with the retinoid X receptor
      gamma (RXR-gamma) gene in two families. The aim of this study is to search for
      mutation within the RXR-gamma gene in unrelated subjects with diagnosed RTH
      without mutations in the TRbeta gene. Four subjects with RTH were studied, and
      sequence variants in the RXR-gamma gene were searched by polymerase chain
      reaction-single-strand conformation polymorphism (PCR-SSCP). Analysis of all the
      10 exons of the RXR-gamma gene, including intron-exon boundaries, promoter region
      and 3' untranslated region (UTR) reveled two variant bands in subjects II and
      III. Sequencing of these variants showed two single nucleotide polymorphisms
      (SNPs): 447C > T in exon 3 for patients II and IVS9 + 6A > G for patient III.
      Both SNPs were also present at high frequency in a group of normal subjects and
      in nonaffected relatives of subject III. In conclusion, in patients with RTH we
      have found two SNPs in the RXR-gamma gene; these SNPS are common in the general
      population, thus excluding a role for the RXR-gamma gene in these patients.

PMID- 15186612
TI  - BRAF mutations are not an alternative explanation for the molecular etiology of
      ras-mutation negative cold thyroid nodules.
AB  - Activation of the RAS/RAF/MEK/ERK/MAP kinase pathway is a known mediator of
      signaling that results in cellular proliferation. Moreover, this activation can
      lead to a growth advantage of tumor cells. Therefore, mitogenic mutations in the
      RAS family of oncogenes are detectable in a significant percentage in most
      tumors. Moreover, mutations in the BRAF gene have recently been suggested as an
      alternate predominant cause of colorectal and papillary thyroid cancers without
      ras mutations. Similar to neoplasms of other organs mutations of all three ras
      genes can be found in thyroid tumors. In our set of 40 cold thyroid adenoma and
      adenomatous nodules ras mutations were detected in only a single case. We
      therefore tested these hypofunctional tumors for BRAF mutations. Genomic DNA was
      extracted from nodular and surrounding tissue. Mutational hot spots in exons 11
      and 15 of the BRAF gene were polymerase chain reaction (PCR) amplified and
      denaturing gradient gel electrophoresis was used to screen for mutations. No
      point mutation could be found in the two exons of the BRAF gene. Our study
      suggests that BRAF mutations are rather rare in solitary cold adenomas and
      adenomatous nodules and do not explain the molecular etiology of ras mutation
      negative cold thyroid nodules.

PMID- 15186613
TI  - Thyroglossal duct cyst with papillary carcinoma: what must be done?
AB  - OBJECTIVE: To present a report series of five cases, compare their clinical
      evolution, and establish the appropriate treatment. METHODS: A retrospective
      study was performed with the clinical records from three health institutions in
      Mexico City, Mexico, in order to search for patients with histologic diagnosis of
      thyroglossal duct carcinoma and were classified by different risk stratifications
      to compare their outcome. RESULTS: We found five patients, three females and two
      males, mean age 49 years. Four were treated by Sistrunk's procedure, total
      thyroidectomy, radioiodine ablation, and thyroxine suppression; one patient
      underwent Sistrunk's procedure only. Four patients were classified in the low-
      and median-risk group and had good outcome; one patient was in the high-risk
      group and had poor outcome. CONCLUSIONS: The thyroglossal duct cyst must be
      studied in the adult population through fine-needle aspiration biopsy (FNAB) and
      a frozen section in cases in which FNAB is inconclusive or unavailable. When a
      diagnosis of a thyroglossal cyst carcinoma is made, an evaluation of the thyroid
      gland during surgery must be done as well as a careful examination to identify
      suspicious lymph nodes and neck dissection should be reserved for confirmed
      adenopathies. When an thyroglossal duct cyst has been excised using Sistrunk's
      procedure and the definitive histologic analysis reports malignancy, the thyroid
      gland must be studied. The extension of the surgery must be handled according to
      the criteria established for differentiated thyroid cancer.

PMID- 15186614
TI  - Intrauterine exposure to maternal enterovirus infection as a risk factor for
      development of autoimmune thyroiditis during childhood and adolescence.
AB  - Maternal intrauterine enterovirus infection during pregnancy increases the risk
      for the offspring to develop type 1 diabetes mellitus. Type 1 diabetes mellitus
      and autoimmune thyroiditits (AIT) are closely linked. A common pathogenetic
      factor is possible. The objective of this study was to investigate a possible
      association between maternal enterovirus infection during pregnancy and the
      development of AIT in the offspring. Sera taken at delivery from 31 mothers whose
      children subsequently developed AIT was analyzed for immunoglobulin (Ig)A, IgG,
      and IgM antibodies against enterovirus, and compared to a control group
      comprising 233 randomly selected maternal sera. Of the mothers whose children
      developed AIT, 5 of 31 (16%) were enterovirus IgM-positive, compared to 17 of 233
      (7%) in the control group (p = 0.16). The age at diagnosis of AIT was
      significantly lower in the group of children with IgM-positive mothers compared
      to children with IgM-negative mothers (p < 0.05). In addition, 3 children (60%)
      in the IgM-positive group were overtly hypothyroid at diagnosis of AIT, compared
      to no child (0%) in the IgM-negative group (p < 0.01). No significant differences
      were found in IgA and IgG antibody titers between the mothers whose children
      developed AIT and the control group. Although this study did not have enough
      power to reveal intrauterine exposure to maternal enterovirus infection during
      pregnancy as a risk factor for development of AIT during childhood and
      adolescence, it suggested an association with earlier onset of clinical disease
      in children to enterovirus IgM-seropositive mothers.

PMID- 15186615
TI  - Impact of long-term administration of amiodarone on the thyroid function of
      patients with Chagas' disease.
AB  - The effect of long-term treatment with amiodarone on patients with Chagas'
      disease has seldom been reported. This nonrandomized observational study
      attempted to analyze the follow-up of patients with Chagas' disease regarding
      their clinical evolution, thyroid dysfunction, and goiter. We compared 72
      patients with long-term use (11 +/- 5 years) of amiodarone, including 22 patients
      who developed goiter, to 33 patients who did not use amiodarone, followed-up for
      2 to 20 years (7 +/- 11 years). Follow-up of 72 patients for 9 +/- 5.4 years with
      periodic cardiac and thyroid function evaluations showed that only 26 maintained
      normal serum thyrotropin (TSH) levels; 24 presented with elevated levels; 4 had
      low levels, and 18 patients presented with fluctuations of TSH level. Among the
      22 patients with goiter, only 3 (14%) patients maintained normal TSH, 8 (36%) had
      elevated TSH, 2 (9%) had low TSH, and 9 (41%) patients presented with fluctuating
      serum TSH levels. Most individuals remained clinically euthyroid with no evidence
      of cardiac impairment that could be attributed to thyroid dysfunction and the
      arrhythmias were adequately controlled by amiodarone. We suggest that amiodarone
      treatment may be continued for patients with Chagas' disease with arrhythmias,
      even in those who develop thyroid function abnormalities or goiter.

PMID- 15186616
TI  - Primary-gaze diplopia in patients with thyroid-related orbitopathy undergoing
      deep lateral orbital decompression with intraconal fat debulking: a retrospective
      analysis of treatment outcome.
AB  - Our goal was to investigate the incidence of postoperative primary gaze diplopia
      in patients with thyroid-related orbitopathy (TRO) undergoing deep lateral wall
      orbital decompression surgery with intraconal fat debulking in the Jules Stein
      Eye Institute over a period of 4(1/4) years. Overall 201 orbital decompression
      surgeries were performed in 116 patients (23 males, 93 females). All surgeries
      were performed by two of the authors (R.A.G. and J.D.M.) and in the
      noninflammatory phase of the disease. Exophthalmos decreased by an average of 3.4
      +/- 2.7 mm from 23.8 +/- 3.2 mm (17-31) to 20.4 +/- 2.5 mm (14-29), p < 0.001,
      95% confidence interval (CI) (3.0:3.8). 31% of patients had preoperative primary
      gaze diplopia and 28.4% had postoperative primary gaze diplopia. Thirty (83%) of
      the 36 patients with preoperative diplopia had also postoperative diplopia; 6
      (16.7%) of the 36 patients had improvement in diplopia following deep lateral
      wall decompression. Of the 80 (69%) of patients without preoperative double
      vision 3 developed postoperative double vision in primary gaze (2.6% of all
      patients). These 3 patients were older (56 versus 46 years, p = 0.047), had more
      limitation in ocular movements (p = 0.017) and achieved more decrease in
      proptosis with surgery (6 versus 3.1 mm, p = 0.024). No complications were
      associated with orbital decompression. In conclusion deep lateral wall orbital
      decompression surgery with intraconal fat debulking is associated with a low rate
      (2.6%) of new-onset primary gaze diplopia. Some patients (5.2%) with preoperative
      diplopia actually had improvement in diplopia postoperatively. This surgery is
      effective in reduction of congestion and exophthalmos, and is not associated with
      detrimental effects on visual acuity.

PMID- 15186618
TI  - Medullary thyroid carcinoma associated with hyperthyroidism: a case report and
      review of the literature.
AB  - Thyroid cancer is occasionally associated with hyperthyroidism. Papillary thyroid
      carcinoma is the most frequently reported histologic type followed by follicular
      thyroid carcinoma. Medullary thyroid carcinoma (MTC) has been rarely described in
      association with Graves' disease or other forms of hyperthyroidism. To our
      knowledge, only 14 cases have been described in which MTC was associated with
      hyperthyroidism. We report a 70-year-old male who had a clinically significant
      MTC discovered in the course of diagnostic work-up for hyperthyroidism. We also
      summarize the clinical features of the other 14 reported cases.

PMID- 15186617
TI  - Ultrasound-guided fine-needle capillary biopsy of thyroid nodules, coupled with
      on-site cytologic review, improves results.
AB  - Fine-needle aspiration biopsy represents the most reliable test for cytologic
      evaluation of thyroid nodules. However, inadequate samples may occur leading to a
      repetition of the procedure with the consequence of patients' discomfort and poor
      compliance. In this paper, we present results from biopsy of thyroid nodules
      obtained by combining: (1) ultrasound (US) guidance, (2) no-aspiration technique,
      and (3) on-site review of specimens. A total of 465 nodules were biopsied in 307
      patients. Solitary nodules and multinodular goiter were present in 36.8% and
      63.1% of patients, respectively. After collection, each sample was smeared in
      duplicates, one of which was stained with hematoxylin and checked on-site by a
      cytopathologist. In cases of inadequate smears, biopsies were immediately
      repeated. All slides were then processed for final cytologic results, which were
      reported as benign in 427 nodules (91.8%), malignant in 12 nodules (2.5%), with
      follicular proliferation or suspicious for malignancy in 23 nodules (4.9%).
      Inadequate final cytology was reported in 3 nodules (0.6%). No statistically
      significant relationship was found between nodule size and adequacy of specimens.
      We conclude that the combination of US guidance, capillary collection with no
      aspiration technique, and on-site review of slides, characterizes an advantageous
      method for thyroid nodule fine-needle biopsy.

PMID- 15186619
TI  - Assessing thyroid hormone status in a patient with thyroid disease and renal
      failure: from theory to practice.
AB  - A 35-year-old Asian male, treated for hyperthyroidism, systemic lupus
      erythematosis, and uremia presented with low serum total thyroxine (T4) and
      normal serum thyrotropin (TSH) levels. He had been receiving prednisone and
      methimazole for 15 weeks. Free T4 measured by direct equilibrium dialysis was in
      the hypothyroid range (0.3 ng/dL; normal, 0.8-2.7). Two possibilities were
      considered: (1) a weakly bound dialyzable inhibitor in uremic serum that
      interfered with this serum free T4 determination or (2) hypothyroidism with
      persistent TSH suppression because of prior hyperthyroidism. To determine whether
      a weakly bound inhibitor was involved, the patient's serum was serially diluted
      using two diluents: (1) an ultrafiltrate of the patient's serum, which would
      contain any unbound inhibitor, as well as free T4 and (2) an inert diluent. Free
      T4 measurements were similar with both, providing evidence against the presence
      of a dialyzable and ultrafilterable inhibitor. In conclusion, this patient was
      hypothyroid because of antithyroid drug administration, associated with prolonged
      central TSH suppression from preexisting hyperthyroidism. Discontinuation of
      methimazole resulted in normalization of serum total T4 and TSH values. Thus,
      paired, serial serum dilutions, using two different diluents, provided evidence
      for differentiation of appropriately low free T4 measurements (because of
      hypothyroidism), from spuriously low free T4 measurements (because of an
      interfering inhibitor).

PMID- 15186620
TI  - Lingual thyroid: marked response to suppression therapy.

PMID- 15186621
TI  - Acute and severe liver damage associated with intravenous glucocorticoid pulse
      therapy in patients with Graves' ophthalmopathy.

PMID- 15186622
TI  - Vagotomy at the time of gastric bypass: can it be harmful?

PMID- 15186623
TI  - Psychological profile of the morbidly obese.
AB  - BACKGROUND: In the surgical treatment of morbid obesity, surgery on its own
      represents only one element. In fact, bariatric surgery is a forced behavior
      modification; in addition to surgery, psychological factors play an important
      role in its results. Because of the importance of the psychological factors and
      the possibility to intervene in them, there is a need for a better understanding
      of morbidly obese patients, especially those who are candidates for bariatric
      surgery. Thus, this article reviews their psychological profile. METHODS: A
      systematic literature search identified relevant variables reflecting personality
      and psychopathology, eating behavior, social problems, and quality of life.
      RESULTS: Morbidly obese patients are described as depressed, anxious,having poor
      impulse control, low self-esteem, and impaired quality of life. Dieting, rigid
      control, and disinhibition characterize their eating behavior. This seems to be
      especially true for morbidly obese patients seeking surgical treatment for their
      obesity. CONCLUSION: The existing literature about the characteristics of the
      morbidly obese is far from conclusive; this may in part be due to the use of poor
      methods of assessment.

PMID- 15186624
TI  - The chronic inflammatory hypothesis for the morbidity associated with morbid
      obesity: implications and effects of weight loss.
AB  - BACKGROUND: Obesity is a worldwide pandemic that causes a multitude of co-morbid
      conditions.However, there has been slow progress in understanding the basic
      pathophysiology that underlies co-morbid conditions associated with obesity.
      Recently, there has been intense interest in the role of inflammation in obesity.
      Using the inflammatory hypothesis, many of the mechanisms by which co-morbid
      conditions are associated with obesity are being elucidated. METHODS: We searched
      the literature and reviewed all relevant articles. We focused on hormones and
      cytokines that have been associated with other inflammatory conditions such as
      sepsis and systemic inflammatory response syndrome. FINDINGS: Angiotensinogen
      (AGT), transforming growth factor beta (TGFbeta), tumor necrosis factor alpha
      (TNFalpha), and interleukin six (IL-6) are all elevated in obesity and correlate
      with several markers of adipocyte mass. These mediators have detrimental effects
      on hypertension, diabetes, dyslipidemia, thromboembolic phenomena, infections,
      and cancer. Weight loss results in a reduction of inflammatory mediators and a
      diminution of the associated co-morbid conditions. CONCLUSIONS: The success of
      weight loss surgery in treating the complications associated with obesity is most
      probably related to the reduction of inflammatory mediators. While some aspects
      of bariatric physiology remain unclear, there appears to be a strong association
      between obesity and inflammation, thereby rendering obesity a chronic
      inflammatory state. A clearer understanding of the physiology of obesity will
      allow physicians who treat the obese to develop better strategies to promote
      weight loss and improve the well-being of millions of individuals.

PMID- 15186625
TI  - Unfractionated heparin infusion for thromboprophylaxis in highest risk gastric
      bypass surgery.
AB  - BACKGROUND: Patients undergoing gastric bypass for obesity are at risk for
      postoperative venous thromboembolic complications. Per our routine, these
      patients receive unfractionated heparin (UFH) per a previously described, blood
      volume-based, subcutaneous prophylactic UFH protocol. However, some patients have
      additional risk factors for thromboembolism, and we consider these patients to be
      at highest risk. To increase the predictability and reliable achievement of
      prophylactic anti-factor Xa levels for these patients at highest risk, we
      developed a prophylactic UFH continuous intravenous infusion protocol. METHODS:
      An UFH prophylactic protocol was developed in which the initial UFH loading dose
      and infusion rate were determined, based on patient blood volume and age. The
      target prophylactic anti-factor Xa activity range was 0.15-0.20 units/mL. 19
      patients were admitted to the hospital the day before gastric bypass surgery. A
      prophylactic UFH infusion was initiated, and anti-factor Xa levels were checked
      and adjusted per protocol. The patients underwent surgery the following day and
      the UFH infusion was continued intra-operatively. RESULTS: No patients were
      diagnosed with a deep venous thromboembolism. 2 patients experienced peri
      operative hemorrhagic complications in spite of anti-factor Xa activity levels
      in, or only slightly above, the targeted range. Both patients recovered without
      further complications. CONCLUSION: For highest risk gastric bypass patients, an
      UFH prophylactic continuous infusion protocol was effective in preventing
      postoperative thromboembolic events. Hemorrhagic complications were easily
      managed and did not result in long-term sequelae.

PMID- 15186626
TI  - The decrease in plasma ghrelin concentrations following bariatric surgery depends
      on the functional integrity of the fundus.
AB  - BACKGROUND: Gastric bypass surgery, which involves the production of a reduced
      stomach pouch,has been shown to markedly suppress circulating ghrelin
      concentrations. Since bypassing the ghrelin-producing cell population may be
      relevant to the disruption of fundic-derived factors participating in food intake
      signaling, the effect of weight loss induced by either adjustable gastric banding
      (AGB), Roux-en-Y gastric bypass (RYGBP) or biliopancreatic diversion (BPD) was
      studied. METHODS: 16 matched obese patients [35.0 + 2.4 years; initial body
      weight 124.8 +/- 5.7 kg; body mass index (BMI) 47.1 +/- 2.2 kg/m(2)] in whom
      similar weight loss had been achieved by either AGB (n=7), RYGBP (n=6) or BPD
      (n=3) were studied. Blood was obtained for biochemical and hormonal analyses.
      Body composition was assessed by air-displacement-plethysmography. RESULTS:
      Comparable weight loss (AGB: 26.1 +/- 5.1 kg; RYGBP: 32.1 +/- 5.0; BPD: 31.7 +/-
      6.1; P=NS) and decrease in percentage body fat (AGB: 10.0 +/- 1.5%; RYGBP: 14.2
      +/- 2.8; BPD: 10.3 +/- 1.0; P=NS) induced by bariatric surgery exerted
      significantly different (P=0.004) effects on plasma ghrelin concentrations,
      depending on the surgical procedure applied (AGB: 480 +/- 78 pg/ml; RYGBP: 117 +/
      34; BPD: 406 +/- 86). Without significant differences in BMI, body fat, glucose,
      triglycerides, cholesterol, insulin and leptin levels, patients who had undergone
      the RYGBP exhibited statistically significant diminished circulating fasting
      plasma ghrelin concentrations compared with the other two bariatric techniques
      which conserve direct contact of the fundus with ingested food (P=0.003 vs AGB
      and P=0.020 vs BPD). CONCLUSION: Fasting circulating ghrelin concentrations in
      patients undergoing diverse bariatric operations depend on the degree of
      dysfunctionality of the fundus.

PMID- 15186627
TI  - Total stapled, total intra-abdominal (TSTI) laparoscopic Roux-en-Y gastric
      bypass: one leak in 1000 cases.
AB  - BACKGROUND: Variations in technique of laparoscopic Roux-en-Y gastric bypass
      (LRYGBP) have been reported. These changes, mainly in the construction of the
      gastro-jejunostomy, are intended to decrease complications. METHODS: 1000
      consecutive LRYGBPs were performed using the Total Stapled Total Intra-abdominal
      (TSTI) technique antecolic and antegastric approach. Technical details and
      results, including perioperative morbidity and mortality, are reported. RESULTS:
      Although the correction or improvement of the most serious co-morbidities with
      the use of the TSTI technique were similar to results reported by other gastric
      bypass surgeons, we noted a considerable difference in the development of leaks
      using this surgical approach. Current literature on gastric bypass reports a 2-5%
      incidence of leaks. Using the TSTI approach, the incidence of leaks at our
      facility was 0.1% (one in 1000 cases). After analysis of the factors involved, it
      was concluded that the use of the antecolic and antegastric approach in gastric
      bypass, as described in the TSTI,should be an important consideration by the
      surgeon. This technique, which uses a circular stapler, was found to be easy to
      perform while maintaining a reproducible, controlled opening of the anastomosis.
      CONCLUSION: Although this was a non-randomized study, the results found a
      considerable improvement in the incidence of morbidity and mortality, and a
      remarkable decrease in the frequency of leaks.

PMID- 15186628
TI  - Lessons learned from the first 100 cases in a new minimally invasive bariatric
      surgery program.
AB  - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGBP) is a technically
      demanding procedure with a steep learning curve. Experienced laparoscopic
      surgeons and bariatric surgeons can learn from the outcomes and complications of
      their initial experience in LRYGBP. METHODS: Between August of 2002 and July of
      2003, we performed our first 100 LRYGBPs. Our surgical technique involves the
      ante-colic, ante-gastric placement of the Roux-limb. A 21-mm circular stapler is
      used to create the gastrojejunostomy. The stapler anvil is placed
      transgastrically. RESULTS: The mean preoperative BMI was 49.7 kg/m(2) (range 37
      70). 12% of patients were male. Early complications (14%) included 3 leaks, 4
      bleeding episodes and 2 gastrogastric fistulas. There was 1 peri-operative
      mortality and 1 conversion to laparotomy. Late complications (17%) included
      stenosis of the gastrojejunostomy which occurred in 14 patients. Leaks occurred
      more commonly in males (16% vs 1%, P<0.05). Elevated BMI was also found to be a
      risk factor for leak (BMI 58.7 leak vs 49.3 no leak, P<0.05). Stenosis was often
      associated with other complications such as leak or marginal ulcer. Stenosis
      responded well to endoscopic dilation. Co-morbid medical conditions responded to
      weight loss in all patients, regardless of initial BMI. Mean excess weight loss
      was 69% at 1 year, but varied according to preoperative BMI. CONCLUSIONS: Careful
      recording of patient outcomes and complications is important, particularly in a
      new minimally invasive bariatric surgery program. Review and analysis of specific
      complications may help to minimize the occurrence of similar subsequent
      complications.

PMID- 15186629
TI  - Laparoscopic vertical banded gastroplasty and laparoscopic gastric bypass: a
      comparison.
AB  - BACKGROUND: Vertical banded gastroplasty (VBG) and gastric bypass (GBP) are the
      two bariatric procedures recommended by NIH consensus conference. Recent
      advancement in laparoscopic (L) techniques has made LVBG and LGBP alternatives
      for the conventional open approach. METHODS: From December 2000 to February 2002,
      80 patients (24 men and 56 women; mean age 32 years, range 18-57) with morbid
      obesity (mean BMI 43.2 kg/m(2), range 36-59.8) were enrolled in a prospective
      trial and randomly assigned to LVBG or LGBP. Changes in quality of life were
      assessed using the Gastro-intestinal quality of life index (GIQLI). RESULTS: The
      conversion rate was zero for LVBG and 2.5% (1/40) for LGBP. There has been no
      mortality. Surgical time was significantly longer for LGBP (209 minvs 126 min for
      LVBG, P<0.001). Mean hospital stay was 3.5 days for the LVBG vs 5.7 days for LGBP
      (P<0.001). Postoperative analgesic usage was also less for LVBG patients (mean
      dose 1.4 vs 2.4, P<0.05). Early complication rate was higher in the LGBP group
      (17.8% vs 2.5%, P<0.001). All 3 major complications were in the LGBP group, of
      which 2 were related to anastomotic leakage (5%). Late complications consisted of
      upper GI bleeding, stenosis and others observed in 4 LGBP patients (10%) and 2
      LVBG patients (5%). Mean follow-up was 20 months (range 18 to 30). BMI fell
      significantly in both groups, with significant improvement of obesity-related co
      morbidities. LGBP had significantly better excess weight loss than LVBG (62.9% vs
      55.4% at 1 year and 71.4% vs 53.1% at 2 years), as well as lower BMI than LVBG
      (29.6 vs 31.1 at 1 year and 28.5 vs 31.9 at 2 years). There was no difference in
      the reduction of obesity-related laboratory abnormalities at 1 year except a
      lower hemoglobin in LGBP (11.8 vs 13.8, P<0.05). Preoperative GIQLI scores were
      similar between the groups; however, at 1 year, LGBP patients had better GIOLI
      scores than LVBG patients (121 vs 106, P<0.01). LVBG had improvement in physical
      condition, social function and emotional conditioning but deterioration in GI
      symptoms which resulted in no increase in total GIQLI score. CONCLUSION: LGBP was
      a time-consuming demanding technique with a higher early complication rate
      compared with LVBG. Although both operations resulted in significant weight
      reduction and decrease in obesity-related co-morbidities, LGBP had a trend of
      greater weight loss and significantly better GIQLI than LVBG at the cost of a
      significant long-term trace element deficiency state. Each patient should be
      individualized for the operations according to the patient's decision.

PMID- 15186630
TI  - The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese
      patients.
AB  - BACKGROUND: Hepatic steatosis is prevalent in obese patients. Although it
      requires histology for diagnosis, ultrasound may indicate its presence. We
      evaluated the importance of ultrasound in the diagnosis of steatosis in morbidly
      obese patients, and considered its clinical relevance for patients with BMI of 35
      40 kg/m(2) without co-morbidities. METHODS: 187 morbidly obese patients submitted
      to bariatric surgery were prospectively studied. All patients had ultrasound
      before the operation, and hepatic biopsies during the operation, which were
      compared. RESULTS: The prevalence of steatosis histologically was 91.4%. The
      sensitivity and specificity of ultrasound in diagnosing steatosis was 49.1% and
      75%, respectively,with a positive predictive value of 95.4%. CONCLUSION: The
      biopsies found a very high prevalence of steatosis in the studied population. The
      ultrasound results yielded a high positive predictive value (95.4%), suggesting
      its use as a diagnostic tool for this co-morbidity in morbidly obese patients.
      The low sensitivity of the method could be related to the lack of objective
      criteria for the ultrasound diagnosis of steatosis, and probably, technical
      problems in performing ultrasound in such patients. We believe that in patients
      with a BMI of 35-40 kg/m(2) without other comorbidities, the ultrasound finding
      of steatosis could be of value as an indication for bariatric surgery.

PMID- 15186631
TI  - Vertical banded gastroplasty converted to Roux-en-Y gastric bypass: little impact
      on nutritional status after 5-year follow-up.
AB  - BACKGROUND: Conversion to a Roux-en-Y gastric bypass (RYGBP) has been advocated
      after the failure of vertical banded gastroplasty (VBG). The aim of this study
      was to analyze the differences in anthropometric and nutritional parameters
      between patients with VBG and those converted to RYGBP. METHODS: 45 patients
      initially underwent VBG. 22 of these patients have maintained this operation for
      more than 5 years (Group A) and 23 have been converted to RYGBP (Group B), after
      2 years of follow-up. We analyzed anthropometric and nutritional parameters
      (macronutrients,micronutrients and lipid profile), and postoperative morbidity
      after both procedures. Data were recorded before the first operation and at 6
      months, 1, 2 and 5 years follow-up. RESULTS: VBG failure rate was 51%. The 23
      patients converted to RYGBP have maintained an excess weight loss (EWL) of 70% 3
      years after the revision, and all the complications related to VBG disappeared.
      Anthropometric parameters were significantly better after RYGBP. We found no
      significant differences in nutritional status between both groups except for
      levels of iron, vitamin B(12) and transferrin saturation index, which
      significantly decreased in converted patients. The redo procedure had a low
      morbidity rate, with no mortality. CONCLUSION: More than 50% of VBGs failed after
      2-year follow-up. Patients converted to RYGBP maintained mean EWL 73% at 5 years.
      The only significant nutritional deficiencies were iron and vitamin B(12), in
      patients converted to RYGBP.

PMID- 15186632
TI  - Plasma cholecystokinin levels after vertical banded gastroplasty: effects of an
      acidified meal.
AB  - BACKGROUND: Although cholecystokinin (CCK) is involved in the short-term
      regulation of satiety, it has not been investigated in obese patients subjected
      to bariatric restrictive operations. METHODS: 8 morbidly obese patients (BMI 49.1
      +/- 6.9), 7F and 1M, were investigated before and after vertical banded
      gastroplasty (VBG). 6 healthy lean volunteers served as the control group. CCK
      was determined (RIA) after an overnight fast and after the administration of an
      acidified (pH 3) liquid meal. Blood samples were taken 45 min before the meal, 5
      min after it and then every 30 min for 3 hours. RESULTS: There were no
      differences between groups in basal CCK levels. However, the peak of CCK after
      the meal was significantly higher (P <0.01) in obese patients after VBG (24.9 +/-
      18 pmol/l) than before VBG (9.8 +/- 6.7 pmol/l) and when compared with the
      control group (8.0 +/- 6.3 pmol/l). The time needed to reach the peak was longer
      in healthy volunteers (105 +/- 24.9 min) than in obese patients before VBG (45 +/
      40 min) and after VBG (7.5+/- 12 min) (P<0.01). CONCLUSIONS: VBG increases the
      peak of CCK secretion and shortens the time to reach it. These changes could
      contribute to the satiety effects of gastric restrictive operations.

PMID- 15186633
TI  - Long-term results, late complications and quality of life in a series of
      adjustable gastric banding.
AB  - BACKGROUND: Adjustable gastric banding is currently the most common bariatric
      operation. This study is a retrospective analysis of the Finnish experience with
      this procedure over the last 10 years. METHODS: Between March 1993 and June 1999,
      123 patients underwent either open (36) or laparoscopic (87) surgery for morbid
      obesity by the application of an adjustable gastric band. Data on preoperative
      clinical characteristics and postoperative outcome and weight-loss patterns up to
      9 years (mean 55 months) are presented and also evaluated by the Bariatric
      Analysis and Reporting Outcome System (BAROS). Sex ratio was 31% males / 69%
      females, mean age 44 years and mean +/- SD preoperative BMI 49 +/- 8 kg/m(2)
      (range 33.6-85.1). RESULTS: During the evaluation period (March 1993 December
      2002), 54% of patients experienced postoperative complications requiring hospital
      treatment >or= 7 days, and 52% underwent a reoperation. 33% of bands were
      removed. The most important late complications were esophagitis (30%),
      obstruction due to slippage / pouch dilatation (21%), incisional hernia (9%) and
      band erosion (9%). Mean excess weight loss at 1 and 2 year follow-up was 36% and
      38%, which later stabilized to 30%. During the evaluation period, there were 10
      deaths, 2 of which were 30-day deaths, and the remainder were not associated with
      the band. According to BAROS, the outcome was regarded as "very good" in 3%,
      "good" in 7%, "fair" in 40% and "failure" in 50%. CONCLUSION: Our long-term data
      found that weight reduction is acceptable,but the incidence of late complications
      and reoperations was high.

PMID- 15186634
TI  - Ventral hernia repair in bariatric surgery.
AB  - BACKGROUND: Obesity is an important risk factor for perioperative complications
      including the development of ventral hernias. METHODS: This retrospective study
      comprises patients who underwent abdominal hernia repair simultaneously with or
      following implantation of a Swedish Adjustable Gastric Band(R) (SAGB). RESULTS: 9
      out of 415 patients (2.2%) who received a SAGB between January 1996 and June 2001
      underwent ventral hernia repair. In 6 patients, hernias preexisted from previous
      abdominal surgery at the time of the bariatric procedure, and another 3 hernias
      occurred at the median and left upper abdominal trocar position following SAGB
      placement. Median BMI at time of SAGB implantation was 44 (range 35-52), and at
      time of hernia repair was 36 (range 25-46). 2 hernias were repaired during SAGB
      placement, 3 during redo surgery, and 2 during abdominoplasty. In 2 patients,
      significant weight loss with loss of soft tissue support of the hernia sac led to
      recurrent episodes of small bowel obstruction necessitating emergency repair.
      Repair included direct defect closure in 7 patients and sublay polypropylene net
      implantation in 2 patients. Recoveries have been uneventful without wound
      infections or recurrence in all patients after a median follow-up of 34 months
      (range 13-69). CONCLUSION: In morbidly obese patients, the optimal management and
      timing of incisional hernia repair should weigh the risk of recurrence and
      perioperative complications against the risk of hernia-associated complications.

PMID- 15186635
TI  - Changes in leptin, plasminogen activator factor and oxidative stress in morbidly
      obese patients following open and laparoscopic Swedish adjustable gastric
      banding.
AB  - BACKGROUND: Oxidative stress is increased in obesity, leading to endothelial
      dysfunction, atherogenesis, and platelet aggregation. The purpose of this study
      was to determine the effects of weight loss after bariatric surgery on serum
      lipids, malondialdehyde (MDA, a marker of oxidative stress), oxidized low-density
      lipoprotein (oxLDL, which is increased in obesity and causes endothelial
      dysfunction), paraoxonase (PON-1, which inhibits lipid peroxidation), leptin and
      plasminogen activator inhibitor type-1 (PAI-1, which contributes to a thrombotic
      state). METHODS: 40 morbidly obese patients had insertion of a Swedish adjustable
      gastric band (SAGB). A lipid profile, MDA, oxLDL, PON-1, leptin and PAI-1 levels
      were drawn before and 6 months after the operation. 20 patients underwent open
      (Group 1) and 20 laparoscopic (Group 2) SAGB, to compare the systemic
      inflammatory response of the two approaches. RESULTS: Patient demographics,
      indications for surgery, and postoperative results were no different between the
      groups. Postoperative BMI and concentrations of lipid, MDA, oxLDL, leptin and PAI
      1 decreased significantly in both groups. PON-1 activity increased and was
      negatively correlated with BMI (r=-0.618, P< 0.01), MDA (r=-0.735, P<0.001),
      oxLDL (r=-0.701, P< 0.01), leptin (r=-0.626, P<0.01) and PAI-1 (r=-0.461,
      P<0.05). There was a correlation between BMI and MDA (r=0.790, P <0.001), and
      also leptin (r=0.900, P<0.001) and PAI-1 (r=0.888, P=0.001). There was no
      correlation between BMI and oxLDL. CONCLUSION: These findings support the
      hypothesis that in morbid obesity, weight loss after surgery has positive effects
      on fibrinolytic function, oxidative stress and antioxidant activity. Both
      operative approaches had similar effects in this study.

PMID- 15186636
TI  - Treatment of morbid obesity with the Transcend Implantable Gastric Stimulator
      (IGS): a prospective survey.
AB  - BACKGROUND: The implantable gastric stimulator (IGS), a pacemaker-like device,
      has been found to be safe and effective to induce and maintain weight loss. We
      present our experience with 20 morbidly obese patients. METHODS: Between
      September 20 and November 22, 2002, 20 patients (F/M 12/8), mean age 40.3 years
      (23-62) underwent IGS implantation. Mean BMI was 40.9 (33.9-48.2), mean weight
      115.0 kg (87.0-137.0) and mean excess weight (EW) 51.3 kg (35.6-70.1).Co
      morbitidies were: 3 cases of hypertension, 1 diabetes, 1 dislipidemia and 1
      depression. Mean operative time was 58.5 min (37-85). The IGS was actived 30 days
      after implantation. Patients were advised to follow a low calorie diet and
      behavior modification (to avoid fat and to ingest more liquids during meals, to
      chew slowly, to eat vegetables before main meals, and to perform exercise daily).
      RESULTS: Mean +/- standard error percent excess weight loss (%EWL) was: 10.6+/
      1.8 at 1 month; 15.0+/-2.3 at 2 months; 16.6+/-2.6 at 3 months; 18.1+/-3.5 at 4
      months; 15.5+/-3.5 at 6 months; 18.9+/-3.5 at 8 months; and 23.8+/-5.0 at 10
      months. There were no intra-operative surgical or long-term complications. There
      were 3 intra-operative gastric penetrations, observed by gastroscopy, without
      sequelae. One patient with hypertension ceased his medical therapy at the 4th
      month. CONCLUSION: IGS can be implanted laparoscopically with minimal
      perioperative complications. The observed weight loss is comparable to other
      noninvasive procedures. If weight loss is maintained, IGS could be considered as
      a first choice therapy in the treatment of morbid obesity in selected patients.

PMID- 15186637
TI  - Preoperative weight loss by intragastric balloon in super-obese patients treated
      with laparoscopic gastric banding: a case-control study.
AB  - BACKGROUND: The authors investigated the usefulness of preoperative treatment
      with the BIB intragastric balloon in super-obese patients before undergoing
      laparoscopic adjustable gastric banding (LAGB). METHODS: The case-control study
      involved 43 case patients treated with the intragastric balloon followed by LAGB
      ("Case" group) and 43 sex-, age- and BMI-matched historical controls treated with
      LAGB alone. RESULTS: Mean length of the intragastric balloon treatment was
      164.4+/-39.7 days, with a fill volume of 609+/-95 ml. Total complication rate
      with balloon was 7.0% and percent excess weight loss (%EWL) was 26.1 +/- SD 9.3
      %. At the time of gastric band placement, both operative time and hospital stay
      were shorter in patients treated previously with the balloon (Case group) than in
      the Control group patients. No Case patients required conversion to open surgery
      or had intraoperative complications. In the Control group, the rate of conversion
      was 16.3% (P<0.05) and the rate of intraoperative complications was 7.0%.
      Postoperative follow-up length was 1.1+/-1.0 years in Case patients and 4.4+/-1.8
      years in Control patients (P<0.001). The %EWL produced by the intragastric
      balloon in the Case patients was identical to the %EWL observed in the first 6
      months after LAGB in the Control group (26.1+/-9.3 vs 25.3+/-12.4%). %EWL 6
      months after banding was higher in the Case patients than in Controls (33.6+/
      12.5 vs 25.3+/-12.4%, P<0.01). However, no significant difference in %EWL between
      the two groups was observed at the subsequent postoperative evaluations.
      CONCLUSION: Preoperative treatment with the intragastric balloon reduced the risk
      of conversion to open surgery and the risk of intraoperative complications in
      super-obese patients treated with LAGB. Preoperative treatment with the
      intragastric balloon did not change the total weight loss after LAGB.

PMID- 15186638
TI  - Combining laparoscopic adjustable gastric banding and biliopancreatic diversion
      after failed bariatric surgery.
AB  - BACKGROUND: A percentage of all types of bariatric surgery will fail. Our
      experience with failed biliopancreatic diversion (BPD) as a primary operation or
      revision operation for failed laparoscopic adjustable gastric banding (LAGB)
      convinced us that uncontrolled hunger is often the underlying cause. To control
      hunger after failed bariatric surgery,a novel approach combining LAGB with BPD
      duodenal switch (DS) has been tried. METHODS: Patients who had failed to lose
      weight after BPD or LAGB were considered in 2 groups. Group 1: patients who had
      failed LAGB underwent laparoscopic BPD-DS without sleeve gastrectomy, with the
      LAGB left in-situ. Group 2: patients who had failed primary (subgroup 2a) or
      revision (subgroup 2b) BPD had a LAGB placed with no other revision of their
      surgery. RESULTS: 11 patients have undergone this form of revision surgery with
      little morbidity. Mean age at the original operation was 45 years, mean (range)
      BMI was 45.3 (38-62) kg/m(2). After the reoperation, at 3 months (9 patients)
      mean BMI was 30 kg/m(2) and at 6 months (4 patients) mean BMI was 27 kg/m(2).
      CONCLUSION: In this small study, combination surgery was safe and effective for
      failed BPD or LAGB. LAGB failure may be best managed with DS malabsorption
      without gastric resection.

PMID- 15186639
TI  - Combination of laparoscopic adjustable gastric banding and gastric bypass:
      current situation and future prospects -- routine use not advised.
AB  - Although bariatric surgery has proven to be the most effective treatment for
      morbid obesity, most surgical techniques do have failures. In an effort to
      improve the reliability, several surgeons started to use a combination of a
      laparoscopic gastric bypass with an adjustable gastric band. Because of concerns
      regarding a possible negative outcome, an expert meeting was organized to
      evaluate the current situation and future application. In total, 104 operations
      were reported,with several technical variations. The overall complication rate
      was acceptable, but the percentage of the band erosions was 6.7%, which is too
      high. The potential advantages (adjustability, maintained access to the stomach
      and biliary tree, and reversibility) do not compensate for this complication
      rate. Based on the results and the opinion of the surgeons experienced in this
      technique, it is concluded that the combination of gastric bypass with an
      adjustable gastric band to form the pouch is not recommended.

PMID- 15186640
TI  - Purpura fulminans due to Streptococcus pneumoniae sepsis following gastric
      bypass.
AB  - An older female underwent bariatric surgery which was followed by a significant
      weight loss and diarrhea, from which C. difficile was isolated just before her
      hospitalization. Less than 48 hours after admission, she became febrile,
      developed deep venous thrombosis of the leg and a pulmonary embolus. Blood
      cultures grew out Streptococcus pneumoniae and the patient developed purpura
      fulminans. There was convincing laboratory evidence for disseminated
      intravascular coagulation and a marked depletion of proteins C and S as well as
      antithrombin. Treatment with ceftriaxone and drotrecogin alfa together with
      parenteral nutrition led to disappearance of the pathogen and ultimate
      normalization of the anticoagulant factors. We believe that malabsorption of
      vitamin K dependent proteins C, S and antithrombin due to bariatric surgery
      predisposed the patient to purpura fulminans and disseminated intravascular
      coagulation.

PMID- 15186642
TI  - Thyrotoxicosis after gastric bypass.
AB  - Obesity surgery is the optimal therapy for morbid obesity. A case is presented of
      a young woman who developed thyrotoxicosis, believed to be part of subacute
      thyroiditis, some days after undergoing laparoscopic Roux-en-Y gastric bypass.
      This clinical entity can present difficulties in differential diagnosis from
      potential postoperative complications. The correct diagnosis and adequate
      treatment made possible a favorable recovery.

PMID- 15186641
TI  - Incomplete reversal of enoxaparin toxicity by protamine: implications of renal
      insufficiency, obesity, and low molecular weight heparin sulfate content.
AB  - The use of low molecular weight heparin (LMWH) is increasing throughout North
      America and Europe for a number of reasons: 1). ease of use; 2). predictable dose
      response; 3). less heparin associated thrombocytopenia. However, aside from
      increased costs, LMWH has significant potential drawbacks: 1). poor
      reversibility; 2). tendency to accumulate in renal insufficiency; 3). less
      experience in subset patient groups such as morbid obesity. We report a case of a
      postoperative morbidly obese patient who developed enoxaparin toxicity secondary
      to acute renal failure that did not reverse with protamine sulfate infusion. In
      addition, we review the use of LMWH in renal insufficiency, dosing in obese
      patients,and the importance of sulfate content in the efficacy of protamine
      sulfate as a reversing agent for LMWH.

PMID- 15186644
TI  - Intussusception after gastric bypass.

PMID- 15186643
TI  - Diagnosis and management of acute gastric distention following laparoscopic
      adjustable gastric banding.
AB  - Laparoscopic adjustable gastric banding (LAGB) is commonly performed for weight
      reduction in the morbidly obese population. Morbidly obese patients often suffer
      from many co-morbid conditions including diabetes. Diabetic patients may suffer
      from symptomatic or asymptomatic gastric dysmotility resulting in intermittent
      gastric distention. Following gastric banding, in the early postoperative period,
      patients may be unable to decompress trapped air in the stomach and may develop
      severe acute distention with associated risk for catastrophic results. We present
      the case of a diabetic patient who underwent an uneventful LAGB but returned to
      the hospital with severe abdominal and back pain. Following the diagnosis of
      acute gastric distention using an abdominal roentgenogram, the stomach was
      decompressed using a naso-gastric tube. Following initiation of promotility
      agents, the patient was successfully discharged home without symptoms. A high
      index of suspicion, prompt diagnosis and appropriate management can prevent
      complications of acute gastric distention in this patient population.

PMID- 15186645
TI  - Endoscopic management of bleeding after gastric bypass -- a therapeutic
      alternative.

PMID- 15186646
TI  - Gastric banding and biliopancreatic diversion in superobesity.

PMID- 15186652
TI  - Toward optimal health: the experts discuss advances in diabetes management in
      women. Interview by Jodi Godfrey.

PMID- 15186651
TI  - Visceral leishmaniasis: consequences to women in a Bangladeshi community.
AB  - Visceral leishmaniasis (VL) or kala-azar (KA) affects the rural poor, causing
      significant morbidity and mortality. We examined the epidemiological and social
      impact of KA in an affected village in Bangladesh. A population-based survey of
      the village residents showed a case fatality rate of 14.7% among females and 5.3%
      among males. Before initiation of the study, female patients were ill longer than
      males before they received treatment. Future work needs to focus on understanding
      the implications of KA on women and to develop sustainable strategies for
      appropriate and timely access to treatment.

PMID- 15186654
TI  - Breast vascular calcification and risk of coronary heart disease, stroke, and
      heart failure.
AB  - OBJECTIVE: Vascular calcification holds promise as a useful cardiovascular risk
      maker. Our objective was to examine the association between breast vascular
      calcification and risk of cardiovascular disease (CVD) outcomes. METHODS: A
      cohort study was performed among 12,761 women, 40-79 years of age at baseline
      (1968-1973), who attended multiphasic health checkups that included mammography.
      The outcome measures included coronary heart disease (CHD), ischemic stroke,
      transient ischemic attack (TIA), hemorrhagic stroke, and heart failure,
      ascertained using discharge diagnosis codes and death records through December
      31, 2000 (median follow-up, 24.8 years). RESULTS: Breast vascular calcification
      was present in 424 (3%) women. It was independently and positively associated
      with age, high parity, and diabetes and inversely associated with education level
      and current cigarette smoking. After adjustment for age, education level, race,
      cigarette smoking, alcohol use, body mass index (BMI), serum total cholesterol,
      hypertension, diabetes, parental history of myocardial infarction (MI), parity,
      and hormone replacement therapy (HRT), breast vascular calcification was
      associated with a 1.32-fold increased risk of CHD (95% confidence interval [CI]
      1.08-1.60), a 1.41-fold increased risk of ischemic stroke (95% CI 1.11-1.78), and
      a 1.52-fold increased risk of heart failure (95% CI 1.18-1.98). CONCLUSIONS:
      Breast vascular calcification detected as part of a screening mammogram was an
      independent risk factor for multiple cardiovascular outcomes among women. The
      value of mammography in cardiovascular risk stratification deserves further
      investigation.

PMID- 15186657
TI  - Inhibition of low-density lipoprotein and high-density lipoprotein oxidation by
      raloxifene.
AB  - BACKGROUND: Raloxifene (RX), a selective estrogen receptor modulator (SERM), has
      demonstrated hypolipidemic and in vitro antioxidant properties. In the
      pathogenesis of atherosclerosis, the oxidative modification of low-density
      lipoprotein (LDL) is implicated to play a crucial role. METHODS: In this study,
      we investigated the antioxidant properties of RX during in vitro LDL and high
      density lipoprotein (HDL) oxidation. The concentrations of RX, chosen ranged from
      5.1 to 5100 nM. Isolated lipoproteins were supplemented with RX, and copper
      mediated oxidation was monitored via the formation of conjugated dienes (CD), and
      oxidation resistance (lag time) was calculated. The formation of thiobarbituric
      acid-reactive substances (TBARS) was measured after 90, 120, 210, and 300 minutes
      of oxidation. RESULTS: We found a dose-dependent inhibition of LDL and HDL
      oxidation in terms of both increased lag time and decreased formation of TBARS.
      Differences in lag time became significant at 51 nM RX added to LDL and HDL,
      respectively. TBARS formation in LDL was significantly reduced after 120 minutes
      incubation with 510 and 5100 nM RX and also after 300 minutes with 51 nM RX
      added. In HDL, significant reduction in TBARS formation was observed after 90
      minutes by the addition of 51, 510, and 5100 nM RX. CONCLUSIONS: These results
      confirm data from previous studies concerning inhibition of in vitro oxidation of
      LDL by RX and additionally show that RX efficiently inhibits in vitro oxidation
      of HDL in a broad concentration range.

PMID- 15186656
TI  - Sex differentials in biological risk factors for chronic disease: estimates from
      population-based surveys.
AB  - BACKGROUND: In light of substantial sex differences in health outcomes,
      researchers need to focus on disentangling the underlying biological and social
      determinants. The objective of this study is to determine whether two populations
      that differ in many cultural and social dimensions--Taiwan and the United States-
      also vary with regard to sex differentials in biological markers of chronic
      disease. METHODS: The analysis is based on three population-based surveys that
      include interviews, urine and blood specimens, and physical examinations: the
      Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan, the Wisconsin
      Longitudinal Survey (WLS), and the MacArthur studies of successful aging. The
      outcomes comprise six indicators of cardiovascular risk (total/high-density
      lipoprotein [HDL] cholesterol, HDL cholesterol, systolic and diastolic blood
      pressure, glycosylated hemoglobin, and waist/hip ratio) and four markers of
      sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis
      functioning (epinephrine, norepinephrine, cortisol, and dehydroepiandrosterone
      sulfate [DHEA-S]). RESULTS: U.S. males have significantly higher risk than
      females for all indicators of cardiovascular risk except glycosylated hemoglobin
      (p < 0.05). Sex differences are less consistent and smaller in Taiwan. Indicators
      of SNS and HPA axis functioning reveal a significant female disadvantage in both
      countries. CONCLUSIONS: The analysis identifies important sex differences between
      Taiwan and the United States in biomarkers of cardiovascular risk that are
      consistent with cause of death data and may emanate from cultural and social
      differences between the two societies. The similarity of sex differences in SNS
      and HPA axis functioning across studies may reflect either stable sex differences
      in biological aging of these axes or commonalities in the social construction of
      gender-based responses to life experiences.

PMID- 15186658
TI  - Reducing cardiovascular risk factors in postmenopausal women through a lifestyle
      change intervention.
AB  - BACKGROUND: The impact of a 6-month lifestyle change intervention on
      cardiovascular risk factors in obese, sedentary, postmenopausal women was
      examined. A secondary aim of this investigation was to determine whether the
      addition of self-control skills training to an empirically supported lifestyle
      change intervention would result in greater cardiovascular risk reduction.
      METHODS: Forty-four women were randomly assigned to receive either a lifestyle
      change or a lifestyle change with self-control skills intervention. Pretreatment
      and posttreatment weight loss, body composition, physical activity,
      cardiorespiratory fitness, diet, blood pressure (BP), blood lipids, and
      psychosocial functioning were assessed. Also, at 1-year posttreatment, weight
      loss, body composition, self-reported physical activity, and psychosocial
      functioning were assessed. RESULTS: The women significantly increased their
      physical activity (+39.6%) and cardiorespiratory fitness (+13.5%) and reduced
      their body weight (-6.5%), fat mass (-7.4%), body fat (-2.4%), BP (SBP -6.2%, DBP
      -9.2%), total cholesterol (-7.4%), triglycerides (-16.5%), and low-density
      lipoprotein (LDL) cholesterol (9.1%) and improved their diet (p < 0.05). At the 1
      year follow-up, women had regained approximately 63% of their posttreatment
      weight loss (p < 0.05), but had maintained their previous increases in physical
      activity. Additionally, there were no significant changes in fat free mass, body
      fat, anxiety, or depression between the end of treatment and 1-year
      posttreatment. The addition of self-control skills training did not significantly
      improve cardiovascular risk reduction. CONCLUSIONS: Lifestyle change
      interventions may be an effective means for reducing cardiovascular risk in
      obese, sedentary, postmenopausal women. However, greater attention should be
      devoted to the maintenance of these positive lifestyle changes.

PMID- 15186659
TI  - Estrogen bioassay of ginseng extract and ArginMax, a nutritional supplement for
      the enhancement of female sexual function.
AB  - PURPOSE: To determine whether ArginMax (The Daily Wellness Co., Sunnyvale, CA) or
      the Panax ginseng extract it contains has any estrogenic activity. ArginMax for
      Women, a nutritional supplement for optimization of sexual health, contains L
      arginine, ginseng, ginkgo, damiana, multivitamins, and minerals. METHODS: A human
      endometrial adenocarcinoma cell line, Ishikawa, which contains an alkaline
      phosphatase (AP) enzyme sensitive to estrogen stimulation, was used in a bioassay
      to determine whether Panax ginseng or ArginMax contained estrogenic components.
      RESULTS: Neither ArginMax nor Panax ginseng stimulated AP at any of the
      concentrations tested. CONCLUSIONS: No estrogenic activity was evident in the
      sample of Panax ginseng extract tested or in a sample of ArginMax containing this
      extract in combination with other ingredients.

PMID- 15186660
TI  - Osteoporosis in women with disabilities.
AB  - Women with physical and cognitive disabilities are at high risk for osteoporosis
      and osteoporosis-related fractures. Women with physical disabilities frequently
      are nonambulatory and have bone loss due to immobility. Women with cognitive
      disabilities have high rates of osteopenia and osteoporosis, likely partially due
      to high rates of anticonvulsant medication use. Women with Down syndrome are at
      especially high risk of osteopenia and osteoporosis, possibly because of lower
      peak bone density levels. Prevention of osteoporosis and related fractures in
      this population includes population-based measures, such as calcium and vitamin D
      supplementation and risk-based screening procedures. Primary care providers and
      specialists need to prioritize osteoporosis prevention strategies when taking
      care of women with disabilities. Future research is needed to determine optimal
      screening and prevention strategies in this very high risk population.

PMID- 15186661
TI  - After the Women's Health Initiative: Postmenopausal women's experiences with
      discontinuing estrogen replacement therapy.
AB  - OBJECTIVE: To gather information about women's responses to the publication of
      the Women's Health Initiative (WHI) and to determine what proportion of women
      stopped hormone replacement therapy (HRT) and whether the technique of
      discontinuation affected the recurrence of menopausal symptoms. METHODS: 73
      subjects were identified through VA pharmacy records and were mailed a letter
      detailing the results of the WHI. A follow-up questionnaire was mailed several
      months later to the same population. RESULTS: 48 subjects responded and were
      eligible for inclusion in the study. Mean age was 62 years; 37 (77%) stopped
      taking HRT, and 11 (23%) continued. Twenty patients stopped abruptly, and 17
      tapered off HRT. Eight (40%) of the group who stopped abruptly experienced
      recurrent menopausal symptoms, compared with 12 (71%) of the group who tapered
      HRT. CONCLUSIONS: In a population of women veterans, 77% stopped HRT after
      publication of the WHI. Tapering HRT, rather than stopping abruptly, did not
      reduce the recurrence of menopausal symptoms in our patient population.

PMID- 15186663
TI  - The professionalism movement: a pause might not be sufficient.

PMID- 15186664
TI  - The professionalism movement: can we pause?
AB  - The topic of developing professionalism dominated the content of many academic
      medicine publications and conference agendas during the past decade. Calls to
      address the development of professionalism among medical students and residents
      have come from professional societies, accrediting agencies, and a host of
      educators in the biomedical sciences. The language of the professionalism
      movement is now a given among those in academic medicine. We raise serious
      concerns about the professionalism discourse and how the specialized language of
      academic medicine disciplines has defined, organized, contained, and made
      seemingly immutable a group of attitudes, values, and behaviors subsumed under
      the label of "professionalism." In particular, we argue that the professionalism
      discourse needs to pay more attention to the academic environment in which
      students are educated, that it should articulate specific positive behaviors,
      that the theory of professionalism must be constructed from a dialogue with those
      we are educating, and that this theoretical and practical discourse must aim at a
      deeper understanding of social justice and the role of medicine within a just
      society.

PMID- 15186665
TI  - Professionalism and the social role of medicine.

PMID- 15186666
TI  - Creating a complete picture of educating for professionalism.

PMID- 15186668
TI  - Discourse as rock formation--fruitcake as professionalism.

PMID- 15186669
TI  - Professionalism: the formation of physicians.

PMID- 15186670
TI  - Professionalism from the apprentice's perspective.

PMID- 15186671
TI  - Taking the history of medical ethics seriously in teaching medical
      professionalism.

PMID- 15186673
TI  - The professionalism movement: behaviors are the key to progress.

PMID- 15186674
TI  - Pausing to consider recommendations for recasting the professionalism movement in
      academic medicine.

PMID- 15186675
TI  - Physician-patient relations: no more models.
AB  - Currently, the common theoretical models of "preferred" decision-making
      relationships do not correspond well with clinical experience. This interview
      study of congestive heart failure (CHF) patients documents the variety of patient
      preferences for decision-making, and the necessity for attention to family
      involvement. In addition, these findings illustrate the confusion as to the
      designation of surrogate decision-makers and physicians in charge. We conclude
      that no single model of physician-patient decision-making should be preferred,
      and that physicians should first ask patients how they want medical information
      and decision-making to be handled.

PMID- 15186676
TI  - Deriving professionalism from its roots.

PMID- 15186677
TI  - Returning to professionalism: the re-emergence of medicine's art.

PMID- 15186678
TI  - The medical exam as political humiliation.

PMID- 15186679
TI  - Professionalism in medical education.

PMID- 15186680
TI  - The genetic difference principle.
AB  - In the newly emerging debates about genetics and justice three distinct
      principles have begun to emerge concerning what the distributive aim of genetic
      interventions should be. These principles are: genetic equality, a genetic decent
      minimum, and the genetic difference principle. In this paper, I examine the
      rationale of each of these principles and argue that genetic equality and a
      genetic decent minimum are ill-equipped to tackle what I call the currency
      problem and the problem of weight. The genetic difference principle is the most
      promising of the three principles and I develop this principle so that it takes
      seriously the concerns of just health care and distributive justice in general.
      Given the strains on public funds for other important social programmes, the
      costs of pursuing genetic interventions and the nature of genetic interventions,
      I conclude that a more lax interpretation of the genetic difference principle is
      appropriate. This interpretation stipulates that genetic inequalities should be
      arranged so that they are to the greatest reasonable benefit of the least
      advantaged. Such a proposal is consistent with prioritarianism and provides some
      practical guidance for non-ideal societies--that is, societies that do not have
      the endless amount of resources needed to satisfy every requirement of justice.

PMID- 15186681
TI  - Where the rubber meets the road: a cyclist's guide to teaching professionalism.

PMID- 15186682
TI  - Professionalism: is diluting core values a good idea?

PMID- 15186683
TI  - Integrity in the relationship between medical ethics and professionalism.

PMID- 15186684
TI  - Toward the operationalization of professionalism: a commentary.

PMID- 15186685
TI  - Telomeres and the ethics of human cloning.
AB  - In search of a potential problem with cloning, I investigate the phenomenon of
      telomere shortening which is caused by cell replication; clones created from
      somatic cells will have shortened telomeres and therefore reach a state of
      senescence more rapidly. While genetic intervention might fix this problem at
      some point in the future, I ask whether, absent technological advances, this
      biological phenomenon undermines the moral permissibility of cloning.

PMID- 15186686
TI  - Avoiding fallacies of misplaced concreteness in medical professionalism.

PMID- 15186687
TI  - When "minimal risk" research yields clinically-significant data, maybe the risks
      aren't so minimal.
AB  - Surveys and routine clinical procedures applied in research protocols are
      typically considered only minimally risky to participants. The apparent benign
      nature of "minimal risk" tasks increases the chance that investigators and
      Institutional Review Boards (IRBs) will overlook the probability that clinical
      tools will identify signs, symptoms, or definitive test results that are
      clinically-relevant to subjects' welfare. "Minimal risk" procedures may also pose
      a particular hazard to participants in clinical research by increasing the
      therapeutic misconception because the tasks mimic clinical care and are often
      conducted in clinical settings. Investigators should anticipate which measures
      could yield clinically-important findings and should describe explicit plans for
      data monitoring, disclosure, and follow-up. Protocols that include reliable and
      valid clinical measures should prompt a more detailed risk assessment by the IRB,
      even when the tasks meet the regulatory criteria for minimal physical,
      psychological, or emotional risk.

PMID- 15186688
TI  - The social-contract model of professionalism: baby or bath water?

PMID- 15186689
TI  - Professionalism and discourse: but wait, there's more!

PMID- 15186690
TI  - The professionalism movement: pausing and reflecting are essential.

PMID- 15186691
TI  - The role of empirical research in defining, promoting, and evaluating
      professionalism in context.

PMID- 15186692
TI  - Justice and the house of medicine: the mortgaging of ecology and economics.

PMID- 15186693
TI  - The professionalism movement: a more optimistic view.

PMID- 15186694
TI  - The theory and practice of professionalism.

PMID- 15186695
TI  - Pausing for professionalism.

PMID- 15186696
TI  - Trumping professionalism.

PMID- 15186697
TI  - Socialization in medical training: exploring "lifelong curiosity" and a
      "community of support".

PMID- 15186698
TI  - Self-preservation: an argument for therapeutic cloning, and a strategy for
      fostering respect for moral integrity.
AB  - The issues of human cloning and stem cell retrieval are inseparable in
      circumstances in which the rationale of self-preservation may be invoked as a
      negative right. I apply this rationale to a hypothetical case in which cloning is
      necessary to preserve the bodily integrity or life of an individual. Self
      preservation as moral integrity is examined in a narrower context, i.e., as
      applicable to those for whom deliberate termination of embryonic life is morally
      problematic. This issue is addressed through comparison with two paradigms
      commonly used in support of clinical practice: the distinction between letting
      die and killing, and the permissibility of vital organ retrieval after death.
      Although these paradigms are questionable in their own right, they offer a
      rationale by which scientists and clinicians may respect the negative right to
      moral integrity of those with whom they disagree.

PMID- 15186699
TI  - Community-based participatory research in United States bioethics: steps toward
      more democratic theory and policy.

PMID- 15186702
TI  - New and emerging theories of cardiovascular disease: infection and elevated iron.
AB  - Heart disease is the leading cause of death in both men and women in
      industrialized countries. Despite the tremendous gains made in decreasing the
      number of deaths due to cardiovascular disease, it still is health care's
      greatest challenge. Traditional risk factors account for only 50% of the
      incidence of cardiac disease. In fact, many individuals who develop heart disease
      have normal cholesterol and blood pressure levels. This suggests that other less
      well-studied risk factors may also play a role. The purpose of this report is to
      examine the role that recently suggested risk factors may play in the development
      of heart disease: coronary artery infection, specifically from Chlamydia
      pneumoniae, and elevated iron levels. Both initiate an inflammatory response,
      which might explain the elevated C-reactive protein levels frequently found in
      those who suffer from cardiac disease.

PMID- 15186703
TI  - The concept of epigenetics and its role in the development of cardiovascular
      disease: commentary on "new and emerging theories of cardiovascular disease".

PMID- 15186704
TI  - Commentary on "new and emerging theories of cardiovascular disease".

PMID- 15186706
TI  - Ebselen decreases oxygen free radical production and iron concentrations in the
      hearts of chronically iron-overloaded mice.
AB  - Chronic iron overload is a major cause of cardiac failure throughout the world,
      but its pathogenesis remains to be clarified. It is conjectured that the toxicity
      of iron is due to its ability to catalyze the formation of oxygen free radicals
      (OFR), which can damage cellular membranes, proteins, and DNA. The authors report
      on the cardioprotective effects of the glutathione peroxidase (GPx) mimic ebselen
      on iron concentrations in the heart and GPx activity, and on the production of
      the cytotoxic aldehydes hexanal, 4-hydroxyl-2-nonenal (HNE), and malondialdehyde
      (MDA). Fifteen B6D2F1 mice were randomized to 1 of 3 treatment groups for a total
      of 20 treatments: 1) control (0.1 mL normal saline i.p. per mouse, per day); 2)
      iron-only (10 mg iron dextran i.p. per mouse, per day); 3) iron plus ebselen (25
      mg/kg p.o. per mouse, per day). In comparison to iron-only treated mice, the
      authors' findings show that supplementation with ebselen can decrease both
      cytotoxic aldehyde and iron concentrations in heart tissue. Additionally, mice
      supplemented with ebselen had an increase in GPx activity level in comparison to
      iron-only treated mice. To the authors' knowledge, this is the first study to
      examine the cardioprotective effects of ebselen against OFR damage in a model of
      chronic iron overload. These findings suggest that ebselen may have significance
      in the management of disorders of iron overload.

PMID- 15186707
TI  - Lifestyle practices and nocturnal sleep in midlife women with and without
      insomnia.
AB  - Relationships between common lifestyle practices important to sleep hygiene
      (e.g., smoking cigarettes, drinking alcohol, ingesting caffeine, exercising, bed
      times, getting-up times) and nocturnal sleep have not been documented for women
      with insomnia in their home environments. This community-based sample of 121
      women, ages 40 to 55 years, included 92 women who had experienced insomnia for at
      least 3 months and 29 women with good-quality sleep. Women recorded lifestyle
      practices and sleep perceptions (time to fall asleep, awakenings during sleep,
      feeling rested after sleeping, and overall sleep quality) in diaries while
      undergoing 6 nights of somnographic sleep monitoring at home. Compared to women
      with good-quality sleep, women with insomnia reported greater night-to-night
      variation in perceived sleep variables, poorer overall sleep quality (M = 2.8, SD
      = 0.7 vs. M = 1.9, SD = 0.5, P < 0.05), and longer times to fall asleep (M = 25
      min, SD = 14.2 vs. M= 12.9 min, SD = 5.8, P < 0.05). Correlations between mean
      individual lifestyle practice scores and mean perceived or somnographic sleep
      variables were low, ranging from 0 to 0.20. An aggregated sleep hygiene practice
      score was not associated with either perceived or somnographic sleep variables.
      Regression analysis using dummy variables showed that combinations of alcohol,
      caffeine, exercise, smoking, and history of physical disease explained 9% to 19%
      of variance in perceived or somnographic sleep variables. Lifestyle practices,
      and combinations thereof, do warrant consideration when assessing or treating
      insomnia, but these data fail to support a dominant relationship between
      lifestyle practices and either perceived or somnographic sleep variables.

PMID- 15186708
TI  - Physiological and psychological correlates of fatigue in HIV disease.
AB  - Fatigue is a frequent symptom reported by persons living with HIV disease and one
      that affects all aspects of quality of life. To improve quality of care of
      persons with HIV disease, it is important to address all factors that contribute
      to fatigue. The purpose of this study was to determine the associations of
      physiological, psychological, and sociological factors with fatigue in an HIV
      infected population. With Piper's integrated fatigue model guiding selection,
      factors examined in this study were hemoglobin, hematocrit, CD4+ cell count, HIV
      RNA viral load, total sleep time, sleep quality, daytime sleepiness, HIV-related
      symptoms, anxiety, depression, and perceived stress. The sample (N = 79) for this
      descriptive correlational study was recruited from a primary health care
      association in South Carolina and consisted of 42 (53.2%) HIV-infected women and
      37 (46.8%) HIV-infected men between the ages of 24 and 63 years (x = 39.9, s =
      7.9). Of the participants, 70 (90%) were African American, 5 (6%) were Caucasian,
      and 3 (4%) were Hispanic. Using Pearson's r, significant relationships were
      observed between fatigue and sleep quality, daytime sleepiness, HIV-related
      symptoms, state anxiety, trait anxiety, depression, and perceived stress. Sleep
      quality (F5,65 = 12.02, P = 0.0009), state anxiety (F5,65 = 8.28, P = 0.0054),
      HIV-related symptoms (F5,65 = 4.87, P = 0.0308), and depression (F5,65 = 7.31, P
      = 0.0087) retained significance in a 3-step, backward stepwise elimination model
      and accounted for 67% of the variance in fatigue. These findings underscore the
      need for addressing psychosocial stressors and sleep quality in developing
      effective care for HIV-infected individuals who experience fatigue.

PMID- 15186709
TI  - Failure of valacyclovir for herpes zoster in a moderately immunocompromised HIV
      infected patient.
AB  - Whereas valacyclovir is widely used and is recommended by some authors in
      moderately immunocompromised HIV-infected patients, its use has not been
      validated by clinical studies. We report a case of herpes zoster in an HIV
      infected patient for whom neurologic complication was not avoided despite
      valacyclovir therapy. Clinical outcome was favorable after intravenous acyclovir.
      This case suggests careful monitoring of valacyclovir in HIV-infected patients is
      necessary.

PMID- 15186710
TI  - Preventing and managing antiretroviral drug resistance.
AB  - Development of resistance to antiretroviral drugs (ARVs) is a major impediment to
      optimum treatment of HIV-1 infection. Although resistance testing can help to
      select subsequent regimens when virologic failure occurs, cross-resistance, which
      affects all classes of ARVs, may make it more difficult to achieve optimum
      control of HIV. We have known for some time that our first choice of
      antiretroviral therapy offers the best chance to control HIV replication and that
      initial therapy should be selected with an eye on future options. Potency is the
      first line of defense against the development of resistance. Other factors that
      affect resistance development include: tolerability, potential for optimum
      adherence, and genetic and pharmacologic barriers to development of resistance.
      If resistance emerges, only a single drug may be affected initially, and a rapid
      change in ARVs may preserve the efficacy of other components. One cautionary note
      is that we can no longer assume that a patient's HIV is fully susceptible to all
      ARVs even in the initial regimen. Transmission of drug-resistant HIV means that
      the genetic composition may be that of an "experienced" virus with reduced
      susceptibility to ARVs. Resistance testing at the time of transmission is most
      likely to reveal this resistance, but over time the dominant genetic pattern may
      revert to wild-type, and be missed by resistance testing. Because "archived"
      resistant HIV may emerge quickly once treatment is initiated, we need to keep
      this in mind when selecting initial therapy.

PMID- 15186711
TI  - Strategies for coping with fatigue among HIV-positive individuals fifty years and
      older.
AB  - Fatigue, a common symptom among persons living with HIV/AIDS, is often
      underreported and undertreated. However, given fatigue's pervasive effects on
      well-being and functioning, the identification of its physiologic and
      psychological causes and strategies to alleviate it are important to patients'
      quality of life. As part of a study to understand better how HIV-positive middle
      aged and older adults (50+) manage common symptoms, 49 participants discussed in
      depth their experience with fatigue. Most engaged in both self-care activities
      and sought the assistance of a health care professional. Frequent strategies
      included dietary changes, vitamins, modification of routines, rest, exercise, and
      prescribed medications for anemia, Vitamin B(12) deficiency, or testosterone
      deficiency. Complementary and alternative medicine (e.g., acupuncture, massage,
      herbal remedies, special juices) was also commonly used. Participants often used
      multiple strategies to alleviate their fatigue, possibly because of their
      tendency to attribute it to multiple causes. These HIV-positive older adults were
      also apt to view fatigue as an indirect indicator of their overall health status
      and immune functioning. This may explain why many of the coping strategies they
      used could be considered approaches to improving their overall health status as a
      means to increasing their energy levels. Health care professionals can play an
      important role in helping HIV-positive individuals manage their fatigue. The
      majority of participants tried to implement the coping suggestions offered by
      health care professionals, as well as those from family, friends, and support
      group members.

PMID- 15186712
TI  - Adherence to HAART among HIV-infected persons in rural Louisiana.
AB  - The purpose of this study was to examine factors associated with nonadherence to
      highly active antiretroviral therapy (HAART) in patients seen in HIV clinics
      throughout nonurban Louisiana. A convenience sample of 273 patients from 8 areas
      in nonurban Louisiana were interviewed to obtain demographic, clinical and
      adherence information. Associations between demographic, clinical, and behavioral
      factors and nonadherence were examined. Ideally, non-adherence should not exceed
      5% in patients for whom HAART was prescribed. Mean age was 38.6 years (range, 19
      66), 29.3% were female, 60.1% were African American, 34.4% reported nonadherence
      to their HAART medication (defined as the subject's self-report of missing any
      doses of HAART medication in the prior week). In the prior month, participants
      reported the following behaviors: binge drinking (12.8%), problem drinking
      (12.8%), and illicit drug use (16.5%). Depression was found in 49.8% of the
      respondents. In logistic regression analysis, problem drinking odds ratio [OR]
      (95% confidence interval [CI]): 3.92 (1.69,9.09) was found to be associated with
      nonadherence. Demographic and behavioral factors such as illicit drug use and
      depression were not associated with nonadherence on multivariable analysis.
      Problem drinking was associated with lack of adherence to HAART over the past
      week. Interventions to treat problem drinking are needed and may improve
      adherence to medication for HIV-infected persons living in rural, town, and small
      city areas.

PMID- 15186713
TI  - Nonadherence to antiretroviral therapy in HIV-positive patients in Costa Rica.
AB  - A cross-sectional study was performed among seropositive individuals who sought
      HIV treatment at an outpatient clinic in San Jose, Costa Rica, to determine the
      prevalence, predictors, and reasons for nonadherence to antiretroviral. A
      structured, face-to-face interview was administered to 88 patients. The primary
      outcome of adherence was measured as taking 100% of medications within 3 days
      prior to interview. A number of risk factors, including demographic information,
      HIV knowledge, logistics of the regimen, and management skills were assessed.
      Statistical analyses included logistic regression. Eighty-five percent of
      patients took 100% of their medications in the last 3 days. Factors that were
      correlated with nonadherence included difficulty in finding transportation to the
      clinic (odds ratio [OR] = 6.3, p = 0.01), not laying pills out as a management
      skill (OR = 9.9, p = 0.01), and prescription instructions to take medication on
      an empty stomach (OR = 6.7, p = 0.03). HIV-positive patients in this Costa Rican
      sample were fairly adherent to their drug regimens. To increase adherence among
      non-adherent individuals, interventions that increase access in remote areas and
      help people manage their regimens may be beneficial.

PMID- 15186714
TI  - Care for people living with HIV/AIDS: an assessment of day care centers in
      northern Thailand.
AB  - A cross-sectional survey of 271 day care center (DCC) members at 9 district
      hospitals was undertaken using an interviewer-administered questionnaire to
      assess the psychosocial and economic impact of the services provided by DCCs to
      people living with HIV/AIDS (PLWHA) and the costs of attending DCCs in Chiang Rai
      Province in Thailand. Data on the socioeconomic and demographic background of the
      participants, their reasons for attending DCCs, their medical services usage, the
      changes DCCs made on their lives, and the cost of attending DCCs were collected.
      "Receiving information" (37%) and "meeting friends" (32%) were the two most
      common reasons while fewer participants gave "physical examination" (6%) and
      "counseling" (0.4%) as their reasons for attending DCCs. Nearly half became more
      positive about their lives and 40% learned how to live with the disease. Through
      DCCs, 24% and 58% were receiving prophylaxis for tuberculosis and Pneumocystis
      carinii pneumonia respectively, and 15% were taking antiretrovirals. The majority
      (85%) lived with 30 minutes of DCCs, and incurred travel cost up to 30 Baht (1
      USD approximately 40 Baht). The mean monthly income of those with jobs was 1,565
      Baht and 42% lost wages when attending DCCs, more than half of whom were the main
      income earners in their families. In conclusion, DCCs benefit PLWHA through their
      educational and psychological support. However, they can be further utilized for
      their medical services. As an expansion of antiretroviral treatment is planned in
      Thailand, the DCCs' role should be fully explored and clearly defined. Minimizing
      economic and geographical barriers to access are some of the most immediate
      challenges.

PMID- 15186715
TI  - Lipodystrophy drug being evaluated.

PMID- 15186716
TI  - MTV program enters seventh year.

PMID- 15186717
TI  - Stem cells and development.

PMID- 15186718
TI  - Interaction between normal and CML hematopoietic progenitors and stroma
      influences abnormal hematopoietic development.
AB  - Several studies have shown defective progenitor-stromal interactions in chronic
      myeloid leukemia (CML), and adhesive defects induced by BCR/ABL have been
      described. However, controversial results have been reported, and the role of the
      stroma in abnormal development of the hematopoietic system is not clear. In this
      study, CML hematopoietic and irradiated stromal cells were co-cultured in
      different combinations for 10 or 21 days. Maintenance of viable cells was
      dependent both on the sources of hematopoietic progenitors and stromal adherent
      layers, with normal cells performing better than their leukemic counterparts. The
      frequency of CD34(+) CD38(-) cells in the non-adherent fraction was more related
      to the source of hematopoietic cells than of stroma, and hematopoietic cells from
      normal subjects showed better performance. The simultaneous analysis of different
      combinations of normal and leukemic precursor cells and stromal layers, as done
      in the present work, suggests that the outcome of the interaction depends on
      characteristics of both compartments. This hematopoietic system development is
      influenced by intrinsic qualities of both hematopoietic stem cells and the
      supportive stroma.

PMID- 15186719
TI  - Identification of the adult human hemangioblast.
AB  - Recent studies show that human CD133(+) (previously known as AC133(+)) cells from
      mobilized peripheral blood consist of stem cells with either hematopoietic or
      endothelial potential. To test whether this population also contains individual
      precursors with both capacities, the defining characteristics of the elusive
      adult hemangioblast, we developed a culture system that allows single-cell
      analyses of differentiation. In the presence of vascular endothelial growth
      factor (VEGF), stem cell growth factor (SCGF), and FLT-3 ligand, CD133(+)
      enriched cells were first expanded and the amplified cells were transduced with a
      vector encoding an enhanced green fluorescent protein (EGFP) marker gene. Single
      EGFP(+) cells were then cocultured with corresponding non-transduced cells from
      the same experiment, yielding 50-100 marked cells in 8% of the wells after 2
      weeks. The resultant cells were divided and differentiated with either
      granulocyte colony-stimulating factor (G-CSF) or with SCGF and VEGF. These
      culture conditions resulted in the formation of neutrophil or endothelial cells,
      respectively, as identified morphologically and by phenotypic staining. Dual
      differentiation of EGFP(+) cells could be observed in one-quarter of clones from
      single-seeded cells, suggesting that 2% of EGFP(+) cells were in fact human
      hemangioblasts. These cells could be expanded for at least 28 days without losing
      this dual capacity. Hence, this culture system may be of clinical relevance in
      the development of cellular therapies for disorders involving hematopoiesis and
      the vascular system. In addition, our results provide important information
      related to the development of the vasculature and the potential role of
      hemangioblasts in vasculogenesis in adult humans.

PMID- 15186720
TI  - Propagation and maintenance of undifferentiated human embryonic stem cells.
AB  - Human embryonic stem (hES) cells, like other stem cells, have the capacity to
      self-renew without differentiation. Although hES cells can be differentiated to
      many different tissue types in vitro, clinical uses have not yet been realized
      from the study of hES cells. Anticipation that these cells would be immediately
      useful for creating models of human disease has not yet been fulfilled. However,
      because of their self-renewing and pluripotential nature, hES cells indeed hold
      unique promise for many areas of research and medicine. A major problem
      complicating developments in hES cell research is the difficulty of propagating
      and maintaining these cells in vitro without differentiation. This review
      addresses this problem and potential solutions in detail. In addition, the
      current state of research regarding the growth and maintenance of hES cells is
      summarized, along with basic protocols utilized by our laboratory for the
      successful propagation, characterization, and investigation of hES cells.

PMID- 15186721
TI  - Stem cell responses in tooth regeneration.
AB  - Scientific advances in the creation of restorative biomaterials, in vitro cell
      culture technology, tissue grafting, tissue engineering, molecular biology, and
      the human genome project provide the basis for the introduction of new
      technologies into dentistry. This review is intended to facilitate the
      development of stem cell therapy for use with established therapeutic modalities
      to restore and regenerate oral tissues. Teeth have been shown to mineralize in
      response to injury for many decades, but only in recent years has the position of
      the stem cells been localized around blood vessels. The cells have been
      identified as myofibroblastoid pericytes. The ability to control the
      differentiation and proliferation of these cells is being examined to create stem
      cell therapies that can solve dental problems more effectively than current
      treatment regimes. Although the problems of introducing these technologies are
      substantial, the potential benefits to patients and the profession are equally
      promising - a cure for caries and diseases, a cure for oral cancer, correction of
      congenital defects, and the regeneration of teeth and tissues to restore oral
      functions. The purpose of this review is to describe how these new technologies
      can most usefully be employed in dentistry to enable clinicians to satisfy
      patient demand for a nondefective dentition.

PMID- 15186722
TI  - Effects of mesenchymal stem cells on differentiation, maturation, and function of
      human monocyte-derived dendritic cells.
AB  - Mesenchymal stem cells (MSCs) reportedly inhibit the mixed lymphocyte reaction.
      Whether this effect is mediated by dendritic cells (DCs) is still unknown. In
      this study, we used an in vitro model to observe the effects of MSCs and their
      supernatants on the development of monocyte-derived DCs. Phenotypes and the
      endocytosic ability of harvested DCs were determined by flow cytometry;
      interleukin 12 (IL-12) secreted by DCs was evaluated by enzyme-linked
      immunosorbent assay (ELISA); and the antigen-presenting function of DCs was
      evaluated by MLR. Our results show that MSCs inhibit the up-regulation of CD1a,
      CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of
      CD40, CD86, and CD83 expression during DC maturation. MSCs supernatants had no
      effect on DCs differentiation, but they inhibited the up-regulation of CD83
      during maturation. Both MSCs and their supernatants interfered with endocytosis
      of DCs, decreased their capacity to secret IL-12 and activate alloreactive T
      cells. Thus, effects of MSCs on DCs contribute to immunoregulation and
      development.

PMID- 15186723
TI  - The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone
      development: effects on osteoblastic differentiation induced by parathyroid
      hormone and vitamin D(3).
AB  - Human bone marrow-derived mesenchymal stem cells (MSCs) represent an ideal source
      for cell therapy for inherited and degenerative diseases, bone and cartilage
      repair, and as target for gene therapy. The role of the combination of human
      parathyroid hormone (PTH) and vitamin D(3) in bone formation and mineralization
      has been established in several osteoblast cell culture studies. The aim of the
      present study was to evaluate the role of this hormonal combination alone and in
      the presence of bone morphogenetic protein-4 (BMP-4) or-6 (BMP-6) in inducing
      osteogenic differentiation of human MSC. Human MSC derived from adult normal bone
      marrow that are positive for CD29, CD44, CD105, and CD166 and negative for CD14,
      CD34, and CD45, were treated with the PTH and 1,25-dihydroxyvitamin D(3) in the
      presence and absence of recombinant human BMP-4 or BMP6. PTH and vitamin D(3)
      induced high levels of expression of two key markers of bone formation:
      osteocalcin and alkaline phosphatase by MSCs. BMP-6 but not BMP-4 increased
      osteocalcin expression induced by PTH and vitamin D(3). Both BMPs enhanced
      calcium formation in MSC cultures and this response was potentiated by PTH and
      vitamin D(3). The present results revealed a novel potent effect of PTH and
      vitamin D(3) plus BMPs in inducing bone development by human MSCs. These results
      may facilitate therapeutic utility of MSCs for bone disease and help clarify
      mechanisms involved in stem cell-mediated bone development.

PMID- 15186724
TI  - Evaluation of sICAM-1, sVCAM-1, and sE-Selectin levels in patients with
      metastatic breast cancer receiving high-dose chemotherapy.
AB  - Soluble forms of some cell adhesion molecules (CAM), sICAM-1, sVCAM-1, and sE
      selectin, are elevated in the sera and plasma of patients with inflammation,
      arthritis, diabetes, and cancer. Increased levels of these soluble molecules in
      patients with cancer have been shown to correlate with disease progression and
      survival. This suggests that increased expression of the soluble forms of CAMs
      may play an important role in cancer cell growth and metastasis and may be
      prognostic and/or predictive of malignant disease. In this retrospective study,
      we assessed the clinical significance of sICAM-1, sVCAM-1, and sE-selectin in 95
      patients with metastatic breast cancer enrolled in clinical trials of high-dose
      chemotherapy (HDC) and autologous stem cell transplantation (ASCT). The
      significance of soluble HER-2 (sHER-2) and sFAS status, determined in previous
      studies for this group of patients, was also included in this analysis.
      Univariate analysis showed that sICAM-1, sVCAM-1, sFas, sHER-2 positive status,
      and the presence of liver metastases were significant prognostic factors for both
      progression-free survival (PFS) and overall survival (OS) in the total patient
      group. In multivariable analysis, HER-2 and sFAS were shown to be independent
      prognostic factors for PFS and OS. Within the various treatment groups examined,
      sICAM-1 was a prognostic factor for clinical outcome for patients with metastatic
      breast cancer enrolled in trials with cyclophosphamide- and carboplatin-based or
      vinblastine-based HDC, but not in trials with paclitaxeland cyclophosphamide
      based HDC.

PMID- 15186725
TI  - Cryopreservation of stem cells using trehalose: evaluation of the method using a
      human hematopoietic cell line.
AB  - While stem cell cryopreservation methods have been optimized using
      dimethylsulfoxide (DMSO), the established techniques are not optimal when applied
      to unfertilized human embryonic cells. In addition, important questions remain
      regarding the toxicity and characteristics of DMSO for treatment of stem cells
      for clinical use. The objective of this study was to establish an optimal method
      for cryopreservation of stem cells using low concentrations (0.2 M) of trehalose,
      a nontoxic disaccharide of glucose, which possesses excellent protective
      characteristics, in place of current methods utilizing high concentrations (1-2
      M) of DMSO. A human hematopoietic cell line was used in this investigation as a
      surrogate for human stem cells. Trehalose was loaded into cells using a
      genetically engineered mutant of the pore-forming protein alpha-hemolysin from
      Staphylococcus aureus. This method results in a nonselective pore equipped with a
      metal-actuated switch that is sensitive to extracellular zinc concentrations,
      thus permitting controlled loading of trehalose. Preliminary experiments
      characterized the effects of poration on TF-1 cells and established optimal
      conditions for trehalose loading and cell survival. TF-1 cells were frozen at 1
      degrees C/min to -80 degrees C with and without intra- and extracellular
      trehalose. Following storage at -80 degrees C for 1 week, cells were thawed and
      evaluated for viability, differentiation capacity, and clonogenic activity in
      comparison to cells frozen with DMSO. Predictably, cells frozen without any
      protective agent did not survive freezing. Colony-forming units (CFU) generated
      from cells frozen with intra- and extracellular trehalose, however, were
      comparable in size, morphology, and number to those generated by cells frozen in
      DMSO. There was no observable alteration in phenotypic markers of differentiation
      in either trehalose- or DMSO-treated cells. These data demonstrate that low
      concentrations of trehalose can protect hematopoietic progenitors from freezing
      injury and support the concept that trehalose may be useful for freezing
      embryonic stem cells and other primitive stem cells for therapeutic and
      investigational use.

PMID- 15186726
TI  - Kinetics and organ distribution of allogeneic natural killer lymphocytes
      transfused into patients suffering from renal cell carcinoma.
AB  - The transfusion of natural killer (NK) lymphocytes into patients suffering from
      malignant diseases is an approach of current interest in the field of
      immunotherapy. Little is known about the organ distribution, survival, and
      clearance of donor immune effector cells in cellular therapy, and no reports
      exist on these important parameters considering NK cells in particular or any
      other type of allogeneic lymphocytes in humans. In the context of a clinical
      Phase I/II study we examined the distribution of transfused allogeneic NK cells
      in patients suffering from renal cell carcinoma. The NK cells were ex vivo
      cultivated and activated before transfusion. To assess the circulation of the
      transfused cells in the peripheral blood, we used a nested PCR technique to
      detect HLA DRB1 alleles of the NK cell donors. Post-transfusion, all patients
      showed evidence of circulating donor cells for up to 3 days. After 7 days, all
      donor cells were cleared from the blood to undetectable levels. To assess organ
      distribution, (111)In-labeled NK cells were injected and monitored by whole-body
      scintiscans. A distribution to the whole body, with preference for liver, spleen,
      and bone marrow, was observed after a short initial uptake in the lungs. No
      activity was observed in lymphatic nodes. A total of 2/4 evaluable metastases
      showed a clear accumulation of transfused NK cells. The half-life corrected
      activity in all body compartments remained almost constant over the 6-day
      observation period in concordance with the absence of any excretion of
      radioactivity. This may indicate an extended survival of the transfused cells,
      despite their foreign nature, in the host organism.

PMID- 15186727
TI  - Cytotoxic difference of T cells expanded with anti-CD3 monoclonal antibody in the
      presence and absence of anti-CD 28 monoclonal antibody.
AB  - Bulk T cells can be expanded by CD3 stimulation alone (CD3-Ts) or by CD3/CD28
      dual stimulation (CD3/CD28-Ts) of peripheral blood mononuclear cells (PBMC).
      However, few reports have described the difference of features between CD3-Ts and
      CD3/CD28-Ts. PBMC were stimulated with anti-CD3 monoclonal antibody (mAb) alone
      or co-stimulated with anti-CD3/CD28 mAbs immobilized on plastic plates, in the
      presence of rhIL-2 for 4 days, subsequently cultured in the presence of rhIL-2
      with no antibody then analyzed. The expansion rate was significantly lower for
      CD3-Ts (965 + 510-fold, n=5) than CD3/CD28-Ts (2263 + 856-fold, n=5) (p<0.05).
      The CD4/CD8 ratio, the percentage of CD28(+) cell, and the percentage of T cells
      with no ability to generate intracytoplasmic interleukin-4 (IL-4) or interferon
      gamma (IFN-gamma) were all significantly higher, but, phenotypically, memory
      cells were lower in CD3/CD28-Ts than in CD3-Ts. The levels of activity of both
      natural killer (NK) and lymphocyte-activated killer (LAK) cells were lower in
      CD3/CD28-Ts than CD3-Ts. In comparison to CD3-Ts, CD3/CD28-Ts showed impaired
      migration toward RANTES. In conclusion, T cells expanded with anti-CD3 and anti
      CD28 mAbs differ from those expanded with anti-CD3 alone with proliferation,
      cytotoxicity, chemotaxis, and phenotype. These differences may exert profound
      influences on the therapeutic potential of output cells.

PMID- 15186728
TI  - PR vs. PR: will press release top peer review in stem cell research?

PMID- 15186729
TI  - Immunotherapy in benzene-induced aplastic anemia using a biotherapeutic approach-
      is it durable?

PMID- 15186731
TI  - Potential use of enucleated embryonic stem cell cytoplasts in investigations of
      stem cell fusion.

PMID- 15186732
TI  - Severe hypogammaglobulinemia and B cell depletion following episodes of post
      transplant viral infections.

PMID- 15186733
TI  - Degeneration of stroma reduces retention of homed cells in bone marrow of
      lethally irradiated mice.
AB  - Cytotoxic drugs or irradiation are generally administered before bone marrow (BM)
      transplantation because of the idea that host bone marrow 'niches' become
      available to the donor cells for engraftment. How BM stromal cells respond to the
      radiation, which ultimately modulates grafting of donor cells, is poorly
      understood. In this study, we examined homing and marrow retention of PKH26+
      donor cells in BM of age-matched C57BL/6J mice conditioned at different doses of
      irradiation. When we injected donor cells into mice that received 900 cGy, the
      percent homing was highest (15.8 +/- 1.5%) as compared to the lower doses of
      radiation. Despite the highest levels of homing of donor cells in these mice,
      about 70% (p < 0.005) homed cells were detached from the marrow within 72 h of
      transplantation. In contrast, a 2- to 2.5-fold (p < 0.03) multiplication of homed
      PKH-26+ Sca-1+ cells was observed in sublethally irradiated mice. While
      determining that CD45- CD106+ cells in BM of the mice received 900 cGy, we found
      that more than 80% of cells were depleted. It was also revealed from this
      investigation that grafted cells conferred partial protection to the endogenous
      myeloid colony-forming cells from radiation injury. Collectively, the present
      study implicates radiation-induced degeneration of stroma as a cause of poor
      retention of donor cells in BM of lethally irradiated mice. These results may
      have important clinical implications in designing conditioning regimens for BM
      transplantation.

PMID- 15186734
TI  - Flt3/Flk-2 ligand in combination with thrombopoietin decreases apoptosis in
      megakaryocyte development.
AB  - The growth factors thrombopoietin (TPO) and Flt3/Flk-2-ligand (FL), either
      independently or in combination, modulate megakaryocyte development. Our results
      show that bone marrow CD34+ cells cultured with TPO and FL differentiate at a
      slower rate into CD41+ cells and are delayed in apoptosis at the later stages of
      the cultures compared to cells cultured with TPO alone. Our data also show that
      FL in synergy with TPO may inhibit apoptosis in megakaryocyte development by up
      regulating bcl-2 and inducing conformational changes of p53, in MK progenitors.
      FL in combination with TPO slows down maturation and consequently delays
      apoptosis of MK progenitor cells.

PMID- 15186735
TI  - Induction of apoptosis and effect on CD20+ using rituximab on autologous
      peripheral blood stem cell harvests from patients with B cell lymphomas.
AB  - Purging of neoplastic cells for autologous stem cell transplantation is usually
      done in vivo by administering chemotherapy and/or other agents before harvesting.
      It is also possible to decrease malignant cells counts directly in the cell
      harvest. In this study, we ascertained the effect of anti-CD20 monoclonal
      antibody and rituximab administration on peripheral blood hematopoietic stem
      cells. Five samples of stem cell harvests from different patients with B cell
      lymphoma were obtained. Each sample was divided in two tubes with calcium
      gluconate (20 mEq/50 microl). Rituximab (1 mg/600,000 mononuclear cells) was
      added to one of the tubes. Using flow cytometry, CD19, CD20 (B cell markers), and
      CD95 (apoptosis marker), expression was measured at baseline and 24 h after the
      addition of rituximab. A one-sided t-test with equal variances was used to
      analyze the results. Immediately after rituximab addition, CD20 expression became
      null. No significant difference in variation of CD19 expression was detected
      after the addition of rituximab (-3.64% control vs. 0.63% rituximab, p = 0.69).
      Mean variations of percentage of CD95 expression were 2.9% (controls) and 10.52%
      (rituximab tubes) (p = 0.06). We conclude that rituximab is capable of initiating
      apoptosis in vitro. We found no decrease in the CD19+ cell count, used as a
      surrogate marker for CD20+ cells, meaning that, at least in 24 h, apoptosis
      activation is not capable of decreasing CD20+ cell numbers. In vitro purging of
      peripheral blood stem cells harvests with rituximab could be part of a broader
      therapeutic strategy to be offered to lymphoproliferative disorder patients.

PMID- 15186736
TI  - Inhibition of cord blood cell expansion by human herpesvirus 6 in vitro.
AB  - To elucidate the role of human herpesvirus 6 (HHV-6) in hematopoiesis, the
      influence of HHV-6A and HHV-6B on the in vitro expansion and differentiation of
      cord blood (CB) progenitor cells was investigated in liquid culture.
      Nonfractionated CB mononuclear cells (CB-MNC) or MACS-enriched CD34+ CB cells
      were seeded in liquid culture under conditions allowing maximal expansion of
      nucleated cells. Cells were either incubated with HHV-6A- or HHV-6B-containing
      cell culture supernatants or a virus-free control. After 7, 14, and 21 days,
      cells were analyzed for growth by cell count, for differentiation by flow
      cytometry, and for HHV-6 infection by antigen detection or PCR. Expansion of CB
      MNC was significantly inhibited by HHV-6A and HHV-6B for a period of 3 weeks,
      including reduced proportions of CD34+ and CD33+ cells in HHV-6-treated cultures
      on day 7. In contrast, when starting with enriched CD34+ cells, the expansion was
      only affected by HHV-6A. Inhibition of CD34 and CD33 cell development was less
      pronounced in these cultures compared to CB-MNC cultures. However, HHV-6 antigen
      and DNA was detectable in these cultures. In conclusion, although HHV-6A
      inhibited expansion of CD34 progenitor cells, HHV-6B inhibited growth of immature
      CB cells only in interaction with nonfractionated CB-MNC.

PMID- 15186737
TI  - Maintenance therapy with interferon-alpha 2b, cyclophosphamide, and prednisone in
      aggressive diffuse large cell lymphoma.
AB  - Maintenance therapy in patients with aggressive malignant lymphoma using
      biological modifiers remains uncertain. We conducted a controlled clinical trial
      to evaluate the efficacy and toxicity of interferon-alpha 2b, cyclophosphamide,
      and prednisone as maintenance therapy in patients with aggressive diffuse large B
      cell lymphomas in complete remission after aggressive chemotherapy. In an intent
      to-treat analysis, 169 patients were eligible for this study; the end points were
      event-free survival (EFS) and overall survival (OS). With a median follow-up of
      49.3 months, no statistical differences were observed and actuarial curves at 5
      years showed that EFS was 71% (95% confidence interval [CI], 63-79%) for patients
      who received maintenance compared to 63% (95% CI, 59-71%) for patients in control
      group (p = 0.05). No statistical differences were observed in OS between
      maintenance arm: 84% (95% CI, 78-89%) and control group 83% (95% CI, 77-88%) in
      control group (p = 0.2). All patients received the maintenance therapy as planned
      and in time, thus dose intensity was considered 1.0 in all cases. Acute toxicity
      was mild, and no delay or suspension of treatment was necessary. Late toxicity
      was not evident until now. We conclude that use of maintenance therapy combining
      interferon-alpha 2b, cyclophosphamide, and prednisone is not useful in patients
      with aggressive lymphoma if they had been treated with aggressive combined
      chemotherapy.

PMID- 15186738
TI  - Priming with dendritic cells can generate strong cytotoxic T cell responses to
      chronic myelogenous leukemia cells in vitro.
AB  - Dendritic cells (DC) are antigen-presenting cells that can elicit potent antigen
      specific responses. Since the development of techniques to cultivate these cells
      from peripheral blood, there has been a great deal of interest in their use in
      immunotherapeutic strategies. Here we show that morphologically, phenotypically,
      and functionally characteristic DC can be generated in vitro from peripheral
      blood mononuclear cells (PBMC) isolated from frozen apheresis product (AP) of
      cancer patients. These DC, when pulsed with whole-tumor lysate, protein, or RNA
      from a chronic myelogenous leukemia (CML) cell line, can induce anti-CML specific
      cytotoxicity in vitro by autologous cytotoxic T lymphocytes (CTL). RNA and
      protein-pulsed DC were more effective than lysate-pulsed DC at inducing
      cytotoxicity at low effector:target (E:T) ratios. These results were comparable
      to those obtained when fresh healthy peripheral blood was used as the source of
      PBMC, indicating that neither the malignant state of the patient nor the storage
      period detrimentally affected the generation or functionality of DC. CML cells
      were found to increase their level of MHC class I expression after exposure to
      CTL and pulsed DC thereby becoming better targets. These investigations lend
      support for the utilization of DC to generate anti-tumor responses in CML.

PMID- 15186739
TI  - Motion-based analysis of spatial patterns by the human visual system.
AB  - BACKGROUND: It is known that the visibility of patterns presented through
      stationary multiple slits is significantly improved by pattern movements. This
      study investigated whether this spatiotemporal pattern interpolation is supported
      by motion mechanisms, as opposed to the general belief that the human visual
      cortex initially analyses spatial patterns independent of their movements.
      RESULTS: Psychophysical experiments showed that multislit viewing could not be
      ascribed to such motion-irrelevant factors as retinal painting by tracking eye
      movements or an increase in the number of views by pattern movements. Pattern
      perception was more strongly impaired by the masking noise moving in the same
      direction than by the noise moving in the opposite direction, which indicates the
      direction selectivity of the pattern interpolation mechanism. A direction
      selective impairment of pattern perception by motion adaptation also indicates
      the direction selectivity of the interpolation mechanism. Finally, the map of
      effective spatial frequencies, estimated by a reverse-correlation technique,
      indicates observers' perception of higher spatial frequencies, the recovery of
      which is theoretically impossible without the aid of motion information.
      CONCLUSIONS: These results provide clear evidence against the notion of separate
      analysis of pattern and motion. The visual system uses motion mechanisms to
      integrate spatial pattern information along the trajectory of pattern movement in
      order to obtain clear perception of moving patterns. The pattern integration
      mechanism is likely to be direction-selective filtering by V1 simple cells, but
      the integration of the local pattern information into a global figure should be
      guided by a higher-order motion mechanism such as MT pattern cells.

PMID- 15186740
TI  - MAP1B is required for Netrin 1 signaling in neuronal migration and axonal
      guidance.
AB  - BACKGROUND: The signaling cascades governing neuronal migration and axonal
      guidance link extracellular signals to cytoskeletal components. MAP1B is a neuron
      specific microtubule-associated protein implicated in the crosstalk between
      microtubules and actin filaments. RESULTS: Here we show that Netrin 1 regulates,
      both in vivo and in vitro, mode I MAP1B phosphorylation, which controls MAP1B
      activity, in a signaling pathway that depends essentially on the kinases GSK3 and
      CDK5. We also show that map1B-deficient neurons from the lower rhombic lip and
      other brain regions have reduced chemoattractive responses to Netrin 1 in vitro.
      Furthermore, map1B mutant mice have severe abnormalities, similar to those
      described in netrin 1-deficient mice, in axonal tracts and in the pontine nuclei.
      CONCLUSIONS: These data indicate that MAP1B phosphorylation is controlled by
      Netrin 1 and that the lack of MAP1B impairs Netrin 1-mediated chemoattraction in
      vitro and in vivo. Thus, MAP1B may be a downstream effector in the Netrin 1
      signaling pathway.

PMID- 15186741
TI  - C. elegans PAR proteins function by mobilizing and stabilizing asymmetrically
      localized protein complexes.
AB  - BACKGROUND: The PAR proteins are part of an ancient and widely conserved
      machinery for polarizing cells during animal development. Here we use a
      combination of genetics and live imaging methods in the model organism
      Caenorhabditis elegans to dissect the cellular mechanisms by which PAR proteins
      polarize cells. RESULTS: We demonstrate two distinct mechanisms by which PAR
      proteins polarize the C. elegans zygote. First, we show that several components
      of the PAR pathway function in intracellular motility, producing a polarized
      movement of the cell cortex. We present evidence that this cortical motility may
      drive the movement of cellular components that must become asymmetrically
      distributed, including both germline-specific ribonucleoprotein complexes and
      cortical domains containing the PAR proteins themselves. Second, PAR-1 functions
      to refine the asymmetric localization of germline ribonucleoprotein complexes by
      selectively stabilizing only those complexes that reach the PAR-1-enriched
      posterior cell cortex during the period of cortical motility. CONCLUSIONS: These
      results identify two cellular mechanisms by which the PAR proteins polarize the
      C. elegans zygote, and they suggest mechanisms by which PAR proteins may polarize
      cells in diverse animal systems.

PMID- 15186742
TI  - The Caenorhabditis elegans centrosomal protein SPD-2 is required for both
      pericentriolar material recruitment and centriole duplication.
AB  - BACKGROUND: The centrosome is composed of a centriole pair and pericentriolar
      material (PCM). By marking the site of PCM assembly, the centrioles define the
      number of centrosomes present in the cell. The PCM, in turn, is responsible for
      the microtubule (MT) nucleation activity of centrosomes. Therefore, in order to
      assemble a functional bipolar mitotic spindle, a cell needs to control both
      centriole duplication and PCM recruitment. To date, however, the molecular
      mechanisms that govern these two processes still remain poorly understood.
      RESULTS: Here we show that SPD-2 is a novel component of the C. elegans
      centrosome. SPD-2 localizes to the centriole throughout the cell cycle and
      accumulates on the PCM during mitosis. We show that SPD-2 requires SPD-5 for its
      accumulation on the PCM and that in the absence of SPD-2, centrosome assembly
      fails. We further show that centriole duplication is also defective in spd
      2(RNAi) embryos, but not in spd-5(RNAi) embryos, where PCM recruitment is
      efficiently blocked. CONCLUSIONS: Taken together, our results suggest that SPD-2
      may link PCM recruitment and centriole duplication in C. elegans. SPD-2 shares
      homology with a human centrosome protein, suggesting that this key component of
      the C. elegans centrosome is evolutionarily conserved.

PMID- 15186743
TI  - Real-time detection of single-molecule DNA compaction by condensin I.
AB  - BACKGROUND: Condensin is thought to contribute to large-scale DNA compaction
      during mitotic chromosome assembly. It remains unknown, however, how the complex
      reconfigures DNA structure at a mechanistic level. RESULTS: We have performed
      single-molecule DNA nanomanipulation experiments to directly measure in real-time
      DNA compaction by the Xenopus laevis condensin I complex. Condensin can bind to
      the nanomanipulated DNA in the absence of ATP, but it compacts the DNA only in
      the presence of hydrolyzable ATP. Linear compaction is evidenced by a reduction
      in the end-to-end extension of nanomanipulated DNA. The reaction results in total
      compaction of the DNA (i.e., zero end-to-end extension). Discrete and reversible
      DNA compaction events are observed in the presence of competitor DNA when the DNA
      is subjected to weak stretching forces (F = 0.4 picoNewton [pN]). The
      distribution of step sizes is broad and displays a peak at approximately 60 nm (
      approximately 180 bp) as well as a long tail. This distribution is essentially
      unaffected by the topological state of the DNA substrate. Increasing the force to
      F = 10 pN drives the system toward step-wise reversal of compaction. The
      distribution of step sizes observed upon disruption of condensin-DNA interactions
      displays a sharp peak at approximately 30 nm ( approximately 90 bp) as well as a
      long tail stretching out to hundreds of nanometers. CONCLUSIONS: The DNA
      nanomanipulation assay allows us to demonstrate for the first time that condensin
      physically compacts DNA in an ATP-hydrolysis-dependent manner. Our results
      suggest that the condensin complex may induce DNA compaction by dynamically and
      reversibly introducing loops along the DNA.

PMID- 15186744
TI  - Learned social preference in zebrafish.
AB  - How social aggregations arise and persist is central to our understanding of
      evolution, behavior, and psychology. When social groups arise within a species,
      evolutionary divergence and speciation can result. To understand this
      diversifying role of social behavior, we must examine the internal and external
      influences that lead to nonrandom assortment of phenotypes. Many fishes form
      aggregations called shoals that reduce predation risk while enhancing foraging
      and reproductive success. Thus, shoaling is adaptive, and signals that maintain
      shoals are likely to evolve under selection. Given the diversity of pigment
      patterns among Danio fishes, visual signals might be especially important in
      mediating social behaviors in this group. Our understanding of pigment pattern
      development in the zebrafish D. rerio allows integrative analyses of how
      molecular variation leads to morphological variation among individuals and how
      morphological variation influences social interactions. Here, we use the
      zebrafish pigment mutant nacre/mitfa to test roles for genetic and environmental
      determinants in the development of shoaling preference. We demonstrate that
      individuals discriminate between shoals having different pigment pattern
      phenotypes and that early experience determines shoaling preference. These
      results suggest a role for social learning in pigment pattern diversification in
      danios.

PMID- 15186746
TI  - Genome compaction and stability in microsporidian intracellular parasites.
AB  - Microsporidian genomes are extraordinary among eukaryotes for their extreme
      reduction: although they are similar in form to other eukaryotic genomes, they
      are typically smaller than many prokaryotic genomes. At the same time, their
      rates of sequence evolution are among the highest for eukaryotic organisms. To
      explore the effects of compaction on nuclear genome evolution, we sequenced
      685,000 bp of the Antonospora locustae genome (formerly Nosema locustae) and
      compared its organization with the recently completed genome of the human
      parasite Encephalitozoon cuniculi. Despite being very distantly related, the
      genomes of these two microsporidian species have retained an unexpected degree of
      synteny: 13% of genes are in the same context, and 30% of the genes were
      separated by a small number of short rearrangements. Microsporidian genomes are,
      therefore, paradoxically composed of rapidly evolving sequences harbored within a
      slowly evolving genome, although these two processes are sometimes considered to
      be coupled. Microsporidian genomes show that eukaryotic genomes (like genes) do
      not evolve in a clock-like fashion, and genome stability may result from
      compaction in addition to a lack of recombination, as has been traditionally
      thought to occur in bacterial and organelle genomes.

PMID- 15186745
TI  - Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling
      pathway.
AB  - In many species, reducing nutrient intake without causing malnutrition extends
      lifespan. Like DR (dietary restriction), modulation of genes in the insulin
      signaling pathway, known to alter nutrient sensing, has been shown to extend
      lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the
      insulin pathways have emerged as major regulators of growth and size. Hence we
      examined the role of TOR pathway genes in regulating lifespan by using
      Drosophila. We show that inhibition of TOR signaling pathway by alteration of the
      expression of genes in this nutrient-sensing pathway, which is conserved from
      yeast to human, extends lifespan in a manner that may overlap with known effects
      of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous
      sclerosis complex genes 1 and 2) act together to inhibit TOR (target of
      rapamycin), which mediates a signaling pathway that couples amino acid
      availability to S6 kinase, translation initiation, and growth. We find that
      overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all
      cause lifespan extension. Modulation of expression in the fat is sufficient for
      the lifespan-extension effects. The lifespan extensions are dependent on
      nutritional condition, suggesting a possible link between the TOR pathway and
      dietary restriction.

PMID- 15186748
TI  - Reproductive consequences of population divergence through sexual conflict.
AB  - Sexual-selection research increasingly focuses on reproductive conflicts between
      the sexes. Sexual conflict, divergent evolutionary interests of males and
      females, can cause rapid antagonistic coevolution of reproductive traits and is a
      potentially powerful speciation engine. This idea has theoretical and comparative
      support but remains controversial. Recent experimental evidence from Sepsis
      cynipsea indicates that populations with greater sexual conflict diverged more
      quickly; females were less likely to mate with males from other populations when
      flies had evolved under high levels of sexual conflict. The consequences of this
      divergence have not been addressed, so here we assess two female fitness
      surrogates after 44 generations of evolving (and diverging) under three different
      levels of sexual conflict. Longevity after copulation was negatively associated
      with the degree of sexual conflict under which flies evolved, and housing females
      with males also reduced female longevity. Female lifetime reproductive success
      (LRS) also tended to decrease with increasing conflict. However, there was
      evidence of either sexual-selection fitness benefits at intermediate levels of
      sexual selection and conflict or inbreeding depression in the smallest
      populations (those with the lowest levels of conflict). Nevertheless, the results
      indicate that there can be a fitness load associated with sexual selection and
      support claims that sexual conflict can lead to reproductive isolation.

PMID- 15186749
TI  - A cluster of Arabidopsis genes with a coordinate response to an environmental
      stimulus.
AB  - Vernalization, the promotion of flowering after prolonged exposure to low
      temperatures, is an adaptive response of plants ensuring that flowering occurs at
      a propitious time in the annual seasonal cycle. In Arabidopsis, FLOWERING LOCUS C
      (FLC), which encodes a repressor of flowering, is a key gene in the vernalization
      response; plants with high-FLC expression respond to vernalization by
      downregulating FLC and thereby flowering at an earlier time. Vernalization has
      the hallmarks of an epigenetically regulated process. The downregulation of FLC
      by low temperatures is maintained throughout vegetative development but is reset
      at each generation. During our study of vernalization, we have found that a small
      gene cluster, including FLC and its two flanking genes, is coordinately regulated
      in response to genetic modifiers, to the environmental stimulus of vernalization,
      and in plants with low levels of DNA methylation. Genes encoded on foreign DNA
      inserted into the cluster also acquire the low-temperature response. At other
      chromosomal locations, FLC maintains its response to vernalization and imposes a
      parallel response on a flanking gene. This suggests that FLC contains sequences
      that confer changes in gene expression extending beyond FLC itself, perhaps
      through chromatin modification.

PMID- 15186747
TI  - Novel role for Netrins in regulating epithelial behavior during lung branching
      morphogenesis.
AB  - The development of many organs, including the lung, depends upon a process known
      as branching morphogenesis, in which a simple epithelial bud gives rise to a
      complex tree-like system of tubes specialized for the transport of gas or fluids.
      Previous studies on lung development have highlighted a role for fibroblast
      growth factors (FGFs), made by the mesodermal cells, in promoting the
      proliferation, budding, and chemotaxis of the epithelial endoderm. Here, by using
      a three-dimensional culture system, we provide evidence for a novel role for
      Netrins, best known as axonal guidance molecules, in modulating the morphogenetic
      response of lung endoderm to exogenous FGFs. This effect involves inhibition of
      localized changes in cell shape and phosphorylation of the intracellular mitogen
      activated protein kinase(s) (ERK1/2, for extracellular signal-regulated kinase-1
      and -2), elicited by exogenous FGFs. The temporal and spatial expression of
      netrin 1, netrin 4, and Unc5b genes and the localization of Netrin-4 protein in
      vivo suggest a model in which Netrins in the basal lamina locally modulate and
      fine-tune the outgrowth and shape of emergent epithelial buds.

PMID- 15186750
TI  - Requirement for Tec kinases in chemokine-induced migration and activation of
      Cdc42 and Rac.
AB  - Cell polarization and migration in response to chemokines is essential for proper
      development of the immune system and activation of immune responses. Recent
      studies of chemokine signaling have revealed a critical role for PI3-Kinase,
      which is required for polarized membrane association of pleckstrin homology (PH)
      domain-containing proteins and activation of Rho family GTPases that are
      essential for cell polarization and actin reorganization. Additional data argue
      that tyrosine kinases are also important for chemokine-induced Rac activation.
      However, how and which kinases participate in these pathways remain unclear. We
      demonstrate here that the Tec kinases Itk and Rlk play an important role in
      chemokine signaling in T lymphocytes. Chemokine stimulation induced transient
      membrane association of Itk and phosphorylation of both Itk and Rlk, and purified
      T cells from Rlk(-/-)Itk(-/-) mice exhibited defective migration to multiple
      chemokines in vitro and decreased homing to lymph nodes upon transfer to wt mice.
      Expression of a dominant-negative Itk impaired SDF-1alpha-induced migration, cell
      polarization, and activation of Rac and Cdc42. Thus, Tec kinases are critical
      components of signaling pathways required for actin polarization downstream from
      both antigen and chemokine receptors in T cells.

PMID- 15186751
TI  - Fears mount over 'fortress' America.

PMID- 15186752
TI  - Europe plans gene testing framework.
AB  - Genetic testing is set to enter mainstream healthcare and further population
      research but needs new regulation according to a European report, writes Nigel
      Williams.

PMID- 15186753
TI  - John Maynard Smith (1920-2004).

PMID- 15186755
TI  - Q&A.

PMID- 15186756
TI  - Humans.

PMID- 15186757
TI  - Chimpanzees.

PMID- 15186759
TI  - Animal cognition.

PMID- 15186760
TI  - Cormorants keep their power: visual resolution in a pursuit-diving bird under
      amphibious and turbid conditions.

PMID- 15186761
TI  - Evolution: sexual arms races.
AB  - The reproductive interests of males and females usually differ, resulting in
      sexual conflict. Recent studies in which experimental selection trials were
      carried out under conditions of either 'high' or 'low' sexual conflict show that
      conflict can promote speciation and reduce female reproductive success.

PMID- 15186762
TI  - Vision: the world through picket fences.
AB  - Our visual system must allow us to see the form of objects in motion. Tracking
      objects of interest stabilises their images on the retina, but is not sufficient,
      as untracked images move on the retina. This problem is solved by cells tuned in
      both space and time, combining information about form with information about
      motion.

PMID- 15186764
TI  - Ribosome function: governing the fate of a nascent polypeptide.
AB  - Recent data highlight how eukaryotic ribosomes connect polypeptide synthesis to
      translational regulation and targeting. Information contained in nascent
      polypeptides can be transmitted by surprisingly diverse routes.

PMID- 15186763
TI  - LKB1 kinase: master and commander of metabolism and polarity.
AB  - LKB1, the product of a tumour suppressor gene, is a serine/threonine kinase that
      coordinates disparate cellular processes. Recent data have revealed novel
      functions for LKB1, providing new insight into the regulation of cell polarity
      and energy-generating metabolism.

PMID- 15186765
TI  - Translesion DNA synthesis: little fingers teach tolerance.
AB  - DNA synthesis on a damaged template requires tolerant DNA polymerases.
      Crystallographic analysis has captured a Y-family polymerase synthesizing across
      an abasic site, providing insight into the mechanisms of DNA damage tolerance and
      mutation.

PMID- 15186766
TI  - Evolutionary genomics: yeasts accelerate beyond BLAST.
AB  - Two new genome sequences confirm that a whole genome duplication occurred in an
      ancestor of Saccharomyces cerevisiae. This left a legacy of about 500 pairs of
      duplicated genes, many of which contribute to this yeast's ability to ferment
      glucose anaerobically; a few have been evolving so quickly they retain almost no
      sequence similarity to each other.

PMID- 15186767
TI  - Plant development: slowing root growth naturally.
AB  - What determines organ size? A screen for plant strains showing natural variation
      in root length has identified a novel gene that modulates root growth rate by
      controlling cell division and elongation at the root tip.

PMID- 15186768
TI  - Peroxisome membrane biogenesis: the stage is set.
AB  - Pex3p and Pex19p are key players in the post-translational import of peroxisomal
      membrane proteins. New data suggest that these peroxins act in tandem, Pex19p as
      a cytosolic chaperone and import receptor for peroxisomal membrane proteins, and
      Pex3p as docking factor at the peroxisomal membrane.

PMID- 15186769
TI  - Flagellar biosynthesis in silico: building quantitative models of regulatory
      networks.
AB  - In this issue of Cell, describe the construction of an in silico model for the
      regulatory network responsible for the control of flagellar biosynthesis in E.
      coli based on quantitative gene expression data. They show how the model can be
      used as a quantitative blueprint to design genetic modifications with predictable
      influence on the dynamics of the system. The work by provides a general approach
      for building detailed models of transcriptional regulatory networks.

PMID- 15186770
TI  - p53-mediated transcriptional activation: from test tube to cell.
AB  - Posttranslational modifications of histones have been strongly correlated with
      transcriptional regulation. In this issue of Cell, comprehensively examined the
      nature of arginine methyltransferases and histone modifications in p53-mediated
      transcription.

PMID- 15186771
TI  - Cilia and flagella revealed: from flagellar assembly in Chlamydomonas to human
      obesity disorders.
AB  - The recent identification in Chlamydomonas of the intraflagellar transport
      machinery that assembles cilia and flagella has triggered a renaissance of
      interest in these organelles that transcends studies on their well-characterized
      ability to move. New studies on several fronts have revealed that the machinery
      for flagellar assembly/disassembly is regulated by homologs of mitotic proteins,
      that cilia play essential roles in sensory transduction, and that mutations in
      cilia/basal body proteins are responsible for cilia-related human disorders from
      polycystic kidney disease to a syndrome associated with obesity, hypertension,
      and diabetes.

PMID- 15186772
TI  - Protein tyrosine phosphatases in the human genome.
AB  - Tyrosine phosphorylation is catalyzed by protein tyrosine kinases, which are
      represented by 90 genes in the human genome. Here, we present the set of 107
      genes in the human genome that encode members of the four protein tyrosine
      phosphatase (PTP) families. The four families of PTPases, their substrates,
      structure, function, regulation, and the role of these enzymes in human disease
      will be discussed.

PMID- 15186773
TI  - Using a quantitative blueprint to reprogram the dynamics of the flagella gene
      network.
AB  - Detailed understanding and control of biological networks will require a level of
      description similar to that of electronic engineering blueprints. Currently,
      however, even the best-studied systems are usually described using qualitative
      arrow diagrams. A quantitative blueprint requires in vivo measurements of (1) the
      relative strength of the interactions (numbers on the arrows) and (2) the
      functions that integrate multiple inputs. Here, we address this using a well
      studied system, the flagella biosynthesis transcription network in Escherichia
      coli. We use theory and high-resolution experiments to obtain a quantitative
      blueprint with (1) numbers on the arrows, finding different hierarchies of
      activation coefficients for the two regulators, FlhDC and FliA; and (2) cis
      regulatory input functions, which summate the input from the two regulators (SUM
      gates). We then demonstrate experimentally how this blueprint can be used to
      reprogram temporal expression patterns in this system, using controlled
      expression of the regulators or point mutations in their binding sites. The
      present approach can be used to define blueprints of other gene networks and to
      quantitatively reprogram their dynamics.

PMID- 15186774
TI  - Mapping global histone acetylation patterns to gene expression.
AB  - Histone acetyltransferases and deacetylases with specificities for different
      sites of acetylation affect common chromatin regions. This could generate unique
      patterns of acetylation that may specify downstream biological processes. To
      search for existence of these patterns and their relationship to gene activity,
      we analyzed the genome-wide acetylation profiles for eleven lysines in the four
      core histones of Saccharomyces cerevisiae. We find that both hyper- and
      hypoacetylation of individual lysines are associated with transcription,
      generating distinct patterns of acetylation that define groups of biologically
      related genes. The genes within these groups are significantly coexpressed,
      mediate similar physiological processes, share unique cis-regulatory DNA motifs,
      and are enriched for binding of specific transcription factors. Our data also
      indicate that the in vivo binding of the transcription factor Bdf1 is associated
      with acetylation on most lysines but relative deacetylation on H4 lysine 16.
      Thus, certain acetylation patterns may be used as surfaces for specific protein
      histone interactions, providing one mechanism for coordinate regulation of
      chromatin processes that are biologically related.

PMID- 15186775
TI  - Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional
      activation by p53.
AB  - Transcriptional coactivators that modify histones represent an increasingly
      important group of regulatory factors, although their ability to modify other
      factors as well precludes common assumptions that they necessarily act by histone
      modification. In an extension of previous studies showing a role for
      acetyltransferase p300/CBP in p53 function, we have used systems reconstituted
      with recombinant chromatin templates and (co)activators to demonstrate (1) the
      additional involvement of protein arginine methyltransferases PRMT1 and CARM1 in
      p53 function; (2) both independent and ordered cooperative functions of p300,
      PRMT1, and CARM1; and (3) mechanisms that involve direct interactions with p53
      and, most importantly, obligatory modifications of corresponding histone
      substrates. ChIP analyses have confirmed the ordered accumulation of these (and
      other) coactivators and cognate histone modifications on the GADD45 gene
      following ectopic p53 expression and/or UV irradiation. These studies thus define
      diverse cofactor functions, as well as underlying mechanisms involving distinct
      histone modifications, in p53-dependent gene activation.

PMID- 15186776
TI  - Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab
      prenylation and choroideremia disease.
AB  - Members of the RabGDI/REP family serve as multifunctional regulators of the Rab
      family of GTP binding proteins. Mutations in members of this family, such as REP
      1, lead to abnormalities, including progressive retinal degradation
      (choroideremia) in humans. The crystal structures of the REP-1 protein in complex
      with monoprenylated or C-terminally truncated Rab7 proteins revealed that Rab7
      interacts with the Rab binding platform of REP-1 via an extended interface
      involving the Switch 1 and 2 regions. The C terminus of the REP-1 molecule
      functions as a mobile lid covering a conserved hydrophobic patch on the surface
      of REP-1 that in the complex coordinates the C terminus of Rab proteins. Using
      semisynthetic fluorescent Rab27A, we demonstrate that although Rab27A can be
      prenylated by REP-2, this reaction can be effectively inhibited by other Rab
      proteins, providing a possible explanation for the accumulation of unprenylated
      Rab27A in choroideremia.

PMID- 15186777
TI  - A palmitoylation switch mechanism in the regulation of the visual cycle.
AB  - RPE65 is essential for the biosynthesis of 11-cis-retinal, the chromophore of
      rhodopsin. Here, we show that the membrane-associated form (mRPE65) is triply
      palmitoylated and is a chaperone for all-trans-retinyl esters, allowing their
      entry into the visual cycle for processing into 11-cis-retinal. The soluble form
      of RPE65 (sRPE65) is not palmitoylated and is a chaperone for vitamin A, rather
      than all-trans-retinyl esters. Thus, the palmitoylation of RPE65 controls its
      ligand binding selectivity. The two chaperones are interconverted by lecithin
      retinol acyl transferase (LRAT) acting as a molecular switch. Here mRPE65 is a
      palmitoyl donor, revealing a new acyl carrier protein role for palmitoylated
      proteins. When chromophore synthesis is not required, mRPE65 is converted into
      sRPE65 by LRAT, and further chromophore synthesis is blocked. The studies reveal
      new roles for palmitoylated proteins as molecular switches and LRAT as a
      palmitoyl transferase whose role is to catalyze the mRPE65 to sRPE65 conversion.

PMID- 15186778
TI  - Disruption of mitochondrial function during apoptosis is mediated by caspase
      cleavage of the p75 subunit of complex I of the electron transport chain.
AB  - Mitochondrial outer membrane permeabilization and cytochrome c release promote
      caspase activation and execution of apoptosis through cleavage of specific
      caspase substrates in the cell. Among the first targets of activated caspases are
      the permeabilized mitochondria themselves, leading to disruption of electron
      transport, loss of mitochondrial transmembrane potential (DeltaPsim), decline in
      ATP levels, production of reactive oxygen species (ROS), and loss of
      mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit
      of respiratory complex I, as a critical caspase substrate in the mitochondria.
      Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels
      during apoptosis, and ROS production in response to apoptotic stimuli is
      dampened. While cytochrome c release and DNA fragmentation are unaffected by the
      noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained,
      and loss of plasma membrane integrity is delayed. Therefore, caspase cleavage of
      NDUFS1 is required for several mitochondrial changes associated with apoptosis.

PMID- 15186779
TI  - Survival of resting mature B lymphocytes depends on BCR signaling via the
      Igalpha/beta heterodimer.
AB  - We previously showed that type I interferon-induced, Cre-mediated ablation of
      surface BCR expression in mature B cells through Ig-heavy chain deletion results
      in apoptosis of these cells. This led to the hypothesis that survival signals
      from the BCR are vital for mature B cells. Here, we test two critical assumptions
      of this model. First, we demonstrate loss of mature B cells upon induced mutation
      of a signaling module of the BCR, not precluding BCR surface expression. Second,
      we show that the cells are also lost upon BCR inactivation in the absence of an
      exogenous inducer like interferon, excluding that cell death depends on previous
      cellular activation by the latter. Kinetic data demonstrate that BCR-less mature
      B cells have a severely reduced lifespan, with a half-life of 3-6 days. Together
      these results establish that BCR signaling is required to keep resting mature B
      cells alive in vivo.

PMID- 15186780
TI  - Gene switching and the stability of odorant receptor gene choice.
AB  - Individual olfactory sensory neurons express only a single odorant receptor from
      a large family of genes, and this singularity is an essential feature in models
      of olfactory perception. We have devised a genetic strategy to examine the
      stability of receptor choice. We observe that immature olfactory sensory neurons
      that express a given odorant receptor can switch receptor expression, albeit at
      low frequency. Neurons that express a mutant receptor gene switch receptor
      transcription with significantly greater probability, suggesting that the
      expression of a functional odorant receptor elicits a feedback signal that
      terminates switching. This process of receptor gene switching assures that a
      neuron will ultimately express a functional receptor and that the choice of this
      receptor will remain stable for the life of the cell.

PMID- 15186781
TI  - A contextual model for axonal sorting into glomeruli in the mouse olfactory
      system.
AB  - No models fully account for how odorant receptors (ORs) function in the guidance
      of axons of olfactory sensory neurons (OSNs) to glomeruli in the olfactory bulb.
      Here, we use gene targeting in mice to demonstrate that the OR amino acid
      sequence imparts OSN axons with an identity that allows them to coalesce into
      glomeruli. Replacements between the coding regions of the M71 and M72 OR genes
      reroute axons to their respective glomeruli. A series of M71-M72 hybrid ORs
      uncover a spectrum of glomerular phenotypes, leading to the concept that the
      identity of OSN axons is revealed depending on what other axons are present.
      Naturally occurring amino acid polymorphisms in other ORs also produce distinct
      axonal identities. These critical amino acid residues are distributed throughout
      the protein and reside predominantly within transmembrane domains. We propose a
      contextual model for axon guidance in which ORs mediate homotypic interactions
      between like axons.

PMID- 15186782
TI  - Axon guidance of mouse olfactory sensory neurons by odorant receptors and the
      beta2 adrenergic receptor.
AB  - Odorant receptors (ORs) provide the core determinant of identity for axons of
      olfactory sensory neurons (OSNs) to coalesce into glomeruli in the olfactory
      bulb. Here, using gene targeting in mice, we examine how the OR protein
      determines axonal identity. An OR::GFP fusion protein is present in axons,
      consistent with a direct function of ORs in axon guidance. When the OR coding
      region is deleted, we observe OSNs that coexpress other ORs that function in
      odorant reception and axonal identity. It remains unclear if such coexpression is
      normally prevented by negative feedback on OR gene choice. A drastic reduction in
      OR protein level produces axonal coalescence into novel, remote glomeruli. By
      contrast, chimeric ORs and ORs with minor mutations perturb axon outgrowth.
      Strikingly, the beta2 adrenergic receptor can substitute for an OR in glomerular
      formation when expressed from an OR locus. Thus, ORs have not evolved a unique
      function in axon guidance.

PMID- 15186783
TI  - Electrical stimulation of the rabbit pulmonary artery increases respiratory
      output.
AB  - This study was conducted to test the hypothesis that the pulmonary artery is
      involved in neural respiratory control and to identify the involved topographical
      region, if any. Six adult rabbits were anesthetized, artificially ventilated, and
      the chest was opened. The outer surface of the extra-pulmonary portion of the
      pulmonary artery was electrically stimulated by monitoring phrenic nerve
      activity. Phrenic nerve activity increased in three of the six rabbits when the
      proximal dorsal surface of the pulmonary trunk was stimulated. This positive
      response was abolished after bilateral vagotomy. In histological examinations we
      found densely grouped cells, i.e. pulmonary glomic tissue, with a fine nerve
      bundle in the tissue adjacent to the dorsal surface of the pulmonary trunk where
      electrical stimulation elicited respiratory augmentation. We suggest that there
      is a neural substrate which is involved in respiratory control inside the wall of
      or in the region adjacent to the proximal dorsal surface of the pulmonary trunk.
      Further studies to anatomically identify the neural substrate and clarify its
      physiological role in respiratory control are necessary.

PMID- 15186785
TI  - Increased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout
      mice.
AB  - To investigate the effects of a permanent excess of acetylcholine (AChE) on
      respiration, breathing and chemosensitivity were analyzed from birth to adulthood
      in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild
      type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief
      exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole
      body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96%
      in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%)
      than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice
      have a slightly blunted response to hypoxia, but increased VE and fR responses to
      hypercapnia. Heterozygous animals present no consistent alterations of breathing
      at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased
      VE/VO2 and a marginally higher normalized VO2. The results suggest that the
      hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect
      alterations of central respiratory control.

PMID- 15186784
TI  - GABAA receptors mediate postnatal depression of respiratory frequency by
      barbiturates.
AB  - We tested the hypothesis that barbiturates depress respiratory motor output by
      actions on the GABAA receptor. We examined the influence of pentobarbital sodium
      on nerve activity recorded from a fourth cervical (C4) ventral root (phrenic
      motoneuron output) in the in vitro brainstem-spinal cord preparation of neonatal
      rats aged 1-3 days. Bath application of pentobarbital slowed the respiratory
      rhythm but this effect could be reversed by drug washout or by simultaneous
      application of 8 microM bicuculline methiodide, a GABAA receptor antagonist.
      Pentobarbital up to a concentration of 80 microM (or 20 mg/l) did not change the
      magnitude of C4 nerve bursts. The GABAA receptor agonist muscimol evoked similar
      changes. The results support the hypothesis that respiratory depression by
      barbiturates is due to GABAA receptor-mediated inhibition, with the principal
      effects on rhythm generation. In the light of recent studies suggesting that
      GABAA receptors may be excitatory in the early neonatal period, we examined
      postnatal changes in the GABAergic slowing of respiratory rhythm. Stimulation of
      GABAA receptors slowed respiratory rhythm from the first postnatal day, with no
      change in efficacy over the first 3 days of life.

PMID- 15186786
TI  - Respiratory chemoreflexes and effects of cortical activation state in urethane
      anesthetized rats.
AB  - Urethane anesthetized (< 1 .3 g/kg), Sprague-Dawley (SD) rats spontaneously
      cycled between a cortically desynchronized state (State I) and a cortically
      synchronized state (State III), which were very similar to awake and slow wave
      sleep (SWS) states in unanesthetized animals, based on EEG criteria. These low
      levels of urethane anaesthesia did not cause significant respiratory depression
      or reductions in sensitivity to hypoxia (10% O2 in nitrogen) or hypercapnia (5%
      CO2 in air) in rats in either State I or State III. Thus, breathing frequency
      (fR), tidal volume (VT) and total ventilation (VTOT) all increased on cortical
      activation in urethane-anaesthetized rats whether breathing air, the hypoxic or
      the hypercapnic gas mixture, in a manner that was very similar to that observed
      in unanaesthetized animals. The relative sensitivity to hypoxia was greater in
      State III than State I, the relative sensitivity to CO2, overall, was equal in
      both states, State III occurred less often during hypoxia and hypercapnia, and
      hypoxic, urethane-anaesthetized rats sighed frequently, particularly in State I.
      This is also similar to the situation seen in unanesthetized rats. Given the
      similarities seen between urethane anesthetized rats in the present study and
      literature values for unanesthetized rats, the data suggest that urethane
      anaesthetized rats provide a good model system for studying respiratory patterns
      and chemoreflexes as a function of cortical activation state.

PMID- 15186787
TI  - Factors contributing to thixotropy of inspiratory muscles.
AB  - Thixotropy is a passive property of the skeletal muscle dependent on the muscle's
      immediate history of contraction and length change. Thixotropic properties of
      inspiratory muscles, introduced by forceful muscle contraction at an inflated
      lung volume, cause an increased end-expiratory position (EEP) of the rib cage. We
      searched for factors contributing to the development of inspiratory muscle
      thixotropy in nine healthy subjects. Using induction plethysmography, we examined
      aftereffects on EEP of the duration of inspiratory muscle contraction and
      subsequent muscle relaxation. We also studied effects of inspiratory effort
      intensity measured by mouth pressure at different lung volumes. EEP elevation was
      noted subsequent to 5-s contraction followed by 2-s relaxation and was enhanced
      when conditioned at higher lung volumes with a strong inspiratory effort. Our
      results suggest four factors that influence inspiratory muscle thixotropy: (1)
      intensity of muscle contraction, (2) lung volume when contraction occurs, (3)
      duration of contraction, and (4) muscle relaxation.

PMID- 15186788
TI  - Airflow synchronous with oscillatory acceleration reflects involuntary
      respiratory muscle activity.
AB  - To explore mechanisms causing involuntary airflow synchronous with oscillatory
      axial whole body acceleration (oscillatory axial acceleration, OAA) such as that
      during locomotion, we monitored airflow, acceleration, and electromyograms (EMGs)
      of the rib cage and abdominal muscles in standing subjects undergoing OAA at 3,
      6, and 9 Hz at accelerations of 0.1-0.95 g. Subjects relaxed or performed static
      respiratory maneuvers at constant lung volume with glottis open. Oscillatory
      airflows (0.01-3.01 s(-1)) synchronous with OAA were not consistent with
      expectations for a passive respiratory system, and were larger during active
      respiratory efforts than during relaxation. Peak inspiratory airflow usually
      preceded peak upward acceleration by 90-180 degrees. In 80% of runs with
      respiratory muscles voluntarily activated or relaxed, EMGs showed activity
      synchronous with OAA. Changes in periodic muscle activity coincided with changes
      in oscillatory airflow. We conclude that periodic muscle activity, probably a
      reflex response to body wall deformation during OAA, strongly influences the
      involuntary airflow synchronous with OAA.

PMID- 15186789
TI  - Differences in alveolar size in inbred mouse strains.
AB  - In this paper we examined structural differences in alveolar size among inbred
      mouse strains which are known to have significant differences in lung pressure
      volume relations. Accordingly, we assessed whether the relative size or number of
      alveoli in the C3H/HeJ, C57BL/6J, and A/J strains are related to these lung
      volume differences. Lungs from each of these strains were fixed in situ and then
      excised for quantitative morphometric analysis of airspace chord lengths. Mean
      chord lengths (in microm) were significantly different (P < 0.0001) among the
      three strains, with the largest alveoli found in the C3H/HeJ mice (45 +/- 5), the
      smallest in the C57BL/6J mice (35 +/- 3), and intermediate in the A/J strain (38
      +/- 2). These findings provide clear evidence that there are significant genetic
      differences in the lung structure among different mouse strains. However, since
      the A/J and C57BL/6J mice had similar lung volumes, there does not yet seem to be
      a clear link between the macroscopic manifestations of the microscopic structure.
      We speculate that these structural differences might have significant influence
      on several mouse models of lung disease, especially those involving the
      development of emphysema.

PMID- 15186790
TI  - Unevenness of ventilation assessed by the expired CO(2) gas volume versus V(T)
      curve in asthmatic patients.
AB  - Recently, we have shown that the expired CO2 gas volume versus tidal volume (VCO2
      VT) curve is a useful tool for assessing unevenness of ventilation because it
      allows the separation of tidal volume into three functional compartments: (a) the
      CO2-free expired air (V0), (b) the transitional volume (Vtr), (c) the alveolar
      volume (VA) and the measurement of alveolar FCO2 during resting breathing in
      normal subjects and patients with COPD. In this paper, we have investigated
      whether changes pertaining to unevenness of ventilation taking place immediately
      after the administration of methacholine can be assessed using the VCO2-VT curve
      in asthmatic patients. The VCO2-VT curve was obtained during tidal breathing from
      16 stable asthmatic patients who underwent a methacholine challenge test. It has
      been found that the Vtr, and hence Bohr's dead space (VD,Bohr = V0 + Vtr), over
      tidal volume ratios were significantly increased immediately after the
      methacholine administration, whilst the V0 over tidal volume ratio was not
      affected. The change of the above ratios was not related to the percentage
      decrease of FEV1.0 following methacholine administration.

PMID- 15186791
TI  - Labeled albumin in plasma and removal paths from pleural space in control and
      increased ventilation.
AB  - Increased ventilation was shown to markedly increase lymphatic drainage and
      plasma content of labeled proteins injected into pleural space relative to
      control ventilation. These proteins reach plasma by lymphatic drainage: directly
      through parietal pleura stomata, and indirectly from pleural interstitium,
      reached by diffusion, convection and transcytosis. Increased drainage from
      interstitium should not involve a comparable increase in protein removal from
      pleural space by these transports, while increased drainage through stomata
      involves a comparable increase in protein removal. Hence, relative increase in
      labeled protein removal from pleural space caused by increased ventilation should
      be marked only if drainage through stomata contributed most of this removal,
      whereas relative increase of labeled proteins in plasma should be marked in
      either case. We injected 3 ml of albumin-Ringer with albumin-Texas red into the
      pleural space of three groups of anesthetized rabbits: control, CO2-, or muscle
      stimulation-increased ventilation. Increased ventilation for 3 h (78 and 61%,
      respectively) increased (P < 0.01) labeled albumin in plasma by 132 and 106%,
      respectively, but did not significantly increase its removal. Hence, lymphatic
      drainage through stomata should not contribute most of liquid and protein removal
      from pleural space.

PMID- 15186792
TI  - Evolutionary differentiation of bimaculatus group anoles based on analyses of
      mtDNA and microsatellite data.
AB  - The bimaculatus group of anoles inhabit the northern Lesser Antilles, as far
      south as Dominica. This study uses 1005 base pairs (bp) of mitochondrial DNA
      sequence data from two genes, cytochrome b (521 bp) and cytochrome oxidase
      subunit I (484 bp) to reconstruct phylogenetic relationships between species and
      populations of anoles from all islands banks. Allele frequency data from nuclear
      microsatellite loci are also analysed to assess their utility in uncovering
      historical relationships and provide independent corroboration for the mtDNA
      tree. Although the number of microsatellite loci used (six) was relatively small,
      some essential elements of the mitochondrial DNA phylogeny were recovered
      successfully. Anoles from Terre de Haut, Les Saintes, previously described as a
      subspecies of Anolis marmoratus, are shown to be more closely related to A.
      oculatus and their elevation to a full species, A. terraealtae, is supported. An
      island colonisation sequence inferred from the phylogeny shows a general pattern
      of North-to South colonisation. However, the Saban anole, A. sabanus, is shown to
      be derived from A. marmoratus populations from western Basse Terre following a
      longer-range, south to north translocation.

PMID- 15186793
TI  - Molecular systematics of New World suboscine birds.
AB  - Phylogenetic relationships among New World suboscine birds were studied using
      nuclear and mitochondrial DNA sequences. New World suboscines were shown to
      constitute two distinct lineages, one apparently consisting of the single species
      Sapayoa aenigma, the other made up of the remaining 1000+ species of New World
      suboscines. With the exception of Sapayoa, monophyly of New World suboscines was
      strongly corroborated, and monophyly within New World suboscines of a tyrannoid
      clade and a furnarioid clade was likewise strongly supported. Relationships among
      families and subfamilies within these clades, however, differed in several
      respects from current classifications of suboscines. Noteworthy results included:
      (1) monophyly of the tyrant-flycatchers (traditional family Tyrannidae), but only
      if the tityrines (see below) are excluded; (2) monophyly of the pipromorphine
      flycatchers (Pipromorphinae of ) as one of two primary divisions of a
      monophyletic restricted Tyrannidae; (3) monophyly of the tityrines, consisting of
      the genus Tityra plus all sampled species of the Schiffornis group (), as sister
      group to the manakins (traditional family Pipridae); (4) paraphyly of the
      ovenbirds (traditional family Furnariidae), if woodcreepers (traditional family
      Dendrocolaptidae) are excluded; and (5) polyphyly of the antbirds (traditional
      family Formicariidae) and paraphyly of the ground antbirds (Formicariidae sensu
      stricto). Genus Melanopareia (the crescent-chests), although clearly furnarioid,
      was found to be distant from other furnarioids and of uncertain affinities within
      the Furnarii. Likewise, the species Oxyruncus cristatus (the Sharpbill), although
      clearly tyrannoid, was distantly related to other tyrannoids and of uncertain
      affinities within the Tyranni. Results of this study provide support for some of
      the more novel features of the suboscine phylogeny of, but also reveal key
      differences, especially regarding relationships among suboscine families and
      subfamilies. The results of this study have potentially important implications
      for the reconstruction of character evolution in the suboscines, especially
      because the behavioral evolution of many suboscine groups (e.g., Furnariidae) is
      of great interest.

PMID- 15186794
TI  - Investigation of molluscan phylogeny using large-subunit and small-subunit
      nuclear rRNA sequences.
AB  - The Mollusca represent one of the most morphologically diverse animal phyla,
      prompting a variety of hypotheses on relationships between the major lineages
      within the phylum based upon morphological, developmental, and paleontological
      data. Analyses of small-ribosomal RNA (SSU rRNA) gene sequence have provided
      limited resolution of higher-level relationships within the Mollusca. Recent
      analyses suggest large-subunit (LSU) rRNA gene sequences are useful in resolving
      deep-level metazoan relationships, particularly when combined with SSU sequence.
      To this end, LSU (approximately 3.5 kb in length) and SSU (approximately 2 kb)
      sequences were collected for 33 taxa representing the major lineages within the
      Mollusca to improve resolution of intraphyletic relationships. Although the LSU
      and combined LSU+SSU datasets appear to hold potential for resolving branching
      order within the recognized molluscan classes, low bootstrap support was found
      for relationships between the major lineages within the Mollusca. LSU+SSU
      sequences also showed significant levels of rate heterogeneity between molluscan
      lineages. The Polyplacophora, Gastropoda, and Cephalopoda were each recovered as
      monophyletic clades with the LSU+SSU dataset. While the Bivalvia were not
      recovered as monophyletic clade in analyses of the SSU, LSU, or LSU+SSU, the
      Shimodaira-Hasegawa test showed that likelihood scores for these results did not
      differ significantly from topologies where the Bivalvia were monophyletic.
      Analyses of LSU sequences strongly contradict the widely accepted Diasoma
      hypotheses that bivalves and scaphopods are closely related to one another. The
      data are consistent with recent morphological and SSU analyses suggesting
      scaphopods are more closely related to gastropods and cephalopods than to
      bivalves. The dataset also presents the first published DNA sequences from a
      neomeniomorph aplacophoran, a group considered critical to our understanding of
      the origin and early radiation of the Mollusca.

PMID- 15186795
TI  - Phylogenetic relationships between Clerodendrum (Lamiaceae) and other Ajugoid
      genera inferred from nuclear and chloroplast DNA sequence data.
AB  - Over the last two centuries the circumscription of the large, pan-tropical genus
      Clerodendrum (Lamiaceae) has changed frequently, as different authorities have
      added or removed taxa on the basis of various morphological characters. With the
      development of molecular methods for systematic research the process of
      circumscribing taxa has become increasingly analytical. When morphology signals
      the possibility that taxa are closely related, molecular methods can be used to
      test the hypothesis objectively. Aegiphila, Amasonia, Huxleya, and Kalaharia are
      similar morphologically to Clerodendrum. In this paper we use nuclear ribosomal
      ITS and chloroplast ndhF sequence data to clarify the positions of these four
      genera relative to Clerodendrum. We show that the Australian monotypic genus
      Huxleya evolved from within Clerodendrum. Accordingly, we sink Huxleya into
      Clerodendrum and make a new combination, Clerodendrum linifolium.

PMID- 15186796
TI  - Nested clade and phylogeographic analyses of the Chagas disease vector Triatoma
      brasiliensis in Northeast Brazil.
AB  - Triatoma brasiliensis (Hemiptera: Reduviidae: Triatominae) is the most important
      Chagas disease vector in the semiarid areas of Northeast Brazil. We analyzed
      mitochondrial cytochrome b sequence variation among 136 individuals representing
      16 populations from across the species' distribution. Neighbor-joining and
      parsimony tree-building methods were used in conjunction with nested clade
      analysis to describe the systematics and phylogeography of this species. Our
      results indicate that T. brasiliensis is composed of four genetically distinct
      chromatic forms (referred to as brasiliensis, macromelasoma, juazeiro, and
      melanica) that present inter-population divergence values (0.027-0.119, corrected
      K2-p) and a pattern of haplotype geographic distribution compatible with the
      existence of a species complex. As a consequence, such forms can be treated as
      isolated targets in vector control programs. We were unable to infer what is
      shaping the population structure of the brasiliensis form as we obtained mutually
      exclusive causes of structure, namely a barrier to gene flow caused by past
      population fragmentation, and isolation by distance between populations (which
      would permit gene flow). We found indication of mitochondrial DNA introgression
      occurring among forms in putative hybrid zones.

PMID- 15186797
TI  - Somatic variation plays a key role in the evolution of the Vf gene family
      residing in the Vf locus that confers resistance to apple scab disease.
AB  - A cluster of four receptor-like genes has been previously identified in the Vf
      locus of the crabapple Malus floribunda clone 821 that confers resistance to five
      races of the fungal pathogen Venturia inaequalis, the casual agent of apple scab
      disease. Pairwise comparisons of the four Vf paralogs in both promoter and coding
      regions reveal their timeline evolutionary history. The four Vf paralogs have
      evolved from four ancient Vf members resulting from two sequential duplication
      events of a single Vf progenitor initially present in the Malus genome. The
      coding sequences of the four Vf paralogs are characterized with high numbers of
      unique polymorphic nucleotides, a number of short duplications/deletions, various
      deletions of complete LRR copy units, and a casual insert of a transposon-like
      element. Significant high ratios of nonsynonymous to synonymous substitutions,
      Ka/Ks, are observed in the putative ligand binding residues in the LRR domains.
      No sequence exchange between the four Vf paralogs is observed. Compared with
      promoter regions, only nucleotide substitutions are dramatically elevated in the
      coding regions. The results presented in this study strongly indicate that the Vf
      locus is under strong and steady horizontal selective pressures imposed by the
      fungal pathogen V. inaequalis, and divergent selection on somatic variations
      plays a key role in shaping the resistance specificity.

PMID- 15186798
TI  - Resolving evolutionary relationships in the lichen-forming genus Porpidia and
      related allies (Porpidiaceae, Ascomycota).
AB  - The lichen-forming genus Porpidia (Porpidiaceae, Ascomycota) provides excellent
      opportunities for evolutionary, reproductive, and ecological studies of crustose
      epilithic lichen symbioses. However, despite the fact that the genus itself
      seemed to be clearly delimited, the group was thought to be a hopeless case with
      regard to intrageneric relationships and species delimitations due to apparently
      rampant homoplasy throughout most character systems. Contrary to the situation
      for non-molecular data, a robust and generally well-resolved phylogeny was
      recovered based on DNA-sequence data. Separate and combined analyses of nuclear
      ribosomal RNA large subunit and nuclear beta-tubulin gene fragments were
      performed using maximum parsimony, maximum likelihood, and Bayesian approaches.
      Branch support was estimated using non-parametic bootstrapping and posterior
      probabilities, while monophyly of a priori defined groups was tested using
      posterior probabilities. The results reveal a highly supported "Porpidia sensu
      lato," however, Porpidia itself is not monophyletic. Several smaller genera of
      the Porpidiaceae and probably the large genus Lecidea (Lecideaceae) are nested
      within the group. Most taxa analyzed fall into one of four major subgroups within
      Porpidia s.l., though the basal relationships among these subgroups could not be
      supported. This phylogeny will make it possible to re-evaluate morphological and
      chemical characters in the group, and to conduct detailed studies of species
      delimitations within the monophyletic subgroups.

PMID- 15186799
TI  - A phylogeny of four mitochondrial gene regions suggests a revised taxonomy for
      Asian pitvipers (Trimeresurus and Ovophis).
AB  - We present a phylogeny of the Asian pitvipers, based on 2403 bp of four
      mitochondrial gene regions. All but six known species of Trimeresurus sensu
      stricto (s.s.) as currently defined, as well as multiple populations of
      widespread species, which may yet be described as full species, and
      representatives of all other Asian pitviper genera, are included. Both the
      greater sampling and larger dataset provide improved resolution over previous
      studies and support the existence of distinct species groups within Trimeresurus
      s.s. Although all but two species currently referred to this genus form a
      monophyletic group, morphological and molecular analyses identify four subgroups
      that warrant recognition at the generic level. We propose a new generic
      arrangement to reflect these findings. We also highlight the non-monophyly of
      Ovophis, and propose a new genus to accommodate a species formerly assigned to
      Ovophis.

PMID- 15186800
TI  - Phylogeny of the Falconidae (Aves): a comparison of the efficacy of
      morphological, mitochondrial, and nuclear data.
AB  - We sequenced 2800+ bp of the RAG-1 exon for representatives of all the currently
      recognized genera in the avian family Falconidae. A phylogenetic analysis of
      these data was compared to prior analyses of mitochondrial (cytochrome-b) and
      morphological (syringeal) data. The nuclear RAG-1 sequences produced results that
      were in agreement with the morphological results, but differed from the
      mitochondrial results with regard to monophyly of the genus Micrastur. A
      reanalysis of the cytochrome-b (cyt-b) data suggested that this result was due to
      heterogeneity in base composition. Comparisons of data quality and quantity
      across the three data sets indicate that the nuclear DNA sequences and the
      morphological data have similar consistency and retention indices as well as
      noise distributions that are superior to those of cyt-b. However, the RAG-1 data
      identify more nodes with high bootstrap support indices than do either morphology
      or mitochondrial sequences. In the final assessment, RAG-1 sequences were
      superior in phylogenetic utility both to syringeal morphology (because of sheer
      number of characters) and to cyt-b sequences (because of reduced noise and
      homogeneity of base composition, but in spite of having many fewer characters).

PMID- 15186801
TI  - Molecular phylogenetics of the allodapine bee genus Braunsapis: A-T bias and
      heterogeneous substitution parameters.
AB  - Extreme AT bias in Hymenopteran mitochondrial genes have created difficulties for
      molecular phylogenetic analyses, especially for older divergences where multiple
      substitutions can erode signal. Heterogeneity in the evolutionary rates of
      different codon positions and different genes also appears to have been a major
      problem in resolving ancient divergences in allodapine bees. Here we examine the
      phylogeny of relatively recent divergences in the allodapine bee genus
      Braunsapis. We examined heterogeneity in nucleotide substitution parameters for
      one nuclear gene and codon positions in two mitochondrial genes, exploring
      various phylogenetic analyses for recovering relationships among species from
      Africa, Madagascar, southern Asia, and Australia. We explored maximum parsimony,
      maximum likelihood, Log determinant and Bayesian analyses. Broad topological
      features of best fit trees tended to be similar for equivalent data sets (e.g.,
      total, or with 3rd mt positions excluded), regardless of the analytic method used
      (e.g., maximum likelihood or Bayesian). Analyses that used the total data set
      without modelling partitions separately gave unlikely results, indicating that
      the Malagasy species was most closely related to Australian species. However,
      analyses that excluded 3rd mitochondrial positions, or modelled partitions
      separately, suggested that the Malagasy species falls within the African clade.
      The unlikely topologies apparently result from long branch attraction, and this
      problem is ameliorated where modelling allows more realistic estimates of base
      composition and evolutionary rates for 3rd mitochondrial positions. However, we
      found that even when codon positions are modelled separately, estimated
      evolutionary rates for 3rd mitochondrial positions are likely to underestimate
      true rates. Long branch attraction and multiple substitutions are likely to be
      much more difficult to circumvent in analyses that explore older, generic-level,
      divergences in allodapine bees where overwriting is expected to be much more
      extreme. Our results indicate an African origin for Braunsapis, followed by a
      single, very early, dispersal event into Asia and then by a later dispersal event
      into Australia. The Malagasy species is derived from within the African clade.

PMID- 15186802
TI  - Molecular phylogenetic evidence for the geographic origin and classification of
      Canary Island Lotus (Fabaceae: Loteae).
AB  - Molecular phylogenetic analyses of Macaronesian Lotus and related genera were
      conducted to assess their biogeographic history and taxonomy. Macaronesian Lotus,
      which are typically classified within one of two subgenera, Lotus subgenus
      Pedrosia or L. subg. Rhyncholotus, are diagnosed by the presence of a forked or
      toothed style and differences in corolla morphology. Maximum parsimony and
      Bayesian analyses of internal transcribed spacer sequences identify a well
      supported northwest African-Cape Verde Island clade that includes all members of
      Lotus subgenus Pedrosia+L. subg. Rhyncholotus. There is modest support for two
      independently nested clades containing the Canary Island species and two non
      Canarian species, Lotus assakensis from Africa and Lotus azoricus endemic to the
      Azores. Biogeographic reconstruction based on a parsimony topology unequivocally
      identifies an African origin for the Canary Island group with subsequent back
      dispersal to the African continent and a single dispersal event to the Azores. A
      phylogeographic assessment of colonization and diversification patterns suggests
      that geographic isolation via interisland colonization of ecologically similar
      habitats is the primary mode of species diversification in Canary Island Lotus.

PMID- 15186803
TI  - Speciation by host-switching in pinyon Cinara (Insecta: Hemiptera: Aphididae).
AB  - Parasite-host cospeciation has received much attention as an important mechanism
      in the diversification of phytophagous insects. However, studies have shown that
      for certain taxa, it is not host fidelity but host-switching that plays the
      critical role in speciation. Cinara are aphids (Insecta: Hemiptera: Aphididae:
      Lachninae) that feed exclusively on the woody parts of conifers of the
      Cupressaceae and Pinaceae. They are unusual aphids because most Pinaceae play
      host to several species of Cinara. The aphids show relatively strong host
      fidelity, and as a consequence historically have been treated based on the
      taxonomy of their hosts. The historical paradigm of aphid evolution implies that
      Cinara species have radiated to different parts of the same host species and/or
      speciated with their host. Using mitochondrial cytochrome oxidase 1 and nuclear
      elongation factor 1-alpha DNA sequences, we performed molecular phylogenetic
      analysis of Cinara species, concentrating on those associated with pinyon pines
      in the southwestern USA. We determined that switching hosts has played a key role
      in the speciation of the genus, reflected in the polyphyly of pinyon-feeding
      Cinara. Furthermore, species sharing a common feeding site on different hosts
      were more closely related to each other than to those sharing the same host but
      at different feeding sites, suggesting that feeding site fidelity plays a more
      important role in speciation than does host fidelity in general. This study also
      elucidated the primary taxonomy of various species: it suggested that Cinara
      rustica Hottes is a junior synonym of C. edulis (Wilson) and that C. wahtolca
      Hottes represents two species on the two different pinyon pine species, Pinus
      edulis Englem. and P. monophylla Torr. & Frem.

PMID- 15186804
TI  - Molecular phylogeny of the armored catfish family Callichthyidae (Ostariophysi,
      Siluriformes).
AB  - The family Callichthyidae comprises eight genera of fishes widely distributed
      across the Neotropical region. In the present study, sequences of the
      mitochondrial genes 12S rRNA, 16S rRNA, ND4, tRNAHis, and tRNASer were obtained
      from 28 callichthyid specimens. The sample included 12 species of Corydoras,
      three species of Aspidoras, two species of Brochis, Dianema, Lepthoplosternum,
      and Megalechis, and two local populations of Callichthys and Hoplosternum.
      Sequences of Nematogenys inermis (Nematogenyidae), Trichomycterus areolatus, and
      Henonemus punctatus (Trichomycteridae), Astroblepus sp. (Astroblepidae), and
      Neoplecostomus paranensis, Delturus parahybae, and Hemipsilichthys nimius
      (Loricariidae) were included as the outgroup. Phylogenetic analyses were
      performed by using the methods of maximum parsimony and maximum likelihood. The
      results of almost all analyses were very similar. The family Callichthyidae is
      monophyletic and comprises two natural groups: the subfamilies Corydoradinae
      (Aspidoras, Brochis, and Corydoras) and Callichthyinae (Callichthys, Dianema,
      Hoplosternum, Lepthoplosternum, and Megalechis), as previously demonstrated by
      morphological studies. The relationships observed within these subfamilies are in
      several ways different from those previously proposed on the basis of
      morphological data. Molecular results were compared with the morphologic and
      cytogenetic data available on the family.

PMID- 15186805
TI  - Phylogenetic hypotheses for the turtle family Geoemydidae.
AB  - The turtle family Geoemydidae represents the largest, most diverse, and most
      poorly understood family of turtles. Little is known about this group, including
      intrafamilial systematics. The only complete phylogenetic hypothesis for this
      family positions geoemydids as paraphyletic with respect to tortoises, but this
      arrangement has not been accepted by many workers. We compiled a 79-taxon
      mitochondrial and nuclear DNA data set to reconstruct phylogenetic relationships
      for 65 species and subspecies representing all 23 genera of the Geoemydidae.
      Maximum parsimony (MP) and maximum-likelihood (ML) analyses and Bayesian analysis
      produced similar, well-resolved trees. Our analyses identified three main clades
      comprising the tortoises (Testudinidae), the old-world Geoemydidae, and the South
      American geoemydid genus Rhinoclemmys. Within Geoemydidae, many nodes were
      strongly supported, particularly based on Bayesian posterior probabilities of the
      combined three-gene dataset. We found that adding data for a subset of taxa
      improved resolution of some deeper nodes in the tree. Several strongly supported
      groupings within the Geoemydidae demonstrate non-monophyly of some genera and
      possible interspecific hybrids, and we recommend several taxonomic revisions
      based on available evidence.

PMID- 15186806
TI  - Incongruence in Veroniceae (Plantaginaceae): evidence from two plastid and a
      nuclear ribosomal DNA region.
AB  - Nucleotide data from nuclear ribosomal and plastid DNA did not agree on all
      relationships within Veroniceae (Plantaginaceae) in previous analyses. We present
      here additional data from a second plastid DNA marker, the rps16 intron, and
      evaluate incongruence between the ribosomal and plastid DNA matrices. Based on
      these evaluations and analysis of secondary structure in ITS, we conclude that
      there is a biological cause for incongruence among the genera of Veroniceae. The
      sequence data imply a history of hybridization and polyploidization, in which
      ancestors of Wulfeniopsis and Veronica+Paederota gave rise to Picrorhiza and
      ancestors of Wulfeniopsis and Wulfenia gave rise to Veronicastrum.

PMID- 15186807
TI  - Recent speciation in the Formica rufa group ants (Hymenoptera, Formicidae):
      inference from mitochondrial DNA phylogeny.
AB  - This study examines phylogenetic relationships among six species of the Formica
      rufa group ants (F. polyctena, F. rufa, F. lugubris, F. paralugubris, F.
      aquilonia, and F. pratensis). The phylogeny based on a 2051bp fragment of mtDNA
      including cyt b, tRNASer, and ND1 genes supports the division of the group into
      three major clusters: one with the species F. polyctena and F. rufa, one with F.
      aquilonia, F. lugubris, and F. paralugubris, and the third one with F. pratensis.
      The interspecific divergence estimates (mean 0.98 +/- 0.15% for the main
      phylogenetic groups) imply that radiation took place during the Pleistocene.
      Comparison of the divergence estimates among the F. rufa group species with
      divergence estimates among other closely related species of insects suggests that
      speciation in the group was relatively fast, and the mitochondrial lineages of F.
      polyctena and F. rufa have not fully separated. The haplotype tree shows also
      signs of transfer of mtDNA between species through hybridisation. The
      distribution of polygyny (multiple queens per nest) along the branches of the
      tree indicates that the social type characterised by highly polygynous societies
      and large colonial networks, has originated at least three times. The species F.
      aquilonia and F. paralugubris that build such large supercolonies, cluster
      tightly together with very little nucleotide variation, suggesting that this type
      of social organisation could be a factor promoting speciation in the ants.

PMID- 15186808
TI  - Molecular phylogeny of Cotesia Cameron, 1891 (Insecta: Hymenoptera: Braconidae:
      Microgastrinae) parasitoids associated with Melitaeini butterflies (Insecta:
      Lepidoptera: Nymphalidae: Melitaeini).
AB  - Phylogenetic relationships among Cotesia Cameron (Braconidae) species
      parasitising Melitaeini butterflies were examined using DNA sequence data
      (mitochondrial cytochrome oxidase subunit I and NADH1 dehydrogenase genes,
      nuclear ribosomal DNA internal transcribed spacer region) as well as 12
      microsatellite loci. Molecular data were available from ostensibly six species of
      Cotesia from 16 host butterfly species in Europe, Asia, and North America.
      Analysis of the combined sequence data using both maximum parsimony and maximum
      likelihood revealed two distinct Cotesia clades. In one clade (C. acuminata
      (Reinhard); C. bignellii (Marshall)) host ranges are apparently narrow and,
      although Euphydryas (s. lato) is well-utilised, permeation of Melitaea (s. lato)
      has been slight. In the other clade (C. melitaearum (Wilkinson); C. lycophron
      (Nixon); C. cynthiae (Nixon)) host utilization across the Melitaeini as a whole
      is more extensive and the data are consistent with more recent, or active,
      speciation processes. Neighbour-joining trees calculated separately for the two
      main clades based on chord distance (DCE) of microsatellite allele frequencies
      were consistent with phylogenetic trees obtained from the sequence data. Our
      analysis strongly suggests the presence of several additional, previously
      unrecognised, Cotesia species parasitising this group of butterflies.

PMID- 15186809
TI  - Patterns of lineage diversification in the genus Naso (Acanthuridae).
AB  - The evolutionary history of the reef fish genus Naso (F. Acanthuridae) was
      examined using a complete species-level molecular phylogeny of all recognized
      (19) species based on three loci (one nuclear ETS2 and two mitochondrial 16S, cyt
      b). This study demonstrates that distinct foraging modes and specialized body
      shapes arose independently at different times in the evolutionary history of the
      genus. Members of the subgenus Axinurus, characterized by a scombriform
      morphology, caudal fin structure and pelagic foraging mode, were consistently
      placed basal to the remaining Naso species, suggesting that pelagic foraging is
      plesiomorphic and benthic foraging derived in this genus. We used a genus-level
      phylogeny (nuclear marker, ETS2), which included several taxa from all other
      acanthurid genera, to obtain a range of age estimates for the most recent common
      ancestor of the genus Naso. These age estimates (range of 52-43.3 MY) were then
      used to estimate divergence times (by nonparametric rate smoothing method) of the
      node giving rise to extant Naso species using the combined sequence data (from
      all loci). The reconstruction of the pattern of divergence of extant species
      indicates two sequences of events. The basal species characterized by pelagic
      foraging modes arose during the Eocene and Oligocene. Most of the remaining Naso
      species, including those characterized by benthic foraging, arose over a period
      of 20 MY during the Miocene. Diversification during this period was associated
      with major plate tectonic and glaciation events, resulting in changes in sea
      level, ocean temperature and productivity regimes. Regardless of the foraging
      mode exhibited, all species of Naso have a caudal propulsive unit similar to that
      observed in pelagic scombriform fishes, a legacy of the basal position of the
      subgenus Axinurus in the phylogeny of the genus.

PMID- 15186810
TI  - Cladogenesis in a starfish species complex from southern Australia: evidence for
      vicariant speciation?
AB  - DNA sequencing (cytochrome oxidase I; 82 sequences; 25 locations) of a species
      complex of Australian six-rayed sea-stars (genus Patiriella) reveals four well
      supported mtDNA clades, corresponding to P. oriens, P. occidens, P. medius, and
      P. gunnii. These clades have non-random geographic distributions along an east to
      west axis that are broadly consistent with the biogeographic provinces of
      southern Australia proposed by. The taxa are deeply divergent (minimum 7.5%) and
      are estimated to have originated during the late Pliocene. By contrast, intra
      clade divergences are small, typically less than 1.0%. Phylogenetic analysis of
      mtDNA provides strong support for the combined monophyly of multicoloured forms
      (P. oriens, P. occidens, and P. medius; 100% bootstrap support) and suggests that
      P. medius (central) and P. occidens (western) may be sister taxa (up to 76%
      bootstrap support). Maximum likelihood analysis of nuclear DNA sequences (actin;
      1437 bp) yields an optimal tree largely consistent with mtDNA groupings, but with
      little bootstrap support. The biogeographic distribution of P. oriens (eastern)
      and P. occidens (western) is roughly consistent with a vicariant model involving
      allopatric divergence during glaciation. In addition, we propose that the Great
      Australian Bight may also have retained isolated populations during glacial
      periods, perhaps explaining the "central" distributions of P. gunnii and P.
      medius.

PMID- 15186811
TI  - Distribution of introns in the mitochondrial gene nad1 in land plants:
      phylogenetic and molecular evolutionary implications.
AB  - Forty-six species of diverse land plants were investigated by sequencing for
      their intron content in the mitochondrial gene nad1. A total of seven introns,
      all belonging to group II, were found, and two were newly discovered in this
      study. All 13 liverworts examined contain no intron, the same condition as in
      green algae. Mosses and hornworts, however, share one intron by themselves and
      another one with vascular plants. These intron distribution patterns are
      consistent with the hypothesis that liverworts represent the basal-most land
      plants and that the two introns were gained in the common ancestor of mosses
      hornworts-vascular plants after liverworts had diverged. Hornworts also possess a
      unique intron of their own. A fourth intron was found only in Equisetum L.,
      Marattiaceae, Ophioglossum L., Osmunda L., Asplenium L., and Adiantum L., and was
      likely acquired in their common ancestor, which supports the monophyly of
      moniliformopses. Three introns that were previously characterized in angiosperms
      and a few pteridophytes are now all extended to lycopods, and were likely gained
      in the common ancestor of vascular plants. Phylogenetic analyses of the intron
      sequences recovered topologies mirroring those of the plants, suggesting that the
      introns have all been vertically inherited. All seven nad1 group II introns show
      broad phylogenetic distribution patterns, with the narrowest being in
      moniliformopses and hornworts, lineages that date back to at least the Devonian
      (345 million years ago) and Silurian (435 million years ago), respectively.
      Hence, these introns must have invaded the genes via ancient transpositional
      events during the early stage of land plant evolution. Potentially heavy RNA
      editing was observed in nad1 of Haplomitrium Dedecek, Takakia Hatt. & Inoue,
      hornworts, Isoetes L., Ophioglossum, and Asplenium. A new nomenclature is
      proposed for group II introns.

PMID- 15186812
TI  - Assessing the passerine "Tapestry": phylogenetic relationships of the
      Muscicapoidea inferred from nuclear DNA sequences.
AB  - This study presents new comparative sequence data from the nuclear RAG-1 gene for
      an increased taxon sample in order to investigate phylogenetic relationships
      among a diverse songbird superfamily, the Muscicapoidea, which has variously
      included the waxwings, silky flycatchers, Palm Chat, dippers, starlings,
      mockingbirds, thrushes, chats, and Old World flycatchers. At the same time, our
      results provide a test of the often-cited relationships inferred from the
      phenetic studies of Sibley and Ahlquist [Phylogeny and Classification of Birds: A
      Study in Molecular Evolution. Yale University Press, New Haven, 1990] using DNA
      hybridization distances. Nuclear DNA sequences confirm the monophyly of the "core
      muscicapoid" group, as defined by Barker et al. [Proc. R. Soc. Lond. B 269 (2002)
      295] and also support the sister-group relationship of the Sturnidae and Mimidae,
      on the one hand, and the large-bodied thrushes (Turdini)+the Old World
      flycatchers and robins, on the other. The results of the phylogenetic analysis
      allow preliminary inferences about muscicapoid biogeographic history.

PMID- 15186813
TI  - Mitogenomic evidence for the monophyly of elopomorph fishes (Teleostei) and the
      evolutionary origin of the leptocephalus larva.
AB  - The monophyly of Elopomorpha (eels and their relatives) has long been one of the
      most problematic issues in systematic ichthyology. Since established the
      Elopomorpha based on the existence of the leaf-like larval form, termed a
      leptocephalus, no one has corroborated their monophyly using character matrices
      derived from both morphological and molecular data during the last 30 years. We
      investigated their monophyly and interrelationships at the ordinal level using
      complete mitochondrial genomic (mitogenomic) data from 33 purposefully chosen
      species (data for nine species being newly determined during the study) that
      fully represent the major teleostean and elopomorph lineages. Partitioned
      Bayesian analyses were conducted with the two data sets that comprised
      concatenated nucleotide sequences from 12 protein-coding genes (with and without
      third codon positions), 22 transfer RNA genes, and two ribosomal RNA genes. The
      resultant trees were well resolved and largely congruent, with most internal
      branches being supported by high statistical values. Mitogenomic data strongly
      supported the monophyly of Elopomorpha, indicating the validity of the
      leptocephalus as an elopomorph synapomorphy. The order Elopiformes occupied the
      most basal position in the elopomorph phylogeny, with the Albuliformes and a
      clade comprising the Anguilliformes and the Saccopharyngiformes forming a sister
      group. The most parsimonious reconstruction of the three previously recognized,
      distinct larval types of elopomorphs onto the molecular phylogeny revealed that
      one of the types (fork-tailed type) had originated as the common ancestor of the
      Elopomorpha, the other two (filament-tailed and round-tailed types) having
      diversified separately in two more derived major clades.

PMID- 15186814
TI  - Mitochondrial evidence for the origin of hamadryas baboons.
AB  - Baboons (Mammalia: Primates, Papio) are found primarily on the continent of
      Africa, but the range of hamadryas baboons (Papio hamadryas) extends to the
      Arabian Peninsula, and the origin of Arabian populations is unclear. To estimate
      the timing of the divergence between Arabian and African hamadryas populations we
      analyzed mitochondrial DNA (mtDNA) sequences from individuals of Arabian and
      African origin, and from representatives of the other major baboon taxa. The
      oldest hamadryas mitochondrial lineages in the Arabian Peninsula form an ancient
      trichotomy with the two major African lineages. This suggests that Arabia was
      colonized by hamadryas very soon after the appearance of the distinctive
      hamadryas phenotype, both events perhaps coinciding with a mid-Pleistocene stage
      of dry climate and low sea-level. The most closely related Arabian and African
      mtDNA haplotypes coalesce at approximately 35 ka, suggesting that no gene flow
      between African and Arabian baboons has occurred since the end of the last ice
      age, when a land bridge at the southern sill of the Red Sea was submerged. The
      mitochondrial paraphyly of Ethiopian hamadryas and anubis (P. anubis) baboons
      suggests an extensive and complex history of sex-specific introgression.

PMID- 15186815
TI  - Plate tectonics and biogeographical patterns of the Pseudophoxinus (Pisces:
      Cypriniformes) species complex of central Anatolia, Turkey.
AB  - We investigated the phylogenetic relationships of Pseudophoxinus (Cyprinidae:
      Leuciscinae) species from central Anatolia, Turkey to test the hypothesis of
      geographic speciation driven by early Pliocene orogenic events. We analyzed 1141
      aligned base pairs of the complete cytochrome b mitochondrial gene. Phylogenetic
      relationships reconstructed by maximum likelihood, Bayesian likelihood, and
      maximum parsimony methods are identical, and generally well supported. Species
      and clades are restricted to geologically well-defined units, and are deeply
      divergent from each other. The basal diversification of central Anatolian
      Pseudophoxinus is estimated to have occurred approximately 15 million years ago.
      Our results are in agreement with a previous study of the Anatolian fish genus
      Aphanius that also shows a diversification pattern driven by the Pliocene
      orogenic events. The distribution of clades of Aphanius and Pseudophoxinus
      overlap, and areas of distribution comprise the same geological units. The
      geological history of Anatolia is likely to have had a major impact on the
      diversification history of many taxa occupying central Anatolia; many of these
      taxa are likely to be still unrecognized as distinct.

PMID- 15186816
TI  - Phylogeny of the orchid bees (Hymenoptera: Apinae: Euglossini): DNA and
      morphology yield equivalent patterns.
AB  - Orchid bees (Euglossini) are spectacular long-tongued Neotropical bees important
      in the pollination of Neotropical long-corolla flowers, particularly some
      orchids. Besides remarkably long tongues, males in particular exhibit other
      flower-related adaptations, including setal brushes on the foretarsi used for
      rasping the petals of orchids while collecting aromatic compounds. These
      compounds are stored in large swollen tibiae and are thought to play an important
      role in courtship behavior. Euglossini are also unusual in lacking sociality;
      they are the only tribe among the corbiculate bees that are not eusocial, and two
      of the genera are cleptoparasitic. Each genus exhibits distinct behavioral traits
      including nest architecture and host-parasite interactions, yet their evolution
      is unknown. Despite previous phylogenetic studies of on morphological characters,
      the relationships among the five euglossine genera remain under debate. We
      investigate euglossine generic relationships using DNA sequence data from four
      genes and new morphological characters. The morphological and molecular data
      yield congruent evolutionary patterns, and combining the data gives a fully
      resolved and well supported phylogeny of Euglossini.

PMID- 15186817
TI  - Paleoclimatic history and vicariant speciation in the "sand goby" group
      (Gobiidae, Teleostei).
AB  - Vicariant and climatic cycling speciation hypotheses of the 'sand gobies'
      belonging to the genera Pomatoschistus, Gobiusculus, Knipowitschia, and
      Economidichthys are tested using molecular phylogenies constructed of nuclear DNA
      (ITS1 locus) and mitochondrial DNA (12S and 16S fragments). These gobies are
      among the most abundant in the Eastern Atlantic-Mediterranean region, and play an
      important role in the ecosystem. Considerable ITS1 length differences, primarily
      due to the presence of several tandem repeats, were found between species and
      even within individuals. Therefore, phylogenetic analyses focused on fragments of
      the 12S and 16S mtDNA region that have been sequenced for 16 goby taxa. The 'sand
      gobies' clustered as a monophyletic group as proposed on morphological grounds.
      However, G. flavescens, E. pygmaeus, and K. punctatissima clustered within the
      Pomatoschistus species, pointing to a paraphyletic origin of these genera.
      Furthermore, the genetic divergence between P. minutus from the Adriatic Sea
      versus the Atlantic-Mediterranean region was as high as the divergence within the
      P. minutus complex, suggesting that P. minutus from the Adriatic Sea should be
      considered as a distinct species. The "star" phylogeny might suggest that these
      gobies evolved in a very short time period, possibly linked to the drastic
      alterations in the Mediterranean Sea during and immediately after the Messinian
      salinity crisis at the end of the Miocene. The freshwater life-style appeared
      monophyletic; equating its origin with the salinity crisis resulted in a
      molecular clock estimate of 1.4% divergence per million years. The last common
      ancestor probably occupied sandy bottoms and a coastal niche while several
      species subsequently adapted to new habitats (pelagic, freshwater or
      stenohaline). The origin of the shallowest clades dated back to the glacial
      cycling during the Pleistocene epoch.

PMID- 15186818
TI  - Pattern of divergence of amino acid sequences encoded by paralogous genes in
      human and pufferfish.
AB  - We used phylogenetic analyses of protein families containing two or more pairs of
      orthologues in the genomes of human and pufferfish (Takifugu rubripes) to test
      the hypothesis that these sequences show a strong signal of polyploidization
      events hypothesized to have occurred early in vertebrate history. In order to
      test for evidence of two distinct rounds of polyploidization (the 2R hypothesis),
      we compared the pattern of amino acid sequence divergence of proteins encoded by
      genes duplicated just prior to the most recent common ancestor of human and
      pufferfish with that of proteins encoded genes duplicated earlier. These sequence
      divergences were statistically indistinguishable, contrary to the prediction of
      the 2R hypothesis. The variance of amino acid sequence divergences between
      paralogues was significantly greater than expected from that of orthologues in
      the same families. Estimation of gene duplication times assuming a molecular
      clock provided earlier estimates than expected, suggesting that it may not be
      appropriate to time the duplication of paralogues using rate estimates derived
      from orthologous comparisons. Overall, the results indicate that amino acid
      sequences do not provide a strong signal supporting the hypothesis that gene
      duplications early in vertebrate history occurred by polyploidization. On the
      other hand, the data are easily explained under an alternative model that gene
      duplications occurred at different times in different vertebrate gene families.

PMID- 15186819
TI  - Investigating phylogenetic relationships of sunfishes and black basses
      (Actinopterygii: Centrarchidae) using DNA sequences from mitochondrial and
      nuclear genes.
AB  - The 32 species of the Centrarchidae are ecologically important components of the
      diverse fish communities that characterize North American freshwater ecosystems.
      In spite of a rich history of systematic investigations of centrarchid fishes
      there is extensive conflict among previous hypotheses that may be due to
      restricted taxon or character sampling. We present the first phylogenetic
      analysis of the Centrarchidae that combines DNA sequence data from both the
      mitochondrial and nuclear genomes and includes all described species. Gene
      sequence data were collected from a complete mtDNA protein coding gene (NADH
      subunit 2), a nuclear DNA intron (S7 ribosomal protein intron 1), and a portion
      of a nuclear DNA protein-coding region (Tmo-4C4). Phylogenetic trees generated
      from analysis of the three-gene dataset were used to test alternative hypotheses
      of centrarchid relationships that were gathered from the literature. Four major
      centrarchid lineages are present in trees generated in maximum parsimony (MP) and
      Bayesian maximum likelihood analyses (BML). These lineages are Acantharchus
      pomotis, Micropterus, Lepomis, and a clade containing Ambloplites, Archoplites,
      Centrarchus, Enneacanthus, and Pomoxis. Phylogenetic trees resulting from MP and
      BML analyses are highly consistent but differ with regard to the placement of A.
      pomotis. Significant phylogenetic incongruence between mtDNA and nuclear genes
      appears to result from different placement of Micropterus treculi, and is not
      characteristic of relationships in all other parts of the centrarchid phylogeny.
      Slightly more than half of the 27 previously proposed hypotheses of centrarchid
      relationships were rejected based on the Shomodaira-Hasegawa test.

PMID- 15186820
TI  - Phylogeny and host-plant association in the leaf beetle genus Trirhabda LeConte
      (Coleoptera: Chrysomelidae).
AB  - The leaf beetle genus Trirhabda contains 26 described species from the United
      States and Canada, feeding on host plants from the families Asteraceae and
      Hydrophyllaceae. In this study, we present a phylogeny for the genus that was
      reconstructed from mitochondrial COI and 12S rRNA fragments, nuclear ITS2 rRNA,
      and morphological characters. Both parsimony and mixed-model Bayesian likelihood
      analyses were performed. Under both methods, the mitochondrial and nuclear
      partitions support the same backbone phylogeny, as do the combined data. The
      utility of the molecular data is contrasted with the low phylogenetic signal
      among morphological characters. The phylogeny was used to trace the evolution of
      the host-plant association in Trirhabda. The recovered phylogeny shows that
      although the host-plant association is phylogenetically conservative, Trirhabda
      experienced one shift to a distantly related host-plant family, 6 shifts between
      host-plant tribes, and 6 between genera within tribes. The phylogeny reveals that
      Trirhabda were plesiomorphically adapted to tolerate complex secondary compounds
      of its host plants and this adaptation is retained in Trirhabda species, as
      evidenced by multiple shifts from chemically simpler host plants back to the more
      complex host plants.

PMID- 15186821
TI  - Molecular phylogeny of the antitropical genus Pseudolabrus (Perciformes:
      Labridae): evidence for a Southern Hemisphere origin.
AB  - The genus Pseudolabrus comprises 11 species of marine nearshore fishes which are
      antitropically distributed: two species occur in East Asia, the remaining nine
      species being distributed in the Southern Hemisphere, mainly in the temperate
      Pacific. The distributions of their closely allied genera, collectively called
      "pseudolabrines" are, however, restricted to the Australia-New Zealand region.
      The molecular phylogeny of six of the 11 Pseudolabrus species from both
      Hemispheres and four of the five other pseudolabrine genera was reconstructed
      from nucleotide sequence data from mitochondrial DNA 12S rRNA, tRNAVal, and 16S
      rRNA genes. Both parsimony and Bayesian analyses were performed. Results are not
      consistent with a previous phylogenetic hypothesis based on osteological data,
      particularly in the relationship between Pseudolabrus and Notolabrus, indicating
      a probable need for reviewing the status of Notolabrus (or the delimitations of
      both Pseudolabrus and Notolabrus). The two Northern Hemisphere species of
      Pseudolabrus were monophyletic and nested deep into the clade of the Southern
      Hemisphere pseudolabrines, which indicates that both pseudolabrines and
      Pseudolabrus originated in the Southern Hemisphere. A dispersal rather than
      vicariance explanation for the antitropical distribution of Pseudolabrus is more
      parsimonious given the number of dispersal events, extinctions, and evolutionary
      adaptations required under the phylogeny. Based on molecular clock calibrations,
      the transequatorial divergence was suggested to be early to mid Pliocene at the
      earliest.

PMID- 15186822
TI  - P elements in the saltans group of Drosophila: a new evaluation of their
      distribution and number of genomic insertion sites.
AB  - Few are studies on P elements that have addressed the saltans group. These
      studies had shown that species from the cordata and elliptica subgroups were
      devoid of any discernible P homologous sequences, while species from the
      parasaltans, sturtevanti, and saltans subgroups all contain P element sequences.
      Our analyses showed the presence of one to 15 P element insertion sites in
      species of the saltans group, including Drosophila neocordata and Drosophila
      emarginata (cordata and elliptica subgroups, respectively). From these species,
      only those from the parasaltans, sturtevanti, and saltans subgroups harbor
      canonical P elements and, only those of the last two subgroups seem to harbor
      putative full-sized elements. Due to the low similarity of the sequences found in
      D. neocordata and D. emarginata to those earlier described, we suggest that these
      sequences might be rudimental P element derivatives that were present in the
      ancestral of the subgenus Sophophora.

PMID- 15186823
TI  - Order level differences in the structure of partial LSU across demosponges
      (Porifera): new insights into an old taxon.

PMID- 15186824
TI  - Multiple trans-Pacific migrations of deep-sea vent/seep-endemic bivalves in the
      family Vesicomyidae.

PMID- 15186826
TI  - Phylogenetics of the new world honey ants (genus Myrmecocystus) estimated from
      mitochondrial DNA sequences.

PMID- 15186825
TI  - Phylogenetic utility of the ribosomal internal transcribed spacer 2 in
      Strumigenys spp. (Hymenoptera: Formicidae).
AB  - Sequence variations and phylogenetic relationships of Strumigenys from different
      localities in Taiwan were inferred from sequences of the internal transcribed
      spacer 2 (ITS2) of nuclear ribosomal RNA genes. The ITS2 sequences of different
      species of Strumigenys vary in length from 659 to 953 bp, because there are many
      large repeated insertion-deletion fragments, and these short tandem repeat units
      form microsatellites. The average GC content of the ITS2 is 60.8%. Secondary
      structures from ITS2 sequences are similar and present several conserved
      structural motifs. Eleven species and three unnamed species were analyzed using
      both the maximum parsimony and maximum likelihood methods. Although diversity of
      the ITS2 sequence is high, these data can still be a potential tool for primary
      analysis of molecular phylogeny and biogeography of Strumigenys at the species
      level on islands around Taiwan.

PMID- 15186827
TI  - Analysis of structure-activity relationships with the N-(3-acyloxy-2
      benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea template for vanilloid
      receptor 1 antagonism.
AB  - In a continuing effort to elucidate the structure-activity relationships of the
      lead antagonist N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[4
      (methylsulfonylamino)benzyl]thiourea (1), the distances between the proposed four
      pharmacophores in 1 have been varied by insertion or deletion of one carbon to
      optimize their fit to the receptor. In addition, the acyloxy group of the C
      region was replaced with amide and N-hydroxy amide to identify the pharmacophoric
      importance of the ester group in the C2 region. The results indicated that the
      pharmacophoric arrangement of 1 was optimal for receptor binding affinity and
      antagonism, and the ester of the C2 region was significant for receptor binding.
      Among the derivatives, compound 19 showed distinct behavior with a 2-fold
      improvement in antagonism but a 13-fold reduction in binding affinity compared to
      1. The partial separation of pharmacophoric requirements of these two assays has
      been noted before and compound 19 is thus selective for the calcium entry-linked
      receptor population. The conformational analysis of 1 generated three distinct
      conformers having different types of hydrophobic interactions, which will be
      utilized for exploring the active conformation of the VR1 ligand.

PMID- 15186828
TI  - Novel iodine-124 labeled EGFR inhibitors as potential PET agents for molecular
      imaging in cancer.
AB  - The in vivo results with our previously reported irreversible labeled inhibitor
      [(11)C]-ML03 suggested that more chemically stable inhibitors, labeled with a
      longer-lived radioisotope, could be better candidates for molecular imaging of
      epidermal growth factor receptor (EGFR) positive tumors. On the basis of this
      hypothesis we synthesized three new irreversible tyrosine kinase (TK) inhibitors
      with various chemical reactivities. The three new inhibitors were successfully
      labeled on the anilino moiety with [(124)I], starting with the 6-amino-4-[(3
      tributylstannylphenyl)amino]-quinazoline (9) precursor. The cell-free results,
      obtained with these new irreversible inhibitors, indicated that compounds 5
      (alpha-chloro-acetamide derivative) and 6 (4-dimethylamino-but-2-enoic amide
      derivative) possessed high potencies toward the EGFR with an irreversible
      inhibition effect. Compound 4 (alpha-methoxy-acetamide derivative) was found to
      be less potent, with only a partially irreversible effect. The high potency of
      compounds 5 and 6 toward the EGFR establishes their potential as PET agents for
      molecular imaging of EGFR positive tumors. Their prospect as PET biomarkers is
      further being investigated.

PMID- 15186829
TI  - Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1:
      discovery of novel orally active inhibitors of human thymidine phosphorylase.
AB  - A series of novel 6-methylene-bridged uracil derivatives have been prepared as
      inhibitors of human thymidine phosphorylase (TP). To enhance the in vivo
      antitumor activity of fluorinated pyrimidine 2'-deoxyribonucleosides such as 2'
      deoxy-5-(trifluoromethyl)uridine (F(3)dThd), a potent TP inhibitor preventing
      their degradation to an inactive compound, has become a target of medicinal
      chemistry. We present here the synthesis and evaluation of novel human TP
      inhibitors. Introduction of an N-substituted aminomethyl side chain at the 6
      position of 5-chlorouracil has improved water solubility and enhanced inhibitory
      activity compared with the known TP inhibitor, 6-amino-5-chlorouracil. Compound
      42 was reasonably well absorbed in mice after oral administration. When combined
      with F(3)dThd, compound 42 exerted its TP inhibitory potency by increasing the
      maximum plasma concentrations of the former as evidenced in experiments with
      monkeys. Positive changes in pharmacokinetic profile were accompanied by the
      enhanced in vivo antitumor activity of this combination when compared to F(3)dThd
      alone, in mice bearing human tumor xenografts. Both biochemical and
      pharmacological effects appeared to fit the concept as anticipated.

PMID- 15186830
TI  - Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2:
      optimization of inhibitors of human thymidine phosphorylase and their selectivity
      with uridine phosphorylase.
AB  - A series of novel 6-methylene-bridged uracil derivatives have been optimized for
      clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe
      their synthesis and evaluation. Introduction of a guanidino or an amidino group
      enhanced the in vitro inhibitory activity of TP comparing with formerly reported
      inhibitor 1. Their selectivity for TP based on uridine phosphorylase inhibitory
      activity was also evaluated. Compound 2 (TPI) has been selected for clinical
      evaluation based on its strong TP inhibition and excellent modulation of 2'-deoxy
      5-(trifluoromethyl)uridine (F(3)dThd) pharmacokinetics. As a result, TAS-102 (a
      combination of F(3)dThd and TPI) is currently in phase 1 clinical studies.

PMID- 15186831
TI  - 15-Fluoro prostaglandin FP agonists: a new class of topical ocular hypotensives.
AB  - A novel series of 15-fluoro prostaglandins with phenoxy termination of the omega
      chain was synthesized and evaluated for binding and functional activation of the
      prostaglandin FP receptor in vitro and for side effect potential and topical
      ocular hypotensive efficacy in vivo. Compounds with the 15alpha-fluoride relative
      stereochemistry displayed EC50 values of <or=20 nM, comparable to the value for
      the endogenous ligand PGF2alpha. Evaluation of selected ester prodrugs of these
      15-fluoro prostaglandins in vivo highlighted their generally low propensity to
      elicit hyperemia or ocular irritation in rabbits and efficacious intraocular
      pressure-lowering property in monkeys. In particular 13,14-dihydro-15-deoxy
      15alpha-fluoro-16-aryloxy-omega-tetranor-cis-Delta4-PGF2alpha isopropyl ester
      (24) caused relatively little ocular irritation in rabbits while lowering
      intraocular pressure in conscious ocular hypertensive monkeys by 39% following a
      topical ocular dose of 3 microg.

PMID- 15186832
TI  - Synthesis and functional activity of (2-aryl-1-piperazinyl)-N-(3
      methylphenyl)acetamides: selective dopamine D4 receptor agonists.
AB  - Diaryl piperazine acetamides were identified as potent and selective dopamine
      D(4) receptor agonists. Our strategy is based on an amide bond reversal of an
      acid sensitive, dopamine D(4) receptor partial agonist, PD 168077. This reversal
      provided compounds with excellent potency and improved stability. Systematic
      evaluation of the substitution on the aryl piperazine portion revealed a
      significant effect on functional activity. The synthesis and biological activity
      of these new dopamine D(4) agonists is discussed.

PMID- 15186833
TI  - Probing the aglycon binding site of a beta-glucosidase: a collection of C-1
      modified 2,5-dideoxy-2,5-imino-D-mannitol derivatives and their structure
      activity relationships as competitive inhibitors.
AB  - A range of new C-1 modified derivatives of the powerful glucosidase inhibitor 2,5
      dideoxy-2,5-imino-D-mannitol has been synthesised and their biological activities
      probed with the beta-glucosidase from Agrobacterium sp. Ki values are compared
      with those of previously prepared close relatives. Findings suggest dramatic
      effects exerted by the aglycon binding site on substrate/inhibitor binding.

PMID- 15186834
TI  - Synthesis and antileishmanial activity of novel buparvaquone oxime derivatives.
AB  - Novel oxime derivatives (2, 3 and 5) of buparvaquone (1) and O-methyl
      buparvaquone (4) were synthesized and their in vitro activities against
      Leishmania donovani, the causative agent of visceral leishmaniasis (VL), were
      determined. Buparvaquone-oxime (2) was also studied as a bioreversible prodrug
      structure of buparvaquone (1). Buparvaquone-oxime (2) released buparvaquone (1)
      in vitro when it was incubated with induced rat liver microsomes, which suggests
      that the oxime-structure is a useful prodrug template for developing novel
      prodrugs of buparvaquone and other hydroxynaphthoquinones. Moreover, the
      formation of NO(2)(-) , formed via oxidation of NO, was confirmed during the
      bioconversion. The release of NO from buparvaquone-oxime (2) may provide an
      additional therapeutic effect in the treatment of leishmaniasis. Buparvaquone
      oxime (2) and buparvaquone-O-methyloxime (3) demonstrated moderate activity
      against amastigotes of the Leishmania species that causes VL. However, the
      studied oximes (2, 3) most probably did not release buparvaquone (1) and NO
      during the present in vitro experiment. Further in vivo studies are needed to
      verify the biological activity of buparvaquone-oximes in the treatment of
      leishmaniasis.

PMID- 15186835
TI  - Novel ketolide antibiotics with a fused five-membered lactone ring--synthesis,
      physicochemical and antimicrobial properties.
AB  - In an effort to find novel semisynthetic macrolides with extended antibacterial
      spectrum and improved activity we prepared a series of compounds based on
      commercially available clarithromycin, a potent and safe antimicrobial agent of
      outstanding clinical and commercial interest. According to the literature,
      improvement of antibacterial activity of erythromycin type antibiotics can be
      achieved by introduction of fused heterocycles such as cyclic carbonates or
      carbamates at positions 11 and 12 (such as in telithromycin). In the course of
      the work presented here, a similar, hitherto unprecedented set of compounds
      bearing a five-membered lactone ring fused to positions 11 and 12 was prepared
      based on carbon-carbon bond formation via intramolecular Michael addition of a
      [(hetero)arylalkylthio]acetic acid ester enolate to an alpha,beta-unsaturated
      ketone as the key step. Some of the ketolide compounds described in this paper
      were highly active against a representative set of erythromycin sensitive and
      erythromycin resistant test strains. The best compound showed a similar
      antimicrobial spectrum and comparable activity in vitro as well as in vivo as
      telithromycin. Furthermore, some physicochemical properties of these compounds
      were determined and are presented here. On the basis of these results, the novel
      ketolide lactones presented in this paper emerged as valuable lead compounds with
      comparable properties as the commercial ketolide antibacterial telithromycin
      (Ketek).

PMID- 15186836
TI  - Study of the green tea polyphenols catechin-3-gallate (CG) and epicatechin-3
      gallate (ECG) as proteasome inhibitors.
AB  - The green tea polyphenol catechin-3-gallate (CG) and epicatechin-3-gallate (ECG)
      were synthesized enantioselectively via a Sharpless hydroxylation reaction
      followed by a diastereoselective cyclization. Their potencies to inhibit the
      proteasome activity were measured. The unnatural enantiomers were found to be
      equally potent to the natural compounds.

PMID- 15186837
TI  - Benzamides and benzamidines as specific inhibitors of epidermal growth factor
      receptor and v-Src protein tyrosine kinases.
AB  - The benzamides 1 and the benzamidines 2 as well as the cyclic benzamidines 3 were
      designed and synthesized as the mimics of 4-anilinoquinazolines for an inhibitor
      of EGFR tyrosine kinase. The specific inhibitions of EGFR tyrosine kinase were
      observed in the benzamides 1c and 1d, and the benzamidine 2a, whereas the
      specific inhibitions of v-Src kinase were observed in the benzamide 1j and the
      benzamidine 2d at a 10microg/mL concentration of compounds. The cyclic
      benzamidines 3a and 3b showed potent kinase inhibition of EGFR at a 1.0microg/mL
      concentration. According to the docking simulation using the X-ray structure of
      EGFR kinase domain in complex with erlotinib, the LigScore2 scoring function
      value of erlotinib was calculated as 5.61, whereas that of the benzamide 1c was
      5.05. In a similar manner, the LigScore2 value of the cyclic benzamidine 3a was
      calculated as 5.10.

PMID- 15186838
TI  - Solution-phase combinatorial synthesis of nonpeptide bradykinin antagonists.
AB  - We describe the solution-phase combinatorial synthesis and pharmacological effect
      of fifty N,N(')-substituted-N"-1-(4-chlorobenzhydryl)piperazine iminodiacetic
      acid triamide derivatives as nonpeptide B2 antagonists. The synthesized compounds
      were tested for their antibradykinin activity by utilizing guinea-pig ileum
      smooth muscle. Most of the compounds showed antagonistic effects on bradykinin
      induced contraction. N-acetyl-N(')-(4-methylbenzyl)-N"-1-(4
      chlorobenzhydryl)piperazine iminodiacetic acid triamide (A3B1C1) showed the 46%
      inhibition at 100nM.

PMID- 15186839
TI  - Synthesis and neuropharmacological evaluation of R(-)-N-alkyl-11
      hydroxynoraporphines and their esters.
AB  - We synthesized several N-substituted-11-hydroxynoraporphines and their esters of
      varying chain length, evaluated their binding affinity at dopamine (DA) receptor
      sites in rat caudate-putamen membranes, and quantified their effects on motor
      activity in normal adult male rats. The 11-hydroxyaporphines showed similar
      neuropharmacological properties to the corresponding 10,11-catecholaporphines. At
      moderate doses, their esters proved to have more prolonged behavioral actions and
      superior oral bioavailability.

PMID- 15186840
TI  - Synthesis and fungicidal activity of enantiomerically pure (R)- and (S)-silicon
      containing azole fungicides.
AB  - Enantiomerically pure (R)- and (S)-1-(1H-1,2,4-triazol-1-yl)-2-(4-fluorophenyl)-3
      trimethylsilylpropan-2-ol 1 were prepared via an enantioselective Grignard
      reaction. The absolute stereochemistry of 1 was determined by X-ray analysis. In
      a comparison of in vitro antifungal activities of the enantiomers, the (-)
      enantiomer with the R-absolute configuration was far more potent than the (+)
      enantiomer.

PMID- 15186841
TI  - Design, synthesis, and structure-activity relationships of novel tetracyclic
      compounds as peripheral benzodiazepine receptor ligands.
AB  - The peripheral benzodiazepine receptor (PBR) is pharmacologically distinct from
      the central benzodiazepine receptor (CBR) and has been identified in a wide range
      of peripheral tissues as well as in the central nervous system. Although numerous
      studies have been performed of it, the physiological roles and functions of the
      PBR are still unclear. In the present study, in exploring new types of ligands
      for PBR, we found that a new series of compounds having a tetracyclic ring
      system, which were designed from FGIN-1-27, exhibited high affinities for PBR. We
      prepared and evaluated them for PBR affinities. The results of binding tests
      showed that 12e and 12f were the most potent PBR ligands among them (12e:
      IC(50)=0.44nM, 12f: IC(50)=0.37nM). In this paper, we present the design,
      synthesis, and structure-activity relationships (SARs) of novel tetracyclic
      compounds.

PMID- 15186842
TI  - Phenolic acid derivatives with potential anticancer properties--a structure
      activity relationship study. Part 1: methyl, propyl and octyl esters of caffeic
      and gallic acids.
AB  - The antiproliferative and cytotoxic properties of polyphenolic acid derivatives,
      structurally related with the natural models caffeic and gallic acids, have been
      tested in human cervix adenocarcinoma cells (HeLa). Simultaneous structural
      information was obtained for these compounds through theoretical ab initio
      methods. This study was conducted for the following esters: methyl caffeate (MC,
      1), propyl caffeate (PC, 2), octyl caffeate (OC, 3), methyl gallate (MG, 4),
      propyl gallate (PG, 5) and octyl gallate (OG, 6). A significant growth-inhibition
      effect was assessed for some of these compounds, clearly dependent on their
      structural characteristics. Marked structure-activity relationships (SARs)-
      namely the number of hydroxyl ring substituents--were found to rule the
      biological effect of such systems.

PMID- 15186843
TI  - Development of CoMFA, advance CoMFA and CoMSIA models in pyrroloquinazolines as
      thrombin receptor antagonist.
AB  - 3D QSAR studies namely CoMFA, advance CoMFA and CoMSIA have been carried out on a
      series of pyrroloquinazolines for their thrombin receptor antagonistic activity.
      The predicted activities by highly significant CoMFA (q2=0.66 and CoMSIA
      (q2=0.67) models were in good accordance with observed activities and the models
      may be useful for optimization of thrombin receptor antagonistic activity.

PMID- 15186844
TI  - Evaluation of hesperetin 7-O-lauryl ether as lipid-lowering agent in high
      cholesterol-fed rats.
AB  - The lipid-lowering efficacy of hesperetin was revealed in preliminary studies on
      experimental animals. As such, the current study compared the effect of
      hesperetin 7-O-lauryl ether, with that of hesperetin and lovastatin on the lipid
      profile and cholesterol-regulating mechanism in high-cholesterol-fed rats. Male
      rats were fed a high-cholesterol diet (1%, wt/wt) or high-cholesterol diet
      supplemented with lovastatin (1, 0.02%, wt/wt), hesperetin (2, 0.02%, wt/wt), or
      hesperetin 7-O-lauryl ether (3, 0.031%, wt/wt) for six weeks. The supplemental
      amount of 3 was 0.066mmol/100g diet as an equivalent to the supplemental amount
      of 2. The plasma total cholesterol and triglyceride levels were significantly
      lowered by the 2 and 3 supplements compared with the control or 1-supplemented
      group. The hepatic HMG-CoA reductase activities were also significantly lower in
      all the supplemented groups compared with the control group, and the hepatic ACAT
      activity was significantly lower in the 2- and 3-supplemented groups. The
      supplementation of 3 resulted in a higher excretion of total neutral sterol and
      total fecal sterol compared with the control or 1-supplemented group.
      Accordingly, overall, compound 3, exhibited a more potent plasma lipid-lowering
      effect than compound 1 based on inhibiting cholesterol biosynthesis and
      esterification, while also increasing the fecal sterol excretion.

PMID- 15186845
TI  - GRIND/ALMOND investigations on CysLT1 receptor antagonists of the
      quinolinyl(bridged)aryl type.
AB  - One of the current routes in developing antiasthmatics is CysLT(1) receptor
      antagonism. For a training set of 54 CysLT(1) receptor antagonists of the
      quinolinyl(bridged)aryl type we developed chemometric QSAR models applying GRID
      independent descriptors (=GRIND). PLS analysis resulted in a two-component model
      explaining 67% of the variance for CysLT(1) receptor binding (r2=0.67, SDEC =
      0.47, q2=0.54). GRIND variables 11-50 and 22-55 are responsible for high-affinity
      binding; variable 11-62 is detrimental. The predictivity of the above chemometric
      model is tested with a set of 69 CysLT(1) receptor antagonists, exhibiting
      varying chemical similarity to the training set. Nearly 50% of the test set are
      quite well predicted. The quality of prediction coincides in part with chemical
      subclassification: phenylene bridged compounds are quite well predicted; for
      structures with bridging heterocycles predictions are rather poor. For explaining
      the outlier behavior, a PLS discriminant analysis including the training set and
      the strongest outliers of the test set was performed. The scores plot of
      discriminant PLS shows an almost complete separation between the two subsets. A
      PLS coefficients plot explains which GRIND variables are important for the
      discrimination between the training set and the outliers of the test set.

PMID- 15186846
TI  - Synthesis and photocytotoxic activity of new alpha-methylene-gamma-butyrolactone
      psoralen heterodimers.
AB  - The synthesis of a new alpha-methylene-gamma-butyrolactone-psoralen heterodimer 2
      is reported. Its photoantiproliferative activity and skin phototoxicity were
      compared with that of 5-methoxypsoralen (5-MOP) and another heterodimer 1. Both
      derivatives show a significant phototoxicity toward malignant cell lines
      including melanoma cells A375 compared to their intrinsic cytotoxicity in the
      dark. Both compounds were found to be nonphototoxic on mice skin and therefore
      could be active potential drugs in photochemotherapy.

PMID- 15186847
TI  - Isolation of quercetin's salts and studies of their physicochemical properties
      and antioxidant relationships.
AB  - Hydroxyflavones in alkaline solutions show high free radical scavenging
      activities. Quercetin, one of these hydroxyflavones may be submitted to chemical
      reactions yielding a mixture of mono-, di- and tri-sodium salts. These salts were
      recovered after solubilization and stepwise precipitation in
      methylalcohol/ethylacetate solvents. The different salts were analyzed using
      sodium emission spectrophotometry and nuclear magnetic resonance to determine the
      number of acid hydrogens at pH10 and the position of these acid hydrogens. Our
      study demonstrates that among the three salts of quercetin, the di-sodium
      compound is endowed with the more efficient scavenging properties in a phosphate
      buffer at physiological pH7.4. Physicochemical parameters and free hydroxyl
      radical scavenging activity relationships were also determined, allowing to
      explain the mechanisms whereby hydroxyl groups exert their radical scavenging
      activities.

PMID- 15186848
TI  - 3-Deazaadenosine analogues of p5'A2'p5'A2'p5'A: synthesis, stereochemistry, and
      the roles of adenine ring nitrogen-3 in the interaction with RNase L.
AB  - Sequence-specific 3-deazaadenosine (c(3)A)-substituted analogues of trimeric
      2',5'-oligoadenylate, p5'A2'p5'A2'p5'A, were synthesized and evaluated for their
      ability to activate human RNase L (EC 3.1.2.6) aiming at the elucidation of the
      nitrogen-3 role in this biochemical process. Substitution of either 5'-terminal
      or 2'-terminal adenosine with c(3)A afforded the respective analogues
      p5'(c(3)A)2'p5'A2'p5'A and p5'A2'p5'A2'p5'(c(3)A) that were as effective as the
      natural tetramer itself as activators of RNase L (EC(50)=1nM). In contrast,
      p5'A2'p5'(c(3)A)2'p5'A showed diminished RNase L activation ability
      (EC(50)=10nM). The extensive conformational analysis of the c(3)A-substituted
      core trimers versus the parent natural core trimer by the (1)H and (13)C NMR, and
      CD spectroscopy displayed close stereochemical similarity between the natural
      core trimer and (c(3)A)2'p5'A2'p5'A and A2'p5'A2'p5'(c(3)A) analogues, thereby
      strong evidences for the syn base orientation about the glycosyl bond of the
      c(3)A residue of the latter were found. On the contrary, an analogue
      A2'p5'(c(3)A)2'p5'A displayed rather essential deviations from the spatial
      arrangement of the parent natural core trimer.

PMID- 15186849
TI  - Discovery and SAR of indole-2-carboxylic acid benzylidene-hydrazides as a new
      series of potent apoptosis inducers using a cell-based HTS assay.
AB  - A series of indole-2-carboxylic acid benzylidene-hydrazides has been identified
      as a new class of potent apoptosis inducers through a novel cell-based caspase
      HTS assay. The screening hit, 5-chloro-3-methyl-indole-2-carboxylic acid (4
      nitrobenzylidene)-hydrazide (3a), was found to arrest T47D cells in G(2)/M and to
      induce apoptosis as measured by the flow cytometric analysis assay. A SAR study
      was carried out by modification of the substitutions on the indole and benzene
      rings. Substitution at the 3-position of the indole ring was found to be
      important for apoptotic activity. A 20-fold increase of apoptotic activity was
      achieved from screening hit 3a to 5-methyl-3-phenyl-indole-2-carboxylic acid (4
      methylbenzylidene)-hydrazide (9a) and 5-chloro-3-phenyl-indole-2-carboxylic acid
      (4-nitrobenzylidene)-hydrazide (9b), with EC(50) value of 0.1microM in the
      caspase activation assay in T47D breast cancer cells. Compound 9b also was found
      to be highly active in a standard growth inhibition assay with a GI(50) value of
      0.9microM in T47D cells. Compound 3a and its analogs were found to inhibit
      tubulin polymerization, which is the most probable primary mechanism of action of
      these compounds.

PMID- 15186850
TI  - Synthesis and antitumor activity of 20-O-linked nitrogen-based camptothecin ester
      derivatives.
AB  - A series of nitrogen-based 20S-hydroxyl camptothecin ester derivatives were
      prepared. 3-Aminopropionate of camptothecin was found more cytotoxic in vitro on
      several human tumor cell lines than 3-amidopropionate of camptothecin. Ester 16
      showed best antitumor activity in vivo and in vitro in all esters we prepared.

PMID- 15186851
TI  - Synthesis, antiviral, and anti-HIV-1 integrase activities of 3-aroyl-1,1-dioxo
      1,4,2-benzodithiazines.
AB  - HIV-1 integrase (IN) is an essential enzyme for effective viral replication and
      is an attractive target for selective blockade of viral infection. Previously, we
      identified a series of sulfones, sulfonamides, and mercaptosalicylhydrazides
      (MBSAs) as IN inhibitors with antiviral activities in cell-based assays. In an
      effort to optimize a series of our active site directed lead compounds, we
      designed and synthesized novel benzodithiazines starting from MBSAs. In contrast
      to all reported IN inhibitors benzodithiazines are essentially nontoxic.
      Significant antiviral potency was only observed at concentration exceedingly
      higher than that required to inhibit purified IN.

PMID- 15186852
TI  - A study of the stability of tri(glucosyloxyphenyl)chlorin, a sensitizer for
      photodynamic therapy, in human colon tumoural cells: a liquid chromatography and
      MALDI-TOF mass spectrometry analysis.
AB  - Asymmetrical glycoconjugated tetrapyrrolic macrocycles are under study as
      efficient sensitizers for photodynamic therapy (PDT). In this context, tri(meta-O
      beta-glucopyranosyloxyphenyl)chlorin [TPC(m-O-Glu)(3)] 2a/3a was found to be four
      times more photoactive in vitro than Foscan. In a further study of this
      interesting glycoconjugate, its metabolism by cellular glycosidases in HT29 cells
      has to be explored. Cellular extracts of HT29 cells incubated with TPC(m-O
      Glu)(3) (24h, 6microM) were analyzed by MALDI-TOF mass spectrometry and high
      performance liquid chromatography (HPLC). In MALDI-TOF mass spectra, the presence
      of compounds distinct from TPC(m-O-Glu)(3) (m/z 1151) were observed at m/z 989,
      827 and 665 corresponding to the loss of one, two or three glucose units (162u)
      and were be ascribed to TPC(m-OH)(m-O-Glu)(2) 2/3b,b',b", TPC(m-OH)(2)(m-O-Glu)
      2/3c,c',c" and TPC(m-OH)(3) isomers 2d/3d, respectively. The porphyrins resulting
      from chlorin oxidation TPP(m-O-Glu)(3) 4a, TPP(m-OH)(m-O-Glu)(2) 4b,b", TPP(m
      OH)(2)(m-O-Glu) 4c,c" and TPP(m-OH)(3) 4d were also observed. The HPLC profile
      (lambda(anal)=420 nm) showed eight peaks consistent with mass spectra. The
      kinetics of deglucosylation was studied from HPLC profiles between 1 and 48h
      incubation. The concentration of triglucoconjugated and diglucoconjugated
      molecules was maximum around 3 and 8h incubation, respectively, whereas, totally
      deglucosylated species appeared only after incubation for more than 10h. The
      fully deglycosylated porphyrin TPP(m-OH)(3) is the final metabolite, being
      observed at a concentration 15 times higher than that of the remaining TPC(m-O
      Glu)(3) 2a/3a. Compared to the photobiological activity of the parent molecule
      [TPC(m-O-Glu)(3)], a three times higher TPP(m-OH)(3) concentration was necessary
      to observe a similar in vitro photoactivity.

PMID- 15186853
TI  - Synthesis and cytotoxicity of 1-substituted 2-methyl-1H-imidazo[4,5-g]phthalazine
      4,9-dione derivatives.
AB  - A series of 1-substituted 2-methyl-1H-imidazo[4,5-g]phthalazine-4,9-dione
      derivatives 8 was synthesized from 6,7-dichlorophthalazine-5,8-dione 5 and
      evaluated for in vitro cytotoxicity against several human tumor cell lines. Most
      of the tested compounds showed potential cytotoxic activity considerably higher
      than that of the reference compounds, ellipticine and doxorubicin.

PMID- 15186854
TI  - Synthesis of carbamate-type caged derivatives of a novel glutamate transporter
      blocker.
AB  - L-threo-beta-Benzyloxyaspartate (L-TBOA) and (2S,3S)-3-[3-[4
      (trifluoromethyl)benzoylamino]benzyloxy]aspartate (L-TFB-TBOA) are potent
      nontransportable blockers for glutamate transporters. We synthesized a carbamate
      type coumarin derivative of L-TBOA 3a as a caged blocker and compared 3a with the
      corresponding ester-type analogs 1. The carbamate 3a was less sensitive to
      photolysis than the ester 1 but was more stable in the aqueous solution. The [6,7
      bis(carboxymethoxy)-coumarin-4-yl]methylcarbonyl (BCMCMC) group exhibited good
      results both in photoreactivity and stability. Therefore, we examined photolysis
      of N-BCMCMC-TBOA 3b and N-BCMCMC-TFB-TBOA 4, which immediately released blockers
      to show glutamate uptake inhibition.

PMID- 15186855
TI  - Topological models for prediction of anti-inflammatory activity of N
      arylanthranilic acids.
AB  - Relationship of anti-inflammatory activity of N-arylanthranilic acids with
      distance based Wiener's index, adjacency based Zagreb indices M1 and M2, and
      distance-cum-adjacency based eccentric connectivity index (ECI) was investigated.
      A dataset comprising of 112 N-arylanthranilic acids was selected. The values of
      all the four indices for each of the 112 compounds were calculated using an in
      house computer program. The dataset was divided randomly into training and test
      sets. The data was analyzed and suitable models were developed after
      identification the active ranges in the training set. Subsequently, a biological
      activity was assigned to each of the compound involved in the test set using
      these models, which was then compared with the reported anti-inflammatory
      activity. High accuracy of prediction ranging from 83% to 90% was observed using
      models based upon topological indices.

PMID- 15186856
TI  - Design of 1-substituted 2-arylmethyl-4,5-methylenedioxybenzene derivatives as
      antiseizure agents.
AB  - A series of 1-substituted 2-[(4-aryl)-methyl]-4,5-methylenedioxybenzene
      derivatives (13-25), structurally related to model compound 5 (2-[(4-aminophenyl)
      (4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl
      ester), were synthesized and tested as anticonvulsant agents in DBA/2 mice
      against sound-induced seizures. The new compounds possess anticonvulsant
      properties lower than those of prototype 5 but, in some instances, comparable to
      that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist.

PMID- 15186857
TI  - Synthesis and anticancer activity evaluation of new 2-alkylcarbonyl and 2-benzoyl
      3-trifluoromethyl-quinoxaline 1,4-di-N-oxide derivatives.
AB  - As a continuation of our research in quinoxaline 1,4-di-N-oxide and with the aim
      of obtaining new anticancer agents, which can improve the current
      chemotherapeutic treatments, new series of 2-alkylcarbonyl and 2-benzoyl-3
      trifluoromethylquinoxaline 1,4-di-N-oxide derivatives have been synthesized and
      evaluated for in vitro antitumor activity against a 3-cell line panel, consisting
      of MCF7 (breast), NCI-H460 (lung), and SF-268 (CNS). These active compounds were
      then evaluated in the full panel of 60 human tumor cell lines derived from nine
      cancer cell types. The results have shown that, in general, anticancer activity
      depends on the substituents in the carbonyl group, improving in the order:
      ethyl<isopropyl<tert-butyl<phenyl-ones. Among these, the compounds 4c, 6e, their
      difluorinated analogs (4g and 6g), and 5c were the most active, with mean GI(50)
      values of 1.02, 0.42, 0.52, 0.15, and 0.49microM, respectively. All of them were
      also found to inhibit the growth of the all of the Leukemia cell lines studied
      (with 75% of the GI(50) values less than 0.15microM) and therefore, were selected
      for further evaluation for the in vivo hollow fiber assays.

PMID- 15186858
TI  - Inhibition of the Staphylococcus aureus sortase transpeptidase SrtA by phosphinic
      peptidomimetics.
AB  - During pathogenesis, Gram-positive bacteria utilize surface protein virulence
      factors such as the MSCRAMMs (microbial surface components recognizing adhesive
      matrix molecules) to aid the initiation and propagation of infection through
      adherence to host endothelial tissue and immune system evasion. These virulence
      associated proteins generally contain a C-terminal LPXTG motif that becomes
      covalently anchored to the peptidoglycan biosynthesis intermediate lipid II. In
      Staphylococcus aureus, deletion of the sortase isoform SrtA results in marked
      reduction in virulence and infection potential, making it an important
      antivirulence target. Here we describe the chemical synthesis and kinetic
      characterization of a nonhydrolyzable phosphinic peptidomimetic inhibitor of SrtA
      derived from the LPXTG substrate sequence.

PMID- 15186859
TI  - Nitro and amino substitution within the A-ring of 5H-8,9-dimethoxy-5-(2-N,N
      dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: influence on
      topoisomerase I-targeting activity and cytotoxicity.
AB  - Recently, 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3
      methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one, 1, was identified as a TOP1
      targeting agent with pronounced antitumor activity. In the present study, the
      effect on activity of substituting a single nitro or amino group in the A-ring in
      lieu of the methylenedioxy moiety of 1 was evaluated. The presence of either a
      nitro or amino substituent at the 4-position had a pronounced adverse affect on
      both TOP1-targeting activity and cytotoxicity. To a lesser extent, derivatives
      with a nitro or amino substituent at the 1-position were also less active than 1.
      Replacement of the methylenedioxy moiety of 1 with either a nitro or amino
      substituent at either the 2- and 3-position did result in analogues with potent
      TOP1-targeting activity and cytotoxicity.

PMID- 15186860
TI  - Synthesis and immunochemical characterization of protein conjugates of
      carbohydrate and carbohydrate-mimetic peptides as experimental vaccines.
AB  - The peptides DRPVPY and MDWNMHAA, which were identified as mimics of the cell
      surface polysaccharides of Streptococcus Group A and Shigella flexneri Y,
      respectively, were used in this study to develop experimental vaccines directed
      against these two bacteria. Both oligopeptides were synthesized employing the
      Fmoc solid-phase strategy and linked via the amino end to a bifunctional linker,
      diethylsquarate. These adducts were then conjugated to the two carrier proteins,
      bovine serum albumin (BSA) and tetanus toxoid (TT) to yield the peptide conjugate
      vaccines. The average level of incorporation of DRPVPY and MDWNMHAA on TT was 65%
      and 75%, respectively, whereas that of both peptide haptens on BSA was 100%. A
      polysaccharide conjugate against S. flexneri Y, which comprises about 10
      tetrasaccharide repeating units, was also prepared based on reductive amination
      at the reducing end with 1,3-diaminopropane, followed by coupling of the aminated
      polysaccharide to diethylsquarate, and subsequent coupling of the adduct to TT.
      An average incorporation of 73% of polysaccharide haptens was achieved. The
      glycoconjugate and the oligopeptide conjugates were shown to bind effectively to
      the respective monoclonal antibodies directed against the cell-surface
      polysaccharides.

PMID- 15186862
TI  - The cognitive orientation of patients with type 2 diabetes in Israel.
AB  - The purpose was to explore the beliefs of patients with type 2 diabetes, in the
      framework of the Cognitive Orientation model which assumes that cognitions could
      promote disease. The major hypotheses were that there is a cluster of beliefs
      characteristic for type 2 diabetes and that it does not differ with disease
      duration. The participants were 112 individuals with type 2 diabetes and 103
      matched healthy controls. They were administered a questionnaire that included
      items representing beliefs about goals, self, rules and norms, and general,
      referring to relevant themes. The results supported the main hypotheses and
      showed that the questionnaire scores identified correctly patients and controls
      in 85%. The themes supported by the patients focus on maintaining the status quo,
      formal relations, authority, following rules, and relying on powerful others. A
      major conclusion is that there is a unique cluster of beliefs characteristic for
      patients with type 2 diabetes. The findings can aid in helping these patients to
      apply self-care procedures and cope with particular stresses.

PMID- 15186863
TI  - Diagnosis of type 2 diabetes: a qualitative analysis of patients' emotional
      reactions and views about information provision.
AB  - Research about diagnosis of chronic illness indicates this is an emotional time
      for patients. Information provision is especially salient for diabetes
      management. Yet current orthodoxy suggests that too much information at the time
      of diagnosis is unhelpful for patients. In this study, we used in-depth
      interviews with 40 newly diagnosed type 2 diabetic (T2DM) patients in Scotland,
      to explore their emotional reactions about diagnosis, and their views about
      information provision at the time of diagnosis. Data were analysed using a
      thematic approach. Our results showed three main 'routes' to diagnosis:
      'suspected diabetes' route; 'illness' route; and 'routine' route. Those within
      the 'routine' route described the most varied emotional reactions to their
      diagnosis. We found that most patients, irrespective of their route to diagnosis,
      wanted more information about diabetes management at the time of diagnosis. We
      suggest that practitioners would benefit from being sensitive to the route
      patients follow to diagnosis, and prompt, simple but detailed advice about T2DM
      management would be helpful for newly diagnosed patients.

PMID- 15186864
TI  - Is weight loss a realistic goal of treatment in type 2 diabetes? The implications
      of restraint theory.
AB  - Obesity is a two-fold problem affecting both physical health and psychological
      well-being and one of the biggest obstacles to the management of type 2 diabetes
      because the most effective treatments frequently lead to weight gain. Recent
      studies have shown that addressing the problem of obesity first can lead to an
      improvement in blood glucose control, accompanied by favourable changes in
      physiological profiles. With the exception of surgical treatments, all obesity
      treatment programmes involve recommending dieting in one form or another, in
      order that individuals lose weight. However, all reviews document the failure of
      all obesity treatment approaches, behavioural, dietetic or pharmacological, to
      achieve significant and long-lasting weight loss. Research further suggests that
      dietary restraint may have many negative consequences and weight fluctuation may
      also have profound effects on psychological and physical health. The present
      paper highlights the need to reappraise the management of obesity in type 2
      diabetes in light of these research findings and suggests an approach to
      treatment, which would help patients to limit the associated physical and
      psychological costs and importantly ensure that the treatment itself does not
      compound their difficulties.

PMID- 15186866
TI  - Experience-based group education in Type 2 diabetes: a randomised controlled
      trial.
AB  - Few studies have demonstrated an effect of educational interventions on glycaemic
      control in persons with Type 2 diabetes longer than 3-6 months after baseline. We
      aimed to investigate the effectiveness of an experience-based group educational
      programme 24 months after baseline and to pinpoint mediators that might play a
      role in achieving desired metabolic outcomes. We conducted a randomised
      controlled trial inviting self-referred persons with Type 2 diabetes (N=77
      randomised). The pharmacist-led, year-long intervention was based on
      participants' experiences of glucose regulation during the monthly group
      discussions. We measured HbA1c at 0, 6, 12, and 24 months and a questionnaire was
      administered at baseline and final follow-up. Our findings indicated that
      participating in the intervention programme significantly decreased HbA1c by 0.4%
      at 24 months after baseline. Initial HbA1c, satisfaction with own diabetes
      related knowledge, and treatment were found directly related to glycaemic
      outcomes. The intervention group exercised more in order to lower blood-glucose
      levels and was also more able to predict current blood-glucose levels before
      measuring it. Experience-based group education was effective in decreasing
      participants' HbA1c 1-year after completed intervention. Early effect of the
      intervention was followed by relapse after 12 months and a new, significant
      decrease at 24 months; this dual course implies that follow-up of educational
      interventions should involve several consecutive measurements to capture possible
      late effects. Both biomedical and subjective factors played a role in accounting
      for the variance of HbA1c at 2-year follow-up after baseline.

PMID- 15186865
TI  - Education and quality of life in diabetic patients.
AB  - The aim of the present randomized, controlled study was to evaluate the effect of
      a 5-day teaching program for diabetic patients on their quality of life 1 and 2
      years afterwards. Three hundred and nineteen insulin-treated patients, of mean
      age 38.2+/-14.1 years and mean duration of the disease 9.0+/-6.9 years were
      followed up at reeducation sessions 1 and 2 years after the program. A group of
      241 insulin-treated patients were also followed up and served as a control group.
      At baseline and 1 and 2 years later, we have assessed patients' well-being, using
      a standard 22-item questionnaire. There was a significant increase in overall
      well-being of patients one (P <0.0001) and 2 years (P <0.001) after the program,
      due to reduction in depression and anxiety and increase in positive well-being
      after 1 year and decrease in depression and increase in positive well-being after
      2 years as compared to the control group. There was an improvement in glycaemic
      control of the educated patients as compared to the control group (P <0.01). The
      results from the present study demonstrate that structured patient education
      improves patients' well-being 1 and 2 years after the teaching program.

PMID- 15186868
TI  - Evaluation of the quality and contents of diabetes mellitus patient education on
      Internet.
AB  - Patient education is widely regarded as an essential component of chronic disease
      care and effective health promotion. Internet is extremely useful medium in this
      respect. Web-based information is seldom the subject of systematic investigation
      for its accuracy and appropriateness for patients. Objective of this study was to
      evaluate of web-based diabetes patient education material for well-accepted
      evaluation criteria and core education concepts. Out of 214 web-sites retrieved
      from meta search engine, 53 sites themselves provide patient information and so
      considered for evaluation. Data obtained was analyzed by cluster analysis and
      classified into four categories with respect to quality. Considerable variability
      in quality of diabetes patient education web-sites was found with respect to core
      educational concepts and HSWG criteria. Inclusion of evidence-based medicine
      concepts, role of family support, enhancement in customized content and easier
      feedback mechanism in the web-sites can be a significant development in the
      direction of patient-centered diabetes care.

PMID- 15186867
TI  - Effects of a group-based counselling programme on diabetes-related stress,
      coping, psychological well-being and metabolic control in adults with type 1 or
      type 2 diabetes.
AB  - This study was designed to determine whether participation in a group-based
      counselling programme would result in reduced diabetes-related stress, improved
      coping and psychological well-being as well as achieving glycaemic control closer
      to an acceptable level. Effects of the programme were evaluated implementing an
      experimental design with a sample comprising 63 Norwegian adults with both types
      of diabetes aged between 25 and 70. At the 6-month follow-up, results indicate
      that the group-based counselling programme tested in the present study has the
      potential to reduce diabetes-related stress and self-blame as well as to improve
      coping in adults with diabetes. Moreover, results suggest that the programme can
      help participants to achieve more acceptable HbA1c levels as well. The present
      study indicates that this group-based counselling programme is feasible in the
      sense of suggesting that cognitive restructuring and problem-solving approaches
      in groups may be useful in helping people adjust to diabetes.

PMID- 15186869
TI  - Comparative analysis of conventional and an adaptive computer-based hypoglycaemia
      education programs.
AB  - Adaptive interactive computer-based education programs which can be personalized
      to patients' needs and skills might be more suitable for patients' training as
      compared to conventional ones. We tested whether there are differences between an
      adaptive and a conventional version of a computer-based hypoglycaemia education
      program concerning successful training and user friendliness. One hundred and
      twenty randomized diabetic patients were enrolled in this study. The two
      different programs were compared by using the following criteria: (1) the number
      of actions needed to get out of or prevent hypoglycaemia, (2) the need for
      external help, (3) the average time needed for completing one task and (4) user
      friendliness as determined by a questionnaire. Patients using the adaptive
      computer-based hypoglycaemia education program needed less actions to get out of
      or prevent hypoglycaemia, less external help and less time to finish tasks.
      Furthermore, the user friendliness of the adaptive computer program received a
      significantly better rating by the patients. The adaptive computer-based
      hypoglycaemia education program shows significantly better results as compared to
      a conventional one. Therefore, using adaptive computer-based programs might be
      helpful for education of patients.

PMID- 15186870
TI  - Implementing empowerment group education in diabetes.
AB  - The overall aim was to gain insight into and understand how physicians and nurses
      view the implementation of empowerment group education (EGE) in diabetes. Prior
      to the study the physicians and nurses attended a 2-day empowerment workshop.
      Further, they had implemented the empowerment approach in two groups of patients
      with type II diabetes. Three to 9 months later they (five physicians and 11
      nurses from six family practices) participated in focus group interviews to
      evaluate the implementation of the EGE. The interviews were audio-taped,
      transcribed and analysed using the constant comparative method. The main result
      showed a conflict in roles. The physicians and nurses knew their role in the
      traditional approach but not with respect to the empowerment approach, which they
      needed to grow into. At the same time as they started a new way of working, their
      role had changed from being an expert to being a facilitator. As experts they
      felt secure; as facilitators they needed support in their educational process. To
      implement EGE they required support both from the family practice and from a
      supervisor in direct connection with the EGE.

PMID- 15186871
TI  - Improving the diabetes-patient encounter by reflective tutoring for staff.
AB  - There is relative consensus about the advantages of patient-centred
      consultations. However, they have not been easy to realise in clinical praxis.
      The aim of this study was to investigate whether an intervention focused on
      health care professionals' understanding of the diabetes-patient encounter could
      facilitate a patient-centred way to encounter these patients. Two GPs and two
      nurses participated in the year-long intervention. The intervention focused on
      the staff's understanding of the encounter. Staff video recorded four to five
      encounters each and reflected together with a supervisor on their understanding
      of the encounters and how they were conducted. The encounters were analysed with
      the Verona-MICS/Dr coding system and patients' comments were analysed separately.
      The content of the consultations and how they were conducted was also assessed.
      There was a significant change of two patient-centred items by the staff over
      time. Two staff seemed to change their educational model. Modern theories of
      competence development seem to be useful in clinical settings.

PMID- 15186872
TI  - Educational and psychosocial programmes for adolescents with diabetes:
      approaches, outcomes and cost-effectiveness.
AB  - Diabetes incurs heavy personal and health system costs. Self-management is
      required if complications are to be avoided. Adolescents face particular
      challenges as they learn to take responsibility for their diabetes. A systematic
      review of educational and psychosocial programmes for adolescents with diabetes
      was undertaken. This aimed to: identify and categorise the types of programmes
      that have been evaluated; assess the cost-effectiveness of interventions;
      identify areas where further research is required. Sixty-two papers were
      identified and subjected to a narrative review. Generic programmes focus on
      knowledge/skills, psychosocial issues, and behaviour/self-management. They result
      in modest improvements across a range of outcomes but improvements are often not
      sustained, suggesting a need for continuous support, possibly integrated into
      normal care. In-hospital education at diagnosis confers few advantages over home
      treatment. The greatest returns may be obtained by targeting poorly controlled
      individuals. Few studies addressed resourcing issues and robust cost
      effectiveness appraisals are required to identify interventions that generate the
      greatest returns on expenditure.

PMID- 15186873
TI  - A developmental perspective on the challenges of diabetes education and care
      during the young adult period.
AB  - There is increasing recognition that the patient education and care provided to
      young adults with chronic physical illnesses, including type 1 diabetes, is
      inattentive to the complex developmental issues facing the older adolescent
      transitioning into the young adult period [Pediatrics 110 (2002) 1307]. In this
      paper, we present a clinical perspective on the challenge of improving diabetes
      education and care during the young adult period focusing on the importance of
      the developmental changes-cognitive, social, emotional, educational, and familial
      that occur during this transitional stage of life. This developmental perspective
      on young adulthood provides a conceptual framework to better understand the young
      adult's "readiness" for engagement in intensive medical therapy. We review
      factors such as the timing and context of diabetes care and education that may be
      important determinants of young adults' ultimate success in becoming independent
      managers of their health care during this difficult transition. Developmentally
      based practice principles for the young adult period are presented which include:
      assessing the patient's expectation at transition, building the relationship,
      working with families, assessing barriers to care, and formulating treatment
      plans and goals.

PMID- 15186874
TI  - Culture-specific diabetes care for Surinam South Asians with a low socio-economic
      position: who benefits?
AB  - The South Asians in The Netherlands have a high diabetes prevalence in
      combination with a low socio-economic position. A new, culture-specific type of
      care was developed. This intervention study investigates which patient
      characteristics are associated with success and whether those in the lowest socio
      economic position have been reached. Before and after the end of the intensive
      guidance, the HbAlc of the patients (n=101) was measured. The following variables
      were significantly related to success (defined as a decrease in HbAlc > or =
      0.8%): a high initial HbAlc, a low BMI and presence of complications. The average
      improvement in HbAlc was significant only in the group with a higher socio
      economic position. Although the patients with the lowest socio-economic position
      did not sufficiently benefit from this intervention, an overall improvement was
      achieved in this poorly educated study population. The further improvements in
      the care after the completion of this study should be evaluated.

PMID- 15186875
TI  - Feasibility of diabetes peer education for Turkish type 2 diabetes patients in
      Dutch general practice.
AB  - The feasibility of a 9-month educational diabetes programme (tailored to Turkish
      patients, provided by Turkish bicultural female educators) was assessed in terms
      of dropout rate, patient and GP satisfaction, and GP's perceived workload. Of the
      54 Turkish patients (39% males) that signed informed consent, 45 actually started
      the education. Dropout rate during the programme was 41% (main reason: going
      abroad for a long period (18%)). The individual education sessions and the
      consultations with the GP were highly appreciated by 87% of the patients and the
      group sessions by 66%. Although all nine interviewed GPs experienced a higher
      workload, overall appreciation of the programme was high in six GPs. Although
      implementation of an ethic-specific diabetes programme in general practice is
      well appreciated by both patients and GPs, the high dropout rate indicates that
      the programme needs to be more finely tuned to the individual patient.

PMID- 15186877
TI  - Mucoceles of the sphenoid sinus.
AB  - PURPOSE: Mucoceles of the sphenoid sinus represent 1-2% of all paranasal sinus
      mucoceles. The aim of this paper is to report our experiences in patients with
      mucoceles of the sphenoid sinus. PATIENTS AND METHOD: In a period of 4 years, we
      observed six patients in whom a mucocele of the sphenoid sinus was suggested pre-
      or intraoperatively. Symptoms and signs included headache, visual loss and
      palsies of the III and VI cranial nerve. All patients were investigated by MRI
      and/or CT. Imaging findings were compared with operative and/or histological
      findings. RESULTS: In three cases there were simple mucoceles, in one case we
      found a tumour (nasopharyngeal carcinoma) associated mucocele and in two cases,
      malignant tumours (carcinoma, chordoma) imitated a mucocele. The diagnosis of
      simple mucoceles was no problem at all by imaging. Difficulties made the two
      malignant tumours and the tumour associated mucocele. In the first two cases,
      repeated histological samples were necessary to make the final diagnosis.
      CONCLUSION: Mucoceles of the sphenoid sinus should be investigated and handled
      very carefully with regard to differential diagnoses and tumour associated cases.

PMID- 15186876
TI  - The influence of diabetic retinopathy on quality of life: interviews to guide the
      design of a condition-specific, individualised questionnaire: the RetDQoL.
AB  - An individualised measure of the impact of diabetic retinopathy on quality of
      life (QoL) was developed, using a four-phase iterative approach, incorporating
      qualitative and quantitative methods. In semi-structured interviews, eleven
      people with diabetic retinopathy in each of two UK and two German hospitals
      described how QoL would be different without diabetic retinopathy. They completed
      and commented on the latest Retinopathy Dependent QoL (RetDQoL) draft. Interviews
      were content analysed before questionnaire revision and translation for the next
      centre. Twenty-six men and 18 women were interviewed: median age 60.5 (28-82)
      years; severity ranged from untreated background diabetic retinopathy to
      proliferative diabetic retinopathy requiring photocoagulation in both eyes, and
      vitrectomy. The resulting 26-domain RetDQoL asks about the impact of 'diabetic
      eye problems'. Iterative methodology ensured good understanding, face and content
      validity. It can be self- or interviewer-completed. Visual impairment, worries
      and movement restrictions impaired many aspects of QoL, with impacts before
      vision loss. Practice implications relate to using the RetDQoL and improving
      practitioner-patient communication.

PMID- 15186878
TI  - Repetitive transarterial chemoembolization (rTACE) of hepatocellular carcinoma:
      comparisons between an arterial port system and conventional angiographic
      technique.
AB  - PURPOSE: To compare the cost and radiation exposure of repetitive transarterial
      chemoembolization (rTACE) using percutaneously implantable port system with rTACE
      using conventional catheterization technique. MATERIALS AND METHODS: In five
      patients with unresectable hepatocellular carcinoma, three cycles of TACE were
      performed using conventional technique and six cycles using port. The cumulative
      cost of material and contrast agent and dose area product (DAP) were compared
      with the cost and DAP that would be expected if the rTACE was performed
      conventionally. RESULTS: The cost of material and contrast agent was 1002.6 Euro
      after three cycles of TACE using conventional technique and six cycles using
      port, but would be 1111.8 Euro if the nine cycles were performed using
      conventional technique alone. The rTACE with three cycles using conventional
      technique and six cycles using port led to approximately 63% of the cumulative
      DAP that would be expected in rTACE using conventional technique alone.
      CONCLUSION: In rTACE, the use of percutaneously implantable port system might
      enable a reduction of cost and radiation exposure.

PMID- 15186879
TI  - Transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma
      invading the portal veins: therapeutic effects and prognostic factors.
AB  - PURPOSE: This retrospective study was undertaken to evaluate the therapeutic
      effects of transcatheter hepatic arterial chemoembolization on hepatocellular
      carcinoma (HCC) invading the portal veins and to identify prognostic factors.
      MATERIALS AND METHODS: Sixty-one patients underwent chemoembolization. The HCC
      had invaded the main portal vein in 23 patients, a first-order branch in 25
      patients and a second-order branch in 13 patients. The hepatic arteries feeding
      the tumors were embolized with gelatin sponge after a mixture of iodized oil and
      anticancer drugs was injected via these vessels. Tumor response was evaluated by
      measuring tumor sizes on CT images. A reduction in maximum diameter of 25% or
      more was considered to indicate response to chemoembolization. Significant
      prognostic factors were identified by univariate and multivariate analyses.
      RESULTS: Tumor size was reduced by 25% or more in 26 patients (43%). The 1-, 3-
      and 5-year survival rates were 42, 11 and 3%, respectively, with mean survival of
      15 months in all patients. In the univariate analysis, the following six
      variables were significantly associated with prognosis: (i) tumor response; (ii)
      ascites; (iii) accumulation of iodized oil in tumor thrombi; (iv) in main tumors;
      (v) Okuda classification; and (vi) tumor size. In the multivariate analysis, the
      first three of these factors showed significantly independent values for patient
      prognosis. CONCLUSION: Chemoembolization appears to be an effective treatment for
      HCCs invading the portal venous system. The prognostic factors identified here
      are expected to be helpful in classifying patients with HCCs invading the portal
      veins and should serve as useful guidelines for chemoembolization in clinical
      practice.

PMID- 15186880
TI  - Clinical evaluation of a computer simulated prediction model of contrast
      enhancement of the liver in spiral CT.
AB  - OBJECTIVE: A software program was developed simulating a compartmental model of
      blood circulation based on differential equations. The aim of this study was to
      compare software-simulated levels of hepatic enhancement with the true values in
      patients and to test how many patients reach the simulated hepatic enhancement
      level. METHODS: As software program the CT application software carebolus 2
      (Siemens, Forchheim, Germany) was used. Hepatic contrast-enhancement curves were
      simulated prior to CT examinations to evaluate a patient specific time delay
      after contrast application. At the time delay, when the simulation curve showed
      an enhancement threshold of 40 Hounsfield Units (HU), the CT spiral scan was
      started applying 120 ml contrast media with 2 ml/s. The simulated curves were
      compared with the empiric curves of each patient. RESULTS: 25 of 28 patients
      (89%) achieved 40 HU. The mean enhancement of empiric patients curves was 46.32
      +/- 11.9 HU, the mean simulated enhancement was 46.62 +/- 4.3 HU S.D. (P= 0.48).
      4.4 values per patient liver could be compared with the simulation curve (122
      points for 28 patients): 50% of the patient curves were within a range of 5 HU
      compared with the simulation curve. CONCLUSION: Software simulation of contrast
      enhancement curves of the liver is a feasible and valuable method to predict
      individual liver enhancement curves. Improvements concerning the integration of
      cardiovascular parameters and preexisting liver parenchymal diseases into the
      simulation software have to be arranged.

PMID- 15186881
TI  - Liver cirrhosis: evaluation of haemodynamic changes using an ultrasound contrast
      agent.
AB  - Liver cirrhosis is associated with haemodynamic changes. Using Levovist, we
      measured and compared Doppler signal arrival and peak enhancement times in the
      hepatic vein of patients with cirrhosis (n= 12) or chronic liver disease (n= 16)
      and in 12 healthy subjects. There were six patients with Child stage A, one
      patient with B, and five patients with C. The signal was recorded starting 20 s
      before contrast infusion until 2 h 20 min after its end. A software of the
      ultrasound (US) machine automatically sampled time-intensity values. Arrival
      times were significantly shorter (P < 0.001) in cirrhotic than non-cirrhotic
      (chronic liver disease + controls) and in patients with Child stage C compared
      with A. Differences in peak enhancement were weakly significant between cirrhotic
      and chronic patients (P < 0.04) and highly significant between the former and
      controls (P < 0.001), whereas differences between Child stages C and A were not
      significant (P > 0.05). Finally, cirrhotic patients had arrival times
      consistently shorter than 17 s. Automatic time-intensity curve analysis made
      measurements objective and conceptual error systematic, thus identifiable.
      Analysis of the passage of Levovist at the hepatic vein can thus become a non
      invasive, well-tolerated and cost-effective diagnostic and monitoring tool in a
      larger number of patients with liver disease.

PMID- 15186883
TI  - Colpocystoproctography in the upright and supine positions correlated with
      dynamic MRI of the pelvic floor.
AB  - PURPOSE: To test whether there are statistically significant differences between
      measurement results on colpocystoproctography in the upright and the supine
      positions, and to correlate these results with dynamic MRI. PATIENTS AND METHODS:
      Seven patients with pelvic floor descent had received colpocystoproctography in
      the upright and supine positions and, additionally, dynamic MRI of the pelvic
      floor. Bladder neck position, angle of urethral inclination, posterior
      vesicourethral angle, and vaginal vault position were measured at relaxed pelvic
      floor and at pelvic strain. Differences between the measurement results of each
      parameter in the upright and supine position on colpocystoproctography were
      calculated and correlated with the measurement results from the dynamic MRI.
      RESULTS: At pelvic strain, bladder neck position, angle of urethral inclination,
      posterior vesicourethral angle and vaginal vault position measurements showed no
      statistically significant differences between colpocystoproctography in the
      upright and supine positions or dynamic MRI. For the bladder neck height at
      pelvic floor relaxation, significant differences were found between
      colpocystoproctography in the upright and supine positions, and
      colpocystoproctography in the upright position versus dynamic MRI. CONCLUSION: At
      pelvic strain, measurement data from dynamic MRI are not statistically different
      from data from colpocystoproctography either in supine and upright positions.

PMID- 15186882
TI  - MR imaging of ovarian hemorrhage.
AB  - BACKGROUND: To review MR appearances of ovarian hemorrhage, and to describe its
      characteristic imaging findings. METHODS: 12 women (age range, 20-44, mean, 26
      years) with suspected ovarian hemorrhage underwent pelvic MR examinations. We
      retrospectively reviewed MR findings regarding signal intensities, localization,
      and wall enhancement of adnexal masses, and signal intensities of ascites.
      RESULTS: Adnexal masses were detected in all cases. In eight cases, adnexal mass
      exhibited intermediate signal intensity on T1WI, and intermediate to low signal
      intensity on T2WI. In other case, adnexal mass exhibited marked hyperintensity on
      T1WI. In the remaining three cases, cystic mass with low signal intensity on T1WI
      and high signal intensity on T2WI was noted. Ascites was present in all cases,
      and showed intermediate signal on T1WI and intermediate to low signal on T2WI.
      CONCLUSIONS: In ovarian hemorrhage, hemorrhagic ascites and adnexal mass was
      visualized with specific MR signal intensity. Due to its sensitivity for
      identifying blood, MR imaging is useful in the diagnosis of ovarian hemorrhage,
      especially when ultrasonography findings are not definitive.

PMID- 15186885
TI  - Mammographic and sonographic features of tuberculous mastitis.
AB  - From December 1999 to April 2001, 10 cases of tuberculous mastitis were presented
      to the Radiology Unit at the Medical Research Institute of Alexandria University
      for mammographic and sonographic evaluation. Sixty percent presented with masses,
      50% mastalgia, 40% discharge, and 10% complained of skin sinus. In 30% of the
      patients the complaint was bilateral. All cases underwent full mammographic and
      ultrasonographic (US) studies, and US-guided fine needle aspiration. Also
      pathological, bacteriological analysis, and polymerase chain reaction (PCR) were
      done to all patients to prove the tuberculous nature of their lesions. Thirty
      percent of the cases had surgical excision on their masses. On mammography 30%
      were found to have mass lesion mimicking malignant tumors, 40% smooth bordered
      masses, 40% axillary or intramammary adenopathy, 30% asymmetric density, 30% duct
      ectasia, 20% with skin thickening and nipple retraction, 20% with
      macrocalcification, and 10% with skin sinus. On US 60% had hypoechoic masses, 40%
      focal or sectorial duct ectasia, and 50% axillary adenopathy. History of
      tuberculosis was found in 30% of the cases. Chest X-ray was positive in 20% and
      breast magnetic resonance imaging was done to one patient who had skin sinus.

PMID- 15186884
TI  - Polycystic ovary syndrome: dynamic contrast-enhanced ovary MR imaging.
AB  - OBJECTIVE: to determine the enhancement behaviour of the ovaries in women with
      polycystic ovary syndrome (PCOS) by dynamic contrast-enhanced magnetic resonance
      (DCE-MR) imaging and to compare these data with those of normal ovulating
      controls. METHOD: 24 women with PCOS and 12 controls underwent DCE-MR imaging.
      Dynamic images were acquired before and after injection of a contrast bolus at 30
      s and the min of 1, 2, 3, 4 and 5. On postprocessing examination: (i) the ovarian
      volumes; (ii) the signal intensity value of each ovary per dynamic study; (iii)
      early-phase enhancement rate; (iv) time to peak enhancement (T(p)); and (v)
      percentage of washout of 5th min were determined. Data of the ovaries of the
      women with PCOS and controls were compared with Mann-Whitney U-test. RESULTS: the
      mean values of T(p) were found to be significantly lower in women with PCOS than
      in controls (p < 0.05). On the other hand, the mean values of ovarian volume, the
      early-phase enhancement rate, and percentage of washout of 5th min of ovaries
      were significantly higher in PCOS patients (p < 0.05). Examination of the mean
      signal intensity-time curve revealed the ovaries in women with PCOS showed a
      faster and greater enhancement and wash-out. CONCLUSION: the enhancement
      behaviour of ovaries of women with PCOS may be significantly different from those
      of control subjects on DCE-MR imaging examination. In our experience, it is a
      valuable modality to highlight the vascularization changes in ovarian stroma with
      PCOS. We believe that improved DCE-MR imaging techniques may also provide us
      additional parameters in the diagnosis and treatment strategies of PCOS.

PMID- 15186886
TI  - Digital spot mammography using an add-on upright unit: diagnostic application in
      daily practice.
AB  - INTRODUCTION: To present the use of digital spot mammography (DSM) in a
      diagnostic practice. METHODS AND PATIENTS: Digital spot images of 779 women
      requiring a spot compression or a spot magnification view were collected. The
      digital images were acquired on a digital spot upright unit using a 61 mm x 61 mm
      field of view. Lesions reported included masses, calcifications, and areas of
      distortions. RESULTS: 1065 lesions required additional views with DSM. Lesions
      reported included masses (n = 113), masses and microcalcifications (n = 53),
      spiculated masses (n = 34), architectural distortions (n = 16), and
      microcalcifications (n = 849). DSMs were considered to be adequate in 97.7% of
      patients. Unsatisfactory exams resulted from difficulties encountered in
      targeting the area of interest at the beginning of our experience. CONCLUSION:
      DSM, most commonly used to perform interventional procedures, can also be used in
      a diagnostic practice taking advantage of post-processing of images not available
      with conventional spot compression and magnification.

PMID- 15186887
TI  - Are unnecessary follow-up procedures induced by computer-aided diagnosis (CAD) in
      mammography? Comparison of mammographic diagnosis with and without use of CAD.
AB  - OBJECTIVE: To evaluate the rate of unnecessary follow-up procedures recommended
      by radiologists using a CAD-system. MATERIALS AND METHODS: 185 patients (740
      images) were consecutively selected from three groups (36 histologically proven
      cancers = group 1; 49 histologically proven benign lesions = group 2 and 100
      screening cases (4 years-follow up = group 3). Mammograms were evaluated by a CAD
      system (Second Look, CADx, Canada). Five blinded radiologists assessed the images
      without/with CAD outputs. Diagnostic decisions were ranked from surely benign to
      surely malignant according to BIRADS classification, follow-up procedures were
      recommended for each observed lesion (a, screening; b, short interval follow-up
      examination in 6 months; c, pathologic clarification). RESULTS: CAD-system
      detected 32/36 cancers (88.9%) (FP-rate: 1.04 massmarks and 0.27
      calcmarks/image). The following values were reached by all observers without/with
      CAD in the mean: Sensitivity 80.6/80.0%, specificity 83.2/86.4%, PPV 53.1/58.1%,
      and NPV 94.6/94.7%. Observers described a similar number of additional lesions
      without/with the use of CAD (325/326). Whereas the number of unnecessary short
      time follow up recommendations increased in all case-subgroups with CAD:
      40.8/42.9% (group 1), 35.6/38.1% (group 2), 44.7/46.8% (group 3), respectively,
      the number of recommended biopsies decreased in all subgroups: group 1:
      34.7/27.1%; group 2: 47.4/41.5%, group 3: 33.3/22.0%, respectively. CONCLUSION:
      In this rather small population additional usage of CAD led to a lower rate of
      unnecessary biopsies. The observed decrease of recommended unnecessary biopsies
      due to the usage of CAD in the screening group suggests a potential financial
      benefit by using CAD as diagnostic aid.

PMID- 15186888
TI  - Significance of prevertebral soft tissue measurement in cervical spine injuries.
AB  - OBJECTIVE: The objective of this study was to evaluate the diagnostic value of
      prevertebral soft tissue swelling in cervical spine injuries. MATERIALS AND
      METHODS: A group of 107 consecutive patients with suspected injuries of the
      cervical vertebrae were reviewed retrospectively to identify the presence of
      prevertebral soft tissue swelling and to investigate the association of
      prevertebral soft tissue swelling with the types and degrees of cervical spine
      injuries. RESULTS: Prevertebral soft tissue swelling occurred in 47 (43.9%)
      patients. Of the 47 patients, 38 were found with bony injury and nine were
      without. The statistic difference was significant (P < 0.05). No correlation was
      demonstrated between soft tissue swelling and either the injured level of the
      cervical vertebrae or the degree of the spinal cord injury (P > 0.05). Anterior
      element injuries in the cervical vertebrae had widening of the prevertebral soft
      tissue more than posterior element injuries (P < 0.05). CONCLUSION: The
      diagnostic value of prevertebral soft tissue swelling for cervical spine injuries
      is significant, but the absence of this sign does not mean that further image
      evaluation can be spared.

PMID- 15186889
TI  - Normal osseous variants presenting as cystic or lucent areas on radiography and
      CT imaging: a pictorial overview.
AB  - We present a number of commonly encountered pseudolesions. These represent areas
      of the skeleton that are relatively radiolucent simulating an osteolytic or
      cystic lesion. Such areas discussed in this article include the superolateral
      humeral head, rhomboid fossa of the clavicle, scapular defect, supratrochlear
      foramen, biceps tendon insertion, vascular channel of the ulna, distal condylar
      area of the knee, 'bone in bone' disturbance, dorsal defect of the patella,
      metadiaphyseal area, 'Wards' triangle', inframalleolar fossa of the fibula, and
      anterior lytic defect of the calcaneus. We provide an overview of commonly
      encountered pseudolesions, that may lead to false positive diagnosis of an
      osteolytic or cystic lesion.

PMID- 15186890
TI  - Congenital diaphragmatic eventration as a cause of anterior mediastinal mass in
      the children: imaging modalities and literature review.
AB  - Congenital eventration of the diaphragm, as a cause of mediastinal mass, is an
      unusual condition and it may be unilateral or bilateral. Although this entity is
      frequently asymptomatic and firstly detected on the chest radiography, it may be
      difficult to distinguish a partial eventration from the other diaphragmatic
      lesions or mediastinal pathologies on the chest radiographs. US may present
      valuable information about diaphragm integrity with eventration content or the
      other diaphragmatic pathologies. Although the other imaging modalities such as
      fluoroscopy, computed tomography, and MR imaging may be performed as adjunct
      techniques in cases of the diagnosis still in doubt, they are frequently
      unnecessary after US. Our goal is to present imaging features and management of
      this entity together with a literature review.

PMID- 15186891
TI  - The efficacy of ultrasonography in hemodynamically stable children with blunt
      abdominal trauma: a prospective comparison with computed tomography.
AB  - PURPOSE: In this prospective study we aimed to investigate the diagnostic value
      of ultrasonography (US) in hemodynamically stable children after blunt abdominal
      trauma (BAT) using computed tomography (CT) as the gold standard. MATERIALS AND
      METHODS: Between 1997 and 2001, 96 children with BAT were evaluated
      prospectively. CT was performed first, followed by US. US and CT examinations
      were independently evaluated by two radiologists for free fluid and organ injury.
      The sensitivity, specificity, positive predictive value, negative predictive
      value and overall accuracy of US were assessed regarding CT as the gold standard.
      RESULTS: Overall 128 organ injuries were determined in 96 patients with CT;
      however, 20 (15.6%) of them could not be seen with US. Free intraabdominal fluid
      (FIF) was seen in 82 of 96 patients by CT (85.4%) and eight of them (9.7%) could
      not be seen by US. We found that sensitivity, specificity, positive predictive
      value, negative predictive value and overall accuracy of the US for free intra
      abdominal fluid were 90.2, 100, 100, 63.6 and 91.7%, respectively. CONCLUSIONS:
      US for BAT in children is highly accurate and specific. It is highly sensitive in
      detecting liver, spleen and kidney injuries whereas its sensitivity is moderate
      for the detection of gastrointestinal tract (GIT) and pancreatic injuries.

PMID- 15186892
TI  - The adapting healer: pioneering through shifting epidemiological and
      sociocultural landscapes.
AB  - While it is true that healers selectively adopt and/or refashion aspects of
      biomedicine, the influence is not unidirectional with information flowing
      exclusively from hospitals into the workplaces of healers. This article examines
      healers in Tanga, Tanzania to explore the reciprocal relations between
      practitioners of indigenous medicine and biomedicine. An abbreviated ethnography
      of one healer in coastal Tanzania is used to illustrate some of the relevant
      influences and possible adaptations of contemporary healers. His experiences
      illuminate how multiple factors, especially sociocultural changes, biomedicine,
      AIDS, and related research(ers) can influence healers' adaptations. In his case,
      biomedical health workers from a non-profit HIV organization call upon him not
      only to act as a liaison between their services and the community, but more
      importantly, to provide treatment for opportunistic infections and counseling for
      patients and to participate in biomedical and scientific projects. Reflecting on
      his experiences as a healer who has negotiated a position that straddles the
      world of biomedicine and the world of healers facilitates examination of
      important issues affecting healers today, including their relationship to
      biomedical health workers, bioprospectors, governments, non-profit organizations,
      and professional organizations of healers. Although the healer featured in this
      article is a pioneer in his own town, there are other examples in Africa where
      healers and biomedical practitioners are interacting. Therefore, he may represent
      a trend in healer adaptation.

PMID- 15186893
TI  - Outcomes associated with participation in a therapeutic recreation camping
      programme for children from 15 European countries: Data from the 'Barretstown
      Studies'.
AB  - In recent years, specialised camping programmes, based largely on the premise of
      therapeutic recreation, have emerged as a form of intervention for children with
      chronic illnesses, and their siblings. Although these programmes are
      proliferating, little systematic evaluation of their outcomes has been
      undertaken, particularly within a European context. The aim of this research was
      to investigate the symptom and psychosocial outcomes of The Barretstown Gang Camp
      therapeutic recreation programme in Ireland, a programme aimed at European
      children with chronic illnesses and their siblings, in the short and longer term.
      Measures assessing children's physical, psychological and social functioning,
      specifically their self-reported physical symptoms, affect, self-esteem and
      quality of life, were translated into 12 European languages and administered at 3
      time periods: 2 weeks before each child participated in the programme (Time 1), 2
      weeks after participation (Time 2) and at 6 months following participation (Time
      3). Benefits were noted in their experience of physical symptoms, affect
      pertaining to physiological hyperarousal and quality of life in the short and
      longer term. Positive changes were also noted in relation to self-esteem as it
      pertains to global self-worth and physical attractiveness though these were, for
      the most part, in the longer term only and were preceded by adverse effects in
      the short term. While some of these positive changes were global, there were
      group differences based mostly on children's age, and patient/sibling status and
      to a lesser extent on their nationality. However, no benefits were evident in
      many aspects of children's functioning, either at a global or a group level, in
      the short and longer term. These findings clarify previous research and suggest
      that camping programmes have an important role to play as a complementary
      intervention in facilitating adjustment to chronic illness.

PMID- 15186894
TI  - Responses of established healthcare to the professionalization of complementary
      and alternative medicine in Ontario.
AB  - This paper examines the reactions of leaders of established health professions in
      Ontario, Canada to the efforts of selected complementary and alternative (CAM)
      occupational groups (chiropractors, naturopaths, acupuncture/traditional Chinese
      doctors, homeopaths and Reiki practitioners) to professionalize. Stakeholder
      theory provides the framework for analysis of competing interests among the
      various groups in the healthcare system. The data are derived from personal
      interviews with 10 formal leaders from medicine, nursing, physiotherapy, clinical
      nutrition and public health. We conceived of these leaders as one group of
      stakeholders, with both common and conflicting interests. The findings
      demonstrate that these stakeholders are reluctant to endorse the
      professionalization of CAM. They propose a series of strategies to contain the
      acceptance of CAM groups, such as insisting on scientific evidence of safety and
      efficacy, resisting integration of CAM with conventional medicine and opposing
      government support for research and education. These strategies serve to protect
      the dominant position of medicine and its allied professions, and to maintain
      existing jurisdictional boundaries within the healthcare system. The popular
      support for CAM will require that health professional stakeholders continue to
      address the challenges this poses, and at the same time protect their position at
      the apex of the healthcare pyramid.

PMID- 15186895
TI  - The performance of different models of primary care provision in Southern Africa.
AB  - Despite the emphasis placed during the last two decades on public delivery of
      comprehensive and equitable primary care (PC) to developing country populations,
      coverage remains far from universal and the quality often poor. Users frequently
      patronise private providers, ranging from informal drug sellers to trained
      professionals. Interest is increasing internationally in the potential for making
      better use of private providers, including contractual approaches. The research
      aim was to examine the performance of different models of PC provision, in order
      to identify their strengths and weaknesses from the perspective of a government
      wishing to develop an overall strategy for improving PC provision. Models
      evaluated were: (a) South African general practitioners (district surgeons)
      providing services under public contracts; (b) clinics provided in Lesotho under
      a sub-contract between a construction company and a South African health care
      company; (c) GP services provided through an Independent Practitioner Association
      to low income insured workers and families; (d) a private clinic chain serving
      low income insured and uninsured workers and their families; and (e) for
      comparative purposes, South African public clinics. Performance was analysed in
      terms of provider cost and quality (of infrastructure, treatment practices,
      acceptability to patients and communities), allowing for differences in services
      and case-mix. The diversity of the arrangements made direct comparisons
      difficult, however, clear differences were identified between the models and
      conclusions drawn on their relative performance and the influences upon
      performance. The study findings demonstrate that contextual features strongly
      influence provider performance, and that a crude public/private comparison is not
      helpful. Key issues in contract design likely to influence performance are
      highlighted. Finally, the study argues that there is a need before contracting
      out service provision to consider how the performance of private providers might
      change when the context within which they are working changes with the
      introduction of a contract.

PMID- 15186896
TI  - Senegalese grandmothers promote improved maternal and child nutrition practices:
      the guardians of tradition are not averse to change.
AB  - The vast majority of community nutrition/health programs in developing countries
      focus on women of reproductive age (WRA) and a few explicitly involve senior
      women, or grandmothers. In Senegal, as in many other places, older, experienced
      women play an influential role in household maternal and child health (MCH)
      matters. Formative research in Serer villages revealed their importance and this
      was taken into account in an action research nutrition education (NE) project in
      which grandmothers were encouraged to promote improved nutritional practices
      related to pregnancy (e.g. decreased work and improved diet) and infant feeding
      (e.g. breastfeeding and complementary feeding). A participatory
      communication/empowerment education approach was used involving songs, stories
      and group discussion. Quantitative and qualitative data were collected to both
      document and evaluate the intervention. Triangulation of the evaluation data
      suggests that 12 months after the intervention was initiated there were
      significant improvements in grandmothers' nutritional knowledge, in their advice
      to WRA, and in the nutrition-related practices of these younger women associated
      both with pregnancy and infant feeding. For example, in the pre-test only 20% of
      grandmothers stated that they advise pregnant women to decrease their workload
      whereas in the post-test 87% reported giving this advice. At the same time, 91%
      of WRA in villages with the grandmother strategy reported having decreased their
      workload during their last pregnancy whereas in villages with NE activities for
      WRA but not with grandmothers, only 34% of younger women reported having done so.
      These findings provide evidence of grandmothers' ability to learn, to integrate
      new information into their practices and to positively influence the practices of
      WRA. These results support the need for future MCH programs, in different
      cultural contexts, to involve grandmothers and in so doing to build on their
      intrinsic commitment to family well-being.

PMID- 15186897
TI  - Racial and ethnic diversity and organizational behavior: a focused research
      agenda for health services management.
AB  - Initiatives to reduce racial and ethnic disparities are conceptualized as a three
      legged stool. Public policy: to ensure a legal and regulatory environment
      designed to eliminate disparities in access and health status; clinical practice:
      to ensure patient satisfaction and loyalty and improve treatment outcomes through
      the cultural competence of clinicians; and organizational behavior: to ensure
      that leadership, staff, and the culture of the health services organization
      represents and values the communities they serve. Our review of the health
      services and general management literature published since 1990 reveals a paucity
      of research on organizational behavior. Based on our review of health services
      and general management organizational behavior and racial/ethnic diversity
      literature, we offer an agenda for future research in this area. Factors that
      will facilitate or inhibit the pursuit of the proposed research agenda are also
      identified and discussed. The literature reviewed is mainly from the United
      States and the proposed research agenda results from that review, which presents
      a potential limitation to its applicability internationally.

PMID- 15186898
TI  - Should "acculturation" be a variable in health research? A critical review of
      research on US Hispanics.
AB  - Acculturation has become a popular variable in research on health disparities
      among certain ethnic minorities, in the absence of serious reflection about its
      central concepts and assumptions. Key constructs such as what constitutes a
      culture, which traits pertain to the ethnic versus "mainstream" culture, and what
      cultural adaptation entails have not been carefully defined. Using examples from
      a systematic review of recent articles, this paper critically reviews the
      development and application of the concept of acculturation in US health research
      on Hispanics. Multiple misconceptions and errors in the central assumptions
      underlying the concept of acculturation are examined, and it is concluded that
      acculturation as a variable in health research may be based more on ethnic
      stereotyping than on objective representations of cultural difference.

PMID- 15186899
TI  - The economic consequences for parents of losing an adult child to AIDS: evidence
      from Thailand.
AB  - An examination of the economic consequences for older-age parents of losing an
      adult child to AIDS in Thailand based on quantitative data derived from a key
      informant study and a direct interview survey with parents yielded the following
      main findings: (1) parents frequently paid for their children's care and
      treatment, but government health insurance and to a lesser extent welfare
      measures helped alleviate these expenses; (2) parental caregiving often disrupted
      economic activity, although the resulting opportunity costs were limited by the
      typically short duration of caregiving; (3) parents commonly paid for funeral
      costs but benefited from funeral society memberships and customary contributions
      from those attending; (4) only a minority of parents supported AIDS orphans
      although orphaned grandchildren often ended up with their grandparents; (5) most
      deceased children had contributed financially to the parental household but only
      a minority were main providers. Poorer parents, however, were most likely to lose
      a main provider and experience severe financial hardship; and (6) although poorer
      parents spent much less on expenses related to the illness and death of their
      children, they were much more likely than better-off parents to be seriously
      burdened by these expenses. Programs are needed to address the plight of AIDS
      parents but should target those who are most susceptible to resulting economic
      hardship.

PMID- 15186900
TI  - Search for a cure: narratives of Thai family caregivers living with a person with
      AIDS.
AB  - Facing an incurable prognosis Thai families search for a cure for AIDS using all
      possible means available to them. This paper reports a longitudinal narrative
      case study of eight family caregivers caring for a relative with AIDS in rural
      Southern Thailand. The paper demonstrates how the caregivers living with a person
      with AIDS made sense of illness episodes, and how they chose and evaluated
      particular treatments and care. Caregivers moved between modern medicine,
      traditional/folk medicine, supernatural healing rites, religious performances,
      and home remedies in their search for a cure. The findings indicate that a more
      holistic and palliative approach is needed toward AIDS care.

PMID- 15186901
TI  - STD care: variations in clinical care associated with provider sex, patient sex,
      patients' self-reported symptoms or high-risk behaviors, partner STD history.
AB  - Sexually transmitted diseases in the United States are frequently diagnosed by
      private, as well as public, physicians. However, we know little about the
      decision processes that physicians employ when faced with people who may or may
      not be infected. To address this gap, we compared physicians' responses to
      different patient vignettes to assess how variations in patients' presentations
      affect physicians' clinical behavior. We systematically varied reported symptoms,
      behavioral risk, partner STD, and sex of patients in 16 different vignettes, with
      one vignette randomly presented to each physician in a national survey.
      Physicians rated the likelihood of 12 clinical management actions they might take
      with the patient vignette presented. Responses varied with self-reported
      symptoms, high-risk behavior, and report of an STD infected partner such that
      female physicians were more attentive to sexual health, and all physicians were
      more likely to treat female patients aggressively, relative to their male
      patients. Overall behavior was broadly congruent with sound medical practice,
      although we discuss several caveats to this general statement.

PMID- 15186902
TI  - The determinants of withdrawal use in Turkey: a husband's imposition or a woman's
      choice?
AB  - This paper seeks to understand why Turkey has one of the highest rates of
      withdrawal (coitus interruptus) use in the world. Despite a pronounced fertility
      decline, a marked increase in contraceptive prevalence, and expansion of family
      planning activities, in 1998 one in four Turkish couples relied on withdrawal,
      and this fraction has remained stable since 1983. In contrast to previous
      research that has focused on women's reports, here we use the husbands' module of
      the 1998 Turkish Demographic and Health Survey to examine user characteristics
      and attitudes, as well as the determinants of withdrawal use among a
      representative sample of 1950 currently married men in Turkey. Multivariate
      methods are employed to estimate these effects and the likelihood of using
      withdrawal rather than other methods. Among other findings, less egalitarian
      minded husbands were more likely to select withdrawal over other contraceptive
      methods, but measures of male authority had only partial predictive power after
      controlling for other variables. Although withdrawal use typically reflects
      husbands' preferences, it is widely practiced as it satisfies user requirements
      and simplifies women's lives. The results of this study are discussed in a
      broader historical and cultural context and used to provide insight into how
      Turkey's family planning and reproductive health programs might be improved. In
      contrast to neighboring countries, there is little sign of withdrawal being
      displaced in Turkey anytime soon by modern methods.

PMID- 15186903
TI  - 'I am not the kind of woman who complains of everything': illness stories on self
      and shame in women with chronic pain.
AB  - In this study, we explore issues of self and shame in illness accounts from women
      with chronic pain. We focused on how these issues within their stories were
      shaped according to cultural discourses of gender and disease. A qualitative
      study was conducted with in-depth interviews including a purposeful sampling of
      10 women of varying ages and backgrounds with chronic muscular pain. The women
      described themselves in various ways as 'strong', and expressed their disgust
      regarding talk of illness of other women with similar pain. The material was
      interpreted within a feminist frame of reference, inspired by narrative theory
      and discourse analysis. We read the women's descriptions of their own (positive)
      strength and the (negative) illness talk of others as a moral plot and
      argumentation, appealing to a public audience of health personnel, the general
      public, and the interviewer: As a plot, their stories attempt to cope with
      psychological and alternative explanations of the causes of their pain. As
      performance, their stories attempt to cope with the scepticism and distrust they
      report having been met with. Finally, as arguments, their stories attempt to
      convince us about the credibility of their pain as real and somatic rather than
      imagined or psychological. In several ways, the women negotiated a picture of
      themselves that fits with normative, biomedical expectations of what illness is
      and how it should be performed or lived out in 'storied form' according to a
      gendered work of credibility as woman and as ill. Thus, their descriptions appear
      not merely in terms of individual behaviour, but also as organized by medical
      discourses of gender and diseases. Behind their stories, we hear whispered
      accounts relating to the medical narrative about hysteria; rejections of the
      stereotype medical discourse of the crazy, lazy, illness-fixed or weak woman.

PMID- 15186904
TI  - Sociocultural context of women's body image.
AB  - In our society, women's bodies are the locus of both increasing rates of obesity
      and body dissatisfaction. While these trends may seem contradictory or to result
      from each other, an alternative explanation is that they are both the products of
      an unfavourable sociocultural environment in the area of food and weight. Both
      body dissatisfaction and excess weight can seriously impact women's physical and
      emotional health. The strong cultural value placed on thinness, especially for
      women, unfortunately may take precedence over health. To effectively address the
      impact of women's body image dissatisfaction requires an understanding of the
      multiple contexts of women's lives. This study used a naturalistic paradigm to
      explore how women's personal and sociocultural context influences their body
      image. Forty-four non-eating disordered women ranging from 21 to 61 years old
      were interviewed twice using a semi-structured interview guide. Women's
      narratives revealed that body image is not a static construct, but is dynamic and
      fluctuates as women encounter new experiences and re-interpret old ones. The
      powerful and unconscious impact of the media on body image was mediated by
      women's internal contexts (self-confident and self-critical) and their
      relationships with others, such as partners and other women. Body image was not
      so much influenced by the nature of others' comments but interpretation of their
      meaning. However, health professionals' comments were typically not reinterpreted
      due to the health context in which they were given. While some women's narratives
      expressed their internalized sociocultural norms, others' described acceptance of
      their bodies following a process of reflection and empowerment. In light of these
      findings, efforts to improve women's body image, and by extension their health,
      can no longer only focus on diminishing the tangible power of industry and media,
      but must include transforming the social ties, practices and conventions in
      everyday relationships, including with health professionals.

PMID- 15186905
TI  - The problem of evidence-based medicine: directions for social science.
AB  - Evidence-based medicine (EBM) is arguably the most important contemporary
      initiative committed to reshaping biomedical reason and practice. The move to
      establish scientific research as a fundamental ground of medical decision making
      has met with an enthusiastic reception within academic medicine, but has also
      generated considerable controversy. EBM and the broader forms of evidence-based
      decision making it has occasioned raise provocative questions about the relation
      of scientific knowledge to social action across a variety of domains. Social
      science inquiry about EBM has not yet reached the scale one might expect, given
      the breadth and significance of the phenomenon. This paper contributes
      reflections, critique and analysis aimed at helping to build a more robust social
      science investigation of EBM. The paper begins with a "diagnostics" of the
      existing social science literature on EBM, emphasizing the possibilities and
      limitations of its two central organizing analytic perspectives: political
      economy and humanism. We further explore emerging trends in the literature
      including a turn to original empirical investigation and the embrace of "newer"
      theoretical resources such as postmodern critique. We argue for the need to move
      the social inquiry of EBM beyond concerns about rationalization and the potential
      erasure of the patient and, to this end, suggest new avenues of exploration. The
      latter include analysis of clinical epidemiology and clinical reason as the
      discursive preconditions of EBM, the role of the patient as a site for the
      production of evidence, and the textually mediated character of EBM.

PMID- 15186906
TI  - 'It takes three to tango': a framework for understanding patient partnership in
      paediatric clinics.
AB  - Since the late 1990s, the term 'partnership' has increasingly been inserted into
      the literature and rhetoric of the UK health-care system. In this paper, the
      assumptions and implications surrounding the usage of the term in relation to
      doctor-patient interaction are examined in the context of paediatric services.
      The paper considers recent ideas about partnership in medical encounters,
      especially those of Charles et al., and the extent to which they are applicable
      to children. The paper then goes on to develop a framework for understanding
      patient-partnership issues. It is argued that any investigation of partnership
      will need to take account of the organisational and legal setting, as well as the
      beliefs and agendas that all parties bring to the medical encounter. In the
      context of paediatrics, the perspectives of three actors--the child, parent and
      health service professional--need to be explored. Our framework allows for
      different sorts of 'coalition' to develop between these actors as they try to
      reconcile their perspectives in the clinic and offers a situationally
      contextualised view of partnership. We also argue that these matters require
      study outside as well as inside the clinic, through the use of a range of
      methods, including those that help children at home review their involvement in
      decision making in the clinic.

PMID- 15186907
TI  - Occupational stressors and hypertension: a multi-method study using observer
      based job analysis and self-reports in urban transit operators.
AB  - This multi-method study aimed to disentangle objective and subjective components
      of job stressors and determine the role of each for hypertension risk. Because
      research on job stressors and hypertension has been exclusively based on self
      reports of stressors, the tendency of some individuals to use denial and
      repressive coping might be responsible for the inconclusive results in previous
      studies. Stressor measures with different degrees of objectivity were contrasted,
      including (1) an observer-based measure of stressors (job barriers, time
      pressure) obtained from experts, (2) self-reported frequency and appraised
      intensity of job problems and time pressures averaged per workplace (group
      level), (3) self-reported frequency of job problems and time pressures at the
      individual level, and (4) self-reported appraised intensity of job problems and
      time pressures at the individual level. The sample consisted of 274 transit
      operators working on 27 different transit lines and four different vehicle types.
      Objective stressors (job barriers and time pressure) were each significantly
      associated with hypertension (casual blood pressure readings and/or currently
      taking anti-hypertensive medication) after adjustment for age, gender and
      seniority. Self-reported stressors at the individual level were positively but
      not significantly associated with hypertension. At the group level, only
      appraisal of job problems significantly predicted hypertension. In a composite
      regression model, both observer-based job barriers and self-reported intensity of
      job problems were independently and significantly associated with hypertension.
      Associations between self-reported job problems (individual level) and
      hypertension were dependent on the level of objective stressors. When observer
      based stressor level was low, the association between self-reported frequency of
      stressors and hypertension was high. When the observer-based stressor level was
      high the association was inverse; this might be indicative of denial of stress or
      alexithymia. We feel that multi-method studies are useful for disentangling the
      relations between objective and subjective stress and hypertension.

PMID- 15186908
TI  - Remaking family life: strategies for re-establishing continuity among Congolese
      refugees during the family reunification process.
AB  - The restrictive immigration and refugee policies of many Western countries force
      most refugee families to remain separated for long periods. Although there is
      much discussion among professionals in the community and the clinical milieu
      about the problems families encounter after reunification, the strategies
      employed by refugees to restore family life have not been paid much attention.
      This longitudinal study documents the pre- and post-reunification experiences of
      12 refugee families from the Democratic Republic of Congo in Montreal. Our
      results suggest that family separation can be understood as an ambiguous loss, in
      that the temporary absence of other family members cannot be fully acknowledged
      because of the perpetual uncertainty and permanent risk to them. Memory work, in
      the form of shared family memories, attenuates the pain of the absence. Once
      reunited, family members must re-establish continuity in spite of the many denied
      rifts between them. The capacity to recall a personal, familial or collective
      history of previous separation and loss appears to be protective, as if the
      memory of life's discontinuities provides an opportunity to recreate a partial
      sense of continuity out of repeating experiences of chaos.

PMID- 15186909
TI  - Self-rated oral health as an independent predictor of self-rated general health,
      self-esteem and life satisfaction.
AB  - Self-rated health (SRH) is a useful summary measure of people's general health
      and was found to predict future health outcomes. Self-rated oral health (SROH) is
      a similarly useful summary measure of people's oral health. Both are related to
      quality of life, especially at old age. The objectives of the study were: (1) to
      assess the independent contribution of SROH to concurrent and future SRH of
      elderly people, controlling for sociodemographics and health measures, and, (2)
      to assess whether SROH adds unique information not captured by SRH by testing
      their independent associations with self-esteem and life satisfaction.
      Participants were 850 residents of a retirement community (mean age 73)
      interviewed in their homes at baseline and 5 years later. The interview included
      single-item self-ratings of general and oral health, self-reports of medical
      history, recent chronic diseases, medication usage, functional disability, self
      esteem and life satisfaction. Multiple regression analyses showed that SROH had
      an independent effect on concurrent and future SRH, controlling for age and other
      measures of health status. Both SRH and SROH independently explained a
      significant amount of variance in concurrent ratings of self-esteem and life
      satisfaction. SROH has a unique role in people's perceptions of their overall
      health yet is not fully captured by SRH. Therefore, it should be considered by
      general health care providers in their assessments of the health status of older
      adults.

PMID- 15186910
TI  - Nonsynaptic communication in the central nervous system.
AB  - Classical synaptic functions are important and suitable to relatively fast and
      discretely localized processes, but the nonclassical receptorial functions may be
      providing revolutionary possibilities for dealing at the cellular level with many
      of the more interesting and seemingly intractable features of neural and cerebral
      activities. Although different forms of nonsynaptic communication (volume
      transmission) often appear in different studies, their importance to modulate and
      mediate various functions is still not completely recognized. To establish the
      existence and the importance of nonsynaptic communication in the nervous system,
      here we cite pieces of evidence for each step of the interneuronal communication
      in the nonsynaptic context including the release into the extracellular space
      (ECS) and the extrasynaptic receptors and transporters that mediate nonsynaptic
      functions. We are now faced with a multiplicity of chemical communication. The
      fact that transmitters can even be released from nonsynaptic varicosities without
      being coupled to frequency-coded neuronal activity and they are able to diffuse
      over large distances indicates that there is a complementary mechanism of
      interneuronal communication to classical synaptic transmission. Nonconventional
      mediators that are also important part of the nonsynaptic world will also be
      overviewed.

PMID- 15186911
TI  - Diffusion properties of the brain in health and disease.
AB  - Extrasynaptic transmission between neurons and communication between neurons and
      glia are mediated by the diffusion of neuroactive substances in the extracellular
      space (ECS)--volume transmission. Diffusion in the CNS is inhomogeneous and often
      not uniform in all directions (anisotropic). Ionic changes and amino acid release
      result in cellular (particularly glial) swelling, compensated for by ECS
      shrinkage and a decrease in the apparent diffusion coefficients of neuroactive
      substances or water (ADCW). The diffusion parameters of the CNS in adult mammals
      (including humans), ECS volume fraction alpha (alpha = ECS volume/total tissue
      volume; normally 0.20-0.25) and tortuosity lambda (lambda2 = D/ADC; normally 1.5
      1.6), hinder the diffusion of neuroactive substances and water. A significant
      decrease in ECS volume and an increase in diffusion barriers (tortuosity) and
      anisoptropy have been observed during stimulation, lactation or learning deficits
      during aging, due to structural changes such as astrogliosis, the re-arrangement
      of astrocytic processes and a loss of extracellular matrix. Decreases in the
      apparent diffusion coefficient of tetramethylammonium (ADCTMA) and ADCW due to
      astrogliosis and increased proteoglycan expression were found in the brain after
      injury and in grafts of fetal tissue. Tenascin-R and tenascin C-deficient mice
      also showed significant changes in ADCTMA and ADCW, suggesting an important role
      for extracellular matrix molecules in ECS diffusion. Changes in ECS volume,
      tortuosity and anisotropy significantly affect neuron-glia communication, the
      spatial relation of glial processes towards synapses, the efficacy of glutamate
      or GABA 'spillover' and synaptic crosstalk, the migration of cells, the action of
      hormones and the toxic effects of neuroactive substances and can be important for
      diagnosis, drug delivery and new treatment strategies.

PMID- 15186912
TI  - Contribution of dead-space microdomains to tortuosity of brain extracellular
      space.
AB  - The extracellular space (ECS) of the brain is a major channel for intercellular
      communication, nutrient and metabolite trafficking, and drug delivery. The
      dominant transport mechanism is diffusion, which is governed by two structural
      parameters, tortuosity and volume fraction. Tortuosity (lambda) represents the
      hindrance imposed on the diffusing molecules by the tissue in comparison with an
      obstacle-free medium, while volume fraction (alpha) is the proportion of tissue
      volume occupied by the ECS. Diffusion of small ECS markers can be exploited to
      measure lambda and alpha. In healthy brain tissue, lambda is about 1.6 but
      increases to 1.9-2.0 in pathologies that involve cellular swelling. Previously it
      was thought that lambda could be explained by the circumnavigation of diffusing
      molecules around cells. Numerical models of assemblies of convex cells, however,
      give an upper limit of about 1.23 for lambda. Therefore, additional factors must
      be responsible for lambda in brain. In principle, two mechanisms could account
      for the measured value: a more complex ECS geometry or an extracellular
      macromolecular matrix. Here we review recent work in ischemic tissue suggesting
      concave geometrical formations, dead-space microdomains, as a major determinant
      of extracellular tortuosity. A theoretical model of lambda based on diffusion
      dwell times supports this hypothesis and predicts that, in ischemia, dead spaces
      occupy approximately 60% of ECS volume fraction leaving only approximately 40%
      for well-connected channels. It is further proposed that dead spaces are present
      in healthy brain tissue where they constitute about 40% of alpha. The presence of
      dead-space microdomains in the ECS implies microscopic heterogeneity of
      extracellular channels with fundamental implications for molecular transport in
      brain.

PMID- 15186913
TI  - Glutamate escape from a tortuous synaptic cleft of the hippocampal mossy fibre
      synapse.
AB  - The time course of neurotransmitter in the synaptic cleft contributes
      substantially to the fast kinetics of synaptic signalling. Hippocampal mossy
      fibres (MFs), a well-characterised excitatory pathway from dentate granule cells
      to the hippocampus proper, form large glutamatergic synapses at branched spiny
      structures in CA3 pyramidal cell dendrites. To what extent transmission at these
      synapses is affected by retarded glutamate clearance from the large tortuous
      synaptic cleft is not known. Here, we propose a simple geometrical approximation
      representing the 'typical' geometry of thorny excrescences that form the tortuous
      cleft interface at a MF synapse. We then employ Monte Carlo simulations to
      monitor movements of 3000 individual glutamate molecules released within the
      cleft. The results predict that, in the absence of neuronal glutamate
      transporters, it should take approximately 10 ms for 50% and 60-70 ms for 90% of
      glutamate molecules to escape the MF synapse.

PMID- 15186914
TI  - Inhibitory effect of nitric oxide on dopamine transporters: interneuronal
      communication without receptors.
AB  - Previously we observed that Nomega-nitro-L-arginine methyl ester (l-NAME)
      decreased the striatal dopamine (DA) release in microdialysis experiments and
      this effect was completely diminished in the presence of the DA uptake inhibitor
      nomifensine, indicating that the effect was mediated via the DA transporter. The
      aim of the present work was to study the direct effect of nitrergic compounds on
      DA uptake. We measured the uptake of [3H]DA in striatal slices and found that the
      nitric oxide (NO) generator sodium nitroprussid (100 microM) decreased the uptake
      by 66%. In contrast, the NO synthase inhibitor L-NAME (100 microM) increased the
      DA uptake by 80%, while the inactive D-NAME had no effect on uptake. Our data
      indicate that NO exerts an inhibitory effect on DA transporters. Since the
      production of NO by neuronal NO synthase is closely related to the activation of
      NMDA receptors, the level of NO around synapses reflects the activity of
      glutamatergic neurotransmission. The strength of excitatory input, therefore, can
      be nonsynaptically signaled by NO to the surrounding dopaminergic neurons via the
      inhibitory tone on transporters. The concomitant elevation of DA concentration
      around the activated synapse represents the response of dopaminergic system,
      which can adapt to the changing excitatory activity without receiving
      glutamatergic input and without expressing glutamate receptors. Thus, the effect
      of NO on transporters represents a new form of interneuronal communication, a
      nonsynaptic interaction without receptors.

PMID- 15186915
TI  - Neuronal, glial and synaptic remodeling in the adult hypothalamus: functional
      consequences and role of cell surface and extracellular matrix adhesion
      molecules.
AB  - The adult hypothalamo-neurohypophysial system (HNS) undergoes activity-dependent
      morphological plasticity which modifies astrocytic coverage of its oxytocinergic
      neurons and their synaptic inputs. Thus, during physiological conditions that
      enhance central and peripheral release of oxytocin (OT), adjacent somata and
      dendrites of OT neurons become extensively juxtaposed, without intervening
      astrocytic processes and receive an increased number of synapses. The
      morphological changes occur within a few hours and are reversible with
      termination of stimulation. The reduced astrocytic coverage has direct functional
      consequences since it modifies extracellular ionic homeostasis, synaptic
      transmission, and the size and geometry of the extracellular space. It also
      contributes indirectly to neuronal function by permitting formation of synapses
      on neuronal surfaces freed of astrocytic processes. Overall, such remodeling is
      expected to potentiate activated neuronal firing, especially in clusters of
      tightly packed neurons, an anatomical arrangement characterizing OT neurons. This
      plasticity connotes dynamic cell interactions that must bring into play cell
      surface and extracellular matrix adhesive proteins like those intervening in
      developing neuronal systems undergoing neuronal-glial and synaptogenic
      transformations. It is worth noting, therefore, that adult HNS neurons and glia
      continue to express such molecules, including polysialic acid (PSA)-enriched
      neural cell adhesion molecule (PSA-NCAM) and the glycoprotein, tenascin-C. PSA is
      a large, complex sugar on the extracellular domain of NCAM considered a negative
      regulator of adhesion; it occurs in large amounts on the surfaces of HNS neurons
      and astrocytes. Tenascin-C, on the other hand, possesses adhesive and repulsive
      properties; it is secreted by HNS astrocytes and occurs in extracellular spaces
      and on cell surfaces after interaction with appropriate ligands. These molecules
      have been considered permissive factors for morphological plasticity. However,
      because of their localization and inherent properties, they may also serve to
      modulate the extracellular environment and in consequence, synaptic and volume
      transmission in a system in which the extracellular compartment is constantly
      being modified.

PMID- 15186916
TI  - Volume transmission in activity-dependent regulation of myelinating glia.
AB  - The importance of neural impulse activity in regulating neuronal plasticity is
      widely appreciated; increasingly, it is becoming apparent that activity-dependent
      communication between neurons and glia is critical in regulating many aspects of
      nervous system development and plasticity. This communication takes place not
      only at the synapse, but also between premyelinating axons and glia, which form
      myelin in the PNS and CNS. Recent work indicates that neural impulse activity
      releases ATP and adenosine from non-synaptic regions of neurons, which activates
      purinergic receptors on myelinating glia. Acting through this receptor system,
      neural impulse activity can regulate gene expression, mitosis, differentiation,
      and myelination of Schwann cells (SCs) and oligodendrocytes, helping coordinate
      nervous system development with functional activity in the perinatal period. ATP
      and adenosine have opposite effects on differentiation of Schwann cells and
      oligodendrocytes, providing a possible explanation for the opposite effects of
      impulse activity reported on myelination in the CNS and PNS.

PMID- 15186917
TI  - Increased release of excitatory amino acids by the actions of ATP and
      peroxynitrite on volume-regulated anion channels (VRACs) in astrocytes.
AB  - Rapid swelling of astrocytes in primary culture by exposure to hyposmotic medium
      (or slower swelling by exposure to high K+ medium) leads to release of the
      excitatory amino acids (EAAs) glutamate and aspartate. One question that arises
      is whether these phenomena are only relevant to pathological states such as
      ischemia and trauma where marked astrocytic swelling occurs or whether much
      smaller astrocytic volume changes, that might be encountered under physiological
      states, will cause such release. We have recently found that extracellular ATP
      strongly potentiated volume-regulated anion channels (VRACs)-mediated-excitatory
      amino acid release in non-swollen and osmotically swollen primary astrocyte
      cultures. However, ATP does not seem to directly activate but instead positively
      modulates VRACs and we postulate that a minor fraction of these are active under
      isoosmotic conditions based on the finding that in hyperosmotic media the ATP
      induced increase was inhibited. Agonist and inhibitor analysis suggests that the
      effect of ATP is mediated by several subtypes of metabotropic P2Y receptors.
      Thus, the concept of volume transmission may be extended to volume-mediated
      transmission, whereby moderate cell swelling causes release of neurotransmitter
      substances. The product of the superoxide oxygen radical and nitric oxide,
      peroxynitrite, formed under pathological conditions such as cerebral ischemia,
      also potentiated the release of D-[3H]aspartate from astrocyte cultures exposed
      to limited or marked swelling via intracellular signaling mechanisms involving
      tyrosine kinases (TKs). Thus, the enhancement of cell volume-dependent release of
      excitatory amino acids from astrocytes can be physiological or pathological and
      its magnitude depends on the degree of the cell volume increase.

PMID- 15186918
TI  - Role of astrocytic transport processes in glutamatergic and GABAergic
      neurotransmission.
AB  - The fine tuning of both glutamatergic and GABAergic neurotransmission is to a
      large extent dependent upon optimal function of astrocytic transport processes.
      Thus, glutamate transport in astrocytes is mandatory to maintain extrasynaptic
      glutamate levels sufficiently low to prevent excitotoxic neuronal damage. In GABA
      synapses hyperactivity of astroglial GABA uptake may lead to diminished GABAergic
      inhibitory activity resulting in seizures. As a consequence of this the
      expression and functional activity of astrocytic glutamate and GABA transport is
      regulated in a number of ways at transcriptional, translational and post
      translational levels. This opens for a number of therapeutic strategies by which
      the efficacy of excitatory and inhibitory neurotransmission may be manipulated.

PMID- 15186919
TI  - Energy transfer from astrocytes to axons: the role of CNS glycogen.
AB  - We tested the hypothesis that astrocytic glycogen supports axon function under
      both pathological and physiological conditions. Functional activity of the rat
      (RON) or mouse optic nerve (MON), representative central white matter tracts, was
      assessed electrophysiologically as the area under the supramaximal compound
      action potential (CAP). During aglycaemia the CAP area of rodent optic nerve
      persisted for up to 30 min, after which the CAP rapidly failed. Glycogen content
      measured biochemically during the aglycaemic insult fell with a time course
      compatible with its rapid degradation in the absence of glucose. Pharmacological
      up-regulation of glycogen content prior to the aglycaemic insult with incubation
      in hyperglycaemic ambient glucose delayed CAP failure, whereas down-regulation of
      glycogen content induced by nor-adrenaline accelerated CAP failure. Inhibiting
      lactate transfer between astrocytes and axons during aglycaemia, where glycogen
      is the only utilisable energy reserve, resulted in accelerated CAP failure,
      implying that glycogen-derived lactate supports function when exogenous energy
      metabolites are withdrawn. Under normoglycaemic conditions glycogen content
      decreased during high frequency axon discharge, although CAP function was fully
      maintained. Both prior depletion of glycogen content, or blocking axonal lactate
      uptake rendered nerves incapable of fully supporting CAP function during high
      frequency firing in the presence of normoglycaemic glucose. These results
      indicated that during aglycaemia and increased metabolic demand, astrocytic
      glycogen was degraded to form lactate, which was used as a supplemental energy
      source when ambient normoglycaemic glucose was incapable of meeting immediate
      tissue energy demands.

PMID- 15186920
TI  - Interactions between glutamate transporters and metabotropic glutamate receptors
      at excitatory synapses in the cerebellar cortex.
AB  - Five glutamate transporter genes have been identified; two of these (EAAT3 and
      EAAT4) are expressed in neurons and are predominantly confined to the membranes
      of cell bodies and dendrites. At an ultrastructural level, glutamate transporters
      have been shown to surround excitatory synapses in hippocampus and cerebellum [J.
      Neurosci. 18 (1998) 3606; J. Comp. Neurol. 418 (2000) 255]. This pattern of
      localization overlaps the well-described perisynaptic distribution of Group I
      metabotropic glutamate receptors or mGluRs [Neuron 11 (1993) 771; J. Chem.
      Neuroanat. 13 (1997) 77]. Both of the principal excitatory synaptic inputs to
      cerebellar Purkinje neurons, the parallel fiber (PF) and climbing fiber (CF)
      synapses, express mGluR-dependent forms of synaptic plasticity [Nat. Neurosci. 4
      (2001) 467]. Prompted by the colocalization of postsynaptic glutamate
      transporters and mGluRs, we have examined whether glutamate uptake limits mGluR
      mediated signals and mGluR-dependent forms of plasticity at PF and CF synapses in
      cerebellar slices. We find that, at PF and, surprisingly also at CF synapses,
      mGluR activation generates a slow synaptic current and triggers intracellular
      calcium release. At both PF and CF synapses, mGluR responses are strongly limited
      by glutamate transporters under resting conditions and are facilitated by short
      trains of stimuli. Nearly every Purkinje neuron expresses an mGluR-mediated
      synaptic current upon inhibition of glutamate transport. Global applications of
      glutamate achieved by photolysis of chemically caged glutamate yield similar
      results and argue that the colocalized transporters can effectively limit
      glutamate access to the mGluRs even in the face of such a large amount of
      transmitter. We hypothesize that neuronal glutamate transporters and Group I
      mGluRs located in the perisynaptic space interact to sense and then regulate the
      amount of glutamate escaping excitatory synapses. This hypothesis is currently
      being tested using electrophysiological methods and the introduction of optically
      tagged glutamate transporter proteins. In the brain, synaptic signals are
      terminated mainly by neurotransmitter transporters. Families of genes encoding
      transporters for the major neurotransmitters (dopamine, GABA, glutamate, glycine,
      norepinephrine and 5-HT) have been identified. Although transporters serve as
      targets for important classes of therapeutic drugs (e.g. selective serotonin
      reuptake inhibitors) and drugs of abuse (amphetamine, cocaine), little is known
      about how they operate at a molecular level or contribute to synaptic
      transmission.

PMID- 15186921
TI  - Evidence for bulk flow of brain interstitial fluid: significance for physiology
      and pathology.
AB  - This review surveys evidence for the flow of brain interstitial fluid (ISF) via
      preferential pathways through the brain, and its relation to cerebrospinal fluid
      (CSF). Studies over >100 years have raised several controversial points, not all
      of them resolved. Recent studies have usefully combined a histological and a
      mathematical approach. Taken together the evidence indicates an ISF bulk flow
      rate of 0.1-0.3 microl min(-1) g(-1) in rat brain along preferential pathways
      especially perivascular spaces and axon tracts. The main source of this fluid is
      likely to be the brain capillary endothelium, which has the necessary ion
      transporters, channels and water permeability to generate fluid at a low rate,
      c1/100th of the rate per square centimeter of CSF secretion across choroid plexus
      epithelium. There is also evidence that a proportion of CSF may recycle from the
      subarachnoid space into arterial perivascular spaces on the ventral surface of
      the brain, and join the circulating ISF, draining back via venous perivascular
      spaces and axon tracts into CSF compartments, and out both through arachnoid
      granulations and along cranial nerves to the lymphatics of the neck. The bulk
      flow of ISF has implications for non-synaptic cell:cell communication (volume
      transmission); for drug delivery, distribution, and clearance; for brain ionic
      homeostasis and its disturbance in brain edema; for the immune function of the
      brain; for the clearance of beta-amyloid deposits; and for the migration of cells
      (malignant cells, stem cells).

PMID- 15186922
TI  - Characterization of central nervous system structures by magnetic resonance
      diffusion anisotropy.
AB  - Diffusion-weighted magnetic resonance imaging (MRI) provides information about
      tissue water diffusion. Diffusion anisotropy, which can be measured with
      diffusion tensor MRI, is a quantitative measure of the directional dependence of
      the diffusion restriction that is introduced by biological structures such as
      nerve fibers. Diffusion tensor MRI data was obtained in the brain, brain stem,
      and cervical spinal cord. For each region, scans were performed in four normal
      volunteers. Fractional anisotropy (FA), an index of diffusion anisotropy, was
      measured within regions of interest located in the corpus callosum, capsula
      interna, thalamus, caudate nucleus, putamen, brain cortex, pyramidal tract of the
      medulla, accessory olivary nucleus, dorsal olivary nucleus, inferior olivary
      nucleus, spinal white and gray matter. The highest FA value was measured in the
      corpus callosum (81 +/- 3%). The values of the other areas decreased in the
      following order: pyramidal tract in the medulla (72 +/- 1%), spinal white matter
      (65 +/- 4%), capsula interna (62 +/- 3%), accessory olivary nucleus (36 +/- 2%),
      spinal gray matter (35 +/- 5%), dorsal olivary nucleus in the medulla (29 +/-
      2%), thalamus (28 +/- 2%), inferior olivary nucleus (15 +/- 2%), putamen (13 +/-
      2%), caudate nucleus (13 +/- 2%), and brain cortex (9 +/- 1%). Our results
      indicate that the underlying fiber architecture, fiber density, and uniformity of
      nerve fiber direction affect anisotropy values of the various structures.
      Characterization of various central nervous system structures with diffusion
      anisotropy is possible and may be useful to monitor degenerative diseases in the
      central nervous system.

PMID- 15186923
TI  - Use of magnetic resonance to measure molecular diffusion within the brain
      extracellular space.
AB  - Ion-selective microelectrode measurements of molecular diffusion have provided
      unique information about the structural characteristics of the extracellular
      compartment of brain tissue. Magnetic resonance (MR) techniques can also be used
      to perform diffusion measurements in living tissue in situ. In MR applications,
      the challenge to study a particular physiological compartment lies in achieving
      the appropriate specificity in the experimentally-observed MR signal, and many
      strategies have been used to provide measurements that reflect molecular
      diffusion within the extracellular space. This review describes how magnetic
      resonance and microelectrode diffusion measurements are performed, and
      applications using the MR technique are summarized. Comparisons of experimental
      results obtained from the two techniques indicate that their use in combination
      may further augment what is known about extracellular space structure.

PMID- 15186924
TI  - Nuclear magnetic resonance (NMR) measurement of the apparent diffusion
      coefficient (ADC) of tissue water and its relationship to cell volume changes in
      pathological states.
AB  - Diffusion-weighted nuclear magnetic resonance (NMR) imaging (DWI) is sensitive to
      the random translational motion of water molecules due to Brownian motion.
      Although the mechanism is still not completely understood, the cellular swelling
      that accompanies cell membrane depolarization results in a reduction in the net
      displacement of diffusing water molecules and thus a concomitant reduction in the
      apparent diffusion coefficient (ADC) of tissue water. Cerebral regions of reduced
      ADC appear hyperintense in a DWI and this technique has been used extensively to
      study acute stroke. In addition to cerebral ischemia, reductions in the ADC of
      cerebral water have been observed following cortical spreading depression,
      ischemic depolarizations (IDs), transient ischemic attack (TIA), status
      epilepticus, and hypoglycemia. Although the mechanism responsible for initiating
      membrane depolarization varies in each case, the ensuing cell volume changes
      follow a similar pattern. Water ADC values are also affected by the presence and
      orientation of barriers to translational motion (such as cell membranes and
      myelin fibers) and thus NMR measures of anisotropic diffusion are sensitive to
      more chronic pathological states where the integrity of these structures is
      modified by disease. Both theoretical prediction and experimental evidence
      suggest that the ADC of tissue water is related to the volume fraction of the
      interstitial space via the electrical conductivity of the tissue. The implication
      is that acute neurological disorders that exhibit electrical conductivity changes
      should also exhibit ADC changes that are detectable by DWI. A qualitative
      correlation between electrical conductivity and the ADC of water has been
      demonstrated in a number of animal model studies and the results indicate that
      reduced ADC values are associated with reductions in the extracellular volume
      fraction and increased extracellular tortuosity. The close relationship between
      ADC changes and cell volume changes in various pathological states suggests that
      NMR measurements are also sensitive to chemical communication between cells
      through the extracellular space (i.e., extrasynaptic or volume transmission, VT).

PMID- 15186925
TI  - Immunohistochemical study of the innervation of pulmonary vessels and smooth
      muscles in the respiratory tract of two frog species.
AB  - The innervation of the respiratory tract of amphibians is still poorly
      understood. Therefore, the respiratory tracts of the frogs Rana esculenta and
      Discoglossus pictus have been investigated in order to describe non-adrenergic
      non-cholinergic (NANC) and adrenergic innervation, and the localization of
      neuromediators that are possibly involved. Immunohistochemical staining of many
      bioactive substances was found in neuroepithelial cells of the buccopharynx,
      larynx, lung septa, nerves and neurons throughout the airway system. The findings
      indicate the occurrence of vasoactive intestinal peptide (VIP)-immunopositive
      nerve fibers in fibromuscular septa and the vasculature, nitrergic innervation of
      the large pulmonary veins showing a plexus of nNOS-immunopositive nerve fibers
      that also innervate the lung wall and the localization of neuronal nitric oxide
      synthase (nNOS) in neurons in the lung wall. In addition, laryngeal blood vessels
      and small arteries in the wall of septa that form capillary networks are supplied
      by enkephalin-immunopositive nerve terminals. We conclude that the airway system
      of the two frog species studied is innervated by a parasympathetic NANC system.
      Adrenergic innervation was also found that was immunostained for tyrosine
      hydroxylase. Adrenergic fibers were mainly present in muscles in septal edges,
      arteries present in septa and the wall of the lung. It is suggested that nNOS
      positive and leu-enkephalin-positive neurons mediate vasodilation via the release
      of NO, but the nature of the NANC innervation remains obscure. Despite the many
      pharmacological studies of the lungs of amphibians, the physiological role of
      pulmonary autonomic innervation remains poorly understood.

PMID- 15186926
TI  - Endocytosis of horse-spleen ferritin in the black tetra, Gymnocorymbus ternetzi
      (Characidae: Teleostei).
AB  - The capability and capacity of various tissues in black tetra Gymnocorymbus
      ternetzi (Boulenger), family Characidae, to take up horse-spleen ferritin from
      the blood stream are described. In the head kidney from specimens injected
      intraperitoneally with horse-spleen ferritin, numerous large cells were tightly
      packed by yellow-brown granules when the period of time between injection and
      sacrifice was over 2h. These cellular granules were tightly packed with Prussian
      blue precipitation in tissues treated with an acid ferrocyanide solution, i.e.,
      they displayed a deep blue colour. Similarly, smaller cells were also observed in
      the trunk kidney, gills and peripheral connective tissue of the pancreas and
      spleen at this stage after ferritin injection, but they were always few in
      number. Yellow-brown granules or Prussian blue granules were not found in
      endothelial cell layers of heart and liver. We suggest that practically all
      clearance of the blood from foreign and scavenger macromolecules is performed by
      macrophages in the head kidney of the black tetra, whereas the spleen seems to
      function mainly as a reservoir for red blood cells in this species.

PMID- 15186927
TI  - ACTH-producing cells of 21-day-old rat fetuses after maternal dexamethasone
      exposure.
AB  - Adrenocorticotrophic hormone (ACTH) is essential for developmental maturation of
      numerous organ systems during the fetal period and for adaptation to
      environmental challenges. Immunocytochemical and stereological methods were used
      in the present study to examine the effects of dexamethasone (Dx) administration
      during pregnancy on fetal rat pituitary ACTH-producing cells. Doses of 0.5, 0.5
      and 1.0 mg Dx/kg body weight/day were given to the dams on 3 consecutive days
      starting on day 16 of gestation. Morphometric analysis of the ACTH-producing
      cells of fetuses at 21 days of gestation revealed significant inhibition by 24%
      and 27%, respectively, of cell volume and cell number after maternal Dx
      administration, whereas the volume of cell nuclei and volume density of ACTH
      stained cells were insignificantly decreased. Immunocytochemical analysis showed
      reduced numbers, sizes and immunopositivity of ACTH cells of 21-day-old fetuses
      from Dx-treated dams as compared with the control group. Maternal Dx treatment in
      the period of intense differentiation of the hypothalamo-hypophyseal-adrenal
      system had an inhibitory effect on fetal function and proliferative activity of
      ACTH-producing cells at 21 days of gestation. Thus, inhibition of activity of
      fetal ACTH-producing cells may lead to adrenal suppression, modified activity of
      the hypothalamo-pituitary-adrenal axis and reduced body weight possibly causing
      lasting functional abnormalities.

PMID- 15186928
TI  - Time-dependent morphological alterations of cold-stored small bowel in Euro
      Collins and Ringer's lactate solutions.
AB  - Small bowel is one of the organs that can in principle be transplanted. Optimum
      preservation of the organ is essential for the success of transplantation. The
      aim of the present study is the investigation of time-related morphological
      changes of rat small bowel during preservation in hypothermic Euro-Collins (EC)
      and Ringer's lactate (RL) solution using light microscopy and transmission
      electron microscopy to evaluate the integrity of intercellular complexes of
      mucosal epithelium, one of the tissues of the intestine that is most susceptible
      to ischemia. Small bowels were perfused with either EC, RL solution or
      physiological saline solution and were placed in the different preservation
      solutions at 4 degrees C for 0, 3, 6 and 12 h. The results of our study suggest
      that both preservation solutions are suitable for short-term preservation of the
      small bowel although RL solution is more effective than EC solution. However, we
      conclude that further improvement of preservation solutions and/or techniques are
      needed to perform long-term preservation.

PMID- 15186929
TI  - Parvalbumin-like immunostaining in the cat inferior colliculus. Light and
      electron microscopic investigation.
AB  - The presence of the calcium-binding protein parvalbumin (PV) was studied in
      neuronal elements of the cat's inferior colliculus (IC) by means of light and
      electron microscopic immunocytochemistry. Immunostaining of PV was detected in
      all three main parts of the IC. Several subtypes of large neurons that differed
      in size and shape were immunostained, comprising approx. 15% of the total number
      of PV-containing neurons. Approx. half of the labeled neurons were medium sized.
      Two types of small neurons were found to be PV synthesizing, and comprised
      approx. 35% of the total PV-containing population. Ultrastructurally, many
      dendrites were heavily immunolabeled, and the reaction product was present in
      dendritic spines as well. Several types of synaptic boutons contained reaction
      product, and terminated on both labeled and unlabeled postsynaptic targets
      forming asymmetric and symmetric synapses. Approx. 70% of all PV-immunolabeled
      terminals contained round synaptic vesicles and formed asymmetric synapses. The
      majority of these boutons were of the "large round" type and corresponded to the
      terminals of cochlear nuclei. A lower number were of the "small round" type, and
      were probably corticotectal terminals. The remaining 30% of PV-containing
      terminals contained pleomorphic or elongated vesicles and formed symmetric
      synapses. These terminals corresponded with "P" and "F1" bouton types. Part of
      these boutons appeared to arise from nuclei of the lateral lemniscus and the
      superior olive, and a certain percentage likely represented endings of inhibitory
      interneurons.

PMID- 15186930
TI  - Immunolocalization of integrins and fibronectin in tubal pregnancy.
AB  - Integrins are a large family of cell adhesion molecules that serve as receptors
      involved in cell-to-cell and cell-to-matrix interactions during implantation. We
      studied immunohistochemical staining of integrins (alpha 3, alpha V, beta 1, and
      alpha 2 beta 1) and fibronectin in ectopic tubal pregnancy. Thirty fallopian tube
      samples with ectopic pregnancies and five normal tubal segments were obtained
      during ligation operations; the latter specimens served as controls in the study.
      Formalin-fixed paraffin-embedded tissue sections were stained with hematoxylin
      eosin or primary antibodies against alpha 3, beta 1, alpha V, and alpha 2 beta 1
      integrins and fibronectin, using the avidin-biotin-peroxidase method. A semi
      quantitative grading system was used to compare staining intensities. In the
      control samples, immunostaining of all integrins was found in a single layer of
      tall columnar epithelial cells, the lamina propria (Lp) and the muscular layer.
      Fibronectin staining was detected in the Lp and the muscular layer. Staining
      intensities of alpha 3 and beta 1 integrins and fibronectin were increased in the
      normal part of fallopian tubes with ectopic pregnancies. Staining of beta 1
      integrin was more intense than staining of alpha 3 and fibronectin, whereas there
      was no difference in alpha V and alpha 2 beta 1 integrin expression between
      normal tubal tissue in the ectopic pregnancy group and control tubal tissue. In
      the tubal pregnancy group at the site of implantation, staining intensity of
      alpha 3 and beta 1 integrins and fibronectin was strong in decidual cells,
      supporting tissue and placental villi, whereas alpha V and alpha 2 beta 1
      staining was mild. We concluded that integrins, especially beta 1 and alpha 3,
      and fibronectin may play a role in progression of tubal implantation. Although
      the role of integrins has not yet been clearly defined, these molecules may
      function as markers of normal and abnormal states of receptivity. We like to
      suggest that integrins and fibronectin, which are needed in utero implantation,
      are expressed in tubal tissues during ectopic pregnancy and are involved in
      ectopic implantation.

PMID- 15186931
TI  - Immunohistochemical analysis of estrogen receptor alpha, estrogen receptor beta
      and progesterone receptor in normal human endometrium.
AB  - The endometrium expresses estrogen (ER) and progesterone receptors (PR), which
      are involved in autocrine and paracrine regulation processes in response to
      estrogen and progesterone. The aim of the present study was to evaluate
      immunohistochemical distribution patterns of estrogen receptor alpha (ER alpha),
      estrogen receptor beta (ER beta) and PR in normal human endometrial tissue with
      the use of monoclonal antibodies. Human endometria were obtained from 17
      premenopausal patients undergoing surgery for non-malignant diseases and were
      classified to be in proliferative, early secretory and late secretory phases by
      histological and anamnestical means. Distribution patterns of the steroid
      receptors were evaluated using the IRS-score and the Mann-Whitney rank-sum test
      was used to compare the means. Correlation was assessed with the Spearman factor
      and linear regression analysis. ER alpha and PR expression decreased
      significantly (p<0.05) in glandular epithelium from the proliferative to the late
      secretory phase. ER beta expression showed a similar significant decrease
      (p<0.05), although staining intensity was lower than that of ER alpha. A
      significant correlation between expression of all three steroid receptors was
      observed (p<0.001). Distribution patterns of ER alpha, ER beta and PR in normal
      human endometrium showed a cyclic variation during the menstrual cycle. A
      significant correlation between expression of ER alpha, ER beta and PR was also
      demonstrated using regression analysis, indicating dependence of expression of
      these three steroid receptors. The present study shows the presence of steroid
      receptors in human endometrial epithelium, indicating that these cells respond to
      estrogen and progesterone and thus playing a significant role in endometrial
      physiology.

PMID- 15186932
TI  - Larvicidal and mosquitocidal extracts, a coumarin, isoflavonoids and pterocarpans
      from Neorautanenia mitis.
AB  - The present study aimed to evaluate extracts and compounds from tubers of
      Neorautanenia mitis against the malaria- and filariasis-transmitting mosquitoes,
      Anopheles gambiae and Culex quinquefaciatus, respectively. The extracts exhibited
      activity against larvae of A. gambiae and C. quinquefaciatus mosquitoes, and were
      also active against adult A. gambiae mosquitoes. The active extracts yielded the
      coumarin derivative pachyrrhizine, the isoflavonoids neotenone and neorautanone,
      and the pterocarpans neoduline, nepseudin and 4-methoxyneoduline as the active
      constituents. The activity of the crude extracts was at about the same magnitude
      as that of the constituent natural products, the latter's efficacy being almost
      at the same level for all the isolated compounds. The mosquitocidal activities of
      the pure compounds were comparable to those of the standard mosquitocides
      deltamethrin and alphacypermethrin. These findings corroborate traditional
      insecticidal application of N. mitis and the results can be extended for the
      control of mosquitoes especially at breeding sites.

PMID- 15186933
TI  - Multiplex nested PCR for Brazilian Alphavirus diagnosis.
AB  - A reverse-transcriptase PCR (RT-PCR) and a multiplex nested PCR were developed
      for the rapid detection and identification of 14 Brazilian alphaviruses. Using
      Alphavirus genus-specific primers in a RT-PCR, we obtained amplified products of
      434 bp. Species-specific primers were selected and simultaneously tested in a
      multiplex nested PCR. The nested PCR increased the test sensitivity 1000-fold and
      was capable of identifying Brazilian Alphavirus showing the expected bands with
      diagnostic sizes for Venezuelan (400 bp), Eastern (124 bp), and Western (208 bp)
      equine encephalitis, Aura (86 bp), and Mayaro (270 bp) viruses. This strategy for
      diagnosis is fast, sensitive, specific and it can be used as a reliable
      alternative for routine Brazilian Alphavirus diagnosis.

PMID- 15186934
TI  - The effect of single dose ivermectin alone or in combination with albendazole on
      Wuchereria bancrofti infection in primary school children in Tanzania.
AB  - Examination of 1829 children from 6 primary schools in coastal Tanzania revealed
      overall Wuchereria bancrofti microfilaria (mf) and circulating filarial antigen
      (CFA) prevalences of 17.3% and 43.7%, respectively. A randomized double-blind
      field trial with a single dose of ivermectin (150-200 microg/kg body weight)
      alone or in combination with albendazole (400 mg) was subsequently carried out
      among these children. Both treatment regimens resulted in a considerable decrease
      in mean mf intensities, with overall reductions being slightly but statistically
      significantly higher for the combination than for ivermectin alone. The
      difference in effect between the two treatment regimens was most pronounced at 6
      months, whereas it was minor at 12 months after treatment. The relative effect of
      treatment on mean CFA units was less pronounced than on mf. For both treatment
      regimens, reductions in CFA intensity appeared to be higher in children who were
      both CFA and mf positive before treatment, which may suggest that treatment
      mainly affected the survival and/or production of mf, rather than the survival of
      adult worms. New cases of infection appeared after treatment with both regimens
      among the pre-treatment mf and CFA negative children. Adverse reactions were few
      and mild in both groups, and mainly reported from pre-treatment mf and CFA
      positive children. The alarmingly high prevalence of W. bancrofti infection in
      primary school children highlights the importance of also determining the
      reversibility of already acquired early lesions, and the development of new
      measures and strategies to specifically protect children from later developing
      clinical disease.

PMID- 15186935
TI  - Evidence for the interruption of transmission of lymphatic filariasis among
      schoolchildren in Trinidad and Tobago.
AB  - This study was carried out to provide some evidence for the interruption of
      transmission of lymphatic filariasis (LF) among schoolchildren in Trinidad and
      Tobago. A cross-sectional survey for LF antigenaemia was performed among 63
      (13.2%) of the 479 primary schools located in eight administrative (and
      geographical) regions of Trinidad and Tobago. From these communities, 2597
      schoolchildren aged 6-12 years were sequentially selected for a survey of
      bancroftian antigenaemia. From each child, 100 microl (finger-prick) whole blood
      sample was applied to a Binax immunochromatographic card test (ICT), and read for
      the presence of antigenaemia. The ICT results showed a negative finding for LF
      antigenaemia and suggest that LF transmission has been interrupted in the survey
      areas.

PMID- 15186936
TI  - Taenia solium metacestode glycoproteins as diagnostic antigens for solitary
      cysticercus granuloma in Indian patients.
AB  - Taenia solium metacestode glycoproteins specific for lentil lectin were evaluated
      as diagnostic antigens for solitary cysticercus granulomas in Indian patients,
      using both an ELISA and immunoblotting. In 250 patients suspected to have
      neurocysticercosis and subjected to a computerized tomography scan or magnetic
      resonance imaging, the proteins were diagnostic by the ELISA in 86 patients (80%)
      and by immunoblots in 67 (62%) of 107 patients with solitary cysticerus
      granuloma. Among 100 non-cysticercosis patients, the ELISA and immunoblot were
      negative in 94% and 97% respectively. No cross-reactions were observed with sera
      from patients with central nervous system tuberculosis. Proteins of </=18 kDa
      were the most diagnostic for solitary cysticercus granuloma.

PMID- 15186937
TI  - Serum vitamin A levels in patients with ocular lesions attributable to non
      complicated malaria in the Brazilian Amazon region.
AB  - In order to evaluate the association between serum vitamin A levels and ocular
      lesions attributable to non-complicated malaria, 200 patients seen consecutively
      at the Malaria Outpatient Clinic of FUNASA, Manaus, Amazonas, Brazil were
      included in this study. Ophthalmologic examination consisted of indirect
      binocular ophthalmoscopy under medicamentous mydriasis, biomicroscopy with a
      portable slit lamp and measurement of central visual acuity. Vitamin A serum
      concentration was determined by HPLC, and deficiency was defined as serum values
      equal to or lower than 0.35 micromol/l. Serum vitamin A values between 0.36 and
      0.70 micromol/l were considered as marginal levels. Hypovitaminosis A (</=0.70
      micromol/l serum levels) was observed in 33% (66/200) of the patients. Ocular
      lesions were associated with serum levels </=0.35 micromol/l (P < 0.001). Vitamin
      A deficiency was more frequent in patients with high parasitaemia (P = 0.029) and
      their first episode of malaria (P = 0.016). None of the patients showed clinical
      or ophthalmologic signs attributable to hypovitaminosis A.

PMID- 15186938
TI  - Human otoacariasis: a retrospective study from an area of Sri Lanka.
AB  - Intra-aural ticks were present in 870 (15.2%) of 5714 patients who reported with
      ear-related complaints to the ear, nose and throat ward at Ratnapura Hospital,
      Sabaragamuwa Province, Sri Lanka, from January 2000 to December 2001. A
      retrospective study of 383 of these otoacariasis cases showed that the majority
      (70.8%) of surgically-removed ticks were nymphal Amblyomma integrum, together
      with nymphal and adult Rhipicephalus haemaphysaloides, R. sanguineus, Hyalomma
      brevipunctata, H. marginatum, and unidentified (damaged) ticks (collectively,
      29.2%). Tick infestations peaked during the period November-February. More female
      than male patients reported with otoacariasis, and more children (aged 0-10
      years) and adults (aged >/=21 years) than adolescents. There was no evidence of
      age-dependent differences in infestation among male and female patients. The tick
      infested cases were widespread, spanning 75 km on a north-south axis and 55 km on
      an east-west axis within Sabaragamuwa Province. The present report represents the
      largest episode of human otoacariasis recorded in the literature, and may be
      indicative of a wider, but little-reported, human tick problem in Sri Lanka.

PMID- 15186939
TI  - Adverse systemic reactions to treatment of onchocerciasis with ivermectin at
      normal and high doses given annually or three-monthly.
AB  - In Cameroon, a 3-year randomized, double-blind controlled trial was conducted to
      determine if ivermectin, given at 3-monthly intervals and/or at high doses (800
      microg/kg), had a greater effect on adult Onchocerca volvulus than standard
      annual doses of 150 microg/kg. Adverse reactions were recorded and analysed in a
      logistic regression model with random effects to assess the influence of the dose
      and rhythm of treatment on their occurrence. After the first dose, 3-monthly
      treatment was associated with a clearly reduced risk of reactions, especially
      oedematous swellings, pruritus and back-pain. Oedematous swellings and subjective
      ocular troubles were found to be associated with high doses of ivermectin. These
      results reinforce former parasitological conclusions that it would be desirable
      to evaluate the feasibility and effects on transmission of large-scale 3-monthly
      treatments with standard doses of ivermectin for onchocerciasis control. Owing to
      the unexpected ocular reactions, the use of high doses to counteract any future
      resistance of O. volvulus to ivermectin should be considered with caution.

PMID- 15186940
TI  - 3-Hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors (statins),
      atherosclerosis and coronary syndromes.

PMID- 15186941
TI  - Aberrant antibody responses to oxidized LDL and increased intimal thickening in
      apoE-/- mice exposed to cigarette smoke.
AB  - Cigarette smoking is associated with increased atherosclerosis and intimal
      thickening, and has immune-suppressive effects. The immune system modulates
      atherosclerosis and intimal thickening. We hypothesized that detrimental effects
      of cigarette smoke (CS) involves modulation of the immune response to oxidized
      low-density lipoprotein (oxLDL). ApoE-/- mice fed Western diet were exposed to CS
      starting at 20 weeks of age. Control mice were exposed to air. After 5 weeks of
      CS, mice were subjected to carotid arterial cuffing for 21 days. Intimal
      thickening was significantly increased in CS mice compared to control (0.050 +/-
      0.034 mm(2) versus 0.023 +/- 0.021 mm(2); P < 0.05). Spleen lymphocyte
      population, cytokine mRNA expression, and total IgM and IgG levels were similar.
      Anti-MDA oxLDL IgG was reduced by 40% (P < 0.05) in CS mice compared to control.
      Copper-oxidized LDL IgG antibodies remained unchanged but IgM increased in CS
      mice, associated with increased intimal thickening. Anti-phosphorylcholine (PC)
      IgM was also increased in the CS mice, associated with increased intimal
      thickening. Lymphocyte signaling molecule lymphotoxin beta (LTbeta) expression
      was significantly decreased in spleens of CS exposed mice. Our results suggest
      that immune modulation by CS characterized by aberrant antibody responses to
      oxLDL and reduced LTbeta mRNA expression is associated with increased intimal
      thickening after arterial cuffing.

PMID- 15186942
TI  - Iron-catalyzed lipid peroxidation in aortic cells in vitro: protective effect of
      extracellular magnesium.
AB  - Low serum Mg2+ has been associated with an increased incidence of cardiovascular
      pathology in human populations. We investigated the effect of extracellular Mg2+
      on Fe-catalyzed lipid peroxidation in rat aortic segments and in human aortic
      smooth muscle cells. Products of phospholipid oxidation [malonaldehyde (MDA) and
      4-hydroxyalkenals (4-HA)], loss of fatty acyl double bonds (by proton-NMR) and
      glutathione levels indicated that exogenous ferric ions were several-fold more
      effective than ferrous ions in causing lipid peroxidation. Increased peroxidation
      was detectable at <1.0 microM Fe3+. Exogenous ferric iron-ionophore, 8
      hydroxyquinoline, did not increase peroxidation by ferric ion, suggesting that Fe
      catalyzed lipid peroxidation occurred at the cell surface. As ionized serum
      [Mg2+](o) was lowered from the physiological (0.7-0.96 mM) into the
      pathophysiological range (0.3-0.5mM) in Fe3+-containing medium, MDA/4-HA levels
      increased two to three-fold, with a concomitant loss of fatty acyl double bonds
      and decreased extracellular glutathione. Conversely, MDA/4-HA decreased as
      ionized Mg2+ was increased, accompanied by a rise in extracellular glutathione.
      The results indicate that Mg2+ protects aortic cell plasma membranes from ferric
      iron-catalyzed lipid peroxidation and that this is a contributing factor in the
      protective action of ionized Mg2+ on the cardiovascular system.

PMID- 15186943
TI  - Inhibition of insulin signaling by oxidized low density lipoprotein. Protective
      effect of the antioxidant Vitamin E.
AB  - Oxidative stress is involved in several pathological conditions, including
      diabetes. Reactive oxygen species (ROS) have been demonstrated to act as second
      messengers for several hormones and cytokines, including insulin (INS). The
      effect of Cu(2+)-oxidized LDL (CuLDL) on INS-induced generation of ROS and on INS
      signaling was investigated on cultured human fibroblasts. Intracellular ROS
      generation was observed either in CuLDL- or in INS-treated cells. Moreover, CuLDL
      and INS had an additive effect on ROS formation in human fibroblasts. CuLDL by
      itself increased the phosphorylation of ERK without affecting the PKB/Akt
      phosphorylation. CuLDL also stimulated the DNA binding activities of the
      transcription factors AP1 and NFkappaB. However, CuLDL dose-dependently prevented
      the INS-signaling pathway, by inhibiting the INS-induced phosphorylation of the
      signaling kinases ERK and PKB/Akt and the INS-induced activation of the
      transcription factors AP1 and NFkappaB. Finally, the lipophilic antioxidant
      Vitamin E (Vit E) partially restored all the studied signaling events initiated
      by INS and impaired after pretreatment with CuLDL. These studies demonstrate that
      the oxidative stress generated by CuLDL has a negative effect on the INS
      signaling pathway, independently of the INS-induced generation of ROS. Thus,
      oxidized LDL might be involved not only in atherosclerosis, as it is commonly
      admitted, but also in the INS-resistance observed in type 2 diabetes mellitus.

PMID- 15186944
TI  - Modulations of shear stress-induced contractile responses and agonist-induced
      vasodilation in hypercholesterolemic rats.
AB  - We used mesenteric arterial beds from normal rats and beef tallow-fed rats
      (hypercholesterolemic model) to study the interaction between the effects of
      viscosity-induced shear stress and agonists mesenteric vasoreactivity. Mesenteric
      arterial beds were perfused under constant-flow conditions (5 ml/min) via a
      peristaltic pump using warm oxygenated modified Krebs-Henseleit solution
      containing either 4% BSA to increase viscosity or 300 microM L-arginine, a NO
      synthase substrate. Whether beds were perfused with BSA alone or L-arginine alone
      as pretreatment, the methoxamine-induced contractile responses were similar to
      those in normal beds. However, methoxamine-induced contractile responses were
      significantly reduced following pretreatment with L-arginine plus BSA. These
      reduced responses underwent significant recovery when either tyrphostin A23 (30
      microM, a tyrosine kinase inhibitor) or wortmannin (300 nM, a PI3K inhibitor) was
      present. The dose-response curve for methoxamine was shifted to the right and the
      maximum contractile response was reduced in mesenteric arterial beds from beef
      tallow-fed rats, but the modulation of this response induced by L-arginine plus
      BSA was preserved. In beef tallow-fed rats, the ACh-induced endothelium-dependent
      vasodilation was attenuated in both thoracic aortic strips and mesenteric
      arterial beds. These results suggest that in hypercholesterolemic rats, agonist
      induced endothelial function is impaired, while shear stress-induced responses
      (tyrosine kinase- and PI3K-mediated NO production) are preserved. These abnormal
      vascular responses may contribute to hypertension in beef tallow-fed
      hypercholesterolemic model rats.

PMID- 15186945
TI  - The antiatherogenic potential of oat phenolic compounds.
AB  - Avenanthramides are phenolic antioxidants, which are present in oats.
      Avenanthramides A, B, and C are the major constituents of the total soluble
      antioxidant phenolic compounds in oats. We tested the potential antiatherogenic
      activity of partially purified avenanthramides from oats by examining their
      effects on adhesion of monocytes to human aortic endothelial cell (HAEC)
      monolayers, expression of adhesion molecules, and production of proinflammatory
      cytokines and chemokines by HAEC. The oat avenanthramides mixture was prepared
      and partially purified by column chromatography. This avenanthramide-enriched
      mixture (AEM) had no toxicity to HAEC as tested up to 40 ng/ml. The pre
      incubation of HAEC with 4, 20, and 40ng/ml AEM for 24h significantly decreased
      adhesion of U937 monocytic cells to interleukin (IL)-1beta-stimulated HAEC in a
      concentration-dependent manner. Pre-incubation of HAEC with AEM at 20 and 40
      microg/ml, but not at 4 microg/ml, for 24h significantly suppressed IL-1beta
      stimulated expressions of intracellular adhesion molecule-1 (ICAM-1), vascular
      cell adhesion molecule-1 (VCAM-1), and E-selectin and the secretion of
      proinflammatory cytokines IL-6, chemokines IL-8 and monocyte chemoattractant
      protein (MCP)-1. These data provide evidence for the potential anti-inflammatory
      and antiatherogenic effects of antioxidant avenanthramides present in oats.

PMID- 15186946
TI  - Removal of heparan sulfate by heparinase treatment inhibits FGF-2-dependent
      smooth muscle cell proliferation in injured rat carotid arteries.
AB  - Smooth muscle cells (SMC) of the rat carotid arterial media proliferate and
      migrate in response to injury during the formation of a neointima. The
      interaction of fibroblast growth factor (FGF-2), which is released at the site of
      injury, with heparan sulfate proteoglycans (HSPGs) is necessary to induce
      signaling, which elicits an FGF-dependent mitogenic response by arterial smooth
      muscle cells, and also serves as a mechanism for storage of the growth factor
      within the extracellular matrix. However, whether these interactions are critical
      during neointimal formation has not been directly tested. In this study, a model
      of FGF-2-dependent medial SMC mitogenic response in balloon-injured rat carotid
      artery was used to test the effect of degradation of vessel wall heparan sulfate
      on subsequent SMC proliferation. Treatment of balloon-catheterized rat carotid
      arteries with chondroitin ABC lyase and/or heparin lyases eliminated heparan
      sulfates in the vessel wall, as determined by immunoperoxidase staining. In
      contrast, the distribution in the carotid vessel wall of the large core protein
      of perlecan, a major vessel wall HSPG that binds FGF-2, is not decreased. The
      effect of glycosaminoglycan digestion in situ on medial SMC proliferation in
      response to a bolus injection of FGF-2 after injury was determined by measuring
      the percentage of SMC nuclei that incorporated 5-bromo-2'-deoxyuridine (BrdU) 48
      h after injury. Enzymatic removal of heparan sulfate reduced BrdU incorporation
      into medial SMC by 60-70% (P < 0.001) at 48 h after injury. Moreover, pre
      incubation of FGF-2 with heparin prior to injection restored SMC replication to
      the levels present in injured vessels treated with buffer alone (P < 0.01). These
      experiments indicate that endogenous HSPGs are essential to promote FGF-2-driven
      medial SMC proliferation following injury, and that heparinase treatment can
      abrogate FGF-2-dependent responses in vivo.

PMID- 15186947
TI  - Irradiation of mechanically-injured human arterial endothelial cells leads to
      increased gene expression and secretion of inflammatory and growth promoting
      cytokines.
AB  - Radiation therapy is applied to inhibit neointima formation after percutaneous
      transluminal coronary angioplasty (PTCA). In this study, we evaluated the effect
      of irradiation on re-endothelialisation of circular denuded tracks made in post
      confluent cultures of arterial endothelial cells (ECs) and on cellular factors
      involved in this process. Image analysis and time-lapse microcinematography
      revealed cell migration into denuded areas starting 4h after injury. Fifty
      percent coverage was achieved at 14.8 +/- 2.0 h. Using competitive PCR and flow
      cytometry techniques, no significant changes in mRNA expression of interleukin
      1beta (IL-1beta), interleukin-8 (IL-8), basic fibroblast growth factor (bFGF or
      FGF-2), transforming growth factor-beta1 (TGF-beta1), platelet-derived growth
      factor A (PDGF-A), platelet-derived growth factor B (PDGF-B) and tissue factor
      (TF), and surface molecule expression of anti-intercellular adhesion molecule-1
      (ICAM-1), anti-vascular cell adhesion molecule-1 (VCAM-1), anti
      platelet/endothelial cell adhesion molecule-1 (PECAM-1), MHC-1, TF and Fas were
      observed. However, injury did significantly (P < 0.05) elevate the release of IL
      8 and FGF-2 protein in the cell culture supernatant, as assessed by ELISA.
      Radiation (15Gy) given immediately after injury did not affect the kinetics of re
      endothelialisation up to 48 h, in spite of the fact that no cell divisions were
      observed. Thereafter cell density decreased and cultures deteriorated. Compared
      to cultures exposed to injury alone, radiation induced significant (P < 0.05)
      increases in mRNA levels of IL-8 (1.35 +/- 0.10-fold increase at 4h), FGF-2 (1.62
      +/- 0.10-fold at 4h; 1.76 +/- 0.33-fold at 24h) and IL-1beta (2.76 +/- 0.40-fold
      at 24h), whereas mRNA levels of TGF-beta1, PDGF-A and PDGF-B increased about 1.2
      fold. IL-8 and FGF-2 protein concentrations in the media were higher than those
      observed in non-irradiated injured cell cultures; however, this difference was
      not significant. Radiation induced a 2.3 +/- 0.3-fold increase (P < 0.05) in Fas
      surface expression only. In conclusion, irradiation of mechanically-injured human
      EC leads to increased gene expression and protein secretion of inflammatory and
      growth promoting cytokines.

PMID- 15186948
TI  - Altered platelet reactivity in peripheral vascular disease complicated with
      elevated plasma homocysteine levels.
AB  - Elevated plasma concentrations of the sulphur-containing amino acid homocysteine
      (Hcy) is associated with increased risk of atherosclerosis and arterial
      thrombosis. The mechanism by which Hcy exerts these effects has yet to be fully
      elucidated, although a variety of possible mechanisms have been proposed,
      including endothelial dysfunction or haemostatic abnormalities. However, the
      influence of Hcy on platelets, cells central to the atherothrombotic process, has
      never been addressed directly in patient studies. Here, the influence of mild
      hyperhomocysteinaemia (hHcy) on platelet function was explored in patients with
      peripheral occlusive arterial disease as evidence by intermittent claudication.
      Claudicants (n = 39) were assigned to one of two subgroups depending on their
      plasma Hcy concentrations. hHcy claudicants had plasma Hcy concentrations of 18.9
      +/- 1.0 microM (n = 24), compared to 11.3 +/- 0.5 microM for normohomocysteinemic
      (nHcy) claudicants (n = 15) and 12.6 +/- 0.7 microM for age-matched controls
      (n=15). Platelet function was evaluated ex vivo in both groups and compared to
      age-matched controls. Platelet activation and sensitivity to nitric oxide
      mediated inhibition was assessed by platelet fibrinogen binding and P-selectin
      expression. At low concentrations of adenosine diphosphate (ADP; 0.1 microM) and
      thrombin (0.02 U/ml), platelets from hHcy claudicants were more reactive than
      those from age-matched controls, but not nHcy claudicants. Agonist-induced P
      selectin expression was significantly raised in hHcy claudicants compared to all
      other groups. Interestingly no differences were observed between nHcy claudicants
      and age-matched controls, indicating that claudication per se did not affect
      platelet function. Since platelet activity in vivo is determined by the exposure
      to both agonists and antagonists, we subsequently tested the sensitivity of
      platelets to inhibition by nitric oxide (NO), using the same platelet markers.
      Platelets from hHcy claudicants were significantly less sensitive to GSNO (1-100
      microM)-mediated inhibition than all other groups. GSNO (1microM) induced 42.6 +/
      10 and 39 +/- 11.5% inhibition of ADP-induced fibrinogen binding for the nHcy
      claudicants and age-matched controls, respectively. However, in hHcy claudicants
      only 16.4 +/- 9.7% inhibition was observed, significantly less than the other
      groups (P < 0.01). Again no differences between nHCy claudicants and controls
      were observed. These results suggest the presence of claudication alone does not
      influence platelet function but if complicated with mild hyperhomocysteinemia,
      the sensitivity to agonists is increased, and more importantly, their sensitivity
      to inhibition is greatly reduced. The overall effect would be an increased
      propensity for platelet activation. The presence of even mildly elevated plasma
      Hcy could dramatically increase thrombotic risk.

PMID- 15186949
TI  - Apolipoprotein e4 allele is predictor of coronary artery disease death in elderly
      patients with type 2 diabetes mellitus.
AB  - The presence of the apolipoprotein (Apo) e4 allele is reported to be associated
      with the increased risk of coronary artery disease (CAD), as well as the
      impairment of endothelium-dependent dilation in type 2 diabetes mellitus.
      Therefore, we hypothesized that the Apo e4 allele increases the death risk from
      coronary artery disease in type 2 diabetes. From January 1993 to December 1999,
      36 type 2 diabetic patients with e4/4 or e4/3, 62 with e3/3 and 33 with e2/2 or
      e3/2 genotypes were recruited. All subjects were unrelated, elderly, type 2
      diabetic patients with coronary artery disease, aged 60-84 years, with cardiac
      function at the Class I stage at time of enrollment. A follow-up study of 3-10
      years was undergone. The results are as follows: At baseline, serum total
      cholesterol and low density lipoprotein (LDL) cholesterol concentrations were
      higher in subjects with e4/3 or e4/4 than in subjects with e2/2 or e3/2 (P =
      0.026). Lipoprotein(a) concentration was lower in subjects with e2/2 or e3/2 than
      in subjects with e3/3 (P = 0.044) and e4/3 or e4/4 (P = 0.038). During the 3-10
      years follow-up period, a total of 39 patients who died from CAD was recorded in
      this sample. Compared with patients with e3/3 (P = 0.030) and patients with e2/2
      or e3/2 genotypes (P = 0.001), the mortality rate of CAD in patients with e4/3 or
      e4/4 genotypes was the highest (50%). Stepwise discriminant analysis revealed
      that in the diabetic population studied the Apo e4 allele was independently and
      significantly associated with CAD death (B = 0.64). However, the strength of the
      association decreased (B = 0.48) when total cholesterol, LDL-cholesterol and
      lipoprotein(a) were included in the model. Therefore, we concluded that Apo e4
      allele increases the risk of CAD death in elderly patients with type 2 diabetes
      mellitus.

PMID- 15186950
TI  - Statin-induced immunomodulatory effects on human T cells in vivo.
AB  - Statins are widely used for treatment of hypercholesterolemia. Recent
      experimental studies revealed that these drugs also exert anti-inflammatory
      effects. The aim of this study was to assess immunomodulatory effects of statins
      in humans in vivo. Twenty-seven healthy volunteers were analyzed for serum
      cytokines and acute phase proteins, HLA-DR and CD38 expression on T cells and
      superantigen-mediated T cell activation ex vivo before and after 14 days of
      statin treatment. First, simvastatin 40 mg was compared to atorvastatin 20 mg.
      Second, two different doses of simvastatin (20 and 40 mg) were tested.
      Atorvastatin treatment led to a significant down-regulation of HLA-DR and the
      CD38 activation marker on peripheral T cells, whereas simvastatin up-regulated
      both of these molecules. In contrast, superantigen-mediated T cell activation was
      inhibited by simvastatin and enhanced by atorvastatin. No significant effect of
      statin treatment on inflammatory serum markers was detected. Thus,
      immunomodulatory effects of statins on human T cells are first demonstrated in
      vivo and are differentially induced by two different statins: atorvastatin led to
      a major histocompatibility class II (MHC II) antigens down-regulation and may
      therefore be investigated for treatment of chronic transplant rejection;
      simvastatin inhibited superantigen-mediated T cell activation, which might
      explain reduced mortality of simvastatin-treated patients with staphylococcal
      bacteremia.

PMID- 15186951
TI  - Threonine for alanine substitution in the eotaxin (CCL11) gene and the risk of
      incident myocardial infarction.
AB  - Recent studies suggest that the chemokine eotaxin may participate in
      atherosclerosis. Threonine (T) for alanine (A) substitution at amino acid 23 in
      the eotaxin gene (CCL11) has been associated with risk of developing allergic
      inflammatory disorders. However, no genetic-epidemiological data are available on
      the risk of cardiovascular disease associated with this polymorphism. Using DNA
      samples collected at baseline in a prospective cohort of 14,916 initially healthy
      American men, we evaluated the A23T polymorphism among 523 individuals who
      subsequently developed myocardial infarction (MI) and among 2092 individuals who
      remained free of reported cardiovascular disease over a mean follow-up period of
      13.2 years. The T23 allele was significantly associated with risk of myocardial
      infarction (odds ratio (OR) in an age and smoking adjusted recessive model of
      inheritance, 1.86; 95% confidence interval (CI), 1.15-3.01; P = 0.012). This risk
      effect remained statistically significant in analyses further controlling for
      body mass index, history of hypertension, the presence of diabetes, and
      randomized treatment assignment (OR, 1.95; 95% CI, 1.19-3.18; P = 0.008). In this
      cohort, a T for A substitution at amino acid 23 in the eotaxin gene is associated
      with increased risk for incident myocardial infarction. If confirmed in other
      cohorts, these data support the emerging hypothesis that eotaxin participates in
      atherosclerosis.

PMID- 15186952
TI  - Association between white blood cell count and carotid arteriosclerosis in
      Japanese smokers.
AB  - Recent studies have shown the relationship between general inflammatory markers
      and ischemic heart and cerebrovascular diseases. Here we have investigated the
      potential association between the circulating white blood cell count and carotid
      arteriosclerosis in apparently healthy individuals. Between 1994 and 1998, 3455
      subjects who had undergone general health screening tests including carotid
      ultrasonography were enrolled in this study. The intertertile cutoff points for
      the white blood cell count were 5.1 x 10(3) and 6.4 x 10(3) microL(-1) in the
      male subjects and 4.6 x 10(3) and microL(-1) in the female subjects. The
      prevalence of carotid plaque in the first (lowest), the second, and the third
      tertiles was 19, 28, and 28% in the male subjects, respectively (P < 0.0001), and
      10, 15, and 14% in the female subjects, respectively (n.s.). The multivariate
      analysis showed that the male subjects in the second and third tertiles had
      increased risk for carotid plaque with odds ratios of 1.54 (95% CI 1.18-2.01) and
      1.47 (95% CI 1.11-1.95), respectively, compared to those in the first tertile.
      When male subjects were subdivided according to their smoking status, the
      association between white blood cell count and carotid plaque was significant in
      those who smoked, but not in those who had never smoked. These data suggested the
      possible association between the circulating white blood cell count and formation
      of carotid plaque in male smokers, but not in male never smokers or in females,
      in an apparently healthy Japanese population.

PMID- 15186953
TI  - Comparison of electrocardiogram findings and lifestyles between urbanized people
      and ger-living people in Ulaanbaatar, Mongolia.
AB  - In Ulaanbaatar, lifestyles differ between urbanized people (group A) and ger
      (tent)-living people (group B). Group A earn high annual incomes and live in
      houses or apartments. Group B (who had moved to Ulaanbaatar from nomadic areas)
      earn low incomes and live in narrow gers. In 2002, we investigated daily food
      intake, health status, and electrocardiogram (ECG) in these groups. In total, 256
      subjects (group A, 142; group B, 114) were enrolled. Group A ate meat,
      vegetables, and fruits high enough by a Western style. Group B consumed meat but
      ate only small amounts of vegetables and fruits. They took a lot of fat, however,
      the serum lipid levels of them were not so high. The fat source as energy was
      plant oil for cooking rather than meat. Several abnormal ECG findings including
      left ventricular hypertrophy (LVH) were found in 32 (22.5%) of group A and 50
      (43.9%) of group B (P < 0.001). LVH was also found more in group B than in group
      A. LVH in group A males was accompanied by high body weight (BW), hypertension,
      and high LDL-cholesterol, whereas LVH in group B males seemed to be related to an
      unbalanced diet, high salt intake, smoking, and some low socio-economic problems.
      In order to promote health condition, such risk factors should securely be
      eliminated from the lifestyles.

PMID- 15186954
TI  - Functional effects of NAD(P)H oxidase p22(phox) C242T mutation in human
      leukocytes and association with thrombotic cerebral infarction.
AB  - BACKGROUND: Previous study showed that polymorphism of the NAD(P)H oxidase
      p22(phox) gene is associated with atherosclerosis, although others could not
      confirm such association. We investigated the association between p22(phox) C242T
      polymorphism and thrombotic cerebral infarction and the role of this polymorphism
      on superoxide-production activity in human neutrophils and promyelocytic HL-60
      cells as a model system. METHODS: PCR-RFLP analysis revealed that genotype and
      allele frequencies of C242T polymorphism in 120 patients with thrombotic cerebral
      infarction and 177 control subjects. The superoxide-production activity in
      neutrophils was determined by cytochrome c reduction assay. To clarify the role
      of p22(phox) C242T polymorphism on NAD(P)H oxidase activity, we used transgenic
      HL-60 cells transfected with expression plasmids carrying p22(phox) cDNAs with or
      without C242T polymorphism. RESULTS: Genotype and allele frequencies of C242T
      polymorphism in patients and control subjects were not significantly different.
      The superoxide-production activity in neutrophils with T allele was higher than
      in neutrophils without T allele. Moreover, expression analysis showed that
      superoxide-production activity in p22(phox) C242T-expressing HL-60 cells were
      significantly higher than in p22(phox)-expressing HL-60 cells. CONCLUSIONS: We
      conclude that C242T of p22(phox) gene is not involved in thrombotic cerebral
      infarction but more likely in increased NAD(P)H oxidase activity in phagocytes.

PMID- 15186955
TI  - Different effects of red wine and gin consumption on inflammatory biomarkers of
      atherosclerosis: a prospective randomized crossover trial. Effects of wine on
      inflammatory markers.
AB  - BACKGROUND: No intervention studies have explored the anti-inflammatory effects
      of different alcoholic beverages on markers of atherosclerosis. We embarked on a
      randomized, crossover, single-blinded trial to evaluate the effects of wine and
      gin on inflammatory biomarkers of atherosclerosis. METHODS AND RESULTS: Forty
      healthy men (mean age, 37.6 years) consumed 30 g ethanol per day as either wine
      or gin for 28 days. Before and after each intervention, we measured the
      expression of lymphocyte function-associated antigen 1 (LFA-1), Mac-1, very late
      activation antigen 4 (VLA-4), and monocyte chemoattractant protein (MCP-1) in
      monocytes, as well as the soluble vascular cell adhesion molecule-1 (VCAM-1),
      intercellular adhesion molecule-1 (ICAM-1), interleukin-1alpha (IL-1alpha), C
      reactive protein (hs-CRP) and fibrinogen. After either gin or wine consumption,
      plasma fibrinogen decreased by 5 and 9%, respectively, and cytokine IL-1alpha by
      23 and 21%. The expression of LFA-1 (-27%), Mac-1 (-27%), VLA-4 (-32%) and MCP-1
      (-46%) decreased significantly after wine, but not after gin. Wine reduced the
      serum concentrations of hs-CRP (-21%), VCAM-1 (-17%) and ICAM-1 (-9%).
      CONCLUSIONS: Both wine and gin showed anti-inflammatory effects by reducing
      plasma fibrinogen and IL-1alpha levels. However, wine had the additional effect
      of decreasing hs-CRP, as well as monocyte and endothelial adhesion molecules.

PMID- 15186956
TI  - Angiographic aspects of ruptured plaque in patients with acute myocardial
      infarction: correlation with clinical and laboratory variables.
AB  - In patients with acute myocardial infarction (AMI), little is known about the
      correlation between prognostic variables and aspects of ruptured plaque at the
      coronary angiography. Five hundred patients with acute myocardial infarction were
      studied in a consecutive and prospective manner; of these, 264 patients were
      excluded mainly because of the presence of an occluded culprit coronary artery.
      The remaining 236 patients were divided according to the presence (113, 52%) or
      absence (126, 48%) of angiographic aspects suggestive of ruptured plaque, and
      correlated with 49 clinical, electrocardiographic, in-hospital complications,
      procedures, and other angiographic prognostic variables. The variables that
      correlated significantly and independently with angiographic aspects of ruptured
      plaque were: presence of thrombi and higher degree of residual stenosis at the
      culprit coronary artery, as well as white ethnic group.

PMID- 15186957
TI  - Prevalence, risk factors and cardiovascular comorbidity of symptomatic peripheral
      arterial disease in Italy.
AB  - The epidemiology of peripheral arterial disease (PAD) has been studied almost
      exclusively in northern European and northern American populations. We report the
      first survey in Italy to describe the prevalence of symptomatic PAD and clinical
      correlates. From the lists of seven general practitioners, all subjects aged 40
      80 years (n = 4352) received a Rose Questionnaire (RQ). In those reporting pain
      in the leg while walking, which did not disappear while continuing to walk (n =
      760), Doppler examination was performed. PAD was defined by ankle/brachial < or =
      0.90, or reduced flow velocity. The prevalence of symptomatic PAD was 1.6% (2.4%
      in men, 0.9% in women). For each PAD patient, three controls matched for sex and
      age were randomly selected. At the multivariate analysis, smoking, diabetes and
      hypertension were significantly associated with PAD. A coexistent cardiovascular
      disease was found in 34% of patients and 11% of controls (P < 0.001). Only PAD
      was shown to be independently associated with a previous cardiovascular event.
      Although symptomatic, 45% of the patients were unaware of their condition. In
      conclusion, prevalence and cardiovascular comorbidity of symptomatic PAD in Italy
      seem to be lower than in other western countries. The finding that PAD was
      unrecognised in about 50% of affected individuals implies that a large proportion
      of PAD population is not given preventive therapy, so remaining at high
      cardiovascular risk. Thus, there is need to alert general practitioners to this
      topic.

PMID- 15186958
TI  - Circulating leptin is associated with oxidized LDL in postmenopausal women.
AB  - Recently, leptin has been suggested as a possible cause of atherosclerotic
      disease. In the present study, we have investigated in postmenopausal women (n =
      60; age: 52 +/- 13) the relationship between circulating levels of leptin,
      oxidized LDL (Ox-LDL) and other biochemical and anthropometric variables of
      atherosclerotic risk. In addition, we have evaluated soluble thrombomodulin (sTM)
      as a marker of endothelial damage. An additional study was conducted in a
      subgroup of obese subjects to determine the short-term effects of weight loss on
      selected variables. Ox-LDL showed a positive correlation with leptin circulating
      levels (r = 0.65, P < 0.0001). A significant association was also found between
      Ox-LDL and body mass index (r = 0.69, P < 0.0001), waist-to-hip ratio (r = 0.50,
      P < 0.0001), insulin levels (r = 0.65, P < 0.0001), HOMA index (r = 0.55, p <
      0.0001) and sTM (r = 0.74, P < 0.0001) levels. After multivariate regression
      analysis leptin was still related to Ox-LDL levels (P = 0.007). In obese women
      who completed the program of weight reduction, leptin changes persisted as a
      significant predictor of plasma changes in Ox-LDL levels. These findings
      suggested a novel link between leptin and Ox-LDL, possibly involved in
      atherosclerotic disease.

PMID- 15186959
TI  - Effects of heparin-mediated extracorporeal low-density lipoprotein precipitation
      beyond lowering proatherogenic lipoproteins--reduction of circulating
      proinflammatory and procoagulatory markers.
AB  - In addition to hypercholesterolemia, proinflammatory and prothrombotic markers
      have been suggested to play an important role in atherogenesis. We examined
      whether heparin-mediated extracorporeal low-density lipoprotein precipitation
      (HELP) therapy modulates the circulating levels of proinflammatory and
      prothrombotic markers. Twenty-two coronary heart disease (CHD) patients
      undergoing regular HELP-apheresis (18 males, 4 females, mean age 57.3 +/- 10.9
      years) were enrolled in this study. A single HELP therapy treatment significantly
      decreased the circulating levels of high sensitivity C-reactive protein (hs-CRP),
      soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin,
      lipopolysaccharide binding protein (LBP), endothelin-1 (ET-1), and monocyte
      chemoattractant protein-1 (MCP-1) on average by 67, 37, 24, 27, 24, and 15%,
      respectively. Prothrombotic factors including fibrinogen, tissue factor (TF),
      soluble CD40 ligand (sCD40L), and homocysteine were decreased by 66, 27, 16, and
      22%, respectively. In accordance with previous studies HELP therapy reduced total
      cholesterol, low density lipoprotein (LDL) cholesterol, and Lp(a) mass by 50, 61,
      and 62%, respectively. Our data suggest that simultaneous reduction of
      proinflammatory and prothrombotic factors together with atherogenic lipoproteins
      by HELP-apheresis may contribute to improvement of endothelial dysfunction and
      thereby inhibit progression of atherosclerotic lesions and stabilize the existing
      plaque.

PMID- 15186960
TI  - Multiple complex stenoses, high neutrophil count and C-reactive protein levels in
      patients with chronic stable angina.
AB  - Inflammation plays an important role in atherosclerosis and the genesis of acute
      coronary syndromes, i.e., atheromatous plaque disruption. Neutrophil count and C
      reactive protein (CRP) levels are markers of ongoing inflammation and predictors
      of cardiovascular risk. We sought to assess whether these inflammatory markers
      are associated with the presence of multiple complex stenoses in patients with
      chronic stable angina. METHODS AND RESULTS: We assessed 150 patients with chronic
      stable angina, 121 with significant coronary artery stenosis (> or =50% diameter
      reduction) and 29 without. CRP levels and neutrophil count were assessed at study
      entry. Stenoses were classified as "complex" (irregular or scalloped borders,
      ulceration or filling defects) or "smooth" (absence of complex features). Eighty
      eight percent of the complex lesions were of type C according to AHA/ACC
      classification whereas the rest were type B. Patients with > or =3 complex
      lesions were considered to have multiple complex stenoses. Extent of coronary
      artery disease was assessed using a validated score. Baseline neutrophil count
      (4.39 x 10(9) L (-1) +/- 28 versus 3.82 x 10(9) L (-1) +/- 0.77; P = 0.004) and
      CRP levels (2.15 mg/L (4.6-1) versus 0.39 mg/L (0.69-0.23); P < 0.0001) were
      higher in patients with significant stenoses compared to patients without. No
      association was found between disease extent and CRP levels or neutrophil count.
      Neutrophil count, however (but not CRP) correlated with stenosis complexity (r =
      0.28; P = 0.002 ) and was also an independent predictor of the presence of
      multiple complex stenoses (OR: 4.05; CI 95% (1.9-10.4); P = 0.038). CONCLUSIONS:
      CRP levels and neutrophil count are higher in angina patients with coronary
      stenoses compared to those without. Neutrophil count, but not CRP levels,
      correlates with angiographic stenosis complexity.

PMID- 15186961
TI  - Population-based study of SR-BI genetic variation and lipid profile.
AB  - The variability of the Class B Type I Scavenger Receptor (SR-BI) gene in human
      populations and the relation of its variants to blood lipids was investigated in
      a random sample of 1756 untreated adult residents of Geneva, Switzerland, during
      1999-2000. A three-step study approach yielded the following results: (1)
      resequencing the gene's exons and flanking regions in 95 subjects identified four
      common single nucleotide polymorphisms (SNPs with rare allele frequency >3%); (2)
      association study of the four common SNPs in subjects with extreme HDL
      cholesterol (HDL-C) and LDL-C phenotypes (186 "atherogenic cases" and 185 "non
      atherogenic controls") showed that the synonymous exon 8 C-T (allelic frequency
      48%) polymorphism, A350A, was associated with atheroprotection in men (odds
      ratios (OR) = 0.36, 95% confidence intervals (CI) = 0.15-0.90, P < 0.03), but not
      in women (2.09, 0.79-5.49, P = 0.14); and (3) population clinical effects of
      A350A genotypes assessed in all 1756 subjects, showed that the case-control study
      findings reflected a protective HDL-C effect in men (CC: 1.17 mmol/L, CT: 1.22
      mmol/L, and TT: 1.24 mmol/L, trend P = 0.0062) and a deleterious LDL-C effect in
      women (CC: 3.58 mmol/L, CT: 3.72 mmol/L, and TT: 3.79 mmol/L, trend P = 0.014).
      The allelic frequencies of the common SR-BI variants appear to be very similar in
      European and North American populations. The HDL-C effect increased with age. SR
      BI A350A appears to have gender-specific and age-related effects on cholesterol
      transport lipoproteins.

PMID- 15186962
TI  - The increase in cholesterol with menopause is associated with the apolipoprotein
      E genotype. A population-based longitudinal study.
AB  - During menopause, a sharp increase in cholesterol concentration occurs with an
      unexplained wide variation in change. Possibly, this is attributable to genetic
      variation. The authors prospectively studied the effect of the apolipoprotein E
      (APOE) genotype on the change in cholesterol level with menopause among 1116
      Dutch women. Women with the APOE3E3 genotype were regarded as the reference
      category and changes were adjusted for age at baseline, years of follow-up, years
      since menopause, and body mass index. At baseline, the women were on average 50.4
      years. After 5.9 years of follow-up, the women were on average 4.3 years (S.D.
      1.5 years) postmenopausal. The mean increase in cholesterol with menopause in
      women with the APOE3E3 genotype was 0.67 mmol/L (95% CI, 0.61-0.72 mmol/L). In
      women with the APOE2E3 genotype the increase in cholesterol was 0.44 mmol/L (CI,
      0.32-0.56 mmol/L). The increase in cholesterol in women with the APOE3E4 genotype
      did not differ from the increase in women with the APOE3E3 genotype. These
      results show that the increase in cholesterol level with menopause is 30% lower
      in women with the APOE2E3 genotype when compared with women with the APOE3E3
      genotype, indicating that the APOE genotype contributes to the variation in
      cholesterol increase with menopause.

PMID- 15186963
TI  - Relation between XbA1 apolipoprotein B gene polymorphism and cardiovascular risk
      in a type 2 diabetic cohort.
AB  - AIM: To evaluate in a prospective study the association of XbA1 apolipoprotein B
      (apoB) gene polymorphism with lipid parameters and cardiovascular (CV) events in
      a type 2 diabetic cohort. METHODS AND RESULTS: A cohort of 212 type 2 diabetic
      patients, free of any cardiovascular complication, was studied. Cardiovascular
      events were registered for all the patients for 5 years. XbA1 apolipoprotein B
      gene polymorphism was analysed by PCR-RFLP method. A mild increase in HbA1c was
      found in X+X+ carriers (P = 0.014). Despite this lower glycemic control, there
      were no differences between genotype subgroups for lipid parameters except for
      apoB, significantly higher in X+X+ than in X-X- subjects. In univariate analysis,
      the cardiovascular events rate was higher in X-X- but did not reach statistical
      significance (P =0.07). In stepwise multivariate regression analysis,
      cardiovascular events risk was significantly higher in X- carriers (P = 0.014)
      and also in smokers, microalbuminuric and older patients. CONCLUSIONS: We report
      for the first time in a prospective study the association of XbA1 apolipoprotein
      B gene polymorphism and cardiovascular events in a diabetic population. The
      mechanism underlying the excess of cardiovascular risk in X- carriers, despite a
      better metabolic profile, is likely to involve a linkage disequilibrium between
      apolipoprotein B gene locus and another gene locus related to cardiovascular
      risk.

PMID- 15186964
TI  - Prevalence of symptomatic and asymptomatic peripheral arterial disease in primary
      care patients.

PMID- 15186966
TI  - The antioxidant effects of statins may extend beyond atherosclerosis: potential
      benefits for atrial fibrillation and heart failure.

PMID- 15186967
TI  - The planning of precision movements.
AB  - Two experiments are reported in which subjects were required to make rapid aiming
      movements to targets of various sizes. Probe reaction time (RT) procedures were
      used to investigate the preparation of the response to the target. It was
      proposed that if the precision of movement was planned in advance, this would be
      reflected by the lengthening of RTs to probes presented during the latency phase
      of the response. The more precise the movement (to smaller targets) the longer
      will be the delays to the probes. The results generally supported the prediction
      and the probe RTs were correlated with target size. There was also some evidence
      that the probe was lengthening during the movement and in the region of the
      target.

PMID- 15186968
TI  - Effect of task similarity on transfer performance.
AB  - Transfer of training was studied using a discrete tracking task which involved
      aiming at targets on a moving paper strip. The effects of target speed, target
      size, and task demand, (number of targets aimed at in each trial) were examined
      separately in three experiments. In Experiment 1, a difference in stimulus input
      (i.e., target speed) produced large differences in task strategy (i.e., speed vs.
      accuracy bias). No significant transfer was found. A difference in target size
      (Experiment 2) involves a change in stimulus input, but this did not result in
      large strategy differences. Significant transfer was found when transferring from
      large to small targets. In Experiment 3, a variation in task demand produced
      different task strategies without a change in stimulus input. Significant
      transfer was found in all groups. The results were discussed in terms of
      similarity in perceptual elements and task strategy between transfer and training
      tasks. Greater similarity overall led to greater transfer.

PMID- 15186969
TI  - Recall and recognition processes in motor memory: effects of feedback and
      knowledge of results delay.
AB  - In linear movement tasks of 200 msec (Experiment 1 -ballistic movement) and 500
      msec (Experiment 2 - nonballistic movement), motor recall strength was assessed
      by absolute, constant, and variable error; recognition strength was assessed by
      Z'-transformed actual-estimate correlations and absolute actual-estimate
      difference scores. Contrary to predictions, neither increased KR delay (45 vs. 5
      sec) nor limited visual-auditory-tactile feedback caused decrements in
      recognition processes over KR-training or KR-withdrawal trial blocks for the 200
      msec task. In the 500-msec task, the independent variables impaired recognition
      through training and transfer trials but impaired recall only in the training
      trials. Results generally did not support the hypothesized independence between
      recall and recognition processes. Several methodological issues related to
      recall, and recognition research were discussed.

PMID- 15186970
TI  - Perception of movement patterns: tracking of movement.
AB  - The tracking of complex two-dimensional movement patterns was studied. Subjects
      were blindfolded, and their right hand moved around stencil patterns in the
      midsagittal plane, while the left hand concurrently reproduced the right-hand
      movement. The accuracy with which the left hand shadowed the criterion movements
      of the right hand was measured in shape and size. Right-hand movements were
      active or passive. Present tracking performance was contrasted with errors in
      recall reported by Bairstow and Laszlo (1978). Results showed that tracking
      performance was accurate. Active and passive criterion movements were tracked
      differently. Tracking was clearly superior to recall performance.

PMID- 15186971
TI  - Movement time and velocity as determinants of movement timing accuracy.
AB  - Three experiments investigated the effect of movement time (MT) and movement
      velocity on the accuracy and initiation of linear timing movements. MTs of 100,
      200, 500, 600, and 1000 msec were examined over various distances; timing
      accuracy decreased with longer MTs and slower average velocities. The velocity
      effect was independent of MT and occurred when the velocities were above and
      below about 15 cm/sec. Self-paced initiation times to movement increased directly
      with MT and inversely as a function of movement velocity. The latency data
      complement the MT findings in suggesting that average velocity is a key parameter
      in the initiation and control of discrete timing movements and, that there is
      some lower velocity below which movement control breaks down.

PMID- 15186972
TI  - Psychomotor reminiscence as a function of sex and length of rest period.
AB  - Sex differences in psychomotor reminiscence were examined as a function of the
      length of the rest period. Five groups of Caucasian subjects, each group
      consisting of 12 males and 12 females, practiced continuously for 3 min on a
      mirror-tracking task, then rested for 0,1, 2, 4, or 8 min before resuming
      continuous practice. Reminiscence in both sexes increased as negatively
      accelerated functions of the amount of rest. The asymptotic level of reminiscence
      was higher for females than for males, but the quadratic slopes of the two
      functions were essentially alike. Analyses of prerest trial gains supported a
      conclusion that females reminisced more because they accumulated more reactive
      inhibition prior to rest.

PMID- 15186973
TI  - Schema: the variability of practice hypothesis.
AB  - An experiment is presented which tested the variability of practice hypothesis of
      Schmidt's (1975) schema theory. Children served as subjects and a complex motor
      task was used. The results supported the variability of practice hypothesis in
      that the group that had more variable practice did perform better on the average
      on a novel variation of the task than did the group with less variable practice.
      There was no support for the suggestion that variability of practice would
      increase the rate of improvement on the novel variation. The results are
      discussed in relation to the differential importance of the four subcomponents of
      the schema in its development.

PMID- 15186974
TI  - Sequential predictability effects on initiation time and movement time for adults
      and children.
AB  - First-grade children and adults performed a two-choice initiation-time/ movement
      time task in which signals were (a) more likely to repeat than alternate, (b)
      more likely to alternate than repeat or (c) equally likely to alternate or
      repeat. Sequential predictability influenced initiation time but not movement
      time for adults and for children. These results do not support the suggestion
      (Wickens, 1974) that sequential predictability affects initiation time and
      movement time for children but only initiation time for adults. Adults and first
      graders did differ in their response to repeated events. Adults averaged faster
      initiation time for alternated than repeated responses and children averaged
      faster initiation time for repeated than alternated responses.

PMID- 15186975
TI  - Warm- and fatigue in skill acquisition and performance.
AB  - Two experiments examined the effects of preliminary exercise on performance and
      learning of the Fitts' reciprocal tapping task. In the first experiment
      preliminary exercise was performed with either the preferred or nonpreferred arm.
      The tapping task was completed with the preferred by both groups. Low levels of
      preliminary exercise resulted in heightened performance for both groups, but
      higher levels resulted in a decrement for the group using the preferred arm. An
      arousal-plus-fatigue hypothesis can explain the results. A subsequent post-test
      without preliminary exercise showed no difference between the groups, indicating
      an effect on performance and not learning. In the second experiment preliminary
      exercise was provided by treadmill running to exhaustion. Again, a facilitatory
      effect of exercise was demonstrated on tapping performance even after exhaustive
      levels of running.

PMID- 15186976
TI  - The effect of movement amplitude and target diameter on reaction time: comments
      on Siegel (1977).
AB  - Siegel's (1977) interpretation that his reaction time results were solely a
      function of response factors (movement amplitude and target diameter) was
      discussed and criticized. It was argued that Siegel's interpretation was
      inappropriate because stimulus factors (eccentric and visual angle) and response
      factors were confounded. It was also argued that the surprising U-shaped relation
      between reaction time and movement amplitude was probably the result of the
      confounding between stimulus and response factors.

PMID- 15186977
TI  - The effects of competition and social reinforcement upon perceptual motor
      performance.
AB  - Junior high school boys (n=180) performed 40 trials on the ball roll-up task in
      order to determine whether competition, initial ability level, and social
      reinforcement interact to influence performance. A 3 x 2 x 3 x 8 factorial
      design, with repeated measures on the last factor (initial ability level x
      competition x social reinforcement x blocks of trials) was used. The analysis of
      the data demonstrated that: (a) competition, initial ability level, and social
      reinforcement factors did not interact with one another; (b) social reinforcement
      (reproof) facilitated performance, while competition had no effect; and (c) the
      competition group had a greater tonic heart rate (increase from basal) than the
      noncompetitive group. Although it was not entirely clear why changes in the
      performance of the experimental groups did not accompany the changes in the
      groups' tonic heart rate, it was concluded that competition was an incentive.

PMID- 15186978
TI  - Motor performance under three levels of trait anxiety and stress.
AB  - In general, the interactive effects of trait anxiety and stress on motor
      performance have been neglected in assessing the viability of the inverted-U
      hypothesis. The present investigation tested the inverted-U hypothesis using
      three levels of trait anxiety and psychological stress. Performance results
      produced an inverted-U curve for the three levels of stress, with subjects in the
      moderate-stress condition displaying the highest performance. In addition, a
      significant trait anxiety x stress interaction indicated that high trait-anxious
      subjects performed best in the low-stress condition, while low trait-anxious
      subjects performed best in the high-stressed condition. The discussion concerns
      theories attempting to explain the relationship between anxiety and motor
      performance.

PMID- 15186979
TI  - Effects of fatigue and laterality on fractionated reaction time.
AB  - Surface EMG enabled fractionation of a simple hand grip total reaction time into
      peripheral and central processing components (motor time and premotor time
      respectively). Changes in reaction time components were investigated in 12 female
      intercollegiate swimmers (bilateral athletes) and 12 female intercollegiate
      tennis players (unilateral athletes) following a 48% strength decrement induced
      by serial maximal voluntary isometric contractions (5 sec in duration). Despite
      significantly greater strength in the dominant arm than in the nondominant arm,
      there was no difference in fatigue effects between arms. Fatigue increased the
      premotor component of reaction time significantly, and indirectly the total
      reaction time, but the motor time remained essentially constant regardless of the
      type of previous athletic training. This indicated that fatigue impaired central
      nervous system or myoneural-junction operations rather than the intramuscular
      ability to initiate force.

PMID- 15186980
TI  - Attention to visual feedback in motor learning.
AB  - Visual guidance and movement to a stop were used to train subjects to make a
      simple movement without experiencing error in practice. Movement to a stop led to
      test performance as accurate as that after training with KR, but visual guidance
      did not. If a continuous visual cue as well as a stop were present during
      practice, subjects also performed less accurately, although they did not need to
      attend to the visual cue. All types of training were better than no training at
      all. Results are discussed in terms of the role of visual feedback in the
      development and assessment of programs for movement.

PMID- 15186981
TI  - A multi-systems theory of the structure and dynamics of motor functions.
AB  - A theoretical analysis of the structure and dynamics of human motor functioning
      is presented from the perspective of a general theory of individuality. Within
      multifactor-systems theory, the structural units of the six systems of
      integrative personality (i.e., sensory, motor, cognitive, affect, style, and
      value) are hierarchical factor structures. Integrative functioning, both within
      and among systems, is described via the principles of general systems and
      information-processing theory. Our theoretical synthesis of the structure and
      dynamics of human motor functioning involves conceptualizing the hierarchy of
      motor factors as: (a) the basic dimensions of individual differences in the motor
      domain, (b) classes of decomposable motor programs that specify the spatio
      temporal organization of behavior, and (c) decomposable classes of processing
      components entailed by motor programs. Some of the implications for understanding
      the role of affect in motor functioning and some research suggestions were
      presented.

PMID- 15186982
TI  - The relationship between estimates of foreperiod duration and simple time
      reaction.
AB  - The relationship between estimates of foreperiod length and simple reaction time
      (RT) was examined using constant foreperiods. It was learned that neither the
      average accuracy nor the variability of the foreperiod estimates necessarily
      manifested themselves in appropriate simple RT change. Of secondary interest was
      the discovery that the average accuracy of foreperiod duration estimations
      differed greatly from that obtained for similar time lengths in a time-estimation
      task. Finally, an attempt was made to determine whether subjects actually
      utilized the directional knowledge of results inherent in the imperative stimulus
      to influence their foreperiod duration judgments. Unfortunately, the evidence
      obtained did not permit a definite answer regarding this possibility.

PMID- 15186983
TI  - Effects of variable fatigue levels on reaction-time components.
AB  - The effects of varying fatigue levels on reaction-time components were determined
      for 20 young, adult males. Each subject squeezed a hand-gripping device until
      strength decrements of 20, 40, or 60% were recorded; then the subject released
      his tension and then reacted to an auditory stimulus by gripping as quickly and
      forcefully as possible. Testing was also conducted under a nonfatigued state, and
      every subject was tested under all conditions. Total reaction time was divided
      into (a) a promoter component, the time from the stimulus to an alteration in the
      EMG of the finger flexors, and (b) a motor component, the time from the change in
      the EMG to the first sign of tension uptake. Analyses of variance failed to
      reveal any alterations in either reaction time or promoter time; however, there
      was a significant (p < .05) elongation of motor time when the muscle was
      fatigued, with motor time tending to increase linearly as fatigue increased. The
      results suggest that localized fatigue of this nature is primarily of peripheral
      (muscular) origin.

PMID- 15186984
TI  - Reaction time and probability on isolated terms.
AB  - The reaction-time probability effect on isolated trials was found to be
      asymmetrical in an experiment on 64 college students. There was a large drop in
      RT for a high-probability probe trial embedded in a block of low-probability
      trials, but a much smaller rise for a low-probability trial embedded in high
      probability trials. Thus, low- but not high-probability responses seem to be
      influenced by characteristics of the trial block. If the basis of the probability
      effect were the strategic placement of the criterion for response initiation,
      symmetrical results should have been obtained. A motivational account which
      accords with the present data is that the subject is ordinarily willing to
      prepare but is averse to doing so in some (not entirely specified) low
      probability circumstances.

PMID- 15186985
TI  - Proprioceptive feedback as a mediator in interlimb timing.
AB  - Prior findings regarded as evidence for proprioceptive feedback as a mediator in
      interlimb timing can also be interpreted as evidence for motor outflow because
      they came from research that had subjects make voluntary movements, and such
      movements allow for both feedback and outflow to operate. The present study was
      designed to resolve this controversy by determining if these findings could be
      replicated with passive movements which allow for feedback, but not outflow, to
      operate. The interlimb timing task studied was one where subjects made the timing
      response with their right hand while moving their left arm during the 1.5-sec
      interval to be timed. Three groups of 16 male college students performed 50
      trials of the right-hand response with knowledge of results, under one of three
      left-arm conditions: (a) passive movement, (b) voluntary movement, and (c) no
      movement. The results indicated that the findings were replicated with passive
      movements and this was interpreted as support for the involvement of
      proprioceptive feedback in interlimb timing.

PMID- 15186986
TI  - Motivation effects of attributions, expectancy, and achievement motivation during
      the learning of a novel motor task.
AB  - Several cognitive motivational theories including achievement motivation,
      attribution theory, and a test of expectancy for future success were linked to
      explain and predict psychomotor performance. Sixty high- and 60 low-need
      achieving male high school students were randomly placed into success and failure
      feedback conditions, and performance scores on a lever-positioning apparatus were
      assessed. Following each block of performance trials, fictitious feedback in the
      form of success and failure information was given, and then each subject rated
      attribution and expectancy questionnaires. Expectancies for future performance
      improved more following success than after failure and were generally predicted
      by attributions to stable elements. Although trends were present, performance
      scores were unaffected by these cognitive beliefs. However, a significant
      prediction of performance was obtained when stepwise multiple regression
      procedures were used with constant error as the criterion variable. The factors
      of expectancy and luck significantly predicted performance.

PMID- 15186987
TI  - Diving, adaptation, and Fitts law.
AB  - To assess Welford's dual controlling factor interpretation of Fitts' law, 20
      scuba divers performed a reciprocal tapping task. In an attempt to separate the
      two factors, the subjects were tested on land and underwater. This does not
      change the basic parameters of the task but does put the subjects under
      informational stress, in that underwater the movement is less ballistic in nature
      and should require the processing of more information (feedback) in each tap. On
      land, the contributions of movement amplitude and precision were approximately
      equal. However, the relative changes in contribution of these factors to movement
      time underwater suggests that these parameters do in fact represent separate
      controlling factors.

PMID- 15186988
TI  - The effect of invalid task parameters on short-term motor memory.
AB  - Two experiments tested the influence of information from an invalid movement
      parameter on short-term motor memory for a valid task parameter. Experiment 1
      showed that invalid task distance information affected location retention.
      Experiment 2 showed that invalid task location information affected task distance
      retention. These findings strengthen the evidence that the codes important for
      short-term motor retention are affected by a variety of factors within the
      movement context.

PMID- 15186989
TI  - Practice effects on fractionated response time related to age and activity level.
AB  - Two days of practice on simple and choice reaction (RT) and movement time (MT)
      were studied using 60 males placed into four groups based upon age and physical
      activity level. Practice effects upon simple and choice RTs were different for
      young and old groups. Only the two inactive groups improved on simple and choice
      MT, with greatest improvement occurring on simple MT. Old Actives had true-score
      variance than the Old Inactives, but much greater than the two young groups.
      Intraindividual variability was greater for the two older groups even in the
      absence of practice effects. Results support the claim that a life style or
      regular physical activity may lessen aging effects upon RT and MT as well as
      attenuating interindividual variability.

PMID- 15186990
TI  - The consistent acceleration of lifted objects: implications for kinesthetic
      illusions and the perception of weight.
AB  - In examining films of lifting movements in a study of the size-weight illusion
      (Davis & Roberts, 1976) a consistency was noted in the values obtained for the
      maximum accelerations of the objects lifted. While at first surprising, this
      finding can be embedded significantly in theories relating to kinesthetic
      illusions and the perception of weight and to theories on the control of general
      physical movement. This study was designed to confirm its existence. Twenty-four
      subjects were filmed lifting four objects differing in size, shape, substance,
      color, and weight. The film was analyzed frame-by-frame and the data were
      subjected to a two-way analysis of variance. Subjects, while differing from one
      another, were consistent in the maximum accelerations they applied to the three
      heaviest of the four objects. The accelerations of the lightest object differed
      significantly from the accelerations of the other three, but it seems likely that
      this was due to the experimental task itself.

PMID- 15186991
TI  - Handedness and hemispheric asymmetry in the control of movements.
AB  - This study investigated the influence of hemispheric specialization of function
      on the motor performance of the hands. Right-handed (n=7), ambidextral (n=21),
      and ambisinistral (n=12) subjects performed Fitts' (1954) reciprocal tapping task
      under two conditions with each hand. Conditions had the same index of difficulty
      but differed in movement precision. The left hand of right-handers was superior
      in the condition requiring the greatest amount of preprogramming. Conversely, the
      right hand was not superior in the condition having the greatest demand for
      feedback control. For ambidextrals, left-hand superiority in the relatively
      preprogrammed condition was also revealed. Ambisinistrals showed no significant
      difference between conditions with either hand. The results partially support the
      hypothesis that the motor performance of the hands mirrors the dominant
      processing mode of their contralateral hemisphere. Failure to find supportive
      evidence in ambisinistrals is consistent with the contention that they lack
      hemispheric specialization of function.

PMID- 15186992
TI  - The compression block technique: use and misuse in the study of motor skills.
AB  - Laszlo and Bairstow (1971b) claim that the compression block technique eliminates
      kinesthetic feedback prior to motor impairment and loss of motor control. They
      use evidence from studies employing the block to infer the nature of motor-skills
      processing. The present study, using two-point threshold, pro-prioceptive
      sensitivity, and hand and finger strength measures, yielded no evidence that
      afferent loss preceded loss of motor control.

PMID- 15186993
TI  - On the structure of motor recognition memory.
AB  - Two experiments determined the influence of the range and number of auditory
      sensory consequences, associated with a rapid timing task, on the development of
      motor recognition. Experiment 1 observed no beneficial effect upon subsequent
      movement-transfer performance from experience with the criterion-movement-time
      sound compared to experience with either a narrow or a wide range of sounds that
      bracketed the criterion sound (not including the criterion); 60 sound trials
      prior to transfer did not produce better transfer than did six sounds. The second
      experiment examined transfer outside of the range of previous listening
      experience by having subjects transfer to one of two possible criterion movement
      times after having received either constant, or one of two types of variable,
      listening experience. Transfer performance was influenced by the amount of
      variability in listening experience. These results were seen as support for a
      schematic representation for motor recognition memory (Schmidt, 1975)

PMID- 15186994
TI  - Social facilitation during the initial stage of motor learning: a re-examination
      of Martens' audience study.
AB  - This study partially replicated Martens' (1969a) social-facilitation study of
      motor behavior. His very robust performance findings provided impressive
      confirmation for Zajonc's hypothesis, and his arousal findings have since been
      used as evidence for a nonlearned-drive basis for social facilitation. The
      present study also extended Martens' investigation by examining the separate and
      combined effects of an audience and videotape camera. The effects due to the
      presence of the audience and camera were not additive; instead, the audience
      detrimentally affected subjects' performance consistency and the camera resulted
      in more trials with errors greater than 30 msec after the performance criteria
      had been attained. Martens' most robust findings for constant error were not
      replicated, nor were some of his physiological arousal findings. His pattern of
      constant error results over all trials is atypical of known learning strategies
      that subjects use to reduce error over successive trials. Overall, audience
      effects accounted for only a very small portion of the variance.

PMID- 15186995
TI  - Differential effect of sepsis on ability of leucine and IGF-I to stimulate muscle
      translation initiation.
AB  - Polymicrobial sepsis impairs skeletal muscle protein synthesis, which results
      from impairment in translation initiation under basal conditions. The purpose of
      the present study was to test the hypothesis that sepsis also impairs the
      anabolic response to amino acids, specifically leucine (Leu). Sepsis was induced
      by cecal ligation and puncture, and 24 h later, Leu or saline (Sal) was orally
      administered to septic and time-matched nonseptic rats. The gastrocnemius was
      removed 20 min later for assessment of protein synthesis and signaling components
      important in peptide-chain initiation. Oral Leu increased muscle protein
      synthesis in nonseptic rats. Leu was unable to increase protein synthesis in
      muscle from septic rats, and synthetic rates remained below those observed in
      nonseptic + Sal rats. In nonseptic + Leu rats, phosphorylation of eukaryotic
      initiation factor (eIF)4E-binding protein 1 (4E-BP1) in muscle was markedly
      increased compared with values from time-matched Sal-treated nonseptic rats. This
      change was associated with redistribution of eIF4E from the inactive eIF4E.4E-BP1
      to the active eIF4E.eIF4G complex. In septic rats, Leu-induced phosphorylation of
      4E-BP1 and changes in eIF4E distribution were completely abrogated. Sepsis also
      antagonized the Leu-induced increase in phosphorylation of S6 kinase 1 and
      ribosomal protein S6. Sepsis attenuated Leu-induced phosphorylation of mammalian
      target of rapamycin and eIF4G. The ability of sepsis to inhibit anabolic effects
      of Leu could not be attributed to differences in plasma concentrations of
      insulin, insulin-like growth factor I, or Leu between groups. In contrast, the
      ability of exogenous insulin-like growth factor I to stimulate the same signaling
      components pertaining to translation initiation was not impaired by sepsis.
      Hence, sepsis produces a relatively specific Leu resistance in skeletal muscle
      that impairs the ability of this amino acid to stimulate translation initiation
      and protein synthesis.

PMID- 15186996
TI  - Regulation of plasma long-chain fatty acid oxidation in relation to uptake in
      human skeletal muscle during exercise.
AB  - In the present study, we investigated possible sites of regulation of long-chain
      fatty acid (LCFA) oxidation in contracting human skeletal muscle. Leg plasma LCFA
      kinetics were determined in eight healthy men during bicycling (60 min, 65% peak
      oxygen uptake) with either high (H-FOX) or low (L-FOX) leg fat oxidation (H-FOX:
      1,098 +/- 140; L-FOX: 494 +/- 84 micromol FA/min, P < 0.001), which was achieved
      by manipulating preexercise muscle glycogen (H-FOX: 197 +/- 21; L-FOX: 504 +/- 25
      mmol/kg dry wt, P < 0.001). Several blood metabolites and hormones were kept
      nearly similar between trials by allocating a preexercise meal and infusing
      glucose intravenously during exercise. During exercise, leg plasma LCFA
      fractional extraction was identical between trials (H-FOX: 17.8 +/- 1.6; L-FOX:
      18.2 +/- 1.8%, not significant), suggesting similar LCFA transport capacity in
      muscle. On the contrary, leg plasma LCFA oxidation was 99% higher in H-FOX than
      in L-FOX (421 +/- 47 vs. 212 +/- 37 micromol/min, P < 0.001). Probably due to the
      slightly higher (P < 0.01) plasma LCFA concentration in H-FOX than in L-FOX, leg
      plasma LCFA uptake was nonsignificantly (P = 0.17) higher (25%) in H-FOX than in
      L-FOX, yet the fraction of plasma LCFA uptake oxidized was 61% higher (P < 0.05)
      in H-FOX than in L-FOX. Accordingly, the muscle content of several lipid-binding
      proteins did not differ significantly between trials, although fatty acid
      translocase/CD36 and caveolin-1 were elevated (P < 0.05) by the high-intensity
      exercise and dietary manipulation allocated on the day before the experimental
      trial. The present data suggest that, in contracting human skeletal muscle with
      different fat oxidation rates achieved by manipulating preexercise glycogen
      content, transsarcolemmal transport is not limiting plasma LCFA oxidation.
      Rather, the latter seems to be limited by intracellular regulatory mechanisms.

PMID- 15186997
TI  - Three-compartment model: critical evaluation based on neutron activation
      analysis.
AB  - There is renewed interest in Siri's classic three-compartment (3C) body
      composition model, requiring body volume (BV) and total body water (TBW)
      estimates, because dual-energy X-ray absorptiometry (DEXA) and in vivo neutron
      activation (IVNA) systems cannot accommodate subjects with severe obesity.
      However, the 3C model assumption of a constant ratio (alpha) of mineral (M) to
      total body protein (TBPro) and related residual mass density (D(RES)) based on
      cadaver analyses might not be valid across groups differing in sex, race, age,
      and weight. The aim of this study was to derive new 3C model coefficients in vivo
      and to compare these estimates to those derived by Siri. Healthy adults (n = 323)
      were evaluated with IVNA and DEXA and the measured components used to derive
      alpha and D(RES). For all subjects combined, values of alpha and D(RES) (means +/
      SD, 0.351 +/- 0.043; 1.565 +/- 0.023 kg/l) were similar to Siri's proposed
      values of 0.35 and 1.565 kg/l, respectively. However, alpha and D(RES) varied
      significantly as a function of sex, race, weight, and age. Expected errors in
      percent body fat arising by application of Siri's model were illustrated in a
      second group of 264 adults, including some whose size exceeded DEXA limits but
      whose BV and TBW had been measured by hydrodensitometry and (2)H(2)O dilution,
      respectively. Extrapolation of predictions by newly developed models to very high
      weights allows percent fat error estimation when Siri's model is applied in
      morbidly obese subjects. The present study results provide a critical evaluation
      of potential errors in the classic 3C model and present new formulas for use in
      selected populations.

PMID- 15186998
TI  - Endogenous ACTH concentration-dependent drive of pulsatile cortisol secretion in
      the human.
AB  - According to current regulatory concepts, pulsatile ACTH concentrations (CON)
      stimulate time-lagged cortisol secretion rates (SEC) via an implicit CON-SEC dose
      response relationship. The present analyses reconstruct nonlinear properties of
      this in vivo agonist-response interface noninvasively in order to investigate
      pulse-by-pulse coupling consistency and to obviate the need to infuse isotopes or
      exogenous effectors, which may disrupt pathway interactions. This approach
      required an ensemble strategy of 1) measuring ACTH and cortisol CON in plasma
      sampled every 10 min for 24 h in 32 healthy adults, and 2) estimating
      simultaneously a) variable-waveform ACTH and cortisol SEC bursts superimposed
      upon fixed basal SEC; b) biexponential kinetics of ACTH and cortisol
      disappearance; c) nonequilibrium exchange of cortisol among free and cortisol
      binding globulin (CBG)- and albumin-bound moieties; d) two SEC-burst shapes
      demarcated by a statistically defined day/night boundary; e) feedforward
      efficacy, potency, and sensitivity; and f) stochastic variability in feedforward
      measures over time. Thereby, we estimate 1) ACTH SEC (microg.l(-1).day(-1)) of
      0.27 +/- 0.04 basal and 0.87 +/- 0.07 pulsatile (means +/- SE); 2) cortisol SEC
      (micromol.l(-1).day(-1)) of 0.10 +/- 0.01 basal and 3.5 +/- 0.20 pulsatile; 3)
      free cortisol half-lives (min) of 1.8 +/- 0.20 (diffusion/advection) and 4.1 +/-
      0.30 (elimination) and a half-life of total cortisol of 49 +/- 2.4 and of ACTH of
      20 +/- 1.3; 4) ACTH potency (EC(50), ng/l) of 26 +/- 2.4, efficacy (nmol.l(
      1).min(-1)) 10 +/- 1.8, and sensitivity (slope units) 0.65 +/- 0.09; 5) night/day
      augmentation of ACTH and cortisol SEC-burst mass by 2.1- and 1.7-fold (median);
      6) abbreviation of the modal time to maximal ACTH and cortisol SEC rates by 4.4-
      and 4.3-fold, respectively, after a change point clock time of 0205 (median); 7)
      in vivo percentage distribution of cortisol as 6% free, 14% albumin bound, and
      80% CBG bound with an absolute free cortisol CON (nmol/l) 11.5 +/- 0.54; and 8)
      significant (mean CV) stochastic variability in feedforward efficacy (140%),
      potency (38%), and sensitivity (56%) within the succession of paired
      ACTH/cortisol pulses of any given subject. In conclusion, the present composite
      formulation illustrates a platform for dissecting mechanisms of in vivo
      regulation of effector-response properties noninvasively in the corticotropic
      axis of the uninfused individual.

PMID- 15186999
TI  - Tissue-specific gene expression of prolactin receptor in the acute-phase response
      induced by lipopolysaccharides.
AB  - Acute inflammation can elicit a defense reaction known as the acute-phase
      response (APR) that is crucial for reestablishing homeostasis in the host. The
      role for prolactin (PRL) as an immunomodulatory factor maintaining homeostasis
      under conditions of stress has been proposed; however, its function during the
      APR remains unclear. Previously, it was shown that proinflammatory cytokines
      characteristic of the APR (TNF-alpha, IL-1beta, and IFNgamma) induced the
      expression of the PRL receptor (PRLR) by pulmonary fibroblasts in vitro. Here, we
      investigated the in vivo expression of PRLR during lipopolysaccharide (LPS)
      induced APR in various tissues of the mouse. We show that PRLR mRNA and protein
      levels were downregulated in hepatic tissues after intraperitoneal LPS injection.
      Downregulation of PRLR in the liver was confirmed by immunohistochemistry. A
      suppressive effect on mRNA expression was also observed in prostate, seminal
      vesicle, kidney, heart, and lung tissues. However, PRLR mRNA levels were
      increased in the thymus, and no changes were observed in the spleen. The
      proportion of transcripts for the different receptor isoforms (long, S1, S2, and
      S3) in liver and thymus was not altered by LPS injection. These findings suggest
      a complex tissue-specific regulation of PRLR expression in the context of the
      APR.

PMID- 15187000
TI  - Selective activation of central NPY Y1 vs. Y5 receptor elicits hyperinsulinemia
      via distinct mechanisms.
AB  - Central administration of neuropeptide Y (NPY) stimulates hyperphagia and
      hyperinsulinemia. Recent evidence has suggested that the Y1 and Y5 receptor
      subtypes may both mediate NPY-stimulated feeding. The present study attempts to
      further characterize the role of central NPY receptor subtypes involved in
      hyperinsulinemia. NPY and peptide analogs of NPY that selectively activated the
      NPY Y1 or Y5 receptor subtype induced feeding and hyperinsulinemia in satiated
      Long Evans rats, whereas NPY analogs that selectively activated the NPY Y2 or Y4
      receptor subtype did not. To determine whether NPY-induced hyperinsulinemia is
      secondary to its hyperphagic effect, we compared the plasma insulin levels in the
      presence and absence of food after a 1-min central infusion of NPY and its
      analogs at 15, 60, and 120 min postinfusion. Our data suggest that selective
      activation of central NPY Y1 receptor subtype induced hyperinsulinemia
      independent of food ingestion, whereas the NPY Y5 receptor-induced
      hyperinsulinemia was dependent on food ingestion. Central administration of the
      selective Y1 receptor agonist D-Arg25 NPY eventually decreased plasma glucose
      levels 2 h postinfusion in Long Evans rats.

PMID- 15187001
TI  - Assessment of biomarkers of protein anabolism in skeletal muscle during the life
      span of the rat: sarcopenia despite elevated protein synthesis.
AB  - Loss of muscle strength is a principal factor in the development of physical
      frailty, a condition clinically associated with increased risk of bone fractures,
      impairments in the activities of daily living, and loss of independence in older
      humans. A primary determinant in the decline in muscle strength that occurs
      during aging is a loss of muscle mass, which could occur through a reduction in
      the rate of protein synthesis, an elevation in protein degradation, or a
      combination of both. In the present study, rates of protein synthesis and the
      relative expression and function of various biomarkers involved in the initiation
      of mRNA translation in skeletal muscle were examined at different times
      throughout the life span of the rat. It was found that between 1 and 6 mo of age,
      body weight increased fourfold. However, by 6 mo, gastrocnemius protein synthesis
      and RNA content per gram of muscle were lower than values observed in 1-mo-old
      rats. Moreover, the relative expression of two proteins involved in the binding
      of initiator methionyl-tRNA to the 40S ribosomal subunit, eukaryotic initiation
      factors (eIF)2 and eIF2B, as well as the 70-kDa ribosomal protein S6 kinase,
      S6K1, was lower at 6 mo compared with 1 mo of age. Muscle mass, protein
      synthesis, and the aforementioned biomarkers remained unchanged until
      approximately 21 mo. Between 21 and 24 mo of age, muscle mass decreased
      precipitously. Surprisingly, during this period protein synthesis, relative RNA
      content, eIF2B activity, relative eIF2 expression, and S6K1 phosphorylation all
      increased. The results are consistent with a model wherein protein synthesis is
      enhanced during aging in a futile attempt to maintain muscle mass.

PMID- 15187003
TI  - Differential regulation of VEGF by TGF-beta and hypoxia in rat proximal tubular
      cells.
AB  - VEGF expression by proximal tubular epithelial cells may play a critical role in
      maintaining peritubular capillary endothelium in renal disease. Two major
      processes involved in renal injury include hypoxia (from vasoconstriction or
      vascular injury) and transforming growth factor (TGF)-beta-dependent fibrosis,
      both of which are known to stimulate VEGF. Because the TGF-beta/Smad pathway is
      activated in hypoxia, we tested the hypothesis that the induction of VEGF in
      hypoxia could be partially dependent on TGF-beta. Rat proximal tubular (NRK52E)
      cells treated with TGF-beta under normoxic conditions secreted VEGF at 24 h, and
      this was significantly reduced by blocking Smad activation by overexpressing the
      inhibitory Smad7 or by blocking p38 and ERK1/2 MAP kinase activation or protein
      kinase C activation with specific inhibitors. With acute hypoxia, rat proximal
      tubular cells also express VEGF mRNA and protein as well as TGF-beta. However,
      the induction of VEGF occurs before synthesis of TGF-beta and is not blocked by
      either a TGF-beta antagonist, by Smad7 overexpression, or by blockage of ERK1/2,
      whereas induction is blocked by PKC inhibition or partially blocked by a p38
      inhibitor. Finally, the addition of TGF-beta with hypoxia results in
      significantly more VEGF expression than either stimulation alone. Thus TGF-beta
      and hypoxia act via additive/synergistic but distinct pathways to stimulate VEGF
      in proximal tubular cells, a finding that may be important in understanding how
      VEGF is stimulated in renal disease.

PMID- 15187002
TI  - Differential expression of collagen- and laminin-binding integrins mediates
      ureteric bud and inner medullary collecting duct cell tubulogenesis.
AB  - Inner medullary collecting ducts (IMCD) are terminally differentiated structures
      derived from the ureteric bud (UB). UB development is mediated by changes in the
      temporal and spatial expression of integrins and their respective ligands. We
      demonstrate both in vivo and in vitro that the UB expresses predominantly laminin
      receptors (alpha3beta1-, alpha6beta1-, and alpha6beta(4-integrins), whereas the
      IMCD expresses both collagen (alpha1beta1- and alpha2beta1-integrins) and laminin
      receptors. Cells derived from the IMCD, but not the UB, undergo tubulogenesis in
      collagen-I (CI) gels in an alpha1beta1- and alpha2beta1-dependent manner. UB
      cells transfected with the alpha2-integrin subunit undergo tubulogenesis in CI,
      suggesting that collagen receptors are required for branching morphogenesis in
      CI. In contrast, both UB and IMCD cells undergo tubulogenesis in CI/Matrigel
      gels. UB cells primarily utilize alpha3beta1- and alpha6-integrins, whereas IMCD
      cells mainly employ alpha1beta1 for this process. These results demonstrate a
      switch in integrin expression from primarily laminin receptors in the early UB to
      both collagen and laminin receptors in the mature IMCD, which has functional
      consequences for branching morphogenesis in three-dimensional cell culture
      models. This suggests that temporal and spatial changes in integrin expression
      could help organize the pattern of branching morphogenesis of the developing
      collecting system in vivo.

PMID- 15187004
TI  - Three-dimensional lateral and vertical relationships of inner medullary loops of
      Henle and collecting ducts.
AB  - Functional reconstruction of inner medullary thin limbs of Henle and collecting
      ducts (CDs) has enabled us to characterize distinctive three-dimensional vertical
      and lateral relationships between these segments. We previously reported that
      inner medullary descending thin limbs (DTLs) that form a bend at a distance
      greater than approximately 1 mm below the inner medullary base express detectable
      aquaporin (AQP) 1 only along the initial 40% of the segment before the bend,
      whereas ClC-K1 is expressed continuously along all ascending thin limbs (ATLs),
      beginning with the prebend segment. We have now reconstructed individual CDs that
      are grouped together in single clusters at the base of the inner medulla; CDs
      belonging to each separate cluster coalesce into a single CD in the deep papilla.
      DTLs are positioned predominantly at the periphery of each individual CD cluster
      at all levels of the inner medulla and are absent from within the cluster. In
      contrast, ATLs are distributed near uniformly among the CDs and DTLs at all
      levels of the inner medulla. A second population of inner medullary DTLs averages
      approximately 700 microm in length from base to bend and, as previously reported,
      expresses no detectable AQP1 and expresses ClC-K1 continuously beginning with the
      prebend segment. ATLs located within the interior of the CD clusters arise
      predominantly from these short AQP1-null inner medullary DTLs, suggesting there
      may be functional interdependence between IMCD1 segments and short-length inner
      medullary thin limbs exhibiting minimal water permeability along their descending
      segments. AQP1-expressing DTLs and CDs are apparently separated into two
      structurally distinct lateral compartments. A similar lateral compartmentation
      between the ATLs and CDs is not apparent. This architectural arrangement
      indicates that fluid and solutes may be preferentially transported transversely
      between multiple inner medullary compartments.

PMID- 15187005
TI  - The intrarenal renin-angiotensin system in autosomal dominant polycystic kidney
      disease.
AB  - Hypertension is a common complication of autosomal dominant polycystic kidney
      disease (ADPKD), often present before the onset of renal failure. A role for the
      renin-angiotensin system (RAS) has been proposed, but studies of systemic RAS
      have failed to show a correlation between plasma renin activity and blood
      pressure in ADPKD. Ectopic renin expression by cyst epithelium was first reported
      in 1992 (Torres VE, Donovan KA, Sicli G, Holley KE, Thibodeau ST, Carretero OA,
      Inagami T, McAteer JA, and Johnson CM. Kidney Int 42: 364-373, 1992). It is not
      known, however, whether other RAS components are also expressed by cysts in
      ADPKD. We show that, in addition to renin, angiotensinogen (AGT) is produced by
      some cysts and dilated tubules. Angiotensin-converting enzyme, ANG II type 1
      receptor, and ANG II peptide are also present within cysts and in many tubules;
      and some cyst fluids contain high ANG II concentrations. Additionally, cyst
      derived cells in culture continue to express the components of the RAS at both
      the protein and mRNA levels. We further show that renin is expressed primarily in
      cysts of distal tubule origin and in cyst-derived cells with distal tubule
      characteristics, whereas AGT is expressed primarily in cysts of proximal tubule
      origin and in cyst-derived cells with proximal tubule characteristics. Renin
      production by cyst-derived cells appears to be regulated by extracellular Na+
      concentration. Based on these observations, we propose a model of an
      autocrine/paracrine RAS in polycystic kidney disease, whereby overactivity of the
      intrarenal system results in sustained increases in intratubular ANG II
      concentrations.

PMID- 15187006
TI  - Proteomics: current techniques and potential applications to lung disease.
AB  - Proteomics aims to study the whole protein content of a biological sample in one
      set of experiments. Such an approach has the potential value to acquire an
      understanding of the complex responses of an organism to a stimulus. The large
      vascular and air space surface area of the lung expose it to a multitude of
      stimuli that can trigger a variety of responses by many different cell types.
      This complexity makes the lung a promising, but also challenging, target for
      proteomics. Important steps made in the last decade have increased the potential
      value of the results of proteomics studies for the clinical scientist. Advances
      in protein separation and staining techniques have improved protein
      identification to include the least abundant proteins. The evolution in mass
      spectrometry has led to the identification of a large part of the proteins of
      interest rather than just describing changes in patterns of protein spots.
      Protein profiling techniques allow the rapid comparison of complex samples and
      the direct investigation of tissue specimens. In addition, proteomics has been
      complemented by the analysis of posttranslational modifications and techniques
      for the quantitative comparison of different proteomes. These methodologies have
      made the application of proteomics on the study of specific diseases or
      biological processes under clinically relevant conditions possible. The quantity
      of data that is acquired with these new techniques places new challenges on data
      processing and analysis. This article provides a brief review of the most
      promising proteomics methods and some of their applications to pulmonary
      research.

PMID- 15187007
TI  - Continual emerging roles of HO-1: protection against airway inflammation.

PMID- 15187008
TI  - Does early treatment of exacerbation improve outcome in chronic obstructive
      pulmonary disease?

PMID- 15187009
TI  - Assessing the performance of a medical journal.

PMID- 15187010
TI  - Central airway obstruction.
AB  - Central airway obstruction is a problem facing all medical and surgical
      subspecialists caring for patients with chest diseases. The incidence of this
      disorder appears to be rising because of the epidemic of lung cancer; however,
      benign causes of central airway obstruction are being seen more frequently as
      well. The morbidity is significant and if left untreated, death from suffocation
      is a frequent outcome. Management of these patients is difficult, but therapeutic
      and diagnostic tools are now available that are beneficial to most patients and
      almost all airway obstruction can be relieved expeditiously. This review examines
      current approaches in the workup and treatment of patients suffering from airway
      impairment. Although large, randomized, comparative studies are not available,
      data show significant improvement in patient outcomes and quality of life with
      treatment of central airway obstruction. Clearly, more studies assessing the
      relative utility of specific airway interventions and their impact on morbidity
      and mortality are needed. Currently, the most comprehensive approach can be
      offered at centers with expertise in the management of complex airway disorders
      and availability of all endoscopic and surgical options.

PMID- 15187011
TI  - Peptide therapy and asthma.

PMID- 15187012
TI  - Renal function in critically ill, morbidly obese patients.

PMID- 15187013
TI  - More respect for respiratory variation in arterial pressure.

PMID- 15187014
TI  - Respiratory variations in arterial pressure.

PMID- 15187015
TI  - Interrupter resistance and wheezing at 4 years.

PMID- 15187017
TI  - Repeatability of spirometry.

PMID- 15187016
TI  - Number of drugs to treat multidrug-resistant tuberculosis.

PMID- 15187018
TI  - Upstream stimulatory factors stimulate transcription through E-box motifs in the
      PF4 gene in megakaryocytes.
AB  - Platelet factor 4 (PF4) is expressed during megakaryocytic differentiation. We
      previously demonstrated that the homeodomain proteins (myeloid ecotropic
      integration site 1 [MEIS1], Pbx-regulating protein 1 [PREP1], and pre-B-cell
      leukemia transcription factors [PBXs]) bind to the novel regulatory element
      tandem repeat of MEIS1 binding element [TME] and transactivate the rat PF4
      promoter. In the present study, we investigated and identified other TME binding
      proteins in megakaryocytic HEL cells using mass spectrometry. Among identified
      proteins, we focused on upstream stimulatory factor (USF1) and USF2 and
      investigated their effects on the PF4 promoter. USF1 and 2 bound to the E-box
      motif in the TME and strongly transactivated the PF4 promoter. Furthermore,
      physiologic bindings of USF1 and 2 to the TME in rat megakaryocytes were
      demonstrated by the chromatin immunoprecipitation (ChIP) assay. Interestingly,
      the E-box motif in the TME was conserved in TME-like sequences of both the human
      and mouse PF4 promoters. USF1 and 2 also bound to the human TME-like sequence and
      transactivated the human PF4 promoter. Expressions of USF1 and 2 were detected by
      reverse-transcriptase-polymerase chain reaction (RT-PCR) in the human
      megakaryocytes derived from CD34+ cells. Thus, these studies demonstrate that the
      novel TME binding transcription factors, USF1 and 2, transactivate rat and human
      PF4 promoters and may play an important role in megakaryocytic gene expression.

PMID- 15187019
TI  - Experimental assessment of disinfection procedures for eradication of Aspergillus
      fumigatus in food.
AB  - Aspergillus fumigatus spores in food may represent an infectious risk for
      neutropenic patients. We examined the efficiency of disinfection procedures
      applicable to foods for eradication of A fumigatus. Boiling and microwave
      treatment fully decontaminated an experimental spore suspension and naturally
      contaminated liquid foods (reconstituted dried food, herbal tea). Full
      decontamination of experimentally contaminated surfaces was only obtained with
      70% ethanol or heating at 220 degrees C for 15 minutes. Pepper was decontaminated
      when heated for 15 minutes at 220 degrees C but not by microwaving. Fruit skin
      was partially decontaminated by 70% ethanol. We conclude that A fumigatus spores
      can be eradicated from food by heating to a temperature of at least 100 degrees
      C. When foods cannot be exposed to high temperature or microwaving, ethanol only
      partially reduces the level of surface contamination.

PMID- 15187020
TI  - Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid
      leukemias.
AB  - The c-myb proto-oncogene has been implicated in leukemogenesis, but possible
      mechanisms remain ill defined. To gain further insight to this process, we used
      transcript profiling in K562 cells expressing a dominant-negative Myb (MERT)
      protein. A total of 105 potential Myb gene targets were identified. Neuromedin U
      (NmU), a peptide affecting calcium transport, underwent the greatest expression
      change ( approximately 5-fold decrease). To verify a linkage between c-myb and
      NmU, their mRNA levels were quantitated using real-time polymerase chain reaction
      in primary acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as
      well as normal hematopoietic cells. We found that c-myb was elevated in AML and
      ALL samples, but NmU expression was increased only in AML cells. Significantly,
      only AML cells expressed the cognate receptor of NmU, NMU1R, suggesting the
      presence of a novel autocrine loop. We examined this possibility in detail.
      Exogenous NmU "rescued" growth suppression in K562-MERT cells and stimulated the
      growth of primary AML cells. Short interfering RNA "knockdown" of NmU in K562
      cells arrested cell growth. Exposing Indo-1-labeled K562 cells to NmU induced an
      intracellular Ca(++) flux consistent with engagement of the NMU1R. Combined,
      these results suggest that NmU expression is related to Myb and that the
      NmU/NMU1R axis constitutes a previously unknown growth-promoting autocrine loop
      in myeloid leukemia cells.

PMID- 15187021
TI  - Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a
      vicious cycle between bone destruction and myeloma expansion.
AB  - Multiple myeloma (MM) expands in the bone marrow and causes devastating bone
      destruction by enhancing osteoclastic bone resorption in its vicinity, suggesting
      a close interaction between MM cells and osteoclasts (OCs). Here, we show that
      peripheral blood mononuclear cell-derived OCs enhanced growth and survival of
      primary MM cells as well as MM cell lines more potently than stromal cells, and
      that OCs protected MM cells from apoptosis induced by serum depletion or
      doxorubicin. OCs produced osteopontin (OPN) and interleukin 6 (IL-6), and
      adhesion of MM cells to OCs increased IL-6 production from OCs. In addition, IL-6
      and OPN in combination enhanced MM cell growth and survival. However, the effects
      of OCs on MM cell growth and survival were only partially suppressed by a
      simultaneous addition of anti-IL-6 and anti-OPN antibodies and were completely
      abrogated by inhibition of cellular contact between MM cells and OCs. These
      results demonstrate that OCs enhance MM cell growth and survival through a cell
      cell contact-mediated mechanism that is partially dependent on IL-6 and OPN. It
      is suggested that interactions of MM cells with OCs augment MM growth and
      survival and, thereby, form a vicious cycle, leading to extensive bone
      destruction and MM cell expansion.

PMID- 15187022
TI  - Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not
      contribute to tumor endothelium.
AB  - Tumor growth is dependent in part on "neoangiogenesis." Functional involvement of
      bone marrow (BM)-derived cells in this process has been demonstrated. However, it
      remains controversial as to whether tumor endothelium itself is BM derived. Here
      we sought to address this issue with an endothelial-specific, inducible
      transgenic model. We generated Cretransgenic mice (endothelial-SCL-Cre-ER(T))
      using the tamoxifen-inducible Cre-ER(T) recombinase driven by the 5' endothelial
      enhancer of the stem cell leukemia (SCL) locus. These mice were intercrossed with
      Cre reporter strains in which beta-galactosidase (LacZ) or enhanced yellow
      fluorescent protein (EYFP) are expressed upon Cre-mediated recombination. After
      tamoxifen administration, endothelial LacZ staining was observed in embryonic and
      adult tissues. Cre-mediated recombination was also observed in newly generated
      tumor endothelium. In adult BM cells we could only detect trace amounts of
      recombination by flow cytometry. Subsequently, BM from endothelial-SCL-Cre
      ER(T);R26R mice was transplanted into irradiated recipients. When tumors were
      grown in recipient mice, which received tamoxifen, no tumor LacZ staining was
      detected. However, when tumors were grown in endothelial-SCL-Cre-ER(T);R26R mice
      3 weeks after the cessation of tamoxifen treatment, there was widespread
      endothelial LacZ staining present. Thus, this genetic model strongly suggests
      that BM cells do not contribute to tumor endothelium and demonstrates the lineage
      relation between pre-existing endothelium and newly generated tumor endothelial
      cells.

PMID- 15187023
TI  - Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats
      and involves signaling through RBP-Jkappa.
AB  - Notch proteins comprise a family of transmembrane receptors. Ligand activation of
      Notch releases the intracellular domain of the receptor that translocates to the
      nucleus and regulates transcription through the DNA-binding protein RBP-Jkappa.
      Previously, it has been shown that the Notch4 intracellular region (N4IC) can
      inhibit endothelial sprouting and angiogenesis. Here, N4IC deletion mutants were
      assessed for their ability to inhibit human microvascular endothelial cell (HMEC)
      sprouting with the use of a quantitative endothelial sprouting assay. Deletion of
      the ankyrin repeats, but not the RAM (RBP-Jkappa associated module) domain or C
      terminal region (CT), abrogated the inhibition of fibroblast growth factor 2 (FGF
      2)- and vascular endothelial growth factor (VEGF)-induced sprouting by Notch4,
      whereas the ankyrin repeats alone partially blocked sprouting. The ankyrin
      repeats were also the only domain required for up-regulation of RBP-Jkappa
      dependent gene expression. Interestingly, enforced expression of the ankyrin
      domain alone was sufficient to up-regulate some, but not all, RBP-Jkappa
      dependent genes. Although N4IC reduced VEGF receptor-2 (VEGFR-2) and vascular
      endothelial (VE)-cadherin expression, neither of these events is necessary and
      sufficient to explain N4IC-mediated inhibition of sprouting. A constitutively
      active RBP-Jkappa mutant significantly inhibited HMEC sprouting but not as
      strongly as N4IC. Thus, Notch4-induced inhibition of sprouting requires the
      ankyrin repeats and appears to involve RBP-Jkappa-dependent and -independent
      signaling.

PMID- 15187024
TI  - Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes
      PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell
      proliferation and angiogenesis.
AB  - Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) plays an important
      role in angiogenesis by regulating the proliferation and migration of endothelial
      cells (ECs). Here we characterize the mechanism by which PILSAP regulates the
      vascular endothelial growth factor (VEGF)-stimulated proliferation of ECs. The
      specific elimination of PILSAP expression or its enzymatic activity inhibited
      VEGF-stimulated G1/S transition in ECs. This G1 arrest correlated with reduced
      cyclin dependent kinase 4/6 (CDK4/6) activity and retinoblastoma (Rb) protein
      phosphorylation. Analyses of signaling molecules upstream of CDK4/6 revealed that
      S6 kinase (S6K) activation was affected by PILSAP, whereas that of
      phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal-related
      kinase 1/2 (ERK1/2) was not. We further demonstrated that PILSAP bound
      phosphatidylinositol-dependent kinase 1 (PDK1) and removed 9 amino acids from its
      N-terminus, which allowed S6K to associate with PDK1 and PILSAP upon VEGF
      stimulation. We constructed mutant PILSAP, which lacked the aminopeptidase
      activity but bound PDK1. Mutant PILSAP abrogated S6K activation upon VEGF
      stimulation in a dominant-negative manner. An N-terminal truncated form of PDK1
      abolished the dominant-negative effect of mutant PILSAP. Finally, the
      introduction of a mutated PILSAP gene in ECs inhibited angiogenesis and retarded
      tumor growth in vivo. These results indicate that PILSAP plays a crucial role in
      the cell cycle progression of ECs and angiogenesis via the binding and
      modification of PDK1.

PMID- 15187025
TI  - Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to
      the Golgi in hematopoietic cells undergoing differentiation: a nuclear export
      signal-mediated event.
AB  - The caspase inhibitor and RING finger-containing protein cellular inhibitor of
      apoptosis protein 1 (c-IAP1) has been shown to be involved in both apoptosis
      inhibition and signaling by members of the tumor necrosis factor (TNF) receptor
      family. The protein is regulated transcriptionally (eg, is a target for nuclear
      factor-kappaB [NF-kappaB]) and can be inhibited by mitochondrial proteins
      released in the cytoplasm upon apoptotic stimuli. The present study indicates
      that an additional level of regulation of c-IAP1 may be cell
      compartmentalization. The protein is present in the nucleus of undifferentiated
      U937 and THP1 monocytic cell lines. When these cells undergo differentiation
      under phorbol ester exposure, c-IAP1 translocates to the cytoplasmic side of the
      Golgi apparatus. This redistribution involves a nuclear export signal (NES)
      mediated, leptomycin B-sensitive mechanism. Using site-directed mutagenesis, we
      localized the functional NES motif in the caspase recruitment domain (CARD) of c
      IAP1. A nucleocytoplasmic redistribution of the protein was also observed in
      human monocytes as well as in tumor cells from epithelial origin when undergoing
      differentiation. c-IAP1 does not translocate from the nucleus of cells whose
      differentiation is blocked (ie, in cell lines and monocytes from transgenic mice
      overexpressing B-cell lymphoma 2 [Bcl-2] and in monocytes from patients with
      chronic myelomonocytic leukemia). Altogether, these observations associate c-IAP1
      cellular location with cell differentiation, which opens new perspectives on the
      functions of the protein.

PMID- 15187026
TI  - Humoral immunity to HIV-1: kinetics of antibody responses in chronic infection
      reflects capacity of immune system to improve viral set point.
AB  - We analyzed the humoral immune response in 46 patients following structured
      treatment interruption (STI) to investigate the general potential of therapeutic
      vaccination in chronic HIV-1 infection. Evoked antibody titer increases to
      glycoprotein 120 (gp120) and p24 were low during 4 short-term STIs and only
      reached significance during a fifth long-term interruption. Although induction of
      binding antibodies to viral antigens was not associated with potent suppression
      of viremia, we observed that individuals with a rapid and high response to p24,
      and to a lesser extent also to gp120, lowered their viral set points
      significantly. Of note, the increase of the anti-p24 response correlated with
      specific CD4 T helper frequency to this antigen. Despite induction of binding
      antibody responses, which correlated with improved viral control, the increase in
      neutralizing activity was marginal and did not lead to this enhanced viral
      suppression. However, a subgroup of patients who potently suppressed viremia
      independently of STI had significantly higher pre-existing neutralization titers,
      suggesting a role of humoral immunity in conferring potent protection. In
      summary, measuring the kinetics of antibody responses provided a marker to
      validate the responsiveness and capacities of the immune system of HIV-1-infected
      individuals and reflected the patients' ability to decrease viral set points.

PMID- 15187027
TI  - Mastermind critically regulates Notch-mediated lymphoid cell fate decisions.
AB  - During lymphoid development, Notch1 plays a critical role in the T-cell/B-cell
      lineage decision, while Notch2 is essential for marginal zone B-cell (MZB)
      development. Notch pathway activation induces translocation of intracellular
      Notch (ICN) to the nucleus, where it interacts with the transcription factor CSL
      (CBF1/RBP-Jk, Suppressor of Hairless, Lag-1). In vitro, ICN binds Mastermind-like
      proteins, which act as potent Notch coactivators. Three MAML family members
      (MAML1-3) have been identified in mammals, but their importance in vivo is
      unknown. To investigate the function of MAMLs in hematopoietic development, we
      introduced a dominant negative (DN) mutant of MAML1, capable of inhibiting Notch1
      4, in murine hematopoietic stem cells. DNMAML1 resulted in early inhibition of T
      cell development and the appearance of intrathymic B cells, phenotypes consistent
      with Notch1 inhibition. The T-cell differentiation block was as profound as that
      produced by enforced expression of the Notch modulator Deltex1. In DNMAML1
      transduced spleen cells, a dramatic decrease in MZB cells was present, consistent
      with Notch2 inhibition. In contrast, Deltex1 did not decrease MZB cell numbers.
      These results suggest a critical role for MAMLs during Notch-mediated cell fate
      decisions in vivo and indicate that DNMAML1, but not Deltex1, can be used to
      interfere with the function of multiple Notch family members.

PMID- 15187028
TI  - Quiescent phenotype of tumor-specific CD8+ T cells following immunization.
AB  - In a human melanoma model of tumor antigen (TA)-based immunization, we tested the
      functional status of TA-specific CD8+ cytotoxic T lymphocytes. A "quiescent"
      phenotype lacking direct ex vivo cytotoxic and proliferative potential was
      identified that was further characterized by comparing its transcriptional
      profile to that of TA-specific T cells sensitized in vitro by exposure to the
      same TA and the T-cell growth factor interleukin 2 (IL-2). Quiescent circulating
      tumor-specific CD8+ T cells were deficient in expression of genes associated with
      T-cell activation, proliferation, and effector function. This quiescent status
      may explain the observed lack of correlation between the presence of circulating
      immunization-induced lymphocytes and tumor regression. In addition, the
      activation of TA-specific T cells by in vitro antigen recall and IL-2 suggests
      that a complete effector phenotype might be reinstated in vivo to fulfill the
      potential of anticancer vaccine protocols.

PMID- 15187029
TI  - Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium
      signaling in human platelets.
AB  - Adenosine diphosphate (ADP), an important platelet agonist, acts through 2 G
      protein-coupled receptors (GPCRs), P2Y(1) and P2Y(12), which signal through Gq
      and Gi, respectively. There is increasing evidence for cross-talk between
      signaling pathways downstream of GPCRs and here we demonstrate cross-talk between
      these 2 ADP receptors in human platelets. We show that P2Y(12) contributes to
      platelet signaling by potentiating the P2Y(1)-induced calcium response. This
      potentiation is mediated by 2 mechanisms: inhibition of adenylate cyclase and
      activation of phosphatidylinositol 3 (PI 3)-kinase. Furthermore, the Src family
      kinase inhibitor PP1 selectively potentiates the contribution to the calcium
      response by P2Y(12), although inhibition of adenylate cyclase by P2Y(12) is
      unaffected. Using PP1 in combination with the inhibitor of PI 3-kinase LY294002,
      we show that Src negatively regulates the PI 3-kinase-mediated component of the
      P2Y(12) calcium response. Finally, we were able to show that Src kinase is
      activated through P2Y(1) but not P2Y(12). Taken together, we present evidence for
      a complex signaling interplay between P2Y(1) and P2Y(12), where P2Y(12) is able
      to positively regulate P2Y(1) action and P2Y(1) negatively regulates this action
      of P2Y(12). It is likely that this interplay between receptors plays an important
      role in maintaining the delicate balance between platelet activation and
      inhibition during normal hemostasis.

PMID- 15187030
TI  - Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute
      promyelocytic leukemia.
AB  - The anti-CD33 antibody calicheamicinconjugate gemtuzumab ozogamicin (GO) was used
      to treat 16 patients with acute promyelocytic leukemia (APL) who had relapsed at
      the molecular level. Of these patients, 8 were experiencing a first, 5 a second,
      2 a third, and 1 a fourth relapse. GO was administered at 6 mg/m2 for 2 doses,
      and patients achieving a new molecular remission (MR) (ie, negativity of the
      reverse transcriptase-polymerase chain reaction [RT-PCR] test for PML/RARalpha)
      received a third dose. MR was obtained in 9 (91%) of 11 patients tested after 2
      doses and in 13 (100%) of 13 patients tested after the third dose. Of the 3
      remaining patients, 1 achieved MR after one GO administration and received no
      further therapy owing to hepatic toxicity, and 2 showed disease progression
      during treatment. Quantitative RT-PCR studies showed that responding patients
      experienced a dramatic decline (at least 2 logs) of the PML/RARalpha transcript
      after the first GO dose. Of 14 responders, 7 remained in sustained MR for a
      median of 15 months (range, 7-31 months) while 7 experienced relapse at 3 to 15
      months. GO was administered again in 2 patients with relapse, and both obtained a
      new MR. These data indicate that GO is highly effective as a single treatment for
      patients with molecularly relapsed APL including those with very advanced
      disease.

PMID- 15187031
TI  - Post-translational modifications of sibling proteins and their roles in
      osteogenesis and dentinogenesis.
AB  - The extracellular matrix (ECM) of bone and dentin contains several non
      collagenous proteins. One category of non-collagenous protein is termed the
      SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family, that
      includes osteopontin (OPN), bone sialoprotein (BSP), dentin matrix protein 1
      (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular
      phosphoglycoprotein (MEPE). These polyanionic SIBLING proteins are believed to
      play key biological roles in the mineralization of bone and dentin. Although the
      specific mechanisms involved in controlling bone and dentin formation are still
      unknown, it is clear that some functions of the SIBLING family members are
      dependent on the nature and extent of post-translational modifications (PTMs),
      such as phosphorylation, glycosylation, and proteolytic processing, since these
      PTMs would have significant effects on their structure. OPN and BSP are present
      in the ECM of bone and dentin as full-length forms, whereas amino acid sequencing
      indicates that DMP1 and DSPP exist as proteolytically processed fragments that
      result from scission of X-Asp bonds. We hypothesized that the processing of DMP1
      and DSPP is catalyzed by the PHEX enzyme, since this protein, an endopeptidase
      that is predominantly expressed in bone and tooth, has a strong preference for
      cleavage at the NH2-terminus of aspartyl residue. We envision that the
      proteolytic processing of DMP1 and DSPP may be an activation process that plays a
      significant, crucial role in osteogenesis and dentinogenesis, and that a failure
      in this processing would cause defective mineralization in bone and dentin, as
      observed in X-linked hypophosphatemic rickets.

PMID- 15187032
TI  - Efficacy and co-morbidity of oral appliances in the treatment of obstructive
      sleep apnea-hypopnea: a systematic review.
AB  - The Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a common sleep-related
      breathing disorder characterized by repetitive obstructions of the upper airway
      during sleep. Modification of pharyngeal patency by Oral Appliance (OA) therapy
      has been suggested as an alternative to various treatment modalities for OSAHS.
      To determine the evidence base with respect to the efficacy and co-morbidity of
      OA therapy in OSAHS, we conducted a systematic review of the available
      literature. Primary outcome measures were the reduction in number of upper-airway
      obstructions and co-morbidity related to the craniomandibular or craniofacial
      complex, respectively. Eligible studies regarding efficacy were independently
      assessed by two assessors using a quality assessment scale. Effect sizes of
      methodologically sound studies were calculated. In identical interventions,
      effect sizes were pooled with the use of a random-effects model. Given the
      scarcity of controlled studies related to co-morbidity, appraisal was confined to
      a description of eligible studies. Sixteen controlled trials related to efficacy
      were identified. With respect to the primary outcome measure, OA therapy was
      clearly more effective than control therapy (pooled effect size, -0.96; 95%
      confidence interval [CI], -1.49 to -0.42) and possibly more effective than
      uvulopalatopharyngoplasty. Although patients generally preferred OA therapy,
      improvement of respiratory variables, such as the number of upper-airway
      obstructions, was usually better in Continuous Positive Airway Pressure (CPAP)
      therapy (pooled effect size, 0.83; 95% CI, 0.59 to 1.06). Moreover, specific
      aspects related to OA design may influence patient-perceived efficacy and
      preference. Twelve patient-series and one controlled trial related to co
      morbidity were identified. Analysis of the data suggests that OA therapy may have
      adverse effects on the craniomandibular and craniofacial complex. Although CPAP
      is apparently more effective and adverse effects of OA treatment have been
      described, it can be concluded that OA therapy is a viable treatment for,
      especially, mild to moderate OSAHS. Controlled studies addressing the specific
      indication and co-morbidity of OA therapy are warranted.

PMID- 15187033
TI  - Altered autoantigen structure in Sjogren's syndrome: implications for the
      pathogenesis of autoimmune tissue damage.
AB  - The etiology and pathogenic mechanisms underlying Sjogren's syndrome (SS) remain
      unclear. Recent studies have emphasized that the specific autoantibodies that
      occur in a high proportion of patients with SS may provide important insights
      into the circumstances that initiate and propagate tissue damage in this disease.
      Although autoantigens targeted in systemic autoimmune diseases share little in
      common in terms of structure, subcellular distribution, or function in normal
      cells, these molecules are unified by becoming clustered and concentrated in the
      surface blebs of apoptotic cells. Furthermore, their structure is altered during
      some types of cell death to generate structures not previously generated during
      development and homeostasis. This review highlights the susceptibility of SS
      autoantigens to undergoing such structural changes during activation of immune
      effector pathways, and synthesizes a model of SS incorporating these concepts. An
      understanding of the mechanisms responsible for activating the specific immune
      response in SS, and the role of specific immune effector pathways in propagating
      both the autoimmune response and tissue damage, is of potential therapeutic
      importance. Abbreviations used in this paper are: CTL, cytotoxic T-lymphocytes;
      ER, endoplasmic reticulum; GluR3, subunit III of the glutamate receptor; GrB,
      granzyme B; M3R, type III muscarinic receptor; NK cells, natural killer cells;
      PARP, poly(ADP-ribose)polymerase; SS, Sjogren's syndrome; SLE, systemic lupus
      erythematosus; and UV, ultraviolet.

PMID- 15187034
TI  - Connective tissue metabolism and gingival overgrowth.
AB  - Gingival overgrowth occurs mainly as a result of certain anti-seizure,
      immunosuppressive, or antihypertensive drug therapies. Excess gingival tissues
      impede oral function and are disfiguring. Effective oral hygiene is compromised
      in the presence of gingival overgrowth, and it is now recognized that this may
      have negative implications for the systemic health of affected patients. Recent
      studies indicate that cytokine balances are abnormal in drug-induced forms of
      gingival overgrowth. Data supporting molecular and cellular characteristics that
      distinguish different forms of gingival overgrowth are summarized, and aspects of
      gingival fibroblast extracellular matrix metabolism that are unique to gingival
      tissues and cells are reviewed. Abnormal cytokine balances derived principally
      from lymphocytes and macrophages, and unique aspects of gingival extracellular
      matrix metabolism, are elements of a working model presented to facilitate our
      gaining a better understanding of mechanisms and of the tissue specificity of
      gingival overgrowth.

PMID- 15187035
TI  - Alternatives in polymerization contraction stress management.
AB  - Polymerization contraction stress of dental composites is often associated with
      marginal and interfacial failures of bonded restorations. The magnitude of stress
      depends on composite composition (filler content and matrix composition) and its
      ability to flow before gelation, which is related to the cavity configuration and
      curing characteristics of the composite. This article reviews variations among
      studies regarding contraction-stress-testing methods and contraction stress
      values of current composites, and discusses the validity of contraction stress
      studies in relation to results from microleakage tests. The effects of lower
      curing rates and alternative curing routines on contraction stress values are
      also discussed, as well as the use of low-elastic-modulus liners. Moreover,
      studies with experimental dimethacrylate-based composites and recent developments
      in low-shrinkage monomers are described.

PMID- 15187036
TI  - Joint effort: scientists engineer solutions for repairing damaged cartilage.

PMID- 15187037
TI  - Report cites shortcomings in quality of pediatric health care.

PMID- 15187043
TI  - Use of antibiotics and risk of cancer.

PMID- 15187044
TI  - Use of antibiotics and risk of cancer.

PMID- 15187045
TI  - Use of antibiotics and risk of cancer.

PMID- 15187047
TI  - Antiphospholipid antibodies and risk for recurrent vascular events.

PMID- 15187046
TI  - Antiphospholipid antibodies and risk for recurrent vascular events.

PMID- 15187048
TI  - Antiphospholipid antibodies and risk for recurrent vascular events.

PMID- 15187049
TI  - Soluble RANKL and risk of nontraumatic fracture.

PMID- 15187050
TI  - Risks and benefits of severe caloric restriction.

PMID- 15187051
TI  - Frequency of symptoms of ovarian cancer in women presenting to primary care
      clinics.
AB  - CONTEXT: Women with ovarian cancer frequently report symptoms prior to diagnosis,
      but distinguishing these symptoms from those that normally occur in women remains
      problematic. OBJECTIVE: To compare the frequency, severity, and duration of
      symptoms between women with ovarian cancer and women presenting to primary care
      clinics. DESIGN, SETTING, AND PATIENTS: A prospective case-control study of women
      who visited 2 primary care clinics (N = 1709) and completed an anonymous survey
      of symptoms experienced over the past year (July 2001-January 2002). Severity of
      symptoms was rated on a 5-point scale, duration was recorded, and frequency was
      indicated as number of episodes per month. An identical survey was administered
      preoperatively to 128 women with a pelvic mass (84 benign and 44 malignant). MAIN
      OUTCOME MEASURES: Comparison of self-reported symptoms between ovarian cancer
      patients and women seeking care in primary care clinics. RESULTS: In the clinic
      population, 72% of women had recurring symptoms with a median number of 2
      symptoms. The most common were back pain (45%), fatigue (34%), bloating (27%),
      constipation (24%), abdominal pain (22%), and urinary symptoms (16%). Comparing
      ovarian cancer cases to clinic controls resulted in an odds ratio of 7.4 (95%
      confidence interval [CI], 3.8-14.2) for increased abdominal size; 3.6 (95% CI,
      1.8-7.0) for bloating; 2.5 (95% CI, 1.3-4.8) for urinary urgency; and 2.2 (95%
      CI, 1.2-3.9) for pelvic pain. Women with malignant masses typically experienced
      symptoms 20 to 30 times per month and had significantly more symptoms of higher
      severity and more recent onset than women with benign masses or controls. The
      combination of bloating, increased abdominal size, and urinary symptoms was found
      in 43% of those with cancer but in only 8% of those presenting to primary care
      clinics. CONCLUSIONS: Symptoms that are more severe or frequent than expected and
      of recent onset warrant further diagnostic investigation because they are more
      likely to be associated with both benign and malignant ovarian masses.

PMID- 15187052
TI  - Natural history of early, localized prostate cancer.
AB  - CONTEXT: Among men with early prostate cancer, the natural history without
      initial therapy determines the potential for survival benefit following radical
      local treatment. However, little is known about disease progression and mortality
      beyond 10 to 15 years of watchful waiting. OBJECTIVE: To examine the long-term
      natural history of untreated, early stage prostatic cancer. DESIGN: Population
      based, cohort study with a mean observation period of 21 years. SETTING:
      Regionally well-defined catchment area in central Sweden (recruitment March 1977
      through February 1984). PATIENTS: A consecutive sample of 223 patients (98% of
      all eligible) with early-stage (T0-T2 NX M0 classification), initially untreated
      prostatic cancer. Patients with tumor progression were hormonally treated (either
      by orchiectomy or estrogens) if they had symptoms. MAIN OUTCOME MEASURES:
      Progression-free, cause-specific, and overall survival. RESULTS: After complete
      follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers
      had an indolent course during the first 10 to 15 years. However, further follow
      up from 15 (when 49 patients were still alive) to 20 years revealed a substantial
      decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival
      without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival
      (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per
      1000 person-years (95% confidence interval, 10-21) during the first 15 years to
      44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of
      follow-up (P =.01). CONCLUSION: Although most prostate cancers diagnosed at an
      early stage have an indolent course, local tumor progression and aggressive
      metastatic disease may develop in the long term. These findings would support
      early radical treatment, notably among patients with an estimated life expectancy
      exceeding 15 years.

PMID- 15187054
TI  - A validated prediction model for all forms of acute coronary syndrome: estimating
      the risk of 6-month postdischarge death in an international registry.
AB  - CONTEXT: Accurate estimation of risk for untoward outcomes after patients have
      been hospitalized for an acute coronary syndrome (ACS) may help clinicians guide
      the type and intensity of therapy. OBJECTIVE: To develop a simple decision tool
      for bedside risk estimation of 6-month mortality in patients surviving admission
      for an ACS. DESIGN, SETTING, AND PATIENTS: A multinational registry, involving 94
      hospitals in 14 countries, that used data from the Global Registry of Acute
      Coronary Events (GRACE) to develop and validate a multivariable stepwise
      regression model for death during 6 months postdischarge. From 17,142 patients
      presenting with an ACS from April 1, 1999, to March 31, 2002, and discharged
      alive, 15,007 (87.5%) had complete 6-month follow-up and represented the
      development cohort for a model that was subsequently tested on a validation
      cohort of 7638 patients admitted from April 1, 2002, to December 31, 2003. MAIN
      OUTCOME MEASURE: All-cause mortality during 6 months postdischarge after
      admission for an ACS. RESULTS: The 6-month mortality rates were similar in the
      development (n = 717; 4.8%) and validation cohorts (n = 331; 4.7%). The risk
      prediction tool for all forms of ACS identified 9 variables predictive of 6-month
      mortality: older age, history of myocardial infarction, history of heart failure,
      increased pulse rate at presentation, lower systolic blood pressure at
      presentation, elevated initial serum creatinine level, elevated initial serum
      cardiac biomarker levels, ST-segment depression on presenting electrocardiogram,
      and not having a percutaneous coronary intervention performed in hospital. The c
      statistics for the development and validation cohorts were 0.81 and 0.75,
      respectively. CONCLUSIONS: The GRACE 6-month postdischarge prediction model is a
      simple, robust tool for predicting mortality in patients with ACS. Clinicians may
      find it simple to use and applicable to clinical practice.

PMID- 15187053
TI  - Participation in cancer clinical trials: race-, sex-, and age-based disparities.
AB  - CONTEXT: Despite the importance of diversity of cancer trial participants with
      regard to race, ethnicity, age, and sex, there is little recent information about
      the representation of these groups in clinical trials. OBJECTIVE: To characterize
      the representation of racial and ethnic minorities, the elderly, and women in
      cancer trials sponsored by the National Cancer Institute. DESIGN, SETTING, AND
      PATIENTS: Cross-sectional population-based analysis of all participants in
      therapeutic nonsurgical National Cancer Institute Clinical Trial Cooperative
      Group breast, colorectal, lung, and prostate cancer clinical trials in 2000
      through 2002. In a separate analysis, the ethnic distribution of patients
      enrolled in 2000 through 2002 was compared with those enrolled in 1996 through
      1998, using logistic regression models to estimate the relative risk ratio of
      enrollment for racial and ethnic minorities to that of white patients during
      these time periods. MAIN OUTCOME MEASURE: Enrollment fraction, defined as the
      number of trial enrollees divided by the estimated US cancer cases in each race
      and age subgroup. RESULTS: Cancer research participation varied significantly
      across racial/ethnic and age groups. Compared with a 1.8% enrollment fraction
      among white patients, lower enrollment fractions were noted in Hispanic (1.3%;
      odds ratio [OR] vs whites, 0.72; 95% confidence interval [CI], 0.68-0.77; P<.001)
      and black (1.3%; OR, 0.71; 95% CI, 0.68-0.74; P<.001) patients. There was a
      strong relationship between age and enrollment fraction, with trial participants
      30 to 64 years of age representing 3.0% of incident cancer patients in that age
      group, in comparison to 1.3% of 65- to 74-year-old patients and 0.5% of patients
      75 years of age and older. This inverse relationship between age and trial
      enrollment fraction was consistent across racial and ethnic groups. Although the
      total number of trial participants increased during our study period, the
      representation of racial and ethnic minorities decreased. In comparison to
      whites, after adjusting for age, cancer type, and sex, patients enrolled in 2000
      through 2002 were 24% less likely to be black (adjusted relative risk ratio,
      0.76; 95% CI, 0.65-0.89; P<.001). Men were more likely than women to enroll in
      colorectal cancer trials (enrollment fractions: 2.1% vs 1.6%, respectively; OR,
      1.30; 95% CI, 1.24-1.35; P<.001) and lung cancer trials (enrollment fractions:
      0.9% vs 0.7%, respectively; OR, 1.23; 95% CI, 1.16-1.31; P<.001). CONCLUSIONS:
      Enrollment in cancer trials is low for all patient groups. Racial and ethnic
      minorities, women, and the elderly were less likely to enroll in cooperative
      group cancer trials than were whites, men, and younger patients, respectively.
      The proportion of trial participants who are black has declined in recent years.

PMID- 15187055
TI  - Estimating prognosis for nursing home residents with advanced dementia.
AB  - CONTEXT: Survival varies for patients with advanced dementia, and accurate
      prognostic tools have not been developed. A small proportion of patients admitted
      to hospice have dementia, in part because of the difficulty in predicting
      survival. OBJECTIVES: To identify factors associated with 6-month mortality in
      newly admitted nursing home residents with advanced dementia and to create a
      practical risk score to predict 6-month mortality in this population. DESIGN,
      SETTING, AND PARTICIPANTS: This was a retrospective cohort study of data from the
      Minimum Data Set (MDS). All Medicare or Medicaid licensed nursing homes in New
      York and Michigan were included. Participants had advanced dementia and were
      admitted to New York nursing homes between June 1, 1994, and December 30, 1998
      (derivation cohort, n = 6799), and to Michigan nursing homes from October 1,
      1998, through July 30, 2000 (validation cohort, n = 4631). MAIN OUTCOME MEASURES:
      MDS factors associated with 6-month mortality were determined in the derivation
      group, and the resulting mortality risk score was evaluated in the validation
      cohort. Risk score performance was compared with the cut point of 7c on the
      Functional Assessment Staging (FAST) scale. RESULTS: Among residents with
      advanced dementia, 28.3% (n = 1922) died within 6 months of nursing home
      admission in the derivation cohort; 35.1% (n = 1626) died in the validation
      cohort. The 6-month mortality rate increased across risk scores (possible range,
      0-19): 0 points, 8.9% mortality; 1 to 2, 10.8%; 3 to 5, 23.2%; 6 to 8, 40.4%; 9
      to 11, 57.0%; and at least 12, 70.0% in the validation cohort. The area under the
      receiver operating characteristic (AUROC) curve for predicting 6-month mortality
      was 0.74 and 0.70 in the derivation and validation cohorts, respectively. Our
      risk score demonstrated better discrimination to predict 6-month mortality
      (AUROC, 0.64 for a cutoff of > or =6 points vs 0.51 for FAST stage 7c).
      CONCLUSION: A risk score based on 12 variables from the MDS estimates 6-month
      mortality for nursing home residents with advanced dementia with greater accuracy
      than existing prognostic guidelines.

PMID- 15187056
TI  - Secondhand tobacco smoke in public places in Latin America, 2002-2003.
AB  - CONTEXT: The success of measures to restrict smoking in indoor environments and
      the intensity of enforcement vary among countries around the world. In 2001, the
      Pan American Health Organization (PAHO) launched the Smoke-Free Americas
      Initiative to build capacity to achieve smoke-free environments in Latin America
      and the Caribbean. OBJECTIVE: To assess secondhand smoke concentrations in public
      places in the capital cities of Argentina, Brazil, Chile, Costa Rica, Paraguay,
      Peru, and Uruguay in conjunction with the Smoke-Free Americas Initiative. DESIGN
      AND SETTING: Multicountry assessment of vapor-phase nicotine concentrations using
      a common protocol in all 7 Latin American countries. A total of 633 sampling
      devices were placed for 7 to 14 days in 1 hospital, 2 secondary schools, 1 city
      government building, 1 airport (2 in Argentina), and restaurants and bars in each
      country. MAIN OUTCOME MEASURE: Concentrations of airborne nicotine. RESULTS:
      Airborne nicotine was detected in most (94%) of the locations surveyed. By
      country, Argentina and Uruguay had the highest median concentrations in most
      environments (eg, in hospitals: 1.33 [interquartile range [IQR], 0.51-3.12]
      microg/m3 and 0.8 [IQR, 0.30-1.69] microg/m3, respectively). Overall, bars and
      restaurants had the highest median concentrations (3.65 [IQR, 1.55-5.12]
      microg/m3 and 1.24 [IQR, 0.41-2.48] microg/m3, respectively). Nicotine
      concentrations were also found in a number of key, sentinel buildings, including
      95% (155/163) of hospital samples (in the physicians' and nurses' stations the
      median was 0.27 [IQR, 0.02-1.94] microg/m3), schools, government buildings,
      and/or airports in most countries. CONCLUSIONS: The finding of airborne nicotine
      in critical locations in Latin America provides a basis for enforcing smoke-free
      initiatives and for strengthening the protection of the public from unwanted
      exposure to secondhand smoke.

PMID- 15187057
TI  - Is this child dehydrated?
AB  - CONTEXT: The ability to assess the degree of dehydration quickly and accurately
      in infants and young children often determines patient treatment and disposition.
      OBJECTIVE: To systematically review the precision and accuracy of symptoms,
      signs, and basic laboratory tests for evaluating dehydration in infants and
      children. DATA SOURCES: We identified 1561 potential articles by multiple search
      strategies of the MEDLINE database through PubMed. Searches of bibliographies of
      retrieved articles, the Cochrane Library, textbooks, and private collections of
      experts in the field yielded an additional 42 articles. STUDY SELECTION: Twenty
      six of 1603 reviewed studies contained original data on the precision or accuracy
      of findings for the diagnosis of dehydration in young children (1 month to 5
      years). DATA EXTRACTION: Two of the 3 authors independently reviewed and
      abstracted data for estimating the likelihood ratios (LRs) of diagnostic tests.
      We eliminated 13 of the 26 studies because of the lack of an accepted diagnostic
      standard or other limitation in study design. The other 13 studies were included
      in the review. DATA SYNTHESIS: The most useful individual signs for predicting 5%
      dehydration in children are an abnormal capillary refill time (LR, 4.1; 95%
      confidence interval [CI], 1.7-9.8), abnormal skin turgor (LR, 2.5; 95% CI, 1.5
      4.2), and abnormal respiratory pattern (LR, 2.0; 95% CI, 1.5-2.7). Combinations
      of examination signs perform markedly better than any individual sign in
      predicting dehydration. Historical points and laboratory tests have only modest
      utility for assessing dehydration. CONCLUSIONS: The initial assessment of
      dehydration in young children should focus on estimating capillary refill time,
      skin turgor, and respiratory pattern and using combinations of other signs. The
      relative imprecision and inaccuracy of available tests limit the ability of
      clinicians to estimate the exact degree of dehydration.

PMID- 15187058
TI  - Symptoms of ovarian cancer--where to set the bar?

PMID- 15187059
TI  - Waiting time in prostate cancer.

PMID- 15187060
TI  - JAMA patient page. Cancer clinical trials.

PMID- 15187061
TI  - Bridging the guideline implementation gap: a systematic, document-centered
      approach to guideline implementation.
AB  - OBJECTIVE: A gap exists between the information contained in published clinical
      practice guidelines and the knowledge and information that are necessary to
      implement them. This work describes a process to systematize and make explicit
      the translation of document-based knowledge into workflow-integrated clinical
      decision support systems. DESIGN: This approach uses the Guideline Elements Model
      (GEM) to represent the guideline knowledge. Implementation requires a number of
      steps to translate the knowledge contained in guideline text into a computable
      format and to integrate the information into clinical workflow. The steps
      include: (1) selection of a guideline and specific recommendations for
      implementation, (2) markup of the guideline text, (3) atomization, (4)
      deabstraction and (5) disambiguation of recommendation concepts, (6) verification
      of rule set completeness, (7) addition of explanations, (8) building executable
      statements, (9) specification of origins of decision variables and insertions of
      recommended actions, (10) definition of action types and selection of associated
      beneficial services, (11) choice of interface components, and (12) creation of
      requirement specification. RESULTS: The authors illustrate these component
      processes using examples drawn from recent experience translating recommendations
      from the National Heart, Lung, and Blood Institute's guideline on management of
      chronic asthma into a workflow-integrated decision support system that operates
      within the Logician electronic health record system. CONCLUSION: Using the
      guideline document as a knowledge source promotes authentic translation of domain
      knowledge and reduces the overall complexity of the implementation task. From
      this framework, we believe that a better understanding of activities involved in
      guideline implementation will emerge.

PMID- 15187062
TI  - A drug database model as a central element for computer-supported dose adjustment
      within a CPOE system.
AB  - The incidence of adverse drug reactions may be decreased by computerized
      physician order entry (CPOE) with decision support. The authors describe the
      development of a drug database model for computer-supported dose adjustment
      within a CPOE system. The following two core elements were included: (1) To allow
      electronic dose and volume calculation, the relation between strength (e.g., 5
      mg/1 mL) and prescribed unit (e.g., 1 ampoule containing 2 mL) must be available
      in coded form. (2) The site of action along with the parent active ingredient,
      i.e., the pure drug without salt or ester, is necessary for linkage to knowledge
      bases. All complex examples of drugs that were examined could be described by the
      data model. With the ultimate goal of increasing prescribing effectiveness and
      quality the authors developed a drug database model for inclusion in a CPOE
      system, which allows dose calculations and may be coupled to decision support
      systems.

PMID- 15187063
TI  - Informatics resources to support health care quality improvement in the veterans
      health administration.
AB  - Information systems are increasingly important for measuring and improving health
      care quality. A number of integrated health care delivery systems use advanced
      information systems and integrated decision support to carry out quality
      assurance activities, but none as large as the Veterans Health Administration
      (VHA). The VHA's Quality Enhancement Research Initiative (QUERI) is a large
      scale, multidisciplinary quality improvement initiative designed to ensure
      excellence in all areas where VHA provides health care services, including
      inpatient, outpatient, and long-term care settings. In this paper, we describe
      the role of information systems in the VHA QUERI process, highlight the major
      information systems critical to this quality improvement process, and discuss
      issues associated with the use of these systems.

PMID- 15187064
TI  - Translating research into practice: organizational issues in implementing
      automated decision support for hypertension in three medical centers.
AB  - Information technology can support the implementation of clinical research
      findings in practice settings. Technology can address the quality gap in health
      care by providing automated decision support to clinicians that integrates
      guideline knowledge with electronic patient data to present real-time, patient
      specific recommendations. However, technical success in implementing decision
      support systems may not translate directly into system use by clinicians.
      Successful technology integration into clinical work settings requires explicit
      attention to the organizational context. We describe the application of a
      "sociotechnical" approach to integration of ATHENA DSS, a decision support system
      for the treatment of hypertension, into geographically dispersed primary care
      clinics. We applied an iterative technical design in response to organizational
      input and obtained ongoing endorsements of the project by the organization's
      administrative and clinical leadership. Conscious attention to organizational
      context at the time of development, deployment, and maintenance of the system was
      associated with extensive clinician use of the system.

PMID- 15187066
TI  - Computer alerts for potassium testing: resisting the temptation of a blanket
      approach.

PMID- 15187067
TI  - A comparison of multiple data sources to identify vaccinations for veterans with
      spinal cord injuries and disorders.
AB  - Monitoring vaccination activity requires regular access to information about
      patient vaccination status. This report describes our experience using multiple
      Department of Veterans Affairs (VA) data sources to determine availability and
      completeness of vaccination information for veterans with spinal cord injuries
      and disorders (SCI&D). Administrative and clinical databases were limited to
      coding vaccine administration, undercounted vaccinations, and were unable to
      account for whether the vaccine was offered and the reasons for nonreceipt.
      Medical record review provided more detail but was labor intensive and costly.
      Patient surveys provided the richest information but were costly, time-consuming,
      and based on a sample of patients. Agreement was poor between data sources. This
      report suggests that while VA is well positioned to use national databases for
      clinical care decisions and to inform policy, vaccination data were incomplete.
      Electronic records must include data that are consistently entered and validated
      before they can be useful for care management and decision making.

PMID- 15187068
TI  - Automated encoding of clinical documents based on natural language processing.
AB  - OBJECTIVE: The aim of this study was to develop a method based on natural
      language processing (NLP) that automatically maps an entire clinical document to
      codes with modifiers and to quantitatively evaluate the method. METHODS: An
      existing NLP system, MedLEE, was adapted to automatically generate codes. The
      method involves matching of structured output generated by MedLEE consisting of
      findings and modifiers to obtain the most specific code. Recall and precision
      applied to Unified Medical Language System (UMLS) coding were evaluated in two
      separate studies. Recall was measured using a test set of 150 randomly selected
      sentences, which were processed using MedLEE. Results were compared with a
      reference standard determined manually by seven experts. Precision was measured
      using a second test set of 150 randomly selected sentences from which UMLS codes
      were automatically generated by the method and then validated by experts.
      RESULTS: Recall of the system for UMLS coding of all terms was .77 (95% CI.72
      .81), and for coding terms that had corresponding UMLS codes recall was .83 (.79
      .87). Recall of the system for extracting all terms was .84 (.81-.88). Recall of
      the experts ranged from .69 to .91 for extracting terms. The precision of the
      system was .89 (.87-.91), and precision of the experts ranged from .61 to .91.
      CONCLUSION: Extraction of relevant clinical information and UMLS coding were
      accomplished using a method based on NLP. The method appeared to be comparable to
      or better than six experts. The advantage of the method is that it maps text to
      codes along with other related information, rendering the coded output suitable
      for effective retrieval.

PMID- 15187069
TI  - Electronic screening of dictated reports to identify patients with do-not
      resuscitate status.
AB  - OBJECTIVE: Do-not-resuscitate (DNR) orders and advance directives are
      increasingly prevalent and may affect medical interventions and outcomes. Simple,
      automated techniques to identify patients with DNR orders do not currently exist
      but could help avoid costly and time-consuming chart review. This study
      hypothesized that a decision to withhold cardiopulmonary resuscitation would be
      included in a patient's dictated reports. The authors developed and validated a
      simple computerized search method, which screens dictated reports to detect
      patients with DNR status. METHODS: A list of concepts related to DNR order
      documentation was developed using emergency department, hospital admission,
      consult, and hospital discharge reports of 665 consecutive, hospitalized
      pneumonia patients during a four-year period (1995-1999). The list was validated
      in an independent group of 190 consecutive inpatients with pneumonia during a
      five-month period (1999-2000). The reference standard for the presence of DNR
      orders was manual chart review of all study patients. Sensitivity, specificity,
      predictive values, and nonerror rates were calculated for individual and combined
      concepts. RESULTS: The list of concepts included: DNR, Do Not Attempt to
      Resuscitate (DNAR), DNI, NCR, advanced directive, living will, power of attorney,
      Cardiopulmonary Resuscitation (CPR), defibrillation, arrest, resuscitate, code,
      and comfort care. As determined by manual chart review, a DNR order was written
      for 32.6% of patients in the derivation and for 31.6% in the validation group.
      Dictated reports included DNR order-related information for 74.5% of patients in
      the derivation and 73% in the validation group. If mentioned in the dictated
      report, the combined keyword search had a sensitivity of 74.2% in the derivation
      group (70.0% in the validation group), a specificity of 91.5% (81.5%), a positive
      predictive value of 80.9% (63.6%), a negative predictive value of 88.0% (85.5%),
      and a nonerror rate of 85.9% (77.9%). DNR and resuscitate were the most
      frequently used and power of attorney and advanced directives the least
      frequently used terms. CONCLUSION: Dictated hospital reports frequently contained
      DNR order-related information for patients with a written DNR order. Using an
      uncomplicated keyword search, electronic screening of dictated reports yielded
      good accuracy for identifying patients with DNR order information.

PMID- 15187070
TI  - Managing complex change in clinical study metadata.
AB  - In highly functional metadata-driven software, the interrelationships within the
      metadata become complex, and maintenance becomes challenging. We describe an
      approach to metadata management that uses a knowledge-base subschema to store
      centralized information about metadata dependencies and use cases involving
      specific types of metadata modification. Our system borrows ideas from production
      rule systems in that some of this information is a high-level specification that
      is interpreted and executed dynamically by a middleware engine. Our approach is
      implemented in TrialDB, a generic clinical study data management system. We
      review approaches that have been used for metadata management in other contexts
      and describe the features, capabilities, and limitations of our system.

PMID- 15187071
TI  - Overview of the Veterans Health Administration (VHA) Quality Enhancement Research
      Initiative (QUERI).
AB  - The U.S. Veterans Health Administration (VHA)'s Quality Enhancement Research
      Initiative (QUERI) is an innovative integration of health services research,
      policy, and clinical care delivery designed to improve the quality, outcomes, and
      efficiency of VHA health care through the identification and implementation of
      evidence-based practices in routine care settings. A total of eight condition
      specific QUERI centers are currently in operation, each pursuing an integrated
      portfolio of activities designed to identify and correct gaps in clinical quality
      and performance and to derive generalizable scientific knowledge regarding
      quality improvement processes and methods and their effectiveness. This overview
      article describes QUERI's mission, history, structure, and activities and
      provides a brief summary of key findings and impacts.

PMID- 15187072
TI  - A network-based system to improve care for schizophrenia: the Medical Informatics
      Network Tool (MINT).
AB  - The Medical Informatics Network Tool (MINT) is a software system that supports
      the management of care for chronic illness. It is designed to improve clinical
      information, facilitate teamwork, and allow management of health care quality.
      MINT includes a browser interface for entry and organization of data and
      preparation of real-time reports. It includes personal computer-based
      applications that interact with clinicians. MINT is being used in a project to
      improve the treatment of schizophrenia. At each patient visit, a nurse briefly
      assesses symptoms, side effects, and other key problems and enters this
      information into MINT. When the physician subsequently opens the patient's
      electronic medical record, a window appears with the assessment information, a
      messaging interface, and access to treatment guidelines. Clinicians and managers
      receive reports regarding the quality of patients' treatment. To date, MINT has
      been used with more than 165 patients and 29 psychiatrists and has supported
      practices that are consistent with improvements in the quality of care.

PMID- 15187074
TI  - Use of a patient-accessible electronic medical record in a practice for
      congestive heart failure: patient and physician experiences.
AB  - OBJECTIVE: The aim of this study was to evaluate the experiences of patients and
      physicians in a clinical trial of an online electronic medical record (SPPARO,
      System Providing Patients Access to Records Online). DESIGN: Quantitative data
      were obtained from questionnaires. Qualitative data were obtained from individual
      interviews and focus groups. MEASUREMENTS: Questionnaire items were based on
      issues identified by patients and physicians in previous studies. Individual
      interviews and focus groups were performed using a semistructured format
      developed through an iterative process. RESULTS: Of the eight physicians who
      participated in the trial, seven completed questionnaires and interviews. Of the
      394 patients in the practice, 107 enrolled in the study, and 54 were assigned
      randomly to the intervention group. Of these, 41 used SPPARO during the trial
      period. In questionnaires and interviews, patients were significantly more likely
      than physicians to anticipate benefits of SPPARO and less likely to anticipate
      problems. Attitudes of subjects did not diverge from controls after the
      intervention period. In posttrial focus groups, SPPARO users described its
      practical benefits. Comprehending medical jargon was a minor obstacle. Physicians
      anticipated that implementing SPPARO might increase their workload and distort
      their clinical interactions. In posttrial interviews, physicians and staff
      reported no change in their workload and no adverse consequences. All of the
      physicians ultimately supported the concept of giving patients online access to
      their clinical notes and test results. CONCLUSION: SPPARO was useful for a number
      of patients. Physicians initially voiced a number of concerns about implementing
      SPPARO, but their experience with it was far more positive.

PMID- 15187073
TI  - Use of electronic medical record data for quality improvement in schizophrenia
      treatment.
AB  - An understanding of the strengths and limitations of automated data is valuable
      when using administrative or clinical databases to monitor and improve the
      quality of health care. This study discusses the feasibility and validity of
      using data electronically extracted from the Veterans Health Administration (VHA)
      computer database (VistA) to monitor guideline performance for inpatient and
      outpatient treatment of schizophrenia. The authors also discuss preliminary
      results and their experience in applying these methods to monitor antipsychotic
      prescribing using the South Central VA Healthcare Network (SCVAHCN) Data
      Warehouse as a tool for quality improvement.

PMID- 15187075
TI  - A consensus action agenda for achieving the national health information
      infrastructure.
AB  - BACKGROUND: Improving the safety, quality, and efficiency of health care will
      require immediate and ubiquitous access to complete patient information and
      decision support provided through a National Health Information Infrastructure
      (NHII). METHODS: To help define the action steps needed to achieve an NHII, the
      U.S. Department of Health and Human Services sponsored a national consensus
      conference in July 2003. RESULTS: Attendees favored a public-private coordination
      group to guide NHII activities, provide education, share resources, and monitor
      relevant metrics to mark progress. They identified financial incentives, health
      information standards, and overcoming a few important legal obstacles as key NHII
      enablers. Community and regional implementation projects, including consumer
      access to a personal health record, were seen as necessary to demonstrate
      comprehensive functional systems that can serve as models for the entire nation.
      Finally, the participants identified the need for increased funding for research
      on the impact of health information technology on patient safety and quality of
      care. Individuals, organizations, and federal agencies are using these consensus
      recommendations to guide NHII efforts.

PMID- 15187076
TI  - Evolution of enzymes for the metabolism of new chemical inputs into the
      environment.

PMID- 15187077
TI  - Membrane topology of the H+-pyrophosphatase of Streptomyces coelicolor determined
      by cysteine-scanning mutagenesis.
AB  - The H+-translocating pyrophosphatase (H+-PPase) is a proton pump that is found in
      a wide variety of organisms. It consists of a single polypeptide chain that is
      thought to possess between 14 and 17 transmembrane domains. To determine the
      topological arrangement of its conserved motifs and transmembrane domains, we
      carried out a cysteine-scanning analysis by determining the membrane topology of
      cysteine substitution mutants of Streptomyces coelicolor H+-PPase expressed in
      Escherichia coli using chemical reagents. First, we prepared a synthetic DNA that
      encoded the enzyme and constructed a functional cysteine-less mutant by
      substituting the four cysteine residues. We then introduced cysteine residues
      individually into 42 sites in its hydrophilic regions and N- and C-terminal
      segments. Thirty-six of the mutant enzymes retained both pyrophosphatase and H+
      translocating activities. Analysis of 29 of these mutant forms using membrane
      permeable and -impermeable sulfhydryl reagents revealed that S. coelicolor H+
      PPase contains 17 transmembrane domains and that several conserved segments, such
      as the substrate-binding domains, are exposed to the cytoplasm. Four essential
      serine residues that were located on the cytoplasmic side were also identified. A
      marked characteristic of the S. coelicolor enzyme is a long additional sequence
      that includes a transmembrane domain at the C terminus. We propose that the basic
      structure of H+-PPases has 16 transmembrane domains with several large
      cytoplasmic loops containing functional motifs.

PMID- 15187078
TI  - Warm temperature-sensitive transient receptor potential vanilloid 4 (TRPV4) plays
      an essential role in thermal hyperalgesia.
AB  - Animals sense various ranges of temperatures by cutaneous thermal stimuli.
      Transient receptor potential vanilloid 4 (TRPV4) is a cation channel activated at
      a warm temperature (over 30 degrees C) in exogenously expressed cells. We found
      in the present study that TRPV4 is essential in thermal hyperalgesia at a warm
      temperature in vivo. TRPV4-/- and TRPV4+/+ mice exhibited the same latency of
      escape from 35-50 degrees C hotplates. Neuronal activity in the femoral nerve,
      however, revealed that the number and activity level of neurons decreased in
      response to a warm temperature in TRPV4-/- mice. TRPV4-/- mice displayed a
      significantly longer latency to escape from the plates at 35- 45 degrees C when
      hyperalgesia was induced by carrageenan without changes in foot volumes. TRPV4
      therefore determines the sensitivity rather than the threshold of painful heat
      detection and plays an essential role in thermal hyperalgesia.

PMID- 15187079
TI  - Transport of meprin subunits through the secretory pathway: role of the
      transmembrane and cytoplasmic domains and oligomerization.
AB  - The meprin alpha subunit, a multidomain metalloproteinase, is synthesized as a
      type I membrane protein and proteolytically cleaved during biosynthesis in the
      endoplasmic reticulum (ER), consequently losing its membrane attachment and COOH
      terminal domains. The meprin alpha subunit is secreted as a disulfide-linked
      dimer that forms higher oligomers. By contrast, the evolutionarily related meprin
      beta subunit retains the COOH-terminal domains during biosynthesis and travels to
      the plasma membrane as a disulfide-linked integral membrane dimer. Deletion of a
      unique 56-amino acid inserted domain (the I domain) of meprin alpha prevents COOH
      terminal proteolytic processing and results in the retention of this subunit
      within the ER. To determine elements responsible for this retention versus
      transport to the cell surface, mutagenesis experiments were performed.
      Replacement of the meprin alpha transmembrane (alphaT) and cytoplasmic (alphaC)
      domains with their beta counterparts allowed rapid movement of the alpha subunit
      to the cell surface. The meprin alphaT and alphaC domains substituted into meprin
      beta delayed movement of this chimera through the secretory pathway. Replacement
      of glycines in the meprin alphaT domain GXXXG motif with leucine residues,
      alanine insertions in the meprin alphaT domain, and mutagenesis of basic residues
      within the meprin alphaC domain did not enhance the movement of the alpha subunit
      through the secretory pathway. By contrast, a mutant of meprin alpha
      (C320AalphaDeltaI) that did not form disulfide-linked dimers or higher order
      oligomers was transported through the secretory pathway, although more slowly
      than meprin beta. Taken together, the data indicate that the meprin alphaT and
      alphaC domains together contain a weak signal for retention within the ER/cis
      Golgi compartments that is strengthened by oligomerization.

PMID- 15187081
TI  - Identification of DRIP205 as a coactivator for the Farnesoid X receptor.
AB  - Farnesoid X receptor (FXR) is a bile acid sensor that regulates the expression of
      a number of genes the products of which control bile acid and cholesterol
      homeostasis; however, the role of DRIP205 in FXR-mediated gene regulation remains
      unexplored. In this study we demonstrate that DRIP205 binds FXR in a ligand
      dependent manner in vitro and in vivo. Glutathione S-transferase pull-down assays
      showed that DRIP205 binds FXR in response to bile acid ligands in a dose
      dependent fashion and that the potency of this interaction is associated with the
      ability of the ligand to activate FXR. In addition, the FXR-DRIP205 interaction
      required the presence of an intact LXXLL nuclear receptor box 1 (N-terminal)
      motif of DRIP205. In gel shift assays FXR was also able to recruit DRIP205 in the
      context of a DNA-bound FXR/RXR (retinoid X receptor) heterodimer. In transient
      transfection assays, DRIP205 efficiently enhanced a bile acid-activated FXRE
      driven reporter gene in a dose-dependent manner in cells overexpressing FXR/RXR,
      demonstrating that DRIP205 enhances FXR-mediated transactivation. By contrast, an
      FXRW469A mutant in the activation function 2 domain that does not bind to DRIP205
      was unable to activate ligand-stimulated FXR transcription, indicating that
      DRIP205 is recruited to activation function 2 of FXR. Requirement for the FXR/RXR
      heterodimer in the DRIP205-FXR interaction was evaluated using an RXR
      heterodimerization-deficient FXR mutant (FXRL433R). FXRL433R was not able to bind
      to DRIP205 and failed to enhance an FXRE-driven reporter gene. In addition,
      DRIP205 was unable to induce FXR-mediated transactivation in the absence of RXR
      overexpression, indicating that FXR heterodimerization with RXR is required for
      coactivation by DRIP205. Finally, in HepG2 cells, overexpression or reduction of
      DRIP205 levels modulated the induction of endogenous FXR target gene mRNA
      expression by ligand. Together, these results demonstrate that DRIP205 acts as a
      bona fide coactivator of FXR and underscore the importance of DRIP205 in
      modulating the bile acid response of FXR target genes.

PMID- 15187080
TI  - Steroids and exogenous gamma-ENaC subunit modulate cation channels formed by
      alpha-ENaC in human B lymphocytes.
AB  - Previous studies using whole-cell recording methods suggest that human B
      lymphocytes express an amiloride-sensitive, sodium-permeable channel. The present
      studies aim to determine whether this channel has biophysical properties and a
      molecular structure related to the alpha, beta, and gamma subunits of the
      epithelial sodium channel (ENaC). Reverse transcriptase polymerase chain reaction
      and Northern blots showed that human B lymphocytes express messages for both
      alpha- and beta- but not gamma-ENaC. Western blots showed that both alpha- and
      beta- but not gamma-ENaC proteins are expressed and strongly reduced by antisense
      oligonucleotides. Patch clamp experiments demonstrated that lymphocyte sodium
      channels are not active in cell-attached patches. However, membrane stretch can
      activate a 21-pS nonselective cation channel. The frequency of observance of this
      channel was significantly reduced by antisense oligonucleotide against alpha-ENaC
      but not by antisense oligonucleotide against beta-ENaC, indicating that only the
      alpha subunit of ENaC is necessary to form stretch-activated cation channels.
      Aldosterone (1.5 microm) reduced the frequency of observance of 21-pS alpha-ENaC
      channels and simultaneously induced the appearance of spontaneously active 10-pS
      channels. Antisense oligonucleotide experiments showed that this 10-pS channel is
      formed from alpha- and beta-ENaC. After expression of exogenous gamma-ENaC,
      aldosterone again reduced the frequency of observance of the 21-pS alpha-ENaC
      channel but induced the appearance of a 5-pS channel, presumably a alphabetagamma
      ENaC channel. In the absence of aldosterone, the alpha subunit forms an alpha
      cryptic channel that is activated by stretch, and in the presence of aldosterone,
      beta and alpha subunits together form an active channel that is modulated by
      aldosterone.

PMID- 15187082
TI  - Effects of inorganic polyphosphate on the proteolytic and DNA-binding activities
      of Lon in Escherichia coli.
AB  - Lon belongs to a unique group of proteases that bind to DNA and is involved in
      the regulation of several important cellular functions, including adaptation to
      nutritional downshift. Previously, we revealed that inorganic polyphosphate
      (polyP) increases in Escherichia coli in response to amino acid starvation and
      that it stimulates the degradation of free ribosomal proteins by Lon. In this
      work, we examined the effects of polyP on the proteolytic and DNA-binding
      activities of Lon. An order-of-addition experiment suggested that polyP first
      binds to Lon, which stimulates Lon-mediated degradation of ribosomal proteins. A
      polyP-binding assay using Lon deletion mutants showed that the polyP-binding site
      of Lon is localized in the ATPase domain. Because the same ATPase domain also
      contains the DNA-binding site, polyP can compete with DNA for binding to Lon. In
      fact, an equimolar amount of polyP almost completely inhibited DNA-Lon complex
      formation, suggesting that Lon binds to polyP with a higher affinity than it
      binds to DNA. Collectively, our results showed that polyP may control the
      cellular activity of Lon not only as a protease but also as a DNA-binding
      protein.

PMID- 15187083
TI  - The proline-rich homeodomain protein recruits members of the Groucho/Transducin
      like enhancer of split protein family to co-repress transcription in
      hematopoietic cells.
AB  - The proline-rich homeodomain protein (PRH/Hex) is important in the control of
      cell proliferation and differentiation and in the regulation of multiple
      processes in embryonic development. We have shown previously that PRH contains
      two domains that can independently bring about transcriptional repression. The
      PRH homeodomain represses transcription by binding to TATA box sequences, whereas
      the proline-rich N-terminal domain of PRH can repress transcription when attached
      to a heterologous DNA-binding domain. The Groucho/transducin-like enhancer of
      split (TLE) family of proteins are transcriptional co-repressors that interact
      with a number of DNA-bound transcription factors and play multiple roles in
      development. Here we demonstrate that the proline-rich N-terminal domain of PRH
      binds to TLE1 in vitro and in yeast two-hybrid assays. We show that PRH and TLE
      proteins are co-expressed in hematopoietic cells and interact in co
      immunoprecipitation assays. We demonstrate that TLE1 increases repression by PRH
      in transient transfection assays and that titration of endogenous TLE proteins by
      co-expression of Grg5, a natural trans-dominant negative protein, alleviates
      transcriptional repression by PRH. Finally, we show that a mutation in the PRH N
      terminal domain that blocks the PRH-TLE1 interaction in vitro eliminates co
      repression. We discuss these results in terms of the roles of PRH and TLE in cell
      differentiation and development.

PMID- 15187084
TI  - Association of excitatory amino acid transporters, especially EAAT2, with
      cholesterol-rich lipid raft microdomains: importance for excitatory amino acid
      transporter localization and function.
AB  - In the present study, we investigated the role of membrane cholesterol in the
      function of glutamate transporters. Depletion of membrane cholesterol by methyl
      beta-cyclodextrin resulted in reduced Na(+)-dependent glutamate uptake in primary
      cortical cultures. Glial glutamate transporter EAAT2-mediated uptake was more
      sensitive to this effect. Cell surface biotinylation and immunostaining
      experiments revealed that the loss of cholesterol significantly altered the
      trafficking of EAAT2 to the plasma membrane as well as their membrane
      distribution. These effects were also observed in neuronal glutamate transporter
      EAAT3 but to a lesser extent. Furthermore, the treatment of mouse brain plasma
      membrane vesicles with methyl-beta-cyclodextrin resulted in a significant
      reduction in glutamate uptake, suggesting that cholesterol depletion has a direct
      effect on the function of the glutamate transporters. Plasma membrane cholesterol
      is localized within discreet microdomains known as lipid rafts. Analyses of
      purified lipid raft microdomains revealed that a large portion of total EAAT2 and
      a minor portion of total EAAT1, EAAT3, and EAAT4 were associated with lipid
      rafts. Artificial aggregation of lipid rafts in vivo resulted in the formation of
      larger EAAT2-immunoreactive clusters on the cell surface. The purified lipid raft
      associated fractions were capable of Na(+)-dependent glutamate uptake. Our data
      suggest that the glutamate transporters, especially EAAT2, are associated with
      cholesterol-rich lipid raft microdomains of the plasma membrane and that the
      association with these cholesterol-rich microdomains is important for excitatory
      amino acid transporter localization and function.

PMID- 15187085
TI  - Insulin regulation of sterol regulatory element-binding protein-1 expression in L
      6 muscle cells and 3T3 L1 adipocytes.
AB  - Sterol regulatory element-binding proteins (SREBPs) are transcription factors
      that regulate enzymes required for cholesterol and fatty acid synthesis.
      Expression of SREBP-1 is enhanced by insulin; however, the actual insulin
      signaling cascades employed are yet unclear. We determined the roles of the
      phosphatidylinositol (PI) 3-kinase and mitogen-activated protein (MAP) kinase
      dependent pathways in the effect of mediating insulin on SREBP-1 in L-6 skeletal
      muscle cells and 3T3 L1 adipocytes, using wortmannin or LY294002 to inhibit the
      PI 3-kinase pathway, and PD98059 to inhibit the MAP kinase-dependent pathway. In
      myocytes, insulin increased SREBP-1 protein in a dose-dependent manner. 1 and 10
      nm insulin significantly increased expression of total cellular SREBP-1 protein
      at 24 and 48 h, nuclear SREBP-1 protein at 24 h, and SREBP-1a mRNA at 24 h.
      Although wortmannin and LY294002 had no effect on this aspect of insulin action,
      PD98059 completely blocked each of these responses. Transfection of a dominant
      negative mutant of Ras similarly blocked the insulin effect on SREBP-1. In
      contrast, in adipocytes, the insulin effect on SREBP-1 was mediated via the PI 3
      kinase and not the MAP kinase pathway. In conclusion, although insulin increases
      skeletal muscle SREBP-1 expression in a dose-dependent fashion via the MAP kinase
      dependent signaling pathway, insulin action on adipocyte SREBP-1 is mediated via
      the PI 3-kinase signaling pathway. In the state of insulin resistance,
      characterized by selective inhibition of the PI 3-kinase pathway, the usual
      stimulation of lipogenesis by insulin in adipocytes may be inhibited, whereas
      intramyocellular lipogenesis via the MAP kinase pathway of insulin may continue
      unabated.

PMID- 15187086
TI  - Nitric oxide inhibits glucocorticoid-induced apoptosis of thymocytes by
      repressing the SRG3 expression.
AB  - Nitric oxide (NO) plays many roles in the immune system. It has been known that
      NO rescues thymocytes from glucocorticoid (GC)-induced apoptosis. However, the
      downstream target of NO in the protection from GC-induced thymocyte apoptosis has
      yet to be identified. We previously reported that GC sensitivity of developing
      thymocytes is dependent on the expression level of SRG3. In the present report,
      we found that NO repressed the SRG3 expression in both primary thymocytes and
      16610D9 thymoma cells. Specifically, NO down-regulated the transcription of SRG3
      via the inactivation of the transcription factor Sp1 DNA-binding activity to the
      SRG3 promoter. In addition, overexpression of SRG3 by a heterologous promoter
      reduced NO-mediated rescue of thymocytes from GC-induced apoptosis. These
      observations strongly suggest that NO may be involved in protecting immature
      thymocytes from GC-induced apoptosis by repressing the SRG3 expression in thymus.

PMID- 15187087
TI  - alpha(v)beta(3) Integrin interacts with the transforming growth factor beta
      (TGFbeta) type II receptor to potentiate the proliferative effects of TGFbeta1 in
      living human lung fibroblasts.
AB  - The alpha(v)beta(3) integrin is known to cooperate with receptor tyrosine kinases
      to enhance cellular responses. To determine whether alpha(v)beta(3) regulates
      transforming growth factor beta (TGFbeta) 1-induced responses, we investigated
      the interaction between alpha(v)beta(3) and TGFbeta type II receptor (TGFbetaIIR)
      in primary human lung fibroblasts. We report that TGFbeta1 up-regulates cell
      surface and mRNA expression of alpha(v)beta(3) in a time- and dose-dependent
      manner. Co-immunoprecipitation and confocal microscopy showed that TGFbetaRII
      associates and clusters with alpha(v)beta(3), following TGFbeta1 exposure. This
      association was not observed with alpha(v)beta(5) or alpha(5)beta(1). We also
      used a novel molecular proximity assay, bioluminescence resonance energy transfer
      (BRET), to quantify this dynamic interaction in living cells. TGFbeta1
      stimulation resulted in a BRET signal within 5 min, whereas tenascin, which binds
      alpha(v)beta(3), did not induce a substantial BRET signal. Co-exposure to
      tenascin and TGFbeta1 produced no further increases in BRET than TGFbeta1 alone.
      Cyclin D1 was rapidly induced in cells co-exposed to TGFbeta1 and tenascin, and
      as a consequence proliferation induced by TGFbeta1 was dramatically enhanced in
      cells co-exposed to tenascin or vitronectin. Cholesterol depletion inhibited the
      interaction between TGFbetaRII and alpha(v)beta(3) and abrogated the
      proliferative effect. The cyclic RGD peptide, GpenGRGDSPCA, which blocks
      alpha(v)beta(3), also abolished the synergistic proliferative effect seen. These
      results indicate a new interaction partner for the alpha(v)beta(3) integrin, the
      TGFbetaIIR, in which TGFbeta1-induced responses are potentiated in the presence
      alpha(v)beta(3) ligands. Our data provide a novel mechanism by which TGFbeta1 may
      contribute to abnormal wound healing and tissue fibrosis.

PMID- 15187088
TI  - The activity of the plexin-A1 receptor is regulated by Rac.
AB  - Plexins constitute a large family of transmembrane proteins that act as receptors
      for the semaphorin family of ligands. They are best known for their role in
      growth cone guidance, although they also are widely expressed outside the nervous
      system. Plexins are thought to control axon guidance by modifying the growth cone
      cytoskeleton, and Rho GTPases have been strongly implicated in this response.
      However, the exact contribution of Rho proteins is unclear. Sema3A/Plexin-A1
      induced growth cone collapse, for example, requires Rac activity, which is a
      surprising result given that this GTPase is usually associated with membrane
      protrusions. We show here that Sema3A-induced collapse of COS-7 cells expressing
      Plexin-A1 also requires Rac but not Rho activity and that the cytoplasmic tail of
      Plexin-A1 interacts directly with activated Rac. However, collapse induced by a
      constitutively activated version of Plexin-A1 does not require Rac. We propose a
      novel function for Rac, namely that it acts upstream of Plexin-A1 during
      semaphoring-induced collapse, to regulate the activity of the receptor.

PMID- 15187089
TI  - The adaptor protein Nck1 mediates endothelin A receptor-regulated cell migration
      through the Cdc42-dependent c-Jun N-terminal kinase pathway.
AB  - Cell migration plays key roles in physiological and pathological phenomena, such
      as development and oncogenesis. The adaptor proteins Grb2, CrkII, and Nck1 are
      composed of only a single Src homology 2 domain and some Src homology 3 domains,
      giving specificity to each signal transduction pathway. However, little is known
      about the relationships between their adaptor proteins and cell migration, which
      are regulated by the G protein-coupled receptor. Here we showed that Nck1, but
      not Grb2 or CrkII, mediated the inhibition of cell migration induced by the
      endothelin-1 and endothelin A receptor. The small interference RNA and dominant
      negative mutants of Nck1 diminished the endothelin-1-induced inhibition of cell
      migration. Although overexpression of wild-type Nck1 was detected in the cytosol
      and did not affect cell migration, expression of the myristoylation signal
      sequence-conjugated Nck1 was detected in the membrane and induced activation of
      Cdc42 and c-Jun N-terminal kinase, inhibiting cell migration. Taken together,
      these results suggest that the endothelin A receptor transduces the signal of
      inhibition of cell migration through Cdc42-dependent c-Jun N-terminal kinase
      activation by using Nck1.

PMID- 15187090
TI  - Crucial role of neuron-enriched endosomal protein of 21 kDa in sorting between
      degradation and recycling of internalized G-protein-coupled receptors.
AB  - Recycling of endocytosed G-protein-coupled receptors involves a series of
      molecular events through early and recycling endosomes. The purpose of this work
      was to study the role of neuron-enriched endosomal protein of 21 kDa (NEEP21) in
      the recycling process of neurotensin receptors-1 and -2. Here we showed that
      suppression of NEEP21 expression does not modify the internalization rate of both
      receptors but strongly inhibited the recycling of the neurotensin receptor-2. In
      contrast, overexpression of NEEP21 changes the behavior of the neurotensin
      receptor-1 from a non-recycling to a recycling state. Recycling of the
      neurotensin receptor-2 involves both the phosphatidylinositol 3-kinase and the
      recycling endosome pathways, whereas recycling of the neurotensin receptor-1
      induced by overexpression of NEEP21 only occurs by the phosphatidylinositol 3
      kinase-dependent pathway. Taken together, these results confirm the essential
      role of NEEP21 in the recycling mechanism and show that this protein acts at the
      level of early endosomes to promote sorting of receptors toward a recycling
      pathway.

PMID- 15187091
TI  - Protein kinase Calpha translocates to the perinuclear region to activate
      phospholipase D1.
AB  - The inhibition of phorbol ester activation of phospholipase D1 (PLD1) by protein
      kinase C (PKC) inhibitors has been considered proof of phosphorylation-dependent
      activation of PLD1 by PKCalpha. We studied the effect of the PKC inhibitors Ro-31
      8220 and bisindolylmaleimide I on PLD1 activation and found that they inhibited
      the activation by interfering with PKCalpha binding to PLD1. Further studies
      showed that only unphosphorylated PKCalpha could bind to and activate PLD1 and
      that both inhibitors induced phosphorylation of PKCalpha. The phosphorylation
      status of either PLD1 or PKCalpha per se did not affect PLD1 activation in vitro.
      Immunofluorescence studies showed that PLD1 remained in the perinuclear region
      after phorbol ester treatment, whereas PKCalpha translocated from cytosol to both
      plasma membrane and perinuclear regions. Both Ro-31-8220 and bisindolylmaleimide
      I blocked the translocation of PKCalpha to the perinuclear region but not to the
      plasma membrane. Studies with okadaic acid suggested that phosphorylation
      regulated the relocation of PKCalpha from the plasma membrane to the perinuclear
      region. It is proposed that localization and interaction of PKCalpha with PLD1 in
      the perinuclear region is required for PLD1 activation and that PKC inhibitors
      inhibit this through phosphorylation of PKCalpha, which blocks its translocation.

PMID- 15187092
TI  - The stability of tristetraprolin mRNA is regulated by mitogen-activated protein
      kinase p38 and by tristetraprolin itself.
AB  - Tristetraprolin (TTP) is an mRNA-destabilizing protein that negatively regulates
      the expression of proinflammatory mediators such as tumor necrosis factor alpha,
      granulocyte/macrophage colony-stimulating factor, and cyclooxygenase 2. Here we
      investigate the regulation of TTP expression in the mouse macrophage cell line
      RAW264.7. We show that TTP mRNA is expressed in a biphasic manner following
      stimulation of cells with lipopolysaccharide and that the second phase of
      expression, like the first, is dependent on mitogen-activated protein kinase
      (MAPK) p38. MAPK p38 acts through a downstream kinase to stabilize TTP mRNA, and
      this stabilization is mediated by an adenosine/uridine-rich region at the 3'-end
      of the TTP 3'-untranslated region. Hence TTP is post-transcriptionally regulated
      in a similar manner to several proinflammatory genes. We also demonstrate that
      TTP is able to bind to its own 3'-untranslated region and negatively regulate its
      own expression, forming a feedback loop to limit expression levels.

PMID- 15187093
TI  - Biochemical and kinetic characterization of the DNA helicase and exonuclease
      activities of werner syndrome protein.
AB  - The WRN gene, defective in the premature aging and genome instability disorder
      Werner syndrome, encodes a protein with DNA helicase and exonuclease activities.
      In this report, cofactor requirements for WRN catalytic activities were examined.
      WRN helicase performed optimally at an equimolar concentration (1 mm) of Mg(2+)
      and ATP with a K(m) of 140 microm for the ATP-Mg(2+) complex. The initial rate of
      WRN helicase activity displayed a hyperbolic dependence on ATP-Mg(2+)
      concentration. Mn(2+) and Ni(2+) substituted for Mg(2+) as a cofactor for WRN
      helicase, whereas Fe(2+) or Cu(2+) (10 microm) profoundly inhibited WRN unwinding
      in the presence of Mg(2+).Zn(2+) (100 microm) was preferred over Mg(2+) as a
      metal cofactor for WRN exonuclease activity and acts as a molecular switch,
      converting WRN from a helicase to an exonuclease. Zn(2+) strongly stimulated the
      exonuclease activity of a WRN exonuclease domain fragment, suggesting a Zn(2+)
      binding site in the WRN exonuclease domain. A fluorometric assay was used to
      study WRN helicase kinetics. The initial rate of unwinding increased with WRN
      concentration, indicating that excess enzyme over DNA substrate improved the
      ability of WRN to unwind the DNA substrate. Under presteady state conditions, the
      burst amplitude revealed a 1:1 ratio between WRN and DNA substrate, suggesting an
      active monomeric form of the helicase. These are the first reported kinetic
      parameters of a human RecQ unwinding reaction based on real time measurements,
      and they provide mechanistic insights into WRN-catalyzed DNA unwinding.

PMID- 15187094
TI  - HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8
      homologues and delipidates microtubule-associated protein light chain 3- and
      GABAA receptor-associated protein-phospholipid conjugates.
AB  - In yeast, Atg4/Apg4 is a unique cysteine protease responsible for the cleavage of
      the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation
      during the formation of autophagosomes. However, it is still unclear whether four
      human Atg4 homologues cleave the carboxyl termini of the three human Atg8
      homologues, microtubule-associated protein light chain 3 (LC3), GABARAP, and GATE
      16. Using a cell-free system, we found that HsAtg4B, one of the human Atg4
      homologues, cleaves the carboxyl termini of these three Atg8 homologues. In
      contrast, the mutant HsAtg4B(C74A), in which a predicted active site Cys(74) was
      changed to Ala, lacked proteolytic activity, indicating that Cys(74) is essential
      for the cleavage activity of cysteine protease. Using phospholipase D, we showed
      that the modified forms of endogenous LC3 and GABARAP are lipidated and therefore
      were designated LC3-PL and GABARAP-PL. When purified glutathione S-transferase
      tagged HsAtg4B was incubated in vitro with a membrane fraction enriched with
      endogenous LC3-PL and GABARAP-PL, the mobility of LC3-PL and GABARAP-PL was
      changed to those of the unmodified proteins. These mobility shifts were not seen
      when Cys(74) of HsAtg4B was changed to Ala. Overexpression of wild-type HsAtg4B
      decreased the amount of LC3-PL and GABARAP-PL and increased the amount of
      unmodified endogenous LC3 and GABARAP in HeLa cells. Expression of CFP-tagged
      HsAtg4B (CFP-HsAtg4B) and YFP-tagged LC3 in HeLa cells under starvation
      conditions resulted in a significant decrease in the punctate pattern of
      distribution of YFP-tagged LC3 and an increase in its cytoplasmic distribution.
      RNA interference of HsAtg4B increased the amount of LC3-PL in HEK293 cells. Taken
      together, these results suggest that HsAtg4B negatively regulates the
      localization of LC3 to a membrane compartment by delipidation.

PMID- 15187095
TI  - 14-3-3sigma mediation of cell cycle progression is p53-independent in response to
      insulin-like growth factor-I receptor activation.
AB  - We investigated the role of 14-3-3sigma protein in insulin-like growth factor-I
      (IGF-I) receptor signaling. It has been previously shown that 14-3-3sigma
      negatively regulates cell cycle especially in response to p53-sensitive DNA
      damage. In this study we demonstrated that 14-3-3sigma is a positive mediator of
      IGF-I receptor-induced cell proliferation. Treatment with IGF-I increased 14-3
      3sigma mRNA and protein levels about 4-fold, in a time-dependent manner in MCF-7
      breast cancer cells. Preincubation with the phosphoinositide 3'-kinase inhibitor
      LY294002 significantly reduced the effects of IGF-I on 14-3-3sigma gene
      expression in these cells, suggesting that this effect of IGF-I occurs via the
      phosphoinositide 3'-kinase pathway. 14-3-3sigma is induced by IGF-I in MCF-7
      cells, which express wild-type p53, as well as in MCF-7 cells transfected with a
      small interference RNA targeting duplex that reduced p53 expression levels. These
      results suggest that IGF-I induces 14-3-3sigma expression in a manner that is
      independent of p53. Using the small interference RNA strategy, we demonstrated
      that a 70-75% reduction of 14-3-3sigma mRNA levels resulted in a similar decrease
      in the effects of IGF-I on cell cycle progression and proliferation in MCF-7
      cells. This effect was also associated with a reduction in IGF-I-induced cyclin
      D1 expression. Taken together, these results suggest that 14-3-3sigma positively
      mediates IGF-I-induced cell cycle progression.

PMID- 15187096
TI  - Influence of coinfecting pathogens on HIV expression: evidence for a role of Toll
      like receptors.
AB  - Immune activation of HIV gene expression as a consequence of the host response to
      coinfecting pathogens has been implicated as an important factor in AIDS
      progression. Immune responsiveness to many of the infectious agents associated
      with HIV has been demonstrated to depend on a family of innate recognition
      molecules, known as Toll-like receptors (TLR). Therefore, TLR-pathogen
      interactions could play an indirect role in regulating HIV-associated disease. In
      this review, we summarize emerging evidence for the influence of TLR recognition
      on HIV gene activation and AIDS progression.

PMID- 15187097
TI  - Cutting Edge: NK cells mediate IgG1-dependent hyperacute rejection of xenografts.
AB  - Classic hyperacute rejection is dependent on the activation of the terminal
      components of complement. Recently, xenoantibodies with limited abilities to
      activate the classical pathway of complement in vitro have been implicated in the
      acute vascular rejection of xenografts. It is unclear how these Abs affect their
      pathogenic activities in vivo. In this study, we demonstrate the ability of an
      anti-Gal-alpha1,3Gal (Gal) IgG1, with modest complement-activating abilities in
      vitro, to induce xenograft rejection. This rejection was dependent on the
      activation of complement, on FcgammaR-mediated interactions, and on the presence
      of NK cells. Inhibition of any one of these factors resulted in the abrogation of
      IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic,
      hyperacute rejection that was solely dependent on complement activation. Our
      observations implicate two types of IgG-mediated rejection; one that is dependent
      on complement activation, and a second that is uniquely dependent on complement,
      FcgammaR, and NK cells.

PMID- 15187098
TI  - Rapid development of T cell memory.
AB  - Prime-boost immunization is a promising strategy for inducing and amplifying
      pathogen- or tumor-specific memory CD8 T cell responses. Although expansion of
      CD8 T cell populations following the second Ag dose is integral to the prime
      boost strategy, it remains unclear when, after priming, memory T cells become
      competent to proliferate. In this study, we show that Ag-specific CD8 T cells
      with the capacity to undergo extensive expansion are already present at the peak
      of the primary immune response in mice. These early memory T cells represent a
      small fraction of the primary immune response and, at early time points, their
      potential to proliferate is obscured by large effector T cell populations that
      rapidly clear Ag upon reimmunization. With sufficient Ag boosting, however,
      secondary expansion of these memory cells can be induced as early as 5-7 days
      following primary immunization. Importantly, both early and delayed boosting
      result in similar levels of protective immunity to subsequent pathogen challenge.
      Early commitment and differentiation of memory T cells during primary
      immunization suggest that a short duration between priming and boosting is
      feasible, providing potential logistic advantages for large-scale prime-boost
      vaccination of human populations.

PMID- 15187099
TI  - Expression characteristics and stimulatory functions of CD43 in human CD4+ memory
      T cells: analysis using a monoclonal antibody to CD43 that has a novel lineage
      specificity.
AB  - We have used HSCA-2, an mAb that recognizes a sialic acid-dependent epitope on
      the low molecular mass (approximately 115-kDa) glycoform of CD43 that is
      expressed in resting T and NK cells, to examine the expression characteristics
      and stimulatory functions of CD43 in human CD4+ memory T cells. Having previously
      reported that the memory cells that respond to recall Ags in a CD4+ CD45RO+ T
      cell population almost all belong to a subset whose surface CD43 expression
      levels are elevated, we now find that exposing these same memory T cells to HSCA
      2 mAb markedly increases their proliferative responsiveness to recall Ags. We
      think it unlikely that this increase in responsiveness is a result of CD43
      mediated monocyte activation, especially given that the HSCA-2 mAb differs from
      all previously used CD43 mAbs in having no obvious binding specificity for
      monocyte CD43. Predictably, treatment with HSCA-2 mAb did not lead to significant
      recall responses in CD4+ CD45RO+ T cells, whose CD43 expression levels were
      similar to or lower than those of naive cells. Other experiments indicated that
      the HSCA-2 mAb was capable of enhancing the proliferative responsiveness of CD4+
      memory T cells that had been exposed to polyclonal stimulation by monocyte-bound
      CD3 mAb and could also act in synergy with CD28 mAb to enhance the responsiveness
      of CD4+ T cells to CD3 stimulation. Taken together, these findings suggest that
      the CD43 molecules expressed on CD4+ memory T cells may be capable of enhancing
      the costimulatory signaling and hence providing accessory functions to TCR
      mediated activation processes.

PMID- 15187100
TI  - Dexamethasone suppresses antigen-induced activation of phosphatidylinositol 3
      kinase and downstream responses in mast cells.
AB  - Dexamethasone and other glucocorticoids suppress FcepsilonRI-mediated release of
      inflammatory mediators from mast cells. Suppression of cytokine production is
      attributed to repression of cytokine gene transcription but no mechanism has been
      described for the suppression of degranulation. We show that therapeutic
      concentrations of dexamethasone inhibit intermediate signaling events, in
      particular the activation of phosphatidylinositol (PI)3-kinase and downstream
      signaling events that lead to degranulation in rat basophilic leukemia 2H3 cells.
      This inhibitory action is mediated via the glucocorticoid receptor and is not
      apparent when cells are stimulated via Kit in a mouse bone marrow-derived mast
      cell line. The primary perturbation appears to be the failure of the regulatory
      p85 subunit of PI3-kinase to engage with the adaptor protein Grb2-associated
      binder 2 leading to suppression of phosphorylation of phospholipase Cgamma2, the
      calcium signal, and degranulation. Suppression of PI3-kinase activation by
      dexamethasone may also contribute to reduced cytokine production because the PI3
      kinase inhibitor LY294002, like dexamethasone, inhibits Ag-induced transcription
      of cytokine genes as well as degranulation.

PMID- 15187101
TI  - The role of mRNA turnover in the regulation of tristetraprolin expression:
      evidence for an extracellular signal-regulated kinase-specific, AU-rich element
      dependent, autoregulatory pathway.
AB  - Tristetraprolin (TTP) is a regulator of TNF-alpha mRNA stability and is the only
      trans-acting factor shown to be capable of regulating AU-rich element-dependent
      mRNA turnover at the level of the intact animal. Using the THP-1 myelomonocytic
      cell line, we demonstrated for the first time that TTP is encoded by an mRNA with
      a short half-life under resting conditions. Using pharmacologic inhibitors of the
      mitogen-activated protein kinase pathways, we show that the induction of TTP by
      LPS activation is mediated through changes in transcription, mRNA stability, and
      translation. A coordinate increase in both TTP and TNF-alpha mRNA stability
      occurs within 15 min of LPS treatment, but is transduced through different
      mitogen-activated protein kinase pathways. This regulation of TTP and TNF-alpha
      mRNA stability is associated with the finding that TTP binds these mRNA under
      both resting and LPS-activated conditions in vivo. Finally, we demonstrate that
      TTP can regulate reporter gene expression in a TTP 3' untranslated region
      dependent manner and identify three distinct AU-rich elements necessary to
      mediate this effect. Thus, TTP regulates its own expression in a manner identical
      to that seen with the TNF-alpha 3' untranslated region, indicating that this
      autoregulation is mediated at the level of mRNA stability. In this manner, TTP is
      able to limit the production of its own proteins as well as that of TNF-alpha and
      thus limit the response of the cell to LPS.

PMID- 15187102
TI  - IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A
      in breast cancer cells.
AB  - Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to
      uncontrolled cell proliferation and tumor growth. We recently demonstrated that
      IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation
      by preventing cells from entering the S phase of the cell cycle, leading to
      G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor
      tyrosine kinase to phosphorylate its major docking protein, insulin receptor
      substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this
      juxtamembrane cross-talk between cytokine and growth factor receptors to
      downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to
      activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent
      phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term
      activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not
      the mammalian target of rapamycin or mitogen-activated protein kinase pathways,
      is required for IGF-I to hyperphosphorylate retinoblastoma and to cause
      accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt
      activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces
      p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2.
      Collectively, these data establish a novel mechanism by which prolonged Akt
      phosphorylation serves as a convergent target for both IGF-I and IL-1beta;
      stimulation by growth factors such as IGF-I promotes G(1)-S phase progression,
      whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce
      cytostasis. In this manner, Akt serves as a critical bridge that links proximal
      receptor signaling events to more distal cell cycle machinery.

PMID- 15187103
TI  - Murine CD8+ recent thymic emigrants are alphaE integrin-positive and CC chemokine
      ligand 25 responsive.
AB  - Recent thymic emigrants (RTE) are an important subpopulation of naive CD8+ T
      cells because of their ability to reconstitute a diverse immune system after
      periods of T cell depletion. In neonatal mice, the majority of peripheral T
      lymphocytes are RTE, cells that have recently left the thymus to populate the
      periphery. Postulating that these cells could have unique trafficking mechanisms,
      we compared adhesion molecule and chemokine receptor expression of neonatal RTE
      with mature adult lymphocytes. Neonatal CD8+ splenocytes uniformly express
      alpha(E) integrin and exhibit a high responsiveness to CC chemokine ligand
      (CCL25) (as compared with adult CD8+ splenocytes). Mature CD8+ thymocytes have a
      similar alpha(E) integrin(+) CCL25 responsive phenotype, as do adult CD8+ RTE
      identified by intrathymic FITC injection. With increasing age, the frequency of
      CD8+ alpha(E) integrin(+) splenocytes decreases, roughly correlating with thymic
      involution. Moreover, halting thymic output by thymectomy accelerates the age
      dependent decline in peripheral CD8+ alpha(E) integrin(+) RTE phenotype cells.
      Low expression of CD44 distinguishes these CD8+ RTE from a population of memory
      phenotype alpha(E) integrin(+) CD8+ cells that are CD44(high). We conclude that
      CD8+ RTE have unique adhesive and chemotactic properties that distinguish them
      from naive CD8+ T cells. These properties may enable specialized
      microenvironmental and cell-cell interactions contributing to the fate of RTE in
      the periphery during the early post-thymic period. This phenotype will also
      facilitate the identification and isolation of RTE for further studies.

PMID- 15187104
TI  - c-Maf and JunB mediation of Th2 differentiation induced by the type 2 G protein
      coupled receptor (VPAC2) for vasoactive intestinal peptide.
AB  - Vasoactive intestinal peptide and its G protein-coupled receptors, VPAC(1) and
      VPAC(2), regulate critical aspects of innate and adaptive immunity. T cell
      VPAC(2)Rs mediate changes in cytokine generation, which potently increase the
      Th2/Th1 ratio and consequently shift the effector responses toward allergy and
      inflammation. To examine mechanisms of VPAC(2) promotion of the Th2 phenotype, we
      analyzed controls of IL-4 transcription in CD4 T cells from T cell-targeted
      VPAC(2) transgenic (Tg), VPAC(2) knockout, and wild-type (WT) mice. c-maf and
      junB mRNA, protein, and activity were significantly up-regulated to a higher
      level in TCR-stimulated CD4 T cells from Tg mice compared with those from
      knockout and WT C57BL/6 mice. In contrast, GATA3, T-bet, and NFATc levels were
      identical in WT and Tg CD4 T cells. Vasoactive intestinal peptide binding to
      VPAC(2) on CD4 T cells specifically induces an up-regulation of the Th2-type
      transcription factors c-Maf and JunB, which consequently enhances IL-4 and IL-5
      production, leading to a Th2-type phenotype.

PMID- 15187105
TI  - Expression of human CD1d molecules protects target cells from NK cell-mediated
      cytolysis.
AB  - The cytotoxic activity of NK cells can be inhibited by classical and nonclassical
      MHC molecules. The CD1 system is formed by a family of glycoproteins that are
      related to classical MHC. CD1a, b, and c molecules present lipids or glycolipids
      to T cells and are involved in defense against microbial infections, especially
      mycobacteria. It has been shown recently that these molecules can inhibit target
      cell lysis by human NK cells. It has also been shown that mouse CD1d molecules
      can protect cells from NK cell-mediated cytotoxicity. In the present study, we
      describe how human CD1d, orthologous to murine CD1 molecules, can inhibit NK cell
      mediated cytolysis. We have expressed CD1d in the HLA class I-deficient cell
      lines L721.221 and C1R. The inhibitory effect is observed when effector NK cells
      from different donors are used, as well as in different cell lines with NK
      activity. The inhibitory effect was reversed by incubating the target cells with
      a mAb specific for human CD1d. Incubation of target cells with the ligands for
      CD1d, alpha-galactosylceramide (alpha-GalCer), and beta-GalCer abolishes the
      protective effect of CD1d in our in vitro killing assays. Staining the effector
      cells using CD1d tetramers loaded with alpha-GalCer was negative, suggesting that
      the putative inhibitory receptor does not recognize CD1d molecules loaded with
      alpha-GalCer.

PMID- 15187106
TI  - Costimulation via glucocorticoid-induced TNF receptor in both conventional and
      CD25+ regulatory CD4+ T cells.
AB  - The glucocorticoid-induced TNF receptor (GITR), which is a member of the TNF
      receptor family, is expressed preferentially at high levels on CD25+CD4+
      regulatory T cells and plays a key role in the peripheral tolerance that is
      mediated by these cells. GITR is also expressed on conventional CD4+ and CD8+ T
      cells, and its expression is enhanced rapidly after activation. In this report we
      show that the GITR provides a potent costimulatory signal to both CD25+ and CD25-
      CD4+ T cells. GITR-mediated stimulation induced by anti-GITR mAb DTA-1 or GITR
      ligand transfectants efficiently augmented the proliferation of both CD25-CD4+
      and CD25+CD4+ T cells under the limited dose of anti-CD3 stimulation. The
      augmentation of T cell activation was further confirmed by the enhanced cell
      cycle progression; early induction of the activation Ags, CD69 and CD25; cytokine
      production, such as IL-2, IFN-gamma, IL-4, and IL-10; anti-CD3-induced redirected
      cytotoxicity; and intracellular signaling, assessed by translocation of NF-kappaB
      components. GITR costimulation showed a potent ability to produce high amounts of
      IL-10, which resulted in counter-regulation of the enhanced proliferative
      responses. Our results highlight evidence that GITR acts as a potent and unique
      costimulator for an early CD4+ T cell activation.

PMID- 15187107
TI  - Initial antigen encounter programs CD8+ T cells competent to develop into memory
      cells that are activated in an antigen-free, IL-7- and IL-15-rich environment.
AB  - Although much is known concerning the immunobiology of CD8+ T memory cells, the
      initial events favoring the generation of CD8+ T memory cells remain poorly
      defined. Using a culture system that yields memory-like CD8+ T cells, we show
      that 1 day after Ag encounter, Ag-activated T cells developed into memory-like T
      cells, but this optimally occurred 3 days after Ag encounter. Key phenotypic,
      functional, and molecular properties that typify central memory T cells were
      expressed within 48 h when the activated CD8+ T cells were cultured with IL-7 or
      IL-15 in the absence of Ag or following transfer into normal mice. These data
      support a model whereby Ag activation of naive CD8+ T cells not only programs
      effector cell expansion and contraction but the potential to develop into a
      memory cell which ensues in an Ag-free environment containing IL-7 or IL-15.

PMID- 15187108
TI  - A novel role for p21-activated protein kinase 2 in T cell activation.
AB  - To identify novel components of the TCR signaling pathway, a large-scale
      retroviral-based functional screen was performed using CD69 expression as a
      marker for T cell activation. In addition to known regulators, two truncated
      forms of p21-activated kinase 2 (PAK2), PAK2DeltaL(1-224) and PAK2DeltaS(1-113),
      both lacking the kinase domain, were isolated in the T cell screen. The PAK2
      truncation, PAK2DeltaL, blocked Ag receptor-induced NFAT activation and TCR
      mediated calcium flux in Jurkat T cells. However, it had minimal effect on
      PMA/ionomycin-induced CD69 up-regulation in Jurkat cells, on anti-IgM-mediated
      CD69 up-regulation in B cells, or on the migratory responses of resting T cells
      to chemoattractants. We show that PAK2 kinase activity is increased in response
      to TCR stimulation. Furthermore, a full-length kinase-inactive form of PAK2
      blocked both TCR-induced CD69 up-regulation and NFAT activity in Jurkat cells,
      demonstrating that kinase activity is required for PAK2 function downstream of
      the TCR. We also generated a GFP-fused PAK2 truncation lacking the Cdc42/Rac
      interactive binding region domain, GFP-PAK2(83-149). We show that this construct
      binds directly to the kinase domain of PAK2 and inhibits anti-TCR-stimulated T
      cell activation. Finally, we demonstrate that, in primary T cells, dominant
      negative PAK2 prevented anti-CD3/CD28-induced IL-2 production, and TCR-induced
      CD40 ligand expression, both key functions of activated T cells. Taken together,
      these results suggest a novel role for PAK2 as a positive regulator of T cell
      activation.

PMID- 15187109
TI  - Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK
      cytotoxicity in cancer patients.
AB  - NK cell function in cancer patients is severely impaired, but the mechanism
      underlying this impairment is not clearly understood. In this study we show
      evidence that TGF-beta1 secreted by tumors is responsible for the poor NK lytic
      activity via down-regulating an NK-activating receptor, NKG2D. The plasma level
      of TGF-beta1 in human lung cancer or colorectal cancer patients was elevated
      compared with that in normal volunteers, and this elevation was inversely
      correlated with surface expression of NKG2D on NK cells in these patients.
      Incubation of NK cells with plasma obtained from cancer patients specifically
      down-modulated surface NKG2D expression, whereas addition of neutralizing anti
      TGF-beta1 mAbs completely restored surface NKG2D expression. Likewise, incubation
      of NK cells and lymphokine-activated killer cells with TGF-beta1 resulted in
      dramatic reduction of surface NKG2D expression associated with impaired NK
      cytotoxicity. Modulation of NKG2D by TGF-beta1 was specific, as expression of
      other NK receptors, CD94/NKG2A, CD44, CD16, 2B4, or CD56, was not affected by TGF
      beta1. Impaired NK cytotoxicity by TGF-beta1 was not due to alteration of lytic
      moieties, such as perforin or Fas, or apoptotic pathway, but, rather, appeared to
      be due to lack of NKG2D expression. Taken together, our data suggest that
      impaired NK function in cancer patients can be attributed to down-modulation of
      activating receptors, such as NKG2D, via secretion of TGF-beta1.

PMID- 15187110
TI  - Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL
      10highIL-12low regulatory dendritic cell.
AB  - Dendritic cells (DC) initiate immunity by the activation of naive T cells and
      control immunity through their ability to induce unresponsiveness of lymphocytes
      by mechanisms that include deletion and induction of regulatory cells. An
      inadequate presentation to T cells by tumor-induced "regulatory" DC, among
      several mechanisms, can explain tolerance to tumor-associated Ags. In this study,
      we show that tumor-derived mucin profoundly affects the cytokine repertoire of
      monocyte-derived DC and switch them into IL-10(high)IL-12(low) regulatory APCs
      with a limited capacity to trigger protective Th1 responses. In fact, DC
      cocultured with pancreatic tumor cell lines in a Transwell system did not reach
      full maturation, had low immunostimulatory functions, did not produce IL-12, and
      released high levels of IL-10. The involvement of known tumor-derived immune
      suppressive factors (e.g., vascular endothelial growth factor, TGF-beta, IL-6,
      and IL-10) was considered and excluded. We provide evidence that tumor-derived
      MUC1 mucins are responsible for the impaired DC maturation and function. DC
      obtained in the presence of tumor microenvironment preferentially polarized IL
      4(+) response. Moreover, T cells primed by these regulatory DC became anergic and
      behaved as suppressor/regulatory cells. These findings identify mucin secretion
      as a novel mechanism of tumor escape from immune surveillance and provide the
      basis for the generation of potentially tolerogenic DC.

PMID- 15187111
TI  - CD4(-)CD8alphaalpha subset of CD1d-restricted NKT cells controls T cell
      expansion.
AB  - Valpha24 invariant (Valpha24i) CD1d-restricted NKT cells are widely regarded to
      have immune regulatory properties. They are known to have a role in preventing
      autoimmune diseases and are involved in optimally mounted immune responses to
      pathogens and tumor cells. We were interested in understanding how these cells
      provide protection in autoimmune diseases. We first observed, using EBV/MHC I
      tetrameric complexes, that expansion of Ag-specific cells in human PBMCs was
      reduced when CD1d-restricted NKT cells were concomitantly activated. This was
      accompanied by an increase in a CD4(-)CD8alphaalpha(+) subset of Valpha24i NKT
      cells. To delineate if a specific subset of NKT cells was responsible for this
      effect, we generated different subsets of human CD4(-) and CD4(+) Valpha24i NKT
      clones and demonstrate that a CD4(-)CD8alphaalpha(+) subset with highly efficient
      cytolytic ability was unique among the clones in being able to suppress the
      proliferation and expansion of activated T cells in vitro. Activated clones were
      able to kill CD1d-bearing dendritic or target cells. We suggest that one
      mechanism by which CD1d-restricted NKT cells can exert a regulatory role is by
      containing the proliferation of activated T cells, possibly through timely lysis
      of APCs or activated T cells bearing CD1d.

PMID- 15187112
TI  - On the relevance of TCR rearrangement circles as molecular markers for thymic
      output during experimental graft-versus-host disease.
AB  - Efficient reconstitution of the pool of peripheral T cells after hemopoietic stem
      cell transplantation (HSCT) is dependent on normal thymic function. However, the
      development of graft-vs-host disease (GVHD) in the context of allogeneic HSCT is
      associated with injurious effects on thymocyte development. In this study, we
      examined in models of syngeneic and allogeneic murine HSCT whether actual
      posttransplant thymic output is accurately reflected by analysis of signal-joint
      TCR rearrangement excision circles (sjTRECs). Our data demonstrate that the de
      novo generation of T cells following syngeneic HSCT of T cell-deficient B6.RAG2(
      /-) (recombination-activating gene 2(-/-)) mice correlates firmly with an
      increase of sjTRECs in the thymus and spleen. However, the altered homeostasis of
      naive peripheral T cells in the presence of GVHD necessitates the combined
      analysis of cell division in vivo and determinations of sjTREC contents and total
      sjTREC numbers to draw informative conclusions. From our data, we substantiate
      that thymic output and peripheral division of newly generated T cells are
      diminished in the presence of acute GVHD in an experimental radiation/allogeneic
      HSCT model.

PMID- 15187113
TI  - IL-12 pretreatments enhance IFN-alpha-induced Janus kinase-STAT signaling and
      potentiate the antitumor effects of IFN-alpha in a murine model of malignant
      melanoma.
AB  - IFN-alpha 2b (IFN-alpha) has been used to treat patients with metastatic
      malignant melanoma and patients rendered disease-free via surgery but at high
      risk for recurrence. We hypothesized that IL-12 pretreatments would result in
      endogenous IFN-gamma production, and that this, in turn, would up-regulate levels
      of Janus kinase-STAT signaling intermediates and lead to increased expression of
      genes regulated by IFN-alpha. Treatment of PBMCs with IL-12 stimulated a
      significant and dose-dependent production of IFN-gamma. Pretreatment of PBMCs and
      tumor cells with IFN-gamma-containing supernatants from IL-12-stimulated PBMCs
      led to up-regulation of STAT1, STAT2, and IFN regulatory factor 9 (IRF9) and
      potentiated IFN-alpha-induced STAT signaling within PBMCs and tumor cells. These
      effects were abrogated by neutralization of IFN-gamma in the PBMC supernatants
      with an anti-IFN-gamma Ab. Pretreatment of HT144 melanoma cells and PBMCs with
      IFN-gamma or IFN-gamma-containing supernatants enhanced the actions of IFN-alpha
      at the transcriptional level, as measured by real-time RT PCR analysis of the IFN
      stimulated gene 15. Experiments in wild-type C57BL/6 and IFN-gamma receptor
      knockout (B6.129S7-Ifngr(tm1Agt)) mice demonstrated that a regimen of IL-12
      pretreatment, followed by IFN-alpha, could cure mice of i.p. B16F1 melanoma
      tumors (p < 0.007), whereas mice treated with either agent alone or PBS succumbed
      to fatal tumor burden. However, this treatment regimen did not significantly
      prolong the survival of IFN-gamma-deficient (B6.129S7-Ifng(tm1Ts)) mice compared
      with mice treated with IFN-alpha alone. These results suggest that the response
      to IFN-alpha immunotherapy can be significantly enhanced by IL-12 pretreatment,
      and this effect is dependent upon endogenous IFN-gamma production and its actions
      on melanoma cells.

PMID- 15187114
TI  - Simvastatin augments lipopolysaccharide-induced proinflammatory responses in
      macrophages by differential regulation of the c-Fos and c-Jun transcription
      factors.
AB  - The 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are
      a widely used class of drugs for cholesterol reduction. The reduction in
      mortality and morbidity in statin-treated patients is incompletely explained by
      their effects on cholesterol, and an anti-inflammatory role for the drug has been
      proposed. We report in this work that, unexpectedly, simvastatin enhances LPS
      induced IL-12p40 production by murine macrophages, and that it does so by
      activating the IL-12p40 promoter. Mutational analysis and dominant-negative
      expression studies indicate that both C/EBP and AP-1 transcription factors have a
      crucial role in promoter activation. This occurs via a c-Fos- and c-Jun-based
      mechanism; we demonstrate that ectopic expression of c-Jun activates the IL-12p40
      promoter, whereas expression of c-Fos inhibits IL-12p40 promoter activity.
      Simvastatin prevents LPS-induced c-Fos expression, thereby relieving the
      inhibitory effect of c-Fos on the IL-12p40 promoter. Concomitantly, simvastatin
      induces the phosphorylation of c-Jun by the c-Jun N-terminal kinase, resulting in
      c-Jun-dependent activation of the IL-12p40 promoter. This appears to be a general
      mechanism because simvastatin also augments LPS-dependent activation of the TNF
      alpha promoter, perhaps because the TNF-alpha promoter has C/EBP and AP-1 binding
      sites in a similar configuration to the IL-12p40 promoter. The fact that
      simvastatin potently augments LPS-induced IL-12p40 and TNF-alpha production has
      implications for the treatment of bacterial infections in statin-treated
      patients.

PMID- 15187116
TI  - Host dendritic cells alone are sufficient to initiate acute graft-versus-host
      disease.
AB  - Alloantigen expression on host APCs is essential to initiate graft-vs-host
      disease (GVHD); however, critical APC subset remains to be elucidated. We
      compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD
      by an add-back study of MHC class II-expressing APCs (II(+/+)) into MHC class II
      deficient (II(-/-)) mice that were resistant to CD4-dependent GVHD. Injection of
      host-derived, but not donor-derived, II(+/+) DCs or host-derived II(+/+) B cells,
      was sufficient to break GVHD resistance of II(-/-) mice and induced lethal acute
      GVHD. By contrast, host-derived II(+/+) B cells, both naive and LPS stimulated,
      failed to induce activation or tolerance of donor CD4(+) T cells. Similarly, in a
      model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic
      DCs, but not B cells, induced robust proliferation of donor CD8(+) T cells and
      broke GVHD resistance of chimeric recipients in which APCs were syngeneic to
      donors. These results demonstrate that host-derived DCs are critical in priming
      donor CD4(+) and CD8(+) T cells to cause GVHD, and selective targeting of host
      DCs may be a promising strategy to prevent GVHD.

PMID- 15187115
TI  - KIR2DL5 can inhibit human NK cell activation via recruitment of Src homology
      region 2-containing protein tyrosine phosphatase-2 (SHP-2).
AB  - Human NK cells use class I MHC-binding inhibitory receptors, such as the killer
      cell Ig-like receptor (KIR) family, to discriminate between normal and abnormal
      cells. Some tumors and virus-infected cells down-regulate class I MHC and thereby
      become targets of NK cells. Substantial evidence indicates that the mechanism of
      KIR-mediated inhibition involves recruitment of the protein tyrosine
      phosphatases, Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1)
      and SHP-2, to two phosphorylated cytoplasmic immunoreceptor tyrosine-based
      inhibitory motifs (ITIMs). KIR2DL5 is a type II member of the KIR2D family with
      an atypical extracellular domain and an intracytoplasmic domain containing one
      typical ITIM and one atypical ITIM sequence. Although KIR2DL5 structure is
      expressed by approximately 50% of humans and is conserved among primate species,
      its function has not been determined. In the present study, we directly compared
      functional and biochemical properties of KIR2DL5, KIR3DL1 (a type I KIR with two
      ITIMs), and KIR2DL4 (the only other type II KIR, which has a single ITIM) in a
      human NK-like cell line. Our results show that KIR2DL5 is an inhibitory receptor
      that can recruit both SHP-1 and SHP-2, and its inhibitory capacity is more
      similar to that of the cytoplasmic domain of KIR2DL4 than KIR3DL1. Interestingly,
      inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative
      SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative
      phosphatases can block inhibition by KIR3DL1. Therefore, the cytoplasmic domains
      of type II KIRs (2DL4 and 2DL5) exhibit distinct inhibitory capacities when
      compared with type I KIRs (3DL1), due to alterations in the canonical ITIM
      sequences.

PMID- 15187117
TI  - Activation of naive CD4+ T cells in vivo by a self-peptide mimic: mechanism of
      tolerance maintenance and preservation of immunity.
AB  - Intrathymic selection generates a peripheral repertoire of CD4(+) T cells with
      receptors that retain low affinity for self-peptide MHC complexes. Despite self
      recognition, T cells remain tolerant even in the setting of microbial challenge
      and resultant costimulatory signals. We demonstrate here a novel mechanism for
      tolerance maintenance under conditions of self-recognition and strong
      costimulation. TCR engagement in vivo with a low-avidity peptide, as a mimic of
      self, provided with poly(I:C) (dsRNA) led to division of naive T cells that was
      dependent upon costimulatory signals; however, the dividing cells rapidly
      underwent deletion. By contrast, the surviving cells that were activated as
      evidenced by up-regulation of CD69 did not become effectors upon restimulation
      with the same ligand and maintained an effective response against agonist
      peptide. We suggest TCR engagement with self-peptide MHC complexes promotes
      tolerance maintenance during pathogen challenge, while preserving efficient
      reactivity for subsequent encounter with foreign Ags.

PMID- 15187118
TI  - Increased and long-term generation of dendritic cells with reduced function from
      IL-6-deficient bone marrow.
AB  - The importance of IL-6 in dendritic cell (DC) development and function has not
      been well defined. To establish the role of IL-6, we studied bone marrow-derived
      DC (BMDC) and freshly isolated splenic DC from IL-6(-/-)-transgenic mice. We
      found that although IL-6(-/-) bone marrow had a similar composition to that of
      wild-type (WT) mice, it generated up to 10 times more DC when cultured in GM-CSF.
      The difference persisted even when IL-6(-/-) and WT bone marrow were cultured
      together, excluding the possibility that the effects were simply due to different
      cytokine microenvironments. In comparison to WT BMDC, IL-6(-/-) BMDC captured at
      least as much Ag, had an equivalent surface phenotype, and matured similarly in
      response to LPS or CpG. However, IL-6(-/-) BMDC induced less T cell
      allostimulation and Ag-specific T cell activation, but only the former was
      related to their inability to generate IL-6. Although WT bone marrow cultures
      died within 4 wk, IL-6(-/-) cultures continued to generate BMDC for >120 days,
      although the BMDC became immature and less functional. In vivo, we found that IL
      6(-/-) mice had similar numbers and types of splenic DC as WT mice, both normally
      and after treatment with either Flt-3 ligand or GM-CSF. These findings
      demonstrate that IL-6 has profound effects on DC development in vitro, although
      the number and subtype composition of DC are unaffected by the absence of IL-6 in
      vivo. Furthermore, secretion of IL-6 is critical to certain DC functions.

PMID- 15187119
TI  - Chemokine monokine induced by IFN-gamma/CXC chemokine ligand 9 stimulates T
      lymphocyte proliferation and effector cytokine production.
AB  - Monokine induced by IFN-gamma (MIG; CXC chemokine ligand (CXCL)9) is important in
      T lymphocyte recruitment in organ transplantation. However, it is not known
      whether this chemokine, in addition to its chemotactic properties, exerts any
      effect on T lymphocyte effector functions. For in vivo studies, we used a
      previously characterized murine model of chronic rejection. The recipient mice
      were treated with anti-MIG/CXCL9 Ab; graft-infiltrating cells were analyzed for
      IFN-gamma production. For in vitro studies, exogenous CXCR3 ligands were added to
      CD4 lymphocytes in MLRs, and the proliferative responses were measured. Separate
      experiments quantitated the number of IFN-gamma-producing cells in MLRs by
      ELISPOT. Neutralization of MIG/CXCL9, in the in vivo model, resulted in
      significant reduction in the percentage of IFN-gamma-producing graft-infiltrating
      T lymphocytes. In vitro experiments demonstrated that 1) exogenous MIG/CXCL9
      stimulated CD4 lymphocyte proliferation in a MHC class II-mismatched MLR, 2)
      MIG/CXCL9 also increased the number of IFN-gamma-producing CD4 lymphocytes in
      ELISPOT, 3) neutralization of MIG/CXCL9 in MLR reduced T lymphocyte
      proliferation, 4) IFN-gamma-inducible protein 10/CXCL10 and IFN-inducible T cell
      alpha chemoattractant/CXCL11 had similar effects on T lymphocyte proliferation,
      5) MIG/CXCL9 stimulated T lymphocyte proliferation in MHC class I- and total MHC
      mismatched MLRs, 6) neutralization of CXCR3 reduced MIG/CXCL9-induced T
      lymphocyte proliferation and the number of IFN-gamma-positive spots on ELISPOT,
      and 7) the proliferative effects of MIG/CXCL9 were mediated via an IL-2
      independent pathway and were controlled by IFN-gamma. This study demonstrates
      that MIG/CXCL9 stimulates T lymphocyte proliferation and effector cytokine
      production, in addition to its chemotactic effects. This novel observation
      expands our current understanding of MIG/CXCL9 biology beyond that of mediating T
      cell trafficking.

PMID- 15187120
TI  - Peptides identified through phage display direct immunogenic antigen to dendritic
      cells.
AB  - Dendritic cells (DC) play a critical role in adaptive immunity by presenting Ag,
      thereby priming naive T cells. Specific DC-binding peptides were identified using
      a phage display peptide library. DC-peptides were fused to hepatitis C virus
      nonstructural protein 3 (NS3) while preserving DC targeting selectivity and Ag
      immunogenicity. The NS3-DC-peptide fusion protein was efficiently presented to
      CD4+ and CD8+ T cells derived from hepatitis C virus-positive blood cells,
      inducing their activation and proliferation. This immunogenic fusion protein was
      significantly more potent than NS3 control fusion protein or NS3 alone. In
      chimeric NOD-SCID mice transplanted with human cells, DC-targeted NS3 primed
      naive CD4+ and CD8+ T cells for potent NS3-specific proliferation and cytokine
      secretion. The capacity of peptides to specifically target immunogenic Ags to DC
      may establish a novel strategy for vaccine development.

PMID- 15187121
TI  - CD27 is acquired by primed B cells at the centroblast stage and promotes germinal
      center formation.
AB  - Studies on human B cells have featured CD27 as a marker and mediator of the B
      cell response. We have studied CD27 expression and function on B cells in the
      mouse. We find that B cells acquire CD27 at the centroblast stage and lose it
      progressively upon further differentiation. It is not a marker for somatically
      mutated B cells and is present at very low frequency on memory B cells.
      Enrichment of CD27 among centroblasts and the presence of its ligand CD70 on
      occasional T and B cells in or near germinal centers (GCs) suggested a role for
      CD27/CD70 interactions in clonal B cell expansion. Accordingly, GC formation in
      response to influenza virus infection was delayed in CD27 knockout mice. CD27
      deficiency did not affect somatic hypermutation or serum levels of virus-specific
      IgM, IgG, and IgA attained in primary and recall responses. Adoptive transfer of
      T and B cells into CD27/CD28(-/-) mice revealed that CD27 promotes GC formation
      and consequent IgG production by two distinct mechanisms. Stimulation of CD27 on
      B cells by CD28(+) Th cells accelerates GC formation, most likely by promoting
      centroblast expansion. In addition, CD27 on T cells can partially substitute for
      CD28 in supporting GC formation.

PMID- 15187122
TI  - CTLA-4 regulates expansion and differentiation of Th1 cells following induction
      of peripheral T cell tolerance.
AB  - Intravenous treatment with Ag (peptide)-coupled, ethylene carbodiimide-fixed
      syngeneic splenocytes (Ag-SP) is a powerful method to induce anergy in vitro and
      peripheral T cell tolerance in vivo. In this study, we examined the effects of Ag
      SP administration on T cell activity ex vivo and in vivo using OVA-specific
      DO11.10 TCR transgenic T cells. Although treatment with OVA323-339-SP resulted in
      a strong inhibition of peptide-specific T cell recall responses in vitro,
      examination of the immediate effects of Ag-SP treatment on T cells in vivo
      demonstrated that tolerogen injection resulted in rapid T cell activation and
      proliferation. Although there was an increase in the number of OVA-specific
      DO11.10 T cells detected in the lymphoid organs, these previously tolerized T
      cells were strongly inhibited in mounting proliferative or inflammatory responses
      upon rechallenge in vivo with peptide in CFA. This unresponsiveness was
      reversible by treatment with anti-CTLA-4 mAb. These results are consistent with
      the hypothesis that Ag-SP injection induces a state of T cell anergy that is
      maintained by CTLA-4 engagement.

PMID- 15187123
TI  - A two-step model of acute CD4 T-cell mediated cardiac allograft rejection.
AB  - CD4 T cells are both necessary and sufficient to mediate acute cardiac allograft
      rejection in mice. This process requires "direct" engagement of donor MHC class
      II molecules. That is, acute rejection by CD4+ T cells requires target MHC class
      II expression by the donor and not by the host. However, it is unclear whether
      CD4+ T cell rejection requires MHC class II expression on donor hemopoietic
      cells, nonhemopoietic cells, or both. To address this issue, bone marrow
      transplantation in mice was used to generate chimeric heart donors in which MHC
      class II was expressed either on somatic or on hemopoietic cells. We report that
      direct recognition of hemopoietic and nonhemopoietic cells are individually rate
      limiting for CD4+ T cell-mediated rejection in vivo. Importantly, active
      immunization with MHC class II(+) APCs triggered acute rejection of hearts
      expressing MHC class II only on the somatic compartment. Thus, donor somatic
      cells, including endothelial cells, are not sufficient to initiate acute
      rejection; but they are necessary as targets of direct alloreactive CD4 T cells.
      Taken together, results support a two-stage model in which donor passenger
      leukocytes are required to activate the CD4 response while direct interaction
      with the somatic compartment is necessary for the efferent phase of acute graft
      rejection.

PMID- 15187124
TI  - Lymphotoxin-beta receptor activation by activated T cells induces cytokine
      release from mouse bone marrow-derived mast cells.
AB  - Lymphotoxin-beta receptor (LTbetaR) signaling is known to play a key role in
      embryonic lymphoid organ formation as well as maintenance of lymphoid
      architecture. Activation of the LTbetaR is induced by either the heterotrimeric
      lymphotoxin-alpha(1)beta(2) (LTalpha(1)beta(2)) or the homotrimeric LIGHT
      (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV
      gpD for herpes virus entry mediator, a receptor expressed by T lymphocyte). Both
      ligands are expressed on activated lymphocytes. As mast cells reside in close
      proximity to activated T cells in some inflammatory tissues, we examined the
      expression of LTbetaR on bone marrow-derived mast cells and asked whether the
      LTbetaR-ligand interaction would allow communication between mast cells and
      activated T cells. We found that mast cells express LTbetaR at the mRNA as well
      as at the protein level. To investigate LTbetaR-specific mast cell activation,
      the LTbetaR on BMMC from either wild-type or LTbetaR-deficient mice was
      stimulated with recombinant mouse LIGHT or agonistic mAbs in the presence of
      ionomycin. LTbetaR-specific release of the cytokines IL-4, IL-6, TNF, and the
      chemokines macrophage inflammatory protein 2 and RANTES was detected. Moreover,
      coculture of mast cells with T cells expressing the LTbetaR ligands also entailed
      the release of these cytokines. Interference with a specific LTbetaR inhibitor
      resulted in significant suppression of mast cell cytokine release. These data
      clearly show that LTbetaR expressed on mast cells can transduce a costimulatory
      signal in T cell-dependent mast cell activation.

PMID- 15187125
TI  - Distinct footprints of TCR engagement with highly homologous ligands.
AB  - T cell receptor engagement promotes proliferation, differentiation, survival, or
      death of T lymphocytes. The affinity/avidity of the TCR ligand and the
      maturational stage of the T cell are thought to be principal determinants of the
      outcome of TCR engagement. We demonstrate in this study that the same mouse TCR
      preferentially uses distinct residues of homologous peptides presented by the MHC
      molecules to promote specific cellular responses. The preference for distinct TCR
      contacts depends on neither the affinity/avidity of TCR engagement (except in the
      most extreme ranges), nor the maturity of engaged T cells. Thus, different
      portions of the TCR ligand appear capable of biasing T cells toward specific
      biological responses. These findings explain differences in functional
      versatility of TCR ligands, as well as anomalies in the relationship between
      affinity/avidity of the TCR for the peptide/MHC and cellular responses of T
      cells.

PMID- 15187126
TI  - MHC-restricted Ig V region-driven T-B lymphocyte collaboration: B cell receptor
      ligation facilitates switch to IgG production.
AB  - B cells spontaneously process their endogenous Ig and present V region peptides
      on their MHC class II molecules. We have here investigated whether B cells
      collaborate with V region-specific CD4+ T cells in vivo. By use of paired Ig L
      chain-transgenic and TCR-transgenic mice and cell transfer into normal hosts, we
      demonstrate that B cell presentation of a V(L) region peptide to CD4+ T cells
      results in germinal centers, plasma cells, and Ab secretion. Because the
      transgenic B cells have a fixed L chain but polyclonal H chains, their B cell
      receptor (BCR) repertoire is diverse and may bind a multitude of ligands. In a
      hapten-based system, BCR ligation concomitant with V region-driven T-B
      collaboration induced germinal center formation and an IgM --> IgG isotype
      switch. In the absence of BCR ligation, mainly IgM was produced. Consistent with
      this, prolonged V region-driven T-B collaboration resulted in high titers of IgG
      autoantibodies against ubiquitous self-Ags, while natural-type Abs against exotic
      bacteria remained IgM. Taken together, V region-driven T-B collaboration may
      explain induction of natural IgM Abs (absence of BCR ligation) and IgG
      autoantibodies (BCR ligation by autoantigen) and may be involved in the
      development of autoimmunity.

PMID- 15187127
TI  - Rat plasmacytoid dendritic cells are an abundant subset of MHC class II+
      CD4+CD11b-OX62- and type I IFN-producing cells that exhibit selective expression
      of Toll-like receptors 7 and 9 and strong responsiveness to CpG.
AB  - We have identified in the rat a new subset of MHC class II(+) CD4(+)CD3(-)CD11b(
      ) leukocytes that produce high amounts of type I IFN upon viral stimulation and
      that appeared homologous to plasmacytoid DC (pDC) previously described in humans
      and mice. These cells exhibited the following phenotype:
      CD5(+),CD90(+),CD45R(+),CD45RC(+),CD11c(
      ),CD161a(+),CD200(+),CD172a(+),CD32(+),CD86(+). Rat pDC did not express the DC
      specific marker OX62 and were more abundant in the spleen than the classical
      CD4(+) and CD4(-) subsets of OX62(+)CD11b(+) DC we previously described that
      produced very little, if any, type I IFN. Spleen pDC exhibited an
      undifferentiated morphology and rapidly died in vitro, but showed extensive
      dendrite formation, survival, maturation, and moderate type I IFN production upon
      stimulation by oligonucleotides containing type B CpG motifs (CpG ODN). Type A
      CpG ODN and CD40 ligand induced pDC to produce large amounts of type I IFN, but
      did not promote maturation. CpG ODN and CD40 ligand, but not influenza virus,
      induced IL-12p40 and IL-6 secretion. Spleen pDC did not produce IL-12p70, TNF
      alpha, IL-1beta, or IL-10 using these stimulation conditions. Correlating with
      their strong responsiveness to virus and CpG ODN, rat pDC specifically expressed
      Toll-like receptor 7 and 9 mRNA. Fresh spleen pDC were poor stimulators of
      allogenic CD4(+) and CD8(+) T cells, but became potent inducers of allogenic T
      cell proliferation as well as Th1 differentiation after stimulation by type B
      CpG. Therefore, rat pDC appear very similar to human pDC, indicating that the
      specific phenotype and functions of pDC have been highly conserved between
      species.

PMID- 15187128
TI  - Coupling in silico and in vitro analysis of peptide-MHC binding: a bioinformatic
      approach enabling prediction of superbinding peptides and anchorless epitopes.
AB  - The ability to define and manipulate the interaction of peptides with MHC
      molecules has immense immunological utility, with applications in epitope
      identification, vaccine design, and immunomodulation. However, the methods
      currently available for prediction of peptide-MHC binding are far from ideal. We
      recently described the application of a bioinformatic prediction method based on
      quantitative structure-affinity relationship methods to peptide-MHC binding. In
      this study we demonstrate the predictivity and utility of this approach. We
      determined the binding affinities of a set of 90 nonamer peptides for the MHC
      class I allele HLA-A*0201 using an in-house, FACS-based, MHC stabilization assay,
      and from these data we derived an additive quantitative structure-affinity
      relationship model for peptide interaction with the HLA-A*0201 molecule. Using
      this model we then designed a series of high affinity HLA-A2-binding peptides.
      Experimental analysis revealed that all these peptides showed high binding
      affinities to the HLA-A*0201 molecule, significantly higher than the highest
      previously recorded. In addition, by the use of systematic substitution at
      principal anchor positions 2 and 9, we showed that high binding peptides are
      tolerant to a wide range of nonpreferred amino acids. Our results support a model
      in which the affinity of peptide binding to MHC is determined by the interactions
      of amino acids at multiple positions with the MHC molecule and may be enhanced by
      enthalpic cooperativity between these component interactions.

PMID- 15187129
TI  - The CD40-induced signaling pathway in endothelial cells resulting in the
      overexpression of vascular endothelial growth factor involves Ras and
      phosphatidylinositol 3-kinase.
AB  - Ligation of endothelial cell (EC) CD40 induces the expression of several
      proinflammatory cytokines as well as angiogenesis factors, including vascular
      endothelial growth factor (VEGF). Moreover, despite the reported importance of
      CD40 in cell-mediated immunity, little is known of the CD40-induced signaling
      pathways in EC. In this study, we have investigated the function of the Ras
      signaling pathway(s) for CD40-induced overexpression of VEGF. EC were transiently
      transfected with a full-length VEGF promoter-luciferase construct and a dominant
      inhibitory mutant of Ras (Ras17N). Following transfection, ligation of CD40 with
      soluble CD40 ligand resulted in a significant increase in VEGF transcriptional
      activation, and the inhibitory mutant of Ras blocked this CD40-induced VEGF
      overexpression. Using EMSA and Western blot analysis, we demonstrated that CD40
      dependent binding of nuclear protein(s) to the VEGF promoter and CD40-induced
      VEGF protein expression in EC were also inhibited by the Ras mutant.
      Immunoprecipitation studies revealed that ligation of CD40 on EC promoted an
      increased association of Ras with its effector molecules Raf, Rho, and
      phosphatidylinositol 3-kinase (PI3K). But, cotransfection of effector-loop
      mutants of Ras determined that only PI3K was functional for Ras-induced VEGF
      transcription. Also, wortmanin and a dominant-inhibitory mutant of PI3K inhibited
      CD40-induced overexpression of VEGF. Together these findings demonstrate that
      both Ras and PI3K are intermediaries in CD40-induced regulation of VEGF in EC. We
      believe our findings are of importance in several chronic inflammatory diseases,
      including atherosclerosis and allograft rejection associated with both CD40-CD40
      ligand signaling as well as VEGF expression and function.

PMID- 15187130
TI  - Characterization of a peptide inhibitor of Janus kinase 2 that mimics suppressor
      of cytokine signaling 1 function.
AB  - Positive and negative regulation of cytokines such as IFN-gamma are key to normal
      homeostatic function. Negative regulation of IFN-gamma in cells occurs via
      proteins called suppressors of cytokine signaling (SOCS)1 and -3. SOCS-1 inhibits
      IFN-gamma function by binding to the autophosphorylation site of the tyrosine
      kinase Janus kinase (JAK)2. We have developed a short 12-mer peptide,
      WLVFFVIFYFFR, that binds to the autophosphorylation site of JAK2, resulting in
      inhibition of its autophosphorylation as well as its phosphorylation of IFN-gamma
      receptor subunit IFNGR-1. The JAK2 tyrosine kinase inhibitor peptide (Tkip) did
      not bind to or inhibit tyrosine autophosphorylation of vascular endothelial
      growth factor receptor or phosphorylation of a substrate peptide by the
      protooncogene tyrosine kinase c-src. Tkip also inhibited epidermal growth factor
      receptor autophosphorylation, consistent with the fact that epidermal growth
      factor receptor is regulated by SOCS-1 and SOCS-3, similar to JAK2. Although Tkip
      binds to unphosphorylated JAK2 autophosphorylation site peptide, it binds
      significantly better to tyrosine-1007 phosphorylated JAK2 autophosphorylation
      site peptide. SOCS-1 only recognizes the JAK2 site in its phosphorylated state.
      Thus, Tkip recognizes the JAK2 autophosphorylation site similar to SOCS-1, but
      not precisely the same way. Consistent with inhibition of JAK2, Tkip inhibited
      the ability of IFN-gamma to induce an antiviral state as well as up-regulate MHC
      class I molecules on cells at a concentration of approximately 10 microM. This is
      similar to the K(d) of SOCS-3 for the erythropoietin receptor. These data
      represent a proof-of-concept demonstration of a peptide mimetic of SOCS-1 that
      regulates JAK2 tyrosine kinase function.

PMID- 15187131
TI  - Transcriptional regulation of human CD5: important role of Ets transcription
      factors in CD5 expression in T cells.
AB  - CD5 is a surface receptor constitutively expressed on thymocytes and mature T and
      B-1a cells. CD5 expression is tightly regulated during T and B cell development
      and activation processes. In this study we shown that the constitutive expression
      of CD5 on human T cells correlates with the presence of a DNase I-hypersensitive
      (DH) site at the 5'-flanking region of CD5. Human CD5 is a TATA-less gene for
      which 5'-RACE analysis shows multiple transcriptional start sites, the most
      frequent of which locates within an initiator sequence. Luciferase reporter
      assays indicate that a 282-bp region upstream of the initiation ATG displays full
      promoter activity in human T cells. Two conserved Ets-binding sites (at positions
      -239 and -185) were identified as functionally relevant to CD5 expression by site
      directed mutagenesis, EMSAs, and cotransfection experiments. A possible
      contribution of Sp1 (-115 and -95), c-Myb (-177), and AP-1-like (-151) motifs was
      also detected. Further DH site analyses revealed an inducible DH site 10 kb
      upstream of the human CD5 gene in both T and B CD5(+) cells. Interestingly, a 140
      bp sequence showing high homology with a murine inducible enhancer is found
      within that site. The data presented indicate that the 5'-flanking region of
      human CD5 is transcriptionally active in T cells, and that Ets transcription
      factors in conjunction with other regulatory elements are responsible for
      constitutive and tissue-specific CD5 expression.

PMID- 15187132
TI  - Repression of IFN-gamma expression by peroxisome proliferator-activated receptor
      gamma.
AB  - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated
      transcription factors expressed in a wide variety of cells. Our studies and
      others have demonstrated that both human and murine T cells express PPARgamma and
      that expression can be augmented over time in mitogen-activated splenocytes.
      PPARgamma ligands decrease proliferation and IL-2 production, and induce
      apoptosis in both B and T cells. PPARgamma ligands have also been shown to be
      anti-inflammatory in multiple models of inflammatory disease. In the following
      study, we demonstrate for the first time that PPARgamma is expressed in both
      murine CD4 and CD8 cells and that PPARgamma ligands directly decrease IFN-gamma
      expression by murine and transformed T cell lines. Unexpectedly, GW9662, a
      PPARgamma antagonist, increases lymphocyte IFN-gamma expression. Transient
      transfection studies reveal that PPARgamma ligands, in a PPARgamma-dependent
      manner, potently repress an IFN-gamma promoter construct. Repression localizes to
      the distal conserved sequence of the IFN-gamma promoter. Our studies also
      demonstrate that PPARgamma acts on the IFN-gamma promoter by interfering with c
      Jun activation. These studies suggest that many of the observed anti-inflammatory
      effects of PPARgamma ligands may be related to direct inhibition of IFN-gamma by
      PPARgamma.

PMID- 15187133
TI  - The electrostatic nature of C3d-complement receptor 2 association.
AB  - The association of complement component C3d with B or T cell complement receptor
      2 (CR2 or CD21) is a link between innate and adaptive immunity. It has been
      recognized in experimental studies that the C3d-CR2 association is pH- and ionic
      strength-dependent. This led us to perform electrostatic calculations to obtain a
      theoretical understanding of the mechanism of C3d-CR2 association. We used the
      crystallographic structures of human free C3d, free CR2 (short consensus repeat
      (SCR)1-2), and the C3d-CR2(SCR1-2) complex, and continuum solvent representation,
      to obtain a detailed atomic-level picture of the components of the two molecules
      that contribute to association. Based on the calculation of electrostatic
      potentials for the free and bound species and apparent pK(a) values for each
      ionizable residue, we show that C3d-CR2(SCR1-2) recognition is electrostatic in
      nature and involves not only the association interface, but also the whole
      molecules. Our results are in qualitative agreement with experimental data that
      measured the ionic strength and pH dependence of C3d-CR2 association. Also, our
      results for the native molecules and a number of theoretical mutants of C3d
      explain experimental mutagenesis studies of amino acid replacements away from the
      association interface that modulate binding of iC3b with full-length CR2.
      Finally, we discuss the packing of the two SCR domains. Overall, our data provide
      global and site-specific explanations of the physical causes that underlie the
      ionic strength dependence of C3d-CR2 association in a unified model that accounts
      for all experimental data, some of which were previously thought to be
      contradictory.

PMID- 15187134
TI  - Bap29/31 influences the intracellular traffic of MHC class I molecules.
AB  - In this study, we examine the role of the putative cargo receptor B cell
      associated protein (Bap)29/31 in the export of MHC class I molecules out of the
      endoplasmic reticulum (ER). We show that Bap31 binds to two allotypes of mouse
      class I molecules, with the interaction initiated at the time of H chain
      association with beta(2)-microglobulin and maintained until the class I molecule
      has left the ER. We also show that Bap31 is part of the peptide-loading complex,
      although is not required for its formation. Bap31 binds not only to class I
      molecules, but can bind to tapasin in the absence of class I. Consistent with an
      important role in recruiting class I molecules to transport vesicles, we show
      that in the absence of Bap29/31, there is a loss of class I colocalization with
      mSec31 (p137), a component of mammalian coat protein complex II coats. This
      observation is also associated with a delay in class I traffic from ER to Golgi.
      Our results are consistent with the view that class I molecules are largely
      recruited to ER exit sites by Bap29/31, and that Bap29/31 is a cargo receptor for
      MHC class I molecules.

PMID- 15187135
TI  - Binding of cytoplasmic proteins to the CD19 intracellular domain is high
      affinity, competitive, and multimeric.
AB  - CD19 is required for the development of B1 and marginal zone B cells, for Ab
      responses, and for B cell memory. CD19 immunoprecipitates contain a complex of
      cytoplasmic proteins, including Lyn, Vav, phospholipase Cgamma2 (PLCgamma2),
      Grb2, and the p85 subunit of phosphatidylinositol 3-kinase. Which of these bind
      directly to CD19 and the strengths of the interactions are unknown. These issues
      are important in understanding the signaling functions of CD19, which are crucial
      for normal B cell physiology. Using purified, recombinant proteins, we now show
      that each of these signaling proteins contains at least one Src homology 2 (SH2)
      domain that interacts directly with the phosphorylated CD19 cytoplasmic domain.
      The affinities of binding of the SH2 domains of Vav, p85, and Grb2 to CD19 are
      each in the nanomolar range by surface plasmon resonance (Biacore) analysis.
      Binding of Lyn and PLCgamma2 do not fit 1:1 modeling. However, analyses of
      binding data (Lyn) and competition experiments (PLCgamma2) suggest that these
      bind with comparable affinity. Competition experiments demonstrate that SH2
      domains whose binding is dependent on the same CD19 tyrosine(s) compete for
      binding, but these SH2 domains do not impede binding of different SH2 domains to
      other CD19 tyrosines. We conclude that binding to the CD19 cytoplasmic domain is
      multimeric, high affinity, and competitive. The high affinity of the interactions
      also suggests that tyrosines that were nonessential in vivo are nevertheless
      functional. A preliminary structural model suggests that CD19 forms a signaling
      complex containing multiple cytoplasmic proteins in close proximity to each other
      and to the plasma membrane.

PMID- 15187136
TI  - Enhancer-mediated control of macrophage-specific arginase I expression.
AB  - Arginase I expression in the liver must remain constant throughout life to
      eliminate excess nitrogen via the urea cycle. In contrast, arginase I expression
      in macrophages is silent until signals from Th2 cytokines such as IL-4 and IL-13
      are received and the mRNA is then induced four to five orders of magnitude.
      Arginase I is hypothesized to play a regulatory and potentially pathogenic role
      in diseases such as asthma, parasitic, bacterial, and worm infections by
      modulating NO levels and promoting fibrosis. We show that Th2-inducible arginase
      I expression in mouse macrophages is controlled by an enhancer that lies -3 kb
      from the basal promoter. PU.1, IL-4-induced STAT6, and C/EBPbeta assemble at the
      enhancer and await the effect of another STAT6-regulated protein(s) that must be
      synthesized de novo. Identification of a powerful extrahepatic regulatory
      enhancer for arginase I provides potential to manipulate arginase I activity in
      immune cells while sparing liver urea cycle function.

PMID- 15187137
TI  - Protection against progressive leishmaniasis by IFN-beta.
AB  - Type I IFNs (IFN-alphabeta) exert potent antiviral and immunoregulatory
      activities during viral infections, but their role in bacterial or protozoan
      infections is poorly understood. In this study, we demonstrate that the
      application of low, but not of high doses of IFN-beta protects 60 or 100% of
      BALB/c mice from progressive cutaneous and fatal visceral disease after infection
      with a high (10(6)) or low (10(4)) number of Leishmania major parasites,
      respectively. IFN-beta treatment of BALB/c mice restored the NK cell cytotoxic
      activity, increased the lymphocyte proliferation, and augmented the production of
      IFN-gamma and IL-12 in the draining lymph node. Low, but not high doses of IFN
      beta caused enhanced tyrosine phosphorylation of STAT1 and STAT4, suppressed the
      levels of suppressor of cytokine signaling-1, and up-regulated the expression of
      inducible NO synthase in vivo. The IFN-beta-induced increase of IFN-gamma
      production was dependent on STAT4. Protection by IFN-beta strictly required the
      presence of inducible NO synthase. In the absence of STAT4 or IL-12, IFN-beta led
      to an amelioration of the cutaneous and visceral disease, but was unable to
      prevent its progression. These results identify IFN-beta as a novel cytokine with
      a strong, dose-dependent protective effect against progressive cutaneous
      leishmaniasis that results from IL-12- and STAT4-dependent as well as 
      independent events.

PMID- 15187138
TI  - Akt decreases lymphocyte apoptosis and improves survival in sepsis.
AB  - Sepsis induces extensive death of lymphocytes that may contribute to the
      immunosuppression and mortality of the disorder. The serine/threonine kinase Akt
      is a key regulator of cell proliferation and death. The purpose of this study was
      to determine whether overexpression of Akt would prevent lymphocyte apoptosis and
      improve survival in sepsis. In addition, given the important role of Akt in cell
      signaling, T cell Th1 and Th2 cytokine production was determined. Mice that
      overexpress a constitutively active Akt in lymphocytes were made septic, and
      survival was recorded. Lymphocyte apoptosis and cytokine production were
      determined at 24 h after surgery. Mice with overexpression of Akt had a marked
      improvement in survival compared with wild-type littermates, i.e., 94 and 47%
      survival, respectively, p < 0.01. In wild-type littermates, sepsis caused a
      marked decrease in IFN-gamma production, while increasing IL-4 production >2
      fold. In contrast, T cells from Akt transgenic mice had an elevated production of
      IFN-gamma at baseline that was maintained during sepsis, while IL-4 had little
      change. Akt overexpression also decreased sepsis-induced lymphocyte apoptosis via
      a non-Bcl-2 mechanism. In conclusion, Akt overexpression in lymphocytes prevents
      sepsis-induced apoptosis, causes a Th1 cytokine propensity, and improves
      survival. Findings from this study strengthen the concept that a major defect in
      sepsis is impairment of the adaptive immune system, and suggest that strategies
      to prevent lymphocyte apoptosis represent a potential important new therapy.

PMID- 15187139
TI  - Pulmonary collectins enhance phagocytosis of Mycobacterium avium through
      increased activity of mannose receptor.
AB  - Collectins, including surfactant proteins A (SP-A) and D (SP-D) and mannose
      binding lectin (MBL), are the important constituents of the innate immune system.
      Mycobacterium avium, a facultative intracellular pathogen, has developed numerous
      mechanisms for entering mononuclear phagocytes. In this study, we investigated
      the interactions of collectins with M. avium and the effects of these lectins on
      phagocytosis of M. avium by macrophages. SP-A, SP-D, and MBL exhibited a
      concentration-dependent binding to M. avium. The binding of SP-A to M. avium was
      Ca(2+)-dependent but that of SP-D and MBL was Ca(2+)-independent. SP-A and SP-D
      but not MBL enhanced the phagocytosis of FITC-labeled M. avium by rat alveolar
      macrophages and human monocyte-derived macrophages. Excess mannan, zymosan, and
      lipoarabinomannan derived from the M. avium-intracellular complex, significantly
      decreased the collectin-stimulated phagocytosis of M. avium. Enhanced
      phagocytosis was not affected by the presence of cycloheximide or chelation of
      Ca(2+). The mutated collectin, SP-A(E195Q, R197D) exhibited decreased binding to
      M. avium but stimulated phagocytosis to a level comparable to wild-type SP-A.
      Enhanced phagocytosis by cells persisted even after preincubation and removal of
      SP-A or SP-D. Rat alveolar macrophages that had been incubated with SP-A or SP-D
      also exhibited enhanced uptake of (125)I-mannosylated BSA. Analysis by confocal
      microscopy and flow cytometry revealed that the lung collectins up-regulated the
      cell surface expression of mannose receptor on monocyte-derived macrophages.
      These results provide compelling evidence that SP-A and SP-D enhance mannose
      receptor-mediated phagocytosis of M. avium by macrophages.

PMID- 15187140
TI  - IL-10 is an important mediator of the enhanced susceptibility to pneumococcal
      pneumonia after influenza infection.
AB  - Secondary pneumococcal pneumonia is a serious complication during and shortly
      after influenza infection. We established a mouse model to study postinfluenza
      pneumococcal pneumonia and evaluated the role of IL-10 in host defense against
      Streptococcus pneumoniae after recovery from influenza infection. C57BL/6 mice
      were intranasally inoculated with 10 median tissue culture infective doses of
      influenza A (A/PR/8/34) or PBS (control) on day 0. By day 14 mice had regained
      their normal body weight and had cleared influenza virus from the lungs, as
      determined by real-time quantitative PCR. On day 14 after viral infection, mice
      received 10(4) CFU of S. pneumoniae (serotype 3) intranasally. Mice recovered
      from influenza infection were highly susceptible to subsequent pneumococcal
      pneumonia, as reflected by a 100% lethality on day 3 after bacterial infection,
      whereas control mice showed 17% lethality on day 3 and 83% lethality on day 6
      after pneumococcal infection. Furthermore, 1000-fold higher bacterial counts at
      48 h after infection with S. pneumoniae and, particularly, 50-fold higher
      pulmonary levels of IL-10 were observed in influenza-recovered mice than in
      control mice. Treatment with an anti-IL-10 mAb 1 h before bacterial inoculation
      resulted in reduced bacterial outgrowth and markedly reduced lethality during
      secondary bacterial pneumonia compared with those in IgG1 control mice. In
      conclusion, mild self-limiting influenza A infection renders normal
      immunocompetent mice highly susceptible to pneumococcal pneumonia. This increased
      susceptibility to secondary bacterial pneumonia is at least in part caused by
      excessive IL-10 production and reduced neutrophil function in the lungs.

PMID- 15187141
TI  - Neuroregulatory events follow adaptive immune-mediated elimination of HIV-1
      infected macrophages: studies in a murine model of viral encephalitis.
AB  - HIV-1-specific cellular immunity serves to eliminate infected cells and disease.
      However, how this process specifically affects the CNS is poorly understood. To
      mirror the regulatory events that occur in human brain after HIV-1 infection, a
      murine model of viral encephalitis was used to study relationships, over time,
      among lymphocyte-mediated infected cell elimination, innate immune responses, and
      neuropathology. Nonobese diabetic SCID mice were reconstituted with human PBL and
      a focal encephalitis induced by intracranial injection of autologous HIV-1
      infected, monocyte-derived macrophages (MDM). On days 7, 14, and 21 after MDM
      injection into the basal ganglia, the numbers of human lymphocytes and mouse
      monocytes, virus-infected MDM, glial (astrocyte and microglial) responses,
      cytokines, inducible NO (iNOS), neurotrophic factors, and neuronal Ags were
      determined in brain by immunohistochemistry, real-time PCR, and Western blot
      assays. Microglia activation, astrocytosis, proinflammatory cytokines, and iNOS
      expression accompanied the loss of neuronal Ags. This followed entry of human
      lymphocytes and mouse monocytes into the brain on days 7 and 14. Elimination of
      virus-infected human MDM, expression of IL-10, neurotropins, and a down
      regulation of iNOS coincided with brain tissue restoration. Our results
      demonstrate that the degree of tissue damage and repair parallels the presence of
      infected macrophages and effectors of innate and adaptive immunity. This murine
      model of HIV-1 encephalitis can be useful in elucidating the role played by
      innate and adaptive immunity in disease progression and resolution.

PMID- 15187142
TI  - Differential immune responses and protective efficacy induced by components of a
      tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant
      protein.
AB  - Key Ags of Mycobacterium tuberculosis initially identified in the context of host
      responses in healthy purified protein derivative-positive donors and infected
      C57BL/6 mice were prioritized for the development of a subunit vaccine against
      tuberculosis. Our lead construct, Mtb72F, codes for a 72-kDa polyprotein
      genetically linked in tandem in the linear order Mtb32(C)-Mtb39-Mtb32(N).
      Immunization of C57BL/6 mice with Mtb72F DNA resulted in the generation of IFN
      gamma responses directed against the first two components of the polyprotein and
      a strong CD8(+) T cell response directed exclusively against Mtb32(C). In
      contrast, immunization of mice with Mtb72F protein formulated in the adjuvant
      AS02A resulted in the elicitation of a moderate IFN-gamma response and a weak
      CD8(+) T cell response to Mtb32c. However, immunization with a formulation of
      Mtb72F protein in AS01B adjuvant generated a comprehensive and robust immune
      response, resulting in the elicitation of strong IFN-gamma and Ab responses
      encompassing all three components of the polyprotein vaccine and a strong CD8(+)
      response directed against the same Mtb32(C) epitope identified by DNA
      immunization. All three forms of Mtb72F immunization resulted in the protection
      of C57BL/6 mice against aerosol challenge with a virulent strain of M.
      tuberculosis. Most importantly, immunization of guinea pigs with Mtb72F,
      delivered either as DNA or as a rAg-based vaccine, resulted in prolonged survival
      (>1 year) after aerosol challenge with virulent M. tuberculosis comparable to
      bacillus Calmette-Guerin immunization. Mtb72F in AS02A formulation is currently
      in phase I clinical trial, making it the first recombinant tuberculosis vaccine
      to be tested in humans.

PMID- 15187143
TI  - Accumulation of gammadelta T cells in the lungs and their regulatory roles in Th1
      response and host defense against pulmonary infection with Cryptococcus
      neoformans.
AB  - The present study was designed to elucidate the role of gammadelta T cells in the
      host defense against pulmonary infection with Cryptococcus neoformans. The
      gammadelta T cells in lungs commenced to increase on day 1, reached a peak level
      on day 3 or 6, and then decreased on day 10 after intratracheal infection. The
      increase of these cells was similar in monocyte chemoattractant protein (MCP)-1
      deficient mice, although that of NK and NKT cells was significantly reduced. The
      number of live microorganisms in lungs on days 14 and 21 was significantly
      reduced in mice depleted of gammadelta T cells by a specific mAb compared with
      mice treated with control IgG. Similarly, elimination of this fungal pathogen was
      promoted in gammadelta T cell-deficient (TCR-delta(-/-)) mice compared with
      control littermate mice. Finally, lung and serum levels of IFN-gamma on days 7
      and 14 and on day 7 postinfection, respectively, were significantly higher in TCR
      delta(-/-) mice than in littermate mice, whereas levels of TGF-beta showed the
      opposite results. IL-4 and IL-10 were not different between these mice. IFN-gamma
      production by draining lymph node cells upon restimulation with cryptococcal Ags
      was significantly higher in the infected TCR-delta(-/-) mice than in control
      mice. Our results demonstrated that gammadelta T cells accumulated in the lungs
      in a manner different from NK and NKT cells after cryptococcal infection and
      played a down-modulatory role in the development of Th1 response and host
      resistance against this fungal pathogen.

PMID- 15187144
TI  - WSX-1: a key role in induction of chronic intestinal nematode infection.
AB  - Chronic infection by the gastrointestinal nematode Trichuris muris in susceptible
      AKR mice, which mount a Th1 response, is associated with IL-27p28 expression in
      the cecum. In contrast to wild-type mice, mice that lack the WSX-1/IL-27R gene
      fail to harbor a chronic infection, having significantly lower Th1 responses. The
      lower level of Ag-specific IFN-gamma-positive cells in WSX-1 knockout (KO) mice
      was found to be CD4(+) T cell specific, and the KO mice also had increased levels
      of IL-4-positive CD4(+) T cells. Polyclonal activation of mesenteric lymph node
      cells from naive WSX-1 KO or wild-type mice demonstrated that there was no
      inherent defect in the production of IFN-gamma by CD4(+) T cells, suggesting the
      decrease in these cells seen in infected WSX-1 KO mice is an in vivo Ag-driven
      effect. IL-12 treatment of WSX-1 KO mice failed to rescue the type 1 response,
      resulting in unaltered type-2-driven resistance. Infection of WSX-1 KO mice was
      also associated with a reduction of IL-27/WSX-1 downstream signaling gene
      expression within the cecum. These studies demonstrate an important role for WSX
      1 signaling in the promotion of type 1 responses and chronic gastrointestinal
      nematode infection.

PMID- 15187145
TI  - Rac1 and Toll-IL-1 receptor domain-containing adapter protein mediate Toll-like
      receptor 4 induction of HIV-long terminal repeat.
AB  - Opportunistic infections, common in HIV-1-infected patients, increase HIV
      replication; however, the intracellular signaling mechanisms involved are not
      clearly known. We have shown that Toll-like receptor 2 (TLR2), TLR4, and TLR9
      mediate microbial Ag-induced HIV-long terminal repeat (HIV-LTR) trans-activation
      and HIV-1 replication, and that LPS-induced HIV-LTR trans-activation is mediated
      through myeloid differentiation adapter protein. Recently, Toll-IL-1R domain
      containing adapter protein (TIRAP) has been identified as an adapter molecule
      that mediates responses to TLR2 and TLR4 ligands, and TIRAP was suggested to
      provide signaling specificity for different TLRs. Rac1, a small GTP-binding
      protein that is activated upon LPS stimulation of macrophages, activates
      phosphatidylinositol 3-kinase and Akt and leads to NF-kappaB activation. The
      roles of Rac1 and TIRAP in LPS activation of HIV replication is not known. In the
      present study we show that LPS stimulation of human microvessel endothelial cells
      leads to Rac1 activation. Constitutively active Rac1 (Rac1V12) simulated the
      effect of LPS to activate HIV-LTR, whereas the expression of dominant negative
      Rac1 (Rac1N17) partially blocked LPS-induced HIV-LTR trans-activation. Rac1V12
      induced HIV-LTR activation was independent of myeloid differentiation adapter
      protein, and dominant negative TIRAP blocked Rac1V12-induced HIV-LTR trans
      activation. In this study we show for the first time that activation of Rac1
      leads to HIV-LTR trans-activation, and this is mediated through TIRAP. Together
      these results underscore the importance of Rac1 and TIRAP in TLR4 activation of
      HIV replication and help delineate the signaling pathways induced by TLRs to
      mediate microbial Ag-induced HIV replication and HIV pathogenesis.

PMID- 15187146
TI  - CCR2-dependent trafficking of F4/80dim macrophages and CD11cdim/intermediate
      dendritic cells is crucial for T cell recruitment to lungs infected with
      Mycobacterium tuberculosis.
AB  - We previously reported that CCR2(-/-) mice are susceptible to Mycobacterium
      tuberculosis infection. Susceptibility was associated with an early and sustained
      macrophage trafficking defect, followed by delayed recruitment of dendritic cells
      (DCs) and T cells to the lungs. However, the relative importance of the lack of
      CCR2 expression by macrophages and DCs vs T cells in susceptibility to infection
      was unclear. In this study, we used mixed bone marrow transplantation to create
      mice in which the genotype of the T cells was either CCR2(+/+) or CCR2(-/-) while
      maintaining the genotype of the myeloid cells as CCR2(+/+). After infection with
      M. tuberculosis, we found that the genotype of the macrophages and/or DCs, but
      not that of the T cells, was critical for both T cell and myeloid cell migration
      to the lungs. Further investigation revealed a critical role for CCR2 in the
      recruitment of F4/80(dim) macrophages and CD11c(dim/intermediate) DCs to the
      infected lung.

PMID- 15187147
TI  - Differential regulation of TNF-R1 signaling: lipid raft dependency of
      p42mapk/erk2 activation, but not NF-kappaB activation.
AB  - The TNFR, TNF-R1, is localized to lipid raft and nonraft regions of the plasma
      membrane. Ligand binding sets in motion signaling cascades that promote the
      activation of p42(mapk/erk2) and NF-kappaB. However, the role of receptor
      localization in the activation of downstream signaling events is poorly
      understood. In this study, we investigated the dynamics of TNF-R1 localization to
      lipid rafts and the consequences of raft localization on the activation of
      p42(mapk/erk2) and NF-kappaB in primary cultures of mouse macrophages. Using
      sucrose density gradient ultracentrifugation and a sensitive ELISA to detect TNF
      R1, we show that TNF-R1 is rapidly and transiently recruited to lipid rafts in
      response to TNF-alpha. Disruption of lipid rafts by cholesterol depletion
      prevented the TNF-alpha-dependent recruitment of TNF-R1 to lipid rafts and
      inhibited the activation of p42(mapk/erk2), while the activation of NF-kappaB was
      unaffected. In addition, phosphorylated p42(mapk/erk2), but not receptor
      interacting protein, I-kappaB kinase-gamma, or I-kappaBalpha was detected in raft
      containing fractions following TNF-alpha stimulation. These findings suggest that
      TNF-R1 is localized to both lipid raft and nonraft regions of the plasma membrane
      and that each compartment is capable of initiating different signaling responses.
      We propose that segregation of TNF-R1 to raft and nonraft regions of the plasma
      membrane contributes to the diversity of signaling responses initiated by TNF-R1.

PMID- 15187148
TI  - NK cells and polymorphonuclear neutrophils are both critical for IL-2-induced
      pulmonary vascular leak syndrome.
AB  - The mechanism of IL-2-induced vascular leak syndrome (VLS) is still poorly
      understood. Cells of both innate and adaptive immune systems have been
      implicated, but no definitive conclusions have been reached concerning their
      respective roles. In this study we report a new mouse model of IL-2-induced
      pulmonary VLS used to obtain a detailed analysis of the early events
      (sequestration of polymorphonuclear neutrophils and bronchoconstriction) and late
      events (modifications in the cell and protein content of bronchoalveolar lavages,
      followed by edema) that characterize this lung injury. This model and knockout
      animals are used to reconsider the importance of the different leukocyte lineages
      in early and late events. Recombinase-activating gene 2(-/-) mice are used to
      demonstrate that adaptive lymphocytes, including NK T cells, are not required for
      pulmonary VLS induction. By contrast, results obtained with newly described
      recombinase-activating gene 2(-/-)/IL-15(-/-) mice indicate that NK cells play a
      key role in both early and late events. In parallel, polymorphonuclear neutrophil
      depletion is used to evaluate the contributions made by these cells to the late
      alterations occurring in the lung. Furthermore, when used in combination with
      inhibition of NO synthase, granulocyte depletion was completely effective in
      protecting mice from the late events of IL-2-induced pulmonary VLS. Together our
      results indicate that both NK and PMN cells play a central role in the late
      events of IL-2-induced VLS.

PMID- 15187149
TI  - An annexin 1 N-terminal peptide activates leukocytes by triggering different
      members of the formyl peptide receptor family.
AB  - The human N-formyl peptide receptor (FPR) is a key modulator of chemotaxis
      directing granulocytes toward sites of bacterial infections. FPR is the founding
      member of a subfamily of G protein-coupled receptors thought to function in
      inflammatory processes. The other two members, FPR-like (FPRL)1 and FPRL2, have a
      greatly reduced affinity for bacterial peptides or do not bind them at all, with
      FPRL2 being considered an orphan receptor so far. In this study we show that a
      peptide derived from the N-terminal domain of the anti-inflammatory protein
      annexin 1 (lipocortin 1) can activate all three FPR family members at similar
      concentrations. The annexin 1 peptide initiates chemotactic responses in human
      monocytes that express all three FPR family members and also desensitizes the
      cells toward subsequent stimulation with bacterial peptide agonists. Experiments
      using HEK 293 cells stably expressing a single FPR family member reveal that all
      three receptors can be activated and desensitized by the N-terminal annexin 1
      peptide. These observations identify the annexin 1 peptide as the first
      endogenous ligand of FPRL2 and indicate that annexin 1 participates in regulating
      leukocyte emigration into inflamed tissue by activating and desensitizing
      different receptors of the FPR family.

PMID- 15187150
TI  - 15-deoxy-Delta12,14-prostaglandin J2 inhibits glucocorticoid binding and
      signaling in macrophages through a peroxisome proliferator-activated receptor
      gamma-independent process.
AB  - 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is involved in the control of
      inflammatory reaction. We tested the hypothesis that 15d-PGJ(2) would exert this
      control in part by modulating the sensitivity of inflammatory cells to
      glucocorticoids. Human U937cells and mouse RAW 264.7 cells were exposed to 15d
      PGJ(2), and binding experiments were performed with [(3)H]dexamethasone as a
      glucocorticoid receptor (GR) ligand. 15d-PGJ(2) caused a transient and
      concentration-dependent decrease in [(3)H]dexamethasone-specific binding to
      either cells through a decrease in the number of GR per cell without significant
      modification of the K(d) value. These changes were related to functional
      alteration of the GR rather than to a decrease in GR protein. They did not
      require the engagement of peroxisome proliferator-activated receptor gamma
      (PPARgamma), because the response to 15d-PGJ(2) was neither mimicked by the
      PPARgamma agonist ciglitazone nor prevented by the PPARgamma antagonist bisphenol
      A diglycidyl ether. 15d-PGJ(2) altered GR possibly through the interaction of its
      cyclopentenone ring with GR cysteine residues because the cyclopentenone ring per
      se could mimic the effect of 15d-PGJ(2), and modification of GR cysteine residues
      with methyl methanethiosulfonate suppressed the response to 15d-PGJ(2). Finally,
      15d-PGJ(2)-induced decreases in glucocorticoid binding to GR resulted in parallel
      decreases in the ability of GR to activate the transcription of a glucocorticoid
      inducible reporter gene and to reduce the expression of monocyte chemoattractant
      protein-1. Together these data suggest that 15d-PGJ(2) limits glucocorticoid
      binding and signaling in monocytes/macrophages through a PPARgamma-independent
      and cyclopentenone-dependent mechanism. It provides a way in which 15d-PGJ(2)
      would exert proinflammatory activities in addition to its known anti-inflammatory
      activities.

PMID- 15187151
TI  - The transcriptional activation program of human neutrophils in skin lesions
      supports their important role in wound healing.
AB  - To investigate the cellular fate and function of polymorphonuclear neutrophilic
      granulocytes (PMNs) attracted to skin wounds, we used a human skin-wounding model
      and microarray technology to define differentially expressed genes in PMNs from
      peripheral blood, and PMNs that had transmigrated to skin lesions. After
      migration to skin lesions, PMNs demonstrated a significant transcriptional
      response including genes from several different functional categories. The up
      regulation of anti-apoptotic genes concomitant with the down-regulation of
      proapoptotic genes suggested a transient anti-apoptotic priming of PMNs. Among
      the up-regulated genes were cytokines and chemokines critical for chemotaxis of
      macrophages, T cells, and PMNs, and for the modulation of their inflammatory
      responses. PMNs in skin lesions down-regulated receptors mediating chemotaxis and
      anti-microbial activity, but up-regulated other receptors involved in
      inflammatory responses. These findings indicate a change of responsiveness to
      chemotactic and immunoregulatory mediators once PMNs have migrated to skin
      lesions and have been activated. Other effects of the up-regulated
      cytokines/chemokines/enzymes were critical for wound healing. These included the
      breakdown of fibrin clots and degradation of extracellular matrix, the promotion
      of angiogenesis, the migration and proliferation of keratinocytes and
      fibroblasts, the adhesion of keratinocytes to the dermal layer, and finally, the
      induction of anti-microbial gene expression in keratinocytes. Notably, the up
      regulation of genes, which activate lysosomal proteases, indicate a priming of
      skin lesion-PMNs for degradation of phagocytosed material. These findings
      demonstrate that migration of PMNs to skin lesions induces a transcriptional
      activation program, which regulates cellular fate and function, and promotes
      wound healing.

PMID- 15187152
TI  - Staging the initiation of autoantibody-induced arthritis: a critical role for
      immune complexes.
AB  - In the K/BxN mouse model of arthritis, autoantibodies against glucose-6-phosphate
      isomerase cause joint-specific inflammation and destruction. We have shown using
      micro-positron emission tomography that these glucose-6-phosphate isomerase
      specific autoantibodies rapidly localize to distal joints of mice. In this study
      we used micro-positron emission tomography to delineate the stages involved in
      the development of arthritis. Localization of Abs to the joints depended upon
      mast cells, neutrophils, and FcRs, but not on C5. Surprisingly, anti-type II
      collagen Abs alone did not accumulate in the distal joints, but could be induced
      to do so by coinjection of irrelevant preformed immune complexes. Control Abs
      localized to the joint in a similar manner. Thus, immune complexes are essential
      initiators of arthritis by sequential activation of neutrophils and mast cells to
      allow Abs access to the joints, where they must bind a target Ag to initiate
      inflammation. Our findings support a four-stage model for the development of
      arthritis and identify checkpoints where the disease is reversible.

PMID- 15187153
TI  - Stat3 activation in acute lung injury.
AB  - Stat3 plays diverse roles in biological processes including cell proliferation,
      survival, apoptosis, and inflammation. Very little is known regarding its
      activation and function in the lung during acute inflammation. We now show that
      Stat3 activation was triggered in lungs and in alveolar macrophages after
      intrapulmonary deposition of IgG immune complexes in rats. Low levels of
      constitutive Stat3 were observed in normal rat lungs as determined by the EMSA.
      Stat3 activity in whole lung extracts increased 2 h after initiation of IgG
      immune complex deposition, reaching maximal levels by 4 h, whereas Stat3
      activation was found in alveolar macrophages as early as 30 min after onset of
      injury. Expression and activation of Stat3 mRNA, protein, and protein
      phosphorylation was accompanied by increased gene expression of IL-6, IL-10, and
      suppressor of cytokine signaling-3 in whole lung tissues. Both Tyr(705) and
      Ser(727) phosphorylation were involved in Stat3 activation as assessed in whole
      lung extracts. C5a (complement 5, fragment a) per se can induce phosphorylation
      of Ser(727) of Stat3. In vivo, Stat3 activation was dramatically suppressed by
      depletion of neutrophils or lung macrophages, resulting in reduced gene
      expression of IL-6 and IL-10 in whole lung tissues. Using blocking Abs to IL-6,
      IL-10, and C5a, Stat3 activation induced by IgG immune complexes was markedly
      diminished. These data suggest in the lung injury model used that activation of
      Stat3 in lungs is macrophage dependent and neutrophil dependent. IL-6, IL-10, and
      C5a contribute to Stat3 activation in inflamed rat lung.

PMID- 15187154
TI  - IL-1beta impairs insulin-like growth factor i-induced differentiation and
      downstream activation signals of the insulin-like growth factor i receptor in
      myoblasts.
AB  - Proinflammatory cytokines are elevated in disorders characterized by muscle
      wasting and weakness, such as inflammatory myopathies and AIDS wasting. We
      recently demonstrated that TNF-alpha impairs the ability of insulin-like growth
      factor (IGF)-I to promote protein synthesis in muscle precursor cells. In this
      study we extend these findings by showing that low concentrations of IL-1beta
      impair IGF-I-dependent differentiation of myoblasts, as assessed by expression of
      the muscle specific protein, myosin heavy chain. In the absence of exogenous IGF
      I, IL-1beta (1 ng/ml) did not impair muscle cell development. However, in the
      presence of IGF-I, 100-fold lower concentrations of IL-1beta (0.01 ng/ml)
      significantly suppressed myoblast differentiation, protein synthesis, and
      myogenin expression. Increasing IL-1beta to 1 ng/ml completely blocked the
      anabolic actions of IGF-I in murine C(2)C(12) myoblasts. Similarly, IL-1beta
      inhibited IGF-I-stimulated protein synthesis in primary porcine myoblasts. IL
      1beta impaired the actions of IGF-I at a point distal to the IGF receptor, and
      this was not due to IL-1beta-induced cell death. Instead, IL-1beta inhibited the
      ability of IGF-I to phosphorylate tyrosine residues on both of its downstream
      docking proteins, insulin receptor substrate 1 and insulin receptor substrate 2.
      These data establish that physiological concentrations of IL-1beta block the
      ability of IGF-I to promote protein synthesis, leading to reduced expression of
      the myogenic transcription factor, myogenin, and the subsequent development of
      more mature differentiated cells that express myosin heavy chain. Collectively,
      the results are consistent with the notion that very low concentrations of IL
      1beta significantly impair myogenesis, but they are unable to do so in the
      absence of the growth factor IGF-I.

PMID- 15187155
TI  - IL-16 is constitutively present in peripheral blood monocytes and spontaneously
      released during apoptosis.
AB  - Constitutive expression of the pro-molecule of IL-16 has been found in T cells,
      mast cells, eosinophils, epithelial cells, fibroblasts, and dendritic cells. Here
      we show that IL-16 is also constitutively present in >98% of freshly isolated
      human CD14-positive peripheral blood monocytes when analyzed by flow cytometry.
      Because pro-IL-16 is cleaved to its bioactive mature form by caspase-3, and
      caspase-3 is also the pivotal effector of apoptosis in monocytes, we asked
      whether IL-16 release occurs in monocytes that undergo spontaneous apoptosis. As
      expected, freshly isolated, unstimulated monocytes underwent spontaneous caspase
      3 activation. This apoptosis was paralleled by the loss of intracellular IL-16,
      as detected by flow cytometry, and the concurrent release of IL-16, as detected
      by ELISA. In contrast, stimulation with bacterial LPS inhibited caspase-3
      activation and significantly inhibited the release of IL-16. As a specificity
      control, IL-1beta and IL-8 were not released during spontaneous monocyte
      apoptosis. In summary, our data demonstrate that monocytes contain IL-16 that is
      released during spontaneous apoptosis.

PMID- 15187156
TI  - Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B
      mediated process involving Th2 cytokines IL-4 and IL-13 with implications for
      asthma.
AB  - Adenosine provokes bronchoconstriction in asthmatics through acute activation of
      mast cells, but its potential role in chronic inflammation has not been
      adequately characterized. We hypothesized that adenosine up-regulates Th2
      cytokines in mast cells, thus promoting IgE synthesis by B lymphocytes. We tested
      this hypothesis in human mast cells (HMC-1) expressing A(2A), A(2B), and A(3)
      adenosine receptors. The adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA)
      (10 microM) increased mRNA expression of IL-1beta, IL-3, IL-4, IL-8, and IL-13,
      but not IL-2 and IFN-gamma. Up-regulation of IL-4 and IL-13 was verified using RT
      PCR and ELISA; 10 microM NECA increased IL-13 concentrations in HMC-1 conditioned
      medium 28-fold, from 7.6 +/- 0.3 to 215 +/- 4 pg/ml, and increased IL-4
      concentrations 6-fold, from 19.2 +/- 0.1 to 117 +/- 2 pg/ml. This effect was
      mediated by A(2B) receptors because neither the selective A(2A) agonist 2-p-(2
      carboxyethyl)phenethylamino-NECA nor the selective A(3) agonist N(6)-(3
      iodobenzyl)-N-methyl-5'-carbamoyladenosine reproduced it, and the selective A(2B)
      antagonist 3-isobutyl-8-pyrrolidinoxanthine prevented it. Constitutive expression
      of CD40 ligand on HMC-1 surface was not altered by NECA. Human B lymphocytes
      cocultured for 12 days with NECA-stimulated HMC-1 produced 870 +/- 33 pg IgE per
      10(6) B cells, whereas lymphocytes cocultured with nonstimulated HMC-1, or
      cultured alone in the absence or in the presence of NECA, produced no IgE. Thus,
      we demonstrated induction of IgE synthesis by the interaction between adenosine
      stimulated mast cells and B lymphocytes, and suggest that this mechanism is
      involved in the amplification of the allergic inflammatory responses associated
      with asthma.

PMID- 15187157
TI  - Basophils infiltrate human gastric mucosa at sites of Helicobacter pylori
      infection, and exhibit chemotaxis in response to H. pylori-derived peptide Hp(2
      20).
AB  - Basophils, which are normally confined to the circulation, can migrate to sites
      of allergic inflammation. Using the specific mAb, BB1, we detected basophil
      infiltration of the gastric mucosa of Helicobacter pylori-infected patients
      affected by moderate and severe gastritis. Basophils were not found in H. pylori
      free individuals or in subjects with mild gastritis. The H. pylori-derived
      peptide, Hp(2-20), was a potent basophil chemoattractant in vitro, whereas the
      control peptide, Hp1, was ineffective. Basophils from peripheral blood of healthy
      volunteers expressed mRNA for the formyl peptide receptors, N-formyl-peptide
      receptor (FPR), FPR-like (FPRL)1, and FPRL2. Preincubation of basophils with FMLP
      or Hp(2-20) caused complete desensitization to a subsequent challenge with
      homologous stimulus. Incubation of basophils with a low concentration of FMLP,
      which binds with high affinity to FPR, but not to FPRL1 or FPRL2, did not affect
      the chemotactic response to Hp(2-20). In contrast, a high concentration of FMLP,
      which binds to FPRL1 and FPRL2, reduced the chemotactic response to Hp(2-20). The
      FPR antagonist, cyclosporin H, prevented chemotaxis induced by FMLP, but not by
      Hp(2-20). Hp(2-20) could be responsible, at least in part, for basophil
      infiltration of the gastric mucosa of H. pylori-infected patients presumably
      through the interaction with FPRL1 and FPRL2.

PMID- 15187158
TI  - CD200 is a ligand for all members of the CD200R family of immunoregulatory
      molecules.
AB  - CD200Fc, a chimeric molecule including the extracellular domain of CD200 and a
      murine IgG2a Fc region, regulates immune responses following engagement of a cell
      surface receptor, CD200R, expressed on cells of the myeloid and T cell lineage. A
      recent report focused attention on a family of CD200Rs, but concluded that only
      one member used CD200 as its ligand. We have also cloned and sequenced a family
      of CD200Rs, but identify an amino terminus to two of the three isoforms not
      recognized by previous researchers. We show by FACS, using FITC-labeled CD200Fc,
      that COS7 cells transfected with all CD200R isoforms bind CD200 as ligand,
      although the functional consequences of this binding likely differs between the
      different isoforms. mAbs directed against the CD200 R1/R4 isoforms altered IL
      2/IL-4 cytokine production and suppressed CTL responses in a fashion comparable
      to CD200Fc, with a significantly lesser effect seen following addition of anti
      CD200 R2/R3.

PMID- 15187159
TI  - Labile zinc and zinc transporter ZnT4 in mast cell granules: role in regulation
      of caspase activation and NF-kappaB translocation.
AB  - The granules of mast cells and other inflammatory cells are known to be rich in
      zinc (Zn), a potent caspase inhibitor. The functions of granular Zn, its
      mechanism of uptake, and its relationship to caspase activation in apoptosis are
      unclear. The granules of a variety of mast cell types fluoresced intensely with
      the Zn-specific fluorophore Zinquin, and fluorescence was quenched by functional
      depletion of Zn using a membrane-permeable Zn chelator N, N, N', N'-tetrakis (2
      pyridyl-methyl)ethylenediamine (TPEN). Zn levels were also depleted by various
      mast cell activators, including IgE/anti-IgE, and Zn was rapidly replenished
      during subsequent culture, suggesting an active uptake mechanism. In support of
      the latter, mast cells contained high levels of the vesicular Zn transporter
      ZnT(4), especially in the more apical granules. Immunofluorescence and immunogold
      labeling studies revealed significant pools of procaspase-3 and -4 in mast cell
      granules and their release during degranulation. Functional depletion of Zn by
      chelation with TPEN, but not by degranulation, resulted in greatly increased
      susceptibility of mast cells to toxin-induced caspase activation, as detected
      using a fluorogenic substrate assay. Release of caspases during degranulation was
      accompanied by a decreased susceptibility to toxins. Zn depletion by chelation,
      but not by degranulation, also resulted in nuclear translocation of the
      antiapoptotic, proinflammatory transcription factor NF-kappaB. These findings
      implicate a role for ZnT(4) in mast cell Zn homeostasis and suggest that granule
      pools of Zn may be distinct from those regulating activation of procaspase-3 and
      NF-kappaB.

PMID- 15187160
TI  - Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived
      chemokine is a dispensable signal for T lymphocyte chemotaxis.
AB  - Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its
      cellular effects principally by binding to its receptor CCR4, and together they
      constitute a multifunctional chemokine/receptor system with homeostatic and
      inflammatory roles in the body. We report the CCL22-induced accumulation of
      phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P(3)) in the leukemic T cell
      line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM
      cells in a pertussis toxin-sensitive manner. Although the PI(3,4,5)P(3)
      accumulation along with the pertussis toxin-susceptible phosphorylation of
      protein kinase B were sensitive to the two phosphoinositide 3-kinase inhibitors,
      LY294002 and wortmannin, cell migration was unaffected. However, cell migration
      was abrogated with the Rho-dependent kinase inhibitor, Y-27632. These data
      demonstrate that although there is PI(3,4,5)P(3) accumulation downstream of CCR4,
      phosphoinositide 3-kinase activity is a dispensable signal for CCR4-stimulated
      chemotaxis of Th2 cells and the CEM T cell line.

PMID- 15187161
TI  - An in vitro model for the lepromatous leprosy granuloma: fate of Mycobacterium
      leprae from target macrophages after interaction with normal and activated
      effector macrophages.
AB  - The lepromatous leprosy granuloma is a dynamic entity requiring a steady influx
      of macrophages (Mphi) for its maintenance. We have developed an in vitro model to
      study the fate of Mycobacterium leprae in a LL lesion, with and without
      immunotherapeutic intervention. Target cells, consisting of granuloma Mphi
      harvested from the footpads of M. leprae-infected athymic nu/nu mice, were
      cocultured with normal or IFN-gamma-activated (ACT) effector Mphi. The bacilli
      were recovered and assessed for viability by radiorespirometry. M. leprae
      recovered from target Mphi possessed high metabolic activity, indicating a viable
      state in this uncultivable organism. M. leprae recovered from target Mphi
      incubated with normal effector Mphi exhibited significantly higher metabolism. In
      contrast, bacilli recovered from target Mphi cocultured with ACT effector Mphi
      displayed a markedly decreased metabolic activity. Inhibition by ACT Mphi
      required an E:T ratio of at least 5:1, a coculture incubation period of 3-5 days,
      and the production of reactive nitrogen intermediates, but not reactive oxygen
      intermediates. Neither IFN-gamma nor TNF-alpha were required during the
      cocultivation period. However, cell-to-cell contact between the target and
      effector Mphi was necessary for augmentation of M. leprae metabolism by normal
      effector Mphi as well as for inhibition of M. leprae by ACT effector Mphi.
      Conventional fluorescence microscopy and confocal fluorescence microscopy
      revealed that the bacilli from the target Mphi were acquired by the effector
      Mphi. Thus, the state of Mphi infiltrating the granuloma may markedly affect the
      viability of M. leprae residing in Mphi in the lepromatous lesion.

PMID- 15187162
TI  - Shear-dependent capping of L-selectin and P-selectin glycoprotein ligand 1 by E
      selectin signals activation of high-avidity beta2-integrin on neutrophils.
AB  - Two adhesive events critical to efficient recruitment of neutrophils at vascular
      sites of inflammation are up-regulation of endothelial selectins that bind sialyl
      Lewis(x) ligands and activation of beta(2)-integrins that support neutrophil
      arrest by binding ICAM-1. We have previously reported that neutrophils rolling on
      E-selectin are sufficient for signaling cell arrest through beta(2)-integrin
      binding of ICAM-1 in a process dependent upon ligation of L-selectin and P
      selectin glycoprotein ligand 1 (PSGL-1). Unresolved are the spatial and temporal
      events that occur as E-selectin binds to human neutrophils and dynamically
      signals the transition from neutrophil rolling to arrest. Here we show that
      binding of E-selectin to sialyl Lewis(x) on L-selectin and PSGL-1 drives their
      colocalization into membrane caps at the trailing edge of neutrophils rolling on
      HUVECs and on an L-cell monolayer coexpressing E-selectin and ICAM-1. Likewise,
      binding of recombinant E-selectin to PMNs in suspension also elicited
      coclustering of L-selectin and PSGL-1 that was signaled via mitogen-activated
      protein kinase. Binding of recombinant E-selectin signaled activation of beta(2)
      integrin to high-avidity clusters and elicited efficient neutrophil capture of
      beta(2)-integrin ligands in shear flow. Inhibition of p38 and p42/44 mitogen
      activated protein kinase blocked the cocapping of L-selectin and PSGL-1 and the
      subsequent clustering of high-affinity beta(2)-integrin. Taken together, the data
      suggest that E-selectin is unique among selectins in its capacity for clustering
      sialylated ligands and transducing signals leading to neutrophil arrest in shear
      flow.

PMID- 15187163
TI  - Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is
      a potent, tissue inhibitor of metalloproteinase-resistant collagenase and
      serpinase.
AB  - Little is known about the cell biology or the biologic roles of polymorphonuclear
      cell (PMN)-derived matrix metalloproteinase-8 (MMP-8). When activated with
      proinflammatory mediators, human PMN release only approximately 15-20% of their
      content of MMP-8 ( approximately 60 ng/10(6) cells) exclusively as latent pro-MMP
      8. However, activated PMN incubated on type I collagen are associated with
      pericellular collagenase activity even when bathed in serum. PMN pericellular
      collagenase activity is attributable to membrane-bound MMP-8 because: 1) MMP-8 is
      expressed in an inducible manner in both pro- and active forms on the surface of
      human PMN; 2) studies of activated PMN from mice genetically deficient in MMP-8
      (MMP-8(-/-)) vs wild-type (WT) mice show that membrane-bound MMP-8 accounts for
      92% of the MMP-mediated, PMN surface type I collagenase activity; and 3) human
      membrane-bound MMP-8 on PMN cleaves types I and II collagens, and alpha(1)
      proteinase inhibitor, but is substantially resistant to inhibition by tissue
      inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Binding of MMP-8 to the PMN
      surface promotes its stability because soluble MMP-8 has t(1/2) = 7.5 h at 37
      degrees C, but membrane-bound MMP-8 retains >80% of its activity after incubation
      at 37 degrees C for 18 h. Studies of MMP-8(-/-) vs WT mice given intratracheal
      LPS demonstrate that 24 h after intratracheal LPS, MMP-8(-/-) mice have 2-fold
      greater accumulation of PMN in the alveolar space than WT mice. Thus, MMP-8 has
      an unexpected, anti-inflammatory role during acute lung injury in mice. TIMP
      resistant, active MMP-8 expressed on the surface of activated PMN is likely to be
      an important form of MMP-8, regulating lung inflammation and collagen turnover in
      vivo.

PMID- 15187164
TI  - Down-regulation of IL-2 production in T lymphocytes by phosphorylated protein
      kinase A-RIIbeta.
AB  - The beta isoform of the type II regulatory subunit (RIIbeta) of protein kinase A
      suppresses CREB transcriptional activity and c-Fos production in T cells
      following activation via the TCR. Because CREB is an integral nuclear
      transcription factor for IL-2 production by T cells, we tested the hypothesis
      that RIIbeta down-regulates IL-2 expression and IL-2 production in T cells.
      Stable transfection of RIIbeta in Jurkat T cells led to an approximately 90%
      reduction in IL-2 mRNA and IL-2 protein following T cell activation. The
      inhibition of IL-2 production was associated with phosphorylation of the RIIbeta
      subunit at serine 114 (pRIIbeta) and localization of pRIIbeta in intranuclear
      clusters. A serine 114 phosphorylation-defective mutant, RIIbeta(S114A), did not
      form these intranuclear clusters as well as wild-type RIIbeta, and did not
      inhibit IL-2 mRNA and protein synthesis, indicating that serine 114
      phosphorylation is required for both nuclear localization and down-regulation of
      IL-2 production by RIIbeta. In contrast to its effect on IL-2, RIIbeta induced
      constitutive up-regulation of CD154 mRNA and cell surface expression. Thus,
      pRIIbeta differentially regulates gene expression following T cell activation.
      Unexpectedly, we also found that stable overexpression of another protein kinase
      A regulatory subunit, RIalpha, had the opposite effect on IL-2 expression,
      causing a 3- to 4-fold increase in IL-2 production following stimulation. In
      summary, our data demonstrate a novel mechanism by which serine 114
      phosphorylation and nuclear localization of RIIbeta controls the regulation of
      gene expression in T cells.

PMID- 15187165
TI  - The allograft defines the type of rejection (acute versus chronic) in the face of
      an established effector immune response.
AB  - Transplanted organs fail due to either acute or chronic rejection. The prevailing
      view is that the nature or magnitude of the recipient's immune response to donor
      Ags determines the type of rejection. In variance with this view, we show in this
      study that the status of the graft itself plays a dominant role in defining the
      type of rejection even in the face of an established alloimmune response. Using
      adoptive transfer mouse models in which the graft is exposed to a constant number
      of effector lymphocytes, we found that newly transplanted heart allografts are
      rejected acutely, while healed-in allografts undergo chronic rejection. Acute
      rejection of healed-in allografts was largely recapitulated by subjecting the
      grafts to ischemia-reperfusion injury similar to that present in newly
      transplanted organs. Ischemia-Reperfusion injury altered the outcome of rejection
      by enhancing the accumulation of effector T cells within the graft. The
      accumulation of effector T cells in the graft was dependent on the presence of
      both ischemia-reperfusion injury (inflammation) and alloantigens. These findings
      demonstrate that the graft plays a dominant role in shaping the outcome of
      rejection by controlling the trafficking of effector T cells.

PMID- 15187166
TI  - Alterations in lipid raft composition and dynamics contribute to abnormal T cell
      responses in systemic lupus erythematosus.
AB  - In response to appropriate stimulation, T lymphocytes from systemic lupus
      erythematosus (SLE) patients exhibit increased and faster intracellular tyrosine
      phosphorylation and free calcium responses. We have explored whether the
      composition and dynamics of lipid rafts are responsible for the abnormal T cell
      responses in SLE. SLE T cells generate and possess higher amounts of ganglioside
      containing lipid rafts and, unlike normal T cells, SLE T cell lipid rafts include
      FcRgamma and activated Syk kinase. IgM anti-CD3 Ab-mediated capping of TCR
      complexes occurs more rapidly in SLE T cells and concomitant with dramatic
      acceleration of actin polymerization kinetics. The significance of these findings
      is evident from the observation that cross-linking of lipid rafts evokes earlier
      and higher calcium responses in SLE T cells. Thus, we propose that alterations in
      the lipid raft signaling machinery represent an important mechanism that is
      responsible for the heightened and accelerated T cell responses in SLE.

PMID- 15187167
TI  - Defective dendritic cell function in HIV-infected patients receiving effective
      highly active antiretroviral therapy: neutralization of IL-10 production and
      depletion of CD4+CD25+ T cells restore high levels of HIV-specific CD4+ T cell
      responses induced by dendritic cells generated in the presence of IFN-alpha.
AB  - We previously demonstrated that GM-CSF/IFN-alpha combination allowed the
      differentiation of monocytes from HIV-infected patients into dendritic cells
      (DCs) exhibiting high CD8(+) T cell stimulating abilities. The present study was
      aimed at characterizing the ability of DCs generated in the presence of GM-CSF
      and IFN-alpha to induce CD4 T cell responses. DCs were generated from monocytes
      of HIV-infected patients in the presence of GM-CSF with either IFN-alpha (IFN
      DCs) or IL-4 (IL-4-DCs) for 7 days. Eleven patients receiving highly active
      antiretroviral therapy and exhibiting CD4 cell counts above 400/mm(3) and plasma
      HIV-RNA <50 copies/ml for at least 1 year were included in the study. Both DC
      populations were found to be defective in inducing autologous (in response to
      tuberculin or HIV-p24) or allogeneic CD4 T cell proliferation. Neutralization of
      IL-10 during the differentiation of IFN-DCs, but not during the DC-T cell
      coculture, significantly increased their ability to stimulate autologous CD4 T
      cell proliferation in response to tuberculin and allogeneic CD4 T cell
      proliferation (4.1-fold and 3.0-fold increases, respectively, at the DC to T cell
      ratio of 1:10). Moreover, IL-10 neutralization and CD4(+)CD25(+) T cell depletion
      synergistically act to dramatically increase HIV-p24-specific CD4 T cell
      responses induced by IFN-DCs (31.7-fold increase) but not responses induced by IL
      4-DCs. Taken together, our results indicate that IFN-DCs are more efficient than
      IL-4-DCs to stimulate CD4(+) T cell proliferation, further supporting their use
      for immune-based therapy in HIV infection.

PMID- 15187168
TI  - Altered p38 mitogen-activated protein kinase expression in different leukocytes
      with increment of immunosuppressive mediators in patients with severe acute
      respiratory syndrome.
AB  - Severe acute respiratory syndrome (SARS) has spread to a global pandemic,
      especially in Asia. The transmission route of SARS has been clarified, but the
      immunopathogenesis of SARS is unclear. In an age-matched case-control design, we
      studied immune parameters in 15 SARS patients who were previously healthy. Plasma
      was harvested for detection of virus load, cytokines, and nitrite/nitrate levels,
      and blood leukocytes were subjected to flow cytometric analysis of intracellular
      mitogen-activated protein kinases (MAPKs) in different leukocytes. Patients with
      SARS had significantly higher IL-8 levels (p = 0.016) in early stage, and higher
      IL-2 levels (p = 0.039) in late stage than normal controls. Blood TNF-alpha, IL
      6, and IL-10, and nitrite/nitrate levels were not significantly elevated. In
      contrast, TGF-beta and PGE(2) levels were significantly elevated in SARS
      patients. Five of the 15 SARS patients had detectable coronaviruses in blood, but
      patients with detectable and undetectable viremia had no different profiles of
      immune mediators. Flow cytometric analysis of MAPKs activation by phospho-p38 and
      phospho-p44/42 (extracellular signal-regulated kinase) expression showed that
      augmented p38 activation (p = 0.044) of CD14 monocytes associated with suppressed
      p38 activation (p = 0.033) of CD8 lymphocytes was found in SARS patients. These
      results suggest that regulation of TGF-beta and PGE(2) production and MAPKs
      activation in different leukocytes may be considered while developing
      therapeutics for the SARS treatment.

PMID- 15187169
TI  - Development of antigen-specific CD8+ CTL in MHC class I-deficient mice through
      CD4 to CD8 conversion.
AB  - CD8+ CTL are the predominant tumoricidal effector cells. We find, however, that
      MHC class I-deficient mice depleted of CD8+ T cells are able to mount an
      effective antitumor immunity after immunization with fused dendritic/tumor cells.
      Such immunity appears to be mediated by the generation of phenotypic and
      functional CD8+ CTL through CD4+ to CD8+ conversion, which we have demonstrated
      at the single cell level. CD4+ to CD8+ conversion depends on effective in vivo
      activation and is promoted by CD4+ T cell proliferation. The effectiveness of
      this process is shown by the generation of antitumor immunity through adoptive
      transfer of primed CD4 T cells to provide protection against tumor cell challenge
      and to eliminate established pulmonary metastases.

PMID- 15187170
TI  - The endocannabinoid 2-arachidonylglycerol decreases the immunological activation
      of Guinea pig mast cells: involvement of nitric oxide and eicosanoids.
AB  - The antigen-induced release of histamine from sensitized guinea pig mast cells
      was dose-dependently reduced by endogenous (2-arachidonylglycerol; 2AG) and
      exogenous [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3
      hydroxypropyl)cyclohexan-1-ol (CP55,940)] cannabinoids. The inhibitory action
      afforded by 2AG and CP55,940 was reversed by N-[(1S)-endo-1,3,3
      trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4
      methylbenzyl)pyrazole-3-carboxamide (SR144528), a selective cannabinoid 2 (CB(2))
      receptor antagonist, and left unchanged by the selective CB(1) antagonist N
      (piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3
      carboxamide (AM251). The inhibitory action of 2AG and CP55,940 was reduced by the
      unselective nitric-oxide synthase (NOS) inhibitor N-monomethyl-L-arginine
      methylester (l-NAME) and reinstated by L-arginine, the physiological substrate.
      The inhibitory action of 2AG and CP55,940 was also reduced by the unselective
      cyclooxygenase (COX) inhibitor indomethacin and the selective COX-2 blocker
      rofecoxib. Both 2AG and CP55,940 significantly increased the production of
      nitrite from mast cells, which was abrogated by L-NAME and N-(3
      (aminomethyl)benzyl)acetamidine (1400W), a selective inducible NOS (iNOS)
      inhibitor. Nitrite production consistently paralleled a CP55,940-induced increase
      in the expression of iNOS protein in mast cells. Both 2AG and CP55,940 increased
      the generation of prostaglandin E(2) from mast cells, which was abrogated by
      indomethacin and rofecoxib and parallel to the CP55,940-induced expression of COX
      2 protein. Mast cell challenge with antigen was accompanied by a net increase in
      intracellular calcium levels. Both cannabinoid receptor ligands decreased the
      intracellular calcium levels, which were reversed by SR144528 and l-NAME. In
      unstimulated mast cells, both ligands increased cGMP levels. The increase was
      abrogated by SR144528, l-NAME, indomethacin, and rofecoxib. Our results suggest
      that 2AG and CP55,940 decreased mast cell activation in a manner that is
      susceptible to a CB(2) receptor antagonist and to inhibition of nitric oxide and
      prostanoid pathways.

PMID- 15187171
TI  - Use of the Bayley Infant Neurodevelopmental Screener with an environmental risk
      group.
AB  - OBJECTIVE: To determine predictive validity of the Bayley Infant
      Neurodevelopmental Screener (BINS) during the first 2 years of life with a group
      of children at risk for developmental delay due to environmental risk factors.
      METHOD: The setting consisted of home visits to participants. The BINS was
      administered to 106 children, ages 6 and 13 months, of low-income, African
      American, adolescent mothers. Three risk groups were identified: low, moderate,
      and high. The Bayley Scales of Infant Development, second edition (BSID-II), were
      administered at 24 months and served as the criterion standard. A cut score of 85
      (1.00 SD below mean) represented a clinically meaningful indicator of delayed
      development on the mental and psychomotor developmental indices, as well as a
      composite of these indices. Two other cut scores on the BSID-II were also
      included for comparison: 90 (0.75 SD below mean) and 77 (1.50 SD below mean).
      RESULTS: Using BSID-II scores at 24 months as the criterion measure, 6- and 13
      month BINS scores yielded low sensitivity values but high specificity values,
      regardless of how BINS risk groups were defined and which cut points on the BSID
      II were used. Positive predictive value was higher when the cut score was set
      below 90 than when it was set below 85. CONCLUSIONS: Low predictive validity of
      the BINS with an environmental risk group highlights the difficulties inherent in
      developmental screening among infants who have environmental, but not biological,
      risk factors. Because infants at environmental risk tend to experience
      developmental declines after infancy, it may be beneficial for primary care
      providers to use psychosocial screening tools to identify which children need
      closer monitoring and referral to enrichment programs to prevent developmental
      declines during toddlerhood.

PMID- 15187172
TI  - Parental reinforcement of recurrent pain: the moderating impact of child
      depression and anxiety on functional disability.
AB  - OBJECTIVE: To examine whether children's distress moderates the relationship
      between parental responses to children's pain behaviors and functional
      disability. METHODS: Participants were 215 children (ages 8 to 16 years)
      diagnosed with either headaches, juvenile idiopathic arthritis, or sickle cell
      disease. Children and parents completed questionnaires assessing
      sociodemographics, pain, depression, anxiety, parental solicitous responses to
      pain behaviors, and functional disability. RESULTS: Hierarchical linear
      regressions computed for parental responses to children's pain significantly
      predicted child functional disability, controlling for children's pain intensity.
      Significant interactions between parental solicitous behaviors and child
      depressive symptoms (beta =.74, p <.01) and between solicitous behaviors and
      child anxiety symptoms (beta =.91, p <.01) indicated that for children with more
      psychological distress, parental solicitous behaviors were associated with
      greater child functional disability. CONCLUSIONS: Child psychological distress
      may exacerbate the impact of parental solicitous responses to pain on
      functioning, suggesting the potential role of family intervention to enhance
      optimal functioning in children with recurrent pain.

PMID- 15187173
TI  - Association of observed family relationship quality and problem-solving skills
      with treatment adherence in older children and adolescents with cystic fibrosis.
AB  - OBJECTIVE: To examine associations between observations of the quality of family
      relationships and problem-solving skills and reported adherence to medical
      treatments for older children and adolescents with cystic fibrosis (CF). METHODS:
      Reports of adherence were obtained from 96 youth with CF and their parents
      recruited from six CF centers in the Midwest and southeastern United States.
      Videotaped observations of family discussions of high conflict issues were used
      to assess quality of relationships and problem-solving skills. RESULTS:
      Hierarchical regression analyses indicated that observed family relationship
      quality (RQ) was related to parent and child reports of adherence to airway
      clearance and aerosolized medications after controlling for demographic variables
      and illness severity. Observed family problem solving was not a significant
      predictor after controlling for RQ. CONCLUSIONS: Older children and adolescents
      who come from families experiencing unhappy and conflicted relationships may be
      at greater risk for poor adherence to treatments; thus, family relationships are
      appropriate targets for interventions aimed at improving adherence.

PMID- 15187174
TI  - Primary care supports for children with chronic health conditions: identifying
      and predicting unmet family needs.
AB  - OBJECTIVE: To examine unmet needs among families of children with chronic health
      conditions treated in primary care settings and to identify predictors of these
      needs. METHOD: Primary care physicians referred 83 caregivers of children with
      chronic health conditions. Mothers completed the Family Needs Survey, as well as
      other measures of child and family functioning. RESULTS: Mothers reported a high
      prevalence and broad range of unmet family needs. The most frequent area of need
      was for information about services and ways to promote child health and
      development. Predictors of total number of family needs included demographic
      characteristics, ratings of social support, and appraisals of family burden.
      Predictors of specific types of family needs varied according to category of
      need. CONCLUSIONS: Innovative psychosocial intervention programs are needed in
      primary care settings to reduce family needs and promote child health. More
      intensive family supports may be indicated for those with minority-group or low
      socioeconomic status, limited social support, or high perceived burden.

PMID- 15187175
TI  - Developmental aspects of children's behavior and safety while cycling.
AB  - OBJECTIVE: To examine children's competence while cycling, as demonstrated in
      mistakes in performance and failure to comply with safety rules. METHODS:
      Children in three age groups (8, 10, and 12 years) participated in a realistic
      yet simulated traffic environment. RESULTS: The boys' cycling speed increased
      steadily with age, while that of the girls increased from 8 to 10 but decreased
      at age 12. Most children had adequate motor control by age 10, and the youngest
      compensated for their less developed skills by cycling slowly and braking early
      at junctions. Serious mistakes, often related to the children's age and gender,
      consisted of the children failing to stop at signals or stopping too late,
      especially at short stopping range. CONCLUSIONS: There are considerable
      individual differences in children's cycling competence that are related to
      biological factors, such as age and gender, and psychological factors, such as
      rule compliance and choice of cycling speed.

PMID- 15187177
TI  - Brief report: a "storybook" ending to children's bedtime problems--the use of a
      rewarding social story to reduce bedtime resistance and frequent night waking.
AB  - OBJECTIVE: To evaluate the efficacy and acceptability of a social story with
      tangible rewards to reduce children's disruptive bedtime behavior and frequent
      night waking. METHOD: Four children (ages 2 to 7), with clinically significant
      disruptive bedtime behavior, received the intervention, which consisted of a
      social story (The Sleep Fairy) that sets forth (a) parental expectations for
      appropriate bedtime behavior and (b) rewards for meeting those expectations.
      RESULTS: Parent sleep diaries indicated that children had a 78% average decrease
      in frequency of disruptive bedtime behaviors from baseline to intervention, with
      another 7% decrease at 3-month follow-up. Night wakings, a problem for 2 children
      during baseline, were not a problem during intervention and follow-up. Parents
      reported improved daytime behavior for 3 of the 4 children. Parents gave the
      intervention high acceptability ratings and maintained a high level of treatment
      fidelity. CONCLUSIONS: Use of a social story helped parents implement a
      multicomponent intervention using a familiar bedtime routine, thereby increasing
      the likelihood that implementation and effects occurred. The book format makes
      this intervention widely available to parents and professionals, with minimal
      costs and inconvenience.

PMID- 15187176
TI  - Role of anticipatory anxiety and anxiety sensitivity in children's and
      adolescents' laboratory pain responses.
AB  - OBJECTIVE: To examine relationships among trait anxiety sensitivity, state task
      specific anticipatory anxiety, and laboratory pain responses in healthy children
      and adolescents. METHODS: Participants (N=118, 49.2% female, ages 8-18 years)
      completed a measure of anxiety sensitivity and rated anticipatory anxiety prior
      to undergoing thermal, pressure, and cold pain tasks. Linear and logistic
      regressions were used to test the hypothesis that anxiety sensitivity and
      anticipatory anxiety would predict incremental variance in pain response after
      controlling for sex, age, and anxious symptoms. RESULTS: Anticipatory anxiety
      accounted for 35-38% of unique variance in pain report across tasks, and 10% of
      unique variance in thermal tolerance. Anxiety sensitivity was unrelated to pain
      responses. CONCLUSIONS: Task-specific anxiety is an important predictor of pain
      report and, in certain cases, pain tolerance. Interventions designed to reduce
      task-specific anticipatory anxiety may help reduce pain responses in children and
      adolescents.

PMID- 15187178
TI  - Brief report: health beliefs among survivors of childhood cancer.
AB  - OBJECTIVE: To describe interest in cancer screening and tobacco-control
      procedures (nicotine-addiction susceptibility testing) among survivors of
      childhood cancer and to identify psychosocial modifying and readiness factors
      associated with survivors' interest, based on the children's health belief model.
      METHODS: Twenty-eight survivor-mother dyads were interviewed as part of a
      preliminary study (mean age of survivors = 15.4 years at time of interview, 10.1
      years at time of diagnosis, and 12.0 years at end of treatment); interviews
      consisted of well-validated self-report items and measures of health beliefs.
      RESULTS: In sum, 57% and 61% of survivors were interested in screening and
      susceptibility testing, respectively. Survivors who rated themselves as more
      competent, more concerned about cancer, and more vulnerable to cancer were more
      interested in participating in screening. Regarding interest in nicotine
      addiction susceptibility testing, survivors were more interested when they
      perceived greater vulnerability to the harm of smoking and when they had mothers
      who perceived themselves to be in better health. CONCLUSIONS: Preliminary data
      suggest that psychosocial modifying and readiness factors are associated with
      survivors' interest in cancer screening and tobacco-control procedures and that
      additional research in this area is warranted.

PMID- 15187179
TI  - Martin P. Levin Award: reflections on the mentoring process.

PMID- 15187180
TI  - A new biology for a new century.
AB  - Biology today is at a crossroads. The molecular paradigm, which so successfully
      guided the discipline throughout most of the 20th century, is no longer a
      reliable guide. Its vision of biology now realized, the molecular paradigm has
      run its course. Biology, therefore, has a choice to make, between the comfortable
      path of continuing to follow molecular biology's lead or the more invigorating
      one of seeking a new and inspiring vision of the living world, one that addresses
      the major problems in biology that 20th century biology, molecular biology, could
      not handle and, so, avoided. The former course, though highly productive, is
      certain to turn biology into an engineering discipline. The latter holds the
      promise of making biology an even more fundamental science, one that, along with
      physics, probes and defines the nature of reality. This is a choice between a
      biology that solely does society's bidding and a biology that is society's
      teacher.

PMID- 15187181
TI  - "Sleeping beauty": quiescence in Saccharomyces cerevisiae.
AB  - The cells of organisms as diverse as bacteria and humans can enter stable,
      nonproliferating quiescent states. Quiescent cells of eukaryotic and prokaryotic
      microorganisms can survive for long periods without nutrients. This alternative
      state of cells is still poorly understood, yet much benefit is to be gained by
      understanding it both scientifically and with reference to human health. Here, we
      review our knowledge of one "model" quiescent cell population, in cultures of
      yeast grown to stationary phase in rich media. We outline the importance of
      understanding quiescence, summarize the properties of quiescent yeast cells, and
      clarify some definitions of the state. We propose that the processes by which a
      cell enters into, maintains viability in, and exits from quiescence are best
      viewed as an environmentally triggered cycle: the cell quiescence cycle. We
      synthesize what is known about the mechanisms by which yeast cells enter into
      quiescence, including the possible roles of the protein kinase A, TOR, protein
      kinase C, and Snf1p pathways. We also discuss selected mechanisms by which
      quiescent cells maintain viability, including metabolism, protein modification,
      and redox homeostasis. Finally, we outline what is known about the process by
      which cells exit from quiescence when nutrients again become available.

PMID- 15187182
TI  - Proteomics of protein secretion by Bacillus subtilis: separating the "secrets" of
      the secretome.
AB  - Secretory proteins perform a variety of important "remote-control" functions for
      bacterial survival in the environment. The availability of complete genome
      sequences has allowed us to make predictions about the composition of bacterial
      machinery for protein secretion as well as the extracellular complement of
      bacterial proteomes. Recently, the power of proteomics was successfully employed
      to evaluate genome-based models of these so-called secretomes. Progress in this
      field is well illustrated by the proteomic analysis of protein secretion by the
      gram-positive bacterium Bacillus subtilis, for which approximately 90
      extracellular proteins were identified. Analysis of these proteins disclosed
      various "secrets of the secretome," such as the residence of cytoplasmic and
      predicted cell envelope proteins in the extracellular proteome. This showed that
      genome-based predictions reflect only approximately 50% of the actual composition
      of the extracellular proteome of B. subtilis. Importantly, proteomics allowed the
      first verification of the impact of individual secretion machinery components on
      the total flow of proteins from the cytoplasm to the extracellular environment.
      In conclusion, proteomics has yielded a variety of novel leads for the analysis
      of protein traffic in B. subtilis and other gram-positive bacteria. Ultimately,
      such leads will serve to increase our understanding of virulence factor
      biogenesis in gram-positive pathogens, which is likely to be of high medical
      relevance.

PMID- 15187184
TI  - RegB/RegA, a highly conserved redox-responding global two-component regulatory
      system.
AB  - The Reg regulon from Rhodobacter capsulatus and Rhodobacter sphaeroides encodes
      proteins involved in numerous energy-generating and energy-utilizing processes
      such as photosynthesis, carbon fixation, nitrogen fixation, hydrogen utilization,
      aerobic and anaerobic respiration, denitrification, electron transport, and
      aerotaxis. The redox signal that is detected by the membrane-bound sensor kinase,
      RegB, appears to originate from the aerobic respiratory chain, given that
      mutations in cytochrome c oxidase result in constitutive RegB
      autophosphorylation. Regulation of RegB autophosphorylation also involves a redox
      active cysteine that is present in the cytosolic region of RegB. Both
      phosphorylated and unphosphorylated forms of the cognate response regulator RegA
      are capable of activating or repressing a variety of genes in the regulon. Highly
      conserved homologues of RegB and RegA have been found in a wide number of
      photosynthetic and nonphotosynthetic bacteria, with evidence suggesting that
      RegB/RegA plays a fundamental role in the transcription of redox-regulated genes
      in many bacterial species.

PMID- 15187185
TI  - Infection and invasion of roots by symbiotic, nitrogen-fixing rhizobia during
      nodulation of temperate legumes.
AB  - Bacteria belonging to the genera Rhizobium, Mesorhizobium, Sinorhizobium,
      Bradyrhizobium, and Azorhizobium (collectively referred to as rhizobia) grow in
      the soil as free-living organisms but can also live as nitrogen-fixing symbionts
      inside root nodule cells of legume plants. The interactions between several
      rhizobial species and their host plants have become models for this type of
      nitrogen-fixing symbiosis. Temperate legumes such as alfalfa, pea, and vetch form
      indeterminate nodules that arise from root inner and middle cortical cells and
      grow out from the root via a persistent meristem. During the formation of
      functional indeterminate nodules, symbiotic bacteria must gain access to the
      interior of the host root. To get from the outside to the inside, rhizobia grow
      and divide in tubules called infection threads, which are composite structures
      derived from the two symbiotic partners. This review focuses on symbiotic
      infection and invasion during the formation of indeterminate nodules. It
      summarizes root hair growth, how root hair growth is influenced by rhizobial
      signaling molecules, infection of root hairs, infection thread extension down
      root hairs, infection thread growth into root tissue, and the plant and bacterial
      contributions necessary for infection thread formation and growth. The review
      also summarizes recent advances concerning the growth dynamics of rhizobial
      populations in infection threads.

PMID- 15187183
TI  - Compartmentalization of gene expression during Bacillus subtilis spore formation.
AB  - Gene expression in members of the family Bacillaceae becomes compartmentalized
      after the distinctive, asymmetrically located sporulation division. It involves
      complete compartmentalization of the activities of sporulation-specific sigma
      factors, sigma(F) in the prespore and then sigma(E) in the mother cell, and then
      later, following engulfment, sigma(G) in the prespore and then sigma(K) in the
      mother cell. The coupling of the activation of sigma(F) to septation and sigma(G)
      to engulfment is clear; the mechanisms are not. The sigma factors provide the
      bare framework of compartment-specific gene expression. Within each sigma regulon
      are several temporal classes of genes, and for key regulators, timing is
      critical. There are also complex intercompartmental regulatory signals. The
      determinants for sigma(F) regulation are assembled before septation, but
      activation follows septation. Reversal of the anti-sigma(F) activity of SpoIIAB
      is critical. Only the origin-proximal 30% of a chromosome is present in the
      prespore when first formed; it takes approximately 15 min for the rest to be
      transferred. This transient genetic asymmetry is important for prespore-specific
      sigma(F) activation. Activation of sigma(E) requires sigma(F) activity and occurs
      by cleavage of a prosequence. It must occur rapidly to prevent the formation of a
      second septum. sigma(G) is formed only in the prespore. SpoIIAB can block
      sigma(G) activity, but SpoIIAB control does not explain why sigma(G) is activated
      only after engulfment. There is mother cell-specific excision of an insertion
      element in sigK and sigma(E)-directed transcription of sigK, which encodes pro
      sigma(K). Activation requires removal of the prosequence following a sigma(G)
      directed signal from the prespore.

PMID- 15187190
TI  - Calcium ions are abnormally distributed in the skin of haemodialysis patients
      with uraemic pruritus.
AB  - BACKGROUND: Although a close relationship between uraemic pruritus and serum
      calcium levels has been demonstrated for some time, the degree of pruritus was
      not always correlated with calcium concentrations. In the present study, we
      assessed calcium ion distribution in the skin of chronic haemodialysis patients
      with and without pruritus. METHODS: We excluded patients with concomitant
      psoriasis or atopic dermatitis or with a previous history of allergy, those who
      had an arteriovenous fistula created prior to induction of haemodialysis, and
      patients with only mild pruritus. From the enrolled 22 haemodialysis patients, we
      obtained forearm skin samples during arteriovenous fistula surgery. These
      patients were divided into two groups based their grade of pruritus. The pruritus
      group included patients with moderate to severe grades of pruritus (n = 11, age
      64 +/-13 years) and the non-pruritus group consisted of patients without pruritus
      (n = 11, age 59 +/-13 years). We compared the distribution of calcium ions in the
      epidermis between the two groups using the ion-capture method (oxalate
      pyroantimonate-osmium technique). In addition, we examined and compared the
      groups for thicknesses of the basal, spinous and granular layers, as well as of
      the stratum corneum using an electron microscope. RESULTS: The pruritus group had
      significantly higher calcium ion deposition in the extracellular fluid and
      cytoplasm of basal cells, and in the extracellular fluid, nuclei and cytoplasm of
      spinous cells compared with the non-pruritus group. In contrast, calcium ion
      depositions were similar between the two groups in the dermis/basal layer
      interface, the nucleus of basal cells, the nucleus and cytoplasm of granular
      cells, exterior of granular cells, the granular cells/stratum corneum interface,
      and in the interior and exterior of corneocytes. Although the stratum corneum was
      significantly thicker in the pruritus group than in the non-pruritus group, there
      were no differences in basal cell, spinal cell or granular cell layer
      thicknesses. CONCLUSION: In chronic haemodialysis patients with pruritus, the
      calcium ion concentration in the deepest layer of the epidermis was increased,
      which indicated a disrupted calcium ion gradient in the skin. These findings
      point to a role for increased skin calcium ion concentrations in the development
      and/or maintenance of uraemic pruritus. However, more extensive studies in larger
      patient cohorts will be necessary to confirm this hypothesis.

PMID- 15187188
TI  - Microbial responses to microgravity and other low-shear environments.
AB  - Microbial adaptation to environmental stimuli is essential for survival. While
      several of these stimuli have been studied in detail, recent studies have
      demonstrated an important role for a novel environmental parameter in which
      microgravity and the low fluid shear dynamics associated with microgravity
      globally regulate microbial gene expression, physiology, and pathogenesis. In
      addition to analyzing fundamental questions about microbial responses to
      spaceflight, these studies have demonstrated important applications for microbial
      responses to a ground-based, low-shear stress environment similar to that
      encountered during spaceflight. Moreover, the low-shear growth environment sensed
      by microbes during microgravity of spaceflight and during ground-based
      microgravity analogue culture is relevant to those encountered during their
      natural life cycles on Earth. While no mechanism has been clearly defined to
      explain how the mechanical force of fluid shear transmits intracellular signals
      to microbial cells at the molecular level, the fact that cross talk exists
      between microbial signal transduction systems holds intriguing possibilities that
      future studies might reveal common mechanotransduction themes between these
      systems and those used to sense and respond to low-shear stress and changes in
      gravitation forces. The study of microbial mechanotransduction may identify
      common conserved mechanisms used by cells to perceive changes in mechanical
      and/or physical forces, and it has the potential to provide valuable insight for
      understanding mechanosensing mechanisms in higher organisms. This review
      summarizes recent and future research trends aimed at understanding the dynamic
      effects of changes in the mechanical forces that occur in microgravity and other
      low-shear environments on a wide variety of important microbial parameters.

PMID- 15187186
TI  - Diversity in chemotaxis mechanisms among the bacteria and archaea.
AB  - The study of chemotaxis describes the cellular processes that control the
      movement of organisms toward favorable environments. In bacteria and archaea,
      motility is controlled by a two-component system involving a histidine kinase
      that senses the environment and a response regulator, a very common type of
      signal transduction in prokaryotes. Most insights into the processes involved
      have come from studies of Escherichia coli over the last three decades. However,
      in the last 10 years, with the sequencing of many prokaryotic genomes, it has
      become clear that E. coli represents a streamlined example of bacterial
      chemotaxis. While general features of excitation remain conserved among bacteria
      and archaea, specific features, such as adaptational processes and hydrolysis of
      the intracellular signal CheY-P, are quite diverse. The Bacillus subtilis
      chemotaxis system is considerably more complex and appears to be similar to the
      one that existed when the bacteria and archaea separated during evolution, so
      that understanding this mechanism should provide insight into the variety of
      mechanisms used today by the broad sweep of chemotactic bacteria and archaea.
      However, processes even beyond those used in E. coli and B. subtilis have been
      discovered in other organisms. This review emphasizes those used by B. subtilis
      and these other organisms but also gives an account of the mechanism in E. coli.

PMID- 15187191
TI  - Efficacy of a second course of immunosuppressive therapy in patients with
      membranous nephropathy and persistent or relapsing disease activity.
AB  - BACKGROUND: A single course of immunosuppressive treatment improves renal
      survival in patients with idiopathic membranous nephropathy (iMN) and renal
      insufficiency. However, not all patients respond and relapses occur within 5
      years in 30% of patients. It is unknown if a second course of immunosuppressive
      therapy is effective in such patients. METHODS: We have prospectively studied and
      evaluated the clinical course in 15 patients (14 male, one female; age: 52+/-12
      years) with iMN who have received a repeated course of immunosuppressive therapy
      because of deteriorating renal function associated with relapsing or persistent
      nephrotic syndrome. RESULTS: The first course of immunosuppression was started 8
      months (range: 0-143 months) after renal biopsy and consisted of chlorambucil (n
      = 8) or cyclophosphamide (n = 7); the second course consisted of cyclophosphamide
      in all patients. The interval between the first and second course was 40 months
      (range: 7-112 months). Total follow-up was 110 months (range: 46-289 months).
      Renal function and proteinuria improved at least temporarily in all patients
      after the second course. During follow-up, an additional course of therapy was
      given in four patients. Status at the end of follow-up was complete remission (n
      = 2), partial remission (n = 8), persistent proteinuria (n = 3), end-stage renal
      disease (n = 1) and death (n = 1, due to cardiovascular disease while nephrotic).
      Renal survival was 86% at 5 and 10 years of follow-up. The repeated courses of
      immunosuppression have resulted in a gain of dialysis-free survival time of > or
      =93 months (range: 43-192 months). CONCLUSIONS: Our results indicate that
      patients with iMN who do not respond well or relapse after a first course of
      immunosuppressive therapy and have renal insufficiency should be offered a second
      course of immunosuppression. Such a strategy maintains renal function in the
      majority of patients.

PMID- 15187187
TI  - ERK and p38 MAPK-activated protein kinases: a family of protein kinases with
      diverse biological functions.
AB  - Conserved signaling pathways that activate the mitogen-activated protein kinases
      (MAPKs) are involved in relaying extracellular stimulations to intracellular
      responses. The MAPKs coordinately regulate cell proliferation, differentiation,
      motility, and survival, which are functions also known to be mediated by members
      of a growing family of MAPK-activated protein kinases (MKs; formerly known as
      MAPKAP kinases). The MKs are related serine/threonine kinases that respond to
      mitogenic and stress stimuli through proline-directed phosphorylation and
      activation of the kinase domain by extracellular signal-regulated kinases 1 and 2
      and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on
      primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress
      activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2
      and 3, and MK5. In the last 5 years, several MK substrates have been identified,
      which has helped tremendously to identify the biological role of the members of
      this family. Together with data from the study of MK-knockout mice, the
      identities of the MK substrates indicate that they play important roles in
      diverse biological processes, including mRNA translation, cell proliferation and
      survival, and the nuclear genomic response to mitogens and cellular stresses. In
      this article, we review the existing data on the MKs and discuss their
      physiological functions based on recent discoveries.

PMID- 15187192
TI  - Plasma ghrelin levels in patients undergoing haemodialysis and peritoneal
      dialysis.
AB  - BACKGROUND: Ghrelin has been characterized as a relevant physiologic regulator of
      appetite and body weight in humans. However, the potential relationships between
      ghrelin levels, inflammation and malnutrition in dialysis patients have not been
      adequately studied. METHODS: We used a cross-sectional design to study 20
      haemodialysis (HD) and 21 peritoneal dialysis (PD) patients, and compared their
      plasma ghrelin (PGhr) levels with that of an age-matched control group. We also
      explored correlations between ghrelin and selected hormonal, renal adequacy,
      nutritional and inflammation markers in both groups. RESULTS: PGhr levels were
      higher in HD (median 119.8 pg/ml, range 71.1-333.7, P = 0.001) and PD (99.3,
      range 45.8-578.5, P = 0.045) patients than in healthy controls (78, range 29-158)
      (HD vs PD, not significant). Ghrelin levels were strongly and inversely
      correlated with age (r = -0.46, P = 0.02 for patients; r = -0.61, P = 0.001 for
      controls). Except for a positive correlation between ghrelin and growth hormone
      (r = 0.48, P = 0.002), univariate analysis failed to detect associations between
      PGhr and the measured hormonal values, renal adequacy, nutritional indicators and
      markers of inflammation. However, multivariate analysis revealed significant
      inverse correlations between PGhr levels and nutritional markers, including
      subjective global assessment (P = 0.013), albumin (P = 0.001), transferrin (P =
      0.01) and protein nitrogen appearance (as an estimate of protein intake) (P =
      0.035), after controlling for the confounding effect of age. CONCLUSIONS: PGhr
      levels were moderately and similarly increased in patients undergoing HD and PD.
      Age was a strong determinant of PGhr levels, both in uraemic patients and in
      healthy controls. Dialysis adequacy, residual renal function and inflammation did
      not appear to influence ghrelin levels in these patients. The negative
      correlation between PGhr and nutritional markers suggests that low dietary intake
      causes increases in ghrelin secretion in dialysis patients.

PMID- 15187193
TI  - Anti-macrophage migration inhibitory factor reduces transforming growth factor
      beta 1 expression in experimental IgA nephropathy.
AB  - BACKGROUND: In human glomerulonephritis, including immunoglobulin-A nephropathy
      (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is
      found to correlate with progressive renal injury. We have shown previously that
      polymeric IgA is capable of inducing MIF production in cultured human mesangial
      cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we
      examined whether IgA deposition and the subsequent renal injury can be
      ameliorated with anti-MIF treatment in an experimental murine model of IgAN.
      METHODS: Glomerular IgA deposition was induced in 4-week-old BALB/c mice by
      intravenous injection of immune complexes consisting of dinitrophenyl-conjugated
      bovine serum albumin (DNP-BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To
      determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg)
      or isotypic control antibody intravenously 2 h before the immune complexes
      administration. The mice were sacrificed 48 h after injection of DNP-IgA.
      Proteinuria and haematuria were determined and the kidneys were removed for
      histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on
      production of TGF-beta 1 by cultured mesangial cells was also examined. RESULTS:
      IgA deposits were detected in glomeruli of all mice receiving the immune
      complexes while no glomerular deposit was detected in the control mice.
      Microscopic haematuria and mesangial hypercellularity were present in mice of the
      three experimental groups and were absent in the control group. Proteinuria was
      absent in all groups. Anti-MIF treatment also resulted in decreased renal
      expression of TGF-beta 1. Moreover, the reduction in TGF-beta 1 expression was
      confined mainly to glomerular mesangium. An in vitro culture experiment
      demonstrated that MIF increased TGF-beta 1 production in a time- and dose
      dependent fashion. MIF-induced TGF-beta 1 synthesis was abolished by incubating
      cells with neutralizing antibody against MIF. CONCLUSIONS: Our finding shows that
      anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-beta 1
      expression in an experimental model of IgAN.

PMID- 15187194
TI  - Hypokalaemia and paralysis in the Thai population.
AB  - BACKGROUND: Hypokalaemia with paralysis is a syndrome common in Thailand. This
      syndrome may result from hypokalaemic periodic paralysis (HypoPP), thyrotoxic
      periodic paralysis (TPP) or distal renal tubular acidosis (dRTA). We
      prospectively investigated the nature of this syndrome in afflicted Thai
      patients. METHODS: Blood and urine samples were collected from 47 patients during
      attacks for multiple biochemical and thyroid function tests. A long acid loading
      test was performed in all euthyroid patients. Mutation analyses were done in all
      HypoPP and TPP patients. RESULTS: Of the subjects, 34 completed the study. Of
      those, 11 (32%), eight (24%) and 15 (44%) had TPP, dRTA and HypoPP, respectively.
      Patients with dRTA and TPP were older than those with HypoPP. Males were more
      prevalent than females in HypoPP and TPP; the reverse was true for dRTA. Two
      thirds of the HypoPP cases were sporadic. The majority of the HypoPP and dRTA
      patients resided in northeastern Thailand. Of the 11 TPP patients, nine (82%) had
      no previous thyroid disease. Moreover, four out of 11 patients (36%) had subtle
      clinical signs of hyperthyroidism; three of eight dRTA patients had renal stones,
      nephrocalcinosis or both. Only two patients had metabolic acidosis at the time of
      presentation. No common mutations were found in the HypoPP and TPP patients.
      CONCLUSIONS: In most of our patients, HypoPP is sporadic and not associated with
      the common mutations reported previously. Clinical clues that can assist in
      differentiating between the causes of hypokalaemia and paralysis are age at
      onset, gender and geographic region residence of the patients. However, the
      absence of previous histories of thyroid disease or overt thyrotoxicosis, and of
      stone disease/nephrocalcinosis or metabolic acidosis does not exclude the
      diagnosis of TPP or dRTA.

PMID- 15187189
TI  - Pathogenesis of human papillomaviruses in differentiating epithelia.
AB  - Human papillomaviruses (HPV) are the etiological agents of cervical and other
      anogenital malignancies. Over 100 different types of HPVs have been identified to
      date, and all target epithelial tissues for infection. One-third of HPV types
      specifically infect the genital tract, and a subset of these are the causative
      agents of anogenital cancers. Other HPV types that infect the genital tract
      induce benign hyperproliferative lesions or genital warts. The productive life
      cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are
      thought to infect cells in the basal layer of stratified epithelia and establish
      their genomes as multicopy nuclear episomes. In these cells, viral DNA is
      replicated along with cellular chromosomes. Following cell division, one of the
      daughter cells migrates away from the basal layer and undergoes differentiation.
      In highly differentiated suprabasal cells, vegetative viral replication and late
      gene expression are activated, resulting in the generation of progeny virions.
      Since virion production is restricted to differentiated cells, infected basal
      cells can persist for up to several decades or until the immune system clears the
      infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53,
      respectively. During the viral life cycle, these proteins facilitate stable
      maintenance of episomes and stimulate differentiated cells to reenter the S
      phase. The E1 and E2 proteins act as origin recognition factors as well as
      regulators of early viral transcription. The functions of the E5 and E1--E4
      proteins are still largely unknown, but these proteins have been implicated in
      modulating late viral functions. The L1 and L2 proteins form icosahedral capsids
      for progeny virion generation. The characterization of the cellular targets of
      these viral proteins and the mechanisms regulating the differentiation-dependent
      viral life cycle remain active areas for the study of these important human
      pathogens.

PMID- 15187195
TI  - Comparison of the effects of calcitriol and maxacalcitol on secondary
      hyperparathyroidism in patients on chronic haemodialysis: a randomized
      prospective multicentre trial.
AB  - BACKGROUND: To identify differences between the effects of calcitriol and the
      calcitriol analogue, maxacalcitol, on parathyroid hormone (PTH) and bone
      metabolisms, we conducted a randomized prospective multicentre study on patients
      on chronic haemodialysis. METHODS: We randomly assigned 91 patients with
      secondary hyperparathyroidism [intact PTH (iPTH) > or =150 pg/ml] to have either
      calcitriol (47 patients) or maxacalcitol (44 patients) therapy, for 12 months
      after a 1 month control period. Serum electrolytes, bone alkaline phosphatase
      (bAP), iPTH, total PTH and PTH(1-84) (whole PTH) levels were measured
      periodically. The first end point was a serum iPTH of <150 pg/ml, the second was
      the iPTH levels obtained. RESULTS: Treatment was discontinued for various reasons
      in nine patients in each group, but no serious side effects were observed in
      either group. The numbers of cases reaching the first end point were not
      significantly different between the two groups. Serum calcium concentration was
      significantly higher in the maxacalcitol than the calcitriol group during early
      treatment, but not at the end of treatment. Throughout the treatment period there
      were no significant differences between the two groups in serum iPTH, inorganic
      phosphate, the product of the serum calcium and inorganic phosphorus
      concentrations, bAP, or the ratio of whole PTH to total PTH minus whole PTH. Nor
      were the changes in these parameters significantly different between the two
      groups comparing the patients with moderate to severe hyperparathyroidism (basal
      iPTH > or =500 pg/ml). CONCLUSION: Calcitriol and maxacalcitol are equally
      effective on PTH and bone metabolism.

PMID- 15187196
TI  - Important differentiation of factors that predict outcome in peritoneal dialysis
      patients with different degrees of residual renal function.
AB  - BACKGROUND: Residual renal function (RRF) is an important predictor of outcome in
      peritoneal dialysis (PD) patients. Whether results from survival studies in
      dialysis patients with RRF can also be extrapolated to anuric patients remains
      uncertain. In this observational study, we examined the characteristics of PD
      patients with a residual glomerular filtration rate (GFR) > or =1 ml/min per 1.73
      m2 vs those with complete anuria and differentiated factors that predict outcome
      in the two groups of patients. METHODS: Two hundred and forty-six continuous
      ambulatory peritoneal dialysis (CAPD) patients (39% being completely anuric) were
      recruited from a single regional dialysis centre. Assessments of haemodynamic,
      echocardiographic, nutritional and biochemical parameters and indices of dialysis
      adequacy were done at study baseline and were related to outcomes. RESULTS:
      During the prospective follow-up of 30.8+/-13.8 (mean+/-SD) months, 28.0% of
      patients with residual GFR > or =1 ml/min per 1.73 m2 vs 50.5% of anuric patients
      had died (P = 0.005). The overall 2 year patient survival was 89.7 and 65.0% for
      patients with GFR > or =1 ml/min per 1.73 m2 and anuric patients, respectively (P
      = 0.0012). Compared with patients with GFR > or =1 ml/min per 1.73 m2, anuric
      patients were dialysed for longer (P<0.001), were more anaemic (P<0.005), and had
      higher calcium-phosphorus product (P<0.01), higher C-reactive protein (P<0.001),
      lower serum albumin (P<0.05), greater prevalence of malnutrition according to
      subjective global assessment (P<0.05) and more severe cardiac hypertrophy
      (P<0.001) at baseline. Using multivariable Cox regression analysis, serum
      albumin, left ventricular mass index and residual GFR were significant factors
      associated with mortality in patients with GFR > or =1 ml/min per 1.73 m2, while
      increasing age, atherosclerotic vascular disease and higher C-reactive protein
      were associated with greater mortality in anuric PD patients. CONCLUSIONS: Our
      study demonstrates more adverse cardiovascular, inflammatory, nutritional and
      metabolic profiles as well as higher mortality in anuric PD patients.
      Furthermore, factors associated with mortality are also not equivalent for PD
      patients with and without RRF, suggesting that patients with and without RRF are
      qualitatively different.

PMID- 15187197
TI  - Role of alpha-adducin DNA polymorphisms in the genetic predisposition to diabetic
      nephropathy.
AB  - BACKGROUND: There is substantial evidence for genetic susceptibility to diabetic
      nephropathy. In particular, genes that predispose to hypertension in the general
      population may confer susceptibility to nephropathy in patients with diabetes. A
      Gly460Trp variant in the alpha-adducin gene has been associated with essential
      hypertension. Our aim was to screen the alpha-adducin gene for polymorphisms and
      to determine if any variants predisposed patients with diabetes to nephropathy. A
      secondary objective was to assess for association between the Gly460Trp variant
      and hypertension. METHODS: The exons of the alpha-adducin gene were resequenced
      in 30 individuals. Selected variants were then genotyped in 155 patients with
      type 1 diabetes and nephropathy (cases) and 216 persons with type 1 diabetes but
      no evidence of nephropathy (controls) from Northern Ireland and in 95 cases and
      118 controls from the Irish Republic. RESULTS: Eleven polymorphisms were
      detected, of which six were novel and three caused amino-acid substitutions. The
      Gly460Trp and a novel Ser617Cys polymorphism were in strong linkage
      disequilibrium (D' = 0.98). Neither the genotype nor allele frequencies for the
      Gly460Trp polymorphism (P = 0.89 and 0.93 respectively) or the Ser617Cys
      polymorphism (P = 0.46 and 0.76) were significantly different between cases and
      controls when the Northern Ireland and Irish Republic sample groups were
      combined. Carriage of the 460Trp allele was not significantly associated with
      systolic or diastolic blood pressure in either the cases (P = 0.48 and 0.06,
      respectively) or in the controls (P = 0.50 and 0.94, respectively). CONCLUSIONS:
      Variation in the alpha-adducin gene does not play a major role in the development
      of nephropathy in persons with type 1 diabetes in the Irish population.
      Furthermore, the Gly460Trp variant was not associated with hypertension in this
      population.

PMID- 15187198
TI  - The effect of proteinase inhibitors on glomerular albumin permeability induced in
      vitro by serum from patients with idiopathic focal segmental glomerulosclerosis.
AB  - BACKGROUND: The putative circulating factor responsible for the glomerular
      permeability alterations induced in vitro by serum from patients affected by
      focal segmental glomerulosclerosis (FSGS) remains unidentified. We have observed
      that a serine proteinase isolated from patient serum increases albumin
      permeability in isolated glomeruli. The objective of the present study was to
      determine the effect of various proteinase inhibitors on glomerular albumin
      permeability (P(alb)) in isolated glomeruli incubated with FSGS serum. METHODS:
      The study population consisted of 12 FSGS patients (eight males; mean age: 21+/
      10 years) previously shown to have elevated serum albumin permeability activity.
      P(alb) was determined by measuring the change in glomerular volume induced by
      applying oncotic gradients to isolated healthy rat glomeruli treated with patient
      serum in comparison to control serum. Solutions of seven different proteinase
      inhibitors (0.5 mg/ml) were added to the incubation media with the sera (1:1
      vol/vol): serine proteinase inhibitors (PMSF, leupeptin, aprotinin, gabexate
      mesylate), the cysteine proteinase inhibitor E-64, the metalloproteinase
      inhibitor EDTA and the aspartate proteinase inhibitor pepstatin. Sera from the
      same patients were also tested with the addition to the incubation media of
      quinaprilat, an inhibitor of the metalloproteinase angiotensin-converting enzyme.
      RESULTS: Mean P(alb) of the sera was 0.86+/-0.11, with the addition of PMSF
      0.41+/-0.09, leupeptin 0.30+/-0.17, aprotinin 0.09+/-0.14, gabexate mesylate
      0.27+/-0.25, E-64 0.81+/-0.09, EDTA 0.68+/-0.10 or pepstatin 0.76+/-0.11. The
      mean P(alb) of the sera combined with quinaprilat was reduced to 0.34+/-0.35.
      Thus, only the serine proteinase inhibitors consistently blocked the increased
      P(alb) induced by the FSGS sera. CONCLUSIONS: In the cascade of events that lead
      to the initiation of glomerular fibrosis in FSGS, the putative glomerular
      permeability factor associated with FSGS may require a serine proteinase to
      effect its activity.

PMID- 15187199
TI  - Cyclosporin exposure correlates with 1 year graft function and histological
      damage in renal transplanted patients.
AB  - BACKGROUND: Cyclosporin (CsA) level obtained 2 h after the morning dose (C(2))
      has been shown to accurately predict total CsA exposure and acute rejection (AR)
      risk, whereas conventional trough levels (C(0)) do not. The impact of C(2)
      monitoring on long-term kidney graft function, independent from AR risk, is still
      unclear, however, and it was assessed in the present study. METHODS: We enrolled
      39 CsA-treated renal transplant recipients and used 1 year graft function and
      histological structure as surrogate markers of graft outcome. CsA dose was
      adjusted according to C(2) levels. RESULTS: In the first 7 days after grafting,
      40-51% of patients failed to reach target C(2) levels; nevertheless, at 1 year
      the incidence of AR was only 2.5% and graft and patient survival was 100%. The
      decrease of serum creatinine (12-6 months) was associated with significantly
      higher C(2) levels over time (P = 0.0003) and lower intrapatient variability of
      CsA relative absorption (CV) (P = 0.0006). One year graft biopsy showed chronic
      tubulointerstitial lesions in 54.5% of patients. Both C(2) mean levels and the
      percentage CV independently predicted the severity of chronic histological
      lesions (R = 0.69, P<0.0001). CONCLUSIONS: Higher C(2) levels, within the
      proposed target range values, seem to be associated with better renal function
      and structure.

PMID- 15187200
TI  - Influence of apolipoprotein E polymorphisms on serum creatinine levels and
      predicted glomerular filtration rate in healthy subjects.
AB  - BACKGROUND: There are conflicting results regarding the effect of apolipoprotein
      (ApoE) polymorphisms on the progression of a variety of renal diseases. However,
      there are no data on the possible effect of the ApoE alleles on serum creatinine
      levels and predicted glomerular filtration rate (GFR) in healthy subjects.
      METHODS: 290 apparently healthy individuals were studied. ApoE genotyping was
      performed by the polymerase chain reaction; the Modification of Diet in Renal
      Disease equation (MDRD) predicted the GFR. RESULTS: ApoE2 was associated with
      lower levels of total cholesterol, low-density lipoprotein cholesterol and non
      high-density lipoprotein cholesterol, as well as with higher levels of
      triglycerides in our population. Furthermore, the ApoE2 allele was associated
      with increased serum creatinine levels compared with both the E3 and E4 alleles
      (1.04+/-0.13 vs 0.92+/-0.13 vs 0.88+/- 0.11 mg/dl, respectively, P = 0.0077),
      while the MDRD-predicted GFR was decreased in ApoE2 carriers compared with both
      E3 and E4 carriers (80.3+/-10.2 vs 88.1+/-9.6 vs 89.3+/-9.7 ml/min/1.73 m(2),
      respectively, P = 0.031). These observations remained significant statistically
      even if the effect of ApoE polymorphisms on age- and body-mass index-adjusted
      serum creatinine and MDRD-predicted GFR was separately analysed in both men and
      women. Although, ApoE4 carriers tended to exhibit lower levels of serum
      creatinine and higher values of predicted GFR compared with the E3 carries, these
      differences did not reach statistical significance. CONCLUSIONS: ApoE2 allele
      seems to be associated with increased serum creatinine levels and decreased MDRD
      predicted GFR in healthy subjects.

PMID- 15187201
TI  - Phage display identification of age-associated TNFalpha-mediated cardiac
      oxidative induction.
AB  - Age-associated alterations in the actions of tumor necrosis factor-alpha
      (TNFalpha) in the heart with impaired cardioprotective pathways and enhanced
      apoptotic induction may contribute to the increased severity of cardiovascular
      pathology in older persons. To identify the molecular events mediating these
      changes in the microvasculature of the aging rodent heart, the biochemical
      properties of in vivo phage-display cyclic peptide cardiac biopanning were
      studied. Analysis of individual amino acid positions revealed that the center of
      the peptide motif (amino acid position 4) had a significantly higher frequency of
      aromatic amino acid side chains in phage homing to the old hearts compared with
      young controls (18 mo old, 11% vs. 3 mo old, 3%, P < 0.05). This subset of phage
      motifs revealed an age-associated homology with oxidoreductase enzymes (homology:
      18 mo, 7/7; 3 mo, 0/2), suggesting the substrates and/or binding sites of these
      enzymes are increased in the aging hearts. Immunostaining for the oxidoreductase
      substrate 4-hydroxy-2-nonenal (HNE), a cardiotoxic lipid peroxidation product,
      demonstrated a twofold higher density of HNE(+) cells in PBS-treated hearts of
      old mice (18 mo) compared with young controls (3 mo) (18 mo, 3.2 +/- 2.8 vs. 3
      mo, 1.0 +/- 0.9 cells/HPF, P < 0.05). Moreover, intracardiac injection of
      TNFalpha resulted in a significantly greater increase in HNE staining in the old
      hearts (18 mo, 16.9 +/- 13.8 vs. 3 mo, 9.1 +/- 6.0 cells/HPF, P < 0.05). Overall,
      these studies demonstrate that aging-associated alterations in TNFalpha-mediated
      pathways with induction of reactive oxidative species and changes in vascular
      surface binding sites may contribute mechanistically to the increased
      cardiovascular pathology of the aging heart.

PMID- 15187202
TI  - Omalizumab: a novel therapy for allergic asthma.
AB  - OBJECTIVE: To review the pharmacology, efficacy, and safety of omalizumab,
      focusing on the treatment of allergic asthma. DATA SOURCES: A MEDLINE search
      (1966-November 2003) was conducted using the key words omalizumab, Xolair, and
      Rhu-MAB25, with studies limited to those in humans and published in English.
      References of identified articles were reviewed for additional citations. STUDY
      SELECTION AND DATA EXTRACTION: Clinical trials evaluating the pharmacology,
      efficacy, and safety of omalizumab for treatment of allergic asthma in patients
      aged >or=12 years were selected. Clinical trials examining utility in pediatric
      patients were also reviewed. DATA SYNTHESIS: Omalizumab's ability to form
      complexes with unbound immunoglobulin E (IgE) translates into decreased unbound
      serum IgE levels and high-affinity IgE receptors on basophils, as well as
      attenuation of early and late allergic response in patients with allergic asthma.
      Results of clinical trials demonstrated that omalizumab administered
      subcutaneously is a safe and effective treatment for moderate to severe allergic
      asthma. Generally, omalizumab has a mild adverse effect profile. Omalizumab may
      be particularly useful for treatment of moderate to severe allergic asthma in
      patients who are poorly controlled on conventional therapy, experience adverse
      effects secondary to high-dose or prolonged corticosteroid treatment, or who have
      frequent exacerbations because of poor medication adherence. The high cost
      associated with omalizumab treatment may be prohibitive for some patients,
      thereby limiting its utility. CONCLUSIONS: Omalizumab is a safe and effective
      therapy for treatment of moderate to severe allergic asthma in difficult-to
      treat, high-risk patients.

PMID- 15187203
TI  - Comparison of natural product use between primary care and nephrology patients.
AB  - BACKGROUND: The use of natural products is increasing, but healthcare
      professionals may underestimate the use of these agents by patients. It is
      unknown whether natural product use differs between primary care and specialty
      clinic patients, such as those in a nephrology clinic. OBJECTIVE: To compare
      patterns of natural product use between primary care and nephrology clinic
      patients. METHODS: One thousand adult patients from each clinic were randomly
      mailed an anonymous questionnaire to determine current and past use of natural
      products. RESULTS: A total of 491 surveys were returned, for an overall response
      rate of 26% (25% primary care; 28% nephrology clinic). Current use of natural
      products was similar between the primary care and nephrology groups (34% vs 29%,
      respectively; p = NS). Primary care patients were more likely to have taken a
      natural product in the past (57% vs 45%; p < 0.05); Echinacea was the most common
      product taken by those patients (26%). Green tea was the most common natural
      product taken by nephrology clinic patients (18%). More primary care patients
      took Echinacea compared with nephrology clinic patients (26% vs 12%; p < 0.01).
      Adverse reactions led to discontinuation of the natural product in 7% of
      respondents. CONCLUSIONS: Active use of natural products was similar between the
      survey respondents. Documentation and monitoring of natural product use by
      healthcare professionals working with primary care and nephrology clinic patients
      are recommended.

PMID- 15187204
TI  - Abacavir/lamivudine/zidovudine continues to be a valid and useful antiretroviral
      regimen.

PMID- 15187205
TI  - Nonsteroidal antiinflammatory drug use among patients with GI bleeding.
AB  - BACKGROUND: Previous studies have suggested that recommended gastroprotective
      strategies such as gastroprotective agents (GPAs) and cyclooxygenase (COX) 2
      inhibitors may be underutilized among individuals at risk for nonsteroidal
      antiinflammatory drug (NSAID)-related gastrointestinal (GI) bleeding. OBJECTIVE:
      To examine the use of traditional NSAIDs, COX-2 inhibitors, and GPAs among
      patients recently hospitalized for GI bleeding. METHODS: This was a retrospective
      cohort study of a national sample of 4338 veterans hospitalized for GI bleeding
      between January and June 1999. Prescription drug use was examined for 6 months
      following hospitalization. We examined relationships of subject characteristics
      (age, race, gender, geographic region, diagnosis of arthritis) to prescription of
      a high-risk NSAID, defined as a traditional NSAID but no GPA within 60 days
      before or after the NSAID. RESULTS: Approximately 20% of subjects were prescribed
      an NSAID or COX-2 inhibitor, but only 5% were prescribed a traditional NSAID with
      no GPA. In a multivariable analysis, subjects <65 years of age and those with
      arthritis were more likely to be prescribed a traditional NSAID without a GPA. No
      other subject characteristics were related to receipt of a high-risk
      prescription. CONCLUSIONS: In a national sample of veterans with a recent
      hospitalization for GI bleeding, high-risk NSAID prescriptions were uncommon.
      Underuse of gastroprotective strategies may be more common in patients with less
      recent GI bleeding-related hospitalization. Strategies to remind physicians and
      pharmacists to screen for GI risk factors may help to sustain appropriate
      prescribing and reduce NSAID-related adverse events.

PMID- 15187207
TI  - Single-class therapy for HIV is not optimal care.

PMID- 15187206
TI  - Lithium intoxication as a result of an interaction with rofecoxib.
AB  - OBJECTIVE: To report the occurrence of lithium intoxication in a patient with
      bipolar disorder after adding rofecoxib to the medication regimen. CASE SUMMARY:
      A 68-year-old woman with bipolar disorder under long-term treatment with lithium,
      carbamazepine, pipamperon, and mirtazapine was prescribed rofecoxib 25 mg twice
      daily for the treatment of leg pain. Within one week, she showed progressive
      hypokinesia and tremor, which was treated with propranolol. Subsequently, she
      developed bradycardia, necessitating treatment with isoproterenol. Her lithium
      serum concentration had doubled compared with those before rofecoxib, and her
      renal function had deteriorated. After stopping lithium and rofecoxib, her
      laboratory values and neurologic signs improved or normalized within 2 days. An
      objective causality assessment revealed a probable relationship between
      concomitant use of the drugs and the resulting symptoms. DISCUSSION: As of May
      24, 2004, only 3 cases of reversible lithium intoxication as a result of a
      possible interaction with rofecoxib or celecoxib have been previously reported.
      The mechanism of the interaction between lithium and cyclooxygenase (COX) 2
      selective inhibitors is most probably related to inhibition of renal synthesis of
      prostaglandins, which are important for the maintenance of renal perfusion and
      tubular function. Impairment of renal blood flow, leading to a decrease in the
      glomerular filtration rate, and increased proximal tubular absorption are the
      most likely mechanisms by which COX-2 selective inhibitors reduce lithium
      clearance. CONCLUSIONS: Coadministration of rofecoxib and lithium may result in
      life-threatening lithium intoxication, especially in patients with a preexisting
      decrease in renal function and/or decreased intravascular volume.

PMID- 15187208
TI  - Leflunomide-associated pancytopenia with or without methotrexate.
AB  - OBJECTIVE: To report 18 cases of pancytopenia associated with leflunomide use in
      Australia, 5 of which were treated at Princess Alexandra Hospital, Brisbane. case
      summaries: Leflunomide was used in the treatment of rheumatoid arthritis in 17 of
      18 patients; the other patient was diagnosed with systemic lupus erythematosus.
      Median age was 65.5 years (range 18-79), and 15 of the patients were female.
      Fourteen patients were on combined treatment with methotrexate. Pancytopenia was
      typically severe, requiring hospital admission, withdrawal of the
      immunosuppressant(s), intensive supportive therapy, and treatment of neutropenic
      sepsis. Five patients died, 4 of whom were receiving concomitant methotrexate.
      Time to onset of pancytopenia ranged from 11 days to 4 years (median 4 mo). In
      one case in which the patient had been stable while receiving leflunomide,
      methotrexate, and hydroxychloroquine for 4 years, fatal pancytopenia was
      triggered by acute renal failure secondary to dehydration and use of nonsteroidal
      antiinflammatory drugs. The Naranjo probability scale suggested a probable causal
      association in 5 cases and possible association in the remainder. DISCUSSION:
      Leflunomide, indicated for treatment of active rheumatoid arthritis, inhibits
      pyrimidine synthesis in lymphocytes and other rapidly dividing cells and may
      rarely be associated with life-threatening pancytopenia. Combination therapy with
      methotrexate may increase the risk. Time to onset is variable, and clinicians
      should remain vigilant, particularly when there is a change in the patient's
      baseline health status. CONCLUSIONS: The risk of pancytopenia during leflunomide
      therapy appears to be increased when the drug is combined with methotrexate and
      in older patients. Onset may be delayed, and ongoing monitoring of blood counts
      is essential.

PMID- 15187209
TI  - Gemifloxacin: a new fluoroquinolone approved for treatment of respiratory
      infections.
AB  - OBJECTIVE: To evaluate the microbiology, pharmacokinetic parameters, drug
      interactions, and results of the available clinical trials of gemifloxacin for
      the treatment of community-acquired pneumonia (CAP) and acute exacerbation of
      chronic bronchitis (AECB). DATA SOURCES: MEDLINE (1966-September 2003) was
      searched for primary and review articles. Data from the manufacturer were also
      included. Key words included adverse effects, clinical trials, drug interactions,
      gemifloxacin, and pharmacokinetic parameters. STUDY SELECTION AND DATA
      EXTRACTION: All articles and product labeling concerning gemifloxacin, a
      fluoroquinolone antibiotic recently approved by the Food and Drug Administration
      for treatment of CAP and AECB, were included for review. DATA SYNTHESIS: Compared
      with currently available fluoroquinolones, gemifloxacin demonstrated improved in
      vitro activity against Streptococcus pneumoniae (minimum inhibitory concentration
      for 90% eradication 0.03 microg/mL) and similar activity against gram-negative
      respiratory pathogens (Haemophilus influenzae, Moraxella catarrhalis) and
      atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila, and
      Mycoplasma pneumoniae. Gemifloxacin, consistent with other available
      fluoroquinolones, has insufficient activity against methicillin-resistant
      Staphylococcus aureus to allow clinical use for such infections. Gemifloxacin has
      adequate bioavailability and a favorable drug interaction profile. Gemifloxacin
      was comparable to commonly employed nonfluoroquinolone regimens for treatment of
      CAP and AECB, although the studies were designed to demonstrate equivalence.
      Gemifloxacin once daily for 5-7 days was well tolerated in controlled and
      uncontrolled clinical studies. Available clinical data, however, are insufficient
      to draw clinical or toxicologic distinctions between gemifloxacin and other
      fluoroquinolones. CONCLUSIONS: Gemifloxacin may be a suitable choice for empiric
      treatment of CAP or AECB. However, due to the significant history of
      fluoroquinolone-induced hepatic failure and dermatologic complications, the use
      of this drug should be closely monitored.

PMID- 15187210
TI  - Dual blockade of the renin-angiotensin system in diabetic nephropathy.
AB  - OBJECTIVE: To review the literature concerning dual blockade of the renin
      angiotensin system (RAS) with an angiotensin-converting enzyme (ACE) inhibitor
      and an angiotensin II receptor blocker (ARB) in diabetic nephrophathy. DATA
      SOURCES: MEDLINE (1998-September 2003), EMBASE (1998-September 2003), and
      International Pharmaceutical Abstracts (1998-September 2003) were used to access
      the literature. Search terms included angiotensin-converting enzyme inhibitor,
      angiotensin II receptor blocker, diabetic nephropathy, dual blockade, renin
      angiotensin system, and combination therapy. DATA SYNTHESIS: Monotherapy with an
      ACE inhibitor provides incomplete blockade of the RAS. Dual blockade of the RAS
      has been studied in approximately 300 patients with diabetic nephropathy. Recent
      randomized controlled studies suggest that dual blockade using an ACE inhibitor
      and an ARB in diabetic nephropathy is well tolerated and will provide an
      additional 11-43% reduction in albuminuria versus monotherapy. CONCLUSIONS: Dual
      blockade of the RAS using an ACE inhibitor and an ARB provide statistically
      significant reductions in albuminuria and blood pressure. Use of dual blockade is
      safe, but requires additional monitoring for hyperkalemia. Long-term studies are
      needed to determine whether the decrease in albuminuria will correlate with an
      actual improvement from overt proteinuria to microalbuminuria or a decreased
      incidence of end-stage renal disease in the overall diabetic population.

PMID- 15187211
TI  - Selective serotonin-reuptake inhibitors for the treatment of hot flashes.
AB  - OBJECTIVE: To review the literature evaluating the use of selective serotonin
      reuptake inhibitors (SSRIs) for the treatment of hot flashes. DATA SOURCES:
      Biomedical literature was accessed through MEDLINE (1966-June 2003), MD Consult,
      and references of reviewed articles. Key search terms used were hot flashes,
      vasomotor symptoms, antidepressants, and SSRIs. DATA SYNTHESIS: Recent evidence
      from the Women's Health Initiative precludes the use of traditional hormonal
      therapy in some women. Nonhormonal therapies are possible options, but
      conflicting evidence of efficacy exists. CONCLUSIONS: Although further studies
      are warranted, preliminary data suggest that SSRIs are generally modestly
      successful in reducing the frequency and severity of hot flashes.

PMID- 15187212
TI  - Imatinib mesylate treatment in two patients with idiopathic hypereosinophilic
      syndrome.
AB  - OBJECTIVE: To report 2 clinical cases of hypereosinophilic syndrome (HES)
      refractory to standard therapy and the variable responses to imatinib mesylate,
      and to review previously reported cases of imatinib mesylate use in the treatment
      of hypereosinophilia. case summaries: Two male patients were diagnosed with
      idiopathic HES complicated with organ involvement. Both were treated with
      imatinib mesylate after failing to respond to or being unable to tolerate
      standard therapy. In one patient, treatment with imatinib mesylate 100 mg/day
      produced resolution of symptoms and peripheral blood cell counts within 6 days.
      The patient has successfully maintained normal blood cell counts and has been
      without symptoms for more than one year after starting imatinib mesylate. The
      other patient failed to respond to imatinib mesylate even at the maximum dose (up
      to 400 mg/day). DISCUSSION: Imatinib mesylate was considered an appropriate
      alternative for standard therapy of HES based on the evidence that other
      treatments used for chronic myelogenous leukemia have also been successful in
      treating HES. Three small studies have supported this hypothesis. However, not
      all patients with HES respond to imatinib mesylate therapy. The cases presented
      here illustrate the marked difference. CONCLUSIONS: Imatinib mesylate has shown
      some promise in the treatment of HES. However, until the etiology of idiopathic
      hypereosinophilia and the role of imatinib mesylate in the resolution of this
      disease are determined, it will continue to be difficult to predict the
      responsiveness of a patient to imatinib mesylate therapy.

PMID- 15187213
TI  - Possible mirtazapine-induced rhabdomyolysis.

PMID- 15187214
TI  - Rhabdomyolysis caused by Commiphora mukul, a natural lipid-lowering agent.
AB  - OBJECTIVE: To report a case of rhabdomyolysis caused by Commiphora mukul, a
      natural lipid-lowering agent. CASE SUMMARY: A 55-year-old man was taking an
      extract of C. mukul 300 mg 3 times daily to lower his cholesterol level. He
      developed rhabdomyolysis with hemoglobinuria after 2 weeks of treatment.
      Laboratory tests showed creatine kinase 144600 IU/L (reference range 24-195),
      myoglobin >3000 ng/mL (28-72), lactate dehydrogenase 7157 IU/L (230-460),
      aspartate aminotransferase 1115 IU/L (10-35), and alanine aminotransferase 205
      IU/L (10-35). Analysis of a urine sample was 2+ positive for hemoglobin. All
      parameters returned to normal after the herbal preparation was discontinued.
      DISCUSSION: The Naranjo probability scale indicates C. mukul as the possible
      cause of rhabdomyolysis in our patient. Drug-induced rhabdomyolysis is an
      established but rare adverse effect of high doses of cholesterol-lowering agents
      (statins) or interactions between drugs (eg, statins and fibrates). As of May 28,
      2004, to our knowledge, this is the first reported case of rhabdomyolysis
      following C. mukul ingestion. CONCLUSIONS: Our report describes a case of
      rhabdomyolysis possibly caused by C. mukul and underlines the need for active
      surveillance of natural products.

PMID- 15187215
TI  - Bevacizumab: an angiogenesis inhibitor with efficacy in colorectal and other
      malignancies.
AB  - OBJECTIVE: To review the pharmacology, pharmacokinetics, and pivotal clinical
      trials for bevacizumab, emphasizing its use in colorectal cancer. DATA SOURCES: A
      PubMed/MEDLINE search was conducted (1966-April 2004) using the following terms:
      bevacizumab, Avastin, anti-VEGF, anti-angiogenesis, and colorectal cancer.
      Additional data sources included meeting abstracts, bibliographies from
      identified articles, and information from the manufacturer. STUDY SELECTION AND
      DATA EXTRACTION: Preclinical and clinical trials that used bevacizumab for the
      treatment of colorectal cancer and other malignancies were selected from the data
      sources. All published, randomized clinical trials evaluating bevacizumab in
      colorectal cancer were included in this review. DATA SYNTHESIS: Despite advances
      in chemotherapy, current therapeutic options for metastatic disease provide only
      temporary benefit for most patients. Bevacizumab is the first anti-cancer agent
      shown to provide benefit for patients with cancer by inhibiting angiogenesis.
      Bevacizumab has shown significant activity in the treatment of many cancers,
      including metastatic colorectal cancer. When used in combination with
      fluorouracil-based chemotherapy, bevacizumab improves overall response rates,
      time to progression, and survival in patients with metastatic colorectal cancer.
      Common toxicities associated with bevacizumab include hypertension, bleeding
      episodes, and thrombotic events. CONCLUSIONS: Although clinical knowledge on the
      effectiveness of bevacizumab is limited, early data indicate that it is a
      promising agent, with a novel mechanism of action, for patients with metastatic
      cancer, including colorectal cancer.

PMID- 15187216
TI  - The paperless labeling initiative: a proof-of-concept study.
AB  - BACKGROUND: Traditional paper professional package inserts (PPIs) are used on a
      daily basis by a variety of healthcare providers to locate and disseminate drug
      information. Unfortunately, paper PPIs are sometimes not accessible to the
      healthcare provider, appear unreadable due to varied font sizes, and are often
      considered not to be user-friendly. In December 2000, the Food and Drug
      Administration proposed regulations that would revise the format of PPIs.
      OBJECTIVE: To determine whether electronic delivery of PPI information is
      achievable in community pharmacy practice settings. METHODS: Electronic PPIs are
      an alternative means of delivering this information. This 12-week proof-of
      concept study evaluated the Health Information Designs/Thomson Healthcare and
      Etreby Computer Company for electronic delivery of PPIs in 6 chain and 4
      independent community pharmacies, with 5 pharmacies evaluating each system.
      Participating pharmacists were asked 9 questions designed to determine the
      feasibility of implementing electronic PPI delivery, as well as pharmacist
      satisfaction with each system. RESULTS: Pharmacists deemed both systems to be
      accessible and user-friendly. Pharmacists from both groups felt that the
      electronic PPIs were challenging to read and that printing took too long.
      CONCLUSIONS: Future studies in a more diverse selection of dispensing sites,
      including pharmacies (community and hospital based), clinics, and physician
      practices, need to be performed to maximize the use of electronic PPIs.

PMID- 15187218
TI  - Conscience, the law, and donation of expired drugs.

PMID- 15187217
TI  - Approximate equivalent rosuvastatin doses for temporary statin interchange
      programs.
AB  - OBJECTIVE: To estimate approximate doses of rosuvastatin equivalent to the other
      hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) for a temporary
      substitution program. DATA SOURCES: A literature search was conducted to locate
      clinical trials directly comparing rosuvastatin with other statins that evaluated
      the magnitude of cholesterol lowering. DATA SYNTHESIS: The mean low-density
      lipoprotein and total cholesterol values from the clinical trials were assessed.
      Study results indicate that rosuvastatin is not equivalent to other statins on a
      milligram-to-milligram basis. CONCLUSIONS: Rosuvastatin appears to be at least 2
      and 4 times as potent as atorvastatin and simvastatin, respectively, and at least
      8 times as potent as pravastatin and lovastatin.

PMID- 15187221
TI  - Comment: safety and efficacy of influenza vaccine in children.

PMID- 15187219
TI  - Intensive insulin therapy for critically ill patients.
AB  - OBJECTIVE: To evaluate the clinical outcomes of glycemic control of intensive
      insulin therapy and recommend its place in the management of critically ill
      patients. DATA SOURCES: Searches of MEDLINE (1966-March 2004) and Cochrane
      Library, as well as an extensive manual review of abstracts were performed using
      the key search terms hyperglycemia, insulin, intensive care unit, critically ill,
      outcomes, and guidelines and algorithms. STUDY SELECTION AND DATA EXTRACTION: All
      articles identified from the data sources were evaluated and deemed relevant if
      they included and assessed clinical outcomes. DATA SYNTHESIS: Mortality among
      patients with prolonged critical illness exceeds 20%, and most deaths are
      attributable to sepsis and multisystem organ failure. Hyperglycemia is common in
      critically ill patients, even in those with no history of diabetes mellitus.
      Maintaining normoglycemia with insulin in critically ill patients has been shown
      to improve neurologic, cardiovascular, and infectious outcomes. Most importantly,
      morbidity and mortality are reduced with aggressive insulin therapy. This
      information can be implemented into protocols to maintain strict control of
      glucose. CONCLUSIONS: Use of insulin protocols in critically ill patients
      improves blood glucose control and reduces morbidity and mortality in critically
      ill populations. Glucose levels in critically ill patients should be controlled
      through implementation of insulin protocols with the goal to achieve
      normoglycemia, regardless of a history of diabetes. Frequent monitoring is
      imperative to avoid hypoglycemia.

PMID- 15187223
TI  - Finding a new vaccine in the ricin protein fold.
AB  - Previous attempts to produce a vaccine for ricin toxin have been hampered by
      safety concerns arising from residual toxicity and the undesirable aggregation or
      precipitation caused by exposure of hydrophobic surfaces on the ricin A-chain
      (RTA) in the absence of its natural B-chain partner. We undertook a structure
      based solution to this problem by reversing evolutionary selection on the
      'ribosome inactivating protein' fold of RTA to arrive at a non-functional,
      compacted single-domain scaffold (sequence RTA1-198) for presentation of a
      specific protective epitope (RTA loop 95-110). An optimized protein based upon
      our modeling design (RTA1-33/44-198) showed greater resistance to thermal
      denaturation, less precipitation under physiological conditions and a reduction
      in toxic activity of at least three orders of magnitude compared with RTA. Most
      importantly, RTA1-198 or RTA1-33/44-198 protected 100% of vaccinated animals
      against supra-lethal challenge with aerosolized ricin. We conclude that
      comparative protein analysis and engineering yielded a superior vaccine by
      exploiting a component of the toxin that is inherently more stable than is the
      parent RTA molecule.

PMID- 15187222
TI  - Characterization of engineered anti-p185HER-2 (scFv-CH3)2 antibody fragments
      (minibodies) for tumor targeting.
AB  - An engineered antibody fragment (minibody; scFv-C(H)3gamma(1) dimer, M(r) 80 000)
      specific for carcinoembryonic antigen (CEA) has previously demonstrated excellent
      tumor targeting coupled with rapid clearance in vivo. In this study, variable (V)
      genes from the anti- p185(HER-2) 10H8 antibody were similarly assembled and
      expressed. Four constructs were made: first, the V genes were assembled in both
      orientations (V(L)-linker-V(H) and V(H)-linker-V(L)) as single chain Fvs (scFvs).
      Then each scFv was fused to the human IgG1 C(H)3 domain, either by a two amino
      acid linker (ValGlu) that resulted in a non-covalent, hingeless minibody, or by
      IgG1 hinge and a GlySer linker peptide to produce a covalent, hinge-minibody. The
      constructs, expressed in NS0 mouse myeloma cells at levels of 20-60 mg/l,
      demonstrated binding to the human p185(HER-2) overexpressing breast cancer cell
      line, MCF7/HER2. Binding affinities (K(D) approximately 2-4 nM) were equivalent
      to that for the parental 10H8 mAb (K(D) approximately 1.6 nM). Radioiodinated
      10H8 hinge-minibody was evaluated in athymic mice, bearing MCF7/HER2 xenografts.
      Maximum tumor uptake was 5.6 (+/-1.65)% injected dose/g (ID/g) at 12 h, which was
      lower than that of the anti-CEA minibody, whereas the blood clearance (beta
      phase, 5.62 h) was similar. Thus, minibodies with different specificities display
      similar pharmacokinetics, while tumor uptake may vary depending on the antigen
      antibody system.

PMID- 15187224
TI  - Stabilized variant of Streptomyces subtilisin inhibitor and its use in
      stabilizing subtilisin BPN'.
AB  - Protein protease inhibitors could potentially be used to stabilize proteases in
      commercial products such as liquid laundry detergents. However, many protein
      protease inhibitors are susceptible to hydrolysis inflicted by the protease. We
      have engineered Streptomyces subtilisin inhibitor (SSI) to resist proteolysis by
      adding an interchain disulfide bond and removing a subtilisin cleavage site at
      leucine 63. When these stabilizing changes were combined with changes to optimize
      the affinity for subtilisin, the resulting inhibitor provided complete protease
      stability for at least 5 months at 31 degrees C in a subtilisin-containing liquid
      laundry detergent and allowed full recovery of the subtilisin activity upon the
      dilution that occurs in a North American washing machine.

PMID- 15187225
TI  - Evaluation of structural similarity based on reduced dimensionality
      representations of protein structure.
AB  - Protein similarity estimations can be achieved using reduced dimensional
      representations and we describe a new application for the generation of two
      dimensional maps from the three-dimensional structure. The code for the
      dimensionality reduction is based on the concept of pseudo-random generation of
      two-dimensional coordinates and Monte Carlo-like acceptance criteria for the
      generated coordinates. A new method for calculating protein similarity is
      developed by introducing a distance-dependent similarity field. Similarity of two
      proteins is derived from similarity field indices between amino acids based on
      various criteria such as hydrophobicity, residue replacement factors and
      conformational similarity, each showing a one factor Gaussian dependence. Results
      on comparisons of misfolded protein models with data sets of correctly folded
      structures show that discrimination between correctly folded and misfolded
      structures is possible. Tests were carried out on five different proteins,
      comparing a misfolded protein structure with members of the same topology,
      architecture, family and domain according to the CATH classification.

PMID- 15187226
TI  - Modification of substrate-binding site of glutamyl endopeptidase from Bacillus
      intermedius.
AB  - Glutamyl endopeptidases (GEPs) are serine proteases belonging to the chymotrypsin
      structural family. Although the family as a whole has been described in detail,
      the molecular mechanism underlying strict substrate specificity of GEPs remains
      unclear. The most popular hypothesis attributes the key role in recognition of
      the charged substrates by GEPs to the conserved amino acid His213 (chymotrypsin
      numbering system). In order to test the role of this residue in the substrate
      specificity, we obtained a GEP from Bacillus intermedius with an amino acid
      substitution (His213-Thr) and studied its catalytic properties. Such modification
      proved not to affect the primary specificity of the enzyme. The introduced
      substitution had little effect on the Michaelis constant (Km increased 4.9 times)
      but considerably affected the catalytic constant (kcat decreased 615 times). The
      obtained data suggest that the conserved His213 residue in Bacillus GEPs is not a
      key element determining their primary substrate specificity.

PMID- 15187227
TI  - Trans-4-hydroxy-2-nonenal inhibits nucleotide excision repair in human cells: a
      possible mechanism for lipid peroxidation-induced carcinogenesis.
AB  - Lipid peroxidation (LPO) is a cellular process that commonly takes place under
      normal physiological conditions. Under excessive oxidative stress, the level of
      LPO becomes very significant, and a growing body of evidence has shown that
      excessive LPO may be involved in carcinogenesis. Trans-4-hydroxy-2-nonenal (4
      HNE) is a major product of LPO, and its level becomes relatively high in cells
      under oxidative stress. 4-HNE is able to react readily with various cellular
      components, including DNA and proteins. We previously found that the 4-HNE-DNA
      adduct is a potent mutagen in human cells and is preferentially formed at codon
      249 of the p53 gene, a mutational hotspot in human cancers. To further understand
      the role of 4-HNE in carcinogenesis, we addressed the question of whether 4-HNE
      affects DNA repair in human cells. We found that the repair capacity for
      benzo[a]pyrene diol epoxide and UV light-induced DNA damage was greatly
      compromised in human cells or human cell extracts treated with 4-HNE, which is
      mainly through interaction of 4-HNE with cellular repair proteins. We also found
      that 4-HNE greatly sensitizes cells to benzo[a]pyrene diol epoxide- and UV
      induced killing. Together these results strongly suggest that this LPO metabolite
      damages not only DNA but also DNA repair mechanisms in human cells. We propose
      that these two detrimental effects of LPO may contribute synergistically to human
      carcinogenesis.

PMID- 15187228
TI  - Selective incorporation of 5-hydroxytryptophan into proteins in mammalian cells.
AB  - An orthogonal tryptophanyl-transfer RNA (tRNA) synthetase (TrpRS)-mutant opal
      suppressor tRNA(Trp) (mutRNA(UCA)(Trp)) pair was generated for use in mammalian
      cells. The anticodon loop of the Bacillus subtilis tRNA(Trp) was mutated to UCA,
      three positions in the D arm were mutated to generate an internal promoter
      sequence, and the mutRNA(UCA)(Trp) gene was inserted between the 5' and 3'
      flanking sequences of the tRNA(Trp-1) gene from Arabidopsis to enhance its
      expression in mammalian cells. In vitro aminoacylation assays and in vivo opal
      suppression assays showed that B. subtilis TrpRS (BsTrpRS) charges only the
      cognate mutRNA(UCA)(Trp) and no endogenous mammalian tRNAs. Similarly, the
      mutRNA(UCA)(Trp) is specifically charged by B. subtilis TrpRS and not by
      endogenous synthetases in mammalian cells. Site-directed mutagenesis was then
      used to alter the specificity of BsTrpRS to uniquely charge 5-hydoxy-l
      tryptophan. The resulting mutant BsTrpRS-mutRNA(UCA)(Trp) pair allows the
      efficient and selective incorporation of 5-hydroxy-l-tryptophan into mammalian
      proteins in response to the codon, TGA. This amino acid can be used as a
      fluorescence probe and also undergoes electrochemical oxidation in situ to
      generate an efficient protein crosslinking.

PMID- 15187229
TI  - TorsinA and torsion dystonia: Unraveling the architecture of the nuclear
      envelope.

PMID- 15187230
TI  - S-nitrosylation: physiological regulation of NF-kappaB.

PMID- 15187231
TI  - Estrogen receptor beta regulates epithelial cellular differentiation in the mouse
      ventral prostate.
AB  - We have previously reported epithelial cellular hyperplasia in ventral prostates
      (VP) of mice lacking estrogen receptor beta (ER beta). To investigate the causes
      of this phenomenon, we measured cellular proliferation and apoptosis in VP of ER
      beta(-/-) and WT mice. With BrdUrd labeling, the number of proliferating cells
      was 3.6-fold higher in ER beta(-/-) mice. There was also a decrease in apoptosis
      as measured by terminal deoxynucleotidyltransferase-mediated dUTP nick end
      labeling assay and an increase in expression of the anti-apoptotic bcl-2. The
      state of differentiation of the epithelial cells of the VP was studied by
      immunohistochemical staining, Western blotting, and fluorescence-activated cell
      sorting (FACS). In ER beta(-/-) mouse VP, the number of p63-positive cells (basal
      phenotype) was 2.6-fold higher, and expression level of cytokeratin (CK) 8, a
      luminal cell marker, was lower. FACS analysis with p63 showed that in WT mice the
      ratio of basal to intermediate/luminal cell populations expressing p63 was 1:2.5,
      whereas in ER beta(-/-) mice it was 1:9. The expression of basal/intermediate
      marker CK 19 in three FACS areas, g1, g2, and g3, gated according to cellular
      size and granularity, was 1:0.6:2 in WT and 1:4:6.7 in ER beta(-/-) mice, showing
      a shift of CK 19-positive cells toward a cell population of intermediate size and
      granularity. We conclude that, in ER beta(-/-) mouse VP, there is increased
      epithelial proliferation, decreased apoptosis, and accumulation of incompletely
      differentiated cells in an intermediate pool. The continued proliferation of
      intermediate cells leads to the prostatic epithelial hyperplasia observed in the
      absence of ER beta signaling.

PMID- 15187232
TI  - Myc degradation: dancing with ubiquitin ligases.

PMID- 15187233
TI  - Selection-subtraction approach (SSA): a universal genetic screening technique
      that enables negative selection.
AB  - Screening of expression libraries for bioactive clones that modulate the growth
      of mammalian cells has been limited largely to positive selections incapable of
      revealing growth suppressive or lethal genetic elements. We have developed a
      technique, selection-subtraction approach (SSA), that allows growth-modulating
      clones to be isolated based on alterations in their relative abundance in growing
      cell populations that have been transduced with an expression library. SSA
      utilizes tagged retroviral libraries in bacteriophage lambda vectors
      (retrophages). Nylon prints from retrophage libraries are used to determine the
      relative abundance of tags in library-transduced cells to identify biological
      activity of individual clones. Applications of SSA for gene discovery, target
      discovery, and generation of mutant proteins have been demonstrated, by using p53
      and ataxia telangiectasia mutated (ATM) as models to isolate growth inhibitory
      proteins, peptides and antisense RNAs, and temperature-sensitive mutant proteins.

PMID- 15187235
TI  - Subacute inhalation toxicity of aniline in rats: analysis of time-dependence and
      concentration-dependence of hematotoxic and splenic effects.
AB  - In this study, thirty male Wistar rats/group were exposed nose-only to mean
      analytical concentrations of 9.2, 32.4, 96.5, and 274.9 mg aniline/m3 using an
      exposure regimen of 6 h/day, 5 days/week for 2 weeks (days 0-11), followed by a 2
      week post-exposure period (up to day 28). Serial sacrifices for specialized
      examinations were performed on days 0, 4, 11, 14, and 28. Clinical signs of
      toxicity, body weights, hematology, and clinical chemistry tests, including total
      iron in liver and spleen, splenic lipid peroxidation, organ weights, gross and
      histological changes in target organs were recorded. No mortality was observed
      during the study. Rats exposed to 96.5 mg/m3 and above displayed cyanosis, with
      no apparent progression during the exposure period. The predominant manifestation
      of toxicity was methemoglobin formation and associated erythrocytotoxicity. The
      changes observed included anemia, red blood cell morphological alterations (e.g.,
      Heinz bodies), decreased hemoglobin and hematocrit, reticulocytosis, and effects
      on the spleen (splenomegaly, hemosiderin accumulation, and increased
      hematopoietic cell proliferation), which gained significance at 96.5 and 274.9
      mg/m3. With regard to increased splenic extramedullary hematopoiesis, borderline
      effects occurred at 32.4 mg/m3. The total content of iron in spleen homogenates
      increased in a concentration-dependent and time-dependent manner with increasing
      duration of exposure. The maximum accumulation of iron in the liver and spleen
      exceeded the respective control levels by approximately 60% and approximately
      500%, respectively. Splenic lipid peroxidation and total iron were highly
      correlated (r2 = 0.93) toward the end of the exposure period. A hepatic
      hemosiderosis was observed at 274.9 mg/m3. Thus, in regard to erythrocytotoxicity
      and associated increased splenic sequestration of erythrocytes, iron accumulation
      and lipid peroxidation 32.4 mg/m3 constitutes the no-observed-adverse-effect
      concentration (NOAEC). However, spleens of the 32.4 mg/m3 exposure group
      exhibited a minimal increase in extramedullary hematopoiesis. Exposure to 9.2
      mg/m3 was not associated with any significant effect.

PMID- 15187234
TI  - A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion
      formation and increases peritoneal fibrinolytic activity.
AB  - Fibrous adhesions remain a major sequela of abdominal surgery. The
      proinflammatory peptide substance P (SP), known to participate in inflammatory
      events, may play a key role in adhesion formation. This hypothesis was tested by
      using an antagonist, CJ-12,255 (Pfizer), that blocks the binding of SP to the
      neurokinin 1 receptor (NK-1R). Adhesion formation was surgically induced in the
      peritoneum of rats receiving daily doses of the NK-1R antagonist (NK-1RA; 5.0 or
      10.0 mg/kg per day) or saline. On postoperative day 7, both the low and high
      doses of NK-1RA significantly (P < 0.05) reduced adhesion formation by 45% and
      53%, respectively, compared with controls. Subsequently, the effect of NK-1RA
      administration on peritoneal fibrinolytic activity was investigated to determine
      a potential mechanism for SP action in the peritoneum. Samples were collected
      from nonoperated controls and from animals 24 h postsurgery that were
      administered either NK-1RA or saline. Fibrinolytic activity in peritoneal fluid
      was assayed by zymography, and expression of tissue plasminogen activator (tPA)
      and plasminogen activator inhibitor 1, both regulators of fibrinolytic activity,
      was assessed in peritoneal tissue and fluid by RT-PCR and bioassay, respectively.
      NK-1RA administration led to a marked (P < 0.05) increase in tPA mRNA levels in
      peritoneal tissue compared with nonoperated and saline-administered animals.
      Likewise, NK-1RA administration significantly (P < 0.05) increased tPA in the
      peritoneal fluid. These data suggest that activation of the NK-1R promotes
      peritoneal adhesion formation by limiting fibrinolytic activity in the
      postoperative peritoneum, thus enabling fibrinous adhesions to persist.

PMID- 15187236
TI  - Human carcinogenic risk evaluation, part IV: assessment of human risk of cancer
      from chemical exposure using a global weight-of-evidence approach.

PMID- 15187237
TI  - N,N-diethyldithiocarbamate produces copper accumulation, lipid peroxidation, and
      myelin injury in rat peripheral nerve.
AB  - Previous studies have demonstrated the ability of the dithiocarbamate,
      disulfiram, to produce a peripheral neuropathy in humans and experimental animals
      and have also provided evidence that N,N-diethyldithiocarbamate (DEDC) is a
      proximate toxic species of disulfiram. The ability of DEDC to elevate copper
      levels in the brain suggests that it may also elevate levels of copper in
      peripheral nerve, possibly leading to oxidative stress and lipid peroxidation
      from redox cycling of copper. The study presented here investigates the potential
      of DEDC to promote copper accumulation and lipid peroxidation in peripheral
      nerve. Rats were administered either DEDC or deionized water by ip osmotic pumps
      and fed a normal diet or diet containing elevated copper, and the levels of
      metals, isoprostanes, and the severity of lesions in peripheral nerve and brain
      were assessed by ICP-AES/AAS, GC/MS, and light microscopy, respectively. Copper
      was the only metal that demonstrated any significant compound-related elevations
      relative to controls, and total copper was increased in both brain and peripheral
      nerve in animals administered DEDC on both diets. In contrast, lesions and
      elevated F2-isoprostanes were significantly increased only in peripheral nerve
      for the rats administered DEDC on both diets. Autometallography staining of
      peripheral nerve was consistent with increased metal content along the myelin
      sheath, but in brain, focal densities were observed, and a periportal
      distribution occurred in liver. These data are consistent with the peripheral
      nervous system being more sensitive to DEDC-mediated demyelination and
      demonstrate the ability of DEDC to elevate copper levels in peripheral nerve.
      Additionally lipid peroxidation appears to either be a contributing event in the
      development of demyelination, possibly through an increase of redox active
      copper, or a consequence of the myelin injury.

PMID- 15187239
TI  - Biological therapies in the spondyloarthritides--the current state.
AB  - Therapeutic options for patients suffering from the more severe
      spondyloarthritides (SpA) have been rather limited in the last decades. Evidence
      is now accumulating that anti-tumour necrosis factor (TNF) therapy is highly
      effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic
      arthritis (PsA). Based on the data recently published concerning more than 1000
      patients with AS and PsA, this treatment seems to be even more effective than in
      rheumatoid arthritis (RA). The anti-TNFalpha agents currently available,
      infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira), are approved
      for the treatment of RA in the USA and Europe. The situation for SpA is different
      from RA because there is an unmet medical need, especially in AS, since no
      therapies with disease-modifying anti-rheumatic drugs (DMARDs) are available for
      severely affected patients, especially those with spinal disease. Thus, TNF
      blockers may even be considered a first-line treatment in a patient with active
      AS and PsA whose condition is not sufficiently controlled with non-steroidal anti
      inflammatory drugs (NSAIDs) in the case of axial disease, and sulphasalazine or
      methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5
      mg/kg is required, and intervals of between 6 and 12 weeks are necessary to
      constantly suppress disease activity-also a major aim for long-term treatment.
      The standard dosage of etanercept is 2 x 25 mg subcutaneously per week. There are
      almost no studies yet on adalimumab (standard dose in RA, 20-40 mg subcutaneously
      every 1-2 weeks) in SpA. Infliximab and etanercept are now both approved for AS
      in Europe. The efficacy of etanercept was first demonstrated in PsA, and it is
      now approved for this indication in the USA and Europe. There is preliminary
      evidence that both agents also work in other SpA, such as undifferentiated SpA
      (uSpA). Studies should be performed to document the long-term efficacy of this
      treatment. There is hope that ankylosis may be preventable, but it remains to be
      shown whether patients benefit from long-term anti-TNF therapy and whether
      radiological progression and ankylosis can be stopped. Severe adverse events have
      remained rare. Complicated infections including tuberculosis have been reported.
      These can largely be prevented by appropriate screening. As it stands now, the
      benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.

PMID- 15187238
TI  - Assessment of the effects of chemicals on the expression of ten steroidogenic
      genes in the H295R cell line using real-time PCR.
AB  - The potential for a variety of environmental contaminants to disturb endocrine
      function in wildlife and humans has been of recent concern. While much effort is
      being focused on the assessment of effects mediated through steroid hormone
      receptor-based mechanisms, there are potentially several other mechanisms that
      could lead to endocrine disruption. Recent studies have demonstrated that a
      variety of xenobiotics can alter the gene expression or activity of enzymes
      involved in steroidogenesis. By altering the production or catalytic activity of
      steroidogenic or steroid-catabolizing enzymes, these chemicals have the potential
      to alter the steroid balance in organisms. To assess the potential of chemicals
      to alter steroidogenesis, an assay system was developed using a human
      adrenocortical carcinoma cell line, the H295R cell line, which retains the
      ability to synthesize most of the important steroidogenic enzymes. Methods were
      developed, optimized, and validated to measure the expression of 10 genes
      involved in steroidogenesis by the use of real-time quantitative reverse
      transcriptase PCR. The effects of several model chemicals known to alter steroid
      metabolism, both inducers and inhibitors, were assessed. Similar expression
      patterns were observed for chemicals acting through common mechanisms of action.
      Time-course studies demonstrated distinct time-dependent expression profiles for
      chemicals able to modulate steroid metabolism. The assay, which allows
      simultaneous analysis of the expression of numerous steroidogenic enzymes, would
      be useful as a sensitive and integrative screen for the many effects of chemicals
      on steroidogenesis.

PMID- 15187240
TI  - Nailfold videocapillaroscopy in primary antiphospholipid syndrome (PAPS).
AB  - OBJECTIVES: To evaluate microcirculatory changes (functional and morphological)
      in primary antiphospholipid syndrome (PAPS) patients. METHODS: Thirty-one
      patients were examined using nailfold videocapillaroscopy (18 PAPS patients and
      13 healthy subjects). The patients were subdivided into two subgroups, with lupus
      anticoagulant (n = 8) and with anticardiolipin (n = 10) antibodies. Capillary
      morphology was determined; diameters ( micro m) and functional capillary density
      (FCD, number capillaries/mm2) were measured in control conditions. Blood flow
      velocity (CBFV, mm/s) was also evaluated at rest and after release of 60 s
      arterial occlusion. RESULTS: The percentage of subjects with at least one
      morphological alteration in the observed capillaries was 77.8% for patients and
      21.3% for healthy subjects. Capillary diameters ( microm) [afferent (AD), apical
      (APD) and efferent (ED)] were significantly smaller (mean +/- s.d.: AD-PAPS, 7.4
      +/- 2.1; control, 9.1 +/- 2.6, P = 0.063; APD-PAPS, 11.6 +/- 2.3; control, 14.4
      +/- 3.8, P = 0.015; ED-PAPS, 8.4 +/- 2.0; control, 10.9 +/- 3.2, P = 0.011) in
      PAPS patients compared with controls. FCD (PAPS, 8.5 +/- 3.2; control, 8.3 +/-
      2.9, P +/- 0.862), mean resting CBFV (PAPS, 0.73 +/- 0.31; control, 0.88 +/-
      0.41, P = 0.278), mean peak CBFV after occlusion (PAPS, 1.07 +/- 0.52; control,
      1.59 +/- 0.91, P = 0.063) and mean time (s) to reach it (PAPS, 5.2 +/- 1.7;
      control, 4.6 +/- 1.8, P = 0.101) were not statistically different between the two
      groups. CONCLUSION: Our results suggest that nailfold capillary morphology is
      altered in patients with PAPS, but these changes could not be correlated to
      impairment of functional parameters.

PMID- 15187241
TI  - Tacrolimus therapy in rheumatoid arthritis.

PMID- 15187242
TI  - Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected
      autologous mesenchymal cells derived from bone marrow.
AB  - OBJECTIVE: Cartilage-derived morphogenetic protein 1 (CDMP1), which is a member
      of the transforming growth factor-beta superfamily, is an essential molecule for
      the aggregation of mesenchymal cells and acceleration of chondrocyte
      differentiation. In this study, we investigated whether CDMP1-transfected
      autologous bone marrow-derived mesenchymal cells (BMMCs) enhance in vivo
      cartilage repair in a rabbit model. METHODS: BMMCs, which had a fibroblastic
      morphology and pluripotency for differentiation, were isolated from bone marrow
      of the tibia of rabbits, grown in monolayer culture, and transfected with the
      CDMP1 gene or a control gene (GFP) by the lipofection method. The autologous
      cells were then implanted into full-thickness articular cartilage defects in the
      knee joints of each rabbit. RESULTS: During in vivo repair of full-thickness
      articular cartilage defects, cartilage regeneration was enhanced by the
      implantation of CDMP1-transfected autologous BMMCs. The defects were filled by
      hyaline cartilage and the deeper zone showed remodelling to subchondral bone over
      time. The repair and reconstitution of zones of hyaline articular cartilage was
      superior to simple BMMC implantation. The histological score of the CDMP1
      transfected BMMC group was significantly better than those of the control BMMC
      group and the empty control group. CONCLUSION: Modulation of BMMCs by factors
      such as CDMP1 allows enhanced repair and remodelling compatible with hyaline
      articular cartilage.

PMID- 15187243
TI  - Right on target: coupling methotrexate to albumin to treat rheumatoid arthritis.

PMID- 15187244
TI  - Management of Paget's disease of bone.
AB  - Paget's disease of bone is a common condition with a strong genetic component,
      characterized by focal increases in bone turnover, affecting one or more bones
      throughout the skeleton. Paget's disease can be asymptomatic but is frequently
      associated with bone pain, bone deformity, pathological fracture, secondary
      osteoarthritis and deafness. Inhibitors of osteoclastic bone resorption, such as
      bisphosphonates and calcitonin, suppress bone turnover and improve bone pain in
      Paget's disease. Many patients also require therapy with analgesics and anti
      inflammatory agents, since pain in Paget's disease can arise not only from
      increased bone turnover but also from complications such as osteoarthritis and
      nerve compression syndromes, which do not respond well to antiresorptive therapy.
      Comparative studies have shown that second- and third-generation bisphosphonates,
      such as tiludronate, alendronate and risedronate, are more effective than
      etidronate at inhibiting bone turnover in Paget's disease but they have not been
      found to be significantly more effective in controlling bone pain. Importantly,
      none of the treatments that are currently available for Paget's disease have been
      shown to prevent complications such as deafness, fracture or bone deformity, or
      to alter the natural history of the disease. More research is required to define
      the long-term effects of antiresorptive treatment on clinical outcomes in Paget's
      disease, so that clinicians and their patients can make better-informed choices
      about the risks and benefits of treatment.

PMID- 15187245
TI  - More 'cries from the joints': assessment of the musculoskeletal system is poorly
      documented in routine paediatric clerking.
AB  - OBJECTIVES: The aim of this study was to describe the assessment of the
      musculoskeletal (MSK) system in comparison with other systems in routine
      paediatric medical clerking. Furthermore, to survey trainee paediatricians (SPRs,
      specialist registrars) about their self-rated confidence in assessing the MSK
      system. METHODS: Case notes of consecutive general paediatric medical patients
      admitted to three UK hospitals over a 4-week period were assessed using a
      standard pro forma. All patients had been assessed by a consultant paediatrician
      during their admission. A postal questionnaire was sent to all SPRs in training
      in each of the hospitals, regarding their confidence in assessing the MSK system
      compared with other systems and their exposure to MSK teaching. RESULTS: Case
      notes of 257 patients [117 females, median age 3 yr (range 1-18 yr)] were
      reviewed. The most common reason for admission was acute infection, although the
      spectrum of other recorded diagnoses varied between hospitals. Thirteen children
      (5%) had an acute problem (e.g. infection) against a background of chronic
      disease. The case note documentation showed that cardiovascular (CVS),
      respiratory (RS) and gastrointestinal (GI) systems were assessed in the vast
      majority (>90%) of patients, irrespective of the underlying diagnosis. However,
      other systems were less well recorded; the trend being the same in each hospital
      and in descending order, the neurological system (38%), skin (32%), eyes (10%)
      and musculoskeletal system (4%). Only 2.7% (7/257) patients were documented to
      have been asked about MSK symptoms, and only 1.6% (4/257) had any documentation
      of joint examination--in all cases this was limited (e.g. range of movement of
      the knee only), and no patients had documentation of gait being examined, even in
      those children presenting with 'limp'. The response rate to the postal
      questionnaire was 60% (67/112). The self-rated confidence in MSK assessment was
      markedly low in comparison with other systems, even though 61/67 recalled some
      teaching of the MSK system as an undergraduate (61/67) or postgraduate (50/67).
      Of note none could recall teaching as an undergraduate in paediatric MSK
      assessment and where there had been postgraduate rheumatology MSK teaching this
      had been delivered by paediatric rheumatologists in many cases (34/50),
      reflecting the centres participating in the study. CONCLUSIONS: In routine
      general paediatric medical in-patient clerking and throughout the admission, MSK
      assessment was rarely documented, and even where present was limited. This
      contrasts markedly with other systems which were examined in most children
      irrespective of the presenting complaint. Self-rated confidence in MSK assessment
      is low amongst SPRs compared with other systems, despite most recalling some
      teaching. This discrepancy between teaching and clinical practice needs to be
      addressed in undergraduate and postgraduate training.

PMID- 15187247
TI  - Do we still miss the chance of effectively treating early rheumatoid arthritis?
      New answers from a new study.

PMID- 15187246
TI  - Combined therapy with rituximab plus
      cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjogren's syndrome
      associated B-cell aggressive non-Hodgkin's lymphomas.
AB  - OBJECTIVE: To determine the safety and therapeutic response of a regimen
      consisting of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) plus
      rituximab in patients with Sjogren's syndrome (SS) and aggressive non-Hodgkin's
      lymphoma (NHL). METHODS: Four SS patients with aggressive marginal zone NHL were
      enrolled in this trial. All patients were classified according to the newly
      proposed revised European-American classification of lymphoid neoplasms. Three
      out of four patients also had mixed cryoglobulinaemia (MC) of type II. They were
      treated every 3 weeks for eight cycles of CHOP. Patients also received rituximab,
      at a dose of 375 mg per square metre, on day 1 of each of the eight cycles of
      CHOP. Four weeks after completion of the eighth course of CHOP plus rituximab and
      every 6 months thereafter, patients were re-evaluated for response. RESULTS:
      Complete remission of lymphoma was achieved in all four patients. The lymphoma
      patients remained in remission for a period of 23, 15, 12 and 10 months
      respectively, while certain signs and symptoms of MC type II (purpura, peripheral
      neuropathy and arthralgias) significantly improved with treatment. In addition,
      the titres of circulating cryoglobulins and RF decreased, while C4 levels
      returned to normal. CONCLUSION: CHOP plus rituximab was well tolerated and proved
      effective in SS patients with aggressive NHL. Our observations may warrant a
      larger controlled trial to assess the effectiveness of this regimen in such
      patients.

PMID- 15187248
TI  - G1 and S-phase checkpoints, chromosome instability, and cancer.
AB  - Mitogen-dependent progression through the first gap phase (G1) of the mammalian
      cell-division cycle is precisely regulated so that normal cell division is
      coordinated with cell growth, while the initiation of DNA synthesis (S phase) is
      precisely ordered to prevent inappropriate amplification of the DNA that may
      cause genome instability. To ensure that these fundamental requirements of cell
      division are met, cells have developed a surveillance mechanism based on an
      intricate network of protein kinase signaling pathways that lead to several
      different types of checkpoints. Since these checkpoints are central to the
      maintenance of the genomic integrity and basic viability of the cells, defects in
      these pathways may result in either tumorigenesis or apoptosis, depending on the
      severity and nature of the defects. This review summarizes the genetic and
      molecular mechanisms of checkpoint activation in the G1/S and S phases of the
      mammalian cell cycle that monitor DNA damage and replication. The relevance of
      these mechanisms to the origin of cancer is also discussed.

PMID- 15187249
TI  - Analyzing the G2/M checkpoint.
AB  - The G2 checkpoint prevents cells from entering mitosis when DNA is damaged,
      providing an opportunity for repair and stopping the proliferation of damaged
      cells. Because the G2 checkpoint helps to maintain genomic stability, it is an
      important focus in understanding the molecular causes of cancer. Many different
      methods have been used to investigate the G2 checkpoint and uncover some of the
      underlying mechanisms. Because cell-cycle controls are highly conserved, a
      remarkable synergy between the genetic power of model organisms and biochemical
      analyses is possible and has uncovered control mechanisms that operate in many
      diverse species, including humans. Cdc2, the cyclin-dependent kinase that
      normally drives cells into mitosis, is an important target of pathways that
      mediate rapid arrest in G2 in response to DNA damage. Additional pathways ensure
      that the arrest is stably maintained. When mammalian cells contain damaged DNA,
      the p53 tumor suppressor and the Rb family of transcriptional repressors work
      together to downregulate a large number of genes that encode proteins required
      for G2 and M. Elimination of these essential cell cycle proteins helps to keep
      the cells arrested in G2.

PMID- 15187250
TI  - Analyzing the spindle checkpoint in yeast and frogs.
AB  - The spindle checkpoint is an evolutionarily conserved regulatory mechanism that
      ensures correct segregation of chromosomes at mitosis and meiosis. The
      kinetochore plays an integral role in spindle checkpoint signaling by integrating
      chromosome attachment to the spindle with cell cycle progression. A single
      kinetochore can inhibit cell cycle progression in the absence of proper spindle
      attachment or tension from bipolar orientation. Recent advances have shed light
      on how the kinetochore measures these situations, transduces a signal, and
      inhibits the entry into anaphase.

PMID- 15187251
TI  - Cell cycle checkpoint control mechanisms that can be disrupted in cancer.
AB  - Maintenance of genomic integrity is essential to avoid cellular transformation,
      neoplasia, or cell death. DNA synthesis, mitosis, and cytokinesis are important
      cellular processes required for cell division and the maintenance of cellular
      homeostasis; they are governed by many extra- and intra-cellular stimuli.
      Progression of normal cell division depends on cyclin interaction with cyclin
      dependent kinases (Cdk) and the degradation of cyclins before chromosomal
      segregation through ubiquitination. Multiple checkpoints exist and are conserved
      in the cell cycle in higher eukaryotes to ensure that if one fails, others will
      take care of genomic integrity and cell survival. Many genes act as either
      positive or negative regulators of checkpoint function through different kinase
      cascades, delaying cell cycle progression to repair the DNA lesions and breaks,
      and assuring equal segregation of chromosomes to daughter cells. Understanding
      the checkpoint pathways and genes involved in the cellular response to DNA damage
      and cell division events in normal and cancer cells, provides information about
      cancer predisposition, and suggests design of small molecules and other
      strategies for cancer therapy.

PMID- 15187252
TI  - Establishment of a cell-free system to study the activation of Chk2.
AB  - The checkpoint kinase Chk2 is activated in response to DNA damage through
      pathways requiring protein kinases ATM and/or ATR. The means by which Chk2 is
      activated by these kinases still remains to be addressed. Here we describe a cell
      free system to study the activation of Chk2. Chk2 produced by a wheat germ
      extract in vitro transcription/translation system is inactive and can be
      activated by incubating with a rabbit reticulocyte lysate. This method will be
      useful for identification of cofactors required for activation of Chk2.

PMID- 15187253
TI  - Analyzing checkpoint controls in human skin.
AB  - A short-term whole-skin organ culture model has been established to enable the
      investigation of cell cycle perturbations in epidermal layer cells following
      exposure to ultraviolet radiation (UVR). This model affords the opportunity to
      manipulate the growth and nutrient conditions, and to perform detailed
      biochemical and immunohistochemical analysis of skin cells in their normal
      epidermal layer microenvironment. The use of this model is described in this
      chapter.

PMID- 15187254
TI  - Generation and analysis of Brca1 conditional knockout mice.
AB  - Germline mutations of the breast tumor suppressor gene BRCA1 predispose women to
      breast and ovarian cancers. However, loss-of-function mutations of mouse Brca1
      results in recessive embryonic lethality, which obscures the functions of BRCA1
      in breast cancer formation. Cre-loxP-mediated tissue-specific knockout was
      employed to overcome this obstacle. We found that the presence of a ploxP-neo
      loxP cassette in intron 10 of Brca1 resulted in severe interference with gene
      expression. The neo cassette was deleted in either embryonic stem cells or mice
      to generate the neo-less conditional knockout allele. Finally, we performed
      functional analysis of mammary tumorigenesis in Brca1 conditional knockout mice.
      The methods to generate and analyze these Brca1 conditional knockout mice are
      described in this chapter.

PMID- 15187255
TI  - Analysis of cell cycle progression and genomic integrity in early lethal
      knockouts.
AB  - Owing to their importance in normal cell division, DNA damage checkpoint and
      repair genes are often required for the earliest stages of embryzonic
      development. For example, conventional deletion of ATR, Chk1, Mad2, NBS, Rad50,
      BRCA1, BRCA2, or Rad51 leads to developmental arrest prior to gastrulation. While
      prior to arrest the number of cells extant in these embryos is low, procedures
      allowing rudimentary analysis of cell cycle checkpoints and genome integrity have
      been developed through culturing blastocysts in vitro. These procedures provide a
      small number of proliferating cells that can be analyzed for cell cycle
      progression, G2/M phase checkpoint responses, and gross chromosome abnormalities
      by mitotic spread preparation. Experiments such as these may help determine the
      essential functions of these genes in cell proliferation and early embryonic
      development. It is interesting to note that recently developed methods to
      introduce single-copy transgenes into one-cell zygotes via lentiviruses may
      provide a means to generate Cre/lox-conditional cell lines from these
      conventional knockouts.

PMID- 15187256
TI  - Xenopus cell-free extracts to study the DNA damage response.
AB  - Cell-free systems derived from Xenopus eggs represent a powerful tool,
      intermediate between in vitro and in vivo model systems. Here, we describe
      protocols to prepare cell-free extracts recapitulating several aspects of the DNA
      damage response, including the DNA damage-dependent activation of ATM/ATR protein
      kinases and several DNA damage checkpoint signaling pathways that inhibit
      initiation of DNA replication. We provide protocols to prepare cell-free
      extracts, DNA templates, protein kinase substrates, and to perform checkpoint
      assays. In addition, we describe related methods that provide useful readouts of
      the DNA damage response.

PMID- 15187257
TI  - A Xenopus cell-free system for analysis of the Chfr ubiquitin ligase involved in
      control of mitotic entry.
AB  - The checkpoint protein Chfr delays entry into mitosis in the presence of mitotic
      stress. We have analyzed the Chfr checkpoint pathway in the Xenopus cell-free
      system. We showed that Chfr is a ubiquitin ligase that targets polo-like kinase
      (Plk1) for degradation, leading to delayed activation of the Cdc25C phosphatase
      and prolonged inhibitory phosphorylation of Cdc2 at the G2/M transition. In this
      chapter, we will describe biochemical methods we developed to analyze the Chfr
      auto-ubiquitination activity and the ubiquitination of its substrate Plk1, as
      well as functional assays to investigate the Chfr pathway in Xenopus extracts.

PMID- 15187258
TI  - Control of mitotic entry after DNA damage in Drosophila.
AB  - In the presence of DNA damage, cells delay the entry into mitosis, presumably to
      allow time for repair. Methods to detect the delay of mitosis in a multicellular
      model organism, Drosophila melanogaster, are described here. These include the
      collection of embryos and larvae, irradiation with x-rays to damage DNA, and
      fixing and staining of tissues with an antibody to phosphorylated histone H3 to
      measure the mitotic index. These methods should be useful in identifying
      potential mutants that are unable to regulate mitosis following DNA damage.

PMID- 15187259
TI  - Methods for analyzing checkpoint responses in Caenorhabditis elegans.
AB  - In response to genotoxic insults, cells activate DNA damage checkpoint pathways
      that stimulate DNA repair, lead to a transient cell cycle arrest, and/or elicit
      programmed cell death (apoptosis) of affected cells. The Caenorhabditis elegans
      germ line was recently established as a model system to study these processes in
      a genetically tractable, multicellular organism. The utility of this system was
      revealed by the finding that upon treatment with genotoxic agents, premeiotic C.
      elegans germ cells transiently halt cell cycle progression, whereas meiotic
      prophase germ cells in the late pachytene stage readily undergo apoptosis.
      Further, accumulation of unrepaired meiotic recombination intermediates can also
      lead to the apoptotic demise of affected pachytene cells. DNA damage-induced cell
      death requires key components of the evolutionarily conserved apoptosis
      machinery. Moreover, both cell cycle arrest and pachytene apoptosis responses
      depend on conserved DNA damage checkpoint proteins. Genetics- and genomics-based
      approaches that have demonstrated roles for conserved checkpoint proteins have
      also begun to uncover novel components of these response pathways. In this
      chapter, we will briefly review the C. elegans DNA damage-response field, and we
      will discuss in detail the methods that are being used to assay DNA damage
      responses in C. elegans.

PMID- 15187261
TI  - Purification and analysis of checkpoint protein complexes from Saccharomyces
      cerevisiae.
AB  - The DNA damage-dependent checkpoint of Saccharomyces cerevisiae is a paradigm for
      eukaryotic checkpoint pathways that regulate cell cycle progression in the
      presence of insults to the genetic material. In order to better understand this
      pathway, we undertook a biochemical study of the proteins implicated in its
      functioning. Analysis of the hydrodynamic properties of a protein in a crude
      mixture can give insights into possible tertiary organization such as
      participation in high-molecular-mass protein complexes. We here describe the
      determination of Stokes radius and sedimentation coefficients for the Rad24
      protein, which enabled us to predict that this protein was a component of a
      protein complex in crude yeast extracts. This led us to develop a protocol to
      purify this complex to homogeneity in order to determine the component proteins.
      The methods described here should be applicable to the hydrodynamic analysis and
      subsequent purification of any soluble protein from organisms amenable to genetic
      manipulation, such as yeast, as long as the function of that protein is not
      perturbed by the addition of an epitope tag.

PMID- 15187260
TI  - Assaying the spindle checkpoint in the budding yeast Saccharomyces cerevisiae.
AB  - The spindle checkpoint is assayed in Saccharomyces cerevisiae using several
      criteria. Sensitivity to benzimidazole drugs is assayed in cells grown in liquid
      medium and cells grown on solid medium on petri plates. Cell cycle delays are
      measured using cells synchronized by treatment with mating pheromone alpha
      factor, and the population is monitored by flow cytometry measuring DNA content
      in cells. There are two different transitions that are monitored, and cytological
      assays for individual cells and biochemical assays for populations of cells are
      presented. The metaphase to anaphase transition is assayed by monitoring sister
      chromatid separation using GFP-tagged chromosomes, Pds1 stability using
      immunofluorescence, and Mcd1/Scc1 association with chromatin using chromosome
      spreads. Pds1 and Mcd1/Scc1 stability is measured in populations by Western
      blots. The exit from mitosis is monitored by Cdc14 immunofluorescence and Clb2
      Western blots.

PMID- 15187262
TI  - Fractionation of thylakoid membranes into grana and stroma thylakoids.
AB  - The chloroplasts contain an extensive system of internal membranes or thylakoids
      in which all the light-harvesting and energy-transducing processes of the
      photosynthesis are located. Thylakoids are differentiated into stacked membrane
      regions (or grana thylakoids) and nonstacked membranes (or stroma thylakoids),
      each with a specialized structure and function. Both kinds of thylakoids can be
      separated by detergent-based methods or mechanical fragmentation such as
      sonication. We describe the fractionation of thylakoid membranes into grana and
      stroma thylakoids by treatment with the detergent digitonin and successive
      ultracentrifugation of the resultant vesicles. After their separation, the
      thylakoid fractions retain electron transport and enzymatic activities and are
      characterized using various parameters. The stroma thylakoids have higher
      chlorophyll a/chlorophyll b and protein/total chlorophyll ratios, and greater
      photosystem I and NADH dehydrogenase activities than the grana thylakoids. In the
      conditions used and on a protein basis of total thylakoids, the yield of stroma
      thylakoids is 5%, which is considerable taking into account that the stroma
      thylakoids are a minor component of total thylakoids.

PMID- 15187263
TI  - Isolation of photosystem I particles from spinach.
AB  - A method to prepare photosystem I (PSI) particles is described. Spinach leaves
      are used to prepare broken chloroplasts that are then solubilized by using a
      detergent (Triton X-100). Solubilized chloroplasts are then applied on an ion
      exchange column. Eluted by a linear concentration gradient of NaCl, fractions
      enriched in PSI particles are collected and applied on a small hydroxyapatite
      column. By eluting with phosphate buffer, a concentrated preparation of PSI
      particles is obtained. The particles consist of PsaA, PsaB, PsaC, PsaD, PsaE, and
      PsaY. Assay methods that involve SDS-PAGE and P700 determination are also
      presented.

PMID- 15187264
TI  - Rapid isolation and purification of photosystem I chlorophyll-binding protein
      from Chlamydomonas reinhardtii.
AB  - The available procedures for isolation and purification of photosystem I (PSI)
      from Chlamydomonas reinhardtii are time consuming and usually require several
      hours of sucrose gradient ultracentrifugation steps. This may lead to structural
      and functional impairment, including release of pigments and/or dissociation of
      protein subunits. Moreover, it is difficult to isolate intact complexes from
      thylakoids containing mutated PSI that accumulate to lower levels. Hence,
      isolation of intact PSI core complex depends on the speed of the procedure and
      the mildness of the extraction and purification. We have, therefore, modified the
      procedure for PSI isolation to both increase the yield of PSI and to reduce
      contamination by other pigment protein complexes. The modified procedure involves
      dodecyl maltoside solubilization of crude-thylakoid membranes followed by single
      step column chromatography using a weak anion-exchanger. PSI eluted from the
      column between 13 mM and 15 mM Mg S04. This new rapid purification procedure
      yielded pure PSI preparations with a Chl/P700 ratio of approx 90 and showing
      typical absorption difference spectra with a maximum bleaching occurring at 696
      nm. Femtosecond transient absorption spectroscopy of purified PSI complex
      revealed a high degree of similarity in terms of excitation energy transfer
      within the PSI core to observations in cyanobacterial PSI.

PMID- 15187265
TI  - Isolation of photosystem II-enriched membranes and the oxygen-evolving complex
      subunit proteins from higher plants.
AB  - Methods for the isolation of highly active oxygen-evolving photosystem (PS)II
      membranes from higher plants and the purification of the oxygen-evolving complex
      (OEC) subunits are described. Membrane samples used as the material for various
      in vitro studies of PSII are prepared by solubilization of thylakoid membranes
      with the non-ionic detergent Triton X-100. The OEC subunit proteins are
      dissociated from the PSII-enriched membranes by alkaline treatment or salt
      treatment, and then purified by ion-exchange chromatography using an automated
      high-performance liquid chromatography system.

PMID- 15187266
TI  - Isolation of functional photosystem II core particles from the Cyanobacterium
      synechocystis sp. PCC 6803.
AB  - This chapter contains the description of several methods used for the isolation
      of functional photosystem (PS)II core particles from wild-type (wt), PSI-less,
      and CP47 histidine-tagged cells of the cyanobacterium Synechocystis sp. PCC 6803.
      These protocols discuss the cultivation of PSI-containing and PSI-less cells,
      isolation of thylakoid membranes, purification of PSII core particles using a
      weak cation exchange or metal affinity column chromatography, and
      characterization of the final preparation. The described isolation procedures,
      which normally yield PSII particles highly active in oxygen evolution, can be
      easily adapted for obtaining preparations from different types of Synechocystis
      mutants with modified PSII.

PMID- 15187267
TI  - Isolation of photosystem I reaction center preparation from spinach.
AB  - This chapter deals with the preparation of photochemically active reaction center
      particles (Type III) that basically contain only two subunits, PsaA and PsaB. The
      preparation is obtained by further treating the Type II preparation described in
      the preceding chapter with a chaotropic agent, sodium iodide, followed by
      ultrafiltration.

PMID- 15187268
TI  - Isolation of photosystem II reaction center complexes from plants.
AB  - Methods to isolate and purify 6- and 5-chlorophyll (Chl) D1/D2/Cyt b559
      photosystem (PS) II reaction center complexes from plants are presented, and the
      advantages and disadvantages of each procedure are discussed. One of the simpler
      6-Chl procedures and a procedure for isolating 5-Chl complexes are described in
      detail. Furthermore, a rapid procedure that produces relatively large amounts of
      less pure 6-Chl material is also described. Criteria to assess the purity of
      photosystem II (PSII) reaction center preparations are presented, and problems
      associated with each of the isolation procedures are discussed.

PMID- 15187269
TI  - Isolation of photosystem I reaction center subunit polypeptides from spinach.
AB  - Methods to prepare photosystem (PS)I reaction center (RC) subunit polypeptides
      are described. For PsaC, PsaD, PsaE, and PsaY, the filtrate resulting from the
      ultrafiltration in Chapter 6 is used for preparative sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE). PsaA and PsaB, Type II PSI
      particles, prepared as described in the preceding chapter, are treated with
      sodium dodecyl sulfate, then applied on preparative SDS-PAGE. After
      electrophoresis, each band is cut out and electroeluted. A simple method to
      prepare PsaC is also presented.

PMID- 15187270
TI  - Purification and crystallization of the cytochrome b6f complex in oxygenic
      photosynthesis.
AB  - The cytochrome b6f complex from the thermophilic cyanobacterium Mastigocladus
      laminosus and spinach chloroplasts has been purified as a dimeric species. It was
      found by electrospray ionization mass spectroscopy to contain eight and nine
      subunits, respectively, and dimeric masses of 217,070 and 286,454 Da. The
      subunits common to the complex from both sources are petA (cytochrome f), B
      (cytochrome b6), C (Rieske iron-sulfur protein), D (subunit IV), and small 3.2
      4.2 kDa polypeptides petG,L,M, and N. The ninth polypeptide, the 35 kDa petH poly
      peptide in the spinach complex, was identified as ferredoxin NADP reductase
      (FNR), which binds to the complex tightly at a stoichiometry of approx 0.9 (cyt
      f)-1. The spinach complex contains diaphorase activity diagnostic of FNR, and is
      active in facilitating ferredoxin-dependent electron transfer from NADPH to the
      cytochrome b6f complex. The purified cytochrome b6f complex contains
      stoichiometrically bound chlorophyll a and beta-carotene at a ratio of one per
      cytochrome f, and bound lipid, in which MGDG and PG are the most abundant
      species. The delipidated highly purified complexes are active immediately after
      preparation and for approx 1 wk if left on ice, transferring 300-350
      electrons/cyt f/s. Both complexes are subject to proteolysis and associated loss
      of activity if left for extended periods (>1 wk) at room temperature. Addition of
      pure synthetic lipid to the delipidated M. laminosus complex (the "lipid
      augmentation" technique) allows rapid and ready formation of large (>0.2 mm)
      crystals suitable for x-ray diffraction analysis and structure determination,
      which diffract with good statistics to 3.0 A.

PMID- 15187271
TI  - Purification of plastocyanin and cytochrome c6 from plants, green algae, and
      cyanobacteria.
AB  - Plastocyanin and cytochrome c6 are widely distributed over the oxygen-evolving
      photosynthetic organisms. The two proteins are functionally equivalent, but
      strongly differ in their global electrostatic charge. In fact, they are acidic in
      eukaryotes, but either neutral or basic in cyanobacteria. The difference in their
      electrostatic features is a critical factor in designing the purification
      procedure, which must be modified and adapted accordingly. This chapter reports
      the methods for producing (including cell cultures), isolating and purifying
      plastocyanin and cytochrome c6-which greatly differ in their isoelectric point
      from a number of eukaryotic and prokaryotic organisms.

PMID- 15187272
TI  - Preparation of native and recombinant light-harvesting chlorophyll-a/b complex.
AB  - Procedures to isolate native light-harvesting chlorophyll-a/b complex (LHCIIb)
      and to reconstitute recombinant LHCIIb are described. Separation of trimeric from
      monomeric forms and free pigment by sucrose density-gradient ultracentrifugation
      can be applied to both native and reconstituted complexes. The preparations are
      characterized by their pigment composition, protein pattern and spectral
      properties.

PMID- 15187273
TI  - Isolation and characterization of lamellar aggregates of LHCII and LHCII-lipid
      macro-assemblies with light-inducible structural transitions.
AB  - In this chapter we describe isolation of loosely stacked lamellar aggregates of
      LHCII that are capable of undergoing light-induced reversible structural changes,
      similar to those in granal thylakoid membranes (LHCII, the main chlorophyll a/b
      light-harvesting antenna complex of photosystem II). This unexpected structural
      flexibility of the antenna complexes depends largely on the lipid content
      retained during the isolation. The essence of the procedure is to adjust-for the
      plant material used-the proper conditions of detergent solubilization and
      purification mild enough for the associated lipids but also provide sufficient
      purity. Microcrystals and most other LHCII preparations, which are more
      delipidated, are not capable of similar changes. The light-induced structural
      reorganizations can be enhanced by the addition of different thylakoid lipids,
      which depending on the lipid species, also lead to the transformation of the
      lamellar structure. The preparation of different LHCII-lipid macro-assemblies is
      also described. In structurally flexible LHCII preparations and in thylakoids,
      the changes originate from a thermo-optic effect: fast local thermal transients,
      T-jumps, resulting from dissipation of the (excess) excitation energy that lead
      to elementary structural transitions in the vicinity of the dissipating centers.
      This can occur because thylakoids and structurally flexible LHCII assemblies but,
      for example, not the microcrystals, exhibit a thermal instability below the
      denaturation temperature, and thus (local) heating lead to reorganizations
      without the loss of the molecular architecture of the constituents. We also list
      the main biochemical and biophysical techniques that can be used for testing the
      structural flexibility of LHCII, and discuss the potential physiological
      significance of the structural changes in light adaptation and photoprotection of
      plants.

PMID- 15187274
TI  - Separation, purification, and characterization of polypeptide composition of
      subcomplexes of the main light-harvesting chlorophyll a/b-protein complex of
      photosystem II.
AB  - The protocols regarding separation and purification of LHCII subcomplexes by non
      denaturing isoelectric focusing (ndIEF), confirmation of trimeric nature of the
      subcomplexes, and establishing their polypeptide composition are described below.

PMID- 15187275
TI  - Isolation of CP43 and CP47 photosystem II proximal antenna complexes from plants.
AB  - A single-column method to purify the CP43 and CP47 pigment-protein complexes of
      photo-system (PS)II from higher plants is presented. To validate the isolation
      procedure, three different species were used (Spinacea oleracea, Beta vulgaris,
      and Glycine max), and the procedure worked similarly with all three. Oxygen
      evolving core complex obtained from highly enriched PSII membrane fragments were
      used as the starting material. The core complex is treated with the chaotropic
      agent LiClO4 and the nonionic detergent n-dodecyl beta-D-maltoside. After
      dialysis against buffer with no detergent or chaotropic agent, the solubilized
      material is separated by weak anion-exchange chromatography using a TSK-GEL
      Toyopearl DEAE 650s column. CP43 complex does not bind to the column and elutes
      with the first pigmented fractions. When the eluate becomes colorless, the column
      is subjected to a 0-175 mM LiClO4 linear gradient. The main pigment elution band
      corresponds to CP47 complex. The last pigmented elution band contains both
      reaction center-CP47 and reaction center complexes.

PMID- 15187276
TI  - The determination and quantification of photosynthetic pigments by reverse phase
      high-performance liquid chromatography, thin-layer chromatography, and
      spectrophotometry.
AB  - Chorophylls and carotenoids are functionally important pigment molecules in
      photosynthetic organisms. Methods for the determination of chlorophylls a and b,
      beta-carotene, neoxanthin, and the pigments that are involved in photoprotective
      cycles such as the xanthophylls are discussed. These cycles involve the
      reversible de-epoxidation of violaxanthin into antheraxanthin and zeaxanthin, as
      well as the reversible de-epoxidation of lutein-5,6-epoxide into lutein. This
      chapter describes pigment extraction procedures from higher plants and green
      algae. Methods for the determination and quantification using high-performance
      liquid chromatograpy (HPLC) are described as well as methods for the separation
      and purification of pigments for use as standards using thin-layer chromatography
      (TLC). In addition, several spectrophotometric methods for the quantification of
      chlorophylls a and b are described.

PMID- 15187277
TI  - Isolation and identification of chloroplast lipids.
AB  - Glycerolipids of photosynthetic organisms are accounted for largely by thylakoid
      membrane lipids consisting of chloroplast-specific glycolipids, such as
      monogalactosyl diacylglycerol, digalactosyl diacylglycerol, sulfoquinovosyl
      diacylglycerol, and a sole phospholipid, phosphatidylglycerol. In this chapter,
      methods for characterization of lipids from plant cells are described. The
      methods include extraction of total lipids from cells, separation of these lipids
      into individual lipid classes by thin-layer chromatography (TLC), and
      identification of respective lipid classes by their mobility. We also show
      methods for determination of compositions of constituent fatty acids,
      distribution of fatty acids between sn-1 and sn-2 positions, and contents of
      individual lipid classes by gas-liquid chromatography. These methods are
      applicable to isolated chloroplasts or membrane fractions such as thylakoid
      membranes.

PMID- 15187278
TI  - DNA adducts with chlorophyll and chlorophyllin as antimutagenic agents:
      synthesis, stability, and structural features.
AB  - Porphyrins and their metal derivatives are strong DNA binders with association
      constants of 10(5) M(-1) to 10(7) M(-1). Some of these compounds have been used
      for radiation sensitization therapy of cancer and are targeted to interact with
      cellular DNA. Chlorophyll (CHL) and chlorophyllin (CHLN), a food-grade derivative
      of chlorophyll, the ubiquitous green plant pigment widely consumed by humans, are
      potent inhibitors of experimental carcinogenesis. The aim of this report was to
      examine the interaction of calf-thymus DNA with CHL and CHLN in aqueous solution
      at physiological pH, with pigment/DNA(phosphate) molar ratios (r) of 1/80 to 1/2.
      Fourier transform infrared (FTIR) difference spectroscopic method was used to
      determine the pigment binding mode, binding constant, sequence selectivity, DNA
      secondary structure and structural variations of the pigment-DNA complexes in
      aqueous solution.

PMID- 15187279
TI  - Incorporation and analysis of LHCII in model systems.
AB  - The largest light-harvesting pigment-protein complex of Photosystem II (LHCII) is
      an antenna complex comprising more than half of photosynthetically active
      chlorophyll pigments. Understanding photophysical processes in this pigment
      protein complex and the relationship between the structure and function of LHCII
      has been the subject of numerous studies, including those in the model systems,
      such as monomolecular layers, Langmuir-Blodgett films, planar lipid bilayers, and
      liposomes. This chapter describes the methods of the incorporation of LHCII into
      these particular model systems, control of intactness of LHCII after
      incorporation, and the examination of this pigment-protein complex in model
      systems.

PMID- 15187280
TI  - Photosystem II reconstitution into proteoliposomes: structure-function
      characterization.
AB  - This chapter discusses the photosystem II (PSII) reconstitution into
      proteoliposomes. In the first part of the chapter, protocols are outlined for the
      preparation of lipid bilayer vesicles (liposomes) constituted of individual
      thylakoid lipids or their mixtures for the preparation of PSII particles, and for
      the incorporation of the PSII particles into the liposomes. In the second part of
      the chapter, methodologies are described for the structure-function
      characterization of the PSII-lipid complexes (proteoliposomes). This includes the
      sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
      determination of the PSII proteins, measurement of oxygen-evolving activity of
      PSII in the proteoliposomes, and the study of structural changes of the PSII
      proteins upon their incorporation into the lipid bilayers by Fourier transform
      infrared (FTIR) spectroscopy.

PMID- 15187281
TI  - Extraction of the functional manganese and calcium from photosystem II.
AB  - Manganese (Mn) and calcium (Ca) are both metal cofactors required for
      photosynthetic oxygen evolution. The functional roles for these ions in the O2
      evolving reactions are not completely known. They are studied by comparative
      spectroscopic measurements between intact and metal-depleted samples. In this
      chapter, we outline three experimental procedures used for the various removal of
      Mn and Ca from photosystem (PS) II-containing (i.e,. O2-evolving) preparations:
      the complete Mn extraction using a strong alkaline Ches buffer (pH 9.4)/MgCl2
      wash, partial Mn extraction using a mild hydroxylamine (pH 6.8) wash, and
      specific Ca extraction through a low pH/citrate (pH 3) wash. The O2 evolution
      activities (measured by a Clarke-type oxygen electrode), protein composition
      (determined by sodium dodecyl sulfate- polyacrylamide gel electrophoresis), and
      the relative Mn and Ca content (measured by atomic absorption spectroscopy) are
      reported for each extraction procedure.

PMID- 15187282
TI  - Assay of photoinhibition of photosystem II and protease activity.
AB  - Under light-stress conditions, the photosystem (PS)II reaction center D1 protein
      is photo-damaged. The damage to the D1 protein is induced by singlet oxygen
      molecules and endogenous free radicals generated by the photochemical reactions
      of PSII. To maintain PSII activity, the oxidatively damaged D1 protein is
      replaced by a newly synthesized protein. Thus, degradation and removal of the
      photodamaged D1 protein in PSII are essential steps for maintaining the viability
      of PSII. In the present chapter, we describe the method to induce photoinhibition
      of PSII both in vitro and in vivo, and also the method to assay the processes
      closely related to the photoinhibition, including degradation of the damaged D1
      protein and its crosslinking with the neighboring polypeptides. The method to
      analyze the protease activity in the stroma that recognizes and digests the
      crosslinked products of the D1 protein generated by the light stress is also
      described.

PMID- 15187283
TI  - Thermoluminescence: a technique for probing photosystem II.
AB  - The noninvasive technique of thermoluminescence (TL) monitors recombination
      reactions of oxidized donors and quinone acceptors of photosystem (PS)II leading
      to light emission. The technique is simple, inexpensive, and yet powerful in
      probing PSII using leaf discs, algal cells, thylakoids, or PSII preparations. The
      procedure for obtaining glow curves from photosynthetic material has been
      described. Interpretation of the obtained data requires a thorough understand-ing
      of the charge pairs responsible for generating different TL bands. This chapter
      discusses characteristics of different TL bands to facilitate interpretation.
      Thermoluminescence and delayed light emission (DLE) are related to each other and
      each TL band represents one component of delayed light. The technique has found
      application in monitoring several aspects of the PSII electron transport. Through
      the possibility of interpreting changes in the redox potentials of donors and
      acceptors on the basis of a shift in glow peak temperature, the technique should
      prove useful in understanding the process of adaptation, responses to abiotic and
      biotic stresses, and structural modifications in the PSII polypeptides.

PMID- 15187284
TI  - Detection of free radicals and reactive oxygen species.
AB  - In plants, reactive oxygen species (ROS), also known as active oxygen species
      (AOS), are associated with normal, physiological processes as well as with
      responses to adverse conditions. ROS are associated with stress in many ways; as
      primary elicitors, as products and propagators of oxidative damage, or as signal
      molecules initiating defense or adaptation. The photosynthetic electron transport
      is a major site of oxidative stress by visible or ultraviolet light, high or low
      temperature, pollutants, or herbicides. ROS production can be presumed from
      detecting oxidatively damaged lipids, proteins, or pigments as well as from the
      alleviating effects of added antioxidants. On the other hand, measuring ROS by
      special sensor molecules provides more direct information. This chapter focuses
      on the application of spin trapping electron paramagnetic resonance (EPR)
      spectroscopy for detecting ROS; singlet oxygen and oxygen free radicals in
      thylakoid membrane preparations.

PMID- 15187285
TI  - Stabilization of photosynthetic materials.
AB  - Isolated photosynthetic materials have a relatively short active lifetime that
      limits their effective use. To circumvent this limitation, various immobilization
      techniques have been designed to improve their stability both under storage and
      working conditions. The immobilization methods are identified either as chemical
      or physical methods. In this chapter, two immobilization methods frequently used
      are described; a physical method based on the entrapment of photosynthetic
      materials in photo-crosslinkable poly(vinylalcohol) polymer bearing
      styrylpyridinium groups (PVA-SbQ) and a chemical method where the photosynthetic
      materials are immobilized by co-reticulation in an albumin-glutaraldehyde
      crosslinked matrix (BSA-Glu). Different immobilization procedures in relation
      with various photosynthetic materials are mentioned.

PMID- 15187286
TI  - Determination of phosphoproteins in higher plant thylakoids.
AB  - Redox-dependent thylakoid protein phosphorylation regulates both short- and long
      term acclimation of the photosynthetic apparatus to changes in environmental
      conditions. The major thylakoid phosphoproteins belong to photosystem (PS)II (D1,
      D2, CP43, PsbH) and its light-harvesting antenna (Lhcb1, Lhcb2, CP29) but a
      number of minor phosphoproteins have also been identified. The detection methods
      traditionally include the radiolabeling techniques, electrophoretic separation of
      the phosphorylated and unphosphorylated forms of the protein, and the use of
      phosphoamino acid antibodies. The recent progress in mass spectrometry (MS)
      techniques and methods of proteomics allow for successful identification and
      analyses of protein phosphorylation. In mass spectrometry approaches, exogenous
      tracer is not needed and natural phosphorylation of proteins can be characterized
      with high sensitivity yielding the mapping of exact phosphorylation sites in the
      proteins as well. Various methods for detection of thylakoid phosphoproteins,
      including the preparation of phosphopeptides for mass spectrometric analyses and
      techniques for phosphopeptide identification by electrospray ionization MS are
      described. The experimental protocols for simultaneous identification of multiple
      phosphopeptides in complex peptide mixtures and for assess of stoichiometry for
      in vivo phosphorylation of multiple proteins are outlined.

PMID- 15187287
TI  - Identifying photoprotection mutants in Arabidopsis thaliana.
AB  - Plants have a range of mechanisms to protect against oxidative damage induced by
      excess light and environmental stress. One of these processes consists of the
      detoxification of reactive oxygen species by the ascorbate peroxidase (APX)
      family of enzymes, which convert H2O2 into H2O. Two of the genes encoding APX in
      Arabidopsis are induced by high light, namely APX1 and APX2. We have applied a
      genetic approach to understanding the mechanisms of photoprotection, using APX2
      as an indicator of oxidative stress. Transgenic plants containing the reporter
      gene luciferase linked to the APX2 promoter were EMS mutagenized and kindly
      provided to us by Mullineaux and colleagues. We have screened this mutagenized
      seed to identify mutants with aberrant photoprotection, based on altered
      luminescence resulting from altered luciferase activity. Here we describe the
      screen and steps involved in the identification of the mutations in an effort to
      identify novel photoprotective genes and products.

PMID- 15187288
TI  - A simple method for chloroplast transformation in Chlamydomonas reinhardtii.
AB  - Photosystem (PS)I is a multi-subunit pigment-protein complex that uses light
      energy to transfer electrons from plastocyanin to ferredoxin. Application of
      genetic engineering to photo-synthetic reaction center proteins has led to a
      significant advancement in our understanding of primary electron transfer events
      and the role of the protein environment in modulating these processes.
      Chlamydomonas reinhardtii provides a system particularly amenable to analyze the
      structure-function relationship of PSI. Chlamydomonas reinhardtii is also a
      favorable organism for chloroplast transformation because it contains a single
      chloroplast and grows heterotrophically when supplemented with acetate.
      Chlamydomonas has served as a model organism for the development of chloroplast
      transformation procedures and the study of photosynthetic mutants generated using
      this method. Exogenous cloned cpDNA can be introduced into the chloroplast by
      using this biolistic gene gun method. DNA-coated tungsten or gold particles are
      bombarded onto cells. Upon its entry into chloroplasts, the transforming DNA is
      released from the particles and integrated into the chloroplast genome through
      homologous recombination. The most versatile chloroplast selectable marker is
      aminoglycoside adenyl transferase (aadA), which can be expressed in the
      chloroplast to confer resistance to spectinomycin or streptomycin. This chapter
      describes the procedures for chloroplast transformation.

PMID- 15187289
TI  - The construction of gene knockouts in the cyanobacterium Synechocystis sp. PCC
      6803.
AB  - A series of protocols are presented for the storage, growth, transformation, and
      characterization of wild-type (wt) and mutant strains of Synechocystis PCC 6803.
      These protocols include the isolation of genomic DNA and the strategies required
      for the construction of specific gene knockouts in this organism. This
      cyanobacterium has been used widely as a model for photosynthesis research and
      the sequence of its genome, together with a database of mutants that have already
      been constructed, is available at CyanoBase (http://kazusa.or.jp/cyano/). The
      details provided in this chapter do not assume any previous experience in working
      with cyanobacteria and are intended to enable new investigators to take advantage
      of a wide-range of gene modification and mutation mapping techniques that have
      been adapted for use in this system.

PMID- 15187290
TI  - Gene inactivation in the cyanobacterium Synechococcus sp. PCC 7002 and the green
      sulfur bacterium Chlorobium tepidum using in vitro-made DNA constructs and
      natural transformation.
AB  - Inactivation of a chromosomal gene is a useful approach to study the function of
      the gene in question and can be used to produce a desired phenotype in the
      organism. This chapter describes how to generate such mutants of the
      cyanobacterium Synechococcus sp. PCC 7002 and the green sulfur bacterium
      Chlorobium tepidum by natural transformation with synthetic DNA constructs. Two
      alternative methods to generate the DNA constructs, both performed entirely in
      vitro and based on the polymerase chain reaction (PCR), are also presented. These
      methods are ligation of DNA fragments with T4 DNA ligase, and megaprimer PCR.

PMID- 15187292
TI  - Separation and identification of photosynthetic antenna membrane proteins by high
      performance liquid chromatography electrospray ionization mass spectrometry.
AB  - Functional proteomics of membrane proteins is an important tool for the
      understanding of protein networks in biological membranes. Nevertheless,
      structural studies on this part of the proteome are limited. The present review
      attempts to cover the vast array of methods that have appeared in the last few
      years for separation and identification of photosynthetic proteins of thylakoid
      membranes present in chloroplasts, a good model for setting up analytical methods
      suitable for membrane proteins. The two major methods for the separation of
      thylakoid membrane proteins are gel electrophoresis and liquid chromatography.
      Isoelectric focusing in a first dimension followed by denaturing sodium
      dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) in a second
      dimension is an effective way to resolve large numbers of soluble and peripheral
      membrane proteins. However, it is not applicable for isolation of native protein
      complexes or for the separation of highly hydrophobic membrane proteins. High
      performance liquid chromatography (HPLC), on the other hand, is highly suitable
      for any type of membrane protein separation due to its compatibility with
      detergents that are necessary to keep the hydrophobic proteins in solution. With
      regard to the identification of the separated proteins, several methods are
      available, including immunological and mass spectrometric methods. Besides
      immunological identification, peptide mass fingerprinting, peptide fragment
      fingerprinting or intact molecular mass determination by electrospray ionization
      mass spectrometry (ESI-MS) or matrix-assisted laser desorption/ionization mass
      spectrometry (MALDI-MS) have been shown to be very sensitive and effective. In
      particular, identification of proteins by their intact molecular mass is
      advantageous for the investigation of numerous biological problems, because it is
      rapid and reflects the full sequence of the protein and all its posttranslational
      modifications. However, intact molecular mass determinations of gel-separated
      membrane proteins are hampered due to the difficulties in extracting the
      hydrophobic proteins from the gel, whereas HPLC on-line interfaced with ESI-MS
      enables the rapid and accurate determination of intact molecular masses and
      consequently an unequivocal protein identification. This strategy can be viewed
      as a multidimensional separation technique distinguishing between hydrophobicity
      in the first dimension and between different mass-to-charge ratios in the second
      dimension, allowing the separation and identification even of isomeric forms.

PMID- 15187293
TI  - Quantitative proteomics: a review of different methodologies.
AB  - The present review attempts to cover the vast array of methods which have
      appeared in the last few years for performing quantitative proteome analysis.
      These methods are divided into two classes: those applicable to conventional two
      dimensional map analysis, coupling orthogonally a charge-based step (isoelectric
      focusing) to a size-based separation [sodium dodecylsulfate (SDS)
      electrophoresis] and those applicable to two-dimensional chromatographic
      protocols. The first method, although being by and large the most popular
      approach, can offer differential display of paired samples with relatively few
      methods, the oldest one being based on statistical analysis performed on sets of
      gels via powerful software packages, such as the MELANIE, PDQuest, Z3 and Z4000,
      Phoretix and Progenesis. Recent developments comprise analysis performed on a
      single gel containing mixed samples differentially labeled, either with
      fluorophors (Cy3 and Cy5) or with d(0)/d(3) acrylamide. Conversely,
      chromatographic approaches, which mostly rely on analysis not of intact proteins
      but of their tryptic digests, offer a panoply of differential labeling protocols,
      most of which rely on stable isotope tagging. Essentially, all possible reactions
      have been described, such as those involving Lys, Asp, Glu, Cys residues, as well
      as a number of methods exploiting differential derivatization of amine and
      carboxyl groups generated during proteolysis. All such methods are described and
      evaluated.

PMID- 15187294
TI  - Mass spectrometric approach for the analysis of food proteins.
AB  - In the study of food proteins, the need for accurate protein structural analysis
      has been acknowledged because of the fact that nucleotide sequencing alone is of
      limited analytical value if not combined with relevant information regarding the
      specific protein expressed and the occurrence of phosphorylation, glycosylation
      and disulphide bridges, and with the modification induced by the technological
      treatment. Mass spectrometry, whether used alone or to complement the traditional
      molecular-based techniques has become fundamental to the structural analysis of
      proteins. It is, moreover, virtually irreplaceable in determining post
      translational modifications as conventional methods cannot deliver reliable data.
      What lies at the root of this methodological breakthrough is the combination of
      high-resolution separation techniques such as two-dimensional electrophoresis or
      capillary reverse- phase high-performance liquid chromatography with mass
      spectrometric analysis, what is termed "proteomic" analysis. Thus, it appears
      appropriate to state that the new mass spectrometric techniques have been
      established as a valuable and efficient tool for protein and peptide analysis in
      complex mixtures, like those from food matrices, enabling us therefore to provide
      accurate information on molecular weight and also to put forth a structural
      assessment at a low-picomole level of material. Thus, a series of alternative
      approaches have been developed based on advanced mass spectrometric analysis in
      conjunction with classic protein chemistry in order to provide an in-depth view
      of food protein structure. This review outlines several of these novel
      methodologies as they apply to structural characterization of food products.

PMID- 15187295
TI  - Mass spectrometry in the characterization of cereal seed proteins.
AB  - In less then a decade, applications of matrix-assisted laser
      desorption/ionisation (MALDI) and electrospray ionisation (ESI) mass spectrometry
      to the investigation of prolamins have rapidly evolved from measurements of the
      molecular mass of isolated proteins to a proteomic approach attempting to
      characterise the complete protein pattern in the seed. Mass spectrometry is
      currently making significant contributions to the understanding of the
      composition and structure of the gluten proteins and, in turn, to the elucidation
      of structure-function relationships. Results obtained using mass spectrometry,
      including determination of the molecular masses of prolamins, direct verification
      of gene-derived sequences, determination of the number of cysteine residues and
      localisation of disulphide bonds, investigation of the gluten toxicity for celiac
      patients, qualitative and quantitative determination of gliadins in food and
      determination of the protein pattern and its modification during seed maturation
      by proteomic approaches, are summarised here, to illustrate current trends and
      individuate possible future perspectives.

PMID- 15187296
TI  - Prion (PrPres) allotypes profiling: a new perspectives from mass spectrometry.
AB  - Biochemical methods employed for PrPres allotypes profiling are reviewed and
      compared with the latest mass spectrometric approaches. Emphasis is put on the
      advantages offered by a recently proposed electrospray strategy.

PMID- 15187297
TI  - Analysis of protein phosphorylation by mass spectrometry.
AB  - Phosphorylation is one of the most frequently occurring post-translational
      modifications in proteins. In eukaryotic cells, protein phosphorylation on
      serine, threonine and tyrosine residues plays a crucial role as a modulator of
      protein function. A comprehensive analysis of protein phosphorylation involves
      the identification of the phosphoproteins, the exact localization of the residues
      that are phosphorylated and the quantitation of phosphorylation. In this short
      review we will summarize and discuss the methodologies currently available for
      the analysis and full characterization of phosphoproteins with special attention
      at mass spectrometry-based techniques. In particular, we will discuss affinity
      based purification of phosphopeptides coupled to MALDI-TOF analysis, their
      detection using mass mapping and precursor ion scan, identification of modified
      sites by MS/MS and quantitation analysis

PMID- 15187298
TI  - Primary structure details of haptoglobin alpha chain proteins from human plasma
      samples are resolved by matrix-assisted laser desorption/ionization quadrupole
      ion trap time-of-flight multiple-stage tandem mass spectrometry sequencing.
AB  - MALDI QIT ToF MS(n) analyses lead to the rapid identification of protein
      structural details, as readily interpretable spectra after peptide fragmentations
      were obtained showing ion signals with high abundance even with sample amounts in
      the low femtomole range. In our studies we show that the Hp alpha 1F form that
      contained a C-terminal arginine residue was found to be the only contributing
      component to spot 149. By contrast, spots 77 and 79 were found to consist of two
      haptoglobin forms each. Spot 77 consists of Hp alpha 1S and deamidated Hp alpha
      1F, whereas spot 79 consists of Hp alpha 1F and of Hp alpha 1S that contains a C-
      terminal arginine residue. The use of ion traps, enabling the acquisition of MSn
      spectra serves as a powerful peptide sequencing method for the analysis of both,
      genetic differences and post-translational modification events as the main reason
      for the observed spot pattern in the 2-D gels of haptoglobin proteins.

PMID- 15187299
TI  - Mapping phosphorylation sites: a new strategy based on the use of isotopically
      labelled DTT and mass spectrometry.
AB  - Phosphoproteomics, nowadays, represents a front line in functional proteomics as
      testified by the number of papers recently appearing in the literature. In an
      attempt to improve and simplify the methods so far suggested we have set up a
      simple isotope-coded approach to label and quantitate phospho-Ser/-Thr residues
      in protein mixtures. First of all, after appropriate oxidation of
      cysteine/cystine residues followed by tryptic hydrolysis, we have optimised and
      simplified the beta-elimination reaction to get the corresponding alkene moiety
      from the phosphate esters. This was achieved by (a) separating the elimination
      reaction from the addition reaction, (b) the use of Ba(OH)(2) as alkali reagent
      and (c) its further elimination by the simple addition of solid CO(2) to the
      peptide mixture. The Michael reaction was then performed, after the removal of
      BaCO(3) by centrifugation, by adding dithiothreitol (DTT) to the peptide mixture.
      Finally, the direct purification of the modified phosphopeptides was performed on
      a thiol-sepharose column. The availability of fully deuterated DTT, introducing a
      6 Da difference with respect to the non-deuterated species, allows quantitation
      of the differential extent of signalling modification when analysed by matrix
      assisted laser desorption/ionisation mass spectrometry (MALDI-MS) and liquid
      chromatography/mass spectrometry. The entire procedure has been set up by using
      bovine alpha-casein, and resulted in the identification of all the phosphorylated
      tryptic peptides, including the tetraphosphorylated peptides, which escaped all
      previously reported procedures

PMID- 15187300
TI  - Characterization of sodium dodecylsulfate polyacrylamide gel electrophoresis
      separated M. agalactiae membrane antigens by mass spectrometry.
AB  - Mycoplasma membrane proteins are generally designated according to their apparent
      molecular weight measured by SDS-PAGE. Several results about mycoplasma membrane
      antigens are conflicting because some doubts are emerging about the accuracy of
      the method utilised to identify the antigens. Aim of this work, was to
      characterise proteins separated after sodium dodecylsulfate polyacrylamide gel
      electrophoresis (SDS-PAGE)-mass spectrometry to allow an uncontroversial
      designation of the antigens. Fifteen proteins with molecular weights ranging from
      15,000 to 80,000 Da had been excised from gel and their whole molecular weight
      and proteolytic pattern had been determined using MALDI-TOF. The peptide pattern
      obtained using trypsin digestion allowed us to identify LipA, P48, P59, P80 and
      P40. Some other proteins showed analogies to proteins of Mycoplasma genitalium or
      Mycoplasma pneumoniae the only Mycoplasmas completely sequenced. There wasn't a
      close correspondence between the SDS-PAGE apparent molecular weight (generally
      used to name the proteins), the gene derived calculated mass and the molecular
      weight of whole proteins measured by MALDI-TOF. Only micro sequence data obtained
      by MS/MS allowed us to identify LipC, described as one of the most important
      Mycoplasma agalactiae antigens. This protein was found in correspondence with the
      50 kDa region, instead of the 25 kDa region, confirming a phenomenon that we
      previously described.

PMID- 15187301
TI  - Study of the oligopeptide fraction in Grana Padano and Parmigiano-Reggiano
      cheeses by liquid chromatography electrospray ionization mass spectrometry.
AB  - The oligopeptide fractions of Grana Padano and Parmigiano Reggiano cheese
      samples, at various stages of ageing (6, 12, 18 and 24 months), were analysed by
      means of high-performance liquid chromatography coupled to electrospray
      ionisation mass spectrometry (ESI-MS). The main oligopeptides (< 5000 Da) present
      in the samples were extracted by using an originally developed method which
      allowed good enrichment of the oligopeptide fractions and identified according to
      their molecular weights. The casein sequences compatible with the found molecular
      weights were determined and the exact oligopeptide sequences were identified by
      using the fragmentation peaks originated by in-source collisionally-induced
      dissociation (CID). The ESI-MS method reported here allowed the sequence
      identification of oligopeptides very quickly with a single liquid chromatography
      mass spectrometry run. Oligopeptides were also semi-quantified by comparison with
      a suitable internal standard (the dipeptide phenylalanyl-phenylalanine, Phe-Phe).
      This methodology demonstrated that, as far as the main oligopeptides are
      concerned, Grana Padano and Parmigiano Reggiano presented very similar
      composition. Anyway, the evolution of the fractions during ageing time was
      characteristically distinct among the two cheeses: in Grana Padano cheeses most
      of the oligopeptides reached a maximum at 12 months of ageing and then decreased,
      whereas in Parmigiano Reggiano cheeses the oligopeptide amounts were usually
      lower and had a less regular trend. The reason for this different behaviour may
      be ascribed to the different production techniques.

PMID- 15187302
TI  - Complexes between recombinant intracellular carriers of vitamin A and their
      specific ligands investigated by electrospray-mass spectrometry.
AB  - The intracellular carriers of vitamin A, cellular retinol-binding protein type I,
      cellular retinol-binding protein type II and cellular retinoic acid-binding
      protein type I are members of the intracellular lipid-binding proteins family, in
      which the ligand-binding cavity is located in the interior of a barrel-like
      structure. The dissociation constants of the specific complexes in water
      solutions around neutrality are very low (in the 0.1 to 10 nM range). Because of
      their high stability, they represent ideal systems to verify the adequacy of
      electrospray ionization-mass spectrometry in the analysis of non-covalent protein
      ligand complexes. The electrospray interface parameters were varied to detect the
      presence of species not present in solution but generated as artefacts during
      transfer of complexes from the condensed state to the gas-phase. The results
      clearly indicate that mass-spectrometry data reflect the situation present in
      solution only if the electrospray conditions are carefully selected. In
      particular, the values of cone voltage and temperature compatible with
      persistence of the complexes in the gas phase were determined for each vitamin A
      carrier. Lack of correlation between complex stability in solution and in the gas
      phase is attributable to the specific and differential effects of the two
      environments on protein conformation and ligand-protein interactions.

PMID- 15187303
TI  - c-Myc and epidermal stem cell fate determination.
AB  - The epidermis is sustained by a multipotent stem cell population that gives rise
      to cells of different fates including those forming hair follicles,
      interfollicular epidermis and associated glands such as sebaceous glands. The
      most intriguing evidence comes from using a variety of mouse models with which
      studies have found the WNT pathway to be involved in regulating stem cell fate
      decisions. These mouse models have been used to analyze different members of the
      WNT pathway in the epidermis and altogether suggest that different levels of beta
      catenin correlate with the adoption of different epidermal stem cell fates.
      Recent data specifically analyzing c-Myc, a downstream target of the WNT pathway,
      has found that c-Myc can divert epidermal stem cells to a sebaceous gland fate at
      the expense of hair follicles. Also, newly emerging data using gene expression
      profiling techniques have uncovered a more direct role of c-Myc in stem cell fate
      determination.

PMID- 15187304
TI  - Multiple NSAID intolerance in chronic idiopathic urticaria is correlated with
      delayed, pronounced and prolonged autoreactivity.
AB  - Autologous serum skin test (ASST) reactivity is positive in up to 60% of patients
      with chronic idiopathic urticaria (CIU). About 21 to 30% of patients with CIU
      have intolerance to acetyl salicylic acid (ASA) and/or other chemically unrelated
      non-steroidal anti-inflammatory drugs (NSAIDs). To investigate the relationship
      between ASA/NSAID intolerance and ASST reactivity, a case-control study was
      performed in 110 patients with CIU and 60 healthy controls. A positive ASST was
      defined as an erythematous wheal with a diameter of > 5 mm more than the saline
      induced response. Patients were assessed at 10-minute intervals for a minimum of
      three hours. ASA/NSAID intolerance was ascertained by a placebo controlled
      provocation test with offending drug (s). Forty-two patients with CIU (38.2%) had
      autoreactivity whereas only two of the controls (3.3%) displayed early and weak
      skin responses (P<.0001). ASA/NSAID intolerance was demonstrated in 30 (27.3%)
      patients with CIU. The prevalences of autoreactivity were 93.3% (28/30) and 17.5%
      (14/80) in patients with and without ASA/NSAID intolerance, respectively
      (P<.001). Thirteen of the 25 ASST-positive patients (52%) who had single (n: 7)
      or multiple (n: 6) NSAID intolerance showed early (before or at 30 min) and mild
      autoreactivity of short duration, whereas 15 of the remaining 17 ASST-positive
      patients (88.2%) who all had multiple NSAID intolerance showed delayed (later
      than 30 min) and prolonged autoreactivity (P<.05). These findings suggest that a
      common mechanism may be responsible for the pathogeneses of both delayed
      autoreactivity and multiple NSAID intolerance in CIU. It might be further
      speculated that delayed, prolonged, and pronounced autoreactivity may be a
      possible predictor for multiple NSAID sensitivity in CIU.

PMID- 15187305
TI  - Monitoring of ELISA for anti-BP180 antibodies: clinical and therapeutic analysis
      of steroid-treated patients with bullous pemphigoid.
AB  - We studied the precise correlation between ELISA values for BP180 NC16A and the
      alternations of disease activity in 5 patients with bullous pemphigoid (BP)
      during various treatments and tried to answer the question of how we can use
      ELISA to determine the timing of prednisolone (PSL) tapering. Disease activity in
      some patients with BP, but not in all, was poorly correlated with ELISA values in
      short-term follow-up. However, all patients showed a good correlation of disease
      activity with ELISA values as a whole in long-term follow-up. Three patients with
      typical BP showed rapid and good responses to PSL for erosion and blister
      formation. Their ELISA values gradually decreased to 40% of initial values during
      PSL therapy after four weeks. Two patients with the vesicular type of BP did not
      show rapid and good responses to PSL for erosion and blister formation. In the
      cases with the vesicular type of BP, diaphenylsulfone in addition to PSL
      dramatically improved the clinical symptoms including erosion and blister
      formation, even though the ELISA values were as high as those before treatment.
      Relapses did not occur with the tapering of PSL dosage when the ELISA values
      decreased to 40% of initial values, although they were still not within the
      normal range.

PMID- 15187306
TI  - Detection of the levels of neuropeptides, ACTH and cortisol in the blood of
      patients with polymyositis/dermatomyositis and their significance.
AB  - Recent research has shown that the neuroendocrine system can regulate the
      function of the immune system and that ACTH and cortisol play important roles in
      maintaining the immune homeostasis. Polymyositis and dermatomyositis (PM/DM) are
      autoimmune diseases with unclear pathogeneses closely related with immune
      disorders, so we detected the levels of neuropeptide Y (NPY), beta-endorphin
      (beta-EP), calcitonin gene-related peptide (CGRP), adrenocoricotropic hormone
      (ACTH), and cortisol in blood of patients with PM/DM to investigate the
      relationship between these indices and the pathogenesis of PM/DM. The detection
      of NPY, beta-EP, CGRP, and ACTH concentrations in plasma and cortisol in serum of
      28 cases of PM/DM was carried out using radioimmunoassay methods, and the results
      were compared with those of 20 normal controls. The levels of NPY in the plasma
      of PM/DM was significantly higher than those of the controls, while beta-EP, CGRP
      and ACTH were significantly lower than those of the controls, and cortisol was
      not significantly different before treatment. Linear correlation analysis
      indicated that NPY was significantly positively correlated with CPK, and beta-EP
      and CGRP were significantly negatively correlated with CPK. There were no
      significant correlations among cortisol ACTH, and CPK and no significant
      correlations between NPY, beta-EP, CGRP, ACTH, cortisol and age or duration of
      disease before treatment. After treatment for three months, NPY, beta-EP and CGRP
      tended to become normal and no longer significantly different from the control
      values. However, ACTH fell further and was significantly lower than the level
      before treatment. Therefore the increase in NPY and the decreases in beta-EP,
      CGRP, and ACTH in the plasma of PM/DM patients may be related to the pathogenesis
      of PM/DM.

PMID- 15187307
TI  - Hereditary Punctate Palmoplantar Keratoderma (PPK) (Brauer-Buschke-Fischer
      Syndrome).
AB  - We describe the first case of a sixty-five-year-old male field worker from India,
      having lesions of hereditary punctate palmoplantar keratoderma with an
      autosomally dominant pattern of inheritance. Associations included nail
      abnormalities in the form of longitudinal ridging, onychorrhexis, onychoschizia,
      trachyonychia and notching, which has been reported only on one previous
      occasion. The article also presents a brief review of the literature.

PMID- 15187308
TI  - A case of docetaxel-induced erythrodysesthesia.
AB  - Chemotherapy-induced acral erythema (CIAE) is a rare cutaneous reaction to high
      dose chemotherapy, clinically featuring painful erythema on the palms and soles.
      Docetaxel (Taxotere), an anticancer agent, is known to cause various reactions,
      including CIAE. We experienced a case of docetaxel-induced acral erythema with
      facial edematous erythema that coincidentally emerged and regressed with
      appearance and disappearance of the acral lesions. Docetaxel-induced acral
      erythema exhibits a widespread distribution and intense sensations of intolerable
      pain and numbness. Therefore, some authors use the term erythrodysesthesia
      instead of acral erythema. We speculated that the facial erythema might be part
      of the spectrum of erythrodysesthesia. Our case was finally diagnosed as
      decetaxel-induced erythrodysesthesia. Although CIAE is self-limiting, the
      patients frequently require treatment because of intolerable pain. Reported
      treatments for CIAE include topical or systemic steroids, elevation of the legs,
      and application of cold compression to the lesion. In our case, application of a
      steroid ointment with the occlusive dressing technique (ODT) alleviated the
      clinical manifestations and was also prophylactic for the erythrodysesthesia.

PMID- 15187309
TI  - A case of herpetiform pemphigus with anti-desmoglein 3 IgG autoantibodies.
AB  - Herpetiform pemphigus (HP) is a rare variant of pemphigus characterized by a
      unique clinical phenotype of erythematous or urticarial plaques and vesicles that
      present in a herpetiform arrangement. Most HP cases have circulating anti
      desmoglein 1 (Dsg1) IgG autoantibodies, but some HP cases have anti-desmoglein 3
      (Dsg3) IgG. A 92-year-old Japanese woman presented with severely pruritic annular
      erythema and vesicles in a herpetiform arrangement on the trunk. No oral mucosal
      lesions were present. Histopathologically, these vesicles showed eosinophilic
      spongiosis as well as suprabasilar acantholysis. Direct immunofluorescence showed
      in vivo IgG deposition on keratinocyte cell surfaces, and indirect
      immunofluorescence showed circulating IgG autoantibodies against keratinocyte
      cell surfaces at a titer of 1:30. Enzyme-linked immunosorbent assay using
      recombinant Dsg1 and Dsg3 revealed the presence of anti-Dsg3 IgG but no anti-Dsg1
      IgG autoantibodies. The lack of oral mucosal involvement and the unique clinical
      features favored the diagnosis of HP. It remains to be clarified why the anti
      Dsg3 IgG autoantibodies in this patient induced this unique features of HP,
      rather than the mucosal dominant type of pemphigus vulgaris.

PMID- 15187310
TI  - Unilateral nevoid telangiectasia and hyperthyroidism: a new association or
      coincidence?
AB  - Telangiectasia and spider angioma were distributed in a unilateral, dermatomal
      pattern in a female patient. Physical examination and laboratory studies revealed
      hyperthyroidism. The possible effects of thyroid hormones on formation of
      vascular nevi were considered to be noteworthy.

PMID- 15187311
TI  - Phakomatosis Pigmentovascularis Type IIB: a case report.
AB  - Phakomatosis Pigmentovasularis (PPV) is a rare condition defined by the presence
      of both vascular and melanocytic nevi occurring in the same patient. We report
      the case of a 27-year-old Chinese female who presented with generalized port-wine
      stains over the left trigeminal region, trunk, and limbs, diffuse dermal
      melanosis on the back, nevus of Ota on the right cheek, and scleral melanosis.
      Her port-wine stain on the trunk was distributed in a checker-board pattern. She
      was otherwise well. She was diagnosed with phakomatosis pigmentovascularis (PPV)
      Type IIb. The 'twin spotting' phenomenon has been proposed in the pathogenesis of
      PPV, and PPV is an example of non-alleleic twin spotting. The checkerboard
      distribution of port-wine stain in our patient follows the type II pattern of
      distribution in cutaneous mosaics. This lends further credence to the proposed
      hypothesis of twin spotting and cutaneous mosaicism in the pathogenesis of PPV.

PMID- 15187312
TI  - Pleomorphic hyalinizing angiectatic tumor of soft parts: report of a case and
      review of the literature.
AB  - We present the case of a 69-year-old man with a subcutaneous pleomorphic
      hyalinizing angiectatic tumor of soft parts on the back. In addition to its rare
      localization, it showed unique clinical features of an exceptionally long
      history. Histological characteristics of this tumor showed thin-walled
      angiectatic blood vessels lined with a thick eosinophilic and hyalinotic
      amorphous material. Tumor cells are composed of pleomorphic cells. It was
      surgically removed, and there was no recurrence by 11 months postoperatively.

PMID- 15187313
TI  - A case of black dot ringworm attributable to Trichophyton violaceum: a simple
      method for identifying macroconidia and microconidia formation by Fungi-Tape and
      MycoPerm-Blue.
AB  - An 85-year-old Japanese woman sought a dermatologic consultation for evaluation
      of a walnut-sized alopecia with pityroid desquamation in the parietal region of
      her scalp. She had been admitted to a nursing home about three months earlier,
      and, at that time, a thumb-tip-sized, scaly alopecia was noted. Several hairs at
      the site were eroded in a black dot. Direct KOH microscopy of affected hair
      showed large spore endothrix infection. To isolate macro- and microconidia for
      fungal identification, we incubated the affected hair and scales and obtained
      giant colonies in a special enriched medium. Using Fungi-tape and MycoPerm-Blue,
      we were able to collect and identify Trichophyton violaceum macro- and
      microconidia from the white, powdery, fluffy colony that slowly developed after
      about six weeks of growth on enriched medium. Over the past 20 years, only about
      20 cases of tinea capitis caused by T. violaceum have been reported in Japan, and
      macroconidia have been identified in only 4 cases, including this one.

PMID- 15187314
TI  - Allergic contact dermatitis to white petrolatum.
AB  - White petrolatum is known for its nonsensitizing and nonirritating properties.
      Only a few cases of allergic contact dermatitis to white petrolatum have been
      reported. Although it is a rare event, the finding of contact sensitization to
      white petrolatum raises the potential problem of its usage of common topical
      agents or vehicles for patch testing. We herein report a case of allergic contact
      dermatitis to white petrolatum.

PMID- 15187315
TI  - Variegate porphyria.
AB  - Variegate porphyria is a rare, hereditary form of hepatic porphyria characterized
      by acute systemic symptoms as in acute intermittent porphyria in addition to
      cutaneous symptoms simulating porphyria cutanea tarda. We describe a 22-year-old
      female from India who first presented to the emergency department with acute
      symptoms and was later confirmed to have variegate porphyria.

PMID- 15187316
TI  - A family with Waardenburg syndrome.

PMID- 15187317
TI  - 3-5 second cryotherapy is effective in idiopathic guttate hypomelanosis.

PMID- 15187318
TI  - A case of idiopathic eruptive macular pigmentation.

PMID- 15187319
TI  - Examination of the relationship between the hepatitis C virus and Behcet's
      disease.

PMID- 15187320
TI  - Immunoregulation of allergic contact dermatitis.
AB  - Allergic contact dermatitis (ACD) to haptens can serve as a valuable paradigm for
      understanding the physiopathology of T cell mediated immune responses. In
      sensitized individuals, exposure to the relevant hapten initiates clinical
      expression of ACD, which depends on the rapid activation of specific T cells.
      Mechanisms of tissue damage include direct cytotoxicity against keratinocytes,
      mostly mediated by CD8+ T cells, and T cell release of cytokines, which amplify
      the inflammatory response by targeting resident skin cells. The expression of ACD
      is actively regulated by specialized subsets of T lymphocytes with suppressive
      functions. In particular, T regulatory cells producing high levels of IL-10
      suppress ACD by blocking the functions of dendritic cells. In contrast CD4+CD25+
      regulatory T cells prevent immunopathological reactions and maintain peripheral
      tolerance to haptens by acting via a cell-to-cell contact mechanism.
      Understanding the role of suppressor T cells and the requirements for their in
      vivo and in vitro expansion are critical steps for the development of specific
      desensitization protocols in hapten-allergic individuals. This information may
      also provide the basis for novel interventions in other immune-mediated diseases.

PMID- 15187321
TI  - Unique keratinization process in psoriasis: late differentiation markers are
      abolished because of the premature cell death.
AB  - The keratinization process in psoriasis is a unique phenomenon. We have proposed
      an organized system for keratinization in psoriasis based on the recognition of
      early and late differentiation markers combined with premature cell death. The
      early differentiation markers, such as involucrin, small proline-rich proteins
      (SPRR), cystatin A and transglutaminase l, are more conspicuously expressed in
      psoriasis, while the late differentiation markers, such as profilaggrin and
      loricrin, are abolished. Keratinization markers that are not observed in the
      normal epidermis are also detected; these include SKALP/elafin as well as K6 and
      K16. With a markedly diminished turnover time, the psoriatic epidermis rapidly
      synthesizes differentiation markers that are mostly under the control of the
      protein kinase C-AP1 transcriptional control system. Because of the premature
      cell death, however, the late differentiation markers are not expressed. During
      the improvement of the lesion and the therefore longer turnover time, the late
      differentiation markers rapidly catch up to reveal their expression. This
      explains the rapid appearance of keratohyalin granules (profilaggrin) in the
      healing lesion of psoriasis. Thus the keratinization process in psoriasis can be
      explained by the accelerated keratinization combined with premature cell death.
      The keratinization process in psoriasis is unique, because both accelerated
      keratinization and premature cell death co-exist, resulting in the disappearance
      of late differentiation markers such as profilaggrin and loricrin. It is
      interesting to note that the premature cell death is also under the control of
      protein kinase C signaling.

PMID- 15187322
TI  - Dosage and adverse effects of topical tacrolimus and steroids in daily management
      of atopic dermatitis.
AB  - Since 1999, combination therapy with tacrolimus and topical steroids has been
      widely used for the treatment of adolescent/adult-type atopic dermatitis. In
      order to determine the clinical doses of topical tacrolimus and steroids for
      daily treatment of atopic dermatitis and to elucidate their beneficial and
      adverse effects, we analyzed the clinical data from 215 patients with atopic
      dermatitis who were more than 16 years old. Less than 70 g of tacrolimus and less
      than 15 g of steroids were applied to 90% of the patients on the face and neck,
      and less than 75.8 g of tacrolimus and less than 322 g of steroids were applied
      to 90% of the patients on the trunk and extremities during the six-month
      treatment period. Topical tacrolimus is much more frequently used on face and
      neck lesions (99.1%); in only 39.5% of cases was it used on the trunk and
      extremities. The majority of patients improved after six months of the
      combination topical therapy; however, atopic dermatitis was not controlled in 6%
      of the patients. The combination therapy did not seem to increase the risk of
      cutaneous infections; however, the incidence of herpes simplex infection on the
      face and neck was 2.8% at pre-treatment and slightly increased to 4.7% during the
      therapy. The incidence of all steroid-induced adverse effects was reduced both in
      frequency and intensity with a decrease in the dose of topical steroids through
      simultaneous tacrolimus application. Combination therapy with topical tacrolimus
      and steroids is useful for treating atopic dermatitis, but a small percentage of
      the patients still cannot be satisfactorily treated. For such patients,
      adjustments of the dose and rank of topical steroids and tacrolimus and other
      therapeutic adjuncts are necessary.

PMID- 15187323
TI  - Treatment of Vitiligo with 308-nm xenon-chloride excimer laser: therapeutic
      efficacy of different initial doses according to treatment areas.
AB  - Many preliminary data suggest that the 308-nm excimer laser can be a highly
      effective therapeutic alternative for treating vitiligo, inducing rapid
      repigmentation with minimal ultraviolet irradiation. We evaluated the clinical
      efficacy of the 308-nm excimer laser treatment for various body areas, using
      different initial UV doses. One hundred forty vitiligo patches from 69 patients
      were assigned to 4 groups; face and neck, trunk, extremities, and acral and joint
      areas. They were then treated twice a week, using different initial UV doses. The
      rate of repigmentation continued to increase with the number of treatments up to
      20 sessions, and then showed plateaus between 20 to 30 sessions. On the other
      hand, the lesions in acral and joint areas showed the worst responses throughout
      the treatment sessions. Our findings extend previous observations that the 308-nm
      excimer laser is an effective treatment option for patients with vitiligo.
      However, further studies will be needed to determine the optimal dosing and
      administration method, especially for acral and joint areas.

PMID- 15187324
TI  - Diabetes and hepatitis frequency in 140 lichen planus cases in Cukurova region.
AB  - The aim of the present study was to determine the Hepatitis B Virus (HBV),
      Hepatitis C Virus (HCV), and diabetes mellitus (DM) frequencies in lichen planus
      (LP) cases in our region. We performed a retrospective review of records from all
      cases that were diagnosed with LP at the our department between 1997 and 2002.
      The results were compared with the control group (any type of dermatosis other
      than LP). The 260 LP cases included 108 (41.5%) males and 152 (58.5%) females
      aged between 5 and 78 years. The clinical distribution of the lesions were 127
      (48.8%) with skin lesions and 133 (51.2%) with oral mucosal lesions. The duration
      of disease ranged from 1 to 240 months. In 140 of 260 LP cases, hepatitis
      serology and pre-prandial blood glucose were examined. We found HBV positivity in
      24 (17.1%) cases, Anti-HCV positivity in 7 (5%) cases, and DM in 22 (15.7%)
      cases. The control group included 116 (41.4%) males and 164 (58.6%) females.
      Their ages ranged between 10 and 82 years. In this group, we found HBV positivity
      in 20 (7.1%), Anti-HCV positivity in 4 (1.4%), and DM in 20 (7.1%) cases. We
      believe that the co-association of LP with HCV is significant and this co
      association ratio indicates variance depending on clinical attributes of the
      lesions and racial characteristics of the patients. Although we found co
      associations between HBV and LP or DM and LP, we believe that further studies are
      necessary to determine if they are significant.

PMID- 15187325
TI  - Histologic progression of B16 F10 metastatic melanoma in C57BL/6 mice over a six
      week time period: distant metastases before local growth.
AB  - B16F10 murine metastatic melanoma in the tails of C57BL/6 mice after subcutaneous
      injection is a well-established model. However, the histologic progression from
      injected cells to established local growth of melanoma has not been studied
      systematically. We therefore have investigated the histologic changes and growth
      of B16F10 melanoma at the injection site over a six-week time period. One million
      B16F10 melanoma cells were injected subcutaneously into the dorsal aspect of
      tails of C57/BL6 mice. Mice were sacrificed at zero, 12, 24, 48, 72 and 96 hours,
      and at one, two, three, four, five and six weeks. Sections were stained with
      Hematoxylin and Eosin and immunostained with antibodies to S100. Beginning at
      time zero, melanoma cells were detected between the dermis and the myofascial
      bundle of the tail. At week four, distant metastases were clinically evident in
      the inguinal region, though injection site tumors did not become evident until
      week six. Histological analysis showed melanoma cells at the injection site at
      all time periods and no injection site tumor until week six. Indeed, the
      injection site tumors arose two weeks after distant metastases were clinically
      apparent. A progression of S100 positivity was also observed. S100 immunostaining
      was negative in all injection site of B16F10 cells until the cells underwent a
      morphologic change from small and monomorphic at the injection site, to large,
      pleomorphic cells at week six in the clinically evident injection site tumors.
      Inguinal metastases were also S100 positive at week four, though injection site
      cells were still S100 negative. We conclude that in this particular established
      model for melanoma, local growth at the injection site may occur after the
      development of regional metastases. This may prove to be a good model for
      investigation of local growth of tumor cells and their interaction with
      metastatic lesions.

PMID- 15187326
TI  - Proliferation patterns reflect architectural dedifferentiation: a study of
      nodular basal cell carcinoma.
AB  - The distribution of proliferating cells in basal cell carcinoma (BCC) may be
      related to lesion type and architecture. Single proliferation indexes may not be
      representative. We aimed to establish the distribution of cell proliferation in
      BCC as related to architecture. We studied an unselected, consecutive series of
      45 resection specimens of nodular BCC from patients in the age range of 25-95
      years using MIB-1 staining and systematically reviewed the cases. These lesions
      included nodular (n=32) and non-nodular (n=9) BCC. Within the nodular BCC, two
      patterns were recognised, not related to age or gender. In small nodular patterns
      with well developed peripheral palisading and central parallel streaming of
      small, elongated nuclei, proliferation is limited to the basal palisading cells
      in a clustered distribution. In large nodular patterns, proliferation is absent
      at the basal membrane (BM) and distributed in single random cells throughout the
      lesion. Both patterns preclude accurate quantitation. Many lesions contained both
      patterns in a side-by-side, unmixed manner. These pattern differences suggest a
      loss of differentiation in nodular BCC. Perhaps a single mutation results in the
      loss of BM associated cell architecture and proliferation control related to
      tumor-stroma interactions. As a result, the lesion reverts to a low frequency,
      non-regulated proliferation, diffusely distributed throughout the lesion. The two
      patterns may exist side-by-side in a single lesion, further supporting the
      concept of polyclonality. This hypothesis explains perilesional clefting and
      previously reported variations in intra-lesional laminin synthesis. Based on our
      findings, representation of tumor cell proliferation activity by a single value
      is not justified. Nodular BCC exists in one of two dedifferentiation-mutation
      determined patterns of cell proliferation; many lesions clearly demonstrate bi
      clonality.

PMID- 15187327
TI  - Therapeutic evaluation of intralesional 5% 5-fluorouracil in condyloma acuminata.
AB  - Condyloma acumianata is one of the most common virally transmitted diseases. Its
      prevalence has increased many fold throughout the world. Because all the
      currently available treatments yield low cure rates with side effects, the search
      for a new alternative continues. Topically, 5-fluorouracil (5-FU) has been in
      used for many years to treat various skin diseases. When applied topically in
      condyloma acuminata, 5-FU results in low cure rates with high recurrences.
      Therefore, intralesional 5% 5-FU is being evaluated to determine its therapeutic
      efficacy in condyloma acuminata.

PMID- 15187328
TI  - Metaplastic ossification in a cutaneous pyogenic granuloma: a case report.
AB  - Cutaneous ossification may occur in association with a variety of cutaneous
      neoplasms and inflammatory conditions, such as pilomatricomas, basal cell
      carcinomas, nevi, chondroid syringomas, venous stasis, and scars. However, it has
      rarely been reported in pyogenic granuloma, a relatively common benign vascular
      tumor of the skin and mucous membranes. We herein presented a rare case of
      cutaneous pyogenic granuloma with ectopic ossification on the big toe of a 37
      year-old man, with high recurrence despite repeated CO2 laser ablations. We
      propose the hypothesis that vascular endothelial growth factor (VEGF) and bone
      morphogenetic proteins (BMPs) play pathologic roles in the development of ectopic
      bone formation in pyogenic granuloma.

PMID- 15187329
TI  - Cutaneous involvement in Hodgkin's lymphoma: report of two cases.
AB  - Hodgkin's lymphoma (HL) comprises 20 to 30% of all lymphomas. Skin involvement is
      almost always secondary to visceral or nodal involvement. Secondary cutaneous HL
      is rare, occurring in only 0.5 to 3.4% of the cases. Herein we report two cases
      of skin involvement in Hodgkin's disease. One was a 25-year-old female admitted
      with a draining sinus in the neck. The other was a 19-year-old female admitted
      with a neck mass and skin papules on her chest and arm. Skin involvement may
      antecede or can be seen during the course of HL. Better understanding of such
      cutaneous involvement, which occasionally may be the initial sign of HL, is
      needed, and a biopsy of any suspicious skin lesion should be considered.

PMID- 15187330
TI  - Successful treatment of pulmonary metastasis and local recurrence of angiosarcoma
      with docetaxel.
AB  - Angiosarcoma of the face and scalp of the elderly frequently recurs locally,
      metastasizes early despite various treatments, and has a poor prognosis. We
      describe a patient who had angiosarcoma of the scalp with pulmonary metastasis.
      Local recurrence occurred after excision and local and arterial administration of
      IL-2. A weekly administration method of docetaxel was therefore selected,
      resulting in complete remission of the pulmonary metastasis and a partial
      response of the local recurrence. This favorable clinical outcome in our case
      suggests that docetaxel therapy may be an option for the treatment of
      angiosarcoma of the scalp with pulmonary metastasis.

PMID- 15187332
TI  - Fluconazole induced fixed drug eruption: a rare offender.

PMID- 15187331
TI  - Successful treatment of pyogenic granuloma with injection of absolute ethanol.
AB  - Pyogenic granuloma (PG) is a small, almost always solitary, sessile or
      pedunculated, raspberry-like vegetation of exuberant granulation tissue.
      Conservative treatment by techniques such as cryosurgery, laser surgery, and
      electrodesiccation are usually adequate, whereas excisional treatment can often
      result in noticeable scars. We attempted a different approach using an injection
      of absolute ethanol in five patients with recurrence due to inadequate
      cryosurgery. This therapy is less invasive than surgical excision and appears to
      be an alternative therapy for PG.

PMID- 15187333
TI  - Lipoatrophic panniculitis treated with antimalarials.

PMID- 15187334
TI  - Unexpected differentiation potential of carcinoma cells.

PMID- 15187335
TI  - Local recurrence of adult onset Spitz nevus.

PMID- 15187336
TI  - Dohi memorial lecture. Heredity and environment in dermatological diseases.

PMID- 15187337
TI  - In vivo function of desmosomes.
AB  - Desmosomes are morphologically and biochemically defined cell-cell junctions that
      are required for maintaining the mechanical integrity of skin and the heart in
      adult mammals. Furthermore, since mice with null mutations in desmosomal plaque
      proteins (plakoglobin and desmoplakin) die in utero, it is also evident that
      desmosomes are indispensable for normal embryonic development. This review
      focuses on the role of desmosomes in vivo. We will summarize the effects of
      mutations in desmosomal genes on pre- and post-embryonic development of mouse and
      man and discuss recent findings relating to the specific role of desmosomal
      cadherins in skin differentiation and homeostasis.

PMID- 15187338
TI  - Role of contact allergens in pompholyx.
AB  - Fifty patients of both sexes with clinically suspected pompholyx were patch
      tested with the Indian Standard Patch Test Battery approved by the Contact &
      Occupational Dermatosis Forum of India (CODFI). Most of these patients were young
      adults between 20-39 years of age with a mean age of 30 years. The mean duration
      of symptoms was 4 years. The occupational profile of the patients included
      students (20%), housewives (16%), housewives engaged in farming (12%), labourers
      (12%), farmers (12%) and paramedical workers (6%). The miscellaneous group,
      including salesmen, teachers and photographers, accounted for the remaining 22%.
      The clinical patterns of presentation of pompholyx included cheiropompholyx
      (60%), cheiropompholyx and podopompholyx (36%) and podopompholyx alone (4%).
      Patch test analysis of these patients revealed that, out of the 50 subjects
      tested, 20 (40%) reacted to one or more allergens. Nickel sulphate was the
      commonest offending allergen (14%) followed by potassium dichromate and phenylene
      diamine and nitrofurazone (8% each), fragrance mix (6%) and cobalt chloride (4%),
      in descending order of frequency. Hence, patch testing may be considered for all
      patients with recurrent episodes of pompholyx as allergic contact dermatitis may
      be relatively common in such patients and the avoidance of offending allergens
      may be of substantial benefit to these patients.

PMID- 15187339
TI  - Effects of tacrolimus ointment on facial eruption, itch, and scratching in
      patients with atopic dermatitis.
AB  - The action of tacrolimus ointment on pruritus in atopic dermatitis is still
      unclear. In this open study we investigated both the relationship between the
      severity of eruptions and the degree of itch and scratching in patients with
      atopic dermatitis and the effects of topical tacrolimus on these symptoms.
      Seventy adults with moderate to severe atopic dermatitis with facial eruptions
      that were recalcitrant to topical steroids applied a 0.1% tacrolimus ointment
      twice per day after discontinuation of topical steroid. The eruption scores and
      an assessment of the itch and scratching were recorded for 12 weeks. Oral
      antihistamine was prescribed at least one month before the study and continued
      unchanged during the study in each patient. The percentage reduction in the score
      of itch and scratching after two weeks (n=59) was significantly higher than in
      the score of eruption. Although there was no significant relationship between the
      severity of the eruptions and the degree of itch and scratching during steroid
      application, a relationship became significant after four weeks (n=59) of
      tacrolimus use by a one-factor ANOVA analysis. This suggests that tacrolimus
      ointment is effective for the itch and scratching in cases where degrees might be
      discrepant from the severity of eruptions in patients with recalcitrant facial
      eruptions of AD.

PMID- 15187340
TI  - Anti-inflammatory effects of tacalcitol (1,24(R)(OH)2D3, TV-02) in the skin of
      TPA-treated hairless mice.
AB  - Tacalcitol (1,24(R)(OH)2D3, TV-02) inhibited the TPA-induced inflammatory cell
      infiltration (largely neutrophils) histopathologically and myeloperoxidase (MPO)
      activity dose-dependently. Tacalcitol inhibited the mRNA expression and protein
      production of TPA-induced macrophage inflammatory protein-2 (MIP-2) and KC, the
      functional analogue of human interleukin (IL)-8, in the skin. Immunohistochemical
      staining of the TPA-applied skin revealed that mast cells expressed MIP-2,
      whereas KC was observed in keratinocytes, fibroblasts and outer root sheath of
      hair follicles. Furthermore, tacalcitol inhibited TPA-induced mast cell
      degranulation 24 hr after application without influence on the total number of
      mast cells. In this study, tacalcitol was found to have an inhibitory effect on
      cutaneous inflammation such as inhibition of neutrophil infiltration, MIP-2 and
      KC production, and mast cell degranulation in TPA-treated hairless mice. These
      results suggest that tacalcitol modulates cutaneous inflammation as well as
      keratinocyte proliferation and differentiation, and the inhibitory effect of
      tacalcitol on cutaneous inflammation may contribute to clinical the effectiveness
      in the treatment of psoriasis.

PMID- 15187341
TI  - Merkel cells in the vellus hair follicles of human facial skin: a study using
      confocal laser microscopy.
AB  - Many cases of Merkel cell carcinoma have recently been reported, and most of them
      have been localized on the facial skin. In this study, we investigated Merkel
      cells in the vellus hair follicles of facial region to characterize these cells
      in human subjects. Skin specimens doubly stained with cytokeratin (CK) 20 and
      either protein gene product (PGP) 9.5 or vasoreactive intestinal polypeptide
      (VIP) were examined by confocal laser microscopy. Many of the Merkel cells in the
      vellus hair follicles of the facial skin were localized in the bulge area. Some
      of these cells were attached to nerve terminals, although most of them were not
      associated with them. Our results suggest that there are two types of Merkel
      cells in the bulge area of the vellus hair follicles of facial skin: cells wholly
      unassociated with the nerve terminals and cells associated with thin nerve
      fibers. We postulate that the former cells may be undifferentiated (immature) and
      the latter differentiated (mature). If this is so, there is a chance that Merkel
      cell carcinoma originates from the undifferentiated Merkel cells in the bulge of
      the vellus hair with the formation of tumor masses in the dermis and no
      involvement of the epidermis. The Merkel cells connected with nerve fibers may
      secrete endocrine substances via a regulation of autonomic nerves.

PMID- 15187342
TI  - Porokeratosis of Mibelli: successful treatment with cryosurgery.
AB  - Porokeratosis of Mibelli, a disorder of keratinization, should be treated because
      of the possibility of development of malignant epithelial tumors on the
      porokeratotic lesions. Liquid nitrogen cryosurgery is considered to be
      particularly useful in the treatment of precancerous and benign skin lesions. We
      aimed to evaluate the efficiency of this method in the treatment of porokeratosis
      of Mibelli. Eight patients with 20 porokeratotic lesions were treated with spray
      cryosurgery. Each lesion was frozen for 30 seconds with a spray tip after the
      keratotic borders were removed conically by sharp dissection. Eighteen of the 20
      lesions were healed successfully with slight atrophy in one session. One more
      session was necessary for the other two lesions. Liquid nitrogen cryosurgery may
      be considered superior to other destructive methods in the treatment of
      porokeratosis of Mibelli, with advantages such as simplicity, high cure rates,
      low cost, short treatment period, and few complications.

PMID- 15187343
TI  - A case of antiepiligrin cicatricial pemphigoid with nephrotic syndrome.
AB  - We report a 71-year-old woman with antiepiligrin cicatricial pemphigoid
      associated with nephrotic syndrome. She presented with a six-month history of
      pruritic blisters over her trunk and legs. She also had episodes of recurrent
      painful oral erosions. A skin biopsy showed a subepidermal bulla, and a direct
      immunofluorescence (DIF) study revealed linear deposition of IgG and C3 at the
      basement membrane zone (BMZ). Indirect immunofluorescence (IIF) staining of 1 M
      NaCl-split skin demonstrated circulating IgG autoantibodies reactive with the
      dermal side. Immunoprecipitation studies of the patient's serum disclosed IgG
      autoantibodies directed against a set of polypeptides that corresponded to
      laminin 5 (beta 3 gamma 2). Based upon the long-standing edema of her legs and
      her hypoproteinemia, she was diagnosed with nephrotic syndrome. To our knowledge,
      the association of antiepiligrin cicatricial pemphigoid with nephrotic syndrome
      has not been reported previously.

PMID- 15187344
TI  - Two cases of subcutaneous trichoblastoma.
AB  - This report concerns two Japanese women, 54 and 53 years old, with
      trichoblastoma. Histopathologically, these neoplasms were mainly composed of
      follicular germinative cells with fibrotic stroma. One of them was a giant
      lesion, but the other was small. Because both lesions were located in the
      subcutis, we termed them subcutaneous trichoblastoma.

PMID- 15187345
TI  - A case of polypoid clear cell acanthoma on the scrotum.
AB  - A red nodule appeared on the left side of the scrotum of a 37-year-old Japanese
      man and slowly grew for four years. When he first visited us, it was 5 mm in
      diameter, polypoid shaped, and had a smooth and slightly moist surface.
      Histologically, acanthosis, parakeratosis, and dilated blood vessels were seen in
      the upper dermis. In higher magnification, the thick epidermis consisted of tumor
      cells with slightly enlarged nuclei and pale cytoplasm, and neutrophils were also
      seen among the tumor cells. The cytoplasm of the tumor cells was stained with
      periodic-acid-Schiff (PAS), and the positive reaction was digested by diastase.
      There has been no previous report of polypoid clear cell acanthoma in Japan, and
      only a few reports from the rest of the world. In addition, clear cell acanthoma
      arising on the scrotum is particularly unusual.

PMID- 15187346
TI  - Squamous cell carcinoma in untreated lichen sclerosus of the penis: a rare
      complication.
AB  - Lichen sclerosus et atrophicus (LSA) is an uncommon disease of the skin and
      mucosae of either sex. Apart from a number of complications, SCC developing from
      a lesion of LSA in males is rare, although it is well known in females. We report
      two cases recently seen by us to alert clinicians of this potentially fatal
      complication in males.

PMID- 15187347
TI  - Up-regulation of IL-6 mRNA in peripheral blood mononuclear cells of patients with
      acute urticaria.

PMID- 15187348
TI  - BsmI polymorphism of the vitamin D receptor gene in patients with the fulminant
      course of rosacea conglobata (rosacea fulminans).

PMID- 15187349
TI  - Griscelli syndrome: a rare immunodeficiency disorder with partial albinism.

PMID- 15187350
TI  - Faun tail: diagnosis of occult spinal dysraphism with a rare cutaneous marker.

PMID- 15187351
TI  - A Japanese case of typical epstein-barr virus non-associated subcutaneous
      panniculitis-like T-cell lymphoma.

PMID- 15187353
TI  - Extensive pityriasis versicolor of the face.

PMID- 15187352
TI  - Pilomatricoma-like changes in the epidermoid cysts of Gardner syndrome with an
      APC gene mutation.

PMID- 15187354
TI  - Characterization of porcine circovirus type 2 in Taiwan.
AB  - In an effort to understand the genetic diversity of porcine circovirus type 2
      (PCV2) and the prevalence of PCV2 infection in Taiwanese herds, we have sequenced
      the complete genomes from PCV2-infected specimens and individually measured the
      antibody titer against PCV2 from pigs reared in Taiwan between the years 2000 and
      2002. A total of 623 specimens originating from pigs displaying varied clinical
      signs were screened with the polymerase chain reaction (PCR). Results showed that
      309 pigs (49.6%) tested positive for PCV2. Eight of the positive specimens were
      used for the amplification of the complete viral genome. Sequence comparison of
      the complete genomes indicated that the 8 Taiwanese PCV2 isolates shared 95-99%
      similarity. Phylogenetic analysis of all 40 PCV2 isolates from North America,
      Europe, Asia and Taiwan revealed that those isolates were grouped together in one
      large group containing two minor subgroups. The Taiwanese PCV2 isolates were
      classified into the two minor subgroups. The prevalence of serum antibodies to
      PCV2 in pigs was investigated, and results showed that approximately 83.5% of the
      pigs in Taiwan were seropositive. Finishing pigs possess the highest titers of
      antibodies, while 9-week-old pigs contained the lowest titers for specific
      antibodies. Our results suggest that PCV2 infections have become common in
      Taiwanese pig farms.

PMID- 15187355
TI  - Effect of season and outdoor climate on litter size at birth in purebred landrace
      and yorkshire sows in Thailand.
AB  - The objective of the present study was to retrospectively investigate causes of
      variation on litter size at birth (total number of piglets born per litter (TB)
      and number of piglets born alive per litter (BA)) of Landrace (L) and Yorkshire
      (Y) sows in swine nucleus herds in Thailand. The data included sows farrowed
      during a four-year period from January 1998 to December 2001. The analyzed data
      set included observations on 8020 litters from 2199 L sows and 6919 litters from
      1680 Y sows. Analysis of variance (ANOVA) was applied for statistical analyses
      using General Linear Mixed Model (MIXED) procedure of SAS. No breed difference
      was found for both TB and BA. Farrowing months significantly influenced TB and BA
      (P<0.001). Sows farrowed in August and September had a lower BA than sows
      farrowed from November to June (P<0.05). Effect of farrowing months on both TB
      and BA was more pronounced in primiparous compared with multiparous sows. Average
      minimum daily temperature during gestation negatively correlated with both TB and
      BA, average maximum daily temperature during gestation negatively correlated with
      BA and average daily humidity during gestation negatively correlated with both TB
      and BA. The correlations were stronger in L than in Y sows.

PMID- 15187356
TI  - Field efficacy of recombinant R7 vaccine against chicken leucocytozoonosis.
AB  - Effectiveness of vaccine that used recombinant R7 protein (rR7) as antigen that
      is derived from second-generation schizont (2GS) of Leucocytozoon caulleryi was
      verified under a field condition against chicken leucocytozoonosis. Chickens
      reared in a poultry farm where the chickens are attacked by leucocytozoonosis in
      every year were inoculated with oil-adjuvanted rR7 vaccine (O-rR7), and the
      immunized chickens were found to have production of antibodies against 2GS at a
      high level by one shot. Leucocytozoonosis was observed at post-injection. During
      the epidemic period of leucocytozoonosis, the unique clinical signs of the
      disease such as discharge of green feces and anemia, and also parasitemia were
      observed, however, compared to chickens in control group, those in O-rR7
      vaccinated group had significantly slight symptoms (P<0.05). In addition to this,
      immunized chickens had better result of egg production than the unvaccinated
      chickens did, and the maximum difference of egg production rate, 22%, was
      observed at the peak of the disease. In conclusion, it is verified that O-rR7
      vaccine has efficacy against leucocytozoonosis under field condition, and this
      vaccine can be put into practical use.

PMID- 15187357
TI  - Radiographic evaluation of obesity-caused oppression of the thoracic cavity in
      beagles.
AB  - Thoracic radiographs of fifteen beagles with mild-to-moderate obesity revealed
      that oppression of the thoracic cavity increased with increasing degree of
      obesity. Oppression of the thoracic cavity was evaluated based on the length,
      depth, width and area of the thoracic cavity. To obtain thoracic radiographs at
      the terminal inspiration and expiration phases, thoracic fluororadiographs were
      recorded with a digital video camera. Bodyweight and the depth of the back fat
      layer at the seventh lumbar vertebra (DB, measured by ultrasonography) were used
      as indicators of the degree of obesity. The length of the thoracic cavity tended
      to become shorter and the depth and width of the thoracic cavity tended to
      increase as bodyweight increased and as DB increased. On the other hand, the area
      of the thoracic cavity was not clearly related to bodyweight or DB. These results
      suggest that oppression of the thoracic cavity due to the cranial shift of the
      diaphragm is compensated for by increases in the depth and width of the thoracic
      cavity in beagles with mild-to-moderate obesity.

PMID- 15187358
TI  - Disappearance of the PHA-E lectin binding site on the surface of ejaculated sperm
      and sperm capacitation in the dog.
AB  - Ejaculated semen and cross sections of the cauda epididymides collected from 3
      normal dogs were smeared or stamped on glass slides, and the sperm on the slides
      were stained with 7 different FITC-lectins (Con A, DBA, GS-1, PHA-E, PSA, UEA-1,
      WGA) to examine the relation between sperm-binding glycoprotein derived from the
      canine prostate and sperm capacitation. The only lectin that stained the
      ejaculated sperm but not the cauda epididymal sperm was PHA-E. The sperm
      ejaculated by 5 other dogs were incubated for 4 hr in fluid flushed from the
      uterine horns or oviducts of estrous bitches, and then the percentages of
      actively motile sperm and hyperactivated sperm (HA-sperm) were determined. The
      percentages of PHA-E-labeled sperm and sperm labeled with fluoresceinated Ca
      indicator to assess the influx of Ca into the sperm were also evaluated. The mean
      percentages of actively motile sperm, HA-sperm, and Ca-labeled sperm after 4 hr
      of incubation in the uterine flush fluid and oviductal flush fluid were
      significantly higher than in control medium (P<0.05, 0.01), but the mean
      percentages of PHA-E-labeled sperm were lower (both P<0.01). The percentages of
      PHA-E-unlabeled sperm correlated with the percentages of both HA-sperm and Ca
      labeled sperm (r(2)=0.787 and 0.812, respectively). The results indicate that
      loss of the glycoprotein secreted by the canine prostate on the sperm surface
      induces the influx of Ca into the sperm, and then hyperactivation of the sperm.

PMID- 15187359
TI  - The effect of tiletamine/zolazepam (Zoletile) combination with xylazine or
      medetomidine on electroencephalograms in dogs.
AB  - The effects of xylazine or medetomidine on tiletamine/zolazepam (Zoletile)
      anesthesia were evaluated by changes in the canine electroencephalogram (EEG).
      Experimental groups were three: the group treated with 10 mg/kg of Zoletile
      intravenously (TZ), the group treated with 1.1 mg/kg of xylazine intramuscularly
      and 10 mg/kg of Zoletile intravenously (XTZ), and the group treated with 30
      microg/kg of medetomidine intramuscularly and 10 mg/kg of Zoletile intravenously
      (MTZ). EEG recording electrode was positioned at Cz, which was applied to
      International 10-20 system. For all recording times, the powers of each band
      (band 1: 1-2.5 Hz, band 2: 2.5-4.5 Hz, band 3: 4.5-8 Hz, band 4: 8-13 Hz, band 5:
      13-20 Hz, band 6: 20-30 Hz, band 7: 30-50 Hz, band 8: 1-50 Hz) were calculated.
      In TZ, at 10 min after Zoletile injection, the powers of bands 3, 4, 5 and 8
      significantly decreased. At 20 min after Zoletile injection, the powers of band 1
      and 8 were significantly decreased. After Zoletile injection, there were
      significant decreases in bands 1, 4, 5, 6, 7 and 8 in XTZ, and in bands 1, 3, 4,
      5, 6, 7 and 8 in MTZ. These significant changes disappeared in all band powers in
      TZ and MTZ in the last 1 min just prior to the dogs showing head-up movement.
      But, in XTZ, all band powers, except band 2, were significantly reduced. EEG
      power spectral analysis revealed the differences in band powers on awakening,
      even though the same kind of drugs were used. We thought that was a useful method
      to compare the effect of xylazine and medetomidine on Zoletile-induced anesthesia
      in dogs.

PMID- 15187360
TI  - A novel repeated sequence located on the bovine Y chromosome: its application to
      rapid and precise embryo sexing by PCR.
AB  - A novel repeated sequence specific to male cattle was identified and named S4. S4
      is a highly repetitive sequence and is a 1.5 kb repeating unit that contains
      various internal repeated sequences. FISH analysis showed that S4 is localized on
      the whole long arm and the proximal region of the short arm of the Y chromosome.
      We found that a PCR primer set for S4 amplified a male-specific 178 bp product in
      addition to a 145 bp product common to both male and female cells. Although the
      origin of the 145 bp product is unknown, it acts as a positive internal control
      in practical embryo sexing. Due to the high copy number of S4, PCR required only
      0.5 pg purified DNA for accurate amplification. This made it possible to reduce
      the amount of biopsy sample required for embryo sexing and thus result in less
      damage to embryos manipulated. These studies indicate that embryo sexing based on
      the S4 sequence is accurate and sensitive.

PMID- 15187361
TI  - Effect of tissue deterioration on postmortem BSE diagnosis by immunobiochemical
      detection of an abnormal isoform of prion protein.
AB  - Surveillance for bovine spongiform encephalopathy (BSE) in fallen stock in Japan
      is conducted with a commercial enzyme-linked immunosorbent assay (ELISA) for mass
      screening, with Western blotting (WB) and immunohistochemistry performed for
      confirmation of the ELISA. All tests are based on immunological detection of an
      abnormal isoform of the prion protein (PrP(Sc)) in brain tissues, which have
      sometimes deteriorated by the time samples from fallen stock reach a diagnostic
      laboratory. To evaluate BSE surveillance procedures for fallen stock, we examined
      PrP(Sc) detection from artificially deteriorated BSE-affected bovine brain
      tissues with a commercial ELISA kit and compared the results with those of WB.
      The optical density (OD) values of the ELISA decreased with advancing
      deterioration of the tissues, whereas no reduction in the signal for PrP(Sc) was
      observed in WB, even when performed after 4 days of incubation at 37 degrees C.
      The progressive decrease in the OD values in the ELISA appear to be caused by a
      partial loss of the N-terminal moiety of PrP(Sc) due to digestion by endogeneous
      and/or contaminated microbial enzymes, and by the presence of ELISA inhibitors
      that are generated in deteriorated tissues. These results suggest that WB is the
      most reliable test for fallen stock, especially for cattle brains within decaying
      carcasses.

PMID- 15187362
TI  - Preconditioning prevents ischemia-induced neuronal death through persistent Akt
      activation in the penumbra region of the rat brain.
AB  - A brief period of ischemia, i.e. preconditioning of the middle cerebral artery
      territory, induces ischemic tolerance reducing the cerebral infarction volume
      caused by subsequent lethal ischemia. Nevertheless, little is known about the
      molecular mechanisms underlying this phenomenon. In the present study, we
      examined the involvement of the activation of Akt, a serine/threonine kinase, in
      the cerebral ischemic tolerance. Western blot analysis showed that Akt was
      activated in both non-preconditioned and preconditioned groups after ischemia for
      1 hr, but the activation was long-lasting in the preconditioned rats.
      Immunohistochemical analysis demonstrated that the preconditioning-induced
      preventive effect on a rapid decrease in the activation level of Akt was due to
      the persistent activation of Akt in the penumbra region. In addition, TUNEL
      staining demonstrated that the preconditioning treatment inhibited the
      augmentation of neuronal death probably through apoptosis in the penumbra region
      to prevent the spread of infarction. Since the activation of Akt has been
      reported to protect cells from stress, the present results suggest that the
      preconditioning-induced persistent activation of Akt in the penumbra region plays
      an important role in ischemic tolerance of the brain.

PMID- 15187363
TI  - Use of herpesvirus papio 2 as an alternative antigen in immunoblotting assay for
      B virus diagnosis.
AB  - Herpesvirus papio 2 (HVP2), which infects baboons, is much more closely related
      genetically and antigenically to monkey B virus (BV) than to human herpes simplex
      virus 1(HSV1) and other related herpes viruses. The usefulness of HVP2 as an
      alternative test antigen in immunoblotting assays to detect BV-antibody in
      macaque monkey sera was assessed. Six HVP2 proteins reacted with BV-positive sera
      in immunoblotting. No specific bands could be detected with BV-negative sera.
      These results show the usefulness of HVP2 antigen as an alternative and safer
      antigen than authentic BV antigen in detecting BV antibody in immunoblotting.

PMID- 15187364
TI  - Postweaning multisystemic wasting syndrome (PMWS) in the Philippines: porcine
      circovirus type 2 (PCV2) detection and characterization.
AB  - Four swine facilities located in Northern Luzon, in the Philippines, showed
      lesions and clinical signs similar to those described in post weaning
      multisystemic wasting syndrome (PMWS). Post-mortem and histopathological
      examination revealed the presence of typical lymphoid lesions caused by porcine
      circovirus type 2 (PCV2). An in situ hybridization (ISH) technique allowed the
      detection of PCV2 nucleic acid associated with the lesions in target tissues.
      PCV2 DNA from paraffin embedded tissues was extracted, purified and sequenced.
      The phylogenetic analysis of the sequences obtained confirmed their identity, and
      grouped them into a PCV2 subgroup, together with some Canadian, French and Dutch
      isolates. This report is the first description of the presence of PMWS in the
      Philippines.

PMID- 15187365
TI  - Immunohistochemical localization of endothelial and inducible nitric oxide
      synthase within neurons of cattle with rabies.
AB  - The expression of constitutive endothelial nitric oxide synthase (eNOS) and
      inducible NOS (iNOS) in the brains of cattle with natural rabies was studied.
      Increased expression of eNOS was detected in neurons of the brain stem and
      Purkinje cells of cerebellum. By contrast, iNOS was diffusely localized in the
      cytoplasm of affected neurons, and some inflammatory cells were positive. eNOS
      and rabies antigen were co-localized in inclusion bodies (Negri bodies) in
      neurons. The specific localization of eNOS, but not iNOS, in the Negri bodies
      suggests that eNOS is involved in the formation of rabies virus inclusion bodies.

PMID- 15187367
TI  - Survey of porcine proliferative enteritis in the Tohoku District of Japan.
AB  - A survey of proliferative enteritis (PE) in pigs at a meat processing plant was
      conducted using polymerase chain reaction (PCR) testing methods. During the
      investigation period, 227 of 83,717 pigs brought to the meat processing plant
      from Iwate, Fukushima, Miyagi, Niigata, and Yamagata Prefectures displayed
      characteristic general pathological features in terminal ileum, including mucosal
      hypertrophy and reticulation of serosal surface. Of these, 179 cases were further
      examined in the laboratory. All cases displayed characteristic histopathological
      features, and the specific band of the Lawsonia intracellularis (Li) causative
      agent of PE in pigs was detected in 155 cases by PCR testing methods. These
      results suggested a general infiltration of Li in the Tohoku district.

PMID- 15187366
TI  - Comparison of microfilaria concentration method for Setaria digitata infection in
      cattle and for Dirofilaria immitis infection in dogs.
AB  - Several peripheral blood microfilaria concentration methods that use Acetone
      (Acetone test), 2% formalin (modified Knott method), 5% Tween 20 solution,
      distilled water, 1% or 0.1% SDS were compared for their efficacy in detecting
      Setaria digitata microfilaria in cattle. The Acetone test was found to be more
      efficacious than the modified Knott method or the 5% Tween 20 solution test for
      detecting the S. digitata microfilaria in bovine blood. However, besides the
      Acetone test, the modified Knott method was also found to be suitable for
      Dirofilaria immitis microfilaria detection in dogs. SDS and distilled water were
      found not to be effective as hemolytic agent for the disruption of the red blood
      cell of both the cattle and dogs. Thus, the Acetone test is recommended for the
      primary screening of microfilaremia of S. digitata in cattle.

PMID- 15187368
TI  - A case of nutritional secondary hyperparathyroidism in a Siberian tiger cub.
AB  - A three-month-old female Siberian tiger cub with hindlimb ataxia was referred to
      the veterinary teaching hospital of Konkuk University. The patient was fed only
      beef without supplementation of calcium and vitamins after weaning. The tiger was
      presented with ataxia and back pain on digital palpation. In addition, abnormal
      gait, reluctance to move, and depressed withdrawal reflex were noted at the
      neurological examination. The overall osteodystrophic change of the lumbosacral
      vertebrae was observed on the lateral and ventrodorsal view of radiographic
      examination. And also PTH level was increased in hormonal assay when compared to
      that of cat reference range. Based on the results of examinations, nutritional
      secondary hyperparathyroidism was diagnosed. Clinical signs of this patient were
      improved after administration of vitamin D and calcium. This case demonstrates
      that nutritional hyperparathyroidism could be occurred in wild animals raised on
      a meat diet containing imbalanced calcium and phosphate.

PMID- 15187369
TI  - Complete nucleotide sequences of S1 and N genes of infectious bronchitis virus
      isolated in Japan and Taiwan.
AB  - The complete nucleotide sequences of the S1 and N genes of three Japanese and one
      Taiwanese field strains of IBV are reported. These Japanese strains were found to
      have S1 sequences most similar to those of Australian strains and N sequences
      most similar to those of North American strains. This result suggested that these
      Japanese strains might all be recombinant viruses derived from recombination of
      Australia- and North America-related viruses. Moreover, the S1 proteins of all
      these Japanese and Taiwanese strains exhibit only a limited sequence homology to
      strains of Massachusetts and Connecticut serotypes that have been commonly used
      as vaccine strains. This result high lightens the importance of development of
      vaccines based on the local strains of IBV.

PMID- 15187370
TI  - Surgical correction of subvalvular aortic stenosis using cardiopulmonary bypass
      in a dog.
AB  - A three-month-old male Golden Retriever had symptoms including exercise
      intolerance, dyspnea and syncope and was diagnosed with subvalvular aortic
      stenosis. Cardiac catheterization revealed a left ventricular-aortic systolic
      pressure gradient of 90 mm Hg. Surgical correction of the condition was achieved
      using cardiopulmonary bypass. The subvalvular fibrous lesion was resected through
      an aortotomy. The stenosis was dilated from 8.5 mm to 12.0 mm in diameter.
      Postoperatively the dog was asymptomatic. Seven months after surgery, the
      pressure gradient decreased to 44 mm Hg. However, after another three months, the
      dog died suddenly without any premonitory signs. Postmortem examination revealed
      that pathologic changes caused by increased left ventricular pressure overload
      were not severe.

PMID- 15187371
TI  - Characterization of canine caspase-3.
AB  - The canine caspase-3 gene was cloned and sequenced. The canine caspase-3 cDNA
      clone was 1473 base pairs in length and encoded 277 amino acids. The predicted
      amino acid sequence showed 88.4%, 88.0%, 85.9%, 65.9% and 60.6% homology with
      that of human, pig, mouse, chicken and zebra fish caspase-3, respectively. The
      caspase-3 mRNA was confirmed to express in skin, lymph node, bone marrow, small
      intestine and lung from a healthy dog by RT-PCR analysis.

PMID- 15187372
TI  - Immunohistochemical detection of growth hormone (GH) in canine hepatoid gland
      tumors.
AB  - The aim of this study was to detect immunohistochemically means growth hormone
      (GH) in 24 hepatoid gland adenomas and 5 hepatoid gland carcinomas and to compare
      the difference of immunoreactivity between types of tumors. The tumors were
      classified according to the WHO standards. Tissue sections which were prepared
      from formalin-fixed, paraffin wax-embedded tissues from 25 male and 4 female dogs
      were carried out immunostaining using polyclonal primary anti-hGH and EnVision
      method. Of 24 hepatoid gland adenomas (perianal gland adenomas) 23 (95.8%) were
      positive. All 5 hepatoid gland carcinomas (perianal gland carcinomas) were
      positive. No statistically significant differences in percentage of labelled
      cells between malignant and benign tumors were seen. The present demonstration of
      GH in hepatoid gland tumors adds new data on GH in extra-pituitary tissues and
      hormon-dependent tumors.

PMID- 15187373
TI  - The incidence of disseminated intravascular coagulation in dogs with malignant
      tumor.
AB  - The incidence of DIC in 208 dogs with a malignant tumor was evaluated. The
      incidence of DIC was 9.6% in dogs with a malignant tumor which was a solid tumor
      in all. In 164 dogs with a malignant solid tumor, the incidence of DIC was 12.2%.
      The incidence of DIC in dogs with hemangiosarcoma, mammary gland carcinoma and
      adenocarcinoma of the lung was significantly higher than that in dogs with other
      malignant tumors. These results suggested that special care in looking for DIC
      should be taken in dogs with a malignant solid tumor.

PMID- 15187374
TI  - Endoscopic findings on alimentary lymphoma in 7 dogs.
AB  - Alimentary lymphoma was evaluated endoscopically in 7 dogs and a
      histopathological examination was made to detect the origin of neoplastic
      lymphocytes in 5 dogs. A solitary mass in the rectum (1 case), irregular
      cobblestone appearance in the duodenum (4 cases) and a moderate irregular
      appearance resembling lymphocytic-plasmacytic enteritis (2 cases) were
      endoscopically detected. Endoscopic ultrasonography demonstrated increased
      thickness of the duodenal wall in 2 cases examined. Neoplastic lymphocytes of
      alimentary lymphoma proved to originate in T cells in all 5 cases examined by
      immunohistochemical analysis.

PMID- 15187375
TI  - Molecular typing of enterotoxigenic Staphylococcus aureus isolated from bovine
      mastitis in Korea.
AB  - One hundred and sixty-six Staphylococcus aureus isolates from mastitic milk
      samples from different cows on 26 farms were investigated for staphylococcal
      enterotoxins(SEs) and toxic shock syndrome toxin-1(TSST-1) by polymerase chain
      reaction(PCR) and reverse passive latex agglutination assay(RPLA). SEs and the
      TSST-1 gene were detected in thirty-seven isolates based on a multiplex PCR; SEA
      was detected in 32 isolates, SEB in 3 isolates, SEC in 1 isolate, and SEA and the
      TSST-1 gene in 1 isolate. Of the 37 enterotoxigenic isolates, thirty-three
      isolates were enterotoxigenic according to RPLA, where 29 isolates produced SEA,
      3 isolates produced SEB, and 1 isolate produced SEC. The enterotoxin-producing S.
      aureus isolates were further characterized by pulsed-field gel
      electrophoresis(PFGE). A macrorestriction analysis revealed 11 PFGE patterns.
      Among the 33 enterotoxigenic S. aureus isolates, 45.4% exhibited the same PFGE
      pattern I. Accordingly, although the enterotoxin-producing S. aureus isolates
      from bovine mastitis were genetically diverse, 1 common genotype prevailed on the
      farms, indicating that PFGE pattern I isolates may be the most disseminated in
      Korea.

PMID- 15187376
TI  - High prevalence of enterohemorrhagic Escherichia coli (EHEC) O157 from cattle in
      selected regions of Japan.
AB  - The prevalence of enterohemorrhagic Escherichia coli (EHEC) O157 was examined in
      bovine faeces. EHEC O157 was isolated from the faeces of 42 (13.0%) of 324
      cattle. Of the 4 farms and the facilities tested, the 3 farms and the facilities
      were found positive for EHEC O157. The highest isolation rate among the farms was
      33.7%. The prevalence of EHEC O157 in heifers was higher than that in calves and
      other cattle. No cattle positive for EHEC O157 showed any clinical signs except 2
      calves with diarrhea in a veterinary hospital. Almost all isolates possessed the
      stx gene, and Stx-positive strains carrying both stx(1) and stx(2) genes were
      predominant. These results indicate that EHEC O157 are distributed in bovine
      faeces, and that dairy and beef farms in selected regions of Japan are heavily
      contaminated with the organisms.

PMID- 15187377
TI  - Brachyspira pilosicoli isolated from two beagles and one mongrel in Japan.
AB  - The feces, colonic contents, and colonic mucosa from two beagles and a mongrel
      with and without mucohemorrhagic diarrhea were anaerobically cultured and after
      72 hr, lucent and rough colonies with weak beta-hemolysis were observed. Small
      spirochetes with one or two loose waves in the colonies were observed under a
      phase contrast microscope and the spirochete cells sometimes aggregated. The
      16SrDNA sequencing results demonstrated that the canine isolates were B.
      pilosicoli and the base alignments registered in DDBJ. This is the first report
      concerning the isolation of B. pilosicoli from dogs in Japan.

PMID- 15187378
TI  - A case report of canine protothecosis.
AB  - A 10-year-old spayed mongrel dog was referred with repeated intercurrent
      hematochezia and anal bleeding. The dog was vigorous and had a normal appetite,
      and the fecal test showed no abnormal signs. Despite treatment primarily with
      sulfasalazine, the condition did not improve and unilateral blindness developed.
      A Prototheca zopfii infection was identified by further examination with bowel
      culture on Sabouraud's agar without cyclohexane and antibiotics. Subsequent to a
      vision loss in the other eye, the dog died showing signs of neurological
      disorder.

PMID- 15187379
TI  - Effect of post-prandial posture on orocecal transit time and digestion of milk
      lactose in humans.
AB  - We examined the effect of post-prandial body posture on orocecal transit time and
      absorption of milk lactose using the breath hydrogen test. In this experiment,
      subjects ingested a cup of commercially available milk to which we had added a
      small amount of lactosucrose (an indigestible trisaccharide), and then they lay
      on their backs or sat on a chair for the first 4 hr (from 08:00 to 12:00). After
      four hours lying or sitting, they remained sedentary on a sofa for the second six
      hr (from 12:00 to 18:00). Participants' end alveolar breath samples were
      collected every 15 min from 08:00 to 12:30, then every 30 min from 13:00 to
      18:00. The experiment was conducted on two consecutive days using a randomized,
      crossover study design. Examination showed that the orocecal transit time of the
      oligosaccharides (lactosucrose and milk lactose) under the post-prandial supine
      condition was significantly longer than that under the sitting condition. In
      addition, the amount of breath hydrogen excretion under the supine condition was
      significantly lower than under the sitting condition, indicating that the
      unabsorbed milk lactose moved into cecum under the supine condition is smaller
      than that under the sitting condition. These findings provide evidence that
      postprandial supine posture works more beneficially to digest and absorb milk
      lactose when compared to the sitting posture.

PMID- 15187380
TI  - Interactive effects of task difficulty and personality on mood and heart rate
      variability.
AB  - Susceptibility to stress would presumably be different from person to person and
      be affected by the cause of the given stress. The purpose of this study was to
      investigate the interactive effects of task difficulty and subject's personality
      on mood and autonomic nervous function when stress was induced experimentally by
      tasks involving 3 degrees of difficulty: easy (Task A), difficult but
      controllable (Task B), and very difficult and uncontrollable (Task C). Twelve
      healthy female subjects volunteered for the experiment. We assessed their
      personalities using the Minnesota Multiphasic Personality Inventory (MMPI)
      questionnaire. Mood states were evaluated by a profile of mood states and a
      frontal alpha laterality ratio (FALR). Autonomic nervous function was estimated
      by a spectral analysis of heart rate variability (HRV). Repeated measures
      analysis of variance applied to two groups (low- and high-) divided by a median
      split of MMPI clinical scales, revealed significant interactions of time course x
      task difficulty x Hs (hypochondriasis) in FALR and time course x task difficulty
      x Pt (psychasthenia) in a low-frequency component and in a high-frequency
      component of HRV, and in FALR. The differences between low- and high-Hs, and low-
      and high-Pt were more obvious in Task B session. High-Hs group, whose members
      tend to place overemphasis on existing physical disorders, showed more negative
      FALR throughout the session, which would indicate prolonged negative mood
      possibly due to the task. High-Pt group, whose members tend to be susceptible to
      stress, showed sympathetic predominance during task period and parasympathetic
      predominance after task period, which would imply a tendency to overreact. These
      results suggest that task difficulties would affect mood states assessed by FALR
      and/or autonomic nervous function differently depending on the subject's
      personality, especially on Hs and Pt.

PMID- 15187381
TI  - Percentage of total body fat as estimated by three automatic bioelectrical
      impedance analyzers.
AB  - The present study aimed to compare the accuracy of estimating the percentage of
      total body fat (%TBF) among three bioelectrical impedance analysis (BIA) devices:
      a single-frequency BIA with four tactile electrodes (SF-BIA4), a single-frequency
      BIA with eight tactile electrodes (SF-BIA8) and a multi-frequency BIA with eight
      tactile electrodes (MF-BIA8). Dual-energy x-ray absorptiometry (DXA) and
      hydrostatic weighing (HW) were used as references for the measured values. Forty
      five healthy college student volunteers (21 males: 172.9 +/- 5.5 cm and 65.8 +/-
      9.1 kg and 24 females: 160.7 +/- 6.6 cm, 52.6 +/- 6.2 kg) were the subjects.
      Correlation coefficients between the BIA measurements and the references were
      calculated. The standard error of estimation (SEE) was calculated by regression
      analysis when estimating the reference measures (DXA and HW) from the predictor
      (SF-BIA4, SF-BIA8 and MF-BIA8). The differences in %TBF between the reference and
      the predictor, calculated by the reference minus the predictor, were plotted
      against the %TBF measured by the references. The MF-BIA 8 here showed the highest
      correspondence to the reference and the least estimation error compared with the
      other BIA methods. It is considered that there is a limit to directly estimate
      FFM from a regression equation using impedance, weight, height and age as
      independent variables, and that %TBF can be more accurately estimated by
      measuring segmental impedances using eight electrodes and multi-frequency
      electric currents and then estimating total body water from these impedances.

PMID- 15187383
TI  - Four new steroid constituents from the waste residue of fibre separation from
      Agave americana leaves.
AB  - Three new steroidal saponins, named agamenosides H-J (1-3), and a new cholestane
      steroid agavegenin D (4) were isolated from the waste residue of fibre separation
      from Agave americana leaves, together with six known steroids. Structures of the
      new compounds 1-4 were deduced to be (22S,23S,24R,25S)-24-[(beta-D
      glucopyranosyl)oxy]-5alpha-spirostane-3beta,6alpha,23-triol 6-O-beta-D
      glucopyranoside (1), (22S,23S,24R,25S)-5alpha-spirostane-3beta,23,24-triol 24-O
      beta-D-glucopyranoside (2), (22S,23S,25R,26S)-23,26-epoxy-5alpha-furostane
      3beta,22,26-triol 26-O-beta-D-glucopyranoside (3), and (22S,25S)-5alpha
      cholestane-3beta,16beta,22,26-tetrol (4), respectively, by means of spectroscopic
      analysis, including extensive 1D and 2D NMR data, and the results of hydrolytic
      cleavage.

PMID- 15187382
TI  - Some physical properties of tabletted seed of Garcinia kola (HECKEL).
AB  - The formulation of Garcinia kola seeds into tablet dosage form and evaluation of
      some physical properties of the tablets are presented. A chemical assay was
      conducted on the dry, powdered seeds as well as the crude aqueous extract of the
      seeds. The dry powdered seeds contain 0.003% of flavonoids while the crude
      extract contained 0.007% of flavonoids based on rutin used as the standard. The
      powdered material (50 mg) and crude extract (10 mg) were formulated into tablets
      using the wet granulation method. Named binders were evaluated in these
      formulations. The various tablet parameters were evaluated, namely: weight
      variation, thickness and diameter, hardness, friability, disintegration time,
      dissolution profile and content uniformity. The results indicated that the
      tablets had good disintegration time, dissolution and hardness/friability
      profiles. Tablets formulated with starch had the best disintegration properties
      but were consequently very friable. Tablets formulated from 10 mg of the crude
      extract needed a larger proportion of diluents, which affected the tablet
      properties.

PMID- 15187384
TI  - A photochemical approach to pyridopyrroloquinoline derivatives as new potential
      anticancer agents.
AB  - Indoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine
      are of great interest because in vitro and in vivo studies revealed their good
      cytotoxic properties. In order to obtain some biologically active analogs of
      these compounds, we developped a synthesis based on the photocyclisation of
      tertiary N-methylated enaminones derived from cyclopentane-1,3-dione and 3 or 6
      aminoquinoline. The angular cyclised compounds thus obtained were submitted to
      Beckmann rearrangement, preceded by the formation of a Z oxime. Finally, the
      delta-lactame ring was oxidized using 10% palladium/carbon in diphenylether and
      pyridopyrroloquinolines were obtained. These compounds and the intermediate
      lactams and cyclopentanopyrroloquinolines were tested in vitro on K 562 cells and
      A 2780 doxorubicine sensitive and resistant cells. All compounds were less
      effective than doxorubicine in sensitive cells but their activity wasn't
      decreased by MDR resistance.

PMID- 15187385
TI  - Syntheses of 10-oxo, 10 alpha-hydroxy, and 10 beta-hydroxy derivatives of a
      potent kappa-opioid receptor agonist, TRK-820.
AB  - Syntheses of 10-oxo, 10alpha-hydroxy, and 10beta-hydroxy derivatives of a potent
      kappa-opioid receptor selective agonist, TRK-820, are described. These
      derivatives were supposed to be potential degradation products in formulation of
      TRK-820 as a result of autoxidation. 10-Oxo-TRK-820 11 was derived from 10-oxo
      4,5-epoxymorphinan 14 in 10 steps in 32% overall yield. Reduction of the 10-oxo
      group in 4,5-epoxymorphinan with NaBH(4) gave 10beta-hydroxy-4,5-epoxymorphinan,
      exclusively. A stepwise inversion method of the 10beta-hydroxy group to produce
      10alpha-hydroxy-4,5-epoxymorphinan was established. By HPLC analyses, 10alpha
      hydroxy-TRK-820 12 was confirmed to be one of the degradation products in
      developing formulation of TRK-820.

PMID- 15187386
TI  - Syntheses of potential metabolites of a potent kappa-opioid receptor agonist, TRK
      820.
AB  - Chemical syntheses of three kinds of potential metabolites of TRK-820, a potent
      kappa-opioid receptor agonist, were described. One of the potential metabolites
      2, 17-N-dealkylated TRK-820, was synthesized starting from noroxycodone through 8
      steps in 21% total yield. Glucuronidation of intermediate 10 and compound 1, the
      free base of TRK-820, was carried out stereoselectively to give 3-O-beta-D
      glucuronides 15 and 16 in good yields, respectively. Syntheses of potential
      conjugated metabolites 3 and 4 were accomplished through 10 steps and 2 steps in
      11% and 43% total yields, respectively. Among the potential metabolites of TRK
      820, compounds 2 and 4 were identified as metabolites in human hepatocytes. The
      results of pharmacological studies of compounds 2, 3, and 4 are described.

PMID- 15187387
TI  - Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine
      as orally-active adhesion molecule inhibitors.
AB  - Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3
      b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on
      the upregulation of adhesion molecules such as intercellular adhesion molecule-1
      (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of
      previously prepared derivatives with a carboxylic acid-containing moiety resulted
      in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H
      pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic
      acid 2q (ER-49890), showed the most potent oral inhibitory activities against
      neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model
      using mice, and leukocyte accumulation in a carrageenan pleurisy model in the
      rat, and therapeutic effect on collagen-induced arthritis in rats.

PMID- 15187388
TI  - Quantitative determination of bitter principles in specimens of Ganoderma lucidum
      using high-performance liquid chromatography and its application to the
      evaluation of ganoderma products.
AB  - For quantitative determination of 19 triterpene constituents, including six
      ganoderma alcohols (1-6) and 13 ganoderma acids (7-19), in the products of
      Ganoderma lucidum, an analytical system was developed using high-performance
      liquid chromatography with an ODS column. The mobile phase was a linear gradient
      of 1% AcOH/H(2)O-CH(3)CN and 2% AcOH/H(2)O-CH(3)CN, and the elution profile was
      monitored at 243 and 250 nm for ganoderma alcohols and acids, respectively. The
      relative standard deviations of this method were less than 2.35% and 2.18% (n=5)
      for intraday and interday assays, and the recoveries were 90.9-100.8% and 93.4
      103.9% for constituents of alcohol and acid groups, respectively. This system was
      applied to a quantitative determination of the constituents in 10 different
      products of G. lucidum: six usual umbrella forms of the fruiting bodies, three
      antlered forms of the fruiting bodies and spores, and eight specimens from the
      same G. lucidum strain, which was parasitized on logs from different plants or
      different fungus beds. The analytical results indicated that the quantity and
      composition of these triterpenes differed appreciably among various specimens,
      but the relative ratio of the alcohols and acids was not significantly different
      when the same strain of G. lucidum was used.

PMID- 15187389
TI  - Reactive oxygen species (ROS) generation inhibited by aporphine and phenanthrene
      alkaloids semi-synthesized from natural boldine.
AB  - Four phenanthrene and one aporphine alkaloids semi-synthesized from boldine were
      evaluated for their inhibitory effect on reactive oxygen species (ROS)
      generation. ROS generation by neutrophils stimulated with N-formyl-methionyl
      leucyl-phenylalanine was inhibited in a concentration dependent manner. Alkaloids
      exerted similar inhibitory effect in the hypoxanthine-xanthine oxidase system
      than in stimulated neutrophils, which could be attributed to a direct ROS
      scavenging activity. None of the alkaloids assayed had any effect on xanthine
      oxidase activity. Therefore the synthesized alkaloids might constitute an
      alternative therapy in inflammation disorders in which ROS generation is
      involved.

PMID- 15187390
TI  - A novel fluorescent probe for zinc ion based on boron dipyrromethene (BODIPY)
      chromophore.
AB  - ZnAB has the combined structure of N,N-bis(2-pyridylmethyl)ethylenediamine as a
      specific chelater for Zn(2+) and 1,3,5,7-tetramethyl-8-phenyl-boron
      dipyrromethene as a fluorophore. Complexation of ZnAB with Zn(2+) produces a
      remarkable enhancement of fluorescence intensity. ZnAB has the advantages of less
      sensitivity to solvent polarity and pH than fluorescein-based Zn(2+) probes.
      Furthermore, it is not influenced by other cations, such as Na(+), K(+), Ca(2+),
      and Mg(2+), which exist at high concentrations under physiological conditions,
      even at 2.5 mM. The results show that ZnAB is a Zn(2+) probe suitable for
      biological applications.

PMID- 15187391
TI  - A new method for disintegration studies of rapid disintegrating tablet.
AB  - The aim of this study was to develop a simple and suitable disintegration method
      specific for rapid disintegrating tablets (RDTs). The new disintegration method
      that we propose employs a rotary shaft to exert mechanical pressure on the RDT.
      To assess our method, we manufactured several placebo RDTs and exposed them to
      severe storage conditions (60 degrees C/75%RH for 1 week) in order to obtain RDTs
      with a wide range of disintegration times. These placebo RDTs were utilized to
      compare the disintegration times obtained by several methods, including the
      proposed method. As expected, the disintegration time of the placebo RDTs in
      human sensory test varied widely. The disintegration times determined by the
      conventional disintegration test were in good correlation to those in human
      sensory test, but the slope was far from 1 (0.241). There was no correlation
      between the disintegration time of RDTs in human sensory test and those
      determined by the conventional dissolution test. In contrast, we acquired good
      correlation between the disintegration times obtained with the new method and
      those in human sensory test, and the slope was very close to 1 (0.858). We
      attribute this to the use of mechanical stress in the new method, similar to that
      the RDT is subject to in the oral cavity. We therefore concluded that the
      proposed method was suitable for the measurement of the disintegration time of
      RDTs. This new method might provide a valuable approach for the establishment of
      the official disintegration test for RDTs in the future.

PMID- 15187392
TI  - Structure and ethanol complexation of cyclic tetrasaccharide in aqueous solution
      studied by NMR and molecular mechanics.
AB  - The structure and ethanol complexation of a cyclic tetrasaccharide (CTS) in
      aqueous solution were investigated by proton NMR spectroscopy and molecular
      mechanics calculations. Two glucose units, A and B, of CTS are alternatively
      bonded by alpha-1,3 and alpha-1,6 linkages. The overlapped signals of protons A5,
      A6S, A6R, B3, B6S and B6R were resolved by spectral simulations to determine
      their chemical shifts and vicinal coupling constants. All vicinal coupling
      constants except for the A5-A6 spin system are consistent with the dihedral
      angles in the X-ray crystal structure. Each of protons A5, A6S, and A6R in the
      two units of A is equivalent with respect to the chemical shift. The vicinal
      coupling constants of (3)J(5-6S) and (3)J(5-6R) for unit A are close to the
      average of two rotamers that are present in crystals. The intensities of cross
      peaks in the rotating frame nuclear Overhauser effect spectroscopy (ROESY)
      spectrum were rather well correlated with the effective distances calculated for
      the X-ray structure and molecular mechanics structures calculated in vacuo and
      water, although they are slightly better correlated with molecular mechanics
      structure in vacuo than with the other structures. From the changes of the
      chemical shifts of several CTS protons with increasing ethanol concentration, it
      was suggested that adsorption sites of ethanol on the plate structure of CTS are
      protons B2 and B4 (site B) in the concave face side and protons A1 and A2 (site
      A) in the convex back side. The binding constants for sites A and B are 0.0061
      and 0.0176 M(-1), respectively. These binding constants are much smaller than a
      value of 4.1 M(-1) for the ethanol-alpha-cyclodextrin complex.

PMID- 15187393
TI  - Phenolic glycosides from Pyrola japonica.
AB  - Five new phenolic glycosides, 2-beta-D-glucopyranosyloxy-5-hydroxyphenylacetic
      acid methyl ester (4), 4-hydroxy-2-[3-hydroxy-3-methylbutyl]-5-methylphenyl beta
      D-glucopyranoside (5), 4-hydroxy-2-[(E)-4-hydroxy-3-methyl-2-butenyl]-5
      methylphenyl beta-D-glucopyranoside (7), 4-hydroxy-2-[(2E,6Z)-8-beta-D
      glucopyranosyloxy-3,7-dimethylocta-2,6-dien-1-yl]-5-methylphenyl beta-D
      glucopyranoside (8), and 2,7-dimethyl-1,4-dihydronaphthalene-5,8-diol 5-O-beta-D
      xylopyranosyl(1-->6)-beta-D-glucopyranoside (10), were isolated from the whole
      plants of Pyrola japonica (Pyrolaceae), together with androsin, (-)
      syringaresinol glucoside, homoarbutin, pirolatin, hyperin, monotropein and
      chimaphilin.

PMID- 15187394
TI  - Quantitative analysis of cannabinoids from Cannabis sativa using 1H-NMR.
AB  - A (1)H-NMR method has been developed for the quantitative analysis of pure
      cannabinoids and for cannabinoids present in Cannabis sativa plant material
      without any chromatographic purification. The experiment was performed by the
      analysis of singlets in the range of delta 4.0-7.0 in the (1)H-NMR spectrum, in
      which distinguishable signals of each cannabinoid are shown. Quantitation was
      performed by calculating the relative ratio of the peak area of selected proton
      signals of the target compounds to the known amount of the internal standard,
      anthracene. For this method no reference compounds are needed. It allows rapid
      and simple quantitation of cannabinoids with a final analysis time of only 5 min
      without the need for a pre-purification step.

PMID- 15187395
TI  - Stereochemistry of NaBH4 reduction of a 19-carbonyl group of 3-deoxy androgens.
      Synthesis of [19S-3H]- and [19R-3H]-labeled aromatase inhibitors having a 19
      hydroxy group.
AB  - To study the stereochemical aspects of the aromatase reaction of androst-4-en-17
      one (1) and its 5-ene isomer 4, competitive inhibitors of aromatase, the [19S
      (3)H]- and [19R-(3)H]-labeled 19-hydroxy derivatives 2 and 5, were synthesized
      through NaB(3)H(4) reduction of the corresponding 19-aldehydes 3 and 6 as a key
      reaction. The hitherto unknown stereochemistry of the NaB(3)H(4) reduction was
      established based on the deuterium-labeling experiments with NaB(2)H(4). A
      comparison of (1)H-NMR spectra of the NaB(2)H(4) reduction products of 19-als 3
      and 6 with those of the respective authentic steroids revealed that the ratios of
      19S-(2)H to 19R-(2)H were 90 : 10 for the 4-ene steroid 2 and 70 : 30 for the 5
      ene isomer 5, respectively. Jones oxidation of the [19S-(2)H]19-ols, followed by
      the non-labeled NaBH(4) reduction, gave the corresponding [19R-(2)H]19-ols 2 and
      5 (R-(2)H : S-(2)H=90 : 10 for steroid 2 and 70 : 30 for steroid 5). The
      stereoselectively (3)H-labeled compounds 2 and 5 were similarly obtained in these
      sequences.

PMID- 15187396
TI  - Diastereoselective synthesis of D- and L-myo-inositol 3,4,5,6-tetrakisphosphates
      from D-glucose via dihydroxylation of (+)-conduritol B derivatives.
AB  - Syntheses of D- and L-myo-inositol 3,4,5,6-tetrakisphosphates were achieved via
      diastereoselective 1,2-addition of vinylcopper reagent with the chiral aldehyde
      prepared from 1,2,5,6-diisopropylidene-D-glucose, ring-closing metathesis of 1,7
      diene with Grubbs catalyst followed by catalytic OsO(4) dihydroxylation of (+)
      conduritol B derivatives.

PMID- 15187397
TI  - Synthesis of chiral sulfinyl-substituted 1-indolyl enones and asymmetric
      conjugate addition by an arylcopper reagent.
AB  - The asymmetric conjugate addition of arylcopper reagents to chiral 1-[2-(p
      tolylsulfinyl)]indolyl and 1-[3-(p-tolylsulfinyl)]indolyl enones was examined.
      With the 2-sulfinyl-indolyl derivatives, the reaction of the arylcopper reagent
      gave high diastereoselectivities (81-88% de's) to afford the adducts in excellent
      yields, although the similar addition reaction of the 3-sulfinyl derivatives
      afforded poor diastereoselectivities.

PMID- 15187398
TI  - Nine regioisomeric and stereoisomeric triterpene dimers from Maytenus
      chuchuhuasca.
AB  - Nine regioisomeric and stereoisomeric triterpene dimers, namely xuxuarine Falpha
      (1), isoxuxuarine Falpha (2; cangorosin B), 7,8-dihydroisoxuxuarine Falpha (3),
      isoxuxuarine Gbeta (4), 7,8-dihydroisoxuxuarine Galpha (5), isoxuxuarine Ebeta
      (6), 7alpha-hydroxyisoxuxuarine Ealpha (7), 7',8'-dihydroxuxuarine Aalpha (8),
      and 7',8'-dihydroxuxuarine Dbeta (9), were isolated from the Brazilian medicinal
      plant "xuxua" (Maytenus chuchuhuasca). Their structures have been elucidated
      based on several spectroscopic analyses including 2D-NMR experiments, MS spectra
      and CD spectral studies.

PMID- 15187399
TI  - The first example of the stereoselective synthesis of 7 beta-carbamoyl-4,5alpha
      epoxymorphinan via a novel and reactive gamma-lactone.
AB  - 7beta-Carbamoyl-4,5alpha-epoxymorphinans 5 were stereoselectively synthesized
      from the 7alpha-carboxylate intermediate 3 in the presence of 1,8
      diazabicyclo[5.4.0]undec-7-ene (DBU) and amines under reflux conditions in
      mesitylene via a novel and reactive gamma-lactone 7. These were the first
      examples of the stereoselective syntheses of 7beta-substituted 4,5alpha
      epoxymorphinans. The mechanism of the reaction process was elucidated as follows:
      1) epimerization of 7alpha-carboxylate 3, 2) intramolecular lactonization of
      7beta-carboxylate 6, and 3) aminolysis of the resultant gamma-lactone 7. The
      aminolysis of the isolated reactive gamma-lactone 7 with allylamine and the
      alcoholysis with MeOH in the presence of NaBH(4) proceeded at room temperature.
      The gamma-lactone 7 can be a useful intermediate for the preparation of 7beta
      substituted 4,5alpha-epoxymorphinans that would be potent selective delta opioid
      receptor ligands. The stereoselective syntheses of the 7alpha-carbamoyl-4,5alpha
      epoxymorphinans 9 from 7alpha-carboxylate 3 via 7alpha-carboxylic acid were also
      successful.

PMID- 15187400
TI  - Application of a self-organizing map to quantitative structure-activity
      relationship analysis of carboquinone and benzodiazepine.
AB  - Self-organizing map (SOM) of Kohonen seems to be a promising approach beyond the
      standard one to regression for some classification problems encountered in the
      field of pharmacy. We apply them, therefore, to the quantitative structure
      activity relationship (QSAR) in carboquinones and benzodiazepines, and show their
      usefulness. Most QSAR analysis using neural networks has been made by adopting
      neural networks with supervised learning. On the contrary, SOM obeys unsupervised
      learning and originally does not involve the use of desired target data. If we
      note that an appreciable fraction of data may be missing without making the
      similarity comparison impossible in SOM if the number of attributes considered is
      appreciable, QSAR analysis using SOM is found to be possible as if supervised
      learning. Similar to target data in supervised learning, we can take into account
      target data (=observed activity) as one of attributes in addition to other
      attributes (=structural descriptors). Choice of optimal descriptors as input
      parameters was found to be essential to generate valuable SOM.

PMID- 15187401
TI  - A new electrochemical system for stereoselective allylic hydroxylation of
      cholesteryl acetate with dioxygen induced by iron picolinate complexes.
AB  - The oxygenation reaction of cholesteryl acetate 1 was examined with the
      Fe(III)(PA)(3)/O(2)/MeCN system using an electrochemical method. The constant
      potential technique gave mainly the 7-hydroxylated product stereoselectively,
      along with the 7-oxo product. This oxygenation system is mechanistically unique,
      requiring iron catalyst, dioxygen, and both cathode and anode.

PMID- 15187402
TI  - (+)-Bornyl piperate, a new monoterpene ester from Piper aff. pedicellatum roots.
AB  - A new monoterpene ester, (+)-bornyl piperate was isolated from the underground
      roots of Piper aff. pedicellatum and its structure was elucidated on the basis of
      spectroscopic evidence and confirmed by X-ray analysis. The compound crystallizes
      in the triclinic space group P1 with a=7.3232(4) A, b=11.4705(7) A, c=23.2520(14)
      A, V=1943.6(2) A(3). This compound showed an antituberculosis activity against
      Mycobacterium tuberculosis (H(37)Ra strain) with the minimum inhibitor
      concentration (MIC) of 25 microg/ml.

PMID- 15187403
TI  - Two new compounds from the leaves of Calocedrus microlepic var. formosana.
AB  - Two new compounds, 15-methoxypinusolidic acid (1) and isonerylgeraniol-18-oic
      acid (2) together with four knowns taiwaniaflavone (3), nerylgeraniol-18-oic acid
      (4), 3-(3,4-dihydroxyphenyl)-1-propanol (5), and amentoflavone (6) are isolated
      from the leaves of Calocedrus microlepic var. formosana. Compounds 1 and 2 were
      elucidated as labdane diterpene and linear diterpene, respectively, through
      spectral studies.

PMID- 15187404
TI  - Novel diterpenes from the heartwood of Chamaecyparis obtusa var. formosana.
AB  - Two novel diterpenes, obtusanal B (1) and obtusadione (2), along with obtusanal A
      (3), obtunone (4), 12-hydroxy-6,7-secoabieta-8,11,13-triene-6,7-dial, 8,12
      dihydroxydielmentha-5,9-diene-7,11-dione and myrcene, isolated from the heartwood
      of Chamaecyparis obtusa var. formosana, were characterized by spectroscopic
      means, including 2D-NMR techniques. Compounds 1 and 2 are 7(6-->2)abeoabietane
      and 14(8-->9)abeoabietane type diterpenes, respectively. Their biosyntheses were
      proposed.

PMID- 15187405
TI  - Ent-kaurane diterpenoids from Isodon rubescens var. rubescens.
AB  - Five new ent-kaurane diterpenoids xindongnins H-L (1-5), together with five known
      ones, xindongnins A and B (6, 7), melissoidesins G (8), dawoensin A (9), and
      glabcensin V (10) were isolated from Isodon rubescens var. rubescens. Their
      structures were elucidated by spectroscopic methods including extensive 2D NMR
      techniques.

PMID- 15187406
TI  - Determination of the absolute structure of (+)-cystothiazole B.
AB  - Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4
      yne-1,2-diol (6) derived from (2R,3S)-epoxy butanoate 5, followed by methylation,
      gave the tetrahydro-2-furylidene acetate (-)-7, which was converted to the left
      half aldehyde (+)-3. A Wittig reaction between (+)-3 and the phosphoranylide
      derived from the bithiazole-type phosphonium iodide 4 using lithium
      bis(trimethylsilyl)amide afforded (+)-cystothiazole B (2), the spectral data of
      which were identical to those of the natural product (+)-2. Thus the
      stereochemistry of cystothiazole B (2) was confirmed to be [4R, 5S, 6(E)].

PMID- 15187407
TI  - Four new andrographolide metabolites in human urine.
AB  - Andrographolide is one of principal components of a famous traditional Chinese
      herbal medicine Andrographis paniculate (BURM) NEES. Four new metabolites of
      andrographolide were isolated from human urine. All of them were characterized as
      sulfate and one of them also as a cysteine S-conjugate. The structures were
      determined to be andrographolide-3-O-sulfate (M-1), isoandrographolide-3-O
      sulfate (M-2), 14-deoxyandrographolide-3-O-sulfate (M-3), 14-deoxy-12-(cysteine-S
      yl)-andrographolide-3-O-sulfate (M-4), respectively, based on chemical evidence
      and spectroscopic analyses.

PMID- 15187408
TI  - Two new galloylglucosides from the leaves of Mallotus furetianus.
AB  - Two new galloylglucosides, mallophenols A (1) and B (2), were isolated from the
      leaves of Mallotus furetianus (Euphorbiaceae), together with seven known
      compounds, (6S,9R)-roseoside (3), aviculin (4), (+)-lyoniresinol-3alpha-O-alpha-L
      rhamnopyranoside (5), (Z)-3-hexenyl-beta-D-glucopyranoside (6), 3,3,8,9,10
      pentahydroxydibenzo[b,d]pyran-6-one (7), 3-hydroxy-4,5(R)-dimethyl-2(5H)-furanone
      (8) and gallic acid (9). The stereostructures of 1 and 2 were elucidated on the
      basis of spectroscopic analysis and chemical evidence.

PMID- 15187409
TI  - First total synthesis of cucurbitaxanthin A applying regioselective ring opening
      of tetrasubstituted epoxides.
AB  - The synthesis of cucurbitaxanthin A 1 was accomplished via the C(15)-3,6-epoxides
      7e and 7f prepared by regioselective ring opening of the 3-hydroxy-5,6-epoxides
      6e and 6f.

PMID- 15187410
TI  - Conditionally immortalized syncytiotrophoblast cell lines as new tools for study
      of the blood-placenta barrier.
AB  - Syncytiotrophoblasts play an essential role in restriction of drug delivery
      through the blood-placenta barrier (BPB). Conditionally immortalized
      syncytiotrophoblast cell lines, TR-TBTs, were established at gestational day 18
      from pregnant transgenic rats (Tg-rats) harboring the temperature-sensitive SV 40
      (ts SV40) large T-antigen. TR-TBTs exhibit temperature-sensitive cell growth due
      to the expression of SV 40 large T-antigen, and thus the cell growth can be
      regulated by changing the culture temperature. TR-TBTs exhibit typical properties
      of syncytiotrophoblast cells, such as syncytium-like morphology, the expression
      of cytokeratins and hormones, and polarized expression of glucose transporter 1
      (GLUT1) and GLUT3. TR-TBTs express in vivo influx and efflux transporters, such
      as taurine transporter (TauT), betaine/GABA transporter (BGT-1), amino acid
      transporter 2 (ATA2), organic anion transporting polypeptide 2 (oatp2), organic
      cation/carnitine transporter (OCTN2), P-glycoprotein (P-gp), and breast cancer
      resistance protein (BCRP/ABCG2). Moreover, TR-TBTs exhibit taurine, GABA, and
      DHEA-S uptake activity via TauT, BGT-1, and oatp2, respectively. Therefore, TR
      TBTs can be used for the analysis of these functions and would be a good in vitro
      models for investigating carrier-mediated transport functions at the BPB.

PMID- 15187412
TI  - Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes.
AB  - The insulin-regulated aminopeptidase (IRAP) is a member of the family of zinc
      dependent membrane aminopeptidases. It is the homolog of the human placental
      leucine aminopeptidase (P-LAP). IRAP is expressed in different cell types but has
      been best characterized in two major insulin target cells, muscle and fat. In
      these cells IRAP localizes to intracellular membrane compartments under basal
      conditions. In response to insulin IRAP redistributes to the cell surface. IRAP
      shares this behavior with the insulin-responsive glucose transporter GLUT4. It is
      established that insulin's dramatic effect on glucose disposal is mediated
      through its action on GLUT4. The role IRAP plays in insulin action is unknown.
      IRAP cleaves several peptide hormones in vitro. In insulin-treated cells,
      concomitant with the appearance of IRAP at the cell surface, aminopeptidase
      activity toward extracellular substrates increases. Thus, insulin, by bringing
      IRAP to the cell surface, could increase the processing of extracellular peptide
      hormones and thereby change their activities. Investigations are underway to
      determine the in vivo substrates for IRAP and to measure the effect of insulin on
      the cleavage of identified substrates. In individuals with type 2 diabetes the
      insulin-stimulated translocation of IRAP to the cell surface of muscle and fat
      cells is impaired. This defect may lead to decreased cleavage and consequently
      increased action of peptide hormones that are substrates for IRAP. Impaired IRAP
      action may thus play a role in the development of complications in type 2
      diabetes. The findings of decreased expression of GLUT4 and increased heart size
      in mice in which IRAP was deleted support this hypothesis.

PMID- 15187413
TI  - Alzheimer's, angiotensin IV and an aminopeptidase.
AB  - The angiotensin AT(4) receptor was originally defined as the specific, high
      affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently,
      the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the
      AT(4) receptor. Central administration of Ang IV or LVV-hemorphin 7 (LVV-H7)
      markedly enhances learning and memory in normal rodents and reverse memory
      deficits observed in animal models of amnesia. The high affinity binding site has
      a broad distribution in the brain including areas such as the hippocampus that
      are involved in memory processing. The high affinity Ang IV binding site (AT(4)
      receptor) has been identified as the transmembrane enzyme, insulin-regulated
      membrane aminopeptidase (IRAP). Insulin-regulated aminopeptidase is a type II
      integral membrane spanning protein belonging to the M1 family of aminopeptidases
      and in insulin-responsive cells colocalizes with GLUT4 in specific intra-cellular
      vesicles. Both Ang IV and LVV-H7 are competitive inhibitors of IRAP catalytic
      activity and are not substrates of the enzyme.

PMID- 15187414
TI  - Role of aminopeptidases in the blood pressure regulation.
AB  - In addition to the neural and autoregulatory factors, blood pressure (BP) is
      regulated by humoral factors including vasoactive peptides. When evaluating the
      peptide actions, degradation by proteases should be also considered in addition
      to the generation of peptides and their receptors. This review describes the
      roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which
      are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP)
      and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the
      association of the proteases with preeclampsia, hypertensive disorder peculiar to
      pregnancy, since one of the representative organs that are rich in theses
      proteases is placenta. Although the physiological roles of the placental
      proteases have not been fully understood, several lines of evidence suggest that
      the proteases are involved in the maintenance of pregnancy homeostasis including
      fetal and maternal BP regulation through the metabolism of bioactive peptides at
      the interface between mother and fetus.

PMID- 15187415
TI  - Role of aminopeptidase in angiogenesis.
AB  - Microvessels are composed of endothelial cells and surrounding pericytes.
      Angiogenesis, a neo-vessel formation from pre-existing microvessels, is a complex
      phenomenon, which requires following sequential steps: detachment of pre-existing
      pericytes for vascular destabilization, extracellular matrix turnover, migration,
      proliferation, tube formation by endothelial cells (ECs), and reattachment of
      pericytes for vascular stabilization. Aminopeptidases regulate the N-terminal
      modification of proteins and peptides for maturation, activation or degradation,
      and thereby relate to a variety of biological processes. Recently, three
      aminopeptidases have been reported to be involved in angiogenesis. They include
      type 2 methionine aminopeptidase, aminopeptidase N, and adipocyte-derived leucine
      aminopeptidase/puromycin insensitive leucyl-specific aminopeptidase. This review
      will focus on the possible role of these aminopeptidases in angiogenesis.

PMID- 15187416
TI  - Processing of antigenic peptides by aminopeptidases.
AB  - Antigenic peptides presented to major histocompatibility complex (MHC) class I
      molecules are generated in the cytosol during degradation of cellular proteins by
      the ubiquitin-proteasome proteolytic pathway. Proteasome can generate N-extended
      precursors as well as final epitopes, and then the precursors are processed to
      mature epitopes by aminopeptidases. Both cytosolic peptidases (i.e. puromycin
      sensitive aminopeptidase, bleomycin hydrolase and interferon-gamma-inducible
      leucine aminopeptidase) and recently identified metallo-aminopeptidase located in
      the endoplasmic reticulum (i.e. adipocyte-derived leucine
      aminopeptidase/endoplasmic reticulum aminopeptidase 1 and leukocyte-derived
      arginine aminopeptidase) can generate final epitopes from precursor peptides.
      Some of these aminopeptidases are also considered to destroy certain antigenic
      peptides to limit the antigen presentation. Taken together, it is getting evident
      that aminopeptidases located in the cytosol and the lumen of endoplasmic
      reticulum play important roles in the generation of antigenic peptides presented
      to MHC class I molecules.

PMID- 15187417
TI  - Enhancement of hepatocyte growth factor-induced cell scattering in N
      acetylglucosaminyltransferase III-transfected HepG2 cells.
AB  - N-Acetylglucosaminyltransferase III (GnT-III), which catalyzes the synthesis of a
      bisecting GlcNAc residue of N-glycans, is thought to be involved in the function
      of glycoproteins such as growth factor receptors. We investigated the effects of
      the overexpression of GnT-III on the hepatocyte growth factor (HGF) receptor c
      Met, a glycoprotein, in human hepatocarcinoma HepG2 cells. GnT-III activity was
      elevated about 250-fold in HepG2 cells stably transfected with the GnT-III gene,
      whereas no significant change in GnT-III activity was observed in mock
      transfectants. Cell scattering assay revealed that HGF-induced cell scattering
      was enhanced depending on the GnT-III activities in the GnT-III transfectants.
      Western blot analysis and E-PHA lectin blot analysis showed that the level of c
      Met protein was the same in both transfectants; however, the bisecting GlcNAc
      residue on c-Met was detected only in the GnT-III transfectants. Although the
      peak level of c-Met phosphorylation was not different in both transfectants, the
      level of tyrosine phosphorylation of c-Met decreased more rapidly in the GnT-III
      transfectants than in the mock transfectants. Furthermore, HGF-induced
      extracellular-regulated kinase (ERK) phosphorylation was slightly higher in the
      GnT-III transfectants than in the mock transfectants. These results show that
      overexpression of GnT-III in HepG2 cells enhances HGF-induced cell scattering,
      which may result from, at least in part, enhancement of HGF-induced ERK
      phosphorylation.

PMID- 15187419
TI  - Orthovanadate stimulates cAMP phosphodiesterase 3 activity in isolated rat
      hepatocytes through mitogen-activated protein kinase activation dependent on cAMP
      dependent protein kinase.
AB  - Orthovanadate (vanadate) as well as insulin stimulated phosphodiesterase 3 (PDE3)
      in the particulate fraction of rat hepatocytes. The vanadate-induced activations
      of PDE3 and mitogen-activated protein kinase (MAPK) were inhibited by H-89 and
      PD98059, suggesting that the MAPK activation via cAMP-dependent protein kinase
      (PKA) and MAPK kinase is involved in the vanadate action. On the other hand, the
      insulin-induced activations of PDE3 and Akt were inhibited by wortmannin,
      suggesting involvement of the Akt activation via phosphatidylinositol 3-kinase
      (PI3K) in the insulin action. The vanadate-induced activations of PKA and PDE3
      were inhibited in part by propranolol or genistein, suggesting that vanadate may
      exert its actions via dual signaling pathways of beta-adrenergic receptors and
      receptor tyrosine kinases of growth factors. Vanadate, in contrast to insulin,
      did not promote the phosphorylation of insulin receptor substrate-1. The vanadate
      induced increase in the phosphorylation of a main isoform of MAPKs, p44 protein,
      was detected by immunoblotting migration patterns of SDS-PAGE. A partially
      purified PDE3 activity was increased by addition of MAPK or Akt to the reaction
      mixture, suggesting that MAPK as well as Akt acts upstream of PDE3. The
      activation of PDE3 by insulin was independent of a transient increase in the MAPK
      activity, probably due to the dephosphorylated inactivation mediated by the
      induced activation of MAPK phosphatases (MKPs). Vanadate did not affect the MKP
      activity. These results indicate that vanadate stimulates the particulate PDE3
      activity by activating mainly p44 MAPK via a PKA-dependent process, and that it
      differs from insulin with regard to a phosphorylation cascade of PDE3 activation.

PMID- 15187418
TI  - Dual inhibition of cyclooxygenases-2 and 5-lipoxygenase by deoxypodophyllotoxin
      in mouse bone marrow-derived mast cells.
AB  - Deoxypodophyllotoxin (Anthricin) is a medicinal herbal product isolated from
      Anthriscus sylvestris HOFFM. that inhibits cyclooxygenase-2 (COX-2) and COX-1
      dependent phases of prostaglandin D(2) (PGD(2)) generation in bone marrow-derived
      mast cells (BMMC) in a concentration-dependent manner with IC(50) values of 1.89
      microM and 65.3 microM, respectively. This study also found that this compound
      inhibited COX-1 and 2-dependent conversion of the exogenous arachidonic acid to
      PGD(2) in a dose-dependent manner with an IC(50) values of 0.01 microM and 12.1
      microM, respectively using a COX enzyme assay kit. However, this compound did not
      inhibit COX-2 protein expression up to a concentration of 30 microM in the BMMC,
      indicating that deoxypodophyllotoxin directly inhibits COX-2 activity.
      Furthermore, this compound consistently inhibited the production of leukotriene
      C(4) (LTC(4)) in a dose dependent manner, with an IC(50) value of 0.37 microM.
      These results demonstrate that deoxypodophyllotoxin has a dual cyclooxygenase-2
      selective/5-lipoxygenase inhibitory activity, and therefore this compound might
      provide a basis for novel anti-inflammatory drugs.

PMID- 15187420
TI  - Neuroprotective effects of phenylethanoid glycosides from Cistanches salsa
      against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic
      toxicity in C57 mice.
AB  - The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been
      employed to create a Parkinson's disease-like model in both rodents and primates
      based primarily on its ability to create a striatal dopamine deficit due to the
      loss of dopaminergic neurons in the substantia nigra compacta. The present study
      was carried out to determine the possible effects of phenylethanoid glycosides
      (PhGs) from Cistanches salsa (C. A. MEY, G. BECK) on attenuating the serious
      behavioral disorder and increasing dopamine (DA) levels in the striata of MPTP
      lesioned C57 mice. MPTP (30 mg/kg i.p. for 4 d) induced serious behavioral
      disorders and significantly reduced striatal DA levels in C57 mice. In
      spontaneous motor activity and rotarod tests, obvious behavioral differences were
      seen between control and model groups. PhGs (10, 50 mg/kg) significantly
      increased the spontaneous movement number and latent period of mice on the
      rotating rod (p<0.01). Injections of MPTP 30 mg/kg for 4 d caused a significant
      reduction in DA, 3,4-dihydroxyphenyl acetic acid, and homovanillic acid in
      striata analyzed by HPLC-electrochemistry (p<0.01). The neurotoxic effects of
      MPTP were attenuated by pretreatment with PhGs (10, 50 mg/kg) in a dose-dependent
      fashion. The apparent neuroprotective effects of PhGs on nigral dopaminergic
      neurons were also confirmed by the results of immunohistochemical staining. The
      present in vivo data clearly demonstrate that PhGs can protect dopaminergic
      neurons against dopamine neurotoxicity induced by MPTP, as suggested by an
      earlier in vitro study. The neuroprotective effects of PhGs were the first
      reported for a natural product.

PMID- 15187421
TI  - Effect of young barley leaf extract and adlay on plasma lipids and LDL oxidation
      in hyperlipidemic smokers.
AB  - Forty hyperlipidemic patients, smokers and non-smokers, were studied. Subjects
      received 15 g young barley leaf extract (BL) or 60 g adlay daily for four weeks.
      Overnight fasting blood samples were drawn immediately prior to and after four
      weeks of supplementation. Blood samples were analyzed for plasma lipid profiles
      and their susceptibility to low-density lipoprotein (LDL) oxidation. The plasma
      total and LDL-cholesterol (LDL-C) levels were reduced following treatment with
      either BL or adlay; furthermore, the lag phase of LDL oxidation increased after
      either supplementation. However, it seemed that BL had stronger antioxidative
      effect on the prevention of LDL oxidation than adlay. Our results also indicated
      that the antioxidative effect was less pronounced in smokers than in non-smokers.
      Therefore, supplementation with BL or adlay can decrease plasma lipids and
      inhibit LDL oxidation in hyperlipidemic smokers and/or non-smokers.

PMID- 15187422
TI  - Inhibitory effect of miconazole on melanogenesis.
AB  - Miconazole (MIC), a regional antifungal agent, has been used worldwide in the
      treatment of superficial mycosis. However, the effect of MIC on skin pigmentation
      is not known. In this study, we investigated the inhibitory effect of MIC on
      melanogenesis in B16 melanoma cells. Tyrosinase activity and melanin content were
      dose dependently decreased by MIC as compared with untreated cells. The level of
      tyrosinase protein expression was reduced with treatment MIC. A decrease in cell
      proliferation was observed in B16 cells treated with MIC 30 microM, indicating
      that the MIC-induced depigmenting effect was caused by inhibition of melanin
      synthesis and not by destruction of B16 cells. Furthermore, MIC markedly
      suppressed alpha-melanocyte stimulating hormone or forskolin-induced tyrosinase
      activity in B16 cells. Therefore the depigmenting effect of MIC might be due to
      the inhibition of tyrosinase activity and tyrosinase expression, which eventually
      slows melanin biosynthesis. These results indicate that MIC may be a useful
      inhibitor of melanogenesis in B16 cells and suggest that it may have beneficial
      effects in the treatment of hyperpigmentation disorders such as ephelis and
      melasma.

PMID- 15187423
TI  - Effect of (3,5,6-trimethylpyrazin-2-yl)methyl 2-[4-(2
      methylpropyl)phenyl]propanoate (ITE), a newly developed anti-inflammatory drug,
      on type II collagen-induced arthritis in mice.
AB  - The effect of (3,5,6-trimethylpyrazin-2-yl)methyl 2-[4-(2
      methylpropyl)phenyl]propanoate (ITE) on type II collagen (CII)-induced arthritis
      in mice was studied. Mice were immunized twice with CII, ITE being given orally
      once a day for 40 d after the 1st immunization. Clinical assessment showed that
      ITE had no effect on the day of onset of arthritis but did lowered the incidence
      rate of arthritis and the arthritis score. And ITE had a marked suppressive
      effect on the mouse hind paw edema induced by CII. ITE suppressed the delayed
      type mouse ear skin reaction to CII but had no effect on the level of serum anti
      CII antibodies. These results suggest that ITE inhibits the development of CII
      induced arthritis in mice by suppressing delayed-type hypersensitivity to CII.

PMID- 15187424
TI  - Measurement of glutamate uptake and reversed transport by rat synaptosome
      transporters.
AB  - To establish an assay system for evaluation of the uptake and reversed transport
      of glutamate, we examined the effects of Na(+)-concentration and pharmacological
      agents on the extracellular glutamate concentration ([Glu](o)) in rat cortical
      synaptosomes in vitro. There was a decrease and increase of the [Glu](o) at high
      and low Na(+) concentrations, respectively, in a Ca(2+)-free medium. The changes
      in [Glu](o) in both directions were temperature-sensitive, and reversed at around
      30 mM of Na(+). Dihydrokainate (DHK), a non-transportable inhibitor selective for
      glial glutamate transporter GLT-1, suppressed the decrease in [Glu](o), and the
      reversal of [Glu](o) change was shifted to about 60 mM Na(+). There was no change
      in the maximum [Glu](o) at total Na(+) substitution. Further pharmacological
      analysis revealed that D-aspartate and DL-threo-beta-hydroxy-aspartate (THA),
      transportable substrates of glutamate transporters, increased the [Glu](o) in
      standard media. In contrast, beta-phenylglutamic acid, a structural analogue of
      glutamate, suppressed both the decrease in [Glu](o) in standard medium and the
      increase in [Glu](o) in low Na(+) medium. It is, thus, concluded that both the
      direction and the amount of [Glu](o) changes are determined by a balance of the
      uptake and reversed transport of glutamate, and that this assay system is
      suitable for evaluation of the effect of this on glutamate transporters.

PMID- 15187425
TI  - Nicergoline enhances glutamate uptake via glutamate transporters in rat cortical
      synaptosomes.
AB  - To elucidate the mechanisms of neuroprotective action of nicergoline, we examined
      its effect on glutamate transport in rat cortical synaptosomes and cloned
      glutamate transporters. In synaptosomes, nicergoline enhanced the glutamate
      uptake at 1-10 microM in standard medium and suppressed the increase of
      extracellular glutamate by reversed transport in low Na(+) medium. Apparent
      increase of extracellular glutamate concentration by dihydrokinate, an inhibitor
      of glial glutamate transporter GLT-1, was antagonized by nicergoline. In Xenopus
      oocytes expressing mouse neuronal glutamate transporter (mEAAC1), the glutamate
      induced inward current was enhanced by nicergoline. These results suggest that
      nicergoline reduces the extracellular glutamate concentration through its effect
      on glutamate transporters.

PMID- 15187426
TI  - Analgesic, antiinflammatory and central depressor effects of the hydroalcoholic
      extract and fractions from Aeolanthus suaveolens.
AB  - This work studied antinociceptive, antiedematogenic and central depressor effects
      of the hydroalcoholic extract (HAE) from Aeolanthus suaveolens and its fractions:
      hexane (ASHAE-H), ethyl acetate (ASHAE-A), aqueous (ASHAE-E) and precipitate
      (ASHAE-PPT) in experimental models in mice. The highest activity in the writhing
      test was presented by ASHAE-A followed by ASHAE-PPT and ASHAE-E and the lowest by
      ASHAE-H. In the formalin test the effect was manifested at both phases, although
      more intensely at the 2nd phase of the response. In this test, the most active
      fraction was ASHAE-PPT causing inhibitions of the order of 76 and 90% of the 2nd
      phase of the test at the doses of 10 and 100 mg/kg i.p., respectively. Naloxone
      reversed the effects of ASHAE-PPT in both phases of the test, suggesting the
      participation of the opioid system in the antinociceptive effect. On the other
      hand, the HAE effect on both phases of the formalin test was only partially
      reversed by naloxone, suggesting that the extract presents more than one active
      compound, and at least one, of a polar nature, acting through the opioid system.
      HAE and ASHAE-PPT presented antiinflammatory activity and were very effective in
      decreasing the mouse paw edema induced by carrageenan. All fractions
      significantly decreased locomotor activity in the open field test in mice.
      However, only the nonpolar fractions presented myorelaxant activity as
      demonstrated by the rota rod test.

PMID- 15187427
TI  - In vitro and in vivo inhibitory effects of disodium cromoglycate on influenza
      virus infection.
AB  - Disodium cromoglycate (DSCG) is one of the safest drugs for the prevention of
      bronchial asthma and allergic rhinitis attacks. The effect of DSCG on acute upper
      respiratory tract viral infection is still controversial. Here we investigated
      DSCG inhibition of influenza virus infection in vivo and in vitro. In vivo
      effects of DSCG on viral infection were assessed using a murine model of
      respiratory tract infection. Intranasal administration of DSCG protected mice
      from death induced by infection with influenza virus A/PR/8/34. We analyzed DSCG
      anti-viral effects in vitro by either (i) treating cells prior to viral
      adsorption, (ii) treating cells concurrently with viral adsorption, or (iii)
      treating cells after viral adsorption. DSCG treatment of cells during or after,
      but not before, viral adsorption significantly inhibited influenza viral
      infection, indicating DSCG acts on events late in viral infection. DSCG exerts
      anti-influenza effect both in vitro and in vivo at the doses compatible with
      treatment for asthma. DSCG marginally inhibited influenza viral neuraminidase and
      membrane fusion functions, suggesting that DSCG inhibition of viral neuraminidase
      and fusion activities may partially mediate this anti-influenza effect. Our
      results indicate that treatment of patients including children with DSCG may take
      advantages for prevention from influenza virus infection.

PMID- 15187428
TI  - Dentin is dissolved by high concentrations of L-ascorbic acid 2-[3,4-dihydro
      2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen
      phosphate] potassium salt with or without hydrogen peroxide.
AB  - L-Ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)
      2H-1-benzopyran-6-yl-hydrogen phosphate] potassium salt (EPC-K(1)) is a conjugate
      of vitamin C and vitamin E that is water-soluble and stable at room temperature.
      EPC-K(1) has been developed as a hydroxyl radical (.OH) scavenger and
      antioxidant. In a previous tooth whitening experiment, it was accidentally found
      that tooth (dentin) blocks were dissolved by EPC-K(1) with H(2)O(2). In the
      current study, high concentrations of EPC-K(1) (2.5, 25 mM) with 3% H(2)O(2)
      dissolved and caused the collapse of dentin blocks. Similar concentrations of EPC
      K(1) without 3% H(2)O(2), however, dissolved the dentin blocks without collapse
      over a 3-week period. In these cases, a.OH-like signal was detected using an ESR
      spin-trapping method. The volume of calcium in solution (including the dentin
      block) increased on the addition of EPC-K(1) in a concentration-dependent manner.
      In addition, the calcium : phosphorus ratio changed from 2 : 1 in sound dentin to
      1 : 2 in the collapsed dentin block. High concentrations of EPC-K(1) are
      therefore considered to have calcium chelating and dentin dissolving activity.
      The dentin dissolving activity was enhanced when EPC-K(1) was used with H(2)O(2).
      EPC-K(1) had no protective effect when used in tooth whitening with H(2)O(2).

PMID- 15187429
TI  - Estrogenic and anti-androgenic activity of nitrophenols in diesel exhaust
      particles (DEP).
AB  - We recently isolated 4-nitrophenol, 2-methyl-4-nitrophenol, 3-methyl-4
      nitrophenol, and 4-nitro-3-phenylphenol from diesel exhaust particles (DEP) and
      identified them as vasodilators. Because these compounds are alkylphenolic
      derivatives that might mimic hormones, we evaluated their estrogenic activity by
      human estrogen receptor (hER)-yeast screen assay. All of these nitrophenol
      derivatives except 2-methyl-4-nitrophenol exhibited estrogenic activity. Some
      estrogenic compounds are also anti-androgenic, so we measured the anti-androgenic
      activity of the same compounds by human androgen receptor (hAR)-yeast screen
      assay. We found anti-androgenicity in all four nitrophenols. Nitrophenols in DEP
      possess not only vasodilatory activity but also estrogenic and anti-androgenic
      activity.

PMID- 15187430
TI  - Small-molecule anthracene-induced cytotoxicity and induction of apoptosis through
      generation of reactive oxygen species.
AB  - A series of anthracene derivatives have been synthesized, and their potential
      individual cytotoxicity was evaluated using Jurkat T cells and peripheral blood
      mononuclear cells (PBMCs) in vitro. These compounds, except for 2l, showed less
      cytotoxicity in PBMCs than mitoxantrone. We also analyzed the antiproliferative
      activity of these derivatives using the annexin V/propidium iodide assay. These
      synthetic compounds induced apoptosis, thus leading to antitumor effects.
      Compounds 2b, 2e, 2f, 2g, 2h, 2i, 2j, and mitoxantrone produced dose-dependent
      cytotoxicity, while the antiproliferative activity of the anthracene
      pharmacophore was retained in Jurkat T cells base on the detection of DNA
      degradation and membrane unpacking. These clearly indicate a correlation between
      cytotoxicity and antitumor activity. Unlike mitoxantrone, cytotoxic properties
      were observed, as documented by the reactivity of these novel compounds against
      Jurkat T cells and PBMCs as normal cells, respectively. Various concentrations of
      2b, 2e, 2f, 2g, 2h, 2i, and 2j preparations also inhibited Jurkat T cell
      proliferation and induced apoptosis of Jurkat T cells, potentially confirmed
      through the detection of DNA degradation and membrane unpacking. In the present
      report we also investigated the antiinflammatory activity against phorbol-12
      myristate-13-acetate induced superoxide anion production, a marker for an
      inflammatory mediator produced by neutrophils, with IC(50) (microM) values of 2b,
      2h, 2l, and 2o of 4.28+/-0.89, 3.31+/-0.88, 4.38+/-0.25, and 5.45+/-1.78,
      respectively. These results suggest that, in addition to the specific chromosomal
      aberrations and cell death, elevated apoptosis could also be a marker for
      exposure to anthracene derivatives.

PMID- 15187431
TI  - New ethacrynic acid derivatives as potent cytoskeletal modulators in trabecular
      meshwork cells.
AB  - A series of ethacrynic acid (ECA) derivatives were synthesized and examined for
      ocular hypotensive activity. Efficacy was evaluated in a cell-shape assay, using
      human trabecular meshwork cells, and cytotoxicity in a (3-(4,5-dimethylthiazole-2
      yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, using
      cultured bovine trabecular meshwork cells. Many of the derivatives demonstrated
      efficacy equal to or greater than that of ECA. SA9000 was selected as the most
      promising candidate for a novel ocular hypotensive drug with few side effects.

PMID- 15187432
TI  - Comparative study of the inhibition of metallo-beta-lactamases (IMP-1 and VIM-2)
      by thiol compounds that contain a hydrophobic group.
AB  - For the purpose of screening of inhibitors that are effective for wide range of
      metallo-beta-lactamases, the inhibitory effect of two series of compounds, 2
      omega-phenylalkyl-3-mercaptopropionic acid (PhenylCnSH (n=1-4)) and N-[(7-chloro
      quinolin-4-ylamino)-alkyl]-3-mercapto-propionamide (QuinolineCnSH (n=2-6)), where
      n denotes the alkyl chain length, on metallo-beta-lactamases IMP-1 and VIM-2 was
      examined. These inhibitors contain a thiol group and a hydrophobic group linked
      by variable-length methylene chain. PhenylCnSH (n=1-4) was found to be a potent
      inhibitor of both IMP-1 and VIM-2. PhenylC4SH was the potent inhibitor of both
      IMP-1 (IC(50)=1.2 microM) and VIM-2 (IC(50)=1.1 microM) among this study. When
      the number of methylene units was varied, QuinolineC4SH showed the maximum
      inhibitory activity against IMP-1 and VIM-2 (IC(50)=2.5 microM and IC(50)=2.4
      microM). The relationship between the inhibitory effect of the alkyl chain length
      was different for both series of inhibitors, suggesting that IMP-1 has a tighter
      binding site than VIM-2. QuinolineCnSH did not serve as a fluorescence reagent
      for metallo-beta-lactamases.

PMID- 15187433
TI  - Suppressive effect of Dai-bofu-to on collagen-induced arthritis.
AB  - Dai-bofu-to (DBT) is a traditional Japanese herbal medicine (Kampo medicine) used
      for the treatment of rheumatoid arthritis (RA). In the present study, to
      establish the usefulness of DBT, we examined the effect of DBT on collagen
      induced arthritis (CIA). DBT (1.72 g/kg/d) significantly reduced the severity of
      arthritis throughout the experiment and significantly delayed the onset of
      arthritis. The induction of CIA decreased T cells and increased B cells in
      popliteal lymph nodes close to the affected joints, while the treatment of CIA
      with DBT counteracted the changes in T and B cells. In pX transgenic mice as a
      spontaneously developed arthritis model, a decrease in T cells and increase in B
      cells in popliteal lymph nodes were observed, as compared to BALB/c mice, the
      littermates of pX transgenic mice. In contrast, DBT returned the cell number of T
      and B cells to the level of BALB/c mice. As osteoclastogenesis is regulated by
      some T cell cytokines and osteotropic factors, we examined the effect of DBT on
      the receptor activator of NF-kappa B (RANK), RANK ligand (RANKL), osteoprotegerin
      (OPG) and M-CSF mRNAs, which were induced by arthritis induction. Although DBT
      had no effect on RNAK or RANKL mRNA levels, DBT stimulated an increase in OPG
      mRNA levels and suppressed an increase in M-CSF mRNA level. These results suggest
      that DBT may possess an anti-osteoclastogenetic effect, which is brought by
      reducing the ratio of RANKL/OPG and by decreasing M-CSF mRNA levels. In
      conclusion, immunomodulatory and anti-osteoclastogenetic effects might be
      involved in the suppression of arthritis by DBT.

PMID- 15187434
TI  - Antibacterial and antifungal effects of essential oils from coniferous trees.
AB  - Essential oils have potential biological effects, i.e., antibiotic,
      anticarcinogenic, and sedative effects during stress. In the present study, we
      investigated the antibacterial and antifungal effects of essential oils extracted
      from the coniferous species Pinus densiflora, Pinus koraiensis, and Chamaecyparis
      obtusa, because their biological activities have not been yet elucidated. The
      essential oils were quantified using gas chromatography and identified in gas
      chromatography-mass spectrometric analysis. Simultaneously, antibacterial and
      antifungal assays were performed using the essential oils distilled from the
      needles of coniferous trees. The major components and the percentage of each
      essential oil were: 19.33% beta-thujene in P. densiflora; 10.49% alpha-pinene in
      P. koraiensis; 10.88% bornyl acetate in C. obtusa. The essential oils from P.
      densiflora and C. obtusa have antibacterial effects, whereas essential oils from
      P. koraiensis and C. obtusa have antifungal effects. These results indicate that
      the essential oils from the three coniferous trees, which have mild antimicrobial
      properties, can inhibit the growth of gram-positive and gram-negative bacteria
      and fungi.

PMID- 15187435
TI  - An anti-aldosteronic diuretic component (drain dampness) in Polyporus sclerotium.
AB  - Polyporus Sclerotium botanically from the Polyporus umbellatus (PERS.) FRIES, was
      traditionally used for the purpose of promoting diuresis. The present study
      investigated the diuretic effect of ergosta-4,6,8(14),22-tetraen-3-one (ergone)
      which is a maker component according to the chemical assay for its quality
      standardization. It resulted in a reversion to ordinary value of the urinary
      ratio of Na/K in deoxycoricosterone acetate (DOCA)-treated and adrenalectomized
      rats, although it had no this effect on the Na or K contents as well as Na/K
      value both in normal rats and in adrenalectomized rats without DOCA. These data
      indicate that ergone possesses an anti-aldosteronic diuretic effect. Moreover, it
      was identified in the blood and bile of rats after its administration to the
      gastrointestinal tract. The above results demonstrate that it is an active
      component of Polyporus Sclerotium.

PMID- 15187436
TI  - A comparative study of laboratory parameters and symptoms effected by Toki
      shakuyaku-san and an iron preparation in rats with iron-deficiency anemia.
AB  - In order to more closely examine the effect of Toki-shakuyaku-san and an iron
      preparation in vivo in an animal experiment, we prepared anemic rats, divided
      them into 4 groups, i.e., an untreated group, a Toki-shakuyaku-san group, an iron
      preparation group and a Toki-shakuyaku-san+iron-preparation group, and assessed
      the results of laboratory parameters, hematology, and general symptoms of anemia.
      The results showed trends toward improvement in indices of anemia, i.e.,
      erythrocyte (RBC) count, hemoglobin (Hb), hematocrit (Ht) and serum iron (Fe),
      and improvement of anemic symptoms in the 3 treated groups. Examination of
      erythrocyte morphology showed that erythrocyte destruction had occurred only
      slightly in the 3 treated groups. The organ weight measurements showed an
      increase in the weight of the heart and spleen in the untreated group, but tended
      to be closer to normal in the 3 treated groups. The number and wet weight of the
      feces in the untreated group were markedly lower than normal, but increased in
      the Toki-shakuyaku-san group. In the iron-preparation group, the hemorrhage of
      stomach and pigmentation of the tail which seem to be a side effect of iron were
      observed, but was not seen in the Toki-shakuyaku-san group. The results animal
      experiment more closely examined the results of clinical study, and we concluded
      that by using Toki-shakuyaku-san and the iron preparation in combination, it is
      possible to lessen the adverse reactions such as gastrointestinal symptoms, and
      that more ameliorative effect on the anemic state can be expected.

PMID- 15187437
TI  - Suppressed permeation of linoleic acid in a liposomal formulation through
      reconstructed skin tissue.
AB  - Since the liposomal formulation of linoleic acid (LA) exhibited an enhanced skin
      whitening effect, the influence of liposomalization on the cutaneous absorption
      of LA was examined using a three-dimensional (3D) reconstructed skin model.
      Liposome entrapped [(14)C]-LA was applied on the skin model, and the permeation
      of LA through the skin was monitored. The permeation rate of LA in the liposomal
      formulation was found to be lower than that in the conventional formulation
      without liposomes, suggesting the increased retention time of LA in the skin by
      the liposomal formulation. Next, to investigate the dependence of the LA
      permeation on melanocyte conditions and intactness of the reconstructed skin
      model, the effect of UV irradiation on LA permeation was examined. Low-dose UVB
      irradiation (0.03 J/cm(2) for 3 times), which activated melanocytes in the skin,
      did not influence the extent of LA permeation, while high-dose irradiation (0.30
      J/cm(2) for 3 times) enhanced the permeation of LA in both the conventional and
      liposomal formulation. The present results suggest the importance of skin
      intactness for LA permeation and that the 3D reconstructed skin model would be
      useful for evaluating the characteristics of skin-oriented cosmetics and drugs.

PMID- 15187438
TI  - Development of TCR alpha beta CD8 alpha alpha intestinal intraepithelial
      lymphocytes is promoted by interleukin-15-producing epithelial cells
      constitutively stimulated by gram-negative bacteria via TLR4.
AB  - The microbes present in the intestine have a strong influence on the development
      and maturation of lymphoid organs. The cross-talk mechanisms between intestinal
      intraepithelial lymphocytes (i-IEL) and noninvasive microbes are still poorly
      understood. The influence of microbes and lipopolysaccharides on the development
      of i-IEL, especially the TCR alpha beta(+) CD8 alpha alpha subset, was
      investigated using the different TLR4-mutant mouse strains C3H/HeJ, BALB/lps(d),
      and C57BL/10ScCr. Intestinal epithelial cells (i-EC) from TLR4-mutant strains did
      not express interleukin (IL)-15 mRNA, while IL-15 mRNA expression in i-EC from
      the corresponding wild-type, C3H/He, BALB/c, and C57BL/10ScSn mice was detected.
      The development of TCR alpha beta(+) CD8 alpha alpha cells in i-IEL significantly
      decreased in TLR4-mutant mice compared with the corresponding wild-type mice,
      while other T cell subsets in i-IEL showed similar percentages in the TLR4-mutant
      and wild-type mice. Adult thymectomized (ATx-) and lethally irradiated C3H/HeJ
      mice reconstituted with T cell-depleted bone marrow cells from C3H/He mice showed
      a significantly lower percentage of TCR alpha beta CD8 alpha alpha i-IEL than ATx
      C3H/He mice after transfer of C3H/HeJ BM cells. The percentage of TCR alpha beta
      CD8 alpha alpha i-IEL and IL-15 mRNA expression in i-EC from BALB/lps(d) mice did
      not increase during Salmonella typhimurium infection but was significantly
      enhanced during Listeria monocytogenes infection. Our findings suggest that LPS
      induces IL-15 production by i-EC, resulting in the development of TCR alpha beta
      CD8 alpha alpha i-IEL.

PMID- 15187439
TI  - Hyphae formation of Candida albicans is regulated by polyamines.
AB  - Candida albicans generally grows in hyphae form in RPMI1640 medium. However,
      addition of 1,4-diamino-2-butanone (DAB), a competitive inhibitor of ornithine
      decarboxylase, decreased the amount of polyamines in C. albicans, and induced the
      proliferation of the C. albicans yeast form. The expression of CYR1 mRNA was
      significantly inhibited by the addition of DAB compared with that of the control.
      The amount of intracellular cAMP was also decreased by the addition of DAB. A
      specific adenylate cyclase inhibitor, cis-N-[2-phenylcyclopentyl]-azacyclotridec
      1-en-2-amine (MDL-12,330A) promoted the growth of the yeast form. These results
      indicated that polyamines exist upstream of the adenylate cyclase-cAMP signal
      pathway and regulate the transformation of C. albicans.

PMID- 15187440
TI  - High-performance liquid chromatographic assay of clonazepam in human plasma using
      a non-porous silica column.
AB  - A new HPLC method has been developed for measuring clonazepam (CZP) in plasma,
      using a reversed-phase non-porous silica column packed with 2 microm particles.
      CZP in plasma was first purified with a column extraction technique and injected
      onto a non-porous silica column. The calibration curve was linear from 5-200
      ng/ml. The recoveries of CZP added to plasma were more than 94.0%, with a
      coefficient of variation in the range of 5.1-13.8%. We developed a rapid routine
      method using a non-porous silica column that was accurate and improved solvent
      consumption in the measurement of CZP.

PMID- 15187441
TI  - The expression of mRNA for calcitonin gene-related peptide receptors in a mucosal
      type mast cell line, RBL-2H3.
AB  - Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) belong to a
      calcitonin-family of regulatory peptides. Receptors for CGRP and ADM have been
      suggested to be present on both mucosal (MMC) and connective tissue (CTMC) type
      of mast cells, based on histamine release by these peptides. Recently, it was
      reported that mRNA for ADM receptors, but not for CGRP receptors, was expressed
      in rat peritoneal mast cells, a representative of type CTMC. However, mRNA
      expression for the receptors in MMC has not been studied yet. Therefore, we
      examined whether mRNAs encoding CGRP or ADM receptor subunit, RDC-1, calcitonin
      receptor-like receptor (CRLR), and receptor activity-modifying proteins (RAMPs)
      are present, and if so, whether their expression is modified by IgE receptor
      triggering, in a mucosal type mast cell line, rat basophilic leukemia (RBL-2H3)
      cells using RT-PCR. RBL-2H3 cells constitutively express mRNA for RDC-1, CRLR,
      RAMP3 but not that for RAMP1 and RAMP2, and IgE receptor triggering was shown
      neither to induce the gene expression of RAMP1 and RAMP2, nor to enhance that of
      RDC-1, CRLR or RAMP3. These results indicate that RBL-2H3 cells posses receptors
      for both CGRP and ADM, suggesting various functions of these peptides in
      physiological and pathophysiological conditions where mast cells of the mucosal
      type are involved.

PMID- 15187442
TI  - Biological activity of alpha-thujaplicin, the isomer of hinokitiol.
AB  - alpha-Thujaplicin, a minor component of Aomori Hiba (Thujopsis dolabrata SIEB. et
      ZUCC. var. hondai MAKINO), showed rather strong antifungal activity against seven
      kinds of plant-pathogenic fungi, their minimum inhibitory concentrations (MICs)
      being in the range of 12.0-50.0 microg/ml. alpha-Thujaplicin and hinokitiol (the
      major component of Aomori Hiba) also showed clear antibacterial activity against
      Legionella pneumophila SG 1 and L. pneumophila SG 3, and their MICs are in the
      range of 6.25-50 microg/ml. This compound showed strong insecticidal activity
      against Reticulitermes speratus [50%-lethal concentration (LC(50)): 0.02 g/m(2)],
      and it also had clear acaricidal activity against Dermatophagoides farinae
      (LC(50): 0.66 g/m(2)). At 24 h after treatment, alpha-thujaplicin at 0.63
      microg/ml inhibited the cell growth of murine P388 lymphocytic leukemia by 78%,
      and its cytotoxic activity at a concentration higher than 0.63 microg/ml was as
      high as that of vincristine, used as a positive control. On the other hand, the
      cytotoxic effect of alpha-thujaplicin at 0.63 microg/ml was weaker than that of
      vinblastine. In this respect, the strong cytotoxic effect of alpha-thujaplicin on
      murine P388 lymphocytic leukemia cell line should be emphasized, considering that
      it has recently been found to be low in toxicity to mice.

PMID- 15187443
TI  - Gene activations of CYP2B1 and CYP3A1 by dihydropyridine calcium channel
      antagonists in the rat liver: the structure-activity relationship.
AB  - We investigated the gene activations of CYP2B1 and CYP3A1 by 1,4-dihydropyridine
      calcium channel antagonists, including nifedipine (Nif), nisoldipine (Nis),
      nitrendipine (Nit), nimodipine (Nim), and nicardipine (Nic), in the rat liver and
      their structure-activity relationships. All calcium channel antagonists used have
      nitrophenyl substituents at the 4-position of the dihydropyridine ring and their
      nitro group was located at o- or m-position. The m-nitro derivatives Nic, Nim,
      and Nit showed much higher capacities for activating CYP3A1 than the o-nitro
      derivatives Nif and Nis. On the other hand, in the activation of CYP2B1, the
      length of the side chain at the 3-position of the dihydropyridine ring was
      correlated with the activating capacity of each chemical, and Nif and Nit, with a
      shorter side chain than the other calcium channel antagonists examined, had
      potent capacities. The present findings suggest that the ability of
      dihydropyridine calcium channel antagonists to activate the CYP2B1 and CYP3A1 are
      mainly dependent on the length of the side chain at the 3-position of the
      dihydropyridine ring and the position of the nitro group in the nitrophenyl
      substituent, respectively.

PMID- 15187445
TI  - Antinociceptive profile of 2-phenylselenenyl-1,8-cineole in mice.
AB  - 2-Phenylselenenyl-1,8-cineole (PSC) increased both the pentobarbital-induced
      sleeping time and the reaction time (up to 2 h) in the tail immersion method. PSC
      also caused dose-dependent inhibition of acetic acid induced writhing with
      maximum inhibition of 93.4% and was approximately 8.5-fold more potent than 1,8
      cineole. These findings show that PSC presents sedative effect and significant
      antinociceptive activity.

PMID- 15187444
TI  - PAP 9704, a Korean herbal medicine attenuates methamphetamine-induced
      hyperlocomotion via adenosine A2A receptor stimulation in mice.
AB  - The effect of PAP 9704, a traditional prescription in Korea consisting of
      Polygala tenuifolia, Acorus gramineus, and Poria cocos at a ratio of 1:1:1 (dry
      weight), on methamphetamine (MA)-induced hyperlocomotion was examined in mice.
      The increased locomotor activity induced by MA (1 mg/kg/d, i.p. x 7) was
      significantly attenuated by co-administration with PAP 9704 (100 or 200 mg/kg/d,
      p.o. x 7) in a dose dependent manner. Consistently, it was found that the
      hyperlocomotor activity occurred in parallel with the expression of striatal fos
      related antigen immunoreactivity. The adenosine A(2A) receptor antagonist, 1,3,7
      trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1.0 mg/kg, i.p.), significantly
      reversed the pharmacological action of PAP 9704 in a dose related manner, but the
      adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (0.5 or 1.0
      mg/kg, i.p.) and the A(2B) receptor antagonist alloxazine (1.5 or 3.0 mg/kg,
      i.p.) did not significantly affect this pharmacological action. Our results
      suggest that PAP 9704 prevents MA-induced hyperlocomotion, at least in part, via
      the stimulation of the adenosine A(2A) receptor.

PMID- 15187447
TI  - HIV-1 inhibition by extracts of Clusiaceae species from Mexico.
AB  - The organic plant extracts of 21 species of Clusiaceae from Mexico were screened
      for anti HIV-1 reverse transcriptase activity in a non-radioactive immuno
      colorimetric assay. The extracts of 5 species (23.8%) exhibited significant
      inhibition (> or =70%) of HIV-1 RT activity; of these, only 4 extracts showed
      reduced toxicity to human lymphocytic MT2 cells and were further tested as
      inhibitors of HIV-1 IIIb/LAV replication in a cellular system. The best extracts
      were Calophyllum brasiliense (hexane) and Clusia quadrangula (CH(2)Cl(2)-MeOH)
      which inhibited HIV-1 RT (IC(50)=29.6 microg/ml and 42 microg/ml), and showed an
      EC(50)=92.5 microg/ml and 91 microg/ml, respectively, on MT2 cells. However, only
      Calophyllum brasiliense hexane extract showed significant inhibition on viral
      replication (ED(50)=37.1 microg/ml), while Clusia quadrangula was less active
      (ED(50)=124 microg/ml). These results support the idea that plant extracts
      represent a valuable source of potential anti HIV compounds.

PMID- 15187446
TI  - Evaluation of the antioxidant effects of some flavonylthiazolidinediones by
      determining their effects on lipid peroxidation, superoxide anion formation, and
      2,2-diphenyl-1-picrylhydrazyl stable free radical.
AB  - The in vitro antioxidant effects of some flavonylthiazolidinediones (Ia-d, IIa-d)
      on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels were
      determined by measuring the formation of 2-thiobarbituric acid reactive
      substance. The free radical-scavenging properties of the compounds were examined
      in vitro by determining the capacity to scavenge superoxide anion formation and
      of the interaction with the stable free radical 2,2-diphenyl-1-picrylhydrazyl
      (DPPH). The compounds had no inhibitory effects on LP. However, they had variable
      inhibitory influence on superoxide anion production and DPPH radical in a
      concentration-dependent manner. The most active compound, 3-(2,5
      dimethoxyphenacyl)-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl)methylenyl]
      thiazolidine-2,4-dione, Id showed 98% inhibition of superoxide anion production
      and 95% inhibition of DPPH stable free radical at 10(-3) M.

PMID- 15187448
TI  - In vitro screening of leishmanicidal activity in myanmar timber extracts.
AB  - Seventy-five Myanmar timber extracts belonging to 27 families were examined for
      their leishmanicidal activities. Some timber extracts had significant
      leishmanicidal activity, especially extracts of Millettia pendula, which
      exhibited the most potent activity (MLC 3.1 microg/ml, MIC 1.6 microg/ml). Other
      timber extracts showing potent activity included those from Cedrela serrata,
      Cedrela toona, Cordia fragrantissima, Calophyllum kunstleri, Dalbergia cultrate,
      Grevillea robusta, Haplophragma adenophyllum, Michelia champaca, and Tectona
      grandis. From a literature search for reports on the chemical constituents of
      these plants, most constituents were found to be quinone derivatives or other
      compounds with unsaturated carbonyl groups.

PMID- 15187449
TI  - Quinolone alkaloids with inhibitory activity against nuclear factor of activated
      T cells from the fruits of Evodia rutaecarpa.
AB  - Nine quinolone alkaloids (1-9) from the fruits of Evodia rutaecarpa were
      investigated for their inhibitory activity on nuclear factor of activated T cells
      (NFAT)-dependent transcription in comparison with nuclear factor (NF)-kappa B
      dependent transcription using a reporter gene assay. These alkaloids showed
      inhibitory effects against NFAT activity, with IC(50) values between 0.91 microM
      and 15.91 microM. Of the N-methylated quinolones, the longer aliphatic side chain
      at the quinolone ring showed stronger inhibition of NFAT activity. These N
      methylated compounds showed comparable inhibitory effects against NF-kappa B
      activity. However, quinolone alkaloids without the N-methyl group showed a more
      selective inhibition of NFAT activity.

PMID- 15187450
TI  - Increased in vitro release of interferon-gamma from ampicillin-stimulated
      peripheral blood mononuclear cells in Stevens-Johnson syndrome.
AB  - Stevens-Johnson syndrome (SJS) was diagnosed in a 39-year-old woman, treated with
      ampicillin (4000-8000 mg daily), phenytoin (250 mg daily), and furosemide (20-40
      mg daily) for 25, 21, and 20 d, respectively, before the appearance of the
      eruption. The lymphocyte stimulation test with the MTT [3-(4,5-dimethyl thiazol-2
      yl)-2,5-diphenyl tetrazolium bromide] assay on ampicillin, phenytoin, and
      furosemide showed a low value of stimulation index, which indicated negative
      reactivity. An in vitro IFN-gamma release test was conducted on the patient with
      SJS and on two healthy controls. IFN-gamma release increased by 52% following the
      in vitro challenge of the patient's peripheral blood mononuclear cells (PBMCs)
      with 15 microg/ml of ampicillin, but not with phenytoin or furosemide. Neither of
      the controls experienced increased IFN-gamma release. In the present case,
      increased in vitro IFN-gamma release was observed on ampicillin-stimulated PBMCs,
      which may indicate the role of ampicillin as the drug responsible for the
      induction of SJS, and may imply the role of IFN-gamma in the pathogenesis of SJS.

PMID- 15187451
TI  - Involvement of P-glycoprotein in blood-brain barrier transport of pentazocine in
      rats using brain uptake index method.
AB  - The involvement of P-glycoprotein (P-gp) in pentazocine (PTZ) transport at the
      blood-brain barrier (BBB) in rats was evaluated by means of an in vivo study
      using the brain uptake index (BUI) method. The amount of radioactivity in the
      brain was estimated at different intervals (up to 240 s) after carotid injection
      in rats. The apparent elimination rate constant (k(test)) due to efflux of PTZ
      from the brain was calculated as 0.22 min(-1). The observed BUI values of [(3)H]
      PTZ (0.35 microM) were not significantly different between 5 and 15 s after the
      carotid injection. The concentration-dependent uptake of PTZ by the brain was
      increased gradually by increasing the concentration (0.01-1 mM) of PTZ in the
      injection solution. The apparent uptake of PTZ by the brain increased in the
      presence of P-gp inhibitors such as cyclosporin A, quinidine, verapamil and
      vinblastine after the carotid injection. These results suggest that the increment
      of PTZ uptake by the brain could be explained by the saturable efflux transport
      system involving a P-gp-mediated efflux mechanism of PTZ transport at the BBB.

PMID- 15187452
TI  - Neutralizing antibody evasion ability of adenovirus vector induced by the
      bioconjugation of methoxypolyethylene glycol succinimidyl propionate (MPEG-SPA).
AB  - Although adenovirus vectors (Ad) which possesses high transduction efficiency are
      widely used for gene therapy in animal models, clinical use is very limited. One
      of the main reason is that nearly 80% of human beings possess anti-Ad antibodies.
      In this study, we tried to modify Ad with methoxypolyethylene glycol (MPEG)
      activated by succinimidyl propionate, and, the neutralizing antibody evasion
      ability of PEGylated Ad was evaluated. The results demonstrated that PEG-Ad
      showed stronger protection ability against anti-Ad neutralizing antibody compared
      to that with unmodified-Ad. Considering there are many people carrying
      neutralizing antibody against Ad and readministration of Ad was necessary for
      treating chronic diseases, this strategy, which was also applicable to other
      vectors, can be used for developing improved vectors.

PMID- 15187453
TI  - [Physiological characteristics of child athletes].
AB  - Physiological characteristics of child athletes cannot be examined independently
      from the changes that occur during growth and maturation. This article reviews
      changes occurring in aerobic and anaerobic capacities, muscle strength and
      endurance in parallel with growth and development, and the factors affecting
      these changes, in particular, training. In addition, a brief evaluation is
      presented concerning the effects of physical activity, participation in sports,
      and training on growth and maturation.

PMID- 15187454
TI  - [Training in children].
AB  - Early participation of children in elite sports and significant achievements at
      younger ages have brought about the need for longer training years and intensive
      training programmes for child athletes. However, the response of children to
      training loads presents some differences from those of adults owing to
      characteristics associated with growth and development. Considering the
      influences of growth and development and in consistent with diverse stages of
      child growth, the course of training is divided into several stages including
      participation, general involvement, special preparation, and elite performance,
      each of which is characterized by distinct responses depending on functional and
      biological features. This article reviews particular aspects of child training in
      relation to growth, endurance, sexual development and maturation, and
      psychosocial development.

PMID- 15187456
TI  - [Stress fractures in children and adolescents].
AB  - The incidence of stress fractures in young athletes has increased with the
      popularization of sports among children and adolescents. Stress fractures are
      less common in children and adolescents than in adults. A combination of
      intrinsic or anatomical factors and extrinsic factors such as training pitfalls
      and environmental insufficiencies predispose athletes to stress fractures. This
      review aims to outline current knowledge about clinical manifestations,
      diagnostic imaging, and treatment of stress fractures in children and
      adolescents.

PMID- 15187455
TI  - [Sports injuries in children and adolescents: etiology, epidemiology, and risk
      factors].
AB  - Growing participation of children in sports has resulted in an increased
      incidence of sports injuries. Although methodological differences in
      epidemiologic studies largely prevent precise comparisons, it appears that young
      athletes participating in combat and contact sports seem to be more prone to
      injuries. Knee and ankle injuries are the most commonly encountered problems and
      chronic events are more prevalent than acute ones. The occurrence of athletic
      injuries is multifactorial and may present differences with respect to sex and
      the sports branch involved. An analytical approach of all relevant groups
      (parents, coaches, physical education teachers, health personnel) is necessary to
      understand, treat, and prevent athletic injuries in children.

PMID- 15187457
TI  - [Muscle and tendon injuries in children and adolescents].
AB  - The pediatric athlete with open physeal plates is more susceptible to growth
      plate injuries and avulsion fractures than to ligament and muscle-tendon injuries
      that most often occur in adults. Muscle contusions and strains are common
      injuries in young athletes. Although they are rare in the early and middle stages
      of childhood, they become quite common during the growth spurt period. Healing of
      muscle tissues is much more rapid in children than that in adults, but it must be
      ensured that full motion and full strength are regained before returning to
      sports activities, because recurrences of injuries may result in more serious
      complications such as myositis ossificans. On the other hand, acute tendinous
      injuries are quite rare in children; however, repetitive submaximal stress may
      lead to overuse syndromes. This article reviews the basic anatomy and function of
      skeletal muscle and discusses the physiopathology of muscle-tendon injuries, and
      the methods of treatment and prevention, with particular focus on the growing
      child.

PMID- 15187458
TI  - [Cervical spine injuries in children].
AB  - Cervical spine injuries in children and adolescents are rare. Common mechanisms
      include motor vehicle accidents, sports injuries, fall from height, and gunshot
      injuries. Cervical spine injuries are classified by Allen and Ferguson according
      to the period they occur, as infantile, early juvenile, and late juvenile.
      Anatomically, two main types are defined as occipitoatlantal (upper cervical) and
      subaxial injuries. The purpose of this paper is to review cervical spine injuries
      in children and adolescents with respect to epidemiology, injury mechanisms,
      diagnosis, clinical and radiologic aspects, and treatment in the light of the
      current literature.

PMID- 15187459
TI  - [Thoracal injuries in adolescents].
AB  - In adolescents, the chest is frequently vulnerable to sports-related trauma due
      to its size and location. Fortunately, most of them are insignificant in nature.
      However, sports physicians should always be alert to rare serious visceral organ
      injuries.

PMID- 15187460
TI  - [Lumbar spine injuries in pediatric and adolescent athletes].
AB  - During the past two decades, there has been a significant increase in sports
      participation by pediatric athletes. Spinal injuries thus have become a great
      concern. The unique nature of the pediatric spine should be well-recognized and
      low back pain in a pediatric athlete should therefore be taken seriously and
      evaluated thoroughly. In this review article, sports-related lumbar spine
      problems will be covered including overuse injuries, spondylolysis, pars stress
      fractures, spondylolysthesis, and lumbar disc herniation. Early identification of
      these problems will eventually minimize these injuries.

PMID- 15187461
TI  - [Shoulder injuries: macrotraumas and overuse problems].
AB  - Injuries to the shoulder are becoming more frequent in pediatric and adolescent
      athletes with widespread participation in sports activities. These injuries can
      result from macrotraumas as well as microtraumas from repetitive stress. Injury
      patterns present differences in this age group due to peculiar physiologic and
      biomechanical features. Most shoulder problems in adolescent athletes can be
      treated conservatively with a good response, while some conditions require
      surgical reconstruction.

PMID- 15187462
TI  - [Elbow problems associated with sports injuries in children].
AB  - Elbow problems associated with sports injuries may result from overuse, micro- or
      macrotraumas. Overuse injuries are frequent and are often closely related to
      mechanical characteristics of sports. Sports-related elbow injuries mainly occur
      in sports involving throwing such as baseball and javelin throwing, which require
      forced valgus and extension of the elbow, predisposing it to overuse injuries.
      Overuse injuries in child athletes are generally defined as Little League elbow,
      the most common of which are medial epicondyle apophysitis, osteochondritis
      dissecans of the capitellum, radial head deformation, flexion contractures, and
      injuries to the olecranon. Most of these injuries can be healed without or with
      minimal sequelae by early diagnosis and proper treatment. Therefore, mechanisms
      of, and risk factors for, elbow problems encountered in pediatric athletes should
      be well-understood in order to avoid the risks for a permanent deformity in the
      child's anatomy.

PMID- 15187463
TI  - [Wrist injuries in children and adolescent athletes: macrotrauma and overuse].
AB  - Young children and adolescents are becoming increasingly involved in recreational
      and professional sports. This inevitably leads to an increase in the number of
      sports-related injuries involving the hand and the wrist. Hence, physicians
      should have a good insight into macro- and microtraumas affecting the hand and
      the wrist. Prevention of injuries, correction of muscle-tendon imbalances, and
      maintenance of strength and flexibility are important issues for the prevention
      of disabilities in this age group.

PMID- 15187464
TI  - [Avulsion injuries of the pelvis in adolescents].
AB  - Avulsion fractures of the apophyses of the pelvis are common in adolescent
      athletes. They usually occur as a result of trauma or overuse, involving
      especially the anterior inferior iliac spine, anterior superior iliac spine,
      anterior third of the iliac crest, tuber ischiadicum, and the symphysis pubis.
      The majority of these injuries occur during vigorous sports, with a male
      preponderance. They are often mistaken for muscle or tendon injuries. History,
      physical examination, and radiologic modalities are often helpful in diagnosis.
      Treatment may vary depending on the localization of the injury and the extent of
      fragment dislocation, but mainly remains conservative including bed rest,
      medications, and rehabilitation. Some patients may require surgical treatment,
      though.

PMID- 15187465
TI  - [Periarticular fractures of the knee in child and adolescent athletes].
AB  - Most of the sports-related lower limb injuries in children and adolescents
      involve the knee. Due to the physiological characteristics of the growing
      skeleton, fractures are more common than ligamentous injuries in this age group.
      The most frequent type of injury is distal femoral physeal fractures followed by
      proximal tibial physeal injuries. Tibial tubercle avulsions are rare. Reduction
      should be gently performed and fixation methods should ensure that no further
      damage to the physeal plate occurs. Even after proper treatment, there is a
      significant risk for subsequent leg length discrepancies and/or angular
      deformities, requiring that children be followed closely for at least two years.
      Arthroscopic techniques have become popular in recent years in the treatment of
      displaced tibial eminence fractures. Residual anterior laxity remains an
      important problem after the healing of these fractures.

PMID- 15187466
TI  - [Anterior cruciate ligament reconstruction in skeletally immature patients].
AB  - Anterior cruciate ligament (ACL) reconstructions in skeletally immature patients
      present unique difficulties, one major concern being reconstruction-induced
      growth disturbances. Another issue is the failure of adolescent patients to
      comply with the treatment programs. Initially, activity limitations and bracing
      can be recommended for isolated ACL tears in young skeletally immature
      adolescents who are at stages I, II, and III according to the modified Tanner
      classification, and for whom reconstruction can be delayed until completion of
      skeletal maturity provided that any joint instability or meniscal injury do not
      develop. For symptomatic patients, partial or complete transphyseal techniques or
      complete transphyseal reconstruction with doubled or quadrupled hamstring tendon
      grafts can be applied, with special care being afforded to keep clear distance
      between fixation materials and the physeal plates. In patients who are at
      pubertal stages of IV or V or with skeletal ages above 13 (F) or 14 (M) years, a
      transphyseal reconstruction with hamstring autografts seems to be the best
      solution. It should be kept in mind that functional outcomes of ACL
      reconstructions in skeletally immature patients are inferior to those obtained in
      adults even after a prudent surgical approach without associated growth
      disturbances.

PMID- 15187467
TI  - [Anterior knee pain in the absence of patellofemoral instability].
AB  - A wide range of disorders other than patellofemoral instability may be
      responsible for anterior knee pain and should therefore be included in the
      differential diagnosis in children and adolescents. The role of overuse and
      repetitive trauma is of utmost importance in these disorders. Moreover, systemic
      or local malignancies, referred pain especially from the hip, and psychiatric
      features specific to this age group should always be kept in mind. This article
      revisits anterior knee pain in the absence of patellofemoral instability with
      regard to etiology, examination methods, diagnosis, and treatment in the light of
      recent data and clinical experience.

PMID- 15187468
TI  - [Patellar instability: arthroscopic surgery, indications and techniques].
AB  - A significant incidence of knee pain and disability arises from patellofemoral
      disorders. An accurate diagnosis relies both on a comprehensive history and a
      careful physical examination; radiologic modalities also play an important part
      in the diagnosis and follow-up. Most patellofemoral disorders can be examined in
      three groups: pain due to soft tissue abnormalities, patellar instability, and
      patellofemoral osteoarthritis. Conservative therapy can be successful in many
      patellofemoral disorders. Surgical treatment consists of lateral release, medial
      plication and reconstruction of the medial patellofemoral ligament, proximal and
      distal realignments, patellar osteotomies, and patellectomy. In traumatic
      dislocations primary reconstruction or arthroscopy assisted medial stabilization
      can be performed.

PMID- 15187469
TI  - [Ankle fractures in children and adolescents].
AB  - Ankle fractures in children and adolescents usually involve the distal tibial and
      fibular epiphysis. Unless adequately treated, these fractures may be associated
      with many complications including limb length discrepancy and angular deformities
      due to growth arrest, and arthritis due to joint involvement. Fractures of the
      distal tibial epiphysis are classified according to the type and mechanism of
      injury. Salter-Harris type 1 and 2 fractures of the ankle have a good prognosis
      and can be treated by closed reduction. However, type 3 and 4 fractures involving
      the medial malleolus require surgical treatment because they usually result in
      compression of the physeal plate and cause angular deformities. External rotation
      of the foot may result in juvenile Tillaux fractures and triplane fractures of
      the distal tibia in the transitional period during which asymmetric physiologic
      closure of the distal tibial physis occurs. These are combinations of Salter
      Harris type 2, 3, and 4 fractures, consisting of two or three fragments. Although
      they are not associated with growth arrest, they may lead to arthritis due to
      joint involvement. The presence of residual displacement of more than two
      millimeters necessitates surgical treatment.

PMID- 15187470
TI  - [Osteochondral lesions of the talus in adolescents].
AB  - Osteochondral lesions of the talus range from those confined to the hyaline
      cartilage covering the articular surface to those involving the subchondral bone.
      The lesion may not be apparent on the surface of the cartilage or it may be
      confined to the subchondral bone without cartilage involvement. These complex
      presentations often necessitates the use of computed tomography and magnetic
      resonance imaging to delineate the exact nature of the lesions. It has been shown
      that the frequency of osteochondral lesions increase following repetitive ankle
      sprains. Although the etiology is not well understood, both traumatic and
      atraumatic causes are thought to be effective. Nevertheless, early diagnosis and
      treatment of these lesions have improved considerably thanks to the developments
      in imaging techniques. It seems that arthroscopic chondral reconstruction methods
      using autologous chondrocyte and osteochondral transplantations will gain much
      interest in the near future.

PMID- 15187471
TI  - [Foot and ankle injuries in child and adolescent athletes].
AB  - Foot and ankle injuries are most commonly encountered in athletes. Of these,
      pediatric and adolescent injuries have unique characteristics because of the
      distinct growth potentials and their consequences specific to this age group. In
      this article, foot and ankle injuries in child and adolescent athletes are
      reviewed in the light of the literature.

PMID- 15187472
TI  - [Rehabilitation and return to sports in children].
AB  - There has been a growing incidence of sports injuries among children and
      adolescents due to increased participation in sports activities. Overuse injuries
      commonly seen in this age group may be due to growth characteristics of the
      immature skeleton. Both the treatment and prevention of these injuries in
      children and adolescents require a good insight into physiologic characteristics
      of the immature skeleton, growth-related changes in musculoskeletal structures,
      and specific injury profiles. The treatment consists of determining the
      predisposing factors, restoring normal biomechanics, alleviating pain and
      inflammation, and implementing an active rehabilitation. It should also enable
      the patients to return to daily living activities and preinjury sport levels,
      with increased awareness to the possibility of recurrences. A rehabilitation
      program involving acute, subacute, and late stages, and return to sports should
      be designed to safely improve motor performance skills, performance, and sport
      specific skills.

PMID- 15187473
TI  - Perceptions and attitudes regarding sex and condom use among Chinese college
      students: a qualitative study.
AB  - Perceptions regarding sex and condom use among Chinese college students were
      examined within a framework provided by protection motivation theory. Data from
      semistructured individual interviews indicate that Chinese students generally
      perceive a low level of vulnerability to HIV and sexually transmitted disease
      (STD) infection and a minimum exposure from family to drugs and risky sexual
      behaviors. While only a small proportion of students reported being sexually
      experienced, the majority of them expressed tolerance toward premarital sex and a
      high level of perceived intrinsic rewards from sexual experience. Students view
      condoms to be efficacious in preventing pregnancy or HIV/STD, but they also
      perceive a high level of response cost for use of condoms. The findings suggest
      that efforts to adapt HIV/STD prevention programs targeting Chinese adolescents
      and young adults need to consider cultural aspects of perceptions regarding sex
      and condoms among Chinese students and to address the conflict between
      traditional Chinese cultural values and modern influences.

PMID- 15187474
TI  - Stress and health-related quality of life among HIV-infected persons in Hong
      Kong.
AB  - This study examines the relationships among illness-related factors, stress,
      health-related quality of life (HRQOL), and psychological distress in persons
      infected with the human immunodeficiency virus (HIV) living in Hong Kong (N =
      55). Participants completed questionnaires including a Symptom Checklist,
      Modified HIV Stressor Scale (HIVSS), Medical Outcomes Study Short-Form 36 (SF
      36), and the Hospital Anxiety and Depression Scale (HADS). In addition, CD4 count
      information was obtained. Multiple regression analyses were used to model the SF
      36 and HADS scores as a function of illness-related factors as well as the stress
      count and intensity. The number of symptoms was found to be inversely related to
      SF-36 general health and positively related to the HADS anxiety score. However,
      CD4 count did not have any significant association with any of the scales on the
      HRQOL or psychological distress. After controlling for the effect of symptoms,
      the HIVSS stress count still accounted significantly for additional variance in
      both HADS anxiety and depression as well as the SF-36 social functioning and role
      emotional scores. The study supports the possible contribution of psychosocial
      factors to the HRQOL and psychological distress after controlling for illness
      related factors. Results are discussed in the context of characteristic social
      factors and services in Hong Kong.

PMID- 15187475
TI  - Factors associated with HIV/AIDS knowledge and risk perception in rural Malawi.
AB  - Measures of HIV/AIDS knowledge and risk perception are important because they are
      often linked to behavioral change both in theory and in practice. This study
      examines knowledge and risk perception by assessing their relationship with
      demographic characteristics, first source of HIV/AIDS information, and behavioral
      and cognitive risk exposures among men and women in a rural district of Malawi.
      The data come from a panel study of 940 women aged 15-34 years and 661 men aged
      20-44 years. Descriptive statistics and multivariate regression models are used
      for the analysis. The results indicate that knowledge of HIV/AIDS does not
      necessarily translate into perceived risk. In addition, there appears to be a
      gender difference in the influence of cognitive and behavioral factors on
      perceived risk.

PMID- 15187476
TI  - Factors influencing medication adherence beliefs and self-efficacy in persons
      naive to antiretroviral therapy: a multicenter, cross-sectional study.
AB  - It is widely recognized that adherence to antiretroviral therapy is critical to
      long-term treatment success, yet rates of adherence to antiretroviral medications
      are frequently subtherapeutic. Beliefs about antiretroviral therapy and
      psychosocial characteristics of HIV-positive persons naive to therapy may
      influence early experience with antiretroviral medication adherence and therefore
      could be important when designing programs to improve adherence to antiretroviral
      therapy. As part of a multicenter AIDS Clinical Trial Group (ACTG 384) study, 980
      antiretroviral-naive subjects (82% male, 47% White, median age 36 years, and
      median CD4 cell count 278 cells/mm3) completed a self-administered questionnaire
      prior to random treatment assignment of initial antiretroviral medications.
      Measures of symptom distress, general health and well-being, and personal and
      situational factors including demographic characteristics, social support, self
      efficacy, depression, stress, and current adherence to (nonantiretroviral)
      medications were recorded. Associations among variables were explored using
      correlation and regression analyses. Beliefs about the importance of
      antiretroviral adherence and ability to take antiretroviral medications as
      directed (adherence self-efficacy) were generally positive. Fifty-six percent of
      the participants were "extremely sure" of their ability to take all medications
      as directed and 48% were "extremely sure" that antiretroviral nonadherence would
      cause resistance, but only 37% were as sure that antiretroviral therapy would
      benefit their health. Less-positive beliefs about antiretroviral therapy
      adherence were associated with greater stress, depression, and symptom distress.
      More-positive beliefs about antiretroviral therapy adherence were associated with
      better scores on health perception, functional health, social-emotional-cognitive
      function, social support, role function, younger age, and higher education (r
      values = 0.09-0.24, all p < .001). Among the subset of 325 participants reporting
      current use of medications (nonantiretrovirals) during the prior month,
      depression was the strongest correlate of nonadherence ( r = 0.33, p < .001). The
      most common reasons for nonadherence to the medications were "simply forgot"
      (33%), "away from home" (27%), and "busy" (26%). In conclusion, in a large,
      multicenter survey, personal and situational factors, such as depression, stress,
      and lower education, were associated with less certainty about the potential for
      antiretroviral therapy effectiveness and one's perceived ability to adhere to
      therapy. Findings from these analyses suggest a role for baseline screening for
      adherence predictors and focused interventions to address modifiable factors
      placing persons at high risk for poor adherence prior to antiretroviral treatment
      initiation.

PMID- 15187477
TI  - Long-term quality-of-life outcomes among adults living with HIV in the HAART era:
      the interplay of changes in clinical factors and symptom profile.
AB  - Changes in quality-of-life perceptions and their relations to clinical status for
      41 adult outpatients living with HIV/AIDS were assessed over a 4-year period.
      Clinical variables and quality-of-life (Medical Outcomes Study Short-Form-36)
      ratings were measured in three waves (T1, 1997; T2, 1999; T3, 2001). Mean T1-T3
      CD4 increase was 196 cells/microL (p < .0001), corresponding to a mean viral load
      reduction of 1.4 log10 copies/mL (p < .0001) and an increase in proportions with
      "undetectable" viral load status from 32% to 61% (p < .01). The T1-T2 increase in
      overall mean number of symptoms (including both disease-related symptom complex
      and treatment side effects) was mitigated by T2-T3 symptom reduction. Quality-of
      life dimensions were generally stable or slightly improved over time for the
      overall sample, a finding that contrasts with pre-highly active antiretroviral
      therapy longitudinal research. Mental aspects of quality of life remained
      consistently lower than reference norms. Results of multiple regression suggested
      that quality of life was less sensitive to immunologic/virologic changes compared
      to responsiveness to symptom changes, consistent with cross-sectional inverse
      relations between symptom burden and quality of life. CD4 repletion offset
      negative effects of symptoms for some aspects of quality of life. The long-term
      course of quality of life was somewhat predicted by viral load suppression due to
      the conjoint influence of symptoms and CD4 count.

PMID- 15187478
TI  - Predictors of HIV risk among Hispanic farm workers in South Florida: women are at
      higher risk than men.
AB  - This study examined factors associated with being at risk of sexually acquiring
      HIV among a community sample of 244 Hispanic migrant and seasonal farm workers.
      Bilingual staff interviewed respondents anonymously at worksites, camps, and
      other public venues in South Florida during the 2002 winter/spring growing
      season. The following variables were positively associated with being at risk of
      sexually acquiring HIV in multivariable analyses: being female; being married;
      having "some" or "a lot" of knowledge about HIV transmission, having ever used
      marijuana, having two or more sex partners in the last 12 months, and having had
      a sexually transmitted infection. The findings heighten the importance of
      recognizing women's elevated risk of HIV infection and conducting further studies
      to examine the factors associated with this increased risk. The study is an
      important first step toward developing tailored HIV prevention interventions for
      this at-risk, understudied population.

PMID- 15187479
TI  - Perceived stress mediates the effects of coping on the quality of life of HIV
      positive women on highly active antiretroviral therapy.
AB  - This study examined the relationship between three HIV-specific coping strategies
      (cognitive coping strategies, denial, and religious coping) and quality of life
      (QoL) in 90 HIV+, predominately minority women on highly active antiretroviral
      therapy. Religious coping was unrelated to QoL; however, use of cognitive coping
      strategies was related to greater QoL, and denial was related to poorer QoL.
      Baron and Kenny's model of mediation was then used to test perceived stress as a
      mediator of the relationships between denial and cognitive coping strategies and
      QoL. These relationships were both mediated by perceived stress. Results suggest
      that utilization of certain coping strategies may lessen or heighten perceptions
      of life stressfulness, thereby influencing QoL in this understudied population.

PMID- 15187480
TI  - Sexual behaviors and risks among bisexually- and gay-identified young Latino men.
AB  - This research compares patterns of sexual behavior and sexual risk of bisexually-
      and gay-identified Latino young men who have sex with men (YMSM). Four hundred
      forty-one Latino YMSM were surveyed at community venues in New York City. Twenty
      two percent of the sample identified as bisexual, and 78% identified as gay.
      Bisexually-identified men were more likely to report having had multiple male sex
      partners in the last 3 months and less likely to report being exclusively
      involved with a main male partner. They were also approximately 3 1/2 times more
      likely to report unprotected insertive anal intercourse at last sexual contact
      with a nonmain male partner and more likely to report being high at last contact
      with both main and nonmain male partners. Findings suggest that prevention
      programs need to address the particular sexual risk patterns of bisexually
      identified Latino YMSM that place them at risk of both HIV infection and
      transmission.

PMID- 15187481
TI  - Medication compliance and satisfaction with treatment for HIV disease in a sample
      of African-American crack cocaine smokers.
AB  - The development of treatment regimes for African-American HIV-infected crack
      cocaine users has often been based on assumptions about compliance with
      medication regimes rather than evidence. This study sought to obtain baseline
      information on the adherence to antiretroviral medications by members of this
      important risk population in Houston, Texas. It was found that for only 5 of a
      range of 16 antiviral medications was there a significant correlation between
      levels of compliance reported by respondents and their beliefs as to how
      effective these medications are. Medication compliance was also found not to be
      associated with frequency of crack cocaine use in the month prior to interview.
      Furthermore, irrespective of both gender and their reported extent of medication
      compliance, the respondents tended to report positive relationships with their
      treating physician, with higher levels of satisfaction reported by women. These
      results suggest that the majority of African-American crack cocaine users are
      able to comply with HIV treatment regimes, with more than half (53%) claiming
      full compliance for one or more medications, and a further one third (31%)
      claiming compliance more than half the time. Moreover, these findings suggest
      that they will continue to take antiretroviral medications even if they have
      doubts about the effectiveness of these medications.

PMID- 15187482
TI  - Relationship violence and women's reactions to male- and female-controlled HIV
      prevention methods.
AB  - This study examined the association of relationship violence and preference for
      three HIV prevention methods among 104 African American and Hispanic women who
      were at some risk for heterosexual transmission of HIV and other sexually
      transmitted diseases (STDs). Women completed a brief questionnaire on sexual
      behaviors and history of relationship violence. All women then watched a video
      describing three HIV/STD prevention methods (male condoms, female condoms, and
      vaginal spermicide) that included a discussion of method effectiveness, how to
      use each method, and their benefits and limitations. Participants then completed
      a questionnaire assessing their reactions to each of the three HIV prevention
      methods discussed in the video. Women in violent relationships indicated less
      likelihood of using male condoms and greater likelihood of using female
      controlled methods, particularly vaginal spermicide, than women in nonviolent
      relationships. In addition, a higher percentage of women in violent compared to
      nonviolent relationships expected their partners to prefer the vaginal spermicide
      and a lower percentage expected partners to prefer male condoms. These data
      suggest that the current focus on finding alternative HIV prevention methods for
      women in violent relationships is warranted and that a vaginal microbicidal
      product may be the preferred alternative for this group of women and their male
      partners.

PMID- 15187483
TI  - A study of condom acceptability among men in an urban population in South India.
AB  - This study examines the acceptability of condoms to men from Chennai, South
      India. A sample of 150 male respondents who, in the main, had at least one risky
      sexual experience with a commercial sex worker or multiple partners was
      interviewed. The respondents included HIV-positive and HIV-negative individuals
      at sexually transmitted disease clinics, college students, and homosexuals.
      Awareness of condom usage was high, and 83% had used condoms at least once. The
      reasons for using condoms were protection from disease (43%), protection from
      AIDS (20%), and partner insistence (25%). Seventy-three percent of the
      respondents expressed dissatisfaction. Of those who used condoms for the first
      time, 72% were HIV negative, compared to 34% among those who did not use condoms.
      This indicates the need for developing the "condom habit," as using condoms at
      the first sexual experience is a strong predictor of future condom use.

PMID- 15187484
TI  - [Urticaria-up to date].

PMID- 15187485
TI  - [Planning, administration, and management of the clinical trial based on EBM 
      what are key points to generate valid evidence?].

PMID- 15187486
TI  - [Acute effect of inhaled beta(2)-agonists with different type of intrinsic
      activity on airway resistance in healthy volunteers].
AB  - Inhaled beta(2)-agonists (long-acting as well as short acting) are used world
      wide for the relief of asthma symptoms. However, there are few reports which have
      evaluated the additive effect of short-acting beta(2)-agonists to long-acting
      beta(2)-agonists on airway resistance measured by a plethysmography. This study
      was designed to evaluate the additive effect of inhaled short-acting beta(2)
      agonists (protecarol) to long-acting beta(2)-agonists (salmeterol) on airway
      resistance in normal healthy volunteers (S+P group). In addition, to compare the
      effects of beta(2)-agonists which have different types of intrinsic activities,
      acute effect of inhaled procaterol adding to procaterol was also evaluated (P+P
      group). Seven healthy volunteers (all male and all non-smokers) were entered in
      this study. Pulmonary function was measured by a body plethysmography. Forced
      expiratory volume per 1 second (FEV1), the maximum flow rate at 25% (V(.) 25),
      the maximum flow rate at 50% of forced vital capacity (V(.) 50), and airway
      resistance were measured before and after inhalation of salmeterol (1 dry powder,
      50 microg) or procaterol (2 puffs, 20 microg). Sixty minutes after inhalation of
      salmeterol, or 15 minutes after inhalation of procaterol, inhalation of
      procaterol (2 puffs, 20 microg) was added, and then pulmonary function was
      monitored. FEV1, V(.) 25, and V(.) 50 were significantly increased after
      inhalation of salmeterol as well as procaterol. In addition, airway resistance
      decreased significantly after inhalation of salmeterol as well as procaterol. In
      the S+P group, additional decrease of airway resistance after inhalation of
      procaterol was relatively small compared with the P+P group. In conclusion,
      although additional bronchodilatoric effects were observed in the S+P and P+P
      group, the effects seemed to be different based on the intrinsic activity of each
      beta(2)-agonist.

PMID- 15187487
TI  - [Comparison of the inhibitory effects of glucocorticoids on the expression of
      eotaxin in airway epithelial cell line BEAS-2B].
AB  - OBJECTIVE: Inhaled corticosteroids play a pivotal role in the treatment of
      asthma. To observe the mechanisms of glucocorticoids, we focused our study on the
      comparison of several glucocorticoids' effects on eotaxin expression in the
      airway epithelial cells. METHODS: Airway epithelial cell line BEAS-2B was
      cultured in vitro. Cells were preincubated with or without glucocorticoids
      (becromethasone dipropionate; BDP, budesonide; BUD, fluticasone propionate; FP)
      and stimulated with TNFalpha and/or IL-4. Protein levels of eotaxin in the
      supernatants of the cultured cells were determined by ELISA. RESULTS AND
      CONCLUSIONS: TNFalpha and IL-4 increased the levels of eotaxin in BEAS-2B cells.
      Combination of these cytokines synergistically upregulated the eotaxin expression
      as reported previously. Each glucocorticoid significantly inhibited the
      expression of eotaxin protein induced with TNFalpha and IL-4 and the compared
      efficacy was in order of FP>BUD>BDP. FP seemed most potent and the inhibitory
      effect was also observed with relatively low concentration such as 10 (-10)M.
      Taken together, the comparison of the potency of each glucocorticoid using airway
      epithelial cells may reflect the efficacy of these drugs in asthmatics.

PMID- 15187488
TI  - [Atopic cough caused by basidiomycetes antigen; the importance as a fungal
      aeroallergen in occupational environment].
AB  - We report here a 28-year-old woman with severe atopic cough in which
      Basidiomycetes antigen was an etiologic agent. She did not have bronchial
      hyperresponsiveness to methacholine or heightened bronchomotor tone.
      Bronchodilator therapy was not effective against her coughing. Her cough worsened
      in her office, suggesting the existence of some etiologic agents. Basidiomycetes
      was isolated from her office, and bronchoprovocation test with Basidiomycetes
      antigen was positive. 19 coworkers and 29 control subjects underwent skin test
      with Basidiomycetes extract. The rate of positive skin test to Basidiomycetes was
      significantly greater in coworkers than in control subjects (P=0.0069). These
      results indicate that a significant number of coworkers are sensitized to
      Basidiomycetes antigen and suggest that the Basidiomycetes may be an important
      fungal aeroallergen in occupational environment.

PMID- 15187489
TI  - [Oral allergy syndrome among patients with birch pollinosis in Sapporo].
AB  - We evaluated the relationships between oral and pharyngeal hypersensitivity to
      fruits and vegetables (oral allergy syndrome) and birch pollinosis in 2003 in
      Sapporo. 1. Of 153 patients with birch pollinosis (seasonal nasal or ocular
      symptom and CAP positive [birch pollen CAP score 2 or more]), 65 patients (42%)
      have episode of oral allergy syndrome (OAS). And that rate in 2003 was higher
      than in 1992 and was equal to in 1998. 2. Among birch pollinosis patients, the
      higher the CAP score of birch pollen, the higher the prevalences of OAS were
      found to be. 3. Among birch pollinosis patients, female have OAS much more than
      male. 4. Among birch pollinosis patients in 1998, patients who visited to ENT
      clinic for medical consultation of birch pollinosis in March and April have OAS
      much more than patients who visited in May and June.

PMID- 15187490
TI  - [A case of eosinophilic gastroenteritis: observation of serum IL-5 and sIL-2R
      levels before and after remission].
AB  - 56 years-old man was admitted to our hospital because of severe diarrhea and
      hypereosinophilia. There was tenderness in the middle part of his abdomen.
      Laboratory examination revealed elevation of serum IL-5 and serum IL-2R value. No
      pathogens were detected from his stool specimen. An abdominal CT showed neither
      ascites nor thickening of intestinal wall. Pathological finding showed marked
      eosinophil infiltration in gastric and colonic mucosa. Eosinophilic
      gastroenteritis was diagnosed. His symptom was gradually improved spontaneously
      at the point of diagnosis. But administration of suplatast tosilate was stared
      because patients with this disease often relapse. Abdominal symptom was
      completely disappeared and value of serum IL-5 and sIL-2R was decreased at the
      end of September. This finding may imply pathogenesis of this disease.

PMID- 15187491
TI  - National Kidney Disease Education Program in 2004: a program in evolution.

PMID- 15187492
TI  - Mortality in patients with microvascular disease.
AB  - Patients with chest pain/ischemic cardiac disease and normal coronary
      arteriography are thought to have a benign prognosis despite diminished quality
      of life. Many patients with hypertension fall into this group, at least in the
      early stage of their disease. Whether abnormalities in coronary flow reserve in
      these patients are associated with increased morbidity and mortality is unknown.
      One hundred sixty-eight patients with chest pain/ischemic cardiac disease and
      normal coronary angiograms who underwent invasive measures of coronary flow
      reserve were followed longitudinally. Mortality and quality of life were
      ascertained by query of the national death index and telephone administration of
      standardized questionnaires. Patient follow-up occurred at a mean of 8.5 years.
      In the abnormal coronary flow reserve group, 12 deaths (20%) were documented in
      60 patients compared with eight out of 108 patients (7%; p=0.016) with normal
      coronary flow reserve. Coronary flow reserve did not predict impairment in
      functional health status in long-term follow-up. Thus, invasive measures of
      coronary flow reserve in patients with chest pain/ischemic cardiac disease and
      normal coronary angiograms predicted increased mortality. Surviving patients with
      chest pain/ischemic cardiac disease and normal coronary angiograms have
      significant morbidity.

PMID- 15187494
TI  - Angiotensin II receptor blockers: the importance of dose in cardiovascular and
      renal risk reduction.
AB  - Numerous clinical studies have established that angiotensin II receptor blockers
      are effective as antihypertensive therapy and are well tolerated. Studies
      demonstrate that adding an angiotensin II receptor blocker to existing
      antihypertensive regimens reduces cardiovascular and renal risk, which may, in
      part, be a result of blocking the effects of angiotensin II. Though the
      antihypertensive dose response of these agents is well documented, the dose
      response for optimal target organ protection has not yet been clarified. A review
      of recent studies of angiotensin II receptor blockers in hypertension, acute
      myocardial infarction, heart failure, and nephropathy provide some data on
      specific drugs, doses, and risk reduction. Taken as a whole, these studies
      suggest the highest doses tested, which are at the upper limit of the
      antihypertensive range, provide greater risk reduction than lower doses. What is
      unknown is whether even higher doses or full-dose angiotensin II receptor
      blockers plus full-dose angiotensin-converting enzyme inhibitors might provide
      even greater risk reduction. Data from ongoing trials will provide additional
      insight.

PMID- 15187493
TI  - Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in
      African-American patients with hypertension.
AB  - African-American patients with hypertension are less responsive to blockers of
      the renin-angiotensin system than white patients. The relative efficacy of
      angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and
      the extent of cross-resistance to these agents has not been studied. Fifty-one
      African-American patients with stage 1-2 hypertension were randomly assigned to
      enalapril or candesartan cilexetil for 8 weeks and then crossed over to the other
      treatment. Nonresponders to enalapril and candesartan used a combination of the
      two. Of the 51 patients randomized (average age 61.2+/-9 years, blood pressure
      148/100 mm Hg, heart rate 74 bpm, and body weight 92.8 kg), 44 completed the
      study. At Week 8, systolic blood pressure (SBP) was reduced by 4.8 mm Hg with
      enalapril and by 4.7 mm Hg with candesartan (p=NS), and diastolic blood pressure
      (DBP) was reduced by 4.4 mm Hg and 5.6 mm Hg, respectively (p<0.04). Of these 44
      patients, 11 (25%) responded to enalapril by SBP criteria and 19 (43%) by DBP
      criteria. Seven patients (16%) responded by both SBP and DBP criteria, and 21
      patients (48%) were nonresponders. With candesartan, 13 patients (29%) responded
      by SBP criteria, 20 (45%) by DBP criteria and 12 (27%) by both SBP and DBP
      criteria (p<0.04, compared with enalapril). Only six patients (14%) responded to
      both enalapril and candesartan by both SBP and DBP criteria. Of the 18
      nonresponders to either enalapril or candesartan, the combination of the two had
      minimal additional effect. Significant changes in plasma-renin activity and
      angiotensin II levels were noted only with the high dose of each drug. In this
      small group of patients, treatment with candesartan resulted in slightly higher
      response and control rates than enalapril, more than 40% of patients who
      responded to enalapril did not respond to candesartan and vice versa, and in
      nonresponders, a combination of candesartan and enalapril offered little
      additional antihypertensive effect.

PMID- 15187495
TI  - Hypertension control among African Americans: an urgent call for action.

PMID- 15187496
TI  - Is sodium restriction important to hypertension? The argument for.

PMID- 15187497
TI  - Is sodium restriction important to hypertension? The argument against.

PMID- 15187499
TI  - Coarctation of the aorta: a secondary cause of hypertension.
AB  - Coarctation of the aorta is a constriction of the aorta located near the
      ligamentum arteriosum and the origins of the left subclavian artery. This
      condition may be associated with other congenital disease. The mean age of death
      for persons with this condition is 34 years if untreated, and is usually due to
      heart failure, aortic dissection or rupture, endocarditis, endarteritis, cerebral
      hemorrhage, ischemic heart disease, or concomitant aortic valve disease in
      uncomplicated cases. Symptoms may not be present in adults. Diminished and
      delayed pulses in the right femoral artery compared with the right radial or
      brachial artery are an important clue to the presence of a coarctation of the
      aorta, as are the presence of a systolic murmur over the anterior chest,bruits
      over the back, and visible notching of the posterior ribs on a chest x-ray. In
      many cases a diagnosis can be made with these findings. Two-dimensional
      echocardiography with Doppler interrogation is used to confirm the diagnosis.
      Surgical repair and percutaneous intervention are used to repair the coarctation;
      however, hypertension may not abate. Because late complications including
      recoarctation, hypertension, aortic aneurysm formation and rupture, sudden death,
      ischemic heart disease, heart failure, and cerebrovascular accidents may occur,
      careful follow-up is required.

PMID- 15187500
TI  - Diastolic blood pressure control: how low is too low?

PMID- 15187501
TI  - Intensive care unit physician staffing: financial modeling of the Leapfrog
      standard.
AB  - OBJECTIVE: To evaluate from a hospital's perspective the costs and savings, over
      a 1-yr period, of implementing The Leapfrog Group's Intensive Care Unit Physician
      Staffing (IPS) standard compared with the existing standard of nonintensivist
      staffing in adult intensive care units. DESIGN: Using published data, we
      developed a financial model of costs and savings for 6-, 12- and 18-bed intensive
      care units using conservative estimates for all variables. Sensitivity analyses,
      including a best-case and worst-case scenario, were performed to evaluate the
      impact of changing assumptions on the outcome of the model. SETTING: Nonrural
      hospitals in the United States. PATIENTS: : All adult intensive care unit
      patients. INTERVENTIONS: The IPS standard requires that intensive care units have
      a dedicated intensivist present during daytime hours. Outside of these hours, an
      intensivist must be immediately available by pager, and a physician or "physician
      extender" must be in the hospital and able to immediately reach intensive care
      unit patients. MEASUREMENTS AND MAIN RESULTS: Cost savings ranged from 510,000 to
      3.3 million US dollars for 6- to 18-bed intensive care units. The best-case
      scenario demonstrated savings of 4.2-13 million US dollars. Under the worst-case
      scenario, there was a net cost of 890,000 to 1.3 million US dollars. CONCLUSIONS:
      Financial modeling of implementation of the IPS standard using conservative
      assumptions demonstrated cost savings to hospitals. Only under worst-case
      scenario assumptions did intensivist staffing result in additional cost to
      hospitals. These economic findings must be interpreted in the context of
      significant reductions in patient morbidity and mortality rates also associated
      with intensivist staffing. Given the magnitude of its clinical and financial
      impact, hospital leaders should be asking "how to" rather than "whether to"
      implement The Leapfrog Group's ICU Physician Staffing standard.

PMID- 15187502
TI  - Critical care medicine in the United States 1985-2000: an analysis of bed
      numbers, use, and costs.
AB  - OBJECTIVE: To establish a database that permits description and analysis of the
      evolving role, patterns of use, and costs of critical care medicine (CCM) in the
      United States from 1985 to 2000. DESIGN: Retrospective study combining data from
      federal (Hospital Cost Report Information System, Center for Medicare and
      Medicaid Services, Baltimore, MD) and private (Hospital Statistics, American
      Hospital Association, Chicago, IL) databases to analyze U.S. hospitals, hospital
      and CCM beds, and occupancy. CCM costs were calculated by the Russell equation
      and compared with national health care and financial indexes. SETTING:
      Nonfederal, acute care hospitals with CCM units in the United States. SUBJECTS:
      None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed hospitals
      with CCM units and focused on hospital and CCM beds, CCM occupancy, and CCM
      costs. CCM costs were compared with national cost indexes. Between 1985 and 2000,
      the total number of U.S. hospitals decreased by 8.9% (6,032 to 5,494) and acute
      care hospitals offering CCM decreased by 13.7% (4,150 to 3,581). The total number
      of beds in hospitals with CCM units decreased by 26.4% (889,600 to 654,400). In
      contrast, CCM beds increased by 26.2% (69,300 to 87,400). CCM occupancy was
      constant at 65%. CCM bed costs per day increased by 126% (1,185 to 2,674 US
      dollars). Although CCM costs increased by 190.4% (19.1 billion to 55.5 billion US
      dollars), the proportion of national health expenditures allocated to CCM
      decreased by 5.4%. In 2000, CCM costs represented 13.3% of hospital costs, 4.2%
      of national health expenditures, and 0.56% of the gross domestic product.
      CONCLUSIONS: CCM is increasingly used and prominent in a shrinking U.S. hospital
      system. CCM occupancy is lower than expected. Despite its increasing use and
      cost, CCM is using proportionally less of national health expenses and the gross
      domestic product than previously estimated.

PMID- 15187503
TI  - Ventilation of patients with acute lung injury and acute respiratory distress
      syndrome: has new evidence changed clinical practice?
AB  - OBJECTIVES: A recent randomized trial of mechanical ventilation in acute lung
      injury (ALI)/adult respiratory distress syndrome (ARDS) demonstrated a 22%
      relative reduction in mortality rate using 6 mL/kg predicted body weight tidal
      volume vs. 12 mL/kg predicted body weight tidal volume. We determined whether
      publication of these findings changed clinical practice. DESIGN: Retrospective
      cohort, 12 months before (Pre) and 12 months after publication (Post) of a
      randomized trial supporting the use of a 6 mL/kg predicted body weight tidal
      volume strategy. SETTING: Three tertiary care hospitals in northern New England.
      PATIENTS: From a sample of 943 patients receiving prolonged mechanical
      ventilation between 1998 and 1999 (Pre) and between 2000 and 2001 (Post), 300
      patients meeting the American-European Consensus Conference definition of ALI or
      ARDS were selected for analysis. INTERVENTIONS: The tidal volume, tidal volume/kg
      predicted body weight, and proportion receiving tidal volume/kg > or =6 mL/kg and
      < or =12 mL/kg predicted body weight were recorded at noon the first day after
      the diagnosis of ALI or ARDS was established. MEASUREMENTS AND MAIN RESULTS: Pre
      and Post mean tidal volume (+/- sd) size and tidal volume size/kg predicted body
      weight were 759 +/- 158 mL (median 750 mL) vs. 639 +/- 138 mL (median 600 mL, p
      <.001) and 12.3 +/- 2.7 mL/kg (median 11.7 mL/kg) vs. 10.6 +/- 2.4 mL/kg (median
      10.7 mL/kg, p <.001) respectively. Pre and Post plateau pressures and peak airway
      pressures were similar. CONCLUSION: Publication of a trial demonstrating large
      mortality reductions using small tidal volume was associated with significant
      reductions in tidal volume delivered to patients with ALI/ARDS. However, wide
      variation in practice persists, and the proportion of patients receiving tidal
      volumes within recommended limits (< or =8 mL/kg) remains modest.

PMID- 15187504
TI  - Endocrinologic response to vasopressin infusion in advanced vasodilatory shock.
AB  - OBJECTIVES: To evaluate the endocrinologic response to a combined arginine
      vasopressin and norepinephrine (AVP/NE) infusion in advanced vasodilatory shock,
      and to examine the relationship between baseline plasma AVP concentrations and
      the hemodynamic response to AVP. DESIGN: Preliminary, prospective, randomized,
      controlled clinical study. SETTING: Twenty-three-bed general and surgical
      intensive care unit. PATIENTS: Thirty-eight patients with advanced vasodilatory
      shock. Hemodynamic and laboratory data of 34 patients have already been presented
      in a recently published prospective, randomized, controlled study. INTERVENTIONS:
      Continuous AVP (4 units/hr) and NE infusion in study patients; NE infusion only
      in control patients. MEASUREMENTS AND MAIN RESULTS: At baseline, 24 hrs, and 48
      hrs after randomization, plasma concentrations of AVP, adrenocorticotropic
      hormone, cortisol, renin, angiotensin II, aldosterone, prolactin, endothelin I,
      and atrial natriuretic factor were determined. Hemodynamic variables were
      recorded at baseline and 1, 12, and 24 hrs after randomization. Linear mixed
      effects models were used to test for differences between groups. The relationship
      between AVP plasma concentrations and hemodynamic response to AVP was analyzed
      using linear regression analyses. AVP/NE patients exhibited significantly higher
      AVP (p <.001) and prolactin (p <.001) plasma concentrations during the study
      period; there were no significant differences in plasma concentrations of other
      hormones. No significant correlation was detected between plasma AVP
      concentrations and the increase in mean arterial pressure after 1 hr (Pearson's
      correlation coefficient =.134, p =.584) and after 24 hrs (Pearson's correlation
      coefficient = -.198, p =.417). There were further no correlations between AVP
      plasma concentrations and the 24-hr response to AVP therapy in heart rate
      (Pearson's correlation coefficient = -.065, p =.791), stroke volume index
      (Pearson's correlation coefficient = -.106, p =.687), and NE requirements
      (Pearson's correlation coefficient =.04, p =.869). CONCLUSIONS: The preliminary
      results of this study indicate that a combined AVP and NE infusion increases
      prolactin plasma concentrations in advanced vasodilatory shock. Hemodynamic
      effects of AVP infusion are independent of baseline plasma AVP concentrations.

PMID- 15187505
TI  - Daily interruption of sedative infusions and complications of critical illness in
      mechanically ventilated patients.
AB  - OBJECTIVE: In critically ill patients receiving mechanical ventilation, daily
      interruption of sedative infusions decreases duration of mechanical ventilation
      and intensive care unit length of stay. Whether this sedation strategy reduces
      the incidence of complications commonly associated with critical illness is not
      known. DESIGN: Blinded, retrospective chart review. SETTING: University-based
      hospital in Chicago, IL. PATIENTS: One hundred twenty-eight patients receiving
      mechanical ventilation and continuous infusions of sedative drugs in a medical
      intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We
      performed a blinded, retrospective evaluation of the database from our previous
      trial of 128 patients randomized to daily interruption of sedative infusions vs.
      sedation as directed by the medical intensive care unit team without this
      strategy. Seven distinct complications associated with mechanical ventilation and
      critical illness were identified: a) ventilator-associated pneumonia; b) upper
      gastrointestinal hemorrhage; c) bacteremia; d) barotrauma; e) venous
      thromboembolic disease; and f) cholestasis or g) sinusitis requiring surgical
      intervention. The incidence of complications was evaluated for each patient's
      hospital course. One hundred twenty-six of 128 charts were available for review.
      Patients undergoing daily interruption of sedative infusions experienced 13
      complications (2.8%) vs. 26 (6.2%) in those subjected to conventional sedation
      techniques (p =.04). CONCLUSIONS: Daily interruption of sedative infusions in
      critically ill patients undergoing mechanical ventilation reduces intensive care
      unit length of stay and, in turn, decreases the incidence of complications of
      critical illness associated with prolonged intubation and mechanical ventilation.

PMID- 15187506
TI  - Cost-effectiveness of proton pump inhibitor therapy for acute peptic ulcer
      related bleeding.
AB  - OBJECTIVE: The purpose of this investigation was to perform a cost-effectiveness
      analysis of adjunctive oral and intravenous proton pump inhibitor (PPI) therapies
      for patients with acute peptic ulcer-related bleeding of sufficient severity to
      warrant hospitalization. DESIGN: Cost-effectiveness investigation. Four clinical
      scenarios were considered: scenario 1, diagnostic endoscopy with oral PPI
      therapy; scenario 2, diagnostic and therapeutic endoscopy with high-dose
      intravenous PPI therapy; scenario 3, diagnostic and therapeutic endoscopy
      available with oral PPI therapy; and scenario 4, diagnostic and therapeutic
      endoscopy (no PPI). Effectiveness was evaluated in terms of episodes of bleeding
      averted and quality-adjusted life years. SETTING: University teaching hospital in
      the United States. PATIENTS: Hospitalized patients with acute peptic ulcer
      bleeding. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Therapeutic
      endoscopy with high-dose intravenous PPI therapy (scenario 2) was the most cost
      effective approach in terms of bleeding episode averted (8,490 vs. 10,201 US
      dollars for scenario 1, 8,756 US dollars for scenario 3, and 12,459 US dollars
      for scenario 4) and per quality-adjusted life year (4,810 vs. 5,533 US dollars
      for scenario 1, 4,946 US dollars for scenario 3, and 5,876 US dollars for
      scenario 4). The high-dose intravenous PPI scenario was the dominant approach as
      evidenced by both superior effectiveness and lower costs over the range of
      probability and cost variables used in the sensitivity analysis. However, the
      dominance would be lost if the purchase cost of the intravenous PPI was
      substantially higher than the baseline cost assumed in this investigation (61 US
      dollars per 3-day course of therapy). CONCLUSION: High-dose intravenous PPI
      therapy in conjunction with therapeutic endoscopy is the most cost-effective
      approach for the management of hospitalized patients with acute peptic ulcer
      bleeding.

PMID- 15187507
TI  - Variability among hospital policies for determining brain death in adults.
AB  - OBJECTIVE: In the absence of federal requirements or state statutes, criteria to
      certify brain death are specified by medical staff and administrative policies in
      individual hospitals. Variability among such policies may allow inconsistency in
      the declaration of death by neurologic criteria. Our intent was to partially
      quantify diversity among hospital standards used in brain death certification.
      DESIGN: Survey. SETTING: Six hundred randomly selected hospitals. PATIENTS: None.
      INTERVENTIONS: A survey was conducted of 600 hospitals randomly selected from the
      American Hospital Association registry representing 200 hospitals each of <300
      beds, 300-500 beds, and >500 beds. One hundred six policies submitted by these
      institutions comprised the final study group. Policies were reviewed for criteria
      of interest and were compared against variables recommended by the American
      Academy of Neurology. MEASUREMENTS AND MAIN RESULTS: Significant variability in
      policy criteria was found compared with the American Academy of Neurology and
      other authoritative standards. Differences were greatest in specifying conditions
      to be excluded before testing and in specific testing methods during a detailed
      physical examination. The few differences noted between larger vs. smaller
      hospitals most likely reflect greater availability of resources in larger
      institutions. CONCLUSIONS: Differences among hospital policies for certification
      of brain death may permit variability among hospitals throughout the United
      States in the pronouncement of death by neurologic criteria. Standardization and
      enforcement of policies that ensure the highest possible accuracy should be
      considered.

PMID- 15187508
TI  - Barriers to providing lung-protective ventilation to patients with acute lung
      injury.
AB  - OBJECTIVE: No studies have explored the barriers to implementing lung-protective
      ventilation in patients with acute lung injury (ALI) and acute respiratory
      distress syndrome (ARDS). Our objective was to identify barriers to using lung
      protective ventilation in patients with ALI/ARDS. DESIGN: Survey with content
      analysis of open-ended responses. SETTING: Medical center. PARTICIPANTS:
      Experienced intensive care unit nurses and respiratory therapists network
      identified through purposive sampling at hospitals from the ARDS Network, a
      National Institutes of Health-sponsored research consortium. INTERVENTIONS:
      Survey. RESULTS: Fifty-five surveys representing all ten ARDS Network sites were
      received. Twenty-seven (49%) of the respondents were intensive care unit nurses,
      24 (44%) were respiratory therapists, and four did not indicate their profession.
      Clinicians had used lung-protective ventilation in a median of 20 (interquartile
      range, 10-50) patients with ALI/ARDS. Respondents identified physician
      willingness to relinquish control of ventilator, physician recognition of
      ALI/ARDS, and physician perceptions of patient contraindications to low tidal
      volumes as important barriers to initiating lung-protective ventilation.
      Important barriers to continuing patients on lung-protective ventilation were
      concerns over patient discomfort and tachypnea and concerns over hypercapnia,
      acidosis, and hypoxemia. Techniques for overcoming barriers were identified
      including specific ventilator setup recommendations, clinician education, and
      tools to assess patient discomfort. CONCLUSIONS: Experienced bedside clinicians
      perceive important barriers to implementing lung-protective ventilation.
      Successful strategies to increase use of lung-protective ventilation should
      target these barriers.

PMID- 15187509
TI  - Prognostic factors in obstetric patients admitted to an Indian intensive care
      unit.
AB  - OBJECTIVES: Obstetric patients form a significant proportion of intensive care
      unit admissions in countries like India, where maternal mortality is high (440
      per 100,000 deliveries). We studied the diseases requiring intensive care and
      prognostic factors in obstetric patients. DESIGN: Retrospective chart review.
      Acute Physiology and Chronic Health Evaluation (APACHE) II data were
      prospectively collected. SETTING: Multidisciplinary intensive care unit of a
      public hospital in Mumbai, India. PATIENTS: Women admitted during pregnancy or 6
      wks post-partum during a 5-yr study period (1997-2001). INTERVENTIONS: None.
      MEASUREMENTS AND MAIN RESULTS: Four hundred fifty-three obstetric patients (age
      25.5 +/- 4.6 yrs [mean +/- SD], mean gestational age 31 wks) were admitted (548
      intensive care unit admissions per 100,000 deliveries), 138 with single organ
      failure and 152 with multiple organ failure. Ninety-eight women died (mortality
      rate 21.6%). Mortality was comparable in antepartum (n = 216) and postpartum (n =
      247) admissions but increased with increasing number of organs affected. There
      were 236 fetal deaths (52%), of which 104 occurred before hospital admission.
      Median APACHE II score was 16 (interquartile range, 10-24), and standardized
      mortality ratio (observed deaths/predicted deaths) was 0.78. Compared with
      pregnant patients admitted with obstetric disorders (n = 313), those with medical
      diseases (n = 140) had significantly lower APACHE II scores (median 14 vs. 17)
      but higher observed mortality rate (28.6% vs. 18.5%; odds ratio, 1.76; 95%
      confidence interval, 1.08-2.87) and standardized mortality ratio (1.09 vs. 0.66).
      On multivariate analysis, increased mortality rate was associated with acute
      cardiovascular (odds ratio, 5.8), nervous system (odds ratio, 4.73) and
      respiratory (odds ratio, 12.9) failure, disseminated intravascular coagulation
      (odds ratio, 2.4), viral hepatitis (odds ratio, 5.8), intracranial hemorrhage
      (odds ratio, 5.4), absence of prenatal care (odds ratio, 1.94), and >24 hrs
      interval between onset of acute symptoms and intensive care unit admission (odds
      ratio, 2.3). CONCLUSIONS: Multiple organ failure is common in obstetric patients;
      mortality rate increases with increasing organ failure. APACHE II scores
      overpredict mortality rate. Standardized mortality ratio is lower in obstetric
      disorders than in medical disorders. Lack of prenatal care and delay in intensive
      care unit referral adversely affect outcome and are easily preventable.

PMID- 15187510
TI  - Autonomic activity in trauma patients based on variability of heart rate and
      respiratory rate.
AB  - OBJECTIVE: To evaluate the effects of sympathetic and parasympathetic nervous
      system activity on the heart rate and other hemodynamic variables in acute
      emergency patients with mild to moderately severe trauma. DESIGN: Clinical study.
      SETTING: Level 1 university-run trauma service. PATIENTS: Fourteen trauma
      patients studied immediately after admission to the emergency department.
      INTERVENTIONS: We measured heart rate and respiratory rate variability by
      spectral analysis in the early period of mildly to moderately injured patients
      and compared the patterns of the low- (Lfa) and high-frequency (Hfa) areas of
      variability. MEASUREMENTS AND MAIN RESULTS: The Lfa is the area under the
      spectral analysis curve within the frequency range of 0.04-0.10 Hz. This area
      reflects primarily the tone of the sympathetic nervous system as mediated by the
      cardiac nerve. The respiratory area or Hfa is a 0.12 Hz-wide frequency range
      centered around the fundamental respiratory frequency defined by the peak mode of
      the respiratory power spectrum. It is indicative of vagal outflow reflecting
      parasympathetic nervous system activity. The Lfa/Hfa, or "L/R ratio," reflects
      the balance between the sympathetic and parasympathetic nervous systems. The
      hemodynamic effects of bursts of autonomic activity in response to injury were
      explored by heart rate and respiratory rate variability measured with non
      invasive hemodynamic monitoring consisting of bioimpedance cardiac output, heart
      rate, and mean arterial pressure to measure cardiac function and transcutaneous
      oxygen (PtcO2) to reflect tissue perfusion. During sudden surges of autonomic
      activity, we described increased heart rate variability reflecting increased Lfa
      and to a lesser degree to Hfa. Slightly later there was increased heart rate,
      mean arterial pressure, and cardiac index but decreased tissue perfusion
      indicated by the decreased PtcO2/FIO2 ratio. CONCLUSIONS: Surges in autonomic
      activity in the period immediately after emergency department admission of trauma
      patients were associated with pronounced increases in cardiac index, mean
      arterial pressure, and heart rate and reduced tissue oxygenation.

PMID- 15187511
TI  - Computerized physician order entry of diagnostic tests in an intensive care unit
      is associated with improved timeliness of service.
AB  - OBJECTIVE: To measure the effect of computerized physician order entry on
      timeliness of urgent laboratory and imaging tests. DESIGN: Before-after. SETTING:
      Eleven-bed medical-surgical intensive care unit in a tertiary teaching hospital.
      PATIENTS: All patients who had "stat" laboratory or imaging tests ordered during
      each of two 1-month periods 10 months before and 2 months after introducing
      computerized physician order entry. INTERVENTIONS: Introduction of computerized
      physician order entry. MEASUREMENTS AND MAIN RESULTS: After computerized
      physician order entry was introduced, median time from ordering to obtaining
      laboratory specimens decreased from 77 to 21.5 mins, median time from ordering to
      laboratory result being reported decreased from 148 to 74 mins, and median time
      from ordering to imaging completed decreased from 96.5 to 29.5 mins. CONCLUSIONS:
      Introduction of computerized physician order entry for ordering "stat" tests in
      an intensive care unit is associated with improved timeliness of these tests.

PMID- 15187512
TI  - Recombinant human atrial natriuretic peptide in ischemic acute renal failure: a
      randomized placebo-controlled trial.
AB  - OBJECTIVE: Acute renal failure is associated with significant morbidity and
      mortality rates. Need for dialysis is an independent risk factor for early
      mortality after complicated cardiac surgery. Human atrial natriuretic peptide (h
      ANP) is a potent endogenous natriuretic and diuretic substance. Exogenous
      administration of h-ANP increases glomerular filtration rate and renal blood flow
      in clinical acute renal failure. We have studied the effects of h-ANP on renal
      outcome in ischemic acute renal failure. DESIGN: A prospective, double-blind,
      randomized, placebo-controlled study. SETTING: Cardiothoracic intensive care
      units of two tertiary care centers. PATIENTS: Sixty-one patients with normal
      preoperative renal function suffering from postcardiac surgical heart failure
      requiring significant inotropic and vasoactive support. INTERVENTIONS: The
      patients were randomized to receive a continuous infusion of either recombinant h
      ANP (50 ng.kg(-1).min(-1)) or placebo when serum creatinine increased by >50%
      from baseline. The treatment with h-ANP/placebo continued until serum creatinine
      decreased below the trigger value for inclusion or the patients fulfilled
      predefined criteria for dialysis. MEASUREMENTS AND MAIN RESULTS: The primary
      outcome variable was dialysis on or before day 21 after the start of treatment.
      Secondary renal outcome variables were dialysis-free survival at day 21 and
      creatinine clearance. Twenty-nine patients were assigned h-ANP and 30 placebo.
      Six (21%) patients in the h-ANP group compared with 14 (47%) in the placebo group
      needed dialysis before or at day 21 (hazard ratio, 0.28; 95% confidence interval,
      0.10-0.73; p =.009). Eight (28%) patients in the h-ANP group compared with 17
      (57%) in the placebo group suffered from the combined end point dialysis or death
      before or at day 21 (hazard ratio, 0.35; 95% confidence interval, 0.14-0.82; p
      =.017). h-ANP improved creatinine clearance in contrast to placebo (p =.040).
      CONCLUSIONS: Infusion of h-ANP at a rate of 50 ng.kg(-1).min(-1) enhances renal
      excretory function, decreases the probability of dialysis, and improves dialysis
      free survival in early, ischemic acute renal dysfunction after complicated
      cardiac surgery.

PMID- 15187513
TI  - Multifactorial risk analysis of bone marrow histiocytic hyperplasia with
      hemophagocytosis in critically ill medical patients--a postmortem
      clinicopathologic analysis.
AB  - OBJECTIVE: Systematic studies of the prevalence and risk factors of histiocytic
      hyperplasia with hemophagocytosis (HHH) in critically ill patients are lacking.
      The aim of our study was a) to determine the frequency and intensity of HHH in
      the bone marrow of patients who died on the medical intensive care unit; b) to
      analyze morphologic bone marrow changes; and c) to identify possible risk factors
      and their interactions in the pathogenesis of HHH. DESIGN: A retrospective
      observational analysis of clinical data and autopsy findings including histologic
      and immunohistological analysis of bone marrow to characterize cellularity,
      siderosis, hemophagocytosis, and T-cell infiltrates. SETTING: The medical
      intensive care unit of a university hospital. PATIENTS: Patients were 107
      consecutive patients who died and underwent autopsy. INTERVENTIONS: None.
      MEASUREMENTS AND MAIN RESULTS: HHH was identified in 69 of the 107 patients
      (64.5%). Moderate to severe HHH was present in 35 of the 107 bone marrows.
      Univariate risk factor analysis showed that HHH was associated with various
      intrinsic and extrinsic factors. However, multivariate analysis identified the
      intensity of therapeutic interventions--represented by the Therapeutic
      Intervention Scoring System--as the only positive, and cardiovascular disease as
      the only significant negative, predictor of HHH (p <.05). Routine laboratory
      tests were of no value in predicting the presence of HHH. The intensity of HHH
      correlated significantly with siderosis and T-cell infiltrates (p <.05) but not
      with bone marrow cellularity. CONCLUSIONS: HHH is common in medical intensive
      care unit nonsurvivors. Treatment intensity and a noncardiovascular cause of
      death are predictors of HHH. Sepsis and blood transfusion may have a synergistic
      effect on the triggering of HHH. HHH in bone marrow is associated with enhanced T
      cell infiltrates, suggesting that T cells may play an important role in its
      mediation.

PMID- 15187514
TI  - Effects of dexmedetomidine on mortality rate and inflammatory responses to
      endotoxin-induced shock in rats.
AB  - OBJECTIVES: The aim of this study was to document the effects of a new sedative
      agent, dexmedetomidine, on the mortality rate and inflammatory responses to
      endotoxin-induced shock in rats. DESIGN: Randomized laboratory study. SETTING:
      University experimental laboratory. SUBJECTS: Fifty-seven male rats.
      INTERVENTIONS: The animals were randomly assigned to one of four groups. The
      endotoxemic group (n = 16) received intravenous Escherichia coli endotoxin (15
      mg/kg over 2 mins). The saline control group (n = 10) was given saline alone. The
      dexmedetomidine alone group (n = 15) was treated identically to the control group
      but also received dexmedetomidine (infusion at 5 microg.kg(-1).hr(-1))
      immediately after the injection of 0.9% saline. The dexmedetomidine-endotoxin
      group (n = 16) was treated identically to the endotoxemic group with the
      additional administration of dexmedetomidine (infusion at 5 microg.kg(-1).hr(-1))
      immediately after endotoxin injection. MEASUREMENTS AND MAIN RESULTS:
      Hemodynamics and arterial blood gases were recorded and plasma cytokine
      concentrations measured during the observation. The mortality rate was assessed
      up to 8 hrs after endotoxin or saline injection. In addition, microscopic
      findings of lung tissue for each group were obtained at necropsy. Mortality rates
      8 hrs after endotoxin injection were 94%, 10%, 0%, and 44% for the endotoxemic,
      saline control, dexmedetomidine alone, and dexmedetomidine-endotoxin groups,
      respectively. Hypotension and increases in plasma cytokine (tumor necrosis factor
      alpha and interleukin-6) concentrations and infiltration of neutrophils in the
      airspace or vessel walls of the lungs were less in the dexmedetomidine-endotoxin
      group than in the endotoxemic group. CONCLUSIONS: Dexmedetomidine reduced
      mortality rate and had an inhibitory effect on inflammatory response during
      endotoxemia. These findings suggest that dexmedetomidine administration may
      inhibit the inflammatory response.

PMID- 15187515
TI  - Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock.
AB  - OBJECTIVE: To determine whether pressor doses of vasopressin impair organ blood
      flow in endotoxic shock. DESIGN: Graded doses of vasopressin or phenylephrine,
      starting at the clinically recommended doses for pressure support in septic
      shock, were intravenously infused during endotoxic shock. SETTING: University
      hospital surgical research laboratory. SUBJECTS: Twelve random-bred female
      Yorkshire pigs. INTERVENTIONS: We measured mean arterial pressure, cardiac
      output, heart rate, pulmonary artery occlusion pressure, and carotid, mesenteric,
      renal, and iliac blood flows. MEASUREMENTS AND MAIN RESULTS: Low doses of
      vasopressin (typically used in the clinical management of septic shock) raised
      arterial pressure by increasing systemic vascular resistance without a
      significant preferential effect in the circulations measured. However, moderately
      greater doses of vasopressin had a very heterogeneous vasoconstrictor action;
      although there was no significant vasoconstriction in the carotid and iliac
      circulations, mesenteric and renal blood flows decreased markedly. Furthermore,
      at pressor doses vasopressin improved cerebral perfusion. CONCLUSIONS: The
      vasoconstrictor action of exogenous low-dose vasopressin in endotoxic shock does
      not impair blood flow to any of the vascular beds examined. However, moderately
      higher doses of vasopressin may induce ischemia in the mesenteric and renal
      circulations. The data indicate that the safe dose range for exogenous
      vasopressin in septic shock is narrow and support the current practice of fixed
      low-dose administration, generally 0.04 units/min and in no case exceeding 0.1
      units/min.

PMID- 15187516
TI  - Matrix metalloproteinase activities are altered in the heart and plasma during
      endotoxemia.
AB  - OBJECTIVE: To investigate whether myocardial and plasma matrix metalloproteinase
      (MMP) activities are altered during endotoxemia. DESIGN: Prospective randomized,
      animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague
      Dawley rats, 250-300 g. INTERVENTIONS: Rats were administered either bacterial
      lipopolysaccharide (LPS) or vehicle (pyrogen-free water). Groups of LPS
      administered animals were killed at 0.5, 1, 3, 6, 12, and 24 hrs postinjection.
      Vehicle injected animals were killed at 6 hrs. Blood pressure was recorded before
      kill. Heart and plasma samples were analyzed by gelatin zymography and
      immunoblot. MEASUREMENTS AND MAIN RESULTS: Blood pressure was significantly
      depressed at 3-24 hrs post-LPS injection; however, overt symptoms of endotoxemia
      and reduction in blood pressure were most significant 6-12 hrs post-LPS. Heart
      samples from control rats revealed MMP-2 activity but no MMP-9 activity. MMP-2
      activity was significantly depressed when overt symptoms of endotoxemia peaked at
      6-12 hrs. Plasma MMP-2 activity significantly decreased 3-12 hrs after LPS
      injection. This loss of activity was associated with a loss of MMP-2 protein. In
      contrast, plasma MMP-9 activities were rapidly elevated following LPS injection,
      peaking between 1 and 12 hrs. MMP-9 activity correlated inversely with blood
      pressure. CONCLUSIONS: Endotoxemia induced rapid changes in MMP activity in both
      the myocardium and plasma. An increase in circulating MMP-9 activity may
      contribute to endotoxemic cardiovascular dysfunction.

PMID- 15187517
TI  - Protective role of heat stress in burn trauma.
AB  - OBJECTIVE: This study was designed to determine whether cutaneous burn injury up
      regulated expression of myocardial heat shock protein (HSP)70 and to determine a
      potential cardioprotective role of inducible HSP70 (iHSP70) in postburn
      myocardial contractile function. DESIGN: Experimental study. SETTING: Research
      laboratory. SUBJECTS: Adult Hartley guinea pigs. INTERVENTIONS: The first set of
      studies determined whether heat stress (increasing body temperature to 42 degrees
      C for 20 mins) in adult Hartley guinea pigs would increase expression of
      myocardial iHSP70. MEASUREMENTS AND MAIN RESULTS: Our model of heat stress
      increased expression of inducible HSP in the myocardium (Western blot), and this
      response persisted 1, 2, 4, and 24 hrs after the initial heat stress. We then
      determined whether burn trauma over 40% total body surface area (TBSA) increased
      myocardial expression of iHSP70. Time-matched sham and burned guinea pigs were
      killed 1, 2, 4, 12, 18, or 24 hrs postburn, and hearts were used either to
      examine myocardial iHSP70 expression by Western blot or to determine myocardial
      contractile function (Langendorff). Burn trauma produced a two-fold increase in
      myocardial iHSP70 that was evident as early as 1 hr postburn and persisted 24 hrs
      postburn; increased iHSP70 expression occurred despite only a modest and
      transient increase in body temperature after burn trauma. We then determined
      whether heat shock stress before burn trauma provided a protective or detrimental
      effect on cardiac function. Body temperature was increased to 42 degrees C for 20
      mins, animals were allowed to recover, and body temperature returned to baseline;
      burn trauma was then produced (40% TBSA) either 1, 2, 4, or 24 hrs after the
      initial heat stress. Myocardial contraction and relaxation deficits were evident
      after burn trauma alone; however, heat stress 1 hr before burn trauma improved
      left ventricular developed pressure and positive or negative maximum change in
      pressure in time and shifted left ventricular function curves upward and leftward
      from those calculated for burn in the absence of heat stress, indicating improved
      ventricular performance. Increasing the time between the initial heat stress and
      burn injury decreased the cardioprotective effects of heat stress. Thus, organ
      protection was evident only when the time period between the initial heat stress
      and the second insult was brief (1 hr). CONCLUSIONS: Our finding that the amount
      of myocardial iHSP70 remained constantly elevated after heat stress while the
      cardio-protective effect afforded by a prior heat stress declined with time
      suggested that the initial heat stress evoked several compensatory/adaptive
      mechanisms that may include modulation of autonomic nervous system responses,
      changes in metabolic function, modulation of pro/anti-inflammatory cytokine
      responses, and heat stress-related alterations in antioxidant capacity.

PMID- 15187518
TI  - Experimental spinal cord ischemia: model characterization and improved outcome
      with arterial hypertension.
AB  - OBJECTIVE: Paraplegia from spinal cord ischemia is a devastating complication of
      thoracoabdominal aortic aneurysm repair. Perioperative hypoperfusion of the
      spinal cord is a critical determinant of residual neurologic deficits. We
      determined if functional and histologic outcome is dependent on systemic blood
      pressure in a rat model of spinal cord ischemia. DESIGN: Randomized, controlled,
      prospective study. SETTING: Research laboratory at a university teaching
      hospital. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Endotracheally
      intubated adult male Wistar rats (300-450 g) anesthetized with halothane
      underwent a thoracotomy and placement of a clip across the descending aorta for
      27 mins. Mean proximal arterial blood pressure (MPABP) was monitored with a
      cannula placed in the left common carotid artery. Halothane was adjusted (1.25
      1.5%) to maintain MPABP between 70 and 90 mm Hg (n = 20) or 140 and 150 mm Hg (n
      = 20). Shamoperated rats (n = 10) had a thoracotomy without aortic clamping at an
      MPABP of 70-90 mm Hg. Following 1, 24, 48, and 72 hrs of recovery from
      anesthesia, motor function of the hind paws was scored as follows: 0, no evidence
      of deficit; 1, toes flat under body when walking but with ataxia; 2, knuckle
      walks; 3, movements in hind limbs but unable to knuckle walk; 4, no movement,
      drags hind limbs. Body temperature was maintained between 37 and 38 degrees C
      throughout the experiment. MEASUREMENTS AND MAIN RESULTS: All sham operated rats
      with MPABP 70-90 mm Hg recovered without neurologic deficits, whereas those that
      underwent aortic occlusion with MPABP between 70 and 90 mm Hg emerged from
      anesthesia with grade 3 and 4 deficits and remained in this condition without
      improvement at 72 hrs. Histopathology at 72 hrs demonstrated moderate to severe
      neuronal loss with involvement of dorsal, intermediate, and ventral horns. Only
      eight of 20 rats that underwent aortic occlusion with MPABP between 140 and 150
      mm Hg had grade 1 and 2 deficits on emergence but had no neurologic deficit after
      1 hr. Most of the surviving neurons in these animals appeared normal
      histologically, particularly motor neurons around the periphery of the ventral
      horn. CONCLUSIONS: Systemic blood pressure is a critical determinant of outcome
      following spinal cord ischemia, and controlled peri-operative blood pressure
      augmentation may ameliorate neurologic deficits in patients who undergo
      thoracoabdominal vascular procedures and are at risk for spinal cord
      hypoperfusion.

PMID- 15187519
TI  - Precountershock cardiopulmonary resuscitation improves initial response to
      defibrillation from prolonged ventricular fibrillation: a randomized, controlled
      swine study.
AB  - OBJECTIVES: To compare immediate countershocks (defibrillation 1st) with
      precountershock cardiopulmonary resuscitation (CPR 1st) for prolonged ventricular
      fibrillation (VF). DESIGN: Randomized, controlled trial. SETTING: University
      animal laboratory. SUBJECTS: Thirty swine (27 +/- 1 kg). INTERVENTIONS: After 8
      mins of untreated ventricular fibrillation, swine were randomly assigned to
      receive either immediate countershocks or CPR for 90 secs followed by
      countershocks. MEASUREMENTS AND MAIN RESULTS: After the first set of shocks, nine
      of 15 CPR 1st animals attained return of spontaneous circulation vs. 0 of 15
      defibrillation 1st animals (p <.001), and pulseless electrical activity occurred
      in only one of 15 CPR 1st animals vs. ten of 15 defibrillation 1st animals (p
      <.01). The ultimate outcomes in the two groups were not different: Return of
      spontaneous circulation and 24-hr survival occurred in 15 of 15 CPR 1st and 13 of
      15 defibrillation 1st animals. Good neurologic outcome at 24 hrs occurred in 12
      of 15 CPR 1st and nine of 15 defibrillation 1st animals. None of the animals was
      successfully resuscitated with defibrillation alone; all successfully
      resuscitated animals were provided with chest compressions during the
      resuscitation. The ventricular fibrillation median frequency by fast Fourier
      transformation decreased during the untreated ventricular fibrillation interval
      in both groups (9.7 +/- 0.3 Hz and 10.1 +/- 0.2 Hz after 1 min vs. 8.8 +/- 0.3 Hz
      and 8.9 +/- 0.5 Hz at 8 mins, respectively). Because the ventricular fibrillation
      median frequency substantially increased after CPR 1st, it was much higher in the
      CPR 1st group before the first shock (15.1 +/- 0.9 Hz vs. 8.9 +/- 0.5 Hz, p
      <.001). The ventricular fibrillation median frequency before the first
      countershock was much higher in the animals that attained return of spontaneous
      circulation after the first set of shocks vs. those that did not (16.1 +/- 1.3 Hz
      vs. 10.0 +/- 0.6 Hz, p <.0001) CONCLUSIONS: Precountershock CPR can result in
      substantial physiologic benefits and superior response to initial defibrillation
      attempts compared with immediate defibrillation in the setting of prolonged
      ventricular fibrillation.

PMID- 15187520
TI  - Peak volume history and peak pressure-volume curve pressures independently affect
      the shape of the pressure-volume curve of the respiratory system.
AB  - OBJECTIVE: To determine the specific effect of peak volume history pressure on
      the inflation limb of the pressure-volume curve and peak pressure-volume curve
      pressure on the deflation limb of the pressure-volume curve. DESIGN: Prospective
      assessment of pressure-volume curves in saline, lung lavage injured sheep.
      SETTING: Large animal laboratory of a university-affiliated hospital. SUBJECTS:
      Eight female Dorset sheep. INTERVENTIONS: : The effect of two volume history
      pressures (40 and 60 cm H2O) and three pressure-volume curve peak pressures (40,
      50, and 60 cm H2O) were randomly compared. MEASUREMENTS AND MAIN RESULTS: Peak
      volume history pressure affected the inflation curve beyond the lower inflection
      point but did not affect the inflection point (Pflex). Peak pressure-volume curve
      pressure affected the deflation curve. Increased peak volume history pressure
      increased inflation compliance (p <.05). Increased peak pressure-volume curve
      pressure increased the point of maximum compliance change on the deflation limb
      and deflation compliance and decreased compliance between peak pressure and the
      point of maximum curvature on the deflation limb (p <.05). CONCLUSION: Peak
      volume history pressure must be considered when interpreting the inflation limb
      of the pressure-volume curve of the respiratory system beyond the inflection
      point. The peak pressure achieved during the pressure-volume curve is important
      during interpretation of deflation compliance and the point of maximum compliance
      change on the deflation limb.

PMID- 15187521
TI  - Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces
      development of septic shock-like syndrome induced by zymosan in mice.
AB  - OBJECTIVE: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide
      by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose)
      glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in
      a variety of animal models of diseases, including septic shock-like syndrome. We
      have previously demonstrated that PARP inhibition by 3-ami-nobenzamide or GPI
      6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present
      study, we investigated whether similar effect could be achieved through PARG
      inhibition to break the cycle of poly(ADP-ribose) turnaround. DESIGN:
      Experimental study. SETTING: University laboratory. SUBJECTS: Male CD mice (20-22
      g). INTERVENTIONS: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally
      bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500
      mg/kg, administered intraperitoneally as a suspension in saline) on the
      development of septic shock-like syndrome in mice. Organ failure and systemic
      inflammation in mice were assessed 18 hrs after administration of zymosan and/or
      GPI 18214 and monitored for 12 days (for loss of body weight and mortality).
      MEASUREMENTS AND MAIN RESULTS: At 18 hrs after zymosan administration, we found a
      significant increase of peritoneal exudates, leukocyte infiltration in peritoneal
      cavity as well as an infiltration of neutrophils in lung and ileum tissues and
      subsequent lipid peroxidation, and increased production of plasma tumor necrosis
      factor-alpha and interleukin-1 beta. Furthermore, zymosan administration induced
      significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a
      systemic toxicity and significant loss of body weight. At the end of observation
      period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg
      intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced
      peritoneal exudates, inflammatory cell infiltration, and organ injury and
      mortality rate in zymosan-treated mice. CONCLUSIONS: This study supports early
      studies that show efficacy from blocking the poly(ADP-ribose) pathway in septic
      shock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor,
      attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that
      PARG may be an alternative therapeutic target for shock treatment.

PMID- 15187522
TI  - Inhibition of coagulation and inflammation by activated protein C or antithrombin
      reduces intestinal ischemia/reperfusion injury in rats.
AB  - OBJECTIVE: To examine whether administration of activated protein C or
      antithrombin reduces local splanchnic derangement of coagulation and inflammation
      and attenuates intestinal dysfunction and injury following intestinal
      ischemia/reperfusion. DESIGN: Randomized prospective animal study. SETTING:
      University research institute. SUBJECTS: Adult male Wistar rats, weighing 300-325
      g (n = 72). INTERVENTIONS: Rats were subjected to superior mesenteric artery
      occlusion consisting of 20 or 40 mins of ischemia and 3 hrs of reperfusion. A
      randomized intravenous administration of vehicle (0.9% NaCl), heparin,
      antithrombin, or activated protein C was performed during ischemia, 15 mins
      before reperfusion. Coagulation and fibrinolysis variables obtained from portal
      blood were correlated with mucosal fibrin deposition (determined by anti-rat
      fibrin antibody staining), intestinal function (glucose/water clearance), and
      intestinal injury (histologic evaluation by Park/Chiu score). MEASUREMENTS AND
      MAIN RESULTS: Activated protein C- or antithrombin-treated animals demonstrated
      less ischemia/reperfusion-induced intestinal dysfunction and histologic changes
      compared with control animals, whereas intravenous administration of heparin only
      showed less histologic derangement. Activated protein C- or antithrombin-treated
      animals showed less thrombin generation, fibrin degradation products, and fibrin
      deposition compared with control animals, as confirmed by histologic examination,
      whereas heparin administration showed only a limited reduction of portal fibrin
      degradation product concentrations. Furthermore, activated protein C or
      antithrombin administration markedly inhibited the inflammatory response, as
      reflected by reduced interleukin-6 plasma concentrations to baseline values,
      whereas heparin had no effect. CONCLUSIONS: Administration of activated protein C
      or antithrombin inhibited local and systemic derangement of coagulation and
      inflammation following intestinal ischemia/reperfusion, diminished mucosal fibrin
      deposition, and attenuated ischemia/reperfusion-induced intestinal injury. These
      observations suggest that activated protein C or antithrombin reduces
      ischemia/reperfusion-induced intestinal injury, both through their anticoagulant
      and anti-inflammatory effects.

PMID- 15187523
TI  - Diffusion limited oxygen delivery following head injury.
AB  - OBJECTIVE: To use a range of techniques to explore diffusion limitation as a
      mechanism of cellular hypoxia in the setting of head injury. DESIGN: A
      prospective interventional study. SETTING: A specialist neurocritical care unit.
      PATIENTS: Thirteen patients within 7 days of closed head injury underwent imaging
      studies. Tissue for ultrastructural studies was obtained from a cohort of seven
      patients who required surgery. INTERVENTIONS: Cerebral tissue PO2 (PtO2) was
      obtained using a multiple-variable sensor, and images of oxygen extraction
      fraction (OEF), derived from positron emission tomography, were used to calculate
      cerebral venous PO2 (PvO2). These data were used to derive the PvO2-PtO2 gradient
      in a region of interest around the sensor, which provided a measure of the
      efficiency of microvascular oxygen delivery. Measurements were repeated after
      PaCO2 was reduced from 37 +/- 3 to 29 +/- 3 torr (4.9 +/- 0.4 to 3.9 +/- 0.4 kPa)
      to assess the ability of the microvasculature to increase oxygen unloading during
      hypocapnia-induced hypoperfusion. Pericontusional tissue was submitted to
      electron microscopy to illustrate the structural correlates of physiologic
      findings. MEASUREMENTS AND MAIN RESULTS: Tissue regions with hypoxic levels of
      PtO2 (<10 torr) had similar levels of PvO2 compared with nonhypoxic areas and
      hence displayed larger PvO2-PtO2 gradients (27 +/- 2 vs. 9 +/- 8 torr, p <.001).
      Despite similar cerebral blood flow reductions with hyperventilation, hypoxic
      regions achieved significantly smaller OEF increases compared with normoxic
      regions (7 +/- 5 vs. 16 +/- 6 %, p <.05). Pericontusional tissue showed varying
      degrees of endothelial swelling, microvascular collapse, and perivascular edema.
      CONCLUSIONS: Increased diffusion barriers may reduce cellular oxygen delivery
      following head injury and attenuate the ability of the brain to increase oxygen
      extraction in response to hypoperfusion. Global or regional OEF underestimates
      tissue hypoxia due to such mechanisms.

PMID- 15187524
TI  - Hypothermic retrograde jugular vein flush in heatstroke rats provides brain
      protection by maintaining cerebral blood flow but not by hemodilution.
AB  - OBJECTIVE: To determine the fundamental mechanism of brain protection by
      hypothermic retrograde jugular vein flush (HRJVF) in heatstroke rats. DESIGN:
      Randomized, controlled, and prospective study. SETTING: University physiology
      research laboratory. SUBJECTS: Sprague-Dawley rats (270-320 g, males).
      INTERVENTIONS: Rats were randomized into four groups as follows: a) normothermic
      control (NC, n = 8); b) heatstroke rats without cold saline delivery (HS, n = 8);
      c) heatstroke rats treated with cold saline via femoral vein (HS+F, n = 8); and
      d) heatstroke rats treated with HRJVF (HS+J, n = 8). Right external jugular vein
      and right femoral vein were cannulated in each rat. The cannulation in the
      jugular vein was with cranial direction. To produce heatstroke, rats were placed
      in a chamber with an ambient temperature of 43 degrees C. The cold saline (4
      degrees C, 1.7 mL/100 g) was delivered via the cannula in either the femoral vein
      or jugular vein immediately after the onset of heatstroke. Glutamate release in
      the brain, cerebral blood flow (CBF), and hematocrit of arterial blood were
      determined. MEASUREMENTS AND MAIN RESULTS: After onset of heatstroke, HRJVF
      significantly decreased the glutamate release. In contrast, cold saline delivery
      via femoral vein could only delay the elevation of glutamate release in the
      brain. The CBF of HS and HS+F rats decreased rapidly after the onset of
      heatstroke, but the CBF of HS+J rats was initially elevated by HRJVF and was
      maintained at baseline 30 mins after onset of heatstroke. Hematocrit in all the
      rats did not change after testing. CONCLUSIONS: HRJVF protects the brain by
      maintaining cerebral blood flow in rats after heatstroke. To preserve brain
      function and prolong survival after severe heatstroke, maintenance of cerebral
      blood flow is important in the management of heatstroke.

PMID- 15187525
TI  - Prevention of hospital-associated pneumonia and ventilator-associated pneumonia.
AB  - OBJECTIVE: To synthesize the available clinical data for the prevention of
      hospital-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP)
      into a practical guideline for clinicians. DATA SOURCE: A Medline database and
      references from identified articles were used to perform a literature search
      relating to the prevention of HAP/VAP. CONCLUSIONS: There is convincing evidence
      to suggest that specific interventions can be employed to prevent HAP/VAP. The
      evidence-based interventions focus on the prevention of aerodigestive tract
      colonization (avoidance of unnecessary antibiotics and stress ulcer prophylaxis,
      use of sucralfate for stress ulcer prophylaxis, chlorhexidine oral rinse,
      selective digestive decontamination, short-course parenteral prophylactic
      antibiotics in high-risk patients) and the prevention of aspiration of
      contaminated secretions (preferred oral intubation, appropriate intensive care
      unit staffing, avoidance of tracheal intubation with the use of mask ventilation,
      application of weaning protocols and optimal use of sedation to shorten the
      duration of mechanical ventilation, semirecumbent positioning, minimization of
      gastric distension, subglottic suctioning, avoidance of ventilator circuit
      changes/manipulation, routine drainage of ventilator circuit condensate).
      Clinicians caring for patients at risk for HAP/VAP should promote the development
      and application of local programs encompassing these interventions based on local
      resource availability, occurrence rates of HAP/VAP, and the prevalence of
      infection due to antibiotic-resistant bacteria (Pseudomonas aeruginosa,
      Acinetobacter species, and methicillin-resistant Staphylococcus aureus).

PMID- 15187526
TI  - Implementation of standards for intensivist staffing: is it time to jump aboard
      the Leapfrog bandwagon?

PMID- 15187527
TI  - No longer the "expensive scare unit"?

PMID- 15187528
TI  - Guideline adoption: a slow process.

PMID- 15187529
TI  - Are vasodilatory shock states due to sepsis and cardiovascular surgery like two
      peas in a pod?

PMID- 15187530
TI  - Wake up and breathe.

PMID- 15187531
TI  - The cost-effectiveness of proton pump inhibitors for bleeding peptic ulcers: The
      unanswered questions.

PMID- 15187532
TI  - Determination of brain death: theme, variations, and preventable errors.

PMID- 15187533
TI  - Obstetric patients requiring intensive care unit admission.

PMID- 15187534
TI  - Autonomic regulation of heart rate variability in trauma: Good intentions but
      poor performance.

PMID- 15187535
TI  - Atrial natriuretic peptide to prevent acute renal failure: old concept with new
      promise.

PMID- 15187536
TI  - Vasopressin in septic shock: does dose matter?

PMID- 15187537
TI  - Protective role of myocardial heat shock protein 70 in burn trauma: another brick
      in the wall?

PMID- 15187538
TI  - Prevention and amelioration of neurologic dysfunction after complex aortic
      surgery: a task for critical care practitioners!

PMID- 15187539
TI  - Defibrillation first versus chest compression first after prolonged ventricular
      fibrillation.

PMID- 15187540
TI  - Moving from macro- to microcirculation in head injury.

PMID- 15187541
TI  - Outcome of patients who underwent mechanical ventilation following intracerebral
      hemorrhage: is the glass really half full?

PMID- 15187542
TI  - Unreported deviations of genotype distributions from Hardy-Weinberg equilibrium
      in articles published in Critical Care Medicine between 1999 and 2003.

PMID- 15187543
TI  - Lessons learned from high-dosage vasopressin infusion in septic shock.

PMID- 15187544
TI  - Platelet-activating factor acetylhydrolase and acute respiratory distress
      syndrome: unanswered questions.

PMID- 15187547
TI  - Rotation of propofol and midazolam for long-term sedation.

PMID- 15187549
TI  - Extracorporeal albumin dialysis for intoxication from protein-bound agents.

PMID- 15187551
TI  - Caution should be exercised when maintaining a serum sodium level >160 meq/L.

PMID- 15187553
TI  - Let's be splitters, rather than "lumpers".

PMID- 15187555
TI  - Deadspace ratio.

PMID- 15187556
TI  - Extremely high-pressure lung recruitment maneuver may be life saving in the most
      severe cases of acute lung injury/acute respiratory distress syndrome.

PMID- 15187558
TI  - Does the age of blood matter?

PMID- 15187560
TI  - Does the storage time of transfused red blood cells influence critically ill
      patients?

PMID- 15187564
TI  - Healthcare facilities should include patients in their compliance program.

PMID- 15187562
TI  - Antioxidants and sepsis: can we find the ideal approach?

PMID- 15187566
TI  - Unraveling the mystery of adrenal failure in the critically ill.

PMID- 15187569
TI  - Insulin resistance in nondiabetic patients is associated with expansive
      remodeling in coronary arterial lesions.
AB  - OBJECTIVE: Insulin resistance has been implicated as an important initiating
      factor in coronary atherosclerosis. However, associations between insulin
      resistance and specific morphologic features of atherosclerotic coronary arteries
      remain unclear. We ultrasonographically evaluated the morphologic features of
      atherosclerotic coronary arteries in nondiabetic patients with insulin
      resistance. METHODS: Before intervention, 90 patients with 105 culprit lesions
      underwent intravascular ultrasound examination through which vessel area, lumen
      area and plaque area were evaluated. Expansive remodeling (lesion vessel area
      more than 5% greater than at the proximal reference segment) and constrictive
      remodeling (lesion vessel area more than 5% less than at the distal reference
      segment) were also evaluated. Insulin resistance was determined by homeostasis
      model assessment and defined as values above the 75th percentile (that is, 1.71).
      RESULTS: Insulin-resistant patients numbered 23, while nonresistant patients
      numbered 67. Culprit lesions in the insulin-resistant group showed larger vessel
      area (18.16 +/- 6.94 compared with 13.64 +/- 4.28 mm, P = 0.0001) and plaque area
      (16.64 +/- 6.78 compared with 12.05 +/- 4.12 mm, P = 0.0001) and more frequently
      showed expansive remodeling (56% compared with 14%, P < 0.0001) and calcific
      plaque (33% compared with 12%, P = 0.01). Multivariable logistic regression
      analysis identified only insulin resistance (odds ratio, 4.9, P = 0.008) as an
      independent predictor of expansive remodeling. CONCLUSIONS: Insulin resistance
      independently predicted expansive remodeling, underscoring the importance of
      insulin resistance in coronary atheroscrelosis.

PMID- 15187570
TI  - Variations in lymphocyte activation during exercise testing in patients with
      coronary artery disease.
AB  - BACKGROUND: Several studies have shown that strenuous exercise induces changes in
      the immune system. Soluble interleukin-2 receptor (sIL-2R) is a marker of immune
      system activation and is known to increase in association with cardiac disease.
      The aim of the present study was to assess sIL-2R levels in patients with
      coronary artery disease (CAD) in conjunction with exercise testing. METHODS:
      Blood levels of sIL-2R were determined in 10 healthy control individuals and 21
      patients with CAD before exercising, at maximal exercise testing (Bruce) and at
      0.5 h and 3-4 h after exercise (T1-T4). The study group had stable angina and
      normal or near-normal left ventricular function. Patients at risk of abnormal
      cytokine levels were excluded. RESULTS: The patients were divided into two
      groups: those with mild to moderate ischemia (according to a thallium scan) (n =
      14, group 1a) and those with severe exercise-induced ischemia (n = 7, group 1b).
      The prevalence of anginal pain at exercise and mean ST depression were similar in
      both groups, however, signs of left ventricular dysfunction during exercise were
      significantly more frequent in group 1b. Mean sIL-2R levels (units per ml) showed
      no significant difference between group 1a and the control group at all time
      points (503 +/- 122, 518 +/- 140, 489 +/- 164, 461 +/- 131 mu/ml compared with
      505 +/- 135, 509 +/- 112, 469 +/- 126, 416 +/- 103 mu/ml, respectively, P = NS),
      while a significant increase in group 1b compared with the control group was
      found at 0.5-h after exercise (T3) (1147 +/- 510 mu/ml, P = 0.03). DISCUSSION:
      This study demonstrated immunological involvement in some patients with severe
      exercise-induced ischemia shortly after exercise, suggesting an association with
      heart failure.

PMID- 15187571
TI  - Imbalance of sex hormone levels in men with coronary artery disease.
AB  - OBJECTIVE: Sex hormones are thought to play a key role in atherogenesis, but the
      available evidence is inconclusive, partly because of a lack of accuracy in
      measurement. The aim of the study was to investigate the potential role of sex
      hormones in coronary atherosclerosis. METHODS: We prospectively applied a simple
      highly-sensitive method using solid-phase extraction followed by
      radioimmunoassay. Both phases were carried out using commercially available kits
      to determine levels of estradiol (E2). We also measured the levels of free
      testosterone (FT), dehydroepiandrosterone sulfate, luteinizing hormone, follicle
      stimulating hormone, and progesterone in 236 consecutive male patients with
      angiographically-defined stable coronary artery disease and in 143 disease-free
      and age-matched controls. RESULTS: The levels of highly-sensitive E2 and FT in
      patients and controls differed slightly in opposing directions, but neither
      difference reached statistical significance. However, the ratio of FT to highly
      sensitive E2 in patients was significantly higher than in the controls (mean +/-
      SD; 2.50 +/- 1.89 versus 2.06 +/- 1.14, P = 0.018), and this difference remained
      significant after adjustments for age and body mass index had been made. Multiple
      regression analysis revealed that age, the association of diabetes, and the
      presence of coronary atherosclerosis were significantly and independently
      associated with the values of the FT/highly-sensitive E2 ratio. Other hormones
      examined did not differ significantly between the patients and the controls.
      CONCLUSIONS: Highly-sensitive E2 measurement demonstrated a significant imbalance
      of FT to E2 in male patients with coronary artery disease, but individual sex
      hormone levels did not differ between the patients and the controls.

PMID- 15187572
TI  - Thrombolysis in myocardial infarction frame count with angiographically normal
      coronary arteries and its relationship to ST-segment depression.
AB  - BACKGROUND: The thrombolysis in myocardial infarction frame count (TFC) has been
      proposed as a simple, reproducible, objective and quantitative method to assess
      coronary blood flow. However, the TFC in normal coronary arteries has not been
      investigated in detail. The aim of this study was to determine normal TFC values
      and investigate their correlation with ST-segment depression during exercise
      testing (ET). METHODS AND RESULTS: The TFC was measured in 116 cases with normal
      coronary arteries who underwent ET. The ST segment was evaluated on 12-lead
      electrocardiograms at 60 ms after the J-point. Horizontal or downsloping ST
      segment depression of > or = 0.5 mm was recorded and the sum of the depressions
      was calculated. When ST-segment depression > or = 1 mm compared to the level of
      PR segment on two or more leads was detected, the test was accepted as positive.
      The TFC for the left anterior descending coronary artery (LAD) was significantly
      higher than those for the left circumflex coronary artery (LCx) and the right
      coronary artery (RCA). The TFC of coronary arteries was significantly higher in
      patients with ET positive (for LAD, 39.5 +/- 10.7 compared with 30.1 +/- 7.6
      frames; for LCx, 29.2 +/- 9.3 compared with 23.6 +/- 6.5 frames; and for RCA,
      30.7 +/- 11 compared with 23.7 +/- 7 frames; P < 0.001 for overall comparisons).
      Women had a lower TFC than men in the LAD. Moreover, it was determined that the
      TFC values for the LAD, LCx and RCA significantly correlated with the sum of ST
      segment depression (r = 0.57, r = 0.46 and r = 0.41, respectively, P < 0.001 for
      overall correlations). It was also determined that the TFC was affected by the
      proximal diameter of the coronary arteries. CONCLUSIONS: The results of this
      study highlight the differences of the TFC in normal LAD, LCx and RCA. In
      patients with normal coronary arteries, the fact that the TFC is higher in ET
      positive than in ET-negative patients may explain false positive results of ET.
      Sex and coronary artery diameter should be taken into consideration in evaluating
      the TFC.

PMID- 15187574
TI  - Bibliography: current world literature.

PMID- 15187573
TI  - Exploring the effects of ACE inhibitor tissue penetration on vascular
      inflammation following acute myocardial infarction.
AB  - BACKGROUND: Questions remain as to the existence of a class effect amongst
      angiotensin converting enzyme (ACE) inhibitors, and some literature suggests that
      pharmacological effects and outcomes may be determined by an ACE inhibitor's
      propensity to penetrate and inhibit the ACE enzyme at the vascular tissue level.
      Because vascular inflammation contributes to adverse outcomes following acute
      myocardial infarction (AMI), and angiotensin II influences inflammation at the
      vascular level, we hypothesized that high-tissue penetrating ACE inhibitors would
      provide more favorable effects on C-reactive protein (CRP) after AMI compared to
      low-tissue penetrating ACE inhibitors. METHODS AND RESULTS: In a randomized open
      label trial, patients received the high-tissue penetrating quinapril (n = 15) or
      low-tissue penetrating enalapril (n = 15) following AMI. C-reactive protein was
      measured at baseline and periodically over 14 days following drug initiation. All
      baseline characteristics and blood pressure response to treatment between groups
      were equivalent. Prior to initiating study medication, CRP concentrations (mg/g)
      were similar between enalapril and quinapril (0.327 +/- 0.571 versus 0.273 +/-
      0.380, respectively, p = 0.77). The percent magnitude of change in CRP
      concentrations favored quinapril at all time points, starting 12 h after
      treatment initiation. When characterizing CRP production during treatments, the
      time courses were significantly different and demonstrated lower CRP
      concentrations with quinapril (p = 0.0107). CONCLUSIONS: Overall, this
      investigation into the importance of ACE inhibitor tissue penetration on a common
      marker of vascular inflammation, suggests a potential vascular anti-inflammatory
      benefit with a more highly tissue penetrating ACE inhibitor following AMI.
      Further investigation into the true pharmacological similarities and differences
      amongst this class of drugs is warranted.

PMID- 15187575
TI  - Differential response to alcohol in light and moderate female social drinkers.
AB  - Individuals who are moderate drinkers are at increased risk to abuse alcohol.
      Moreover, women are more vulnerable than men to the adverse consequences of
      alcohol consumption and recent data indicate that the drinking pattern in women
      is becoming more similar to that of men. However, few studies have determined
      whether female moderate drinkers (MD) show a differential response to the
      subjective and performance effects of alcohol, compared to female light drinkers
      (LD). Fifteen female MD who consumed an average of 34.7 drinks/month were
      compared to 15 female LD who consumed an average of 6.7 drinks/month. None of the
      participants had a first-degree family history of alcoholism or substance abuse.
      The acute effects of alcohol (0, 0.25, 0.50, 0.75 mg/kg) were evaluated using a
      double-blind, placebo-controlled outpatient design. Drug effects were assessed
      using a full range of performance measures, subjective-effects questionnaires and
      observer ratings. Alcohol impaired performance in a dose-related manner on all
      performance tasks for both groups of females. However, MD were less impaired than
      LD on balance and Digit Symbol Substitution Test (DSST). This reduced response
      was also evident from the observer ratings, with MD being viewed as less impaired
      by alcohol than LD. While ratings of Drug Liking increased in both groups of
      women on the ascending limb of the breath alcohol curve, alcohol was disliked by
      LD on the descending limb and LD reported increased ratings of Bad Drug Effects
      following the high dose of alcohol. The reduced performance impairment, coupled
      with the positive subjective effects and relative absence of adverse subjective
      effects, suggestive of behavioral tolerance, could result in a progression
      towards increased alcohol consumption among moderate female social drinkers.

PMID- 15187576
TI  - Nicotine serves as a feature-positive modulator of Pavlovian appetitive
      conditioning in rats.
AB  - The present experiments examined whether a nicotine state could set the occasion
      for a pairing between visual cues and a rewarding outcome in rats. Following
      nicotine administration, presentation of a conditional stimulus (CS; light-on)
      was followed by brief access to a sucrose solution. When saline was administered,
      the same CS was presented but was not followed by any consequence. In Experiment
      1, two groups assessed whether rats could acquire this Pavlovian feature-positive
      discrimination via different training procedures. An anticipatory food-seeking
      conditioned response (CR) developed during the CS on nicotine sessions but not on
      saline sessions in both groups. In Experiment 2, centrally acting antagonists of
      nicotinic acetylcholine and opiate receptors (mecamylamine and naloxone,
      respectively) dose-dependently blocked nicotine's control of the CR, whereas the
      peripherally acting nicotinic antagonist hexamethonium had no effect. Increasing
      or decreasing the interval between nicotine administration and testing also
      attenuated the CR. These results are consistent with the hypothesis that nicotine
      can occasion appetitive Pavlovian relations via its action at central nervous
      system cholinergic receptors.

PMID- 15187577
TI  - Differential effects of psychomotor stimulants on attentional performance in
      rats: nicotine, amphetamine, caffeine and methylphenidate.
AB  - Nicotine can improve attentional performance in the rat as assessed by a modified
      five-choice serial reaction time task (5-CSRTT), but it is not known if the
      effect is shared with other psychomotor stimulants. This study compared the
      effects of nicotine, amphetamine, caffeine and methylphenidate on performance in
      the 5-CSRTT and determined whether presenting stimuli at unpredictable times by
      using variable inter-trial intervals (ITI) influenced the sensitivity of the task
      to the drugs. One group of male hooded rats was trained to obtain food
      reinforcers by nose-poking in response to 1 s light stimuli presented randomly in
      one of five apertures, with fixed ITI; for a second group of rats, ITI varied
      randomly (n=12 per group). As observed previously, nicotine (tested in doses of
      0.05-0.2 mg/kg) produced dose-related improvements in accuracy, reduced omission
      errors and response latencies, but increased anticipatory responding. Amphetamine
      (0.1-0.8 mg/kg) and methylphenidate (2.5-10 mg/kg) increased accuracy and reduced
      response latency, and decreased anticipatory responding. Caffeine (2.5-20 mg/kg)
      did not improve performance except at a small dose that decreased omission errors
      only. Training at different levels of stimulus predictability influenced
      performance in the undrugged state but had little impact on profiles of responses
      to the drugs. The findings with methylphenidate support the potential value of
      the 5-CSRTT for testing drugs that may be useful in the treatment of attention
      deficit hyperactivity disorder.

PMID- 15187578
TI  - Caffeine withdrawal syndrome in social interaction test in mice: effects of the
      NMDA receptor channel blockers, memantine and neramexane.
AB  - Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been
      demonstrated repeatedly to attenuate the expression of drug and alcohol
      withdrawal syndromes. The present study aimed to evaluate the effects of NMDA
      receptor blockade on the expression of behavioural signs of caffeine withdrawal
      syndrome, assessed using the social interaction paradigm. Adult male Swiss mice
      were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily)
      for 8 days. Twenty-four hours after the last injection of caffeine, there were
      significant increases in duration and frequency of defensive behaviours, as well
      as decreased locomotor activity. These changes faded within 72 hours.
      Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of
      repeated caffeine administration and 30 min prior to the test) completely
      reversed these withdrawal-related changes. Separate groups of mice were treated
      i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ
      2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds
      dose-dependently reduced the expression of defensive behaviours while increasing
      motor activity. These data suggest that NMDA receptor blockade may counteract the
      acute behavioural effects of caffeine withdrawal.

PMID- 15187579
TI  - Agonist and antagonist effects of benzodiazepines on motor performance: influence
      of intrinsic efficacy and task difficulty.
AB  - Previous studies have shown that low-efficacy benzodiazepines may function as
      full agonists, partial agonists or antagonists, depending upon the sensitivity of
      the assay to detect a drug's agonist effects. To date, these differential effects
      have only been observed across tasks, as these drugs rarely produce full agonist
      and antagonist effects in a single preparation. The purpose of the present study
      was to examine the agonist and antagonist effects of various benzodiazepines in a
      motor task in which the sensitivity of the task differed across conditions. To
      this end, rats were trained to walk on a rotorod apparatus rotating at low (4
      rpm), medium (20 rpm) and high (36 rpm) speeds, and the motor-impairing effects
      of representative low (bretazenil), intermediate (clonazepam) and high (diazepam)
      efficacy benzodiazepines were examined. Diazepam and clonazepam reduced the
      latency for rats to fall from the rotorod at all three speeds, with both drugs
      being more potent at the high speed than at lower speeds. Bretazenil was also
      effective at decreasing motor performance at the high speed, but was not
      effective at lower speeds. In drug combination tests, bretazenil antagonized the
      effects of diazepam and clonazepam under conditions in which it was not effective
      when administered alone, effectively demonstrating both full agonist and
      antagonist effects in the same preparation. These data indicate that the
      sensitivity of a motor task to detect a drug's agonist effects can be manipulated
      by altering its relative level of difficulty, and that lower-efficacy
      benzodiazepines are more sensitive than higher-efficacy benzodiazepines to these
      manipulations.

PMID- 15187580
TI  - Effects of chlordiazepoxide on extinction and re-acquisition of operant behaviour
      in mice.
AB  - Relatively little is known about the role of the inhibitory neurotransmitter
      gamma-aminobutyric acid (GABA) in extinction of appetitively motivated tasks. The
      benzodiazepine (BZ) chlordiazepoxide (CDP) was administered during extinction and
      re-acquisition of lever pressing by mice following food reinforced discrete-trial
      fixed-ratio 5 (FR-5) training. Typical FR behaviour was established during
      baseline training and persisted for several extinction sessions. There were 15
      extinction sessions in all, followed by six re-acquisition sessions where food
      reinforcement was re-introduced. In a 2x2x2 between-group design, CDP (15 mg/kg)
      or vehicle injections were given prior to either the last two food reinforcement
      sessions and the first 10 extinction sessions, or the final five extinction
      sessions, or the six re-acquisition sessions. Initially CDP had no effect on the
      rate of extinction, but after several extinction sessions it significantly
      facilitated it. Surprisingly, if CDP was administered only after several sessions
      of extinction, it immediately produced facilitation. Thus the delayed effects of
      CDP are not due to drug accumulation. These data suggest that some neural change
      must occur before CDP can affect extinction processes. In re-acquisition
      sessions, CDP facilitated the reinstatement of food-reinforced lever pressing.
      Implications for neural and behavioural accounts of operant extinction are
      discussed.

PMID- 15187581
TI  - Central injection of botulinum neurotoxins: behavioural effects in mice.
AB  - Strains of Clostridium botulinum produce seven antigenically distinct botulinum
      neurotoxins (BoNTs) designated as serotypes A-G. All serotypes interfere with
      neural transmission by blocking the release of acetylcholine in cholinergic
      neurons. They cleave specific sites on proteins of the SNARE [soluble n
      ethylmaleimide-sensitive factor (NSF) attachment protein receptor] complex, which
      play a key role in neuroexocytosis. This study assessed the behavioural effects
      due to central administration of BoNTs in mice. CD1 mice were injected
      intracerebroventricularly (icv) with sub-lethal doses of BoNT/A or /B and their
      behavioural responses in conditioning of active avoidance, object recognition
      test and pharmacologically induced locomotor activity were tested. Compared to
      control mice, BoNT-treated mice showed: (1) a reduced capacity to discriminate a
      novel object within a familiar environment; (2) an enhanced stimulant effect by
      scopolamine and a depressant effect by oxotremorine on locomotor activity. In
      contrast, central injection of BoNTs did not alter active avoidance acquisition.
      These results suggest an in vivo functional alteration due to the action of BoNTs
      directly administered into the central nervous system. The present data
      demonstrate that BoNTs may represent an analytical tool for studying the
      functional role of cholinergic neurons.

PMID- 15187582
TI  - 'Compulsive' lever-pressing in rats is attenuated by the serotonin re-uptake
      inhibitors paroxetine and fluvoxamine but not by the tricyclic antidepressant
      desipramine or the anxiolytic diazepam.
AB  - Rats undergoing extinction of lever-pressing for food after the attenuation of an
      external feedback for this behavior, exhibit excessive lever-pressing
      unaccompanied by an attempt to collect a reward, which may be analogous to the
      excessive and unreasonable behavior seen in obsessive-compulsive disorder (OCD).
      Given that one of the most salient features of OCD is its selective response to
      treatment with serotonin re-uptake inhibitors (SRIs), the present study compared
      the effects of the SRIs paroxetine and fluvoxamine on compulsive lever-pressing,
      with those of the tricyclic antidepressant, desipramine, and the benzodiazepine,
      diazepam, which are not effective in the treatment of OCD. Paroxetine (1-15
      mg/kg) and fluvoxamine (10-20 mg/kg) dose-dependently reduced the number of
      compulsive lever-presses and the number of lever-presses followed by an attempt
      to collect a reward; desipramine (5-15 mg/kg) dose-dependently reduced only the
      number of lever-presses followed by an attempt to collect a reward; diazepam (2
      10 mg/kg) did not affect either type of lever-pressing, except for the highest
      dose (10 mg/kg), which almost completely abolished lever-press responding. When
      administered in an extinction session not preceded by signal attenuation,
      paroxetine, fluvoxamine and desipramine affected only the number of lever-presses
      followed by an attempt to collect a reward, whereas diazepam (4-8 mg/kg)
      decreased both types of lever-presses. The present findings strengthen the
      suggestion that compulsive lever-pressing may serve to model compulsive behavior
      in OCD, and lends the model predictive validity.

PMID- 15187583
TI  - Who says it's an error? Research highlights a disagreement among health care
      workers.

PMID- 15187584
TI  - Is 'skilled nursing home' a misnomer? Least educated providers constitute largest
      proportion of workforce.

PMID- 15187585
TI  - Phantom limb pain.

PMID- 15187586
TI  - Nurses' addictions.

PMID- 15187587
TI  - Monitoring noise.

PMID- 15187589
TI  - Medicine for all?

PMID- 15187591
TI  - Nursing in the media.

PMID- 15187593
TI  - Relishing 'hit lists'.

PMID- 15187594
TI  - Back to sleep: many nurses don't follow the recommended sleep guidelines for
      infants.

PMID- 15187596
TI  - tPA after stroke: the sooner the better: clinical benefit is gone by six hours.

PMID- 15187603
TI  - Premature births on the rise: the March of Dimes and AWHONN educate providers and
      patients.

PMID- 15187604
TI  - Nightingales vs. big tobacco: nurses confront the nation's greatest public health
      threat.

PMID- 15187606
TI  - Reflections: to mania and back.

PMID- 15187607
TI  - An error by any other name.
AB  - Recent reports from the Institute of Medicine and other sources have shown that
      far too many avoidable medical errors occur; other research has shown a strong
      association between patient outcomes and characteristics of nursing staff. The
      authors of this paper present findings from multimethod research conducted over
      three years in 29 small rural hospitals in nine Western states. They examined the
      organizational processes used to recognize medical errors and assign
      responsibility for them to resolve patient-safety issues. The research comprises
      seven substudies that used surveys, questionnaires, interviews, and case studies
      to gather data from nurses, physicians, administrators, pharmacists, and other
      health care workers.Generally, participants responded positively to questions
      about an institution's receptivity to communicating about errors and agreed on
      the most common kinds of errors that occur. But other data suggest that
      providers' understanding of patient safety is heavily conditioned by preconceived
      notions of what constitutes an error and of professional roles. Participants'
      analyses of case studies showed that they don't agree on what constitutes error
      or what kinds of events should be reported. And in one substudy, even when there
      was overwhelming agreement among participants (97%) that an error had occurred,
      only 64% would disclose the error to the patient affected. Physicians,
      administrators, and nurses tended to perceive patient safety as primarily a
      nursing responsibility. Only 22% of respondents to one survey said that
      physicians, nurses, pharmacists, and administrators should share responsibility
      equally for patient safety. The research was not designed to answer specific
      questions about the recruitment and retention of nurses, but the data collected
      suggest that institutional processes used to identify errors, assign
      responsibility for them, and resolve patient-safety issues may have unintended,
      harmful effects on nurse recruitment and retention. The authors propose that "a
      systems approach to patient safety" be adopted, one in which responsibility for
      safety is shared by all members of the health care team.

PMID- 15187608
TI  - Assessing the research: Some comments on multimethod studies.

PMID- 15187611
TI  - Pulmonary embolism: quick diagnosis can save a patient's life.

PMID- 15187613
TI  - HRT Reconsidered: What should you tell patients about it now?

PMID- 15187614
TI  - Malaria: a leading cause of death continues to challenge here and abroad.

PMID- 15187616
TI  - Rehab instead of prison: drug courts provide opportunities for nurse
      practitioners.

PMID- 15187617
TI  - Medicare savings programs: helping those on Medicare pay for health care.

PMID- 15187621
TI  - What's wrong with U? JCAHO places limits on abbreviations used in practice.

PMID- 15187622
TI  - Teacher, teach thyself: an ANA-backed campaign hopes to lure more RNs into the
      role of nurse educator.

PMID- 15187623
TI  - Laboring to ease the birth process: a perinatal clinical nurse specialist finds
      her niche in research and patient safety.

PMID- 15187624
TI  - An organized disaster: conducting health care facility emergency drills.

PMID- 15187625
TI  - Editorial: The semiotics of backache.

PMID- 15187626
TI  - Tissue-engineered composites of anulus fibrosus and nucleus pulposus for
      intervertebral disc replacement.
AB  - STUDY DESIGN: By the technique of tissue engineering, composite intervertebral
      disc implants were fabricated as novel materials for disc replacement, implanted
      into athymic mice, and removed at times up to 12 weeks. OBJECTIVES: The goal of
      this study was to construct composite intervertebral disc structures consisting
      of anulus fibrosus cells and nucleus pulposus cells seeded on polyglycolic acid
      and calcium alginate matrices, respectively. SUMMARY OF BACKGROUND DATA: Previous
      work has documented the growth of anulus fibrosus cells on collagen matrices and
      nucleus pulposus cells cultured on multiple matrices, but there is no
      documentation of composite disc implants. METHODS: Lumbar intervertebral discs
      were harvested from sheep spine, and the nucleus pulposus was separated from
      surrounding anulus fibrosus. Each tissue was digested in collagenase type II.
      After 3 weeks in culture, cells were seeded into implants. The shape of the
      anulus fibrosus scaffold was fabricated from polyglycolic acid and polylactic
      acid, and anulus fibrosus cells were pipetted onto the scaffold and allowed to
      attach for 1 day. Nucleus pulposus cells were suspended in 2% alginate and
      injected into the center of the anulus fibrosus. The disc implants were placed in
      the subcutaneous space of the dorsum of athymic mice and harvested at 4, 8, and
      12 weeks. At each time point, 4 samples were stored in -70 degrees C for collagen
      typing and analysis of proteoglycan, hydroxyproline, and DNA. Other samples were
      fixed in 10% formalin for Safranin-O staining. RESULTS: The gross morphology and
      histology of engineered discs strongly resembled those of native intervertebral
      discs. Biochemical markers of matrix synthesis were present, increasing with
      time, and were similar to native tissue at 12 weeks. Tissue-engineered anulus
      fibrosus was rich in type I collagen but nucleus pulposus contained type II
      collagen, similar to the native disc. CONCLUSION: These results demonstrate the
      feasibility of creating a composite intervertebral disc with both anulusfibrosus
      and nucleus pulposus for clinical applications.

PMID- 15187628
TI  - Tissue engineered nucleus pulposus tissue formed on a porous calcium
      polyphosphate substrate.
AB  - STUDY DESIGN: This study describes the formation of nucleus pulposus tissue using
      a novel tissue engineering approach. OBJECTIVES: To determine if a construct
      composed of nucleus pulposus tissue on the surface of a calcium polyphosphate
      substrate could be formed in vitro with properties similar to native nucleus
      pulposus tissue. SUMMARY OF BACKGROUND DATA: There is no optimal treatment for
      the persistent pain associated with intervertebral disc degeneration. Disc
      replacement using artificial intervertebral discs has met with some success, and
      biologic transplantation is limited by the availability of donor tissues.
      METHODS: Nucleus pulposus cells were isolated from bovine caudal intervertebral
      discs. Cells were seeded at high density on the upper surface of a porous bone
      substitute material (calcium polyphosphate) and maintained up to 6 weeks in
      culture. In vitro formed tissue was compared to native nucleus pulposus for
      histologic appearance, biochemical composition (tissue cellularity, proteoglycan
      and collagen accumulation), and compressive mechanical properties. RESULTS: When
      maintained on the surface of a three-dimensional substrate, nucleus pulposus
      cells formed a continuous layer of tissue with a proteoglycan content equivalent
      to the native tissue. Although collagen accumulation attained only 26% than that
      of the native tissue, there was no difference in tissue stiffness, viscosity, or
      weight-bearing capacity of the in vitro formed tissue when compared with the
      native tissue. CONCLUSION: Nucleus pulposus-like tissue formed in vitro on the
      surface of a calcium polyphosphate substrate resembles the native tissue in terms
      of proteoglycan content and compressive mechanical properties. These studies are
      the first step toward developing a functional spinal unit in vitro.

PMID- 15187630
TI  - Accuracy and interobserver agreement for determinations of rabbit posterolateral
      spinal fusion.
AB  - STUDY DESIGN: The accuracy and interobserver agreement of fine detail radiography
      and computed tomography (CT) determination of spinal fusion were evaluated in an
      established animal spine fusion model. OBJECTIVE: To determine the accuracy and
      interobserver agreement of radiographic determinations of spinal fusion in rabbit
      posterolateral spine fusion. SUMMARY OF BACKGROUND DATA: The rabbit
      posterolateral intertransverse process spine fusion model is an established
      animal model for evaluating bone graft alternatives for spinal fusion. However,
      little is known regarding the accuracy and interobserver agreement of
      radiographic determinations of spondylodesis in this model. METHODS: Forty-two
      New Zealand White rabbits underwent posterolateral spinal fusion. The animals
      were killed at 9 weeks and the lumbar spine harvested. Manual manipulation, fine
      detail radiography, and CT images were used to assess spinal fusion. RESULTS:
      Using manual palpation testing as the standard by which to assess fusion, there
      was high sensitivity and negative predictive value for both radiographic methods.
      Positive predictive value, however, was poor (26% fine detail radiography, 61% CT
      scan). CT correlated better with manual palpation testing when compared with fine
      detail radiographs. There was substantial interobserver agreement of successful
      fusion using CT scan imaging (kappa = 0.63) and moderate interobserver agreement
      radiographs (kappa = 0.52). CONCLUSIONS: Both radiographic techniques used in the
      study recorded high sensitivity and negative predictive value. However, positive
      predictive value was poor, especially with fine detail radiographs. Nevertheless,
      CT with reformatted images did appear to be superior to fine detail radiographs
      in accurately identifying nonunions in this animal model.

PMID- 15187631
TI  - Biomechanical assessment of conventional unit rod fixation versus a unit rod
      pedicle screw construct: a human cadaver study.
AB  - STUDY DESIGN: Fresh frozen human cadaver specimens were used to perform a
      biomechanical assessment focusing on spinal-pelvic fixation. Unit rod fixation
      alone was compared with that of unit rod fixation supplemented with L5 pedicle
      screws. OBJECTIVES: To investigate the biomechanical effects of adding L5 pedicle
      screw fixation to a unit rod construct. SUMMARY OF BACKGROUND DATA: The treatment
      of neuromuscular scoliosis associated with pelvic obliquity continues to evolve.
      Spinal fusion using fixation extending from the thoracic spine to the pelvis
      supplemented with segmental instrumentation has become the standard of care. The
      instrumentation of choice used at this institution has been a unit rod construct.
      Traditional Luque-Galveston technique with sublaminar wiring from T2 to L5 has
      been used. A noted complication has been a loss of distal fixation, the emphasis
      for this study. We have subsequently modified this technique, replacing wires at
      L5 with pedicle screws. This was done to improve the strength of the distal
      fixation, with the goal of decreasing the rate of instrumentation failure before
      fusion. METHODS: Twelve fresh-frozen human cadavers, between the ages of 45 and
      60 years, were instrumented from T4 to the pelvis with a Unit Rod (Sofamor
      Danek). The specimens were randomized into two groups. Segmental sublaminar
      wiring was performed from T4 to L5 in one group of six spines. The remaining six
      spines underwent sublaminar wiring from T4 to L4, with pedicle screws used for L5
      fixation. The spines were then potted from T4 to T7 in preparation for
      biomechanical testing. The spines were tested in a randomized fashion for
      subfailure stiffness in anteroposterior, oblique, and lateral planes with an
      Instron 1321 servo-hydraulic load frame (Instron Corp., Canton, MA). Each spine
      was then loaded to failure in forward flexion. RESULTS: Our results demonstrate a
      statistically significant increase in lateral stiffness (P = 0.0006) and oblique
      stiffness (P = 0.003) associated with the use of L5 pedicle screws. Statistical
      significance was also achieved with load to failure testing (P = 0.0007). The
      mean load to failure was 1377 Newtons for the pedicle screw construct and 467
      Newtons for the wire construct. CONCLUSIONS: We conclude that the addition of L5
      pedicle screws increases the stiffness and strength of the unit rod construct.
      Clinically, this should help to avoid complications associated with loss of
      fixation in this area.

PMID- 15187632
TI  - Measurement of in vivo intradiscal pressure in healthy thoracic intervertebral
      discs.
AB  - STUDY DESIGN: In vivo pressures were measured in radiologically healthy middle
      and lower thoracic discs in 6 adult volunteers. OBJECTIVES: To quantify and
      compare intradiscal pressures from the middle and lower thoracic spine during
      various body positions and maneuvers, and to investigate the potential variation
      of these pressures with orientation of the measurement transducer. SUMMARY OF
      BACKGROUND DATA: In vivo intradiscal pressures have been reported for the lumbar
      spine; however, the authors are unaware of any studies presenting intradiscal
      pressures in the thoracic spine. METHODS: A specially constructed pressure
      sensing needle was inserted into the nucleus pulposa, and pressures were recorded
      during a variety of body positions and maneuvers in middle and lower thoracic
      discs in 6 study participants. In three of the body positions, pressures were
      measured with the needle in both vertical and horizontal orientations to
      investigate whether the measured pressures were directionally dependent. RESULTS:
      Intradiscal pressure varied significantly with body position and maneuver, with
      pressures being greatest in positions where study participants held 10-kg weights
      in each hand. Disc level and orientation of the pressure needle did not
      significantly influence intradiscal pressure. In some body positions, thoracic
      intradiscal pressures were significantly different from previously reported
      pressures from the lumbar spine. CONCLUSIONS: Thoracic intradiscal pressure was
      significantly influenced by body position and maneuver but not disc level.
      Intradiscal pressures are useful for gaining greater insight into the
      biomechanics of the thoracic spine.

PMID- 15187633
TI  - The effects of load carriage on spinal curvature and posture.
AB  - STUDY DESIGN: This is a repeated-measures design where the subjects acted as
      their own controls. Curvature of the spine, as well as mean trunk and head
      flexion were noted twice during 21 minutes of load carriage: in rested and
      fatigued conditions. OBJECTIVE: To determine if spinal curvature and posture were
      affected by mild fatigue in load carriage. SUMMARY OF BACKGROUND DATA:
      Researchers have found a link between load carriage and low back problems.
      Changes in gait and posture resulting from load carriage are largely a result of
      the body's attempt to increase stability. METHODS: Apparently healthy females (n
      = 25) carried a 9-kg backpack at 1.79 m/s for 21 minutes around a 200-m circuit.
      The pack had spring-loaded displacement rods intended to measure displacement
      from the pack to the spine. Subjects were filmed (60 Hz) and displacement data
      were collected during minute 3 (rested condition) and minute 18 (fatigued
      condition). RESULTS: The MANOVA revealed that the thoracic to lumbar region cubic
      curve significantly increased as subjects fatigued. Rested trunk and head angles
      were not significantly different from the fatigued condition. Trunk and head
      angles were not indicative of spinal curvature at 18 minutes; therefore, they may
      not be the best measures of fatigue during load carriage. CONCLUSIONS: Spine and
      back health may be adversely affected by load carriage sooner than was previously
      thought, and it may be important to use spinal curvature as a measure of posture
      for future load carriage studies.

PMID- 15187634
TI  - Spinal canal narrowing during simulated whiplash.
AB  - STUDY DESIGN: A biofidelic whole cervical spine model with muscle force
      replication was used to evaluate spinal canal pinch diameter (CPD) narrowing
      during simulated whiplash. OBJECTIVES: To quantify CPD narrowing during simulated
      whiplash and to determine if whiplash resulted in a narrower post-whiplash CPD.
      SUMMARY OF BACKGROUND DATA: Spinal cord injuries are uncommon in whiplash
      patients, although such injuries have been reported in those with narrow canals.
      It has been hypothesized that increased cerebral spinal fluid pressure during
      whiplash could injure neural tissues. METHODS: The biofidelic model and a bench
      top whiplash apparatus were used to simulate whiplash at 3.5, 5, 6.5, and 8 g
      accelerations of the T1 vertebra. The CPD was measured in the intact specimen in
      the neutral posture (neutral posture CPD) and under a 1.5 Nm static extension
      load (pre-whiplash CPD), during simulated whiplash (dynamic whiplash CPD), and
      again under a 1.5 Nm extension load following each whiplash simulation (post
      whiplash CPD). RESULTS: The average dynamic whiplash CPDs were significantly
      narrower (P < 0.05) than the corresponding pre-whiplash CPDs at accelerations of
      3.5 g and above. The narrowest CPD was observed at C5-C6 during the 6.5 g
      simulation and was 3.5 mm narrower than the neutral posture CPD. In general, the
      average post-whiplash CPDs were not significantly narrower than the corresponding
      pre-whiplash CPDs. CONCLUSIONS: Spinal cord injury during whiplash is unlikely in
      patients with average normal canal diameters. Cord compression following whiplash
      due to physiologic extension loading is not likely. Previous clinical studies
      have found that whiplash patients with narrow canals may be at risk of injury,
      and our results do not disprove it.

PMID- 15187635
TI  - Circumferential cervical surgery for ossification of the posterior longitudinal
      ligament: a multianalytic outcome study.
AB  - STUDY DESIGN: Three outcome measures, Nurick grades, Odom's criteria, and the
      Short Form (SF-36) were analyzed following circumferential cervical surgery in 47
      patients. OBJECTIVES: To analyze three outcome measures following circumferential
      surgery. SUMMARY OF BACKGROUND DATA: Few studies use multiple outcome criteria to
      assess circumferential surgery. METHODS: Patients averaged 54 years of age and
      exhibited severe myelopathy (Nurick grade 3.6). Corpectomies of 2.6 vertebrae (on
      average) were followed by posterior fusions (C2-T1) with halo stabilization.
      Initial fixed-plates (n = 28) and subsequent dynamic ABC plates (Aesculap,
      Tuttlingen, Germany) (n = 19) were applied, Fusion was confirmed on dynamic
      radiographs and two-dimensional CT studies 3, 6, and up to 12 months after
      surgery. Nurick grades and Odom's criteria were evaluated 1 and 2 years after
      surgery. Results of SF-36 questionnaires, obtained before surgery, 6 weeks, 3
      months, 6 months, 1 year, 2 years after surgery, were calculated. RESULTS:
      Neurodiagnostic studies confirmed fusion on average 5.0 months after surgery. One
      and 2 years after surgery, mean Nurick grades were 0.8 (+2.8 points) and 0.4
      (+3.2 points), respectively. One year (2 years) postoperative Odom's criteria
      revealed excellent 26 (30), good 14 (11), fair 6 (5), and poor 1 (1) patient
      outcomes. Comparing preoperative with 1-year postoperative SF-36 questionnaires
      revealed moderate improvement on 5 health scales: Social Function (+19.9), Bodily
      Pain (+19.6), Role-Physical (+18.8), Physical Function (+12.5), and Role
      Emotional (+11.1). Minimal additional improvement occurred over the second year:
      Role-Physical (+21.6), Social Function (+16.4), Bodily Pain (+13.4), Physical
      Function (+12.8), and Role Emotional (+9.5). CONCLUSION: Based on three outcome
      measures, the greatest improvement occurs 1 year following circumferential
      surgery.

PMID- 15187636
TI  - The use of muscle relaxant medications in acute low back pain.
AB  - STUDY DESIGN: Prospective cohort study. OBJECTIVES: To determine the
      characteristics of patients who take muscle relaxants for back pain after seeking
      care and to determine the relationship of muscle relaxant use with recovery from
      the episode of low back pain. SUMMARY OF BACKGROUND DATA: Low back pain is a
      common condition with a generally favorable short-term prognosis. Physicians in
      the acute setting commonly prescribe muscle relaxants. The indications for use
      and outcomes are not clear. METHODS: We performed a secondary data analysis of a
      cohort of 1633 patients who sought care from a variety of practitioners (primary
      care, physician of chiropractic, orthopedic surgeon, Health Maintenance
      Organization) for low back pain. Patients were enrolled in the physician's office
      and interviewed at baseline, 2, 4, 8, 12, and 24 weeks. Pain, functional status,
      medication use, health care utilization, and satisfaction with care were
      assessed. RESULTS: Muscle relaxants were used by 49% of patients; among those who
      sought care from doctors, 64% used muscle relaxants. Muscle relaxant users were
      more impaired at baseline. Over time, among patients with greater functional
      status impairment (Roland disability score > 12) at baseline, muscle relaxant
      users had somewhat slower recovery from the episode of back pain. This finding
      persisted after controlling for baseline functional status, age, worker's
      compensation status, and use of nonsteroidal inflammatory agents. CONCLUSIONS:
      Use of muscle relaxants was very common among patients with acute low back pain.
      Muscle relaxant use was not associated with more rapid functional recovery.

PMID- 15187637
TI  - Complications of lumbar facet radiofrequency denervation.
AB  - STUDY DESIGN: Retrospective. OBJECTIVE: To assess the incidence of complications
      associated with fluoroscopically guided percutaneous radiofrequency denervation
      of the lumbar facet joints. SUMMARY OF BACKGROUND DATA: Based on the results of
      previous efficacy studies, complications associated with facet joint
      radiofrequency denervation procedures appear to be rare. No formal safety
      assessment for this procedure has been performed to date. METHODS: We conducted
      retrospective chart reviews to identify complications that occurred within 8
      weeks of facet joint radiofrequency denervation procedures performed at the Mayo
      Clinic in Jacksonville during a 5-year period. Only procedures that included
      radiofrequency electrode placement between the L1 transverse process and the
      sacral ala were included. The chart of each patient was reviewed and adjudicated
      by a panel of 4 physicians before being classified as a complication. RESULTS:
      Ninety-two patients received a total of 616 radiofrequency lesions during 116
      separate denervation procedures. An average of 5 +/- 3 lesions were performed
      during each radiofrequency denervation procedure. Six minor complications were
      identified, yielding a 1.0% overall incidence of minor complications per
      radiofrequency site. Complications included: 3 cases of localized pain lasting
      more than 2 weeks (0.5%) and 3 cases of neuritic pain lasting less than 2 weeks
      (0.5%). No cases of infection, new motor deficits, or new sensory deficits were
      identified. CONCLUSIONS: Fluoroscopically guided percutaneous radiofrequency
      denervation of the lumbar facets is associated with an overall 1.0% incidence of
      minor complications per lesion site.

PMID- 15187638
TI  - Low back pain in a representative sample of Greek population: analysis according
      to personal and socioeconomic characteristics.
AB  - STUDY DESIGN: A cross-sectional study of low back pain and its related aspects in
      a representative sample of Greek population. OBJECTIVES: To estimate the
      prevalence of low back pain in the Greek population and to study the association
      of low back pain frequency and severity with socioeconomic and demographic
      characteristics. SUMMARY OF BACKGROUND DATA: Several prevalence studies carried
      out in different populations suggest a high frequency of this condition in the
      general population. Socioeconomic and demographic factors are likely to influence
      frequency and severity of low back pain. In Greece, there have been no previous
      studies investigating low back pain frequency and severity and its related
      aspects in the general population. Studies carried out in selected Greek
      populations suggest a 3-month prevalence of about 50%. METHODS: A 2000-person
      sample of the Greek population older than 15 years was selected by multiple-stage
      sampling, with definition of sample quotas based on demographic characteristics.
      Information about low back pain and its related aspects, as well as about
      socioeconomic and demographic characteristics, was collected by personal
      interviews. The study was carried out between March 10 and April 12, 2000.
      RESULTS: A total of 635 persons (31.7%) reported low back pain the last month.
      Among them 126 (19.9%) stayed in bed for some time, with a mean duration of
      staying in bed of 5.5 days. Work absenteeism represented a 19.1% of people
      younger than 65 years (54 persons) with a mean duration of 4.52 days. Low back
      pain frequency and severity were related to several socio-demographic factors at
      a statistically significant level. Sex, age, and kind of job presented a
      significant association with risk of low back pain independently from other
      socioeconomic factors. CONCLUSIONS: According to the results of the study, low
      back pain is a frequent symptom in the general Greek population. Low back pain
      frequency and severity are associated with several socio-demographic factors,
      especially with age, sex, and kind of job.

PMID- 15187641
TI  - Weather conditions and spinal patients.
AB  - STUDY DESIGN: A retrospective study. OBJECTIVES: To evaluate the effects of
      various weather conditions on reported health status. SUMMARY OF BACKGROUND DATA:
      Existing literature shows no definite conclusions regarding the effect of weather
      on patients with spinal pathology. METHODS: Initial visit data from 23 American
      centers participating in the National Spine Network included demographic
      information and SF-36-based health status. Weather conditions when and where
      patients were seen were obtained from the National Climatic Data Center and U.S.
      Naval Observatory. SF-36 outcomes were predicted using multiple regression
      techniques from weather parameters, which included high and low temperature,
      average dew point, wet bulb, barometric pressure, total precipitation, phase of
      the moon, and length of sunlight. RESULTS: A total of 26,862 of 54,062 patients
      were identified. Two models were compared: model 1 included the above weather
      predictors and model 2 added age and gender. For each SF-36 scale and subscale
      and the Physical and Mental composite Scores, both models were statistically
      significant, although only model 2 for physical function produced an R value
      greater than 1%. Barometric pressure was the only weather predictor that was
      consistently significant. Increased pressure was associated with worse outcomes.
      Although age and gender were significant additions to the prediction equation,
      overall, the practical contribution was minimal. CONCLUSION: A statistically
      significant relationship between weather factors and SF-36-based health status
      exists but has minimal clinical significance. These factors had minimal if any
      effect on mental health-related scores bringing into question either the
      relationship between weather and psychological status, at least in patients with
      spinal problems or the usefulness of the instrument used.

PMID- 15187640
TI  - Patterns of care for low back pain in a working population.
AB  - STUDY DESIGN: A prospective longitudinal study with 1-year follow-up. SUMMARY OF
      BACKGROUND DATA: Little is known about the consequences of having back pain and
      the patterns underlying the decisions to use medical care. OBJECTIVES: The aim of
      this study is to describe care utilization for low back pain (LBP) and to
      investigate which factors determine use of care for LBP. METHODS: We used a self
      administered questionnaire to collect data on individual, health-related, and
      work-related factors and the type of medical care sought among 529 employees of
      nursing homes and homes for the elderly in the Netherlands. Logistic regression
      models were used to present associations between aforementioned factors and care
      utilization for LBP. RESULTS: A large proportion of the working population was
      afflicted with LBP, and only one third sought care. Individuals who use care had
      more intense pain, chronic pain, and functional limitations. Patients'
      characteristics varied among the different type of health care providers. Well
      known work-related risk factors for the occurrence of LBP did not determine use
      of care for workers with LBP. CONCLUSIONS: Care utilization due to LBP was
      associated with severity and nature of back pain. Patients' characteristics vary
      among the different type of health care providers, but work-relatedness of LBP
      seems similar across all providers.

PMID- 15187643
TI  - Back-related functional limitations among full-time homemakers: a comparison with
      women employed full-time outside the home.
AB  - STUDY DESIGN: Two-year prospective study with repeated measurements. OBJECTIVES:
      To describe back-related functional limitations and their evolution among full
      time female homemakers and to compare them to that of women employed full-time
      outside the home. SUMMARY OF BACKGROUND DATA: Back pain is not limited to the
      formal "working" population. However, there is little information on the
      consequences of back pain in "nonworking" individuals. METHODS: Subjects were
      members of a large Health Maintenance Organization who consulted a physician for
      nonspecific back pain. Telephone interviews were conducted 4 to 6 weeks after the
      consultation and 1 and 2 years later. Back-related functional limitations were
      measured with a modified 16-item Roland-Morris scale. Analyses were conducted on
      104 full-time homemakers and 288 women employed full-time outside the home.
      RESULTS: The mean Roland-Morris score among homemakers was 34.4% at baseline and
      dropped to 22.8% at 2 years. In multiple regression analyses, 2-year back-related
      functional limitations were significantly associated with symptoms of depression,
      pain intensity, and the number of days with back pain in the past 6 months
      measured at baseline, but not with employment status. Functional limitations were
      not different between homemakers and women employed outside the home, even after
      adjustment for confounders. CONCLUSIONS: In this study, the functional
      consequences of back pain had a similar nature and 2-year evolution among full
      time homemakers and women employed full-time outside the home. These results did
      not demonstrate an effect of formal employment on the functional consequences of
      back pain among women.

PMID- 15187645
TI  - The use of recombinant factor VIIa for severe intractable bleeding during spine
      surgery.
AB  - STUDY DESIGN: A report on the use of recombinant activated factor VII in 4
      patients who developed severe intractable bleeding and coagulopathy during spine
      surgery. OBJECTIVE: To describe the role of recombinant activated factor VII for
      hemostasis during spine surgery. SUMMARY OF BACKGROUND DATA: Recombinant
      activated factor VII is indicated for the treatment of bleeding episodes and the
      prevention of bleeding during surgery in patients with hemophilia with
      inhibitors. However, its use in adults undergoing spine surgery has not yet been
      reported. METHODS: Four patients who underwent multilevel spine surgery through
      an anterior approach incurred massive bleeding and subsequently became
      coagulopathic. Standard hemostatic techniques were performed and blood products
      were transfused. Persistence of the bleeding prompted the use of recombinant
      activated factor VII. RESULTS: Treatment with recombinant activated factor VII
      led to an improvement in prothrombin time and partial thromboplastin time and
      brought about cessation in gross, nonsurgical bleeding intraoperatively. No
      clinically relevant thrombotic complications related to the drug were noted.
      CONCLUSIONS: Recombinant activated factor VII is promising as an adjunctive
      hemostatic agent for patients with perioperative bleeding problems during spine
      surgery. Efficacy is seen even at low doses.

PMID- 15187647
TI  - The value of motor and somatosensory evoked potentials in evaluation of cervical
      myelopathy in the presence of peripheral neuropathy.
AB  - STUDY DESIGN: Patterns and rates of motor-evoked potential (MEP) and
      somatosensory-evoked potential (SEP) abnormalities were evaluated in 9 patients
      with combined cervical cord compression and diabetic neuropathy and 15 patients
      with asymptomatic cervical cord compression. The results were compared with those
      of 8 patients with pure cervical myelopathy and 7 patients with pure diabetic
      neuropathy. OBJECTIVE: To assess the efficacy of MEPs and SEPs in the evaluation
      of cervical myelopathy in the presence of peripheral neuropathy. SUMMARY OF
      BACKGROUND DATA: Previous studies have demonstrated a high sensitivity of MEPs
      and SEPs in documenting a functional involvement of motor and somatosensory
      pathways in pure or preclinical cervical myelopathy. However, there have been no
      detailed reports on MEPs and SEPs in cervical cord compression associated with
      peripheral neuropathy. METHODS: Central somatosensory conduction was assessed by
      median and tibial SEPs using peak-to-peak and onset-to-onset methods. Central
      motor conduction was measured by MEPs and F-waves elicited from upper and lower
      limb muscles in response to transcranial magnetic stimulation, magnetic
      stimulation of cervical motor roots, and electrical stimulation of peripheral
      nerves. RESULTS: MEPs were more sensitive than SEPs in detecting central
      conduction impairments in patients with either pure or preclinical or combined
      forms of cervical myelopathy. The rate of MEP abnormalities suggesting the
      corticospinal tract involvement in the combined cervical cord compression
      neuropathy group did not differ significantly from that in the asymptomatic
      cervical cord compression group but was lower than in the pure cervical
      myelopathy group. Combined MEP and SEP analysis improved the test sensitivity in
      detecting clinically "silent" cervical cord dysfunctions. CONCLUSIONS: MEPs
      associated with SEPs are a valuable tool for assessing the presence and severity
      of cervical cord involvement in combined cervical cord compression and peripheral
      neuropathy lesions.

PMID- 15187648
TI  - Rapid resolution of chronic sciatica with intravenous infliximab after failed
      epidural steroid injections.
AB  - STUDY DESIGN: A case study of the use of infliximab to treat sciatica associated
      with disc herniation in a man who had failed extensive treatment, including 3
      epidural injections, for several months. OBJECTIVE: To compare and contrast the
      clinical and imaging data before and after treatment with infliximab and to
      compare these results to those of a previously published case series. SUMMARY OF
      BACKGROUND DATA: One prior case series had reported good results in patients with
      sciatica and disc herniation of up to 3 months' duration. However, patients had
      not had previous epidural steroid injections, and no comparative imaging data
      were reported. METHODS: After 8 months of unrelenting sciatica, the patient
      received a single infusion of infliximab. He was evaluated using the same
      measures used in the previously published case series. Pain scales, functional
      assessments, physical examinations, and imaging studies were performed
      immediately before infusion and for several months after treatment, with a final
      evaluation 6 months following infliximab treatment. RESULTS: One week after
      treatment, he reported >50% reduction in back and leg pain. Six months
      posttreatment, his back and leg pains were reduced by 89% and 86%, respectively.
      Strength and reflexes were restored to normal. Magnetic resonance imaging
      performed 3 months postinfliximab showed a 50% reduction in the herniation and
      disappearance of previously noted S1 root compression. There were no side effects
      from the treatment. CONCLUSION: This report extends the potential use of
      infliximab to patients with more chronic sciatica and to those who have had prior
      epidural steroids. Larger, randomized trials are warranted.

PMID- 15187649
TI  - Brown tumor of the spine and progressive paraplegia in a hemodialysis patient.
AB  - STUDY DESIGN: Case report. OBJECTIVE: To describe the radiographic features and
      management of spinal brown tumor and to document tumor mineralization after
      parathyroidectomy. SUMMARY OF BACKGROUND DATA: Brown tumors are classic skeletal
      manifestations of hyperparathyroidism usually seen in severe forms. They are
      increasingly rare because hyperparathyroidism is now diagnosed and treated at an
      early stage. METHODS: A case of brown tumor of the spine in a 37-year-old woman
      on chronic hemodialysis is described. The imaging findings before and after
      parathyroidectomy are discussed. RESULTS: In a woman on chronic hemodialysis, a
      brown tumor of T8 caused acute spinal cord compression with paraplegia. Magnetic
      resonance imaging provided an accurate evaluation of the lesion, and needle
      biopsy confirmed the diagnosis. Emergent surgery was needed to relieve the spinal
      compression and stabilize the spine. The vertebral lesion underwent
      remineralization after parathyroidectomy. CONCLUSION: Brown tumor is a benign
      tumor that resolves after parathyroidectomy. When brown tumor arises in the
      spine, surgery may be needed to preserve neurologic function.

PMID- 15187650
TI  - Coccygeal retroversion.
AB  - STUDY DESIGN: A retrospective review of a case of coccygodynia caused by a
      previously unreported coccygeal morphology. OBJECTIVES: To draw attention to a
      previously undiagnosed pathology. BACKGROUND: This case adds to the recently
      described variants of coccygeal anatomy. METHODS: The authors present the case of
      a 42-year-old woman with intractable coccygodynia and a retroverted coccyx.
      RESULTS: The histologic examination of the resected specimen after coccygectomy
      revealed a bony lesion covered with thick fibrous tissue and evidence of mature
      adipocytes within trabecular spaces. (The latter was described in a supplementary
      report as an intraosseous lipoma.) CONCLUSION: A retroverted coccyx and
      adventitious bursa represent a pathoanatomy not formally reported on in the
      literature. This type of coccyx that is symptomatic may not respond to the
      traditional prolonged period of conservative management.

PMID- 15187651
TI  - Hypotension-induced loss of intraoperative monitoring data during surgical
      correction of scheuermann kyphosis: a case report.
AB  - STUDY DESIGN: Presentation of a case report of Scheuermann kyphosis surgical
      correction. OBJECTIVE: To describe a scenario where both neurogenic mixed evoked
      potentials and somatosensory-evoked potentials were lost due solely to
      hypotension before any correction of a kyphotic spinal deformity was performed.
      SUMMARY OF BACKGROUND DATA: Multimodality intraoperative neurophysiologic
      monitoring of the spinal cord has become widely utilized during surgical
      correction of scoliotic and kyphotic deformities. Most spinal surgeries also
      benefit from a state of hypotension to minimize blood loss, but unchecked and
      persistent hypotension may lead to inadequate perfusion to the spinal cord,
      resulting in spinal cord dysfunction noted by diminution of neuromonitoring data.
      METHODS: An 18-year-old boy with a 95 degrees Scheuermann kyphosis underwent a
      posterior spinal fusion for correction of his deformity. Intraoperative
      neurophysiologic monitoring consisting of neurogenic mixed evoked potentials and
      somatosensory-evoked potentials were performed throughout surgery. RESULTS: After
      placement of segmental pedicle screw fixation points and multiple osteotomies,
      before any instrumented correction of the deformity, all lower extremity
      neuromonitoring data were acutely lost. The surgeon was immediately warned of the
      data loss, with the mean arterial pressure noted to be 50 mm Hg. The mean
      arterial pressure was raised with the use of epinephrine bolus and dopamine
      infusion. Subsequently, all lower extremity neuromonitoring data returned. A
      Stagnara wake-up test was performed, which the patient passed, and the surgical
      correction was performed with his pressure maintained on a dopamine infusion. He
      awakened without neurologic deficits and had an uneventful recovery. CONCLUSIONS:
      Although a state of mild hypotension may be beneficial to limit blood loss during
      spinal deformity corrective surgery, acute and/or prolonged hypotension may
      jeopardize spinal cord vascularity and should be avoided especially during
      surgical treatment of high-risk deformities such as kyphosis. Early warning by
      multimodality physiologic neuromonitoring appears to be a useful method to alert
      surgeons of the potentially devastating problem of hypotension-induced spinal
      cord dysfunction and allows immediate corrective actions.

PMID- 15187653
TI  - Vitrectomy for chronic macular holes.
AB  - PURPOSE: To address the efficacy of surgical intervention for chronic macular
      holes. METHODS: The cases of 22 patients (23 eyes) who underwent pars plana
      vitrectomy with or without internal limiting membrane (ILM) peeling and use of
      10% to 16% C3F8 gas for macular holes of duration of >1 year (mean, 4.2 years;
      range, 1.2-15 years) were retrospectively reviewed. Preoperative visual acuity
      ranged from 20/60 to 5/200 (mean, 20/278). Thirteen eyes (56.5%) had stage 3
      macular holes, and 10 eyes (43.5%) had stage 4 macular holes. The mean age of the
      patients was 70.2 years (range, 47-78 years), and 20 (87%) were female. RESULTS:
      Nineteen (83%) of 23 macular holes were closed at final follow-ups at >/=9 months
      (mean, 4.67 years; range, 0.9-10.8 years). With one operation that included ILM
      peeling, 13 (81%) of 16 eyes had holes that closed. Seven eyes on which initial
      surgery without ILM peeling failed underwent reoperation with ILM peeling, and
      all but one had closed holes. ILM peeling was significant for surgical success of
      one operation (Fisher exact test, P = 0.0005). Postoperative visual acuity ranged
      from 20/30 to 20/800 (mean, 20/166). Improved vision with halving of the visual
      angle occurred in 16 eyes (70%). Nine eyes (39%) achieved visual acuity of 20/70
      or better, and two eyes (8.7%) achieved visual acuity of 20/40 or better. One eye
      (4%) had worse visual acuity, and three eyes (13%) remained unchanged. Cataract
      was a possible cause of decreased vision in six eyes (26%) at the end of follow
      up. CONCLUSION: Chronic macular holes can be surgically closed with visual
      improvement in most patients. ILM peeling is an important surgical factor for
      closure of the macular hole with one operation.

PMID- 15187654
TI  - Internal limiting membrane peeling for decompression of macular edema in retinal
      vein occlusion: a report of 14 cases.
AB  - BACKGROUND: Currently, there is no proven treatment for macular edema due to
      central retinal vein occlusion (CRVO). Moreover, not all cases with macular edema
      due to branch retinal vein occlusion (BRVO) respond to laser photocoagulation. We
      postulated that internal limiting membrane (ILM) peeling for decompression of
      macular edema in cases of retinal vein occlusion would facilitate egress of blood
      and extracellular fluid out of the inner retinal layers, leading to reduction of
      macular edema and improvement in visual acuity. METHODS: Fourteen consecutive
      patients with macular edema due to CRVO or selected cases of BRVO, not eligible
      for laser photocoagulation, underwent pars plana vitrectomy with removal of
      preretinal hyaloid and peeling of the ILM stained with indocyanine green dye.
      RESULTS: In all cases, intraretinal blood and retinal thickening diminished
      within 6 weeks of surgery. Visual acuity improved in 78.6% of cases. No surgical
      complications occurred, although one patient developed nuclear cataract 10 months
      postoperatively. CONCLUSION: Pars plana vitrectomy with ILM peeling in selected
      cases of CRVO and BRVO showed improvement in visual acuity in this nonrandomized,
      noncontrolled study. This pilot study adds support to the concept that ILM
      peeling may of visual benefit when compared with the natural history in these
      vaso-occlusive diseases.

PMID- 15187655
TI  - Retinal choroidal collateral circulation after radial optic neurotomy correlated
      with the lessening of macular edema.
AB  - PURPOSE: To evaluate patients who had undergone radial optic neurotomy for
      central retinal vein occlusion for the presence of retinal choroidal collateral
      circulation and to correlate these collaterals with changes in macular thickness
      during follow-up. Radial optic neurotomy is designed to release proposed pressure
      within the scleral canal. METHODS: Retrospective review of patients undergoing
      radial optic neurotomy. The patients had a baseline examination including
      ophthalmoscopy, fluorescein angiography, and optical coherence tomography. At an
      interval follow-up at approximately 3 months the patients were reevaluated with
      ophthalmoscopy, optical coherence tomography, and indocyanine green angiography.
      RESULTS: There were 6 patients, and the mean age was 68.3 years. The mean time
      from onset of the central retinal vein occlusion to the radial optic neurotomy
      was 2.3 months. One patient had no collateral vessels, three patients had
      significant collaterals, and two patients had moderate-caliber collaterals. The
      mean central macular thickness preoperatively was 1,021 microm and the mean
      central macular thickness postoperatively was 733 microm. The change in macular
      thickness was highly correlated with the degree of development of collaterals
      from the retinal to the choroidal circulation (P = 0.008, Spearman's rho = 0.93).
      CONCLUSION: Although all patients had a radial optic neurotomy a significant
      determinant in reduction of macular edema was the presence of retinal-choroidal
      collateral circulation. This suggests that there may be additional mechanisms,
      other than simple release of alleged pressure in the scleral canal, for any
      observed effects from radial optic neurotomy.

PMID- 15187656
TI  - Outcome of macular hole surgery in diabetic patients with nonproliferative
      retinopathy.
AB  - PURPOSE: To determine the outcome of macular hole surgery in a diabetic
      population with no evidence of proliferative retinopathy. METHODS: This is a
      retrospective chart review of 183 patients (194 eyes) undergoing pars plana
      vitrectomy for an idiopathic macular hole. RESULTS: The anatomic closure rate for
      the diabetic patients without proliferative retinopathy was 93.8% (15/16),
      compared with 94.9% (169/178) for nondiabetic patients. A best corrected visual
      acuity of 20/50 or greater was obtained in 50% of diabetic patients (8/16),
      compared to 58.4% of nondiabetic patients (104/178). There was no difference in
      postoperative complications between the two groups. CONCLUSION: The anatomic
      closure rate and visual outcome after macular hole surgery in diabetic patients
      without proliferative retinopathy is comparable to that of nondiabetic patients.

PMID- 15187657
TI  - Delayed visual loss after pars plana vitrectomy for retained lens fragments.
AB  - PURPOSE: To report visual results and postoperative complications in patients
      undergoing vitrectomy for retained lens fragments. METHODS: Retrospective,
      noncomparative, interventional case series of 42 consecutive patients undergoing
      vitrectomy for retained lens fragments by a single surgeon, all with a minimum of
      6 months' follow-up. The main outcome measurement was best corrected visual
      acuity at 3 months and at final follow-up visit. RESULTS: Although 67% of eyes
      achieved a postoperative visual acuity of 20/40 or better at 3 months, 17% had
      events during follow-up that resulted in loss of vision to less than 20/40. Final
      best corrected visual acuity 20/40 or better was achieved in 50% of eyes. Retinal
      detachment occurred in 17%, and 21% of eyes required long-term therapy for
      glaucoma. CONCLUSION: Patients undergoing vitrectomy for retained lens fragments
      often develop delayed visual loss. Long-term surveillance is necessary in these
      patients.

PMID- 15187658
TI  - Retinal detachment of regressed retinopathy of prematurity in children aged 2 to
      15 years.
AB  - PURPOSE: To reveal the clinical features and surgical results of retinal
      detachment of regressed retinopathy of prematurity (ROP) that occur in the
      children aged 2 to 15 years. PATIENTS AND METHODS: The records of patient who had
      a retinal detachment of a regressed ROP were retrospectively reviewed. Sixteen
      eyes from 15 patients that required surgical treatments due to retinal detachment
      of a regressed ROP were included. RESULTS: After treatment of acute phase of ROP,
      eight eyes showed grade II of cicatricial change and eight eyes showed grade III.
      We did not find any evidence that the acute stages of ROP and its treatment
      affect the degree of the cicatricial changes. All eight eyes with grade III of
      cicatricial ROP showed tractional retinal detachment (TRD) and five of eight eyes
      (62.5%) with grade II showed rhegmatogenous retinal detachment (RRD). The mean
      interval between regressed ROP and development of late retinal detachment was
      20.7 months (range, 12-61 months) in the TRD group and 85.8 months (range, 33
      148) in the RRD group. The mean age at onset of late detachment was 34.1 months
      (range, 26-73 months) in the TRD group and 98.6 months (range, 45-162) in the RRD
      group. Anatomical success was achieved at one of five eyes (20%) with RRD and six
      of 11 eyes (54.5%) with TRD. Compared with the preoperative visual acuity, visual
      improvement, no change, and decreased visual acuity were achieved, respectively,
      in two eyes, three eyes, and no eyes in the RRD group and three eyes, six eyes,
      and two eyes in the TRD group. However, only two of 16 eyes with late retinal
      detachment achieved a visual acuity of 20/200 or better. CONCLUSION: Late retinal
      detachment is the main vision-threatening condition in patients with regressed
      ROP during childhood. The visual prognoses of these patients are poorer than
      those with late retinal detachments that occur in adult ROP patients. Therefore,
      a periodic fundus examination should be performed more frequently during
      childhood than in adulthood, particularly in nonverbal children.

PMID- 15187659
TI  - Long-term results of treatment of macular complications in eyes with immune
      recovery uveitis using a graded treatment approach.
AB  - PURPOSE: To evaluate the results of a graded treatment approach in a cohort of
      eyes with macular complications of immune recovery uveitis. METHODS: A cohort of
      18 eyes of 13 patients representing all eyes with these complications at the
      University of California, San Diego AIDS Ocular Treatment Unit was studied. Eyes
      were classified into three groups and treated according to a graded protocol.
      RESULTS: Eyes with mild disease (macular edema and vision of 20/30 or better)
      were observed. These six eyes maintained good vision with only one dropping to
      20/40. In eyes with worse macular edema and vision of 20/30 or worse (10 eyes of
      9 patients), repository sub-Tenon steroid injections were used repeatedly. There
      were no complications of steroid use but visual improvement occurred in only 40%
      of eyes. Macular edema persisted. In eyes with structural macular changes, such
      as epiretinal membrane, vitrectomy resulted in vision improvement in three of
      four eyes. The cystoid macular edema persisted despite surgery. CONCLUSION: Mild
      cases of immune recovery uveitis and macular edema may be observed. In eyes with
      reduction of vision due to cystoid macular edema, there was only a modest
      treatment effect using repository corticosteroids. Eyes with immune recovery
      uveitis that develop epiretinal membrane undergo some visual improvement after
      removal of the membrane. The macular edema of immune recovery uveitis is
      resistant to corticosteroid treatment.

PMID- 15187660
TI  - A 10-year comparison of endogenous endophthalmitis outcomes: an east Asian
      experience with Klebsiella pneumoniae infection.
AB  - PURPOSE: To evaluate the infection sources and causative organisms in cases of
      endogenous endophthalmitis and review the outcomes for patients with Klebsiella
      pneumoniae infection during a 10-year period. METHODS: All cases of endogenous
      endophthalmitis treated at one Taiwanese hospital from July 1992 to June 2002
      were retrospectively reviewed (n = 74; 86 eyes). The study was divided into two 5
      year periods, with patients stratified into Group F or Group L according to onset
      date within the first or last of these periods, respectively. The outcomes of
      cases of K. pneumoniae infection in Group L (21 eyes) and Group F (32 eyes) were
      compared. RESULTS: The major source of infection (liver abscess) and the
      causative organism (K. pneumoniae) did not change throughout the 10-year review
      period; however, outcomes for Group L appeared superior. The interval from onset
      of ocular symptoms to ophthalmic consultation was shorter for Group L; however, a
      statistically significant difference was not demonstrated by between-group
      comparison. Patients with good final vision typically had good initial vision in
      cases of K. pneumoniae infection. CONCLUSION: The authors' experience with
      endogenous endophthalmitis has confirmed the findings of analogous East Asian
      studies, with liver abscess as the major source of infection and K. pneumoniae as
      the causative organism. Superior outcome may be achieved with more comprehensive
      and collaborative management, ideally through the combined efforts of multiple
      medical subspecialties.

PMID- 15187661
TI  - Applicability of rapid antibiotic susceptibility testing in the management of
      bacterial endophthalmitis.
AB  - PURPOSE: To compare the applicability of the Kirby-Bauer disk diffusion method
      (conventional method) and the rapid antibiotic susceptibility test (RAST) for
      susceptibility testing of bacteria in the management of bacterial
      endophthalmitis. METHODS: Vitreous samples from 114 consecutive patients with
      endophthalmitis who were seen between June 2002 and October 2002 were subjected
      to microbiological processing (smears and cultures for bacteria and fungi). Forty
      seven of 114 samples could be tested by RAST. In addition, the bacterial isolates
      from 47 patients were tested for antibiotic susceptibility by the conventional
      method, and minimum inhibitory concentrations (MICs) of various antibiotics were
      determined. Clinical and microbiological data for these 47 patients were
      analyzed. RESULTS: Bacteria were isolated by routine culture from 18 (38.3%) of
      47 samples; all 18 were tested by the conventional method, and MICs were
      determined for antibiotic susceptibility. Only 10 (55.6%) of these 18 samples
      were analyzed by RAST. Low inoculum and the slow-growing nature of the organisms
      (Streptococcus, 3; Staphylococcus epidermidis, 5) accounted for no growth on RAST
      plates in eight cases. Of four patients who were treated with repeated
      intraocular antibiotics, only one received RAST result-guided intraocular
      injection. Considering MIC testing as the gold standard, the sensitivity and
      specificity of RAST were either equal to (gentamicin, cefazolin, vancomycin, and
      chloramphenicol) or lower than (ciprofloxacin) those of the conventional
      technique. CONCLUSION: This comparative study failed to demonstrate a distinct
      advantage of RAST as a routine procedure in the management of bacterial
      endophthalmitis because of the need for trained staff to perform RAST, the nearly
      50% negativity of culture, and the occasionally unreliable results.

PMID- 15187662
TI  - Photodynamic therapy and vitelliform lesions.
AB  - PURPOSE: To investigate the effect of photodynamic therapy (PDT) with verteporfin
      on patients with vitelliform lesions caused by cuticular drusen or adult-onset
      foveomacular vitelliform dystrophy (AOFVD). DESIGN: Observational case series.
      PATIENTS AND METHODS: Eight eyes of seven patients from two centers were examined
      prospectively. Each patient received PDT with verteporfin applied to the
      vitelliform lesions. RESULTS: Photodynamic therapy did not significantly affect
      the median visual acuity outcome (20/50 before PDT and 20/66 after PDT) in all
      seven treated patients. Of note, however, were four eyes of four patients who
      experienced a severe decrease in visual acuity after PDT with verteporfin. The
      temporary relationship of the vision loss to the treatment suggests that this may
      represent an adverse effect from therapy. The fluorescein angiographic appearance
      was virtually unchanged in all treated patients, whereas indocyanine green
      angiography showed typical PDT-associated reduction of choroidal perfusion in the
      treatment area. CONCLUSION: Photodynamic therapy does not have a positive
      influence on the visual outcome in patients with vitelliform lesions and may have
      a negative impact on vision in some treated patients. It is important for
      physicians using PDT to exercise caution in distinguishing between choroidal
      neovascular membranes and vitelliform lesions because the outcome in this latter
      group may be worse with application of PDT than with the natural course.

PMID- 15187663
TI  - Bioptic significance of incarcerated contents at sclerotomy sites during
      vitrectomy.
AB  - PURPOSE: To study the clinical significance of incarcerated materials at
      sclerotomy sites during vitrectomy. METHODS: Fifty samples prolapsed from the
      entries to standard three-port pars plana vitrectomies were collected along the
      scleral surface. Samples from rhegmatogenous retinal detachments (RD) (n = 28),
      traumatic RD (n = 4), miscellaneous vitreous hemorrhages (n = 12), and
      intraocular foreign bodies (n = 6) were stained with hematoxylineosin and
      examined under light microscopy after being fixed in paraffin sections or smeared
      on slides. RESULTS: The specimens collected after sclerotomy contained vitreous
      tissue mixed with dispersive and sheet nonpigmented ciliary epithelia, scattered
      pigment granules, and small pigment gobbets. Specimens collected during
      vitrectomy contained pigment granules and various cells with a jellylike
      appearance. Fibrous tissue and remnants of ciliary body and retina were found in
      some specimens. The incarcerated tissues caused 12 cases of iatrogenic retinal
      breaks, among which RD recurred in six cases postoperatively due to anterior
      proliferative vitreoretinopathy. In the noniatrogenic retinal break group, only 4
      RD recurred (6/12 versus 4/38, chi2 = 6.586, P = 0.01). CONCLUSION: The
      incarcerated contents at sclerotomy sites were mainly adjacent tissues and cells.
      Prolapsed and incarcerated ciliary body and retina fragments were common and
      might cause iatrogenic retinal breaks. Attention should be paid to this material
      intraoperatively.

PMID- 15187664
TI  - Nonaxoplasmic transfer of indocyanine green into the optic nerve after
      intravitreal application.
AB  - PURPOSE: To investigate whether indocyanine green (ICG) migrates into the optic
      nerve after intravitreal application in the rabbit eye. METHODS: Gas vitrectomy
      was performed in one eye of adult Dutch belted rabbits by pars plana injection of
      0.4 ml of 100% C3F8 (n = 10). One week later, vitrectomy was performed and 0.2 ml
      of 0.25% ICG was instilled into the vitreous cavity of these vitrectomized eyes.
      After 30 seconds of ICG application, the vitreous cavity was rinsed with balanced
      salt solution plus. Unoperated rabbits served as controls (n = 2). Globes, optic
      nerves, and the entire brain were removed, and ICG fluorescence of the specimens
      was examined with a digital fundus camera starting from the first day to the
      fourth postoperative week. Other rabbit eyes (n = 2) were injected with ICG
      directly into the vitreous without vitrectomy, and assessed for ICG signal after
      1 day of ICG application. In the second part of the experiment, four rabbit eyes
      were gas vitrectomized and ICG was instilled onto retina after blockage of axonal
      flow by vinblastine. They were evaluated on the first (n = 2) and seventh
      postoperative days (n = 2). RESULTS: No fluorescein was detected in the visual
      pathways and the brains of the control group of rabbits. The optic nerves of the
      ICG-instilled eyes were stained diffusely with ICG starting from the first day
      after surgery. ICG injected nonvitrectomized eyes showed similar ICG staining
      patterns when compared with vitrectomized eyes. ICG staining pattern of the optic
      nerve did not differ in vinblastine-pretreated eyes. Fluorescence extended along
      the intraorbital portion of the optic nerve but did not transport more
      posteriorly in all animals. At the fourth week after vitrectomy, ICG signal was
      still detectable, but staining was less intense. CONCLUSION: Intravitreal ICG
      injection results in nonaxoplasmic extension into the optic nerve in the rabbit.

PMID- 15187665
TI  - Bietti's crystalline corneoretinal dystrophy: a cross-sectional study.
AB  - OBJECTIVE: To evaluate the prevalence of Bietti's corneoretinal dystrophy (BCD)
      in a reference population of retinitis pigmentosa (RP), and to document the
      disease course clinically and angiographically by a cross-sectional approach.
      METHODS: Two hundred seven consecutive RP patients were ascertained within a 3
      year period. All patients had a complete eye examination, including fluorescein
      and indocyanine green angiography (FA, ICG). Blood samples were collected for
      electron microscopy evaluation of circulating lymphocytes of BCD patients.
      RESULTS: Six patients were diagnosed with BCD. Prevalence was 3% of nonsyndromic
      RP cases. Limbal corneal and intraretinal crystals were found in all cases. In
      the early phase of BCD, ICG revealed focal lobular areas of choriocapillary
      atrophy at the equator, with concomitant retinal pigment epithelium (RPE) changes
      at the posterior pole on FA. These lesions gradually progressed both anteriorly
      and posteriorly, sparing an incomplete peripapillary ring and macular island
      until late in the disease. Progressive sclerosis of ciliary and choroidal
      arteries was noted upon ICG. The presence of lysosomal crystals was documented in
      a subpopulation of circulating lymphocytes that seemed to increase with age.
      CONCLUSION: The present study is the first to assess BCD prevalence in a
      population of retinitis pigmentosa patients, to describe clinically and
      angiographically its evolution from first symptom to legal blindness, and to
      localize the first fundus alterations not only at the posterior pole but also at
      the equator.

PMID- 15187666
TI  - The chick chorioallantoic membrane as a model tissue for surgical retinal
      research and simulation.
AB  - PURPOSE: We describe the use of chick chorioallantoic membrane (CAM) as a model
      system for the study of the precision and safety of vitreoretinal microsurgical
      instruments and techniques. METHODS: The CAM was prepared for experimentation
      with and without its inner shell membrane (ISM) attached for in vivo and in vitro
      experiments that simulated medical and surgical interventions on the retina.
      RESULTS: The CAM's ease of use, low cost, and anatomic structure make it a
      convenient model for surgical retinal and retinal vascular modeling. CONCLUSION:
      While CAM has been used extensively in the past for ocular angiogenesis studies,
      we describe the tissue as a useful tool for a variety of other applications,
      including (1) testing of novel surgical tools and techniques for cutting and
      coagulating retina and its vasculature, (2) testing vessel cannulation and
      injection techniques, (3) angiographic studies, and (4) endoscopic surgery.

PMID- 15187667
TI  - An engineering approach to vitreoretinal surgery.

PMID- 15187668
TI  - Diagnostic and therapeutic challenges.

PMID- 15187669
TI  - Pars plana vitrectomy for exuduative retinal detachment in coats-type retinitis
      pigmentosa.

PMID- 15187670
TI  - Combined central retinal vein and artery occlusion associated with an isolated
      superior ophthalmic vein thrombosis.

PMID- 15187671
TI  - Choroidal melanoma in an immunosuppressed child with minimal change nephrotic
      syndrome.

PMID- 15187672
TI  - Central retinal vascular occlusion by orbital pseudotumor.

PMID- 15187673
TI  - Severe ocular pain secondary to occipital neuralgia following vitrectomy surgery.

PMID- 15187674
TI  - Intravitreal triamcinolone acetonide injection in ocular ischemic syndrome.

PMID- 15187675
TI  - Central retinal artery occlusion in a patient with fibromuscular dysplasia.

PMID- 15187676
TI  - Bilateral vitelliform maculopathy and deferoxamine toxicity.

PMID- 15187678
TI  - Nonsurgical management of subretinal cysticercosis.

PMID- 15187677
TI  - Posterior scleritis causing combined central retinal artery and vein occlusion.

PMID- 15187679
TI  - Central serous chorioretinopathy associated with topical dermal corticosteroids.

PMID- 15187680
TI  - Juxtafoveal telangiectasis-a name change?

PMID- 15187681
TI  - Endogenous endophthalmitis due to alternaria in an immunocompetent host.

PMID- 15187682
TI  - Treatment of cystoid macular edema with oral acetazolamide in a patient with best
      vitelliform macular dystrophy.

PMID- 15187683
TI  - Complete occlusion of the anterior capsular opening by fibrocellular membrane
      associated with retained silicone oil: a clinicopathologic correlation.
AB  - BACKGROUND: To report the clinicopathologic features of a fibrocellular membrane
      in a pseudophakic eye with retained silicone oil in the absence of any capsular
      contraction syndrome, necessitating repeat anterior capsulorhexis. METHODS:
      Clinicopathologic report of a case. RESULTS: Histopathologic study of the
      membrane showed absence of any true periodic acid Schiff-positive capsule within
      the specimen. Clinically, there was no evidence of any anterior capsular
      contraction. The fibrocellular membrane may have occurred as a result of
      inflammatory and mechanical effects of silicone oil in the anterior chamber or as
      a result of the intraocular lens design. CONCLUSION: The authors report the
      clinicopathologic features of a fibrocellular membrane occluding the anterior
      capsular opening in a pseudophakic eye with retained silicone oil, in the absence
      of any capsular contraction. The stimulus for its formation may have been the
      inflammatory and mechanical effects of retained silicone oil in the anterior
      chamber.

PMID- 15187684
TI  - Intravitreal triamcinolone acetonide.

PMID- 15187685
TI  - Dural arteriovenous malformation and superior ophthalmic vein occlusion.

PMID- 15187687
TI  - Removing nurses from the menu.

PMID- 15187688
TI  - Heart transplants: competing beats.

PMID- 15187689
TI  - Postcards from the past.

PMID- 15187690
TI  - The scoop on green tea.

PMID- 15187691
TI  - Conquering peripheral neuropathic pain.

PMID- 15187692
TI  - No bottoms up.

PMID- 15187693
TI  - Well...what'll it be?

PMID- 15187694
TI  - Flutamide or thalidomide?

PMID- 15187695
TI  - How does a PEG tube stay in?

PMID- 15187696
TI  - Signed under duress?

PMID- 15187699
TI  - Reducing postprocedure emesis.

PMID- 15187704
TI  - How to administer a subcutaneous injection.

PMID- 15187709
TI  - Fast oral test gets FDA okay.

PMID- 15187712
TI  - Care for teenagers falls short.

PMID- 15187716
TI  - Sorting out the 3 D's: delirium, dementia, and depression.

PMID- 15187717
TI  - Simple pleasures.

PMID- 15187718
TI  - Finding alternatives to blood transfusion.

PMID- 15187719
TI  - Should you dive into that float assignment?

PMID- 15187720
TI  - Night shift shenanigans.

PMID- 15187721
TI  - Scare tactics.

PMID- 15187722
TI  - Why you should avoid reverse pressure ulcer staging.

PMID- 15187724
TI  - Myths & facts... About wearing seat belts.

PMID- 15187723
TI  - A tale of two safety conversions.

PMID- 15187725
TI  - Smart cards may make passwords passe.

PMID- 15187727
TI  - Choosing the right shoes.

PMID- 15187726
TI  - Beating botulism.

PMID- 15187728
TI  - Tips on dealing with the heat.

PMID- 15187729
TI  - Walking on eggshells.

PMID- 15187733
TI  - Fat embolism.

PMID- 15187734
TI  - Incidence of asymptomatic pulmonary embolism in moderately to severely injured
      trauma patients.
AB  - BACKGROUND: Chest computed tomographic (CT) scanning is used frequently to
      evaluate symptomatic patients for pulmonary embolus (PE). The incidence of PE
      diagnosed by helical CT scanning in asymptomatic patients is unknown. METHODS:
      Asymptomatic trauma patients with an Injury Severity Score > or = 9 were studied
      with contrast-enhanced helical CT images of the chest, pelvis, and lower
      extremities. Clot burden was assessed using an anatomic scoring system. Patients
      not receiving anticoagulation were followed. RESULTS: Twenty-two of 90 patients
      had a PE. Four had major clot burden, including one patient with a saddle
      embolus. Risk factors for asymptomatic PE include age (odds ratio [OR], 1.04),
      head injury (OR, 6.78), chest injury (OR, 4.51), lower extremity injury (OR,
      5.03), and transfusion (OR, 3.42). Thirty percent of patients receiving
      pharmacologic prophylaxis had a PE. CONCLUSION: Asymptomatic PE occur in 24% of
      moderately to severely injured patients. Age, head, chest, and lower extremity
      injury are associated with an increased risk. Standard thromboembolic prophylaxis
      is not reliably protective.

PMID- 15187735
TI  - Male sexual function after bilateral internal iliac artery embolization for
      pelvic fracture.
AB  - BACKGROUND: Bilateral internal iliac artery embolization (BIIAE) effectively
      controls unlocalized bleeding from pelvic fractures. Its short-term safety has
      been documented, but its long-term effect on urogenital function has not been
      evaluated. METHODS: Patients having temporary BIIAE with gelatin sponge slurry
      for pelvic fractures were prospectively identified. Two control groups were
      created--one with similar pelvic fractures but no embolization, and the other
      with nonpelvic injuries. The groups were matched for risks of urogenital
      dysfunction: age, time elapsed since injury, Injury Severity Score, pelvic
      Abbreviated Injury Scale score, and presence of urethral or bladder injuries.
      Urogenital function was assessed at least 1 year after injury using a validated
      questionnaire. RESULTS: Sexual function was significantly compromised in patients
      having pelvic fractures compared with those not having fractures. There was no
      difference in sexual function between patients having pelvic fractures treated
      with BIIAE and those having pelvic fractures alone. CONCLUSION: BIIAE does not
      produce lasting adverse effects on urogenital function. Sexual dysfunction
      frequently occurs after traumatic pelvic fracture and is produced by the injury
      itself.

PMID- 15187736
TI  - Putative mechanism of hemorrhage-induced leukocyte hyporesponsiveness: induction
      of suppressor of cytokine signaling-3.
AB  - BACKGROUND: After hemorrhagic shock, macrophages are less responsive to
      lipopolysaccharide (LPS) regarding cytokine production and receptor expression.
      However, mechanisms responsible for this are poorly understood. Suppressors of
      cytokine signaling (SOCS) proteins have been found to play a prominent role in
      LPS tolerance and cytokine desensitization in macrophages. Therefore, the purpose
      of this study was to determine whether hemorrhagic shock induced SOCS expression.
      METHODS: Male C3H/HeN mice were subjected to hemorrhage or sham hemorrhage.
      Twenty-four hours after each procedure, tissues were harvested, the cells were
      processed for protein, and SOCS expression was examined. RESULTS: Our data show
      that SOCS-1 expression does not change after hemorrhage, but SOCS-3 is up
      regulated in a tissue and cell population (e.g., macrophage)-specific manner.
      CONCLUSION: These data suggest that cytokines or other inflammatory mediators
      present during the first 24 hours after the induction of shock have the ability
      to induce tolerance to LPS or cytokines and suppress the function of immune cells
      by up-regulating SOCS-3.

PMID- 15187737
TI  - Hypertonic saline prevents inflammation, injury, and impaired intestinal transit
      after gut ischemia/reperfusion by inducing heme oxygenase 1 enzyme.
AB  - BACKGROUND: Hypertonic saline (HTS) has been shown to modulate the inflammatory
      response after shock. We have previously demonstrated that heme oygenase-1 (HO-1)
      induction is protective against gut dysfunction in models of shock-induced gut
      ischemia/reperfusion (I/R). We therefore hypothesized that HTS prevents gut
      inflammation, injury, and impaired transit by inducing HO-1 in a model of gut
      I/R. METHODS: Rats underwent 60 minutes of superior mesenteric artery occlusion
      (SMAO) and then were resuscitated with 4 mL/kg of HTS, an equal volume of
      lactated Ringer's (LR) solution (4 mL/kg, low volume), or equal salt LR solution
      (32 mL/kg, high volume) and compared with SMAO alone or shams. A separate group
      was pretreated with the HO-1 blocker Sn protoporphyrin IX (SNP IX) before SMAO
      plus HTS. At 6 hours of reperfusion, transit was determined and ileum harvested
      for HO-1 (anti-inflammatory) and inducible nitric oxide synthase
      (proinflammatory) immunoreactivity, myeloperoxidase (MPO) activity, and
      histologic injury. Data are expressed as mean +/- SEM (analysis of variance).
      RESULTS: Intestinal transit was severely impaired after SMAO (2.5 +/- 0.1),
      improved with low- and high-volume LR solution (3.2 +/- 0.2 and 3.1 +/- 0.1, not
      significant), but returned to sham (4.6 +/- 0.2) with HTS (4.8 +/- 0.2).
      Pretreatment with SNP abrogated this protective effect. Myeloperoxidase activity
      was significantly increased by SMAO (SMAO, 2.3 +/- 0.3; sham, 0.4 +/- 0.05),
      lessened by low- and high-volume LR solution (1.5 +/- 0.3 and 1.7 +/- 0.4), but
      returned to sham levels with HTS (1.0 +/- 0.01). Activity with SNP IX
      pretreatment was significantly increased (4.04 +/- 0.8). Mucosal injury followed
      a similar pattern. Inducible nitric oxide synthase was increased by SMAO and low-
      and high-volume LR solution (0.8 +/- 0.2, 0.8 +/- 0.03, and 0.8 +/- 0.02,
      respectively; sham, 0.5 +/- 0.02), but significantly reduced by HTS (0.7 +/-
      0.02). HO-1 was induced by SMAO and low- and high-volume LR solution (0.33 +/-
      0.02, 0.32 +/- 0.03, and 0.37 +/- 0.4, respectively; sham, 0.0 +/- 0.0), but was
      further increased with HTS (0.49 +/- 0.04). CONCLUSION: HTS resuscitation
      protects against inflammation, injury, and impaired intestinal transit after gut
      I/R in part by inducing HO-1. This is a novel mechanism of HO-1 protection.

PMID- 15187738
TI  - Improving the TRISS methodology by restructuring age categories and adding
      comorbidities.
AB  - BACKGROUND: The Trauma and Injury Severity Score (TRISS) methodology was
      developed to predict the probability of survival after trauma. Despite many
      criticisms, this methodology remains in common use. The purpose of this study was
      to show that improving the stratification for age and adding an adjustment for
      comorbidity significantly increases the predictive accuracy of the TRISS model.
      METHODS: The trauma registry and the hospital administrative database of a
      regional trauma center were used to identify all blunt trauma patients older than
      14 years of age admitted with International Classification of Diseases, Ninth
      Revision codes 800 to 959 from April 1993 to March 2001. Each individual medical
      record was then reviewed to ascertain the Revised Trauma Score, the Injury
      Severity Score, the age of the patients, and the presence of eight comorbidities.
      The outcome variable was the status at discharge: alive or dead. The study
      population was divided into two subsamples of equal size using a random sampling
      method. Logistic regression was used to develop models on the first subsample; a
      second subsample was used for cross-validation of the models. The original TRISS
      and three TRISS-derived models were created using different categorizations of
      Revised Trauma Score, Injury Severity Score, and age. A new model labeled
      TRISSCOM was created that included an additional term for the presence of
      comorbidity. RESULTS: There were 5,672 blunt trauma patients, 2,836 in each
      group. For original TRISS, the Hosmer-Lemeshow statistic (HL) was 179.1 and the
      area under the receiver operating characteristic (AUROC) curve was 0.873.
      Sensitivity and specificity were 99.0% and 27.8%, respectively. For the best
      modified TRISS model, the HL statistic was 20.35, the AUROC curve was 0.902, the
      sensitivity was 99.0%, and the specificity was 27.8%. For TRISSCOM, the HL
      statistic was 14.95 and the AUROC curve was 0.918. Sensitivity and specificity
      were 99.0% and 29.7%, respectively. The difference between the two models almost
      reached statistical significance (p = 0.086). When TRISSCOM was applied to the
      cross-validation group, the HL statistic was 10.48 and the AUROC curve was 0.914.
      The sensitivity was 98.6% and the specificity was 34.9%. CONCLUSION: TRISSCOM can
      predict survival more accurately than models that do not include comorbidity. A
      better categorization of age and the inclusion of comorbid conditions in the
      logistic model significantly improves the predictive performance of TRISS.

PMID- 15187739
TI  - Use of splenic artery embolization as an adjunct to nonsurgical management of
      blunt splenic injury.
AB  - BACKGROUND: Splenic artery embolization (SAE) has been used as an adjunct to the
      nonsurgical treatment of blunt splenic injuries since 1981. It is imperative to
      define the role of SAE in the management of splenic trauma and to establish a
      guideline for its use. METHODS: In this study, 39 consecutive patients with blunt
      splenic ruptures were evaluated. All the patients were treated according to the
      authors' protocol, which included SAE as an adjunct. Angiographic study was
      performed for patients with any of the following presentations: recurrent
      hypotension despite fluid resuscitation, significant hemoperitoneum or
      extravasation of contrast media on computed tomography, grade 4 or 5 splenic
      injury, or progressive need for blood transfusion. Laparotomy was reserved for
      patients with unstable hemodynamics or failure of SAE. RESULTS: Four patients
      were excluded from the study, and 6 of the 35 remaining patients (male-to-female
      ratio, 22:13) received SAE. One of the six SAE patients underwent operation
      because of persistent hemorrhage after SAE. Nonoperative treatment was successful
      for 31 patients. Splenic artery embolization increased the success rate for
      nonsurgical management from 74% (26 of 35 patients) to 89% (31 of 35 patients).
      CONCLUSIONS: Judicious use of SAE for patients with blunt splenic injury avoids
      unnecessary surgery and expands the number of patients who can retain their
      spleen.

PMID- 15187740
TI  - Management of blunt major pancreatic injury.
AB  - BACKGROUND: Major duct injury is the principal determinant of outcome for
      patients with pancreatic trauma, and there are a number of therapeutic choices
      available specific to the location of the insult. We report a series of blunt
      major pancreatic injury cases, with a review of the different procedures used and
      a discussion of the results. METHODS: A total of 48 cases of blunt major
      pancreatic injury treated during a 10-year period at one trauma center were
      reviewed retrospectively. Diagnosis and assessment of injury severity were based
      on imaging studies and proved by surgical findings. Charts were reviewed to
      establish the mechanism of injury, surgical indications and imaging studies,
      management strategy, and outcome. RESULTS: Of the 32 grade III patients, 19
      underwent distal pancreatectomy with splenectomy, 8 had pancreatectomy with
      preservation of the spleen, and 2 received a pancreatic duct stent, with the
      remaining 3 individuals undergoing nonsurgical treatment, pancreaticojejunostomy,
      and drainage alone, respectively. The grade III complication rate was 60.6%. Of
      the 14 grade IV patients, 4 underwent drainage alone because of the severity of
      the associated injuries, 4 underwent pancreaticojejunostomy, 3 had distal
      pancreatectomy with splenectomy, and 1 underwent distal pancreatectomy. The two
      remaining patients received a pancreatic duct stent. The grade IV complication
      rate was 53.8%. The Whipple procedure was performed for two grade V patients; one
      died subsequently. For all 48 patients, intraabdominal abscess was the most
      common morbidity (n = 11) followed, in order of prevalence, by major duct
      stricture (n = 4), pancreatitis (n = 2), pseudocyst (n = 2), pancreatic fistula
      (n = 1), and biliary fistula (n = 1). All stented cases developed complications,
      with one dying and three experiencing major duct stricture. CONCLUSION: The
      complication rate for our cases of blunt major pancreatic injury was high
      (62.2%), especially when treatment was delayed more than 24 hours; the same
      result was also noted for cases transferred from other institutions. Distal
      pancreatectomy with spleen preservation had a lower complication rate (22.2%)
      compared with other procedures and is suggested for grade III and grade IV
      injuries. Magnetic resonance pancreatography was unreliable early after injury
      but was effective in the chronic stage. Although pancreatic duct stenting can be
      used to treat posttraumatic pancreatic fistula and pseudocyst, the major duct
      stricture in the chronic stage of recovery and the risk of sepsis in the acute
      stage must be overcome.

PMID- 15187741
TI  - Traumatic injuries to the portal vein: case study.
AB  - BACKGROUND: Injuries to the portal vein are rare but devastating. Contemporary
      studies have debated the most effective management for this injury. The purpose
      of this case study was to provide an update on portal vein injury and add
      information regarding its management. METHODS: A retrospective review
      investigated the 10-year experience with portal vein injury in a level 1 trauma
      center. RESULTS: Of the 18,900 trauma patients (0.08%) evaluated during a 10-year
      period, 15 sustained injuries to the portal vein. All the injuries resulted from
      penetrating trauma, and the overall survival rate was 60% (9 of the 15 patients).
      Four patients died of exsanguination and two patients died later as a result of
      multisystem organ failure. Postoperative complications were common. Sepsis and
      wound infection were the most common postoperative complications, occurring in
      seven (78%) of the nine survivors. All the patients had associated nonvascular
      injuries, whereas 9 (60%) of the 15 had associated vascular injuries. Associated
      injuries to the other structures in the portal triad occurred in 7 (47%) of the
      15 patients, and 5 (71%) of these patients survived. Survival rates by procedure
      were 86% for venorrhaphy and 67% for ligation. CONCLUSIONS: Injuries to the
      portal vein are rare. In this study, exsanguination was the main cause of death.
      The key to a favorable outcome is prompt control of hemorrhage with an early
      decision to proceed with either venorrhaphy or ligation. Ligation can be
      effective for the management of hemodynamically unstable patients.

PMID- 15187742
TI  - The trend of using computed tomography in the detection of acute thoracic aortic
      and branch vessel injury after blunt thoracic trauma: single-center experience
      over 13 years.
AB  - BACKGROUND: The purpose of this study was to review the trend of using chest
      computed tomography (CT) and aortography in evaluating patients with blunt
      thoracic trauma. METHODS: A total of 85 patients who had blunt aortic injury
      diagnosed by chest CT, aortography, or both were included in this study. RESULTS:
      Aortography was the dominant modality before 1998, and the use of chest CT has
      increased to 50% of patients with aortic injuries as of 2001. Isolated aortic,
      branch vessel, or combined injuries were found in 71 (84%), 11 (13%), and 3 (4%)
      patients, respectively. All 14 patients with branch vessel injuries were
      diagnosed by aortography. Ninety-eight percent of patients with aortography were
      true-positives, and 20% of patients with chest CT had indirect signs of aortic
      injury. CONCLUSION: Our institution has increased the use of chest CT to evaluate
      blunt thoracic trauma. Patients with indirect signs of aortic injuries shown on
      chest CT require further evaluation. In our experience, angiography remains the
      optimal diagnostic modality for evaluating aortic branch vessel injuries.

PMID- 15187743
TI  - The role of arteriography in assessing popliteal artery injury in knee
      dislocations.
AB  - BACKGROUND: This study aimed to review the need for angiography among patients
      with traumatic knee dislocations, and to evaluate any adverse consequences
      associated with the clinical decision to pursue or defer angiography. METHODS: A
      retrospective analysis was performed for 55 patients (57 knees) with traumatic
      knee dislocation during a 7-year period. The presence or absence of arterial
      injury was assessed via physical examination (to determine presence of foot
      pulses and ankle-brachial index > or = 0.80) and, in selected cases, via
      angiography. RESULTS: At the vascular examination, 32 knees (56%) were found to
      be normal and 25 (44%) to be abnormal. None of the 32 knees with normal
      examination results had substantial vascular injuries, as determined by
      angiography in 13 cases (41%) or by clinical follow-up assessment in 19 cases
      (59%). All 25 patients with abnormal vascular examination results underwent
      angiography, with 12 patients (48%) demonstrating vascular injury (7 major and 5
      minor injury). Seven patients (6 with major and 1 with minor injury) underwent
      surgical repair with reverse saphenous vein grafting. CONCLUSIONS: No limb with
      initial normal vascular examination results was found to have a vascular injury
      that required treatment. Routine screening angiography may not be necessary for
      all patients with traumatic knee dislocations.

PMID- 15187744
TI  - Comparison of a sliding hip screw with a trochanteric lateral support plate to an
      intramedullary hip screw for fixation of unstable intertrochanteric hip
      fractures: a cadaver study.
AB  - BACKGROUND: The lateral trochanteric support plate (LSP) was developed to prevent
      excessive sliding of unstable intertrochanteric femur fractures fixed with a
      sliding hip screw (SHS). This study compared the fracture stability and screw
      sliding characteristics of unstable intertrochanteric femur fractures fixed with
      either an SHS and LSP or an Intramedullary Hip Screw (IMHS). METHODS: Six matched
      pairs of cadaveric human femurs with simulated, unstable intertrochanteric femur
      fractures were stabilized with either an IMHS or a 135-degree SHS with an
      attached LSP. Inferior and lateral head displacements and lag screw sliding
      distances were measured for applied static loads of 750 N, before and after
      cycling. RESULTS: Four-part unstable intertrochanteric femur fractures showed
      comparable screw sliding characteristics and stability whether instrumented with
      an SHS and LSP or an IMHS. CONCLUSION: A sliding hip screw with an attached
      lateral support plate provides stability and ability to resist medial
      displacement of the femoral shaft similar to that seen with the IMHS.

PMID- 15187745
TI  - Indirect traumatic optic neuropathy complicated with periorbital facial bone
      fracture.
AB  - This study evaluated the outcome for 45 consecutive, nonrandomized patients whose
      indirect type traumatic optic neuropathy and periorbital facial bone fracture
      were treated at the Chang Gung Memorial Hospital in Kaohsiung between June of
      1996 and June of 2001. There were a total of 48 eye injuries in 45 patients (3
      patients sustained bilateral eye injuries). Data related to megadose steroid
      treatment, timing of open reduction and internal fixation for periorbital facial
      fractures, and pretreatment and post-treatment of visual acuities were collected
      from the medical records. Measurements of visual improvement in terms of degree
      and percentage were calculated after the visual acuities were converted into the
      log of the minimum angle of resolution units. Visual acuities were significantly
      improved according to mechanism of injury, gender, or associated periorbital skin
      laceration wound. However, no light perception for eight patients at initial
      presentation and gradually deteriorating vision in four injured eyes of three
      patients were identified as poor prognostic factors. Therefore, repeated visual
      measurements are recommended to detect any gradually deteriorating vision, which
      although uncommon, has a poor prognosis. No significantly improved vision was
      found after treatment with megadose steroids. However, if improvement in vision
      did occur, treatment with megadose steroids resulted in a much greater visual
      improvement in terms of degree (p = 0.001) and percentage (p = 0.02). Thus
      treatment with megadose steroid is recommended. No significant differences were
      found in the visual improvement between those who received and those who did not
      receive periorbital open reduction and internal fixation operations, and between
      those who received early repair within 48 hours and those who received late
      repair after more than 48 hours. However, it seems medicolegally prudent to delay
      the procedure because some patients may experience gradually deteriorating
      vision, which has a poor prognosis, and because postoperative visual loss after
      facial fracture repair did happen.

PMID- 15187746
TI  - Preinjury warfarin use among elderly patients with closed head injuries in a
      trauma center.
AB  - BACKGROUND: This study aimed to determine the impact of warfarin use on the
      severity of injury among elderly patients presenting with closed head injuries.
      METHODS: A cohort of patients 55 years of age or older with closed head injuries
      taken to a tertiary trauma center between April 1993 and March 2001 was
      retrospectively identified. Patient characteristics, mechanism of injury, type
      and severity of injury, and hospital survival data were obtained from the trauma
      registry. Each case then was reviewed for completeness of information, assessment
      of preinjury warfarin use, and comorbidity. RESULTS: Among the 384 patients
      presenting with closed head injuries, 35 (9%) were receiving warfarin before
      their trauma. As compared with nonusers, anticoagulated patients had a higher
      frequency of isolated head trauma (54% vs. 32%; p = 0.008), more severe head
      injuries (65.7% vs. 44.1%; p = 0.02), and a higher rate of mortality (40% vs.
      21%, p = 0.01). These associations remained evident even after population
      differences in age, gender, comorbidities, and mechanism of injury were taken
      into account. Indeed, according to multivariate logistic regression models,
      warfarin use was associated with a statistically significant risk of death (odds
      ratio [OR], 2.73; 95% confidence interval [CI], 1.22-6.12), statistically
      significant odds for more severe head injury (OR, 2.39; 95% CI, 1.10-5.17), and
      odds for isolated head injury that almost reached statistical significance (OR,
      1.79; 95% CI, 0.82-3.90). CONCLUSIONS: Among patients 55 years of age or older
      who present with closed head injury, the use of warfarin before trauma appears to
      be associated with a higher frequency of isolated head trauma, more severe head
      trauma, and a higher likelihood of death. The findings of this retrospective
      study support the concern about the adverse effects of anticoagulants in cases of
      head trauma.

PMID- 15187747
TI  - The use of quantitative end-tidal capnometry to avoid inadvertent severe
      hyperventilation in patients with head injury after paramedic rapid sequence
      intubation.
AB  - BACKGROUND: This study aimed to determine whether field end-tidal carbon dioxide
      CO2 (ETCO2) monitoring decreases inadvertent severe hyperventilation after
      paramedic rapid sequence intubation. METHODS: Data were collected prospectively
      as part of the San Diego Paramedic Rapid Sequence Intubation Trial, which
      enrolled adults with severe head injuries (Glasgow Coma Score, 3-8) that could
      not be intubated without neuromuscular blockade. After preoxygenation, the
      patients underwent rapid sequence intubation using midazolam and succinylcholine.
      A maximum of three intubation attempts were allowed before Combitube insertion
      was mandated. Tube confirmation was accomplished by physical examination,
      qualitative capnometry, pulse oximetry, and syringe aspiration. Standard
      ventilation parameters (tidal volume, 800 mL; 12 breaths/minute) were taught. One
      agency used portable ETCO2 monitors, with ventilation modified to target ETCO2
      values of 30 to 35 mm Hg. Trial patients transported by aeromedical crews also
      underwent ETCO2 monitoring. The primary outcome measure was the incidence of
      inadvertent severe hyperventilation, defined as arterial blood gas partial
      pressure of CO2 (pCO2) of less than 25 mm Hg at arrival, for patients with and
      those without ETCO2 monitoring. These groups also were compared in terms of age,
      gender, clinical presentation, Abbreviated Injury Score, Injury Severity Score,
      arrival arterial blood gas data, and survival. RESULTS: The study enrolled 426
      patients and administered neuromuscular blocking agents to 418 patients.
      Endotracheal intubation was successful for 355 of these patients (85.2%). Another
      58 patients (13.6%) underwent Combitube insertion. For 291 successfully intubated
      patients, arrival pCO2 values were documented, with continuous ETCO2 monitoring
      performed for 144 of these patients (49.4%). Patients with ETCO2 monitoring had a
      lower incidence of inadvertent severe hyperventilation than those without ETCO2
      monitoring (5.6% vs. 13.4%; odds ratio, 2.64; 95% confidence interval, 1.12-6.20;
      p = 0.035). There were no significant differences in terms of age, gender,
      clinical presentation, Abbreviated Injury Score, Injury Severity Score, arrival
      partial pressure of oxygen (PO2) and pH, or survival. The patients in both groups
      with severe hyperventilation had a significantly higher mortality rate than the
      patients without hyperventilation (56 vs. 30%; odds ratio, 2.9; 95% confidence
      interval, 1.3-6.6; p = 0.016), which could not be explained solely on the basis
      of their injuries. CONCLUSIONS: The use of ETCO2 monitoring is associated with a
      decrease in inadvertent severe hyperventilation.

PMID- 15187748
TI  - Effect of the LT-alpha (+250 G/A) polymorphism on markers of inflammation and
      clinical outcome in critically ill patients.
AB  - BACKGROUND: Tumor necrosis factor alpha as a central mediator of the inflammation
      cascade is correlated to sepsis outcome. Tumor necrosis factor beta (LT-alpha)
      binds the same cell receptor and polymorphisms in both genes have been described.
      To evaluate the importance of the LT-alpha (+250 G/A) polymorphism for the
      clinical outcome of patients developing postsurgical sepsis, 85 patients were
      consecutively included into this study. METHODS: Blood samples were obtained for
      analysis of the biallelic LT-alpha (+250 G/A) polymorphism and for determination
      of serum levels of sTNF-R1, TNF-alpha, IL-6, IL-8, IL-10, procalcitonin, and
      neopterin. Cytokine levels were measured repeatedly until the patients' discharge
      from the ICU. RESULTS: The allele frequency was 0.28 for TNFB1 and 0.72 for
      TNFB2. The genotype distribution was TNFB1 homozygotes 4/79 (5.1%), TNFB1/TNFB2
      heterozygotes 37/79 (46.8%), and TNFB2 homozygotes 38/79 (48.1%). Fifty-four out
      of 80 (67.5%) fulfilled the criteria for severe sepsis; 36/80 (45.0%) developed
      septic shock. Multiple organ failure occurred in 60/80 patients (75.0%), and the
      overall mortality was 26/80 (32.5%). Concerning the LT-alpha-genotypes, there was
      no difference in the frequency of severe sepsis or shock or in the development of
      multi-organ failure or death between the three subgroups. The peak plasma TNF
      alpha levels were similar for all genotype subgroups. CONCLUSIONS: There was no
      correlation between the biallelic LT-alpha (+250 G/A) polymorphism and the
      outcome of critically ill patients. Genotyping this locus does not seem to be
      useful in predicting sepsis outcome.

PMID- 15187749
TI  - Enhanced production of endothelial microparticles with increased binding to
      leukocytes in patients with severe systemic inflammatory response syndrome.
AB  - BACKGROUND: The vascular endothelium sustains substantial damage after severe
      insult. Recently, activated endothelial cells have been reported to produce
      microparticles in vitro. The objective of this study was to evaluate endothelial
      microparticle formation and microparticle-leukocyte interaction among patients
      with severe systemic inflammatory response syndrome (SIRS). METHODS: The
      participants in this study were 28 patients with severe SIRS (SIRS criteria and
      serum C-reactive protein > 10 mg/dL) and 18 healthy volunteers. Endothelial
      microparticles in the blood, microparticle-polymorphonuclear leukocyte (PMNL)
      binding, and PMNL oxidative activity were measured by flow cytometry. Soluble E
      selectin, thrombomodulin, and plasminogen activator inhibitor-1 levels in the
      blood, variables representing systemic vascular endothelial cell activation and
      damage, and coagulative activity in the blood also were measured. RESULTS:
      Endothelial microparticle levels in the blood, microparticle binding to PMNLs,
      and oxidative activity in PMNLs increased significantly in patients with severe
      SIRS, as compared with the values in healthy volunteers. Soluble E-selectin,
      thrombomodulin, plasminogen activator inhibitor-1, and procoagulant activity in
      the blood also increased in these patients. CONCLUSIONS: Activated vascular
      endothelial cells with increased procoagulant activity enhance production of
      microparticles with increased binding to leukocytes in patients with severe SIRS.
      Endothelial microparticles may be involved in the pathogenesis of endothelial
      injury after severe insult.

PMID- 15187750
TI  - Endothelin-1 decreases microvessel permeability after endothelial activation.
AB  - BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor that is released
      during shock and sepsis. We hypothesized that ET-1 plays a role in the modulation
      of the elevated microvascular permeability state of the activated endothelium.
      METHODS: Hydraulic permeability (Lp) was measured using the modified Landis micro
      occlusion technique. The effect of different ET-1 doses on Lp was determined by
      obtaining paired measures of Lp at baseline and after the vessels were perfused
      with ET-1 at doses of 2.0 pg/mL (n = 6), 20 pg/mL (n = 6), 200 pg/mL (n = 6), or
      2,000 pg/mL (n = 6). To evaluate the effects of ET-1 in the activated
      endothelium, additional vessels were perfused with either 10 micromol/L adenosine
      triphosphate (ATP) (n = 6) or 1 nmol/L bradykinin (n = 6). The vessels were then
      perfused with 200 pg/mL ET-1 followed by the final L determination. RESULTS: ET-1
      significantly decreased Lp at doses of 20 pg/mL (p = 0.03), 200 pg/mL (p = 0.03),
      and 2,000 pg/mL (p = 0.01). Endothelial activation with ATP and bradykinin
      increased Lp to 4.21 +/- 0.39 (p < 0.0001) and 2.72 +/- 0.24 (p = 0.001),
      respectively. ET-1 significantly decreased the Lp to 1.99 +/- 0.48 after
      activation with ATP (p = 0.004). ET-1 also decreased the Lp to 1.10 +/- 0.19
      after activation with bradykinin (p = 0.001). Units for Lp are x10(-7) cm x s(-1)
      x cm H2O(-1). CONCLUSION: In this model, ET-1 attenuated the increase in
      microvascular permeability that can be seen in inflamed vessels. In addition to
      its vasopressor function, ET-1 may be of benefit in pathophysiologic states by
      decreasing third-space fluid loss. This receptor-mediated function of ET-1 may be
      amenable to pharmacologic manipulation.

PMID- 15187751
TI  - Red blood cell damage after trauma-hemorrhage is modulated by gender.
AB  - BACKGROUND: Previous studies have shown that trauma-hemorrhagic shock (T/HS)
      causes significant alterations in red blood cell (RBC) deformability and shape.
      Gender is becoming well recognized as a modulating factor in the pathophysiologic
      response to trauma. We hypothesize that female subjects are more resistant to
      adverse effects of T/HS on RBC deformability and shape than male subjects because
      of estrogen protection. METHODS: Elongation index, a measure of RBC
      deformability, was examined in six male rats and four groups of female rats at
      different stages of the estrous cycle (six animals per group) before and 6 hours
      after T/HS by laser ektacytometry. RBC shape was determined by scanning electron
      microscopy. Lipid peroxidation was evaluated by measurement of malonyldialdehyde
      in plasma 6 hours after T/HS. RESULTS: Male rats had a significant decrease in
      RBC elongation index after T/HS as compared with preshock values. RBC
      deformability of the proestrous (PES) and estrous female rats did not decrease
      after T/HS. Postshock RBC deformability values in metestrous and diestrous female
      rats did not differ from male rats. Male rats and metestrous and diestrous
      females had a significant increase in the percentage of abnormally shaped RBCs
      immediately after shock and during the postresuscitation period. In PES and ES
      female rats, RBC shape distribution did not significantly change after T/HS.
      Plasma malonyldialdehyde levels at 6 hours post-T/HS were higher in the male rats
      than in PES female rats. CONCLUSION: These data show that high levels of estrogen
      in female rats are protective against shock-induced RBC damage and suggest that
      this effect is associated with a decrease in lipid peroxidation.

PMID- 15187752
TI  - Decrease in left ventricular ejection time on digital arterial waveform during
      simulated hypovolemia in normal humans.
AB  - BACKGROUND: Left ventricular ejection time (LVET) measured in central arteries is
      modified during hypovolemia. We compared modifications of the pulse wave in a
      central artery (carotid) and in a peripheral artery (digital) during central
      hypovolemia induced by lower body negative pressure (LBNP) in conscious
      volunteers. METHODS: Hypovolemia was simulated with progressive LBNP (baseline, 
      10, -20, and -30 mm Hg) in nine young healthy volunteers. The carotid arterial
      pressure waveform was recorded using a Millar tonometric method. The digital
      pulse wave was measured with a volume-clamp method (Finapres) and the stroke
      volume with a thoracic impedance method (Biomed). RESULTS: Mean arterial pressure
      did not change during LBNP. Compared with baseline values, heart rate increased
      significantly at the -30 mm Hg level (68 +/- 13 beats/min vs. 59 +/- 11
      beats/min), and stroke volume decreased as soon as -10 mm Hg was achieved (113 +/
      41 mL vs. 127 +/- 35 mL). Both carotid and digital LVET decreased significantly
      at the -10 mm Hg level (337 +/- 26 and 339 +/- 24 ms vs. 360 +/- 35 and 361 +/-
      24 ms, respectively). CONCLUSION: Peripheral LVET could reflect variation of
      central LVET during LBNP and be a reliable noninvasive parameter for monitoring
      hypovolemia.

PMID- 15187754
TI  - Survival benefit conferred by topical antimicrobial preparations in burn
      patients: a historical perspective.
AB  - BACKGROUND: Topical antimicrobial agents have proven efficacy in preventing life
      threatening invasive burn wound infection. Under wartime or mass-casualty
      conditions, however, there may be an inadequate supply of these agents. This
      study aimed to identify those patients most likely to benefit therefrom. METHODS:
      Logistical regression analysis of data from the U.S. Army Burn Center was
      performed. Mortality data for the period immediately preceding the introduction
      of topical mafenide acetate (MA) (1950-1963) were compared with data for the
      subsequent period (1964-1968). During the second period, MA was routinely applied
      but treatment was otherwise similar. The mortality decrement attributed to MA was
      determined for various ages and burn sizes. RESULTS: For patients of combatant
      age (20-50 years), MA was associated with a greater than 10% reduction in
      mortality for those with burns of 40-79% of the total body surface area (TBSA).
      Only a minimal effect on mortality was noted for those patients with burns
      smaller than 40% or greater than 79%. CONCLUSIONS: When resources are limited,
      topical therapy (specifically, MA) is likely to confer the greatest survival
      benefit for combatants with burns of 40-79% TBSA.

PMID- 15187753
TI  - Administration of aerosolized terbutaline and budesonide reduces chlorine gas
      induced acute lung injury.
AB  - BACKGROUND: The pathophysiology and treatment of chlorine gas-induced acute lung
      injury is poorly characterized and based on anecdotal data. This study aimed to
      assess the effects of aerosolized beta-2 adrenergic agonist and corticosteroid
      therapy on chlorine gas-induced lung injury. METHODS: Anesthetized, ventilated
      pigs were exposed to chlorine gas (400 parts per million for 20 minutes), then
      assigned randomly 30 minutes later to receive aerosolized terbutaline,
      budesonide, terbutaline followed by budesonide or placebo (6 pigs in each group).
      Hemodynamics, gas exchange, and lung mechanics were evaluated for another 5
      hours. RESULTS: All the animals demonstrated an immediate increase in airway and
      pulmonary artery pressure as well as sharp drops in arterial oxygen tension
      (PaO2) and lung compliance (CL). Recovery of PaO2 and CL was greatest in the
      terbutaline plus budesonide group, but therapy with terbutaline and budesonide
      alone also was associated with significant improvement in PaO2 and CL, as
      compared with placebo. CONCLUSIONS: Treatment of acute chlorine gas lung injury
      with aerosolized terbutaline followed by aerosolized budesonide improved lung
      function. Combined treatment was more effective than treatment with either drug
      alone.

PMID- 15187755
TI  - Analysis of occupational exposures associated with emergency department
      thoracotomy.
AB  - BACKGROUND: Although previous studies have examined the cost effectiveness of
      emergency department thoracotomy (EDT), provider risk has not been included in
      these analyses. This study examined the costs associated with provider exposure
      to human immunodeficiency virus (HIV) and hepatitis from percutaneous injury
      during EDT. METHODS: A decision tree describing the occupational risks and costs
      associated with EDT was created. Exposed providers undergo initial counseling,
      evaluation, and HIV postexposure prophylaxis and treatment as recommended by the
      Centers for Disease Control. Costs are reported from a health care system
      perspective in year-2000 dollars. The following prevalences were assumed: HIV
      (7.1%), hepatitis C (18%), and provider percutaneous injury rate (10%).
      Sensitivity analyses were performed by varying the prevalence of disease and the
      probability of seroconversion. RESULTS: According to the authors' model
      assumptions, the probability is 0.00004 for HIV and 0.0027 for chronic hepatitis
      C seroconversion. The total additional cost per thoracotomy associated with an
      exposure is dollars 1,377. CONCLUSIONS: Emergency department thoracotomy is
      associated with important provider medical risks. Future analyses of EDT should
      include these factors in reports on the value of this procedure.

PMID- 15187757
TI  - The economic costs of traffic accidents in Spain.
AB  - BACKGROUND: This study aimed to evaluate the economic impact of traffic accidents
      in Spain during 1997. METHODS: The cost-of-illness method was used. Direct costs
      were divided into health services costs, insurance administration costs, and the
      costs of the material damages to the vehicles. Indirect costs were obtained
      through transformation of physical units into monetary units using the approach
      based on the human capital theory. RESULTS: The total cost of traffic accidents
      was 6,280.36 million euros, which amounts to 157.59 euros for each inhabitant in
      Spain and represents 1.35% of the gross national product. The total direct cost
      was 3,397.00 million euros, representing 54.1% of the total cost. The total
      indirect cost was 2,883.36 million euros, accounting for 45.9% of the total cost.
      CONCLUSIONS: The high socioeconomic cost of traffic accidents clearly indicates
      the need for the different administrations in Spain to collaborate in
      implementing preventive measures.

PMID- 15187756
TI  - Comparison of trauma center patient self-reports and proxy reports on the Alcohol
      Use Identification Test (AUDIT).
AB  - BACKGROUND: There has been increased attention on identifying alcohol problems
      among individuals admitted to trauma centers. Reports about patients' drinking
      made by significant others represent one potential method to address both
      concerns about the validity of patients' self-reports and the need to have a
      proxy measure for trauma patients who are unable to provide information about
      their drinking behavior. The present study evaluated the level of agreement
      between trauma patients' self-report and proxy report on the Alcohol Use
      Disorders Identification Test (AUDIT). METHODS: The study consisted of patients
      admitted to a Level I trauma center who screened positive for potential alcohol
      problems, who completed the AUDIT and National Institute of Mental Health
      Diagnostic Interview Schedule (Form III-R), and who had a collateral who provided
      proxy information about the patient. Proxy informants completed the AUDIT on the
      basis of their knowledge and perception of patients' drinking behavior, as well
      as a checklist of alcohol-related problems experienced by the patients in the 30
      days before admission. RESULTS: Patient- and proxy-completed AUDIT total and
      subscale scores were highly correlated and did not differ from one another except
      for the dependence subscale, with proxies indicating a higher number of symptoms
      than did patients. A relatively high percentage of agreement (77.5%) was found
      overall in the classification of patients as having or not having problem
      drinking on the basis of self-report and proxy AUDITs; 56.4% of both sources
      indicated a drinking problem and 21.1% of both agreed that there was not a
      problem. Patients classified as having problem drinking on self-report AUDITs
      were rated by proxies as having significantly higher levels of hazardous
      drinking, alcohol-related problems, and dependence symptoms than patients whose
      AUDIT classified their drinking as nonproblematic. CONCLUSION: The relative
      comparability of proxy- and patient-completed AUDIT scores and classifications
      suggests that patient and proxy reports corroborate and, in cases of trauma
      patients' inability to provide self-reports, may serve as proxies for patients'
      reports of drinking.

PMID- 15187758
TI  - Motor vehicle deaths in Hong Kong: opportunities for improvement.
AB  - OBJECTIVE: This study was undertaken to describe the epidemiology of motor
      vehicle mortality in Hong Kong, and to assess its impact on trauma service
      delivery. SETTING: Hong Kong has an area of 1,072 km2 and a population of
      6,800,000. There were 500,000 registered vehicles in 2001. METHODS: All motor
      vehicle deaths must be reported to the coroner in Hong Kong. A manual
      retrospective review of all coroner case notes involving motor vehicles for 2001
      was performed. RESULTS: The review identified 165 cases involving 111 male and 54
      female patients. Elderly cases were predominant, with 37% of the cases involving
      individuals older than 60 years. Most of the cases involved pedestrians (59%),
      and half of these pedestrians had experienced collisions with public light buses
      and trucks. Alcohol was not commonly involved, and when it was, it was isolated
      to the group 20 to 40 years of age. Most individuals died of major head injury
      alone or multiple injuries. There were very few major vessel injuries, and these
      included 13 aortic transections. DISCUSSION: Hong Kong has a very low motor
      vehicle death rate relative to its population (2.4 per 100,000), but the rate is
      less impressive when it is related to motor vehicle registrations (33 per 100,000
      vehicles). The low incidence of motor vehicle trauma has implications for trauma
      service delivery in terms of trauma expertise and specialization. Despite the low
      incidence of trauma, there still are opportunities for prevention, especially in
      relation to elderly pedestrians and public light buses.

PMID- 15187759
TI  - Microcirculation study of rabbit ear arterial and venous flow-through flaps using
      a window chamber model.
AB  - Venous flaps are used widely for finger reconstruction because they provide thin
      tissue, and the flap harvest is associated with less donor-site morbidity. The
      viability of the venous flap, however, is not as good as that of the ordinary
      perfused skin flap, and its microcirculation is questionable according to various
      indirect observations and hypotheses in the literature. Using a window chamber
      model in a rabbit ear, both arterial and venous flow-through flaps were studied.
      Factors evaluated were flap viability, flap weight, flap circulation as assessed
      by laser Doppler flowmetry, and direct observation of the microcirculation.
      Statistical analysis was performed using the two-sample t test. There was no
      statistically significant difference in viability between arterial and venous
      flow-through flaps (p = 0.661). The arterial flow-through flap had better
      perfusion than thevenous flow-through flap, as measured by laser Doppler
      perfusion studies (10.40 perfusion units [PU] vs 4.50 PU). However, no
      statistically significant difference was noted (p = 0.0717). Flap weight
      assesseed 1 week after surgery and oxygen saturation measured immediately after
      surgery showed significant differences between the arterial and venous flow
      through flaps (p = 0.0001 and 0.0279). These datasuggest that the arterial flow
      through flap is subjected to more congestion becauseof the abnormal flow pattern
      seen, andpossibly because of a superior inflow or nutritional status found in
      these flaps. Using vital microscopy, direct evaluation of the microcirculation
      was performed. A to-and-fro phenomenon was noted in both arterial and venous flow
      through flaps,which was followed by a reversed direction of flow in part of the
      microvasculature. With both types of flaps, the blood was directed eventually
      from the postcapillary venules to the capillaries, through the terminal
      arterioles, and then to the arterioles. These findings may be explained partially
      by the normal physiologic pressure gradients present in the microvasculature of
      these flaps. In this study, direct observation of the microcirculation was used
      as well as other objective measures to determine the flow patterns and clinical
      behaviors found in these types of flaps. A model in a rabbit ear for the study of
      venous and arterial flow-through flaps is described, and clinical correlations
      are discussed.

PMID- 15187761
TI  - Predicting future injury among women in abusive relationships.
AB  - STUDY OBJECTIVE: Intimate partner violence (IPV) is a major cause of injury and
      death among women, and it is a problem with significant relevance to health care
      providers. In this study, we examined risk factors for IPV-related injury within
      9 months of an index episode of abuse in a population of police- or court
      identified victims of IPV. METHODS: This was a prospective cohort study of 354
      women in abusive relationships. The outcome measured was injury within 9 months.
      Stepwise logistic regression was used for the statistical analysis. RESULTS: Two
      factors were found to be independently associated with increased risk of injury:
      victim's lack of full-time employment (RR 3.47, 95% CI 1.43-8.41) and physical
      abuse on the index incident date (RR 3.06, 95% CI 1.16-8.06). CONCLUSIONS: By
      questioning our patients about these issues, we can begin to identify the complex
      risk factors that predispose women in abusive relationships to future injury.

PMID- 15187760
TI  - Increased postoperative concentrations of tenascin-C in wound fluid.
AB  - BACKGROUND: Tenascin-C (Tn-C) is the most studied member of a family comprising
      large oligomeric glycoproteins in the extracellular matrix. The function of Tn-C
      still is unclear, and the levels of Tn-C in human wound fluid have not been
      studied. METHODS: The participants in this study were 24 patients referred for
      elective major gastrointestinal surgery. Concentrations of Tn-C and procollagen
      propeptides type 1 and type 3 in serum and wound fluid were measured after
      surgery. RESULTS: In wound fluid, Tn-C was present on postoperative day 1, and
      the concentration increased from day 5 up to day 7. CONCLUSIONS: The
      concentration of Tn-C increases postoperatively in wound fluid. The concentration
      of Tn-C in wound fluid is markedly higher than that of serum. The differences in
      expression between Tn-C and the procollagen propeptides may reflect different
      tasks of these extracellular matrix proteins.

PMID- 15187762
TI  - Microbubble ultrasound demonstrates liver trauma.

PMID- 15187763
TI  - The evolving role of FAST scan for the diagnosis of pericardial fluid.

PMID- 15187764
TI  - Repair of a juxtahepatic inferior vena cava injury using a simple endovascular
      technique.

PMID- 15187765
TI  - Prolonged clamping of the liver parenchyma: a salvage maneuver in exsanguinating
      liver injury.

PMID- 15187766
TI  - Intussusception after damage-control laparotomy: a case report.

PMID- 15187767
TI  - Intraluminal aortic thrombi associated with self-inflicted gunshot wound to the
      chest.

PMID- 15187769
TI  - The Authors' Reply.

PMID- 15187768
TI  - The use of single or multiple injury descriptions in the assessment of injury
      severity.

PMID- 15187771
TI  - WAME makes a necessary statement of the obvious.

PMID- 15187772
TI  - Obesity surgery in pediatrics.

PMID- 15187773
TI  - Developmental disorders of the enteric nervous system: genetic and molecular
      bases.

PMID- 15187774
TI  - Infliximab: how to use it in pediatric Crohn's disease.

PMID- 15187775
TI  - Nutrition support for pediatric patients with inflammatory bowel disease: a
      clinical report of the North American Society for Pediatric Gastroenterology,
      Hepatology And Nutrition.
AB  - Impairment of growth and malnutrition are significant complications of
      inflammatory bowel disease (IBD) in pediatric patients. Since this topic was last
      reviewed in these pages (), a number of studies have further explored the
      epidemiology and pathogenesis of these nutritional complications of IBD in an
      effort to provide more effective interventions to prevent the long-term
      consequences of chronic nutrient deficiencies in childhood. In addition, during
      the past 15 years, the use of selected nutrients and microorganisms (probiotics)
      as primary or adjunctive therapy for the treatment of IBD has become an emerging
      area of great interest. The following is a Clinical Report from the Nutrition and
      Inflammatory Bowel Disease Committees of the North American Society for Pediatric
      Gastroenterology, Hepatology and Nutrition.

PMID- 15187776
TI  - Effects of protein deprivation on growth and small intestine morphology are not
      improved by glutamine or glutamate in gastrostomy-fed rat pups.
AB  - OBJECTIVES: Critically ill neonates often have their enteral intake severely
      limited shortly after birth. Whether glutamine (Gln) or glutamate (Glu) can
      preserve intestinal structure and function in the neonate undergoing limited
      enteral feeding is not clear. We hypothesize that Gln and Glu can similarly
      preserve intestinal structure in the developing small intestine of infant rats
      fed a low protein diet. METHODS: Using a gastrostomy-fed "pup-in-a-cup" rat
      model, the effects of Gln and Glu on the developing rat small intestine were
      examined. Four groups of 6- to 7-day-old pups were fed rat milk substitute (RMS)
      via gastrostomy tube. One group was provided 100% and three were provided 25% of
      the protein normally received from their mothers. Two of the groups fed 25%
      protein received additional Gln or Glu for 6 days. RESULTS: Pups receiving the
      100% protein RMS were larger than pups receiving the 25% protein RMS with or
      without Gln/Glu supplementation (P < 0.001). Average villus height (P < 0.01) and
      area (P < 0.01) were greater in pups receiving 100% protein RMS than in pups
      given 25% protein RMS formula. There was no significant difference among the
      groups in mucosal maltase or alkaline phosphatase activities. Tight junction
      protein claudin-1 was significantly higher in the group fed 100% protein RMS
      diet, while occludin did not differ among the 4 groups. Neither Gln nor Glu
      increased claudin-1 or occludin in rats fed 25% protein. CONCLUSIONS: These
      results suggest that neither Gln nor Glu supplementation can substitute
      effectively for whole protein in the developing rat small intestine for the
      outcomes that were evaluated.

PMID- 15187777
TI  - Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients
      with alpha-1-antitrypsin deficiency: a preliminary study.
AB  - OBJECTIVE: In homozygotes with ZZ genotype alpha-1-antitrypsin (alpha1AT)
      deficiency, mutant alpha1ATZ protein (alpha1ATZ) accumulates in hepatocytes,
      rather than being secreted into the blood. Homozygous individuals experience
      emphysema as a result of reduced levels of circulating alpha1AT in the lung with
      which to inhibit connective tissue breakdown. Homozygotes may also experience
      liver disease from the accumulation of alpha1ATZ within hepatocytes, which causes
      liver damage. A previous study indicated that the compound 4-phenylbutyrate (4
      PBA) mediated a significant increase in release of alpha1ATZ from cells in tissue
      culture and in a mouse model of alpha1AT deficiency. The authors hypothesized
      that 4-PBA could be used to treat both the liver and lung disease of humans with
      alpha1AT deficiency. METHODS: In this preliminary, open label study the authors
      evaluated the effect of 14 days of oral 4-PBA therapy on alpha1AT blood levels in
      10 patients with alpha1AT deficiency. RESULTS: There was no significant increase
      in alpha1AT blood level associated with 4-PBA administration. Symptomatic and
      metabolic side effects were significant. CONCLUSION: 4-PBA did not increase
      alpha1AT blood levels in humans with alpha1AT deficiency in this preliminary
      trial.

PMID- 15187778
TI  - Dietary nucleotides and intestinal blood flow velocity in term infants.
AB  - OBJECTIVES: Two previous studies have shown that the addition of nucleotides to
      single feedings of formula is associated with increased 90-minute postprandial
      superior mesenteric artery (SMA) blood flow velocity (BFV). To assess the effect
      of chronic feeding of nucleotide-supplemented formula, we measured pre- and
      postprandial SMA BFV in term infants fed formula with or without added
      nucleotides for 4 weeks. METHODS: At 1 week of age, healthy, term infants were
      randomized to receive formula with added nucleotides (NT+), or formula without
      added nucleotides (NT-) from age 1 to 5 weeks. When the infants were 5 weeks of
      age, SMA BFV was measured by Doppler ultrasound 15 minutes before the assigned
      feeding (baseline) and 30, 60, and 90 minutes after the start of feeding. A
      reference group of human milk-fed infants was studied before and after breast
      feeding. RESULTS: Thirty formula-fed (NT+ = 17; NT- = 13) and 10 human milk-fed
      infants were studied. Baseline BFV was similar among the three groups. BFV
      increased in each group from baseline to 30 minutes after initiation of feeding
      and progressively declined from 30 to 90 minutes in infants fed NT- formula or
      human milk. In infants fed NT+ formula, BFV decreased between 30 and 60 minutes.
      However, from 60 to 90 minutes, velocity was unchanged or increased. At 90
      minutes, mean and peak systolic velocities were significantly greater in the NT+
      group than the NT- group (P < 0.001). CONCLUSIONS: These data agree with those of
      previous studies showing increased 90-minute postprandial SMA BFV after a feeding
      with nucleotide-supplemented formula. The clinical significance of these findings
      is unknown.

PMID- 15187779
TI  - Mucous fistula refeeding in premature neonates with enterostomies.
AB  - BACKGROUND: Premature neonates with short bowel syndrome often have diverting
      enterostomies and distal mucous fistulae. The authors reviewed their experience
      in 12 premature neonates in whom proximal bowel contents were re-fed into the
      mucous fistula. METHODS: We reviewed the records of 12 premature neonates who
      presented with acute abdomen and who underwent intestinal resection with
      formation of diverting enterostomy and mucous fistula between July 1999 and
      December 2002. All received parenteral nutrition. Refeeding of enterostomy
      contents into the distal mucous fistula was commenced after patency of the distal
      intestine was confirmed by radiologic examination. Demographic data, body weight
      and clinical outcomes were recorded. RESULTS: Median gestational age was 31 weeks
      and mean birth weight was 1.59 kg. Diagnoses included necrotizing enterocolitis
      (n = 6), meconium ileus-like conditions (n = 2), ileal atresia (n = 2),
      malrotation with volvulus (n = 1) and focal intestinal perforation (n = 1).
      Refeeding was successfully established in all patients with no complications. The
      mean duration of refeeding was 63.5 days. All patients achieved good weight gain
      after refeeding (18.9 +/- 2.9 g/d) with a reduction of parenteral nutrition
      requirements. All enterostomies were subsequently closed. Four patients died of
      unrelated causes after reanastomosis and the remaining eight were discharged.
      CONCLUSIONS: Mucous fistula refeeding is safe in premature neonates with
      enterostomies. It can prevent disuse atrophy in the distal loop and facilitate
      subsequent reanastomosis. Furthermore, the increased absorptive function provided
      by the small bowel incorporated in the mucous fistula can reduce the requirement
      for total parenteral nutrition.

PMID- 15187780
TI  - Infliximab therapy in 30 patients with refractory pediatric crohn disease with
      and without fistulas in The Netherlands.
AB  - OBJECTIVE: The purpose of this study was to describe the clinical experience with
      the anti-tumor necrosis factor chimeric monoclonal antibody, infliximab, in
      pediatric patients with Crohn disease in The Netherlands. DESIGN: Descriptive.
      METHODS: Clinical response and adverse effects of infliximab were recorded for
      pediatric patients with Crohn disease treated from October 1992 to January 2003.
      RESULTS: Thirty patients (aged 7-18 years) with refractory Crohn disease (with or
      without severe fistulas) were treated with infliximab. Patients were treated with
      up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were
      administered. Thirteen patients had refractory Crohn disease without fistulas.
      Six patients showed good long-term response to infliximab treatment (defined as
      clinical index < or =10 points). Sixteen patients had refractory Crohn disease
      with draining fistulas. Nine showed good long-term response (closure or
      nonproductiveness of fistulas). One patient with metastatic Crohn disease in the
      skin had a good long-term response. Six patients developed an allergic reaction
      during infusion. In one patient, the allergic reaction occurred after an
      infliximab-free interval of 9 years. One patient died of sepsis. CONCLUSIONS:
      Infliximab was an effective therapy in 53% of patients with refractory pediatric
      Crohn disease, with or without fistulas. Approximately half of the patients
      become unresponsive to infliximab therapy. Randomized controlled studies are
      mandatory to assess long-term efficacy and safety to define the optimal
      therapeutic strategy of infliximab therapy in children with Crohn disease.

PMID- 15187782
TI  - A new model for studying eosinophil migration across cultured intestinal
      epithelial monolayers.
AB  - OBJECTIVE: Eosinophils play an important role in some gastrointestinal
      inflammatory conditions. Stimulated eosinophils migrate across the vascular
      endothelial wall and into the intestinal epithelium where by-products such as
      proteases may contribute to intestinal epithelial damage. Little is known about
      the epithelial migration of the eosinophils in the gut. The lack of data is
      attributable in part to the scarcity of human eosinophils for studies. HL-60
      differentiated eosinophils present a means to perform studies on eosinophil
      function and chemotaxis. HL-60 clone 15 can be induced to differentiate into
      cells closely resembling human eosinophils. The authors describe a novel model
      for studying eosinophil migration across the intestinal epithelium. METHODS:
      Fluorescent-labeled HL-60 eosinophils were incubated for 150 minutes on the
      basolateral surface of confluent and inverted T-84 monolayers separated by
      fluoroblock insert membranes. Chemotactic gradients of n-formyl methionyl leucyl
      phenylalanine (fMLP), eotaxin, and platelet aggregating factor (PAF) were used in
      variable concentrations. Changes in transepithelial electrical resistance (TEER)
      were compared with baseline values. RESULTS: Differentiated HL-60 eosinophils
      undergo migration in response to fMLP, PAF, and eotaxin. Migration is associated
      with a drop in TEER. CONCLUSION: In this model, HL-60-differentiated eosinophils
      migrate in response to stimulants chemotactic for human eosinophils. The
      transepithelial migration of eosinophils is associated with epithelial barrier
      dysfunction, which may contribute to the development of disease.

PMID- 15187781
TI  - Abnormal oral mucosal light reflectance in infantile hypertrophic pyloric
      stenosis.
AB  - OBJECTIVES: Infantile hypertrophic pyloric stenosis (IHPS) is the most common
      condition requiring surgical intervention during the first weeks of life. The
      etiology of IHPS is unknown, although both neuronal nitric oxide synthase
      upregulation and an extracellular matrix abnormality are suspected. Familial
      predisposition is an important feature. Phenotypical markers of IHPS, such as
      hypoplasia or agenesis of the inferior labial frenulum, have been described. The
      authors tested the hypothesis that IHPS is associated with abnormal reflectance
      of the oral mucosa. METHODS: Twenty-five children with surgically confirmed IHPS
      and 25 gender- and age-matched control subjects participated in the study.
      Reflectance of the lower gingival and vestibular oral mucosa in the optical
      spectrum was measured using an imaging spectrophotometer. RESULTS: Patients with
      IHPS had significantly higher light reflectance values in the violet, blue, blue
      green, green, yellow, and orange sections of the spectrum (all P values <
      0.0001), with a maximum distance between group means at the 450-nm wavelength (t
      value: 27.66, df = 48). A reflectance cutoff >5.26% at the 450-nm wavelength
      identified patients with IHPS with 100% sensitivity and 100% specificity.
      CONCLUSIONS: This study reports a previously unrecognized mucosal reflectance
      abnormality of the oral mucosa in IHPS, thus offering a new, accurate, and
      noninvasive phenotypic marker for the condition.

PMID- 15187783
TI  - Stool antigen test for diagnosis of Helicobacter pylori infection in children
      with symptomatic disease: a prospective study.
AB  - OBJECTIVE: Noninvasive tests for the diagnosis of Helicobacter pylori (Hp)
      infection in children are limited by low accuracy rates and lack of validation.
      Existing studies indicate that the stool antigen test (HpSA) has an acceptable
      level of accuracy for the diagnosis of Hp infection in adults but not children.
      The aim of this study was to evaluate the accuracy of the HpSA test for the
      detection of Hp infection in U.S. children. METHODS: Children requiring upper
      endoscopic procedures were prospectively recruited from two pediatric
      gastroenterology clinics. Stool samples were collected from each participant
      before endoscopy. The presence of Hp infection was determined by positive
      histologic findings and positive rapid urease test (RUT). The presence of Hp
      organisms in stool was determined by an enzyme-linked immunosorbent assay using a
      commercially available polyclonal antibody kit (Meridian Diagnostics, Cincinnati,
      OH, U.S.A.). Results of the stool antigen test were compared with histology
      findings and RUT results. RESULTS: One hundred twenty-one children (mean age,
      10.1 +/- 3.7 years) participated, of whom 9 (7.4%) had Hp infection. Histologic
      findings and RUT results were concordant in 95% of the children. Per study
      protocol, HpSA had a sensitivity, specificity, positive and negative predictive
      value, and accuracy rate of 67%, 99%, 86%, 97%, and 96.5%, respectively.
      CONCLUSION: HpSA, a polyclonal antibody test, had a low sensitivity for infection
      in children in the United States and at present cannot replace histologic
      findings as the gold standard for the diagnosis of Hp infection in the pediatric
      population.

PMID- 15187784
TI  - Is an abbreviated Pediatric Crohn's Disease Activity Index better than the
      original?
AB  - OBJECTIVE: The Pediatric Crohn's Disease Activity Index (PCDAI) is a validated
      measure of disease activity comprised of historical, laboratory and physical
      examination parameters. It has been suggested that an abbreviated PCDAI may be of
      similar utility without requiring laboratory evaluations or calculated height
      velocity. The aim of this study was to compare an abbreviated PCDAI and the
      original PCDAI and also compare the abbreviated PCDAI and a quality-of-life
      measurement. METHODS: The authors prospectively analyzed quality of life and
      disease activity, using the IMPACT-35 Questionnaire, the PCDAI and an abbreviated
      PCDAI consisting of three historical items (abdominal pain, stools and patient
      functioning) and three physical examination items (weight, abdomen and perirectal
      disease). RESULTS: Forty subjects aged 5-24 years (22 males) were included in
      analysis. Correlations were performed between the original PCDAI, an abbreviated
      PCDAI and the IMPACT-35. There was a significant, strong correlation between the
      PCDAI and the abbreviated PCDAI (n = 40, r = 0.849, p <0.001), a significant,
      moderate correlation between PCDAI and IMPACT-35 (n = 29, r = -0.547, p = 0.002)
      and a significant, moderate correlation between the abbreviated PCDAI and IMPACT
      35 (n = 29, r = -0.579, p <0.001). CONCLUSIONS: An abbreviated PCDAI predicted
      disease activity as well as the full PCDAI. The IMPACT-35 correlated well with
      disease activity based on both PCDAI and an abbreviated PCDAI. An abbreviated
      PCDAI may offer advantages over the original PCDAI and should be prospectively
      validated in future studies.

PMID- 15187785
TI  - Neutrophil and small intestinal lymphocyte migration after Salmonella typhimurium
      infection: impact of fermentable fiber.
AB  - OBJECTIVES: Formula-fed infants have more episodes of acute diarrhea and
      intestinal infection than do breast-fed infants. Nutrient additions to infant
      formula that could confer some of the immune benefits of breast milk to formula
      fed infants are currently under investigation. This study examined the impact of
      enteral formulas supplemented with fermentable substrates on small intestinal
      lymphocyte and neutrophil migration in piglets infected with Salmonella
      typhimurium. Small intestinal proinflammatory cytokine messenger RNA abundance
      and in vitro lipopolysaccharide-stimulated interleukin-6 release in whole blood
      were assessed. METHODS: Piglets were randomized to receive sow milk replacer
      formula supplemented with methylcellulose (control), soy polysaccharides (SPS) or
      fructooligosaccharides (FOS). On day 7, half of the piglets were infected with S.
      typhimurium. Intestinal lymphocyte, neutrophil and whole blood samples were
      obtained on day 14. RESULTS: After infection, there was decreased lymphocyte
      migration in the control group but not in the SPS and FOS groups. The SPS group
      had greater neutrophil migration compared with the control and FOS groups,
      regardless of infection. Small intestinal abundance of proinflammatory cytokine
      messenger RNA was not significantly changed by either infection or diet. Blood
      from the FOS group challenged with lipopolysaccharide for 2 hours exhibited
      decreased interleukin-6 production compared with blood from the control and SPS
      groups, regardless of infection. CONCLUSIONS: Supplementation of enteral formulas
      with SPS maintains the migratory function of small intestinal lymphocytes while
      increasing that of neutrophils.

PMID- 15187787
TI  - Assessment of phospholipid malabsorption by quantification of fecal phospholipid.
AB  - OBJECTIVES: The standard methods for quantifying fat absorption involve
      extraction of fat from fecal samples with heptane, ether and ethanol. These
      solvents do not quantitatively recover phospholipids. Malabsorption of dietary
      and biliary phosphatidylcholine could potentially result in choline deficiency.
      Therefore, the authors developed a method extracting and quantifying fecal
      phospholipids. METHODS: Fecal samples were collected for 72 hours from 18
      children with cystic fibrosis and 10 control children. Fat was extracted first
      with hexane/diethyl ether/ethanol and then with chloroform/methanol. Total fat
      was quantitated gravimetrically. Phospholipids in extracted fat were separated
      and quantified using high-performance liquid chromatography with evaporative
      light-scattering detection (HPLC-ELSD). Phospholipid quantification was validated
      with a phosphomolybdate colorimetric assay. RESULTS: The combination of solvent
      systems used in this study significantly improved total fat (p < 0.05) and
      phospholipid (p < 0.001) extraction compared with either hexane/diethyl
      ether/ethanol or chloroform/methanol alone. Fecal phospholipid measured by HPLC
      ELSD was significantly correlated with lipid-soluble phosphorous using the
      phosphomolybdate assay (r = 0.75, p < 0.001). This method also allows
      quantification of fecal phosphatidylcholine and lysophosphatidylcholine.
      CONCLUSIONS: Hexane/diethyl ether/ethanol followed by chloroform/methanol
      extraction of fecal samples and quantification of phospholipids using HPLC-ELSD
      is a new method for investigating phospholipid malabsorption.

PMID- 15187786
TI  - Prospective population screening for celiac disease: high prevalence in the first
      3 years of life.
AB  - BACKGROUND: Celiac disease (CD) is an autoimmune enteropathy that develops in
      genetically susceptible individuals exposed to gliadin. Early diagnosis of CD may
      reduce the risk of complications, and several studies have related the duration
      of gluten exposure to the risk of other autoimmune diseases. It has been proposed
      that silent CD be diagnosed as soon as possible to avoid potential complications.
      OBJECTIVES: The purpose of this study was to determine the prevalence of CD among
      children less than 3 years and to provide treatment to those patients diagnosed
      with CD. PATIENTS AND METHODS: Parents of 1100 healthy children born between
      October 1998 and December 1999 were asked at the time of delivery to enroll their
      children in a program for the early diagnosis of CD. The parents of 830 children
      agreed to participate. Patients in the study were examined and anti-tissue
      transglutaminase antibody was first measured at about 1.5 years of age. A second
      antibody titer was obtained at about 2.5 years of age. Patients with detectable
      autoantibodies underwent intestinal biopsy for confirmation of CD. RESULTS: Of
      the 830 children initially enrolled, 613 and 484 returned for the first and
      second visits, respectively. None had anti-tissue transglutaminase antibodies at
      the first visit, but 9 had anti-tissue transglutaminase immunoglobulins at the
      second visit. In 7 of these 9, intestinal biopsy confirmed the diagnosis of CD
      which suggests a minimum prevalence of CD of 1 per 118 healthy newborns.
      CONCLUSIONS: The authors observed a very high prevalence of CD, comparable to
      that observed in other European populations, which might even be higher if all of
      the children initially examined had returned for their second visit. If general
      screening for CD were accepted, the authors would recommend age 2-3 years as the
      best time for measuring tissue transglutaminase antibodies.

PMID- 15187788
TI  - Ectopic pancreas and foveolar hyperplasia in a newborn: a unifying
      etiopathogenesis for gastric outlet obstruction.

PMID- 15187789
TI  - N-acetyl tyrosyluria caused by parenteral or enteral administration of N-acetyl-L
      tyrosine: differentiation from hereditary and acquired tyrosinemias.

PMID- 15187790
TI  - Clinical quiz. Brunner's gland adenoma.

PMID- 15187791
TI  - A consistent pattern of minor immunodeficiency and subtle enteropathy in children
      with multiple food allergy.

PMID- 15187792
TI  - To treat or not to treat: that is the question.

PMID- 15187793
TI  - Polyethylene glycol 3350 without electrolytes: a new safe, effective, and
      palatable bowel preparation for colonoscopy in children.

PMID- 15187795
TI  - British warnings on SSRIs questioned.

PMID- 15187796
TI  - Ziprasidone and mania.

PMID- 15187797
TI  - Imputing missing data.

PMID- 15187798
TI  - Childhood reactions to terrorism-induced trauma: a review of the past 10 years.
AB  - OBJECTIVE: To summarize the literature about the clinical presentation and
      treatment interventions of childhood reactions to terrorism-induced trauma.
      METHOD: The literature on children's responses to terrorist activities was
      reviewed. RESULTS: Over the past 10 years, more research has emerged on the
      subject of terrorism in children. Many of the effects of terrorism-induced trauma
      are similar to the effects of natural and man-made trauma. Children's responses
      include acute stress disorder, posttraumatic stress disorder, anxiety,
      depression, regressive behaviors, separation problems, sleep difficulties, and
      behavioral problems. However, several aspects of terrorist attacks result in
      unique stressors and reactions and pose specific challenges for treatment. The
      unpredictable, indefinite threat of terrorist events, the profound effect on
      adults and communities, and the effect of extensive terrorist-related media
      coverage exacerbates underlying anxieties and contributes to a continuous state
      of stress and anxiety. Intervention strategies include early community-based
      interventions, screening of children at risk, triage and referral, and trauma
      loss-focused treatment programs. CONCLUSIONS: Advances have been made in the
      research of childhood reactions to terrorism-induced trauma. Further research is
      needed to identify children at risk and to determine the long-term impact on
      children's development. Although the preliminary results of interventions
      developed to help children are promising, outcome data have not been examined,
      and further research is needed to evaluate their effectiveness.

PMID- 15187799
TI  - A multisite, randomized controlled trial for children with sexual abuse-related
      PTSD symptoms.
AB  - OBJECTIVE: To examine the differential efficacy of trauma-focused cognitive
      behavioral therapy (TF-CBT) and child-centered therapy for treating posttraumatic
      stress disorder (PTSD) and related emotional and behavioral problems in children
      who have suffered sexual abuse. METHOD: Two hundred twenty-nine 8- to 14-year-old
      children and their primary caretakers were randomly assigned to the above
      alternative treatments. These children had significant symptoms of PTSD, with 89%
      meeting full DSM-IV PTSD diagnostic criteria. More than 90% of these children had
      experienced traumatic events in addition to sexual abuse. RESULTS: A series
      analyses of covariance indicated that children assigned to TF-CBT, compared to
      those assigned to child-centered therapy, demonstrated significantly more
      improvement with regard to PTSD, depression, behavior problems, shame, and abuse
      related attributions. Similarly, parents assigned to TF-CBT showed greater
      improvement with respect to their own self-reported levels of depression, abuse
      specific distress, support of the child, and effective parenting practices.
      CONCLUSIONS: This study adds to the growing evidence supporting the efficacy of
      TF-CBT with children suffering PTSD as a result of sexual abuse and suggests the
      efficacy of this treatment for children who have experienced multiple traumas.

PMID- 15187800
TI  - Predicting child PTSD: the relationship between acute stress disorder and PTSD in
      injured children.
AB  - OBJECTIVE: To examine the prevalence of acute stress disorder (ASD) and
      posttraumatic stress disorder (PTSD) in injured children and to evaluate the
      utility of ASD as a predictor of PTSD. METHOD: Children hospitalized for injuries
      sustained in a traffic crash were enrolled in a prospective study. ASD was
      assessed in 243 children within 1 month after injury, and PTSD was assessed in
      177 of these children 3 or more months after injury. The relationship between ASD
      and PTSD was examined via correlations between symptom severity scores and
      calculation of sensitivity, specificity, and positive and negative predictive
      values for categorical prediction of PTSD from ASD or subsets of ASD symptoms.
      RESULTS: Eight percent of children met the symptom criteria for ASD and another
      14% had subsyndromal ASD; 6% met the symptom criteria for PTSD and another 11%
      had subsyndromal PTSD. ASD and PTSD symptom severity were associated. Sensitivity
      was low for prediction of child PTSD from child ASD. Subsyndromal ASD was a more
      effective predictor of PTSD. CONCLUSIONS: A substantial minority of injured
      children are affected by traumatic stress disorders. ASD in children may not be
      an optimal categorical predictor of PTSD. With increasing attention to early
      posttrauma services for children, empirically valid assessment/triage models
      deserve further study.

PMID- 15187801
TI  - Psychiatric symptoms in children with primary headache.
AB  - OBJECTIVE: To examine the association of psychiatric symptoms with migraine and
      tension-type headache in children. METHOD: A questionnaire completed by 1,135
      Finnish children in the sixth grade identified 154 children with migraine, 138
      with tension-type headache, and 407 children who were headache-free. Seventy
      children were randomly selected from each group and evaluated by a structured
      interview to confirm headache type, resulting in a sample of 59 children with
      migraine, 65 with tension-type headache, and 59 without headache. The children
      completed the Children's Depression Inventory, and the parents completed the
      Child Behavior Checklist and General Functioning scale of the McMaster Family
      Assessment Device. RESULTS: Children with migraine had significantly higher
      levels of total, internalizing, and somatic symptoms, as well as social and
      family problems, than those without headache and had higher levels of somatic
      symptoms than children with tension-type headache. Children with tension-type
      headache had significantly higher levels of somatic symptoms and family problems
      than those without headache. CONCLUSIONS: The association between psychiatric
      symptoms and headaches shows differences between different headache types.
      However, a minority of children with migraine or tension-type headache have high
      levels of psychiatric symptoms.

PMID- 15187802
TI  - A randomized controlled trial of pemoline for attention-deficit/hyperactivity
      disorder in substance-abusing adolescents.
AB  - OBJECTIVE: In adolescents with substance use disorder (SUD), comorbid attention
      deficit/hyperactivity disorder (ADHD) is associated with greater severity of
      substance abuse, conduct problems, and worse treatment outcomes. Although many
      controlled trials have established the efficacy of psychostimulants, including
      pemoline, for ADHD in children and adolescents, none have been conducted in
      adolescents with SUD. This randomized, placebo-controlled trial, conducted
      between 1996 and 2000, evaluated the safety and efficacy of pemoline on substance
      abuse and conduct problems. METHOD: Sixty-nine adolescents (aged 13-19) with
      conduct disorder (CD), SUD, and ADHD were recruited from the community and
      randomly assigned to a 12-week clinical trial of pemoline (n = 35) or placebo (n
      = 34), titrated over 4 weeks to a single morning dose of 75 to 112.5 mg as
      tolerated. RESULTS: Pemoline had greater efficacy than placebo for ADHD as
      determined by significantly more Clinician's Global Impression-Improvement (CGI
      I) ratings of 1 (very much improved) or 2 (much improved) at the study endpoint
      (n = 69; p <.05). There was also greater reduction in ADHD severity on the parent
      rated Conners Hyperactivity-Impulsivity scale in pemoline-treated study
      completers compared to placebo-treated completers (pemoline, n = 17; placebo, n =
      16; p <.01), but no difference between groups in the intent-to-treat analysis (n
      = 68; p <.13). Substance use did not decline in either group, and there was no
      difference between groups in baseline to study endpoint change in substance use
      or CD symptoms. Overall, pemoline was well tolerated, demonstrating a good safety
      profile and no elevation in liver enzyme levels. CONCLUSIONS: Pemoline was
      efficacious for ADHD but did not have an impact on CD or substance abuse in the
      absence of specific treatment for SUD.

PMID- 15187803
TI  - A statewide screening of mental health symptoms among juvenile offenders in
      detention.
AB  - OBJECTIVE: As awareness of the high prevalence of mental health problems among
      juvenile offenders has grown, researchers and practitioners have recognized the
      need for reliable and efficient methods of assessing such problems among large
      numbers of offenders to ensure that limited treatment resources are applied to
      those with the greatest need. METHOD: Between May 2000 and October 2002, 18,607
      admissions were administered the computerized version of the Massachusetts Youth
      Screening Instrument Version 2 (MAYSI-2) 24 to 48 hours after their arrival at
      detention centers throughout Pennsylvania. RESULTS: Approximately 70% of the
      males and 81% of the females scored above the clinical cutoff on at least one of
      the following five MAYSI-2 scales: Alcohol/Drug Use, Angry-Irritable, Depressed
      Anxious, Somatic Complaints, and/or Suicide Ideation. Girls were more likely than
      boys to exhibit internalizing as well as externalizing problems. Mental health
      problems were most prevalent among white youths and least prevalent among African
      American youths. When youths repeated the screen upon subsequent visits to
      detention, their scores generally remained stable. CONCLUSIONS: The findings
      suggest that the MAYSI-2 is a promising triage tool for emergent risk. The use of
      such a screen may reduce bias in allocation of treatment resources and improves
      our understanding of the nature of mental health problems in delinquent
      populations.

PMID- 15187805
TI  - Informant disagreement for separation anxiety disorder.
AB  - OBJECTIVE: To characterize informant disagreement for separation anxiety disorder
      (SAD). METHOD: The sample comprised 2,779 8- to 17-year-old twins from a
      community-based registry. Children and their parents completed a personal
      interview about the child's psychiatric history. Parents completed a personal
      interview about their own psychiatric history and a questionnaire about their
      marital relationship. RESULTS: Informant agreement for SAD ranged between chance
      and extremely poor. Most cases of SAD were diagnosed by interview with only one
      informant. SAD diagnosed only by child interview was associated with an increased
      odds of father-rated oppositional defiant disorder, and vice versa. SAD diagnosed
      only by parent interview was predicted by the parental informant's history of
      antisocial personality disorder. SAD diagnosed only by paternal interview was
      also predicted by mother-rated marital conflict and dissatisfaction. CONCLUSIONS:
      Parents and children rarely agree about the presence of any level of child
      separation anxiety. A symptom "or-rule" mostly indexes diagnoses based on
      interview with only one informant, but the relative validity of such diagnoses
      remains unclear.

PMID- 15187806
TI  - Cortisol levels and conduct disorder in adolescent mothers.
AB  - OBJECTIVE: To examine the association between cortisol levels and conduct
      disorder (CD) in adolescent mothers. Past research has shown that low levels of
      cortisol were associated with CD, particularly with its aggressive symptoms. The
      authors tested the hypothesis that adolescent mothers with CD would show lower
      levels of salivary cortisol compared to mothers without CD at 4 and 9 months
      postpartum. METHOD: Midmorning salivary cortisol levels were measured in 228
      adolescent mothers (age at delivery 16.9 +/- 1 years [mean +/- SD]) during a
      laboratory visit at 4 and 9 months postpartum. CD was diagnosed during pregnancy
      according to the CD subsection on the criteria for antisocial personality
      disorder (DSM-III-R). RESULTS: Results did not confirm the hypothesis. Lower
      cortisol levels were not significantly associated with a CD diagnosis, the number
      of CD symptoms, or aggressive symptoms. CONCLUSIONS: Despite valid measures and
      strong statistical power, this study failed to find an association between
      cortisol levels and CD in a sample of adolescent mothers. The results may have
      been influenced by the fact that participants were 4 and 9 months postpartum and
      by comparisons of mothers with CD to mothers living in stressful circumstances.

PMID- 15187804
TI  - Symptom, family, and service predictors of children's psychiatric
      rehospitalization within one year of discharge.
AB  - OBJECTIVE: To investigate predictors of readmission to inpatient psychiatric
      treatment for children aged 5 to 12 discharged from acute-care hospitalization.
      METHOD: One hundred nine children were followed for 1 year after discharge from
      inpatient care. Time to rehospitalization was the outcome of interest. Predictors
      of readmission, examined via the Cox proportional hazards model, were symptom and
      family factors assessed at admission, aspects of psychiatric treatment, and
      demographic variables. RESULTS: The Kaplan-Meier rehospitalization risk within 1
      year of discharge, taking into account known readmissions and censored
      observations, was 0.37. Most readmissions (81%) occurred within 90 days of
      discharge. Four variables contributed simultaneously to predicting readmission
      risk. More severe conduct problems, harsh parental discipline, and disengaged
      parent-child relations conferred a higher risk for rehospitalization; these risks
      were attenuated when parents disclosed higher stress in their parenting roles.
      CONCLUSIONS: Findings showed that psychiatric rehospitalization of children is
      common, most likely in the trimester after discharge, and highly related to both
      child symptoms and family factors measurable at admission. Results suggest that
      efforts to improve postdischarge outcomes of children should target the initial
      period following inpatient care, address vigorously the complex treatment needs
      of those with severe conduct problems, and aim to improve parent-child relations.

PMID- 15187808
TI  - Emotional attribution in high-functioning individuals with autistic spectrum
      disorder: a functional imaging study.
AB  - OBJECTIVE: To determine whether expertise in the attribution of emotion from
      basic facial expressions in high-functioning individuals with autistic spectrum
      disorder (ASD) is supported by the amygdala, fusiform, and prefrontal regions of
      interest (ROI) and is comparable to that of typically developing individuals.
      METHOD: Functional magnetic resonance imaging scans were acquired from 14 males
      with ASD and 10 matched adolescent controls while performing emotion match (EM)
      (perceptual), emotion label (EL) (linguistic), and control tasks. Accuracy,
      response time, and average activation were measured for each ROI. RESULTS: There
      was no significant difference in accuracy, response time, or ROI activation
      between groups performing the EL task. The ASD group was as accurate as the
      control group performing the EM task but had a significantly longer response time
      and lower average fusiform activation. CONCLUSIONS: Expertise in the attribution
      of emotion from basic facial expressions was task-dependent in the high
      functioning ASD group. The hypothesis that the high-functioning ASD group would
      be less expert and would have reduced fusiform activation was supported in the
      perceptual task but not the linguistic task. The reduced fusiform activation in
      the perceptual task was not explained by reduced expertise; it is therefore
      concluded that reduced fusiform activation is associated with the diagnosis of
      ASD.

PMID- 15187809
TI  - Neural correlates of facial affect processing in children and adolescents with
      autism spectrum disorder.
AB  - OBJECTIVE: To examine the neural basis of impairments in interpreting facial
      emotions in children and adolescents with autism spectrum disorders (ASD).
      METHOD: Twelve children and adolescents with ASD and 12 typically developing (TD)
      controls matched faces by emotion and assigned a label to facial expressions
      while undergoing functional magnetic resonance imaging. RESULTS: Both groups
      engaged similar neural networks during facial emotion processing, including
      activity in the fusiform gyrus (FG) and prefrontal cortex. However, between-group
      analyses in regions of interest revealed that when matching facial expressions,
      the ASD group showed significantly less activity than the TD group in the FG, but
      reliably greater activity in the precuneus. During the labeling of facial
      emotions, no between-group differences were observed at the behavioral or neural
      level. Furthermore, activity in the amygdala was moderated by task demands in the
      TD group but not in the ASD group. CONCLUSIONS: These findings suggest that
      children and adolescents with ASD in part recruit different neural networks and
      rely on different strategies when processing facial emotions. High-functioning
      individuals with ASD may be relatively unimpaired in the cognitive assessment of
      basic emotions, yet still show differences in the automatic processing of facial
      expressions.

PMID- 15187810
TI  - Platelet serotonin levels in pervasive developmental disorders and mental
      retardation: diagnostic group differences, within-group distribution, and
      behavioral correlates.
AB  - OBJECTIVE: To investigate group differences, the within-group distributions, and
      the clinical correlates of platelet serotonin (5-HT) levels in pervasive
      developmental disorders (PDD). METHOD: Platelet 5-HT levels were measured in
      Dutch children and young adults, recruited from 2001 through 2003, with PDD
      (autism, Asperger's, and PDD-not otherwise specified [PDD-NOS]; n = 81) or with
      mental retardation (MR; n = 54) but without PDD, and in normal controls (n = 60).
      The distribution of platelet 5-HT levels was assessed using mixture-modeling
      analyses. Relationships between platelet 5-HT levels and a full range of
      demographic, clinical, and behavioral variables were examined. RESULTS: Group
      mean (+/- SD) platelet 5-HT levels (nmol/10 platelets) were significantly higher
      in the autistic (4.51 +/- 1.61, n = 33) and PDD-NOS (4.90 +/- 1.54, n = 43)
      groups compared to the MR (3.48 +/- 1.33, n = 54) or the normal control (3.58 +/-
      1.08, n = 60) groups (F4,190 = 9.35, p <.001). Platelet 5-HT values in the
      combined PDD group showed a bimodal distribution, and an empirical cutpoint for
      hyperserotonemia was determined. None of the behavioral variables examined was
      significantly associated with platelet 5-HT levels. CONCLUSIONS: The platelet
      hyperserotonemia of autism was replicated in Dutch subjects. Platelet 5-HT levels
      were also increased in PDD-NOS, while no elevation was seen in MR. Platelet 5-HT
      levels appeared to be bimodally distributed in the PDD group, with an apparent
      hyperserotonemic subgroup.

PMID- 15187811
TI  - Promoting heart health--a European consensus.

PMID- 15187812
TI  - Promoting heart health--a European consensus. Background paper prepared by the
      Irish Presidency for a meeting in Cork, Ireland, February 2004.

PMID- 15187813
TI  - Is smokeless tobacco a risk factor for coronary heart disease? A systematic
      review of epidemiological studies.
AB  - BACKGROUND: There is on-going debate about the wisdom of substituting smokeless
      tobacco products for cigarette smoking as a 'harm reduction' strategy. It is
      generally believed that health risks associated with smokeless tobacco use (ST)
      are lower than those with cigarette smoking. However, the population attributable
      risk of smoking is higher for cardiovascular diseases than for any cancers, and
      few studies or reviews have considered the cardiovascular outcomes of ST use. A
      systematic review was therefore carried out to highlight the gaps in the evidence
      base. METHODS: Electronic databases were searched, supplemented by screening
      reference lists, smoking-related websites, and contacting experts. Analytical
      observational studies of ST use (cohorts, case-control, cross-sectional studies)
      were included if they reported on cardiovascular disease (CVD) outcomes, or risk
      factors. Data extraction covered control of confounding, selection of cases and
      controls, sample size, clear definitions and measurements of the health outcome
      and ST use. One or two independent reviewers carried out selection, extraction
      and quality assessments. RESULTS: A narrative review was carried out. Very few
      studies were identified; only three from Sweden consider CVD outcomes and these
      are discrepant. There may be a modest association between use of Swedish snuff
      (snus) and cardiovascular disease (e.g., relative risk=1.4, 95% confidence
      interval 1.2-1.6) in one prospective cohort study. Several other studies have
      considered associations between ST use and intermediate outcomes (CVD risk
      factors). CONCLUSIONS: There may be an association between ST use and
      cardiovascular disease. However, further rigorous studies with adequate sample
      sizes are required.

PMID- 15187814
TI  - Prevalence and magnitude of classical risk factors for coronary heart disease in
      a cohort of 4400 Chinese steelworkers over 13.5 years follow-up.
AB  - BACKGROUND: The incidence and mortality of cardiovascular disease among Orientals
      are very different than among Caucasians. This study addresses the prevalence and
      magnitude of classic cardiovascular disease risk factors associated with coronary
      heart disease (CHD) in an Oriental cohort of at-risk men (blood pressure, total
      cholesterol, Body Mass Index [BMI] and smoking), compared to Caucasian
      populations. We also address which blood pressure index (SBP, DBP, mean arterial
      pressure [MAP] and pulse pressure [PP]) is the best predictor of CHD. METHODS AND
      RESULTS: A cohort of 5092 male steelworkers (18-74 years old) recruited between
      1974-1980 was followed up for an average of 13.5 years. The prevalence of risk
      factors was lower in Orientals than in Caucasians, except for smoking. The
      relative risks (RRs) of CHD associated with classic risk factors in this Oriental
      population were similar to Caucasians, except for blood pressure. The RRs of CHD
      associated with both SBP and DBP in this Oriental group were higher than in
      Caucasians; RR of CHD was approximately 3 for each 40 mmHg rise of SBP versus
      approximately 2 in Caucasians. SBP was the single best predictor for CHD,
      followed by MAP, and DBP. The population attributable risk (PAR%) for
      hypertension (140/90 mmHg) was 42.4. CONCLUSION: Our results would indicate that
      the lower incidence of CHD in Orientals is at least partly due to the lower
      prevalence of hypertension, hypercholesterolemia, and obesity. The magnitude of
      the risk associated with these factors is similar to that in Caucasians, except
      perhaps for a greater risk associated with hypertension. The most predictive BP
      index for CHD is SBP. These results are based on indirect comparisons only and
      should be studied further in prospective multi-ethnic cohorts.

PMID- 15187815
TI  - The absolute risk of recurrent myocardial infarction is similar amongst both
      sexes: MONICA Iceland Study 1981-1999.
AB  - BACKGROUND: To do a gender comparison of absolute risk of recurrent myocardial
      infarction (MI). DESIGN: Registration of all first and second MI amongst
      Icelandic males and females 1981-1999. METHODS: The whole of Icelandic
      population, 40-74 years of age. RESULTS: The mean recurrence rate (second attack)
      for men was 45.7/1000 MI survivors/year and for women 39.0/1000 per year. The
      male/female (M/F) ratio was 1.17, 95% confidence interval 1.00-1.37, P = 0.05 and
      did not change significantly with age. The M/F ratio for first MI in comparison
      was two to seven, lowest in the oldest group. The recurrence rate decreased
      significantly and similarly in both sexes during the observation period.
      CONCLUSION: The absolute risk of MI is closely similar amongst both sexes and has
      decreased similarly suggesting that the same kind of secondary intervention is
      effective amongst both sexes in a general population.

PMID- 15187816
TI  - Extent of regression dilution for established and novel coronary risk factors:
      results from the British Regional Heart Study.
AB  - BACKGROUND: Imprecision in measurement of risk factors leads to underestimation
      of associations with disease outcomes (through regression dilution bias). We
      examine the extent of this bias for established and novel risk factors for
      coronary heart disease (CHD) and consider the consequences for CHD prevention.
      DESIGN: Prospective cardiovascular study of middle-aged British men followed up
      over 20 years. METHODS: Repeated measurements of blood lipids, blood pressure and
      insulin were available at intervals of 1 week, 4, 16 and 20 years; repeated
      measurements of homocysteine and haemostatic factors were available over 1 week
      and 4 years. RESULTS: The use of single baseline measures of both established and
      novel risk factors in analysis results in marked underestimation of risk
      associations, increasing over time. The use of a single baseline measurement of
      total cholesterol results in a 47% (95% confidence interval 44 to 50%)
      underestimation of its association with CHD risk during the third decade of
      follow-up; for diastolic blood pressure the corresponding underestimation is 76%
      (95% confidence interval 73 to 78%). Ignoring the consequences of regression
      dilution can also lead to error in the assessment of other risk markers, even
      those measured precisely. CONCLUSIONS: The importance of risk factors for CHD can
      be greatly underestimated by using a single baseline measure in prospective study
      analyses. Studies that wish to estimate associations between disease risk and
      usual exposure levels need to take regression dilution effects into account.
      Failure to do so can lead to serious misinterpretation of the importance of CHD
      risk factors.

PMID- 15187817
TI  - Is hypoglycaemia a marker for increased long-term mortality risk in patients with
      coronary artery disease? An 8-year follow-up.
AB  - BACKGROUND: No information is available regarding the association between low
      plasma glucose levels and cause-specific and all-cause mortality in patients with
      coronary artery disease (CAD). We aimed to investigate the relationship between
      hypoglycaemia and all-cause, cardiovascular and cancer mortality in a large
      population of patients with CAD. DESIGN: Patients were recruited from the BIP
      (Bezafibrate Infarction Prevention) registry, a secondary prevention prospective
      multicentre randomized, placebo-controlled, double-blind trial aimed to assess
      the efficacy of bezafibrate in reduction of coronary events. METHODS: The study
      included 14,670 CAD patients aged 45-74, divided into six groups: (1)
      hypoglycaemic (up to 69 mg/dl); (2) low normal (70-79 mg/dl); (3) euglycaemic (80
      109 mg/dl); (4) impaired fasting glucose (IFG) (110-125 mg/dl); (5) borderline
      diabetics (126-139 mg/dl); (6) diabetics (> or 140 mg/dl). RESULTS: Patients
      comprised 131 with hypoglycaemia (0.9%), 731 with low normal glucose (5%), 9308
      euglycaemic (63.4%), 1577 with IFG (10.7%), 617 borderline diabetics (4.2%) and
      2306 diabetics (15.7%). Over a mean 8-year follow-up, crude all-cause mortality
      was higher in both diabetic (31.8%) and hypoglycaemic groups (25.2%) as compared
      with euglycaemics (14.9%; P<0.0001); CAD mortality was higher in diabetic and
      borderline groups (17.8 and 13.3%, respectively, versus 7.9% in euglycaemics;
      P<0.0001). The highest prevalence of cancer mortality was documented in the
      hypoglycaemic group (6.1 versus 2.9% in euglycaemics; P<0.02). Actuarial survival
      curves showed the lowest mortality in euglycaemic and low normal groups; the
      highest was seen in diabetic and hypoglycaemic patients. Intermediate values were
      found in borderline and IFG patients. After adjustment for variables, a
      significantly higher mortality rate was seen in hypoglycaemics when compared with
      euglycaemics (P<0.0001). Hypoglycaemia was identified as a predictor of increased
      all-cause and cancer mortality with a hazard ratio (HR) of 1.84 [95% confidence
      interval (CI) 1.29-2.61] and 2.26 (95% CI 1.12-4.57), respectively, but not of
      increased CAD mortality, with HR 1.30 (95% CI 0.73-2.29). CONCLUSIONS: Over a
      mean 8-year follow-up, hypoglycaemia emerges as a marker for substantially
      increased all-cause and cancer mortality among patients with CAD presenting with
      low fasting glucose levels.

PMID- 15187818
TI  - Supplementation of wheat fibre can improve risk profile in patients with
      dysmetabolic cardiovascular syndrome.
AB  - OBJECTIVES: We explored the effects of regular consumption of wheat fibre in
      patients with dysmetabolic cardiovascular syndrome (MCVS). SUBJECTS AND METHODS:
      Forty-two patients with MCVS (mean age 49+/-8 years) were randomly assigned to a
      treated group (n=21) or to a control group (n=21). Patients in the treated group
      ate 10.5 g of wheat fibre powder per day for the first week, followed by 21 g per
      day for the next 4 weeks. A standard high-fibre diet was recommended to both
      groups. Blood pressure, metabolic parameters, fibrinolytic parameters and factor
      VII activity were measured at entry and after 5 and 9 weeks. RESULTS: After
      completing treatment, patients from both groups lost an average of 1 kg weight.
      Consumption of wheat fibre resulted in a significant (P<0.05) decrease of
      systolic and diastolic blood pressure, fasting glucose, glucose 2 h after oral
      glucose challenge (OGC), total cholesterol, low-density and high-density
      lipoprotein cholesterol, ranging from 7% to 18%. Furthermore, no significant
      reductions in fasting insulin, insulin 1 and 2 h after OGC, and glucose 1 h after
      OGC were found, whereas no differences in fibrinolytic parameters and factor VII
      activity were observed. Almost all beneficial effects of wheat fibre diminished 4
      weeks after its withdrawal. In the non-treated group only a significant decrease
      of systolic pressure was observed. CONCLUSIONS: Our results suggest that
      supplementation of wheat fibre, not just a standard high-fibre diet, may improve
      cardiovascular risk profile in patients with MCVS, in a manner independent of
      weight reduction.

PMID- 15187819
TI  - Effect of ascorbic acid on forearm reactive hyperaemia in patients with
      hypercholesterolaemia.
AB  - BACKGROUND: This study was designed to research the effect of
      hypercholesterolaemia and ascorbic acid on forearm blood flow (FBF) reactive
      hyperaemia (RH). Reactive hyperaemia seems to be at least partly endothelium
      dependent. Endothelial dysfunction has been described in patients with
      hypercholesterolaemia, and has been reversed with ascorbic acid administration.
      METHOD: Forearm blood flow was studied with venous occlusion plethsmography in 26
      healthy volunteers and 46 hypercholesterolaemic patients. Hypercholesterolaemic
      patients were divided into two groups. Group A comprised 25 patients, who
      received ascorbic acid and group B comprised 21 patients, who received placebo.
      All subjects underwent measurement of FBF at baseline and during RH (phase A).
      Forearm blood flow during RH was measured every 15 seconds for three minutes.
      Subsequently patients in group A received 2 g of ascorbic acid orally in the form
      of effervescent tablets, and patients in group B received placebo orally in the
      same form. Forearm blood flow measurements at baseline and during RH were
      repeated two hours later (phase B). RESULTS: Maximal percent increase of FBF was
      significantly higher in healthy subjects than in hypercholesterolaemic patients
      (139.1+/-12.1% versus 73.1+/-11.0% respectively, P<0.05). Duration of RH was
      smaller in hypercholesterolaemic patients compared to normal subjects (60.9+/
      17.1 seconds versus 105.6+/-10.2 seconds, P<0.05). Administration of ascorbic
      acid but not of placebo increased the duration of RH (69.1+/-11.1 seconds versus
      104.1+/-12.2 seconds, P<0.05) but not of peak RH FBF. CONCLUSION:
      Hypercholesterolaemia seems to impair both the early and late phase of RH.
      Ascorbic acid improves only the duration of RH, possibly due to its antioxidant
      effect on endothelium.

PMID- 15187820
TI  - Functional and morphological skeletal muscle abnormalities correlate with reduced
      electromyographic activity in chronic heart failure.
AB  - BACKGROUND: Exercise intolerance and early muscle fatigue are key symptoms in
      patients with chronic heart failure (CHF). In advanced stages of the disease,
      profound metabolic abnormalities have been described finally leading to a
      catabolic state with progressive loss of muscle bulk. The aim of this study was
      to investigate morphological, functional and electromyographical parameters of
      the skeletal muscle in CHF. METHODS: We included 17 patients with CHF and 12 age
      matched healthy controls (left ventricular ejection fraction 25+/-2 versus 68+/
      1%, body mass index 26.6+/-0.8 versus 28.0+/-1.0 kg/m2; P=NS) in this study.
      Cross-sectional area (CSA) of the thigh was assessed by computed tomography.
      Under electromyographical control, maximal and submaximal (30%) isometric
      strength as well as the relative decrease of muscle strength of the quadriceps
      muscle over a period of 20 s were determined. RESULTS: Patients with CHF showed a
      significant reduction of muscle CSA (134.8+/-5.3 versus 165.2+/-7.4 cm2, P=0.002)
      as compared with healthy controls. The maximal quadriceps muscle strength was
      found to be significantly reduced in patients with CHF (226.7+/-22.3 versus
      286.9+/-17.1 N, P<0.05) who also exhibited a higher extent of muscular
      fatigability (-2.18+/-0.33 versus -0.54+/-0.20 N/s, P<0.01). Electromyographic
      activity at 30% submaximal contraction showed a lower increase in patients with
      CHF (66+/-22 versus 114+/-36%; P<0.05) indicating impaired muscle fibre
      recruitment. Furthermore, a significant correlation between muscular fatigability
      and reduced electromyographic activity was found in CHF (r=0.84; P<0.001).
      CONCLUSIONS: Our findings demonstrate an impaired electromyographic activity and
      muscular function in patients with CHF suggesting a new pathomechanism
      contributing to functional abnormalities of the skeletal muscle in advanced
      stages of this disease.

PMID- 15187821
TI  - Effect of exercise training in patients with heart failure: a pilot study on
      autonomic balance assessed by heart rate variability.
AB  - BACKGROUND: Heart rate variability (HRV) is decreased in patients with congestive
      heart failure (CHF) and is a prognostic marker in this disease. Exercise training
      is now regarded as an important part of the treatment of patients with CHF, but
      the effect on HRV and the association between this effect and the effect on
      neurohormones are not well assessed. METHODS: Heart rate recording was performed
      in 12 patients with CHF (mean age 67+/-8 years) with CHF NYHA functional class
      III, before and after 12 weeks of exercise training. The association with
      exercise capacity and serum levels of atrial natriuretic peptide was assessed. We
      also evaluated the correlation between HRV and survival at follow-up 87 months
      later. RESULTS: At baseline there was a significant correlation between mean
      heart rate and work performed during max cycle test (r=0.650, P=0.022) and the
      HRV parameter standard deviation normal to normal (SDNN) (r=0.678, P=0.015).
      After exercise training there was a significant increase in work performed
      (30.3+/-14.2 versus 38.1+/-14.1 kJ), 6-min walk test (502+/-88 versus 552+/-59 m,
      P=0.006) and SDNN (117.3+/-40.7 versus 128.6+/-42.3 ms, P=0.028). At 87 months of
      follow-up, there was a borderline significant difference between survivors and
      non-survivors. Only the survivors had a significant increase in SDNN after
      exercise training. CONCLUSION: This pilot study demonstrates an improvement with
      regard to parameters for HRV after exercise training in patients with CHF. The
      study suggests that the positive effect of exercise training in patients with CHF
      involves an attenuation of the reduced HRV response, and that this improvement
      might have prognostic significance.

PMID- 15187822
TI  - Editorial comment on effect of exercise training in patients with heart failure.

PMID- 15187825
TI  - Advances in surgery and molecular medicine.

PMID- 15187823
TI  - Cardiorespiratory adaptations during the six-minute walk test in chronic heart
      failure patients.
AB  - BACKGROUND: The six-minute walk test (6-MWT) is widely used to assess exercise
      tolerance in chronic heart failure patients (CHF). The aim of this study was to
      analyse cardiorespiratory parameters kinetics during the 6-MWT in CHF and in
      healthy subjects. METHODS: A treadmill, symptom-limited exercise test and a 6-MWT
      were performed by 14 CHF under optimal drug treatment (CHFD), 17 CHF with cardiac
      resynchronization (CHFP), and 12 healthy subjects. Cardiorespiratory responses
      were assessed by a validated portable system. RESULTS: All subjects exceeded
      their ventilatory threshold during the 6-MWT. Healthy subjects and CHF performed
      the 6-MWT around 75 and 90% of peak oxygen uptake (V'O2) respectively (P<0.001).
      In CHF, a steady state was observed only for walking speed and V'O2, with a
      slight delay in comparison with healthy subjects, for whom a steady state was
      also observed for carbon dioxide production and ventilation (V'E). During the 6
      MWT, the V'E adaptation was due mainly to an increase in tidal volume (VT) in
      CHFD, whereas in CHFP, it was due to a similar increase in VT and breathing
      frequency (f). In these patients, the 6-MWT VT/f slope was lower than in CHFD
      (P<0.01). CONCLUSIONS: During the 6-MWT, the V'O2 steady state is slightly
      delayed in CHF, which could be related partly to their higher exercise intensity.
      Moreover, each CHF group is characterized by a specific ventilation components
      response during the 6-MWT.

PMID- 15187826
TI  - On the nature and treatment of the primary effects of injuries. 1837.

PMID- 15187827
TI  - Early versus delayed stabilization of femoral fractures: a prospective randomized
      study. 1989.

PMID- 15187828
TI  - Trauma system development in North America.
AB  - The concepts of organized trauma care, many of which originated in military
      medicine, have been proven effective in the civilian sector. A formal trauma
      system includes all phases of care from prehospital through rehabilitation.
      Although trauma centers assume the leadership role, in a truly inclusive system,
      all healthcare providers (prehospital providers, community hospitals, and trauma
      centers) have a defined role in providing care to patients with trauma. As a
      result, patients receive treatment at the appropriate institution, resources are
      allocated appropriately, and the clinical outcome is optimized. Such a system
      ideally is suited to the unique needs of the mass casualty scenario.

PMID- 15187829
TI  - Level I center triage and mass casualties.
AB  - The world has been marked by a recent series of high-profile terrorist attacks,
      including the attack of September 11, 2001, in New York City. Similar to natural
      disasters, these attacks often result in a large number of casualties
      necessitating triage strategies. The end of the twentieth century was marked by
      the development of trauma systems in the United States and abroad. By their very
      nature, trauma centers are best equipped to handle mass casualties resulting from
      natural and manmade disasters. Triage assessment tools and scoring systems have
      evolved to facilitate this triage process and to potentially reduce the morbidity
      and mortality associated with these events.

PMID- 15187830
TI  - Initial care of the patient with blunt polytrauma.
AB  - The initial care of the patient with blunt polytrauma involves a systematic
      search for causes of hemodynamic instability. Bleeding most often occurs in the
      pleural space, peritoneal cavity, and retroperitoneum. Orthopaedic injuries also
      can contribute to instability after blunt trauma. Blood loss from open fractures
      may be substantial, and exposure with direct vessel control should be performed
      early. Pelvic fractures can be associated with severe retroperitoneal bleeding.
      The treatment of patients with complex pelvic fractures includes closing the
      pelvic space with a binding device, and early pelvic angiography with
      embolization. Care of patients with multiple organ and bone injuries requires
      coordination by one trauma team leader. This physician oversees the resuscitation
      and sets treatment priorities, including the type and amount of time allowed for
      fracture stabilization. In many cases, nonorthopaedic injuries will need to be
      addressed before definitive fracture care. However, optimal care typically
      involves a coordinated multispeciality approach that sometimes includes
      concurrent operative procedures. Patients with severe physiologic derangements
      may require damage control techniques to decrease blood loss and operative time.
      Understanding the overall care of patients who are injured critically will
      facilitate the integration of the orthopaedic surgeon into the trauma team.

PMID- 15187831
TI  - Fluid resuscitation and blood replacement in patients with polytrauma.
AB  - Hemorrhage is the most common cause of shock in patients with polytrauma, leading
      to cellular hypoxia and death. A large body of experimental and clinical research
      has greatly expanded our knowledge of cellular mechanisms and clinical outcomes
      in resuscitation of patients with hypovolemic shock. However, the fundamental
      principles of fluid resuscitation have not changed during the past few decades.
      Aggressive resuscitation to correct tissue hypoperfusion within 24 hours of
      injury is associated with improved clinical outcomes. Initial volume expanders of
      choice are crystalloid solutions, with blood and blood products used for patients
      who are hemodynamically unstable, patients with Class III and Class IV
      hemorrhage, and patients with ongoing uncontrolled sources of bleeding. The
      incidence of immunologic and infectious complications associated with blood
      transfusions in resuscitation of patients with polytrauma has not been shown to
      be any higher than in other clinical settings. Massive resuscitations, however,
      are associated with specific complications such as hypothermia, coagulopathy, and
      abdominal compartment syndrome. Novel blood substitutes, hypertonic saline, and
      minimally invasive hemodynamic monitoring techniques have the potential of
      optimizing fluid resuscitation in patients with polytrauma. Additional research
      using standardized animal models and randomized clinical trials is needed.

PMID- 15187832
TI  - Evaluation and treatment of spinal injuries in the patient with polytrauma.
AB  - Spinal injuries occur frequently in the patient with polytrauma making the
      knowledge of the evaluation and treatment of these injuries invaluable to the
      trauma team. In the immediate moments after these injuries, critical steps can be
      taken to prevent additional injury and insure maximum neurologic and functional
      recovery of the patient. A simple, standardized approach to treating the patient
      at the scene, examining the patient in the trauma admitting area, ordering
      appropriate radiographic studies, and instituting early treatment can markedly
      influence a patient's maximal recovery. Furthermore, background knowledge in the
      classification and ultimate treatment goals allows for an effective communication
      between the initial treating team and the spinal surgeons involved. The work on
      indicators of potential spinal instability by White and Panjabi and the three
      column classification of spinal injuries of Denis lends insight to the potential
      consequences of spinal trauma. A thorough appreciation of these concepts puts
      evaluation and treatment of these injuries into a logical framework with which
      spinal injuries initially can be approached.

PMID- 15187833
TI  - Skeletal injury patterns in older females.
AB  - Injury patterns in elderly patients are different from those in younger patients.
      With recent emphasis on osteoporosis and its effects, we looked at a continuous
      series of patients from one Level 1 trauma center regarding injury patterns by
      gender. For all patients older than 65 years, and including all mechanisms, older
      women were more likely to sustain forearm and wrist fractures than were older
      men. For the individual mechanism of motor vehicle collision there was a
      significant increase in the extremity Abbreviated Injury Scores in older women
      compared with older men. Similarly, older women were more likely to sustain lower
      leg fractures and distal upper extremity fractures than were older men. This
      raises the possibility that increased bone loss, as seen in older women, may be
      reflected in the injury patterns they sustained given the same mechanism. More
      work is warranted in this region to potentially diminish these effects.

PMID- 15187834
TI  - Cytokines in patients with polytrauma.
AB  - Patients with multiple injuries have alterations in hemodynamic, metabolic, and
      immune responses that largely are orchestrated by endogenous mediators referred
      to as cytokines. At the molecular level cytokines act as architects constructing
      a blueprint which ultimately will become the clinical "Big Picture"; however, the
      exact role and extent each cytokine has is still in question. In addition, the
      surface of research opportunities has nearly been scratched regarding the best
      way to control or manipulate the cytokine response in efforts to improve care for
      the trauma patient. Systemically organisms respond to injury regardless of the
      cause (hemorrhage, ischemia, reperfusion, fracture, and tissue damage) by
      attempting to restore homeostasis, which involves a coordination of the immune,
      cardiovascular, endocrine, and nervous systems. This systemic response can result
      in severe immunologic compromise that threatens the survival of patients with
      trauma. It seems that it is this balance or imbalance of cytokines, along with
      other associative factors, that controls the eventual clinical pathway a patient
      will take. Blood mediator concentrations often parallel the inflammatory process,
      and high levels of cytokines can be followed by severe organ dysfunction. Certain
      cytokine levels, such as the interleukins, can be used in predictive ways to
      correlate organ failure in multiply injured patients. Although much more research
      must be done, there is great promise in the study of cytokines through basic
      science research and clinical trials.

PMID- 15187835
TI  - Pulmonary aspects of treatment of long bone fractures in the polytrauma patient.
AB  - During the past decade, there have been significant advances in the treatment of
      long bone fractures in the polytraumatized patient. The major controversy in this
      area is whether definitive long bone stabilization needs to be done emergently.
      In general, definitive fixation should be done early in the patient's hospital
      course after it is determined that the patient is hemodynamically stable and is
      resuscitated adequately. The major benefits of fixation are: (1). improve
      mobilization to enhance pulmonary function; (2). decreased narcotic requirements
      with improved pain control after fixation; and (3). early aggressive fluid
      resuscitation associated with operative intervention. Patients with multisystem
      injury who are underresuscitated or are unstable should have early external
      fixation because temporizing skeletal stabilization until definitive fixation can
      be done.

PMID- 15187836
TI  - Femur fractures and lung complications: a prospective randomized study of
      reaming.
AB  - Reaming the intramedullary canal during fixation of femoral shaft fractures may
      contribute to pulmonary morbidity in patients with trauma. The purpose of our
      study was to compare acute and late pulmonary complications after reamed or
      nonreamed nailing of femur fractures. Patients who had femoral shaft fractures
      were randomized prospectively to a reamed (n = 41) or nonreamed (n = 41) femoral
      nailing group. Arterial blood gases were measured before and after femur
      fixation. Ratios of PaO2/FiO2 and alveolar arterial gradients were calculated.
      Pulmonary complications (acute respiratory distress syndrome) (ARDS), pneumonia,
      and respiratory failure) were monitored. Age, gender, fracture site, fracture
      type, time to nailing, length of operation, Injury Severity Score, and
      Abbreviated Injury Scale-thorax were similar for the two groups. No significant
      differences were observed in the ratio of PaO2/FiO2 ratios or alveolar arterial
      (A-a) gradients before and after nailing. The overall incidence of pulmonary
      complications was 14.6% (eight patients who had reamed nailing and four patients
      who had nonreamed nailing), and given the sample size, definitive conclusions
      could not be reached because of inadequate statistical power. We were unable to
      document differences in pulmonary physiologic response or clinical outcome
      between patients having reamed and nonreamed femoral nailing. This study may
      serve as a pilot investigation for other clinical investigations.

PMID- 15187837
TI  - Mass casualties in the Oklahoma City bombing.
AB  - The Alfred P. Murrah Federal Building in Oklahoma City was partially destroyed by
      a terrorist bomb on April 19, 1995. Injuries were sustained by 759 people, 168 of
      whom died. Fatalities occurred primarily among victims in the collapse zone of
      the federal building. Only 83 survivors required hospitalization. Twenty-two
      surviving victims sustained multiple fractures. Most victims arrived at local
      emergency departments by private vehicle within 2 hours. More severely injured
      survivors were transported by ambulance. The closer receiving hospitals used
      emergency department facilities and minor treatment areas. Few survivors were
      extricated from the bombing site more than 3 hours after the detonation. Mass
      casualty plans must provide for improved communications, diversion and retriage
      from facilities nearest the disaster site, and effective coordination of
      community and hospital resources.

PMID- 15187838
TI  - Terrorism and blast phenomena: lessons learned from the attack on the USS Cole
      (DDG67).
AB  - Blast phenomena and injuries to the musculoskeletal system have been well
      documented for the past 50 years. The USS Cole was attacked in Aden Harbor in
      Yemen on October 12, 2000. Seventeen sailors were killed and 39 were wounded. The
      bombing of the USS Cole and an analysis of the pattern of injury are unique
      compared with previous terrorist bombing attacks in which the predominant injury
      pattern is from Type II and Type III blast phenomena. Because the ship
      superstructure did not collapse, there were no confounding variables in examining
      the pattern of injury as there would have been with shrapnel-generating devices
      or detonations with subsequent building collapse. The morbidity and mortality
      sustained by the victims was almost exclusively from Type I and Type III blast
      effects. The musculoskeletal system was a clear marker for mortality and
      morbidity. Fractures of the cranium, spine, pelvis, and long bones denoted
      increasing severity of injury to critical organ systems. Shipboard firefighting
      was successful in containing fires and there was very little morbidity from
      inhalational injuries or burns. Blast phenomena that affect ships or buildings
      that have been specifically built to absorb a blast attack likely will manifest a
      different mode and pattern of injury than those seen in traditional terrorist
      blast events.

PMID- 15187839
TI  - Treatment of the mangled lower extremity after a terrorist blast injury.
AB  - Terrorist bombings, with resultant blast injuries, have been increasing in
      frequency during the past 30 years. Injury to the musculoskeletal system is
      common in victims who survive such attacks. Substantial injury to the limbs may
      occur through several different mechanisms, each of which may affect prognosis
      and alter the treatment algorithm. An analysis of the available literature on
      terrorism and blast events revealed that resource use of the treating medical
      facility is high during the initial hours after a blast attack, but usually is
      manageable. A resource management protocol was developed to organize the
      treatment of limb salvage into four phases. This management protocol may improve
      the medical facility's ability to manage system resources while treating patients
      with severe blast injuries. The decision of whether to salvage or proceed with
      limb amputation is one of the most difficult in orthopaedic trauma. A basic
      education in the mechanisms of blast damage, a methodical approach to
      resuscitation, and mangled extremity treatment, likely can improve surgical
      success.

PMID- 15187840
TI  - Blast injury research: modeling injury effects of landmines, bullets, and bombs.
AB  - Terrorist blasts and landmine injuries have become more common in the past
      several decades generating thousands of casualties. Preventive and prognostic
      measures are limited by the lack of knowledge of these complex events. Previous
      blast research has focused on primary blast injuries that involve the lung,
      despite musculoskeletal injuries being the most common. Through the use of
      instrumented cadavers, Hybrid III test dummies, and other surrogates, unique
      models of these events have been created. The investigations studied the
      effectiveness of antimine footwear, forces and injury mechanisms in temporary
      shelters subjected to blast, modeling of blast-induced glass fragmentation, and
      helmet deformation and injury potential under ballistic load. Despite blasts
      being much higher rate events than those seen in automotive blunt trauma, we were
      able to measure forces and create injury models. We found that antimine footwear
      will require additional development to be effective. Guidelines for shelter
      placement have been altered, and tempered glass seems to offer no protection when
      compared with annealed glass. Although these models are in their nascent phase,
      the thorough understanding of the biomechanical nature of these blast injuries
      will assist in developing strategies to reduce injuries and in the creation of
      forecasting models.

PMID- 15187841
TI  - Planning for mass civilian casualties overseas: IMSuRT-International
      Medical/Surgical Response Teams.
AB  - The increased likelihood of mass casualties involving Americans living abroad has
      prompted the development of a mobile, civilian medical and surgical unit
      available for rapid deployment overseas. Using past experience derived from the
      National Disaster Medical Service, and from recent rescue efforts following the
      African embassy bombings in 1998, an International Medical-Surgical Response Team
      was developed. Organized under the Department of Homeland Security, it is staffed
      by civilian professionals from medical and bioengineering fields. Initial
      deployments to the World Trade Center (2001) and Guam (2002) have shown the
      ability to rapidly mobilize appropriate manpower and equipment to a mass casualty
      site, whether domestic or international. The goals of this organization are to
      work in cooperation with local authorities at the mass casualty site to provide
      rapid assessment and medical stabilization of injured persons. When the mass
      casualty is overseas, rapid evacuation of casualties is accomplished by the
      responding military air evacuation service.

PMID- 15187844
TI  - Leonard F. Peltier, MD, PhD, 1920-2003.
AB  - Leonard F. Peltier, MD, PhD, was an orthopaedic surgeon, academician,
      administrator, laboratory investigator, historian, and mentor. His career spanned
      nearly six decades, beginning with graduate education at the University of
      Minnesota (UM) under the auspices of Owen H. Wangensteen, MD, PhD. In addition to
      obtaining a PhD in physiology in the UM Graduate School, he completed general and
      orthopaedic surgery residencies and attained board certification in each
      specialty. He served in the US Army Occupation Force Medical Corps in Germany
      just after World War II. In 1957, at 37 years old, he assumed the chairmanship of
      the orthopaedic training program at the University of Kansas. In 1971, he
      couldn't resist the opportunity to become one of the founding members of the
      "start-up" University of Arizona College of Medicine, accepting an appointment as
      chair of the new orthopaedic training program, where he remained until his
      retirement in 1990. He took clinical problems to the laboratory, and made
      important scientific contributions, particularly in the area of fat embolism and
      in using calcium sulfate (plaster of Paris) to fill bone defects. He served on
      governing boards of national professional organizations and presided over the
      American Association for the Surgery of Trauma from 1980-1981. Throughout his
      career, he was fascinated by, and published extensively in, the history of
      medicine arena. Known fondly as "the professor" to many of his residents and
      colleagues, he had a pragmatic, honest, upbeat, and often humorous approach to
      life's challenges, valuing personal integrity above other virtues. He explored
      various eclectic interests far beyond his professional contributions while
      maintaining his family as a central priority. With his exemplary productivity and
      interests in the surgical and laboratory sciences, history of medicine,
      appreciation of fine arts, and perceptive and effective interactions with family,
      friends, patients, and colleagues, the memory of Leonard Peltier evokes the image
      of a modern-day Renaissance man.

PMID- 15187842
TI  - Organizing the orthopaedic trauma association mass casualty response team.
AB  - Physicians and surgeons in the United States have become increasingly aware of
      the requirement for an organized response to mass casualty and disaster
      situations. This has not always been the case. The terrorist acts in Oklahoma
      City in 1995 and at the World Trade Center in 1993 and 2001 showed the
      inefficiencies and confusion of the civilian managed disaster response. Trauma
      surgeons are uniquely suited to play a leadership role in the planning and
      coordination of disaster care because of their integration in prehospital
      emergency medical systems and trauma centers. The Orthopaedic Trauma Association
      has developed strategies to facilitate the orthopaedic response to mass
      casualties and to develop an educated approach to disaster management. The
      current initiatives include the establishment of a link with the American College
      of Surgeons Committee on Trauma in addition to the development of training
      programs for orthopaedic surgeons as responders to disaster and mass casualty
      situations. A team of volunteer orthopaedic traumatologists also has been
      credentialed to become part of the National Disaster Medical System's
      International Medical-Surgical Response Team.

PMID- 15187845
TI  - Fractures and dislocations of the spine complicating ankylosing spondylitis: a
      report of six cases. 1967.

PMID- 15187846
TI  - Acute knee dislocations and their complications. 1969.

PMID- 15187847
TI  - The treatment of fractures of the femur in patients with head injuries. 1973.

PMID- 15187848
TI  - Treatment of unicameral bone cysts by curettage and packing with plaster-of-Paris
      pellets. 1978.
AB  - Long-term follow-up of twenty-six patients with unicameral bone cysts treated by
      curettage and packing with plaster-of-Paris pellets showed a recurrence in only
      two cases and no serious complications.

PMID- 15187850
TI  - Risk factors for pulmonary emboli after total hip or knee arthroplasty.
AB  - Because it is difficult to predict which patients may sustain a pulmonary
      embolism after total hip or knee arthroplasty, we assessed multiple thrombophilic
      and hypofibrinolytic parameters to identify risk factors. Twenty-nine patients
      who survived a known pulmonary embolism after total knee or total hip
      arthroplasty were matched by age, gender, race, arthritic diagnosis, procedure,
      and surgery date with 29 patient-controls who had a total hip or knee
      arthroplasty but who did not have a symptomatic known pulmonary embolism or deep
      vein thrombosis. Twenty-one serologic measures and five genes associated with
      thrombophilia, hypofibrinolysis, or both were assessed without knowledge of group
      assignment. All patients with pulmonary embolism had at least one abnormality of
      plasminogen activator inhibitor activity, dilute Russell's viper venom time,
      prothrombin time, or total cholesterol versus 13 of 27 (48%) control patients.
      Forty-seven percent of patients who experienced pulmonary embolism had at least
      two abnormalities of plasminogen activator inhibitor activity, dilute Russell's
      viper venom time, prothrombin time, or total cholesterol, versus 7% of control
      patients. Preoperatively, to identify patients at high risk of pulmonary
      embolism, plasminogen activator inhibitor activity, dilute Russell's viper venom
      time, prothrombin time, and cholesterol levels were most predictive. Using at
      least one abnormality of these four measures as a screening test to detect risk
      of pulmonary embolism, the test is sensitive (100%), and the predictive value of
      a negative test is high (100%). After additional prospective study, this may
      allow identification of patients at low risk (the majority of patients) in whom
      anticoagulation may not be required and a small group of patients at high risk
      for pulmonary embolism in whom prophylactic anticoagulation should be provided.

PMID- 15187851
TI  - Dislocation after long-necked total hip arthroplasty.
AB  - Dislocation after total hip arthroplasty is problematic and not completely
      understood. Skirted long-necked implants have been used to reestablish soft
      tissue tension with the assumption that their use will reduce dislocation. It is
      unknown whether the dislocation rates with long-necked implants are different
      than those with standard neck length devices. The records of 250 consecutive
      total hip arthroplasties were reviewed, 125 primary and 125 revision, in which
      long-necked femoral prostheses were used. A matched control sample with standard
      neck length prostheses was defined. Dislocation rates and radiographic indices of
      leg length were calculated and compared with the control group. Dislocation rates
      in the long-necked groups were 10.6% and 18% for primary and revision surgeries,
      respectively. These rates were significantly higher than the rates seen in
      standard neck length controls (1.6% and 10%, respectively). There was no
      difference in leg-length discrepancy between long-necked prostheses and standard
      neck length matched controls. Long-necked prostheses are associated with higher
      rates of dislocation after total hip arthroplasty. The higher rates may be
      attributable to impingement of the neck, inadequate restoration of soft tissue
      tension, and/or other factors. Although this study cannot claim to have shown a
      cause and effect relationship between the skirted neck and dislocation, the
      association between the two variables is clearly shown.

PMID- 15187852
TI  - Computed tomography to assess pelvic lysis after total hip replacement.
AB  - To assess the accuracy of a computer-assisted computed tomography image analysis
      program in determining the location and volume of periacetabular osteolysis, we
      designed an osteolysis model by implanting bilateral total hip replacements in
      human pelvic cadavers and creating osteolytic lesions of varying sizes. The
      volumes of 48 defects were measured physically, and axial computed tomography
      scans were obtained. The computed tomography images were processed with streak
      artifact reduction and segmentation algorithms. The location and volume of
      lesions were determined from these images. Eighty-one percent (39 lesions) were
      identified correctly from the computed tomography scans. Detection was location
      dependent. More lesions were detected in the ilium (100%) and at the rim (89%)
      than in the ischium (78%) or the pubis (50%). Computed tomography overestimated
      lesion volume by a mean of 0.5 +/- 2.3 cm. The volumetric error was unrelated to
      lesion location but was dependent on lesion size. As lesion size increased above
      10 cm, the mean percentage error decreased to 1.8%. Computed tomography image
      analysis can be used more accurately than plain radiographs to investigate the
      effectiveness of treatment and the natural history of pelvic osteolysis.

PMID- 15187853
TI  - Increased external tibial torsion and osteochondritis dissecans of the knee.
AB  - In the past, osteochondritis dissecans of the knee was associated with increased
      tibial exotorsion, established with a clinical measuring method. Now the gold
      standard for determining tibial torsion is computed tomography. The aim of the
      current study was to establish whether the abovementioned association could be
      confirmed in the current patients, measured with computed tomography. Confounding
      aberrations of femoral torsion were ruled out. Twenty-three patients with
      osteochondritis dissecans in 27 knees were treated between 1991 and 1999.
      Symptoms and treatment results were comparable with those reported in the
      literature. Femoral and tibial torsion were measured with a computed tomography
      scan. The average femoral antetorsion was comparable with that in the literature.
      The average tibial exotorsion was significantly higher than the control value.
      Exotorsion was increased more in patients with bilateral osteochondritis, and
      extremely high in patients with persisting complaints. Increased tibial
      exotorsion could play a role in development of osteochondritis dissecans of the
      knee. Extreme exotorsion might be prognostic for persistent complaints.

PMID- 15187854
TI  - Midterm results of a modified evans repair for chronic lateral ankle instability.
AB  - Twenty-eight ankles in 27 patients with chronic instability were treated with a
      modification of the Evans procedure during a 10-year period. The diagnosis was
      assessed by clinical evaluation and radiographic stress tests. The reconstruction
      procedure consists of using the peroneal brevis tendon to repair ankle
      instability and restore the loss of anatomic integrity of the injured structures.
      Twenty-five patients (26 ankles) were available at a mean followup of 99.6 months
      or 8.3 years (range, 28-117 months). Midterm results were evaluated using the
      ankle-hindfoot score of the American Orthopaedic Foot and Ankle Society, and
      postoperative radiographic stress tests. According to this scoring system, the
      current reconstruction procedure resulted in 92.64 points (range, 63-100 points).
      However, moderate restriction in hindfoot inversion was seen in nine patients
      (34.61%). Three ankles (11.5%) had a positive anterior drawer sign (> 8 mm). In
      five ankles (19.2%), there were mild degenerative joint changes. Therefore, the
      current reconstruction method led to a satisfactory clinical and functional
      midterm outcome shown by a numeric scale.

PMID- 15187855
TI  - Gamma probe assisted biopsy of suspected metastatic rib lesions.
AB  - Retrieving diagnostic tissue from a rib lesion can be challenging. Using a hand
      held intraoperative gamma probe to target and biopsy the areas of increased
      radioisotope uptake has been limited largely to use by thoracic surgeons and
      interventional radiologists. Such techniques also have been used by orthopaedic
      oncologists in localizing osteoid osteomas. We pursued a similar technique in
      localizing the rib lesion. During the 10 months, two patients with a history of
      cancer and recent bone scans indicative of possible rib metastasis required
      biopsies for definitive tissue diagnosis. Both patients had gamma-probe
      localization of their rib lesions intraoperatively using minimally invasive
      techniques. The operation of the probe was simple with a short learning curve.
      Both patients had biopsies that yielded diagnoses verifying the abnormality on
      the staging bone scan. Localization was sensitive and accurate with histologic
      confirmation in both patients. The length and extent of surgery were markedly
      reduced with no complications. These results match those reported in the
      literature by thoracic surgeons and radiologists. The hand-held gamma probe
      assisted biopsy of suspicious rib abnormalities can be an effective surgical
      technique that the orthopaedic surgeon should consider. Additional experience
      with the technique will allow an assessment of the sensitivity and specificity.

PMID- 15187856
TI  - Insufficiency fracture of the body of the calcaneus in elderly patients with
      osteoporosis: a report of two cases.
AB  - Two cases of insufficiency fracture of the body of the calcaneus are presented to
      show its clinical presentation and diagnosis. It often is overlooked as a cause
      of pain in the ankle region. Both patients were elderly women with pain
      developing at the lateral aspect of the hindfoot in the absence of significant
      trauma. Physical examination was significant for marked tenderness at the
      superolateral aspect of the calcaneus. These clinical features suggested the
      diagnosis, which was confirmed by radionuclide bone scan and magnetic resonance
      imaging. Magnetic resonance imaging was the diagnostic tool in both cases, after
      abnormal bone scans and normal plain radiographs. Radiologic alterations were not
      seen for up to 2 months after the onset of pain. Treatment consisted of rest and
      protected weightbearing for 8 weeks, with complete resolution of symptoms in both
      patients. An insufficiency fracture of the body of the calcaneus should be
      considered in a differential diagnosis of elderly patients with osteoporosis with
      spontaneous pain in the ankle region.

PMID- 15187857
TI  - Effect of postoperative delirium on outcome after hip fracture.
AB  - Nine-hundred twenty-one community-dwelling patients 65 years of age or older, who
      sustained an operatively treated hip fracture from July 1, 1987 to June 30, 1998
      were followed up for the development of postoperative delirium. The outcomes
      examined in the current study were postoperative complication rates, in-hospital
      mortality, hospital length of stay, hospital discharge status, 1-year mortality
      rate, place of residence, recovery of ambulatory ability, and activities of daily
      living 1 year after surgery. Forty-seven (5.1%) patients were diagnosed with
      postoperative delirium. Patients who had delirium develop were more likely to be
      male, have a history of mild dementia, and have had surgery under general
      anesthesia. Patients who had postoperative delirium develop had a significantly
      longer length of hospitalization. They also had significantly higher rates of
      mortality at 1 year, were less likely to recover their prefracture level of
      ambulation, and were more likely to show a decline in level of independence in
      basic activities of daily living at the 1-year followup. There was no difference
      in the rate of postoperative complications, in-hospital mortality, discharge
      residence, and recovery of instrumental activities of daily living at 1 year.

PMID- 15187858
TI  - Computer-guidance in percutaneous screw stabilization of the iliosacral joint.
AB  - Nine patients with instability and one patient with degeneration of the
      iliosacral joint were treated surgically. The posterior pelvic ring was
      stabilized with the assistance of an optoelectronic navigation system.
      Registration was ensured by using fiducial screws in the iliac crest or by
      collecting landmarks on the external fixator. Computed tomography scans taken
      postoperatively provided additional information regarding implant localization in
      all patients. Accurate placement of 21 of 22 implanted iliosacral screws was
      observed. Two of the 21 screws touched the wall of the second sacral foramen
      without perforating the canal. One screw perforated the anterior wall of the
      sacrum because the navigated guide wire was bent during implantation. The initial
      results indicate that computer-aided frameless navigation in surgery of the
      iliosacral joint can facilitate surgical performance during screw stabilization
      in selected patients. Two important issues must be considered in the clinical
      application of this technique: first, any relative migration of the iliac and
      sacral bone structures between computed tomography scans taken preoperatively and
      intraoperative navigation may result in an intolerable inaccuracy of computer
      guidance. Second, bending of the guide wire of the tracked power drive, which
      cannot be accommodated by the navigation system, will lead to misguidance;
      therefore, only navigated drill sleeves should be used.

PMID- 15187859
TI  - Vitamin D status and bone turnover in women with acute hip fracture.
AB  - Hypovitaminosis D is common in elderly women. Few data are available on vitamin D
      status and bone turnover in women with acute hip fracture. The aims of this study
      were to determine whether elderly Italian women with an acute hip fracture also
      had low vitamin D levels and an increase of bone turnover compared with elderly
      women with osteoporosis but without fractures. Seventy-four women with acute
      osteoporotic hip fracture and 73 women with postmenopausal osteoporosis were
      studied. All women were self-sufficient and had adequate sunlight exposure. To
      exclude the effect of trauma on serum 25-hydroxycolecalciferol levels and bone
      markers (bone alkaline phosphatase and C-terminal telopeptides of Type I collagen
      as indices of bone formation and bone resorption), blood samples were drawn
      within 24 hours of the fracture. Current data indicated that in our patients the
      prevalence of hypovitaminosis D is common although to a lesser extent than in
      women who are housebound. Women with acute hip fractures had a higher prevalence
      of vitamin deficiency defined as serum 25-hydroxycolecalciferol lower than 12
      ng/mL, compared with women with osteoporosis. Moreover, the presence of fracture
      did not influence the rate of bone formation, whereas the increase in bone
      resorption could be attributed to an older age of women with acute hip fracture
      because of similar values of parathyroid hormone levels in the two groups.

PMID- 15187860
TI  - Magnetic resonance imaging appearance of cartilage repair in the knee.
AB  - Assessment of surgically repaired cartilage lesions with standardized cartilage
      sensitive magnetic resonance imaging was done to evaluate the integrity,
      morphologic features, and signal of the articular surface, thereby obtaining
      information about the natural history of these procedures in the knee. Magnetic
      resonance imaging also assessed the interface between the repaired and native
      cartilage, changes in the subchondral bone, and the appearance of cartilage over
      the opposite and adjacent (native) surfaces. One hundred eighty magnetic
      resonance imaging examinations were obtained in 112 patients who had cartilage
      resurfacing procedures, including 86 microfractures and 35 autologous chondrocyte
      implantations, at a mean of 15 and 13 months after surgery, respectively.
      Autologous chondrocyte implantations showed consistently better fill of the
      defects at all times compared with microfracture. The graft hypertrophied in 63%
      of surgeries. The repair cartilage over the microfracture generally was depressed
      with respect to native cartilage. Propensity for bony overgrowth was most marked
      in the microfracture group, with loss of adjacent cartilage evident with
      progressive followup.

PMID- 15187861
TI  - Increased intercellular communication through gap junctions may contribute to
      progression of osteoarthritis.
AB  - Our aim was to support the hypothesis of a specific association between gap
      junctions in synovial tissue and the presence of osteoarthritis, as evidenced by
      differences between osteoarthritis and non-osteoarthritis synovia in the number
      of gap junctions, the amount of gap-junction protein, and the amount of enzymatic
      activity produced through a pathway mediated by gap-junction intercellular
      communication. An average of 4.41 gap junctions were found per 100 cells counted
      in the osteoarthritis synovia, compared with 1.00 in the controls. The amount of
      the gap-junction protein connexin 43 in synovial lining cells was approximately
      50% greater in patients with osteoarthritis. Synovial lining cells from patients
      with osteoarthritis produced matrix metalloproteinases constitutively and, at
      higher levels, in response to stimulation by interleukin-1 beta. In both cases,
      intercellular communication through gap junctions was shown to be critical to the
      ability of the cells to secrete matrix metalloproteinases. Overall, the results
      indicated that gap junctions between synovial lining cells were altered
      significantly in patients with osteoarthritis, as a consequence of the disease
      process or as part of the causal chain. In either case, gap junctions seem to be
      a rational therapeutic target.

PMID- 15187862
TI  - Decreased proliferation precedes growth factor changes after physeal irradiation.
AB  - The effects of irradiation on growth plate chondrocytes and mediators of
      chondrocytic differentiation are poorly understood. In earlier work on rat growth
      plate changes 1/2 to 4 weeks after irradiation, a nadir was identified at 1 week
      in proliferation and growth factor expression coincident with maximal
      histomorphometric derangement. The purpose of this study was to determine the
      earlier sequential relationship of proliferative, growth factor, and
      histomorphometric changes after irradiation leading to the 1-week nadir. Twenty
      four weanling 5-week-old male Sprague-Dawley rats had right knee irradiation with
      single fraction 17.5 Gy whereas the left leg served as an internal control. The
      earliest change identified was a significant decrease in BrdU evidence of
      proliferative activity between 6 and 12 hours after irradiation, which persisted
      through 48 hours. Twelve to 24 hours after irradiation, caspase-3 staining for
      apoptosis was higher than that in growth plates not having received radiotherapy.
      Histomorphometric changes after irradiation were observed as early as 24 hours.
      Growth factors and their downstream antiapoptotic and proapoptotic mediators did
      not differ significantly between limbs through 48 hours. The current study
      suggests that decreased proliferation and apoptosis precede any change in
      histomorphometric features of the growth plate after irradiation and that
      decreased growth factor expression occurs later.

PMID- 15187863
TI  - Repetitively stretched tendon fibroblasts produce inflammatory mediators.
AB  - We studied the expression of cytosolic phospholipase-A2 and activity of secretory
      phospholipase-A2 by human patellar tendon fibroblasts subjected to cyclic
      mechanical stretching. The effect of different stretching frequencies on the
      production of prostaglandin-E2 and expression of cyclooxygenase enzyme were also
      examined. An in vitro system that can control alignment, shape, and mechanical
      loading conditions of tendon fibroblasts was used for this study. Cyclic
      stretching of fibroblasts increased the expression level of cytosolic
      phospholipase-A2 by 88% and activity level of secretory phospholipase-A2 by 190%,
      compared with those of nonstretched fibroblasts. Cyclic stretching of tendon
      fibroblasts at 0.1 Hz and 1.0 Hz also increased prostaglandin-E2 production by
      40% and 69%, respectively. Furthermore, cyclooxygenase-1 and cyclooxygenase-2
      expression levels were increased in a stretching frequency-dependent manner, but
      cyclooxygenase-2 expression was increased more than that of cyclooxygenase-1.
      Because cytosolic phospholipase-A2 and secretory phospholipase-A2 are involved in
      the production of prostaglandin-E2 and other inflammatory mediators, this study
      suggests that regulation of phospholipase-A2 expression level may be an
      alternative approach to control in vivo tendon inflammation. The results of this
      study also may explain in part why activities that involve repetitive motion and
      high frequency loading of tendons are more likely to result in tendon
      inflammation.

PMID- 15187865
TI  - The development of American medical education from the turn of the century to the
      era of managed care.

PMID- 15187864
TI  - Genetic background of osteonecrosis: associated with thrombophilic mutations?
AB  - Intravascular coagulation is considered a major pathogenetic mechanism for
      nontraumatic osteonecrosis. The aim of our study was to evaluate the association
      of thrombophilic factor V G1691A mutation (factor V Leiden) and G20210A
      prothrombin mutation with the disease. Mutation presence was investigated by
      polymerase chain reaction techniques in a study population of 72 adult Caucasian
      patients with osteonecrosis of the femoral head and 300 healthy Caucasian control
      subjects. The disease was considered idiopathic in 23 patients and secondary in
      49. The factor V Leiden mutation was present in 18% of patients, compared with
      4.6% of control subjects, resulting in a statistically significant odds ratio of
      4.5. The prothrombin mutation was not significantly increased in the idiopathic
      osteonecrosis subgroup (8.7% versus 2.6%) with an odds ratio of 3.5. Overall,
      either of these coagulation disorders was present in 22.2% of patients and in
      7.3% of control subjects resulting in a significant odds ratio of 3.6. Factor V
      Leiden, a genetic risk factor for venous thrombosis, is associated with
      nontraumatic osteonecrosis of the femoral head, supporting the hypothesis that
      intravascular coagulation is a major pathogenetic mechanism of the disease.

PMID- 15187866
TI  - Painless ankle mass in a 12-year-old boy.

PMID- 15187867
TI  - Bone anatomy and rotational alignment in total knee arthroplasty.

PMID- 15187870
TI  - Metal-on-metal versus polyethylene in hip arthroplasty: a randomized clinical
      trial.

PMID- 15187871
TI  - Methodologic issues in systematic reviews and meta-analyses.

PMID- 15187873
TI  - Blood management after bilateral total knee arthroplasties.

PMID- 15187875
TI  - Effect of neoadjuvant chemotherapy on distraction osteogenesis in the goat model.

PMID- 15187877
TI  - Bone marrow transplantation in a patient with fibrodysplasia.

PMID- 15187879
TI  - Operative management of lower extremity fractures in patients with head injuries.

PMID- 15187881
TI  - Serum markers of bone metabolism show bone loss in hibernating bears.

PMID- 15187883
TI  - Management of metastatic (parenchymal, leptomeningeal, and epidural) lesions.
AB  - PURPOSE OF REVIEW: Metastases involving the central nervous system are notorious
      for the functional neurologic deficits they often cause. For many patients, the
      overall prognosis is determined by the systemic disease status, but a subset of
      patients may benefit from more intensive treatment. RECENT FINDINGS: Patients in
      a subgroup with brain metastases qualify for more intensive treatments, like
      stereotactic radiosurgery, the efficacy of which seems to be similar to that of
      surgery for single brain metastases. Although whole brain radiotherapy after
      stereotactic radiosurgery decreases the outfield recurrences, there are no
      indications that it improves survival. So far, studies on radiosensitizers have
      not resulted in clear evidence of improved outcome for good prognosis in patients
      with brain metastases. A variety of surgical procedures offer better palliation
      for a subset of patients with epidural spinal metastases than radiotherapy alone.
      The roles of the blood-brain barrier and of the blood-cerebrospinal fluid barrier
      remain a source of discussion. It may be relevant for patients with
      micrometastases, which can potentially be cured by systemic treatment. SUMMARY:
      For many patients with central nervous system complications, adequate palliation
      can be achieved, but this requires rapid and thorough evaluation of patients with
      central nervous system symptoms. Early diagnosis and proper patient selection for
      further and more intensive treatment are the cornerstones of good palliative care
      in these patients.

PMID- 15187884
TI  - Management of epileptic seizures.
AB  - PURPOSE OF REVIEW: Acquired epileptic seizures are common in cancer patients.
      They heavily impact on the quality of life and may affect survival. Most patients
      are medically treated, but the use of antiepileptic drugs (AEDs) in neuro
      oncology is complicated by serious specific side effects and interference of AEDs
      with other commonly prescribed drugs such as chemotherapeutic agents and
      corticosteroids. The main purpose of this review is to help the clinician to
      select the most appropriate drug or drug combination, and to minimize drug side
      effects and drug interactions in epilepsy treatment of cancer patients. RECENT
      FINDINGS: Considerable progress has been achieved recently in epileptology. They
      include the development of new AEDs and better understanding of their subcellular
      mechanism of action and of drug interactions. Most studies concerning the
      efficacy of AEDs have not been performed specifically in neuro-oncological
      patients, and the extrapolation of their results to tumor-related epilepsy
      requires some caution. The most significant findings specific to tumor-related
      epilepsy are (a) the indication that their pathogenesis may be due to a decrease
      of focal GABA-ergic inhibition, and (b) the guidelines for prophylaxis based on a
      report by a subcommittee of the American Academy of Neurology. SUMMARY: The
      quality of life of epileptic patients has been improved by both a better control
      of seizures and the use of drugs with fewer side effects. Cancer patients
      probably benefit from this progress. However, treatment of tumor-related epilepsy
      faces several specific problems, and there is a real need for conducting clinical
      trials restricted to cancer patients.

PMID- 15187885
TI  - Psychiatric disorders in oncology: recent therapeutic advances and new conceptual
      frameworks.
AB  - PURPOSE OF REVIEW: Major advances achieved in anticancer treatment have resulted
      in significant increases in cancer patients' survival periods. At the same time,
      growing awareness of the psychologic impact of the diagnosis and treatment of
      cancer on quality of life has created the need for deeper insights into the
      adjustment process, its disorders, and effective strategies for the treatment of
      psychiatric morbidity. The wider availability of brain imaging techniques and
      other neurobiologic tools is creating major opportunities for a scientific
      understanding of psychodynamic processes. RECENT FINDINGS: Several elements
      indicate a stress-system activation in response to cancer. The existence of
      traumatic stress-like syndromes has received increasing support. Structural brain
      imagery has revealed volumetric alterations of the amygdala, a major participant
      in emotional and fear responses. Hypotheses about functional modifications at the
      hypothalamic-pituitary-adrenal axis level may have significant implications for
      the identification, treatment, and even prevention of psychopathology. Finally,
      longitudinal studies assessing psychologic adjustment confirm the need for
      psychosocial and pharmacologic interventions. SUMMARY: Our understanding of the
      cancer experience at the emotional and cognitive levels remains insufficient,
      leading to weakly positive results of psychosocial intervention models. The use
      of antidepressant medication has received substantial empiric and scientific
      support, but a risk of antidepressant-induced carcinogenesis has not been
      excluded, which should keep clinicians from overprescribing attitudes. Finally,
      improving the quality of doctor-patient communication and the psychologic impact
      of carrying a genetic marker of cancer risk should be the focus of further
      attention.

PMID- 15187886
TI  - Uterine leiomyosarcoma: present management.
AB  - PURPOSE OF REVIEW: To review current investigations impacting management of
      uterine leiomyosarcoma (LMS). RECENT FINDINGS: Patients with uterine LMS
      typically present with vaginal bleeding, pain, and a pelvic mass. Atypical
      presentations with hypercalcemia or eosinophilia have been reported. Radiographic
      evaluation with combined positron emission tomography/computed tomography may
      assist in diagnosis and surveillance in women with uterine LMS. Stage and tumor
      grade continue to appear to be valid prognostic indicators. A recently developed
      risk-assessment index is highly predictive of disease-specific survival. Ovarian
      preservation does not appear to negatively impact outcome. The addition of
      adjuvant therapy after surgical management does not seem to improve survival.
      Novel therapies may result from continued improvements in our knowledge of the
      molecular biology of uterine LMS. SUMMARY: Despite the infrequency of uterine
      LMS, several recent investigations have advanced our understanding of the
      disease.

PMID- 15187888
TI  - Update in management of head and neck sarcoma.
AB  - PURPOSE OF REVIEW: This update addressing head and neck sarcoma presents new data
      published after January 2003. This new information is presented following review
      of contemporary management principles established before 2003. RECENT FINDINGS:
      The application of advances in molecular and genetic techniques to characterize
      individual sarcomas has improved classification schemes and hopefully will lead
      to individually tailored therapy. Maturation and refinements of large tumor
      registries are permitting more detailed analysis of larger contemporary series of
      the rare head and neck sarcomas. Improved long-term survival of patients treated
      for sarcoma in their childhood has allowed study of the morbidity induced by
      treatment. Novel treatment strategies are under study to decrease morbidity
      without diminishing the chance for cure. SUMMARY: Progress in improving the
      treatment of sarcoma of the head and neck has been slow due to the lack of a
      large clinical experience with this rare neoplasm. Advances continue and are
      anticipated to be most striking in the study of genetic mechanisms.

PMID- 15187887
TI  - Surveillance strategies for patients following surgical resection of soft tissue
      sarcomas.
AB  - PURPOSE OF REVIEW: To examine the factors predictive of recurrence for soft
      tissue sarcomas, the role of salvage therapy, and the data in support of current
      surveillance strategies. RECENT FINDINGS: There are multiple primary tumor
      characteristics and other factors that can stratify patients into low- or high
      risk groups for developing recurrent disease. The available data also support a
      limited role for salvage therapy in the setting of isolated local recurrence or
      distant metastases. The use of routine chest computed tomography as opposed to
      conventional chest x-ray for pulmonary surveillance is costly and provides little
      additional benefit if the risk for lung metastases is low. When examined
      scientifically, standard laboratory studies and surveillance imaging of the
      primary tumor site for extremity soft tissue sarcomas add little to the detection
      of recurrent disease. In addition to predictive variables, physician experience
      and opinion influence surveillance strategies. SUMMARY: For soft tissue sarcomas,
      patient education and office visits with thorough history and physical
      examination will detect the vast majority of recurrent disease. Routine
      surveillance imaging is only of significant benefit if the risk for asymptomatic
      recurrence is high or if other factors make clinical assessment difficult. There
      is no benefit to basic laboratory studies in standard follow-up regimens.

PMID- 15187889
TI  - Genetics of chondrosarcoma and related tumors.
AB  - PURPOSE OF REVIEW: The burgeoning body of information on the genetic changes
      present in and underlying the development and biology of human cancers has
      carried implications regarding the possible genetic events that are responsible
      for not only the genesis of these cancers but also the hope of the cure for these
      cancers. Chondrosarcomas are a group of tumors that fall into this category. The
      purpose of this review is to summarize the genetic findings in these tumors.
      RECENT FINDINGS: The histopathologic variability of chondrosarcomas is reflected
      in the complexity and lack of specificity of their cytogenetic and molecular
      genetic findings, except for extraskeletal myxoid chondrosarcomas. These are
      characterized in the preponderant number of cases by a translocation,
      t(9;22)(q22;q12), and in a small number of cases by variant translocations
      t(9;17)(q22;q11) and t(9;15)(q22;q21). These translocations lead to the formation
      of abnormal fusion genes and gene products (proteins). In each of these
      translocations, the CHN gene is involved, resulting in the chimeric fusion genes
      EWS/CHN, RBP56/CHN, and TCF12/CHN, respectively. The specific translocations and
      their associated molecular genetic changes are diagnostic of extraskeletal myxoid
      chondrosarcomas. The abnormal proteins resulting from these fusion genes
      aberrantly affect gene transcription and cellular signaling pathways thought to
      be responsible for initiating sarcoma formation. In skeletal (central)
      chondrosarcomas of varying histopathologic types, the cytogenetic and molecular
      genetic findings are variable, complex, and apparently lacking in specificity.
      These changes may reflect a stepwise process (or processes) of oncogenesis
      involving an array of genes. SUMMARY: Although some cartilaginous tumors are
      characterized by specific or recurrent chromosome alterations and molecular
      genetic changes, much is yet to be learned about the nature and sequence of these
      genetics events and about their unique role in the stepwise process involved in
      the development and biology of each tumor type, both malignant and nonmalignant.
      Until such time, some of the genetic changes, particularly the presence of
      specific translocations, can be of definite diagnostic value.

PMID- 15187890
TI  - Atypical lipomatous tumor: molecular characterization.
AB  - PURPOSE OF REVIEW: Atypical lipomatous tumors/well-differentiated liposarcomas
      (ALT/WDLs) are one of the more frequent mesenchymal neoplasms and are
      characterized by specific chromosome aberrations: supernumerary chromosome or
      giant marker chromosome or both. Extra copies of known oncogenes such as MDM2,
      CDK4, SAS, HMGA2 and others are present in this abnormal genetic material. RECENT
      FINDINGS: In the past few years, several papers have further dissected the
      genetic alterations present in these tumors, allowing the identification of new
      potential oncogenes. SUMMARY: ALT/WDLs represent therefore an interesting model
      for assessing the potential role of these oncogenes, not only in the
      pathogenesis, but also as a therapeutic target.

PMID- 15187892
TI  - Biliary tract neoplasms: update 2003.
AB  - PURPOSE OF REVIEW: Biliary tract neoplasm is one of the most aggressive
      malignancies, with a very poor prognosis. Most cancers of the biliary tract will
      have grown beyond the limits of curative resection by the time they become
      clinically evident. This reality has fostered therapeutic nihilism, and most
      physicians and surgeons, in their pessimism, have to run ambitious trials
      evaluating new diagnostic tools and therapeutic techniques in this disease.
      RECENT FINDINGS: Advances in imaging over the period of the last 5 years now
      allow for earlier diagnosis and better surgical planning. Recent improvements in
      operative technique have substantially improved the outlook of patients with this
      cancer. Palliative management of obstructive disease recently has been improved
      with the advent of photodynamic therapy. Among the different drugs tested in this
      disease, gemcitabine seems to have the best efficacy:toxicity ratio. However,
      efficacy results remain disappointing, and combination schedules need to be
      developed to improve the results. Among them, the gemcitabine-oxaliplatin
      combination seems to be one of the most promising schedules. Biological studies,
      especially those evaluating mutation-independent activation of the Hedgehog
      pathway, have provided interesting information on the carcinogenesis of this rare
      tumor. Furthermore, these results bring us the opportunity of development of
      future targeted therapies in biliary tract cancer. SUMMARY: Biliary tract
      neoplasm remains one of the most aggressive malignancies. However, as for other
      gastrointestinal malignancies, biological studies and diagnostic and therapeutic
      improvements have provided interesting results that could lead to a major
      improvement in the prognosis of this disease.

PMID- 15187891
TI  - Positron emission tomography in gastric and esophageal cancer.
AB  - PURPOSE OF REVIEW: Positron emission tomography using the positron emitting
      glucose analogue 18F-fluorodeoxyglucose has recently emerged as a promising
      metabolism-based whole-body imaging tool for cancer diagnosis and follow-up.
      Several reports have recently appeared indicating the potential and limitations
      of this technique. The review limits its scope to the recent advances of 18F
      fluorodeoxyglucose positron emission tomography in the clinical management of
      gastric and esophageal cancer. RECENT FINDINGS: New studies have been reported on
      the use of 18F-fluorodeoxyglucose positron emission tomography to assess the
      early and late metabolic response of a gastroesophageal tumor to chemo(radiation)
      therapy. The metabolic response as measured by serial 18F-fluorodeoxyglucose
      positron emission tomography, performed before and during treatment or some weeks
      thereafter, can be used to predict the clinical and histopathologic response.
      Moreover, the metabolic positron emission tomography response seems to be related
      to overall and disease-free survival. SUMMARY: Gastroesophageal 18F
      fluorodeoxyglucose positron emission tomography could add significant diagnostic
      information to the different phases of patient management. At initial diagnosis
      of esophageal cancer, positron emission tomography detects more distant lymph
      node and organ metastases compared with conventional diagnostics, allowing a more
      accurate selection of the most appropriate treatment. Serial 18F
      fluorodeoxyglucose positron emission tomography performed before and during
      chemotherapy allows early identification of nonresponding tumors. 18F
      fluorodeoxyglucose positron emission tomography performed after a treatment
      allows accurate assessment of the residual tumor load. 18F-fluorodeoxyglucose
      positron emission tomography allows accurate detection and restaging of recurrent
      disease.

PMID- 15187893
TI  - Barrett metaplasia: reassessment of treatment and follow-up.
AB  - PURPOSE OF REVIEW: The incidence of esophageal adenocarcinoma continues to rise
      in the Western world, with a mean 5-year survival of less than 20%. There has
      therefore been increasing interest in the precursor lesion, Barrett's esophagus.
      However, adenocarcinoma will not develop in most patients with Barrett's
      esophagus. This review summarizes the data on the management of Barrett's
      esophagus that have been published since January 2003. RECENT FINDINGS: The
      control of reflux symptoms significantly improves quality of life, and surgical
      antireflux therapy may gradually cause regression of the Barrett segment compared
      with proton pump inhibitor therapy. The data substantiate the claim that the
      cancer risk in Barrett esophagus is lower than had hitherto been suggested. The
      risk factors for progression include increasing age and length of segment,
      macroscopic inflammatory changes, loss of heterozygosity over several genetic
      loci, and increased proliferation status. The extent of high-grade dysplasia may
      not accurately predict cancer development, and continued surveillance, rather
      than intervention, for such patients may decrease the chances of curative
      treatment. Long-term follow-up data are beginning to accumulate for nonsurgical
      treatment strategies. Chemoprevention trials are under way to evaluate the role
      of acid suppression and nonsteroidal anti-inflammatory drugs and their
      derivatives. SUMMARY: At this time, endoscopic surveillance and surgical
      management remain the mainstay, but continued research efforts should enable risk
      stratification and cancer prevention in the future.

PMID- 15187894
TI  - Hepatic arterial chemotherapy for colorectal cancer liver metastases: a review of
      advances in 2003.
AB  - PURPOSE OF REVIEW: During 2003, two new randomized trials comparing
      fluoropyrimidine-based hepatic arterial chemotherapy (HAC) with systemic
      chemotherapy were published. These new data will be reviewed in the context of
      previous trials and new observations of novel approaches involving HAC. RECENT
      FINDINGS: The large Medical Research Council (MRC)/European Organization for the
      Research and Treatment of Cancer (EORTC) and the smaller Cancer and Leukaemia
      Group B (CALGB) trials reported conflicting conclusions. Lack of difference in
      response rates and survival outcomes was noted by the European trial groups
      whereas the contrary was reported by the US investigators, with statistically
      significant difference in response rates of 48% and 25% and median survival of
      22.7 months and 19.8 months, respectively, being observed, favoring HAC. Early
      studies testing incorporation of irinotecan or oxaliplatin into HAC, either as
      additional systemic chemotherapy or as integral components of the HAC infusional
      regimen, confirmed feasibility, safety, and efficacy, with response rates between
      30% and 60% being reported in some series. Other studies showed that combination
      with internal irradiation with lipiodol I-131 and biologic agents, eg,
      replication-selective adenovirus and cytokines, could be achieved with tolerable
      toxicity. Molecular prognostic factors that may help tailor treatment for
      individual patients were being investigated and low expression of thymidylate
      synthase (TS) and p21 was shown to correlate with better outcome, whereas
      patients with positive TS seemed to derive more benefit from HAC plus systemic
      chemotherapy than systemic chemotherapy alone. SUMMARY: These studies confirmed
      that fluoropyrimidine-based HAC cannot be recommended routinely outside clinical
      trial as yet, but this treatment has its own merits and will continue to evolve
      with the availability of novel chemotherapeutic and biologic agents. Further
      studies into molecular prognostic factors will eventually define the role of HAC
      by selecting the right drug and the best route of administration for an
      individual patient.

PMID- 15187896
TI  - Bibliography current world literature. Supportive care.

PMID- 15187895
TI  - Monoclonal antibodies against vascular endothelial growth factor and epidermal
      growth factor receptor in advanced colorectal cancers: present and future
      directions.
AB  - PURPOSE OF REVIEW: Targeted therapies are emerging as potentially important
      therapeutic interventions in the treatment of advanced colorectal cancer. There
      have been considerable developments in this field within the past few years, with
      some agents entering the clinic and others soon to follow. Monoclonal antibodies
      against important tumorigenic targets have been in development for over a decade.
      Recently, cetuximab and bevacizumab have generated significant interest and are
      the focus of this review. RECENT FINDINGS: Cetuximab, a monoclonal antibody
      against the epidermal growth factor receptor, and bevacizumab, a monoclonal
      antibody against vascular endothelial growth factor, have now been subject to
      rigorous assessment within several clinical studies, including a large randomized
      phase II study of cetuximab and a randomized phase III study of bevacizumab. The
      demonstration of efficacy and safety with these agents has led to the issue of
      licenses for cetuximab in Switzerland and bevacizumab in the United States.
      SUMMARY: These results have led to a rapid expansion of further studies to define
      the role of these antibodies and to aid their future integration with
      conventional approaches for the management of advanced colorectal cancer.

PMID- 15187897
TI  - The awful truth about abuse of older people.

PMID- 15187898
TI  - pH testing in catheter maintenance: the clinical debate.
AB  - The pH of urine is widely recognized as being a major contributory factor in
      urinary catheter encrustation. What is less widely appreciated is the range of
      factors that affect the pH of urine, and which therefore affect the reliability
      and validity of urine pH testing. This article examines the validity of various
      urinary pH testing methods and discusses the theoretical and practical
      implications of the uncertainty surrounding their practical value.

PMID- 15187899
TI  - Preventing falls in older people: evaluating a peer education approach.
AB  - Initiatives in falls prevention usually rely on the expertise of health
      professionals and are therefore limited in scope. In order to reach a wider
      audience, a peer education programme in Bradford gave one-off sessions to groups
      of older people providing information about falls prevention and demonstrating
      simple balance and strength building exercises. Although evaluation found the
      programme to be well received, it also revealed a high rate of undisclosed falls
      and a reluctance to inform, or seek advice from, health professionals. It was not
      clear how far this was to do with embarrassment or being seen as not coping, but
      suggests that a more appropriate role for health professionals may be one that is
      complementary and supportive within a broad educational and facilitative
      programme embodying peer education.

PMID- 15187900
TI  - Childhood H. pylori: disappearing disease or chronic infection?
AB  - Helicobacter pylori is one of the commonest chronic bacterial infections
      worldwide. It is acquired during childhood and its persistence has implications
      for health in later life. In adults, it is the principle cause of duodenal ulcer
      disease and there is evidence of an association between H. pylori and gastric
      cancer. However, most colonized people are asymptomatic. The prevalence of H.
      pylori increases with age but there is a striking difference between the rates in
      developed and developing countries. As no significant non-human or environmental
      source for this infection has been identified, person to person spread is almost
      certainly the main mode of transmission. Community nurses should be aware of this
      micro-organism as a potential cause of illness in children, and that they can
      play a role in promoting hygiene practices and educating families so that the
      risk of acquisition may be reduced. This review discusses the clinical features,
      prevalence, risk factors for transmission, diagnosis and treatment of H. pylori.

PMID- 15187901
TI  - The effectiveness of pin site care for patients with external fixators.
AB  - The aim of this mini-review was to establish if cleaning, dressing and removing
      crusts from external fixator or skeletal pin sites affected the risk of
      infection. A systematic search was conducted using Cochrane, Medline, CINAHL and
      Embase databases. Inclusion criteria were orthopaedic patients with skeletal pins
      or external fixator devices applied to either upper or lower limbs. The databases
      were searched for controlled studies comparing at least one aspect of pin site
      care (cleansing, dressing or crust removal) with a control group of 'observation
      only'. Only one study met the inclusion criteria. It focused on cleansing
      external fixator pin sites. The study included two treatment groups, one using
      0.9% normal saline and one using 70% alcohol, and a control group which had no
      cleansing. While the control group had a more favourable outcome than the
      treatment groups, there is still insufficient evidence from this one study to
      recommend no cleansing. It is also important to note that the most frequently
      recommended solution for cleansing pin sites in UK protocols (0.9% normal saline)
      had the worst outcome, therefore its efficacy in this population may need to be
      challenged.

PMID- 15187902
TI  - Legal requirements for safe handling in community care.
AB  - CASE STUDY: Andrea, a district nurse, together with home carers from the local
      social services department, has been caring for a wheelchair-bound patient with
      multiple sclerosis for 3 years. The patient requires assistance with going to the
      toilet and going to bed. She has always been reluctant to be moved using a hoist
      because of sudden spasms and this causes her great anxiety. Now the patient is
      refusing to be move mechanically and will only consent to being lifted manually.
      Andrea and the home care staff are concerned that this might place them at risk
      of injury and argue that it is against the trust and local authority moving and
      handling policy, which has a no-lift clause. Andrea would like to refuse to
      manually lift the patient but decides to check the legal position first.

PMID- 15187903
TI  - Exploring the contribution of district nurses to public health.
AB  - To date the public health role of district nursing has been less well defined
      than in other branches of community nursing. A qualitative study examining the
      public health role of district nurses was undertaken in a West Yorkshire primary
      care trust. The study explored the range of public health activities currently
      undertaken by district nurses, the agendas perceived as most conducive to input
      and the organizational barriers that prevented greater involvement in public
      health from district nurses. Focus group and individual semi-structured
      interviews were undertaken with 21 members of the district nursing team and
      analysed using thematic content analysis. The findings suggest that district
      nurses were already undertaking a range of public health and health education
      activities but much of the work was opportunistic. District nurses perceived
      themselves as well placed to undertake locally based health action because of
      their profile in the local communities together with local intelligence. However,
      ineffective referral criteria were considered to be the most prohibitive barrier
      against making a greater contribution to health improvement.

PMID- 15187904
TI  - Who takes responsibility for care failures?

PMID- 15187905
TI  - 9th Congress of the European Hematology Association, 10 - 13 June 2004, Geneva,
      Switzerland. Abstracts.

PMID- 15187981
TI  - Allelic variation of serotonin transporter function modulates the brain
      electrical response for error processing.
AB  - A functional length variation in the transcriptional control region of the
      serotonin transporter gene (5-HTTLPR) influences brain function, personality
      traits, and susceptibility to psychiatric disorders. Here we measured prefrontal
      brain function by means of event-related potentials during an error processing
      paradigm. Physiologically, occurrence of an error elicits two specific electrical
      responses in the prefrontal cortex, the early error related negativity (Ne/ERN)
      and the later occurring error positivity (Pe), reflecting different components of
      error processing. Healthy subjects with one or two copies of the low-activity 5
      HTTLPR short variant showed significantly higher amplitudes of the Ne/ERN and a
      trend to higher amplitudes of the Pe as compared to age- and gender-matched
      individuals homozygous for the long allele. Performance measures and latencies of
      these ERP-components did not differ between groups. These results indicate that
      the 5-HTTLPR short variant is associated with enhanced responsiveness of the
      brain and further supports the notion that prefrontal brain function is
      influenced by allelic variation in serotonin transporter function.

PMID- 15187982
TI  - Repetitive transcranial magnetic stimulation increases the release of dopamine in
      the nucleus accumbens shell of morphine-sensitized rats during abstinence.
AB  - Recent studies in rodents have shown that withdrawal from chronic drug abuse is
      associated with a significant decrease in dopamine (DA) release in mesolimbic
      structures, especially in the shell region of the nucleus accumbens. Since the DA
      system is known to play an important role in reward processes, a withdrawal
      associated impairment in mesolimbic DA-mediated transmission could possibly
      implicate reward deficit and thus enhance vulnerability to drug craving and
      relapse. We have previously demonstrated that acute repetitive transcranial
      magnetic stimulation (rTMS) has a modulatory effect on DA release in several
      areas of the rat brain, including dorsal striatum, hippocampus, and nucleus
      accumbens shell. In the present study, we investigated the possible use of rTMS
      as a tool in re-establishing the dysregulated DA secretion observed during
      withdrawal in morphine-sensitized male Sprague-Dawley rats. Using intracerebral
      microdialysis, we monitored the effects of acute rTMS (20 Hz) on the intra
      accumbal release-patterns of DA in freely moving animals that were subjected to a
      morphine sensitization scheme for a period of 8 days. We provide first evidence
      that acute rTMS (20 Hz) is able to increase DA concentration in the shell region
      of the nucleus accumbens in both control animals and morphine-sensitized rats
      during abstinence. The DA release in morphine-sensitized rats was significantly
      higher than in controls. rTMS, therefore, might gain a potential therapeutic role
      in the treatment of dysphoric and anhedonic states during drug withdrawal in
      humans.

PMID- 15187983
TI  - A missense variation in human casein kinase I epsilon gene that induces
      functional alteration and shows an inverse association with circadian rhythm
      sleep disorders.
AB  - Recent studies have shown that functional variations in clock genes, which
      generate circadian rhythms through interactive positive/negative feedback loops,
      contribute to the development of circadian rhythm sleep disorders in humans.
      Another potential candidate for rhythm disorder susceptibility is casein kinase I
      epsilon (CKIepsilon), which phosphorylates clock proteins and plays a pivotal
      role in the circadian clock. To determine whether variations in CKIepsilon induce
      vulnerability to human circadian rhythm sleep disorders, such as delayed sleep
      phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24), we analyzed all of
      the coding exons of the human CKIepsilon gene. One of the variants identified
      encoded an amino-acid substitution S408N, eliminating one of the putative
      autophosphorylation sites in the carboxyl-terminal extension of CKIepsilon. The
      N408 allele was less common in both DSPS (p = 0.028) and N-24 patients (p =
      0.035) compared to controls. When DSPS and N-24 subjects were combined, based on
      an a priori prediction of a common mechanism underlying both DSPS and N-24, the
      inverse association between the N408 allele and rhythm disorders was highly
      significant (p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22-0.79).
      In vitro kinase assay revealed that CKIepsilon with the S408N variation was
      approximately 1.8-fold more active than wild-type CKIepsilon. These results
      indicate that the N408 allele in CKIepsilon plays a protective role in the
      development of DSPS and N-24 through alteration of the enzyme activity.

PMID- 15187984
TI  - Decreased serotonin 5-HT2A receptor-stimulated phosphoinositide signaling in
      fibroblasts from melancholic depressed patients.
AB  - Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal
      transduction systems have been widely reported in mood disorders. This study was
      intended to evaluate 5-HT(2A) receptor-coupled activation of phosphatidylinositol
      (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were
      obtained from patients with major depression with or without melancholia, and
      normal controls. Dose response curves were determined for 5-HT-induced PI
      hydrolysis. PI response was determined for bradykinin and l-alpha
      lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [125I]LSD
      binding for 5-HT(2A) also was conducted. Finally, Western blot analysis was
      performed for phospholipase Cbeta1 (PLCbeta1) and Galpha(q/11) proteins. The
      maximum PI response observed with 5-HT was significantly lower in melancholics
      but not nonmelancholic patients relative to controls. Activation of PI hydrolysis
      by bradykinin and LPA was not reduced in melancholic vs melancholics and
      controls; responses to both agonists actually were increased in the melancholic
      group. [125I]LSD binding, PLCbeta1, and Galpha(q/11) protein levels did not
      differ between groups. The data raise the possibility that the reduced 5-HT(2A)
      receptor-induced PI hydrolysis is intrinsic to the receptor itself or its
      coupling to Gq protein, and is not related to altered availability of the 5
      HT(2A) receptor, Gq or PLC.

PMID- 15187985
TI  - Impoverished rearing environment alters metabotropic glutamate receptor
      expression and function in the prefrontal cortex.
AB  - Rearing rats in impoverished (IC) and enriched (EC) environmental conditions
      alters synaptic plasticity and cognitive processes. Metabotropic glutamate
      receptors (mGluRs) are known to play a key role in synaptic and behavioral
      plasticity. In the present study, the effect of rearing conditions on the
      expression of mGluR proteins in the prefrontal cortex (PFC) was assessed by
      immunoblotting. A significant difference in the content of prefrontal mGluR1 and
      mGluR5 (ie group I) and mGluR2/3 (ie group II) was observed between IC and EC
      rats. To functionally characterize this difference, in vivo microdialysis was
      used to verify differences in mGluR regulation of extracellular glutamate in the
      PFC. The results indicate that the capacity of group I and II mGluRs to elevate
      extracellular glutamate levels was significantly blunted in the PFC of IC rats
      compared to either EC subjects, or rats reared in normal environmental conditions
      (ie NIH standards). Group II mGluR receptors regulate performance in a forced T
      maze spatial memory task that involves the PFC, and IC rats demonstrated deficits
      in this task relative to EC rats. These data suggest that reduced mGluR
      transmission in the PFC produced by impoverished, relative to enriched, rearing
      environments may contribute to cognitive deficits.

PMID- 15187986
TI  - Association between particulate matter and emergency room visits, hospital
      admissions and mortality in Spokane, Washington.
AB  - There is conflicting evidence regarding the association between different size
      fractions of particulate matter (PM) and cardiac and respiratory morbidity and
      mortality. We investigated the short-term associations of four size fractions of
      particulate matter (PM(1), PM(2.5), PM(10), and PM(10-2.5)) and carbon monoxide
      with hospital admissions and emergency room (ER) visits for respiratory and
      cardiac conditions and mortality in Spokane, Washington. We used a log-linear
      generalized linear model to compare daily averages of PM and carbon monoxide with
      daily counts of the morbidity and mortality outcomes from January 1995 to June
      2001. We examined pollution lags ranging from 0 to 3 days and compared our
      results to a similar log-linear generalized additive model. Effect estimates
      tended to be smaller and have larger standard errors for the generalized linear
      model. Overall, we saw no association with respiratory ER visits and any size
      fraction of PM. However, there was a suggestion of greater respiratory effect
      from fine PM when compared to coarse fraction. Carbon monoxide was associated
      with both all respiratory ER visits and visits for asthma at the 3-day lag. We
      feel that carbon monoxide may be serving as a marker for combustion-derived
      pollutants, which is one large component of the diverse air pollutant mixture. We
      also found no association with any size fraction of PM or CO with cardiac
      hospital admissions or mortality at the 0- to 3-day lag. We found no consistent
      associations between any size fraction of PM and cardiac or respiratory ER visits
      or hospital admissions.

PMID- 15187987
TI  - Comparison of organophosphorus pesticide metabolite levels in single and multiple
      daily urine samples collected from preschool children in Washington State.
AB  - A total organophosphorus pesticide exposure study was conducted in Washington
      State in 1998 in a sample population of 13 children aged 2.5-5.5 years. The
      children were roughly split between rural and suburban populations and had been
      previously identified as having potentially elevated organophosphorus pesticide
      exposures. One component of the study was urine collection and analysis. Urine
      samples were collected from each subject up to four times in 24 h in two
      different seasons. Samples were collected at specific time points: before bed,
      first morning void, after lunch, and before dinner. Urine samples were analyzed
      initially for the six nonspecific dialkylphosphate (DAP) metabolites and
      subsequently for eight specific metabolites including malathion dicarboxylic acid
      (MDA), 3,5,6-trichloro-2-pyridinol (TCPy), and paranitrophenol (PNP). Relatively
      large percentages of the urine samples contained quantifiable amounts of two of
      the nonspecific DAP metabolites (DMTP-97%; DETP-67%), and three of the specific
      metabolites (MDA (71%), TCPy (79%), and PNP (96%)). A percent deviation analysis
      was employed to determine which of the spot sample time points was the best
      predictor of the estimated volume-weighted daily average. Of the four spot
      samples collected, first morning void samples were consistently found to be the
      best predictors of weighted-average daily metabolite concentration. This finding
      also held when the data were creatinine-adjusted. The results of this analysis
      suggest that if spot sampling is to be conducted as part of a biological
      monitoring study, first morning void samples should be preferentially collected.

PMID- 15187988
TI  - Inmate exposure to secondhand smoke in correctional facilities and the impact of
      smoking restrictions.
AB  - This study was undertaken to measure the passive smoking exposure of prisoners at
      three correctional facilities in the US and to evaluate the effectiveness of a
      ban on smoking in reducing these exposures at two of these facilities. The
      average weekly concentration of nicotine was measured in fixed locations within
      the correctional facilities using passive samplers. Samples were collected before
      and after a smoking ban was instituted, and after the policy was modified to
      allow smoking outdoors. Samples were collected in the living areas, near where
      inmates slept and watched TV, and in selected central facilities, including
      dining halls, visiting rooms, booking areas, and learning centers. Average weekly
      concentrations of nicotine were measured in 84 locations while smoking was
      allowed; changes in these concentrations were measured with 112 weekly samples 4
      and 9 months after the policy restricting smoking was implemented The average
      concentrations of nicotine were high while smoking was allowed: most living and
      sleeping areas averaged 3-11 microg/m(3), but the gym that was used as a bunkroom
      averaged 25 microg/m(3); these values compare to an average of 2 microg/m(3) in
      the homes of smokers. The smoking ban significantly reduced nicotine
      concentrations in the living areas (P<0.01 at facility A and P<0.05 at facility
      B) to averages of 1.5-2.2 microg/m(3); all postban samples were less than 5
      microg/m(3). In conclusion, secondhand smoke concentrations in correctional
      facilities can be quite high; however, policies banning smoking are effective in
      reducing, but not eliminating, these exposures.

PMID- 15187990
TI  - Candidate target genes for loss of heterozygosity on human chromosome 17q21.
AB  - Loss of heterozygosity (LOH) on chromosome 17q21 has been detected in 30% of
      primary human breast tumours. The smallest common region deleted occurred in an
      interval between the D17S746 and D17S846 polymorphic sequences tagged sites that
      are located on two recombinant P1-bacteriophage clones of chromosome 17q21: 122F4
      and 50H1, respectively. To identify the target gene for LOH, we defined a map of
      this chromosomal region. We found the following genes: JUP, FK506BP10, SC65,
      Gastrin (GAS) and HAP1. Of the genes that have been identified in this study,
      only JUP is located between D17S746 and D17S846. This was of interest since
      earlier studies have shown that JUP expression is altered in breast, lung and
      thyroid tumours as well as cell lines having LOH in chromosome 17q21. However, no
      mutations were detected in JUP using single-strand conformation polymorphism
      analysis of primary breast tumour DNAs having LOH at 17q21. We could find no
      evidence that the transcription promoter for JUP is methylated in tumour DNAs
      having LOH at 17q21. We suspect that the target gene for LOH in primary human
      breast tumours on chromosome 17q21 is either JUP and results in a
      haploinsufficiency for expression or may be an unidentified gene located in the
      interval between D17S846 and JUP.

PMID- 15187994
TI  - Analysis of epidermal growth factor receptor expression as a predictive factor
      for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer.
AB  - Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor
      (EGFR) tyrosine kinase inhibitor that has demonstrated antitumour activity and
      favourable tolerability in Phase II studies. We investigated whether EGFR
      expression levels could predict for response to gefitinib in patients with
      advanced non-small-cell lung cancer (NSCLC), who received gefitinib (250 mg day(
      1)) as part of a worldwide compassionate-use programme. Tissue samples were
      analysed by immunohistochemistry to assess membrane EGFR immunoreactivity. Of 147
      patients enrolled in our institution, 50 patients were evaluable for assessment
      of both clinical response and EGFR expression. The objective tumour response rate
      was 10% and disease control was achieved in 50% of patients. Although high EGFR
      expression was more common in squamous-cell carcinomas than adenocarcinomas, all
      objective responses were observed in patients with adenocarcinoma. Response and
      disease control with gefitinib were not associated with high EGFR expression.
      Overall, median survival was 4 months, and the 1-year survival rate was 18%.
      Strong EGFR staining correlated with shorter survival time for all patients.
      Gefitinib demonstrated promising clinical activity in this group of patients with
      NSCLC. These results have also shown that EGFR expression is not a significant
      predictive factor for response to gefitinib.

PMID- 15187995
TI  - Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric
      derivative of camptothecin (CPT).
AB  - Polymeric cytotoxic conjugates are being developed with the aim of preferential
      delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I
      inhibitor camptothecin linked to a water-soluble polymeric backbone
      methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It
      was administered as a 30-min infusion once every 4 weeks to patients with
      advanced solid malignancies. The objectives of our study were to determine the
      maximum tolerated dose, dose-limiting toxicities, and the plasma and urine
      pharmacokinetics of MAG-CPT, and to document responses to this treatment. The
      starting dose was 30 mg m(-2) (dose expressed as mg equivalent camptothecin). In
      total, 23 patients received 47 courses at six dose levels, with a maximum dose of
      240 mg m(-2). Dose-limiting toxicities were myelosuppression, neutropaenic
      sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum
      dose. The maximum tolerated dose and dose recommended for further clinical study
      was 200 mg m(-2). The half-lives of both MAG-CPT and released CPT were prolonged
      (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4
      weeks after treatment. However, subsequent pharmacodynamic studies of this agent
      have led to its withdrawal from clinical development.

PMID- 15187996
TI  - Primary breast sarcoma: clinicopathologic series from the Mayo Clinic and review
      of the literature.
AB  - Primary sarcomas of the breast are extremely rare, with less than 0.1% of all
      malignant tumours of the breast. Mayo Clinic Surgical Pathology database was
      searched for all breast sarcoma from 1910 to 2000. Pathology reports and slides
      were reviewed and tumour types were determined. Metaplastic carcinomas and
      phyllodes tumours were excluded. There were 25 women ranging in age 24-81 years
      (mean 45 years). All but one patient presented with a palpable lump. Mastectomy
      was performed in 19 patients and lumpectomy in five patients. Histopathological
      diagnoses were fibrosarcoma (six), angiosarcoma (six), pleomorphic sarcoma (six),
      leiomyosarcoma (two), myxofibrosarcoma (three), hemangiopericytoma (one) and
      osteosarcoma (one). Tumour size ranged from 0.3 to 12 cm (mean 5.7). Low-grade
      lesions were observed in 10 cases and high-grade in 15. Overall, mean follow-up
      was 10.5 years. Local recurrence was observed in 11 patients and ranged from 2 to
      36 months (mean 15 m), while distant metastasis was observed in 10 patients (40%)
      affecting lungs, bones, liver, spleen, and skin. Of the 25 patients, 12 have died
      of disease and six of other causes. Five-year overall (OS) and cause-specific
      survival (CSS) were 66 and 70%, respectively. OS and DFS at 5 years were 91% for
      tumours < or =5 cm and 50% for tumours >5 cm. Tumour size was significantly
      associated with OS (risk ratio=1.3 per 1 cm increase; 95% CI, 1.02-1.7; P=0.036).
      There was no significant difference in OS or CSS between low- and high-grade
      lesions. In this series, tumour size was a more valuable prognostic factor than
      tumour grade.

PMID- 15187997
TI  - Does increased lymphatic density contribute to fast drainage and metastatic
      spread to sentinel lymph nodes in melanoma?

PMID- 15187998
TI  - Induction of hyperammonia in irradiated hepatoma cells: a recapitulation and
      possible explanation of the phenomenon.

PMID- 15187999
TI  - Alterations in neuroblastoma ganglioside synthesis by induction of GD1b synthase
      by retinoic acid.
AB  - Recent findings link increased expression of the structurally complex 'b' pathway
      gangliosides GD1b, GT1b, GQ1b (CbG) to a favourable clinical and biological
      behaviour in human neuroblastoma (NB). Seeking a model to probe these
      observations, we evaluated four human NB cell lines. Very low CbG content (4-10%)
      in three of the four cell lines (LAN-5, LAN-1, SMS-KCNR) reflected the
      ganglioside pattern observed in the most aggressive NB tumours. Pharmacological
      alterations of complex ganglioside synthesis in vitro by a 5-7 day exposure to 5
      10 microM retinoic acid, which is employed in maintenance therapy of disseminated
      NB, included markedly increased (i) relative expression of CbG (6.6+/-2.0-fold
      increase, P=0.037), (ii) relative expression of the analogous 'a' pathway
      gangliosides, termed CaG (6.4+/-1.4-fold increase in GM1a and GD1a; P=0.010), and
      (iii) total cellular ganglioside content (2.0-6.3-fold), which in turn amplified
      the accumulation of structurally complex gangliosides. Substantial increases (2.7
      2.9-fold) in the activity of GD1b/GM1a synthase (beta-1,3-galactosyltransferase),
      which initiates the synthesis of CbG and CaG, accompanied the all-trans retinoic
      acid (ATRA)-induced ganglioside changes. Thus, increased CbG synthesis in NB cell
      lines is attributable to a specific effect of ATRA, namely induction of GD1b/GM1a
      synthase activity. Since the shift towards higher expression of CbG and CaG
      during retinoic acid-induced cellular differentiation reflects a ganglioside
      pattern found in clinically less-aggressive tumours, our studies suggest that
      complex gangliosides may play a role in the biological and clinical behaviour of
      NB.

PMID- 15188001
TI  - Interaction of dense breast patterns with other breast cancer risk factors in a
      case-control study.
AB  - The question of interactions between breast density and other breast cancer risk
      factors is of interest, since it bears upon the use of density as a marker for
      changes in breast cancer risk. We studied breast parenchymal patterns and 13
      other potential risk factors for breast cancer in 172 breast cancer cases and 338
      age-matched controls in Singapore. Dense breast patterns were defined as having
      Tabar parenchymal pattern IV or V. We found significant interactions between
      dense patterns and ethnic group (P=0.046), and between dense patterns and number
      of deliveries (P=0.04). Among women with nondense breast patterns, the non
      Chinese had lower risk than the Chinese with an odds ratio (OR) of 0.47 (95% CI
      0.24, 0.88), whereas in those with dense patterns, the non-Chinese had
      considerably higher risks (OR=5.34, 95% CI 0.54, 52.51). Alternatively expressed,
      the increased risk with dense patterns was only observed in the non-Chinese
      (OR=13.99, 95% CI 1.33, 146.99). Among parous women, the protective effect of
      three or more deliveries was only observed in those with dense breast patterns
      (OR=0.21, 95% CI 0.06, 0.70). Suggestive but nonsignificant interactions with
      dense patterns were observed for ever having delivered, age at first delivery,
      breast feeding and body mass index. The results are consistent with dense breast
      patterns as a marker for hormonal modification of breast cancer risk.

PMID- 15188000
TI  - Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B
      signalling and apoptosis.
AB  - Epidemiological evidence indicates that non-steroidal anti-inflammatory drugs
      (NSAIDs) protect against colorectal cancer (CRC) to a greater degree than other
      non-gastrointestinal cancers, but the molecular basis for this difference is
      unknown. We previously reported that aspirin induces signal-specific I kappa B
      alpha degradation followed by NF kappa B nuclear translocation in CRC cells, and
      that this mechanism contributes substantially to aspirin-induced apoptosis. Here,
      we explored the hypothesis that cell-type specific effects on NF kappa B
      signalling are responsible for the observed differences in protection by aspirin
      against CRC compared to breast and gynaecological cancers. We also assessed
      whether COX-2 expression, mutation status of adenomatous polyposis coli (APC),
      beta-catenin, p53, or DNA mismatch repair (MMR) genes in CRC lines influenced
      aspirin-induced effects. We found that aspirin induced concentration-dependent I
      kappa B alpha degradation, NF kappa B nuclear translocation and apoptosis in all
      CRC lines studied. However, there was no such effect on the other cancer cell
      types, indicating a considerable degree of cell-type specificity. The lack of
      effect on NF kappa B signalling, paralleled by absence of an apoptotic response
      to aspirin in non-CRC lines, strongly suggests a molecular rationale for the
      particular protective effect of NSAIDs against CRC. Effects on NF kappa B and
      apoptosis were observed irrespective of COX-2 expression, or mutation status in
      APC, beta-catenin, p53 and DNA MMR genes, underscoring the generality of the
      aspirin effect on NF kappa B in CRC cells. These findings raise the possibility
      of cell-type specific targets for the development of novel chemopreventive
      agents.

PMID- 15188002
TI  - Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for
      antileukaemic therapy.
AB  - Activation of PKA by cAMP agonists, such as 8-Cl-cAMP activation, selectively
      causes rapid apoptosis in v-abl transformed fibroblasts by inhibiting the Raf-1
      kinase. Here we investigated whether 8-Cl-cAMP is useful for the treatment of
      chronic myelogenous leukaemia (CML), which is hallmarked by the expression of the
      p210(bcr/abl) oncogene. Autologous bone marrow transplantation is a feasible
      alternative for patients with no suitable donor, but hampered by the risk of
      relapse due to the persistence of leukaemia cells in the transplant. To study the
      effects of 8-Cl-cAMP on primary leukaemic cells, bone marrow cells (BMCs) from
      eight CML patients (one at diagnosis, three in chronic and four in accelerated
      phase) were treated. Ex vivo treatment of BMCs obtained in chronic phase of CML
      with 100 microM 8-Cl-cAMP for 24-48 h led to the selective purging of
      Philadelphia Chromosome (Ph1 chromosome) without toxic side effects on BMCs from
      healthy donors as measured by colony-forming unit (CFU) assays. BMCs from
      patients in accelerated phase showed selective, but incomplete elimination of Ph1
      chromosome positive colony forming cells. The mechanism of 8-Cl-cAMP was
      investigated in FDCP-mix cells transformed by p210(bcr/abl), a cell culture model
      for CML. The results showed that 8-Cl-cAMP reduced DNA synthesis and viability
      independent of Raf inhibition as Raf inhibitors had no effect. MEK inhibitors
      interfered with DNA synthesis, but not with viability. In summary, our results
      indicate that 8-Cl-cAMP could be useful to purge malignant cells from the bone
      marrow of patients with CML and certain other forms of leukaemias.

PMID- 15188004
TI  - Missing covariate data within cancer prognostic studies: a review of current
      reporting and proposed guidelines.
AB  - Prognostic models play a crucial role in the clinical decision-making process.
      Unfortunately, missing covariate data impede the construction of valid and
      reliable models, potentially introducing bias, if handled inappropriately. The
      extent of missing covariate data within reported cancer prognostic studies, the
      current handling and the quality of reporting this missing covariate data are
      unknown. Therefore, a review was conducted of 100 articles reporting multivariate
      survival analyses to assess potential prognostic factors, published within seven
      cancer journals in 2002. Missing covariate data is a common occurrence in studies
      performing multivariate survival analyses, being apparent in 81 of the 100
      articles reviewed. The percentage of eligible cases with complete data was
      obtainable in 39 articles, and was <90% in 17 of these articles. The methods used
      to handle incomplete covariates were obtainable in 32 of the 81 articles with
      known missing data and the most commonly reported approaches were complete case
      and available case analysis. This review has highlighted deficiencies in the
      reporting of missing covariate data. Guidelines for presenting prognostic studies
      with missing covariate data are proposed, which if followed should clarify and
      standardise the reporting in future articles.

PMID- 15188003
TI  - Assessment of vascular reactivity in rat brain glioma by measuring regional blood
      volume during graded hypoxic hypoxia.
AB  - While morphological and molecular events during angiogenesis in brain glioma have
      been extensively studied, the functional properties of tumour vessels have yet
      received little attention. We have determined changes in regional blood volume
      (BV) during graded hypoxic hypoxia using susceptibility contrast magnetic
      resonance imaging in a model of rat brain glioma. Nine anaesthetised and
      ventilated rats with C6 glioma were subjected to incremental reduction in the
      fraction of inspired oxygen (FiO(2)): 0.35, 0.25, 0.15, 0.12, 0.10 and
      reoxygenation to 0.35. At each episode, BV was determined in peritumoral,
      intratumoral and contralateral regions. Baseline BV values (FiO(2) of 0.35) were
      higher in peritumoral than in the contralateral and intratumoral regions.
      Progressive hypoxia resulted in a graded increase in BV in contralateral and
      peritumoral regions. At FiO(2) of 0.10, BV increases were comparable between
      these two regions: 49+/-22% (s.d.) and 28+/-17% with respect of control values,
      respectively. These BV changes reversed during the reoxygenation episode. By
      contrast, the intratumoral region had a significant increase in BV at FiO(2) of
      0.10 only, with no evidence of return to the basal value during reoxygenation.
      Immunohistochemical staining of alpha-smooth muscle actin confirmed reactivity of
      vessels in the peritumoral region. Our findings indicate that peritumoral vessels
      present a vascular reactivity to hypoxia, which is comparable to that of
      nontumoral vessels. A method is thus available for noninvasively demonstrating
      whether any particular vascular modifying strategy results in the desired outcome
      in terms of tumour blood volume changes.

PMID- 15188005
TI  - Oestrogen inhibits resveratrol-induced post-translational modification of p53 and
      apoptosis in breast cancer cells.
AB  - Resveratrol, a naturally occurring stilbene, induced apoptosis in human breast
      cancer MCF-7 cells. The mechanism of this effect was dependent on mitogen
      activated protein kinase (MAPK, ERK1/2) activation and was associated with serine
      phosphorylation and acetylation of p53. Treatment of MCF-7 cells with resveratrol
      in the presence of 17beta-oestradiol (E(2)) further enhanced MAPK activation, but
      E(2) blocked resveratrol-induced apoptosis, as measured by nucleosome ELISA and
      DNA fragmentation assays. E(2) inhibited resveratrol-stimulated phosphorylation
      of serines 15, 20 and 392 of p53 and acetylation of p53 in a concentration- and
      time-dependent manner. These effects of E(2) on resveratrol action were blocked
      by ICI 182,780 (ICI), an inhibitor of the nuclear oestrogen receptor-alpha (ER).
      ICI 182,780 did not block the actions of resveratrol, alone. Electrophoretic
      mobility studies of p53 binding to DNA and of p21 expression indicated that E(2)
      inhibited resveratrol-induced, p53-directed transcriptional activity. These
      results suggest that E(2) inhibits p53-dependent apoptosis in MCF-7 cells by
      interfering with post-translational modifications of p53 which are essential for
      p53-dependent DNA binding and consequent stimulation of apoptotic pathways. These
      studies provide insight into the complex pathways by which apoptosis is induced
      by resveratrol in E(2)-depleted and -repleted environments.

PMID- 15188006
TI  - Effect of nonsteroidal anti-inflammatory drugs on beta-catenin protein levels and
      catenin-related transcription in human colorectal cancer cells.
AB  - Elevated beta-catenin levels in human colorectal cancer (CRC) cells lead to
      increased trans-activation of 'protumorigenic' beta-catenin/T-cell factor (TCF)
      target genes such as cyclin D1. Therefore, possible targets for the anti-CRC
      activity of nonsteroidal anti-inflammatory drugs (NSAIDs) are beta-catenin and
      catenin-related transcription (CRT). We tested the antiproliferative activity and
      the effects on levels of beta-catenin and cyclin D1 protein, as well as CRT
      (measured using a synthetic beta-catenin/TCF-reporter gene [TOPflash]), of a
      panel of NSAIDs (indomethacin, diclofenac, sulindac sulphide and sulphone,
      rofecoxib; range 10-600 microM) on SW480 human CRC cells in vitro. Following
      NSAID treatment, there was no consistent relationship between reduced cell
      proliferation, induction of apoptosis and changes in beta-catenin protein levels
      or CRT. All the NSAIDs, except rofecoxib, decreased nuclear beta-catenin content
      and cyclin D1 protein levels in parallel with their antiproliferative activity.
      However, cyclin D1 downregulation occurred prior to a decrease in total beta
      catenin protein levels and there was no correlation with changes in CRT,
      suggesting the existence of CRT-independent effects of NSAIDs on cyclin D1
      expression. In summary, NSAIDs have differential effects on beta-catenin protein
      and CRT, which are unlikely to fully explain their effects on cyclin D1 and their
      antiproliferative activity on human CRC cells in vitro. British Journal of Cancer
      (2004) 91, 153-163. doi:10.1038/sj.bjc.6601901 www.bjcancer.com Published online
      8 June 2004

PMID- 15188007
TI  - DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous
      cell carcinoma.
AB  - This is the first report to correlate DARPP-32 immunoreactivity (dopamine and
      cAMP-regulated phosphoprotein, M(r) 32 000) to clinicopathological status in
      human cancer. DARPP-32 is recognised as a neuronal protein. A recent study
      demonstrated that DARPP-32, and a truncated isoform t-DARPP, are overexpressed in
      gastric carcinoma during the process of carcinogenesis. The biological function
      of DARPP-32, however, is still unclear. The purpose of this study was to clarify
      the roles of DARPP-32 and t-DARPP in oesophageal squamous cell carcinoma (OSCC).
      Initially, we investigated DARPP-32 and t-DARPP expression in OSCC cell lines by
      Reverse transcription-polymerase chain reaction and Western blot. DARPP-32
      expression was observed in four out of seven (57.1%) cell lines, but t-DARPP
      expression was not observed in any cell lines. In oesophageal tissue sample,
      DARPP-32 expression was observed in four out of seven (57.1%) tumour tissues,
      while t-DARPP was not observed in any tissues. Subsequently, DARPP expression was
      assessed by immunohistochemistry, using a polyclonal antibody, in tissue sections
      from 122 patients with primary OSCC. DARPP immunoreactivity was not observed in
      any normal oesophageal mucous membranes. On the other hand, positive DARPP
      immunostaining was detected in 37 patients (30.3%) and correlated inversely with
      pathologic stage (P=0.0284), pT (P=0.0438), pN (P=0.0303) and tumour size
      (P=0.012). The overall survival rate was worse in patients with DARPP-negative
      tumours than in patients with DARPP-positive tumours (P=0.0453). Interestingly,
      DARPP expression was observed in only one out of 45 cases of dysplasia. These
      observations suggest that DARPP-32 (rather than t-DARPP) expression arises after
      a phase of dysplasia in OSCC, and that tumours expressing DARPP-32 progress less
      rapidly than DARPP-32-negative tumours.

PMID- 15188008
TI  - Downregulation of Bcl-2 sensitises interferon-resistant renal cancer cells to
      Fas.
AB  - Interferon alpha (IFNalpha) is used to treat patients with advanced renal cell
      carcinoma (RCC) despite limited clinical benefit. IFNalpha can induce Fas
      receptor-mediated apoptosis by direct activation of pro-caspase-8 followed by
      activation of caspase-3. Alternative, indirect activation of caspase-3 via
      mitochondrial release of cytochrome c can occur and may explain the rescue from
      Fas-activated cell death by the antiapoptotic members of the Bcl-2 family. In
      this study, we examined G3139, a novel antisense compound targeting Bcl-2, in
      combination with IFNalpha. Human RCC lines (SK-RC-44 and SK-RC-07) were treated
      with IFNalpha, G3139 or a combination of the two. Fas-mediated cytotoxicity was
      induced by anti-Fas mAb, CH11. An analysis of Bcl-2, Fas and the cleavage of PARP
      was performed. IFNalpha induced Fas and Bcl-2 in SK-RC-44 and SK-RC-07. IFNalpha
      sensitised SK-RC-44 to anti-Fas and induced PARP cleavage confirming that
      IFNalpha has a cytotoxic effect on RCC lines by induction of the Fas antigen.
      Cytotoxicity was not evident in SK-RC-07 cells treated with IFNalpha. G3139
      induced a specific downregulation of Bcl-2 in SK-RC-07 cells, which were then
      sensitised to anti-Fas after treatment with IFNalpha. Taken together, these
      results suggest that Fas-dependent pathways as well as alternative pathways,
      which can be inhibited by Bcl-2, exist in renal cell carcinoma. G3139 in
      combination with IFNalpha is a potential therapy in patients with metastatic
      renal cell carcinoma.

PMID- 15188009
TI  - The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website.
AB  - The discovery of mutations in cancer genes has advanced our understanding of
      cancer. These results are dispersed across the scientific literature and with the
      availability of the human genome sequence will continue to accrue. The COSMIC
      (Catalogue of Somatic Mutations in Cancer) database and website have been
      developed to store somatic mutation data in a single location and display the
      data and other information related to human cancer. To populate this resource,
      data has currently been extracted from reports in the scientific literature for
      somatic mutations in four genes, BRAF, HRAS, KRAS2 and NRAS. At present, the
      database holds information on 66 634 samples and reports a total of 10 647
      mutations. Through the web pages, these data can be queried, displayed as figures
      or tables and exported in a number of formats. COSMIC is an ongoing project that
      will continue to curate somatic mutation data and release it through the website.

PMID- 15188010
TI  - Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in
      metastatic or recurrent, unresectable gastric cancer.
AB  - Based on single agent activities and the additive or synergistic effects of three
      individual drugs in gastric cancer, we performed a phase II study of a new
      regimen combining epirubicin, docetaxel and cisplatin (EDP) for unresectable
      gastric cancer. The patients with histologically confirmed metastatic or
      recurrent, unresectable gastric cancer and no history of palliative chemotherapy
      were eligible for this trial. In total, 40 mg m(-2) epirubicin (reduced to 30 mg
      m(-2) due to high incidence of febrile neutropaenia; 75%) intravenously (i.v.)
      over 30 min, followed by 60 mg m(-2) docetaxel i.v. over 1 h, then 75 mg m(-2)
      cisplatin i.v. over 1 h was administered every 3 weeks. Between January 2002 and
      February 2003, 30 patients (epirubicin 40 mg m(-2), eight; 30 mg m(-2), 22) were
      enrolled. The median age was 52 years (range, 33-68). The patients received a
      median of four cycles (range, 1-8). One patient (3%) achieved a complete
      response, 13 (43%) showed partial responses, 13 (43%) had stable diseases and
      three (10%) progressed. The overall response rate was 47% (95% CI, 28-66%), and
      the median duration of response was 5.0 months (95% CI, 3.0-7.0). The median time
      to progression was 4.1 months (95% CI, 2.4-5.9), and the median overall survival
      was 11.0 months (95% CI, 9.5-12.4). Grade 4 neutropaenia were observed in 41%,
      and febrile neutropaenia in 32%, out of the patients receiving 30 mg m(-2) of
      epirubicin. Grade 3 nonhaematological toxicities included nausea, vomiting,
      anorexia and peripheral neuropathy. In conclusion, EDP is active in gastric
      cancer, with a manageable and predictable toxicity profile.

PMID- 15188011
TI  - Cost of managing women presenting with stage IV breast cancer in the United
      Kingdom.
AB  - This study estimated lifetime cost of treatment for patients in the United
      Kingdom (UK) presenting with stage IV breast cancer. To determine patterns of
      treatment and resource use in the absence of direct observational data, a cancer
      physician panel was surveyed. The survey questionnaire described four predefined
      treatment phases: active treatment; follow-up after active treatment until
      disease progression; active supportive care after progression; and end-of-life
      care. Physicians were asked their major treatment strategies for each phase.
      Monthly cost and average lifetime cost per patient were calculated. Only five
      cancer registries in the UK document the proportion of breast cancer patients
      diagnosed with stage IV disease. Their data was used to estimate the incidence of
      metastatic breast cancer at presentation throughout the UK. This value, together
      with lifetime cost per patient and projected survival time, allowed approximation
      of the overall cost for this population of cancer patients in the UK. Annual
      incidence of stage IV breast cancer at presentation in the UK is approximately
      2100; according to treatment practice in 2002, lifetime cost per patient is pound
      12 500 and total population cost is approximately pound 26 million. The
      substantial economic burden associated with patients diagnosed with metastatic
      breast cancer should be considered when developing strategies for reducing its
      incidence such as increased awareness, screening and preventative measures.

PMID- 15188012
TI  - Sentinel lymph-node biopsy in head and neck cancer.
AB  - The aim of the study was to assess the diagnostic value of the sentinel node
      method in patients suffering from squamous cell carcinoma of the upper
      aerodigestive tract. In 50 patients with oral, pharyngeal or laryngeal carcinomas
      staged N0 up to 50 MBq technetium-99m colloid were injected peritumorally.
      Sentinel nodes were localised using a gamma-probe in the setting of an elective
      neck dissection. Pathological findings of sentinel nodes and corresponding neck
      specimens were compared. In 46 patients sentinel nodes were detected. Of these 34
      patients were free of metastatic disease in the sentinel nodes and in the neck
      specimens. In 12 patients clinically occult metastases were found in the sentinel
      nodes. Three metastases were detected only after additional sectioning of the
      sentinel nodes. In four patients, a sentinel lymph node could not be localised.
      Our results support the sentinel node concept in head and neck cancer and a
      definition of the sentinel nodes as the three nodes with the highest activity.
      Careful clinical staging of the neck and thorough pathological evaluation of the
      sentinel nodes are necessary to avoid false-negative results.

PMID- 15188014
TI  - Fluorescence Resonance Energy Transfer (FRET) as a method to calculate the
      dimerization strength of basic Helix-Loop-Helix (bHLH) proteins.
AB  - Post-translational modifications such as phosphorylation play a vital role in the
      regulation of protein function. In our study of the basic Helix-loop-Helix (bHLH)
      transcription factor HAND1, we show that HAND1 is phosphorylated during the
      trophoblast giant cell differentiation on residues residing in Helix I of the
      bHLH domain. Our hypothesis is that these modifications result in changes in
      HAND1 dimerization affinities with other bHLH factors. To test this idea, we
      employed FRET to measure the protein-protein interactions of HAND1 and HAND1
      point mutants in HEK293 cells using YFP and CFP fusion proteins and laser
      scanning confocal microscopy.

PMID- 15188013
TI  - Effectiveness of preoperative staging in rectal cancer: digital rectal
      examination, endoluminal ultrasound or magnetic resonance imaging?
AB  - In rectal cancer, preoperative staging should identify early tumours suitable for
      treatment by surgery alone and locally advanced tumours that require therapy to
      induce tumour regression from the potential resection margin. Currently, local
      staging can be performed by digital rectal examination (DRE), endoluminal
      ultrasound (EUS) or magnetic resonance imaging (MRI). Each staging method was
      compared for clinical benefit and cost-effectiveness. The accuracy of high
      resolution MRI, DRE and EUS in identifying favourable, unfavourable and locally
      advanced rectal carcinomas in 98 patients undergoing total mesorectal excision
      was compared prospectively against the resection specimen pathological as the
      gold standard. Agreement between each staging modality with pathology assessment
      of tumour favourability was calculated with the chance-corrected agreement given
      as the kappa statistic, based on marginal homogenised data. Differences in
      effectiveness of the staging modalities were compared with differences in costs
      of the staging modalities to generate cost effectiveness ratios. Agreement
      between staging and histologic assessment of tumour favourability was 94% for MRI
      (kappa=0.81, s.e.=0.05; kappa(W)=0.83), compared with very poor agreements of 65%
      for DRE (kappa=0.08, s.e.=0.068, kappa(W)=0.16) and 69% for EUS (kappa=0.17,
      s.e.=0.065, kappa(W)=0.17). The resource benefits resulting from the use of MRI
      rather than DRE was 67164 UK pounds and 92244 UK pounds when MRI was used rather
      than EUS. Magnetic resonance imaging dominated both DRE and EUS on cost and
      clinical effectiveness by selecting appropriate patients for neoadjuvant therapy
      and justifies its use for local staging of rectal cancer patients.

PMID- 15188015
TI  - Recombinant antigens for immunodiagnosis of cystic echinococcosis.
AB  - Three cDNAs, termed EpC1, TPxEg and EgG5, were isolated by immunoscreening from
      an Echinococcus granulosus cDNA library. The recombinant phages exhibited strong
      reactivity with sera from humans with confirmed cystic echinococcosis (CE) and
      with sera from mice infected with E. granulosus oncospheres. The cDNAs were
      subcloned into a pET vector, expressed as fusion proteins tagged with GST and
      affinity purified against the GST tag. Of the three recombinant proteins, EpC1
      achieved the highest performance for serodiagnosis of CE in Western blot analysis
      using a panel of clinically defined human sera to initially address the
      sensitivity and specificity of the molecules. The protein yielded an overall
      sensitivity of 92.2% and specificity of 95.6%, levels unprecedented taking into
      account the large panel of 896 human sera that were tested. The strategy used may
      also prove suitable for improved immunodiagnosis of other parasitic infections.

PMID- 15188016
TI  - The antisocial attitudes and associates of sex offenders.
AB  - INTRODUCTION: Meta-analyses have demonstrated that attitudes and associates (peer
      group behaviour) are among the best predictors of antisocial behaviour in
      offender populations. Research on sex offender attitudes has typically focused on
      sex-related content and not antisocial attitudes in general. This study
      investigates the antisocial attitudes of sex offenders by comparing them with non
      sex offenders on responses to the Measures of Criminal Attitudes and Associates
      (MCAA). METHOD: The MCAA comprises two parts. Part A is a quantified self-report
      measure of criminal friends. Part B contains four attitude scales: Violence,
      Entitlement, Antisocial Intent and Associates. Ninety sex offenders were compared
      with 119 nonsex offenders on their endorsement of the MCAA and criminal history.
      RESULTS: Sex offenders endorsed fewer antisocial attitudes, reported fewer
      criminal friends and had fewer incarcerations than did non-sex offenders. Rapists
      endorsed antisocial attitudes more than did child molesters and incest offenders.
      However, these differences disappeared on controlling for age. A finding of fewer
      previous incarcerations among sex offenders was robust even controlling for age.
      CONCLUSION: The MCAA appears to be a reliable and valid instrument with sex
      offender samples. General antisocial attitudes appear to have a similar
      relationship with criminal history for both sex offenders and non-sex offenders,
      and should not be ignored in future studies or clinical practice. While a general
      sense of entitlement was not associated with sex offending per se, its stronger
      association with incarceration among sex offenders than non-sex offenders might
      suggest that this has the potential for identifying an important, perhaps more
      serious sub-group of sex offenders.

PMID- 15188017
TI  - Presentation of antisocial personality disorder: mounting evidence on optimal
      timing and methods.

PMID- 15188019
TI  - Understanding sexual offending in schizophrenia.
AB  - BACKGROUND: Studies have found an elevated incidence of violent sexual offences
      in males with schizophrenia. The relationship between sexual offending and
      psychiatric illness is, however, complex and poorly defined. AIMS: The aim of the
      present article is to delineate possible mechanisms that underlie offensive
      sexual behaviour in schizophrenia that can be used as a framework for assessing
      and treating these behaviours. A review of research pertaining to the aetiology
      of sexual deviance in schizophrenia was conducted, focusing in particular on the
      role of early childhood experiences, deviant sexual preferences, antisocial
      personality traits, psychiatric symptomatology and associated treatment effects,
      the impact of mental illness on sexual and social functioning, and other
      potential contributory factors. TOWARDS A TYPOLOGY: It is proposed that
      schizophrenic patients who engage in sexually offensive activities fall into four
      broad groups: (1) those with a pre-existing paraphilia; (2) those whose deviant
      sexuality arises in the context of illness and/or its treatment; (3) those whose
      deviant sexuality is one manifestation of more generalized antisocial behaviour,
      and (4) factors other than the above. This classification provides a useful
      framework for evaluating and treating sexually offensive behaviours in
      schizophrenic patients.

PMID- 15188018
TI  - Precursors and correlates of criminal behaviour in women.
AB  - BACKGROUND: The precursors and correlates of criminal behaviour in women were
      examined in this longitudinal study of women in their late thirties. METHODS: The
      sample consisted of a high-risk group of women (n = 86) and a comparison group (n
      = 97): the former had been raised in institutional care. Questionnaire measures
      of childhood behaviour problems and detailed interview data from two time points
      in adulthood were obtained, along with official records of offending. RESULTS: In
      terms of childhood precursors, antisocial behaviour, institutional rearing,
      hyperactivity and adolescent conduct disorder were found to be significantly
      related to offending. Later adolescent factors were also found to be important:
      mixing with deviant peers and leaving school without any qualifications or plans
      for work. Correlates of offending in adulthood included difficulties in mental
      health, drug use, marriage and parenting. Further analysis was undertaken to
      clarify the associations by using ex-care status and conduct disorder as
      covariates. DISCUSSION: Well-established predictors of offending in male samples
      seem quite as important for women and girls. The findings also suggested strong
      links between offending and problems in parenting.

PMID- 15188020
TI  - Characteristics of spousal homicide perpetrators: a study of all cases of spousal
      homicide in Sweden 1990-1999.
AB  - BACKGROUND: In Sweden 20 000 cases of assault against women are reported to the
      police every year. METHOD: All data on the perpetrators of spousal homicide in
      Sweden between 1990 and 1999 were investigated (n = 164). A control group of all
      other perpetrators of homicide in Sweden during the same period, i.e. cases of
      homicide not committed in the context of spouse violence (n = 690) was used. All
      verdicts, as well as all material in the police investigations, including
      interviews with all of the police investigators, were analysed. Copies of police
      examinations of the suspects, and forensic reports from the autopsies, were also
      examined. Data on all registered criminality were collected from the National
      Police Register, and in cases where the perpetrators had been subject to forensic
      psychiatric examinations, those reports were obtained from the Swedish National
      Board of Forensic Medicine. In addition, the Psychopathy Checklist: Screening
      Version scores were rated from the forensic psychiatric examinations. RESULTS:
      There was a four times higher suicide rate among the spousal homicide
      perpetrators (24%, n = 40) compared with the perpetrators in the control-group
      (6%, n = 39, chi-squared = 55,42 df = 1, p < 0.001). Consequently, suicidal
      ideation must be considered as an important risk factor for spousal homicide. In
      79% of the cases the spousal homicide perpetrators were subject to forensic
      psychiatric examinations. All except 5% were diagnosed with at least one
      psychiatric diagnosis, and 34% were sentenced to forensic psychiatric treatment.
      If it is assumed that the psychiatric morbidity was high in the 24% of the
      perpetrators who committed suicide, then 80% of all perpetrators of spouse
      homicide during the study period can be characterized as mentally disordered.
      'Psychopathic' perpetrators, who generally are over-represented in most violent
      criminality, were comparatively uncommon. Only seven (4%) in the study group met
      the diagnostic criteria for psychopathy as measured with the PCL:SV. DISCUSSION:
      The group of spouse killers studied here fits the dysphoric/borderline group of
      spouse assaulters. This is a group that may benefit from treatment. Perhaps
      police officers could help identify this kind of spouse assaulter before a
      fatality occurs.

PMID- 15188021
TI  - Tumor stem cells.
AB  - Stem cells possess two basic characteristics: they are able to renew themselves
      and to develop into different cell types. The link between normal stem cells and
      tumor cells could be examined in three aspects: what are the differences and
      similarities in the control of self-renewal capacity between stem cells and tumor
      cells; whether tumor cells arise from stem cells; do tumorous stem cells exist?
      Since tumor cells also exhibit self-renewal capacity, it seems plausible that
      their regulation is similar to that of the stem cells. The infinite self-renewal
      ability (immortalization) is assured by several, so far only partly known,
      mechanisms. One of these is telomerase activity, another important regulatory
      step for survival is the inhibition of apoptosis. Other signal transduction
      pathways in stem cell regulation may also play certain roles in carcinogenesis:
      e.g. Notch, Sonic hedgehog (SHH), and Wnt signals. Existence of tumor stem cells
      was suggested since it is simpler to retain the self-renewal capacity than to
      reactivate the immortality program in an already differentiated cell. Moreover,
      stem cells live much longer than the differentiated ones, and so they are exposed
      for a long period of time to impairments, collecting gene errors leading to the
      breakdown of the regulation. However, it is still an open question whether all
      cells in the tumor possess the capacity that produces this tissue or not, that
      is: are there tumor stem cells or there are not. If tumor stem cells exist, they
      would be the main target for therapy: only these must be killed since the other
      tumor cells possess limited proliferative capacity, therefore limited life span.
      The only problem is that during tumor progression stem-like cells can develop
      continuously and the identification but mainly the prevention of their formation
      is still a great challenge.

PMID- 15188023
TI  - Immunophenotyping of tumor-infiltrating mononuclear cells in ovarian carcinoma.
AB  - Infiltrating mononuclear cells play an important role in many types of cancer.
      The aim of this work was to determine the immunologic characteristics of
      mononuclear cellular infiltrate in ovarian cancer as compared to benign ovarian
      tumors. Paraffin-embedded tissues obtained from 52 ovarian carcinomas and 21
      benign ovarian neoplasms were examined immunohistochemically to demonstrate
      suppressor/cytotoxic T cells and macrophages by using CD8 and CD68 monoclonal
      antibodies, respectively. The mean percentage of CD8+ cells was much higher in
      the malignant than in the benign group (P=0.00009). Similarly, the mean level of
      CD68+ cells was significantly higher in carcinomas than in benign cases
      (P=0.006). There was a significant negative correlation between the percentage of
      CD8+ cells and CD68+ cells in the malignant group (P=0.000002). Conversely, no
      correlation could be obtained between the values of these two cell types in the
      benign lesions. In the malignant group, although the percentages of CD8+ cells
      and CD68+ cells were not related to tumor differentiation, they were
      significantly related to tumor type. CD8+ cells were significantly higher in the
      serous (P=0.02), and CD68+ cells were higher in the mucinous carcinomas
      (P=0.0005). CD8+ T cells and macrophages constitute a major component of the
      infiltrating mononuclear cells in ovarian carcinoma. Their frequency seems to be
      related to the tumor type rather than the degree of tumor differentiation.

PMID- 15188022
TI  - Clinicopathological significance of metallothioneins in breast cancer.
AB  - Metallothioneins (MTs) are a family of metal binding proteins that play an
      important role in maintaining transition metal ion homoeostasis, redox balance in
      the cell and fundamental cellular processes such as proliferation and apoptosis.
      In humans, there are 4 groups of MT proteins which are encoded by 10 functional
      MT isoforms. In breast tissues, MT is primarily expressed in myoepithelial and
      malignant epithelial cells. Immunohistochemical studies have revealed that 26% to
      100% of invasive ductal breast cancers express the MT protein. The MT-1F and MT
      2A isoforms have been reported to be associated with higher histological grade in
      breast cancer, whereas higher MT-1E mRNA expression was found in estrogen
      receptor-negative tumors compared to their estrogen receptor-positive
      counterparts. A number of studies have shown that MT expression in breast cancer
      is associated with poorer prognosis. In addition, metallothionein expression may
      have a potential role in protecting the breast cancer cell from chemotherapeutic
      threats to survival.

PMID- 15188024
TI  - The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas.
AB  - Thyroid transcription factor-1 (TTF-1) is a sensitive marker for pulmonary and
      thyroid adenocarcinomas. The aim of this work was to determine its usefulness in
      distinction between primary and metastatic lung adenocarcinomas. We have examined
      the expression of TTF-1 in 100 solitary pulmonary nodules. They included 50 stage
      I peripheral primary bronchial adenocarcinomas (30 men, 20 women, mean age: 60
      years) and 50 metastatic pulmonary adenocarcinomas (21 men, 29 women, mean age:
      57 years) of different origins, such as breast (13), colon (13), rectum (13),
      kidney (7), stomach (2), and thyroid gland (2). TTF-1 immunohistochemistry was
      performed on formalin-fixed, paraffin-embedded tissues. In primary bronchial
      adenocarcinomas we found immunopositivity in 46/50 cases, among them 30 cases
      showed strong nuclear immunostaining. In four primary adenocarcinoma cases the
      observed immunopositivity was localized to the cytoplasm. Out of the metastatic
      adenocarcinomas all but the 2 thyroid cancers were negative. Both thyroid tumors
      showed strong immunopositivity. Our results confirm that TTF-1
      immunohistochemistry is a very sensitive and highly specific method in the
      differential diagnosis of primary and metastatic lung adenocarcinomas and should
      be used in the everyday clinical practice.

PMID- 15188025
TI  - Significantly decreased P27 expression in endometrial carcinoma compared to
      complex hyperplasia with atypia (correlation with p53 expression).
AB  - P27 expression was examined on paraffin-embedded specimens in proliferative,
      secretory, hyperplastic and neoplastic human endometrium by immunohistochemistry.
      The results of p27 immunoreactivity in endometrial carcinomas were compared with
      clinicopathological indicators as well as with p53 expression. Thirty-eight cases
      of endometrial carcinoma, 30 normal functional (15 proliferative, 15 secretory),
      24 hyperplastic endometrium (12 without atypia, 12 with atypia) specimens were
      studied by using monoclonal p27 and p53 antibodies. The streptavidin-biotin
      peroxidase detection system was used and the intensity and the distribution of
      immunoreactivity was evaluated semiquantitatively. p27 expression was present
      both in the proliferative and secretory phases; the expression being stronger in
      the secretory period. In complex hyperplasia with atypia, p27 expression was even
      higher and it was significantly reduced in the endometrial carcinoma group
      (p<0.05). No significant correlation was found between p27 expression and any of
      the clinicopathologic prognostic parameters (p>0.05). Nuclear p53 expression was
      detected in 13 (34.2%) patients with endometrial carcinoma and was higher in non
      endometrioid carcinomas and in tumors with increasing FIGO grade (p<0.05). High
      expression of p53 was not found to be a significant prognostic indicator of
      survival (p>0.05). No p53 expression was detected in the endometria with
      proliferation, secretion or hyperplasia either simple without atypia or complex
      with atypia. Surprisingly, tumors with absent/low p27 expression showed
      absent/low p53 expression. Our data suggest that p27 is necessary to control the
      proliferation of endometrium and its loss of expression seems to play a role in
      some aspects of endometrial carcinogenesis.

PMID- 15188026
TI  - Apoptosis and P53, Bcl-2 and Bax gene expression in parathyroid glands of
      patients with hyperparathyroidism.
AB  - Altogether 107 patients were operated on at the Department of Transplantation and
      Surgery of Semmelweis University in the past four years, for clinical symptoms of
      hyperparathyroidism. Clinical and laboratory data of the patients supported the
      diagnosis of primary or secondary hyperparathyroidism. Chronically impaired renal
      function was found in 52 cases. The removed parathyroid glands showed hyperplasia
      in 54, adenoma in 50 and carcinoma in 3 cases. The majority of parathyroid
      lesions in primary hyperparathyroidism were adenomas (41 cases) and in secondary
      hyperparathyroidism were hyperplasias (43 cases). The ratio of oxyphil to chief
      cells as well as occasional mitotic and apoptotic figures were determined. The
      oxyphil component was present in both hyperplastic and tumorous lesions.
      Apoptosis and mitosis were rarely seen in hyperplasias and adenomas (under 2%),
      whereas in carcinomas 3% of the tumor cells were apoptotic and 4% showed mitosis.
      Cytoplasmic p53 positivity could be observed in 3 of the adenomas and in 2 of the
      hyperplasias. The carcinomas, four adenomas and 3 hyperplasias showed nuclear p53
      positivity. Bcl-2 and Bax were detected in the cytoplasm of the tumor cells in
      the majority of adenomas and in the cells of hyperplasias. Oxyphil cells were
      more frequently positive than chief cells or clear cells. Colocalization of Bcl-2
      and Bax was found randomly in all types of lesions. The very low incidence of
      carcinoma, the low mitotic and apoptotic ratio in adenomas and hyperplasias
      suggest a potent antiproliferative defense mechanism in the parathyroid cell
      population. This may also be reflected in the cytoplasmic colocalization of
      various gene products which regulate cell death and cell proliferation. No
      significant differences in the p53, Bcl-2 and Bax spectrum were found between the
      primary and secondary (i.e. renal failure) parathyroid alterations.

PMID- 15188027
TI  - Isolation and purification of vascular endothelial growth factor (VEGF) from
      ascitic fluid of ovarian cancer patients.
AB  - Vascular Endothelial Growth Factor (VEGF) or Vascular Permeability Factor (VPF)
      is an angiogenic cytokine expressed by many human and animal tumors. Because of
      the importance of VEGF in animal tumors, we purified VEGF/VPF from ascitic fluid
      of ovarian cancer patients with heparin sepharose column. The purified protein
      gave protein bands of 37 and 26 kD, respectively in 12% SDS PAGE. The specificity
      of the purified protein was determined with dot blot, trans-immunoblot and ELISA
      using polyclonal goat anti-VEGF antibody (Santa Cruz Biotechnology). The
      vasodilatatory effect of the purified protein was confirmed by a vascular
      permeability assay on mouse. A polyclonal mouse antibody was raised against the
      purified protein, which recognized the same protein by ELISA, transimmunoblot and
      dot-blot analysis. It has been also found that the raised polyclonal antibody in
      mouse- and the commercial VEGF polyclonal antibody (Santa Cruz Biotechnology)
      both inhibited in vitrocell proliferation of human MCF-7 cell line. This study
      shows for the first time an effort to purify VEGF from human source.

PMID- 15188029
TI  - Simultaneous bilateral occurrence of a mixed mesodermal tumor and
      cystadenocarcinoma in the ovary.
AB  - The mixed mesodermal tumor is a very uncommon malignancy. The aggressiveness of
      this lesion is illustrated by extremely poor prospects for afflicted patients:
      postoperative survival is usually shorter than 24 months. According to the
      literature, malignant mixed tumor of the ovary is rather rare and its occurrence
      with other malignancy is exceptional. We report here a case of a 62-years old
      woman with serous cystadenocarcinoma in the right ovary and a heterologous
      malignant mixed mesodermal tumor in the left one. Both tumors expressed
      cytokeratins, while only the mesodermal tumor expressed S-100 and focal NSE.

PMID- 15188028
TI  - The pattern of cytokine gene expression in human colorectal carcinoma.
AB  - Systemic and local cytokine environment may modulate the immunogenicity of
      colorectal cancer cells, and affect anti-tumor immune functions of tumor
      infiltrating lymphocytes. We therefore investigated cytokine mRNA expression
      patterns in tumors and peripheral blood mononuclear cells (PBMC) from patients
      with colorectal adenocarcinoma. IL-2, IFN-gamma, tumor necrosis factor-alpha (TNF
      alpha), IL-4, IL-6, IL-8, IL-10 and IL-1 beta mRNAs in single cell suspension of
      freshly isolated colorectal cancer tissue were studied by RT-PCR. Frequencies of
      cytokine gene expression were compared to those in normal colonic mucosa from
      tumor patients. The frequencies of IL-2, IFN-gamma, IL-4 and IL-10 gene
      expression were also determined in peripheral blood mononuclear cells from
      patients with colorectal adenocarcinoma and compared to those of healthy
      individuals. Tumor samples were more frequently positive for IFN-gamma, IL-2, TNF
      alpha and IL-10 gene expression than normal mucosa (p=0.0001, p=0.0118, p=0.001
      and p<0.0001, respectively). Frequencies of IL-2 and TNF-alpha gene expressions
      were significantly higher in tumors with a diameter <5 cm, than in those with a
      diameter >5 cm. The genes for IL-6, IL-1 beta and IL-8 were commonly expressed in
      both tumor tissue and normal colonic mucosa. IFN-gamma transcripts were detected
      in more PBMC samples from patients with colorectal cancer than those from normal
      controls (p=0.0449). Thus, colorectal cancer tissue is characterized by a
      specific pattern of cytokine gene expression. It is likely that multiple
      interactions between pro- and anti-inflammatory cytokines regulate tumor growth
      and the functional activity of tumor-infiltrating lymphocytes.

PMID- 15188030
TI  - Mazabraud's syndrome: intramuscular myxoma associated with fibrous dysplasia.
AB  - The association of fibrous dysplasia and intramuscular myxoma is a rare disease
      known as Mazabraud's syndrome. Both lesions tend to occur in the same anatomical
      region. The relationship between fibrous dysplasia and myxoma remains unclear,
      where an underlying localized error in tissue metabolism has been proposed to
      explain this occasional coexistence. Another example of this syndrome in a 52
      year-old woman is reported. The patient presented with a soft tissue mass at the
      anteromedial mid part of the left thigh. After excision of the mass, three
      separate bone lesions were detected in her control MRI. The soft tissue mass was
      misdiagnosed as liposarcoma in another center, and the bone lesions were
      interpreted as metastasis. The hypocellularity and the indistinct vascular
      pattern of the lesion were consistent with myxoma. The Jam-Shidi needle biopsies
      of the osseous lesions were diagnosed as fibrous dysplasia. The recognition of
      this entity is important for appropriate management of the patient. Patients with
      soft tissue myxomas should be thoroughly examined for fibrous dysplasia. The
      greater risk of sarcomatous transformation in fibrous dysplasia with Mazabraud's
      syndrome should also be kept in mind.

PMID- 15188031
TI  - Complete functionalisation of small and large diameter bromopolystyrene beads;
      applications for solid-supported reagents, scavengers and diversity-oriented
      synthesis.
AB  - Bromopolystyrene beads with diameters of up to 600 microm have been derivatized
      completely, via bromine-magnesium exchange and interception with electrophiles,
      to yield high quality solid-supported reagents, scavengers and solid supports for
      use in diversity-oriented synthesis.

PMID- 15188032
TI  - Synthesis and application in asymmetric C-C bond formation of solution phase
      ligand libraries of monodentate phosphoramidites.
AB  - A library of 96 unique monodentate phosphoramidite ligands has been synthesized
      in solution and used in the asymmetric conjugate addition of potassium
      vinyltrifluoroborate to enones resulting in up to 88% ee.

PMID- 15188033
TI  - Synthesis of novel selenium-containing donors as selenium analogues of
      diiodo(ethylenedithio)diselenadithiafulvalene (DIETS).
AB  - Novel selenium analogues of diiodo(ethylenedithio)diselenadithiafulvalene (DIETS)
      have been successfully derived from 1,3-diselenole-2-thione, which could be
      synthesized without the use of the highly toxic reagent CSe(2).

PMID- 15188034
TI  - Sequential enolboration/hydroformylation/aldol addition: a new one-pot cascade
      reaction for the regio- and diastereoselective formation of carbocyclic
      quaternary centres from acyclic olefins.
AB  - Starting from unsaturated carbonyl compounds a mild new cascade reaction
      involving enolboration, rhodium-catalysed hydroformylation and intramolecular
      aldol addition in a regio- and diastereoselective fashion leads to cyclic
      compounds containing highly-functionalised quaternary carbon centres.

PMID- 15188035
TI  - Conformational analysis of mixed oxathia crown ethers and their complexational
      ability towards Ag(I) and Pd(II)-an experimental solution NMR and theoretical
      molecular modelling study.
AB  - Both the conformation and flexibility of four mixed oxathia crown ethers and
      their Ag(I) and Pd(II) complexes were studied by (1)H NMR (delta, J, NOE, T(1)),
      (13)C NMR, dynamic (1)H NMR spectroscopy and molecular modelling. The
      stoichiometry and stability constants of the complexes were determined from
      corresponding Job's plots in the case of Ag(I) complexes as the interchange
      between free and complexed states was fast on the NMR timescale; interchange for
      the Pd(II) complexes was sufficiently slow such that distinct sub-spectra were
      observable for the free and complexed states. In all cases where complexation was
      observed, 1 : 1 complexes were formed. Global minima structures determined from
      the modelling studies were analysed with respect to the barriers to ring
      interconversion, the flexibility of the species in solution and the preferred
      complexation of Ag(I) and Pd(II) to the sulfur atoms of the crown ethers.

PMID- 15188036
TI  - Solvent-free reactions of C60 with active methylene compounds, either with or
      without carbon tetrabromide, in the presence of bases under high-speed vibration
      milling conditions.
AB  - Solvent-free reactions of C(60) with active methylene compounds, either with or
      without carbon tetrabromide (CBr(4)), in the presence of a base under high-speed
      vibration milling (HSVM) conditions were investigated. The reaction of C(60) with
      diethyl bromomalonate was conducted under HSVM conditions in the presence of
      piperidine, triethylamine or Na(2)CO(3) to afford cyclopropane derivative. In the
      presence of CBr(4), methanofullerenes, and could be obtained by the direct
      reaction of C(60) with diethyl malonate, dimethyl malonate, ethyl acetoacetate
      and ethyl cyanoacetate, respectively, with the aid of 1,8
      diazabicyclo[5,4,0]undec-7-ene, piperidine, triethylamine or Na(2)CO(3). More
      interestingly, 1,4-bisadducts and were produced by the reaction of C(60) with
      diethyl malonate and dimethyl malonate in the presence of piperidine,
      triethylamine or Na(2)CO(3) under HSVM conditions. On the other hand,
      dihydrofuran-fused C(60) derivatives, and were obtained from the reaction of
      C(60) with ethyl acetoacetate, 2,4-pentanedione and 5,5-dimethyl-1,3
      cyclohexanedione with the aid of a base. Under the same conditions, less
      activated aryl methyl ketones such as 2-acetylpyridine, 2-acetylpyrazine and
      acetophenone provided monocarbonylated methanofullerene derivatives, and. Except
      for the Bingel reactions, all other reactions under the HSVM conditions are
      considered to proceed according to a single-electron-transfer mechanism.

PMID- 15188037
TI  - Evaluating the contributions of desolvation and base-stacking during translesion
      DNA synthesis.
AB  - DNA polymerases catalyze the insertion of a nucleoside triphosphate into the
      growing polymer chain using the template strand as a guide. Numerous factors such
      as hydrogen bonding interactions, base-stacking contributions, and desolvation
      play important roles in controlling the efficiency and fidelity of this process.
      We previously demonstrated that 5-nitro-indolyl-2'-deoxyriboside triphosphate, a
      non-natural nucleobase with enhanced base-stacking properties, was more
      efficiently inserted opposite a non-templating DNA lesion compared to natural
      templating nucleobases (E. Z. Reineks and A. J. Berdis, Biochemistry, 2004, 43,
      393-404). The catalytic enhancement was proposed to reflect increased base
      stacking interactions of the non-natural nucleobase with the polymerase and DNA.
      However, the effects of desolvation could not be unambiguously refuted. To
      further address the contributions of base stacking and desolvation during
      translesion DNA replication, we synthesized indolyl-2'-deoxyriboside
      triphosphate, a nucleobase devoid of nitro groups, and measured its efficiency of
      enzymatic insertion into modified and unmodified DNA. Removal of the nitro group
      reduces the catalytic efficiency for insertion opposite an abasic site by 3600
      fold. This results from a large decrease in the rate of polymerization (similar
      450-fold) coupled with a modest decrease in binding affinity (similar 8-fold).
      Since both non-natural nucleobases show the same degree of hydrophobicity, we
      attribute this reduction to the loss of base-stacking contributions rather than
      desolvation capabilities. Indolyl-2'-deoxyriboside triphosphate can also be
      inserted opposite natural nucleobases. Surprisingly, the catalytic efficiency for
      insertion is nearly identical to that measured for insertion opposite an abasic
      site. These data are discussed within the context of pi-electron interactions of
      the incoming nucleobase with the polymerase:DNA complex. Despite this lack of
      insertion selectivity, the polymerase is unable to extend beyond the non-natural
      nucleobase. This result indicates that indolyl-2'-deoxyriboside triphosphate acts
      as an indiscriminate chain terminator of DNA synthesis that may have unique
      therapeutic applications.

PMID- 15188038
TI  - Recognition of alpha-amino acid derivatives by N,N'-dibenzylated S,S-(+)
      tetrandrine.
AB  - Complexation of free and N-acetylated alpha-amino acid anions (Gly, Ala, Phe) and
      some structurally related guests by a dicationic cyclophane-type N,N'
      dibenzylated chiral derivative of a bisisoquinoline macrocyclic alkaloid S,S-(+)
      tetrandrine (DBT) has been studied by (1)H-NMR titrations in D(2)O. In contrast
      to other macrocyclic hosts like cyclodextrins and calixarenes, DBT shows highest
      affinity and large enantioselectivity (K(S)/K(R) >/=10) toward smaller N
      acetylalanine and binds larger phenylalanine derivatives more weakly and non
      selectively. With 1,2,3,4-tetrahydroisoquinoline-3-carboxylate, a rigid analog of
      phenylalanine, binding again becomes enantioselective with K(S)/K(R)= 3.8. The
      binding specificity of DBT is rationalized on the basis of molecular mechanics
      calculations.

PMID- 15188039
TI  - The nucleophilic addition of alpha-metallated 1,3-dioxanes to planar chiral
      cationic eta3-allylmolybdenum complexes. Synthesis of (2E,5S,6R,7E)-6-methyl-8
      phenylocta-2,7-dienoic acid methyl ester, a key component of the Cryptophycins.
AB  - Two adjacent stereogenic centres and a pendant alkene were constructed via
      nucleophilic addition of a 1,3-dioxan-4-ylcopper(I) reagent to a cationic eta3
      allylmolybdenum complex as part of a synthesis of (2E,5S,6R,7E)-6-methyl-8
      phenylocta-2,7-dienoic acid, a key component of the Cryptophycins. Oxidative
      addition of Mo(CO)(4)(THF)(2) to allyl benzoates provides an efficient synthesis
      of eta3-allylmolybdenum(dicarbonyl) complexes.

PMID- 15188040
TI  - Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin
      diphosphate.
AB  - 3-Deazathiamin diphosphate (deazaTPP) and a second thiamin diphosphate (TPP)
      analogue having a benzene ring in place of the thiazolium ring have been
      synthesised. These compounds are both extremely potent inhibitors of pyruvate
      decarboxylase from Zymomonas mobilis; binding is competitive with TPP and is
      essentially irreversible even though no covalent linkage is formed. DeazaTPP
      binds approximately seven-fold faster than TPP and at least 25,000-fold more
      tightly (K(i) less than 14 pM). DeazaTPP is also a potent inhibitor of the E1
      subunit of alpha-ketoglutarate dehydrogenase from E. coli and binds more than 70
      fold faster than TPP. In this case slow reversal of the inhibition could be
      observed and a K(i) value of about 5 nM was calculated (ca. 500-fold tighter
      binding than TPP).

PMID- 15188041
TI  - Generation of transient neutrals in the gas phase from anionic precursors. Does
      energised CNCCO rearrange to NCCCO?
AB  - The stability and reactivity of the neutral species CNCCO generated by one
      electron oxidation of the anion [CNCCO](-) have been investigated by a
      combination of theoretical calculations (carried out at the CCSD(T)/aug-cc
      pVDZ//B3LYP/6-31G(d) level of theory) and tandem mass spectrometric experiments.
      Some of the neutrals formed in this way are stable for the microsecond duration
      of the experiment, but others are energised. The neutrals which are energised may
      either (i) dissociate [CNCCO --> CNC + CO (+92 kJ mol(-1))], and/or (ii), undergo
      the isonitrile to nitrile rearrangement to yield NCCCO energised neutrals
      (barrier 133 kJ mol(-1), reaction exothermic by 105 kJ mol(-1)). Some of these
      rearranged neutrals NCCCO have excess energies as high as 238 kJ mol(-1) and will
      dissociate [NCCCO --> NCC + CO (+203 kJ mol(-1))].

PMID- 15188042
TI  - Bis(phenylthienyl)ethene-tethered beta-cyclodextrin dimers as photoswitchable
      hosts.
AB  - Two beta-cyclodextrin dimers tethered by photoswitchable bis(phenylthienyl)ethene
      moieties were synthesized as potentially tunable receptor molecules. The
      cyclodextrin cavities of these dimers were linked via their secondary sides, with
      the photochromic bis(phenylthienyl)ethene unit either directly connected to the
      secondary rim (7) or via propyl spacers (10). By irradiation with light the
      dimers were reversibly switched between a relatively flexible (open) form and a
      rigid (closed) form. The photostationary states for both dimers consisted of 92%
      of the open and 8% of the closed form, enabling the nearly complete conversion
      between the two forms. The binding properties of the open and closed forms of
      dimers 7 and 10 were assessed by complexation studies with meso-tetrakis(4
      sulfonatophenyl)porphyrin (TSPP) using isothermal titration calorimetry. For the
      rigidly tethered dimer 7, a factor 8 difference in binding affinity between the
      open and closed form of the dimer was found. This difference in binding affinity
      reflects the difference in enthalpy of binding for the two dimers, indicating
      that the beta-cyclodextrin cavities of the closed dimer 7b are spaced too far
      apart from each other by the rigid closed bis(phenylthienyl)ethene tether to
      cooperatively bind TSPP. The difference in binding affinity was sufficient to
      enable the phototriggered release of TSPP from dimer. The thermodynamic
      parameters obtained for dimer 10 suggested that the closed tether substantially
      contributes to the binding of TSPP. The open and closed form of dimer 10 bound
      TSPP with similar association constants, although the enthalpy of binding for the
      complexation of TSPP by the closed form of dimer 10 was more favorable than that
      found for the open form of the dimer.

PMID- 15188043
TI  - Influence of substitution on kinetics and mechanism of ring transformation of
      substituted S-[1-phenylpyrrolidin-2-on-3-yl]isothiuronium salts.
AB  - Twelve new substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium bromides and
      twelve corresponding 2-imino-5-(2-phenylaminoethyl)thiazolidin-4-ones have been
      prepared and characterised. Kinetics and mechanism of transformation reaction of
      S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide and its N,N
      dimethyl derivative 5a into corresponding substituted thiazolidin-4-ones 2a and
      6a have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and
      sodium hydroxide solutions (0.005-0.5 mol l(-1)) at 25 degrees C and at I= 1 mol
      l(-1) under pseudo-first-order reaction conditions. The kinetics observed show
      that the transformation reaction is subject to general acid-base, and hydroxide
      ion catalyses. Acid catalysis does not operate in the transformation of 1a; the
      rate-limiting step of the base-catalysed transformation is the decomposition of
      bicyclic tetrahedral intermediate In(+/-) and the Bronsted dependence is non
      linear (pK(a) approximately 9.8). In the case of derivative 5a both base and acid
      catalyses make themselves felt. In the base catalysis, the rate-limiting step
      consists of the decomposition of bicyclic intermediate In, and the Bronsted
      dependence is linear (beta = 0.9; pK(a) > 11.5). The acid-catalysed
      transformation of 5a also proceeds via the intermediate In, and the reaction is
      controlled by diffusion (alpha approximately equal to 0). With compound 5a in
      triethylamine and butylamine buffers, the general base catalysis changes into
      specific base catalysis. The effect of substitution in aromatic moiety of
      compounds 1a-h and 3a-h on the course of the transformation reaction has been
      studied in solutions of sodium hydroxide (0.005-0.5 mol l(-1)) at 25 degrees C by
      the stopped-flow method. The electron-acceptor substituents 4-NO(2) and 4-CN do
      not obey the Hammett correlation, which is due to a suppression of cross
      conjugation in the ring-closure step of the transformation reaction.

PMID- 15188044
TI  - C2 symmetrical double chromophores: cooperativity effects in lanthanide ion
      complexation.
AB  - We describe the synthesis and characterization of C(2) symmetrical double
      chromophores, in which two identical chromophores are linked through ethylene
      glycol spacers of increasing lengths. The complexation ability of the trans
      stereopure form for each diastereoisomeric pair showed how the two chromophores,
      when the spacer unit is comprised of a diethylene or a triethylene glycol moiety,
      are able to interact in a positive way, stabilizing the resulting complexes when
      compared with single chromophore analogous compounds.

PMID- 15188045
TI  - Gel-phase 19F NMR spectral quality for resins commonly used in solid-phase
      organic synthesis; a study of peptide solid-phase glycosylations.
AB  - The spectroscopic properties for seven different commercial resins used in solid
      phase synthesis were investigated with (19)F NMR spectroscopy. A fluorine-labeled
      dipeptide was synthesized on each resin, and the resolution of the (19)F
      resonances in CDCl(3), DMSO-d(6), benzene-d(6) and CD(3)OD were measured with a
      conventional NMR spectrometer, i.e. without using magic angle spinning. In
      general, resins containing poly(ethylene glycol) chains (ArgoGel, TentaGel and
      PEGA) were found to be favorable for the (19)F NMR spectral quality. Three serine
      containing tri-, penta-, and heptapeptides were then prepared on an ArgoGel resin
      functionalized with a fluorine-labeled linker. The resin bound peptides were
      glycosylated utilizing a thiogalactoside glycosyl donor carrying fluorine-labeled
      protective groups. Monitoring of the glycosylations with gel-phase (19)F NMR
      spectroscopy allowed each glycopeptide to be formed in similar 80% yield, using a
      minimal amount of glycosyl donor (3 x 2 equivalents). In addition, it was found
      that the glycosylation yields were independent of peptide length.

PMID- 15188046
TI  - Determination of the binding specificity of the 12S subunit of the
      transcarboxylase by saturation transfer difference NMR.
AB  - In this study we present the characterization of the interaction of biotin and
      methylmalonyl-CoA (MMCoA) with the carboxyltransferase subunit (12S) from the
      transcarboxylase (TC) from Propionibacterium shermanii. This biotin dependent
      multienzyme complex catalyses the transfer of carbon dioxide from methylmalonyl
      CoA (MMCoA) to pyruvate. The Saturation Transfer Difference NMR (STD) technique
      was performed to determine the binding epitope from biotin and MMCoA to the 12S
      subunit. We could show by titrations during STD experiments that biotin and MMCoA
      bind cooperatively in one binding pocket.

PMID- 15188047
TI  - Studies on pyridazine azide cyclisation reactions.
AB  - Reaction of sodium azide with 4-methyl-3,5,6-tribromopyridazine results in the
      formation of 3,5,6-triazide intermediate which could cyclise to give two possible
      bicyclic products while ab initio calculations show that the formation of a
      tricyclic compound is extremely energetically unfavourable. However,
      experimentally, only one major product is isolated. The structure of this
      unstable product has been conclusively established by X-ray crystallography as
      3,5-diazido-4-methyl[1,5-b]tetrazolopyridazine confirming theoretical
      predictions.

PMID- 15188048
TI  - The Kemp elimination in membrane mimetic reaction media. Probing catalytic
      properties of cationic vesicles formed from a double-tailed amphiphile and linear
      long-tailed alcohols or alkyl pyranosides.
AB  - Vesicles formed from synthetic, double-tailed amphiphiles are often used as
      mimics for biological membranes. However, biological membranes are a complex
      mixture of various compounds. In the present paper we describe a first attempt to
      study the importance of additives on vesicular catalysis. The rate-determining
      deprotonation of 5-nitrobenzisoxazole (Kemp elimination) by hydroxide ion is
      efficiently catalysed by vesicles formed from dimethyldi-n-octadecylammonium
      chloride (C(18)C(18)(+)) as a result of (partial) dehydration of the reactants
      (especially the hydroxide ion) at the vesicular binding sites. Gradual addition
      of linear alcohols, such as n-decanol (C(10)OH), n-octadecanol (C(18)OH) and
      batyl alcohol (C(18)GlyOH) leads to a decrease in the observed catalysis. By
      contrast, gradual addition of oleyl alcohol, n-dodecyl-beta-glucoside (C(12)Glu)
      and n-dodecyl-beta-maltoside (C(12)Mal) leads to an increase in the observed
      catalysis. A detailed kinetic analysis, taking into account substrate binding
      site polarities, counterion binding percentages and binding affinity of the
      kinetic probe, suggests that the catalytic changes depend strongly on subtle
      changes in the structure of the additive. Whereas the C(12)Glu-induced effect can
      be explained by an increase in the vesicular rate constant, the effect of
      C(12)Mal can only be explained by an increase in the binding constant of the
      kinetic probe. However, for these pyranoside-containing vesicles others factors,
      such as a more extensive dehydration of the hydroxide ion, and micelle formation
      have to be considered. For the linear alcohols, besides a decrease in the
      counterion binding, changes in the vesicular rate constant and the binding
      constant should be taken into account. These two parameters change to a different
      extent for the different alcohols. The kinetic analysis is supported by
      differential scanning calorimetry (DSC), E(T)(30) absorbance data and Nile Red,
      Laurdan, ANS and pyrene fluorescence measurements. The overall kinetic results
      are illustrative for the highly complex mix of factors which determines catalytic
      effects on reactions occurring in biological cell membranes.

PMID- 15188049
TI  - Enantiopure bicyclic piperidinones: stereocontrolled conjugate additions leading
      to substituted piperidinones.
AB  - The conjugate additions of Reformatsky reagents, organocuprate reagents, and
      hydroxylamines to a [4.3.0]-bicyclic enelactam derived from 6-oxopipecolic acid
      have been investigated, and found to be efficient, proceeding with excellent exo
      stereocontrol, with the exception of N-benzyl-O-benzylhydroxylamine, which gives
      predominantly the product of endo-addition. These adducts can be readily
      converted to substituted piperidinones.

PMID- 15188051
TI  - High throughput SNP genotyping with two mini-sequencing assays.
AB  - Two mini-sequencing methods, FP-TDI (template-directed dye-terminator
      incorporation with fluorescence-polarization) and MassArray (matrix assisted
      laser desorption ionization time of flight detection mass spectrometry), were
      optimized. A numeric standard was introduced to evaluate the SNP scoring quality
      of FP-TDI assay, thus made the optimization work easier. At the same time, using
      multi-PCR technology, 8-plex genotyping of MassArray assay was successfully
      carried out, some softwares were developed and the data process of MassArray was
      highly automated. Then these two methods were applied to high throughput SNP
      genotyping, the accuracy, efficiency and robustness were compared. The result
      shows FP-TDI is more sensitive to the concentration of SNPprimer and PCR product,
      as well as extension cycles, the SNPprimer length of FP-TDI should be 24 to 30 bp
      long, whereas MassArray assay prefers to be as short as only 16 bp. Altogether
      6440 SNP sites of human chromosome 3 were genotyped in a sample of 90
      individuals, 4792 sites by FP-TDI assay and 1648 sites by MassArray assay, the
      success rates of FP-TDI and MassArray were 67.7% and 93.6% respectively. The
      throughput of MassArray was higher than FP-TDI, and the cost of MassArray was
      lower, MassArray was more suitable for high throughput SNP genotyping.

PMID- 15188052
TI  - Synthesis and characteristics of an aspartame analogue, L-asparaginyl L-3
      phenyllactic acid methyl ester.
AB  - An aspartame analogue, L-asparaginyl L-3-phenyllactic acid methyl ester was
      synthesized with aspartic acid replaced by asparagine and peptide bond replaced
      by ester bond. The aspartic acid of aspartame could be replaced by asparagine as
      reported in the literature. In this analogue, the hydrogen of amide group could
      still form a hydrogen bond with the oxygen of ester bond and the ester bond was
      isosteric with peptide bond. However, the product was not sweet, showing that the
      peptide bond could not be replaced by ester bond. The peptide C-N bond behaves as
      a double bond that is not free to rotate and the C, O, N and H atoms are in the
      same plane. The replacement of peptide bond by ester bond destroyed the unique
      conformation of peptide bond, resulting in the loss of sweet taste.

PMID- 15188053
TI  - Multiple signaling pathways control Tbx6 expression during Xenopus myogenesis.
AB  - Tbx6 is critical for somite specification and myogenesis initiation. It has been
      shown that Activin/Nodal, VegT/Nodal, FGF, and BMP signaling pathways are
      involved early in specifying mesoderm or later in patterning mesoderm, and Xnot
      plays roles in setting up the boundary between notochord and paraxial mesoderm.
      In this study, we introduce the dominant negative form of above genes into
      embryos to evaluate if they are responsible for regulating Tbx6 expression. The
      results show that: (1) Activin/Nodal and VegT/Nodal signals are necessary for
      both initiation and maintenance of Tbx6 expression, and Nodal is sufficient to
      induce ectopic Tbx6 expression; (2) FGF signal is necessary for the initiation
      and maintenance of Tbx6, but it is not sufficient to induce Tbx6 expression; (3)
      BMP is also necessary for the expression of Tbx6, and the induction of Tbx6
      expression by BMP is dose dependent; (4) Xnot has no effect on the expression of
      Tbx6. Our results suggest that several signaling pathways are involved in
      regulating Tbx6 expression, and pave the route to reveal the molecular mechanism
      of initiating myogenesis.

PMID- 15188054
TI  - Expression of overlapping PreS1 fragment recombinant proteins for the
      determination of immunogenic domains in HBsAg PreS1 region.
AB  - In this study, eight preS1 fragments overlapped in preS1 (21-119) region of HBV
      adr subtype, i.e. preS1 (21-47), preS1 (34-59), preS1 (48-70), preS1 (60-85),
      preS1 (71-94), preS1 (86-109), preS1 (95-119) and preS1 (21-119), were cloned by
      PCR, and expressed as GST fusion proteins. These GSTpreS1 fusion proteins were
      highly expressed in soluble form in E. coli, and about 50 to 90 mg soluble fusion
      proteins were purified from 1 L culture. Using these fusion proteins, the
      immunogenic domains in preS1 (21-119) region were identified by Western blot
      analysis and competitive ELISA. The results showed that the immunogenic domains
      mainly existed in preS1 (21-59) in N-terminus and preS1 (95-109) in C-terminus,
      and more importantly, a major immunogenic domain preS1 (34-59), which has much
      stronger immunogenicity, was identified. It was also supported by the predictions
      of secondary structure and immunological property in the preS1 (21-119) region.
      The results here would be helpful for the design of new vaccines against HBV.

PMID- 15188055
TI  - Transcriptional regulation of urokinase receptor in high- (95D) and low
      metastatic (95C) human lung cancer cells.
AB  - To study the transcriptional regulation of urokinase receptor (uPAR) in high-
      (95D) and low-metastatic (95C) human lung cancer cells, we performed PCR to
      amplify 2238 bp uPAR promoter from 95C and 95D cells. According to the results of
      sequencing, five different bases are found in uPAR promoter between 95C and 95D
      cells. The results of luciferase activity assay showed that these differences
      have no significant effect on the uPAR promoter activity. Based on a normal uPAR
      promoter, progressive truncated mutants were constructed. The transient
      transfection/reporter assay showed that the promoter region from -136 to +9 may
      interact with relevant nuclear factors, which result in different levels of uPAR
      expression between 95C and 95D cells.

PMID- 15188057
TI  - Role of apolipoprotein A-I in protecting against endotoxin toxicity.
AB  - High density lipoprotein (HDL) binds lipopolysaccharide (LPS or endotoxin) and
      neutralizes its toxicity. We investigated the function of Apolipoprotein A-I
      (ApoA-I), a major apolipoprotein in HDL, in this process. Mouse macrophages were
      incubated with LPS, LPS+ApoA-I, LPS+ApoA-I+LFF (lipoprotein-free plasma fraction
      d>1.210 g/ml), LPS+HDL, LPS+HDL+LFF, respectively. MTT method was used to detect
      the mortality of L-929 cells which were attacked by the release-out cytokines in
      LPS-activated macrophages. It was found that ApoA-I significantly decreased L-929
      cells mortality caused by LPS treatment (LPS vs. LPS+ApoA-I, P<0.05) and this
      effect became even more significant when LFF was utilized (LPS vs. LPS+ApoA
      I+LFF, P<0.01; LPS vs. LPS+HDL+LFF, P<0.01). There was no significant difference
      between LPS+ApoA-I+LFF and LPS+HDL+LFF treatment, indicating that ApoA-I was the
      main factor. We also investigated in vivo effects of ApoA-I on mouse mortality
      rate and survival time after LPS administration. We found that the mortality in
      LPS+ApoA-I group (20%) and in LPS+ApoA-I+LFF group (10%) was significantly lower
      than that in LPS group (80%) (P<0.05, P<0.01, respectively); the survival time
      was (43.20 +/- 10.13) h in LPS+ApoA-I group and (46.80 +/- 3.79) h in LPS+ApoA
      I+LFF group, which were significantly longer than that in LPS group (16.25 +/-
      17.28) h (P<0.01). We also carried out in vitro binding study to investigate the
      binding capacity of ApoA-I and ApoA-I+LFF to fluorescence labeled LPS (FITC-LPS).
      It was shown that both ApoA-I and ApoA-I+LFF could bind with FITC-LPS, however,
      the binding capacity of ApoA-I+LFF to FITC-LPS (64.47 +/- 8.06) was significantly
      higher than that of ApoA-I alone (24.35 +/- 3.70) (P<0.01). The results suggest
      that: (1) ApoA-I has the ability to bind with and protect against LPS; (2) LFF
      enhances the effect of ApoA-I; (3) ApoA-I is the major contributor for HDL anti
      endotoxin function.

PMID- 15188056
TI  - Characterization of MR-1, a novel myofibrillogenesis regulator in human muscle.
AB  - The actin-myosin contractile apparatus consists of several thick filament and
      thin filament proteins. Specific regulatory mechanisms are involved in this
      highly ordered process. In this paper, we reported the identification and
      characterization of a novel myofibrillogenesis regulator, MR-1. The MR-1 gene was
      cloned from human skeletal muscle cDNA library by using a strategy that involves
      EST data base searching, PCR and RACE. The MR-1 gene is located on human
      chromosome 2q35 and encodes a 142 aa protein. Northern blot revealed that the
      mRNA level of MR-1 was highest in the skeletal muscle and certain level of MR-1
      expression was also observed in heart, liver and kidney. Immunohistochemical
      assay confirmed that the MR-1 protein existed in human myocardial myofibrils. It
      was found by yeast two-hybrid screening and confirmed by in vitro binding assay
      that MR-1 could interact with sarcomeric proteins, such as myosin regulatory
      light chain, myomesin 1 and beta-enolase. These studies suggested that MR-1 might
      play a regulatory role in the muscle cell and it was worth investigating further.

PMID- 15188059
TI  - Human recombinant B7-H3 expressed in E. coli enhances T lymphocyte proliferation
      and IL-10 secretion in vitro.
AB  - To explore the biofunctions of human B7-H3 on activated T lymphocyte, the gene of
      human B7-H3 encoding the extracellular region (IgV-like and IgC-like domains) was
      obtained by RT-PCR from human lung cells and subcloned into the prokaryotic
      expression vector pGEX-5X-3 to express glutathione S-transferase (GST) fusion
      protein. A 49 kD fusion protein (named as GST/hB7-H3 hereafter) was induced by
      IPTG and purified by standard methods reported in prokaryotic system. In the
      presence of the first signal imitated by anti-CD3 monoclonal antibody, T
      lymphocyte proliferation was observed by incubating purified T cells with soluble
      GST/hB7-H3 fusion protein by MTT assay. The concentrations of IFN-gamma and IL-10
      in the supernatants of T cells were determined by ELISA. The results showed that
      the GST/hB7-H3 protein produced in bacteria had modest biological activities to
      proliferate the T lymphocyte and enhance IFN-gamma as well as IL-10 secretion.

PMID- 15188058
TI  - Cloning and characterization of Adinbitor, a novel disintegrin from the snake
      venom of Agkistrodon halys brevicaudus stejneger.
AB  - Adinbitor was cloned from Agkistrodon halys brevicaudus stejneger and
      characterized as a novel disintegrin. In this study, total RNA was extracted from
      venom gland and used in RT-PCR to generate a cDNA which is 219 bp long. The
      sequence encoded a polypeptide composed of 73 amino acids, including 12
      cysteines, an RGD motif, and the signature motif of disintergrin. Recombinant
      Adinbitor (rAdinbitor) was expressed in E. coli and purified by using the His.
      Bind affinity chromatography. The IC(50) for inhibiting human platelet
      aggregation and bFGF-induced proliferation of ECV304 cells was 6 microM and 0.89
      microM respectively. Furthermore, Adinbitor significantly inhibited angiogenesis
      both in vivo and in vitro. Taken together, these results suggested that Adinbitor
      had typical functions of disintegrins.

PMID- 15188060
TI  - Fusion protein of interleukin 4 and diphtherial toxin with high cytotoxicity to
      cancer cells.
AB  - Receptor of human interleukin 4 (hIL4R) has been found to be present on many
      types of cancer, so it may be a good target for cancer therapy. Here, fusion
      toxin gene DT4H has been constructed by fusing DNA sequence encoding the first
      389 amino acids of diphtherial toxin (DT), which can not bind its own receptor,
      to human interleukin 4 (hIL4) gene. In order to improve the affinity of fusion
      toxin for hIL4R, a circularly permuted form of hIL4 (cpIL4) was used. The fusion
      gene was expressed in Escherichia coli where the fusion toxin DT4H was highly
      expressed. Purified DT4H was very cytotoxic to cancer cell line U251 cells, and
      moderate cytotoxic to HepG2 and MCF-7 cells. SGC-7901 cells were insensitive to
      it. The cytotoxic action of DT4H was specific because it was blocked by excess
      hIL4. These results suggest that DT4H may be a useful agent in the treatment of
      certain malignancies.

PMID- 15188062
TI  - Noise and the respiratory system.
AB  - Noise-induced pulmonary pathology is still an issue that is regarded with much
      suspicion despite the significant body of evidence demonstrating that acoustic
      phenomena target the respiratory tract. The goal of this review paper is
      threefold: a) to describe acoustic phenomena as an agent of disease, and the
      inadequacies of current legislation regarding noise-induced, non-auditory
      pathology; b) to trace how the interest in noise-induced pulmonary pathology
      emerged within the scope of studies on vibroacoustic disease; and c) to bring to
      light other studies denouncing noise as an agent of disease that impinges on the
      respiratory tract. As concluding remarks, future perspectives in LFN-related
      research will be discussed. The need for animal models will be emphasized.

PMID- 15188063
TI  - Respiratory epithelia in Wistar rats.
AB  - Morphofunctional changes of respiratory epithelia became the object of intense
      study in Wistar rats after previous research showed that occupationally-simulated
      exposure to low frequency noise (500 Hz, including infrasound) induced
      irreversible lesions in these tissues. Aspects of normal respiratory epithelia in
      rats are lacking in the literature, and are the object of this report. Ten Wistar
      rats were kept in silence, fed standard rat food, and had unrestrained access to
      water (treated in accordance with 86/609/CE). The animals were sacrificed at 3.5
      months of age, and respiratory epithelial fragments were excised and prepared for
      scanning (SEM) and transmission (TEM) electron microscopy. Brush cells (BC) were
      frequently observed with TEM, but with SEM they were often covered by the cilia
      of neighbouring cells. BC were always observed at the center of a ring of
      secretory cells (SC), in a rosetta-shaped formation. In TEM, the microvilli of SC
      surrounding the BC were uniform, and had the same density and shape in all cells.
      Multivesicular bodies were identified in areas within the BC. Formation and
      budding of vesicles from ciliary plasma membranes and from BC microvilli were
      frequently observed in both TEM and SEM. These data contribute to the
      understanding of the BC function.

PMID- 15188066
TI  - [Malignant mesothelioma--a diagnostic challenge].
AB  - Malignant mesothelioma is a rare neoplasm associated, in 80% of the cases, with
      exposure to asbestos fibres, with a latency period between 20 and 50 years. The
      treatment is palliative in most cases because of the extension of the disease at
      the time of diagnosis. Mesothelioma is a resistant tumour to chemotherapy and
      radiotherapy. Overall survival varies between 4 and 18 months, rarely over 5
      years. The authors present a case of a 82-year-old man, ex-sailor, with prostatic
      neoplasm in hormonal "escape" phase, admitted with cough and dyspnea. The chest
      radiograph showed extensive right pleural effusion. The diagnostic hypothesis
      were metastatic, infectious and primitive neoplasm origin. Pleural biopsy
      revealed epithelial malignant mesothelioma confirmed by thoracoscopy, associated
      with prolongated occupational exposure to asbestos fibres. Without surgery
      indication the patient was submitted to chemotherapy with gencitabin and
      cisplatin associated with pleurodesis. Although he improved clinically, the
      presence of two malignant neoplasms, a rare situation in clinical practice, is
      associated with a poor prognosis, especially condicionated by the epithelial
      malignant mesothelioma in Butchart stage II. Finally, we discussed new
      differential diagnostic techniques with metastatic adenocarcinoma and target
      therapies under study.

PMID- 15188065
TI  - [Treatment and prevention of Staphylococcus aureus].
AB  - The number of Staphylococcus aureus (S. aureus) community and nosocomial acquired
      infections have increased in the last twenty years. Between 1990 and 1992, this
      pathogen has become the most frequent source of nosocomial infections 1,2. On the
      other hand, as result of antibiotherapy selection pressure, we observe a dramatic
      increase in the methicillin-resistant S. aureus (MRSA) infections 3,4. With the
      recent emergence of multiresistant strains, including glycopeptides resistance,
      the treatment of these infections became still more difficult 2,4-6. It's
      important to prevent resistant strains emergence. To prevent further emergence of
      resistant strains, the use of antibiotherapy must be optimised, laboratory
      methods for the detection of resistant pathogens must be enhanced and strict
      precautions should be taken following of the infection or colonization of
      patients 6-10. In this paper, we review anti-staphylococci history evolution and
      point out the present recommendations for the treatment and prevention of
      Staphylococcus aureus infections and colonization.

PMID- 15188064
TI  - [Evaluation of coefficient of variation of age in pleural effusion in Antonio
      Pedro Hospital, Niteroi city, state of Rio de Janeiro, Brazil].
AB  - Pleural effusion is a frequent syndrome in Brazil. Tuberculosis is the most
      prevalent (P) cause. The coefficient of variation (CV) is a useful single measure
      of variability. The objective of the present work was to evaluate the coefficient
      of variation in pleural effusion, having as variable the age. 215 patients had
      appeared after diagnostic physician and for image of syndrome of pleural
      effusions. Diagnostic thoracentesis, tests on pleural fluid and others invasive
      surgical procedures to the approach to a patient with pleural effusion.
      Tuberculosis (P=56.0%; CV=39,7%), adenocarcinoma (P=11.0%; CV=25.1%), transudates
      (P=12.0%; CV=19.6%), lymphomas (P=2.0%; CV=34.6%), systemic lupus erythematosus
      (P=2.0%; CV=38.7%), empyema pleural not tuberculosis (P=5.0%; CV=42.2%),
      pulmonary infarction (P=4.0 %; CV=30.1%) and parapneumonic (P=4.0 %; CV=38.9%)
      are the causes more prevalent. The analysis on the date showed that the
      coefficient of variation of age in pleural effusions was high and very high. The
      values of the coefficient of variation translate a high degree of dispersion of
      the age of the patients in each cause of pleural effusion.

PMID- 15188068
TI  - [Portuguese Respiratory Society guidelines for the management of community
      acquired pneumonia in immunocompetent adults].
AB  - The Portuguese Respiratory Society makes a series of recommendations as to the
      state of the art of the diagnostic, therapeutic and preventive approach to
      community-acquired pneumonia in immunocompetent adults in Portugal. These
      proposals should be regarded as general guidelines and are not intended to
      replace the clinical sense used in resolving each individual case. Our main goal
      is to stratify the patients according to the risk of morbidity and mortality in
      order to justify the following decisions more rationally: the choice of place of
      treatment (outpatient or inpatient), diagnostic tests and antimicrobial therapy.
      We also make a set of recommendations for the prevention of CAP. We plan to
      conduct multi-centre prospective studies, preferably in collaboration with other
      scientific societies, in order to be able to characterise the situation in
      Portugal more accurately and regularly update this document.

PMID- 15188069
TI  - Towards a better understanding of HCV transmission and course of infection.

PMID- 15188067
TI  - [Obstructive sleep apnea syndrome associated with cervical osteophyt due to
      diffuse idiopathic skeletal hyperostosis--clinical case].
AB  - Obstructive sleep apnea syndrome and diffuse idiopathic skeletal hyperostosis are
      frequent diseases in the elderly, however its association has rarely been
      described. The authors describe a case of obstructive sleep apnea syndrome in a
      patient with diffuse idiopathic skeletal hyperostosis, with a giant osteophyt of
      the cervical column, which leads to obstruction of the pharynx and they discuss
      the association between both entities.

PMID- 15188071
TI  - Prevalence and risk factors of hepatitis C infection after cardiac surgery in
      childhood before and after blood donor screening.
AB  - BACKGROUND: Since 1974, the risk of acquiring non-A non-B hepatitis by blood
      transfusion is well known. In 1999, children having had polytransfusions (group
      1) after cardiac surgery prior to the establishment of routine blood donor
      screening could be identified as a risk group for hepatitis C (HCV) infection.
      PATIENTS AND METHODS: In 1991, Germany began screening blood donors for hepatitis
      C. To describe the risk after the implementation of blood donor screening, we
      studied 211 children (group 2) having had open heart surgery after 1991 and
      compared prevalence for anti-HCV antibodies and known risk factors to group 1.
      RESULTS: None of the 211 patients with cardiac surgery after 1991 had detectable
      anti-HCV antibodies, compared to 67 of the 458 patients (14.6%) of group 1 (p <
      0.001). The mean number of operations in both groups was virtually the same (mean
      1.7 +/- 0.9 in group 1, mean 1.6 +/- 0.9 in group 2, p = 0.075), whereas the
      total number of blood products per patient differed significantly (group 1 mean 8
      +/- 17.6, group 2 mean 3.5 +/- 2.8; p < 0.001). Multivariate analysis of risk
      factors demonstrates affiliation to group 1, transfusion of fresh blood, warm
      whole blood, heparinized blood (p < 0.001) and plasma (p = 0.004) as significant.
      CONCLUSION: After the implementation of blood donor screening, the risk for HCV
      infection after cardiac surgery in childhood dropped significantly from 14.6% to
      < 0.5%. These data show the necessity of HCV screening for patients at risk
      (operations before 1991) and do not favor a general screening for all patients.

PMID- 15188070
TI  - Risk factors for undervaccination against measles in a large sample of preschool
      children from rural Bavaria.
AB  - BACKGROUND: Due to insufficient vaccination rates, measles outbreaks still pose a
      threat to public health in Germany. The purpose of this study was to identify
      risk factors for undervaccination against measles. PATIENTS AND METHODS: Datasets
      from two cross-sectional surveys were analyzed by logistic regression models. The
      surveys had been done prior to and after an intervention aiming to raise measles,
      mumps, and rubella vaccination rates among children entering primary school in
      five Bavarian counties. Subjects were 9,582 children aged 6 to 7 years and their
      parents. RESULTS: Main independent predictors of non-immunization were doctors
      advising against vaccination (OR 84.8; 95% CI 19.9-360.4), doctors abstaining
      from advice (OR 6.3; 95% CI 4.8-8.4), and parental reservations due to
      alternative health beliefs (OR 27.9; 95% CI 17.6-44.1). CONCLUSION: Doctors
      advising against measles vaccination and doctors not giving any advice proved to
      be important risk factors for childhood undervaccination against measles. Future
      strategies to increase measles vaccination rates in Germany should focus more on
      family doctors.

PMID- 15188072
TI  - Natural history of acute symptomatic hepatitis type C.
AB  - BACKGROUND: Spontaneous clearance of hepatitis C virus (HCV) after acute
      hepatitis C, and the course of chronic HCV infection in patients who did not
      clear the virus, were studied. PATIENTS AND METHODS: Patients with acute C or non
      A, non-B hepatitis who were hospitalized between 1988 and 1998 were called for
      evaluation in 2001. They were tested for anti-HCV, serum HCV-RNA, HCV-RNA in
      peripheral blood mononuclear cells (PBMC) and liver enzymes. A liver biopsy was
      performed on chronically infected patients. The course of acute hepatitis C was
      compared between HCV-RNA-positive and negative subjects to look for factors that
      might influence spontaneous viral clearance. Factors influencing more progressive
      liver disease were analyzed in chronic hepatitis C. RESULTS: Out of 159 acute
      hepatitis C patients, 77 (48.4%) participated in the study, and the median
      observation time was 8 years. Spontaneous clearance of serum HCV was found in 23
      subjects (29.9%), but in two cases HCV-RNA was detected in peripherical blood
      mononuclear cells (PBMC). Only three patients negative for HCV-RNA in serum and
      PBMC lost anti-HCV. Severity of acute HCV infection and previous alcohol abuse
      seemed to influence resolution. In non-alcoholic patients, older age at time of
      primary infection was a significant predictor of virus clearance. In chronic
      hepatitis C, more than 75% of patients had minimal or mild activity in biopsy,
      but 40% had advanced fibrosis. Older age at infection, male gender, alcohol
      abuse, and higher iron content were connected with advanced fibrosis. CONCLUSION:
      Studies on HCV infection resolution should include at least PBMC testing for HCV
      RNA. A healthy carrier state of HCV can be discussed. A longer observation time
      increased the likelihood of seroreversion. Fibrosis in chronic hepatitis C
      probably is not a direct result of inflammatory activity.

PMID- 15188073
TI  - Influence of chronic coinfection with hepatitis B and C virus on liver histology.
AB  - BACKGROUND: Few data are available on histological features of chronic hepatitis
      B (HBV) and C (HCV) virus coinfection. PATIENTS AND METHODS: We enrolled 142
      consecutive patients with viral chronic hepatitis on their first liver biopsy: 27
      HBsAg and anti-HCV positive (case BC group), 57 HBsAg positive and anti-HCV
      negative (control B group) and 58 anti-HCV positive, HBsAg/anti-HBs/anti-HBc
      negative (control C group). RESULTS: Patients in the case BC group showed serum
      HBVDNA (37% vs 71.9%, p < 0.005) and ground-glass hepatocytes (37% vs 66.7%, p <
      0.01) less frequently than those in the control B group. The case BC group showed
      a lower prevalence of patients with detectable HCV-RNA than the control C group
      (60% vs 92.3%, p < 0.001) and a significantly higher fibrosis score (2.1 +/- 1.2
      vs 1.5 +/- 1.1, p < 0.05). Of the 27 patients in the case BC group, 10 lacked
      serum HCV-RNA and showed significantly higher histological activity index (HAI)
      and fibrosis scores than those found in the 17 HCV-RNA positive (8.5 +/- 4.4 vs
      5.4 +/- 2.4 for HAI, p < 0.05; 3.0 +/- 1.3 vs 1.69 +/- 1.0, p < 0.05 for
      fibrosis). CONCLUSION: Liver histology seems to be more severe in chronic
      coinfection with HBV and HCV than in single infection, particularly when HCV
      replication is impaired.

PMID- 15188074
TI  - Rapid antibody response after vaccination with a virosomal hepatitis a vaccine.
AB  - BACKGROUND: This study was designed to assess the early antibody kinetics after a
      priming dose, and the extent of the antibody increase after a booster dose of an
      inactivated virosomal hepatitis A virus (HAV) vaccine (Epaxal). PATIENTS AND
      METHODS: This was an open, uncontrolled study in 30 healthy subjects. The vaccine
      was injected intramuscularly on day 1 and month 12. Serum antibody titers were
      measured by ELISA on day 1 (pre dose) and at various time points thereafter until
      month 12 (pre-booster dose). After the booster dose, antibody titers were
      measured at various intervals until month 24. Neutralizing antibody titers were
      measured in 12 subjects a number of times during the 1st month by an antibody
      neutralization assay. Titers > or = 10 mIU/ml were considered seroprotective.
      RESULTS: ELISA antibody titers showed a rapid increase post vaccination. By day
      15, 96% of subjects were seroprotected, which increased to 100% by day 22 (n = 27
      evaluable subjects, aged 18-43 years; 13 male, 14 female). All subjects achieved
      seroprotective HAV-neutralizing antibody titers by day 11 (n = 12). The booster
      vaccination at month 12 resulted in a strong response in all subjects, with a
      sustained anti-HAV antibody titer (1,155 mIU/ml) at month 24. Both the priming
      and booster doses were well tolerated. CONCLUSION: Primary vaccination with this
      virosomal HAV vaccine is well tolerated and induces a rapid HAV-neutralizing
      antibody response resulting in seroprotection in all subjects within 10 days. In
      addition, the booster vaccination results in prolonged seroprotective antibody
      levels.

PMID- 15188075
TI  - Sequential changes of hepatitis C virus antibody profiles during treatment of
      chronic hepatitis C of genotype 1b: pretreatment antibody response to E2/NS1
      correlated sustained response.
AB  - BACKGROUND: This study aimed to investigate the relation between hepatitis C
      virus (HCV) antibody profiles and response to therapy of chronic HCV infection of
      genotype 1b. MATERIALS AND METHODS: Quantitative assays of antibody response to
      HCV antigens were performed sequentially using immunoblot confirmatory assays in
      25 patients with genotype 1b chronic hepatitis C who received a 24-week course of
      interferon and ribavirin therapy. RESULTS: 12 patients had a sustained response
      (group A), and 13 did not (group B). Serum titers of HCV RNA were significantly
      higher in group B than in group A (p = 0.02). Pretreatment antibody reactivity to
      core, NS3, NS4, and NS5 antigens did not differ significantly between the two
      groups, but group A had significantly higher titers of anti-E2/NS1 than group B
      (p = 0.04). Sustained response was noted in none of seven patients with HCV RNA >
      10(6) copies/ml, but did occur in 12 of 18 patients with HCV RNA < 10(6)
      copies/ml (p < 0.01). Among the latter, all seven patients with anti- E2/NS1 had
      sustained responses, as did five (45%) of 11 without (p = 0.04). Antibody
      profiles changed little or not at all at the end of treatment or at 6 months
      after treatment in both groups. CONCLUSION: In chronic hepatitis C of genotype
      1b, patients with HCV RNA > 10(6) copies/ml respond poorly to therapy compared to
      those with HCV RNA < 10(6) copies/ml. Among the latter, the presence of
      pretreatment anti-E2/NS1 correlated with sustained response. Quantitative assay
      of antibody response to HCV antigens at the end of treatment had no additional
      value to predict a sustained response.

PMID- 15188076
TI  - Update on glycopeptide use in german university hospitals.
AB  - BACKGROUND: A previous study has shown considerable variation in glycopeptide use
      from 1992 through 1994 among four university hospitals in southern Germany.
      Active antimicrobial management in one of the hospitals was associated with the
      containment of glycopeptide consumption in the medical and surgical service at <
      1.5 defined daily doses (DDD)/100 patient days in the subsequent period. In the
      present study, more recent data on comparative glycopeptide use in German
      university hospitals were analyzed. MATERIALS AND METHODS: Hospital pharmacy
      records from 1998 through 2000 were evaluated. The number of DDD (definition
      according to the World Health Organization [WHO]/Anatomic and Therapeutic
      Classification [ATC] index) per 100 patient days was calculated to compare
      glycopeptide use in different medical and surgical service areas between eight
      German university hospitals. RESULTS: The 3-year averages in recent glycopeptide
      use for the eight hospitals ranged between 1.3 and 8.8 DDD/100 patient days in
      the medical services, and between 0.7 and 1.8 DDD/100 patient days in the
      surgical services. Only one of the eight hospitals showed medical service
      glycopeptide use of < 1.5 DDD/100 patient days. In most hospitals, glycopeptide
      use was higher in the medical intensive care units (ICU) (median 8.6; range 4.3
      to 12 DDD/100 patient days, data for the year 2000) than in the surgical ICUs
      (median 6.7; range 1.2 to 8.6 DDD/100 patient days, data for the year 2000). High
      use was also observed for hematology-oncology services (median 7.5; range 2.7 to
      15.7 DDD/100 patient days, data for the year 2000). CONCLUSION: These recent data
      from a larger hospital sample confirm large variations in glycopeptide use,
      identify hematology-oncology services as a significant prescribing source along
      with ICUs, and indicate areas of probable overuse of glycopeptide antibiotics.
      The data may be useful as a benchmark for further focused drug use control
      interventions.

PMID- 15188077
TI  - Staphylococcus aureus infections in injection drug users: risk factors and
      prevention strategies.
AB  - Infections, in particular soft tissue infections (cellulitis, skin abscesses),
      are the leading cause for emergency department visits and hospital admissions of
      drug injection users (IDUs). Staphylococcus aureus is the most relevant bacterial
      pathogen in this population. It is the main cause of soft tissue infections and
      of severe infections such as endocarditis and bacteremia. Moreover, epidemic
      spread of methicillin-resistant S. aureus (MRSA) among IDUs has occurred in
      Europe and North America. Nasal carriage of S. aureus is associated with an
      increased risk of subsequent S. aureus infections, and it has been shown that
      active IDUs have a higher rate of colonization with S. aureus than the general
      population. However, it is still unknown why an individual carries S. aureus. In
      particular, repeated injections do not appear to be the main predisposing factor
      for S. aureus carriage. Infections associated with injection drug use are
      frequently the consequence of the illegal status of street drugs. Harm reduction
      programs, including needle exchange programs, safer injecting facilities and
      injection opiate substitution programs can reduce the incidence of infections
      among severely addicted IDUs.

PMID- 15188078
TI  - Isolated pulmonic valve infective endocarditis: a persistent challenge.
AB  - Isolated pulmonic valve infective endocarditis is an uncommon clinical entity. We
      report our experience with three patients diagnosed with pulmonic valve
      endocarditis from our institution. Two cases were caused by Enterococcus faecalis
      (one was resistant to vancomycin) and one by coagulase-negative staphylococci
      (CNS). One of the cases of isolated pulmonic valve endocarditis due to the E.
      faecalis was nosocomially acquired; the case of CNS pulmonic valve endocarditis
      was dialysis catheter related. Each patient with isolated pulmonic valve
      endocarditis presented with hypotension and interstitial pulmonary infiltrates.
      Two patients were treated with linezolid. Both vancomycin-resistant enterococci
      (VRE) and CNS were eliminated from blood cultures on linezolid therapy. The
      challenges inherent in the management of pulmonic valve endocarditis mandate the
      development of individual patient-specific guidelines.

PMID- 15188079
TI  - Trimethoprim-sulfamethoxazole exacerbates posthypoxic action myoclonus in a
      patient with suspicion of Pneumocystis jiroveci infection.
AB  - We describe a 58-year-old patient with relapsing high-grade non-Hodgkin's
      lymphoma who exhibited exacerbation of posthypoxic action myoclonus during high
      dose intravenous trimethoprim-sulfamethoxazole (TMP-SMX) treatment for highly
      suspicious Pneumocystis jiroveci pneumonia (PCP). Three months previously the
      patient had experienced a hypoxic insult caused by respiratory arrest due to an
      anaphylactic reaction to antibiotic therapy. He had developed posthypoxic action
      myoclonus (Lance-Adams syndrome), which was well controlled by oral treatment
      with piracetam. However, after TMP-SMX therapy (115 mg/kg daily) was started for
      suspicion of newly developed PCP, posthypoxic action myoclonus worsened
      dramatically resulting in complete disability. Anti-myoclonic therapy with
      increased doses of piracetam and valproic acid did not significantly improve his
      clinical condition. Only when TMPSMX doses were reduced (38 mg/kg daily) on day
      12 did action myoclonus cease within 2 to 3 days. We suggest that TMP-SMX can
      exacerbate posthypoxic action myoclonus.

PMID- 15188080
TI  - Legionella in two splenectomized patients. Coincidence or causal relationship?
AB  - We describe two splenectomized patients admitted with pneumonia. The course in
      one was complicated by overwhelming multiorgan failure when the only indicative
      laboratory result was seropositivity for Legionella hackeliae and Legionella
      longbeachae. He was initially treated with ceftriaxone and roxithromycin,
      followed by levofloxacin as well as intensive supportive treatment, and survived.
      The second patient was seroreactive for Legionella micdadei. In some cases of
      pneumonia in splenectomized patients tentatively considered to be caused by
      Streptococcus pneumoniae, the causative agent might have, in fact, been
      Legionella. We suggest that splenectomy be considered a possible predisposing
      factor for Legionella pneumonia. Since prompt diagnosis of Legionella infection,
      especially the non- pneumophila species, is extremely difficult, alertness to
      this diagnostic option and early empirical initiation of appropriate aggressive
      antibiotic treatment may be of critical importance.

PMID- 15188081
TI  - Linezolid-resistant Enterococcus faecium and Enterococcus faecalis isolated from
      a septic patient: report of first isolates in Germany.
AB  - Here we report the first German case of necrotizing pancreatitis, peritonitis,
      and septic shock caused by linezolid-resistant Enterococcus faecium and
      Enterococcus faecalis.

PMID- 15188082
TI  - How to start antiretroviral therapy?

PMID- 15188083
TI  - The standard of laparoscopic cholecystectomy.
AB  - BACKGROUND: Laparoscopic cholecystectomy today is the standard operation for all
      gall stone disease. Nevertheless, a number of questions are still being
      discussed: What are the optimal steps? Or, more important, is the laparoscopic
      technique really superior to the open procedure according to the criteria of
      evidence-based medicine? How should we proceed in case of an occult
      choledocholithiasis? Is intraoperative cholangiography mandatory, and does the
      concept for the treatment of silent gall stones need to be revised in the era of
      laparoscopic cholecystectomy? METHOD: Literature review. RESULTS: Eleven
      randomised studies show the superiority of the laparoscopic technique. Only one
      study shows no advantage provided the length of the incision in the open
      procedure is less than 8 cm. According to our own experience, up to 98% of all
      gall bladders can be removed laparoscopically when following the described
      standard technique, with a conversion rate of less than 1%. In the case of an
      occult choledocholithiasis the concept of "therapeutic splitting" has proved
      successful; the risk of a residual stone is below 1%. Routine intraoperative
      cholangiography is not cost effective. The risk of complications for a silent
      gall stone in the long term is higher than for laparoscopic cholecystectomy in
      young patients with incidental gall stones. CONCLUSION: The laparoscopic
      technique has given new impulses to the surgery of the gall bladder and has
      proven to be an effective, patient-friendly alternative to open surgery.

PMID- 15188084
TI  - Primary signet-ring cell carcinoma of the colorectum.
AB  - BACKGROUND: Objective of the study was to investigate particular
      clinicopathological features of colorectal signet-ring cell carcinoma. METHODS:
      The data of 34 patients with primary colorectal signet-ring cell carcinoma were
      compared with those of 4,458 consecutive patients with primary non-signet-ring
      cell colorectal adenocarcinoma between 1978 and 1999. For outcome analysis
      patients, after curative resection of signet-ring cell cancer, were matched for
      age, gender, tumour site and stage with patients suffering from poorly
      differentiated non-signet-ring cell colorectal adenocarcinoma. RESULTS: Signet
      ring cell carcinoma patients were significantly younger than patients with non
      signet-ring cell colorectal adenocarcinoma (median age 60 years vs 64 years,
      P=0.033). The most common tumour sites were the rectum (47%) and the right
      hemicolon (29%). They presented with significantly more advanced tumour stages
      and a significantly higher frequency of distant metastases (44% vs 21%, P=0.002).
      The rate of curative resections was significantly lower (35% vs 79%, P<0.001).
      However, the prognosis after curative resection of signet-ring cell cancer was as
      poor as in poorly differentiated non-signet-ring cell colorectal adenocarcinoma
      of the same stage (5-year survival rate 46% vs 57%, p=0.935). CONCLUSIONS:
      Colorectal signet-ring cell carcinoma is characterized by diagnosis in more
      advanced tumour stages resulting in lower rates of curative resection. Prognosis
      is as poor as in non-signet-ring cell colorectal cancer of low differentiation in
      the same stage.

PMID- 15188085
TI  - Previous synovectomy or epiphyseal stapling and the influence on knee replacement
      in juvenile chronic arthritis.
AB  - Seventy-seven anatomically graduated components (AGC) total knee arthroplasties
      (TKA) were performed on 52 patients with juvenile chronic arthritis. According to
      the nature of previous surgery on the knee, the patients were subdivided into
      three groups. The mean age at onset of disease in 23 patients with previous
      synovectomy of the knee was 11 (1.5-16) years, the mean age at the time of
      synovectomy was 20 (4-42) and the mean age when arthroplasty was performed was 31
      (18-45) years. In nine patients with previous epiphyseal stapling, the mean age
      at disease onset was 4 (1.5-8) years, at stapling 8 (4-16) years, and at
      arthroplasty 23 (18-30) years. In patients with no previous surgery, the mean age
      at disease onset in this group was 7 (1.5-16) years and the mean age at
      arthroplasty 34 (16-64) years. Patients with need for epiphyseal arrest had an
      early disease onset and knee replacement in early adulthood. The mean age at knee
      replacements was highest in the group with no prior surgery.

PMID- 15188086
TI  - Coccygectomy for instability of the coccyx.
AB  - Between 1993 and 2000, 61 patients with instability-related coccygodynia were
      operated on by a single surgeon using the same technique. There were 49 women and
      12 men, mean age 45.3 (18-72) years. Twenty-seven patients had hypermobility of
      the coccyx and 33 subluxation. In all cases, the unstable portion was removed
      through a limited incision directly over the coccyx. The outcome was assessed
      using a detailed questionnaire. Follow-up was between 12 months and more than 30
      months. The outcome was rated excellent or good in 53 patients, fair in one, and
      poor in seven. There were nine patients with infection requiring reoperation.

PMID- 15188087
TI  - Use of Tn KPK2 for sequencing a 10.6-kb PstI DNA fragment of Bradyrhizobium
      japonicum and for the construction of aspA and ndvA mutants.
AB  - Transposon Tn KPK2 was used to saturate a randomly cloned Bradyrhizobium
      japonicum PstI fragment and the insertions were used as starting points for the
      sequence determination. The first gene of the 10.6-kb DNA insert encodes a
      homologue to ndvA, the product of which is known to be involved in the formation
      of periplasmic cyclic glucans. Selected Tn KPK2 insertions were introduced into
      the B. japonicum wild-type strain. The resulting mutants were subsequently tested
      for their symbiotic interactions with soybeans. As in Sinorhizobium meliloti, a
      B. japonicum ndvA mutant was affected in salt-stress tolerance and exhibited
      symbiotic defects in that it induced the formation of ineffective soybean
      nodules. The central nodule tissue was infected by bacteroids, but within the
      infected cells the mutant was not properly maintained. Another gene was found to
      be highly similar to bacterial aspartases and thus was named aspA. The putative
      function of the product of this gene was confirmed by genetic complementation of
      aspartase-less Escherichia coli strain TK237. The symbiotic phenotype of a B.
      japonicum aspA:Tn KPK2 mutant consisted of enlarged symbiosomes that made the
      system ineffective. In general, Tn KPK2 is a suitable means for fast sequencing.
      In combination with pJQ200SK, the resulting recombinant plasmids can be directly
      used to create genetically defined mutants.

PMID- 15188088
TI  - [Effects of slow-stroke massage as complementary treatment of depressed
      hospitalized patients].
AB  - BACKGROUND AND OBJECTIVE: Among methods of complementary treatment of depression,
      massage plays an important role, at least in the U.S.A. Although there are some
      pointers to the antidepressive and anxiolytic action of slow-stroke massage in
      various randoms studies of patient cohorts, there have been no controlled trials
      of depressed hospitalized patients. PATIENTS AND METHODS: 32 depressed patients
      (24 women, 8 men; average 48 years - coveringthe entire spectrum of affective
      disorders listed in the ICD but without comorbidity in axis 2) with a minimum
      BRMS score of 16,7 - were included in the study. The randomized cross-over trial
      involved three massage sessions at set times (M) and sessions in two control
      groups (C) (relaxation and perception) lasting for 60 min 2-3 days apart. Under
      the control conditions there was no touching. The effects of depression-specific
      variables (e.g. mood, drive, abnormal cognition, as well as typical progress
      variables of the slow-stroke massage (bodily awareness, general state of health,
      etc.) were measured by both the patients' own assessment and that of an
      independent observer. RESULTS: Under condition of both M and C, comparison of
      before and after effects, there was not only the primarily postulated mood
      enhancing effect, but also some very marked changes in almost all dimension, the
      mean improvement ratio under M often being stronger than under C. After
      Bonferroni correction for multiple tests, the statistical significance there
      remained the stronger effect of M in four dimensions (global tenseness,
      restlessness, depressed mood, neck/shoulder tension). The intensive effect of M
      compared with C was confirmed by both female and male patients regarding the
      answers to various open questions. CONCLUSIONS: Slow-stroke massage is suitable
      for adjuvant acute treatment of patients with depression. It is very readily
      accepted also by very ill patients. In relation to the skin as an organ that aids
      identity, non-hedonic depressed patients are able to recognize the sensory
      quality of therapeutic touching as a positive stimulus. In view of the latent
      period of many weeks and the only moderate efficacy of antidepressants, the
      described complementary method, which does not require physiotherapeutic
      training, should be more often applied in both a hospital and general practice
      setting.

PMID- 15188089
TI  - [Diagnostic utility of capsule endoscopy in occult gastrointestinal bleeding].
AB  - BACKGROUND AND OBJECTIVE: The video-capsule endoscopy (CE) of the small intestine
      is a novel innovative procedure for outpatient use that can detect even small
      lesions of the mucosa of the small intestine. Aim of this retrospective clinical
      study was to evaluate the diagnostic value of CE in a clinical routine setting.
      PATIENTS AND METHODS: Between July 2001 and October 2002 we investigated 42
      patients with suspected gastrointestinal bleeding by CE. In all patients, the
      previous upper and lower endoscopy work-up was normal. In some cases additional
      procedures such as bloodpool scintigraphy, angiography, small-bowel enteroclysis
      or push-enteroscopy were performed. RESULTS: CE detected relevant pathological
      findings in 23 out of 42 Patients (55 %). The majority of findings in the CE
      consisted of angiodysplasia (n = 16), ulcer and haemorrhagical erosions (n = 10),
      one Ulcus Dieulafoy and additional polyps of the small intestine (n = 2). In 4
      cases an inflammatory small-bowel disease was detected. These findings could be
      confirmed by Re-endoscopy. The information provided was helpful to direct further
      diagnostic and treatment options. In 14 cases (33 %) CE-findings steered
      additional diagnostic and therapeutic steps. We conclude that CE is safe and has
      a high diagnostic yield. CONCLUSION: M2A video CE is likely to become an integral
      part of the algorithm of diagnostic of occult gastrointestinal bleeding after
      exclusion of other causes of anemia and negative upper and lower endoscopy work
      up.

PMID- 15188090
TI  - [Lymphangioleiomyomatosis (LAM): a rare cause of ascites and pleural effusion].
AB  - HISTORY AND CLINICAL FINDINGS: A 45 year old woman presented at our hospital for
      further evaluation of intermittent abdominal pain. The patient reported that she
      had suffered a spontaneous pneumothorax 8 years and a pleural effusion 3 years
      before. DIAGNOSTIC FINDINGS AND THERAPY: Abdominal ultrasound showed abdominal
      fluid which proved to be chylous ascites by diagnostic paracentesis. Radiologic
      (lymphangiography) findings were consistent with lymphangioleiomyomatosis (LAM).
      Remarkably, lymphangiography resulted in an immediate disappearance of the
      ascitic fluid. CONCLUSION: This report depicts a case of LAM which involved both
      pulmonary and intestinal symptoms. Previous pulmonary problems gave a hint
      towards the right diagnosis. Though lymphangiography is rarely performed in these
      days, the method was both diagnostic and therapeutic in the case presented.

PMID- 15188091
TI  - [Hyperammonemia: pathogenesis, diagnosis and therapy].

PMID- 15188092
TI  - [Therapeutic options in patients with diabetes mellitus type 2 and coronary
      artery disease: intensified secondary prevention versus percutaneous or surgical
      revascularization].
AB  - Diabetes mellitus is a major risk factor for coronary artery disease and is
      associated with accelerated disease progression and adverse prognosis. Although
      relief of symptoms can quickly be obtained by percutaneous intervention or bypass
      surgery, it does not change patients' prognoses, with the exception of stenoses
      of the left main stem or left anterior descending artery. A multifactorial
      intervention, which consists of a low-fat diet, glucose and arterial blood
      pressure control, smoking cessation and regular physical exercise, emerges as an
      alternative strategy since it leads to improvement of the modifiable risk
      factors, exercise tolerance and quality of life.

PMID- 15188093
TI  - [Growth hormone, bone metabolism and osteoporosis in adulthood].

PMID- 15188094
TI  - [Can ezetimib also be used as a treatment for beta-sitosterol].

PMID- 15188095
TI  - [Which paradoxes can bear weight?].

PMID- 15188097
TI  - Edge loading in third generation alumina ceramic-on-ceramic bearings: stripe
      wear.
AB  - Alumina ceramic-on-ceramic bearings perform exceptionally well under standard hip
      simulator conditions, but in vivo some retrieved bearings have shown an unusual
      stripe pattern of wear. We studied 16 bearings retrieved from a series of 1,588
      cementless hip arthroplasties with third generation alumina ceramic-on-ceramic
      bearings to characterize the mechanism of stripe wear formation. None of these
      bearings were retrieved for bearing failure. The average wear volume was 0.4
      mm(3) per year in the heads and 0.3 mm(3) per year in the liners. Mapping of wear
      stripes on the heads and liners showed that the majority do not occur with normal
      walking; instead they probably occur with edge loading when the hip is flexed,
      such as with rising from a chair or with climbing a high step.

PMID- 15188098
TI  - Isolated liner exchange in revision total hip arthroplasty: clinical results
      using the direct lateral surgical approach.
AB  - Twenty-four hips (23 patients) underwent isolated polyethylene liner exchange
      (modular and nonmodular liners) via the direct lateral surgical approach for a
      preoperative diagnosis of polyethylene wear and acetabular osteolysis. Accessible
      osteolytic lesions were bone grafted with cancellous allograft. Patients were
      followed up clinically and radiographically, with a mean follow-up time of 36
      months (range, 12-100 months). A computer-assisted method measured lesional area
      from the radiographs of the 18 hips that presented with osteolysis. Seventeen of
      18 lesions either regressed or resolved since the procedure. Two patients
      required repeat revisions, and no dislocations were noted. Clinically, both
      Harris Hip and Western Ontario and McMaster Universities Osteoarthritis Index
      scores improved postoperatively. In selected patients, isolated liner exchange
      with or without bone grafting is effective for treating polyethylene wear and
      associated osteolysis. Dislocation rates with revision may be reduced using a
      surgical approach that preserves an adequate capsular layer for closure in liner
      exchange surgery.

PMID- 15188099
TI  - Modular revision for recurrent dislocation of primary or revision total hip
      arthroplasty.
AB  - Two surgeons who used the same implants and surgical approach performed 23
      revisions for recurrent dislocation of modular total hip arthroplasty (THA) with
      retention of components. For 17 primary hips, there was a mean of 3.8 (range, 2
      10) dislocations before revision. Fifteen hips had exchange of the acetabular
      liner, 13 had a change in neck length, and 5 had a change in size of the femoral
      head. At a mean follow-up of 4 years (range, 2-7 years), 14 patients (82%) had no
      further dislocation, 1 had 1 additional dislocation, and 2 required additional
      surgery. For the 6 revision procedures, the mean number of dislocations was 3.8
      (range, 2-10) before re-revision. Liner exchange was performed in 4 hips, neck
      length changed in 3 hips, and head size increased in 2 hips. At a mean follow-up
      of 3 years (range, 2-5 years), only 3 patients (50%) had no further dislocation,
      and 2 required additional surgery. Modular revision can be a successful method of
      treatment of recurrent dislocation after primary THA, but is much less successful
      after revision THA.

PMID- 15188100
TI  - Bone and tissue allograft use by orthopaedic surgeons.
AB  - The purpose of our study was to determine the involvement of orthopaedic surgeons
      in the process of acquiring allografts they transplant. A questionnaire regarding
      allograft acquisition and use was directed to 340 hospitals. In approximately 85%
      of the institutions, nonorthopaedic personnel selected and acquired the
      allografts. In most, those responsible for providing surgeons with allografts had
      little or no knowledge of the practices of tissue banking and allograft
      transplantation biology. In about 15% of the hospitals, the surgeon was involved
      in the selection of the source of allografts. It is imperative that orthopaedic
      surgeons who transplant bone and tissue allografts become actively involved in
      determining the source and processing of tissue transplants they place in their
      patients.

PMID- 15188101
TI  - Complications of ilioischial reconstruction rings in revision total hip
      arthroplasty.
AB  - The complications, management, and outcome of a consecutive series of 61
      ilioischial reconstruction rings performed by 1 surgeon over a 15-year period are
      reported. Structural corticocancellous allografts were used in 48 cases. Twenty
      seven cases had no complications, 9 had medical complications, and 5 had
      complications related to femoral revision. Other complications included 4 sciatic
      and 2 peroneal nerve palsies, 4 rings that lost fixation, 1 possibly loose ring,
      3 fractured flanges, 3 loose cups, 7 dislocations, and 3 deep infections.
      Success, defined as a stable reconstruction with no further acetabular revision
      and bone graft incorporation, was 76%. We recommend a constrained acetabular
      liner to avoid dislocation in selected cases, slotting the ischial flange into
      bone for further ring stability and protection of the sciatic nerve.

PMID- 15188102
TI  - The incidence of heterotopic ossification after total knee arthroplasty.
AB  - Five hundred consecutive patients undergoing primary cemented knee arthroplasties
      were prospectively followed up and evaluated for the presence of heterotopic
      ossification. Of the patients studied, 95% had osteoarthritis and 5% had
      inflammation. A radiographic grading system was devised based on the size and
      location of the heterotopic bone. The overall incidence of heterotopic
      ossification in this group was 15%. The patients who developed HO tended to be
      heavier than the average and were more likely to be men. This is the most
      comprehensive prospective study of the incidence of HO in primary cemented knee
      arthroplasty. Other than a small subset of the patients (4 of 500), HO does not
      appear to have a major influence on the outcome of knee arthroplasty.

PMID- 15188103
TI  - Periprosthetic supracondylar femur fractures following total knee arthroplasty.
AB  - Periprosthetic supracondylar femur fractures following total knee arthroplasty
      (TKA) are an infrequent, but devastating, complication. From 1998 to 2000, we
      treated 30 supracondylar femur fractures above TKAs. Eighteen fractures were
      managed with retrograde intramedullary rod fixation (FIMR) and the other 12
      fractures with traditional open reduction with internal fixation (ORIF). Follow
      up averaged 3 years, with Knee Society knee scores being 84 and 82, respectively.
      Complications included 1 above-knee amputation for deep sepsis and 1 nonunion
      with varus alignment. FIMR appears to be the treatment of choice when it is
      feasible. However, traditional ORIF also may yield satisfactory results in those
      designs that cannot accommodate retrograde FIMR fixation.

PMID- 15188104
TI  - Lateral retinacular release as a function of femoral component rotation in total
      knee arthroplasty.
AB  - A consensus exists in the orthopaedic community that proper rotational placement
      of components may reduce the need for lateral release. This study compares the
      rates and results of lateral release before and after femoral component placement
      was defined by the transepicondylar axis (TEA). Between 1990 and 1991, 104
      primary total knee arthroplasties (TKA) were reviewed during which equal amounts
      of bone from the posterior femoral condyles were removed. In this group, the
      lateral release incidence was 24% for varus deformities and 33% for valgus
      deformities. When the femoral component was externally rotated approximating the
      TEA, a review of 246 primary TKAs performed between 1998 and 1999 showed lateral
      release rates of 7% in varus deformities and 29% in valgus deformities. This
      study documents the statistically significant decline in the lateral release rate
      with external rotation of the femoral component during TKA in varus deformities
      (P<.0001), and a decreasing trend in valgus knees (P =.09).

PMID- 15188105
TI  - Does preoperative hip rehabilitation advice improve recovery and patient
      satisfaction?
AB  - The goal of the current study was to investigate whether preoperative
      rehabilitation advice reinforced by a patient information booklet can aid
      recovery after total hip arthroplasty in terms of pain, function, satisfaction,
      and quality of life. Thirty-five patients awaiting primary total hip arthroplasty
      were recruited into this study and randomly allocated before admission to receive
      either the standard pathway of care or the rehabilitation program and booklet.
      All patients showed increases in function and psychological variables with time.
      The preoperative class and booklet, however, seemed to have the greatest impact
      on length of hospital stay, reducing the hospital stay by 3 days, and therapy
      input required, significantly influencing the cost of the procedure (the
      rehabilitation class led to a cost saving of 587 British pounds; approximately
      810 dollars, per patient). In addition, patients attending the class reported
      higher levels of satisfaction (99% satisfied in the preoperative rehabilitation
      class compared with 80% in the control group 3 months postoperatively) and had
      more realistic expectations of surgery.

PMID- 15188106
TI  - The long-term clinical relevance of calcar atrophy caused by stress shielding in
      total hip arthroplasty: a 10-year, prospective, randomized study.
AB  - Eighty osteoarthritic female patients were randomly allocated to 4 equal groups;
      the Zwey-Muller, the Corail, the Optifix, or Autophor 900S cementless total hip
      arthroplasties (THAs) were implanted; and bone density changes, at different
      sites, were prospectively studied. In zone 7, the greatest reduction of bone
      density values was observed at 2 years (group A: 24%, group B: 8%, group C:
      14.8%, and group D: 18.5%). In all groups, a similar pattern of slow but
      progressive recovery of bone mineral density changes after the third year was
      observed, approaching baseline values at 10 years, during which all patients
      showed satisfactory clinical results. We suggest that the clinical and
      theoretical relevance of the stress-shielding phenomenon in THA has been
      overestimated in the literature.

PMID- 15188107
TI  - Advancement of the vastus lateralis muscle for the treatment of hip abductor
      discontinuity.
AB  - Impaired abductor function of the hip resulting from a discontinuous gluteus
      medius often is encountered in revision hip surgery. If the gluteus medius can be
      reattached to the proximal femur, functional results are satisfactory. If this is
      not possible, it would be desirable to restore the continuity of the gluteus
      medius by bridging the defect with local tissue. An anatomic study was performed
      in 15 cadavers, and proximal advancement of the vastus lateralis without injury
      to the neurovascular pedicle was 8 cm (range, 7-10 cm). Clinically, the technique
      was used in 3 patients. At follow-up, both living patients walked without a cane
      and both were able to hold the leg abducted against moderate pressure. Proximal
      advancement of the vastus lateralis can successfully bridge defects of the
      gluteus medius and partially restores abductor function.

PMID- 15188109
TI  - Bone bleeding during total hip arthroplasty after administration of tranexamic
      acid.
AB  - Numerous methods of controlling bleeding during total hip arthroplasty have been
      used. Thromboplastic agents have been used with some success, but the resultant
      fibrin layer interposed between the bone and cement weakens the interface.
      Topical freezing saline and hypotensive anesthesia have proved to be the most
      effective to date. The goal of this randomized, double blind, controlled study is
      to determine the effect of a single bolus dose of tranexamic acid, administered
      at the time of anesthesia, on bleeding during primary total hip arthroplasty.
      Fifty patients were randomized to receive either 10 mg/kg of tranexamic acid or a
      similar volume of normal saline as a preoperative bolus. Patients were not given
      pharmacologic thrombotic prophylaxis until 48 hours after surgery. The goal was
      to measure blood loss from the femoral canal at the time of surgery. An estimate
      of the internal and external blood loss during and after surgery was performed,
      and the transfusion requirement was recorded. No significant difference was found
      between the groups in terms of blood loss from the femoral canal, the
      perioperative bleeding, and postoperative hemoglobin. In the group that received
      tranexamic acid, a greater number of patients required transfusion than in the
      placebo group. The results of this study do not support the routine use of
      tranexamic acid in primary total hip arthroplasty.

PMID- 15188108
TI  - Histologic reactions to particulate wear debris in different mesenchymal tissues:
      studies on the nonreplaced compartment from revised uni-knees.
AB  - The interface between bone and artificial-joint implants consists of soft tissue.
      This tissue varies from fibrocartilage to loose fibrous tissue. Tissues that
      resemble those can be found in normal joints. Sixteen knees with unicompartmental
      knee prostheses, revised because of excessive wear of the tibial insert, were
      studied. Synovium, synovial fluid, cartilage, and bone from the nonreplaced
      compartment were studied with light microscopy. We found wear particles and
      reactions to those in all tissues except cartilage. In the subchondral bone, we
      found osteolytic-like processes undermining the cartilage peripherally. Our
      conclusion from these findings is that the histologic composition of the bone
      implant interface might be an important factor regarding the reaction of the
      tissue to wear particles and, thus, component fixation.

PMID- 15188110
TI  - Femoral component sizing in total knee arthroplasty: size matched resection
      versus flexion space balancing.
AB  - Generally, 2 different methods are used to select femoral size. These can be
      termed "size-matched resection" and "flexion-space balancing." The purpose of
      this paper is to compare these 2 methods during 50 sequential total knee
      arthroplasty surgeries. The flexion-space-balancing method led to a smaller size
      selection than the size-matched-resection method in 28 (56%) knees. In the
      remaining 22 knees, the measurement methods led to the selection of the same size
      femoral component. The difference in measurement methods was significant (P<.05).
      The preoperative varus knees were more sensitive to the differences in
      measurement methods than the valgus knees (P<.05). A flexion space that is too
      small may adversely affect the clinical outcome of knee arthroplasty.

PMID- 15188112
TI  - Reamer breakage in the femoral medulla during total knee arthroplasty: should
      reamers have a finite life?
AB  - We present a case of intraoperative breakage of an intramedullary reamer in the
      femoral canal during a total knee arthroplasty (TKA). The reamer snapped at the
      junction of its distal and middle thirds leaving the distal fragment of the
      reamer at the level of the femoral isthmus. The broken part was in the middle
      third of the femoral medulla invisible from the lower part of the femur. That was
      removed using a Kuntscher intramedullary nail inserted proximally through the
      piriformis fossa. After removing it from the knee joint, the TKA was performed as
      initially planned. Our case highlights the rare however potential complication of
      intraoperative instrumentation failure and raises requests of metal fatigue and
      failure with repeated use. Further to that a technical note is made describing
      how to remove the broken instrument from the femoral medulla and complete the
      planned TKA.

PMID- 15188111
TI  - Isolated acetabular polyethylene exchange through the anterolateral approach.
AB  - Isolated exchange of an acetabular liner, in the presence of a well-fixed
      acetabular component, has become an established method for the management of
      polyethylene wear. Various experienced adult-reconstruction surgeons have noted a
      high incidence of instability following isolated liner exchange. We report the
      results of isolated liner exchange in 35 patients with polyethylene wear and
      osteolysis (16 patients) or polyethylene wear and instability (19 patients) with
      a minimum follow-up of 2 years. Isolated liner exchange was performed through an
      anterolateral approach in all cases. Postoperative dislocation occurred in 2 of
      the 35 patients (6%), both with polyethylene wear and osteolysis. Isolated liner
      exchange was successful in addressing instability in all 19 patients who
      presented with polyethylene wear and dislocation. Isolated acetabular liner
      exchange performed through an anterolateral approach carries an acceptable
      dislocation rate.

PMID- 15188113
TI  - Revision of distal femoral endoprosthetic arthroplasty with impacted morsellized
      allograft.
AB  - We report the use of contained impacted morsellized allograft to revise an
      aseptically loose, massive distal femoral cemented endoprosthetic replacement in
      a 27-year-old caucasian woman. The prosthesis was inserted 4 years earlier,
      following neoadjuvant chemotherapy and resection of a distal femoral high grade
      osteosarcoma. Impaction grafting was used to restore bone stock and maintain
      femoral length. The patient remains disease free with excellent function, at one
      year after revision with no evidence of loosening and maintenance of bone stock.
      We believe it is the first time this technique has been used in revision of a
      distal femoral endoprosthetic replacement.

PMID- 15188114
TI  - Revascularization of a total bulk acetabular allograft at 14 years.
AB  - This case report describes the long-term outcome of a total bulk acetabular
      allograft placed for bone substitution after resection of recurrent pigmented
      villonodular synovitis of the hip joint. After 14 years in situ, the graft had
      completely incorporated and showed viable bleeding bone surfaces in all areas of
      the acetabular implant interface. The possibility of a bulk corticocancellous
      allograft to undergo revascularization over a long period of time has not been
      previously documented.

PMID- 15188115
TI  - Failed closed reduction of hip arthroplasty secondary to prosthetic incarceration
      in the pelvis.
AB  - This report describes a patient with dislocation of a unipolar hemiarthroplasty
      that could not be reduced by closed reduction methods because of perforation of
      the prosthesis through the ileum.

PMID- 15188116
TI  - Meperidine-induced seizure after revision hip arthroplasty.
AB  - Musculoskeletal injuries secondary to seizures are well documented and have a
      variable incidence. Meperidine (Demerol [Abbott, Abbott Park, IL]) has been used
      for many years in the postoperative setting for pain control; however, in high
      doses, it has been associated with seizure. We report the case of patient who
      experienced a tonic-clonic seizure 5 days after hip revision surgery, resulting
      in dissociation of the socket from the acetabulum with an associated acetabular
      fracture. In this patient, meperidine administered for patient-controlled
      analgesia within recommended range caused the seizure.

PMID- 15188117
TI  - Neurovascular injury during primary total hip arthroplasty caused by a threaded
      acetabulum cup.
AB  - We report an iatrogenic neurovascular injury during hip arthroplasty surgery.
      During insertion of a threaded titanium cup into a dysplastic acetabulum (lack of
      anterior wall), both the common femoral artery and nerve were crushed. It is
      therefore recommended that, if the soft tissues are exposed and can interfere
      with the instruments, inserts that require rotation should not be selected to be
      placed in the acetabulum. To the best of our knowledge, such a mechanism of
      injury has never been reported.

PMID- 15188118
TI  - Prosthetic joint infection with Pasturella multocida following cat scratch: a
      report of 2 cases.
AB  - Infection is a known cause of failure in a total joint arthroplasty. Secondary or
      delayed infections are caused by a wider variety of pathogens, including Gram
      negative organisms. Pasturella multocida is a Gram-negative bacillus that forms
      part of the normal nasopharyngeal and gastrointestinal flora of cats and many
      other animals. Nontrauma-associated infections also have been reported, but these
      are more often confined to animal handlers. We report 2 patients who had cat
      scratch and who developed infection of their total hip arthroplasties with P
      multocida. Both patients were immunocompromised and required revision of their
      hip arthroplasty. One patient had 1-stage revision, because infective cause was
      not obvious at the time of surgery. These patients were followed for 18 months to
      2 years after surgery, with good results.

PMID- 15188119
TI  - Total knee arthroplasty with long stem for treatment of nonunion after high
      tibial osteotomy.
AB  - Nonunion is an uncommon complication of high tibial osteotomy (HTO), and thus
      literature regarding treatment of it is very limited. The usual treatment for
      nonunion after HTO is repeat fixation of the osteotomy site. When union is not
      achieved, hinge or constrained total knee arthroplasty (TKA) is used. We describe
      a patient for whom nonunion after HTO was successfully treated using long-stem
      TKA with bone graft to have the nonunion site unite simultaneously.

PMID- 15188120
TI  - Wear of a highly cross-linked polyethylene liner associated with metallic
      deposition on a ceramic femoral head.
AB  - A 68-year-old patient underwent revision surgery for recurrent dislocation of a
      ceramic-on-polyethylene uncemented hip arthroplasty implanted 6 months
      previously. The aluminum oxide femoral head was found to have titanium deposition
      measuring 5 by 10 mm in an area articulating with the highly cross-linked
      polyethylene liner. The liner was observed to possess severe scratching produced
      by articulation with the titanium deposited on the ceramic head. Despite improved
      scratch resistance of ceramic-bearing surfaces, irregularities introduced by
      metallic deposition after recurrent dislocation can damage a highly cross-linked
      polyethylene liner.

PMID- 15188129
TI  - The 9 lives of beta-catenin.

PMID- 15188130
TI  - Prognostic parameters of endometrial carcinoma.
AB  - Endometrial carcinoma is the most common malignant tumor of the female genital
      tract in the Western world. Approximately 80% of cases are well- to moderately
      differentiated (endometrioid) adenocarcinomas, which are confined to the uterine
      corpus at diagnosis, and thus most can be cured. Conversely, high-grade (ie,
      clear cell and serous) carcinomas account for only 15% to 20% of cases and show
      marked nuclear atypia. These tumors usually invade the myometrium and may extend
      beyond the uterus at the time of hysterectomy. In addition to clinical and
      morphological differences, these 2 groups of endometrial carcinomas differ in
      their pathogenesis. Whereas prognosis in the latter group is generally poor, the
      pathologist's role in establishing the outcome in the former group is crucial.
      Furthermore, it has become progressively apparent that both groups overlap to
      some extent, making the dualistic model a guideline at best. Over the last 2
      decades, several studies have demonstrated the prognostic importance of various
      key surgical and pathological parameters, including histological type,
      histological grade, surgical-pathological stage, depth of myometrial invasion,
      vascular invasion, and cervical involvement. This review presents the most
      important prognostic factors of endometrial carcinomas from the pathologist's
      viewpoint, and attempts to clarify existing conflicts in the classification and
      diagnosis of these tumors.

PMID- 15188131
TI  - Association of E-cadherin and beta-catenin immunoexpression with
      clinicopathologic features in primary ovarian carcinomas.
AB  - Epithelial cadherin forms a complex with alpha-, beta-, and gamma-catenin
      proteins. Reduced expression of E-cadherin-catenins has been shown in human
      carcinomas and is associated with low histologic differentiation, increased risk
      of invasion, and metastatic disease. The immunoexpression pattern of E-cadherin
      and beta-catenin (reduced versus preserved phenotype) was evaluated in 104
      primary ovarian carcinomas and related to clinicopathologic features of the
      tumors. The immunoexpression pattern of E-cadherin was associated with
      International Federation of Gynaecology and Obstetrics (FIGO) staging (P =
      0.043), histologic subtype (P = 0.001), peritoneal metastasis (P = 0.006), and
      residual tumor (P = 0.036). The reduced phenotype of E-cadherin that was observed
      in 64% of the carcinomas (67/104) was associated with advanced stage tumors,
      serous carcinomas, presence of peritoneal metastasis, and residual tumor larger
      than 2 cm. The immunoexpression pattern of beta-catenin was associated with
      histologic subtype (P = 0.005), tumor differentiation (P = 0.025), and peritoneal
      metastasis (P = 0.041). The reduced phenotype of beta-catenin that was observed
      in 74% of the carcinomas (77/104) was associated with advanced stage tumors,
      poorly differentiated serous and clear cell carcinomas, presence of peritoneal
      metastasis, and residual tumor. The immunoexpression pattern of E-cadherin was
      correlated with beta-catenin (P = 0.001). The reduced phenotype for both E
      cadherin and beta-catenin was associated with histologic subtype (P < 0.001) and
      peritoneal metastasis (P = 0.001). In conclusion, the immunohistochemical profile
      of E-cadherin and beta-catenin may be useful in identifying a particular
      subpopulation of ovarian cancer patients who are characterized by an adverse
      clinical outcome, because the reduced phenotype of these molecules was associated
      with poor tumor differentiation, peritoneal metastasis, and advanced FIGO stage
      tumors.

PMID- 15188132
TI  - The role of beta-catenin, TGF beta 3, NGF2, FGF2, IGFR2, and BMP4 in the
      pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids.
AB  - A subset of midgut carcinoids (MCs) result in mesenteric angiopathy (MA) and
      bowel infarction as a consequence of vascular compression caused by extensive
      mesenteric sclerosis (MS). The goal of this study was to determine whether the
      level of expression of several fibrosing-related growth factors was related to
      the finding of MA and/or MS in MCs. Eighteen cases of MC, 6 with both extensive
      MS and MA (group I), 5 with extensive MS only (group II), and 7 with ordinary MS
      only (group III), were analyzed for immunoexpression of beta-catenin,
      transforming growth factor-beta 2 (TGF beta 2), nerve growth factor 2 (NGF2),
      fibroblast growth factor 2 (FGF2), insulin growth factor receptor (IGFR), and
      bone morphogenic protein 4 (BMP4) in formalin-fixed, paraffin-embedded sections.
      Standard immunohistochemical technique was used following antigen retrieval.
      Immunostaining was scored semiquantitively as the product of the percentage and
      intensity (0 to 2+) of the immunostaining, giving a possible range of 0 to 200.
      One-way analysis of variance and Mann-Whitney nonparametric analyses were used
      for statistical analysis. The mean scores of immunoreactivity of each factor in
      groups I, II, and III were as follows: 135, 174, and 147 for beta-catenin
      (cytoplasmic reactivity only); 106, 112, and 92 for TGF beta 3; 1.67, 32, and 36
      for NGF-2; 2.5, 48, and 55 for FGF-2; 19, 112, and 66 for IGFR2; 140, 45, and 52
      for BMP4. There were significant differences in NGF-2 immunoreactivity between
      groups I and III (P = 0.0023) and in BMP4 immunoreactivity between groups I and
      II (P = 0.017) and groups I and III (P = 0.022). All MCs expressed high levels of
      membranous beta-catenin, moderate levels of TGF beta 3 and IGFR2, and low levels
      of FGF-2, with no significant differences seen among the groups. MCs with
      prominent MS and MA (group I) expressed significantly higher BMP4 than those in
      groups II and III, suggesting a potential role of BMP4 in the pathogenesis of MA.
      The level of NGF-2 expression was significantly lower in group I than in group
      III, possibly indicating abnormal angiogenesis in the formation of angiopathy.

PMID- 15188134
TI  - Is gliomatosis peritonei derived from the associated ovarian teratoma?
AB  - Gliomatosis peritonei, a rare condition that occurs almost exclusively in the
      setting of ovarian immature teratoma, is characterized by the occurrence of
      nodules of mature glial tissues in the peritoneum. It is controversial whether
      glial tissues are derived from maturation of the associated teratomatous tissue
      that has implanted in the peritoneum, or glial differentiation of subperitoneal
      stem cells. In this study, we employed the unique genetic characteristics of
      ovarian teratomas (often with a duplicated set of maternal chromosomes and thus
      homozygous at many polymorphic microsatellite loci) versus normal tissues
      (heterozygous pattern due to presence of maternal and paternal genetic materials)
      to investigate the origin of gliomatosis peritonei. DNA samples were extracted
      from microdissected paraffin-embedded tissues, including the glial implants, the
      associated ovarian teratomas, and normal tissues, to determine their patterns of
      microsatellite loci in a multiplex polymerase chain reaction system. Two cases
      were not informative because the ovarian teratoma showed a heterozygous
      microsatellite pattern. In the 5 informative cases, the normal tissues showed a
      heterozygous pattern in the microsatellite loci, the associated teratomas showed
      a homozygous pattern, and the glial tissues showed a heterozygous pattern. Thus,
      gliomatosis peritonei is genetically unrelated to the associated teratoma but is
      probably derived from nonteratomatous cells, such as through metaplasia of
      submesothelial cells.

PMID- 15188133
TI  - Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel
      cleansing.
AB  - Nephrocalcinosis is a chronic tubulointerstitial nephropathy characterized by
      tubular calcium phosphate deposition and slowly progressive renal insufficiency.
      We report a novel association of acute nephrocalcinosis and acute renal failure
      (ARF) with colonoscopy preceded by a bowel-cleansing regimen consisting of oral
      sodium phosphate solution (OSPS). A cohort of 5 patients (mean age, 69.2 years)
      had normal renal function (mean serum creatininem 0.9 mg/dL) before colonoscopy
      and presented with ARF (mean serum creatinine, 4.9 mg/dL) from 3 days to 2 months
      postcolonoscopy. Past medical history included hypertension in all 5 patients.
      Medications included an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) or
      angiotensin receptor blocker (ARB) in 4 patients and diuretics in 2 patients. In
      all patients, colonoscopy was preceded by bowel cleansing with OSPS; OSPS was
      contraindicated in a single patient with hyperparathyroidism and was used at
      excessive doses in another. Renal biopsy specimens obtained from all 5 patients
      revealed diffuse tubular injury and abundant tubular deposition of calcium
      phosphate. Although the tubular injury involved all tubular segments, lectin and
      immunohistochemical staining disclosed calcium phosphate deposition confined to
      distal tubules and collecting ducts. At a mean of 5.8 weeks of postbiopsy follow
      up, renal function was unchanged in 4 patients and mildly improved in 1 patient.
      We conclude that acute nephrocalcinosis is a seemingly rare complication of bowel
      cleansing with OSPS. The pathophysiology of acute nephrocalcinosis after
      treatment with OSPS likely involves transient hyperphosphatemia; volume depletion
      exacerbated by intercurrent ACE-I, ARB, and diuretic use; and elevated distal
      tubular phosphate and calcium concentrations. Greater awareness of this entity is
      needed to identify potential risk factors.

PMID- 15188135
TI  - Evaluation of p16INK4a and pRb expression in cervical squamous and glandular
      neoplasia.
AB  - p16(INK4a) is known to play a critical role as a negative regulator of cell cycle
      progression and differentiation by controlling the activity of the tumor
      suppressor protein pRb. The present study evaluated the expression of p16(INK4a)
      and pRb in cervical squamous and glandular neoplasia. Immunohistochemical
      staining was performed for p16(INK4a) and pRb in formalin-fixed, paraffin
      embedded tissue sections of the uterine cervix using an indirect immunoperoxidase
      method. p16(INK4a) staining was detected in 7 of 108 sections (6.5%) of normal
      squamous mucosa, in scattered ciliated columnar cells in 33 of 88 sections
      (37.5%) of normal endocervical glands, in 9 of 30 sections (30%) with Nabothian
      cysts, and in 4 of 4 areas (100%) of tubal metaplasia. In contrast, strong
      p16(INK4a) staining was found in 13 of 18 cases (72.2%) of cervical
      intraepithelial neoplasia (CIN) I and in all cases of CIN II/III (n = 46),
      squamous cell carcinoma (n = 18), endocervical glandular dysplasia (n = 10),
      adenocarcinoma in situ (n = 23), and invasive adenocarcinoma (n = 12). pRb
      expression was detected in each diagnostic category; however, the proportion of
      pRb-positive cells was relatively decreased in high-grade premalignant and
      malignant lesions of the squamous and endocervical mucosa and showed a generally
      inverse correlation with the expression of p16(INK4a) at the tissue level. These
      findings confirm a correlation between the expression of p16(INK4a) and pRb in
      cervical neoplasias and indicate that p16(INK4a) is a specific marker for
      premalignant and malignant lesions of the squamous and endocervical mucosa.

PMID- 15188136
TI  - The diagnostic utility of immunohistochemistry in distinguishing between
      mesothelioma and renal cell carcinoma: a comparative study.
AB  - Both mesotheliomas and renal cell carcinomas can present a wide variety of
      morphological patterns. Because of this, renal cell carcinomas that metastasize
      to the pleura and lung may be confused with mesotheliomas. The aim of the present
      study was to compare the value of the various immunohistochemical markers
      currently available for the diagnosis of mesothelioma and renal cell carcinoma. A
      total of 48 mesotheliomas (40 epithelioid, 8 sarcomatoid), and 48 renal cell
      carcinomas (24 conventional, 12 chromophobe, 8 papillary, 4 sarcomatoid) were
      investigated for the expression of the following markers: calretinin, mesothelin,
      cytokeratin 5/6, WT1, thrombomodulin (TM), N-cadherin, CD15 (leu-M1), MOC-31, Ber
      EP4, BG-8 (Lewis(y)), CD10, renal cell carcinoma marker (RCC Ma),
      carcinoembryonic antigen (CEA), and B72.3. All (100%) of the epithelioid
      mesotheliomas reacted for calretinin, mesothelin, and cytokeratin 5/6; 93% for
      WT1; 78% for TM; 75% for N-cadherin, 48% for CD10, 15% for Ber-EP4, 8% for MOC
      31, 8% for RCC Ma, 5% for BG-8, and none for CEA, B72.3, or CD15. Of the
      sarcomatoid mesotheliomas, 88% expressed calretinin, 75% N-cadherin, 38% CD10,
      and 13% each expressed cytokeratin 5/6, WT1, and TM. All of the remaining markers
      were negative. Among the RCCs, 81% expressed CD10, 75% N-cadherin, 63% CD15, 50%
      RCC Ma, 50% MOC-31, 42% Ber-EP4, 8% BG-8, and 2% TM. The remaining markers were
      negative. The results indicate that calretinin, mesothelin, and cytokeratin 5/6
      are the best positive mesothelioma markers for differentiating epithelioid
      mesotheliomas from renal cell carcinomas. The best discriminators among the
      antibodies considered negative markers for mesothelioma are CD15, MOC-31, and RCC
      Ma. An accurate differential diagnosis can be reached with the use of any 2 of
      the 3 recommended positive markers, which should be selected based on
      availability and on which ones yield the best staining results in a given
      laboratory. One of the recommended negative markers may be added to the panel if
      deemed necessary. If confirmation of renal origin is needed, RCC Ma could be
      useful. Calretinin is the only marker that appears to have any utility in
      distinguishing between sarcomatoid mesotheliomas and sarcomatoid renal cell
      carcinomas.

PMID- 15188137
TI  - Expression of anaplastic lymphoma kinase in soft tissue tumors: an
      immunohistochemical and molecular study of 249 cases.
AB  - Although anaplastic lymphoma kinase (ALK) has been considered a diagnostic marker
      specifying a subset of anaplastic large cell lymphomas and inflammatory
      myofibroblastic tumors (IMTs), the existence of this receptor in some other
      mesenchymal malignancies has been recently reported. We examined a wider variety
      of soft tissue tumors to further advance the survey of ALK status in mesenchymal
      lesions. ALK protein expression was evaluated immunohistochemically with 2
      specific antibodies (ALK1 and 5A4) in 249 benign and malignant soft tissue
      tumors, and the expression of ALK transcripts and 8 types of ALK fusion
      transcripts was assessed using reverse transcription-polymerase chain reaction
      (RT-PCR) in 165 and 100 tumors, respectively. Moreover, ALK gene status was
      analyzed by interphase fluorescence in situ hybridization (FISH) in 17 tumors
      with ALK expression. Immunohistochemically, ALK protein was detected in 69 cases
      (28%), including IMTs (4 of 4), rhabdomyosarcomas (4 of 7), various lipogenic
      tumors (35 of 65), Ewing's sarcoma/peripheral primitive neuroectodermal tumors (6
      of 10), malignant fibrous histiocytomas (8 of 37), leiomyosarcomas (3 of 18), and
      other non-IMT tumors (9 of 108); however, most of these, except the IMTs,
      displayed merely low-level expression. Although ALK transcripts were identified
      in 85 (52%) of the 165 cases examined by RT-PCR, the full-length (wild-type) ALK,
      rather than the truncated or chimeric forms detected in IMTs, predominated in
      most non-IMT tumors. Except for 2 IMTs, all cases with the expression of ALK
      messages displayed no detectable ALK fusion transcripts. More than 67% of the
      cases analyzed by both RT-PCR and immunohistochemical assays demonstrated
      concordant results. ALK gene amplification was found in 4 non-IMT tumors (2
      leiomyosarcomas and 1 case each of rhadomyosarcoma and malignant fibrous
      histiocytoma) analyzed by FISH, and the rearrangement of this gene was identified
      in 2 IMTs. The current data expands the variety of non-IMT soft tissue tumors
      with ALK expression, and warrants further investigation of its underlying
      molecular mechanisms.

PMID- 15188138
TI  - Expression of interleukin-18 by nasopharyngeal carcinoma cells: a factor that
      possibly initiates the massive leukocyte infiltration.
AB  - Interleukin-18 (IL-18) is a single-chain cytokine that is produced by various
      cells. With interleukin-12 (IL-12), it synergistically stimulates activated T
      cells and natural killer (NK) cells to produce interferon-gamma (IFN-gamma).
      Nasopharyngeal carcinoma (NPC) is the most common form of nasal and
      nasopharyngeal malignancy, and in NPC tumor tissues there is an intense leukocyte
      infiltration comprising predominantly T cells and macrophages. We previously
      showed an increased expression of IFN-gamma in the infiltrating T cells. To
      identify the cells that provide IL-12 and IL-18 for stimulating the expression of
      IFN-gamma in activated T cells, NPC cell lines CNE-2 and HK-1, as well as
      biopsies obtained from NPC and control individuals, were examined. CNE-2 and HK-1
      cells were found to express messenger RNA encoding IL-18, but not IL-12. Secreted
      IL-18 was detected in the culture supernatant. Addition of a caspase-1 inhibitor
      decreased the secretion level, indicating that this IL-18 secretion was caspase-1
      dependent. Moreover, the in vitro IL-18 production in NPC cell lines correlated
      with the NPC tumor cells in situ. NPC tumor cells in the biopsies produced IL-18,
      as detected by immunohistochemistry and immunofluorescent double staining. In
      contrast, IL-18 expression was not observed in the control biopsies. We suggest
      that IL-18 secreted by NPC tumor cells plays a role in initiating the leukocyte
      infiltration process. IL-18 stimulates T cells and NK cells to produce IFN-gamma,
      which consequently activates macrophages and other immune cells to secrete
      chemokines to start a leukocyte recruitment cascade.

PMID- 15188139
TI  - Placental pathology in fetal thrombophilia.
AB  - The aim of this study was to test the hypothesis that placental vascular lesions
      of the fetal circulation are caused by fetal thrombophilic mutations. The study
      included 64 newborns of women with one or more of the following pregnancy
      complications: preeclampsia, placental abruption, and intrauterine growth
      restriction. The most prevalent inherited thrombophilias--factor V Leiden, factor
      II (prothrombin) G20210A, and homozygosity for methyltetrahydrofolate reductase
      C677T--were examined in maternal blood and fetal umbilical cord blood. One
      pathologist reviewed all of the slides for fetal vascular lesions. Associations
      between fetal thrombotic vasculopathy and fetal thrombophilia were tested for
      using Fisher's exact test; Z scores and gestational age were compared using the
      Student t-test. Fetal thrombophilic mutations were diagnosed in 19 of 64
      newborns, 15 of whom had coexistent maternal thrombophilia. There was no
      statistical difference in the prevalence of thrombotic lesions of the fetal
      circulation between newborns with and without thrombophilia. The combination of
      maternal and fetal thrombophilia was also not associated with increased fetal
      vascular lesions. The results indicate that fetal thrombophilia alone, even in
      the context of maternal underperfusion, is not associated with fetal vascular
      lesions of the placenta, although it may represent an underlying risk factor for
      lesions triggered by other process(es).

PMID- 15188140
TI  - Clinicopathologic findings in patients with infantile hemiparesis and epilepsy.
AB  - Infantile hemiparesis may be associated with significant morbidity and may have a
      profound impact on a child's physical and social development. There are little
      published data evaluating the clinicopathologic features of patients with
      infantile hemiparesis. The present study retrospectively examines these
      clinicopathologic features in a surgical series of 21 patients with infantile
      hemiparesis. The study group was comprised of 21 patients, 13 females and 8
      males, ranging in age from 5 to 41 years (mean, 20 years) at the time of surgery.
      Hemiparesis involved the right side in 16 patients and the left side in 5
      patients. Imaging studies identified porencephaly in 8 patients (38%),
      encephalomalacia in 5 patients (24%), focal cerebral atrophy in 9 patients (43%),
      ventricular dilatation in 6 patients (29%), and white matter hyperintensities in
      4 patients (19%). Concomitant neurologic diseases included medically intractable
      epilepsy in all 21 patients and visual field defects in 11 patients (52%).
      Significant perinatal history included prematurity in 7 patients (33%) and
      cesarean section, forceps delivery, placental abruption, fetal distress, and
      prolonged rupture of membranes each in 1 patient (5%). The remainder of the
      patients had an uncomplicated perinatal course (43%). Twelve patients underwent
      functional hemispherectomy (57%), 8 patients underwent lobectomy (38%) and 1
      patient underwent "cyst" resection (5%). Histological evaluation demonstrated
      lesional (corresponding to radiographic findings) tissue in 15 of the 21 cases
      (71%). Infarction, malformations due to abnormalities of cortical development
      (cortical dysplasia) and gliosis with microcalcifications were each found in 6
      patients (29%). Infarction and a geographically distinct area of cortical
      dysplasia were found to coexist in 1 case. Histopathologic findings in the 6
      cases in which excised tissue was considered nonlesional included gliosis in all
      6 of the cases, hippocampal sclerosis in 2 cases (10%), and neuronal heterotopia
      in 2 cases (10%). An osteoma was identified in 1 patient. The most common
      pathological findings observed in our series were infarction and cortical
      dysplasia, although radiographically, infarct-related changes were the most
      evident. Hippocampal sclerosis was encountered in 2 patients, suggesting that a
      subset of cortical dysplasias and hippocampal sclerosis may be caused by an in
      utero ischemic event.

PMID- 15188143
TI  - Determination of DNA ploidy by fluorescence in situ hybridization (FISH) in
      hydatidiform moles: evaluation of FISH on isolated nuclei.
AB  - In the past 20 years, the diagnosis of hydatidiform moles has become more
      difficult because of the widespread use of early uterine evacuation.
      Differentiating hydropic degeneration, partial, and complete moles is important
      because of their different prognosis. However, clinical diagnosis is less
      obvious, and the pathologist has to separate the different entities on the basis
      of very subtle morphologic criteria. In difficult cases, ploidy may be determined
      by various methods, including fluorescence in situ hybridization (FISH) on
      routine histological sections from paraffin-embedded specimens. However, FISH
      analysis is often difficult because of the presence of numerous truncated nuclei.
      In this context, we have tested the advantages of FISH on isolated nuclei, a well
      known variant of the technique that might be more sensitive. We reviewed 24 cases
      of products of abortion: hydropic degenerations, complete hydatidiform moles,
      partial moles, and nonmolar triploidies. After histological review, FISH on
      isolated nuclei proved conclusive in all cases. The results could be easily
      interpreted thanks to the reduced number of truncated nuclei. The percentage of
      cells with 2 signals was always >70% in the diploid cases and >60% in the
      triploid cases. In conclusion, this sensitive technique seems to be a valuable
      tool for the diagnosis of moles.

PMID- 15188142
TI  - Immunohistochemical study of DNA topoisomerase I, DNA topoisomerase II alpha,
      p53, and Ki-67 in oral preneoplastic lesions and oral squamous cell carcinomas.
AB  - Human DNA topoisomerase I (topo I) is the molecular target of the camptothecin
      group of anticancer drugs. Laboratory studies have shown that the cellular
      response to topo I-targeted drugs depends on the topo I expression and DNA
      replication rate and the apoptotic pathway activity. In this study, we tested
      potential indicators of the sensitivity of topo I-targeted drugs in 36 cases of
      oral squamous cell carcinoma (OSCC). Formalin-fixed, paraffin-embedded tissue
      sections were immunostained with monoclonal antibodies against Ki-67, p53, and
      topo I, and with polyclonal antibodies against DNA topoisomerase II-alpha (topo
      II-alpha). These markers were also tested in 18 epithelial hyperplastic lesions
      and 18 mild dysplasias. Immunostaining was quantified by the percentage of
      stained nuclei in each sample (the labeling index); 200 immunoreactive epithelial
      nuclei were counted per case for each antibody. The results support the
      possibility of using topo II-alpha staining for assessing the proliferative
      activity. High expression of topo II-alpha and topo I in OSCCs suggests that they
      may serve as potential indicators of sensitivity to topo I inhibitors. However,
      the apoptotic pathway assessed by p53 immunostaining was found to be
      uninformative. Analysis of the relationship between immunohistochemical results
      and clinical and pathologic parameters (the T and N stages and differentiation)
      showed that only the differentiation parameter correlated with the topo I
      expression rate. Thus, significant increase in the topo I expression in the
      poorly differentiated OSCCs suggests their higher sensitivity to drug treatment.

PMID- 15188144
TI  - Array-based comparative genomic hybridization of ductal carcinoma in situ and
      synchronous invasive lobular cancer.
AB  - It has been increasingly recognized that ductal carcinoma in situ (DCIS), lobular
      carcinoma in situ (LCIS) and invasive cancer of the breast are often closely
      associated with one another. However, the genomic relationship between these
      histologically distinct entities has not been well characterized. Refinements in
      high-resolution comparative genomic hybridization (CGH) techniques allow for a
      detailed comparison of genomic alterations in synchronously occurring tumors. The
      following case illustrates how array CGH may be used to better understand whether
      synchronous neoplasms share a common origin.

PMID- 15188141
TI  - Infantile hemangioma is a proliferation of beta 4-negative endothelial cells
      adjacent to HLA-DR-positive cells with dendritic cell morphology.
AB  - Although hemangioma is referred as to the most common tumor in infancy, the
      underlying pathogenetic events and the biologic origin of this benign vascular
      neoplasm have remained obscure. By using immunohistochemistry on frozen sections
      of infantile hemangiomas, we show here that proliferating endothelial cells
      abundantly expressed alpha(v)beta(3) but lacked beta(4) integrins. Instead,
      regressing and involuting infantile hemangiomas due to treatment with IFN-alpha
      showed positive staining of beta(4) integrin, which might point to the angiogenic
      significance of beta(4) integrin in infantile hemangiomas. Moreover,
      immunofluorescence analysis revealed the existence of HLA-DR(+), mostly CD68(+)
      and partly DC-SIGN/CD209(+) cells with dendritic cell morphology in the intimate
      vicinity of hemangiomatous vessels. Such cells were also detected in the dermal
      microvascular unit in normal skin. The coupled occurrence of vascular structures
      and perivascular cells that were stained positive with markers of monocyte or
      macrophage or dendritic cells might suggest that the development of infantile
      hemangioma is a result of vasculogenesis, that is, the formation of primitive
      blood vessels from angioblasts, rather than of angiogenesis, that is, the
      sprouting of capillaries from preexisting vessels.

PMID- 15188145
TI  - Pulmonary sclerosing hemangioma associated with familial adenomatous polyposis.
AB  - A 45-year-old woman presented with asymptomatic solid tumor in the lower right
      lobe of the lung. Histologically, the tumor comprised a monolayer of surface
      cells and round stromal cells displaying sclerotic areas. Immunohistochemical
      studies suggested a diagnosis of sclerosing hemangioma. Interestingly, morular
      lesions were also observed. Analyses of the gastrointestinal (GI) tract showed
      mild familial adenomatous polyposis (FAP) and numerous fundal gland polyps,
      indicating attenuated FAP (AFAP). All components of the sclerosing hemangioma
      displayed aberrant nuclear and cytoplasmic expression of beta-catenin. However,
      such findings were much weaker in adenomas of the GI tract and were barely
      observed in fundal gland polyps. These results strongly suggest an association
      between sclerosing hemangioma and the AFAP. To the best of our knowledge, this is
      only the second report of lung tumor associated with FAP and is the first
      describing an association with sclerosing hemangioma. A new category of FAP
      associated lung tumors may be indicated.

PMID- 15188146
TI  - Urothelial carcinoma of the urinary bladder with a component of acinar/tubular
      type differentiation simulating prostatic adenocarcinoma.
AB  - We report a case of an 83-year-old man with a high-grade carcinoma of the urinary
      bladder who underwent cystoprostatectomy. The invasive carcinoma showed mixed,
      morphologically distinct patterns consisting of conventional high-grade
      urothelial carcinoma, glandular differentiation resembling enteric type
      adenocarcinoma, and acinar/tubular type differentiation, morphologically similar
      to Gleason grade 3 prostatic adenocarcinoma. Immunohistochemical studies revealed
      the acinar/tubular component of the tumor to be negative for prostate-specific
      antigen and prostatic acid phosphatase, but positive for cytokeratin 7,
      cytokeratin 20, high molecular weight cytokeratin (34 beta E12), and
      thrombomodulin, consistent with origin from the bladder rather than the prostate.
      Although bladder carcinomas composed of mixed morphologic patterns are not
      uncommon, to our knowledge, the presence of acinar/tubular type features
      simulating prostatic adenocarcinoma in such tumors has not been described
      elsewhere.

PMID- 15188149
TI  - Pseudomonas pneumonia in infants.

PMID- 15188147
TI  - Abdominal small round cell tumor with osteoid and EWS/FLI1.
AB  - In this report, we described a case of multiple intraperitoneal tumors.
      Histologically, the tumors were composed of small round cells with malignant
      phenotype, necrotic areas, and islands of osteoid matrix in the stroma. In
      immunohistochemical and molecular analyses, the tumors expressed CD99 and EWS
      Fli1 fusion gene. Production of osteoid by small round tumor cells was consistent
      with the histologic criteria of small-cell osteosarcoma, whereas expression of
      EWS-Fli1 was a characteristic genetic feature of Ewing's sarcoma family of tumor.
      Such tumors have been limited to a case in which histologically proven small-cell
      osteosarcoma of the scapula showed a chromosomal translocation,
      t(11;22)(q24;q12).

PMID- 15188151
TI  - FDA white paper offers solution to therapy pipeline problem.

PMID- 15188154
TI  - Changes proposed to rules governing research misconduct.

PMID- 15188155
TI  - This month at the NIH: new special emphasis program announcements from NIDDK.

PMID- 15188156
TI  - Is irritable bowel syndrome an inherited disorder? Asking the question right.

PMID- 15188157
TI  - Image of the month.

PMID- 15188158
TI  - Molecular defects in mucosal serotonin content and decreased serotonin reuptake
      transporter in ulcerative colitis and irritable bowel syndrome.
AB  - BACKGROUND & AIMS: Serotonin (5-HT) is a critical signaling molecule in the gut.
      5-HT released from enterochromaffin cells initiates peristaltic, secretory,
      vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically
      divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both
      associated with clinical symptoms that include alterations in the normal patterns
      of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT
      signaling is defective in these disorders. METHODS: Rectal biopsy specimens were
      obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D),
      and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including
      measures of 5-HT content, release, and reuptake, were analyzed with these
      samples. RESULTS: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin
      transporter messenger RNA, and serotonin transporter immunoreactivity were all
      significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell
      population was decreased in severe UC samples but was unchanged in IBS-C and IBS
      D. When 5-HT release was investigated under basal and mechanical stimulation
      conditions, no changes were detected in any of the groups relative to controls.
      CONCLUSIONS: These data show that UC and IBS are associated with similar
      molecular changes in serotonergic signaling mechanisms. While UC and IBS have
      distinct pathophysiologic properties, these data suggest that shared defects in 5
      HT signaling may underlie the altered motility, secretion, and sensation. These
      findings represent the first demonstration of significant molecular alterations
      specific to the gut in patients with IBS and support the assertion that
      disordered gastrointestinal function in IBS involves changes intrinsic to the
      bowel.

PMID- 15188159
TI  - Irritable bowel syndrome and surgery: a multivariable analysis.
AB  - BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) have high
      surgical rates. We investigated the demographic and medical factors independently
      associated with surgical histories of health examinees. METHODS: We applied
      multiple stepwise logistic regression analysis to self-completed questionnaire
      data from 89,008 examinees, assessing 6 surgeries as outcomes. We assessed
      questionnaire/physician record agreement of physician-diagnosed IBS and surgical
      history on 201 randomly selected examinees with > or =3 years of records.
      RESULTS: Questionnaire/record agreement for IBS and surgery was 83.6% (kappa =
      0.68) and 95.5%-100.0% (kappa = 0.82-1), respectively. IBS was reported by 4587
      examinees (5.2%) (1382 men [3.0%] and 3205 women [7.5%]). Subjects with and
      without IBS, respectively, reported the following surgical procedures:
      cholecystectomy, 569 (12.4%) versus 3428 (4.1%), P < 0.0001; appendectomy, 967
      (21.1%) versus 9906 (11.7%), P < 0.0001; hysterectomy, 1063 (33.2%) versus 6751
      (17.0%), P < 0.0001; back surgery, 201 (4.4%) versus 2436 (2.9%), P < 0.0001;
      coronary artery surgery, 127 (2.8%) versus 2033 (2.4%), P > 0.05; peptic ulcer
      surgery, 22 (0.5%) versus 277 (0.3%), P > 0.05. Among independent surgery
      associations, IBS was associated with cholecystectomy (adjusted odds ratio [OR],
      2.09; 95% confidence interval [CI], 1.89-2.31; P < 0.0001), appendectomy (OR,
      1.45; 95% CI, 1.33-1.56; P < 0.0001), hysterectomy (OR, 1.70; 95% CI, 1.55-1.87;
      P < 0.0001), and back surgery (OR, 1.22; 95% CI, 1.05-1.43; P = 0.0084).
      CONCLUSIONS: Health examinees with physician-diagnosed IBS report rates of
      cholecystectomy 3-fold higher, appendectomy and hysterectomy 2-fold higher, and
      back surgery 50% higher than examinees without IBS; IBS is independently
      associated with these surgical procedures.

PMID- 15188160
TI  - Reduction in colorectal cancer mortality by fecal occult blood screening in a
      French controlled study.
AB  - BACKGROUND & AIMS: Several randomized population-based studies have shown that
      screening for colorectal cancer (CRC) by fecal occult blood tests (FOBTs) can
      reduce CRC mortality. The aim of this French population-based study was to assess
      whether a similar benefit could be obtained in countries characterized by high
      performances in the diagnosis and management of CRC. METHODS: Small-sized
      geographic areas, including 91,199 individuals aged 45-74 years, were allocated
      to either FOBT screening or no screening. Six screening rounds were performed.
      The FOBT was performed without diet restriction and was sent to a central
      analysis center and processed without rehydration. Screening group participants
      who had a positive test result were offered a full colonoscopy. The entire
      population was followed up for 11 years after study entry. RESULTS: Acceptability
      of the test was 52.8% at the first screening round and varied between 53.8% and
      58.3% in the successive rounds. Positivity rates were 2.1% initially and 1.4% on
      average in the successive rounds. CRC mortality was significantly lower in the
      screening population compared with the control population (mortality ratio, 0.84;
      95% confidence interval, 0.71-0.99). The reduction in CRC mortality was more
      pronounced in those who participated at least once (mortality ratio, 0.67; 95%
      confidence interval, 0.56-0.81). CONCLUSIONS: Our findings, together with the
      results of other trials, suggest that biennial screening by FOBTs can reduce CRC
      mortality regardless of the quality of the health system and support attempts to
      introduce large-scale screening programs into the general population.

PMID- 15188161
TI  - High frequency of MYH gene mutations in a subset of patients with familial
      adenomatous polyposis.
AB  - BACKGROUND & AIMS: Inherited colorectal polyposis has been linked to constitutive
      mutations of the APC tumor suppressor gene. Recently, germline mutations in the
      base excision repair gene MYH have been associated with a recessively inherited
      form of the disease. The aim of this study was to evaluate germline mutation
      frequencies of both MYH and APC susceptibility genes in Italian patients with
      attenuated familial adenomatous polyposis. METHODS: The analysis was performed in
      14 unrelated patients by using the protein truncation test for APC and genomic
      DNA sequencing for MYH. RESULTS: Overall, we identified 7 of 14 (50%) mutation
      carriers. Two patients were heterozygotes for an APC truncating mutation (2 of 14
      [14%]), whereas 5 proved to be homozygotes or compound heterozygotes for MYH gene
      alterations (5 of 14 [36%]). Two MYH missense mutations, Y165C and G382D, already
      found to be frequent among patients from northern Europe, were also preponderant
      in our survey. Individuals with APC-associated syndrome showed a dominant family
      history of polyposis, whereas patients with MYH-associated disease were either
      apparently sporadic cases or had a family history consistent with recessive
      inheritance. MYH biallelic mutation carriers were up to 60% (5 of 8) among
      patients showing at least 30 adenomas and a family history with no vertical
      transmission of polyposis. CONCLUSIONS: On the basis of our data, patients with
      attenuated familial adenomatous polyposis with >30 adenomas and no obvious
      vertical transmission of the disease should be considered for MYH gene testing.

PMID- 15188163
TI  - Afferent limb ulcers predict Crohn's disease in patients with ileal pouch-anal
      anastomosis.
AB  - BACKGROUND & AIMS: Some patients who undergo ileal pouch-anal anastomosis (IPAA)
      surgery for ulcerative colitis (UC) or indeterminate colitis are subsequently
      diagnosed with Crohn's disease (CD). Making the diagnosis of CD in patients with
      IPAA can be difficult, but it is important for prognostic and therapeutic
      purposes. The aim of this study was to identify diagnostic features of CD in
      patients with IPAA. METHODS: We evaluated 87 patients who had undergone IPAA for
      inflammatory bowel disease. Patients were classified as having UC (n = 28), CD (n
      = 27), or indeterminate colitis (n = 32) based on review of the original
      colectomy pathology and the postoperative clinical course. Each patient underwent
      a pouch endoscopy with biopsies of the pouch and afferent limb. Both the
      endoscopist and pathologist were blinded to the patient's diagnosis. RESULTS:
      Afferent limb ulcers (ALUs) were seen on endoscopy in 12 of 27 patients with CD
      (45%) and 4 of 28 patients with UC (14%) (P = 0.019). After excluding patients
      who had taken nonsteroidal anti-inflammatory drugs (NSAIDs) within the past
      month, ALUs were found in 7 of 18 patients with CD (39%) and 0 of 17 patients
      with UC (P = 0.010). Controlling for NSAID use and smoking, the odds ratio for
      ALUs indicating CD was 4.67 (P = 0.03). In the UC population, ALUs were seen in 4
      of 11 patients (36%) who had taken NSAIDs in the past month and 0 of 17 patients
      who had not taken NSAIDs (P = 0.016). CONCLUSIONS: ALUs seen on endoscopy are
      suggestive of CD in patients with inflammatory bowel disease who are not taking
      NSAIDs.

PMID- 15188164
TI  - Gastroesophageal reflux among different racial groups in the United States.
AB  - BACKGROUND & AIMS: White people in the United States are several-fold more
      affected by esophageal adenocarcinoma than black people. It remains unknown
      whether this racial discrepancy reflects a higher prevalence of gastroesophageal
      reflux disease (GERD) symptoms or a higher degree of esophageal damage. METHODS:
      A cross-sectional survey followed by endoscopy was performed among employees at a
      VA medical center. The association between race and GERD symptoms and erosive
      esophagitis was analyzed in logistic regression analyses controlling for
      demographic, clinical, and histologic variables. RESULTS: A total of 496 of 915
      people (54%) returned interpretable questionnaires, and endoscopy was performed
      in 215 participants. The mean age was 45 years, and 336 (68%) were women. Racial
      distribution was 43% black, 34% white, and 23% other races. Heartburn occurring
      at least weekly was reported in 27%, 23%, and 24% of these racial groups,
      respectively. The age-adjusted prevalence of heartburn or regurgitation was not
      significantly different among the groups. Erosive esophagitis was found in 50 of
      215 participants (23%); 31 of these cases were mild. Only one person had
      Barrett's esophagus (0.4%). For weekly heartburn or regurgitation, black
      participants had significantly less frequent erosive esophagitis than white
      participants (24% vs. 50%; P = 0.03). With multiple adjustments, black
      participants had a persistently lower risk of esophagitis (adjusted odds ratio,
      0.22-0.46; P < 0.001). CONCLUSIONS: White and black people in the United States
      have a similarly high prevalence of GERD symptoms. However, black people have a
      lower prevalence of esophagitis for the same frequency of GERD symptoms.
      Barrett's esophagus was rare in this study, even among those with frequent
      symptoms.

PMID- 15188165
TI  - Are claims of equivalency in digestive diseases trials supported by the evidence?
AB  - BACKGROUND & AIMS: Traditionally, randomized controlled trials (RCTs) have
      attempted to show the superiority of one intervention over another. However, when
      effective treatment already exists, it is sometimes more useful to prove that an
      intervention is equivalent, or at least not inferior, to the standard of care.
      Our aim was to determine whether claims of equivalency in digestive diseases
      trials are supported by the evidence. METHODS: Medline was searched for RCTs
      published between 1989 and 2002 using the MeSH headings "exp therapeutic
      equivalency" and "exp digestive diseases" and the text words "equivalence,"
      "equal," "equals," or "equivalent," yielding 902 articles. Of these, 73 articles
      met the inclusion criteria. These articles were evaluated using previously
      published criteria for equivalency. RESULTS: Of the included articles, 33% stated
      an a priori research aim of equivalency, 92% reported differences of <20% between
      "equal" interventions, 34% set an equivalency boundary and tested it
      appropriately, and 19% performed a sample size calculation for equivalency.
      Overall, 12% of the reviewed articles met all 5 criteria. Fifty-two percent of
      our sample inappropriately used a failed superiority test (i.e., a P value >
      0.05) as statistical "proof" of equivalency. Nonsurgical trials and those
      published between 1996 and 2002 were more likely to meet criteria than were
      surgical trials (P = 0.07) or trials published before 1996 (P = 0.003).
      CONCLUSIONS: Claims of equivalency between interventions in digestive diseases
      trials tend to be poorly supported by the evidence. Erroneous claims of
      equivalency are potentially dangerous and may lead to substandard patient care.

PMID- 15188166
TI  - Cytokine-dependent transcriptional down-regulation of epithelial sodium channel
      in ulcerative colitis.
AB  - BACKGROUND & AIMS: The main limiting factor for sodium absorption in distal colon
      is the amiloride-sensitive epithelial sodium channel (ENaC). This study aimed to
      characterize mechanisms involved in the dysregulation of ENaC expression in
      ulcerative colitis (UC). METHODS: Epithelial preparations from surgically removed
      inflamed and control sigmoid colons were used. Active electrogenic Na(+)
      transport (J(Na)) was determined after 8-hour aldosterone stimulation in Ussing
      chambers (corrected for the altered epithelial/subepithelial resistance ratio).
      Subsequently, ENaC alpha-, beta-, and gamma-subunits were analyzed
      immunohistochemically and in Western and Northern blots (corrected for the
      inflammatory increase in subepithelial protein content). To study gene
      regulation, the promoters of beta- and gamma-ENaC were analyzed in reporter gene
      assays. RESULTS: In controls, aldosterone stimulated J(Na) and induced ENaC beta-
      and gamma-subunit expression, whereas this response was virtually abolished in
      UC. Preservation of surface epithelium in UC was indicated by unchanged ENaC
      alpha-subunit expression, which points also against a mere immaturity or
      epithelial cell loss. Inhibition of electrogenic sodium transport as well as beta
      and gamma-ENaC mRNA expression could be mimicked in control colon by in vitro
      preexposure for 8 hours to tumor necrosis factor alpha and interferon gamma.
      Promoter analysis revealed that down-regulation of beta- and gamma-ENaC gene
      expression was primarily induced by tumor necrosis factor alpha. CONCLUSIONS: We
      conclude that, in UC, elevated proinflammatory cytokines selectively impair beta-
      and gamma-ENaC expression, which contributes to diarrhea by reducing colonic
      sodium absorption.

PMID- 15188167
TI  - Testing for celiac sprue in irritable bowel syndrome with predominant diarrhea: a
      cost-effectiveness analysis.
AB  - BACKGROUND & AIMS: Some patients with diarrhea-predominant irritable bowel
      syndrome (IBS-D) may have undiagnosed celiac sprue (CS). Because the symptoms of
      CS respond to a gluten-free diet, testing for CS in IBS may prevent years of
      morbidity and attendant expense. We sought to determine whether this might be a
      cost-effective diagnostic strategy in IBS-D. METHODS: We used decision analysis
      to calculate the cost-effectiveness of 2 competing strategies in IBS-D: (1) start
      empirical IBS treatment and (2) perform serologic test for CS followed by
      endoscopic biopsy for positive tests. The base-case cohort had a CS prevalence of
      3.4%, which was varied between 0% and 100% in sensitivity analysis. The outcome
      measure was cost per symptomatic improvement. RESULTS: Under base-case
      conditions, testing for CS instead of starting empiric IBS therapy cost an
      incremental $11,000 to achieve one additional symptomatic improvement. Testing
      for CS became the dominant strategy when the prevalence of CS exceeded 8%, the
      specificity of CS testing exceeded 98%, or the cost of IBS therapy exceeded
      $130/month. The incremental cost-effectiveness of testing for CS exceeded $50,000
      when the prevalence fell below 1%. CONCLUSIONS: Testing for CS in patients with
      IBS-D has an acceptable cost when the prevalence of CS is above 1% and is the
      dominant strategy when the prevalence exceeds 8%. The decision to test should be
      based on a consideration of the population prevalence of underlying CS, the
      operating characteristics of the screening test employed, and the cost of
      proposed therapy for IBS.

PMID- 15188168
TI  - 5-aminosalicylic acids and the risk of renal disease: a large British
      epidemiologic study.
AB  - BACKGROUND & AIMS: This study was performed to quantify the risk of renal disease
      in patients using aminosalicylates (5-ASA). METHODS: Data from the United Kingdom
      General Practice Research Database were used to estimate the incidence of renal
      disease in adult patients with inflammatory bowel disease (IBD) or prescription
      for 5-ASA and in patients without IBD. In a nested case-control analysis, each
      case of renal disease was matched to 5 controls. RESULTS: Among the 19,025 5-ASA
      users with IBD, 130 patients developed renal disease (incidence rate of 0.17
      cases per 100 patients per year). The incidence among patients with IBD but
      without 5-ASA use was 0.25 and among patients without IBD was 0.08. In the case
      control analysis, the crude odds ratio (OR) for renal disease in current 5-ASA
      users was 1.60 (95% confidence interval [95% CI]: 1.14-2.26); the adjusted OR was
      0.86 (95% CI: 0.53-1.41). For recent users, the crude OR was 4.18 (95% CI: 2.59
      6.76) and adjusted OR 2.48 (95% CI: 1.33-4.61); for past users (last prescription
      more than 12 months before), 1.71 (95% CI: 1.09-2.70) and 0.99 (95% CI: 0.55
      1.76), respectively. Although the numbers were small, mesalazine and
      sulfasalazine users had comparable risks (crude OR for current and recent users
      of OR 2.08 [95% CI: 1.44-3.01] and 1.84 [95% CI: 1.20-2.82], respectively). In
      only a few records was renal disease attributed to interstitial nephritis or 5
      ASA use. CONCLUSIONS: Users of 5-ASA have an increased risk of renal disease that
      may be partly attributable to the underlying disease. Although renal disease is a
      recognized adverse effect of 5-ASA, the incidence appears to be low and does not
      appear to be related to either the dose or type of 5-ASA used.

PMID- 15188169
TI  - Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression
      of advanced hepatic fibrosis.
AB  - BACKGROUND & AIMS: Little is known about the long-term effects of interferon
      alpha on clinical outcome and survival of patients with chronic hepatitis D.
      METHODS: Thirty-six patients with chronic hepatitis D who participated in a
      randomized controlled trial of a 48-week course of high (9 million units) or low
      (3 million units) doses of interferon alpha or no treatment were followed for an
      additional 2 to 14 years. RESULTS: Long-term survival was significantly longer in
      the high-dose group than in untreated controls (P = 0.003) or in the low-dose
      group (P = 0.019) but did not differ between patients treated with 3 million
      units and controls. Among surviving patients at 12 years of follow-up, a
      biochemical response was present in 7 of 12 treated with 9 million units, in 2 of
      4 who received 3 million units, and in none of 3 controls. Long-term alanine
      aminotransferase (ALT) normalization correlated with improved hepatic function
      and loss of IgM antibody to hepatitis delta antigen (anti-HD). Patients in the
      high-dose group had a sustained decrease in HDV replication (P = 0.008), leading
      to clearance of HDV RNA and, eventually, hepatitis B virus (HBV) in some
      patients, as well as a dramatic improvement in liver histology with respect to
      activity grade (P = 0.0004) and fibrosis stage (P = 0.007). Strikingly, we
      documented an absence of fibrosis in the final biopsy of 4 patients with a long
      term biochemical response and an initial diagnosis of active cirrhosis.
      CONCLUSIONS: High doses of interferon alpha-2a significantly improved the long
      term clinical outcome and survival of patients with chronic hepatitis D, even
      though the majority had active cirrhosis before the onset of therapy.

PMID- 15188170
TI  - Persistence of cccDNA during the natural history of chronic hepatitis B and
      decline during adefovir dipivoxil therapy.
AB  - BACKGROUND & AIMS: Hepatitis B virus (HBV) covalently closed circular DNA
      (cccDNA) is a unique episomal replicative intermediate responsible for persistent
      infection of hepatocytes. Technical constraints have hampered the direct study of
      cccDNA maintenance and clearance mechanisms in patients. The aim of this study
      was to develop a sensitive and specific assay for quantifying cccDNA in biopsy
      samples from chronic hepatitis B patients during different natural history phases
      and in patients undergoing antiviral therapy. METHODS: Intrahepatic cccDNA levels
      were quantified by a specific real-time PCR assay. Ninety-eight liver biopsy
      samples from patients in the major phases of the natural history of chronic
      hepatitis B and 32 pairs of samples from patients receiving adefovir dipivoxil
      (ADV) therapy were assessed. RESULTS: cccDNA was detected, at levels ranging over
      3 orders of magnitude, in patients in different phases of the natural history of
      chronic hepatitis B. cccDNA levels were strongly correlated with levels of total
      intracellular HBV DNA and serum HBV DNA. Forty-eight weeks of ADV therapy
      resulted in a significant 0.8 log decrease in cccDNA copies/cell. Changes in
      cccDNA were correlated with a similar reduction in serum HBsAg titer but not with
      a decrease in the number of HBV antigen-positive cells during ADV treatment.
      CONCLUSIONS: cccDNA persists throughout the natural history of chronic hepatitis
      B, even in patients with serologic evidence of viral clearance. Long-term ADV
      therapy significantly decreased cccDNA levels by a primarily noncytolytic
      mechanism.

PMID- 15188172
TI  - Failure to induce oral tolerance to a soluble protein in patients with
      inflammatory bowel disease.
AB  - BACKGROUND & AIMS: Defective suppressor/regulatory T-cell activation has been
      proposed as a mechanism to explain the uncontrolled inflammatory process seen in
      inflammatory bowel disease (IBD). Previous studies have suggested that
      inappropriate activation of CD4+ T cells may occur in the gastrointestinal tract
      in these patients. Because suppressor/regulatory T cells are thought to be one
      mechanism for the promotion of oral tolerance, we attempted to induce tolerance
      in normal controls (n = 21) and patients with either Crohn's disease (CD, n = 12)
      or ulcerative colitis (UC, n = 13). METHODS: Subjects were fed keyhole limpet
      hemocyanin (KLH) before subcutaneous immunization and booster immunization. Blood
      for KLH-induced T-cell proliferation and serum for anti-KLH antibody was obtained
      at baseline and after feeding, immunization, and booster. RESULTS: In the control
      group, KLH feeding (50 and 250 mg) before immunization and booster resulted in
      reduced KLH-specific T-cell proliferation compared with the group that was not
      fed KLH (P < 0.002). However, both CD and UC patients showed significantly
      enhanced proliferation, without tolerance induction, when compared with baseline
      values (P < 0.035 and 0.02, respectively). Serum antibody to KLH was present only
      after immunization in the control group; however, anti-KLH antibody was seen
      after oral administration in both the UC and CD groups. CONCLUSIONS: Taken
      together, these data suggest that oral antigen administration does not result in
      tolerance in CD and UC patients, and might actually result in active immunity.
      This may reflect an in vivo functional defect in mucosal suppression of immune
      responses in IBD.

PMID- 15188171
TI  - Colitis is associated with thymic destruction attenuating CD4+25+ regulatory T
      cells in the periphery.
AB  - BACKGROUND & AIMS: Syngeneic bone marrow transplantation into the adult
      tgepsilon26 mouse results in severe wasting disease and colitis. On
      transplantation, the rudimentary thymus of the adult tgepsilon26 mouse
      repopulates briefly but quickly regresses in temporal association with the onset
      of colitis. The aim of this study is to test the hypothesis that treatment of
      colitis restores thymic capability to generate regulatory T cells (CD4+25+ T(R)
      cells). METHODS: Colitis was induced by bone marrow transplantation into adult
      irradiated tgepsilon26 mice. Colitis was prevented by 3 distinct modalities.
      CD4+25+ T cells were collected from both the thymus and spleen and studied for
      regulatory function by an in vitro suppression assay. RESULTS: CD4+25+ T(R) cells
      do not develop efficiently in the thymus of bone marrow transplanted adult
      tgepsilon26 mice, which have a developmental arrest affecting thymic epithelium.
      By contrast, the thymic epithelium of neonatal tgepsilon26 mice supports
      development of T(R) cells. Consequently, colitis develops only in adult
      transplanted mice but not in the neonatally transplanted mice. Treatment of
      colitis prevents destruction of the thymus of adult transplanted tgepsilon26 mice
      and T(R) cells are produced. CONCLUSIONS: The negative impact of colitis on T(R)
      development in the thymus, which was confirmed in a second model of colitis, has
      profound implications for the pathogenesis and treatment of human inflammatory
      bowel disease.

PMID- 15188173
TI  - Efficient gene transfer into the epithelial cell layer of embryonic mouse
      intestine using low-voltage electroporation.
AB  - BACKGROUND & AIMS: Gene-targeted and transgenic mice have provided profound
      insights into the genetic control of intestinal development and differentiation.
      Here we describe a complementary approach using an innovative embryonic gut
      culture system in which the tubular architecture of the gut is maintained and
      rapid analysis of gene function can be achieved by introduction of expression
      constructs into the epithelial cell layer by using low-voltage square-wave
      electroporation. METHODS: Electroporation of embryonic gut explants was optimized
      by using an electrosquareporator to vary the voltage and number of electric
      pulses. The pulses were applied unidirectionally to confine electroporation of
      plasmids to one side of the epithelium, providing experimental and control
      regions within the same gut segment. The expression of constructs was examined by
      fluorescence and confocal microscopy, immunohistochemistry, and beta
      galactosidase activity assays. RESULTS: Conditions were identified in which a
      high proportion of cells (5% to 20%) within the epithelial cell layer of gut
      explants expressed transfected genes without cell death. Electroporation of a
      construct encoding a Cre-enhanced green fluorescent protein (EGFP) fusion protein
      into explants from ROSA26 reporter animals resulted in extensive activation of
      beta-galactosidase expression, indicating that the electroporated construct
      produced functionally active protein. CONCLUSIONS: A novel embryonic gut culture
      system has been developed to explore the influence of genes on intestinal
      epithelial cell behavior in situ. Complementing the powerful genetics available
      in the mouse, electroporation provides a rapid method for the analysis of genes
      that play pivotal roles in intestinal differentiation.

PMID- 15188174
TI  - Relative frequency and morphology of cancers in STK11 mutation carriers.
AB  - BACKGROUND & AIMS: There is limited data on the spectrum and risk for cancer
      associated with germline serine/threonine protein kinase 11 (STK11) mutations
      that cause Peutz-Jeghers syndrome (PJS). METHODS: We analyzed the incidence of
      cancer in 240 individuals with PJS possessing germline mutations in STK11.
      RESULTS: Fifty-four cancers were found among carriers. Overall, the risk for
      developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 1%, 3%, 19%, 32%,
      63%, and 81%, respectively. Kaplan-Meier analysis showed similar cancer risks
      between missense and truncating mutation carriers (log-rank chi(2) = 2.48; P =
      0.12). There was some evidence that mutations in exon 3 of STK11 were associated
      with a higher cancer risk than mutations within other regions of the gene. We
      found no difference in overall cancer risk between male and female carriers (log
      rank chi(2) = 1.31; P = 0.25) or between familial and sporadic cases (log-rank
      chi(2) = 1.16, with 1 df; P = 0.28). The most common cancers represented were
      gastrointestinal in origin--gastroesophageal, small bowel, colorectal, and
      pancreatic--and the risk for these cancers at ages 30, 40, 50, and 60 years was
      1%, 10%, 18%, and 42%, respectively. In women, the risk for breast cancer was
      substantially increased, being 32% by age 60 years. CONCLUSIONS: These results
      quantitatively show the spectrum of cancer risk associated with STK11 germline
      mutations in the context of PJS and provide a valuable reference for defining
      surveillance regimens.

PMID- 15188175
TI  - Spontaneous recovery from micronodular cirrhosis: evidence for incomplete
      resolution associated with matrix cross-linking.
AB  - BACKGROUND & AIMS: Liver fibrosis and cirrhosis result from the excessive
      secretion of matrix proteins by hepatic stellate cells (HSCs). Previously
      considered irreversible, we have studied a model of cirrhosis to determine the
      mechanisms mediating and limiting spontaneous recovery. METHODS: A micronodular
      cirrhosis was induced in rats after 12 weeks of CCl(4) intoxication. Livers were
      analyzed for evidence of matrix degradation, matrix metalloproteinase (MMP) and
      tissue inhibitor of metalloproteinase (TIMP) expression, stellate cell apoptosis,
      tissue transglutaminase (tTg) expression, and matrix cross-linking during
      spontaneous recovery of up to 366 days. RESULTS: Over 366 days of recovery,
      micronodular cirrhosis underwent significant remodeling to a macronodular
      cirrhosis. Expression of collagen-1 and TIMP messenger RNA (mRNA) decreased
      significantly and active MMPs were shown in livers during remodeling of fibrosis.
      Resolution also was characterized by apoptosis of HSCs, predominantly at the
      margins of fibrotic septa. Residual septa, not remodeled at 366 days, were
      characterized by tTg-mediated cross-linking and relative hypocellularity.
      CONCLUSION: Recovery from comparatively advanced cirrhosis is possible and
      results in remodeling from a micronodular cirrhosis to a macronodular cirrhosis.
      We suggest resolution is limited by tTg-mediated matrix cross-linking and a
      failure of HSC apoptosis.

PMID- 15188176
TI  - Serum response factor promotes re-epithelialization and muscular structure
      restoration during gastric ulcer healing.
AB  - BACKGROUND & AIMS: Serum response factor (SRF) regulates transcription of
      immediate early genes and muscle genes. In this study, we examined the role of
      SRF in gastric ulcer healing and the mechanisms involved. METHODS: Gastric ulcers
      were induced in rats by serosal application of acetic acid. Gastric specimens
      were obtained sequentially after ulcer induction for analyses of SRF messenger
      RNA (mRNA), protein expression, and for immunohistochemistry. We examined the
      role of SRF in ulcer healing by local injection of an SRF expression plasmid into
      ulcers (gene therapy). To elucidate the cellular mechanisms of the action of SRF,
      we examined the effect of SRF overexpression on actin dynamics, cell migration,
      and proliferation in rat gastric epithelial cell (RGM1) and smooth muscle cell
      (A7R5). To determine the clinical relevance, we examined SRF expression in human
      gastric ulcer specimens. RESULTS: Gastric ulceration activated SRF expression in
      epithelial cells lining regenerating glands and in myofibroblasts and smooth
      muscle cells of granulation tissue. SRF up-regulation in human gastric ulcers was
      similar to that found in rat gastric ulcers. Gene therapy with SRF significantly
      accelerated experimental gastric ulcer healing and promoted re-epithelialization
      and muscle restoration. Overexpression of SRF in RGM1 and A7R5 cells accelerates
      migration and proliferation of these cells by promoting actin polymerization and
      activation of immediately early genes. CONCLUSIONS: Activation of SRF is an
      important component of ulcer healing. SRF promotes migration and proliferation of
      gastric epithelial and smooth muscle cells, which are essential for re
      epithelialization and restoration of muscular structures.

PMID- 15188177
TI  - Molecular characterization of hepatocystin, the protein that is defective in
      autosomal dominant polycystic liver disease.
AB  - BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is characterized
      by the presence of numerous cysts spread throughout the liver parenchyma.
      Recently, we discovered that polycystic liver disease is caused by mutations in
      the protein kinase C substrate 80K-H gene, which encodes a protein named
      hepatocystin. Previous studies have identified hepatocystin as a protein kinase C
      substrate, a component of a cytosolic signal transduction complex, a receptor for
      advanced glycation end products, a vacuolar protein, and the beta subunit of
      endoplasmic reticulum glucosidase II. Thus, the exact localization and cellular
      function of hepatocystin remain unclear. METHODS: The localization and
      biochemical properties of normal and polycystic liver disease mutant forms of
      hepatocystin were examined by using a combination of immunofluorescence
      microscopy, immunoblotting, metabolic labeling, immunoprecipitation, and
      carbohydrate analyses. RESULTS: Normal hepatocystin localizes to the endoplasmic
      reticulum, where it assembles with the glucosidase II alpha subunit. The 1338-2A-
      >G truncating mutation in hepatocystin observed in some polycystic liver disease
      patients produces a protein that is not retained in the endoplasmic reticulum but
      is secreted into the medium. This mutant protein fails to assemble with the
      glucosidase II alpha subunit. As a consequence, mutant hepatocystin is
      undetectable in liver cysts. In addition, levels of normal hepatocystin and of
      the glucosidase II alpha subunit are substantially reduced in liver and Epstein
      Barr virus-immortalized B lymphoblasts from patients with polycystic liver
      disease. CONCLUSIONS: These findings are consistent with a role of hepatocystin
      in carbohydrate processing and quality control of newly synthesized glycoproteins
      in the endoplasmic reticulum. Therefore, altered endoplasmic reticulum processing
      of some key regulator of cell proliferation may underlie polycystic liver
      disease.

PMID- 15188178
TI  - Activin A stimulates vascular endothelial growth factor gene transcription in
      human hepatocellular carcinoma cells.
AB  - BACKGROUND & AIMS: Up-regulation of vascular endothelial growth factor is known
      to play a critical role in hepatocellular tumor biology. In an attempt to
      identify factors responsible for vascular endothelial growth factor induction in
      human hepatocellular carcinoma, we evaluated the effects of activin A, a member
      of the transforming growth factor-beta cytokine superfamily, on vascular
      endothelial growth factor gene expression. METHODS: Expression of vascular
      endothelial growth factor, activin A, and its receptors was analyzed by
      immunohistochemistry, polymerase chain reaction, and enzyme-linked immunosorbent
      assay. Functional vascular endothelial growth factor promoter analysis and gel
      shift assays were performed to define minimal promoter requirements and potential
      transcription factors. Nuclear expression and biochemical modifications of Sp1,
      as well as subcellular distribution, expression, and physical interaction of Smad
      proteins with Sp1, were assessed with immunoprecipitation and Western blot
      analysis. RESULTS: Hepatocellular carcinoma tumors and cell lines expressed
      activin A and its receptors. Activin A stimulated vascular endothelial growth
      factor gene transcription through Sp1-dependent induction of vascular endothelial
      growth factor promoter activity. Furthermore, activin A stimulated the DNA
      binding and transactivation potential of Sp1. Immunoprecipitation showed activin
      A-dependent nuclear translocation of Smad2 and induction of Sp1/Smad2
      interaction. The functional relevance of Sp1/Smad2 interaction was confirmed by
      transient transfection experiments, which showed that overexpression of Smad2
      increased vascular endothelial growth factor promoter activity and endogenous
      vascular endothelial growth factor protein expression, whereas dominant negative
      Smad2 blocked activin A responsiveness. CONCLUSIONS: This study identifies
      activin A as a novel stimulus of vascular endothelial growth factor gene
      expression in hepatocellular carcinoma and delineates physical and functional
      cooperation of Sp1 and Smad2 as the underlying mechanism.

PMID- 15188179
TI  - Protease-activated receptor 2 exerts local protection and mediates some systemic
      complications in acute pancreatitis.
AB  - BACKGROUND & AIMS: Protease-activated receptor 2 can be stimulated by
      interstitially released trypsin during acute inflammation of the pancreas. In
      this study, we investigated the roles of pancreatic and circulatory protease
      activated receptor 2 in the pathogenesis of acute pancreatitis by using in vitro
      and in vivo model systems. METHODS: Physiological and pathologic effects of
      protease-activated receptor 2 activation were measured in isolated pancreatic
      cells and in rats with experimental pancreatitis. Consequences of protease
      activated receptor 2 activation on the systemic and inflammatory responses were
      measured after treatments with trypsin or protease-activated receptor 2
      activating peptide. RESULTS: Stimulation of protease-activated receptor 2 in rat
      pancreatic acinar cells activated short-lasting (Ca(2+) signaling) and long
      lasting (extracellular signal-related kinase) signaling pathways and protected
      the cells against bile-induced cell damage. More importantly, protease-activated
      receptor 2 activation ameliorated the pathologic effects observed in the in vivo
      model of cerulein-induced pancreatitis. Trypsin in the circulation of rats with
      taurocholate-induced severe acute pancreatitis reached levels sufficient to
      activate endothelial and immune cells to stimulate nitric oxide and interleukin-8
      production, respectively. Most notably, activation of systemic protease-activated
      receptor 2 by circulating protease-activated receptor 2 agonists induced a
      hemodynamic response pattern similar to that observed in rats with severe acute
      pancreatitis. The effects of protease-activated receptor 2 agonists and acute
      pancreatitis were not additive. CONCLUSIONS: These findings suggest that protease
      activated receptor 2 may have a dual role in acute pancreatitis: protecting
      acinar and duct cells against pancreatitis-induced cell damage while mediating or
      aggravating the systemic complications of acute pancreatitis, which are the major
      cause of mortality in the early phase of necrotizing pancreatitis.

PMID- 15188180
TI  - Incidental esophageal varices.

PMID- 15188181
TI  - Successful treatment of cap polyposis with infliximab.
AB  - Cap polyposis is a disorder characterized by bloody diarrhea with rectosigmoid
      polyps covered by a cap of fibropurulent exudate. The pathogenesis is unknown,
      but histological features suggest that mucosal prolapse may play a role. Drug
      therapies are usually unsuccessful, and treatment requires sigmoid resection or,
      if the disease recurs after initial surgical resection, panproctocolectomy. We
      report the case of a 36-year-old woman with characteristic clinical, endoscopic,
      and histological features of cap polyposis. Investigations included normal
      anorectal manometry and defecography, without evidence of prolapse. The patient's
      disease was unresponsive to treatment with mesalamine, antibiotics, lidocaine
      enemas, and corticosteroids. One infusion of infliximab 5 mg/kg provided dramatic
      symptomatic improvement but minimal endoscopic or histological change. After 4
      infliximab infusions at 8-week intervals, endoscopy of the rectum and sigmoid
      colon was normal, and biopsies showed complete histological resolution of the
      inflammatory process. Well-being with normal endoscopy and histology has been
      maintained at 38 months, without further treatment. It was concluded that
      infliximab is effective therapy for cap polyposis and avoids the requirement for
      surgery. No clinical evidence was obtained to support mucosal prolapse as a
      causative factor, but the response to infliximab suggests a role for tumor
      necrosis factor-alpha in the pathogenesis of this disorder.

PMID- 15188182
TI  - Inflammatory neuropathies of the enteric nervous system.
AB  - Inflammatory neuropathy of the enteric nervous system is emerging as an important
      topic in the field of neurogastroenterology. Enteric ganglionitis can be either
      primary or secondary to a wide array of diseases (i.e., paraneoplastic,
      infectious, and neurological disorders) and is characterized by a dense
      infiltrate of inflammatory/immune cells mainly confined to the neural
      microenvironment. The clinical picture reflects the involved segment of the
      gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and
      megacolon). In these settings, symptoms may develop either acutely (frequently
      after a flulike episode in otherwise previously healthy individuals) or more
      slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in
      enteric ganglionitis leads to neuronal dysfunction and degeneration over time and
      sometimes results in a complete loss of enteric neurons. The diagnosis of enteric
      ganglionitis is supported by detection of circulating antineuronal antibodies
      against select molecular targets, including Hu and Yo proteins, neurotransmitter
      receptors, and ion channels. Potential mechanisms involved in neuronal
      dysfunction include viral antigen expression in the enteric neural environment,
      molecular mimicry (onconeural antigens), and the role exerted by cellular and
      humoral autoimmunity. A short course of steroid or other immunosuppressive
      therapy has been shown to be helpful in the treatment of these conditions. This
      feature reinforces the concept of a cause/effect relationship of the immune
      mediated insult damaging the enteric innervation. An increased awareness of the
      clinical features and the immunologic and neurodegenerative mechanisms of these
      forms of peripheral neuropathy is important to correctly diagnose this problem
      during the early stages of the disease process and to provide appropriate
      immunosuppressive therapies.

PMID- 15188183
TI  - Posthumous presentation of the Julius M. Friedenwald medal to Jon I. Isenberg,
      M.D.

PMID- 15188184
TI  - Douglas B. McGill, 1929-2004.

PMID- 15188185
TI  - AGA 2004 distinguished achievement award to Raymond N. Dubois, M.D., Ph.D.

PMID- 15188187
TI  - Unnecessary abdominal and back surgery in irritable bowel syndrome: time to stem
      the flood now?

PMID- 15188186
TI  - 5-hydroxytryptamine, ulcerative colitis, and irritable bowel syndrome: molecular
      connections.

PMID- 15188188
TI  - The other way round: colitis regulates regulatory T cells.

PMID- 15188189
TI  - Proteinase activated receptor 2: a protean effector comes of age.

PMID- 15188190
TI  - Virtual colonoscopy--finally a credible contender.

PMID- 15188193
TI  - Barrett's esophagus after repair of esophageal atresia with tracheoesophageal
      fistula: yet another morbidity.

PMID- 15188195
TI  - In for a penny, out for a pound.

PMID- 15188197
TI  - Built to last? Durability of lamivudine-induced seroconversion in patients with
      chronic hepatitis B.

PMID- 15188202
TI  - Preemptive lamivudine in hepatitis B patients undergoing chemotherapy.

PMID- 15188204
TI  - Clinical impact of the videocapsule.

PMID- 15188206
TI  - Meta-analysis of the relationship between CagA seropositivity and gastric cancer.

PMID- 15188207
TI  - Helicobacter pylori and gastric cancer.

PMID- 15188210
TI  - The role of alcoholic and metabolic co-factors in chronic hepatitis C.

PMID- 15188211
TI  - Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in
      South Wales, United Kingdom.

PMID- 15188212
TI  - The -2518 promotor polymorphism in the MCP-1 gene is not associated with liver
      cirrhosis in chronic hepatitis C virus infection.

PMID- 15188214
TI  - Is it meaningful to pursue the safety of long-term lamivudine treatment in
      patients with chronic hepatitis B?

PMID- 15188219
TI  - Synthesis of new 2-[1(2H)-phthalazinon-2-yl]acetamide and 3-[1(2H)-phthalazinon-2
      yl]propanamide derivatives as antinociceptive and anti-inflammatory agents.
AB  - As a consequence of our ongoing studies on heterocyclic compounds for new
      antinociceptive and anti-inflammatory agents bearing lactam functional group, new
      2-[1(2H)-phthalazinon-2-yl]acetamide and 3-[1(2H)-phthalazinon-2-yl]propanamide
      derivatives have been synthesized. Among the compounds synthesized, compound (4e)
      was found the most active derivative in terms of antinociceptive and anti
      inflammatory activities, without gastric lesions and bleeding at the given dose.

PMID- 15188220
TI  - New antithrombotics with an indazole structure.
AB  - Fifteen new indazole derivatives have been synthesized. In the Born test,
      compounds (4f) and (4g) were most active. They inhibited the blood platelet
      aggregation induced by collagen with an IC(50) = 85 or 90 microM, respectively.
      After oral administration to rats (60 mg/kg) three of the compounds significantly
      inhibited the formation of thrombi in arterioles and venules. The strongest
      effect was observed with (4j) which showed an inhibition of 15% in arterioles and
      7% in venules. Further experiments showed that compound (4j) does not mediate
      these effects by activating soluble guanylate cyclase, but likely by inhibiting
      phosphodiesterase isoform PDE 5.

PMID- 15188221
TI  - Lead identification for modulators of multidrug resistance based on in silico
      screening with a pharmacophoric feature model.
AB  - Considerable effort has been devoted to the characterization of P-glycoprotein -
      drug interaction in the past. Systematic quantitative structure-activity
      relationship (QSAR) studies identified both predictive physicochemical parameters
      and pharmacophoric substructures within homologous series of compounds.
      Comparative molecular field analysis (CoMFA) led to distinct 3D-QSAR models for
      propafenone and phenothiazine analogs. Recently, several pharmacophore models
      have been generated for diverse sets of ligands. Starting from a training set of
      15 propafenone-type MDR-modulators, we established a chemical function-based
      pharmacophore model. The pharmacophoric features identified by this model were
      (i) one hydrogen bond acceptor, (ii) one hydrophobic area, (iii) two aromatic
      hydrophobic areas, and (iv) one positive ionizable group. In silico screening of
      the Derwent World Drug Index using the model led to identification of 28
      compounds. Substances retrieved by database screening are diverse in structure
      and include dihydropyridines, chloroquine analogs, phenothiazines, and
      terfenadine. On the basis of its general applicability, the presented 3DQSAR
      model allows in silico screening of virtual compound libraries to identify new
      potential lead compounds.

PMID- 15188222
TI  - Intramolecular distribution of hydrophobicity influences pharmacological activity
      of propafenone-type MDR modulators.
AB  - Lipophilicity is one of the major determining physicochemical descriptors for P
      glycoprotein (P-gp) inhibitory activity. Recently, Pajeva and Wiese showed that
      in case of P-gp interaction, lipophilicity may be regarded as space-directed
      property. In the present study, a series of propafenone-type P-gp inhibitors with
      systematically varying hydrophobicity distribution within the molecules were
      synthesised and pharmacologically tested. QSAR studies on the basis of multiple
      linear regression analysis showed that with increasing lipophilicity of the
      substituents on the amine moiety, the statistical significance of the indicator
      variables, denoting the substitution pattern on the central aromatic ring system,
      also increases. This indicates that the distribution of hydrophobicity within the
      molecules influences the mode of interaction with P-gp.

PMID- 15188223
TI  - [1, 2-Bis(2, 6-difluoro-3-hydroxyphenyl)ethylene-diamine]platinum(II) complexes,
      compounds for the endocrine therapy of breast cancer - mode of action I:
      antitumor activity due to the reduction of the endogenous estrogen level.
AB  - Aqua[meso-1, 2-bis(2, 6-difluoro-3
      hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-3-PtSO(4)) and its
      racemate (rac-3-PtSO(4)) are highly active on the hormone-sensitive MXT-M-3, 2
      breast cancer of the mouse. In vitro, on the MXT(+) cell culture derived from
      this tumor, however, they are inactive (meso-3-PtSO(4)) or moderately active (rac
      3-PtSO(4)) in concentrations corresponding to levels of these drugs in animal
      experiments. The in vivo effect is mainly caused by a reduction of the endogenous
      estrogen level in the host animals due to an interference with the ovarian
      steroid biosynthesis as demonstrated for meso-3-PtSO(4). Therefore, a reversal of
      the breast cancer inhibiting effect of meso-3-PtSO(4) can be achieved by
      simultaneous estrone administration. Histological results on ovaries, uterus, and
      tumor of meso-3-PtSO(4)-treated mice also favor such a mode of action. However,
      especially for rac-3-PtSO(4) cytotoxic effects contributing to the anti-breast
      cancer activity cannot be excluded. Considerations on the mode of action of Pt
      complexes which inhibit breast cancer by interference with estrogen receptor
      mediated processes of growth control and with DNA replication are presented.

PMID- 15188224
TI  - [1, 2-Bis(2, 6-difluoro-3-hydroxyphenyl)ethylene-diamine]platinum(II) complexes,
      compounds for the endocrine therapy of breast cancer - mode of action II:
      contribution of drug inactivation, cellular drug uptake and sterical factors in
      the drug-target interaction to the antitumor activity.
AB  - The marked activity of [meso-1, 2-bis(2, 6-difluoro-3
      hydroxyphenyl)ethylenediamine]platinum(II) (meso-3-PtLL', L, L' = Cl(2) or L =
      OH(2), L' = OSO(3)) on the hormone-sensitive MXT-M-3, 2 breast cancer implanted
      in mice is most probably due to a mechanism based on the reduction of the
      endogenous estrogen level. Cytotoxic effects which are poorly pronounced in
      experiments on several breast cancer cell lines (e.g. MCF-7), do not
      significantly contribute to the anti-breast cancer activity of this compound. In
      contrast to this, the standard cisplatin and the structurally related comparison
      compound [meso-1, 2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (meso-4
      PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) are strongly active in vivo as
      well as in vitro. Both effects entail programmed cell death, which is responsible
      for the inhibition of the tumor growth. The minor cytotoxicity of meso-3-PtLL' in
      breast cancer cell cultures is caused neither by an inappropriate rate of
      reaction with bionucleophiles (e.g. by a too fast inactivation by plasma
      proteins) nor solely by the observed poor absorption by the tumor cells resulting
      in an insufficient drug concentration at the DNA. Additionally, an impeded
      reaction with biologically important, guanine-rich sequences of DNA (owing to the
      2, 6-standing F atoms which hinder the drug-target inter action) must be assumed
      as cause of its marginal cytotoxicity.

PMID- 15188225
TI  - Forensic DNA typing by capillary electrophoresis using the ABI Prism 310 and 3100
      genetic analyzers for STR analysis.
AB  - DNA typing with short tandem repeat (STR) markers is now widely used for a
      variety of applications including human identification. Capillary electrophoresis
      (CE) instruments, such as the ABI Prism 310 and ABI 3100 Genetic Analyzers, are
      the method of choice for many laboratories performing STR analysis. This review
      discusses issues surrounding sample preparation, injection, separation,
      detection, and interpretation of STR results using CE systems. Requirements for
      accurate typing of STR alleles are considered in the context of what future
      analysis platforms will need to increase sample throughput and ease of use.

PMID- 15188226
TI  - A critical evaluation of high performance liquid chromatography-electrospray
      ionisation-mass spectrometry and capillary electrophoresis-electrospray-mass
      spectrometry for the detection and determination of small molecules of
      significance in clinical and forensic science.
AB  - A critical review of applications for the period 2000-2003, taken from the Web of
      Knowledge database, of the techniques high performance liquid chromatography
      electrospray ionisation-mass spectrometry (HPLC-ESI-MS) and capillary
      electrophoresis-electrospray ionisation-mass spectrometry (CE-ESI-MS) to the
      detection and determination of small molecules of significance in clinical and
      forensic science is presented. The molecules of mass less than 500 Da are chosen
      according to selected structural classes in which they give ESI signals primarily
      as [M+H](+) ions although other ions such as [M-H](-), [M+Na](+) and [M+NH(4)](+)
      are also reported. The structural classes are drugs with amine-containing side
      chains, drugs with N-containing saturated ring structures, 1,4-benzodiazepines,
      carbohydrates, benzimidazoles, other heterocycles, sulphonylureas,
      anthracyclines, sulphonamides, penicillins, cephalosporins, tetracyclines,
      nitrocatechols, steroids, flavonoids, oxazaphosphorines, cannabinols, and
      miscellaneous molecules. Details are given on the fragmentations, where
      available, that these ionic species exhibit in-source and in ion-trap, triple
      quadrupole and time-of-flight mass spectrometers. The review then gives a
      critical evaluation of these recent HPLC-ESI-MS and CE-ESI-MS analytical methods
      for the detection and determination of small molecules of clinical and forensic
      significance. Analytical information on, for example, sample concentration
      techniques, HPLC and CE separation conditions, recoveries from biological media
      and limits of detection (LODs) are provided.

PMID- 15188227
TI  - Capillary electrophoresis and mass spectrometry for screening of metabolic
      disorders in newborns.
AB  - Clinical analyses always represent a challenge for the sensitivity and
      selectivity of the analytical techniques. Of the most critical are the techniques
      required for the quick determination of the disease state and application of the
      proper treatment in newborns. This short critical review overviews the present
      state of the art of the use of mass spectrometry and capillary electrophoresis
      for screening of metabolic disorders in newborns.

PMID- 15188228
TI  - Determination of aminothiols in body fluids, cells, and tissues by capillary
      electrophoresis.
AB  - Oxidative stress is present in cardiovascular diseases and hyperhomocysteinemia,
      an independent risk factor for these diseases. It may play a role by inducing
      production of oxygen free radicals. Reduced glutathione is the most abundant
      intracellular low-molecular-weight thiol and plays an essential role in
      protecting cells from toxic species. The thiol-containing compounds which are the
      most often considered in biological analysis, are homocysteine (Hcy), cysteine
      (Cys), glutathione (GSH), cysteinyl-glycine (Cys-Gly), gamma-glutamyl-cysteine
      (gammaGlu-Cys), and their derivatives. These aminothiols are present in body
      fluids or cells, associated with proteins or occur free (reduced and oxidized).
      These free forms may play a role in the pathogenesis of disease. Because Hcy
      (with Cys) exhibits pro-oxidative properties and GSH (with Cys-Gly) antioxidative
      properties, and because there is extensive interconversion between these
      metabolites, their simultaneous analysis in biological samples is necessary to
      examine their role in human disease. Capillary electrophoresis (CE) seems to be a
      solution to reach this goal. No extensive review reports the analysis of
      aminothiols using CE. This review describes the different CE approaches which
      have been used to separate and assay aminothiols, and the different obtained
      datas.

PMID- 15188229
TI  - Recent developments in the determination of urinary cancer biomarkers by
      capillary electrophoresis.
AB  - Investigation of effective biomarkers for cancers is currently a popular area of
      study in clinical and cancer researches, because it can potentially lead to pre
      cancer screening or pre-cancer diagnosis and may provide useful information on
      cancer type and the disease's stage of progression. More and more biochemical or
      chemical fluid components of the human body such as urine, blood, and
      cerebrospinal fluid have been considered to contain biomarkers, which are useful
      in cancer researches, pre-cancer diagnosis, and cancer follow-ups during or after
      cancer treatment. Several modern analytical techniques, such as gas
      chromatography (GC), high-performance liquid chromatography (HPLC), capillary
      electrophoresis (CE), and other separation techniques as well as hyphenated
      techniques, have been extensively used in study of cancer biomarkers. Among these
      techniques, CE is considered to be a highly efficient and practical analytical
      technique because of the small sample volume requirement and its wide separation
      versatility, ranging from small inorganic molecules to large biomolecules. This
      review discusses the latest developments involving biomarkers and their analysis
      by CE, including a discussion of instrumental conditions, method developments,
      and data analysis.

PMID- 15188230
TI  - Interferences in clinical capillary zone electrophoresis of serum proteins.
AB  - Capillary zone electrophoresis (CZE) of serum proteins has become a well-accepted
      method for the separation of serum proteins and for the detection of monoclonal
      proteins in clinical laboratories. As CZE uses ultraviolet detection for direct
      protein quantification, exogenous ultraviolet-absorbing substances are a novel
      challenge, not present in conventional gel-based methods in which protein is
      quantified by dye binding. This minireview gives a survey of interfering
      substances, including iodinated contrast agents and antibiotics.

PMID- 15188231
TI  - Determination of nonsteroidal anti-inflammatory drugs in human specimens by
      capillary zone electrophoresis and micellar electrokinetic chromatography.
AB  - Therapeutic drug monitoring of anti-inflammatory drugs is necessary for the
      identification of the agents that cause toxic events and for the decision on the
      treatment for intoxication. Recently, capillary electrophoresis (CE) has been
      developed for the simple and rapid analyses of a variety of chemical agents.
      Micellar electrokinetic chromatography (MEKC) can separate acidic, neutral and
      basic anti-inflammatory drugs in serum. Furthermore, serum samples are directly
      applied to the CE system without any pretreatments, and some anti-inflammatory
      drugs can be separated from serum albumin in the MEKC analysis. On the other
      hand, capillary zone electrophoresis (CZE) enables us to determine a few
      microg/mL levels of acidic anti-inflammatory drugs with simple running buffer and
      stacking technique. A rapid and simultaneous determination of several analgesic
      anti-inflammatory agents, including ibuprofen, acetaminophen, indomethacin, and
      salicylic acid in human serum has been developed by using CZE. Therefore, the CZE
      and MEKC analysis may become a potentially useful alternative to high-performance
      liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) for
      therapeutic drug monitoring, particularly in serum of patients suffering from
      intoxication by overdosage of nonsteroidal anti-inflammatory agents.

PMID- 15188232
TI  - Simultaneous determination of polyamines and catecholamines in PC-12 tumor cell
      extracts by capillary electrophoresis with laser-induced fluorescence detection.
AB  - A method to detect polyamines and catecholamines in PC-12 tumor cell extracts by
      capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) is
      described for the first time. Both derivatization conditions and buffer
      concentrations and pH were optimized. Under optimized conditions the polyamines
      (putresine, spermine, spermidine) and catecholamines (dopamine, norepinephrine,
      epinephrine, serotonin) were derivatized with fluorescein isothiocyanate and
      separated at 25 kV in a fused-silica capillary (50 microm ID x 40 cm) with 0.1 M
      borate, pH 9.0, in less than 18 min. The influence of running buffer conditions,
      such as buffer pH and concentrations, were also investigated. Linearity of the
      analytes ranged from 0.05 to 1.0 micromol/L, and the detection limit (S/N = 3 )
      ranged from 0.03 to 2.50 nmol/L. The concentrations of polyamines and
      catecholamines in PC-12 tumor cell extracts were determined with this method.

PMID- 15188233
TI  - A comparative study of microemulsion electrokinetic capillary chromatography and
      micellar electrokinetic capillary chromatography for the analysis of UV-absorbing
      compounds in human urine.
AB  - Separations of human urine by microemulsion electrokinetic chromatography (MEEKC)
      and micellar electrokinetic capillary chromatography (MEKC) with respect to
      resolution, migration times and efficiencies were optimized and compared. The
      optimised MEEKC and MEKC methods were simple and fast, both of which are
      excellent characteristics for the complex separations required in clinical and
      biomedical studies. However, resolution in MEKC was significantly greater than in
      MEEKC although migration times were 30% faster for the optimised MEEKC method. In
      addition, a faster analysis method (short-end injection) specifically for routine
      screening purposes was also investigated. With both MEEKC and MEKC modes, this
      provided short separations (less than 4 min for urine) with no major compromise
      in resolution. In conclusion, we found that MEEKC offered no real advantage over
      MEKC for urine analysis.

PMID- 15188234
TI  - Capillary electrophoresis combined with microdialysis in the human spinal cord: a
      new tool for monitoring rapid peroperative changes in amino acid
      neurotransmitters within the dorsal horn.
AB  - A method originally developed for the separation of the three neurotransmitters
      gamma-aminobutyric acid (GABA), glutamate (Glu) and L-aspartate (L-Asp) in
      microdialysis samples from rat brain (Sauvinet et al., Electrophoresis 2003, 24,
      3187-3196) was applied to human spinal dialysates obtained during peroperative
      microdialysis from patients undergoing surgery against chronic pain. Molecules
      were tagged on their primary amine function with the fluorogene agent,
      naphthalene-2,3-dicarboxaldehyde (NDA), and, after separation by capillary
      electrophoresis (CE, 75 mmol/L borate buffer, pH 9.2, containing 70 mmol/L sodium
      dodecyl sulfate and 10 mmol/L hydroxypropyl-beta-cyclodextrin, + 25 kV voltage),
      were detected by laser-induced fluorescence detection (LIFD) using a 442 nm
      helium-cadmium laser. The complete method, including microdialysis sampling and
      analysis by CE-LIFD, has been validated for the analysis of human spinal
      microdialysates. The analytical detection limits were 1, 3.7 and 17 nmol/L for
      GABA, Glu and L-Asp respectively. This method allows an accurate measurement of
      the three amino acid neurotransmitters during an in vivo monitoring performed as
      rapidly as every minute in the human spinal dorsal horn. In addition, the effect
      of a brief peroperative electrical stimulation of the dorsal rootlets was
      investigated. The results obtained illustrate the advantages of combining
      microdialysis with CE-LIFD for studying neurotransmitters with such a high
      sampling rate.

PMID- 15188235
TI  - S-Adenosyl methionine/S-adenosyl-L-homocysteine ratio determination by capillary
      electrophoresis employed as a monitoring tool for the antiviral effectiveness of
      adenosine analogs.
AB  - S-Adenosyl-L-homocysteine hydrolase (SAHh) inhibitors have long been used as
      broad-range antivirals and have been recently evaluated as an experimental
      therapy of filovirus infections. In response to the need for a rapid laboratory
      testing method that could assess antiviral potency in vivo, our group developed a
      capillary electrophoresis (CE) method for the determination of the S-adenosyl-L
      homocysteine (SAH) to S-adenosyl-L-methionine (SAM) ratio. After
      chloroacetaldehyde derivatization, SAH and SAM were detected using laser-induced
      fluorescence detection with a HeCd laser. Separation and quantitation of both SAH
      and SAM in human plasma were achieved in less than 1 min. The proposed method is
      rapid and reliable, and could be easily applied to routine monitoring of clinical
      and preclinical trials subjects.

PMID- 15188236
TI  - Quantitation of reduced glutathione and cysteine in human immunodeficiency virus
      infected patients.
AB  - Plasma viral load (VL) values and CD4(+) cell count are employed clinically for
      initiation of therapy in the treatment of patients infected with human
      immunodeficiency virus (HIV), as previous clinical studies have shown a marked
      prevalence of acquired immunodeficiency syndrome (AIDS) development in
      seropositive individuals with VL values over 30 000 copies/mL. Many studies have
      shown that reduced glutathione (GSH) and cysteine (Cys) deficiency play an
      important role in the infection. We have developed capillary zone electrophoresis
      (CZE)-based assays and have used them to investigate the relationship between
      plasma and intracellular thiol levels and HIV-1 viremia in plasma. Blood samples
      from healthy volunteers and seropositive patients undergoing different
      antiretroviral regimes were analyzed in the study. The VL assay was based on CZE
      UV detection of viral RNA at 260 nm. Determination of endogenous reduced Cys and
      GSH was achieved by CZE-UV detection of their mercurial complexes at 200 nm. We
      found that a decrease in GSH and Cys levels may be associated with disease
      progress. In fact, reduced GSH and Cys levels appear progressively reduced with
      increasing VL.

PMID- 15188237
TI  - Quantitative analysis of DNA methylation in chronic lymphocytic leukemia
      patients.
AB  - Changes in the genomic DNA methylation level have been found to be closely
      associated with tumorigenesis. In order to analyze the relation of aberrant DNA
      methylation to clinical and biological risk factors, we have determined the
      cytosine methylation level of 81 patients diagnosed with chronic lymphocytic
      leukemia (CLL). The analysis was based on DNA hydrolysis followed by
      derivatization of the 2'-desoxyribonucleoside-3'-monophosphates with BODIPY FL
      EDA. Derivatives were separated by micellar electrokinetic chromatography, and
      laser-induced fluorescence was used for detection. We analyzed potential
      correlations between DNA methylation levels and numerous patient parameters,
      including clinical observations and biological data. As a result, we observed a
      significant correlation with the immunoglobulin variable heavy chain gene (VH)
      mutation status. This factor has been repeatedly proposed as a reliable
      prognostic marker for CLL, which suggests that the methylation level might be a
      valuable factor in determining the prognostic outcome of CLL. We are now in the
      process of refining our method to broaden its application potential. In this
      context, we show here that the oxidation of the fluorescence marker in the
      samples and the evaporation of methanol in the electrolytes can be prevented by a
      film of paraffin oil. In summary, our results thus establish capillary
      electrophoresis as a valuable tool for analyzing the DNA methylation status of
      clinical samples.

PMID- 15188238
TI  - Rapid analysis of antimicrobial metabolites monoacetylphloroglucinol and 2,4
      diacetylphloroglucinol using capillary zone electrophoresis.
AB  - A rapid capillary electrophoretic (CE) method was developed for the determination
      of phloroglucinol compounds, monoacetylphloroglucinol (MAPG) and 2,4
      diacetylphloroglucinol (DAPG), in microbial supernatants of Pseudomonas
      fluorescens F113 over a 24-h growth cycle. Prior to electrophoretic separation,
      solid-phase extraction of supernatant samples on octadecylsilica for the purpose
      of sample cleanup is recommended. The optimum electrophoretic conditions were
      found to be 25 mM sodium tetraborate running buffer at pH 9.3, temperature at 25
      degrees C with an applied voltage of 25 kV. The capillary was an Agilent fused
      silica capillary of total length 33 cm x 50 microm inner diameter, 375 microm
      outer diameter, with effective length 24.5 cm. While MAPG and DAPG were monitored
      at selected wavelengths in the range of 214-320 nm, analysis at 214 nm was used
      and a CE separation time of less than 2 min was achieved. A partial method
      validation study was performed in accordance with European Agency for Evaluation
      of Medicinal Products (EMEA) guidelines. The method displayed linearity over the
      investigated range of 10-200 microg/mL, with limits of detection of 1.2 microg/mL
      for MAPG and 1.3 microg/mL for DAPG.

PMID- 15188239
TI  - Analysis of organic components of smokeless gunpowders: high-performance liquid
      chromatogaphy vs. micellar electrokinetic capillary chromatography.
AB  - The aim of the present study was to verify the analytical performances of high
      performance liquid chromatography (HPLC) and micellar electrokinetic capillary
      chromatography (MEKC) for the separation and qualitative determination of a
      selected group of organic components of smokeless gunpowders. The HPLC method was
      based on a gradient reversed-phase elution with a mobile phase composed of 0.17 M
      H(3)PO(4)/methanol; detection was performed by UV absorption at the wavelengths
      of 220, 254, and 270 nm. The MEKC experiments were carried out by using uncoated
      fused-silica capillaries (50 microm inside diameter, 50 cm effective length) and
      a running buffer composed of 10 mM sodium tetraborate at pH 9.24 added with 25 mM
      sodium dodecyl sulfate (SDS); the applied voltage was 25 kV; detection was either
      at a fixed wavelength UV of 214 nm or with a diode-array detector operating in
      the wavelength range from 190 to 350 nm. Both reversed-phase HPLC and MEKC
      techniques succeeded in resolving the tested standard mixtures of organic
      components of smokeless powders. Although the sequence of elution of the
      different analytes was slightly different between HPLC and MEKC, a statistical
      analysis based on the Spearman's rank correlation test showed that the two
      separation patterns were highly correlated. HPLC and MEKC were comparable in
      terms of elution/migration time precision, whereas MEKC showed higher
      reproducibility of peak areas. The interfacing of capillary electrophoresis with
      diode array UV detection provided distinct UV spectra of the individual analytes,
      thus improving, on the detection side, the analytical selectivity and
      identification power of capillary electrophoresis.

PMID- 15188240
TI  - Conflicting results between electrophoresis methods of serum M-proteins.
AB  - The quantification of monoclonal immunoglobulins by protein electrophoresis has
      been helpful in determining the prognosis for the patient. In a 65-year old man
      with documented IgG lambda monoclonal gammopathy, a discrepancy in the detection
      and quantification of this M-protein was found when studied by four different
      electrophoretic methods. On a high-resolution agarose method with acid violet
      staining a prominent peak was seen in the fast gamma-region. A lower resolution
      agarose method using an amido black staining showed a small mid-gamma
      restriction, and no spike was detected by high-resolution or lower resolution
      capillary zone electrophoresis. The discrepancy was not attributable to a
      migration in the beta-region leading to masking by transferrin or C3 peak,
      incorrect separation on CZE due to a high isoelectric point (pI > 8.5) or
      pentamerization of IgM M-proteins. Therefore, other causes for discrepancies
      should be investigated.

PMID- 15188241
TI  - High-density lipoproteins contribute to the alpha-1-globulin zone in capillary
      electrophoresis of human serum proteins.
AB  - Alpha-1-antitrypsin (AAT) and alpha-1-acid glycoprotein (AAG) are reported to be
      the main proteins contributing to the alpha-1-globulin capillary zone
      electrophoresis (CZE) zone, but the sum (AAT + AAG) showed lower than the alpha-1
      globulin. We investigated the role of high-density lipoprotein (HDL), an
      additional protein migrating in the alpha-1-globulin zone, as a possible cause
      for such a gap. In a set of 98 sera we measured the alpha-1-globulin with a
      dedicated clinical capillary electrophoresis system, and AAT, AAG and
      apolipoprotein A-1 (ApoA) by immunonephelometry. The alpha-1-globulin were
      consistently higher than the sum (AAT + AAG), by (mean value +/- standard
      deviation) 1.70 +/- 0.88 g/L in 49 sera with low ApoA, and by 3.59 +/- 0.75 g/L
      in 49 sera with high ApoA. Corresponding figures in the comparison alpha-1
      globulin/(AAT + AAG + ApoA) were reduced to 1.08 +/- 0.77 g/L and 1.67 +/- 0.70
      g/L. It is concluded that HDL significantly contribute to the CZE alpha-1
      globulin zone, but do not completely explain the differences between the
      electrophoretic and the immunochemical measurements. However, CZE alpha-1
      globulin measurements give information about increases of the two major acute
      phase proteins comparable to specific protein measurements.

PMID- 15188242
TI  - Quality control and quality assurance aspects of the routine use of capillary
      electrophoresis for serum and urine proteins in clinical laboratories.
AB  - Using capillary electrophoresis (CE) for serum protein electrophoresis, the
      quality of results begins with monitoring a well-functioning instrument, using
      scrupulously clean capillaries, well-calibrated methods as well as regular use of
      an internal quality control material. Quality assurance programs are available in
      countries such as Australia, United Kingdom, United States, and European
      countries such as Sweden and Germany. The present commercial control material
      that is available gives percentages of albumin, alpha 1, alpha 2, beta- and gamma
      globulins, the gamma-component being of normal distribution, and not containing
      any monoclonal protein component. We feel that a quantitative commercial control
      material containing a monoclonal protein at decision level for treating myeloma
      patients would be beneficial to all laboratories as a serum protein
      electrophoresis control, whether the analysis is by CE or agarose gels. The same
      applies for control material for urinary protein electrophoresis.

PMID- 15188243
TI  - Characterization of the interaction between human complement protein C4 and a
      single-chain variable fragment antibody by capillary electrophoresis and surface
      plasmon resonance.
AB  - Immunoaffinity capillary electrophoresis and surface plasmon resonance have been
      used for the characterization of the interaction between two large-sized
      proteins, the human complement protein C4 and the single-chain variable fragment
      C43. The rather high kinetic rate constants as determined by surface plasmon
      resonance pointed out that a capillary electrophoresis method had to be applied,
      in which the labeled C4 is preincubated with C43 before injection and the same
      concentration of C43 is included in the running buffer. Analysis of the
      concentration dependence of the small mobility shift of the fluorescent C4 signal
      upon binding of C43 resulted in a dissociation constant that was comparable to
      the one obtained with surface plasmon resonance. This study is one of the few
      examples where capillary electrophoresis is successfully used to characterize the
      interaction between large proteins.

PMID- 15188244
TI  - Selection of migration parameters for a highly reliable assignment of bands of
      isoforms of erythropoietin separated by capillary electrophoresis.
AB  - Capillary zone electrophoresis of samples of recombinant human erythropoietin is
      performed. An in-house computer program is developed to compare the reliability
      of different migration parameters to assign the close migration bands of isoforms
      of erythropoietin. The migration time relative to the electroosmotic flow marker
      and the effective electrophoretic mobility are selected as the most accurate
      parameters. Percentages of correct assignment of bands higher than 99% are
      obtained with these parameters even when changes in operational factors are
      introduced. The chosen parameters have been applied to assign bands of isoforms
      in commercial samples of alpha- and beta-epoetin. The same capillary
      electrophoresis method has been applied to separate bands of isoforms of an
      erythropoietin analogue, darbepoetin alpha, the novel erythropoiesis-stimulating
      protein.

PMID- 15188245
TI  - Capillary electrophoresis analysis of a wide variety of seized drugs using the
      same capillary with dynamic coatings.
AB  - Capillary electrophoresis methodology is presented for the routine analysis of a
      wide variety of seized drugs using the same capillary with dynamic coatings and
      multiple run buffers. The types of exhibits analyzed using diode array UV
      detection include phenethylamines, cocaine, oxycodone, heroin, lysergic acid
      diethylamide (LSD), opium, hallucinogenic mushrooms, and gamma-hydroxybutyrate
      gamma-butyrolactone (GHB-GBL). Both qualitative and quantitative analyses are
      achieved using run buffers that contain additives that provide for secondary
      equilibrium and/or dynamic coating of the capillary. Dynamic coating of the
      capillary surface is accomplished by rapid flushes of 0.1 N sodium hydroxide,
      water, buffer containing polycation coating reagent, and a buffer containing a
      polyanionic coating reagent (with or without cyclodextrin(s)) or a micelle
      coating reagent. Dynamic coating with a polyanionic coating reagent is used for
      the analysis of moderately basic seized drugs and adulterants. The use of
      cyclodextrin in the run buffer not only allows for chiral analysis but also
      greatly enhances separation selectivity for achiral solutes. A capillary
      dynamically coated with a micelle allows for the analysis of neutral, acidic, and
      weakly basic drugs (GHB, GBL and neutral, acidic, and weakly basic adulterants).
      Dynamic coating, which gives rise to a relatively high and robust electroosmotic
      flow at pH < 7, allows for rapid, precise and reproducible separations. For a
      wide variety of drugs, excellent linearity and migration time precision and good
      peak area precision (external and internal standard) is obtained. Quantitative
      results for synthetic mixtures are in good agreement with actual values.
      Screening for adulterants is greatly enhanced by the use of automated library
      searches.

PMID- 15188246
TI  - Determination of multiple drugs of abuse in human urine using capillary
      electrophoresis with fluorescence detection.
AB  - Methods for separation and determination of multiple drugs of abuse in biological
      fluids using capillary electrophoresis (CE) with native fluorescence and laser
      induced fluorescence (LIF) detection are described herein. Using native
      fluorescence, normorphine, morphine, 6-acetyl morphine (6-AM), and codeine were
      analyzed by CE without any derivatization procedure and detected at an excitation
      wavelength of 245 nm with a cut-off emission filter of 320 nm, providing a rapid
      and simple analysis. The detection limits were in the range of 200 ng/mL. For a
      highly sensitive analysis, LIF detection was also examined using a two-step
      precolumn derivatization procedure. In this case, drugs extracted from human
      urine were first subjected to an N-demethylation reaction involving the use of 1
      chloroethyl chloroformate (ACE-Cl) and then derivatized using fluorescein
      isothiocyanate isomer I (FITC) and analyzed by CE coupled to a LIF detector.
      Variables affecting this derivatization: yield of demethylation reaction, FITC
      concentration, reaction time and temperature, were studied. The estimated
      instrumental detection limits of the FITC derivatives were in the range of 50-100
      pg/mL, using LIF detection with excitation and emission wavelengths of 488 nm and
      520 nm, respectively. The linearity, reproducibility and reliability of the
      methods were evaluated. In addition, a comparison of the characteristics for both
      native fluorescence and LIF detections was also discussed.

PMID- 15188248
TI  - Identification of diphenhydramine metabolites in human urine by capillary
      electrophoresis-ion trap-mass spectrometry.
AB  - The identification of diphenhydramine (DH) metabolites that are frequently
      observed in the capillary zone electrophoresis (CZE) and micellar electrokinetic
      capillary chromatography (MEKC) analyses of alkaline liquid/liquid and solid
      phase extracts of patient urines is demonstrated. Having standards for DH and
      diphenhydramine-N-oxide (DHNO), the presence of these two compounds could be
      confirmed in urines that were collected overnight after administration of 25 mg
      DH chloride. Using CZE coupled to ion-trap mass spectrometry (CE-MS(n)) with
      positive electrospray ionization and an acetate buffer at pH 5.6, the [M+H](+)
      ions of DH (m/z = 256), DHNO (m/z = 272), and nordiphenhydramine (NDH, m/z = 242)
      and their fragmentation to a common m/z 167 product ion (diphenylcarbinol moiety)
      was monitored. The data indicate that all three compounds are cations in an
      acidic environment, the migration order being NDH, DH, and DHNO. Data obtained
      under negative electrospray ionization conditions suggest the presence of
      diphenylmethoxyacetic acid-glycine amide ([M-H](-) ion of m/z 298 and
      fragmentation to m/z 254, loss of CO(2)), a metabolite that could tentatively be
      assigned to a characteristic peak observed in the MEKC electropherogram at
      alkaline pH. The data presented in this paper illustrate the value of using CE
      MS(n) for identification of urinary drug metabolites for which no standards are
      available.

PMID- 15188247
TI  - Stacking and low-temperature technique in nonaqueous capillary electrophoresis
      for the analysis of 3,4-methylenedioxymethamphetamine.
AB  - Low-temperature and ambient-temperature nonaqueous stacking techniques in
      capillary electrophoresis (CE) are described for the first time. A low
      temperature bath was used to control the temperature from ambient to subzero
      degrees, by which a novel hyphenated method, low-temperature bath-nonaqueous
      capillary electrophoresis stacking (LTB-NACE stacking) is demonstrated. 3,4
      Methylenedioxymethamphetamine (3,4-MDMA) was determined at a concentration of 4.7
      x 10(-6) M (at a 92.1% confidence level) by normal nonaqueous capillary zone
      electrophoresis (NACZE) and this was improved to 2.6 x 10(-8) M and 5.0 x 10(-9)
      M, respectively, when the NACZE stacking and LTB-NACZE stacking techniques were
      applied. The content of 3,4-MDMA in an illicit drug and a suspect urine sample
      was readily detected. Upon application of the LTB to the separation of isomers
      the resolution (R) for the separation of 2,3-/3,4-MDMA was improved from 0.6
      (LTB, 22 degrees C) to 1.6 (LTB, -55 degrees C) and for (+)3,4-MDMA/(-)3,4-MDMA,
      from 0.4 (LTB, 25 degrees C) to 1.0 (LTB, -10 degrees C).

PMID- 15188250
TI  - Monitoring of drugs and metabolites in body fluids by capillary electrophoresis
      with XeHg lamp-based and laser-induced fluorescence detection.
AB  - Commercial capillary electrophoresis instrumentation with XeHg lamp-based and
      laser induced fluorescence (LIF) detection is employed for analysis of urinary
      3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its major metabolites,
      urinary metabolites of acetylsalicylic acid, urinary benzoylecgonine in an
      immunoassay format, and albendazole sulfoxide and albendazole sulfone in plasma.
      For the examples studied, the data suggest that the lamp-based detector can be
      employed for the monitoring of pharmacological and toxicological relevant solute
      concentrations, and thus represents an attractive alternative to LIF detection.

PMID- 15188249
TI  - Determination of ribavirin in human serum and plasma by capillary
      electrophoresis.
AB  - The electrophoretic separation of ribavirin and 5-methylcytidine (internal
      standard) by capillary electrophoresis was examined. Separation was achieved
      using reverse polarity in a 100 mM borate electrolyte, pH 9.1, with 5 mM spermine
      added to reduce the electroosmotic flow. Sample preparation based on acetonitrile
      protein precipitation was found to be unsuitable for ribavirin analysis in
      patient samples due to insufficient sensitivity and interferences. Solid-phase
      extraction employing phenyl boronic acid cartridges provided cleaner separations.
      Using this approach with 500 microL sample and reconstitution of the dried
      extract into 100 microL of 33% v/v 100 mM phosphate buffer, pH 6.4 / 67% v/v
      acetonitrile, the detection and quantitation limits were determined to be 0.05
      and 0.10 microg/mL, respectively, a sensitivity that is suitable for therapeutic
      drug monitoring of ribavirin in human plasma and serum samples. The method was
      validated and compared to a high-performance liquid chromatography (HPLC) method,
      showing excellent agreement between the two for a set of samples that stemmed
      from patients being treated with ribavirin and interferon-alpha-2b for a
      hepatitis C virus infection.

PMID- 15188251
TI  - Determination of salbutamol enantiomers in human urine using heptakis(2,3-di-O
      acetyl-6-O-sulfo)-beta-cyclodextrin in nonaqueous capillary electrophoresis.
AB  - Nonaqueous capillary electrophoresis (NACE) was successfully applied to the
      resolution and the determination of salbutamol enantiomers in urine samples using
      heptakis(2,3-di-O-acetyl-6-O-sulfo)-beta-cyclodextrin (HDAS-beta-CD). After
      optimization of the electrophoretic parameters, namely the background electrolyte
      (BGE) composition and the HDAS-beta-CD concentration, salbutamol enantiomers were
      completely resolved using a BGE made up of 10 mM ammonium formate and 15 mM HDAS
      beta-CD in methanol acidified with 0.75 M formic acid. Isoprenaline was selected
      as internal standard. Solid-phase extraction (SPE) was used for sample cleanup
      prior to the CE separation. Different sorbents involving polar, nonpolar
      interactions or dual retention mechanisms were evaluated and extraction
      cartridges containing both nonpolar and strong cation-exchange functionalities
      were finally selected. Salbutamol enantiomers recoveries from urine samples were
      determined. The method was then successfully validated using a new approach based
      on accuracy profiles over a concentration range from 375 to 7500 ng/mL for each
      enantiomer.

PMID- 15188252
TI  - Determination of cefepime in plasma and cerebrospinal fluid by micellar
      electrokinetic chromatography with direct sample injection.
AB  - A simple micellar capillary electrokinetic chromatography (MEKC) with UV
      detection is described for analysis of cefepime in plasma and cerebrospinal fluid
      by direct injection without any sample pretreatment. The separation of cefepime
      from biological matrix was performed at 25 degrees C using a background
      electrolyte consisting of tris(hydroxymethyl)aminomethane (Tris) buffer with
      sodium dodecyl sulfate (SDS) as the electrolyte solution. Under optimal MEKC
      condition, good separation with high efficiency and short analyses time is
      achieved. Several parameters affecting the separation of the drug were studied,
      including the pH and concentrations of the Tris buffer and SDS. Using cefazolin
      as an internal standard, the linear ranges of the method for the determination of
      cefepime in plasma and cerebrospinal fluid were 1-50 and 1-20 microg/mL,
      respectively; the detection limits of plasma (signal-to-noise ratio = 3;
      injection, 5 kV, 5 s) and cerebrospinal fluid (signal-to-noise ratio = 3;
      injection, 0.5 psi, 3 s) were 0.2 microg/mL and 0.3 microg/mL, respectively.
      Application of the proposed method for determination of cefepime in plasma and
      cerebrospinal fluid collected after intravenous administration of 2 g cefepime in
      patients with meningitis was demonstrated.

PMID- 15188253
TI  - Fenofibrate and fenofibric acid analysis by capillary electrophoresis.
AB  - A capillary electrophoresis method has been developed to measure fenofibrate in
      capsules based on micellar electrokinetic capillary chromatography with detection
      at 280 nm using a borate buffer containing sodium dodecyl sulfate (SDS). However,
      the metabolite of this drug (fenofibric acid) in serum and whole blood was
      analyzed by capillary zone electrophoresis (CZE) in a borate-carbonate buffer
      using acetonitrile stacking. The analysis is rapid, < 7 min with no
      interferences. Incubation of fenofibrate in whole blood caused hydrolysis of the
      ester bond with the release of fenofibric acid.

PMID- 15188254
TI  - Rapid analysis of inflammatory cytokines in cerebrospinal fluid using chip-based
      immunoaffinity electrophoresis.
AB  - A chip-based capillary electrophoresis system has been designed for rapidly
      measuring the concentrations of inflammatory cytokines in the cerebrospinal fluid
      of patients with head trauma. Isolation of the reactive cytokines was achieved by
      immunoaffinity capture using a panel of six immobilized antibodies, directly
      attached to the injection port of the chip. The captured cytokines were labeled
      in situ with a red light-emitting laser dye and electroeluted into the separation
      channel. Separation of the isolated cytokines was achieved by electrophoresis in
      under 2 min with quantification of the resolved peaks being achieved by on-line
      laser-induced fluorescence and integration of each peak area. Comparison of the
      results to commercially available high-sensitivity immunoassays demonstrates that
      the chip-based assay provides a fast, accurate procedure for studying the
      concentrations of these analytes in complex biological materials. The degree of
      accuracy and precision achieved by the chip-based CE is comparable to
      conventional immunoassays, the system being able to analyze between 10-12 samples
      per hour. With the ever-expanding array of antibodies that are commercially
      available, this chip-based system can be applied to a wide variety of different
      analyses.

PMID- 15188255
TI  - Direct measurement of lithium in whole blood using microchip capillary
      electrophoresis with integrated conductivity detection.
AB  - The direct measurement of lithium in whole blood is described. Using microchip
      capillary electrophoresis (CE) with defined sample loading and applying the
      principles of column coupling, alkali metals were determined in a drop of whole
      blood. Blood collected from a finger stick was mixed with anticoagulant and
      transferred onto the chip without extraction or removal of components. The
      electrokinetic transport of red blood cells inside the channels was studied to
      find sample loading conditions suitable for the analysis of lithium without
      injecting cells into the separation channel. Both bare glass chips and chips
      coated with polyacrylamide were used showing the behavior of the cells under
      different electroosmotic flow conditions. In serum a detection limit for lithium
      of 0.4 mmol/L was reached. Proteins quickly contaminated untreated chip surfaces
      but devices with coating gave reproducible electropherograms. In addition,
      potassium and sodium were also detected in the same separation run. To our
      knowledge, this is the first device to directly measure ions in whole blood with
      the use of capillary zone electrophoresis on a microchip.

PMID- 15188256
TI  - Capillary and microelectrophoretic separations of ligase detection reaction
      products produced from low-abundant point mutations in genomic DNA.
AB  - Capillary gel electrophoresis (CGE) and polymer-based microelectrophoretic
      platforms were investigated to analyze low-abundant point mutations in certain
      gene fragments with high diagnostic value for colorectal cancers. The
      electrophoretic separations were carried out on single-stranded DNA (ssDNA)
      products generated from an allele-specific ligation assay (ligase detection
      reaction, LDR), which was used to screen for a single base mutation at codon 12
      in the K-ras oncogene. The presence of the mutation generated a ssDNA fragment
      that was >40 base pairs (bp) in length, while the primers used for the ligation
      assay were <30 bp in length. Various separation matrices were investigated, with
      the success of the matrix assessed by its ability to resolve the ligation product
      from the large molar excess of unligated primers when the mutant allele was lower
      in copy number compared to the wild-type allele. Using CGE, LDR product models
      (44 and 51 bp) could be analyzed in a cross-linked polyacrylamide gel with a 1000
      fold molar excess of LDR primers (25 bp) in approximately 45 min. However, when
      using linear polyacrylamide gels, these same fragments could not be detected due
      to significant electrokinetic biasing during injection. A
      poly(methylmethacrylate) (PMMA) microchip of 3.5 cm effective column length was
      used with a 4% linear polyacrylamide gel to analyze the products generated from
      an LDR. When the reaction contained a 100-fold molar excess of wild-type DNA
      compared to a G12.2D mutant allele, the 44 bp ligation product could be
      effectively resolved from unligated primers in under 120 s, nearly 17 times
      faster than the CGE format. In addition, sample cleanup was simplified using the
      microchip format by not requiring desalting of the LDR prior to loading.

PMID- 15188257
TI  - A high-performance multilane microdevice system designed for the DNA forensics
      laboratory.
AB  - We report preliminary testing of "GeneTrack", an instrument designed for the
      specific application of multiplexed short tandem repeat (STR) DNA analysis. The
      system supports a glass microdevice with 16 lanes of 20 cm effective length and
      double-T cross injectors. A high-speed galvanometer-scanned four-color detector
      was specially designed to accommodate the high elution rates on the microdevice.
      All aspects of the system were carefully matched to practical crime lab
      requirements for rapid reproducible analysis of crime-scene DNA evidence in
      conjunction with the United States DNA database (CODIS). Statistically
      significant studies demonstrate that an absolute, three-sigma, peak accuracy of
      0.4-0.9 base pair (bp) can be achieved for the CODIS 13-locus multiplex,
      utilizing a single channel per sample. Only 0.5 microL of PCR product is needed
      per lane, a significant reduction in the consumption of costly chemicals in
      comparison to commercial capillary machines. The instrument is also designed to
      address problems in temperature-dependent decalibration and environmental
      sensitivity, which are weaknesses of the commercial capillary machines for the
      forensics application.

PMID- 15188258
TI  - Isotachophoresis of beta-blockers in a capillary and on a poly(methyl
      methacrylate) chip.
AB  - Analysis of the beta-blockers oxprenolol, atenolol, timolol, propranolol,
      metoprolol, and acebutolol in human urine by a combination of isotachophoresis
      (ITP) and zone electrophoresis (ZE) was investigated. Methods were developed with
      a conventional capillary electrophoresis (CE) apparatus and a poly(methyl
      methacrylate) (PMMA) microchip system. With CE the separation of oxprenolol,
      atenolol, timolol, and acebutolol from a standard solution containing 5 microg/mL
      of each compound was accomplished by performing ZE with transient ITP. The
      electrolyte system consisted of 10 mM sodium morpholinoethane sulfonate (pH 5.5)
      and 0.1% methylhydroxyethylcellulose as the leading electrolyte and 30 mM ortho
      phosphoric acid (pH 2.0) as both the terminating and the ZE background
      electrolyte. With the microchip system the separation of oxprenolol and
      acebutolol from a standard solution containing 10 microg/mL of each compound was
      accomplished by a coupled-channel ITP-ZE device using the same leading
      electrolyte solution as the CE system but 5 mM glutamic acid (pH 3.4) as
      terminating and background electrolytes. The systems were used for analyses of
      patient urine samples. Water-soluble hydrophilic matrix compounds were removed
      from the urine samples by solid-phase extraction (SPE). Limits of quantification
      below 5 microg/mL could be achieved. The PMMA ITP-ZE chip has not earlier been
      used for analyses of any drugs from urine samples.

PMID- 15188259
TI  - Insulator-based dielectrophoresis for the selective concentration and separation
      of live bacteria in water.
AB  - Insulator-based dielectrophoresis (iDEP) was utilized to separate and concentrate
      selectively mixtures of two species of live bacteria simultaneously. Four species
      of bacteria were studied: the Gram-negative Escherichia coli and the Gram
      positive Bacillus subtilis, B. cereus, and B. megaterium. Under an applied direct
      current (DC) electric field all the bacterial species exhibited negative
      dielectrophoretic behavior. The dielectrophoretic separations were carried out in
      a glass microchannel containing an array of insulating posts. The insulating
      posts in the microchannel produced nonuniformities in the electric field applied
      along the channel. Mixtures of two species of bacteria were introduced into the
      microchannel and the electric field was applied. The bacterial species exhibited
      different dielectrophoretic mobilities under the influence of the nonuniform
      field. From these experiments a trapping order was established with E. coli
      trapping at the weakest applied electric field, while the Bacillus species were
      trapped at different characteristic threshold fields. At stronger applied
      electric fields, the two different species of bacteria in the microchannel were
      dielectrophoretically trapped into two spatially distinct bands. The results
      showed that iDEP has the potential to selectively concentrate and separate
      different species of bacteria.

PMID- 15188260
TI  - Microfluidic tectonics platform: A colorimetric, disposable botulinum toxin
      enzyme-linked immunosorbent assay system.
AB  - A fabrication platform for realizing integrated microfluidic devices is
      discussed. The platform allows for creating specific microsystems for multistep
      assays in an ad hoc manner as the components that perform the assay steps can be
      created at any location inside the device via in situ fabrication. The platform
      was utilized to create a prototype microsystem for detecting botulinum neurotoxin
      directly from whole blood. Process steps such as sample preparation by
      filtration, mixing and incubation with reagents was carried out on the device.
      Various microfluidic components such as channel network, valves and porous filter
      were fabricated from prepolymer mixture consisting of monomer, cross-linker and a
      photoinitiator. For detection of the toxoid, biotinylated antibodies were
      immobilized on streptavidin-functionalized agarose gel beads. The gel beads were
      introduced into the device and were used as readouts. Enzymatic reaction between
      alkaline phosphatase (on secondary antibody) and substrate produced an insoluble,
      colored precipitate that coated the beads thus making the readout visible to the
      naked eye. Clinically relevant amounts of the toxin can be detected from whole
      blood using the portable enzyme-linked immunosorbent assay (ELISA) system.
      Multiple layers can be realized for effective space utilization and creating a
      three-dimensional (3-D) chaotic mixer. In addition, external materials such as
      membranes can be incorporated into the device as components. Individual
      components that were necessary to perform these steps were characterized, and
      their mutual compatibility is also discussed.

PMID- 15188261
TI  - A novel microstep device for the size separation of cells.
AB  - We report on a series of preliminary experiments investigating the applicability
      of a novel method for the size separation of nano- and microsized particles and
      cells. The working principle is based on the application of a shear-driven flow
      through stepwise tapered micro- or nanochannels. Size separations of mixtures of
      0.5 and 1.0 microm carboxylated polystyrene beads as well as of binary mixtures
      of Staphylococcus aureus and Saccharomyces cerevisiae cells and of S. cerevisiae
      and Escherichia coli cells are demonstrated.

PMID- 15188262
TI  - Comments on "Capillary zone electrophoresis for determination of carbohydrate
      deficient transferrin in human serum".

PMID- 15188267
TI  - Seasonal plasticity in the copulatory neuromuscular system of green anole
      lizards: a role for testosterone in muscle but not motoneuron morphology.
AB  - The copulatory system of green anoles is highly sexually dimorphic. Males possess
      bilateral copulatory organs called hemipenes, each independently controlled by
      two muscles: the transversus penis (TPN) and retractor penis magnus (RPM). The
      TPN everts the hemipene through the cloaca and the RPM retracts it. Adult females
      do not possess hemipenes or either of these two muscles. The spinal nucleus
      projecting to the TPN and RPM contains more and larger motoneurons in males than
      females. Because anoles breed seasonally, two experiments were designed to test
      whether adult copulatory morphology varies with environmental condition, and if
      so, whether the effect is mediated by testicular androgens. Three groups of adult
      males were used in each experiment: males from breeding environmental conditions
      with reproductive testes (BS); males in breeding conditions with regressed testes
      (BS-X); and males in nonbreeding conditions with regressed testes (NBS).
      Experiment 1 compared gonadally intact males and Experiment 2 compared castrated
      males treated with either testosterone (T) or an empty implant. In both
      experiments, copulatory and control motoneurons appeared smaller in NBS males,
      but T did not affect their size. In contrast, while hemipene and RPM muscle fiber
      size were not plastic across season in gonadally intact males, T in castrated
      males significantly increased both measures under BS and BS-X, but not NBS,
      conditions. These results demonstrate that neuron soma size might change on a
      general level and environmental cues can mediate T-induced changes in peripheral
      structures, suggesting that plasticity across copulatory system components is
      regulated by different mechanisms.

PMID- 15188268
TI  - Neurotrophic activities of trk receptors conserved over 600 million years of
      evolution.
AB  - The trk family of receptor tyrosine kinases is crucial for neuronal survival in
      the vertebrate nervous system, however both C. elegans and Drosophila lack genes
      encoding trks or their ligands. The only invertebrate representative of this gene
      family identified to date is Ltrk from the mollusk Lymnaea. Did trophic functions
      of trk receptors originate early in evolution, or were they an innovation of the
      vertebrates? Here we show that the Ltrk gene conserves a similar exon/intron
      order as mammalian trk genes in the region encoding defined extracellular motifs,
      including one exon encoding a putative variant immunoglobulin-like domain.
      Chimeric receptors containing the intracellular and transmembrane domains of Ltrk
      undergo ligand-induced autophosphorylation followed by MAP kinase activation in
      transfected cells. The chimeras are internalized similarly to TrkA in PC12 cells,
      and their stimulation leads to differentiation and neurite extension. Knock-down
      of endogenous Ltrk expression compromises outgrowth and survival of Lymnaea
      neurons cultured in CNS-conditioned medium. Thus, Ltrk is required for neuronal
      survival, suggesting that trophic activities of the trk receptor family
      originated before the divergence of molluscan and vertebrate lineages
      approximately 600 million years ago.

PMID- 15188269
TI  - Syllable repertoire and the size of the song control system in captive canaries
      (Serinus canaria).
AB  - In songbirds, there is considerable interest in relationships between song
      structure and the size of the song control system in the forebrain. In male
      canaries, earlier studies have reported that repertoire size increased with age,
      and positive correlations were obtained between repertoire size and the volume of
      song control nuclei such as high vocal center (HVC). Here we investigate whether
      age has an effect upon both the song structure and the morphology of two song
      control nuclei [HVC and robustus archistriatalis (RA)] that are important in song
      production. We recorded songs from an aviary population of 1- and 2-year-old male
      domesticated canaries. We found that repertoire size, number of sexually
      attractive (sexy) syllables, and size of song nuclei did not differ between 1-
      and 2-year-old males. Neither did we find significant correlations between
      syllable repertoire size and the size of the song control nuclei. However, HVC
      size was positively correlated with the proportion of sexy syllables in the
      repertoires of 2-year-old males. Some older males may enhance vocal performance
      by modifying the control of syllables rather than by increasing repertoire size
      or neural space.

PMID- 15188270
TI  - Tonotopic gradients of Eph family proteins in the chick nucleus laminaris during
      synaptogenesis.
AB  - Topographically precise projections are established early in neural development.
      One such topographically organized network is the auditory brainstem. In the
      chick, the auditory nerve transmits auditory information from the cochlea to
      nucleus magnocellularis (NM). NM in turn innervates nucleus laminaris (NL)
      bilaterally. These projections preserve the tonotopy established at the level of
      the cochlea. We have begun to examine the expression of Eph family proteins
      during the formation of these connections. Optical density measurements were used
      to describe gradients of Eph proteins along the tonotopic axis of NL in the
      neuropil, the somata, and the NM axons innervating NL at embryonic day 10, when
      synaptic connections from NM to NL are established. At E10-11, NL dorsal neuropil
      expresses EphA4 at a higher concentration in regions encoding high frequency
      sounds, decreasing in concentration monotonically toward the low frequency
      (caudolateral) end. In the somata, both EphA4 and ephrin-B2 are concentrated at
      the high frequency end of the nucleus. These tonotopic gradients disappear
      between E13 and E15, and expression of these molecules is completely
      downregulated by hatching. The E10-11 patterns run counter to an apparent
      gradient in dendrite density, as indicated by microtubule associated protein 2
      (MAP2) immunolabeling. Finally, ephrin-B2 is also expressed in a gradient in
      tissue ventral to the NL neuropil. Our findings thus suggest a possible conserved
      mechanism for establishing topographic projections in diverse sensory systems.
      These results of this study provide a basis for the functional examination of the
      role of Eph proteins in the formation of tonotopic maps in the brainstem.

PMID- 15188271
TI  - Foraging experience, glomerulus volume, and synapse number: A stereological study
      of the honey bee antennal lobe.
AB  - The primary antennal sensory centers (antennal lobes) in the brain of the
      honeybee are highly compartmentalized into discrete spheres of synaptic neuropil
      called glomeruli. Many of the glomeruli can be identified according to their
      predictable size and location. This study examines T1-44, a prominent glomerulus
      on the dorsal surface of the antennal lobe. Previously, we have shown that the
      volume of T1-44 in 4-day-old workers performing tasks within the hive is
      significantly smaller than in foragers and that increases in volume are
      accompanied by an increase in total synapse number in this glomerulus. Here we
      examine whether foraging experience is essential for either changes in volume or
      for changes in synapse numbers in glomerulus T1-44. Five-day-old bees reared
      under normal colony conditions were compared with 5-day-old bees reared under
      isolated conditions, and also to 5-day-old bees that had been induced to forage
      precociously. A combination of light and electron microscopy was used to compare
      T1-44 volumes and synapse numbers in these three groups. Two groups of 11-day-old
      bees, precocious foragers and nonforagers, were also examined. The Cavalieri
      direct estimator of volume was applied to 1.5 microm sections of resin embedded
      brains. Selected sections were then re-embedded and prepared for transmission
      electron microscopy. Synapse densities were determined using the physical
      disector method on electron micrographs. Synapse density and glomerulus volume
      were combined to give an unbiased estimate of the total number of synapses. This
      study shows that while both volume and synapse numbers can be induced to increase
      prematurely in young (5-day-old) precocious foragers, foraging experience is not
      essential for these structural changes to occur in glomerulus T1-44.

PMID- 15188272
TI  - Nicotine decreases agrin signaling and acetylcholine receptor clustering in C2C12
      myotube culture.
AB  - The clustering of acetylcholine receptors (AChRs) in skeletal muscle fibers is a
      critical event in neuromuscular synaptogenesis. AChRs in concert with other
      molecules form postsynaptic scaffolds in response to agrin released from motor
      neurons as motor neurons near skeletal muscle fibers in development. Agrin drives
      an intracellular signaling pathway that precedes AChR clustering and includes the
      tyrosine phosphorylation of AChRs. In C2C12 myotube culture, agrin application
      stimulates the agrin signaling pathway and AChR clustering. Previous studies have
      determined that the frequency of spontaneous AChR clustering is decreased and
      AChRs are partially inactivated when bound by the acetylcholine agonist nicotine.
      We hypothesized that nicotine interferes with AChR clustering and consequent
      postsynaptic scaffold formation. In the present study, C2C12 myoblasts were
      cultured with growth medium to stimulate proliferation and then differentiation
      medium to stimulate fusion into myotubes. They were bathed in a physiologically
      relevant concentration of nicotine and then subject to agrin treatment after
      myotube formation. Our results demonstrate that nicotine decreases agrin-induced
      tyrosine phosphorylation of AChRs and decreases the frequency of spontaneous as
      well as agrin-induced AChR clustering. We conclude that nicotine interferes with
      postsynaptic scaffold formation by preventing the tyrosine phosphorylation of
      AChRs, an agrin signaling event that precedes AChR clustering.

PMID- 15188273
TI  - Correlation of Pax-2 expression with cell proliferation in the developing chicken
      inner ear.
AB  - In vertebrates, the paired-box transcription factor Pax-2 is one of the earliest
      markers of the developing inner ear and is robustly expressed in the otic placode
      and the otic vesicle. Mutations in the Pax-2 gene result in developmental defects
      of the vestibular and auditory apparatus. We set out to investigate whether
      regions of Pax-2 expression in the developing otic vesicle correlate with areas
      of cell proliferation or cell death, which would indicate a possible role of Pax
      2 in these processes. Regionalized proliferation and local apoptosis are the
      principal mechanisms that lead to the complex morphogenesis of the highly
      compartmentalized inner ear starting from a simple vesicle. We found a high
      correlation of Pax-2 expression with proliferating cells in the walls of the
      early otic vesicle. Apoptotic cells were mostly localized outside of the Pax-2
      expressing regions. At later stages, we found the highest intensity of
      proliferating and Pax-2-positive cells in areas of the developing sensory
      epithelia. When hair cells begin to differentiate, they maintain a lower level of
      Pax-2 expression than neighboring cells for a brief period, before they
      completely down-regulate expression of this transcription factor. We conclude
      that a significant proportion of proliferating cells in the developing otocyst
      express Pax-2, in particular in regions that include developing sensory patches.
      This implicates Pax-2 as a marker for proliferating hair and supporting cell
      progenitors. Furthermore, the likelihood that Pax-2-expressing cells in the
      otocyst die by apoptosis is much lower when compared with cells residing in Pax-2
      negative regions.

PMID- 15188274
TI  - Evidence for a secreted chemorepellent that directs glioma cell invasion.
AB  - Secreted chemotropic cues guide the migration of neuronal and glial cell
      precursors during neural development. It is not known if chemotropism contributes
      to directing the invasion of brain tissue by glioma cells. A model system has
      been developed that allows quantification of invasive behavior using gliomas
      spheroids embedded in collagen gels. Here we provide evidence that glioma
      spheroids secrete a chemorepellent factor(s) that directs cells away from the
      spheroid and into the collagen matrix. The relationship between total invasion,
      cell number, and implantation distance suggests that glioma cells respond to a
      gradient of the chemorepellent cue(s) that is well established at 48 h. C6
      astrocytoma cells normally invade the collagen at an angle perpendicular to the
      spheroid edge. In contrast, an adjacent spheroid causes cells to turn away from
      their normal trajectory and slow their rate of invasion. Astrocytoma cells are
      repelled by an adjacent glioma spheroid but rapidly infiltrate astrocyte
      aggregates, indicating that astrocytes do not express the repellent cue. Uniform
      concentrations of repellent factor(s) in spheroid conditioned medium overwhelm
      endogenous gradients and render glioma cells less able to exhibit this
      chemotropic response. Concentration gradients of spheroid conditioned medium in
      cell migration assays also demonstrate the chemorepellent cue(s)'s tropic effect.
      Our findings indicate that glioma spheroids produce a secreted diffusible cue(s)
      that promotes glioma cell invasion. Identification of this factor(s) may advance
      current therapies that aim to limit tumor cell invasion.

PMID- 15188276
TI  - Ethanol exposure alters neurotrophin receptor expression in the rat central
      nervous system: Effects of prenatal exposure.
AB  - Developmental ethanol exposure produces significant central nervous system (CNS)
      abnormalities. The cellular mechanisms of ethanol neurotoxicity, however, remain
      elusive. Recent data implicate altered neurotrophin signaling pathways in ethanol
      mediated neuronal death. The present study investigated ethanol-induced
      alterations in neurotrophin receptor proteins in the rat CNS following chronic
      ethanol treatment during gestation, via liquid diet to pregnant dams. Brains were
      dissected on P1 and P10, and Western blots for the neurotrophin receptors TrkA,
      TrkB, TrkC, and p75 were quantified. Such ethanol treatment produced significant
      changes in neurotrophin receptor levels in the hippocampus, septum, cerebral
      cortex, and cerebellum. Receptor levels in hippocampus, septum, and cerebellum,
      tended to be decreased, while levels in cortex were consistently increased. Males
      were generally more affected than females. While most of these alterations were
      transient, sustained or delayed changes were present in P10 septum, cortex, and
      cerebellum. These results indicate that developmental ethanol exposure produces
      major changes in the normal physiological levels of the neurotrophin receptors
      throughout the CNS. These changes in the receptor complement during critical
      prenatal stages could relate to the anomalous development of the CNS seen in the
      fetal alcohol syndrome. This relationship is discussed, together with the
      potential biological effects of such dramatic changes in neurotrophin receptor
      expression.

PMID- 15188275
TI  - Overexpression of Bcl-2 prevents neomycin-induced hair cell death and caspase-9
      activation in the adult mouse utricle in vitro.
AB  - Mechanosensory hair cells of the inner ear are especially sensitive to death
      induced by exposure to aminoglycoside antibiotics. This aminoglycoside-induced
      hair cell death involves activation of an intrinsic program of cellular suicide.
      Aminoglycoside-induced hair cell death can be prevented by broad-spectrum
      inhibition of caspases, a family of proteases that mediate apoptotic and
      programmed cell death in a wide variety of systems. More specifically,
      aminoglycoside-induced hair cell death requires activation of caspase-9. Caspase
      9 activation requires release of mitochondrial cytochrome c into the cytoplasm,
      indicating that aminoglycoside-induced hair cell death is mediated by the
      mitochondrial (or "intrinsic") cell death pathway. The Bcl-2 family of pro
      apoptotic and anti-apoptotic proteins are important upstream regulators of the
      mitochondrial apoptotic pathway. Bcl-2 is an anti-apoptotic protein that
      localizes to the mitochondria and promotes cell survival by preventing cytochrome
      c release. Here we have utilized transgenic mice that overexpress Bcl-2 to
      examine the role of Bcl-2 in neomycin-induced hair cell death. Overexpression of
      Bcl-2 significantly increased hair cell survival following neomycin exposure in
      organotypic cultures of the adult mouse utricle. Furthermore, Bcl-2
      overexpression prevented neomycin-induced activation of caspase-9 in hair cells.
      These results suggest that the expression level of Bcl-2 has important effects on
      the pathway(s) important for the regulation of aminoglycoside-induced hair cell
      death.

PMID- 15188278
TI  - Association of Surgeons of Great Britain and Ireland, Annual Meeting, Harrogate,
      28-30 April 2004. Abstracts.

PMID- 15188277
TI  - Ethanol exposure alters neurotrophin receptor expression in the rat central
      nervous system: Effects of neonatal exposure.
AB  - The detrimental effects of ethanol exposure during nervous system development
      have been well established. The cellular mechanisms of ethanol neurotoxicity,
      however, have not been clearly defined. Recent studies suggest that neurotrophin
      signaling pathways may be involved in ethanol-mediated neuronal death. The
      present investigation, therefore, was designed to examine ethanol-induced
      alterations in neurotrophin receptor protein levels in the developing central
      nervous system (CNS) following chronic ethanol treatment administered during the
      early neonatal period. For this study, rats were exposed to ethanol via vapor
      inhalation from postnatal day 4 (P4) to P10. Brains were then dissected on P10 or
      P21, and Western blots used to quantify expression of neurotrophin receptors
      TrkA, TrkB, TrkC, and p75. This early postnatal ethanol treatment produced
      significant alterations in receptor levels in hippocampus, septum, cerebral
      cortex, and cerebellum. The alterations seen were variable, with decreases
      generally found in hippocampus and cerebellum, increases noted in septum, and
      changes in both directions occurring in cortex. These alterations were generally
      more prevalent in males than in females. While most of the receptor changes
      observed were transient, sustained or delayed alterations were occasionally seen
      in hippocampus, cortex, and cerebellum. These results suggest that developmental
      ethanol exposure modulates expression of these neurotrophin receptors throughout
      the CNS, alterations which could have wide-ranging effects on functional CNS
      development. The possible linkage between such changes and abnormalities
      encountered in the fetal alcohol syndrome are considered.

PMID- 15188309
TI  - Organization mentorship for the 21st century: a vision for ARHP.

PMID- 15188310
TI  - Rheumatology care, patient expectations, and the limits of time.

PMID- 15188311
TI  - Anti-tumor necrosis factor alpha therapy in rheumatoid arthritis: hitting two
      birds with one stone?

PMID- 15188312
TI  - Could the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) be a valid
      measure of disease activity in patients with psoriatic arthritis?
AB  - OBJECTIVE: To determine whether the Bath Ankylosing Spondylitis Disease Activity
      Index (BASDAI) could be a valid indicator of disease activity in psoriatic
      arthritis (PsA). METHODS: Patients with PsA identified from a disease-register
      and case-note review answered a questionnaire by mail (n = 133); some patients (n
      = 86) consented to examination. In a second sample of 47 consecutive clinic
      attendees with PsA, logistic regression examined the independent contribution of
      BASDAI to disease activity, as judged by treatment decisions at that time.
      RESULTS: BASDAI correlated highly with patient perception of disease activity (r
      = 0.739) and there was no significant effect of the pattern of disease (axial or
      peripheral) on this relationship. However, only physician perception of disease
      activity was significantly associated with high or low disease activity (odds
      ratio 18.4, 95% confidence interval 2.9-118.3). BASDAI, patient perception, and
      erythrocyte sedimentation rate failed to contribute significantly to the model.
      CONCLUSION: BASDAI performs similarly for axial and peripheral PsA but does not
      correlate well with external indicators of disease activity, such as treatment
      decisions.

PMID- 15188313
TI  - Validation exercise of the Ankylosing Spondylitis Assessment Study (ASAS) group
      response criteria in ankylosing spondylitis patients treated with biologics.
AB  - OBJECTIVES: To define what expert clinicians consider a dramatic response in
      ankylosing spondylitis (AS) patients treated with biologic therapies based on
      patient and physician assessments of global disease activity. To compare this
      expert clinician-derived criteria to the Ankylosing Spondylitis Assessment Study
      (ASAS) Group criteria for improvement. METHODS: Forty consecutive AS patients
      were treated in a 1-year open-label protocol with infliximab. Response to
      treatment at week 52 was defined using ASAS response criteria. For the purpose of
      this exercise, improvement using ASAS criteria was defined by consensus among
      experts as good with 50% improvement from baseline (ASAS(50)) and dramatic with
      70% improvement from baseline (ASAS(70)). Experts established separate criteria
      for improvement in disease activity as good or dramatic based on patient and
      physician global assessment of disease activity. RESULTS: Twelve of 40 patients
      met the ASAS(70) criteria, however, only 8 met the expert definition of a
      dramatic improvement based on physician global scores and 5 met the expert
      definition of a dramatic improvement based on patient global assessment of
      disease activity. Agreement was poor between ASAS(50) or ASAS(70) and expert
      definition of improvement based on physician global scores (kappa < 0.3), but
      agreement was moderate to good between ASAS(50) or ASAS(70) and expert definition
      of improvement based on patient global scores, (kappa = 0.6-0.7). CONCLUSIONS:
      Differential response experienced by AS patients treated with infliximab was
      adequately captured by the ASAS composite improvement criteria. Overall, this
      study demonstrates the validity of the ASAS criteria for the detection of
      improvement in AS patients treated with biologics. However, the patient global
      assessment of disease activity may be sufficient to monitor changes in disease
      activity in these patients.

PMID- 15188314
TI  - A retrospective study of the relationship between serum urate level and recurrent
      attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis
      with antihyperuricemic therapy.
AB  - OBJECTIVE: To evaluate the proposed relationship between persistent reduction of
      serum urate into the subsaturating range and reduction in the frequency of acute
      gouty attacks. METHODS: We retrospectively examined data derived from 267
      patients who had experienced at least 1 gouty attack before their first visit to
      our clinic. Serum urate concentration, history of recurrent gouty attacks, and
      information about antihyperuricemic drug use were collected on each visit for up
      to 3 years from the first visit of each patient. Data derived from visits >1 year
      after study entry were subjected to statistical analysis. RESULTS: When adjusted
      for baseline serum urate level and the number of gouty attacks prior to study
      entry, reduction of followup serum urate concentration and antihyperuricemic drug
      use were each significantly associated with a reduced risk of gouty attacks (odds
      ratio [OR] 0.42, 95% confidence interval [95% CI] 0.31-0.57; OR 0.22, 95% CI 0.10
      0.47, respectively). CONCLUSION: The data indicate that reduction of serum urate
      concentrations to 6 mg/dl or lower will eventually result in a reduced frequency
      or prevention of future gouty attacks.

PMID- 15188315
TI  - Health-related quality of life and health service use among older adults with
      osteoarthritis.
AB  - OBJECTIVE: To examine the relationship between health-related quality of life
      (HRQOL) and health service use among older adults with osteoarthritis (OA).
      METHODS: Subjects were 9,043 Medicare-enrolled survey respondents with a prior
      International Classification of Diseases, Ninth Revision code for OA. Analyses
      examined the relationship of 5 Centers for Disease Control and Prevention HRQOL
      items (general health, mental health, pain, activity limitation, and sleep) to
      physician visits, prescription analgesic or antiinflammatory use, and
      arthroplasty during 1 year of followup. RESULTS: In analyses controlling for
      demographic and health-related variables, greater pain frequency was associated
      with increased odds of visiting a physician, using analgesic or antiinflammatory
      drugs, and having arthroplasty (P < 0.001). Poorer general health was associated
      with increased odds of analgesic or antiinflammatory use but decreased odds of
      arthroplasty (P < 0.01). More days of activity limitation and poor mental health
      were associated with decreased odds of analgesic or antiinflammatory use (P <
      0.01). CONCLUSION: These HRQOL variables, especially pain frequency, can be
      valuable tools for estimating future health care use among older adults with OA.

PMID- 15188316
TI  - Spanish Arthritis Empowerment Program: a dissemination and effectiveness study.
AB  - OBJECTIVE: To evaluate the effectiveness of the Spanish Arthritis Empowerment
      Program as presented by the Arthritis Foundation, Southern California Chapter, in
      Orange County, California. METHODS: Participants with arthritis (n = 141)
      enrolled in the program between October 1999 and May 2001. All materials were in
      Spanish. Written pretest, 6-week posttest, and 6-month followup tests measured
      pain rating, self-report joint counts, function (modified Health Assessment
      Questionnaire [mHAQ]), self efficacy, self-care behavior, and arthritis
      knowledge. RESULTS: Mean age was 51 years, 92% were female, 84% were born in
      Mexico, 55% had sixth grade education or less, and 60% had no medical insurance.
      Of the 141 participants, 118 completed 6-month followup testing. Repeated
      measures analysis of variance showed significant improvement from pretest to 6
      month followup in pain (6.0 versus 3.4); self efficacy (5.5 versus 8.4), self
      care behavior (1.7 versus 4.9), arthritis knowledge (1.6 versus 4.5), and general
      health (2.1 versus 2.5), all at P < 0.001. Small improvement was reported in mHAQ
      (0.56 versus 0.50; P = 0.024). CONCLUSION: The Spanish Arthritis Empowerment
      Program was successfully disseminated. Significant improvements in self efficacy
      and in arthritis symptoms were maintained at the 6-month followup.

PMID- 15188317
TI  - Measuring quality in arthritis care: the Arthritis Foundation's quality indicator
      set for analgesics.
AB  - OBJECTIVE: To develop systematically validated quality indicators (QIs)
      addressing analgesic safety. METHODS: A comprehensive literature review of
      existing quality measures, clinical guidelines, and evidence supporting potential
      QIs concerning nonselective (traditional) nonsteroidal anti-inflammatory drugs
      (NSAIDs) and newer cyclooxygenase 2-selective NSAIDs was undertaken. An expert
      panel then validated or refuted potential indicators utilizing a proven
      methodology. RESULTS: Eleven potential QIs were proposed. After panel review, 8
      were judged to be valid; an additional 10 were proposed by the panel, of which 7
      were rated as valid. Quality indicators focused upon informing patients about
      risk, NSAID choice and gastrointestinal prophylaxis, and side effect monitoring.
      CONCLUSION: The 15 validated indicators were combined, where appropriate, to
      yield 10 validated processes of care indicators for the safe use of NSAIDs. These
      indicators developed by literature review and finalized by our expert panel
      process can serve as a basis to compare the quality of analgesic use provided by
      health care providers and delivery systems.

PMID- 15188318
TI  - Quality of life of people with rheumatoid arthritis as measured by the World
      Health Organization Quality of Life Instrument, short form (WHOQOL-BREF): score
      distributions and psychometric properties.
AB  - OBJECTIVE: To assess the psychometric properties, including responsiveness, of
      the World Health Organization Quality of Life instrument, short form (WHOQOL
      BREF) in people with rheumatoid arthritis. METHODS: A sample of 142 persons with
      rheumatoid arthritis were randomly selected from a regional disease register and
      completed questionnaires by postal survey. An additional sample of 72 consecutive
      inpatients completed questionnaires a few days prior to admission, the day of
      admission, the day of discharge, and 2 weeks following discharge. RESULTS: Test
      retest reliability was adequate (intraclass correlation coefficient 0.71-0.91).
      Internal consistency was adequate except for the social relationships domain
      (Cronbach's alpha 0.64-0.87). Factor structure was fairly similar to that
      previously reported. Correlation with other measures of quality of life was
      supportive of concurrent validity. Indices of responsiveness were satisfactory
      except for the social relationships and environment domains, although there was
      actually no statistical difference in the area under a receiver operating
      characteristic plot between the WHOQOL-BREF domains and the Health Assessment
      Questionnaire. CONCLUSION: The WHOQOL-BREF has adequate psychometric properties
      in people with rheumatoid arthritis and should be considered a valid outcome
      measure for interventions that aim to improve quality of life for people with
      this disease.

PMID- 15188319
TI  - Development and validation of Cedars-Sinai Health-Related Quality of Life in
      Rheumatoid Arthritis (CSHQ-RA) short form instrument.
AB  - OBJECTIVE: To develop an abridged version of the 33-item Cedars-Sinai Health
      Related Quality of Life in Rheumatoid Arthritis instrument (CSHQ-RA) and test the
      validity and reliability of the abridged instrument. METHODS: Items from the
      original 33-item, 5-domain CSHQ-RA were assessed using psychometric and
      regression analyses of survey responses from 274 patients with rheumatoid
      arthritis. Items were retained in the final instrument based on statistical
      analysis and evaluation by an expert panel. Test-retest reliability, internal
      consistency, convergent and discriminant validity, and ceiling and floor effects
      were examined for the shortened CSHQ-RA. RESULTS: Statistical analysis and expert
      assessment yielded an 11-item instrument including questions in 4 domains. Test
      retest reliability and internal consistency were high and the instrument showed
      good convergent and discriminant validity. CONCLUSION: The abridged CSHQ-RA short
      form is a valid and reliable instrument that can be used to examine the impact of
      RA on patients' health-related quality of life. Prospective validation in
      clinical trial settings is warranted.

PMID- 15188320
TI  - Normal scores for nine maneuvers of the Childhood Myositis Assessment Scale.
AB  - OBJECTIVE: To document and evaluate the scores that normal, healthy children
      achieve when performing 9 maneuvers of the Childhood Myositis Assessment Scale
      (CMAS). METHODS: A total of 303 healthy children, 4-9 years of age, were scored
      as they performed 9 CMAS maneuvers. The data were then evaluated to determine
      whether normal scores for some maneuvers are age and sex dependent. RESULTS: All
      children were able to achieve maximum possible scores for the supine to prone,
      supine to sit, floor sit, floor rise, and chair rise maneuvers. All but 2 4-year
      olds achieved a maximum possible score for the arm raise/duration maneuver.
      Performance of the head lift and sit-up maneuvers varied significantly, depending
      primarily on age. Children in all age groups had less difficulty performing the
      leg lift than the head lift or sit-up. CONCLUSION: The normative data generated
      by this study are of value for interpreting the serial CMAS scores of children
      with idiopathic inflammatory myopathies.

PMID- 15188321
TI  - Knee adduction moment and development of chronic knee pain in elders.
AB  - OBJECTIVE: To determine whether the adduction moment at the knee during locomotor
      activity contributes to the development of future chronic knee pain. METHODS: We
      studied 132 community-dwelling elders who had undergone a full kinetic and
      kinematic motion analysis while performing 4 different activities: standing,
      walking, rising from a chair, and descending stairs. We contacted the
      participants 3-4 years after their baseline locomotion analysis and identified
      those who reported no knee pain at the time of motion analysis but who
      subsequently developed new chronic knee pain at followup. We examined whether the
      development of new chronic knee pain was associated with higher peak adduction
      moment at the knee during activities, measured at baseline. RESULTS: Of the 132
      elders evaluated in 1995-1996, 118 (89%) were contacted in 1999. Of the 118
      contacted, 80 (mean age 75 years; 78% women) had no lower extremity prosthetic
      joints at baseline, no known underlying inflammatory arthritis at baseline nor
      followup, and no baseline knee pain. At followup, 7 had developed new chronic
      knee pain defined as pain or stiffness on most days of the month and with walking
      2 blocks or using stairs. Compared with those who did not develop knee pain,
      those who did develop new chronic knee pain had higher baseline adduction moments
      for all activities (P = 0.01), ranging from 8% higher during chair rise to 39%
      higher during stair descent. CONCLUSION: We found that greater adduction moment
      at the knee during activities contributes to the development of future chronic
      knee pain. Our results suggest that biomechanical factors may play an important
      role in the pathogenesis of knee pain and should be studied further.

PMID- 15188322
TI  - Effect of knee osteoarthritis on the perception of quality of life in Venezuelan
      patients.
AB  - OBJECTIVE: To measure the perception of quality of life in Venezuelan patients
      with knee osteoarthritis and to identify those variables that may influence it.
      METHODS: A multicenter, cross-sectional study of 126 mestizo patients with knee
      osteoarthritis recruited from 8 rheumatology centers in Venezuela. We used a
      Spanish-translated version of the Arthritis Impact Measurement Scales (AIMS), as
      adapted in Venezuela. One-way analysis of variance was used to compare the AIMS
      mean total score among subgroups of knee pain, anatomic stage, and socioeconomic
      status (SES); a post-hoc test was performed to identify significant intragroup
      differences. Pearson's correlation coefficient was used to examine correlations
      between age, body mass index (BMI), disease duration, knee pain, and AIMS score.
      Associations between radiologic stage, SES, and AIMS scores were examined using
      Spearman's rank correlation. Multiple regression analysis was used to estimate
      predictor factors of AIMS scores. RESULTS: A significant correlation was found
      between total AIMS scores and knee pain, age, and socioeconomic status, but not
      with BMI, disease duration, or anatomic stage. Patients with severe knee pain
      differed from those with mild and moderate pain, and the highest AIMS mean total
      score was seen in patients within the severe knee pain subset. Patients in the
      highest socioeconomic levels differed from those within lowest categories.
      Patients classified as being at the levels of relative and critical poverty
      showed the highest AIMS scores. Multiple regression analysis showed that knee
      pain was the only variable that exerted an independent effect on the quality of
      life in our patients. CONCLUSION: The perception of quality of life is negatively
      affected by increasing levels of joint pain, old age, and low socioeconomic
      status in Venezuelan patients with knee osteoarthritis. Our study supports the
      need for an early and vigorous approach to treat pain in this group of patients.

PMID- 15188323
TI  - Multifaceted intervention to improve rheumatologists' management of
      glucocorticoid-induced osteoporosis: a randomized controlled trial.
AB  - OBJECTIVE: To assess the effectiveness of a multifaceted intervention to improve
      the management of glucocorticoid-induced osteoporosis (GIOP). METHODS: Of 21
      rheumatologists, 11 were randomly assigned to a 3-part intervention consisting of
      a lecture and discussion regarding optimal management of GIOP, a confidential
      doctor-specific audit regarding management of GIOP, and a reminder mailing
      including concise pharmacologic recommendations. The remaining 10 rheumatologists
      received no special education. Patients with rheumatoid arthritis (RA) taking
      oral glucocorticoids seen in the 2 months after the intervention were followed
      for 6 months. Medical records were assessed to determine the proportion
      undergoing bone mineral density testing or receiving pharmacologic interventions
      for GIOP during the 6 months before and 6 months after the intervention. RESULTS:
      There were 373 patients with RA taking oral glucocorticoids whose records were
      assessed. Patients in both arms of the trial were similar with respect to age,
      sex, menopausal status, glucocorticoid dosage and duration, duration of RA,
      disease-modifying antirheumatic drug use, and the proportion with comorbid
      conditions. At baseline, there was no significant difference between the patients
      with respect to osteoporosis medication use (intervention 32% versus control 34%)
      or bone densitometry use (intervention 9% versus control 5%). After the
      intervention and a 6-month followup period, there were no differences in
      treatment (intervention 33% versus control 38%) or bone densitometry use
      (intervention 8% versus control 8%). Adjusting for patient and physician
      characteristics did not significantly change these results. CONCLUSION: A
      multifaceted intervention for GIOP, including doctor education, practice audit,
      and treatment suggestions, had no significant benefit on testing or treatment by
      rheumatologists over a 6-month followup period. Other intervention approaches
      need to be tested.

PMID- 15188324
TI  - Gap between short- and long-term effects of patient education in rheumatoid
      arthritis patients: a systematic review.
AB  - OBJECTIVE: To systematically review educational or psychoeducational
      interventions for patients with rheumatoid arthritis focusing on long-term
      effects, especially health status. METHODS: Two independent reviewers appraised
      the methodologic quality of the included randomized controlled trials, published
      between 1980 and July 2002. RESULTS: Validity scores of studies ranged from 3 to
      9 (of 11). The 7 educational programs mainly improved knowledge and compliance in
      the short and long term, but there was no improvement in health status. All 4
      psychoeducational programs improved coping behavior in the short term, 2 of them
      showing a positive long-term effect on physical or psychological health
      variables. CONCLUSION: Methodologically better-designed studies had more
      difficulties demonstrating positive outcome results. Short-term effects in
      program targets are generally observed, whereas long-term changes in health
      status are not convincingly demonstrated. There is a need to find better
      strategies to enhance the transfer of short-term effects into gains in health
      status.

PMID- 15188325
TI  - Latent variable approach to the measurement of physical disability in rheumatoid
      arthritis.
AB  - OBJECTIVE: To measure physical disability in rheumatoid arthritis (RA) using a
      latent variable derived from a generic and a disease-specific self-reported
      disability instrument and an observer-assessed functional status scale. METHODS:
      Consecutive patients with RA completed the modified Health Assessment
      Questionnaire (M-HAQ) and the Short Form 36 (SF-36) physical function scale. An
      observer assigned a Steinbrocker functional classification. We used principal
      component factor analysis to extract a latent variable from the 3 scales. We used
      the Bayesian Information Criterion to compare how well the new latent variable
      and the 3 primary scales fit the criterion standards of current work status;
      vital status at 6 years; grip strength; walking velocity; the timed-button test;
      pain; and joint tenderness, swelling, and deformity. RESULTS: Complete data were
      available for 776 RA patients. The extracted latent variable explained 75% of the
      variance in the 3 primary scales. On a scale of 0-100, higher scores representing
      less disability, its mean +/- SD was 56.4 +/- 22.5. Correlation between the
      latent variable and the M-HAQ was -0.87; between the latent variable and SF-36
      physical function scale was 0.89, and between the latent variable and
      Steinbrocker class was -0.85. Multivariate models that included the latent
      variable had superior fit than did models containing the primary scales for the
      criteria of current working; death by 6 years; pain; joint tenderness, swelling,
      or deformity; grip strength; walking velocity; and timed button test. CONCLUSION:
      A latent variable derived from the M-HAQ, the SF-36 physical function scale, and
      the Steinbrocker functional class provides a parsimonious scale to measure
      physical disability in RA. The fit of the latent variable to comparison standards
      is equivalent or superior to that of the primary scales.

PMID- 15188326
TI  - Anxiety in rheumatoid arthritis.
AB  - OBJECTIVE: To examine the level of anxiety experienced by individuals with
      rheumatoid arthritis (RA). METHODS: Data from 2 previous studies were used to
      compare the level of anxiety (measured by the State-Trait Anxiety Inventory) in
      the following 4 subgroups: a general RA sample, a general osteoarthritis sample,
      a sample with both RA and major depression, and a normative sample of age
      equivalent, working adults. Canonical correlations were used to examine
      associations between measures of anxiety and measures of both stress and
      depression. The relationship between anxiety and duration of RA was also
      explored. RESULTS: The general RA sample had state anxiety levels that were
      comparable to the normative sample, although trait anxiety levels were
      significantly higher (P < 0.001). In addition, individuals with RA who also met
      criteria for depression exhibited significantly higher levels of both state
      anxiety (P < 0.0001) and trait anxiety (P < 0.0001) than was observed in the
      normative sample. Canonical correlations revealed that measures of anxiety were
      correlated with both measures of depression (r = 0.83) and measures of stress (r
      = 0.50). Anxiety was not found to be significantly related to RA disease
      duration. CONCLUSION: These findings demonstrated that individuals with RA,
      especially if concomitantly depressed, tend to exhibit levels of anxiety that are
      generally higher than a normative group of age-equivalent, working adults. The
      substantial canonical correlations between anxiety and both depression and stress
      revealed that anxiety shares variance with these more frequently studied
      variables in RA. However, anxiety was not found to be related to RA disease
      duration.

PMID- 15188327
TI  - Survey of the use and effect of assistive devices in patients with early
      rheumatoid arthritis: a two-year followup of women and men.
AB  - OBJECTIVE: To identify activity limitation in early rheumatoid arthritis (RA) to
      detect patients needing assistive devices. To evaluate the effects of assistive
      devices. METHODS: A multicenter cohort of 284 early RA patients was examined
      using the Evaluation of Daily Activity Questionnaire 12 and 24 months after
      diagnosis. RESULTS: The extent of activity limitation was stable over time for
      both women and men. Most limitations concerned eating and drinking. Women
      reported more difficulties than did men. The use of assistive devices was related
      to subgroups with severe disease and more disability. Use of assistive devices
      reduced difficulties significantly. For both women and men, assistive devices
      were mostly used in activities related to eating and drinking. CONCLUSION:
      Already 1 year after diagnosis, RA patients reported activity limitation that
      remained stable over time. Use of assistive devices was related to more severe
      disease and more pronounced disability. Use of devices reduced difficulties
      significantly.

PMID- 15188328
TI  - Factors associated with attrition of African Americans during the recruitment
      phase of a clinical trial examining adherence among individuals with rheumatoid
      arthritis.
AB  - OBJECTIVE: To examine factors contributing to the loss of potential minority
      participants in a study of medication adherence among rheumatoid arthritis
      patients. METHODS: Chi-square statistics were used to test for differences in
      refusal/ineligibility by race and site at 4 screening points (initial eligibility
      review, initial patient contact, adherence screening, and informed consent).
      Differences in criteria-specific risks for exclusion at initial eligibility
      review were examined across 4 sites by race. Odds ratios (95% confidence
      intervals) were estimated if differences were significant. Multivariate logistic
      regression was used to examine sociodemographic factors associated with the
      probability for ineligibility at the initial eligibility review. Stated reasons
      for refusal were qualitatively quantified. RESULTS: A greater percentage of
      African Americans were lost at every screening point when compared with whites,
      but only the difference at the initial eligibility review was statistically
      significant. CONCLUSION: Factors associated with attrition included selection of
      area medical sites, research design issues, comorbid conditions, alcohol abuse,
      and being younger, unmarried, African American, and male.

PMID- 15188329
TI  - Cardiovascular care and cancer screening in female nurses with and without
      rheumatoid arthritis.
AB  - OBJECTIVE: To compare frequencies of cancer screening and cardiovascular
      treatments aimed at reducing acute myocardial infarction in women with and
      without rheumatoid arthritis (RA). METHODS: Data from the prospective Nurses'
      Health Study were analyzed for the 491 women diagnosed with RA prior to 1998 and
      the 82,884 women without RA. Cardiovascular treatments included aspirin use,
      treatment with a cholesterol-lowering agent, cardiac catheterization, and
      coronary artery revascularization; cancer screening consisted of mammography and
      bimanual pelvic examinations. Adjustments were made for potential confounders
      using multivariate logistic regression. RESULTS: After adjusting for
      cardiovascular risk factors, use of nonsteroidal antiinflammatory drugs, and a
      history of gastric or duodenal ulcer, women with RA and no history of cardiac
      disease were 35% less likely to report taking aspirin regularly (odds ratio [OR]
      0.65, 95% confidence interval [95% CI] 0.51-0.84). The use of cholesterol
      lowering treatment, angiography, and revascularization was not statistically
      different in women with and without RA. After adjusting for cancer risk factors,
      there appeared to be an increased likelihood of mammography in women with RA
      compared with those without RA (OR 1.41, 95% CI 0.97-2.04), although this result
      was not statistically significant. Bimanual pelvic examination was reported with
      similar frequency between the 2 groups. CONCLUSION: Other than aspirin use, care
      to prevent acute myocardial infarction and cancer screening practices were
      similar among women with RA compared with women without RA.

PMID- 15188330
TI  - High work disability rate among rheumatoid arthritis patients in Lithuania.
AB  - OBJECTIVE: To evaluate labor force characteristics among patients with rheumatoid
      arthritis (RA) in Lithuania. To assess if Lithuania's transition from a state
      planned to a free-market economy after 1990 changed the employment perspectives
      of patients with RA. METHODS: RA patients, age 16-65 years (n = 238), were
      randomly selected from the RA register in Vilnius. They completed questions about
      sociodemographics, working status, and disease characteristics, they underwent a
      clinical examination, and they completed the modified Health Assessment
      Questionnaire and the Short Form 36. RESULTS: Age- and sex-adjusted employment
      was 24.2% lower and work disability 51.7% higher in patients compared with the
      general population in Lithuania. After 10 years of disease, 48% of the patients
      had withdrawn from the labor force. In those with a paid job, the average sick
      leave in the past year was 31.9 days compared with the national average of 10.8
      days. Although disease activity was not significantly different in employed
      compared with work-disabled patients, physical function and perceived quality of
      life (except general health) were worse among patients with work disability. The
      change in economic organization in 1990 was noted to increase the risk for work
      withdrawal by a factor of 2.75 (95% confidence interval 1.68-4.53). CONCLUSION:
      In Lithuania, the impact of RA on work disability is important. Although work
      disability in Lithuanian patients with RA seems more pronounced compared with
      reports from Western societies, variables associated with work disability are
      comparable. The transition to a market-orientated economy in 1990 increased the
      risk of becoming work disabled.

PMID- 15188331
TI  - Unmet demands for health care among patients with rheumatoid arthritis:
      indications for underuse?
AB  - OBJECTIVE: To assess the prevalence of unmet health care demands among rheumatoid
      arthritis (RA) patients, and to determine if these unmet demands indicate
      underuse. METHODS: A total of 679 patients with RA participated in a
      questionnaire survey and clinical examination. Unmet health care demands and
      health care use were assessed for orthopedic care, allied health care, home care,
      and psychosocial care. Indications for underuse were determined by comparing
      health outcomes of patients with unmet health care demands and of health care
      users. RESULTS: Of the 679 patients, 28.7% had an unmet demand for 1 of the 4
      services: 13.4% for allied health care, 9.7% for orthopedic care, 9.4% for home
      care, and 6.2% for psychosocial care. Underuse of allied health care, home care
      and psychosocial care was observed. CONCLUSION: Unmet demands for health care are
      frequent among RA patients. Most unmet demands indicate underuse. Health care
      professionals should therefore be more responsive to the demands of patients.

PMID- 15188332
TI  - Active but transient improvement of endothelial function in rheumatoid arthritis
      patients undergoing long-term treatment with anti-tumor necrosis factor alpha
      antibody.
AB  - OBJECTIVE: Cardiovascular disease is the major cause of excessive mortality in
      rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory
      mechanisms that include involvement of tumor necrosis factor alpha (TNF alpha).
      Anti-TNF alpha antibody improved endothelial function in RA patients after a 12
      week treatment. The aim of the present study was to assess whether improvement of
      endothelial function is still effective in long-term infliximab-treated RA
      patients. METHODS: Seven RA patients (5 women; age range 25-73 years) were
      studied. They had been treated with infliximab for at least 1 year and were
      currently being treated with this drug every 8 weeks. Endothelial-dependent and
      independent vasodilatation were measured by brachial ultrasonography. RESULTS:
      Following infliximab infusion, a rapid increase in the percentage of endothelial
      dependent vasodilatation was found in all patients (mean +/- SD 9.4 +/- 5.5% 2
      days postinfusion compared with 2.8 +/- 2.5% 2 days before infusion). However,
      values returned to baseline by 4 weeks after infusion. There were no differences
      in the percentage of endothelial-independent vasodilatation prior to and after
      infusion. A decrease in the individual disease activity score for each patient
      was observed at day 7 postinfusion (P = 0.02). CONCLUSION: Our study confirms an
      active but transient effect of infliximab on endothelial function in RA patients
      treated periodically with this drug. It may support long-term use of drugs that
      block TNF alpha function to reduce the high incidence of cardiovascular
      complications in RA.

PMID- 15188333
TI  - Assessment of atherosclerotic risk factors and endothelial function in children
      and young adults with pediatric-onset systemic lupus erythematosus.
AB  - OBJECTIVE: To characterize atherosclerotic risk factors and endothelial function
      in pediatric-onset systemic lupus erythematosus (SLE). METHODS: Lipoproteins,
      oxidized state, and autoantibodies to oxidized low-density lipoprotein (Ox-LDL)
      were assessed. Endothelial function was evaluated using brachial artery
      reactivity. RESULTS: Thirty-three SLE patients and 30 controls were studied. SLE
      subjects had significantly decreased mean high-density lipoprotein (HDL)
      cholesterol (41 mg/dl versus 51 mg/dl; P = 0.002) and apolipoprotein A-I (97
      mg/dl versus 199 mg/dl; P = 0.0004). There was no difference between groups in
      markers of oxidized state (including nitric oxide metabolites, isoprostanes, and
      Ox-LDL) or in endothelial function. However, SLE subjects had increased median
      anti-Ox-LDL IgG (2,480 relative light units [RLU] versus 1,567 RLU; P = 0.0007)
      and IgG immune complexes with LDL (4,222 RLU versus 2,868 RLU; P = 0.002).
      CONCLUSION: Pediatric SLE patients had significantly decreased levels of HDL
      cholesterol and apolipoprotein A-I and elevated titers of autoantibodies to Ox
      LDL. Despite these atherosclerotic risk factors, SLE patients had normal measures
      of oxidized state and endothelial function.

PMID- 15188334
TI  - Health-related quality of life in juvenile-onset systemic lupus erythematosus and
      its relationship to disease activity and damage.
AB  - OBJECTIVE: To assess the health-related quality of life (HRQL) of patients with
      juvenile-onset systemic lupus erythematosus (JSLE) and its relationship with
      disease activity and accumulated damage. METHODS: In this cross-sectional study,
      HRQL was assessed using the Child Health Questionnaire (CHQ), disease activity
      using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and
      accumulated damage using the Systemic Lupus International Collaborating
      Clinics/American College of Rheumatology Damage Index (SDI). RESULTS: A total of
      297 patients were included. The mean +/- SD physical and psychosocial summary
      scores of the CHQ were 40.2 +/- 15.0 and 44.8 +/- 10.7, respectively. The most
      impaired CHQ subscales were global health, general health perceptions, and parent
      impact-emotional. The SLEDAI score was significantly correlated with both the
      physical summary score (r = -0.29, P < 0.0001) and psychosocial summary score (r
      = -0.25, P < 0.0001), whereas the SDI score was significantly correlated only
      with the physical summary score (r = -0.23, P = 0.0001). CONCLUSION: We found
      that patients with JSLE have significant impairment of their HRQL, particularly
      in the physical domain. HRQL may be affected by both disease activity and
      accumulated damage, particularly in the renal, central nervous, and
      musculoskeletal systems.

PMID- 15188335
TI  - Systemic lupus erythematosus in a multiethnic lupus cohort (LUMINA). XVII.
      Predictors of self-reported health-related quality of life early in the disease
      course.
AB  - OBJECTIVE: To determine the baseline factors predictive of self-reported health
      related quality of life (HRQOL) early in the course of systemic lupus
      erythematosus patients (SLE) from a multiethnic LUMINA (Lupus in Minorities:
      Nature versus nurture) cohort. METHODS: LUMINA patients with > or =2 visits were
      studied. Self-reported HRQOL was examined with the 8 subscales and 2 summary
      measures (the Physical Component Summary [PCS], and the Mental Component Summary
      [MCS]) of the Short Form 36 (SF-36). Bivariable and multivariable analyses were
      done with the PCS, MCS and 8 subscales as the dependent variables. The analyses
      were performed including and excluding the corresponding SF-36 measure from the
      independent variables. Age, sex, and ethnicity were included in all models. Time
      was modeled in all regressions. RESULTS: A total of 1,351 visits (346 patients
      [80 Hispanics-Texas, 34 Hispanics-Puerto Rico, 126 African Americans, and 106
      Caucasians]) were included in these analyses. Mean +/- SD PCS and MCS scores were
      36.7 +/- 12.0 and 46.6 +/- 11.5, respectively. The scores for the eight subscales
      of the SF-36 were also lower than those for the general population. Baseline SF
      36 measures were highly predictive of subsequent HRQOL. In the same set of
      regressions, older age was found to consistently predict poor self-reported HRQOL
      whereas fibromyalgia, helplessness, fatigue, and abnormal illness-related
      behaviors were also predictive, but less consistently. Estimated adjusted
      variances in these regressions ranged from 23% (Role-Emotional [RE]) to 43%
      (Physical Functioning [PF]). CONCLUSION: In patients with SLE, poor baseline
      HRQOL was highly predictive of subsequent poor HRQOL. Other predictive variables
      of poor functioning were primarily psychological/behavioral and socioeconomic
      demographic.

PMID- 15188336
TI  - Health-related quality of life in systemic sclerosis as measured by the Short
      Form 36: relationship with clinical and biologic markers.
AB  - OBJECTIVE: To evaluate health-related quality of life (HRQOL) in patients with
      systemic sclerosis (SSc) using the Short Form 36 (SF-36) and to correlate SF-36
      scores with clinical and biologic markers. METHODS: The SF-36 was administered to
      24 controls and 24 SSc patients. SSc patients also were evaluated for subset
      (limited SSc [lSSc] and diffuse SSc [dSSc]), age, disease duration, angiotensin
      converting enzyme (ACE) levels, autoantibodies, and skin and internal organ
      involvement. RESULTS: The physical summary score (PSS) was lower in SSc patients
      than in controls (P < 0.05), whereas the mental summary score (MSS) was higher in
      dSSc than in lSSc patients (P < 0.05). Five of 8 single SF-36 domain scores were
      lower in SSc patients than in controls (P < 0.05). Vitality was higher in dSSc
      than in controls (P < 0.001). In SSc, elder age correlated with lower PSS; low
      ACE levels and high skin score correlated with higher general mental health and
      role limitations due to physical problems, respectively (P < 0.05). Patients with
      heart involvement had higher scores in general health perceptions (P < 0.05).
      CONCLUSION: The SF-36 shows that HRQOL is impaired in patients with SSc. Higher
      scores in MSS and vitality in patients with dSSc and correlations of high SF-36
      scores with specific organ involvement suggest that SSc patients with severe
      disease are more able to cope with HRQOL modification.

PMID- 15188337
TI  - Short-term corticosteroids then lamivudine and plasma exchanges to treat
      hepatitis B virus-related polyarteritis nodosa.
AB  - OBJECTIVE: To assess the efficacy and safety of lamivudine, an antiviral agent
      that strongly inhibits hepatitis B virus (HBV) DNA replication, combined with
      plasma exchanges after short-term corticosteroids for HBV-related polyartertitis
      nodosa (PAN). METHODS: Ten patients (8 men, 2 women, mean +/- SD age 50.4 +/-
      14.4 years) with previously untreated HBV-related PAN were included in a
      multicenter, prospective, observational trial. Oral prednisone (1 mg/kg/day) was
      given for 1 week, then tapered and withdrawn within 1 week. Then, lamivudine (100
      mg/day or less in the case of renal insufficiency) was started for a maximum of 6
      months. Plasma exchanges were performed simultaneously and scheduled as follows:
      3/week for 3 weeks, 2/week for 2 weeks, then 1/week until hepatitis B e antigen
      (HBeAg) to anti-HBe antibody (HBeAb) seroconversion was obtained or until 2-3
      months of clinical recovery was sustained. The primary trial endpoint was
      clinical recovery from HBV-PAN at 6 months. The secondary endpoint was loss of
      detectable serum HBeAg and HBV DNA, and HBeAg to HBeAb seroconversion at 9
      months. RESULTS: One death, attributed to catheter-related septicemia, was
      recorded. At 6 months, all 9 survivors had achieved clinical recovery and by 9
      months, 6 of 9 (66%) had seroconverted. CONCLUSION: The strategy of short-term
      steroids followed by lamivudine and plasma exchanges effectively led to recovery
      from HBV-PAN. Because of its oral administration and good safety profile,
      lamivudine should henceforth be considered the antiviral agent of choice to treat
      HBV-related PAN.

PMID- 15188338
TI  - Overview of work disability in rheumatoid arthritis patients as observed in cross
      sectional and longitudinal surveys.

PMID- 15188339
TI  - Degos' disease mimicking vasculitis.

PMID- 15188340
TI  - Effect of handwritten, hand-stamped envelopes on response rate in a followup
      study of hip replacement patients.

PMID- 15188341
TI  - Prominent adverse effects of thalidomide in primary Sjogren's syndrome.

PMID- 15188344
TI  - Anti-tumor necrosis factor alpha therapy and the risk of lymphoma in rheumatoid
      arthritis: no clear answer.

PMID- 15188345
TI  - Familial clustering of disease features: implications for the etiology and
      investigation of systemic autoimmune disease.

PMID- 15188346
TI  - Biomarkers in systemic lupus erythematosus. I. General overview of biomarkers and
      their applicability.

PMID- 15188347
TI  - Is systemic sclerosis an antigen-driven T cell disease?

PMID- 15188348
TI  - Making an impact on mortality in rheumatoid arthritis: targeting cardiovascular
      comorbidity.

PMID- 15188349
TI  - Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor
      necrosis factor therapy in 18,572 patients.
AB  - OBJECTIVE: The risk of lymphoma is increased in patients with rheumatoid
      arthritis (RA), and spontaneous reporting suggests that methotrexate (MTX) and
      anti-tumor necrosis factor (anti-TNF) therapy might be associated independently
      with an increased risk of lymphoma. However, data from clinical trials and
      clinical practice do not provide sufficient evidence concerning these issues
      because of small sample sizes and selected study populations. The objective of
      this study was to determine the rate of and standardized incidence ratio (SIR)
      for lymphoma in patients with RA and in RA patient subsets by treatment group.
      Additionally, we sought to determine predictors of lymphoma in RA. METHODS: We
      prospectively studied 18,572 patients with RA who were enrolled in the National
      Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and
      potential lymphoma cases received detailed followup. The SEER (Survey,
      Epidemiology, and End Results) cancer data resource was used to derive the
      expected number of cases of lymphoma in a cohort that was comparable in age and
      sex with the RA cohort. RESULTS: The overall SIR for lymphoma was 1.9 (95%
      confidence interval [95% CI] 1.3-2.7). The SIR for biologic use was 2.9 (95% CI
      1.7-4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95%
      CI 1.4-4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI
      1.9-7.5). The SIR for MTX was 1.7 (95% CI 0.9-3.2), and was 1.0 (95% CI 0.4-2.5)
      for those not receiving MTX or biologics. Lymphoma was associated with increasing
      age, male sex, and education. CONCLUSION: Lymphomas are increased in RA. Although
      the SIR is greatest for anti-TNF therapies, differences between therapies are
      slight, and confidence intervals for treatment groups overlap. The increased
      lymphoma rates observed with anti-TNF therapy may reflect channeling bias,
      whereby patients with the highest risk of lymphoma preferentially receive anti
      TNF therapy. Current data are insufficient to establish a causal relationship
      between RA treatments and the development of lymphoma.

PMID- 15188350
TI  - The safety of anakinra in high-risk patients with active rheumatoid arthritis:
      six-month observations of patients with comorbid conditions.
AB  - OBJECTIVE: To determine in a placebo-controlled, double-blind trial the safety
      profile of daily anakinra (Kineret) use in patients with active rheumatoid
      arthritis (RA) and concurrent comorbid conditions. METHODS: In 169 centers in 9
      countries, 1,414 patients with active RA were randomly assigned to receive either
      anakinra (100 mg) or placebo treatment (4:1 anakinra-to-placebo allocation
      ratio), with study drug administered by daily subcutaneous injection for 6
      months. The current post hoc analysis assessed baseline comorbid conditions, and
      patients were considered at high risk for the occurrence of adverse events if
      they had a history of at least one of the following: cardiovascular event,
      pulmonary event, central nervous system-related event, infection, diabetes,
      malignancy, or renal impairment. Within each treatment group (anakinra or
      placebo), incidence rates were summarized for serious adverse events, infectious
      events, and serious infectious events in high-risk patients and compared with
      these incidence rates in patients without comorbid conditions. RESULTS: The
      majority of patients in the trial had one or more comorbid conditions. In these
      high-risk patients, there were no differences in the incidence of serious adverse
      events or infectious events between treatment groups. The incidence of serious
      infectious events with anakinra use was similar between high-risk patients (2.5%)
      and the entire study population (2.1%) and was not attributable to any single
      comorbidity. CONCLUSION: Results of the analysis of adverse events in patients
      with active RA and coexisting comorbidities suggest that the favorable safety
      profile of anakinra is maintained in a high-risk patient population.

PMID- 15188351
TI  - Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor
      antibody: a multicenter, double-blind, placebo-controlled trial.
AB  - OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the
      immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays
      pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be
      therapeutically effective for the disease. This study was undertaken to evaluate
      the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in
      patients with RA. METHODS: In a multicenter, double-blind, placebo-controlled
      trial, 164 patients with refractory RA were randomized to receive either MRA (4
      mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered
      intravenously every 4 weeks for a total of 3 months. The clinical responses were
      measured using the American College of Rheumatology (ACR) criteria. RESULTS:
      Treatment with MRA reduced disease activity in a dose-dependent manner. At 3
      months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the
      placebo group achieved at least a 20% improvement in disease activity according
      to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus
      placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo
      group achieved an ACR50 response (P < 0.001). The overall incidences of adverse
      events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups,
      respectively, and the adverse events were not dose dependent. A blood cholesterol
      increase was observed in 44.0% of the patients. Liver function disorders and
      decreases in white blood cell counts were also observed, but these were mild and
      transient. There was no increase in antinuclear antibodies or anti-DNA
      antibodies. Anti-MRA antibodies were detected in 2 patients. CONCLUSION:
      Treatment with MRA was generally well tolerated and significantly reduced the
      disease activity of RA.

PMID- 15188352
TI  - Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid
      arthritis negative for rheumatoid factor and the shared epitope.
AB  - OBJECTIVE: To study the frequency of allele A of polymorphism PD-1.3 of the PDCD1
      gene in patients with rheumatoid arthritis (RA) and its subsets, based on the
      presence of rheumatoid factor (RF) and the shared epitope (SE) alleles. METHODS:
      A total of 1,175 patients with RA and 3,404 controls were genotyped for the PD
      1.3 A/G polymorphism, which previously was identified as being involved in
      susceptibility to systemic lupus erythematosus (SLE) in patients of European
      descent. RESULTS: We first detected a trend for association of allele A of the
      single-nucleotide polymorphism PD-1.3 with RA (P = 0.053, odds ratio [OR] 1.18,
      95% confidence interval [95% CI] 0.99-1.41). To further clarify the nature of
      this association, patients with RA were divided into 4 groups according to the
      presence of RF and the SE alleles. Association was found only in the group of
      patients negative for both RF and the SE alleles (P = 0.0054 [corrected P =
      0.015], OR 1.75, 95% CI 1.15-2.65). CONCLUSION: Patients negative for both RF and
      the SE alleles showed association with the same allele that we previously
      identified as being involved in susceptibility to SLE. These results provide the
      first evidence of the involvement of the human PDCD1 gene in arthritis.

PMID- 15188353
TI  - Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis
      synovium.
AB  - OBJECTIVE: Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the
      formation of PGE(2) from cyclooxygenase-derived PGH(2). Microsomal PGES-1 is
      induced by proinflammatory cytokines and is strongly linked to conditions that
      result in high PGE(2) biosynthesis. PGE(2) contributes to the pathogenesis of
      rheumatoid arthritis (RA), acting as a mediator of inflammation and promoting
      bone destruction. Induction of mPGES-1 in rheumatoid synoviocytes by
      proinflammatory cytokines has been demonstrated in vitro, indicating an important
      role in RA pathogenesis. Recent studies using mPGES-1-deficient mice demonstrated
      the importance of this gene in chronic inflammation. The aim of this study was to
      investigate the expression and localization of mPGES-1 in synovial biopsy
      specimens obtained from patients with RA. METHODS: Synovial tissue samples from
      24 patients with RA were obtained, and immunohistologic analysis was performed
      using polyclonal antibodies against mPGES-1. Double immunofluorescence staining
      was performed with antibodies to CD3, CD19, CD20, CD68, CD163, and prolyl 4
      hydroxylase. RESULTS: Intracellular mPGES-1 staining was observed in synovial
      membranes from all of the RA patients studied. Specifically, strong expression of
      mPGES-1 was detected in synovial lining cells. In sublining mononuclear and
      fibroblast-like cells, the extent of mPGES-1 staining was less than that in the
      synovial lining cells. In some patients, positive staining was observed in
      endothelial cells. With the double immunofluorescence technique, mPGES-1
      production was detected in synovial macrophages and fibroblasts, while mPGES-1
      expression was not observed in lymphocytes. CONCLUSION: The demonstration of
      mPGES-1 expression in synovial tissues from patients with RA suggests a role for
      mPGES-1 in the RA disease process. Microsomal PGES-1 might be a potential new
      target for treatment strategies to control PGE(2) synthesis in patients with RA,
      without the systemic side effects associated with cyclooxygenase inhibitors.

PMID- 15188354
TI  - Increased synovial tissue NF-kappa B1 expression at sites adjacent to the
      cartilage-pannus junction in rheumatoid arthritis.
AB  - OBJECTIVE: To compare the expression of the Rel/NF-kappa B subunits, NF-kappa B1
      (p50) and RelA (p65), in paired synovial tissue samples selected from sites
      adjacent to and remote from the cartilage-pannus junction (CPJ) in patients with
      inflammatory arthritis. METHODS: Synovial tissue was selected at arthroscopy from
      sites adjacent to the CPJ and from the suprapatellar pouch of patients who were
      referred to an early arthritis clinic. Tissue samples from patients with
      osteoarthritis (OA) undergoing knee arthroplasty were also studied. Rel/NF-kappa
      B subunit activation and expression were measured by electrophoretic mobility
      shift assay and supershift analyses and by immunohistochemistry. RESULTS: Tissue
      samples were obtained from 10 patients with rheumatoid arthritis (RA), 7 with a
      seronegative arthropathy (SnA), and 6 with OA. Rel/NF-kappa B was abundantly
      expressed in all samples. In both RA and SnA synovial tissue, the absolute number
      of NF-kappa B1+ cells at the CPJ was significantly higher than at non-CPJ sites
      (P = 0.006 and P = 0.02, respectively). The proportion of cells expressing NF
      kappa B1 was also significantly higher at the CPJ compared with non-CPJ sites (P
      = 0.003 in RA, P = 0.009 in SnA). The numbers of RelA+ cells were consistently
      lower throughout. In RA synovial tissue, but not in SnA synovial tissue, both the
      absolute number and the proportion of RelA+ cells were significantly higher at
      the CPJ than at non-CPJ sites (P = 0.003 and P = 0.01, respectively). In OA
      synovial tissue, the numbers of cells expressing NF-kappa B1 and RelA were
      similar to those observed at the non-CPJ sites in all inflammatory tissues
      studied. CONCLUSION: In this study of early inflammatory arthritis, expression of
      NF-kappa B1 in synovial tissue was highest at sites most likely to be associated
      with joint erosion. These observations are consistent with a critical role of NF
      kappa B1 in joint destruction, and support the rationale for specific therapeutic
      inhibition of NF-kappa B in RA.

PMID- 15188355
TI  - Local expression of the serum amyloid A and formyl peptide receptor-like 1 genes
      in synovial tissue is associated with matrix metalloproteinase production in
      patients with inflammatory arthritis.
AB  - OBJECTIVE: To evaluate the regulation of acute-phase serum amyloid A (A-SAA)
      production in inflamed synovial tissue, and to elucidate a possible
      pathophysiologic role in the induction of matrix metalloproteinase (MMP) release
      by fibroblast-like synoviocytes (FLS). METHODS: Synovial tissue samples were
      obtained by arthroscopic biopsy from the knee joints of patients with
      inflammatory arthritis. Primary cultures of FLS from patients with rheumatoid
      arthritis (RA), psoriatic arthritis, sarcoid arthritis, and undifferentiated
      arthritis were established. Total RNA was extracted from FLS and analyzed by
      reverse transcription-polymerase chain reaction (PCR) using specific primers for
      A-SAA and formyl peptide receptor-like 1 (FPRL1), an A-SAA receptor. Southern
      blot analysis confirmed the PCR products generated. Immunohistochemical analysis
      demonstrated the expression of A-SAA protein production by several synovial cell
      populations, and immunofluorescence analysis confirmed A-SAA colocalization with
      the macrophage marker CD68. Primary FLS cultures stimulated with recombinant
      human A-SAA resulted in dose-dependent MMP-1 and MMP-3 production, as measured by
      an enzyme-linked immunosorbent assay. RESULTS: A-SAA messenger RNA (mRNA) and
      FPRL1 mRNA were present in FLS, macrophages, and endothelial cells isolated from
      the synovial tissue of patients with RA and other categories of inflammatory
      arthritis. A-SAA expression was regulated by proinflammatory cytokines and
      occurred in association with FPRL1 expression in FLS and endothelial cells, which
      is consistent with a biologic role at the sites of inflammation. Recombinant
      human A-SAA induced both MMP-1 and MMP-3 secretion by FLS. The mean fold
      increases in A-SAA-induced MMP-1 and MMP-3 production were 2.6 and 10.6,
      respectively, compared with 7.6-fold and 41.9-fold increases in interleukin-1
      beta-induced MMP-1 and MMP-3 production. CONCLUSION: The up-regulation of the A
      SAA and FPRL1 genes in inflamed synovial tissue suggests an important role in the
      pathophysiology of inflammatory arthritis. A-SAA induces the production of MMPs.
      Therapeutic targeting of A-SAA, or FPRL1, may modulate pathophysiologic pathways
      that are associated with matrix degradation in patients with RA and other forms
      of progressive inflammatory arthritis.

PMID- 15188356
TI  - Regulation of interleukin-18 binding protein production by blood and synovial
      cells from patients with rheumatoid arthritis.
AB  - OBJECTIVE: To study the regulation of interleukin-18 binding protein (IL-18BP)
      production by rheumatoid arthritis (RA) or control peripheral blood mononuclear
      cells (PBMCs) and by RA synovial tissue cells, and to compare the levels of IL
      18BP messenger RNA (mRNA) expression in whole blood from RA patients and
      controls. METHODS: Unstimulated or phytohemagglutinin and phorbol myristate
      acetate (PHA/PMA)-stimulated PBMCs from 10 RA patients and 12 healthy controls
      and unstimulated or PHA/PMA-stimulated synovial tissue cells from 8 RA patients
      were cultured with or without IL-12 (1 ng/ml) and IL-18 (5 ng/ml) alone or in
      combination. IL-18BP and interferon-gamma (IFN gamma) levels in supernatants were
      measured by enzyme-linked immunosorbent assay. Levels of IL-18BP and IFN gamma
      mRNA expression in whole blood samples from 22 RA patients and 12 healthy
      controls were determined by quantitative reverse transcriptase-polymerase chain
      reaction. RESULTS: IL-12 decreased the basal levels of IL-18BP production by
      freshly isolated RA or control PBMCs, but increased those of synovial cells or
      PHA/PMA-stimulated PBMCs. IL-18 alone had no direct effect on IL-18BP production
      by PBMCs or RA synovial cells, with or without stimulation. Unstimulated whole
      blood samples from RA patients showed lower levels of IL-18BP mRNA expression
      than those from healthy controls. CONCLUSION: The production of IL-18BP in
      response to IL-12 and IL-18 was regulated differently in blood and synovial
      cells. The difference appears to be related to the level of cell activation.

PMID- 15188357
TI  - Up-regulated expression and activation of the orphan chemokine receptor, CCRL2,
      in rheumatoid arthritis.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory condition
      characterized by a cellular influx and destruction of the joint architecture.
      Chemokines characteristically regulate leukocyte recruitment and activation.
      Chemokine (CC motif) receptor-like 2 (CCRL2) is an orphan receptor with homology
      to other CC chemokine receptors. We undertook this study to examine CCRL2
      expression in RA, cytokine regulation of expression, and the source of a putative
      ligand in an attempt to determine the role of this receptor during inflammation.
      METHODS: Expression of CCRL2 on joint-infiltrating leukocytes was examined by
      immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary
      neutrophils using Northern and Western blotting and reverse transcriptase
      polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2
      (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system,
      and their migration in response to fractions of synovial fluid (SF) from RA
      patients was examined using a 48-well chamber. RESULTS: CCRL2 expression was
      observed on all infiltrating neutrophils and on some macrophages obtained from
      the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that
      CCRL2 messenger RNA (mRNA) was rapidly up-regulated following stimulation with
      lipopolysaccharide (1 microg/ml) or tumor necrosis factor (5 ng/ml). The mRNA for
      both CCRL2A and CCRL2B were expressed in cytokine-stimulated neutrophils. Cells
      expressing either of these splice variants migrated in response to a fraction of
      RA SF. CONCLUSION: CCRL2 expression is up-regulated on synovial neutrophils of RA
      patients. Inflammatory products present in the SF activate this receptor,
      indicating that CCRL2 is a functional receptor that may be involved in the
      pathogenesis of RA.

PMID- 15188358
TI  - Quadriceps weakness and its relationship to tibiofemoral and patellofemoral knee
      osteoarthritis in Chinese: the Beijing osteoarthritis study.
AB  - OBJECTIVE: Weakness has been documented as a feature of tibiofemoral knee
      osteoarthritis (OA) and may cause disease in this compartment by shock absorption
      during impulse loading at heel strike, when the patellofemoral joint is not
      engaged. Our objective was to determine the association of muscle weakness with
      compartment-specific knee OA, to evaluate sex-specific differences in this
      relationship, and to determine, by evaluating asymptomatic individuals with OA,
      whether symptoms may produce the weakness seen in OA. METHODS: This cross
      sectional study involved 2,472 subjects (1,475 women and 997 men) ages 60 years
      or older from 4 central districts of Beijing, China. For all subjects, a skyline
      view of each knee and an anteroposterior (AP) or posteroanterior (PA) radiograph
      of both knees were obtained during weight bearing. Radiographs were read by one
      reader for Kellgren/Lawrence (K/L) grade, joint space narrowing (JSN), and
      osteophytes. We defined a subject as having tibiofemoral OA when the K/L grade
      was > or =2 on AP/PA view, patellofemoral OA on skyline view when the osteophyte
      score was > or =2 (or when the JSN score was > or =2 and the osteophyte score was
      > or =1), and mixed OA when the knee had both patellofemoral and tibiofemoral
      radiographic OA. Strength was measured isometrically for each leg separately, and
      knee pain was evaluated by questionnaire. RESULTS: In women, quadriceps weakness
      was associated with tibiofemoral OA (odds ratio [OR] 0.7, 95% confidence interval
      [95% CI] 0.4-1.0), patellofemoral OA (OR 0.6, 95% CI 0.4-0.9), and mixed OA (OR
      0.4, 95% CI 0.3-0.6). In men, weakness was associated with mixed OA (OR 0.5, 95%
      CI 0.3-0.8), and the ORs suggesting an association of patellofemoral OA with
      weakness were the same as those in women, although in men this trend did not
      reach statistical significance (P = 0.12). In men, isolated tibiofemoral disease
      was not associated with weakness; however, the sample size in this analysis was
      limited. When subjects with knee symptoms were excluded, the relationship of
      quadriceps weakness to OA was attenuated, with only the relationship between
      muscle weakness and mixed OA remaining significant. CONCLUSION: There is a
      relationship between quadriceps weakness and knee OA in all compartments, with
      the strongest association in mixed disease. Pain may contribute to some of this
      weakness.

PMID- 15188360
TI  - A randomized clinical trial of a psychoeducational intervention to improve
      outcomes in systemic lupus erythematosus.
AB  - OBJECTIVE: In a cross-sectional study, we previously identified 2 potentially
      modifiable risk factors for adverse outcomes in systemic lupus erythematosus
      (SLE): self-efficacy and social support. The goal of this study was to evaluate
      in a randomized controlled trial a theory-based intervention to improve patient
      self-efficacy and partner support to manage SLE. METHODS: Patients with SLE ages
      18 years and older who met the American College of Rheumatology criteria and were
      able to identify a partner (spouse or family member) were recruited from 2
      academic medical centers and randomized into an experimental group or a control
      group. Patients in the experimental group and their partners received an
      intervention designed to enhance self-efficacy, couples communication about
      lupus, social support, and problem solving, in the form of a 1-hour session with
      a nurse educator followed by monthly telephone counseling for 6 months. Patients
      in the control group and their partners received an attention placebo, including
      a 45-minute video presentation about lupus, and monthly telephone calls. Measures
      of physical and mental health status, disease activity, and psychosocial factors
      were collected at baseline, 6 months, and 12 months. The effect of the
      intervention on physical and mental health and disease activity at 6 and at 12
      months was modeled with linear regression and adjusted for baseline health
      status, disease activity, sociodemographic factors, treatment change, and
      psychosocial factors. RESULTS: One hundred twenty-two patients (plus their
      partners) were enrolled and randomized as follows: 64 to the experimental
      intervention and 58 to the attention control group. The participants were
      predominantly white, approximately half were college educated, and the groups
      were balanced for sociodemographic factors. At 6 months, significantly higher
      scores for couples communication (P = 0.01) and problem-focused coping (P = 0.03)
      were seen in the experimental group compared with the control group. At 12 months
      (6 months after the intervention ended), social support was higher (4.4 versus
      4.1; P = 0.03), self-efficacy was higher (7.2 versus 6.2; P = 0.02), couples
      communication was higher (3.5 versus 3.1; P = 0.03), and fatigue was lower (5.1
      versus 6.3; P = 0.02) in the experimental group compared with the control group.
      Global mental health status at 12 months, as measured by the Short Form 36
      survey, was 69 points in the experimental group compared with 58 points in the
      control group (P = 0.04). In multivariate models, adjusting for baseline
      covariates, scores for couple communication (P = 0.01) were significantly higher
      at 6 months, and scores for self-efficacy (P = 0.004) and global mental health
      status (P = 0.03) were significantly higher at 12 months in the experimental
      group compared with the control group, and the mean score for global physical
      function was higher by 7 points, which was a clinically meaningful change (P =
      0.2). The mean score for fatigue was also significantly lower in the experimental
      group than in the control group (P = 0.05). SLE disease activity was unchanged by
      this intervention. CONCLUSION: This randomized, controlled trial of a theory
      based educational intervention in SLE demonstrated significantly higher scores
      for couple communication, self-efficacy, and mental health status, and lower
      fatigue scores in the experimental group compared with the control group. Because
      couple communication and self-efficacy appear to be modifiable risk factors, they
      may also be potential targets in more disadvantaged populations.

PMID- 15188359
TI  - Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a
      guinea pig model.
AB  - OBJECTIVE: To determine whether ascorbic acid might be of benefit for the
      treatment of spontaneous osteoarthritis (OA) when administered over a long period
      of time. METHODS: We investigated the effects of 8 months' exposure to low,
      medium, and high doses of ascorbic acid on the in vivo development of histologic
      knee OA in the male Hartley guinea pig. The low dose represented the minimum
      amount needed to prevent scurvy. The medium dose was the amount present in
      standard laboratory guinea pig chow and resulted in plasma levels comparable with
      those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily).
      The high dose was the amount shown in a previous study of the guinea pig to slow
      the progression of surgically induced OA. RESULTS: We found an association
      between ascorbic acid supplementation and increased cartilage collagen content
      but, in contrast to findings in a previous study of surgically induced OA in the
      guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active
      transforming growth factor beta (TGF beta) was expressed in marginal osteophytes,
      whose size and number were significantly increased with increasing intake of
      ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a
      biomarker of cartilage turnover, corroborated the histologic findings.
      CONCLUSION: Ascorbic acid has been shown to activate latent TGF beta. Prolonged
      intraarticular exposure to TGF beta has been shown to cause OA-like changes. We
      found expression of active TGF beta in osteophytes, a prominent feature of the
      joint histology seen in association with ascorbic acid treatment. Thus, the
      deleterious effects of prolonged ascorbic acid exposure may be mediated in part
      by TGF beta. This worsening of OA with ascorbic acid supplementation suggests
      that ascorbic acid intake should not be supplemented above the currently
      recommended dietary allowance (90 mg/day for men and 75 mg/day for women).

PMID- 15188361
TI  - Strong association of a functional polymorphism in the monocyte chemoattractant
      protein 1 promoter gene with lupus nephritis.
AB  - OBJECTIVE: Lupus nephritis (LN) is a major contributor to morbidity and mortality
      in patients with systemic lupus erythematosus (SLE). There is evidence that
      polymorphisms in the genes of inflammatory mediators may predispose to the
      development of LN in patients with SLE. In this study, we examined the role of a
      functional monocyte chemoattractant protein 1 (MCP-1) polymorphism in SLE and LN.
      METHODS: DNA and paired urine and serum samples were obtained from 134 SLE
      patients (> or =4 American College of Rheumatology criteria for SLE; 49 with and
      85 without LN) and 118 controls. MCP-1 genomic variants were detected by
      polymerase chain reaction followed by restriction enzyme-fragment analysis.
      Urinary and serum MCP-1 levels and MCP-1 production by peripheral blood
      macrophages were measured by enzyme-linked immunosorbent assay. RESULTS: The A/A
      genotype was more common in controls than in SLE patients (P = 0.0002), whereas
      both the A/G (P = 0.009) and G/G (P = 0.0212) genotypes were more frequent in SLE
      patients. The A/A genotype was observed in only 23% of the patients with LN
      compared with 58% of those without LN (P < 0.0001). MCP-1 production by
      peripheral blood mononuclear cells from patients with the A/G and G/G phenotypes
      was markedly higher than the production by cells from patients with the A/A
      genotype. Urinary levels of MCP-1 were significantly higher in patients with LN.
      CONCLUSION: These results suggest that an A/G or G/G genotype may predispose to
      the development of SLE and further indicate that SLE patients with these
      genotypes may be at higher risk of developing LN. Moreover, measurement of
      urinary levels of MCP-1 may be a useful tool for the detection and management of
      LN.

PMID- 15188362
TI  - Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and
      T cells treated with DNA methylation inhibitors.
AB  - OBJECTIVE: Generalized DNA hypomethylation contributes to altered T cell function
      and gene expression in systemic lupus erythematosus (SLE). Some of the
      overexpressed genes participate in the disease process, but the full repertoire
      of genes affected is unknown. Methylation-sensitive T cell genes were identified
      by treating T cells with the DNA methyltransferase inhibitor 5-azacytidine and
      comparing gene expression with oligonucleotide arrays. CD70, a costimulatory
      ligand for B cell CD27, was one gene that reproducibly increased. We then
      determined whether CD70 is overexpressed on T cells treated with other DNA
      methylation inhibitors and on SLE T cells, and determined its functional
      significance. METHODS: Oligonucleotide arrays, real-time reverse transcription
      polymerase chain reaction, and flow cytometry were used to compare CD70
      expression in T cells treated with 2 DNA methyltransferase inhibitors (5
      azacytidine and procainamide) and 3 ERK pathway inhibitors known to decrease DNA
      methyltransferase expression (U0126, PD98059, and hydralazine). The consequences
      of CD70 overexpression were tested by coculture of autologous T and B cells with
      and without anti-CD70 and measuring IgG production by enzyme-linked immunosorbent
      assay. The results were compared with those of T cells from lupus patients.
      RESULTS: SLE T cells and T cells treated with DNA methylation inhibitors
      overexpressed CD70 and overstimulated B cell IgG production. The increase in IgG
      synthesis was abrogated by anti-CD70. CONCLUSION: SLE T cells and T cells treated
      with DNA methyltransferase inhibitors and ERK pathway inhibitors overexpress
      CD70. This increased B cell costimulation and subsequent immunoglobulin
      overproduction may contribute to drug-induced and idiopathic lupus.

PMID- 15188363
TI  - Induction of interferon-alpha production in plasmacytoid dendritic cells by
      immune complexes containing nucleic acid released by necrotic or late apoptotic
      cells and lupus IgG.
AB  - OBJECTIVE: To investigate the release of interferon-alpha (IFN alpha)-inducing
      material by necrotic or apoptotic cells, its properties, and the necessity of
      autoantibodies from systemic lupus erythematosus (SLE) patients for the
      interferogenic activity. METHODS: U937 monocytic leukemia cells or peripheral
      blood mononuclear cells (PBMCs) were rendered necrotic by freeze-thawing or
      apoptotic by treatment with ultraviolet light. Cell culture supernatants from
      these cells and IgG from SLE patients (SLE IgG) were added to cultures of normal
      PBMCs or purified plasmacytoid dendritic cells (PDCs). The importance of nucleic
      acids for IFN alpha induction was investigated by RNase and DNase treatment. The
      IFN alpha levels were measured by immunoassay. RESULTS: Both necrotic and
      apoptotic U937 cells released material that, combined with SLE IgG, induced IFN
      alpha production in PDCs. The release from apoptotic cells occurred with a 16
      hour delay, in late apoptosis. Also, normal PBMCs released IFN alpha-inducing
      material, but only during necrosis. The interferogenic activity of the necrotic
      material required the presence of RNA, while both RNA and DNA were important in
      the apoptotic material. In both cases, the presence of SLE IgG was necessary, and
      its activity correlated with the presence of antibodies to RNA-binding proteins,
      but not anti-DNA antibodies. CONCLUSION: Necrotic and late apoptotic cells
      release material that, combined with SLE IgG, induces production of IFN alpha in
      PDCs. The IFN alpha inducers probably consist of immune complexes (ICs)
      containing RNA and possibly DNA as essential interferogenic components. The
      presence of such interferogenic ICs could explain the ongoing production of IFN
      alpha in SLE and could be of etiopathogenic importance.

PMID- 15188364
TI  - Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system.
AB  - OBJECTIVE: Dnase1-deficient mice with the 129 x C57BL/6 genetic background
      develop symptoms of systemic lupus erythematosus, such as high titers of
      antinuclear autoantibodies directed against nucleosomes. In this study we
      analyzed a potential molecular pathomechanism leading to this autoimmunity, by
      exploring the influence of extracellular Dnase1 present in serum on the breakdown
      of chromatin in necrotic cells in vitro. METHODS: Human breast adenocarcinoma
      cells (MCF-7) and other cell lines were subjected to necrosis induced by hydrogen
      peroxide, streptolysin O, or freeze-thawing. Subsequently, the influence of sera
      from Dnase1-deficient and wild-type mice as well as the influence of purified
      enzymes present in the culture medium on the process of necrotic chromatin
      breakdown was investigated. RESULTS: Necrotic chromatin breakdown resembled
      apoptotic DNA laddering and was catalyzed by serum Dnase1 in conjunction with
      plasmin. During necrosis, Dnase1 and plasminogen penetrated the cell and
      accumulated in the cytoplasm and nucleus. Plasminogen bound to the cytoskeleton
      and nuclear structures, was activated to plasmin by either tissue-type or
      urokinase-type plasminogen activator, and degraded histone H1, thereby
      facilitating internucleosomal DNA cleavage by Dnase1. CONCLUSION: Our results
      suggest that serum Dnase1 in cooperation with the plasminogen system guarantees a
      fast and effective breakdown of chromatin during necrosis by the combined
      cleavage of DNA as well as of DNA binding proteins. The failure of such a
      clearance mechanism might lead to antinuclear autoimmunity similar to that
      observed in the Dnase1-deficient mouse.

PMID- 15188365
TI  - Control of spontaneous B lymphocyte autoimmunity with adenovirus-encoded soluble
      TACI.
AB  - OBJECTIVE: Serum B lymphocyte stimulator (BLyS) is increased in autoimmune
      diseases, both in animal models and in humans. This study examined the effect of
      BLyS blockade in 3 animal models of lupus. METHODS: Antibodies and lupus-like
      disease manifestations were examined in mice after administration of a single
      injection of an adenoviral construct for the transmembrane activator and CAML
      interactor receptor (AdTACI) that produces high serum levels of TACI-Fc fusion
      protein. RESULTS: In C57BL/6 (B6) lpr/lpr mice (B6.lpr/lpr), which were used to
      model autoimmunity in the absence of severe disease, treatment of younger mice
      with AdTACI prevented the development of hypergammaglobulinemia. In contrast, use
      of AdTACI for BLyS blockade had only transient effects on the levels of IgG in
      normal B6 mice. AdTACI blocked the development of autoantibodies in younger
      B6.lpr/lpr mice and reversed the production of autoantibodies in older B6.lpr/lpr
      mice, and also reduced the numbers of splenic plasma cells. In MRL.lpr/lpr mice,
      which were used to examine disease manifestations, AdTACI reduced the extent of
      glomerulonephritis and proteinuria and improved survival, but had little effect
      on T cell infiltration and interstitial nephritis. However, in (NZB x NZW)F(1)
      mice, AdTACI induced neutralizing anti-TACI antibodies and failed to reduce the
      numbers of B cells. CONCLUSION: BLyS blockade has little effect on IgG levels in
      normal mice, but reverses the production of spontaneously produced IgM and IgG
      autoantibodies in the setting of established autoimmunity. Blockade of BLyS
      ameliorates B cell-dependent disease manifestations even in the MRL.lpr/lpr
      model, but its effectiveness on autonomous T cell aspects of the disease is
      limited. Moreover, its effectiveness is neutralized by anti-TACI antibodies when
      present. These results provide a basis for understanding the potential effects of
      BLyS blockade in human disease.

PMID- 15188366
TI  - Abnormalities in peripheral B cell memory of patients with primary Sjogren's
      syndrome.
AB  - OBJECTIVE: To delineate disturbances in peripheral B cell memory in primary
      Sjogren's syndrome (SS). METHODS: Isotype-specific immunoglobulin (Ig) heavy
      chain transcripts were analyzed in single-sorted CD19+,CD27- naive and
      CD19+,CD27+ memory B cells from patients with primary SS and normal healthy
      control subjects. RESULTS: A significantly higher frequency of B cells expressing
      mu-, alpha-, and/or gamma-chain transcripts were found in patients with primary
      SS compared with controls (58.0% versus 14.3%; P < 0.0001). Notably, 30.5% of
      individual B cells (for primary SS, 38.7%; for controls, 12.7% [P < 0.0001])
      simultaneously expressed transcripts for different Ig heavy-chain isotypes using
      identical V(H)-D-J(H) rearrangements. However, these cells lacked surface
      expression of more than one of the respective Ig heavy-chain isotypes as well as
      messenger RNA (mRNA) transcripts for 2 germinal center markers, activation
      induced cytidine deaminase, and Bcl-6. In contrast with the findings in normal
      healthy controls, peripheral B cell memory in patients with primary SS was
      characterized by 1) circulating CD27+ B cells expressing heavily mutated Ig V(H)
      transcripts (mutational frequency 8.6% versus 4.3%; P < 0.0001), 2) significantly
      enhanced mutational frequencies of C mu transcripts (9.6% versus 2.5%; P <
      0.0001), 3) a high proportion (61.2%) of CD27+ B cells expressing transcripts for
      multiple Ig heavy-chain isotypes, and 4) a CD27- memory-type B cell subpopulation
      expressing mutated C mu transcripts. CONCLUSION: Altogether, both B cell
      hyperactivity and striking abnormalities in peripheral B cell memory are
      indicated at the single-cell mRNA level in patients with primary SS. Detection of
      multiple Ig heavy-chain transcripts in peripheral CD19+,CD27+ memory B cells of
      patients with SS may represent the abnormal retention of pre-switch mRNA
      transcripts in circulating post-switch B cells.

PMID- 15188367
TI  - Regional differences in bronchoalveolar lavage and thoracic high-resolution
      computed tomography results in dyspneic patients with systemic sclerosis.
AB  - OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of death in
      systemic sclerosis (SSc). Although early identification and treatment of
      alveolitis may prevent deterioration of lung function, the best approach for
      diagnosing active alveolitis remains controversial. This study was undertaken to
      investigate the utility of high-resolution computed tomography (HRCT) of the
      chest, in comparison with bronchoalveolar lavage (BAL), in the diagnosis of
      alveolitis in these patients. METHODS: Eighteen patients with SSc and dyspnea
      were evaluated for ILD by pulmonary function testing and bronchoalveolar lavage
      (BAL), and 15 of these patients underwent chest HRCT. BAL was performed in either
      the middle lobe or the lingula, and also in a lower lung segment. Differential
      cell counts were determined by clinical cytopathology, with retrospective
      recounting in a blinded manner by a single technician. Active alveolitis was
      defined as the presence of > or =3.0% polymorphonuclear cells and/or > or =2%
      eosinophils in BAL fluid. BAL fluids were cultured for bacteria, mycobacteria,
      and fungi. HRCT scans were evaluated in a blinded manner for ground-glass
      opacification and fibrosis in the lavaged lobes. RESULTS: Nine of the 18 patients
      had active alveolitis recorded in both lavaged segments, while in 4 patients it
      was recorded in only 1 segment (lower lobe in 3). Following repeat differential
      cell counting, 3 patients were reclassified as having active alveolitis and 1 as
      having no alveolitis. Culture of BAL fluid identified clinically unsuspected
      infection in 3 patients. For the right middle lung lobe or lingula there was
      excellent agreement between ground-glass opacification and the finding of
      alveolitis on BAL from segments in the same lung regions, but this was not
      observed for the lower lobes. The correlation between fibrosis on HRCT and the
      presence of alveolitis on BAL was significant for the lower lobes but not the
      middle lung fields. CONCLUSION: BAL of the middle lobe or lingula may
      underestimate the presence of active alveolitis. Similarly, while ground-glass
      opacification on HRCT accurately predicted alveolitis in the middle lung fields,
      HRCT did not detect all sites of inflammation and did not identify infectious
      etiologies. These data suggest that, in addition to HRCT, BAL with lavage,
      differential cell counting, and culture from at least 2 segments of lung be
      performed for diagnosing SSc alveolitis.

PMID- 15188368
TI  - Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B
      cells and diminished but activated memory B cells.
AB  - OBJECTIVE: To determine phenotypic and functional abnormalities of blood B cell
      subsets in patients with systemic sclerosis (SSc). METHODS: Cell surface marker
      expression was determined by flow cytometry. Spontaneous apoptosis was evaluated
      by annexin V expression with flow cytometric analysis. IgG production by isolated
      IgD- memory B cells was examined by enzyme-linked immunosorbent assay. RESULTS:
      The numbers of blood CD27- naive B cells from SSc patients were increased
      compared with normal control cells, while memory B cells expressing medium levels
      of CD27 and plasmablasts expressing high levels of CD27 were reduced. In
      contrast, plasmablasts were the predominant population in patients with systemic
      lupus erythematosus (SLE). Memory B cells in SSc showed increased expression of
      activation markers, including CD80, CD86, and CD95, relative to normal controls.
      Consistent with CD95 up-regulation, SSc memory B cells exhibited augmented
      spontaneous apoptosis after 24-hour incubation; augmented apoptosis may explain
      the reduced memory B cell number. Nonetheless, isolated IgD- SSc memory B cells
      treated with stimuli had an enhanced ability to produce IgG. Furthermore,
      expression of CD19, a critical signal transduction molecule of B cells that
      regulates autoantibody production, was significantly increased in memory B cells
      as well as in naive B cells in SSc. In contrast, CD19 expression was decreased in
      SLE B cells. CONCLUSION: SSc patients have distinct abnormalities of blood
      homeostasis and B cell compartments, characterized by expanded naive B cells and
      activated but diminished memory B cells. Our results suggest that CD19
      overexpression in SSc memory B cells is related to their hyperreactivity.

PMID- 15188369
TI  - Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype
      concordance.
AB  - OBJECTIVE: To investigate the clinical phenotypes and demographic characteristics
      of 183 affected sibling pairs (ASPs) with juvenile rheumatoid arthritis (JRA) and
      to determine whether there are differences between the clinical phenotypes of the
      ASP cohort compared with patients with sporadic disease and whether there is
      greater sharing of specific clinical features within versus between sibpairs.
      METHODS: Details of the JRA Affected Sibpair Registry operations have been
      described previously. The frequencies of phenotypes in the 2 cohorts were
      tabulated, summary statistics were determined, and comparisons were made by chi
      square test or t-test. Sibling risk, sibling risk ratios (lambda(s)), and odds
      ratios were calculated to assess familial aggregation of several different
      clinical manifestations. RESULTS: The most common onset type among the 164
      nontwin ASPs was pauciarticular (65% overall). Fifty-three percent of the ASPs
      were concordant for pauciarticular-onset JRA; 19% were concordant for a
      polyarticular disease onset. Among subjects with polyarticular-onset disease,
      significantly more joints were involved at onset in simplex patients than in ASPs
      (P = 0.008). The difference in age at JRA onset within sibpairs (sibling 1 versus
      sibling 2) was not significantly different. ASPs developed disease at a mean real
      time difference of 5.1 years apart. Familial aggregation was found for
      tenosynovitis (lambda(s) 29.5), leukocytosis (lambda(s) 25), rheumatoid factor
      (lambda(s) 11.0), anemia (lambda(s) 1.7), and antinuclear antibodies (lambda(s)
      1.3). CONCLUSION: This study confirms the findings of earlier studies showing
      that a high proportion of ASPs overall show concordance of disease-onset type,
      except for the subset of patients with systemic disease, and that nontwin ASPs do
      not develop disease at the same point in real time. We conclude that JRA and its
      clinical manifestations do not differ substantially between ASPs and the simplex
      population. The exception is the number of affected joints at JRA onset among
      patients with polyarticular-onset disease. Familial aggregation of clinical
      features among ASPs adds strong evidence for a genetic background in this
      disease.

PMID- 15188370
TI  - Increased interleukin-18 expression in bone marrow of a patient with systemic
      juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome.
AB  - The aberrant induction of proinflammatory cytokines is considered to be crucial
      in the pathogenesis of systemic juvenile idiopathic arthritis and adult-onset
      Still's disease. Interleukin-18 (IL-18) in particular has been reported to be a
      candidate for the key cytokine in both diseases; however, the origin of IL-18 is
      unclear. To clarify the origin, we investigated specimens from various organs
      obtained during autopsy of a child with systemic JIA and macrophage activation
      syndrome, using immunohistochemical staining. Our results showed a high number of
      cells expressing IL-18 in the bone marrow but not in the other organs. This
      finding suggests that bone marrow is the origin of increased serum IL-18 and
      raises the possibility that other proinflammatory cytokines are also induced by
      IL-18 in bone marrow in this disease. Bone marrow may be an essential organ in
      the pathogenesis of systemic JIA.

PMID- 15188371
TI  - Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and
      psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical
      trial.
AB  - OBJECTIVE: Current treatment options for psoriatic arthritis (PsA) are limited.
      Leflunomide, an oral pyrimidine synthesis inhibitor, is highly effective in the
      treatment of rheumatoid arthritis, and small studies have suggested similar
      efficacy in PsA. We undertook this double-blind, randomized, placebo-controlled
      trial to evaluate the efficacy and safety of leflunomide in patients with PsA and
      psoriasis. METHODS: One hundred ninety patients with active PsA and psoriasis (at
      least 3% skin involvement) were randomized to receive leflunomide (100 mg/day
      loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks.
      The primary efficacy end point was the proportion of patients classified as
      responders by the Psoriatic Arthritis Response Criteria (PsARC). Additional
      efficacy (joint and skin involvement), safety, and quality-of-life assessments
      were performed. RESULTS: At 24 weeks, 56 of 95 leflunomide-treated patients
      (58.9%; 95% confidence interval [95% CI] 48.4-68.9) and 27 of 91 placebo-treated
      patients (29.7% [95% CI 20.6-40.2]) were classified as responders by the PsARC (P
      < 0.0001). Significant differences in favor of leflunomide were also observed in
      the proportions of patients achieving modified American College of Rheumatology
      20% improvement criteria, improvement in the designated psoriasis target lesion,
      and mean changes from baseline in Psoriasis Area and Severity Index scores and
      quality-of-life assessments. Diarrhea and alanine aminotransferase increases
      occurred at higher rates in the leflunomide group. No cases of serious liver
      toxicity were observed. CONCLUSION: Leflunomide is an effective treatment for PsA
      and psoriasis, providing a safe and convenient alternative to current therapies.

PMID- 15188372
TI  - Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical
      presentation typical of the hyperimmunoglobulinemia D with periodic fever
      syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier
      possibly influences the phenotype of hyperimmunoglobulinemia D with periodic
      fever syndrome or vice versa.
AB  - OBJECTIVE: To describe biochemical findings and the spectrum of mevalonate kinase
      (MVK) gene mutations as well as an associated TNFRSF1A low-penetrance variant in
      a series of patients with clinical features of the hyperimmunoglobulinemia D with
      periodic fever syndrome (HIDS). METHODS: The MVK gene was sequenced in 8 children
      and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In
      addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed
      in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme
      activity in leukocytes and renal excretion of mevalonic acid were also measured.
      RESULTS: Mutations in the coding region of the MVK gene were detected in 6
      patients, and the most common mutation was V377I. Among these patients were 2
      novel mutations, both of which were located in exon 6. These novel mutations
      resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino
      acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG)
      at amino acid position 203 (V203A). In 1 patient, a combination of one MVK
      (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's
      clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis
      factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied
      between normal and slightly increased, and the MK activity was in the low-normal
      range, while urinary mevalonate concentrations were always normal. CONCLUSION:
      The genotype findings indicate that a relatively small number of genes may be
      involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A
      variants possibly influencing the HIDS phenotype or MVK mutations contributing to
      TRAPS.

PMID- 15188373
TI  - Increased risk of coccidioidomycosis in patients treated with tumor necrosis
      factor alpha antagonists.
AB  - OBJECTIVE: To describe a group of patients who were treated with tumor necrosis
      factor alpha (TNF alpha) antagonists and who developed coccidioidomycosis, and to
      test the hypothesis that patients with inflammatory arthritis receiving TNF alpha
      antagonist therapy are at higher risk for developing symptomatic
      coccidioidomycosis. METHODS: Cases of coccidioidomycosis were identified and
      reviewed from among patients receiving TNF alpha antagonist therapy from May 1998
      through February 2003 in 5 practices within the areas endemic for
      coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative
      risk of developing symptomatic coccidioidomycosis was calculated in patients with
      inflammatory arthritis who were receiving treatment with infliximab, in
      comparison with patients with inflammatory arthritis who were not receiving
      infliximab, from January 2000 to February 2003 in a single medical center.
      RESULTS: Thirteen cases of documented coccidioidomycosis were associated with TNF
      alpha antagonist therapy. Twelve cases were associated with the use of infliximab
      and 1 case with etanercept. Among the cohort of patients from a single medical
      center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients
      receiving other therapies developed symptomatic coccidioidomycosis (relative risk
      5.23, 95% confidence interval 1.54-17.71; P < 0.01). CONCLUSION: Patients with
      inflammatory arthritis who are undergoing treatment with infliximab appear to be
      at higher risk for developing symptomatic coccidioidomycosis as compared with
      those not receiving infliximab.

PMID- 15188374
TI  - 17 beta-estradiol regulates cytokine release through modulation of CD16
      expression in monocytes and monocyte-derived macrophages.
AB  - OBJECTIVE: Macrophages release cytokines, such as tumor necrosis factor alpha
      (TNF alpha), interleukin-1 (IL-1), and IL-6, which modulate the symptoms of
      rheumatoid arthritis (RA). Macrophage release of these cytokines can be modulated
      by estrogen. Fc gamma receptor type IIIA (CD16a) is a receptor expressed on
      macrophages that selectively binds IgG molecules, an important rheumatoid factor
      in RA. Binding of CD16 by anti-CD16 monoclonal antibodies stimulates macrophage
      cytokine release. We undertook this study to test the hypothesis that decreased
      concentrations of estrogen (17 beta-estradiol) directly cause an increase in CD16
      expression, resulting in increased release of proinflammatory cytokines from
      monocytes and/or macrophages upon receptor binding. METHODS: THP-1 cells and
      female human primary monocytes and monocyte-derived macrophages were treated with
      no 17 beta-estradiol, physiologic levels (1 x 10(-8)M) of 17 beta-estradiol, or 1
      x 10(-8)M 17 beta-estradiol followed by withdrawal of 17 beta-estradiol. Surface
      expression of CD16 and CD16 messenger RNA was measured using fluorescence
      activated cell sorting (FACS) and semiquantitative reverse transcription
      polymerase chain reaction, respectively. Cytokine release from 17 beta-estradiol
      treated or untreated monocytes was then quantitated by enzyme-linked
      immunosorbent assay and FACS after crosslinking the receptor with anti-CD16
      antibodies. RESULTS: CD16 transcript significantly increased in macrophage-like
      THP-1 cells and in primary, peripheral blood macrophages in the absence of 17
      beta-estradiol, and the observed increase in message was dependent on
      transcription. CD16 receptor levels on CD14+, transforming growth factor beta
      treated primary monocytes also increased in cells deprived of 17 beta-estradiol.
      Analysis of the cytokines released showed that CD16 crosslinking stimulated
      significant increases in TNF alpha, IL-1 beta, and IL-6 due to the absence of
      estrogen. CONCLUSION: Estrogen can modulate proinflammatory cytokine release from
      activated monocytes and/or macrophages, in part through modulation of CD16
      expression.

PMID- 15188375
TI  - Correlation of polymorphic variation in the promoter region of the interleukin-1
      beta gene with secretion of interleukin-1 beta protein.
AB  - OBJECTIVE: Significant variation in interleukin-1 beta (IL-1 beta) protein
      secretion between subjects has been observed when using a lipopolysaccharide
      (LPS)/ATP-mediated ex vivo blood stimulation assay. To explore the potential
      relationships between genetic polymorphisms in the IL1B cytokine gene and
      cellular responses to inflammatory stimuli such as LPS, we investigated the
      hypothesis that polymorphisms within the promoter and exon 5 of the IL1B gene
      contribute to the observed differences in IL-1 beta protein secretion. METHODS:
      The IL1B gene polymorphisms C-511T, T-31C, and C3954T were tested for association
      with LPS-induced secretion of IL-1 beta protein as measured by an ex vivo blood
      stimulation assay. Samples from 2 independent study populations (n = 31 and n =
      25) were available for use in the ex vivo assay after consent was obtained to
      analyze the DNA. RESULTS: A specific haplotype, composed of the T allele at -511
      and the C allele at -31, was significantly associated with a 2-3-fold increase in
      LPS-induced IL-1 beta protein secretion. This association was observed in both of
      the independent study populations (P = 0.0084 and P = 0.0017). CONCLUSION: These
      data suggest that polymorphisms within the promoter region of the IL1B gene
      contribute to observed differences in LPS-induced IL-1 beta protein secretion.

PMID- 15188377
TI  - T cell receptors recognizing type II collagen in HLA-DR-transgenic mice
      characterized by highly restricted V beta usage.
AB  - OBJECTIVE: To determine the T cell receptor (TCR) structure recognizing type II
      collagen (CII) in HLA-DR-transgenic mice, and to examine the role of T cells with
      certain V(beta)-chains in collagen-induced arthritis (CIA). METHODS: T cell
      hybridomas were established from DR1- and DR4-transgenic mice and selected for
      their responses to CII and CII peptide containing the T cell determinants. RNA
      was extracted and reverse transcribed into complementary DNA, which was then
      amplified using appropriate V(beta)- and V(alpha)-subfamily-specific primers. The
      polymerase chain reaction products were purified and directly sequenced. To
      determine the role of T cells with certain V(beta)-chains in CIA, V(beta)
      subfamily-specific antibodies were administered and the development and
      characteristics of arthritis were determined. RESULTS: TCRs of 23 clonally
      distinct T cell hybridomas that were derived from DR1-transgenic mice and that
      were reactive to the CII peptide containing the immunodominant determinant were
      analyzed. These hybridomas predominantly used the TCR V(beta)14 and V(beta)8 gene
      segments (70% and 30%, respectively). The same restriction in V(beta) usage was
      also found in CII-reactive T cell hybridomas from DR4-transgenic mice. There was
      also restricted use of V(alpha) genes, although this was less marked than that of
      V(beta). In contrast, the hybridomas expressed a diverse third complementarity
      determining region. Deletion of both V(beta)14-bearing and V(beta)8-bearing T
      cells significantly reduced the incidence and severity of CIA. CONCLUSION: These
      data demonstrate that DR1 and DR4 not only bind and present the same CII
      immunodominant peptide, but also stimulate a highly restricted subset of T cells.

PMID- 15188376
TI  - Induction of arthritis in HLA-DR4-humanized and HLA-DQ8-humanized mice by human
      cartilage proteoglycan aggrecan but only in the presence of an appropriate (non
      MHC) genetic background.
AB  - OBJECTIVE: To determine whether the rheumatoid arthritis (RA)-predisposing class
      II molecules of the major histocompatibility complex (MHC) can present cartilage
      proteoglycan (PG) aggrecan, and if so, to determine the epitope repertoire of the
      human cartilage PG in HLA-transgenic mice and determine whether HLA-transgenic
      mice develop arthritis in response to immunization with human cartilage PG.
      METHODS: Mice transgenic for HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), and DQ8.Ab(0),
      lacking their own (mouse) class II antigens (Ab(0)), on the original (arthritis
      resistant) and the arthritis-susceptible BALB/c backgrounds, were immunized with
      human cartilage PG. The T cell epitope repertoire presented by these class II MHC
      alleles was determined using a synthetic peptide library (143 peptides of the
      core protein of human cartilage PG), and arthritis development was monitored and
      compared in wild-type and HLA-transgenic/congenic BALB/c mice. RESULTS: Mice of
      the 4 HLA-transgenic lines, either on the original mixed, arthritis-resistant
      background or DR4.Ab(0)- and DQ8.Ab(0)-transgenic/congenic mice on the arthritis
      susceptible BALB/c genetic background, responded well to PG immunization (as
      assessed by T cell responses and antibody and cytokine production), and a number
      of T cell epitopes along the core protein of human cartilage PG were identified.
      DR4.Ab(0)- and DQ8.Ab(0)-transgenic mice immunized with human cartilage PG
      developed arthritis, but only when these class II MHC molecules were present on
      the arthritis-susceptible (BALB/c) genetic background. CONCLUSION: A number of
      human cartilage PG epitopes can be presented by HLA alleles that predispose to
      the development of RA, but the epitopes of the cartilage PG presented by HLA-DR4
      or HLA-DQ8 can induce arthritis only in the presence of an appropriate genetic
      (non-MHC) background.

PMID- 15188378
TI  - Role of interleukin-18 in experimental group B streptococcal arthritis.
AB  - OBJECTIVE: To assess the role of interleukin-18 (IL-18) in the evolution of
      septic arthritis induced by group B streptococci (GBS) in mice. METHODS: CD1 mice
      were inoculated intravenously with 8 x 10(6) colony-forming units (CFU) of type
      IV GBS (strain 1/82), and administered intraperitoneally 1 hour before infection
      with anti-IL-18 monoclonal antibodies (0.25 mg/mouse). In a subsequent set of
      experiments, mice infected with a suboptimal arthritogenic dose of GBS (4 x 10(6)
      CFU/mouse) were administered different doses of recombinant IL-18 for 4 days,
      starting 1 hour after infection. Mortality, evolution of arthritis, bacterial
      clearance, joint histopathology, and cytokine production were examined in
      infected mice that did or did not receive treatment with anti-IL-18 antibodies or
      IL-18. RESULTS: IL-18 was produced during GBS infection. Neutralization of IL-18
      resulted in a decrease in mortality rates, and in the incidence and severity of
      arthritis. Amelioration of arthritis was accompanied by a dramatic reduction in
      local IL-1 beta, IL-6, macrophage inflammatory protein 1 alpha (MIP-1 alpha) and
      MIP-2 production, and reduced bacterial burden. Administration of exogenous IL-18
      resulted in increased mortality rates and increased incidence and severity of GBS
      arthritis, concomitant with a higher number of GBS and increased levels of IL-6,
      IL-1 beta, MIP-1 beta, and MIP-2 production in the joints. CONCLUSION: The
      present study indicated some involvement of IL-18 in the pathogenesis of GBS
      induced arthritis. The role of IL-18 in joint pathology is shown by a regulatory
      effect on inflammatory mediator levels and local cell influx. Thus, IL-18 should
      be regarded as a potential therapeutic target in GBS infection and arthritis.

PMID- 15188379
TI  - Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan
      induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout
      mice.
AB  - OBJECTIVE: STAT proteins play an important role in cytokine signaling. Some
      investigators have reported preferential activation of STAT-1, and others have
      reported preferential activation of STAT-3, in response to endogenous interleukin
      6 (IL-6), in patients with rheumatoid arthritis. The present study was undertaken
      to investigate synovial STAT-1 and STAT-3 activation in an experimental animal
      model of arthritis. METHODS: Zymosan was injected intraarticularly into naive
      wild-type (WT), IL-6(-/-), and STAT-1(-/-) mice to induce arthritis. Western
      blots of synovial lysates were probed with phosphospecific antibodies to detect
      STAT-1/STAT-3 activation. Inflammation was assessed histologically. Synovial gene
      expression of the STAT-induced feedback inhibitors suppressor of cytokine
      signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1(-/-) mice was investigated by
      reverse transcriptase-polymerase chain reaction. RESULTS: STAT-3 was activated in
      inflamed synovium of WT mice throughout the course of disease, whereas activated
      STAT-1 was observed only during the chronic phase. In IL-6(-/-) mice, STAT
      activation was limited to STAT-3 on day 1. Although macrophage influx was not
      inhibited, disease went into remission after day 7 in IL-6(-/-) mice. STAT-1
      deficiency resulted in exacerbation of chronic joint inflammation and granuloma
      formation. In STAT-1(-/-) mice, STAT-3 activation in the inflamed joints was
      unaltered as compared with WT mice. However, synovial SOCS-1, but not SOCS-3,
      gene expression was markedly reduced in STAT-1(-/-) mice. CONCLUSION: The results
      in the IL-6(-/-) mice suggest that STAT-3 is involved in the chronicity of ZIA.
      Exacerbation of arthritis in STAT-1(-/-) mice suggests an opposing effect of STAT
      1, i.e., suppression of joint inflammation. The expression of SOCS-1 could be the
      underlying mechanism by which STAT-1 controls joint inflammation.

PMID- 15188380
TI  - Initiation of degenerative joint damage by experimental bleeding combined with
      loading of the joint: a possible mechanism of hemophilic arthropathy.
AB  - OBJECTIVE: To investigate the effect of a limited number of experimental joint
      bleedings, combined with loading of the affected joint, on the development of
      progressive degenerative joint damage. METHODS: The right knee of 8 mature beagle
      dogs was injected with freshly collected autologous blood 3 times per week for 4
      weeks, to mimic a limited number of joint hemorrhages occurring over a short
      period. To ensure loading of the experimental joint, the contralateral control
      knee of the animals was fixed to the trunk 4 hours per day, 3 days per week. Ten
      weeks after the last injection, cartilage tissue and synovium were collected from
      both knees to analyze features of joint degeneration. Cartilage was prepared for
      analysis of proteoglycan turnover (synthesis, retention, release, and content)
      and histologic features. Synovium was prepared for histologic analysis. RESULTS:
      The rate of proteoglycan synthesis was significantly increased, characteristic of
      degenerative cartilage damage as seen in osteoarthritis. Release of newly formed
      proteoglycans (as a measure of retention) and total loss of proteoglycans from
      the cartilage matrix were increased. Cartilage matrix integrity was adversely
      altered, as shown by histologic damage. Histologic analysis also revealed signs
      of synovial inflammation. These effects were not observed 10 weeks after the
      experimental bleedings in joints that did not undergo forced loading. CONCLUSION:
      Experimental joint bleedings when combined with loading of the affected joint
      resulted in features of progressive degenerative joint damage, whereas similar
      joint hemorrhages without joint loading did not. This might reflect a possible
      mechanism of joint damage in hemophilia.

PMID- 15188381
TI  - Lack of association between the I kappa BL promoter polymorphism and rheumatoid
      arthritis.

PMID- 15188382
TI  - Distribution of TNFA haplotypes in healthy Caucasians: comment on the articles by
      Newton et al and Zeggini et al.

PMID- 15188384
TI  - Bone mass in adolescents with early-onset juvenile idiopathic arthritis: comment
      on the article by Lien et al.

PMID- 15188385
TI  - Intraarticular injection of anti-tumor necrosis factor: Comment on the letter by
      Arnold et al.

PMID- 15188386
TI  - Concerns in reporting of serum vascular endothelial growth factor levels: comment
      on the article by Nakahara et al.

PMID- 15188387
TI  - Induction of ADAMTS-4 by interleukin-1: comment on the article by Pratta et al.

PMID- 15188391
TI  - The Human Proteome Organization Plasma Proteome Project pilot phase: reference
      specimens, technology platform comparisons, and standardized data submissions and
      analyses.
AB  - A comprehensive, systematic characterization of cirolating proteins in health and
      disease will greatly facilitate development of biomarkers for prevention,
      diagnosis, and therapy of cancers and other diseases. The Human Proteome
      Organization Plasma Proteome Project pilot phase aims to (1) compare the
      advantages and limitations of many technology platforms; (2) contrast reference
      specimens of human plasma (ethylenediaminetetra acetic acid, heparin, citrate
      anticoagulated) and serum, in terms of numbers of proteins identified and any
      interferences with various technology platforms; and (3) create a global
      knowledge base/data repository.

PMID- 15188392
TI  - Proteome analysis of intraclonal diversity of two Pseudomonas aeruginosa TB clone
      isolates.
AB  - Two strains, Pseudomonas aeruginosa TB10839 and TB121838, which belong to the TB
      clonal lineage, have been isolated from sputa of cystic fibrosis patients.
      Despite the fact that the strains are closely related, their pathogenic potential
      differs dramatically: while strain TB10839 is capable of proliferating in
      polymorphonuclear granulocytes, strain TB121838 is not. Comparative two
      dimensional polyacrylamide gel electrophoresis coupled to matrix-assisted laser
      desorption/ionization-time of flight (MALDI-TOF)-mass spectrometry was employed
      to map the extracellular, intracellular, and surface sub-proteomes of TB10839 and
      TB121838 and to identify differentially expressed proteins. About 4% of all
      detected protein spots were differentially expressed between both strains
      including absent or present spots and spots with a more than 2-fold changed
      intensity. This percentage reflects a relatively high degree of intraclonal
      variability. Many of the protein spots in TB10839 that were missing or expressed
      at lower levels in TB121838 were identified as quorum-sensing regulated virulence
      factors. It might be speculated that the increased expression of these proteins
      contributes to pathogenic competence of TB10839.

PMID- 15188393
TI  - Comparison of the proteome of Methylobacterium extorquens AM1 grown under
      methylotrophic and nonmethylotrophic conditions.
AB  - Methylobacterium extorquens AM1 is a facultative methylotrophic bacterium that is
      capable of growing in the presence of methanol as the sole carbon and energy
      source, but is also able to grow on a limited number of C(2), C(3), and C(4)
      compounds, for example succinate. This study provides a proteomic view of the
      cellular adaptation of M. extorquens AM1 to growth on methanol and succinate,
      respectively. Cytosolic proteins were separated by two-dimensional gel
      electrophoresis employing overlapping pH ranges and visualized by silver nitrate
      or fluorescence staining. A proteomic reference map containing 229 different
      proteins identified by peptide mass fingerprinting of tryptic fragments was
      established. Comparative proteome profiling of methanol- and succinate-grown
      cells led to the identification of 68 proteins that are induced under
      methylotrophic growth conditions in comparison to growth on succinate. This group
      includes most proteins known to be directly involved in methanol oxidation to
      CO(2) and in assimilation of one carbon units by the serine cycle as well as 18
      proteins without any assigned function and two proteins with a predicted
      regulatory function. Furthermore, the proteome analysis revealed putative
      isoenzymes for formaldehyde-activating enzyme Fae, malyl-CoA lyase, malate
      dehydrogenase, and fumarase, that need to be characterized functionally in future
      studies.

PMID- 15188394
TI  - Effect of high concentration of Co (II) on Enterobacter liquefaciens strain C-1:
      a bacterium highly resistant to heavy metals with an unknown genome.
AB  - Heavy metals are required as nutrients for essential functions in microorganisms.
      However, higher concentrations of these cations are generally toxic and may
      produce contrasting effects on living organisms. Enterobacter liquefaciens strain
      C-1, a bacterium isolated from the Moa mine in Cuba, is able to survive in the
      presence of high concentrations of heavy metals. The proteomes of Enterobacter
      liquefaciens strain C-1, grown under aerobic conditions in the presence and
      absence of Co (II) were compared using two-dimensional gel electrophoresis
      analysis in the isoelectric point range of 4-7 and the mass range of 15-120 kDa.
      Significant changes in the expression level (> two-fold) were detected for 13
      spots: seven and six were up- and down-regulated, respectively. Because the
      genome of this bacterium is unknown, identification by peptide mass
      fingerprinting only succeeded in four cases and most of the cross-species
      identifications were supported by de novo sequencing of tryptic peptides followed
      by sequence alignment using the MS BLAST program. Twelve different proteins were
      identified, ten are involved in cellular antioxidant defence probably induced by
      the presence of Co (II). This is the first step towards understanding the role of
      proteins participating in the mechanism of resistance to heavy metals in this
      bacterium.

PMID- 15188395
TI  - Proteome analysis of Madrid E strain of Rickettsia prowazekii.
AB  - Rickettsia prowazekii, an obligate intracellular Gram-negative bacterium, is the
      etiologic agent of epidemic typhus. The threat of typhus as a biological weapon
      lies in its stability in the dried louse feces and in its infection by inhalation
      of an aerosol. Consequently, it is listed as a select agent and warrants more
      research to understand its pathogenesis. Although the genomic DNA sequence of
      strain Madrid E has been completed, the actual expression of the individual
      protein has not been investigated. In order to provide a global view of the
      expressed protein profile, the whole cell lysate of purified rickettsia (Madrid E
      strain) was reduced, alkylated, and digested with trypsin. The total digest was
      characterized by a two-dimensional liquid chromatography mass spectrometry system
      and analyzed with a modified version of the ProteomeX workstation. A total of 252
      proteins out of 834 predicted protein-coding genes were identified, 238 proteins
      were identified by the detection of at least two unique peptides. Only 14
      proteins were identified by the detection of one unique peptide in all three
      separate analyses. Among the 238 proteins identified by multiple unique peptides,
      230 proteins were found in at least two of three separate analyses. The
      reproducible and convenient methodology and the information described here have
      provided a foundation for future proteome study of various R. prowazekii strains
      with different virulence.

PMID- 15188396
TI  - Setting up standards and a reference map for the alkaline proteome of the Gram
      positive bacterium Lactococcus lactis.
AB  - Despite the fact that almost 39% of the theoretical expressed proteins of
      Lactococcus lactis have a predicted isoelectric point above 7, these proteins
      have not been studied in previous proteome analyses. In the present study, we set
      up a reference map of alkaline lactococcal proteins by using immobilized pH
      gradients (IPG) spanning pH 6 to 12 and 9 to 12, and protein identification by
      matrix-assisted laser desorption/ionization-time of flight mass spectrometry
      (MALDI-TOF MS). Different electrophoresis systems for isoelectric focusing were
      evaluated to optimize the first dimension. Best results were obtained by sample
      application using cup-loading at the anodic side and increasing the final voltage
      up to 8000 V for IPGs, using N,N-dimethylacrylamide as monomer. After two
      dimensional gel electrophoresis of extracts obtained from exponentially growing
      cells, about 200 protein spots were selected for identification by peptide mass
      fingerprinting. With MALDI-TOF MS, 153 proteins were identified that were the
      products of 85 different genes. Their predicted isoelectric points range from as
      high as 11.31 to as low as 6.34. Ribosomal proteins, hypothetical proteins and
      proteins with unknown function represent the largest groups of identified
      proteins. For further classification, the codon adaptation index (CAI) and grand
      average of hydropathicity (GRAVY) for each lactococcal protein were calculated.
      The protein with the lowest CAI identified in this study is the manganese ABC
      transporter ATP-binding protein. Less than 10% of the alkaline lactococcal
      proteins have a smaller CAI. The highest GRAVY for an identified protein is 0.26.
      The complete in silico data of Lactococcus lactis as well as clickable reference
      maps are available at www.wzw.tum.de/proteomik/lactis.

PMID- 15188397
TI  - Web-accessible proteome databases for microbial research.
AB  - The analysis of proteomes of biological organisms represents a major challenge of
      the post-genome era. Classical proteomics combines two-dimensional
      electrophoresis (2-DE) and mass spectrometry (MS) for the identification of
      proteins. Novel technologies such as isotope coded affinity tag (ICAT)-liquid
      chromatography/mass spectrometry (LC/MS) open new insights into protein
      alterations. The vast amount and diverse types of proteomic data require adequate
      web-accessible computational and database technologies for storage, integration,
      dissemination, analysis and visualization. A proteome database system
      (http://www.mpiib-berlin.mpg.de/2D-PAGE) for microbial research has been
      constructed which integrates 2-DE/MS, ICAT-LC/MS and functional classification
      data of proteins with genomic, metabolic and other biological knowledge sources.
      The two-dimensional polyacrylamide gel electrophoresis database delivers
      experimental data on microbial proteins including mass spectra for the validation
      of protein identification. The ICAT-LC/MS database comprises experimental data
      for protein alterations of mycobacterial strains BCG vs. H37Rv. By formulating
      complex queries within a functional protein classification database "FUNC_CLASS"
      for Mycobacterium tuberculosis and Helicobacter pylori the researcher can gather
      precise information on genes, proteins, protein classes and metabolic pathways.
      The use of the R language in the database architecture allows high-level data
      analysis and visualization to be performed "on-the-fly". The database system is
      centrally administrated, and investigators without specific bioinformatic
      competence in database construction can submit their data. The database system
      also serves as a template for a prototype of a European Proteome Database of
      Pathogenic Bacteria. Currently, the database system includes proteome information
      for six strains of microorganisms.

PMID- 15188398
TI  - Towards a standardized human proteome database: quantitative proteome profiling
      of living cells.
AB  - Comparative proteome profiling, performed by two-dimensional polyacrylamide gel
      electrophoresis or multidimensional protein identification technology, usually
      relies on the relative comparison of samples of interest with respect to a
      reference. Currently, no standardized quantitative protein expression database of
      human cells, facilitating data comparisons between different laboratories,
      exists. Recently, we have published two-dimensional polyacrylamide gel
      electrophoresis-based techniques to assess absolute protein data comprising
      protein amounts, synthesis rates and biological half-lives (Mol. Cell. Proteomics
      2002, 1, 528-537). Determination of protein amounts by fluorography of two
      dimensional gels was followed by the exact quantification of the amount of
      incorporated (35)S radiolabel. Here we demonstrate an application of this highly
      standardized method to quiescent human T cells, phythaemagglutinin-stimulated T
      cells and Jurkat cells, a human T lymphoblast cell line. While the protein
      composition of quiescent T cells differed significantly compared to that of
      Jurkat cells, it was only slightly different compared to the activated T cells.
      Synthesis profile analyses demonstrated that activated T cells clearly differed
      from the quiescent cells, performing apparently almost like lymphoblast cells.
      The great sensitivity of this approach was further demonstrated with human
      umbilical vein endothelial cells treated for six hours with vascular endothelial
      growth factor. While no significant alteration of protein amounts was detected at
      all upon activation, the synthesis rate of several proteins was found to be more
      than doubled.

PMID- 15188399
TI  - Tumor suppressor Smad4 mediates downregulation of the anti-adhesive invasion
      promoting matricellular protein SPARC: Landscaping activity of Smad4 as revealed
      by a "secretome" analysis.
AB  - We have demonstrated previously that restoration of Smad4 expression in Smad4
      deficient SW480 human colon carcinoma cells was adequate to suppress
      tumorigenicity and invasive potential, whereas cell growth in vitro was not
      affected. Here we show that Smad4-positive and Smad4-negative SW480 cells deposit
      extracellular matrices in tissue culture which are functionally different with
      respect to their adhesiveness. We present a "differential secretomics analysis"
      as the most direct approach to identify the underlying alterations. The protein
      composition of conditioned media produced by Smad4-positive and Smad4-negative
      SW480 cells was compared by two-dimensional (2-D) gel electrophoresis. A major
      group of protein spots was detected in media derived from Smad4-negative cells,
      only, which were identified as "secreted protein, acidic and rich in cysteins"
      (SPARC) by mass spectrometry. SPARC expression in SW480 cells was suppressed by
      Smad4 at the level of transcription. SPARC is a glycoprotein of the extracellular
      matrix, characterized as an anti-adhesive and invasion-promoting protein.
      Differential secretomics appeared as a powerful method to identify a novel Smad4
      target gene, which may be one of the players involved in reduced adhesiveness of
      extracellular matrices and thus consistent with Smad4's emerging role as an
      invasion suppressor.

PMID- 15188400
TI  - Proteomic approach to the identification of voltage-dependent anion channel
      protein isoforms in guinea pig brain synaptosomes.
AB  - Voltage-dependent anion channel (VDAC) proteins are small, abundant, pore-forming
      proteins belonging to the eukaryotic mitochondrial porins. At least three
      different VDAC genes have been identified in vertebrates. VDAC proteins are known
      to play an essential role in cellular metabolism and in the early stages of
      apoptosis. A proteomic approach, consisting of two-dimensional gel
      electrophoresis followed by two-dimensional immunoblotting with anti-VDAC and
      anti-phosphotyrosine antibodies and by matrix-assisted laser
      desorption/ionization-time of flight mass spectrometry, was exploited to define
      the expression pattern of VDAC isoforms in guinea pig brain synaptosomes, both in
      normoxic and hypoxic conditions. In this way a total of five different VDAC
      isoforms were identified, as both VDAC1 and VDAC2 were detected in more than one
      electrophoretic spot. Moreover, VDAC isoforms selectively undergo hypoxia-induced
      tyrosine phosphorylation, suggesting that tyrosine phosphorylation may contribute
      to the modulation of VDAC protein function/conformation or interaction with other
      proteins in hypoxic conditions.

PMID- 15188401
TI  - Heterogeneous nuclear ribonucleoprotein A2/B1 identified as an autoantigen in
      autoimmune hepatitis by proteome analysis.
AB  - Our aim was to characterize antinuclear antibody (ANA) targets in type 1
      autoimmune hepatitis (AIH1) using a proteomic tool. ANA-positive sera from 29
      patients with AIH1 and 14 negative controls were analyzed by sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. The
      principal antigens identified were a 30 kDa triplet band which was recognized by
      79% of patient sera and 14% of control sera, and a 36 kDa antigen which was
      recognized by 52% and 14% of sera, respectively. The latter antigen was studied
      in more detail using two-dimensional electrophoresis (2-DE) and mass spectrometry
      (MS). Its identification corresponded to heterogeneous nuclear ribonucleoprotein
      A2/B1. This paper presents the first description of this protein as an antigen in
      AIH1.

PMID- 15188402
TI  - Proteins associated with type II bone morphogenetic protein receptor (BMPR-II)
      and identified by two-dimensional gel electrophoresis and mass spectrometry.
AB  - Bone morphogenetic proteins (BMP) are polypeptide growth factors that regulate
      cell differentiation and proliferation. BMPs bind to type I and type II
      serine/threonine kinase receptors to initiate intracellular signalling. BMPR-II
      is the type II receptor, its mutations lead to hereditary pulmonary hypertension,
      and knockout of Bmpr-II results in early embryonic lethality. To identify novel
      interacting proteins and explore signalling pathways that can be initiated by
      BMPR-II, we performed glutathione-S-transferase (GST) pull-down assays with BMPR
      II protein constructs fused to GST and extracts of mouse myoblast C2C12 cells. We
      generated three constructs which contain different parts of the cytoplasmic
      region of BMPR-II: full-length cytoplasmic part of BMPR-II, only the kinase
      domain, or only the C-terminal tail of BMPR-II. Proteins which formed complexes
      with these BMPR-II constructs were analyzed by two-dimensional gel
      electrophoresis (2-D GE), and specifically interacting proteins were identified
      by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry
      (MALDI-TOF-MS). We identified 33 interacting proteins; 11 proteins interacted
      with the C-terminal tail of BMPR-II, 4 with full-length BMPR-II, and 18 with a
      short form of the receptor with a deleted tail. Fourteen proteins have assigned
      functions in various signalling processes, suggesting links of BMP signalling to
      regulation of MAP kinase pathway, apoptosis, transcription, PKCss, and PKA. Five
      of the identified proteins are components of the cytoskeleton, and four are
      enzymes involved in metabolism, e.g., processing of estrogens or lipids. We
      confirmed interaction of PKC beta and CtBP with BMPR-II using immunodetection. We
      showed that the C-terminal tail of BMPR-II provides binding sites for a number of
      regulatory proteins that may initiate Smad-independent signalling.

PMID- 15188403
TI  - Proteomics analysis of human endothelial cell line EA.hy926 after exposure to GSM
      900 radiation.
AB  - The human endothelial cell line EA.hy926 was exposed to mobile phone radiation
      and the effect on protein expression was examined using two-dimensional
      electrophoresis (2-DE). Up to 38 various proteins have statistically
      significantly altered their expression levels following the irradiation. Four
      proteins were identified with matrix-assisted laser desorption/ionization-mass
      spectrometry (MALDI-MS). Two of the affected proteins were determined to be
      isoforms of cytoskeletal vimentin. This finding supports our earlier presented
      working hypothesis which indicated that the mobile phone radiation might affect
      the cytoskeleton and might have an effect on the physiological functions that are
      regulated by the cytoskeleton.

PMID- 15188404
TI  - Microheterogeneity of the major grass group 6 allergen Phl p 6: Analysis by mass
      spectrometry.
AB  - The precise structural characterization of allergens is a basic requirement to
      improve diagnostics and to find therapeutic strategies against allergic
      disorders. Natural grass pollen allergens exhibit a wide variety of isoforms and
      it is still unknown whether this microheterogeneity is essential for the allergic
      reaction or has a functional effect on sensitization. Well-defined recombinant
      allergens are considered to replace natural allergens for clinical trials. For
      the major timothy grass pollen allergen Phl p 6 (approximately 12 kDa) and a
      recombinant rPhl p 6 we determined the structural microheterogeneity by two
      dimensional electrophoresis (2-DE), high-resolution electrospray ionization
      Fourier transform-mass spectrometry (ESI-FT-MS) of the intact molecules, and by
      tryptic peptide mass fingerprinting using matrix-assisted laser
      desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Natural
      Phl p 6 is a mixture of mainly two isoforms that differ by two amino acids
      leading to a mass difference of 5 Da. For each of this two isoforms six variants
      were identified with modifications at the C- and/or N-terminus. The recombinant
      Phl p 6 comprises the same structure as one of the main isoforms indicating that
      it represents a major part of the natural Phl p 6.

PMID- 15188405
TI  - Proteomic investigation of natural variation between Arabidopsis ecotypes.
AB  - Two-dimensional (2-D) gel electrophoresis and peptide mass fingerprinting were
      used to investigate the natural variation in the proteome among 8 Arabidopsis
      thaliana ecotypes, of which 3 were previously shown to display atypical responses
      to environmental stress. Comparison of 2-D maps demonstrated that only one
      quarter of spots was shared by all accessions. On the other hand, only 15% of the
      25 majors spots accounting for half the total protein amount could be classified
      as major spots in all ecotypes. Identification of these major spots demonstrated
      large differences between the major functions detected. Accordingly, the
      proteomes appeared to reveal important variations in terms of function between
      ecotypes. Hierarchical clustering of proteomes according to either the amount of
      all anonymous spots, that of the 25 major spots or the functions of these major
      spots identified the same classes of ecotypes, and grouped the three atypical
      ecotypes. It is proposed that proteome comparison has the capacity to evidence
      differences in the physiological status of ecotypes. Results are discussed with
      respect to the possibility to infer such differences from limited comparisons of
      major proteins. It is concluded that classical proteomics could constitute a
      powerful tool to mine the biodiversity between ecotypes of a single plant
      species.

PMID- 15188406
TI  - A combination of different mass spectroscopic techniques for the analysis of
      dynamic changes of histone modifications.
AB  - The N-terminal tails of the histones are subject to many enzyme-mediated post
      translational modifications, such as lysine acetylation, lysine and arginine
      methylation, serine phosphorylation, poly-ADP ribosylation and the attachment of
      the small peptide ubiquitin. These modifications, singly or in combination, are
      thought to generate an epigenetic code that specifies different patterns of gene
      activity. We present a detailed study on the mapping of histone post
      translational modifications using a combination of matrix-assisted laser
      desorption/ionization-time of flight and electrospray ionization tandem mass
      spectrometry analysis of peptides generated by protease cleavage of individual
      histones isolated from different developmental stages. Due to their high content
      in basic amino acid residues and in order to be able to quantitatively compare
      two different samples we developed a chemical derivatization protocol. This
      strategy enabled us to determine the primary sequence of the peptides and to
      unambiguously assign specific modifications. This method is generally applicable
      to histone samples from various sources and can be used to study changes of
      modification patterns during early embryonic development or tissue
      differentiation and regeneration.

PMID- 15188407
TI  - Convenient and versatile subcellular extraction procedure, that facilitates
      classical protein expression profiling and functional protein analysis.
AB  - Standardized sample preparation to reduce proteome complexity facilitates
      subsequent proteome analysis. Here we describe a robust sequential extraction
      method that enables simple fractionation of proteins in their native state
      according to their subcellular localization, yielding four subproteomes enriched
      in (a) cytosolic; (b) membrane and membrane organelle-localized; (c) soluble and
      DNA-associated nuclear and (d) cytoskeletal proteins. Efficiency and selectivity
      is demonstrated by morphological-, two-dimensional electrophoresis image-,
      immunological- as well as enzymatic-analysis. In pilot studies, subcellular
      redistribution of regulatory proteins was successfully measured.

PMID- 15188408
TI  - Nondenaturing two-dimensional electrophoresis enzyme profile involving activity
      and sequence structure of cytosol proteins from mouse liver.
AB  - After cytosol proteins in the mouse liver were separated by nondenaturing two
      dimensional electrophoresis (2-DE), activities of several enzymes, such as
      fructose bisphosphatase, sorbitol dehydrogenase and malate dehydrogenase,
      transferase and sorbitol dehydrogenase, or several dehydrogenases, were analyzed
      on the same 2-D gel. Further, peptidase (or protease) activity can be examined by
      matrix-assisted laser desorption/ionization-time of flight-mass spectrometry
      (MALDI-TOF-MS) when peptides such as angiotensin and adenocorticotropic hormone
      are incubated in the presence of the cytosol protein separated by nondenaturing 2
      DE. Sequence structures of proteins on the 2-D gel were analyzed by peptide mass
      fingerprinting using MALDI-TOF-MS or by peptide sequencing using electrospray
      ionization-tandem mass spectrometry (ESI-MS/MS). The combination of activity and
      sequence structure accurately verified the position and activity range of the
      separated enzymes on the nondenaturing 2-D gel. From these results, we created a
      nondenaturing 2-D enzyme profile involving activities and sequence structure of
      cytosol proteins from mouse liver. This profile can be used for checking whether
      activities of enzymes were specifically or nonspecifically inhibited by
      inhibitors.

PMID- 15188409
TI  - A comprehensive approach for establishment of the platform to analyze functions
      of KIAA proteins: generation and evaluation of anti-mKIAA antibodies.
AB  - Since December 2001 we have been conducting a project to isolate and determine
      entire sequences of mouse KIAA cDNA clones which encode polypeptides
      corresponding to human KIAA proteins. The ultimate goal of this project is the
      elucidation of the functions of KIAA proteins. A critical step in this project is
      the generation of antibodies based on the cDNA sequence information. Although
      antibodies are the most optimal tools for biological analysis, the production and
      isolation of multiple recombinant proteins for an antigen is a rate-limiting step
      in antibody production. To address this problem, we established a system
      utilizing the in vitro recombination-assisted method and shotgun clones that were
      generated during the sequencing of mouse KIAA cDNAs (DNA Res. 2003, 10, 129-136).
      The authenticity of the expressed proteins was confirmed by matrix-assisted laser
      desorption/ionization-time of flight mass spectrometry. Another critical step for
      antibody production is the evaluation of the antibodies. Thus, we also made
      efforts to develop a systematic approach for evaluation of the titer and the
      specificity of the antibodies. Using these systems, we have produced and
      evaluated more than 500 antibodies raised against mouse KIAA proteins to date. We
      are currently generating antibody arrays for analysis of protein expression
      profiles. We will verify protein-protein interactions using immunoprecipitation
      and tandem mass spectrometry analysis.

PMID- 15188410
TI  - Double chip protein arrays using recombinant single-chain Fv antibody fragments.
AB  - Protein arrays permit the parallel analysis of many different markers in a small
      sample volume. However, the problem of cross-reactivity limits the degree of
      multiplexing in parallel sandwich immunoassays (using monoclonal antibodies
      (mAbs)), meaning antibodies must be prescreened in order to reduce false
      positives. In contrast, we use a second chip surface for the local application of
      detection antibodies, thereby efficiently eliminating antibody cross-reactions.
      Here, we illustrate the potential advantages of using single-chain Fv fragments
      rather than mAbs as capture and detection molecules with this double chip
      technology.

PMID- 15188411
TI  - Determining a significant change in protein expression with DeCyder during a pair
      wise comparison using two-dimensional difference gel electrophoresis.
AB  - Two-dimensional difference gel electrophoresis (DIGE) is a tool for measuring
      changes in protein expression between samples involving pre-electrophoretic
      labeling with cyanine dyes. Here we assess a common method to analyze DIGE data
      using the DeCyder software system. Experimental error was studied by a series of
      same sample comparisons. Aliquots of sample were labeled with N-hydroxyl
      succinimidyl ester-derivatives of Cy2, Cy3, and Cy5 dyes and run together on one
      gel. This allowed assessment of how experimental error influenced differential
      expression analysis. Bias in the log volume ratios was observed, which could be
      explained by differences in dye background. Further complications are caused by
      significant gel-to-gel variation in the spot volume ratio distributions. Using
      DeCyder alone results in an inability to define ratio thresholds for 90 or 95%
      confidence. An alternative normalization method was thus applied which resulted
      in improved data distribution and allowed greater sensitivity in analysis. When
      combined with a standardizing function, this allowed gel-independent thresholds
      for 90% confidence. The new approach, detailed here, represents a method to
      greatly improve the success of DIGE data analysis.

PMID- 15188412
TI  - Differential phosphoproteome profiling by affinity capture and tandem matrix
      assisted laser desorption/ionization mass spectrometry.
AB  - Protein phosphorylation is a ubiquitous post-translational modification that
      affects a significant subset of the proteome and plays an especially important
      role in signal transduction and cell cycle control in eukaryotic organisms.
      Recently developed methods that couple multidimensional liquid chromatography to
      electrospray mass spectrometers can be used to analyze entire phosphoproteomes.
      However, they require considerable investments and technical skills that are only
      available in a few highly specialized laboratories. These methods also appear to
      be biased. Statistical analyses show that peptides from abundant proteins and
      multiply phosphorylated peptides are disproportionately identified. We describe
      an economic alternative that utilizes a phospho-affinity step to isolate the
      intact phosphoproteins. These are subsequently characterized by electrophoresis
      and identified by direct de novo sequencing using tandem mass spectrometry. We
      applied this technique to probe signal-induced changes in the phosphoproteome of
      human U937 cells, and found that the pools of two cancer-related phosphoproteins
      implicated in intracellular hormones signaling are dramatically altered in the
      course of monocyte to macrophage differentiation.

PMID- 15188414
TI  - Brain proteome of mice lacking the receptors for tumor necrosis factor alpha.
AB  - Tumor necrosis factor alpha (TNF alpha) is involved in regulation of food intake,
      inflammatory response, and cancer cachexia. Its actions are mediated by at least
      two receptors: TNFR1 and TNFR2. We show that mice lacking the TNF alpha receptors
      have altered levels of proteins that take part in signal transduction, stress
      response, protein folding, glucose and amino acid metabolism, vesicle
      trafficking, and cytoskeletal arrangements. This is the first time that some of
      them have been associated with TNF alpha signaling pathways.

PMID- 15188413
TI  - RELIC--a bioinformatics server for combinatorial peptide analysis and
      identification of protein-ligand interaction sites.
AB  - Phage display technology provides a versatile tool for exploring the interactions
      between proteins, peptides and small molecule ligands. Quantitative analysis of
      peptide population sequence diversity and bias patterns has the power to
      significantly enhance the impact of these methods [1, 2]. We have developed a
      suite of computational tools for the analysis of peptide populations and made
      them accessible by integrating fifteen software programs for the analysis of
      combinatorial peptide sequences into the REceptor LIgand Contacts (RELIC)
      relational database and web-server. These programs have been developed for the
      analysis of statistical properties of peptide populations; identification of weak
      consensus sequences within these populations; and the comparison of these peptide
      sequences to those of naturally occurring proteins. RELIC is particularly suited
      to the analysis of peptide populations affinity selected with a small molecule
      ligand such as a drug or metabolite. Within this functional context, the ability
      to identify potential small molecule binding proteins using combinatorial peptide
      screening will accelerate as more ligands are screened and more genome sequences
      become available. The broader impact of this work is the addition of a novel
      means of analyzing peptide populations to the phage display community.

PMID- 15188415
TI  - A proteomic view of cell physiology of Bacillus licheniformis.
AB  - The still ongoing sequencing of Bacillus licheniformis at the Gottingen
      Sequencing Laboratory provides the basis for proteome studies of the bacterium.
      By using two-dimensional (2-D) electrophoresis and protein identification by mass
      spectrometry, we were able to create master gels for B. licheniformis cells grown
      either in minimal medium or in complex medium containing about 300 and 180
      entries, respectively. With the DECODON Delta 2D software we identified the most
      abundant protein spots on the gels, which were shown to perform mainly basic
      metabolic functions in the cell such as translation, amino acid metabolism,
      glycolysis, and tricarboxylic acid (TCA) cycle. Based on the master gels, we were
      able to study the regulation of metabolic pathways such as glycolysis and TCA
      cycle. In cells grown in the presence of glucose a significant increase of the
      amount of some glycolytic enzymes (TpiA, GapA, Pgk, Pgm, Eno, Pyk) and of the
      pyruvate dehydrogenase (PdhA-D) was found. At the same time, there is a strong
      repression of almost all TCA cycle enzymes and of the ATP synthase. Glucose also
      stimulates the acetate kinase (AckA) and the phosphotransacetylase (Pta) which
      are known to be involved in the overflow metabolism in B. subtilis. Furthermore,
      we began developing proteomic signatures for growth of B. licheniformis in
      complex medium. For this purpose, we compared the proteome pattern of
      exponentially growing cells with that of cells in different stages during
      stationary phase. The most obvious proteomic signature indicates that cells
      during stationary phase are subjected to a severe oxidative stress and a
      resulting protein stress. Furthermore, the level of many vegetative proteins is
      strongly reduced when the growth is arrested after entry into stationary phase.
      The data indicate that proteomics can be a valuable tool to describe the
      physiological state of B. licheniformis cell populations, e.g., of cells growing
      in a bioreactor.

PMID- 15188416
TI  - A proteome reference map for Vibrio cholerae El Tor.
AB  - A proteome reference map has been constructed for Vibrio cholerae El Tor, in the
      pI range of 4.0 to 7.0. The map is based on two-dimensional gels (2-D) and the
      identification, by peptide mass fingerprint, of proteins in 94 spots,
      corresponding to 80 abundant proteins. Two strains are compared, strain N16961
      and a Latin American El Tor strain C3294. The consensus map contains 340 spots
      consistently seen with both strains grown in Luria-Bertani broth (LB) or minimal
      M9 medium. The results were obtained from nine gels run with 18 cm immobilized pH
      gradient strips and precast gels. The 2-D gels were anchored to real N16961
      proteins identified by mass spectrometry. Various energy metabolism components
      and periplasmic ATP-binding cassette (ABC) transporter proteins were identified
      among the abundant proteins. Two isoforms of OmpU were found. Five operons are
      proposed and seven hypothetical proteins were experimentally confirmed.
      Comparisons are made with protein 2-D gels for a classical strain and to
      microarray analysis available for the N16961 El Tor strain. New results were
      obtained from the proteome analysis, indicating an abundance of periplasmic ABC
      transporter proteins not found in microarray studies.

PMID- 15188417
TI  - Intregrated analysis of the human cardiac transcriptome, proteome and
      phosphoproteome.
AB  - Altered expression of different classes of genes has been shown to differentiate
      between failing and nonfailing human hearts. However, characterization of
      proteins and the post-translational modifications that regulate their functions
      is required for understanding both the physiology of cardiac muscle and the
      mechanisms leading to pathological states associated with cardiac diseases. We
      present in this paper, an analysis of the human cardiac transcriptome, proteome
      and phosphoproteome. Data from two sources (i) experiments performed in our
      laboratory and (ii) bioinformatics searches of public databases (SWISS-PROT,
      NCBI, Cardiac Gene Expression Knowledge Base, Gene Ontology Consortium and
      Affymetrix) are reported in a relational database that allows user-designed
      specific queries. Microarray experiments were performed with Affymetrix Hu95Av2.
      Cardiac proteins were digested with trypsin. An 11 step cation exchange procedure
      produced fractions for analysis in separate reversed phase high-performance
      liquid chromatography-tandem mass spectrometry (MS/MS) experiments. Immobilized
      metal affinity chromatography was used to select the phosphopeptides from the
      same tryptic peptide mixture. They were then further investigated by MS/MS. Gel
      free approaches were used to detect 267 proteins and 47 phosphopeptides. Our
      human cardiac database contains 447 entries. We propose the use of this platform,
      built with data derived from nonfailing hearts, as a template for initiating the
      effort to characterize the human cardiac proteome and its associated post
      translational modifications.

PMID- 15188423
TI  - Proteomic Forum 2003. Proceedings of the international meeting on proteome
      analysis. September 14-17, 2003, Munich, Germany.

PMID- 15188424
TI  - A bigger bang for your buck: enhanced access to your chick data.

PMID- 15188425
TI  - Basic leucine zipper transcription factors C/EBP and MafL in the hydrozoan
      jellyfish Podocoryne carnea.
AB  - Members of the CCAAT/enhancer binding protein (C/EBP) and the Maf protein
      subfamilies have been characterized in a variety of bilaterian organisms. This is
      the first report of C/EBP and MafL genes in a basal organism, the hydrozoan
      jellyfish Podocoryne carnea. Transcripts of both genes are present in all life
      cycle stages: egg, embryo, larva, polyp, and medusa. During early development,
      both factors appear to regulate metamorphosis of the larva to the primary polyp.
      Both genes are also expressed in the striated muscle of the developing and adult
      medusa. During in vitro transdifferentiation of striated muscle cells to smooth
      muscle and nerve cells, C/EBP is continuously expressed, whereas MafL expression
      is turned off during transdifferentiation and reactivated when nerve cells
      differentiate. Thus, both factors may be involved in muscle and nerve cell
      differentiation. In the mature medusa both genes are also implicated in
      gametogenesis. Developmental and evolutionary aspects of the gene structures and
      expression patterns are discussed.

PMID- 15188426
TI  - Two Frodo/Dapper homologs are expressed in the developing brain and mesoderm of
      zebrafish.
AB  - Members of the Wnt family of extracellular proteins play essential roles during
      many phases of vertebrate embryonic development. The molecular mechanism of their
      action involves a complex cascade of intracellular signaling events, which
      remains to be understood completely. Recently, two novel cytoplasmic modulators
      of Wnt signaling, Frodo and Dapper, were identified in Xenopus. We report
      isolation of their homologs in zebrafish, and show that these genes, frd1 and
      frd2, are expressed in restricted domains during embryogenesis. Both genes are
      expressed during early gastrulation in the future mesendoderm, and continue to be
      expressed in distinct patterns in the forming neurectoderm and mesoderm.
      Comparative sequence analysis and similar expression patterns argue that frd1 is
      the zebrafish ortholog of Frodo and Dapper, whereas frd2 is a more divergent
      member of the same family. Our data suggest important roles for zebrafish frd1
      and frd2 in patterning the neural plate and several mesodermal derivatives.

PMID- 15188427
TI  - Functional link between retinoblastoma family of proteins and the Wnt signaling
      pathway in mouse epidermis.
AB  - The retinoblastoma family of proteins (pRb, p107, and p130) modulates cell cycle
      progression and differentiation of several tissues. We have demonstrated recently
      that p107 and p130 regulate keratinocyte terminal differentiation and hair
      follicle morphogenesis and development in vivo. This last aspect appears to be
      mediated by defective signaling from the mesenchyme and is associated with
      altered bone morphogenetic protein-4 (BMP4) -dependent signaling. However, many
      alterations were also found in the epithelial compartment. Given the importance
      of betacatenin in hair biology and in BMP signaling, we studied its expression in
      p107/p130-deficient skin. Although normal expression of betacatenin was found in
      p107/p130-deficient hair follicles, we found increased nuclear accumulation of
      betacatenin in the basal keratinocytes of the p107/p130-deficient mice skin.
      Biochemical analysis revealed that such an increase in betacatenin was due to the
      disruption of Axin/GSK3beta/betacatenin complexes promoted by the increased
      expression of Frat, the mouse homologue of GSK3betabinding protein (GBP), in
      epidermis, precluding the degradation of betacatenin. Collectively, these data
      represent the first evidence that retinoblastoma family and Wnt signaling
      pathways might be interconnected by functional links in skin.

PMID- 15188428
TI  - Genetic interactions underlying otic placode induction and formation.
AB  - The formation of the otic placode is a complex process requiring multiple
      inductive signals. In zebrafish, fgf3 and fgf8, dlx3b and dlx4b, and foxi1 have
      been identified as the earliest-acting genes in this process. fgf3 and fgf8 are
      required as inductive signals, whereas dlx3b, dlx4b, and foxi1 appear to act
      directly within otic primordia. We have investigated potential interactions among
      these genes. Depletion of either dlx3b and dlx4b or foxi1 leads to a delay of
      pax2a expression in the otic primordia and reduction of the otic vesicle.
      Depletion of both foxi1 and dlx3b results in a complete ablation of otic placode
      formation. A strong synergistic interaction is also observed among foxi1, fgf3,
      and fgf8, and a weaker interaction among dlx3b, fgf3, and fgf8. Misexpression of
      foxi1 can induce expression of pax8, an early marker for the otic primordia, in
      embryos treated with an inhibitor of fibroblast growth factor (FGF) signaling.
      Conversely, morpholino knockdown of foxi1 blocks ectopic pax8 expression and otic
      vesicle formation induced by misexpression of fgf3 and/or fgf8. The observed
      genetic interactions suggest a model in which foxi1 and dlx3b/dlx4b act in
      independent pathways together with distinct phases of FGF signaling to promote
      otic placode induction and development.

PMID- 15188429
TI  - Vertebrate crossveinless 2 is secreted and acts as an extracellular modulator of
      the BMP signaling cascade.
AB  - In vertebrates and invertebrates, BMP/Dpp (Bone Morphogenetic
      Protein/Decapentaplegic) signaling regulates the orchestrated processes of
      embryogenesis. Recent studies have revealed that BMP/Dpp signaling is controlled
      extracellularly as well as intracellularly. One extracellular regulatory molecule
      is the Chordin/Short gastrulation protein (Chordin/Sog), a secreted protein that
      acts as an antagonist to BMP/Dpp. Chordin/Sog contains four cysteine-rich (CR)
      domains that bind to and inactivate BMP/Dpp. In contrast, a positive regulator
      has been identified in Drosophila. Named crossveinless 2 (cv-2), this molecule
      contains five CR domains at the N-terminal half and a von Willebrand factor D
      domain at the C-terminal part. Genetic data suggest that Cv-2 potentiates Dpp
      signaling. We isolated chick and mouse CV-2 genes and found that CV-2 is secreted
      and enhances BMP signaling. Expression patterns were closely related to those of
      BMPs, supporting the likelihood of a tight link. Our data show for the first time
      that CV-2 is a conserved, positive regulator of BMP signaling and that CR domain
      proteins act as both positive and negative modulators of BMP signaling.

PMID- 15188430
TI  - Msx1 disruption leads to diencephalon defects and hydrocephalus.
AB  - We have analyzed the expression of the Msx1 gene in the developing mouse brain
      and examined the brain phenotype in homozygotes. Msx1 is expressed in every
      cerebral vesicle throughout development, particularly in neuroepithelia, such as
      those of the fimbria and the medulla. Timing analysis suggests that Msx1(nLacZ)
      cells delaminate and migrate radially from these epithelia, mainly at embryonic
      days 14-16, while immunohistochemistry studies reveal that some of the beta
      galactosidase migrating cells are oligodendrocytes or astrocytes. Our results
      suggest that the Msx1 neuroepithelia of fimbria and medulla may be a source of
      glial precursors. The Msx1 mutants display severe hydrocephalus at birth, while
      the subcommissural organ, the habenula, and the posterior commissure fail to
      develop correctly. No label was detected in the mutant subcommissural organ using
      a specific antibody against Reissner's fiber. Besides, the fasciculus retroflexus
      deviates close to the subcommissural organ, while the paraventricular thalamic
      nucleus shows histological disorganization. Our results implicate the Msx1 gene
      in the differentiation of the subcommissural organ cells and posterior commissure
      and that Msx1 protein may play a role in the pathfinding and bundling of the
      fasciculus retroflexus and in the structural arrangement of the paraventricular
      thalamic nucleus.

PMID- 15188431
TI  - Independent induction and formation of the dorsal and ventral fins in Xenopus
      laevis.
AB  - It has been known since the 1930s that the dorsal fin is induced by the
      underlying neural crest. The inducer of the ventral fin, however, has remained
      elusive. We have investigated the source of the inducer of the ventral fin in
      Xenopus and show that it is the ventral mesoderm and not the neural crest. This
      induction takes place during mid-neurula stages and is completed by late
      neurulation. In terms of cell composition, the dorsal fin mesenchyme core arises
      from neural crest cells, while the mesenchyme of the ventral fin has a dual
      origin. The ventral fin contains neural crest cells that migrate in from the
      dorsal side of the embryo, but a contribution is also made by cells from the
      ventral mesoderm.

PMID- 15188433
TI  - Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish.
AB  - We mined the zebrafish genomic sequence database and identified contigs
      containing segments of several dopamine receptor genes. By using a polymerase
      chain reaction amplification strategy, we generated full-length cDNAs encoding a
      single dopamine D3 receptor and three distinct D2 receptor subtypes. Zebrafish
      dopamine receptor genes were mapped by using the T51 radiation hybrid panel. The
      D3 receptor gene (drd3) mapped to linkage group (LG) 24. The three D2 receptor
      genes were localized to LG 15 (drd2a), LG 16, (drd2b), and LG 5 (drd2c). With the
      exception of the drd2b gene, each of these map positions was syntenic with
      regions of human chromosomes containing orthologs of the zebrafish dopamine
      receptor genes. Whole-mount in situ hybridization was used to investigate
      expression of the D2 and D3 receptor genes. Expression of the drd3 gene was first
      detected at mid-somitogenesis and was particularly prominent in somites.
      Thereafter, the drd3 gene was expressed diffusely throughout the brain and spinal
      cord. The three D2 receptor genes were expressed throughout the central nervous
      system (CNS) in distinct but overlapping patterns. In early embryos, the drd2a
      gene was expressed exclusively in the epiphysis, whereas the drd2c gene was
      localized to the notochord. After 24 hpf, the drd2a, drd2b, and drd2c genes were
      differentially expressed throughout the CNS. The identification of dopamine
      receptor genes in zebrafish should allow us to use the power of zebrafish
      genetics to analyze the functional properties of this important class of
      neurotransmitter receptors.

PMID- 15188432
TI  - Influence of endostatin on embryonic vasculo- and angiogenesis.
AB  - The proteolytic fragment of collagen XVIII, endostatin, acts as an inhibitor of
      angiogenesis. To date, only limited knowledge exists on the effects of endostatin
      on endothelial cells during embryonic development. Therefore, we analysed the
      role of endostatin on embryonic vasculo- and angiogenesis. Endostatin is
      accumulated in embryonic tissue of mouse embryos. Similarly, in vessels of
      embryoid bodies (EBs), endostatin and its binding sites are distributed in
      vessels and sprouting areas. In EBs, endostatin increases endothelial cells
      (control, 279.3 +/- 76.5; 50 ng/ml, 566.3 +/- 90.1; 200 ng/ml, 594.5 +/- 166.3
      tube-like structures per EB) and endothelial tubes by proliferation (control,
      21.4 +/- 7.5; 50 ng/ml, 160.2 +/- 9.9; 200 ng/ml, 184.2 +/- 16.5 Ki67-positive
      nuclei per 50 tube-like structures); it also enhances migration (control, 380.5
      +/- 159.8 cells; 50 ng/ml, 718.3 +/- 251 cells; 200 ng/ml, 706 +/- 89.4 cells)
      and apoptosis (control, 16.8 +/- 6.7; 50 ng/ml, 94.4 +/- 23.6; 200 ng/ml, 106 +/-
      42 PARP-positive nuclei per 50 tube-like structures). Furthermore, endostatin
      modulates the morphology of the endothelial tubes by inducing contraction.
      Endostatin modulates the embryonic vascular development by enhancing
      proliferation, migration, and apoptosis as well as by regulating morphogenesis.

PMID- 15188434
TI  - Functional and hierarchical interactions among zebrafish vox/vent homeobox genes.
AB  - The vertebrate Vox/Vent family of transcription factors plays a crucial role in
      the establishment of the dorsoventral (DV) axis, by repressing organizer genes
      such as bozozok/dharma, goosecoid, and chordino. In Danio rerio (zebrafish),
      members of the vox/vent gene family (vox/vega1, vent/vega2, and ved) are thought
      to share expression patterns and functional properties. Bringing novel insights
      in the differential activity of the zebrafish vox/vent genes, we propose a
      critical role for the ved gene in DV patterning of vertebrate embryos. ved is not
      only expressed as a maternal gene, but it also appears to function as a repressor
      of dorsal factors involved in organizer formation. At early- and mid-gastrula
      stage, ved appears to be finely controlled by antagonist crosstalks in a complex
      regulatory network, involving gradients of bone morphogenetic protein (BMP)
      activity, dorsal factors, and vox/vent family members. We show that ved
      transcripts are ventrally restricted by BMP factors such as bmp2b, bmp7, smad5,
      and alk8, and by dorsal factors (chd and gsc). Alteration of ved expression in
      both vox and vent deletion mutants and vox and vent mRNAs-injected embryos,
      suggests that vox and vent function downstream of BMP signaling to negatively
      regulate ved expression. This inhibitory role is emphasized by a vox and vent
      redundant activity, compared with single gene effects.

PMID- 15188435
TI  - Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and
      a comparative analysis of the Cyp26 enzymes.
AB  - We have cloned a novel retinoic acid (RA) catabolizing enzyme, Cyp26C1, in the
      chick and describe here its distribution during early stages of chick
      embryogenesis. It is expressed from stage 4 in the presumptive anterior
      (cephalic) mesoderm, in a subset of cephalic neural crest cells, the ventral otic
      vesicle, mesenchyme adjacent to the otic vesicle, the branchial pouches and
      grooves, a part of the neural retina, and the anterior telencephalon, and shows a
      dynamic expression in the hindbrain rhombomeres and neuronal populations within
      them. By examining the distribution of Cyp26C1 in the RA-free quail embryo, we
      can determine which of these expression domains is dependent on RA, and it is
      only the rhombomeric sites that do not appear, suggesting a role for RA in this
      location. The most striking domain of Cyp26C1 distribution is in the anterior
      cephalic mesoderm, which is adjacent to the domain of Raldh2 in the trunk
      mesoderm, but separated from it by a gap dorsal to which the posterior hindbrain
      will develop. We suggest that a gradient of RA within the mesoderm generated by
      Raldh2 and catabolized by Cyp26C1 could be responsible for patterning the
      hindbrain. We have compared this distribution of Cyp26C1 with that of Cyp26A1 and
      Cyp26B1 in the chick and shown that they generally occupy nonoverlapping sites of
      expression in the embryo, and as a result, we suggest individual roles for each
      of the Cyp enzymes in the developing embryo.

PMID- 15188437
TI  - Laser capture microdissection (LCM) for analysis of gene expression in specific
      tissues during embryonic epithelial-mesenchymal transformation.
AB  - The analysis of gene expression in developing organs is a valuable tool for the
      assessment of genetic fingerprints during the various stages of tissue
      differentiation and epithelial-mesenchymal transformation (EMT). However, the
      variety of differentiating cells and the close association of epithelial and
      mesenchymal cells makes it difficult to extract protein and mRNA from specific
      cells and tissue and, thus, to assign expressed genes to specific cell
      populations. We report here the analysis of LEF1 mRNA in epithelial and
      mesenchymal cells isolated by LCM from different stages of EMT during development
      of the mouse palate and describe our techniques in detail. By applying a laser
      capture microdissection (LCM) technique and real-time polymerase chain reaction,
      we were able to determine mRNA levels that accurately reflect changes in gene
      expression in specific cells. The sensitivity of the technique is remarkable.
      Indeed, the mRNAs can be detected for many proteins too low in abundance to stain
      with antibodies. These techniques will enable embryologists to collect
      homogeneous groups of cells from heterogeneous populations in developing organs,
      which otherwise would not be available for gene analysis.

PMID- 15188436
TI  - Regional distribution of alpha9beta1 integrin within the limbus of the mouse
      ocular surface.
AB  - The epithelial basal cells of the corneal limbus are known to contain adult
      corneal epithelial stem cells, but the properties of these cells are not well
      understood. In addition, how and when the limbal epithelium forms during
      postnatal development in mammals is not clear. To better understand the anatomy
      and cell biology of the limbus, a whole-mount procedure was used to show that the
      nasal, inferior, temporal, and superior regions of the mouse limbus contain
      different numbers of alpha9 integrin-positive cells most of which are observed in
      the nasal region. We also show that this pattern develops progressively over time
      from 1 to 8 weeks after birth. High magnification image projections and three
      dimensional reconstructions of the limbal region were generated from confocal
      images obtained after tissues were dual stained with alpha9 integrin and
      propidium iodide (PI) or triple stained with alpha9 integrin, E-cadherin, and PI.
      Data show that alpha9 integrin is present on the adult mouse cornea in the limbal
      basal cells and is more abundant in the apical-most cytoplasm of the limbal basal
      cells, where it can be found colocalized within the plasma membrane with E
      cadherin. These studies are an important step toward improving our understanding
      of the development and cell biology of limbal basal cells.

PMID- 15188438
TI  - spoonbill, a new Drosophila female-sterile mutation, interferes with chromosome
      organization and dorsal-ventral patterning of the egg.
AB  - We have identified a new mutation, spoonbill (spoon), which interferes with two
      developmental processes during Drosophila oogenesis, nurse cell-nuclei chromatin
      organization and anterior-dorsal patterning of the eggshell. Here, we describe
      the localization patterns of key regulators of axis determination and the
      expression of follicle cell-specific markers involved in eggshell patterning in
      egg chambers from spoonbill females. Our molecular characterization of the
      patterning defects associated with the mutation reveals abnormalities in two
      major signaling pathways, the grk/Egfr and the Dpp/TGF-beta, that together
      control the elaborate patterning of the anterior follicular epithelium. The
      function of spoonbill appears to be required for dpp transcription in a
      specialized population of follicle cells and for the selective transport of grk
      mRNA from the nurse cells into the oocyte, as well as for its proper localization
      and translation. This finding places the spoonbill gene upstream of both
      pathways.

PMID- 15188439
TI  - Zinc finger gene fez-like functions in the formation of subplate neurons and
      thalamocortical axons.
AB  - fez-like (fezl) is a forebrain-expressed zinc finger gene required for the
      formation of the hypothalamic dopaminergic and serotonergic (monoaminergic)
      neurons in zebrafish. To reveal its function in mammals, we analyzed the
      expression of the mouse orthologue of fezl and generated fezl-deficient mice by
      homologous recombination. Mouse fezl was expressed specifically in the forebrain
      from embryonic day 8.5. At mid-gestation, fezl expression was detected in
      subdomains of the forebrain, including the dorsal telencephalon and ventral
      diencephalon. Unlike the zebrafish fezl mutant too few, the fezl-deficient mice
      displayed normal development of hypothalamic monoaminergic neurons, but showed
      abnormal "hyperactive" behavior. In fezl(-/-) mice, the thalamocortical axons
      (TCA) were reduced in number and aberrantly projected to the cortex. These
      mutants had a reduced number of subplate neurons, which are involved in guiding
      the TCA from the dorsal thalamus, although the subplate neurons were born
      normally. These results suggest that fezl is required for differentiation or
      survival of the subplate neurons, and reduction of the subplate neurons in fezl
      deficient mice leads to abnormal development of the TCA, providing a possible
      link between the transcriptional regulation of forebrain development and
      hyperactive behavior.

PMID- 15188440
TI  - Novel metalloprotease-disintegrin, meltrin epsilon (ADAM35), expressed in
      epithelial tissues during chick embryogenesis.
AB  - Members of the ADAM (a disintegrin and metalloprotease) family are involved in
      fertilization, morphogenesis, and pathogenesis. Their metalloprotease domains
      mediate limited proteolysis, including ectodomain shedding of membrane-anchored
      growth factors and intercellular-signaling proteins, and their disintegrin
      domains play regulatory roles in cell adhesion and migration. In screening for
      cDNAs encoding chicken ADAM proteins expressed during muscle development, we
      identified Meltrin epsilon as a novel member of this family. To elucidate its
      functions, we investigated its expression during development by using antibodies
      raised against its protease domain. In the somites, Meltrin epsilon protein was
      specifically expressed in the myotomal cells, which delaminate from the
      dermomyotome to form epithelial sheets. It was also found in the surface
      ectoderm, lens placodes, otic vesicles, and the gut epithelia. Basolateral
      localization of Meltrin epsilon in these epithelial cells suggests its unique
      roles in the organization of the epithelial tissues and development of the
      sensory organs and the gut.

PMID- 15188441
TI  - Isoforms vatB1 and vatB2 of the vacuolar type ATPase subunit B are differentially
      expressed in embryos of the zebrafish (Danio rerio).
AB  - The v-type ATPase is a membrane anchored, multi-subunit proton pump, which in
      freshwater fish appears to play a major role in ionoregulative processes in the
      apical membrane of specialized gill cells. Very little is known about free-living
      fish embryos and larvae that are exposed to hypo-osmotic conditions with spawning
      but do not have their gills fully developed. By using reverse transcriptase
      polymerase chain reaction and immunological methods, we could demonstrate the
      presence of two isoforms of the subunit B of this v-type ATPase in the early
      development of the zebrafish. Immunohistochemical analysis revealed the presence
      of one isoform (vatB1) in the apical membrane of embryonic skin cells, while
      vatB2 has been found ubiquitously. This differential localization of the two
      isoforms supports the hypothesis that vatB1 is preferentially involved in
      ionoregulative functions, while vatB2 may be preferentially responsible for
      acidification of intracellular vesicles.

PMID- 15188442
TI  - Expression of tbx20 RNA during chick heart development.
AB  - The T-box gene family encodes a set of transcription factors that are involved in
      various developmental processes. We isolated tbx20 gene from chick embryos and
      examined in detail its expression patterns during heart development. In situ
      hybridization showed that tbx20 was expressed in the lateral plate mesoderm and
      subsequently in the primitive heart tube. At stages of looped heart, tbx20 was
      localized in the outflow tract (OT) and atrioventricular (AV) canal, in which
      valvuloseptal endocardial cushion develops. At later stages, although tbx20 was
      expressed predominantly in the nascent right ventricle, transcripts of tbx20 were
      down-regulated in the left ventricle. These results suggest that tbx20 may play
      important roles in a variety of developmental processes in cardiogenesis, such as
      chamber-specification and septation.

PMID- 15188443
TI  - Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable
      severity of cerebellar phenotypes.
AB  - Two mouse models are widely used for Down syndrome (DS) research. The Ts65Dn
      mouse carries a small chromosome derived primarily from mouse chromosome 16,
      causing dosage imbalance for approximately half of human chromosome 21 orthologs.
      These mice have cerebellar pathology with direct parallels to DS. The Ts1Cje
      mouse, containing a translocated chromosome 16, is at dosage imbalance for 67% of
      the genes triplicated in Ts65Dn. We quantified cerebellar volume and granule cell
      and Purkinje cell density in Ts1Cje. Cerebellar volume was significantly affected
      to the same degree in Ts1Cje and Ts65Dn, despite that Ts1Cje has fewer
      triplicated genes. However, dosage imbalance in Ts1Cje had little effect on
      granule cell and Purkinje cell density. Several mice with dosage imbalance for
      the segment of the Ts65Dn chromosome not triplicated in Ts1Cje had phenotypes
      that contrasted with those in Ts1Cje. These observations do not readily
      differentiate between two prevalent hypotheses for gene action in DS.

PMID- 15188444
TI  - Coping after cancer: risk perceptions, worry, and health behaviors among
      colorectal cancer survivors.
AB  - This study asks whether the experience of cancer motivates healthy behavior
      change. Further, we asked whether such changes relate to risk perceptions and
      worry, as suggested by Leventhal's Parallel Processing Model. Male (n=41) and
      female (n=40) survivors of colorectal cancer were interviewed 1-14 years after
      they first completed treatment. Younger age was associated with stronger risk
      perceptions, more worry, and greater anxiety. Shorter-term, compared to longer
      term survivors, reported higher risk perceptions and more frequent intrusive
      thoughts. Greater perceived risk, worry and anxiety correlated positively with
      intentions to make positive health behavior changes. Overall, these survivors did
      not report exaggerated risk perceptions, and they were not overly worried or
      anxious about cancer recurrence. However, low-level risk perceptions, worry, and
      anxiety motivated interest in adopting protective health behaviors.

PMID- 15188445
TI  - Posttraumatic growth in Chinese cancer survivors.
AB  - To investigate the dimensions and determinants of posttraumatic growth among
      Chinese cancer survivors, 188 participants were asked to complete a Chinese
      posttraumatic growth inventory, translated from the Posttraumatic Growth
      Inventory (PTGI; J Trauma Stress 1996; 9: 455-471), together with the Chinese
      versions of the Hospital Anxiety and Depression scale, the Mini-Mental Adjustment
      to Cancer scale, and the General Health Questionnaire. Confirmatory factor
      analysis showed a different factor structure than the original English-language
      version of the PTGI. The dimensions of growth could also be broadly dichotomized
      into an Interpersonal and an Intrapersonal dimension in our Chinese sample.
      Multiple regression analysis showed that positive coping was the most important
      determinant of posttraumatic growth when compared with negative coping and
      psychological symptoms. A Chinese Posttraumatic Growth Inventory was developed to
      facilitate future research.

PMID- 15188446
TI  - The impact of childhood cancer on the family: a qualitative analysis of strains,
      resources, and coping behaviors.
AB  - Clinical research has led to tremendous improvements in treatment efficacy for
      most childhood cancers; overall 5-year survival is now greater than 75%. Long
      term consequences of cure (i.e. adverse medical and psychosocial effects) have
      only recently begun to emerge as a primary focus of clinical research, including
      studies of health-related quality of life among survivors. Usually lacking in
      such efforts, however, is consideration of the impact of the cancer experience on
      the family, and the influence that the family's response to cancer has on quality
      of life in the child. From this qualitative analysis of seven focus groups with
      45 parents of children a year or more out of cancer treatment, we report those
      aspects of a child's cancer diagnosis, treatment, and recovery that parents
      perceived as particularly difficult for their family, and the resources and
      coping behaviors parents perceived as helpful to their family in dealing with and
      managing the cancer experience. Using the Family Adjustment and Adaptation
      Response theoretical model to organize the data, the domains of strains and
      resources were delineated into themes and sub-themes related to the cancer,
      child, family, health-care system, and community. Within a third domain, coping,
      sub-themes were identified within the themes of appraisal-focused, problem
      focused, and emotion-focused coping behaviors. Integration of this information
      should serve to improve future studies of health-related quality of life among
      children who survive cancer.

PMID- 15188448
TI  - Quality of life of patients with cancer in India: challenges and hurdles in
      putting theory into practice.
AB  - Although well establish in west, quality of life is a relatively new concept in
      India. The success of treatment is still measured in term of number of years and
      not as number of quality years. We carried out a systematic review of the reports
      published from India on quality of life in cancer patients. Majority of the
      studies originated from the southern part of India, this was not surprising as
      this part has literacy rates and health indices at par with developed countries.
      The studies mainly dealt with translation of existing tools in local vernacular,
      development of new tools, cross-sectional studies, and studies on palliative
      care. This article reviews these studies and presents the results of what has
      been done so far and goes on to stipulate what more needs to be done.

PMID- 15188447
TI  - Understanding the breast cancer experience of women: a qualitative study of
      African American, Asian American, Latina and Caucasian cancer survivors.
AB  - Breast cancer is the most common form of cancer in American women across most
      ethnic groups. Although the psychosocial impact of breast cancer is being
      studied, there is little information on women from diverse ethnic and
      socioeconomic backgrounds. We conducted a qualitative study with breast cancer
      survivors (BCS) of various ethnicities. A total of 102 BCS participated in focus
      group interviews (24 African Americans, 34 Asians, 26 Latinas and 18 Caucasians);
      20 health professionals participated in key informant interviews. Important
      ethnic differences in type of treatment were noted, Asians and Latinas were more
      likely to receive mastectomies and African American BCS were least likely to
      receive adjuvant therapies, including radiation and chemotherapy. These BCS
      enjoyed a fairly good overall health-related quality of life (HRQOL) with some
      persistent concerns. The prevailing concerns among all women included overall
      health, moderate physical concerns, cancer recurrence or metastases, psychosocial
      concerns related to worry about children and burdening the family, and body image
      and sexual health concerns. Additional challenges included: lack of knowledge
      about breast cancer; medical care issues such as insurance, cost and amount of
      time spent with physician; cultural sensitivity of providers, language barriers,
      cultural factors related to beliefs about illness, gender role and family
      obligations (e.g. self-sacrifice). These BCS, particularly the women of color,
      voiced that their spiritual beliefs and practices are central to their coping.
      This study accomplishes two goals; it adds to the sparse literature concerning
      the psychosocial sequelae of breast cancer among women of color, and it increases
      our knowledge of specific cultural influences (e.g. dietary practices, coping)
      and socio-ecological factors on HRQOL. More importantly, the study addressed
      areas that have not been studied before, specifically, an in-depth study on BCS
      QOL comparing multiple ethnic groups in the US. The results of this investigation
      will provide preliminary information to survivors and health-care providers about
      the impact of culture and socio-ecological contexts on survivorship. Among women
      of all major ethnic groups, breast cancer is the most common form of cancer and
      the second leading cause of cancer death (American Cancer Society (ACS), 2002).
      In 2002, over 203,000 women in the United States will be diagnosed with breast
      cancer (ACS, 2002). Ethnic disparities exist for cancer stage, diagnosis,
      survival, morbidity and mortality. In general, ethnic minority women are
      diagnosed with more advanced disease and experience greater morbidity and
      mortality (Haynes & Smedley, 1999; Miller et al., 1996; Ries et al., 2000;
      Shinagawa, 2000). In general, increases in survival rates have prompted greater
      interest in the quality of life (QOL) of breast cancer survivors (BCS) over the
      past two decades. Additionally, the QOL of cancer survivors from diverse ethnic,
      cultural and socioeconomic backgrounds is an emerging priority area for studies
      on survivorship research and clinical care (Haynes and Smedley, 1999; National
      Cancer Institute (NCI), 2002; President's Cancer Panel, 2000).

PMID- 15188450
TI  - Loss of heterozygosity on chromosome 6 in HPV-16 positive cervical carcinomas
      carrying the DRB1*1501-DQB1*0602 haplotype.
AB  - High-risk human papillomaviruses (HPVs), specifically HPV-16 and -18, have been
      associated with the development of carcinoma in situ (CIS) and of invasive
      cervical cancer (CC). However, only a small fraction of HPV-infected women will
      show signs of disease progression, suggesting that other factors in the
      carcinogenic pathway are needed. We previously demonstrated that human leukocyte
      antigen (HLA) DRB1*1501-DQB1*0602 (high risk) was associated with the development
      of CIS and CC tumors in HPV-16-positive patients. To characterize the molecular
      changes that could be relevant to tumor progression, we compared the extent of
      loss of heterozygosity (LOH) on chromosome 6 in HPV-16-positive CIS patients who
      were carriers of high-risk and neutral HLA haplotypes. CIS and CC cases
      demonstrated similar LOH patterns. A wide range of LOH frequencies was found at
      6p (10-53%) and 6q (5-28%) in CIS cases, suggesting that LOH is an early event in
      the carcinogenic process. A comparative analysis of LOH frequencies in the high
      risk versus the neutral HLA haplotypes showed a statistically significant
      difference in the extent of LOH at 6p24-p25 (58.6% versus 25.8%; P = 0.018) and
      at 6p21.3 (79.3% versus 35.5%; P = 0.001), a region that contains the HLA
      complex. LOH at this region could affect genes encoding HLA class I-II molecules,
      as well as factors responsible for the assembly, transport, and stable expression
      of HLA molecules. These losses may be a reflection of both an abnormal immune
      response and a general genome-wide instability resulting from virus persistence.

PMID- 15188451
TI  - DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in
      humans and mouse.
AB  - Our group previously identified two novel genes, RFP2/LEU5 and DLEU2, within a
      13q14.3 genomic region of loss seen in various malignancies. However, no specific
      inactivating mutations were found in these or other genes in the vicinity of the
      deletion, suggesting that a nonclassical tumor-suppressor mechanism may be
      involved. Here, we present data showing that the DLEU2 gene encodes a putative
      noncoding antisense RNA, with one exon directly overlapping the first exon of the
      RFP2/LEU5 gene in the opposite orientation. In addition, the RFP2/LEU5 transcript
      can be alternatively spliced to produce either several monocistronic transcripts
      or a putative bicistronic transcript encoding two separate open-reading frames,
      adding to the complexity of the locus. The finding that these gene structures are
      conserved in the mouse, including the putative bicistronic RFP2/LEU5 transcript
      as well as the antisense relationship with DLEU2, further underlines the
      significance of this unusual organization and suggests a biological function for
      DLEU2 in the regulation of RFP2/LEU5.

PMID- 15188452
TI  - Order of genetic events is critical determinant of aberrations in chromosome
      count and structure.
AB  - A sequential acquisition of genetic events is critical in tumorigenesis. A key
      step is the attainment of infinite proliferative potential. Acquisition of this
      immortalization requires the activation of telomerase in addition to other
      activities, including inactivation of TP53 and the retinoblastoma family of tumor
      suppressor proteins. However, the importance of the order in which these genetic
      events occur has not been established. To address this question, we used a panel
      of normal mammary fibroblasts and endothelial cultures that were immortalized
      after transduction with the catalytic subunit of telomerase (hTERT) and a
      temperature-sensitive mutant of the SV40 large-tumor (tsLT) oncoprotein in
      different orders in early- and late-passage stocks. These lines were maintained
      in continuous culture for up to 90 passages, equivalent to >300 population
      doublings (PDs) post-explantation during 3 years of continuous propagation. We
      karyotyped the cultures at different passages. Cultures that received hTERT first
      followed by tsLT maintained a near-diploid karyotype for more than 150 PDs.
      However, in late-passage stocks (>200 PDs), metaphase cells were mostly
      aneuploid. In contrast, the reverse order of gene transduction resulted in a
      marked early aneuploidy and chromosomal instability, already visible after 50
      PDs. These results suggest that the order of genetic mutations is a critical
      determinant of chromosome count and structural aberration events.

PMID- 15188453
TI  - Construction of tree models for pathogenesis of nasopharyngeal carcinoma.
AB  - Pathogenesis of nasopharyngeal carcinoma (NPC) is a multistep and multipathway
      process that cannot be fully explained by a fixed linear progression model. We
      used distance-based and branching-tree methods to construct more general tree
      like models for NPC carcinogenesis from 170 comparative genomic hybridization
      (CGH) samples previously published in five smaller studies. Imbalances were
      classified into "overlap regions," each containing the most commonly gained or
      lost band on each chromosome arm as well as adjacent bands that were gained or
      lost almost as often. The chromosome abnormalities associated with NPC were -3p26
      13 (48.9%), -11q22-25 (38.1%), -16q12-24 (38.1%), -14q24-32 (32.4%), -13q21-32
      (22.3%), -9p23-21(21.6%), +12p12 (46%), +12q13-15 (43.9%), +1q22-32 (33.1%),
      +3q13.1-26.2 (30.2%), and +8q22.1-24.2 (27.3%). NPC can be classified into two
      groups, one marked by +12p12 and +8q22.1-24.2 and the other by -3p26-13, -11q22
      25, -14q24-32, and +1q22-32. The tree models predicted -3p26-13 and +12p12 as
      early events and +8q22.1-24.2 as a late event. The predictions for -3p26-13 and
      +8q22.1-24.2 were consistent with previous studies. The prediction for +12p12 is
      being reported for the first time. Many known NPC-related genes on chromosomal
      regions of these tree models are discussed, some of which may merit additional
      study. The potential applications of tree models are also discussed.

PMID- 15188454
TI  - Microcell-mediated chromosome transfer provides evidence that polysomy promotes
      structural instability in tumor cell chromosomes through asynchronous replication
      and breakage within late-replicating regions.
AB  - It was reported earlier that normal chromosome 3 (chr3) transfer into tumor cells
      of different origin may suppress their ability to grow in SCID mice.
      Tumorigenicity may be restored by the loss of certain 3p regions. We transferred
      a normal cell-derived chr3 into cells of a human renal cell carcinoma line and
      followed the chromosomal changes during in vivo and in vitro growth. In cells
      cultivated for 6 weeks or more and in the tumors grown in SCID mice,
      supernumerary chrs3 were always rearranged, accompanied by 3p losses.
      Unexpectedly, we found that the rearrangements affected not only the transferred
      exogenous chr3, but also the endogenous chrs3. Other chromosomes that were
      polysomic in the recipient cells were affected as well, suggesting that polysomy
      may be associated with structural chromosome instability. The dominant
      chromosomal aberrations were unbalanced translocations with preferentially
      pericentromeric breakpoints. The breakpoint distribution on chr3 preferentially
      affected the pericentromeric 3p11 (8 breaks) and 3p12-13 (5 breaks) regions. The
      regions 3p14 and 3q26-27 occasionally were involved as well (one break in each
      case). These four regions were the latest replicating, as shown by BrdU
      incorporation-based replication banding. Using fluorescence in situ hybridization
      based replication timing, we detected asynchronous and incomplete centromere
      replication in cells with 3 or 4 copies of chr3, but not in cells with 2. We
      concluded that in tumor cells, asynchronous and incomplete replication of
      polysomic chromosomal parts is associated with aberrations that have breakpoints
      within the late-replicating regions. This may explain the increased structural
      chromosome instability and preferential pericentromeric localization of
      breakpoints in hyperploid tumors.

PMID- 15188455
TI  - TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.
AB  - Extraskeletal myxoid chondrosarcoma (EMC) is characterized by recurrent
      chromosomal translocations resulting in fusions of the nuclear receptor gene NOR1
      (also known as CHN or TEC) to various N-terminal partners, including EWS and
      TAF2N (or RBP56). Significant structural homology of EWS or TAF2N to TLS (or FUS)
      prompted us to investigate a potential novel gene fusion of NOR1 to TLS in EMCs
      without detectable known NOR1 fusions. In one of the EMCs examined, our reverse
      transcription polymerase chain reaction using NOR1 and TLS primers unexpectedly
      amplified a cDNA sequence derived not from a TLS/NOR1 fusion but from a TFG/NOR1
      fusion, a hitherto undescribed fusion type in EMC, probably a result of
      incidental misannealing by the TLS primer, which has a sequence partially
      identical to TFG. Encoding a protein with a putative coiled-coil structure, TFG
      previously was identified by a homology search in the Expressed Sequence Tag
      Database as having an SPYGQ-rich region similar to the N-terminal parts of EWS
      and TLS. TFG/NOR1 fusion appears to play an oncogenic role equivalent to those of
      other NOR1 fusions in EMC.

PMID- 15188456
TI  - Centrosome amplification and aneuploidy in bone marrow failure patients.
AB  - Patients with bone marrow failure are at risk for development of hematopoietic
      progenitor clones with abnormal numbers of chromosomes (aneuploidy) and leukemia.
      Numerical centrosome abnormalities or mutations in genes associated with the
      mitotic spindle checkpoint (BUB1 and MAD2) are two important mechanisms that can
      induce abnormal mitosis resulting in aneuploid daughter cells. To assess the role
      of these mechanisms, we used fluorescence in situ hybridization techniques to
      determine aneuploidy and centrosome copy number and PCR-SSCP to identify gene
      mutations of BUB1 and MAD2 in marrow cells of 25 patients. No mutations were
      found in BUB1 or MAD2 genes. However, we found that cells with more than two
      centrosomes exhibited aneuploidy for three or more chromosomes. We conclude that
      centrosome amplification may be associated with the development of a clonal
      population of potentially preleukemic aneuploid cells.

PMID- 15188457
TI  - Helicobacter pylori infection activates FOS and stress-response genes and alters
      expression of genes in gastric cancer-specific loci.
AB  - We studied human gene expression changes caused by Helicobacter pylori infection
      by using an in vitro model and 13k cDNA microarrays. A gastric cancer cell line
      was infected with H. pylori strain NCTC 11637. H. pylori infection was found to
      induce differential expression of genes in chromosomal locations known to contain
      frequent chromosomal aberrations and gene mutations specific to gastric cancer.
      Based on the results of time series experiments, the primary transcription target
      of the infection seemed to be FOS, the expression of which significantly
      increased after H. pylori infection. H. pylori infection also activated
      transcription of several stress-response genes. H. pylori infection may
      predispose the host cell to DNA damage in the chromosomal locations specific to
      gastric cancer by activating transcription and promoting histone removal from
      these sites, thus exposing its target DNA to mutations.

PMID- 15188458
TI  - Analysis of cytogenetic alterations in stage III serous ovarian adenocarcinoma
      reveals a heterogeneous group regarding survival, surgical outcome, and substage.
AB  - Ovarian cancer is the leading cause of death among patients with gynecological
      cancers, but the biology of these tumors is still among the least understood of
      all major human malignancies. In this study, comparative genomic hybridization
      was used to determine chromosomal alterations in 98 stage III serous papillary
      adenocarcinomas. The tumors were grouped according to survival and the main
      prognostic factors stage and surgical outcome. There were chromosomal imbalances
      that were significantly more common in tumors from patients who died than in
      tumors from patients who survived: gains of 1q24-qter and losses of 4p, 4q31.1
      qter, 5q12-q22, 8p, 16q, and X. Furthermore, we observed that gains of 8q23
      8q24.2 and losses of 4p, 4q13-4q26, 4q31.1-qter, 5q12-q22, 8p, and 16q were
      significantly more common in tumors from patients with macroscopic residual tumor
      after primary surgery, compared to tumors from those who had undergone radical
      surgery. Gains of 3q13.3-qter, 6p, 7q21-q31, and 11q13-q23 and losses of 4q31.1
      qter and 16q were more common in stage IIIc tumors than in stage IIIa+b tumors.
      On the basis of our results, we suggest that there are biological differences
      among the groups mentioned above and that absence of chromosomal aberrations in
      specific regions predicts a good clinical outcome for individual patients.

PMID- 15188459
TI  - Cryptic insertion of MLL gene into 9p22 leads to MLL-MLLT3 (AF9) fusion in a case
      of acute myelogenous leukemia.
AB  - The formation of a leukemogenic fusion product in hematopoietic malignancies is
      commonly achieved by chromosomal translocation. Alternate and cytogenetically
      undetectable mechanisms of fusion transcript generation have been documented for
      BCR-AB1, AML1-ETO, PML-RARA, NPM/ALK, and MLL-MLLT2 (AF4). Here, we report the
      investigation of a cryptic rearrangement leading to MLL-MLLT3 transcript
      formation. Cytogenetic analysis of peripheral blood from a 50-year-old acute
      myeloid leukemia patient yielded a karyotype of 47,XY,+8,del(11)(q21q23) in all
      metaphase cells examined. Metaphase fluorescence in situ hybridization analysis
      using the MLL probe at 11q23 revealed that the 5' portion of the MLL gene was
      inserted into chromosome 9 at band p22, whereas the 3' region of the MLL gene
      remained on chromosome 11. Whole-chromosome paint analysis confirmed the cryptic
      transfer of chromosome 11 material to 9p22. With this information, the karyotype
      was reassigned as 47,XY,+8,der(9)ins(9;11)(p22;q23q23),del(11)(q21q23). RT-PCR
      was used to show that the cryptic rearrangement in this patient led to the fusion
      of the MLL and MLLT3 transcripts on the der(9). The presence of the MLL-MLLT3
      transcript is consistent with the clinical findings in this patient.

PMID- 15188466
TI  - Chemistry and electronics of carbon nanotubes go together.

PMID- 15188460
TI  - Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a
      controversial entity.
AB  - The majority of thyroid tumors are classified as papillary (papillary thyroid
      carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and
      carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern.
      However, classification of the follicular variant of papillary thyroid carcinoma
      (FVPTC) remains an issue of debate. These tumors contain a predominantly
      follicular growth pattern but display nuclear features and overall clinical
      behavior consistent with PTC. In this study, we used comparative genomic
      hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the
      PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed
      the presence of peroxisome proliferator-activated receptor-gamma (PPARG)
      alteration, a genetic event specific to FTA/FTC, using Southern blot and
      immunohistochemistry analyses. In sharp contrast to the findings in classical PTC
      (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and
      FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002).
      Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q,
      4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the
      follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG
      were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger
      relationship between the FVPTC and FTA/FTC than previously appreciated and
      support further consideration of the current classification of thyroid neoplasms.

PMID- 15188467
TI  - Organocatalyzed asymmetric alpha-aminoxylation of aldehydes and ketones--an
      efficient access to enantiomerically pure alpha-hydroxycarbonyl compounds, diols,
      and even amino alcohols.

PMID- 15188461
TI  - PRDX4, a member of the peroxiredoxin family, is fused to AML1 (RUNX1) in an acute
      myeloid leukemia patient with a t(X;21)(p22;q22).
AB  - The AML1 gene (also known as RUNX1) at 21q22 codes for core binding factor (CBF)
      alpha, which forms a heterodimer with CBF beta that acts as a transcriptional
      activating factor. CBF is a critical regulator in the generation and
      differentiation of definitive hematopoietic stem cells and is frequently
      disrupted in leukemia through chromosome translocations. We cloned a novel AML1
      partner gene, PRDX4, in an X;21 translocation in a 74-year-old male patient
      diagnosed with acute myeloid leukemia-M2. Chromosome analysis detected a
      t(X;21)(p22;q22) as the sole abnormality in bone marrow samples. The involvement
      of AML1 was confirmed by fluorescence in situ hybridization studies. Using 3'
      RACE-PCR, we cloned a fusion between exon 5 of AML1 and exon 2 of PRDX4. RT-PCR
      confirmed the fusion and detected another fusion between exon 6 of AML1 and exon
      2 of PRDX4, indicating alternative splicing of exon 6 of AML1 in the fusion
      transcripts. PRDX4 is one of six peroxiredoxin-family genes that are highly
      conserved in eukaryotes and prokaryotes and are ubiquitously expressed.
      Peroxiredoxin genes exhibit thioredoxin-dependent peroxidase activity and have
      been implicated in a number of other cellular functions such as cell
      proliferation and differentiation. PRDX4 plays a regulatory role in the
      activation of the transcription factor NF-kappaB and is significantly down
      regulated in acute promyelocytic leukemia. This is the first example of
      antioxidant enzyme involvement in a chromosome translocation in leukemia.

PMID- 15188468
TI  - Dendrimers in solution: insight from theory and simulation.
AB  - A variety of experimental and theoretical approaches show that, akin to linear
      polymers, dendrimers in good solvent conditions are best described as flexible
      macromolecular aggregates with a dense core and fluctuating monomer groups. We
      present theoretical and simulational evidence of how the shape and inner
      structure of dendrimers depends on the generation number as well as the effective
      interactions that exist between dendrimers in solution. These approaches based on
      simplified dendritic structures show there is a tunable and ultrasoft interaction
      between the centers of the solublized dendrimers. Results from small-angle
      neutron scattering data confirm the theory and indicate that dendrimers are model
      systems of ultrasoft colloids that bridge the gap between polymers and hard
      spheres. Dendrimers can form a class of materials analogous to the related
      systems of star polymers and block copolymer micelles which exhibit special
      properties.

PMID- 15188469
TI  - Metallic conductivity down to 2 K in a polyoxometalate-containing radical salt of
      BEDO-TTF.

PMID- 15188470
TI  - Modular control of lectin function: redox-switchable agglutination.

PMID- 15188471
TI  - Temperature antiquenching of the luminescence from capped CdSe quantum dots.

PMID- 15188472
TI  - A packing-density metric for exploring the interior of folded RNA molecules.

PMID- 15188473
TI  - Cubic mesoporous frameworks with a mixed semiconductor nanocrystalline wall
      structure and enhanced sensitivity to visible light.

PMID- 15188474
TI  - Modification of 2D water that contains hexameric units in chair and boat
      conformations--a contribution to the structural elucidation of bulk water.

PMID- 15188475
TI  - Controlled molecular orientation in an adlayer of a supramolecular assembly
      consisting of an open-cage C60 derivative and ZnII octaethylporphyrin on Au(111).

PMID- 15188476
TI  - Multicomponent magnetic nanorods for biomolecular separations.

PMID- 15188477
TI  - A DFT study of the acidity of ultrastable Y zeolite: where is the Bronsted/Lewis
      acid synergism?

PMID- 15188478
TI  - Zwitterionic silver complexes as carriers for facilitated-transport composite
      membranes.

PMID- 15188479
TI  - Conversion of alkyltrifluoroborates into alkyldichloroboranes with
      tetrachlorosilane in coordinating solvents.

PMID- 15188480
TI  - Efficient one-pot synthesis of secondary cyclic phosphanes with easy regeneration
      of the phosphorus-donor reagent used.

PMID- 15188481
TI  - Structure and phase behavior of a 2:1 complex between arene- and fluoroarene
      based conjugated rigid rods.

PMID- 15188483
TI  - A manganese(II) allyl complex: synthesis, structure, and magnetic properties of
      [Li(thf)4][Mn[eta3-(Me3Si)2C3H3][eta1-(Me3Si)2C3H3]2].

PMID- 15188482
TI  - Single DNA rotaxanes of a transmembrane pore protein.

PMID- 15188485
TI  - Mutual stabilization between imine ligands and copper(I) ions in aqueous
      solution.

PMID- 15188484
TI  - Potent, versatile, and stable: thiazolyl thioglycosides as glycosyl donors.

PMID- 15188486
TI  - Intermolecular dienyl Pauson-Khand reaction.

PMID- 15188488
TI  - Milling of wheat, maize and rice: effects on fibre and lipid content and health.

PMID- 15188489
TI  - Surgery for pancreatic necrosis: "whom, when and what".

PMID- 15188490
TI  - Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury.
AB  - Deficiencies in vitamins or other factors (B6, B12, folic acid, betaine) and
      genetic disorders for the metabolism of the non-protein amino acid-homocysteine
      (Hcy) lead to hyperhomocysteinemia (HHcy). HHcy is an integral component of
      several disorders including cardiovascular disease, neurodegeneration, diabetes
      and alcoholic liver disease. HHcy unleashes mediators of inflammation such as
      NFkappaB, IL-1beta, IL-6, and IL-8, increases production of intracellular
      superoxide anion causing oxidative stress and reducing intracellular level of
      nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can
      explain many processes of Hcy-promoted cell injury such as apoptosis, fat
      accumulation, and inflammation. Animal models have played an important role in
      determining the biological effects of HHcy. ER stress may also be involved in
      other liver diseases such as alpha (1)-antitrypsin (alpha(1)-AT) deficiency and
      hepatitis C and/or B virus infection. Future research should evaluate the
      possible potentiative effects of alcohol and hepatic virus infection on ER stress
      induced liver injury, study potentially beneficial effects of lowering Hcy and
      preventing ER stress in alcoholic humans, and examine polymorphism of Hcy
      metabolizing enzymes as potential risk-factors for the development of HHcy and
      liver disease.

PMID- 15188493
TI  - Reversal of multidrug resistance in drug-resistant human gastric cancer cell line
      SGC7901/VCR by antiprogestin drug mifepristone.
AB  - AIM: To explore the reversal effect of mifepristone on multidrug resistance (MDR)
      in drug-resistant human gastric cancer cell line SGC7901/VCR and its mechanisms.
      METHODS: Expression of multidrug resistance-associated protein(MRP) was detected
      using reverse transcription-polymerase chain reaction(RT-PCR). Flow cytometry was
      used to assay the expression of P-glycoprotein(P-gp), Bcl-2, Bax, and the mean
      fluorescent intensity of intracellular rhodamine 123 in the cells. Meanwhile, the
      protein levels of Bcl-2 and Bax were also detected by Western blotting analysis.
      The sensitivity of cells to the anticancer agent, vincrimycin(VCR), and the
      intracellular [(3) H]VCR accumulation were determined by tetrazolium blue (MTT)
      assay and a liquid scintillation counter, respectively. RESULTS: Expression of
      MRP and P-gp in SGC7901/VCR cells was 6.04-and 8.37-fold higher as compared with
      its parental SGC7901 cells, respectively. After treatment with 1, 5, 10, and 20
      micromol/L mifepristone, SGC7901/VCR cells showed a 1.34-, 2.29-, 3.11-, and 3.71
      fold increase in the accumulation of intracellular VCR, a known substrate of MRP,
      and a 1.03-, 2.04-, 3.08-, and 3.68-fold increase in the retention of rhodamine
      123, an indicator of P-gp function, respectively. MTT assay revealed that the
      resistance of SGC7901/VCR cells to VCR was 11.96-fold higher than that of its
      parental cells. The chemosensitivity of SGC7901/VCR cells to VCR was enhanced by
      1.02-, 7.19-, 12.84-, and 21.17-fold after treatment with mifepristone at above
      mentioned dose. After 96 h of incubation with mifepristone 10 micromol/L, a
      concentration close to plasma concentrations achievable in human, the expression
      of Bcl-2 protein was decreased to (9.21+/-0.65)% from (25.32+/-1.44)%, whereas
      the expression of Bax protein was increased to (19.69+/-1.13)% from (1.24+/
      0.78)% (P<0.01). Additionally, the effects of mifepristone on the expression of
      Bcl-2 and Bax proteins in SGC7901/VCR cells were further demonstrated by Western
      blotting analysis. CONCLUSION: Mifepristone has potent reversal effect on MDR in
      SGC7901/VCR via inhibiting the function of MRP and P-gp, modulating the
      expression of Bcl-2 and Bax proteins, and enhancing the sensitivity to anticancer
      agent VCR.

PMID- 15188494
TI  - Effects of mifepristone on invasive and metastatic potential of human gastric
      adenocarcinoma cell line MKN-45 in vitro and in vivo.
AB  - AIM: To investigate the effects of mifepristone on the invasive and metastatic
      potential of human gastric adenocarcinoma cell line MKN-45 and its mechanisms.
      METHODS: After incubation with various concentrations of mifepristone (5, 10, 20
      micromol/L), the adhesion to artificial basement membrane, Matrigel, and the
      migration of MKN-45 cells were assayed using MTT assay and Transwell cell culture
      chambers, respectively. Enzyme- linked immunoabsorbent assay (ELISA) and flow
      cytometry were used to determine the expression of vascular endothelial growth
      factor (VEGF) and integrin beta3 in the cells. After subcutaneous transplantation
      of MKN-45 cells in nude mice, mifepristone (50 mg/kg.d) was administrated
      subcutaneously for 8 wk to assess its effects on tumor metastasis.
      Immunohistochemical analysis was used to detect the expression of VEGF and
      microvascular density (MVD) in xenografted tumors. RESULTS: Mifepristone dose
      dependently inhibited the heterotypic adhesion to Matrigel of MKN-45 cells. The
      inhibition was accompanied by a significant down-regulation of integrin beta3
      expression in the cells. After incubation with 5, 10, 20 micromol/L mifepristone,
      the number of migrated MKN-45 cells was 72+/-8, 50+/-6, 41+/-5 in experiment
      group, and 94+/-16 in control group (P<0.01). Meanwhile, secreted VEGF protein of
      MKN-45 cells in mifepristone-treated group (14.2+/-2.9, 8.9+/-3.1, 5.4+/-2.1 ng/g
      per liter) was significantly lower than that in control group (22.7+/-4.3 ng/g
      per liter, P<0.01). In vivo, mifepristone decreased the number of metastatic foci
      in lungs of nude mice and down-regulated the expression of VEGF and MVD in the
      xenograted tumors. CONCLUSION: Mifepristone can effectively inhibit the invasive
      and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in
      vitro and in vivo through inhibition of heterotypic adhesion to basement
      membrane, cell migration and angiogenesis.

PMID- 15188492
TI  - Differential gene expression between squamous cell carcinoma of esophageus and
      its normal epithelium; altered pattern of mal, akr1c2, and rab11a expression.
AB  - AIM: To identify the altered gene expression patterns in squamous cell carcinoma
      of esophagus (ESCC) in relation to adjacent normal esophageal epithelium.
      METHODS: Total RNA was extracted using SV total RNA isolation kit from snap
      frozen tissues of ESCC samples and normal esophageal epithelium far from the
      tumor. Radio-labeled cDNA were synthesized from equal quantities of total RNAs of
      tumor and normal tissues using combinations of 24 arbitrary 13-mer primers and
      three different anchoring oligo-dT primers and separated on sequencing gels. cDNA
      with considerable different amounts of signals in tumor and normal tissue were
      reamplified and cloned. Using southern blot, the clones of each band were
      controlled for false positive results caused by probable heterogeneity of cDNA
      population with the same size. Clones that confirmed differential expression by
      slot blot selected for sequencing and northern analysis. Corresponding full
      length gene sequences was predicted using human genome project data, related
      transcripts were translated and used for various protein/motif searches to
      speculate their probable functions. RESULTS: The 97 genes showed different levels
      of cDNA in tumor and normal tissues of esophagus. The expression of mal gene was
      remarkably down regulated in all 10 surveyed tumor tissues. Akr1c2, a member of
      the aldo-keto reductase 1C family, which is involved in metabolism of sex
      hormones and xenobiotics, was up-regulated in 8 out of 10 inspected ESCC samples.
      Rab11a, RPL7, and RPL28 showed moderate levels of differential expression. Many
      other cDNAs remained to further studies. CONCLUSION: The mal gene which is
      switched-off in all ESCC samples can be considered as a tumor suppressor gene
      that more studies in its regulation may lead to valuable explanations in ESCC
      development. Akr1c2 which is up-regulated in ESCC probably plays an important
      role in tumor development of esophagus and may be proposed as a potential
      molecular target in ESCC treatments. Differential display technique in spite of
      many disadvantages is still a valuable technique in gene function exploration
      studies to find new candidates for improved ones like gene chips.

PMID- 15188491
TI  - Review of cytokine profiles in patients with hepatitis.
AB  - The development of T helper 1 versus T helper 2 cells is a major branch point in
      the immune response and is an important determinant of the body's response to an
      infectious pathogen, leading to protection of the host or dissemination of the
      disease. Recent studies have shown that there exist macrophage activation states
      in parallel to the T helper cell type 1/2 paradigm, and the T helper 1
      development process is governed to a great degree by cytokine IL-12 provided
      mainly by antigen presenting cells such as macrophages and dendritic cells. A
      model in patients with hepatitis is proposed that links the pathogen, macrophage
      activation and T helper cell polarization.

PMID- 15188495
TI  - Microvessel density of malignant and benign hepatic lesions and MRI evaluation.
AB  - AIM: To study the difference of microvessel density (MVD) between malignant and
      benign hepatic lesions and study the relationship between MVD and dynamic
      enhanced magnetic resonance imaging (MRI) for evaluation of microvessels within
      malignant and benign hepatic lesions. METHODS: A total of 265 specimens of
      hepatocellular carcinoma (HCC), 122 cirrhosis tissues and 22 hepatic benign
      lesions were enrolled for MVD by immunohistochemistry on tissue microarray, of
      which 49 underwent MRI examination before surgery, then contrast-to-noise ratios
      (CNR) and enhancement index (EI) in all the phases were calculated. Pearson
      correlation was performed for correlation analysis between CNR, EI and MVD.
      RESULTS: MVD of HCC was 22.7+/-15.8 (mean+/-SD), which was obviously higher than
      that of cirrhosis tissue (8.3+/-7.6, P<0.01), but was not statistically different
      from that of benign lesions (31.3+/-22.7, P>0.05). Among HCC, MVD of grades I-II
      was 29.9+/-18.6, which was much higher than those of grade III (22.2+/-18.2,
      P<0.01) and grade IV (22.9+/-19.0, P<0.01). MVD of HCC (P=0.018) and of benign
      lesions (P=0.014) were both correlative with CNR in arterial phase. CONCLUSION:
      Neoangiogenesis is an important feature for malignant tumor, and MVD may act as a
      biological marker in differentiating malignant from benign hepatic lesions.
      Dynamic enhanced MRI, especially image in arterial phase, may act as an MVD
      evaluation criterion for malignant and benign hepatic lesions.

PMID- 15188497
TI  - Gene expression profiles in an hepatitis B virus transfected hepatoblastoma cell
      line and differentially regulated gene expression by interferon-alpha.
AB  - AIM: To study interactions between hepatitis B virus (HBV) and interferon-alpha
      in liver- derived cells. METHODS: mRNAs were separately isolated from an HBV
      transfected cell line (HepG(2)2.2.15) and its parental cell line (HepG(2)) pre-
      and post-interferon-alpha (IFN-alpha) treatment at 6, 24 and 48 h, followed by
      hybridization with a cDNA microarray filter dotted with 14 000 human genes. After
      hybridization and scanning of the arrays, the data were analyzed using ArrayGauge
      software. The microarray data were further verified by Northern blot analysis.
      RESULTS: Compared to HepG(2) cells, 14 genes with known functions were down
      regulated 3 to 12- magnitudes, while 7 genes were up-regulated 3-13 magnitudes in
      HepG(2)2.2.15 cells prior to IFN-alpha treatment. After interferon-alpha
      treatment, the expression of four genes (vascular endothelial growth factor,
      tyrosine phosphate 1E, serine protein with IGF-binding motif and one gene of
      clathrin light chain) in HepG(2)2.2.15 were up-regulated, while one gene encoding
      a GTP-binding protein, two genes of interferon-induced kinases and two proto
      oncogenes were further down- regulated. Interestingly, under IFN-alpha treatment,
      a number of differentially regulated genes were new ESTs or genes with unknown
      functions. CONCLUSION: The up-regulated genes in HepG(2)2.2.15 cell line
      suggested that under IFN-alpha treatment, these repressed cellular genes in HBV
      infected hepatocytes could be partially restored, while the down- regulated genes
      were most likely the cellular genes which could not be restored under interferon
      treatment. These down-regulated genes identified by microarray analysis could
      serve as new targets for anti-HBV drug development or for novel therapies.

PMID- 15188496
TI  - Cloning and identification of NS5ATP2 gene and its spliced variant transactivated
      by hepatitis C virus non-structural protein 5A.
AB  - AIM: To clone, identify and study new NS5ATP2 gene and its spliced variant
      transactivated by hepatitis C virus non-structural protein 5A. METHODS: On the
      basis of subtractive cDNA library of genes transactivated by NS5A protein of
      hepatitis C virus, the coding sequence of new gene and its spliced variant were
      obtained by bioinformatics method. Polymerase chain reaction (PCR) was conducted
      to amplify NS5ATP2 gene. RESULTS: The coding sequence of a new gene and its
      spliced variant were cloned and identified successfully. CONCLUSION: A new gene
      has been recognized as the new target transactivated by HCV NS5A protein. These
      results brought some new clues for studying the biological functions of new genes
      and pathogenesis of the viral proteins.

PMID- 15188498
TI  - Transactivating effect of hepatitis C virus core protein: a suppression
      subtractive hybridization study.
AB  - AIM: To investigate the transactivating effect of hepatitis C virus (HCV) core
      protein and to screen genes transactivated by HCV core protein. METHODS:
      pcDNA3.1(-)-core containing full-length HCV core gene was constructed by
      insertion of HCV core gene into EcoRI/BamHI site. HepG2 cells were cotransfected
      with pcDNA3.1(-)-core and pSV-lacZ. After 48 h, cells were collected and detected
      for the expression of beta-gal by an enzyme-linked immunosorbent assay (ELISA)
      kit. HepG2 cells were transiently transfected with pcDNA3.1(-)-core using
      Lipofectamine reagent. Cells were collected and total mRNA was isolated. A
      subtracted cDNA library was generated and constructed into a pGEM-Teasy vector.
      The library was amplified with E. coli strain JM109. The cDNAs were sequenced and
      analyzed in GenBank with BLAST search after polymerase chain reaction (PCR).
      RESULTS: The core mRNA and protein could be detected in HepG2 cell lysate which
      was transfected by the pcDNA3.1(-)-core. The activity of beta-galactosidase in
      HepG2 cells transfected by the pcDNA3.1(-)-core was 5.4 times higher than that of
      HepG2 cells transfected by control plasmid. The subtractive library of genes
      transactivated by HCV core protein was constructed successfully. The amplified
      library contained 233 positive clones. Colony PCR showed that 213 clones
      contained 100-1 000 bp inserts. Sequence analysis was performed in 63 clones. Six
      of the sequences were unknown genes. The full length sequences were obtained with
      bioinformatics method, accepted by GenBank. It was suggested that six novel cDNA
      sequences might be target genes transactivated by HCV core protein. CONCLUSION:
      The core protein of HCV has transactivating effects on SV40 early
      promoter/enhancer. A total of 63 clones from cDNA library were randomly chosen
      and sequenced. Using the BLAST program at the National Center for Biotechnology
      Information, six of the sequences were unknown genes. The other 57 sequences were
      highly similar to known genes.

PMID- 15188500
TI  - Effects of lactose as an inducer on expression of Helicobacter pylori rUreB and
      rHpaA, and Escherichia coli rLTKA63 and rLTB.
AB  - AIM: To demonstrate the effect of lactose as an inducer on expression of the
      recombinant proteins encoded by Helicobacter pylori ureB and hpaA, and
      Escherichia coli LTB and LTKA63 genes and to determine the optimal expression
      parameters. METHODS: By using SDS-PAGE and BIO-RAD gel image analysis system, the
      outputs of the target recombinant proteins expressed by pET32a-ureB-E.coliBL21,
      pET32a-hpaA-E.coliBL21, pET32a-LTKA63-E.coliBL21 and pET32a-LTB-E.coliBL21 were
      measured when using lactose as inducer at different dosages, original bacterial
      concentrations, various inducing temperatures and times. The results of the
      target protein expression induced by lactose were compared to those by isopropyl
      beta-D-thiogalactoside (IPTG). The proteins were expressed in E.coli. RESULTS:
      Lactose showed higher efficiency of inducing the expression of rHpaA, rUreB, rLTB
      and rLTKA63 than IPTG. The expression outputs of the target recombinant proteins
      induced at 37 degrees were remarkably higher than those at 28 degrees. Other
      optimal expression parameters for the original bacterial concentrations, dosages
      of lactose and inducing time were 0.8, 50 g/L and 4 h for rHpaA; 0.8, 100 g/L and
      4 h for rLTKA63; 1.2, 100 g/L and 5 h for both rUreB and rLTB, respectively.
      CONCLUSION: Lactose, a sugar with non-toxicity and low cost, is able to induce
      the recombinant genes to express the target proteins with higher efficiency than
      IPTG. The results in this study establish a beneficial foundation for industrial
      production of H pylori genetic engineering vaccine.

PMID- 15188499
TI  - Effects of Helicobacter pylori infection on gastric emptying rate in patients
      with non-ulcer dyspepsia.
AB  - AIM: The pathogenesis of delayed gastric emptying in patients with non-ulcer
      dyspepsia (NUD) remains unclear. We aimed to examine whether gastric emptying
      rate in NUD patients was associated with Helicobacter pylori (H pylori) infection
      and whether it was affected by eradication of the infection. METHODS: Gastric
      emptying rate of a mixed solid-liquid meal was assessed by the paracetamol
      absorption method in NUD patients and asymptomatic controls (n=17). H pylori
      status was assessed by serology and biopsy urease test. H pylori-positive NUD
      patients (n=23) received 10-day triple eradication therapy. H pylori status was
      re-assessed by biopsy urease test four weeks later, and if eradication was
      confirmed, gastric emptying rate was re-evaluated. RESULTS: Thirty-three NUD
      patients and 17 controls were evaluated. NUD patients had significantly delayed
      gastric emptying compared with controls. The mean maximum plasma paracetamol
      concentration divided by body mass (Cmax/BM) was 0.173 and 0.224 mg/L.kg
      respectively (P=0.02), the mean area under plasma paracetamol concentration-time
      curve divided by body mass (AUC/BM) was 18.42 and 24.39 mg.min/L.kg respectively
      (P=0.01). Gastric emptying rate did not differ significantly between H pylori
      positive and H pylori-negative NUD patients. The mean Cmax/BM was 0.172 and 0.177
      mg/L.kg respectively (P=0.58), the mean AUC/BM was 18.43 and 18.38 mg.min/L.kg
      respectively (P=0.91). Among 14 NUD patients who were initially H pylori
      positive, confirmed eradication of the infection did not significantly alter
      gastric emptying rate. The mean Cmax/BM was 0.171 and 0.160 mg/L.kg before and
      after Hp eradication, respectively (P=0.64), the mean AUC/BM was 17.41 and 18.02
      mg.min/L.kg before and after eradication, respectively (P=0.93). CONCLUSION:
      Although gastric emptying is delayed in NUD patients compared with controls,
      gastric emptying rate is not associated with H pylori status nor it is affected
      by eradication of the infection.

PMID- 15188501
TI  - Coordinate increase of telomerase activity and c-Myc expression in Helicobacter
      pylori-associated gastric diseases.
AB  - AIM: To detect the telomerase activity and c-Myc expression in gastric diseases
      and to examine the relation between these values and Helicobacter pylori (H
      pylori) as a risk factor for gastric cancer. METHODS: One hundred and seventy-one
      gastric samples were studied to detect telomerase activity using a telomerase
      polymerase chain reaction enzyme linked immunosorbent assay (PCR-ELISA), and c
      Myc expression using immunohistochemistry. RESULTS: The telomerase activity and c
      Myc expression were higher in cancers (87.69% and 61.54%) than in noncancerous
      tissues. They were higher in chronic atrophic gastritis with severe intestinal
      metaplasia (52.38% and 47.62%) than in chronic atrophic gastritis with mild
      intestinal metaplasia (13.33% and 16.67%). In chronic atrophic gastritis with
      severe intestinal metaplasia, the telomerase activity and c-Myc expression were
      higher in cases with H pylori infection (67.86% and 67.86%) than in those without
      infection (21.43% and 7.14%). c-Myc expression was higher in gastric cancer with
      H pylori infection (77.27%) than in that without infection (28.57%). The
      telomerase activity and c-Myc expression were coordinately up-regulated in H
      pylori infected gastric cancer and chronic atrophic gastritis with severe
      intestinal metaplasia. CONCLUSION: H pylori infection may influence both
      telomerase activity and c-Myc expression in gastric diseases, especially in
      chronic atrophic gastritis.

PMID- 15188502
TI  - Differential Cl- and HCO3- mediated anion secretion by different colonic cell
      types in response to tetromethylpyrazine.
AB  - AIM: Colonic epithelium is known to secrete both Cl(-) and HCO(3)(-), but the
      secretory mechanisms of different colonic cell types are not fully understood.
      The present study aimed to investigate the differential activation of Cl(-) and
      HCO(3)(-) secretion by tetramethylpyrazine (TMP) in human crypt-like cell line,
      T84, and villus-like cell line, Caco-2, in comparison to the TMP-induced
      secretory response in freshly isolated rat colonic mucosa. METHODS: Colonic
      epithelial anion secretion was studied by using the short circuit current (I(SC))
      technique. RT-PCR was used to examine the expression of Na(+)-HCO(3)(-)
      cotranspoter in different epithelial cell types. RESULTS: TMP produced a
      concentration-dependent I(SC) which was increase in both T84 and Caco-2 cells.
      When extracellular Cl(-) was removed, TMP-induced I(SC) was abolished by 76.6% in
      T84 cells, but not in Caco-2 cells. However, after both Cl(-) and HCO(3)(-) were
      removed, TMP-induced I(SC) in Caco-2 cells was reduced to 10%. Bumetanide, an
      inhibitor of Na(+)-K(+)-Cl(-)-cotranspoter, inhibited the TMP-induced I(SC) by
      96.7% in T84 cells, but only 47.9% in Caco-2 cells. In the presence of bumetanide
      and 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid, an inhibitor of Na(+)
      HCO(3)(-) cotransporter, inhibited the TMP-induced current in Caco-2 cells by
      93.3%. In freshly isolated rat colonic mucosa, TMP stimulated distinct I(SC)
      responses similar to that observed in T84 and Caco-2 cells depending on the
      concentration used. RT-PCR revealed that the expression of Na(+)-HCO(3)(-)
      cotransporter in Caco-2 cells was 4-fold more greater than that in T84 cells.
      CONCLUSION: TMP exerts concentration-dependent differential effects on different
      colonic cell types with stimulation of predominant Cl(-) secretion by crypt cells
      at a lower concentration, but predominant HCO(3)(-) secretion by villus cells at
      a higher concentration, suggesting different roles of these cells in colonic Cl(
      ) and HCO(3)(-) secretion.

PMID- 15188503
TI  - Time- and pH-dependent colon-specific drug delivery for orally administered
      diclofenac sodium and 5-aminosalicylic acid.
AB  - AIM: To investigate Time- and pH-dependent colon-specific drug delivery systems
      (CDDS) for orally administered diclofenac sodium (DS) and 5-aminosalicylic acid
      (5-ASA), respectively. METHODS: DS tablets and 5-ASA pellets were coated by
      ethylcellulose (EC) and methacrylic acid copolymers (Eudragit L100 and S100),
      respectively. The in vitro release behavior of the DS coated tablets and 5-ASA
      coated pellets were examined, and then in vivo absorption kinetics of DS coated
      tablets in dogs were further studied. RESULTS: Release profile of time-dependent
      DS coated tablets was not influenced by pH of the dissolution medium, but the lag
      time of DS release was primarily controlled by the thickness of the coating
      layer. The thicker the coating layer, the longer the lag time of DS release is.
      On the contrary, in view of the pH-dependent 5-ASA coated pellets, 5-ASA release
      was significantly governed by pH. Moreover, the 5-ASA release features from the
      coated pellets depended upon both the combination ratio of the Eudragit L100 and
      S100 pH-sensitive copolymers in the coating formulation and the thickness of the
      coating layer. The absorption kinetic studies of the DS coated tablets in dogs
      demonstrated that in vivo lag time of absorption was in a good agreement with in
      vitro lag time of release. CONCLUSION: Two types of CDDS, prepared herein by
      means of the regular coating technique, are able to achieve site-specific drug
      delivery targeting at colon following oral administration, and provide a
      promising strategy to control drug release targeting the desired lower
      gastrointestinal region.

PMID- 15188504
TI  - Inhibition of Fas/FasL mRNA expression and TNF-alpha release in concanavalin A
      induced liver injury in mice by bicyclol.
AB  - AIM: Bicyclol, 4, 4'-dimethoxy-5, 6, 5', 6'-dimethylene-dioxy-2-hydroxymethyl -2'
      carbonyl biphenyl, is a new anti-hepatitis drug. The aim of the present study was
      to investigate the protective effect of bicyclol on concanavalin A (Con A)
      induced immunological liver injury in mice and its mechanism. METHODS: Liver
      injury was induced by injection of Con A via tail vein of mice and assessed
      biochemically and histologically. Serum transaminase and tumor necrosis factor
      alpha (TNF-alpha) were determined. Liver lesions were observed by light
      microscope. Expressions of TNF-alpha, interferon gamma (IFN-gamma), Fas and Fas
      ligand (FasL) mRNA in the livers were measured by RT-PCR. RESULTS: Serum
      transaminase level and liver lesions in Con A-induced mice were markedly reduced
      by oral administration of 100, 200 mg/kg of bicyclol. TNF-alpha level in serum
      was also reduced by bicyclol. Con A injection induced up-regulation of TNF-alpha,
      IFN-gamma, Fas and FasL mRNA expression in liver tissues. Bicyclol significantly
      down-regulated the expression of IFN-gamma, Fas and FasL mRNA, but only slightly
      affected TNF-alpha mRNA expression in liver tissues. CONCLUSION: Bicyclol
      protects against Con A-induced liver injury mainly through inhibition of Fas/FasL
      mRNA expression in liver tissues and TNF-alpha release in mice.

PMID- 15188505
TI  - Expression of gonadotropin-releasing hormone receptor and effect of gonadotropin
      releasing hormone analogue on proliferation of cultured gastric smooth muscle
      cells of rats.
AB  - AIM: To investigate the expression of gonadotropin-releasing hormone (GnRH)
      receptor and the effects of GnRH analog (alarelin) on proliferation of cultured
      gastric smooth muscle cells (GSMC) of rats. METHODS: Immunohistochemical ABC
      methods and in situ hybridization methods were used to dectect protein and mRNA
      expression of GnRH receptor in GSMC, respectively. Techniques of cell culture, OD
      value of MTT test, measure of (3)H-TdR incorporation, average fluorescent values
      of proliferating cell nuclear antigen (PCNA) and flow cytometric DNA analysis
      were used in the experiment. RESULTS: The cultured GSMC of rats showed
      immunoreactivity for GnRH receptor; positive staining was located in cytoplasm.
      GnRH receptor mRNA hybridized signals were also detected in cytoplasm. When
      alarelin (10(-9), 10(-7), 10(-5) mol/L) was administered into the medium and
      incubated for 24 h, OD value of MTT, (3)H-TdR incorporation and average
      fluorescent values of PCNA all decreased significantly as compared with the
      control group (P<0.05). The maximum inhibitory effect on cell proliferation was
      achieved a concentration of 10(-5) mol/L and it acted in a dose-dependent manner.
      Flow cytometric DNA analysis revealed that alarelin could significantly enhance
      ratio of G(1) phase and decrease ratio of S phase of GSMC of rats (P<0.05). The
      maximum inhibitory effect on ratio of S phase was at the concentration of 10(-5)
      mol/L and also acted in a dose-dependent manner. CONCLUSION: Our data suggest
      that GnRH receptor can be expressed by GSMC of rats. GnRH analogue can directly
      inhibit proliferation and DNA synthesis of rat GSMC through GnRH receptors.

PMID- 15188506
TI  - Evaluation of the viability and energy metabolism of canine pancreas graft
      subjected to significant warm ischemia damage during preservation by UW solution
      cold storage method.
AB  - AIM: To evaluate the viability and energy metabolism of long warm ischemically
      damaged pancreas during preservation by the UW solution cold storage method.
      METHODS: The pancreas grafts subjected to 30-120 min warm ischemia were preserved
      by the UW solution cold storage method for 24 h. The tissue concentrations of
      adenine nucleotides (AN) and adenosine triphosphate (ATP) and total adenine
      nucleotides (TAN) were determined by using high performance liquid chromatography
      (HPLC) and the viability of the pancreas graft was tested in the canine model of
      segmental pancreas autotransplantation. RESULTS: The functional success rates of
      pancreas grafts of groups after 30 min, 60 min, 90 min, 120 min of warm ischemia
      were 100%, 100%, 67.7%, 0%, respectively. There was an excellent correlation
      between the posttransplant viability and tissue concentration of ATP and TAN at
      the end of preservation. CONCLUSION: The UW solution cold storage method was
      effective for functional recovery of the pancreas suffering 60-min warm ischemia.
      The tissue concentration of ATP and TAN at the end of 24 h preservation by the UW
      solution cold storage method would predict the posttransplant outcome of pancreas
      graft subjected to significant warm ischemia.

PMID- 15188508
TI  - Investigation of regurgitation and other symptoms of gastroesophageal reflux in
      Indonesian infants.
AB  - AIM: To evaluate the incidence of regurgitation and other symptoms of
      gastroesophageal reflux in Indonesian infants. METHODS: In a cross-sectional
      study at the University Outpatient Clinic for vaccination in Jakarta, 138 mothers
      of healthy infants less than 12-mo old were prospectively asked to report the
      frequency of regurgitation. RESULTS: Whatever the age was, some infants did not
      regurgitate (from 10% during the first month of life to 67% in 1-year-old
      infants). Regurgitation of at least once a day was reported in 77% of infants
      younger than 3 mo. Daily regurgitation decreased to 12% in the 9-12 mo old group.
      Reported peak prevalence was 81%(26/32) during the first month of life.
      Regurgitation decreased sharply between the 4-6 and 7-9 mo old groups (from 44%
      to 9%). The longer the regurgitation persisted, the more frequently the mother
      perceived regurgitation as a problem. Volume and frequency of regurgitation, back
      arching, irritability, crying and refusal of feeding were the symptoms causing
      maternal anxiety. The longer the regurgitation persisted, the more frequently the
      mothers viewed it as a health problem. CONCLUSION: Regurgitation occurs
      frequently in Indonesian infants, and is a frequent cause of concern to mothers.

PMID- 15188507
TI  - Heme oxygenase-1 in cholecystokinin-octapeptipe attenuated injury of pulmonary
      artery smooth muscle cells induced by lipopolysaccharide and its signal
      transduction mechanism.
AB  - AIM: To study the effect of cholecystokinin-octapeptide (CCK-8) on
      lipopolysaccharide (LPS) -induced pulmonary artery smooth muscle cell (PASMCs)
      injury and the role of heme oxygenase-1 (HO-1), and to explore the regulation
      mechanism of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) signal
      transduction pathway in inducing HO-1 expression further. METHODS: Cultured
      PASMCs were randomly divided into 4 or 6 groups: normal culture group, LPS (10
      mg/L), CCK-8 (10(-6) mol/L) plus LPS (10 mg/L) group, CCK-8 (10(-6) mol/L) group,
      zinc protoporphyrin 9 (ZnPPIX) (10(-6) mol/L) plus LPS (10 mg/L) group, CCK-8
      (10(-6) mol/L) plus ZnPPIX and LPS (10 mg/L) group. Seven hours after LPS
      administration, ultrastructural changes and content of malondialdehyde (MDA) of
      PASMCs in each group were investigated by electron microscopy and biochemical
      assay respectively. HO-1 mRNA and protein of PASMCs in the former 4 groups were
      examined by reverse transcriptase polymerase chain reaction (RT-PCR) and
      immunocytochemistry staining. Changes of c-fos expression and activation of JNK
      of PASMCs in the former 4 groups were detected with immunocytochemistry staining
      and Western blot 30 min after LPS administration. RESULTS: The injuries of PASMCs
      and the increases of MDA content induced by LPS were alleviated and significantly
      reduced by CCK-8 (P<0.05). The specific HO-1 inhibitor- ZnPPIX could worsen LPS
      induced injuries and weaken the protective effect of CCK-8. The expressions of c
      fos, p-JNK protein and HO-1 mRNA and protein were all slightly increased in LPS
      group, and significantly enhanced by CCK-8 further (P<0.05). CONCLUSION: HO-1 may
      be a key factor in CCK-8 attenuated injuries of PASMCs induced by LPS, and HO-1
      expression may be related to the activation of JNK and activator protein (AP-1).

PMID- 15188509
TI  - Severity of gastroesophageal reflux disease influences daytime somnolence: a
      clinical study of 134 patients underwent upper panendoscopy.
AB  - AIM: To asses the relationship between severity of gastroesophageal refluxe
      disease and Epworth sleepiness scale as an indicator of daytime somnolence.
      METHODS: One hundred and thirty-four patients underwent an upper panendoscopy as
      indicated by the typical reflux symptoms and were also investigated with regard
      to somnolence. Sleepiness was evaluated by Epworth Sleepiness Scale, which was
      compared to the severity of endoscopic findings (Savary-Miller/modified by
      Siewert). Patients with psychiatric disorders or being on sedato-hypnotics as
      well as shift workers were excluded from the study. The relationship between the
      severity of the reflux disease and daytime somnolence was analyzed with the help
      of multivariate regression analysis. RESULTS: A positive tendency was found
      between the severity of the reflux disease and the corresponding Epworth
      Sleepiness Scale. In the case of the more severe type - Savary-Miller III - at
      least a mild hypersomnia was found. For this group daytime somnolence was
      significantly higher than in the case of the non-erosive type of Gastroesophageal
      Reflux Disease representing the mildest stage of reflux disease. CONCLUSION: The
      severity of Gastroesophageal Reflux Disease influences daytime somnolence.

PMID- 15188510
TI  - Intestinal microecology and quality of life in irritable bowel syndrome patients.
AB  - AIM: It has been noticed that gastroenteritis or dysentery plays a role in
      pathogenesis of irritable bowel syndrome (IBS), and antibiotics can increase
      functional abdominal symptoms, both of which may be partly due to intestinal
      flora disorders. This study was to determine the change of gut flora of IBS, a
      cluster of abdominal symptoms. Because of the chronic course and frequent
      occurrence of the disease, IBS patients suffered much from it. So the quality of
      life (Qol) of IBS patients was also evaluated in this study. METHODS: Twenty-five
      Rome II criteria-positive IBS patients were recruited, and 25 age and gender
      matched healthy volunteers were accepted as control. The fecal flora, including
      Lactobacillus, Bifidobacterium, Bacteroides, C. perfringens Enterobacteriacea and
      Enterococus, were analyzed quantitatively and qualitatively. We also calculated
      the ratio of Bifidobacterium to Enterobacteriaceae (B/E ratio) in both IBS
      patients and controls. In both groups, the data were further analyzed based on
      age difference, and comparisons were made between the younger and elder
      subgroups. We also evaluated the quality of life (QoL) of IBS patients and the
      control group using the Chinese version of SF-36 health questionnaire. RESULTS:
      In IBS patients, the number of fecal Bifidobacterium was significantly decreased
      and that of Enterobacteriaceae was significantly increased compared with that in
      healthy controls (both P<0.05). The mean microbial colonization resistance (CR)
      of the bowel in IBS patients was smaller than 1, making a significant difference
      compared with that in control which was more than 1 (P<0.01). There was no
      significant difference in gut flora between two subgroups. While in control, the
      elder subgroup presented more Enterobacteriacea than the younger one (P<0.05).
      Compared with the control group, IBS patients had significantly lower scores on
      all SF-36 scales, with the exception of physical functioning. However, there was
      no significant correlation between quality of life and enteric symptoms in IBS
      patients. CONCLUSION: There are intestinal flora disorders in IBS patients, which
      may be involved in triggering the IBS-like symptoms. IBS patients experience
      significant impairment in QoL, however, the impairment is not caused directly by
      enteric symptoms.

PMID- 15188511
TI  - Management of nonfunctioning islet cell tumors.
AB  - AIM: To more clearly define the clinical and pathological characteristics and
      appropriate diagnosis and treatment of nonfunctioning (NFICTs) islet cell tumors,
      and to review our institutional experience over the last 30 years. METHODS: The
      records of 43 patients confirmed to have nonfunctioning islet cell tumors of
      pancreas were retrospectively reviewed. Survival was estimated by the Kaplan
      Meier methods and potential risk factors for survival were compared with the log
      rank tests. RESULTS: The mean age was 31.63 years (range, 8 to 67 years). There
      were 7 men and 36 women. Twenty-eight patients had a confirmed diagnosis of
      nonfunctioning islet cell carcinoma (NFICC) and benign islet cell tumors were
      found in 15 patients. The most common symptoms in patients with NFICTs were
      abdominal pain (55.8%), nausea and/or vomiting (32.6%), fatigue (25.6%) and
      abdominal mass (23.3%). Preoperative ultrasonic and computed tomography localized
      the tumors in all patients. Forty-three NFICTs were distributed throughout the
      pancreas, with 21 located to the right of the superior mesenteric vessels, 10 in
      the body of the pancreas, 6 in the tail of the pancreas, and multiple tumors were
      found in one patient. Thirty-nine of 43 patients (91%) underwent surgical
      resection. Surgical treatment was curative in 30 patients (70%) and palliative in
      9(21%). The resectability and curative resection rate in patients with NFICC of
      pancreas were 89% and 61%, respectively. The overall cumulative 5- and 10-year
      survival rates for patients with NFICC were 58.05% and 29.03%, respectively.
      Radical operation and diameter of cancer small than 10 cm were positive
      prognostic factors in females younger than 30 years old. Multivariate Cox
      regression analysis indicated that radical operation was the only independent
      prognostic factor, P=0.007. CONCLUSION: Nonfunctioning islet cell tumors of
      pancreas are found mainly in young women. The long-term results for patients
      undergone surgery, especially curative resection are good.

PMID- 15188512
TI  - Association of -238G/A polymorphism of tumor necrosis factor-alpha gene promoter
      region with outcomes of hepatitis B virus infection in Chinese Han population.
AB  - AIM: To clarify whether -238G/A polymorphism of tumor necrosis factor-alpha (TNF
      alpha) gene promoter region was associated with outcomes of hepatitis B virus
      (HBV) infection in Han population of northern China, and to analyze the gene
      environment interaction between -238G/A polymorphism and cigarette smoking or
      alcohol consumption. METHODS: A case-control study was conducted to analyze the
      association of TNF-alpha gene promoter polymorphism with HBV infection outcomes.
      A total of 207 patients with chronic hepatitis B (HB) and 148 cases of self
      limited HBV infection from Ditan Hospital and Shunyi District Hospital in
      Beijing, respectively were recruited. History of smoking and alcohol drinking was
      inquired by a questionnaire. The -238G/A polymorphism of TNF-alpha gene promoter
      was genotyped by polymerase chain reaction-restricted fragment length
      polymorphism (PCR-RFLP). RESULTS: The frequencies of GG and GA genotypes were
      98.07% and 1.93% in chronic HB patients and 93.24% and 6.76% in self-limited HBV
      infection individuals, respectively (chi(2)=5.30, P=0.02). The frequency of G
      allele was significantly higher in patients with chronic HB that in individuals
      with self-limited HBV infection (99.03% vs 96.62%, chi(2)=5.20, P=0.02). Only
      modestly increased risk of onset of chronic HB was found in smokers (OR=1.40, 95%
      CI: 0.87-2.28, P=0.14) and drinkers (OR=1.26, 95%CI: 0.78-2.05, P=0.32). There
      was a positive interaction between genotype GG and cigarette smoking with an
      interaction index (II) of 2.95, or alcohol consumption with an II of 1.64.
      CONCLUSION: The -238G/A polymorphism of TNF-alpha gene promoter region is
      independently associated with different outcomes of HBV infection.

PMID- 15188513
TI  - Hypermethylation of Syk gene in promoter region associated with oncogenesis and
      metastasis of gastric carcinoma.
AB  - AIM: To investigate the relationship between methylation of Syk (spleen tyrosine
      kinase) gene in promoter region and oncogenesis, metastasis of gastric carcinoma.
      The relation between silencing of the Syk gene and methylation of Syk promoter
      region was also studied. METHODS: By using methylation-specific PCR (MSP)
      technique, the methylation of Syk promoter region in specimens from 61 gastric
      cancer patients (tumor tissues and adjacent normal tissues) was detected.
      Meanwhile, RT-PCR was used to analyse syk expression exclusively. RESULTS: The
      expression of the Syk gene was detected in all normal gastric tissues. Syk
      expression in gastric carcinoma was lower in 14 out of 61 gastric cancer samples
      than in adjacent normal tissues (chi(2)=72.3, P<0.05). No methylation of Syk
      promoter was found in adjacent normal tissues. hypermethylation of Syk gene in
      promoter was detected 21 cases in 61 gastric carcinoma patients. The rate of
      methylation of Syk promoter in gastric carcinoma was higher than that in adjacent
      normal tissues (chi(2)=25.1, P<0.05). In 31 patients with lymph node metastasis,
      17 were found with Syk promoter methylation. A significant difference was noted
      between two groups (chi(2)=11.4,P<0.05). CONCLUSION: Hypermethylation leads to
      silencing of the Syk gene in human gastric carcinoma. Methylation of Syk promoter
      is correlated to oncogenesis and metastasis of gastric carcinoma. Syk is
      considered to be a potential tumor suppressor and anti-metastasis gene in human
      gastric cancer.

PMID- 15188514
TI  - Comparison of nuclear matrix proteins between gastric cancer and normal gastric
      tissue.
AB  - AIM: To study the alteration of nuclear matrix proteins (NMPs) in gastric cancer.
      METHODS: The NMPs extracted from 22 cases of gastric cancer and normal gastric
      tissues were investigated by SDS-PAGE technique and the data were analyzed using
      Genetools analysis software. RESULTS: Compared with normal gastric tissue, the
      expression of 30 ku and 28 ku NMPs in gastric cancer decreased significantly
      (P=0.002, P=0.001, P<0.05). No significant difference was found in the expression
      of the two NMPs between the various differentiated grades (P=0.947, P=0.356) and
      clinical stages of gastric cancer (P=0.920, P=0.243, P>0.05). CONCLUSION: The
      results suggested that the alteration of NMPs in gastric cancer occurred at the
      early stage of gastric cancer development.

PMID- 15188515
TI  - Apoptosis of human primary gastric carcinoma cells induced by genistein.
AB  - AIM: To investigate the apoptosis in primary gastric cancer cells induced by
      genistein, and the relationship between this apoptosis and expression of bcl-2
      and bax. METHODS: MTT assay was used to determine the cell growth inhibitory rate
      in vitro. Transmission electron microscope and TUNEL staining were used to
      quantitatively and qualitatively detect the apoptosis of primary gastric cancer
      cells before and after genistein treatment. Immunohistochemical staining and RT
      PCR were used to detect the expression of apoptosis-associated genes bcl-2 and
      bax. RESULTS: Genistein inhibited the growth of primary gastric cancer cells in
      dose-and time-dependent manner. Genistein induced primary gastric cancer cells to
      undergo apoptosis with typically apoptotic characteristics. TUNEL assay showed
      that after the treatment of primary gastric cancer cells with genistein for 24 to
      96 h, the apoptotic rates of primary gastric cancer cells increased time
      dependently. Immunohistochemical staining showed that after the treatment of
      primary gastric cancer cells with genistein for 24 to 96 h, the positivity rates
      of Bcl-2 proteins were apparently reduced with time and the positivity rates of
      Bax proteins were apparently increased with time. After exposed to genistein at
      20 micromol/L for 24, 48, 72 and 96 respectively, the density of bcl-2 mRNA
      decreased progressively and the density of bax mRNA increased progressively with
      elongation of time. CONCLUSION: Genistein is able to induce the apoptosis in
      primary gastric cancer cells. This apoptosis may be mediated by down-regulating
      the apoptosis- associated bcl-2 gene and up-regulating the expression of
      apoptosis-associated bax gene.

PMID- 15188516
TI  - Polymorphisms of interleukin-1B and interleukin-1 receptor antagonist genes in
      patients with chronic hepatitis B.
AB  - AIM: To investigate the relationships between polymorphisms of interleukin-1B (IL
      1B) promoter region -511C/T and interleukin-1 receptor antagonist gene (IL-1RN)
      and susceptibility to chronic hepatitis B in Chinese population. METHODS: Genomic
      DNA was extracted from the peripheral blood of 190 patients with chronic
      hepatitis B and 249 normal controls and then subjected to polymerase chain
      reaction (PCR) amplification. The PCR products were digested by restriction
      endonuclease AvaI. The products of digestion were subjected to 20 g/L gel
      electrophoresis and ethidium bromide staining. RESULTS: The frequencies of IL-1B
      (-511) genotypes CC, CT and TT in patients with chronic hepatitis B were 23.7%,
      49.5% and 26.8%, while 26.1%, 47.4% and 26.5% respectively in controls. The
      results showed that there was no significant difference in the frequencies of
      alleles or genotypes in IL-1B between patients with chronic hepatitis B and
      controls. The distributions of IL-1B (-511) genotype CC were significantly
      different between the two subgroups (HBV-DNA </=1x10(3) copies/mL as subgroup I,
      HBV-DNA >1x10(3) copies/mL as subgroup II) of chronic hepatitis B (P=0.029). Only
      four of the five kinds of polymorphism (1/1, 1/2, 2/2 and 1/4) were found in this
      study. The frequencies of IL-1RN genotypes 1/1, 1/2, 2/2 and 1/4 were 88.9%,
      9.0%, 0.5% and 1.6% in patients with chronic hepatitis B respectively, while were
      81.1%, 16.9%, 0.4% and 1.6% respectively in controls. The frequencies of
      genotype1/2 and IL-1RN allele 2 in patients with chronic hepatitis B were lower
      than those in controls (P=0.016 and P=0.029, respectively). CONCLUSION: There is
      an association between polymorphisms of the promoter region -511C/T of IL-1B and
      IL-1RN intron 2 and chronic hepatitis B virus infection. Subjects with IL-1RN
      allele 2 may be resistant to HBV infection, and IL-1B(-511)genotype CC is closely
      related with HBV-DNA replication, which gives some new clues to the study of
      pathogenesis of chronic hepatitis B.

PMID- 15188517
TI  - Effects of tegaserod on Fos, substance P and calcitonin gene-related peptide
      expression induced by colon inflammation in lumbarsacral spinal cord.
AB  - AIM: To investigate the mechanisms of tegaserod, a partial 5-HT4 agonist, in
      reducing visceral sensitivity by observing Fos, substance P (SP) and calcitonin
      gene-related peptide (CGRP) expression in the lumbarsacral spinal cord induced by
      colonic inflammation in rats. METHODS: Twenty-four male rats with colonic
      inflammation induced by intraluminal instillation of trinitrobenzenesulfonic acid
      (TNBS) were divided into 3 groups. Treatment group 1: intra-gastric
      administration of tegaserod, 2 mg/kg.d; Treatment group 2: intra-gastric
      administration of tegaserod, 1 mg/kg.d; CONTROL GROUP: intra-gastric
      administration of saline, 2.0 mL/d. After 7 d of intra-gastric administration,
      lumbarsacral spinal cord was removed and processed for Fos, SP and CGRP
      immunohistochemistry. RESULTS: In rats of the control group, the majority of Fos
      labeled neurons was localized in deeper laminae of the lumbarsacral spinal cord
      (L(5)-S(1)). SP and CGRP were primarily expressed in the superficial laminae of
      the spinal cord after TNBS injection. Intra-gastric administration of tegaserod
      (2 mg/kg.d) resulted in a significant decrease of Fos labeled neurons (22.0+/
      7.7) and SP density (12.5+/-1.4) in the dorsal horn in the lumbarsacral spinal
      cord compared to those of the control group (62.2+/-18.9, 35.9+/-8.9, P<0.05).
      However, CGRP content in dorsal horn did not significantly reduce in rats of
      treatment group 1 (1.2+/-1.1) compared to that of the control group (2.8+/-2.4,
      P>0.05). Neither Fos expression nor SP or CGRP density in the dorsal horn
      significantly declined in rats of treatment group 2 compared to those of the
      control group (P>0.05). CONCLUSION: Tegaserod can significantly reduce Fos
      labeled neurons in the lumbarsacral spinal cord induced by colonic inflammation.
      Tegaserod may reduce visceral sensitivity by inhibiting SP expression in the
      dorsal horn of spinal cord.

PMID- 15188519
TI  - Fathal pulmonary hypertension after distal splenorenal shunt in schistosomal
      portal hypertension.

PMID- 15188518
TI  - Epidemiological investigation of esophageal carcinoma.
AB  - AIM: To review the characteristics of esophageal carcinoma in recent 30 years in
      the epidemiological investigation. METHODS: A total of 1 520 cases of esophageal
      carcinoma in the First Affiliated Hospital of Zhejiang University Medical College
      admitted from 1970 until now were reviewed. Their age, gender, position of
      carcinoma and histological type were analyzed. RESULTS: The morbidity of
      esophageal carcinoma was increasing during the observation period. Compared with
      the 1970s (9.5%), the ratio of adenocarcinoma significantly increased after the
      1980s (19.1%). The difference was significant (P</=0.05). CONCLUSION: The
      morbidity of esophageal adenocarcinoma was increasing and advanced clinical study
      should be strengthened.

PMID- 15188520
TI  - Gastric ulcer penetrating to liver diagnosed by endoscopic biopsy.
AB  - Liver penetration is a rare but serious complication of peptic ulcer disease.
      Usually the diagnosis is made by operation or autopsy. Clinical and laboratory
      data were no specific. A 64-year-old man was admitted with upper gastrointestinal
      bleeding. Hepatic penetration was diagnosed as the cause of bleeding. Endoscopy
      showed a large gastric ulcer with a pseudotumoral mass protruding from the ulcer
      bed. Definitive diagnosis was established by endoscopic biopsies of the ulcer
      base.

PMID- 15188521
TI  - Inflammatory pseudotumor of the liver in association with a gastrointestinal
      stromal tumor: a case report.
AB  - Inflammatory pseudotumor of the liver is a rare benign lesion that can mimic a
      malignant liver neoplasm. A case of inflammatory pseudotumor of the liver found
      in association with a malignant gastrointestinal stromal tumor (GIST) of the
      small bowel was reported. The inflammatory pseudotumor was misdiagnosed as a
      metastasis from the GIST by frozen section. A correct diagnosis was made only
      after histopathological examination of the paraffin section of the resected
      specimen. This case is particularly interesting because of the association of the
      two rare pathological entities and the diagnostic dilemma that arose from the
      similarity of their histological appearances. To our knowledge, this association
      has not been reported in the literature.

PMID- 15188523
TI  - The 'M' word.

PMID- 15188522
TI  - Human cyclosporiosis in Turkey.
AB  - Six patients infected with Cyclospora cayetanensis who sought medical care at
      three different hospitals in Turkey are herein presented. Four patients were male
      and the others were female and their ages ranged from 7 to 62 years. The first
      patient was HIV-positive and presented with watery diarrhea with a frequency of
      up to 18 times a day for more than ten months and diagnosed as cyclosporiosis in
      Kayseri, 1996. The second patient was also HIV positive and diagnosed as
      cyclosporiosis in Kayseri, 2000. The third patient was an acute myeloblastic
      leukemia (AML) patient and diagnosed in Istanbul, 2000. The fourth patient was
      idiopathic hepatic cirrhosis complaining of diarrhea and weakness and diagnosed
      in Kayseri, 2001. The fifth and sixth patients were immunocompetent patients
      complaining of diarrhea and diagnosed in Izmir and Kayseri, 2002. Diarrhea
      occurring from one to ten times a day continued for 7 to 70 d in the last 5
      patients. Treatment with a trimethoprim/sulfamethoxazole compound was done for
      all patients. Both symptomatic and parasitologic improvements were quickly
      observed. In summary, C. cayetanensis infection is rare in Turkey and most
      patients infected with this pathogen tend to be immunosuppressive individuals at
      present.

PMID- 15188524
TI  - Diabetes mellitus and oral care.
AB  - Diabetes is a common condition. Its incidence is increasing. It can lead to
      medical complications including visual impairment, neuropathies, renal and
      cardiovascular disease. Diabetes can have an adverse effect on oral health and
      healthcare. Conversely, poor oral health can have an adverse effect on blood
      glucose control. Repeated oral infections can indicate uncontrolled diabetes and
      lead to its diagnosis. Whereas hyperglycaemia may occur in untreated diabetes,
      hypoglycaemic episodes are not uncommon in well-controlled diabetes Type 2. The
      tight glycaemic control required to prevent its long-term complications can be
      destabilized by infection, anxiety or missed meals.

PMID- 15188525
TI  - Use of dental photography by general dental practitioners in Great Britain.
AB  - This study assesses, by means of a postal questionnaire, the numbers of general
      dental practitioners who use clinical photography, and the uses to which this is
      applied. The questionnaire was distributed to 1000 randomly selected GDPs in
      Great Britain. A response rate of 76% was achieved. Of the respondents, 36% used
      clinical photography, with 65% of those using an intra-oral 35 mm camera, 18% a
      digital camera and 12% an intra-oral digital video camera. Principal uses of
      clinical photography were patient instruction/motivation (72%), medico-legal
      reasons (68%), treatment planning (63%), and liaison with laboratory (43%).

PMID- 15188526
TI  - Managing discoloured non-vital teeth: the inside/outside bleaching technique.
AB  - The discoloured, non-vital anterior tooth is a common aesthetic concern for many
      patients. It can have a profound effect on their self-esteem, interaction with
      others and employability. Discoloured non-vital teeth are frequently compromised
      owing to previous trauma, caries, endodontic therapy and failed restorations.
      Destructive invasive treatment options are likely to weaken the residual
      structure of the tooth. This can reduce the prognosis and challenge the long-term
      viability of the tooth, thereby initiating further prosthetic predicaments. This
      paper discusses modern approaches to the treatment of discoloured teeth. The
      importance of preventing and eliminating the potential for discoloration will be
      highlighted. The paper will include a detailed technical account on the
      application of the inside/outside bleaching technique, with several clinical
      examples.

PMID- 15188527
TI  - The contemporary use of removable orthodontic appliances.
AB  - Although apparently simple and efficient to use, removable appliances are no
      longer the appliance of choice for comprehensive orthodontic treatment in the
      permanent dentition. Their mechanical properties result in simple tipping of
      teeth, therefore multiple simultaneous tooth movements with apical control are
      not possible. It is for these and other reasons that removable appliances are
      usually only indicated for specific interventions in the mixed dentition, and as
      an adjunct to more complex fixed appliance treatment. Removable appliances, once
      popular because of their case of use, are no longer seen as the appliance of
      choice. This article discusses the rationale behind this statement and indicates
      cases suitable for removable appliance treatment.

PMID- 15188528
TI  - Management of a supra-erupted premolar: a case report.
AB  - Supra-erupted teeth often lead to occlusal instability that can result in a poor
      appearance and make subsequent restoration problematical. This case report
      discusses the options in the management of supra-erupted teeth and presents a
      novel approach. The use of a direct composite platform to intrude an upper
      premolar tooth using the Dahl concept is illustrated.

PMID- 15188529
TI  - Giant osteomata of the mandible.
AB  - Osteomas are benign tumours of bone. They are uncommon in the jaws and usually
      present because of facial asymmetry or trismus. Osteomas arising from the lingual
      aspect of the mandibular ramus are rare and asymptomatic, usually discovered on
      routine radiography. We present two cases, and discuss their aetiology,
      presentation and management.

PMID- 15188530
TI  - The potentially fatal vascular anomaly and orthodontic treatment--a case report.
AB  - Oral vascular lesions are of clinical importance to the dental profession because
      they pose serious bleeding risks. A case report is presented here where a patient
      with a complex palatal vascular malformation was successfully treated with fixed
      appliances. The problems encountered during treatment are discussed.

PMID- 15188531
TI  - Dental management of the myasthenic patient.
AB  - Myasthenia gravis (MG) is an auto-immune disorder of neuromuscular transmission
      which results in weakness and fatigue of skeletal muscles. The defect in
      neuromuscular transmission is most commonly seen in the muscles of the eyes,
      face, neck and shoulders but, in some patients, the respiratory muscles are
      involved. Patients with this condition may present with problems that necessitate
      special consideration when managing their dental treatment. Patients who are only
      mildly affected by MG can be treated in general dental practice for routine care.
      There are no contra-indications to the use of local anaesthetic agents and the
      presence of a vasoconstrictor is desirable. More severely affected patients and
      those who are very anxious about dental treatment should be cared for within the
      hospital environment. In these patients, respiratory muscles may be affected and,
      as a result, a myasthenic crisis may arise which requires assisted ventilation
      and, in some cases, intubation. Those patients who are fearful of the dental
      environment are likely to be emotionally stressed during such times and this
      increases the risk of a myasthenic crisis; sedation techniques can be beneficial
      in this group of patients.

PMID- 15188532
TI  - Physical signs for the general dental practitioner. Case 14.

PMID- 15188533
TI  - [Methodical basis for creation of the military telemedicine system in the Russian
      Federation Armed Forces].
AB  - Today the telemedicine (TM) is the perspective and rapidly developing direction
      in the health service. It also concerns the military medicine. In the RF Armed
      Forces' interests the work on creation of military telemedicine system within the
      framework of experimental-and-designers' work "Telemed" is conducted. During the
      development of software to realize the functions of military telemedicine system
      and to provide the development of its functional potentials the work was done
      connected with problem description in order to realize all medical technologies
      for each direction of its application. To solve this problem there are enough
      specialists in the field of computer and informative technologies capable of
      bringing the diagnostic and consultation possibilities of district (naval) and
      Central Military Hospitals as well as republican and regional centers closer to
      the solution of medical problems of distant garrisons.

PMID- 15188534
TI  - [Methodical and practical approaches to the management of health care quality
      control in a large military polyclinic].
AB  - The experience of creation and practical use of the medical care quality (MCQ)
      control system in the Diagnostic center N 52 is summarized. The measures
      realizing the functions of planning, motivation and organization during MCQ
      control are described. The goals, objects and system elements, functional duties
      and algorithm of officials' actions during the continuous MCQ support are
      substantiated. Introduction of some elements of MCQ control system caused the
      decrease in the number of patients' complaints, defects in rendering of medical
      care and complications.

PMID- 15188535
TI  - [Surgical tactics in thyroid nodular neoplasms associated with chronic autoimmune
      thyroiditis].
AB  - There were analyzed the results of surgical treatment of 628 patients with
      different thyroid nodular neoplasms combined with autoimmune thyroiditis, who
      were operated in the surgical department of the Mandryka Central Military
      Clinical Hospital in 1989-2001. The use of organ-preserving operations is
      substantiated by the necessity of maximal decrease of the post-operative
      complication level and preservation of thyroid hormonogenic function. Resection
      with node removal within the limits of healthy tissues is substantiated by the
      results of analysis of morphologic structure of nodular neoplasm and adjacent
      thyroid tissue. The analysis of repeated operations has shown that the etiology
      and morphologic structure of nodular neoplasm (but not the volume of operation)
      play the main role in the pathogenesis of relapse development.

PMID- 15188536
TI  - [Modern methods of radiodiagnostics of urological diseases].

PMID- 15188537
TI  - [Gastroesophageal reflux disease as the cause of retrosternal pain: differential
      diagnosis of ischemic heart disease].

PMID- 15188538
TI  - [Efficiency of mass screening system and routine medical check-up of glaucoma
      patients].

PMID- 15188539
TI  - [Course of arterial hypertension associated with atherosclerosis of
      brachiocephalic arteries].

PMID- 15188540
TI  - [Surveillance of prostate adenoma patients administering selective alpha-1a
      adrenoblocker].

PMID- 15188541
TI  - [Rational approach to drug therapy is the basis for life quality management in
      patients with Parkinson's disease].

PMID- 15188542
TI  - [Circadian rhythm of arterial pressure in patients with cerebral lacunar
      infarction].

PMID- 15188543
TI  - [New tactics in caring patients with diffused mastopathy: detection,
      classification, diagnosis].

PMID- 15188544
TI  - [Analysis of itch incidence among the Russia population and Armed Forces
      personnel].

PMID- 15188545
TI  - [Landmarks in the history of the Madryka Central Military Clinical Hospital].

PMID- 15188546
TI  - [The outstanding figure of Russian military medicine].

PMID- 15188547
TI  - [Development of angioneurology in the Mandryka Central Military Clinical
      Hospital].

PMID- 15188548
TI  - [Functional diagnostics in the Mandryka Central Military Clinical Hospital: the
      history of formation, development perspectives].

PMID- 15188549
TI  - [Characterization of Vibrio cholerae O1 cultures isolated from environmental
      objects on the territory of the Russian Federation in 2002].
AB  - The biological properties of 46 V. cholerae O1 eltor cultures isolated in 2002
      from water environment on the territory of Russia are presented. All isolated
      vibrios proved to be typical in their cultural, morphological, biochemical and
      serological properties. The atypical character of some of them was mainly linked
      with their phage resistance. The appearance of vibrios, sensitive to
      bacteriophage ctx+ and containing gene tcp in the absence gene ctx, was noted.
      Multilocus VNTR typing made it possible to group the cultures under study in 34
      genotypes. The presence of toxin coregulated pili was found to be directly
      related to locus VcB. The necessity of the systematic study of the pheno- and
      genotypes of the isolated cultures with the aim of epidemiological surveillance
      of this infection is emphasized.

PMID- 15188550
TI  - [Transition of Vibrio cholerae into the non-culturable state under the conditions
      of low temperature, different mineralization and illumination of artificial
      culture medium].
AB  - The importance of the combined influence of temperature, mineralization and
      illumination of the medium on the time of the transition of V. cholerae into the
      uncultivable state has been shown. The reversion of 5- to 60-day variants of
      uncultivable forms after the elevation of temperature to 20-22 degrees C has been
      obtained.

PMID- 15188551
TI  - [Triacylglycerol lipase activity of hemolytic Vibrio cholerae].
AB  - The new method for the determination of the lipase activity of purified
      preparations of hemolysins and live V. cholerae cell has been developed. On the
      basis of the determination of triacylglycerollipase (lipase) activity the test
      for the differentiation of hemolytic and nonhemolytic V. cholerae has been
      proposed.

PMID- 15188552
TI  - [Development of the controlled model of persisting infection , caused by
      Pseudomonas aeruginosa and bacteria of the complex Burkholderia cepacia].
AB  - As the result of testing three different variants, the experimental models of
      persisting infection for P. aeruginosa and B. cepacia have been developed. These
      doses differ in the time of administration, doses of antibiotics and the
      infective doses of the microorganisms. The administration of the sub-inhibiting
      concentration of antibiotics for 5 days and the subsequent infection of
      laboratory animals (non-inbred mice) B. cepacia strains in a dose of LD50 leads
      to a considerable increase in the survival rate of mice and to a longer period
      (up to 20 days) of obtaining inoculative material from the spleen. The isolated
      cultures are characterized by a sharply slower growth on artificial culture media
      (up to 5-7 days as compared with 24-48 hours for the initial culture). The newly
      developed models have made it possible to control different stages of the
      infectious process in the induced increase or decrease of the virulent properties
      of the infective agent and in changes in the immune status of the host. As the
      result of these studies, in some mice (10%) infected with B. cepacia after the
      injection of gamma-hydroxybutyric acid lactone the infection has taken the acute
      form, while in the mice infected with P. aeruginosa no such effect has been
      observed. On the contrary, in the mice infected with P. aeruginosa and then
      receiving cyclophosphamide the transition of the infection into the acute form
      has been observed in 30% of the animals. In the mice infected with B. cepacia no
      such effect has been noted after the injection of this preparation. Different
      effects produced by cyclophosphamide and lactone are discussed from the positions
      of "quorum sensing" in pathogenic bacteria.

PMID- 15188553
TI  - [Multilocus VNTR-typing of Francisella tularensis strains].
AB  - In the analysis of F. tularensis genome with the use of the specially developed
      program "DNA" a great number of loci containing tandem repeats were found. For
      analysis, 3 of them were selected and designated as FtA, FtB, FtC. The study of
      DNA of 40 F. tularensis strains in the polymerase chain reaction with specific
      primers to these loci a great variability in the number of repeats was
      established, the presence of 17 alleles being found in locus FtA, 5 alleles in
      locus FtB and 5 alleles in locus FtC. The strains under study formed 24 variants
      of genotypes, whose occurrence varied from 0.025 to 0.125. Taking into account
      the variability of the detected loci and a great number of potential loci VNTR in
      the genome, further development of this method will facilitate the creation of
      local and general data bases of the strains, thus ensuring more effective genetic
      typing of F. tularensis.

PMID- 15188554
TI  - [Detection of Rickettsia hulinii in ticks of the Haemaphysalis concinna species
      in Russia].
AB  - The presence of Rickettsia hulinii was detected in ticks of the Haemaphysalis
      concinna species in the Asiatic part of Russia. It was the first detection of
      these rickettsiae outside the territory of the Chinese People's Republic. This
      tick is spread over a broken area and may occur in different regions of Eurasia.
      At present at least 3 rickettsial species of the tick-borne spotted fever group
      were found in Ixodes ticks on the territory of Eastern Siberia: R. sibirica,
      known to be the etiological agent of tick-borne rickettsiosis, R. hulinii with
      proved pathogenicity for laboratory animals and R.DnS14 with no data available on
      its pathogenicity.

PMID- 15188555
TI  - [Influence of temperature on the variability of Listeria monocytogenes in the
      course of its prolonged existence in soil-packed water-circulating columns].
AB  - The capacity of L. monocytogenes for prolonged existence in the soil at different
      temperatures (18-20 degrees C and 6-8 degrees C) has been shown. The viability of
      these bacteria in the soil depends both on their properties and the temperature
      factor. Low temperatures (6-8 degrees C) ensure, on the whole, the stable
      preservation of the biological properties of the bacteria. More pronounced
      variability of L. monocytogenes at a temperature of 18-20 degrees C is an
      adaptive property, ensuring high ecological plasticity of the bacteria and their
      prolonged existence in the soil.

PMID- 15188557
TI  - [Experimental study on the possibility of using live tularemia vaccine to
      increase resistance to heterologous infection disease].
AB  - In experiments on guinea pigs immunized with Francisella tularensis 15, or live
      tularemia vaccine (LTV), the level of heterologous protective effect to dangerous
      infectious diseases caused by Yersinia pestis, Burkholderia pseudomallei, B.
      mallei, Mycobacterium tuberculosis was studied. The study revealed that during
      the first 4 weeks after the subcutaneous immunization with LTV the level of
      resistance of the immunized animals to heterologous infective agent reliably
      increased as indicated by the survival rate of the animals, as well as by the
      survival time of those killed by infection, in comparison with the controls.
      Later (on day 150 after immunization) differences in death rate between the
      groups perceptibly decreased. Nevertheless, the 1 1/2-fold increase of the
      survival time of the challenged immunized animals in comparison with the controls
      proved the possibility of using immunization with LTV for the urgent prophylaxis
      and treatment not only of tularemia, but also of plague, glanders, melioidosis
      and tuberculosis.

PMID- 15188556
TI  - [Molecular epidemiology of HIV-infection in drug addicts of Southern Ural].
AB  - The analysis of HIV-1 variants circulating among drug addicts in 16 settlements
      of the Sverdlov, Chelyabinsk and Orenburg regions (72, 90 and 42 patients
      respectively) was carried out. As shown by the serological analysis, the spread
      of HIV-1 variant IDU-A among the drug addicts in this area continued in this area
      and could be detected in 99.5% of the samples (203 out of 204 samples). These
      data were confirmed by the results of the analysis of 35 samples by the
      Heteroduplex Mobility Assay for genes env and gag. The analysis of nucleotide
      sequences of gene env revealed that HIV-1 variants in the Southern Urals, where
      the greatest outbreak of HIV infection in Russia had been registered, were
      genetically related to viruses of subtype A, detected earlier in this group of
      risk in other regions of Russia, as well as in Ukraine, Belarus and other East
      European countries.

PMID- 15188558
TI  - [Immunobiological properties of monoclonal antibodies to Mycoplasma hominis
      antigens].
AB  - Approaches to obtaining stable mouse hybridomas synthesizing monoclonal
      antibodies (McAb) to M. hominis key antigens were developed. 4 clones capable of
      the stable synthesis of McAb of different IgG classes were obtained. Clones A3/2
      and A5/D produced antibodies to the thermostable determinant to with a mol. wt.
      of 80-120 kD, sensitive to sodium periodate and resistant to potassium
      proteinase. Clone H9/B2 synthesized McAb which interacted with potassium
      proteinase-sensitive M. hominis thermolabile determinant with a mol. wt. of 80
      kD. McAb of clone A3/2, labeled with fluorescein isothiocyanate and horse-radish
      peroxidase, specifically reacted with M. hominis antigens in the
      immunofluorescence test and the immunoenzyme assay (EIA). The sensitivity of EIA
      was 0.25 ng/ml of antigen protein. These data may serve as prerequisites for the
      development of diagnostic test systems aimed at the detection of M. hominis
      antigens in different clinical substances.

PMID- 15188560
TI  - [Interrelation between the activity of hepatitis, liver fibrosis and immune
      status in children with chronic hepatitis B and C].
AB  - The lesion of the liver in viral hepatitis was found to depend on the state of
      the immune system. Relationship between the content of lymphocyte subpopulations
      (CD3+, CD4+, CD8+, CD20+) in the blood and immunoglobulins (IgG, IgM, IgA) with
      parameters of semi-quantitative evaluation of the activity of hepatitis and the
      stage of liver fibrosis in children with chronic virus hepatitis B, C, B + C was
      studied. The characteristic feature of all hepatitis was a decrease in the number
      of T lymphocytes CD4+ below the normal level and an increase in the content of B
      lymphocytes. The correlation between the morphological activity of hepatitis and
      the amount of T lymphocytes CD8+ was established only in chronic hepatitis B. In
      chronic hepatitis B and B + C the absolute amount of blood lymphocytes decreased
      with the increase of the age of the patients, but in chronic hepatitis B this was
      accompanied by the decrease of the morphological activity of hepatitis and in
      hepatitis B + C by its increase. The amount of lymphocytes CD4+ rose with the
      increase of liver fibrosis in chronic hepatitis B. In children with chronic
      hepatitis C and B + C the amount of blood lymphocytes was found to be unrelated
      to the morphological activity of hepatitis.

PMID- 15188559
TI  - [Tumor necrosis factor-alpha and interleukin-4 in the blood sera of chronic
      hepatitis patients].
AB  - The concentration of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4
      (IL-4) in the blood sera of chronic hepatitis patients was, on the average,
      reliably higher than in the control group. A more pronounced increase in the
      concentration of TNF-alpha in the blood sera was observed in patients with
      chronic hepatitis of viral etiology in comparison with toxic hepatitis. The
      pronounced cytokine response of type Th2, manifested by the excessive production
      of IL-4, was typical for hepatitis B virus and hepatitis C virus infections, but
      not characteristic of hepatitis D virus infection. The replication activity of
      hepatotropic viruses induced a powerful cytokine response. In the presence of
      active virus replication in patients with chronic hepatitis B the levels of both
      TNF-alpha and IL-4 in their blood sera proved to be reliably higher than in
      patients with hepatitis B virus in the interactive phase.

PMID- 15188561
TI  - [Study of allergens from vegetables, fruits and berries].
AB  - Different methods of obtaining allergens from vegetables, fruit and berries have
      been evaluated. Two technologies for obtaining food allergens have been
      considered; of these, Coca's method has proved to be more technological,
      economical and less labor-consuming. The newly developed technology has made it
      possible to obtain stable, safe and specifically active allergens which may be
      used for diagnosing food allergy.

PMID- 15188562
TI  - [Immunomodulating effect of protein fractions isolated from bifidobacteria].
AB  - The screening of the immunomodulating activity (IMA) of different protein
      fractions isolated from bifidobacteria was carried out and the capacity of these
      fractions for changing the proliferative activity of immunocompetent cells was
      evaluated. Soluble proteins were extracted from lyophilized and sonicated
      bacterial mass of B. bifidum strain 1 in Na2HPO4 (pH 8) in a water bath at 65
      degrees C for 30 minutes. After the formation and removal of nucleic acid
      sediment the resulting supernatant fluid was dialyzed, its adsorption spectra
      were analyzed and the fluid was fractionated in a specially proposed device for
      preparative electrophoresis. Protein fractions were tested for IMA on spleen
      cells of CBA mice in the reaction of lymphocyte blast-transformation by the level
      of the inclusion 3H thymidine. The analysis of IMA of protein fractions revealed
      that their high-molecular components produced a pronounced dose-dependent effect
      on the proliferative activity of spleen cells. The fractions containing low
      molecular components were either inactive (fraction 4) or active only in the
      maximum dose (fraction 5).

PMID- 15188563
TI  - [Search of promising strains of bifidobacteria and lactobacillus for the
      development of new biopreparations].
AB  - For the first time the species composition of bifidobacteria and lactobacilli in
      clinically healthy young children has been studied. As revealed in this study,
      the dominating species of bifidobacteria are B. longum, B. adolescentis and B.
      infantis, while the dominating species of lactobacilli are Lactobacillus
      acidophilus and L. rhamnosus. In 83 isolated cultures of bifidobacteria and 34
      isolated species of lactobacilli the activity of acid formation and the
      antagonistic activity with respect to Escherichia coli, Klebsiella pneumoniae,
      Staphylococcus aureus, Enterococcus faecalis, Clostridium perfringens have been
      tested. B. longum strain 58B, B. infantis strain 37B, L. rhamnosus strain 12L and
      L. acidophilus strain 27L, typical for children of this age group, having good
      antagonistic activity and pronounced acid-forming properties, have been selected.
      These strains hold good promise to be used as the basis for the development of a
      complex probiotic preparation for correcting intestinal microflora in young
      children.

PMID- 15188564
TI  - [In vitro evaluation of influence of medicinal plant decoctions and antibacterial
      antibodies to bifidobacteria on bifidobacterium adhesion].
AB  - Natural antibodies to the surface antigens of bifidobacteria contained in blood
      sera and determined in the passive hemagglutination test blocked the adhesion of
      bifidobacteria to human red blood cells in vitro. The decoctions of medicinal
      plants, often used by pediatricians for therapeutic purposes, were found to have
      a pronounced inhibiting effect on the adhesion of bifidobacteria after the
      preliminary treatment of both microorganisms and human red blood cells by these
      decoctions. Suggestion was made on the possible role of natural human antibodies
      in changing the contents of the indigenous intestinal microflora; the prolonged
      use of preparations obtained from medicinal plants could probably produce
      negative influence on the microbiocenosis of the intestine.

PMID- 15188565
TI  - [Disturbances in the intestinal microflora and immune system in children with
      vitiligo].
AB  - A total of 91 children, aged 3-16 years, with vitiligo were examined. These
      examinations showed that the total number of T lymphocytes decreased irrespective
      of the degree of intestinal dysbacteriosis. The average number of T suppressors
      increased as dysbiotic changes in the intestine became more profound. The amount
      of natural killers, B lymphocytes, as well as the content of IgG and IgA (p <
      0.001), increased irrespectively of the degree of intestinal dysbacteriosis. Thus
      the unbalance of the immunity system and dysbiotic changes in the intestine of
      children having vitiligo were Inter-related.

PMID- 15188566
TI  - [Correction of intestinal dysbacteriosis in elderly patients with the use of
      bifidobacterin introduced by different routes].
AB  - The results of the correction of disturbances in intestinal microflora in elderly
      patients with the use of bifidumbacterin in the form of powder or suppositories
      are presented. The effectiveness of the rectal administration of bifidumbacterin
      (by microinjections through an enema or in suppositories) is shown in comparison
      with the oral administration of the preparation. The administration of
      bifidumbacterin in suppositories for 15 days resulted in decreased content of
      hemolytic Escherichia below the threshold of determination in all examined
      patients.

PMID- 15188567
TI  - [Microbial ecology and the state of the gastrointestinal mucosa in patients with
      allergic diseases].
AB  - Patients with allergic diseases of the skin and the respiratory system were found
      to have a high rate of disturbances in the microbial ecology of the
      gastrointestinal tract and the involvement of all its sections into the
      pathological process. On the mucous membrane of different sections of the
      digestive tract spiral-like bacteria were detected in a large percentage of
      cases. The possibility of the fact that the development and maintenance of the
      allergic process were evidently linked with the detected changes in the microbial
      ecology and pathomorphological features of the gastrointestinal mucosa could
      hardly be excluded, which made it necessary to make corrections in the
      therapeutic process.

PMID- 15188568
TI  - [Antibiotic resistance of Streptococcus pneumoniae isolated from patient with
      home care pneumonia].
AB  - The monitoring of the resistance of Streptococcus pneumoniae, one of the most
      important causative agents of extrahospital pneumonia, has been carried out. The
      data on its sensitivity to antibacterial preparations, widely used in clinical
      practice, have been summarized.

PMID- 15188569
TI  - [Bacteriological pattern of acute purulent balanoposthitis in children].
AB  - The microflora of the prepucial sac in 94 children (aged 2 months to 15 years)
      with acute purulent balanoposthitis (APB) was studied. In the overwhelming
      majority of cases APB in children was caused by facultative anaerobic and aerobic
      bacteria (96.7%); of these, Gram positive bacteria occurred most frequently
      (85.7% of cases). In 51.6% of children these bacteria were represented by
      staphylococci, constituting 60.3% of all Gram positive flora. Gram negative
      bacteria were isolated in 40.6% of cases, Escherichia coli taking the first place
      among them. The isolated microflora was highly resistant to frequently used wide
      spectrum antibiotics.

PMID- 15188570
TI  - [Adhesiveness and antibiotic resistance of the causative agents of salmonella
      infection in Gomel' region].
AB  - The adhesive capacity, resistance to antibiotics and biological properties of
      Salmonella strains of different serogroups, circulating in the Gomel region, were
      under study. Resistance to antibiotics and changes in biological properties were
      accompanied by an increased adhesiveness of these strains. A high degree of
      adhesiveness was noted in S. hadar, a new for Belarus strains.

PMID- 15188571
TI  - [Immunobiological properties of 100 years old Bacillus anthracis vaccine strains
      Lange].
AB  - The results of the study of B. anthracis vaccine strains Lange 1 and 2 in the
      form of spores after prolonged storage in 30% glycerine solution at room
      temperature are presented. The study revealed that spores stored for 100 years
      germinated and bacterial cells proved to be viable when cultivated in artificial
      nutrient media and in vivo. They exhibited typical cultural, morphological,
      biochemical, virulent, antigenic and immunogenic properties.

PMID- 15188572
TI  - [Methods of detection of tick allergens in house dust].
AB  - Different detection methods of housing dust allergens (belonging to the tick
      species Dermatophagoides pteronyssinus, D. farinae) were considered. As shown in
      this study, the immunochemical method in combination with acarological analysis
      proved to be most promising. On the basis of the data on the cross activity of
      tick allergens and changes in their content in dust, grounds were given for the
      expediency of detection by the immunochemical method with the use of polyclonal
      antibodies to specially obtained immunogen.

PMID- 15188573
TI  - [Properties of the isolated Bacillus subtilis strains and their influence on the
      intestinal microflora of experimental mice].
AB  - The cultural, physiologo-biochemical adhesive and antagonistic properties of B.
      subtilis strains with good prospects for use as biotherapeutic preparations were
      studied. For further studies B. subtilis strain No. 1719 was chosen. In
      experiments on non-inbred white mice the animals were treated by the preparation
      Cifran used for their selective decontamination from opportunistic microflora and
      for the creation of the state of dysbiosis. The influence of the spore-forming
      microbe on the parietal microflora of the large intestine of the animals was
      shown. Reliable data on the changes in the number of microorganisms (CFU/ml) per
      1 cm of the surface of the large intestine were established. As markers making it
      possible to evaluate the action of biotherapeutic and other medicinal remedies,
      easily determinable ratios of lac+/lac- of bacteria and Staphylococcus
      aureus/Staphylococcus spp. was proposed.

PMID- 15188574
TI  - [Vaccinal prophylaxis of infarction, insult and lethality in the epidemic rise of
      influenza].
AB  - The data of literature on the evaluation of the medical consequences of influenza
      and the role of vaccinal prophylaxis are presented and analyzed. The causes of
      differences in the characteristics of delayed lethality in influenza are noted.
      The fact was substantiated that delayed death in influenza may be essentially
      decreased if patients belonging to the group of risk (mainly persons over 65
      years) were vaccinated before the beginning of the seasonal rise of infection.
      Vaccination against influenza was shown to decrease the frequency of
      hospitalization for pneumonia and influenza by 20-40%. In the group of vaccines
      the number of lethal outcomes due to infarctions and insults decreased by 48-50%,
      the risk of hospitalization for cardiovascular diseases decreased by 19% and that
      for disturbances of cerebral circulation, by 16%. The conclusion was made that
      the modern strategy of vaccination against influenza was aimed at the protection
      of the groups of risk and the prevention of complications appearing in the course
      of development of this infection (the exacerbation of chronic pathology,
      hospitalization, delayed death).

PMID- 15188575
TI  - [Invariable chain (Ii-chain) as a highly important molecular chaperone of
      histocompatibility class II molecules].
AB  - The publications on the structural and functional features of the main molecular
      shaperon of li-chain were updated. In the 1990s the determination of molecular
      shaperon as a group of mutually unrelated protein molecules taking part in the
      assembly of other polypeptides was worked out. In humans the main isoform of li
      chain is the protein with a mol. wt. of 31-33 kD. A great variety of functions of
      this shaperon is linked with definite amino acid sequences. In particular, the
      molecular shaperon of the molecules of the main histocompatibility complex-II has
      functions connected with the presentation of antigen and the differentiation of B
      lymphocytes.

PMID- 15188576
TI  - [Immunologic methods in the diagnostics and treatment of nosocomial cases of
      pneumonia].
AB  - The publications on the etiology, bacteriological and immunochemical diagnostics
      of pneumonia, as well as on the role of immunotherapy and prophylaxis in the
      treatment of this disease, are analyzed. The importance of immunological methods
      in the diagnostics of pneumonia is pointed out. Approaches to the immunotherapy
      and immunoprophylaxis of pneumonia are updated.

PMID- 15188577
TI  - [Immunotropic properties of the causative agent of viral hepatitis C].
AB  - In this review the immunomodulating properties of the causative agent of viral
      hepatitis C are characterized on the basis of experimental data, obtained by
      Russian and foreign researchers during recent 3-5 years. The short
      characterization of the causative agent is presented and a number of adaptation
      mechanisms making it possible for hepatitis C virus to resist the action of the
      immune protective system of the host are considered. The role of individual
      protein products of the virus in the immunopathogenesis of the disease and the
      mechanisms of their action on the molecular level are discussed in detail on the
      basis of the results of mouse and in vitro experiments.

PMID- 15188578
TI  - [Epidemics of enteric infections in Moscow in the last 10 years (1993-2002):
      institutions amd contingents of epidemic risk].

PMID- 15188579
TI  - [Serological diagnosis of latent and non-erythematous forms of ixodid tick-borne
      borrelioses].

PMID- 15188580
TI  - [Immunization--future cure against atherosclerosis?].

PMID- 15188581
TI  - [The effect of gargling documented with a picture in the Lakartidningen in 1940.
      The article's conclusion: pharyngitis can not be treated with gargle water].

PMID- 15188583
TI  - [A vaccine for protection against atherosclerosis. Oxidized LDL plays a major
      role in the immunologic defence].

PMID- 15188582
TI  - [Case reports of devitalization because of depression. Refugee children seeking
      asylum develop life-threatening losses of function].
AB  - Five children were admitted and treated at the department of child psychiatry in
      Stockholm due to severe generalised losses of functions without underlying
      physical illness. They were all from asylum seeking refugee families with severe
      traumatic experience in their homelands and a prevailing state of hopelessness,
      helplessness and unimpressionable time perspective in Sweden. Result of treatment
      was very good when the life circumstances could be recuperated and particularly
      the obviously disease maintaining symbiotic despair of the mother could be
      abolished. The specific expression of psychic ill health in refugee children
      described here has not been systematically reported and this study indicates some
      practical aspects of treating the state as well as preventing its development.

PMID- 15188584
TI  - [Thoracic and abdominal aorta aneurysms demand an experienced team work].
AB  - Patients with combined aneurysms in the thoracic and abdominal aorta need to be
      treated at experienced centres. These complicated aneurysms are today treated
      with various combinations of open and/or endovascular techniques. The complexity
      of the interventions is associated with high morbidity and mortality. By forming
      a structured organisation for care of these patients a better outcome can be
      expected. In this article we present the approach taken in Goteborg to meet these
      challenges.

PMID- 15188585
TI  - [Low molecular weight heparin--a safer anticoagulant in thrombosis and cancer].

PMID- 15188586
TI  - [Chronic inflammation can cause type 2 diabetes].

PMID- 15188587
TI  - [Incident reporting to mass media--difficult for emergency care physicians.
      Standard formularies as a help in the judicial jungle of interpretations].

PMID- 15188588
TI  - [Gunnar Bauer--a pioneer in the research on thrombosis].

PMID- 15188590
TI  - [Elective ventilation of potential donors--need of ethical reflections and
      guidelines].

PMID- 15188589
TI  - [In spite of the WHO's recommendation: the last work not yet said about breast
      feeding and complementary foods].

PMID- 15188592
TI  - [Patients should get more responsibility for their own health care].

PMID- 15188591
TI  - ["Quality assurance" of terminology in drug trials].

PMID- 15188593
TI  - [Headache after lumbar puncture should be avoided as far as possible].

PMID- 15188595
TI  - [Wanted: ergonomic software].

PMID- 15188594
TI  - [Politically correct on gender and cataract extraction?].

PMID- 15188596
TI  - [Misleading assessment--8 out of 10 (not 4 out of 10) return unused drugs to
      pharmacies!].

PMID- 15188597
TI  - [Concerning radiologists reported to the HSAN--is everything unclear to be
      punctured?].

PMID- 15188598
TI  - [About Olof Kinberg and "disturbing" people then and now].

PMID- 15188599
TI  - [Tear dynamics and dry eye].

PMID- 15188600
TI  - [The application of cross-linked hyaluronate hydrogel to trabeculectomy].
AB  - PURPOSE: We investigated the possibility of applying cross-linked hyaluronate
      hydrogel (HA gel) during trabeculectomy in rabbit eyes. SUBJECTS AND METHODS: 1.
      We injected 0.9% salt solution (n = 3), Opegan-HI (n = 3), or HA gel (n = 3) into
      the subconjunctiva to make a follicle, and investigated its size. 2. After making
      a limbal-based conjunctival flap and a scleral flap, we injected HA gel or 0.9%
      salt solution into the subconjunctiva of rabbit eyes and sutured each flap (n = 4
      each). Three weeks after the operation, we incised the conjunctiva and
      investigated the case of peeling away the conjunctival flap or the scleral flap.
      3. We performed trabeculectomy with and without subconjunctival HA gel (n = 7 and
      6, respectively), and compared the reduction of intraocular pressure between the
      two groups. RESULTS: The results showed that the formation of the follicle was
      excellent and it was easy to peel away the adhesion. The reduction of intraocular
      pressure was statistically significant 4 weeks after the operation in which the
      HA gel was used. CONCLUSIONS: It could be useful to apply HA gel in
      trabeculectomy to prevent adhesion.

PMID- 15188601
TI  - [Results of surgery on white cataract using trypan blue capsule staining to
      visualize capsulorrhexis].
AB  - PURPOSE: To evaluate surgery on white cataracts using trypan blue capsule
      staining. METHODS: A retrospective study comprised 64 eyes of 60 patients with
      white cataract that had surgery with trypan blue capsule staining. The average
      age was 62.4 years and progress observation periods were 5.6 months. The rate of
      successful continuous curvilinear capsulorrhexis(CCC), complications, visual
      acuity, intraocular pressure(IOP), flare value, and corneal endothelial cell loss
      were studied. RESULTS: The CCC was completed uneventfully in 93.8% eyes.
      Posterior capsule rupture occurred in 2 eyes, and early perforation in 1 eye.
      Accidental vitreous staining and endothelial staining with trypan blue were
      observed in 1 eye each. There were no postoperative complications associated with
      trypan blue. Forty-five eyes had a best corrected visual acuity of 0.8 or better
      at the last visit. Twelve eyes had some ocular pathology resulting in visual
      loss, and a reliable visual acuity test could not be performed in 6 eyes. The
      mean postoperative IOP was within the normal range. The mean postoperative flare
      returned to within normal range 1 month after surgery. The mean corneal
      endothelial loss was 13.7%, and that of eyes with nucleus of grade 2 or softer
      was only 2.9%. CONCLUSIONS: Cataract surgery using trypan blue was safe and
      effective in managing white cataracts.

PMID- 15188602
TI  - [Reliable parameters for assessing the birefringence of retinal nerve fiber layer
      under various conditions of corneal birefringence].
AB  - PURPOSE: To find a reliable parameter for the assessment of parafoveal nerve
      fiber layer using scanning laser polarimetry. METHODS: The retinal nerve fiber
      layer was imaged using a Nerve Fiber Analyzer II (NFA II) along the parafoveal
      circle with a 90-pixel diameter in 4 dilated eyes of 4 normal subjects. The
      average thickness was measured in the superior(S), temporal(T), inferior(I), and
      nasal(N) quadrants. The image was obtained by means of a laser beam passing
      through 4 different locations in the cornea: the center, 2 mm temporal from the
      center, 2 mm lower temporal from the center, and 2 mm lower from the center.
      RESULTS: The circumference profile of the nerve fiber layer around the fovea
      showed a biphasic pattern similar to that obtained around the optic disc.
      However, the peaks of the pattern varied according to the corneal location
      through which the laser beam passed. Accordingly, the average thickness of the
      nerve fiber layer in each quadrant showed great fluctuation when using a
      displaced laser beam. The coefficient of variance was large (0.265-0.313) for the
      nerve fiber layer thickness itself; however, it was far less for the ratio of the
      nerve fiber layer thickness in the opposite direction, such as temporal-to-nasal
      (0.082) or superior-to-inferior (0.089). CONCLUSIONS: Although the measurement of
      the retinal nerve fiber thickness itself depends largely on the location in the
      birefringent cornea through which the laser beam passes, the ratios of nerve
      fiber layer thickness such as temporal-to-nasal or superior-to-inferior are
      reliable and show less fluctuation in the measured values.

PMID- 15188603
TI  - [Tumor necrosis factor-alpha in tears of patients with Sjogren syndrome].
AB  - PURPOSE: To determine the pathological role of tumor necrosis factor alpha (TNF
      alpha) in ocular surface disorder of patients with Sjogren syndrome (SS), TNF
      alpha in the tears of patients with SS were analyzed. In addition, the
      relationship between TNF-alpha levels in the tear samples and the severity of the
      corneal epithelial disorder was evaluated. MATERIAL AND METHODS: Tear samples
      were obtained from the 60 eyes of 30 patients with primary SS and the 60 eyes of
      30 normal subjects. Tear samples were analyzed using a sandwich enzyme-linked
      immunosorbent assay to detect TNF-alpha. Corneal epithelial cell damage was
      examined with a slit-lamp biomicroscope and scored by the van Bijsterveld scoring
      system. RESULTS: TNF-alpha was detected in the tears of patients with SS at
      concentrations ranging from 8 to 1,500 pg/ml in 33 of the 60 eyes of the
      patients. In contrast, TNF-alpha was not detected in the tears of normal
      controls. The concentration of TNF-alpha was significantly higher in the tear
      samples from patients whose clinical scores were two or three points compared
      with patients whose scores were zero or one point (Mann-Whitney U test: p <
      0.03). CONCLUSIONS: TNF-alpha was detected in the tears of patients with SS, and
      tear TNF-alpha levels showed a significant correlation with the grade of corneal
      epithelial damage, suggesting that TNF-alpha is a potent mediator in
      keratoconjunctivitis sicca.

PMID- 15188604
TI  - [Fixation points and retinal sensitivity observed in reading text by patients
      with bilateral macular atrophy].
AB  - PURPOSE: To study by use of a scanning laser ophthalmoscope(SLO). How patients
      with bilateral macular atrophy use their retinas in reading Japanese sentences of
      varying sizes. METHODS: Thirty-eight eyes of 19 patients with bilateral macular
      atrophy were examined. Sentences of a fixed length (MNREAD-J sentences) were
      projected onto the patients' retinas with the SLO, and the size of the letters
      was varied. Patients were asked to read aloud the sentences slowly, and both
      their voices and retinal images were recorded simultaneously on videotape so that
      we could locate the retinal area they were using for reading. We compared these
      fixation points in reading with simple fixation points obtained by SLO
      microperimetry. RESULTS: In 21 eyes, the patients used the same area of the
      retina in all measurements. In 15 eyes, the fixation points for reading differed
      from the fixation area measured by microperimetry. In 8 of the 15 eyes, the
      fixation area for reading changed as the letter size was altered. In 2 eyes, oral
      reading was impossible, and no fixation point was established. CONCLUSIONS: The
      combination of SLO with reading evaluation clarified the fixation area for oral
      reading. Multiple fixation points were thought to be present quite commonly in
      eyes with macular degeneration. The fixation point was thought to be determined
      by the macular condition and the size of the letters being read.

PMID- 15188605
TI  - [Assessment of retention and drug-release of ophthalmic ointment on the ocular
      surface].
AB  - PURPOSE: The dynamics of ophthalmic ointment on the ocular surface were
      investigated using a fluorescent ointment. METHODS: Ten healthy volunteers were
      enrolled. Ointment (1.0 cm length, 0.05 g) containing 0.1% flavin adenine
      dinucleotide sodium was squeezed out from the tube and placed in the left lower
      conjunctival sac. The eyes were then closed for 30 seconds and permitted to blink
      naturally. Two examinations including observation of tear film lipid layer
      interference pattern and fluorophotometric measurement of fluorescence intensity,
      both at the center of the cornea, were performed before examination and at 1, 3,
      6, 9, 12, 15, 30, 60 minutes after instillation. RESULTS: In all cases, even 1
      hour after instillation, tear film interference patterns were observed, and
      fluorescence intensity greater than before instillation, was present. CONCLUSION:
      Ointment placed in the conjunctival sac is thought to remain and release agents
      on the ocular surface for at least one hour.

PMID- 15188606
TI  - [Cited references in a review; molecular mechanism for choroidal
      neovascularization in age-related macular degeneration].

PMID- 15188607
TI  - [Predictive factors of deteriorating left ventricular function after direct
      percutaneous coronary intervention for acute anterior myocardial infarction].
AB  - OBJECTIVES: To evaluate useful predictors for the deterioration of left
      ventricular function after direct percutaneous coronary intervention in patients
      with acute myocardial infarction. METHODS: This study included 96 consecutive
      patients with first acute anterior myocardial infarction reperfused successfully
      by direct percutaneous coronary intervention within 6 hr of the onset, who
      underwent left ventriculography in the acute (soon after reperfusion therapy) and
      chronic (20 +/- 8 days after onset) phases. The left ventricular ejection
      fraction (LVEF), and the difference in LVEF (delta LVEF) between the two stages
      were calculated. The patients were divided into two groups according to the delta
      LVEF (low delta LVEF group: delta LVEF < 0%, n = 30; high delta LVEF group: delta
      LVEF > or = 0%, n = 66). RESULTS: There were significantly more patients with
      diabetes mellitus (53% vs 18%, p = 0.0009), older age (73 +/- 11 vs 67 +/- 12
      years, p = 0.003) and complete occlusion of the culprit artery (13% vs 35%, p =
      0.03) in the low delta LVEF group than in the high delta LVEF group. Left
      ventricular end-diastolic volume index (LVEDVI: 75 +/- 14 vs 62 +/- 15 ml/m2, p =
      0.002) in the chronic stage and delta LVEDVI(5 +/- 8 vs -3 +/- 14 ml/m2, p =
      0.04) were significantly worse in the low delta LVEF group than in the high delta
      LVEF group. Multivariate analysis identified diabetes mellitus as the only
      independent predictor of reduction of LVEF (odds ratio 4.44, 95% confidence
      interval 1.27-15.52, p = 0.02). CONCLUSIONS: Some patients with acute anterior
      myocardial infarction treated by direct percutaneous coronary intervention had
      reduction of the LVEF. There was a close relationship between reduction of the
      LVEF and left ventricular remodeling. Diabetes mellitus was the most useful
      predictor of reduction of the LVEF.

PMID- 15188608
TI  - [Sex differences in coronary atherosclerosis: coronary angiography and
      intravascular ultrasonography].
AB  - OBJECTIVES: Women have higher mortality and frequency of complications compared
      with men after coronary intervention. Possible differences in coronary
      atherosclerosis between men and women were investigated. METHODS: The left
      anterior descending arteries of 214 patients (164 men, mean age 62.3 +/- 9.10
      years; 50 women, mean age 67.8 +/- 7.76 years) were examined. Lesion length,
      reference diameter, percentage diameter stenosis and minimal lumen diameter were
      measured by quantitative coronary angiography. Vessel area, lumen area,
      percentage area stenosis, and remodeling index were measured by intravascular
      ultrasonography, and presence of calcification in the lesion was classified.
      These parameters were compared between men and women. RESULTS: There were no
      significant differences in quantitative coronary angiography, but intravascular
      ultrasonography showed calcification was more severe in women, vessel area was
      significantly smaller in women (13.25 +/- 4.21 vs 15.91 +/- 4.35 mm2, p = 0.004),
      and remodeling index was significantly lower in women (0.95 +/- 0.13 vs 1.04 +/-
      0.18, p = 0.015). CONCLUSIONS: Vessel area measured by intravascular
      ultrasonography was significantly smaller in women, and calcification was more
      severe in women. Such factors may be involved in the higher mortality in women.

PMID- 15188609
TI  - [Influence of serum homocysteine level on coronary atherosclerosis in Japanese].
AB  - OBJECTIVES: This study investigated the relationship between serum homocysteine
      level and coronary artery disease in Japanese. METHODS: Serum homocysteine level
      was measured in 200 consecutive patients who underwent coronary angiography for
      the assessment of ischemic heart disease. Patients with acute myocardial
      infarction were excluded, so 197 patients were included in this study. The
      patients were classified into four groups based on number of diseased vessels
      identified by coronary angiography: no significant stenosis group (non-vessel
      group), one-vessel group, two-vessel group, and three-vessel group. More than 50%
      stenosis was defined as diseased vessels. RESULTS: Serum homocysteine level in
      the three-vessel group (13.5 +/- 8.0 microM) was significantly higher than that
      in the non-vessel group (9.9 +/- 2.7 microM), one-vessel group (9.1 +/- 2.3
      microM), and two-vessel group (10.4 +/- 3.3 microM). Patients were classified
      into quartile groups according to the serum homocysteine level. The number of
      diseased vessels and frequency of three-vessel disease tended to be higher with
      increasing serum homocysteine level. There was no significant relationship
      between serum homocysteine level and coronary risk factors (diabetes mellitus,
      hyperlipidemia, smoking habit) except hypertension. Multivariate analysis for the
      predictor of number of diseased vessels showed diabetes mellitus, hypertension,
      and serum homocysteine level were independent predictors. CONCLUSIONS: Elevation
      of plasma homocysteine level is related to the severity of coronary artery
      disease in Japanese.

PMID- 15188610
TI  - [Post-myocardial infarction ventricular aneurysm and intractable ventricular
      tachycardia supported by left ventricular assist device: a case report].
AB  - A 57-year-old man was admitted under a diagnosis of myocardial infarction.
      Cardiac catheterization revealed total occlusions of the right coronary artery
      and the left anterior descending artery, and ventriculography showed aneurysmal
      change in the anterior and septal segments. Circulatory support was introduced
      with intraaortic balloon pumping, but intractable ventricular tachycardia
      developed. Electrophysiological mapping and cryoablation to the myocardium were
      performed intraoperatively, and then coronary artery bypass grafting with
      endoventricular circular patch plasty of the left ventricle was carried out.
      Weaning from the cardiopulmonary bypass was attempted, but a left ventricular
      assist device was subsequently implanted to support the deteriorated ventricular
      function. The hemodynamics of the ventricle improved several days after the
      circulatory support was introduced, and the left ventricular assist device was
      removed successfully. This case suggests that the left ventricular assist device
      is an effective method to support recovery from serious complications after
      myocardial infarction.

PMID- 15188611
TI  - [Coronary artery dissection after blunt chest trauma: subacute and chronic phase
      assessment by intravascular ultrasonography: a case report].
AB  - A 35-year-old man sustained a steering wheel injury in a motor vehicle accident.
      Initial electrocardiography showed ST-segment elevation. Coronary angiography
      revealed a dissection of the right coronary artery and perfusion delay in the
      left anterior descending artery. Coronary stents were inserted into the left
      anterior descending artery. One month later, coronary angiography and
      intravascular ultrasonography showed that the dissection of the right coronary
      artery was still present. Coronary stents were inserted from the aorto-ostial
      lesion to the mid portion of the right coronary artery. Six months later,
      coronary angiography and intravascular ultrasonography revealed diffuse
      neointimal hyperplasia inside all of the stents, and the aorto-ostial stent had
      severe stenosis with perfusion delay. Severe neointimal hyperplasia was found
      inside the stents used for repair of the coronary artery dissection.

PMID- 15188613
TI  - [Treatment for phimosis with an estrogen-containing ointment in children].
AB  - We evaluated the effectiveness of topical application of an ointment containing
      0.1% estrogen for phimosis in children. Fifty children 1 to 12 years old (average
      age 4 years) presenting to our department with phimosis were enrolled in this
      study and treated with an estrogen-containing ointment for 4 weeks. The ointment
      was applied on the narrow preputed skin twice a day by the child's parents. The
      success rate was 82%. There were no side effects. The application of an estrogen
      containing ointment is a viable alternative for treating phimosis in children.

PMID- 15188612
TI  - [A 79-year-old woman with simultaneous anterior and inferior ST-segment
      elevation].

PMID- 15188614
TI  - [The clinical significance of 50 cases of percutaneous nephroureteral
      lithotripsy].
AB  - Percutaneous nephroureteral lithotripsy (PNL) was conducted in 50 patients with
      renal or ureteral calculi between March 2000 and August 2002. The mean age of
      patients was 56.6 years (range 25-82 years) and they included 29 males (58.0%)
      and 21 females (42.0%). The calculi were renal calculi in 38 patients (76.0%) and
      ureteral calculi in 12 patients (24.0%). The mean number of calculi was 1.5 (1-10
      calculi, median number 1). The mean of the maximum calcule diameter was 30.9 mm
      (15.0-83.0 mm) for the renal calculi and 17.4 mm (8.0-27.0 mm for the ureteral
      calculi. The lithotripsy device was an ultrasonic lithotriptor (ALOKA) or
      Lithoclast (SWISS), as appropriate, and was used with a 24 Fr rigid endoscope
      (TAKEI). All operations were performed under lumbar spinal anesthesia. Eighteen
      of the 38 renal calculus patients were treated with PNL alone. In the other 19
      PNL was combined with postoperative extracorporeal shock wave lithotripsy (ESWL).
      Seven of the 12 patients with ureteral calculi were treated with PNL alone, and 5
      with PNL combined with postoperative ESWL. After 3 months, the treatment results
      were Tx(3)-0 in 45 patients (90.0%), and Tx(3)-2 in 5 patients (10.0%). The mean
      period of postoperative hospitalization was 30.3 days (10-86 days), with a median
      of 26 days. Complications were renal pelvis perforation in 1 patients and fever
      of 38.0 degrees C or above in 16 patients, but there was no hemorrhaging that
      required transfusion or other serious complications. PNL is a safe and reliable
      treatment method, and should be considered as a treatment option in cases of
      large calculi when a short treatment period is desired.

PMID- 15188616
TI  - [A case of ectopic ureterocele in a male adult found during examination of a
      traumatic injury].
AB  - We report a case of ectopic ureterocele in a male adult found during examination
      of a traumatic injury. A 26-year-old man sustained a blow to his left back during
      a football game and was admitted to the hospital with a complaint of abdominal
      pain. The computed tomographic scan showed a huge cystic mass in the
      retroperitoneum. A cystoscope revealed a large bulge from the left ureteral
      orifice to the bladder neck and another ureteral orifice distal to the bulge.
      Retrograde pyelography revealed an ectopic ureterocele showing a complete
      duplication, a lateral deviation of the left ureter and a bladder deviation to
      the right. An ectopic ureteral orifice was opening in the posterior urethra. An
      ureteral catheter inserted into this orifice revealed a dilated left ureter from
      the upper half of the kidney. Because the function of left upper of kidney was
      maintained, a transurethral incision was performed. Vesicoureteral reflux
      remained, but the postoperative course was uneventful. We discuss 11 cases of
      ectopic ureterocele in male adults including this case.

PMID- 15188615
TI  - A case of renal cell carcinoma found after skin metastasis.
AB  - A case of renal cell carcinoma, found after skin metastasis is presented. A 79
      year-old man visited Osaka JR hospital, complaining of a painless nodular mass on
      his right chest. The mass was resected and histopathological examination revealed
      a clear cell carcinoma (alveolar type, G1) with no involvement of the mammary
      gland. Abdominal ultrasound and magnetic resonance imaging revealed a
      heterogenous lower pole mass in the right kidney. Ultrasound-guided needle biopsy
      of the right renal mass was performed for histopathological diagnosis, which was
      clear cell carcinoma (alveolar type, G1). At that time, multiple metastases
      appeared in bilateral lung fields. The patient is currently receiving interferon
      alpha therapy, without surgical treatment.

PMID- 15188617
TI  - [Post-traumatic high-flow priapism: a case report].
AB  - A 48-year-old man, who previously had normal erectile function, visited our
      hospital complaining of a painless erection that had persisted for 6 days. He had
      suffered perineal trauma in a traffic accident 9 days earlier. A diagnosis of
      post-traumatic high-flow priapism was suggested from the findings on penile blood
      gas analysis. Selective internal pudendal arteriography showed an arterial blush
      along the bilateral cavernous arteries. Subsequently, embolization of a cavernous
      fistula was performed with an autologous clot. However, the embolus was removed
      within a minute, so the procedure was repeated with Gelfoam. This patient had
      normal erectile function after 11 months, with no recurrence of priapism.

PMID- 15188618
TI  - [A case of bladder tumor producing granulocyte colony-stimulating factor].
AB  - A 75-year-old male was admitted with high grade fever, general fatigue, and
      appetite loss. The laboratory examinations revealed leukocytosis of 31,700/mm3
      (neutrophils: 88%) in the peripheral blood. Cystoscopy demonstrated multiple
      bladder tumor. Computed tomography revealed bilateral hydronephrosis due to
      bladder tumor. Bilateral nephrostomy and transurethral resection bladder tumor
      were performed. Histological diagnosis was squamous cell carcinoma and
      immunohistochemical staining of the resected tumor using antihuman granulocyte
      colony-stimulating factor (G-CSF) antibody showed positive staining in the
      cytoplasm of the tumor cells. Serum analysis revealed a high level of G-CSF 126
      pg/ml (normal: less than 18.1 pg/ml). Total cystectomy and bilateral cutaneous
      ureterostomy were performed. He died of cancer 3.5 months after admission. This
      is the 48th case in Japanese literature.

PMID- 15188620
TI  - [A case of primary choriocarcinoma of the bladder].
AB  - A 75-year-old man visited our hospital presenting with gross hematuria.
      Cystoscopy revealed a bladder tumor with coagulated blood and necrotic tissue at
      the dome. We resected the bladder tumor transurethrally. Pathologically, the
      tumor was shown to be a transitional cell carcinoma with choriocarcinomatous
      differentiation, G3, > or = pT2. Immunohistochemical staining showed human
      chorionic gonadotropin (HCG)-positive tumor cells. Just after surgery, the serum
      HCG-beta concentration was less than 0.1 ng/ml. Total cystectomy and an ileal
      conduit operation were performed. The histological classification was TCC, G3,
      pTis. In later blood chemistry tests, HCG-beta elevation was observed. Pulmonary
      metastases appeared on a chest X-ray, and combination chemotherapy with cisplatin
      and etoposide was administered. Although the serum HCG-beta decreased with one
      course of chemotherapy, it increased immediately thereafter. The patient died of
      the disease about 8 months after the total cystectomy. Autopsy revealed multiple
      metastases in the lungs, liver, kidneys, stomach, pancreas, thyroid gland,
      adrenal glands, heart, jejunum, and vertebral body (Th10). Lymph node metastases
      in the pulmonary hilum, mediastinum, and right submaxillary gland were also
      found.

PMID- 15188619
TI  - [A case of anaphylactic shock induced by pirarubicin hydrochloride].
AB  - A 75-year-old man was admitted to our hospital for treatment of superficial
      bladder tumor. Transurethral resection (TUR) was performed and histopathological
      examination revealed a transitional cell carcinoma (G2). Despite one course of
      post-TUR bladder instillation therapy using pirarubicin hydrochloride, carcinoma
      in situ (CIS) was found 4 months later. CIS disappeared after another course of
      bladder instillation therapy using BCG; but, it recurred a month later. BCG
      bladder instillation therapy was performed again, and no malignant cells were
      detected in the urinary tract thereafter. Four months later, lung metastasis was
      diagnosed and an MVAC regimen (cisplatin, methotrexate, vinblastin adriamycin)
      was administered. However, anaphylactic shock was induced by intravenous
      injection of pirarubicin hydrochloride, so this therapy was stopped in the middle
      of the second course. Even though the lung metastasis disappeared once after the
      same MVAC treatment, it recurred the following year. At that time, 3 courses of a
      cisplatin-methotrexate-vinblastin regimen were administered, and a complete
      response was achieved.

PMID- 15188621
TI  - [A case report of splenic abscesses due to pyonephrosis].
AB  - We report a rare case of splenic abscesses that were derived from left
      pyonephrosis. A 58-year-old woman was referred to our hospital with complaints of
      fever and epigastralgia. Computed tomography revealed splenic abscesses and left
      pyonephrosis with staghorn calculi. After admission, her condition improved with
      conservative therapy. Eight months later, the splenic abscesses had disappeared.
      The patient was then readmitted and left nephrectomy was performed to prevent
      relapse of the splenic abscesses. We suspected that direct invasion of
      inflammation from the left pyonephrosis caused the splenic abscesses, as her left
      kidney had adhered to the spleen. Only one case of splenic abscesses derived from
      a urinary tract infection has been reported in Japan.

PMID- 15188622
TI  - [Small cell carcinoma of the prostate: a case report].
AB  - An 80-year-old man visited our hospital because of dysuria and pollakisuria. He
      had undergone anti-androgen therapy for prostate cancer for 8 months at another
      hospital. His serum prostate specific antigen (PSA) level was 14.4 ng/ml. We
      performed a prostate biopsy and identified poorly differentiated adenocarcinoma
      with Gleason score 4 + 5. After 4 months, his serum PSA level increased to 24.8
      ng/ml, and we started maximum androgen blockade therapy using additional
      luteinizing hormone-releasing hormone (LH-RH) analogue. Subsequently, although
      his serum PSA level declined favorably, his condition worsened rapidly and he
      died at 16 months after the diagnosis. The autopsy pathology of his prostate
      revealed small cell carcinoma. We reviewed the initial biopsy specimens and found
      both small cell carcinoma and adenocarcinoma histologic types of prostate cancer.

PMID- 15188624
TI  - [A case of microscopic pulmonary tumor emboli 14 months after total cystectomy].
AB  - A 70-year-old man was admitted with slight dyspnea and fever up. The patient had
      had total cystectomy for urothelial carcinoma of urinary bladder 14 months
      earlier and had a ureterocutaneostomy. At 2 days after the admission, he had a
      sudden attack of dyspnea. He was transferred to the intensive care unit, and
      mechanical ventilation was initiated. The pulmonary arterial pressure was
      measured at 65/30 mmHg, but the etiology for the pulmonary hypertension was
      unclear. Although highly suggestive of pulmonary embolism, chest roentgenogram
      and chest computed tomography (CT) showed clear lung fields. Pulmonary
      angiography disclosed no evidence of embolism. Despite anticoagulation therapy he
      died of respiratory failure. Autopsy revealed diffuse microscopic pulmonary tumor
      embolism with urothelial cacinoma in the pulmonary arterial vasculature.
      Microscopic pulmonary tumor embolism has rarely been reported with urothelial
      carcinoma.

PMID- 15188623
TI  - [Active chemotherapy with gemcitabine, carboplatin and docetaxel for three
      patients with MVAC-resistant liver metastasis of urothelial carcinoma].
AB  - We report three cases with methotrexate-vinblastin-adriamycin-cisplatin (MVAC)
      resistant multiple liver metastases of urothelial carcinoma that responded to
      combination chemotherapy consisting of gemcitabine plus carboplatin (GC) with
      additional docetaxel (GCD) as salvage chemotherapy. Case 1: A 55-year-old man
      underwent left nephroureterectomy for ureteral cancer (TCC, G3, pT3pN1M0). Three
      courses of GC followed by three courses of GCD were given via intra-hepatic
      arterial infusion for multiple liver metastases, which appeared after adjuvant
      high-dose MVAC therapy. Complete response was obtained and maintained for 11
      months. Case 2: A 46-year-old man underwent radical cystectomy for locally
      advanced bladder cancer (TCC G3 + adenocarcinoma. pT3pN0M0). Two courses of GC
      followed by 2 courses of GCD systemic therapies were performed for multiple liver
      metastases, which appeared after adjuvant high-dose MVAC therapy. Partial
      response was obtained and maintained for six months. Case 3: A 66-year-old man
      received three courses of MVAC for multiple metastases of the bladder cancer
      (TCC, G3, > pT2), which resulted in disease progression. Eight courses of GC
      followed by six courses of GCD were administrated via intra-hepatic arterial
      infusion. Partial response was obtained and maintained for 12 months. Although
      the response duration was still short, GC and GCD may be promising salvage
      chemotherapeutic regimens for the patients with MVAC-resistant liver metastases
      of urothelial carcinoma.

PMID- 15188626
TI  - [Recent advances in sleep medicine].

PMID- 15188625
TI  - [A case of vaginal metastasis of transitional cell carcinoma].
AB  - A 74-year-old female with a complaint of genital bleeding was referred to our
      hospital. In her past history, 4 times of transurethral resection of bladder
      tumor (TUR-BT) for bladder cancers and right nephroureterectomy with cuff for
      right ureteral tumors were performed during these 17 years, followed by simple
      cystectomy 3 years before. A punch biopsy of anterior vaginal wall demonstrated
      metastases of transitional cell carcinoma. Although total histero-vaginectomy was
      performed, recurrence of disease was observed in bone, skin and inguinal lymph
      nodes 9 months after the operation. This case is the 13th report of vaginal
      metastases of transitional cell carcinoma in the world.

PMID- 15188627
TI  - [Diagnosis and treatment of sleep disorders related to psychiatry].

PMID- 15188628
TI  - [Physical and social problems of obstructive sleep apnea syndrome].

PMID- 15188629
TI  - [Diagnosis and treatment of obstructive sleep apnea syndrome].

PMID- 15188630
TI  - [System of sleep medical center in Kurume University Hospital].

PMID- 15188631
TI  - [Psychological and physiological evaluations of music listening for mental
      stress].
AB  - Music elicits emotional and physiological responses in humans, providing
      excitement, mood elevation, relaxation, sedation and so on. Previous studies have
      been conducted on the effects of music, while little is known about the effects
      for the cognitive information processing. In this study we introduced various
      types of physiological indices, and explored the effects of music on
      participants' subjective and physiological responses to stress. First, eight
      participants (mean age; 25.6) were requested to perform a mental calculation task
      for 30 minutes. After that, they were exposed to music ("Bolero" by M. Ravel) for
      13 minutes, while others were exposed to noise or just stayed in silence as
      controls. State-Trait Anxiety Inventory (STAI), salivary Immunoglobulin A (sigA),
      auditory event-related potentials (ERPs), heart rate (HR) and spectral analysis
      of heart rate variability (HRV) were assessed through the experiment. RESULTS: 1)
      After the calculation task: P300 amplitude of auditory ERPs significantly
      diminished (p = 0.027). Saliva secretion rate decreased (p = 0.028) and salivary
      IgA levels rose (p = 0.017) significantly. LF/HF ratio significantly increased (p
      = 0.042). 2) After music ("Bolero"): P300 amplitude significantly expanded (p =
      0.048). State anxiety levels significantly lowered (p = 0.007). No significant
      physiological effect was found in those exposed to noise or silence. Our results
      of salivary IgA and LF/HF ratio suggest that the calculation task activates
      immune and sympathetic nervous system, while these systems are not affected by
      music. On the other hand, the result of P300 amplitude suggests that the central
      nervous system for the cognitive information processing is inactivated by the
      calculation task, and it can be recovered by music. The results of this study
      indicated that relaxing music is useful for the stress management, which invite
      further empirical investigation.

PMID- 15188632
TI  - Circulating cytokines during early pregnancy in women with recurrent spontaneous
      abortion: decreased TNF-alpha levels in abortion with normal chromosome
      karyotype.
AB  - OBJECTIVE: The aim of the present study was to assess whether or not serum
      cytokine concentrations during early pregnancy are related to the subsequent
      outcomes in women with recurrent spontaneous abortion (RSA). PATIENTS AND
      METHODS: Serum concentrations of five cytokines--tumor necrosis factor (TNF)
      alpha, interferon (IFN)-gamma, interleukin (IL)-4, IL-6, and IL-10--were measured
      by ELISA methods. Sera were collected from 73 RSA women at 6-7 weeks of
      gestation. Of the 73 pregnancies, 10 subsequently ended in abortion with normal
      fetal chromosome karyotype (AbNK), 12 ended in abortion with abnormal karyotype
      (AbAK), and the other 51 pregnancies ended in live birth (Lb). RESULTS: The serum
      TNF-alpha concentration in women with AbNK (mean 0 pg/ml) was lower than that in
      women with subsequent AbAK (0.06 pg/ml) (p < 0.05). The TNF-alpha positive
      percentage among women with AbNK (0%) was also lower than that among women with
      AbAK (50.0%) (p < 0.05). CONCLUSIONS: Decreased serum TNF-alpha concentration
      during early pregnancy might be associated with subsequent abortion in RSA women.

PMID- 15188633
TI  - Ambulatory surgery centers--current legal issues 2004 (Part 2).
AB  - This article covers several of the emerging issues related to ASCs, the anti
      kickback statute and safe harbors, other regulations and relevant court
      decisions. The ASC Safe Harbors raise several concerns either because they are
      vague, silent, or provide little guidance as to their requirements. Perhaps the
      most challenging question under the ASC safe harbor relates to the handling of
      physicians who do not comply with the various safe harbor tests. As discussed, an
      ASC should address early on whether physicians who fail to meet or comply with
      the safe harbor will be redeemed from the venture. In redeeming such physicians,
      it is important to consider whether the company's operating agreement or
      shareholder agreement provides for redemption upon such event and whether the
      redemption will lead to litigation or compliance risks. Along the same lines,
      since it is illegal to provide any form of value in exchange for referrals under
      the anti-kickback statute, share sales at below fair market value may be viewed
      as an illegal kickback in exchange for referrals. Thus, in terms of adding
      physician owners, a number of guidelines should be followed. An ASC should also
      carefully consider situations in which it waives or discounts co-payments or
      deductibles. The safest course for a provider remains to collect the entire co
      payment and deductible amounts from patients. Moreover, in the case of Medicare
      and Medicaid patients, an ASC should never waive or discount co-payments and
      deductibles unless the patient demonstrates financial hardship. Either way, such
      a waiver or discount should only be in accord with an applicable charity care or
      discount policy. A new issue involving the anti-kickback statue, state and
      federal self referral laws, and Medicare regulations, has gained attention as
      ASCs are increasingly finding themselves approached by third party vendors to
      enter into an arrangement, where the vendor owns the equipment and bills a third
      party payor for the technical component of the procedure performed with the
      equipment, and the vendor then pays the ASC a fee for its lease of ASC space to
      house the equipment. These types of relationships can raise several legal
      compliance concerns. An ASC should understand that the arrangement could
      jeopardize its state ASC license and its Medicare certification even though the
      arrangement does not involve Medicare certified procedures or Medicare patients.
      Furthermore, this type of business venture might not comply with state and
      federal self referral laws. ASCs are also increasingly facing situations where a
      provider performs a procedure for which there is no facility charge for the ASC,
      but the physician is receiving a professional fee from Medicare. In this
      situation, ASCs should implement a policy, similar to the example provided in
      this article, to avoid even the appearance of providing an inducement or reward
      for referrals of Medicare or Medicaid business by requiring physicians to pay the
      Center a fee, consistent with fair market value, for the use of the Center for
      non-Covered Procedures or for performing multiple procedures within the same
      operative session. Lastly, as touched upon by this article, in the joint venture
      context, ASCs must take into account several guidelines in order to steer clear
      from risks associated with tax-exempt entities as an investor and antitrust price
      fixing issues. Whether a joint venture, of which a tax exempt entity is an
      investor, is deemed organized and operated in furtherance of the charitable
      purposes of a tax-exempt partner as set forth in Section 501(c)(3) of the Code
      depends on the facts and circumstances of each case. Generally, a joint venture
      will satisfy the guidelines if the tax-exempt investor in the joint venture
      retains sufficient control over the joint venture to ensure that the joint
      venture furthers the charitable purposes of the tax-exempt investor and
      adequately serves the community. In the ASC physician hospital joint venture
      arena, the principal antitrust concern relates to potential claims of price
      fixing. Where a hospital is a partner in a joint venture, the hospital and joint
      venture must take action to assure that the pricing and negotiations of the
      hospital and the ASC are handled separately. In all of these situations, ASCs and
      their investors must pay close attention and stay current of the safe harbor
      concepts, as well as the other regulations, guidelines, and court decisions
      discussed in this article in order to avoid potential regulatory and litigation
      risks.

PMID- 15188634
TI  - [Glycosaminoglycans, proteoglycans, atherosclerosis].
AB  - Glycosaminoglycans, proteoglycans have fundamental roles in the building up of
      the vascular walls. The research work of the correlations between
      glycosaminoglycans, proteoglycans and the pathogenesis of atherosclerosis was
      since more decades proceeding. The prominent experts of the scope are paying more
      and more attention to the significant influence of the inflammation ongoing in
      the arterial vessel wall. Glycosaminoglycans, proteoglycans are equally
      contributing to the development, stopping or remaining, turning into chronic type
      of the inflammatory process. On the ground of all these this article makes an
      attempt to outline, using up the newest results of the investigations being in
      relation with the fundamental structures, the alterations in the composition, the
      occurrences, the essential functions of the glycosaminoglycans, proteoglycans.
      Afterwards the diverse important roles of these molecular organizations played in
      the pathogenesis, in the progression of atherosclerosis, and in the arising of
      its complications are surveyed. Basing on the considerable data of the
      observations it can be established that glycosaminoglycans, proteoglycans have
      determining importance in the individual, peculiar inflammation progressing in
      the arterial vessel wall, in the surviving of the special vasculitis, in the
      appearance of atherosclerosis, in the focal nature and progression of that and in
      the development of its complications. The knowledge becoming continuously more
      complete affords, a long-range expectation in relation to both the prevention and
      therapeutic intervention of that widespread disease.

PMID- 15188635
TI  - [New treatment option for decreasing blood cholesterol level--clinical
      significance of inhibition of both, cholesterol absorption and synthesis].
AB  - In the development of hypercholesterinaemia two factors play an important role.
      There is the cholesterol-uptake through the gastrointestinal tract, about 300-700
      mg daily depending on the diet, on the other hand gastrointestinal tract plays
      important role in the reabsorption of cholesterol excreted through the bile by
      the liver, the amount of which takes 1000 mg. It means that about 1300-1700 mg
      cholesterol is absorbed in the small intestine daily. Previous major studies have
      demonstrated that statins, the drugs that have been proved to be the most
      efficient in decreasing the cholesterol level, can decrease both total and
      cardiovascular mortality. This effect highly depends on the rate of cholesterol
      level decrease. Thus, their application in higher doses has been recently
      suggested to reach the target level, which is performed by dose titration. If the
      desired effect is not achieved with the starting dose of statins, a doubling of
      dosage only leads to 6% additional LDL-cholesterol level decrease. During long
      term administration the so called "escape phenomenon" can be observed, which
      means that the use of these drugs for a longer period reduces their cholesterol
      decreasing effect. Higher doses increase the risk of adverse effects, and the
      "escape phenomenon" decreases the effectiveness. To avoid these effects the
      combination therapy is recommended for use. In combination therapy drugs with
      different mechanisms of action should be administered, which increase therapeutic
      effect, but keep the number of adverse effects decreased or unchanged.
      Concomitant administration of former known lipid lowering agents--beyond
      enhancing cholesterol level decrease--has unfortunately increased the frequency
      of adverse effects as well. In this regard, ezetemibe, the cholesterol absorption
      inhibitor appears to be promising since it selectively decreases the absorption
      of cholesterol from intestinal epithelial cell, resulting in an 18-22% LDL
      cholesterol decrease. At the same time the decreased uptake from the
      gastrointestinal tract triggers the endogen cholesterol synthesis in the liver.
      When this process is inhibited by statin, more impressive cholesterol decreasing
      effect can be reached. Clinical studies with concurrent use of ezetimibe and
      statin have confirmed this view. Decreasing cholesterol level at more attack
      points offers a possibility to reach target values without a significant increase
      in the risk of adverse effects. So with combination and dual inhibition a more
      significant cholesterol lowering effect can be obtained beside the decrease of
      side effects.

PMID- 15188636
TI  - [Familial adenomatous polyposis coli--case report].
AB  - The authors report the case of a young 35 year-old male patient, investigated due
      to thrombocytosis for three years. First the diagnosis of chronic
      myeloproliferative disease was made. The diagnosis of familial adenomatous
      polyposis was only evident in advanced stage of the disease. Upper abdominal US,
      abdominal CT, double-contrast barium enema examination and colonoscopy proved
      advanced synchronous colorectal cancers (sigmoid and descending colon) with liver
      metastases along with polyposis throughout the whole large bowel. Days after the
      diagnosis was made the patients condition deteriorated rapidly and he died with
      septic symptoms suggesting bowel perforation and pneumonia. Beside the case
      report the authors try to give a short overview of the current literature of
      relatively rare but potentially fatal hereditary colon cancer syndromes to awake
      the attention of the clinicians to investigate more cautiously the background of
      unexplained clinical-laboratory signs in young adults.

PMID- 15188637
TI  - [Minimally invasive surgical techniques in the treatment of pituitary and
      peripituitary tumors: experience with the paraseptal approach].
AB  - INTRODUCTION: The direct endonasal, paraseptal approach, performed with the aid
      of an operating microscope, for removal of pituitary and peripituitary tumors has
      the potential advantage over the traditional sublabial, transseptal routes of
      minimizing postoperative rhinological complications, yet maintaining a high
      degree of efficacy and safety. Combination of this approach with the endoscope or
      neuronavigation may improve the effectiveness of the operation. METHODS AND
      RESULTS: Between June, 2000 and June, 2003 two hundred and seventeen patients
      underwent 221 paraseptal operations for tumor removal at the National Institute
      of Neurosurgery, Budapest. To asses the effectiveness of this procedure, duration
      of the operation, tumor remission rates and surgical complications as well as
      postoperative complaints of patients were reviewed. Surgical remission rates for
      pituitary adenomas were as follows: 94% for microadenomas, 67% for macroadenomas
      and 29% for giant adenomas. There were five surgical complications and no
      operative deaths. Ten out of 12 patients, who had undergone transseptal surgery
      previously, preferred the endonasal approach in terms of pain and ease of
      recovery. CONCLUSIONS: The direct paraseptal route for pituitary and pericellar
      tumor removal has an efficacy and complication rates comparable to those of the
      transseptal and sublabial routes. Patients generally recovered rapidly from this
      minimally invasive procedure and had no or minimal sinonasal complaints. For
      patients requiring a repeated operation, the paraseptal route appears to be less
      painful and easier to recover from, than the transseptal route.

PMID- 15188638
TI  - [Successful treatment of Weber-Christian panniculitis with cyclosporin-A].
AB  - The inflammatory disease of the subcutaneous fatty tissue are called
      panniculitis. The panniculitis has got a septal and a lobular histopathologic
      type. In the opinion of the etiologic classification occurs idiopathic (primary)
      or secondary entity. The secondary illnesses develop as the result of physical,
      chemical, biochemical, immunological, degenerative and proliferative reactions.
      In a part of panniculitis the etiologic factor is unknown. The authors
      demonstrate a rare type of the panniculitis, the Weber-Christian syndrome. This
      disease is an acute relapsing panniculitis with unknown etiology, fever, general
      symptoms and typical subcutaneous nodes. In their case the histological
      examination of the subcutaneous node resulted in non-suppurative, lobular
      panniculitis. The oral metilprednisolon and the occurring twice parenteral
      cyclophosphamide treatment had been proved to be unsuccessful, for this reason
      they started cyclosporin A therapy. Because of the cyclosporin A treatment the
      subcutaneous nodes regressed, the general symptoms ceased and the pathological
      laboratory findings became normal. The patient is asymptomatic under permanent
      therapy now. The authors discuss the differential diagnostic of this illness and
      the ways of treatments.

PMID- 15188639
TI  - [Treatment in Parkinson disease].

PMID- 15188640
TI  - [Necessity of chip technology in stomach cancer].
AB  - Gastric cancer is one of the most frequent cancer type in the world today. This
      fact emphasises the importance of identification of useful diagnostic and
      prognostic markers for gastric cancers in their earliest stages. Aim of this
      review is to summarize the genetic knowledge related to gastric carcinogenesis
      and progression and to offer a survey of the gene expression pattern changes and
      their functional classification. Microarray results show that the gene expression
      pattern detected in gastric cancers highly depends on the histological type and
      heterogeneity of the sample, array type and data analyzing softwares. Recent
      experiments point out the changes of not just the alterations of tumor
      suppression, apoptosis, cell cycle regulation and signal transduction, but tumor
      cell metabolism and cell-microenvironment interactions, too. All results show
      connection to and complete the already known molecular background of gastric
      cancer.

PMID- 15188641
TI  - [Risk factors to be considered at the beginning of antihypertensive therapy in
      diabetes mellitus].
AB  - The treatment of hypertension in diabetic patients due to its high prevalence
      rate belongs to the everyday clinical practice of internists, diabetologists and
      general practitioners. The main points of the initiation on of antihypertensive
      treatment in diabetic patients are reviewed. In order to decrease the target
      organ damages the treatment of early recognized cardiovascular risk factors are
      of great importance. The target value of antihypertensive treatment in diabetic
      patients is < 130/80 mmHg (in case of proteinuria > 1 g daily: < 125/75 mmHg).
      The global cardiovascular risk is high or very high in diabetic patients both
      with grade I-III hypertension and with high normal blood pressure, therefore,
      treatment with antihypertensive drug (besides life style optimalisation) should
      be initiated promptly in these cases. In case of micro- or macroalbuminuria
      antihypertensive drug (mainly with characteristics of blocking the renin
      angiotensin-system) should be given to each diabetic subject irrespective of
      actual blood pressure values. Success of antihypertensive treatment in diabetic
      patients could be achieved mainly with combination therapy only. It is reasonable
      to initiate antihypertensive therapy primarily with a low dose combination of two
      agents in diabetic patients with hypertension.

PMID- 15188642
TI  - [Bronchoscopy in intensive care units].
AB  - The authors report their 1535 urgent bronchoscopic examinations performed between
      1998-2002. The examinations/interventions were requested mostly by surgical and
      internal medicine intensive care units. The main indications were: postoperative
      excretion removal, stump control, suspicion of fistula, foreign body, injury of a
      large bronchus, tracheal stenosis, specimen taking and bronchoscopic local drug
      treatment. The authors mention the most important contraindications for urgent
      bronchofiberscopy too: missing written consent of the patient (except the cases
      of unconsciousness), size discrepancy between the tool and tracheal lumen, and
      asthmatic attack. The authors also underline the emerging importance of both
      diagnostic and therapeutic bronchoscopy performed on emergency wards and
      intensive care units. They conclude: it's necessary for the anesthetists to get a
      basic level ability to work with bronchofiberscope and for pulmonologist
      bronchologists to be experienced to answer the questions of other specialists.

PMID- 15188644
TI  - [Diagnosis and therapy of acute pulmonary embolism].

PMID- 15188643
TI  - [Berry syndrome: successful neonatal repair of a rare complex cardiac
      malformation].
AB  - Aortopulmonary septal defect, interrupted aortic arch, aortic origin of the right
      pulmonary artery, intact ventricular septum, and patent ductus arteriosus (Berry
      Syndrome) is a rarely reported malformation. A 6-day-old girl underwent
      successful one-stage complete repair of direct anastomosis between the ascending
      and descending aorta, reimplantation of the right pulmonary artery augmented with
      pericardium patch. Stenosis of the origin of the reimplanted right pulmonary
      artery was treated by balloon angioplasty at the age of 3 months. The authors
      emphasize the additive nature of surgical correction and interventional
      cardiology. Review of the literature reveals this patient to be the 25th reported
      case with Berry syndrome, and the first of that in Hungary.

PMID- 15188645
TI  - [Role of the (Hungarian) Journal of Natural Sciences in 1904].

PMID- 15188646
TI  - [Chemical safety in Hungary and in the European Union].

PMID- 15188647
TI  - [Memorable dates in the history of Russian medical science and virology:
      establishment, on June 30th 1944, of the Academy of Medical Sciences of the USSR
      and of the Institute of Virology].

PMID- 15188648
TI  - [Issues related to rubella, measles and epidemic parotiditis in the Russian
      Federation].
AB  - Measles, rubella and epidemic parotitis are classified as controllable infections
      with vaccination of children being the key method of preventing them. Live mono
      vaccines and combined vaccines against measles and epidemic parotitis have been
      developed and successfully used in our country; research work on creating
      preparations against rubella has been underway. The vaccine-based prevention of
      the above viral infections is shown to be a most active, safe, effective and cost
      saving method preventing them. There is also described in the paper an analysis
      of the morbidity rate due to measles, rubella and epidemic parotitis in the
      territory of the Russian Federation and elucidated the resolved and yet unsettled
      issues related with the vaccine-based prevention of the above widespread and
      highly contagious infections of today.

PMID- 15188650
TI  - [Ecology and evolution of influenza viruses in Russia (1979-2002)].
AB  - The research results on ecology and evolution of influenza A viruses, which has
      been conducted by the Center of Ecology and Evolution of influenza Viruses of
      Ivanovsky's Institute of Virology, Russian Academy of Medical Sciences, for more
      than 30 years, are summarized in the paper. A gene pool of influenza A viruses
      circulating in Russia's territory was defined. Foci of influenza A viruses were
      detected in natural biocenosis. Issues conditioned by the population
      interrelations of influenza viruses, i.e. between the populations of wild and
      home animals and the populations of people, are also under discussion.

PMID- 15188649
TI  - [Influenza viruses which preconditioned the epidemic rise in Russia in 2002-2003.
      A resumed circulation of influenza viruses similar to V/Victoria/2/87].
AB  - According to research, the epidemic rise of influenza was preconditioned, during
      2002-2003, in Russia by the circulation of influenza A(H1N1), A(H3N2) and B
      viruses. The Center of Influenza Ecology and Epidemiology undertook a study of
      178 epidemic strains: 41 strains A(H1N1), 116 strains A(H3N2) and 21 strains of
      influenza B were among them. All strains were isolated in the MDCK cell culture.
      A simultaneous isolation in embryonated eggs as well as changing of the isolation
      system from MDCK to embryonated eggs were found to be effective only for
      influenza A(H1N1) viruses. According to the antigenic analysis, all A(H1N1)
      viruses were variants of the etalon A/New Caledonia/20/99. The A(H3N2) viral
      strains' population was heterogeneous by its antigenic properties: among its
      isolates, there were variants similar to the etalons of A/Moscow/10/99 and of
      A/Panama/200/99 as well as strains, which weakly reacted with sera of both above
      etalons; possibly the latter were close to the etalon of A/Fujian/411/02. All
      epidemic strains of influenza B virus belonged, according to the antigenic
      properties of hemagglutinin, to the virus group of B/Victoria/2/87-like and were
      antigenic variants of the etalon of B/Hong Kong/22/01. This confirmed that
      influenza B viruses with the antigenic hemagglutinin structure of the virus group
      of B/Victoria/2/87-like, which were not present in Russia for more than 10 years,
      re-entered the active circulation. An analysis of antigenic properties of
      neuraminidases (NA) of the mentioned epidemic strains showed their different
      degrees of relationship with the NA etalons of both evolutionary groups, i.e.
      B/Victoria/2/87 and B/Yamagata/16/88-like. A study of paired sera obtained from
      patients showed a growth of antibodies to the etalons of influenza A(H1N1),
      A(H3N2) and B viruses of the season in question, which confirmed the virology
      data.

PMID- 15188651
TI  - [Evolution of the receptor specificity of influenza viruses hemagglutinin in its
      transfer from duck to pig and man].
AB  - The receptor properties of H1 and H2 influenza viruses (IV), isolated from duck,
      pig and man were studied by using the natural and synthetic sialoglycoconjugates.
      It was shown that viruses, isolated from different hosts, adapt themselves to the
      host cell receptors. The IV affinity was increasing to 6'sialy(N
      acetyllactosamine) in proportion as amino acids (in positions 138, 190, 194 and
      225), which are for avian IV, were increasingly replacing. Some of the porcine
      viruses display adaptation to the human receptor, i.e. 6'sialy(N
      acetyllactosamine), however, all tested porcine influenza viruses, belonging to
      different evolution branches, acquired even more affinity to sulphated and
      fucozyled derivatives of 3'sialy(N-acetyliactosamine)-(Neu5AC alpha 2-3 g AL beta
      1-4(fUC alpha 1-3)(6-sulfo)GlcNAc beta).

PMID- 15188652
TI  - [HIV-infection in Russia: a prediction].
AB  - It is pointed out in the paper that the number of HIV-infected persons is to a
      great extent understated in Russia. Demographic parameters of sexually
      transmitted HIV-infection are briefly forecasted for the country. A variety of
      scenarios for further epidemic progression are elucidated.

PMID- 15188653
TI  - [Etiotropic medicinal therapy of viral infections].
AB  - The paper contains a description of modern data on etiotropic therapy
      (chemotherapy) for widespread and socially-significant viral infections, like
      influenza, acute respiratory lesions, herpes-virus infections, hepatitis, AIDS
      and other extra dangerous viral infections. The survey focuses on the
      contribution of Russian researchers to creating antiviral chemopreparations.

PMID- 15188654
TI  - [Hantaviruses and hantavirus infections].
AB  - Hemorrhagic fever with renal syndrome (HVRS) has been for decades a topical
      problem for healthcare systems of many countries in the Eurasian continent.
      Viruses triggering HVRS alongside with other related viruses (but not pathogenic
      to man) were discovered in 70-80-ies and formed a new genus Hantavirus of the
      Bunyaviridae family. The study results of a severe outbreak of the respiratory
      disease with the mortality rate of 60% (South-West of the USA, 1933) showed that
      hantaviruses were also among the causative agents. Later, the disease was
      designated as hantavirus cardio-pulmonary syndrome. By now, it has been
      established that hantaviruses are wide spread with different rodents being their
      carriers. The discussed viruses cause, in rodents, a chronic asymptomatic
      infection and are transferred, later, to man by the aerogenic path through
      excretions of infected animals. Studies of hantaviruses have been restricted for
      a long time due to their high pathogenicity (protection equipment not below than
      the P-3 level is needed), because of a lack of a laboratory model of infected
      animals and because of a low growth in cell cultures. With the rapid development
      and application of molecular biological techniques of the recent years,
      substantial progress has been made in studies of hantaviruses. Different aspects
      of hantavirus ecology, molecular biology, morphology, pathogenesis and
      diagnostics are discussed in the offered survey.

PMID- 15188655
TI  - [Circulation of West Nile virus (Flaviviridae, Flavivirus) and some other
      arboviruses in the ecosystems of Volga delta, Volga-Akhtuba flood-lands and
      adjoining arid regions (2000-2002)].
AB  - Comprehensive virological, serological as well as genetic studies of the ecology
      of West Nile Virus (WNV) as well as of some other arboviruses were undertaken in
      different ecosystems in the territories of the Astrakhan Region and of the Kalmyk
      Republic. The main carriers (mosquitoes, ticks, birds and mammals) were defined
      as involved in the circulation of viruses within the natural and anthropogenic
      biocenosis. Phylogenetic examinations of isolated strains and samples, which were
      positive in RT-PCR, showed an absolute predominance of genotype I virus that was
      most closely related to American and Israeli strains. At the same time, epidemic
      strains had up to 6% of nucleotide differences versus the historic strains
      isolated in the same region 20-30 years ago. Besides, the circulation of genotype
      IV was discovered; it was characterized by a lower pathogenicity, which,
      possibly, ensures the shaping of a pronounced immune interlayer bearing no
      epidemic consequences. An analysis of the study results on the WNV ecology
      denotes the epicenter of the endemic territory located in the middle part of the
      Volga delta.

PMID- 15188656
TI  - [Detection of West Nile virus in birds in the territories of Baraba and Kulunda
      lowlands (West Siberian migration way) during summer-autumn of 2002].
AB  - West Nile Virus (WNV) was discovered in 3 species of birds collected in summer
      autumn, 2002, in the South of Western Siberia. WNV was identified by ELISA and RT
      PCR. Three of 5 dead rooks (Corvus frugilegus), which were found in the territory
      of the Kulunda plain, were WNV-infected. WNV RNA was detected in 2% of samples of
      internal organs of aquatics birds, i.e. teal (Anas crecca) and garganey (Anas
      querquedula), caught in the Chany Lake (Baraba plain). Nucleotide sequencing of
      the 300-472 aa fragment of WNV protein E gene showed the maximum level of
      homology with strain WNV/LEIV-Vlg99-27889, which was isolated from a patient in
      Volgograd (1999). A high homology level of nucleotide sequencing denotes the
      relationship between the WNV circulating in the Northern Caspian Region and in
      the South of Western Siberia.

PMID- 15188657
TI  - [Analysis of genome determinants of virulence and setting-up of a library of full
      size genome copies of the attenuated virus strain of the porcine reproductive and
      respiratory syndrome virus North American type].
AB  - Primary genome structures of 3 variants of the NADC-8 North American virulent
      strain of porcine reproductive and respiratory syndrome virus (PRRSV) were
      compared for the purpose of detecting any potential genetic virulence
      determinants of genus Arterivirus. Apart from the virulent variant, we also
      investigated the attenuated variant, obtained after 251 passages in cell culture,
      and the intermediate variant isolated from a pig after a partial reversion of the
      attenuated virus. The attenuated variant genome acquired a 3-nucleotide deletion
      and 50 mutations versus its virulent precursor. A comparison of the attenuated
      and intermediary virus variants denoted 8 nucleotide mutations entailing
      substitutions of 6 amino acids in 3 open reading frames (ORF1a, ORF1b and ORF6).
      A 32-clone library was constructed in the pACYC177 plasmid vector, which
      comprised full-size copies of the genome of the NADC-8 attenuated variant strain
      (251), virus PPCC, for the purpose of experimentally verifying the functional
      role of the obtained mutations. Full-size analogues ((+)-chain of RNA) of the
      viral genome, comprising the CAP-structures and polyadenylated ones were obtained
      in vitro on the basis of the cloned DNA. Seven of the 8 analyzed clones of the
      viral genome were infected and their insertion into the MARC-145 cell resulted in
      obtaining of infectious PRRSVs. Four of the constructed recombinant viruses had
      delayed growth parameters, and 3 of them were similar to the parental strain. The
      described technology (inverse genetics) would make it possible to introduce
      changes into the viral genome in applied and fundamental research of
      Arteriviruses.

PMID- 15188658
TI  - The Scandinavian Sarcoma Group--background, organization and the SSG Register-
      the first 25 years.

PMID- 15188659
TI  - The Scandinavian Sarcoma Group Register 1986-2001.

PMID- 15188660
TI  - The Scandinavian Sarcoma Group Skeletal Metastasis Register. Survival after
      surgery for bone metastases in the pelvis and extremities.
AB  - INTRODUCTION: The assessment of the prognosis for the individual patient is
      important for the choice of surgical treatment of skeletal metastases. In 1999
      the Scandinavian Sarcoma Group (SSG) initiated the Skeletal Metastasis Register
      as a multicentric, prospective study to provide a scientific basis for treatment
      recommendations. To improve prognostication we analyzed the survival of patients
      with skeletal metastases surgically treated at 9 SSG centres. PATIENTS AND
      METHODS: 460 patients with an average age of 64 years underwent 501 operations
      for non-spinal skeletal metastases. 7% were operated for more than one
      metastasis. Carcinoma of the breast, prostate, kidney and lung were the
      dominating primary tumors. RESULTS: The survival rate was 0.4 at 1 year, 0.3 at 2
      years and 0.2 at 3 years. Univariate analysis showed that survival was related to
      bone localization, skeletal metastatic load, presence of visceral metastases,
      Karnofsky performance score, primary tumor type, presence of a complete
      pathological fracture and preoperative hemoglobin content. Multivariate
      regression analysis showed that pathological fracture, visceral metastases,
      haemoglobin content < 7 mmol/L and lung cancer were negative prognostic factors
      for survival. Myeloma was the sole positive prognostic factor for survival.

PMID- 15188661
TI  - An updated review of the epidemiology of soft tissue sarcoma.

PMID- 15188662
TI  - Genetic characterization of bone and soft tissue tumors.

PMID- 15188663
TI  - Experiences from tissue microarray in soft tissue sarcomas.
AB  - The tissue microarray (TMA) technology was introduced in 1998 as a tissue
      preserving, high-throughput technique that allows studies of multiple markers in
      large sample sets. TMA slides can be analyzed using techniques such as
      immunohistochemistry and in situ hybridization and represents a powerful tool for
      the investigation of potential diagnostic and prognostic markers identified in
      DNA microarray studies. We review the TMA method, its reproducibility,
      advantages, limitations and future perspectives with specific focus on soft
      tissue sarcomas.

PMID- 15188664
TI  - Lessons from genetic profiling in soft tissue sarcomas.
AB  - Soft tissue sarcomas represent a heterogeneous group of tumors and include over
      50 histotypes. Some of these tumor types are characterized by specific
      chromosomal translocations, whereas other types show complex genetic aberrations.
      The recent developments within gene expression technologies have now been applied
      to studies of soft tissue sarcomas (STS) and the first results indicate that
      genetic signatures are useful for classification and diagnosis. Distinctive
      expression profiles have been found in e.g. gastrointestinal stromal tumors
      (GISTs), synovial sarcomas, malignant peripheral nerve sheath tumors (MPNSTs),
      and in subsets of liposarcomas. The more pleomorphic tumor types, such as high
      grade variants of leiomyosarcomas, malignant fibrous histiocytomas (MFHs),
      fibrosarcomas, and subtypes of liposarcomas, show a greater variability among the
      expression profiles, but interestingly subsets with distinctive expression
      profiles can be identified also among these tumors. The data available place many
      of the genes hypothesized to be involved in the development of a certain type of
      STS, such as the KIT gene in GIST development, among the top discriminating
      genes. Thereby expression profiling provides novel insights into the pathogenesis
      of STS. Although much work remains to be done to validate the data and to define
      optimal discriminating gene lists, the current lessons from gene expression
      studies in STS are encouraging and imply that genetic signatures may serve as
      diagnostic and prognostic markers and may help identify novel therapeutic
      strategies.

PMID- 15188665
TI  - Combined radiology and cytology in the diagnosis of bone lesions--a review of 399
      cases.

PMID- 15188666
TI  - Diagnostic procedures and surgical treatment of bone sarcomas. Experience from
      the Scandinavian Sarcoma Group and Karolinska Hospital.

PMID- 15188667
TI  - Gastrointestinal stromal tumors--a review.
AB  - Gastrointestinal stromal tumors (GISTs) may be defined as intraabdominal
      nonepithelial (mesenchymal) tumors that express the KIT protein or have an
      activating mutation in a class III receptor tyrosine kinase gene (KIT or PDGFRA).
      GISTs are diagnosed at a frequency of about 15 new cases annually per million,
      though small indolent GISTs are likely to occur more frequently in the general
      population. The clinical behavior is variable, and assessment of the malignancy
      potential is usually based mainly on the size and the proliferation
      characteristics of the tumor. The overwhelming majority of GISTs express the KIT
      protein, the transmembrane receptor tyrosine kinase for the stem cell factor. The
      majority of GISTs harbor a mutation in the KIT proto-oncogene that translates
      into constitutively activated KIT protein kinase, and a minority have mutated
      PDGFRA gene resulting in activated platelet-derived growth factor alpha receptor
      tyrosine kinase. Most GISTs respond to imatinib mesylate, which selectively
      inhibits both KIT and PDGFRA, and is now considered as the standard systemic
      therapy for advanced GIST. In contrast, responses to conventional chemotherapy
      are infrequent (generally less than 10%), but combination therapies with imatinib
      have not been explored. Research on adjuvant imatinib and novel targeted
      therapies is ongoing.

PMID- 15188668
TI  - Diagnosis and tumor response in osteosarcoma and Ewing's sarcoma.

PMID- 15188669
TI  - Chemotherapy in soft tissue sarcoma. The Scandinavian Sarcoma Group experience.
AB  - The Scandinavian Sarcoma Group (SSG) started its first chemotherapy study in soft
      tissue sarcoma (STS) in 1981 (SSG I). This study evaluated single agent
      doxorubicin given adjuvant in a prospective randomized trial in patients with
      high-grade STS. Neither overall survival nor disease-free survival was improved.
      Combination chemotherapy was hereafter studied in a phase II study (1991-1994)
      combining ifosfamide and continuous infusion etoposide with growth factor support
      (SSG X). The response rate in previously untreated patients was high (42%), but
      complete remissions were few. Analysis made on patients operated after
      chemotherapy indicated improved survival in this subgroup. Meta-analyses of
      adjuvant chemotherapy for localised resectable STS in adults, including the SSG I
      trial, has indicated improved disease-free survival and a trend towards improved
      overall survival. Presently, SSG is testing whether such a benefit can be found
      for adjuvant ifosfamide and doxorubicin treatment given after primary surgery in
      selected patients with high-grade STS and other well defined unfavourable
      prognostic factors (SSG XIII).

PMID- 15188670
TI  - Chemotherapy in Ewing's sarcoma. The Scandinavian Sarcoma Group experience.

PMID- 15188671
TI  - Chemotherapy in osteosarcoma. The Scandinavian Sarcoma Group experience.

PMID- 15188672
TI  - ["Risk analysis"].

PMID- 15188673
TI  - [Policy related research: future tasks of the Federal Institute for Risk
      Assessment].
AB  - The Federal Institute for Risk Assessment wants to be a competent scientific
      adviser for politics, administration and the public in risk evaluation and risk
      communication regarding consumer products. Fields of research needed for this
      advice are compared with the research universities have to carry out. Examples
      were given.

PMID- 15188674
TI  - [Performance of risk analysis at the Federal Veterinary office].
AB  - The risk management at the Federal Veterinary Office (FVO) is responsible for the
      arrangement and initiation of actions to minimize or prevent risks in the fields
      of animal health and food safety of animal products. In absence of a scientific
      basis, the risk management may initiate a formal risk assessment according to a
      standardised protocol. The risk assessment is conducted by an assigned team of
      risk analysts, according to scientific criteria, international standards and
      methods. The "Basic principles for risk analysis at the Swiss Federal Veterinary
      Office" describe the principles and the procedure of a risk analysis (risk
      management, risk communication and risk assessment), furthermore the interactions
      of concerned divisions at the FVO are laid down. Experience at the FVO confirms,
      that risk analyses may be performed efficiently, if the following decisive
      conditions are met. The responsibilities of all parties involved are defined, the
      risk profile and the precise question are amicably phrased, necessary resources
      are provided, well-trained risk analysts with experience in project management
      coordinate the risk assessment and interdisciplinary expertise is available.

PMID- 15188675
TI  - Principles, application areas and an example of risk assessment conducted at the
      Danish Institute for Food and Veterinary Research.
AB  - The Department for Epidemiology and Risk Analysis at the Danish Institute for
      Food and Veterinary Research (DFVF) is concerned with risk analyses in the areas
      of food safety, zoonoses, antimicrobial resistance and OIE (World Organisation
      for Animal Health) list A and B diseases. The DFVF is responsible for the risk
      assessment component of the risk analysis process and provides advice and support
      for the risk management and risk communication component, which is generally
      under the auspices of the Danish Veterinary and Food Administration (DVFA). The
      paper presents guidelines for the conduct of risk assessments at the DFVF.
      Important elements of these guidelines are the independence between risk
      assessment and risk management, the commitment to science-based, transparent and
      fully documented procedures and adherence to a protocol that regulates the
      cooperation between DFVF and DVFA. Typical steps of a quantitative risk
      assessment are the description of the risk scenario, information retrieval,
      mathematical modelling with stochastic simulation, final risk estimation with a
      sensitivity analysis and reporting. The procedure is exemplified using a Monte
      Carlo simulation model for the assessment of the risk of BSE transmission to
      calves by tallow-based calf milk replacer.

PMID- 15188676
TI  - [Assessing risks in relation to international trade with food and animals: a
      review of methods currently applied].
AB  - Since approximately 10 years, risk assessments in the context of international
      trade with animals and food are being conducted. International standards provide
      guidelines for such assessments. However, the methods to be applied are only very
      broadly defined. A review of published or otherwise accessible examples
      demonstrated that most assessments in this field are qualitative in nature. When
      quantitative risk assessments are conducted, simulation modeling is often used.
      Further methodological development is required regarding the consideration of
      uncertainty, the use of expert knowledge and standardization of qualitative risk
      estimates. In order to maintain quality assurance in risk assessments, a wider
      use of peer-review is desirable, e.g. through publication of results in
      scientific journals.

PMID- 15188677
TI  - [Import risk analysis in animal disease control].
AB  - At the Swiss Federal Veterinary Office risk analyses are conducted according to
      international standards. A risk analysis contains the elements risk management,
      risk assessment and risk communication. A risk assessment is based on risk
      profile, hazard identification and a pathway model. All available information is
      gathered, documented and assessed and the risk estimated. The question. "What is
      the probability that unprocessed wild boar meat imported to Switzerland from the
      federal state Mecklenburg Western Pommerania is contaminated with classical swine
      fever virus?" was answered by a release assessment. The hazard identification
      recognized classical swine fever virus and attenuated live virus vaccine used for
      oral immunization as hazards. The probability of contamination was estimated to
      be small. The question: "What is the likelihood to introduce Aujeszky's disease
      to Switzerland and infect the indigenous pig population with the disease, by
      means of importing pork and meat products?" was answered by assessing the
      release, exposure and resulting consequences. The risk of an infection of the
      indigenous pig population was estimated to be very small, as 80% of the imported
      products derive from countries or zones free from Aujeszky's disease. Furthermore
      the majority of the imported products are processed. The strict implementation of
      the regulations governing feeding of food wastes to pigs reduces the probability
      of exposure. In all assessments the risk management decides on a strategy to deal
      with the risk, taking into consideration the results and recommendations derived
      from the risk assessment as well as other relevant factors.

PMID- 15188678
TI  - [Sampling plans and microbiological criteria as risk management options in
      recently developed food safety concerns].
AB  - In connection with the World Trade Organization SPS-Agreement new concepts for
      ensuring food safety have been discussed for some years now. Main topics have
      been quantitative risk analyses investigating relationships between microbial
      concentrations in foods and disease probabilities as well as the concept of food
      safety objectives developed by ICMSF. So far food safety demands have been
      defined as microbiological criteria. However, usually it is not transparent,
      whether sampling plans incorporated in such criteria are based on specific
      prescriptions with regard to decision reliability and tolerable food qualities.
      In addition, it is still to be discussed, which parts microbiological criteria
      can play in connection with new concepts of food risk management, for instance as
      an option to test whether food safety objectives are met or not. The performance
      of microbiological sampling plans, as visualized by operation characteristic
      curves, assumptions made in this context, and relationships between food safety
      objectives and microbiological criteria as well as implications for food safety
      issues are investigated in this paper.

PMID- 15188679
TI  - [The entry of bound residues of tetracyclines into the food chain--a contribution
      to hazard identification].
AB  - Actually, some 67% of therapeutical used antibiotics in livestock in the European
      Union are tetracyclines. Their use can result in unwanted residues in food of
      animal origin. Apart the risk of the possible development of resistances in
      enterobacteriaceae we have to keep in mind secondary circuits. This paper focuses
      on tetracycline residues in bones. Bones have been widely used as raw material
      for meat and bone meal and gelatine, and are also a frequent contamination of
      mechanical recovered meat. Bones contain tetracycline residues in concentrations
      up to 50 mg/kg. These bound tetracycline residues have ever been thought to be of
      no significance to health. Nevertheless, recent studies have shown that these
      tetracyclines could be released in vivo and re-obtain their bioavailability.
      Further, several toxic degradation products of tetracyclines could be formed
      during heating. Additionally, in acid solutions from the production of gelatine
      high tetracycline concentrations have been found. These solutions are processed
      to dicalciumphosphate, which is used as a feed supplement in animal husbandry and
      as fertilizer in agriculture.

PMID- 15188681
TI  - [Risk assessment of bluetongue disease incursion into Germany using geographic
      information system (GIS)].
AB  - Using a geographic information system (GIS), by analysis of the relationship
      between the spatial distribution of cattle density and the risk factors
      temperature, altitude and rainfall, we defined geographical habitats enabling
      optimal development and competence of Culicoides spp. to transmit Bluetongue
      Virus (BTV): Risk zones (low, high, highest risk) were identified mainly in Baden
      Wurttemberg, Hessen and Rheinland-Pfalz if persistently infected ruminants are
      imported into these zones in summer (June to August mainly), based on the current
      climatic conditions, BTD outbreaks are considered a real possibility.
      Overwintering of the virus seems unlikely. However, global warming will lead to a
      steady increase of the size of the risk zones. In addition, the possibility of
      primary outbreaks increases. The reason for this is not only the expected
      northern shift of Culicoides imicola, but in addition an increasing vector
      competence of domestic Culicoides species. We therefore recommend the storage of
      vaccines as well as conducting ecological studies analysing the presence of
      Culicoides vectors. Using the data from these studies, it will be possible to
      produce updated quantitative risk assessment via GIS.

PMID- 15188680
TI  - [Dose-response-models and their implications for quantitative risk assessment for
      Campylobacter infections].
AB  - For some time now there have been several projects dealing with the assessment of
      campylobacteriosis risks for consumers. Dose-response relationships form a
      crucial part of such assessments, as they specify disease probabilities depending
      on different microbial concentrations in foods. Evaluation of such models,
      however, is difficult because of problems to find data on which reliable
      assumptions could be based. Ongoing risk analyses for Campylobacter mainly refer
      to a single administration study with human volunteers published by Black et al.
      (1988). However, whether results from this study can be transferred to target
      populations envisaged in risk assessments remains questionable for several
      reasons. In this paper some alternative dose-response models, their fit to the
      data of Black et al., and risk estimates resulting in a fictitious scenario are
      discussed and compared. Depending on the dose-response model assumed risk
      estimates can differ remarkably. Therefore it is hardly possible to make reliable
      quantifications of risks in reality, however, it can be determined how much they
      may vary assuming different scenarios.

PMID- 15188682
TI  - [Functional risk assessment of handling of sheep housing and pasture areas at a
      scrapie-infested farm in Mecklenburg-West Pomerania].
AB  - In the wake of a scrapie monitoring programme 2002 in Mecklenburg-Westpomerania a
      total of 10 positive cases were identified after culling at a suffolk-farm with
      about 1000 animals. Scientific based recommendations are difficult to judge as
      longitudinal studies and subsequent quantitative risk factors regarding the
      epidemiology of scrapie are either not available or conflicting. Given this
      background a risk assessment was developed that is based on the probability of
      validated risk factors considering special husbandry and circumstances at the
      very farm.

PMID- 15188683
TI  - [Model calculation to explain the BSE-incidence in Germany].
AB  - The future development of BSE-incidence in Germany is investigated using a simple
      epidemiological model calculation. Starting point is the development of the
      incidence of confirmed suspect BSE-cases in Great Britain since 1988, the
      hitherto known mechanisms of transmission and the measures taken to decrease the
      risk of transmission as well as the development of the BSE-incidence in Germany
      obtained from active post mortem laboratory testing of all cattle older then 24
      months. The risk of transmission is characterized by the reproduction ratio of
      the disease. There is a shift in time between the risk of BSE transmission and
      the BSE incidence caused by the incubation time of more than 4 years. The
      observed decrease of the incidence in Germany from 2001 to 2003 is not a
      consequence of the measures taken at the end of 2000 to contain the disease. It
      can rather be explained by an import of BSE contaminated products from countries
      with a high BSE incidence in the years 1995/96 being used in calf feeding in
      Germany. From the future course of the BSE-incidence in Germany after 2003 a
      quantification of the recycling rate of BSE-infected material within Germany
      before the end of 2000 will be possible by use of the proposed model if the
      active surveillance is continued.

PMID- 15188684
TI  - Meniscal tear--a feature of osteoarthritis.
AB  - Meniscectomy is recognized as an important risk factor for the development of
      knee osteoarthritis (OA), a disease that traditionally has been considered as a
      simple "wear and tear" phenomenon. However, despite numerous reports, little
      evidence has been presented that a limited meniscal resection, compared with a
      more extensive resection, reduces the risk of OA by preserving meniscal function.
      Why? This thesis provides one possible answer to that question. Patients, who had
      undergone isolated meniscal resection in 1973, 1978, or between 1983 and 1985 at
      Lund University Hospital, Sweden, were reviewed clinically and radiographically
      15-22 years after the surgical procedure. Of the subjects (n = 317) almost 50%
      had developed radiographic OA in their operated knee, but just over half of these
      patients were symptomatic. An additional 20% of the patients had knee symptoms,
      but did not have radiographic knee OA. These results confirm a limited
      correlation between radiographic features of the disorder and symptoms. A
      degenerative type of meniscal tear and obesity were the factors most strongly
      associated with both radiographic knee OA and symptomatic radiographic knee OA.
      Partial meniscal resection induced less radiographic changes related to knee OA
      compared with total meniscectomy, but the patient-relevant outcomes remained
      essentially the same. If radiographic hand OA was present there was an increased
      likelihood of the patient also having knee OA following meniscectomy. This
      finding was independent of age, and therefore an inherited susceptibility to the
      disease contributes to the risk of knee OA after meniscal tear. Genetic and
      environmental risk factors interact in OA development. A degenerative meniscal
      lesion is often associated with early-stage knee OA, a disorder also involving
      the meniscal tissue. The tear may thus represent the first "signal" feature of
      OA. The challenge for the health professional is to discriminate between symptoms
      caused by a meniscal tear and those caused by OA. Meniscal resection may not
      benefit the patient with early-stage knee OA. The intervention merely removes
      evidence of the disorder, while the OA joint degradation proceeds.

PMID- 15188685
TI  - Check out your background checker.

PMID- 15188686
TI  - Did OSHA lower the mineral oil mist PEL?

PMID- 15188687
TI  - Whose fundraising really helps firefighters?

PMID- 15188688
TI  - 'Chemically challenged' OSHA should sit tight.

PMID- 15188689
TI  - OSHA's alliances are the wrong strategy.

PMID- 15188690
TI  - Generating quality interaction.

PMID- 15188691
TI  - Automating safety inspections.

PMID- 15188692
TI  - Apparel selection for chemical barrier.

PMID- 15188693
TI  - Effective education.

PMID- 15188694
TI  - Loading dock security.

PMID- 15188695
TI  - Accurate measurement of flammable gases.

PMID- 15188696
TI  - A guide to gas monitoring instruments.

PMID- 15188697
TI  - Direct reading sensors for toxic killers.

PMID- 15188698
TI  - The ABCs of mold remediation.

PMID- 15188699
TI  - Plug-and-play equipment.

PMID- 15188700
TI  - Respirator fit testing. Requirements and procedures.

PMID- 15188701
TI  - Measuring your respiratory program.

PMID- 15188702
TI  - Thirsty no more.

PMID- 15188703
TI  - Quenching the summer heat.

PMID- 15188704
TI  - Issues in system design.

PMID- 15188705
TI  - Plan your FOI policy.

PMID- 15188706
TI  - Pityriasis rosea--evidence for and against an infectious aetiology.
AB  - Pityriasis rosea, first named as such in 1860, probably holds the longest record
      for an exanthem suspected to be associated with an infection but for which an
      exact cause has not been found. The distinctly programmed clinical course, the
      lack of recurrence for most patients, and the presence of temporal case
      clustering provide the strongest evidence to support an infectious aetiology.
      Further support comes from seasonal variation and the association with
      respiratory tract infections, the unfavourable social and economic background of
      cases, and a history in some cases of contact with patients with pityriasis
      rosea. The apparent therapeutic efficacy of several treatment modalities does not
      provide strong evidence for or against an infectious aetiology. The roles of
      human herpesvirus 7 and to a lesser extent human herpesvirus 6 remain
      controversial. There exists reasonable evidence that pityriasis rosea is not
      associated with cytomegalovirus, Epstein-Barr virus, parvovirus B19,
      picornavirus, influenza and parainfluenza viruses, Legionella spp., Mycoplasma
      spp. and Chlamydia spp. infections. Evidence is also unsubstantiated as yet for
      alternative aetiological hypotheses such as autoimmunity, atopy, and genetic
      predisposition.

PMID- 15188707
TI  - Mumps and rubella: a year of enhanced surveillance and laboratory testing.
AB  - In Victoria (Australia) surveillance for mumps and rubella has historically been
      passive, with most notified cases clinically diagnosed. In July 2001, the
      Victorian Department of Human Services implemented an enhanced surveillance
      system focusing on improved laboratory testing. We tested 85% of notifications
      and only 9% of all mumps and 27% of rubella notifications were laboratory
      confirmed. While most notified cases were children who had been clinically
      diagnosed, we found most laboratory-confirmed cases were in adults. The positive
      predictive value of the clinical case definition was low: mumps (10%); rubella
      (22%). These results highlight the value of laboratory confirmation of the
      diagnosis when mumps and rubella are rare, failure to do so is likely to
      overestimate disease incidence.

PMID- 15188708
TI  - Amino-acid change on the antigenic region B1 of H3 haemagglutinin may be a
      trigger for the emergence of drift strain of influenza A virus.
AB  - Sera from 27 children and eight older persons, which had been collected in 1998
      and 1999 and showed haemagglutination-inhibition (HI) activity against influenza
      A/Sydney/5/97 (H3N2) strain, were characterized with a binding assay using
      chimeric haemagglutinin (HA) proteins between A/Aichi/2/68 (A/AI/68) and
      A/Sydney/5/97 (A/SD/97) strains. Sera from the young children had a tendency to
      recognize only the antigenic site B1 of the HA1 region. On the other hand, sera
      of the older individuals were fully reactive to all antigenic sites of HA1 except
      antigenic site D. Recent epidemic strains, A/Panama/2007/99 (A/PM/99)-like
      viruses have differences in amino acids in antigenic sites A, C, and B2 but not
      B1. However, human antisera obtained even from young children had HI activity to
      Panama-like viruses. The limited epidemic of A/PM/99-like viruses may have been
      due to the existence of antibody against B1, which had been produced in response
      to infection by the A/SD/97-like viruses.

PMID- 15188709
TI  - Hospitalized patients with bacterial infections: a potential focus of SARS
      transmission during an outbreak.

PMID- 15188710
TI  - The prevalence and the risk behaviours associated with the transmission of
      hepatitis C virus in Australian correctional facilities.
AB  - This study measured the prevalence and the risk factors associated with HCV
      antibody-positive prisoners. A total of 630 prisoners completed a questionnaire
      about risk behaviours associated with HCV transmission and were tested for HCV
      antibody from a blood test. Of these 362 (57.5%) prisoners were HCV antibody
      positive. A total of 436 (68.8%) prisoners reported ever injecting drugs and 332
      reported injecting drugs in prison. HCV-positive prisoners were more likely to
      have injected drugs (OR 29.9) and to have injected drugs in prison during their
      current incarceration (OR 3.0). Tattooing was an independent risk factor for
      being HCV positive (OR 2.7). This is the first study conducted on prisoners that
      has identified having a tattoo in prison as a risk factor for HCV. Injecting
      drugs whilst in prison during this incarceration was also a risk factor for HCV.
      Our results show prisoners who injected drugs outside of prison continue to
      inject in prison but in a less safe manner.

PMID- 15188711
TI  - Legionnaires' disease in Europe 2000-2002.
AB  - Each year, countries that participate in the European Surveillance Scheme for
      Travel Associated Legionnaires' Disease (EWGLINET) are requested to complete a
      set of standardized reporting forms that provide epidemiological and
      microbiological information on the total number of cases (non-travel as well as
      travel-related cases) detected in their country. Trends at the national and
      aggregated European level have been analysed for 2000-2002. For this period,
      10,322 cases of Legionnaires' disease were reported and national infection rates
      ranged from 0 to 34.1 cases per million population. A total of 189 outbreaks were
      associated with nosocomial infection, community exposure or travel. The upward
      trend in diagnosis through the urinary antigen detection test has resulted in a
      higher ascertainment of cases in many countries. However, the decline in
      diagnosis by culture of the organism is likely to severely hamper outbreak
      investigations in the future if fewer clinical isolates are available for
      matching with environmental isolates. This important data-set has been used for
      studying the effectiveness of surveillance and legionella control and prevention
      programmes within Europe.

PMID- 15188712
TI  - Incidence and molecular typing of Mycobacterium kansasii in a defined
      geographical area in Catalonia, Spain.
AB  - A retrospective population-based study was conducted between January 1990 and
      December 1998 to investigate the incidence of Mycobacterium kansasji disease and
      the heterogeneity of the isolates in a well-defined geographical area in
      Catalonia, Spain. A total of 136 patients were identified. Overall incidence and
      incidence in AIDS patients was 1.5 (95% CI 1.2-1.8) and 1089.6 (95% CI 689-1330)
      cases/100,000 persons per year respectively, which is comparable to that reported
      from most of other geographical areas. Surprisingly, although 7 subtypes of M.
      kansasii have been consistently reported, in the present study 91 of the 93
      isolates (97.8%) tested for genotype were subtype I, regardless of HIV status of
      the patients. In conclusion, the high rate of infection observed in the AIDS
      population contributes significantly to the burden of the M. kansasii disease in
      our area. M. kansasii disease in our geographical area was almost exclusively
      caused by subtype I regardless of HIV status.

PMID- 15188713
TI  - Estimating the transmission parameters of pneumococcal carriage in households.
AB  - This paper analyses Streptococcus pneumoniae transmission dynamics in households
      using longitudinal data on pneumococcal (Pnc) carriage in the United Kingdom. Ten
      consecutive swabs were taken at 4-week intervals from all members of 121
      households. The family status is derived from the observed Pnc carriage status of
      each family member. Transition matrices are built for each family size and
      composition containing the observed frequency of transitions between family
      statuses over a 28-day interval. A density-dependent transmission model is fitted
      to derive maximum-likelihood estimates of the duration of carriage and
      acquisition rates from the community and from infected individuals within the
      household. Parameter values are estimated for children (< 5 years) and adults (5+
      years). The duration of carriage is longer in children < 5 years of age than in
      older family members (51 vs. 19 days). Children are 3-4 times more likely than
      adults to acquire Pnc infection from the community. Transmission rates within the
      household suggest that adults are more infectious but less susceptible than
      children. Transmission within the household is most important in large families.
      The proportion of household-acquired infection ranges from 29 to 46% in
      households of three persons to 38-50% in larger households. Evidence of density
      dependent within-household transmission is found, although the strength of this
      relationship is not clear from the model estimates.

PMID- 15188714
TI  - The effect of temperature on food poisoning: a time-series analysis of
      salmonellosis in ten European countries.
AB  - We investigated the relationship between environmental temperature and reported
      Salmonella infections in 10 European populations. Poisson regression adapted for
      time-series data was used to estimate the percentage change in the number of
      cases associated with a 1 degree C increase in average temperature above an
      identified threshold value. We found, on average, a linear association between
      temperature and the number of reported cases of salmonellosis above a threshold
      of 6 degrees C. The relationships were very similar in The Netherlands, England
      and Wales, Switzerland, Spain and the Czech Republic. The greatest effect was
      apparent for temperature 1 week before the onset of illness. The strongest
      associations were observed in adults in the 15-64 years age group and infection
      with Salmonella Enteritidis (a serotype of Salmonella). Our findings indicate
      that higher temperatures around the time of consumption are important and
      reinforce the need for further education on food-handling behaviour.

PMID- 15188715
TI  - An epidemic of gastroenteritis and mild necrotizing enterocolitis in two neonatal
      units of a University Hospital in Rome, Italy.
AB  - In the summer of 1999 a cluster of 18 cases of necrotizing enterocolitis (NEC)
      occurred in a University Hospital in Rome, Italy. The cases presented with mild
      clinical and radiological signs, and none died. Seventy-two per cent had a birth
      weight of > 2500 g, 66.7% had a gestational age of > 37 weeks, 30% presented with
      respiratory diseases and/or hypoglycaemia. All cases occurred within 10 days of
      birth and between 5 and 7 days after two clusters of diarrhoea (14 cases). The
      NEC outbreak had two phases; most cases in the first phase occurred in the at
      risk unit, whereas those in the second phase occurred in the full-term unit. In
      the multivariate analysis, invasive therapeutic procedures, pathological
      conditions and formula feeding were associated with NEC. Although no predominant
      common bacteria were isolated, we suggest an infective origin of this outbreak.

PMID- 15188716
TI  - Disease burden in The Netherlands due to infections with Shiga toxin-producing
      Escherichia coli O157.
AB  - Surveys carried out between 1990 and 2000 indicated that the incidence of STEC
      O157-associated gastroenteritis in The Netherlands was 1250 cases/year (median),
      of which 180 visited a general practitioner, 40 are reported and 0.6 are fatal,
      mainly in the elderly. There are approximately 20 cases of STEC O157-associated
      haemolytic-uraemic syndrome (HUS) per year, mainly in children. There are 2.5 HUS
      patients per year who develop end-stage renal disease (ESRD). There are an
      estimated 2 HUS-related and 0.5 ESRD-related fatalities per year. The mean
      disease burden associated with STEC O157 in the Dutch population is 116 (90%
      confidence interval 85-160) Disability Adjusted Life Years (DALYs) per year.
      Mortality due to HUS (58 DALYs), and ESRD (21 DALYs) and dialysis due to ESRD (21
      DALYs) constitute the main determinants of disease burden. Sensitivity analysis
      indicates that uncertainty associated with model assumptions did not have a major
      effect on these estimates.

PMID- 15188717
TI  - Risk factors for Salmonella typhimurium DT104 and non-DT104 infection: a Canadian
      multi-provincial case-control study.
AB  - To identify risk factors for sporadic Salmonella Typhimurium definitive phage
      type 104 (DT104) and non-DT104 diarrhoeal illness in Canada, we conducted a
      matched case-control study between 1999 and 2000. Cases were matched 1:1 on age
      and province of residence. Multivariate analysis suggested that recent antibiotic
      use [odds ratio (OR) 5.2, 95% confidence interval (CI) 1.8-15.3], living on a
      livestock farm (OR 4.9, 95% CI 1.9-18.9), and recent travel outside Canada (OR
      4.1, 95% CI 1.2-13.8) are independent risk factors for DT104 illness. Similar
      analyses suggested that recent travel outside North America is a sizable risk
      factor for non-DT104 illness (OR 66.8, 95% CI 6.7-665.3). No food exposure was a
      risk factor in either analysis. Educating health-care providers and the public
      about appropriate antibiotic use and antimicrobial resistance is important.
      Appropriate administration of antibiotics to livestock, particularly cattle, and
      hygienic measures such as handwashing after contact with farm animals may reduce
      risk. Travel represents an important and probably underestimated risk factor for
      sporadic illness with S. Typhimurium. Improved national surveillance and detailed
      investigation of travel-related illness are required.

PMID- 15188718
TI  - GIS-supported investigation of human EHEC and cattle VTEC O157 infections in
      Sweden: geographical distribution, spatial variation and possible risk factors.
AB  - This article describes the spatial and temporal distribution of verotoxin
      producing Escherichia coli among humans (EHEC) and cattle (VTEC) in Sweden, in
      order to evaluate relationships between the incidence of EHEC in humans,
      prevalence of VTEC O157 in livestock and agricultural structure by an ecological
      study. The spatial patterns of the distribution of human infections were
      described and compared with spatial patterns of occurrence in cattle, using a
      Geographic Information System (GIS). The findings implicate a concentration of
      human infection and cattle prevalence in the southwest of Sweden. The use of
      probability mapping confirmed unusual patterns of infection rates. The comparison
      of human and cattle infection indicated a spatial and statistical association.
      The correlation between variables of the agricultural structure and human EHEC
      incidence was high, indicating a significant statistical association of cattle
      and farm density with human infection. The explained variation of a multiple
      linear regression model was 0.56.

PMID- 15188719
TI  - Epidemiological and molecular evidence of a monophyletic infection with
      Staphylococcus aureus causing a purulent dermatitis in a dairy farmer and
      multiple cases of mastitis in his cows.
AB  - An epidemiological and molecular investigation of a cutaneous suppurative
      infection with Staphylococcus aureus in a dairy farmer, occurring concurrently
      with an outbreak of clinical mastitis in his herd, was carried out. A common
      aetiology for the diseases in the farmer and his cows was established by
      combining clinical evidence with a molecular genomic analysis of the bacterial
      isolates using pulsed field gel electrophoresis of DNA macro-restriction
      fragments. This case indicates the possibility of the emergence and circulation
      of anthropozoonotic clones of S. aureus in dairy herds. It also provides further
      evidence of the severe impact of infection with highly virulent clones on dairy
      lactating cattle.

PMID- 15188720
TI  - Temporal dynamics of rabies in a wildlife host and the risk of cross-species
      transmission.
AB  - An epidemiological model was developed for rabies, linking the risk of disease in
      a secondary species (cats) to the temporal dynamics of disease in a wildlife
      reservoir (raccoons). Data were obtained from cats, raccoons, and skunks tested
      for rabies in the northeastern United States during 1992-2000. An epizootic
      algorithm defined a time-series of successive intervals of epizootic and inter
      epizootic raccoon rabies. The odds of diagnosing a rabid cat during the first
      epizootic of raccoon rabies was 12 times greater than for the period prior to
      epizootic emergence. After the first raccoon epizootic, the risk for cat rabies
      remained elevated at levels six- to seven-fold above baseline. Increased monthly
      counts of rabid raccoons and skunks and decreasing human population density
      increased the probability of cat rabies in most models. Forecasting of the public
      health and veterinary burden of rabies and assessing the economics of control
      programmes, requires linking outcomes to dynamic, but predictable, changes in the
      temporal evolution of rabies epizootics.

PMID- 15188721
TI  - A first molecular epidemiological study of SAT-2 type foot-and-mouth disease
      viruses in West Africa.
AB  - Thirty-one viruses causing SAT-2 outbreaks in seven West African countries
      between 1974 and 1991, and four viruses representative of East and Central Africa
      were genetically characterized in this study. Four major viral lineages (I-IV)
      were identified by phylogenetic analysis of an homologous 480 nucleotide region
      corresponding to the C-terminus end of VP1. Lineage I comprised two West African
      genotypes with viruses clustering according to year of isolation rather than
      geographical origin. Lineage II was represented by viruses isolated between 1979
      and 1983 in two neighbouring West African countries, Senegal and The Gambia.
      Viruses from Nigeria and Eritrea, representative of West and East Africa
      respectively, constituted lineage III, whilst lineage IV, comprising viruses from
      Central and East Africa, was regionally and genetically distinct. This study
      revealed that unrestricted animal movement in West Africa is a major factor in
      disease dissemination and has also provided the first indication of trans
      regional virus transmission.

PMID- 15188722
TI  - Importance of screening household members of acute brucellosis cases in endemic
      areas.
AB  - Isolated reports of brucellosis among family members have been documented. The
      aim of this study is to determine if active serological screening of the
      households' members of acute brucellosis cases will detect additional
      unrecognized cases. From May 2000 to October 2001, patients with acute
      brucellosis were enrolled and their household members were serologically screened
      for brucellosis using the Standard Agglutination Test (SAT). Fifty-five index
      cases with acute brucellosis and 404 household members were enrolled. The
      majority of index cases (48%) were young adults, and 79% were illiterate.
      Ownership of animals and ingestion of unpasteurized raw milk were reported by 45
      and 75% of the index cases respectively. Of the 55 families screened, 23 (42%)
      had two family members or more with serological evidence of brucellosis and 32
      (58%) had only the index case. Households of > or = 5 members and a history of
      raw-milk ingestion by family members were risk factors associated with the
      seropositives (P < 0.05). Of the 404 household members screened, 53 (13%) were
      seropositive; of these 39 (74%) were symptomatic, and 9 (35%) had brucella
      bacteraemia. Symptomatic seropositives tended to have bacteraemia and higher
      brucella antibody titres compared to asymptomatic seropositives (P < or = 0.05).
      Screening family members of an index case of acute brucellosis will detect
      additional cases.

PMID- 15188723
TI  - Duration of the IgM response in women acquiring Toxoplasma gondii during
      pregnancy: implications for clinical practice and cross-sectional incidence
      studies.
AB  - We followed up a cohort of 446 toxoplasma-infected pregnant women to determine
      the median and variability of the duration of positive toxoplasma-IgM
      (immunoglobulin M) results measured by an immunofluorescence test (IFT) and an
      immunosorbent agglutination assay (ISAGA). IgM antibodies were detected for
      longer using the ISAGA test [median 12.8 months, interquartile range (IQR) 6.9
      24.9] than the IFT (median 10.4, IQR 7.1-14.4), but the variability between
      individuals in the duration of IgM positivity was greatest for the ISAGA test.
      IgM-positive results persisted beyond 2 years in a substantial minority of women
      (27.1% ISAGA, 9.1% IFT). Variation in the duration of the IgM response measured
      by ISAGA and IFT limit their usefulness for predicting the timing of infection in
      pregnant women. However, measurement of IgM and IgG antibodies in a cross
      sectional serosurvey offers an efficient method for estimating the incidence of
      toxoplasma infection.

PMID- 15188724
TI  - Rapid field test for detection of hantavirus antibodies in rodents.
AB  - Puumala virus (PUUV) is the causative agent of nephropathia epidemica, a mild
      form of haemorrhagic fever with renal syndrome. PUUV is transmitted to humans via
      aerosolized excreta of the infected bank vole (Clethrionomys glareolus). Current
      methods for screening of the PUUV prevalence among bank vole populations are
      laborious, combining sampling in the field and subsequent analyses in the
      laboratory. In order to facilitate animal testing, a new serological
      immunochromatographic rapid test was developed. The test uses PUUV nucleocapsid
      protein as antigen, and it detects anti-PUUV IgG antibodies in rodents. With
      fresh and undiluted bank-vole blood samples (n = 105) the efficacy of the test
      was 100%, and with frozen and diluted samples (n = 78) the efficacy was 91%. The
      test was also shown to detect related hantavirus infections in Norway lemmings
      and sibling voles (n = 31) with 99% efficacy. The test provides an applicable
      tool for studying PUUV and related hantavirus infections in arvicoline rodents.

PMID- 15188726
TI  - Private sector loosens its grip on NHS staffing.

PMID- 15188725
TI  - Epidemiology of rabbit haemorrhagic disease virus in the United Kingdom: evidence
      for seasonal transmission by both virulent and avirulent modes of infection.
AB  - Rabbit haemorrhagic disease virus (RHDV) has killed many millions of wild rabbits
      in Europe and Australia, but has had little impact in the United Kingdom, despite
      outbreaks having occurred since 1994. High seroprevalence detected in the absence
      of associated mortality had suggested the presence of an endemic non-pathogenic
      strain which may be 'protecting' UK populations. Following the first detailed
      field study of RHDV epidemiology in the United Kingdom, using mark-recapture with
      serum sampling, we report that RHDV caused highly prevalent persistent infection
      in seropositive rabbits in the absence of associated mortality. Furthermore the
      virus strains responsible could not be distinguished phylogenetically from known
      pathogenic isolates, and were clearly very different from the only previously
      identified non-pathogenic strain of RHDV. These findings suggest that many-
      perhaps most--strains of RHDV may be propagated through both 'pathogenic' and
      'non-pathogenic' modes of behaviour. Transmission occurred predominantly during
      and just after the breeding season.

PMID- 15188727
TI  - The HSJ interview: Dr Richard Smith. United he stands. Interview by Nick Edwards.

PMID- 15188728
TI  - Data briefing. Evidence-based choice.

PMID- 15188729
TI  - Clinical management. Where medicine meets management. Pumping iron.
AB  - Non-haemodialysis renal patients requiring intravenous iron therapy are
      increasing the pressure on renal units. A new form of iron therapy can
      dramatically reduce patient visits, but takes longer to administer. Sunday
      provision of nurse-led clinics has enabled a switch to this new therapy. Cost
      savings have more than offset the additional nurse-led sessions and eliminated
      waiting lists for this group.

PMID- 15188730
TI  - Performance management. Score values.

PMID- 15188731
TI  - Finance. Putting a price on quality.

PMID- 15188732
TI  - HSJ people. Off the wall.

PMID- 15188733
TI  - Complementary and alternative medicine use among adults: United States, 2002.
AB  - OBJECTIVE: This report presents selected estimates of complementary and
      alternative medicine (CAM) use among U.S. adults, using data from the 2002
      National Health Interview Survey (NHIS), conducted by the Centers for Disease
      Control and Prevention's (CDC) National Center for Health Statistics (NCHS).
      METHODS: Data for the U.S. civilian noninstitutionalized population were
      collected using computer-assisted personal interviews (CAPI). This report is
      based on 31,044 interviews of adults age 18 years and over. Statistics shown in
      this report were age adjusted to the year 2000 U.S. standard population. RESULTS:
      Sixty-two percent of adults used some form of CAM therapy during the past 12
      months when the definition of CAM therapy included prayer specifically for health
      reasons. When prayer specifically for health reasons was excluded from the
      definition, 36% of adults used some form of CAM therapy during the past 12
      months. The 10 most commonly used CAM therapies during the past 12 months were
      use of prayer specifically for one's own health (43.0%), prayer by others for
      one's own health (24.4%), natural products (18.9%), deep breathing exercises
      (11.6%), participation in prayer group for one's own health (9.6%), meditation
      (7.6%), chiropractic care (7.5%), yoga (5.1%), massage (5.0%), and diet-based
      therapies (3.5%). Use of CAM varies by sex, race, geographic region, health
      insurance status, use of cigarettes or alcohol, and hospitalization. CAM was most
      often used to treat back pain or back problems, head or chest colds, neck pain or
      neck problems, joint pain or stiffness, and anxiety or depression. Adults age 18
      years or over who used CAM were more likely to do so because they believed that
      CAM combined with conventional medical treatments would help (54.9%) and/or they
      thought it would be interesting to try (50.1%). Most adults who have ever used
      CAM have used it within the past 12 months, although there is variation by CAM
      therapy.

PMID- 15188734
TI  - [C-reactive protein: physico-chemical properties, identification methods, and
      diagnostic significance].

PMID- 15188735
TI  - [Lipid spectrum of lymphocyte plasma membranes in abstinent syndrome in patients
      with opioid dependence].
AB  - The lipid composition of the lymphocyte plasmatic membranes was studied in the
      withdrawal syndrome as observed in patients with opioid addiction. The method of
      thin-layer chromatography was used to identify the lipid fractions. Higher
      cholesterol content, a bigger trans-membrane asymmetry index and a higher ratio
      between cholesterol and total phospholipids were detected. The contents of the
      lysophospholipid fraction and of the total fraction of phosphatidylcholine and
      serine were increasing. The contents of cholesterol ethers as well as of the
      fractions of sphingomyelin and phosphatidyl ethanolamine were found to be lower.

PMID- 15188736
TI  - [Clinical, biochemical and ultrasonic changes in the liver in small intestine
      enzymopathy in children].
AB  - We followed 70 patients, aged 1 to 11 years: 30 children had primary celiac
      enzymopathy (CE), the other had secondary fermentopathy represented by the celiac
      syndrome in 20 subjects and by the disaccharidase insufficiency syndrome (DIS) in
      another 30 subjects. Distinct disorders were registered in the liver and
      hepatobiliary system in children with enzymopathy variations of the small
      intestine (ESI). Despite a general identity of the clinical signs observed in
      ESI, the ultrasound signs of the fat hepatosis were more often the case in the
      celiac disease rather than in the celiac syndrome. The results should be
      considered in the rational diet- and drug therapy in children with the above
      pathology.

PMID- 15188737
TI  - [Correlation of clinical manifestations of atopic dermatitis in children and the
      activity of NAD(PH)-dependent dehydrogenases in blood lymphocytes].
AB  - The bioluminescence was used to study the activity levels of NAD (P)-dependent
      dehydrogenases in blood lymphocytes of 88 children with atopic dermatitis. The
      nature and intensity of the investigated enzymes were found to be dependent on
      age and a disease severity with changes being most pronounced and resistant in
      the elder age group and in patients with a continuously relapsing disease course.
      Besides, it was shown that the changes of NAD (P)-dependent dehydrogenases in
      blood lymphocytes are objectively related with an allergic inflammation clinical
      course in patients with atopic dermatitis and could be clinically valuable in
      monitoring the dermatitis progression at the metabolic level, in prognosticating
      possible relapses and in evaluating a chosen therapy.

PMID- 15188739
TI  - [Correlation of erythrocyte electrophoretic mobility and the velocity of their
      sedimentation in the norm and renal pathology].
AB  - It was established, while making blood tests for healthy males and for patients
      with glomerular nephritis at exacerbation, that there is a statistically reliable
      interrelation between the erythrocyte electrophoretic mobility and their
      sedimentation velocity. Its nature is subject to modifications as the functional
      body state and the investigated range of concurrently altering parameters are
      changing. Such hierarchy, in neuropathy, can be also the case at the level of
      mean parameters; and in health, it can be observed only as a conjugated
      reconstruction of the erythrocyte population structure.

PMID- 15188738
TI  - [Detection of rearranged immunoglobulin and T-cell receptor genes as a method for
      characterization of tumor cell clonality in acute lymphoblast leukemia in
      children].
AB  - Selection of primers for polymerase chain reaction (PCR) as used in detection of
      the reconstructed genes of immunoglobulins and T-cells receptor in tumor cells in
      children with acute lymphatic leukemia is described in the paper. PCR
      potentialities and limitations in characterizing the monoclonality observed in
      primary acute lymphatic leukemia are demonstrated. Cross linkages of the heavy
      chain of immunoglobulins and of T-cell receptor were found between T- and B
      linear acute lymphatic leukemia forms, but not between acute lymphatic leukemia
      forms and myeloleukemia in children.

PMID- 15188741
TI  - [Disseminated intravascular blood coagulation (lecture)].

PMID- 15188740
TI  - [Level of cation proteins in blood neutrophils of healthy individuals and
      patients with arterial hypertension residing in the North].
AB  - The functional state of neutrophilic leukocytes in peripheral blood (content of
      cation protein) was studied in 30 healthy donors an in 32 patients with arterial
      hypertension who have been residing in the North for a long time. The mean age of
      the examinees was 49. It was found that the changing functional condition of
      neutrophils is evidenced in healthy Northerners by a lower content of cation
      proteins versus the reference values. As for the patients with arterial
      hypertension, the content of the above proteins in their neutrophilic leukocytes
      was higher, versus the healthy subjects, and closer to the reference values.

PMID- 15188742
TI  - [Development of the immunoenzyme test system for detection of antibodies against
      individual proteins of human immunodeficiency virus type 1 by immunoblotting
      (Western blot)].
AB  - An ELISA test-system was designed for immune-blotting of HIV-I individual
      proteins by Western Blot with a self-manufactured immune sorbent. The parameters
      of the test-system sensitivity and specificity are in line with those of similar
      foreign-made systems registered in Russia.

PMID- 15188743
TI  - [Cellular immunity in patients with urogenital chlamydiosis].
AB  - Abnormalities in the cellular immunity chain (CIC) were found in 63.04% of
      patients with urogenital chlamydiosis (UGC) within a study of cellular immunity
      in patients with the above pathology. According to the study results, the below
      listed were the main CIC impairments: a lack or reaction to the inducer of T
      helpers (CD3+ and CD4+), and to activated T-lymphocytes (CD3+ and CD25+); higher
      counts of cytotoxic T-lymphocytes (CD3+ and CD8+), a higher content of B
      lymphocytes (CD3+ and CD19+, and lower counts of NK-cells (CD3- and CD56+).
      However, research of the lymphocyte subpopulation alone is not enough to evaluate
      adequately the immune system of a patient. In order to choose an adequate scheme
      for the treatment of UGH patients it is necessary to undertake a study of the
      immune status that should comprise, apart CIC investigations, the following:
      humoral immunity, phagocyte function, factors of non-specific body resistance and
      cytokine status.

PMID- 15188744
TI  - [Comparative assessment of various methods of determination of interleukin-5
      production and their clinical significance in bronchial asthma].
AB  - Interleukin-5 (IL-5) is an important marker of inflammation in bronchial asthma
      (BA). The level of IL-5 was investigated by immune-enzyme assay (IEA); the
      expression degree of IL-5 mRNA was studied, before and after the conducted
      therapy, by the inhibition reaction-IEA (IR-IEA) in sputum and blood serum of
      patients. No differences between contents of IL-5 were found in blood plasma of
      patients with various disease degrees or of patients with different BA
      etiologies. The IL-5 contents in sputum were reliably different in different
      groups and depended on a disease severity, exacerbation and remission. An
      evaluation of an expression degree of the IL-5 RNAm in eosinophiles, derived from
      patients' blood, provided for clarifying the differences between acute asthma and
      other disease forms and for defining the therapy influence on the parameter in
      question. The IL-5 RNAm expression in sputum was reliably different in patients
      with moderate forms and with acute forms of the disease; it was decreasing due to
      treatment. Finally, the results of the evaluation of the IL-5 level and the study
      of mRNA expression of the cytokine mutually supplement one another and make it
      possible to evaluate the disease degree and therapy efficiency.

PMID- 15188745
TI  - [Prevalence of antithyroid autoantibodies in the female residents of the Middle
      Ural region].

PMID- 15188746
TI  - [Comparison of efficacy of three test-systems for identification of
      Staphylococcus: PBDS (Russia), "STAPHYtest-16" (Check Republic), "API-STAPH"
      (France)].
AB  - The diagnostic efficiency of three test-systems designed for staphylococci
      identification including the definition of opportunistic errors was comparatively
      studied. The identification results coincidence (IRC) made, versus the reference
      method, 57 +/- 14% for Staphylococci Differentiation Biochemical Plate (SDBP-
      Russia) 73.83 +/- 3.6% for STAPHYtest-16 (Check Republic) and 58.33 +/- 5.03% for
      API-Staph (France). The diagnostic efficiency of the studied test-systems was
      found to be in proportion with the total information density of the
      identification tests belonging to each of them, which could be used for
      determining an optimal test list that would ensure the maximum diagnostic effect
      with minimal cost.

PMID- 15188747
TI  - [Modified nested polymerase chain reaction in one tube for detection of
      Enterovirus].
AB  - A method of a modified nest-type polymerase chain reaction (MN-PCR), made in one
      tube, was elaborated that enhances the sensitivity and cuts the risk of cross
      contamination in enteroviruses (EV) detection. The method, as described in detail
      above, was used to detect EV RNA in 76.9% and 31.25% of examined autopsy samples
      (13 liquor and 16 cardiac-tissue samples, respectively). It enabled the detection
      of EV RNA in 6.25% of samples that used to be negative, when tested by MN-PCR in
      2 tubes. MN-PCR with one tube is a reliable, sensitive and specific diagnostic
      tool; it can be recommended for the routine diagnostics of enterovirus infection.

PMID- 15188749
TI  - [Standardization in clinical laboratory services: a new phase].

PMID- 15188748
TI  - [Detection of antibodies against Lamblia antigens in serum from atopic patients].
AB  - The method of solid-phase immune-enzyme assay was used to test the sera of atopic
      patients for the purpose of detecting IgG to lamblias. A high degree of protozoal
      invasion was established especially among pre-school and school children. It was
      proven as expedient to make the serological examinations of atopic patients in
      cases the clinical finding is unclear.

PMID- 15188750
TI  - [Neuroendocrine factors in pathogenesis of motion sickness and the protective
      effect of drugs].
AB  - The paper presents a generalization of many-year complex investigations performed
      at various departments of the Institute of Medico-Biological Problems (Moscow)
      and various laboratories and institutes of the Ministry of Public Health and the
      Russian Academy of Medical Sciences, devoted to the pathogenesis of motion
      disease (sea sickness, vestibulo vegetative syndrome, various forms of
      kinetosis). The main attention is given to interpretation of the mechanisms of
      therapeutic and prophylactic action of drugs used for the treatment of such
      disorders. In particular, the role of a hormonal component of the system of
      regulation of physiological functions is considered as manifested in the models
      of the vestibulovegetative syndrome and in the pharmacotherapy of the motion
      disease.

PMID- 15188751
TI  - [Semax potentiates effects of D-amphetamine on the level of extracellular
      dopamine in the Sprague-Dawley rat striatum and on the locomotor activity of
      C57BL/6 mice].
AB  - The synthetic peptide semax (a fragment of ACTH 4-7 Pro-Gly-Pro) enhances the
      release of extracell dopamine (DA) induced by D-amphetamine (5 mg/kg) in the
      striatum of Spraig-Dowley (SD) rats and increases the locomotor activity
      stimulated by D-amphetamine (2 mg/kg) in C57/BL6 mice. The basal content of DA,
      3,4-dihydroxyphenylacetic acid (DHPAA), and homovanillic acid (HVA) in dialysate
      of SD rats was 0.5-1.0, 996 +/- 25, and 761 +/- 37 pmole/ml, respectively (n =
      7). D-amphetamine (5 mg/kg) induced a sharp increases in the DA level (up to 20
      pmole/ml) 20-40 min after treatment and reduced the extracell DHPAA content to
      30% of the basal level for a prolonged time (over the entire experimental
      period). Preliminary (20 min before D-amphetamine) administration of semax
      resulted in a greater peak of DA concentration (p < 0.05) and a more pronounced
      drop in DHPAA level (p < 0.01) as compared to the effects produced by the
      psychostimulant alone. In behavioral tests on C57/BL6 mice, D-amphetamine (2
      mg/kg) increased the locomotor activity to a level of 182% (p < 0.01).
      Simultaneous introduction of semax (0.6 mg/kg) and D-amphetamine (2 mg/kg) led to
      a more pronounced increase in the locomotor activity of mice (261%, p < 0.01). It
      is suggested that the peptide modulates dopaminergic systems involved in the
      formation of the psychostimulant effect.

PMID- 15188752
TI  - [Effect of ladasten on the proteinase C activity in the rat brain cells].
AB  - The effect of ladasten (50 mg/kg) on the activity of protein kinase C (PKC) in
      rat brain was studied depending on the duration of drug action. In the initial
      stage of the drug action, the PKC activity in the cytosol fraction of rat brain
      proteins exhibits a more than twofold increase. The effect is independent of the
      presence of exogenous Ca2+ and is inhibited by cinnarizine and nifedipine. The
      optimum Ca2+ concentration is maintained due to the activation of Ca2+ ATPase. It
      is concluded that the pharmacological activity of ladasten is related to
      activation of Ca2+ phospholipid-dependent protein kinases.

PMID- 15188753
TI  - [Comparative study of neurophysiological effects of adamantane derivatives in the
      experimental parkinsonism model].
AB  - The activity of the adamantane derivative PK-Merz and the new aminoadamantane
      derivative hemantane was studied by methods of electromyography and
      electroneuromyography in rats with a model of Parkinson syndrome induced by the
      neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The toxin
      produced an increase in the pulse conduction velocity (PCV) in the motor fibers
      of peripheral nerves and a decrease in the amplitude and frequency of the maximum
      muscle stress curve. A singe administration of both PK-Merz and hemantane
      produced unidirectional changes in the neuromyographic parameters and reduced the
      PCV down to a level in the control group. These results give ground for the
      clinical investigation of hemantane.

PMID- 15188754
TI  - [Cardioprotective effect of energostim in toxic allergic myocarditis].
AB  - Energostim is a combined drug comprising a mixture of nicotinamide adenine
      dinucleotide (0.5 mg), cytochrome C (10 mg), and inosine (80 mg), representing
      antihypoxant and antioxidant of direct action in one ampule. After pretreatment
      and subsequent 3-day energostim therapy of animals with 3-day toxico-allergic
      myocarditis (3d-TAM), the ECG was free of any rhythm disorders and showed
      evidence of improved conduction, restoration of the normal form of T-wave and the
      position of ST segment, while the content of myofibrillar fraction of creatine
      phosphokinase and toxic products of disturbed metabolism (degree of endotoxemia)
      decreased to the upper normal level. Under the action of energostim, neither
      pressure nor the maximum rate of pressure buildup in the left ventricle are
      reduced (as they do upon 3d-TAM); neither systolic and diastolic functions are
      disturbed, nor their coordination (r = 0.79 between dP/dtmin and dP/dtmax, p <
      0.01). The restoration of contractile activity and maximum rate of relaxation of
      myocardial microfibrils during 3d-TAM is accompanied by an increase in the
      content of adenyl nucleotides, in the ATP/ADP, ADP/AMP, NAD/NADH, and NADP/NADPH
      ratios, and in the cytosol phosphorylation potential. The energostim-induced
      improvement in the energy supply system are accompanied by restoration of the
      ability of sarcoplasmic reticulum to efflux Ca2+. Thus, it is demonstrated that
      the effect of energostim is related to its ability to actively participate in
      intracell metabolic processes in myocardium, abolish necrotic changes and
      endotoxicosis, and restore homeostasis in the systems responsible for the
      contraction--relaxation process (thus preventing from the development of
      dysfunction of the left ventricle and the heart failure).

PMID- 15188755
TI  - [Effect of trimecaine derivatives and lidocaine on hemodynamics].
AB  - The results of experiments on cats showed that quaternidine, a quaternary
      ammonium derivative of trimecaine, does not induce significant variations in the
      hemodynamic parameters, being advantageous in this respect to some well-known
      antiarrhythmic drugs. LKhT-3-00 (dialkylaminophenylacetamide glutaminate)--a
      tertiary derivative of lidocaine--leads to a slight decrease in the heart rate,
      an insignificant decrease in the arterial pressure for 10 min, and a pronounced
      enhancement of the pumping ability of the left ventricle over a time period of 30
      min.

PMID- 15188756
TI  - [The protective effect of trimetazidine on the myocardium against reperfusion
      injury during thrombolytic therapy of acute infarction].
AB  - Investigation of the protective action of the antiischemic drug trimetazidine (60
      mg/kg) used during thrombolytic treatment of acute infarction showed that the
      drug effectively inhibits lipid peroxidation and reduces the degree of the
      reperfusive damage of myocardium, as determined from ECG (QRS index calculation)
      or from data on the blood creatinin phosphokinase level.

PMID- 15188757
TI  - [Effect of blockers of NO-synthase, NO donors, and exogenous E2 and F2alpha
      prostaglandins on mouse oocytes].
AB  - The effects of nitric oxide (NO) synthase (NOS) blocker (L-NMMA), NO donor
      (sodium nitroprusside, Na-NP), and exogenous prostaglandins (PGs) F2 alpha and E2
      on the meiotic maturation (MM) of murine oocytes were studied. The exogenous PGs
      in a dose of 3.00 micrograms/kg inhibited the MM of oocytes. The effect of L-NMMA
      on the MM of oocytes was studied for the first time depending on the size of a
      follicle from which they were isolated. The maximum inhibition was observed for
      oocytes isolated from small follicles. Na-NP induced an increase in the number of
      oocytes from small and medium follicles, capable of forming polar bodies after a
      20-h cultivation. The introduction of PG F2 alpha to the test animals pretreated
      with L-NMMA potentiated the inhibition of MM. The NO donor decreased the
      inhibiting effect of PG F2 alpha on the MM of oocytes isolated from small and
      medium follicles. The results confirm that NO/NOS ovarian system is involved into
      the mechanism of the PG action on the MM of murine oocytes and, probably, in the
      general mechanism of PG activity.

PMID- 15188758
TI  - [Introduction of dimephosphon in the early stage of pregnancy and its effect on
      the rat progeny].
AB  - Some anticholinesterase organophosphorus compounds introduced into the organism
      in the course of pregnancy lead to the development of behavioral and
      morphological disturbances in both human and animal kids. In this context, the
      potential teratogenic effect of dimephosphon (1,1-dimethyl-3-ketobutylphosphonic
      acid dimethyl ester), representing nonanticholinesterase derivatives of
      organophosphoric acids, was evaluated in rats. The drug was introduced in a dose
      of 200 mg/kg over the period from 1st to 6th day of pregnancy and the results
      were assessed on the 20th day. It was found that dimephosphon did not lead to the
      loss of embryos. The results of morphological investigation showed neither
      anomalies in the development of embryo nor evidence of changes in the sex
      differentiation. Thus, dimephosphon exhibited no teratogenicity upon introduction
      in the early stage of pregnancy in rats.

PMID- 15188759
TI  - [Delayed response of the red blood system (erythron) to carboplatin
      administration during pregnancy].
AB  - Pregnant rats exhibited regenerative anemia development 3 months upon a single
      intravenous injection of carboplatin in a maximum tolerated dose; the effect
      increased by the end of pregnancy. The character of changes in parameters of the
      peripheral and central erythron parts (increased level of erythrocyte hemolysis,
      decrease in the amount of erythrocytes, increase in the number of reticulocytes,
      development of erythropoietic hyperplasia in bone marrow and spleen) was
      indicative of the hemolytic type of anemia.

PMID- 15188760
TI  - [Effect of delta-sleep-inducing peptide on trypsin and pronase E activities in a
      model experiment].
AB  - A delta-sleep-inducing peptide in various concentrations inhibits the
      pharmacological activity of trypsin and pronase E under experimental conditions.

PMID- 15188761
TI  - [Parameters of carbohydrate metabolism in the myocardium and the liver during
      general anesthesia with propofol].
AB  - The effect of propofol upon carbohydrate metabolism in rat myocardium is
      manifested by activated anaerobic glucolysis and glycogenolysis leading to
      devastation of glycogen. In the liver, the drug leads to activated anaerobic
      glycolysis and decreases the contribution of pentosophosphate pathways of glucose
      oxidation to carbohydrate metabolism and produces glycogen-preserving action.

PMID- 15188762
TI  - [Effect of lysozyme on the functional and metabolic activity of polymorphonuclear
      leukocytes in the acute blood loss].
AB  - Acute hemorrhage leads to a decrease in the phagocyte number and index, the NBT
      test parameters, and the NADPH oxidase activity and to an increase in the Ca2+
      ATPase activity in polymorphonuclear leukocytes on the peripheral blood. Lysozyme
      produces effective correction of the above parameters of the functional-metabolic
      activity of these cells. The drug effect is mediated by cytokines of splenocytes
      sticking to the glass.

PMID- 15188764
TI  - [Pharmacokinetics of mifepristone and kinetics of chorionic gonadotropin beta
      subunit (beta-HCG) and progesterone in plasma of pregnant women during
      pharmacological interruption of early pregnancy].
AB  - Reliable correlations between the parameters of mifepriston pharmacokinetics
      describing the rate of drug elimination from the blood plasma and the levels of
      beta-human chorionic gonadotropin (beta-HCG) and progesterone reflecting the
      state of gestation in females have been established fore the first time.
      According to these relationships, the half elimination time, the mean retention
      time, and the plasma clearance of mifepriston can be considered as predictors of
      the clinical efficacy of this drug for the early pregnancy interruption.

PMID- 15188763
TI  - [Immunomodulating effect of the novel water-soluble gossypol derivative Mebavin
      in adjuvant arthritis].
AB  - Investigation of the effect of mebavin on the model of adjuvant arthritis showed
      that this drug administered in a dose of 100 mg/kg exhibits immunomodulant and
      anti-inflammatory activity without negative influence on the nonspecific response
      of the organism. Combined administration of mebavin with prednisolone provides
      for a more effective and nontoxic treatment of adjuvant arthritis.

PMID- 15188765
TI  - [Experimental pharmacokinetics of phenazepam during transdermal administration of
      the therapeutic phenaperkuten system].
AB  - The pharmacokinetics of fenazepam upon application of the transdermal therapeutic
      system (TTS) fenapercuten in various forms and under different conditions was
      studied in rabbits. The rate of the transdermal transfer of fenazepam from TTS to
      blood varied from 0.76 to 2.89 mg/(ml cm2). It was found that the drug transfer
      rate remains constant for 2-3 days. After removal of the TTS, fenazepam is
      eliminated within 3 days.

PMID- 15188766
TI  - [Pharmacokinetic evaluation of the tablet dosage forms of gidazepam prepared by
      various technologies].
AB  - The pharmacokinetics of gidazepam administered in tablets prepared using
      different technologies was studied in rabbits. The optimum properties (high
      relative bioaccessibility and low degree of dealkylation of the parent substance)
      were observed for the tablets fabricated using a solid disperse system.

PMID- 15188767
TI  - [Effect of damages of capsaicin-sensitive nerves on alpha1-antitrypsin activity
      in the rat blood].
AB  - Systemic administration of capsaicin (a neurotoxin of afferent nerves) in a dose
      of 150 mg/kg led to a decrease in the activity of alpha 1-antitrypsin (alpha 1
      AT) in the blood of male Wistar rats. This effect is related to impairment of the
      local effector function of capsaicin-sensitive nerves in the liver, which is the
      main source of alpha 1-AT in the blood. Analogous results were obtained upon
      cutting of the hepatic branch of the vagus nerve involving capsaicin-sensitive
      afferent fibers of the liver.

PMID- 15188768
TI  - [Functional organization ant therapeutic potential of the endogenous cannabinoid
      system].

PMID- 15188769
TI  - Assuring quality and performance of sustained and controlled released
      parenterals.

PMID- 15188771
TI  - [Symposium on "Lupus and the anti-phospholipid syndrome", Lyon 26 September
      2003].

PMID- 15188770
TI  - Deubiquitinating enzymes are IN/(trinsic to proteasome function).
AB  - Covalent conjugation of the ubiquitin tag to cellular proteins plays a central
      role in a number of processes, the most notable among them being degradation by
      the 26S proteasome. A fundamental property of this process is that
      ubiquitination, in contrast to subsequent degradation, is reversible due to a
      number of deubiquitinating enzymes that mediate the disassembly of ubiquitin
      protein conjugates. The uniqueness of ubiquitin as a reversible tag necessitates
      mechanisms to guarantee its efficiency. Interestingly, some deubiquitinating
      enzymes are associated with the 26S proteasome itself. We include a brief
      overview of the key proteasome-associated deubiquitinating enzymes such as
      Rpn11/POH1, UCH37/Uch2, Ubp6/Usp14 and Doa4/Ubp4. We go on to discuss how these
      enzymes may contribute to, or possibly counteract, proteolysis by the proteasome.
      For example, cumulative evidence points to a partitioning of proteasome action
      between proteolysis and deubiquitination. On the one hand, inhibition of
      proteolysis promotes deubiquitination, while on the other hand, inhibition of
      deubiquitination can promote proteolysis. The plethora of deubiquitinating
      enzymes may serve as proof reading devices altering the equilibrium between these
      two processes and allowing for reversal of fortune at various stages of the
      process. To promote degradation over deubiquitination, certain polyubiquitin
      conformations could be stabilized or protected from deubiquitinating enzymes in
      order that they can serve as efficient targeting signals leading to the
      proteasome. We hypothesize that polvubiquitin chains could also serve as
      "timers": by slowing down chain disassembly, longer chains allow ample time for
      unfolding and proteolysis of the substrate.

PMID- 15188772
TI  - Severe reversible left ventricular systolic and diastolic dysfunction due to
      accidental iatrogenic epinephrine overdose.
AB  - Catecholamine-induced cardiomyopathy due to chronic excess of endogenous
      catecholamines has been recognized for decades as a clinical phenomenon. In
      contrast, reports of myocardial dysfunction due to acute iatrogenic overdose are
      rare. A 35-year-old woman whose cervix uteri was inadvertently injected with 8 mg
      of epinephrine developed myocardial stunning that was characterized by severe
      hemodynamic compromise, profound, albeit transient, left ventricular systolic and
      diastolic dysfunction, and only modestly elevated biochemical markers of
      myocardial necrosis. Our case illustrates the serious consequences of medical
      errors that can be avoided through improved medication labeling and staff
      supervision.

PMID- 15188773
TI  - Epithelioid haemangioendothelioma (2004:3b.

PMID- 15188774
TI  - [Neck, larynx, hypopharynx. III].

PMID- 15188775
TI  - [Triple arthrodesis correction in pes equinovarus and tetra-spasticity].

PMID- 15188776
TI  - [The infected hip prosthesis].
AB  - Therapy of infected hip prosthesis should always be based on a structured
      treatment concept. When short-termed early infection is present or impending,
      with meticulous debridement of the soft tissue surroundings, the implant may be
      left in place. Chronic infection (>30 days) should lead to complete removal of
      implant and cement. A one-staged revision of the implant may be considered for
      patients without additional chronic disease, good vascularization of soft tissue
      and bones and bacteria susceptible to antibiotics. In most cases though two
      staged revision is indicated. The interval between implant removal and re
      implantation ranges between one and four months. Re-implantation should only be
      performed when laboratory parameters are normalized and the local wound site has
      turned to an unsuspicious condition. By insertion of a cement spacer during the
      interval period soft tissue shortening and local scar formation can be prevented.
      Parenteral antibiotics should be applied for four to six weeks. In patients with
      reduced general health state and extremely severe infection permanent resection
      of the hip or limp ablation may be indicated.

PMID- 15188777
TI  - Extraction of the two-dimensional cardiothoracic ratio from digital PA chest
      radiographs: correlation with cardiac function and the traditional cardiothoracic
      ratio.

PMID- 15188778
TI  - Ethics guidelines for population genetics research.

PMID- 15188779
TI  - Pierre Gloor, 1923-2003.

PMID- 15188780
TI  - Revised medical criteria for evaluating skin disorders. Final rules.
AB  - We are revising the criteria in the Listing of Impairments (the listings) that we
      use to evaluate claims involving skin disorders. We apply these criteria when you
      claim benefits based on disability under title II and title XVI of the Social
      Security Act (the Act). The revisions reflect advances in medical knowledge,
      treatment, and methods of evaluating skin disorders.

PMID- 15188781
TI  - International Conference on Harmonisation; guidance on the M4 Common Technical
      Document--Quality: Questions and Answers/Location Issues; availability. Notice.
AB  - The Food and Drug Administration (FDA) is announcing the availability of a
      guidance entitled "M4: The CTD--Quality: Questions and Answers/Location Issues."
      The guidance was prepared under the auspices of the International Conference on
      Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
      Human Use (ICH). This guidance provides further clarification for preparing the
      quality components of an application file in the common technical document (CTD)
      format. The guidance addresses the relationship between linked sections for
      certain parameters (such as polymorphism and particle size), and it addresses
      location issues (by indicating the section in which to place requested
      information). The guidance is intended to ease the preparation of paper and
      electronic submissions, facilitate regulatory reviews, and simplify the exchange
      of regulatory information among regulatory authorities.

PMID- 15188782
TI  - Global fund signs major new AIDS and TB grants for India.

PMID- 15188783
TI  - MRI scans for predicting brain damage in babies.

PMID- 15188784
TI  - Bibliography. Current world literature. Cardiac failure.

PMID- 15188785
TI  - Elder abuse--an ethical dilemma for caregivers.
AB  - The mistreatment of elders by their adult children, spouses, or other caregivers
      is a problem of increasing magnitude. We have few laws and even fewer policies to
      help caregivers identify and prevent abuse, partly because it has no common
      pattern, and partly because it so often goes unreported. Abuse can be intentional
      or unintentional, and as often results from failing to act, as from acts of anger
      or cruelty. Therefore, we must do a better job of enforcing mandatory reporting
      and educating and supporting our caregivers to prevent stress and burnout. Above
      all, we must seek an ethical course of action, knowing that there are legal,
      personal, and professional ethical ideals and standards that can guide us,
      whether the elderly are being cared for in their own home or in nursing homes.

PMID- 15188786
TI  - Cultural competency--the caregiver connection.
AB  - Healthcare that is respectful and ethical must also be culturally competent, and
      a variety of tools are available to empower caregivers to provide culturally
      competent care. This article reviews the tools that the University of Michigan
      Health Care System's Program for Multicultural Health provides to caregivers
      throughout its many services. Cultural competency begins with self-awareness and
      knowledge, but it is also to embark upon a lifelong journey. Progress is
      cumulative, and assessment is an important part of the process.

PMID- 15188787
TI  - Supporting persons with developmental disability--a new model.
AB  - The way we think about and care for people with developmental disability has
      changed. Twenty-five years ago, society believed that caregivers always knew what
      was best for their individual and that he or she must be shielded, even shut away
      from, the harms that could occur in society. Now, people with disability
      participate in all aspects of community life. They are educated in local schools,
      live at home or in their own home, and compete with others in the job market.
      Caregiving for people with developmental disability is no longer modeled on
      medicine or stigmatizing labels. Instead, caregivers have become support persons
      who focus on identifying community resources and making the environment
      friendlier and safer for persons with disability.

PMID- 15188788
TI  - Saying goodbye: the Terri Schiavo case.

PMID- 15188789
TI  - [Sentinel node biopsy in breast carcinoma. Interdisciplinary agreement consensus
      of the German Society for Serology for quality controlled application in routine
      clinical testing].

PMID- 15188790
TI  - Report of an expert panel to review the socio-economic models and related
      components supporting the development of Canada-Wide Standards (CWS) for
      particulate matter (PM) and ozone to the Royal Society of Canada.

PMID- 15188791
TI  - Second overview of relationships between antenatal pharmacologic magnesium
      sulfate and neurologic outcomes in children.
AB  - In the last ten years, the body of scientific knowledge concerning the use of
      antenatal pharmacologic magnesium sulfate (MgSO4) has become substantially
      larger. Several randomized controlled trials have provided compelling evidence
      that MgSO4 is the drug of choice for maternal seizure prophylaxis in toxemia. In
      contrast, the recent Cochrane Systematic Review, as well as other studies, have
      shown there is no evidence basis for the use of MgSO4 for tocolysis. Furthermore,
      when tocolytic-strength doses of MgSO4 are employed, there is an excess risk for
      total pediatric mortality (Cochrane Systematic Review and our own previous work).
      It is conceivable, nonetheless, that low doses of MgSO4, when used as prophylaxis
      in some selected cases of preterm labor, may ultimately be shown to be
      neuroprotective for a relatively small number of children. Unfortunately, the
      indiscriminate use of high-dosage MgSO4 for attempted tocolysis in preterm labor
      is much more likely to cause harm than do good.

PMID- 15188792
TI  - Prevention of toxoplasmosis during pregnancy--an epidemiologic survey over 22
      consecutive years.
AB  - BACKGROUND: Prevention of congenital toxoplasmosis is most often based on the
      results of a serological screening program in pregnant women followed by prenatal
      and postnatal treatment of women and their newborns when infection is already
      established during pregnancy or on cord blood (secondary prevention). Little
      effort has been made to study primary prevention of toxoplasmosis during
      pregnancy. OBJECTIVE: To assess the possibilities of two different programs aimed
      at preventing the acquisition of toxoplasmosis during pregnancy. METHODS: During
      the first study period (1979-1982) the natural incidence of toxoplasmosis in
      pregnancy was studied in 2986 pregnant women. In the second study period (1983
      1990) the incidence of toxoplasmosis was studied in 8300 women. During this
      period, seronegative women received a written list of recommendations on how to
      avoid a toxoplasma infection during pregnancy. In the third study period (1991
      2001) the incidence of toxoplasmosis was studied in 16,541 women. During this
      period, the prevention campaign consisted of a leaflet explaining a)
      toxoplasmosis as a disease and b) what measures should be taken to avoid
      toxoplasmosis during pregnancy. The third part of the campaign involved a
      reiteration of these recommendations during antenatal classes held around mid
      gestation. The impact of the two prevention programs was studied by measuring the
      seroconversion rate in seronegative women. RESULTS: Twenty of 1403 seronegative
      women in the first period (1.43%), 19 of 3605 women in the second period (0.53%)
      and 8 of 8492 in the third period (0.09%) seroconverted during pregnancy. The
      first prevention campaign reduced the seroconversion rate by 63% (p<0.05 OR 2.729
      95% CI 1.452-5.084). The second prevention program resulted in a reduction rate
      of 92% compared to the seroconversion rate in the first period (p<0.0001 OR 15.34
      95% CI 6.741-34.89). CONCLUSION: Promotion of simple measures is very effective
      in the prevention of toxoplasmosis during pregnancy. Primary prevention should
      not only be based on education about preventive measures given by physicians, but
      these guidelines should be reiterated during antenatal classes and leaflets
      distributed containing written recommendations on the nature of the disease and
      its avoidance.

PMID- 15188793
TI  - The impact of multiple pregnancies and malformations on perinatal mortality.
AB  - AIM: To evaluate the impact of the rate of multiple pregnancies and congenital
      malformations on perinatal mortality. METHODS: The study is based on data from
      the perinatal audit in Vejle County Denmark. Fetal deaths with gestational age >
      or = 22 weeks and deaths in livebirths within the first 28 days after birth were
      included in the calculated perinatal mortality. Total number of births was 30,181
      and 252 pregnancies and 268 fetuses/infants were evaluated. The study period was
      1995-2000. There was no routine ultrasound screening for congenital malformations
      in the county, though midtrimester ultrasound was used to assess gestational age.
      RESULTS: Perinatal mortality was 8.9 per 1000 births with no significant change
      over time. Rate of multiple pregnancies was 1.94% ranging from 1.81% during the
      first 3 years to 2.06% for the last 3 years (not significant). Fetuses and
      infants from multiple pregnancies contributed 18% of all deaths. Perinatal
      mortality for single births was 7.6 per 1000 births and for multiple births
      42.2/1000 (P<0.0001). The distribution of gestational age for single and multiple
      births was highly significant (P<0.0001) with 67% of multiple pregnancies with GA
      < 28 weeks compared to 26% of single pregnancies. Nineteen percent of all deaths
      were caused by congenital malformations and the majority of these were
      potentially detectable by ultrasound investigation. CONCLUSIONS: The increasing
      rate of multiple pregnancies makes it difficult to see improvements in perinatal
      mortality. Calculated from the perinatal mortality in single and multiple
      pregnancies in Vejle County assisted conceptions contribute with an an excess of
      45 perinatal deaths per year in Denmark. The difference between countries in rate
      of multiple pregnancies and in prenatal ultrasound screening recommendations for
      malformations makes it difficult to compare perinatal mortality.

PMID- 15188794
TI  - Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm
      labor.
AB  - AIMS: Our aim was to evaluate the efficacy of maintenance oral nifedipine in
      pregnant women initially treated with intravenous ritodrine plus verapamil for
      preterm labor. METHODS: The study included 73 patients with preterm labor with
      intact membranes. Patients were randomized to receive either maintenance oral
      nifedipine therapy (n=37) administered 20 mg every six hours or no treatment
      (controls, n=36) after discontinuation of acute intravenous tocolysis. RESULTS:
      Compared to the control group, the mean +/- SD time gained from initiation of
      maintenance therapy to delivery (26.65 +/- 18.89 vs. 16.14 +/- 12.91 days,
      p=0.007) and the gestational age at delivery (37.03 +/- 2.06 vs. 35.1 +/- 3
      weeks, p=0.003) were higher in the nifedipine maintenance therapy group. The
      proportion of patients who required one or more courses of subsequent intravenous
      therapy and perinatal outcomes were similar in the maintenance therapy and
      control groups. CONCLUSIONS: The gestational age and time gained from initiation
      of maintenance therapy to delivery were longer in women receiving oral
      maintenance tocolysis with nifedipine. However, maintenance therapy did not
      decrease the recurrence of preterm labor episodes or improve perinatal outcomes.

PMID- 15188795
TI  - Perinatal outcome in women with severe pregnancy complications and multiple
      thrombophilias.
AB  - Hypercoagulability leading to placental thrombosis has been implicated in severe
      pregnancy complications. We compared the perinatal outcome in women with severe
      preeclampsia, intrauterine growth retardation (IUGR) and severe abruptio
      placentae and multiple acquired and inherited thrombophilias (study group, n=22)
      to matched women with similar complications and single thrombophilia (control
      group, n=22). Gestational age at delivery and birth weight were significantly
      lower in the study group compared to the control group (p<0.01) and among the
      study women with severe preeclampsia and IUGR. Severe pregnancy complications may
      occur earlier during pregnancy and more seriously affect perinatal outcome in
      women with multiple thrombophilias.

PMID- 15188796
TI  - Reproducibility of the study of placental vascularization by three-dimensional
      power Doppler.
AB  - AIMS: To assess the reproducibility of 3D power Doppler study of placental
      vascularization in order to establish its methodological bases for its further
      application in normal and pathological pregnancies. METHODS: A prospective study
      was carried on 30 normal singleton pregnancies from 14 to 40 weeks. To evaluate
      placental vascularization 3D power Doppler was applied to obtain a "placental
      biopsy". The spherical volume acquired was analyzed using the VOCAL imaging
      program. Two consecutive measurements were taken from each patient by a single
      observer, obtaining a total of 60 datasets. Placental volume (PV), Mean Gray
      (MG), Vascularization Index (VI), Flow Index (FI) and Vascularization Flow Index
      (VFI) were calculated. Intra-class correlation coefficient (ICC) and intra
      observer agreement was evaluated. RESULTS: PV and MG presented an ICC of 0.98 and
      0.94 respectively, with differences approaching zero. All 3D power Doppler
      vascular indices (VI, FI and VFI) showed a correlation greater than 0.85, with a
      better intra-observer agreement for the flow indices (FI and VFI). CONCLUSIONS:
      Placental vascular biopsy through 3D power Doppler is a new and simple tool to
      routinely study placental vascularization in human pregnancy. Our results provide
      the validation of the technique demonstrating a good reproducibility of the 3D
      power Doppler parameters when applied to the study of the placental vascular tree
      in normal pregnancies.

PMID- 15188797
TI  - The prevalence of preterm deliveries in Berlin has not changed over 7 years: the
      impact of multiple births.
AB  - The problem of preterm deliveries has worsened in developed countries over the
      past decade. To evaluate whether multiple deliveries had an impact on this
      development, we analyzed the data of the Berlin Perinatal Survey from 1993-1999
      for 206,308 deliveries. The prevalence of preterm deliveries was fairly constant
      during this period, and the proportion of preterm deliveries in the case of
      multiples remained constant. But the prevalence of preterm neonates increased
      significantly in Berlin due to an increased prevalence of multiple births. There
      was a significant increase of mothers aged over 30, of German nationality, and
      with preceding infertility treatment, while the prevalence rates of nearly all
      other risk factors for prematurity decreased over time. The risk of infertility
      treatments resulting in multiple deliveries increased in these years. On average,
      infertility treatment led to an about 10 times higher risk of producing multiples
      than singletons OR (95% CI) of 9.6 (8.6-10.6).

PMID- 15188798
TI  - Amniotic fluid and cord plasma erythropoietin levels in pregnancies complicated
      by preeclampsia, pregnancy-induced hypertension and chronic hypertension.
AB  - AIMS: The purpose of the present study was to compare fetal and neonatal outcomes
      with amniotic fluid erythropoietin (EPO) levels obtained in the antepartum period
      in pregnancies complicated by preeclampsia, pregnancy-induced hypertension or
      chronic hypertension. METHODS: Erythropoietin concentrations were measured in
      amniotic fluid within 2 days before delivery and in cord blood at birth in 75
      hypertensive women and in 23 healthy controls delivered by cesarean section
      before labor contractions. Erythropoietin levels did not influence clinical
      decisions. RESULTS: Amniotic fluid erythropoietin levels correlated highly
      significantly with cord plasma EPO levels and were significantly higher in
      pregnancies complicated by hypertension than in control pregnancies. Umbilical
      arterial pH, acid-base and blood gas values at birth were not different from
      controls. Both cord plasma and amniotic fluid erythropoietin levels correlated
      with cord blood pH, acid-base and blood gas values at birth in the study group.
      Newborn infants admitted to the newborn intensive care unit had significantly
      higher fetal erythropoietin levels and were more acidotic, hypoxemic and
      hypoglycemic than infants admitted to the normal care nursery. CONCLUSIONS: Our
      findings suggest that elevated amniotic fluid erythropoietin levels are markers
      of chronic or subchronic fetal hypoxia and are associated with neonatal morbidity
      in pregnancies complicated by hypertension.

PMID- 15188800
TI  - Risk factors for fetal-to-maternal transfusion in Rh D-negative women--results of
      a prospective study on 942 pregnant women.
AB  - AIMS: To investigate the incidence of severe fetal-to-maternal transfusion after
      delivery and to identify risk factors. MATERIAL AND METHODS: In a prospective
      study at the Department of Obstetrics, Charite, Campus Virchow-Klinikum, Berlin,
      Germany, we analyzed the incidence of severe fetal-to-maternal transfusion (>10
      ml) and fetal-to-maternal hemorrhage (>25 ml) in Rh D-negative pregnant women
      after delivery of Rh D-positive infants. 942 women were included in the study and
      Kleihauer-Betke tests were performed. The results were compared to perinatal
      data. RESULTS: Fetal-to-maternal hemorrhage occurred in 13 cases out of 942
      (incidence of 1.3%) and severe fetal-to-maternal transfusion in 61 cases (6.5%).
      In all of the cases with fetal-to-maternal hemorrhage, mothers were compatible
      with their infants in ABO-system. The incidence of fetal-to-maternal transfusion
      and its severe form was significantly higher in twin pregnancies (7/21 cases and
      5/21 cases respectively, 33.3% and 23.8%) than in singleton pregnancies (22.5%,
      and 5.9%, P<0.001). All other factors, such as maternal age, parity, ethnicity,
      mode of delivery, presentation, duration of first and second stage of labor, CTG,
      or Apgar score were not associated with an increased risk of severe fetal-to
      maternal transfusion. CONCLUSIONS: Twin pregnancy is the only independent risk
      factor for severe fetal-to-maternal transfusion. ABO-incompatibility between
      mother and infant seems to be protective against Rh D-alloimmunization.

PMID- 15188799
TI  - N-glycans of human amniotic fluid transferrin stimulate progesterone production
      in human first trimester trophoblast cells in vitro.
AB  - AIMS: During pregnancy, the placenta produces a variety of steroid hormones and
      proteins. Several of these substances have been shown to exert immunomodulatory
      effects. Progesterone is thought to mediate some of these effects by regulating
      uterine responsiveness. The aim of this study was to clarify the effect of
      amniotic fluid transferrin and its N-glycans on the release of progesterone by
      first trimester trophoblast cells in vitro. METHODS: Cytotrophoblast cells were
      prepared from human first trimester placentae by trypsin-DNAse dispersion of
      villous tissue followed by a percoll gradient centrifugation and depletion of
      CD45 positive cells by magnetic cell sorting. Trophoblasts were incubated with
      varying concentrations (50-300 microg/ml) of transferrin from human amniotic
      fluid and serum as well as with N-glycans obtained from amniotic fluid
      transferrin. Culture supernatants were assayed for progesterone by enzyme
      immunometric methods. RESULTS: The release of progesterone increased in amniotic
      fluid transferrin- and N-glycan-treated trophoblast cell cultures compared to
      untreated trophoblast cells. There was no stimulating effect of serum transferrin
      on the progesterone production of trophoblast cells. CONCLUSIONS: The results
      suggest that amnion-transferrin and especially its N-glycans modulate the
      endocrine function of trophoblasts in culture by up regulating progesterone
      secretion.

PMID- 15188801
TI  - Does fetal head position at the term plus 12 scan influence induction, labor and
      delivery outcome?
AB  - AIMS: To assess the influence that fetal head position has on induction, labor
      and delivery outcome for both mother and baby. METHODS: During a one month
      period, in November 1999, all women attending for a post-dates scan were enrolled
      as the study population. In total, 91 women formed our study population for
      analysis of data. The sonographic, induction and labor details of all women were
      recorded on a dedicated data sheet. As well as documenting the maternal age,
      parity, liquor volume (mm) and BPS, the position of the fetal head was noted by
      the sonographer as occipitoanterior, occipitotransverse or occipitoposterior. All
      women had gestation confirmed by ultrasound early during the course of their
      pregnancy. Maternal, ultrasonographic, induction and labor variables were
      correlated with fetal head presentation at scan. RESULTS: There was no positive
      correlation found between fetal head position at the term plus 12 scan and
      associated induction, labor or delivery complications in the 91 women studied.
      CONCLUSIONS: Our study shows no positive correlation between fetal head position
      and induction, labor or delivery complications.

PMID- 15188802
TI  - Doppler examinations of fetal and uteroplacental blood flow in AGA and IUGR
      fetuses before and after maternal physical exercise with the bicycle ergometer.
AB  - OBJECTIVE: To study changes in uteroplacental and fetal circulation after
      maternal exercise in appropriate-for-gestational-age fetuses (AGA) and
      intrauterine-growth-retarded fetuses (IUGR). MATERIALS AND METHOD: 33 women with
      an uncomplicated course of pregnancy and ten women with IUGR were examined.
      Physical stress was caused through a bicycle ergometer with 1.25 W/kg maternal
      weight. Doppler examinations were performed in the umbilical artery, fetal aorta,
      middle cerebral and in the uterine artery. Fetal heart rate was documented by
      monitoring. Maternal lactate and glucose levels as well as maternal blood
      pressure and heart rate were recorded. RESULTS: No significant changes after
      cycling could be observed in umbilical and uterine vessels either in the normal
      pregnancies or in pregnancies with IUGR. In contrast, in the fetal aorta an
      increase of the RI was recorded in both groups (an increase of 16% [P<0.01] and
      18% [P<0.05], respectively for AGA and IUGR cases). In cerebral arteries a
      decrease of the RI was observed after cycling in both groups (a decrease of 24%
      [P<0.01] and 13% [P<0.05], respectively for AGA and IUGR cases). In AGA fetuses
      the RI of the aorta and middle cerebral artery returned to pre-test level by the
      18th minute of examination. In IUGR fetuses the RI of the aorta and middle
      cerebral artery did not return to pre-test levels at the end of the test. Fetal
      heart rate remained unchanged in both groups. Maternal blood pressure and heart
      rate increased during the exertion phase but returned to initial values at the
      end of the test. A 21% and 24% (for AGA and IUGR groups respectively) reduction
      of maternal glucose values after exercise was observed (P<0.001). Lactate values
      doubled in both groups after exercise (P<0.001). CONCLUSION: From the results
      obtained we conclude that maternal exercise does not significantly alter uterine
      and umbilical perfusion in AGA and IUGR pregnancies, suggesting an absence of
      change in the uterine vascular bed resistance. However, submaximal maternal
      exercise was followed by fetal cerebral vasodilatation and an increase of
      resistance in the fetal aorta that was more evident in IUGR fetuses. This might
      be due to slight fetal hemoglobin desaturation in those cases.

PMID- 15188803
TI  - Maternal serum, amniotic fluid and cord leptin levels at term: their correlations
      with fetal weight.
AB  - AIMS: To investigate the relationship between fetal weight and leptin levels in
      maternal serum, amniotic fluid and umbilical cord. METHODS: Forty pregnant women
      presenting for antenatal care at early weeks of gestation were enrolled for the
      study. Maternal and cord blood samples for leptin measurement were obtained at
      birth. Amniotic fluid samples were recovered by amniotomy performed during labor.
      Maternal body mass index and placental weight were also recorded. Leptin
      measurement was carried out using the ELISA method. Spearman's correlation test
      was used for comparison of non-parametric data. RESULTS: Leptin concentration in
      venous cord blood correlated significantly with birth weight and placental weight
      whereas maternal serum and amniotic fluid leptin levels did not show correlation
      with birth weight. There were no significant correlations between leptin levels
      in maternal serum, cord blood and amniotic fluid. CONCLUSION: We conclude that
      lack of correlation between leptin levels in mother, cord and amniotic fluid
      suggest that these compartments may be non-communicating separate units or have
      different mechanisms regulating leptin synthesis or degradation, and that leptin
      in maternal blood and amniotic fluid may not have a direct effect on fetal growth
      but rather a different role in pregnancy.

PMID- 15188804
TI  - Intrauterine smoke exposure: a new risk factor for bronchopulmonary dysplasia?
AB  - OBJECTIVE: To evaluate the role of intrauterine smoke exposure and other
      variables on the development of bronchopulmonary dysplasia (BPD) in infants with
      birth weight < 1500 g (VLBW). METHODS: This case-control study investigated 277
      VLBW infants (141 cases, 136 controls) admitted at birth to neonatal intensive
      care unit and survived to discharge. A retrospective telephone interview provided
      detailed parental information supplementing clinical data. Logistic regression
      assessed the effects of birth weight < 1000 g, gestational age < 30 weeks
      (GA<30), respiratory distress syndrome (RDS), neonatal mechanical ventilation > 7
      days (MV>7), patent ductus arteriosus (PDA), intrauterine smoke exposure > or = 3
      months (ISE), and of parental history of asthma on BPD (oxygen dependency at 28
      days with characteristic radiographic abnormalities) occurrence. RESULTS:
      Including all variables, only GA<30, RDS and MV>7 were significantly associated
      with BPD. ISE did not contribute significantly to this model (odds ratio [OR]
      1.94; 95% confidence interval 0.88-4.26). Excluding iatrogenic variable MV>7,
      GA<30, RDS, PDA and ISE (OR 2.21; 95% confidence interval 1.03-4.76) were
      significantly associated with BPD. Analyzing GA as a continuous variable, the OR
      was 0.63 for each additional week. CONCLUSIONS: Prolonged mechanical ventilation,
      RDS and low gestational age were the major BPD determinants. Intrauterine smoke
      exposure seems to influence independently BPD development.

PMID- 15188805
TI  - Effect of phenobarbital on free radicals in neonates with hypoxic ischemic
      encephalopathy--a randomized controlled trial.
AB  - BACKGROUND: Phenobarbital is one of the oldest, cheapest and easily available
      cerebroprotective drugs for the hypoxic brain. However, its potential and various
      actions have not been fully explored. AIM: To evaluate the effects of
      Phenobarbital on levels of oxidants and anti-oxidants in term and near term
      neonates with hypoxic ischemic encephalopathy. METHODS: Design--randomized
      controlled trial. Setting--tertiary care referral perinatal centre. Procedure-
      asphyxiated neonates (gestation > or = 34 weeks) with HIE were randomized to
      receive Phenobarbital 20 mg/kg i.v. within first six hours of life or to control
      group. CSF levels of malondialdehyde (MDA), superoxide dismutase (SOD),
      glutathione peroxidase (GPx) and blood levels of vitamins A and E were estimated
      at 10-12 hours of age. RESULTS: CSF levels of MDA, SOD, GPx and blood levels of
      vitamins A and E were significantly lower in the Phenobarbital group (p<0.001).
      There was a trend towards lower levels of CSF MDA, SOD, GPx and blood vitamins A
      and E in babies with normal outcome as compared to babies with adverse outcome
      (death or neurologically abnormal at discharge). CONCLUSION: Phenobarbital in the
      dose of 20 mg/kg i.v. given within 6 hours of life in term and near-term neonates
      with HIE, was associated with a decrease in lipid peroxides, anti-oxidant enzymes
      and anti-oxidant vitamins.

PMID- 15188806
TI  - Increase in cord blood soluble E-selectin and tracheal aspirate neutrophils at
      birth and the development of new bronchopulmonary dysplasia.
AB  - AIM: To test the hypothesis that preterm infants who develop new type of
      bronchopulmonary dysplasia BPD have higher cord blood sE-selectin levels and
      neutrophil counts in the tracheal aspirate at birth than those who do not.
      METHODS: The relationship between cord blood sE-selectin levels and neutrophil
      counts in the tracheal aspirate at birth and the development of BPD was examined
      in 30 preterm infants. Levels of sE-selectin and neutrophil counts were measured
      by specific immunoassay and by cytospin analysis. RESULTS: Median cord blood
      levels of sE-selectin and neutrophil counts in the tracheal aspirate at birth
      were higher in preterm infants who developed BPD than in those who did not
      (P<0.01 for each). These differences persisted significantly after adjusting for
      the effects of gestational age and the presence of histologic chorioamnionitis
      and patent ductus arteriosus PDA (P<0.01 for each). CONCLUSION: Fetal pulmonary
      inflammation, as measured by increased cord blood levels of sE-selectin and
      neutrophil counts in the tracheal aspirate at birth, may be a risk factor for the
      development of new BPD in preterm infants. These results support the hypothesis
      that the lung injury responsible for new BPD in preterm infants can begin in the
      prenatal period and could be associated with a fetal pulmonary inflammation.

PMID- 15188807
TI  - Biliary atresia due to delayed maturation of the gut hormones' system?-
      Introducing a new treatment modality.
AB  - BACKGROUND: Congenital biliary atresia is suspected to originate from prenatal
      biliary duct inflammation of unknown etiology. OBJECTIVE: Based on clinical
      grounds, we aimed to establish a hypothesis on the primary cause of inflammation,
      and to suggest a causal treatment modality. CASE REPORT: History. A 28 years old
      Turkish woman had lost her first child aged two years from congenital biliary
      atresia (parents second degree cousins). After a miscarriage, in her otherwise
      uneventful third pregnancy sonography at 34 wks revealed echogenic material in
      the fetal gallbladder. Nine days later the gallbladder was completely filled with
      sludge. Chemical inflammation was suspected, and birth was induced at 36+3 weeks
      in order to allow for surgical flushing of the bile duct. Neonatal clinical
      chemistry was insuspicious. There was no spontaneous resolution of the sludge
      within the first 24 hours of life. A trial of medical treatment with intermittent
      i.v. secretin (0.03 CU/kg/h) and i.v. coeruletid (60 ng/kg/h) was started. Within
      24 hours, sludge had resolved. CONCLUSIONS: We hypothesize that dysmaturation may
      lead to insufficient induction/production/activity of intrinsic gut hormones
      resulting in prenatally impaired bile flow, or even inspissated bile. Familial
      occurrence suggests a genetic defect. Exogenous hormone therapy might be an
      appropriate treatment modality.

PMID- 15188808
TI  - DNA testing for inherited diseases in animals.

PMID- 15188809
TI  - Comparison of serum-free thyroxine concentrations determined by standard
      equilibrium dialysis, modified equilibrium dialysis, and 5 radioimmunoassays in
      dogs.
AB  - Measurement of serum-free thyroxine (fT4) concentration provides a more accurate
      assessment of thyroid gland function than serum thyroxine (T4) or 3,5,3'
      triiodothyronine (T3). Techniques for measuring serum fT4 concentration include
      standard equilibrium dialysis (SED), radioimmunoassay (RIA), and a combination of
      both (modified equilibrium dialysis [MED]). This study compared results of serum
      fT4 measurements by means of SED, MED, and 5 RIAs in 30 healthy dogs, 10 dogs
      with hypothyroidism, and 31 euthyroid dogs with concurrent illness for which
      hypothyroidism was a diagnostic consideration. Serum fT4 concentrations were
      comparable when determined by the SED and MED techniques, and mean serum fT4
      concentrations were significantly (P < .01) lower in dogs with hypothyroidism
      than in healthy dogs and euthyroid dogs with concurrent illness. Significant (P <
      .05) differences in fT4 concentrations were identified among the 5 RIAs and among
      the RIAs and MED and SED. Serum fT4 concentrations were consistently lower when
      fT4 was determined by the RIAs, compared with either equilibrium dialysis
      technique. Serum fT4 concentrations were significantly lower (P < .01) in dogs
      with hypothyroidism than in healthy dogs for all RIAs; were significantly lower
      (P < .05) in dogs with hypothyroidism than in euthyroid dogs with concurrent
      illness for 4 RIAs; and were significantly lower (P < .01) in euthyroid dogs with
      concurrent illness than in healthy dogs for 4 RIAs. RIAs had the highest number
      of low serum fT4 concentrations in euthyroid dogs with concurrent illness. This
      study documented differences in test results among fT4 assays, emphasizing the
      importance of maintaining consistency in the assay used to measure serum fT4
      concentrations in the clinical or research setting.

PMID- 15188810
TI  - Prevalence and risk factors of hypoglycemia in virulent canine babesiosis.
AB  - Hypoglycemia is a common complication of virulent canine babesiosis. A study was
      conducted to determine the prevalence of and potential risk factors for
      hypoglycemia in canine babesiosis from Babesia canis rossi. Plasma glucose
      concentration was measured at presentation in 250 dogs with babesiosis, of which
      111 were admitted to hospital. The prevalence of hypoglycemia (<60 mg/dL) was 9%
      (23/250). Twenty-two hypoglycemic dogs required admission, making the prevalence
      of hypoglycemia in admitted dogs 19.8%. Sixteen dogs had severe hypoglycemia (<40
      mg/dL), of which 5 had glucose < 18 mg/dL. Hyperglycemia (>100 mg/dL) was present
      in 38 dogs, of which 21 were admitted. Risk factors for hypoglycemia identified
      by univariate analysis were collapsed state (P < .00001), severe anemia (P =
      .0002), icterus (P = .003), age < 6 months (P = .02), and vomiting (P = .03).
      After logistic regression analysis, collapsed state (odds ratio [OR] = 18; 95%
      CI, 1.9-171; P = .01) and young age (OR = 2.8; 95% CI, 0.8-9.7; P = .1) remained
      significantly associated with hypoglycemia. Toy breeds and pregnant bitches were
      not at higher risk for hypoglycemia than other dogs. Blood glucose concentration
      should ideally be measured in all dogs requiring inpatient treatment for
      babesiosis but is mandatory in collapsed dogs; puppies; and dogs with severe
      anemia, vomiting, or icterus. Many dogs have probably been misdiagnosed with
      cerebral babesiosis in the past, and hypoglycemia should be suspected in any dog
      with coma or other neurological signs.

PMID- 15188811
TI  - Digital fluoroscopic excretory urography, digital fluoroscopic urethrography,
      helical computed tomography, and cystoscopy in 24 dogs with suspected ureteral
      ectopia.
AB  - The purpose of this study was to determine the diagnostic utility of helical
      computed tomography (CT) for the diagnosis of ectopic ureters in the dog and to
      compare these findings with those of digital fluoroscopic excretory urography and
      digital fluoroscopic urethrography. Ureteral ectopia was confirmed or disproved
      based on findings from cystoscopy and exploratory surgery or postmortem
      examination. Of 24 dogs (20 female, 4 male) evaluated, 17 had ureteral ectopia.
      Digital fluoroscopic excretory urography and CT correctly identified ureteral
      ectopic status and site of ureteral ectopia (P < .05). Urethrography did not
      reliably detect ureteral ectopia. No false-positive diagnoses of ureteral ectopia
      were made in any of the imaging studies. Cystoscopic findings significantly
      agreed with findings during surgery in determining ureteral ectopic status and
      ectopic ureter site. One false-positive cystoscopic diagnosis of unilateral
      ureteral ectopia was made in a male dog. Kappa statistics showed better agreement
      between CT and both cystoscopy and surgical or postmortem examination findings
      with regard to presence and site of ureteral ectopia compared with other imaging
      techniques. CT was more useful than other established diagnostic imaging
      techniques for diagnosing canine ureteral ectopia.

PMID- 15188812
TI  - DNA testing for type III von Willebrand disease in Dutch Kooiker dogs.
AB  - Von Willebrand disease type III is widespread in Dutch Kooiker dogs. To eradicate
      von Willebrand disease from the breed, affected dogs and nonsymptomatic carriers
      must be excluded from breeding. Previous efforts to detect carriers in Kooiker
      dogs by a von Willebrand factor antigen assay were not satisfactory because of
      considerable overlap of plasma concentrations in normal dogs and carriers. The
      aim of this study was to develop and apply a DNA test for the detection of von
      Willebrand disease carriers in the Kooiker breed. Two mutations in the von
      Willebrand factor gene in affected Kooiker dogs have been described previously, a
      splice site mutation at the border of intron 16 and exon 16 and a missense
      mutation in exon 3. We have developed polymerase chain reaction tests for both
      mutations in genomic DNA. The missense mutation most likely is a neutral variant
      and appears to be a polymorphism present in many breeds. The allele-specific
      oligonucleotide test for the splice site mutation was applied in the selection of
      animals cleared to breed by the Dutch breeding club. In a few years, the mutation
      has been eliminated from the breeding stock without apparent increase of
      inbreeding or preferential sire usage.

PMID- 15188813
TI  - Association of systemic hypertension with renal injury in dogs with induced renal
      failure.
AB  - Systemic hypertension is hypothesized to cause renal injury to dogs. This study
      was performed on dogs with surgically induced renal failure to determine whether
      hypertension was associated with altered renal function or morphology. Mean
      arterial pressure (MAP), heart rate (HR), systolic arterial pressure (SAP), and
      diastolic arterial pressure (DAP) were measured before and after surgery.
      Glomerular filtration rate (GFR) and urine protein:creatinine ratios (UPC) were
      measured at 1, 12, 24, 36, and 56-69 weeks after surgery, and renal histology was
      evaluated terminally. The mean of weekly MAP, SAP, and DAP measurements for each
      dog over the 1st 26 weeks was used to rank dogs on the basis of MAP, SAP, or DAP
      values. A statistically significant association was found between systemic
      arterial pressure ranking and ranked measures of adverse renal responses. When
      dogs were divided into higher pressure and lower pressure groups on the basis of
      SAP, group 1 (higher pressure, n = 9) compared with group 2 (lower pressure, n =
      10) had significantly lower GFR values at 36 and 56-69 weeks; higher UPC values
      at 12 and 56-69 weeks; and higher kidney lesion scores for mesangial matrix,
      tubule damage, and fibrosis. When dogs were divided on MAP and DAP values, group
      1 compared with group 2 had significantly lower GFR values at 12, 24, 36, and 56
      69 weeks; higher UPC values at 12 and 56-69 weeks; and higher kidney lesion
      scores for mesangial matrix, tubule damage, fibrosis, and cell infiltrate. These
      results demonstrate an association between increased systemic arterial pressure
      and renal injury. Results from this study might apply to dogs with some types of
      naturally occurring renal failure.

PMID- 15188814
TI  - Hepatic abscesses in cats: 14 cases (1985-2002).
AB  - In this retrospective study, we describe 14 cats diagnosed with hepatic
      abscesses. The objective of the study was to report the clinical signs, physical
      examination findings, clinicopathologic findings, and outcomes in affected cats.
      These findings were then compared with those previously reported in dogs and
      humans. Clinical signs were vague and included anorexia, lethargy, and weight
      loss. Only 23% of cats had fever, whereas 31% were hypothermic. Increases in
      serum activities of alanine aminotransferase and alkaline phosphatase were found
      in 45 and 18%, respectively, of the 11 cats that had laboratory work performed.
      Abdominal ultrasound examinations were performed in 7 cats, and abnormalities
      were found in 71% of them. Four cats had solitary abscesses, all of which were
      located in the right liver lobes. The other 10 cats had multifocal small
      abscesses or microabscesses, and all of these cats had clinical signs suggestive
      of sepsis. Cytologic evaluation of samples obtained by abdominocentesis indicated
      septic inflammation in 67% of cats in which peritoneal fluid was analyzed.
      Hepatic abscess cultures yielded polymicrobial growth in 66% of the cats:
      Escherichia coli was the most commonly cultured organism. Overall mortality rate
      was 79%. All survivors underwent exploratory laparotomy for partial hepatectomy
      to resect the abscess followed by medical management. Hepatic abscesses should be
      considered in cats with signs consistent with sepsis. More routine use of
      ultrasonography may aid in earlier diagnosis of hepatic abscesses, potentially
      improving prognosis and outcome.

PMID- 15188815
TI  - Molecular investigation of Escherichia coli strains associated with apparently
      persistent urinary tract infection in dogs.
AB  - Persistent Escherichia coli urinary tract infection (UTI) in dogs is a
      frustrating clinical problem. Affected dogs often appear to fail to respond to
      therapy or to reacquire infection shortly after therapy is completed.
      Urovirulence factors (UVFs) of the infecting E. coli, antibiotic resistance, and
      tissue colonization may be contributory but have not been evaluated in dogs with
      persistent E. coli UTI. In this study, the strain types of E. coli in dogs with
      persistent UTI were evaluated with pulsed-field gel electrophoresis (PFGE) to
      determine whether persistence was due to acquisition of new isolates or failure
      to eradicate existing isolates. UVFs in these isolates, assessed by polymerase
      chain reaction, and antibiograms were correlated with treatment outcome in these
      dogs. Results documented a mixed pattern: 9 dogs remained chronically infected
      with 1 or 2 strains, each with distinct reproducible UVFs, but 1 dog was infected
      with numerous unrelated E. coli strains over time. Two dogs had a mixed pattern,
      consisting of 1 or more episodes of persistent E. coli infection attributable to
      a single strain in addition to episodes caused by unrelated strains. Many
      isolates had no detectable UVFs, highlighting the likely importance of impaired
      colonization resistance in the affected dogs. Antibiotic resistance was common,
      often in response to previous treatments, especially with trimethoprim
      sulfamethoxazole. Antibiotic resistance patterns differed significantly within
      PFGE strain types, suggesting lateral acquisition of resistance plasmids or
      integrons. These results can be used to help guide testing for and management of
      persistent E. coli UTI in dogs.

PMID- 15188816
TI  - Thoracic duct ligation and pericardectomy for treatment of idiopathic
      chylothorax.
AB  - Chylothorax is a devastating disease, and the success rates from either medical
      or surgical management are less than satisfactory. In some animals with
      chylothorax, a thickening of the pericardium occurs that is associated with
      chronic irritation induced by chyle. We hypothesized that pericardial thickening
      would lead to increased right-sided venous pressures and that abnormal venous
      pressures would act to impede the drainage of chyle via lymphaticovenous
      communications after thoracic duct (TD) ligation. We also hypothesized that
      serosanguineous effusions that occurred after TD ligation could effectively be
      treated or prevented by pericardectomy in affected animals. TD ligation plus
      pericardectomy was performed in 17 animals, and pericardectomy alone was
      performed in an additional 3 animals that presented during a 5.5-year period to
      the Texas A&M University (College Station, TX). Nineteen animals presented for an
      evaluation of idiopathic chylothorax (9 dogs and 10 cats), and 1 dog presented
      for serosanguineous pleural fluid after TD ligation that had been performed
      elsewhere. Echocardiography was normal in all animals, except for a subjectively
      thickened pericardium in 7 cats and 6 dogs. Clinical signs of pleural fluid
      accumulation resolved in 10 of 10 dogs and in 8 of 10 cats after surgery. The
      overall success rate for the surgical treatment of chylothorax (ie, the
      resolution of pleural fluid accumulation) in this study was 90% (100% in dogs and
      80% in cats). These data suggest that TD ligation in conjunction with
      pericardectomy has a favorable outcome in animals with idiopathic chylothorax.

PMID- 15188817
TI  - Allometric scaling of M-mode cardiac measurements in normal adult dogs.
AB  - Indices for M-mode measurements in dogs usually have been based on the assumption
      that a linear relationship exists between these measurements and body weight (BW)
      or body surface area (BSA). The relationships between the geometry of 3
      dimensional objects do not support this assumption. The purposes of this study
      were to retrospectively examine M-mode data from a large number of dogs of
      varying sizes and breeds that were examined by a large number of
      ultrasonographers, to use the allometric equation to determine the appropriate BW
      exponent required to predict these cardiac dimensions, and to determine normal
      mean values and prediction intervals for common M-mode variables. Linear
      regression analyses of data from 494 dogs (2.2-95 kg) revealed a good correlation
      between M-mode measurements and BW after logarithmic transformation of the data
      (r2 = .55-.88). Most variables were most closely related to an index of body
      length, BW(1/3), although the exponent that best predicted diastolic and systolic
      left ventricular wall thicknesses was closer to 0.25. No variable indexed well to
      BW or BSA. With these data, appropriate mean values and prediction intervals were
      calculated for normal dogs, allowing veterinarians to correctly and appropriately
      index M-mode values. The equations developed from this study appear to be
      applicable to adult dogs of most breeds.

PMID- 15188818
TI  - Cardiac troponins I and T in dogs with pericardial effusion.
AB  - Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are sensitive and
      specific markers for myocardial ischemia and necrosis. Dogs with pericardial
      effusion frequently have myocardial ischemia and necrosis, and these changes are
      more severe in dogs with hemangiosarcoma (HSA). We investigated the utility of
      using serum cTnI and cTnT concentrations to identify the idiopathic pericardial
      effusion from that associated with HSA. Blood samples for measurement of cTnI and
      cTnT concentrations were collected before pericardiocentesis in 37 dogs with
      pericardial effusion. Eighteen dogs had a mass consistent with HSA, 6 dogs had
      idiopathic pericardial effusion, 1 dog had mesothelioma, and 1 dog had a heart
      base tumor. No final diagnosis was achieved for 11 dogs. Dogs with pericardial
      effusion had significantly higher serum concentrations of cTnI (P < .001) but not
      cTnT (P = .16) than did normal dogs. Dogs with HSA had significantly higher
      concentrations of cTnI (2.77 ng/dL; range: 0.09-47.18 ng/dL) than did dogs with
      idiopathic pericardial effusion (0.05 ng/dL; range: 0.03-0.09 ng/dL) (P < .001).
      There was no difference in the concentration of cTnT between dogs with HSA and
      those with idiopathic pericardial effusion (P = .08). Measurement of cTnI may be
      useful in helping to distinguish between idiopathic pericardial effusion and
      pericardial effusion caused by HSA.

PMID- 15188819
TI  - Transarterial coil embolization of patent ductus arteriosus in small dogs with
      0.025-inch vascular occlusion coils: 10 cases.
AB  - Patent ductus arteriosus (PDA) is the most common congenital cardiac disease in
      the dog and generally leads to severe clinical signs, including left-sided
      congestive heart failure. Historically, definitive treatment consisted of
      surgical ligation; however, the use of vascular occlusion devices by minimally
      invasive techniques has gained popularity in veterinary medicine during the past
      decade. Adequate vascular access is a major limiting factor for these minimally
      invasive techniques, precluding their use in very small dogs. The clinical
      management of PDA with 0.025-in vascular occlusion coils in a minimally invasive
      transarterial technique in 10 dogs is described. The dogs were small (1.38 +/-
      0.22 kg), were generally young (6.70 +/- 5.74 months), and had small minimal
      ductal diameters (1.72 +/- 0.81 mm from angiography). Vascular access was
      achieved, and coil deployment was attempted in all dogs with a 3F catheter
      uncontrolled release system. Successful occlusion, defined as no angiographic
      residual flow, was accomplished in 8 of 10 (80%) dogs. Successful occlusion was
      not achieved in 2 dogs (20%), and both dogs experienced embolization of coils
      into the pulmonary arterial tree. One of these dogs died during the procedure,
      whereas the other dog underwent a successful surgical correction. We conclude
      that transarterial PDA occlusion in very small dogs is possible with 0.025-in
      vascular occlusion coils by means of a 3F catheter system and that it represents
      a viable alternative to surgical ligation. The risk of pulmonary arterial
      embolization is higher with this uncontrolled release system, but this risk may
      decrease with experience.

PMID- 15188820
TI  - Magnetic resonance imaging of focal splenic and hepatic lesions in the dog.
AB  - Focal hepatic and splenic lesions in the dog are common, and approximately half
      of such lesions are malignant. Both incidentally discovered lesions and lesions
      in patients with known malignancies represent diagnostic dilemmas. Ultrasound
      often fails to characterize such lesions adequately. This uncertainty may result
      in unnecessary splenectomies and liver biopsies for benign lesions or noncurative
      surgery for advanced-stage malignancies. In humans, ultrasound largely has been
      supplanted by computed tomography and magnetic resonance imaging (MRI) for the
      characterization of focal hepatic and splenic lesions. The inherently high soft
      tissue contrast of MRI allows the differentiation of benign from malignant
      hepatic and splenic lesions in the human patients. In this prospective study, 35
      focal lesions of either the spleen (n = 8) or the liver (n = 27) were
      characterized by MRI in 23 dogs. Lesions were presumptively classified as
      malignant or benign on the basis of MRI findings. Imaging results then were
      correlated with histopathologic (29) or cytologic (6) evaluation of the lesions.
      The overall accuracy in differentiating malignant from benign lesions was 94% (33
      of 35 lesions). The overall sensitivity and specificity were 100% (95% CI, 78
      100%) and 90% (95% CI, 68-99%), respectively. MRI classified malignant hepatic
      lesions as hepatocellular carcinoma (HCC) in all confirmed cases and correctly
      predicted the histologic grade of 5 HCC lesions. These results suggest that MRI
      is a useful modality for abdominal imaging in veterinary patients, and MRI
      accurately differentiated benign from malignant focal hepatic and splenic lesions
      in this sample of patients.

PMID- 15188821
TI  - Relationship between red blood cell thiopurine methyltransferase activity and
      myelotoxicity in dogs receiving azathioprine.
AB  - Thiopurine methyltransferase (TPMT) produces inactive metabolites of azathioprine
      and, in humans, has a variable amount of activity. Humans with low TPMT activity
      commonly develop myelotoxicity when receiving azathioprine. Our study sought to
      characterize the distribution of TPMT activity in a population of dogs and to
      determine whether the pretreatment knowledge of red blood cell (RBC) TPMT
      activity could predict myelotoxicity in dogs receiving azathioprine. RBC TPMT
      activity was measured in 299 healthy dogs, and 9 dogs that represented a wide
      range of enzyme activity received azathioprine at a standard therapeutic dose for
      30 days. TPMT activity in healthy dogs was log normally distributed and varied
      over an approximately 7-fold range. Geometric mean, minimum, and maximum RBC TPMT
      activities were 37.1, 16.3, and 115 nmol per gram of hemoglobin (gHb) per hour,
      respectively. TPMT deficiency was not identified. Two populations of TPMT
      activity in dogs were detected by statistical modeling (commingling analysis).
      Dogs with intermediate TPMT activity (14-38 nmol/gHb/h) receiving azathioprine
      had significantly lower neutrophil counts during week 4 than during weeks 0-3,
      whereas those with high activity (>39 nmol/gHb/h) did not have a significant
      change in neutrophil count. An analysis of TPMT activity in 6 dogs with a history
      of azathioprine-associated myelotoxicity in a clinical setting revealed either
      intermediate or high TPMT enzyme activity in all dogs, suggesting that TPMT
      activity, as measured in RBCs, is not the sole cause of severe azathioprine
      associated myelosuppression in dogs.

PMID- 15188822
TI  - Dietary risk factors and colonic pH and mineral concentrations in horses with
      enterolithiasis.
AB  - A prospective, unmatched case control study was performed to identify dietary and
      environmental risk factors for enterolithiasis in horses in California and to
      determine whether colonic ingesta analyses differed between horses with and
      without enteroliths. Forty-three horses with enterolithiasis were compared with
      19 horses with surgical colic attributable to nonstrangulating obstruction of the
      colon without enteroliths. Colonic ingesta samples were collected at surgery from
      horses with enteroliths and control horses. Colonic pH and colonic concentrations
      of magnesium, phosphorus, sulfur, sodium, calcium, potassium, and nitrogen were
      measured. Questionnaires were distributed to owners to determine diet and
      management practices. Student's t-test and Mann-Whitney tests were used to
      evaluate differences in pH, dry matter content, percent nitrogen, and mineral
      content. Associations between dietary and management risk factors and enterolith
      occurrence were quantified by odds ratios. Mean pH of colonic contents from
      horses with enterolithiasis was significantly higher than for control horses.
      Horses with enterolithiasis had significantly lower percent dry matter in colonic
      fecal samples and higher mean mineral concentrations than controls. On the basis
      of reported feeding and management practices, horses with enterolithiasis were
      fed a significantly higher proportion of alfalfa in their diet and were less
      likely to have daily access to pasture grass than horses without enteroliths.
      Results suggest that decreasing alfalfa consumption and allowing daily access to
      pasture grazing might reduce the risk of enterolithiasis. Dietary modifications
      promoting acidification of colonic contents and dilution of minerals might be
      beneficial as preventive measures for enterolithiasis in horses.

PMID- 15188823
TI  - Phenytoin sodium as a treatment for ventricular dysrhythmia in horses.
AB  - Five adult horses with ventricular extra systoles (VES) and 2 with ventricular
      tachycardia (VT) refractory to treatment with rest, anti-inflammatory drugs,
      lidocaine, or procainamide were treated with phenytoin sodium p.o. q12h. The
      starting dosage of phenytoin was 20 or 22 mg/kg body weight (BW) q12h, and the
      maintenance dosage varied from 8 to 17 mg/kg BW q12h. The mean +/- standard
      deviation therapeutic blood concentration of total phenytoin was 8.8 +/- 2.1
      mg/L, and the mean concentration of free phenytoin of 2.5 +/- 0.5 mg/L was
      relatively constant at a range of 24 to 29% of the total phenytoin concentration.
      In all horses, both VES and VT were abolished after treatment with phenytoin. On
      the basis of the results of this clinical study, the authors propose an initial
      dose of 20 mg/kg BW q12h for the first 3 or 4 dosages, followed by a maintenance
      dose of 10 to 15 mg/kg BW q12h. Phenytoin plasma concentrations should be
      monitored during therapy. High plasma concentrations were associated with adverse
      effects such as recumbency and excitement. In this study, which included a
      limited number of diverse patients, phenytoin sodium appeared to be an
      inexpensive and effective treatment for persistent VES or VT in cases where
      conventional treatment had failed.

PMID- 15188824
TI  - Cholesterol-based pericardial effusion and aortic thromboembolism in a 9-year-old
      mixed-breed dog with hypothyroidism.

PMID- 15188825
TI  - Tracheobronchopathia osteochondroplastica in a dog.

PMID- 15188826
TI  - Treatment of conidiobolomycosis with fluconazole in two pregnant mares.

PMID- 15188827
TI  - Encephalomyelitis from West Nile flavivirus in 3 alpacas.

PMID- 15188828
TI  - Postanesthetic cerebellar dysfunction in cats.
AB  - Eleven cats with signs of cerebellar dysfunction, developed on recovery from a
      brief and uneventful general anesthesia, were examined at the Koret School of
      Veterinary Medicine Teaching Hospital (KSVMTH) between 1998 and 2002.
      Neurological signs included mild to severe ataxia of all 4 limbs, intentional
      tremor, lack of menace response, and delayed hopping. The cats were of different
      ages when anesthetized and none had shown any prior signs of neural disease. They
      were examined 1 day to 4 years after onset of clinical signs, and the
      neurological deficits remained unchanged in a follow-up period of 6 months to 8
      years. Medical and anesthetic records showed that all were Persian cross cats, 7
      of them originating in the same city in Israel. Ketamine was the only anesthetic
      drug that had been used with all cats. It might be that a genetic component
      predisposes Persian cross cats to nonreversible cerebellar damage after exposure
      to an anesthetic dose of ketamine.

PMID- 15188829
TI  - Effects of trimethoprim-sulfadiazine on thyroid function of horses.
AB  - Trimethoprim-sulfadiazine was administered to horses in a randomized, placebo
      controlled study to determine the effects of potentiated sulfonamides on thyroid
      function in normal horses. The treatment group included eight horses that
      received trimethoprim-sulfadiazine mixed with molasses orally at 30 mg/kg once
      daily for eight weeks. The control group included 8 horses that received an oral
      placebo (flour mixed with molasses) once daily for the same period. Thyroid
      function was evaluated prior to initiation of treatment and after 8 weeks of
      treatment. Serum concentrations of total and free triiodothyronine (T3), total
      and free thyroxine (T4), and thyroid stimulating hormone (TSH) were determined at
      rest and after a thyrotropin-releasing hormone (TRH) stimulation test. There was
      no detectable difference between treatment and control groups.

PMID- 15188830
TI  - Neurological complications in eclampsia: a case series.
AB  - OBJECTIVES: Neurological abnormalities contribute significantly to maternal
      mortality in eclampsia. We studied the epidemiology and neurological and
      obstetric outcome of such patients. METHODS: A retrospective analysis was done at
      a referral center. 19 cases of eclampsia with recurrent convulsions (n = 8) or
      coma without convulsions (n = 5) or cerebrovascular accidents (n = 4) or
      blindness (n = 2) were studied. We excluded cases with primary neurological
      abnormalities. Management included initial stabilization followed by early
      delivery. Primary anticonvulsant was magnesium sulphate. RESULTS: The incidence
      of eclampsia was 0.71%. Among 61 cases, 19 (31.14%) had neurological
      abnormalities; 15 patients had no antenatal care. Three cases were postpartum.
      Comatose patients had the highest mean arterial pressure (MAP) (mean 154.66 mm
      Hg, p = 0.027). Fundoscopy was usually normal. Computerized tomography revealed
      mild cerebral edema in six cases and accurately diagnosed all cerebrovascular
      accidents. Phenytoin controlled convulsions in 7/8 cases with recurrent seizures.
      The cesarean section rate was 37.5% and admission to delivery interval was 10.38
      hours. Five perinatal and two maternal deaths were recorded among 19 cases.
      Neurological recovery was complete in all survivors. CONCLUSIONS: Critical care
      back-up is essential at tertiary referral centers for a large proportion of
      neurological abnormalities in eclampsia. High MAP and accompanying
      thrombocytopenia may be key factors in cerebral pathology. CT scan is a simple
      and effective investigation in these cases. Phenytoin is an effective second-line
      anticonvulsant. No maternal death was related directly to cesarean section. Early
      delivery prevents worsening of systemic status.

PMID- 15188831
TI  - Estrogen therapy in older patients with recurrent urinary tract infections: a
      review.
AB  - Although urogenital complaints, such as recurrent lower urinary tract infections
      (UTI), and dysuria, are commonly encountered in elderly women, few women have
      participated in randomized studies of estrogen therapy for this condition. This
      is a paradox in view of the often cited beneficial effect of estrogen in reducing
      the incidence of UTI. Present evidence documents that in postmenopausal women,
      hormone replacement therapy using topical estrogen normalizes the vaginal flora
      and greatly reduces the risk of vaginal atrophy. Similarly, vaginal estrogen
      administration seems to be effective for preventing recurrent urinary tract
      infections (UTI).

PMID- 15188832
TI  - Comparison of the effects of leuprorelin acetate and danazol treatments on serum
      CA-125 levels in women with endometriosis.
AB  - OBJECTIVE: To investigate the effects of danazol and leuprorelin acetate on CA
      125 levels during treatment for endometriosis. PATIENTS AND METHODS: Fifty women
      with laparoscopically diagnosed and treated endometriosis, and 50 women without
      pelvic disease as a control group. Following surgical treatment, 35 women with
      endometriosis were divided into two groups. The first group (20 women) received
      200 mg danazol three times daily for 6 months; the second group (15 women)
      received 3.75 mg leuprorelin acetate depot every 28 days for 6 months. Serum CA
      125 levels were measured before medical treatment, during the last 15 days of the
      6-month treatment course, and 3 months after treatment. RESULTS: Serum CA-125
      levels were significantly higher in women with endometriosis than in women in the
      control group. Before treatment, CA-125 levels in patients with stage III/IV
      endometriosis were significantly higher than those in stage I/II endometriosis.
      Six months of danazol or leuprorelin acetate depot treatment decreased serum CA
      125 levels. Three months after stopping danazol, CA-125 levels remained
      significantly lower than pretreatment levels. On the other hand, 3 months after
      stopping leuprorelin acetate, CA-125 levels returned to pretreatment levels.
      CONCLUSIONS: (a) Danazol and leuprorelin acetate are equally effective in the
      treatment of endometriosis. (b) Moreover, the results support the view that the
      determination of CA-125 levels may assist in evaluating progress of endometriosis
      treatment.

PMID- 15188833
TI  - Gestational carrier is an optimal method for pregnancy in patients with vaginal
      agenesis (Rokitansky syndrome).
AB  - OBJECTIVE: To evaluate the results of successful pregnancy for patients with
      Mayer-Rokitansky-Kuster-Hauser syndrome using a gestational carrier. METHODS: All
      gestational carrier patients who attended our infertility clinic between 1995 and
      2002 were reviewed for this study. Of the patients, 6 women with MRKH syndrome
      had 12 ovarian stimulation cycles, which resulted in 12 fresh and 5 frozen embryo
      transfers into six gestational carriers. RESULTS: The mean number (+/-SD) of
      embryos obtained per cycle was 4.8 (+/-2.9). Either two (n = 15) or three (n = 2)
      embryos were transferred to the gestational carrier. Three pregnancies were
      achieved following fresh embryo transfer, which included one clinical pregnancy
      that ended in spontaneous abortion, a singleton, and a set of twins. The
      pregnancy rate for fresh embryo transfer was 25% per retrieval and 50% per
      patient. No pregnancy was achieved following frozen embryo transfer. CONCLUSION:
      Gestational carrier is shown to be an effective treatment for patients with Mayer
      Rokitansky-Kuster-Hauser syndrome.

PMID- 15188834
TI  - The value of laboratory tests and ultrasonography in evaluating ovarian response
      to ovulation induction treatment with low-dose recombinant follicle-stimulating
      hormone.
AB  - OBJECTIVE: To compare basal (cycle day 3) follicle-stimulating hormone (FSH)
      level, clomiphene citrate challenge test (CCCT), gonadotropin-releasing hormone
      agonist stimulation test (GAST), and mean ovarian volume estimation by ultrasound
      for predicting the subsequent ovarian response. DESIGN: Prospective, randomized,
      clinical study. SETTING: Referral university hospital. PATIENTS: One hundred and
      forty-four women with unexplained infertility undergoing their first ovulation
      induction treatment with low-dose recombinant FSH. INTERVENTIONS: Patients were
      randomized into four groups. Basal FSH levels were evaluated in group I (n = 36).
      Clomiphene citrate challenge test (CCCT) and gonadotropin-releasing hormone
      agonist stimulation test (GAST) were carried out in group II (n = 36) and group
      III (n = 36), respectively. Transvaginal ultrasound was performed for ovarian
      volume measurements in group IV (n = 36). In the subsequent cycle, all women
      received ovulation induction therapy with recombinant FSH. MAIN OUTCOME MEASURES:
      Number of mature (> or = 14 mm) follicles and the number of recombinant FSH
      ampules required for successful ovulation induction. RESULTS: Ovarian volume
      estimation by transvaginal ultrasound, compared to the other three tests, had the
      most powerful positive correlation with the number of mature follicles (r = 0.84,
      P < .0001) and the most powerful negative correlation (r = -0.75, P < .0001) with
      the amount of recombinant FSH used per cycle. CONCLUSION: Mean ovarian volume
      estimation by transvaginal ultrasound might be more useful than basal FSH values,
      CCCT, and GAST for predicting ovarian response to low-dose recombinant FSH
      treatment.

PMID- 15188835
TI  - Differences in vaginal dryness according to hormone therapy schedule using pH
      test strip in two groups of postmenopausal women.
AB  - OBJECTIVE: To compare vaginal dryness in two groups of postmenopausal women
      according to hormone replacement therapy schedule using pH test strip. METHODS:
      Twenty-two healthy postmenopausal women were divided into two groups according to
      the treatment they received: Group I, conjugated equine estrogens (CEE) 0.625
      mg/day (n = 15); Group II, CEE 0.625 mg/day plus medroxyprogesterone 2.5 mg/day
      (n = 7). Vaginal dryness intensity was analyzed using an analog visual scale and
      vaginal humidity by measuring the moistening, in millimeters, of a pH test strip.
      Both were evaluated at baseline and 3 months after the beginning of treatment.
      The comparison among groups and between baseline and final results was done with
      Student's t test for paired and independent samples, respectively. RESULTS: No
      differences were found in age and in anthropometric variables among the groups.
      In both groups, vaginal dryness intensity significantly decreased and the pH test
      strip moistening significantly increased, but the magnitude of the moistening was
      greater in the group with medroxyprogesterone. CONCLUSIONS: When
      medroxyprogesterone was added to estrogen therapy, a greater vaginal moistening
      of pH test strip was observed than when estrogen was used alone.

PMID- 15188836
TI  - Initiating a novel therapy in preventing postpartum hemorrhage in rural India: a
      joint collaboration between the United States and India.
AB  - BACKGROUND: Maternal mortality rates in India are estimated at 560/100,000 live
      births and postpartum hemorrhage (PPH) accounts for 35-56% of these deaths. Given
      that 50% of births in rural India occur at home, oral Misoprostol administered by
      minimally trained midwives may be an effective uterotonic agent for preventing
      PPH when the use of other uterotonics is not feasible. While the import for
      testing the effectiveness of this intervention may be readily obvious, the
      elements essential for the conduct of a scientific study in rural areas served by
      indigenous health workers may not be as evident. METHODS: We present the design
      as well as the preparation and development of an ongoing NICHD sponsored U.S.
      Indian collaborative randomized, placebo-controlled, clinical trial (RCT)
      conducted in four Primary Health Center areas of Belgaum District, Karnataka,
      India. The primary goal of the trial is to assess the effectiveness of
      Misoprostol 600 microg orally in reducing the incidence of acute PPH (> or = 500
      mL) in women delivering at home or in neighboring sub-centers. 1600 pregnant
      women will be randomized to receive Misoprostol or placebo immediately post
      delivery of the infant. However, beyond testing the scientific merit of the RCT,
      this study also tests the feasibility of having indigenous midwives regularly
      using Misoprostol in rural areas as well as the willingness of these communities
      to accept this intervention. In addition, this paper also explores the
      international and community collaborations necessary for the conduct of this
      study. FINDINGS: It is necessary to have several critical elements in place,
      including international collaboration between the Indian and US research sites,
      funding through a private/public collaboration and trained scientists, as well as
      commitment from the community for the successful conduct of such a study. In the
      development and implementation of a RCT, careful attention must be paid to the
      training of field personnel involved in the delivery process and developing a
      data collection and monitoring system to ensure that information gathered is
      valid. CONCLUSIONS: A joint U.S.-Indian collaboration to test the efficacy and
      the feasibility of an innovative method to reduce PPH can serve as collaborative
      model to develop additional interventions to improve maternal mortality and
      morbidity. If Misoprostol is shown to be sufficiently safe and efficacious in the
      prevention of PPH, the appropriate government agencies will be encouraged to make
      the drug available to midwives (ANMs) and rurally located physicians for whom
      parenteral medications are either not permitted or impractical and/or
      unavailable. Such a project can serve as a model applicable to rural settings
      throughout the developing world for improving delivery practices and reducing
      maternal mortality and morbidity. These are important public health concerns in
      India and other developing nations.

PMID- 15188837
TI  - Is methicillin-resistant Staphylococcus aureus more contagious than methicillin
      susceptible S. aureus in a surgical intensive care unit?

PMID- 15188838
TI  - Is nasal carriage of methicillin-resistant Staphylococcus aureus more prevalent
      among student healthcare workers?

PMID- 15188840
TI  - Controlling antimicrobial-resistant pathogens.

PMID- 15188839
TI  - Resistance to penicillin and erythromycin in viridans streptococcal bloodstream
      isolates from cancer and non-cancer patients within 10 years.

PMID- 15188841
TI  - Increased susceptibility to vancomycin-resistant Enterococcus intestinal
      colonization persists after completion of anti-anaerobic antibiotic treatment in
      mice.
AB  - BACKGROUND: Antibiotic-associated disruption of the indigenous intestinal
      microflora may persist beyond the treatment period. Although
      piperacillin/tazobactam inhibits the establishment of vancomycin-resistant
      Enterococcus (VRE) stool colonization in mice during treatment, we hypothesized
      that this agent and other anti-anaerobic antibiotics would increase
      susceptibility to colonization during the period of recovery of the intestinal
      microflora. DESIGN: Mice received 10(4) colony-forming units of vancomycin
      resistant E. faecium by orogastric inoculation 2, 5, or 10 days after completing
      5 days of subcutaneous antibiotic treatment, or both during and 2 days after the
      completion of treatment. Denaturing gradient gel electrophoresis (DGGE) was
      performed to assess changes in the intestinal microflora. RESULTS: Anti-anaerobic
      antibiotics (ie, piperacillin/ tazobactam, cefoxitin, and clindamycin) caused
      significant disruption of the indigenous microflora (mean DGGE similarity indices
      < or = 27% in comparison with saline controls) and promoted the establishment of
      high-density colonization when VRE was inoculated 2 or 5, but not 10, days
      following treatment (P < .001). Piperacillin/tazobactam exhibited a biphasic
      effect on the establishment of colonization (ie, inhibition when exposed to VRE
      during treatment and promotion when exposed to VRE after discontinuation of
      treatment), resulting in greater overall promotion of colonization than did
      agents with minimal anti-anaerobic activity (ie, levofloxacin, cefepime, and
      aztreonam) when VRE was inoculated both during and 2 days after treatment (P <
      .001). CONCLUSION: Patients receiving anti-anaerobic antibiotics, including
      piperacillin/tazobactam, may be susceptible to the establishment of high-density
      VRE colonization during the period of recovery of the anaerobic microflora.

PMID- 15188842
TI  - Effect of the increasing use of piperacillin/tazobactam on the incidence of
      vancomycin-resistant enterococci in four academic medical centers.
AB  - BACKGROUND: The substitution of piperacillin/tazobactam, ampicillin/sulbactam, or
      both for third-generation cephalosporins has been associated with reduced
      vancomycin-resistant enterococci (VRE). However, piperacillin/tazobactam came
      into widespread use during a period in which the prevalence of VRE increased. We
      hypothesized that the increasing use of piperacillin/tazobactam and other agents
      with relatively enhanced anti-enterococcal activity (ie, piperacillin,
      ampicillin/sulbactam, and ampicillin) has been associated with increased or
      unchanged rates of VRE in some hospitals. DESIGN: We retrospectively evaluated
      the correlation between hospital antibiotic use (defined daily doses per 10,000
      patient-days of care) and incidence of stool or non-stool VRE isolation. We
      assessed whether a high or increasing proportion of use of beta-lactam agents
      with relatively enhanced versus minimal (ie, third-generation cephalosporins and
      ticarcillin/clavulanate) anti-enterococcal activity would prevent increased VRE.
      SETTING: Four academic medical centers. RESULTS: With the increasing use of
      piperacillin/tazobactam, the use of beta-lactam agents with enhanced activity
      against enterococci surpassed the combined use of third-generation cephalosporins
      and ticarcillin/clavulanate in each hospital. In one hospital, the incidence of
      VRE was positively correlated with the use of piperacillin/tazobactam or beta
      lactam agents with enhanced anti-enterococcal activity (P < .0001). The incidence
      of VRE rose steadily in another hospital despite relatively high use of beta
      lactam agents with enhanced versus minimal anti-enterococcal activity. A negative
      correlation between VRE and piperacillin/tazobactam or beta-lactam agents with
      enhanced anti-enterococcal activity was observed in one hospital, but this
      correlation was not statistically significant. CONCLUSION: Increasing the
      hospital use of piperacillin/tazobactam and other beta-lactams with relatively
      enhanced anti-enterococcal activity may not be an effective control measure for
      VRE.

PMID- 15188843
TI  - Eradication of a large outbreak of a single strain of vanB vancomycin-resistant
      Enterococcus faecium at a major Australian teaching hospital.
AB  - OBJECTIVE: To demonstrate that nosocomial transmission of vancomycin-resistant
      enterococci (VRE) can be terminated and endemicity prevented despite widespread
      dissemination of an epidemic strain in a large tertiary-care referral hospital.
      INTERVENTIONS: Two months after the index case was detected in the intensive care
      unit, 68 patients became either infected or colonized with an epidemic strain of
      vanB vancomycin-resistant Enterococcus faecium despite standard infection control
      procedures. The following additional interventions were then introduced to
      control the outbreak: (1) formation of a VRE executive group; (2) rapid
      laboratory identification (30 to 48 hours) using culture and polymerase chain
      reaction detection of vanA and vanB resistance genes; (3) mass screening of all
      hospitalized patients with isolation of carriers and cohorting of contacts; (4)
      environmental screening and increased cleaning; (5) electronic flagging of
      medical records of contacts; and (6) antibiotic restrictions (third-generation
      cephalosporins and vancomycin). RESULTS: A total of 19,658 patient and 24,396
      environmental swabs were processed between July and December 2001. One hundred
      sixty-nine patients in 23 wards were colonized with a single strain of vanB
      vancomycin-resistant E. faecium. Introducing additional control measures rapidly
      brought the outbreak under control. Hospital-wide screening found 39 previously
      unidentified colonized patients, with only 7 more nonsegregated patients being
      detected in the next 2 months. The outbreak was terminated within 3 months at a
      cost of dollar 2.7 million (Australian dollars). CONCLUSION: Despite widespread
      dissemination of VRE in a large acute care facility, eradication was achievable
      by a well-resourced, coordinated, multifaceted approach and was in accordance
      with good clinical governance.

PMID- 15188844
TI  - Impact of surveillance for vancomycin-resistant enterococci on controlling a
      bloodstream outbreak among patients with hematologic malignancy.
AB  - OBJECTIVE: To determine the impact of stool surveillance cultures of critically
      ill patients on controlling vancomycin-resistant enterococci (VRE) outbreak
      bacteremia. DESIGN: Stool surveillance cultures were performed on patients who
      had hematologic malignancy or were critically ill at the time of hospital
      admission to identify those colonized with VRE. Hence, contact isolation was
      initiated. SETTING: A tertiary-care cancer center with a high prevalence of VRE.
      PARTICIPANTS: All patients with hematologic malignancy who were admitted to the
      hospital as well as all of those admitted to the intensive care unit were
      eligible. RESULTS: Active stool surveillance cultures performed between 1997 and
      2001 decreased the incidence density of VRE bacteremias eightfold while
      vancomycin use remained constant. In fiscal year (FY) 1997 and FY 1998, there
      were five and three VRE outbreak bacteremias, respectively. The outbreak clones
      were responsible for infection in 69% of those patients with VRE bacteremia.
      However, the stool surveillance program resulted in the complete control of VRE
      bacteremia by FY 1999 until the end of the study. CONCLUSION: Despite the steady
      use of vancomycin, the active surveillance program among high-risk patients with
      hematologic malignancy and those who were critically ill resulted in the complete
      control of VRE outbreak bacteremia at our institution.

PMID- 15188845
TI  - Do infection control measures work for methicillin-resistant Staphylococcus
      aureus?
AB  - OBJECTIVE: To review evidence regarding the effectiveness of control measures in
      reducing transmission of methicillin-resistant Staphylococcus aureus (MRSA) in
      hospitals. DESIGN: Literature review and surveillance cultures of hospitalized
      patients at high risk for MRSA colonization or infection. SETTING: A 500-bed,
      university-affiliated, community teaching hospital. RESULTS: The percentage of
      nosocomial S. aureus infections caused by MRSA increased significantly between
      1982 and 2002, despite the use of various isolation and barrier precaution
      policies. The apparent ineffectiveness of control measures may be due to several
      factors including the failure to identify patients colonized with MRSA. For
      example, cultures of stool specimens submitted for Clostridium difficile toxin
      assays at one hospital found that 12% of patients had MRSA in their stool, and
      41% of patients with unrecognized colonization were cared for without using
      barrier precautions. Other factors include the use of barrier precaution
      strategies that do not account for multiple reservoirs of MRSA, poor adherence of
      healthcare workers (HCWs) to recommended barrier precautions and handwashing,
      failure to identify and treat HCWs responsible for transmitting MRSA, and
      importation of MRSA by patients admitted from other facilities. Control programs
      that include active surveillance cultures (ASCs) of high-risk patients and use of
      barrier precautions have reduced MRSA prevalence rates and have been cost
      effective. Using a staged approach to implementing ASCs can minimize logistic
      problems. CONCLUSION: MRSA control programs are effective if they include ASCs of
      high-risk patients, use of barrier precautions when caring for colonized or
      infected patients, hand hygiene, and treating HCWs implicated in MRSA
      transmission.

PMID- 15188846
TI  - Intervention to reduce the incidence of methicillin-resistant Staphylococcus
      aureus skin infections in a correctional facility in Georgia.
AB  - BACKGROUND AND OBJECTIVE: In August 2001, a cluster of MRSA skin infections was
      detected in a correctional facility. An investigation was conducted to determine
      its cause and to prevent further MRSA infections. DESIGN: Case-control study.
      SETTING: A 200-bed detention center. PATIENTS: A case was defined as a detainee
      with a skin lesion from which MRSA was cultured from July 24 through December 31,
      2001. Case-patients were identified by review of laboratory culture results and
      by skin lesion screening through point-prevalence survey and admission
      examination. Controls were randomly selected from an alphabetized list of
      detainees. INTERVENTION: Medical staff implemented measures to improve skin
      disease screening, personal hygiene, wound care, and antimicrobial therapy.
      RESULTS: Sixteen cases were identified: 11, 5, and 0 in the preintervention, peri
      intervention, and postintervention periods, respectively. Seven case-patients and
      19 controls were included in the case-control study. On multivariable analysis,
      working as a dormitory orderly (OR, 9.8; CI95, 0.74-638; P = .10) and a stay of
      longer than 36 days (OR, 6.9; CI95, 0.65-128.2; P = .14) were the strongest
      predictors for MRSA skin infection. The preintervention, peri-intervention, and
      postintervention MRSA infection rates were 11.6, 8.8, and 0 per 10,000 detainee
      days, respectively. The rate of MRSA skin infections declined significantly
      between both the preintervention and peri-intervention periods and the
      postintervention period (P < .01 for both comparisons). CONCLUSIONS: MRSA skin
      disease can become an emergent problem in a correctional facility. Interventions
      targeted at skin disease screening, appropriate antimicrobial treatment, and
      hygiene may decrease the risk of acquiring MRSA infection in correctional
      facilities.

PMID- 15188847
TI  - Emergence of vancomycin-resistant enterococci in San Francisco Bay area hospitals
      during 1994 to 1998.
AB  - OBJECTIVE: To determine the magnitude of vancomycin-resistant enterococci (VRE)
      in three counties in the San Francisco Bay area. DESIGN: Active laboratory-based
      surveillance for VRE from January 1995 through December 1996 and a laboratory
      based and hospital-based questionnaire survey for 1993 to 1994 and 1997 to 1998.
      SETTING: All 33 general acute care hospitals in three counties in the San
      Francisco Bay area. PARTICIPANTS: Laboratories and infection control
      professionals serving these hospitals, and staff of the California Emerging
      Infections Program. RESULTS: The number of hospitals reporting 1 or more patient
      clinical VRE isolates was 1 (3%) in 1993, 7 (21%) in 1994, 31 (94%) in 1995, and
      33 (100%) in 1996 to 1998. The number of patient isolates increased from 1 in
      1993 to 24 in 1994, 176 in 1995, 429 in 1996, 730 in 1997, and 864 in 1998. Most
      VRE isolates in 1995 and 1996 were from urine and were not associated with
      serious clinical disease. However, the number of isolates from blood increased
      from 9 (6% of total) in 1995 to 44 (12% of the total) in 1996, 90 (14%) in 1997,
      and 100 (13%) in 1998. CONCLUSIONS: Our data document the rapid emergence and
      increase of VRE in all hospitals in three counties in the San Francisco Bay area
      during 1994 to 1998. Infection control measures for VRE together with antibiotic
      utilization programs should be implemented to limit further spread.

PMID- 15188848
TI  - Failure to develop vancomycin-resistant Enterococcus with oral vancomycin
      treatment of Clostridium difficile.
AB  - OBJECTIVE: Oral vancomycin therapy has been a risk factor for turning culture
      positive for vancomycin-resistant Enterococcus (VRE). VRE colonization status was
      reviewed for all patients who received oral vancomycin and underwent prospective
      cultures. METHODS: Data were extracted from the medical records of all patients
      receiving oral vancomycin between August 1995 and February 2001 regarding
      history, hospital course, and perirectal VRE cultures. Hospital policy required
      contact isolation for patients receiving oral vancomycin until colonization with
      VRE was excluded. RESULTS: Twenty-six courses of oral vancomycin were given to 22
      patients. VRE colonization status after completion of therapy was evaluated for
      23 courses in 20 (91%) of these patients. None of these patients became VRE
      culture positive during a median follow-up of 18 days (range, 9 to 39 days), with
      a median duration of treatment of 10 days (range, 3 to 58 days), and with a
      median total dose of 6,500 mg (range, 1,250 to 29,000 mg). All patients received
      other antibiotics within 30 days prior to therapy with oral vancomycin, during
      therapy with oral vancomycin, or both; 95% had received anti-anaerobic therapy
      and 35% had received parenteral vancomycin. CONCLUSIONS: Even when other risk
      factors were present, no patient receiving oral vancomycin at our facility
      subsequently became culture positive for VRE. This suggests that oral vancomycin
      therapy or other antibiotic use, including anti-anaerobic therapy, may not be a
      significant independent risk factor for turning culture positive for VRE among
      patients not previously exposed to the microbe.

PMID- 15188849
TI  - A cost-benefit analysis of gown use in controlling vancomycin-resistant
      Enterococcus transmission: is it worth the price?
AB  - OBJECTIVE: To determine the net benefit and costs associated with gown use in
      preventing transmission of vancomycin-resistant Enterococcus (VRE). DESIGN: A
      cost-benefit analysis measuring the net benefit of gowns was performed. Benefits,
      defined as averted costs from reduced VRE colonization and infection, were
      estimated using a matched cohort study. Data sources included a step-down cost
      allocation system, hospital informatics, and microbiology databases. SETTING: The
      medical intensive care unit (MICU) at Barnes-Jewish Hospital, St. Louis,
      Missouri. PATIENTS: Patients admitted to the MICU for more than 24 hours from
      July 1, 1997, to December 31, 1999. INTERVENTIONS: Alternating periods when all
      healthcare workers and visitors were required to wear gowns and gloves versus
      gloves alone on entry to the rooms of patients colonized or infected with VRE.
      RESULTS: On base-case analysis, 58 VRE cases were averted with gown use during 18
      months. The annual net benefit of the gown policy was dollar 419,346 and the cost
      per case averted of VRE was dollar 1,897. The analysis was most sensitive to the
      level of VRE transmission. CONCLUSIONS: Infection control policies (eg, gown use)
      initially increase the cost of health services delivery. However, such policies
      can be cost saving by averting nosocomial infections and the associated costs of
      treatment. The cost savings to the hospital plus the benefits to patients and
      their families of avoiding nosocomial infections make effective infection control
      policies a good investment.

PMID- 15188850
TI  - Risk factors and costs associated with methicillin-resistant Staphylococcus
      aureus bloodstream infections.
AB  - OBJECTIVES: To compare the cost of hospitalization of patients with methicillin
      resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) versus
      patients with methicillin-sensitive S. aureus (MSSA) BSI, controlling for
      severity of underlying illness; and to identify risk factors associated with MRSA
      BSI. DESIGN: Retrospective case-control study based on medical chart review.
      SETTING: A 640-bed, tertiary-care hospital in Seattle, Washington. PATIENTS: All
      patients admitted to the hospital between January 1, 1997, and December 31, 1999,
      with S. aureus BSI confirmed by culture. RESULTS: Twenty patients with MRSA BSI
      were compared with 40 patients with MSSA BSI. Univariate analysis identified 5
      risk factors associated with MRSA BSI. Recent hospital admission (P = .006) and
      assisted living (P = .004) remained significant in a multivariate model. Costs
      were significantly higher per patient-day of hospitalization for MRSA BSI than
      for MSSA BSI (dollar 5,878 vs dollar 2,073; P = .003). When patients were
      stratified according to severity of illness as measured by the case mix index, a
      difference of dollar 5,302 per patient-day was found between the two groups for
      all patients with a case mix index greater than 2 (P < .001). CONCLUSION: These
      observations suggest that MRSA BSI significantly increases hospitalization costs
      compared with MSSA BSI, even when controlling for the severity of the patient's
      underlying illness. As MRSA BSI was also found to be significantly associated
      with a group of patients who have repeated hospitalizations, such infections
      contribute substantially to the increasing cost of medical care.

PMID- 15188852
TI  - Control of nosocomial acquisition of vancomycin-resistant Enterococcus through
      active surveillance of hemodialysis patients.
AB  - Hemodialysis-dependent patients are an important VRE source. After implementation
      of active surveillance for VRE targeting hemodialysis patients, the hospital-wide
      nosocomial VRE rate increased by 41%, but decreased by 41% among non-hemodialysis
      patients (P = .05). To assess the effectiveness of active surveillance, patients
      undergoing active surveillance should be analyzed separately from other patients.

PMID- 15188851
TI  - Emergence of resistant staphylococci on the hands of new graduate nurses.
AB  - OBJECTIVE: To describe the aerobic microbial flora on the hands of experienced
      and new graduate nurses over time. DESIGN: A prospective cohort design that
      examined the relationship between duration of employment in an intensive care
      unit (ICU) and the microbial flora on the hands of experienced and new graduate
      nurses during a 23-month period. SETTING: A 50-bed, level III-IV neonatal ICU in
      New York City. PARTICIPANTS: Twelve experienced nurses and 9 new graduate nurses
      working full time in the NICU. INTERVENTION: One hundred fifty samples were
      obtained from the clean, dominant hands of the nurses. Cultures were performed at
      baseline and then quarterly for each experienced and new graduate nurse. Baseline
      and final cultures of Staphylococcus epidermidis were further examined using
      pulsed-field gel electrophoresis. RESULTS: At baseline, a significantly larger
      proportion of the experienced nurses had methicillin-resistant, coagulase
      negative staphylococci isolated from their hands compared with the new graduate
      nurses (95% and 33%, respectively; P = .0004). For a second culture, performed 1
      to 4 months later, there were no longer significant differences between the two
      groups (82% and 54%, respectively; P = .12). By the last culture, all
      staphylococcal isolates were methicillin resistant in both groups of nurses; 3
      were methicillin-resistant S. aureus. CONCLUSIONS: Colonization with methicillin
      resistant staphylococci occurred after brief exposure to the hospital
      environment, despite the use of antiseptic hand hygiene agents. Furthermore, at
      final culture, the two groups shared one dominant hospital-acquired strain of S.
      epidermidis.

PMID- 15188853
TI  - Prevalence of and risk factors for nasal colonization with Staphylococcus aureus
      among human immunodeficiency virus-positive outpatients in Singapore.
AB  - We studied the prevalence of and risk factors for Staphylococcus aureus nasal
      colonization in HIV-positive outpatients in Singapore. Overall prevalence was 23%
      (45 of 195), with 3% (6 of 195) being MRSA. Recent antibiotic use and
      hospitalization were independent predictors of MRSA colonization. Isolates were
      genotypically identical to our hospital's inpatient circulating strain.

PMID- 15188854
TI  - Nanostructured surface modification of ceramic-based microelectrodes to enhance
      biocompatibility for a direct brain-machine interface.
AB  - Many different types of microelectrodes have been developed for use as a direct
      Brain-Machine Interface (BMI) to chronically recording single neuron action
      potentials from ensembles of neurons. Unfortunately, the recordings from these
      microelectrode devices are not consistent and often last for only a few weeks.
      For most microelectrode types, the loss of these recordings is not due to failure
      of the electrodes but most likely due to damage to surrounding tissue that
      results in the formation of nonconductive glial-scar. Since the extracellular
      matrix consists of nanostructured microtubules, we have postulated that neurons
      may prefer a more complex surface structure than the smooth surface typical of
      thin-film microelectrodes. We, therefore, investigated the suitability of a nano
      porous silicon surface layer to increase the biocompatibility of our thin film
      ceramic-insulated multisite electrodes. In-vitro testing demonstrated, for the
      first time, decreased adhesion of astrocytes and increased extension of neurites
      from pheochromocytoma cells on porous silicon surfaces compared to smooth silicon
      sufaces. Moreover, nano-porous surfaces were more biocompatible than macroporous
      surfaces. Collectively, these results support our hypothesis that nano-porous
      silicon may be an ideal material to improve biocompatibility of chronically
      implanted microelectrodes. We next developed a method to apply nano-porous
      surfaces to ceramic insulated, thin-film, microelectrodes and tested them in
      vivo. Chronic testing demonstrated that the nano-porous surface modification did
      not alter the electrical properties of the recording sites and did not interfere
      with proper functioning of the microelectrodes in vivo.

PMID- 15188855
TI  - Microelectrode array fabrication by electrical discharge machining and chemical
      etching.
AB  - Wire electrical discharge machining (EDM), with a complementary chemical etching
      process, is explored and assessed as a method for developing microelectrode array
      assemblies for intracortically recording brain activity. Assembly processes based
      on these methods are highlighted, and results showing neural activity
      successfully recorded from the brain of a mouse using an EDM-based device are
      presented. Several structures relevant to the fabrication of microelectrode
      arrays are also offered in order to demonstrate the capabilities of EDM.

PMID- 15188856
TI  - Chronic neural recording using silicon-substrate microelectrode arrays implanted
      in cerebral cortex.
AB  - An important aspect of the development of cortical prostheses is the enhancement
      of suitable implantable microelectrode arrays for chronic neural recording. The
      objective of this study was to investigate the recording performance of silicon
      substrate micromachined probes in terms of reliability and signal quality. These
      probes were found to consistently and reliably provide high-quality spike
      recordings over extended periods of time lasting up to 127 days. In a consecutive
      series of ten rodents involving 14 implanted probes, 13/14 (93%) of the devices
      remained functional throughout the assessment period. More than 90% of the probe
      sites consistently recorded spike activity with signal-to-noise ratios sufficient
      for amplitudes and waveform-based discrimination. Histological analysis of the
      tissue surrounding the probes generally indicated the development of a stable
      interface sufficient for sustained electrical contact. The results of this study
      demonstrate that these planar silicon probes are suitable for long-term recording
      in the cerebral cortex and provide an effective platform technology foundation
      for microscale intracortical neural interfaces for use in humans.

PMID- 15188857
TI  - Evaluation of spike-detection algorithms for a brain-machine interface
      application.
AB  - Real time spike detection is an important requirement for developing brain
      machine interfaces (BMIs). We examined three classes of spike-detection
      algorithms to determine which is best suited for a wireless BMI with a limited
      transmission bandwidth and computational capabilities. The algorithms were
      analyzed by tabulating true and false detections when applied to a set of
      realistic artificial neural signals with known spike times and varying signal to
      noise ratios. A design-specific cost function was developed to score the relative
      merits of each detector; correct detections increased the score, while false
      detections and computational burden reduced it. Test signals both with and
      without overlapping action potentials were considered. We also investigated the
      utility of rejecting spikes that violate a minimum refractory period by occurring
      within a fixed time window after the preceding threshold crossing. Our results
      indicate that the cost-function scores for the absolute value operator were
      comparable to those for more elaborate nonlinear energy operator based detectors.
      The absolute value operator scores were enhanced when the refractory period check
      was used. Matched-filter-based detectors scored poorly due to their relatively
      large computational requirements that would be difficult to implement in a real
      time system.

PMID- 15188858
TI  - On the variability of manual spike sorting.
AB  - The analysis of action potentials, or "spikes," is central to systems
      neuroscience research. Spikes are typically identified from raw waveforms
      manually for off-line analysis or automatically by human-configured algorithms
      for on-line applications. The variability of manual spike "sorting" is studied
      and its implications for neural prostheses discussed. Waveforms were recorded
      using a micro-electrode array and were used to construct a statistically similar
      synthetic dataset. Results showed wide variability in the number of neurons and
      spikes detected in real data. Additionally, average error rates of 23% false
      positive and 30% false negative were found for synthetic data.

PMID- 15188859
TI  - Transmission latencies in a telemetry-linked brain-machine interface.
AB  - To be clinically viable, a brain-machine interface (BMI) requires transcutaneous
      telemetry. Spike-based compression algorithms can be used to reduce the amount of
      telemetered data, but this type of system is subject to queuing-based
      transmission delays. This paper examines the relationships between the ratio of
      output to average input bandwidth of an implanted device and transmission latency
      and required queue depth. The examination was performed with a computer model
      designed to simulate the telemetry link. The input to the model was presorted
      spike data taken from a macaque monkey performing a motor task. The model shows
      that when the output bandwidth/average input bandwidth is in unity, significant
      transmission latencies occur. For a 32-neuron system, transmitting 50 bytes of
      data per spike and with an average neuron firing rate of 8.93 spikes/s, the
      average maximum delay was approximately 3.2 s. It is not until the output
      bandwidth is four times the average input bandwidth that average maximum delays
      are reduced to less than 10 ms. A comparison of neuron firing rate and resulting
      latencies shows that high latencies result from neuron bursting. These results
      will impact the design of transcutaneous telemetry in a BMI.

PMID- 15188860
TI  - Model-based neural decoding of reaching movements: a maximum likelihood approach.
AB  - A new paradigm for decoding reaching movements from the signals of an ensemble of
      individual neurons is presented. This new method not only provides a novel
      theoretical basis for the task, but also results in a significant decrease in the
      error of reconstructed hand trajectories. By using a model of movement as a
      foundation for the decoding system, we show that the number of neurons required
      for reconstruction of the trajectories of point-to-point reaching movements in
      two dimensions can be halved. Additionally, using the presented framework, other
      forms of neural information, specifically neural "plan" activity, can be
      integrated into the trajectory decoding process. The decoding paradigm presented
      is tested in simulation using a database of experimentally gathered center-out
      reaches and corresponding neural data generated from synthetic models.

PMID- 15188861
TI  - Modeling and decoding motor cortical activity using a switching Kalman filter.
AB  - We present a switching Kalman filter model for the real-time inference of hand
      kinematics from a population of motor cortical neurons. Firing rates are modeled
      as a Gaussian mixture where the mean of each Gaussian component is a linear
      function of hand kinematics. A "hidden state" models the probability of each
      mixture component and evolves over time in a Markov chain. The model generalizes
      previous encoding and decoding methods, addresses the non-Gaussian nature of
      firing rates, and can cope with crudely sorted neural data common in on-line
      prosthetic applications.

PMID- 15188862
TI  - Ascertaining the importance of neurons to develop better brain-machine
      interfaces.
AB  - In the design of brain-machine interface (BMI) algorithms, the activity of
      hundreds of chronically recorded neurons is used to reconstruct a variety of
      kinematic variables. A significant problem introduced with the use of neural
      ensemble inputs for model building is the explosion in the number of free
      parameters. Large models not only affect model generalization but also put a
      computational burden on computing an optimal solution especially when the goal is
      to implement the BMI in low-power, portable hardware. In this paper, three
      methods are presented to quantitatively rate the importance of neurons in neural
      to motor mapping, using single neuron correlation analysis, sensitivity analysis
      through a vector linear model, and a model-independent cellular directional
      tuning analysis for comparisons purpose. Although, the rankings are not
      identical, up to sixty percent of the top 10 ranking cells were in common. This
      set can then be used to determine a reduced-order model whose performance is
      similar to that of the ensemble. It is further shown that by pruning the initial
      ensemble neural input with the ranked importance of cells, a reduced sets of
      cells (between 40 and 80, depending upon the methods) can be found that exceed
      the BMI performance levels of the full ensemble.

PMID- 15188863
TI  - Toward a direct brain interface based on human subdural recordings and wavelet
      packet analysis.
AB  - Highly accurate asynchronous detection of movement related patterns in individual
      electrocorticogram channels has been shown using detection based on either event
      related potentials (ERPs) or event-related desynchronization and synchronization
      (ERD/ERS). A method using wavelet-packet features selected with a genetic
      algorithm was proposed to simultaneously detect ERP and ERD/ERS and was tested on
      data from seven subjects and four motor tasks. The proposed wavelet method
      performed better than previous methods with perfect detection for four
      subject/task combinations and hit percentages greater than 90% with false
      positive percentages less than 15% for at least one task for all seven subjects.

PMID- 15188864
TI  - Force field apparatus for investigating movement control in small animals.
AB  - As part of our overall effort to build a closed loop brain-machine interface
      (BMI), we have developed a simple, low weight, and low inertial torque
      manipulandum that is ideal for use in motor system investigations with small
      animals such as rats. It is inexpensive and small but emulates features of large
      and very expensive systems currently used in monkey and human research. Our
      device consists of a small programmable torque-motor system that is attached to a
      manipulandum. Rats are trained to grasp this manipulandum and move it to one or
      more targets against programmed force field perturbations. Here we report several
      paradigms that may be used with this device and results from rat's making
      reaching movements in a variety of force fields. These and other available
      experimental manipulations allow one to experimentally separate several key
      variables that are critical for understanding and ultimately emulating the
      feedforward and feedback mechanisms of motor control.

PMID- 15188865
TI  - Principles of a brain-computer interface (BCI) based on real-time functional
      magnetic resonance imaging (fMRI).
AB  - A brain-computer interface (BCI) based on functional magnetic resonance imaging
      (fMRI) records noninvasively activity of the entire brain with a high spatial
      resolution. We present a fMRI-based BCI which performs data processing and
      feedback of the hemodynamic brain activity within 1.3 s. Using this technique,
      differential feedback and self-regulation is feasible as exemplified by the
      supplementary motor area (SMA) and parahippocampal place area (PPA). Technical
      and experimental aspects are discussed with respect to neurofeedback. The
      methodology now allows for studying behavioral effects and strategies of local
      self-regulation in healthy and diseased subjects.

PMID- 15188866
TI  - An EEG-driven brain-computer interface combined with functional magnetic
      resonance imaging (fMRI).
AB  - Self-regulation of slow cortical potentials (SCPs) has been successfully used to
      prevent epileptic seizures as well as to communicate with completely paralyzed
      patients. The thought translation device (TTD) is a brain-computer interface
      (BCI) that was developed for training and application of SCP self-regulation. To
      investigate the neurophysiological mechanisms of SCP regulation the TTD was
      combined with functional magnetic resonance imaging (fMRI). The technical aspects
      and pitfalls of combined fMRI data acquisition and EEG neurofeedback are
      discussed. First data of SCP feedback during fMRI are presented.

PMID- 15188867
TI  - An exploratory study of factors affecting single trial P300 detection.
AB  - A threshold detector for single-trial P300 detection has been evaluated. The
      detector operates on the 0-4 Hz band, isolated from the raw electroencephalogram
      using low-pass filtering, wavelet transforms, or the piecewise prony method
      (PPM). A detection rate around 70% was found, irregardless of stimulus type,
      interstimulus interval (ISI), probability of occurrence (Pr) of the target
      stimuli, intrasession and intersession effects, or filtering method. This
      suggests that P300-based brain-machine interfaces can use an ISI as short as 1 s
      and a Pr of 45%, to increase throughput.

PMID- 15188868
TI  - An asynchronously controlled EEG-based virtual keyboard: improvement of the
      spelling rate.
AB  - An improvement of the information transfer rate of brain-computer communication
      is necessary for the creation of more powerful and convenient applications. This
      paper presents an asynchronously controlled three-class brain-computer interface
      based spelling device [virtual keyboard (VK)], operated by spontaneous
      electroencephalogram and modulated by motor imagery. Of the first results of
      three able-bodied subjects operating the VK, two were successful, showing an
      improvement of the spelling rate sigma, the number of correctly spelled
      letters/min, up to sigma = 3.38 (average sigma = 1.99).

PMID- 15188869
TI  - Brain-computer interface design for asynchronous control applications:
      improvements to the LF-ASD asynchronous brain switch.
AB  - The low-frequency asynchronous switch design (LF-ASD) was introduced as a direct
      brain-computer interface (BCI) technology for asynchronous control applications.
      The LF-ASD operates as an asynchronous brain switch (ABS) which is activated only
      when a user intends control and maintains an inactive state output when the user
      is not meaning to control the device (i.e., they may be idle, thinking about a
      problem, or performing some other action). Results from LF-ASD evaluations have
      shown promise, although the reported error rates are too high for most practical
      applications. This paper presents the evaluation of four new LF-ASD designs with
      data collected from individuals with high-level spinal cord injuries and able
      bodied subjects. These new designs incorporated electroencephalographic energy
      normalization and feature space dimensionality reduction. The error
      characteristics of the new ABS designs were significantly better than the LF-ASD
      design with true positive rate increases of approximately 33% for false positive
      rates in the range of 1%-2%. The results demonstrate that the dimensionality of
      the LF-ASD feature space can be reduced without performance degradation. The
      results also confirm previous findings that spinal cord-injured subjects can
      operate ABS designs to the same ability as able-bodied subjects.

PMID- 15188871
TI  - Support vector channel selection in BCI.
AB  - Designing a brain computer interface (BCI) system one can choose from a variety
      of features that may be useful for classifying brain activity during a mental
      task. For the special case of classifying electroencephalogram (EEG) signals we
      propose the usage of the state of the art feature selection algorithms Recursive
      Feature Elimination and Zero-Norm Optimization which are based on the training of
      support vector machines (SVM). These algorithms can provide more accurate
      solutions than standard filter methods for feature selection. We adapt the
      methods for the purpose of selecting EEG channels. For a motor imagery paradigm
      we show that the number of used channels can be reduced significantly without
      increasing the classification error. The resulting best channels agree well with
      the expected underlying cortical activity patterns during the mental tasks.
      Furthermore we show how time dependent task specific information can be
      visualized.

PMID- 15188870
TI  - Boosting bit rates in noninvasive EEG single-trial classifications by feature
      combination and multiclass paradigms.
AB  - Noninvasive electroencephalogram (EEG) recordings provide for easy and safe
      access to human neocortical processes which can be exploited for a brain-computer
      interface (BCI). At present, however, the use of BCIs is severely limited by low
      bit-transfer rates. We systematically analyze and develop two recent concepts,
      both capable of enhancing the information gain from multichannel scalp EEG
      recordings: 1) the combination of classifiers, each specifically tailored for
      different physiological phenomena, e.g., slow cortical potential shifts, such as
      the pre-movement Bereitschaftspotential or differences in spatio-spectral
      distributions of brain activity (i.e., focal event-related desynchronizations)
      and 2) behavioral paradigms inducing the subjects to generate one out of several
      brain states (multiclass approach) which all bare a distinctive spatio-temporal
      signature well discriminable in the standard scalp EEG. We derive information
      theoretic predictions and demonstrate their relevance in experimental data. We
      will show that a suitably arranged interaction between these concepts can
      significantly boost BCI performances.

PMID- 15188872
TI  - Brain-computer communication and slow cortical potentials.
AB  - A thought translation device (TTD) has been designed to enable direct brain
      computer communication using self-regulation of slow cortical potentials (SCPs).
      However, accuracy of SCP control reveals high intersubject variability. To
      guarantee the highest possible communication speed, some important aspects of
      training SCPs are discussed. A baseline correction of SCPs can increase
      performance. Multichannel recordings show that SCPs are of highest amplitude
      around the vertex electrode used for feedback, but in some subjects more global
      distributions were observed. A new method for control of eye movement is
      presented. Sequential effects of trial-to-trial interaction may also cause
      difficulties for the user. Finally, psychophysiological factors determining SCP
      communication are discussed.

PMID- 15188873
TI  - Classification of single-trial electroencephalogram during finger movement.
AB  - We present an algorithm to discriminate between the single-trial
      electroencephalograms (EEG) of two different finger movement tasks. The method
      uses a spatio-temporal analysis to classify the EEG recorded during voluntary
      left versus right finger movement tasks. This algorithm produced a classification
      accuracy of 92.1% on the data from five subjects, without requiring subject
      training or data selection. This technique can be employed in an EEG-based brain
      computer interface due to its high recognition rate, insensitivity to noise, and
      simplicity in computation.

PMID- 15188874
TI  - Noninvasive brain-actuated control of a mobile robot by human EEG.
AB  - Brain activity recorded noninvasively is sufficient to control a mobile robot if
      advanced robotics is used in combination with asynchronous electroencephalogram
      (EEG) analysis and machine learning techniques. Until now brain-actuated control
      has mainly relied on implanted electrodes, since EEG-based systems have been
      considered too slow for controlling rapid and complex sequences of movements. We
      show that two human subjects successfully moved a robot between several rooms by
      mental control only, using an EEG-based brain-machine interface that recognized
      three mental states. Mental control was comparable to manual control on the same
      task with a performance ratio of 0.74.

PMID- 15188875
TI  - BCI2000: a general-purpose brain-computer interface (BCI) system.
AB  - Many laboratories have begun to develop brain-computer interface (BCI) systems
      that provide communication and control capabilities to people with severe motor
      disabilities. Further progress and realization of practical applications depends
      on systematic evaluations and comparisons of different brain signals, recording
      methods, processing algorithms, output formats, and operating protocols. However,
      the typical BCI system is designed specifically for one particular BCI method and
      is, therefore, not suited to the systematic studies that are essential for
      continued progress. In response to this problem, we have developed a documented
      general-purpose BCI research and development platform called BCI2000. BCI2000 can
      incorporate alone or in combination any brain signals, signal processing methods,
      output devices, and operating protocols. This report is intended to describe to
      investigators, biomedical engineers, and computer scientists the concepts that
      the BC12000 system is based upon and gives examples of successful BCI
      implementations using this system. To date, we have used BCI2000 to create BCI
      systems for a variety of brain signals, processing methods, and applications. The
      data show that these systems function well in online operation and that BCI2000
      satisfies the stringent real-time requirements of BCI systems. By substantially
      reducing labor and cost, BCI2000 facilitates the implementation of different BCI
      systems and other psychophysiological experiments. It is available with full
      documentation and free of charge for research or educational purposes and is
      currently being used in a variety of studies by many research groups.

PMID- 15188876
TI  - The BCI Competition 2003: progress and perspectives in detection and
      discrimination of EEG single trials.
AB  - Interest in developing a new method of man-to-machine communication--a brain
      computer interface (BCI)--has grown steadily over the past few decades. BCIs
      create a new communication channel between the brain and an output device by
      bypassing conventional motor output pathways of nerves and muscles. These systems
      use signals recorded from the scalp, the surface of the cortex, or from inside
      the brain to enable users to control a variety of applications including simple
      word-processing software and orthotics. BCI technology could therefore provide a
      new communication and control option for individuals who cannot otherwise express
      their wishes to the outside world. Signal processing and classification methods
      are essential tools in the development of improved BCI technology. We organized
      the BCI Competition 2003 to evaluate the current state of the art of these tools.
      Four laboratories well versed in EEG-based BCI research provided six data sets in
      a documented format. We made these data sets (i.e., labeled training sets and
      unlabeled test sets) and their descriptions available on the Internet. The goal
      in the competition was to maximize the performance measure for the test labels.
      Researchers worldwide tested their algorithms and competed for the best
      classification results. This paper describes the six data sets and the results
      and function of the most successful algorithms.

PMID- 15188877
TI  - BCI Competition 2003--Data set Ia: combining gamma-band power with slow cortical
      potentials to improve single-trial classification of electroencephalographic
      signals.
AB  - In one type of brain-computer interface (BCI), users self-modulate brain activity
      as detected by electroencephalography (EEG). To infer user intent, EEG signals
      are classified by algorithms which typically use only one of the several types of
      information available in these signals. One such BCI uses slow cortical potential
      (SCP) measures to classify single trials. We complemented these measures with
      estimates of high-frequency (gamma-band) activity, which has been associated with
      attentional and intentional states. Using a simple linear classifier, we obtained
      significantly greater classification accuracy using both types of information
      from the same recording epochs compared to using SCPs alone.

PMID- 15188878
TI  - BCI Competition 2003--Data sets Ib and IIb: feature extraction from event-related
      brain potentials with the continuous wavelet transform and the t-value scalogram.
AB  - The t-CWT, a novel method for feature extraction from biological signals, is
      introduced. It is based on the continuous wavelet transform (CWT) and Student's t
      statistic. Applied to event-related brain potential (ERP) data in brain-computer
      interface (BCI) paradigms, the method provides fully automated detection and
      quantification of the ERP components that best discriminate between two samples
      of EEG signals and are, therefore, particularly suitable for classification of
      single-trial ERPs. A simple and fast CWT computation algorithm is proposed for
      the transformation of large data sets and single trials. The method was validated
      in the BCI Competition 2003, where it was a winner (provided best classification)
      on two data sets acquired in two different BCI paradigms, P300 speller and slow
      cortical potential (SCP) self-regulation. These results are presented here.

PMID- 15188879
TI  - BCI Competition 2003--Data set IIa: spatial patterns of self-controlled brain
      rhythm modulations.
AB  - A brain-computer interface (BCI) is a system that should in its ultimate form
      translate a subject's intent into a technical control signal without resorting to
      the classical neuromuscular communication channels. By using that signal to,
      e.g., control a wheelchair or a neuroprosthesis, a BCI could become a valuable
      tool for paralyzed patients. One approach to implement a BCI is to let users
      learn to self-control the amplitude of some of their brain rhythms as extracted
      from multichannel electroencephalogram. We present a method that estimates
      subject-specific spatial filters which allow for a robust extraction of the
      rhythm modulations. The effectiveness of the method was proved by achieving the
      minimum prediction error on data set IIa in the BCI Competition 2003, which
      consisted of data from three subjects recorded in ten sessions.

PMID- 15188880
TI  - BCI Competition 2003--Data set IIb: enhancing P300 wave detection using ICA-based
      subspace projections for BCI applications.
AB  - An algorithm based on independent component analysis (ICA) is introduced for P300
      detection. After ICA decomposition, P300-related independent components are
      selected according to the a priori knowledge of P300 spatio-temporal pattern, and
      clear P300 peak is reconstructed by back projection of ICA. Applied to the
      dataset IIb of BCI Competition 2003, the algorithm achieved an accuracy of 100%
      in P300 detection within five repetitions.

PMID- 15188881
TI  - BCI Competition 2003--Data set IIb: support vector machines for the P300 speller
      paradigm.
AB  - We propose an approach to analyze data from the P300 speller paradigm using the
      machine-learning technique support vector machines. In a conservative
      classification scheme, we found the correct solution after five repetitions.
      While the classification within the competition is designed for offline analysis,
      our approach is also well-suited for a real-world online solution: It is fast,
      requires only 10 electrode positions and demands only a small amount of
      preprocessing.

PMID- 15188882
TI  - BCI Competition 2003--Data set III: probabilistic modeling of sensorimotor mu
      rhythms for classification of imaginary hand movements.
AB  - Brain-computer interfaces require effective online processing of
      electroencephalogram (EEG) measurements, e.g., as a part of feedback systems. We
      present an algorithm for single-trial online classification of imaginary left and
      right hand movements, based on time-frequency information derived from filtering
      EEG wideband raw data with causal Morlet wavelets, which are adapted to
      individual EEG spectra. Since imaginary hand movements lead to perturbations of
      the ongoing pericentral mu rhythm, we estimate probabilistic models for amplitude
      modulation in lower (10 Hz) and upper (20 Hz) frequency bands over the
      sensorimotor hand cortices both contra- and ipsilaterally to the imagined
      movements (i.e., at EEG channels C3 and C4). We use an integrative approach to
      accumulate over time evidence for the subject's unknown motor intention.
      Disclosure of test data labels after the competition showed this approach to
      succeed with an error rate as low as 10.7%.

PMID- 15188883
TI  - BCI Competition 2003--Data set IV: an algorithm based on CSSD and FDA for
      classifying single-trial EEG.
AB  - This paper presents an algorithm for classifying single-trial
      electroencephalogram (EEG) during the preparation of self-paced tapping. It
      combines common spatial subspace decomposition with Fisher discriminant analysis
      to extract features from multichannel EEG. Three features are obtained based on
      Bereitschaftspotential and event-related desynchronization. Finally, a perceptron
      neural network is trained as the classifier. This algorithm was applied to the
      data set (self-paced 1s) of "BCI Competition 2003" with a classification accuracy
      of 84% on the test set.

PMID- 15188884
TI  - Antimicrobial peptides derived from heme-containing proteins: hemocidins.
AB  - Deprived of heme and partially unfolded hemoglobin, myoglobin and cytochrome c
      display microbicidal activity against a broad spectrum of microorganisms with
      half maximal lethal dose estimated at micromolar concentrations. The intact
      proteins were ineffective. Antibacterial activity of these apohemoproteins was
      also sustained after digestion to approximately 50 amino acids long peptides but
      further fragmentation abolished microbicidal properties. The most active fragment
      of apomyoglobin (corresponding to 56-131 region) showed a pronounced effect on
      the E. coli membrane permeabilization and its action was sensitive to salt as
      well as to divalent cations concentrations. The membrane-directed effect was
      specific toward bacteria but no lipopolysaccharide binding properties were
      observed. No hemolytic properties, even at high peptide concentrations were
      found; however, a slight but dose-independent cytotoxic effect was observed on
      fibroblasts and hepatoma cells. The presented data suggest a 'carpet-like'
      mechanism of the membrane-directed activity and may result from exceptional
      abilities of hemoprotein-derived peptides to form alpha-helical structures. We
      postulate that the antimicrobial peptides obtained from the heme-containing
      proteins should be named hemocidins, in contrast to, e.g., hemorphins displaying
      opioid-like activity.

PMID- 15188885
TI  - Cycloheximide-induced inhibition of chitin synthesis, and decay of apical
      vesicles and chitosomes in Phycomyces blakesleeanus.
AB  - Addition of cycloheximide rapidly inhibited protein synthesis in Phycomyces
      blakesleeanus. In contrast, chitin biosynthesis decreased with biphasic kinetics
      displaying a slow and a rapid decay phases. Electron microscopic studies revealed
      a decrease in the number of apical vesicles and chitosomes after cycloheximide
      addition; and no change in wall thickness. It is proposed that the slow phase of
      decay in chitin biosynthesis represents the exhaustion of the pool of chitosomes
      which transport the chitin synthase necessary to maintain apical wall growth;
      whereas the second one corresponds to inactivation of the enzyme, which is short
      lived in vivo. Data also rule out a change in the polarization of wall synthesis
      induced by cycloheximide, as suggested in other systems.

PMID- 15188886
TI  - Purification and characterization of an acid phosphatase from the commercial
      mushroom Agaricus bisporus.
AB  - Acid phosphatase [AP; EC 3.1.3.2], a key enzyme involved in the synthesis of
      mannitol in Agaricus bisporus, was purified to homogeneity and characterized. The
      native enzyme appeared to be a high molecular weight type glycoprotein. It has a
      molecular weight of 145 kDa and consists of four identical 39-kDa subunits. The
      isoelectric point of the enzyme was found at 4.7. Maximum activity occurred at 65
      degrees C. The optimum pH range was between 3.5 and 5.5, with maximum activity at
      pH 4.75. The enzyme was unaffected by EDTA, and inhibited by tartrate and
      inorganic phosphate. The enzyme exhibits a Km for p-nitrophenylphosphate and
      fructose-6-phosphate of 370 microM and 3.1 mM, respectively. A broad substrate
      specificity was observed with significant activities for fructose-6-phosphate,
      glucose-6-phosphate, mannitol-1-phosphate, AMP and beta-glycerol phosphate. Only
      phosphomonoesters were dephosphorylated. Antibodies raised against the purified
      enzyme could precipitate AP activity from a cell-free extract in an anticatalytic
      immunoprecipitation test.

PMID- 15188887
TI  - Saccharomyces bulderi sp. nov., a yeast that ferments gluconolactone.
AB  - An unknown yeast species was isolated from maize silage and was determined to be
      novel on the basis of morphological and physiological characteristics, nucleotide
      sequence of domain D1/D2 of LSU rDNA and from its electrophoretic karyotype. The
      name for the proposed new species is Saccharomyces bulderi Middelhoven, Kurtzman
      et Vaughan-Martini (type strain CBS 8638, NRRL Y-27203, DBVPG 7127). S. bulderi
      is closely related to S. barnettii and S. exiguus from which it can be
      distinguished by having a double vitamin requirement of biotin and thiamine and
      by no or slow aerobic growth on raffinose, a sugar that on the contrary is
      fermented rapidly. Gluconolactone is rapidly fermented with ethanol, glycerol and
      carbon dioxide being the main products.

PMID- 15188888
TI  - Hydrolysis of RNA monomers by extracts of Aspergillus niger NRRL3.
AB  - Extracts of Aspergillus niger NRRL3 catalyzed dephosphorylation of AMP, GMP, CMP
      and UMP over a wide range of pH values from pH 1.5 to pH 10. They also catalyzed
      hydrolytic deamination of only cytidine out of the tested ribonucleotides,
      ribonucleosides and bases. Neither cleavage of the N-glycosidic linkages of these
      nucleotides nor those of the corresponding nucleosides could be effected by the
      extracts. Phosphate liberation from the four RNA monomers seemed to be effected
      by two phosphate-non repressible phosphatases, acid and alkaline. Optimum
      activity of the acid phosphatase with all the substrates was at pH2 and 40
      degrees C while that of the alkaline phosphatase was at pH8 and 40 degrees-70
      degrees C. Affinities of both phosphatases for the different ribonucleotides were
      in the order of magnitude AMP, CMP and phph > GMP > UMP. Freezing and thawing of
      the extracts had no effect either on the activities of two phosphatases or on
      that of the aminohydrolase. However, heating the extracts at 55 degrees for 25
      min, in absence of the substrate, inactivated the phosphatases and had no effect
      on the deaminase. No evidence for the involvement of specific nucleotidases in
      ribonucleotides dephosphorylation was recorded.

PMID- 15188889
TI  - Phylogenetic analysis of newly described Neosartorya species.
AB  - Isolates representing newly described Neosartorya species, and isolates with
      abnormal morphologies from Aspergillus section Fumigati were examined by
      phylogenetic analysis of sequences of part of their beta-tubulin gene.
      Phylogenetic analyses supported the earlier suggestions that heterothallism is a
      derived character, and that sexuality was lost several times during the evolution
      of Aspergillus section Fumigati. The heterothallic N. fennelliae and N. udagawae
      strains were found to be closely related to the homothallic Neosartorya sp. NRRL
      4179 and N. aureola, respectively. Aspergillus sp. FRR 1266, which was earlier
      described as a variant of A. fumigatus, was found to be closely related to A.
      viridinutans. Another abnormal asexual isolate was found to be closely related to
      A. fumigatus and N. fischeri. Phylogenetic relationships among newly described
      Neosartorya species and other taxa were successfully established based on
      phylogenetic analysis of beta-tubulin sequences.

PMID- 15188890
TI  - Features of dnaK operon genes of the obligate thermophile Bacillus
      thermoglucosidasius KP1006.
AB  - The dnaK gene was cloned from the obligate thermophile Bacillus
      thermoglucosidasius KP1006, together with the grpE and dnaJ genes in the same
      operon. The dnaK, grpE and dnaJ genes showed high identity with those of other
      bacterial strains, particularly with those of Bacillus stearothermophilus NUB36,
      despite an extremely low homology for the corresponding total genomic DNA. There
      were significant differences in the proline content of the DnaK operon proteins
      which is closely correlated with the thermostability of enzyme proteins. The
      proline content was higher in the GrpE, DnaK and DnaJ proteins of the
      thermophilic as opposed to the mesophilic strains. The overexpression of the B.
      thermoglucosidasius DnaK protein in Escherichia coli MV1184 results in extreme
      filamentation without inhibition on cell growth. The B. thermoglucosidasius DnaK
      protein seemed to exclusively disturb septation in E. coli cells which suggests
      that it interacts with key protein(s) involved in cell septation.

PMID- 15188891
TI  - Isolation and characterization of alkaliphilic, chemolithoautotrophic, sulphur
      oxidizing bacteria.
AB  - Alkaliphilic sulphur-oxidizing bacteria were isolated from samples from alkaline
      environments including soda soil and soda lakes. Two isolates, currently known as
      strains AL 2 and AL 3, were characterized. They grew over a pH range 8.0-10.4
      with an optimum at 9.5-9.8. Both strains could oxidize thiosulphate, sulphide,
      polysulphide, elemental sulphur and tetrathionate. Strain AL 3 more actively
      oxidized thiosulphate and sulphide, while isolate AL 2 had higher activity with
      elemental sulphur and tetrathionate. Isolate AL 2 was also able to oxidize
      trithionate. The pH optimum for thiosulphate and sulphide oxidation was between 9
      10. Some activity remained at pH 11, but was negligible at pH 7. Metabolism of
      tetrathionate by isolate AL 2 involved initial anaerobic hydrolysis to form
      sulphur, thiosulphate and sulphate in a sequence similar to that in other
      colourless sulphur-oxidizing bacteria. Sulphate was produced by both strains.
      During batch growth on thiosulphate, elemental sulphur and sulphite transiently
      accumulated in cultures of isolates AL 2 and AL 3, respectively. At lower pH
      values, both strains accumulated sulphur during sulphide and thiosulphate
      oxidation. Both strains contained ribulose bisphosphate carboxylase. Thiosulphate
      oxidation in isolate AL 3 appeared to be sodium ion-dependent. Isolate AL 2
      differed from AL 3 by its high GC mol % value (65.5 and 49.5, respectively),
      sulphur deposition in its periplasm, the absence of carboxysomes, lower sulphur
      oxidizing capacity, growth kinetics (lower growth rate and higher growth yield)
      and cytochrome composition.

PMID- 15188892
TI  - Ammonium and methylammonium uptake in a fertilizer-degrading strain of
      Ochrobactrum anthropi.
AB  - The transport of ammonium and methylammonium was studied in a strain of
      Ochrobactrum anthropi, a microorganism isolated from garden soil and able to
      degrade methyleneureas which are used as slow-release nitrogen fertilizer. The
      activity of both transport systems was determined using [14C]methylammonium.
      Differences between the two transport systems were observed with regard to their
      pH- and temperature dependence as well as their kinetic parameters and regulation
      during growth with various nitrogen sources. Ammonium transport was subject to
      repression by ammonium and to derepression in its absence, while the
      methylammonium carrier was induced in the presence of methylamine. The ammonium
      but not the methylammonium transport system was severely inhibited by ammonium,
      and metabolic poisons inhibited both uptake systems. The analysis of
      intracellular metabolites using thin-layer chromatography and matrix-assisted
      laser desorption/ionisation time-of-flight mass spectrometry indicated that
      methylammonium was rapidly metabolized to N-methylglutamate via gamma-N
      methylglutamine.

PMID- 15188893
TI  - Overexpression, purification and immunodetection of DsrD from Desulfovibrio
      vulgaris Hildenborough.
AB  - Dissimilatory sulfite reductase (DsrAB) of the sulfate-reducing bacterium
      Desulfovibrio vulgaris Hildenborough is an alpha2beta2 tetramer of 180 kDa,
      encoded by the dsr operon. In addition to the dsrA and dsrB genes, this operon
      contains a gene (dsrD) encoding a protein of only 78 amino acids. Although, the
      function of DsrD is currently unknown, the presence of a dsrD gene has been
      demonstrated in a variety of sulfate-reducing bacteria and archaea. DsrD was
      expressed in Escherichia coli at a very high level and purified to homogeneity.
      Protein blotting experiments, using antisera raised against purified DsrD,
      demonstrated that it is expressed constitutively in D. vulgaris and does not
      copurify with DsrAB. Spectroscopic analysis of DsrD indicated that it does not
      bind either sulfite or sulfide, the substrate and product, respectively of the
      reaction catalyzed by DsrAB. Thus, although the conservation of this protein and
      its demonstrated presence in D. vulgaris, suggest an essential function in
      dissimilatory sulfite reduction, this function remains to be elucidated.

PMID- 15188894
TI  - Adaptation of methane formation and enzyme contents during growth of
      Methanobacterium thermoautotrophicum (strain deltaH) in a fed-batch fermentor.
AB  - During growth of Methanobacterium thermoautotrophicum in a fed-batch fermentor,
      the cells are confronted with a steady decrease in the concentration of the
      hydrogen energy supply. In order to investigate how the organism responds to
      these changes, cells collected during different growth phases were examined for
      their methanogenic properties. Cellular levels of the various methanogenic
      isoenzymes and functionally equivalent enzymes were also determined. Cells were
      found to maintain the rates of methanogenesis by lowering their affinity for
      hydrogen: the apparent Km(H2) decreased in going from the exponential to the
      stationary phase. Simultaneously, the maximal specific methane production rate
      changed. Levels of H2-dependent methenyl-tetrahydromethanopterin dehydrogenase
      (H2-MDH) and methyl coenzyme M reductase isoenzyme II (MCR II) decreased upon
      entry of the stationary phase. Cells grown under conditions that favored MCR II
      expression had higher levels of MCR II and H2-MDH, whereas in cells grown under
      conditions favoring MCR I, levels of MCR II were much lower and the cells had an
      increased affinity for hydrogen throughout the growth cycle. The use of
      thiosulfate as a medium reductant was found to have a negative effect on levels
      of MCR II and H2-MDH. From these results it was concluded that M.
      thermoautotrophicum responds to variations in hydrogen availability and other
      environmental conditions (pH, growth temperature, medium reductant) by altering
      its physiology. The adaptation includes, among others, the differential
      expression of the MDH and MCR isoenzymes.

PMID- 15188895
TI  - Emendation of the basidiomycetous yeast genus Kondoa and the description of
      Kondoa aeria sp. nov.
AB  - The genus Kondoa Y. Yamada, Nakagawa & Banno was erected to accommodate a single
      taxon, K. malvinella (Fell & Hunter) Y. Yamada, Nakagawa & Banno, which was
      transferred from the teliospore-forming genus Rhodosporidium Banno based on
      pronounced differences in the 5S and 26S ribosomal RNA (rRNA) nucleotide
      sequences to R. toruloides Banno. In contrast with the original description,
      reinvestigation of K. malvinella revealed the formation of transversely septate
      (auricularioid) basidia that did not arise on teliospores, but formed directly on
      the dikaryotic mycelium. The four-celled basidia developed sterigmata on which
      forcibly discharged asymmetric basidiospores (ballistospores) were produced.
      Additionally, a new taxon emerged from the study of recent isolates, for which
      the name K. aeria sp. nov. is proposed. This new species produced two-celled
      auricularioid basidia on hyphae with incomplete clamp connections. Ballistospores
      arose on the basidia at the tip of sterigmata and, after ejection, germinated by
      budding. These observations led us to present an emended diagnosis for the genus
      Kondoa. Analysis of the sequence data from the D1/D2 region of the 26S rRNA gene
      showed a very close resemblance between K. aeria and K. malvinella in a cluster
      that also contained several Bensingtonia species. Taxa in this cluster share
      specific physiological traits and produce characteristic pinkish-cream to mauve
      colonies; in contrast, formation of ballistoconidia is only observed in the
      Bensingtonia species. Sequence data supported placement of K. malvinella and K.
      aeria in the 'Agaricostilbum clade' of the Urediniomycetes.

PMID- 15188896
TI  - Total and corneal optical aberrations induced by laser in situ keratomileusis for
      hyperopia.
AB  - PURPOSE: To evaluate changes induced by standard laser in situ keratomileusis
      (LASIK) for hyperopia on total and corneal optical quality. METHODS: Total and
      corneal aberrations were measured before and after standard hyperopic LASIK in 13
      eyes (preoperative spherical equivalent refractive error +3.17 +/- 1.10 D). The
      Chiron Technolas 217C laser with PlanoScan was used. Total aberrations (measured
      using laser ray tracing) and corneal aberrations (estimated from a
      videokeratoscope) were described using Zernike terms. Root-mean-square wavefront
      error for both total and corneal aberrations, and through-focus Strehl ratio for
      the point spread function of the whole eye were used to assess optical changes
      induced by surgery. RESULTS: Third and higher order aberrations increased
      significantly after hyperopic LASIK (by a factor of 2.20 for total and 1.78 for
      corneal aberrations, for a 6.5-mm pupil). Spherical aberration changed to
      negative values (corneal average decreased by -0.85 +/- 0.48 microm and total
      average by -0.70 +/- 0.30 microm). Best Strehl ratio for the whole eye decreased
      by a factor of 1.84. Hyperopic LASIK induced larger changes than myopic LASIK,
      compared to an equivalent group of myopic eyes from a previous study. Induced
      corneal spherical aberration was six times larger after hyperopic LASIK, for a
      similar range of correction, and of opposite sign. As with myopic LASIK, changes
      in internal spherical aberration are of opposite sign to those induced on the
      corneal anterior surface. CONCLUSIONS: Hyperopic LASIK induced significant
      amounts of aberrations. The largest increase occurred in spherical aberration,
      which showed a shift (toward negative values) of opposite sign; increase was
      greater than for myopic LASIK.

PMID- 15188897
TI  - Prospective, randomized, paired comparison of laser epithelial keratomileusis and
      photorefractive keratectomy for myopia less than -6.50 diopters.
AB  - PURPOSE: We compared predictability, efficacy, safety, and patient satisfaction
      following laser epithelial keratomileusis (LASEK) and photorefractive keratectomy
      (PRK) for low to moderate myopia with either the Nidek EC-5000 excimer laser or
      the Technolas 217C excimer laser. METHODS: Forty-two patients with spherical
      equivalent refraction in the range -1.00 to -6.50 D were enrolled in this
      prospective study, each randomized for choice and sequence of LASEK and PRK on
      each of their eyes. Patients were examined daily for 7 days, and at 1 and 3
      months. Patient satisfaction and quality of vision were assessed using a
      subjective questionnaire. RESULTS: Mean baseline refraction was -3.57 +/- 1.25 D
      in LASEK eyes and -3.44 +/- 1.13 D in PRK eyes. Follow-up rates were 100% up to 1
      month and 76% at 3 months. At 3 months, 32 (100%) of LASEK eyes and 31 (97%) of
      PRK eyes had uncorrected visual acuity > or = 20/40, 25 (79%) of LASEK eyes and
      26 (82%) of PRK eyes had uncorrected visual acuity > or = 20/20, mean refraction
      was 0.08 +/- 0.53 D in LASEK eyes and 0.12 +/- 0.50 D in PRK eyes, 26 (81%) of
      LASEK eyes and 23 (72%) of PRK eyes had a refraction within +/- 0.50 D and 29
      (91%) of LASEK eyes and 30 (94%) of PRK eyes had refraction within +/- 1.00 D.
      Epithelial healing time and pain in LASEK and PRK eyes were not statistically
      different, and patients were equally satisfied. CONCLUSION: LASEK had similar
      predictability, efficacy, safety, and patient satisfaction to PRK in the
      treatment of low to moderate myopia.

PMID- 15188898
TI  - Prospective, paired comparison of laser in situ keratomileusis and laser
      epithelial keratomileusis for myopia less than -6.00 diopters.
AB  - PURPOSE: To compare visual and refractive results, contrast sensitivity, and tear
      stability after laser in situ keratomileusis (LASIK) in one eye and laser
      epithelial keratomileusis (LASEK) in the fellow eye for low myopia. METHODS:
      Patients diagnosed with low myopia, with a maximum difference of 1 D between
      their two eyes, were randomly assigned to receive LASEK on one eye and LASIK on
      the other eye. A total of 64 eyes of 32 patients with a mean age of 26.83 +/-
      5.33 years were included in the study. Preoperative myopia ranged from -1.00 to 
      6.00 D. Follow-up was 6 to 12 months. Uncorrected (UCVA) and best spectacle
      corrected visual acuity (BSCVA), Schirmer test results, tear break-up time,
      corneal asphericity, corneal uniformity index, predicted corneal acuity, and
      contrast sensitivity values were compared with preoperative values. A Wilcoxon
      test was used for statistical comparisons and a P-value less than .05 was
      considered significant. RESULTS: At 6 months after surgery, there was no
      statistically significant difference in UCVA, BSCVA, spherical and cylindrical
      refractive error, Schirmer test, or tear break-up time between groups. Contrast
      sensitivity values in the LASIK eyes were lower in comparison to preoperative
      values, but there was no change in the LASEK group. CONCLUSIONS: Based on 6-month
      results, LASEK for low myopia was safe and effective with predictable results,
      offered early refractive stability, and may be considered an alternative for
      LASIK.

PMID- 15188899
TI  - Recovery of corneal sensitivity to mechanical and chemical stimulation after
      laser in situ keratomileusis.
AB  - PURPOSE: To evaluate the time course of changes in corneal sensitivity to
      mechanical and chemical stimuli produced by laser in situ keratomileusis (LASIK)
      in humans. METHODS: We performed a cross-sectional study of 17 LASIK-operated
      eyes (VisX S2, equipped with version 2.50-3.10 software) and 15 control eyes of
      17 individuals to evaluate regeneration of corneal sensitivity after LASIK. Gas
      pulses of variable flow and compositions were applied to the cornea by a non
      contact gas esthesiometer. Mechanical stimuli consisted of air puffs at flows
      from 0 to 200 ml/min. Chemical stimulation was made with gas pulses containing 0%
      to 80% CO2 in air at subthreshold flow. Mechanical and chemical thresholds and
      intensity-response curves for the evoked sensations were determined prior to
      surgery, and 7 to 9 days, 3 to 5 months, and 1.5 to 2.5 years after surgery.
      RESULTS: Corneal sensitivity to mechanical stimulation was enhanced 7 to 9 days
      after surgery but subsequently dropped markedly and remained significantly below
      control levels 3 to 5 months after LASIK. Sensitivity to both mechanical and
      chemical types of stimuli was close to normal 2 years postoperatively.
      CONCLUSIONS: Corneal sensitivity decreased immediately after LASIK but mechanical
      sensitivity showed a transient hyperesthesia 7 to 9 days afterward. Subsequently,
      a long-lasting and deep hypoesthesia to mechanical and chemical stimuli was
      observed. Gas esthesiometry revealed that disturbances of corneal sensation still
      exist at times when coarse mechanical sensitivity appeared to be normal.

PMID- 15188901
TI  - Wavefront analysis of higher order aberrations in dry eye patients.
AB  - PURPOSE: To compare ocular wavefront aberrations of normal and dry eyes and to
      describe the characteristics of higher order aberration in dry eyes. METHODS:
      Wavefront analysis of higher order ocular aberrations (total S3+4+5, spherical
      like S4, coma-like S3+5) was performed with a Hartmann-Shack aberrometer in 20
      dry eyes and 20 normal control eyes. RESULTS: Total, spherical-like, and coma
      like aberrations were significantly greater in dry eyes than in normal controls
      (P < .01) both for a 4-mm (total S3+4: factor of 2.58; spherical S4: factor of
      2.50; coma S3: factor of 2.70) and 6-mm-diameter pupil (S3+4+5: factor of 2.29,
      S4: x2.53, and S3+5: factor of 2.40). CONCLUSIONS: Eyes of dry eye patients
      showed greater optical aberrations compared with normal control eyes. Increase in
      higher order aberrations in dry eyes resulted from increased tear film
      irregularity.

PMID- 15188900
TI  - Diurnal fluctuation of higher order ocular aberrations: correlation with
      intraocular pressure and corneal thickness.
AB  - PURPOSE: Optimal wavefront-guided refractive corneal laser surgery requires
      sufficiently exact data of optical higher order aberrations. We investigated
      whether these aberrations had a systematic during-the-day variation, studied the
      range of variation, and changes in intraocular pressure and central corneal
      thickness. METHODS: In 22 eyes of 22 young volunteers the optical aberrations of
      higher order were measured by means of a Tscherning-type ocular aberrometer three
      times during one day (7 AM, 12 noon, 4 PM). In addition, in 12 of these eyes the
      intraocular pressure and central corneal thickness were measured. The intraocular
      wavefront aberration was computed using Zernike polynomials up to the sixth
      order, and Zernike coefficients of third and fourth order were analyzed. RESULTS:
      Only the coefficient Z 2/4 (C13) showed a significant increase during the day by
      a mean 0.016 microm. A significant regression could be detected between changes
      of coefficients Z3/3, Z-2/4, Z0/4, Z4/4, and changes of intraocular pressure or
      central corneal thickness during the day. CONCLUSIONS: Due to the small values,
      the measured during-the-day changes of higher order aberrations had no direct
      practical consequences for the aberrometry-guided corneal laser surgery.
      Alterations of some Zernike coefficients during the day may be explained by the
      biomechanical behavior of the cornea.

PMID- 15188902
TI  - Comparison of the Colvard pupillometer and the Zywave for measuring scotopic
      pupil diameter.
AB  - PURPOSE: To evaluate the accuracy and repeatability of two pupillometers.
      METHODS: Two pupillometers, the Colvard and Zywave, were used to measure scotopic
      pupil diameter for 64 consecutive patients. Accuracy and repeatability were
      assessed by two independent examiners and statistical analysis was performed
      using the comparison method described by Bland and Altman. RESULTS: Mean scotopic
      pupil diameter was 5.96 +/- 0.69 mm with the Colvard pupillometer and 5.77 +/-
      0.85 mm with the Zywave. The difference between the Colvard and Zywave
      measurements was 0.21 +/- 0.56 mm (P < .001). The coefficient of interrater
      repeatability was smaller for the Colvard (0.59) than for the Zywave (1.17). The
      mean difference between the pupillometers for each examiner was 0.17 +/- 0.47 mm
      (P < .01) for examiner 1 and 0.26 +/- 0.64 mm (P < .01) for examiner 2.
      CONCLUSIONS: Scotopic pupil diameter measured with the Zywave was statistically
      but not clinically significantly smaller than that measured with the Colvard
      pupillometer. The Zywave produced an inter-rater repeatability comparable to
      other devices although not as good as the Colvard pupillometer.

PMID- 15188903
TI  - Holmium laser thermal keratoplasty for hyperopia in eyes overcorrected with laser
      in situ keratomileusis for myopia.
AB  - PURPOSE: To assess the efficacy and safety of holmium laser thermal keratoplasty
      (Ho:LTK) for hyperopia in eyes overcorrected after laser in situ keratomileusis
      (LASIK) for myopia. METHODS: We performed a prospective evaluation of Ho:LTK in
      eyes with secondary hyperopia from +1.00 to +5.50 D after LASIK. Thirty-seven
      eyes of 23 patients received one concentric 8-spot application at the 6-mm
      diameter zone. Mean patient age was 41.3 +/- 13.0 years (range 20 to 68 yr). Mean
      corneal thickness was 455.86 +/- 31.20 microm (range 373 to 506 microm). RESULTS:
      Mean spherical equivalent refraction changed from +2.30 +/- 1.08 D to +0.45 +/-
      1.00 D at 12 months after Ho:LTK. Thirty-one eyes (84%) were within +/- 1.00 D of
      emmetropia and 25 eyes (68%) were within +/- 0.50 D at 1 year. Mean change in
      refraction was 1.84 +/- 0.92 D. No eye lost 2 lines of best spectacle-corrected
      visual acuity. CONCLUSIONS: Ho:LTK is a suitable alternative for correcting
      secondary hyperopia resulting from LASIK for myopia. Parameter adjustments may be
      necessary for improving the results.

PMID- 15188904
TI  - Flap quality in single versus multiple use of the same blade in the Flapmaker
      microkeratome.
AB  - PURPOSE: We evaluated experimentally the variability of cut thickness, flap
      diameter, and cut quality produced by the Flapmaker corneal microkeratome
      (IOLTech), with single and repeated use of the same cutting blade. METHODS:
      Keratectomy was performed with twelve cutting heads (8.5-mm diameter, 160-microm
      cutting depth) on 47 corneas and with six cutting heads (8.0-mm diameter, 180
      microm cutting depth) on 18 freshly enucleated swine eyes in a repeated manner.
      Ultrasonic pachymetry was determined at the initial, central, and final
      microkeratome pass zones, first before the flap was created and subsequently
      after the flap was reflected. Flap diameter was measured by planimetry. After the
      procedure stromal portions were submitted for scanning electron microscopy.
      RESULTS: On the first blade use, mean central flap thickness was 145 +/- 32
      microm and mean vertical flap diameter was 8.4 +/- 0.26 mm with the 8.5-mm
      blades. With the 8.0-mm blades, mean central flap thickness was 155 +/- 23 microm
      and mean vertical flap diameter was 8.0 +/- 0.27 mm. Scanning electron microscopy
      disclosed smooth cut surfaces when new blades were used, but with repeated blade
      use, increasingly prominent stromal bed folds were observed. CONCLUSIONS: The
      evaluated blades produced reproducible flap size and thickness and good cut
      quality with single use, but after the first use, cut quality markedly
      deteriorated. Repeated use of Flapmaker cutting blades is not recommended.

PMID- 15188905
TI  - Outcomes of laser in situ keratomileusis in a Refractive Surgery fellowship
      program.
AB  - PURPOSE: The purpose of this study was to document the learning curve and
      evaluate the success of laser in situ keratomileusis (LASIK) performed by fellows
      in a Cornea/External Disease and Refractive fellowship program. METHODS: Two
      surgeons performed LASIK within a fellowship training program between July 2000
      and August 2001. A retrospective review was conducted to determine the visual
      outcomes and operative complications from this non-comparative case series of 755
      consecutive eyes. All LASIK procedures were performed using a Bausch & Lomb
      Technolas 217A laser and the Bausch & Lomb Hansatome or the Automated Corneal
      Shaper microkeratome. All eyes were evaluated for operative complications. Visual
      acuity was reported with a minimum of 1 month follow-up. RESULTS: Data analysis
      revealed that uncorrected visual acuity of 20/40 or better was attained in 99.4%
      of treated eyes, and 20/20 or better in 77.2%. With both eyes open, 100% of
      patients saw 20/30 or better, 94% saw 20/20 or better, 70% saw 20/15 or better,
      and 5.5% saw 20/10. Flap related complications occurred in 7 of 755 eyes (0.9%)
      and all were successfully treated. Forty-two eyes (5.6%) were lost to follow-up
      prior to the 1-month examination and were excluded from analysis of visual
      acuity. CONCLUSIONS: Favorable operative and visual acuity 1-month results in 755
      eyes after LASIK with the Bausch & Lomb Technolas 217A laser were in part due to
      a well organized system of education, patient examination, execution of surgery,
      and postoperative care. A team approach was essential.

PMID- 15188906
TI  - Ocular surface treatment before laser in situ keratomileusis in patients with
      severe dry eye.
AB  - PURPOSE: To evaluate the efficacy and safety of laser in situ keratomileusis
      (LASIK) in patients with severe dry eye associated with Sjogren's syndrome.
      METHODS: Three patients (six eyes) with Sjogren's syndrome who underwent
      bilateral LASIK were retrospectively evaluated for visual outcome, intraoperative
      and postoperative complications, dry eye status (subjective symptoms and
      objective findings, Schirmer test, vital staining of the ocular surface), and
      outcome satisfaction by subjective questionnaire. All patients had negative
      reflex tearing and were treated with topical autologous serum and/or punctal
      occlusion prior to LASIK to improve the ocular surface. This treatment was
      continued postoperatively. RESULTS: Mean attempted correction of six eyes was 
      8.46 +/- 1.55 D (range -7.00 to -10.63 D). One year after LASIK, mean uncorrected
      visual acuity was 1.07 (range 0.7 to 1.5), mean best spectacle-corrected visual
      acuity was 1.29 (range 1.2 to 1.5), and mean refraction was -0.19 +/- 0.51 D
      (range -1.00 to +0.50 D). Tear production, rose bengal and fluorescein staining,
      and dry eye symptoms were not exacerbated after LASIK. No complications, such as
      intraoperative epithelial defect, diffuse lamellar keratitis, epithelial
      ingrowth, or recurrent erosion occurred. All three patients were satisfied with
      the outcome of their surgery. CONCLUSION: LASIK can be safely and effectively
      managed in patients with severe dry eye with reduced reflex tearing by
      preoperative and postoperative treatments consisting of a combination of
      artificial tears, topical autologous serum, and punctal occlusion. Careful
      assessment of preoperative and postoperative ocular surface status is mandatory
      in such patients.

PMID- 15188907
TI  - Laser in situ keratomileusis for residual hyperopic astigmatism after conductive
      keratoplasty.
AB  - PURPOSE: To report a case of laser in situ keratomileusis (LASIK) in a patient
      with previous conductive keratoplasty. METHODS: A 48-year-old man underwent
      conductive keratoplasty for low hyperopic astigmatism (manifest refraction OD:
      +2.25 -0.50 x 77 degrees; OS: +2.50 -0.50 x 105 degrees). Three months
      postoperatively, UCVA was 20/25 and BSCVA was 20/20 in both eyes; manifest
      refraction OD: -0.25 -0.75 x 110 degrees; OS: +0.75 -0.75 x 50 degrees. Sixteen
      months after the operation, regression of refractive outcome was (manifest) OD:
      +1.75 -1.25 x 90 degrees; OS: +2.50 -0.50 x 85 degrees; UCVA was 20/40 in the
      right eye and 20/63 in the left eye and BSCVA was 20/20 in both eyes. LASIK was
      performed for hyperopic regression in the left eye using an automated
      microkeratome (Alcon SKBM, 130-microm plate; Aesculap-Meditec MEL 70 excimer
      laser). RESULTS: LASIK was uneventful and no intraoperative or postoperative
      complications related to the previous conductive keratoplasty procedure or LASIK
      were observed. Three months after LASIK and 19 months after the initial
      conductive keratoplasty, the patient's left eye was emmetropic; UCVA was 20/20(
      2), BSCVA was 20/20 and manifest refraction was +0.25 -0.25 x 35 degrees. There
      was a uniform increase in topographical steepening. Visual acuity, refraction and
      topographic findings remained unchanged at 6 months. CONCLUSIONS: Even though our
      experience is limited, treatment of hyperopia with LASIK in an eye with
      refractive regression following previous conductive keratoplasty resulted in a
      predicted refractive outcome, with no complications, and improvement in visual
      acuity at 6 months follow-up.

PMID- 15188908
TI  - Ultrasound evaluation of flap thickness, ablation depth, and corneal edema after
      laser in situ keratomileusis.
AB  - PURPOSE: The aim of our study was to evaluate the predictability of flap
      thickness and changes in flap edema over time after laser in situ keratomileusis
      (LASIK). METHODS: LASIK was carried out in 30 eyes. The corneal flap was created
      with a Moria CB manual microkeratome with a flap thickness of 130 microm.
      Photoablation was performed with the Zeiss-Meditec MEL 70(G-Scan) flying spot
      excimer laser. Ultrasound pachymetric measurements were performed with the
      Humphrey Model 855 pachymeter. RESULTS: Preoperative mean corneal thickness was
      568.43 +/- 34.6 microm. After LASIK, mean flap thickness was 133 +/- 26.4 microm.
      After excimer laser treatment, mean central corneal thickness decreased to a mean
      392.4 +/- 37.4 microm. Five minutes after repositioning the flap, mean central
      corneal thickness was 572.1 +/- 43.4 microm. On the first postoperative day, it
      decreased to a mean 501.6 +/- 46.6 microm followed by additional decreases: mean
      487.4 microm on day 5, 481.8 microm after 1 month, and 479.6 microm at 6 months.
      The actual photoablation depth was 10 microm less than the predicted depth
      (paired sample t-test, no statistically significant difference, P = .018). A
      significant linear correlation was found (Pearson, R =.725, P = .001) between
      predicted and measured photoablation depth. CONCLUSIONS: Corneal flap thickness
      had greater variability than expected. After flap creation, stromal and flap
      edema occurred, but decreased during the first five postoperative days and
      stabilized thereafter.

PMID- 15188909
TI  - Artiflex (foldable iris claw IOL) secondary implantation for correction of
      aphakia after penetrating ocular injury.

PMID- 15188910
TI  - Traumatic corneal rupture 18 years after radial keratotomy.

PMID- 15188911
TI  - Videokeratography to calculate intraocular lens power after radial keratotomy.

PMID- 15188912
TI  - Corneal ectasia after LASIK.

PMID- 15188913
TI  - Assessment of surveillance of human West Nile virus infection in Quebec, 2003.

PMID- 15188914
TI  - Dying alone with the TV.

PMID- 15188915
TI  - Sudden withdrawal of corticosteroids: a commentary.

PMID- 15188916
TI  - Joy.

PMID- 15188917
TI  - Hospital charges for a community inpatient palliative care program.
AB  - Defining financial parameters of palliative care (PC) is important for providing
      sustainable programming. In our study, we evaluated hospital length of stay (LOS)
      and charges for the first 164 inpatient PC consultations performed by the
      Advanced Illness Assistance (AIA) team at Blount Memorial Hospital (BMH). These
      AIA patients had a median LOS of 11 days (range, 3-114 days), mean total charges
      per patient of 65,795 dollars, and mean daily charges of 3,809 dollars. Higher
      mean daily charges (p = 2.74 E-08, chi-square) were associated with patients who
      received consultation because of nonphysical symptom reasons. Patients were
      followed in PC consultation (AIA follow-up days) for a median of five days
      (range, 1-48), and had mean daily charges of 3,117 dollars. These mean daily
      charges were 414 dollars less than the charges for the five days prior to PC
      consultation (pre-AIA days) (p = 0.04, t-test). There was a significant decrease
      in laboratory and imaging charges during AIA follow-up (p = 0.04, t-test). The
      study included a reference group of patients whose information was obtained
      retrospectively from the BMH Atlas (MediQual, Marlborough, MA) database. These
      reference group patients were hospitalized at BMH during the same time, but they
      were not seen by the AIA team. The reference group was matched by Diagnosis
      Related Group (DRG), Admission Severity Grade (ASG), and disposition to the AIA
      patients. The Atlas patients had a shorter median LOS of six days (range, 1-105
      days), and significantly greater mean daily charges of 4,105 dollars (p = 0.006,
      t-test) compared with AIA patients. Mean daily charges decreased for Atlas
      patients, as their day of discharge approached (p < 0.001). Estimates of
      potential charge savings were calculated in two ways: 1) by evaluating the effect
      of decreasing the LOS of Atlas patients with long LOS (more than seven days) to
      the level of AIA patients with long LOS, and 2) by comparing the actual mean
      patient charges during AIA follow-up with using the pre-AIA mean daily charges
      during the AIA follow-up period and correcting for the effect of decreasing
      charges that occurred as discharge approached. The estimated savings achieved by
      decreasing long LOS were more than 100,000 dollars per year, and estimated
      savings achieved using AIA follow-up charges were more than 1,801,930 dollars per
      year.

PMID- 15188918
TI  - Telehospice in Michigan: use and patient acceptance.
AB  - Telehospice, the use of telemedicine technologies to provide services to hospice
      patients, offers an innovative solution to the challenges of providing high
      quality, cost-effective end-of-life care. Specifically, the technology allows
      caregivers to transmit video images of patients, which provide off-site nurses
      with the information they need to assist the caregiver. Our telehospice project
      was conducted in urban and rural Michigan between 2000-2002 and collected data
      from 187 patients receiving telehospice services in their homes during this
      study. Overall, nurses were the primary providers of telehospice services and
      initiated the majority of routine televisits. Often, patients who described
      themselves as "overwhelmed" at the time of enrollment declined telehospice.
      However, patients were extremely satisfied with telehospice and often expressed
      frustration that nurses did not use the telehospice equipment more frequently.

PMID- 15188919
TI  - Hospice referral decisions: the role of physicians.
AB  - In our study, we collected and evaluated the opinions of physicians in the
      Lowcountry of South Carolina (Berkeley, Charleston, and Dorchester counties)
      regarding their referrals to hospice programs and the extent of influence that
      their patients and families had on the decision. The research questionnaire was
      sent to 362 physicians who made referrals to hospice (53 percent response rate)
      and to 337 physicians who did not make referrals (40 percent response rate).
      Results revealed that medical doctors take the initiative in referrals. They felt
      that late referrals were due to reluctance on the part of the patient and the
      patient's family to admit that death was imminent. No differences were found in
      age, sex, medical specialty percent of terminally ill patients per practice, or
      initiative taken. However when the age and sex of physicians were evaluated, a
      statistically significant difference was found; females younger than 45 years of
      age were more likely to make referrals than younger males. Younger physicians
      were more likely to perceive that the family's reluctance to admit that death was
      near was a barrier to hospice referrals.

PMID- 15188920
TI  - Religious maturity in the midst of death and dying.
AB  - Healthy religious experience is defined by certain qualities of expression. In an
      effort to explore the concept of mature religious phenomenology, this article
      includes descriptions of two encounters from personal pastoral experience. The
      first encounter shows how a person with an unhealthy religious experience faces
      death. The second encounter describes an expression of mature religious
      experience in the face of death and how a pastoral caregiver can facilitate its
      outcome. This is followed by a pastoral theological response.

PMID- 15188921
TI  - Joining forces, joining futures: hospice at the crossroads.
AB  - Faced with health-policy changes, increased competition, and limited funding,
      hospices must either find more efficient ways to provide end-of-life care or risk
      organizational demise. Increasingly, hospices are re-evaluating their
      organizations to stretch resources and remain viable. Prevalent restructuring
      options for addressing environmental pressures are integration, alliance, and
      collaboration with other organizations. This study examines the restructuring
      phenomenon by evaluating trends among nonprofit hospices in six states. The study
      identifies demographic characteristics predictive of organizational decisions to
      join forces, and it examines the dominant political and economic reasons that
      propel or impede restructuring decisions. In addition, the study evaluates the
      results of restructuring actions.

PMID- 15188922
TI  - The business of palliative medicine--part 4: Potential impact of an acute-care
      palliative medicine inpatient unit in a tertiary care cancer center.
AB  - In this study, a hematology/oncology computerized discharge database was
      qualitatively and quantitatively reviewed using an empirical methodology. The
      goal was to identify potential patients for admission to a planned acute-care,
      palliative medicine inpatient unit. Patients were identified by the International
      Classifications of Disease (ICD-9) codes. A large heterogenous population,
      comprising up to 40 percent of annual discharges from the Hematology/Oncology
      service, was identified. If management decided to add an acute-care, palliative
      medicine unit to the hospital, these are the patients who would benefit. The
      study predicted a significant change in patient profile, acuity, complexity, and
      resource utilization in current palliative care services. This study technique
      predicted the actual clinical load of the acute-care unit when it opened and was
      very helpful in program development. Our model predicted that 695 patients would
      be admitted to the acute-care palliative medicine unit in the first year of
      operation; 655 patients were actually admitted during this time.

PMID- 15188923
TI  - Gefitinib: a new agent in palliative care.
AB  - In 2003, gefitinib (Iressa, AstraZeneca, London, UK) in 250 mg tablet form
      received accelerated approval by the US Food and Drug Administration. Gefitinib
      targets the cancer cell at the molecular level and has the ability to palliate
      lung cancer symptoms. Gefitinib's ability to control symptoms with minimal
      toxicity provides physicians with a new option to complement current symptom
      control methods. It is nonmarrow suppressive and seems to have an ability to
      control symptoms quickly, even in the absence of obvious tumor reduction.
      However, further studies are needed to compare gefitinib's ability to control
      symptoms with intensive palliative modalities for lung cancer, such as opioids,
      oxygen, and radiation therapy.

PMID- 15188924
TI  - Reduction of edema of lower extremities by subcutaneous, controlled drainage:
      eight cases.
AB  - This paper discusses the pathophysiology and modern treatment of edema.
      Dissatisfied with the treatment available, the authors report on the use of a
      closed, controlled drainage procedure in eight patients with severe edema of the
      lower limbs. It is important to note that this technique is used as a palliative
      procedure. Seven out of the eight patients considered the procedure to have been
      worthwhile, experienced improvement, and died comfortably.

PMID- 15188926
TI  - ICD-10-CM.

PMID- 15188925
TI  - Honoring the patient's wishes or passive euthanasia?

PMID- 15188927
TI  - Strategic planning--getting started: mission, vision, and values.

PMID- 15188928
TI  - An evaluation of the Moffitt Cancer Center's Laryngectomee Visitor program.

PMID- 15188929
TI  - Here we go again!
AB  - New CPT procedure codes are added annually (quarterly for Category II and
      Category III codes), definitions of existing codes are changed, and codes we have
      memorized are often deleted and replaced. In addition, guidelines for code
      assignment are constantly revised and may be altered based upon individual
      insurance payer interpretation. Remember, a code must accurately represent the
      service performed, and a code that is "close" to the procedure performed cannot
      be assigned. If the service performed is not defined by an existing procedure
      code (CPT Category I, II, III or HCPCS Level II), then an unlisted procedure code
      must be used. The forms and guidelines to request new codes or changes to
      procedure code descriptors are currently located on the American Medical
      Association website in the "CPT Process" section (www.ama-assn.org/ama/
      pub/category/3112.html).

PMID- 15188931
TI  - Epidemiology of transient ischemic attack and ischemic stroke in patients with
      underlying cardiovascular disease.
AB  - It is estimated that 15 to 30% of ischemic strokes are cardioembolic in origin,
      and that atrial fibrillation, valvular heart disease, coronary artery disease,
      congestive heart failure, and myocardial infarction are significant risk factors
      for stroke, which underscores the importance for cardiologists to understand this
      condition. The high incidence and substantial cost of stroke justify aggressive
      treatment of stroke risk factors, especially in the elderly, diabetic, and black
      populations, and in patients who have had an initial stroke. Antiplatelet therapy
      and administration of oral anticoagulants have both been shown to have a
      substantial impact on stroke in specified populations at risk.

PMID- 15188930
TI  - Secondary stroke: new horizons in prevention.

PMID- 15188932
TI  - Pathophysiology and therapeutic targets for ischemic stroke.
AB  - The increased risk for stroke among those who have had a previous stroke or
      transient ischemic attack (TIA) and the tremendous burden of disability among
      stroke sufferers make both primary and secondary preventative strategies
      imperative. An understanding of the pathophysiology of stroke and TIA can help
      identify appropriate therapeutic targets.

PMID- 15188933
TI  - Secondary stroke prevention: review of clinical trials.
AB  - Patients who experience a stroke or transient ischemic attack (TIA) are at high
      risk for subsequent vascular events, most commonly stroke. This article focuses
      on clinical trials examining secondary prevention of stroke and reviews the
      various commonly used methods of stroke prevention: surgical approaches,
      antihypertensive treatment, lipid- and cholesterol-lowering medications,
      anticoagulant therapies, and antiplatelet therapies.

PMID- 15188935
TI  - Comparison of hemostatic activation created by right- and left-heart
      radiofrequency catheter ablation.

PMID- 15188934
TI  - Medical prevention of secondary stroke: a cardiologist's perspective.
AB  - Post-stroke patients are at greatest risk from a second stroke rather than an
      event in another vascular bed. Thus treatment strategies must be aimed at
      preventing recurrent stroke. Recent evidence suggests that the pathophysiology
      underlying stroke may differ from that of coronary artery disease. Secondary
      events may replicate primary events, and treatment strategies for patients who
      experienced an initial stroke must therefore focus on preventing recurrent
      stroke. Medical strategies for secondary stroke prevention focus on four areas:
      control of hypertension, control of blood lipids, anticoagulant therapy, and
      treatment with antiplatelet agents such as aspirin, clopidogrel, and aspirin
      combined with extended-release dipyridamole, all of which the American College of
      Chest Physicians deems acceptable for first-line treatment for preventing
      secondary stroke.

PMID- 15188936
TI  - Quiet! Hospital zone.

PMID- 15188937
TI  - Reperfusion therapy for acute myocardial infarction: drugs or devices? Is this
      the right question?

PMID- 15188938
TI  - Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis.
AB  - Lipoprotein(a) (Lp[a]) continues to be a controversial molecule regarding its
      role in human vascular disease. Although the physiologic role of this molecule is
      still unclear, novel discoveries within the last few years have suggested
      numerous mechanisms whereby Lp(a) may contribute to atherosclerosis and its
      complications in human subjects. These effects may differentially occur in
      vascular tissue and circulating blood compartments. A complex interplay between
      tissue-specific effects is probably more relevant to the pathogenicity of this
      molecule than one single effect alone. This review briefly describes the
      structure of Lp(a) in relation to its biochemical function, summarizing the
      current literature on various pathophysiologic mechanisms of Lp(a)-induced
      vascular disease and the role of cell and tissue-specific effects in promoting
      atherogenesis and thrombosis.

PMID- 15188939
TI  - Importance of a history of hypertension for the prognosis after acute myocardial
      infarction--for the Bucindolol Evaluation in Acute myocardial infarction Trial
      (BEAT) study group.
AB  - BACKGROUND: Arterial hypertension is a major risk factor for cardiovascular
      events. The prognosis for hypertensive patients after acute myocardial infarction
      (MI) is uncertain because of the sparse and somewhat contradictionary data.
      HYPOTHESIS: Our study aimed to investigate the importance of hypertension to
      prognosis after an MI in patients receiving contemporary medical therapy.
      METHODS: We performed a retrospective study using a large register from the
      Bucindolol Evaluation in Acute myocardial infarction Trial (BEAT). The register
      comprised 3,326 patients admitted between June 1998 and August 1999 with an
      enzyme-verified MI to 33 Danish coronary care units. Hypertension was considered
      present when a previous diagnosis of hypertension was accompanied by relevant
      medical therapy. Survival information for all patients was obtained in January
      2002. RESULTS: Of the 3,326 patients studied, 825 were hypertensive. Overall,
      28.4% had died by January 2002. The unadjusted hazard ratio associated with
      hypertension was 1.2 (95% confidence limit [CI] 1.1-1.4, p = 0.004). Hypertensive
      patients were older, and after adjustment for age the hazard ratio associated
      with hypertension was 1.04 (CI 0.9-1.2, p = 0.6). Adjustment for further
      covariates did not change the result. CONCLUSION: Our study showed that after an
      acute MI the survival rate of patients with and without a history of hypertension
      was identical when they received contemporary medical therapy.

PMID- 15188940
TI  - Diagnosis of pseudoaneurysm of the aortic arch with transesophageal
      echocardiogram.

PMID- 15188941
TI  - Reduced quality of life after myocardial infarction in women compared with men.
AB  - BACKGROUND: Psychosocial factors have been suggested as risk factors for
      atherosclerotic disease. HYPOTHESIS: The purpose of the present study was to
      examine whether there is a gender difference in quality of life after a
      myocardial infarction with modem treatment of acute ischemic heart disease.
      METHODS: In all, 123 men and women aged between 31 and 80 years, and with a
      hospital-diagnosed myocardial infarction occurring 1-12 months prior to
      inclusion, were studied. Minor symptoms evaluation profile (MSEP) was used to
      estimate quality of life at entry. RESULTS: Age, hemodynamic data, smoking
      habits, as well as laboratory data, concomitant cardiovascular disease, and
      revascularization rate did not differ between men and women. Women had
      significantly more negative feelings regarding all the estimated dimensions of
      quality of life (Contentment, Vitality, and Sleep) than did men. CONCLUSION: Self
      assessed quality of life after a myocardial infarction was significantly lower
      among women than among men despite similar age, treatment, and hemodynamic and
      laboratory data. The causal relationship is however, not known. Further studies
      are needed to evaluate the underlying mechanism of this observation. This may
      lead to the development of novel treatment strategies in female patients after a
      myocardial infarction.

PMID- 15188942
TI  - Ethnic differences in utilization of invasive cardiac procedures and in long-term
      survival following acute myocardial infarction.
AB  - BACKGROUND: Ethnic differences in coronary mortality have been documented, and
      South Asians from the Indian subcontinent are particularly vulnerable.
      HYPOTHESIS: This study sought to determine whether there was a difference in the
      utilization of invasive cardiac procedures and long-term mortality in survivors
      of myocardial infarction (MI) among Chinese, Malays, and South Asians in
      Singapore. METHODS: All MI events in the country were identified and defined by
      the Singapore Myocardial Infarction Register, which uses modified procedures of
      the World Health Organization MONICA Project. Information on utilization of
      coronary angiography, coronary angioplasty, coronary artery bypass graft, and
      survival was obtained by data linkage with national billing and death registries.
      Hazard ratios (HR) were calculated using the Cox proportional hazards model with
      adjustment for baseline characteristics. RESULTS: From 1991 to 1999, there were
      10,294 patients who survived > or = 3 days of MI. Of these, 40.6% underwent
      coronary angiography and 16.5% a revascularization procedure < or = 28 days.
      Malays received substantially less angiography (34.0%) and revascularization
      (11.4%) than Chinese (41.9%, 17.9%) and South Asians (40.0%, 16.3%). The ethnic
      disparity increased during the 1990s, particularly in the performance of coronary
      angiography (p = 0.038). While fatality declined during the study period for
      Chinese and South Asians, the rate remained stable for Malays. After a median
      follow-up period of 4.1 years, survival was lowest among Malays (adjusted HR,
      1.28; 95% confidence interval, 1.15-1.42, compared with Chinese). CONCLUSION:
      Ethnic inequalities in invasive cardiac procedures exist in Singapore and were
      exacerbated in the 1990s. Inequalities in medical care may contribute to the
      poorer longterm survival among Malays.

PMID- 15188943
TI  - Heterotopic heart transplantation.

PMID- 15188944
TI  - Plasma vascular endothelial growth factor level is elevated in patients with
      multivessel coronary artery disease.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) has been implicated in both
      angiogenesis and ischemia. However, the relationship between plasma VEGF level
      and coronary artery disease remains unknown. HYPOTHESIS: Plasma VEGF level may be
      associated with severe coronary artery disease and other cardiovascular risk
      factors. METHODS: We examined plasma VEGF concentration and coronary risk factors
      in 73 patients who underwent coronary angiography and 70 apparently healthy
      control subjects. According to the number of the three major coronary vessels
      with significant (> or = 75%) stenosis, we divided the patients into two groups:
      the mild stenosis group (0- and single-vessel disease, n = 36) and the severe
      stenosis group (double- and triple-vessel disease, n = 37). RESULTS: The log VEGF
      value of the severe stenosis group was significantly higher than that of the mild
      stenosis (p < 0.05) and control groups (p < 0.05). Furthermore, there was a
      significant positive trend in the log VEGF value according to the number of
      vessels with significant stenosis (p = 0.016). However, there was no significant
      difference in log VEGF value between the mild stenosis and control groups.
      Soluble vascular cellular adhesion molecule, soluble intracellular adhesion
      molecule, and other coronary risk factors were found to be associated with the
      presence of vessel stenosis. CONCLUSION: Unlike established coronary risk
      factors, the plasma VEGF level may be associated with only severe coronary
      ischemia such as multiple coronary vessel disease.

PMID- 15188945
TI  - Gender-specific association between preproendothelin-1 genotype and reduction of
      systolic blood pressure during antihypertensive treatment--results from the
      Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol
      (SILVHIA).
AB  - BACKGROUND: Studies suggest that endothelin-1 contributes to the pathogenesis of
      hypertension. A G5665T gene polymorphism of preproendothelin-1 has been shown to
      be associated with higher blood pressure in overweight patients. No study has yet
      determined the effect of this polymorphism on the change in blood pressure during
      antihypertensive treatment. HYPOTHESIS: This study aimed to determine this effect
      in hypertensive patients with left ventricular (LV) hypertrophy during
      antihypertensive treatment with either irbesartan or atenolol. METHODS: We
      determined the preproendothelin-1 genotype using minisequencing in 102 patients
      with essential hypertension and LV hypertrophy verified by echocardiography,
      randomized in a double-blind fashion to treatment with either the AT1-receptor
      antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: The
      change in systolic blood pressure (SBP) after 12 weeks of treatment was related
      to the preproendothelin-1 genotype in men; after adjustment for potential
      covariates (age, blood pressure, and LV mass index at study entry, dose of
      irbesartan/atenolol, and type of treatment), those carrying the T-allele
      responded on average with a more than two-fold greater reduction than those with
      the G/G genotype (-21.9 mmHg 13.9] vs. -8.9 [2.3], p = 0.007). No significant
      differences in blood pressure change between G/G and carriers of the T-allele
      were seen among women. CONCLUSIONS: Our finding suggests a gender-specific
      relationship between the G5665T preproendothelin-1 polymorphism and change in SBP
      in response to antihypertensive treatment with irbesartan or atenolol, suggesting
      the endothelin pathway to be a common mechanism included in the hypertensive
      action of the drugs.

PMID- 15188946
TI  - The importance of gender on coronary artery size: in-vivo assessment by
      intravascular ultrasound.
AB  - BACKGROUND: It remains controversial whether women have smaller coronary arteries
      than men because of a gender-specific trait, or whether the observed differences
      are primarily due to a difference in body size. Intravascular ultrasound (IVUS),
      with its ability to provide unique coronary images that allow precise measurement
      of arterial size in vivo, is ideally suited to address this issue. HYPOTHESIS:
      Female gender, independent of body size, is associated with smaller coronary
      artery size as measured by intracoronary ultrasound. METHODS: Intravascular
      ultrasound images of normal left main arteries were identified retrospectively
      from a single center database. Associations between demographic and clinical
      characteristics (including body size) and left main coronary dimensions were
      assessed with univariant and multivariate regression analyses. RESULTS: We
      identified 257 completely normal left main arteries. Mean left main arterial
      areas were smaller in women than in men (17.2 vs. 20.6 mm2, p < 0.001), as were
      mean luminal areas (14.0 vs. 16.7 mm2, p < 0.001). By multiple regression
      analysis, the independent predictors of left main lumen were body surface area (p
      < 0.001) and gender (p = 0. 003). CONCLUSIONS: Body surface area and gender are
      both independent predictors of coronary artery size, although body size has a
      greater influence than gender.

PMID- 15188947
TI  - Coenzyme Q10 in patients with end-stage heart failure awaiting cardiac
      transplantation: a randomized, placebo-controlled study.
AB  - BACKGROUND: The number of patients awaiting heart transplantation is increasing
      in proportion to the waiting period for a donor. Studies have shown that coenzyme
      Q10 (CoQ10) has a beneficial effect on patients with heart failure. HYPOTHESIS:
      The purpose of the present double-blind, placebo-controlled, randomized study was
      to assess the effect of CoQ10 on patients with end-stage heart failure and to
      determine if CoQ10 can improve the pharmacological bridge to heart
      transplantation. METHODS: A prospective double-blind design was used. Thirty-two
      patients with end-stage heart failure awaiting heart transplantation were
      randomly allocated to receive either 60 mg U/day of Ultrasome--CoQ10 (special
      preparation to increase intestinal absorption) or placebo for 3 months. All
      patients continued their regular medication regimen. Assessments included
      anamnesis with an extended questionnaire based partially on the Minnesota Living
      with Heart Failure Questionnaire, 6-min walk test, blood tests for atrial
      natriuretic factor (ANF) and tumor necrosis factor (TNF), and echocardiography.
      RESULTS: Twenty-seven patients completed the study. The study group showed
      significant improvement in the 6-min walk test and a decrease in dyspnea, New
      York Heart Association (NYHA) classification, nocturia, and fatigue. No
      significant changes were noted after 3 months of treatment in echocardiography
      parameters (dimensions and contractility of cardiac chambers) or ANF and TNF
      blood levels. CONCLUSIONS: The administration of CoQ10 to heart transplant
      candidates led to a significant improvement in functional status, clinical
      symptoms, and quality of life. However, there were no objective changes in echo
      measurements or ANF and TNF blood levels. Coenzyme Q10 may serve as an optional
      addition to the pharmacologic armamentarium of patients with end-stage heart
      failure. The apparent discrepancy between significant clinical improvement and
      unchanged cardiac status requires further investigation.

PMID- 15188948
TI  - Beneficial effect of candesartan treatment on cardiac autonomic nervous activity
      in patients with chronic heart failure: simultaneous recording of ambulatory
      electrocardiogram and posture.
AB  - BACKGROUND: Reclining in the right lateral decubitus position in chronic heart
      failure (CHF) is a self-protective mechanism for normalizing impaired cardiac
      autonomic nervous activity (CANA). HYPOTHESIS: Candesartan, an angiotensin II
      receptor blocker, exerts beneficial effects on CANA and postural preferences in
      patients with CHF. METHODS: We studied 15 patients with CHF due to coronary
      artery disease. Cardiac autonomic nervous activity was assessed using spectral
      heart rate variability (HRV) analysis based on 24-h ambulatory electrocardiogram
      monitoring before and after an 8-week treatment with candesartan. The patients'
      posture was simultaneously recorded using a specially devised detector, as the
      right (R) or left (L) lateral decubitus or supine (S) positions, to evaluate
      postural modulations of CANA. Normalized high-frequency (0.15 to 0.40 Hz) power
      (nHF) and the low-frequency (0.04 to 0.15 Hz)/high-frequency power ratio (LF/HF)
      were used as indices of vagal activity and sympathovagal balance, respectively.
      RESULTS: When HRV was analyzed in each position, CANA was changed in L and S, but
      not in R, from sympathetic to parasympathetic prevalence by the treatment (R,
      nHF, 50 +/- 20 vs. 52 +/- 19 nu, p = 0.87; LF/HF, 1.39 +/- 1.11 vs. 1.32 +/-
      1.32, p =0.93; L, nHF, 28 +/- 13 vs. 47 +/- 19 nu, p = 0.019; LF/HF, 3.34 +/-
      2.48 vs. 1.56 +/- 1.39, p = 0.029; S, nHF, 38 +/- 17 vs. 53 +/- 16 nu, p =
      0.0023; LF/HF, 2.43 +/- 2.21 vs. 1.03 +/- 0.59, p = 0.025). The fractions of the
      time in R and L were decreased and increased, respectively, by the treatment (R,
      40 +/- 30 vs. 18 +/- 24%, p = 0.0018; L, 11 +/- 20 vs. 27 +/- 26%, p = 0.025).
      CONCLUSIONS: In patients with CHF, candesartan treatment improves cardiac
      autonomic balance, and the preference for the right lateral decubitus position
      disappears after the treatment.

PMID- 15188949
TI  - Meyer Friedman.

PMID- 15188950
TI  - Surface polysaccharides and iron-uptake systems of Actinobacillus
      pleuropneumoniae.
AB  - Actinobacillus pleuropneumoniae is the etiologic agent of porcine
      pleuropneumonia. Infection by A. pleuropneumoniae is a multifactorial process
      governed by many virulence factors acting alone or, more often, in concert to
      establish the pathogen in the porcine host. The aim of this short review is to
      present recent data concerning important surface molecules of A.
      pleuropneumoniae; namely, lipopolysaccharides, capsular polysaccharides, and a
      subset of outer membrane proteins involved in iron uptake.

PMID- 15188951
TI  - Substance P and neurotensin are up-regulated in the lumbar spinal cord of animals
      with neuropathic pain.
AB  - Many neuropeptides have been shown to be up-regulated in response to pain. The
      purpose of this study was to identify pain-related peptides in a rat model of
      neuropathic pain induced by sciatic nerve cuff implantation. Rats were tested for
      touch sensitivity prior to and 7 days following cuff implantation or sham
      surgeries. The lumbar spinal cord was removed on the 8th day post-surgery and the
      lumbar enlargement was processed for the detection of selected peptides using
      time-of-flight mass spectrometry. Only substance P (MW 1346.74) and neurotensin
      (MW 1673.0) were detected in the lumbar spinal cord of animals with mechanical
      allodynia (P < 0.01) following innocuous tactile stimulation of the affected hind
      paw. Therefore, substance P and neurotensin may be target candidates for the
      understanding and treatment of neuropathic pain.

PMID- 15188952
TI  - Effects of biotin supplementation on serum biotin levels and physical properties
      of samples of solar horn of Holstein cows.
AB  - Effects of dietary biotin supplementation on serum biotin levels and physical
      properties of sole horn of 40 Holstein cows were evaluated. The mean serum biotin
      level in biotin-supplemented cows after 10 mo of biotin supplementation (1163.2
      +/- 76.2 pg/mL) was significantly higher (P = 0.007) than that in control cows
      (382.0 +/- 76.2 pg/mL). The sole horn of biotin-supplemented cows was
      significantly harder (P = 0.026) and had a significantly lower moisture content
      (P = 0.021) than that of control cows. No morphologic differences in horn tubules
      or intertubular horn were found between the biotin-supplemented and control cows.
      The total lipid content of sole horn was significantly higher (P = 0.030) in the
      biotin-supplemented cows than in the control cows. These results suggest that
      dietary biotin supplementation causes increases in serum biotin levels and
      changes in physical properties and fat content of sole horn.

PMID- 15188954
TI  - The use of phenothiazine dyes to inactivate bovine viral diarrhea virus in goat
      colostrum.
AB  - The objectives of this study were to determine the optimal concentration of
      phenothiazine dye required to inactivate bovine viral diarrhea virus (BVDV) in
      goat colostrum following 60 min of illumination and determine if immunoglobulin
      concentration is affected by this technique. In addition, the potential of
      continuous agitation of colostrum during illumination to affect viral kill was
      investigated. This experiment was designed to more closely approximate on-farm
      use than a previous pilot study performed by the same investigators. Bovine viral
      diarrhea virus was used as a model for caprine arthritis-encephalitis virus. Goat
      colostrum containing BVDV was illuminated for 60 min following the addition of
      either methylene blue (MB) or methylene violet (MV). Four different
      concentrations of each dye were evaluated. Illumination was performed in a small,
      portable chest-type freezer equipped on the inside with white fluorescent lights.
      Some samples were continuously rocked during illumination, while others remained
      stationary. Virus levels were determined before and after illumination.
      Immunoglobulin concentrations were determined for time 0 and 60 min. One microM
      MB reduced virus to undetectable levels following 60 min of illumination. A
      concentration of 20 microM MV was required to reduce virus levels to zero.
      Agitation of colostrum samples had no effect with either MB or MV on whether
      virus levels were reduced. High concentrations of MB and MV had no important
      effect on immunoglobulin concentrations.

PMID- 15188953
TI  - Cortisol and free thyroxine determination by time-resolved fluorometry in canine
      serum.
AB  - Validation for canine serum of 2 commercially available time-resolved
      fluoroimmunoassays (TR-FIAs) designed for analysis of cortisol and free thyroxine
      (fT4) in human serum was carried out. Included was the study of interference by
      hemolysis, lipemia, and bilirubinemia. With the dissociation enhancement
      lanthanide fluoroimmunoassay kits, the intra-assay coefficient of variation (CV)
      ranged from 6.4% to 8.7% for cortisol and from 5.3% to 9.8% for fT4; the
      interassay CVs ranged from 5.8% to 10.8% and from 3.9% to 14.1%, respectively.
      Accuracy was evaluated by comparing cortisol and fT4 results obtained with TR-FIA
      and those obtained with a validated enzyme-linked immunosorbent assay (ELISA) and
      an equilibrium dialysis (ED) assay, respectively. The regression equations
      obtained were y = 0.57x + 1.18 (r2 = 0.90) for cortisol and y = 0.87x + 0.82 (r2
      = 0.93) for fT4. The limits of detection for cortisol and fT4 were 4.84 nmol/L
      and 2.68 pmol/L, respectively. The results of adrenocorticotropin-stimulation and
      dexamethasone-suppression tests were similar to those published previously;
      likewise, serial dilution of a canine serum sample with a high cortisol content
      demonstrated that the TR-FIA was immunologically specific. Serial dilution of a
      serum sample with a high fT4 concentration showed a methodologic bias, a
      dependence on serum binding capacity, which indicates that the results obtained
      with this method should be interpreted with caution. Finally, hemolysis and
      lipemia significantly interfered with cortisol and fT4 measurements, whereas
      bilirubinemia did not affect the results.

PMID- 15188955
TI  - A modified critical test for the efficacy of pyrantel pamoate for Anoplocephala
      perfoliata in equids.
AB  - Aims of this study with 13 equids naturally infected with Anoplocephala
      perfoliata were to document (i) a critical test with a period of 48 h from
      treatment to necropsy to assess the efficacy of an anthelmintic against the
      tapeworm, (ii) the efficacy of pyrantel pamoate oral paste at 13.2 mg pyrantel
      base/kg body weight, and (iii) the time after treatment when fecal egg counts
      would best estimate the tapeworm's prevalence in a herd. Feces passed in
      successive 12-h periods after treatment were examined for tapeworms. At necropsy,
      tapeworms in equids were identified as attached to the mucosa or unattached and,
      with a stereoscope, as normal or abnormal. At the time of treatment and at 6-h
      intervals thereafter, fecal samples were taken for egg counts. The efficacy of
      pyrantel pamoate was 96.6%; in 1 equid the efficacy was 75.3%, and in 8 it was
      100%. "Major fragments" (worms without a scolex) accounted for 10% of the
      tapeworms recovered; they were not included in the efficacy analysis but should
      be. In 3 untreated equids necropsied, tapeworms were in the cecum, and 21.3% were
      detached. This protocol, when compared with a 24-h one without examination of
      feces, was more efficient in the treatment of trial animals and reduced
      underestimation and overestimation of an anthelmintic's efficacy. However, a
      protocol similar to this 48-h critical test but with a 24- or 36-h post-treatment
      period should be investigated. The mean egg count peaked 18 to 24 h after
      treatment and the samples taken at that time would provide the best estimate of
      prevelance of tapeworms in a herd. The Cornell-Wisconsin centrifugal flotation
      technique had a sensitivity and specificity of 100% at 18 h and 92% and 100%,
      respectively, at 24 h.

PMID- 15188956
TI  - Experimental infectious respiratory disease in groups of calves: lobar
      distribution, variance, and sample-size requirements for vaccine evaluation.
AB  - The distribution and variance of respiratory disease produced with aerosols of
      bovine herpesvirus 1 (BHV-1) and Mannheimia haemolytica in control (183 calves in
      44 experiments) and vaccinated calves were studied in experiments conducted at
      the Animal Diseases Research Institute, Lethbridge, Alberta, from 1975 to 1989.
      All calves had been born and raised at this institute and exposed similarly for 5
      min by means of a face mask to viral and bacterial aerosols produced by a
      Collison atomizer (particles < 3 microm in diameter). We summarized the
      macroscopic pathological responses of pneumonia (main end point), tonsillitis,
      tracheitis, and other microbiologic and experimental variables. We also
      summarized the lobar distribution of pneumonia in 202 control and 192 vaccinated
      calves with this disease model and in calves similarly exposed to parainfluenza 3
      virus/M. haemolytica or BHV-1/Pasteurella multocida. Pneumonia in control calves
      began in ventral tissues of all lobes, with lobar preferences, and progressed
      dorsally, the dorsal parts of both large caudal lobes being least affected. A
      high variance of pneumonia was evident within and among experiments. From the
      magnitude of variance observed in the control groups, the number of calves per
      group required in vaccine-challenge studies using this BHV-1/M. haemolytica
      disease model was estimated. Such estimates are required for any disease model
      used in vaccine-challenge studies.

PMID- 15188957
TI  - An experimental model to evaluate the role of transport vehicles as a source of
      transmission of porcine reproductive and respiratory syndrome virus to
      susceptible pigs.
AB  - The objectives of this study were to determine the concentration of porcine
      reproductive and respiratory syndrome virus (PRRSV) in a scale-model trailer that
      was required to infect susceptible pigs, evaluate the potential of PRRSV
      contaminated transport vehicles to infect naive pigs and assess 4 sanitation
      programs for the prevention of virus spread. To maximize study power, scale
      models (1:150) of weaned-pig trailers were constructed that provided an animal
      density equal to that of an actual weaned-pig trailer capable of transporting 300
      pigs. The 1st aim involved contaminating the interior of the model trailers with
      various concentrations (10(1) to 10(4) TCID50/mL) of PRRSV MN 30-100, then
      housing sentinel pigs in the trailers for 2 h. Pigs exposed to trailers
      contaminated with > or = 10(3) TCID50/mL became infected. The 2nd aim involved
      housing experimentally infected seeder pigs in trailers for 2 h, then directly
      introducing sentinel pigs for 2 h. Infection of sentinels was demonstrated in 3
      of 4 replicates. The 3rd aim involved applying 1 of 4 sanitation procedures
      (treatments) to contaminated trailers. Treatment 1 consisted of manual scraping
      of the interior to remove soiled bedding (wood chips). Treatment 2 consisted of
      bedding removal, washing (80 degrees C, 20,500 kPa), and disinfecting (with 1:256
      phenol; 10-min contact time). Treatment 3 consisted of treatment 2, followed by
      freezing and thawing. Treatment 4 consisted of bedding removal, washing,
      disinfecting, and drying. Ten replicates were conducted per treatment.
      Pretreatment swabs from all trailers tested positive by polymerase chain reaction
      (PCR). Post-treatment swabs were PCR-positive for all trailers except those that
      were washed, disinfected, and dried. Infection of sentinel pigs by PRRSV was also
      detected by PCR after all treatments except washing, disinfecting, and drying.
      Under the conditions of this study, drying appeared to be an important component
      of a sanitation program for ensuring PRRSV biosecurity of transport vehicles.

PMID- 15188958
TI  - Evaluation of a covalent mix-enzyme linked immunosorbent assay for screening of
      Salmonella antibodies in pig serum.
AB  - In this study, a commercial Salmonella covalent mix-enzyme linked immunosorbent
      assay (ELISA) for serological detection of Salmonella infection in swine was
      evaluated by comparing it with the conventional fecal culture method and inter
      laboratory proficiency testing, using a panel of sera tested in 5 laboratories
      from Europe and North America. Comparison with culture results showed that 88.5%
      of 26 culture-positive animals were ELISA positive, as were 55% of 60 animals
      from 2 culture-positive pig herds. Of 90 animals from 2 high health farms with no
      clinical symptoms of salmonellosis, 98.9% tested negative. The interlaboratory
      comparison study found a kappa value of 0.9 between our laboratory (using an
      automated system) and the manufacturer laboratory (using the manual method).
      Comparison of ELISA results from all 5 participating laboratories showed very
      good to excellent agreement, between 85% and 97.5%. We found this assay to be
      useful for the screening of antibodies against Salmonella present in swine serum.
      It agrees well with bacterial cultures, is reproducible, sensitive, specific,
      repeatable, and suitable for automation.

PMID- 15188959
TI  - Characterization of avipoxviruses from wild birds in Norway.
AB  - Avipoxviruses from different geographic regions of the world have been
      characterized to study their genetic and biological properties, but so far, no
      such work has been performed on Norwegian isolates. Lesions suggestive of avian
      pox, found on a Norwegian wild sparrow (Passer domesticus) and wood pigeon
      (Palumbus palumbus), were obtained in 1972 and 1996, respectively.
      Histologically, these lesions were demonstrated to be characteristic of poxvirus
      infections and the poxvirus was observed using an electron microscope. The
      resulting viruses were propagated in chicken embryo fibroblast cells. Restriction
      fragment length polymorphism of genomes from 2 Norwegian isolates and fowl pox
      vaccine strain, generated by BamHI, revealed a high degree of heterogeneity among
      the isolates. The profiles of avipoxviruses isolated from wild birds were clearly
      distinct from each other and also to the fowl poxvirus strain. Furthermore,
      chickens experimentally infected with pigeon poxvirus had higher antibody titers
      and extensive lesions compared to other isolates. This may suggest that pigeon
      poxvirus is more virulent than the other isolates.

PMID- 15188960
TI  - Detection of surfactant protein A (SP-A) and surfactant protein D (SP-D) in
      equine synovial fluid with immunoblotting.
AB  - Once considered unique to the lung, surfactant proteins have been clearly
      identified in the intestine and peritoneum and are suggested to exist in several
      other organs. In the lung, surfactant proteins assist in the formation of a
      monolayer of surface-active phospholipid at the liquid-air interface of the
      alveolar lining, reducing the surface tension at this surface. In contrast,
      surface-active phospholipid adsorbed to articular surfaces has been identified as
      the load-bearing boundary lubricant of the joint. This raises the question of
      whether surfactant proteins in synovial fluid (SF) are required for the formation
      of the adsorbed layer in normal joints. Proteins from small volumes of equine SF
      were resolved by 1- and 2-dimensional polyacrylamide gel electrophoresis and
      detected by Western blotting to investigate the presence of surfactant proteins.
      The study showed that surfactant proteins A and D (SP-A and SP-D) are present in
      the SF of normal horses. We suggest that, like surface-active phospholipid, SP-A
      and SP-D play a significant role in the functioning of joints. Next will be
      clarification of the roles of surfactant proteins as disease markers in a variety
      of joint diseases, such as degenerative joint disease and inflammatory problems.

PMID- 15188961
TI  - Shiga toxin-producing Escherichia coli in the feces of Alberta feedlot cattle.
AB  - Shiga toxin-producing Escherichia coli (STEC) are a public health concern.
      Bacterial culture techniques commonly used to detect E. coli O157:H7 will not
      detect other STEC serotypes. Feces from cattle and other animals are a source of
      O157:H7 and other pathogenic serotypes of STEC. The objective of this study was
      to estimate the pen-level prevalence of Shiga toxins and selected STEC serotypes
      in pre-slaughter feedlot cattle. Composite fecal samples were cultured and a
      polymerase chain reaction (PCR) was used to detect genes for Shiga toxins (stx1
      and stx2) and genes for O157:H7, O111:H8, and O26:H11 serotypes. Evidence of
      Shiga toxins was found in 23 pens (92%), O157:H7 in 2 (8%), O111:H8 in 5 (20%),
      and O26:H11 in 20 (80%) of the 25 pens investigated. Although pen-level
      prevalence estimates for Shiga toxins and non-O157 serotypes seem high relative
      to O157:H7, further effort is required to determine the human health significance
      of non-O157 serotypes of STEC in feedlot cattle.

PMID- 15188962
TI  - Observation of Helicobacter-like organisms in gastric mucosa of grey foxes
      (Urocyon cinereoargenteus) and bobcats (Lynx rufus).
AB  - Archival specimens of gastric mucosa of 10 raccoons (Procyon lotor), 9 porcupines
      (Erethizon dorsatum), 6 grey foxes (Urocyon cinereoargenteus), 6 bobcats (Lynx
      rufus), 4 skunks (Mephitis mephitis), and 3 black bears (Ursus americanus) were
      microscopically examined for evidence of Helicobacter-like organisms. Such
      organisms were seen in the specimens from the grey foxes and bobcats only.
      Histochemical stains (modified Steiner and carbol fuchsin methods) revealed long
      spiral organisms within lumina of gastric glands; however, neither gross nor
      microscopic lesions were observed. By electron microscopy (EM), the organisms
      were found to be free in the glandular lumina and were seen occasionally in the
      cytoplasm of gastric epithelial cells. Morphologically, 2 different phenotypes of
      spiral organisms were identified by EM. The organisms associated with bobcats
      appeared to be more tightly coiled than those seen in grey foxes. The presence of
      Helicobacter-like organisms in the gastric mucosa of grey foxes has not
      previously been described.

PMID- 15188963
TI  - Use of a commercial methylcellulose medium with and without recombinant bovine
      granulocyte colony-stimulating factor for culturing bovine bone marrow cells.
AB  - A commercial methylcellulose culture medium, with and without the addition of
      recombinant bovine granulocyte colony-stimulating factor (rbG-CSF), was utilized
      for culturing bovine bone marrow cells in a colony-forming unit assay. Bone
      marrow mononuclear cells were isolated and cultured in a commercial
      methylcellulose-based medium containing several recombinant human cytokines.
      Cultures were prepared with and without 100 ng/mL of rbG-CSF. The size and mean
      number of colonies per plate from culture days 3 to 9 were compared. We concluded
      that bovine bone marrow colony growth was supported by this culture medium. The
      addition of rbG-CSF yielded larger and more numerous colonies. There were
      significantly more colonies on day 3 (P < 0.001), day 4 (P < 0.001), and day 5 (P
      = 0.03) with rbG-CSF. Both culture media had the highest colony counts on day 5.

PMID- 15188964
TI  - Iron deficiency and iron deficiency anaemia during infancy and childhood.
AB  - The present definition of iron deficiency and iron deficiency anaemia is under
      debate. Our present figures for the prevalence of iron deficiency in infants and
      toddlers are thus disputed. CONCLUSION: Better understanding of the regulation of
      iron metabolism and requirement during the critical early period of growth and
      development is needed for relevant control of iron deficiency anaemia.

PMID- 15188965
TI  - Insulin treatment in children and adolescents.
AB  - The management of diabetes in children presents a number of challenges. The ideal
      is to achieve optimal glycaemic control using an insulin regimen that is
      acceptable to the child and family, which improves glycaemic control, whilst
      avoiding hypoglycaemia. The paediatric population differ from their adult
      counterparts in several ways, such as variability of exercise and eating
      patterns, and the hormonal influences of puberty, which means that the insulin
      regimen must be tailored to suit an individual child and their family.
      CONCLUSION: This review will focus on the particular difficulties of managing
      diabetes in children and, in particular, the problem of avoiding hypoglycaemia
      while maintaining adequate glycaemic control.

PMID- 15188966
TI  - Preterm male infants need more initial respiratory support than female infants.
AB  - Female infants have a significantly greater chance of surviving than male infants
      at similar birthweights and gestational ages, and have an advantage over males
      for a better outcome with less morbidity. CONCLUSION: The exact mechanisms
      responsible for the gender differences, with a better chance of survival of
      female infants, remain to be determined. The paper by Elsmen et al. provides an
      important contribution to this most important area of clinical research.

PMID- 15188967
TI  - Vitamin K in human milk--still not enough.
AB  - The breastfed infant has limited sources of vitamin K, as it is transmitted
      poorly across the placenta and is present in very low concentrations in human
      milk. The author of this paper reports a concentration of vitamin K in human milk
      (0.517 +/- 1.521 microg/dl) that is about twice the average of earlier reports
      (0.25 microg/dl). About half of the increased concentration (0.235 +/- 0.144
      microg/dl) is accounted for by vitamin K2 (menaquinone) rather than vitamin K1
      (phylloquinone); the latter generally thought to be more important in human
      nutrition. The significance of these findings is discussed.

PMID- 15188968
TI  - SIDS prevention--good progress, but now we need to focus on avoiding nicotine.
AB  - Chong et al. examined risk factors for sudden infant death syndrome (SIDS) before
      and after the start of the Swedish campaign to reduce the risk of SIDS. They
      found that maternal smoking was the strongest risk factor for SIDS in the post
      campaign compared to the pre-campaign period. CONCLUSION: After successful
      results of the SIDS campaigns to prevent prone sleeping, strong efforts need to
      be undertaken to eliminate maternal smoking during pregnancy altogether without
      replacing cigarette smoking with other nicotine delivery devices such as snuff,
      gum or patches.

PMID- 15188969
TI  - Analgesic effect of expressed breast milk in procedural pain in neonates.
AB  - Prevention, treatment and assessment of neonatal pain have been of major clinical
      and scientific interest the last decades. Non-pharmacological interventions such
      as sweet oral solutions are successful in pain relief. Whether breast milk, with
      its lactose content of 7%, has any effect on the prevention of pain has been
      debated. CONCLUSION: Randomized studies of breast milk in prevention and
      treatment of neonatal pain are needed.

PMID- 15188970
TI  - Antireflux or antiregurgitation milk products for infants and young children: a
      commentary by the ESPGHAN Committee on Nutrition.

PMID- 15188971
TI  - Vitamin K concentrations in the maternal milk of Japanese women.
AB  - AIM: To determine the concentration of vitamin K including K1 (phylloquinone) and
      K2 (menaquinone-n; MK-n) in the maternal milk of Japanese women. METHODS: We
      collected human milk samples from more than 4000 mothers living throughout Japan
      from December 1998 to September 1999, and analysed the contents of vitamin K1 and
      K2 in 834 of the samples. We defined as group A the 555 samples among them that
      met the following conditions: breast milk of mothers who were under 40 y old, not
      in the habit of smoking and/or using vitamin supplements, and whose babies showed
      no symptoms of atopy and whose birthweights were 2.5 kg or more. Vitamins
      extracted from the enzymatic hydrolysates of the human milk were purified with a
      Sep-Pak Plus silica cartridge, and then measured by a method based on high
      performance liquid chromatography (HPLC) combined with coulometric reduction and
      fluorometric detection. RESULTS: The mean concentration of vitamin K (K1 + K2) of
      mothers of group A and all groups were 0.434 +/- 0.293 and 0.517 +/- 1.521
      microg/100 ml (average +/- SD), respectively, and menaquinones containing 4, 6
      and 7 isoprenoid residues could be detected in the milk samples. Vitamins K1 and
      MK-4 were found to be predominant in the milk samples, and the concentration of
      MK-4 in colostrum was higher than that of MK-4 in mature milk. We also found that
      the MK-7 concentration in the milk of mothers living in eastern Japan was higher
      than that of mothers living in western Japan. CONCLUSION: The different features
      of vitamin K1 and MK-7 concentrations in the milk of Japanese women may be due to
      differences in dietary foods.

PMID- 15188972
TI  - Introduction of food during the infant's first year: a study with emphasis on
      introduction of gluten and of egg, fish and peanut in allergy-risk families.
AB  - AIM: The aim of the current study was to retrospectively examine introduction of
      food during the first year in a representative sample of Swedish children. A
      secondary aim was to study how parents with history of atopy introduced food to
      their infants. METHODS: Data derive from 467 infants who visited child health
      centres in three different counties in Sweden for health check-up at 12 mo of
      age. The parents were asked to fill in a questionnaire about breastfeeding and/or
      formula feeding, time of introduction of weaning food focusing on cow's milk,
      follow-on formula, porridge, fish and egg. Questions regarding hypersensitivity
      in the family, peanut consumption of mother as well as in the child, and
      questions about number of siblings, ethnic background and parental education were
      included. RESULTS: Compliance with suggested introduction of gluten-containing
      food was low; as many as 45% had avoided gluten until 6 mo of age, instead of
      introducing gluten between 4 and 6 mo. Only 33% of parents with stated family
      hypersensitivity avoided giving their child fish and 23% avoided egg during the
      first year, even though this recommendation was present at the time of the study.
      Almost 50% of all mothers had avoided peanuts during pregnancy even though there
      was no such advice. The avoidance of peanut was not connected to hypersensitivity
      in the family. CONCLUSION: These results suggest that time of introduction of
      gluten was not in accordance with the current recommendation. The results imply
      that there is a need to follow up if and how this feeding information is
      distributed to parents with infants and also to sharpen the information to the
      right target groups, otherwise implementation of preventive strategies will be
      less useful.

PMID- 15188973
TI  - Maternal smoking: an increasing unique risk factor for sudden infant death
      syndrome in Sweden.
AB  - AIM: To assess the change of risk factors that are specific to sudden infant
      death syndrome (SIDS) after the initialization of a campaign to reduce the risk
      (RTR) of SIDS compared to non-SIDS postneonatal deaths. METHODS: Data were
      extracted from the Swedish Medical Birth Registry, 1982-1991 and 1993-1998. 1105
      infants died from SIDS during the postneonatal period. 2115 postneonatal deaths
      were from other causes and 11,050 live birth controls were selected. Risk factors
      previously identified to be related to SIDS were defined as high parity,
      prematurity, young maternal age, low Apgar score, birth during the night, single
      motherhood, multiple births, maternal smoking, male gender, short length standard
      deviation score (SDS) and small weight-to-length SDS. RESULTS: Non-SIDS deaths
      were more significantly related to a low 5-min Apgar score, smaller weight-to
      length SDS, and/or short length SDS values; while SIDS deaths were more closely
      related to mothers with higher parity or multiple births, mothers who smoked
      during pregnancy and single-parent (mother) families. Maternal smoking was even
      more prominent among SIDS deaths in the post-campaign period. The adjusted odds
      ratios, compared with non-SIDS deaths, increased from 1.84 (95% CI: 1.48, 2.28)
      in the pre-campaign period to 4.11 (95% CI: 2.72, 6.21) in the post-campaign
      period. CONCLUSIONS: Maternal smoking during pregnancy remains the most important
      modifiable risk factor for SIDS in the post-campaign period in comparison with
      non-SIDS postneonatal deaths. Other than putting babies in a supine sleeping
      position, maternal smoking should be the next most important issue to be
      considered, if there is to be a second campaign.

PMID- 15188974
TI  - Ultrasound scanning may reduce the need for barium radiology in the assessment of
      small-bowel Crohn's disease.
AB  - AIM: Bowel wall thickening on transabdominal ultrasound scanning (USS) correlates
      well with Crohn's disease (CD) activity. However, the role of USS in the
      assessment of CD has not been fully defined. This study compared USS and barium
      follow-through (BaFT) in the assessment of CD. METHODS: A retrospective case
      series was undertaken of 24 children with CD who underwent USS and BaFT during
      the same period of clinical disease activity. RESULTS: For terminal ileum
      abnormality, all 13 cases with abnormal USS had abnormality on BaFT. USS did not
      detect five cases with affected terminal ileum and two cases with isolated
      proximal small-bowel CD. CONCLUSION: BaFT is a more sensitive indicator of small
      bowel CD than USS. USS has good positive predictive value of distal small-bowel
      CD, but BaFT should be performed in the presence of a normal USS where there is
      strong clinical evidence of CD.

PMID- 15188975
TI  - Lactose malabsorption in young Lithuanian children with atopic dermatitis.
AB  - AIM: To determine the prevalence of lactose malabsorption in young Lithuanian
      atopic dermatitis children; to evaluate the relationship between lactose
      malabsorption and the duration of exclusive breastfeeding, and the relationship
      between lactose malabsorption and cow's milk intolerance in parents and
      grandparents. METHODS: 144 children with atopic dermatitis aged 1.5-24 mo (study
      group) and 32 children without symptoms of allergic diseases aged 1.5-23 mo
      (control group) were investigated. Lactose and glucose-galactose absorption tests
      based on serial blood glucose determination, culture of stool, latex
      agglutination test for rotavirus and microscopic examination of stool for
      parasites were performed. RESULTS: Lactose malabsorption was determined in 59
      (40.9%) and glucose-galactose malabsorption in 17 (11.8%) children with atopic
      dermatitis. The risk of developing lactose malabsorption was higher in children
      fed exclusively on breast milk up to 1 mo of age than in children fed exclusively
      on breast milk for 4 to 6 mo (OR: 2.62; 95% CI: 1.02-6.75). Lactose malabsorption
      was significantly more frequent in patients whose mothers did not tolerate cow's
      milk (20/30; 66.7%) than in patients whose mothers were tolerant to it (39/95;
      41.1%) (p = 0.02). CONCLUSION: Lactose malabsorption was determined in 40.9% of
      Lithuanian atopic dermatitis children aged under 2 y. Lactose malabsorption
      appeared to be associated with the duration of exclusive breastfeeding up to only
      1 mo and mothers' milk intolerance.

PMID- 15188976
TI  - Antimicrobial resistance in Escherichia coli in urine samples from children and
      adults: a 12 year analysis.
AB  - AIM: To investigate the distribution and antimicrobial resistance in urinary
      tract pathogens, primarily Escherichia coli, in two age groups, children < or = 2
      y and adults 18-50 y, over a period of 12 y. METHODS: From the database of the
      microbiological laboratory all urinary tract culture data were extracted and
      structured according to date, patient age, bacteriological findings,
      antimicrobial susceptibility results and sample type. Statistical longitudinal
      analysis of bacteriological findings and antimicrobial resistance trends in the
      two age groups were performed. RESULTS: Statistical significance was obtained for
      the following results. Escherichia coli was the most common pathogen in both age
      groups and irrespective of sample type. In E. coli resistance to ampicillin and
      trimethoprim was higher in children than in adults and increased over time in
      both age groups. Resistance to fluoroquinolones was higher in adults than in
      children and increased over time in both groups. Resistance to pivmecillinam,
      cefadroxil and nitrofurantoin was below 2% in 2001 in both age groups.
      CONCLUSION: The steadily increasing and now high E. coli resistance levels in
      children to ampicillin and trimethoprim render empirical therapy with these drugs
      doubtful. The stable and low levels of resistance to pivmecillinam, cefadroxil
      and nitrofurantoin (< 2% in 2001) make these drugs reasonable alternatives in
      uncomplicated lower urinary tract infections.

PMID- 15188977
TI  - Feeding practices of infants through the first year of life in Italy.
AB  - AIM: To investigate infant feeding practices through the first year of life in
      Italy, and to identify factors associated with the duration of breastfeeding and
      early introduction of solid foods. METHODS: Structured phone interviews on
      feeding practices were conducted with 2450 Italian-speaking mothers randomly
      selected among women who delivered a healthy-term singleton infant in November
      1999 in Italy. Interviews were performed 30 d after delivery and when the infants
      were aged 3, 6, 9 and 12 mo. Type of breastfeeding was classified according to
      the WHO criteria. RESULTS: Breastfeeding started in 91.1% of infants. At the age
      of 6 and 12 mo, respectively, 46.8% and 11.8% of the infants was still breastfed,
      68.4% and 27.7% received formula, and 18.3% and 65.2% were given cow's milk.
      Solids were introduced at the mean age of 4.3 mo (range 1.6-6.5 mo). Introduction
      of solids occurred before age 3 and 4 mo in 5.6% and 34.2% of infants,
      respectively. The first solids introduced were fruit (73.1%) and cereals (63.9%).
      The main factors (negatively) associated with the duration of breastfeeding were
      pacifier use (p < 0.0001), early introduction of formula (p < 0.0001), lower
      mother's age (p < 0.01) and early introduction of solids (p = 0.05). Factors
      (negatively) associated with the introduction of solids foods before the age of 3
      mo were mother not having breastfed (p < 0.01), early introduction of formula (p
      < 0.01), lower infant bodyweight at the age of 1 mo (p = 0.05) and mother smoking
      (p = 0.05). CONCLUSION: The duration of breastfeeding in Italy is still
      inadequate, as well as compliance with international recommendations for timing
      of introduction of complementary foods. National guidelines, public messages and
      educational campaigns should be promoted in Italy.

PMID- 15188978
TI  - Preschool outcome in children born very prematurely and cared for according to
      the Newborn Individualized Developmental Care and Assessment Program (NIDCAP).
AB  - AIM: Care based on the Newborn Individualized Developmental Care and Assessment
      Program (NIDCAP) has been reported to exert a positive impact on the development
      of prematurely born infants. The aim of the present investigation was to
      determine the effect of such care on the development at preschool age of children
      born with a gestational age of less than 32 wk. METHODS: All surviving infants in
      a randomised controlled trial with infants born at a postmenstrual age less than
      32 wk (11 in the NIDCAP group and 15 in the control group) were examined at 66.3
      (6.0) mo corrected for prematurity [mean (SD)]. In the assessment we employed the
      Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) for
      cognition, Movement Assessment Battery for Children (Movement ABC) for motor
      function, subtests of the NEPSY test battery for attention and distractibility,
      and the WHO definitions of impairment, disability and handicap. Exact binary
      logistic regression was employed. RESULTS: There were no significant differences
      between the intervention group in Full-Scale IQ 93.4 (14.2) [mean (SD)] versus
      the control group 89.6 (27.2), Verbal IQ 93.6 (16.4) versus 93.7 (26.8) or
      Performance IQ 94.3 (14.7) versus 86.3 (24.8). In the NIDCAP group 8/13 (62%)
      survived without disability and for the children with conventional care this
      ratio was 7/19 (37%). The corresponding ratios for surviving without mental
      retardation were 10/13 (77%) and 11/19 (58%), and for surviving without attention
      deficits 10/13 (77%) and 10/19 (53%). Overall, the differences were not
      statistically significant, although the odds ratio for surviving with normal
      behaviour was statistical significant after correcting for group imbalances in
      gestational age, gender, growth retardation and educational level of the parents.
      CONCLUSION: Our trial suggests a positive impact by NIDCAP on behaviour at
      preschool age in a sample of infants born very prematurely. However, due to
      problems of recruitment less than half of the anticipated subjects were included
      in the study, which implies a low power and calls for caution in interpreting our
      findings. Larger trials in different cultural contexts are warranted.

PMID- 15188979
TI  - Is a large family a protective factor against behavioural and emotional problems
      at the age of 8 years?
AB  - AIM: To study the prevalence of behavioural and emotional problems among children
      from different family types, sibship size and birth order. METHODS: A prospective
      birth cohort (n = 9357) study where parents filled in two questionnaires and
      teachers assessed children's behaviour using the Rutter scale (RB2). RESULTS:
      14.3% scored above the cut-off point (RB2 > or = 9) indicating probable
      psychiatric disturbance, boys more often than girls (OR 2.6, 95% CI 2.3-3.0).
      Behavioural problems (9.2%) were more common than emotional ones (4.1%). Boys
      living in families other than two-parent families were at risk for probable
      psychiatric disturbance, and a corresponding risk was observed for girls living
      in single-parent or always one-parent families. Other than two-parent family was
      also a risk for behavioural problems; for boys adjusted odds ratios ranged
      significantly from 1.8 to 2.4 and for girls from 2.0 to 3.7. "Only children" had
      the highest prevalence of behavioural problems, while children in very large
      families had the lowest. Living in a very large family was a protective factor
      against behavioural problems among boys but not among girls. Eldest children were
      at lower risk of behavioural problems than the other children. The single-parent
      and always one-parent family was associated with higher risk of emotional
      problems among girls. CONCLUSION: Children's psychiatric problems are manifested
      at school mostly as behavioural problems. A two-parent family and being the
      oldest in the sibling series seem to be protective factors. Very large family
      size, if not connected to social disadvantages, does not seem to be a risk factor
      for children's behaviour.

PMID- 15188980
TI  - Analgesic effect of expressed breast milk in procedural pain in term neonates: a
      randomized, placebo-controlled, double-blind trial.
AB  - AIM: To assess the effectiveness of expressed breast milk (EBM) in reducing pain
      due to venepuncture, in term neonates, as measured by behavioural and
      physiological observations. METHODS: This randomized, placebo-controlled, double
      blind trial involved 81 full-term neonates, up to 4 wk of postnatal age, who
      needed venepuncture for blood investigations. Two minutes before the
      venepuncture, in the intervention arm, 40 babies received 5 ml of EBM, while 41
      babies in control group received 5 ml of distilled water (DW) as placebo. Two
      observers who were blinded to the intervention recorded the physiological (heart
      rate and oxygen saturation) and behavioural parameters [duration of crying and
      modified Neonatal Facial Coding Scores (NFCS)] after the venepuncture. RESULTS:
      There was no difference in the baseline characteristics of the neonates in the
      two groups. The duration of crying was significantly shorter in babies fed EBM
      [median 38.5 s, interquartile range (IQR) 9.5-57.5 s] than in those fed DW
      (median 90 s, IQR 28-210 s). The mean duration of crying in EBM group was shorter
      by 70.7 (95% confidence interval 36.6-104.9) s. The modified NFCS at 0, 1 and 3
      min was significantly lower (p < 0.01) in the EBM than in the DW group. The
      change in heart rate and oxygen saturation was significantly lower in the EBM
      group and returned to baseline values sooner than in the DW group. CONCLUSION:
      Feeding 5 ml of EBM before venepuncture is effective in reducing symptoms due to
      pain in term neonates.

PMID- 15188981
TI  - Cerebral blood-flow velocities in predicting outcome of asphyxiated newborn
      infants.
AB  - AIM: To evaluate the role of early (up to 12 h) changes in cerebral blood-flow
      (CBF) velocity in predicting the severity of hypoxic-ischaemic encephalopathy
      (HIE) and long-term outcome in asphyxiated term infants. METHODS: CBF velocities
      were investigated by colour Doppler ultrasonography in 81 healthy and 60
      asphyxiated term infants at least three times during the first 5 d of life. The
      psychomotor development of infants was followed up to 18 mo. RESULTS: No
      differences in CBF velocities were found at the age of 2-6 h between infants with
      severe and mild-moderate HIE, mean CBF velocity [mean (95% CI of mean CBF
      velocity)] in anterior cerebral artery [14.9 (1.4-28.4)cm/s] and [13.9 (11.1
      16.7) cm/s], respectively, and between infants with poor outcome (death or severe
      disability) and with normal development/mild impairments. By the age of 12 h
      infants with mild-moderate HIE and infants with normal development/mild
      impairments had decreased CBF velocity in the anterior cerebral artery, and
      infants with severe HIE or poor outcome had increased mean CBF velocity in
      anterior, medial cerebral and basilar artery compared to the control group.
      CONCLUSION: The value of CBF velocity changes to predict poor outcome in
      asphyxiated infants is low 2-6 h after asphyxia, but increases by the age of 12
      ho.

PMID- 15188982
TI  - Preterm male infants need more initial respiratory and circulatory support than
      female infants.
AB  - AIM: The aim of this study was to investigate possible gender-related differences
      in clinical parameters during the first week of life that could explain the
      higher morbidity and mortality of preterm male infants. METHODS: In total, 130
      clinical variables were collected from 236 inborn infants (130 male and 106
      female infants) with gestational age (GA) < 29 wk. A subgroup of 175 extremely
      low birthweight infants (ELBW) < 1000 g (n = 86 males; n = 89 females) was
      analysed separately. RESULTS: At 6 postnatal h, 60.8% of the male infants needed
      mechanical ventilation versus 46.2% of the females (p = 0.026). Chronic lung
      disease (CLD) developed in 36.2% of males versus 9.8% of female infants (p =
      0.004). Inotrope support with dopamine was used in more than 50% of the infants;
      additional inotrope support to dopamine was needed by 19.4% of male and 9.7% of
      female infants (p = 0.041). The gender-related difference in need for inotrope
      support was more evident among the ELBW infants; 67.1% of male infants needed
      inotrope support versus 50.6% of females (p = 0.028). At 12-24 h, male ELBW
      infants had lower minimum mean arterial blood pressure (mean (SD) 25(4) mmHg vs
      28(6) mmHg, p = 0.004)) and lower minimum PaCO2 than females infants (4.3 (1.1)
      kPa vs 4.7 (0.9) kPa, p = 0.043). CONCLUSIONS: There are early gender-related
      differences in need for ventilatory and circulatory support that may contribute
      to the worse long-term outcome in prematurely born male infants.

PMID- 15188983
TI  - Human neutrophil lipocalin: normal levels and use as a marker for invasive
      infection in the newborn.
AB  - AIM: To evaluate human neutrophil lipocalin (HNL) as a marker of neonatal
      invasive infection and determine the normal serum levels of HNL in newborns.
      METHODS: HNL is released from neutrophil granulocytes and is regarded as a
      specific marker of neutrophil activity. In 81 newborns < or = 28 d of age with
      signs of infection on a total of 87 occasions, HNL and C-reactive protein (CRP)
      were measured at inclusion and on the three following days. As controls, term
      healthy newborns were recruited at birth (cord blood, n = 45) and at ages 3-5 d
      (n = 46). Serum HNL was measured by a radioimmunoassay. RESULTS: 25/87 episodes
      were classified as infection and 62 as non-proven infection. HNLmax was
      significantly higher in the infected group (mean 587.6 microg/l) than in the non
      proven infected group (mean 217.7 microg/, p < 0.001). HNL peaked at inclusion, 1
      d earlier than CRP. In the healthy controls. HNL was the same at 3-5 d of age as
      at birth (mean 82.4-81.7 microg/l) and similar to normal adult levels.
      CONCLUSIONS: The release of HNL is not increased in healthy newborns at birth,
      but neonatal neutrophils rapidly release HNL upon microbial stimulation in vivo.
      HNL might be useful as an early marker of neonatal infection.

PMID- 15188984
TI  - Immediate and short-term effects of pulmonary artery banding on left ventricular
      performance in foetal sheep.
AB  - AIM: To evaluate foetal left ventricular performance when its preload was
      increased by banding the pulmonary artery, a study design where a simultaneous
      change in left ventricular afterload is unlikely. METHODS: Nine ovine foetuses
      were studied with real-time images and Doppler echocardiography before, 3-4 and 6
      8 d after surgery. Seven of these foetuses were also studied during the surgical
      intervention, immediately before and within 2 min after banding. RESULTS: The
      immediate effects of a 90-95% reduction of the pulmonary artery cross-sectional
      area were: a 53 +/- 20% (mean +/- SD) decrease and a 38 +/- 10% increase of right
      (RvQ) and left ventricular output (LvQ), respectively. Comparing measurements
      before and 3-4 d after operation, there was a 64 +/- 16% decrease of RvQ and a 64
      +/- 25% increase of LvQ. The increase in LvQ was due to an increase in both heart
      rate (19 +/- 10%) and stroke volume (38 +/- 18%). After an additional 3-4
      postoperative days, heart rate remained increased to the same extent, but there
      was a more pronounced increase of LvQ (93 +/- 19%) and stroke volume (59 +/-
      22%). CONCLUSION: The parallel foetal circulation has a capacity to handle a
      severely increased afterload for the right ventricle by immediately improving and
      maintaining an increased left ventricular performance. This improvement was in
      part accomplished by an increase in stroke volume.

PMID- 15188985
TI  - Postnatal nicotine exposure does not further compromise hypoxia defense
      mechanisms in prenatally nicotine-exposed lambs.
AB  - AIMS: To determine whether combined pre- and postnatal nicotine exposure compared
      with prenatal exposure alone results in more compromised postnatal hypoxia
      defense mechanisms and further alteration of the postnatal breathing pattern
      (reduced tidal volume and increased respiratory rate). METHODS: Seven lambs
      exposed to nicotine prenatally (pN) (approximate maternal dose: 0.5 mg/kg/d) and
      seven lambs exposed to nicotine pre- and postnatally (ppN) (postnatal dose: 1.6-2
      mg/kg/d) were studied without sedation at an average age of 5 d and 21 d during
      resting (room air) conditions, during exposure to 10% O2 and during a brief
      exposure to 100% O2. RESULTS: Resting minute ventilation, occlusion pressure,
      effective impedance, heart rate and mean arterial blood pressure were similar in
      the two groups during wakefulness and quiet sleep. Resting tidal volume was
      significantly higher in ppN than in pN lambs during wakefulness (9.4 +/- 0.7 vs
      7.7 +/- 1.4 ml/kg, p < 0.05) and quiet sleep (9.8 +/- 0.6 vs 7.6 +/- 1.5 ml/kg, p
      < 0.01) at 5 d and also at 21 d during wakefulness (7.7 +/- 1.0 vs 6.2 +/- 1.1
      ml/kg, p < 0.05). The ventilatory, heart rate and blood pressure responses to
      hypoxia were comparable in the two groups during both activity states. Time to
      arousal from quiet sleep in response to hypoxia was equivalent in the two groups.
      The ventilatory response to hyperoxia was not significantly different in the two
      groups during either activity state. CONCLUSION: Continued postnatal nicotine
      exposure after prenatal exposure did not further compromise hypoxia defense
      mechanisms after birth.

PMID- 15188986
TI  - Feeding infants with undiluted goat's milk can mimic tyrosinaemia type 1.
AB  - Undiluted goats milk should not be given to infants. High protein infant feeds
      are a forgotten cause of metabolic acidosis. CONCLUSION: The metabolic
      abnormalities associated with goat's milk ingestion can cause a clinical picture
      very similar to tyrosinaemia type 1.

PMID- 15188987
TI  - Evaluation of quality of life in indian children with bronchial asthma using a
      disease-specific and locally appropriate questionnaire.
AB  - AIM: To evaluate quality of life (QOL) in Indian children with bronchial asthma.
      METHODS: A disease-specific, locally appropriate QOL questionnaire was
      administered in asthmatic children and compared with FEV1, FVC, PEFR and asthma
      symptom score, on three occasions. RESULTS: QOL score had strong negative
      correlation with symptom score and weaker positive correlation with pulmonary
      function tests. CONCLUSION: Disease-specific QOL score correlates inversely with
      symptom score in children with bronchial asthma.

PMID- 15188988
TI  - Neonatal management of symptomatic transplacental cryoglobulinaemia.
AB  - This study reports the first case of symptomatic placental transfer of
      cryoglobulins and discusses the potential pathogenic processes and the basic
      guidelines for neonatal management. A 32-y-old woman was affected by essential
      type I cryoglobulinaemia and displayed the cold-triggered cutaneous symptoms of
      the disease due to a monoclonal immunoglobulin G (IgG) cryoglobulin. She gave
      birth to healthy dizygotic twins who were placed in incubators immediately after
      birth and did not show any cutaneous or visceral lesion in the first 2 d.
      Cyanotic macules appeared on the hand and foot of one of the newborns when they
      were removed from the incubators. The same monoclonal IgG-lambda cryoglobulin was
      identified in the two newborns' cord blood and in the mother's serum. The skin
      lesions disappeared within 1 wk as both twins were transiently replaced in
      incubators. No recurrence of skin lesions was observed even at room temperature
      and, 6 mo later, both twins were healthy and their clinical examination was
      normal. CONCLUSION: To the authors' knowledge, this is the first report of
      placental transfer of cryoglobulins and the first description of any neonatal
      effect. Neonates born to mothers suffering from IgG cryoglobulinaemia should be
      protected against cold to avoid precipitation of the pathogenic cryoglobulins,
      until spontaneous resolution.

PMID- 15188989
TI  - Burst suppression on amplitude-integrated electroencephalogram may be induced by
      midazolam: a report on three cases.
AB  - Continuous amplitude-integrated electroencephalogram (aEEG) recording with a
      cerebral function monitor is a useful tool to evaluate prognoses following
      perinatal asphyxia in term infants. Drugs may change the pattern of the
      conventional EEG. This report presents three infants treated with midazolam for
      status epilepticus and repetitive seizures who proved resistant to other
      anticonvulsants (phenobarbitone, lidocaine). The infants developed burst
      suppression patterns on aEEG concurrent with high serum levels of midazolam (900
      7093 microg l(-1)). Following discontinuation of midazolam treatment, serum
      levels normalized and background patterns returned to normal voltage traces.
      CONCLUSION: These findings indicated that midazolam can cause burst suppression
      on aEEG. Therefore, the prognostic value of aEEG is limited in case of high serum
      levels of midazolam. Serum levels of midazolam should be measured in infants who
      have burst suppression patterns on aEEG during midazolam treatment.

PMID- 15188990
TI  - Necrosis of the epididymis in a premature infant with patent ductus arteriosus
      and diastolic aortic steal: ischemia or torsion?
AB  - We describe a case of isolated ischemic necrosis of the epididymis in a premature
      newborn with aortic steal syndrome, secondary to a large patent ductus arteriosus
      (PDA). Neither this finding nor the possible underlying pathogenesis has been
      previously described. CONCLUSION: In this report our knowledge of the potential
      complications of PDA in the premature neonate is extended.

PMID- 15188991
TI  - Congenital subglottic stenosis in two unrelated pairs of siblings.
AB  - Subglottic stenosis in infants is mostly acquired (secondary) and caused by
      granulation tissue or submucosal mucous gland hyperplasia after prolonged
      endotracheal intubation. Subglottic stenosis may also be congenital (primary),
      and it usually occurs sporadically. There are some reports of its association
      with inherited anomalies, but there are no previous reports of its familial
      occurrence in otherwise healthy children. This report describes two pairs of
      siblings referred for acute inspiratory stridor in whom subglottic stenosis was
      diagnosed by endoscopy. They were all born at term, and their parents were
      unrelated. One child had an anteriorly located anus but no other abnormalities.
      CONCLUSION: Without any surgical intervention all had normal breathing at rest,
      but inspiratory stridor during respiratory infections and upon physical exercise
      at follow-up 4-9 y later.

PMID- 15188992
TI  - Celiac disease and glycogenic acanthosis: a new association?
AB  - A 6-y-old boy and an 8-y-old girl were admitted to our clinic with anaemia and
      failure to thrive. Laboratory tests revealed iron deficiency anaemia and positive
      antigliadin antibodies in both of the patients. Slightly raised grey-white
      plaques were observed on oesophageal mucosa during endoscopical investigation of
      the patients. While intestinal mucosal samples confirmed diagnosis of celiac
      disease histologically, histopathological assessment of oesophageal lesions
      demonstrated glycogenic acanthosis. Since glycogenic acanthosis associated with
      celiac disease hasn't been reported in the literature previously to our
      knowledge, case reports of our patients were presented. CONCLUSION: We suggest
      that glycogenic acanthosis needs to be investigated as a possible new association
      of celiac disease in greater paediatric series.

PMID- 15188993
TI  - Mayer-Rokitansky-Kuster-Hauser syndrome associated with pulmonary stenosis.
AB  - Two siblings with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome associated with
      pulmonary valvular stenosis are reported. Although the syndrome is well
      documented, the genetic background and familial occurrence is not known and the
      association with cardiac anomalies has not previously been reported. This report
      is the first report which describes the combination of cardiac anomaly with MRKH
      syndrome.

PMID- 15188994
TI  - Identifying children at risk for language impairment: screening of communication
      at 18 months.

PMID- 15188995
TI  - Plasma homocysteine concentrations in children of families with proven myocardial
      infarction before the age of 55 years.

PMID- 15188997
TI  - The occupational, safety, and health of Florida farm workers: environmental
      justice in the fields.
AB  - This study involves a survey of farm workers in two South Florida counties
      questioning the workers about pesticide exposure, health problems, and laws and
      legal rights. A finding is that the federal and state laws which are currently in
      place to protect the workers from pesticide exposure are not adequately
      implemented. Several of the health problems farm workers noted match the symptoms
      of moderate and mild pesticide poisoning. The study concludes with policy recom
      mendations for federal and Florida officials to change and better enforce the
      current laws pertaining to farm workers.

PMID- 15188996
TI  - Managing the quality of health care.
AB  - This article reviews quality of health care initiatives beginning with the
      quality assessment/quality assurance movement of the 1970s. Conceptually, modern
      quality of care management is rooted in the intellectual work of Avedis
      Donabedian who defined quality of care as a combination of structure, process,
      and outcome. Donabedian's model is presented and some limitations are pointed
      out. In the late 1980s and 1990s. the health care industry adopted total quality
      management (TQM). More recently, the pursuit of health care quality has led to
      substantial performance measurement initiatives such as ORYX by the Joint
      Commission on Accreditation of Healthcare Organizations and MEDIS by the National
      Commission of Quality Assurance. The importance of CONQUEST, a freely available
      performance measurement database developed at the Harvard School of Public
      Health, is noted and discussed. The article concludes with a list of challenges
      facing public and private parties interests in health care quality improvement.

PMID- 15188998
TI  - Nonprofit ownership and quality in Medicaid's longterm care program for persons
      with developmental disabilities.
AB  - To assess ownership-related differences in the Intermediate Care Facility Program
      for persons with Mental Retardation (ICF/MR) Industry, this article analyzes a
      nationally representative sample of data on Medicaid certified facilities from
      the Health Care Financing Administration On-line Survey and Certification
      Reporting System. This study found that nonprofit providers provided a higher
      level of quality than for-profit facilities when organizational size and facility
      mix were controlled. The size and case-mix composition of these facilities were
      also influenced by nonprofit ownership type. Nonprofit providers offered smaller
      facilities, on average, and were more likely to enroll heavy case-mix residents
      than their for-profit counterparts.

PMID- 15188999
TI  - Change in the U.S. health care system: effects on physician retirement and
      implications for health care managers.
AB  - Several authors have postulated that managed care and other related changes in
      the U.S. health care system, perceived negatively by mature physicians, may
      contribute to their early retirement. This, in turn, may produce adverse effects
      on the availability of medical care. The authors investigate this and other
      related issues through analysis of a unique data set obtained from a survey of
      nearly four thousand physicians that elicited responses to numerous factors
      potentially relevant to their retirement decisions. The empirical analysis
      reveals that, while managed care is an important factor in the retirement
      decision of physicians, it does not necessarily lead to earlier retirement.
      Physicians rank other factors, related to financial and personal issues, as more
      important in their retirement decisions and the authors find that several of
      these factors significantly impact their expected retirement age. The results
      have several implications for health care managers relating to the retention or
      retirement of practicing physicians, successful planning, and seamless generation
      of income.

PMID- 15189000
TI  - Interorganizational networks: using a theoretical model to predict effectiveness
      of rural health care delivery networks.
AB  - Interorganizational health care delivery networks have potential for sustaining
      health services delivery in rural areas faced with economic and demographic
      challenges. Four Nebraska rural health care delivery networks (Albion-Ord, Blue
      River Valley, Rural Partners, Inc., and Western Nebraska) were compared to an
      interorganizational model based on theories of interorganizational relations,
      exchange, population ecology, and synthesized collaboration. It assumes that
      outcomes, including effectiveness, are influenced by external and internal
      factors that are operationalized through external control, technology, structure,
      and operational process variables. Data were collected by a non-random, two-level
      cluster mail survey of network members (45/59 = 76.3% response rate). All
      networks received technical assistance from the Nebraska Office of Rural Health.
      Networks have formal organization, strategic plans, and official coordinators.
      Hospital administrators hold most leadership positions; few doctors or citizens
      are involved. Correlation and multiple regression analysis show partial fit
      between the research model and study networks. Effectiveness, measure by the gap
      between best possible and actual practice, increased with network connectivity
      (r=.36, p<.05), group methods of administrative decision-making (r=.52, p<.001)
      and sequential pattern of service delivery (r=.39, p<.05). Greater dependence on
      vertical funding corresponds to greater external control (r=.43, p<.01). The
      prediction that, as scope narrows, task intensity (r=.56, p<.001), duration
      (r=.41, p<.01), and task volume (r=.50, p<.01) increase is upheld. Centrality and
      network size decrease together (r=.43, p<.01) where there is little reliance on
      vertical sources of funds (r=.36, p<.05). The integrated interorganizational
      model demonstrates some efficacy for testing potential effectiveness of networks.

PMID- 15189002
TI  - HMO middle manager perceptions of the legality of specified practices.
AB  - If Health Maintenance Organizations (HMOs) are to survive and prosper, they must
      abide by a large volume of potentially disruptive laws and regulations at the
      federal, state, and local levels. Some have suffered extreme financial loss and
      even been driven out of business because of legal transgressions. This study
      explores the ability of middle managers in large and small HMOs to distinguish
      between legal and illegal practices in light of federal laws. The study uncovered
      evidence of lack of this ability especially for managers in small HMOs. Various
      remedial measures are proposed for this problem.

PMID- 15189003
TI  - Protecting the public interests: issues in contracting managed behavioral health.
AB  - In recent years, state governments have begun contracting out behavioral health
      care to large managed case for-profit organizations. This approach to mental
      health service delivery has resulted in realignment in roles for both state
      agencies and the managed care organizations. Overnight state agencies have been
      transformed into contract managers of multi-million dollar capitated health
      plans, Management care companies, in turn, moving into the public-sector market
      must adjust their service delivery to include key concepts of public interest
      involvement such as consumer input, public comment, and outreach. This article
      analyzes three public-sector transitions. Common issues in these transformations
      are used as a springboard for identifying key concerns which states need to
      monitor when developing managed care contracts.

PMID- 15189004
TI  - The use of hospital care: do insurance status, prospective payment, and the unit
      of payments make a difference?
AB  - Limited to 251,768 discharges during 1999 from short-term hospitals located in
      Oklahoma, the objective of this study was to examine the influence of insurance
      status, prospective payment, and the unit of payment on variation in the length
      of stay. The regression analysis indicated that elderly patients whose care was
      financed by the Medicare pricing system and the uninsured experienced a
      significantly shorter episode of hospitalization than their commercially insured
      counterparts. Conversely, Medicaid recipients, whose care was financed by a fixed
      per diem and uninsured or self-responsible patients, experienced a significantly
      shorter hospital stay than the commercially insured. The results also indicate
      that the type and source of admissions, the discharge destination of the patient,
      and case complexity significantly influenced the hospital stay. African-Americans
      and Native Americans also experienced a longer episode of hospital care than
      their white counterparts. The article concludes with a discussion of policy
      implications and the need to develop alternate methods of financing hospital care
      thereby reducing the risks of premature discharge and iatrogenic injury.

PMID- 15189001
TI  - High performance public health: assessing agencies' strategic management
      capabilities.
AB  - Limited knowledge about state health agencies' strategic management capabilities
      constrains their capacity to improve public health. The current study addresses
      this gap through two objectives: 1) To assess agencies' strategic management
      capabilities, conceptualized through a learning framework and 2) To portray both
      those capabilities and where the agencies have progressed along a developmental
      pathway of strategic management ability. Forty-one state health agencies'
      documents from 1995-2000 were content analyzed. Latent Trait Analysis (LTA) was
      used to depict both the progressive levels of strategic management capabilities
      and states' relative mastery along the continuum. Findings indicate that
      strategic management capabilities have path dependent characteristics and a
      distinct learning paradigm exists. Therefore, policy-makers wishing to improve
      agency performance can utilize this framework to assess and target capabilities
      that need improvement.

PMID- 15189005
TI  - Linking public relations processes and organizational effectiveness at a state
      health department.
AB  - This qualitative case study explored a state health department's relationships
      with strategic constituencies from a public relations perspective. The
      relationships were explored within the theoretical framework of the Excellence
      Theory, the dominant paradigm in public research. Findings indicate application
      of the Excellence Theory has the potential to increase organizational
      effectiveness at public health entities. With respect to the case investigated,
      findings indicate that the state health department could increase its
      organizational effectiveness through the adoption of recommendations based on the
      Excellence Theory.

PMID- 15189006
TI  - Age-related relationships between muscle fat content and metabolic traits in
      growing rabbits.
AB  - This study was aimed at ascribing muscle fat accretion in growing rabbits to
      changes in several extra-muscular and intra-muscular metabolic pathways. At 10 wk
      or 20 wk of age (n = 8 per group), tissue lipid content and metabolic indicators
      of nutrient anabolic or catabolic pathways were simultaneously assessed in the
      liver, perirenal fat, the heart and the Longissimus lumborum (LL) muscle,
      together with plasma concentrations in energy-yielding metabolites. Lipid content
      significantly increased with age (P < or = 0.01) in the glycolytic LL muscle
      (+67%) and the oxidative heart (+30%). In the former muscle, it was statistically
      correlated (r2 = 0.68; P < 0.01) to the changes in the orientation of muscle
      metabolism towards an enhanced lipogenic capacity and a depressed capacity for
      fatty acid transport and nutrient oxidation, and to indications of lower
      availability in plasma glucose and triglycerides. In the heart, age-related fat
      accretion was positively associated (r2 = 0.48, P < 0.01) to intrinsic metabolic
      changes towards an enhanced lipogenic capacity, together with a lower
      availability in plasma glucose. Variables representative of cardiac catabolic
      capacity tended to be negatively correlated to fat content in the heart (r2 =
      0.15, P = 0.07). In growing rabbits, muscle fat content variation was proven to
      result from a reciprocal balance between catabolic and anabolic fatty acid
      fluxes, rather than to be assigned to one specific energy metabolic pathway.

PMID- 15189007
TI  - Validation of the measurement of glucose appearance rate with [6,6-2H2]glucose in
      lactating dairy cows.
AB  - The aim of this study was to validate the measurement of glucose appearance rate
      using [6,6-2H2]glucose i.v. infusion in lactating dairy cows. Sample enrichments
      were analysed by gas chromatography/mass spectrometry. Linearity (enriched
      solutions) and specificity (enriched plasma) were good: for enrichments ranging
      between 1.6 and 6.3 mol% excess, the slopes were about 1 and the ordinates at the
      origin were not different from zero. For a plasma enriched at 3.74 mol% excess,
      repeatability and long term intralaboratory reproducibility coefficients of
      variation were 1.31 and 1.90%, respectively. The appearance rates were calculated
      by two models. The values provided by the steady-state model were not different
      from those provided by the non-steady-state Steele model. Both models can be used
      because the treatment effects were similarly discriminated regardless of the
      model. In our experiments analysing the nutritional effects on Ra in mid
      lactating cows, the precision of the method (1.90%) was not the limiting factor
      to detect a significant difference in Ra compared to the statistical precision
      obtained with the experimental scheme (4 x 4 and 5 x 5 Latin square design). We
      conclude that in lactating dairy cows, the measurement of glucose fluxes with
      this method is relevant and minimally invasive for the animals.

PMID- 15189008
TI  - The effect of duration and time of food availability on the photoperiodic
      response in the male house sparrow, Passer domesticus.
AB  - We investigated the effects of food availability on the seasonal testicular
      growth in the photoperiodic house sparrow (Passer domesticus). Two experiments
      were performed, each lasting 4 weeks. In experiment 1, sparrows were exposed to
      natural (NDL; group 1), short (8L:16D; group 2) and long (16L:8D; groups 3-5) day
      lengths with access to food ad libitum (groups 1-3) or for 10 h (zeitgeber time
      (zt) 0-10, group 4; zt 0 is the time of light onset) or for 8 h (zt 8-16, group
      5). Testes recrudesced under long, but not short and natural, day lengths, and
      the recrudescence under long days was influenced by the duration of food
      availability. In experiment 2, the sparrows were exposed to short (8L:16D, group
      1) and long (16L:8D, groups 2-5) day lengths with access to food ad libitum (for
      groups 1 and 2) or for 6 h (for groups 3-5) at different times during the 16 h
      light period (group 3- zt 0-6, group 4- zt 5-11, group 5- zt 10-16). As the
      expected, the testes recrudesced only under long lengths, but the photoinduction
      was variable among the 4 groups. The testes grew to full size in groups 2 and 3
      that received food either ad libitum or for 6 h at zt 0-6, but to sub-maximal
      size in the groups that received 6 h food either at zt 5-11 (group 4) or at zt 10
      16 (group 5). Altogether, these results support the idea that the photoperiodic
      regulation of reproduction in a seasonally breeding species is influenced both by
      the duration and the time of food availability.

PMID- 15189009
TI  - Effect of intrauterine infusion of Escherichia coli on hormonal patterns in gilts
      during the oestrous cycle.
AB  - The aim of this study was to determine the effect of intrauterine Escherichia
      coli infusion on the patterns of plasma LH, prolactin, progesterone,
      androstenedione, testosterone, oestrone, oestradiol-17beta, cortisol and 13,14
      dihydro-15-keto-prostaglandin F2alpha (PGFM) in gilts during the oestrous cycle.
      On day 4 of the oestrous cycle (day 0), 25 mL of saline or 25 mL of Escherichia
      coli suspension, containing 10(7) colony forming units x mL(-1), was infused once
      into the each uterine horn in group I or II respectively. The control gilts
      developed a new oestrous cycle at the expected time but not bacteria-treated.
      Endometritis and vaginal discharge developed in all gilts after Escherichia coli
      infusion. The administration of Escherichia coli resulted in a reduction of
      plasma levels of LH, prolactin, oestrone and oestradiol-17beta (P < 0.05-0.001),
      mainly on days 15-18 after treatment (expected perioestrous period). During this
      time, the plasma androstenedione level was elevated (P < 0.05-0.001) after
      bacteria infusion. In the gilts receiving bacteria, progesterone concentration
      decreased from day 8 after treatment and was low until the end of the study (P <
      0.05-0.001). On days 8-12 after bacteria administration, the level of PGFM was
      higher (P < 0.001) than that found in the control group. These results suggest
      that the developing inflammatory process of the endometrium in gilts following
      Escherichia coli infusion significantly affects the pituitary-ovarian axis
      function as well as prostaglandin production leading to anoestrus.

PMID- 15189010
TI  - Rearing management of rabbit males selected by high growth rate: the effect of
      diet and season on semen characteristics.
AB  - A total of sixty-six young males were used to evaluate the effect of low (L),
      medium (M) and high (H) concentrations of dietary digestible energy received
      during the rearing seasons (autumn and spring) on the performance and main semen
      characteristics of males for artificial insemination selected by a high growth
      rate. Males reared during the spring season presented a significantly higher
      weight at weaning than those reared during the autumn season (P < 0.001), and
      these differences were maintained until the end of the trial. The requirements of
      the males were easily covered as a general rule. In the autumn group, the males
      were unable to intake the digestible protein recommended only during their 3rd
      month of life, especially with low concentrate diets (P < 0.05). H males showed
      higher semen concentration and production during the autumn season, while L males
      showed a higher semen concentration and production than M males during the spring
      season, the H group showed intermediate values (P < 0.001). Males reared during
      the spring season showed significantly higher values of sperm concentration (P <
      0.01) and production (P < 0.01). H males presented a lower percentage of
      spermatozoa with cytoplasmic droplets than the L group (P < 0.05) and the lowest
      values for sperm abnormalities during the autumn season, while the L group
      presented higher values for percentage abnormalities, especially during the last
      month controlled (P < 0.05). As a general rule, the main motility parameters
      controlled were not affected by the rearing diet received nor the season. These
      results seem to indicate that the management of rabbit males during the growing
      and rearing periods seem to significantly affect their subsequent performance and
      semen production.

PMID- 15189011
TI  - Development of swamp buffalo (Bubalus bubalis) embryos after parthenogenetic
      activation and nuclear transfer using serum fed or starved fetal fibroblasts.
AB  - The knowledge of oocyte activation and somatic cell nuclear transfer in the swamp
      buffalo (Buballus bubalis) is extremely rare. The objectives of this study were
      the following: (1) to investigate the various activation treatments on the
      parthenogenetic development of buffalo oocytes, (2) to examine the events of
      nuclear remodeling and in the in vitro development of cloned buffalo embryos
      reconstructed with serum fed or starved fetal fibroblasts, and (3) to investigate
      the in vivo development of cloned embryos derived from serum fed or starved cells
      after transfer into the recipients. The rates of cleavage and blastocyst
      development were found to be significantly higher (P < 0.05) when the oocytes
      were activated by the combination treatment of calcium ionophore (A23187) or
      ethanol followed by 6-DMAP than those activated by electrical pulses and 6-DMAP
      or other single treatments. Flow cytometric analysis revealed that the percentage
      in the G0/G1 phase in serum starved cells was significantly (P < 0.05) higher
      than that in serum fed cells (88.8 +/- 6.2 vs. 68.2 +/- 2.6). At 1 h post fusion
      (hpf), most of the transferred nuclei (71%) from serum fed cells did not change
      in size, and the nuclear envelope remained intact, whereas 29% underwent NEBD and
      PCC. When serum starved cells were used, 83% of the transferred nuclei underwent
      NEBD and PCC whereas 17% remained intact. The nuclear swelling and pronucleus
      (PN) formation were observed at 2-4 and 12 h post activation (hpa), respectively.
      The remodeled nuclei underwent mitotic division and developed to the 2-cell stage
      within 18-24 hpa. Fifty-five percent of oocytes reconstructed with serum fed
      cells were 2PN and 45% were 1PN, whereas 79% of the embryos reconstructed from
      starved cells were 1PN and 21% were 2PN. The percentage of blastocyst development
      of the embryos derived from starved cells was higher than that from the serum fed
      cells (35% vs. 21%, P < 0.05). Pregnancy was detected after the transfer of
      cloned blastocysts into the recipients but no recipients supported the
      development to term. The results of this work can be used to establish effective
      activation protocols for buffalo oocytes which can be used during nuclear
      transfer experiments.

PMID- 15189012
TI  - Ovulation induction in rabbit does submitted to artificial insemination by adding
      buserelin to the seminal dose.
AB  - This study was aimed at determining if a GnRH analogue, buserelin, could be used
      for ovulation induction in rabbit does submitted to artificial insemination (AI)
      by intravaginal administration, by adding the hormone to the seminal dose. In a
      first experiment, 39 secondiparous experimental does (Hyplus strain PS19, Grimaud
      Freres, France, of about 30 weeks of age) were divided into 3 groups of 13 does
      each, which at the moment of AI received the following treatments, respectively:
      (1) control: an intramuscular injection of buserelin (0.8 microg/doe), (2) 8
      microg/doe of buserelin added to the insemination dose, and (3) 16 microg/doe of
      buserelin added to the insemination dose. The experiment was done using 3
      consecutive cycles at 42 day-intervals (n = 39). Four does from each of the 3
      groups had blood taken at the fourth cycle for LH determination at 0, 60, 90, 120
      and 150 min relative to AI. Kindling rates were 82% (28/34), 56% (29/36) and 85%
      (33/39), respectively for treatments 1, 2 and 3. In the does of groups 2 and 3,
      LH peaks were detected 60 min after AI, whereas in the does from group 1, the LH
      peak was detected 90 min after AI. Prolificacy was not different for the 3
      treatments (average litter sizes ranged from 10.4 to 10.8). In a second
      experiment, 3 buserelin concentrations (8, 12 and 16 microg/doe) were used
      intravaginally and compared with the control treatment (0.8 microg/doe, via
      intramuscular). This experiment was done using 100 nulliparous rabbit does
      (Hyplus strain PS19, Grimaud Freres, France, of about 19 weeks of age) (4 groups
      of 25 does each) located on a commercial farm, to test if the previous results
      would be confirmed under field conditions. Kindling rates were no different (P <
      0.05) for the 4 treatment groups [91.7% (22/24), 79.2% (19/24), 87.0% (20/23) and
      87.5% (21/24) respectively for the control, 8, 12 and 16 microg of intravaginal
      buserelin], however, prolificacy was higher when using the maximal dose of
      intravaginal buserelin (11.7 vs. 9.4 for the control group). It was concluded
      that buserelin can be used for ovulation induction in rabbit does when included
      in the seminal dose, with similar AI results as those obtained when the hormone
      is administered intramuscularly.

PMID- 15189014
TI  - The application of an external wrist extension force reduces electromyographic
      activity of wrist extensor muscles during gripping.
AB  - STUDY DESIGN: Experimental repeated-measures study. OBJECTIVE: To investigate the
      effect of different extension forces applied to the palm of the hand on
      electromyographic (EMG) activity of the wrist extensor muscles during hand
      gripping. BACKGROUND: Lateral epicondylitis is usually caused by repetitive wrist
      extension that leads to an overuse injury. The current theory is that the process
      of lateral epicondylitis begins with an overuse injury that leads to microtearing
      of the extensor carpi radialis brevis muscle and occasionally the extensor
      digitorum communis muscle. Use of an external wrist extension force might reduce
      muscle activity during gripping. METHODS: Muscle activity was measured using
      surface EMG while subjects gripped at an intensity of 10%, 20%, and 30% of the
      maximum voluntary contraction force without, and with, an applied external wrist
      extension force of 1%, 2%, and 3% of maximum voluntary contraction. RESULTS:
      Applying an extension force to the palm of the hand reduced EMG activity of the
      extensor muscles at the same strength generation during hand gripping. The
      muscles with the most significant reduction in EMG level, the extensor carpi
      radialis brevis and extensor digitorum communis, are those muscles that are most
      often involved with lateral epicondylitis. CONCLUSIONS: This study shows that an
      external extension force reduces EMG activity of the wrist extensor muscles
      during gripping in healthy volunteers. As the extension force increased, a
      greater reduction in muscle activity was noted.

PMID- 15189013
TI  - Response of anestrous ewes to the ram effect after follicular wave
      synchronization with a single dose of estradiol-17beta.
AB  - Anestrous ewes respond to the introduction of rams with either an ovulation
      within 2-3 days that may be followed by luteal phases of normal or short length,
      with delayed ovulations (5-6 days later), or with the luteinization of follicles.
      The aim of this work was to study the relationship between the growth status of
      the largest follicle present when rams are introduced and the type of ovarian
      response in non-treated ewes and in ewes treated with estradiol-17beta before ram
      introduction. Thirteen anestrous Corriedale ewes were divided into 2 groups: E2
      (n = 7) and C (n = 6). The E2 ewes received a single dose of 50 microg estradiol
      17beta 5 days before the introduction of the rams to synchronize the onset of
      their follicle waves, while C ewes remained untreated. When the rams were
      introduced, all E2 ewes had the largest follicle in a growing stage in contrast
      with the C ewes (3 out of 6; P < 0.05). Five C and 4 E2 ewes ovulated after the
      introduction of the rams (Day 3.4 +/- 0.4 for C vs. 4.8 +/- 0.3 for E2 ewes,
      respectively, P < 0.05). Only one ewe from each group developed a normal luteal
      phase: 4 C and 3 E2 ewes had short luteal phases. One C ewe and 2 E2 ewes had
      short luteal phases originating from follicles that did not ovulate. After the
      first luteal phase, all ewes returned to anesirus without a second ovulation or
      luteal phase. The remaining E2 ewe did not ovulate or show any changes in
      progesterone serum concentrations. We conclude that the growth status of the
      largest follicle alone does not determine the ovarian responding pattern of
      anestrous ewes to the ram effect.

PMID- 15189015
TI  - Comparing the function of the upper and lower parts of the serratus anterior
      muscle using surface electromyography.
AB  - STUDY DESIGN: Prospective single-group repeated-measures design. OBJECTIVE: To
      use electromyographic (EMG) analysis during muscle testing to determine if there
      is a difference in function of the upper and lower parts of the serratus anterior
      (SA) muscle. BACKGROUND: The SA muscle is a very important scapular protractor
      and upward rotator. Authors have anatomically described the muscle as being
      divided into 2 or 3 parts, and have suggested that the upper part is more suited
      for protraction and the lower part for upward rotation of the scapula. METHODS
      AND MEASURES: Surface electrodes recorded EMG activity of the upper and lower
      parts of the SA muscle during 9 different muscle tests in 29 healthy subjects.
      RESULTS: Three muscle tests demonstrated significantly greater (P<.05) EMG
      activity in the lower part of the SA as compared to the upper part. There was no
      significant difference in the EMG activity of the upper and lower parts of the SA
      when the other 6 muscle tests were analyzed. CONCLUSION: When upward rotation was
      the primary position of the scapula during the muscle tests, the lower part of
      the SA was activated to a greater degree than the upper part. Muscle tests with
      maximum scapular protraction with varying degrees of upward rotation produced EMG
      activity with no significant difference when comparing the upper and lower parts
      of the SA. This information may be helpful for clinicians when muscle testing and
      developing exercise programs for the SA muscle.

PMID- 15189016
TI  - Performance of a high-repetition, high-force task induces carpal tunnel syndrome
      in rats.
AB  - STUDY DESIGN: A randomized controlled prospective experimental study with some
      repeated measures. OBJECTIVES: To characterize behavioral, sensory, motor, and
      nerve conduction decrements, and histological changes in the median nerve in rats
      trained to perform a high-force repetitive task. BACKGROUND: Understanding of
      work-related carpal tunnel syndrome is hampered by the lack of experimental
      studies of the causes and mechanisms of nerve compression induced by repetitive
      motion. Most animal models of nerve compression have not employed voluntary
      repetitive motion as the stimulus for pathophysiological changes. METHODS AND
      MEASURES: Thirty Sprague-Dawley rats served as controls for 1 or more studies.
      Ten rats were trained to pull on a bar with 60% maximum force 4 times per minute,
      2 h/d, 3 d/wk for 12 weeks. Motor behavior and limb withdrawal threshold force
      were characterized weekly. Grip strength and median nerve conduction velocity
      were measured after 12 weeks. Median nerves were examined immunohistochemically
      for ED1-positive macrophages, collagen, and connective tissue growth factor.
      RESULTS: Reach rate and duration of task performance declined over 12 weeks. Grip
      strength and nerve conduction velocity were significantly lower after 12 weeks
      than in controls. Limb withdrawal threshold increased between weeks 6 and 12.
      Median nerves at the level of the wrist showed increases in macrophages,
      collagen, and connective-tissue growth-factor-positive cells. These effects were
      seen in both the reach and nonreach limbs. CONCLUSIONS: This animal model
      exhibits all the features of human carpal tunnel syndrome, including impaired
      sensation, motor weakness, and decreased median nerve conduction velocity. It
      establishes a causal relationship between performance of a repetitive task and
      development of carpal tunnel syndrome.

PMID- 15189017
TI  - Differences in back extensor strength between smokers and nonsmokers with and
      without low back pain.
AB  - STUDY DESIGN: Cross-sectional study comparing isometric lumbar extensor strength
      (ILES) in individuals who smoke and nonsmokers with and without low back pain
      (LBP). OBJECTIVES: To examine the differences in ILES between individuals who
      smoke and nonsmokers with and without LBP. BACKGROUND: Given the evidence for
      general muscle weakness in individuals who smoke and in individuals with LBP, we
      were interested in examining the interrelationships between back strength, in
      particular ILES, and LBP in individuals who smoke and nonsmokers. METHODS AND
      MEASURES: The study involved 76 men (age range, 30-50 years) in 4 groups, namely,
      nonsmokers with LBP (NS-LBP), a control group of nonsmokers without LBP (NS-C),
      smokers with LBP (S-LBP), and a control group of smokers without LBP (S-C). ILES
      was measured at 7 angles of lumbar flexion, specifically 72 degrees, 60 degrees,
      48 degrees, 36 degrees, 24 degrees, 12 degrees, and 0 degrees. ANOVA and Scheffe
      post hoc comparison tests were used to analyze the data. RESULTS: Nonsmokers with
      LBP had less muscle strength than those without LBP (P<.01). However, the
      strength of smokers with and without LBP was comparable (P>.05). Both groups of
      individuals who did not smoke were stronger than the 2 groups comprised of
      smokers. CONCLUSIONS: Individuals who smoke were weaker than those who did not
      smoke, but no difference in strength was noted between smokers with and without
      LBP. Although smoking appears to be an important cofactor in the etiology of LBP,
      the degree to which smoking is a primary, secondary, or a component of a combined
      etiology warrants further study.

PMID- 15189018
TI  - An assessment of high school cheerleading: injury distribution, frequency, and
      associated factors.
AB  - STUDY DESIGN: Mail survey of cheerleading-related training and injuries.
      OBJECTIVE: To collect and describe injury frequency, distribution, and associated
      factors related to the activity of cheerleading. BACKGROUND: Estimates indicate
      that more than 1 million participants are involved in cheerleading at various
      levels; however, little information exists relative to injuries and training.
      Unlike most other sports, cheerleader injuries are not tracked in a central
      database. METHODS AND MEASURES: High school cheerleaders (mean age, 16.3 years)
      in 3 midwest states completed questionnaires mailed to their respective high
      schools. Of the surveys mailed to 104 schools, 425 (32.2%) were returned and
      sufficiently completed for analysis. RESULTS: Participants reported an average of
      4.1 years of experience and 61.9% of the respondents had sustained 1 or more
      career injury. During the previous year, 41.3% had sustained 1 or more injuries
      (mean +/- SD, 1.7 +/- 1.9), resulting in an average of 3.4 reported missed
      practice or performance days. Of all injuries, the ankle (24.4%), back (16.1%),
      and wrist or hand (15.6%) were the most frequent sites of injury. CONCLUSION: The
      rates of injury in cheerleading are comparable to rates of other sports. To
      accurately provide safety guidelines for all levels of cheerleading, a nationwide
      injury tracking system is necessary.

PMID- 15189019
TI  - Overview. Accreditation in health administration education: a call for change.

PMID- 15189020
TI  - Introduction. The continuous pursuit of quality through accreditation.

PMID- 15189021
TI  - The final report of the Blue Ribbon Task Force on Accreditation.

PMID- 15189022
TI  - The report of the Blue Ribbon Task Force: challenges and opportunities.
AB  - The BRTF report can serve as a catalyst for change in health services management
      and accreditation. Many of their recommendations should be widely endorsed by our
      professional community; others demand careful consideration and will promote a
      useful dialog. There are a good many challenges involved with implementing these
      changes, and they will require time, creativity and a great deal of hard work.
      Only time will tell if history affords the Blue Ribbon Task Force's Report the
      same stature as the Prall, Olsen, and Dixon reports. Other position papers will
      no doubt follow that extend as well as refute its recommendations. The real value
      of this report will be in the dialog and change process it promotes.

PMID- 15189023
TI  - Must we broaden the definition of health services administration? A response to
      the Final Report of the Blue Ribbon Task Force.

PMID- 15189024
TI  - Blue Ribbon kudos.

PMID- 15189025
TI  - Contemporary models for accreditation: lessons for health administration
      education accreditation.

PMID- 15189026
TI  - Definition and scope of health services administration.
AB  - The definition and scope of health services administration are important to
      public policy, educational programs, new entrants to the field, and
      practitioners. Formal definition of the field of health services administration
      has not received concerted attention since 1975. Significant changes in the field
      have occurred since that time, widening opportunities for graduates of
      educational programs and increasing interdependencies between health services
      organizations and public policy organizations, supplier organizations, insurers,
      and other businesses that are not involved directly in health services delivery.
      Stakeholders in the field of health services administration should consider a
      broadened definition of the field that would institutionalize and build on those
      increased opportunities and interdependencies.

PMID- 15189027
TI  - Stakeholder satisfaction with the accreditation process.

PMID- 15189028
TI  - ACEHSA accreditation safeguards the public interest.
AB  - Daily, we are reminded that the public's investment in attaining quality health
      and medical care is among the most important priorities of our nation's citizens.
      Central to realizing that attainment is the level of professional competence of
      those charged with managing the nation's health resources. The not-for-profit
      Accrediting Commission on Education for Health Services Administration is the
      sole national organization governing the standards by which future health
      managers, administrators, and executives are educated and trained in accredited
      graduate programs. The impact of the ACEHSA is growing as health and medical
      leaders, government and regulatory policy-makers, insurance executives, special
      interest groups, and, of course, members of the public increasingly realize that
      top-flight healthcare delivery requires excellence in the management of health
      resources.

PMID- 15189029
TI  - Per-6-substituted-per-6-deoxy beta-cyclodextrins inhibit the formation of beta
      amyloid peptide derived soluble oligomers.
AB  - Recent studies have indicated that the most important role of beta-amyloid
      peptide (Abeta) in the etiology of Alzheimer's disease may not be in plaque
      formation but in the formation of soluble, metastable Abeta(1-42) neurotoxic
      intermediates (called ADDLs). In the present work we describe the preparation of
      per-6-amino-6-deoxy-beta-cyclodextrins, which inhibit ADDLs formation in vitro.

PMID- 15189030
TI  - Assessment of multiple binding modes in ligand-protein docking.
AB  - Computational ligand-protein docking is routinely used for binding mode
      prediction. We have quantified the effect of considering multiple docking
      solutions on the success rate of obtaining the crystallographic binding mode. By
      selection of a small set of representatives, the experimentally observed binding
      mode can be predicted with a higher probability after a ligand-protein docking
      simulation. The proportion of correctly predicted complexes improved from 69% to
      87% when five distinct binding modes were considered.

PMID- 15189031
TI  - Design and synthesis of novel biologically active thrombin receptor non-peptide
      mimetics based on the pharmacophoric cluster Phe/Arg/NH2 of the Ser42-Phe-Leu-Leu
      Arg46 motif sequence: platelet aggregation and relaxant activities.
AB  - The identification of the thrombin receptor has promoted the interest for the
      development of new therapeutic agents capable of selectively inhibiting unwanted
      biological effects of thrombin on various cell types. In this study we have
      designed and synthesized two series of new thrombin receptor antagonists based on
      the thrombin receptor motif sequence S42FLLR46, one possessing two (Phe/Arg)
      pharmacophoric groups and the other possessing three (Phe/Arg/NH2). N-(6
      Guanidohexanoyl)-N'-(phenylacetyl)piperazine (1), N-(phenylacetyl)-4-(6
      guanidohexanoylamidomethyl)piperidine (2), and N-(phenylacetyl)-3-(6
      guanidohexanoylamido)pyrrolidine (3) (group A) carry the two pharmacophoric side
      chains of Phe and Arg residues incorporated on three different templates
      (piperazine, 4-aminomethylpiperidine, and 3-aminopyrrolidine). Compounds with
      three pharmacophoric groups (group B) were built similarly to group A using the
      same templates with the addition of an extra methylamino group leading to (S)-N
      (6-guanidohexanoyl)-N'-(2-amino-3-phenylpropionyl)piperazine (4), (S)-N-(2-amino
      3-phenylpropionyl)-4-(6-guanidohexanoylamidomethyl)piperidine (5), and (S)-N-(2
      amino-3-phenylpropionyl)-3-(6-guanidohexanoylamido)pyrrolidine (6). Compounds
      were able to inhibit thrombin-induced human platelet activation even at low
      concentrations. In particular, among compounds in group A, compound 3 was found
      to be the most powerful thrombin receptor activation inhibitor, showing an IC50
      of approximately 0.11 mM on platelet aggregation assay. Among compounds in group
      B, compound 4 was the most powerful to inhibit thrombin-induced platelet
      aggregation, showing an IC50 of approximately 0.09 mM. All compounds were also
      found to act as agonists in the rat aorta relaxation assay. Interestingly, the
      order of potency of these compounds as agonists of the endothelial thrombin
      receptor was the inverse of the order of potency of the same compounds as
      antagonists of the platelet thrombin receptor. Such compounds that are causing
      vasodilation while simultaneously inhibiting platelet aggregation would be very
      useful in preventing the installation of atherosclerotic lesions and deserve
      further investigation as potential drugs for treating cardiovascular diseases.
      The above findings coupled with computational analysis molecular dynamics
      experiments support also our hypothesis that a cluster of phenyl, guanidino, and
      amino groups is responsible for thrombin receptor triggering and activation.

PMID- 15189032
TI  - Design and synthesis of potent inhibitors of the malaria aspartyl proteases
      plasmepsin I and II. Use of solid-phase synthesis to explore novel statine
      motifs.
AB  - Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin
      (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been
      identified from sets of libraries containing novel statine-like templates
      modified at the amino and carboxy terminus. The syntheses of the novel statine
      templates were carried out in solution phase using efficient synthetic routes and
      resulting in excellent stereochemical control. The most promising statine
      template was attached to solid support and diversified by use of parallel
      synthesis. The products were evaluated for their Plm I and II inhibitory activity
      as well as their selectivity over cathepsin D. Selected inhibitors were, in
      addition, evaluated for their inhibition of parasite growth in cultured infected
      human red blood cells. The most potent inhibitor in this report, compound 16,
      displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16
      is also effective in attenuating parasite growth in red blood cells showing 51%
      inhibition at a concentration of 5 microM. Several inhibitors have been
      identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II.
      Some of these inhibitors also show excellent selectivity vs cathepsin D.

PMID- 15189034
TI  - Progesterone receptor ligand binding pocket flexibility: crystal structures of
      the norethindrone and mometasone furoate complexes.
AB  - Although progesterone, the natural ligand of the progesterone receptor (PR), has
      a hydrogen atom at the 17alpha position, other potent steroid agonists such as
      norethindrone and mometasone furoate have larger substituents at this position
      that are accommodated by the PR ligand binding pocket. Crystallographic analysis
      of PR ligand binding domain complexes clearly demonstrated that these moieties
      were accommodated by local shifts of the protein main chain and by adoption of
      alternative side chain rotamer conformations of ligand-proximal amino acids.
      These conformational changes imparted a ligand-specific volume to the binding
      pocket, from 490 A3 in the metribolone complex to 520 A3 in the norethindrone
      complex, 565 A3 in the progesterone complex, and 730 A3 in the mometasone furoate
      complex. Despite these marked alterations in binding pocket volume, critical
      interactions essential for establishment of an active AF2 conformation were
      maintained.

PMID- 15189033
TI  - 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
AB  - Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms
      is a hallmark of virtually all cancer cells. Compounds targeting complexes
      between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and
      CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising
      antitumor agents to complement the existing therapies. From a high-throughput
      screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The
      hit-to-lead expansion of this class is described. X-ray crystallographic data of
      early compounds in this series, as well as in vitro testing funneled for rapidly
      achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5
      cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37
      nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a
      dose devoid of toxic effects.

PMID- 15189035
TI  - Structure-activity relationships at monoamine transporters for a series of N
      substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular
      field analysis, synthesis, and pharmacological evaluation.
AB  - The development of structure-activity relationships (SAR) with divergent classes
      of monoamine transporter ligands and comparison of their effects in animal models
      of cocaine abuse have provided insight into the complex relationship among
      structure, binding profiles, and behavioral activity. Many 3alpha
      (diphenylmethoxy)tropane (benztropine) analogues are potent dopamine uptake
      inhibitors but exhibit behavioral profiles that differ from those of cocaine and
      other compounds in this class. One of the most potent and dopamine transporter
      (DAT) selective N-substituted benztropine analogues (N-(4-phenyl-n-butyl)-3alpha
      (bis[4-fluorophenyl]methoxy)tropane, 1c) is devoid of cocaine-like behaviors in
      rodent models but is also highly lipophilic (cLogD = 5.01), which compromises its
      water solubility and may adversely affect its pharmacokinetic properties. To
      further explore the SAR in this series and ultimately to design dopamine uptake
      inhibitors with favorable lipophilicities for drug development, a comparative
      molecular field analysis (CoMFA) was performed on a set of benztropine analogues
      previously synthesized in our laboratory. The CoMFA field analysis on the
      statistically significant (r2(cv) = 0.632; r2(ncv) = 0.917) models provided
      valuable insight into the structural features required for optimal binding to the
      DAT, which was used to design a series of novel benztropine analogues with
      heteroatom substitutions at the tropane N-8. These compounds were evaluated for
      binding at DAT, serotonin (SERT) and norepinephrine (NET) transporters, and
      muscarinic M1 receptors in rat brain. Inhibition of [3H]DA uptake in synaptosomes
      was also evaluated. Most of the analogues showed high DAT affinity (12-50 nM),
      selectivity (10- to 120-fold), potent inhibition of dopamine uptake, and lower
      lipophilicities as predicted by cLogD values.

PMID- 15189037
TI  - On the function of the 14 A long internal cavity of histone deacetylase-like
      protein: implications for the design of histone deacetylase inhibitors.
AB  - Histone deacetylases (HDACs) play an important role in gene transcription.
      Inhibitors of HDACs induce cell differentiation and suppress cell proliferation
      in tumor cells. AutoDock calculations of known and novel HDAC inhibitors as well
      as of several probe molecules to histone deacetylase-like protein (HDLP), using a
      modified scoring function for metalloproteins, demonstrate excellent agreement (R
      = 0.92) between experimental and computed binding constants. Analysis of the
      docked structures allows a determination of the different binding motifs in known
      inhibitors. Such calculations are a useful tool for the prediction of binding
      constants for new HDAC inhibitors. Exploration of the 14 A long internal cavity
      adjacent to the active site by docking of small molecular probes suggest that it
      plays a crucial role by accepting the cleaved acetate and releasing it at the far
      side of the cavity. The importance of the findings for the design of new
      inhibitors is discussed.

PMID- 15189036
TI  - Synthesis, structure-activity relationships, and drug resistance of beta-d-3'
      fluoro-2',3'-unsaturated nucleosides as anti-HIV Agents.
AB  - Our recent studies demonstrated that d- and l-2'-fluoro-2',3'-unsaturated
      nucleosides (d- and l-2'-F-d4Ns) display moderate to potent antiviral activities
      against HIV-1 and HBV. As an extension of these findings, beta-d-3'-fluoro-2',3'
      unsaturated nucleosides were synthesized as potential antiviral agents. The key
      intermediate (2S)-5-(1,3-dioxolan)-1-benzoyloxy-3,3-difluoropentan-2-ol 6 was
      prepared from 2,3-O-isopropylidene-d-glyceraldehyde 1, which was converted to 5-O
      benzoxy-d-2-deoxy-3,3-difluoropentofuranosyl acetate 7 by the ring-closure
      reaction under acidic conditions. The acetate 7 was condensed with silylated
      purine and pyrimidine bases, which produced the alpha and beta isomers. The 3',3'
      difluoro nucleosides were then treated with t-BuOK to give the desired 3'-fluoro
      unsaturated nucleosides. We studied the structure-activity relationships of d-3'
      fluoro-2',3'-unsaturated nucleosides against HIV-1 in human peripheral blood
      mononuclear cells, from which we found that the cytosine derivative 26 was the
      most potent among the synthesized compounds. To understand the mode of action and
      drug resistance profile, with particular regard to the role of fluorine, we
      performed the molecular modeling studies of the cytidine analogue d-3'F-d4C and
      found a good correlation between calculated relative binding energies and
      activity/resistance data. Our model also shows interactions of the 3'-fluorine
      and the 2',3' double bond, which can be correlated to the observed biological
      data. Differences between fluorine substitution at the 3' and 2' positions may
      account for the higher cross-resistance with lamivudine observed in the 2'
      fluorinated series.

PMID- 15189038
TI  - Hybrids of [TSAO-T]-[foscarnet]: The first conjugate of foscarnet with a non
      nucleoside reverse transcriptase inhibitor through a labile covalent ester bond.
AB  - This paper describes the first example of combination of non-nucleoside reverse
      transcriptase inhibitors such as TSAO derivatives and foscarnet (PFA) in a single
      molecule through a labile covalent ester bond. The essential criteria in the
      design of these hybrids [TSAO-T]-[PFA] was to explore if the conjugation of
      foscarnet with the highly lipophilic TSAO derivative may facilitate the
      penetration of the conjugates through the cell membrane and if the hybrids escape
      extracellular hydrolysis and regenerate the parent inhibitors intracellulary.
      Several [TSAO-T]-[PFA] conjugates proved markedly inhibitory to HIV-1. Some of
      them also showed potent activity against PFA-resistant HIV-1 strains but fewer
      had detectable inhibitory activity against TSAO-resistant HIV-1 strains. These
      results indicated a pivotal role of the TSAO component of the hybrid but not the
      PFA component in the activity of the conjugates. Moreover, stability studies of
      the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS
      whereas some of the conjugates regenerated the parent inhibitors in extracts from
      CEM cells.

PMID- 15189039
TI  - Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by
      high-energy intermediate and transition-state analogues.
AB  - Two series of compounds were designed to mimic the transition state and high
      energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate
      dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the
      transition state during the oxidation of the substrate to 3-keto-6
      phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and
      amide derivatives of d-erythronic acid were designed to mimic the 1,2-cis-enediol
      HEI of the 6PGDH reaction. These two series of compounds were assayed as
      competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and
      their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide
      transition-state analogues showed weak and selective inhibition of the T. brucei
      enzyme. The hydroxamic derivatives showed potent and selective inhibition of the
      T. brucei 6PGDH with a Ki in the nanomolar range.

PMID- 15189040
TI  - Synthesis, X-ray crystal structures, stabilities, and in vitro cytotoxic
      activities of new heteroarylacrylonitriles.
AB  - Twenty-three acrylonitriles, substituted at position 2 with either triazoles or
      benzimidazoles and at position 3 with various substituted furan, thiophene, or
      phenyl rings, were prepared by Knoevenagel condensation and tested for in vitro
      cytotoxic potency on 11 human cancer cell lines. X-ray crystal analysis of two
      representative compounds showed that the olfenic bond is E-configured. Structure
      activity-relationships (SAR) indicated that position 2 is flexible for
      substituents with various nitrogen heterocyclics while position 3 is very
      sensitive to change; the most potent compounds contained a 5-nitrothiophen-2-yl
      ring at position 3 and either benzimidazol-2-yl (11) or a 5-benzyl-1H-[1,2,4]
      triazol-3-yl (7) group at position 2 of acrylonitrile. SARs for the thiophen-2-yl
      benzimidazoles show the following trend for position 5: NO2 >> H > Cl = CH3.
      Compound 11 was on average 10- and 3-fold more potent than cisplatin and
      etoposide, respectively. However, the acrylonitrile functionality is not an
      absolute requirement for cytotoxic activity because replacement of the nitrile
      group for either a hydrogen or a methyl group also gave active compounds. The
      acrylonitriles caused delayed cell death characterized by giant cells with
      multilobed nuclei. Compound 11 was found to bring about the increase in the
      activities of caspases 3 and 9 in the HL-60 cell line in a manner similar to
      etoposide, strongly indicating that apoptosis is the mechanism of cell death. The
      selectivity of various compounds toward cancer cells was estimated by comparing
      the IC50 values obtained from a noncancerous epithelial cell line, h-TERT-RPE1,
      with the average IC50 value from the cancer cell lines; 11 showed an average 1.7
      fold greater activity toward cancer cells. The stabilities of the new compounds
      under cell culture conditions, estimated by HPLC, indicated that a major fraction
      of the compounds were lost from the medium over the first 24 h.

PMID- 15189041
TI  - Determinants of corticotropin releasing factor. Receptor selectivity of
      corticotropin releasing factor related peptides.
AB  - The corticotropin-releasing factor (CRF) peptide family is an important target in
      pharmaceutical research. The CRF system consists of two receptors, corticotropin
      releasing factor receptor 1 (CRF1R) and corticotropin releasing factor receptor 2
      (CRF2R), a nonreceptor binding protein, and the peptide agonists of these
      receptors. The recent discovery of the CRF2R selective peptide agonists, UCN2,
      UCN3 and URP, prompted investigations into the structural source of CRF1R versus
      CRF2R selectivity of CRF peptide family members. Data from chimeric peptides
      demonstrated that amino acids in the N-terminus and C-terminus of CRF, UCN1, UCN2
      and Sauvagine peptide families influence CRFR selectivity. Analysis of specific
      amino acid residues in the N-terminus and C-terminus demonstrated that the
      presence of a proline at position 11 and alanine at positions 35 and 39 (hCRF
      numbering) decreases CRF1R activity and increases CRF2R selectivity in CRF, UCN1
      and sauvagine peptides. The availability of a large group of selective and
      nonselective CRF receptor peptide agonists will facilitate the development of CRF
      receptor selective drugs.

PMID- 15189043
TI  - The human toxicology of polychlorinated biphenyls: 209 isomers in search of a
      disease.

PMID- 15189042
TI  - Novel pyridazino[4,3-b]indoles with dual inhibitory activity against
      Mycobacterium tuberculosis and monoamine oxidase.
AB  - Tuberculosis is one of the most common infectious diseases known to man. About
      37% of the world's population (about 1.86 billion people) are infected with
      Mycobacterium tuberculosis. According to the World Health Organization, every
      year approximately 8 million people develop active tuberculosis and almost 2
      million of those die from the disease. The incidence of multidrug-resistant
      tuberculosis (MDR-TB) is increasing. The present drug regimen for treating
      tuberculosis has been in existence for 30 years. New drugs that will shorten
      total treatment duration, improve the treatment of MDR-TB, and address latent
      tuberculosis are the most urgent need of tuberculosis control programs. A new
      series of synthetic 3-amino-4-arylpyridazino[4,3-b]indoles (pyridazinoindoles)
      were identified as inhibitors of Mycobacterium tuberculosis. The design,
      synthesis, and antimycobacterial activity of these compounds are described. While
      the most active compounds are still not comparable to the front-line drugs
      rifampicin and isoniazid, they do show promise. Most of the pyridazinoindoles
      with appreciable antituberculosis activity also inhibit monoamine oxidase,
      suggestive of a novel inhibitory effect on mycobacterial redox reactions.

PMID- 15189044
TI  - Pharmacokinetics and blood levels of polychlorinated biphenyls.
AB  - Despite the enormous number of reports on polychlorinated biphenyl (PCB)
      toxicology, both the causal interpretation of epidemiological studies and the
      risk assessment of human exposures have been hampered by the lack of information
      on the pharmacokinetics of various PCB isomers and congeners. Thus, the
      assessment of exposure by means of measuring either total PCBs or individual
      congeners in the blood has so far been unsatisfactory. For example, the
      concentration and the pattern of congeners in the blood did not correlate with
      that at site(s) of action. In fact, the same levels of blood PCBs correlated with
      either toxic effects or no effects (both in clinical and epidemiological
      studies). In addition, when toxicity caused by PCBs was observed, the severity of
      the signs did not correlate with blood levels. Reasons for such a qualified
      failure are manifold and include different ways of reporting blood measurements,
      the different toxicological characteristics of each PCB, and different timing of
      sampling the blood, etc. Therefore, only limited conclusions can be drawn
      concerning what blood PCB measurements mean.

PMID- 15189045
TI  - Human exposure to polychlorinated biphenyls and health effects: a critical
      synopsis.
AB  - Polychlorinated biphenyls (PCBs) are a mixture of chemicals. Some congeners of
      the mixture are highly persistent both in the environment and in humans. Although
      PCBs have not been used commercially since about 1977 in the US, they can still
      be detected in human blood and tissues in this country. PCB levels are declining
      and are often no longer detectable in younger people. A cursory review of recent
      animal studies is provided. Studies to determine whether PCBs cause cancer in
      humans, neurobehavioural effects, abnormal thyroid and immune function in
      children and low birth weight are discussed in more detail. These studies are
      inconclusive and do not provide clinical evidence that PCBs at levels encountered
      with human exposure produce adverse health effects. The differences in PCB blood
      or tissue concentrations between controls and cases, or between the upper and
      lower end of various environmentally exposed groups of children or adults, are
      small. Although some effects are statistically significantly different, they do
      not appear to be biologically significant. Many studies on the effects of PCBs
      are difficult to interpret because the range of normal values for clinical and
      neurobehavioural tests are not provided or appropriately considered, there was
      no, or inadequate, control for potential confounders. In occupational mortality
      studies, exposures were much higher. In some studies, various specific cancers
      were elevated. However, these appear to be chance observations resulting from
      multiple comparisons since the increase of specific cancers was not consistent
      between studies and was no longer present in some cohorts when studies were
      repeated at a later date with longer follow-up. Overall, the data fail to
      demonstrate conclusive adverse health effects of PCBs at concentrations
      encountered with human exposures.

PMID- 15189046
TI  - Idiopathic environmental intolerance: Part 1: A causation analysis applying
      Bradford Hill's criteria to the toxicogenic theory.
AB  - Idiopathic environmental intolerance (IEI) is a descriptor for a phenomenon that
      has many names including environmental illness, multiple chemical sensitivity and
      chemical intolerance. Toxicogenic and psychogenic theories have been proposed to
      explain IEI. This paper presents a causality analysis of the toxicogenic theory
      using Bradford Hill's nine criteria (strength, consistency, specificity,
      temporality, biological gradient, biological plausibility, coherence,
      experimental intervention and analogy) and an additional criteria (reversibility)
      and reviews critically the scientific literature on the topic. The results of
      this analysis indicate that the toxicogenic theory fails all of these criteria.
      There is no convincing evidence to support the fundamental postulate that IEI has
      a toxic aetiology; the hypothesised biological processes and mechanisms are
      implausible.

PMID- 15189047
TI  - Idiopathic environmental intolerance: Part 2: A causation analysis applying
      Bradford Hill's criteria to the psychogenic theory.
AB  - Toxicogenic and psychogenic theories have been proposed to explain idiopathic
      environmental intolerance (IEI). Part 2 of this article is an evidence-based
      causality analysis of the psychogenic theory using an extended version of
      Bradford Hill's criteria. The psychogenic theory meets all of the criteria
      directly or indirectly and is characterised by a progressive research programme
      including double-blind, placebo-controlled provocation challenge studies. We
      conclude that IEI is a belief characterised by an overvalued idea of toxic
      attribution of symptoms and disability, fulfilling criteria for a somatoform
      disorder and a functional somatic syndrome. A neurobiological diathesis similar
      to anxiety, specifically panic disorder, is a neurobiologically plausible
      mechanism to explain triggered reactions to ambient doses of environmental
      agents, real or perceived. In addition, there is a cognitively mediated fear
      response mechanism characterised by vigilance for perceived exposures and bodily
      sensations that are subsequently amplified in the process of learned sensitivity.
      Implications for the assessment and treatment of patients are presented.

PMID- 15189049
TI  - Spatial chaos of trapped Bose-Einstein condensate in one-dimensional weak optical
      lattice potential.
AB  - The spatially chaotic attractor in an elongated cloud of Bose-Einstein condensed
      atoms perturbed by a weak optical lattice potential is studied. The analytical
      insolvability and numerical incomputability of the atomic number density are
      revealed by a perturbed solution that illustrates the unpredictability of the
      deterministic chaos. Although this could lead the nonphysical explosion and
      unboundedness to the numerical solution, the theoretical analysis offers a
      criterion to avoid them. Moreover, the velocity field is investigated that
      exhibits the superfluid property of the chaotic system.

PMID- 15189048
TI  - Boolean networks with variable number of inputs (K).
AB  - We studied a random Boolean network model with a variable number of inputs K per
      element. An interesting feature of this model, compared to the well-known fixed-K
      networks, is its higher orderliness. It seems that the distribution of
      connectivity alone contributes to a certain amount of order. In the present
      research, we tried to disentangle some of the reasons for this unexpected order.
      We also studied the influence of different numbers of source elements (elements
      with no inputs) on the network's dynamics. An analysis carried out on the
      networks with an average value of K=2 revealed a correlation between the number
      of source elements and the dynamic diversity of the network. As a diversity
      measure we used the number of attractors, their lengths and similarity. As a
      quantitative measure of the attractors' similarity, we developed two methods, one
      taking into account the size and the overlapping of the frozen areas, and the
      other in which active elements are also taken into account. As the number of
      source elements increases, the dynamic diversity of the networks does likewise:
      the number of attractors increases exponentially, while their similarity
      diminishes linearly. The length of attractors remains approximately the same,
      which indicates that the orderliness of the networks remains the same. We also
      determined the level of order that originates from the canalizing properties of
      Boolean functions and the propagation of this influence through the network. This
      source of order can account only for one-half of the frozen elements; the other
      half presumably freezes due to the complex dynamics of the network. Our work also
      demonstrates that different ways of assigning and redirecting connections between
      elements may influence the results significantly. Studying such systems can also
      help with modeling and understanding a complex organization and self-ordering in
      biological systems, especially the genetic ones.

PMID- 15189050
TI  - Convergence of the natural approximations of piecewise monotone interval maps.
AB  - We consider piecewise monotone interval mappings which are topologically mixing
      and satisfy the Markov property. It has previously been shown that the invariant
      densities of the natural approximations converge exponentially fast in uniform
      pointwise topology to the invariant density of the given map provided its
      derivative is piecewise Lipshitz continuous. We provide an example of a map which
      is Lipshitz continuous and for which the densities converge in the bounded
      variation norm at a logarithmic rate. This shows that in general one cannot
      expect exponential convergence in the bounded variation norm. Here we prove that
      if the derivative of the interval map is Holder continuous and its variation is
      well approximable (gamma-uniform variation for gamma>0), then the densities
      converge exponentially fast in the norm.

PMID- 15189051
TI  - Estimation of dynamical invariants without embedding by recurrence plots.
AB  - In this paper we show that two dynamical invariants, the second order Renyi
      entropy and the correlation dimension, can be estimated from recurrence plots
      (RPs) with arbitrary embedding dimension and delay. This fact is interesting as
      these quantities are even invariant if no embedding is used. This is an important
      advantage of RPs compared to other techniques of nonlinear data analysis. These
      estimates for the correlation dimension and entropy are robust and, moreover, can
      be obtained at a low numerical cost. We exemplify our results for the Rossler
      system, the funnel attractor and the Mackey-Glass system. In the last part of the
      paper we estimate dynamical invariants for data from some fluid dynamical
      experiments and confirm previous evidence for low dimensional chaos in this
      experimental system.

PMID- 15189052
TI  - Retracting fronts induce spatiotemporal intermittency.
AB  - The intermittent route to spatiotemporal complexity is analyzed in simple models
      which display a subcritical bifurcation without hysteresis. A new type of
      spatiotemporal complex behavior is found, induced by fronts which "clean" the
      perturbations around an unstable state. The mechanism which generates these
      "retracting fronts" through nonlinear dispersion is analyzed in the frame of the
      complex Ginzburg-Landau equation. For sufficiently strong nonlinear dispersion
      the effects also occur for a supercritical bifurcation.

PMID- 15189053
TI  - The structure of synchronization sets for noninvertible systems.
AB  - Unidirectionally coupled systems (x,y) --> (f(x),g(x,y)) occur naturally, and are
      used as tractable models of networks with complex interactions. We analyze the
      structure and bifurcations of attractors in the case the driving system is not
      invertible, and the response system is dissipative. We discuss both cases in
      which the driving system is a map, and a strongly dissipative flow. Although this
      problem was originally motivated by examples of nonlinear synchrony, we show that
      the ideas presented can be used more generally to study the structure of
      attractors, and examine interactions between coupled systems.

PMID- 15189054
TI  - Modeling of heat explosion with convection.
AB  - The work is devoted to numerical simulations of the interaction of heat explosion
      with natural convection. The model consists of the heat equation with a nonlinear
      source term describing heat production due to an exothermic chemical reaction
      coupled with the Navier-Stokes equations under the Boussinesq approximation. We
      show how complex regimes appear through successive bifurcations leading from a
      stable stationary temperature distribution without convection to a stationary
      symmetric convective solution, stationary asymmetric convection, periodic in time
      oscillations, and finally aperiodic oscillations. A simplified model problem is
      suggested. It describes the main features of solutions of the complete problem.

PMID- 15189055
TI  - Breaking a secure communication scheme based on the phase synchronization of
      chaotic systems.
AB  - A security analysis of a recently proposed secure communication scheme based on
      the phase synchronization of chaotic systems is presented. It is shown that the
      system parameters directly determine the cipher text waveform, hence it can be
      readily broken by system parameter estimation from the cipher text signal.

PMID- 15189056
TI  - Dynamics and bistability in a reduced model of the lac operon.
AB  - It is known that the lac operon regulatory pathway is capable of showing bistable
      behavior. This is an important complex feature, arising from the nonlinearity of
      the involved mechanisms, which is essential to understand the dynamic behavior of
      this molecular regulatory system. To find which of the mechanisms involved in the
      regulation of the lac operon is the origin of bistability, we take a previously
      published model which accounts for the dynamics of mRNA, lactose, allolactose,
      permease and beta-galactosidase involvement and simplify it by ignoring permease
      dynamics (assuming a constant permease concentration). To test the behavior of
      the reduced model, three existing sets of data on beta-galactosidase levels as a
      function of time are simulated and we obtain a reasonable agreement between the
      data and the model predictions. The steady states of the reduced model were
      numerically and analytically analyzed and it was shown that it may indeed display
      bistability, depending on the extracellular lactose concentration and growth
      rate.

PMID- 15189057
TI  - A self-learning coupled map lattice for vortex shedding in cable and cylinder
      wakes.
AB  - A coupled map lattice (CML) with self-learning features is developed to model
      flow over freely vibrating cables and stationary cylinders at low Reynolds
      numbers. Coupled map lattices that combine a series of low-dimensional circle
      maps with a diffusion model have been used previously to predict qualitative
      features of these flows. However, the simple nature of these CML models implies
      that there will be unmodeled wake features if a detailed, quantitative comparison
      is made with laboratory or simulated wake flows. Motivated by a desire to develop
      an improved CML model, we incorporate self-learning features into a new CML that
      is first trained to precisely estimate wake patterns from a target numerical
      simulation. A new convective-diffusive map that includes additional wake dynamics
      is developed. The new self-learning CML uses an adaptive estimation scheme
      (multivariable least-squares algorithm). Studies of this approach are conducted
      using wake patterns from a Navier-Stokes solution (spectral element-based NEKTAR
      simulation) of freely vibrating cable wakes at Reynolds numbers Re=100. It is
      shown that the self-learning model accurately and efficiently estimates the
      simulated wake patterns. The self-learning scheme is then successfully applied to
      vortex shedding patterns obtained from experiments on stationary cylinders. This
      constitutes a first step toward the use of the self-learning CML as a wake model
      in flow control studies of laboratory wake flows.

PMID- 15189058
TI  - Topology-based signal separation.
AB  - Traditional noise-filtering techniques are known to significantly alter features
      of chaotic data. In this paper, we present a noncausal topology-based filtering
      method for continuous-time dynamical systems that is effective in removing
      additive, uncorrelated noise from time-series data. Signal-to-noise ratios and
      Lyapunov exponent estimates are dramatically improved following the removal of
      the identified noisy points.

PMID- 15189059
TI  - Wave chaos and mode-medium resonances at long-range sound propagation in the
      ocean.
AB  - We study how the chaotic ray motion manifests itself at a finite wavelength at
      long-range sound propagation in the ocean. The problem is investigated using a
      model of an underwater acoustic waveguide with a periodic range dependence. It is
      assumed that the sound propagation is governed by the parabolic equation, similar
      to the Schrodinger equation. When investigating the sound energy distribution in
      the time-depth plane, it has been found that the coexistence of chaotic and
      regular rays can cause a "focusing" of acoustic energy within a small temporal
      interval. It has been shown that this effect is a manifestation of the so-called
      stickiness, that is, the presence of such parts of the chaotic trajectory where
      the latter exhibit an almost regular behavior. Another issue considered in this
      paper is the range variation of the modal structure of the wave field. In a
      numerical simulation, it has been shown that the energy distribution over normal
      modes exhibits surprising periodicity. This occurs even for a mode formed by
      contributions from predominantly chaotic rays. The phenomenon is interpreted from
      the viewpoint of mode-medium resonance. For some modes, the following effect has
      been observed. Although an initially excited mode due to scattering at the
      inhomogeneity breaks up into a group of modes its amplitude at some range points
      almost restores the starting value. At these ranges, almost all acoustic energy
      gathers again in the initial mode and the coarse-grained Wigner function
      concentrates within a comparatively small area of the phase plane.

PMID- 15189060
TI  - A subharmonic dynamical bifurcation during in vitro epileptiform activity.
AB  - Epileptic seizures are considered to result from a sudden change in the
      synchronization of firing neurons in brain neural networks. We have used an in
      vitro model of status epilepticus (SE) to characterize dynamical regimes
      underlying the observed seizure-like activity. Time intervals between spikes or
      bursts were used as the variable to construct first-return interpeak or
      interburst interval plots, for studying neuronal population activity during the
      transition to seizure, as well as within seizures. Return maps constructed for a
      brief epoch before seizures were used for approximating the local system dynamics
      during that time window. Analysis of the first-return maps suggests that
      intermittency is a dynamical regime underlying the observed epileptic activity.
      This type of analysis may be useful for understanding the collective dynamics of
      neuronal populations in the normal and pathological brain.

PMID- 15189061
TI  - Estimating the Lyapunov exponents of discrete systems.
AB  - In the present paper, our aim is to determine both upper and lower bounds for all
      the Lyapunov exponents of a given finite-dimensional discrete map. To show the
      efficiency of the proposed estimation method, two examples are given, including
      the well-known Henon map and a coupled map lattice.

PMID- 15189062
TI  - Optically injected laser system: characterization of chaos, bifurcation, and
      control.
AB  - A single mode semiconductor laser subjected to optical injection, described by a
      set of three coupled nonlinear ordinary differential equations, exhibiting chaos
      is considered. By means of a recurrence analysis, quantification of the strange
      attractor is made. Analytical studies of the system using asymptotic averaging
      technique, derive certain conditions describing the prediction of 1-->2
      bifurcation, which have subsequently been verified on numerical simulation.
      Furthermore, the locus of points on the parameter phase space representing Hopf
      bifurcation has been derived. The problem of control of chaos by a new procedure
      based on adaptive stabilization is also addressed. The results of such control
      are shown explicitly. Though this analysis deals with a very specific set of
      equations, the overall features that come out of the study remains valid for
      almost all laser systems.

PMID- 15189063
TI  - Chaotic digital communication by encoding initial conditions.
AB  - We investigate the possibility to improve the noise performance of a chaotic
      digital communication scheme by utilizing further dynamical information. We show
      that by encoding the initial information of the chaotic carrier according to the
      transmitting bits, extra redundance can be introduced into the segments of
      chaotic signals corresponding to the consecutive bits. Such redundant information
      can be exploited effectively at the receiver end to improve the noise performance
      of the system. Compared to other methods (e.g., differential chaos shift keying),
      straightforward application of the proposed modulation/demodulation scheme
      already provides significant performance gain in the low signal-to-noise ratio
      (SNR) region. Furthermore, maximum likelihood precleaning procedure based on the
      Viterbi algorithm can be applied before the demodulation step to overcome the
      performance degradation in the high SNR region. The study indicates that it is
      possible to improve the noise performance of the chaotic digital communication
      scheme if further dynamics information is added to the system.

PMID- 15189064
TI  - Integrator-based circuit-independent chaotic oscillator structure.
AB  - An integrator-based chaotic oscillator structure composed of three cascaded
      inverting, noninverting, and differential integrators is presented. The
      nonlinearity responsible for folding the trajectories is introduced by a single
      switching diode which is controlled by the output of the first integrator in the
      cascade. Chaotic behavior is verified on the functional level of the structure
      rendering it circuit-independent. A possible circuit realization is given and a
      canonical single-parameter-controlled ordinary differential equation capturing
      the qualitative dynamics of similar fourth-order integrator-based chaotic
      oscillators is proposed.

PMID- 15189065
TI  - Introduction: Global dynamics in spatially extended mechanical systems.

PMID- 15189066
TI  - Multi-scale continuum mechanics: from global bifurcations to noise induced high
      dimensional chaos.
AB  - Many mechanical systems consist of continuum mechanical structures, having either
      linear or nonlinear elasticity or geometry, coupled to nonlinear oscillators. In
      this paper, we consider the class of linear continua coupled to mechanical
      pendula. In such mechanical systems, there often exist several natural time
      scales determined by the physics of the problem. Using a time scale splitting, we
      analyze a prototypical structural-mechanical system consisting of a planar
      nonlinear pendulum coupled to a flexible rod made of linear viscoelastic
      material. In this system both low-dimensional and high-dimensional chaos is
      observed. The low-dimensional chaos appears in the limit of small coupling
      between the continua and oscillator, where the natural frequency of the primary
      mode of the rod is much greater than the natural frequency of the pendulum. In
      this case, the motion resides on a slow manifold. As the coupling is increased,
      global motion moves off of the slow manifold and high-dimensional chaos is
      observed. We present a numerical bifurcation analysis of the resulting system
      illustrating the mechanism for the onset of high-dimensional chaos. Constrained
      invariant sets are computed to reveal a process from low-dimensional to high
      dimensional transitions. Applications will be to both deterministic and
      stochastic bifurcations. Practical implications of the bifurcation from low
      dimensional to high-dimensional chaos for detection of damage as well as global
      effects of noise will also be discussed.

PMID- 15189067
TI  - Using chaotic interrogation and attractor nonlinear cross-prediction error to
      detect fastener preload loss in an aluminum frame.
AB  - Structural health monitoring is an important field concerned with assessing the
      current state (or "health") of a structural system or component with regard to
      its ability to perform its intended function appropriately. One approach to this
      problem is identifying appropriate features obtained from time series vibration
      responses of the structure that change as structural degradation occurs. In this
      work, we present a novel technique adapted from the nonlinear time series
      prediction community whereby the structure is excited by an applied chaotic
      waveform, and predictive maps built between structural response attractors are
      used as the feature space. The structural response is measured at several points
      on the structure, and pairs of attractors are used to predict each other. As the
      dynamics of the structure change due to damage, the prediction error rises. This
      approach is applied to detecting the preload loss in a bolted joint in an
      aluminum frame structure.

PMID- 15189068
TI  - Non-Lipschitzian control algorithms for extended mechanical systems.
AB  - We derive the properties of a general control algorithm [Braiman et al., Phys.
      Rev. Lett. 90, 094301 (2003)] for quantities describing global features of
      nonlinear extended mechanical systems. The control algorithm is based on the
      concepts of non-Lipschitzian dynamics and global targeting. We show that (i)
      certain average quantities of the controlled system can be driven-exactly or
      approximately-towards desired targets which become linearly stable attractors for
      the system's dynamics; (ii) the basins of attraction of these targets are reached
      in very short times; and (iii) while within reasonably broad ranges the time
      scales of the control and of the intrinsic dynamics may be quite different, this
      disparity does not affect significantly the overall efficiency of the proposed
      scheme, up to natural fluctuations.

PMID- 15189069
TI  - Machine failure forewarning via phase-space dissimilarity measures.
AB  - We present a model-independent, data-driven approach to quantify dynamical
      changes in nonlinear, possibly chaotic, processes with application to machine
      failure forewarning. From time-windowed data sets, we use time-delay phase-space
      reconstruction to obtain a discrete form of the invariant distribution function
      on the attractor. Condition change in the system's dynamic is quantified by
      dissimilarity measures of the difference between the test case and baseline
      distribution functions. We analyze time-serial mechanical (vibration) power data
      from several large motor-driven systems with accelerated failures and seeded
      faults. The phase-space dissimilarity measures show a higher consistency and
      discriminating power than traditional statistical and nonlinear measures, which
      warrants their use for timely forewarning of equipment failure.

PMID- 15189070
TI  - Identification of pre-sliding friction dynamics.
AB  - The hysteretic nonlinear dependence of pre-sliding friction force on displacement
      is modeled using different physics-based and black-box approaches including
      various Maxwell-slip models, NARX models, neural networks, nonparametric (local)
      models and dynamical networks. The efficiency and accuracy of these
      identification methods is compared for an experimental time series where the
      observed friction force is predicted from the measured displacement. All models,
      although varying in their degree of accuracy, show good prediction capability of
      pre-sliding friction. Finally, we show that even better results can be achieved
      by using an ensemble of the best models for prediction.

PMID- 15189071
TI  - Presliding friction identification based upon the Maxwell Slip model structure.
AB  - The problem of presliding friction identification based upon the Maxwell Slip
      model structure, which is capable of accounting for the presliding hysteresis
      with nonlocal memory, is considered. The model structure's basic properties are
      examined, based upon which a priori identifiability is established, the role of
      initial conditions on identification is investigated, and the necessary and
      sufficient conditions for a posteriori identifiability are derived. Using them,
      guidelines for excitation signal design are also formulated. Building upon these
      results, two new methods, referred to as Dynamic Linear Regression (DLR) and
      NonLinear Regression (NLR), are postulated for presliding friction
      identification. Both may be thought of as different extensions of the
      conventional Linear Regression (LR) method that uses threshold preassignment: The
      DLR by introducing extra dynamics in the form of a vector finite impulse response
      filter, and the NLR by relaxing threshold preassignment through a special
      nonlinear regression procedure. The effectiveness of both methods is assessed via
      Monte Carlo experiments and identification based upon laboratory signals. The
      results indicate that both methods achieve significant improvements over the LR.
      The DLR offers the highest accuracy, with the NLR striking a very good balance
      between accuracy and parametric complexity.

PMID- 15189072
TI  - Modeling of dry sliding friction dynamics: from heuristic models to physically
      motivated models and back.
AB  - After giving an overview of the different approaches found in the literature to
      model dry friction force dynamics, this paper presents a generic friction model
      based on physical mechanisms involved in the interaction of a large population of
      surface asperities and discusses the resulting macroscopic friction behavior. The
      latter includes the hysteretic characteristic of friction in the presliding
      regime, the velocity weakening and strengthening in gross-sliding regime, the
      frictional lag and the stick-slip behavior. Out of the generic model, which is
      shown to be a good, but rather computationally intensive, simulation tool, a
      simpler heuristic model, which we call the generalized Maxwell-slip friction, is
      deduced. This model is appropriate for quick simulation and control purposes
      being easy to implement and to identify. Both of the generic and heuristic model
      structures are compared, through simulations, with each other and with
      experimental data.

PMID- 15189073
TI  - Combustion process in a spark ignition engine: dynamics and noise level
      estimation.
AB  - We analyze the experimental time series of internal pressure in a four cylinder
      spark ignition engine. In our experiment, performed for different spark advance
      angles, apart from the usual cyclic changes of engine pressure we observed
      additional oscillations. These oscillations are with longer time scales ranging
      from one to several hundred engine cycles depending on engine working conditions.
      Based on the pressure time dependence we have calculated the heat released per
      combustion cycle. Using the time series of heat release to calculate the
      correlation coarse-grained entropy we estimated the noise level for internal
      combustion process. Our results show that for a larger spark advance angle the
      system is more deterministic.

PMID- 15189074
TI  - Spiral dynamics of pulsating methane-oxygen flames on a circular burner.
AB  - A premixed flame stabilized on a circular porous plug burner produces a uniform,
      steady luminous flame front. Throughout much of the parameter range hydrocarbon
      oxygen mixtures form spiral-shaped fronts. In methane-oxygen flames at low
      pressure, the flame exhibits a sequence of states as a control parameter is
      decreased. These states include periodic rotation of a spiral front; precession
      of the spiral front in a direction opposite to its rotation, corresponding to
      doubly periodic petals-out meandering; and nonperiodic states with intermittent
      jumps associated with linear excursions of the tip, which occur after the spiral
      front has reached the boundary of the circular burner. We use Karhunen-Loeve (KL)
      analysis to find the coefficients of the dominant KL spatial eigenfunctions.
      Their phase space portraits and power spectra provide a description of the
      dynamics as flow rates are reduced and the system destabilizes. We discuss how
      these experimental results relate to previous theoretical studies that assume
      Euclidean symmetry for the experimental configuration.

PMID- 15189075
TI  - Period-adding bifurcations and chaos in a bubble column.
AB  - We obtained period-adding bifurcations in a bubble formation experiment. Using
      the air flow rate as the control parameter in this experiment, the bubble
      emission from the nozzle in a viscous fluid undergoes from single bubbling to a
      sequence of periodic bifurcations of k to k+1 periods, occasionally interspersed
      with some chaotic regions. Our main assumption is that this period-adding
      bifurcation in bubble formation depends on flow rate variations in the chamber
      under the nozzle. This assumption was experimentally tested by placing a tube
      between the air reservoir and the chamber under the nozzle in the bubble column
      experiment. By increasing the tube length, more period-adding bifurcations were
      observed. We associated two main types of bubble growth to the flow rate
      fluctuations inside the chamber for different bubbling regimes. We also studied
      the properties of piecewise nonlinear maps obtained from the experimental
      reconstructed attractors, and we concluded that this experiment is a spatially
      extended system.

PMID- 15189076
TI  - Dynamic interacting bubble simulation (DIBS): an agent-based bubble model for
      reacting fluidized beds.
AB  - In this paper we explore the global dynamics of an agent-type model for bubbles
      in gas-fluidized beds and demonstrate that these features are consistent with
      experimentally observed behavior. The model accounts for the simultaneous
      interactions of thousands of individual bubbles and includes mass-transfer and
      first-order reactions between the gas and solids so that the impact of the
      dynamics is reflected in reactant conversion. We start with model parameters that
      have been demonstrated to produce time average behavior consistent with
      experimental reactor measurements. By observing the temporal variations of
      spatially averaged bubble properties, we are able to clearly distinguish the
      onset of global low-dimensional features that appear to be consistent with
      previous observations. The most prominent of these features is a large-scale
      oscillation that exhibits intermittency with power-law scaling in the vicinity of
      a critical gas flow. We show that the oscillation occurs as the result of a
      globally synchronized horizontal movement of the bubbles toward the center of the
      reactor. The oscillation appears to be consistent with the occurrence of the so
      called "slugging" phenomenon, which is known to have large effects on fluidized
      bed reactor performance. Although this model can clearly be further improved, its
      success in replicating several of the key features of slugging indicates that
      this approach can serve as a useful tool for understanding and possibly
      controlling fluidized bed dynamics. We also conjecture that this model may be
      useful for more generally understanding the occurrence of global features in high
      dimensional, multi-agent systems.

PMID- 15189077
TI  - Experimental analysis and visualization of spatiotemporal patterns in spouted
      fluidized beds.
AB  - A numerical characterization based on experimental data of the spouting regime in
      a two-dimensional fluidized bed is presented. The aspect ratio of the bed allowed
      for good visualization of the spouting and solids circulation as the spouting jet
      gas velocity was varied to highlight the visited bifurcation sequence. Digital
      video sequences were recorded and then preprocessed for numerical analysis. In
      this paper, the proper orthogonal decomposition (POD) was applied to these data
      sets in order to identify and separate the dominant spatial features from the
      temporal evolution of the spouting dynamics. The results indicate that the
      overall spatiotemporal dynamics can be captured by a few POD eigenfunctions, and
      that the POD amplitudes can be used to distinguish between varying degrees of
      spouting.

PMID- 15189079
TI  - Nonlinear matching measure for the analysis of on-off type DNA microarray images.
AB  - We propose a new nonlinear matching measure for automatic analysis of the on-off
      type DNA microarray images in which the hybridized spots are detected by a
      template-matching method. The proposed measure is obtained by binary thresholding
      over the entire template region and taking the number of white pixels inside the
      spotted area. This measure is compared with the normalized covariance method in
      terms of classifying the ability to successfully locate markers. The proposed
      measure was evaluated for scanned images of human papillomavirus (HPV) DNA
      microarrays where locating markers is a critical issue because of the small
      number of spots. The targeting spots of HPV DNA chips are designed for genotyping
      twenty-two types of the human papillomavirus. The proposed measure is proven to
      give a more discriminative response, reducing the missed cases of successful
      marker location. The locating accuracy of the proposed method is also shown to
      have the same performance as that of the normalized covariance.

PMID- 15189080
TI  - Screening for the breast cancer gene (BRCA1) using a biochip system and molecular
      beacon probes immobilized on solid surfaces.
AB  - We describe the use of a biochip based on complementary metal oxide semiconductor
      (CMOS) technology for detection of specific genetic sequences using molecular
      beacons (MB) immobilized on solid surfaces as probes. The applicability of this
      miniature detection system for screening for the BRCA1 gene is evaluated using MB
      probes, designed especially for the BRCA1 gene. MB probes are immobilized on a
      zeta-probe membrane by biotin-streptavidin immobilization. Two immobilization
      strategies are investigated to obtain optimal assay sensitivity. The MB is
      immobilized by manual spotting on zeta-probe membrane surfaces with the use of a
      custom-made stamping system. The detection of the BRCA1 gene using an MB probe is
      successfully demonstrated and expands the use of the CMOS biochip for medical
      applications.

PMID- 15189081
TI  - Automatic segmentation of histological structures in mammary gland tissue
      sections.
AB  - Real-time three-dimensional (3-D) reconstruction of epithelial structures in
      human mammary gland tissue blocks mapped with selected markers would be an
      extremely helpful tool for diagnosing breast cancer and planning treatment.
      Besides its clear clinical application, this tool could also shed a great deal of
      light on the molecular basis of the initiation and progression of breast cancer.
      We present a framework for real-time segmentation of epithelial structures in two
      dimensional (2-D) images of sections of normal and neoplastic mammary gland
      tissue blocks. Complete 3-D rendering of the tissue can then be done by surface
      rendering of the structures detected in consecutive sections of the blocks.
      Paraffin-embedded or frozen tissue blocks are first sliced and sections are
      stained with hematoxylin and eosin. The sections are then imaged using
      conventional bright-field microscopy and their background corrected using a
      phantom image. We then use the fast-marching algorithm to roughly extract the
      contours of the different morphological structures in the images. The result is
      then refined with the level-set method, which converges to an accurate (subpixel)
      solution for the segmentation problem. Finally, our system stacks together the 2
      D results obtained in order to reconstruct a 3-D representation of the entire
      tissue block under study. Our method is illustrated with results from the
      segmentation of human and mouse mammary gland tissue samples.

PMID- 15189082
TI  - Digital signal processor-based real-time optical Doppler tomography system.
AB  - We present a real-time data-processing and display unit based on a custom
      designed digital signal processor (DSP) module for imaging tissue structure and
      Doppler blood flow. The DSP module is incorporated into a conventional optical
      coherence tomography system. We also demonstrate the flexibility of embedding
      advanced Doppler processing algorithms in the DSP module. Two advanced velocity
      estimation algorithms previously introduced by us are incorporated in this DSP
      module. Experiments on Intralipid flow demonstrate that a pulsatile flow of
      several hundred pulses per minute can be faithfully captured in M-scan mode by
      this DSP system. In vivo imaging of a rat's abdominal blood flow is also
      presented.

PMID- 15189083
TI  - Clinical trial of time-resolved scanning optical mammography at 4 wavelengths
      between 683 and 975 nm.
AB  - The first time-resolved optical mammograph operating beyond 900 nm (683, 785,
      913, and 975 nm) is presently being used in a clinical trial to test the
      diagnostic potential of the technique in detecting and characterizing breast
      lesions. Between November 2001 and October 2002, 101 patients with malignant and
      benign lesions were analyzed retrospectively. Scattering plots, as derived from a
      homogeneous model, and late gated intensity images, to monitor spatial changes in
      the absorption properties, are routinely used. The intensity images available at
      four wavelengths provide sensitivity to the main tissue constituents (oxy- and
      deoxyhemoglobin, water, and lipids), in agreement with expected tissue
      composition and physiology, while the scattering plots mirror structural changes.
      Briefly, tumors are usually identified due to the strong blood absorption at
      short wavelengths, cysts to the low scattering, and fibroadenomas to low
      absorption at 913 nm and high at 975 nm, even though the optical features of
      fibroadenomas seem not to be uniquely defined. The effectiveness of the technique
      in localizing and discriminating different lesion types is analyzed as a function
      of various parameters (lesion size, compressed breast thickness, and breast
      parenchymal pattern). .

PMID- 15189084
TI  - Optical biopsy of bone tissue: a step toward the diagnosis of bone pathologies.
AB  - In vivo absorption and reduced scattering spectra of the human calcaneous from
      650 to 1000 nm were assessed using a laboratory system for time-resolved
      transmittance spectroscopy. Measurements were performed on the calcaneous of
      seven female volunteers ranging from 26 to 82 years of age. The analysis of the
      absorption spectra, using a linear combination of the key tissue absorbers (bone
      mineral, water, lipids, oxy- and deoxyhemoglobin), revealed a general decrease in
      bone mineral content and an increase in lipids with age, which is in agreement
      with the aging transformations that occur in bone tissues. The scattering spectra
      were less effective in detecting such changes in older subjects, showing only a
      minor decrease in the coefficient for these subjects. The capability to
      noninvasively quantify bone tissue composition suggests a possible use of optical
      biopsy for the diagnosis of bone pathologies such as osteoporosis, which are
      characterized by a progressive reduction and transformation of the mineral in the
      bone matrix.

PMID- 15189085
TI  - Localization of fluorescence spots with space-space MUSIC for mammographylike
      measurement systems.
AB  - Breast cancer diagnosis may be improved by optical fluorescence imaging
      techniques in the near-infrared wavelength range. We have shown that the recently
      proposed space-space MUSIC (multiple signal classification) algorithm allows the
      3-D localization of focal fluorophore-tagged lesions in a turbid medium from 2-D
      fluorescence data obtained from laser excitations at different positions. The
      data are assumed to be measured with two parallel planar sensor arrays on the top
      and bottom of the medium. The laser sources are integrated at different positions
      in one of the planes. The space-space data are arranged into an MxN matrix (M,
      number of sensors; N, number of excitation sources). A singular-value
      decomposition (SVD) of this matrix yields the detectable number of spot regions
      with linearly independent behavior with respect to the laser excitation positions
      and thus allows definition of a signal subspace. Matches between this signal
      subspace and data from model spots are tested at scanned points in a model medium
      viewed as the breast region under study. The locations of best matches are then
      considered the centers of gravity of focal lesions. The optical model used was
      unbounded and optically homogeneous. Nevertheless, simulated spots in bounded,
      inhomogeneous media modeling the breast could be localized accurately.

PMID- 15189086
TI  - Diagnostic imaging of breast cancer using fluorescence-enhanced optical
      tomography: phantom studies.
AB  - Molecular targeting with exogenous near-infrared excitable fluorescent agents
      using time-dependent imaging techniques may enable diagnostic imaging of breast
      cancer and prognostic imaging of sentinel lymph nodes within the breast. However,
      prior to the administration of unproven contrast agents, phantom studies on
      clinically relevant volumes are essential to assess the benefits of fluorescence
      enhanced optical imaging in humans. Diagnostic 3-D fluorescence-enhanced optical
      tomography is demonstrated using 0.5 to 1 cm(3) single and multiple targets
      differentiated from their surroundings by indocyanine green (micromolar) in a
      breast-shaped phantom (10-cm diameter). Fluorescence measurements of referenced
      ac intensity and phase shift were acquired in response to point illumination
      measurement geometry using a homodyned intensified charge-coupled device system
      modulated at 100 MHz. Bayesian reconstructions show artifact-free 3-D images
      (3857 unknowns) from 3-D boundary surface measurements (126 to 439). In a
      reflectance geometry appropriate for prognostic imaging of lymph node
      involvement, fluorescence measurements were likewise acquired from the surface of
      a semi-infinite phantom (8x8x8 cm(3)) in response to area illumination (12 cm(2))
      by excitation light. Tomographic 3-D reconstructions (24,123 unknowns) were
      recovered from 2-D boundary surface measurements (3194) using the modified
      truncated Newton's method. These studies represent the first 3-D tomographic
      images from physiologically relevant geometries for breast imaging.

PMID- 15189087
TI  - Emission and absorption properties of indocyanine green in Intralipid solution.
AB  - Emission and absorption properties of indocyanine green (ICG) in Intralipid
      solution have been investigated. The study is focused on relatively low ICG
      concentration at a range of 0 to 20 microM. A diffusion model was used to analyze
      the emission properties of ICG solution at different concentrations. In the low
      concentration region, the emission strength increases with the concentration of
      ICG, while in the high-concentration region, the emission decreases with the
      concentration. In general, a maximum of emission strength exists and its position
      (concentration) depends on the wavelength of the excitation light, the distance
      between the source and the detector, and the sample geometry and size. A so
      called "inner-cell-effect" and re-absorption of emission photons are found to
      contribute to the decay of emission strength. Also, in the concentration range of
      0 to 2 microM, ICG solution always has a higher absorption coefficient at
      wavelength 830 nm than that at 660 nm, which is quite different from the ICG in
      water case.

PMID- 15189088
TI  - Portable near-infrared diffusive light imager for breast cancer detection.
AB  - We present a frequency-domain near-infrared optical tomography system designed
      for breast cancer detection, in conjunction with conventional ultrasound. It
      features fast optical switching, three-wavelength excitations, and avalanche
      photodiode as detectors. Laser diodes at 660, 780, and 830 nm are used as light
      sources and their outputs are distributed sequentially to one of nine source
      fibers. An equivalent 130-dB isolation between electrical signals from different
      source channels is achieved with the optical switches of very low crosstalk. Ten
      detection channels, each of which includes a silicon avalanche photodiode, detect
      diffusive photon density waves simultaneously. The dynamic range of an avalanche
      photodiode is about 20 to 30 dB higher than that of a photomultiplier tube, thus
      eliminating the need for multistep system gain control. The entire system is
      compact in size (<0.051 m(3)) and fast in data acquisition (less than 2 sec for a
      complete scan). Calibration and the clinical experiment results are presented in
      the paper.

PMID- 15189089
TI  - Analytical model to describe fluorescence spectra of normal and preneoplastic
      epithelial tissue: comparison with Monte Carlo simulations and clinical
      measurements.
AB  - Fluorescence spectroscopy has shown promise for the detection of precancerous
      changes in vivo. The epithelial and stromal layers of tissue have very different
      optical properties; the albedo is relatively low in the epithelium and approaches
      one in the stroma. As precancer develops, the optical properties of the
      epithelium and stroma are altered in markedly different ways: epithelial
      scattering and fluorescence increase, and stromal scattering and fluorescence
      decrease. We present an analytical model of the fluorescence spectrum of a two
      layer medium such as epithelial tissue. Our hypothesis is that accounting for the
      two different tissue layers will provide increased diagnostic information when
      used to analyze tissue fluorescence spectra measured in vivo. The Beer-Lambert
      law is used to describe light propagation in the epithelial layer, while light
      propagation in the highly scattering stromal layer is described with diffusion
      theory. Predictions of the analytical model are compared to results from Monte
      Carlo simulations of light propagation under a range of optical properties
      reported for normal and precancerous epithelial tissue. In all cases, the mean
      square error between the Monte Carlo simulations and the analytical model are
      within 15%. Finally, model predictions are compared to fluorescence spectra of
      normal and precancerous cervical tissue measured in vivo; the lineshape of
      fluorescence agrees well in both cases, and the decrease in fluorescence
      intensity from normal to precancerous tissue is correctly predicted to within 5%.
      Future work will explore the use of this model to extract information about
      changes in epithelial and stromal optical properties from clinical measurements
      and the diagnostic value of these parameters.

PMID- 15189090
TI  - Effect of probe pressure on cervical fluorescence spectroscopy measurements.
AB  - Fluorescence spectroscopy is a promising technology for detection of epithelial
      precancers and cancers. While age and menopausal status influence measurements in
      the cervix, other variables do not significantly affect the diagnosis. In this
      study we examine probe pressure as a variable. A fiber optic probe to measure
      fluorescence spectra at different calibrated levels of pressure was designed and
      tested. A pilot study was conducted measuring fluorescence excitation emission
      matrices in 20 patients at light, medium, and firm pressure. Spectroscopic data
      were pre-processed and analyzed to compare mean peak intensities as a function of
      pressure. Further statistical analyses tested for differences in intensities at
      each excitation/emission wavelength pair. Four providers made measurements from
      41 sites; 33 yielded good quality spectroscopic data (22 squamous normal, 7
      squamous abnormal, 3 columnar normal, 1 transformation zone) from 17 of 20
      patients. At all pressure levels, abnormal tissue showed less fluorescence
      intensity than normal tissue, and post-menopausal patients showed higher
      fluorescence intensity than premenopausal patients, consistent with previous
      analyses. A permutation analysis suggests that pressure does not significantly
      affect fluorescence intensity or lineshape. While other studies are needed to
      confirm these findings, this study suggests that fluorescence spectroscopy is a
      robust technology likely not influenced by fiber optic probe pressure.

PMID- 15189091
TI  - Spatial variations in optical and physiological properties of healthy breast
      tissue.
AB  - Near-infrared (NIR) diffuse optical spectroscopy (DOS) and diffuse optical
      imaging (DOI) show promise as noninvasive clinical techniques for breast cancer
      screening and diagnosis. Since NIR methods are based on optical contrast between
      healthy and diseased tissue, it is essential to characterize the sources of
      endogenous contrast in normal subjects. We report intra- and inter-subject
      variation and bilateral asymmetry of the optical and physiological parameters of
      31 women using a seven-wavelength NIR frequency-domain photon migration (FDPM)
      instrument. Wavelength-dependent absorption and reduced scattering parameters
      (micro(a) and micro(s'), respectively) were measured in four major quadrants and
      the areolar regions of left and right breasts. These values were used to
      determine tissue concentrations of oxy-(HbO(2)) and deoxy-(Hb-R) hemoglobin,
      lipid content, water concentration, and tissue "scatter power." Mean total
      hemoglobin for premenopausal (PRE) women (20 to 30 microM) is approximately two
      fold higher than for postmenopausal (POST) subjects at all positions. POST women
      have approximately 50% higher lipid content (50 to 60%) than PRE at all
      positions. Water concentration on average is 1.8-fold higher for PRE subjects (30
      to 40%) than POST. These differences are most pronounced when comparing the
      areolar complex to the other regions of the breast. In premenopausal women, the
      areolar regions have 40 to 45% increased total hemoglobin concentration (THC), 20
      to 25% lower lipid content, and 30 to 60% higher scatter power versus the
      quadrants. Small-scale (3 cm) changes in optical properties are negligible
      compared to large-scale variations over all quadrants, where the intrinsic
      spatial heterogeneity of healthy breast tissue is 20 to 40% for micro(a) and 5 to
      12% for micro(s'). Although no consistent right-left differences are observed in
      the study population, relative differences between symmetric positions ranged
      from 18 to 30% for THC, 10 to 40% for adipose, 10 to 25% for water, and 4 to 9%
      for scattering (674 nm) within an individual.

PMID- 15189092
TI  - Characterization of hemoglobin, water, and NIR scattering in breast tissue:
      analysis of intersubject variability and menstrual cycle changes.
AB  - Near-infrared imaging was used to quantify typical values of hemoglobin
      concentration, oxygen saturation, water fraction, scattering power, and
      scattering amplitude within the breast tissue of volunteer subjects. A systematic
      study of the menstrual variations in these parameters was carried out by
      measuring a group of seven premenopausal normal women (aged 41 to 47 years) in
      the follicular (days 7 to 14 of the cycle) and secretory phases (days 21 to 28)
      of the cycle, for two complete menstrual cycles. An average increase in
      hemoglobin concentration of 2.6 microM or 13% of the background breast values was
      observed in the secretory phase relative to the follicular phase (p<0.0001), but
      no other average near-infrared parameter changes were significant. While
      repeatable and systematic changes were observed in all parameters for individual
      subjects, large intersubject variations were present in all parameters. In a
      survey of thirty-nine normal subjects, the total hemoglobin varied from 9 to 45
      microM, with a systematic correlation observed between total hemoglobin
      concentration and breast radiographic density. Scattering power and scattering
      amplitude were also correlated with radiographic density, but oxygen saturation
      and water fraction were not. Images of breast lesions indicate that total
      hemoglobin-based contrast can be up to 200% relative to the background in the
      same breast. Yet, since the background hemoglobin values vary considerably among
      breasts, the maximum hemoglobin concentrations observed in cancer tumors may vary
      considerably as well. In light of these observations, it may be important to use
      hemoglobin contrast values relative to the background for a given breast, rather
      than absolute hemoglobin contrast when trying to compare the features of breast
      lesions among subjects.

PMID- 15189093
TI  - Online monitoring of urea concentration in dialysate with dual-beam Fourier
      transform near-infrared spectroscopy.
AB  - The robustness of a dual-beam, optical null, Fourier-transform near-infrared
      (FTNIR) spectrometer was investigated by means of online, near-infrared
      measurements and predictions of urea concentrations in spent dialysate during
      hemodialysis treatment. Simple multivariate calibration using a few factors based
      on a small number of prepared samples provided stable and accurate predictions
      over a period of 1 month. The calibration was robust when faced with adjustment
      of reference cell intensity and did not require a daily measured reference
      spectrum. The root-mean-square error of prediction of urea was 0.4 mM based on a
      two-factor partial least-squares regression model.

PMID- 15189094
TI  - Fourier transform infrared microspectroscopy as a quantitative diagnostic tool
      for assignment of premalignancy grading in cervical neoplasia.
AB  - The early diagnosis and proper identification of cervical squamous
      intraepithelial lesions plays an important role in a good prognosis for the
      patient. However, the present practice of screening based on PAP (Papanicolaou)
      smear and histopathology makes it tedious and prone to human errors. We assess
      the validity of FTIR microspectroscopy (FTIR-MSP) of biopsies as a method to
      properly assign the correct stage of premalignancy in patients with symptoms of
      cervical intraepithelial neoplasia. For the first time we evaluate the biopsies
      based on the FTIR spectra for different grades of neoplasia in tandem with
      probabilistic neural networks (PNNs) and histopathology. The results show that
      the grading of neoplasia based on FTIR-MSP and a PNN differentiates the normal
      from premalignant with a high level of accuracy. The false positive
      identification of the normal as cervical intraepithelial neoplasia 1 (CIN1),
      CIN2, and CIN3 patients is 9.04, 0.01, and 0.01%, respectively. The false
      negative identification of CIN2 patients as normal and CIN1 patients is 0.01 and
      4.4%, respectively. Similarly, the false negative identification of CIN3 patients
      as normal, CIN1, and CIN2 is 0.14, 6.99, and 9.61%, respectively. The small
      errors encountered in the grading are comparable to current methods, encouraging
      advanced studies for the development of mechanized equipment for the diagnosis
      and grading of premalignant cervical neoplasia.

PMID- 15189095
TI  - Appearance of enhanced tissue features in narrow-band endoscopic imaging.
AB  - This study was performed to examine the usefulness of medical endoscopic imaging
      utilizing narrow-band illumination. The contrast between the vascular pattern and
      the adjacent mucosa of the underside of the human tongue was measured using five
      narrow-band illuminations and three broadband illuminations. The results
      demonstrate that the pathological features of a vascular pattern are dependent on
      the center wavelength and the bandwidth of illumination. By utilizing narrow-band
      illumination of 415+/-30 nm, the contrast of the capillary pattern in the
      superficial layer was markedly improved. This is an important benefit that is
      difficult to obtain with ordinary broadband illumination. The appearances of
      capillary patterns on color images were evaluated for three sets of filters. The
      narrow, band imaging (NBI) filter set (415+/-30 nm, 445+/-30 nm, 500+/-30 nm) was
      selected to achieve the preferred appearance of the vascular patterns for
      clinical tests. The results of clinical tests in colonoscopy and esophagoscopy
      indicated that NBI will be useful as a supporting method for observation of the
      endoscopic findings of early cancer.

PMID- 15189096
TI  - Optical imaging of Renilla luciferase, synthetic Renilla luciferase, and firefly
      luciferase reporter gene expression in living mice.
AB  - We have recently demonstrated that Renilla luciferase (Rluc) is a promising
      bioluminescence reporter gene that can be used for noninvasive optical imaging of
      reporter gene expression in living mice, with the aid of a cooled charged couple
      device (CCD) camera. In the current study, we explore the expression of a novel
      synthetic Renilla luciferase reporter gene (hRluc) in living mice, which has
      previously been reported to be a more sensitive reporter than native Rluc in
      mammalian cells. We explore the strategies of simultaneous imaging of both
      Renilla luciferase enzyme (RL) and synthetic Renilla luciferase enzyme
      (hRL):coelenterazine (substrate for RL/hRL) in the same living mouse. We also
      demonstrate that hRL:coelenterazine can yield a higher signal when compared to
      Firefly luciferase enzyme (FL): D-Luciferin, both in cell culture studies and
      when imaged from cells at the surface and from lungs of living mice. These
      studies demonstrate that hRluc should be a useful primary reporter gene with high
      sensitivity when used alone or in conjunction with other bioluminescence reporter
      genes for imaging in living rodents.

PMID- 15189097
TI  - Near-infrared autofluorescence imaging for detection of cancer.
AB  - Near-infrared autofluorescence imaging of tissues under long-wavelength laser
      excitation in the green and red spectral region complemented by cross-polarized
      elastic light scattering was explored for cancer detection. Various types of
      normal and malignant human tissue samples were utilized in this investigation. A
      set of images for each tissue sample was recorded that consisted of two
      autofluorescence images obtained under 532- and 632.8-nm excitation and light
      scattering images obtained under linearly polarized illumination at 700, 850, and
      1000 nm. These images were compared with the histopathology of the tissue sample.
      The experimental results indicated that for various tissue types, the intensity
      of the autofluorescence integrated over the 700 to 1000-nm spectral region was
      considerably different in cancer tissues than in that of the contiguous non
      neoplastic tissues. This difference provided the basis for the detection of
      cancer and delineation of the tumor margins. Variations on the relative intensity
      were observed among different tissue types and excitation wavelengths.

PMID- 15189098
TI  - Resonance Raman spectroscopy of optically trapped functional erythrocytes.
AB  - We introduce a novel setup combining a micro-Raman spectrometer with external
      optical tweezers, suitable for resonance Raman studies of single functional
      trapped cells. The system differs from earlier setups in that two separate laser
      beams used for trapping and Raman excitation are combined in a double-microscope
      configuration. This has the advantage that the wavelength and power of the
      trapping and probe beam can be adjusted individually to optimize the
      functionality of the setup and to enable the recording of resonance Raman
      profiles from a single trapped cell. Trapping is achieved by tightly focusing
      infrared (IR) diode laser radiation (830 nm) through an inverted oil-immersion
      objective, and resonance Raman scattering is excited by the lines of an
      argon:krypton ion laser. The functionality of the system is demonstrated by
      measurements of trapped single functional erythrocytes using different excitation
      lines (488.0, 514.5, and 568.2 nm) in resonance with the heme moiety and by
      studying spectral evolution during illumination. We found that great care has to
      be taken in order to avoid photodamage caused by the visible Raman excitation,
      whereas the IR trapping irradiation does not seem to harm the cells or alter the
      hemoglobin Raman spectra. Stronger photodamage is induced by Raman excitation
      using 488.0- and 514.5-nm irradiation, compared with excitation with the 568.2-nm
      line.

PMID- 15189099
TI  - Vicker's hardness and Raman spectroscopy evaluation of a dental composite cured
      by an argon laser and a halogen lamp.
AB  - We present the results of the Vicker's hardness test and the use of near-infrared
      Raman spectroscopy (RS) to measure in vitro the degree of conversion (DC) of a
      bis(phenol)-A-glycidyl-dimethacrylate-based composite resin, photoactivated by
      both a halogen lamp (power density=478 mW/cm(2); 8-mm diameter spot) and an argon
      laser (power density=625 mW/cm(2); 7-mm diameter spot). The degree of conversion
      was estimated by analyzing the relative intensities between the aromatic C=C
      stretching Raman mode at 1610 cm(-1) and the methacrylate C=C stretching Raman
      mode (1640 cm(-1)) on top and bottom surfaces. For the hardness evaluation, the
      samples were embedded in polyester resin and three indentations with a 50-g load
      for 10 s were made on the top surface. The higher relative DC values achieved by
      the photoactivation of a composite resin by the argon laser suggest a better
      biocompatibility in the bottom surface. The correlation test showed that the
      higher Vicker's hardness number (VHN) values were associated with higher DC
      values. The derivative analysis showed a greater curing rate from 5 to 20 s of
      exposure. The comparison of VHN and DC values with both light sources at each
      curing time showed that a small change in conversion is related to a large change
      in hardness. Raman spectroscopy is more sensitive to changes in the first stages
      of curing reaction than later ones, and the Vicker's hardness assay is more
      sensitive to changes in the last stages.

PMID- 15189100
TI  - Dual closed-loop, optoelectronic, auto-oscillatory detection circuit for
      monitoring fluorescence lifetime-based chemical sensors and biosensors.
AB  - We present a new detection instrument for sensor measurements based on excited
      state fluorescence lifetimes. This system consists of a primary optoelectronic
      loop containing a resonance-type rf amplifier, a modulatable fluorescence
      excitation light source, a fiber optic feedback loop (with a gap for a
      fluorescent sensor), and a photomultiplier tube. A secondary, phase-feedback
      optoelectronic circuit consists of a long-wavelength-pass optical filter, a
      second photomultiplier tube, a photodiode, an electronic phase detector, a dc
      amplifier, and an electronic phase shifter (inserted into the main loop). This
      phase-feedback circuit is new with respect to our previous work. Under the
      appropriate conditions, the main loop exhibits self-oscillations, manifesting
      themselves as sinusoidal rf modulation of light intensity. The phase-feedback
      circuit detects the modulation phase shift resulting from the finite excited
      state lifetimes of a fluorophore. As the excited state lifetime changes, the
      phase shift from the electronic phase shifter also changes, which results in a
      shift in self-oscillation frequency. The detection system uses self-oscillation
      frequency as the detection parameter and has excellent resolution with respect to
      changes in excited-state lifetime ( approximately 1 ps). (c) 2004 Society of
      Photo-Optical Instrumentation Engineers.

PMID- 15189101
TI  - Dual modality instrument for simultaneous optical coherence tomography imaging
      and fluorescence spectroscopy.
AB  - We develop a dual-modality device that combines the anatomical imaging
      capabilities of optical coherence tomography (OCT) with the functional
      capabilities of laser-induced fluorescence (LIF) spectroscopy. OCT provides cross
      sectional images of tissue structure to a depth of up to 2 mm with approximately
      10-microm resolution. LIF spectroscopy provides histochemical information in the
      form of emission spectra from a given tissue location. The OCT subsystem utilizes
      a superluminescent diode with a center wavelength of 1300 nm, whereas a helium
      cadmium laser provides the LIF excitation source at wavelengths of 325 and 442
      nm. Preliminary data are obtained on eight postmortem aorta samples, each 10 mm
      in length. OCT images and LIF spectra give complementary information from normal
      and atherosclerotic portions of aorta wall. OCT images show structures such as
      intima, media, internal elastic lamina, and fibrotic regions. Emission spectra
      ratios of 520/490 (325-nm excitation) and 595/635 (442-nm excitation) could be
      used to identify normal and plaque regions with 97 and 91% correct classification
      rates, respectively. With miniaturization of the delivery probe and improvements
      in system speed, this dual-modality device could provide a valuable tool for
      identification and characterization of atherosclerotic plaques.

PMID- 15189102
TI  - Optical characterization of bovine retinal tissues.
AB  - An in-depth characterization of the optical properties of bovine retinal and
      retinal pigment epithelium-choroidal tissues has been performed. The indices of
      refraction of these ocular tissues were determined by applying Brewster's law.
      The inverse adding doubling method based on the diffusion approximation and
      radiative transport theory is applied to the measured values of the total diffuse
      transmission, total diffuse reflection, and collimated transmission to calculate
      the optical absorption, scattering, and scattering anisotropy coefficients of the
      bovine retinal and retinal pigment epithelium-choroidal tissues. The values of
      the optical properties obtained from the inverse adding doubling method are
      compared with those generated by the Monte Carlo simulation technique. Optical
      polarization measurements are also performed on bovine retinal tissues. Our
      studies show that both retina and retinal pigment epithelium-choroid possess
      strong polarization characteristics.

PMID- 15189103
TI  - Radiative transport in the delta-P1 approximation: accuracy of fluence rate and
      optical penetration depth predictions in turbid semi-infinite media.
AB  - Using the delta-P(1) approximation to the Boltzmann transport equation we develop
      analytic solutions for the fluence rate produced by planar (1-D) and Gaussian
      beam (2-D) irradiation of a homogeneous, turbid, semi-infinite medium. To assess
      the performance of these solutions we compare the predictions for the fluence
      rate and two metrics of the optical penetration depth with Monte Carlo
      simulations. We provide results under both refractive-index matched and
      mismatched conditions for optical properties where the ratio of reduced
      scattering to absorption lies in the range 0< or =(micro(s')/micro(a))< or
      =10(4). For planar irradiation, the delta-P(1) approximation provides fluence
      rate profiles accurate to +/-16% for depths up to six transport mean free paths
      (l*) over the full range of optical properties. Metrics for optical penetration
      depth are predicted with an accuracy of +/-4%. For Gaussian irradiation using
      beam radii r(0) > or =3 l*, the accuracy of the fluence rate predictions is no
      worse than in the planar irradiation case. For smaller beam radii, the
      predictions degrade significantly. Specifically for media with
      (micro(s')/micro(a))=1 irradiated with a beam radius of r(0)=l*, the error in the
      fluence rate approaches 100%. Nevertheless, the accuracy of the optical
      penetration depth predictions remains excellent for Gaussian beam irradiation,
      and degrades to only +/-20% for r(0)=l*. These results show that for a given set
      of optical properties (micro(s')/micro(a)), the optical penetration depth
      decreases with a reduction in the beam diameter. Graphs are provided to indicate
      the optical and geometrical conditions under which one must replace the delta
      P(1) results for planar irradiation with those for Gaussian beam irradiation to
      maintain accurate dosimetry predictions.

PMID- 15189104
TI  - Optimization of selective hyperthermia.
AB  - Selective hyperthermia can be a feasible treatment modality for deep tissue
      abnormalities. It is accomplished by using a laser or ultrasound noninvasively to
      transfer energy to a desired target causing tissue damage. This process has two
      potential benefits to medical professionals: simplicity of procedure and safety
      to patient. However, optimizing these selective interactions is difficult due to
      the number of variables. We propose an optimization coefficient relating the
      dynamic and geometric parameters of selective hyperthermia, and proceed to
      measure it in an experimental setup consisting of a near-infrared laser and laser
      absorbing dye. To simulate tissue, gelatin phantoms are created using a
      combination of water, intralipid, and gelatin. Our experiments use a 1.00-cm-diam
      spherical phantom that is homogeneously enhanced with an indocyanine green (ICG)
      solution and placed inside a nontarget phantom and irradiated by an 805-nm diode
      laser. Temperature measurements taken at different locations are analyzed so
      optimization coefficients can be calculated for different parameters. This
      optimization coefficient compares the difference in temperatures from inside and
      outside the target. Analysis of the values after thermal equilibrium provides
      information about the best parameter selection. Our findings indicate that the
      optimal ICG concentration and power combination for our tested parameters are
      0.083% and 0.97 W, respectively. Based on our analysis, optimization can be
      obtained by using this coefficient to compare the selectivity of several
      parameter combinations.

PMID- 15189105
TI  - Historical perspective on movement disorders.
AB  - Before atypical antipsychotics were developed, neuroleptics given to patients for
      the treatment of psychosis often caused movement disorders. Although the role of
      neuroleptics in the development of tardive dyskinesia was never certain, this
      adverse effect was of great concern to physicians because its effects could be
      irreversible and devastating to the patient. It is important to understand
      whether involuntary movement disorders are an intrinsic part of schizophrenia,
      because if so, then a certain percentage of patients will develop the dyskinetic
      syndromes whether they are treated or not. To uncover the role of antipsychotic
      medications in tardive dyskinesia, it is necessary to examine the descriptions of
      abnormal movements made by those who were first researching schizophrenia, as
      well as modern descriptions of neuroleptic-naive individuals with schizophrenia.
      The physicians who initially described the syndrome of tardive dyskinesia had
      observed pre-neuroleptic schizophrenia first hand and saw a difference in the
      movements of treated and untreated patients. Nevertheless, the idea of a chronic
      movement disorder caused by treatment with neuroleptics would become
      controversial for many years. With the development of the atypical
      antipsychotics, the incidence and prevalence of tardive dyskinesia have dropped
      remarkably, suggesting that psychosis, its treatment, and dyskinesias are not
      inextricably linked.

PMID- 15189106
TI  - New nomenclature for drug-induced movement disorders including tardive
      dyskinesia.
AB  - Psychotropic agents are increasingly being prescribed by different specialty
      clinicians for a variety of psychiatric illnesses, making it necessary to improve
      understanding of the etiology, diagnosis, and management of drug-induced movement
      disorders (D-IMD) across medical specialties. Early descriptions of movement
      disorders were based on identifiable disease states such as parkinsonism,
      dystonia deformans, and Huntington's chorea, which introduced complicated and
      often overlapping nomenclature. This has hindered communication about,
      description of, and diagnosis of these drug-induced disorders. Research criteria
      for tardive dyskinesia, a specific, purposeless, involuntary, hyperkinetic,
      potentially persistent D-IMD, have varied, with relatively few data-driven
      conclusions available to support clinical decision-making. The differences in
      research criteria among published reports on rates of tardive dyskinesia with
      atypical antipsychotics make it difficult to find meaningful comparisons and
      conclusions between atypicals. A novel system for classifying D-IMD according to
      whether they are reversible or persistent, hypokinetic or hyperkinetic, and
      dystonic or nondystonic is proposed. This new classification system will provide
      clinicians and researchers across specialties a more precise language, which will
      hopefully improve the diagnosis of and research criteria for D-IMD.

PMID- 15189107
TI  - Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and
      incidence.
AB  - Both conventional and atypical antipsychotics cause an up-regulation of dopamine
      2 receptors and have been associated with tardive dyskinesia. Studies of adult
      and elderly subjects have shown a greater incidence of tardive dyskinesia among
      patients who were administered conventional antipsychotic drugs than those given
      atypical antipsychotic drugs. This article will review studies of the prevalence
      and incidence of tardive dyskinesia in patients taking antipsychotic agents.

PMID- 15189108
TI  - Tardive dyskinesia rates with atypical antipsychotics in older adults.
AB  - Tardive dyskinesia is a chronic drug-induced movement disorder that tends to be
      persistent in older adults who are treated with antipsychotics. Tardive
      dyskinesia can affect older patients both physically and psychologically, leading
      to frequent falls, difficulty eating, and depression. While atypical
      antipsychotics may cause tardive dyskinesia, the percentage is usually
      significantly lower than with conventional antipsychotics. Using atypical
      antipsychotics, particularly at lower doses, may aid in preventing symptoms of
      tardive dyskinesia in older adults.

PMID- 15189109
TI  - Pathophysiology of antipsychotic drug-induced movement disorders.
AB  - Explaining the underlying mechanisms of antipsychotic drug-induced movement
      disorders remains a substantial challenge. The association of atypical
      antipsychotic agents with fewer drug-induced movement disorders than conventional
      agents has engendered several pathophysiologic hypotheses: (1) the hypothesis
      that, unlike conventional antipsychotic agents, atypical antipsychotics have
      greater activity in blocking serotonin-2A (5-HT(2A)) receptors than dopamine-2
      (D(2)) receptors, which mitigates extrapyramidal symptoms; (2) the hypothesis
      that atypical antipsychotics block D(2) receptors only long enough to cause an
      antipsychotic action, but not as long as conventional agents; (3) the hypothesis
      that, in tardive dyskinesia, the nigrostriatal dopamine receptor system might
      develop increased sensitivity to dopamine as a result of treatment with
      conventional antipsychotic drugs, but this may not occur with atypical
      antipsychotics; and (4) the hypothesis that there might be a genetic association
      in tardive dystonia relating to the dopamine D(3) allele. A number of factors
      contribute to the difficult task of gaining insight into the pathophysiologic
      processes of antipsychotic agents and why these agents may lead to drug-induced
      movement disorders.

PMID- 15189110
TI  - On becoming a nutritional biochemist.
AB  - Much of the science underlying nutrition has come from biochemical studies. This
      certainly is true in our understanding of the metabolism and function of such
      micronutrient cofactors as vitamins and metal ions. My own interest stems from an
      early desire to understand the molecular events in an organism and ultimately to
      know the fate of those nutrients that are needed to maintain life. My training in
      chemistry, biochemistry, and nutrition was helpful in gaining knowledge about the
      interface among these disciplines. My interests followed an understandable trail,
      beginning with those factors that cause plant galls and continuing through
      carbohydrate metabolism to vitamins. After all, from studying such pentitols as
      ribitol with Professor Touster at Vanderbilt University through indoctrination
      with enzymes, vitamins, and coenzymes with Professor Snell at the University of
      California-Berkeley, it was rational to begin my independent academic life
      investigating the enzymes that convert a ribityl-containing vitamin, namely
      riboflavin, to its operational flavocoenzymes. While at Cornell University, I
      encountered Professor Wright, who shared an interest in biotin. My realization
      that there was a similar need to determine the metabolism of lipoate followed
      logically. Interactions with inorganic chemists such as Professor Sigel at Basel
      University, as well as inorganic chemists at Cornell, led to an interest in metal
      ions. As summarized in this article, my colleagues and I are pleased to have
      contributed to both basic knowledge about cofactors and to have utilized much of
      this information in extensions to applications. Along the way, I have served by
      teaching, researching, and administrating at the universities that provided my
      positions in academe, and I have worked to share the load of numerous public and
      professional duties that are summarized herein. Altogether it has been an
      enjoyable career to be a nutritional biochemist. I recommend it for those who
      follow.

PMID- 15189111
TI  - Calcium and bone mineral metabolism in children with chronic illnesses.
AB  - Increased longevity and improved medical management of children with chronic
      illnesses has led to a focus on the short- and long-term consequences of these
      conditions on bone health. Bone loss is influenced by diet, malabsorption, and
      disease-related imbalances in bone turnover. It may be exacerbated by common
      medications, especially corticosteroids. Assessment of bone mass and quality,
      calcium absorption, kinetically derived rates of bone turnover, and biochemical
      markers of bone turnover have increased our knowledge of the pathophysiology of
      bone loss in these children as well as provided insights into possible
      therapeutic interventions. Increased intake of calcium and vitamin D, while
      useful, is unlikely to prevent or resolve bone loss in many chronically ill
      children. Emphasis on combination of nutritional interventions with exercise and
      newer bone-sparing therapies may be necessary.

PMID- 15189112
TI  - Isoflavones in soy infant formula: a review of evidence for endocrine and other
      activity in infants.
AB  - Soy infant formulas are widely used, but few studies have evaluated long-term
      safety or examined specific forms of toxicity, such as to the endocrine or immune
      systems. This review focuses on newer experimental studies of the effects on
      estrogen activity, immune function, and thyroid economy of genistein and
      daidzein, two isoflavones in soy infant formula, and existing human studies of
      soy formula use. In order to judge the likelihood that an endpoint seen in
      laboratory studies might occur in soy-fed infants, we examined the doses and the
      resulting serum or plasma concentrations from the laboratory studies and compared
      them with doses and concentrations seen in soy-fed infants. We also summarized
      the estimates of the potency of the isoflavone compounds relative to estradiol.
      Given the scarcity and inconsistency of existing human data and the substantial
      laboratory evidence of hormonal and other activity at doses relevant to the soy
      fed infant, we conclude that more clinical and epidemiological study is
      warranted.

PMID- 15189113
TI  - Molecular aspects of alcohol metabolism: transcription factors involved in early
      ethanol-induced liver injury.
AB  - Alcohol metabolism takes place primarily in the liver. Initial exposures to
      ethanol have a major impact on the hepatic redox state and intermediary
      metabolism as a consequence of ethanol metabolism via alcohol dehydrogenase.
      However, upon continued exposure to ethanol, the progression of liver injury
      involves ethanol metabolism via CYP2E1 and consequent oxidant stress, as well as
      potential direct effects of ethanol on membrane proteins that are independent of
      ethanol metabolism. Multiple organ systems contribute to liver injury, including
      the innate immune system and adipose tissue. In response to ethanol exposure,
      specific signal transduction pathways, including NFkappaB and the mitogen
      activated protein kinase family members ERK1/2, JNK, and p38, are activated.
      These complex responses to ethanol exposure translate into activation of nuclear
      transcription factors and altered gene expression within the liver, leading to
      the development of steatosis and inflammation in the early stages of alcohol
      induced liver injury.

PMID- 15189114
TI  - Developmental aspects and factors influencing the synthesis and status of
      ascorbic Acid in the pig.
AB  - Ascorbic acid synthesis in the pig occurs at mid-pregnancy, but activity of the
      enzyme l-gulono-gamma-lactone oxidase (GLO) declines thereafter during gestation
      and remains low when the pig nurses the sow. During late gestation the ascorbic
      acid concentration in the fetus increases, but serum and liver ascorbic acid
      concentration in the sow declines without affecting the dam's liver GLO activity.
      It is presumed that as gestation progresses an increased amount of maternal
      ascorbic acid is transferred to the fetus and to the mammary gland. Colostrum and
      milk are rich sources of the vitamin and supply the nursing pig with ascorbic
      acid. The available data suggest that high amounts of ascorbic acid appear to
      suppress liver GLO activity in the pig. Upon weaning, when exogenous vitamin C is
      generally not provided, liver GLO activity and serum ascorbic acid increases.
      During the initial periods postweaning, some reports have indicated growth
      benefits of supplemental vitamin C. Body tissues differ in their concentrations
      of ascorbic acid, but tissues of high metabolic need generally have greater
      concentrations. The corpus luteum in the female, the testis in the male, and the
      adrenal glands in all pigs contain greater concentrations of the vitamin.
      Knockout genes preventing ascorbic acid synthesis in pigs have demonstrated poor
      skeletal and collagen formation and poor antioxidant protection. Under periods of
      stress ascorbic acid declines in the adrenal, but the pig rapidly recovers to its
      resting state once the stressor agent is removed. Although there are periods when
      supplemental vitamin C has been shown to promote pig performance (e.g., during
      high environmental stress and early postweaning), supplemental vitamin C has not
      been shown to routinely enhance pig performance.

PMID- 15189115
TI  - New insights into erythropoiesis: the roles of folate, vitamin B12, and iron.
AB  - Erythropoiesis is the process in which new erythrocytes are produced. These new
      erythrocytes replace the oldest erythrocytes (normally about one percent) that
      are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have
      crucial roles in erythropoiesis. Erythroblasts require folate and vitamin B12 for
      proliferation during their differentiation. Deficiency of folate or vitamin B12
      inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes
      erythroblast apoptosis, resulting in anemia from ineffective erythropoiesis.
      Erythroblasts require large amounts of iron for hemoglobin synthesis. Large
      amounts of iron are recycled daily with hemoglobin breakdown from destroyed old
      erythrocytes. Many recently identified proteins are involved in absorption,
      storage, and cellular export of nonheme iron and in erythroblast uptake and
      utilization of iron. Erythroblast heme levels regulate uptake of iron and globin
      synthesis such that iron deficiency causes anemia by retarded production rates
      with smaller, less hemoglobinized erythrocytes.

PMID- 15189116
TI  - The critical role of the melanocortin system in the control of energy balance.
AB  - Animals have developed highly adaptive and redundant mechanisms to maintain
      energy balance by matching caloric intake to caloric expenditure. Recent evidence
      has pointed to a variety of peripheral signals that inform specific central
      nervous system (CNS) circuits about the status of peripheral energy stores as
      critical to the maintenance of energy balance. A critical component of these CNS
      circuits is the melanocortin system. Regulation of signaling by melanocortin 3
      and melanocortin 4 receptors in the CNS is controlled via neuronal cell bodies in
      the arcuate nucleus of the hypothalamus that synthesize melanocortin receptor
      agonists such as alpha-melanocyte-stimulating hormone (alpha-MSH) or antagonists
      such as agouti-related protein (AgRP). The activity of these two populations of
      neurons is reciprocally regulated by a number of peripheral and central systems
      that influence energy balance. Further, increased melanocortin signaling via
      pharmacological or genetic means in the CNS causes potent reductions in food
      intake and weight loss. Decreased melanocortin signaling via pharmacological or
      genetic means results in increased food intake and weight gain. Reviewed here is
      the wide range of evidence that points to the melanocortin system as a critical
      node in the diverse neurocircuitry that regulates food intake and body weight.

PMID- 15189117
TI  - Mammalian zinc transporters.
AB  - New insights into mammalian zinc metabolism have been acquired through the
      identification and characterization of zinc transporters. These proteins all have
      transmembrane domains, and are encoded by two solute-linked carrier (SLC) gene
      families: ZnT (SLC30) and Zip (SLC39). There are at least 9 ZnT and 15 Zip
      transporters in human cells. They appear to have opposite roles in cellular zinc
      homeostasis. ZnT transporters reduce intracellular zinc availability by promoting
      zinc efflux from cells or into intracellular vesicles, while Zip transporters
      increase intracellular zinc availability by promoting extracellular zinc uptake
      and, perhaps, vesicular zinc release into the cytoplasm. Both the ZnT and Zip
      transporter families exhibit unique tissue-specific expression, differential
      responsiveness to dietary zinc deficiency and excess, and differential
      responsiveness to physiologic stimuli via hormones and cytokines.

PMID- 15189118
TI  - Nutritional protection against skin damage from sunlight.
AB  - The concept of systemic photoprotection by dietary means is gaining momentum.
      Skin is continuously exposed to ultraviolet (UV) radiation, the major cause of
      skin disorders such as sunburn, photodamage, and nonmelanoma skin cancer. Most of
      the erythemal annual UV dose is encountered under nonvacation conditions, when no
      sunscreen is applied. In the absence of topically added compounds, skin
      protection depends solely on endogenous defense. Micronutrients can act as UV
      absorbers, as antioxidants, or can modulate signaling pathways elicited upon UV
      exposure. UV-induced erythema is a suitable parameter to assess photoprotection.
      Dietary protection is provided by carotenoids, tocopherols, ascorbate,
      flavonoids, or n-3 fatty acids, contributing to maintenance resistance as part of
      lifelong protection.

PMID- 15189119
TI  - Retinoic acid receptors and cancers.
AB  - Studies utilizing experimental animals, epidemiological approaches, cellular
      models, and clinical trials all provide evidence that retinoic acid and some of
      its synthetic derivatives (retinoids) are useful pharmacological agents in cancer
      therapy and prevention. In this chapter, we first review the current knowledge of
      retinoic acid receptors (RARs) and their role in mediating the actions of
      retinoic acid. We then focus on a discussion of RARalpha and acute promyelocytic
      leukemia followed by a discussion of the role of RARs, in particular RARbeta
      expression, in other cancer types. Loss of normal RAR function in the presence of
      physiological levels of RA (either due to alterations in the protein structure or
      level of expression) is associated with a variety of different cancers. In some
      cases treatment with pharmacological doses of RA can be effective.

PMID- 15189120
TI  - Nutrition and cancer prevention: a multidisciplinary perspective on human trials.
AB  - More than one million Americans were expected to be diagnosed with cancer in 2003
      (7a). Compelling experimental, epidemiological, and clinical evidence indicates
      that many cancers are preventable, especially because diet and nutrition are key
      factors in the modulation of cancer risk. The road to nutritional intervention in
      cancer prevention has led to successful trials as well as trials that did not
      reach their intended endpoints. This chapter reviews four case studies of trials,
      with two ending in success and two ending in null findings or adverse effects.
      The goal is to identify lessons learned from all four case studies and from the
      investigations of the complexities inherent to nutritional intervention trials.
      Additional insights are presented by the research addressing potential mechanisms
      underlying the endpoints of human trials. Future progress in nutrition and cancer
      prevention will require expertise from multidisciplinary teams to develop new
      knowledge about specific nutrients and dietary modifications within a framework
      of interaction between animal and human research.

PMID- 15189121
TI  - Zinc and the risk for infectious disease.
AB  - Zinc is an essential micronutrient for human growth, development, and immune
      function. Zinc deficiency impairs overall immune function and resistance to
      infection. Mild to moderate zinc deficiency can be best detected through a
      positive response to supplementation trials. Zinc supplementation has been shown
      to have a positive effect on the incidence of diarrhea (18% reduction, 95% CI: 7
      28%) and pneumonia (41% reduction, 95% CI: 17-59%), and might lead to a decrease
      in the incidence of malaria. Zinc has also proven to decrease the duration of
      diarrhea by 15% (95% CI: 5-24%). Maternal zinc supplementation may lead to a
      decrease in infant infections. Studies assessing the role of zinc supplementation
      among persons with HIV, tuberculosis, and the common cold have not been
      conclusive. Two studies have shown zinc supplementation to decrease child
      mortality by more than 50%. Zinc clearly has an important role in infant and
      childhood infectious diseases; programs to increase the intake of zinc among
      deficient populations are needed.

PMID- 15189122
TI  - Reprogramming of the immune system during zinc deficiency.
AB  - Thymic atrophy, lymphopenia, and compromised cell- and antibody-mediated
      responses that cause increased rates of infections of longer duration are the
      immunological hallmarks of zinc deficiency (ZD) in humans and higher animals. As
      the deficiency advances, a reprogramming of the immune system occurs, beginning
      with the activation of the stress axis and chronic production of glucocorticoids
      that accelerate apoptosis among pre-B and -T cells. This reduces lymphopoiesis
      and causes atrophy of the thymus. In contrast, myelopoiesis is preserved, thereby
      providing protection for the first line of immune defense or innate immunity.
      Changes in gene expression for cytokines, DNA repair enzymes, zinc transporters,
      signaling molecules, etc., suggest that cells of the immune system are attempting
      to adapt to the stress of suboptimal zinc. Better understanding of the molecular
      and cellular changes made in response to inadequate zinc should lead to the
      development of immunotherapeutic interventions.

PMID- 15189123
TI  - Vitamin B12 deficiency as a worldwide problem.
AB  - Pernicious anemia is a common cause of megaloblastic anemia throughout the world
      and especially in persons of European or African descent. Dietary deficiency of
      vitamin B12 due to vegetarianism is increasing and causes hyperhomocysteinemia.
      The breast-fed infant of a vitamin B12-deficient mother is at risk for severe
      developmental abnormalities, growth failure, and anemia. Elevated methylmalonic
      acid and/or total homocysteine are sensitive indicators of vitamin B12-deficient
      diets and correlate with clinical abnormalities. Dietary vitamin B12 deficiency
      is a severe problem in the Indian subcontinent, Mexico, Central and South
      America, and selected areas in Africa. Dietary vitamin B12 deficiency is not
      prevalent in Asia, except in vegetarians. Areas for research include intermittent
      vitamin B12 supplement dosing and better measurements of the bioavailability of
      B12 in fermented vegetarian foods and algae.

PMID- 15189124
TI  - Iron, ferritin, and nutrition.
AB  - Ferritin, a major form of endogenous iron in food legumes such as soybeans, is a
      novel and natural alternative for iron supplementation strategies where
      effectiveness is limited by acceptability, cost, or undesirable side effects. A
      member of the nonheme iron group of dietary iron sources, ferritin is a complex
      with Fe3+ iron in a mineral (thousands of iron atoms inside a protein cage)
      protected from complexation. Ferritin illustrates the wide range of chemical and
      biological properties among nonheme iron sources. The wide range of nonheme iron
      receptors matched to the structure of the iron complexes that occurs in
      microorganisms may, by analogy, exist in humans. An understanding of the
      chemistry and biology of each type of dietary iron source (ferritin, heme, Fe2+
      ion, etc.), and of the interactions dependent on food sources, genes, and gender,
      is required to design diets that will eradicate global iron deficiency in the
      twenty-first century.

PMID- 15189125
TI  - Structure, function, and dietary regulation of delta6, delta5, and delta9
      desaturases.
AB  - Fatty acid desaturases introduce a double bond in a specific position of long
      chain fatty acids, and are conserved across kingdoms. Degree of unsaturation of
      fatty acids affects physical properties of membrane phospholipids and stored
      triglycerides. In addition, metabolites of polyunsaturated fatty acids are used
      as signaling molecules in many organisms. Three desaturases, Delta9, Delta6, and
      Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated
      fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty
      acid in mammalian adipose triglycerides, and is also used for phospholipid and
      cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the
      synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified
      into phospholipids and contribute to maintaining membrane fluidity. While HUFAs
      may be required for cold tolerance in plants and fish, the primary role of HUFAs
      in mammals is cell signaling. Arachidonic acid is required as substrates for
      eicosanoid synthesis, while docosahexaenoic acid is required in visual and
      neuronal functions. Desaturases in mammals are regulated at the transcriptional
      level. Reflecting overlapping functions, three desaturases share a common
      mechanism of a feedback regulation to maintain products in membrane
      phospholipids. At the same time, regulation of Delta9 desaturase differs from
      Delta6 and Delta5 desaturases because its products are incorporated into more
      diverse lipid groups. Combinations of multiple transcription factors achieve this
      sophisticated differential regulation.

PMID- 15189126
TI  - Secular trends in dietary intake in the United States.
AB  - This review focuses on dietary intake and dietary supplement use among the U.S.
      population age 1-74 based on four National Health and Nutrition Examination
      Surveys conducted in 1971-74, 1976-80, 1988-94, and 1999-2000. Secular trends in
      intake of energy, macronutrients, cholesterol, sodium, calcium, iron, folate,
      zinc, vitamins A and C, fruits, vegetables, and grain products are summarized.
      During the 30-year period, mean energy intake increased among adults, and changed
      little among children age 1-19, except for an increase among adolescent females.
      Factors contributing to increases in energy intake include increases in the
      percentage of the population eating away from home (particularly at fast-food
      restaurants), larger portion sizes of foods and beverages, increased consumption
      of sweetened beverages, changes in snacking habits, and improved dietary
      methodology. Dietary supplement use increased among adult men and women,
      decreased among children age 1-5, and was stable for children age 6-11 and
      adolescents.

PMID- 15189127
TI  - Nutrient regulation of cell cycle progression.
AB  - Cell replication is tightly controlled in normal tissues and aberrant during
      disease progression, such as in tumorigenesis. The replication of cells can be
      divided into four distinct phases: Gap 1 (G1), synthesis (S), gap 2 (G2), and
      mitosis (M). The progression from one phase to the next is intricately regulated
      and has many "checkpoints" that take into account cellular status and
      environmental cues. Among the modulators of cell cycle progression are specific
      nutrients, which function as energy sources or regulate the production and/or
      function of proteins needed to advance cells through a replicative cycle. In this
      review, we focus on the roles of specific nutrients (vitamin A, vitamin D, iron,
      folic acid, vitamin B12, zinc, and glucose) in the control of cell cycle
      progression and discuss how insights into the mechanisms by which these nutrients
      modulate this process can be and have been used to control aberrant cell growth
      in the treatment of prevalent pathologies.

PMID- 15189128
TI  - Environmental factors that increase the food intake and consumption volume of
      unknowing consumers.
AB  - Package size, plate shape, lighting, socializing, and variety are only a few of
      the environmental factors that can influence the consumption volume of food far
      more than most people realize. Although such environmental factors appear
      unrelated, they generally influence consumption volume by inhibiting consumption
      monitoring and by suggesting alternative consumption norms. For researchers, this
      review suggests that redirecting the focus of investigations to the psychological
      mechanisms behind consumption will raise the profile and impact of research. For
      health professionals, this review underscores how small structural changes in
      personal environments can reduce the unknowing overconsumption of food.

PMID- 15189129
TI  - Extracellular thiols and thiol/disulfide redox in metabolism.
AB  - Many proteins present on cell surfaces and located in extracellular fluids
      contain cysteine and methionine residues that are subject to oxidation. These
      proteins, which include transporters, receptors, and enzymes, respond to
      variations in the extracellular thiol/disulfide redox environment. Changes in
      activity of these proteins can alter the ability of organs to function normally
      and influence processes such as nutritional absorption, secretory function,
      neurotransmission, and susceptibility to toxicants. In addition, extracellular
      redox can regulate tissue homeostasis through effects on cell proliferation,
      differentiation, apoptosis, and immune function. Consequently, extracellular
      redox can have important influences on health status and disease states and thus
      could be a target for nutritional interventions.

PMID- 15189130
TI  - Bioactive compounds in nutrition and health-research methodologies for
      establishing biological function: the antioxidant and anti-inflammatory effects
      of flavonoids on atherosclerosis.
AB  - Identifying bioactive compounds and establishing their health effects are active
      areas of scientific inquiry. There are exciting prospects that select bioactive
      compounds will reduce the risk of many diseases, including chronic diseases such
      as cardiovascular disease. Recent findings have established that cardiovascular
      disease is a disease of inflammation, and consequently is amenable to
      intervention via molecules that have anti-inflammatory effects. In addition,
      research demonstrating adverse effects of oxidants on atherogenesis raises the
      possibility that antioxidants can confer cardioprotective effects. This review
      provides an overview of research approaches that can be used to unravel the
      biology and health effects of bioactive compounds. Because of the number of
      bioactive compounds and the diversity of likely biological effects, numerous and
      diverse experimental approaches must be taken to increase our understanding of
      the biology of bioactive compounds. Recognizing the complexity of this biology,
      sophisticated experimental designs and analytical methodologies must be employed
      to advance the field. The discovery of novel health effects of bioactive
      compounds will provide the scientific basis for future efforts to use
      biotechnology to modify/fortify foods and food components as a means to improve
      public health.

PMID- 15189131
TI  - Sulfur amino acid metabolism: pathways for production and removal of homocysteine
      and cysteine.
AB  - Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are
      maintained at low levels by regulated production and efficient removal of these
      thiols. The regulation of the metabolism of methionine and Cys is discussed from
      the standpoint of maintaining low levels of Hcy and Cys while, at the same time,
      ensuring an adequate supply of these thiols for their essential functions. S
      Adenosylmethionine coordinately regulates the flux through remethylation and
      transsulfuration, and glycine N-methyltransferase regulates flux through
      transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio.
      Cystathionine beta-synthase activity is also regulated in response to the redox
      environment, and transcription of the gene is hormonally regulated in response to
      fuel supply (insulin, glucagon, and glucocorticoids). The H2S-producing capacity
      of cystathionine gamma-lyase may be regulated in response to nitric oxide. Cys is
      substrate for a variety of anabolic and catabolic enzymes. Its concentration is
      regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is
      upregulated in a Cys-responsive manner via a decrease in the rate of
      polyubiquitination and, hence, degradation by the 26S proteasome.

PMID- 15189132
TI  - Identification of trace element-containing proteins in genomic databases.
AB  - Development of bioinformatics tools provided researchers with the ability to
      identify full sets of trace element-containing proteins in organisms for which
      complete genomic sequences are available. Recently, independent bioinformatics
      methods were used to identify all, or almost all, genes encoding selenocysteine
      containing proteins in human, mouse, and Drosophila genomes, characterizing
      entire selenoproteomes in these organisms. It also should be possible to search
      for entire sets of other trace element-associated proteins, such as metal
      containing proteins, although methods for their identification are still in
      development.

PMID- 15189133
TI  - Dietary n-6 and n-3 fatty acid balance and cardiovascular health.
AB  - Epidemiological and clinical studies have established that the n-6 fatty acid,
      linoleic acid (LA), and the n-3 fatty acids, linolenic acid (LNA),
      eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) collectively protect
      against coronary heart disease (CHD). LA is the major dietary fatty acid
      regulating low-density lipoprotein (LDL)-C metabolism by downregulating LDL-C
      production and enhancing its clearance. Further, the available mass of LA is a
      critical factor determining the hyperlipemic effects of other dietary fat
      components, such as saturated and trans fatty acids, as well as cholesterol. By
      contrast, n-3 fatty acids, especially EPA and DHA, are potent antiarryhthmic
      agents. EPA and DHA also improve vascular endothelial function and help lower
      blood pressure, platelet sensitivity, and the serum triglyceride level. The
      distinct functions of these two families make the balance between dietary n-6 and
      n-3 fatty acids an important consideration influencing cardiovascular health.
      Based on published literature describing practical dietary intakes, we suggest
      that consumption of ~6% en LA, 0.75% en LNA, and 0.25% en EPA + DHA represents
      adequate and achievable intakes for most healthy adults. This corresponds to an n
      6/n-3 ratio of ~6:1. However, the absolute mass of essential fatty acids
      consumed, rather than their n-6/n-3 ratio, should be the first consideration when
      contemplating lifelong dietary habits affecting cardiovascular benefit from their
      intake.

PMID- 15189134
TI  - America's obesity: conflicting public policies, industrial economic development,
      and unintended human consequences.
AB  - The chapter reviews the historical development and interactions of U.S.
      agricultural, economic, nutrition, and development policies relating to the
      creation of the commercial environment of social, economic, technological, and
      political factors that favor the development of American obesity.

PMID- 15189135
TI  - The excitement of discovery.
AB  - I had the good luck to start research at the dawn of molecular biology when it
      was possible to ask fundamental questions about the nature of the nucleic acids
      and how information is transferred in living systems. The search for answers led
      me into many different areas, often with the question of how molecular structure
      leads to biological function. Early work in this period provided some of the
      roots supporting the current explosive developments in life sciences. Here I give
      a brief account of my development, describe some contributions, and provide a
      hint of the exhilaration in discovering new things. Most of all, I had the good
      fortune to have inspiring teachers, stimulating colleagues, and excellent
      students.

PMID- 15189136
TI  - Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
AB  - DNA damage is a relatively common event in the life of a cell and may lead to
      mutation, cancer, and cellular or organismic death. Damage to DNA induces several
      cellular responses that enable the cell either to eliminate or cope with the
      damage or to activate a programmed cell death process, presumably to eliminate
      cells with potentially catastrophic mutations. These DNA damage response
      reactions include: (a) removal of DNA damage and restoration of the continuity of
      the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell
      cycle progression so as to allow for repair and prevention of the transmission of
      damaged or incompletely replicated chromosomes; (c) transcriptional response,
      which causes changes in the transcription profile that may be beneficial to the
      cell; and (d) apoptosis, which eliminates heavily damaged or seriously
      deregulated cells. DNA repair mechanisms include direct repair, base excision
      repair, nucleotide excision repair, double-strand break repair, and cross-link
      repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM,
      ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to
      initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases
      and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin
      dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S
      checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M
      checkpoint). In this review the molecular mechanisms of DNA repair and the DNA
      damage checkpoints in mammalian cells are analyzed.

PMID- 15189137
TI  - Cytochrome C-mediated apoptosis.
AB  - Apoptosis, or programmed cell death, is involved in development, elimination of
      damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may
      cause diseases, such as cancers, immune diseases, and neurodegenerative
      disorders. Apoptosis is executed by a subfamily of cysteine proteases known as
      caspases. In mammalian cells, a major caspase activation pathway is the
      cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli
      cause cytochrome c release from mitochondria, which in turn induces a series of
      biochemical reactions that result in caspase activation and subsequent cell
      death. In this review, we focus on the recent progress in understanding the
      biochemical mechanisms and regulation of the pathway, the roles of the pathway in
      physiology and disease, and their potential therapeutic values.

PMID- 15189138
TI  - Nuclear magnetic resonance spectroscopy of high-molecular-weight proteins.
AB  - Recent developments in NMR spectroscopy, which include new experiments that
      increase the lifetimes of NMR signals or that precisely define the orientation of
      internuclear bond vectors with respect to a common molecular frame, have
      significantly increased the size of proteins for which quantitative structural
      and dynamic information can be obtained. These experiments have, in turn,
      benefited from new labeling strategies that continue to drive the field. The
      utility of the new methodology is illustrated by considering applications to
      malate synthase G, a 723 residue enzyme, which is the largest single polypeptide
      chain for which chemical shift assignments have been obtained to date. New
      experiments developed specifically to address the complexity and low sensitivity
      of spectra recorded on this protein are presented. A discussion of the chemical
      information that is readily available from studies of systems in the 100 kDa mol
      wt range is included. Prospects for membrane protein structure determination are
      discussed briefly in the context of an application to an Escherichia coli enzyme,
      PagP, localized to the outer membrane of gram-negative bacteria.

PMID- 15189139
TI  - Incorporation of nonnatural amino acids into proteins.
AB  - The genetic code is established by the aminoacylation of transfer RNA, reactions
      in which each amino acid is linked to its cognate tRNA that, in turn, harbors the
      nucleotide triplet (anticodon) specific to the amino acid. The accuracy of
      aminoacylation is essential for building and maintaining the universal tree of
      life. The ability to manipulate and expand the code holds promise for the
      development of new methods to create novel proteins and to understand the origins
      of life. Recent efforts to manipulate the genetic code have fulfilled much of
      this potential. These efforts have led to incorporation of nonnatural amino acids
      into proteins for a variety of applications and have demonstrated the
      plausibility of specific proposals for early evolution of the code.

PMID- 15189140
TI  - Regulation of telomerase by telomeric proteins.
AB  - Telomeres are essential for genome stability in all eukaryotes. Changes in
      telomere functions and the associated chromosomal abnormalities have been
      implicated in human aging and cancer. Telomeres are composed of repetitive
      sequences that can be maintained by telomerase, a complex containing a reverse
      transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC
      in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and
      dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase
      is regulated in cis by proteins that bind to telomeric DNA. This regulation can
      take place at the telomere terminus, involving single-stranded DNA-binding
      proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to
      contribute to the recruitment of telomerase and may also regulate the extent or
      frequency of elongation. In addition, proteins that bind along the length of the
      telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are
      part of a negative feedback loop that regulates telomere length. Here we discuss
      the details of telomerase and its regulation by the telomere.

PMID- 15189141
TI  - Crawling toward a unified model of cell mobility: spatial and temporal regulation
      of actin dynamics.
AB  - Crawling cells of various morphologies displace themselves in their biological
      environments by a similar overall mechanism of protrusion through actin assembly
      at the front coordinated with retraction at the rear. Different cell types
      organize very distinct protruding structures, yet they do so through conserved
      biochemical mechanisms to regulate actin polymerization dynamics and vary the
      mechanical properties of these structures. The moving cell must spatially and
      temporally regulate the biochemical interactions of its protein components to
      exert control over higher-order dynamic structures created by these proteins and
      global cellular responses four or more orders of magnitude larger in scale and
      longer in time than the individual protein-protein interactions that comprise
      them. To fulfill its biological role, a cell globally responds with high
      sensitivity to a local perturbation or signal and coordinates its many
      intracellular actin-based functional structures with the physical environment it
      experiences to produce directed movement. This review attempts to codify some
      unifying principles for cell motility that span organizational scales from single
      protein polymer filaments to whole crawling cells.

PMID- 15189142
TI  - ATP-binding cassette transporters in bacteria.
AB  - ATP-binding cassette (ABC) transporters couple ATP hydrolysis to the uptake and
      efflux of solutes across the cell membrane in bacteria and eukaryotic cells. In
      bacteria, these transporters are important virulence factors because they play
      roles in nutrient uptake and in secretion of toxins and antimicrobial agents. In
      humans, many diseases, such as cystic fibrosis, hyperinsulinemia, and macular
      dystrophy, are traced to defects in ABC transporters. Recent advances in
      structural determination and functional analysis of bacterial ABC transporters,
      reviewed herein, have greatly increased our understanding of the molecular
      mechanism of transport in this transport superfamily.

PMID- 15189143
TI  - Structural basis of ion pumping by Ca2+-ATPase of the sarcoplasmic reticulum.
AB  - The structures of the Ca2+-ATPase (SERCA1a) have been determined for five
      different states by X-ray crystallography. Detailed comparison of the structures
      in the Ca2+ bound form and unbound (but thapsigargin bound) form reveals that
      very large rearrangements of the transmembrane helices take place accompanying
      Ca2+ dissociation and binding and that they are mechanically linked with equally
      large movements of the cytoplasmic domains. The meanings of the rearrangements of
      the transmembrane helices and those of the cytoplasmic domains as well as the
      mechanistic roles of phosphorylation are now becoming clear. Furthermore, the
      roles of critical amino acid residues identified by extensive mutagenesis studies
      are becoming evident in terms of atomic structure.

PMID- 15189144
TI  - DNA polymerase gamma, the mitochondrial replicase.
AB  - DNA polymerase (pol) gamma is the sole DNA polymerase in animal mitochondria.
      Biochemical and genetic evidence document a key role for pol gamma in
      mitochondrial DNA replication, and whereas DNA repair and recombination were
      thought to be limited or absent in animal mitochondria, both have been
      demonstrated in recent years. Thus, the mitochondrial replicase is also
      apparently responsible for the relevant DNA synthetic reactions in these
      processes. Pol gamma comprises a catalytic core in a heterodimeric complex with
      an accessory subunit. The two-subunit holoenzyme is an efficient and processive
      polymerase, which exhibits high fidelity in nucleotide selection and
      incorporation while proofreading errors with its intrinsic 3' 5' exonuclease.
      Incorporation of nucleotide analogs followed by proofreading failure leads to
      mitochondrial toxicity in antiviral therapy, and misincorporation during DNA
      replication leads to mitochondrial mutagenesis and dysfunction. This review
      describes our current understanding of pol gamma biochemistry and biology, and it
      introduces other key proteins that function at the mitochondrial DNA replication
      fork.

PMID- 15189145
TI  - Lysophospholipid receptors: signaling and biology.
AB  - Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1
      phosphate, are membrane-derived bioactive lipid mediators. LPs can affect
      fundamental cellular functions, which include proliferation, differentiation,
      survival, migration, adhesion, invasion, and morphogenesis. These functions
      influence many biological processes that include neurogenesis, angiogenesis,
      wound healing, immunity, and carcinogenesis. In recent years, identification of
      multiple cognate G protein-coupled receptors has provided a mechanistic framework
      for understanding how LPs play such diverse roles. Generation of LP receptor-null
      animals has allowed rigorous examination of receptor-mediated physiological
      functions in vivo and has identified new functions for LP receptor signaling.
      Efforts to develop LP receptor subtype-specific agonists/antagonists are in
      progress and raise expectations for a growing collection of chemical tools and
      potential therapeutic compounds. The rapidly expanding literature on the LP
      receptors is herein reviewed.

PMID- 15189146
TI  - Protein modification by SUMO.
AB  - Small ubiquitin-related modifier (SUMO) family proteins function by becoming
      covalently attached to other proteins as post-translational modifications. SUMO
      modifies many proteins that participate in diverse cellular processes, including
      transcriptional regulation, nuclear transport, maintenance of genome integrity,
      and signal transduction. Reversible attachment of SUMO is controlled by an enzyme
      pathway that is analogous to the ubiquitin pathway. The functional consequences
      of SUMO attachment vary greatly from substrate to substrate, and in many cases
      are not understood at the molecular level. Frequently SUMO alters interactions of
      substrates with other proteins or with DNA, but SUMO can also act by blocking
      ubiquitin attachment sites. An unusual feature of SUMO modification is that, for
      most substrates, only a small fraction of the substrate is sumoylated at any
      given time. This review discusses our current understanding of how SUMO
      conjugation is controlled, as well as the roles of SUMO in a number of biological
      processes.

PMID- 15189147
TI  - Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary
      considerations.
AB  - Pyridoxal phosphate (PLP)-dependent enzymes are unrivaled in the diversity of
      reactions that they catalyze. New structural data have paved the way for targeted
      mutagenesis and mechanistic studies and have provided a framework for
      interpretation of those results. Together, these complementary approaches yield
      new insight into function, particularly in understanding the origins of substrate
      and reaction type specificity. The combination of new sequences and structures
      enables better reconstruction of their evolutionary heritage and illuminates
      unrecognized similarities within this diverse group of enzymes. The important
      metabolic roles of many PLP-dependent enzymes drive efforts to design specific
      inhibitors, which are now guided by the availability of comprehensive structural
      and functional databases. Better understanding of the function of this important
      group of enzymes is crucial not only for inhibitor design, but also for the
      design of improved protein-based catalysts.

PMID- 15189148
TI  - The Sir2 family of protein deacetylases.
AB  - The yeast SIR protein complex has been implicated in transcription silencing and
      suppression of recombination. The Sir complex represses transcription at
      telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2
      gene is highly conserved in organisms ranging from archaea to humans.
      Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly
      conserved from bacteria to higher eukaryotes. In this review, we discuss the role
      of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure,
      and the Sir2 chemical inhibitors and activators that were recently identified. We
      summarize the current knowledge of the Sir2 homologs from different organisms,
      and finally we discuss the role of Sir2 in caloric restriction and aging.

PMID- 15189149
TI  - Inositol 1,4,5-trisphosphate receptors as signal integrators.
AB  - The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel
      that responds to the second messenger IP3. Exquisite modulation of intracellular
      Ca2+ release via IP3Rs is achieved by the ability of IP3R to integrate signals
      from numerous small molecules and proteins including nucleotides, kinases, and
      phosphatases, as well as nonenzyme proteins. Because the ion conduction pore
      composes only approximately 5% of the IP3R, the great bulk of this large protein
      contains recognition sites for these substances. Through these regulatory
      mechanisms, IP3R modulates diverse cellular functions, which include, but are not
      limited to, contraction/excitation, secretion, gene expression, and cellular
      growth. We review the unique properties of the IP3R that facilitate cell-type and
      stimulus-dependent control of function, with special emphasis on protein-binding
      partners.

PMID- 15189150
TI  - Structure and function of TolC: the bacterial exit duct for proteins and drugs.
AB  - The bacterial TolC protein plays a common role in the expulsion of diverse
      molecules, which include protein toxins and antibacterial drugs, from the cell.
      TolC is a trimeric 12-stranded alpha/beta barrel, comprising an alpha-helical
      trans-periplasmic tunnel embedded in the outer membrane by a contiguous beta
      barrel channel. This structure establishes a 140 A long single pore fundamentally
      different to other membrane proteins and presents an exit duct to substrates,
      large and small, engaged at specific inner membrane translocases. TolC is open to
      the outside medium but is closed at its periplasmic entrance. When TolC is
      recruited by a substrate-laden translocase, the entrance is opened to allow
      substrate passage through a contiguous machinery spanning the entire cell
      envelope, from the cytosol to the external environment. Transition to the
      transient open state is achieved by an iris-like mechanism in which entrance
      alpha-helices undergo an untwisting realignment, thought to be stabilized by
      interaction with periplasmic helices of the translocase. TolC family proteins are
      ubiquitous among gram-negative bacteria, and the conserved entrance aperture
      presents a possible cheomotherapeutic target in multidrug-resistant pathogens.

PMID- 15189151
TI  - Role of glycosylation in development.
AB  - Researchers have long predicted that complex carbohydrates on cell surfaces would
      play important roles in developmental processes because of the observation that
      specific carbohydrate structures appear in specific spatial and temporal patterns
      throughout development. The astounding number and complexity of carbohydrate
      structures on cell surfaces added support to the concept that glycoconjugates
      would function in cellular communication during development. Although the
      structural complexity inherent in glycoconjugates has slowed advances in our
      understanding of their functions, the complete sequencing of the genomes of
      organisms classically used in developmental studies (e.g., mice, Drosophila
      melanogaster, and Caenorhabditis elegans) has led to demonstration of essential
      functions for a number of glycoconjugates in developmental processes. Here we
      present a review of recent studies analyzing function of a variety of
      glycoconjugates (O-fucose, O-mannose, N-glycans, mucin-type O-glycans,
      proteoglycans, glycosphingolipids), focusing on lessons learned from human
      disease and genetic studies in mice, D. melanogaster, and C. elegans.

PMID- 15189152
TI  - Structural insights into the signal recognition particle.
AB  - The signal recognition particle (SRP) directs integral membrane and secretory
      proteins to the cellular protein translocation machinery during translation. The
      SRP is an evolutionarily conserved RNA-protein complex whose activities are
      regulated by GTP hydrolysis. Recent structural investigations of SRP functional
      domains and interactions provide new insights into the mechanisms of SRP activity
      in all cells, leading toward a comprehensive understanding of protein trafficking
      by this elegant pathway.

PMID- 15189153
TI  - Palmitoylation of intracellular signaling proteins: regulation and function.
AB  - Protein S-palmitoylation is the thioester linkage of long-chain fatty acids to
      cysteine residues in proteins. Addition of palmitate to proteins facilitates
      their membrane interactions and trafficking, and it modulates protein-protein
      interactions and enzyme activity. The reversibility of palmitoylation makes it an
      attractive mechanism for regulating protein activity, and this feature has
      generated intensive investigation of this modification. The regulation of
      palmitoylation occurs through the actions of protein acyltransferases and protein
      acylthioesterases. Identification of the protein acyltransferases Erf2/Erf4 and
      Akr1 in yeast has provided new insight into the palmitoylation reaction. These
      molecules work in concert with thioesterases, such as acyl-protein thioesterase
      1, to regulate the palmitoylation status of numerous signaling molecules,
      ultimately influencing their function. This review discusses the function and
      regulation of protein palmitoylation, focusing on intracellular proteins that
      participate in cell signaling or protein trafficking.

PMID- 15189154
TI  - Flap endonuclease 1: a central component of DNA metabolism.
AB  - One strand of cellular DNA is generated as RNA-initiated discontinuous segments
      called Okazaki fragments that later are joined. The RNA terminated region is
      displaced into a 5' single-stranded flap, which is removed by the structure
      specific flap endonuclease 1 (FEN1), leaving a nick for ligation. Similarly, in
      long-patch base excision repair, a damaged nucleotide is displaced into a flap
      and removed by FEN1. FEN1 is a genome stabilization factor that prevents flaps
      from equilibrating into structures that lead to duplications and deletions. As an
      endonuclease, FEN1 enters the flap from the 5' end and then tracks to cleave the
      flap base. Cleavage is oriented by the formation of a double flap. Analyses of
      FEN1 crystal structures suggest mechanisms for tracking and cleavage. Some flaps
      can form self-annealed and template bubble structures that interfere with FEN1.
      FEN1 interacts with other nucleases and helicases that allow it to act
      efficiently on structured flaps. Genetic and biochemical analyses continue to
      reveal many roles of FEN1.

PMID- 15189155
TI  - Emerging principles of conformation-based prion inheritance.
AB  - The prion hypothesis proposes that proteins can act as infectious agents.
      Originally formulated to explain transmissible spongiform encephalopathies
      (TSEs), the prion hypothesis has been extended with the finding that several non
      Mendelian traits in fungi are due to heritable changes in protein conformation,
      which may in some cases be beneficial. Although much remains to be learned about
      the specific role of cellular cofactors, mechanistic parallels between the
      mammalian and yeast prion phenomena point to universal features of conformation
      based infection and inheritance involving propagation of ordered beta-sheet-rich
      protein aggregates commonly referred to as amyloid. Here we focus on two such
      features and discuss recent efforts to explain them in terms of the physical
      properties of amyloid-like aggregates. The first is prion strains, wherein
      chemically identical infectious particles cause distinct phenotypes. The second
      is barriers that often prohibit prion transmission between different species.
      There is increasing evidence suggesting that both of these can be manifestations
      of the same phenomenon: the ability of a protein to misfold into multiple self
      propagating conformations. Even single mutations can change the spectrum of
      favored misfolded conformations. In turn, changes in amyloid conformation can
      shift the specificity of propagation and alter strain phenotypes. This model
      helps explain many common and otherwise puzzling features of prion inheritance as
      well as aspects of noninfectious diseases involving toxic misfolded proteins.

PMID- 15189156
TI  - The molecular mechanics of eukaryotic translation.
AB  - Great advances have been made in the past three decades in understanding the
      molecular mechanics underlying protein synthesis in bacteria, but our
      understanding of the corresponding events in eukaryotic organisms is only
      beginning to catch up. In this review we describe the current state of our
      knowledge and ignorance of the molecular mechanics underlying eukaryotic
      translation. We discuss the mechanisms conserved across the three kingdoms of
      life as well as the important divergences that have taken place in the pathway.

PMID- 15189157
TI  - Mechanical processes in biochemistry.
AB  - Mechanical processes are involved in nearly every facet of the cell cycle.
      Mechanical forces are generated in the cell during processes as diverse as
      chromosomal segregation, replication, transcription, translation, translocation
      of proteins across membranes, cell locomotion, and catalyzed protein and nucleic
      acid folding and unfolding, among others. Because force is a product of all these
      reactions, biochemists are beginning to directly apply external forces to these
      processes to alter the extent or even the fate of these reactions hoping to
      reveal their underlying molecular mechanisms. This review provides the conceptual
      framework to understand the role of mechanical force in biochemistry.

PMID- 15189158
TI  - Intermediate filaments: molecular structure, assembly mechanism, and integration
      into functionally distinct intracellular Scaffolds.
AB  - The superfamily of intermediate filament (IF) proteins contains at least 65
      distinct proteins in man, which all assemble into approximately 10 nm wide
      filaments and are principal structural elements both in the nucleus and the
      cytoplasm with essential scaffolding functions in metazoan cells. At present, we
      have only circumstantial evidence of how the highly divergent primary sequences
      of IF proteins lead to the formation of seemingly similar polymers and how this
      correlates with their function in individual cells and tissues. Point mutations
      in IF proteins, particularly in lamins, have been demonstrated to lead to severe,
      inheritable multi-systemic diseases, thus underlining their importance at several
      functional levels. Recent structural work has now begun to shed some light onto
      the complex fine tuning of structure and function in these fibrous, coiled coil
      forming multidomain proteins and their contribution to cellular physiology and
      gene regulation.

PMID- 15189159
TI  - Directed evolution of nucleic acid enzymes.
AB  - Just as Darwinian evolution in nature has led to the development of many
      sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful
      approach for obtaining similar results in the laboratory. This review focuses on
      the development of nucleic acid enzymes starting from a population of random
      sequence RNA or DNA molecules. In order to illustrate the principles and practice
      of in vitro evolution, two especially well-studied categories of catalytic
      nucleic acid are considered: RNA enzymes that catalyze the template-directed
      ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former
      reaction, which involves attack of a 2'- or 3'-hydroxyl on the alpha-phosphate of
      a 5'-triphosphate, is more difficult. It requires a comparatively larger
      catalytic motif, containing more nucleotides than can be sampled exhaustively
      within a starting population of random-sequence RNAs. The latter reaction
      involves deprotonation of the 2'-hydroxyl adjacent to the cleavage site,
      resulting in cleaved products that bear a 2',3'-cyclic phosphate and 5'-hydroxyl.
      The difficulty of this reaction, and therefore the complexity of the
      corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a
      divalent metal cation or small molecule, is present in the reaction mixture.

PMID- 15189160
TI  - Using protein folding rates to test protein folding theories.
AB  - The fastest simple, kinetically two-state protein folds a million times more
      rapidly than the slowest. Here we review many recent theories of protein folding
      kinetics in terms of their ability to qualitatively rationalize, if not
      quantitatively predict, this fundamental experimental observation.

PMID- 15189161
TI  - Eukaryotic mRNA decapping.
AB  - Eukaryotic mRNAs are primarily degraded by removal of the 3' poly(A) tail,
      followed either by cleavage of the 5' cap structure (decapping) and 5'->3'
      exonucleolytic digestion, or by 3' to 5' degradation. mRNA decapping represents a
      critical step in turnover because this permits the degradation of the mRNA and is
      a site of numerous control inputs. Recent analyses suggest decapping of an mRNA
      consists of four central and related events. These include removal, or
      inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active
      translation, assembly of a decapping complex on the mRNA, and sequestration of
      the mRNA into discrete cytoplasmic foci where decapping can occur. Each of these
      steps is a demonstrated, or potential, site for the regulation of mRNA decay. We
      discuss the decapping process in the light of these central properties, which
      also suggest fundamental aspects of cytoplasmic mRNA physiology that connect
      decapping, translation, and storage of mRNA.

PMID- 15189162
TI  - Novel lipid modifications of secreted protein signals.
AB  - Secreted signaling proteins function in a diverse array of essential patterning
      events during metazoan development, ranging from embryonic segmentation in
      insects to neural tube differentiation in vertebrates. These proteins generally
      are expressed in a localized manner, and they may elicit distinct concentration
      dependent responses in the cells of surrounding tissues and structures, thus
      functioning as morphogens that specify the pattern of cellular responses by their
      tissue distribution. Given the importance of signal distribution, it is notable
      that the Hedgehog (Hh) and Wnt proteins, two of the most important families of
      such signals, are known to be covalently modified by lipid moieties, the membrane
      anchoring properties of which are not consistent with passive models of protein
      mobilization within tissues. This review focuses on the mechanisms underlying
      biogenesis of the mature Hh proteins, which are dually modified by cholesteryl
      and palmitoyl adducts, as well as on the relationship between Hh proteins and the
      self-splicing proteins (i.e., proteins containing inteins) and the Hh-like
      proteins of nematodes. We further discuss the cellular mechanisms that have
      evolved to handle lipidated Hh proteins in the spatial deployment of the signal
      in developing tissues and the more recent findings that implicate palmitate
      modification as an important feature of Wnt signaling proteins.

PMID- 15189164
TI  - Opioid receptors.
AB  - Opioid receptors belong to the large superfamily of seven transmembrane-spanning
      (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental
      physiological importance mediating the actions of the majority of known
      neurotransmitters and hormones. Opioid receptors are particularly intriguing
      members of this receptor family. They are activated both by endogenously produced
      opioid peptides and by exogenously administered opiate compounds, some of which
      are not only among the most effective analgesics known but also highly addictive
      drugs of abuse. A fundamental question in addiction biology is why exogenous
      opioid drugs, such as morphine and heroin, have a high liability for inducing
      tolerance, dependence, and addiction. This review focuses on many aspects of
      opioid receptors with the aim of gaining a greater insight into mechanisms of
      opioid tolerance and dependence.

PMID- 15189163
TI  - Return of the GDI: the GoLoco motif in cell division.
AB  - The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation
      inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory
      subclass. The GoLoco motif is present as an independent element within
      multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as
      well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and
      Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical
      mechanisms of GoLoco motif action on G-alpha subunits in light of the recent
      crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there
      is sparse evidence for GoLoco motif regulation of canonical G-protein-coupled
      receptor signaling. Rather, studies of asymmetric cell division in Drosophila and
      Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins,
      such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and
      force generation. We discuss potential mechanisms by which GoLoco/Galpha
      complexes might modulate spindle dynamics.

PMID- 15189165
TI  - Structural aspects of ligand binding to and electron transfer in bacterial and
      fungal P450s.
AB  - Cytochrome P450 enzymes are heme-containing monooxygenases that are named after
      an absorption band at 450 nm when complexed with carbon monoxide. They catalyze a
      wide variety of reactions and are unique in their ability to hydroxylate
      nonactivated hydrocarbons. P450 enzymes are involved in numerous biological
      processes, which include the biosynthesis of lipids, steroids, antibiotics, and
      the degradation of xenobiotics. In line with the variety of reactions catalyzed,
      the size of their substrates varies significantly. Some P450s have open active
      sites (e.g., BM3), and some have shielded active sites that open only transiently
      (e.g., P450cam), whereas others bind the substrate only when attached to carrier
      proteins (e.g., Oxy proteins). Structural aspects of both organic and gaseous
      ligand binding and electron transfer are described.

PMID- 15189166
TI  - Roles of N-linked glycans in the endoplasmic reticulum.
AB  - From a process involved in cell wall synthesis in archaea and some bacteria, N
      linked glycosylation has evolved into the most common covalent protein
      modification in eukaryotic cells. The sugars are added to nascent proteins as a
      core oligosaccharide unit, which is then extensively modified by removal and
      addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi
      complex. It has become evident that the modifications that take place in the ER
      reflect a spectrum of functions related to glycoprotein folding, quality control,
      sorting, degradation, and secretion. The glycans not only promote folding
      directly by stabilizing polypeptide structures but also indirectly by serving as
      recognition "tags" that allow glycoproteins to interact with a variety of
      lectins, glycosidases, and glycosyltranferases. Some of these (such as
      glucosidases I and II, calnexin, and calreticulin) have a central role in folding
      and retention, while others (such as alpha-mannosidases and EDEM) target
      unsalvageable glycoproteins for ER-associated degradation. Each residue in the
      core oligosaccharide and each step in the modification program have significance
      for the fate of newly synthesized glycoproteins.

PMID- 15189168
TI  - Aristolochic acid nephropathy: what we know and what we have to do.

PMID- 15189167
TI  - Analyzing cellular biochemistry in terms of molecular networks.
AB  - One way to understand cells and circumscribe the function of proteins is through
      molecular networks. These networks take a variety of forms including webs of
      protein-protein interactions, regulatory circuits linking transcription factors
      and targets, and complex pathways of metabolic reactions. We first survey
      experimental techniques for mapping networks (e.g., the yeast two-hybrid
      screens). We then turn our attention to computational approaches for predicting
      networks from individual protein features, such as correlating gene expression
      levels or analyzing sequence coevolution. All the experimental techniques and
      individual predictions suffer from noise and systematic biases. These problems
      can be overcome to some degree through statistical integration of different
      experimental datasets and predictive features (e.g., within a Bayesian
      formalism). Next, we discuss approaches for characterizing the topology of
      networks, such as finding hubs and analyzing subnetworks in terms of common
      motifs. Finally, we close with perspectives on how network analysis represents a
      preliminary step toward a systems approach for modeling cells.

PMID- 15189169
TI  - Atherosclerosis and Folic Acid Supplementation Trial: untangling the web of
      cardiac risk in chronic kidney disease.

PMID- 15189170
TI  - Avoidance of direct injury to the peripheral nerve with maxacalcitol (22oxa
      1,25(OH)2D3) in rats.
AB  - BACKGROUND: Secondary hyperparathyroidism is one of the most common complications
      in patients with long-term end-stage renal disease. A recent report has stated
      that high doses of vitamin D derivatives injected directly into the parathyroid
      glands can reduce serum parathyroid hormone levels and suppress further
      enlargement of the parathyroid glands without side-effects. Maxacalcitol (22oxa
      1,25(OH)(2)D(3); OCT) is a new vitamin D derivative that can be administered
      intravenously, and is available in Japan. Direct injection of OCT into enlarged
      parathyroid glands is a promising new treatment for moderate renal
      hyperparathyroidism. It is considered to be safe for surrounding tissues, such as
      peripheral nerves, but the actual effects of OCT on nerves have not yet been
      documented. METHODS: We measured nerve conduction velocity (NCV) in 24 rat
      femoral nerves soaked in saline, ethanol, or OCT at various concentrations.
      Nerves from each group (saline, ethanol, OCT groups) were also examined by
      microscopy. RESULTS: The mean NCV of rat femoral nerves was 33.67 +/- 1.39 m/s in
      the saline group. In the OCT group, the velocities were not changed at any of the
      concentrations tested, and there were no significant differences in NCVs between
      the saline and OCT groups. In the 50% ethanol group, the velocity decreased
      significantly to 8.98 +/- 4.78 m/s (P < 0.01). A histological study demonstrated
      the nerves soaked in OCT at 10 microg/mL to essentially be intact, while those
      soaked in anhydrous ethanol were damaged. CONCLUSIONS: This study demonstrated
      that OCT administration does not affect peripheral NCV, indicating that OCT could
      possibly be used for the treatment of moderate renal hyperparathyroidism safely
      without nerve damage.

PMID- 15189171
TI  - Apolipoprotein and anticardiolipin antibodies in patients with renal amyloidosis.
AB  - BACKGROUND: Thromboembolic events are seen more frequently in patients with
      chronic renal failure (CRF) and amyloidosis. The anticardiolipin antibody (ACA)
      that is important for thromboembolic events has never been studied. METHODS: This
      study included 43 amyloidosis patients of different aetiologies; 28 with CRF as
      well as 20 patients who had CRF without amyloidosis. Thirty normal subjects were
      included as a control group. We determined the serum levels of ACA,
      apolipoprotein AI (ApoAl), ApoE and lipoprotein (a) (Lp(a)) in these groups.
      RESULTS: Anticardiolipin antibody was found to be positive in 30.2% of patients
      with amyloidosis, this is in contrast to 3.3% in the control group (chi = 8.25, P
      < 0.005). We also showed that there was a statistically significant difference
      (chi = 5.03, P < 0.05) between the CRF patients with amyloidosis (31%) and the
      CRF patients without amyloidosis (5%). The average levels of serum ApoAI were
      shown to be significantly lower (P < 0.05) in CRF patients with amyloidosis in
      comparison with the amyloidosis patients who had normal renal functions (93.60 +/
      27.84 vs 119.8 +/- 36.26 mg/dL, P < 0.05). There was also significant a
      difference in ApoAI levels between CRF patients with and without amyloidosis (P <
      0.001). The serum Lp (a) levels were significantly higher in CRF patients with
      amyloidosis when compared with the controls (41.2 +/- 22.39 vs 19.13 +/- 8.78
      mg/dL, P < 0.001). The serum Lp (a) levels were also positively correlated with
      ACA (r = 0.211; P < 0.05). CONCLUSION: In conclusion, ACA positivity is more
      common in all patients with amyloidosis as compared with CRF patients and normal
      controls. This study is the first to show the presence of high levels of ACA in
      patients with CRF, which is caused by secondary amyloidosis. Further studies are
      recommended to investigate the mechanism of this finding.

PMID- 15189172
TI  - A case of primary immunoglobulin light chain amyloidosis with a delayed
      appearance of Bence Jones protein in urine.
AB  - We report here a case of a 58-year-old man who had nephrotic syndrome and
      immunoglobulin light chain (AL) amyloidosis. This patient underwent a renal
      biopsy to confirm the diagnosis. Treatment with permanganate before Congo red
      staining showed systemic secondary amyloidosis (AA) fibrils, which were sensitive
      to permanganate oxidation. Although this patient was initially diagnosed as
      having AA amyloidosis, he did not have any chronic inflammatory disease and/or
      malignancy. The level of amyloid A protein (7.9 microg/mL) in sera was within the
      normal range (0-8.0 microg/mL). Therefore, we performed an immunostaining of the
      precursor protein (amino terminus of constant region: kappa and lambda light
      chains, and AA protein) using duodenal biopsy specimens for a precise diagnosis.
      Immunostaining was positive for the amino terminus of constant region of the
      lambda light chain, and negative for the amino terminus of constant region of the
      kappa light chain and AA protein. No plasma cell proliferation in the bone marrow
      was observed. We finally diagnosed this patient as having primary AL amyloidosis.
      It appears that a pathological diagnosis must be performed by immunostaining the
      precursor proteins with the permanganate digestion technique in tissue of
      patients with amyloidosis. There were no abnormalities in serum and urine
      immunoelectrophoresis at the time of renal biopsy in this patient. During the
      follow-up period, after discharge, Bence Jones protein appeared in the urine, but
      not in the serum. It is necessary to observe patients with primary AL amyloidosis
      carefully to determine if they their condition will progress to multiple myeloma.

PMID- 15189173
TI  - Fanconi's syndrome and subsequent progressive renal failure caused by a Chinese
      herb containing aristolochic acid.
AB  - Chinese herb nephropathy contains a variety of clinical features of progressive
      renal failure (indicated by studies conducted in Belgium) to the variant type of
      Fanconi's syndrome. Fanconi's syndrome has mostly been reported in Asian
      countries, and is characterized by proximal tubular dysfunction and slower
      progression to end-stage renal disease (ESRD); it also often revealed a
      reversible clinical course. We describe a 43-year-old woman who presented with
      polyuria and polydipsia caused by Fanconi's syndrome. The cause of Fanconi's
      syndrome was not identified because the patient denied the intake of the Chinese
      herbal mixture at first. Fanconi's syndrome seemed to be reversible in its early
      stage, but it rapidly progressed to renal failure after 3 months, despite the
      interruption of Chinese mixture use. A renal biopsy revealed typical findings of
      aristolochic acid-induced nephropathy. Aristolochic acids were also detected in
      the Chinese herbs that were consumed. This case highlights the variety of the
      clinical spectrum of aristolochic acid induced nephropathy (AAN). We emphasize
      that AAN should be suspected in all patients with Fanconi's syndrome, even if
      patients deny the intake of any Chinese herbal preparation.

PMID- 15189175
TI  - Renoprotective effect of Hemidesmus indicus, a herbal drug used in gentamicin
      induced renal toxicity.
AB  - BACKGROUND AND AIMS: Owing to the global trend towards improved 'quality of
      life', there is considerable evidence of an increase in demand for medicinal
      plants. The WHO guidelines define basic criteria for the standardization of
      herbal medicines. The present work is an effort in this direction to prove the
      safety and efficacy of Hemidesmus indicus Linn. in the management of
      nephrotoxicity induced by aminoglycosides such as gentamicin. METHODS AND
      RESULTS: Simple, quality control methods using high performance thin layer
      chromatographic (HPTLC) phytochemical fingerprint, proximate analysis, and the
      stability of the H. indicus root powder were developed. From the toxicity study
      using albino Swiss mice, it was observed that the drug (H. indicus) was
      relatively safe up to 7 g/kg bodyweight dose. Efficacy was evaluated against
      gentamicin-induced nephrotoxicity in albino Wister rats. The study examined
      animals from the following groups: no treatment, gentamicin treated, gentamicin
      treated recovery, and gentamicin and plant treated. Animals from all groups were
      killed on day 13 of the study; those from gentamicin treated group were killed on
      the seventh day. Assessment of the drug efficacy drug was conducted by using
      haematological and histological examination. CONCLUSION: The treatment with H.
      indicus helped in the management of renal impairment, which was induced by
      gentamicin in rats. This is evident from the results obtained for various kidney
      function tests for gentamicin, along with the results from the plant treated
      group, and is in comparison with the results found for the gentamicin recovery
      group. A histological examination of kidneys also supports the findings from
      haematological evaluations. The plant shows promise as an adjunct therapy along
      side aminoglycosides as it reduces nephrotoxicity caused by aminoglycosides.

PMID- 15189174
TI  - Atherosclerosis and folic acid supplementation trial in chronic renal failure:
      baseline results.
AB  - BACKGROUND: Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) is a
      randomized placebo controlled trial assessing whether high-dose folic acid can
      reduce cardiovascular events and atherosclerosis progression in patients with
      chronic renal failure (CRF). Here we report the baseline results and compare
      indices of arterial structure (carotid intima-medial thickness (IMT)) and
      function (systemic arterial compliance (SAC)), pressure augmentation index
      (AI(x)) and pulse wave velocity (PWV a-f and PWV f-d)) to age- and sex-matched
      controls. METHODS: Three hundred and fifteen subjects with CRF (serum creatinine
      > or = 0.40 mmol/L) aged 24-79 years (mean +/- SD: 56.6 +/- 13.6 years) and 213
      healthy controls (58.2 +/- 10.2 years) were studied. Fasting blood samples were
      assayed for lipids (both groups), total homocysteine (tHcy), red cell folate,
      cobalamin and fibrinogen (CRF group). Ultrasound B mode measurements were used to
      determine mean carotid IMT and applanation tonometry techniques to determine SAC,
      AI(x), PWV (a-f), PWV (f-d) and central pressures. RESULTS: Ninety-six per cent
      of the CRF group had at least one of: hypertension, hypercholesterolaemia,
      diabetes or smoking; 35% had established cardiovascular disease. The mean IMT was
      greater in CRF patients than in controls (0.86 +/- 0.19 vs 0.68 +/- 0.11 mm, P <
      0.001). The SAC was significantly lower, and PWV (a-f) and AI(x) significantly
      higher. The tHcy was increased in 97% of the CRF group (27.3 +/- 2.9 micromol/L
      (normal < 13)). Total homocysteine did not correlate with IMT or any other
      measure of arterial function. However, those in the upper quantile of tHcy (> or
      =25 micromol/L) did have higher PWV (a-f) and lower SAC than those in the lower
      quantile. CONCLUSIONS: Compared to normals, patients with CRF exhibited a 10-15
      year shift to the right in age-related increases in carotid IMT and PWV (a-f),
      and significantly increased central pressure augmentation. This 5-year study is
      examining the impact of high-dose folic acid therapy on cardiovascular end
      points, IMT progression and arterial function in CRF.

PMID- 15189176
TI  - Haemoglobin response to subcutaneous versus intravenous epoetin alfa
      administration in iron-replete haemodialysis patients.
AB  - BACKGROUND: Numerous prior studies have reported that a substantially higher dose
      of epoetin is required to maintain haemoglobin (Hb) concentration when patients
      are switched from a subcutaneous (s.c.) to intravenous (i.v.) route of
      administration. Many of the reported trials, however, involved patients who did
      not have adequate serum iron levels. It was hypothesized that patients with
      adequate iron stores who are switched from one route of administration to the
      other without a change in dose will experience substantially less change in their
      Hb concentration. METHODS: Haemodialysis patients who were iron replete (ferritin
      300-800 microg/L, transferrin saturation (TSAT) 25-50%) participated in a
      prospective, randomized cross-over trial receiving epoetin for 3 months either by
      s.c. or i.v. injection followed by a further 3 months of epoetin via the other
      route. The principal aim was to determine changes in Hb concentration without
      altering the weekly epoetin dose. The secondary aim was to assess whether the
      frequency of dosing (once, twice or thrice weekly) influenced the Hb
      concentration response. RESULTS: Eighty-one patients (mean age 62 years, 60%
      male) entered the study and 15 withdrew prior to study completion. Forty-three
      patients began s.c. epoetin alfa administration (group A) and 38 on i.v. (group
      B). Median ferritin and TSAT at entry for groups A and B were 409 and 394
      microg/L (NS) and 31 and 32% (NS), respectively, which remained within the target
      range during the study. Median epoetin doses for groups A and B were similar (90
      vs 93 IU/kg per week, NS). After 3 months, the mean Hb concentration rose for
      group A (SC; 118.7-121.9 g/L (P = 0.03)) but it fell for group B (i.v.; 119.1
      116.0 g/L (P = 0.019)). Following the change in route of administration, the Hb
      concentration for group A (i.v.) fell by 5.1% over 3 months (121.9-115.4, P <
      0.001) and rose by 2.8% for group B (s.c.) over 3 months (116.0-119.7, P =
      0.001). Similar significant changes in the Hb concentration were seen at
      different dosing frequencies. CONCLUSION: Subcutaneous administration of epoetin
      produces a significant, although slight clinical change in Hb concentration
      compared with i.v. administration in stable, iron replete, haemodialysis
      patients. A similar effect appears to prevail regardless of the frequency of
      injections given.

PMID- 15189177
TI  - Relationship of predialytic intact parathyroid hormone on secondary
      hyperparathyroidism in chronic maintenance haemodialysis patients.
AB  - METHODS AND RESULTS: In order to clarify the predialytic factors influencing the
      onset of secondary hyperparathyroidism (SHPT) in patients on chronic maintenance
      haemodialysis, the time-course changes of serum levels of intact-PTH (i-PTH)
      during haemodialysis for 5 years were investigated. The subjects were 69 non
      diabetic patients who had a serum aluminium level of less than 1.85 nmol/L at the
      end of observation. Patients were divided into two groups based on i-PTH levels
      obtained at the start of dialysis; the high group (H group) consisted of patients
      whose i-PTH levels were more than 22.00 pmol/L, the low group (L group) had
      levels less than 22.00 pmol/L. In the H group, i-PTH was 41.46 +/- 2.87 pmol/L at
      the start of dialysis (vs L group, P < 0.0001) and 15.82 +/- 2.85 pmol/L after
      haemodialysis initiation. In the L group, i-PTH levels did not significantly
      change and was 11.69 +/- 2.50 pmol/L 12 months after the start of dialysis (at
      the 12th month). However, at the 60th month, the i-PTH level was 33.24 +/- 5.30
      pmol/L in the H group, and 9.85 +/- 2.13 pmol/L in the L group (P < 0.005).
      CONCLUSION: It is suggested that control of i-PTH levels in the predialytic
      period may be important to suppress SHPT throughout haemodialysis.

PMID- 15189178
TI  - Antibiotic prophylaxis in dialysis patients undergoing invasive dental treatment.
AB  - BACKGROUND AND AIMS: The role of antibiotic prophylaxis for invasive dental
      procedures in patients on dialysis therapy is unclear. We examined current
      clinical practice in Australia and New Zealand and compared our findings to a
      systematic review of the current literature. METHODS: Australian and New Zealand
      nephrology units were surveyed with regard to their use of antibiotic prophylaxis
      for dental procedures. A systematic review of the literature was performed by
      using an online web-based search engine (PubMed) using the key words: renal
      patients, dental and antibiotic prophylaxis. RESULTS: Forty-one per cent of
      respondents do not routinely give antibiotic prophylaxis to haemodialysis
      patients prior to dental surgery, but a majority (53%) would consider antibiotic
      prophylaxis if the patient had a synthetic arteriovenous fistula. CONCLUSIONS:
      The majority of clinicians follow the American Heart Association (AHA) guidelines
      with a single oral preoperative dose of 2 g amoxycillin or 600 mg clindamycin if
      patients are allergic to penicillin. From the literature and the data obtained by
      questionnaire, it would appear that renal patients receiving haemodialysis in
      Australia and New Zealand receive antibiotic prophylaxis prior to invasive dental
      procedures. The standard single dose of 2 g amoxycillin orally or 600 mg
      clindamycin orally 1 h preoperatively, as recommended by the AHA, is most
      frequently used. Peritoneal dialysis patients generally do not receive a
      prophylactic dose of antibiotics.

PMID- 15189179
TI  - Relationship of plasma Dendroaspis natriuretic peptide-like immunoreactivity and
      echocardiographic parameters in chronic haemodialysis patients.
AB  - BACKGROUND AND AIMS: The Dendroaspis natriuretic peptide (DNP), which was
      recently isolated from the venom of the green Mamba snake, Dendroaspis
      angusticeps, is a 38 amino acid peptide containing a 17 amino acid disulfide ring
      structure. The purpose of this study was to evaluate the effect of haemodialysis
      (HD) on the plasma concentration of DNP, and to investigate the relationship
      between the 2-D echocardiographic parameters and the changes in the plasma DNP
      levels during HD. METHODS: Forty-five haemodialysis patients and 22 healthy
      individuals underwent a measurement of plasma DNP-like immunoreactivity, serum
      creatinine, haematocrit, blood pressure and bodyweight before and after each HD
      session. Echocardiography was performed before and after HD. The peak early
      diastolic transmitral flow velocity (E), peak late diastolic transmitral flow
      velocity (A), and E/A ratio were measured by using a pulsed Doppler
      echocardiogram. RESULTS: The plasma DNP-like immunoreactivity of those in the pre
      HD state was significantly higher (235.6 +/- 45.8 pg/mL) than those of the
      healthy subjects (105.3 +/- 31.1 pg/mL). In addition, the plasma DNP-like
      immunoreactivity was significantly decreased after HD (204.4 +/- 55.4 pg/mL). The
      left atrial diameter, left ventricular diameter at end diastole and end systol, E
      velocity, A velocity, E/A ratio and inferior vena cava diameter were
      significantly decreased after HD. There were significant correlations between the
      changes of plasma DNP-like immunoreactivity and the changes in the bodyweight and
      inferior vena cava diameter, respectively. CONCLUSION: These results suggest that
      the plasma DNP-like immunoreactivity might be involved in the regulation of the
      blood volume in patients undergoing HD.

PMID- 15189180
TI  - In vitro activities of voriconazole (UK-109, 496), fluconazole, itraconazole and
      amphotericin B against 132 non-albicans bloodstream yeast isolates (CANARI
      study).
AB  - The aim was to evaluate the in vitro activity of voriconazole compared with those
      of amphotericin B, itraconazole and fluconazole against 132 bloodstream isolates
      of Candida non-albicans and Saccharomyces cerevisiae species. The minimal
      inhibitory concentrations (MICs) were determined by an adapted National Committee
      for Clinical Laboratory Standards (NCCLS) M27-A method using RPMI 1640 as test
      medium supplemented with 2% glucose. MIC end-points were determined with a
      spectrophotometer after incubation for 48 h at 35 degrees C. Optical density data
      were used for the calculation of the MIC end-points. For amphotericin B, the end
      point was defined as the minimal antifungal concentration that exerts 90%
      inhibition compared with the control well growth. For the azoles, the end-points
      were determined at 50% inhibition of growth. Amphotericin B is highly active with
      97% of isolates inhibited by < or =1 microg ml(-1). Decreased susceptibility or
      resistance to fluconazole was the rule among C. krusei, which is intrinsically
      resistant to fluconazole. For C. glabrata isolates, resistance to fluconazole and
      itraconazole was measured in 13% and 17% of the isolates respectively.
      Voriconazole was quite active in vitro against all the isolates with a MIC90% of
      < or =1 microg ml(-1) and we conclude that it may be useful in the treatment of
      non-albicans bloodstream infections.

PMID- 15189181
TI  - Agar sublimation test for the in vitro determination of the antifungal activity
      of morpholine derivatives.
AB  - We studied the in vitro antifungal activities of a wide range of antimycotic
      agents, including amorolfine, terbinafine, naftifine, five morpholine
      derivatives, ciclopiroxolamine, bifonazole, clotrimazole, ketoconazole,
      itraconazole, fluconazole, voriconazole, flucytosine, amphotericin B, nystatin,
      and caspofungin, against Candida albicans and Trichophyton rubrum by conventional
      agar diffusion tests and by a novel sublimation method. For the sublimation
      method, 6 mm filter paper disks were soaked with defined amounts of antimycotic
      drugs, air dried, placed in the center of the lids of 9 cm Petri dishes, and
      incubated upside down with inoculated agar plates 10 mm above the disks. The
      conventional disk diffusion tests produced inhibition zones as previously
      described. The disk sublimation tests produced large inhibition zones with
      amorolfine, five amorolfine derivatives, and terbinafine, but with none of the
      other antifungal agents. Possible therapeutic advantages of agents, which are
      able to overcome air cavities in mycotic lesions, e.g. in onychomycosis, are
      discussed.

PMID- 15189182
TI  - Candida albicans-induced inflammatory response in human keratinocytes.
AB  - Candida albicans strains 3153a, ATCC 48867, CBS 2730, DSM 70014, and Vir 13 were
      cultivated and sterile C. albicans filtrates were produced. The interaction of
      soluble Candida factors of these infiltrates with human HaCaT keratinocytes was
      assayed in vitro. The following parameters were analyzed: cell proliferation,
      protein synthesis, nuclear matrix protein (NMP) 41 release, cytokine release (IL
      1beta, soluble IL-2 receptor, IL-6, and IL-8), and reactive oxygen species (ROS).
      Cell counts at 1, 12, and 24 h were significantly lower for C. albicans strains
      CBS 2730 and VIR 13 (P < 0.05). There was no significant change for the remaining
      strains. Neither the protein synthesis nor the NMP-41 release was significantly
      affected. IL-6 and IL-8 were stimulated by C. albicans filtrates to different
      amounts with higher levels in strains of low virulence. There was no effect on
      the other cytokines. The production of ROS by HaCaT keratinocytes was suppressed.
      The induction of an inflammatory keratinocyte response by soluble C. albicans
      factors may play a role among the host-yeast interactions.

PMID- 15189183
TI  - Fungal peritonitis at a tertiary care community teaching hospital: epidemiology,
      treatments, and outcome over a 3 year timespan.
AB  - Fungal species isolated from the peritoneal cavity over a 3-year period were
      equally divided among dialysis and intra-abdominal sources and demonstrated that
      triazole antifungal susceptible species predominated. The evolution toward
      triazole-resistant species/strains noted in bloodstream infections has not yet
      developed in fungal peritonitis. A trend toward non-albicans species in
      continuous ambulatory peritoneal dialysis (CAPD) cases, however, requires careful
      monitoring. .

PMID- 15189184
TI  - A probable cause of paradoxical thrombosis in zygomycosis.
AB  - Invasive zygomycoses (syn. mucormycoses) are rather rare but life-threatening
      diseases which often take a peracute course. Particularly endangered are
      diabetics and patients suffering from siderophilia. Zygomycosis is regularly
      complicated by thrombosis and subsequent necrosis. Usually it evolves from
      sinusitis in a rhinocerebral form. With the use of a clinical isolate (Rhizopus
      microsporus) and sera of the same female survivor, we investigated possible
      sources of the typical blood clotting. The results suggest that coagulation is
      probably initiated in a bimodal manner by an extracellular serine proteinase of
      the fungus and by elastase from the patients' leukocytes. The former causes a
      partial hydrolysis of fibrinogen, while the latter activates coagulation factor
      XIII (fibrin stabilizing factor). Both proteinases were present in the patient at
      the site of infection, and in vitro they jointly bring about regular clotting of
      fibrinogen.

PMID- 15189185
TI  - Etiology of tinea capitis in Athens, Greece -- a 6-year (1996-2001) retrospective
      study.
AB  - A total of 577 patients with tinea capitis have been diagnosed at the Mycology
      laboratory of 'A. Sygros' Hospital of Skin and Venereal Diseases, Athens, Greece
      between 1996 and 2001. From these patients, 100 were immigrants from Balkan, Near
      East and African countries. The vast majority of the patients (95%) were
      children, mainly at preschool and school age and only 5% were adults. Zoophilic
      dermatophytes accounted for 86.5% followed by anthropophilic (12.4%) and
      geophilic (1.2%) dermatophytes. The majority of anthropophilic infections (59.5%)
      were recorded in the sub-population of immigrants. Microsporum canis (84.5%) was
      the main etiologic agent.

PMID- 15189186
TI  - Keratinophilic fungi on feathers of pigeon in Maharashtra, India.
AB  - Results of a preliminary survey of keratinophilic fungi associated with feathers
      of pigeon on high rise buildings in Thane district of Maharashtra (India) are
      reported. A total of 100 samples were examined, of which 67 samples were positive
      for keratinophilic fungi. Altogether 67 fungal strains belonging to 10 species of
      seven genera were isolated viz. Chrysosporium indicum (24%), Chrysosporium sp.
      (2%), Chr. tropicum (8%), Chrysosporium state of Arthroderma tuberculatum (3%),
      Chrysosporium state of Ctenomyces serratus (15%), Malbranchea pulchella (3%),
      Malbranchea sp. (1%), Microsporum gypseum (5%), Myriodontium keratinophilum (2%)
      and Trichophyton terrestre (4%).

PMID- 15189187
TI  - Susceptibility of sequential Fonsecaea pedrosoi isolates from chromoblastomycosis
      patients to antifungal agents.
AB  - Fourteen Fonsecaea pedrosoi isolates from six chromoblastomycosis patients were
      submitted to susceptibility testing. Some patients were undergoing treatment with
      itraconazole (ITZ) and/or cryosurgery with liquid nitrogen. The antifungal agents
      amphotericin B (AMB), ITZ, fluconazole (FCZ), ketoconazole (KCZ), 5
      fluorocytosine (5-FC), and terbinafine (TBF) were tested. AMB and FCZ showed less
      activity for all isolates. The most active agents were KCZ and TBF. Sequentially
      isolates from four patients presented ITZ minimal inhibitory concentration (MIC)
      higher than the previous ones; for two of these patients, response to therapy
      with this agent was not observed. These results suggest development of
      microbiologic resistance to ITZ in four instances, two of them coinciding with
      lack of clinical response to this drug.

PMID- 15189188
TI  - The epidemiology of Microsporum canis infections in Rijeka area, Croatia.
AB  - The aim of the study was to analyze the Microsporum canis infections in the
      Rijeka area, Croatia, observed between 1990 and 2001. A total of 724 cases of
      dermatophytosis caused by M. canis were diagnosed in 320 individuals with the
      tinea capitis and 404 with tinea corporis. The M. canis infections constituted
      32.8% of all dermatophytes isolated during the study period.

PMID- 15189189
TI  - Cutaneous alternariosis revealing acute myeloid leukaemia in an adult patient.
AB  - We report a case of cutaneous alternariosis in a 69-year-old male patient. During
      hospitalization for treatment of the skin disorder, acute myeloid leukaemia was
      diagnosed. He received multiple chemotherapeutic agents but the leukaemia
      remained refractory to therapy and the patient died. The clinical picture,
      diagnosis and treatment of cutaneous alternariosis will be discussed and a review
      of the literature regarding patients with haematological diseases will be given.

PMID- 15189190
TI  - Pichia anomala fungaemia in immunocompromised children.
AB  - Pichia anomala is an emerging yeast causing serious nosocomial infections in
      newborn and immunocompromised children. We describe nosocomial port catheter
      infection due to P. anomala in three children who were receiving cancer
      chemotherapy, bloodstream infection in a preterm infant and in an infant with
      severe combined immunodeficiency. All patients were treated with amphotericin B.
      All isolates were susceptible to amphotericin B and fluconazole. No recurrence
      was observed during follow-up in four of five patients. The common clinical
      feature in all of our patients was the presence of prior antimicrobial therapy.

PMID- 15189191
TI  - Kerion Celsi in a newborn due to Microsporum canis.
AB  - The present study deals with a case of a 40-day-old girl with kerion Celsi caused
      by Microsporum canis. The source of the infection were the parents who presented
      tinea corporis caused by M. canis. Systemic treatment was carried out with
      terbinafine and complete recovery was achieved. Tinea capitis is unusual in
      children during their first year of life and its evolution towards kerion is very
      rare in newborns.

PMID- 15189192
TI  - Disseminated dermatophytosis caused by Microsporum gypseum in an AIDS patient:
      response to terbinafine and amorolfine.
AB  - A 51-year-old white male, native of Rio de Janeiro, Brazil, with advanced AIDS
      and in chronic use of imidazoles for oral candidosis, presented erythematous,
      desquamative, pruriginous plaques of 1 month evolution on the trunk,
      inguinal/crural region, and lower limbs. The diagnosis of dermatophytosis was
      based on the isolation of Microsporum gypseum from scales scraped from the skin
      lesions. The lesions regressed after 30 days treatment with itraconazole, 100 mg
      day(-1). After interruption of this antifungal, the mycosis recurred 2 months
      later, along with a toe onychomycosis also caused by M. gypseum. Attempted
      reintroduction of itraconazole at higher dose was unsuccessful. Patient responded
      well to treatment with terbinafine 250 mg day(-1) for 45 days. However, the
      medication had to be interrupted as a result of the emergence of a disseminated
      erythematous/papulous rash. Topical treatment with amorolfine cream was then
      performed, with a good clinical and mycological response.

PMID- 15189193
TI  - Central nervous system infection due to Penicillium chrysogenum.
AB  - Penicillium chrysogenum was isolated from three subsequent cerebrospinal fluid
      (CSF) specimens of a 73-year-old male patient without immunological compromise.
      The isolated was tested against five antifungal agents according to the NCCLS M38
      P macrodilution method. MICs were determined as follows: amphotericin B (AMB), 2
      microg ml(-1); fluconazole (FLZ), 8 microg ml(-1); itraconazole (ITZ), 1 microg
      ml(-1); flucytosine (5FC), 0.125 microg ml(-1); and terbinafine (TRB), 0.06
      microg ml(-1). The patient has been cured with FLZ.

PMID- 15189194
TI  - Pityriasis versicolor on the groin mimicking erythrasma.
AB  - Pityriasis versicolor (PV) is a widespread dermatomycosis caused by yeasts.
      Erythrasma is a superficial bacterial skin disease affecting the major folds of
      the body, particularly the groin. We report the case of a 45-year-old man,
      affected by PV, exclusively localized in the inguinal folds and in the inner
      surface of the thighs, characterized by lesions clinically reproducing
      erythrasma. The authors underline the possibility that PV mimics erythrasma and
      vice versa, especially in those countries in which both diseases are quite
      common, and stress the importance of performing a simple mycological examination
      to avoid gross diagnostic and therapeutic errors.

PMID- 15189195
TI  - Aspergillus endocarditis presenting as femoral artery embolism.
AB  - Fungal valvular endocarditis is an unusual cause of endocarditis, yet very
      important because of its historically poor prognosis. We report two fatal cases
      of fungal valvular endocarditis following cardiovascular surgery, presenting as
      femoral artery embolism. Aspergillus terreus and A. flavus were the causative
      agents of endocarditis in the two patients. Diagnosis was established very early
      by culture of the emboli and was confirmed later by isolation of the same
      Aspergillus species from the resected valve tissue.

PMID- 15189196
TI  - Tinea capitis favosa in Poland.
AB  - Tinea capitis favosa is uncommon in Europe. We describe two patients who had
      local alopecia caused by Trichophyton schoenleinii. In the first case, we
      observed good clinical response after griseofulvin treatment and in the second
      case after topical application of ciclopirox cream.

PMID- 15189198
TI  - Population Graphs: the graph theoretic shape of genetic structure.
AB  - Patterns of intraspecific genetic variation result from interactions among both
      historical and contemporary evolutionary processes. Traditionally, population
      geneticists have used methods such as F-statistics, pairwise isolation by
      distance models, spatial autocorrelation and coalescent models to analyse this
      variation and to gain insight about causal evolutionary processes. Here we
      introduce a novel approach (Population Graphs) that focuses on the analysis of
      marker-based population genetic data within a graph theoretic framework. This
      method can be used to estimate traditional population genetic summary statistics,
      but its primary focus is on characterizing the complex topology resulting from
      historical and contemporary genetic interactions among populations. We introduce
      the application of Population Graphs by examining the range-wide population
      genetic structure of a Sonoran Desert cactus (Lophocereus schottii). With this
      data set, we evaluate hypotheses regarding historical vicariance, isolation by
      distance, population-level assignment and the importance of specific populations
      to species-wide genetic connectivity. We close by discussing the applicability of
      Population Graphs for addressing a wide range of population genetic and
      phylogeographical problems.

PMID- 15189199
TI  - Influence of volcanic activity on the population genetic structure of Hawaiian
      Tetragnatha spiders: fragmentation, rapid population growth and the potential for
      accelerated evolution.
AB  - Volcanic activity on the island of Hawaii results in a cyclical pattern of
      habitat destruction and fragmentation by lava, followed by habitat regeneration
      on newly formed substrates. While this pattern has been hypothesized to promote
      the diversification of Hawaiian lineages, there have been few attempts to link
      geological processes to measurable changes in population structure. We
      investigated the genetic structure of three species of Hawaiian spiders in
      forests fragmented by a 150-year-old lava flow on Mauna Loa Volcano, island of
      Hawaii: Tetragnatha quasimodo (forest and lava flow generalist), T. anuenue and
      T. brevignatha (forest specialists). To estimate fragmentation effects on
      population subdivision in each species, we examined variation in mitochondrial
      and nuclear genomes (DNA sequences and allozymes, respectively). Population
      subdivision was higher for forest specialists than for the generalist in
      fragments separated by lava. Patterns of mtDNA sequence evolution also revealed
      that forest specialists have undergone rapid expansion, while the generalist has
      experienced more gradual population growth. Results confirm that patterns of
      neutral genetic variation reflect patterns of volcanic activity in some
      Tetragnatha species. Our study further suggests that population subdivision and
      expansion can occur across small spatial and temporal scales, which may
      facilitate the rapid spread of new character states, leading to speciation as
      hypothesized by H. L. Carson 30 years ago.

PMID- 15189200
TI  - Microsatellite variation and population structure in a declining Australian Hylid
      Litoria aurea.
AB  - The green and golden bell frog (Litoria aurea) was once a common Australian
      Hylid. Today, many populations are small and fragmented as a result of dramatic
      declines in distribution and abundance. We undertook a large-scale assessment of
      genetic structure and diversity in L. aurea using four species-specific
      microsatellite markers. Twenty-one locations were sampled from throughout the
      species range covering 1000 km of the east coast of Australia. Levels of allelic
      diversity and heterozygosity were high (uncorrected mean alleles/locus and H(E)
      were 4.8-8.8 and 0.43-0.8, respectively) compared to other amphibian species and
      significant differences among sampled sites were recorded. Despite recent
      population declines, no sites displayed a genetic signature indicative of a
      population bottleneck. Significant genetic structuring (overall F(ST) 0.172) was
      detected throughout the species range, but was relatively low compared to
      previous amphibian studies employing microsatellites. In addition we found that
      some areas sampled within continuous habitat showed evidence of weak genetic
      structuring (data subset F(ST) 0.034). We conclude that maintaining areas of
      continuous habitat is critical to the conservation of the species and argue that
      population recovery and/or persistence in all areas sampled is possible if
      appropriate protection and management are afforded.

PMID- 15189201
TI  - Genetic evaluation of a proposed introduction: the case of the greater prairie
      chicken and the extinct heath hen.
AB  - Population introduction is an important tool for ecosystem restoration. However,
      before introductions should be conducted, it is important to evaluate the
      genetic, phenotypic and ecological suitability of possible replacement
      populations. Careful genetic analysis is particularly important if it is
      suspected that the extirpated population was unique or genetically divergent. On
      the island of Martha's Vineyard, Massachusetts, the introduction of greater
      prairie chickens (Tympanuchus cupido pinnatus) to replace the extinct heath hen
      (T. cupido cupido) is being considered as part of an ecosystem restoration
      project. Martha's Vineyard was home to the last remaining heath hen population
      until its extinction in 1932. We conducted this study to aid in determining the
      suitability of greater prairie chickens as a possible replacement for the heath
      hen. We examined mitochondrial control region sequences from extant populations
      of all prairie grouse species (Tympanuchus) and from museum skin heath hen
      specimens. Our data suggest that the Martha's Vineyard heath hen population
      represents a divergent mitochondrial lineage. This result is attributable either
      to a long period of geographical isolation from other prairie grouse populations
      or to a population bottleneck resulting from human disturbance. The mtDNA
      diagnosability of the heath hen contrasts with the network of mtDNA haplotypes of
      other prairie grouse (T. cupido attwateri, T. pallidicinctus and T.
      phasianellus), which do not form distinguishable mtDNA groupings. Our findings
      suggest that the Martha's Vineyard heath hen was more genetically isolated than
      are current populations of prairie grouse and place the emphasis for future
      research on examining prairie grouse adaptations to different habitat types to
      assess ecological exchangeability between heath hens and greater prairie
      chickens.

PMID- 15189202
TI  - Population genetics of the roan antelope (Hippotragus equinus) with suggestions
      for conservation.
AB  - The roan antelope (Hippotragus equinus) is the second largest African antelope,
      distributed throughout the continent in sub-Saharan savannah habitat.
      Mitochondrial DNA (mtDNA) control region sequencing (401 bp, n = 137) and
      microsatellite genotyping (eight loci, n = 137) were used to quantify the genetic
      variability within and among 18 populations of this species. The within
      population diversity was low to moderate with an average mtDNA nucleotide
      diversity of 1.9% and average expected heterozygosity with the microsatellites of
      46%, but significant differences were found among populations with both the mtDNA
      and microsatellite data. Different levels of genetic resolution were found using
      the two marker sets, but both lent strong support for the separation of West
      African populations (samples from Benin, Senegal and Ghana) from the remainder of
      the populations studied across the African continent. Mismatch distribution
      analyses revealed possible past refugia for roan in the west and east of Africa.
      The West African populations could be recognized together as an evolutionarily
      significant unit (ESU), referable to the subspecies H. e. koba. Samples from the
      rest of the continent constituted a geographically more diverse assemblage with
      genetic associations not strictly corresponding to the other recognized
      subspecies.

PMID- 15189203
TI  - Differential population structuring of two closely related fish species, the
      mackerel (Scomber scombrus) and the chub mackerel (Scomber japonicus), in the
      Mediterranean Sea.
AB  - Population genetic structures of the mackerel (Scomber scombrus) and chub
      mackerel (Scomber japonicus) were studied in the Mediterranean Sea. Fragments of
      272 bp (S. scomber) and 387 bp (S. japonicus) of the 5'-end of the mitochondrial
      control region were sequenced from spawning individuals collected off the coasts
      of Greece, Italy, Spain, and Portugal. High levels of mitochondrial control
      region haplotypic diversity (> 0.98) were found for both Scomber species.
      Nucleotide diversity was higher in the mackerel (0.022) than in the chub mackerel
      (0.017). Global F(ST) values were also higher and significant in the mackerel
      (0.024, P < 0.0001) as opposed to the chub mackerel (0.003, P > 0.05). Molecular
      variance analyses showed differential genetic structuring for these two closely
      related species. There is extensive gene flow between Mediterranean Sea and
      Atlantic Ocean populations of chub mackerel, which are organized into a larger
      panmictic unit. In contrast, Mediterranean Sea populations of mackerel show some
      degree of genetic differentiation and are structured along an east-west axis. The
      analysed eastern Mediterranean Sea mackerel populations (Greece, Italy) are
      clearly separated from that of the western Mediterranean Sea (Barcelona), which
      forms a panmictic unit with eastern Atlantic Ocean populations. The genetic
      structures of both species showed asymmetric migration patterns and indicated
      population expansion.

PMID- 15189204
TI  - Inverse relationship between F and microsatellite polymorphism in the marine
      fish, walleye pollock (Theragra chalcogramma): implications for resolving weak
      population structure.
AB  - Microsatellites have proved to be useful for the detection of weak population
      structure in marine fishes and other species characterized by large populations
      and high gene flow. None the less, uncertainty remains about the net effects of
      the particular mutational properties of these markers, and the wide range of
      locus polymorphism they exhibit, on estimates of differentiation. We examined the
      effect of varying microsatellite polymorphism on the magnitude of observed
      differentiation in a population survey of walleye pollock, Theragra chalcogramma.
      Genetic differentiation at 14 microsatellite loci among six putative populations
      from across the North Pacific Ocean and Bering Sea was weak but significant on
      large geographical scales and conformed to an isolation-by-distance pattern. A
      negative relationship was found between locus variability and the magnitude of
      estimated population subdivision. Estimates of F(ST) declined with locus
      polymorphism, resulting in diminished power to discriminate among samples, and we
      attribute this loss to the effects of size homoplasy. This empirical result
      suggests that mutation rates of some microsatellite loci are sufficiently high to
      limit resolution of weak genetic structure typical of many marine fishes.

PMID- 15189205
TI  - Specialization and habitat: spatial and environmental effects on abundance and
      genetic diversity of forest generalist and specialist Carabus species.
AB  - Habitat specialist species are supposed to be more susceptible to variations in
      local environmental characteristics than generalists. To test this hypothesis, we
      conducted a comparative analysis on abundance and genetic diversity of forest
      carabids differing in their habitat requirements. Four species were sampled in
      forests characterized by abiotic, landscape and biotic environmental variables. A
      statistical framework based on canonical correspondence analysis was used for one
      habitat generalist and one habitat specialist species to determine the relative
      contribution of environmental variables in structuring inter- and
      intrapopulational genetic diversity depicted by microsatellites. Our results
      showed that sympatric species differed in their sensitivity to environmental
      variables. The same variables were found to be important in analyses of abundance
      and genetic data. However, specialization was not related to a greater
      sensitivity to local environmental characteristics. The strong impact of spatial
      variables on genetic data suggested that genetic variation among populations
      would largely reflect the response of individual species to dispersal
      opportunities more than the effect of habitat quality.

PMID- 15189206
TI  - Hidden biodiversity of the extremophilic Cyanidiales red algae.
AB  - The Cyanidiales is a group of asexual, unicellular red algae, which thrive in
      acidic and high temperature conditions around hot springs. These unicellular taxa
      have a relatively simple morphology and are currently classified into three
      genera, Cyanidium, Cyanidioschyzon and Galdieria. Little is known, however, about
      the biodiversity of Cyanidiales, their population structure and their
      phylogenetic relationships. Here we used a taxonomically broadly sampled three
      gene data set of plastid sequences to infer a robust phylogenetic framework for
      the Cyanidiales. The phylogenetic analyses support the existence of at least four
      distinct Cyanidiales lineages: the Galdieria spp. lineage (excluding Galdieria
      maxima), the Cyanidium caldarium lineage, a novel monophyletic lineage of
      mesophilic Cyanidium spp. and the Cyanidioschyzon merolae plus Galdieria maxima
      lineage. Our analyses do not support the notion of a mesophilic ancestry of the
      Cyanidiales and suggest that these algae were ancestrally thermo-acidotolerant.
      We also used environmental polymerase chain reaction (PCR) for the rbcL gene to
      sample Cyanidiales biodiversity at five ecologically distinct sites at
      Pisciarelli in the Phlegrean Fields in Italy. This analysis showed a high level
      of sequence divergence among Cyanidiales species and the partitioning of taxa
      based on environmental conditions. Our research revealed an unexpected level of
      genetic diversity among Cyanidiales that revises current thinking about the
      phylogeny and biodiversity of this group. We predict that future environmental
      PCR studies will significantly augment known biodiversity that we have discovered
      and demonstrate the Cyanidiales to be a species-rich branch of red algal
      evolution.

PMID- 15189207
TI  - Effects of variation at the flower-colour A locus on mating system parameters in
      Ipomoea purpurea.
AB  - Although alleles at both the W and A loci in the common morning glory, Ipomoea
      purpurea, produce similar white-flowered phenotypes, these alleles differ by over
      an order of magnitude in average frequency. In this initial attempt to determine
      the causes of this difference, we employed artificial arrays of plants to
      estimate mating system characteristics (total siring success, selfing rates and
      contribution to the outcross pollen pool) for the homozygous pigmented and white
      flowered genotypes at the A locus. This experiment demonstrates that: (1) at both
      low and high frequencies, white-flowered plants were visited by pollinators at
      the same rate as plants with pigmented flowers; (2) at both frequencies, the a
      allele exhibited a greater total siring success (self and outcross pollen) than
      the A allele; (3) individuals of both genotypes contributed equally to the
      outcross pollen pool; and (4) aa plants may have a higher selfing rate than AA
      plants. Coupled with minimal inbreeding depression in I. purpurea, these
      observations indicate that the allele producing white flowers enjoys a
      transmission advantage that would tend to cause this allele to increase in
      frequency. This transmission advantage is very similar to that shown previously
      to be operating on the white-flowered allele at the W locus, although the
      specific causes of the advantage appear to differ between loci. The frequency
      difference between the two alleles is thus not likely to be due to differences in
      the effect of flower-colour variation on transmission. Rather, substantially
      greater deleterious pleiotropic effects associated with the white-flower a allele
      is likely to be the primary cause of the frequency difference.

PMID- 15189208
TI  - Limited phylogeographical structure across Eurasia in two red wood ant species
      Formica pratensis and F. lugubris (Hymenoptera, Formicidae).
AB  - The phylogeography and demographic history of two closely related species of the
      red wood ant (Formica pratensis and F. lugubris) were examined across Eurasia.
      The phylogeny based on a 1.5-kilobase mitochondrial DNA fragment, including the
      cytochrome b gene and part of the ND6 gene, showed one phylogeographical division
      in F. pratensis. This division (0.7% of nucleotide divergence) suggests
      postglacial colonization of western Europe and of a wide area ranging from Sweden
      on the west to Lake Baikal on the east from separate forest refugia. In two
      localities, mitochondrial DNA has been transferred from F. lugubris to F.
      pratensis and all the individuals of F. pratensis sampled from the Pyrenees had
      haplotypes clustering in the lugubris clade. No phylogeographical divisions were
      detected in F. lugubris. Comparison of species-wide phylogeography between the
      two sympatrically distributed species of ant demonstrates a difference in
      phylogeographical structure that implies different vicariant histories. However,
      over most of the species' distribution ranges, similar signs of demographic
      expansion predating the last glaciation and the lack of phylogeographical
      structure were found in both the eastern phylogroup of F. pratensis and F.
      lugubris. This finding is highly consistent with the results reported for all
      other boreal forest animal species studied to date in Eurasia. Contraction of the
      distribution range of each species to a single refugial area at different times
      during the late Pleistocene and a subsequent population expansion seem to be an
      explanation for the lack of phylogeographical structure across most of Eurasia in
      species that are ecologically associated with the boreal forest.

PMID- 15189209
TI  - Phylogeography of a parasitoid wasp (Diaeretiella rapae): no evidence of host
      associated lineages.
AB  - The exceptional diversity of insects is often attributed to the effects of
      specialized relationships between insects and their hosts. Parasite-host
      interactions are influenced by current natural selection and dispersal, in
      addition to historical effects that may include past selection, vicariance, and
      random genetic drift. Both current and historical events can lead to reduced
      fitness on some hosts. If trade-offs in fitness on alternate hosts are common,
      adaptation to one host can prevent adaptation to another, giving rise to genetic
      differentiation among host-associated lineages. Previous studies of Diaeretiella
      rapae (Hymenoptera: Aphidiidae), a parasitoid of aphids, have revealed additive
      genetic differences in performance between populations that parasitize different
      aphid host species. To determine whether D. rapae populations collected from
      different aphid hosts have diverged into genetically independent lineages, we
      constructed a haplotype network based on sequence variation in mitochondrial DNA
      (mtDNA). We used single strand conformation polymorphism (SSCP) analysis to
      examine 2041 base pairs of mtDNA and to identify nucleotide sequences of 42
      unique SSCP haplotypes. We found no association between mtDNA haplotypes and host
      species in either the ancestral range (Europe, Mediterranean region, Middle East,
      Asia) or part of the introduced range (western North America). Haplotypes likely
      to be ancestral were geographically widespread and found on both hosts,
      suggesting that the ability to use both hosts evolved prior to the
      diversification of the mtDNA. Ongoing gene flow appears to prevent the formation
      of host races.

PMID- 15189210
TI  - Population structure and phylogeography of Solanum pimpinellifolium inferred from
      a nuclear gene.
AB  - Phylogeographical studies are emerging as a powerful tool for understanding the
      population structure and evolution of wild relatives of crop species. Because of
      their value as genetic resources, there is great interest in exploring the
      distribution of variation in wild relatives of cultivated plants. In this study,
      we use sequence variation from the nuclear gene, fruit vacuolar invertase (Vac),
      to investigate the population history of Solanum pimpinellifolium. Solanum
      pimpinellifolium is a close relative of the cultivated tomato and has repeatedly
      served as a source of valuable traits for crop improvement. We sequenced the
      second intron of the Vac gene in 129 individuals, representing 16 populations
      from the northern half of Peru. Patterns of haplotype sharing among populations
      indicate that there is isolation by distance. However, there is no congruence
      between the geographical distribution of haplotypes and their genealogical
      relationships. Levels of outcrossing decrease towards the southernmost
      populations, as previously observed in an allozyme study. The geographical
      pattern of Vac variation supports a centre of origin in northern Peru for S.
      pimpinellifolium and a gradual colonization along the Pacific coast. This implies
      that inbreeding populations are derived from outcrossing ones and that variation
      present at the Vac locus predates the spread of S. pimpinellifolium. The
      expansion of cities and human agricultural activity in the habitat of S.
      pimpinellifolium currently pose a threat to the species.

PMID- 15189211
TI  - Isolation by distance and sharp discontinuities in gene frequencies: implications
      for the phylogeography of an alpine insect species, Carabus solieri.
AB  - Analysis of genetic isolation by distance (IBD) is of prime importance for the
      study of processes responsible for spatial population genetic structure and is
      thus frequently used in case studies. However, the identification of a
      significant IBD pattern does not necessarily imply the absence of sharp
      discontinuities in gene frequencies. Therefore, identifying barriers to gene flow
      and/or secondary contact between differentiated entities remains a major
      challenge in population biology. Geographical genetic structure of 41 populations
      (1080 individuals) of an alpine insect species, Carabus solieri, was studied
      using 10 microsatellite loci. All populations were significantly differentiated
      and spatially structured according to IBD over the entire range. However,
      clustering analyses clearly identified three main clusters of populations, which
      correspond to geographical entities. Whereas IBD also occurs within each cluster,
      population structure was different according to which group of populations was
      considered. The southernmost cluster corresponds to the most fragmented part of
      the range. Consistently, it was characterized by relatively high levels of
      differentiation associated with low genetic diversity, and the slope of the
      regression of genetic differentiation against geographical distances was
      threefold those of the two other clusters. Comparisons of within-cluster and
      between-cluster IBD patterns revealed barriers to gene flow. A comparison of the
      two approaches, IBD and clustering analyses, provided us with valuable
      information with which to infer the phylogeography of the species, and in
      particular to propose postglacial colonization routes from two potential refugia
      located in Italy and in southeastern France. Our study highlights strongly the
      possible confounding contribution of barriers to gene flow to IBD pattern and
      emphasizes the utility of the model-based clustering analysis to identify such
      barriers.

PMID- 15189212
TI  - Phylogeography of olive ridley turtles (Lepidochelys olivacea) on the east coast
      of India: implications for conservation theory.
AB  - Orissa, on the east coast of India, is one of the three mass nesting sites in the
      world for olive ridley turtles (Lepidochelys olivacea). This population is
      currently under threat as a result of fishery-related mortality; more than 100
      000 olive ridleys have been counted dead in the last 10 years in Orissa. In
      general, the globally distributed olive ridley turtle has received significantly
      less conservation attention than its congener, the Kemp's ridley turtle (L.
      kempi), because the latter is recognized as a distinct species consisting of a
      single endangered population. Our study of mitochondrial DNA haplotypes suggests
      that the ridley population on the east coast of India is panmictic, but distinct
      from all other populations including Sri Lanka. About 96% of the Indian
      population consisted of a distinct 'K' clade with haplotypes not found in any
      other population. Nested clade analysis and conventional analysis both supported
      range expansions and/or long-distance colonization from the Indian Ocean clades
      to other oceanic basins, which suggested that these are the ancestral source for
      contemporary global populations of olive ridley turtles. These data support the
      distinctiveness of the Indian Ocean ridleys, suggesting that conservation
      prioritization should be based on appropriate data and not solely on species
      designations.

PMID- 15189213
TI  - Phylogeographic structure, gene flow and species status in blue grouse
      (Dendragapus obscurus).
AB  - We investigated the genetic population structure and species status of a
      relatively sedentary bird that is a permanent resident of western North American
      forests, the blue grouse (Dendragapus obscurus). Phylogenetic analysis of
      complete mitochondrial control region DNA sequences resulted in the
      identification of three basal clades of haplotypes that were largely congruent
      with well-known biogeographical regions. These clades corresponded to the
      parapatric sooty (D. o. fuliginosus) and dusky (D. o. obscurus) subspecies groups
      of blue grouse plus a previously unrecognized division between northern and
      southern dusky grouse populations; the latter does not correspond closely to any
      currently recognized subspecies boundary. Approximately 66% of the total genetic
      variation was distributed among these three regions. Maximum likelihood estimates
      of gene flow between the regions were low or asymmetric; gene flow has been
      insufficient to prevent genetic divergence between dusky and sooty grouse.
      Estimates of gene flow among populations within sooty grouse were large except
      across the Columbia River valley. Among populations of dusky grouse, estimates of
      gene flow were heterogeneous and asymmetrical, reflecting large-scale
      fragmentation of the distribution due to landscape features and associated
      vegetation. Genetic, morphological and behavioural evidence suggest that sooty
      and dusky grouse are species-level taxa; the specific status of a third clade
      remains ambiguous.

PMID- 15189214
TI  - North Atlantic phylogeography and large-scale population differentiation of the
      seagrass Zostera marina L.
AB  - As the most widespread seagrass in temperate waters of the Northern Hemisphere,
      Zostera marina provides a unique opportunity to investigate the extent to which
      the historical legacy of the last glacial maximum (LGM18 000-10 000 years bp) is
      detectable in modern population genetic structure. We used sequences from the
      nuclear rDNA-internal transcribed spacer (ITS) and chloroplast matK-intron, and
      nine microsatellite loci to survey 49 populations (> 2000 individuals) from
      throughout the species' range. Minimal sequence variation between Pacific and
      Atlantic populations combined with biogeographical groupings derived from the
      microsatellite data, suggest that the trans-Arctic connection is currently open.
      The east Pacific and west Atlantic are more connected than either is to the east
      Atlantic. Allelic richness was almost two-fold higher in the Pacific. Populations
      from putative Atlantic refugia now represent the southern edges of the
      distribution and are not genetically diverse. Unexpectedly, the highest allelic
      diversity was observed in the North Sea-Wadden Sea-southwest Baltic region.
      Except for the Mediterranean and Black Seas, significant isolation-by-distance
      was found from ~150 to 5000 km. A transition from weak to strong isolation-by
      distance occurred at ~150 km among northern European populations suggesting this
      scale as the natural limit for dispersal within the metapopulation. Links between
      historical and contemporary processes are discussed in terms of the projected
      effects of climate change on coastal marine plants. The identification of a high
      genetic diversity hotspot in Northern Europe provides a basis for restoration
      decisions.

PMID- 15189215
TI  - Mating system and population structure of the primitively eusocial wasp Ropalidia
      revolutionalis: a model system for the evolution of complex societies.
AB  - Mating systems are important determinants of genetic structure in cooperative
      groups, and their effects can influence profoundly the interactions of group
      members. The primitively eusocial wasp, Ropalidia revolutionalis, has an
      interesting genetic and social structure that makes it an excellent model system
      for examining the evolution of more complex societies. In particular, its
      colonies sometimes have multiple queens, a key characteristic of more advanced
      wasp societies. In this study, we have characterized the mating system of the
      social wasp Ropalidia revolutionalis to understand better its colony genetic
      structure. R. revolutionalis females nearly always mate singly and they are
      unrelated to their mates. However, different females in the same colony do mate
      with males, on average, who are related as cousins. Single mating will help to
      maintain high relatedness, which should be important for continued cooperation in
      multiple queen societies, but it creates potential conflicts in single queen
      colonies over the production of males as well as over the timing of male
      production. We have also characterized the population structure of R.
      revolutionalis from Townsville, in tropical north Queensland, to Brisbane in the
      subtropics. Even at such a large scale, the population is remarkably unstructured
      with an average F(ST) of 0.0546. There is weak isolation by distance, and
      evidence for subtle differentiation between a southern region with no dry season,
      which extends as far north as Rockhampton, and a northern region with a severe to
      moderate dry season. This may reflect historical effects of extreme aridity on
      the population structure.

PMID- 15189216
TI  - Multiple paternity in an aggregate breeding amphibian: the effect of reproductive
      skew on estimates of male reproductive success.
AB  - Aggregate, or explosive, breeding is widespread among vertebrates and likely
      increases the probability of multiple paternity. We assessed paternity in seven
      field-collected clutches of the explosively breeding spotted salamander
      (Ambystoma maculatum) using 10 microsatellite loci to determine the frequency of
      multiple paternity and the number of males contributing to a female's clutch.
      Using the Minimum Method of allele counts, multiple paternity was evident in 70%
      of these egg masses. Simple allele counts underestimate the number of
      contributing males because this method cannot distinguish multiple fathers with
      common or similar alleles. Therefore, we used computer simulations to estimate
      from the offspring genotypes the most likely number of contributing fathers given
      the distributions of allele frequencies in this population. We determined that
      two to eight males may contribute to A. maculatum clutches; therefore, multiple
      paternity is a common strategy in this aggregate breeding species. In aggregate
      mating systems competition for mates can be intense, thus differential
      reproductive success (reproductive skew) among males contributing to a female's
      clutch could be a probable outcome. We use our data to evaluate the potential
      effect of reproductive skew on estimates of the number of contributing males. We
      simulated varying scenarios of differential male reproductive success, ranging
      from equal contribution to high reproductive skew among contributing sires in
      multiply sired clutches. Our data suggest that even intermediate levels of
      reproductive skew decrease confidence substantially in estimates of the number of
      contributing sires when parental genotypes are unknown.

PMID- 15189217
TI  - Predominance of genetic monogamy by females in a hammerhead shark, Sphyrna
      tiburo: implications for shark conservation.
AB  - There is growing interest in the mating systems of sharks and their relatives
      (Class Chondrichthyes) because these ancient fishes occupy a key position in
      vertebrate phylogeny and are increasingly in need of conservation due to
      widespread overexploitation. Based on precious few genetic and field
      observational studies, current speculation is that polyandrous mating strategies
      and multiple paternity may be common in sharks as they are in most other
      vertebrates. Here, we test this hypothesis by examining the genetic mating system
      of the bonnethead shark, Sphyrna tiburo, using microsatellite DNA profiling of 22
      litters (22 mothers, 188 embryos genotyped at four polymorphic loci) obtained
      from multiple locations along the west coast of Florida. Contrary to expectations
      based on the ability of female S. tiburo to store sperm, the social nature of
      this species and the 100% multiple paternity observed in two other coastal shark
      species, over 81% of sampled bonnethead females produced litters sired by a
      single male (i.e. genetic monogamy). When multiple paternity occurred in S.
      tiburo, there was an indication of increased incidence in larger mothers with
      bigger litters. Our data suggest that sharks may exhibit complex genetic mating
      systems with a high degree of interspecific variability, and as a result some
      species may be more susceptible to loss of genetic variation in the face of
      escalating fishing pressure. Based on these findings, we suggest that knowledge
      of elasmobranch mating systems should be an important component of conservation
      and management programmes for these heavily exploited species.

PMID- 15189218
TI  - 'O father: where art thou?'--Paternity assessment in an open fission-fusion
      society of wild bottlenose dolphins (Tursiops sp.) in Shark Bay, Western
      Australia.
AB  - Sexually mature male bottlenose dolphins in Shark Bay cooperate by pursuing
      distinct alliance strategies to monopolize females in reproductive condition. We
      present the results of a comprehensive study in a wild cetacean population to
      test whether male alliance membership is a prerequisite for reproductive success.
      We compared two methods for inferring paternity: both calculate a likelihood
      ratio, called the paternity index, between two opposing hypotheses, but they
      differ in the way that significance is applied to the data. The first method, a
      Bayesian approach commonly used in human paternity testing, appeared to be overly
      conservative for our data set, but would be less susceptible to assumptions if a
      larger number of microsatellite loci had been used. Using the second approach,
      the computer program cervus 2.0, we successfully assigned 11 paternities to nine
      males, and 17 paternities to 14 out of 139 sexually mature males at 95% and 80%
      confidence levels, respectively. It appears that being a member of a bottlenose
      dolphin alliance is not a prerequisite for paternity: two paternities were
      obtained by juvenile males (one at the 95%, the other at the 80% confidence
      level), suggesting that young males without alliance partners pursue different
      mating tactics to adults. Likelihood analyses showed that these two juvenile
      males were significantly more likely to be the true father of the offspring than
      to be their half-sibling (P < 0.05). Using paternity data at an 80% confidence
      level, we could show that reproductive success was significantly skewed within at
      least some stable first-order alliances (P < 0.01). Interestingly, there is
      powerful evidence that one mating was incestuous, with one calf apparently
      fathered by its mother's father (P < 0.01). Our study suggests that the
      reproductive success of both allied males, and of nonallied juveniles, needs to
      be incorporated into an adaptive framework that seeks to explain alliance
      formation in male bottlenose dolphins.

PMID- 15189219
TI  - Pronounced genetic population structure in a potentially vagile fish species
      (Pristipomoides multidens, Teleostei; Perciformes; Lutjanidae) from the East
      Indies triangle.
AB  - The East Indies triangle, bordered by the Phillipines, Malay Peninsula and New
      Guinea, has a high level of tropical marine species biodiversity. Pristipomoides
      multidens is a large, long-lived, fecund snapper species that is distributed
      throughout the East Indies and Indo-Pacific. Samples were analysed from central
      and eastern Indonesia and northern Australia to test for genetic discontinuities
      in population structure. Fish (n = 377) were collected from the Indonesian
      islands of Bali, Sumbawa, Flores, West Timor, Tanimbar and Tual along with 131
      fish from two northern Australian locations (Arafura and Timor Seas) from a
      previous study. Genetic variation in the control region of the mitochondrial
      genome was assayed using restriction fragment length polymorphism and direct
      sequencing. Haplotype diversity was high (0.67-0.82), as was intraspecific
      sequence divergence (range 0-5.8%). F(ST) between pairs of populations ranged
      from 0 to 0.2753. Genetic subdivision was apparent on a small spatial scale;
      F(ST) was 0.16 over 191 km (Bali/Sumbawa) and 0.17 over 491 km (Bali/Flores).
      Constraints to dispersal that contribute to, and maintain, the observed degree of
      genetic subdivision are experienced presumably by all life history stages of this
      tropical marine finfish. The constraints may include (1) little or no movement of
      eggs or larvae, (2) little or no home range or migratory movement of adults and
      (3) loss of larval cohorts due to transport of larvae away from suitable habitat
      by prevailing currents.

PMID- 15189220
TI  - Spatio-temporal variation in the genetic composition of wild populations of pearl
      oyster (Pinctada margaritifera cumingii) in French Polynesia following 10 years
      of juvenile translocation.
AB  - Abstract The genetic impact of the cultural practice of spat collection and
      translocation between genetically distinct stocks of black-lipped pearl oyster,
      Pinctada margaritifera cumingii, was studied by comparing samples collected in
      the 1980s and 2000s from seven atolls in French Polynesia. An amova revealed
      homogenization of the previously genetically distinct wild stocks of Tuamotu
      Gambier and Society archipelagos (the indices of genetic differentiation among
      archipelagos and among populations within archipelagos, respectively, Phi(CT) and
      Phi(ST), decreased from 0.032* and 0.025*, respectively, to 0.006(NS) and
      0.007(NS)). These results suggest high success of spontaneous reproduction in
      farms, probably due to the very high density of cultivated pearl oysters, and
      underline the importance of genetic monitoring of future hatchery produced
      stocks.

PMID- 15189221
TI  - Distribution of the bacterial symbiont Cardinium in arthropods.
AB  - Abstract 'Candidatus Cardinium', a recently described bacterium from the
      Bacteroidetes group, is involved in diverse reproduction alterations of its
      arthropod hosts, including cytoplasmic incompatibility, parthenogenesis and
      feminization. To estimate the incidence rate of Cardinium and explore the limits
      of its host range, 99 insect and mite species were screened, using primers
      designed to amplify a portion of Cardinium 16S ribosomal DNA (rDNA). These
      arthropods were also screened for the presence of the better-known reproductive
      manipulator, Wolbachia. Six per cent of the species screened tested positive for
      Cardinium, compared with 24% positive for Wolbachia. Of the 85 insects screened,
      Cardinium was found in four parasitic wasp species and one armoured scale insect.
      Of the 14 mite species examined, one predatory mite was found to carry the
      symbiont. A phylogenetic analysis of all known Cardinium 16S rDNA sequences shows
      that distantly related arthropods can harbour closely related symbionts, a
      pattern typical of horizontal transmission. However, closely related Cardinium
      were found to cluster among closely related hosts, suggesting host specialization
      and horizontal transmission among closely related hosts. Finally, the primers
      used revealed the presence of a second lineage of Bacteroidetes symbionts, not
      related to Cardinium, in two insect species. This second symbiont lineage is
      closely allied with other arthropod symbionts, such as Blattabacterium, the
      primary symbionts of cockroaches, and male-killing symbionts of ladybird beetles.
      The combined data suggest the presence of a diverse assemblage of arthropod
      associated Bacteroidetes bacteria that are likely to strongly influence their
      hosts' biology.

PMID- 15189222
TI  - Clonal structure and flowering traits of a bamboo [Phyllostachys pubescens
      (Mazel) Ohwi] stand grown from a simultaneous flowering as revealed by AFLP
      analysis.
AB  - Abstract Although many bamboo species are characterized by simultaneous flowering
      at long intervals of up to 120 years, few studies have revealed the length of the
      flowering interval for very-long-lived bamboo species by observing the whole life
      cycle of a single clone. The flowering interval of Phyllostachys pubescens had
      been determined to be 67 years by means of observation through the entire life
      cycle from 1912 to 1979. We observed and analysed the clonal structure and
      flowering traits of a P. pubescens community which had regenerated from seed in
      1930 and began to flower in 1997. Although this interval was again 67 years,
      flowering and nonflowering culms were mixed, and the flowering event lasted three
      years in the community. AFLP analysis of DNA samples showed distinct genets that
      originated from the previous flowering event and that each genet had its own
      flowering time. This is the first report to show that (i) different genets are
      mixed in a community of a large bamboo species with a leptomorphic rhizome
      system, and (ii) a community that originated from a single flowering event can
      have a range of flowering years.

PMID- 15189223
TI  - Population biology of the invasive freshwater snail Physa acuta approached
      through genetic markers, ecological characterization and demography.
AB  - Abstract The respective role of factors acting on population functioning can be
      inferred from a variety of approaches, including population genetics and
      demography. We here investigated the role of four of these factors (mating
      systems, population size, bottlenecks and migration) in the hermaphroditic
      freshwater snail Physa acuta. Twenty-four populations were sampled either around
      Montpellier (local scale), or at the scale of France (global scale). At local
      scale, eight populations were sampled twice, before and after summer drying out.
      The genetic structure of these populations was studied using microsatellite loci.
      Populations were classified according to openness (ponds vs. rivers) and water
      regime (permanent vs. temporary) allowing predictions on genetic patterns (e.g.
      diversity within populations and differentiation). At local scale, progeny-arrays
      analysis of the selfing rate was conducted, and size distributions of individuals
      were followed over two years. Results with regard to the four factors mentioned
      above were: (i) Estimates of population selfing rates derived from inbreeding
      coefficients were only slightly higher than those from progeny-arrays. (ii) More
      variation was detected in rivers than in ponds, but no influence of water regime
      was detected. One reason might be that permanent populations are not going less
      often through low densities than those from temporary habitats at the time scale
      studied. (iii) There was limited evidence for genetic bottlenecks which is
      compatible with the fact that even marked reduction in water availability was not
      necessarily associated with demographic bottlenecks. More generally, bottlenecks
      reducing genetic variation probably occur at population foundation. (iv) Lower
      genetic differentiation was detected among rivers than among ponds which might be
      related to limitations on gene flow. Demographic and temporal genetic data
      further indicates that flooding in rivers is unlikely to induce marked gene flow
      explaining the strong genetic differentiation at short geographical scale in such
      habitats. Finally, the demographic data suggest that some populations are
      transitory and subject to recurrent recolonization, a pattern that was also
      detected through genetic data.

PMID- 15189224
TI  - Assessment of prey overlap between a native (Polistes humilis) and an introduced
      (Vespula germanica) social wasp using morphology and phylogenetic analyses of 16S
      rDNA.
AB  - Abstract In newly invaded communities, interspecific competition is thought to
      play an important role in determining the success of the invader and its impact
      on the native community. In southern Australia, the native Polistes humilis was
      the predominant social wasp prior to the arrival of the exotic Vespula germanica
      (Hymenoptera: Vespidae). Both species forage for similar resources (water, pulp,
      carbohydrate and protein prey), and concerns have arisen about potential
      competition between them. The aim of this study was to identify the protein foods
      that these wasps feed on. As many prey items are masticated by these wasps to the
      degree that they cannot be identified using conventional means, morphological
      identification was complemented by sequencing fragments of the mitochondrial 16S
      rRNA gene. GenBank searches using blast and phylogenetic analyses were used to
      identify prey items to at least order level. The results were used to construct
      complete prey inventories for the two species. These indicate that while P.
      humilis is restricted to feeding on lepidopteran larvae, V. germanica collects a
      variety of prey of invertebrate and vertebrate origin. Calculated values of prey
      overlap between the two species are used to discuss the implications of V.
      germanica impacting on P. humilis. Results obtained are compared to those gained
      by solely 'conventional' methods, and the advantages of using DNA-based taxonomy
      in ecological studies are emphasized.

PMID- 15189225
TI  - Evidence of genetic selection for growth in new recruits of a marine fish.
AB  - Abstract A cohort of Diplodus sargus, a coastal marine fish abundant in the
      Mediterranean Sea, has been surveyed from its settlement following the pelagic
      larval stage up to 4 months of age, when the juveniles are moving to adult
      habitats in order to assess selective processes. We followed the mortality by
      looking at the decrease in population abundance and, simultaneously, the genetic
      structure using allozymes and the growth associated with each genotype to test
      for a relationship between genotype and phenotype. The recruitment survey
      demonstrated that 80% of individuals arrived within a single night and that they
      show very similar age providing a discrete pulse of new recruits that we followed
      for changes in survival and allele frequencies. After 4 months, there was a total
      mortality of 80.8%, with the disappearance of 181 of 224 fish that initially
      colonized the rocky barrier. The decrease in number followed a logarithmic model
      with a maximum decrease in the early period (first 30 days). The model derived
      from the 4 months of data demonstrates that most of the mortality in the cohort
      occurs over the first 120 days following settlement and the model predicted a
      final abundance of 10 individuals after 1 year. Within the same period of 4
      months, we observed significant decrease in multilocus heterozygosity. Such a
      decrease in heterozygosity partly resulted from a purge of the Pgm-80* allele.
      Together with this major change in a natural population, an aquarium experiment
      demonstrated that individuals with Pgm-80* alleles show significantly lower
      growth than other new recruits. We propose that the decrease in frequency of Pgm
      80* in the natural environment is the result of targeted predation that
      eliminates smaller individuals and therefore individuals bearing Pgm-80*. The
      potential metabolic effect as well as a scenario that could lead to the
      maintenance of polymorphism is discussed.

PMID- 15189226
TI  - The Midas cichlid species complex: incipient sympatric speciation in Nicaraguan
      cichlid fishes?
AB  - Abstract Sympatric speciation is a contentious concept, although theoretical
      models as well as empirical evidence support its relevance in evolutionary
      biology. The Midas cichlid species complex (Amphilophus citrinellus, labiatus,
      zaliosus) from several crater lakes in Nicaragua fits several of the key
      characteristics of a sympatric speciation model. In particular, in A. citrinellus
      (i) strong assortative mating on the basis of colour polymorphism and (ii)
      ecological differentiation based on morphological polymorphisms involving the
      feeding apparatus and body shape might both be mechanisms of incipient
      speciation. Seven microsatellite markers and mtDNA control region sequences [836
      base pairs (bp)] were used to study the population genetic structure of 519
      specimens of Midas cichlid populations from the two Great Lakes Managua and
      Nicaragua, and three crater lakes in Nicaragua, Central America. The three named
      species of the species complex occupy different ecological niches, are
      morphologically distinct and can be distinguished genetically. We uncovered
      allopatric genetic differentiation of populations of A. citrinellus from
      different lakes and distant locations within Lake Managua and, more
      interestingly, incipient genetic differentiation of several sympatric populations
      based on colouration (in A. citrinellus and A. labiatus) but not on the
      morphology of the pharyngeal jaws (in A. citrinellus). Sexual selection and
      assortative mating might be the driven forces of diversification within named
      species. The Midas cichlid species complex in Nicaragua is an excellent model
      system for the study of the incipient stages of adaptation, speciation and the
      formation of species flocks.

PMID- 15189227
TI  - Infiltration by alien predators into invertebrate food webs in Hawaii: a
      molecular approach.
AB  - Abstract Alien invertebrate predators have been introduced to Hawaii to control
      pests, particularly in lowland areas where most crops are grown. We developed
      techniques for assessing the impact of these predators on native food webs in
      relatively pristine upland areas where, it was hypothesized, few lowland
      predators might be found. Predator densities were assessed along transects within
      the Alakaii Swamp on Kaua'i. The most numerous alien biocontrol agents found were
      Halmus chalybeus (Coccinellidae), a species known to feed on Lepidoptera eggs.
      Laboratory experiments were conducted using two genera of endemic Lepidoptera,
      Scotorythra and Eupithecia (Geometridae), that are of considerable conservation
      value, the former because of its recent speciation across Hawaii, the latter for
      its unique predatory larvae. Techniques were developed for detecting Lepidoptera
      DNA within the guts of alien predators using prey-specific PCR primers. General
      primers amplified fragments of the mitochondrial cytochrome oxidase I gene from
      beetles and Lepidoptera. The sequences were aligned and used successfully to
      design target-specific primers for general detection of the remains of
      Geometridae and for particular species, including Scotorythra rara and Eupithecia
      monticolans. DNA fragments amplified were short [140-170 base pairs (bp)],
      optimizing detection periods following prey ingestion. Trials using the
      introduced biocontrol agent Curinus coeruleus (Coccinellidae) demonstrated
      detection of Lepidoptera DNA fragments = 151 bp in 85-100% of beetles after 24 h
      digestion of an early instar larva. This study provides a framework for future
      use of molecular gut analysis in arthropod conservation ecology and food web
      research with considerable potential for quantifying threats to endemic species
      in Hawaii and elsewhere.

PMID- 15189228
TI  - Factors affecting the amount of genomic DNA extracted from ape faeces and the
      identification of an improved sample storage method.
AB  - Abstract Genetic analysis using noninvasively collected samples such as faeces
      continues to pose a formidable challenge because of unpredictable variation in
      the extent to which usable DNA is obtained. We investigated the influence of
      multiple variables on the quantity of DNA extracted from faecal samples from wild
      mountain gorillas and chimpanzees. There was a small negative correlation between
      temperature at time of collection and the amount of DNA obtained. Storage of
      samples either in RNAlater solution or dried using silica gel beads produced
      similar results, but significantly higher amounts of DNA were obtained using a
      novel protocol that combines a short period of storage in ethanol with subsequent
      desiccation using silica.

PMID- 15189229
TI  - Very low genetic variability in the Indian queenless ant Diacamma indicum.
AB  - Abstract We developed microsatellite markers and combined them with mitochondrial
      markers to analyse the population genetic structure of the queenless ant Diacamma
      indicum. This species, lacking winged queens, is likely to have a restricted
      female dispersal but exhibits various life history traits suggesting higher
      dispersal abilities than the other Diacamma species. Only 4 of 11 microsatellites
      were polymorphic and only 1 had more than 4 alleles over 166 individuals
      originating from 7 populations from the south of India. Only one mitochondrial
      DNA (mtDNA) haplotype was detected throughout India (including one population in
      the north) and Sri Lanka. Such a level of polymorphism is particularly low
      compared with other Diacamma species having much smaller ranges in the south of
      India. A strong genetic differentiation was observed between populations
      separated by more than a few kilometres. We also analysed the genetic
      differentiation between the Indian populations and two populations from the
      Japanese island of Okinawa, which are morphologically similar and might belong to
      the same species. The genetic differentiation was high for both markers,
      suggesting an absence of ongoing gene flow between these populations.

PMID- 15189230
TI  - A simple method for the calculation of microsatellite genotype distances
      irrespective of ploidy level.
AB  - Abstract Microsatellites are powerful molecular markers, used commonly to
      estimate intraspecific genetic distances. With the exception of band sharing
      similarity index, available distance measures were developed specifically for
      diploid organisms and are unsuited for comparisons of polyploids. Here, we
      present a simple method for calculation of microsatellite genotype distances,
      which takes into account mutation processes and permits comparison of individuals
      with different ploidy levels. This method should provide a valuable tool for
      intraspecific analyses of polyploid organisms, which are widespread among plants
      and some animal taxa. An illustration is given using data from the planarian
      flatworm Schmidtea polychroa (Platyhelminthes).

PMID- 15189232
TI  - Spatial distribution of bluetongue virus and its Culicoides vectors in Sicily.
AB  - During the recent Mediterranean epizootic of bluetongue, an extensive programme
      of serological and vector (Culicoides biting midges (Diptera: Ceratopogonidae))
      surveillance was carried out across Sicily. This paper presents the analysis of
      911 light trap catches collected at the times of peak Culicoides abundance
      (summer to autumn 2000-2002) in 269 sites, in order to produce detailed maps of
      the spatial distribution of the main European vector, Culicoides imicola Kieffer
      and that of potential novel vectors. Whereas C. imicola was found at only 12% of
      sites, potential novel vectors, Culicoides obsoletus group Meigen, Culicoides
      pulicaris Linnaeus and Culicoides newsteadi Austen were present at over 50% of
      sites. However, the spatial distribution of C. imicola showed the closest
      correspondence to that of the 2000 and 2001 bluetongue (BT) outbreaks and its
      presence and abundance were significant predictors of the probability of an
      outbreak, suggesting that it was the main vector during these years. Although C.
      imicola may have played a role in transmission in several sites near Paterno, it
      was absent from the majority of sites at which outbreaks occurred in 2002 and
      from all sites in the province of Messina. All three potential novel vectors were
      widespread across sites at which outbreaks occurred during 2002. Of these, C.
      newsteadi was an unlikely candidate, as it was significantly less prevalent in
      outbreak vs. non-outbreak sites in Messina. It is hypothesized that the yearly
      distribution and intensity of outbreaks is directly attributable to the
      distribution and abundance of the vectors involved in transmission during each
      year. When C. imicola operated as the main vector in 2000 and 2001, outbreaks
      were few in number and were restricted to coastal regions due to low abundance
      and prevalence of this species. In 2002, it is hypothesized that BTV transmission
      was handed over to more prevalent and abundant novel vector species, leading to
      numerous and widespread outbreaks and probably to overwintering of the virus
      between 2001 and 2002. Based on catch ranges in outbreak vs. non-outbreak sites,
      it is tentatively suggested that nightly catches of 400 or more C. obsoletus and
      150 or more C. pulicaris allow BTV transmission at a site, and provide a strategy
      for a fuller examination of the relationship between BTV transmission and the
      abundance and distribution of different vector species.

PMID- 15189233
TI  - Modelling the distributions of Culicoides bluetongue virus vectors in Sicily in
      relation to satellite-derived climate variables.
AB  - Surveillance data from 268 sites in Sicily are used to develop climatic models
      for prediction of the distribution of the main European bluetongue virus (BTV)
      vector Culicoides imicola Kieffer (Diptera: Ceratopogonidae) and of potential
      novel vectors, Culicoides pulicaris Linnaeus, Culicoides obsoletus group Meigen
      and Culicoides newsteadi Austen. The models containing the 'best' climatic
      predictors of distribution for each species, were selected from combinations of
      40 temporally Fourier-processed remotely sensed variables and altitude at a 1 km
      spatial resolution using discriminant analysis. Kappa values of around 0.6 for
      all species models indicated substantial levels of agreement between model
      predictions and observed data. Whilst the distributions of C. obsoletus group and
      C. newsteadi were predicted by temperature variables, those of C. pulicaris and
      C. imicola were determined mainly by normalized difference vegetation index
      (NDVI), a variable correlated with soil moisture and vegetation biomass and
      productivity. These models were used to predict species presence in unsampled
      pixels across Italy and for C. imicola across Europe and North Africa. The
      predicted continuous presence of C. pulicaris along the appenine mountains, from
      north to south Italy, suggests BTV transmission may be possible in a large
      proportion of this region and that seasonal transhumance (seasonal movement of
      livestock between upland and lowland pastures) even in C. imicola-free areas
      should not generally be considered safe. The predicted distribution of C. imicola
      distribution shows substantial agreement with observed surveillance data from
      Greece and Iberia (including the Balearics) and parts of mainland Italy (Lazio,
      Tuscany and areas of the Ionian coast) but is generally much more restricted than
      the observed distribution (in Sardinia, Corsica and Morocco). The low number of
      presence sites for C. imicola in Sicily meant that only a restricted range of
      potential C. imicola habitats were included in the training set and that
      predictions could only be made within this range. Future modelling exercises will
      use abundance data collected according to a standardized protocol across the
      Mediterranean and, for Sicily in particular, should include non-climatic
      environmental variables that may influence breeding site suitability such as soil
      type.

PMID- 15189234
TI  - Anopheles gambiae feeding and survival on honeydew and extra-floral nectar of
      peridomestic plants.
AB  - It is widely believed that the malaria vector Anopheles gambiae Giles (Diptera:
      Culicidae) rarely or never feeds on sugar in nature. If so, the need for
      supplemental blood-feeding may be increased and this would help to explain why it
      is such an efficient malaria vector. Nonetheless, both sexes of this mosquito
      species readily imbibe and digest sugar solutions, and sugar is a staple of
      laboratory colonies. In this study, we investigated whether An. gambiae will feed
      on the extra-floral nectar of three common peridomestic plants in Africa, and on
      honeydew of the mealybug Pseudococcus longispinus (Targioni-Tozetti) (Hemiptera:
      Homoptera: Pseudococcidae), and how this affects survivorship. We found that both
      males and females of An. gambiae provided with vegetative parts of cassava
      (Manihot esculenta Crantz) survived as well (x = 26.3 and 19.2 days,
      respectively) as they did on 50% sucrose solution (x = 29.7 and 24.3 days,
      respectively) and much longer than they did on water alone (x = 1.8 days, both
      sexes). Females provided with mealybug honeydew also lived substantially longer
      (x = 16.5 days) than those on water alone. Males and females provided with
      vegetative parts of castorbean (Ricinus communis L.) also survived much longer (x
      = 12.7 and 7.8 days, respectively) than on water, but those provided with
      flowering lantana (Lantana camara L.) did not. Anthrone tests of females after
      one night of exposure to these potential energy sources confirmed that they
      obtained fructose from cassava, from mealybug honeydew, and from non-flowering
      castorbean, but not from lantana or from castorbean lacking its petiolar
      nectaries. Previous laboratory studies had shown that sugar availability affects
      the survival and biting frequency of An. gambiae. It now appears that this
      mosquito can locate natural sources of plant sugar readily and utilize them
      effectively. Nectar-producing plants in the domestic environment may play a
      significant role in this mosquito's energy budget and malaria vectorial capacity.

PMID- 15189235
TI  - Feeding and survival of the malaria vector Anopheles gambiae on plants growing in
      Kenya.
AB  - The propensity of the malaria vector mosquito Anopheles gambiae Giles (Diptera:
      Culicidae) to ingest sugars from various plants, and subsequent survival rates,
      were assessed with laboratory-reared males and females offered eight species of
      plants commonly cultivated and/or growing wild in western Kenya. In cages (no
      choice bioassay), mosquitoes given the opportunity to feed on castorbean (Ricinus
      communis L.) had the longest survival times (mean and median survival time of
      6.99 +/- 0.23 and 5.67 +/- 0.17 days, respectively), comparable to mosquitoes
      given 6% glucose (mean and median survival time of 8.70 +/- 0.23 and 6.67 +/-
      0.33 days, respectively). Survival rates of An. gambiae were low on the other
      plants, comparable to mosquitoes given only water. Three plants: sweet potato
      (Ipomoea batatas L.), wild sage (Lantana camara L.) and castorbean provided
      levels of sugar ingestion by both sexes of An. gambiae detectable using the cold
      anthrone method, showing a positive correlation between median survival and sugar
      consumption (Spearman rank correlation coefficient = 0.905, P < 0.0001). Equal
      numbers of males and females were released in an enclosed semi-field screenhouse
      system containing a range of local plants, but no host for blood, and allowed to
      feed ad libitum: 6.7 +/- 0.5% (11/64) of those recaptured were found to contain
      detectable fructose (all females). Common plants are clearly a viable source of
      nutrition for adult female An. gambiae, as well as males, and may constitute and
      important resource for this important malaria vector.

PMID- 15189236
TI  - Blowflies Calliphora vicina and Lucilia sericata as passive vectors of
      Mycobacterium avium subsp. avium, M. a. paratuberculosis and M. a. hominissuis.
AB  - Mycobacterium avium subsp. paratuberculosis (Actinomycetales: Mycobacteriaceae)
      isolates of identical restriction fragment length polymorphism (RFLP) type B-C1
      were isolated from: intestinal mucosa of two cows showing clinical signs of
      paratuberculosis, a specimen of the blowfly Calliphora vicina Robineau-Desvoidy
      (Diptera: Calliphoridae) captured while perched on these cattle intestines in a
      waste container at the site of the slaughter, and the blowflies C. vicina and
      Lucilia caesar Linnaeus captured the next day at the same site when no infected
      cattle with paratuberculosis were slaughtered. Subsequently, second-stage larvae
      of the blowflies C. vicina and Lucilia sericata (Meigen) were experimentally
      infected by feeding them liver from hens with avian tuberculosis caused by M. a.
      avium (serotype 1, genotype IS901+ and IS1245+) and small cuts of pork meat
      contaminated with M. a. hominissuis (serotype 8, genotype IS901- and IS1245+).
      Mycobacterium a. avium of identical serotype, genotype and RFLP type F-C3 was
      isolated from C. vicina larvae on days 4 and 11 post infection (p.i.) and from L.
      sericata larvae on day 4 p.i. Identical RFLP type B-C1 of M. a. paratuberculosis
      was isolated from adult C. vicina fed with artificially contaminated saccharose
      solution on day 2 p. i. Investigation of M. a. paratuberculosis distribution
      inside the adult C. vicina showed that the majority of Colony Forming Units (CFU)
      were isolated from the abdomen and head, fewer from the thorax and wings and none
      from the legs. Larvae and adults may participate in spreading causal agents of
      mycobacterial infections and this fact should be considered during sanitation of
      infected herds and in slaughterhouses when materials from animals affected by
      mycobacterial infections are processed.

PMID- 15189237
TI  - Species composition, distribution, and ecological preferences of the ticks of
      grazing sheep in north-central Spain.
AB  - The distribution and ecological preferences of tick (Acari: Ixodidae) parasites
      of grazing sheep in the region of Aragon (north-central Spain) were surveyed on
      flocks four times a year and mapped into a 5 x 5 km grid. Nine tick species were
      found. These were species of the Rhipicephalus sanguineus group (about 95% of
      them Rhipicephalus turanicus Pomerantsev, in 91% of cells of the grid),
      Rhipicephalus bursa Canestrini & Fanzago (79% of cells), Dermacentor marginatus
      (Sulzer) (58% of cells), Haemaphysalis punctata Canestrini & Fanzago (74% of
      cells) and Ixodes ricinus (Linnaeus) 14% of cells. Other species weakly
      represented in the surveys were Dermacentor reticulatus (Fabricius),
      Haemaphysalis sulcata Canestrini & Fanzago and Hyalomma m. marginatum Koch. Data
      on temperature, Normalized Difference Vegetation index (NDVI), topography,
      vegetation categories and plant productivity were used to build models of
      distribution and abundance of D. marginatus, H. punctata, R. bursa and R.
      turanicus. The occurrence models largely incorporated climatic variables and had
      good discrimination ability (P < 0.0001 for every modelled species, correct
      classification rate or sensitivity within 0.89 and 0.99), whereas the abundance
      models had a lower explanatory power. These models are relevant in the
      understanding of the variables composing the main distribution patterns, but they
      are unable adequately to predict the density. Abundance models produce good
      predictions in cells with low tick density, whereas poor correlation is observed
      in sites with high tick abundance. Several causes may be responsible for this low
      predictive power of the abundance models. Model output might be sensible to host
      density, to local farming practices, or to the size of the grid used to refer the
      results of the survey. In the latter case, small patches may support locally
      important populations of ticks, influencing largely the results of the survey.
      These patches of particular abiotic conditions, or supporting large host
      densities, may have been undetected at the resolution of the survey, thus
      obscuring the impact of the predictive variables.

PMID- 15189238
TI  - Experimental hut comparisons of nets treated with carbamate or pyrethroid
      insecticides, washed or unwashed, against pyrethroid-resistant mosquitoes.
AB  - The efficacy against mosquitoes (Diptera: Culicidae) of a bednet treated with
      carbamate insecticide [carbosulfan capsule suspension (CS) 200 mg/m(2)] was
      compared with four types of pyrethroid-treated nets in veranda-trap huts at
      Yaokoffikro near Bouake, Cote d'Ivoire, where the malaria vector Anopheles
      gambiae Giles carries the kdr gene (conferring pyrethroid resistance) at high
      frequency and Culex quinquefasciatus Say is also pyrethroid resistant.
      Pyrethroids compared were lambdacyhalothrin CS 18 mg/m(2), alphacypermethrin
      water dispersible granules (WG) 20 mg/m(2), deltamethrin 50 mg/m(2) (Permanet)
      and permethrin emulsifiable concentrate (EC) 500 mg/m(2). Insecticidal power and
      personal protection from mosquito bites were assessed before and after the nets
      were used for 8 months and hand washed five times in cold soapy water. Before
      washing, all treatments except permethrin significantly reduced blood-feeding and
      all had significant insecticidal activity against An. gambiae. The carbosulfan
      net gave significantly higher killing of An. gambiae than all pyrethroid
      treatments except the Permanet. Against Culex spp., carbosulfan was more
      insecticidal and gave a significantly better protective effect than any of the
      pyrethroid treatments. After washing, treated nets retained various degrees of
      efficacy against both mosquito genera - but least for the carbosulfan net. Washed
      nets with three types of pyrethroid treatment (alphacypermethrin,
      lambdacyhalothrin, permethrin) gave significantly higher mortality rates of Culex
      than in huts with the same pyrethroid-treated nets before washing. After five
      washes, the Permanet, which is sold as a long-lasting insecticidal product,
      performed no better than the other nets in our experimental conditions.

PMID- 15189239
TI  - Adult anopheline ecology and malaria transmission in irrigated areas of South
      Punjab, Pakistan.
AB  - Surface irrigation in the Punjab province of Pakistan has been carried out on a
      large scale since the development of the Indus Basin Irrigation System in the
      late 19th century. The objective of our study was to understand how the
      population dynamics of adult anopheline mosquitoes (Diptera: Culicidae) could be
      related to malaria transmission in rural areas with intensive irrigation and a
      history of malaria epidemics. In this paper we present our observations from
      three villages located along an irrigation canal in South Punjab. The study was
      carried out from 1 April 1999 to 31 March 2000. Mosquitoes were collected from
      bedrooms using the pyrethroid spraycatch method and from vegetation and animal
      sheds using backpack aspirators. Overall, Anopheles subpictus Grassi sensu lato
      predominated (55.6%), followed by An. stephensi Liston s.l. (41.4%), An.
      culicifacies Giles s.l. (2.0%), An. pulcherrimus Theobald (1.0%) and An.
      peditaeniatus Leicester (0.1%). Most mosquitoes (98.8%) were collected from
      indoor resting-sites whereas collections from potential resting-sites outdoors
      accounted for only 1.2% of total anopheline densities, confirming the endophilic
      behaviour of anophelines in Pakistan. Anopheles stephensi, An. culicifacies and
      An. subpictus populations peaked in August, September and October, respectively.
      High temperatures and low rainfall negatively affected seasonal abundance in our
      area. There were interesting differences in anopheline fauna between villages,
      with An. culicifacies occurring almost exclusively in the village at the head of
      the irrigation canal, where waterlogged and irrigated fields prevailed. Monthly
      house-to-house fever surveys showed that malaria transmission remained low with
      an overall slide positivity rate of 2.4% and all cases were due to infection with
      Plasmodium vivax. The most plausible explanation for low transmission in our
      study area seems to be the low density of Pakistan's primary malaria vector, An.
      culicifacies. The role of other species such as An. stephensi is not clear. Our
      observations indicate that, in South Punjab, irrigation-related sites support the
      breeding of anopheline mosquitoes, including the vectors of malaria. As our study
      was carried out during a year with exceptionally hot and dry climatic conditions,
      densities and longevity of mosquitoes would probably be higher in other years and
      could result in more significant malaria transmission than we observed. To assess
      the overall importance of irrigation-related sites in the epidemiology of malaria
      in the Punjab, more studies are needed to compare irrigated and non-irrigated
      areas.

PMID- 15189240
TI  - Field issues related to effectiveness of insecticide-treated nets in Tanzania.
AB  - Insecticide-treated nets (ITNs) impregnated with pyrethroid insecticides have
      become one of the most promising interventions to prevent malaria in highly
      endemic areas. Despite the large body of experience documenting their health
      impact and the best way to distribute them, some key practical issues remain
      unresolved. For example, the duration of effective life of a net under field
      conditions is unknown. The most important factor affecting net effectiveness is
      the issue of regular re-treatment with insecticide. Washing is also an important
      determinant of insecticide longevity in the field. Trials were undertaken to
      provide some essential field information on ITNs within the site of an extended
      ITN programme in the Morogoro region of Tanzania. It was found that 45% of all
      nets were in bad condition (defined as more than seven large holes). It is
      concluded that an effective 'life' for polyester nets is 2-3 years. Further, two
      thirds of the 20% of nets that were reported as having been re-treated within the
      last 12 months had less than 5 mg/m(2) of insecticide. According to the World
      Health Organization this is insufficient to be effective. People reported that
      they washed their nets four to seven times per year, usually with soap.
      Observations showed that such washing does not harm the nets and that the wash
      water was unlikely to have an impact on the environment. Finally, bioassays were
      carried out with Anopheles gambiae on polyester netting with 0.5, 2, 5, 10 and 30
      mg/m(2) of deltamethrin, alphacypermethrin and lambdacyhalothrin to assess the
      effectiveness of pyrethroids. The results confirmed that even with low
      insecticide concentrations, nets can still provide partial protection.

PMID- 15189241
TI  - Molecular identification of two species of myiasis-causing Cuterebra by multiplex
      PCR and RFLP.
AB  - The myiasis-causing flies Cuterebra grisea (Coquillet) and Cuterebra fontinella
      (Clark) (Diptera: Oestridae) are normally parasites of mice, predominantly of the
      genus Peromyscus. The morphological similarities of these species and the
      existence of intermediate morphotypes bearing characters of both species make the
      identification of adults problematic; furthermore the identification of larvae is
      apparently not possible. This study presents two molecular approaches to
      discriminate between these species using specific band patterns: (i) species
      specific primers designed in the cytochrome oxidase II (COII) region used in
      multiplex polymerase chain reaction (PCR) and (ii) restriction fragment length
      polymorphism (RFLP) on amplified segments of cytochrome oxidase I (COI) gene.
      Both methods were tested on Cuterebra larvae and on adult museum specimens. The
      two techniques showed a clear difference between C. grisea and C. fontinella,
      although species-specific primers were more successful than RFLP for degraded
      DNA. No intraspecific variation in RFLP and species-specific amplifications were
      detected for the two species of Cuterebra. The results exhibit discrepancies
      between molecular and morphological identification, suggesting that some of the
      adults were misidentified.

PMID- 15189243
TI  - Temperature-related duration of aquatic stages of the Afrotropical malaria vector
      mosquito Anopheles gambiae in the laboratory.
AB  - Vector abundance is an important factor governing disease risk and is often
      employed when modelling disease transmission. The longevity of the aquatic stages
      of mosquitoes (Diptera: Culicidae) dictates the rate of production of adults and
      hence the intensity of disease transmission. We examined how temperature
      influences the survival of larval stages (larvae and pupae) of Anopheles gambiae
      Giles sensu stricto and subsequent adult production of this most efficient
      malaria vector. Groups of 30 mosquitoes were reared at constant temperatures
      (from 10 to 40 degrees C) from the first instar and observed until death or
      metamorphosis of the last individual. Larvae developed into adults at
      temperatures ranging from 16 to 34 degrees C. Larval survival was shortest (< 7
      days) at 10-12 degrees C and 38-40 degrees C, and longest (> 30 days) at 14-20
      degrees C. Within the temperature range at which adults were produced, larval
      mortality was highest at the upper range 30-32 degrees C, with death (rather than
      adult emergence) representing over 70% of the terminal events. The optimal
      survival temperatures were lower than the temperatures at which development was
      quickest, suggesting a critical relationship between temperature and the life
      cycle of the insect. These data provide fundamental information about An. gambiae
      s.s. adult productivity at different temperatures, which may facilitate the
      construction of process-based models of malaria risk in Africa and the
      development of early warning systems for epidemics.

PMID- 15189242
TI  - Efficiency of Simulium sanctipauli as a vector of Onchocerca volvulus in the
      forest zone of Ghana.
AB  - The role of Simulium sanctipauli Vajime & Dunbar (Diptera: Simuliidae) as a
      vector of Onchocerca volvulus (Leuckart) (Spirurida: Onchocercidae) in the forest
      zone of central Ghana was studied in the Upper Denkyira district, where
      onchocerciasis is hyperendemic. Simulium sanctipauli was found to be a highly
      efficient vector, with a mean of 377 infective (L3) larvae in the heads of 1000
      parous and 122 in the heads of 1000 biting flies. The overall infection rate of
      44% of the parous flies with L1, L2 and L3 stages of O. volvulus (identity
      confirmed by polymerase chain reaction) demonstrates marked anthropophily. Female
      flies dispersed over a wide area and can transmit onchocerciasis up to at least
      10 km away from their breeding sites. Annual community-directed treatments with
      ivermectin did not have a noticeable effect on the infection rates and parasitic
      loads of fly populations, which were as high 2 months after as 3 months before
      the distribution of ivermectin. This failure can be attributed to poor coverage,
      with treatment taken by only 24.4% of the population of the six study villages.

PMID- 15189244
TI  - Population structure of the peridomestic mosquito Ochlerotatus notoscriptus in
      Australia.
AB  - Ochlerotatus notoscriptus (Skuse) (Diptera: Culicidae) is the predominant
      peridomestic mosquito in Australia where it is the primary vector of dog
      heartworm, Dirofilaria immitis (Leidy), and a potentially important vector of
      arboviruses (Barmah Forest, Ross River) with geographical variation of vector
      competence. Although widespread, Oc. notoscriptus has low dispersal ability, so
      it may have isolated subpopulations. The identification of gene flow barriers may
      assist in understanding arbovirus epidemiology and disease risk, and for
      developing control strategies for this species. We investigated the population
      structure of Oc. notoscriptus from 17 sites around Australia, using up to 31
      putative allozyme loci, 11 of which were polymorphic. We investigated the effect
      of larval environment and adult morphology on genetic variation. At least five
      subpopulations were found, four in New South Wales (NSW) and one unique to
      Darwin. Perth samples appear to be a product of recent colonization from the
      Australian east coast. For NSW sites, a Mantel test revealed an isolation by
      distance effect and spatial autocorrelation analysis revealed an area of
      effective gene flow of 67 km, which is high given the limited dispersal ability
      of this species. No consistent difference was observed between 'urban' and
      'sylvan' habitats, which suggests frequent movement between these sites. However,
      a finer-scaled habitat study at Darwin revealed small but significant allele
      frequency differences, including for Gpi. No fixed allozyme differences were
      detected for sex, size, integument colour or the colour of species-diagnostic
      pale scales on the scutum. The domestic habit of Oc. notoscriptus and assisted
      dispersal have helped to homogenize this species geographically but population
      structure is still detectable on several levels associated with geographical
      variation of vector competence.

PMID- 15189245
TI  - Differential modulation of murine host immune response by salivary gland extracts
      from the mosquitoes Aedes aegypti and Culex quinquefasciatus.
AB  - Mosquitoes (Diptera: Culicidae) are major vectors of numerous infectious agents.
      Compounds in mosquito saliva not only facilitate blood-feeding, but may also have
      an impact upon the immune system of vertebrate hosts. Consequently, the exposure
      to mosquito saliva may influence pathogen transmission, establishment and disease
      development. Using two medically important vector mosquitoes, Aedes aegypti (L.)
      and Culex quinquefasciatus Say, we examined the effects of mosquito saliva on
      immune cells of host mice. After antigen-specific or non-specific stimulation,
      murine splenocyte proliferation and production of both Th1 and Th2 cytokines were
      significantly reduced in the presence of salivary gland extract (SGE) from Ae.
      aegypti, but not SGE from Cx. quinquefasciatus. T cell populations were highly
      susceptible to this suppression, showing increased mortality and reduced division
      rates - judged by flow cytometric analyses. Evidently these two culicine
      mosquitoes differ in their host immunomodulatory activities.

PMID- 15189246
TI  - Assessment of arbovirus vector infection rates using variable size pooling.
AB  - Pool testing of vector samples for arboviruses is widely used in surveillance
      programmes. The proportion of infected mosquitoes (Diptera: Culicidae) is often
      estimated from the minimum infection rate (MIR), based on the assumption of only
      one infected mosquito per positive pool. This assumption becomes problematic when
      pool size is large and/or infection rate is high. By relaxing this constraint,
      maximum likelihood estimation (MLE) is more useful for a wide range of infection
      levels that may be encountered in the field. We demonstrate the difference
      between these two estimation approaches using West Nile virus (WNV) surveillance
      data from vectors collected by gravid traps in Chicago during 2002. MLE of
      infection rates of Culex mosquitoes was as high as 60 per 1000 at the peak of
      transmission in August, whereas MIR was less than 30 per 1000. More importantly,
      we demonstrate roles of various pooling strategies for better estimation of
      infection rates based on simulation studies with hypothetical mosquito samples of
      18 pools. Variable size pooling (with a serial pool sizes of 5, 10, 20, 30, 40
      and 50 individuals) performed consistently better than a constant size pooling of
      50 individuals. We conclude that variable pool size coupled with MLE is critical
      for accurate estimates of mosquito infection rates in WNV epidemic seasons.

PMID- 15189247
TI  - Acaricidal activity of aqueous extracts of camomile flowers, Matricaria
      chamomilla, against the mite Psoroptes cuniculi.
AB  - Arcaricidal properties of decoctions, infusions and macerates of dried flower
      heads of camomile, Matricaria chamomilla L. (Asterales: Asteraceae) were tested
      in vitro against the mite Psoroptes cuniculi Delafond (Parasitiformes:
      Psoroptidae). This mite species is responsible for otoacariasis in domestic
      animals. Mites were exposed to the extracts for 24, 48 or 72 h. All the extracts
      tested showed highly significant acaricidal activity when compared with controls.
      Among them, a decoction of 10% was the only formulation which gave 100% activity
      at all the three observations times.

PMID- 15189248
TI  - Horseflies of Jordan.
AB  - The horsefly (Diptera: Tabanidae) fauna of Jordan consists of 21 species
      belonging to seven genera. The present study adds 17 new records to this little
      known group of haematophagous insects. Most of the new records were collected
      from several localities within the Jordan Valley. These new records are Chrysops
      flavipes Meigen, Atylotus farinosus (Szilady), Dasyrhamphis umbrinus (Meigen),
      Haematopota coronata Austen, Hybomitra decora (Loew), Hybomitra mendica
      (Villeneuve), Tabanus accensus Austen, T. albifacies Loew, T. bifarius Loew, T.
      darimonti Leclercq, T. laetetinctus Becker, T. leleani Austen, T. pallidipes
      Austen, T. regularis Jaennicke, T. rupinae Austen, T. sufis Jaennicke and
      Therioplectes tunicatus (Szilady). Tabanus albifacies and T. sufis were the most
      common species collected by hand nets (19.85% and 17.73%, respectively) and D.
      umbrinus, Haematopota minuscula Austen, and Haematopota coronata were the least
      common species (0.12% for each). Zoogeographical analysis of the recorded species
      showed that 12 species are of Mediterranean origin, four are of Afrotropical
      origin, two of European origin and at least three species can be considered as
      endemic to the Middle East.

PMID- 15189249
TI  - Infestation of people with lice in Kathmandu and Pokhara, Nepal.
AB  - The prevalence of infestation with head lice and body lice, Pediculus spp.
      (Phthiraptera: Pediculidae) and pubic (crab) lice Pthirus pubis (L.)
      (Phthiraptera: Pthiridae), was recorded from 484 people in Nepal. The prevalence
      of head lice varied from 16% in a sample of people aged 10-39 years of age, to
      59% in street children. Simultaneous infestations with head and body lice (double
      infestations) varied from 18% in slum children to 59% in street children.

PMID- 15189251
TI  - Clarity of outcomes in medical education: do we know if it really makes a
      difference?

PMID- 15189252
TI  - Applying global standards across national boundaries: lessons learned from an
      Asia-Pacific example.

PMID- 15189253
TI  - Changing course.

PMID- 15189254
TI  - Monkey see, monkey do: a critique of the competency model in graduate medical
      education.
AB  - BACKGROUND: Graduate medical education in the UK is in danger of being subsumed
      in a minimalist discourse of competency. ARGUMENT: While accepting that
      competence in a doctor is a sine qua non, the author criticises the construction
      of a graduate and specialist medical education based solely upon a competency
      model. Many competency models follow the concepts of either academic competence
      or operational competence, both of which have lately been subject to criticism.
      CONCLUSION: The author discusses the need for replacing such criterion-referenced
      models in favour of a model that engages the higher order competence, performance
      and understanding which represent professional practice at its best.

PMID- 15189255
TI  - The problem with outcomes-based curricula in medical education: insights from
      educational theory.
AB  - BACKGROUND: Educators across the world are charged with the responsibility of
      producing core learning outcomes for medical curricula. However, much educational
      theory exists which deliberates the value of learning outcomes in education.
      AIMS: This paper aims to discuss the problems surrounding outcomes-based
      curricula in medical education, using insights from educational theory.
      DISCUSSION: The paper begins with a discussion of the traditions, values and
      ideologies of medical curricula. It continues by analysing the issue of control
      within the curriculum and argues that curriculum designers and teachers control
      product-orientated curricula, leading to student disempowerment. The paper
      debates outcomes-based curricula from an ideological perspective and argues that
      learning outcomes cannot specify exactly what is to be achieved as a result of
      learning. CONCLUSIONS: The paper argues that medical schools should adopt a model
      for co-operative control of the curriculum, thus empowering learners. The paper
      also suggests that medical educators should determine the value of precise
      learning outcomes before blindly adopting an outcomes-based model.

PMID- 15189256
TI  - Learning management systems: technology to measure the medical knowledge
      competency of the ACGME.
AB  - AIMS: We report how the learning management system (LMS) Web Course Tools (WebCT)
      was used to design, implement and evaluate the web-based course "Principles of
      Ambulatory Paediatrics", taken by paediatric residents during an ambulatory block
      rotation. This report also illustrates how WebCT can be used to measure the
      medical knowledge competency required by the Accreditation Council for Graduate
      Medical Education (ACGME). METHODS: Eighty paediatric residents completed a 1
      month outpatient rotation between July 1, 2001 and June 30, 2002. During this
      rotation residents were required to complete 4 modules in asthma, otitis media,
      gastroenteritis and fever, respectively. Each module was evaluated using a
      standard questionnaire. RESULTS: Completion rates for the required modules ranged
      from 64-72%. Residents in all 3 years of training showed improvement between the
      pre- and post-test scores for each module, except for postgraduate Year 2
      residents in the asthma module. Most residents somewhat agreed, agreed or
      strongly agreed that the module components were useful and that the experience of
      completing the modules would improve their ability to take care of patients.
      CONCLUSIONS: The LMS WebCT is an innovative and adaptable approach for designing
      a web-based course for primary care education in paediatrics. The LMS addresses
      the educational needs of both a clinical division and a residency programme. The
      LMS also provides an information technology infrastructure to measure the medical
      knowledge competency required by the ACGME.

PMID- 15189257
TI  - Inter-rater agreement in judging errors in diagnostic reasoning.
AB  - CONTEXT AND OBJECTIVE: Inter-rater agreement is essential in rating clinical
      performance of doctors and other health professionals. The purpose of this study
      was to establish inter-rater agreement in categorising errors in the diagnostic
      process made by clinicians using computerised decision support systems. METHODS:
      Eight possible error categories were developed for coding errors in diagnostic
      hypotheses and plans for next steps in the work-up. Two independent doctor judges
      rated 54 work-ups (representing 2 cases, each worked-up by 27 doctors). Inter
      rater agreement between the 2 raters was computed using the kappa coefficient.
      RESULTS: High inter-rater agreement was achieved in all categories except where
      the manual was not sufficiently specific and raters had to use their judgement.
      As is typical of the kappa coefficient, however, agreement corrected for chance
      fell markedly into the "poor" range when the percentages of expected and observed
      agreement were about the same. CONCLUSION: Raters can achieve good agreement in
      categorising errors provided they are given explicit scoring rules and do not
      rely solely upon clinical judgement. The kappa coefficient has limitations in
      cases where the expected agreement between judges is high and variability is low.
      The use of 2 indices to assess agreement, analogous to test sensitivity and
      specificity, is recommended.

PMID- 15189258
TI  - Case representation by medical experts, intermediates and novices for laboratory
      data presented with or without a clinical context.
AB  - BACKGROUND: Based on cognitive psychological research, a number of theoretical
      frameworks have been put forward to describe the structure of experts' medical
      knowledge and to explain experts' case-processing. PURPOSE: To provide evidence
      for the theory of knowledge encapsulation, which states that medical knowledge
      constitutes of interlinked biomedical and clinical knowledge. METHODS: Fourth
      year medical students, clerks and medical experts evaluated six case
      descriptions, consisting of laboratory data either with or without a clinical
      context. For each case description, the participants were required to study the
      case, to formulate a diagnosis, and to write down everything they could remember
      of the case. RESULTS: When the laboratory data were not embedded within a
      clinical context, medical experts' case-processing increased and their diagnostic
      accuracy became worse. Furthermore, laboratory data recall of medical experts was
      more elaborate in cases where the laboratory data were presented without a
      clinical context. Similar results were obtained for students and clerks.
      CONCLUSIONS: The findings are only partially consistent with a prediction made by
      the theory of knowledge encapsulation. Further research, using a different
      paradigm than the traditionally used method of free recall, is required to
      unearth whether medical experts use qualitatively different knowledge structures
      than novices while solving cases.

PMID- 15189259
TI  - Evaluation of a handheld clinical decision support tool for evidence-based
      learning and practice in medical undergraduates.
AB  - INTRODUCTION: Handheld computers (PDAs) uploaded with clinical decision support
      software (CDSS) have the potential to facilitate the adoption of evidence-based
      medicine (EBM) at the point-of-care among undergraduate medical students. Further
      evaluation of the usefulness and acceptability of these tools is required.
      METHODS: All 169 Year 4 undergraduate medical students at the University of Hong
      Kong completed a post-randomised controlled trial survey. Primary outcome
      measures were CDSS/PDA usefulness, satisfaction, functionality and utilisation.
      Focus groups were also conducted to derive complementary qualitative data on the
      students' attitudes towards using such new technology. RESULTS: Overall, the
      students found the CDSS/PDA useful (mean score = 3.90 out of 6, 95% confidence
      interval (CI) = 3.78, 4.03). They were less satisfied with the functional
      features of the CDSS (mean score = 3.45, 95% CI = 3.32, 3.59) and the PDA (mean
      score = 3.51 95% CI = 3.40, 3.62). Utilisation was low, with the average
      frequency of use less than once per week. Although students reported a need for
      information in patient care at least once daily, they infrequently used the CDSS
      in a clinical setting (20.4 +/- 10.4% of the time), with an average information
      retrieval success rate of 37.6 +/- 22.1% requiring 63.7 +/- 86.1 seconds.
      Multivariable regression shows that higher perceived CDSS/PDA usefulness was
      associated with more supportive faculty attitudes, greater knowledge of EBM,
      better computer literacy skills and increased use in a clinical setting. Greater
      satisfaction with the CDSS/PDA was associated with increased use in a clinical
      setting and higher successful search rates. Qualitative results were consistent
      with these quantitative findings and yielded additional information on students'
      underlying feelings that may explain the observations. CONCLUSIONS: While PDAs
      uploaded with the CDSS are able to provide students with better access to high
      quality information, improvements in faculty attitudes, students' knowledge of
      EBM and computer literacy skills, and having the CDSS specially designed for
      undergraduate use are essential to increasing student adoption of such point-of
      care tools.

PMID- 15189260
TI  - Supporting the problem-based learning process in the clinical years: evaluation
      of an online Clinical Reasoning Guide.
AB  - PURPOSE: Implementing problem-based learning (PBL) in the clinical years of a
      medical degree presents particular challenges. This study investigated the
      effectiveness of using an online Clinical Reasoning Guide to assist integration
      of PBL in the clinical setting and promote further development of students'
      clinical reasoning abilities. METHOD: A total of 52 students in 6 PBL groups,
      together with their 6 clinical tutors, participated in the study. Data were
      analysed from videotaped observations of tutorial activity and follow-up,
      semistructured interviews. RESULTS: From both the student facilitators' and the
      clinical tutors' perspectives, the Guide proved an effective tool for augmenting
      the PBL process in clinical settings and promoting the development of clinical
      reasoning. By combining computer-aided learning with collaborative PBL tutorials
      it promoted individual as well as collaborative reasoning. There is also evidence
      to suggest that the Guide prompted students to look more critically at their own,
      their colleagues' and other clinicians' reasoning processes.

PMID- 15189261
TI  - Evaluation of interns by senior residents and faculty: is there any difference?
AB  - INTRODUCTION: Both senior residents and faculty members evaluate family practice
      interns (PGY-1) on the inpatient family medicine service at the University of
      Missouri-Columbia. The purpose of this study was to investigate the content and
      nature of narrative comments on a clinical evaluation sheet. METHODS: Objective
      1. The authors placed the subjective comments made by faculty and senior
      residents in their evaluations of PGY-1 residents into 12 distinctive categories.
      Objective 2. Comments were coded with a positive or negative valence. Objective
      3. The genders of the evaluator and learner were recorded. RESULTS: All
      evaluations made between 1996 and 1999 were analysed. A total of 1341 individual
      comments were reviewed. Objective 1. Categories used most often were generic
      comments (20.2%), personal attributes (18%), and clinical competence (14.1%).
      There was no difference in category use based on the experience level of the
      evaluator (P = 0.17). Objective 2. The majority of the comments (81.9%) were
      positive in nature. Senior faculty members were significantly less likely to make
      negative comments than were junior faculty members or senior residents (P =
      0.004). Objective 3. There were no differences in category use based on the
      gender of the evaluator (P = 0.13). CONCLUSIONS: Objective 1. Narrative
      evaluation comments may be placed into 12 distinctive categories. Most comments
      are generic and do not help to inform learning. Objective 2. A total of 82% of
      comments were positive. Residents were more likely to make negative comments than
      senior faculty members. Objective 3. There was no demonstrable gender bias in
      writing negative comments.

PMID- 15189263
TI  - Clinical students' initial reports of the educational climate in a single medical
      school.
AB  - INTRODUCTION: The quality of the educational environment has frequently been
      identified as crucial to effective learning. Aspects of the clinical context
      differ from those of other higher education environments. This study explored the
      educational climate (the environment perceived by students) at a single medical
      school. The article focuses on the perceptions of students in the early stages of
      their clinical course. METHODS: A longitudinal study of the school was carried
      out over a 5-year period from 1995 to 2000, using ethnographic methods. Data
      collection methods included participant observation, in-depth interviews, focus
      groups, and collection of written documentation. Analysis was conducted using a
      grounded theory approach. RESULTS: At the beginning of their clinical course,
      students were motivated by the patient contact and enjoyed clinical teaching.
      However, they also felt daunted because the earlier years of the course had not
      prepared them in terms of the knowledge or style of learning required. Aspects of
      the hospital environment were perceived as being unhelpful to learning, for
      example, doctors' frequent late arrival for, or cancellation of, teaching.
      Students often perceived that they were "in the way", and that their
      individuality was not valued. Maturity, gender and ethnicity impacted on
      students' perceptions and on their career aspirations and expectations.
      DISCUSSION: Students' transition to the hospital environment was difficult. This
      may become less of an issue as medical curricula become more integrated. Specific
      strategies to induct students into the hospital, and increased staff awareness of
      their needs, could also help. Ensuring an inclusive atmosphere may be more
      difficult, requiring cultural change.

PMID- 15189264
TI  - Evaluation of self-directed clinical education: validation of an instrument.
AB  - AIM: To explore the evaluation of self-directed, integrated clinical education.
      METHODS: We delivered a quantitative and qualitative, self-report questionnaire
      to students through their web-based learning management system. The questionnaire
      was distributed 4 times over 1 year, each time in 2 parts. A generic part
      evaluated boundary conditions for learning, teaching activities and "real patient
      learning". Factor analysis with varimax rotation was used to validate the
      constructs that made up the scale and to stimulate hypotheses about how they
      interrelated. A module-specific part evaluated real patient learning of the
      subject matter in the curriculum. RESULTS: A total of 101 students gave 380 of a
      possible 404 responses (94%). The generic data loaded onto 4 factors,
      corresponding to: firm quality; hospital-based teaching and learning; community
      and out-patient learning, and problem-based learning (PBL). A 5-item quality
      index had content, construct and criterion validity. Quality differed greatly
      between firms. Self-evaluation of module-specific, real patient learning was also
      valid. It was strongly influenced by the specialty interests of hospital firms.
      CONCLUSIONS: Quality is a multidimensional construct. Self-report evaluation of
      real patient learning is feasible, and could be capitalised on to promote
      reflective self-direction. The social and material context of learning is an
      important dimension of educational quality.

PMID- 15189262
TI  - Prospective randomised comparison of traditional, personal bedside and problem
      oriented practical dermatology courses.
AB  - PURPOSE: This paper reports a prospective, randomised study comparing a problem
      oriented practical (POP) course based on paper cases to a personal bedside
      teaching (PBT) practical course and a standard practical course. METHODS: During
      2 consecutive terms, students were randomly allocated to either 2 POP groups/term
      (n = 10/group), 2 PBT groups/term (n = 10/group) or the standard practical
      course, which consisted of a rotating system of lectures and bedside teaching
      with randomly appointed tutors. Each course was evaluated with the same 12-item
      questionnaire and multiple-choice test administered at the beginning and end of
      the course. RESULTS: The numbers of students evaluated were 36 for the POP
      groups, 37 for the PBT groups, and 155 for the standard course. The PBT and POP
      courses were rated significantly better (P < 0.001) than the standard course for
      all items. Aggregate marks (mean +/- SD) were: 1.59 +/- 0.8 for the POP course;
      1.69 +/- 0.68 for the PBT course, and 2.71 +/- 0.98 for the standard course.
      There were no significant differences between the POP and PBT courses.
      Significantly better learning rates as indicated by an increase in the number of
      correctly answered questions were observed in students attending the POP and PBT
      courses. CONCLUSION: This prospective study demonstrated that there was no
      difference in the rating of a POP course and a bedside teaching course by
      students randomly assigned to 1 of 3 different pedagogical approaches.
      Furthermore, both alternative options achieved better ratings than the standard
      course, which is current teaching practice in our medical school. The PBT and POP
      approaches provided superior learning success and POP helped solve the problems
      of standardisation and patient recruitment.

PMID- 15189266
TI  - Daily oscillations in liver function: diurnal vs circadian rhythmicity.
AB  - The rodent suprachiasmatic nucleus (SCN), a site in the brain that contains a
      light-entrained biological (circadian) clock, has been thought of as the master
      oscillator, regulating processes as diverse as cell division, reproductive
      cycles, sleep, and feeding. However, a second circadian system exists that can be
      entrained by meal feeding and has an influence over metabolism and behavior.
      Recent advances in the molecular genetics of circadian clocks are revealing clock
      characteristics such as rhythmic clock gene expression in a variety of non-neural
      tissues such as liver. Although little is known regarding the function of these
      clock genes in the liver, there is a large literature that addresses the
      capabilities of this organ to keep time. This time-keeping capability may be an
      adaptive function allowing for the prediction of mealtime and therefore improved
      digestion and energy usage. Consequently, an understanding of these rhythms is of
      great importance. This review summarizes the results of studies on diurnal and
      circadian rhythmicity in the rodent liver. We hope to lend support to the
      hypothesis that there are functionally important circadian clocks outside of the
      brain that are not light- or SCN-dependent. Rather, these clocks are largely
      responsive to stimuli involved in nutrient intake. The interaction between these
      two systems may be very important for the ability of organisms to synchronize
      their internal physiology.

PMID- 15189267
TI  - Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA
      treated patients with primary biliary cirrhosis.
AB  - BACKGROUND/AIM: We have previously shown that the histological stage and severity
      of lymphocytic piecemeal necrosis (LPN) are independent predictive factors of
      cirrhosis development in ursodeoxycholic acid (UDCA)-treated patients with
      primary biliary cirrhosis (PBC). Our aim during this study was to determine
      whether biochemical parameters classically used in PBC management and measured
      under UDCA could be considered as reliable surrogate markers for these
      histological prognostic indices in clinical practice. METHOD: The study included
      153 patients with PBC who had undergone a control liver biopsy after 2 years of
      UDCA therapy. The relationships between histological and biological features were
      assessed by variance analysis and logistic regression. The diagnostic value of
      independent markers was assessed in terms of their sensitivity, specificity,
      positive predictive value (PPV) and negative value (NPV) and receiver-operating
      characteristic curves. RESULTS: Two variables were independently associated with
      extensive fibrosis (i.e. advanced histological stages): serum levels of bilirubin
      and hyaluronic acid (HA). A fibrosis index ([bilirubin (micromol/l)/14]+[HA
      (microg/l)/143]) higher than 1.5 exhibited good PPV and specificity (>74%) but
      rather poor NPV and sensitivity (<64%) regarding a diagnosis of extensive
      fibrosis. The only independent marker of LPN was aspartate aminotransferase (AST)
      activity. AST activity of more than twice the upper limit of normal showed
      acceptable PPV (>70%) but very low sensitivity (<25%) for a diagnosis of LPN.
      CONCLUSIONS: Serum bilirubin and HA levels measured under UDCA therapy are of
      acceptable diagnostic value for extensive fibrosis, but none of the biochemical
      tests commonly employed in the management of PBC can be considered as surrogate
      markers of LPN. Taken together with our previous results, these findings suggest
      that liver biopsy may be necessary to screen UDCA-treated patients who might
      require additional therapies.

PMID- 15189268
TI  - Tamoxifen: a novel treatment for primary biliary cirrhosis?
AB  - Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, which
      predominantly affects women. It is characterised histologically by
      necroinflammation of small intrahepatic bile ducts and biochemically by elevated
      serum alkaline phosphatase, levels of which at diagnosis predict survival.
      Ursodeoxycholic acid (UDCA) is the only treatment shown to improve liver
      biochemistry and survival. We report two patients with PBC who show a fall in
      serum alkaline phosphates levels whilst receiving tamoxifen therapy. Tamoxifen
      may exert this effect, which warrants further study, either via cholangiocyte
      estrogen receptors, inhibiting cholangiocyte proliferation and inducing apoptosis
      or by activating pregnane X receptor, analogous to the mode of action of UDCA.

PMID- 15189269
TI  - Hepatocyte proliferation in chronic hepatitis C: correlation with degree of liver
      disease and serum alpha-fetoprotein.
AB  - AIMS: Hepatocyte proliferation (HP) is an adaptive response to liver injury. The
      relationships between HP and necroinflammation, fibrosis, and serum alpha
      fetoprotein (AFP) levels in chronic hepatitis C virus (HCV) infection, however,
      are not well understood. METHODS: Proliferative hepatocytes (Ki-67+) were
      identified using immunohistochemical staining in formalin-fixed, paraffin
      embedded liver tissue from 156 HCV RNA-positive patients with different degrees
      of liver histopathology. Twenty high-power fields (HPFs) in lobular areas were
      counted in each specimen. RESULTS: HP increased by 1.22 +/- 0.25 cells/HPF per
      increase in necroinflammation from grade 0 (median: 0.13; range: [0.1-0.5]
      cells/HPF) through grade 3 (median: 1.80; range: [0.0-25.2] cells/HPF; P=0.002).
      HP increased by 0.81 +/- 0.20 cells/HPF per increase in fibrosis from stage 0
      (median: 0.33; range: [0.0-1.3] cells/HPF) through stage 3 (median: 1.70; range:
      [0.0-25.2] cells/HPF) and then decreased in stage 4 (to median: 0.90; range: [0.0
      5.3] cells/HPF). HP also increased with advancing age (P=0.03). Among patients
      with advanced liver disease, HP was no higher in patients with elevated serum AFP
      levels (median: 1.68; range: [0.1-5.3] cells/HPF) than in those with normal serum
      AFP levels (median: 1.70; range: [0.0-25.2] cells/HPF; P=0.26). CONCLUSIONS: In
      patients with chronic HCV infection, HP increases with histologic progression of
      liver disease, but is impaired in cirrhosis. HP was not increased in patients
      with elevated serum AFP levels.

PMID- 15189270
TI  - Virological, immunological and histological aspects in adult beta-thalassemic
      patients with chronic hepatitis C virus infection.
AB  - OBJECTIVES: Multitransfused adult beta-thalassemic patients constitute a
      population with high prevalence of hepatitis C virus (HCV) infection, because of
      transmission of HCV from infected blood donors prior to the introduction of anti
      HCV screening. The aim of this study was to compare them with otherwise normal
      patients with HCV infection. METHODS: Forty-two adult multitransfused beta
      thalassemics and 49 otherwise normal patients of the same age, with chronic HCV
      infection were studied. Viral parameters, autoimmunity indices and liver
      histology were evaluated. RESULTS: Serum HCV RNA levels were found significantly
      lower in thalassemic (median: 65,150 international units per milliliter (IU/ml);
      range: 3 059 380 IU/ml) than in non-thalassemic (NT) patients (median: 580,000
      IU/ml; range: 10,956,000 IU/ml; P=0.001). The most prevalent genotype in
      thalassemic group was genotype 4 (32.4%) while in NT group was genotype 3a
      (59.2%). Cryoglobulins were detected in 8/42 (19%) thalassemic patients and in
      12/49 (24.5%) NTs. Thalassemic patients had significantly lower levels of C3 and
      C4 components of complement and higher incidence of anti-nuclear antibodies than
      those without thalassemia. In patients with thalassemia a lower grading score was
      noted in liver biopsy compared with those without thalassemia (4.41+/-1.98 vs
      5.38 +/- 2.09, P=0.038). On the contrary, thalassemic patients were found to have
      a higher staging score (3.08 +/- 1.51 vs 2.33 +/- 1.34, P=0.024). CONCLUSIONS:
      Adult beta-thalassemic patients, compared with other patients with HCV infection,
      present lower necroinflammatory activity and lower viral load but higher staging
      score. Autoimmune features are marginally different. Age of acquiring the
      infection, iron overload and modulation of immune system by transfusions are the
      proposed causes of these differences.

PMID- 15189272
TI  - Intrahepatic accessory spleen: imaging features.
AB  - The authors present a case report of a 60-year-old man with a hepatic unknown
      mass. For diagnosis, they used ECO, CT (with and without contrast), MR (with and
      without contrast) and an ultrasound-assisted percutaneous lesion biopsy. Thus the
      mass-lesion in the liver appeared to be an intrahepatic accessory spleen in a
      patient afflicted with chronic hepatitis.

PMID- 15189271
TI  - Incidence and risk factors for acute renal failure in patients with
      hepatocellular carcinoma undergoing transarterial chemoembolization: a
      prospective study.
AB  - BACKGROUND: Transarterial chemoembolization (TACE) is effective for
      hepatocellular carcinoma (HCC). Considerable amounts of radiocontrast agent are
      used for TACE and may induce renal dysfunction. METHOD: This study prospectively
      investigated the incidence and risk factors of acute renal failure (ARF), defined
      as an increase of serum creatinine level >1.5 mg/dl after TACE. RESULTS: ARF
      developed in 12 (8.6%) of 140 patients after TACE. Univariate analysis showed
      that number of treatment sessions (2.3 +/- 1.4 vs 1.3 +/- 1.6, P=0.013), Child
      Pugh class B (50% vs 21%, P=0.035) and the occurrence of severe postembolization
      syndrome (75% vs 30%, P=0.020) were significantly associated with the development
      of ARF. Multivariate logistic regression analysis disclosed that the proportional
      increased risk of ARF was 65% for each additional TACE therapy (odds ratio [OR]:
      1.65, 95% confidence interval [CI]: 1.13-2.41, P=0.010). Other independent risk
      factors were Child-Pugh class B (OR: 12.82, 95% CI: 2.44-67.29, P=0.003) and
      severe postembolization syndrome (OR: 6.64, 95% CI: 1.60-27.49, P=0.009). Four
      (33%) of the patients with ARF developed irreversible renal function impairment,
      and diabetes mellitus was the only associated factor (P=0.067) in this group.
      CONCLUSIONS: ARF after TACE is closely associated with number of treatment
      sessions, severity of cirrhosis and development of severe postembolization
      syndrome. Effective preventive measures should be undertaken especially in high
      risk patients.

PMID- 15189273
TI  - Hepatocyte survival depends on beta1-integrin-mediated attachment of hepatocytes
      to hepatic extracellular matrix.
AB  - BACKGROUND: A major drawback of allogeneic hepatocyte transplantation is the lack
      of sustained survival of the transplanted cells in the recipient liver
      parenchyma. The purpose of this study was to determine the effect of the presence
      or absence of hepatic extracellular matrix (ECM) molecules on hepatocyte survival
      and function following hepatocyte isolation for transplantation purposes, and the
      role of beta1-integrin molecules therein. METHODS: Hepatocytes, either untreated
      or treated with anti-beta1 integrin antibodies or RGD peptides, were seeded on
      wells precoated with collagen type I, type IV, laminin, fibronectin or
      polyhydroxyethylmehacrylate. The extent of attachment and apoptosis was
      evaluated. RESULTS: When hepatocytes were added into wells precoated with either
      fibronectin, or collagen type IV, rapid spreading and prolonged survival
      occurred, in contrast to hepatocytes that were seeded in wells precoated with
      collagen type I or polyhydroxyethylmehacrylate. Pretreatment of the cells with
      anti-beta1-integrin antibodies resulted in reduction of cell attachment to
      laminin, fibronectin, collagen I, and collagen IV. Synthetic RGD (arginine
      glycine-aspartate)-peptides and anti-beta1 antibodies inhibited apoptosis of
      cultured hepatocytes. CONCLUSIONS: Our findings indicate that embedding of
      hepatocytes within their normal liver ECM surroundings maintains their survival.
      When detached from their natural surrounding hepatocytes enter into apoptosis,
      unless treated with anti-beta1-integrin antibodies or RGD peptides. This
      knowledge will allow improvement of hepatocyte transplantation efficiency.

PMID- 15189274
TI  - Role of NF-kappaB activation and nitric oxide expression during PGE protection
      against d-galactosamine-induced cell death in cultured rat hepatocytes.
AB  - Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver
      dysfunction. Nitric oxide (NO) mediates PGE1 protection against D-galactosamine
      (D-GalN)-induced cell death. Nuclear factor kappa-B (NF-kappaB) plays a
      protective role in different experimental models of cell death. We investigated
      if NF-kappaB was responsible for inducible nitric oxide synthase (iNOS)
      expression and cytoprotection induced by PGE1 against D-GalN cell death in
      cultured hepatocytes. Rat hepatocytes were isolated following the classical
      method of collagenase perfusion of liver. A kinetic study of cell death, NF
      kappaB activation, mRNA and protein iNOS expression, and NO production was
      carried in hepatocytes treated with D-GalN (5 mM) in the presence or absence of
      PGE1 (1 microM) administered 2 h before the hepatotoxin. A proteasome inhibitor
      was used to evaluate the role of NF-kappaB activation in our experimental
      conditions. PGE1 protection against D-GalN-induced cell death was associated with
      its capacity to rapidly enhance NF-kappaB activation, mRNA and protein iNOS
      expression, and NO production in D-GalN-treated hepatocytes. The inhibition of NF
      kappaB activation abolished iNOS expression and cell protection by PGE1 in
      hepatocytes treated with the hepatotoxin. The present study shows that the
      cytoprotection by PGE1 against D-GalN-induced apoptosis was related to NF-kappaB
      dependent iNOS expression.

PMID- 15189275
TI  - High-ratio differentiation of embryonic stem cells into hepatocytes in vitro.
AB  - BACKGROUND/PURPOSE: To date, in differentiating system of embryonic stem (ES)
      cells into hepatocytes, hepatic differentiation ratio was still not shown. Here,
      after investigating hepatic differentiation from ES cells, we determined the
      differentiation ratios of hepatocytes and studied how to improve the ratios in ES
      cell differentiating system. METHODS: Embryonic bodies (EBs) formed from ES cells
      for 5 days were plated onto culture dishes and some growth factors were added
      into medium for hepatic differentiation. Expressions of hepatic genes and
      proteins were analysed using reverse transcriptase-polymerase chain reaction,
      immunocytochemistry (ICC) and radioimmunoassay. The relative counts of hepatocyte
      like cells among all EBs cells were analysed by flow cytometry by which hepatic
      differentiation ratios were determined. Then, we observed the spatial
      distribution of ICC-positive cells in EB cells cluster and isolated the cells of
      positive areas in other EBs clusters without ICC examined. At last, isolated
      cells were re-cultured with previous condition and hepatic differentiation ratios
      were also determined. RESULTS: The hepatic genes and proteins were, respectively,
      expressed in cytoplasm. Hepatic differentiation ratio was first determined at day
      11 to be 12.1% and the level reached maximum to be 33.4% at day 21. In isolated
      cells culture system, hepatic genes and proteins expressed stronger than that
      expressed in EBs cluster and hepatic differentiation ratio was got to 72.6% at
      day 21. CONCLUSIONS: Isolating hepatocyte-like cells from EBs cell cluster and re
      culturing them could produce hepatocytes with high differentiation ratio. This
      culture system may produce a new source of cell types for hepatocytes replacement
      therapies in hepatic failure.

PMID- 15189276
TI  - Liver-targeted doxorubicin: effects on rat regenerating hepatocytes.
AB  - BACKGROUND/AIMS: The conjugate of doxorubicin (DOXO) with lactosaminated human
      albumin (L-HSA) has the potential of improving DOXO efficacy in the treatment of
      hepatocellular carcinomas (HCCs) expressing the asialoglycoprotein receptor (ASGP
      R). In view of an adjuvant chemotherapy with L-HSA-DOXO after the surgical
      removal of the tumour, in the present experiments we verified whether DOXO
      accumulation produced by the conjugate can impair the liver regeneration
      following hepatic resection in non-cirrhotic liver. METHODS: Using saline
      injected hepatectomised rats as controls, we studied the effects of the conjugate
      on the ultrastructure of regenerating hepatocytes and evaluated [3H]thymidine
      incorporation, mitotic index and rate of DNA recovery in the liver remnant.
      RESULTS: L-HSA-DOXO caused a selective drug accumulation in liver remnant, with
      low DOXO levels in extra-hepatic tissues. It did not change the ultrastructure of
      hepatocytes and did not increase serum alanine aminotransferase. It decreased
      [3H]thymidine incorporation and mitotic index, causing a moderate delay in
      hepatic DNA recovery. CONCLUSIONS: The experiments indicate a substantial
      resistance of rat regenerating hepatocytes to high intracellular concentrations
      of DOXO. They support the possibility of using L-HSA-DOXO in an adjuvant
      chemotherapy after the surgical removal of HCCs which maintain the ASGP-R.

PMID- 15189277
TI  - Gene expression profile analysis of regenerating liver after portal vein ligation
      in rats by a cDNA microarray system.
AB  - AIMS: We assessed changes in gene expression of hypertrophied liver after portal
      vein ligation (PL) in a test group of rats compared to a control group, which had
      the same size liver but no PL. METHODS: The portal veins of the left and median
      lobes in the test group were ligated in an initial operation. Four days after the
      PL, the liver volume of the posterior caudate lobe (5%) increased two-fold and
      comprised 10% of the liver. A 90% hepatectomy was then performed, leaving only
      the hypertrophied posterior caudate lobe, and leaving the normal anterior and
      posterior caudate lobes (10%) in the control (sham) group. A comparison of the
      expression profiles between two groups was performed using cDNA microarrays and
      the hepatic ATP level was measured. RESULTS: The survival rate for the PL group
      was significantly higher than for the sham group at 4 days after the hepatectomy
      (56.3% and 26.7%, P < 0.05). Gene expression of cyclin D1, proliferating cell
      nuclear antigen, cyclin A and B was upregulated, and the cyclin-dependent kinase
      inhibitor was downregulated. Increases were observed in: (i) pyruvate
      dehydrogenase, the tricarboxylic acid cycle cycle regulator, (ii) acyl-CoA
      dehydrogenase, the oxidation regulator, and (iii) cytochrome oxidases, the
      oxidative phosphorylation regulator. Hepatic ATP concentration after hepatectomy
      was better maintained in the PL group than in the sham group (0.48 +/- 0.01
      micromol/ml vs. 0.33 +/- 0.01 micromol/ml, P < 0.05). CONCLUSION: The
      regenerating liver increased tolerance for extended hepatectomy compared to
      normal liver. It is believed that this is because the induced rapid regeneration
      of the remaining liver after hepatectomy increases ATP metabolism.

PMID- 15189278
TI  - Hepatitis C virus infection in human liver tissue engrafted in mice with an
      infectious molecular clone.
AB  - BACKGROUND/AIMS: Recent advances in molecular cloning of hepatitis C virus (HCV)
      have enabled us to apply some available HCV molecular clones to experimental
      studies. However, these investigations have been restricted to chimpanzee models
      or 'isolated hepatocytes' from tree shrews. In this study, we engrafted 'human
      liver tissue' into immunodeficient mice and investigated HCV infection using an
      infectious molecular clone. METHODS: Human liver tissues from normal (non-HCV
      infected) liver were transplanted into non-obese diabetic/severe combined
      immunodeficiency (NOD/SCID) mice. We then inoculated the mice with sera from HCV
      infected patients or an infectious HCV molecular clone. HCV RNA was assessed
      using nested reverse-transcription polymerase chain reaction (PCR), real-time
      detection PCR and in situ PCR. RESULTS: Without any growth support, normal human
      liver tissues survived in NOD/SCID mice while maintaining the original viable
      hepatic architecture. HCV RNA was detected in the mice serum until the fourth
      week after the inoculation. In situ PCR and immunohistochemistry clearly
      demonstrated positive signals for HCV in the cytoplasm of infected hepatocytes,
      while the engrafted human liver tissues showed no apparent morphological changes
      indicative of infection. CONCLUSION: Engraftment of human liver tissues into
      NOD/SCID mice and infection with HCV molecular clones could offer a reverse
      genetic strategy for HCV infection.

PMID- 15189279
TI  - Progenitor cell activation in chronic viralhepatitis.
AB  - BACKGROUND/AIM: Oval cell proliferation is known to occur in experimental models
      of hepatic regeneration and carcinogenesis. Recent studies have suggested that
      activation of progenitor cells, representing the human counterpart of oval cells,
      may play a role in hepatic diseases. Therefore, we evaluated putative progenitor
      cells in chronic viral hepatitis. METHODS: Forty-one needle liver biopsy
      specimens from patients with chronic hepatitis B and 43 specimens from patients
      with chronic hepatitis C were examined histologically. The grade (histological
      activity index (HAI)) and stage (degree of fibrosis) were determined on routinely
      stained sections. The number of progenitor cells was assessed semiquantitatively
      on cytokeratin 7- (CK 7-) stained sections. RESULTS: In both aetiological
      categories of chronic viral hepatitis, progenitor cell numbers were found to
      increase in parallel to the HAI, as well as to the stage of disease. Features
      suggestive of hepatocytic differentiation of progenitor cells were also noted on
      immunohistochemical stains for CK 7 and 'hepatocyte-specific' antigen.
      CONCLUSIONS: In chronic hepatitis B and chronic hepatitis C, progenitor cell
      activation is correlated with the grade and stage of disease. Proliferating
      progenitor cells may play a role in hepatic regeneration occurring in this
      setting.

PMID- 15189281
TI  - In vitro fungitoxic activity of Larrea divaricata cav. extracts.
AB  - AIMS: To evaluate the fungitoxic activity of Larrea divaricata Cav. extract and
      one of its components against yeasts and fungi. This activity was compared with
      the action of ketoconazole, a known synthetic antimycotic. METHODS AND RESULTS:
      Antifungal activity of Larrea divaricata extract and of a fraction (Fr. B)
      purified by thin layer chromatography, was investigated using different
      methodologies. Both exhibited strong activity against the majority of the assayed
      fungi. Only Fusarium oxysporum and Schizophyllum commune growth was not affected
      with the assayed conditions. The fungitoxic and cytotoxic activity of the
      ethanolic extract and ketoconazole were compared. CONCLUSIONS: Ethanolic extracts
      of L. divaricata Cav. produce growth inhibition of several fungi. One of its
      constituents with the same activity was purified and identified as a glycoside of
      a flavanone. A comparison with the action of ketoconazole, which is currently
      used as antimycotic and can cause adverse health effects was made. SIGNIFICANCE
      AND IMPACT OF THE STUDY: Our data suggest that L. divaricata extract contains, at
      least, one compound of phenolic nature, with fungitoxic potency against yeasts
      and fungi.

PMID- 15189282
TI  - Kinetics of enhanced ethanol productivity using raw starch hydrolyzing
      glucoamylase from Aspergillus niger mutant produced in solid state fermentation.
AB  - AIMS: The present investigation deals with the effect of raw starch hydrolyzing
      glucoamylase by a derepressed mutant of Aspergillus niger on enhanced
      productivity of ethanol from uncooked starch under non-aseptic conditions.
      METHODS AND RESULTS: The parental culture of Aspergillus niger was improved using
      gamma-ray treatment. One derepressed mutant was isolated after extensive
      screening and optimization and grown on corn cobs, maize starch, soluble starch
      and wheat bran solid media moistened with Vogel's salts solution and corn steep
      liquor. The mutant was 2.5-fold improved over its parent with respect to enzyme
      productivity, product yield and specific activity. The enzyme from mutated
      culture was also improved for enzyme properties and could effectively hydrolyze
      raw starch without the aid of alpha-amylase. Starch hydrolyzed with mutant
      derived glucoamylase supported higher volumetric and product yields of ethanol
      than those of parental and other strains. SIGNIFICANCE AND IMPACT OF THE STUDY:
      The results of the present study are of commercial value. Ethanol product yield
      coefficient, and volumetric productivity revealed the hyper-productivity of
      ethanol from raw starch hydrolyzate obtained with mutant-derived glucoamylase
      without addition of liquefying alpha-amylase under non-aseptic conditions.

PMID- 15189283
TI  - The expression of COX2 protein induced by Lactobacillus rhamnosus GG, endotoxin
      and lipoteichoic acid in T84 epithelial cells.
AB  - AIMS: Lactobacillus rhamnosus GG (L. rhamnosus GG) possess immunomodulatory
      effects in the host. In the present study, the effect of L. rhamnosus GG on
      cyclooxygenase 2 (COX2) expression and its pharmacological control was
      investigated in human T84 colon epithelial cells. METHODS AND RESULTS: T84 cells
      were exposed to freeze-dried L. rhamnosus GG in vitro, and the expression of COX2
      was detected by Western blot. CONCLUSIONS: L. rhamnosus GG induced COX2
      expression in a time- and concentration-dependent manner in T84 cells. COX2
      expression was inhibited by tyrosine kinase inhibitor genistein (100 micromol l(
      1)), p38 mitogen-activated protein kinase (MAP kinase) inhibitor (SB203580; 1
      micromol l(-1)) and dexamethasone (10 micromol l(-1)), whereas inhibitors of
      p42/44 MAP kinase (PD98095; 10 micromol l(-1)), protein kinase C (Ro 31-8220; 1
      micromol l(-1)) and transcription factor nuclear factor kappa B (NF-kappaB)
      [pyrrolidinedithiocarbamate (PDTC) 100 micromol l(-1)] had practically no effect.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The results provide novel information on
      the cellular mechanisms involved in the interaction between L. rhamnosus GG and
      colon epithelial cells.

PMID- 15189285
TI  - Use of rpoB gene analysis for identification of nitrogen-fixing Paenibacillus
      species as an alternative to the 16S rRNA gene.
AB  - AIM: To avoid the limitations of 16S rRNA-based phylogenetic analysis for
      Paenibacillus species, the usefulness of the RNA polymerase beta-subunit encoding
      gene (rpoB) was investigated as an alternative to the 16S rRNA gene for taxonomic
      studies. METHODS AND RESULTS: Partial rpoB sequences were generated for the type
      strains of eight nitrogen-fixing Paenibacillus species. The presence of only one
      copy of rpoB in the genome of P. graminis strain RSA19(T) was demonstrated by
      denaturing gradient gel electrophoresis and hybridization assays. A comparative
      analysis of the sequences of the 16S rRNA and rpoB genes was performed and the
      eight species showed between 91.6-99.1% (16S rRNA) and 77.9-97.3% (rpoB)
      similarity, allowing a more accurate discrimination between the different species
      using the rpoB gene. Finally, 24 isolates from the rhizosphere of different
      cultivars of maize previously identified as Paenibacillus spp. were assigned
      correctly to one of the nitrogen-fixing species. CONCLUSIONS, SIGNIFICANCE AND
      IMPACT OF THE STUDY: The data obtained in this study indicate that rpoB is a
      powerful identification tool, which can be used for the correct discrimination of
      the nitrogen-fixing species of agricultural and industrial importance within the
      genus Paenibacillus.

PMID- 15189284
TI  - A PCR-based method that permits specific detection of Paenibacillus larvae subsp.
      larvae, the cause of American Foulbrood of honey bees, at the subspecies level.
AB  - AIMS: A reliable procedure for the identification of Paenibacillus larvae subsp.
      larvae, the causal agent of American Foulbrood disease of honey bees (Apis
      mellifera L.) based on the polymerase chain reaction (PCR) and subspecies -
      specific primers is described. METHODS AND RESULTS: By using ERIC-PCR, an
      amplicon of ca 970 bp was found among P. l. larvae strains but not in other
      closely related species. Based on the nucleotide sequence data of this amplicon,
      we designed the pair of oligonucleotides KAT 1 and KAT 2, which were assayed as
      primers in a PCR reaction. A PCR amplicon of the expected size ca 550 bp was only
      found in P. l. larvae strains. CONCLUSIONS: This PCR assay provides a specific
      detection for P. l. larvae. SIGNIFICANCE AND IMPACT OF THE STUDY: The developed
      PCR assay is highly specific because can differentiate Paenibacillus larvae
      subsp. larvae from the closely related Paenibacillus larvae subsp. pulvifaciens.
      The technique can be directly used to detect presence or absence of P. l. larvae
      spores in honey bee brood samples and contaminated honeys.

PMID- 15189286
TI  - Investigation of extended-spectrum beta-lactamases produced by clinical isolates
      of Klebsiella pneumoniae and Escherichia coli in Korea.
AB  - AIMS: Isolates obtained from various regions in Korea in 2002 were identified and
      their susceptibility to extended-spectrum cephalosporins, monobactams and/or
      cephamycins was studied along with any production of extended-spectrum beta
      lactamases (ESBLs). METHODS AND RESULTS: Bacteria identified by the conventional
      techniques and Vitek GNI card were Klebsiella pneumoniae and Escherichia coli.
      Using disk diffusion and double-disk synergy tests, we found that 39.2% of
      strains produced ESBLs. About 52% of isolates transferred resistance to
      ceftazidime by conjugation. Banding patterns of PCR amplification with the
      designed primers showed that 837- and 259-bp fragments specific to bla(TEM) genes
      were amplified in 63.3% of strains. 929- and 231-bp fragments (bla(SHV)), 847-
      and 520-bp fragments (bla(CMY)), 597- and 858-bp fragments (bla(CTX-M)) were
      amplified in 61.5, 17.3 and 7.7% of strains respectively. About 51.9% of strains
      contained more than two types of beta-lactamase genes. Especially, one strain
      contained bla(TEM), bla(CMY) and bla(CTX-M) genes. SIGNIFICANCE: Resistance
      mechanisms to beta-lactams, comprising mostly ESBL production, lead to the
      resistance against even recently developed beta-lactams in enterobacteria, which
      is now a serious threat to antibiotic therapy. The high prevalence of bla(CMY)
      genes and multidrug-resistant genes may also make therapeutic failure and lack of
      eradiation of these strains by extended-spectrum cephalosporins or cephamycins.

PMID- 15189287
TI  - Typical metabolic traits of two Oenococcus oeni strains isolated from
      Valpolicella wines.
AB  - AIMS: Physiological comparison of two indigenous Oenococcus oeni strains, U1 and
      F3 isolated in the same area (Valpolicella, Italy) in order to select a
      performant starter for MLF in wine. METHODS AND RESULTS: Growth rate, sugar and
      malate metabolism in FT80 media at pH 5.3 and 3.5 were analysed. The amount of
      total protein synthesized and the level of expression of the small Hsp Lo18 were
      evaluated by radiolabelling and immunodetection experiments after heat (42
      degrees C), acid (pH 3.5) and ethanol (12% v/v) stresses. Strain U1 showed
      significantly lower specific growth rate and growth yield in acid conditions than
      strain F3. However, strain U1 had a higher malate consumption capacity at pH 3.5
      than strain F3, in relation with an higher malolactic activity determined on
      whole cells. Strain U1 exhibited about half the total protein synthesis level
      than strain F3, but both strains expressed Lo18 similarly. Evaluation of
      malolactic fermentation (MLF) performance by microvinification trials was carried
      out. Strain U1 was able to complete MLF, whereas strain F3 degraded malic acid
      partially when inoculated in Amarone wine. CONCLUSIONS: Considering its
      performances in microvinifications experiments, strain U1 could be a good
      candidate for malolactic starter as an alternative to deficient commercial
      starters.

PMID- 15189288
TI  - Interaction between endophytic bacteria from citrus plants and the
      phytopathogenic bacteria Xylella fastidiosa, causal agent of citrus-variegated
      chlorosis.
AB  - AIMS: To isolate endophytic bacteria and Xylella fastidiosa and also to evaluate
      whether the bacterial endophyte community contributes to citrus-variegated
      chlorosis (CVC) status in sweet orange (Citrus sinensis [L.] Osbeck cv. Pera).
      METHODS AND RESULTS: The presence of Xylella fastidiosa and the population
      diversity of culturable endophytic bacteria in the leaves and branches of
      healthy, CVC-asymptomatic and CVC-symptomatic sweet orange plants and in
      tangerine (Citrus reticulata cv. Blanco) plants were assessed, and the in vitro
      interaction between endophytic bacteria and X. fastidiosa was investigated. There
      were significant differences in endophyte incidence between leaves and branches,
      and among healthy, CVC-asymptomatic and CVC-symptomatic plants. Bacteria
      identified as belonging to the genus Methylobacterium were isolated only from
      branches, mainly from those sampled from healthy and diseased plants, from which
      were also isolated X. fastidiosa. CONCLUSIONS: The in vitro interaction
      experiments indicated that the growth of X. fastidiosa was stimulated by
      endophytic Methylobacterium extorquens and inhibited by endophytic Curtobacterium
      flaccumfaciens. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides the
      first evidence of an interaction between citrus endophytic bacteria and X.
      fastidiosa and suggests a promising approach that can be used to better
      understand CVC disease.

PMID- 15189289
TI  - Antimicrobial activities of eucalyptus leaf extracts and flavonoids from
      Eucalyptus maculata.
AB  - AIMS: We investigated the antimicrobial activities of eucalyptus leaf extracts to
      find effective antibacterial agents. METHODS AND RESULTS: The antimicrobial
      activities of leaf extracts from 26 species of eucalyptus were measured. Extracts
      of Eucalyptus globulus, E. maculata and E. viminalis significantly inhibited the
      growth of six Gram-positive bacteria (Staphylococcus aureus, MRSA, Bacillus
      cereus, Enterococcus faecalis, Alicyclobacillus acidoterrestris,
      Propionibacterium acnes), and of a fungus (Trichophyton mentagrophytes), but they
      did not show strong antibacterial activity against Gram-negative bacteria
      (Escherichia coli, Pseudomonas putida). 2',6'-dihydroxy-3'-methyl-4'-methoxy
      dihydrochalcone, eucalyptin and 8-desmethyl-eucalyptin, isolated from E. maculata
      extracts, exhibited potent antimicrobial activities against seven micro-organisms
      with minimum inhibitory concentrations (MIC) ranging from 1.0 to 31 mg l(-1).
      CONCLUSIONS: The eucalyptus extracts and three compounds from E. maculata were
      found to be effective against micro-organisms that cause food poisoning, acne and
      athlete's foot. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows potential
      uses of extracts from E. globulus, E. maculata and E. viminalis, and
      antimicrobial compounds isolated from E. maculata.

PMID- 15189290
TI  - The Bacillus secretion stress response is an indicator for alpha-amylase
      production levels.
AB  - AIMS: Overproduced alpha-amylases in Bacillus subtilis provoke a specific stress
      response involving the CssRS two-component system, which controls expression of
      the HtrA and HtrB proteases. Previously, the B. subtilis TepA protein was
      implicated in high-level alpha-amylase secretion. Our present studies were aimed
      at investigating a possible role of TepA in secretion stress management, and
      characterizing the intensity of the secretion stress response in relation to
      alpha-amylase production. METHODS AND RESULTS: The expression of a
      transcriptional htrB-lacZ gene fusion, and the levels of alpha-amylase production
      were monitored simultaneously using tepA mutant B. subtilis strains. TepA was
      shown to be dispensable for secretion stress management. Importantly, however,
      the levels of htrB-lacZ expression can be correlated with the levels of alpha
      amylase production. CONCLUSION: Our observations show that the secretion stress
      response can serve as an indicator for alpha-amylase production levels.
      SIGNIFICANCE AND IMPACT OF STUDY: Conceivably, this stress response can be
      employed to monitor the biotechnological production of various secretory proteins
      by the Bacillus cell factory.

PMID- 15189291
TI  - Differential impact of some Aspergillus species on Meloidogyne javanica
      biocontrol by Pseudomonas fluorescens strain CHA0.
AB  - AIMS: The aim was to determine the influence of some Aspergillus species on the
      production of nematicidal agent(s) in vitro and biocontrol of Meloidogyne
      javanica in tomato by Pseudomonas fluorescens strains CHA0 and CHA0/pME3424.
      METHODS AND RESULTS: Six species of Aspergillus, isolated from the rhizosphere of
      certain crops, produced a variety of secondary metabolites in vitro. Culture
      filtrate (CF) obtained from Ps. fluorescens strain CHA0 and its2,4
      diacetylphloroglucinol overproducing mutant CHA0/pME3424 grown in King's B liquid
      medium caused significant mortality of M. javanica juveniles in vitro. Bacterial
      growth medium amended with CF of A. niger enhanced nematicidal and beta
      galactosidase activities of fluorescent pseudomonads while A. quadrilineatus
      repressed such activities. Methanol or ethyl acetate extracts of the CF of A.
      niger markedly optimized bacterial efficacy to cause nematode deaths while hexane
      extract of the fungus had no influence on the nematicidal activity of the
      bacterial strains. A. niger applied alone or in conjunction with the bacterial
      inoculants inhibited root-knot nematode galling in tomato. On the other hand, A.
      quadrilineatus used alone or together with CHA0 did not inhibit nematode galling
      but when used in combination with strain CHA0/pME3424 did reduce galling
      intensity. CONCLUSIONS: Aspergillus niger enhances the production of nematicidal
      compounds by Ps. fluorescensin vitro and improves biocontrol potential of the
      bacterial inoculants in tomato while A. quadrilineatus reduces bacterial
      performance to suppress root-knot nematodes. SIGNIFICANCE AND IMPACT OF THE
      STUDY: Rhizosphere harbours a variety of micro-organisms including bacteria,
      fungi and viruses. Aspergillus species are ubiquitous in most agricultural soils
      and generally produce a variety of secondary metabolites. Such metabolites
      synthesized by Aspergillus species may influence the production of nematicidal
      agents and subsequent biocontrol performance of the bacterial inoculants against
      plant-parasitic nematodes. This fact needs to be taken into consideration when
      using biocontrol strains in an agriculture system.

PMID- 15189292
TI  - Molecular heterogeneity among north Indian isolates of Group A Streptococcus.
AB  - AIM: To monitor molecular heterogeneity among the clinical isolates of group A
      Streptococcus (GAS) from north India by Vir and emm typing. METHODS AND RESULTS:
      GAS isolates, 31 from pharyngitis and nine from rheumatic fever (RF)/rheumatic
      heart disease (RHD) patients were differentiated into 16 Vir types (VT). These
      isolates were further discriminated into 23 emm types. Most of emm types were Vir
      type specific, except few (7.5%), which revealed different Vir types within same
      emm type. The most prevalent emm type found was emm 49 (15%) followed by 7.5% of
      emm 69, emm 71 and emm 75 which were different from emm type distribution
      reported from south India. CONCLUSIONS: Analysis of data revealed 40%
      heterogeneity by Vir typing and 57.5% by emm typing among GAS isolates which is
      significant in view of small number of isolates studied. SIGNIFICANCE OF IMPACT
      OF THE STUDY: The molecular study for the first time demonstrates different emm
      types prevalent and circulating in northern region of India and such data may
      help in selection of types for vaccine development.

PMID- 15189293
TI  - Bacillus thuringiensis serovar shandongiensis strain 89-T-34-22 produces multiple
      cytotoxic proteins with similar molecular masses against human cancer cells.
AB  - AIMS: To prove that Bacillus thuringiensis serovar shandongiensis strain 89-T-34
      22 produces several novel cytotoxic proteins against human leukaemic T cells.
      METHODS AND RESULTS: Parasporal inclusion protein was solubilized and processed
      by proteinase K and was separated by anion-exchange chromatography. Cytopathic
      effects of each fraction against MOLT-4 and Jurkat cells were monitored.
      CONCLUSIONS: Existence of at least two novel cytotoxic proteins was suggested and
      N-terminal sequences of the newly identified proteins were determined to be
      QSTTDVIREY and X (Y or I) (P or I) NLANELA (X indicates uncertain amino acids).
      Molecular masses of the two proteins were approx. 27-28 kDa. SIGNIFICANCE AND
      IMPACT OF THE STUDY: In this study, we demonstrated that the strain 89-T-34-22
      produces at least two novel cytotoxic proteins with similar molecular masses
      against human cancer cells. This is the first strain of B. thuringiensis which
      produces multiple cytotoxic proteins against human cancer cells.

PMID- 15189294
TI  - Antimicrobial activity of isocytisoside and extracts of Aquilegia vulgaris L.
AB  - AIMS: The aim of this study was to analyse the antimicrobial properties extracts
      of Aquilegia vulgaris, and their principial flavonoid component and to compare
      the obtained results with the activity of gentamicin and nystatin. METHODS AND
      RESULTS: The ethanol, acetone and isopropanol extracts as well as the subextracts
      isolated from the methanol extract together with the main flavonoid: 4'-methoxy
      5,7-dihydroxyflavone 6-C-glucoside (isocytisoside) were obtained from the leaves
      with stems of Aquilegia vulgaris L. All the extracts were analysed by TLC to
      confirm flavonoids and phenolic acids occurrence. The antimicrobial activity was
      tested by the method of series dilutions against different Gram-positive, Gram
      negative bacteria and also fungi. The results have shown that the extracts,
      subextracts and isocytisoside inhibit growth of all studied micro-organisms,
      revealing the greatest activity against Gram-positive Staphylococcus aureus,
      Staph. epidermidis and the mould Aspergillus niger. CONCLUSIONS: The
      antimicrobial activity of the tested materials it is possibly related to the
      content of isocytisoside. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has
      determined new activity of A. vulgaris and suggested the necessity of further
      studies.

PMID- 15189295
TI  - Application of electrospray ionization mass spectrometry in rapid typing of
      fengycin homologues produced by Bacillus subtilis.
AB  - AIMS: To rapidly type the fengycin homologues produced by Bacillus subtilis
      strains with electrospray ionization/collision-induced dissociation (ESI/CID)
      mass spectrometry. METHODS AND RESULTS: Fengycin homologues produced by Bacillus
      subtilis JA were analysed. When each homologue was subjected to ESI/CID analysis,
      ions representing characteristic fragmentations were detected. These ions can
      help to identify the homologues; even homologues of the same nominal mass can be
      discriminated by their ESI/CID spectra. Based on the CID results, fengycin
      homologues can be correctly assigned. CONCLUSIONS AND SIGNIFICANCE OF THIS STUDY:
      ESI/CID leads to rapid detection and structural characterization of fengycin
      homologues or lipopeptides with similar properties. It will be very useful in
      studying the regulatory expression of these peptides.

PMID- 15189296
TI  - Comparison of the biotypes of Yersinia enterocolitica isolated from pigs, cattle
      and sheep at slaughter and from humans with yersiniosis in Great Britain during
      1999-2000.
AB  - AIMS: To investigate the relationship between livestock carriage of Yersinia
      enterocolitica and human disease. The biotypes/serotypes of strains recovered
      from the faeces of pigs, cattle and sheep at slaughter during a national survey
      in Great Britain in 1999-2000, were compared with those of strains isolated from
      human cases of yersiniosis during the same period. METHODS AND RESULTS: The
      faecal carriage of Y. enterocolitica by cattle, sheep and pigs at slaughter was
      6.3, 10.7 and 26.1%, respectively. Yersinia enterocolitica biotype (BT) 1a was
      the most frequently isolated biotype from livestock (58%) and was the predominant
      biotype (53%) isolated from human cases over the same period. The main recognized
      pathogenic Y. enterocolitica biotype isolated from livestock was BT3 (O:5,27)
      (35% of sheep, 22% of pigs and 4% of cattle) but this biotype was not detected in
      any of the human isolates investigated. The major pathogenic biotypes of strains
      isolated from humans were BT3 (O:9) (24%) and BT4 (O:3) (19%) whereas of the
      veterinary isolates investigated, only pigs (11%) carried BT3 (O:9) strains.
      CONCLUSIONS: Because of significant overlaps in phenotypes of the veterinary and
      human strains it is not possible to comment on the correlation between host and
      pathogenicity, especially of biotype 1a. SIGNIFICANCE AND IMPACT OF THE STUDY:
      The data suggest that further investigations using methods with greater
      discriminatory power are required. However the data also suggests that pigs may
      be the primary reservoir for human pathogenic Y. enterocolitica infection.

PMID- 15189297
TI  - Design of a 5' exonuclease-based real-time PCR assay for simultaneous detection
      of Bacillus licheniformis, members of the 'B. cereus group' and B. fumarioli in
      gelatine.
AB  - AIMS: The design of a fast, sensitive and specific detection method for Bacillus
      licheniformis, members of the 'B. cereus group' and B. fumarioli in gelatine.
      METHODS AND RESULTS: Specific Taqman probes were designed and tested in a real
      time PCR setting. A specific fluorescent signal could be obtained for all
      gelatine isolates attributed to these species in one single real-time PCR
      reaction. After sample preparation, a gelatine sample spiked with 1 CFU provided
      enough template DNA for a significant signal. CONCLUSION: The potential of a real
      time PCR assay for simultaneous detection of B. licheniformis, members of the 'B.
      cereus group' and B. fumarioli in gelatine is demonstrated. SIGNIFICANCE AND
      IMPACT OF THE STUDY: Implementation of the assay in gelatine producing plants may
      shorten delivery terms and inform on hazards to public health and suitable
      remediation procedures.

PMID- 15189298
TI  - Idiosyncratic toxicity associated with potentiated sulfonamides in the dog.
AB  - Idiosyncratic toxicity to potentiated sulfonamides occurs in both humans and
      dogs, with considerable clinical similarities. The syndrome in dogs can consist
      of fever, arthropathy, blood dyscrasias (neutropenia, thrombocytopenia, or
      hemolytic anemia), hepatopathy consisting of cholestasis or necrosis, skin
      eruptions, uveitis, or keratoconjunctivitis sicca. Other manifestations seen less
      commonly include protein-losing nephropathy, meningitis, pancreatitis,
      pneumonitis, or facial nerve palsy. The pathogenesis of these reactions is not
      completely understood, but may be due to a T-cell-mediated response to proteins
      haptenated by oxidative sulfonamide metabolites. Our laboratory is working on
      tests to characterize dogs with possible idiosyncratic sulfonamide reactions, to
      include ELISA for anti-drug antibodies, immunoblotting for antibodies directed
      against liver proteins, flow cytometry for drug-dependent anti-platelet
      antibodies, and in vitro cytotoxicity assays. The management of idiosyncratic
      sulfonamide toxicity involves client education to identify clinical signs early
      and allow rapid drug discontinuation, supportive care to include possibly
      ascorbate and glutathione precursors, and avoidance of subsequent re-exposure. It
      is important to realize that only antimicrobial sulfonamides, such as
      sulfamethoxazole, sulfadiazine, and sulfadimethoxine, share this clinical
      syndrome. There is no evidence for cross-reactivity with drugs that have
      different underlying structures but share a sulfonamide moiety, such as
      acetazolamide, furosemide, glipizide, or hydrochlorthiazide.

PMID- 15189299
TI  - Allometric analysis of ciprofloxacin and enrofloxacin pharmacokinetics across
      species.
AB  - The purpose of this study was to examine the allometric analysis of ciprofloxacin
      and enrofloxacin using pharmacokinetic data from the literature. The
      pharmacokinetic parameters used were half-life, clearance and volume of
      distribution. Relationships between body weight and the pharmacokinetic parameter
      were based on the empirical formula Y = aW(b), where Y is half-life, clearance or
      volume of distribution, W the body weight and a is an allometric coefficient
      (intercept) that is constant for a given drug. The exponential term b is a
      proportionality constant that describes the relationship between the
      pharmacokinetic parameter of interest and body weight. A total of 21 different
      species of animals were studied. Results of the allometric analyses indicated
      similarity between clearance and volume of distribution as they related to body
      weight for both drugs. Results of the current analyses indicate it is possible to
      use allometry to predict pharmacokinetic variables of enrofloxacin or
      ciprofloxacin based on body size of species. This could provide information on
      appropriate doses of ciprofloxacin and enrofloxacin for all species.

PMID- 15189300
TI  - Treatment of canine pyoderma with ibafloxacin and marbofloxacin--fluoroquinolones
      with different pharmacokinetic profiles.
AB  - Dogs with superficial or deep pyoderma (n = 228) presented to first opinion
      veterinarians (n = 20) were treated orally with either ibafloxacin, at a dosage
      of 15 mg/kg, or marbofloxacin, at a dosage of 2 mg/kg, once daily for 3-16 weeks.
      On initial presentation, 35% of the cases were classified as having recurrent
      pyoderma and 40% as having deep pyoderma. Staphylococci (mainly Staphylococcus
      intermedius) were isolated from over 90% of the cases. The average treatment
      periods were 41 +/- 26 and 38 +/- 21 days in the ibafloxacin and marbofloxacin
      groups, respectively. One week after the cessation of treatment, 74 and 81% of
      dogs (P > 0.05) in the ibafloxacin and marbofloxacin groups, respectively, were
      classified as having responded to treatment. One month after the cessation of
      treatment, 70% of the dogs in each group were still classified as cured or
      improved, and 3 and 11% (P < 0.05) in the ibafloxacin and marbofloxacin groups,
      respectively, were classified as having relapsed. Despite having different
      pharmacokinetic profiles, ibafloxacin and marbofloxacin produced similar results
      when used under field conditions at the recommended dosages.

PMID- 15189301
TI  - Pharmacokinetics of ciprofloxacin after single intravenous and repeat oral
      administration to cats.
AB  - The pharmacokinetic properties of ciprofloxacin, a second-generation
      fluoroquinolone, were investigated in six cats after single intravenous and
      repeat oral administration at a dosage of 10 mg/kg b.i.d. Ciprofloxacin serum
      concentration was analyzed by microbiological assay using Klebsiella pneumoniae
      ATCC 10031 as microorganism test. Serum ciprofloxacin disposition was best fitted
      to a bicompartmental and a monocompartmental open models with first-order
      elimination after intravenous and oral dosing respectively. After intravenous
      administration, distribution was rapid (t(1/2(d)), 0.22 +/- 0.23 h) and wide as
      reflected by the steady-state volume of distribution of 3.85 +/- 1.34 L/kg.
      Furthermore, elimination was rapid with a plasma clearance of 0.64 +/- 0.28
      L/h.kg and a t(1/2(el)) of 4.53 +/- 0.74 h. After repeat oral administration,
      absorption was rapid with a half-life of 0.23 +/- 0.22 h and T(max) of 1.30 +/-
      0.67 h. However bioavailability was low (33 +/- 12%), the peak plasma
      concentration at steady-state was 1.26 +/- 0.67 microg/mL. Drug accumulation was
      not significant after seven oral administrations. When efficacy predictors were
      estimated ciprofloxacin showed a good profile against gram-negative bacteria when
      administered either intravenously or orally, although its efficacy against gram
      positive microorganisms is lower.

PMID- 15189302
TI  - Bioavailability and pharmacokinetics of florfenicol in healthy sheep.
AB  - A study on bioavailability and pharmacokinetics of florfenicol was conducted in
      20 crossbred healthy sheep following a single intravenous (i.v.) and
      intramuscular (i.m.) doses of 20 and 30 mg/kg body weight (b.w.). Florfenicol
      concentrations in serum were determined by a validated high-performance liquid
      chromatography method with UV detection at a wavelength of 223 nm in which serum
      samples were spiked with chloramphenicol as internal standard. Serum
      concentration-time data after i.v. administration were best described by a three
      compartment open model with values for the distribution half-lives (T(1/2alpha))
      1.51 +/- 0.06 and 1.59 +/- 0.10 h, elimination half-lives (T(1/2beta)) 18.83 +/-
      6.76 and 18.71 +/- 1.85 h, total body clearance (Cl(B)) 0.26 +/- 0.03 and 0.25 +/
      0.01 L/kg/h, volume of distribution at steady-state (V(d(ss))) 1.86 +/- 0.11 and
      1.71 +/- 0.20 L/kg, area under curve (AUC) 76.31 +/- 9.17 and 119.21 +/- 2.05
      microg.h/mL after i.v. injections of 20 and 30 mg/kg b.w. respectively. Serum
      concentration-time data after i.m. administration were adequately described by a
      one-compartment open model. The pharmacokinetic parameters were distribution half
      lives (T(1/2k(a) )) 0.27 +/- 0.03 and 0.25 +/- 0.09 h, elimination half-lives
      (T(1/2k(e) )) 10.34 +/- 1.11 and 9.57 +/- 2.84 h, maximum concentrations (C(max))
      4.13 +/- 0.29 and 7.04 +/- 1.61 microg/mL, area under curve (AUC) 67.95 +/- 9.61
      and 101.95 +/- 8.92 microg.h/mL, bioavailability (F) 89.04% and 85.52% after i.m.
      injections of 20 and 30 mg/kg b.w. respectively.

PMID- 15189304
TI  - Disposition of flunixin meglumine injectable preparation administered orally to
      healthy horses.
AB  - An injectable preparation of flunixin meglumine was administered orally and
      intravenously at a dose of 1.1 mg/kg to six healthy adult horses in a cross-over
      design. Flunixin meglumine was detected in plasma within 15 min of administration
      and peak plasma concentrations were observed 45-60 min after oral administration.
      Mean bioavailability of the oral drug was 71.9 +/- 26.0%, with an absorption half
      life of 0.76 h. The apparent elimination half-life after oral administration was
      2.4 h. The injectable preparation of flunixin meglumine is suitable for oral
      administration to horses.

PMID- 15189303
TI  - Interrelationships among physicochemical properties, absorption and anthelmintic
      activities of 2-desoxoparaherquamide and selected analogs.
AB  - The interrelationships between physicochemical properties, absorption and potency
      of 2-desoxoparaherquamide and five analogs, representing a new anthelmintic
      class, were evaluated in in vitro and in vivo assays. At pH 7.5, rates of drug
      absorption by the gastrointestinal nematode Haemonchus contortus and jird small
      intestine, parameterized by the permeability coefficient, P(e), ranged from 1.2
      2.4 x 10(-4) cm/min (nematode) to 2.5-5.5 x 10(-3) cm/min (jird). In the jird
      intestine, absorption was pH-dependent, with P(e) at pH 7.5 being twice that at
      pH 4.5, reflecting the negative influence of protonation on transport of these
      weakly basic molecules. Each compound rapidly paralyzed H. contortus during in
      vitro exposure to therapeutically relevant concentrations (1-10 microm). The
      kinetics of drug action on motility in vivo mirrored their in vitro effects;
      motility concentrations were reduced in nematodes collected from jird stomach 3 h
      following oral drug dosing, by which time > or =50% clearance of the parasites
      had occurred. The nematode/medium partition coefficient K ranged from 10.1 to
      16.1, consistent with the lipophilic nature of the compounds. The time required
      to reduce motility in vitro by 50% (t50*) and P(e) were used to determine C(n)*,
      the concentration of drug in the nematode at t50*, as an indicator of intrinsic
      potency. In the jird, the apparent potencies of the compounds were insensitive to
      route of administration (i.e. oral = i.v. = i.p. = i.m.) for H. contortus and two
      other gastrointestinal nematodes, Ostertagia ostertagi and Trichostrongylus
      colubriformis; topical administration, however, required three to 10-fold higher
      doses for equivalent efficacy.

PMID- 15189305
TI  - The pharmacokinetics of topical doramectin in llamas (Lama glama) and alpacas
      (Lama pacos).

PMID- 15189306
TI  - Prediction of demand for treatment of temporomandibular disorders based on a 20
      year follow-up study.
AB  - The purpose was to test the hypothesis that signs and symptoms characteristic of
      temporomandibular disorders (TMD) at age 15 would predict demand for treatment
      during a 20-year follow-up period. Of originally 135 examined 15-year-old
      subjects, 103 completed a questionnaire and 84 were examined clinically at the 10
      year follow-up (at age 25). After 20 years (at age 35), 114 completed a
      questionnaire and 100 were also examined clinically. During the 20-year follow-up
      period, 21 subjects received some kind of treatment of TMD. At baseline (age 15),
      the treated group reported tooth grinding at night more often than the non
      treated group (P = 0.0042). At the 10-year follow-up (at age 25), the treated
      group reported more symptoms of TMD and oral parafunctions than the non-treated
      group. Among the clinical registrations, there was only one significant
      difference between the groups: anterior tooth wear was more extensive in the
      treated group. At the 20-year follow-up (at age 35), the treated group reported
      significantly more symptoms of TMD and oral parafunctions than the non-treated
      group. The clinical dysfunction index was also higher in the treated group.
      Logistic regression revealed tooth grinding at night as a significant predictor
      of received treatment of TMD. However, the positive predictive value was low
      whereas the negative predictive value was high (90%). The findings indicate that
      nocturnal tooth grinding is related to demand for treatment of TMD.

PMID- 15189307
TI  - Oral parafunctions and association with symptoms of temporomandibular disorders
      in Japanese university students.
AB  - We examined whether oral parafunctions are associated with symptoms of
      temporomandibular disorders (TMD) in 3557 Japanese university students, aged
      between 18 and 26 years. Participants completed a questionnaire regarding various
      oral parafunctions and subjective symptoms related to TMD, and underwent a dental
      examination. The prevalence of temporomandibular joint (TMJ) noise, TMJ pain and
      impaired mouth opening was 41.7, 16.0 and 16.3%, respectively. The most prevalent
      parafunction was sleeping on one side (60.2%), followed by supporting the jaw by
      leaning on the palm of the hand (44.8%). Mean age, decayed, missing and filled
      teeth, and number of teeth were not significantly different between TMD positive
      and negative groups according to unpaired t-test. The chi-squared test revealed
      that the ratio of females was significantly higher among students with TMD than
      without TMD. Multiple logistic regression models adjusted for age and gender
      demonstrated that chewing on one side caused an increased risk of TMJ noise [odds
      ratio (OR) = 1.52, P < 0.001], TMJ pain (OR = 1.54, P < 0.001), and impaired
      mouth opening (OR = 2.00, P < 0.001). Tooth clenching also increased the risk of
      TMJ noise (OR = 1.86, P < 0.001), TMJ pain (OR = 1.79, P = 0.001) and impaired
      mouth opening (OR = 1.88, P < 0.001). Further prospective cohort studies,
      including other potential risk factors, are required to clarify these
      relationships.

PMID- 15189308
TI  - Effects of a functional appliance on masticatory muscles of young adults
      suffering from muscle-related temporomandibular disorders.
AB  - The aim of this study was to investigate the effects of an original orthodontic
      functional appliance [function generating bite for deep bite correction (FGB-D)]
      on masticatory muscle activity in subjects suffering from muscle-related
      temporomandibular disorders (TMD). Electromyographic (EMG) analysis was performed
      on 33 young adults (nine men, 24 women) to evaluate the contractile symmetry of
      the right and left masseter and anterior temporalis muscles. The subjects were
      divided into three groups: a muscle-related TMD group requiring orthodontic
      treatment for deep bite correction (three men, eight women) and treated with FGB
      D; a muscle-related TMD group not requiring orthodontic treatment (three men,
      eight women) and treated with a Michigan occlusal splint; and a TMD-free group
      (three men, eight women) as a control group. Records were made by surface EMG of
      maximum voluntary teeth clenching, with and without the functional appliance or
      occlusal splint in place, before and after 12 months of therapy. A torque index
      was derived from the surface EMG recordings to estimate lateral displacement of
      the mandible. The results show that the FGB-D corrects the torque index and thus
      the lateral displacement of the mandible.

PMID- 15189309
TI  - The effect of an interocclusal appliance on bite force and masseter
      electromyography in asymptomatic subjects and patients with temporomandibular
      pain and dysfunction.
AB  - The aims of this study were to assess the effect of clenching with or without the
      presence of an interocclusal appliance (IOA) on bite force (BF) and masseter
      electromyography (EMG) in patients with temporomandibular pain dysfunction
      disorders (TMPD) and to compare these results with an asymptomatic age- and
      gender-matched control group. Ten patients with TMPD (mean age 26.9 years) were
      compared with eight healthy controls (mean age 25.3 years). Bilateral masseter
      EMG activity was recorded at rest, while clenching on the BF meter, while
      clenching on an IOA and while clenching on an IOA together with the BF meter.
      Significant left to right EMG activity asymmetry was found in the patient group
      at rest and during multiple clenching tasks in the control group. The patient
      group had significantly greater EMG activity at rest than controls. For all other
      tasks, the control group EMG activity was greater than the patient group. Use of
      an IOA significantly decreased EMG activity in both patient and control groups.
      BF was significantly greater in the control group on the right side for the
      different clenching tasks. Insertion of the IOA significantly increased BF in the
      control group. The results of this study indicate differences in EMG activity and
      BF during different clenching tasks and between patients with TMPD and
      asymptomatic subjects.

PMID- 15189310
TI  - Evaluation of proximal tooth contact tightness at rest and during clenching.
AB  - The aims of this study were to develop a device for measuring the tightness of
      proximal tooth contact and to evaluate the proximal contact tightness using this
      device at rest and during clenching. Twenty young adult volunteers with healthy
      dentition participated in this experiment. The tightness of proximal tooth
      contact between the second premolar and the first molar of both the maxilla and
      the mandible was measured by pulling a stainless steel strip between them at
      rest, and at 20 and 50% clenching levels of maximum voluntary contraction of
      masseter muscles at intercuspal position. Proximal contact tightness increased as
      the clenching levels of both the maxilla and the mandible increased. At rest,
      proximal contact tightness was less in the maxilla than in the mandible, whereas
      during clenching it was less in the mandible. These results indicate that during
      clenching, the teeth are displaced and they contact appropriately with adjacent
      teeth, making it possible to exert sufficient occlusal force while maintaining
      the integrity of dental arches.

PMID- 15189311
TI  - Influence of the inclination of the plate of an intra-oral tracing device on the
      condylar position registered by tapping movement.
AB  - The object of this study was to determine the best inclination of the intra-oral
      tracing device to get optimum condylar position with the registration of tapping
      movement. Three appliances with different tracing plate inclinations were used in
      five healthy subjects. The tracing plates were set at 0 degrees to occlusal plane
      (horizontal); at the angle formed by drawing a line from condylar point to the
      stylus position at occlusal plane (inclined); then at the angle half to inclined
      (half-inclined). Subjects made Gothic arch and tapping movements (n = 30) at a 30
      mm interincisal distance with the head Camper plane horizontal. The incisal and
      condylar points were tracked with a 6-degree-of-freedom jaw movement tracking
      system. The location of gothic arch apex, the distribution and mean position of
      30 tapping points from intercuspal position were analyzed in incisal and condylar
      point between the appliances. Data were analyzed with repeated measures one-way
      anova. Results showed that mean position of tapping points were significantly
      different among the appliances. Half-inclined appliance recorded tapping points
      in a convergent area nearer to intercuspal position (IP) than other appliances.
      In all appliances, the contact points of the tapping movement were anterior to
      Gothic arch apex.

PMID- 15189312
TI  - Functional impression and jaw registration: a single session procedure for the
      construction of complete dentures.
AB  - The conventional fabrication of complete dentures involves two separate clinical
      sessions for functional impression making and jaw registration. The presented
      method combines both procedures in one session. The aim of this study was to
      survey the three-dimensional tooth positions in complete dentures with reference
      to the ridges to establish arbitrary guideline values that could be used for the
      manufacturing of tooth-position analogue plastic rims on functional impression
      trays. New complete dentures were fabricated by supervised undergraduate students
      in the conventional manner for 104 edentulous patients. The position of the
      maxillary teeth was surveyed in the horizontal plane using the Schmuth 'vizor
      measuring plate'. The vertical dimension of occlusion, represented as the
      distance between opposing ridge areas of the dentures in maximum intercuspation,
      was measured at different sites by means of a Gutowski gauge. The tooth positions
      on the dentures varied widely, e.g. the horizontal distances between the incisive
      papilla and the maxillary incisors was 7.1 +/- 2.3 (3-14) mm. The vertical
      dimension of occlusion, which is most important in the jaw registration, varied
      equally with an anterior inter-alveolar distance between 12 and 33 (20.4 +/- 4.0)
      mm. Arbitrary moulding of the tooth position-analogue plastic rims does not seems
      to be an ideal method of pre-shaping functional impression trays, because the
      individual anatomical variation is considerable. Alternatively, the horizontal
      and vertical tooth positions of functionally and aesthetically pleasing dentures
      should be measured to pre-shape the rims of functional impression trays in the
      maxillary and the mandibular jaw. Such trays are a valuable tool for functional
      impressions and an immediate preliminary jaw registration in the fabrication of
      new complete dentures. This method allows a first try-in of the full set-up in
      the third clinical visit without loosing precision.

PMID- 15189313
TI  - The bitewing radiograph as an assessment tool in fixed prosthodontics.
AB  - Molar crown preparations, as described in the literature, have standard forms
      dictated by the demands of retention, resistance and the physical properties of
      materials. Standard designs may not be appropriate for all patients because of
      ethnic variations in tooth shape, pulp size and dentine thickness. Accurate data
      on these features could assist clinicians to minimize the risk of accidental
      pulpal injury. The aim of this study was to compare the first molar crown and
      pulp dimensions between Asian (Chinese, Korean, Malay) and other ethnic groups,
      using measurements from the bitewing radiographs of 121 subjects. Comparisons
      revealed the following significantly different features of Asian first molars:
      larger total pulp areas in uppers (P < 0.0005); shorter crowns (P < 0.0005);
      narrower upper teeth at the cervix (P < 0.0005); wider pulps at the cervix of
      lowers (P < 0.02); more bulbous crowns (P < 0.0005 for uppers; P < 0.01 for
      lowers), and finally significantly thinner dentine interproximally at the cervix
      (P=0.001 for uppers; P=0.011 for lowers). Preparations with wide shoulders could
      pose hazards to the pulps in Asian subjects. This study emphasizes the value of
      bitewing films in assessing crown and pulp size and shape before making crown
      preparations. The experienced practitioner may intuitively include tooth and pulp
      morphology in treatment planning, but this appears not to be taught or documented
      in textbooks.

PMID- 15189314
TI  - Effect of saliva on an antimicrobial tissue conditioner containing silver
      zeolite.
AB  - The purpose of this study was to evaluate the influence of human saliva on the
      antimicrobial effect of a tissue conditioner containing an antibiotic agent,
      silver-zeolite. Samples of each tissue conditioner with or without silver-zeolite
      were prepared and a plastic disk was used as a control. Candida albicans and
      nosocomial respiratory infection-causing bacteria, Staphylococcus aureus,
      methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa and the
      Streptococcus milleri group (S. constellatus and S. intermedius), were selected
      as test microorganisms. Antimicrobial effects of samples after water or saliva
      immersion for 28 days were evaluated by counting the number of viable cells
      [colony forming unit (CFU)] in each microbial suspension (100 microL). All data
      were statistically analysed by one-way anova and Bonferroni's test (P < 0.05).
      The antimicrobial effects of samples with silver-zeolite immersed in saliva
      against C. albicans, S. aureus and MRSA were observed while CFU of P. aeruginosa
      indicated no significant difference from that of the control. As for the S.
      milleri group, its CFU after saliva immersion showed the significantly smaller
      value than that of the control. It is concluded that the antimicrobial effects of
      samples containing silver-zeolite against all tested microbes except for P.
      aeruginosa and the S. milleri group are not influenced by saliva immersion for 28
      days.

PMID- 15189315
TI  - Effects of self-etching primers on vascular responses in rat carotid artery.
AB  - To investigate the effect of self-etching bonding systems on the control of
      pulpal haemorrhage in direct pulp exposures by observing the contraction of pulp
      blood vessels using the rat carotid artery model. Six dentine-bonding agents (Mac
      Bond, One-Up Bond F, Clearfil SE Bond, FL Bond, Prompt L-Pop and Prime and Bond
      NT) were used. The efficacy of bonding agents were compared with that of
      epinephrine for dose and the contraction forces (vasoconstriction) induced on the
      smooth muscle and the results recorded using a force displacement transducer.
      Dose-dependent relaxations caused by the test materials were recorded in the same
      manner in comparison with papaverine. FL Bond, SE Bond, One Up Bond, Mac Bond
      produced dose-dependent relaxations, while Prompt L-Pop and Prime&Bond NT
      produced epinephrine-like contractions on the rat carotid artery. For self
      etching primers, which produce vascular relaxation, haemorrhage control with
      additional chemicals should be considered if direct pulp capping is to be
      performed using such adhesive systems.

PMID- 15189316
TI  - The effect of dentin desensitizers on thermal changes in the pulp chamber during
      fabrication of provisional restorations.
AB  - The purpose of this study was to evaluate the effect of two dentin desensitizers
      on the pulp chamber temperature increase during fabrication of provisional
      restorations by a direct method. Sixty intact extracted mandibular third molars
      were prepared for a metal-ceramic complete crown. Then the teeth were randomly
      divided into three groups of 20 each. Group 1, no dentin desensitizer was used as
      the control group; group 2, a resin-based dentin desensitizer was selected; and
      group 3, the prepared teeth surfaces were coated with polyurethane cyanoacrylate
      adhesive. Each of the three groups was further divided into two polymerizing
      systems (autopolymerizing and a photopolymerizing) of 10 each. After insertion of
      the resin-filled matrix, the temperature change in the pulpal chamber was
      recorded with thermocouple connected to a data logger. anova indicated no
      significant differences for all combinations of desensitizing agents and curing
      methods (P > 0.05). When light cured composite or chemical curing acrylics were
      used to make temporary crowns, the presence of desensitizing agent did not reduce
      the temperature transmitted from the provisional material; the residual
      temperature rise transmitted was of such a magnitude as to cause concern
      regarding possible thermal injury to pulp.

PMID- 15189317
TI  - The retentive effects of pre-fabricated posts by luting cements.
AB  - The purpose of this study was to compare the retention of two different pre
      fabricated posts cemented to the root canal with four different adhesive luting
      cements and a zinc phosphate cement. The crowns of 100 freshly extracted human
      mandibular central and lateral incisors were removed at the cementoenamel
      junction and divided into two main groups (A = ParaPost and B = Flexi-Post) and
      further divided into five subgroups to evaluate the effects of five different
      cements (Rely-X ARC, Panavia F, ParaPost Cement, Flexi-Flow Natural and Adhesor)
      each with 10 samples. Post-holes were prepared on all of the roots following the
      manufacturer's instructions. Each sample was placed into a specialized jig and
      tensile strength tests performed by using testing machine with a crosshead speed
      of 0.638 cm min(-1) and force applied until failure. The data were analysed with
      one-way anova (Post Hoc a Scheffe's S test) and two-way anova (P < 0.001). The
      Flexi-Post dowels had a mean of 54.21 kg (s.d. = 9.37) and demonstrated
      statistically higher retention than ParaPost dowels with a mean of 33.93 kg (s.d.
      = 10.69) for all of the cement groups (P < 0.001). In Flexi-Post and ParaPost
      dowel groups; Rely-X ARC was statistically higher than the Panavia F, ParaPost
      Cement, Flexi-Flow Natural and Adhesor (P < 0.05). Adhesor was significantly
      lower than the other subgroups (P < 0.05). Resin luting cements have demonstrated
      very high tensile strength potential for a strong bond to dentin.

PMID- 15189318
TI  - In vitro evaluation of the effect of core diameter for removing radicular post
      with ultrasound.
AB  - The removal of radicular posts for endodontic reasons as well as their
      replacement is a common procedure in dental practice. The use of ultrasound is
      becoming a standard practice since it reduces the stress to displace the core
      from the canal minimizing the risks of root fractures, perforations and further
      wearing of dental structure. Thus, the objective of this study was to evaluate
      the effect of a reduction in the core diameter when removing radicular posts with
      ultrasound. Twenty-four teeth were divided in two groups. Group I received posts
      with the dowel and core of the same diameter (1.7 mm) and group II received posts
      with the dowel diameter 2 mm larger (3.7 mm) than the core diameter. Zinc
      phosphate cement was used to cement the posts in all groups. Half of the samples
      of each group received ultrasonic energy for 8, 2 min for each face. All samples
      were submitted to traction on an Instron machine (model 4444). Data were analysed
      statistically with anova and the Tukey test, revealing significant differences (P
      < 0.05) between groups. The authors concluded that the mean tension necessary to
      displace the posts from the roots was reduced by 26% when ultrasound was applied.
      The reduction of the post-diameter reduced the necessary tension to remove them
      by 24% compared with larger posts.

PMID- 15189320
TI  - Oral health-related quality of life in southern Chinese following radiotherapy
      for nasopharyngeal carcinoma.
AB  - Although the complications of head and neck radiotherapy in the treatment of
      nasopharyngeal carcinoma (NPC) have been described, there is limited information
      on the effect of oral complications on oral health related quality of life. The
      aim of this study was to describe the psychosocial and functional impact of oral
      conditions in southern Chinese following radiotherapy for NPC. A cross-sectional
      study design was used with a sample of 109 subjects including NPC survivors,
      newly diagnosed NPC cases and a control group. Oral health related quality of
      life was assessed through the SF-36 and the Oral Health Impact Profile measures
      and a dry mouth measure. Data on socio-demographic variables and treatment
      seeking were also collected. The psychosocial and functional impact of oral
      conditions as revealed by the health status measures was significantly greater in
      NPC survivors than newly diagnosed NPC cases and controls. The oral specific and
      condition specific measures appeared to discriminate more effectively between
      groups than the generic measure. NPC survivors sought significantly more dental
      treatment than the other groups. The oral complications of radiotherapy for NPC,
      notably sequelae of salivary gland damage, have a significant negative effect on
      oral health related quality of life and result in an increased burden of dental
      care in the long-term.

PMID- 15189319
TI  - Corrosion behaviour of high copper dental amalgams.
AB  - This study evaluated the corrosion behaviour of two high copper dental amalgam
      alloys [Dispersalloy (Dentsply-Caulk) and Tytin (Kerr)] in different
      electrolytes. Amalgam specimens were prepared, coupled to a copper wire, cemented
      into glass tubes and polished to a 600-grit finish. A corrosion cell was prepared
      using a carbon counter-electrode, a standard calomel electrode as the reference
      and amalgam as the working electrode. The alloys were tested in the following
      mediums at 37 degrees C: (i) artificial saliva based on Fusayama's solution (FS),
      (ii) artificial saliva with citric acid adjusted to pH 4.0 (FC) and (iii) 1%
      sodium chloride solution (SC). Corrosion potentials (E(corr)) and corrosion rates
      (I(corr)) were determined using potentiostatic and impedance spectroscopy
      methods. Data was subjected to anova/Scheffe's post hoc test at 0.05 significance
      level. For both alloys, the corrosion potential in FS was significantly greater
      than in SC. Corrosion potential of Tytin in FS and SC was also significantly
      greater than in FC. The corrosion rate of Dispersalloy in FC was significantly
      greater than in FS and SC. For Tytin, corrosion rate in SC was significantly
      greater than in FS and FC. Although no significant difference in corrosion
      potential/rate was observed between the alloys when tested in FS, significant
      differences were observed when electrochemical testing was carried out in FC and
      SC. The corrosion behaviour of high copper amalgam alloys are both material and
      environment dependent. Certain food substances may increase the corrosion of high
      copper amalgams.

PMID- 15189321
TI  - The Liverpool Oral Rehabilitation Questionnaire: a pilot study.
AB  - There are several validated health-related quality of life (HRQOL) questionnaires
      designed to record patient-derived outcomes in head and neck cancer. None deals
      specifically with oral rehabilitation. The aim of this study was to pilot a new
      questionnaire, the Liverpool Oral Rehabilitation Questionnaire (LORQ). The
      questionnaire consists of 25 items about oral function and denture satisfaction.
      A four-point Likert scale is used. Sixty-one consecutive patients attending oral
      rehabilitation clinics completed the LORQ in combination with the University of
      Washington Head and Neck questionnaire version 3 (UW-QOL) and European
      Organisation for Research and Treatment of Cancer H and N quality of life
      questionnaire (EORTC H and N 35). Forty-two patients received questionnaires at
      baseline, whereas the rest were provided with the questionnaires at various
      stages of oral rehabilitation. For each item on the questionnaire, a full range
      of possible responses were given by patients. Kappa coefficients of agreement for
      test-retest data indicated moderate to very good agreement between repeat
      questionnaires. There were significant correlations (P < 0.001) between items in
      the LORQ and those in the UW-QOL and EORTC HN questionnaires. The LORQ also
      identified differences in responses between non-cancer and cancer groups of
      patients undergoing oral rehabilitation. This study of the LORQ is encouraging,
      although data on its responsiveness over time and to intervention is awaited.

PMID- 15189322
TI  - Use of bar-clip attachments to enhance the retention of a maxillofacial
      prosthetic obturator: a clinical report.
AB  - Precision attachments are commonly used in prosthetic dentistry but are still
      questioned in maxillofacial prosthetics. The aesthetic enhancement and functional
      rigidity provided by attachments are favourable features to many challenging
      clinical situations such as class-III defect (Aramany's maxillectomy
      classification). Surgical reconstruction is the standard treatment for this type
      of defect repair. However, owing to the need for dental rehabilitation and
      patient reserve, prosthetic rehabilitation was the modality chosen in this
      clinical case. The use of bar attachments is described in this paper as providing
      increased stability and retention of the prosthesis, and improved obturator water
      and airtightness.

PMID- 15189323
TI  - Ageing and the diurnal expression of the mRNAs for vasopressin and for the V1a
      and V1b vasopressin receptors in the suprachiasmatic nucleus of male rats.
AB  - Changes in the function of neuropeptide synthesizing cells within the
      suprachiasmatic nucleus (SCN), the site of the predominant circadian pacemaker,
      may underlie the disturbance of rhythms observed during ageing. Arginine
      vasopressin (AVP) is synthesized by nearly one-third of SCN neurones in the rat.
      This peptide has predominantly excitatory actions within the SCN mediated by V(1)
      type receptors; the extent to which the V(1a) and/or V(1b) receptor subtypes are
      involved in SCN functions remains to be determined. The present study used
      isotopic in situ hybridization histochemistry to examine the effects of ageing on
      expression of mRNAs for AVP and V(1a) in the SCN and for V(1b) in the SCN and
      supraoptic nucleus (SON) of male rats kept under a 12 : 12 h light/dark cycle.
      Analysis of film autoradiographs from young adult (2-3-month-old; n = 40) or aged
      (19-20-month-old; n = 40) animals, at eight time points across the light/dark
      cycle, revealed an equivalent pattern and amplitude for the diurnal rhythm of AVP
      mRNA in the SCN of the young adult and aged groups. Both groups also displayed a
      significant diurnal rhythm in the expression of V(1a) receptor mRNA; however, the
      amplitude of this rhythm was reduced in the aged group, due to increased levels
      during the light phase and early part of night. Although the expression of V(1b)
      mRNA did not display a significant diurnal rhythm within the SCN or SON,
      persistently elevated levels for V(1b) mRNA were observed in the aged group at
      both sites.

PMID- 15189324
TI  - Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before
      birth.
AB  - In the adult, a hypothalamic neural network acts to maintain energy balance in
      response to nutritional feedback from the periphery. Although there is an
      immediate requirement for this system to be functional at birth, it is unknown
      whether the components of this central neural network are expressed in the
      developing brain before birth. We therefore examined in the fetal sheep
      hypothalamus during late gestation gene expression for leptin receptor (OB-Rb)
      and neuropeptides that regulate energy balance in the adult. Brains were
      collected from fetal sheep at 110 days (n = 12) and 140 days of gestation (n = 5)
      (term = 150 days) and gene expression was detected in all hypothalami using in
      situ hybridization with radiolabelled riboprobes for OB-Rb, neuropeptide Y (NPY),
      agouti-related peptide, pro-opiomelanocortin and cocaine- and amphetamine
      regulated transcript (CART). All mRNAs were expressed in the arcuate nucleus of
      fetuses at both time points. Additional sites of mRNA expression were the
      dorsomedial hypothalamus (DMH) for NPY, the paraventricular nucleus (PVN),
      ventromedial hypothalamus (VMH) and lateral hypothalamic area for CART, and the
      DMH, PVN and VMH for OB-Rb. We have therefore demonstrated that adult-like
      localization of gene expression for OB-Rb and key appetite regulatory
      neuropeptides is established in the ovine hypothalamus before birth. Thus, the
      fetus possesses a central appetite regulatory neural network with the potential
      to respond to changes in nutrient supply, which could impact on energy balance
      regulation both before and after birth.

PMID- 15189325
TI  - Oestrogenic regulation of brain angiotensinogen.
AB  - Oestrogens are now recognized as playing a regulatory role on components of the
      systemic renin-angiotensin system, such as its precursor, angiotensinogen (AGT).
      In the brain, this role is poorly understood. The aim of this study was to
      investigate the influence of oestrogens on brain AGT of female rats at different
      stages of the oestrous cycle, in pregnancy and following ovariectomy with and
      without hormone replacement. AGT content of different brain regions was also
      studied in male rats treated with oestrogens. The brain was divided into five
      regions: cortex, cerebellum, brainstem, midbrain and thalamus/hypothalamus, and
      AGT was measured by direct radioimmunoassay using a highly specific AGT antibody.
      Cyclical fluctuations in AGT content were observed in all regions except the
      cerebellum over the course of the 4-day oestrous cycle, with peak concentrations
      at estrus and lowest concentrations at metestrus. Following ovariectomy, brain
      AGT was significantly decreased in the thalamic/hypothalamic region, an effect
      that was reversed by oestrogen-replacement. In pregnant rats, AGT contents were
      elevated in the brainstem region. Oestrogen treatment of male rats induced
      significant increases in AGT concentrations in all areas except the cortex. In
      summary, these results show that oestradiol has actions on brain AGT that are
      region-specific and dependent on the particular physiological and reproductive
      context. Moreover, the changes in AGT concentrations in the oestrous cycle
      suggest the involvement of other factors besides oestrogen. Finally, this study
      supports the view that the brain renin-angiotensin system has a broad role in
      oestrogen-modulated brain functions beyond those specific to the hypothalamic
      pituitary-ovarian axis.

PMID- 15189326
TI  - Gonadectomy reverses the sexually diergic patterns of circadian and stress
      induced hypothalamic-pituitary-adrenal axis activity in male and female rats.
AB  - Enhanced corticosterone release by female compared to male rats under basal and
      stress conditions is well documented. The demonstration that gonadectomy enhances
      stress-induced corticosterone secretion in male rats, but reduces such levels in
      female rats, suggests a causal association between gonadal steroids and
      corticosterone release. The present study examined the corticosterone profile of
      sham gonadectomized and gonadectomized female and male rats under basal and
      stress conditions. An automated sampling system collected blood from each freely
      moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following
      noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide,
      LPS). Plasma was analysed for corticosterone content using radioimmunoassay.
      Castration resulted in a significant increase in basal corticosterone release
      compared to the sham-castrated male rats. Pulsar analysis revealed a significant
      two-fold increase in the number of corticosterone pulses over 24 h.
      Corticosterone increases in response to noise stress and to LPS injection were
      enhanced following castration. Conversely, ovariectomy resulted in a two-fold
      reduction in the number of corticosterone pulses as well as the stress response
      compared to sham-ovariectomized female rats. Arginine vasopressin (AVP),
      corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the
      paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior
      pituitary were analysed post-LPS administration by in situ hybridization.
      Significantly higher values were found for AVP, CRH and POMC mRNAs examined for
      sham females and castrated males compared to sham males and ovariectomized
      females. This study confirms previous reports concerning the influence of gonadal
      factors in regulating HPA axis activity and stress responsiveness. The present
      results extend these observations to the regulation of the dynamic pattern of
      corticosterone release under basal conditions and suggests that this alteration
      in pulsatility is important for the differences in stress responsiveness when
      comparing males and females.

PMID- 15189327
TI  - Cellular expression of V1a vasopressin receptor mRNA in the female rat preoptic
      area: effects of oestrogen.
AB  - The preovulatory luteinizing hormone (LH) surge in female rats is dependent upon
      signals from the suprachiasmatic nucleus (SCN), the site of a dominant circadian
      pacemaker. Various lines of evidence indicate that arginine-vasopressin (AVP)
      containing projections from the SCN to the preoptic area (POA) contribute to the
      production of the surge of LH-releasing hormone (LHRH). These actions may be
      mediated by V(1a) because the transcript for this AVP receptor subtype is
      predominant within the POA of the female rat. In this study, in situ
      hybridization histochemistry was used to examine V(1a) mRNA expression, either by
      itself or together with LHRH or glutamic acid decarboxylase 65 (GAD(65)) mRNA,
      within the POA of ovariectomized rats in the presence or absence of oestrogen.
      V(1a) mRNA was found in cells across the rostro-caudal axis of the POA; some were
      in close proximity to cells expressing LHRH mRNA. Coexpression of V(1a) and LHRH
      mRNAs was detected only very rarely. By contrast, cells with V(1a) mRNA commonly
      displayed GAD(65) mRNA. The density of V(1a) mRNA-expressing cells was
      particularly high within the anteroventral periventricular nucleus; at this site,
      V(1a) mRNA expression was elevated following oestrogen treatment. The present
      results indicate that V(1a)-mediated AVP actions may influence LHRH release via
      cells in the immediate vicinity of LHRH neurones and/or via oestrogen-regulated
      cells in the anteroventral periventricular nucleus, which is a site that lacks
      LHRH neurones but plays an essential role in initiating the preovulatory LH
      surge.

PMID- 15189328
TI  - Immunocytochemical investigation of nuclear progestin receptor expression within
      dopaminergic neurones of the female rat brain.
AB  - Progesterone influences most processes involved in female reproduction, including
      ovulation, sexual behaviour, pregnancy, parturition, lactation and maternal
      behaviour. One neurotransmitter through which progesterone might regulate many of
      these functions is dopamine. To determine where in the brain progesterone might
      alter dopaminergic activity necessary for these and other processes in rats via
      cell nuclear progestin receptors, ovariectomized rats were injected
      subcutaneously with either 4 micro g oestradiol benzoate to induce high levels of
      hypothalamic progestin receptor expression, or oil, and perfused 48 h later. Dual
      label immunocytochemistry was used to visualize cells having immunoreactivity
      (ir) for progestin receptors and tyrosine hydroxylase, a rate-limiting enzyme for
      dopamine synthesis. Many cells containing both progestin receptor-ir and tyrosine
      hydroxylase-ir were found throughout the periventricular hypothalamus of
      oestradiol-treated females. Conversely, very few cells in the hypothalamus of oil
      treated controls contained progestin receptor-ir and, consequently, few dual
      labelled cells were found in this group. The greatest percentage of tyrosine
      hydroxylase immunoreactive cells expressing progestin receptors in oestradiol
      treated females was in, or near, the arcuate nucleus (A12 group), where up to 55%
      of tyrosine hydroxylase-expressing cells coexpressed progestin receptors.
      Notably, dual-labelled cells in oestradiol-treated females were also found more
      rostrally than previously reported, with approximately 15-20% of tyrosine
      hydroxylase-ir cells in the preoptic area/anterior hypothalamus (A14 group) also
      containing progestin receptor-ir. No dual-labelled cells were found for either
      group in the posterodorsal hypothalamus (A11 group), zona incerta (A13 group),
      retrorubral field (A8 group), ventral tegmental area (A10 group) or substantia
      nigra (A9 group) because little or no progestin receptor-ir was found in these
      sites. These data provide new information about the neural substrate where
      progesterone might regulate dopamine release in the preoptic area/anterior
      hypothalamus. Using more sensitive techniques than those used previously, they
      also confirm the relationship between progestin receptor and tyrosine hydroxylase
      in the arcuate nucleus, which could be important for the regulation of prolactin
      release throughout the female reproductive cycle. Additionally, although
      progesterone alters mesolimbic and nigrostriatal dopamine release, and the
      numerous behaviours that these pathways influence, these data again suggest that
      it does not do so via nuclear progestin receptor in dopaminergic cells of the
      ventral tegmental area and substantia nigra.

PMID- 15189329
TI  - Depletion of oestrogen receptor-beta expression in magnocellular arginine
      vasopressin neurones by hypovolaemia and dehydration.
AB  - Oestrogen receptor (ER)-beta expression correlates inversely with osmotic control
      of arginine vasopressin (AVP) release such that cellular dehydration induced by
      72 h of 2% saline consumption depletes ER-beta in the magnocellular AVP neurones
      in the supraoptic (SON) and paraventricular nuclei (PVN). The current studies
      were performed to determine whether other pathways that stimulate AVP release,
      such as hypovolaemia, also regulate ER-beta expression in these nuclei, and to
      evaluate the time course of the change in ER-beta expression during water
      deprivation and subsequent rehydration. ER-beta expression was evaluated
      immunocytochemically. In rats made hypovolaemic with a subcutaneous injection of
      40% polyethylene glycol (PEG), a significant depletion of ER-beta in both SON and
      magnocellular PVN (P </= 0.001) was evident 8 h post PEG injection. ER-beta was
      also significantly depleted following 20 h and 26 h of water deprivation in SON
      (P = 0.003) and magnocellular PVN (P < 0.001). Six hours of rehydration in rats
      that had been water deprived for 26 h induced recovery of expression that was
      statistically significant, although not complete (P </= 0.015 in PVN). Thus, for
      the first time, the present studies demonstrate that haemodynamic in addition to
      osmotic influences are capable of regulating ER-beta expression in the
      magnocellular system, and that the combination of these factors induced by a
      physiological manipulation (e.g. 20 h of water deprivation) can eliminate ER-beta
      expression. Because ER-beta has been shown to mediate inhibition of AVP secretion
      in explants of the hypothalamic-neurohypophyseal system, these data suggest that
      down-regulation of ER-beta may contribute to stimulated AVP release during
      hypovolaemic states such as fluid deprivation and haemorrhage.

PMID- 15189330
TI  - Chronic glucocorticoid deficiency-induced abnormal aggression, autonomic
      hypoarousal, and social deficit in rats.
AB  - Certain aggression-related psychopathologies are associated with decreased
      glucocorticoid production and autonomic functions in humans. We have previously
      shown that experimentally-induced chronic glucocorticoid deficiency leads to
      abnormal forms of attack in rats. Here, we compared the effects of acute and
      chronic glucocorticoid deficiency on aggressive behaviour, autonomic responses to
      challenges, and anxiety. Glucocorticoid synthesis was blocked acutely by the
      glucocorticoid synthesis blocker metyrapone or chronically by adrenalectomy and
      low glucocorticoid replacement (ADXr). As shown previously, chronic
      glucocorticoid deficiency facilitated aberrant attacks directed towards the most
      vulnerable parts of the opponent's body. The acute inhibition of glucocorticoid
      synthesis lowered aggressive behaviour without affecting attack targeting. In a
      different experiment, ADXr rats and their sham-operated controls were exposed to
      different challenges whereas their heart rate and locomotion were telemetrically
      recorded. Autonomic responses to social challenges were lowered by chronic, but
      not by acute glucocorticoid deficiency. Autonomic responses to the elevated plus
      maze were only slightly affected by chronic glucocorticoid deficiency. Locomotor
      behaviour was not affected in either challenge; thus, the altered autonomic
      reactions were not due to interference from workload. The behaviour of ADXr rats
      was similar to that of sham-operated controls in the elevated plus-maze, but ADXr
      rats showed reduced social interactions in the social interaction test. Our data
      demonstrate that, in rats, chronic but not acute glucocorticoid deficiency
      induces abnormal attack patterns, deviant cardiovascular responses and social
      deficits that are similar to those seen in abnormally violent humans. Thus, the
      similar correlations found in humans probably cover a causal relationship.
      Experimentally-induced glucocorticoid deficiency may be used to assess the
      mechanisms underlying glucocorticoid deficiency-induced abnormal forms of
      aggressiveness.

PMID- 15189333
TI  - Glycogen synthase kinase 3: a drug target for CNS therapies.
AB  - Abstract Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target
      in the CNS. The most exciting of the possibilities of GSK3 lies within the
      treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and
      activity have been associated with neuronal death, paired helical filament tau
      formation and neurite retraction as well as a decline in cognitive performance.
      Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used
      drug for affective disorders, inhibits GSK3 at therapeutically relevant
      concentrations. Thus while the rationale remains testable, pharmaceutical
      companies are investing in finding a selective inhibitor of GSK3. In the present
      review, we summarize the properties of GSK3, and discuss the potential for such a
      therapy in AD, and other CNS disorders.

PMID- 15189331
TI  - Stimulation of luteinizing hormone subunit gene expression by pulsatile
      intracerebroventricular microinjection of galanin in female rats.
AB  - Although galanin, which exerts its effects both at the hypothalamic and pituitary
      level, has been implicated as an important neuroendocrine regulator of
      hypothalamic-pituitary-gonadal axis activity, there is a lack of data concerning
      its involvement in the regulation of gonadotropin subunit gene expression. To
      elucidate whether galanin can influence luteinizing hormone (LH) subunit mRNA
      content, as well as affect gonadotropin-releasing hormone (GnRH) receptor
      activity, a model based on pulsatile (one pulse per hour over 5 h) galanin (1 nM)
      microinjections directly into the third cerebral ventricle of ovariectomized
      (OVX) and/or oestrogen/progesterone-pretreated rats was used. Furthermore, to
      determine galanin effects on GnRH-induced LH subunit mRNA synthesis, a cocktail
      of 1 nM GnRH and 1 nM galanin was coadministered in a pulsatile manner to
      OVX/steroid primed rats. Subsequently, to obtain data concerning the role of
      galanin receptors in the regulation of pituitary alpha (common to LH, follicle
      stimulating hormone, thyroid-stimulating hormone) and LHbeta subunit gene
      expression, OVX/oestrogen/progesterone rats received microinjections of 1 nM of
      the receptor antagonist galantide and 1 nM of galanin. In this case, both
      substances were administered separately, with a 30 min lag, according to which
      each galantide pulse always preceded a galanin pulse. Northern-blot analysis
      revealed that intracerebroventricular pulsatile galanin injections were effective
      in stimulation of both alpha and LHbeta subunit mRNA levels and that this effect
      was apparently steroid-dependent. Moreover, galanin also up-regulated GnRH
      receptor functional parameters (affinity and maximum binding capacity) but was
      ineffective in potentiating GnRH-induced accumulation of both subunit mRNAs. The
      results from the study also indicate that galanin acts through its own
      receptor(s) because a receptor antagonist, galantide, significantly reduced the
      stimulatory effect exerted by galanin on the expression of both LH subunit genes
      in vivo.

PMID- 15189334
TI  - Could a loss of alpha-synuclein function put dopaminergic neurons at risk?
AB  - The alpha-synuclein gene is implicated in Parkinson's disease, the symptoms of
      which occur after a marked loss of substantia nigra dopamine neurons. While the
      function of alpha-synuclein is not entirely elucidated, one function appears to
      be as a normal regulatory protein that can bind to and inhibit tyrosine
      hydroxylase, the rate-limiting enzyme in dopamine synthesis. Soluble alpha
      synuclein levels may be diminished in Parkinson's disease substantia nigra
      dopamine neurons both by reduced expression and by alpha-synuclein aggregation as
      Lewy bodies and Lewy neurites form. The loss of functional alpha-synuclein may
      then result in dysregulation of tyrosine hydroxylase, dopamine transport and
      dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and
      its metabolites are reactive molecules capable of generating highly reactive
      quinones and reactive oxygen species, a failure to package dopamine into vesicles
      could cause irreversible damage to cellular macromolecules and contribute to
      resultant neurotoxicity. This review focuses on how a loss of normal alpha
      synuclein function may contribute to the dopamine-related loss of substantia
      nigra neurons during Parkinson's disease pathogenesis.

PMID- 15189335
TI  - Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of
      amyotrophic lateral sclerosis.
AB  - Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a
      familial form of amyotrophic lateral sclerosis (fALS). The present study
      demonstrated impaired proteasomal function in the lumbar spinal cord of
      transgenic mice expressing human SOD-1 with the ALS-causing mutation G93A (SOD
      1(G93A)) compared to non-transgenic littermates (LM) and SOD-1(WT) transgenic
      mice. Chymotrypsin-like activity was decreased as early as 45 days of age. By 75
      days, chymotrypsin-, trypsin-, and caspase-like activities of the proteasome were
      impaired, at about 50% of control activity in lumbar spinal cord, but unchanged
      in thoracic spinal cord and liver. Both total and specific activities of the
      proteasome were reduced to a similar extent, indicating that a change in
      proteasome function, rather than a decrease in proteasome levels, had occurred.
      Similar decreases of total and specific activities of the proteasome were
      observed in NIH 3T3 cell lines expressing fALS mutants SOD-1(G93A) and SOD
      1(G41S), but not in SOD-1(WT) controls. Although overall levels of proteasome
      were maintained in spinal cord of SOD-1(G93A) transgenic mice, the level of 20S
      proteasome was substantially reduced in lumbar spinal motor neurons relative to
      the surrounding neuropil. It is concluded that impairment of the proteasome is an
      early event and contributes to ALS pathogenesis.

PMID- 15189336
TI  - A novel lipopolysaccharide-modulated Jun binding repressor in intron 2 of CYP2E1.
AB  - Cytochrome P450 2E1 (CYP2E1) exhibits a pronounced oxidase activity that may
      mediate apoptotic injury in glial cells as well as hepatocytes. Strict regulation
      of CYP2E1 and it's activity is therefore thought to be crucial. We have studied
      CYP2E1 transcriptional regulation in primary cortical glial cells and have
      identified a novel repressor element at +1452/+1460 in intron 2 of the rat CYP2E1
      gene. The element very potently repressed CYP2E1 and SV40 promoters and consisted
      of the non-palindromic core sequence 5'-TTCCACTCA-3'. Jun proteins were found to
      interact with the site. The protein complexes were also found to contain an as
      yet unidentified protein of approximately 60 kDa, probably with DNA binding
      properties similar to G-box binding factors found in, e.g. Arabidopsis thaliana.
      Stimulation with lipopolysaccharide, or overexpression of the mitogen-activated
      protein kinase kinase kinase, MEKK-1, further deepened the repression in primary
      cortical glial cells. It is suggested that this novel Jun binding repressor helps
      to control basal expression levels of CYP2E1, and modulates the response to
      inflammatory factors. Future in vivo experiments will, however, be required for a
      full appreciation of the role of this repressor in the complex regulation of
      CYP2E1 during inflammatory conditions.

PMID- 15189337
TI  - Brain-specific potential guanine nucleotide exchange factor for Arf, synArfGEF
      (Po), is localized to postsynaptic density.
AB  - We cloned from a rat brain cDNA library a novel cDNA and named it a potential
      synaptic guanine nucleotide exchange factor (GEF) for Arf (synArfGEF (Po))
      (GenBank Accession no. AB057643) based on its domain structure and localization.
      The cloned gene was 7410 bases long with a 3585-bp coding sequence encoding a
      protein of 1194 amino acids. The deduced protein contained a coiled-coil
      structure in the N-terminal portion followed by Sec7 and Plekstrin homology (PH)
      domains. Thus, the protein was a member of the Sec7 family of proteins, GEFs.
      Conservation of the ADP-ribosylation factor (Arf)-binding sequence suggested that
      the protein was a GEF for Arf. The gene was expressed specifically in the brain,
      where it exhibited region-specific expression. The protein was highly enriched in
      the postsynaptic density (PSD) fraction prepared from the rat forebrain.
      Uniquely, the protein interacted with PSD-95, SAP97 and Homer/Vesl 1/PSD-Zip45
      via its C-terminal PDZ-binding motif and co-localized with these proteins in
      cultured cortical neurons. These results supported its localization in the PSD.
      The postsynaptic localization was also supported by immunohistochemical
      examination of the rat brain. The mRNA for the synArfGEF was also localized to
      dendrites, as well as somas, of neuronal cells. Thus, both the mRNA and the
      protein were localized in the postsynaptic compartments. These results suggest a
      postsynaptic role of synArfGEF in the brain.

PMID- 15189338
TI  - Valproic acid reduces brain damage induced by transient focal cerebral ischemia
      in rats: potential roles of histone deacetylase inhibition and heat shock protein
      induction.
AB  - Growing evidence from in vitro studies supports that valproic acid (VPA), an anti
      convulsant and mood-stabilizing drug, has neuroprotective effects. The present
      study investigated whether VPA reduces brain damage and improves functional
      outcome in a transient focal cerebral ischemia model of rats. Subcutaneous
      injection of VPA (300 mg/kg) immediately after ischemia followed by repeated
      injections every 12 h, was found to markedly decrease infarct size and reduce
      ischemia-induced neurological deficit scores measured at 24 and 48 h after
      ischemic onset. VPA treatment also suppressed ischemia-induced neuronal caspase-3
      activation in the cerebral cortex. VPA treatments resulted in a time-dependent
      increase in acetylated histone H3 levels in the cortex and striatum of both
      ipsilateral and contralateral brain hemispheres of middle cerebral artery
      occlusion (MCAO) rats, as well as in these brain areas of normal, non-surgical
      rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC)
      inhibitor. Similarly, heat shock protein 70 (HSP70) levels were time-dependently
      up-regulated by VPA in the cortex and striatum of both ipsilateral and
      contralateral sides of MCAO rats and in these brain areas of normal rats.
      Altogether, our results demonstrate that VPA is neuroprotective in the cerebral
      ischemia model and suggest that the protection mechanisms may involve HDAC
      inhibition and HSP induction.

PMID- 15189339
TI  - Alterations in hippocampal phospholipid profile by prenatal exposure to ethanol.
AB  - It has been suggested that hippocampus-related cognitive processes are especially
      sensitive to ethanol. To provide an insight into the biochemical mechanisms
      underlying the hippocampus-related functional deficits associated with prenatal
      ethanol exposure, we investigated the effects of chronic ethanol exposure on the
      phospholipid profile in developing rat hippocampi. High-performance liquid
      chromatography/electrospray ionization-mass spectrometry analysis revealed that
      ethanol lowered the levels of total phosphatidylserine (PS) by 15-20% at all ages
      examined, primarily owing to the reduction in 1-stearoyl-2-docosahexaenoyl-PS
      (18:0,22:6n-3-PS) species. Ethanol exposure also led to a decrease in
      phosphatidylcholine (PC) and an increase in phosphatidylethanolamine (PE), but
      the total phospholipid content was not significantly changed. At the fatty acid
      level, ethanol exposure significantly decreased the 22:6n-3 content at postnatal
      days 0 and 21, with a slight increase in 22:5n-6, without changing the total
      fatty acid content significantly. In conclusion, ethanol depleted PS, especially
      22:6-containing species, and PC from hippocampal membranes with concomitant
      increase in PE. Alteration of the phospholipid profile in the hippocampus
      resulting from exposure to ethanol during prenatal and developmental stages may
      have significant implications with respect to the cognitive dysfunction observed
      in fetal alcohol syndrome.

PMID- 15189340
TI  - Reduction of excitotoxicity and associated leukocyte recruitment by a broad
      spectrum matrix metalloproteinase inhibitor.
AB  - An important step in the cascade leading to neuronal cell death is degradation of
      laminin and other components of the brain extracellular matrix by microglia
      derived proteases. Excitotoxic cell death of murine hippocampal neurones in vivo
      can be prevented by inhibitors of tissue plasminogen activator (tPA) or by
      inhibitors of plasmin. Plasmin is a potent activator of the matrix
      metalloproteinases (MMPs), which are made by resident and recruited leukocytes
      following CNS injury. In this study, we show, using Taqman RT-PCR, that MMP
      mRNAs, but not other calcium-dependent proteases such as calpain mRNAs, are
      acutely up-regulated after an excitotoxic challenge in vivo. alpha(2)-antiplasmin
      or BB-3103, a broad-spectrum inhibitor of the MMPs, co-injected with kainic acid
      into the striatum, inhibits excitotoxic cell death in the rat striatum, and
      reduces both the number of recruited macrophages and the size of the lesion. We
      also show that leukocyte populations differentially express MMPs, which may
      account, in part, for the expression profile we observe in the challenged brain.
      Our results show that inhibition of the MMPs in the rat will prevent kainic acid
      induced cell death in the brain. These studies suggest that MMP inhibitors have
      therapeutic potential for use in stroke, and support the increasing evidence that
      microglial activation may contribute to neuronal cell death.

PMID- 15189341
TI  - A non-peptidyl neurotrophic small molecule for midbrain dopaminergic neurons.
AB  - Abstract A small organic molecule (CUR-162590) that selectively enhances survival
      of midbrain dopaminergic neurons was identified by screening small molecule
      compound libraries. In embryonic midbrain cultures, CUR-162590 increased dopamine
      uptake and the number of dopaminergic neurons without altering the number of
      total neurons or astroglia or the uptake of GABA or serotonin. CUR-162590 reduced
      apoptosis of cultured dopaminergic neurons and protected against death induced by
      toxins such as MPP(+). Several synthetic analogs of CUR-162590 also had similar
      bioactivities. CUR-162590 thus represents a new class of neurotrophic small
      molecules that may have utility in the treatment of Parkinson's disease, which is
      marked by degeneration of midbrain dopaminergic neurons.

PMID- 15189342
TI  - Brain antioxidant systems in human methamphetamine users.
AB  - Animal data suggest that the widely abused psychostimulant methamphetamine can
      damage brain dopamine neurones by causing dopamine-dependent oxidative stress;
      however, the relevance to human methamphetamine users is unclear. We measured
      levels of key antioxidant defences [reduced (GSH) and oxidized (GSSG)
      glutathione, six major GSH system enzymes, copper-zinc superoxide dismutase
      (CuZnSOD), uric acid] that are often altered after exposure to oxidative stress,
      in autopsied brain of human methamphetamine users and matched controls. Changes
      in the total (n = 20) methamphetamine group were limited to the dopamine-rich
      caudate (the striatal subdivision with the most severe dopamine loss) in which
      only activity of CuZnSOD (+ 14%) and GSSG levels (+ 58%) were changed. In the six
      methamphetamine users with severe (- 72 to - 97%) caudate dopamine loss, caudate
      CuZnSOD activity (+ 20%) and uric acid levels (+ 63%) were increased with a trend
      for decreased (- 35%) GSH concentration. Our data suggest that brain levels of
      many antioxidant systems are preserved in methamphetamine users and that GSH
      depletion, commonly observed during severe oxidative stress, might occur only
      with severe dopamine loss. Increased CuZnSOD and uric acid might reflect
      compensatory responses to oxidative stress. Future studies are necessary to
      establish whether these changes are associated with oxidative brain damage in
      human methamphetamine users.

PMID- 15189343
TI  - In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors.
AB  - We have previously reported structure-based design of memapsin 2 (beta-secretase)
      inhibitors with high potency. Here we show that two such inhibitors covalently
      linked to a "carrier peptide" penetrated the plasma membrane in cultured cells
      and inhibited the production of beta-amyloid (Abeta). Intraperitoneal injection
      of the conjugated inhibitors in transgenic Alzheimer's mice (Tg2576) resulted in
      a significant decrease of Abeta level in the plasma and brain. These observations
      verified that memapsin 2 is a therapeutic target for Abeta reduction and also
      establish that transgenic mice are suitable in vivo models for the study of
      memapsin 2 inhibition.

PMID- 15189344
TI  - Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity.
AB  - Alzheimer's disease (AD) brain reveals high rates of oxygen consumption and
      oxidative stress, altered antioxidant defences, increased oxidized
      polyunsaturated fatty acids, and elevated transition metal ions. Mitochondrial
      dysfunction in AD is perhaps relevant to these observations, as such may
      contribute to neurodegenerative cell death through the formation of reactive
      oxygen species (ROS) and the release of molecules that initiate programmed cell
      death pathways. In this study, we analyzed the effects of beta-amyloid peptide
      (Abeta) on human teratocarcinoma (NT2) cells expressing endogenous mitochondrial
      DNA (mtDNA), mtDNA from AD subjects (AD cybrids), and mtDNA from age-matched
      control subjects (control cybrids). In addition to finding reduced cytochrome
      oxidase activity, elevated ROS, and reduced ATP levels in the AD cybrids, when
      these cell lines were exposed to Abeta 1-40 we observed excessive mitochondrial
      membrane potential depolarization, increased cytoplasmic cytochrome c, and
      elevated caspase-3 activity. When exposed to Abeta, events associated with
      programmed cell death are activated in AD NT2 cybrids to a greater extent than
      they are in control cybrids or the native NT2 cell line, suggesting a role for
      mtDNA-derived mitochondrial dysfunction in AD degeneration.

PMID- 15189345
TI  - Ceramide influences neurite outgrowth and neuroblastoma cell apoptosis regulated
      by novel protein kinase C isoforms.
AB  - We have previously seen that protein kinase C (PKC) epsilon induces neurite
      outgrowth and that PKCdelta and PKCtheta elicit apoptosis in neuroblastoma cells.
      In this study we investigate the effects of cell-permeable C(2)-ceramide on these
      events in SK-N-BE(2) neuroblastoma cells. C(2)-ceramide abolishes neurite
      formation induced by overexpression of PKCepsilon and, in cells overexpressing
      PKCdelta or PKCtheta, ceramide treatment leads to apoptosis. Exposure to C(2)
      ceramide also suppressed neurite outgrowth induced by retinoic acid, but ceramide
      did not abrogate neurite induction by treatment with the ROCK inhibitor Y-27632,
      demonstrating that C(2)-ceramide is not a general inhibitor of neurite outgrowth.
      The neurite-suppressing effect occurs independently of cell-death. Furthermore,
      C(2)-ceramide relocated PKCepsilon and the isolated regulatory domain of
      PKCepsilon from the cytosol to the perinuclear region. In contrast, neither the
      localization of PKCdelta nor of PKCtheta was affected by C(2)-ceramide. Taken
      together, the data indicate that the neurite-inhibiting effect of C(2)-ceramide
      treatment may be caused by a re-localization of PKCepsilon and thus identify a
      functional consequence of ceramide effects on PKCepsilon localization.

PMID- 15189346
TI  - Transfection of 2,6 and 2,3-sialyltransferase genes and GlcNAc-transferase genes
      into human glioma cell line U-373 MG affects glycoconjugate expression and
      enhances cell death.
AB  - Human glioma cell line U-373 MG expresses CMP-NeuAc : Galbeta1,3GlcNAc alpha2,3
      sialyltransferase [EC No. 2.4.99.6] (alpha2,3ST), UDP-GlcNAc : beta-d-mannoside
      beta1,6-N-acetylglucosaminyltransferase V [EC 2.4.1.155] (GnT-V) and UDP-GlcNAc3:
      beta-d-mannoside beta1,4-N-acetylglucosaminyltransferase III [EC 2.4.1.144] (GnT
      III) but not CMP-NeuAc : Galbeta1,4GlcNAc alpha2,6-sialyltransferase [EC
      2.4.99.1] (alpha2,6ST) under normal culture conditions. We have previously shown
      that transfection of the alpha2,6ST gene into U-373 cells replaced alpha2,3
      linked sialic acids with alpha2,6 sialic acids, resulting in a marked inhibition
      of glioma cell invasivity and a significant reduction in adhesivity. We now show
      that U-373 cells, which are typically highly resistant to cell death induced by
      chemotherapeutic agents (< 10% death in 18 h), become more sensitive to apoptosis
      following overexpression of these four glycoprotein glycosyltransferases. U-373
      cell viability showed a three-fold decrease (from 20 to 60% cell death) following
      treatment with staurosporine, C2-ceramide or etoposide, when either alpha2,6ST
      and GnT-V genes were stably overexpressed. Even glycosyltransferases typically
      raised in cancer cells, such as alpha2,3ST and GnT-III, were able to decrease
      viability two-fold (from 20 to 40% cell death) following stable overexpression.
      The increased susceptibility of glycosyltransferase-transfected U-373 cells to
      pro-apoptotic drugs was associated with increased ceramide levels in Rafts,
      increased caspase-3 activity and increased DNA fragmentation. In contrast, the
      same glycosyltransferase overexpression protected U-373 cells against a different
      class of apoptotic drugs, namely the phosphatidylinositol 3-kinase inhibitor
      LY294002. Thus altered surface protein glycosylation of a human glioblastoma cell
      line can lead to lowered resistance to chemotherapeutic agents.

PMID- 15189348
TI  - Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat
      inner blood-retinal barrier.
AB  - The purpose of this study was to elucidate the mechanisms of blood-to-retina
      creatine transport across the blood-retinal barrier (BRB) in vivo and in vitro,
      and to identify the responsible transporter(s). The creatine transport across the
      BRB in vivo and creatine uptake in an in vitro model of the inner BRB (TR-iBRB2
      cells) were examined using [(14)C]creatine. Identification and localization of
      the creatine transporter (CRT) were carried out by RT-PCR, western blot, and
      immunoperoxidase electron microscopic analyses. An in vivo intravenous
      administration study suggested that [(14)C]creatine is transported from the blood
      to the retina against the creatine concentration gradient that exists between the
      retina and blood. [(14)C]Creatine uptake by TR-iBRB2 cells was saturable, Na(+)-
      and Cl(-)-dependent and inhibited by CRT inhibitors, suggesting that CRT is
      involved in creatine transport at the inner BRB. RT-PCR and western blot analyses
      demonstrated that CRT is expressed in rat retina and TR-iBRB2 cells. Moreover,
      using an immunoperoxidase electron microscopic analysis, CRT immunoreactivity was
      found at both the luminal and abluminal membranes of the rat retinal capillary
      endothelial cells. In conclusion, CRT is expressed at the inner BRB and plays a
      role in blood-to-retina creatine transport across the inner BRB.

PMID- 15189347
TI  - 3,4-Methylenedioxymethamphetamine increases interleukin-1beta levels and
      activates microglia in rat brain: studies on the relationship with acute
      hyperthermia and 5-HT depletion.
AB  - 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces acute
      hyperthermia and 5-HT release. Interleukin-1beta (IL-1beta) is a pro-inflammatory
      pyrogen produced by activated microglia in the brain. We examined the effect of a
      neurotoxic dose of MDMA on IL-1beta concentration and glial activation and their
      relationship with acute hyperthermia and 5-HT depletion. MDMA, given to rats
      housed at 22 degrees C, increased IL-1beta levels in hypothalamus and cortex from
      1 to 6 h and [(3)H]-(1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)3
      isoquinolinecarboxamide) binding between 3 and 48 h. Increased immunoreactivity
      to OX-42 was also detected. Rats became hyperthermic immediately after MDMA and
      up to at least 12 h later. The IL-1 receptor antagonist did not modify MDMA
      induced hyperthermia indicating that IL-1beta release is a consequence, not the
      cause, of the rise in body temperature. When MDMA was given to rats housed at 4
      degrees C, hyperthermia was abolished and the IL-1beta increase significantly
      reduced. The MDMA-induced acute 5-HT depletion was prevented by fluoxetine
      coadministration but the IL-1beta increase and hyperthermia were unaffected.
      Therefore, the rise in IL-1beta is not related to the acute 5-HT release but is
      linked to the hyperthermia. Contrary to IL-1beta levels, microglial activation is
      not significantly modified when hyperthermia is prevented, suggesting that it
      might be a process not dependent on the hyperthermic response induced by MDMA.

PMID- 15189349
TI  - 4-Hydroxy-trans-2-nonenoic acid is a gamma-hydroxybutyrate receptor ligand in the
      cerebral cortex and hippocampus.
AB  - Elevated production of 4-hydroxy-trans-2-nonenal (HNE) occurs in numerous
      neurological disorders involving oxidative damage. HNE is metabolized to the non
      toxic 4-hydroxy-trans-2-nonenoic acid (HNEAcid) by aldehyde dehydrogenases in the
      rat cerebral cortex. Based upon the structural similarity of HNEAcid to ligands
      of the gamma-hydroxybutyrate (GHB) receptor, we hypothesized that HNEAcid is an
      endogenous ligand for the GHB receptor. HNEAcid displaced the specific binding of
      the GHB receptor ligand (3)H-NCS382 (30 nm) in membrane preparations of human
      frontal cerebral cortex and whole rat cerebral cortex with IC(50s) of 3.9 +/- 1.1
      and 5.6 +/- 1.2 micro m, respectively. Inhibition was attenuated when the
      carboxyl group of HNEAcid was replaced with an aldehyde or an alcohol. HNEAcid
      (300 micro m) did not displace the binding of beta-adrenergic receptor and
      GABA(B) receptor antagonists, demonstrating the selectivity of HNEAcid for the
      GHB receptor. HNEAcid is formed in homogenates of human frontal cortical gray
      matter in an NAD(+)-dependent (V(Max), 0.71 nmol/min/mg) and NADP(+)-dependent
      (V(Max), 0.12 nmol/min/mg) manner. Lastly, (3)H-NCS382 binding is elevated 2.7
      fold with age in the cerebral cortex of rats. Our data demonstrate that an HNE
      metabolite, formed in rat and human brain, is a signaling molecule analogous to
      other bioactive lipid peroxidation products.

PMID- 15189350
TI  - Increased expression of the gene for the Y1 receptor of neuropeptide Y in the
      amygdala and paraventricular nucleus of Y1R/LacZ transgenic mice in response to
      restraint stress.
AB  - A sustained increase in the brain concentrations of neuroactive steroids was
      previously shown to induce Y1 receptor gene expression in the amygdala of
      Y1R/LacZ transgenic mice which harbour a construct comprising the murine Y1
      receptor gene promoter and the lacZ reporter gene. We now investigated the
      effects of restraint stress on both the cerebrocortical concentrations of
      neuroactive steroids and Y1 receptor gene expression in the amygdala and
      hypothalamic paraventricular nucleus (PVN) of Y1R/LacZ transgenic mice. The
      cerebrocortical concentrations of allopregnanolone and
      allotetrahydrodeoxycorticosterone were significantly increased immediately after
      a 1-h exposure to restraint stress and had returned to control values within 30
      min. Expression of Y1R/LacZ was increased in the amygdala and PVN 6 h after
      restraint. The 5alpha-reductase inhibitor finasteride, that prevented the
      increase in neuroactive steroid concentrations, did not block that in transgene
      expression induced by 1-h restraint. Daily exposure to restraint for 10 days also
      increased the cerebrocortical concentrations of neuroactive steroids but failed
      to affect transgene expression. Acute but not repeated restraint thus increases
      Y1 receptor gene expression in the amygdala and PVN, suggesting that tolerance
      develops towards this stressor. The effect of acute restraint is not mediated by
      the increase in the brain concentrations of neuroactive steroids but may rather
      reflect a ligand-induced increase in Y1 receptor gene transcription. Data support
      a role of Y1 receptors in the behavioural and neuroendocrine responses to stress.

PMID- 15189351
TI  - Neuroprotective effects of the mGlu5R antagonist MPEP towards quinolinic acid
      induced striatal toxicity: involvement of pre- and post-synaptic mechanisms and
      lack of direct NMDA blocking activity.
AB  - The aim of this work was to investigate the potential neuroprotective effects of
      the metabotropic glutamate receptor 5 (mGlu5R) antagonist 2-Methyl-6
      (phenylethynyl)-pyridine (MPEP) towards quinolinic acid (QA)-induced striatal
      excitoxicity. Intrastriatal MPEP (5 nmol/0.5 micro L) significantly attenuated
      the body weight loss, the electroencephalographic alterations, the impairment in
      spatial memory and the striatal damage induced by bilateral striatal injection of
      QA (210 nmol/0.7 micro L). In a second set of experiments, we aimed to elucidate
      the mechanisms underlying the neuroprotective effects of MPEP. In microdialysis
      studies in naive rats MPEP (80-250 micro m through the dialysis probe)
      significantly reduced the increase in glutamate levels induced by 5 mm QA. In
      primary cultures of striatal neurons MPEP (50 micro m) reduced the toxicity
      induced by direct application of glutamate [measured as release of lactate
      dehydrogenase [LDH]). Finally, we found that 50 micro m MPEP was unable to
      directly block NMDA-induced effects (namely field potential reduction in
      corticostriatal slices, as well as LDH release and intracellular calcium increase
      in striatal neurons). We conclude that: (i) MPEP has neuroprotective effects
      towards QA-induced striatal excitotoxicity; (ii) both pre- and post-synaptic
      mechanisms are involved; (iii) the neuroprotective effects of MPEP do not appear
      to involve a direct blockade of NMDA receptors.

PMID- 15189352
TI  - Parkin attenuates manganese-induced dopaminergic cell death.
AB  - Manganese as environmental factor is considered to cause parkinsonism and induce
      endoplasmic reticulum stress-mediated dopaminergic cell death. We examined the
      effects of manganese on parkin, identified as the gene responsible for familial
      Parkinson's disease, and the role of parkin in manganese-induced neuronal cell
      death. Manganese dose-dependently induced cell death of dopaminergic SH-SY5Y and
      CATH.a cells and cholinergic Neuro-2a cells, and that the former two cell types
      were more sensitive to manganese toxicity than Neuro-2a cells. Moreover,
      manganese increased the expression of endoplasmic reticulum stress-associated
      genes, including parkin, in SH-SY5Y cells and CATH.a cells, but not in Neuro-2a
      cells. Treatment with manganese resulted in accumulation of parkin protein in SH
      SY5Y cells and its redistribution to the perinuclear region, especially
      aggregated Golgi complex, while in Neuro-2a cells neither expression nor
      redistribution of parkin was noted. Manganese showed no changes in proteasome
      activities in either cell. Transient transfection of parkin gene inhibited
      manganese- or manganese plus dopamine-induced cell death of SH-SY5Y cells, but
      not of Neuro-2a cells. Our results suggest that the attenuating effects of parkin
      against manganese- or manganese plus dopamine-induced cell death are dopaminergic
      cell-specific compensatory reactions associated with its accumulation and
      redistribution to perinuclear regions but not with proteasome system.

PMID- 15189353
TI  - Dopamine D2 receptor activates extracellular signal-regulated kinase through the
      specific region in the third cytoplasmic loop.
AB  - To investigate whether the third cytoplasmic loop and the C-terminal cytoplasmic
      tail of dopamine D(2) receptor (D2R) are involved in extracellular signal
      regulated kinase (ERK) activation and subsequent regulation of transcription
      factors, we established NG108-15 cells stably expressing D2LR and D2SR deleted 40
      amino acid residues in the third cytoplasmic loop (NGD2LR-3rd-dele and NGD2SR-3rd
      dele) or the C-terminal cytoplasmic tail (NGD2LR-C-dele and NGD2SR-C-dele) and
      evaluated these receptors' functions using luciferase reporter gene assay.
      Immunocytochemical studies showed similar intracellular distributions of D2LR-3rd
      dele and D2SR-3rd-dele to D2LR and D2SR, respectively. Quinpirole-induced
      inhibition of forskolin-induced cyclic AMP responsive element (CRE) activation
      was not affected by the deletion of 40 amino acid residues. However, nuclear
      factor-kappa B (NF-kappaB) activation by D2R-3rd-dele was largely attenuated
      compared to that by D2R. Similarly, ERK or serum-responsive element (SRE)
      activation by quinpirole treatment was totally abolished in NGD2R-3rd-dele cells.
      Moreover, D2R-C-dele was diffusely distributed or clustered in the cell bodies
      and lost the receptor functions. Taken together, the 40 amino acid residues in
      the third cytoplasmic loop are essential for the ERK activation but not for
      inhibition of adenylyl cyclase through Gi/o proteins. In addition, the C-terminal
      cytoplasmic tail is essential for membrane association of D2Rs to elicit the
      receptor functions.

PMID- 15189354
TI  - Multi-modal regulation of endogenous D1 dopamine receptor expression and function
      in the CAD catecholaminergic cell line.
AB  - Dopamine receptors exhibit tissue- and cell type-specific expression that is
      modulated during development, aging and in diseases such as Parkinson's. The
      molecular mechanisms regulating expression of dopamine receptors are not well
      understood, in part due to the lack of a model cell line that not only expresses
      endogenous dopamine receptors but also has the requisite regulatory mechanisms.
      Here, we demonstrate that the CAD catecholaminergic cell line expresses D1, D2,
      D3 and D5 dopamine receptor subtypes and associated signaling proteins. CAD cell
      differentiation induced by serum withdrawal increases the levels of D1 receptor
      mRNA by transcriptional up-regulation. This increase is also mimicked by the
      neurotrophin NT3. Interestingly, the increase of D1 receptor mRNA does not result
      in increased levels of D1 receptor protein in differentiated CAD cells.
      Furthermore, while the D1 receptor protein is expressed in differentiated CAD
      cells, it loses its ability to activate adenylyl cyclase. We demonstrate that the
      post-transcriptional regulation is not due to decreased D1 receptor mRNA
      stability or generation of a truncated D1 receptor mRNA, and that the down
      regulation of D1 receptor function in differentiated CAD cells is mediated by
      post-translational mechanisms that decrease cell surface receptor expression by
      altering receptor processing and trafficking.

PMID- 15189355
TI  - Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin:
      identification of nicastrin mutants that selectively interact with APH-1.
AB  - Gamma-secretase is a high molecular mass aspartyl protease complex composed of
      presenilin (PS1 or PS2), nicastrin (Nct), anterior pharynx-defective-1 (APH-1)
      and presenilin enhancer-2 (PEN-2). The complex mediates the intramembraneous
      proteolysis of beta-secretase cleaved beta-amyloid precursor protein (APP)
      leading to the secretion of the Alzheimer's disease-associated amyloid beta
      peptide (Abeta). In order to dissect functionally important domains of Nct
      required for gamma-secretase complex assembly, maturation, and activity we
      mutated evolutionary conserved amino acids. The mutant Nct variants were
      expressed in a cellular background with significantly reduced endogenous Nct.
      Mutant Nct was functionally investigated by its ability to restore PS, APH-1 and
      PEN-2 expression as well as by monitoring the accumulation of the APP C-terminal
      fragments, the immediate substrates of gamma-secretase. We identified three
      independent mutations within the ectodomain of Nct, which rescued expression of
      APH-1 but not of PEN-2 or PS and thus failed to restore gamma-secretase activity.
      Interestingly, these immature Nct variants selectively bound to APH-1, suggesting
      a stable Nct/APH-1 interaction independent of PS and PEN-2. Consistent with this
      finding, expression of APH-1 remained largely unaffected in the PS double knock
      out and immature Nct co-immunoprecipitated with APH-1 in the absence of PS and
      PEN-2. Taken together, our findings suggest that immature Nct can stably interact
      with APH-1 to form a potential scaffold for binding of PS and PEN-2. Moreover,
      binding of the latter two complex partners critically depends on the integrity of
      the Nct ectodomain.

PMID- 15189356
TI  - MGLuR5 activation reduces beta-amyloid-induced cell death in primary neuronal
      cultures and attenuates translocation of cytochrome c and apoptosis-inducing
      factor.
AB  - Activation of metabotropic glutamate receptor 5 (mGluR5) has been shown to reduce
      caspase-dependent apoptosis in primary neuronal cultures induced by staurosporine
      and etoposide. beta-Amyloid (Abeta)-induced neurotoxicity in culture appears to
      be in part caspase mediated. In the present studies the effects of treatment with
      an mGluR5 agonist or antagonist on Abeta-induced neuronal apoptosis were examined
      in rat cortical neuronal cultures. Pretreatment with the selective mGluR5 agonist
      (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) markedly reduced the number of
      apoptotic cells after exposure to Abeta (25-35), as well as associated LDH
      release. Blockade of mGluR5 by the selective antagonist, 2-methyl-6
      (phenylethynyl)pyridine (MPEP) attenuated these effects of CHPG. A similar
      neuroprotective effect of mGluR5 activation by CHPG was observed in cultures
      treated with full-length Abeta peptide (1-42). CHPG attenuated Abeta (25-35)
      induced cytochrome c release and decreased levels of active caspase-3 protein.
      CHPG also reduced translocation of apoptosis-inducing factor (AIF) induced by
      Abeta (25-35). Thus, mGluR5 activation limits the release of mitochondrial
      proteins associated with induction of both caspase-dependent and -independent
      apoptosis.

PMID- 15189358
TI  - Netrin-1 is crucial for the establishment of the dorsal column-medial lemniscal
      system.
AB  - The dorsal column-medial lemniscal system is a significant sensory pathway that
      mediates touch and limb position sense. In this system, axons from the second
      order neurons in the dorsal column nuclei form the internal arcuate fibers, cross
      the ventral midline (floor plate) within the medulla oblongata, and then project
      to the thalamus as the medial lemniscus. Here we demonstrate that Netrin-1, which
      is secreted from the floor plate in the medulla oblongata, is indispensable to
      the formation of the dorsal column-medial lemniscal system. Axons from the dorsal
      column nuclei cross the midline at around embryonic day 11 in mice. Concurrently,
      Netrin-1 mRNA and its receptor DCC (deleted in colorectal cancer) were expressed
      in the floor plate and commissural axons there, respectively. In our explant
      culture experiments, the floor plates of the embryonic 11-day-old mutant Netrin-1
      homozygous mice did not attract axons from the dorsal column nuclei of ICR mice,
      while those from the wild type littermates did. Moreover, we observed that
      although the dorsal column nuclei developed in situ in mutant mice, their axons
      were not attracted toward the floor plate: they did not cross midline and
      remained ipsilaterally, without forming the internal arcuate fibers, in embryonic
      17-day-old mutant Netrin-1 homozygous mice.

PMID- 15189357
TI  - NMDA-receptor regulation of muscarinic-receptor stimulated inositol 1,4,5
      trisphosphate production and protein kinase C activation in single cerebellar
      granule neurons.
AB  - Inositol 1,4,5-trisphosphate (InsP(3)) production in single cerebellar granule
      neurons (CGNs) grown in culture was measured using the PH domain of phospholipase
      C delta1 tagged with enhanced green fluorescent protein (eGFP-PH(PLCdelta1)).
      These measurements were correlated with changes in intracellular free Ca2+
      determined by single cell imaging. In control CGNs, intracellular Ca2+ stores
      appeared replete. However, the refilling state of these stores appeared dependent
      on the fluorophore used to measure Ca2+-release. Thus, methacholine (MCH), acting
      via muscarinic acetylcholine-receptors (mAchRs), mobilised intracellular Ca2+ in
      cells loaded with fluo-3 and fura-4f, but not fura-2. Confocal measurements of
      single CGNs expressing eGFP-PH(PLCdelta1) demonstrated that MCH stimulated a
      robust peak increase in InsP(3), which was followed by a sustained plateau phase
      of InsP(3) production. In contrast, glutamate-induced InsP(3) signals were weak
      or not detectable. MCH-stimulated InsP(3) production was reduced by chelation of
      intracellular Ca2+ with BAPTA, and emptying of intracellular stores with
      thapsigargin, indicated a positive feedback effect of Ca2+ mobilisation onto PLC
      activity. In CGNs, NMDA- and KCl-mediated Ca2+-entry significantly enhanced MCH
      induced InsP(3) production. Furthermore, mAchR-mediated PLC activation appeared
      sensitive to the full dynamic range of intracellular Ca2+ increases stimulated by
      100 microm NMDA. This dynamic regulation was also observed at the level of PKC
      activation indicated by an enhanced translocation of eGFP-tagged myristoylated
      alanine-rich C kinase substrate (MARCKS) protein in cells stimulated with MCH.
      Thus, NMDA-mediated Ca2+ influx and PLC activation may represent a coincident
      detection system whereby ionotropic and metabotropic signals combine to stimulate
      InsP(3) production and PKC-mediated phosphorylation events in CGNs.

PMID- 15189359
TI  - Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice.
AB  - Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by
      mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for
      these mutations recapitulate many features of this devastating neurodegenerative
      disease. Here we show that the amount of anandamide (AEA) and 2
      arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective
      properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase
      occurs in the lumbar section of spinal cords, the first section to undergo
      neurodegeneration, and is significant before overt motor impairment. Our results
      show that chronic neurodegeneration induced by a genetic mutation increases
      endocannabinoid production possibly as part of an endogenous defense mechanism.

PMID- 15189360
TI  - The effect of metformin on blood pressure, plasma cholesterol and triglycerides
      in type 2 diabetes mellitus: a systematic review.
AB  - BACKGROUND: The UKPDS 34 showed that intensive treatment with metformin
      significantly reduces macrovascular end-points and mortality in individuals with
      newly diagnosed type 2 diabetes compared with intensive treatment with insulin or
      sulphonylurea derivatives, despite similar glycaemic control. How this should be
      explained is as yet unclear. We hypothesized that metformin may have a glucose
      lowering independent effect on blood pressure and lipid profile. In order to test
      this hypothesis we systematically reviewed the literature and pooled the data
      obtained in a meta-analysis. METHODS: Included were randomized-controlled trials
      in patients with type 2 diabetes mellitus and metformin treatment lasting at
      least 6 weeks. To identify all eligible trials we conducted electronic searches
      using the bibliographic databases Medline and Embase, contacted the manufacturer
      and checked obtained publications for cross-references. RESULTS: Forty-one
      studies (3074 patients) provided data on blood pressure and/or lipid profile.
      When compared with control treatment, metformin associated effects on systolic
      and diastolic blood pressure and HDL cholesterol were small and statistically not
      significant [-1.09 mmHg 95% confidence interval (-3.01-0.82), P = 0.30; -0.97 (
      2.15-0.21) mmHg, P = 0.11 and +0.01 (-0.02-0.03) mmol L(-1), P = 0.50,
      respectively]. Compared with control treatment, however, metformin decreased
      plasma triglycerides, total cholesterol and LDL cholesterol significantly [-0.13
      (-0.21--0.04) mmol L(-1), P = 0.003; -0.26 (-0.34--0.18) mmol L(-1), P < 0.0001
      and -0.22 (-0.31--0.13) mmol L(-1), P < 0.00001, respectively]. We found no
      indications for publication bias. Of note, glycaemic control as assessed by HbA1c
      was better with metformin than with control treatment [-0.74 (-0.84--0.65)
      percentage point; P < 0.00001]. When studies were subdivided into tertiles
      according to increasing difference in glycaemic control between metformin and
      control treatment, it appeared that in case of near similar glycaemic control
      metformin had no effect versus control treatment on triglycerides, whereas still
      there was a significant effect on total and LDL cholesterol. CONCLUSIONS: This
      meta-analysis of randomized-controlled clinical trials suggests that metformin
      has no intrinsic effect on blood pressure, HDL cholesterol and triglycerides in
      patients with type 2 diabetes. This drug, however, independent of its effect on
      glycaemia, reduces total and LDL cholesterol significantly, but the reductions in
      these variables are relatively small.

PMID- 15189361
TI  - Low and high circulating cortisol levels predict mortality and cognitive
      dysfunction early after stroke.
AB  - OBJECTIVE: Elevated cortisol levels are associated with confusion and poor
      outcome after stroke. Dehydroepiandrosterone sulphate (DS), the most abundant
      adrenal androgen may act as an anti-glucocorticoid. An altered regulation of
      these steroids may affect numerous brain functions, including neuronal survival.
      The purpose of this study was to investigate serum cortisol and DS levels and the
      cortisol/DS ratio early after stroke and relate our findings to the presence of
      disorientation and mortality. DESIGN: Patients with acute ischaemic stroke (n =
      88, 56 men and 32 women) admitted to a stroke unit were investigated with
      repeated clinical assessments and scores for degree of confusion, extent of
      paresis and level of functioning. Serum cortisol (C) and DS were measured on day
      1 and/or day 4. Data for 28-day and 1-year mortality are presented. A control
      group of 65 age-matched healthy individuals was used. Multivariate analyses of
      mortality rates in the different tertiles or sixtiles of serum cortisol were
      performed with logistic regression, adjusting for age, sex, diabetes and level of
      consciousness. RESULTS: There was no difference in serum cortisol levels on day 1
      for stroke patients when compared with control group values. Initial cortisol
      levels were significantly higher in the patients with acute disorientation versus
      orientated patients (P < 0.05). Cortisol levels on day 1 were an independent
      predictor of 28-day mortality, and patients with low cortisol levels (<270 nmol
      L(-1)) and increased levels (>550 nmol L(-1)) both had an increased 1-year
      mortality. DS levels on day 1 were significantly elevated in stroke patients.
      CONCLUSION: Hypercortisolism is associated with cognitive dysfunction early after
      ischaemic stroke. High and low circulating cortisol levels are associated with
      increased mortality after stroke. DS levels were not associated with clinical
      outcome.

PMID- 15189362
TI  - Relationship between albumin excretion rate and aortic stiffness in untreated
      essential hypertensive patients.
AB  - OBJECTIVES: To evaluate, in a group of nondiabetic essential hypertensive
      patients with normal renal function, the relationship between albumin excretion
      rate (AER) and carotid-femoral pulse wave velocity (PWV), as an index of aortic
      stiffness. DESIGN: Cross-sectional study. SETTING: Outpatient hypertension
      clinic. SUBJECTS: Seventy patients with mild-to-moderate essential hypertension,
      aged 42 +/- 8 years, never pharmacologically treated. All subjects underwent
      routine laboratory tests, 24-h ambulatory blood pressure (BP) monitoring,
      measurement of carotid-femoral PWV, by means of a computerized method, and AER.
      RESULTS: Microalbuminuric patients (AER > or = 20 microg min(-1); n = 19), when
      compared with normoalbuminuric subjects, showed more elevated 24-h BP (136/88 +/-
      10/10 vs. 128/83 +/- 7/6 mmHg; P < 0.001 and P = 0.013, for systolic and
      diastolic BP respectively) and higher values of carotid-femoral PWV (10.4 +/- 2 m
      s(-1) vs. 9.2 +/- 1.3; P = 0.006). This latter difference remained statistically
      significant, even after correction by ancova for 24-h systolic and diastolic BP,
      and body mass index (BMI, P = 0.016). Univariate regression analysis disclosed a
      tight correlation between AER and carotid-femoral PWV (r = 0.42; P = 0.0003).
      This association was confirmed in a multiple regression model (beta = 0.35; P =
      0.009) in which, as independent variables, besides PWV, 24-h BP, age, serum
      glucose values, smoking status, gender and BMI, were added. CONCLUSIONS: Our
      results seem to confirm that microalbuminuria may represent the early renal
      manifestation of a widespread vascular dysfunction, and therefore it is an
      integrated marker of cardiovascular risk.

PMID- 15189363
TI  - Lipoprotein lipase gene variants and progression of nephropathy in
      hypercholesterolaemic patients with type 2 diabetes.
AB  - OBJECTIVE: Recent prospective studies have identified hyperlipidaemia as an
      independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a
      key enzyme in the postprandial processing of triglycerides and VLDL. Among a
      number of common sequence variants of the LPL, HindIII has been associated with
      coronary heart disease and, more recently, with microalbuminuria in type 2
      diabetes. We evaluated the progression of renal disease in hypercholesterolaemic
      type 2 diabetic patients in relation to this polymorphism. DESIGN AND SUBJECTS:
      We followed up for 4 years 65 consecutively enrolled microalbuminuric patients
      with type 2 diabetes; of whom 28 had hypercholesterolaemia (6.62 +/- 0.9 mmol L(
      1), group A) and 37 were normocholesterolaemic (4.68 +/- 0.5 mmol L(-1), group
      B). MAIN OUTCOME MEASURES: After performing the genetic analyses, albumin
      excretion rate (AER) and estimated glomerular filtration rate (GFR), calculated
      by the simplified equation of the MDRD Study Group, were repeated every year.
      RESULTS: In group A, AER increased more (deltaAER: 11 [38] vs. 4 [18] microg min(
      1) per year in group B, P < 0.0001) while GFR declined faster (-3.5 +/- 2.1 vs. 
      2.0 +/- 1.4 mL min(-1) per year, P < 0.02). Patients homozygous for the allele +
      of HindIII showed a significantly faster decline of GFR and a higher increase of
      AER (both P = 0.0001) even after adjustment for cholesterol levels and
      anthropometric variables. CONCLUSIONS: In hypercholesterolaemic type 2 diabetic
      patients with microalbuminuria, the renal disease has an accelerated course,
      particularly in those carrying the H+/H+ genotype of the HindIII polymorphism at
      the LPL locus.

PMID- 15189364
TI  - High incidence of type 2 diabetes and increasing conversion rates from impaired
      fasting glucose and impaired glucose tolerance to diabetes in Mauritius.
AB  - OBJECTIVE: To describe the incidence of different stages of glucose intolerance
      in a population from Mauritius followed over 11 years. RESEARCH DESIGN, METHODS
      AND SUBJECTS: Population-based surveys were undertaken in the multi-ethnic nation
      of Mauritius in 1987, 1992 and 1998 with 5083, 6616 and 6291 participants,
      respectively. Questionnaires, anthropometric measurements, and a 2-h 75-g oral
      glucose tolerance test were included. Three cohorts aged between 25 and 79 years
      with classifiable glucose tolerance data were identified; 3680 between 1987 and
      1992, 4178 between 1992 and 1998, and 2631 between 1987 and 1998. Glucose
      tolerance was classified according to WHO 1999 criteria. RESULTS: The incidence
      rate of type 2 diabetes was higher between 1992 and 1998 than between 1987 and
      1992. In men, the incidence was similar between cohorts (24.5 and 25.4 per 1000
      person-years) whereas the incidence increased in women (23.3 and 16.4 per 1000
      person-years). The incidence of diabetes peaked in the 45-54 year age group and
      then plateaued or fell. The incidences of impaired glucose tolerance (IGT) and
      impaired fasting glucose (IFG) decreased in both men and women. Of normoglycaemic
      subjects at baseline, more women than men developed IGT and more men than women
      developed IFG. Of those labelled as IFG in 1987, 38% developed diabetes after 11
      years. The corresponding figure for IGT was 46%. CONCLUSIONS: In this study, we
      report changes in incidence rates of glucose intolerance over a 11-year period.
      In particular, differences between men and women were observed. The increased
      incidence of IGT in women compared with men, and increased incidence of IFG in
      men compared with women was consistent with, and explains the sex biases seen in
      the prevalences of these states.

PMID- 15189365
TI  - Tyrosine phosphatase 1B and leptin receptor genes and their interaction in type 2
      diabetes.
AB  - OBJECTIVES: The association between three tyrosine phosphatase 1B (PTP1B) gene
      polymorphisms and type 2 diabetes was examined by comparing the prevalence rates
      of these polymorphisms in type 2 diabetic patients and healthy control subjects.
      Furthermore, the association of the polymorphisms and PTP1B and leptin receptor
      (LepR) gene-gene interactions with complications of type 2 diabetes were examined
      in type 2 diabetic patients. SUBJECTS AND METHODS: A total of 257 Finnish
      patients with type 2 diabetes and 285 nondiabetic subjects were screened. Single
      nucleotide polymorphisms were determined using polymerase chain reaction and
      restriction enzymes. The diagnosis of coronary heart disease was based on
      clinical and ECG criteria. The prevalences of cerebrovascular and peripheral
      vascular diseases were assessed on the basis of clinical criteria. Laboratory
      analyses were carried out in the hospital laboratory. RESULTS: We did not find
      any differences in the genotype distributions or allele frequencies of IVS6 +
      G82A and Pro387Leu polymorphisms between the type 2 diabetics and controls. There
      were differences in the genotype frequencies of the Pro303Pro (C981T)
      polymorphism between the two studied groups (P = 0,018); there were eight T981T
      subjects in the control population but none amongst the type 2 diabetics.
      However, there were no differences in the allele frequencies. In addition,
      significant associations between the IVS6 + G82A polymorphism and body mass index
      (BMI), albuminuria, glycohaemoglobin A1 (GHBA1) and hypertension in type 2
      diabetic patients (P = 0,026-0,031) were observed. Pro387Leu and Pro303Pro did
      not associate with risk factors or diabetic complications. We also found a gene
      gene interaction effect between PTP1B and the LepR gene with the genotype
      combination IVS6 + A82A and Arg223Arg having the highest BMI compared with the
      other genotype combinations (P = 0.0043 for trend). The interaction between these
      two polymorphisms explained 3% of the variation in BMI in diabetic patients when
      the other covariates were taken into account. CONCLUSIONS: We conclude that the
      PTP1B IVS6 + G82A polymorphism was associated with BMI, albuminuria, GHBA1 and
      hypertension in type 2 diabetic patients. The 981T/T-genotype of the Pro303Pro-
      polymorphism might have some protective role against the development of type 2
      diabetes. The interaction effects between the PTP1B IVS6 + A82A and LepR
      Arg223Arg genotypes influenced BMI, explaining 3% of its variation. A synergistic
      effect of PTP1B and LepR variants on the leptin signalling may be involved.

PMID- 15189366
TI  - Vitamin D deficiency, bone mineral density and weight in patients with advanced
      pulmonary disease.
AB  - OBJECTIVE: To study the influence of underweight, body composition and vitamin D
      deficiency on bone mineral density in patients with advanced pulmonary disease.
      DESIGN: Cross-sectional study with time span for inclusion set at 5 years.
      SETTING: The clinical work and biochemical analyses were carried out at
      Rikshospitalet University Hospital, Norway. Analyses for vitamin D metabolites
      and bone markers were carried out at Aker University Hospital, and bone
      measurements at Clinic of Osteoporosis. SUBJECTS: Seventy-one candidates for lung
      transplantation (63% chronic obstructive pulmonary disease, 42 underweight and 29
      normal weight) were included. MAIN OUTCOME MEASURES: Body composition, bone
      mineral density at lumbar spine and femur neck, serum concentration of calcidiol
      and vitamin D intake. RESULTS: Subnormal calcidiol levels were present in 52% of
      the underweight patients and 69% of the normal-weight patients. The resulting
      models of linear regression showed that for the lumbar spine T scores model, the
      total variation of 16.7% was explained by group (underweight/normal weight), sex
      and age. For the femur neck T scores model, the total variation of 20.4% was
      explained by the interaction of underweight and vitamin D deficiency (with
      borderline significance) and by arm muscle circumference percentage of standard.
      In patients with normal calcidiol levels, the median intake of vitamin D was 17
      microg in the underweight patients and 11 microg in the normal-weight patients.
      CONCLUSIONS: Vitamin D deficiency was common in both underweight and normal
      weight patients, but only in the underweight patients, an association between
      vitamin D deficiency and reduced femur neck T scores was indicated.

PMID- 15189367
TI  - An open, randomized, controlled study of transdermal hormone replacement therapy
      on the rate of bone loss in primary biliary cirrhosis.
AB  - OBJECTIVES: The prevalence of osteoporosis amongst patients with primary biliary
      cirrhosis (PBC) is high and may be a serious clinical problem. Hormone
      replacement therapy (HRT) is effective in preventing bone loss but has not been
      evaluated in randomized trials in PBC. The primary aim was to study the effect of
      transdermal HRT in combination with daily vitamin D and calcium supplementation
      on bone loss compared with vitamin D and calcium supplementation only in
      postmenopausal women with PBC. The secondary aim was to study the safety of
      transdermal HRT. SUBJECTS/INTERVENTIONS: Eighteen females with PBC were
      randomized to receive 2 years therapy with either (i) transdermal oestradiol 50
      microg 24 h(-1) two times per week + medroxyprogesterone 2.5 mg day(-1) +
      alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1) or (ii) alfacalcidol
      0.25 microg day(-1) and calcium 1 g day(-1). Dual-energy X-ray absorptiometry for
      measurement of bone mineral density (BMD) and sampling of blood and serum for
      measurements of biochemical markers of liver function was performed before,
      during and at the end of treatment. RESULTS: BMD increased significantly at the
      lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas
      no significant change was found in the control group. One oestrogen-treated
      patient was excluded after 1 year because of deteriorating, but reversible,
      aminotransferases. Dropout frequency because of nonliver-related causes was
      higher in the HRT group. Otherwise, no difference with respect to adverse liver
      reactions was found between the groups. CONCLUSION: Transdermal HRT increases BMD
      in PBC patients with few severe side effects related to the liver.

PMID- 15189368
TI  - Estimation of glomerular filtration rate in the elderly: a comparison of
      creatinine-based formulae with serum cystatin C.
AB  - OBJECTIVES: To estimate the prevalence of decreased kidney function in an elderly
      population and to evaluate the impact of using alternative markers of glomerular
      filtration rate (GFR), focusing on serum cystatin C (Cys C) and the Modification
      of Diet in Renal Disease (MDRD) Study prediction equation. DESIGN AND METHODS: In
      a cross-sectional community-based survey renal function was assessed by serum
      creatinine (SCreat), Cys C and GFR predicted by the Cockcroft-Gault (CG) and the
      MDRD Study formulae. Associations with age, gender and proteinuria were analysed
      by linear models. SUBJECTS: A total of 1246 elderly residents in Lieto, Finland,
      64-100 years of age. RESULTS: The prevalence of moderately or severely decreased
      renal function, estimated by the MDRD Study equation, was 35.7%; the CG formula
      yielded 58.6%. The profile of Cys C performance, including variation across age
      groups and level of health status, showed greater similarity to GFR estimated
      using the MDRD Study equation than to SCreat alone, or GFR estimated using the CG
      formula. Discordance between high Cys C levels and only mildly decreased GFR
      estimates was observed in subjects with functional limitations. Microalbuminuria
      was associated with Cys C levels only (P =0.047). CONCLUSION: Prevalence
      estimates of decreased renal function amongst the elderly vary considerably
      depending on prediction formula used. Variation in creatinine metabolism amongst
      elderly comorbid patients and the critical dependence on the SCreat assay and
      exact calibration, make the use of creatinine-based formulae to predict GFR
      questionable in geriatric clinical practice. In this setting, Cys C is a
      promising alternative.

PMID- 15189369
TI  - The incidence and survival of acute de novo leukaemias in Estonia and in a well
      defined region of western Sweden during 1982-1996: a survey of patients aged > or
      =65 years.
AB  - OBJECTIVES: To compare the incidence and survival of acute de novo leukaemias
      with particular reference to political/socio-economic and environmental factors
      in two neighbouring countries over the three 5-year periods (1982-1996).
      PATIENTS: The present report covers only patients diagnosed when aged > or =65
      years. SETTING: A well-defined area of Sweden, the so-called Western Swedish
      Health Care Region and Estonia. Population-wise, the western Swedish Region and
      Estonia are very similar; area-wise they are also well comparable. RESULTS: The
      number of acute de novo leukaemias was quite dissimilar in the two countries
      (Estonia, n = 137, Sweden, n = 354). The age standardized incidence rates
      regarding the total number of acute de novo leukaemias was 5.31 per 100,000
      inhabitants/year for Estonia and 7.99 for Sweden, this difference being
      statistically significant. However, the difference was merely attributable to
      incidence rates as regards acute myeloblastic leukaemias (AML); on the contrary,
      differences as regards acute lymphoblastic leukaemias (ALL) and non-classifiable,
      undifferentiated or biphenotypic acute leukaemias (uAL) were negligible. The
      relative survival for the total material of patients was significantly higher for
      Swedish when compared with Estonian patients (P < 0.001). Thus, the relative
      survival for the total material of patients aged > or =65 years in Estonia at 1
      year was 8.5% and at 3 years 3.5% respectively. The corresponding figures for the
      Swedish patients were considerably higher, 22.7 and 7.7% respectively. This
      difference, however, applied only for patients with AML (P < 0.001), whereas the
      results for patients with ALL and uAL were equally dismal. CONCLUSION: The
      results clearly reflect how political and socio-economic factors may influence
      the survival of acute leukemia patients in two neighbouring countries.

PMID- 15189371
TI  - Zbigniew Kabata.

PMID- 15189370
TI  - Comment on the article 'Genotype, obesity and cardiovascular disease--has
      technical and social advancement outstripped evolution?'.

PMID- 15189372
TI  - Competition for attachment of aquaculture candidate probiotic and pathogenic
      bacteria on fish intestinal mucus.
AB  - Probiotics for aquaculture are generally only selected by their ability to
      produce antimicrobial metabolites; however, attachment to intestinal mucus is
      important in order to remain within the gut of its host. Five candidate
      probiotics (AP1-AP5), isolated from the clownfish, Amphiprion percula (Lacepede),
      were examined for their ability to attach to fish intestinal mucus and compete
      with two pathogens, Aeromonas hydrophila and Vibrio alginolyticus. Two different
      radioactive isotopes were used to quantify competition between pathogens and
      probionts. Attachment of the pathogens was enhanced by the presence of the
      candidate probiotics. However, the addition of the candidate probiotics after the
      pathogens resulted in reduced pathogen attachment. Only AP5 caused lower
      attachment success of V. alginolyticus when added before the pathogen. When AP5
      was added first, the average attachment change was 41% compared with 72% when
      added after V. alginolyticus, suggesting that the probiotic is displaced but that
      enhanced attachment of the pathogen does not occur. Conversely, when V.
      alginolyticus was added first, followed by AP5, attachment change was 37% while
      AP5 had 92% attachment change when added second. This implies that the pathogen
      was displaced by the candidate probiotic and therefore it appeared that, based on
      the ability of probiont AP5 to attach to mucus, the growth of the pathogen in the
      digestive tract might be suppressed by the candidate probiont's presence.

PMID- 15189373
TI  - A sequential study of pathological findings in Atlantic halibut, Hippoglossus
      hippoglossus (L), throughout one year after an acute outbreak of viral
      encephalopathy and retinopathy.
AB  - Following a natural outbreak of viral encephalopathy and retinopathy (VER) at a
      commercial farm in Norway, surviving Atlantic halibut, Hippoglossus hippoglossus,
      were sequentially studied for distribution of nodavirus, immune response and
      histopathology over 1 year. Typical clinical signs and histopathology of VER were
      observed during the acute stage of the disease. Most of the surviving fish became
      subclinical carriers of nodavirus with clusters of nodavirus-containing cells in
      the central nervous system. Four random samplings of presumably healthy fish were
      performed from two fish groups, with low and high growth rates respectively, over
      a 7-month period. Immunohistochemical (IHC) examination revealed a higher number
      of nodavirus-positive cells in fish with a low growth rate than in fish with a
      high growth rate. All IHC positive fish were also reverse transcriptase
      polymerase chain reaction (RT-PCR) positive for nodavirus and for nodavirus
      antibodies detected by enzyme-linked immunosorbent assay (ELISA) at all sampling
      points. The percentage of PCR- and ELISA-positive fish remained high throughout
      the year, while the number of IHC-positive fish decreased, especially in the
      group with a high growth rate. Several other histopathological changes were
      observed, including pericarditis, steatitis, changes in liver and kidney, and
      necrosis of the intestinal wall. None of these findings seemed to be related to
      the nodavirus infection. Nodavirus was reisolated in cell culture from
      subclinically infected fish one year after the acute VER outbreak, which
      indicates that the virus was still infectious.

PMID- 15189374
TI  - In vitro interactions between Neoparamoeba sp. and Atlantic salmon epithelial
      cells.
AB  - Neoparamoeba sp., including the putative aetiological agent of amoebic gill
      disease in cultured fish (N. pemaquidensis), were incubated in vitro with an
      Atlantic salmon gill epithelium (RGE-2) cell line. Proliferation by the amoeba
      population was dependent upon culture osmolarity; no growth occurred at 330 mm x
      kg(-1) but a sixfold increase was observed at 1000 mm x kg(-1). At 780 mm x kg(
      1) there was a fourfold increase in the amoeba population but a concurrent
      decrease in RGE-2 cell density that was significantly greater than that caused by
      the high culture osmolarity alone. This apparent cytopathic effect (CPE)
      developed rapidly and resulted in complete cytolysis of the monolayer in 5 days.
      CPE occurred in multiple foci and presented as cell vacuolation, rounding and
      clumping, and the rapid clearance of large areas of the cell monolayer. The
      possibility that CPE is because of the presence of Neoparamoeba sp. derived
      cytolytic products is discussed in the context of the pathology of the disease in
      vivo and the occurrence of secreted cytopathogenic compounds in other amoeba
      species.

PMID- 15189375
TI  - Heart and skeletal muscle inflammation in Atlantic salmon, Salmo salar L: a new
      infectious disease.
AB  - Heart and skeletal muscle inflammation (HSMI) is a disease syndrome of unknown
      aetiology first observed in farmed Atlantic salmon, Salmo salar, in 1999. In the
      present study we have demonstrated for the first time that HSMI is an infectious
      disease. It was induced in Atlantic salmon post-smolts after injection with
      tissue homogenate from farmed Atlantic salmon previously diagnosed with HSMI. The
      lesions were also induced in cohabitating salmon given a corresponding injection
      without tissue homogenate. Six weeks post-challenge the fish that had been
      injected with tissue homogenate developed a serious epicarditis and myocarditis
      with mononuclear cell infiltrations in compact and spongy layers of the heart.
      Similar lesions were found in cohabitants after 10 weeks. The lesions were
      consistent with samples from field outbreaks of HSMI. No lesions were found in
      control fish. A viral aetiology is strongly suggested, as no difference in
      disease induction between an inoculum containing antibiotics and a non-treated
      inoculum was found. Further investigations are required in order to make
      conclusions regarding the cause and pathogenesis of HSMI.

PMID- 15189376
TI  - Effect of diets containing gossypol on blood parameters and spleen structure in
      tilapia, Oreochromis sp., reared in a recirculating system.
AB  - The high cost of fish meal in tilapia diets warrants the potential use of
      cottonseed meal (CSM) as an alternative source of high quality protein. The
      effects of varying levels of CSM (0, 25, 50, 75 and 100%) as fish meal protein
      replacement on growth, blood parameters, spleen characteristics, free and bound
      gossypol in blood plasma, haemoglobin and haematocrit were determined in tilapia.
      Gossypol (C(30)H(30)O(8)) is a polyphenolic substance found in cottonseed that
      has known toxic effects in fish. Tilapias (n = 219, average weight = 11.3 +/- 3.9
      g) were randomly distributed into 15, 32-L glass aquaria, representing five
      dietary treatments and three replicates per treatment. Each aquarium containing
      13-16 fish was supplied with thermoregulated, recirculating water (27 +/- 1
      degrees C) at 1 L min(-1) flow rate and photoperiod was constant (12 h L/12 h D).
      Fish fed 25-50% CSM protein replacement showed similar body weights and total
      lengths as the controls at the completion of the 16-week trial. Fish fed 75 and
      100% CSM protein replacement showed a significant decline in body weight and
      total length. Fish fed 25-100% CSM protein replacement had significantly lower
      haematocrit and haemoglobin (ANOVA/LSD, P < 0.05) compared with levels in
      controls. The decline was most prominent in groups fed diets with 50-100% CSM
      protein replacement. Total and free gossypol concentrations of blood plasma
      significantly increased with increasing levels of CSM replacement (P < 0.05). No
      gossypol was found in blood plasma of fish from the control group. The occurrence
      of immature and abnormal erythrocytes was significantly greater among fish fed 75
      and 100% CSM diets compared with fish fed 0-50% CSM diets. Spleen-somatic index
      (spleen weight/body weight x 100) did not differ between control fish and fish
      fed 50-100% CSM diets. Spleen abnormalities, such as large depositions of
      haemosiderin and melanin pigments and proliferation of melano-macrophage centres,
      lymphocytic depletion of the white pulp areas (hypocellularity), and presence of
      vacuoles and necrotic areas were observed among fish fed 50-100% CSM protein
      diets. In general, the pathological effects of gossypol in tilapia (low
      haemoglobin and haematocrit levels, abundance of immature red blood cells or
      polychromatocytes, abnormal spleen morphology) were similar to the effects of
      vitamin E and/or vitamin C deficiencies observed in other studies.

PMID- 15189377
TI  - Epithelio-reticular cell thymoma in carp, Cyprinus carpio L: an ultrastructural
      study.

PMID- 15189378
TI  - Developments in the evidence-based health care debate - 2004.

PMID- 15189379
TI  - Reconsidering rationality and ethics in the evidence-based medicine debate: a
      reply to commentators.

PMID- 15189380
TI  - Is there life after evidence-based medicine?
AB  - Recent years have witnessed the rising star of evidence-based medicine (EBM) as
      an approach towards rationalizing clinical practice in the face of an
      exponentially growing body of knowledge. Along with it, however, a sense of
      unease is rising among practising doctors, as they feel that well-intentioned
      principles may be increasingly applied to disease management, with its economic
      and cost-cutting implications, rather than disease cure or treatment. There is a
      fear that any procedure, however time-honoured, that was not or cannot be
      subjected to randomized controlled clinical trial, may some day be discouraged,
      more or less strongly, based on statistical rather than clinical considerations.
      Resistance to EBM ranges from a 'we-know-best' uncompromising non-acceptance to a
      'you-may-be-right-sometimes-but-don't-ever-tell-me-what-to-do' sort of openness.
      The problem is one of measure, in more than one sense: measure of how effective
      individual practitioners are in treating their patients, measure of how useful
      EBM is, measure in promoting what may become a dogmatic application of
      probability laws to the very improbable practice of medicine, measure in siding
      with the supporters of health care on a budget. There is much that EBM can give
      to clinical medicine by its ability to organize complex data sets for the
      ultimate benefit of patients, but there is also much that can stifle practice by
      forcing a dogmatic implementation, rather than a flexible common sense approach,
      of its principles.

PMID- 15189381
TI  - The view of evidence-based medicine from the trenches: liberating or
      authoritarian?
AB  - Evidence-based medicine at first promised to be a popularistic movement, bringing
      the fruits of research to all practising physicians. Instead it has created its
      own religion and dogma, further codifying daily practice.

PMID- 15189382
TI  - Critique of (im)pure reason: evidence-based medicine and common sense.
AB  - While the goal of evidence-based medicine (EBM) is certainly laudable, it is
      completely based on the proposition that 'truth' can be gleaned exclusively from
      statistical studies. In many instances, the complexity of human physiology and
      pathophysiology makes this a reasonable, if not necessary, assumption. However,
      there are two additional large classes of medical 'events' that are not well
      served by this paradigm: those that are based on physically required causality,
      and those that are so obvious (to the casual observer) that no self-respecting
      study will ever be undertaken (let alone published). Frequently, cause-and-effect
      relationships are so evident that they fall into both categories, and are best
      dealt with by the judicious use of common sense. Unfortunately, the use of common
      sense is not encouraged in the EBM literature, as it is felt to be diametrically
      opposed to the very notion of EBM. As is more fully discussed in the manuscript,
      this active disregard for common sense leaves us at a great disadvantage in the
      practical practice of medicine.

PMID- 15189383
TI  - The doctor, his patient, and the computerized evidence-based guideline.
AB  - This paper explores some of the issues raised by the finding in a randomized
      controlled trial (RCT) that general practitioners (GPs) taking part failed to use
      a computerized evidence-based guideline, nor did it have any impact on patient
      outcomes. GPs are expected to 'make an initial decision on every problem
      [patients] may present' and to address psychological and social problems in
      addition to biomedical ones. The computerized guideline imposed an external,
      largely biomedical, agenda that superseded the patient's. This disrupted the
      normal pattern of GP consultations and it was therefore ignored. Guidelines for
      any particular disease are effective if backed up by a detailed programme of
      education and audit. However, the large number of different conditions seen in
      general practice means that it is impractical to have such programmes for more
      than a small fraction of the clinical workload. The reductionist assumptions
      underlying the construction of evidence-based guidelines from systematic reviews
      lead to inflexible recommendations on the management of disease. Anthropologists
      and sociologists make an important distinction between scientifically defined
      diseases and the culturally constructed experience of illness. Because GPs deal
      with patients suffering illness that may or may not result from disease, disease
      centred guidelines often conflict with their needs and wishes. The development of
      evidence-based medicine (EBM) was intended as a tool to help doctors make sense
      of evidence in the context of individual patients' problems. Few GPs are skilled
      in it, and it has been appropriated by powerful expert groups such as guidelines
      developers and the pharmaceutical industry. It is suggested that more
      understanding of EBM by GPs leads to better informed decision making by them and
      their patients.

PMID- 15189384
TI  - Nursing based evidence: moving beyond evidence-based practice in mental health
      nursing.
AB  - Various authors suggest mental health nursing is dominated by knowledge borrowed
      from psychiatry, pharmacology and the behavioural sciences. These disciplines
      favour knowledge developed using quantitative methodologies so they and evidence
      based practice (EBP) and evidence-based nursing (EBN), increasingly called for in
      mental health nursing, fit seamlessly together. Nevertheless, as these movements
      dismiss qualitative approaches to knowledge (evidence) development, I argue
      against the move toward EBP/EBN in mental health nursing. This is because the
      specialty's primary interests - human experiences of illness/health care and
      human relationships, often do not lend themselves to being quantitatively
      researched. Using nursing examples, I demonstrate how qualitative research,
      wholly unacceptable in relation to EBP/EBN quality of evidence scales, is
      indispensable to mental health nursing. The need for evidence arising from
      qualitative research in no way precludes the need for quantitatively derived
      evidence. Indeed, the specialty's twofold interest - the work of nurses with
      clients and the explication of phenomena which inform practice, require diverse
      knowledge and thus, diverse research approaches. This twofold interest defines
      the area of mental health nursing practice, and knowledge informing it is
      referred to as nursing based evidence (NBE). Because it values multiple
      approaches to knowledge development, NBE provides a way to articulate the
      specialty's distinct contribution to the health care of people experiencing
      mental illness and advances mental health nursing.

PMID- 15189385
TI  - Evidence-based practice - an incomplete model of the relationship between theory
      and professional work.
AB  - RATIONALE, AIMS AND OBJECTIVES: Current day realities of diminishing resources,
      reductions in spending and organizational change within health care systems have
      resulted in an increased emphasis on a multidisciplinary team approach to quality
      patient care. The movement of nursing towards more autonomous practice combined
      with the current trend towards 'evidence-based practice' in health care demands
      increased accountability in clinical decision making. This paper focuses on one
      aspect of nurses' clinical decision making within the demands of evidence-based
      practice and cardiac surgery. In this field recent advances, combined with
      increasing demands on health care institutions, have promoted early extubation of
      post-operative cardiac patients. While this remains a medical role in many
      institutions, an increasing number of intensive care units now consider it as a
      nursing role. METHOD: This paper explores the realities of nurses' clinical
      decision making through a discussion of current practice in the extubation of
      patients following cardiac surgery. In addition, it considers the implications of
      current practice for both nurse education and the continued development of
      clinical nursing practice. CONCLUSION: The findings indicate that evidence-based
      practice appears to be an incomplete model of the relationship between theory and
      professional work.

PMID- 15189386
TI  - Attitudes and knowledge of primary care professionals towards evidence-based
      practice: a postal survey.
AB  - OBJECTIVES: To describe the attitudes, awareness and use of evidence across key
      professional groups working in primary care. METHODS: A postal questionnaire was
      sent to all lead/chairs, general managers, clinical governance leads, lead
      nurses, lead pharmacists and public health practitioners working in local health
      care cooperatives in Scotland. RESULTS: 289 (66.1%) health care professionals
      responded, ranging from 51% of general managers to 80% of lead nurses. All
      professional groups supported evidence-based practice. General practitioners
      (GPs) were less likely to agree that they had the skills to carry out literature
      reviews or appraise evidence compared to nurses and public health facilitators
      (36% vs. 75% vs. 80%; 51% vs. 64% vs. 70%). Access to the internet and
      bibliographic databases was good for all groups but GPs used a narrower spectrum
      of evidence-based journals, relying mainly on medical literature. Only nurses and
      public health practitioners appeared to have any understanding of qualitative
      research terms. Public health practitioners were also least likely to view
      guidelines or protocols developed by others as the best source of evidence for
      primary care. The major perceived barrier to practising evidence-based practice
      was time. Consequently the most important facilitator was protected time, but
      increased resources (financial and staff) and training were also cited.
      Professional groups other than GPs perceived inter-professional boundaries as a
      barrier and suggested multi-professional teamworking and learning as potential
      supports for evidence-based practice. CONCLUSIONS: While all professional groups
      welcome and support evidence-based practice, there are clear differences in the
      starting point and perspectives across the groups. These need to recognized and
      addressed to ensure that learning the skills of evidence-based practice and
      implementing evidence are effective. This will also enhance the ability of
      primary care organizations to develop robust mechanisms for supporting key
      aspects of clinical governance.

PMID- 15189387
TI  - Do physiotherapists' attitudes towards evidence-based practice change as a result
      of an evidence-based educational programme?
AB  - RATIONALE: The concept of evidence-based practice (EBP) encourages health care
      professionals to provide the most effective health care, and to be accountable
      for the interventions they provide. Little work has been undertaken to examine
      how practically allied health professionals' encompass EBP and how they
      perceptive and understand the concept of EBP. The use of opinion leaders to
      disseminate new evidence into practice, and thereby encourage the behaviour of
      health care professionals has been proposed. AIMS: The aims of this study were to
      investigate physiotherapists' attitudes towards EBP and to examine change in
      their attitudes following an education package, which utilized local opinion
      leaders. METHOD: Thirty musculoskeletal physiotherapists from a Community Trust
      in North Staffordshire were cluster randomized by location of work to two groups.
      The intervention group received an evidence-based programme on aspects of EBP
      including literature searching and critical appraisal. The attention control
      group received a standard in-service training package on the management of common
      knee pathologies. The physiotherapists' attitudes towards EBP were measured at
      baseline (before randomization) and at 3 and 6 months follow-up. RESULTS:
      Physiotherapists reported that they primarily relied on 'courses' and 'in-service
      training' for informing their clinical practice. Most agreed that clinical
      practice should be based on the best available evidence and that they would
      change their clinical practice if evidence suggested they should do so. However,
      many of the physiotherapists reported difficulty in reading journals and could
      not identify opinion leaders in key areas. In terms of clinical practice,
      literature, journals and research were ascribed low priority throughout.
      Differences in attitudes between the intervention and control groups were
      observed in relation to management support for EBP at 3 and 6 months follow-up.
      CONCLUSIONS: In this study, physiotherapists appeared to be in favour of the idea
      of EBP, yet they remained reluctant to change their practice. Opinion leaders
      were not easily identifiable by physiotherapists, suggesting that this method
      alone may not be an effective method of changing attitudes in clinical practice.
      The process of changing attitudes in the clinical environment is a complex issue
      worthy of further research.

PMID- 15189388
TI  - Hospital doctors' self-rated skills in and use of evidence-based medicine - a
      questionnaire survey.
AB  - RATIONALE, AIMS AND OBJECTIVES: Problems in understanding basic aspects of
      evidence-based medicine (EBM) may form barriers to its implementation into
      clinical practice. We examined hospital doctors' skills in EBM terms and related
      these skills to their use of information sources, critical appraisal, and
      implementation of EBM into clinical practice. METHODS: A self-administered
      questionnaire was sent to all hospital doctors (n = 376) at a university hospital
      in Denmark, including 12 questions on methodological terms frequently used in
      evidence-based literature plus one non-existing dummy term. Furthermore,
      participants were asked about their use of various information sources, self
      rated skills of critical appraisal of standard scientific literature, and level
      of implementation of evidence-based principles in daily clinical settings. Based
      on the answers to the 12 evidence-based methodological terms, we calculated a
      familiarity score. RESULTS: Proportion of responding was 60% (n = 225), but
      representative for all hospital doctors regarding background data. Ten doctors
      (4.4%) could define and explain all 12 methodological terms. The majority of all
      doctors showed interest in knowing more about the terms. Fifty-six per cent knew
      the dummy term. Doctors mainly consulted traditional and possibly insufficient
      sources (textbooks, colleagues, scientific journals) when searching for clinical
      evidence. The Cochrane Library was the least consulted information source and had
      never been consulted by 49%. Only 18% always practised EBM. More reliance on
      PubMed and The Cochrane Library as information sources, more competence of
      critical appraisal, and more frequent practise of EBM were significantly (P <
      0.001) associated with a higher familiarity score. Compared to seldom or never
      users of The Cochrane Library, frequent users had significantly higher academic
      degree (P = 0.01), familiarity score (P < 0.001), and use of PubMed (P = 0.0004).
      DISCUSSION AND CONCLUSIONS: Most hospital doctors seem to lack knowledge of key
      methodological evidence-based medicine terms. This may form a barrier when
      consulting EBM sources and to the implementation of EBM into clinical practice.

PMID- 15189389
TI  - Provider-perceived barriers and facilitators for ischaemic heart disease (IHD)
      guideline adherence.
AB  - RATIONALE, AIMS AND OBJECTIVES: Clinical practice guidelines have become a
      standard way of implementing evidence-based practice, yet research has shown that
      clinicians do not always follow guidelines. METHOD: As part of a larger study to
      test the effects of an intervention on provider adherence to ischaemic heart
      disease (IHD) guidelines, we conducted five focus groups at three Veterans
      Administration Medical Centers with 32 primary care providers, cardiologists, and
      internists to identify key barriers and facilitators to adherence of the
      guidelines. Using content analysis, responses were grouped into categories.
      RESULTS: The main perceived advantages of using the IHD guidelines were
      improvements in quality and the cost of care. Perceived barriers were the lack of
      ability of guidelines to manage the care of any one individual patient, the
      difficulty of accessing guidelines, and high workloads with many complex
      patients. While providers agreed on the benefits of aspirin, beta-blockers and
      angiotensin converting enzyme inhibitors, barriers for use of these medications
      were lack of consensus about contraindications, difficulty in providing follow-up
      during medication titration, and lack of patient adherence. Sources of influence
      for guideline use were: professional cardiology organizations, colleagues, mainly
      cardiologists, and key cardiology journals. However, most providers acknowledged
      that following guidelines was a personal practice decision. CONCLUSIONS: While
      results validated the influences of using clinical practice guidelines, our
      results highlight the importance of ascertaining guideline-specific barriers for
      building effective interventions to improve provider adherence. An advisory panel
      reviewed results and, using a modified nominal group process, chose
      implementation strategies targeting key barriers.

PMID- 15189391
TI  - Systematic review of published multi-practice audits from British general
      practice.
AB  - BACKGROUND: Audit has been a major part of attempts to improve patient care in
      Britain, with substantial resources devoted to it since the 1990 National Health
      Service reforms. Systematic reviews have considered audit to be of variable, but
      often moderate, effectiveness. However, these have included few studies from
      British primary care, and as quality improvement activities may be context
      specific, it is hard to judge how effective audit has been here. RESULTS: A
      search for audits published in peer-reviewed journals revealed 48 two-stage
      projects carried out in British general practice, of which 27 principally
      concerned chronic disease management and nine prescribing. Most audits showed
      some improvements in performance, and those using controls showed 27/56 (48%)
      parameters had changed significantly (P < 0.05). CONCLUSIONS: This review adds
      further evidence that audit can often be moderately effective. However, it is
      frequently used as one of a complex set of interventions making precise
      evaluation difficult. Those responsible for clinical governance will need to
      choose carefully the subjects they audit in order to use their limited resources
      to maximum effect. These projects are illustrative examples but once again do not
      identify any 'magic bullets' that would be highly likely to improve professional
      performance.

PMID- 15189390
TI  - A multidisciplinary guideline for the acute phase of stroke: barriers perceived
      by Dutch neurologists.
AB  - RATIONALE, AIMS AND OBJECTIVES: Guidelines for stroke management should improve
      quality of care. Dissemination of guidelines, however, does not guarantee
      guideline adherence. The aim of this paper is to investigate barriers for
      guideline adherence to bring about suggestions for possible implementation
      strategies. METHOD: Questionnaire survey among all Dutch neurologists working on
      neurology wards in general hospitals during the year 2000 in The Netherlands.
      RESULTS: The neurologists expressed a high degree of agreement with the
      diagnostic and preventive recommendations, but expressed doubts with regard to
      the therapeutic recommendations, especially for the recombinant tissue
      plasminogen activator therapy. In general, barriers at the organizational and the
      multidisciplinary team level were most prominent. CONCLUSIONS: Active
      implementation of the guidelines seems necessary. Implementation strategies
      should be focused on the different sources of barriers: the caregiver, the
      patient and the organization of care.

PMID- 15189392
TI  - National clinical sentinel audit of evidence-based prescribing for older people.
AB  - OBJECTIVES: To audit the performance of hospitals in evidence-based prescribing.
      SETTING: All hospitals in England were invited to participate. The audit was
      completed in 62 hospitals. SUBJECTS: Prescribing and clinical data were collected
      on 100 consecutive medical inpatients aged >/= 65 years at each site, enabling
      evaluation of eight prescribing indicators before and after intervention. The
      data were collected using a specifically designed database. INTERVENTIONS: The
      results of the first audit were available immediately from the software and a
      national report with locally identifiable information was returned to hospitals.
      Hospitals were encouraged to design and deliver their own intervention strategy.
      A questionnaire was sent to all hospitals to document prioritization of
      indicators. RESULTS: Generic names were used for 36 061 (82.6%) in 1999 and 39
      188 (86.4)% in 2000. In 1999, 50% (3074) of patients had documentation of allergy
      status. This increased to 60% (3684) in 2000. For 21.2% of patients prescribed
      paracetamol in 1999 and 18.1% in 2000, the prescription was written such that it
      was possible to exceed the maximum recommended dose of 4 g in 24 hours. Long
      acting hypoglycaemic drugs were prescribed to 29 patients in 1999 and 20 patients
      in 2000. Anti-thrombotics were used appropriately for 54% (520/966) of patients
      in atrial fibrillation in the first audit and 57% (579/1019) in the second audit.
      The appropriate use of aspirin increased from 91% (595/651) to 94% (725/772) and
      the appropriate use of benzodiazepines dropped from 49% (537/1088) to 47%
      (460/966) between the audits. For three indicators, the allocating of a high
      priority translated into a bigger improvement between the audits. CONCLUSIONS:
      Local ownership of data and the quality improvement process, and provision of
      national benchmarking data did not result in a significant improvement in
      prescribing in the second audit.

PMID- 15189393
TI  - A prospective study of the practical issues of local involvement in national
      audit of COPD.
AB  - RATIONALE, AIMS AND OBJECTIVES: Variation in quality of local services is of
      great concern to the government and public. National audit is an important means
      of providing data of comparative performance but is hampered at local level by
      poor methodology including audit design, standard setting and data collection
      tools. A pilot audit of the hospital care of patients admitted with acute chronic
      obstructive pulmonary disease (COPD) was performed in preparation for a national
      audit programme and was designed and supported by experts. It was hoped to
      overcome these barriers. We report a prospective evaluation of the practical
      issues involved in local participation of hospital audit of COPD care within a
      national framework. METHODS: Hospitals were recruited to the study by random
      selection and voluntary participation. A clinical audit study was completed over
      an 8-week period immediately followed by a survey of clinicians and audit staff
      to identify positive and negative issues of participation and the process
      required to achieve a successful outcome. RESULTS: Forty-one hospitals were
      invited to participate, 26 (63%) accepted, and four others volunteered to meet
      the target of 30 enrolled centres. Reasons cited for non-participation were of
      inadequate resources amongst either clinicians or audit departments or prior
      engagement in other national or local audit schemes. Following completion of the
      audit most (81%) participating units reported it was a useful exercise and were
      willing to be involved in future audits. Negative aspects of involvement included
      the lack of dedicated time and manpower for audit, poor information technology
      and inadequate systems for identifying patient diagnoses either at admission or
      at discharge and incomplete case note entries. Methodological issues such as
      study design and data collection tools were not cited as important barriers to
      participation. CONCLUSION: There is local willingness to be involved in national
      audit of hospital care of COPD and central provision of expert design of methods
      and tools may reduce some audit barriers. Nevertheless, priority must be given to
      improving resources identified to support audit and in improving methods and
      systems for data capture. These issues appear to be important in most units and
      represent a potentially serious barrier to achieving widespread local involvement
      in a national audit programme of COPD care and may also apply to other national
      audits designed to provide comparative assessment of National Health Service
      services.

PMID- 15189394
TI  - Clinical trials: deliberations on their essence and value.
AB  - RATIONALE, AIM & OBJECTIVES: In the context of the evidence-based medicine (EBM)
      movement, the clinical trial has come to be hailed as the ultimate source of
      medical knowledge, and especially of clinical pharmacology. By subjecting the
      premises of this procedure to a thorough analysis, the author hopes to achieve a
      sound rating of its epistemological significance in the context of medical
      research. METHOD: Current claims on the basic importance of the evidence provided
      by standardized clinical trials are confronted with conflicting observations
      concerning their current application in medical practice. The stereotyped trials
      of present research in multiple sclerosis serve as an example to illustrate this
      point. RESULTS: Traditional assumptions concerning the validity of standardized
      clinical trials are based on an illusion of absolute objectivity and reliability.
      Apart from being subject to tough publish (conveniently)-or-perish and commercial
      influences, the results of clinical trials, especially drug trials, are of
      limited informative value in diverse respects, such as (i) clinical trials do not
      identify every possible drug reaction for every instance of a disease; (ii) their
      results never allow the prediction of the efficacy of a specific drug in any
      given individual; (iii) clinical trials have no inherent potential to provide
      concrete insights into the nature and cause(s) of a definite morbid condition;
      and (iv) extensions of clinical drug trials to ever-larger study groups indicate
      serious problems in basic theoretical respects. CONCLUSION: A clinical trial
      cannot indicate a certain prevention or cure for any particular instance of a
      disease, and the correctness of its individual predictions is always only
      contingent. This can be explained by the fact that the correspondence between the
      nature of each of all pathological conditions presented by the different members
      of a clinical trial population and by the individual patients being treated
      according to the results of the trial is never complete.

PMID- 15189395
TI  - Evaluating the effectiveness of asthma treatment in real-life practice.
AB  - RATIONALE, AIMS AND OBJECTIVES: The randomized controlled trial (RCT) is
      considered the gold standard methodology for determining the efficacy and
      tolerability of new treatments. However, RCTs cannot provide information on the
      effectiveness of interventions as they are used in real life. This study was
      conducted to investigate the effectiveness of montelukast, a leukotriene receptor
      antagonist, in the real-world management of asthma, through a large-scale,
      retrospective, observational study: the National Montelukast Survey. METHODS: In
      order to ensure a robust methodology for the National Montelukast Survey we
      performed three pilot studies involving a total of almost 400 patients. During
      the pilots, the design of the study was extensively modified from a simple
      prescriber questionnaire used in the first pilot to the 'triangulated'
      methodology encompassing the perspectives of patient, prescriber and independent
      observer used in the National Montelukast Survey. Good levels of interobserver
      agreement confirmed the robustness of the final methodology. CONCLUSIONS:
      Achieving a robust methodology was dependent on the extensive piloting. It is
      possible to collect reliable observational data relating to treatment outcomes.
      We believe our methods are likely to have more widespread applicability and offer
      a potential improvement over postmarketing surveillance.

PMID- 15189396
TI  - Design and analysis of pilot studies: recommendations for good practice.
AB  - Pilot studies play an important role in health research, but they can be misused,
      mistreated and misrepresented. In this paper we focus on pilot studies that are
      used specifically to plan a randomized controlled trial (RCT). Citing examples
      from the literature, we provide a methodological framework in which to work, and
      discuss reasons why a pilot study might be undertaken. A well-conducted pilot
      study, giving a clear list of aims and objectives within a formal framework will
      encourage methodological rigour, ensure that the work is scientifically valid and
      publishable, and will lead to higher quality RCTs. It will also safeguard against
      pilot studies being conducted simply because of small numbers of available
      patients.

PMID- 15189397
TI  - Adjusting for publication bias: modelling the selection process.
AB  - RATIONALE, AIMS AND BACKGROUND: Systematic review with meta-analysis, a
      statistical technique for combining results of several studies, is progressively
      being used to guide decisions in medicine. Publication bias is acknowledged as a
      threat to the validity of systematic reviews and its existence may lead to
      inappropriate decisions about patient management or health policy. It is said to
      occur when the results of research available in the literature are not
      representative of the totality of all research. The selection mechanism that
      causes publication bias is complex, yet despite an extensive literature of
      empirical research identifying risk factors for publication, little work has been
      done to improve models of selection. Methods METHODS: that adjust combined meta
      analytic estimates for publication bias are compared and applied to a systematic
      review of oral rehydration solution in the treatment of dehydration. Within a
      weighted distributions framework models of the selection process are considered
      and developed further. CONCLUSIONS: Weighted distributions offer a flexible
      approach that allows the potential to modify the selection function to
      incorporate other factors. Methods that adjust combined estimates should not be
      used to provide an alternative answer but to consider the robustness of the
      combined estimate to publication bias.

PMID- 15189398
TI  - A practical approach to a multi-level analysis with a sparse binary outcome
      within a large surgical trial.
AB  - OBJECTIVES: To assess the potential source of variation that surgeon may add to
      patient outcome in a clinical trial of surgical procedures. METHODS: Two large (n
      = 1380) parallel multicentre randomized surgical trials were undertaken to
      compare laparoscopically assisted hysterectomy with conventional methods of
      abdominal and vaginal hysterectomy; involving 43 surgeons. The primary end point
      of the trial was the occurrence of at least one major complication. Patients were
      nested within surgeons giving the data set a hierarchical structure. A total of
      10% of patients had at least one major complication, that is, a sparse binary
      outcome variable. A linear mixed logistic regression model (with logit link
      function) was used to model the probability of a major complication, with surgeon
      fitted as a random effect. Models were fitted using the method of maximum
      likelihood in SAS. RESULTS: There were many convergence problems. These were
      resolved using a variety of approaches including; treating all effects as fixed
      for the initial model building; modelling the variance of a parameter on a
      logarithmic scale and centering of continuous covariates. The initial model
      building process indicated no significant 'type of operation' across surgeon
      interaction effect in either trial, the 'type of operation' term was highly
      significant in the abdominal trial, and the 'surgeon' term was not significant in
      either trial. CONCLUSIONS: The analysis did not find a surgeon effect but it is
      difficult to conclude that there was not a difference between surgeons. The
      statistical test may have lacked sufficient power, the variance estimates were
      small with large standard errors, indicating that the precision of the variance
      estimates may be questionable.

PMID- 15189399
TI  - Reviewing measures of outcome: reliability of data extraction.
AB  - RATIONALE, AIMS AND OBJECTIVES: Although there is wide acceptance of the
      necessary domains for the evaluation of measures of health outcome, there has
      been little development or evaluation of methods of data extraction, such as
      checklists. This study aimed to assess the inter-rater reliability of data
      extraction from published articles using a new electronic database developed for
      structured reviews of health outcome measures. METHODS: Domains considered
      important in the evaluation of measures of health outcome provided the foundation
      for a checklist for data extraction using a new electronic database. The database
      utilized Microsoft Access 2000 software (Microsoft Corporation, 2000). Following
      training, three independent reviewers extracted data from seven selected articles
      using the electronic database, and assessed article and measure quality against
      pre-defined criteria. Data extraction was compared for consistency and item
      content. Inter-reviewer agreement for categorical data was assessed by multiple
      kappa correlation. RESULTS: Analysis demonstrated strong agreement between
      reviewers for all aspects of data extraction. However, lack of clarity in
      published articles affected the ability to clearly identify measures of outcome.
      CONCLUSIONS: The high level of inter-reviewer agreement supports the use of
      multiple trained reviewers in data extraction for reviews of measures of outcome
      using the checklist and Access software described. The electronic database
      supports standardized data extraction from published articles, benefiting from
      the combination of data extraction and data entry in a single step. Adaptation of
      the database to support structured reviews of measures of outcome adopted in the
      evaluation of other health states is proposed.

PMID- 15189400
TI  - Multi-item outcome measures for lateral ligament injury of the ankle: a
      structured review.
AB  - OBJECTIVE: To identify and review evidence relating to the measurement properties
      of published multi-item outcome measures for the conservative management of
      lateral ligament injuries of the ankle. METHODS: Systematic literature searches
      were used to identify measures, which were then assessed against pre-defined
      criteria relating to development, item content, reliability, validity and
      responsiveness. RESULTS: Seven disease-specific measures of ankle status [Ankle
      Joint Functional Assessment Tool, Clinical Trauma Severity Score, Composite
      Inversion Injury Scale, Kaikkonen Functional Scale (KFS), Karlsson Ankle Function
      Score (KAFS), Olerud and Molander Ankle Score (OMAS), and the Point System] and
      two generic measures of health (McGill Pain Questionnaire, Sickness Impact
      Profile) met the review inclusion criteria. While all measures had been used in
      acute injuries, only two had also been applied during later stages of recovery
      (>6 months). The studies covered a comprehensive range of graded ligament
      injuries. Expert opinion dominated item generation for all measures. All measures
      lack evidence of test-retest or internal consistency reliability in patients with
      ankle sprain. Several measures were assessed for validity through comparison with
      other measures, but there was limited evidence of construct validity and no
      formal assessment of responsiveness for any measure. CONCLUSION: The
      disappointing lack of evidence for measurement properties suggests that any
      measure should be used with caution until appropriate evidence is provided. On
      the basis of limited evidence, the KFS offers the most promising approach to a
      combined clinician- and patient-assessment of ankle function, and the KAFS or
      OMAS if a patient-assessed evaluation of function is required.

PMID- 15189401
TI  - Knowledge base of scientific gnosis: I. Knowledge base of scientific gnosis as
      one of occurrence relations.

PMID- 15189402
TI  - Knowledge base of scientific gnosis: II. Gnostic occurrence relations: elements
      and temporal structures.

PMID- 15189403
TI  - Knowledge base of scientific gnosis: III. Gnostic occurrence relations as
      regression functions.

PMID- 15189404
TI  - Knowledge base of scientific gnosis: IV. Knowledge base of scientific gnosis vis
      a-vis evidence base of this.

PMID- 15189405
TI  - Discharge from hospital: crocodile-infested water.

PMID- 15189406
TI  - Lecturer practitioners in six professions: combining cultures.
AB  - BACKGROUND: Whilst research has been undertaken in relation to the lecturer
      practitioner role in nursing, there have been no cross-professional studies.
      There is an explicit political agenda in the United Kingdom on interprofessional
      education and enhancing the status of those who provide practice-based teaching.
      AIM: This paper reports a study to investigate the commonalities and differences
      between lecturer practitioners across professions and to generate hypotheses
      about the role, which follows different models of practice in the different
      professions. METHODS: An exploratory research design was adopted, using semi
      structured interviews with a purposive sample of lecturer practitioners from six
      professions (architecture, clinical psychology, law, medicine, nursing and social
      work). A grounded theory approach was used. FINDINGS: All lecturer practitioners
      perceived a clear dichotomy between their professional practice role and their
      university role. All used similar strategies to adapt to and deal with combining
      two very differently perceived cultures. There were striking similarities in
      response to the consequences of serving "two masters" in the areas of time
      management and role identity/definition. CONCLUSIONS: The role not only bridges
      theory and practice, but has to operate within very different organizational
      cultures. Further research is needed to test the generalizability of the
      findings. Relevance to clinical practice. This investigation aims to inform
      higher education and health service policy on lecturer practitioners, and also
      provide support for those undertaking this challenging role. The study poses
      challenging questions for policymakers in the current climate of
      interprofessional learning, which need to be addressed if future initiatives in
      this area are to be successful.

PMID- 15189407
TI  - Blood exposure: factors promoting health care workers' compliance with guidelines
      in connection with risk.
AB  - BACKGROUND: Health care workers compliance with guidelines, universal
      precautions, in connection with tasks that could involve contact with patient's
      blood is unsatisfactory. In a previous paper, we identified different forces that
      undermine compliance. Socialization into infection control, routinization,
      stereotyping, perceptions of patients' wishes and the presence of competing
      values and norms are examples of such forces. AIMS AND OBJECTIVES: The aim of
      this article is to describe and analyse different forces that promote adherence
      to universal precautions. Behavioural variations are seen as a consequence of
      differences between wards with regard to the safety culture. Safety culture is
      conceptualized as the outcome of a constant interplay between deactivating and
      reactivating forces. In this article the focus is on the latter. METHOD: The
      grounded theory approach. Data were collected through interviews with nurses and
      assistant nurses. RESULTS: The charge nurse, informal leaders, students,
      infection control nurses, type of work, availability of equipment, blood-exposure
      incidents and media-coverage of infectious diseases are described as potentially
      important for compliance. The properties these agents must possess in order to be
      influential are also described. RELEVANCE TO CLINICAL PRACTICE: The outcome of an
      occupationally acquired infection can be fatal. Hence it is important that health
      care workers take protective measures. The results imply that mere information
      about safe practices alone is insufficient to achieve that goal. All factors of
      importance for compliance must be taken in to consideration in clinical work and
      in education.

PMID- 15189408
TI  - Technology--an actor in the ICU: a study in workplace research tradition.
AB  - BACKGROUND: The present study focuses on human-machine interaction in an
      intensive care unit in the West of Sweden. AIMS: The aim of the present study was
      to explore how technology intervenes and challenges the ICU staff's knowing in
      practice. THEORETICAL PERSPECTIVE: The study's theoretical starting point draws
      on workplace research tradition. Workplace studies encompass the interaction
      between the actors' situated activities and the technological tools that make
      their activities possible. METHOD: Fieldwork or in situ studies of everyday
      practice in an intensive care unit documented in written field notes constituted
      the data. RESULTS: The findings show first how technology intervenes in the
      division of labour when the taken-for-granted "old" everyday practice is
      disrupted when a new machine intervenes in the morning's work; secondly, it
      reveal how technology challenges practical knowing and thirdly, it shows how
      technology reformulates practice. Staff members' awareness of routine problems is
      often connected to the ability to see, which is always related to
      cultural/contextual competence. CONCLUSION: It is concluded that it is not talk
      alone that helps the caregivers to "(dis)solve" the problems. The ability to see
      the problems, the work environment and to find the relevant supporting tools for
      "(dis)solving" the routine problems is also crucial. But it is not possible to
      say that it is the skillful work of humans that solve problems, nor do we claim
      it is the tools that do so. Humans and tools are interwoven in the problem
      solving process. Relevance to clinical practice. Routine problems in the
      intensive care unit are not "(dis)solved" through the cognitive work of
      individual staff members alone. Problems are also "(dis)solved" jointly with
      other staff members. Staff members "borrow" the knowing from each other and
      problems are re-represented through communication. The knowing has to be
      distributed among the intensive care unit staff to make the everyday work
      flexible.

PMID- 15189409
TI  - Discharge planning: "fooling ourselves?"--patient participation in conferences.
AB  - BACKGROUND: The aim of discharge planning conferences (DPCs) is to co-ordinate
      resources and to enhance patient involvement in care in connection with
      relocation from hospital. DPCs can be characterized as institutional
      conversations, and are often executed as standard procedures, but the scientific
      basis for the activity is weak. AIMS AND OBJECTIVES: The aim of this study was to
      illuminate and describe the communication at DPCs. DESIGN: A purposeful and
      consecutive sample of eight DPCs was collected in which the future care of eight
      women, aged 70 years or more, was discussed. METHODS: Transcribed video
      recordings were analysed in two steps. "The initial analysis" aimed at describing
      the structure and content of the communication. This description constituted the
      basis for an interpretation, leading to "the focused analysis" aiming at finding
      evidence for the assumptions made in the interpretation. RESULTS: The result
      revealed that the participation of patients was very less the DPCs. The decisions
      had often already been made, and the women were expected to be pleased with the
      decision; institutional representatives (IRs) frequently justified their actions
      by referring to bureaucratic praxis. CONCLUSIONS: The women were both encouraged
      and excluded from participation by the IRs. This dichotomy occurred because the
      IRs, as professionals, struggled to simultaneously realize their caring mission
      and their obligation to enforce the values and rules of the institution, i.e.
      efficiency and rationality. Thus, IRs and patients were equally imprisoned within
      the institutional system. RELEVANCE TO CLINICAL RESEARCH: This result illustrates
      how conflicting paradigms are imbedded and reproduced by healthcare professionals
      in their communicative praxis. Awareness of this is a prerequisite for
      improvements in working procedures congruent with a caring paradigm that support
      patient participation.

PMID- 15189410
TI  - Learning disabilities: a survey of community nurses for people with prevalence of
      challenging behaviour and contact demands.
AB  - BACKGROUND: There is scant knowledge on the contacts community nurses for people
      with learning disabilities have with clients who display challenging behaviours,
      or the numbers of such people on these nurses' caseloads. This study was
      undertaken in a UK region with a population of 1.68 million people. In this
      region it is estimated that there are 8500 people with learning disabilities who
      are in contact with services, this includes around 500 people remaining in
      hospitals awaiting resettlement. AIMS AND OBJECTIVES: The research aims were to
      identify the overall caseload sizes of the nurses, the prevalence of people with
      learning disabilities who have challenging behaviours on the nurses' caseloads
      and what contact demands these people required. An additional aim was to discover
      courses or training that helped the nurses to fulfill their roles. DESIGN AND
      METHODS: A postal survey was undertaken of the total population of community
      nurses for people with learning disabilities in the region. The method of data
      collection was a self-completion questionnaire. RESULTS: The study found that
      people with challenging behaviours accounted for over a quarter of the combined
      caseloads, and these clients required the most frequent visits from the nurses.
      There was a wide range in the number of clients on the caseloads of each nurse
      but overall these were higher than in other parts of the UK. CONCLUSIONS: It is
      concluded that community nurses for people with learning disabilities have large
      caseloads and people with learning disabilities who have challenging behaviours,
      who account for over one-quarter of the clients they visit, require much more
      frequent contact visits than other clients. The combination of high numbers of
      clients (or low numbers of these nurses) may impact on how such nurses are able
      to perform their role and functions. RELEVANCE TO CLINICAL PRACTICE: An increase
      in the numbers of community nurses for people with learning disabilities and
      skill development in caring for people with challenging behaviours is
      recommended. If this is not performed the clinical effectiveness of this group of
      nurses with respect to their work with people who challenge services may be
      unduly hampered.

PMID- 15189411
TI  - Kidney transplantation: determination of the problems encountered by Turkish
      patients and their knowledge and practices on healthy living.
AB  - BACKGROUND: Although renal transplantations remove many limitations, dialysis can
      improve quality life in patients with end-stage renal disease, once
      transplantation has been performed and the patient has been discharged with a
      functioning graft, life with a chronic illness continues. AIMS AND OBJECTIVES:
      This study was carried out to define problems encountered by patients undergoing
      kidney transplantation and their knowledge and practices on healthy living.
      DESIGN: This study was designed as a retrospective and descriptive survey.
      METHODS: This study was performed on 125 patients who were followed at Social
      Insurance Institute's Ankara Specialty Hospital Transplantation Clinic between
      March and August 2001. A convenience sample was drawn from the population of
      renal transplant patients. A questionnaire was prepared based on the literature,
      which included patients' socio-demographic information, physiological problems,
      diseases and repeated hospitalizations; side-effects and usage of
      immunosuppressive drugs, knowledge and practices of patients regarding healthy
      living and their knowledge needs. Data were collected through interviews.
      Percentage and chi-square test were used in evaluation of the data. RESULTS:
      Physiological problems and diseases after renal transplantations were seen such
      as 38.4% had infections in urinary and respiratory tract. Some had hypertension
      (22.4%) hypercholesterolaemia (26.5%) and 5.6% had malignancy. Most (67.2%)
      developed antirejection drugs side-effects. About 55.2% were admitted to hospital
      after renal transplantation and 68.8% had not received any training after
      transplantation from a health professional. Only 35.2% knew the signs and
      symptoms of rejection entirely or partly. It was determined that 55.2% stated
      that they avoid sunlight and 56% stated that they exercise regularly. Only 26.8%
      of female patients do regular breast self-examination. While 52.8% listed the
      forbidden foods correctly, only 27.2% could list the forbidden beverages
      accurately. CONCLUSIONS: According to the results, patients undergoing renal
      transplantation experience various problems that may influence their quality of
      life adversely and their knowledge and practice is not adequate for them to
      continue to lead healthy lives. RELEVANCE TO CLINICAL PRACTICE: In accordance
      with the results of the study, offering continuing education and counselling
      services, preparing training guides, brochures, video cassettes and CDs for
      patient education, improving the national web sites to inform the public and
      creation of a home care system were suggested.

PMID- 15189412
TI  - CSF circulation disorders: measuring progress in patients through quality of life
      and hope.
AB  - BACKGROUND: Cerebrospinal fluid circulation disorders are complex and
      multifaceted conditions making reliable assessment of progress problematic. AIMS
      AND OBJECTIVES: It is the aim of this paper to explore how efficient measures of
      quality of life and hope might be used to assess clinical progress for patients
      with disorders of cerebrospinal fluid circulation. It will be argued that a
      single-item 10-point quality of life scale and the Herth Hope Index are as
      effective at measuring progress as the more widely used, but considerably more
      complex, Short-Form 36. DESIGN: Patients attending a cerebrospinal fluid clinic
      were sent a questionnaire containing the three measures of progress.
      Questionnaires were returned in a stamp-addressed envelope to allow initial
      analysis before the clinic appointment and to enable discussion of results during
      the clinic appointment. Patients were also assessed using the Mini-Mental State
      Examination during the clinic appointment. METHODS: The relationship between the
      three measures of progress was calculated using Spearman's rank order
      correlation. Correlations of 0.40-0.70 are considered modest and correlations of
      0.70 are considered strong; 5% levels of significance are considered significant
      and 1% levels are highly significant. Internal consistency of the Short-Form 36
      was assessed using Cronbach's alpha coefficient. Reliability was considered
      acceptable for dimension comparisons when alpha > 0.70. RESULTS: All patients
      were diagnosed with benign intracranial hypertension (n = 74), congenital
      hydrocephalus (n = 35) or normal pressure hydrocephalus (n = 171). There was a
      modest to strong correlation between the quality of life-10 and all eight
      dimensions of the Short-Form 36 for benign intracranial hypertension and
      congenital hydrocephalus patients. A slightly weaker correlation was demonstrated
      in seven of the eight Short-Form 36 dimensions for normal pressure hydrocephalus
      patients. Normal pressure hydrocephalus patients scored significantly lower on
      the Mini-Mental State Examination, which may contribute to explaining the weaker
      correlation between the three measures and the weaker internal consistency
      between the dimensions with the Short-Form 36. Conclusions. This paper
      demonstrates that efficient indicators of progress (quality of life-10 and Herth
      Hope Index) can be as effective at assessing clinical progress as more complex
      indicators (Short-Form 36) in patients who do not demonstrate cognitive deficit.
      RELEVANCE TO CLINICAL PRACTICE: For clinical application, the Short-Form 36 is
      too long, difficult to complete, score and analyse for these patient groups.
      Quality of life-10 and Herth Hope Index could provide efficient and effective
      measures of clinical progress but this requires further psychometric examination.

PMID- 15189413
TI  - Head injury: long-term consequences for patients and families and implications
      for nurses.
AB  - BACKGROUND: Head injury as a result of trauma is an important cause of long-term
      disability. Recently published guidance from the National Institute for Clinical
      Excellence on Acute Head Injuries and a forthcoming National Service Framework
      for Long-Term Neurological Conditions provides renewed focus on this practice
      specialty. AIMS AND OBJECTIVES: This article presents a narrative review of a
      range of quantitative and qualitative studies that have explored the impact of
      head injury and postinjury disabilities on patients' and families lives. RESULTS:
      Patients may experience a range of physical, emotional, cognitive, social and
      behavioural problems after head injury that will have a significant impact on
      both their own and their families' everyday lives. It is important that the
      behavioural, physical and psychological aspects of head injury are addressed.
      Carers may be vulnerable to stress and anxiety as a result of their caring role.
      CONCLUSIONS: It is often in the longer term that the true complexity and impact
      of head injury may become apparent. Ongoing support, from a range of services,
      will be required to assist both patient and family to cope with their
      circumstances. Ensuring that practice is evidence based, it is necessary to
      conduct further research, both to explore the effectiveness of current service
      provision and investigate those aspects deemed important by patients and carers.
      RELEVANCE TO CLINICAL PRACTICE: As nurses play an important role in both the
      acute and long-term care and support of those who have suffered a head injury, it
      is vital that they are aware of the wide ranging needs with which patients and
      families may present.

PMID- 15189414
TI  - Delirium: behavioural changes before and during the prodromal phase.
AB  - BACKGROUND: Delirium is an important form of psychopathology in older people and
      is associated with increased morbidity and functional decline. In the prodromal
      phase of delirium early symptoms occur, before all criteria have been met. AIM:
      The aim of this study was to delineate behavioural changes before and during the
      prodromal phase of delirium. That was considered to include the time from the
      first behavioural change up to the point when all DSM-IV criteria for delirium
      were met. DESIGN: Prospective and descriptive observation study. METHODS: One
      hundred and three hip surgery patients (hip fracture and hip replacement) aged >
      or = 80 years participated in this study. On admission none of them was delirious
      or had severe cognitive decline, but 32 patients met the DSM-IV criteria for
      delirium during the hospital stay. Frequent observations were performed up to
      delirium onset or 48 hours postoperatively. The observations included 37 items on
      the patient's state of mind, cognition, activity and behaviour. The first
      observation on admission was used as a reference and behavioural changes were
      defined as deviations from this first observation. RESULTS: Twenty-one patients
      out of the 32 who met the DSM-IV criteria (62%, D group) demonstrated behavioural
      changes before delirium onset, as did 34 (48%, R group) out of the remaining 71
      patients. The D group had different and more numerous behavioural changes than
      the R group. Anxiety was common in both groups. Disorientation and urgent calls
      for attention were the most frequent changes in the D group. The D group
      presented a pattern of behavioural changes and early symptoms of the approaching
      delirium. Six hours immediately before the onset of delirium, the behavioural
      changes were more numerous and evident. CONCLUSIONS AND RELEVANCE TO CLINICAL
      PRACTICE: It is necessary to pay attention to each behavioural change in the
      patients and to be aware of the prodromal phase of delirium in order to prevent
      its onset and to maintain the patient's well-being.

PMID- 15189415
TI  - Older people living in nursing homes or other community care facilities:
      Registered Nurses' views of their working situation and co-operation with family
      members.
AB  - BACKGROUND: Little attention has been paid to Registered Nurses' working
      conditions and how they experience their working situation in community health
      care. The nurses' vocational background is of interest, as well as their
      apprehension about communicating and co-operating with the older persons' family
      members. AIMS AND OBJECTIVES: The aim of the study was to describe Registered
      Nurses' views of their working situation in community health care and of co
      operation with family members of older people living in nursing homes or similar
      facilities. DESIGN: The study was carried out in a geographically defined area in
      the south of Sweden. A questionnaire was sent to all the Registered Nurses (n =
      314) working within community health care of whom 210 Registered Nurses replied
      to the questionnaires. METHODS: Latent content analysis was used on the comments
      to six questions, in order to illuminate the statistical findings from the
      statements of the questions measured by the Likert scale. RESULTS: The results
      showed that almost half of the Registered Nurses working in care of older people
      are not satisfied with their working situation. The nurses with less than 5 years
      working experience find their working situation most stimulating. All of them
      expressed that it is important that there is co-operation between themselves and
      the family members and it was also considered important to develop models that
      could improve co-operation. Male nurses believed, to a lesser extent, that family
      members were a resource in caring, compared with female nurses; however, all male
      nurses stressed the importance of facilitating informal caregivers. Nurses with
      more than 5 years of working experience expressed that it was important that
      family members show engagement in caring for older people. Furthermore, they
      expressed that it was necessary that the family members took care of the older
      persons' interests. RELEVANCE TO CLINICAL PRACTICE: The findings that half of the
      Registered Nurses are dissatisfied with their working situation have relevance in
      clinical practice because of the risk of losing competent nurses in this area.

PMID- 15189416
TI  - Perimenopausal knowledge of mid-life women in northern Taiwan.
AB  - BACKGROUND: This work has been carried out keeping in view that although
      knowledge related to perimenopause is an important health issue for women
      worldwide, little information is known about mid-life Taiwanese women's knowledge
      of perimenopause. OBJECTIVE: The aim of this paper was to explore the level of
      perimenopausal knowledge of mid-life women in northern Taiwan, to describe the
      relationship between demographic factors and women's knowledge, and to identify
      what information health providers need to offer them. DESIGN: A cross-sectional
      descriptive survey was conducted. METHOD: The Perimenopausal Knowledge
      Questionnaire was used to collect data. The study was carried out in August 2000
      to September 2001. A convenience sample was recruited from traditional Chinese
      medicine clinics, gynecology clinics and communities in northern Taipei. RESULTS:
      Our findings indicated that the overall mean correct answer weighted
      Perimenopausal Knowledge score of these mid-life women was 46.31. The rank of
      weighted scores from highest to lowest was: (1) self-care during perimenopause,
      (2) the perception of perimenopause, (3) knowledge related to hormone replacement
      therapy and (4) body changes associated with the declined oestrogen in
      perimenopause. Only educational level was significantly associated with
      Perimenopause Knowledge level (P < 0.01). Less than 20% (n = 353) of the women
      answered the items that measured self-management of symptoms related to
      perimenopause correctly. Less than 1.4% of the women knew that taking hormone
      replacement therapy required a physician's prescription and subsequent regular
      health check-ups. CONCLUSION: Participants lacked adequate knowledge about
      perimenopause. RELEVANCE TO CLINICAL PRACTICES: Health providers need to provide
      factual information about the normal body changes of perimenopause, self
      management of perimenopausal disturbances and appropriate use of hormone
      replacement therapy.

PMID- 15189418
TI  - Paediatric oncology nurse education: the development of a national framework.
AB  - BACKGROUND: It is recognized that there is a need for specialist nursing courses
      in a range of paediatric nursing specialities. Paediatric oncology nurses are
      facing challenges with clinical advances and the need for specialized care. At
      present there are no available courses in Scotland offering preparation for
      nurses working in a paediatric oncology setting. AIMS AND OBJECTIVES: This
      project, supported by Macmillan Cancer Relief, addresses this deficit by
      developing a comprehensive framework for a small and widely dispersed speciality.
      METHODS: Information on the needs and expectations of nurses and service managers
      in this field was obtained through postal questionnaires and focus groups. Due to
      the need for collaboration between higher educational institutions and service
      colleagues the views of educators were also established through questionnaires
      and semi-structured interviews. RESULTS: Problematic practice issues were cited
      and these issues were further discussed and recognized as the main educational
      needs. Availability and accessibility of education were of great importance.
      CONCLUSION: The framework developed aims to provide ongoing opportunities for
      continuing professional development within this speciality. Development of the
      educational framework is required to provide a course accessible to a wide
      geographical area of nurses. RELEVANCE TO CLINICAL PRACTICE: A National Framework
      for Paediatric Oncology Nurse Education was developed in response to views of
      experts working in the field, to the views of other stakeholders and to what is
      known about needs and preferences of children with cancer and their families.

PMID- 15189417
TI  - Concept development of family resilience: a study of Korean families with a
      chronically ill child.
AB  - AIMS: To clarify and delineate the concept of family resilience in the context of
      the chronic illness of a child. This study also investigated the concept of
      family resilience in relation to family functioning in order to compare and
      contrast family resilience and family functioning. DESIGN AND METHOD: Three
      phases of the hybrid model of concept development were applied: theoretical,
      fieldwork and final analytical. In the theoretical phase, a working definition of
      family resilience was developed by a literature review. The fieldwork phase
      comprised in-depth interviews with 11 parents with a chronically ill child, in
      the paediatric oncology unit of a university hospital in South Korea. The
      qualitative data obtained from the interviews were analysed to find attributes of
      family resilience. The final analytical phase compared and interpreted the
      findings from the theoretical and fieldwork phases in order to clarify and refine
      the concept of resilience. RESULTS: The definition of family resilience was of an
      enduring force that leads a family to change its functioning dynamics in order to
      solve problems encountered. Twenty-one conceptual attributes of family resilience
      emerging from this study were differentiated into four dimensions: (i) intrinsic
      family characteristics, (ii) family member orientation related to family
      characteristics, (iii) responsiveness to stress and (iv) external orientation.
      CONCLUSIONS: Family resilience is an enduring force that leads a family to change
      its dynamics of functioning in order to solve problems associated with stresses
      encountered. This conceptualization led to the development of a model of family
      coping that incorporates both family resilience and family functioning, as the
      property and as the process of change, respectively. RELEVANCE TO CLINICAL
      PRACTICE: In order to build a family that functions better under stress, it is
      necessary for nurses to focus more attention on family resilience, especially in
      terms of the development of intervention strategies to strengthen family
      resilience.

PMID- 15189419
TI  - Effectiveness of a needs-based education programme for families with a critically
      ill relative in an intensive care unit.

PMID- 15189422
TI  - Effect of feeding intensity and time on feed on intramuscular fatty acid
      composition of Simmental bulls.
AB  - Seventy-two Simmental bulls, weighing 489 kg initially and approximately 15
      months old, were divided into four groups to determine the effects of feeding
      intensity and time on feed on intramuscular fatty acid (FA) composition. Two
      groups of 18 bulls each were extensively (E) or intensively (I) fed on maize
      silage and concentrates with a daily gain of 943 g (E) or 1371 g (I). Half of
      each group were slaughtered after 100 days (S) or 138 days (L) on feed. In
      addition to carcass fatness parameters, intramuscular FA composition was also
      measured. Only small differences in the sum of saturated FA (SFA) percentages
      were found with 47.7 and 47.5% FA methyl esters (FAME) for SE and LE,
      respectively, and 48.7% FAME for each of SI and LI. Monounsaturated fatty acids
      (MUFA) significantly increased with longer, and higher feeding intensity to 44.2%
      FAME (LI), whereas the other groups had similar contents of 41.9, 42.2 and 42.0%
      FAME (SE, LE and SI respectively). Polyunsaturated FA (PUFA) decreased with
      higher feeding intensity to 8.39% (SI) and 6.71% (LI) FAME (p < 0.05) in
      comparison with 9.48% (SE) and 9.54% (LE). Intensive feeding decreased the ratio
      of PUFA : SFA to 0.17 (SI) and 0.14 (LI, p < 0.05) in comparison with 0.20 (SE
      and LE). The mean conjugated linoleic acid (CLA) concentration was 0.41% FAME.
      Time on feed had only a small effect on the FA composition compared with feeding
      intensity. No significant relationships were detected between meat quality
      attributes and the pattern of FA.

PMID- 15189423
TI  - Inhibition of ruminal microbial methane production by beta-cyclodextrin
      iodopropane, malate and their combination in vitro.
AB  - The objective of this study was to evaluate the effects of different
      concentrations of l-malate (0, 5, 10 and 20 mm), 2-iodopropane-beta-cyclodextrin
      complex (CD-IP) (0, 0.1, 0.2 and 0.4 mm) and a combination of malate (10 and 20
      mm) plus CD-IP (0.2 and 0.4 mm) on methane production from corn starch. Ruminal
      fluid was collected from dairy cows, mixed with phosphate buffer (1 : 2) and
      incubated (30 ml) anaerobically at 38 degrees C for 6 h with or without
      additives. Fermentation of corn starch in the presence of malate resulted in an
      increase (p < 0.05) in pH of the medium, total volatile fatty acid (VFA), total
      gas production and molar proportion of propionate. Acetate and ammonia-N
      concentration were unchanged. Methane production was decreased (p < 0.05) (15.5
      to 20.4%). Addition of CD-IP in corn starch resulted in an increase (p < 0.05) in
      total VFA and molar proportion of propionate. Acetate, pH and ammonia-N
      concentration of the medium were decreased (p < 0.05). Total gas production was
      unchanged. Methane production was decreased (p < 0.05) (25.2 to 97.1%) and
      hydrogen production was increased (p < 0.05). Addition of l-malate to CD-IP
      resulted in an increase (p < 0.05) in total VFA, total gas production and molar
      proportion of propionate. Acetate and ammonia-N concentration were decreased (p <
      0.05). No effects were observed on medium pH. Methane production was decreased (p
      < 0.05) (49.5 to 97.1%). Hydrogen production was also decreased (p < 0.05) (54.5
      to 64.1%) compared with those of CD-IP alone. Therefore, these additives may be
      used as supplements to inhibit methane production as well as to improve rumen
      fermentation and animal performance.

PMID- 15189424
TI  - Potential for protein deposition and threonine requirement of modern genotype
      barrows fed graded levels of protein with threonine as the limiting amino acid.
AB  - The study was conducted to estimate the actual genetic potential for daily
      protein deposition of growing barrows [genotype: Pietrain x (Duroc x Landrace)].
      Twenty-four pigs with an average initial body weight (BW) of 43.7 +/- 0.7 kg were
      used in a N-balance study. Semi-purified diets with graded levels of crude
      protein (45.8, 94.2, 148.0, 198.9, 255.5 and 300.2 g/kg DM) were used, based on a
      constant mixture of wheat, soya bean protein concentrate and potato protein
      concentrate as protein sources. The amino acid pattern of the diets was according
      to the ideal amino acid ratio for growing pigs (Wang and Fuller, 1989), with the
      exception of threonine (adjusted as limiting amino acid). N-balance data were
      used to estimate daily N-maintenance requirement (NMR = 446 mg N/BW0.67 kg/day)
      by regression method and the theoretical maximum of daily N-retention (PDmaxT =
      3115 mg N/BW0.67 kg/day) based on N-utilization model of Gebhardt (1966) using
      program Mathematica 3.0. The results indicate that PDmaxT of pigs under study is
      much higher than results from earlier studies with older genotypes. In summary,
      pigs of modern genotype have a very high genetic potential for daily protein
      deposition and these actual data are important basic informations for estimation
      of amino acid requirement within the model used. Threonine requirement data
      depending on threonine efficiency and protein deposition (8.96, 10.45 and 12.22
      g/day for 130, 145 and 160 g daily protein deposition; 50 kg body weight) are
      discussed.

PMID- 15189425
TI  - Influence of dietary linseed, fish and coconut oil on growth performance of
      growing pigs kept on small holdings in central Vietnam.
AB  - The aim of the study was to investigate the effect on growth performance of the
      addition of 5% of either linseed, fish or coconut oil to the diet of growing pigs
      kept on small holdings in central Vietnam. The diets were fed on six different
      farms; there were three animals per treatment per farm. The farmers fed a base
      diet according to personal choice, but were instructed to use linseed, fish and
      coconut oil. The diets were fed to the pigs from 70 to 130 days of age. The diets
      with 5% linseed oil on average contained 2.4 g alpha-linolenic acid/MJ of
      metabolizable energy (ME) and the diets with 5% fish oil on average contained
      0.06 and 0.75 g eicosapentaenoic and docosahexaenoic acid/MJ ME, respectively.
      The relative percentages of docosahexaenoic, eicosapentaenoic, alpha-linolenic
      and linoleic acid in adipose tissue were determined by the intake of the
      corresponding fatty acids. Dietary linseed oil vs. coconut oil significantly
      enhanced daily weight gain and vs. fish oil it also stimulated growth, but this
      effect just failed to reach statistical significance. It is concluded that extra
      intake of alpha-linolenic acid may stimulate growth in growing-finishing pigs,
      this effect being independent of the conversion of alpha-linolenic acid into
      eicosapentaenoic and docosahexaenoic acid.

PMID- 15189426
TI  - Requirement of true ileal digestible threonine of growing and finishing pigs.
AB  - Ninety-six crossbred barrows and gilts were used to investigate the optimum
      supply of true ileal digestible threonine for growing (approximately 35-65 kg
      body weight) and finishing (approximately 65-110 kg body weight) pigs. For this
      purpose, according to a bifactorial arrangement in the grower as well as in the
      finisher phase four dietary threonine levels were combined with two dietary
      levels of lysine. Measurement criteria were body weight gain, feed intake, feed
      conversion rate and carcass characteristics. In the grower stage at the lower
      lysine level daily gain increased numerically (p < 0.1) and the feed to gain
      ratio decreased significantly with an increasing dietary true ileal digestible
      threonine concentration. Increasing the true ileal digestible lysine
      concentration of the diet from 7.8 to 9.2 g/kg increased average daily gain in
      the grower stage significantly from 815 to 855 g and decreased the feed to gain
      ratio significantly. In finishing pigs, daily gain and feed to gain ratio were
      significantly improved by an increasing dietary true ileal digestible threonine
      concentration from 821 to 902 g and from 3.14 to 2.94 kg/kg, respectively, but
      not by the differing lysine supply. As in the grower stage, barrows consumed more
      feed than gilts at similar growth rates and this resulted in a significantly
      reduced feed to gain ratio in gilts compared with barrows. The requirements of
      true ileal digestible threonine for optimize both, daily gain and feed to gain
      ratio, as derived by the broken-line model were 10.3 g/animal and day for growing
      and 10.7 g/animal and day for finishing pigs respectively.

PMID- 15189427
TI  - Changes in plasma non-esterified fatty acids, glucose and alpha-amino nitrogen
      and their relationship with body weight and plasma growth hormone in growing
      buffaloes (Bubalus bubalis).
AB  - A study was undertaken to investigate the changes of plasma non-esterified fatty
      acids (NEFA), glucose and alpha-amino nitrogen and their relationship with age,
      body weight (BW) and plasma growth hormone (GH) in growing buffaloes. For the
      purpose, six growing female Murrah buffalo calves of 6-8 months of age were
      selected on the basis of their BW and fed according to Kearl standard (Nutrient
      Requirements of Ruminants in Developing Countries, International Feedstuffs
      Institute, Utah State University, Utah, USA, 1982, p. 89) for growing buffaloes
      (target growth rate 500 g/day) to meet energy and protein requirement of the
      animals. Blood samples collected at fortnight intervals for 1 year were analysed
      for plasma NEFA, glucose, alpha-amino nitrogen and GH. The animals were also
      weighed at fortnight intervals. Plasma NEFA and glucose levels were found to
      decrease (p < 0.01) with age. Unlike plasma NEFA and glucose, plasma alpha-amino
      nitrogen level increased (p < 0.01) as the buffaloes become older. Plasma NEFA
      and glucose concentrations in growing buffaloes were found to be positively
      correlated with plasma GH (r = 0.379 and 0.420 respectively), but these were non
      significant (p > 0.01). However, plasma NEFA and glucose showed a good
      correlation (p < 0.01; r = 0.780 and 0.652 respectively) with plasma GH per 100
      kg live weight. Plasma alpha-amino nitrogen exhibited non-significant (p > 0.01)
      negative correlation (r = -0.295) with plasma GH but a negative correlation (p <
      0.01; r = -0.641) with GH per 100 kg BW. So, plasma metabolites showed a definite
      pattern of change during growth and these have a significant (p < 0.01)
      correlation with plasma GH per 100 kg BW than GH.

PMID- 15189428
TI  - Effects of supplemental L-carnitine in drinking water on performance and egg
      quality of laying hens exposed to a high ambient temperature.
AB  - The present study was conducted to investigate effects of L-carnitine supplied
      with drinking water on performance and egg quality of laying hens under high
      environmental temperature. In the study, 47-week-old laying hens (Brown hisex)
      were divided into two groups (control and treatment) and fed with a standard
      layer diet. Treatment group was received 50 p.p.m L-carnitine with drinking water
      for an 8-week period. Throughout the study, 8 h hot (35-37 degrees C) and 16 h
      thermoneutral (20-22 degrees C) environmental temperature regime was employed
      daily. The results showed that L-carnitine supplementation affected some egg
      quality characteristics of layers under high environmental temperature. Relative
      albumen weight and height were increased (p < 0.05) by supplemental L-carnitine.
      Live weight gain, feed intake, egg mass, egg weight, yolk weight, shell weight,
      yolk index, egg-shape index, yolk colour score and shell thickness were not
      affected (p < 0.05) by L-carnitine. It is concluded that L-carnitine
      supplementation in laying hens could have potential to improve albumen quality
      under high environmental temperature.

PMID- 15189429
TI  - Effect of exercise on the mobilization of retinol and retinyl esters in plasma of
      sled dogs.
AB  - Fasting dogs do transport vitamin A (VA) in plasma not only as retinol but
      predominantly as retinyl esters. Contrary to retinol, nothing is known concerning
      the effects of athletic performance on plasma retinyl ester concentrations. The
      aim of this study was therefore to examine whether physical stress because of
      exercise and modification of the oxidative stress by supplementation of alpha
      tocopherol influences the concentrations of retinol and retinyl esters in plasma
      of sled dogs. The study was carried out on 41 trained adult sled dogs, which were
      randomly assigned into two groups. One group (19 dogs) was daily substituted with
      50 mg dl-alpha-tocopheryl acetate per kilogram body weight and the control group
      (22 dogs) was maintained on a basal diet during 3 months prior to exercise. The
      plasma concentrations of retinol, retinyl esters, alpha-tocopherol and
      triglycerides were measured immediately before, directly after and 24 h after
      exercise. The supplementation of alpha-tocopheryl acetate had no effect on plasma
      retinol and retinyl ester concentrations at any measurement time point. However,
      retinyl ester levels doubled in the non-supplemented group immediately after the
      race (p < 0.001), whereas in the supplemented group similar high levels were
      observed not until 24 h post-racing (p < 0.001). The high levels of retinyl
      esters were paralleled to some extent by an increase in plasma triglyceride
      concentrations, which were significantly higher 24 h post-racing than immediately
      before (p < 0.001) and after exercise (p < 0.001) in both groups. The increase in
      retinyl ester concentrations might be indicative of their mobilization from liver
      and adipose tissue. Whether plasma retinyl esters can be used as an indicator for
      the extent of nutrient mobilization during and post-exercise in sled dogs remains
      to be elucidated.

PMID- 15189430
TI  - Dynamics of yolk sac resorption and post-hatching development of the
      gastrointestinal tract in chickens, ducks and geese.
AB  - Under similar environmental conditions, 100 male Shaver-Starbro hybrid chickens,
      100 male Mulard cross-line ducklings and 100 male Landaise goslings kept in 30
      metabolic cages from the first day of life (10 birds of each species separately
      per cage) were chosen for the study. The animals were fed semi ad libitum diets
      with crude protein content and energy density similar to that used for poultry
      species, avoiding feed residues. During the first 21 days of life they received
      starter diets and from day 22 to 42 grower diets. Maize accounted for 23-40% and
      barley constituted 10-18%. Wheat accounted for 20.0% in starter diets and 10-18%
      in grower diets. Resorption of yolk sac residues, performance, development of the
      intestinal tract in young chickens, ducklings and goslings were assessed. During
      the first 5 days of life intensive absorption of yolk sac ingredients was
      observed. On day 7, residues of the yolk sac were found in more than 30% of
      chickens compared with approximately 10% in geese. In ducklings residues of the
      yolk sac were not found. On day 16 unabsorbed yolk sacs were found in
      approximately 10% of chickens. Liver and pancreas weighed the highest in geese
      and in ducks; in chickens the weight of these organs was significantly lower (p <
      0.01). The relative values calculated to 100 g of metabolic body weight show that
      the average small intestine in chickens was significantly longer (p < 0.01) than
      in ducks or geese. The intestinal tract developed earlier in the chicken than in
      the water fowl.

PMID- 15189431
TI  - Electronic apex locators.
AB  - Prior to root canal treatment at least one undistorted radiograph is required to
      assess canal morphology. The apical extent of instrumentation and the final root
      filling have a role in treatment success, and are primarily determined
      radiographically. Electronic apex locators reduce the number of radiographs
      required and assist where radiographic methods create difficulty. They may also
      indicate cases where the apical foramen is some distance from the radiographic
      apex. Other roles include the detection of root canal perforation. A review of
      the literature focussed first on the subject of electronic apex location. A
      second review used the names of apex location devices. From the combined
      searches, 113 pertinent articles in English were found. This paper reviews the
      development, action, use and types of electronic apex locators.

PMID- 15189432
TI  - Antimicrobial activity of varying concentrations of sodium hypochlorite on the
      endodontic microorganisms Actinomyces israelii, A. naeslundii, Candida albicans
      and Enterococcus faecalis.
AB  - AIM: To determine the resistance of microorganisms associated with refractory
      endodontic infections to sodium hypochlorite used as a root canal irrigant.
      METHODOLOGY: Two strains each of Actinomyces naeslundii, Candida albicans and
      Enterococcus faecalis were tested as late logarithmic phase inocula, against
      sodium hypochlorite adjusted to 0.5, 1.0, 2.5 and 5.25% w/v. Contact times used
      were 0, 10, 20, 30, 60 and 120 s. In the case of E. faecalis, additional
      experiments used contact times of 1.0, 2.0, 5.0, 10.0 and 30.0 min. Anti
      microbial action was halted by sodium thiosulphate addition. Survivors were
      measured primarily using viable counts on drop plates. Additionally, pour plates
      were used to count low colony-forming units (cfu) and dilutions to 10(-6) were
      used to count high cfu. RESULTS: All concentrations of NaOCl lowered cfu below
      the limit of detection after 10 s in the case of A. naeslundii and C. albicans.
      However, E. faecalis proved to be more resistant to NaOCl. Using 0.5% NaOCl for
      30 min reduced cfu to zero for both strains tested. This compares with 10 min for
      1.0%, 5 min for 2.5% and 2 min for 5.25% (P < 0.001). Regression analysis for the
      dependent variable log(e)(count + 1) with log(e)(time + 1) and concentration as
      explanatory variables gave rise to a significant interaction between time and
      concentration (P < 0.001). CONCLUSION: The published association of E. faecalis
      with refractory endodontic infection may result, at least partially, from high
      resistance of this species to NaOCl. This does not appear to be the case with A.
      naeslundii or C. albicans.

PMID- 15189434
TI  - Detection of acid diffusion through bovine dentine after adhesive application.
AB  - AIM: Acidic diffusion through bovine dentine was investigated by measuring pH
      changes on dentine surfaces after applying three adhesive systems. METHODOLOGY:
      Coronal incisor bovine dentine discs, 0.5 mm thick, were prepared from dentine
      close to the pulp chamber. A single-bottle adhesive system-Single Bond, a self
      etching primer system-Clearfil SE Bond and an 'all-in-one' adhesive system-AQ
      Bond were used. The labial dentine surfaces were conditioned as follows: Single
      Bond groups: (SB-1) 35% phosphoric acid etchant was applied and left in place;
      (SB-2) the etchant was applied for 15 s and rinsed off for 10 s; (SB-3)
      application of adhesive agent and light curing following step SB-2; Clearfil SE
      Bond groups: (SE-1) SE primer was applied for 20 s and dried; (SE-2) application
      of adhesive agent and light curing following step SE-1; AQ Bond groups: (AQ-1) AQ
      Bond adhesive was applied for 20 s and dried, applied for additional 5 s and
      dried again; (AQ-2) light curing following step AQ-1. The pH change on the pulpal
      dentine surface was measured using a pH-imaging microscope. RESULTS: All the
      Single Bond groups revealed a lower pH on the pulpal surface (pH 6.25, 6.59 and
      6.64 for SB-1, SB-2 and SB-3, respectively) compared with intact dentine.
      Clearfil SE Bond and AQ Bond groups showed no significant deference in pH value
      from intact dentine. CONCLUSIONS: Acid diffusion from phosphoric acid etching was
      observed when placed on 0.5 mm-thick dentine discs; however, there was only
      limited evidence of acid diffusion from SE primer and AQ Bond.

PMID- 15189433
TI  - Ultrasonic condensation of gutta-percha: the effect of power setting and
      activation time on temperature rise at the root surface - an in vitro study.
AB  - AIM: To determine the effect of power setting and duration of activation on the
      temperature rise at the root surface during root canal obturation by ultrasonic
      condensation of gutta-percha. METHODOLOGY: A human maxillary canine was used in
      an in vitro split tooth model to allow repeated obturation of the root canal
      system using an ultrasonic device to thermocompact gutta-percha. Combinations of
      power settings (1, 3 and 5) and durations of activation (4, 10 and 15 s) were
      used to test their effect on temperature rise at the root surface using eight K
      type thermocouples at the mid-root and apical levels. At the end of each
      obturation, the tooth was disassembled to remove the gutta-percha in preparation
      for the next obturation (n = 10 for each combination). Multiple linear regression
      models were used to investigate the effects of power setting, duration of
      activation and thermocouple location on the maximum temperature rise recorded.
      RESULTS: Only one combination of power setting (5) and duration of activation (15
      s) resulted in temperature rise in excess of 10 degrees C. The maximum
      temperature rise at the mid-root level was significantly (P < 0.001) greater than
      that recorded apically. It is also significantly affected by the combination of
      power setting and duration of activation. CONCLUSIONS: Temperature rises at the
      root surface during ultrasonic condensation of gutta-percha in excess of 10
      degrees C were evident in only one combination of power (5) and time (15 s)
      settings at the mid-root level.

PMID- 15189435
TI  - Laser Doppler flow measurements of pulpal blood flow and severity of dental
      injury.
AB  - AIM: To evaluate laser Doppler flowmetry (LDF) measurements of pulpal blood flow
      (PBF) and severity of dental injury. METHODOLOGY: The relationship between
      adverse outcomes and PBF measurements was analysed in 94 permanent maxillary
      incisors of 71 consecutive dental trauma patients. The diagnostic adverse outcome
      group was comprised of 72 incisors in 52 patients with a type I (loss of
      sensitivity), type II (loss of sensitivity and periapical radiolucency), or type
      III (loss of sensitivity, periapical radiolucency and grey discoloration of
      crown) diagnosis. The nonadverse outcome group consisted of 22 incisors in 19
      patients with the finding of an absence of an adverse outcome. At each session,
      when an injured permanent maxillary incisor was recorded, a contralateral
      homologous tooth was used as a control. An ordinal stepwise regression was
      completed to assess the degree of association between PBF measurements and
      adverse outcomes RESULTS: Using chi-square analysis for pairwise comparison, a
      significant relationship between PBF measurements and types of adverse outcomes
      (chi(2) =119.635, d.f. = 12, P = 0.000) was observed. PBF measurements that were
      significantly associated with more severe outcome were PBF levels of </=3
      perfusion units (PU) (119.1 odds ratio) (P = 0.000), and those of >3 PU and </=6
      PU (12.7 odds ratio) (P = 0.000). CONCLUSIONS: PBF measurements were related to
      the severity of adverse outcomes. Further studies are required to evaluate
      whether PBF measurements can predict dental injuries that progress to adverse
      treatment outcomes.

PMID- 15189436
TI  - Efficacy, cleaning ability and safety of different rotary NiTi instruments in
      root canal retreatment.
AB  - AIM: To evaluate the efficacy, cleaning ability and safety of three different
      rotary nickel-titanium instruments with and without a solvent (eucalyptol) versus
      hand files in the removal of gutta-percha root fillings. METHODOLOGY: Eighty
      extracted single-rooted anterior teeth were enlarged to size 35 and obturated
      with laterally condensed gutta-percha using AHPlus as the sealer. Removal of
      gutta-percha was performed with the following devices and techniques: FlexMaster,
      GT Rotary, ProTaper and Hedstrom files. All techniques were used with and without
      the solvent eucalyptol. The following data were recorded: time taken to reach the
      calculated working length and time required for the removal of gutta-percha. The
      teeth were split longitudinally and photographed. Cleanliness of the root canal
      walls was scored using the projected slides with a total magnification of
      approximately 70x. Statistical analysis was performed using the two-way anova (P
      < 0.001) for the analysis of working time. RESULTS: The technique that reached
      the working length most rapidly was that using ProTaper instruments and
      eucalyptol (+E), followed by FlexMaster + E, ProTaper, FlexMaster, Hedstrom files
      + E, GT Rotary + E, Hedstrom files, and GT Rotary. No significant differences
      were found for retreatment with or without a solvent in all groups. ProTaper and
      FlexMaster worked significantly more rapidly than Hedstrom files and GT Rotary
      (anova, P < 0.001). Time for complete removal of gutta-percha was again shortest
      with ProTaper + E, followed by FlexMaster + E, ProTaper, FlexMaster, GT Rotary +
      E, Hedstrom files + E, Hedstrom files, and GT Rotary. ProTaper and FlexMaster
      again worked significantly faster than the other techniques (anova, P < 0.001).
      There was no visible filling material extruded apically. Root canal cleanliness
      proved best following the use of FlexMaster + E, and Hedstrom files + E, followed
      by ProTaper + E, and GT Rotary + E. CONCLUSION: Under the experimental
      conditions, FlexMaster and ProTaper NiTi instruments proved to be efficient and
      time-saving devices for the removal of gutta-percha. The use of eucalyptol as a
      solvent shortened the time to reach the working length and to remove the gutta
      percha, but this was not significant.

PMID- 15189437
TI  - Effect of root-end resection and root-end filling on apical leakage in the
      presence of core-carrier root canal obturation.
AB  - AIM: To evaluate the apical seal of canals filled with a core-carrier obturator
      following root-end resection with and without a root-end filling. METHODOLOGY:
      Thirty single-rooted human teeth with single canals were used. Root canal
      treatment was performed and canals filled with a core-carrier obturation
      technique. The teeth were then randomly assigned to three groups (n = 10). In the
      first group root canal filling only was performed. After orthograde filling, the
      teeth of the second group were resected apically, perpendicular to the major axis
      of the root. In the third group after apical resection, a root-end cavity was
      prepared using ultrasonic diamond retrotips and the cavities filled with Super
      EBA cement. During a period of 3 h and with a headspace pressure of 0.12 atm,
      methylene-blue solution was forced through a tube that was connected to the
      apical end of each tooth specimen. The coronal end of the tooth was connected to
      a capillary tube containing an air bubble. Leakage was evaluated by observing the
      distal displacement of the air bubble. The roots were then sectioned along their
      long axis. Using a stereomicroscope, linear dye infiltration at the dentine
      cement interface was determined. Kruskal-Wallis and Mann-Whitney tests were used
      to compare the three groups. RESULTS: Linear dye infiltration was significantly
      greater in root canals filled with the core-carrier obturators and resected
      apically (0.9 +/- 0.9 mm) when compared with those that had root-end fillings
      (0.2 +/- 0.4 mm). Air bubble displacement was not observed. CONCLUSION: Root-end
      filling improves the sealing of roots with core-carrier obturation following root
      end resection.

PMID- 15189438
TI  - An in vitro comparison of the bleaching efficacy of 35% carbamide peroxide with
      established intracoronal bleaching agents.
AB  - AIM: To evaluate the bleaching efficacy of 35% carbamide peroxide, 35% hydrogen
      peroxide and sodium perborate for intracoronal bleaching of root filled
      discoloured teeth. METHODOLOGY: Extracted premolars were artificially stained
      using whole blood then root canal treatment was performed. After obturation, a 2
      mm intermediate base was placed 1 mm below the buccal amelo-cemental junction.
      Intracoronal bleaching was performed in 11 teeth per group, using either 35%
      carbamide peroxide gel (group CP), 35% hydrogen peroxide gel (group HP) or sodium
      perborate mixed with distilled water (group SP). The bleaching agents were
      replaced after 7 days. The shade of the teeth was evaluated at day 0, 7 and 14.
      The results were analysed using Kruskal-Wallis one-way analysis of variance and
      Mann-Whitney U-test. RESULTS: At the end of 7 days, both groups CP and HP
      lightened by 8 +/- 3 Vita tab positions, respectively, whereas group SP lightened
      by 5 +/- 3 tab positions (P < 0.05). At the end of the second bleaching period at
      day 14, group CP and HP lightened by a further 2 +/- 2 and 2 +/- 3 tab positions,
      respectively, whereas group SP lightened by a further 3 +/- 4 tab positions.
      There were no statistical differences between groups at day 14. CONCLUSIONS:
      Thirty-five per cent carbamide peroxide and 35% hydrogen peroxide were equally
      effective for intracoronal bleaching, and significantly better than sodium
      perborate after 7 days. After 14 days, there were no significant differences
      between the groups. Thirty-five per cent carbamide peroxide can be recommended as
      an equally effective alternative to hydrogen peroxide for intracoronal bleaching.

PMID- 15189439
TI  - FT-Raman spectroscopy of calcium hydroxide medicament in root canals.
AB  - AIM: To investigate chemical changes in calcium hydroxide introduced into human
      root canals as a medicament using Fourier transform-(FT) Raman spectroscopy.
      METHODOLOGY: Ten necrotic maxillary anterior teeth were selected in 10 patients.
      The teeth were divided into five treatment groups, according to the survey time.
      Root canal instrumentation was performed with hand instruments until the master
      apical file was size 40. Calcium hydroxide paste, in a 1 : 1.25 mixture by weight
      of powder and distilled water, was introduced directly into the root canal with a
      lentulo-spiral filler and then condensed with a finger plugger. The access cavity
      was sealed with a temporary dressing. After 2 and 4 days, then 2, 4 and 6 weeks,
      the calcium hydroxide paste was sampled with a K-file and then analysed using FT
      Raman spectroscopy. The excitation source was an Nd : YAG laser with an
      excitation wavelength of 1064 nm. All spectra were taken with a laser power of
      200 mW, 275-1185 scans, and 4 cm(-1) resolution. The conversion of calcium
      hydroxide to calcium carbonate was calculated on the basis of the spectral data
      obtained from the mixtures of both compounds. RESULTS: The calcium hydroxide
      paste in the apical region showed weak bands at 1088 and 284 cm(-1), in addition
      to bands associated with calcium hydroxide. The weak bands, assigned to calcium
      carbonate, became stronger with time. Calcium carbonate content increased rapidly
      in the first 2 days and then tended to increase slowly. Approximately 11% of the
      calcium hydroxide at the apical portion of the canal was converted to calcium
      carbonate after 6 weeks. However, little alteration of the paste was noticed in
      the samples from the middle portion of the canal. CONCLUSIONS: Calcium hydroxide
      medicament in root canals became transformed into calcium carbonate in the apical
      region within 2 days. Although the transformation continued with time,
      approximately 90% of the calcium hydroxide remained unchanged after 6 weeks.

PMID- 15189440
TI  - Investigation of the root canal configurations of mandibular permanent teeth in
      the Turkish population.
AB  - AIM: To investigate the root and canal morphology of mandibular permanent teeth
      collected from an indigenous Turkish population. METHODOLOGY: A total of 1400
      extracted mandibular permanent teeth were evaluated. The teeth were divided into
      seven groups as central incisors, lateral incisors, canines, first premolars,
      second premolars, first molars and second molars in order to evaluate their root
      canal configurations. Access cavities were prepared and pulp tissue removed using
      5.25% sodium hypochlorite solution. The teeth were stored in 5% nitric acid
      solution for 5 days, then rinsed under running water for 4 h and placed in
      increasing concentrations of ethyl alcohol. The teeth were rendered transparent
      by immersion in xylene solution for 3 days until complete transparency was
      achieved. Following this procedure, India ink was injected in the root canal
      systems and their configurations were examined and compared with the
      classification of Vertucci. The following observations were made: (i) root canal
      classification of mandibular teeth; (ii) morphology of the mandibular permanent
      teeth. The classification of Vertucci was taken as a reference during the
      evaluation; however additional canal morphological types were evaluated as
      separate groups. RESULTS: The presence of a second canal was detected in 68% of
      mandibular central incisors and 63% of lateral incisors. Lateral canals were
      found in 6.5% of mandibular central incisors and in 13% of lateral incisors.
      Overall, 62% of mandibular first premolar teeth had a single canal whereas 71% of
      second premolars had a single canal. The mandibular first and second molar teeth
      exhibited similar root canal configurations except for a group of second molar
      teeth that had a single root and canal. CONCLUSIONS: The morphological
      characteristics of teeth in this Turkish population were consistent with those of
      other studies performed on different populations using similar methodology.

PMID- 15189442
TI  - Use of a molar clamp to isolate two adjacent single-rooted teeth: a clinical aid.
AB  - AIM: To emphasize the importance of rubber dam isolation in root canal treatment
      and to present a technique to simultaneously isolate two single-rooted teeth
      using a molar clamp. SUMMARY: Isolation of two adjacent teeth with inadequate
      tooth structure is a challenge. The split-dam technique or using two clamps have
      drawbacks. This report presents a technique to simultaneously isolate two
      adjacent single-rooted teeth that are difficult to isolate by conventional
      methods. Its advantages are efficiency, reduction of radiation exposure, better
      access, good visibility and isolation. KEY LEARNING POINTS: The basis of this
      technique is to isolate two teeth as two roots of a molar tooth. The indications
      for this technique are two adjacent prepared crowns and crownless roots. The
      appropriate molar clamp can be selected on the basis of the mesial-distal clamp
      jaw distance being equal to the mesial-distal spacing of the two roots. The
      buccal-lingual jaw distance of the clamp should be smaller than the dimension of
      the roots to provide adequate retention.

PMID- 15189441
TI  - Extraradicular diffusion of hydrogen peroxide and pH changes associated with
      intracoronal bleaching of discoloured teeth using different bleaching agents.
AB  - AIM: To evaluate the extraradicular pH and hydrogen peroxide (HP) diffusion when
      either 35% carbamide peroxide (CP), 35% HP or sodium perborate (SP) is used for
      intracoronal bleaching of artificially discoloured teeth. METHODOLOGY: Single
      rooted extracted human premolars were stained with whole blood cells. After
      shaping and cleaning, they were root filled and a base cement placed 1 mm below
      the buccal cementoenamel junction (CEJ). Four cemental defects were prepared just
      below the CEJ on each root surface. The teeth were randomly divided into four
      groups of 11 specimens, and intracoronally bleached using CP, HP, SP or distilled
      water (CL). Each tooth was suspended in a vial of distilled water and bleached
      for 7 days. The pH of the extraradicular distilled water was tested at 0, 1, 2
      and 7 days and the HP that diffused through the root quantified using the Ferrous
      Oxidation-Xylenol Orange 2 Assay. The results were analysed using the one-way
      anova and Scheffe tests. RESULTS: Carbamide peroxide produced the greatest
      increase and HP the least pH change (P < 0.05 except day 1), SP was intermediate.
      From day 1 onwards, radicular diffusion of HP was greatest with HP and least with
      CP (P < 0.01), again SP was intermediate. There was no significant difference
      between CP and SP. CONCLUSIONS: Carbamide peroxide had very low levels of
      extraradicular diffusion of HP, in the presence of cemental defects. It could be
      an alternative to the other intracoronal bleaching agents.

PMID- 15189444
TI  - Partition of distinct chromosomal regions: negotiable border and fixed border.
AB  - Chromosomes are partitioned into distinct functional regions. For example,
      heterochromatin regions consist of condensed chromatin and contain few
      transcriptionally active genes, whereas euchromatin regions are less condensed
      and majority of active genes reside in the euchromatin regions. Because distinct
      regions reside in each chromosome, borders are accordingly established between
      these regions. A prevailing view of the borders is that they are 'walls' that
      actively inhibit communication between distinct regions on chromosomes. Although
      little is known about the molecular bases of these walls, specific DNA elements
      are considered to recruit these walls to define the positions of the borders. We
      call the borders established with this mechanism as 'fixed borders'. Past studies
      have identified various insulators (boundary DNA elements) that have been
      suggested to recruit fixed borders to them. Another mechanism, which we introduce
      and focus on in this review, does not require walls recruited by specific DNA
      elements at the chromosomal borders. Instead, the borders are defined by a
      balance of opposing enzymatic activities located at the opposite sides of the
      resultant borders. We name these borders 'negotiable borders'. Here we review
      some of the recent progress in the field that offer valuable insight into
      mechanisms of establishing structural and functional borders on chromosomes.

PMID- 15189445
TI  - Molecular mechanism of DNA replication-coupled inactivation of the initiator
      protein in Escherichia coli: interaction of DnaA with the sliding clamp-loaded
      DNA and the sliding clamp-Hda complex.
AB  - In Escherichia coli, the ATP-DnaA protein initiates chromosomal replication.
      After the DNA polymerase III holoenzyme is loaded on to DNA, DnaA-bound ATP is
      hydrolysed in a manner depending on Hda protein and the DNA-loaded form of the
      DNA polymerase III sliding clamp subunit, which yields ADP-DnaA, an inactivated
      form for initiation. This regulatory DnaA-inactivation represses extra initiation
      events. In this study, in vitro replication intermediates and structured DNA
      mimicking replicational intermediates were first used to identify structural
      prerequisites in the process of DnaA-ATP hydrolysis. Unlike duplex DNA loaded
      with sliding clamps, primer RNA-DNA heteroduplexes loaded with clamps were not
      associated with DnaA-ATP hydrolysis, and duplex DNA provided in trans did not
      rescue this defect. At least 40-bp duplex DNA is competent for the DnaA-ATP
      hydrolysis when a single clamp was loaded. The DnaA-ATP hydrolysis was inhibited
      when ATP-DnaA was tightly bound to a DnaA box-bearing oligonucleotide. These
      results imply that the DnaA-ATP hydrolysis involves the direct interaction of ATP
      DnaA with duplex DNA flanking the sliding clamp. Furthermore, Hda protein formed
      a stable complex with the sliding clamp. Based on these, we suggest a mechanical
      basis in the DnaA-inactivation that ATP-DnaA interacts with the Hda-clamp complex
      with the aid of DNA binding.

PMID- 15189446
TI  - Interaction of hREV1 with three human Y-family DNA polymerases.
AB  - Polkappa is one of many DNA polymerases involved in translesion DNA synthesis
      (TLS). It belongs to the Y-family of polymerases along with Poleta, Poliota and
      hREV1. Unlike Poleta encoded by the xeroderma pigmentosum variant (XPV) gene,
      Polkappa is unable to bypass UV-induced DNA damage in vitro, but it is able to
      bypass benzo[a]pyrene (B[a]P)-adducted guanines accurately and efficiently. In an
      attempt to identify factor(s) targeting Polkappa to its cognate DNA lesion(s), we
      searched for Polkappa-interacting proteins by using the yeast two-hybrid assay.
      We found that Polkappa interacts with a C-terminal region of hREV1. Poleta and
      Poliota were also found to interact with the same region of hREV1. The
      interaction between Polkappa and hREV1 was confirmed by pull-down and co
      immunoprecipitation assays. The C-terminal region of hREV1 is known to interact
      with hREV7, a non-catalytic subunit of Polzeta that is another structurally
      unrelated TLS enzyme, and we show that Polkappa and hREV7 bind to the same C
      terminal region of hREV1. Thus, our results suggest that hREV1 plays a pivotal
      role in the multi-enzyme, multi-step process of translesion DNA synthesis.

PMID- 15189447
TI  - Interaction of U-box-type ubiquitin-protein ligases (E3s) with molecular
      chaperones.
AB  - Members of the U-box family of proteins constitute a class of ubiquitin-protein
      ligases (E3s) distinct from the HECT-type and RING finger-containing E3 families.
      Two representative mammalian U-box proteins, UFD2a and CHIP, interact with the
      molecular chaperones VCP and either Hsp90 or Hsc70, respectively, and are
      implicated in the degradation of damaged proteins. We have now investigated the
      roles of mammalian U-box proteins by performing a comprehensive screen for
      molecules that interact with these proteins in the yeast two-hybrid system. All
      mammalian U-box proteins tested were found to interact with molecular chaperones
      or cochaperones, including Hsp90, Hsp70, DnaJc7, EKN1, CRN, and VCP. These
      observations suggest that the function of U box-type E3s is to mediate the
      degradation of unfolded or misfolded proteins in conjunction with molecular
      chaperones as receptors that recognize such abnormal proteins.

PMID- 15189448
TI  - DREG, a developmentally regulated G protein-coupled receptor containing two
      conserved proteolytic cleavage sites.
AB  - We have identified and characterized a novel member of the G protein-coupled
      receptor (GPCR) family, termed DREG. DREG belongs to the LNB-TM7 subfamily and
      possesses a long amino-terminus that contains a CUB domain, a PTX domain, a
      hormone binding domain and a GPCR proteolytic site (GPS) domain. RT-PCR
      experiments and whole mount in situ hybridization in mice showed that DREG is
      expressed at high levels in the heart and somite during embryogenesis and in the
      adult lung. When DREG was transiently expressed in mammalian cultured cells, a 35
      kD fragment was generated by endogenous proteolytic processing at the conserved
      GPS domain. This short fragment was found associated with the cell membrane,
      typical of GPCRs. DREG was further cleaved in the middle of the extracellular
      domain, generating a soluble 70-kD fragment containing the CUB and PTX domains.
      This processing was inhibited by an inhibitor of the endoprotease furin but not
      of matrix metalloproteinases. These results raise the possibility that DREG plays
      a role in development, not only as a receptor or an adhesion molecule but also as
      a secreted ligand.

PMID- 15189449
TI  - Sorting nexin homologues are targets of phosphatidylinositol 3-phosphate in
      sporulation of Schizosaccharomyces pombe.
AB  - Schizosaccharomyces pombe defective in phosphatidylinositol (PtdIns) 3-kinase
      shows various defects in forespore membrane formation, including onset, growth
      orientation, and closure. Downstream factors of PtdIns 3-kinase in this system
      were explored. Among various phox homology (PX) domain-containing proteins, Vps5p
      and Vps17p, homologues of sorting nexins, were found to be required for efficient
      sporulation. Cells defective in these proteins showed a disordered growth
      orientation of the forespore membrane, as is the case with Deltapik3 cells. Vps5p
      and Vps17p with mutations in the PX domains failed to suppress the defects of
      their relevant disruptants. Vps5p and Vps17p migrated toward the the forespore
      membrane in a pik3+-dependent manner, suggesting that these proteins may interact
      with PtdIns(3)P. Electron-microscopic analysis revealed that the forespore
      membrane fails to engulf the nucleus in some of these cells, accumulating vesicle
      like bodies similar to those seen in Deltaspo3 cells. These results suggest that
      Vps5p and Vps17p are the targets of PtdIns(3)P in vesicle transport required for
      onset of the forespore membrane formation.

PMID- 15189450
TI  - Impaired spermatogenesis and male fertility defects in CIZ/Nmp4-disrupted mice.
AB  - CIZ (Cas interacting zinc finger protein), also called Nmp4 (nuclear matrix
      protein 4), is a nucleo-cytoplasmic shuttling transcription factor that regulates
      the expression of collagen and matrix metalloproteinases. CIZ/Nmp4 was originally
      cloned by its binding to p130(Cas), a focal adhesion protein, and was recently
      shown to suppress BMP2 (bone mophogenetic protein 2) signalling. To explore the
      physiological role of CIZ/Nmp4, we disrupted CIZ/Nmp4-gene by inserting beta
      galactosidase and neomycin resistance genes into the 2nd exon of CIZ/Nmp4-gene,
      which is utilized by all the sequenced alternative forms. CIZ-/- mice were born
      and grew to adulthood. Although they tend to be smaller than wild-type mice, no
      pathological abnormality was observed except in the testis. Histological analysis
      of the testes revealed variable degrees of spermatogenic cell degeneration within
      the seminiferous tubules of CIZ-/- mice, resembling the histology of the
      'Germinal-cell aplasia with focal spermatogenesis'. Some of the CIZ-/- male mice
      developed infertility. TUNEL assay on testis sections revealed an increased
      occurrence of apoptosis of spermatogenic cells in the testes of CIZ-/- mice.
      CIZ/Nmp4 was co-localized with Smad1 in the testis, suggesting that a
      disregulation of BMP signalling could cause these phenotypes. These results
      suggest that CIZ/Nmp4 plays roles in the progress and the maintenance of
      spermatogenesis.

PMID- 15189451
TI  - Caspase-mediated cleavage and activation of LIM-kinase 1 and its role in
      apoptotic membrane blebbing.
AB  - Actin cytoskeletal reorganization plays a critical role in cell morphological
      changes, including membrane blebbing during apoptosis. LIM-kinase 1 (LIMK1)
      regulates actin cytoskeletal reorganization by phosphorylating and inactivating
      cofilin, an actin filament-depolymerizing and -severing protein. We now report
      that LIMK1 is cleaved and activated during anti-Fas antibody-induced apoptosis in
      Jurkat T cells. The cleavage and activation of LIMK1 were blocked by z-DEVD-fmk,
      an inhibitor for caspase-3 or related proteases, thus indicating that caspase-3
      like proteases are responsible for LIMK1 cleavage. The caspase-mediated cleavage
      of LIMK1 occurs at Asp-240, a site at the N-terminal side of the protein kinase
      domain, which leads to the production of an N-terminally truncated,
      constitutively active LIMK1 fragment. Expression of an N-terminally truncated
      LIMK1 fragment, LIMK1(241-647), induced membrane blebbing in both Jurkat and HeLa
      cells, with an extent significantly higher than that of wild-type LIMK1. Down
      regulation of endogenous LIMK1 expression by small interfering RNA (siRNA)
      reduced the Fas-induced membrane blebbing in Jurkat cells. These findings suggest
      that caspase-mediated cleavage and activation of LIMK1 play a role in the
      membrane bleb formation during apoptosis.

PMID- 15189452
TI  - Dok-1 tyrosine residues at 336 and 340 are essential for the negative regulation
      of Ras-Erk signalling, but dispensable for rasGAP-binding.
AB  - Dok-1 is a common substrate of many protein tyrosine kinases (PTKs). It recruits
      rasGAP and other SH2-containing proteins and negatively regulates Ras-Erk
      signalling downstream of PTKs. However, the mechanisms of its inhibitory effect
      are yet unclear. Here, a series of C-terminal deletion mutants of Dok-1
      delineated the core domain for the inhibition of Erk from 334 to 346 amino acid,
      which contains two SH2-binding motifs having Tyr-336 or Tyr-340. The Dok-1
      mutants having tyrosine-to-phenylalanine (YF) substitution(s) at Tyr-336 and/or
      Tyr-340 lost their inhibitory effect on Ras and Erk downstream of Src-like PTK,
      Lyn or Fyn, whereas the rasGAP-binding of each mutant remained intact. However,
      the Dok-1 mutant having YF substitutions at the rasGAP-binding sites (Tyr-295 and
      Tyr-361) also showed incapability of Ras and Erk inhibition. Moreover, the Dok-1
      mutant having YF substitutions at Tyr-336 and Tyr-340 showed an impaired
      inhibitory effect on v-Abl-induced transformation of NIH-3T3 cells. These results
      demonstrate that Tyr-336 and Tyr-340 of Dok-1 are dispensable for rasGAP-binding
      but essential for inhibition of Ras-Erk signalling and cellular transformation
      downstream of PTKs. Thus, Dok-1 probably recruits as yet unidentified
      molecule(s), which, in concert with rasGAP, negatively regulate Ras-Erk
      signalling.

PMID- 15189454
TI  - Skilled attendance at childbirth: let us go beyond the rhetorics.

PMID- 15189455
TI  - Retail supply of malaria-related drugs in rural Tanzania: risks and
      opportunities.
AB  - OBJECTIVES: To characterize availability of fever and malaria medicines within
      the retail sector in rural Tanzania, assess the likely public health
      implications, and identify opportunities for policy interventions to increase the
      coverage of effective treatment. METHODS: A census of retailers selling drugs was
      undertaken in the areas under demographic surveillance in four Tanzanian
      districts, using a structured questionnaire. RESULTS: Drugs were stocked by two
      types of retailer: a large number of general retailers (n = 675) and a relatively
      small number of drug shops (n = 43). Almost all outlets stocked
      antipyretics/painkillers. One-third of general retailers stocking drugs had
      antimalarials, usually chloroquine alone. Almost all drug shops stocked
      antimalarials (98%): nearly all had chloroquine, 42% stocked quinine, 37%
      sulphadoxine-pyrimethamine and 30% amodiaquine. A large number of antimalarial
      brands were available. Population ratios indicate the relative accessibility of
      retail drug providers compared with health facilities. Drug shop staff generally
      travelled long distances to buy from drugs wholesalers or pharmacies. General
      retailers bought mainly from local general wholesalers, with a few general
      wholesalers accounting for a high proportion of all sources cited. CONCLUSIONS:
      Drugs were widely available from a large number of retail outlets. Potential
      negative implications include provision of ineffective drugs, confusion over
      brand names, uncontrolled use of antimalarials, and the availability of
      components of potential combination therapy regimens as monotherapies. On the
      other hand, this active and highly accessible retail market provides
      opportunities for improving the coverage of effective antimalarial treatment.
      Interventions targeted at all drug retailers are likely to be costly to deliver
      and difficult to sustain, but two promising points for targeted intervention are
      drug shops and selected general wholesalers. Retail quality may also be improved
      through consumer education, and modification of the chemical quality, packaging
      and price of products entering the retail distribution chain.

PMID- 15189456
TI  - Measuring the efficacy of insecticide treated bednets: the use of DNA
      fingerprinting to increase the accuracy of personal protection estimates in
      Tanzania.
AB  - Summary Insecticide-treated nets have proved successful in the prevention of
      malaria as a result of both the personal protection with which they provide the
      sleeper and also the 'mass effect' on the local mosquito population when they are
      used on a community-wide basis. Personal protection estimates are normally based
      on comparisons of the numbers of bloodfed mosquitoes found in rooms with and
      without nets, however it seemed possible that a number of those mosquitoes may
      not have fed on the occupants of the rooms in which they were found but had
      entered after feeding elsewhere. To address this possible source of error, we
      used an 8-locus microsatellite system to identify the source of bloodmeals of
      Anopheles gambiaes.l. and A. funestus mosquitoes collected in rooms and window
      traps in Tanzanian villages with and without nets treated with alphacypermethrin.
      DNA fingerprints were produced from blood samples taken from people who had slept
      in these rooms and were matched to fingerprints obtained from the mosquito
      bloodmeals. We were able to type successfully over 90% of the bloodmeals
      collected and found that proportions of bloodfed mosquitoes that had fed on
      occupants of the rooms in which they were found were high and only slightly
      greater in villages without treated nets than those with them (95% and 88%,
      respectively). When these percentages were used to adjust estimates of personal
      protection, it was found that the error due to mosquitoes not feeding in the
      rooms in which they were collected is negligible.

PMID- 15189457
TI  - [Efficacy of therapeutic combinations with artemisinin derivatives in the
      treatment of non complicated malaria in Burundi].
AB  - Faced with the problem of resistance to chloroquine and sulfadoxine
      pyrimethamine, the Ministry of Public Health of Burundi decided to study the
      efficacy of two artemisinin-based combinations, the fixed combination of
      artemether-lumefantrine and the combination of amodiaquine + artesunate. The
      efficacy of these combinations for the treatment of uncomplicated falciparum
      malaria was studied in two sites representative of the country, in Kigobe
      neighbourhood of Bujumbura, the capital city, and in Buhiga, a rural area. The
      study followed the standardized WHO protocol from October 2001 to November 2002.
      A total of 295 children under 5 years were included; 153 children were treated
      with artesunate and amodiaquine (77 at Buhiga and 76 at Kigobe), and 142 children
      with the combination of artemether-lumefantrine (64 at Buhiga and 78 at Kigobe).
      Among the 295 children, 290 were followed up to 14 days. In the group of 149
      children treated with artesunate and amodiaquine, 142 (95.3%, 95% CI: 91.9-98.7%)
      presented with adequate clinical and parasitological response, five (3.3%) with
      late parasitological failure, one (0.7%) with late clinical failure and one
      (0.7%) with early treatment failure. Among the 141 children treated with
      artemether-lumefantrine, 140 (99.3%, 95% CI: 97.9-100%) presented with adequate
      clinical and parasitological response and one (0.7%) with late parasitological
      failure at Buhiga. Side-effects were comparable in both groups except for the
      vomiting. Vomiting was more frequent in the artesunate + amodiaquine on D1 and
      D2. Both treatments decreased the gametocyte carriage but without getting full
      clearance in all the patients. During a consensus workshop, the Ministry of
      Public Health agreed on the combination of artesunate and amodiaquine as the
      first line drug for the treatment of uncomplicated falciparum malaria in Burundi
      including epidemic outbreak.

PMID- 15189458
TI  - Drug resistance in Plasmodium falciparum from the Chittagong Hill Tracts,
      Bangladesh.
AB  - OBJECTIVE: To assess the efficacy of antimalarial treatment and molecular markers
      of Plasmodium falciparum resistance in the Chittagong Hill Tracts of Bangladesh.
      METHODS: A total of 203 patients infected with P. falciparum were treated with
      quinine 3 days plus sulphadoxine/pyrimethamine (SP) combination therapy, and
      followed up during a 4-week period. Blood samples collected before treatment were
      genotyped for parasite mutations related to chloroquine (pfcrt and pfmdr1 genes)
      or SP resistance (dhfr and dhps). RESULTS: Of 186 patients who completed follow
      up, 32 patients (17.2%) failed to clear parasitaemia or became positive again
      within 28 days after treatment. Recurring parasitaemia was related to age (chi(2)
      = 4.8, P < 0.05) and parasite rates on admission (t = 3.1, P < 0.01). PCR
      analysis showed that some of these cases were novel infections. The adjusted
      recrudescence rate was 12.9% (95% CI 8.1-17.7) overall, and 16.6% (95% CI 3.5
      29.7), 15.5% (95% CI 8.3-22.7) and 6.9% (95% CI 0.4-13.4) in three age groups (<5
      years, 5-14, > or =15). The majority of infections carried mutations associated
      with chloroquine resistance: 94% at pfcrt and 70% at pfmdr. Sp-resistant
      genotypes were also frequent: 99% and 73% of parasites carried two or more
      mutations at dhfr and dhps, respectively. The frequency of alleles at dhfr, dhps
      and pfmdr was similar in cases that were successfully treated and those that
      recrudesced. CONCLUSIONS: The clinical trial showed that quinine 3-days combined
      to SP is still relatively effective in the Chittagong Hill Tracts. However, if
      this regimen is continued to be widely used, further development of SP resistance
      and reduced quinine sensitivity are to be expected. The genotyping results
      suggest that neither chloroquine nor SP can be considered a reliable treatment
      for P. falciparum malaria any longer in this area of Bangladesh.

PMID- 15189459
TI  - The prevalence, intensities and risk factors associated with geohelminth
      infection in tea-growing communities of Assam, India.
AB  - OBJECTIVE: To determine the prevalence, intensity and associated risk factors for
      infection with Ascaris, hookworms and Trichuris in three tea-growing communities
      in Assam, India. METHODS: Single faecal samples were collected from 328
      individuals and subjected to centrifugal flotation and the Kato Katz quantitation
      technique and prevalence and intensities of infection with each parasite
      calculated. Associations between parasite prevalence, intensity and host and
      environmental factors were then made using both univariate and multivariate
      analysis. RESULTS: The overall prevalence of Ascaris was 38% [95% confidence
      interval (CI): 33, 43], and the individual prevalence of hookworm and Trichuris
      was 43% (95% CI: 38, 49). The strongest predictors for the intensity of one or
      more geohelminths using multiple regression (P < or = 0.10) were socioeconomic
      status, age, household crowding, level of education, religion, use of footwear
      when outdoors, defecation practices, pig ownership and water source. CONCLUSION:
      A universal blanket treatment with broad-spectrum anthelmintics together with
      promotion of scholastic and health education and improvements in sanitation is
      recommended for helminth control in the communities under study.

PMID- 15189460
TI  - Coverage, compliance and some operational issues of mass drug administration
      during the programme to eliminate lymphatic filariasis in Orissa, India.
AB  - This paper reports the coverage, compliance and other operational issues of mass
      drug administration (MDA) of diethylcarbamazine and albendazole under a programme
      to eliminate lymphatic filariasis (LF) in Orissa state of India. Both
      quantitative and qualitative methods were used to collect data from 90 villages
      and nine urban areas of four districts of Orissa, India. In Orissa, 67% of people
      older than 2 years had received the drugs during MDA and 42% had consumed them.
      About 25% of people had not taken the tablets although they received them. Urban
      areas recorded lower rates than rural areas. The paper discusses some
      policy/health system-, community- and drug-related issues that influenced
      coverage and compliance of MDA. It is essential to improve compliance in future
      rounds of MDA to achieve targets of control and eventual elimination of LF in a
      reasonable time frame.

PMID- 15189461
TI  - Control of human African trypanosomiasis: trap and odour preference of tsetse
      flies (Glossina morsitans submorsitans) in the upper Didessa river valley of
      Ethiopia.
AB  - Ethiopia is one of the endemic countries for Human African Trypanosomiasis (HAT)
      as over 100,000 people are at risk of having the disease. The control of HAT
      using odour preference of tsetse flies (Glossina morsitans submorsitans) was
      studied in upper Didessa river valley of Ethiopia. No information exists on the
      effectiveness of attractants for these species of tsetse flies in Ethiopia. Three
      attractants and their combinations namely: acetone, octenol, cow urine, acetone +
      octenol, acetone + octenol + cow urine, were evaluated using biconical and NGU
      traps for their efficacy as a first step in developing a sustainable community
      based HAT control initiative. The biconical traps baited with acetone, octenol or
      cow urine, or when combined, were more effective in catching G. m. submorsitans
      than the NGU traps (P < 0.05). However, the NGU traps caught more female tsetse
      flies than the biconical traps (P < 0.05). The acetone, octenol and cow urine
      combination was the most effective in attracting tsetse flies in both the
      biconical and NGU traps. Acetone was the best attractant while octenol was the
      least effective. Cow urine showed great promise for possible use in community
      based HAT control activities, especially urine that has been kept for several
      days. The use of cow urine in HAT control in Ethiopia is likely to succeed in the
      future because of its sustainability.

PMID- 15189462
TI  - Out of hospital treatment of patients with melioidosis using ceftazidime in 24 h
      elastomeric infusors, via peripherally inserted central catheters.
AB  - BACKGROUND: In the tropical north of the Northern Territory, Australia, 25-50
      patients are admitted to Royal Darwin Hospital (RDH) each year with Burkholderia
      pseudomallei infection, or melioidosis. Treatment consists of initial intensive
      therapy with 2-4 weeks of intravenous antibiotics. Clinical improvement may occur
      early and patients often prefer to be managed out of hospital in the Hospital in
      the Home (HITH). OBJECTIVES: To evaluate safety and efficacy of HITH management
      of patients with melioidosis. METHODS: A prospective observational study of our
      standard management which consists of 24 h infusions of ceftazidime infused
      through a peripherally inserted central catheter (PICC) line, plus oral
      sulphamethoxazole trimethoprim. Treatment is administered in the home, which may
      be in Darwin, regional areas or remote communities, or in a self-care unit
      located in the hospital grounds. RESULTS: From February 1998 to December 2001 150
      patients were admitted to RDH with culture confirmed B. pseudomallei infection.
      Of these, 73 patients were treated with 24 h infusions of ceftazidime, of which
      70 patients were managed by HITH. Complications of treatment include a PICC line
      complication rate of 10.6/1000 days in situ. Nine patients had relapse or
      recrudescence of disease, nearly all as a result of poor adherence to subsequent
      oral eradication therapy, these patients were all re-treated successfully. One
      patient remains infected with B. pseudomallei. CONCLUSION: This clinical outcome
      study suggests that out of hospital management of melioidosis with 24 h infusions
      of ceftazidime via a PICC line is safe and effective.

PMID- 15189463
TI  - Features distinguishing amoebic from pyogenic liver abscess: a review of 577
      adult cases.
AB  - Distinguishing amoebic from pyogenic liver abscesses is crucial because their
      treatments and prognoses differ. We retrospectively reviewed the medical records
      of 577 adults with liver abscess in order to identify clinical, laboratory, and
      radiographic factors useful in differentiating these microbial aetiologies.
      Presumptive diagnoses of amoebic (n = 471; 82%) vs. pyogenic (n = 106; 18%)
      abscess were based upon amoebic serology, microbiological culture results, and
      response to therapy. Patients with amoebic abscess were more likely to be young
      males with a tender, solitary, right lobe abscess (P = 0.012). Univariate
      analysis found patients with pyogenic abscess more likely to be over 50 years
      old, with a history of diabetes and jaundice, with pulmonary findings, multiple
      abscesses, amoebic serology titres <1:256 IU, and lower levels of serum albumin
      (P < 0.04). Multivariate logistic regression analysis confirmed that age >50
      years, pulmonary findings on examination, multiple abscesses, and amebic serology
      titres <1:256 IU were predictive of pyogenic infection. Several clinical and
      laboratory parameters can aid in the differentiation of amebic and pyogenic liver
      abscess. In our setting, amebic abscess is more prevalent and, in most
      circumstances, can be identified and managed without percutaneous aspiration.

PMID- 15189464
TI  - Evaluation of a urinary antigen-based latex agglutination test in the diagnosis
      of kala-azar in eastern Nepal.
AB  - BACKGROUND: We evaluated the diagnostic accuracy as well as the reproducibility
      of the urine latex agglutination test 'KAtex' in the diagnosis of kala-azar in
      patients recruited at a tertiary care centre in Dharan, Nepal, between November
      2000 and January 2002. METHODS: All patients presenting with fever of 2 weeks or
      more and splenomegaly were consecutively enrolled. Bone marrow and--if negative-
      spleen aspirates were examined for Leishmania donovani. Serum and urine samples
      were taken in duplicate for the Direct Agglutination Test (DAT) and KAtex. The
      reference laboratory determined sensitivity and specificity of KAtex.
      Reproducibility between both laboratories was assessed. RESULTS: KAtex was
      performed on urine from 155 parasitologically confirmed kala-azar and 77 non-kala
      azar cases (parasitology and DAT-negative). KAtex showed a sensitivity of 47.7%
      (74/155, 95% CI: 39.7-55.9) and a specificity of 98.7% (76/77, 95% CI: 93.0
      100.0). Reproducibility of KAtex showed a kappa of 0.684 (P < 0.001, n = 232).
      CONCLUSION: KAtex evaluation showed high specificity, low sensitivity and
      moderate reproducibility. A urine test for kala-azar could become a real
      breakthrough in kala-azar management if its reproducibility and sensitivity could
      be further improved.

PMID- 15189465
TI  - Outbreak of West Nile virus causing severe neurological involvement in children,
      Nuba Mountains, Sudan, 2002.
AB  - An atypical outbreak of West Nile virus (WNV) occurred in Ngorban County, South
      Kordophan, Sudan, from May to August 2002. We investigated the epidemic and
      conducted a case-control study in the village of Limon. Blood samples were
      obtained for cases and controls. Patients with obvious sequelae underwent
      cerebrospinal fluid (CSF) sampling as well. We used enzyme-linked immunosorbent
      assay (ELISA) and neutralization tests for laboratory diagnosis and identified 31
      cases with encephalitis, four of whom died. Median age was 36 months. Bivariate
      analysis did not reveal any significant association with the risk factors
      investigated. Laboratory analysis confirmed presence of IgM antibodies caused by
      WNV in eight of 13 cases, indicative of recent viral infection. The unique
      aspects of the WNW outbreak in Sudan, i.e. disease occurrence solely among
      children and the clinical domination of encephalitis, involving severe
      neurological sequelae, demonstrate the continuing evolution of WNV virulence. The
      spread of such a virus to other countries or continents cannot be excluded.

PMID- 15189466
TI  - Asking semi-literate adolescents about sexual behaviour: the validity of assisted
      self-completion questionnaire (ASCQ) data in rural Tanzania.
AB  - OBJECTIVES: To develop and test a sexual behaviour survey method for semi
      literate populations, combining the privacy of a self-completion questionnaire
      (SCQ) with the clarity of a face-to-face questionnaire (FFQ). METHODS: In 1998,
      6079 Tanzanian primary school students (mean age 15.1 years) were surveyed using
      an innovative assisted self-completion questionnaire (ASCQ). The format of the
      questionnaire was simple, all responses were closed, and conceptually complex
      questions such as those involving ranking or multiple answers were avoided. The
      ASCQ was administered to groups of 20 by a research assistant who read questions
      and answers aloud in two languages so pupils could tick or write responses
      independently. A total of 4958 of respondents from the 1998 ASCQ Cohort also
      participated in a 1998 FFQ interview and, in 2000, 4424 again completed an ASCQ.
      RESULTS: In the 1998 ASCQ survey, 55.0% of males and 21.1% of females reported
      they had had vaginal intercourse, of whom 71.5% and 66.0%, respectively reported
      their first sexual relationship lasted for a week or less, and 49.5% and 59.6%,
      respectively reported they had had sex in the last 4 weeks. After adjustment for
      age, reported sex was associated with alcohol use in both males (OR = 1.57) and
      females (OR = 1.69), earning money for males (OR = 1.32) and not living with a
      mother for females (OR = 0.77). The vast majority of respondents did not appear
      to have difficulty completing the ASCQ, but 7.4% of 1998 respondents and 2.9% of
      2000 respondents selected all first or all last answers in a section for which
      this was inconsistent. This bias was associated with female, less educated and
      more geographically remote respondents. Of those respondents who reported sex in
      the 1998 ASCQ survey, 32.1% reported fewer total partners in the 2000 ASCQ
      survey, 25.2% reported having had sex fewer times than originally reported, and
      61.9% of those who reported having used a condom in 1998 reported never having
      used one in 2000. While the proportions reporting sex were very similar in the
      1998 ASCQ and FFQ surveys, 37.9% of males and 59.2% of females reporting sex only
      did so on one of the two questionnaires. Higher proportions of respondents
      reported sensitive information in the ASCQ than the FFQ, although in some cases
      this may have related to answer order bias. CONCLUSION: The results suggest that
      an ASCQ may be useful in assessing sexual behaviour in African adolescents,
      particularly for older, male and/or educated respondents. However, triangulation
      with data from other surveys raises questions about the validity of self-reported
      sexual behaviour in general.

PMID- 15189467
TI  - A framework for analysing the relationship between disease control programmes and
      basic health care.
AB  - In this paper, we present a framework for analysing the complex relationship
      between disease control programmes and basic health care systems. Many of the
      ideas and concepts presented in this paper were developed by the staff of the
      Public Health Department of the Antwerp Institute of Tropical Medicine (ITM) over
      the last 20 years. They are thus the product of the reflection of an entire team.

PMID- 15189468
TI  - Integration and disease control: notes from the Prince Leopold Institute of
      Tropical Medicine Colloquium 2002.
AB  - The discussion on the desirability or not to integrate disease control activities
      with general health services is a longstanding one. The recent creations of
      global health initiatives for poverty-related disease control have refueled the
      debate. The Prince Leopold Institute of Tropical Medicine (ITM) convened a
      colloquium in Antwerp to clarify concepts involved in integrated disease control
      and contribute to the creation of a common scientific language and a better
      understanding of the issues at stake. We present an overview of highlights from
      the colloquium sessions. Some of the contributions reported here are presented in
      more detail elsewhere in this special issue.

PMID- 15189469
TI  - Integrating tuberculosis and HIV care in the primary care setting in South
      Africa.
AB  - BACKGROUND: In many countries including South Africa, the increasing human
      immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have impacted
      significantly on already weakened public health services. This paper reviews the
      scope, process and performance of the HIV and TB services in a primary care
      setting where antiretroviral therapy is provided, in Khayelitsha, South Africa,
      in order to assess whether there is a need for some form of integration. METHODS:
      The scope and process of both services were assessed through observations of the
      service and individual and group interviews with key persons. The performance was
      assessed by examining the 2001-2002 reports from the health information system
      and clinical data. RESULTS: The TB service is programme oriented to the
      attainment of an 85% cure rate amongst smear-positive patients while the HIV
      service has a more holistic approach to the patient with HIV. The TB service is
      part of a well-established programme that is highly standardized. The HIV service
      is in the pilot phase. There is a heavy load at both services and there is large
      degree of cross-referral between the two services. There are lessons that can be
      learnt from each service. There is an overlap of activities, duplication of
      services and under-utilization of staff. There are missed opportunities for TB
      and HIV prevention, diagnosis and management. CONCLUSIONS: The study suggests
      that there may be benefits to integrating HIV and TB services. Constraints to
      this process are discussed.

PMID- 15189470
TI  - Quantitative evaluation of integrated schistosomiasis control: the example of
      passive case finding in Ghana.
AB  - Passive case finding based on adequate diagnosis and treatment of symptomatic
      individuals with praziquantel by the health care facilities is a minimum
      requirement for integrated schistosomiasis control. Two field studies were
      conducted in Ghana to obtain quantifications about the steps in this process: (1)
      a study of health-seeking behaviour through interview of individuals with
      reported schistosomiasis-related symptoms; (2) a study of the performance of the
      Ghanaian health system with regard to schistosomiasis case management by
      presenting clinical scenarios to health workers and collecting information about
      availability of praziquantel. It appeared that cases of blood in urine (the most
      typical symptom of Schistosoma haematobium) and blood in stool (the most typical
      symptom of S. mansoni) have a very small probability of receiving praziquantel
      (4.4% and 1.4%, respectively) from health facilities. Programmes aimed at making
      the drug available at all levels of the health care delivery system and
      encouraging health-seeking behaviour through health education are not likely to
      increase these probabilities beyond 30%. This is because many cases with blood in
      urine do not consider it serious enough to seek health care, and blood in stool
      usually requires (imperfect) diagnostic testing and referral. We therefore
      conclude that additional control activities, especially for high-risk groups,
      will remain necessary.

PMID- 15189471
TI  - Disease control in primary health care: a historical perspective.
AB  - The effectiveness of disease control by mobile teams decreased when countries
      became independent. Early case-finding and continuity of care require permanently
      accessible health care facilities where rationalization by professionals and
      participation of the users are well balanced. The Primary Health Care concept, a
      plea for this equilibrium, has been discredited by different types of
      misapplication. Correctly functioning and accessible first line health services,
      completed by a referral level, are a precondition for effective participation of
      the users. Where 'ideal health districts' cannot be realized, a form of steady
      exchanges between generalists and the specialists of the referral level has lead
      to diverse 'functional districts'.

PMID- 15189473
TI  - Stability, consistency, and heritability of electrodermal response lability in
      middle-aged male twins.
AB  - We examined individual differences in nonspecific electrodermal response (EDR)
      lability in terms of retest stability, cross-situational consistency, and
      heritability in a sample of 345 adult monozygotic and dizygotic twin pairs. We
      also examined the phenotypic and genetic relationships between EDR lability and
      speed of habituation of the specific EDR to a nonsignal stimulus. Individual
      variation in EDR lability showed substantial retest stability and cross
      situational consistency and also predicted resistance to specific EDR
      habituation. Structural equation modeling showed that the covariation among EDR
      lability measures and resistance to specific EDR habituation operated through a
      single latent phenotype, which was influenced in approximately equal measure by
      genetic and unique environmental factors. We discuss these findings in terms of
      an information processing account of individual differences in phasic EDR
      activation.

PMID- 15189474
TI  - The psychophysiology of the maternal-fetal relationship.
AB  - The enigmatic quality of the maternal-fetal relationship has been extolled
      throughout history with little empirical support. We apply time series analysis
      to data for 137 maternal-fetal pairs collected at 20, 24, 28, 32, 36, and 38
      weeks gestation. Maternal heart rate and skin conductance data were digitized in
      tandem with fetal heart rate and motor activity. No temporal relations between
      fetal heart rate and either maternal variable were found, although averaged
      maternal and fetal heart rates were correlated from 32 weeks. Consistent temporal
      associations between fetal movement and maternal heart rate and skin conductance
      were detected. Fetal movement stimulated rises in each parameter, peaking at 2
      and 3 s, respectively. Associations did not change over gestation, were
      unaffected by a maternal stressor, and showed within-pair stability. The
      bidirectional nature of the maternal-fetal relationship is considered.

PMID- 15189476
TI  - Heart rate and skin conductance analysis of antecendents and consequences of
      decision making.
AB  - The current study examined the pattern of heart rate and skin conductance changes
      preceding risky choices and following outcome for bad, moderate, and good
      performers on an analogue of the Iowa gambling task (Bechara, Damasio, Damasio, &
      Anderson, 1994). The task required a choice between four options; two options
      were followed by a high reward and, unpredictably, an even higher loss
      (disadvantageous options) and two other options were followed by a small reward
      but the unpredictable loss was also small (advantageous options). Anticipatory
      heart rate slowing and skin conductance level were higher preceding
      disadvantageous relative to advantageous options, but only for good performers.
      In contrast, heart rate slowed and skin conductance level increased following
      loss relative to reward outcomes, and these changes were similar for all
      performance groups. These findings were interpreted to suggest that decision
      making impairments in bad performers arise from a weak somatic response generated
      by secondary inducers (i.e., somatic markers), rather than a weak somatic
      response generated by primary inducers of reward and punishment.

PMID- 15189475
TI  - Regional cerebral blood flow correlates with heart period and high-frequency
      heart period variability during working-memory tasks: Implications for the
      cortical and subcortical regulation of cardiac autonomic activity.
AB  - The aim of the present study was to characterize the functional relationships
      between behaviorally evoked regional brain activation and cardiac autonomic
      activity in humans. Concurrent estimates of regional cerebral blood flow (rCBF;
      obtained by positron emission tomography), heart period, and high-frequency heart
      period variability (HF-HPV; an indicator of cardiac parasympathetic activity)
      were examined in 93 adults (aged 50-70 years) who performed a series of
      increasingly difficult working-memory tasks. Increased task difficulty resulted
      in decreased heart period (indicating cardioacceleration) and decreased HF-HPV
      (indicating decreased cardiac parasympathetic activity). Task-induced decreases
      in heart period and HF-HPV were associated with concurrent increases and
      decreases in rCBF to cortical and subcortical brain regions that are speculated
      to regulate cardiac autonomic activity during behavioral processes: the medial
      prefrontal, insular, and anterior cingulate cortices, the amygdala-hippocampal
      complex, and the cerebellum. These findings replicate and extend a small number
      of functional neuroimaging studies that suggest an important role for both
      cortical and subcortical brain systems in human cardiac autonomic regulation.

PMID- 15189477
TI  - Mental stress-induced hemoconcentration: Sex differences and mechanisms.
AB  - Given the possible role of hemoconcentration in myocardial infarction and
      apparent sex differences in susceptibility, three studies examined sex
      differences in mental stress-induced hemoconcentration, and explored possible
      underlying mechanisms. Blood pressure, heart rate, and hematocrit were monitored
      at rest and in response to a mental stress task that was contrived to be
      increasingly provocative across the three studies. This was confirmed by self
      report, performance, and cardiovascular reactivity data. The most convincing
      evidence for hemoconcentration effects and sex differences in hemoconcentration
      emerged from exposure to the more provocative of the stress tasks, with men also
      showing greater hemoconcentration than women. Blood pressure reactivity was a
      strong and consistent predictor of stress-induced hemoconcentration. These
      findings may help to explain sex differences in susceptibility to myocardial
      infarction.

PMID- 15189478
TI  - Aerobic exercise training and cardiovascular reactivity to psychological stress
      in sedentary young normotensive men and women.
AB  - Forty-five (22 women) sedentary young (18-30 years old) nonsmoking normotensive
      volunteers engaged in either 6 weeks of aerobic training (AT), weight training
      (WT), or a no-treatment (NT) condition to determine whether AT lowers systolic
      (SBP) and diastolic (DBP) blood pressure, heart rate (HR), and rate-pressure
      product (RPP) during rest, psychological stress, and recovery periods. Estimated
      VO(2)max increased for the AT (32.1+/-1.1 to 38.4+/-1.0 ml.kg(-1).min(-1)). A
      smaller increase for the WT (30.5+/-1.1 to 33.8+/-1.0) was likely due to
      increased leg strength, and VO(2)max did not change for the NT (32.5+/-1.1 to
      32.9+/-1.0). Heart rate and RPP levels were lower during psychological stress and
      recovery after training for AT relative to the WT and NT. Overall SBP was also
      lower in the AT relative to the NT but not the WT. In conclusion, aerobic
      training lowered cardiovascular activity levels during psychological stress and
      recovery in healthy young adults, implying a protective role against age-related
      increases in coronary heart disease for individuals who adopt aerobic exercise
      early in life and maintain the behavior across the life span.

PMID- 15189480
TI  - Life-span changes in P3a.
AB  - The relationship of visual P3a to age was investigated in a life-span sample. The
      aims of the study were (1) to assess to what extent P3a, relative to P3b,
      decreases with increasing age; (2) To assess at which recording sites the
      relationship between P3a and age is strongest; (3) to investigate whether the
      relationship between P3a and age is best described as linear or nonlinear. One
      hundred and three well-functioning adults, 20-92 years old, were given a health
      interview, a battery of neuropsychological tests, and performed a visual three
      stimuli oddball ERP task yielding both a P3a and a P3b. P3a and age was
      moderately correlated, with coefficients reaching.53 (Cz) and -.52 (Pz) for
      latency and amplitude, respectively. P3b was to a much lesser extent related to
      age. Generally, the age-P3a relationship was strongest at midline and central
      electrodes. Finally, the relationship between age and P3a was best described as
      linear. P3a seems selectively more impaired with age than P3b, but this
      impairment seems less pronounced at Fz than at Cz and Pz. There is a need for
      complex theoretical integration of these and previous findings.

PMID- 15189479
TI  - Brain electrocortical activity during and after exercise: a quantitative
      synthesis.
AB  - Investigators of brain electrocortical responses to exercise have interpreted
      increased activity, or frontal hemispheric asymmetry, in the alpha frequency band
      as indicative of relaxation or a change in affect. However, few studies compared
      alpha activity with other frequencies and within or across hemispheres. To
      clarify the cumulative evidence in this area, we provide a quantitative review of
      the effects of exercise on brain electrocortical activity according to frequency
      bands and recording sites. Fifty-eight effects from 18 studies and 282
      participants were retrieved. The mean effect size was moderately large (0.54 SD,
      95% CI: 0.43 to 0.65) but heterogeneous. Compared to before exercise, alpha
      activity was greater immediately after and during exercise when expressed as
      absolute power but not as relative to power in other frequency bands; delta,
      theta, and beta activity also increased (0.38 to 0.75 SD). Effects did not differ
      significantly by recording sites. The cumulative evidence does not indicate that
      change in brain electrocortical activity after exercise is specific to alpha
      activity or hemispheric site.

PMID- 15189481
TI  - Neurophysiological correlates of word and pseudo-word processing in well
      recovered aphasics and patients with right-hemispheric stroke.
AB  - Neurophysiological correlates of language recovery after stroke were
      investigated. Neurological patients with single focal lesions in their left or
      right hemisphere and healthy control subjects made lexical decisions on written
      words and pseudo-words while EEG responses were recorded. At the time of testing,
      patients did not show clinically apparent language dysfunction, although those
      with left-hemisphere lesions had suffered from aphasia in the first months after
      their stroke. A P3-like positive deflection of the event-related potential (ERP)
      was reduced in the patients relative to healthy controls, this reduction being
      most pronounced over the hemisphere affected by stroke. Consistent with earlier
      research, healthy control subjects showed more positive ERPs to words than to
      pseudo-words. This pattern was reversed in both patient groups, where words
      elicited more negative-going ERPs than pseudo-words already 160-320 ms after
      stimulus onset. Because ERPs showed between-group differences only for words,
      these word-specific neurophysiological signatures altered in stroke patients with
      well-recovered language functions may be a correlate of cortical lesions or an
      index of reorganization of language after stroke.

PMID- 15189482
TI  - The effect of the menstrual cycle on electrophysiological and behavioral measures
      of memory and mood.
AB  - Event-related potentials (ERPs) were compared between the menses and ovulatory
      phase of the menstrual cycle in response to visually presented words, some of
      which were repeated as part of direct and indirect memory tasks. Twelve
      spontaneously cycling women were tested during the menses and ovulatory phases.
      For the direct task, participants had to discriminate between new words and those
      repeated after a mean of six trials. In the indirect task, subjects were required
      to discriminate between target and nontarget words. Some of the nontarget words
      were repeated after a mean of six trials. The ERP repetition effect mean
      amplitude was significantly greater in response to repeated words at both cycle
      phases but did not differ across the cycle. P300 amplitude was significantly
      greater during menses than the ovulatory phase. We conclude that context updating
      mechanisms as indexed by the P300 are sensitive to cyclic hormonal fluctuations.

PMID- 15189483
TI  - Comparison of sensory gating to mismatch negativity and self-reported perceptual
      phenomena in healthy adults.
AB  - To better understand the possible functional significance of electrophysiological
      sensory gating measures, response suppression of midlatency auditory event
      related potential (ERP) components was compared to the mismatch negativity (MMN)
      and to self-rated indices of stimulus filtering and passive attention-switching
      phenomena in an age-restricted sample of healthy adults. P1 sensory gating,
      measured during a paired-click paradigm, was correlated with MMN amplitude,
      measured during an acoustic oddball paradigm (intensity deviation). Also,
      individuals that exhibited less robust P1 suppression endorsed higher rates of
      "perceptual modulation" difficulties, whereas component N1 suppression was more
      closely related to "over-inclusion" of irrelevant sounds into the focus of
      attention. These findings suggest that the ERP components investigated are not
      redundant, but correspond to distinct-possibly related-pre-attentive processing
      systems.

PMID- 15189484
TI  - Distraction produces an increase in pain-evoked anterior cingulate activity.
AB  - This study examined the effects of distraction on pain-evoked activity in the
      anterior cingulate cortex (ACC). Twenty-eight healthy adults were given painful
      electrical stimulation of the sural nerve during an attend condition, where they
      rated the subjective magnitude of each electrical stimulus, and during a
      distraction condition, where they performed an arithmetic distraction task. The
      magnitude of the pain-evoked ACC activity was estimated from the dipole source
      localization analysis of the somatosensory evoked potential. Subjective pain
      ratings were smaller and pain-evoked ACC activity was larger during the
      distraction condition than during the attend condition. Recent regional cerebral
      blood flow studies have also reported a distraction-related increase in pain
      evoked ACC activity. Our results confirm these reports, and verify that the
      distraction effect specifically involves pain-evoked ACC activity. The cognitive
      demands of the distraction task present the possibility that the pain-evoked ACC
      activity might be involved, at least in part, in response competition and/or
      orienting attention toward painful stimuli.

PMID- 15189485
TI  - The electrophysiological correlates sustaining the retrieval of face-name
      associations: an ERP study.
AB  - An ERP study on 9 healthy participants was carried out to temporally constrain
      the neural network proposed by Campanella et al. (2001) in a PET study
      investigating the cerebral areas involved in the retrieval of face-name
      associations. Three learning sessions served to familiarize the participants with
      24 face-name associations grouped in 12 male/female couples. During EEG
      recording, participants were confronted with four experimental conditions,
      requiring the retrieval of previously learned couples on the basis of the
      presentation of name-name (NN), face-face (FF), name-face (NF), or face-name (FN)
      pairs of stimuli. The main analysis of this experiment consisted in the
      subtraction of the nonmixed conditions (NN and FF) from the mixed conditions (NF
      and FN). It revealed two main ERP components: a negative wave peaking at left
      parieto-occipital sites around 285 ms and its positive counterpart recorded at
      left centro-frontal electrodes around 300 ms. Moreover, a dipole modeling using
      three dipoles whose localization corresponded to the three cerebral areas
      observed in the PET study (left inferior frontal gyrus, left medial frontal
      gyrus, left inferior parietal lobe) explained more than 90% of the variance of
      the results. The complementarity between anatomical and neurophysiological
      techniques allowed us to discuss the temporal course of these cerebral activities
      and to propose an interactive and original anatomo-temporal model of the
      retrieval of face-name associations.

PMID- 15189486
TI  - Latent inhibition mediates N1 attenuation to repeating sounds.
AB  - Sound repetition typically reduces auditory N1 amplitudes, more so at higher
      rates. This has been attributed to refractoriness of N1 generators. However,
      evidence that N1 attenuation is delayed 300-400 ms after the first occurrence of
      a repeated sound suggests an alternative process, such as inhibition, that
      requires 300-400 ms to become fully operational. We examined the N1 to trains of
      fixed-interval (100, 200, 300, 400 ms) tones for evidence of effects predicted by
      models of refractoriness and of latent inhibition. Regardless of interval,
      latency of the eliciting tone from train onset determined N1 amplitudes during
      the first 400 ms of the train, which decreased in this window. The results show
      that N1 attenuation cannot be due simply to refractoriness, which would elicit
      the smallest N1 to the second tone. An inhibitory neural circuit can account for
      these and previous results, and may be important to auditory perceptual
      processing.

PMID- 15189487
TI  - Spatiotemporal analysis of event-related potentials to upright, inverted, and
      contrast-reversed faces: effects on encoding and recognition.
AB  - In an n-back face recognition task where subjects responded to repeated stimuli,
      ERPs were recorded to upright, inverted, and contrast-reversed faces. The effects
      of inversion and contrast reversal on face encoding and recognition were
      investigated using the multivariate spatiotemporal partial least squares (PLS)
      analysis. The configural manipulations affected early processing (100-200 ms) at
      posterior sites: Inversion effects were parietal and lateral, whereas contrast
      reversal effects were more occipital and medial, suggesting different underlying
      generators. A later reactivation of face processing areas was unique to inverted
      faces, likely due to processing difficulties. PLS also indicated that the "old
      new" repetition effect was maximal for upright faces and likely involved
      frontotemporal areas. Marked processing differences between inverted and contrast
      reversed faces were seen, but these effects were similar at encoding and
      recognition.

PMID- 15189488
TI  - Pre-attentive perception of vowel phonemes from variable speech stimuli.
AB  - Understanding speech requires the construction of phonetic representations while
      abstracting from specific sound features. To understand different speakers of
      varying pitches of voice, loudness, or timbre, categorical phoneme information
      needs to be rapidly extracted from dynamic, changing speech input. The present
      study demonstrated a genuine MMN to tokens of /a/ and /i/ vowels varying in pitch
      of voice and amplitude envelope when they occurred infrequently among the
      respective other vowels. These data indicate that the speech perception system
      pre-attentively extracted the F1/F2 formant information despite the language
      irrelevant variation in the sound input.

PMID- 15189489
TI  - Automatic time perception in the human brain for intervals ranging from
      milliseconds to seconds.
AB  - Time perception in everyday life deals with various intervals. Here we
      investigated whether an automatic duration-discrimination mechanism in audition
      operates even for intervals of an order of seconds, by using the mismatch
      negativity (MMN), an index of automatic change detection in audition. In
      Experiment 1, occasional decrements of the duration of a repetitive "standard"
      tone elicited an MMN in subjects ignoring auditory stimulation, even with the
      standard-stimulus durations over a second. Nevertheless, the MMN amplitude was
      significantly diminished with standard-stimulus durations of 800 ms and above,
      despite the fact that a constant deviant versus standard duration ratio was used.
      Complementary experiments varying the interstimulus interval (Experiment 2) and
      the magnitude of duration change (Experiment 3) yielded corroborating results.
      The present results suggest that automatic duration discrimination in audition
      operates even for durations of the order of seconds; yet its optimum time scale
      might be of the order of milliseconds.

PMID- 15189490
TI  - Does moderately severe hypoglycemia cause cognitive dysfunction in children?

PMID- 15189491
TI  - A prospective study of severe hypoglycemia and long-term spatial memory in
      children with type 1 diabetes.
AB  - In a previous retrospective study, severe hypoglycemia (SH) was associated with
      decreased long-term spatial memory in children with type 1 diabetes mellitus
      (T1DM). In this study, we tested the hypothesis that prospectively ascertained SH
      would also be associated with decreased spatial long-term memory over time.
      Children with T1DM (n = 42) and sibling controls (n = 25) performed a spatial
      delayed response (SDR) task with short and long delays and other
      neuropsychological tests at baseline and after 15 months of monitoring. Extreme
      glycemic events and other medical complications were recorded prospectively
      during follow-up. Fourteen T1DM children experienced at least one episode of SH
      during the follow-up period (range = 1-5). After controlling for long-delay SDR
      performance at baseline, age, gender, and age of onset, the presence of SH during
      the prospective period was statistically associated with decreased long-delay SDR
      performance at follow-up (semipartial r = -0.38, p = 0.017). This relationship
      was not seen with short-delay SDR or with verbal or object memory, attention, or
      motor speed. These results, together with previously reported data, support the
      hypothesis that SH has specific, negative effects on spatial memory skills in
      T1DM children.

PMID- 15189492
TI  - Preservation of C-peptide secretion in subjects at high risk of developing type 1
      diabetes mellitus--a new surrogate measure of non-progression?
AB  - Individuals at high risk of developing type 1 diabetes mellitus can be identified
      using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention
      Trial-1 (DPT-1), annual intravenous infusions of low doses of regular insulin,
      together with daily subcutaneous injection of a single low dose of Ultralente
      insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in
      high-risk non-diabetic relatives. In our study, we attempted to achieve beta-cell
      rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin
      twice daily to high-risk non-diabetic subjects in an effort to prevent or delay
      the onset of the disease. The maximum tolerable dose was given with the dose
      reduced for any hypoglycemia (mean dose 0.33 +/- 0.15; range 0.09-0.66
      units/kg/d). We treated 26 subjects who were confirmed to have islet cell
      antibodies (ICAs) and a low first-phase insulin response (FPIR) to intravenous
      glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance
      (IGT). The median duration of follow-up was 5.5 yr. Diabetes occurred in 10 of 12
      subjects with IGT and five of 14 subjects with normal glucose tolerance. The
      cumulative incidence of diabetes was the same as with that seen in a matched,
      observation group (subjects followed prospectively as part of the University of
      Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration
      of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the
      rate of progression (p = 0.79). There was a higher rate of progression to
      diabetes in the group with abnormal glucose tolerance at baseline than in those
      with normal baseline glucose tolerance (p = 0.003). Interestingly, in non
      progressors, as opposed to progressors, there was no fall in C-peptide (peak and
      area under the curve) production regardless of the type of tolerance testing
      (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the
      dose and regimen of NPH insulin used, insulin did not delay or prevent the
      development of type 1 diabetes. However, preservation of C-peptide production in
      the prediabetic period appears to indicate non-progression to clinical disease
      and may serve as a new surrogate for determining response to preventative
      efforts.

PMID- 15189493
TI  - Initiation of insulin glargine in children and adolescents with type 1 diabetes.
AB  - BACKGROUND: Glargine (Lantus) is a recently approved, long-acting insulin analog
      that is increasingly being used in children with diabetes. The aim of this
      retrospective chart review was to summarize our experience in starting glargine
      in children and adolescents with diabetes. SUBJECTS AND STUDY METHODS: We
      reviewed the medical records of 71 children with type 1 diabetes (29 boys and 42
      girls) who initiated glargine therapy to improve glycemic control between 1 June
      2001 and 30 June 2002. Data were collected for 6 months before and 6 months after
      adding glargine. RESULTS: Subjects' mean age [+/-standard deviation (SD)] at
      diagnosis of diabetes was 7.5 +/- 4.1 yr. Mean age at initiation of glargine
      therapy was 11.5 +/- 4.9 yr. The total daily long-acting insulin dose decreased
      by about 20% after initiating glargine therapy. There were no significant
      differences in hemoglobin A1c (HbA1c) and blood glucose control prior to and
      after initiating glargine therapy (HbA1c at baseline 8.9 +/- 1.6% and HbA1c after
      6 months of glargine therapy was 8.9 +/- 1.5%). Overall, blood glucose
      concentrations did not differ significantly throughout the study. Patients who
      switched to glargine because of nocturnal hypoglycemia had a 65% decrease in
      nocturnal blood glucose reading less than 50 mg/dL. There were three seizures in
      the first week after initiating glargine therapy. CONCLUSION: This retrospective
      study suggests that glargine is at least as effective as other long-acting
      insulins but that care must be taken during the conversion process to avoid
      hypoglycemia.

PMID- 15189494
TI  - Angiotensin-converting enzyme gene polymorphism and lipid profiles in Kuwaiti
      children with type 1 diabetes.
AB  - METHODS: We studied angiotensin-converting enzyme (ACE) gene polymorphism and
      lipid profiles in Kuwaiti children with uncomplicated type 1 diabetes. A total of
      125 children with type 1 diabetes were matched in a case-control study on age and
      gender to 125 non-diabetic children as controls. Serum lipids (total cholesterol,
      TC; high-density lipoprotein cholesterol, HDL; low-density lipoprotein
      cholesterol, LDL-c; triglycerides, TG; apolipoprotein A1 and B, apo A1 and B;
      lipoprotein(a), Lp(a)); and glycated hemoglobin, HbA1c were evaluated according
      to ACE genotypes. RESULTS: Genotype distributions were found to be similar in
      cases [ACE insertion/insertion (II) 9.6%, ACE insertion/deletion (ID) 38.4%, ACE
      deletion/deletion (DD) 52.0%], and controls (II 8.8%, ID 43.2%, DD 48.0%), and
      were characterized by higher frequencies of DD, ID, and lower frequencies of II.
      Diabetic children with DD genotype showed significantly higher levels of TC (p <
      0.01), HDL (p < 0.001), and apo A1 (p < 0.001) than controls. There was a higher
      proportion of diabetic children with family history of cardiovascular disease
      (CVD) in the DD genotype group (51.9%) than those with II genotype group (11.1%)
      (p < 0.001). Also, there was a significant increase in the frequency of diabetic
      children with Lp(a) > 30 mg/dL in children with a family history of CVD (p =
      0.008). Lp(a) levels were correlated with HbA1c in the diabetic group (r = 0.239,
      p = 0.019), but when patients with poor glycemic control (HbA1c > 9%) were
      excluded, the significant correlation disappeared (r = 0.127, p = 0.381). After
      adjusting confounding between variables, the logistic regression analysis showed
      that the two significantly related variables with the rise in Lp(a) were
      increasing TC level and poor glycemic control. CONCLUSIONS: In children with type
      1 diabetes, the role of ACE polymorphism as a probable contributor to CVD seems
      to be partially mediated through other factors such as poor glycemic control, TC,
      and Lp(a) level. A longitudinal study is recommended with a larger number of
      patients in each ACE genotype group in order to assess such associations.

PMID- 15189495
TI  - Clinical presentation of childhood type 1 diabetes mellitus in the Al-Madina
      region of Saudi Arabia.
AB  - AIM: To describe the clinical pattern and the laboratory characteristics at
      presentation of childhood type 1 diabetes mellitus in the Al-Madina region of the
      north-west province of Saudi Arabia. METHODS: The clinical and laboratory data of
      a total of 230 children who presented with diabetes during a 10-year period (1992
      2001) were retrospectively analyzed based on hospital records. RESULTS: Polyuria
      and polydipsia were by far the most frequent symptoms at presentation (96%);
      three quarters of the children (76.6%) had weight loss at presentation. One
      hundred and twenty-seven children (55.2%) of 230 presented with ketoacidosis. The
      mean age at diagnosis was 6.9 yr. The average duration of presenting symptoms
      before the hospital encounter was 17.1 d ranging from 3.0 to 45.0 d, with an
      average of 16.2 d in boys and 17.7 d in girls, a difference which was not
      significant. CONCLUSION: Polyuria, polydipsia, and weight loss are the most
      common symptoms at presentation of childhood diabetes mellitus in our region. The
      frequency of diabetic ketoacidosis was relatively high. The commonly recognized
      symptoms of diabetes were present in most of the children for a relatively long
      duration before the diagnosis. This calls for a collaboration of efforts for the
      early recognition of symptoms by patients and physicians to avoid the more severe
      types of presentation.

PMID- 15189496
TI  - Cystic fibrosis presenting as new onset diabetes mellitus in adolescent twins.
AB  - We describe identical adolescent twin girls who presented with symptoms
      consistent with type 1 diabetes. Medical work up for evaluation of
      gastrointestinal symptoms led to a diagnosis of cystic fibrosis (CF) in both.
      These cases suggest that diabetes can be a presenting symptom of CF in the
      absence of pulmonary symptomatology.

PMID- 15189497
TI  - Reducing injection pain in children and adolescents with diabetes: a review of
      indwelling catheters.
AB  - Most children and adolescents find the pain when injecting insulin quite minimal
      but still significantly more painful than a placebo injection. However, injection
      pain and needle phobia are major problems for a small number of patients, even
      after many years of diabetes. Needle diameter is of less importance for the
      experienced pain. The use of indwelling catheters (Insuflon, Unomedical, Lynge,
      Denmark) for introducing insulin injections at the onset of diabetes results in
      an evident relief of preinjection anxiety, injection problems, and the procedural
      pain of repeated injections. The average indwelling time is 3-5 d. Fixation
      problems and local redness at the insertion site are the most frequent side
      effects. However, the frequency is low and they can be dealt with effectively.
      Needles of 8-10 mm should be used for injecting to avoid penetration of the
      tubing of the catheter. Using indwelling catheters for up to 4-5 d does not
      affect the absorption of insulin, when the catheter is inserted in an area free
      from lipohypertrophies. The long-term (measured by hemoglobin A1c) and short-term
      metabolic control (measured by blood glucose profiles and serum-free insulin) is
      not altered. Using this type of injection aid may decrease the risk of future
      injection problems, such as needle phobia, in very select patients. In
      conclusion, indwelling catheters can safely be used from the onset of diabetes to
      lessen injection pain in children and adolescents, and may facilitate the use of
      intensive insulin therapy in this age group.

PMID- 15189500
TI  - Cooperative interactions among p53, bcl-2 and Epstein-Barr virus latent membrane
      protein 1 in nasopharyngeal carcinoma cells.
AB  - Interactions among p53, bcl-2 and Epstein-Barr virus (EBV) latent membrane
      protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) cells were evaluated by gene
      cotransfections. The data showed that bcl-2 expression was not only able to
      prevent the growth suppression induced by wild-type p53 but was also
      paradoxically able to inhibit the growth enhancement induced by mutant p53.
      Latent membrane protein 1 was shown to be capable of overcoming the growth
      inhibition induced by wild-type p53 and the synergistic cooperation with bcl-2 to
      enhance cellular growth. Latent membrane protein 1 could also cooperate with
      mutant p53 to provide a growth advantage for NPC cells. Most NPC revealed
      detectable overexpression of p53, and the majority of those were a wild type
      possibly responding to EBV infection. The coexpression of bcl-2 and LMP1 was
      thought to inhibit the growth suppression induced by wild-type p53 in NPC. But
      there was no associated expression between LMP1 and bcl-2 because we demonstrated
      that transfected LMP1 failed to induce bcl-2 expression in NPC cells in contrast
      to the findings in B cells. It is theorized that the cooperative expression of
      bcl-2 and LMP1 exists in the majority of NPC, while a minority of NPC have
      cooperative expression of LMP1 and mutant p53. Each cooperative interaction could
      play an important role in the development and progression of NPC.

PMID- 15189499
TI  - Acute inflammatory reactions caused by histamine via monocytes/macrophages
      chronically participate in the initiation and progression of atherosclerosis.
AB  - Previously we demonstrated that histidine decarboxylase (HDC), which produces
      histamine from l-histidine, was detected in monocytes/macrophages located in
      human atherosclerotic lesions. As monocytic migration is a key event of
      atherogenesis, we investigated whether histamine induces monocytic expression of
      monocyte chemoattractant protein (MCP)-1 and its receptors CCR2-A and -B, and
      also endothelial expression of ICAM-1 and VCAM-1. Furthermore, we studied the
      effect of interleukin (IL)-4, which inhibits the HDC expression, on the
      expression of MCP-1 and CCR2. Histamine stimulated monocytes, but not
      macrophages, to express MCP-1 and CCR2-A and -B. The expression of MCP-1 was
      inhibited by histamine H2 blocker. In contrast, IL-4 enhanced CCR2 expression but
      not MCP-1. Histamine stimulated endothelial cells to express ICAM-1 and VCAM-1.
      These results indicate that histamine and IL-4, which are both synthesized in the
      arterial intima, chronically participates in the pathogenesis of atherosclerosis
      via the enhanced expression of monocytic MCP-1, CCR2 and endothelial adhesion
      molecules.

PMID- 15189501
TI  - Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in
      adenocarcinoma of the lung.
AB  - We investigated the aberrant promoter hypermethylation of p16, p15 and p14 genes
      and loss of heterozygosity (LOH) at 9p21-22 in 48 cases of adenocarcinoma of the
      lung. The frequencies of hypermethylation of genes were as follows: p16, 25.0%;
      p15, 22.9%; and p14, 18.8%. The frequency of LOH at chromosome 9p21-22 was 60.9%.
      The frequency of two-hit inactivation of the p16 gene by hypermethylation and LOH
      was 21.7%. Two-hit inactivation of the p16 gene showed loss of protein expression
      and was significantly correlated with tumor size, tumor grade and the Ki-67
      labeling index. Hypermethylation of the p16 gene was not significantly correlated
      with hypermethylation of the p15 and p14 genes, both of which are close to the
      p16 gene locus, suggesting that hypermethylation of these genes occurs
      selectivity. In conclusion, biallelic inactivation of the p16 gene by
      hypermethylation and LOH might cause loss of p16 expression and play an important
      role in the development of adenocarcinoma of the lung. Therefore, controlling and
      monitoring for hypermethylation of the p16 gene may be partially useful for
      treatment and early diagnosis of adenocarcinoma of the lung.

PMID- 15189503
TI  - alpha-Smooth muscle actin immunoreactivity may change in nature in interlobular
      fibrosis of the pancreas in patients with congenital biliary dilatation.
AB  - Pancreatic fibrosis in patients with congenital biliary dilatation (CBD) or
      choledochal cyst was studied to determine why biliary pancreatitis seldom
      progresses to chronic pancreatitis/more progressive state. Pancreatic
      collagenization in eight patients (three adults with pancreatoduodenectomy and
      five children with biopsy of the pancreas performed when excising the cyst) with
      CBD was evaluated histopathologically and immunohistochemically. Interlobular and
      periductal fibrosis with both collagen Type I and Type III immunoreactivities was
      found in six out of eight cases and in all four cases in which the pancreatic
      duct was included, respectively. The interlobular area was seldom immunoreactive
      for alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblasts, but was
      usually positive for CD34, a human progenitor cell antigen. In contrast, the
      periductal area was usually immunoreactive for alpha-SMA, but usually negative
      for CD34 and immunopositive for bcl-2, indicating a continuously progressive
      state of fibrosis, in which 'pre-existing'alpha-SMA immunoreactivity in the
      interlobular area may change in nature and lead to CD34-positive fibrosis or
      apoptosis. In conclusion, biliary pancreatitis is not likely to evolve into
      chronic pancreatitis/more progressive state because 'pre-existing'alpha-SMA
      immunoreactivity in the interlobular area may change in nature.

PMID- 15189502
TI  - Interaction between morphology and angiogenesis in human early colorectal
      cancers.
AB  - Morphologically, early colorectal cancers are divided into two types: polypoid
      cancers and non-polypoid cancers. They vary in growth pattern, progression, and
      genetic alteration. Angiogenesis between polypoid and non-polypoid cancers may
      also be different. Therefore, the present study aims to evaluate angiogenesis in
      the early stages of colorectal malignancy, with particular attention to the
      morphological differences. The serial slides of all materials (48 polypoid
      cancers, 10 non-polypoid cancers, 20 adenomas and 10 normal tissues) were
      immunohistochemically stained for three endothelial cell markers (CD31, von
      Willebrand factor and CD105), counted for the number of microvessels in the same
      hot spots, and the angiogenic status was estimated. Polypoid cancers had higher
      microvessel counts and were more predominantly supplied by activated (CD105
      positive, newly forming) microvessels than non-polypoid cancers. The present
      study indicated the possibility that the difference in growth pattern might be
      explained by the difference in angiogenesis between polypoid and non-polypoid
      cancers.

PMID- 15189504
TI  - Frequent expression of CD30 antigen in the primary gastric non-B, non-Hodgkin
      lymphomas.
AB  - Most primary gastric lymphomas are of B-cell origin. Fourteen cases of primary
      gastric non-B, non-Hodgkin lymphomas were studied to evaluate their
      clinicopathological and immunophenotypic findings. The cases were comprised of 11
      men and three women, with a median age of 56.5 years. Most patients underwent
      surgery either with or without chemotherapy, exhibiting a 5 year survival rate of
      57.5%. Morphologically, the neoplastic cells showed various histological
      features, such as anaplastic large cell lymphoma (ALCL) (n = 3), peripheral T
      cell lymphoma, unspecified, large (n = 4), medium-sized (n = 2) and mixed cell (n
      = 5). Two cases displayed a non-B, non-T cell phenotype, whereas the remaining
      cases displayed a T-cell phenotype. Six cases were CD4+, while two were CD8+. The
      neoplastic cells were CD30+ in 10 cases. TIA-1 was positive in six cases. In one
      case, anaplastic large cell lymphoma kinase (ALK) was identified with
      immunostaining and chromosomal rearrangement of ALK was detected by fluorescence
      in situ hybridization (FISH). In conclusion, although the mechanism of CD30
      expression is unknown, primary gastric non-B, non-Hodgkin lymphomas tend to
      express CD30. We consider that some of the cases in the present study may be
      derived from cytotoxic T cells, similar to systemic and cutaneous ALCL, the
      majority of which exhibit TIA-1.

PMID- 15189505
TI  - Estrogen receptor is significantly associated with the epithelioid variants of
      renal angiomyolipoma: a clinicopathological and immunohistochemical study of 67
      cases.
AB  - Perivascular epithelioid cells (PEC) in angiomyolipoma (AML) were recently
      proposed to be its most common progenitor cells. Histologically, triphasic
      components were present in various proportions, but were overwhelmingly myogenic
      in epithelioid variants of AML. Despite histological discrimination, the
      immunophenotypic profiles between triphasic and epithelioid AML have never been
      compared. The aim of the present study was to clarify the identity of PEC by
      using immunoreactivity to estrogen receptor (ER), progesterone receptor (PR), bcl
      2 and placenta alkaline phosphatase (PLAP), and to use this information to
      compare triphasic and epithelioid AML. A total of 33 out of 67 cases of renal
      angiomyolipoma that underwent surgery were reviewed over the period 1998-2003.
      Two cases were associated with tuberous sclerosis. Ten patients had other
      malignant tumors, and three patients had a nodal extension. Immunohistochemistry
      showed that bcl-2 (59.4%), PLAP (46.9%), HMB-45 (100%) was predominantly
      localized around vessels. The stem cell markers were absolutely negative in all
      AML types. The estrogen receptors were positive in 14 cases (42.4%) and the
      progesterone receptors were positive in five cases. Bcl-2 and both female sex
      hormone receptors were significantly more frequent in the epithelioid variant of
      AML than in the triphasic type. Perivascular epithelioid cells express bcl-2, ER,
      PR and PLAP, and ER could be partly associated with myogenic proliferation.

PMID- 15189506
TI  - Chorionic plate vessels as an origin of amniotic fluid neutrophils.
AB  - The present study was conducted to investigate the potential anatomical source of
      amniotic fluid neutrophils. Microdissection of neutrophils from the chorioamnion
      of the fetal membranes and the amnion of the chorionic plates of 10 preterm
      placentas with acute chorioamnionitis was performed and the genotypes of the
      neutrophils were compared with those of the mother and fetus using polymerase
      chain reaction of nine autosomal STR loci. In separate analyses, we reviewed
      eight cases of fetal autopsies with increased amniotic fluid neutrophils for the
      presence of neutrophils in the alveoli, and also analyzed the relationship
      between the amniotic fluid white blood cell (WBC) count and the histological
      pattern of placental inflammation. The genotypes of all of the neutrophils found
      in the chorioamnion of the fetal membrane matched those of the mother (n = 10).
      The genotypes of neutrophils found in the chorionic plate were of mixed maternal
      and fetal origin (n = 4). In the autopsy series of the fetuses with amniotic
      fluid WBC (n = 8), only five cases showed neutrophils in the alveolar space,
      while all the placentas had chorioamnionitis. There was no significant difference
      in amniotic fluid WBC count between the cases with or without acute membranitis,
      while among the cases with placental inflammation, those with inflammation of the
      chorionic plate had a significantly higher amniotic fluid WBC count than both the
      membranitis-only cases (P < 0.001) and the membranitis and funisitis cases (P <
      0.05). These results imply that fetal vasculature at the chorionic plate is the
      main source of amniotic fluid neutrophils, especially in the cases without
      funisitis.

PMID- 15189507
TI  - Gardner's syndrome associated fibromas.
AB  - Three patients with Gardner's syndrome having benign fibrous proliferations in
      the soft tissues and the oral cavity are presented. Lesions in all three patients
      were morphologically different. Two excised lesions in Case 1 were histologically
      identical to nuchal-type fibroma (NTF) and one lesion in this patient was an
      epidermal cyst. Case 2 had a lesion located in the soft tissues of the shoulder,
      which was morphologically similar to NTF and, in addition, contained mildly
      atypical and multinucleated fibroblastic cells. The oral lesion in Case 3 looked
      like a fibroma and was morphologically different from all fibrous lesions that
      have ever been described in Gardner's syndrome. The cases in the present report
      show that the term Gardner's fibroma is just a descriptive name encompassing a
      spectrum of morphologically different benign fibrous proliferations associated
      with this syndrome. Therefore, the term Gardner's fibroma should not be used as a
      specific name for NTF arising in patients with Gardner's syndrome as suggested in
      the most recent WHO classification of soft tissue and bone tumors.

PMID- 15189508
TI  - Lipoma-like tumor mass probably arising in the retroperitoneal heterotopic
      pancreas: a previously undescribed lesion.
AB  - Heterotopic pancreatic tissue is found in several locations of the body. However,
      to the best of our knowledge, there have been no reports on heterotopic pancreas
      in the retroperitoneum. A case of retroperitoneal lipoma-like large tumor mass
      probably arising in the heterotopic pancreas is reported. A 45-year-old Japanese
      woman was admitted to hospital because of back pain. Imaging modalities showed an
      abnormal mass in the retroperitoneum separate from the surrounding organs,
      including the pancreas and kidney. Histologically, the mass consisted of mature
      adipose tissue and scattered ductal and acinar elements. Although there was no
      islet tissue in this fatty mass, the epithelial elements suggested heterotopic
      pancreatic tissue in origin. The present case is very unusual; however,
      heterotopic pancreas should be considered in the differential diagnosis of
      retroperitoneal tumors.

PMID- 15189509
TI  - Autopsy case of congenital pulmonary lymphangiectasis.
AB  - Congenital pulmonary lymphangiectasis (CPL) is a rare anomaly. We report a female
      infant born at 39 weeks of gestation who was found to have CPL. Cyanosis and
      tachypnea were noted immediately after birth, and, at room air, PaO2 was 30.7
      mmHg, PaCO2 was 82.5 mmHg and pH was 7.12. The infant's symptoms did not improve
      even with the initiation of artificial ventilation. Chest X-ray film showed
      cotton-like infiltrates in both lungs and an air-leak surrounding the cardiac
      shadow. Echocardiography study showed no abnormality. The neonate died 3 days
      after birth due to hypoxemic cardiac failure. At autopsy, the pleural surface
      contained numerous dilated vessels that had the appearance of lymphatics.
      Microscopic features of the lungs were marked lymphatic dilatation of the
      perivascular, subpleural and interlobular areas. Lymphangiectasis was found in
      the liver, kidney, pancreas, thyroid and alimentary canals, such as the
      esophagus, stomach and rectum. Patients with lymphatic dilatations in
      extrapulmonary organs have mild pulmonary involvement and symptoms and a better
      prognosis. However, a few cases of CPL with lymphatic dilatations in
      extrapulmonary organs and an aggressive course, such as the present case, have
      been reported. The clinical behavior and prognosis of CPL depend on the extent of
      pulmonary involvement of the lymphatic dilatations regardless of systemic
      lymphatic dilations.

PMID- 15189510
TI  - Spontaneous regression of malignant lymphoma of the breast.
AB  - A complete spontaneous regression of diffuse large B cell lymphoma involving the
      right breast, confirmed by aspiration cytology, is reported. The patient visited
      a hospital due to the rapid growth of a tumor in the right breast. Five years
      previously she underwent a craniotomy for a brain tumor, diagnosed as B-cell
      malignant lymphoma, and received several courses of irradiation to the brain.
      Analysis of the breast tumor cells obtained by aspiration revealed lymphoma cells
      morphologically, which were similar to the tumor cells in the brain expressing
      CD20. While waiting for further examination, the tumor regressed rapidly and was
      not palpable after 20 days. An excisional biopsy of the breast exhibited no
      definite malignant lymphoma cells among a diffuse population of CD45RO and CD8
      positive small lymphocytes. Nucleotide sequencing of HCDR3s of the brain tumor
      and breast tumor cells showed a completely matched sequence, revealing the breast
      mass to be a metastatic lesion from the tumor of the brain. Although there was no
      tumorous lesion, the patient received additional chemotherapy and has shown no
      sign of recurrence in the breast for 7 years. We were able to confirm that the
      breast lymphoma shown in the aspiration cytology was a metastatic one, which was
      not proven histologically prior to chemotherapy, and regard the present case as a
      malignant lymphoma of the breast showing spontaneous regression. The present case
      shows a rare occurrence of spontaneous regression of diffuse large B cell
      malignant lymphoma after aspiration and suggests that CD8-positive T cells might
      be related to the regression.

PMID- 15189511
TI  - Meningioma in mature cystic teratoma of the ovary.
AB  - A case of meningioma arising in a mature cystic teratoma of the ovary in a 60
      year-old woman is described. The tumor was located in the right ovary, and
      salpingo-oophorectomy was performed. The right ovary was 10 x 10 x 8 cm in size
      and contained an unilocular cyst. In the wall, a solid nodule measuring 3 x 3 x 2
      cm was noted. Histologically, the cyst wall was composed of typical mature cystic
      teratoma. In contrast, the mural nodule was composed of the proliferating spindle
      and polygonal-shaped cells showing positive staining for epithelial membrane
      antigen and microcystic change was prominent. These findings were consistent with
      microcystic meningioma. The arachnoidal cells around mature brain tissue may be
      the origin of this unusual tumor. To the best of our knowledge, this is the first
      case of mature cystic teratoma with meningioma of the ovary reported in English
      medical literature. This case may further indicate the totipotential nature of
      mature cystic teratoma.

PMID- 15189512
TI  - Selective site pacing: the future of cardiac pacing?

PMID- 15189513
TI  - The left ventricular apex is the optimal site for pediatric pacing: correlation
      with animal experience.
AB  - Pacing at the commonly used right ventricular (RV) apex results in impaired
      ventricular performance. Previous animal studies indicated that the left
      ventricular (LV) apex is a superior pacing site. The purpose of this study was to
      investigate in dogs whether this good performance is associated with a more
      synchronous electrical activation pattern of the LV and whether the LV apex is
      also a good pacing site in children. In 11 healthy dogs and 8 children undergoing
      cardiac surgery, dual chamber pacing was performed at the RV apex, LV apex and LV
      lateral free wall (LVFW). In dogs, a basket electrode was inserted into the LV to
      assess pattern and timing of LV endocardial activation. In the children,
      hemodynamic measurements were performed immediately after recovery from
      cardiopulmonary bypass. In dogs, LV apex pacing resulted in synchronous
      activation around the LV circumference whereas RV apex and LVFW pacing resulted
      in asynchrony of activation between the septum and LVFW. In both canine and
      children's hearts most hemodynamic variables remained at sinus rhythm level
      during LV apex pacing, but LVdPdtmax, stroke work (dogs), and pulse pressure
      (children) were reduced as compared with sinus rhythm during RV apex and LVFW
      pacing. LV apex pacing results in synchronous activation of the LV and is, in
      adult dogs and in children, associated with superior hemodynamic performance.

PMID- 15189514
TI  - Chronic right ventricular pacing and cardiac performance: the pediatric
      perspective.
AB  - Cardiac stimulation from right ventricular apical or free-wall lead positions
      alters inter- and intraventricular impulse conduction and distorts biventricular
      contractility. This may contribute to eventual cellular remodeling and the
      development of histopathological changes which, over time, adversely affect left
      ventricular systolic and diastolic functions. This concept has especially
      important implications when pacemaker therapy is initiation in young patients.
      Recent studies demonstrating physiological benefits of right ventricular septal,
      outflow, or bundle of His pacing, in deference to the apical implant site, have
      gained interest to potentially prevent dysfunction and improve paced myocardial
      contractility. Pacing initiated in children can be expected to have more far
      reaching consequences than pacing initiated in the elderly. Unfortunately, there
      have been limited clinical pediatric studies that evaluate precise site-specific
      lead locations. This current report presents a review of pacemaker applications
      in children, both with and without structural congenital heart defects, including
      the earliest applications in which patient survival was the prime concern, to
      more recent studies attempting to optimize physiological and histological
      parameters associated with pacemaker induced contractility. The past decade has
      seen direct evidence that right ventricular apical pacing in children contributes
      to adverse histological remodeling and eventual contractile dysfunction. More
      recent studies demonstrate that selective site pacing can be effectively applied
      to all children with and without structural congenital defects and shows promise
      in the prevention of previously documented adverse remodeling and deterioration
      of systemic ventricular contractility.

PMID- 15189515
TI  - Atrial septal pacing: a new approach to prevent atrial fibrillation.
AB  - Atrial pacing may prevent the onset of atrial fibrillation (AF) because of: (1)
      prevention of the relative bradycardia that triggers paroxysmal AF; (2)
      prevention of the bradycardia induced dispersion of refractoriness;
      (3)suppression or reduction of premature atrial contractions that initiate
      reentry and predispose to AF; (4) preservation of AV synchrony, which might
      prevent switch induced changes in atrial repolarization predisposing to AF.
      Atrial pacing locations that decrease atrial activation and dispersion of
      refractoriness may be preferable in patients with a history of AF. Two different
      interatrial septum sites have been proposed: the Bachmann's bundle and the
      coronary sinus ostium. The results of two prospective randomized studies indicate
      that septal pacing, when compared to the traditional right atrial appendage
      pacing, significantly reduces : (1) paroxysmal AF recurrences and burden; and (2)
      progression to chronic AF.

PMID- 15189516
TI  - Selective site pacing: the right ventricular approach.
AB  - Animal data and recent findings in humans have questioned the appropriateness of
      pacing the heart from the right ventricular apex. Numerous, mostly small sized,
      studies have evaluated alternative sites within the right ventricle. There is now
      sufficient evidence that right ventricular apical pacing in patients with left
      ventricular dysfunction with or without heart failure is detrimental. Pacing from
      the right side of the heart as an attempt at nonpharmacological therapy for heart
      failure, turns out to be obsolete. In antibradycardia pacing with the need for
      continuous ventricular support, the interest in preserving left ventricular
      function drives the ongoing search for the most favorable pacing site within the
      right ventricle. Results, so far, are conflicting which may be attributed to the
      inhomogeneity of patient groups, the small cohorts studied, the differing
      protocols used, and the lack of accepted definitions of right ventricular lead
      positions. Larger studies are needed to evaluate intraoperative criteria for
      optimal lead placement and the potential benefit of nonapical right ventricular
      pacing.

PMID- 15189517
TI  - Direct His-bundle pacing: present and future.
AB  - Direct His-bundle pacing (DHBP) produces rapid sequential multisite synchronous
      ventricular activation and, therefore, would be an ideal alternative to right
      ventricular apical (RVA) pacing. In 54 patients with cardiomyopathy, ejection
      fraction (EF) 0.23 +/- 0.11, persistent atrial fibrillation, and normal QRS < 120
      ms. DHBP was attempted. This was successful in 39 patients. In seven patients,
      the effect of increasing heart rate on contractility (Treppe effect) was
      investigated. Twelve patients who also received a RVA lead underwent
      cardiopulmonary testing. After a mean follow-up of 42 months, 29 patients are
      still alive with EF improving from 0.23 +/- 0.11 to 0.33 +/- 0.15. Functional
      class improved from 3.5 to 2.2. DP/dt increased at each pacing site (P < 0.05) as
      the heart rate increased to 60, 100, and 120 beats/min. Rise in dP/dt by DHBP
      pacing at 120 beats/min was at least 170 +/- mmHg/s, greater than any other site
      in the ventricle (P < 0.05). Cardiopulmonary testing revealed longer exercise
      time (RVA 255 +/- 110 s) (His 280 +/- 104 s) (P < 0.05), higher O2 uptake (RVA 15
      +/- 4 mL/kg per minute) (His 16 +/- 4 mL/kg minute) (P < 0.05), and later
      anaerobic threshold (RVA 126 +/- 71 s) (His 145 +/- 74 s) (P < 0.05) with DHBP
      compared to RVA pacing. Long-term DHBP is safe and effective in humans. DHBP is
      associated with a superior Treppe effect and increased cardiopulmonary reserve
      when compared to RVA pacing.

PMID- 15189518
TI  - Is right ventricular outflow tract pacing an alternative to left
      ventricular/biventricular pacing?
AB  - The right ventricular apex has been used as the traditional pacing site since the
      development of transvenous pacing in 1959. Some studies suggest that pacing the
      right ventricular apex may cause remodeling and is harmful. In the past decade,
      there have been a multitude of studies of the hemodynamic, electrophysiological,
      electrocardiographic, and clinical effects of ventricular pacing at other sites.
      Pacing of the left ventricle singly or with biventricular pacing has emerged as
      an effective and safe therapy for moderate to severe congestive heart failure in
      patients with prolonged QRS complexes. Studies of alternate right ventricular
      sites, like the right ventricular outflow tract, have given mixed results. Not
      all patients can be treated with left ventricular pacing, which is a time
      consuming and difficult procedure. Right ventricular pacing is easier and less
      expensive than left ventricular pacing and further study of additional right
      ventricular sites seems warranted.

PMID- 15189519
TI  - Randomized trials for selective site pacing: do we know where we are going?
AB  - Clinical evidence is accumulating that pacing from traditional right-sided sites
      (right ventricular apex and right atrial appendage) may be associated with long
      term detriment to left ventricular function and promotion of atrial arrhythmias.
      Large numbers of small studies, some randomized, have addressed the effects of
      pacing from nontraditional or alternate sites, but the studies have varied in
      design such that comparison of results is often difficult. Many studies show data
      from acute studies only, although more recently longer-term data have started to
      become available; definition and description of pacing site also varies, adding
      further to the difficulties in comparing data. This article attempts to examine
      the randomized studies available to date, and to consider how future studies may
      contribute to our understanding of the effects of pacing from traditional and
      selected, specific sites on the right side of the heart.

PMID- 15189520
TI  - Selective site pacing: defining and reaching the selected site.
AB  - Selective site right ventricular pacing has been suggested as an approach to
      reduce the incidence of ventricular dysfunction and hopefully influence the
      morbidity resulting from traditional right ventricular apical pacing. Pacing from
      the right ventricular apex allows a stable ventricular rate, and together with
      atrial pacing and sensing, helps maintain atrioventricular synchrony but does not
      allow physiological activation of the left ventricle. Traditional atrial pacing
      sites like the right atrial appendage may encourage atrial tachyarrhythmias,
      whereas lead placement in right atrial septal sites may reduce the frequency of
      symptomatic atrial tachyarrhythmia episodes, especially when combined with
      prevention algorithms. Researchers attempting to pace the heart from these
      selective sites have been hindered by the lack of uniform definitions of where
      these sites actually lie and the inadequacy of tools to consistently reach these
      locations and verify correct placement. This lack of definition consensus may
      have contributed to the apparent conflict of data, particularly in the right
      ventricle. There is an urgent need for a standardization of terms and identifying
      measures for selective pacing sites.

PMID- 15189521
TI  - Implantable transvenous pacing leads: the shape of things to come.
AB  - With the dawn of a new millennium, physicians' demands for very thin transvenous
      leads able to be positioned in nontraditional sites like the Bachmann's bundle,
      the high and mid-right ventricular septum, and the His bundle have created new
      and exciting challenges for lead engineers. Bipolar leads can now be as thin and
      reliable as unipolar leads. Cathode electrodes are very small, porous, and
      demonstrate high impedance. To optimize stimulation thresholds, steroid-eluting
      passive- and active-fixation electrodes have become popular for use in the atrium
      and ventricle. To create thin lead body diameters, new insulation and conductor
      materials and lead body designs are necessary. Hybrid medical materials having
      the best features of silicone rubber and polyurethane will allow for reliable
      insulation. Conductor cables instead of helical coils permit strong thin diameter
      leads to be designed. Transvenous lead implantation using the traditional stylet
      may not be possible with thin diameter leads, necessitating the use of
      sophisticated workstations using steerable catheters to guide these new active
      fixation leads to selective sites in the right heart. The pacing lead of the
      future may be very different from the one used today. Ironically, it will have
      features and implantation techniques similar to the transvenous leads designed
      prior to the use of the stylet. We are now approaching full circle in lead
      development, retracing the footprints of the early implanters of three and a half
      decades ago.

PMID- 15189522
TI  - Selective site pacing: tools and training.
AB  - Current tools and techniques for pacemaker and ICD lead insertion have been
      optimized for implantation of leads at traditional sites but may be ill-suited
      for achieving alternate or selective site placement. If clinical studies confirm
      that optimal pacing is achieved from locations other than the right atrial
      appendage and right ventricular apex, new tools for reliably, easily and safely
      implanting leads at these sites will need to be created and methods for
      identifying these optimal pacing site(s) in each patient will be needed. Implant
      centers will need to understand the benefits of selective site pacing and make
      the transition to using these new tools. The various factors affecting the change
      from traditional to selective site pacing lead placement are discussed.

PMID- 15189523
TI  - The digital pacemaker.

PMID- 15189524
TI  - Concentric remodeling detection by magnetocardiography in patients with recent
      onset arterial hypertension.
AB  - The aim of this work was to evaluate a number of magnetocardiographic (MCG)
      indices in their predictive ability for left ventricular (LV) concentric
      remodeling. Twenty-five male patients affected by essential hypertension for no
      longer than 15 months and presenting signs of LV remodeling participated in the
      study; 25 normal men volunteers of comparable age were evaluated as controls. All
      participants underwent echocardiography (ECHO), electrocardiography (ECG), and
      magnetocardiography (MCG). Several MCG based indices were evaluated, namely the
      QRS Integral, T Integral, QRS-T Integral, T/QRS Integral, RS Index, and the
      variations of the electrical cardiac axis (ECA) orientation. MCG indices were
      compared with ECHO parameters, i.e., left ventricular mass index (LVMI) and
      relative wall thickness (RWT), and with ECG parameters, i.e., 12-lead standard
      ECG LVH Sokolow-Lyon and Cornell voltages. QRS Integral values for patients and
      controls were significantly different (P = 0.03), whereas T Integral values
      showed only a tendency to differentiate between patients and controls (P = 0.15).
      No significant correlation between MCG and echocardiographic indices in patients
      was found; RWT showed a tendency to correlate with QRS Integral (r = 0.34, P =
      0.17) and with RS Index (r = 0.49, P = 0.15), and LVMI showed a tendency to
      correlate with the variations of the ECA orientation (r = 0.38, P = 0.10). Our
      findings, also supported by preliminary results on patients affected by
      hypertension induced LV hypertrophy, suggest a potential role of MCG in the
      evaluation of early electrophysiological alterations due to LV concentric
      remodeling.

PMID- 15189526
TI  - Use of a sterile, disposable, radiation-absorbing shield reduces occupational
      exposure to scatter radiation during pectoral device implantation.
AB  - The aim of this study was to demonstrate the effectiveness of a radiation
      absorbing shield in reducing physicians' occupational radiation exposure during
      pectoral device implantation. A sterile, disposable, lead-free radiation
      absorbing surgical drape containing x-ray attenuation material was evaluated.
      Twenty procedures used the radiation absorbing drape, and 20 were performed
      without the shielding. Radiation exposure was measured using thermoluminescent
      dosimetry collar badges. Use of the protective shield was associated with a time
      adjusted 80% reduction in radiation dose (0.009 mrem/s with shielding vs 0.047
      mrem/s without shielding, P < 0.05) to the physician performing the procedures.
      The radiation-absorbing surgical drape did not interfere with technical
      performance nor add procedural time, and all procedures were successfully
      completed. This study demonstrates that a sterile, disposable, radiation
      absorbing drape provides a convenient means of augmenting conventional radiation
      shielding. Use of this protective shielding greatly reduces operators'
      occupational exposure to scatter radiation during pectoral device implantation
      without compromising sterility or procedural technique.

PMID- 15189525
TI  - Intramural radiofrequency ablation: effects of electrode temperature and length.
AB  - The aim of this study was to evaluate intramural temperature-controlled
      radiofrequency ablation by determining the intramural temperature profile during
      ablation and by correlating lesion geometry with intramural electrode size and
      temperature. Intramural ablation might be useful to create deeper lesions for
      ventricular tachycardia secondary to underlying heart disease. Intramural
      radiofrequency ablation was performed in 17 greyhounds at thoracotomy, from an
      epicardial approach, using a 21-gauge needle electrode. Sixty-eight lesions were
      created in 11 dogs at electrode temperatures of 70 degrees C, 80 degrees C, 90
      degrees C, and 100 degrees C for 60 seconds. Intramural thermocouples at 1-, 2-,
      3-, 4-, and 5-mm distances were used to identify simultaneous intramural
      temperature profile. An epicardial approach was used to ensure accurate
      positioning of the ablating and temperature monitoring needles within the
      myocardium with fixed interneedle distances. Ninety-nine radiofrequency ablations
      were performed in six greyhounds using three different intramural electrode
      lengths (1 mm, 2.5 mm, and 5.5 mm). Lesions were created at 70 degrees C, 80
      degrees C, and 90 degrees C for 60 seconds. All lesions were measured after
      staining with Gomori Trichrome. Lesion dimensions increased in a highly
      predictable manner with increasing electrode temperature or length. There was no
      popping or charring, even with target electrode temperature of 100 degrees C.
      There was significant correlation between intramural temperature 4 mm from the
      ablating electrode and lesion width (P < 0.001, R2= 0.45) and depth (P = 0.02,
      R2= 0.08). Feedback control of electrode temperature enables reliable intramural
      radiofrequency ablation without impedance rise even with target electrode
      temperature of 100 degrees C. Increasing the length of the intramural ablating
      electrode to > or = 5.5 mm and increasing temperatures to 90 degrees C-100
      degrees C creates the largest lesions.

PMID- 15189527
TI  - Ventricular activation onset-triggered left ventricular pacing: safety and
      feasibility in initial clinical experience.
AB  - Ventricular activation onset-triggered (VAOT) left ventricular pacing modalities
      synchronize left ventricular paced activation with existing intrinsic ventricular
      activation, in patients with complete LBBB and adequate rate. The purpose of this
      study was to evaluate the safety and feasibility of VAOT pacing with one left
      ventricular pacing lead, during temporary pacing in the postoperative period
      following open heart surgery. VAOT pacing was studied in five patients with LBBB
      and two patients with previously implanted right ventricular pacemakers. The VAOT
      pacing system used was assembled by modifying the function of existing equipment
      and its programming is described in detail. Comparative ECGs are reported,
      documenting the changes in ventricular activation produced by VAOT pacing.
      Stability of surface ECG acquisition was found to be essential to the success of
      temporary VAOT pacing and inappropriate pacing due to ECG instability is
      described. Patients were studied at rest and none experienced congestive heart
      failure. In the comparison of cardiac output, with and without VAOT pacing, no
      significant differences were found in LBBB patients or those with right
      ventricular pacemakers. In the comparison of arterial pressure, with and without
      VAOT pacing, no significant differences were found in six patients, however, in
      one LBBB patient with intrinsic predominant ventricular trigeminy, VAOT pacing
      was observed to have an antiarrhythmic effect resulting in suppression of
      ventricular ectopy and stabilization of arterial pressure. All patients survived
      VAOT pacing and the postoperative period without complications requiring
      additional intervention or treatment.

PMID- 15189528
TI  - Computer three-dimensional reconstruction of the atrioventricular conduction
      system.
AB  - The human atrioventricular conduction system (AVCS), which includes the AV node
      and its approaches, AV bundle (penetrating, branching, and bifurcating parts),
      and the bundle branches, is a curved complex structure that has not been
      reconstructed in three dimensions using computer technology. Microscopic slides
      of every 40(th) serial section (cut at 7 micron level) of the AVCS were digitized
      into 600 dots/inch color images. External outlines of each section were manually
      segmented using commercially available three-dimensional rendering software
      (Rhinoceros). The AVCS was traced from light microscopy and superimposed onto the
      external outlines. To account for inherent errors in histological slide
      preparation, an optimization procedure was used to align external outlines of all
      sections. The optimal rotation and translation of each section was established by
      maximizing area of overlap between adjacent sections. A sequential one
      dimensional minimization algorithm was used for optimization. Rotation and
      translation values were then used to align external outlines and the superimposed
      conduction system, reconstructing the AVCS in three-dimensions. To validate the
      method, the algorithm was applied to a digitized image transformed with known
      translations and rotations. The validation procedure demonstrated that each test
      image aligned in translations and to within 0.01 degree in rotations. Spatial
      error determined by resolution of the digitized images was +/-0.5/600 inch (+/-21
      microns). Three-dimensional reconstruction of every 40th serial section clearly
      demonstrated the complex curved shape of the AVCS. Three-dimensional
      reconstruction of the human and canine AVCS permits accurate pathological and
      electrophysiological correlation of the conduction system.

PMID- 15189529
TI  - P waves in patients with changing edematous states: implications on interpreting
      repeat P wave measurements in patients developing anasarca or undergoing
      hemodialysis.
AB  - Reported associations between weight and amplitude of QRS complexes in patients
      with anasarca and those undergoing hemodialysis (HD) led to the hypothesis that
      similar alterations in the P waves may occur with changing edematous states. The
      objective of this study was to explore whether anasarca or the state prior to HD
      are associated with attenuated P waves. The sum of P wave amplitude in
      millimeters measured in the 12 leads of the ECG (SigmaP) was calculated in 28
      patients with anasarca, 28 "controls," without change in their weight during
      hospitalization, and in 1 patient before and after 26 HD sessions. Admission
      SigmaP (10.5 +/- 4.9 mm) decreased at peak weight (3.8 +/- 2.0 mm, P = 0.0005) in
      patients with anasarca and increased at subsequent lowest weight in those who
      lost weight (2.3 +/- 1.3 vs 6.15 +/- 1.6 mm, P = 0.002). Admission and discharge
      SigmaPs were 10.9 +/- 4.5 and 9.8 +/- 3.8 mm, P = 0.062 in the controls, and 13.7
      +/- 2.8 mm before and 18.2 +/- 3.0 mm after HD, P = 0.0005. In the patients with
      anasarca, the percent of decrease in SigmaP correlated well with the percent of
      increase in weight (r = 0.70, P = 0.0028) and percent of decrease in the sum of
      QRS complexes from all 12 ECG leads (r = 0.62, P = 0.01). After HD, the percent
      of increase in SigmaP correlated with percent of increase in the body electrical
      resistance (r = 0.44, P = 0.029), reactance (r = 0.46, P = 0.020), and impedance
      (r = 0.44, P = 0.029). Alterations in P wave amplitudes, commensurate with the
      ones affecting the corresponding QRS complexes, occur in patients developing
      anasarca, and those undergoing HD. This observation suggests that accurate
      measurement of the P wave amplitudes in such patients cannot be made until the
      fluid overload is alleviated, and this factor should be taken into consideration
      when repeat P wave measurements are compared.

PMID- 15189531
TI  - Efficacy of biphasic shock for transthoracic cardioversion of persistent atrial
      fibrillation: can we predict energy requirements?
AB  - Although electrical cardioversion of atrial fibrillation (AF) is frequently
      performed, initial energy requirements for cardioversion of persistent AF is
      still a matter of debate. The aim of the study was to determine the efficacy of
      biphasic shocks for transthoracic cardioversion of persistent AF and to predict
      adequate initial energy. A prospective study enrolled 94 consecutive patients
      with persistent AF, who were referred for elective cardioversion with a biphasic
      waveform. The paddles were placed in the anterolateral position. A step-up
      protocol was used to estimate the cardioversion threshold. The initial shock
      energy was 50 J, with subsequent increments to 100, 200, and 300 J in the event
      of cardioversion failure. The mean age of the study group was of about 65 years
      (6 +/- 11 years) and a median duration of AF was 65 days (3-324). Sixty-two out
      of 94 patients were men, 55% of the study population was classified as having
      well-controlled hypertension. The overall success rate of cardioversion was 89%,
      with a mean 2.2 +/- 1.4 shocks, and effective J 217.8 +/- 113 delivered during
      repeated cardioversions. The success rate of low energy shocks: 50 and 50 +100 J
      was 51%. By logistic regression analysis the only independent predictor of
      success at low energy shock was shorter duration of AF (r =-0.51; P = 0.02).
      Patients with shorter duration of AF have a higher probability for successful
      cardioversion with low energy. In patients with longer AF duration, a 200 J shock
      should be considered for cardioversion as the initial energy.

PMID- 15189530
TI  - Remote monitoring of implantable cardioverter defibrillators: a prospective
      analysis.
AB  - A prospective study evaluating the functionality and ease of use of the Medtronic
      CareLink Network, "CareLink," was conducted at ten investigational sites. This
      internet-based remote monitoring service allows clinicians to remotely manage
      their patients' implantable cardioverter defibrillators (ICDs) and chronic
      diseases. The network is comprised of a patient monitor, a secure server, and
      clinician and patient websites. Under clinician direction, patients interrogated
      their ICDs at home, and transmitted data to secure servers via a standard
      telephone line. Comprehensive device data and a 10-second presenting rhythm
      electrogram were captured by the monitor and available for access and review on
      the clinician website. The information could also be printed using a standard
      desktop computer with internet access. During this study, patients were asked to
      transmit device data twice, at least 7 days apart, as scheduled by the clinic.
      Monitor functionality was assessed, and ease of using the system components was
      evaluated via questionnaires completed by patients and clinicians following each
      data transmission and review. Fifty-nine patients (64 +/- 14 years, range 22-85
      years) completed 119 transmissions with only 14 calls to the study support
      center. Clinician review of data transmissions revealed several clinically
      significant findings, including silent AF discovery, assessment of antiarrhythmic
      drug efficacy in a previously diagnosed AF patient, previously unobserved atrial
      undersensing, and ventricular tachycardia. ICD patients found the monitor easy to
      use. Clinicians were pleased with the performance of the network and the quality
      of the web-accessed data, and found it comparable to an in-office device
      interrogation. CareLink is a practical tool for routine device management and may
      allow timely identification of clinically important issues.

PMID- 15189532
TI  - Gender differences in the dynamics of terminal T wave intervals.
AB  - This study was designed to investigate gender differences in the dynamic changes
      of the terminal T wave (Ta-e interval) of healthy subjects. Holter ECGs were
      recorded in 24 healthy volunteers (12 men aged 23 +/- 2 years). The intervals
      from QRS onset to the apex (QaT) and to the end of the T wave (QeT), and the
      interval between the apex and the end of the T wave (Ta-e) were measured. Then,
      the QeT/RR, QaT/RR, and Ta-e/RR relationship was evaluated by linear regression
      analysis in each subject. The QeT and QaT intervals were significantly longer in
      women than men and the slope of the QeT/RR and QaT/RR relationship was steeper in
      women than men. The Ta-e intervals showed a significant but weaker positive
      correlation with the preceding RR intervals in 7 (58.3%) men and 9 (75.0%) women.
      The average values of the slope and the correlation coefficient of the Ta-e/RR
      relationship were significantly smaller compared to those of QeT and QaT in both
      men and women (P < 0.0001). The slope of the Ta-e/RR relationship was
      significantly greater in women than men (0.025 +/- 0.009 vs 0.011 +/- 0.012, P <
      0.005). However, the Ta-e intervals were significantly longer over the entire
      range of RR intervals in men than women (P < 0.0001). The rate-correcting
      formulas of Bazett and Framingham overcorrected the Ta-e intervals. The observed
      gender difference in the measurement and dynamics of the Ta-e interval may help
      to understand the mechanisms underlying the gender difference in the incidence of
      ventricular arrhythmias.

PMID- 15189533
TI  - Catheter inversion: a technique to complete isthmus ablation and cure atrial
      flutter.
AB  - Cure of typical atrial flutter (AFL) by catheter ablation to produce
      bidirectional block across the tricuspid annulus-inferior vena cava isthmus (IS)
      is highly effective, but failures may occur. We describe a technique that may
      allow creation of bidirectional block where a conventional strategy has failed.
      AFL ablation was performed using the conventional approach with a
      mapping/ablation (ablation) catheter introduced via the right femoral vein (RFV)
      to create a line of bidirectional block across the IS. If this was not achieved
      after five passes of the ablation catheter from the tricuspid annulus to the
      inferior vena cava (IVC) a catheter inversion technique was used. This allowed
      stable positioning of the ablation catheter at the IVC end of the isthmus. In 11
      patients, a mean of 17 (range 3 to 45) radiofrequency (RF) applications was given
      before the catheter inversion technique was applied. Following catheter inversion
      a mean of 4 (1 to 14) further RF applications achieved bidirectional isthmus
      block in every patient. No complications occurred. Catheter inversion provides a
      simple, safe, and effective means of achieving bidirectional isthmus conduction
      block in cases where a conventional ablation strategy might have failed.

PMID- 15189534
TI  - Implantation of submammary implantable cardioverter defibrillators.
AB  - Implantable cardioverter defibrillators (ICDs) are routinely placed in the left
      pectoral area using a transvenous approach. This approach may result in poor
      cosmetic outcome and cause psychological problems, especially in younger
      patients. To avoid this, several alternative implantation techniques have been
      developed. For cosmetic reasons, we used a submammary technique to implant ICDs
      into three young women. Apart from defibrillation threshold testing, the
      procedures were performed under local anesthesia. Threshold testing was done
      under general anesthesia. Appropriate defibrillation thresholds were obtained in
      all three cases, and all the patients tolerated the procedure well. There were no
      complications in a mean of 22 months of follow-up, and the cosmetic results were
      very good.

PMID- 15189535
TI  - Technical aspects of implantation of LV lead for cardiac resynchronization
      therapy in chronic heart failure.
AB  - The goal of this study was to analyze total procedural and fluoroscopic time
      during initial experience with implantation of LV lead in a single center, and to
      assess the performance of electrophysiologically-guided approach for cannulation
      of the coronary sinus (CS) in a subsequent period. Over an initial period of 29
      months, a total of 46 attempts to implant biventricular pacing system were
      revised. During the first phase, only one type of LV electrode was available for
      three implanters (11 attempts). The second phase covered their early experience
      with other stylet-controlled LV leads (10 attempts). Additional LV leads
      including the over-the-wire design were available in the third phase and 25
      attempts were done by he most experienced implanter. In a period of advanced
      experience, 92 implant procedures performed by four implanters using an
      electrophysiologically-guided approach to CS cannulation were revised. In the
      first period, success rates for different phases reached 70%, 90%, and 96%,
      respectively. Significant decrease in both procedural and fluoroscopic times was
      achieved with increased experience (Phase I: 247.1 +/- 104.5 minutes and 31.2 +/-
      34.3 minutes, Phase II: 219.4 +/- 85.6 minutes, and 22.9 +/- 19.1 minutes, Phase
      III: 116.4 +/- 89.9 minutes and 6.6 +/- 4.4 minutes, respectively, P < 0.05).
      Advanced experience with electrophysiologically-guided approach to CS cannulation
      allowed achievement of this target within a reasonable amount of time (15.4 +/-
      16.3 minutes) and with minimum fluoroscopic time (2.1 +/- 2.9 minutes). In
      conclusion, both individual learning curve and technical advances significantly
      influence success rate, procedural, and fluoroscopic times for biventricular
      system implantation. Electrophysiologically-guided approach makes cannulation of
      the CS a highly reproducible procedure that requires minimum fluoroscopic time.

PMID- 15189536
TI  - Differences between study-specific and subject-specific heart rate corrections of
      the QT interval in investigations of drug induced QTc prolongation.
AB  - A computational study was designed to investigate the differences between the so
      called study-specific and subject-specific heart rate corrections of QT interval.
      In 53 healthy subjects (25 women, mean age 26.7 +/- 8.7 years), serial 10-second
      electrocardiograms (ECG) were obtained during daytime hours. In each subject, 200
      ECGs were selected representative of the individual QT/RR relationship. Of the
      population of 53 subjects, 30,000 different subgroups of 16 subjects were
      considered and their data used to model drug induced QT interval prolongation by
      0, 5, 10, and 20 ms combined with drug induced heart rate acceleration and
      deceleration. In each modeled study, QTc changes were assessed by: (1) Six study
      specific heart rate corrections designed by regression modeling of the baseline
      QT/RR data pooled from all subjects; (2) Six subject-specific heart rate
      corrections designed by the same regression modeling of the baseline QT/RR data
      in each subject separately; (3) subject optimized correction that selected the
      best fitting regression model for each individual; and (4) by Bazett and
      Fridericia corrections. In each modeled study, the errors of the correction
      approaches were estimated and statistically summarized over all modeled studies.
      The subject-specific corrections led to maximum errors in single milliseconds
      (error range of 2.4, 5.7, and 2.6 ms with linear, log/log linear, and exponential
      models, respectively) while the study-specific corrections led to substantially
      greater errors (error range of 17.8, 19.4, and 16.9 ms with linear, log/log
      linear, and exponential models, respectively). Both Bazett and Fridericia
      corrections led not only to substantial errors (error range of 28.3 and 16.9 ms)
      but also to regular bias with systematically false negative and false positive
      conclusions dependent on modeled heart rate acceleration and deceleration. Thus,
      subjects-specific corrections should be used in the intensive and definite
      studies aimed at providing the final answer on the ability of a drug to prolong
      the QT interval.

PMID- 15189537
TI  - Radiofrequency catheter ablation of a macroreentrant ventricular tachycardia late
      after surgical repair of tetralogy of Fallot using the electroanatomic mapping
      (CARTO).
AB  - This case report describes a patient with a sustained monomorphic VT after
      surgical repair of a tetralogy of Fallot (TOF). In combination with the three
      dimensional electroanatomic mapping system, CARTO, and conventional mapping
      techniques the VT was identified as a macro-reentrant tachycardia circling around
      the border between pulmonary graft and right ventricular outflow tract (RVOT). A
      y-shaped ablation line crossing this zone was created. The VT terminated during
      RF application and was not inducible again. This case underlines the use of a
      combined conventional and three-dimensional electroanatomic mapping technique can
      be helpful for catheter ablation of ventricular arrhythmias in TOF patients.

PMID- 15189538
TI  - Long-term effectiveness of dual site left ventricular cardiac resynchronization
      therapy in a patient with congestive heart failure.
AB  - This article describes a case of cardiac resynchronization therapy (CRT)
      performed with dual site left ventricular pacing. The main clinical and
      functional long-term results are in agreement with the most recent data regarding
      traditional CRT. Furthermore, this innovative pacing modality allowed optimal
      inter- and intraventricular resynchronization.

PMID- 15189539
TI  - Inferolateral myocardial perfusion defect caused by right ventricular outflow
      tract pacing.
AB  - This case report describes a patient who was free of coronary artery disease and
      showed reversible inferolateral myocardial perfusion defect after having
      undergone a permanent dual chamber pacemaker implantation and an active-fixation
      ventricular lead insertion in the right ventricular outflow tract.

PMID- 15189540
TI  - Unidirectional atrio-atrial conduction after surgical isolation of the posterior
      part of the left atrium and pulmonary veins for atrial fibrillation: simple
      postsurgical procedure electrophysiological evaluation.
AB  - A 66-year-old woman underwent mitral valve replacement and surgical isolation of
      the posterior part of the left atrium for persistent AF. During sinus rhythm an
      isolated atrial rhythm was recorded from the isolated posterior left atrium using
      an esophageal electrode catheter. After the intravenous administration of
      adenosine triphosphate sinus rhythm was suppressed and 1:1 conduction from the
      posterior left atrium to the rest of the atrium was recorded. Unidirectional
      atrio-atrial conduction was revealed by a simple electrophysiological evaluation

PMID- 15189541
TI  - Asystole following left ventricular pacing.
AB  - During biventricular ICD implantation, pacing the epicardial inferior posterior
      lateral surface of the left ventricle via the coronary sinus produced asystole.
      The proposed mechanism is a Bezold-Jarisch reflex manifested by a drop in heart
      rate and blood pressure through direct C fiber stimulation.

PMID- 15189542
TI  - Double target method (double marker-guided extrathoracic introducer insertion).
AB  - Incidence of damage to pacemaker and implantable cardioverter defibrillator leads
      is an emerging problem that should be prevented. The extrathoracic venipuncture
      approach has been suggested as a technique for venous access to avoid the
      problem. This report describes the method of double marker-guided venipuncture of
      extrathoracic subclavian and/or axillary vein. This approach achieves definite,
      safe, and speedy extrathoracic venipuncture and may be especially suitable for
      multiple lead placement for cardiac resynchronization therapy.

PMID- 15189543
TI  - Successful use of quinidine in treatment of electrical storm in Brugada syndrome.
AB  - We report an adolescent with a malignant form of Brugada syndrome who presented
      with 15 episodes of ventricular fibrillation (VF) over 10 days, shortly after
      implantation of an implantable cardioverter defibrillator. Oral quinidine
      bisulphate at a dose of 1000 mg/day successfully suppressed the electrical storm
      and recurrence of VF over 18-month follow-up. It also normalized the ST-segment
      elevation in his right precordial leads, suppressed all ambient unifocal
      ventricular extrasystoles and induction of VF on programmed electrical
      stimulation. This case suggests that quinidine, by virtue of its blocking action
      on Ito, may be useful as adjunctive therapy in Brugada syndrome.

PMID- 15189544
TI  - Pacemaker mediated tachycardia as a complication of the autointrinsic conduction
      search function.
AB  - The autointrinsic conduction search (AICS) option, featured on some DDD
      pacemakers, performs periodic assessments of atrioventricular (AV) conduction
      capability during a single beat AV delay extension. Demonstration of ventricular
      conduction during the prolonged AV delay, permits ongoing AV delay extension if
      the patient's intrinsic conduction is preferred to ventricular pacing. A case is
      presented where the wide separation of atrial and ventricular pacing during the
      conduction search permitted retrograde ventriculoatrial conduction, precipitating
      pacemaker mediated tachycardia (PMT) on seven occasions in one patient. Two onset
      patterns are reported, both attributable to the AICS option. Recommendations for
      prevention strategies are made.

PMID- 15189545
TI  - QT dynamics and the risk of sudden arrhythmic cardiac death in ischemic heart
      disease.
AB  - The relationship between altered QT dynamics and the risk of sudden arrhythmic
      death has not been established so far. This article describes the behavior of QT
      dynamics assessed in a patient with ischemic heart disease after two documented
      cardiac arrests due to sustained ventricular arrhythmia.

PMID- 15189546
TI  - Two-to-one conduction block between left atrium and right lower pulmonary vein
      preceding complete vein isolation during radiofrequency current ablation.
AB  - A 56-year-old patient with paroxysmal atrial fibrillation who developed a
      transient 2:1 block between the left atrium and right inferior pulmonary vein
      during a single application of radiofrequency current was described. The
      production of transient and complete atriovenous block by a single application of
      radiofrequency current demonstrates that a single connection between the
      pulmonary veins muscle and the left atrium may exist.

PMID- 15189547
TI  - Syndrome of inappropriate antidiuretic hormone secretion induced by amiodarone
      therapy.
AB  - We describe a case of amiodarone induced hyponatremia consistent with the
      syndrome of inappropriate antidiuretic hormone (SIADH) that developed during
      amiodarone loading, similar to three prior reports. The hyponatremia improved
      after a lower maintenance dose was initiated. This episode was reported online to
      the FDA (http://www.fda.gov/medwatch), and future amiodarone labeling will
      include SIADH as a potential side effect (personal communication, Wyeth Medical
      Science). Clinicians should be aware of this rare but serious complication,
      especially in light of the neurological effect of profound hyponatremia.
      Amiodarone induced SIADH may develop during the loading phase, and may respond to
      dose reduction without termination of drug.

PMID- 15189548
TI  - Undersensing of VF in a patient with optimal R wave sensing during sinus rhythm.
AB  - We describe a case of potentially fatal undersensing of VF by a third generation
      ICD with predetermined automatic gain control. In this patient, ventricular
      sensing was optimal, as R wave amplitudes during sinus rhythm were at least 16
      mV. Cyclical, high amplitude signals during VF elevated the sensing floor to such
      an extent that complete undersensing of subsequent lower amplitude local
      electrograms occurred. This led to bradypacing and complete ICD therapy failure.
      Therefore, high R wave amplitudes during sinus rhythm do not warrant flawless
      sensing during VF.

PMID- 15189550
TI  - Nursing in a postemotional society.
AB  - Globalization is often seen as the final stage in the transition towards a market
      economy. It is argued that a side-effect of globalization is cultural homogeneity
      and loss of life world, or 'McDonaldization'. McDonaldization represents the
      rationalization of society in the quest for extreme efficiency. More recently,
      Mestrovic has argued that the rationalization of emotions has also occurred and
      that Western societies are entering a postemotional phase. In postemotional
      societies there has been a separation of emotion from action. The result is
      synthetic, manufactured emotions manipulated and standardized for mass
      consumption. In this paper I explore what it means to nurse in a 'postemotional
      society' and what impact this dulling of the emotions has had on a profession
      that locates 'care' as its central defining concept. My aim is to generate
      critical discussion of the shape and direction of contemporary society and the
      role of nursing within it.

PMID- 15189549
TI  - Postautistic theorizing?

PMID- 15189551
TI  - Intellectual seductions.
AB  - In this paper it is argued that we have three dispositions, each of which is very
      laudable in itself: a preference for the positive, constructive and creative
      aspects of human endeavours; a desire to be open-minded and tolerant concerning
      ideas and beliefs; and an admiration of profundity. I have suggested that these
      dispositions can, if exaggerated or employed uncritically, seduce us into
      intellectual positions that are very dubious. These arguments are applied to some
      of the debates within the philosophy of nursing.

PMID- 15189552
TI  - Gadow's romanticism: science, poetry and embodiment in postmodern nursing.
AB  - Sally Gadow's work is a sophisticated version of a familiar line of thought in
      nursing. She creates a chain of distinctions which is intended to differentiate
      cultural narratives, and particularly the 'science narrative', from imaginative
      narratives, especially poetry. Cultural narratives regulate and restrict;
      imaginative narratives are creative, liberating and potentially transcendent.
      These ideological effects are (supposedly) achieved through different structures
      of language. Scientific language, for example, is abstract and literal, while
      poetry is sensuous and metaphorical. In this paper, I argue that Gadow's way of
      discriminating between science and poetry fails. In the first place, the
      ideological valence she assigns to each of them is unwarranted. Science and
      poetry can both be harnessed to the project of emancipation, just as both can be
      incorporated in a strategy of oppression. In the second place, the claim that
      poetry and science are distinguished by their respective linguistic features-
      specifically, that one is metaphorical and the other literal--cannot be
      sustained. I illustrate this argument, as Gadow illustrates hers, by reference to
      the concept of embodiment, and consider whether Gadow is correct in thinking that
      poetry, not science, makes it possible for individuals (especially women) to
      'reclaim the body'. I also suggest that Gadow's brand of postmodernism echoes
      Romanticism, whose defining characteristic was an insistent contrast between
      poetry and science. This is 'flip side' postmodernism, which merely opposes
      modernist values, preferring subjectivity to objectivity, feeling to rationality,
      and multiple realities to truth. It is less radical, and far less interesting,
      than 'remix' postmodernism, whose objective is not to reverse the polarities, but
      to reconfigure the entire circuit.

PMID- 15189553
TI  - Integrity and moral residue: nurses as participants in a moral community.
AB  - This paper will examine the concepts of integrity and moral residue as they
      relate to nursing practice in the current health care environment. I will begin
      with my definition and conception of ethical practice, and, based on that, will
      go on to argue for the importance of recognizing that nurses often find
      themselves in the position of compromising their moral integrity in order to
      maintain their self-survival in the hospital or health care environment. I will
      argue that moral integrity is necessary to a moral life, and is relational in
      nature. When integrity is threatened, the result is moral distress, moral
      residue, and in some cases, abandonment of the profession. The solution will
      require more than teaching bioethics to nursing students and nurses. It will
      require changes in the health care environment, organizational culture and the
      education of nurses, with an emphasis on building a moral community as an
      environment in which to practise ethically.

PMID- 15189554
TI  - 'Double b(l)ind': Peer-review and the politics of scholarship.
AB  - Abstract The double-blind peer-review of manuscripts for potential publication is
      a longstanding tradition in the production of scholarship. Nursing has adopted
      this tradition to secure a place of legitimacy and authority for its scholarship
      amongst the other disciplines in the academy. However, despite its ubiquity and
      avowed utility, the peer-review has not generally been the subject of much
      research let alone intense philosophical scrutiny and debate. This manuscript
      attempts such an engagement with a view to uncovering specific concerns about the
      essentially conservative and sometimes restrictive effects the double-blind peer
      review produces. Drawing on the deconstructionist writings of Derrida and his
      acolytes this paper attempts to dig beneath the surface mechanics of the double
      blind peer-review and in so doing, expose its rather shaky philosophical
      foundations. It is written to open debate from others who too, have harboured
      doubts about its adequacy and supremacy as a technology in the production of
      (legitimate) knowledge.

PMID- 15189555
TI  - The problem of pain management among persons with dementia, personhood, and the
      ontology of relationships.
AB  - While pain is common among seniors, it is not adequately treated or managed. In
      particular, pain in seniors with dementia is often undertreated and undermanaged.
      Although the undertreatment of pain among persons with cognitive impairments
      represents a serious ethical concern for pain clinicians, most writers in the
      area explain the undertreatment of pain by focusing on issues related to
      liability, fears of addiction to opioids, and erroneous beliefs that pain is a
      normal part of the ageing process. We argue that the philosophical notion of
      personhood must also be given careful attention when considering the problem of
      pain undermanagement. In this paper, we consider the undertreatment of pain among
      seniors with dementia, while focusing on the ontology of relationships and on
      existential philosophy. Moreover, we outline a series of recommendations to help
      minimize the probability of pain undertreatment in this population and to
      encourage considerations relating to personhood when treating people with
      dementia.

PMID- 15189556
TI  - Medical and nursing clinical decision making: a comparative epistemological
      analysis.
AB  - The aim of this article is to explore the complex forms of knowledge involved in
      diagnostic and interventional decision making by comparing the processes in
      medicine and nursing, including nurse practitioners. Many authors assert that the
      practice of clinical decision making involves the application of theoretical
      knowledge (acquired in the classroom and textbooks) as well as research evidence,
      upon concrete particular cases. This approach draws on various universal
      principles and algorithms to facilitate the task. On the other hand, others argue
      that this involves an intuitive form of judgement that is difficult to teach, one
      that is acquired principally through experience. In an exploration of these
      issues, this article consists of three sections. A clarification of terms
      commonly used when discussing decision making is provided in the first section.
      In the second section, an epistemological analysis of decision making is
      presented by examining several perspectives and comparing them for their use in
      the nursing and medical literature. Bunge's epistemological framework for
      decision making (based on scientific realism) is explored for its fit with the
      aims of medicine and nursing. The final section presents a discussion of
      knowledge utilization and decision making as it relates to the implications for
      the education and ongoing development of nurse practitioners. It is concluded
      that Donald Schon's conception of reflective practice best characterizes the
      skillful conduct of clinical decision making.

PMID- 15189557
TI  - Saving Heidegger from Benner and Wrubel.

PMID- 15189558
TI  - Philosophy of sport.

PMID- 15189559
TI  - Re: Keane, K. A philosophy of nursing conference. Nurs Philos. 2003 Apr;4(1):77
      81.

PMID- 15189561
TI  - Developing optimal search strategies for detecting clinically sound prognostic
      studies in MEDLINE: an analytic survey.
AB  - BACKGROUND: Clinical end users of MEDLINE have a difficult time retrieving
      articles that are both scientifically sound and directly relevant to clinical
      practice. Search filters have been developed to assist end users in increasing
      the success of their searches. Many filters have been developed for the
      literature on therapy and reviews but little has been done in the area of
      prognosis. The objective of this study is to determine how well various
      methodologic textwords, Medical Subject Headings, and their Boolean combinations
      retrieve methodologically sound literature on the prognosis of health disorders
      in MEDLINE. METHODS: An analytic survey was conducted, comparing hand searches of
      journals with retrievals from MEDLINE for candidate search terms and
      combinations. Six research assistants read all issues of 161 journals for the
      publishing year 2000. All articles were rated using purpose and quality
      indicators and categorized into clinically relevant original studies, review
      articles, general papers, or case reports. The original and review articles were
      then categorized as 'pass' or 'fail' for methodologic rigor in the areas of
      prognosis and other clinical topics. Candidate search strategies were developed
      for prognosis and run in MEDLINE - the retrievals being compared with the hand
      search data. The sensitivity, specificity, precision, and accuracy of the search
      strategies were calculated. RESULTS: 12% of studies classified as prognosis met
      basic criteria for scientific merit for testing clinical applications.
      Combinations of terms reached peak sensitivities of 90%. Compared with the best
      single term, multiple terms increased sensitivity for sound studies by 25.2%
      (absolute increase), and increased specificity, but by a much smaller amount
      (1.1%) when sensitivity was maximized. Combining terms to optimize both
      sensitivity and specificity achieved sensitivities and specificities of
      approximately 83% for each. CONCLUSION: Empirically derived search strategies
      combining indexing terms and textwords can achieve high sensitivity and
      specificity for retrieving sound prognostic studies from MEDLINE.

PMID- 15189562
TI  - Regulation of trophoblast beta1-integrin expression by contact with endothelial
      cells.
AB  - BACKGROUND: In human and non-human primates, migratory trophoblasts penetrate the
      uterine epithelium, invade uterine matrix, and enter the uterine vasculature.
      Invasive trophoblasts show increased expression of beta1 integrin. Since
      trophoblast migration within the uterine vasculature involves trophoblast
      attachment to endothelial cells lining the vessel walls, this raises the
      possibility that cell-cell contact and/or factors released by endothelial cells
      could regulate trophoblast integrin expression. To test this, we used an in vitro
      system consisting of early gestation macaque trophoblasts co-cultured on top of
      uterine microvascular endothelial cells. RESULTS: When cultured alone,
      trophoblasts expressed low levels of beta1 integrin as determined by quantitative
      immunofluorescence microscopy. When trophoblasts were cultured on top of
      endothelial cells for 24 h, the expression of trophoblast beta1 integrin was
      significantly increased as determined by image analysis. beta1 Integrin
      expression was not increased when trophoblasts were cultured with endothelial
      cell-conditioned medium, suggesting that upregulation requires direct contact
      between trophoblasts and endothelial cells. To identify endothelial cell surface
      molecules responsible for induction of trophoblast integrin expression,
      trophoblasts were cultured in dishes coated with recombinant platelet endothelial
      cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1),
      or alphaVbeta3 integrin. Trophoblast beta1 integrin expression (assessed by
      immunofluorescence microscopy and Western blotting) was increased when PECAM-1 or
      alphaVbeta3 integrin, but not ICAM-1, was used as substrate. CONCLUSIONS: Direct
      contact between trophoblasts and endothelial cells increases the expression of
      trophoblast beta1 integrin.

PMID- 15189563
TI  - Does parallel item content on WOMAC's pain and function subscales limit its
      ability to detect change in functional status?
AB  - BACKGROUND: Although the Western Ontario and McMaster University Osteoarthritis
      Index (WOMAC) is considered the leading outcome measure for patients with
      osteoarthritis of the lower extremity, recent work has challenged its factorial
      validity and the physical function subscale's ability to detect valid change when
      pain and function display different profiles of change. This study examined the
      etiology of the WOMAC's physical function subscale's limited ability to detect
      change in the presence of discordant changes for pain and function. We
      hypothesized that the duplication of some items on the WOMAC's pain and function
      subscales contributed to this shortcoming. METHODS: Two eight-item physical
      function scales were abstracted from the WOMAC's 17-item physical function
      subscale: one contained activities and themes that were duplicated on the pain
      subscale (SIMILAR-8); the other version avoided overlapping activities
      (DISSIMILAR-8). Factorial validity of the shortened measures was assessed on 310
      patients awaiting hip or knee arthroplasty. The shortened measures' abilities to
      detect change were examined on a sample of 104 patients following primary hip or
      knee arthroplasty. The WOMAC and three performance measures that included
      activity specific pain assessments--40 m walk test, stair test, and timed-up-and
      go test--were administered preoperatively, within 16 days of hip or knee
      arthroplasty, and at an interval of greater than 20 days following the first post
      surgical assessment. Standardized response means were used to quantify change.
      RESULTS: The SIMILAR-8 did not demonstrate factorial validity; however, the
      factorial structure of the DISSIMILAR-8 was supported. The time to complete the
      performance measures more than doubled between the preoperative and first
      postoperative assessments supporting the theory that lower extremity functional
      status diminished over this interval. The DISSIMILAR-8 detected this
      deterioration in functional status; however, no significant change was noted for
      the SIMILAR-8. The WOMAC pain scale demonstrated a slight reduction in pain and
      the performance specific pain measures did not reflect a change in pain. All
      measures showed substantial improvement over the second assessment interval.
      CONCLUSIONS: These findings support the hypothesis that activity overlap on the
      pain and function subscales plays a causal role in limiting the WOMAC physical
      function subscale's ability to detect change.

PMID- 15189564
TI  - Prevalence of musculoskeletal disorders in dentists.
AB  - BACKGROUND: The prevalence of musculoskeletal complaints in dentists is high
      although relatively few studies had focus in this profession. The aim of this
      study was to investigate the relations between physical, psychosocial, and
      individual characteristics and different endpoints of musculoskeletal complaints
      of low back, neck, shoulders and hand/wrist. METHODS: A questionnaire survey was
      carried out among 430 dentists (response 88%) in Thessaloniki, Greece. Questions
      include data on physical and psychosocial workload, need for recovery, perceived
      general health and (i) the occurrence of musculoskeletal complaints in the past
      12 months, (ii) chronic complaints during at least 1 month, complaints which led
      to (iii) sickness absence, and (iv) medical care seeking. In logistic regression
      analysis odds ratios were estimated for all relevant risk factors. RESULTS: 62%
      of dentists reported at least one musculoskeletal complaint, 30% chronic
      complaints, 16% had spells of absence and, 32% sought medical care. Self-reported
      factors of physical load were associated with the occurrence of back pain (OR =
      1.59), shoulder pain (OR = 2.57) and, hand/wrist pain (OR = 3.46). With the
      exception of hand/wrist complaints, the physical factors were not associated with
      chronic complaints and musculoskeletal sickness absence. Physical load showed a
      trend with the number of musculoskeletal complaints with ORs of 2.50, 3.07 and
      4.40 for two, three and four musculoskeletal complaints, respectively. No
      consistent influence of psychosocial factors on complaints, chronicity, sickness
      absence and medical care seeking was observed. A perceived moderate general
      health was a significant factor for chronic complaints, comorbidity and medical
      care seeking where high perceived exertion was significant for absenteeism.
      Living alone was also related with increased absenteeism due to shoulder pain (OR
      = 5.01) and hand/wrist (OR = 4.07). CONCLUSIONS: The physical load among dentists
      seems to put them at risk for the occurrence of musculoskeletal disorders. More
      than one and severe complaints are related to perceived general health while high
      perceived exertion and social characteristics are associated with sickness
      absence. Chronic symptoms seem to determine medical care seeking. Ergonomic
      interventions may have a greater impact in prevention of hand/wrist complaints.
      When investigating the influence of work-related risk factors on musculoskeletal
      health, psychosocial and other personal characteristics should be taken into
      account.

PMID- 15189565
TI  - Barriers to asymptomatic screening and other STD services for adolescents and
      young adults: focus group discussions.
AB  - BACKGROUND: Sexually transmitted diseases (STDs) are a major public health
      problem among young people and can lead to the spread of HIV. Previous studies
      have primarily addressed barriers to STD care for symptomatic patients. The
      purpose of our study was to identify perceptions about existing barriers to and
      ideal services for STDs, especially asymptomatic screening, among young people in
      a southeastern community. METHODS: Eight focus group discussions including 53
      White, African American, and Latino youth (age 14-24) were conducted. RESULTS:
      Perceived barriers to care included lack of knowledge of STDs and available
      services, cost, shame associated with seeking services, long clinic waiting
      times, discrimination, and urethral specimen collection methods. Perceived
      features of ideal STD services included locations close to familiar places,
      extended hours, and urine-based screening. Television was perceived as the most
      effective route of disseminating STD information. CONCLUSIONS: Further research
      is warranted to evaluate improving convenience, efficiency, and privacy of
      existing services; adding urine-based screening and new services closer to
      neighborhoods; and using mass media to disseminate STD information as strategies
      to increase STD screening.

PMID- 15189566
TI  - Serratia marcescens internalization and replication in human bladder epithelial
      cells.
AB  - BACKGROUND: Serratia marcescens, a frequent agent of catheterization-associated
      bacteriuria, strongly adheres to human bladder epithelial cells in culture. The
      epithelium normally provides a barrier between lumal organisms and the
      interstitium; the tight adhesion of bacteria to the epithelial cells can lead to
      internalization and subsequent lysis. However, internalisation was not shown yet
      for S. marcescens strains. METHODS: Elektronmicroscopy and the common gentamycin
      protection assay was used to assess intracellular bacteria. Via site directed
      mutagenesis, an hemolytic negative isogenic Serratia strain was generated to
      point out the importance of hemolysin production. RESULTS: We identified an
      important bacterial factor mediating the internalization of S. marcescens, and
      lysis of epithelial cells, as the secreted cytolysin ShlA. Microtubule filaments
      and actin filaments were shown to be involved in internalization. However,
      cytolysis of eukaryotic cells by ShlA was an interfering factor, and therefore
      hemolytic-negative mutants were used in subsequent experiments. Isogenic
      hemolysin-negative mutant strains were still adhesive, but were no longer
      cytotoxic, did not disrupt the cell culture monolayer, and were no longer
      internalized by HEp-2 and RT112 bladder epithelial cells under the conditions
      used for the wild-type strain. After wild-type S. marcescens became
      intracellular, the infected epithelial cells were lysed by extended vacuolation
      induced by ShlA. In late stages of vacuolation, highly motile S. marcescens cells
      were observed in the vacuoles. S. marcescens was also able to replicate in
      cultured HEp-2 cells, and replication was not dependent on hemolysin production.
      CONCLUSION: The results reported here showed that the pore-forming toxin ShlA
      triggers microtubule-dependent invasion and is the main factor inducing lysis of
      the epithelial cells to release the bacteria, and therefore plays a major role in
      the development of S. marcescens infections.

PMID- 15189567
TI  - NF-kappaB p50 facilitates neutrophil accumulation during LPS-induced pulmonary
      inflammation.
AB  - BACKGROUND: Transcription factors have distinct functions in regulating immune
      responses. During Escherichia coli pneumonia, deficiency of NF-kappaB p50
      increases gene expression and neutrophil recruitment, suggesting that p50
      normally limits these innate immune responses. p50-deficient mice were used to
      determine how p50 regulates responses to a simpler, non-viable bacterial stimulus
      in the lungs, E. coli lipopolysaccharide (LPS). RESULTS: In contrast to previous
      results with living E. coli, neutrophil accumulation elicited by E. coli LPS in
      the lungs was decreased by p50 deficiency, to approximately 30% of wild type
      levels. Heat-killed E. coli induced neutrophil accumulation which was not
      decreased by p50 deficiency, demonstrating that bacterial growth and metabolism
      were not responsible for the different responses to bacteria and LPS. p50
      deficiency increased the LPS-induced expression of kappaB-regulated genes
      essential to neutrophil recruitment, including KC, MIP-2, ICAM-1, and TNF-alpha
      suggesting that p50 normally limited this gene expression and that decreased
      neutrophil recruitment did not result from insufficient expression of these
      genes. Neutrophils were responsive to the chemokine KC in the peripheral blood of
      p50-deficient mice with or without LPS-induced pulmonary inflammation.
      Interleukin-6 (IL-6), previously demonstrated to decrease LPS-induced neutrophil
      recruitment in the lungs, was increased by p50 deficiency, but LPS-induced
      neutrophil recruitment was decreased by p50 deficiency even in IL-6 deficient
      mice. CONCLUSION: p50 makes essential contributions to neutrophil accumulation
      elicited by LPS in the lungs. This p50-dependent pathway for neutrophil
      accumulation can be overcome by bacterial products other than LPS and does not
      require IL-6.

PMID- 15189568
TI  - Molecular characterization of the singed wings locus of Drosophila melanogaster.
AB  - BACKGROUND: Hormones frequently guide animal development via the induction of
      cascades of gene activities, whose products further amplify an initial hormonal
      stimulus. In Drosophila the transformation of the larva into the pupa and the
      subsequent metamorphosis to the adult stage is triggered by changes in the titer
      of the steroid hormone 20-hydroxyecdysone. singed wings (swi) is the only gene
      known in Drosophila melanogaster for which mutations specifically interrupt the
      transmission of the regulatory signal from early to late ecdysone inducible
      genes. RESULTS: We have characterized singed wings locus, showing it to
      correspond to EG:171E4.2 (CG3095). swi encodes a predicted 68.5-kDa protein that
      contains N-terminal histidine-rich and threonine-rich domains, a cysteine-rich C
      terminal region and two leucine-rich repeats. The SWI protein has a close homolog
      in D. melanogaster, defining a new family of SWI-like proteins, and is conserved
      in D. pseudoobscura. A lethal mutation, swit476, shows a severe disruption of the
      ecdysone pathway and is a C>Y substitution in one of the two conserved CysXCys
      motifs that are common to SWI and the Drosophila Toll-4 protein. CONCLUSIONS: It
      is not entirely clear from the present molecular analysis how the SWI protein may
      function in the ecdysone induced cascade. Currently all predictions agree in that
      SWI is very unlikely to be a nuclear protein. Thus it probably exercises its
      control of "late" ecdysone genes indirectly. Apparently the genetic regulation of
      ecdysone signaling is much more complex then was previously anticipated.

PMID- 15189569
TI  - Simultaneous stimulation of GABA and beta adrenergic receptors stabilizes
      isotypes of activated adenylyl cyclase heterocomplex.
AB  - BACKGROUND: We investigated how the synthesis of cAMP, stimulated by
      isoproterenol acting through beta-adrenoreceptors and Gs, is strongly amplified
      by simultaneous incubation with baclofen. Baclofen is an agonist of delta
      aminobutyric acid type B receptors [GABAB], known to inhibit adenylyl cyclase via
      Gi. Because these agents have opposite effects on cAMP levels, the unexpected
      increase in cAMP synthesis when they are applied simultaneously has been
      intensively investigated. From previous reports, it appears that cyclase type II
      contributes most significantly to this phenomenon. RESULTS: We found that
      simultaneous application of isoproterenol and baclofen specifically influences
      the association/dissociation of molecules involved in the induction and
      termination of cyclase activity. Beta/gamma from [GABA]B receptor-coupled Gi has
      a higher affinity for adenylyl cyclase isoform(s) when these isoforms are co
      associated with Gs. Our data also suggest that, when beta/gamma and Galphas are
      associated with adenylyl cyclase isoform(s), beta/gamma from [GABA]B receptor
      coupled Gi retards the GTPase activity of Galphas from adrenergic receptor. These
      reciprocal regulations of subunits of the adenylyl cyclase complex might be
      responsible for the drastic increase of cAMP synthesis in response to the
      simultaneous signals. CONCLUSIONS: Simultaneous signals arriving at a particular
      synapse converge on molecular detectors of coincidence and trigger specific
      biochemical events. We hypothesize that this phenomenon comes from the complex
      molecular architectures involved, including scaffolding proteins that make
      reciprocal interactions between associated molecules possible. The biochemistry
      of simultaneous signaling is addressed as a key to synaptic function.

PMID- 15189570
TI  - A Bayesian method for identifying missing enzymes in predicted metabolic pathway
      databases.
AB  - BACKGROUND: The PathoLogic program constructs Pathway/Genome databases by using a
      genome's annotation to predict the set of metabolic pathways present in an
      organism. PathoLogic determines the set of reactions composing those pathways
      from the enzymes annotated in the organism's genome. Most annotation efforts fail
      to assign function to 40-60% of sequences. In addition, large numbers of
      sequences may have non-specific annotations (e.g., thiolase family protein).
      Pathway holes occur when a genome appears to lack the enzymes needed to catalyze
      reactions in a pathway. If a protein has not been assigned a specific function
      during the annotation process, any reaction catalyzed by that protein will appear
      as a missing enzyme or pathway hole in a Pathway/Genome database. RESULTS: We
      have developed a method that efficiently combines homology and pathway-based
      evidence to identify candidates for filling pathway holes in Pathway/Genome
      databases. Our program not only identifies potential candidate sequences for
      pathway holes, but combines data from multiple, heterogeneous sources to assess
      the likelihood that a candidate has the required function. Our algorithm emulates
      the manual sequence annotation process, considering not only evidence from
      homology searches, but also considering evidence from genomic context (i.e., is
      the gene part of an operon?) and functional context (e.g., are there functionally
      related genes nearby in the genome?) to determine the posterior belief that a
      candidate has the required function. The method can be applied across an entire
      metabolic pathway network and is generally applicable to any pathway database.
      The program uses a set of sequences encoding the required activity in other
      genomes to identify candidate proteins in the genome of interest, and then
      evaluates each candidate by using a simple Bayes classifier to determine the
      probability that the candidate has the desired function. We achieved 71%
      precision at a probability threshold of 0.9 during cross-validation using known
      reactions in computationally-predicted pathway databases. After applying our
      method to 513 pathway holes in 333 pathways from three Pathway/Genome databases,
      we increased the number of complete pathways by 42%. We made putative assignments
      to 46% of the holes, including annotation of 17 sequences of previously unknown
      function. CONCLUSIONS: Our pathway hole filler can be used not only to increase
      the utility of Pathway/Genome databases to both experimental and computational
      researchers, but also to improve predictions of protein function.

PMID- 15189572
TI  - M-CGH: analysing microarray-based CGH experiments.
AB  - BACKGROUND: Microarray-based comparative genomic hybridisation (array CGH) is a
      technique by which variation in relative copy numbers between two genomes can be
      analysed by competitive hybridisation to DNA microarrays. This technology has
      most commonly been used to detect chromosomal amplifications and deletions in
      cancer. Dedicated tools are needed to analyse the results of such experiments,
      which include appropriate visualisation, and to take into consideration the
      physical relation in the genome between the probes on the array. RESULTS: M-CGH
      is a MATLAB toolbox with a graphical user interface designed specifically for the
      analysis of array CGH experiments, with multiple approaches to ratio
      normalization. Specifically, the distributions of three classes of DNA copy
      numbers (gains, normal and losses) can be estimated using a maximum likelihood
      method. Amplicon boundaries are computed by either the fuzzy K-nearest neighbour
      method or a wavelet approach. The program also allows linking each genomic clone
      with the corresponding genomic information in the Ensembl database
      http://www.ensembl.org. CONCLUSIONS: M-CGH, which encompasses the basic tools
      needed for analysing array CGH experiments, is freely available for academics
      http://www.uio.no/~junbaiw/mcgh, and does not require any other MATLAB toolbox.

PMID- 15189571
TI  - Interaction profile-based protein classification of death domain.
AB  - BACKGROUND: The increasing number of protein sequences and 3D structure obtained
      from genomic initiatives is leading many of us to focus on proteomics, and to
      dedicate our experimental and computational efforts on the creation and analysis
      of information derived from 3D structure. In particular, the high-throughput
      generation of protein-protein interaction data from a few organisms makes such an
      approach very important towards understanding the molecular recognition that make
      up the entire protein-protein interaction network. Since the generation of
      sequences, and experimental protein-protein interactions increases faster than
      the 3D structure determination of protein complexes, there is tremendous interest
      in developing in silico methods that generate such structure for prediction and
      classification purposes. In this study we focused on classifying protein family
      members based on their protein-protein interaction distinctiveness. Structure
      based classification of protein-protein interfaces has been described initially
      by Ponstingl et al. 1 and more recently by Valdar et al. 2 and Mintseris et al.
      3, from complex structures that have been solved experimentally. However, little
      has been done on protein classification based on the prediction of protein
      protein complexes obtained from homology modeling and docking simulation.
      RESULTS: We have developed an in silico classification system entitled HODOCO
      (Homology modeling, Docking and Classification Oracle), in which protein Residue
      Potential Interaction Profiles (RPIPS) are used to summarize protein-protein
      interaction characteristics. This system applied to a dataset of 64 proteins of
      the death domain superfamily was used to classify each member into its proper
      subfamily. Two classification methods were attempted, heuristic and support
      vector machine learning. Both methods were tested with a 5-fold cross-validation.
      The heuristic approach yielded a 61% average accuracy, while the machine learning
      approach yielded an 89% average accuracy. CONCLUSION: We have confirmed the
      reliability and potential value of classifying proteins via their predicted
      interactions. Our results are in the same range of accuracy as other studies that
      classify protein-protein interactions from 3D complex structure obtained
      experimentally. While our classification scheme does not take directly into
      account sequence information our results are in agreement with functional and
      sequence based classification of death domain family members.

PMID- 15189573
TI  - Geopolitics and the CJU.

PMID- 15189574
TI  - Egocentrism, event frequency, and comparative optimism: when what happens
      frequently is "more likely to happen to me".
AB  - Three studies investigated the role of nonmotivated egocentric processes in
      comparative optimism (and pessimism). According to an egocentric-processes
      account, when people judge their comparative likelihood of experiencing an event
      (e.g., "Compared to the average person, how likely are you to become wealthy?"),
      they consider their own chances of experiencing the event more so than the
      referent's chances. This should produce higher comparative estimates when an
      event's absolute frequency is high rather than low-a prediction supported in
      Study 1, which manipulated event frequency through a novel, time frame
      manipulation. Study 2 empirically distinguished egocentrism from a related
      focalism account. In Study 3, comparative estimates were related to the perceived
      frequency of events, independent of the events' perceived desirability and
      controllability. Path analyses provided additional support for egocentrism, and
      systematic cases of comparative pessimism were observed as predicted by the
      egocentric-processes account.

PMID- 15189575
TI  - Implicit romantic fantasies and women's interest in personal power: a glass
      slipper effect?
AB  - Three experiments investigated the relationship between women's romantic
      fantasies and their interest in personal power. Romantic fantasies (associating
      partners with chivalry and heroism) were assessed using the Implicit Association
      Test and self-reports. In each experiment, women's implicit romantic fantasies
      were dissociated with their conscious beliefs. More important, implicit (but not
      explicit) romantic fantasies negatively predicted women's interest in personal
      power, including projected income, education goal, interest in high-status jobs,
      and group leadership appeal. By contrast, men's implicit romantic fantasies were
      not routinely linked to their interest in personal power. In concert, the
      findings are consistent with positing a "glass slipper" effect for women that may
      be an implicit barrier to gender equity.

PMID- 15189576
TI  - Asymmetrical attributions for approach versus avoidance behavior.
AB  - Five studies examined responsibility inferences and/or person and situation
      attributions in positively versus negatively valenced motivational contexts. In
      Experiment 1, participants received information about a teaching assistant who
      was promised a reward or threatened with a punishment when asked for compliance
      with a requested transgression. The teaching assistant was perceived as more
      responsible for complying given the positive than the negative incentive. This
      finding was replicated in Experiment 2 using different vignettes and incentives.
      Experiment 3 revealed that the effect of incentive valence on perceived
      responsibility for compliance remains significant when statistically controlling
      for perceived compliance rates. Experiment 4 then demonstrated that there are not
      only greater responsibility judgments given a positive than a negative incentive
      but also greater dispositional attributions. Finally, Experiment 5 revealed that
      a similar incentive valence effect is found in other appetitive versus aversive
      motivational contexts. Theoretical explanations of this phenomenon are discussed.

PMID- 15189577
TI  - Fostering group identification and creativity in diverse groups: the role of
      individuation and self-verification.
AB  - A longitudinal study examined the interplay of identity negotiation processes and
      diversity in small groups of master's of business administration (MBA) students.
      When perceivers formed relatively positive impressions of other group members,
      higher diversity predicted more individuation of targets. When perceivers formed
      relatively neutral impressions of other group members, however, higher diversity
      predicted less individuation of targets. Individuation at the outset of the
      semester predicted self-verification effects several weeks later, and self
      verification, in turn, predicted group identification and creative task
      performance. The authors conclude that contrary to self-categorization theory,
      fostering individuation and self-verification in diverse groups may maximize
      group identification and productivity.

PMID- 15189578
TI  - The effects of self-esteem and ego threat on interpersonal appraisals of men and
      women: a naturalistic study.
AB  - A naturalistic study examined the effects of self-esteem and threats to the self
      on interpersonal appraisals. Self-esteem scores, ego threat (operationalized as a
      substantial decrease in self-esteem across an average of 9 months), and their
      interaction were used to predict likability and personality perceptions of
      college men and women. The results revealed a curvilinear function explaining
      likability: Moderate to low self-esteem men and women were higher in likability
      when threatened, whereas high self-esteem men were seen as less likable when
      threatened. Personality ratings indicated that high self-esteem men and women who
      were threatened were rated highest on Antagonism (i.e., fake, arrogant,
      unfriendly, rude, and uncooperative). Mediational analyses revealed that
      differences in Antagonism statistically accounted for differences in likability.
      These patterns are interpreted with respect to gender and time in interpersonal
      perceptions as well as naturalistic versus laboratory investigations.

PMID- 15189579
TI  - Location, location, location: the misprediction of satisfaction in housing
      lotteries.
AB  - People tend to overestimate the emotional consequences of future life events,
      exhibiting an impact bias. The authors replicated the impact bias in a real-life
      context in which undergraduates were randomly assigned to dormitories (or
      "houses"). Participants appeared to focus on the wrong factors when imagining
      their future happiness in the houses. They placed far greater weight on highly
      variable physical features than on less variable social features in predicting
      their future happiness in each house, despite accurately recognizing that social
      features were more important than physical features when asked explicitly about
      the determinants of happiness. In Experiment 2, we found that this discrepancy
      emerged in part because participants exhibited an isolation effect, focusing too
      much on factors that distinguished between houses and not enough on factors that
      varied only slightly, such as social features.

PMID- 15189580
TI  - The dynamic structure of relationship perceptions: differential importance as a
      strategy of relationship maintenance.
AB  - How do couples maintain relationship satisfaction despite specific negative
      perceptions of their relationships? One way to minimize the global implications
      of negative perceptions is to attribute differential importance to positive and
      negative features of the relationship. As those features change over time,
      satisfied intimates may alter their perceived importance, ensuring that positive
      features are always more closely associated with global satisfaction than
      negative ones. The current study examined the specific perceptions of 82 newly
      married couples at five assessments across their first 3 years of marriage. A
      tendency to view positive perceptions as more important than negative perceptions
      was associated with higher marital satisfaction. Moreover, a tendency to alter
      the importance of specific perceptions as those perceptions changed over time was
      associated with more stable global satisfaction. These findings highlight the
      interplay between the content and the structure of intimates' perceptions in
      determining relationship outcomes.

PMID- 15189581
TI  - Predicting the subjective experience of intrinsic motivation: the roles of self
      determination, the balance of challenges and skills, and self-realization values.
AB  - A series of studies was conducted to investigate the contributions of self
      determination, perceived competence, and self-realization values to the
      subjective experience of intrinsic motivation. Using varying sets of instructions
      in these studies, college undergraduates generated and subsequently evaluated
      panels of identity-related activities. Three measures of the subjective
      experience of intrinsic motivation were used as outcome variables: (a) interest,
      (b) flow experiences, and (c) feelings of personal expressiveness. These
      subjective experience measures were strongly intercorrelated. Across studies,
      self-determination was found to be strongly associated with all of the subjective
      experience measures. In contrast, self-realization values made larger
      contributions to flow experiences and to personal expressiveness than to
      interest. Perceived competence, although significantly correlated with all
      subjective experience measures, played a considerably smaller role in the
      prediction of intrinsic motivation.

PMID- 15189582
TI  - On difficult questions and evident answers: dispositional inference from role
      constrained behavior.
AB  - The present research investigated the underlying processes of how perceivers draw
      correspondent dispositional inferences about two interacting targets in the
      presence of situationally induced role constraints. Specifically, it is argued
      that a sufficient under-standing of role-dependent attributional biases (e.g.,
      the fundamental attribution error) requires a separate consideration of the
      respective dispositional inference processes about each of the tar-gets involved,
      particularly with respect to deliberate attributional inferences. Employing the
      quiz-role paradigm results from four experiments generally support this
      assumption. Moreover, the present findings suggest that perceivers are much more
      sensitive to situationally induced role constraints than previous results may
      suggest. Implications for the fundamental attribution error and theories of
      dispositional inference are discussed.

PMID- 15189583
TI  - Values and behavior: strength and structure of relations.
AB  - Three studies address unresolved issues in value-behavior relations. Does the
      full range of different values relate to common, recurrent behaviors? Which
      values relate more strongly to behavior than others? Do relations among different
      values and behaviors exhibit a meaningful overall structure? If so, how to
      explain this? We find that stimulation and tradition values relate strongly to
      the behaviors that express them; hedonism, power, universalism, and self
      direction values relate moderately; and security, conformity, achievement, and
      benevolence values relate only marginally. Additional findings suggest that these
      differences in value-behavior relations may stem from normative pressures to
      perform certain behaviors. Such findings imply that values motivate behavior, but
      the relation between values and behaviors is partly obscured by norms. Relations
      among behaviors, among values, and jointly among values and behavior exhibit a
      similar structure. The motivational conflicts and congruities postulated by the
      theory of values can account for this shared structure.

PMID- 15189584
TI  - Connectionist simulation of attitude learning: asymmetries in the acquisition of
      positive and negative evaluations.
AB  - Connectionist computer simulation was employed to explore the notion that, if
      attitudes guide approach and avoidance behaviors, false negative beliefs are
      likely to remain uncorrected for longer than false positive beliefs. In Study 1,
      the authors trained a three-layer neural network to discriminate "good" and "bad"
      inputs distributed across a two-dimensional space. "Full feedback" training,
      whereby connection weights were modified to reduce error after every trial,
      resulted in perfect discrimination. "Contingent feedback," whereby connection
      weights were only updated following outputs representing approach behavior, led
      to several false negative errors (good inputs misclassified as bad). In Study 2,
      the network was redesigned to distinguish a system for learning evaluations from
      a mechanism for selecting actions. Biasing action selection toward approach
      eliminated the asymmetry between learning of good and bad inputs under contingent
      feedback. Implications for various attitudinal phenomena and biases in social
      cognition are discussed.

PMID- 15189585
TI  - The good, the bad, and the healthy: impacts of emotional disclosure of trauma on
      resilient self-concept and psychological distress.
AB  - This study examined the impact of disclosing traumas on resilient self
      perceptions and psychological distress. Participants (N = 50) wrote about a
      traumatic life event or their plans for the next day and completed measures of
      resilience and distress before disclosing (pretest) and 3 months later
      (posttest). Results revealed that trauma participants increased in positive self
      perceptions (mastery, personal growth, self-acceptance) and decreased in distress
      (depression, interpersonal sensitivity, anxiety, somatization) from pretest to
      posttest. Control participants showed no changes except for autonomy, on which
      they decreased. Results suggest that in addition to reducing psychological
      distress, disclosing traumas change self-perception, resulting in a more
      resilient self-concept.

PMID- 15189586
TI  - Experimental tests of an attitudinal theory of the gender gap in voting.
AB  - This research examined the hypothesis that gender gaps in voting stem from
      differences in the extent to which men and women agree with candidates' issue
      stances. Two initial experiments portraying candidates by their sex and attitudes
      and a third experiment that also included information about political party
      produced the predicted attitudinal gender-congeniality effect: Participants of
      each sex reported greater likelihood, compared with participants of the other
      sex, of voting for the candidate who endorsed positions typically favored more by
      their own sex than the other sex. In addition, this gender-congeniality effect
      was present among Republican and independent participants but absent among
      Democratic participants because Democratic men as well as women favored
      candidates who advocated the positions typically favored by women. Interpretation
      invoked the importance of group interest based on gender as an influence on
      women's voting.

PMID- 15189587
TI  - Effects of accusations on the accuser: the moderating role of accuser
      culpability.
AB  - Recent research has shown that people can enhance their own reputations by
      accusing others of faults they possess. However, it is unclear by what mechanism
      accusing others of one's own misdeeds helps to enhance the reputation of the
      accuser, and there is no evidence for boundary conditions for this devious
      tactic. The present research provides evidence that accusations suggest
      information about the accuser's values and that it is the assumed values of the
      accuser that are responsible for increases in the accuser's reputation.
      Furthermore, the present research demonstrates that accusations may only be
      effective in increasing an individual's reputation when the individual has faults
      to deflect. When an individual possesses no faults, accusations can actually
      damage the individual's reputation.

PMID- 15189588
TI  - Culture, education, and the attribution of physical causality.
AB  - Two studies investigated the impact of culturally instilled folk theories on the
      perception of physical events. In Study 1, Americans and Chinese with no formal
      physics education were found to emphasize different causes in their explanations
      for eight physical events, with Americans attributing them more to dispositional
      factors (e.g., weight) and less to contextual factors (e.g., a medium) than did
      Chinese. In Study 2, Chinese Americans' identity as Asians or as Americans was
      primed before having them explain the events used in Study 1. Asian-primed
      participants endorsed dispositional explanations to a lesser degree and
      contextual explanations to a greater degree than did American-primed
      participants, although priming effects were observed only for students with
      little physics education. Together, these studies suggest that culturally
      instilled folk theories of physics produce cultural differences in the perception
      of physical causality.

PMID- 15189589
TI  - Psychological-state theories about significant others: implications for the
      content and structure of significant-other representations.
AB  - Three studies tested a theory-based approach to significant-other
      representations. The central hypothesis was that perceivers are especially likely
      to possess lay theories to explain the responses of their significant others, and
      this is reflected in the content and structure of significant-other
      representations. Theories were defined in IF-THEN terms as beliefs about the
      psychological states (e.g., "IF Bill wants to make a good impression.") that
      explain others' responses (e.g., ". THEN he acts friendly"). All three studies
      yielded evidence indicating that the content of significant-other representations
      is especially likely to include such psychological-state theories (PSTs). Study 3
      assessed the internal structure of PSTs-specifically, the strength of the
      linkages between psychological-state IFs and the THENs they are believed to
      elicit-and showed that such linkages are particularly strong for PSTs about
      significant others. Overall, the findings add to the growing literature on the
      role of explanatory or lay-theoretical forms of knowledge in how perceivers make
      sense of the social world.

PMID- 15189590
TI  - The persuasiveness of racial arguments as a subtle measure of racism.
AB  - These studies provide evidence of the reliability and validity of a new indirect
      measure of racism, the Racial Argument Scale (RAS). On the RAS, participants rate
      how well arguments support conclusions that are positive or negative toward
      Blacks rather than their agreement with the arguments and conclusions. These
      studies show that the RAS has good internal consistency, high levels of test
      retest reliability, good convergent validity with other self-report measures of
      racism, and does not correlate with social desirability or right-wing
      authoritarianism. Furthermore, these studies show that the RAS predicts
      behavioral measures of racism and that the RAS is able to predict positivity and
      negativity toward Blacks that is not measured by other self-report measures of
      racism. These studies suggest that the RAS is a reliable and valid measure of
      racial attitudes.

PMID- 15189591
TI  - The fundamental attribution error in detecting deception: the boy-who-cried-wolf
      effect.
AB  - Most people are unable to detect accurately when others are lying. Many
      explanations for this inability have been suggested but the cognitive heuristics
      involved in lie detection have received little attention. The present study
      offers evidence from two experiments, based on two different groups of observers,
      judging two different kinds of lies, presented in two different testing
      situations, that the fundamental attribution error significantly undermines the
      ability to detect honesty and deception accurately. Trait judgments of
      trustworthiness were highly correlated with state judgments of truthfulness,
      leading, as predicted, to positive correlations with honest detection accuracy
      and negative correlations with deception detection accuracy. More accurate lie
      detectors were significantly more likely than less accurate lie detectors to
      separate state and trait judgments of honesty. The effect of other biases, such
      as the halo effect and the truthfulness bias, also are examined. Implications for
      future research and practice are discussed.

PMID- 15189592
TI  - An on-line look at automatic contrast and correction of behavior categorizations
      and dispositional inferences.
AB  - The current study examined on-line behavior recategorization as a mechanism
      underlying corrections for contextual influences in dispositional inferences.
      After watching an initial comparison video that portrayed either a successful or
      unsuccessful performance on a spatial ability task, cognitive load and no load
      participants watched and made real-time ratings of a target performance. The
      comparison video was expected to exert a contrastive influence on participants'
      automatic impressions of the performance (behavior categorizations) and the
      child's intelligence (dispositional inferences). Load participants' on-line and
      post-video performance and ability ratings showed this expected effect, as did no
      load participants' initial on-line performance ratings. However, no load
      participants' later on-line and post-video ratings did not. These findings
      support the notion that corrections for contextual influence can occur at the
      level of behavior identification as perceivers encode behavioral cues.

PMID- 15189593
TI  - Beta-eudesmol, a new sesquiterpene component in intact and organized root of
      chamomile (Chamomilla recutita).
AB  - Gas chromatography (GC) and GC-mass spectrometry are used to identify a new
      sesqiterpene, beta-eudesmol, which seems to be a characteristic essential oil
      component of the intact and in vitro organized root of chamomile [Chamomilla
      recutita (L.) Rauschert]. It is identified on three types of stationary phases by
      GC. The confirmation of identity is carried out by comparison of mass spectra
      with those reported in the literature and measured from a reference compound. The
      percentage evaluation of the oil component is made by area normalization, on the
      basis of three parallel measurements. Among the cultivated and wild chamomile
      species examined, the wild species from the areas of Szeghalom contain the
      highest quantity of beta-eudesmol (9.25% in the total essential oil).

PMID- 15189594
TI  - Determination of donepezil hydrochloride (E2020) in plasma by liquid
      chromatography-mass spectrometry and its application to pharmacokinetic studies
      in healthy, young, Chinese subjects.
AB  - A sensitive, simple, and specific liquid chromatographic method coupled with
      electrospray ionization-mass spectrometry for the determination of donepezil in
      plasma is developed, and its pharmacokinetics in healthy, male, Chinese is
      studied. Using loratadine as the internal standard, after extraction of the
      alkalized plasma by isopropyl alcohol-n-hexane (3:97, v/v), solutes are separated
      on a C(18) column with a mobile phase of methanol-acetate buffer (pH 4.0) (80:20,
      v/v). Detection is performed with a time-of-flight mass spectrometer equipped
      with an electrospray ionization source operated in the positive-ionization mode.
      Quantitation of E2020 is accomplished by computing the peak area ratio (donepezil
      [M+H](+) m/z 380-loratadine [M+H](+) m/z 383) and comparing them with the
      calibration curve (r = 0.9998). The linear calibration curve is obtained in the
      concentration range 0.1-15 ng/mL. The limit of quantitation is 0.1 ng/mL. The
      mean recovery of E2020 from human plasma is 99.4% +/- 6.3% (ranging 93.4-102.6%).
      The inter- and intraday relative standard deviation is less than 15%. After an
      oral administration of 5 mg E2020 to 20 healthy Chinese volunteers, the main
      pharmacokinetic parameters of E2020 are as follow: T(max), 3.10 +/- 0.55 h;
      t((1/2)), 65.7 +/- 12.8 h; C(max), 10.1 +/- 2.02 ng/mL; MRT, 89.4 +/- 13.4 h; and
      CL/F, 9.9 +/- 4.3 L/h.

PMID- 15189595
TI  - Separation of benzodiazepines using capillary electrochromatography.
AB  - Benzodiazepines are often used for the treatment of epilepsy, convulsions, and
      many psychiatric disorders. The widespread use of this class of drugs has
      occasionally raised concern about recreational benzodiazepine abuse and has led
      to the erroneous impression that benzodiazepines have a relatively high abuse
      liability among recreational drug users. Therefore, the separation and
      identification of these compounds is of great interest. In general, the
      separation of benzodiazepines is performed using high-performance liquid
      chromatography (HPLC). Recently, capillary electrochromatography, which combines
      the high efficiency of capillary zone electrophoresis and the high selectivity of
      HPLC, has gained much attention. The focus of the work reported here is the use
      of a 40-cm packed bed of Reliasil 3- microm C(18) stationary phase to separate
      seven benzodiazepines. Optimal conditions are established by varying the mobile
      phase, amount of organic modifier, buffer concentration, applied voltage, and
      column temperature. A mobile phase composition of Tris-HCl (pH 8)-acetonitrile
      (60:40), an electrolyte concentration of 30mM, and a temperature of 15 degrees C
      with an applied voltage of 20 kV proves to be optimum. In addition, the method
      developed here is applied to the characterization of oxazepam in a standard urine
      sample.

PMID- 15189596
TI  - Chromatographic analysis of sagebrush monoterpenes in blood plasma.
AB  - An analytical method is required for the analysis of monoterpenes in animal
      plasma to support a pharmacokinetic study. Monoterpenes common to sagebrush are
      extracted from sheep plasma by employing solid-phase extraction (SPE), followed
      by analysis of the extracts by gas chromatography with flame ionization
      detection. The analytes are quantitated versus an external standard and by
      comparison with a surrogate standard added to the sample prior to extraction. In
      addition to comparing the two quantitative methods, the storage stability of the
      analytes in plasma and SPE columns is evaluated. Both methods employed for
      quantitation yield precision suitable for pharmacokinetic studies. However,
      determination of monoterpenes residues versus external standards produces
      improved accuracy as compared with use of the surrogate standard. Some analyte
      loss is observed from plasma samples stored for five weeks at -12 degrees C.
      However, storage of extracts on the SPE columns affords excellent stability.

PMID- 15189597
TI  - Solid-phase extraction and HPTLC determination of isoniazid and acetylisoniazid
      in serum. Comparison with HPLC.
AB  - A new solid-phase extraction (SPE) and quantitative determination of isoniazid
      (INH) and its acetyl metabolite (AcINH) in serum by high-performance thin-layer
      chromatography (HPTLC) is presented. Alkalized serum samples with nicotinamide as
      an internal standard are applied to an SPE cartridge containing a new SPE
      sorbent, [poly (divinylbenzene-co-N-vinylpyrrolidone )]. A simple procedure of
      conditioning, washing, and eluting steps is described. After evaporation of the
      eluates to dryness and reconstitution, one-dimensional HPTLC is performed on
      silica gel plates with ethyl acetate-methanol (70:30) as a mobile phase.
      Quantitation is done by densitometry. Convenient validation parameters are
      obtained (linearity, limits of detection and quantitation, precision, and
      accuracy) for INH and AcINH. The method is compared with a high-performance
      liquid chromatographic (HPLC) technique developed in the laboratory, and
      satisfactory correlation is found between data from the two techniques. The HPTLC
      method is sensitive and specific and is used to quantitate INH and AcINH in
      patient blood serum, and the results are compared with those obtained by HPLC.

PMID- 15189599
TI  - Mass selective detection of amphetamine, methamphetamine, and related compounds
      in urine.
AB  - A method is presented for the routine analysis of amphetamine, methamphetamine,
      and related compounds in urine with gas chromatography coupled with mass
      spectrometry operated in the selective ion monitoring mode. The analytes are
      isolated by liquid-liquid extraction and are derivatized with trifluoroacetic
      anhydride. 3,4-Methylenedioxy-methamphetamine-D(5) is employed as the internal
      standard. Standard solutions are prepared using spiked urine samples, which are
      subjected to all phases of sample preparation. Disposable deactivated glass
      containers are employed throughout the process.

PMID- 15189598
TI  - Rapid and sensitive liquid chromatography-electrospray ionization-mass
      spectrometry method for the determination of eperisone in human plasma: method
      and clinical applications.
AB  - A sensitive liquid chromatography-electrospray ionization-mass spectrometry (LC
      ESI-MS) method for determination of eperisone in human plasma using buflomedil as
      the internal standard (IS) is established. After being made alkaline with
      saturated sodium bicarbonate solution, plasma samples are extracted with a
      mixture of diethyl ether-cyclohexane (1:1, v/v) and separated by high-performance
      liquid chromatography on a reversed-phase C(18) column with a mobile phase of
      10mM ammonium acetate buffer (adjusted the pH to 3.9 with acetic acid)-methanol
      (20:80, v/v). Eperisone is determined using ESI in a single-quadrupole MS. LC-ESI
      MS is performed in the selected ion monitoring mode using target ions at m/z 260
      for eperisone and m/z 308 for the IS. Calibration curves are linear over the
      ranges 0.02-20 ng/mL for eperisone. The intra- and interassay variability values
      are less than 9.0% and 11.5%, respectively. The mean plasma extraction recovery
      of eperisone is 91.7 +/- 6.6%. The method has been successfully applied to study
      the pharmacokinetics of eperisone in healthy, male, Chinese volunteers.
      Pharmacokinetic parameters of the reference and test tablets have been compared.

PMID- 15189601
TI  - Application of curve fitting in thin-layer chromatography-flame ionization
      detection analysis of the carbohydrate fraction in marine mucilage and marine
      snow samples from Italian seas.
AB  - This paper presents a thin-layer chromatographic-flame ionization detection (TLC
      FID) procedure to characterize the carbohydrate fraction of marine mucilage and
      marine snow samples from the Italian Seas. The identification of the different
      carbohydrate subfractions is supported by the application of a deconvolution
      procedure based on a new mathematical function for describing chromatographic
      peaks and enhancing their resolution. The joint-approach TLC-FID analysis and
      deconvolution procedure allows for the characterization of the carbohydrate
      fraction of the marine samples in a single step without using the different
      derivatization procedures requested by the most common gas chromatography and
      high-performance liquid chromatographic methods for carbohydrate analysis. In
      fact, the results obtained by the TLC-FID procedure show that different neutral,
      uronic acid, and aminosugar subfractions can be present simultaneously in these
      samples. Moreover, the results support some hypotheses about the causes of the
      presence of mucilages in the Italian Seas.

PMID- 15189600
TI  - Determination of salbutamol in human plasma and urine by high-performance liquid
      chromatography with a coulometric electrode array system.
AB  - A method is developed to determine salbutamol in human plasma and urine using
      high-performance liquid chromatography (HPLC) with a coulometric electrode array
      system, based on the electrochemical behavior of salbutamol at graphite
      electrode. The mobile phase component A is 30 mM sodium dihydroxy phosphate-30 mM
      triethylamine and is adjusted to pH 6.0 with 20% phosphate acid. The mobile phase
      component B is methanol. The optimized mobile phase composition was A and B in
      the proportion of 90:10 (v/v). Paracetamol is selected as the external standard.
      The human plasma and urine samples are pretreated using solid-phase extraction
      cartridges (Sep-Pak Silica), and the eluting solution is monitored by the
      coulometric electrode array system. The electrode potentials are set at 300, 400,
      550, and 650 mV, respectively. Calibration curves show good linearity, and the
      recovery of salbutamol proves to be constant and unaffected by the concentration
      of the drug. This method, developed using HPLC-electrochemical detection, is
      reproducible and sensitive enough for the determination of salbutamol in human
      plasma and urine.

PMID- 15189602
TI  - Preparative scale purification of shidasterone, 2-deoxy-polypodine b and 9a,20
      dihydroxyecdysone from Silene italica ssp. nemoralis.
AB  - A suitable combination of preparative scale separation methods results in
      effective clean-up of the ecdysteroids of Silene italica ssp. nemoralis (Waldst.
      and Kit.) Nyman. The isolation of minor ecdysteroids from the partially purified
      extract is based on the use of both droplet counter-current chromatography and
      low-pressure reversed-phase liquid chromatography. The purification is completed
      by preparative thin-layer chromatography and preparative high-performance liquid
      chromatography to obtain the minor ecdysteroids, such as 2-deoxy-20
      hydroxyecdysone, shidasterone, 2-deoxy-polypodine B, makisterone C, and 9alpha,20
      dihydroxyecdysone.

PMID- 15189603
TI  - Determination of 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide in a gel
      pharmaceutical formulation by high-performance liquid chromatography.
AB  - An isocratic reversed-phase high performance liquid chromatographic method is
      developed and validated for the determination of 2-(diethylamino)-N-(2,6
      dimethylphenyl) acetamide (0.3%, w/w) in a gel formulation. The chromatographic
      separation is achieved with potassium phosphate buffer (pH 7.0)-acetonitrile
      (47:53, v/v) as mobile phase, a C(18) column, and UV detection at 254 nm. The
      calibration curve is linear (r(2) = 1.000) from 20-140% of the analytical
      concentration of 1.4 microg/mL. The mean percent relative standard deviation
      values for intra- and interday precision studies are < 1%. The recovery ranges
      99.95-100.23% from a gel formulation. The method is specific and successfully
      routinely used in quality control for the analysis of bulk gel samples and final
      product release.

PMID- 15189604
TI  - Self-awareness, deindividuation, and social identity: unraveling theoretical
      paradoxes by filling empirical lacunae.
AB  - In an effort to examine paradoxes involving self-awareness, deindividuation, and
      social identity, this article reports the results of a study that examines the
      effects of a range of manipulation operationalizations of self and social
      identity on a complement of measurement operationalizations of self and social
      identity. Specifically, participants completed measures of self-awareness and
      ethnic social identity while confronted with their mirror image, while wearing a
      mask, or while exposed to a family tree delineating their ethnicity. Patterns of
      mean levels of self-awareness and ethnic social identity are used to examine the
      paradox of depersonalization and deindividuation, the paradox of (a)symmetrical
      activation of components of identity, and the paradox of deindividuation and the
      search for identity. Discussion considers the limitations of this approach and
      considers the implications of these results for the long-standing study of the
      interplay between self and social identity.

PMID- 15189605
TI  - Complementarity of interpersonal behaviors in dyadic interactions.
AB  - An important assumption of interpersonal theory is that during social
      interactions the behavior of one person tends to invite complementary behavior
      from the other person. Past research examining complementarity has usually used
      either confederates or fictitious interaction partners in their designs and has
      produced inconsistent results. The current study used observational ratings of
      behaviors of 158 participants as they interacted with partners across three
      different dyadic social situations. Randomization tests of hypothesized order
      relations found that the behaviors exhibited during these interactions tended to
      occur in a circular pattern predicted by the interpersonal circumplex. These
      tests also indicated support for Leary's (1957) orientation of the control and
      affiliation dimensions of the interpersonal circumplex and Carson's (1969) notion
      that dominant behavior induces submissive responses and friendly behavior
      encourages friendly responses.

PMID- 15189606
TI  - How "fun/importance" fit affects performance: relating implicit theories to
      instructions.
AB  - People experience a regulatory fit when they employ means of goal pursuit that
      fit their regulatory orientation, and this fit increases motivation that can
      enhance performance. The present studies extend previous research on regulatory
      fit to the classic motivational variables of fun and importance. They also
      examine for the first time the effect on performance of the fit between
      individuals' implicit theories about a task's fun or importance and their
      strategic engagement of the task as fun or important as induced by task
      instructions. In all three studies, task performance was better when the external
      task instructions "fit" rather than did not fit participants' implicit theory for
      the task. The implications of these findings for understanding the motivational
      effects of fun and importance are discussed.

PMID- 15189607
TI  - Wisdom-related knowledge: affective, motivational, and interpersonal correlates.
AB  - This study investigated the connection between wisdom as a body of expert
      knowledge about the meaning and conduct of life and indicators of affective,
      motivational, and interpersonal functioning. Structural equation analyses showed
      that individuals higher on wisdom-related knowledge reported (a) higher affective
      involvement combined with lower negative and pleasant feelings, (b) a value
      orientation that focused conjointly on other-enhancing values and personal growth
      combined with a lesser tendency toward values revolving around a pleasurable
      life, and (c) a preference for cooperative conflict management strategies
      combined with a lower tendency to adopt submissive, avoidant, or dominant
      strategies. These findings corroborate the theoretical notion that wisdom
      involves affective modulation and complexity rather than the predominant seeking
      of pleasure and also a joint motivational commitment to developing the potential
      of oneself and that of others.

PMID- 15189608
TI  - Spontaneous skepticism: the interplay of motivation and expectation in responses
      to favorable and unfavorable medical diagnoses.
AB  - The quantity of processing view of motivated reasoning predicts that individuals
      are more likely to spontaneously question the validity of unfavorable than
      favorable feedback even when the objective likelihood of the feedback is
      equivalent. Participants were videotaped self-administering a bogus medical test
      revealing either a favorable or an unfavorable result. In Studies 1 and 2,
      unfavorable result participants required more time to accept the validity of the
      test result and were more likely to spontaneously recheck its validity than were
      favorable result participants. However, unfavorable results also were perceived
      as less expected than were favorable results, even though the information
      supplied about their objective likelihood was identical. Study 3 showed that
      participants evaluating another student's results perceived favorable and
      unfavorable outcomes as equally likely, suggesting that the subjective likelihood
      of positive and negative feedback is also subject to motivational influence.

PMID- 15189609
TI  - The relational context of social support: Relationship satisfaction moderates the
      relations between enacted support and distress.
AB  - In two studies of kidney transplant patients and their significant others, the
      authors examined whether the relations between enacted social support and patient
      distress were moderated by patients' satisfaction with their relationship with
      the support provider (i.e., their significant other). In Study 1 (n = 121
      couples), unsupportive spousal behaviors were associated with more distress only
      among patients who were less satisfied with their marital relationship. In Study
      2 (n = 112 couples), the relations between unsupportive behaviors and distress
      again varied as a function of the patient's relationship satisfaction, although
      the particular pattern of the interaction depended on the specific unsupportive
      behaviors offered to the patient. In both studies, relationship dissatisfaction
      was associated with higher levels of patient distress. Supportive behaviors were
      not related to distress and did not interact with relationship satisfaction.
      Implications for future research on social support in marriage are discussed.

PMID- 15189610
TI  - Convergent, discriminant, and incremental validity of competing measures of
      emotional intelligence.
AB  - This study investigated the convergent, discriminant, and incremental validity of
      one ability test of emotional intelligence (EI)--the Mayer-Salovey-Caruso
      Emotional Intelligence Test (MSCEIT)--and two self-report measures of EI--the
      Emotional Quotient Inventory (EQ-i) and the self-report EI test (SREIT). The
      MSCEIT showed minimal relations to the EQ-i and SREIT, whereas the latter two
      measures were moderately interrelated. Among EI measures, the MSCEIT was
      discriminable from well-studied personality and well-being measures, whereas the
      EQ-i and SREIT shared considerable variance with these measures. After
      personality and verbal intelligence were held constant, the MSCEIT was predictive
      of social deviance, the EQ-i was predictive of alcohol use, and the SREIT was
      inversely related to academic achievement. In general, results showed that
      ability EI and self-report EI are weakly related and yield different measurements
      of the same person.

PMID- 15189611
TI  - Social projection of transient drive states.
AB  - The authors hypothesized that people's predictions of how other people feel in
      emotionally arousing situations are often based on people's predictions of how
      they themselves would feel in those situations. Indeed, most participants in
      Study 1 reported predicting hungry hikers' feelings by mentally trading places
      with them, imagining what their own feelings would be in the hikers' situation.
      Because people's predictions of their own feelings tend to be biased in the
      direction of their current drive states, we hypothesized that mentally trading
      places would lead to social projection of transient drive states. In Study 2,
      participants' predictions of whether thirst or hunger would be more bothersome to
      hikers lost without food or water were biased in the direction of participants'
      own exercise-induced thirst. Furthermore, participants' predictions of how they
      would feel in the hikers' situation statistically mediated the effect of exercise
      on their predictions of the hikers' feelings.

PMID- 15189612
TI  - Connecting terror management and dissonance theory: Evidence that mortality
      salience increases the preference for supporting information after decisions.
AB  - From the perspective of terror management theory, reminders of mortality should
      intensify the desire to pursue cognitive consistency. The authors investigated
      this notion with regard to dissonance theory starting from the finding of
      research on "selective exposure to information" that after having made a
      decision, people prefer consonant over dissonant information. The authors found
      that following mortality salience, people indeed showed an increased preference
      for information that supported their decision compared to information conflicting
      with it. However, this only occurred with regard to a worldview-relevant decision
      case. For a fictitious decision scenario, mortality salience did not affect
      information seeking. Practical and theoretical implications are discussed.

PMID- 15189613
TI  - "... As you would have them do unto you": Does imagining yourself in the other's
      place stimulate moral action?
AB  - Philosophers, psychologists, and religious teachers have suggested that imagining
      yourself in another's place will stimulate moral action. The authors tested this
      idea in two different situations. In Experiment 1, participants had the
      opportunity to assign themselves and another research participant to tasks, with
      one task clearly more desirable than the other. Imagining oneself in the other's
      place did little to increase the morality (fairness) of the decision. A different
      form of perspective taking, imagining the other's feelings, increased direct
      assignment of the other to the desirable task, apparently due to increased
      empathy. In Experiment 2, participants confronted a different decision: either
      accept an initial task assignment that would give them highly positive
      consequences and the other participant nothing or change the assignment so they
      and the other would each receive moderately positive consequences. In this
      situation, imagining oneself in the other's place did significantly increase
      moral action.

PMID- 15189614
TI  - Culture and well-being: the cycle of action, evaluation, and decision.
AB  - Two studies were conducted to examine how European and Asian Americans experience
      and remember their task performance, make a decision about a future task, and how
      that decision affects enjoyment of the task. In Study 1, although Asians solved
      as many anagrams as European Americans, Asians remembered solving fewer than did
      European Americans at Time 2. European Americans' Time 2 choice of task was
      predicted from Time 1 performance, but Asians' Time 2 choice was not. In Study 2,
      European Americans chose the same task if they had previously done well and a
      different task if they had not. Their actual enjoyment of the Time 2 task,
      furthermore, was significantly higher than at Time 1. In contrast, there was no
      change in actual enjoyment of the task at Time 2 among Asians because their
      choice was not based on their performance at Time 1.

PMID- 15189615
TI  - Motivations for caregiving in adult intimate relationships: influences on
      caregiving behavior and relationship functioning.
AB  - This study identified and examined the correlates of specific motivations for
      caregiving in romantic couples (N = 194 couples). At Time 1, couple members
      completed measures assessing motivations for caregiving, the quality of
      caregiving that occurs in the relationship, and personal and relationship
      characteristics that might influence caregiving motivations. Relationship
      functioning was then assessed 2 to 3 months later. Results revealed that (a)
      there are a number of distinct motivations for providing and for not providing
      care to one's partner, (b) the motivations are associated with various personal
      features of the caregiver and the recipient, (c) the caregiver's perceptions of
      the relationship influence his or her caregiving motives, (d) different
      motivations for caregiving predict different patterns of caregiving behavior, and
      (e) responsive caregiving predicts the recipient's perceptions of healthy
      relationship functioning both immediately and over time. Implications of
      identifying the motivations that promote or inhibit the provision of responsive
      support in intimate relationships are discussed.

PMID- 15189616
TI  - Evidence that projection of a feared trait can serve a defensive function.
AB  - Two experiments tested the notion that allowing people to project a feared trait
      onto another individual would facilitate denial of the trait. In Study 1,
      participants were given feedback that they were high or low in repressed anger
      and were allowed to rate an ambiguous target on anger or not. Participants who
      received high (vs. low) anger feedback rated the target especially high on anger.
      In addition, participants who received high anger feedback and who were allowed
      to project their anger had the lowest anger accessibility on a word completion
      exercise. Study 2 replicated these basic findings using a different trait
      dimension (dishonesty) and a direct measure of denial (self-attributions of
      dishonesty). Specifically, in Study 2, participants who received high dishonesty
      feedback and who were allowed to project dishonesty reported having an especially
      low level of dishonesty. Discussion focused on the relationship between classic
      projection and other forms of psychological defense.

PMID- 15189617
TI  - Personality traits in adolescence as predictors of religiousness in early
      adulthood: findings from the Terman Longitudinal Study.
AB  - The authors examined the associations of the Big Five personality factors with
      religiousness in adulthood for a 19-year longitudinal sample of 492 adolescents
      age 12 to 18. Among the Big Five, Conscientiousness in adolescence was uniquely
      related to higher religiousness in early adulthood. For adolescents high in
      Emotional Stability, the link between strength of religious upbringing and
      religiousness in adulthood was weaker than it was for adolescents who were less
      emotionally stable. These findings replicate the work of others demonstrating the
      importance of Conscientiousness as a predictor of religiousness and suggest that
      emotionally unstable adolescents might be more likely to adopt levels of
      religiousness that are similar to those of their parents.

PMID- 15189618
TI  - On the hierarchical structure of self-determined motivation: a test of top-down,
      bottom-up, reciprocal, and horizontal effects.
AB  - This article aimed to test some hypotheses about the hierarchical structure of
      self-determined motivation in two longitudinal studies. First, the authors
      verified the stability of global self-determined motivation and school self
      determined motivation over time. Second, they tested top-down, bottom-up,
      reciprocal, and horizontal effects between global self-determined motivation and
      school self-determined motivation. In Study 1, 122 college students were
      evaluated on two occasions with a 5-year interval on their global and school self
      determined motivation. In Study 2, 294 college students were evaluated on the
      same variables with a 1-year interval. Results from both studies revealed that
      (a) global self-determined motivation was not more stable than self-determined
      school motivation over time and (b) a cross-lag model including reciprocal
      effects between self-determined global and self-determined school motivation
      offered the best fit indices comparatively to a model involving only horizontal
      (or stability) effects. Discussion emphasizes the theoretical implications of the
      results.

PMID- 15189619
TI  - Group identification moderates emotional responses to perceived prejudice.
AB  - Two studies tested the prediction that group identification (importance of the
      group in the self-concept) moderates the impact of perceived discrimination on
      self-evaluative emotions (depression and self-esteem). In Study 1, women low in
      gender identification experienced less depressed emotion and higher self-esteem
      if a negative evaluation was due to sexism than when it was not. The self
      evaluative emotions of women high in gender identification were not buffered by
      attributions to sexism. In Study 2, ethnic identification and depressed emotions
      were positively related when Latino-Americans read about pervasive prejudice
      against the ingroup but were negatively related when they read about prejudice
      against an outgroup. Both studies demonstrated that for highly group identified
      individuals, prejudice against the ingroup is a threat against the self. Thus,
      the self-protective strategy of attributing negative feedback to discrimination
      may be primarily effective for individuals who do not consider the group a
      central aspect of self.

PMID- 15189620
TI  - Nifty ways to leave your lover: The tactics people use to entice and disguise the
      process of human mate poaching.
AB  - Although a number of studies have explored the ways that men and women
      romantically attract mates, almost no research exists on the special tactics
      people use when already in a relationship and trying to attract someone new--a
      process known as mate poaching enticement. In Study 1, the authors investigated
      the tactics people use to entice others into making mate poaching attempts.
      Enticement tactic effectiveness conformed to evolutionary-predicted patterns
      across sex and temporal context. In Study 2, the authors examined the tactics men
      and women use to disguise mate poaching enticement. The most effective camouflage
      for poaching also varied between sex in evolutionary-predicted ways, regardless
      of the target of deception (i.e., current partner vs. larger community).
      Discussion focuses on limitations of this research, future investigative
      directions, unexpected findings, and the utility of placing mate poaching
      attraction within the broader context of human sexual strategies.

PMID- 15189621
TI  - Daily supportive equity in close relationships.
AB  - Receiving support in committed relationships has frequently been associated with
      negative psychological outcomes in the recipient, such as increased distress. The
      authors hypothesized that these negative effects could be offset by support
      recipients' reciprocation of support, that is, by creating a sense of supportive
      equity. To investigate this hypothesis, the authors obtained daily reports of
      mood and of received and given emotional support from both partners in 85 couples
      throughout a 4-week period. Reciprocity in support transactions was associated
      with higher levels of positive mood and lower levels of negative mood. In line
      with previous research, receiving support without reciprocation was associated
      with increases in negative mood. Giving support, regardless of receipt, was
      associated with a decrease in negative mood.

PMID- 15189622
TI  - Implicit and explicit motives influence accessibility to different
      autobiographical knowledge.
AB  - In two studies, participants completed implicit and explicit measures of
      achievement and intimacy/affiliation motivation. In Study 1, they recalled an
      emotional and a self-descriptive memory. In both domains, implicit motive scores
      were higher when motivational content was present in the emotional memory. When
      motivational content was present in the self-descriptive memory, explicit motive
      scores were higher in both domains. In Study 2, participants recalled four
      autobiographical memories (two agentic, two communal) that were then categorized
      as specific or general events. Implicit motive scores were higher for
      participants who recalled specific agentic and communal events. Explicit motive
      scores were higher for participants who recalled general achievement events but
      not general communal events. Findings suggest that implicit motives are linked to
      accessibility of specific and emotional experiences, whereas explicit motives are
      linked more strongly to accessibility of specific and general memories that
      relate to the self-concept.

PMID- 15189623
TI  - Ethnophaulisms and exclusion: the behavioral consequences of cognitive
      representation of ethnic immigrant groups.
AB  - Ethnophaulisms are the words used as slurs to refer to ethnic immigrant
      outgroups. This article explores the effects of these cognitive representations
      of ethnic immigrant groups on exclusion behavior directed toward these immigrant
      groups. Using archival data spanning a 150-year period of American history, the
      results of these analyses provide a sobering picture of the effects of the
      cognitive representation of immigrants: a century and a half of thinking about
      ethnic immigrant groups in a simplistic and negative manner and a corresponding
      tendency to exclude those immigrant groups from the receiving society. The
      implications of these results for theoretical approaches to intergroup relations
      are considered.

PMID- 15189624
TI  - Continuing and changing group identities: the effects of merging on social
      identification and ingroup bias.
AB  - A social identity approach to the investigation of group-based reactions to a
      merger is outlined, in which a merger is analyzed in terms of the continuation or
      change of the pre-merger group identity. In two experiments, the relationship
      between pre-merger identification, post-merger identification, and ingroup bias
      was investigated using a minimal group paradigm. Results from both studies showed
      that the perceived continuation of the pre-merger group identity in the post
      merger group strengthened the positive relationship between pre-merger
      identification and identification with the superordinate post-merger group.
      Moreover, perceived continuation strengthened, rather than reduced, ingroup bias
      at the subordinate level of the merged groups. Some theoretical and practical
      implications are discussed.

PMID- 15189625
TI  - Prior source exposure and persuasion: further evidence for misattributional
      processes.
AB  - To assess the persuasive impact of prior source exposure, two studies paired
      persuasive messages with a source to whom participants had previously been
      exposed subliminally, explicitly, or not at all. In Experiment 2, participants'
      attention also was drawn to information that potentially undermined the
      implications of any reaction to re-exposure. Compared to no exposure, prior
      subliminal exposure increased the source's persuasiveness, an effect not mediated
      by source liking. Explicit exposure increased source persuasiveness to the extent
      that the source was liked more and only absent a recall cue. Results favored
      misattributional accounts of prior exposure effects.

PMID- 15189626
TI  - Level of self-esteem and contingencies of self-worth: unique effects on academic,
      social, and financial problems in college students.
AB  - The unique effects of level of self-esteem and contingencies of self-worth
      assessed prior to college on academic, social, and financial problems experienced
      during the freshman year were examined in a longitudinal study of 642 college
      students. Low self-esteem predicted social problems, even controlling for
      demographic and personality variables (neuroticism, agreeableness, and social
      desirability), but did not predict academic or financial problems with other
      variables controlled. Academic competence contingency predicted academic and
      financial problems and appearance contingency predicted financial problems, even
      after controlling for relevant personality variables. We conclude that
      contingencies of self-worth uniquely contribute to academic and financial
      difficulties experienced by college freshmen beyond level of self-esteem and
      other personality variables. Low self-esteem, on the other hand, appears to
      uniquely contribute to later social difficulties.

PMID- 15189627
TI  - Social interactions and cardiovascular reactivity during problem disclosure among
      friends.
AB  - The authors examined the relations of social interactions with cardiovascular
      response in the context of two friends disclosing a problem. They also examined
      the relations of the sex composition of the dyad and partner gender-related
      traits (communion/agency) with social interactions. Same-sex and opposite-sex
      dyads (N = 79) came to the lab. One friend disclosed a real-life problem while
      the partner provided support; cardiovascular response was monitored. Women
      provided more emotional support than men, and this sex difference was due to
      women's higher levels of communion. Agency was linked with greater advice,
      whereas unmitigated communion was linked with greater negative interactions.
      Negative interactions predicted slower diastolic blood pressure (DBP) recovery,
      whereas advice predicted slower heart rate (HR) recovery. Sex composition of dyad
      moderated some of these effects.

PMID- 15189628
TI  - Identification and status revisited: the moderating role of self-enhancement and
      self-transcendence values.
AB  - Two studies examined the moderating role of the importance attributed to self
      enhancement and self-transcendence values on the association of group status with
      identification. In the first study, students reported their personal value
      priorities, their identification with a group, and their perception of the status
      of that group. The more importance respondents attributed to self-enhancement and
      the less importance to self-transcendence, the more their identification with a
      group depended on the group's status. In the second study, the salience of self
      enhancement and of self-transcendence values was experimentally manipulated.
      Identification with a group depended more on the status of that group when self
      enhancement values were salient than when self-transcendence values were salient.

PMID- 15189629
TI  - Intrinsic and extrinsic work orientations as moderators of the effect of annual
      income on subjective well-being: a longitudinal study.
AB  - Income is only weakly associated with both subjective well-being (SWB) and job
      satisfaction in the United States, a surprising finding in light of the
      importance placed on financial status in capitalistic societies. To explore this
      further, the authors examined intrinsic and extrinsic work orientations as
      potential moderators of the effects of financial compensation on SWB and job
      satisfaction. Master's of business administration students (N = 124) completed
      measures of work orientation and, 4 to 9 years later, reported their current
      salary, SWB, and job satisfaction. As predicted, individuals high in extrinsic
      orientation experienced higher SWB and job satisfaction to the degree that they
      earned more money, whereas those high in intrinsic orientation were lower on SWB
      at higher income levels. These findings are discussed in terms of the Values as
      Moderators Perspective of SWB and Cognitive Evaluation Theory.

PMID- 15189630
TI  - A four-component model of procedural justice: defining the meaning of a "fair"
      process.
AB  - Two studies test the prediction of the four-component model of procedural justice
      that people evaluate the fairness of group procedures using four distinct types
      of judgment. The model hypothesizes that people are influenced by two aspects of
      the formal procedures of the group: those aspects that relate to decision making
      and those that relate to the quality of treatment that group members are entitled
      to receive under the rules. In addition, people are hypothesized to be separately
      influenced by two aspects of the authorities with whom they personally deal: the
      quality of decision making by those authorities and the quality of the treatment
      that they receive from them. The results of two studies support the hypothesis of
      the four-component model by finding that all four of the procedural judgments
      identified by the model contribute to overall evaluations of the fairness of
      group procedures.

PMID- 15189631
TI  - Measuring individual differences in the tendency to forgive: construct validity
      and links with depression.
AB  - Four studies examine the construct validity of the Tendency to Forgive Scale
      (TTF), a brief measure of dispositional forgiveness. Study 1 showed that romantic
      partners' ratings of targets converged with targets' self-ratings, and Study 2
      demonstrated that higher scores on the TTF were associated with lower offense
      accessibility. Study 3 examined the TTF's relation to self-reported depression
      symptoms, both independent of and interacting with attitudes toward forgiveness
      and dispositional vengeance. Lower TTF scores were associated with higher degrees
      of depression, especially for individuals with positive attitudes toward
      forgiveness or those low in dispositional vengeance, although neither of these
      latter variables displayed significant zero-order relations with depression.
      Finally, Study 4 examined relations between the TTF, dispositional empathy,
      another recent measure of dispositional forgiveness, and the dimensions of the
      Big Five, providing both convergent and discriminant validity evidence for the
      TTF.

PMID- 15189632
TI  - It's not my fault: when and why attributions to prejudice protect self-esteem.
AB  - This study tested the hypothesis that awareness of the possibility of being a
      target of discrimination can provide individuals with a means of self-esteem
      protection when they are faced with negative outcomes. Men and women contemplated
      being rejected from a course due to sexism, personal deservingness, or an
      exclusively external cause. Regardless of gender, participants in the sexism
      condition blamed themselves less, attributed the rejection less to internal
      causes, and anticipated feeling less depressed than those in the personal
      deservingness condition. Furthermore, the more participants discounted the
      rejection--blamed it more on discrimination than themselves--the less depressed
      emotions they anticipated feeling. Discounting did not buffer participants from
      feeling hostility or anxiety. These findings advance our understanding of when
      and why attributions to prejudice protect emotional well-being.

PMID- 15189633
TI  - Stereotype threat and arousal: effects on women's math performance.
AB  - Theories of arousal suggest that arousal should decrease performance on difficult
      tasks and increase performance on easy tasks. An experiment tested the hypothesis
      that the effects of stereotype threat on performance are due to heightened
      arousal. The authors hypothesized that telling participants that a math test they
      are about to take is known to have gender differences would cause stereotype
      threat in women but not in men. In the experiment, each participant took two
      tests--a difficult math test and an easy math test. Compared to women in a "no
      differences" condition, women in the "gender differences" condition scored better
      on the easy math test and worse on the difficult math test. Men's performance was
      unaffected by the manipulation. These data are consistent with an arousal-based
      explanation of stereotype threat effects. Data were inconsistent with expectancy,
      evaluation apprehension, and persistence explanations of the stereotype threat
      phenomenon.

PMID- 15189634
TI  - The antecedents and implications of interracial anxiety.
AB  - Drawing on previous theorizing from both the prejudice and social anxiety
      literatures, a model of the antecedents and implications of intergroup anxiety is
      offered. It is argued that a lack of positive previous experiences with outgroup
      members creates negative expectancies about interracial interactions, which
      result in intergroup anxiety. This anxiety is posited to result in heightened
      hostility toward outgroup members and a desire to avoid interacting with outgroup
      members. Study 1 examined White participants' responses to interacting with Black
      people using a range of self-report measures; the associations between these
      responses supported the relationships outlined in the model. Study 2 explored
      White participants' responses to an anticipated interaction with a Black person
      or a White person. The findings revealed that high levels of anxiety about an
      interaction with a Black person, but not a White person, were associated with a
      lower likelihood of returning for the interaction.

PMID- 15189635
TI  - A review of clinical characteristics and residential treatments for adolescent
      delinquents with mental health disorders: a promising residential program.
AB  - As treatment systems throughout the country have deinstitutionalized, under-use
      of community-based residential treatment systems has escalated. Reliance on
      juvenile justice systems for the care of the mentally ill adolescent has
      increased. There is considerable overlap between the mentally ill adolescent
      population within the community-based mental health systems and the offender
      population within the juvenile justice systems. With the inconsistent
      epidemiological prevalence and longitudinal treatment data, mental health
      treatment providers have also begun addressing this problem. This is currently
      being done by designing and implementing community-based residential mental
      health programs for delinquent adolescents of the juvenile justice system as well
      as nondelinquent adolescents within the mental health treatment systems.
      Providers have relied on both systems' literature in establishing theoretical
      treatment programs. The authors review critical treatment components currently
      used by both the treatment and juvenile justice systems. A promising integrative
      program is described.

PMID- 15189636
TI  - The effects and treatment of community violence in children and adolescents: what
      should be done?
AB  - The amount of community violence that children and adolescents are exposed to is
      unsettling. Intensifying the issue, the amount of community violence that is wit
      nessed or experienced directly by children and adolescents is increasing with
      time. It has been documented that children and adolescents who are exposed to
      community violence display a wide array of psychological symptoms, ranging from
      depression and anxiety to antisocial and suicidal behaviors. Many variables have
      been studied in an attempt to determine correlates, moderators, and mediators of
      exposure to community violence. Furthermore, many intervention strategies have
      been developed from the discovery of relationships among these variables. Despite
      these efforts, many children continue to suffer from the negative effects of
      exposure to community violence. The purpose of this article is to encourage
      mental health professionals to mobilize their efforts to help children,
      adolescents, and their families cope with the effects of community violence.

PMID- 15189637
TI  - Predictors of change among male batterers: application of theories and review of
      empirical findings.
AB  - The efficacy of batterer treatment is a concern of clinicians, researchers, and
      policy makers. Most past research on batterer treatment has defined success as a
      cessation of men's physical abuse against their intimate partner. Although
      clearly an important outcome, focus on assault leaves many questions unanswered
      about the broader impact of batterer treatment and the processes through which
      successful change may be promoted. With the aim of encouraging complexity in the
      consideration of change among batterers, the current article reviews studies that
      go beyond dichotomous outcomes. First, evidence for the success of batterer
      treatment is considered from multiple perspectives: men's, women's, and the
      intervention system. Next, an in-depth review of research on factors relating to
      change in abusive men is completed using feminist, family systems, individual,
      and typology theories as an organizing framework. Numerous recommendations are
      made for integrating theories of change with investigations of treatment success
      in future work.

PMID- 15189638
TI  - A systematic research synthesis of EMDR studies: implementation of the platinum
      standard.
AB  - Eye movement desensitization and reprocessing (EMDR) is a psychological treatment
      method used primarily for people who have experienced trauma. This article
      provides a systematic research synthesis of EMDR studies targeting trauma
      symptomatology published between 1997 and 2003. This synthesis builds on the
      Revised Gold Standard (RGS) as a guide to evaluate empirical EMDR studies.
      Modifications and additions to the RGS criteria are proposed. The resulting
      standard is referred to as the Platinum Standard (PS). Sixteen EMDR studies are
      reviewed and critiqued using the PS criteria. None of the studies reviewed met
      full PS criteria. The mean score for the studies on the PS was 8.28, with 9 of
      the studies exceeding the mean. The review calls for researchers to employ more
      rigorous research designs for EMDR effectiveness using PS criteria. Implications
      for practice, policy, and research are discussed.

PMID- 15189639
TI  - Native American nurse leadership.
AB  - PURPOSE: To identify which characteristics, wisdom, and skills are essential in
      becoming an effective Native American nurse leader. This will lead to the
      development of a curriculum suitable for Native American nurses. DESIGN: A
      qualitative, descriptive design was used for this study. Focus groups were
      conducted in Polson, Montana. A total of 67 Native and non-Native nurses
      participated. Sixty-seven percent of them were members of Indian tribes. Data
      were content analyzed using Spradley's ethnographic methodology. FINDINGS: Three
      domains of analysis emerged: point of reference for the leader (individual,
      family, community), what a leader is (self-actualized, wise, experienced,
      political, bicultural, recognized, quiet presence, humble, spiritual, and
      visionary), and what a leader does (mentors, role models, communicates, listens,
      demonstrates values, mobilizes, and inspires). DISCUSSION: Native nurse leaders
      lead differently. Thus, a leadership curriculum suitable for Native nurses may
      lead to increased work productivity and therefore improved patient care for
      Native Americans.

PMID- 15189640
TI  - Voicing the strengths of Pacific Island parent caregivers of children who are
      medically fragile.
AB  - Research is deficient regarding the strengths of Pacific Island parents of
      children who are medically fragile. The purpose of this qualitative ethnographic
      study was to explore the strengths of Pacific Island parents of these children.
      Audiotaped interviews were analyzed using Text Smart and peer review. The core
      theme reflecting strength was positive energy. Participants believed that parents
      needed to have the ability to handle emotional feelings, solve problems, connect
      with their spirituality, find meaning, take care of themselves, use family
      support, use community support, use a positive attitude, be resourceful, meet a
      challenge, interact with nature, and focus on the present. Themes were affirmed
      by the literature with the exception of interacting with nature, which may be
      indigenous to the population's cultural orientation.

PMID- 15189641
TI  - School-based asthma: a study in an African American elementary school.
AB  - ISSUES AND PURPOSE: Chronic illnesses, such as asthma experienced by children,
      are difficult for families and school professionals to manage. This study
      explored beliefs about asthma and asthma management among schoolchildren,
      parents, and teachers in an African American school. DESIGN AND METHODS: Focus
      groups were conducted with schoolchildren, parents, and teachers. Data were
      analyzed by content analysis; segments of information were categorized into
      groups that were later abstracted into themes illustrating beliefs and behaviors
      about asthma. RESULTS: The children reported fear of not being able to breathe
      and the limitations of living with asthma. The teachers were concerned that they
      did not have a sufficient understanding of asthma to manage children's asthma
      during the school day. Parents described complex lifestyles and the challenges of
      asthma management.

PMID- 15189642
TI  - A hypothesized model of Korean women's responses to abuse.
AB  - Many abused married Korean women have a strong desire to leave their abusive
      husbands but remain in the abusive situations because of the strong influence of
      their sociocultural context. The article discusses Korean women's responses to
      spousal abuse in the context of patriarchal, cultural, and social exchange
      theory. Age, education, and income as component elements share common effects on
      the emergent variable, sociostructural power. Gender role attitudes, traditional
      family ideology, individualism/collectivism, marital satisfaction, and marital
      conflict predict psychological-relational power as a latent variable.
      Sociostructural, patriarchal, cultural, and social exchange theories are
      reconceptualized to generate the model of Korean women's responses to abuse.

PMID- 15189643
TI  - Contrasting experiences with child health care services by mothers and
      professional caregivers in transitional housing.
AB  - The study examined experiences of mothers and health care providers with
      preventive child health care services using qualitative methods at a primary care
      clinic located in transitional housing for homeless families in an urban
      community with predominantly Black American residents. Participants were 20
      mothers and 4 health care professionals. Three major domains emerged: (a). the
      infrastructure of the clinic and health care delivery poses barriers to mothers'
      access and use of services for their children; (b). specialized, biomedical
      driven care produces fragmented care delivery not responsive to the comprehensive
      nature of problems of mothers and their children; and (c). organizational
      strategies for improving access and use of health care services are directed by
      health care providers' value orientations. Findings support existence of
      infrastructural characteristics of the health care system that maintains
      differential value orientations and power structure, and care delivery processes
      that are non responsive to racially diverse and poor mothers.

PMID- 15189645
TI  - Development of a multilingual resource manual.
AB  - Providing culturally competent health care is a growing need as the population of
      culturally diverse women continues to rise. Compilation of a multilingual
      resource manual about maternal-child and women's health topics that can be used
      by health educators to provide care to non-English-speaking and limited English
      proficiency (LEP) clients was achieved to address this need. In this article,
      significant details of this process are described allowing the reader to produce
      a similar version of the manual.

PMID- 15189644
TI  - Outcomes of Swedish nursing students' field experiences in a hospital in
      Tanzania.
AB  - This study describes the experiences of a group of nursing students from Sweden
      in a hospital in Tanzania. Students were interviewed on their return after the
      trip. Although students experienced considerable upheaval and frustration working
      in a different context, they learned valuable lessons as to how nursing can be
      conducted in conditions entirely different from those familiar to them. They
      attempted to understand the value and behavioral divergences they encountered,
      yet values of their home culture remained their frame of reference. This project
      reflected the importance of working through students' experience if knowledge and
      understanding of self and others are to be enhanced or developed.

PMID- 15189646
TI  - Searching electronically for information on transcultural nursing and health
      subjects.
AB  - With the proliferation of electronic resources available to search for subjects
      related to transcultural nursing and health, nurses must keep abreast of computer
      based tools that enable them to quickly and efficiently obtain information on a
      variety of topics. This article provides suggestions for narrowing and focusing a
      search on transcultural nursing and related subjects using important research
      databases such as Medline and Cumulative Index to Nursing and Allied Health
      Literature (CINAHL). Information about additional useful databases such as
      Educational Resources Information Center (ERIC) and Psychological Abstracts
      (PsycINFO) is also provided. In the article, selected examples of Internet sites
      of interest in transcultural nursing and health are identified and described in
      brief annotations. Web sites for U.S. government agencies, organizations, and
      commercial groups that concern transcultural nursing and health care are cited.
      Global transcultural health and nursing Internet resources also are included.

PMID- 15189647
TI  - President's message: revisiting cultural competence.

PMID- 15189653
TI  - Vena caval filters: a review for intensive care specialists.
AB  - Venous thromboembolism (VTE) is a common complication among patients in the
      intensive care unit. While anticoagulation remains standard therapy, vena caval
      filters are an important alternative when anticoagulation is contraindicated. To
      determine the safety and efficacy of vena caval filters in the treatment of VTE,
      a comprehensive review of the English-language medical literature was performed.
      Except for one randomized controlled trial, the literature supporting the use of
      vena caval filters consists almost exclusively of case series, which in many
      instances are limited by incomplete and short follow-up. While case series
      suggest that filters function effectively in the prevention of pulmonary embolism
      (2%-4% symptomatic pulmonary embolism [PE], fatal PE < 2%), recent higher quality
      studies indicate that filters may not provide significant additional protection
      to that provided by anticoagulation alone. Furthermore, filters are associated
      with a 2- fold increase in the incidence of recurrent DVT. Until randomized
      comparative studies are available, the safety and efficacy of all the available
      devices should be considered to be roughly equivalent. Since filters do not
      inhibit continued clot formation, all filter patients should receive
      anticoagulation for durations appropriate for their thrombotic disorder. Although
      extended anticoagulation may prevent thrombotic complications associated with
      filter placement, this strategy has yet to be experimentally tested. While many
      additional indications for vena caval filter use have been proposed (VTE in
      cancer patients, PE prophylaxis in trauma patients, etc), well-designed clinical
      trials demonstrating their efficacy in these situations are lacking. Further
      development of temporary/retrievable filters, which offer the potential to avoid
      the long-term complications of permanent filters, should be a research priority.
      Until additional data are available, vena caval filters should generally be
      restricted to patients with VTE who cannot receive anticoagulation.

PMID- 15189654
TI  - Influenza in the intensive care unit.
AB  - Influenza remains an important epidemic viral infection. Thousands of deaths
      occur and billions of dollars are spent each year with influenza-related
      illnesses. Morbidity and mortality are largely attributed to respiratory
      complications that may require intensive care unit (ICU) admission. Medical and
      neonatal ICUs, transplant units, chronic-care wards, and nursing homes are at
      increased risk for nosocomial outbreaks of influenza, which are characterized by
      abrupt onset and rapid spread. In this article, the authors review the current
      concepts, recent advances, and management strategies in influenza-associated
      pneumonia. Pertinent issues to the critical care practitioner are discussed in
      detail.

PMID- 15189655
TI  - Hemodynamic consequences of heart-lung interactions.
AB  - The management of critically ill patients requires a fundamental understanding of
      cardiopulmonary interactions associated with mechanical ventilation. The
      hemodynamic changes due to ventilation are a result of changes in lung volume and
      intrathoracic pressure (ITP) and can occur during spontaneous or positive
      pressure ventilation despite constant tidal volumes. Pulmonary vascular
      resistance (PVR) and mechanical heart-lung interactions play prominent roles in
      determining the hemodynamic response to mechanical ventilation. Lung inflation
      alters PVR and right ventricular wall tension and, at high lung volume,
      mechanically limits cardiac volumes. The authors will consider the mechanisms of
      the effects of ITP on the pulmonary arterial and venous branches. These effects
      will aid in understanding the complex interactions between ventilation and right
      and left ventricular pressures and volumes, as well as the influence of lung
      inflation pressure on ventricular interdependence.

PMID- 15189656
TI  - The effect of tube thoracostomy on oxygenation in ICU patients.
AB  - Previous research found that in noncritically ill patients, thoracocentesis has
      an unpredictable effect on oxygenation, possibly due to re-expansion pulmonary
      edema and systemic hypotension. The authors performed a retrospective analysis to
      study the effect of tube thoracostomy on oxygenation in ICU patients, and the
      complications associated with it. The authors reviewed the charts of 58 ICU
      patients in whom 74 procedures were performed. Demographic data, APACHE II score,
      and indication for thoracocentesis were retrieved from the patient's file. The
      P(a)O(2)/FiO(2) ratio was calculated before, 12, 24, and 48 hours after tube
      thoracostomy. P(a)O(2)/FiO(2) ratios at the mentioned time intervals were
      compared using 1-way analysis of variances (ANOVA) with repeated measures.
      Logistic regression analysis was used to identify factors associated with a good
      response to treatment. Age of the patients was 53 +/- 19.0 years (range, 17-88),
      APACHE II score was 21 +/- 8.3 (range, 6-38), and median length of stay was 13.5
      days (interquartile range, 7-25). The volume drained during the first 24 hours
      was 1077 +/- 667 ml. P(a)O(2)/FiO(2) ratio was 185 +/- 79.3 before chest
      drainage, 197 +/- 79.1 at 12 hours, 217 +/- 88.9 at 24 hours, and 233 +/- 99.8 at
      48 hours. In only 54% of the procedures, a response to therapy was present.
      Multivariate analysis identified a P(a)O(2)/FiO(2) below 180 to be independently
      associated with improvement in oxygenation. At 24 and 48 hours, the
      P(a)O(2)/FiO(2) ratio was significantly higher than before drainage (P <.001).
      There were 13 complications in 11 procedures (14.9%). The authors' results
      suggest that tube thoracostomy can be used as an adjunct in the treatment of
      selected patients with hypoxemic respiratory failure in the ICU. A low
      P(a)O(2)/FiO(2) seems to be a good predictor of response to therapy. However, the
      complication rate is considerable, especially in patients with a prolonged ICU
      stay.

PMID- 15189657
TI  - Vena cava filters: let's not be "blinded by science".

PMID- 15189662
TI  - Hyponatremia in critically ill patients.
AB  - Disorders of sodium and water metabolism are frequently encountered in
      hospitalized patients. Hyponatremia in critically ill patients can cause
      significant morbidity and mortality. Inappropriate treatment of hyponatremia can
      add to the problem. The diagnosis and management of salt and water abnormalities
      in critically ill patients is often challenging. The increasing knowledge about
      aquaporins and the role of vasopressin in water metabolism has enhanced our
      understanding of these disorders. The authors have outlined the general approach
      to the diagnosis and management of hyponatremia. A systematic approach by
      clinicians, using a detailed history, physical examination, and relevant
      diagnostic tests, will assist in efficient management of salt and water problems.

PMID- 15189663
TI  - Pneumothorax in patients with acute respiratory distress syndrome:
      pathophysiology, detection, and treatment.
AB  - Pneumothorax is a frequent and potentially fatal complication of mechanical
      ventilation in patients with acute respiratory distress syndrome (ARDS). Prompt
      recognition and treatment of pneumothoraces is necessary to minimize morbidity
      and mortality. The radiologic and clinical signs of pneumothoraces in ARDS
      patients may have unusual and subtle features. Furthermore, small pneumothoraces
      in these patients can cause severe hemodynamic or pulmonary compromise. Sparse
      clinical literature exists on when or how to treat pneumothoraces once they
      develop in patients with ARDS. In this article, the authors review the
      pathogenesis, radiologic signs, clinical significance, and treatment of
      pneumothoraces in ARDS patients. Treatment options include traditional tube
      thoracostomy, open thoracotomy, and image-guided percutaneous catheters.

PMID- 15189664
TI  - The utility of open lung biopsy in patients with diffuse pulmonary infiltrates as
      related to respiratory distress, its impact on decision making by urgent
      intervention, and the diagnostic accuracy based on the biopsy location.
AB  - Patients with diffuse pulmonary infiltrates (DPI), especially those who present
      with respiratory distress (RD), may benefit from early open lung biopsy (OLB) to
      guide management. Benefits of urgent OLB would be expected by saving the time to
      reach accurate specific diagnoses. The objectives of this study were (1) to
      evaluate the impact of OLB between patients presenting with and without RD, (2)
      to focus on the impact of an urgent OLB as compared to an elective OLB, and (3)
      to compare the different yields of specific diagnoses in the middle lobe or
      lingula as compared to the other lobes. Thirty-four patients (17 patients
      presented with RD and 17 patients did not) with an average age of 43 years who
      presented with DPI were selected to undergo an OLB. An urgent OLB was performed
      in 11 unselected patients. Twelve specimens from the middle lobe or lingula were
      compared to 25 specimens from the other lobes. The impact of the OLB results on
      decision making did not differ significantly between patients with and without
      RD. Patients with RD suffered a higher in-hospital mortality rate, OLB-related
      complications, and longer mechanical ventilation requirements than the patients
      without RD. The impact on decision making and complications between urgent OLB
      and elective OLB was comparable. The diagnostic yield from biopsy sites in the
      middle lobe or lingula resembled those specimens from the other lobes. The
      authors conclude that OLB may play a role in decision making for patients with
      DPI. However, OLB makes no difference in decision making between patients with
      and without RD. Patients with RD undergoing OLB procedures may suffer a poorer
      outcome. Urgent OLB may not benefit patients with DPI in decision making. The
      biopsy site does not appear to affect the accuracy of the diagnostic yield from
      an OLB procedure.

PMID- 15189665
TI  - The role of the alpha2-adrenoceptor agonist dexmedetomidine in postsurgical
      sedation in the intensive care unit.
AB  - Dexmedetomidine was evaluated for sedation of 401 post-surgical patients in this
      double-blind, randomized, placebo-controlled, multicenter trial. Dexmedetomidine
      or saline was started on arrival in the intensive care unit (ICU) (1.0 mcg/kg for
      10 minutes), then titrated at 0.2 to 0.7 mcg/kg/h to effect. Patients could be
      given propofol if necessary. Morphine was administered for pain. Sixty percent of
      the dexmedetomidine patients required no other sedative to maintain an RSS > or =
      3; 21% required < 50 mg propofol. In contrast, 76% of the control group received
      propofol; 59% required > or = 50 mg. Dexmedetomidine patients required
      significantly less morphine for pain relief (P <.001). Continuously given
      throughout the ICU stay, dexmedetomidine had no effect on respiratory rate,
      oxygen saturation, duration of weaning, or times to extubation. Nurses judged the
      dexmedetomidine patients were easier to manage. Later, fewer dexmedetomidine
      patients remembered pain or discomfort. The majority of dexmedetomidine patients
      maintained blood pressures within normal range, without rebound. Hypertension,
      atelectasis, and rigors occurred more frequently in the control group, while
      hypotension and bradycardia occurred more frequently in the dexmedetomidine
      group. Preoperative cardiovascular conditions were not risk factors for
      dexmedetomidine patients.

PMID- 15189666
TI  - Accidental oral poisoning caused by RDX (cyclonite): a report of 5 cases.
AB  - The explosive RDX (hexogen, cyclonite) is usually used for the production of C-4
      explosive. The rare occurrence of accidental and intentional RDX intoxications
      has been reported during manufacturing process or in wartime. In this article,
      the authors report 5 cases of accidental oral RDX poisoning. On admission,
      observed signs and symptoms included repetitive generalized tonic-clonic
      convulsions, postictal coma, lethargy, confusion, hyperreflexia, postictal
      amnesia, nausea, vomiting, abdominal tenderness, sinusal tachycardia, dysrhythmia
      with frequent ventricular premature beats, generalized muscle spasms, and
      myoclonus. Leukocytosis, mild anemia, methemoglobinemia, elevated levels of blood
      glucose, serum aspartate transaminase, alanine transaminase, lactic
      dehydrogenase, creatine phosphokinase, amilase, hypokalemia, metabolic acidosis,
      proteinuria, glucosuria, and myoglobinuria were also noted. Plasma RDX
      concentrations were 268 to 969 ng/mL at 3 hours of ingestion. For management,
      supportive and symptomatic measures were taken. Whole-bowel irrigation might have
      been an effective therapeutic procedure due to probable slow gastrointestinal
      absorption of RDX. Three patients who developed severe metabolic acidosis
      underwent urgent hemodialysis. All patients were discharged 7 to 21 days after
      admission without any sequelae. Plasma RDX levels were strongly correlated with
      the clinical and laboratory manifestations. The available toxicological data on
      this rare accidental poisoning are reviewed in light of the literature.

PMID- 15189667
TI  - Pericardial infusion of tissue plasminogen activator in fibropurulent
      pericarditis.
AB  - A 61-year-old man developed a loculated fibropurulent pericarditis, a rare
      complication of bacteremia. This occurred as a complication of a Staphylococcal
      aureus bacteremia from a head and neck abscess following self-extraction of a
      tooth. Despite surgical intervention and placement of 2 pericardial drains, a
      refractory, inadequately drained infected pericardial effusion persisted.
      Although there is limited experience with thrombolytic therapy to dissolve a
      fibrin clot in the pericardium, break down loculated adhesions, and facilitate
      free drainage of infected material, lysis is well described in the management of
      exudative pleural effusions. After infusion of 30 mg of tissue plasminogen
      activator in 100 cc normal saline through the pericardial drain of the patient, a
      large amount of infected serosanginous material subsequently drained during the
      next 2 days. The patient became afebrile and culture negative, remained
      hemodynamically stable, and had resolution of his pericarditis and pericardial
      effusion on electrocardiogram and echocardiogram, respectively.

PMID- 15189671
TI  - Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug
      drug interactions.
AB  - Recent surveys suggest that the abuse of drugs, often in combination, is
      pervasive throughout society. Adverse consequences of drug abuse tend to be
      attributed to the single drug "most likely" to be responsible. This is frequently
      seen in fatality cases, particularly those involving opioids. However, it is
      difficult to determine the specific cause of death when multiple drugs are
      involved. Although enhanced toxicity of alcohol and other centrally acting drugs
      with opioids has been well established in animal studies, there is a paucity of
      data in well-controlled human studies. We evaluated 1014 fatality cases involving
      oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug
      drug interactions. We previously reported on these cases, and we classified them
      by a standardized method into groups that distinguished cases unrelated to drug
      abuse from those related to drug abuse, cases that involved only OXC from cases
      involving multiple drugs, drug-induced fatalities from drug-related fatalities,
      and cases in which the specific drug product OxyContin (oxycodone HCl controlled
      release) tablets were identified from cases where OxyContin was not identified.
      Our working hypothesis was that OXC in combination with other centrally acting
      drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood
      concentrations of OXC in multiple drug-induced deaths compared to single (OXC
      only) drug-induced deaths. Assessment of blood levels determined by specific
      assay methodology (primarily gas chromatography-mass spectrometry) in these cases
      provided the following mean postmortem concentrations of OXC: multiple drug
      induced deaths, OxyContin identified, 0.93 mg/mL (N = 167); multiple drug-induced
      deaths, OxyContin not identified, 0.73 mg/mL (N = 579); single (OXC) drug-induced
      deaths, OxyContin identified, 1.55 mg/mL (N = 12); and single (OXC) drug-induced
      deaths, OxyContin not identified, 1.70 mg/mL (N = 15). Overall, mean OXC
      concentration trends were as follows: single (OXC), drug-induced, drug abuse
      deaths > multiple, drug-induced drug abuse deaths > drug-related drug abuse
      deaths approximately deaths unrelated to drug abuse; and deaths in which
      OxyContin was identified approximately deaths in which OxyContin was not
      identified, whether the deaths involved oxycodone alone or multiple drugs. Drug
      abuse patterns in the multiple drug-induced cases were complex. Over 135 drugs
      that were considered to be plausibly contributory to enhanced toxicity were
      identified in body fluids and tissues. Evaluation of mean OXC blood
      concentrations in cases that contained one, two, three, four, five, and six or
      more contributory drugs in combination demonstrated consistently lower mean OXC
      concentrations than those cases in which OXC was the only drug identified. A
      smaller number of cases were evaluated in the multiple drug-induced groups in
      which OXC was paired with a single other contributory drug. The overall mean OXC
      concentration for these cases was 0.71 mg/mL (N = 90) as compared to 1.64 mg/mL
      (N = 27) for the cases in the single drug-induced groups. The consistent finding
      of lower mean OXC blood levels associated with multiple drug-induced fatalities
      supports the stated hypothesis that OXC in combination with other centrally
      active drugs is more toxic than when OXC was the only drug involved. It was
      concluded that in cases of multiple drug fatalities, cause of death (COD) should
      not be attributed to any single drug. Rather, the unique combination of drugs,
      the pattern of drug use/abuse, and individual factors, such as tolerance to the
      respiratory depressant effects of opioids, must be taken into account in arriving
      at a valid COD statement.

PMID- 15189672
TI  - Detection and confirmation of ractopamine and its metabolites in horse urine
      after Paylean administration.
AB  - We have investigated the detection, confirmation, and metabolism of the beta
      adrenergic agonist ractopamine administered as Paylean to the horse. A Testing
      Components Corporation enzyme-linked imunosorbent assay (ELISA) kit for
      ractopamine displayed linear response between 1.0 and 100 ng/mL with an I-50 of
      10 ng/mL and an effective screening limit of detection of 50 ng/mL. The kit was
      readily able to detect ractopamine equivalents in unhydrolyzed urine up to 24 h
      following a 300-mg oral dose. Gas chromatography-mass spectrometry (GC-MS)
      confirmation comprised glucuronidase treatment, solid-phase extraction, and
      trimethylsilyl derivatization, with selected-ion monitoring of ractopamine
      tris(trimethylsilane) (TMS) m/z 267, 250, 179, and 502 ions. Quantitation was
      elaborated in comparison to a 445 Mw isoxsuprine-bis(TMS) internal standard
      monitored simultaneously. The instrumental limit of detection, defined as that
      number of ng on column for which signal-to-noise ratios for one or more
      diagnostic ions fell below a value of three, was 0.1 ng, corresponding to roughly
      5 ng/mL in matrix. Based on the quantitation ions for ractopamine standards
      extracted from urine, standard curves showed a linear response for ractopamine
      concentrations between 10 and 100 ng/mL with a correlation coefficient r > 0.99,
      whereas standards in the concentration range of 10-1000 ng/mL were fit to a
      second-order regression curve with r > 0.99. The lower limit of detection for
      ractopamine in urine, defined as the lowest concentration at which the identity
      of ractopamine could be confirmed by comparison of diagnostic MS ion ratios,
      ranged between 25 and 50 ng/mL. Urine concentration of parent ractopamine 24 h
      post-dose was measured at 360 ng/mL by GC-MS after oral administration of 300 mg.
      Urinary metabolites were identified by electrospray ionization (+) tandem
      quadrupole mass spectrometry and were shown to include glucuronide, methyl, and
      mixed methyl-glucuronide conjugates. We also considered the possibility that an
      unusual conjugate added 113 amu to give an observed m/z 415 [M+H] species or two
      times 113 amu to give an m/z 528 [M+H] species with a daughter ion mass spectrum
      related to the previous one. Sulfate and mixed methyl-sulfate conjugates were
      revealed following glucuronidase treatment, suggesting that sulfation occurs in
      combination with glucuronidation. We noted a paired chromatographic peak
      phenomenon of apparent ractopamine metabolites appearing as doublets of
      equivalent intensity with nearly identical mass spectra on GC-MS and concluded
      that this phenomenon is consistent with Paylean being a mixture of RR, RS, SR,
      and SS diastereomers of ractopamine. The results suggest that ELISA-based
      screening followed by glucuronide hydrolysis, parent drug recovery, and TMS
      derivatization provide an effective pathway for detection and GC-MS confirmation
      of ractopamine in equine urine.

PMID- 15189673
TI  - Cypermethrin residues determination in the milk of a lactating dairy cow by gas
      chromatography-ion trap mass spectrometry.
AB  - The aim of this work was to detect and quantitate residues of the pyrethroid
      insecticide cypermethrin in the milk of a lactating dairy cow. The efficiency of
      the method was settled through recovery experiments in which certain amounts of
      the pyrethroid cypermethrin were spiked up to milk. For this purpose, the matrix
      solid-phase dispersion method was applied followed by clean-up with silica-gel
      column. The extracts obtained were analyzed by gas chromatography-ion trap mass
      spectrometry. With the aid of the selected ion storage technique, it was feasible
      to select specific ions from the analyte of interest, which could be separated
      from the organic matrix. After the establishment of optimum conditions for the
      detection of pyrethroid residues of cypermethrin, samples of milk were collected
      from a cow submitted to a veterinary treatment for elimination of parasites using
      an insecticide with 50 g/L of active ingredient in its formula. The data obtained
      showed milk contamination with a maximum concentration of 0.168 mg/kg 24 h after
      insecticide treatment. Considering the maximum residual limit for cypermethrin in
      milk of 0.010 mg/kg, samples collected 15 and 24 h after treatment showed
      concentrations about 16 times above this value, and samples collected 11 days
      after treatment showed concentrations about 7 times above this value. Seventeen
      days after treatment, cypermethrin was not detected in the milk.

PMID- 15189674
TI  - Rapid and sensitive quantitative analysis of alkyl phosphates in urine after
      organophosphate poisoning.
AB  - Organophosphate compounds are widely used as pesticides. After ingestion by
      humans, organophosphates decompose into alkyl phosphates. Decomposition continues
      postmortem. We developed a rapid (< 3 h), quantitative, and sensitive analysis of
      the human organosphosphate metabolites O,O-dimethylphosphate (DMP), O,O
      diethylphosphate (DEP), O,O-dimethylthiophosphate (DMTP), O,O
      diethylthiophosphate (DETP), O,O-dimethyldithiophosphate (DMDTP), and O,O
      diethyldithiophosphate (DEDTP). Urine is dried under azeotropic conditions with
      isopropanol and nitrogen. All metabolites are converted into their corresponding
      benzyl esters reacting with benzyl bromide and diazotoluene. The protocol
      prevents the isomerization of DMTP and DETP occurring when diazo compounds are
      used exclusively. The benzyl ester derivatives are purified on solid-phase
      extraction silica columns. The quantitative analysis is performed by gas
      chromatography-mass spectrometry. All metabolites can be identified by the parent
      molecular ions. Urine samples from eight cases of fatal suicidal poisoning
      dialkyl phosphates were quantitated. The limits of detection ranged from 3 to 6
      ng/mL. Hence, this protocol is sufficiently sensitive to detect and quantitate
      organophosphate metabolites beyond cases of fatal poisoning, in the clinical
      setting, and even following average environmental exposure.

PMID- 15189675
TI  - Nail and bone surface as biomarkers for acute fluoride exposure in rats.
AB  - When acute exposure to fluoride is thought to be the cause of death, confirmation
      often depends on the analysis of some body fluid or tissue. The aim of this study
      was to evaluate the use of nails and the periosteal surface of bone as indicators
      of acute exposure to fluoride. Six groups of rats were given a single oral dose
      of fluoride (50 mg/kg body weight), while the control group was given deionized
      water. The rats were killed at 2, 4, 8, 16, 24, and 48 h after fluoride
      administration. Plasma and nails (the proximal halves) were collected and
      analyzed for fluoride with an ion-specific electrode after hexamethyldisiloxane
      facilitated diffusion. A circular area of the femur (4.52 mm(2)) was etched with
      0.5M HCl for 15 s, and, after the addition of a buffer, the solution was analyzed
      with an ion-specific electrode. Peak plasma concentration occurred at 2 h,
      followed by progressively declining concentrations. Peak nail fluoride
      concentrations occurred at 8 h. The mean nail concentrations at 8, 16, and 24 h
      were significantly higher than that of the control group. Bone surface
      concentrations were significantly higher than that of the control group at 4 h
      and thereafter. Thus, the proximal portion of nails and bone surface are suitable
      biomarkers for acute fluoride exposure in rats.

PMID- 15189676
TI  - Cocaine levels in sweat collection patches vary by location of patch placement
      and decline over time.
AB  - Sweat collection patches are used for drug abuse monitoring. We investigated the
      effect of sweat patch location (back and shoulder) on cocaine levels after
      controlled intravenous cocaine exposure (210 mg/70 kg) in 12 subjects (Experiment
      1). Gas chromatographic-mass spectrometric analyses show cocaine and metabolites
      levels in Pharmchek trade mark patches were eightfold higher on the back than
      those on the shoulders. To assess the mechanisms for possible loss of cocaine
      from patches during wear, 48 sweat patches with a small amount of cocaine-d(5)
      (100 ng as base/patch) were placed on the backs of eight cocaine-naive volunteers
      for up to 72 h (Experiment 2). Drug-free patches were applied over eight of the
      cocaine-d(5) (100 ng) containing patches to measure loss through the patch.
      Cocaine levels in spiked patches declined over time (p = 0.002), with levels at
      48 h postapplication 30% less than control, consistent with possible drug
      reabsorption. Cocaine was detectable (> 2 ng/patch, LOQ) in four of eight
      initially cocaine-free patches placed on top of the cocaine-containing patches,
      indicating transfer through the patch outer membrane. Conversion to
      benzoylecgonine was detectable but at low levels (< 2%). Reabsorption (back
      transfer), degradation or hydrolysis, and loss of cocaine to the environment may
      account for substantial loss of cocaine from skin sweat collection patches during
      patch wear.

PMID- 15189677
TI  - Postmortem distribution of heroin metabolites in femoral blood, liver,
      cerebrospinal fluid, and vitreous humor.
AB  - The presence of 6-monoacetylmorphine (6-MAM) is often used to distinguish between
      heroin (diacetylmorphine) and morphine exposures. 6-MAM, however, is rapidly
      metabolized to morphine and may not be present in detectable quantities in blood
      following heroin exposure. Recent studies have shown that 6-MAM may persist in
      cerebrospinal fluid (CSF) and this specimen may be preferable for establishing
      heroin exposure. This study reports postmortem distribution of 6-MAM,
      unconjugated morphine, and codeine in different tissues from 25 deceased
      individuals. In all cases, 6-MAM was detected in vitreous humor, and in CSF in 16
      of the 25 cases (64%). When 6-MAM was detected in blood (13 of 25 cases), the
      level of 6-MAM in vitreous humor and CSF was higher than in blood, with a mean
      concentration ratio of 11.3 (range: 1.7-27) for vitreous humor and 6.6 (range:
      2.6-17.3) for CSF. 6-MAM was not detected in liver in any of the cases examined.
      Free morphine levels were highest in liver, followed by blood, CSF, and vitreous
      humor. The concentration ratios (mean +/- standard deviation) for free morphine
      in vitreous humor, CSF, and liver to that in blood were 0.36 +/- 0.18, 0.64 +/-
      0.27, and 2.99 +/- 2.12, respectively. The liver/blood ratio was consistent with
      previously reported values for morphine in heart and femoral blood. Codeine
      levels following heroin overdose were consistently low relative to the morphine
      concentration. For blood, liver, and CSF, the ratio of codeine to morphine was
      essentially the same (0.06), whereas the vitreous codeine/morphine concentration
      ratio was slightly higher (0.19). These results characterize the distribution of
      heroin metabolites in postmortem tissues. Vitreous humor appears to be a useful
      specimen for determining 6-MAM and establishing the morphine was derived from
      heroin.

PMID- 15189678
TI  - Postmortem distribution of the novel antipsychotic drug quetiapine.
AB  - The objective of this research was to determine the concentrations and
      distribution of the atypical antipsychotic drug, quetiapine, in postmortem
      tissues from eight Medical Examiner cases. Quetiapine was isolated from liquid
      specimens and tissue homogenates by extraction at an alkaline pH into 1
      chlorobutane. The 1-chlorobutane was decanted, and quetiapine, plus the internal
      standard (prochlorperazine), was back-extracted into 0.1N sulfuric acid. The acid
      layer was made basic, and quetiapine, plus the internal standard, was re
      extracted into 1-chlorobutane. Quantitation was by gradient, high-pressure liquid
      chromatography on a C-8 ODS (2.1 x 150 mm, 5 mu) column with acetonitrile/0.1M
      ammonium hydroxide (pH 10) mobile phase and a photodiode array detector set at
      258 nm. The apparent linear range of the assay was from 0.05 to 5.0 microg/mL. At
      known concentrations of 0.1 and 0.5, interday accuracy (n = 5) was 103.8 and
      107.2%, respectively. Interday precision (% cv) at the same concentrations was
      9.8 and 9.0, respectively. In the cases where quetiapine was not considered to
      have contributed to the death, the postmortem concentrations in blood, liver, and
      bile ranged between 0.15 and 2.7 mg/L (n = 6), 1.3 and 9.5 mg/kg (n = 8), and 10
      and 46 mg/L (n = 5), respectively. In the one case involving a quetiapine
      overdose, concentrations in blood (19.8 mg/L), liver (12.6 mg/kg), and bile (161
      mg/L) exceeded the ranges of concentrations determined in specimens from the
      quetiapine-unrelated deaths.

PMID- 15189679
TI  - Redistribution of diltiazem in the early postmortem period.
AB  - We determined tissue distribution of diltiazem after it was used to treat
      hypertension in two cases. The postmortem interval was 16 h in both cases.
      Diltiazem was isolated using liquid-liquid extraction, and it was identified and
      quantitated using gas chromatography-mass spectrometry (GC-MS) and GC,
      respectively. In one case, diltiazem concentrations in the lungs and pulmonary
      vessel blood were 62-82 and 27-30 times higher than right femoral blood,
      respectively. Although blood was not obtained from the left cardiac chambers,
      aortic blood showed a 10-times higher level of diltiazem than right femoral
      venous blood. Diltiazem concentration in blood in the right cardiac chambers was
      3.6 times higher than that in right femoral venous blood. In another case,
      diltiazem concentrations in the lungs were 7.4-7.6 times higher than right
      femoral venous blood. Blood in the pulmonary arteries, pulmonary veins, left
      cardiac chambers, and aorta showed 2.0-3.1 times higher levels of diltiazem than
      right femoral venous blood. Blood in the right cardiac chambers displayed only
      1.3 times higher level of diltiazem than right femoral venous blood. Our results
      strongly suggest that diltiazem accumulated in the lungs and was rapidly
      redistributed into pulmonary venous blood and then into the left cardiac
      chambers.

PMID- 15189680
TI  - Common herbal supplements did not produce false-positive results on urine drug
      screens analyzed by enzyme immunoassay.

PMID- 15189681
TI  - [Ethic issues in pediatric medicine].

PMID- 15189682
TI  - [Emphasize and strengthen causal relationship argumentation in medical research].

PMID- 15189683
TI  - [Approaches to the models of urban child health care services in the new
      century].

PMID- 15189684
TI  - [Misdiagnosis of rhabdomyosarcoma in a child].

PMID- 15189685
TI  - [Geographic and population difference of BMI in Chinese school-age youth].
AB  - OBJECTIVE: By analyzing the group variations of Chinese school-aged youth, to
      gather scientific bases for establishing a screening norm for obesity. METHODS:
      More than 228,250 students aged 6 through 18 years participated in the 2000
      National Surveillance on Students Health and Physical Fitness were enrolled as
      subjects, and were divided into various groups. The P(5), P(50) and P(95) of BMI
      were calculated and compared. RESULTS: The differences of BMI among various
      groups were mainly reflected in the P95 high level of BMI, e.g., the means of BMI
      of boys aged 13 in large cities and in relatively underdeveloped rural areas were
      25.7 and 21.1 with a difference of 4.6, and 22.8 and 20.3 for girls aged 11 with
      a difference of 2.5. Evident north-south differences were also found, especially
      during adolescent growth spurt. The means of BMI of those lived in the north and
      south China were 22.3 and 21.0 for girls aged 11 (difference 1.3), and 25.4 and
      23.5 for boys aged 14 (difference 1.9), respectively. These findings clearly
      showed that much more obese youth exist in the metropolis than in the rural
      areas, and in the north than in the south China. The difference in BMI between
      the developed areas and developing areas could be found in early school ages.
      They were 22.5 and 16.7 for boys aged 7, and 19.8 and 16.7 for girls aged 7,
      respectively, which is a dominant difference among Chinese youth groups. However,
      that the BMI differences in the P(5) level were not as evident as in the high
      level means that malnutrition and under-weight were still popular in all Chinese
      youth groups. CONCLUSION: In making a national norm for screening obesity in
      China, we'd better take high-level growth population as reference, to adapt the
      secular growth changes of Chinese youth. However, the huge urban-rural, north
      south, developed-developing differences shown in this study should also be taken
      into full consideration, in order to make the screen norm be accepted by most of
      the Chinese youth groups.

PMID- 15189686
TI  - [A case with neonatal hyperinsulinemic hypoglycemia].

PMID- 15189687
TI  - [Effects of a comprehensive intervention program on simple obesity of children in
      kindergarten].
AB  - OBJECTIVE: The purpose of the study was to explore a comprehensive management
      program for the obese children in kindergarten. The program should be scientific,
      rational, suitable for kindergarten, and easy to apply. Child care workers,
      parents, and child health care doctors participated in the program to help obese
      children establish a scientific life style through their daily life, to control
      their weight and to maintain their physical and mental health. METHODS: The
      theories of behavior science, nutriology and kinematics were applied to make the
      weight control of obese children in kindergarten quantified and relatively
      standardized. Children were divided into three groups, intervened obese children,
      non-intervened obese children and normal children. Data such as weight, height,
      and body mass index (BMI) were observed to assess the effect of weight control
      and define whether it affects the linear gain of children's height. RESULTS: The
      recovery rate of intervened obese group, non-intervened group was 62.5% and 5.3%,
      respectively. The general effective rate was 91.7% and 15.8%, respectively. The
      weight gain of intervened group was 4.15 kg lower than that of non-intervened
      group. The BMI of intervened group significantly decreased by 2.9 as compared to
      the non-intervened group. The height gain of intervened group was similar to that
      of normal group. Parents and health care workers' realization of children obesity
      and their corresponding actions, the behaviors of obese children at home and in
      kindergarten were changed toward the direction beneficial to weight control.
      CONCLUSION: The implementation of the comprehensive intervention program for
      obesity in children, which involved obese children, child care worker, parents,
      and child care doctors alleviated the obesity level of those obese children
      without affecting their normal height gain. The program was safe and effective.
      Through the comprehensive intervention, the obese children could establish good
      habits during the sensitive period.

PMID- 15189688
TI  - [Clinical analysis of 91 cases with articulation error].
AB  - OBJECTIVE: To study classification of the articulation errors, find the related
      factors which affect the therapy effect, and compare the therapy effect in the
      different patterns of the phonemic errors and build up a clinical model of the
      speech therapy on the basis of more than 4 years speech therapy in the clinic.
      METHOD: After excluding the organic articulation disorders, 91 cases of consonant
      phonemic errors were classified into different patterns according to the phonemic
      placement errors. The 91 cases were divided into two groups as effective one and
      ineffective one depending on whether the symptoms disappeared or not after the
      speech therapy. Ten factors including sex, age, oral-motor function problem,
      developmental delay, history of language development delay, history of middle ear
      affection, lingua frenata, mental retardation, the therapy frequency and times,
      were analyzed. The statistics software SPSS (SPSS Inc, 1997) was applied to show
      the factors related to the therapy effect by logistic multiple stepwise
      regression analysis. The therapy effect was compared between the single pattern
      (phonemic error < 2 groups) and multiple pattern (phonemic errors > or = 2
      groups). RESULTS: The 91 cases with consonant phonemic errors were classified
      into four groups. The multiple pattern of the articulation errors was the most
      common (37 cases, 41%) among the 4 groups, followed by velar errors (33 cases,
      36%). The third one was the apico-dental errors (12 cases, 13%) and the last one
      was the linguo-alveolar errors (8 cases, 9%). Only one case had labiodental error
      (/f/). The logistic multiple stepwise regression analysis showed that the history
      of the positive developmental delay, language delay and the frequency of the
      speech therapy were related to the therapy effect. The effective rate of the
      speech therapy in the single pattern of the phonemic error was as high as 87%
      while the one in the multiple pattern group was only 2.7%. The difference was
      significant (P < 0.000 1) when the therapy effect in these two groups was
      compared. The clinical model of the speech therapy included speech assessment,
      designing of the goal, choice of the target sound, sound production and oral
      motor functional training. CONCLUSION: The consonant phonemic errors in the
      clinic represent four groups. The developmental delay, the language delay and
      frequency of the speech therapy influence the therapy effect. The frequency of
      the speech therapy should be increased every week, for example not less two times
      a week. The therapy effect of the single pattern of the phonemic errors is much
      better than that of the multiple pattern. The primary model of the speech therapy
      has been built in the clinics.

PMID- 15189689
TI  - [Effects of vitamin A on the differentiation, maturation and functions of
      dendritic cells from cord blood].
AB  - OBJECTIVE: It is well known that vitamin A can improve mucosal immunity and anti
      infection immunity. But the mechanisms thereof remain to be clarified. Previous
      studies on the role of vitamin A in immune regulation focused on lymphocytes,
      whereas little had been done about dendritic cells, which play very important
      roles in immune response. The objective of this study was to understand the
      effects of retinoic acid (RA), the metabolic product of vitamin A in vivo,on the
      differentiation, maturation and functions of dendritic cells from cord blood.
      METHODS: Cord blood samples were collected from nine well-nourished full-term
      neonates. Mononuclear cells were isolated by Ficoll-Hypaque gradient
      centrifugation and cultured in the presence of 1000 u/ml GM-CSF, 500 u/ml IL-4
      for 6 days, then TNF-alpha 20 ng/ml was added into the medium and cultured for
      another 3 days. The cells were incubated with or without 1 x 10(-6) MRA.
      Expression of surface molecules, CD1a, CD83, HLA-DR on DC was measured by flow
      cytometry. The ability of DC derived from the culture to induce proliferation of
      T cells in the mixed lymphocyte reaction (allo-MLR) was used for the evaluation
      of their function. IL-12, IFN-gamma, IL-4 and IL-10 were detected at mRNA levels
      by RT-PCR to understand the roles of DC treated with RA in regulation of Th1/Th2
      balance. RESULTS: On the sixth day of cell culture, the percentage of DC
      incubated with RA (57.28 +/- 9.22) was much lower than that without RA (79.57 +/-
      11.85) (P < 0.001), but on the ninth day, there were no differences between the
      presence or absence of RA (76.18 +/- 10.27 vs. 73.72 +/- 15.58). When RA was
      added to the medium and the culture was continued for nine days, the percent of
      immature DC (CD1a + HLA-DR+) was much higher than that of the control (absence of
      RA) (58.93 +/- 4.70 vs. 45.80 +/- 7.88, t = 6.575, P < 0.001); whereas, mature DC
      (CD83 + HLA-DR+) percentage was markedly lower than that of the control (17.25 +/
      8.49 vs. 27.92 +/- 13.94, t = 4.435, P = 0.002). The T lymphocytes proliferation
      induced by the DC treated with RA was reduced from 16 857 +/- 3 643 to 11 924 +/-
      2 576 cpm (t = 5.598, P < 0.001) in allo-MLR. Expression of mRNA for IL-12p35, IL
      12p40, IFN-gamma in the cells that had been incubated with RA declined, but IL
      10, IL-4 increased significantly. CONCLUSION: Vitamin A inhibited the
      differentiation and maturation of cord blood DC, reduced it's ability to
      stimulate allo-T lymphocytes proliferation, and down-regulated Th1 cytokines, up
      regulated Th2 cytokines, consequently made immune response inclined to Th2.

PMID- 15189691
TI  - [Study on the bone nutrition of children with quantitative ultrasound].

PMID- 15189690
TI  - [Expression of TSG-6 gene during 3T3-L1 preadipocyte differentiation and
      regulative role of tumor necrosis factor-alpha].
AB  - OBJECTIVE: Tumor necrosis factor alpha-stimulated gene-6 (TSG-6 gene)
      differentially expressed in adipose tissue of obese and normal human subjects or
      rats. To explore the relationship between the differential expression of TSG-6
      and adipocyte differentiation, adipogenesis and obesity, the present study aimed
      to investigate the changes of TSG-6 gene expression during 3T3-L1 preadipocyte
      differentiation and to analyze the regulative role of TNF-alpha on TSG-6 gene
      expression in matured 3T3-L1 adipocytes. METHODS: 3T3-L1 preadipocytes were
      cultured in vitro and differentiated into the matured adipocytes. TNF-alpha in
      different concentrations (0.1 ng/ml, 1.0 ng/ml, 10.0 ng/ml) was added into the
      culture medium of fully differentiated adipocytes (day 10) for various times (0.5
      h, 2 h, 6 h, 12 h, 24 h). Total RNA from these adipocytes was extracted and the
      levels of TSG-6 gene mRNA expression were evaluated by RT-PCR. RESULTS: (1) In
      preadipocytes, the level of TSG-6 gene mRNA expression remained low. In the
      presence of dexamethasone (Dex), MIX and insulin, with the 3T3-L1 preadipocytes
      being differentiated into the matured adipocytes, the level of TSG-6 gene mRNA
      expression was upregulated and reached the higher level in fully differentiated
      adipocytes. There is a significant difference between any two detected phases in
      the levels of TSG-6 gene mRNA expression (P < 0.05), except that the levels of
      TSG-6 gene mRNA expression did not increase obviously on day 0 to day 2, day 3 to
      day 5, day 4 to day 6 and day 7 to day 10 (P > 0.05). (2) Treatment of day 10 3T3
      L1 adipocytes with TNF-alpha of different concentrations (0.1 ng/ml, 1.0 ng/ml,
      10.0 ng/ml) resulted in a significant decrease in the level of TSG-6 gene mRNA
      expression. The inhibition effect of TNF-alpha on TSG-6 gene mRNA expression
      generally tended to be reinforced with the increasing concentrations of TNF-alpha
      and the elongation of time course, except for the period of 6 - 24 h after the
      stimulation of 10.0 ng/ml TNF-alpha. When 0.1 ng/ml TNF-alpha was applied, the
      level of TSG-6 gene expression decreased by 33.73% at 6 h, 97.39% at 12 h. While
      1.0 ng/ml TNF-alpha was used, the level of TSG-6 gene expression decreased by
      78.68% at 6 h, which remained until 24 h. At a concentration of TNF-alpha up to
      10.0 ng/ml, the level of TSG-6 gene expression decreased by 96.27% at 2 h. TSG-6
      gene expression was almost fully inhibited. CONCLUSION: (1) TSG-6 gene may be
      involved in adipocyte differentiation and adipogenesis. (2) TNF-alpha can
      downregulate the mRNA expression of TSG-6 gene in matured adipocytes. The
      inhibitory effect of TNF-alpha on TSG-6 gene expression is generally dose
      correlated.

PMID- 15189692
TI  - [Platelet-activating factor and neonatal necrotizing enterocolitis].

PMID- 15189693
TI  - [Advances in clinical studies on brain natriuretic peptide and N-terminal pro
      brain natriuretic peptide].

PMID- 15189694
TI  - [Routines for normal frequency mechanical ventilation of neonates].

PMID- 15189695
TI  - [Scintigraphic assessment of the anorectal function in children with idiopathic
      constipation].
AB  - OBJECTIVE: The ability of the rectum to evacuate is valuable information in
      patients with constipation, or those who find defecation difficult. However, few
      published studies are available to evaluate this ability in most common
      examinations of anorectal function. A new, low-radiation, real-time scintigraphic
      technique has been used by several investigators to outline the 'neo-rectum'
      following ileoanal pouch anastomosis and the efficiency of rectal evacuation in
      adult patients with constipation. There was no similar report about the abilities
      of rectal evacuation in children with constipation. The aim of this study was to
      investigate the value and reliability of isotope defecography as an objective
      method for evaluation of anorectal function in patients with chronic idiopathic
      constipation. METHODS: Twenty five patients (10 were male and 15 were female,
      range of age was 5 - 15 years, mean age 8.99 years) suffering from chronic
      idiopathic constipation and 11 normal children were assessed by isotope
      defecography. The radiopharmaceuticals used were rehydrated potato labelled with
      200 MBq (99m)TcO(4)(-). The volume of the potato paste used in each subject was
      determined by prior balloon proctometrogram studies, which measured the maximum
      rectal capacity. The patient was seated upright on a commode, and the computer
      was then set for the dynamic acquisition of 3-second images over 5 min per
      session. Using a region of interest program on computer, the dynamic
      radioactivity in anorectum during defecation showed as emptying curves by
      computer. The half defecation time, the rectal emptying rate and the residual
      rate could be calculated from the rectal emptying curves. The anorectal angles
      were measured from the images of anorectum during resting, squeezing and
      evacuation. All patients underwent X-ray defecography and colonic transit time
      measurement simultaneously. RESULTS: The rectal emptying curves showed a prompt
      evacuation in normal children, but it disappeared in most of patients with
      idiopathic constipation. The abilities of evacuation were damaged severely in
      patients. In normal group the half defecation time, the rectal emptying rate and
      the residual rate were 1.97 +/- 0.86 minutes, 78.30% +/- 12.03% and 20.50% +/-
      7.67%, respectively, whereas they were 15.16 +/- 3.67 minutes, 44.84% +/- 14.00%
      and 53.52% +/- 15.02%, respectively, in patients group. There were significant
      differences between two groups (P < 0.05). According to the results of colonic
      transit time there were 6 patients with slow transit constipation, 17 patients
      with outlet dysfunction and 2 patients with normal colonic transit time. The
      abilities of evacuation were more seriously impaired in patients with outlet
      dysfunction compared with those patients with slow transit constipation. For the
      isotope defecography the mean anorectal angles at resting in patient group and
      normal group were 109 +/- 12 degrees and 101 +/- 17 degrees. There were no
      significant differences in anorectal angles between patient group and normal
      group or by both methods of isotope defecography and X-ray defecography. The
      correlation coefficients for anorectal angles at resting, squeezing and
      evacuation were 0.87, 0.82 and 0.73, respectively. CONCLUSION: The isotope
      defecography can be used to evaluate the anorectal function and the ability of
      defecation dynamically, also it was simple and safe because of the low dose
      radiation involved.

PMID- 15189696
TI  - [Decreased peripheral nerve conduction velocity may be associated with lower
      serum level of vitamin E in patients with infantile hepatitis syndrome].
AB  - OBJECTIVE: To explore the influence of vitamin E (VitE) concentration in serum on
      peripheral nerve conduction in patients with infantile hepatitis syndrome (IHS).
      METHODS: A retrospective study was carried out in 58 infants suffered from IHS
      without congenital biliary atresia and 31 of them were followed up. Thirty-two
      healthy infants were as control. The level of VitE in serum was detected with
      high performance liquid chromatography and nerve conduction was tested with
      surface electrodes along the nerves of limbs. The relationship between the level
      of VitE or total bilirubin (TB) or direct bilirubin (DB) and the nerve conduction
      velocity was analyzed comparatively. RESULTS: (1) The serum level of VitE was
      below the lower limit of 90% the normal value (13.78 micromol/L) in 71% (41/58)
      of patients, and was below the lower limit of 99% the normal level (9.17
      micromol/L) in 48% (28/58) of patients. (2) The level of DB was more than 25.7
      micromol/L in 86% (50/58) of the patients and was more than 102.6 micromol/L in
      47% (27/58) of patients. Severe conjugated hyperbilirubinemia with cholestasis
      was demonstrated in most patients. (3) At least one abnormal parameter in nerve
      conduction test was found in 86% (50/58) patients. In 144 nerves tested, 60.4%
      (87/144) had at least one abnormal parameter. (4) Analysis for the association
      between bilirubin levels and VitE concentration in serum: in groups of DB > or =
      25.7 micromol/L and DB < 25.7 micromol/L, the percentage of decreased VitE
      concentrations was 78% (39/50) and 25% (2/8), respectively, and the difference
      was significant (P < 0.01). Similar association between low VitE concentration
      and increased level of TB in serum could not be demonstrated. (5) Analysis for
      the association between abnormal nerve conduction and VitE concentration in
      serum: in the two groups with low and normal level of VitE, the percentage of
      abnormal nerve conduction was 93% (38/41) and 71% (12/17), respectively
      (chi(c)(2) = 4.93, P < 0.05). (6) Analysis for the association between abnormal
      nerve conduction and bilirubin in serum: There was no significant association
      between abnormal nerve conduction and serum level of either DB or TB. (7) Eight
      patients died and 9 patients had motor development delay in 31 patients during
      follow up. In these 17 patients with poor outcome, 88% (15/17) had very low VitE
      levels (< 9.17 micromol/L), which was markedly higher than the proportion of
      cases (43%, 6/14) with better prognosis (chi(c)(2) = 7.235, P < 0.01).
      CONCLUSIONS: (1) Low VitE serum levels were found in excess of the two thirds of
      patients with IHS and severely decreased levels in nearly a half of them. (2) A
      conjugated hyperbilirubinemia with cholestasis could be found in most patients
      (86%) suffered from IHS without congenital biliary atresia and about a half of
      them had serious cholestasis. (3) Conjugated hyperbilirubinemia with cholestasis
      could be the predominant cause of decreased serum VitE level in this study. (4)
      Abnormality of nerve conduction in patients with IHS might be related to VitE
      deficiency.

PMID- 15189697
TI  - [Detection of four human herpesviruses DNA and virus-specific IgM antibody in
      blood specimens of infants].
AB  - OBJECTIVE: To establish a restriction endonuclease pattern which could detect and
      differentiate four major human herpesviruses by polymerase chain reaction (PCR),
      restriction fragment length polymorphism (RFLP), DNA cloning and sequence
      analysis. METHODS: A pair of primer, which was designed according to sequences in
      well-conserved regions of the DNA polymerase gene in human herpesviruses, was
      designed to amplify herpes simplex virus type 1 and 2 (HSVI/II), Epstein-Barr
      virus (EBV) and cytomegalovirus (CMV). Sequences of the primers are as follows:
      P(1) (5'-CGACTTTGCCAGCCTGACC-3') and P(2) (5'-AGTCCGTGTCCCCGTAGATG-3'). DNA of
      four strains of standard herpesviruses were amplified by PCR, and further studied
      by DNA cloning, sequence analysis and RFLP. At last, the authors established the
      PCR-RFLP technique to differentiate the four different herpesviruses. Meanwhile,
      75 clinical blood specimens from infants with suspected viral infection and 38
      blood specimens from healthy children were evaluated for herpesviruses DNA or
      virus-specific IgM antibody by PCR-RFLP or by ELISA. RESULTS: The PCR amplified
      products of four human herpesviruses were from 510 bp to 592 bp in length and
      were analyzed for herpesvirus types with restriction endonuclease technique. The
      specificity and sensitivity of this PCR-RFLP were examined. There was no cross
      reaction with Escherichia coli, Staphylococcus aureus, hepatitis B virus (HBV),
      Clostridium neoformans and human-genomic DNA and the lowest detection level was
      0.1 fg DNA. Among 75 specimens, 23 were positive by PCR and the positive rate was
      30.7%, including 13 for CMV, four for EBV, five for HSVII and one for HSVI after
      restriction enzyme digestion with BamHI and BstUI, while 10 were positive by
      ELISA and positive rate was 13.3%. All ELISA-positive specimens were likewise
      positive by PCR. Thirteen of 65 specimens that were ELISA-negative were tested
      positive by PCR. An infant with CMV infection was determined with viral DNA and
      virus-specific IgM antibody in blood at 3, 4 and 6 months after birth,
      respectively. The result showed that she was still CMV DNA-positive in blood
      whereas IgM antibody was positive only at month 3 after birth. None of the 38
      control blood specimens was positive for herpesvirus by this PCR-RFLP or by
      ELISA. CONCLUSIONS: This PCR-RFLP technique was specific, sensitive, rapid and
      accurate in diagnosing herpesviruses infection in infants, and it could detect
      herpesviruses DNA in specimens which were negative for IgM antibody by ELISA.

PMID- 15189698
TI  - [Head-up tilt testing potentiated with sublingual nitroglycerin for the diagnosis
      of unexplained syncope in children].
AB  - OBJECTIVE: Syncope is one of the common problems in clinical pediatrics. In
      recent years, vasovagal reflex was identified as the most common reason for
      unexplained syncope. Head-up tilt test (HUT) was regarded as one of the important
      diagnostic criteria. But the sensitivity of baseline head-up tilt test (BHUT) is
      low. To improve the sensitivity of HUT, we evaluated the diagnostic value of head
      up tilt testing potentiated with sublingual nitroglycerin (SNHUT) in children
      with unexplained syncope. METHODS: Twenty-five patients (11 male and 14 female,
      mean age 11.8 +/- 2.1 years, ranged from 8 to 15) with unexplained syncope and 10
      healthy children in control group (5 male and 5 female, mean age 11.4 +/- 2.1
      years, ranged from 9 to 15) were studied. The patients and healthy children were
      tilted upright to 60 degrees for 45 minutes at BHUT. If syncope did not occur,
      sublingual nitroglycerin (4 - 6 microg/kg, maximum dose 300 microg) was
      administered, and continued at same degree for 20 minutes. RESULTS: Compared with
      controls, there was no significant difference in sex, age, supine blood pressure
      and supine heart rate of syncopal group (P > 0.05). During BHUT, 12 patients
      (48%) and none of the controls had positive response, whereas another 8 patients
      and 2 controls had positive response during SNHUT. In syncopal group, total
      positive rate was 80%. The sensitivity, specificity, and diagnostic value of
      SNHUT were all 80%. During SNHUT, the mean time to positive response was 5.9 +/-
      2.9 minutes (from 4 to 11 minutes), and only 1 patient had mild headache.
      CONCLUSION: Head - up tilt testing potentiated with sublingual nitroglycerin (4 -
      6 microg/kg, maximum dose 300 microg) as pharmacological provocation test was a
      useful and an objective diagnostic tool for evaluating vasovagal syncope in
      children.

PMID- 15189699
TI  - [Effect of elastase inhibitor on pulmonary hypertension induced by
      monocrotaline].
AB  - OBJECTIVE: Pulmonary hypertension is a proliferative vascular disease
      characterized by pulmonary vascular structural remodeling. Until now, the
      pathogenesis of pulmonary hypertension is still not fully understood. Although
      considerable progress has been made, there is, to date, no cure for advanced
      pulmonary vascular disease. Recently, a number of studies suggest that endogenous
      vascular elastase (EVE) play a role in the vascular changes associated with
      pulmonary hypertension. The purpose of the study was to determine whether an
      elastase inhibitor might reverse advanced pulmonary vascular disease produced in
      rats by injection of monocrotaline. METHODS: One hundred and twenty male Sprague
      Dawley rats were used in this study. The rats were divided into three groups:
      control, model and ZD-0892 groups. In the model and ZD-0892 groups, the rats were
      subjected to a single subcutaneous injection of monocrotaline (60 mg/kg) in the
      hind flank, while the rats in control group received an equivalent volume of 0.9%
      saline. From day 21, the rats in the ZD-0892 and model groups received twice
      daily gavage tube feedings of either ZD-0892 at a dose of 240 mg/kg per day or
      its administration vehicle, while the rats in control group were subjected to an
      equivalent volume of 0.9% saline. On days 21, 28 and 35 post-injection, the
      elastolytic activity was measured with a fluorescence microplate reader and
      pulmonary artery pressure was detected via catheterization. Meanwhile, the lungs
      were evaluated morphologically, using the barium-gelatin perfusion technique.
      RESULTS: The injection of monocrotaline led to severe pulmonary hypertension in
      rats 21 days later and pulmonary artery elastolytic activity increased
      remarkably. A 1-week treatment with ZD-0892 resulted in declines in elastase
      activity. This was associated with significant declines in pulmonary artery
      pressure, decreases in muscularization of peripheral arteries and reductions in
      medial hypertrophy. After 2 weeks, elastase activity returned to normal level.
      Pulmonary artery pressure and structure were normalized. CONCLUSION: Increased
      elastase activity is important in the development of vascular changes and
      progressive pulmonary hypertension. ZD-0892 can suppress the elastase activity
      and completely reverse the fatal pulmonary hypertension induced by monocrotaline
      in rats.

PMID- 15189700
TI  - [Antineutrophil cytoplasmic autoantibody positive vasculitis induced by
      propylthiouracil: a case report].
AB  - OBJECTIVE: Propylthiouracil (PTU) as a drug used during the treatment of
      hyperthyroidism could induce antineutrophil cytoplasmic autoantibody-positive
      vasculitis. Here the author reported a childhood case of antineutrophil
      cytoplasmic autoantibody-positive vasculitis induced by PTU, which is rarely
      described. METHODS: The diagnosis was made according to the symptoms, signs,
      serum markers and renal biopsy, and the relevant literature was reviewed.
      RESULTS: The 12-year-old girl presented with gross hematuria, proteinuria, renal
      function damage [Ccr 52.46 ml/(min. 1.73 m(2))], positive antineutrophil
      cytoplasmic autoantibody (ANCA-MPO) (MPO ELISA 140%) and a vasculitis lesion in
      the renal biopsy sample. She had been treated with PTU for 5 years because of
      Graves disease. After the diagnosis, the PTU was withdrawn, and prednisone (40
      mg/d) and cyclophosphamide (25 mg, Bid) were applied. Three weeks after the
      therapy with prednisone and cyclophosphamide the gross hematuria disappeared.
      Three months after the treatment the renal function returned to normal [Ccr 124
      mg/(min.1.73 m(2))], and the titer of ANCA-MPO decreased from 140% to 57%.
      CONCLUSION: PTU may induce antineutrophil cytoplasmic autoantibody positive
      vasculitis. A right diagnosis and treatment can improve its prognosis of the
      disease.

PMID- 15189701
TI  - [Clinical characteristics of bronchiolitis caused by human metapneumovirus in
      infants].
AB  - OBJECTIVE: The fact that the acute lower respiratory infections (ALRI) are
      associated with a newly discovered virus, human metapneumovirus (hMPV), has been
      shown in several studies. The authors conducted this study to understand the
      etiological and clinical characteristics of bronchiolitis, one of the most common
      ALRI in infants, caused by hMPV. METHODS: Nasopharyngeal aspirate specimens from
      54 out of 126 infants with bronchiolitis admitted to the Children's Hospital
      Affiliated to Capital Institute of Pediatrics, Beijing from November 2002 to
      February 2003 were examined for hMPV gene fragments by reverse transcription
      polymerase chain reaction (RT-PCR). Prior to the detection, the specimens were
      confirmed as negative for the common respiratory pathogens including RSV,
      influenza A and B, parainfluenza I, II, III, adenovirus, Mycoplasma pneumoniae by
      indirect immunofluorescence test, virus isolation and ELISA test. The clinical
      data of the patients diagnosed etiologically as hMPV infection analyzed included
      the infants' age, sex, the degree of fever, the severity of wheezing and clinical
      Lowell score, the findings of chest examination and chest X-ray, the white blood
      cell count and blood gas analysis, the course of the disease, the major
      treatments and the outcome of the disease. RESULTS: Twenty-one specimens showed
      the predicted 213 bp PCR products in agarose gel and the positive rate was 16.7%
      of all patients (21/126) and 39% of the patients with negative results for common
      respiratory pathogens detections (21/54). The range of patients' age was 2 - 15
      months and the young infants with hMPV bronchiolitis (1 - 6 month of age)
      accounted for 62% and the male:female ratio was 3.2:1. The patients presented a
      low-medium grade fever (T < 39 degrees C) accounted for 86%; 81.0% of patients
      had a white blood cell count lower than 10.0 x 10(9)/L. The radiological findings
      were patchey opacity in both lungs (68%) and(or) hyperinflation (62%). Assessed
      by the Lowell score system, 5 out of 21 cases were considered as severe cases.
      The major clinical findings of hMPV bronchiolitis had no significant difference
      compared with that of subgroup A hRSV bronchiolitis, and showed longer course of
      disease than that of subgroup B hRSV bronchiolitis (P < 0.01). CONCLUSIONS: Of
      the infants with bronchiolitis hospitalized in our hospital from November of 2002
      through February of 2003, 16.7% were caused by hMPV infection. These data showed
      that the major clinical characteristics and the outcome of treatment of hMPV
      bronchiolitis had no statistically significant difference compared to the cases
      with either subgroup A or subgroup B hRSV infection.

PMID- 15189702
TI  - [Effects of ketamine on hypoxic-ischemic brain damage in newborn rats].

PMID- 15189703
TI  - [Use of serum transferrin receptor detection in diagnosis of iron deficiency
      anemia in children].

PMID- 15189704
TI  - [Effects of estrogen on cerebral cells of hypoxic-ischemic neonatal rats].

PMID- 15189705
TI  - [Diagnosis and treatment of neonatal disseminated intravascular coagulation
      caused by placental abruption and analysis of relevant factors].

PMID- 15189706
TI  - [Effects of different first dose calcium tetrahydro-folate on toxicity and side
      effects of large dose methotrexate treated standard risk group children with
      acute lymphoblastic leukemia].

PMID- 15189707
TI  - [One case of neonatal myocardial infarction].

PMID- 15189708
TI  - [Fulminant purpura in a case].

PMID- 15189709
TI  - [A case with systemic disseminated fungal disease and reactive histiocytosis].

PMID- 15189710
TI  - [Report of a case with central nuclear type myopathy].

PMID- 15189711
TI  - [Primary hemophagocytic syndrome in a case].

PMID- 15189712
TI  - Hospitalists: scourge or salvation?

PMID- 15189713
TI  - Fetal fibronectin does not affect outcomes of preterm labor.

PMID- 15189715
TI  - No long-term benefit shown for bones after HRT.

PMID- 15189714
TI  - Prochlorperazine more effective than ketorolac for pediatric migraine.

PMID- 15189716
TI  - 3 days ciprofloxacin adequate for UTI in older women.

PMID- 15189717
TI  - Useful signs and symptoms to evaluate vaginal complaints.

PMID- 15189718
TI  - Long-term management of patients with unstable angina and non-ST-elevation MI.

PMID- 15189719
TI  - Incidental splenic lesions.

PMID- 15189720
TI  - How should we evaluate a solitary pulmonary nodule found on chest x-ray?

PMID- 15189721
TI  - FIRSTConsult: a useful point-of-care clinical reference.

PMID- 15189722
TI  - Hospitalists and family physicians: understanding opportunities and risks.
AB  - BACKGROUND: Emergence of the hospitalist as a specialist in inpatient medicine
      provides an opportunity to examine a new provider type and its relation to family
      physicians. OBJECTIVES: To review the hospitalist literature to understand the
      hospitalist role, identify benefits and risks of the hospitalist model to family
      physicians, and discuss future opportunities to study and work with hospitalists.
      METHODS: An integrative review of published literature about the hospitalist
      model focused on the influence of hospitalists on family practice. RESULTS: Three
      main themes were identified as interest areas for family physicians: descriptions
      of the hospitalist role and responsibilities; hypothesized benefits and risks of
      the hospitalist model; and reported research results evaluating the effect of the
      hospitalist model. Two major opportunities related to hospitalists and family
      physicians were also uncovered: opportunities to conduct future research to study
      the influence of hospitalists on family physicians; and opportunities to create
      workable relationships with these new practitioners. CONCLUSIONS: Despite some
      opposition to hospitalist programs, the economic climate and increasing
      productivity standards suggest that these programs are here for the foreseeable
      future, and it is in family physicians' best interests to understand the
      opportunities and risks of the hospitalist model. Family physicians can work
      proactively with this new patient care model by participating in the development
      of standardized and efficient ways to communicate and to partner with
      hospitalists. Meanwhile, future research studies can help inform the debate by
      investigating the specific influence of hospitalist models on family practice.

PMID- 15189723
TI  - Infection control in the outpatient setting.

PMID- 15189724
TI  - Clinical inquiries. Does injection of steroids and lidocaine in the shoulder
      relieve bursitis?

PMID- 15189725
TI  - Clinical inquiries. What treatments are safe and effective for mild to moderate
      hypertension in pregnancy?

PMID- 15189726
TI  - Clinical inquiries. Are beta-2-agonists or anticholinergics more effective for
      treating COPD?

PMID- 15189727
TI  - Clinical inquiries. Should the varicella vaccine be given to all children to
      prevent chickenpox?

PMID- 15189728
TI  - Clinical inquiries. Do antibiotics prevent recurrent UTI in children with
      anatomic abnormalities?

PMID- 15189729
TI  - Clinical inquiries. Does acetaminophen and NSAID combined relieve osteoarthritis
      pain better than either alone?

PMID- 15189730
TI  - Tipping the scales of selection with BAFF.
AB  - Two recent Immunity papers link peripheral tolerance with the ability of
      developing B cells to capture BAFF. These findings suggest that an increase in
      effective BAFF levels leads to autoreactive B cell maturation.

PMID- 15189731
TI  - He who laughs last laughs best--innate immunity and viral selection.
AB  - In this issue of Immunity, the Jonjic and Yokoyama teams provide evidence that
      beta-herpesvirus mutants can emerge under the selective pressure of innate
      immunity during primary infections. These rare mutants that escape natural killer
      cell recognition cause disease and death in mice that lack sterilizing T cell
      immunity.

PMID- 15189732
TI  - AID: how does it aid antibody diversity?
AB  - Activation-induced cytidine deaminase (AID) is an essential enzyme to regulate
      class switch recombination (CSR), somatic hypermutation (SHM), and gene
      conversion (GC). AID is known to be required for DNA cleavage of S regions in
      CSR. However, its molecular mechanism is a focus of extensive debate. RNA editing
      hypothesis postulates that AID edits yet unknown mRNA to generate specific
      endonucleases for CSR and SHM. By contrast, DNA deamination hypothesis assumes
      that AID deaminates cytosine in DNA, followed by DNA cleavage by base excision
      repair enzymes. We discuss available evidence for the two proposed models. Recent
      findings, namely requirement of protein synthesis for DNA breakage and
      dispensability of U removal activity of uracil DNA glycosylase, force us to
      reconsider DNA deamination hypothesis.

PMID- 15189733
TI  - Illuminating autoimmune regulators through controlled variation of the mouse
      genome sequence.
AB  - Gene variants in mice that have strong, Mendelian effects on autoimmune
      susceptibility have been one of the most productive entry points for identifying
      genes and processes regulating human autoimmunity. With the tools now available
      to map and identify new mouse Mendelian gene variants, the handful of spontaneous
      mutations accumulated over several decades have all been identified, and the main
      bottleneck lies in producing new Mendelian immune variants. We outline here a
      strategy to generate large sets of functional variants in genes controlling lupus
      and humoral immunity, based upon limited variation of the mouse genome sequence
      with the chemical mutagen, ENU, combined with a set of sensitive immunological
      screens.

PMID- 15189734
TI  - Induced reactivity of intestinal CD4(+) T cells with an epithelial cell lectin,
      galectin-4, contributes to exacerbation of intestinal inflammation.
AB  - Inflammatory bowel disease is an immune-mediated intestinal inflammatory
      condition that is associated with an increase in autoantibodies that bind to
      epithelial cells. However, it is unknown whether the epithelial cell-derived
      products that are recognized by such autoantibodies are involved in the
      pathogenic process. Through a combined antigen-screening approach utilizing
      humoral and cellular immune responses, we identify herein an epithelial lectin,
      galectin-4, that specifically stimulates IL-6 production by CD4(+) T cells.
      Interestingly, the reactivity of CD4(+) T cells to galectin-4 is precisely
      elicited under intestinal inflammatory conditions. The galectin-4-mediated
      production of IL-6 is MHC class II independent and induced by PKCtheta-associated
      pathway through the immunological synapse. The galectin-4-mediated stimulation of
      CD4(+) T cells is shown to exacerbate chronic colitis and delay the recovery from
      acute intestinal injury. These studies identify the presence of an immunogenic,
      endogenous lectin in the intestine and dissect the biological role of
      lectin/CD4(+) T cell interactions under inflammatory conditions.

PMID- 15189735
TI  - Immunological unresponsiveness characterized by increased expression of CD5 on
      peripheral T cells induced by dendritic cells in vivo.
AB  - In the steady state, interaction between T cells and antigen-presenting dendritic
      cells (DCs) leads to T cell tolerance. To examine the role of DC regulated
      peripheral tolerance in a model autoimmune disease, we delivered an
      encephalitogenic oligodendrocyte glycoprotein (MOG) peptide to DCs in vivo. We
      found that targeting MOG peptide to DCs resulted in a novel form of peripheral T
      cell tolerance that was sufficiently profound to prevent autoimmune experimental
      acute encephalomyelitis (EAE). The tolerized T cells were severely impaired in
      specific secondary responses to antigen in vivo but they were not intrinsically
      anergic since they remained highly responsive to T cell receptor (TCR)
      stimulation in vitro. The mechanism that mediates this dynamic antigen-specific T
      cell unresponsiveness differs from previously described forms of tolerance in
      that it requires that DCs induce CD5 expression on activated T cells.

PMID- 15189736
TI  - Cellular niches controlling B lymphocyte behavior within bone marrow during
      development.
AB  - In bone marrow, hematopoiesis is thought to depend on special microenvironments
      known as niches that maintain blood cells. However, the identity of niches and
      interaction of blood cells with niches remain poorly understood. Here we identify
      stage-specific cellular niches for B lymphopoiesis. The earliest precursors, pre
      pro-B cells and end-stage B cells, plasma cells require CXC chemokine ligand
      (CXCL)12. CXCL12-expressing cells are a small population of stromal cells,
      scattered throughout bone marrow and located some distance from the cells
      expressing interleukin (IL)-7. Multipotent hematopoietic progenitors are attached
      to the processes of CXCL12-expressing cells and pre-pro-B cells adjoin their cell
      bodies. Maturer pro-B cells that require IL-7 have moved away and adjoin the IL-7
      expressing cells. Plasma cells again seed CXCL12-expressing cells. We demonstrate
      the B lymphocyte characteristic location and movement between specific niches
      within bone marrow during development and suggest that CXCL12 maintains the cells
      in the niche.

PMID- 15189737
TI  - The chromatin remodeler Mi-2beta is required for CD4 expression and T cell
      development.
AB  - Changes in chromatin structure underlie the activation or silencing of genes
      during development. The chromatin remodeler Mi-2beta is highly expressed in
      thymocytes and is presumed to be a transcriptional repressor because of its
      presence in the nucleosome remodeling deacetylase (NuRD) complex. Using
      conditional inactivation, we show that Mi-2beta is required at several steps
      during T cell development: for differentiation of beta selected immature
      thymocytes, for developmental expression of CD4, and for cell divisions in mature
      T cells. We further show that Mi-2beta plays a direct role in promoting CD4 gene
      expression. Mi-2beta associates with the CD4 enhancer as well as the E box
      binding protein HEB and the histone acetyltransferase (HAT) p300, enabling their
      recruitment to the CD4 enhancer and causing histone H3-hyperacetylation to this
      regulatory region. These findings provide important insights into the regulation
      of CD4 expression during T cell development and define a role for Mi-2beta in
      gene activation.

PMID- 15189738
TI  - Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different
      capacities to generate T cell and non-T cell lineages.
AB  - The nature of early T lineage progenitors in the thymus or bone marrow remains
      controversial. Here we assess lineage capacity and proliferative potential among
      five distinct components of the earliest intrathymic stage (DN1, CD25(-)44(+)).
      All of these express one or more hemato-lymphoid lineage markers. All can produce
      T lineage cells, but only two of them display kinetics of differentiation,
      proliferative capacity, and other traits consistent with being canonical T
      progenitors. The latter also appeared limited to producing cells of the T or NK
      lineages, while B lineage potential derived mainly from the other, less typical T
      progenitors. In addition to precisely defining canonical early progenitors in the
      thymus, this work reconciles conflicting results from numerous groups by showing
      that multiple progenitors with a DN1 phenotype home to the thymus and make T
      cells, but possess different proliferative potentials and lineage capacities.

PMID- 15189739
TI  - Escape of mutant double-stranded DNA virus from innate immune control.
AB  - As innate immune system components, natural killer (NK) cells respond rapidly to
      infections and effectively control replication of pathogens, including murine
      cytomegalovirus (MCMV), a double-stranded DNA beta-herpesvirus. In the absence of
      NK cell control, MCMV infection results in early mortality due to uncontrolled
      viral replication. However, here we show that even in the face of initial NK cell
      control, there is late recrudescence of disease and mortality in immunodeficient
      mice due to the outgrowth of MCMV mutants that escape recognition by innate NK
      cells. These data suggest that viral infections in certain clinical settings also
      may be due to viral escape from innate immunity.

PMID- 15189740
TI  - NKG2D blockade prevents autoimmune diabetes in NOD mice.
AB  - NKG2D is an activating receptor on CD8(+) T cells and NK cells that has been
      implicated in immunity against tumors and microbial pathogens. Here we show that
      RAE-1 is present in prediabetic pancreas islets of NOD mice and that autoreactive
      CD8(+) T cells infiltrating the pancreas express NKG2D. Treatment with a
      nondepleting anti-NKG2D monoclonal antibody (mAb) during the prediabetic stage
      completely prevented disease by impairing the expansion and function of
      autoreactive CD8(+) T cells. These findings demonstrate that NKG2D is essential
      for disease progression and suggest a new therapeutic target for autoimmune type
      I diabetes.

PMID- 15189742
TI  - Excess BAFF rescues self-reactive B cells from peripheral deletion and allows
      them to enter forbidden follicular and marginal zone niches.
AB  - The role of BAFF in B cell self tolerance was examined by tracking the fate of
      anti-HEL self-reactive B cells in BAFF transgenic mice using four different
      models of self-reactive B cell deletion. BAFF overexpression did not affect the
      development of self-reactive B cells normally deleted in the bone marrow or
      during the early stages of peripheral development. By contrast, self-reactive B
      cells normally deleted around the late T2 stage of peripheral development were
      rescued from deletion, matured, and colonized the splenic follicle. Furthermore,
      self-reactive B cells normally selectively deleted from the marginal zone
      repopulated this compartment when excess BAFF was present. Self-reactive B cells
      rescued by excess BAFF were not anergic. BAFF overexpression therefore rescued
      only self-reactive B cells normally deleted with relatively low stringency and
      facilitated their migration into otherwise forbidden microenvironments. This
      partial subversion of B cell self tolerance is likely to underlie the
      autoimmunity associated with BAFF overexpression.

PMID- 15189741
TI  - Human neonatal Fc receptor mediates transport of IgG into luminal secretions for
      delivery of antigens to mucosal dendritic cells.
AB  - Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts
      contain significant quantities of IgG. The mechanism by which IgG reaches luminal
      secretions and the function of IgG in these locations are unknown. Here, we find
      that the human neonatal Fc receptor (FcRn) is the vehicle that transports IgG
      across the intestinal epithelial barrier into the lumen where the IgG can bind
      cognate antigen. The FcRn can then recycle the IgG/antigen complex back across
      the intestinal barrier into the lamina propria for processing by dendritic cells
      and presentation to CD4(+) T cells in regional organized lymphoid structures.
      These results explain how IgG is secreted onto mucosal surfaces and scavenges
      luminal antigens for recognition by the immune system.

PMID- 15189744
TI  - Assessment of the optimal daily dose of valsartan in patients with hypertension,
      heart failure, or both.
AB  - BACKGROUND: Recent data suggest that use of relatively high doses of angiotensin
      II-receptor blockers (ARBs) in hypertensive patients at high cardiovascular risk
      may reduce the incidence of clinical complications to a greater extent than would
      be predicted based on blood-pressure (BP) lowering alone. There is also evidence
      that a sustained reduction in BP, however small, may be important in reducing the
      risk of cardiovascular disease. Therefore, it is necessary to determine the ARB
      dosages that optimize the efficacy/tolerability ratio. OBJECTIVE: This article
      reviews experimental and clinical studies of the ARB valsartan to define the
      daily dose that provides the best ratio between efficacy and tolerability in
      patients with hypertension, heart failure, or both. METHODS: Relevant studies
      were identified through searches of EMBASE and Science Citation Index for
      articles published before December 15, 2003. No language restrictions were
      applied. Search terms were angiotensin II-receptor blockers, cardiovascular
      disease, hypertension, heart failure, type 2 diabetes mellitus, and angiotensin
      converting enzyme inhibitors. RESULTS: In several randomized, double-blind, dose
      finding studies, the antihypertensive effect of valsartan increased in a
      predictable fashion over a wide dose range (20-320 mg). The antihypertensive
      efficacy of the 80-mg dose was enhanced by doubling it to 160 mg, and the
      tolerability profile remained comparable to that of placebo over a broad dose
      range. Valsartan has been investigated in patients with heart failure at dosages
      ranging from 40 to 160 mg BID. Because of the need for careful individualization
      of therapy in these patients, rigid dose standardization may not be appropriate.
      CONCLUSIONS: Based on the efficacy/tolerability profile of valsartan at various
      doses, it appears that 160 mg may be the optimal dose for initial therapy in
      patients with essential hypertension and in most patients with heart failure.

PMID- 15189743
TI  - Leflunomide in the treatment of rheumatoid arthritis.
AB  - BACKGROUND: Current drug therapies for rheumatoid arthritis (RA), including
      nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs,
      help control inflammation but can cause significant toxicity. Drugs are needed
      that are able to suppress inflammation and modify the underlying immune response
      with improved tolerability. Leflunomide is an agent that affects the inflammatory
      process, particularly in RA. OBJECTIVE: This paper reviews the pharmacology of
      leflunomide, its approved use in RA, and the results of major clinical trials,
      including adverse events. METHODS: Relevant trials were identified through a
      search of the English-language literature indexed on EMBASE, MEDLINE, Current
      Contents, and the Cochrane Controlled Trials Register from January 1980 to
      November 2003. Search terms were limited to leflunomide. RESULTS: In 3 large
      Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent
      clinical efficacy and tolerability to methotrexate and sulfasalazine and superior
      efficacy and tolerability compared with placebo. In US301 (N = 482), the ACR
      (American College of Rheumatology) 20 response rate (proportion of patients with
      > or =20% improvement from baseline in tender and swollen joint counts, patient's
      assessment of pain, patient's and physician's global assessment of disease
      activity, physical function, and acute-phase reactant value) at 1 year was
      similar with leflunomide and methotrexate and significantly greater with both
      active treatments than with placebo (52%, 46%, and 26%, respectively; both, P <
      0.001). The efficacy of leflunomide was seen early (after 4 weeks of treatment)
      and was sustained throughout the study. There was less radiographic damage in
      both active-treatment groups compared with placebo (leflunomide, P < or = 0.001;
      methotrexate, P = 0.02). In MN301 (N = 358), the ACR20 response rate at 6 months
      was similar with leflunomide and sulfasalazine and significantly greater with
      both active treatments compared with placebo (55%, 56%, and 29%, respectively;
      both, P < 0.001). Radiographic progression was also similar with leflunomide and
      sulfasalazine, both of which were significantly superior to placebo (Larsen
      score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study revealed
      maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat
      population, N = 999), 50.5% of patients in the leflunomide group were ACR20
      responders at the end of 1 year, compared with 64.8% in the methotrexate group (P
      < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with
      leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of
      leflunomide appears promising, although monitoring for elevations in liver
      enzymes and bone marrow suppression is recommended. The most common drug-related
      adverse events associated with leflunomide in these clinical trials were
      diarrhea, abnormalities in liver enzymes, rash, and hypertension.

PMID- 15189745
TI  - Once-daily budesonide aqueous nasal spray for allergic rhinitis: a review.
AB  - BACKGROUND: Allergic rhinitis (AR) is a highly prevalent inflammatory condition
      with substantial direct and indirect costs. Intranasal corticosteroids are
      recommended as first-line therapy for moderate to severe persistent AR.
      Intranasal budesonide is effective and well tolerated; budesonide aqueous nasal
      spray (BANS) offers several advantages of potential importance to patients,
      including once-daily dosing at a low volume of spray in a formulation that is
      free of chlorofluorocarbon propellants, alcohol, benzalkonium chloride, and
      scents. OBJECTIVE: This article reviews the findings of randomized, blinded
      studies assessing the efficacy, safety profile, quality-of-life effects, patient
      preference, and cost-effectiveness of once-daily BANS in the treatment of AR.
      METHODS: A MEDLINE search (1966-April 2003) was conducted to identify potentially
      relevant English-language articles. Pertinent abstracts from recent allergy
      society meetings were also identified. The search strategy employed the medical
      subject heading terms budesonide, intranasal corticosteroid, or nasal steroid and
      allergic rhinitis. Selected studies were randomized, controlled clinical trials
      of once-daily BANS in patients with AR. RESULTS: Based on the results of
      randomized, double-blind, controlled trials, once-daily BANS is an effective
      treatment for both seasonal and perennial AR at doses as low as 64 microg (one 32
      microg spray per nostril). BANS was well tolerated in these studies, with an
      adverse-event profile similar to that of placebo, and caused no clinically
      meaningful suppression of hypothalamic-pituitary-adrenal axis function at doses 4
      fold higher than the recommended starting dose. Once-daily administration of BANS
      64 microg was similar in efficacy to mometasone furoate nasal spray 200 microg
      once daily; comparable doses of BANS and fluticasone propionate nasal spray
      (FPNS) were similar in efficacy as well. Based on specific sensory attributes,
      patients preferred BANS to FPNS at the recommended once-daily starting doses.
      BANS was associated with more days of treatment per prescription at a lower cost
      per day compared with other intranasal corticosteroids. CONCLUSIONS: Based on the
      studies reviewed, BANS administered once daily is an effective and well-tolerated
      treatment for seasonal and perennial AR in both children and adults. Due to its
      sensory attributes, efficacy, safety profile, and relatively low cost, BANS may
      help improve patient adherence.

PMID- 15189746
TI  - Pharmacokinetic properties and stability of continuous-infusion meropenem in
      adults with cystic fibrosis.
AB  - BACKGROUND: Meropenem is commonly used to treat lung infections in adults with
      cystic fibrosis (CF). Although continuous infusion is the ideal method to
      maximize the pharmacodynamic properties of this betalactam antibiotic, meropenem
      is stable for only approximately 4 to 6 hours at room temperature, and its
      pharmacokinetic (PK) properties, when administered by continuous infusion to
      patients with CF, are largely unknown. OBJECTIVE: This study was undertaken to
      determine the PK properties and stability of meropenem when administered to
      adults with CF by a continuous ambulatory drug-delivery infusion pump stored in a
      cold pouch between 2 freezer packs. METHODS: This open-label, multidose,
      randomized, crossover PK study was conducted at the Clinical Research Center at
      Hartford Hospital (Hartford, Connecticut). Adults aged > or = 18 years with CF
      were eligible. Study participants were randomized to receive meropenem 125 mg/h
      or 250 mg/h (equivalent to 3 g and 6 g, respectively, over 24 hours) by
      continuous IV infusion for 12 hours. Serum samples were collected throughout the
      infusion and then for 6 hours after infusion to determine the PK properties
      (volume of distribution [V(d)], elimination rate constant, total body clearance
      [CL], terminal half-life [t 1/2], and steady-state concentration [C(ss)]). Serum
      meropenem concentrations were assayed using high-performance liquid
      chromatography, and PK profiles were determined using compartmental analysis.
      Meropenem stability was ascertained by sampling the drug directly from the
      infusion pump at prespecified time points. Meropenem tolerability was assessed
      throughout the study by questioning subjects on how they felt. In addition,
      laboratory values of serum chemistries and liver enzymes were compared with
      baseline values. RESULTS: Seven adult volunteers with CF (4 women, 3 men; mean
      [SD] age, 27 [10] years [range, 19-46 years]) participated in the study. Mean
      (SD) C(ss) values were 8.31 (0.68) mg/L and 18.50 (3.31) mg/L for the 125-mg/h
      and 250-mg/h infusion rates, respectively. V(d), CL, and t 1/2 were dose
      independent and similar between the 2 infusion rates. Meropenem stability was
      maintained over 12 and 24 hours. Meropenem by continuous infusion was well
      tolerated. One patient complained of a headache during the study. CONCLUSIONS: In
      this study of adults with CF, meropenem infusion rates of 125 mg/h and 250 mg/h
      provided serum drug concentrations greater than the minimum inhibitory
      concentration for pathogens considered meropenem susceptible (< or =4 microg/mL)
      and intermediately resistant (8 microg/mL), respectively.

PMID- 15189747
TI  - Effects of multiple daily injection therapy with Humalog mixtures versus
      separately injected insulin lispro and NPH insulin in adults with type I diabetes
      mellitus.
AB  - BACKGROUND: Injection of insulin lispro (LP) before meals provides a more
      physiologic insulin activity profile than regular human insulin, but the
      relatively short duration of action of LP may allow the blood glucose (BG) level
      to increase during the late postprandial period (4-7 hours after meals) unless
      basal insulin is optimally replaced. One approach to basal insulin optimization
      has been to combine small doses of NPH with LP before meals. When used in a
      similar fashion, premixed, fixed-ratio insulin preparations containing LP and NPL
      (an LP-based intermediate-acting insulin) may provide the basis for an optimized
      basal-bolus insulin regimen. OBJECTIVE: This study assessed mean late
      postprandial glycemic control during treatment with a premixed formulation
      consisting of a high proportion of LP (75% LP/25% NPL; H) and a premixed
      formulation consisting of a medium proportion of LP (50% LP/50% NPL; M). The H/M
      formulation was given before meals and was compared with treatment with
      preprandial LP + NPH (LP + N) in patients with type 1 diabetes mellitus (DM).
      METHODS: This multicenter, randomized, open-label, 2-period crossover study was
      conducted at 4 centers in Italy and 1 center in France. Patients eligible for the
      study had type 1 DM, were > or = 18 years of age, and had a glycosylated
      hemoglobin (HbA(1c)) <150% of the upper limit of normal. Patients were randomly
      assigned to 1 of 2 treatment sequences: LP self-mixed with NPH before meals plus
      NPH alone at bedtime for 8 weeks (LP + N) followed by preprandial H or M, plus
      NPH alone at bedtime for 8 weeks (H/M), or the opposite sequence. Assessments
      included 8-point self-monitored BG profiles, HbA(1c), and hypoglycemia (any sign
      or symptom of hypoglycemia or BG < 3.0 mmol/L [<54.0 mg/dL]). The primary outcome
      measure was the late postprandial BG value, calculated as the mean of the
      combined prelunch (late postbreakfast), predinner (late postlunch), and bedtime
      (late postdinner) values. RESULTS: A total of 89 patients with type 1 DM were
      enrolled (44 men, 45 women; mean [SD] age, 38.3 [12.8] years; mean [SD] body
      weight, 70.8 [11.6] kg; mean [SD] body mass index, 24.6 [3.0] kg/m(2); mean [SD]
      duration of diabetes, 17.8 [10.5] years; mean HbA(1c), 7.9% [0.88%]). The mean
      (SD) late postprandial BG values were similar between treatments (8.9 [2.1]
      mmol/L [160.3 (37.8) mg/dL] for H/M vs 9.0 [1.8] mmol/L [162.1 (32.4) mg/dL] for
      LP + N), as were the end point HbA(1c) values (7.8% [0.9%] for H/M vs 7.9% [0.8%]
      for LP + N). The rate of hypoglycemia was significantly higher during treatment
      with H/M, primarily because of episodes occurring between 12 PM and 6 PM, but was
      relatively low in both groups (mean/median rate per patient per 30 days:
      2.87/2.14 for H/M and 2.11/1.07 for LP + N; P < 0.05). CONCLUSIONS: In this
      population of patients with type 1 DM, preprandial H/M provided an effective
      alternative regimen for prandial and basal insulin replacement. Late postprandial
      BG control, an indicator of basal insulin sufficiency, was similar to that
      achieved with an intensified regimen of LP + N injected separately before meals,
      and the end point HbA(1c) was similar between the 2 treatments.

PMID- 15189749
TI  - Comparative in vitro activity of telithromycin and beta-lactam antimicrobials
      against community-acquired bacterial respiratory tract pathogens in the United
      States: findings from the PROTEKT US study, 2000-2001.
AB  - BACKGROUND: Telithromycin is a new ketolide antimicrobial that was developed to
      provide good activity against resistant respiratory tract pathogens. PROTEKT US
      (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide
      Telithromycin in the United States) is a multicenter in vitro surveillance study
      that was initiated in 2000 to chart the emergence and spread of antimicrobial
      resistant pathogens in patients with community-acquired respiratory tract
      infections (CARTIs). OBJECTIVE: This article reports first-year results from
      PROTEKT US pertaining to the comparative in vitro activity of telithromycin and
      beta-lactam antimicrobials against community-acquired bacterial respiratory tract
      pathogens. METHODS: Data were compiled on the comparative in vitro activity of
      telithromycin and beta-lactams against Streptococcus pneumoniae (10,103
      isolates), Streptococcus pyogenes (3918 isolates), and Haemophilus influenzae
      (2706 isolates). Minimum inhibitory concentrations (MICs) and susceptibilities
      were determined according to National Committee for Clinical Laboratory Standards
      methods. RESULTS: In total, 38.8% (3920/10,103) of pneumococcal isolates were not
      susceptible to penicillin (12.5% [1266] intermediate [MIC, > or =0.12-1.0 mg/dL],
      26.3% [2654] resistant [MIC, > or =2 mg/dL]). Telithromycin was highly active
      against S pneumoniae (MIC required to inhibit 90% of isolates [MIC(90)], 0.5
      mg/L), with 99.6% (10,062/10,103) of isolates fully susceptible (MIC, < or =1
      mg/L). Based on MIC(90)s, the rank order of antimicrobial activity was
      telithromycin (0.5 mg/L), followed by amoxicillin/clavulanate (2 mg/L),
      penicillin (4 mg/L), and cefuroxime (8 mg/L). Telithromycin retained high
      activity (MIC(90), 1 mg/L) against penicillin-resistant penumococci that showed
      high levels of coresistance to beta-lactams. All isolates of S pyogenes were
      fully susceptible to the beta-lactams tested. Beta-lactamase production was
      common among H influenzae isolates (28.3% [765/2706]). Telithromycin was active
      against H influenzae (MIC(90), 4 mg/L), irrespective of beta-lactamase
      production. CONCLUSION: Overall, these findings from the first year of PROTEKT US
      support the potential value of telithromycin in the treatment of CARTIs.

PMID- 15189748
TI  - A multicenter, open-label, phase II study of the immunogenicity and safety of a
      new prefilled syringe (liquid) formulation of Avonex in patients with multiple
      sclerosis.
AB  - BACKGROUND: A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a])
      in a prefilled syringe has been developed to make administration of the drug
      easier for patients with multiple sclerosis (MS). This formulation does not
      contain human serum albumin (HSA), often added to interferon (IFN) products for
      stabilization. However, formulation changes may alter the secondary, tertiary,
      and quaternary structures of IFNbeta products. These kinds of structural changes
      could lead to the formation of antibodies directed against IFNbeta. Some of these
      anti-IFN antibodies may neutralize the biologic activity of IFNbeta. OBJECTIVE:
      This study was designed to determine the immunogenicity and safety of the new
      prefilled syringe (liquid) HSA-free formulation of Avonex in patients with
      relapsing MS. METHODS: This was a multicenter, single-arm, open-label study.
      Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM
      injection from a prefilled syringe once weekly for up to 24 months.
      Immunogenicity and safety were assessed every 3 months. Serum levels of
      neutralizing antibodies (NAbs) were measured at baseline and every 3 months using
      a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay.
      RESULTS: A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9]
      years; age range, 19.0-59.0 years) were enrolled in the study. Sera were
      available for analysis from 125 and 119 patients after 18 and 24 months of
      treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive
      titers of > or =20, a level at which the persistent presence of NAbs has been
      shown in some studies to have clinical consequences. By 24 months, 1 additional
      patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5
      patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had
      > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable
      to the lyophilized form containing HSA. CONCLUSIONS: The prefilled syringe
      (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level
      of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or
      =2 consecutive titers of > or =20).

PMID- 15189750
TI  - Randomized, multinational, open-label, 2-period, crossover comparison of biphasic
      insulin aspart 30 and biphasic insulin lispro 25 and pen devices in adult
      patients with type 2 diabetes mellitus.
AB  - OBJECTIVE: The goal of this study was to compare the efficacy and safety profiles
      of biphasic insulin aspart 30 (30% soluble insulin aspart and 70% protaminated
      insulin aspart [BIAsp 30]) and biphasic insulin lispro 25 (25% soluble insulin
      lispro and 75% neutral protamine lispro [Mix25]) used in a BID injection regimen
      in patients with type 2 diabetes mellitus (DM). Also assessed was patients'
      preference for pen device--the NovoMix 30 FlexPen /NovoLog Mix 70/30 FlexPen
      (FlexPen) versus the Humalog Mix25 Pen/Humalog Mix75/25 Pen (Humalog Pen).
      METHODS: Patients with type 2 DM receiving current insulin treatment were
      randomized to a multinational, multicenter, open-label, 2-period, crossover
      comparison of BIAsp 30 and Mix25. Efficacy (by analyses of variance) and safety
      profiles were assessed after 12 weeks of treatment. Patients' preference for pen
      device was assessed by questionnaires. RESULTS: A total of 137 patients were
      randomized to treatment; 4 were withdrawn during the 2-week run-in treatment with
      biphasic human insulin 30. The mean (SD) characteristics of the remaining 133
      patients (79 men, 54 women) were as follows: age, 62.3 (9.2) years; body mass
      index, 28.1 (3.9) kg/m(2); and glycosylated hemoglobin (HbA(1c)), 8.5% (1.1).
      Glycemic control was assessed by the measurement of HbA(1c) after 12 weeks of
      treatment. Treatment with BIAsp 30 was noninferior to treatment with Mix25 (upper
      limit of 90% CI for estimated difference [BIAsp 30 - Mix25] was <0.4%). Self
      monitored blood glucose levels were comparable (P = NS). Adverse-event profiles
      were similar between treatments, as was the incidence of hypoglycemic episodes
      (0.69 episode/mo with BIAsp 30 and 0.62 episode/mo with Mix25, P = 0.292). For
      all device features assessed, the FlexPen consistently received higher scores
      (all P < 0.005). A total of 9.0% of patients experienced problems with the
      FlexPen, compared with 32.4% with the Humalog Pen (P < 0.001). Furthermore, 74.6%
      preferred to continue using the FlexPen, whereas 14.3% preferred the Humalog Pen
      (P < 0.001). CONCLUSIONS: In this study, glycemic control with BIAsp 30 and Mix25
      was found to be comparable in these patients with type 2 DM. Safety profiles were
      similar for both regimens. Patients preferred and experienced fewer problems with
      the FlexPen than the Humalog Pen.

PMID- 15189751
TI  - A 12-month, multicenter, randomized, double-masked, parallel-group comparison of
      timolol-LA once daily and timolol maleate ophthalmic solution twice daily in the
      treatment of adults with glaucoma or ocular hypertension.
AB  - BACKGROUND: Timolol maleate, a nonselective beta-adrenoceptor antagonist applied
      topically to the eye as a solution, is well known for its ocular hypotensive
      efficacy. A gellan formulation of timolol maleate is given once daily and has
      been shown to be as effective as timolol maleate solution, but is associated with
      ocular symptoms that may limit its utility. A new timolol maleate solution has
      been formulated that contains potassium sorbate (timolol-LA [TLA; Istalol(R)]) to
      enhance the ocular bioavailability of timolol instilled into the eye, as well as
      half the benzalkonium chloride preservative found in timolol maleate. OBJECTIVE:
      The objective of this trial was to assess the ocular hypotensive efficacy and
      safety profile of TLA 0.5% solution once daily with those of timolol maleate
      ophthalmic solution (TIM) 0.5% twice daily in patients with open-angle glaucoma
      (OAG) or ocular hypertension (OHT). METHODS: This multicenter, prospective,
      randomized, double-masked, parallel-group clinical trial was conducted at 21
      participating private practices across the United States. Patients aged > or =18
      years with OAG or OHT in 1 or both eyes and an unmedicated intraocular pressure
      (IOP) of > or =22 mm Hg were randomized to receive either TLA once daily or TIM
      twice daily bilaterally for 12 months. The primary outcome measure was IOP (95%
      CIs) on treatment difference at each visit (ie, equivalence analysis). The safety
      profile was assessed based on biomicroscopic and ophthalmoscopic examination and
      patient symptoms. RESULTS: A total of 332 patients (203 women, 129 men; mean
      [SEM] age, 64.6 [11.8] years [range, 29-92 years]) entered the study. Of these,
      290 patients (87.3%) completed it. At none of the visits did the 95% CIs for
      between-treatment comparisons exceed 1.5 mm Hg and, at most of the visits, these
      intervals did not exceed 1.0 mm Hg. Mean baseline IOP was approximately 25 mm Hg
      in both groups. IOP was reduced at all posttreatment visits to 18 to 19 mm Hg at
      peak and to approximately 19 to 20 mm Hg at trough drug level in both treatment
      groups. Mean reductions from baseline were 6 to 7 mm Hg at peak and 5 to 6 mm Hg
      at trough (25.5%-28.7% and 20.8%-24.7%, respectively). Seventeen patients (5.1%)
      withdrew due to adverse events (AEs) (10 patients [6.0%] and 7 patients [4.2%] in
      the TLA and TIM groups, respectively). Based on biomicroscopic and
      ophthalmoscopic examination and volunteered symptoms, the safety profile was
      similar between the 2 treatments, except for burning and stinging on
      instillation, with an incidence of 41.6% in the TLA group and 22.9% in the TIM
      group (P = 0.001). Nearly all cases of burning and stinging were mild (94.2% [65
      events] with TLA and 90.0% [36 events] with TIM), and none of the patients
      discontinued treatment due to this AE. CONCLUSIONS: TLA solution, a nonselective
      beta-adrenoceptor antagonist, given once daily in the morning, was found to be
      statistically equivalent in ocular hypotensive efficacy (as defined a priori)
      compared with TIM, given twice daily, and with an acceptable safety profile in
      this study population of adult patients.

PMID- 15189752
TI  - A new tool to assess and document pain outcomes in chronic pain patients
      receiving opioid therapy.
AB  - BACKGROUND: Opioid analgesics are the cornerstone of management for malignant
      pain. Their use in managing chronic, nonmalignant pain, albeit controversial, has
      increased in recent years. The decisions about whether to initiate opioid therapy
      or continue it over time should be guided by a comprehensive patient assessment.
      During long-term treatment, this assessment should focus on a broad range of
      outcomes, each of which should be documented in the medical record. OBJECTIVE:
      The goal of this study was to develop an instrument, the Pain Assessment and
      Documentation Tool (PADT), to focus on key outcomes and provide a consistent way
      to document progress in pain management therapy over time. METHODS: Items that
      assess 4 domains (pain relief, patient functioning, adverse events, and drug
      related behaviors) were generated with input from a MEDLINE literature search and
      experts in pain and addiction management. The original tool was field tested by
      clinicians who applied it to the assessment of patients receiving long-term
      opioid therapy for the management of chronic, nonmalignant pain. Data analysis
      and debriefing telephone interviews with a formalized set of questions were then
      used to rephrase, delete, and refine items to create the final tool. RESULTS: A 6
      member expert panel contributed to the initial development of the PADT. Twenty
      seven clinicians completed the preliminary version of PADT for 388 patients. The
      original 59-item tool was modified to create a 41-item tool. The revised PADT was
      formatted for use as a chart note designed to assist clinicians in assessing and
      documenting 4 main outcome domains during long-term opioid use. CONCLUSIONS: In
      this study, the PADT appeared to be a useful tool for clinicians to guide the
      evaluation of several important outcomes during opioid therapy and provide a
      simple means of documenting patient care.

PMID- 15189753
TI  - Supporting the validity of outcomes research.

PMID- 15189754
TI  - Development and validation of the insulin treatment satisfaction questionnaire.
AB  - BACKGROUND: Treatment of diabetes mellitus (DM) is complex, requiring
      multifaceted lifestyle change or regulation and, for many, self-regulation of
      insulin levels in the blood. Historically, daily insulin treatment has been
      viewed as burdensome to patients, prompting newer formulations and improved
      delivery methods. OBJECTIVE: This multicenter, clinical study was designed to
      develop a conceptually sound, clinically meaningful, and psychometrically valid
      measure of insulin treatment satisfaction, applicable to a wide range of insulin
      therapies. METHODS: A 3-phase iterative process was employed to develop and
      validate the Insulin Treatment Satisfaction Questionnaire (ITSQ): (1) conceptual
      development of items, (2) preliminary validation among patients with DM, and (3)
      confirmatory validation among patients with DM. RESULTS: The ITSQ was validated
      with 170 patients in phase 2 and 402 patients in phase 3. Confirmatory factor
      analysis produced a 5-factor, 22-item instrument assessing regimen inconvenience,
      lifestyle flexibility, glycemic control, hypoglycemic control, and satisfaction
      with the insulin delivery device. Results for reliability and construct validity
      of the final version were consistent in both samples of patients treated with
      insulin, with different data collection methods. Internal consistency (using
      Cronbach alpha coefficient) of the subscales ranged from 0.79 to 0.91. Test
      retest reliability (using Spearman rank correlation coefficients) ranged from
      0.63 to 0.94. ITSQ scores showed moderate to high correlation with related
      measures of treatment burden. The ITSQ differentiated among insulin delivery
      methods, glycosylated hemoglobin values, the number of times the patient required
      assistance administering insulin, and insulin adherence. CONCLUSION: In our study
      samples, the ITSQ appeared to be conceptually and psychometrically sound and
      applicable to a wide range of insulin therapies.

PMID- 15189755
TI  - Cost-benefit analysis of capecitabine versus 5-fluorouracil/leucovorin in the
      treatment of colorectal cancer in the Netherlands.
AB  - BACKGROUND: Capecitabine is an oral prodrug of 5-fluorouracil and has been
      studied for the treatment of colorectal cancer. In 2 Phase III trials,
      capecitabine was at least as effective as 5-fluorouracil plus leucovorin and had
      a more favorable toxicity profile. OBJECTIVE: A cost-benefit analysis was used to
      assess the pharmacoeconomic profile of capecitabine compared with 5
      fluorouracil/leucovorin, given according to the Mayo regimen, for colorectal
      cancer patients treated in the Netherlands. METHODS: The medical files of
      patients treated for colorectal cancer at a single center from 1999 to 2002 were
      examined to determine the numbers of outpatient visits for 5
      fluorouracil/leucovorin administration, health care use and medication to manage
      adverse effects, and travel distance to and from the hospital. The costs of
      capecitabine treatment were simulated by assuming that the same patients were
      treated with capecitabine instead of 5-fluorouracil/leucovorin. Toxicity data for
      capecitabine were derived from 2 Phase III studies that compared capecitabine and
      5-fluorouracil/leucovorin. RESULTS: The files of 65 patients were reviewed.
      Thirty-two patients received adjuvant treatment and 33 patients were treated
      palliatively for metastatic disease. The mean total costs of palliative treatment
      were Euro 4004 with capecitabine and Euro 5614 with 5-fluorouracil/leucovorin.
      These results were robust in sensitivity analyses. The cost savings were
      primarily related to the number of outpatient visits for capecitabine versus the
      number of day-care treatment days for 5-fluorouracil/leucovorin, despite the
      higher acquisition costs of capecitabine. CONCLUSIONS: Based on this analysis,
      treatment of colorectal cancer with oral capecitabine is cost saving in the
      Netherlands compared with 5-fluorouracil plus leucovorin administered according
      to the Mayo regimen. Baseline savings were estimated at Euro 1610 for palliative
      treatment and Euro 934 for adjuvant treatment.

PMID- 15189756
TI  - Development of an instrument to assess expectations of and preference for an
      insulin injection pen compared with the vial and syringe.
AB  - BACKGROUND: Before using a product, patients form expectations regarding the
      extent of a product's desirable attributes. These expectations can be used to
      understand their preference and anticipate potential satisfaction with the
      product. OBJECTIVE: The aim of this study was to produce a valid and reliable
      data collection instrument (the Insulin Injection Preference questionnaire [IIP
      q]) to measure expectations of and preference for the insulin injection pen
      compared with the vial and syringe. METHODS: This study was initiated at the
      University of Mississippi (University, Mississippi). The IIP-q was developed to
      determine the extent to which respondents' prepurchase expectations of a
      product's attributes relate to preference for an insulin injection pen compared
      with the vial and syringe. Instrument development began with item generation
      related to product attributes important to patients who inject insulin. Items
      originated from an extensive search of the peer-reviewed Internet-based
      literature, marketing reports, clinical studies, and existing instruments.
      Content validity also was assessed using expert panel and focus group review. The
      resultant instrument (the IIP-q) was mailed to 1200 patients known to have type 1
      or type 2 diabetes mellitus who either did or did not use insulin. Subscales were
      identified through exploratory factor analysis. Reliability and validity were
      assessed using Cronbach alpha for subscale items. Product-moment correlations
      between subscale dimensions and 2 global measures of preference were used to test
      the relationship between attribute expectations and preference. RESULTS:
      Seventeen of the questionnaires were returned as undeliverable, leaving 1183 in
      the sample population. Questionnaires were received from 302 individuals, 55 of
      whom failed to complete > or = 85% of the items and thus were not included in the
      final analysis. Of the 247 respondents (135 women, 112 men; mean [SD] age, 52.4
      [13.2] years (range, 18-83 years]), 99 (40.1%) were current insulin users and 143
      (57.9%) were not using insulin. Exploratory factor analysis resulted in a 13-item
      solution (Cronbach alpha = 0.92), accounting for 73.6% of the total explained
      variance. Ease of use, activity interference, and social acceptability emerged as
      expectation subscales from exploratory factor analysis. Cronbach alpha for items
      comprising the subscales ranged from 0.82 to 0.92. The 3 subscales were
      significantly correlated with patient preference (ease of use, r = 0.520, P <
      0.001; activity interference, r = 0.570, p < 0.001; social acceptability, r =
      0.602, p < 0.001). CONCLUSIONS: The results of the present study provide support
      for the IIP-q as a reliable and valid instrument to assess patient expectations
      of product attributes and preference. This instrument can be modified for use in
      clinical trials to determine the role of patient expectations and preference in
      their judgments regarding satisfaction with insulin delivery devices.

PMID- 15189757
TI  - Treatment gaps for hypertension management in rural Canadian patients with type 2
      diabetes mellitus.
AB  - BACKGROUND: There were a reported 2.2 million Canadians living with diabetes
      mellitus (DM) in 2002, of whom 1.98 million (90.0%) had type 2 DM. In addition,
      there are approximately 60,000 new cases of type 2 DM diagnosed in Canada each
      year. However, the research shows that evidence and guidelines for management of
      hypertension in DM are not always translated into clinical practice. In rural
      areas, factors affecting implementation of recommendations and/or guidelines are
      less well understood, although some studies suggest that urban practices provide
      higher quality of care overall than rural areas. OBJECTIVE: The goal of this
      study was to describe the patterns of medication use for hypertension for
      patients with type 2 DM in rural northern Alberta, Canada. We also tried to
      identify treatment gaps and opportunities for prescribing antihypertensives
      relative to the Canadian Diabetes Association's 1998 Clinical Practice Guidelines
      for the Management of Diabetes in Canada and the Canadian Hypertension Society
      Recommendations Working Group's 2003 Canadian Recommendations for the Management
      of Hypertension: Therapy. METHODS: This study was conducted at the Institute of
      Health Economics and the University of Alberta (Edmonton, Alberta, Canada). We
      collected information from a cohort of patients aged >or =20 years with type 2 DM
      living in 2 adjacent rural regions of northern Alberta, Canada, at the time of
      enrollment in a diabetes care quality-improvement program as part of the Diabetes
      Outreach Van Enhancement (DOVE) study. Treatment gaps were determined by
      comparing antihypertensive pharmacotherapy with a blood pressure (BP) target of <
      or =130/< or =85 mm Hg. We used multivariate regression analyses to determine the
      associations between sociodemographic and clinical characteristics and treatment
      gaps. RESULTS: A total of 392 patients (229 women, 164 men; mean [SD] age, 62.3
      [12.5] years) with type 2 DM were included in this analysis. Patients had a mean
      (SD) duration of diabetes of 8.3 (8.5) years. A total of 75.8% (297/392) of the
      study population had hypertension, and most (236/392[60.2%]) were receiving some
      pharmacotherapy. Treatment gaps were present; 42.7% (n = 67) of patients not
      receiving pharmacotherapy for hypertension were above the established BP targets.
      For patients receiving monotherapy, 70% were not at BP targets. For patients
      receiving dual, triple, and > or =4 medications, 65%, 66%, and 46%, respectively,
      were not at BP targets. After controlling for systolic blood pressure, male sex
      (adjusted odds ratio [aOR], 2.17; 95% CI, 1.17-4.03), older age (aOR, 1.80 per
      decade; 95% CI, 1.51-2.09), lower self-reported physical health (aOR, 0.68; 95%
      CI, 0.41-0.96), higher body mass index (aOR, 1.05; 95% CI, 1.01-1.10), and
      past/current smoking (aOR, 1.95; 95% CI, 1.01-3.76) were all significantly
      associated with a lack of treatment for hypertension. CONCLUSIONS: Treatment maps
      in the management of hypertension exist in these rural Canadian patients with
      type 2 DM. Cardiovascular risk may be underestimated in these patients,
      particularly among younger patients and women, and those with multiple non-DM
      risk factors. These are patient subgroups that should be targeted as
      opportunities to improve hypertension management at the population level.

PMID- 15189758
TI  - Drug affordability and prescription noncompliance in the United States: 1997
      2002.
AB  - BACKGROUND: Prescription drug costs have risen rapidly since the mid-1990s.
      Inability to pay for medications has consequences for population health and
      health system costs. However, national data on the scope of prescription
      noncompliance due to cost are surprisingly inconsistent. OBJECTIVE: The goals of
      this study were to use data from a large, all-ages survey that accurately
      represents the civilian, noninstitutionalized population to estimate the national
      prevalence of medication noncompliance due to cost, identify sources of variation
      in rates of noncompliance due to cost, and assess changes in these rates over a
      recent 6-year interval (1997-2002). METHODS: We undertook a trend analysis of the
      National Health Interview Surveys for 1997 through 2002 and detailed
      subpopulation analysis of the 2002 survey to determine rates of noncompliance due
      to cost. RESULTS: Our analyses used a total sample size of 276,425 respondents
      for the 6-year period and a sample size of 43,568 respondents for the year-2002
      subpopulation analysis. Self-reported rates of noncompliance due to cost grew
      from 4.7% in 1997 to 5.9% in 2002. The results of the 2002 survey suggested that
      noncompliance varied by subpopulation, with relatively high rates (P < 0.001)
      among working-age adults (ie, aged 18-64 years), women, blacks, Medicaid and
      Medicare beneficiaries, those with low incomes, and those without health
      insurance. CONCLUSION: A relatively small but growing proportion of Americans are
      unable to afford the medications they are prescribed. Cost-associated
      noncompliance, like other health care access problems, is unevenly distributed in
      the population.

PMID- 15189759
TI  - Spider and wasp neurotoxins: pharmacological and biochemical aspects.
AB  - Venoms from several arthropods are recognized as useful sources of bioactive
      substances, such as peptides, acylpolyamines, and alkaloids, which show a wide
      range of pharmacological effects on synaptic transmission. In this work, we
      summarize and compile several biochemical and pharmacological aspects related to
      spider and wasp neurotoxins. Their inhibitory and stimulatory actions on ion
      channels, receptors, and transporters involved in mammalian and insect
      neurotransmission are considered.

PMID- 15189760
TI  - Sigma-2 receptors are specifically localized to lipid rafts in rat liver
      membranes.
AB  - We have previously shown that sigma-2 receptors are relatively difficult to
      solubilize (Eur. J. Pharmacol. 304 (1996) 201), suggesting possible localization
      in detergent-resistant lipid raft domains. Rat liver membranes were treated on
      ice with 1% Triton X-100 or 20 mM 3-[(3-cholamidopropyl)dimethylammonio]-1
      propanesulfonate (CHAPS), and the extract subjected to centrifugation on a
      discontinuous gradient of 5%, 38%, and 40% sucrose. Gradient fractions were
      analyzed for sigma-1 receptors using [3H]+-pentazocine and for sigma-2 receptors
      using [3H]1,3-di-o-tolylguanidine ([3H]DTG), in the presence of dextrallorphan.
      Flotillin-2 was assessed by immunoblotting as a marker for lipid rafts. Sigma-2
      receptors were found to discretely co-localize with flotillin-2 in lipid raft
      fractions. However, sigma-1 receptors were found throughout the gradient. Rafts
      prepared in CHAPS had sigma-2 receptors with normal pharmacological
      characteristics, whereas those in Triton X-100-prepared rafts had about seven
      fold lower affinity for [3H]DTG and other ligands. Thus, sigma-2 receptors are
      resident in membrane lipid rafts, whereas sigma-1 receptors appear in both raft
      and non-raft membrane domains. Lipid rafts may play an important role in the
      mechanism of sigma-2 receptor-induced apoptosis.

PMID- 15189761
TI  - Comparison of kinetic properties of quinidine and dofetilide block of HERG
      channels.
AB  - Many drugs inhibit human ether-a-go-go related gene (HERG) current and prolong
      cardiac action potential duration. We examined the kinetic properties of
      quinidine block of HERG channels expressed in Xenopus oocytes in comparison with
      those of the block by a class III antiarrhythmic dofetilide. Both of the drugs
      inhibited HERG currents in a use-dependent and frequency-independent manner.
      However, the underlying mechanisms were different. Under the steady state,
      quinidine block was voltage- and time-dependent. At positive membrane potentials,
      the onset of block was very fast. Thus, quinidine caused frequency-independent
      block mainly through this fast blocking kinetic. In contrast, dofetilide blocked
      HERG currents in a voltage- and time-independent manner under the steady state
      because of very slow unblocking at negative potentials, which also caused
      frequency-independent block. Therefore, quinidine and dofetilide might cause the
      reverse frequency-dependent prolongation of action potential duration through
      distinct mechanisms with regard to blocking and unblocking kinetics.

PMID- 15189762
TI  - Resistin, but not adiponectin, inhibits dopamine and norepinephrine release in
      the hypothalamus.
AB  - Adiponectin (Adipocyte Complement-Related Protein of 30 kDa, ACRP30) and resistin
      are adipocyte-derived polypeptide hormones playing a role in metabolic
      homeostasis. Their plasma levels are inversely (adiponectin) or directly
      (resistin) correlated to obesity and they have opposite effects on insulin
      sensitivity. Adipose tissue hormones such as leptin have been shown to modulate
      neurotransmitters which control feeding in the hypothalamus. We have studied the
      effects of adiponectin and resistin on dopamine, norepinephrine and serotonin
      release from hypothalamic neuronal endings (synaptosomes) in vitro. We have found
      that adiponectin does not modify either basal or depolarization-induced amine
      release, while resistin inhibits the stimulated release of dopamine and
      norepinephrine, leaving unaffected serotonin release. We can conclude that,
      similarly to leptin, but differently from adiponectin, the adipose tissue hormone
      resistin could affect the central mechanisms of feeding by inhibiting
      catecholamine release in the hypothalamus.

PMID- 15189764
TI  - Avermectins inhibit multidrug resistance of tumor cells.
AB  - The modification of the sensitivity of Hep-2 and P388 tumor cells to taxol and
      vincristine, substrates of multidrug resistance proteins, by naturally occurring
      avermectins and the effect of avermectins on the accumulation of calcein in cells
      and the efflux of rhodamine 123 were studied. While avermectins did not affect
      the sensitivity of tumor cells to hydrogen peroxide and cisplatin, they
      significantly enhanced the sensitivity of cells of both wild-type and resistant
      strains to taxol and vincristine. The coefficients of modification for resistant
      strains were substantially higher. Avermectins suppressed the efflux of rhodamine
      123 from cells and increased the accumulation of calcein in cells. The relative
      inhibitory activity of avermectins depended on the cell type and on the substrate
      of multidrug resistance proteins whose transport they suppressed (vincristine,
      taxol, rhodamine 123, calcein acetoxymethyl ester). The least active was
      avermectin B1 or ivermectin; the most active avermectins varied depending on the
      substrate and the cell type. In the case of vincristine transport, the most
      active avermectin was almost by one order of magnitude more effective than the
      traditional inhibitor of multidrug resistance cyclosporin A. This property of
      avermectins can be used in tumor therapy by combining application of avermectins
      with antitumor preparations, the substrates of multidrug resistance proteins.

PMID- 15189763
TI  - Opposing effects of cyclooxygenase-2 selective inhibitors on oxygen-glucose
      deprivation-induced neurotoxicity.
AB  - Cyclooxygenase-2 inhibitors protect against excitotoxicity in vitro yet provide
      conflicting results in in vivo models of ischemia. To bridge the gap in
      understanding the discrepancies among these studies, the effects of different
      cyclooxygenase-2 inhibitors were studied in an in vitro model of ischemia. Oxygen
      glucose deprivation (OGD) induced cyclooxygenase-2 protein expression in neuronal
      cortical cultures. Cyclooxygenase-2 inhibitors exhibited opposing effects on
      neuronal death induced by OGD. The acidic sulfonamides, N-(2-cyclohexyloxy-4
      nitrophenyl) methanesulfonamide (NS-398) and N-(4-nitro-2-phenoxyphenyl)
      methanesulfonamide (nimesulide), aggravated neuronal death by enhancing OGD
      induced increases in extracellular glutamate and intracellular Ca2+ levels. In
      contrast, 1-[(4-methylsulfonyl)phenyl]-3-tri-fluoromethyl-5-(4
      fluorophenyl)pyrazole (SC-58125) dose-dependently protected cultures against OGD
      by suppressing increases in extracellular glutamate and intracellular Ca2+
      levels. The NS-398-induced aggravation of neuronal death was lost if the
      inhibitor was added only following the OGD. The timing of inhibitor application
      also determined its effects on N-methyl-D-aspartate (NMDA)-induced excitoxicity.
      NS-398 was protective when added both during and post-NMDA exposure, but not if
      NS-398 was also applied for 60 min prior to the insult. In contrast, SC-58125
      afforded protection against NMDA in the presence or absence of a pre-incubation
      period. This study demonstrates that certain cyclooxygenase-2 inhibitors have
      opposing effects on neuronal survival depending on the timing of application and
      the nature of the insult. These results may account for the discrepancies among
      previous studies which used different inhibitors and different models of
      neurotoxicity.

PMID- 15189765
TI  - The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat.
AB  - Our study addressed the hypothesis that spinal release of endogenous opioids
      underlies Delta9-tetrahydrocannabinol (Delta9-THC)-induced antinociception in
      Freund's adjuvant-induced arthritic and nonarthritic rats. The paw-pressure test
      was used to assess the antinociceptive effects of Delta9-THC versus those of
      morphine, and opioid and cannabinoid receptor-selective antagonists were used to
      characterize the involved receptors. Cerebrospinal fluid was collected after
      Delta9-THC injection (i.p.) for the measurement of endogenous opioid peptides.
      Our results indicate that morphine or Delta9-THC is equally potent and
      efficacious in both nonarthritic and arthritic rats. Delta9-THC-induced
      antinociception is attenuated by the kappa opioid receptor antagonist, nor
      binaltorphimine, in arthritic rats only. Delta9-THC induces increased
      immunoreactive dynorphin A (idyn A) levels in nonarthritic rats while decreasing
      idyn A in arthritic rats. We hypothesize that the elevated idyn A level in
      arthritic rats contributes to hyperalgesia by interaction with N-methyl-D
      aspartate receptors, and that Delta9-THC induces antinociception by decreasing
      idyn A release.

PMID- 15189766
TI  - Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine
      release in the prefrontal cortex and hippocampus in rat brain.
AB  - Aripiprazole,7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro
      carbostycil (OPC-14597), a novel atypical antipsychotic drug, is a dopamine D2
      receptor partial agonist with functional 5-HT2A receptor antagonist, and 5-HT1A
      receptor partial agonist properties as well. Other atypical antipsychotic drugs,
      e.g. clozapine, but not typical antipsychotic drugs, e.g. haloperidol, produce
      significant increases in dopamine and acetylcholine release in the medial
      prefrontal cortex in rats, effects believed to be related to the ability to
      improve cognitive function. The increase in the medial prefrontal cortex dopamine
      release by the atypical antipsychotic drugs has been shown to be partially
      inhibited by N-[2[4-)2-methoxyl)-1-piperazinyl]ethyl]-N-(2
      pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT1A
      receptor antagonist. Aripiprazole, 0.1 and 0.3 mg/kg, significantly increased
      dopamine release in the hippocampus. Moreover, aripiprazole, 0.3 mg/kg, slightly
      but significantly increased dopamine release in the medial prefrontal cortex but
      not in the nucleus accumbens. These increases were significantly inhibited by
      WAY100635. By contrast, aripiprazole, 3.0 mg/kg and 10 mg/kg, significantly
      decreased dopamine release in the nucleus accumbens but not the medical
      prefrontal cortex. However, aripiprazole 10 mg/kg significantly decreased
      dopamine release in the both regions. Aripiprazole had no effect on acetylcholine
      release in the medial prefrontal cortex, hippocampus, or nucleus accumbens at any
      dose, except for 3.0 mg/kg, which decreased acetylcholine release in the nucleus
      accumbens only. Aripiprazole, 0.3 mg/kg, transiently potentiated haloperidol (0.1
      mg/kg)-induced dopamine release in the medial prefrontal cortex but inhibited
      that in the nucleus accumbens. The present study demonstrated that aripiprazole,
      at low doses of 0.1 and 0.3 mg/kg, increases dopamine release in the medial
      prefrontal cortex and hippocampus. It also suggests that the function of both the
      medial prefrontal cortex and hippocampus may contribute to the ability of
      aripiprazole to improve negative symptom and cognition.

PMID- 15189767
TI  - The role of the 5-HT1D receptor as a presynaptic autoreceptor in the guinea pig.
AB  - The present study investigated the role of the 5-hydroxytryptamine (5-HT,
      serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping
      with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'
      (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro
      [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT
      outflow from pre-labelled slices of guinea pig cerebral cortex confirming its
      role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D
      receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H
      pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642),
      (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4
      dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol
      3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6
      carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3
      dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from
      this preparation with potencies (EC50 values=31-140 nM) in the same range as
      their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The
      selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5
      [1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate
      (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration
      of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route,
      potentiated the increase in extracellular 5-HT concentration produced by a
      maximally effective dose of the selective serotonin re-uptake inhibitor,
      fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring
      antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated
      extracellular 5-HT concentrations to a greater extent than a maximally effective
      dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B
      receptor, may be a presynaptic autoreceptor in the guinea pig.

PMID- 15189768
TI  - Urotensin-II, a neuropeptide ligand for GPR14, induces c-fos in the rat brain.
AB  - The vasoactive peptide urotensin-II and its receptor, GPR14 (now known as UT
      receptor), are localised in the mammalian central nervous system. Accordingly,
      various centrally mediated effects of urotensin-II on behaviour, neuroendocrine
      hormones and neurochemistry have been described. To investigate neuroanatomical
      substrates for the central actions of urotensin-II, expression of the immediate
      early gene c-fos was examined following intracerebroventricular administration to
      rats. Urotensin-II increased Fos expression in the cingulate cortex and
      periaqueductal grey, suggesting important central roles for urotensin-II and its
      receptor.

PMID- 15189769
TI  - Neuroprotective effect of wogonin in hippocampal slice culture exposed to oxygen
      and glucose deprivation.
AB  - A poor supply of oxygen and glucose to the brain can cause severe brain damage.
      Therefore, neuroprotective drugs against ischemia need to be developed. In this
      study, wogonin, a flavone found in Scutellaria baicalensis, had a protective
      effect on neuronal cells damaged by oxygen and glucose deprivation in rat
      hippocampal slices in culture. In particular, the protective effect on the
      pyramidal cell layer was significant. On the basis of these experimental results,
      wogonin may be a therapeutic agent for treating ischemia in patients.

PMID- 15189770
TI  - Exposure to an elevated platform increases plasma corticosterone and hippocampal
      acetylcholine in the rat: reversal by chlordiazepoxide.
AB  - There is evidence that the septohippocampal cholinergic system is activated in
      response to stressful stimuli. In addition, prior studies indicate that
      stimulating the hippocampal cholinergic neurotransmission increases open arm
      exploration in the elevated plus-maze. This raises the possibility that exposing
      the rat to an elevated platform, which would be similar to confining the animal
      to the open arms of the plus-maze, would alter hippocampal acetylcholine levels.
      Results from the present study suggest that an elevated platform can be used as
      an animal model of stress in that exposure to the platform significantly
      increased plasma corticosterone levels. Importantly, exposure to a platform
      significantly increased hippocampal acetylcholine efflux. Interestingly, the
      increase in plasma corticosterone and hippocampal acetylcholine levels upon
      exposure to an elevated platform could be prevented by chlordiazepoxide at a dose
      that had no effect on basal hippocampal acetylcholine or plasma corticosterone
      levels. However, the elevated platform-induced increase in hippocampal
      acetylcholine could not be blocked by prior administration of buspirone. These
      results provide direct evidence for the importance of the hippocampal cholinergic
      system in stress and provide validation for the elevated platform as a model of
      stress.

PMID- 15189771
TI  - Pharmacological and biochemical studies on the possible role of nitric oxide in
      stress adaptation in rats.
AB  - The involvement of nitric oxide (NO) in stress adaptation was evaluated in rats
      using the elevated plus maze test. Repeated restraint stress RS(x 5) for 5 days
      resulted in an increase in the percentage number of entries and percentage time
      spent when compared to a single restraint stress RS(x 1) exposure. In the
      repeated RS treatment groups, the nitric oxide donor, L-arginine (500 and 1000
      mg/kg, i.p.) slightly increased the elevated plus maze test parameters when
      compared to the corresponding vehicle-treated group. The nitric oxide synthase
      (NOS) inhibitors, N-nitro-L-arginine methyl ester (L-NAME, 10 and 50 mg/kg, i.p.)
      and 7-nitroindazole (10 and 50 mg/kg, i.p.) produced differential responses in
      both the parameters with L-NAME exhibiting greater reduction in open arm entries
      and open arm time, whereas 7-nitroindazole produced only small differences in
      both the elevated plus maze parameters. Biochemical data showed that repeated
      restraint stress resulted in higher levels of brain nitrates and nitrites (NOx)
      as compared to that of single restraint stress exposure. Further, in L-arginine
      (1000 mg/kg, i.p.)-treated rats, brain NOx was lowest in the single restraint
      stress group, followed by repeated restraint stress and (no restraint stress)
      controls. The results are suggestive of the role of nitric oxide in stress
      adaptation and this may be due to the effects of restraint stress on brain NOS
      activity.

PMID- 15189772
TI  - Reinforcing effect of pseudoephedrine isomers and the mechanism of action.
AB  - It has been proposed that ephedrine and its isomers may have abuse potential.
      When made available to rhesus monkeys (n = 4) for self-administration, +
      pseudoephedrine functioned as a positive reinforcer in all monkeys, as did (-)
      pseudoephedrine in two of three monkeys. Pseudoephedrine isomers were 10- to 33
      fold less potent than cocaine. In in vitro binding in monkey brain tissue, both
      isomers had low affinity for dopamine and serotonin transporters by at least 200
      fold relative to cocaine, but comparable affinity for norepinephrine
      transporters. +-Pseudoephedrine also blocked dopamine uptake in 293 hDAT cells
      with low potency relative to cocaine. When given in vivo +-pseudoephedrine
      significantly displaced radioligand binding to dopamine transporters with a
      potency comparable to that in self-administration. Therefore, pseudoephedrine
      isomers can function as reinforcers and the mechanism at dopamine transporters
      may underlie this effect. However, pseudoephedrine appears to be a weak
      reinforcer and may have relatively low abuse potential.

PMID- 15189773
TI  - Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from
      M3R-/- mice.
AB  - Acetylcholine interacts with endothelial muscarinic receptors to enhance nitric
      oxide (NO) release and thereby cause vasodilation. The present study was designed
      to determine if this effect of acetylcholine is mediated by muscarinic M3
      receptors. Thoracic aortae were isolated from wild-type (WT) and M3 receptor
      knock out (M3R-/-) male mice, and endothelium-intact (I) and -denuded (D) aortic
      rings were bathed in physiological buffer. Preparations were utilized to examine
      the contractile response to phenylephrine (1 x 10(-8) - 3 x 10(-4) M added
      cumulatively) and the vasodilatory actions of acetylcholine (10(-8) - 10(-4) M),
      carbachol (10(-9) - 10(-4) M), ATP (3 x 10(-5) M) and the NO donor SIN-1 (10(-4)
      M), each added in the presence of phenylephrine. Endothelium-dependent
      vasodilatory effects of acetylcholine and carbachol were obvious in aortae
      isolated from WT mice (56.3 +/- 9.8% and 49.1 +/- 4.1% reductions, respectively,
      in phenylephrine-induced contraction; p < 0.05), while acetylcholine and
      carbachol-associated relaxations observed in endothelium-intact M3R-/-
      preparations (17.9 +/- 2.6% and 13.5 +/- 4.2% reductions, respectively) did not
      differ significantly from time-control values. ATP-induced, endothelium-dependent
      vasodilation was similar in preparations from M3R-/- and WT mice, and SIN-1
      elicited similar dilatory effects in intact and denuded WT and M3R-/- segments.
      Phenylephrine concentration-response curves were shifted leftwards by removal of
      the endothelium in both groups (EC50 values: WT-I/D--25.59 +/- 6.86/3.13 +/- 1.01
      x 10(-7) M; M3R-/-I/D--13.92 +/- 4.21/1.52 +/- 0.46 x 10(-7) M; both p < 0.05);
      however, the phenylephrine response did not differ significantly when compared
      between the WT and M3R-/- groups. These results indicate that the attenuated
      vasodilatory effect of acetylcholine in endothelium-intact aortae from M3R-/-
      mice is due to the absence of muscarinic M3 receptors, and thus suggest that in
      mouse aorta, muscarinic M3 receptors play a major role in the endothelium
      dependent acetylcholine-induced vasodilation.

PMID- 15189774
TI  - Neurogenic vasodilation of dural blood vessels is not mediated by cholinergic
      transmission in the anaesthetised rat.
AB  - Dural vessel dilation induced by activation of trigeminal sensory fibres may be
      responsible for some component of the migraine attack. The presence in some
      patients with migraine and cluster headache of clinical features, such as
      lacrimation, suggests cranial parasympathetic activation and poses the question
      as to whether neurogenic meningeal dilatation has a cholinergic component. Rats
      were prepared in order to record on-line the diameter of a middle meningeal
      artery branch through a closed cranial window using an intravital microscope
      coupled to a video dimension analyser. Acetylcholine (1 microg, intravenously,
      i.v.) was administered before and after muscarinic receptor inhibition (n=5) with
      scopolamine (2 mg/kg, i.v.) or nicotinic receptor inhibition (n=6) with
      mecamylamine (4 mg/kg, i.v.). Further vasodilation was induced by electrical
      stimulation of the cranial window surface before and after muscarinic receptor
      inhibition with i.v. scopolamine (n=8). The mean dural vessel percentage increase
      caused by acetylcholine stimulation was significantly different before and after
      muscarinic receptor inhibition (P=0.045). Moreover, there was no difference
      between the post receptor inhibition values and those obtained after vehicle
      infusion (P=0.431). In contrast, no difference was detected in the effect of
      acetylcholine before and after nicotinic receptor inhibition (P=0.688). In the
      second experiment, where the effect of muscarinic receptor inhibition on the
      neurogenic dilation model was assessed, no significant difference was
      demonstrated (P=0.538). Cholinergic dilation of the rat dural arteries is
      mediated by muscarinic receptors, but this mechanism does not play a significant
      role in the rat dural vessel dilation induced by closed cranial window electrical
      stimulation.

PMID- 15189775
TI  - Pertussis toxin-induced histamine sensitisation: an aspecific phenomenon
      independent from the nitric oxide system?
AB  - Mechanisms were studied initially to develop an in vitro safety test for
      detecting pertussis toxin toxicity in acellular pertussis vaccines based on the
      histamine sensitisation test. Maximal contractions and sensitivities to different
      agonists and adrenoceptor-induced contractions in Ca2+-free medium of isolated
      rat small mesenteric resistance arteries were significantly reduced by in vivo
      [30 microg/kg, intravenously (i.v.), day 5] or in vitro (10 microg/ml, 2 h)
      pertussis toxin pretreatment. Pertussis toxin-induced decrease in sensitivity of
      small mesenteric resistance arteries to noradrenaline was endothelium-dependent.
      Nomega-nitro-L-arginine methyl ester (L-NAME) (100 microM, 20 min) did not
      reestablish the sensitivity to noradrenaline. In vivo L-NAME treatment (0, 1, 10
      or 30 mg/kg) of pertussis toxin-pretreated (15 microg/kg) rats did not reduce
      pertussis toxin-induced enhancement of the histamine-induced decrease in blood
      pressure and histamine (10, 30, 100 or 300 mg/kg) induced mortality. Finally, in
      vivo pertussis toxin pretreatment sensitises rats for sodium nitroprusside (50
      microg/kg/min). We conclude that pertussis toxin-induced histamine sensitisation
      is caused by an interference of pertussis toxin with the contractile mechanisms
      of vascular smooth muscle of resistance arteries which indicates only an indirect
      role for histamine in the histamine sensitisation test.

PMID- 15189777
TI  - Angiotensin deficiency in mice leads to dilated cardiomyopathy.
AB  - To explore the role of angiotensin II, we assessed hemodynamics and cardiac
      function in angiotensinogen-deficient mice in comparison to wild-type animals.
      Left ventricular end-diastolic diameter and wall thickness were evaluated by
      echocardiography and systolic and diastolic left ventricular function by pressure
      volume relations using a micro-conductance catheter. Compared to wild-type
      animals, the angiotensinogen-deficient mice were hypotensive and showed impaired
      systolic function. The hearts were dilated, demonstrated by echocardiography and
      by a right-ward shift of the pressure-volume loops, but end-diastolic pressure,
      isovolumic relaxation (tau) and diastolic stiffness were unchanged. Afterload,
      however, was reduced leading to maintained cardiac output. Although a blockade of
      the renin-angiotensin system via angiotensin converting enzyme inhibitors or
      angiotensin AT1 receptor antagonist is beneficial after cardiac failure, the
      absence of angiotensin peptides during the ontogenesis leads to dilated
      cardiomyopathy.

PMID- 15189776
TI  - Sex-linked differences in the vasorelaxant effects of anandamide in vascular
      mesenteric beds: role of oestrogens.
AB  - Anandamide (0.01 to 10 microM) caused greater concentration-dependent reductions
      of the contractile-induced responses to noradrenaline in female than in male
      mesenteric vascular beds isolated from adult Sprague-Dawley rats. Greater
      relaxant responses in females were also induced by the vanilloid TRPV1 receptor
      agonist capsaicin (0.01 to 10 microM), whereas no sex differences were observed
      for the relaxations caused by either acetylcholine or sodium nitroprusside. The
      effect of anandamide in either sex was reduced by the vanilloid TRPV1 receptor
      antagonist capsazepine but not by the cannabinoid CB1 receptor antagonist N
      piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole
      carboxamide (SR141716A). In males, the anandamide-induced relaxations were
      potentiated by in vitro exposure during 5 min to 0.5 microM 17beta-oestradiol and
      unmodified by the protein synthesis inhibitor cycloheximide. The vasorelaxant
      effects of anandamide in female rats were decreased by ovariectomy. This decrease
      was prevented by in vivo treatment with 17beta-oestradiol-3-benzoate (450
      microg/kg i.m., once a week during 3 weeks) and counteracted by in vitro exposure
      to oestrogen. In vivo treatment with 17beta-oestradiol also potentiated
      anandamide-induced responses in males. In conclusion, this study shows an
      oestrogen-dependent sensitivity to the vanilloid TRPV1 receptor-mediated
      vasorelaxant effects of anandamide in the mesenteric vasculature of Sprague
      Dawley rats, that could be mediated by both genomic and non-genomic mechanisms.

PMID- 15189778
TI  - Partial protective effect of Y-27632, a Rho kinase inhibitor, against hepatic
      ischemia-reperfusion injury in rats.
AB  - (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)-cyclohexanecarboxamide
      dihydrochloride (Y-27632), a Rho kinase inhibitor, has a suppressive effect on
      the functions of polymorphonuclear leukocytes. In this study, the influence of Y
      27632 on ischemia-reperfusion injury of the liver was examined in rats. Y-27632
      (3 mg/kg) or vehicle alone was intravenously injected into rats 60 min before
      occlusion. Blood samples were obtained for 48 h after reperfusion. At the end of
      the experiment, the hepatic content of myeloperoxidase, which reflects the number
      of polymorphonuclear leukocytes in liver tissues, was determined. The increases
      in serum hepatic aminotransferases and inflammatory cytokines [tumor necrosis
      factor-alpha (TNF-alpha), interleukin (IL)-6] after reperfusion were partially,
      but significantly, inhibited by Y-27632. The increased hepatic myeloperoxidase
      content was significantly lowered by Y-27632. These results suggest that Y-27632
      has a partial protective effect against hepatic ischemia-reperfusion injury
      through the suppression of polymorphonuclear leukocytes and inflammatory
      cytokines.

PMID- 15189779
TI  - A specific chymase inhibitor, NK3201, suppresses bleomycin-induced pulmonary
      fibrosis in hamsters.
AB  - We evaluated whether a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6
      dihydropyrimidine-1-yl)-N-[(3,4-dioxo-1-phenyl-7-(2-pyridyloxy))-2
      heptyl]acetamide (NK3201), suppressed bleomycin-induced pulmonary fibrosis.
      Hamsters were orally administered NK3201 (30 mg/kg per day) or placebo, beginning
      5 days before intratracheal instillation of bleomycin (10 mg/kg). Four weeks
      after the instillation of bleomycin, pulmonary chymase activity in placebo
      treated hamsters was significantly higher than in control hamsters, whereas the
      activity in NK3201-treated hamsters was significantly lower than in placebo
      treated hamsters. The ratio of fibrotic area to total area in NK3201-treated
      hamsters was significantly decreased to 54.0% of the ratio in placebo-treated
      hamsters. Therefore, NK3201 may be useful in the prevention of pulmonary
      fibrosis.

PMID- 15189780
TI  - Potentiation by amino acid of the therapeutic effect of highly purified vitamin
      B2 in mice with lipopolysaccharide-induced shock.
AB  - The aim of this experiment was to clarify whether an amino acid supplement could
      enhance the therapeutic effect of vitamin B2 (riboflavin 5'-sodium phosphate;
      purity > 97%) in mice with lipopolysaccharide-induced shock. Six hours after
      injection of a lethal dose of lipopolysaccharide, treatment (6-h i.v. infusion)
      was commenced. All mice died in the groups treated with saline or aminolevane (an
      amino acids mixture used to treat hepatopathy); however, the survival rates in
      the vitamin B2 (10 mg/kg/6 h) and vitamin B2 plus aminolevane groups were 45% (P
      < 0.05) and 80% (P < 0.05), respectively. Valine (200 mg/kg/6 h) alone had little
      effect on the survival rate (10%), but the combination of vitamin B2 (10 mg/k/g/6
      h) and valine was highly effective (80%, P < 0.05). Clinical trials of vitamin B2
      plus amino acids for the treatment of patients with sepsis would appear to be
      warranted.

PMID- 15189782
TI  - Acute hyperthyroidism alters adrenoceptor- and muscarinic receptor-mediated
      responses in isolated rat renal and femoral arteries.
AB  - The effects of acute hyperthyroidism on the vasorelaxing responses to
      isoprenaline and acetylcholine were investigated in isolated rat renal and
      femoral arteries. In the renal artery, isoprenaline- and acetylcholine-induced
      relaxations were significantly greater in hyperthyroid rats than in control rats.
      In the femoral artery, only the acetylcholine-induced relaxation was
      significantly greater in hyperthyroid rats than in control rats. In the renal
      artery, NG-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide (NO)
      synthase, reduced isoprenaline- and acetylcholine-induced relaxations in both
      hyperthyroid and control rats and the isoprenaline-induced relaxation was still
      greater in hyperthyroid rats than in control rats, but no difference in the
      acetylcholine-induced relaxation was seen between the two groups of rats since L
      NOARG almost abolished the acetylcholine-induced relaxation. In the femoral
      artery, L-NOAGR reduced the isoprenaline-induced relaxation in control rats but
      not in hyperthyroid rats, while it almost abolished the acetylcholine-induced
      relaxation in both groups of rats. 17-Octadecynoic acid (17-ODYA), a cytochrome P
      450 monooxygenase inhibitor, reduced the isoprenaline-induced relaxation in renal
      and femoral arteries from hyperthyroid and control rats, but it did not change
      the acetylcholine-induced relaxation in both arteries. These results indicate
      that acute hyperthyroidism significantly enhances beta-adrenoceptor-mediated
      relaxation of the renal artery and muscarinic receptor-mediated relaxation of
      both renal and femoral arteries, suggesting that these effects may be due to an
      alteration in the NO and cytochrome P-450 systems of the artery.

PMID- 15189783
TI  - "Barebacking": intentional condomless anal sex in HIV-risk contexts. Reasons for
      and against it.
AB  - Intentional condomless anal sex in HIV-risk contexts ("barebacking") has been
      heatedly debated in gay circles, the gay media, and, to a lesser degree, the
      mainstream media. Yet it has received little attention in the scientific
      literature. In order to better understand the reasons behind this behavior, we
      conducted a content analysis of messages posted on an Internet message board
      following Gay.com's decision to close a company-sponsored bareback chat room.
      Individuals posting messages self-identified in their online profiles as being
      mostly White/ European gay men residing in the US, with an average age of 35
      years. Out of 130 messages, 62 (48%) were pro-barebacking, 55 (42%) were against
      barebacking, and 13 (10%) referred to other topics. The content analysis of the
      messages showed that both those in favor of and against barebacking felt well
      informed about HIV/AIDS and the risks of HIV transmission. Those in favor
      considered condomless sex more enjoyable than sex with condoms (both in actual
      experience and in erotic imagery), felt that condomless sex conferred a sense of
      freedom, minimized the risks involved in barebacking (assuming that practitioners
      were already HIV infected and that the risk of superinfection was small), and
      ultimately believed that barebacking was a personal decision and responsibility.
      Those against barebacking believed the behavior was dangerous, advocated for
      condom use and personal and social responsibility, and felt barebackers needed to
      be sensitized to the burdens of HIV disease. Implications of these results are
      discussed, pointing out the need for further scientific inquiry in this area.

PMID- 15189781
TI  - Effect of simvastatin and fenofibrate on endothelium in Type 2 diabetes.
AB  - Statins and fibrates influence endothelial activity and consequently
      atherogenesis but the mechanisms are not well understood. Twenty Type 2 diabetic
      patients with dyslipidemia were treated 3 months with simvastatin (20 mg daily)
      and then 3 months with fenofibrate (200 mg daily) with 2 months of wash-out
      between the two treatments. Laboratory parameters of oxidative stress,
      fibrinolysis and endothelial function were evaluated before and at the end of
      each treatment period. The significant decrease in serum total and LDL
      cholesterol concentrations (P<0.0001) caused by simvastatin was associated with
      an increase in serum N-acetyl-beta-glucosaminidase activity (P<0.001), ascorbic
      acid (P<0.001), plasminogen activator inhibitor (PAI-1) (P<0.01), vonWillebrand
      factor (P<0.05), E-selectin (P<0.01) and vascular endothelial growth factor
      (P<0.05) concentrations and with a decrease in plasma glutathione (P<0.01)
      levels. Fenofibrate caused a significant decrease in serum triglyceride
      concentration (P<0.0001) associated with a decrease in plasma malondialdehyde
      (P<0.001) and an increase in plasma PAI-1 (P<0.05) and P-selectin (P<0.05)
      concentrations. We conclude that simvastatin and fenofibrate interact, by
      different mechanisms, with oxidative stress, a key factor in the modification of
      fibrinolysis and endothelial function in Type 2 diabetes.

PMID- 15189784
TI  - Officer friendly and the tough cop:gays and lesbians navigate homophobia and
      policing.
AB  - Despite attempts to expand social diversity, policing is still dominated by a
      white, masculine, heterosexual ethos. As a consequence, employment of lesbians
      and gay men as police officers may be especially threatening to members of this
      occupation. Within the context of potential hostility and homophobia,
      nontraditional officers must negotiate their contradictory presence on the police
      force. This paper investigates that negotiation. Using the Bem Sex Role Inventory
      and open-ended survey data from a sample of "out" and "closeted" gay and lesbian
      police officers, we ask how gays and lesbians manage their images as "good cops"
      in the face of gender norm violations associated with their sexual orientation.
      Our findings indicate that masculinity and femininity do not hold together in a
      cohesive, dichotomous manner for these officers. Instead, other characteristics
      that enhance policing are emphasized to support their occupational competence.
      These officers see themselves as "good cops." The gendered/sexualized character
      of their self-perceptions appears to matter less than the context of the job,
      more than for a comparison sample of heterosexual police officers. We conclude
      that although gay and lesbian officers see their sexuality as an occupational
      asset, they are also likely to work harder to prove themselves as crime fighters.

PMID- 15189785
TI  - Black masculinity matters in attitudes toward gay males.
AB  - Recent work on attitudes toward homosexuals promotes the view that males
      typically have more negative attitudes than females; and African Americans have
      more negative attitudes than their white counterparts. However, among African
      Americans, women are thought to have the greatest negative attitudes because they
      perceive themselves as competing for a limited pool of black male partners. This
      study uses the National Black Politics Study to examine African American gender
      differences in attitudes toward homosexual men. Multivariate findings show that
      of the variables analyzed: (1) Among African American females, age, income,
      education, and urban residence are statistically significant; and (2) among
      African American males, frequency of religious attendance was the only
      statistically significant variable. It is, therefore, argued that black
      masculinity explains the gendered differences and that negative attitudes within
      the African American community toward gay men contribute to debilitating both the
      physical and mental health of the entire black community.

PMID- 15189786
TI  - Immutability, science, and legislative debate over gay, lesbian and bisexual
      rights.
AB  - Many gay rights advocates argued in the 1990s that scientific research claiming
      that sexual orientation is immutable should contribute to gaining civil rights
      for gays, lesbians and bisexuals. This paper analyzes ten legislative debates
      that took place at the local, state and federal levels over whether to adopt
      antidiscrimination laws, before and after the research was published. We
      hypothesize that if the research has had the impacts hoped for by gay rights
      supporters, then debates over gay rights should reflect certain changes
      consistent with such impacts. Although discussion of the origins of sexual
      orientation among legislators rose in the aftermath of the studies, we fail to
      find that the science had a major impact on the debate strategies pursued by
      either pro- or antigay rights legislators. Whether sexual orientation is
      immutable or a choice has not been a central claim of the two sides in the
      debate. Gay rights opponents even appear somewhat more willing to assert that
      sexual orientation is a choice after the studies than before. Furthermore, when
      the proponents of gay rights assert the immutability argument, they are as likely
      as not to invoke the cultural authority of science. We explain these outcomes by
      showing why the immutability issue is not of central relevance to most
      legislators or necessary for either side's key arguments. We also show that the
      scientific evidence merely supplemented a large amount of anecdotal information
      that legislators already possessed that spoke to the origins of sexual
      orientation.

PMID- 15189787
TI  - Telling tales in school: a queer response to the heterosexist narrative structure
      of higher education.
AB  - If we look at general education programs, we find that implicit in them is a
      narrative structure. Drawing on the work of Judith Roof, I argue that this
      structure can promote a heterosexist logic which has among its implications the
      marginalization of gay and lesbian studies. I further argue, however, that this
      need not be the case. By appealing to Paul Ricoeur's account of narrative and to
      Immanuel Levinas's description of one's obligation to respond to the face of the
      Other, I articulate a mode of engaging the narratives at play in general
      education programs that mitigates their potential for marginalization. More
      pointedly, I argue that truly vital and ethically sound programs must work
      against marginalization, which means, among other things, that they must promote
      the cultivation of gay and lesbian and queer studies.

PMID- 15189788
TI  - Economic analysis of same-sex marriage.
AB  - This article applies the neoclassical microeconomic analysis of marriage as
      developed by Nobel laureate economist Gary Becker to same-sex marriage. The
      objective is to demonstrate that the economic analysis of marriage supports
      allowing same-sex marriage, and that same-sex marriages would strengthen the
      incentive to marry, increase the efficiency of marriage markets, provide for more
      children to be raised in two-parent optimum environments, and benefit states
      economically overall. The article concludes with an overview of the economic
      impact of same-sex marriages on states based on the analysis, data and fiscal
      information currently available from researchers and economists in the field.

PMID- 15189789
TI  - Relational factors in understanding satisfaction in the lasting relationships of
      same sex and heterosexual couples.
AB  - Satisfying relationships are important to the well-being of individuals and
      families. Because of increased longevity, many couples are staying together for
      extended periods of time. Thus, it is valuable to understand the factors that
      contribute to a sense of satisfaction among partners in lasting relationships.
      Relatively little attention has been paid in the research literature to
      relationships among older couples who have remained together for many years. Even
      less attention has been paid to the lasting relationships of couples of color and
      to gay male and lesbian couples. This paper focuses on understanding the factors
      that contribute to satisfaction of partners in the long-term relationships of a
      purposive sample of heterosexual and same-sex couples. Data was collected through
      in-depth interviews with 216 partners in 108 relationships that had lasted an
      average of 30 years. Using logistic regression analysis, two factors were
      identified as predictive of satisfaction during the recent years of these
      relationships: containment of relational conflict and psychologically intimate
      communication between partners. Based on these findings, a theoretical model for
      understanding satisfaction in lasting relationships is discussed.

PMID- 15189790
TI  - "Some stars aren't like you and me": a talk with Wayne Koestenbaum on Andy
      Warhol.
AB  - Over twenty-five years after his unexpected death in 1987 following routine gall
      bladder surgery, avant-garde artist Andy Warhol remains a controversial artistic
      and cultural figure. In a wide-ranging interview, Wayne Koestenbaum--professor of
      English at the Graduate Center of the City University of New York and author of a
      biography about Warhol published in 2001--discusses the reasons for that
      controversy as they relate to Warhol's gay sexual orientation and queer outsider
      contributions to contemporary culture. The introduction to the interview explores
      why, despite the problems Warhol encountered personally and professionally over
      the years because of his queer outsider status, his art and personality have had
      a deep impact on mainstream culture.

PMID- 15189792
TI  - In memoriam: C. A. Tripp.

PMID- 15189793
TI  - The implications of managed care and welfare reform for the integration of health
      and welfare services.
AB  - In this era of managed care and welfare reform, the two systems of public health
      and public welfare are increasingly focused on a shared population and the
      services designed to promote self-sufficiency and good health among low-income
      individuals, families and communities. The two service systems are often
      constrained by categorical funding mechanisms that contribute to service
      fragmentation, discontinuity and redundancy. This paper focuses on the changing
      nature of health and welfare, the impact of categorical funding mechanisms, the
      barriers to service integration, the potentials for partnership, and concludes
      with implications for enhancing service integration and the quality of services.

PMID- 15189794
TI  - Presidential rhetoric and the strategy of going public: President Clinton and the
      health care reform.
AB  - Going public represents a new style of presidential leadership in which the
      president sells his programs directly to the American public. Several scholars
      have argued that presidents need to go to the public more often and make skillful
      use of public rhetoric to galvanize public support for their policy agenda. This
      article examines President Clinton's public rhetoric and his failed strategy of
      going public to rally support for his health care reform proposal during 1993
      1994. It concludes with a discussion of factors that help explain President
      Clinton's failure to rally public support for the Health Security Act of 1993 and
      secure its passage in the Congress.

PMID- 15189795
TI  - Drugs, prisons, and harm reduction.
AB  - The use of drugs in society raises important considerations for health and social
      policy. Critical health and social care issues arise when drugs are used inside
      prisons. This paper argues that there is an urgent need for prison drug policies
      to adopt the principles of harm reduction. However, current policy orthodoxy
      emphasises the control of drugs and punishment for drug taking. Key components of
      harm reduction are operationalised in this article by exploring the potential for
      harm reduction in prison within the context of English drug policy. Whilst the
      focus is on English policy debates, the discussion will have wider international
      resonance.

PMID- 15189796
TI  - Elderly Bedouins and Jews in Israel: the effects of visual impairment on
      perceived functional and health status.
AB  - Age-related vision impairment is a major cause of functional limitations in
      mobility and independent living. Research findings suggest that vision impairment
      in later life affects social, emotional, mental as well as physical well-being,
      and daily functioning. The purpose of this study was to examine the relationship
      between ethnicity and visual problems, i.e., whether Bedouin and Jewish elderly
      persons differed in terms of visual impairment prevalence and the extent to which
      visual impairment affected their ability to perform activities of everyday life.
      This study sampled 88 Bedouin and 111 Jewish elderly persons aged 60 and older in
      the southern region of Israel. The findings show that the majority of the
      respondents reported visual problems. Bedouin elderly tended to have more
      problems with distance sight as a result of living conditions than Jewish
      elderly. In terms of ability to perform ADL and IADL functions, elderly Bedouins
      reported more problems. The study findings are discussed in terms of policy and
      service provision. In addition, recommendations for additional research are
      presented.

PMID- 15189797
TI  - Assessing predictors of influenza and pneumonia vaccination in rural senior
      adults.
AB  - The overall purpose of this study was to identify predictors of influenza and
      pneumonia vaccination among rural senior adults. A mail survey was conducted in
      eight rural counties. Reported immunization rate for influenza (81.5%) among
      respondents was higher as compared to pneumonia (74.7%). Knowing someone with
      influenza was the strongest predictor of influenza vaccination and knowing
      someone with pneumonia was the strongest predictor of pneumonia vaccination.
      Belief that vaccinations are always beneficial was also a significant predictor.
      While several of the findings of this study are consistent with factors reported
      in literature to be significant predictors of immunization behavior for this age
      group, surprisingly, access was not a significant predictor for this rural
      sample.

PMID- 15189798
TI  - Physician medical records and the Health Insurance Portability and Accountability
      act.
AB  - The Health Insurance Portability and Accountability Act (HIPAA) requires
      physicians to place greater responsibility on protecting electronic transfer of
      medical records to patients and other medical providers, while allowing them
      greater access to their owned medical records. The required protections on use of
      electronic medical records will be very costly to the physician's office
      practice. This paper highlights the HIPAA requirements to protect medical records
      and assure access to consumers. The new HIPAA provisions will require physicians
      and managed care plans to develop new safeguards and management procedures to
      enhance the protection of electronic medical information and data base systems.

PMID- 15189799
TI  - Improving adolescent pregnancy outcomes and maternal health:a case study of
      comprehensive case managed services.
AB  - Our findings indicate how health outcomes regarding adolescent pregnancy and
      maternal and infant health care are intertwined with a case management process
      that fosters measures that are social in nature-the provision of direct services,
      as well as the encouragement of informal social supports systems. They also show
      how case managed services in a small, nongovernmental organization (NGO) with a
      strong commitment to its clients may provide the spontaneity and caring which
      results in a "match" between client needs and the delivery of services-and
      positive outcomes for pregnant women, early maternal health and infant health.
      The delivery of such case managed services in a manner which is intensive,
      comprehensive, flexible and integrated contributes significantly to such improved
      health outcomes.

PMID- 15189800
TI  - Chronic fatigue syndrome versus neuroendocrineimmune dysfunction
      syndrome:differential attributions.
AB  - Since 1988, when the term chronic fatigue syndrome (CFS) was coined, considerable
      discussion has occurred about stigma associated with this diagnostic term. In
      particular, patients with CFS have felt that this term trivializes the serious
      nature of this disorder. A Name Change Work group, appointed by the CFS
      Coordinating Committee, developed an umbrella term: chronic neuroendocrineimmune
      dysfunction syndrome (CNDS), and proposed that there would be sub-types under
      this term, one being CFS. The present study examined attributions of this new
      umbrella term when compared with CFS. Nurses and physician assistants (PAs) were
      presented a case study of a patient with symptoms of CFS. They were told that the
      patient had either "chronic fatigue syndrome," "chronic neuroendocrineimmune
      dysfunction syndrome," or "chronic neuroendocrineimmune dysfunction syndrome,
      which had formerly been called chronic fatigue syndrome." The different terms led
      to different attributions, with PA respondents rating the "CNDS" label as more
      severe. Results suggest that a more medical sounding term (CNDS) may lead to
      attributions that this syndrome is a more serious, disabling illness. The policy
      implications of these findings are discussed.

PMID- 15189801
TI  - An analysis of the impact of gender on physician practice patterns.
AB  - Through analysis of Community Tracking Study Physician Survey, a nationally
      representative survey of U.S. physicians, we find that women physicians are
      significantly less satisfied with time for patients than their male colleagues.
      Among primary care physicians, about one third of the gender difference is
      explained by physician attributes, practice characteristics, geographical
      location and patient profiles. Control variables explain all of the gender gap
      among specialist physicians. Among primary care physicians, the effects of
      practice type and perceptions of patient complexity on satisfaction with time for
      patients are mediated by physician gender. Among specialist physicians, gender
      interacts with practice ownership and hours spent in medically related activity
      to determine satisfaction with time for patients.

PMID- 15189802
TI  - Simple and choice reaction time methods in the study of motor programming.
AB  - In an extensive series of experiments Sternberg, Monsell, Knoll, and Wright
      (1978) reported that simple RT increased as a linear function of the number of
      items to be pronounced or typed. The present experiments replicate a portion of
      these results, but show that the effect is less general than may have been
      supposed. Since the effect does not occur in every case in which a response
      programming interpretation would predict it, this interpretation must be
      rejected. This conclusion is consistent with the viewpoint that response
      programming should be investigated in a choice- rather than simple-RT paradigm.
      In this view, motivated subjects can program responses in advance of the simple
      RT interval because the particular response to be made has been precued. Effects
      of response parameters which are observed for motivated subjects in the simple-RT
      paradigm, such as those reported by Sternberg et al. (1978), should be attributed
      to processes other than programming motor responses.

PMID- 15189803
TI  - Left-handers and right-handers compared on a motor task.
AB  - Finger-tapping performance of 45 subjects of each sex and handedness combination,
      for a total of 180, was compared. Performance measures were speed (mean intertap
      interval) and regularity (standard deviation of intertap interval). Males tapped
      faster but not more regularly than females. The between-hand differences in
      performance were smaller for both measures in left-handers. When absolute
      magnitudes of between hand differences were compared, females showed smaller
      differences in regularity of tapping than males. Speed and regularity of tapping
      were statistically independent; both measures discriminated well between the
      preferred and nonpreferred hand of both handedness groups, but the differences in
      speed were more marked than the differences in regularity. Data on the
      performance of children on the same task are included for comparative purposes.

PMID- 15189804
TI  - The prediction of group motor performance from individual member abilities.
AB  - Two experiments were conducted to investigate the prediction of group performance
      on the motor-maze task from individual member abilities. In both experiments
      subjects performed 20 individual trials on the maze task in an initial session
      prior to the actual experiment. On the basis of these individual performance
      scores, two-person groups were formed so that the groups represented a range of
      average ability levels and a range of discrepancies in abilities between
      partners. In Experiment 1, all groups performed a cooperative and a
      noncooperative group task in separate sessions both involving competition with
      another group. Only the cooperative group task was used in Experiment 2, but all
      groups performed under both competitive and noncompetitive conditions. Multiple
      regression analyses yielded a moderate, positive relationship between member
      abilities and group performance in both experiments; group performance on the
      highly cooperative task was dominated by the lower-ability partner.

PMID- 15189805
TI  - Directional errors of movement and their correction in a discrete tracking task.
AB  - Many studies have shown that subjects can correct their own errors of movement
      more quickly than they can react to external stimuli. In the control of
      movements, three general categories of feedback have been defined as follows: (a)
      knowledge of results, primarily visually mediated, (b) proprioceptive or
      kinesthetic, such as from muscle spindles and joint receptors, and (c) corollary
      discharge or efference copy within the central nervous system. Experiments were
      conducted on eight normal human subjects to study the effects of these feedbacks
      on simple RT, choice RT, and error correction time. The movement used was
      plantarflexion and dorsiflexion of the ankle joint. The feedback loops were
      modified (a) by inverting the visual display to alter the subject's perception of
      results and (b) by applying a 100-Hz vibration simultaneously to both flexor and
      extensor muscles of the ankle joint. Central processing was altered by giving the
      subjects moderated doses of alcohol (blood-alcohol concentration levels of up
      to.10%). Vibration and alcohol increased both simple and choice RT but not the
      error correction time. These data reinforce the concept that there is a central
      pathway which can mediate error correcting responses.

PMID- 15189806
TI  - Orienting task specificity in incidental motor learning.
AB  - The manipulation of the retention of a linear movement by means of different
      orienting tasks in an incidental learning paradigm was investigated. Subjects
      were presented with a target position followed by a different nontarget position
      on each of four presentation trials. After the presentation trials subjects were
      required to recall the target and nontarget positions. One group made verbal
      estimates of the distance between the target and nontarget positions, another
      group discriminated between the target and nontarget positions, while no verbal
      responses were required for a third group. The verbal-response groups, while not
      differing from each other, had less error at recall than the nonverbalizing
      group. These findings were discussed in terms of the levels of processing
      framework for memory research (Craik & Lockhart, 1972).

PMID- 15189807
TI  - The independence of recall and recognition in motor learning.
AB  - A basic tenet of both current closed-loop theories of motor learning (Adams,
      1971; Schmidt, 1975) is that the generation of response specifications during
      learning is required for the development of recall memory. Two experiments were
      performed to test this tenet by attempting to demonstrate the development of
      recall memory in the absence of response specification production. The task in
      both experiments required blindfolded subjects to learn to produce a rapid, novel
      criterion movement on a linear positioning device. Control subjects in both
      experiments actively produced movements during learning with knowledge of results
      (KR) while experimental subjects in Experiment 1 experienced only the endpoint
      locations and in Experiment 2 were passively moved to the endpoint locations.
      Following initial KR trials, both experimental and control groups attempted to
      actively produce the criterion movement in the absence of KR. The results of both
      experiments support closed-loop theory that active practice is required to
      develop recall memory. There was some suggestion, however, that passive
      experience with sensory feedback may also aid recall memory development, contrary
      to the two closed-loop theories.

PMID- 15189808
TI  - Effector localization and transfer of reactive inhibition.
AB  - An experimental test was made of Hull's (1943) notions that reactive inhibition
      is effector-specific and that it has primary negative motivational properties.
      Four groups of 20 subjects (10 males and 10 females in each) executed two
      segments of continuous right-hand practice on a mirror-tracking task. The two
      segments were separated either by 0 min rest, 5 min rest, 5 min continuous right
      hand practice on rotary pursuit, or 5 min continuous left-hand practice on rotary
      pursuit. Effects of interpolated conditions were measured in terms of main-task
      reminiscence arid initial post-treatment performance. When interpolated practice
      was conducted with the right hand, reminiscence and post-treatment performance
      were significantly depressed relative to the rest effect, but not when
      interpolated practice was conducted with the left hand. Thus, Hull's views were
      supported, while competing views, such as the task specificity concept of lr and
      the consolidation theory of reminiscence, were impugned.

PMID- 15189809
TI  - Further tests of Schmidt's schema theory: development of a schema rule for a
      coincident timing task.
AB  - The present study investigated the generalizability of Schmidt's (1975) schema
      theory to an open-skill (Poulton, 1957) situation. Subjects attempted to time a
      preferred-hand button press so that it was coincident with the lighting of the
      last of a series of run way lights whose apparent velocity was 4023 mm/sec. Prior
      to five trials of performance on the criterion task, subjects received 40 trials
      in which they either (a) watched (low response requirements) or (b) responded
      with the nonpreferred hand (high response requirements) to a stimulus moving at
      (a) a constant (2235, 3129, 4917, or 5812 mm/sec) velocity (low stimulus
      variability) or (b) different velocities (high stimulus variability) from trial
      to trial. Subjects receiving high stimulus variability and high response
      requirements during training had significantly lower absolute error on the
      criterion task than did those in the other conditions. The results were discussed
      in terms of the type of practice which facilitates development of a schema rule
      for coincident-timing situations.

PMID- 15189810
TI  - Microarray analyses identify JAK2 tyrosine kinase as a key mediator of ligand
      independent gene expression.
AB  - Mice lacking a functional Janus kinase 2 (JAK2) allele die embryonically,
      indicating the mandatory role of JAK2 in basic developmental cellular
      transcription. Currently, however, the downstream target genes of JAK2 are
      largely unknown. Here, in vitro conditions were created using a cell line lacking
      JAK2 expression. Microarray analysis was then used to identify genes that are
      differentially expressed as a result of the presence, or absence, of JAK2. The
      data identified 621 JAK2-dependent genes as having at least a twofold change in
      expression. Surprisingly, these genes did not require ligand-dependent activation
      of JAK2 but merely its expression in the cell. Thirty-one of these genes were
      found to have a greater than sevenfold change in expression levels, and a subset
      of these were further characterized. These genes represent a diverse cluster of
      ontological functions including transcription factors, signaling molecules, and
      cell surface receptors. The expression levels of these genes were validated by
      Northern blot and/or quantitative RT-PCR analysis in both the JAK2 null cells and
      cells expressing a JAK2-dominant negative allele. As such, this work demonstrates
      for the first time that, in addition to being a key mediator of ligand-activated
      gene transcription, JAK2 can perhaps also be viewed as a critical mediator of
      basal level gene expression.

PMID- 15189811
TI  - cAMP-activated maxi-Cl(-) channels in native bovine pigmented ciliary epithelial
      cells.
AB  - The eye's aqueous humor is secreted by a bilayered ciliary epithelium comprising
      pigmented (PE) and nonpigmented (NPE) epithelial cell layers. Stromal Cl(-)
      enters the PE cells and crosses gap junctions to the NPE cells for release into
      the aqueous humor. Maxi-Cl(-) channels are expressed in PE cells, but their
      physiological significance is unclear. To address this question, excised patches
      and whole native bovine PE cells were patch clamped, and volume was monitored by
      calcein fluorescence. In symmetrical 130 mM NaCl, cAMP at the cytoplasmic surface
      of inside-out patches produced concentration-dependent activation of maxi-Cl(-)
      channels with a unitary conductance of 272 +/- 2 pS (n = 80). Voltage steps from
      0 to +/-80 mV, but not to +/-40 mV, produced rapid channel inactivation
      consistent with the typical characteristics of maxi-Cl(-) channels. cAMP also
      activated the maxi-Cl(-) channels in outside-out patches. In both cases, maxi-Cl(
      ) channels were reversibly inhibited by SITS and 5-nitro-2
      (phenylpropylamino)benzoate (NPPB). Decreasing cytoplasmic Cl(-) concentration
      reduced both open-channel probability and unitary conductance. Similarly, the
      membrane-permeant 8-bromo-cAMP stimulated outward and inward whole cell currents;
      the stimulation was larger at higher intracellular Cl(-) concentration. As with
      unitary currents, cAMP-triggered whole cell currents displayed inactivation at +/
      80 but not at +/-40 mV. Moreover, cAMP triggered NPPB-sensitive shrinkage of PE
      cells. The results suggest that cAMP directly activates maxi-Cl(-) channels of
      native PE cells that contribute to Cl(-) release particularly from Cl(-)-loaded
      cells. These cAMP-activated channels provide a potential mechanism for reducing
      and modulating net aqueous humor secretion by facilitating Cl(-) reabsorption
      into the ciliary stroma.

PMID- 15189813
TI  - Molecular analysis of fiber type-specific expression of murine myostatin
      promoter.
AB  - Myostatin is a negative regulator of muscle growth, and absence of the functional
      myostatin protein leads to the heavy muscle phenotype in both mouse and cattle.
      Although the role of myostatin in controlling muscle mass is established, little
      is known of the mechanisms regulating the expression of the myostatin gene. In
      this study, we have characterized the murine myostatin promoter in vivo. Various
      constructs of the murine myostatin promoter were injected into the quadriceps
      muscle of mice, and the reporter luciferase activity was analyzed. The results
      indicate that of the seven E-boxes present in the 2.5-kb fragment of the murine
      myostatin promoter, the E5 E-box plays an important role in the regulation of
      promoter activity in vivo. Furthermore, the in vitro studies demonstrated that
      MyoD preferentially binds and upregulates the murine myostatin promoter activity.
      We also analyzed the activity of the bovine and murine promoters in murine
      skeletal muscle and showed that, despite displaying comparable levels of activity
      in murine myoblast cultures, bovine myostatin promoter activity is much weaker
      than murine myostatin promoter in mice. Finally, we demonstrate that in vivo, the
      2.5-kb region of the murine myostatin promoter is sufficient to drive the
      activity of the reporter gene in a fiber type-specific manner.

PMID- 15189812
TI  - Characterization of a human colonic cDNA encoding a structurally novel urea
      transporter, hUT-A6.
AB  - Two closely related genes, UT-A (Slc14a2) and UT-B (Slc14a1), encode specialized
      transporter proteins that modulate the movement of urea across cell membranes. In
      this article, we report the characterization of a cDNA isolated from human
      colonic mucosa encoding a novel UT-A urea transporter, hUT-A6. The encoded
      protein is 235 amino acids (aa) in length, making it the smallest UT-A member
      characterized. On the basis of previous structural predictions, hUT-A6 is
      structurally unique in that it consists of a single hydrophobic core flanked by
      hydrophilic NH(2)- and COOH-terminal domains. The transcript encoding hUT-A6
      contains a novel 129-bp exon, exon 5a, which, as a result of alternative
      splicing, introduces a unique 19-aa segment and a stop codon. Functionally, the
      protein transports urea, and this activity is inhibited by phloretin.
      Interestingly, despite the lack of a protein kinase A (PKA) consensus site
      [RK](2)-X-[ST], transport of urea by hUT-A6 is stimulated by PKA agonists.
      Deletion of the two PKA consensus sites from murine UT-A3 (mUT-A3) did not affect
      the stimulatory response of PKA agonists, which, together with the lack of PKA
      consensus sites in hUT-A6, indicates that regulation of hUT-A6 and mUT-A3 is not
      mediated through a classic PKA phosphorylation consensus.

PMID- 15189814
TI  - Gene delivery of l-caldesmon protects cytoskeletal cell membrane integrity
      against adenovirus infection independently of myosin ATPase and actin assembly.
AB  - The cytoskeleton is critical to the viral life cycle. Agents like cytochalasin
      inhibit viral infections but cannot be used for antiviral therapy because of
      their toxicity. We report the efficacy, safety, and mechanisms by which gene
      delivery of human wild-type low-molecular-weight caldesmon (l-CaD) protects cell
      membrane integrity from adenovirus infection in a DF-1 cell line, an immortalized
      avian fibroblast that is null for l-CaD. Transfection with an adenovirus (Ad)
      controlled construct mediated a dose-dependent decline in transcellular
      resistance. In accordance with a computational model of cytoskeletal membrane
      properties, Ad disturbed cell-cell and cell-matrix adhesion and membrane
      capacitance. Transfection with the Ad-l-CaD construct attenuated adenovirus
      mediated loss in transcellular resistance. Quantitation of vinculin-stained
      plaques revealed an increase in total focal contact mass in monolayers
      transfected with the Ad-l-CaD construct. Expression of l-CaD protected
      transcellular resistance through primary effects on membrane capacitance and
      independently of actin solubility and effects on pre-stress, as measured by the
      decline in isometric tension in response to cytochalasin D. Expression of l-CaD
      exhibited less Trypan blue cell toxicity than cytochalasin, and, unlike
      cytochalasin, it did not interfere with wound closure or adversely effect
      transcellular resistance. These findings demonstrate the gene delivery of wild
      type human l-CaD as a potentially efficacious and safe agent that inhibits some
      of the cytopathic effects of adenovirus.

PMID- 15189815
TI  - A P2X7 receptor stimulates plasma membrane trafficking in the FRTL rat thyrocyte
      cell line.
AB  - Thyroid cells express a variety of P2Y and P2X purinergic receptor subtypes. G
      protein-coupled P2Y receptors influence a wide variety of thyrocyte-specific
      functions; however, functional P2X receptor-gated channels have not been
      observed. In this study, we used whole cell patch-clamp recording and
      fluorescence imaging of the plasma membrane marker FM1-43 to examine the effects
      of extracellular ATP on membrane permeability and trafficking in the Fisher rat
      thyroid cell line FRTL. We found a cation-selective current that was gated by ATP
      and 2',3'-O-(4-benzoylbenzoyl)-ATP but not by UTP. The ATP-evoked currents were
      inhibited by pyridoxal phosphate 6-azophenyl-2',4'-disulfonic acid, adenosine 5'
      triphosphate-2',3'-dialdehyde, 100 microM Zn(2+), and 50 microM Cu(2+).
      Fluorescence imaging revealed pronounced, temperature-sensitive stimulation of
      exocytosis and membrane internalization by ATP with the same pharmacological
      profile as observed for activation of current. The EC(50) for ATP stimulation of
      internalization was 440 microM in saline containing 2 mM Ca(2+) and 2 mM Mg(2+),
      and 33 microM in low-Mg(2+), nominally Ca(2+)-free saline. Overall, the results
      are most consistent with activation of a P2X(7) receptor by ATP(4-). However, low
      permeability to N-methyl-d-glucamine(+) and the propidium cation YO-PRO-1
      indicates absence of the cytolytic pore that often accompanies P2X(7) receptor
      activation. ATP stimulation of internalization occurs in Na(+)-free, Ca(2+)-free,
      or low-Mg(2+) saline and therefore does not depend on cation influx through the
      ATP-gated channel. We conclude that ATP activation of a P2X(7) receptor
      stimulates membrane internalization in FRTL cells via a transduction pathway that
      does not depend on cation influx.

PMID- 15189816
TI  - Force-induced focal adhesion translocation: effects of force amplitude and
      frequency.
AB  - Vascular endothelial cells rapidly transduce local mechanical forces into
      biological signals through numerous processes including the activation of focal
      adhesion sites. To examine the mechanosensing capabilities of these adhesion
      sites, focal adhesion translocation was monitored over the course of 5 min with
      GFP-paxillin while applying nN-level magnetic trap shear forces to the cell apex
      via integrin-linked magnetic beads. A nongraded steady-load threshold for
      mechanotransduction was established between 0.90 and 1.45 nN. Activation was
      greatest near the point of forcing (<7.5 microm), indicating that shear forces
      imposed on the apical cell membrane transmit nonuniformly to the basal cell
      surface and that focal adhesion sites may function as individual mechanosensors
      responding to local levels of force. Results from a continuum, viscoelastic
      finite element model of magnetocytometry that represented experimental focal
      adhesion attachments provided support for a nonuniform force transmission to
      basal surface focal adhesion sites. To further understand the role of force
      transmission on focal adhesion activation and dynamics, sinusoidally varying
      forces were applied at 0.1, 1.0, 10, and 50 Hz with a 1.45 nN offset and a 2.25
      nN maximum. At 10 and 50 Hz, focal adhesion activation did not vary with spatial
      location, as observed for steady loading, whereas the response was minimized at
      1.0 Hz. Furthermore, applying the tyrosine kinase inhibitors genistein and PP2, a
      specific Src family kinase inhibitor, showed tyrosine kinase signaling has a role
      in force-induced translocation. These results highlight the mutual importance of
      force transmission and biochemical signaling in focal adhesion
      mechanotransduction.

PMID- 15189817
TI  - Granule neurons in cerebellum express distinct splice variants of the inositol
      trisphosphate receptor that are modulated by calcium.
AB  - Primary cultures of granule cells (GC) from rat cerebellar cortex were used to
      determine whether bioelectric activity, via a Ca(2+)/calmodulin-dependent kinase
      (CaMK) signaling cascade, modulates expression and exon selection in the inositol
      trisphosphate receptor type 1 (IP(3)R1). IP(3)R1 contains or lacks three exons
      (S1, S2, and S3) that are regulated in a regionally and temporally specific
      manner. The neuronal, or long, form of IP(3)R1 is distinguished from peripheral
      tissues by inclusion of the S2 exon. Although previous studies indicated that
      IP(3)R1 are undetectable in the cerebellar granular layer in vivo, receptor
      protein and mRNA are induced in cultured GC grown in medium supplemented with 25
      mM KCl or NMDA, two trophic agents that promote long-term survival, compared with
      GC grown in 5 mM KCl. IP(3)R1 induction in response to 25 mM KCl or NMDA is
      attenuated by coaddition of voltage-sensitive calcium channel or NMDA receptor
      antagonists, respectively. Actinomycin D, CaMK, and calcineurin antagonists
      likewise suppress induction. Unlike the major variants of IP(3)R1 in Purkinje
      neurons, which lack S1 and S3, GC grown with trophic agents express mRNA
      containing these exons. Both neuronal types contain S2. Evidence obtained using
      mutant mice with Purkinje cell lesions, laser-microdissected GC neurons from
      slices, and explant cultures indicates that GC predominantly express the S1
      containing variant of IP(3)R1 in vivo.

PMID- 15189819
TI  - Cell mechanics and mechanotransduction: pathways, probes, and physiology.
AB  - Cells face not only a complex biochemical environment but also a diverse
      biomechanical environment. How cells respond to variations in mechanical forces
      is critical in homeostasis and many diseases. The mechanisms by which mechanical
      forces lead to eventual biochemical and molecular responses remain undefined, and
      unraveling this mystery will undoubtedly provide new insight into strengthening
      bone, growing cartilage, improving cardiac contractility, and constructing
      tissues for artificial organs. In this article we review the physical bases
      underlying the mechanotransduction process, techniques used to apply controlled
      mechanical stresses on living cells and tissues to probe mechanotransduction, and
      some of the important lessons that we are learning from mechanical stimulation of
      cells with precisely controlled forces.

PMID- 15189818
TI  - EST clustering error evaluation and correction.
AB  - MOTIVATION: The gene expression intensity information conveyed by (EST) Expressed
      Sequence Tag data can be used to infer important cDNA library properties, such as
      gene number and expression patterns. However, EST clustering errors, which often
      lead to greatly inflated estimates of obtained unique genes, have become a major
      obstacle in the analyses. The EST clustering error structure, the relationship
      between clustering error and clustering criteria, and possible error correction
      methods need to be systematically investigated. RESULTS: We identify and quantify
      two types of EST clustering error, namely, Type I and II in EST clustering using
      CAP3 assembling program. A Type I error occurs when ESTs from the same gene do
      not form a cluster whereas a Type II error occurs when ESTs from distinct genes
      are falsely clustered together. While the Type II error rate is <1.5% for both 5'
      and 3' EST clustering, the Type I error in the 5' EST case is approximately 10
      times higher than the 3' EST case (30% versus 3%). An over-stringent identity
      rule, e.g., P >/= 95%, may even inflate the Type I error in both cases. We
      demonstrate that approximately 80% of the Type I error is due to insufficient
      overlap among sibling ESTs (ISO error) in 5' EST clustering. A novel statistical
      approach is proposed to correct ISO error to provide more accurate estimates of
      the true gene cluster profile.

PMID- 15189820
TI  - Glucose activates H(+)-ATPase in kidney epithelial cells.
AB  - The vacuolar H(+)-ATPase (V-ATPase) acidifies compartments of the vacuolar system
      of eukaryotic cells. In renal epithelial cells, it resides on the plasma membrane
      and is essential for bicarbonate transport and acid-base homeostasis. The factors
      that regulate the H(+)-ATPase remain largely unknown. The present study examines
      the effect of glucose on H(+)-ATPase activity in the pig kidney epithelial cell
      line LLC-PK(1). Cellular pH was measured by performing ratiometric fluorescence
      microscopy using the pH-sensitive indicator BCECF-AM. Intracellular acidification
      was induced with NH(3)/NH(4)(+) prepulse, and rates of intracellular pH (pH(i))
      recovery (after in situ calibration) were determined by the slopes of linear
      regression lines during the first 3 min of recovery. The solutions contained 1
      microM ethylisopropylamiloride and were K(+) free to eliminate Na(+)/H(+)
      exchange and H(+)-K(+)-ATPase activity. After NH(3)/NH(4)(+)-induced
      acidification, LLC-PK(1) cells had a significant pH(i) recovery rate that was
      inhibited entirely by 100 nM of the V-ATPase inhibitor concanamycin A. Acute
      removal of glucose from medium markedly reduced V-ATPase-dependent pH(i) recovery
      activity. Readdition of glucose induced concentration-dependent reactivation of V
      ATPase pH(i) recovery activity within 2 min. Glucose replacement produced no
      significant change in cell ATP or ADP content. H(+)-ATPase activity was
      completely inhibited by the glycolytic inhibitor 2-deoxy-d-glucose (20 mM) but
      only partially inhibited by the mitochondrial electron transport inhibitor
      antimycin A (20 microM). The phosphatidylinositol 3-kinase (PI3K) inhibitor
      wortmannin (500 nM) abolished glucose activation of V-ATPase, and activity was
      restored after wortmannin removal. Glucose activates V-ATPase activity in kidney
      epithelial cells through the glycolytic pathway by a signaling pathway that
      requires PI3K activity. These findings represent an entirely new physiological
      effect of glucose, linking it to cellular proton secretion and vacuolar
      acidification.

PMID- 15189821
TI  - Critical role of p63 in the development of a normal esophageal and
      tracheobronchial epithelium.
AB  - The trachea and esophagus originate from the foregut endoderm during early
      embryonic development. Their epithelia undergo a series of changes involving the
      differentiation of stem cells into unique cell types and ultimately forming the
      mature epithelia. In this study, we monitored the expression of p63 in the
      esophagus and the trachea during development and examined in detail morphogenesis
      in p63(-/-) mice. At embryonic day 15.5 (E15.5), the esophageal and
      tracheobronchial epithelia contain two to three layers of cells; however, only
      the progenitor cells express p63. These progenitor cells differentiate first into
      ciliated cells (p63(-)/beta-tubulin IV(+)) and after birth into mature basal
      cells (p63(+)/K14(+)/K5(+)/BS-I-B4(+)). In the adult pseudostratified, columnar
      tracheal epithelium, K14(+)/K5(+)/BS-I-B4(+) basal cells stain most intensely for
      p63, whereas ciliated and mucosecretory cells are negative. In stratified
      squamous esophageal epithelium and during squamous metaplasia in the trachea,
      cells in the basal layer stain strongest for p63, whereas p63 staining declines
      progressively in transient amplifying and squamous differentiated cells.
      Generally, p63 expression is restricted to human squamous cell carcinomas, and
      adenocarcinomas and Barrett's metaplasia do not stain for p63. Examination of
      morphogenesis in newborn p63(-/-) mice showed an abnormal persistence of ciliated
      cells in the esophagus. Significantly, in both tissues, lack of p63 expression
      results in the development of a highly ordered, columnar ciliated epithelium
      deficient in basal cells. These observations indicate that p63 plays a critical
      role in the development of normal esophageal and tracheobronchial epithelia and
      appears to control the commitment of early stem cells into basal cell progeny and
      the maintenance of basal cells.

PMID- 15189822
TI  - Transgenic mice produced by retroviral transduction of male germ line stem cells
      in vivo.
AB  - Spermatogonial stem cells are the only stem cells in the postnatal body that can
      transmit parental genetic information to the offspring, making them an attractive
      target cell population for animal transgenesis. Although transgenic mice and rats
      were recently produced by retrovirus transduction of these cells in vitro, with
      transplantation of the transduced cells into infertile recipients, the difficulty
      of restoring fertility and preparing recipients using spermatogonial
      transplantation limits practical application of the technique. In this article,
      we describe a novel approach for producing transgenic animals by transducing
      spermatogonial stem cells in vivo using a retrovirus vector. Microinjection of
      retrovirus into immature seminiferous tubules resulted in the direct transduction
      of spermatogonial stem cells in situ, and the animals produced transgenic
      offspring after mating with females. Transgenic mice were produced in C57BL/6,
      BALB/C, A, and C3H backgrounds, with an average efficiency of 2.8%. The transgene
      was transmitted stably and expressed in the next generation. The technique
      overcomes the drawback of the in vitro-transduction approach, and will be useful
      as a novel method for producing transgenic animals as well as providing a means
      for analyzing the self-renewal and differentiation processes of spermatogonial
      stem cells in vivo.

PMID- 15189823
TI  - Secreted and placental membrane forms of folate-binding protein occur
      sequentially during pregnancy in swine.
AB  - The objective was to understand how two forms of folate-binding protein interact
      to accomplish folate transport during pregnancy in swine. Specific folate binding
      was measured in uterine flushings during the estrous cycle and early pregnancy
      and in allantoic fluid (secreted form) and placental membranes (membrane form)
      throughout later pregnancy. In addition, the localization of the secreted form of
      folate-binding protein (sFBP) in uterine wall sections was assessed. Uterine
      flushings were collected on Days 10, 13, and 15 of the estrous cycle and
      pregnancy. Allantoic fluid and placentas were collected on Days 20, 35, 50, 70,
      90, and 105 of pregnancy. Uterine-wall sections were collected on all days of the
      experiment. Folate binding was measured by incubation of aliquots of uterine
      flushings, allantoic fluid, or placental microsomal membranes with 0.5-4 nM
      [(3)H]folate. Uterine-wall sections were incubated with purified anti-FBP IgG or
      normal rabbit serum IgG to localize sFBP. Folate binding did not differ between
      early pregnancy and the estrous cycle in uterine flushings, was greatest from Day
      50 to 70 of pregnancy in allantoic fluid, and was greatest from Day 50 of
      pregnancy onward in placental microsomal membranes. Staining for sFBP was present
      in the endometrial glands from Day 10 to 15 in cyclic gilts and from Day 10 to 20
      in pregnant gilts. The pattern of folate binding and sFBP staining supports the
      concept that sFBP transports folate to the developing conceptus until
      placentation and then the placental form takes over folate transport.

PMID- 15189824
TI  - Comparative study of the dynamics of follicular waves in mares and women.
AB  - Deviation in growth rates of the follicles of the ovulatory wave begins at the
      end of a common growth phase and is characterized by continued growth of the
      developing dominant follicle (F1) and regression of the largest subordinate
      follicle (F2). Follicle diameters during an interovulatory interval were compared
      between 30 mares and 30 women, using similar methods for collecting and analyzing
      data. Follicles were tracked and measured daily by ultrasonography. Diameter at
      follicle emergence (mares, 13 mm; women, 6 mm) and the required minimal attained
      diameter for assessment of follicles (mares, 17 mm; women, 8 mm) were chosen to
      simulate the reported ratio between the two species in mean diameter of F1 at the
      beginning of deviation (mares, 22.5 mm; women, 10.5 mm). F1 emerged before F2 (P
      < 0.02) in each species, and the interval between emergence of the two follicles
      was similar (not significantly different) between species. Growth rate for F1 and
      F2 during the common growth phase was similar within species, and the percentage
      of diameter increase was similar between species. Proportionality between species
      in diameter of F1 at deviation (2.2 times larger for mares than for women) and at
      maximum preovulatory diameter (2.1 times larger) indicated that relative growth
      of F1 after deviation was similar between species. A predeviation follicle was
      identified in 33% of mares and 40% of women and was characterized by growth to a
      diameter similar to F1 at deviation but with regression beginning an average of 1
      day before the beginning of deviation. The incidence of a major anovulatory wave
      preceding the ovulatory wave was not different between species (combined, 25%).
      Results indicated that mares and women have comparable follicle
      interrelationships during the ovulatory wave, including 1) emergence of F1 before
      F2, 2) similar length of intervals between sequential emergence of follicles
      within a wave, 3) similar percentage growth of follicles during the common growth
      phase, and 4) similar relative diameter of F1 from the beginning of deviation to
      ovulation. Similar follicle dynamics between mares and women indicate the mare
      may be a useful experimental model for study of folliculogenesis in women, with
      the advantage of larger follicle size.

PMID- 15189825
TI  - Developmental pattern of small antral follicles in the bovine ovary.
AB  - The study was designed to characterize the developmental pattern of 1- to 3-mm
      follicles and to determine the stage at which the future dominant follicle first
      attains a size advantage among its cohorts. In experiment 1, heifers (n = 18)
      were examined every 24 h by transrectal ultrasonography for one interovulatory
      interval (IOI). In experiment 2, cows (n = 9) were examined every 6 h from 5 to
      13 days after ovulation to monitor precisely the diameter changes of individual
      follicles >/=1 mm during emergence of wave 2. Results revealed a change over days
      (P < 0.05) in the number of 1- to 3-mm follicles, with a maximum (P < 0.05) 1 or
      2 days before wave emergence (conventionally defined as the time when the
      dominant follicle is first detected at 4 mm), followed 3-4 days later by a
      maximum (P < 0.05) in the number of >/=4-mm follicles. The profiles of small (1-3
      mm) and large (>/=4-mm) follicles were inversely proportional (r = -0.79; P =
      0.01). The profile of the number of 1- to 3-mm follicles during wave emergence
      was similar (P = 0.63) between waves in two-wave IOI, but differed (P < 0.01)
      among waves in three-wave IOI as a result of a greater number of follicles in the
      ovulatory wave (P < 0.04). As well, the number of follicles in the ovulatory wave
      tended to be greater (P < 0.06) in three-wave IOI than in two-wave IOI. The
      future dominant follicle was first identified at a diameter of 1 mm and emerged 6
      12 h earlier than the first subordinate follicle (P < 0.01). After detection of
      the dominant follicle at 1 mm (0 h), its diameter differed from that of the first
      and second subordinate follicles at 24 h (P = 0.04) and 12 h (P = 0.01), when the
      dominant follicle was 2.4 +/- 0.17 mm and 1.7 +/- 0.14 mm, respectively. The
      growth rate of the dominant follicle differed from that of the first and second
      subordinate follicles at 120 h (P = 0.03) and 108 h (P = 0.02), when the dominant
      follicle was 9.5 +/- 0.30 mm and 8.8 +/- 0.49 mm, respectively. Emergence of the
      future dominant (r = 0.71), first (r = 0.73), and second (r = 0.76) subordinate
      follicles was temporally associated (P < 0.01) with a rise in circulating
      concentrations of FSH. Transient, nocturnal elevations in plasma FSH
      concentration were followed within 6 h by an increase in the growth rate of 1- to
      3-mm follicles. We conclude that 1) 1- to 3-mm follicles develop in a wave-like
      manner in association with surges in plasma concentrations of FSH, 2) 1- to 3-mm
      follicles are exquisitely responsive to transient elevations in FSH, and 3)
      selection of the dominant follicle is manifest earlier than previously documented
      and is characterized by a hierarchical progression over a period encompassing the
      entire FSH surge (5 days).

PMID- 15189827
TI  - Novel aspect of perinuclear theca assembly revealed by immunolocalization of non
      nuclear somatic histones during bovine spermiogenesis.
AB  - The perinuclear theca (PT) is an important accessory structure of the sperm head,
      yet its biogenesis is not well defined. To understand the developmental origins
      of PT-derived somatic histones during spermiogenesis, we used affinity-purified
      antibodies against somatic-type histones H3, H2B, H2A, and H4 to probe bovine
      testicular tissue using three different immunolocalization techniques. While
      undetectable in elongating spermatid nuclei, immunoperoxidase light microscopy
      showed all four somatic histones remained associated to the caudal head region of
      spermatids from steps 11 to 14 of the 14 steps in bovine spermiogenesis.
      Immunogold electron microscopy confirmed the localization of somatic histones on
      two nonnuclear structures, namely transient manchette microtubules of step-9 to
      step-11 spermatids and the developing postacrosomal sheath of step-13 and -14
      spermatids. Immunofluorescence demonstrated somatic histone immunoreactivity in
      the developing postacrosomal sheath, and on anti-beta-tubulin decorated manchette
      microtubules of step-12 spermatids. Focal antinuclear pore complex labeling on
      the base of round spermatid nuclei was detected by electron microscopy and
      immunofluorescence, occurring before the nucleoprotein transition period during
      spermatid elongation. This indicated that, if nuclear histone export precedes
      their degradation, this process could only occur in this region, thereby
      questioning the proposed role of the manchette in nucleocytoplasmic trafficking.
      Somatic histone immunodetection on the manchette during postacrosomal sheath
      formation supports a role for the manchette in PT assembly, signifying that some
      PT components have origins in the distal spermatid cytoplasm. Furthermore, these
      findings suggest that somatic histones are de novo synthesized in late
      spermiogenesis for PT assembly.

PMID- 15189826
TI  - Effect of the post-fertilization culture environment on the incidence of
      chromosome aberrations in bovine blastocysts.
AB  - We have previously shown that the postfertilization embryo culture environment
      has a significant influence on the quality of the resulting bovine blastocyst
      measured in terms of its cryotolerance and relative abundance for several
      developmentally important gene transcripts. Using three different culture
      conditions known to produce blastocysts of differing quality, the objective of
      this study was to examine whether the postfertilization culture environment had
      an effect on the incidence of mixoploidy in bovine blastocysts. Presumptive
      zygotes, produced by in vitro maturation and fertilization, were cultured in
      vitro in synthetic oviduct fluid (SOF) medium in the absence or presence of fetal
      calf serum (FCS), or in vivo in the ewe oviduct. Blastocysts were recovered from
      the three systems at Day 7 and the incidence of mixoploidy was assessed using
      fluorescence in situ hybridization with chromosome 6- and chromosome 7-specific
      probes. A total of 10 025 nuclei were scored in 122 blastocysts. The frequency of
      normal, diploid, blastocysts was 8.8%, 21.4%, and 34.8% in embryos derived from
      culture in SOF+FCS, SOF, and the ewe oviduct, respectively, the remainder showing
      some degree of mixoploidy. The incidence of mixoploidy was apparently not related
      to the presence of serum; omission of serum from SOF resulted in a reduction in
      the incidence of mixoploidy (91.2% vs. 78.6%), although this difference was not
      significant. Culture in vivo, however, resulted in a significant (P < 0.01)
      reduction in the incidence of mixoploidy compared with culture in vitro in the
      presence of serum (65.2% vs. 91.2%, respectively). Among the mixoploid
      blastocysts, the majority contained less than 10% polyploid cells, irrespective
      of culture group (SOF, 69.7%; SOF+FCS, 64.5%; ewe oviduct, 60.0%). More than one
      type of polyploidy was frequently observed in mixoploid blastocysts. Overall,
      diploidy-triploidy was the most frequent abnormality, but diploid-tetraploid and
      diploid-triploid-tetraploid mosaics were also observed. A significantly higher
      proportion (P < 0.05) of blastocysts derived from SOF+FCS had more than one type
      of abnormality (80.6%, 25/ 31) compared with those derived from SOF (45.4%,
      15/33) or in vivo culture (53.3%, 16/30). In conclusion, the postfertilization
      culture environment of the developing embryo can affect the incidence and
      severity of mixoploidy in the resulting blastocyst.

PMID- 15189828
TI  - Spatio-temporal expression of the germ cell marker genes MATER, ZAR1, GDF9,
      BMP15,andVASA in adult bovine tissues, oocytes, and preimplantation embryos.
AB  - We have cloned the bovine homologue of Mater (maternal antigen that embryos
      require) cDNA, potentially the first germ cell-specific maternal-effect gene in
      this species. The 3297 base-pair longest open reading frame encodes a putative
      protein of 1098 amino acids with a domain organization similar to its human
      counterpart. By reverse transcription coupled to polymerase chain reaction, we
      have analyzed the spatiotemporal expression of MATER, along with other potential
      markers of germ cells or oocytes: ZAR1 (zygotic arrest 1), GDF9 (growth and
      differentiation factor 9), BMP15 (bone morphogenetic protein 15), and VASA. In
      agreement with a preferential oocyte origin, MATER, ZAR1, GDF9, and BMP15
      transcripts were detected in the oocyte itself at a much higher level than in the
      gonads, while no significant expression was detected in our panel of somatic
      tissues (uterus, heart, spleen, intestine, liver, lung, mammary gland, muscle).
      In situ hybridization confirmed oocyte-restricted expression of MATER and ZAR1
      within the ovary, as early as preantral follicle stages. VASA was highly
      represented in the testis and the ovary, and still present in the oocyte from
      antral follicles. Maternal MATER, ZAR1, GDF9, and BMP15 transcripts persisted
      during oocyte in vitro maturation and fertilization and in preimplantation embryo
      until the five- to eight-cell or morula stage, but transcription was not
      reactivated at the time of embryonic genome activation.

PMID- 15189829
TI  - Estradiol-17beta induced a reversible sex change in the fingerlings of
      protandrous black porgy, Acanthopagrus schlegeli Bleeker: the possible roles of
      luteinizing hormone in sex change.
AB  - The objectives of the present study were to investigate the effects of oral
      administration of estradiol-17beta (E(2)) on luteinizing hormone (LH) in plasma,
      aromatase activity in gonad, and sex change in the fingerlings of protandrous
      black porgy, Acanthopagus schlegeli Bleeker. The expression of estrogen receptor
      (ER) and androgen receptor (AR) transcripts in gonad was also analyzed.
      Undifferentiated (2-mo-old) black porgy were divided into two groups, one fed a
      control diet and the other a diet mixed with E(2) (6.0 mg/kg feed) for 5 mo. Fish
      treated with E(2) for 3 mo showed complete suppression of spermatogenesis and
      spermiation and induced sex change with primary oocytes. Aromatase activity in
      forebrain and midbrain was increased in the control in December-March (during the
      spawning season). E(2) stimulated aromatase activity in the brain. Higher gonadal
      aromatase activity in concordance with elevated levels of plasma LH was observed
      in the E(2) group compared with the control. After 2-mo of E(2) termination,
      regressed testicular tissue recovered and controlled females gradually reversed
      back to functional males in January and March. Plasma LH levels were higher in
      the E(2)-terminated group during the period of reversible sex change (from a
      controlled female to male) compared with the control. The expression of ER and AR
      transcripts was closely related to the development of testis and ovary. The data
      showed that E(2) induced a reversible sex change with high plasma LH. Increase of
      gonadal aromatase and decrease of ER/AR were associated with controlled sex
      change. Plasma LH levels were correlated with the conversion from a controlled
      female to male in black porgy.

PMID- 15189830
TI  - The 3' untranslated region of bovine follicle-stimulating hormone beta messenger
      RNA downregulates reporter expression: involvement of AU-rich elements and
      transfactors.
AB  - FSHbeta mRNA has a unique 3' untranslated region (3'UTR) that is highly conserved
      across the species. Sequence analyses of the mouse, rat, human, bovine, and ovine
      3'UTRs revealed the presence of elements implicated in mRNA instability and
      translational control such as AU-Rich Element (ARE) and lipoxygenase
      differentiation control elements. Bovine FSHbeta 3'UTR down-regulated reporter
      expression in alphaT3-1 and NIH3T3 cells, but not in HEK 293 cells, suggesting
      the involvement of a cell-specific factor or mechanism. The presence of a 3'UTR
      did not influence reporter mRNA stability, but it did decrease its association
      with polysomes, indicating that the downregulatory effect may be exerted at the
      translational level. The segment spanning 601-800 bases (U4) of the bovine
      FSHbeta 3'UTR was found to be the most effective downregulating segment, its
      effect being equal to that of the full-length 3'UTR. RNA electrophoretic mobility
      shift assay with U4 showed the presence of specific transfactors in the cytosolic
      preparations of bovine pituitary and the cell lines. U4 contained an ARE that
      appeared to be functional, because the mutated U4 ARE was ineffective in
      downregulating the reporter expression and inhibiting [(32)P]-labeled U4
      transfactor complex formation. Downregulation of reporter activity by the full
      length 3'UTR and U4 could be overcome by overexpression of HuR, a protein known
      to stabilize ARE-containing mRNAs in NIH3T3 cells, but not in the alphaT3-1
      cells, once again indicating that factors other than HuR may also be involved in
      the regulation of FSHbeta in the pituitary.

PMID- 15189831
TI  - Characterization of growth hormone binding sites in granulosa and theca layers at
      different stages of follicular maturation and ovulatory cycle in the domestic
      hen.
AB  - The currently available evidence points to a possible influence of growth hormone
      (GH) on avian folliculogenesis, which can be mediated by both hepatic- and
      ovarian-derived IGF-I. Therefore, the purpose of the present study was to reveal
      GH-binding sites in granulosa and theca layers of preovulatory follicles and to
      determine the binding characteristics depending on the degree of follicular
      maturation and the stage of the ovulatory cycle in the hen. Hens were killed 2 h
      (stage I), 9 h (stage II), 16 h (stage III), and 23 h (stage IV) after
      oviposition, and the five largest yellow follicles (from F1 to F5) were removed.
      GH-binding sites in granulosa and theca layers from F1 to F5 follicles were
      characterized using a radioreceptor assay. Equilibrium dissociation constants
      (K(d)) and binding capacities (B(max)) were determined by Scatchard analysis of
      saturation curves, which revealed a single class of high-affinity GH-binding
      sites in both theca tissue and granulosa cells. In F1, F2, and F5 follicles,
      B(max) and K(d) for GH-binding sites in the granulosa layer changed during the
      ovulatory cycle, decreasing between stages I and III, to increase again at stage
      IV, with alterations in K(d) being less profound. No significant differences in
      binding capacities and affinities of GH-binding sites in the theca layer were
      found between various stages of the cycle. Furthermore, the concentration of GH
      binding sites in the granulosa layer rose, whereas that in the theca layer fell
      with follicular enlargement. These findings indicate the presence of high
      affinity GH-binding sites in both granulosa and theca layers of hen preovulatory
      follicles. Data also demonstrate that GH-binding sites in these tissues are
      regulated in a tissue-specific manner. Furthermore, the regulation of binding
      capacity of GH binding in granulosa cells by hormonal factors associated with
      ovulatory cycle is apparently not dependent on the state of follicular
      maturation.

PMID- 15189832
TI  - Estrogen regulates vaginal sensory and autonomic nerve density in the rat.
AB  - Vaginal function is strongly influenced by reproductive hormone status. Vaginal
      dysfunction during menopause is generally assumed to occur because of diminished
      estrogen-mediated trophic support of vaginal target cells. However, peripheral
      neurons possess estrogen receptors and are potentially responsive to gonadal
      steroid hormones. In the present study, we investigated whether sensory and
      autonomic innervation of the vagina varies among rats during the estrus phase of
      the estrous cycle, following chronic ovariectomy, and after sustained estrogen
      replacement. Relative to rats in estrus, ovariectomized rats showed a 59%
      elevation in nerve density, as determined using the panneuronal marker PGP 9.5.
      This increase persisted even after correcting for differences in vaginal tissue
      size, indicating true axonal proliferation after ovariectomy rather than changes
      secondary to altered volume. Increased total innervation after ovariectomy was
      attributable to increased densities of sympathetic nerves immunostained for
      tyrosine hydroxylase (70%), cholinergic parasympathetic nerves immunoreactive for
      vesicular acetylcholine transporter (93%), and calcitonin gene-related peptide
      immunoreactive sensory nociceptor nerves (84%). Myelinated primary sensory
      innervation revealed by RT-97 immunoreactivity did not appear to be affected.
      Sustained 17beta-estradiol administration reduced innervation density to an
      extent comparable to that of estrus, implying that estrogen is the hormone
      mediating vaginal neuroplasticity. These findings indicate that some aspects of
      vaginal dysfunction during menopause may be attributable to changes in
      innervation. Increased sympathetic innervation may augment vasoconstriction and
      promote vaginal dryness, while sensory nociceptor axon proliferation may
      contribute to symptoms of pain, burning, and itching associated with menopause
      and some forms of vulvodynia.

PMID- 15189833
TI  - Presence of permanently activated signal transducers and activators of
      transcription in nuclear interchromatin granules of unstimulated mouse oocytes
      and preimplantation embryos.
AB  - We previously described that mouse oocytes and preimplantation embryos express
      the two subunits of interferon-gamma receptor. We now report that, despite the
      presence of STAT1 (signal transducer and activator of transcription 1) at both
      the mRNA and protein levels, interferon gamma (IFNgamma) as well as IFNalpha are
      unable to trigger massive nuclear translocation of STAT1 in these cells, even at
      high cytokine concentrations. Conversely, nuclear accumulation of STAT1 was
      readily observed in murine L929 somatic cells under the same conditions. However,
      in the absence of any stimulation, both tyrosine (Y701p) and serine (S727p)
      phosphorylated forms of STAT1 were already detected in the nuclei of oocytes and
      early embryos. Phosphorylated STAT1 appeared concentrated in large nuclear dots,
      which were identified by indirect immunofluorescence and electron microscopy as
      clusters of interchromatin granules (IGCs or speckles). A similar distribution
      was also observed for the serine (S727p) phosphorylated form of STAT3 as well as
      for tyrosine (Y689p) phosphorylated STAT2. Western blot analysis confirmed that
      STAT factors present in mouse oocytes are predominantly phosphorylated. In
      parallel, we showed that the transcription of two IFNgamma-target genes, namely
      interferon regulatory factor-1 (IRF-1) and suppressor of cytokine signaling-1
      (SOCS-1) is indeed increased in two-cell embryos in response to IFNgamma.
      Altogether, our results suggest that, despite the lack of massive nuclear
      accumulation of STAT1 in response to exogenous IFNs and the permanent presence of
      phosphorylated STATs in the nucleus, JAK/ STAT pathways are functional during
      early development.

PMID- 15189834
TI  - Abnormalities and reduced reproductive potential of sperm from Tnp1- and Tnp2
      null double mutant mice.
AB  - Previous studies have demonstrated the importance of transition nuclear proteins,
      TP1 and TP2, in spermatogenesis and male fertility. However, importance of the
      overall level of transition proteins and their level of redundancy in the
      production of normal sperm is not clear. Epididymal sperm from the nine possible
      Tnp1 and Tnp2 null genotypes demonstrated a general decrease in normal
      morphology, motility, chromatin condensation, and degree of protamine 2
      processing with decreasing levels of transition proteins in mutant sperm. Nuclei
      of some mutant epididymal sperm stained poorly with hematoxylin and DNA
      fluorochromes, suggesting that the DNA of these sperm underwent degradation
      during epididymal transport. When epididymal sperm were injected directly into
      oocytes, fertilization and embryonic development were reduced only in the two
      most severely affected genotypes. These phenotypes indicated some functional
      redundancy of transition proteins; however, redundancy of transition protein
      function was not complete, as, for example, sperm from double heterozygous males
      had fewer abnormalities than sperm from males homozygous for a single Tnp null
      mutation. Our study suggests that each TP fulfills some unique function during
      spermiogenesis even though sperm phenotypes strongly indicate defects are largely
      attributable to an overall gene dosage effect. Similarities between sperm defects
      found in Tnp mutants and infertile patients make the Tnp mutants a valuable tool
      with which to study outcomes following fertilization using sperm with compromised
      DNA integrity.

PMID- 15189835
TI  - Functional significance of the pentose phosphate pathway and glutathione
      reductase in the antioxidant defenses of human sperm.
AB  - Glutathione peroxidase is one of the principal antioxidant defense enzymes in
      human spermatozoa, but it requires oxidized glutathione to be reduced by
      glutathione reductase using NADPH generated in the pentose phosphate pathway. We
      investigated whether flux through the pentose phosphate pathway would increase in
      response to oxidative stress and whether glutathione reductase was required to
      protect sperm from oxidative damage. Isotopic measurements of the pentose
      phosphate pathway and glycolytic flux, thiobarbituric acid assay of
      malondialdehyde for lipid peroxidation, and computer-assisted sperm analysis for
      sperm motility were assessed in a group of normal, healthy semen donors. Applying
      moderate oxidative stress to human spermatozoa by adding cumene hydroperoxide,
      H(2)O(2), or xanthine plus xanthine oxidase or by promoting lipid peroxidation
      with ascorbate increased flux through the pentose phosphate pathway without
      changing the glycolytic rate. However, adding higher concentrations of oxidants
      inhibited both the pentose phosphate pathway and glycolytic flux. At
      concentrations of 50 microg/ml or greater, the glutathione reductase-inhibitor
      1,3-bis-(2-chloroethyl) 1-nitrosourea decreased flux through the pentose
      phosphate pathway and blocked the response to cumene hydroperoxide. It also
      increased lipid peroxidation and impaired the survival of motility in sperm
      incubated under 95% O(2). These data show that the pentose phosphate pathway in
      human spermatozoa can respond dynamically to oxidative stress and that inhibiting
      glutathione reductase impairs the ability of sperm to resist lipid peroxidation.
      We conclude that the glutathione peroxidase-glutathione reductase-pentose
      phosphate pathway system is functional and provides an effective antioxidant
      defense in normal human spermatozoa.

PMID- 15189836
TI  - Expression of growth differentiation factor 9 messenger RNA in porcine growing
      and preovulatory ovarian follicles.
AB  - We have shown previously that porcine cumulus and mural granulosa cells produce a
      factor that is very similar, if not identical, to the oocyte-derived cumulus
      expansion-enabling factor (CEEF). Because growth differentiation factor 9 (GDF9)
      is the most likely candidate for the CEEF, in the present study we tested the
      hypothesis that GDF9 is expressed not only in oocytes in the pig but also in
      somatic follicular cells. In addition, we asked whether the relative abundance
      (RA) of GDF9 mRNA changes in oocytes and/or follicular cells during the
      periovulatory period or culture of oocyte-cumulus complexes (OCCs) in vitro.
      Denuded oocytes, OCCs, cumulus, and mural granulosa cells were isolated from
      growing and preovulatory follicles. Total RNA was extracted from the cells, and
      reverse transcription-polymerase chain reaction (RT-PCR) was carried out using
      specific oligonucleotide primers. The RT-PCR resulted in amplification of a
      product of expected size (277 base pairs) in samples prepared from all follicular
      cell types. The identity of the RT-PCR products with GDF9 was confirmed by
      analysis of their nucleotide sequence, which was 88% and 91% identical to human
      and ovine GDF9, respectively. The RA of GDF9 mRNA in the somatic follicular cells
      was approximately fourfold lower than in oocytes. Assessment of the RA of GDF9
      mRNA during the periovulatory period and during culture and expansion of OCCs in
      vitro revealed that it remained stable in oocytes and mural granulosa cells and
      decreased significantly in expanding cumulus cells. We conclude that GDF9 mRNA
      can be produced by somatic follicular cells in the pig and that cumulus expansion
      is not preceded or accompanied by an increase in the RA of GDF9 mRNA in any of
      the tested cell types.

PMID- 15189837
TI  - Effect of specific phosphodiesterase isoenzyme inhibitors during in vitro
      maturation of bovine oocytes on meiotic and developmental capacity.
AB  - Compared with oocytes matured in vivo, in vitro-matured oocytes are compromised
      in their capacity to support early embryo development. Delaying spontaneous in
      vitro meiotic maturation using specific phosphodiesterase (PDE) isoenzyme
      inhibitors may permit more complete oocyte cytoplasmic maturation, possibly by
      prolonging cumulus cell (CC)-oocyte gap junctional communication during meiotic
      resumption. This study aimed to investigate the effect of the isoenzyme 3-
      (oocyte) and isoenzyme 4- (granulosa cell) specific PDE inhibitors on the
      kinetics of in vitro maturation and on subsequent oocyte developmental
      competence. Cumulus-oocyte complexes from antral bovine follicles were isolated
      and cultured in the presence of the specific PDE inhibitors milrinone (type 3) or
      rolipram (type 4) (100 microM). In the presence of FSH, both PDE inhibitors only
      slightly extended CC-oocyte gap junctional communication over the first 9 h, but
      they completely blocked meiotic resumption during this period (P < 0.001). The
      indefinite inhibitory effect of milrinone on meiotic resumption (30% at germinal
      vesicle stage after 48 h) was overridden by 24 h when treated with FSH, but not
      with hCG, suggesting a form of induced meiotic resumption. Oocytes treated with
      FSH with or without either PDE inhibitor were inseminated at either 24, 26, or 28
      h. Treated with either the type 3 or type 4 PDE inhibitor significantly (P <
      0.05) increased embryo development to the blastocyst stage by 33%-39% (to an
      average of 52% blastocysts) compared with control oocytes (38%) after
      insemination at 28 h, and significantly (P < 0.05) increased blastocyst cell
      numbers when inseminated at 24 h. These results suggest that delayed spontaneous
      meiotic maturation, coupled with extended gap junctional communication between
      the CCs and the oocyte has a positive effect on oocyte cytoplasmic maturation,
      thereby improving oocyte developmental potential.

PMID- 15189838
TI  - A structural model of EmrE, a multi-drug transporter from Escherichia coli.
AB  - Using a recently reported computational method, we describe an approach to model
      the structure of EmrE, a proton coupled multi-drug transporter of Escherichia
      coli. EmrE is the smallest ion-coupled transporter known; it functions as an
      oligomer and each monomer comprises four transmembrane segments. Because of its
      size, EmrE provides a unique experimental paradigm. The computational method does
      not afford a unique solution for the monomer. The experimental constraints
      available were used to select the most likely structure and to dock two monomers
      together to yield a dimer. The model is further validated by modeling of Hsmr, an
      EmrE homolog with a remarkable amino acid composition with over 40% of Ala and
      Val. The Hsmr model is similar to that of EmrE, with the majority of the Ala or
      Val residues facing the lipid. In addition, the model of EmrE features a putative
      substrate-binding site very similar to that observed in BmrR, a transcription
      activator of multi-drug transporters, with a similar substrate profile. The two
      crucial residues that couple proton fluxes with substrate binding in the homo
      dimer of EmrE, Glu-14, have a spatial arrangement that agrees with proposed
      molecular mechanisms of transport.

PMID- 15189839
TI  - The dependence of all-atom statistical potentials on structural training
      database.
AB  - An accurate statistical energy function that is suitable for the prediction of
      protein structures of all classes should be independent of the structural
      database used for energy extraction. Here, two high-resolution, low-sequence
      identity structural databases of 333 alpha-proteins and 271 beta-proteins were
      built for examining the database dependence of three all-atom statistical energy
      functions. They are RAPDF (residue-specific all-atom conditional probability
      discriminatory function), atomic KBP (atomic knowledge-based potential), and
      DFIRE (statistical potential based on distance-scaled finite ideal-gas reference
      state). These energy functions differ in the reference states used for energy
      derivation. The energy functions extracted from the different structural
      databases are used to select native structures from multiple decoys of 64 alpha
      proteins and 28 beta-proteins. The performance in native structure selections
      indicates that the DFIRE-based energy function is mostly independent of the
      structural database whereas RAPDF and KBP have a significant dependence. The
      construction of two additional structural databases of alpha/beta and alpha +
      beta-proteins further confirmed the weak dependence of DFIRE on the structural
      databases of various structural classes. The possible source for the difference
      between the three all-atom statistical energy functions is that the physical
      reference state of ideal gas used in the DFIRE-based energy function is least
      dependent on the structural database.

PMID- 15189840
TI  - Brownian adhesive dynamics (BRAD) for simulating the receptor-mediated binding of
      viruses.
AB  - Current viral docking models have relied upon the assumption that bond formation
      and breakage are independent of viral and docking surface geometry, as well as
      the forces exerted on the bonds. This assumption, known as the equivalent site
      hypothesis (ESH), is examined in detail using a newly developed simulation
      technique-Brownian adhesive dynamics (BRAD). The simulation couples the thermal
      motion of viral particles with adhesive dynamics models to characterize the
      effect of bonding on viral motion. We use the binding of HIV-like particles to
      CD4 expressing cells as a model system to illustrate the utility of BRAD.
      Comparison of the transition rates between bound states predicted by ESH and the
      rates resulting from BRAD simulations show dramatic differences; at values of the
      equilibrium crosslinking constant, K(x)R(T), where ESH suggests all virus
      adhesion proteins will be bound (K(x)R(T) = 10(6)), BRAD predicts not all virus
      adhesion proteins will be bound. At values of the equilibrium crosslinking
      constant used in typical ESH calculations of virus docking (K(x)R(T) = 1) we find
      BRAD simulations predict no binding. The mean bond density from BRAD models is
      often much lower than that predicted by ESH for equivalent parameter values. BRAD
      suggests that the viruses are much less well bound than ESH predicts. The
      differences suggest that binding models for viruses need to be reexamined
      closely. BRAD is a simulation technique that will be useful for quantifying the
      receptor-mediated binding of a wide variety of viruses to cells.

PMID- 15189841
TI  - Dynamics of molecular motors and polymer translocation with sequence
      heterogeneity.
AB  - The effect of sequence heterogeneity on polynucleotide translocation across a
      pore and on simple models of molecular motors such as helicases, DNA
      polymerase/exonuclease, and RNA polymerase is studied in detail. Pore
      translocation of RNA or DNA is biased due to the different chemical environments
      on the two sides of the membrane, whereas the molecular motor motion is biased
      through a coupling to chemical energy. An externally applied force can oppose
      these biases. For both systems we solve lattice models exactly both with and
      without disorder. The models incorporate explicitly the coupling to the different
      chemical environments for polymer translocation and the coupling to the chemical
      energy (as well as nucleotide pairing energies) for molecular motors. Using the
      exact solutions and general arguments, we show that the heterogeneity leads to
      anomalous dynamics. Most notably, over a range of forces around the stall force
      (or stall tension for DNA polymerase/exonuclease systems) the displacement grows
      sublinearly as t(micro), with micro < 1. The range over which this behavior can
      be observed experimentally is estimated for several systems and argued to be
      detectable for appropriate forces and buffers. Similar sequence heterogeneity
      effects may arise in the packing of viral DNA.

PMID- 15189842
TI  - Highly organized but pliant active site of DNA polymerase beta: compensatory
      mechanisms in mutant enzymes revealed by dynamics simulations and energy
      analyses.
AB  - To link conformational transitions noted for DNA polymerases with kinetic results
      describing catalytic efficiency and fidelity, we investigate the role of key DNA
      polymerase beta residues on subdomain motion through simulations of five single
      residue mutants: Arg-283-Ala, Tyr-271-Ala, Asp-276-Val, Arg-258-Lys, and Arg-258
      Ala. Since a movement toward a closed state was only observed for R258A, we
      suggest that Arg(258) is crucial in modulating motion preceding chemistry.
      Analyses of protein/DNA interactions in the mutant active site indicate
      distinctive hydrogen bonding and van der Waals patterns arising from compensatory
      structural adjustments. By comparing closed mutant complexes with the wild-type
      enzyme, we interpret experimentally derived nucleotide binding affinities in
      molecular terms: R283A (decreased), Y271A (increased), D276V (increased), and
      R258A (decreased). Thus, compensatory interactions (e.g., in Y271A with adjacent
      residues Phe(272), Asn(279), and Arg(283)) increase the overall binding affinity
      for the incoming nucleotide although direct interactions may decrease. Together
      with energetic analyses, we predict that R258G might increase the rate of
      nucleotide insertion and maintain enzyme fidelity as R258A; D276L might increase
      the nucleotide binding affinity more than D276V; and R283A/K280A might decrease
      the nucleotide binding affinity and increase misinsertion more than R283A. The
      combined observations regarding key roles of specific residues (e.g., Arg(258))
      and compensatory interactions echo the dual nature of polymerase active site,
      namely versatility (to accommodate various basepairs) and specificity (for
      preserving fidelity) and underscore an organized but pliant active site essential
      to enzyme function.

PMID- 15189843
TI  - Bayesian estimation for species identification in single-molecule fluorescence
      microscopy.
AB  - In this article we describe a recursive Bayesian estimator for the identification
      of diffusing fluorophores using photon arrival-time data from a single spectral
      channel. We present derivations for all relevant diffusion and fluorescence
      models, and we use simulated diffusion trajectories and photon streams to
      evaluate the estimator's performance. We consider simplified estimation schemes
      that bin the photon counts within time intervals of fixed duration, and show that
      they can perform well in realistic parameter regimes. The latter results indicate
      the feasibility of performing identification experiments in real time. It will be
      straightforward to generalize our approach for use in more complicated scenarios,
      e.g., with multiple spectral channels or fast photophysical dynamics.

PMID- 15189844
TI  - A molecular dynamics study of reovirus attachment protein sigma1 reveals
      conformational changes in sigma1 structure.
AB  - Molecular dynamics simulations were performed using the recently determined
      crystal structure of the reovirus attachment protein, sigma1. These studies were
      conducted to improve an understanding of two unique features of sigma1 structure:
      the protonation state of Asp(345), which is buried in the sigma1 trimer
      interface, and the flexibility of the protein at a defined region below the
      receptor-binding head domain. Three copies of aspartic acids Asp(345) and
      Asp(346) cluster in a solvent-inaccessible and hydrophobic region at the sigma1
      trimer interface. These residues are hypothesized to mediate conformational
      changes in sigma1 during viral attachment or cell entry. Our results indicate
      that protonation of Asp(345) is essential to the integrity of the trimeric
      structure seen by x-ray crystallography, whereas deprotonation induces structural
      changes that destabilize the trimer interface. This finding was confirmed by
      electrostatic calculations using the finite difference Poisson-Boltzmann method.
      Earlier studies show that sigma1 can exist in retracted and extended
      conformations on the viral surface. Since protonated Asp(345) is necessary to
      form a stable, extended trimer, our results suggest that protonation of Asp(345)
      may allow for a structural transition from a partially detrimerized molecule to
      the fully formed trimer seen in the crystal structure. Additional studies were
      conducted to quantify the previously observed flexibility of sigma1 at a defined
      region below the receptor-binding head domain. Increased mobility was observed
      for three polar residues (Ser(291), Thr(292), and Ser(293)) located within an
      insertion between the second and third beta-spiral repeats of the crystallized
      portion of the sigma1 tail. These amino acids interact with water molecules of
      the solvent bulk and are responsible for oscillating movement of the head of
      approximately 50 degrees during 5 ns of simulations. This flexibility may
      facilitate viral attachment and also function in cell entry and disassembly.
      These findings provide new insights about the conformational dynamics of sigma1
      that likely underlie the initiation of the reovirus infectious cycle.

PMID- 15189845
TI  - Multisite phosphorylation and network dynamics of cyclin-dependent kinase
      signaling in the eukaryotic cell cycle.
AB  - Multisite phosphorylation of regulatory proteins has been proposed to underlie
      ultrasensitive responses required to generate nontrivial dynamics in complex
      biological signaling networks. We used a random search strategy to analyze the
      role of multisite phosphorylation of key proteins regulating cyclin-dependent
      kinase (CDK) activity in a model of the eukaryotic cell cycle. We show that
      multisite phosphorylation of either CDK, CDC25, wee1, or CDK-activating kinase is
      sufficient to generate dynamical behaviors including bistability and limit
      cycles. Moreover, combining multiple feedback loops based on multisite
      phosphorylation do not destabilize the cell cycle network by inducing complex
      behavior, but rather increase the overall robustness of the network. In this
      model we find that bistability is the major dynamical behavior of the CDK
      signaling network, and that negative feedback converts bistability into limit
      cycle behavior. We also compare the dynamical behavior of several simplified
      models of CDK regulation to the fully detailed model. In summary, our findings
      suggest that multisite phosphorylation of proteins is a critical biological
      mechanism in generating the essential dynamics and ensuring robust behavior of
      the cell cycle.

PMID- 15189846
TI  - Prediction of charge-induced molecular alignment of biomolecules dissolved in
      dilute liquid-crystalline phases.
AB  - Alignment of macromolecules in nearly neutral aqueous lyotropic liquid
      crystalline media such as bicelles, commonly used in macromolecular NMR studies,
      can be predicted accurately by a steric obstruction model (Zweckstetter and Bax,
      2000). A simple extension of this model is described that results in improved
      predictions for both the alignment orientation and magnitude of protein and DNA
      solutes in charged nematic media, such as the widely used medium of filamentous
      phage Pf1. The extended model approximates the electrostatic interaction between
      a solute and an ordered phage particle as that between the solute's surface
      charges and the electric field of the phage. The model is evaluated for four
      different proteins and a DNA oligomer. Results indicate that alignment in charged
      nematic media is a function not only of the solute's shape, but also of its
      electric multipole moments of net charge, dipole, and quadrupole. The relative
      importance of these terms varies greatly from one macromolecule to another, and
      evaluation of the experimental data indicates that these terms scale differently
      with ionic strength. For several of the proteins, the calculated alignment is
      sensitive to the precise position of the charged groups on the protein surface.
      This suggests that NMR alignment measurements can potentially be used to probe
      protein electrostatics. Inclusion of electrostatic interactions in addition to
      steric effects makes the extended model applicable to all liquid crystals used in
      biological NMR to date.

PMID- 15189847
TI  - Cationic DMPC/DMTAP lipid bilayers: molecular dynamics study.
AB  - Cationic lipid membranes are known to form compact complexes with DNA and to be
      effective as gene delivery agents both in vitro and in vivo. Here we employ
      molecular dynamics simulations for a detailed atomistic study of lipid bilayers
      consisting of a mixture of cationic dimyristoyltrimethylammonium propane (DMTAP)
      and zwitterionic dimyristoylphosphatidylcholine (DMPC). Our main objective is to
      examine how the composition of the DMPC/DMTAP bilayers affects their structural
      and electrostatic properties in the liquid-crystalline phase. By varying the mole
      fraction of DMTAP, we have found that the area per lipid has a pronounced
      nonmonotonic dependence on the DMTAP concentration, with a minimum around the
      point of equimolar DMPC/DMTAP mixture. We show that this behavior has an
      electrostatic origin and is driven by the interplay between positively charged
      TAP headgroups and the zwitterionic phosphatidylcholine (PC) heads. This
      interplay leads to considerable reorientation of PC headgroups for an increasing
      DMTAP concentration, and gives rise to major changes in the electrostatic
      properties of the lipid bilayer, including a significant increase of total dipole
      potential across the bilayer and prominent changes in the ordering of water in
      the vicinity of the membrane. Moreover, chloride counterions are bound mostly to
      PC nitrogens implying stronger screening of PC heads by Cl ions compared to TAP
      headgroups. The implications of these findings are briefly discussed.

PMID- 15189848
TI  - Analysis of binding reactions by fluorescence recovery after photobleaching.
AB  - Fluorescence recovery after photobleaching (FRAP) is now widely used to
      investigate binding interactions in live cells. Although various idealized
      solutions have been identified for the reaction-diffusion equations that govern
      FRAP, there has been no comprehensive analysis or systematic approach to serve as
      a guide for extracting binding information from an arbitrary FRAP curve. Here we
      present a complete solution to the FRAP reaction-diffusion equations for either
      single or multiple independent binding interactions, and then relate our solution
      to the various idealized cases. This yields a coherent approach to extract
      binding information from FRAP data which we have applied to the question of
      transcription factor mobility in the nucleus. We show that within the nucleus,
      the glucocorticoid receptor is transiently bound to a single state, with each
      molecule binding on average 65 sites per second. This rapid sampling is likely to
      be important in finding a specific promoter target sequence. Further we show that
      this predominant binding state is not the nuclear matrix, as some studies have
      suggested. We illustrate how our analysis provides several self-consistency
      checks on a FRAP fit. We also define constraints on what can be estimated from
      FRAP data, show that diffusion should play a key role in many FRAP recoveries,
      and provide tools to test its contribution. Overall our approach establishes a
      more general framework to assess the role of diffusion, the number of binding
      states, and the binding constants underlying a FRAP recovery.

PMID- 15189850
TI  - How to impose microscopic reversibility in complex reaction mechanisms.
AB  - Most, but not all, ion channels appear to obey the law of microscopic
      reversibility (or detailed balance). During the fitting of reaction mechanisms it
      is therefore often required that cycles in the mechanism should obey microscopic
      reversibility at all times. In complex reaction mechanisms, especially those that
      contain cubic arrangements of states, it may not be obvious how to achieve this.
      Three general methods for imposing microscopic reversibility are described. The
      first method works by setting the 'obvious' four-state cycles in the correct
      order. The second method, based on the idea of a spanning tree, works by finding
      independent cycles (which will often have more than four states) such that the
      order in which they are set does not matter. The third method uses linear algebra
      to solve for constrained rates.

PMID- 15189849
TI  - Lipid bilayer pressure profiles and mechanosensitive channel gating.
AB  - The function of membrane proteins often depends on the proteins' interaction with
      their lipid environment, spectacularly so in the case of mechanosensitive
      channels, which are gated through tension mediated by the surrounding lipids.
      Lipid bilayer tension is distributed quite inhomogeneously, but neither the scale
      at which relevant variation takes place nor the effect of varying lipid
      composition or tension has yet been investigated in atomic detail. We calculated
      lateral pressure profile distributions in lipid bilayers of various composition
      from all-atom molecular dynamics simulations totaling 110.5 ns in length.
      Reproducible pressure profile features at the 1 A length scale were determined.
      Lipids with phosphatidylcholine headgroups were found to shift the lateral
      pressure out of the hydrophobic core and into the headgroup region by an amount
      that is independent of area per lipid. POPE bilayers simulated at areas smaller
      than optimal exerted dramatically higher lateral pressure in a narrow region at
      the start of the aliphatic chain. Stretching of POPC bilayers increased tension
      predominantly in the same region. A simple geometric analysis for the gating of
      the mechanosensitive channel MscL suggests that pressure profiles affect its
      gating through the second moment of the profile in a tension-independent manner.

PMID- 15189851
TI  - Two-state model for outer hair cell stiffness and motility.
AB  - With discovery of the protein prestin and the gathering evidence linking it to
      outer hair cell electromotility, the working mechanism of outer hair cells is
      becoming clearer. Recent experiments have established the voltage-dependent
      stiffness of outer hair cells and given an insight into the nature of variation
      of stiffness with respect to voltage. These and earlier experiments are used to
      analyze and develop models of outer hair cell response. In this article, recent
      modeling efforts have been reconciled and placed into a common mechanics-based
      framework. The constitutive models are analyzed with regard to their capability
      to replicate experimental results. We extend the area motor model to include
      elastic constants dependent on motor state. The modified model successfully
      captures stiffness variations of outer hair cells and capacitance changes with
      respect to voltage.

PMID- 15189852
TI  - Ionic permeation free energy in gramicidin: a semimicroscopic perspective.
AB  - Ion permeation through the gramicidin channel is studied using a model that
      circumvents two major difficulties inherent to standard simulational methods. It
      exploits the timescale separation between electronic and structural contributions
      to dielectric stabilization, accounting for the influence of electronic
      polarization by embedding the channel in a dielectric milieu that describes this
      polarization in a mean sense. The explicit mobile moieties are the ion,
      multipolar waters, and the carbonyls and amides of the peptide backbone. The
      model treats the influence of aromatic residues and the membrane dipole
      potential. A new electrical geometry is introduced that treats long-range
      electrostatics exactly and avoids problems related to periodic boundary
      conditions. It permits the translocating ion to make a seamless transition from
      nearby electrolyte to the channel interior. Other degrees of freedom (more
      distant bulk electrolyte and nonpolar lipid) are treated as dielectric continua.
      Reasonable permeation free energy profiles are obtained for potassium, rubidium,
      and cesium; binding wells are shallow and the central barrier is small. Estimated
      cationic single-channel conductances are smaller than experiment, but only by
      factors between 2 (rubidium) and 50 (potassium). When applied to chloride the
      internal barrier is large, with a corresponding miniscule single-channel
      conductance. The estimated relative single-channel conductances of gramicidin A,
      B, and C agree well with experiment.

PMID- 15189854
TI  - Simulations of a membrane-anchored peptide: structure, dynamics, and influence on
      bilayer properties.
AB  - A three-dimensional structure of a model decapeptide is obtained by performing
      molecular dynamics simulations of the peptide in explicit water. Interactions
      between an N-myristoylated form of the folded peptide anchored to
      dipalmitoylphosphatidylcholine fluid phase lipid membranes are studied at
      different applied surface tensions by molecular dynamics simulations. The lipid
      membrane environment influences the conformational space explored by the peptide.
      The overall secondary structure of the anchored peptide is found to deviate at
      times from its structure in aqueous solution through reversible conformational
      transitions. The peptide is, despite the anchor, highly mobile at the membrane
      surface with the peptide motion along the bilayer normal being integrated into
      the collective modes of the membrane. Peptide anchoring moderately alters the
      lateral compressibility of the bilayer by changing the equilibrium area of the
      membrane. Although membrane anchoring moderately affects the elastic properties
      of the bilayer, the model peptide studied here exhibits conformational
      flexibility and our results therefore suggest that peptide acylation is a
      feasible way to reinforce peptide-membrane interactions whereby, e.g., the
      lifetime of receptor-ligand interactions can be prolonged.

PMID- 15189855
TI  - Translocation of a single-stranded DNA through a conformationally changing
      nanopore.
AB  - We investigate the translocation of a single-stranded DNA through a pore which
      fluctuates between two conformations, using coupled master equations. The
      probability density function of the first passage times of the translocation
      process is calculated, displaying a triple-, double-, or monopeaked behavior,
      depending on the interconversion rates between the conformations, the applied
      electric field, and the initial conditions. The cumulative probability function
      of the first passage times, in a field-free environment, is shown to have two
      regimes, characterized by fast and slow timescales. An analytical expression for
      the mean first passage time of the translocation process is derived, and
      provides, in addition to the interconversion rates, an extensive characterization
      of the translocation process. Relationships to experimental observations are
      discussed.

PMID- 15189853
TI  - Computational simulations of interactions of scorpion toxins with the voltage
      gated potassium ion channel.
AB  - Based on a homology model of the Kv1.3 potassium channel, the recognitions of the
      six scorpion toxins, viz. agitoxin2, charybdotoxin, kaliotoxin, margatoxin,
      noxiustoxin, and Pandinus toxin, to the human Kv1.3 potassium channel have been
      investigated by using an approach of the Brownian dynamics (BD) simulation
      integrating molecular dynamics (MD) simulation. Reasonable three-dimensional
      structures of the toxin-channel complexes have been obtained employing BD
      simulations and triplet contact analyses. All of the available structures of the
      six scorpion toxins in the Research Collaboratory for Structural Bioinformatics
      Protein Data Bank determined by NMR were considered during the simulation, which
      indicated that the conformations of the toxin significantly affect both the
      molecular recognition and binding energy between the two proteins. BD simulations
      predicted that all the six scorpion toxins in this study use their beta-sheets to
      bind to the extracellular entryway of the Kv1.3 channel, which is in line with
      the primary clues from the electrostatic interaction calculations and mutagenesis
      results. Additionally, the electrostatic interaction energies between the toxins
      and Kv1.3 channel correlate well with the binding affinities (-logK(d)s), R(2) =
      0.603, suggesting that the electrostatic interaction is a dominant component for
      toxin-channel binding specificity. Most importantly, recognition residues and
      interaction contacts for the binding were identified. Lys-27 or Lys-28, residues
      Arg-24 or Arg-25 in the separate six toxins, and residues Tyr-400, Asp-402, His
      404, Asp-386, and Gly-380 in each subunit of the Kv1.3 potassium channel, are the
      key residues for the toxin-channel recognitions. This is in agreement with the
      mutation results. MD simulations lasting 5 ns for the individual proteins and the
      toxin-channel complexes in a solvated lipid bilayer environment confirmed that
      the toxins are flexible and the channel is not flexible in the binding. The
      consistency between the results of the simulations and the experimental data
      indicated that our three-dimensional models of the toxin-channel complex are
      reasonable and can be used as a guide for future biological studies, such as the
      rational design of the blocking agents of the Kv1.3 channel and mutagenesis in
      both toxins and the Kv1.3 channel. Moreover, the simulation result demonstrates
      that the electrostatic interaction energies combined with the distribution
      frequencies from BD simulations might be used as criteria in ranking the binding
      configuration of a scorpion toxin to the Kv1.3 channel.

PMID- 15189856
TI  - Modeling amyloid beta-peptide insertion into lipid bilayers.
AB  - Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (Abeta)
      can insert into cell membranes and form harmful ion channels, we model insertion
      of the 40- and 42-residue forms of the peptide into cell membranes using a Monte
      Carlo code which is specific at the amino acid level. We examine insertion of the
      regular Abeta peptide as well as mutants causing familial Alzheimer's disease,
      and find that all but one of the mutants change the insertion behavior by causing
      the peptide to spend more simulation steps in only one leaflet of the bilayer. We
      also find that Abeta42, because of the extra hydrophobic residues relative to
      Abeta40, is more likely to adopt this conformation than Abeta40 in both wild-type
      and mutant forms. We argue qualitatively why these effects happen. Here, we
      present our results and develop the hypothesis that this partial insertion
      increases the probability of harmful channel formation. This hypothesis can
      partly explain why these mutations are neurotoxic simply due to peptide insertion
      behavior. We further apply this model to various artificial Abeta mutants which
      have been examined experimentally, and offer testable experimental predictions
      contrasting the roles of aggregation and insertion with regard to toxicity of
      Abeta mutants. These can be used through further experiments to test our
      hypothesis.

PMID- 15189857
TI  - Kinetic analysis of a model for double substrate cycling: highly amplified ADP
      (and/or ATP) quantification.
AB  - A mathematical description has been made of an enzyme amplification mechanism
      involving the coupling of two substrate cycles. In this amplification system one
      of the noncycling products of a first substrate cycle acts as a trigger molecule
      that continuously feeds a second substrate cycle. Time-concentration equations
      describing the evolution of the species involved in the system have been
      obtained. The model is illustrated by the quantification of nanomolar levels of
      ADP (and/or ATP) in a continuous assay involving the enzymes L-lactate
      dehydrogenase and L-lactate oxidase to cycle the pyruvate accumulated in a first
      enzymatic cycle constituted by the enzymes pyruvate kinase and hexokinase.
      Progress curves were seen to be parabolic, and, according to the kinetic
      equations obtained, followed second-order polynomials of the reaction time.
      Mathematical equations for minimizing the cost of the assays are also given. The
      model is applicable to the amplified analytical determination of low levels of a
      metabolite or an enzyme activity, and its amplification capacity, together with
      the simplicity of determining kinetic parameters, enable it to be employed in
      enzyme immunoassays to increase the magnitude of the measured response.

PMID- 15189858
TI  - Membrane perturbation induced by interfacially adsorbed peptides.
AB  - The structural and energetic characteristics of the interaction between
      interfacially adsorbed (partially inserted) alpha-helical, amphipathic peptides
      and the lipid bilayer substrate are studied using a molecular level theory of
      lipid chain packing in membranes. The peptides are modeled as "amphipathic
      cylinders" characterized by a well-defined polar angle. Assuming two-dimensional
      nematic order of the adsorbed peptides, the membrane perturbation free energy is
      evaluated using a cell-like model; the peptide axes are parallel to the membrane
      plane. The elastic and interfacial contributions to the perturbation free energy
      of the "peptide-dressed" membrane are evaluated as a function of: the peptide
      penetration depth into the bilayer's hydrophobic core, the membrane thickness,
      the polar angle, and the lipid/peptide ratio. The structural properties
      calculated include the shape and extent of the distorted (stretched and bent)
      lipid chains surrounding the adsorbed peptide, and their orientational (C-H) bond
      order parameter profiles. The changes in bond order parameters attendant upon
      peptide adsorption are in good agreement with magnetic resonance measurements.
      Also consistent with experiment, our model predicts that peptide adsorption
      results in membrane thinning. Our calculations reveal pronounced, membrane
      mediated, attractive interactions between the adsorbed peptides, suggesting a
      possible mechanism for lateral aggregation of membrane-bound peptides. As a
      special case of interest, we have also investigated completely hydrophobic
      peptides, for which we find a strong energetic preference for the transmembrane
      (inserted) orientation over the horizontal (adsorbed) orientation.

PMID- 15189860
TI  - Functional properties of the Drosophila melanogaster inositol 1,4,5-trisphosphate
      receptor mutants.
AB  - The inositol (1,4,5)-trisphosphate receptor (InsP(3)R) is an intracellular
      calcium (Ca(2+)) release channel that plays a crucial role in cell signaling. In
      Drosophila melanogaster a single InsP(3)R gene (itpr) encodes a protein
      (DmInsP(3)R) that is approximately 60% conserved with mammalian InsP(3)Rs. A
      number of itpr mutant alleles have been identified in genetic screens and studied
      for their effect on development and physiology. However, the functional
      properties of wild-type or mutant DmInsP(3)Rs have never been described. Here we
      use the planar lipid bilayer reconstitution technique to describe single-channel
      properties of embryonic and adult head DmInsP(3)R splice variants. The three
      mutants chosen in this study reside in each of the three structural domains of
      the DmInsP(3)R-the amino-terminal ligand binding domain (ug3), the middle
      coupling domain (wc703), and the channel-forming region (ka901). We discovered
      that 1), the major functional properties of DmInsP(3)R (conductance, gating, and
      sensitivity to InsP(3) and Ca(2+)) are remarkably conserved with the mammalian
      InsP(3)R1; 2), single-channel conductance of the adult head DmInsP(3)R isoform is
      89 pS and the embryonic DmInsP(3)R isoform is 70 pS; 3), ug3 mutation affects
      sensitivity of the DmInsP(3)Rs to activation by InsP(3), but not their InsP(3)
      binding properties; 4), wc703 channels have increased sensitivity to modulation
      by Ca(2+); and 5), homomeric ka901 channels are not functional. We correlated the
      results obtained in planar lipid bilayer experiments with measurements of InsP(3)
      induced Ca(2+) fluxes in microsomes isolated from wild-type and heterozygous itpr
      mutants. Our study validates the use of D. melanogaster as an appropriate model
      for InsP(3)R structure-function studies and provides novel insights into the
      fundamental mechanisms of the InsP(3)R function.

PMID- 15189861
TI  - The force exerted by the membrane potential during protein import into the
      mitochondrial matrix.
AB  - The force exerted on a targeting sequence by the electrical potential across the
      inner mitochondrial membrane is calculated on the basis of continuum
      electrostatics. The force is found to vary from 3.0 pN to 2.2 pN (per unit
      elementary charge) as the radius of the inner membrane pore (assumed aqueous) is
      varied from 6.5 to 12 A, its measured range. In the present model, the decrease
      in force with increasing pore width arises from the shielding effect of water.
      Since the pore is not very much wider than the distance between water molecules,
      the full shielding effect of water may not be present; the extreme case of a
      purely membranous pore without water gives a force of 3.2 pN per unit charge,
      which should represent an upper limit. When applied to mitochondrial import
      experiments on the protein barnase, these results imply that forces between 11 +/
      2 pN and 13.5 +/- 2.5 pN catalyze the unfolding of barnase in those experiments.
      A comparison of these results with unfolding forces measured using atomic force
      microscopy is made.

PMID- 15189859
TI  - Bilayer thickness modulates the conductance of the BK channel in model membranes.
AB  - The conductance of the BK channel was evaluated in reconstituted bilayers made of
      POPE/POPS (3.3:1), or POPE/POPS with an added 20% of either SPM (3.3:1:1), CER
      (3.3:1:1), or CHL (3.3:1:1). The presence of SPM, which is known to increase
      bilayer thickness, significantly reduced the conductance of the BK channel. To
      directly test the role of membrane thickness, the conductance of the BK channel
      was measured in bilayers formed from PCs with acyl chains of increasing length
      (C14:1-C24:1), all in the absence of SPM. Slope conductance was maximal at a
      chain length of (C18:1) and much reduced for both thinner (C14:1) and thicker
      (C24:1) bilayers, indicating that membrane thickness alone can modify slope
      conductance. Further, in a simplified binary mixture of DOPE/SPM that forms a
      confined, phase-separated bilayer, the measured conductance of BK channels shows
      a clear bimodal distribution. In contrast, the addition of CER, which has an acyl
      chain structure similar to SPM but without its bulky polar head group to
      POPE/POPS, was without effect, as was the addition of CHL. The surface structure
      of membranes made from these same lipid mixtures was examined with AFM.
      Incorporation of both SPM and CER resulted in the formation of microdomains in
      POPE/POPS monolayers, but only SPM promoted a substantial increase in the amount
      of the high phase observed for the corresponding bilayers. The addition of CHL to
      POPE/POPS eliminated the phase separation observed in the POPE/POPS bilayer. The
      decrease in channel conductance observed with the incorporation of SPM into
      POPE/POPS membranes was, therefore, attributed to larger SPM-rich domains that
      appear thicker than the neighboring bilayer.

PMID- 15189862
TI  - Thermal activation and photoactivation of visual pigments.
AB  - A visual pigment molecule in a retinal photoreceptor cell can be activated not
      only by absorption of a photon but also "spontaneously" by thermal energy.
      Current estimates of the activation energies for these two processes in
      vertebrate rod and cone pigments are on the order of 40-50 kcal/mol for
      activation by light and 20-25 kcal/mol for activation by heat, which has forced
      the conclusion that the two follow quite different molecular routes. It is shown
      here that the latter estimates, derived from the temperature dependence of the
      rate of pigment-initiated "dark events" in rods, depend on the unrealistic
      assumption that thermal activation of a complex molecule like rhodopsin (or even
      its 11-cis retinaldehyde chromophore) happens through a simple process, somewhat
      like the collision of gas molecules. When the internal energy present in the many
      vibrational modes of the molecule is taken into account, the thermal energy
      distribution of the molecules cannot be described by Boltzmann statistics, and
      conventional Arrhenius analysis gives incorrect estimates for the energy barrier.
      When the Boltzmann distribution is replaced by one derived by Hinshelwood for
      complex molecules with many vibrational modes, the same experimental data become
      consistent with thermal activation energies that are close to or even equal to
      the photoactivation energies. Thus activation by light and by heat may in fact
      follow the same molecular route, starting with 11-cis to all-trans isomerization
      of the chromophore in the native (resting) configuration of the opsin. Most
      importantly, the same model correctly predicts the empirical correlation between
      the wavelength of maximum absorbance and the rate of thermal activation in the
      whole set of visual pigments studied.

PMID- 15189863
TI  - Revisiting voltage-dependent relief of block in ion channels: a mechanism
      independent of punchthrough.
AB  - Voltage dependence of block was investigated in a simple model for permeation in
      a multiion pore. Internal blocker could bind to three states of the open channel
      that differed in the locations and number of permeant ion bound; blocker
      dissociation occurs exclusively to the internal solution, and the blocker does
      not itself enter the electric field. By changing the relative stability of
      blocker binding to these three states, block displayed voltage dependence with
      relief of block at high potentials. Similar patterns of block could also be
      generated in more detailed models of ion permeation. These results illustrate
      that the observation of relief of block at high potentials is not a sufficient
      criterion for establishing that a blocker is permeant in a channel that has a
      complex permeation cycle.

PMID- 15189864
TI  - Time-resolved charge translocation by sarcoplasmic reticulum Ca-ATPase measured
      on a solid supported membrane.
AB  - Sarcoplasmic reticulum vesicles were adsorbed on an
      octadecanethiol/phosphatidylcholine mixed bilayer anchored to a gold electrode,
      and the Ca-ATPase contained in the vesicles was activated by ATP concentration
      jumps both in the absence and in the presence of K(+) ions and at different pH
      values. Ca(2+) concentration jumps in the absence of ATP were also carried out.
      The resulting capacitive current transients were analyzed together with the
      charge under the transients. The relaxation time constants of the current
      transients were interpreted on the basis of an equivalent circuit. The current
      transient after ATP concentration jumps and the charge after Ca(2+) concentration
      jumps in the absence of ATP exhibit almost the same dependence upon the Ca(2+)
      concentration, with a half-saturating value of approximately 1.5 microM. The pH
      dependence of the charge after Ca(2+) translocation demonstrates the occurrence
      of one H(+) per one Ca(2+) countertransport at pH 7 by direct charge-transfer
      measurements. The presence of K(+) decreases the magnitude of the current
      transients without altering their shape; this decrease is explained by K(+)
      binding to the cytoplasmic side of the pump in the E(1) conformation and being
      released to the same side during the E(1)-E(2) transition.

PMID- 15189865
TI  - Peptaibol zervamicin IIb structure and dynamics refinement from transhydrogen
      bond J couplings.
AB  - Zervamicin IIB (Zrv-IIB) is a channel-forming peptaibol antibiotic of fungal
      origin. The measured transhydrogen bond (3h)J(NC') couplings in methanol solution
      heaving average value of -0.41 Hz indicate that the stability of the Zrv-IIB
      helix in this milieu is comparable to the stability of helices in globular
      proteins. The N-terminus of the peptide forms an alpha-helix, whereas 3(10)
      helical hydrogen bonds stabilize the C-terminus. However, two weak transhydrogen
      bond peaks are observed in a long-range HNCO spectrum for HN Aib(12). Energy
      calculations using the Empirical Conformation Energy Program for Peptides
      (ECEPP)/2 force field and the implicit solvent model show that the middle of the
      peptide helix accommodates a bifurcated hydrogen bond that is simultaneously
      formed between HN Aib(12) and CO Leu(8) and CO Aib(9). Several lowered (3h)J(NC')
      on a polar face of the helix correlate with the conformational exchange process
      observed earlier and imply dynamic distortions of a hydrogen bond pattern with
      the predominant population of a properly folded helical structure. The refined
      structure of Zrv-IIB on the basis of the observed hydrogen bond pattern has a
      small ( approximately 20 degrees ) angle of helix bending that is virtually
      identical to the angle of bending in dodecylphosphocholine (DPC) micelles,
      indicating the stability of a hinge region in different environments. NMR
      parameters ((1)HN chemical shifts and transpeptide bond (1)J(NC') couplings)
      sensitive to hydrogen bonding along with the solvent accessible surface area of
      carbonyl oxygens indicate a large polar patch on the convex side of the helix
      formed by three exposed backbone carbonyls of Aib(7), Aib(9), and Hyp(10) and
      polar side chains of Hyp(10), Gln(11), and Hyp(13). The unique structural
      features, high helix stability and the enhanced polar patch, set apart Zrv-IIB
      from other peptaibols (for example, alamethicin) and possibly underlie its
      biological and physiological properties.

PMID- 15189866
TI  - Cholera toxin assault on lipid monolayers containing ganglioside GM1.
AB  - Many bacterial toxins bind to and gain entrance to target cells through specific
      interactions with membrane components. Using neutron reflectivity, we have
      characterized the structure of mixed DPPE:GM(1) lipid monolayers before and
      during the binding of cholera toxin (CTAB(5)) or its B-subunit (CTB(5)).
      Structural parameters such as the density and thickness of the lipid layer,
      extension of the GM(1) oligosaccharide headgroup, and orientation and position of
      the protein upon binding are reported. The density of the lipid layer was found
      to decrease slightly upon protein binding. However, the A-subunit of the whole
      toxin is clearly located below the B-pentameric ring, away from the monolayer,
      and does not penetrate into the lipid layer before enzymatic cleavage. Using
      Monte Carlo simulations, the observed monolayer expansion was found to be
      consistent with geometrical constraints imposed on DPPE by multivalent binding of
      GM(1) by the toxin. Our findings suggest that the mechanism of membrane
      translocation by the protein may be aided by alterations in lipid packing.

PMID- 15189867
TI  - Tilt angles of transmembrane model peptides in oriented and non-oriented lipid
      bilayers as determined by 2H solid-state NMR.
AB  - Solid-state NMR methods employing (2)H NMR and geometric analysis of labeled
      alanines (GALA) were used to study the structure and orientation of the
      transmembrane alpha-helical peptide acetyl-GWW(LA)(8)LWWA-amide (WALP23) in
      phosphatidylcholine (PC) bilayers of varying thickness. In all lipids the peptide
      was found to adopt a transmembrane alpha-helical conformation. A small tilt angle
      of 4.5 degrees was observed in di-18:1-PC, which has a hydrophobic bilayer
      thickness that approximately matches the hydrophobic length of the peptide. This
      tilt angle increased slightly but systematically with increasing positive
      mismatch to 8.2 degrees in di-C12:0-PC, the shortest lipid used. This small
      increase in tilt angle is insufficient to significantly change the effective
      hydrophobic length of the peptide and thereby to compensate for the increasing
      hydrophobic mismatch, suggesting that tilt of these peptides in a lipid bilayer
      is energetically unfavorable. The tilt and also the orientation around the
      peptide axis were found to be very similar to the values previously reported for
      a shorter WALP19 peptide (GWW(LA)(6)LWWA). As also observed in this previous
      study, the peptide rotates rapidly around the bilayer normal, but not around its
      helix axis. Here we show that these properties allow application of the GALA
      method not only to macroscopically aligned samples but also to randomly oriented
      samples, which has important practical advantages. A minimum of four labeled
      alanine residues in the hydrophobic transmembrane sequence was found to be
      required to obtain accurate tilt values using the GALA method.

PMID- 15189868
TI  - Mesoscopic structure in the chain-melting regime of anionic phospholipid
      vesicles: DMPG.
AB  - In a range of low ionic strength, aqueous dispersions of the anionic phospholipid
      DMPG (dimyristoylphosphatidylglycerol) have a transparent intermediate phase (IP,
      between T(m)(on) congruent with 20 degrees C and T(m)(off) congruent with 30
      degrees C) between the turbid gel and fluid membrane phases, evidenced in
      turbidity data. Small angle x-ray scattering results on DMPG dispersions show
      that, besides the bilayer peak present in all phases, a peak corresponding to a
      mesoscopic structure at approximately 400 A is detected only in IP. The
      dependence of this peak position on DMPG concentration suggests a correlation in
      the bilayer plane, consistent with the stability of vesicles in IP. Moreover,
      observation of giant DMPG vesicles with phase contrast light microscopy show that
      vesicles "disappear" upon cooling below T(m)(off) and "reappear" after reheating.
      This further proves that although vesicles cannot be visualized in IP, their
      overall structure is maintained. We propose that the IP in the melting regime
      corresponds to unilamellar vesicles with perforations, a model which is
      consistent with all described experimental observations. Furthermore, the opening
      of pores across the membrane tuned by ionic strength, temperature, and lipid
      composition is likely to have biological relevance and could be used in
      applications for controlled release from nanocompartments.

PMID- 15189870
TI  - Molecular dynamics simulation of lipid reorientation at bilayer edges.
AB  - Understanding cellular membrane processes is critical for the study of events
      such as viral entry, neurotransmitter exocytosis, and immune activation.
      Supported lipid bilayers are commonly used to model these membrane processes
      experimentally. Despite the relative simplicity of such a system, many important
      structural and dynamic parameters are not experimentally observable with current
      techniques. Computational approaches allow the development of a high-resolution
      model of bilayer processes. We have performed molecular dynamics simulations of
      dimyristoylphosphatidylcholine (DMPC) bilayers to model the creation of bilayer
      gaps-a common process in bilayer patterning-and to analyze their structure and
      dynamics. We propose a model for gap formation in which the bilayer edges form
      metastable micelle-like structures on a nanosecond timescale. Molecules near
      edges structurally resemble lipids in ungapped bilayers but undergo small-scale
      motions more rapidly. These data suggest that lipids may undergo rapid local
      rearrangements during membrane fusion, facilitating the formation of fusion
      intermediates thought key to the infection cycle of viruses such as influenza,
      Ebola, and HIV.

PMID- 15189869
TI  - SP-B and SP-C alter diffusion in bilayers of pulmonary surfactant.
AB  - The hydrophobic proteins SP-B and SP-C promote rapid adsorption of pulmonary
      surfactant to an air/water interface by an unknown mechanism. We tested the
      hypothesis that these proteins accelerate adsorption by disrupting the structure
      of the lipid bilayer, either by a generalized increase in fluidity or by a focal
      induction of interfacial boundaries within the bilayer. We used fluorescence
      recovery after photobleaching to measure diffusion of nitrobenzoxadiazolyl
      dimyristoyl-phosphatidylethanolamine between 11 and 54 degrees C in multilayers
      containing the complete set of lipids and proteins in calf lung surfactant
      extract (CLSE), or the complete set of neutral and phospholipids without the
      proteins. Above 35 degrees C, Arrhenius plots of diffusion were parallel for CLSE
      and neutral and phospholipids, but shifted to lower values for CLSE, suggesting
      that the proteins rigidify the lipid bilayer rather than producing the proposed
      increase in membrane fluidity. The slopes of the Arrhenius plots for CLSE were
      steeper below 35 degrees C, suggesting that the proteins induce phase separation
      at that temperature. The mobile fraction fell below 27 degrees C, consistent with
      a percolation threshold of coexisting gel and liquid-crystal phases. The
      induction of lateral phase separation in CLSE, however, does not correlate with
      apparent changes in adsorption kinetics at this temperature. Our results suggest
      that SP-B and SP-C accelerate adsorption through a mechanism other than the
      disruption of surfactant bilayers, possibly by stabilizing a high-energy, highly
      curved adsorption intermediate.

PMID- 15189871
TI  - Infrared reflection absorption spectroscopy of amphipathic model peptides at the
      air/water interface.
AB  - The linear sequence KLAL (KLALKLALKALKAALKLA-NH(2)) and its corresponding d,l
      isomers k(9)a(10)-KLAL (KLALKLALkaLKAALKLA-NH(2)) and l(11)k(12)-KLAL
      (KLALKLALKAlkAALKLA-NH(2)) are model compounds for potentially amphipathic alpha
      helical peptides which are able to bind to membranes and to increase the membrane
      permeability in a structure- and target-dependent manner (Dathe and Wieprecht,
      1999) We first studied the secondary structure of KLAL and its analogs bound to
      the air/water using infrared reflection absorption spectroscopy. For the peptide
      films the shape and position of the amide I and amide II bands indicate that the
      KLAL adopts at large areas per molecule an alpha-helical secondary structure,
      whereas at higher surface pressures or smaller areas it converts into a beta
      sheet structure. This transition could be observed in the compression isotherm as
      well as during the adsorption at the air/water interface from the subphase as a
      function of time. The secondary structures are essentially orientated parallel to
      the air/water interface. The analogs with d-amino acids in two different
      positions of the sequence, k(9)a(10)-KLAL and l(11)k(12)-KLAL, form only beta
      sheet structures at all surface pressures. The observed results are interpreted
      using a comparison of hydrophobic moments calculated for alpha-helices and beta
      sheets. The differences between the hydrophobic moments calculated using the
      consensus scale are not large. Using the optimal matching hydrophobicity scale or
      the whole-residue hydrophobicity scale the beta-sheet even has the larger
      hydrophobic moment.

PMID- 15189872
TI  - Structure of supported bilayers composed of lipopolysaccharides and bacterial
      phospholipids: raft formation and implications for bacterial resistance.
AB  - Lipopolysaccharide (LPS), the major lipid on the surface of Gram-negative
      bacteria, plays a key role in bacterial resistance to hydrophobic antibiotics and
      antimicrobial peptides. Using atomic force microscopy (AFM) we characterized
      supported bilayers composed of LPSs from two bacterial chemotypes with different
      sensitivities to such antibiotics and peptides. Rd LPS, from more sensitive "deep
      rough" mutants, contains only an inner saccharide core, whereas Ra LPS, from
      "rough" mutants, contains a longer polysaccharide region. A vesicle fusion
      technique was used to deposit LPS onto either freshly cleaved mica or
      polyethylenimine-coated mica substrates. The thickness of the supported bilayers
      measured with contact-mode AFM was 7 nm for Rd LPS and 9 nm for Ra LPS,
      consistent with previous x-ray diffraction measurements. In water the Ra LPS
      bilayer surface was more disordered than Rd LPS bilayers, likely due to the
      greater volume occupied by the longer Ra LPS polysaccharide region. Since deep
      rough mutants contain bacterial phospholipid (BPL) as well as LPS on their
      surfaces, we also investigated the organization of Rd LPS/BPL bilayers.
      Differential scanning calorimetry and x-ray diffraction indicated that
      incorporation of BPL reduced the phase transition temperature, enthalpy, and
      average bilayer thickness of Rd LPS. For Rd LPS/BPL mixtures, AFM showed
      irregularly shaped regions thinner than Rd LPS bilayers by 2 nm (the difference
      in thickness between Rd LPS and BPL bilayers), whose area increased with
      increasing BPL concentration. We argue that the increased permeability of deep
      rough mutants is due to structural modifications caused by BPL to the LPS
      membrane, in LPS hydrocarbon chain packing and in the formation of BPL-enriched
      microdomains.

PMID- 15189873
TI  - Changes in phosphatidylcholine headgroup tilt and water order induced by
      monovalent salts: molecular dynamics simulations.
AB  - The association between monovalent salts and neutral lipid bilayers is known to
      influence global bilayer structural properties such as headgroup conformational
      fluctuations and the dipole potential. The local influence of the ions, however,
      has been unknown due to limited structural resolution of experimental methods.
      Molecular dynamics simulations are used here to elucidate local structural
      rearrangements upon association of a series of monovalent Na(+) salts to a
      palmitoyl-oleoyl-phosphatidylcholine bilayer. We observe association of all ion
      types in the interfacial region. Larger anions, which are meant to rationalize
      data regarding a Hofmeister series of anions, bind more deeply within the bilayer
      than either Cl(-) or Na(+). Although the simulations are able to reproduce
      experimentally measured quantities, the analysis is focused on local properties
      currently invisible to experiments, which may be critical to biological systems.
      As such, for all ion types, including Cl(-), we show local ion-induced
      perturbations to headgroup tilt, the extent and direction of which is sensitive
      to ion charge and size. Additionally, we report salt-induced ordering of the
      water well beyond the interfacial region, which may be significant in terms of
      hydration repulsion between stacked bilayers.

PMID- 15189874
TI  - Investigation of temperature-induced phase transitions in DOPC and DPPC
      phospholipid bilayers using temperature-controlled scanning force microscopy.
AB  - Under physiological conditions, multicomponent biological membranes undergo
      structural changes which help define how the membrane functions. An understanding
      of biomembrane structure-function relations can be based on knowledge of the
      physical and chemical properties of pure phospholipid bilayers. Here, we have
      investigated phase transitions in dipalmitoylphosphatidylcholine (DPPC) and
      dioleoylphosphatidylcholine (DOPC) bilayers. We demonstrated the existence of
      several phase transitions in DPPC and DOPC mica-supported bilayers by both atomic
      force microscopy imaging and force measurements. Supported DPPC bilayers show a
      broad L(beta)-L(alpha) transition. In addition to the main transition we observed
      structural changes both above and below main transition temperature, which
      include increase in bilayer coverage and changes in bilayer height. Force
      measurements provide valuable information on bilayer thickness and phase
      transitions and are in good agreement with atomic force microscopy imaging data.
      A De Gennes model was used to characterize the repulsive steric forces as the
      origin of supported bilayer elastic properties. Both electrostatic and steric
      forces contribute to the repulsive part of the force plot.

PMID- 15189876
TI  - Unconstrained steps of myosin VI appear longest among known molecular motors.
AB  - Myosin VI is a two-headed molecular motor that moves along an actin filament in
      the direction opposite to most other myosins. Previously, a single myosin VI
      molecule has been shown to proceed with steps that are large compared to its neck
      size: either it walks by somehow extending its neck or one head slides along
      actin for a long distance before the other head lands. To inquire into these and
      other possible mechanism of motility, we suspended an actin filament between two
      plastic beads, and let a single myosin VI molecule carrying a bead duplex move
      along the actin. This configuration, unlike previous studies, allows
      unconstrained rotation of myosin VI around the right-handed double helix of
      actin. Myosin VI moved almost straight or as a right-handed spiral with a pitch
      of several micrometers, indicating that the molecule walks with strides slightly
      longer than the actin helical repeat of 36 nm. The large steps without much
      rotation suggest kinesin-type walking with extended and flexible necks, but how
      to move forward with flexible necks, even under a backward load, is not clear. As
      an answer, we propose that a conformational change in the lifted head would
      facilitate landing on a forward, rather than backward, site. This mechanism may
      underlie stepping of all two-headed molecular motors including kinesin and myosin
      V.

PMID- 15189875
TI  - Molecular dynamics analysis of structural factors influencing back door pi
      release in myosin.
AB  - The back door has been proposed to be an exit pathway from the myosin active site
      for phosphate (P(i)) generated by adenosine 5'-triphosphate hydrolysis. We used
      molecular dynamics simulations to investigate the interaction of P(i) with the
      back door and the plausibility of P(i) release via this route. Molecular dynamics
      simulations were performed on the Dictyostelium motor domain with bound
      Mg.adenosine 5'-diphosphate (ADP) and P(i), modeled upon the Mg.ADP.BeF(x) and
      Mg.ADP.V(i) structures. Simulations revealed that the relaxation of ADP and free
      P(i) from their initial positions reduced the diameter of the back door via
      motions of switch 1 and switch 2 located in the upper and lower 50-kDa
      subdomains, respectively. In neither simulation could P(i) freely diffuse out the
      back door. Water molecules, however, could flux through the back door in the
      Mg.ADP.BeF(x)-based simulation but not in the Mg.ADP.V(i)-based simulation. In
      neither structure was water observed fluxing through the main (front door)
      entrance. These observations suggest that the ability of P(i) to leave via the
      back door is linked tightly to conformational changes between the upper and lower
      50-kDa subdomains. The simulations offer structural explanations for (18)O
      exchange with P(i) at the active site, and P(i) release being the rate-limiting
      step in the myosin adenosine 5'-triphosphatase.

PMID- 15189877
TI  - Single-molecule investigations of RNA dissociation.
AB  - Given the essential cellular roles for ribonucleic acids (RNAs) it is important
      to understand the stability of three-dimensional structures formed by these
      molecules. This study aims to investigate the dissociation energy landscape for
      simple RNA structures via atomic-force-microscopy-based single-molecule force
      spectroscopy measurements. This approach provides details on the locations and
      relative heights of the energy barriers to dissociation, and thus information
      upon the relative kinetic stabilities of the formed complexes. Our results
      indicate that a simple dodecamer RNA helix undergoes a forced dissociation
      process similar to that previously observed for DNA oligonucleotides.
      Incorporating a UCU bulge motif is found to introduce an additional energy
      barrier closer to the bound state, and also to destabilize the duplex. In the
      absence of magnesium ions a duplex containing this UCU bulge is destabilized and
      a single, shorter duplex is formed. These results reveal that a bulge motif
      impacts upon the forced dissociation of RNA and produces an energy landscape
      sensitive to the presence of magnesium ions. Interestingly, the obtained data
      compare well with previously reported ensemble measurements, illustrating the
      potential of this approach to improve our understanding of RNA stability and
      dissociation kinetics.

PMID- 15189878
TI  - Hydration of ds-DNA and ss-DNA by neutron quasielastic scattering.
AB  - Quasielastic neutron scattering measurements were performed in hydrated samples
      of ds-DNA and ss-DNA. The samples were hydrated in a high relative humidity
      atmosphere, and their final water content was 0.559 g H(2)O/g ds-DNA and 0.434 g
      H(2)O/g ss-DNA. The measurements were performed at 8 and 5.2 A for the ds-DNA
      sample, and at 5.2 A for the ss-DNA sample. The temperature was in both cases 298
      K. Analysis of the obtained data indicates that in the ds-DNA sample we can
      distinguish two types of protons-those belonging to water molecules strongly
      attached to the ds-DNA surface and another fraction belonging to water that
      diffuses isotropically in a sphere of radius 2.8 A, with a local diffusion
      coefficient of 2.2 x 10(-5) cm(2) s(-1). For ss-DNA, on the other hand, no
      indication was found of motionally restricted or confined water. Further, the
      fraction of protons strongly attached to the ds-DNA surface corresponds to 0.16 g
      H(2)O/g ds-DNA, which equals the amount of water that is released by ds-DNA upon
      thermal denaturation, as studied by one of us (G.M.) by differential scanning
      calorimetry. This value also equals the difference between the critical hydration
      values of ds-DNA and ss-DNA, also determined by DSC. These results represent,
      thus, a completely independent measurement of water characteristics and behavior
      in ds- and ss-DNA at critical hydration values, and therefore substantiate the
      previous suggestions/conclusions of the results obtained by calorimetry.

PMID- 15189879
TI  - Conformational effects on tryptophan fluorescence in cyclic hexapeptides.
AB  - The peptide bond quenches tryptophan fluorescence by excited-state electron
      transfer, which probably accounts for most of the variation in fluorescence
      intensity of peptides and proteins. A series of seven peptides was designed with
      a single tryptophan, identical amino acid composition, and peptide bond as the
      only known quenching group. The solution structure and side-chain chi(1) rotamer
      populations of the peptides were determined by one-dimensional and two
      dimensional (1)H-NMR. All peptides have a single backbone conformation. The -,
      psi-angles and chi(1) rotamer populations of tryptophan vary with position in the
      sequence. The peptides have fluorescence emission maxima of 350-355 nm, quantum
      yields of 0.04-0.24, and triple exponential fluorescence decays with lifetimes of
      4.4-6.6, 1.4-3.2, and 0.2-1.0 ns at 5 degrees C. Lifetimes were correlated with
      ground-state conformers in six peptides by assigning the major lifetime component
      to the major NMR-determined chi(1) rotamer. In five peptides the chi(1) = -60
      degrees rotamer of tryptophan has lifetimes of 2.7-5.5 ns, depending on local
      backbone conformation. In one peptide the chi(1) = 180 degrees rotamer has a 0.5
      ns lifetime. This series of small peptides vividly demonstrates the dominant role
      of peptide bond quenching in tryptophan fluorescence.

PMID- 15189880
TI  - Fast dynamics and stabilization of proteins: binary glasses of trehalose and
      glycerol.
AB  - We present elastic and inelastic incoherent neutron scattering data from a series
      of trehalose glasses diluted with glycerol. A strong correlation with recently
      published protein stability data in the same series of glasses illustrates that
      the dynamics at Q >or= 0.71 A(-1) and omega > 200 MHz are important to
      stabilization of horseradish peroxidase and yeast alcohol dehydrogenase in these
      glasses. To the best of our knowledge, this is the first direct evidence that
      enzyme stability in a room temperature glass depends upon suppressing these short
      length scale, high-frequency dynamics within the glass. We briefly discuss the
      coupling of protein motions to the local dynamics of the glass. Also, we show
      that T(g) alone is not a good indicator for the protein stability in this series
      of glasses; the glass that confers the maximum room-temperature stability does
      not have the highest T(g).

PMID- 15189881
TI  - Molecular mechanism of domain swapping in proteins: an analysis of slower
      motions.
AB  - Domain swapping is a structural phenomenon that plays an important role in the
      mechanism of oligomerization of some proteins. The monomer units in the
      oligomeric structure become entangled with each other. Here we investigate the
      mechanism of domain swapping in diphtheria toxin and the structural criteria
      required for it to occur by analyzing the slower modes of motion with elastic
      network models, Gaussian network model and anisotropic network model. We take
      diphtheria toxin as a representative of this class of domain-swapped proteins and
      show that the domain, which is being swapped in the dimeric state, rotates and
      twists, in going from the "open" to the "closed" state, about a hinge axis that
      passes through the middle of the loop extending between two domains. A
      combination of the intra- and intermolecular contacts of the dimer is almost
      equivalent to that of the monomer, which shows that the relative orientations of
      the residues in both forms are almost identical. This is also reflected in the
      calculated B-factors when compared with the experimentally determined B-factors
      in x-ray crystal structures. The slowest modes of both the monomer and dimer show
      a common hinge centered on residue 387. The differences in distances between the
      monomer and the dimer also shows the hinge at nearly the same location (residue
      381). Finally, the first three dominant modes of anisotropic network model
      together shows a twisting motion about the hinge centered on residue 387. We
      further identify the location of hinges for a set of another 12 domain swapped
      proteins and give the quantitative measures of the motions of the swapped domains
      toward their "closed" state, i.e., the overlap and correlation between vectors.

PMID- 15189882
TI  - Extended molecular dynamics simulation of the carbon monoxide migration in sperm
      whale myoglobin.
AB  - We report the results of an extended molecular dynamics simulation on the
      migration of photodissociated carbon monoxide in wild-type sperm whale myoglobin.
      Our results allow following one possible ligand migration dynamics from the
      distal pocket to the Xe1 cavity via a path involving the other xenon binding
      cavities and momentarily two additional packing defects along the pathway.
      Comparison with recent time resolved structural data obtained by Laue
      crystallography with subnanosecond to millisecond resolution shows a more than
      satisfactory agreement. In fact, according to time resolved crystallography, CO,
      after photolysis, can occupy the Xe1 and Xe4 cavities. However, no information on
      the trajectory of the ligand from the distal pocket to the Xe1 is available. Our
      results clearly show one possible path within the protein. In addition, although
      our data refer to a single trajectory, the local dynamics of the ligand in each
      cavity is sufficiently equilibrated to obtain local structural and thermodynamic
      information not accessible to crystallography. In particular, we show that the CO
      motion and the protein fluctuations are strictly correlated: free energy
      calculations of the migration between adjacent cavities show that the migration
      is not a simple diffusion but is kinetically or thermodynamically driven by the
      collective motions of the protein; conversely, the protein fluctuations are
      influenced by the ligand in such a way that the opening/closure of the passage
      between adjacent cavities is strictly correlated to the presence of CO in its
      proximity. The compatibility between time resolved crystallographic experiments
      and molecular dynamics simulations paves the way to a deeper understanding of the
      role of internal dynamics and packing defects in the control of ligand binding in
      heme proteins.

PMID- 15189883
TI  - Interaction of horse heart and thermus thermophilus type c cytochromes with
      phospholipid vesicles and hydrophobic surfaces.
AB  - The binding of horse heart cytochrome c (cyt-c) and Thermus thermophilus
      cytochrome c(552) (cyt-c(552)) to dioleoyl phosphatidylglycerol (DOPG) vesicles
      was investigated using Fourier transform infrared (FTIR) spectroscopy and
      turbidity measurements. FTIR spectra revealed that the tertiary structures of
      both cytochromes became more open when bound to DOPG vesicles, but this was more
      pronounced for cyt-c. Their secondary structures were unchanged. Turbidity
      measurements showed important differences in their behavior bound to the
      negatively charged DOPG vesicles. Both cytochromes caused the liposomes to
      aggregate and flocculate, but the ways they did so differed. For cyt-c, more than
      a monolayer was adsorbed onto the liposome surface prior to aggregation due to
      charge neutralization, whereas cyt c(552) caused aggregation at a protein/lipid
      ratio well below that required for charge neutralization. Therefore, although cyt
      c may cause liposomes to aggregate by electrostatic interaction, cyt-c(552) does
      not act in this way. FTIR-attenuated total reflection spectroscopy (FTIR-ATR)
      revealed that cyt-c lost much of its secondary structure when bound to the
      hydrophobic surface of octadecyltrichlorosilane, whereas cyt-c(552) folds its
      domains into a beta-structure. This hydrophobic effect may be the key to the
      difference between the behaviors of the two cytochromes when bound to DOPG
      vesicles.

PMID- 15189884
TI  - Phosphate binding in the active site of alkaline phosphatase and the interactions
      of 2-nitrosoacetophenone with alkaline phosphatase-induced small structural
      changes.
AB  - To monitor structural changes during the binding of Pi to the active site of
      mammalian alkaline phosphatase in water medium, reaction-induced infrared
      spectroscopy was used. The interaction of Pi with alkaline phosphatase was
      triggered by a photorelease of ATP from the inactive P(3)-[1-(2
      nitrophenyl)]ethyl ester of ATP. After photorelease, ATP was sequentially
      hydrolyzed by alkaline phosphatase giving rise to adenosine and three Pi.
      Although a phosphodiesterase activity was detected prior the photorelease of ATP,
      it was possible to monitor the structural effects induced by Pi binding to
      alkaline phosphatase. Interactions of Pi with alkaline phosphatase were evidenced
      by weak infrared changes around 1631 and at 1639 cm(-1), suggesting a small
      distortion of peptide carbonyl backbone. This result indicates that the motion
      required for the formation of the enzyme-phosphate complex is minimal on the part
      of alkaline phosphatase, consistent with alkaline phosphatase being an almost
      perfect enzyme. Photoproduct 2-nitrosoacetophenone may bind to alkaline
      phosphatase in a site other than the active site of bovine intestinal alkaline
      phosphatase and than the uncompetitive binding site of L-Phe in bovine intestinal
      alkaline phosphatase, affecting one-two amino acid residues.

PMID- 15189885
TI  - Unusual heme iron-lipid acyl chain coordination in Escherichia coli
      flavohemoglobin.
AB  - Escherichia coli flavohemoglobin is endowed with the notable property of binding
      specifically unsaturated and/or cyclopropanated fatty acids both as free acids or
      incorporated into a phospholipid molecule. Unsaturated or cyclopropanated fatty
      acid binding to the ferric heme results in a spectral change observed in the
      visible absorption, resonance Raman, extended x-ray absorption fine spectroscopy
      (EXAFS), and x-ray absorption near edge spectroscopy (XANES) spectra. Resonance
      Raman spectra, measured on the flavohemoglobin heme domain, demonstrate that the
      lipid (linoleic acid or total lipid extracts)-induced spectral signals correspond
      to a transition from a five-coordinated (typical of the ligand-free protein) to a
      hexacoordinated, high spin heme iron. EXAFS and XANES measurements have been
      carried out both on the lipid-free and on the lipid-bound protein to assign the
      nature of ligand in the sixth coordination position of the ferric heme iron.
      EXAFS data analysis is consistent with the presence of a couple of atoms in the
      sixth coordination position at 2.7 A in the lipid-bound derivative (bonding
      interaction), whereas a contribution at 3.54 A (nonbonding interaction) can be
      singled out in the lipid-free protein. This last contribution is assigned to the
      CD1 carbon atoms of the distal LeuE11, in full agreement with crystallographic
      data on the lipid-free protein at 1.6 A resolution obtained in the present work.
      Thus, the contributions at 2.7 A distance from the heme iron are assigned to a
      couple of carbon atoms of the lipid acyl chain, possibly corresponding to the
      unsaturated carbons of the linoleic acid.

PMID- 15189886
TI  - The intermediate filament architecture as determined by X-ray diffraction
      modeling of hard alpha-keratin.
AB  - Despite investigation since the 1950s, the molecular architecture of intermediate
      filaments has not yet been fully elucidated. Reliable information about the
      longitudinal organization of the molecules within the filaments and about the
      lateral interfilament packing is now available, which is not the case for the
      transverse architecture. Interesting results were recently obtained from in vitro
      microscopy observations and cross-linking of keratin, desmin, and vimentin
      analyses. The structural features that emerge from these analyses could not be
      fully representative of the in vivo architecture because intermediate filaments
      are subject to polymorphism. To bring new light to the transverse intermediate
      filament architecture, we have analyzed the x-ray scattering equatorial profile
      of human hair. Its comparison with simulated profiles from atomic models of a
      real sequence has allowed results to be obtained that are representative of hard
      alpha-keratin intermediate filaments under in vivo conditions. In short, the
      alpha-helical coiled coils, which are characteristic of the central rod of
      intermediate filament dimers, are straight and not supercoiled into oligomers;
      the radial density across the intermediate filament section is fairly uniform;
      the coiled coils are probably assembled into tetrameric oligomers, and finally
      the oligomer positions and orientations are not regularly ordered. These features
      are discussed in terms of filament self-assembling and structural variability.

PMID- 15189887
TI  - Competing hydrophobic and screened-coulomb interactions in hepatitis B virus
      capsid assembly.
AB  - Recent experiments show that, in the range from approximately 15 to 45 degrees C,
      an increase in the temperature promotes the spontaneous assembly into capsids of
      the Escherichia coli-expressed coat proteins of hepatitis B virus. Within that
      temperature interval, an increase in ionic strength up to five times that of
      standard physiological conditions also acts to promote capsid assembly. To
      explain both observations we propose an interaction of mean force between the
      protein subunits that is the sum of an attractive hydrophobic interaction,
      driving the self-assembly, and a repulsive electrostatic interaction, opposing
      the self-assembly. We find that the binding strength of the capsid subunits
      increases with temperature virtually independently of the ionic strength, and
      that, at fixed temperature, the binding strength increases with the square root
      of ionic strength. Both predictions are in quantitative agreement with
      experiment. We point out the similarities of capsid assembly in general and the
      micellization of surfactants. Finally we make plausible that electrostatic
      repulsion between the native core subunits of a large class of virus suppresses
      the formation in vivo of empty virus capsids, that is, without the presence of
      the charge-neutralizing nucleic acid.

PMID- 15189888
TI  - Studies of chi(2)/chi(3) tensors in submicron-scaled bio-tissues by polarization
      harmonics optical microscopy.
AB  - Optical second- and third-harmonic generations have attracted a lot of attention
      in the biomedical imaging research field recently due to their intrinsic
      sectioning ability and noninvasiveness. Combined with near-infrared excitation
      sources, their deep-penetration ability makes these imaging modalities suitable
      for tissue characterization. In this article, we demonstrate a polarization
      harmonics optical microscopy, or P-HOM, to study the nonlinear optical anisotropy
      of the nanometer-scaled myosin and actin filaments inside myofibrils. By using
      tight focusing we can avoid the phase-matching condition due to micron-scaled,
      high-order structures in skeletal muscle fibers, and obtain the submicron-scaled
      polarization dependencies of second/third-harmonic generation intensities on the
      inclination angle between the long axes of the filaments and the polarization
      direction of the linear polarized fundamental excitation laser light. From these
      dependencies, detailed information on the tensor elements of the second/third
      order nonlinear susceptibilities contributed from the myosin/actin filaments
      inside myofibrils can thus be analyzed and obtained, reflecting the detailed
      arrangements and structures of the constructing biomolecules. By acquiring a
      whole, nonlinearly sectioned image with a submicron spatial resolution, we can
      also compare the polarization dependency and calculate the nonlinear
      susceptibilities over a large area of the tissue at the same time-which not only
      provides statistical information but will be especially useful with complex
      specimen geometry.

PMID- 15189889
TI  - Photobleaching-corrected FRET efficiency imaging of live cells.
AB  - Fluorescent resonance energy transfer (FRET) imaging techniques can be used to
      visualize protein-protein interactions in real-time with subcellular resolution.
      Imaging of sensitized fluorescence of the acceptor, elicited during excitation of
      the donor, is becoming the most popular method for live FRET (3-cube imaging)
      because it is fast, nondestructive, and applicable to existing widefield or
      confocal microscopes. Most sensitized emission-based FRET indices respond
      nonlinearly to changes in the degree of molecular interaction and depend on the
      optical parameters of the imaging system. This makes it difficult to evaluate and
      compare FRET imaging data between laboratories. Furthermore, photobleaching poses
      a problem for FRET imaging in timelapse experiments and three-dimensional
      reconstructions. We present a 3-cube FRET imaging method, E-FRET, which overcomes
      both of these obstacles. E-FRET bridges the gap between the donor recovery after
      acceptor photobleaching technique (which allows absolute measurements of FRET
      efficiency, E, but is not suitable for living cells), and the sensitized-emission
      FRET indices (which reflect FRET in living cells but lack the quantitation and
      clarity of E). With E-FRET, we visualize FRET in terms of true FRET efficiency
      images (E), which correlate linearly with the degree of donor interaction. We
      have defined procedures to incorporate photobleaching correction into E-FRET
      imaging. We demonstrate the benefits of E-FRET with photobleaching correction for
      timelapse and three-dimensional imaging of protein-protein interactions in the
      immunological synapse in living T-cells.

PMID- 15189890
TI  - High field/high frequency saturation transfer electron paramagnetic resonance
      spectroscopy: increased sensitivity to very slow rotational motions.
AB  - Saturation transfer electron paramagnetic resonance (ST-EPR) spectroscopy has
      been employed to characterize the very slow microsecond to millisecond rotational
      dynamics of a wide range of nitroxide spin-labeled proteins and other
      macromolecules in the past three decades. The vast majority of this previous work
      has been carried out on spectrometers that operate at X-band ( approximately 9
      GHz) microwave frequency with a few investigations reported at Q-band (
      approximately 34 GHz). EPR spectrometers that operate in the 94-250-GHz range and
      that are capable of making conventional linear EPR measurements on small aqueous
      samples have now been developed. This work addresses potential advantages of
      utilizing these same high frequencies for ST-EPR studies that seek to
      quantitatively analyze the very slow rotational dynamics of spin-labeled
      macromolecules. For example, the uniaxial rotational diffusion (URD) model has
      been shown to be particularly applicable to the study of the rotational dynamics
      of integral membrane proteins. Computational algorithms have been employed to
      define the sensitivity of ST-EPR signals at 94, 140, and 250 GHz to the
      correlation time for URD, to the amplitude of constrained URD, and to the
      orientation of the spin label relative to the URD axis. The calculations
      presented in this work demonstrate that these higher microwave frequencies
      provide substantial increases in sensitivity to the correlation time for URD, to
      small constraints in URD, and to the geometry of the spin label relative to the
      URD axis as compared with measurements made at X-band. Moreover, the calculations
      at these higher frequencies indicate sensitivity to rotational motions in the 1
      100-ms time window, particularly at 250 GHz, thereby extending the slow motion
      limit for ST-EPR by two orders of magnitude relative to X- and Q-bands.

PMID- 15189891
TI  - Methionine adenosyltransferase alpha-helix structure unfolds at lower
      temperatures than beta-sheet: a 2D-IR study.
AB  - Two-dimensional infrared spectroscopy has been used to characterize rat liver
      methionine adenosyltransferase and the events taking place during its thermal
      unfolding. Secondary structure data have been obtained for the native recombinant
      enzyme by fitting the amide I band of infrared spectra. Thermal denaturation
      studies allow the identification of events associated with individual secondary
      structure elements during temperature-induced unfolding. They are correlated to
      the changes observed in enzyme activity and intrinsic fluorescence. In all cases,
      thermal denaturation proved to be an irreversible process, with a T(m) of 47-51
      degrees C. Thermal profiles and two-dimensional infrared spectroscopy show that
      unfolding starts with alpha-helical segments and turns, located in the outer part
      of the protein, whereas extended structure, associated with subunit contacts,
      unfolds at higher temperatures. The data indicate a good correlation between the
      denaturation profiles obtained from activity measurements, fluorescence
      spectroscopy, and the behavior of the infrared bands. A study of the sequence of
      events that takes place is discussed in light of the previous knowledge on
      methionine adenosyltransferase structure and oligomerization pathway.

PMID- 15189892
TI  - Detection and analysis of tumor fluorescence using a two-photon optical fiber
      probe.
AB  - The utility of a two-photon optical fiber fluorescence probe (TPOFF) for sensing
      and quantifying tumor fluorescent signals was tested in vivo. Xenograft tumors
      were developed in athymic mice using MCA207 cells expressing green fluorescent
      protein (GFP). The TPOFF probe was able to detect ex vivo fluorescence from
      excised tumors containing as little as 0.3% GFP-expressing cells. TPOFF results
      were similar to both flow-cytometric analysis of tumor cells after isolation and
      suspension, and fluorescence determined by microscope images of cryosectioned
      tumors. TPOFF was then used to measure GFP fluorescence from tumors in live mice.
      The fiber probe detected fluorescently-labeled Herceptin antibody targeted to
      HER2-expressing tumors in severe combined immunodeficient mice. Dendrimer
      nanoparticles targeted by folic acid and having 6-TAMRA as a fluorescent probe
      were also used to label KB cell tumors in vivo. The fiber probe documented a
      fourfold increase in tumor fluorescence in animals that received the targeted
      dendrimer. These results suggest TPOFF can be used as a minimally invasive system
      for identifying tumor markers and monitoring drug therapy.

PMID- 15189893
TI  - Detecting rearrangements of shaker and NaChBac in real-time with fluorescence
      spectroscopy in patch-clamped mammalian cells.
AB  - Time-resolved fluorescence detection of site-directed probes is a major tool in
      the investigation of structure-function relationships of voltage-dependent ion
      channels. However, the technique has been limited so far to the Xenopus-oocyte
      system making it difficult to study proteins, like, e.g., the prokaryotic sodium
      channel NaChBac, whose expression in oocytes is insufficient or whose
      physiological functions are distorted in oocytes. To expand the application of
      site-directed fluorescence detection to these proteins, we used two techniques
      semiconfocal epifluorescence and total internal reflection fluorescence-to detect
      time-resolved fluorescence changes from site-directed labeled proteins expressed
      in mammalian cells under patch-clamp conditions, and investigated the
      characteristics and limitations of the techniques. The voltage-sensitive dye, di
      8-ANEPPS, was used to monitor control of the membrane voltage in epifluorescence
      and total internal reflection fluorescence. Fluorescence changes in patch-clamped
      cells were recorded from a Shaker channel mutant (M356C) labeled in the S3-S4
      linker using semiconfocal epifluorescence. The gating kinetics and fluorescence
      changes were in accordance with previous studies using fluorescence spectroscopy
      in Xenopus-oocyte systems. We applied our technique to the prokaryotic sodium
      channel NaChBac. Voltage-dependent protein-rearrangements of S4 could be detected
      that are independent of inactivation. Comparison of the S3-S4 linker regions
      revealed structural differences to the KvAP voltage sensor. The results from the
      NaChBac channel point to structural requirements for the S3-S4 loop to generate a
      fluorescence signal.

PMID- 15189894
TI  - Cumulant analysis in fluorescence fluctuation spectroscopy.
AB  - A novel technique for the analysis of fluorescence fluctuation experiments is
      introduced. Fluorescence cumulant analysis (FCA) exploits the factorial cumulants
      of the photon counts and resolves heterogeneous samples based on differences in
      brightness. A simple analytical model connects the cumulants of the photon counts
      with the brightness epsilon and the number of molecules N in the optical
      observation volume for each fluorescent species. To provide the tools for a
      rigorous error analysis of FCA, expressions for the variance of factorial
      cumulants are developed and tested. We compare theory with experiment by
      analyzing dye mixtures and simple fluorophore solutions with FCA. A comparison of
      FCA with photon-counting histogram (PCH) analysis, a related technique, shows
      that both methods give identical results within experimental uncertainty. Both
      FCA and PCH are restricted to data sampling times that are short compared to the
      diffusion time of molecules through the observation volume of the instrument. But
      FCA theory, in contrast to PCH, can be extended to treat arbitrary sampling
      times. Here, we derive analytical expressions for the second factorial cumulant
      as a function of the sampling time and demonstrate that the theory successfully
      models fluorescence fluctuation data.

PMID- 15189895
TI  - Automatic and quantitative measurement of protein-protein colocalization in live
      cells.
AB  - We introduce a novel statistical approach that quantifies, for the first time,
      the amount of colocalization of two fluorescent-labeled proteins in an image
      automatically, removing the bias of visual interpretation. This is done by
      estimating simultaneously the maximum threshold of intensity for each color below
      which pixels do not show any statistical correlation. The sensitivity of the
      method was illustrated on simulated data by statistically confirming the
      existence of true colocalization in images with as little as 3% colocalization.
      This method was then tested on a large three-dimensional set of fixed cells
      cotransfected with CFP/YFP pairs of proteins that either co-compartmentalized,
      interacted, or were just randomly localized in the nucleolus. In this test, the
      algorithm successfully distinguished random color overlap from colocalization due
      to either co-compartmentalization or interaction, and results were verified by
      fluorescence resonance energy transfer. The accuracy and consistency of our
      algorithm was further illustrated by measuring, for the first time in live cells,
      the dissociation rate (k(d)) of the HIV-1 Rev/CRM1 export complex induced by the
      cytotoxin leptomycin B. Rev/CRM1 colocalization in nucleoli dropped exponentially
      after addition of leptomycin B at a rate of 1.25 x 10(-3) s(-1). More generally,
      this algorithm can be used to answer a variety of biological questions involving
      protein-protein interactions or co-compartmentalization and can be generalized to
      colocalization of more than two colors.

PMID- 15189897
TI  - Information bounds and optimal analysis of dynamic single molecule measurements.
AB  - Time-resolved single molecule fluorescence measurements may be used to probe the
      conformational dynamics of biological macromolecules. The best time resolution in
      such techniques will only be achieved by measuring the arrival times of
      individual photons at the detector. A general approach to the estimation of
      molecular parameters based on individual photon arrival times is presented. The
      amount of information present in a data set is quantified by the Fisher
      information, thereby providing a guide to deriving the basic equations relating
      measurement uncertainties and time resolution. Based on these information
      theoretical considerations, a data analysis algorithm is presented that details
      the optimal analysis of single-molecule data. This method natively accounts and
      corrects for background photons and cross talk, and can scale to an arbitrary
      number of channels. By construction, and with corroboration from computer
      simulations, we show that this algorithm reaches the theoretical limit,
      extracting the maximal information out of the data. The bias inherent in the
      algorithm is considered and its implications for experimental design are
      discussed. The ideas underlying this approach are general and are expected to be
      applicable to any information-limited measurement.

PMID- 15189896
TI  - Colloid surface chemistry critically affects multiple particle tracking
      measurements of biomaterials.
AB  - Characterization of the properties of complex biomaterials using microrheological
      techniques has the promise of providing fundamental insights into their
      biomechanical functions; however, precise interpretations of such measurements
      are hindered by inadequate characterization of the interactions between tracers
      and the networks they probe. We here show that colloid surface chemistry can
      profoundly affect multiple particle tracking measurements of networks of fibrin,
      entangled F-actin solutions, and networks of cross-linked F-actin. We present a
      simple protocol to render the surface of colloidal probe particles protein
      resistant by grafting short amine-terminated methoxy-poly(ethylene glycol) to the
      surface of carboxylated microspheres. We demonstrate that these poly(ethylene
      glycol)-coated tracers adsorb significantly less protein than particles coated
      with bovine serum albumin or unmodified probe particles. We establish that
      varying particle surface chemistry selectively tunes the sensitivity of the
      particles to different physical properties of their microenvironments.
      Specifically, particles that are weakly bound to a heterogeneous network are
      sensitive to changes in network stiffness, whereas protein-resistant tracers
      measure changes in the viscosity of the fluid and in the network microstructure.
      We demonstrate experimentally that two-particle microrheology analysis
      significantly reduces differences arising from tracer surface chemistry,
      indicating that modifications of network properties near the particle do not
      introduce large-scale heterogeneities. Our results establish that controlling
      colloid-protein interactions is crucial to the successful application of multiple
      particle tracking techniques to reconstituted protein networks, cytoplasm, and
      cells.

PMID- 15189898
TI  - Neutrophil string formation: hydrodynamic thresholding and cellular deformation
      during cell collisions.
AB  - Neutrophils unexpectedly display flow-enhanced adhesion (hydrodynamic
      thresholding) to L-selectin in rolling or aggregation assays. We report that the
      primary collision efficiency (epsilon) of flowing neutrophils with preadhered
      neutrophils on intercellular adhesion molecule-1 (ICAM-1) or fibrinogen also
      displayed a maximum of epsilon approximately 0.4-0.45 at a wall shear rate of 100
      s(-1), an example of thresholding. Primary collision lifetime with no detectable
      bonding decreased from 130 to 10 ms as wall shear rate increased from 30 to 300
      s(-1), whereas collision lifetimes with bonding decreased from 300 to 100 ms over
      this shear range using preadhered neutrophils on ICAM-1, with similar results for
      fibrinogen. Antibodies against L-selectin, but not against CD11a, CD11b, or CD18,
      reduced epsilon at 100 s(-1) by >85%. High resolution imaging detected large
      scale deformation of the flowing neutrophil during the collision at 100 s(-1)
      with the apparent contact area increasing up to approximately 40 microm(2). We
      observed the formation of long linear string assemblies of neutrophils downstream
      of neutrophils preadhered to ICAM-1, but not fibrinogen, with a maximum in string
      formation at 100 s(-1). Secondary capture events to the ICAM-1 or fibrinogen
      coated surfaces after primary collisions were infrequent and short lived,
      typically lasting from 500 to 3500 ms. Between 5 and 20% of neutrophil
      interactions with ICAM-1 substrate converted to firm arrest (>3500 ms) and
      greatly exceeded that observed for fibrinogen, thus defining the root cause of
      poor string formation on fibrinogen at all shear rates. Additionally, neutrophils
      mobilized calcium after incorporation into strings. Static adhesion also caused
      calcium mobilization, as did the subsequent onset of flow. To our knowledge, this
      is the first report of 1). hydrodynamic thresholding in neutrophil string
      formation; 2). string formation on ICAM-1 but not on fibrinogen; 3). large
      cellular deformation due to collisions at a venous shear rate; and 4),
      mechanosensing through neutrophil beta(2)-integrin/adhesion. The increased
      contact area during deformation was likely responsible for the hydrodynamic
      threshold observed in the primary collision efficiency since no increase in
      primary collision lifetime was detected as shear forces were increased (for
      either surface coating).

PMID- 15189899
TI  - Nanoelectropulse-induced phosphatidylserine translocation.
AB  - Nanosecond, megavolt-per-meter, pulsed electric fields induce phosphatidylserine
      (PS) externalization, intracellular calcium redistribution, and apoptosis in
      Jurkat T-lymphoblasts, without causing immediately apparent physical damage to
      the cells. Intracellular calcium mobilization occurs within milliseconds of pulse
      exposure, and membrane phospholipid translocation is observed within minutes.
      Pulsed cells maintain cytoplasmic membrane integrity, blocking propidium iodide
      and Trypan blue. Indicators of apoptosis-caspase activation and loss of
      mitochondrial membrane potential-appear in nanoelectropulsed cells at later
      times. Although a theoretical framework has been established, specific mechanisms
      through which external nanosecond pulsed electric fields trigger intracellular
      responses in actively growing cells have not yet been experimentally
      characterized. This report focuses on the membrane phospholipid rearrangement
      that appears after ultrashort pulse exposure. We present evidence that the
      minimum field strength required for PS externalization in actively metabolizing
      Jurkat cells with 7-ns pulses produces transmembrane potentials associated with
      increased membrane conductance when pulse widths are microseconds rather than
      nanoseconds. We also show that nanoelectropulse trains delivered at repetition
      rates from 2 to 2000 Hz have similar effects, that nanoelectropulse-induced PS
      externalization does not require calcium in the external medium, and that the
      pulse regimens used in these experiments do not cause significant intra- or
      extracellular Joule heating.

PMID- 15189900
TI  - The fast tumble signal in bacterial chemotaxis.
AB  - We have analyzed repellent signal processing in Escherichia coli by flash
      photorelease of leucine from photolabile precursors. We found that 1). response
      amplitudes of free-swimming cell populations increased with leucine jump
      concentration, with an apparent Hill coefficient of 1.3 and a half-maximal dose
      of 14.4 microM; 2). at a 0-0.5 mM leucine concentration jump sufficient to obtain
      a saturation motile response, the swimming cell response time of approximately
      0.05 s was several-fold more rapid than the motor response time of 0.39 +/- 0.18
      s measured by following the rotation of cells tethered by a single flagellum to
      quartz coverslips; and 3). the motor response time of individual cells was
      correlated with rotation bias but not cell size. These results provide
      information on amplification, rate-limiting step, and flagellar bundle mechanics
      during repellent signal processing. The difference between the half-maximal dose
      for the excitation response and the corresponding value reported for adaptation
      provides an estimate of the increase in the rate of formation of CheYP, the
      phosphorylated form of the signal protein CheY. The estimated increase gives a
      lower limit receptor kinase coupling ratio of 6.0. The magnitude and form of the
      motor response time distribution argue for it being determined by the
      poststimulus switching probability rather than CheYP turnover, diffusion, or
      binding. The temporal difference between the tethered and swimming cell response
      times to repellents can be quantitatively accounted for and suggests that one
      flagellum is sufficient to cause a measurable change of direction in which a
      bacterium swims.

PMID- 15189901
TI  - Beta-1 integrin-mediated adhesion may be initiated by multiple incomplete bonds,
      thus accounting for the functional importance of receptor clustering.
AB  - The regulation of cell integrin receptors involves modulation of membrane
      expression, shift between different affinity states, and topographical
      redistribution on the cell membrane. Here we attempted to assess quantitatively
      the functional importance of receptor clustering. We studied beta-1 integrin
      mediated attachment of THP-1 cells to fibronectin-coated surfaces under low shear
      flow. Cells displayed multiple binding events with a half-life of the order of 1
      s. The duration of binding events after the first second after arrest was
      quantitatively accounted for by a model assuming the existence of a short-time
      intermediate binding state with 3.6 s(-1) dissociation rate and 1.3 s(-1)
      transition frequency toward a more stable state. Cell binding to surfaces coated
      with lower fibronectin densities was concluded to be mediated by single molecular
      interactions, whereas multiple bonds were formed <1 s after contact with higher
      fibronectin surface densities. Cell treatment with microfilament inhibitors or a
      neutral antiintegrin antibody decreased bond number without changing
      aforementioned kinetic parameters whereas a function enhancing antibody increased
      the rate of bond formation and/or the lifetime of intermediate state. Receptor
      aggregation was induced by treating cells with neutral antiintegrin antibody and
      antiimmunoglobulin antibodies. A semiquantitative confocal microscopy study
      suggested that this treatment increased between 40% and 100% the average number
      of integrin receptors located in a volume of approximately 0.045 microm(3)
      surrounding each integrin. This aggregation induced up to 2.7-fold increase of
      the average number of bonds. Flow cytometric analysis of fluorescent ligand
      binding showed that THP-1 cells displayed low-affinity beta-1 integrins with a
      dissociation constant in the micromolar range. It is concluded that the initial
      step of cell adhesion was mediated by multiple incomplete bonds rather than a
      single equilibrium-state ligand receptor association. This interpretation
      accounts for the functional importance of integrin clustering.

PMID- 15189902
TI  - Ultrafine membrane compartments for molecular diffusion as revealed by single
      molecule techniques.
AB  - Plasma membrane compartments, delimited by transmembrane proteins anchored to the
      membrane skeleton (anchored-protein picket model), would provide the membrane
      with fundamental mosaicism because they would affect the movement of practically
      all molecules incorporated in the cell membrane. Understanding such basic
      compartmentalized structures of the cell membrane is critical for further studies
      of a variety of membrane functions. Here, using both high temporal-resolution
      single particle tracking and single fluorescent molecule video imaging of an
      unsaturated phospholipid, DOPE, we found that plasma membrane compartments
      generally exist in various cell types, including CHO, HEPA-OVA, PtK2, FRSK,
      HEK293, HeLa, T24 (ECV304), and NRK cells. The compartment size varies from 30 to
      230 nm, whereas the average hop rate of DOPE crossing the boundaries between two
      adjacent compartments ranges between 1 and 17 ms. The probability of passing a
      compartment barrier when DOPE is already at the boundary is also cell-type
      dependent, with an overall variation by a factor of approximately 7. These
      results strongly indicate the necessity for the paradigm shift of the concept on
      the plasma membrane: from the two-dimensional fluid continuum model to the
      compartmentalized membrane model in which its constituent molecules undergo hop
      diffusion over the compartments.

PMID- 15189904
TI  - Asthma: the epidemic has ended, or has it?

PMID- 15189903
TI  - The proton-driven rotor of ATP synthase: ohmic conductance (10 fS), and absence
      of voltage gating.
AB  - The membrane portion of F(0)F(1)-ATP synthase, F(0), translocates protons by a
      rotary mechanism. Proton conduction by F(0) was studied in chromatophores of the
      photosynthetic bacterium Rhodobacter capsulatus. The discharge of a light-induced
      voltage jump was monitored by electrochromic absorption transients to yield the
      unitary conductance of F(0). The current-voltage relationship of F(0) was linear
      from 7 to 70 mV. The current was extremely proton-specific (>10(7)) and varied
      only slightly ( approximately threefold) from pH 6 to 10. The maximum conductance
      was approximately 10 fS at pH 8, equivalent to 6240 H(+) s(-1) at 100-mV driving
      force, which is an order-of-magnitude greater than of coupled F(0)F(1). There was
      no voltage-gating of F(0) even at low voltage, and proton translocation could be
      driven by deltapH alone, without voltage. The reported voltage gating in F(0)F(1)
      is thus attributable to the interaction of F(0) with F(1) but not to F(0) proper.
      We simulated proton conduction by a minimal rotary model including the rotating c
      ring and two relay groups mediating proton exchange between the ring and the
      respective membrane surface. The data fit attributed pK values of approximately 6
      and approximately 10 to these relays, and placed them close to the
      membrane/electrolyte interface.

PMID- 15189905
TI  - Influenza vaccination in vulnerable populations.

PMID- 15189906
TI  - Asthma and obesity: a real connection or a casual association?

PMID- 15189907
TI  - QT dispersion: much ado about something?

PMID- 15189908
TI  - Atrial fibrillation: nonpharmacologic therapies coming of age.

PMID- 15189909
TI  - Legionella pneumonia: the spectrum continues to expand.

PMID- 15189910
TI  - Cytokines: the tomb markers of the ICU.

PMID- 15189911
TI  - SARS, pneumothorax, and our response to epidemics.

PMID- 15189912
TI  - Coughing during mannitol challenge is associated with asthma.
AB  - STUDY OBJECTIVES: To define whether coughing during mannitol challenge is a
      nonspecific side effect of this challenge or is associated with asthma. DESIGN: A
      prospective study. SETTING: University hospital. PARTICIPANTS: Thirty-seven
      steroid-naive, asthmatic subjects and 10 healthy subjects. MEASUREMENTS: The
      participants completed a symptom questionnaire, recorded peak expiratory flows
      (PEFs), and underwent spirometry, skin tests, and bronchial provocations with
      mannitol, histamine, and cold air. Seventeen of the asthmatic subjects were
      treated with budesonide, 800 micro g per day, and the measurements were repeated
      after 3 and 6 months of treatment. Coughs were recorded during the mannitol
      challenges, and the cough sensitivity was expressed as the cumulative number of
      coughs divided by the cumulative dose of mannitol. RESULTS: The asthmatic
      subjects coughed more during the mannitol challenge than the healthy subjects
      (8.3 coughs per 100 mg [95% confidence interval (CI), 6.2 to 11.0] vs 1.1 coughs
      per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001). Even those asthmatic subjects who
      did not develop bronchoconstriction after the maximal cumulative dose of mannitol
      (635 mg) coughed significantly more than the healthy subjects (53 coughs [95% CI,
      34 to 72] vs 12 coughs [95% CI, 4 to 21]; p = 0.003). Budesonide treatment
      decreased the cough sensitivity (p = 0.023), which was significantly associated
      with improvements in overall symptom frequency, cough frequency, diurnal PEF
      variation, FEV(1), and bronchial hyperresponsiveness. CONCLUSIONS: Coughing
      during mannitol challenge is associated with asthma and occurs independently of
      bronchoconstriction. It can be used to study the mechanisms of asthmatic cough.
      Furthermore, the measurement of the mannitol-provoked coughing may be useful both
      in the diagnosis of asthma as well as in the assessment of the effects of an anti
      inflammatory therapy on this common disorder.

PMID- 15189913
TI  - Trends of asthma in Mexico: an 11-year analysis in a nationwide institution.
AB  - STUDY OBJECTIVES: Asthma prevalence is increasing in many countries. Some recent
      articles, however, claim that this tendency is ending. Our aim was to investigate
      asthma trends in Mexico. DESIGN: Annual data on health services provided to
      asthmatic patients were retrospectively analyzed from 1991 to 2001. SETTING: The
      Instituto Mexicano del Seguro Social, the largest nationwide medical institution
      in Mexico (approximately 24 to 32 million insured subjects). PARTICIPANTS: Health
      services provided to subjects of any age. INTERVENTIONS: None. MEASUREMENTS AND
      RESULTS: Asthma-associated health services, either expressed as absolute number
      or as rate per insured subjects, progressively increased until 1997 in family
      physician office visits (FPOVs) [newly diagnosed cases only], emergency
      department visits (ERVs), and hospital discharges (HDs). From that year onward,
      the number and rates of asthma-associated health services decreased. The same
      trends were observed for age groups 0 to 4 years, 5 to 14 years, 15 to 44 years,
      and 45 to 64 years. Using a different approach, asthma was diagnosed each year in
      approximately 0.4% of all FPOVs, but a decrease in this percentage was observed
      from 1997 onward. Likewise, asthma caused increasing percentages of all ERVs and
      HDs until 1997, followed by a sharp decline thereafter. CONCLUSIONS: A decline in
      absolute and relative numbers of asthma-associated health services occurred over
      recent years in all medical settings, suggesting that the epidemic of new asthma
      cases is ending and/or that better control of the disease has been achieved.

PMID- 15189914
TI  - Development of chronic airway obstruction in patients with eosinophilic
      bronchitis: a prospective follow-up study.
AB  - STUDY OBJECTIVES: Eosinophilic bronchitis (EB) presents as a chronic cough and
      sputum eosinophilia without airflow limitation or bronchial hyperreactivity. Its
      long-term clinical course remains unknown. This study evaluated how frequently EB
      recurs and whether it develops chronic airway obstruction. DESIGN: This study was
      a prospective analysis. METHODS: Cough severity, FEV(1), provocative
      concentration of methacholine causing a 20% fall in FEV(1), and sputum eosinophil
      percentages were serially measured in 36 subjects for up to 48 months. All
      subjects inhaled corticosteroids until cough subsided. RESULTS: Five of the
      twenty four follow-up subjects (21%) had a recurrent episode of EB 4 to 6 months
      after disappearance of the first episode of EB (recurrent eosinophilic
      bronchitis). Progressive FEV(1) reduction > 20% was observed in three of the
      subjects, including a subject with asthma developing at the ninth month. Nineteen
      subjects had no recurrence of cough (nonrecurrent eosinophilic bronchitis) and no
      progressive FEV(1) reduction > 20%. However, sputum eosinophilia recurred between
      4 months and 24 months in 10 subjects. Mean values of FEV(1) at the ninth and
      12th months of the study were significantly lower in the recurrent eosinophilic
      bronchitis group than in the nonrecurrent eosinophilic bronchitis group (p <
      0.01). CONCLUSION: These results suggest that repeated episode of EB is
      associated with the development of chronic airflow obstruction, including asthma.

PMID- 15189915
TI  - Breath condensate pH in children with cystic fibrosis and asthma: a new
      noninvasive marker of airway inflammation?
AB  - STUDY OBJECTIVES: The noninvasive assessment and monitoring of airway
      inflammation could be important in respiratory disease. The pH of exhaled breath
      condensate (EBC) is a promising marker. Although pH has been measured in the EBC
      of adults with inflammatory airway diseases, no study has measured this in
      children. DESIGN: This study aimed to assess whether there is a change in pH in
      the EBC of children with cystic fibrosis (CF) and asthma, and to try to determine
      whether pH could be used as a marker of airway inflammation. Furthermore, the
      relationships among EBC pH, severity of disease, and oxidative stress were
      studied. PATIENTS AND METHODS: We studied 20 children with CF (mean [+/- SEM]
      age, 7 +/- 3 years), 20 children with asthma (mean age, 7 +/- 2 years), and 15
      age-matched healthy children (mean age, 7 +/- 2 years). The pH of EBC was
      measured using a pH meter. MEASUREMENTS AND RESULTS: Lower pH values were
      observed in the EBC of children with CF and asthma compared to control subjects
      (mean pH, 7.23 +/- 0.03 and 7.42 +/- 0.01 vs 7.85 +/- 0.02, respectively).
      Furthermore, relationships among EBC pH, severity of asthma, and the presence of
      an infective exacerbation of CF was found. There was a negative correlation
      between exhaled pH and exhaled leukotriene B(4) concentrations (r = -0.5; p <
      0.005). CONCLUSION: We conclude that the measurement of EBC pH may be useful in
      the evaluation of airway inflammation in children with asthma and CF.

PMID- 15189916
TI  - Acute respiratory illness in patients with COPD and the effectiveness of
      influenza vaccination: a randomized controlled study.
AB  - STUDY OBJECTIVES: To determine the effectiveness of influenza vaccination on
      influenza-related acute respiratory illness (ARI) and overall ARI in patients
      with COPD, and its relationship to the degree of airflow obstruction. DESIGN:
      Stratified, randomized, double-blind, placebo-controlled trial. SETTING: From
      June 1997 to November 1998 at a single university hospital. PATIENTS AND
      INTERVENTIONS: One hundred twenty-five patients with COPD were stratified based
      on their FEV(1) as having mild, moderate, and severe COPD. Within each group,
      they were randomized to the vaccine group (62 patients who received purified,
      trivalent, split-virus vaccine) or the placebo group (63 patients). MEASUREMENTS:
      The number of episodes and severity of total ARI, classified as outpatient
      treatment, hospitalization, and requirement of mechanical ventilation; and the
      number of episodes and severity of influenza-related ARI. RESULTS: The incidence
      of influenza-related ARI was 28.1 per 100 person-years and 6.8 per 100 person
      years in the placebo group and vaccine group, respectively (relative risk [RR],
      0.24 [p = 0.005]; vaccine effectiveness, 76%). The incidences were 28.2, 23.8,
      and 31.2 per 100 person-years in the patients with mild, moderate, and severe
      COPD, respectively, in the placebo group, and 4.5, 13.2, and 4.6 per 100 person
      years in the patients with mild, moderate, and severe COPD, respectively, in the
      vaccine group (RR, 0.16 [p = 0.06]; vaccine effectiveness, 84%; RR, 0.55 [p =
      0.5]; vaccine effectiveness, 45%; and RR, 0.15 [p = 0.04]; vaccine effectiveness,
      85%, in the patients with mild, moderate, and severe COPD, respectively).
      Bivariate analysis revealed that the effectiveness of influenza vaccination was
      not modified by the severity of COPD, comorbid diseases, age, gender, or current
      smoking status. There was no difference in the incidence or severity of total ARI
      between the placebo group and the vaccine group. CONCLUSIONS: Influenza
      vaccination is highly effective in the prevention of influenza-related ARI
      regardless of the severity of COPD. Influenza vaccination does not prevent other
      ARIs unrelated to influenza. The effectiveness of influenza vaccination in the
      prevention of overall ARI in patients with COPD will depend on how much the
      proportion of influenza-related ARI contributes to the incidence of total ARI.
      Influenza vaccination should be recommended to all patients with COPD.

PMID- 15189917
TI  - Effects of whole-body exercise training on body composition and functional
      capacity in normal-weight patients with COPD.
AB  - BACKGROUND: Skeletal muscle wasting is related to muscle dysfunction, exercise
      intolerance, and increased mortality risk in patients with COPD. STUDY
      OBJECTIVES: The aims of this study were to investigate the effects of whole-body
      exercise training on body composition in normal-weight patients with COPD, and to
      study the relationship between changes in body composition and functional
      capacity. SETTING AND PARTICIPANTS: Fifty patients with COPD (FEV(1), 39% of
      predicted [SD, 16]) admitted to the pulmonary rehabilitation center at
      Hornerheide, and 36 healthy age-matched control subjects (for baseline
      comparison) were included. INTERVENTIONS: Patients participated in a standardized
      inpatient exercise training program consisting of daily submaximal cycle
      ergometry, treadmill walking, weight training, and gymnastics during 8 weeks.
      MEASUREMENTS: Fat-free mass (FFM) was measured by bioelectrical impedance
      analysis. None of the patients met the criteria for nutritional supplementation
      (body mass index </= 21, or FFM index </= 15 kg/m(2) in women and </= 16 kg/m(2)
      in men). Exercise capacity was measured using incremental cycle ergometry.
      Isokinetic quadriceps strength was measured with a Biodex dynamometer (Biodex
      Medical Corporation; Shirley, NY). RESULTS: At baseline, patients were
      characterized by a significantly lower FFM than the control subjects. Age and FFM
      were independent predictors of skeletal muscle function and exercise capacity in
      patients. After rehabilitation, weight (72.4 +/- 9.8 to 73.0 +/- 9.4 kg, p <
      0.05) significantly increased, as a result of increased FFM (52.4 +/- 7.3 to 53.4
      +/- 7.7 kg, p < 0.05), while fat mass (20.0 +/- 6.1 to 19.6 +/- 5.7 kg) tended to
      decrease. Peak work rate (63 +/- 29 to 84 +/- 42 W, p < 0.001), maximal oxygen
      consumption (O(2)max) [1,028 +/- 307 to 1,229 +/- 421 mL/min, p < 0.001], and
      isokinetic quadriceps strength (82.5 +/- 36.4 to 90.3 +/- 34.9 Newton-meters, p <
      0.05) all improved. Changes in FFM were proportionally smaller than functional
      improvements, and were related to changes in O(2)max (r = 0.361, p < 0.05), but
      not to other changes in functional capacity. CONCLUSIONS: Intensive exercise
      training per se is able to induce an anabolic response in normal-weight patients
      with COPD classified into Global Initiative for Chronic Obstructive Lung Disease
      stages III-IV. Improvements in exercise performance and muscle function are
      proportionally larger than increases in FFM.

PMID- 15189918
TI  - Bronchodilatory effect of deep inspiration is absent in subjects with mild COPD.
AB  - STUDY OBJECTIVES: To investigate whether the bronchodilatory effect of deep
      inspiration is impaired in subjects with COPD. METHODS: We measured deep
      inspiration-induced bronchodilation in 19 patients with COPD and 17 healthy
      subjects (mean age, 67.8 +/- 7.1 years vs 62.5 +/- 9.3 years, respectively [+/-
      SEM]). Each subject underwent a series of single-dose methacholine provocations
      to induce at least a 15% reduction in inspiratory vital capacity (IVC). When this
      was achieved, subjects were asked to perform four consecutive deep inspirations,
      after which the IVC measurement was repeated and the percentage of
      bronchodilation by deep inspiration was calculated. RESULTS: The percentage of
      reduction in IVC from baseline prior to the deep inspirations did not differ
      between the two groups (COPD, 20.1 +/- 1.6%; healthy, 22.7 +/- 2.4%; p = 0.38);
      median single methacholine doses employed were 20 mg/mL (range, 0.025 to 75
      mg/mL) and 25 mg/mL (range, 10 to 75 mg/mL), respectively (p = 0.19). Deep
      inspirations were not able to reverse bronchoconstriction in patients with COPD
      (bronchodilation, 3.9 +/- 2.6%; p = 0.15 by one-sample t test). Bronchodilation
      by deep inspiration was present in healthy subjects (13.7 +/- 3.0%, p = 0.0003),
      and was significantly higher than that of patient with COPD (p = 0.02). In
      patients with COPD, deep inspiration-induced bronchodilation correlated with the
      percentage of predicted transfer factor of the lung for carbon monoxide (r =
      0.53, p = 0.05), but not with airway obstruction, as assessed by FEV(1) or
      FEV(1)/FVC. CONCLUSIONS: The bronchodilatory ability of deep inspiration is lost
      in mild COPD. We speculate that the absence of deep inspiration-induced
      bronchodilation contributes to the development and severity of chronic
      respiratory symptoms in patients with COPD.

PMID- 15189919
TI  - Endurance and strength training in patients with COPD.
AB  - STUDY OBJECTIVES: The purpose of this study was to compare the effects of
      endurance training only to endurance plus strength (combined) training in a
      randomized trial of patients with COPD. METHODS: Twenty-four patients completed
      the study: 11 patients in the combined training group (FEV(1) 45 +/- 5%
      predicted), and 13 patients in the endurance training group (FEV(1) 40 +/- 4%
      predicted) [mean +/- SE]. Muscle strength, quality of life, exercise performance,
      and quadriceps fatigability were measured before and after rehabilitation.
      RESULTS: Combined training led to significant improvements in quadriceps (23.6%),
      hamstring (26.7), pectoralis major (17.5%), and latissimus dorsi (20%) muscle
      strength. Endurance training alone did not produce significant improvements in
      muscle strength: quadriceps (1.1% decrease), hamstring (12.2% increase),
      pectoralis major (7.8% increase), and latissimus dorsi (2.8% decrease). The
      increase in strength after training was significantly greater in the combined
      group compared to the endurance group for the quadriceps and latissimus dorsi
      muscles but not for the hamstring and pectoralis major muscles. Six-minute walk
      distance, endurance exercise time, and quality of life (as measured by the
      Chronic Respiratory Questionnaire) significantly increased in both groups after
      rehabilitation with no significant differences in the extent of improvement
      between groups. The extent of improvement in quadriceps fatigability after
      training (assessed by quadriceps twitch force before and after exercise) was not
      significantly different between groups. CONCLUSION: Strength training can lead to
      significant improvement in muscle strength in elderly patients with COPD.
      However, this improvement in muscle strength does not translate into additional
      improvement in quality of life, exercise performance or quadriceps fatigability
      compared to that achieved by endurance exercise alone.

PMID- 15189920
TI  - Effect of weight reduction on respiratory function and airway reactivity in obese
      women.
AB  - BACKGROUND: Population-based studies have documented an association between
      obesity and an increased prevalence of asthma in women. METHODS: We prospectively
      studied 58 obese women with a body mass index of > 30 kg/m(2), 24 of whom had
      asthma, who were enrolled in an intensive 6-month weight loss program to
      determine whether loss of body mass would be correlated with improvements in
      bronchial reactivity, lung function, and disease-specific health status. RESULTS:
      Patients lost an average of 20 kg over the 6-month period. For every 10% relative
      loss of weight, the FVC improved by 92 mL (p = 0.05) and the FEV(1) improved by
      73 mL (p = 0.04), however, bronchial reactivity did not significantly change with
      weight loss (p = 0.23). Patients who lost > 13% of their pretreatment weight
      experienced improvements in FEV(1) (p = 0.01), FVC (p = 0.02), and total lung
      capacity (p = 0.05) compared to patients in the lowest quartile who failed to
      lose significant amounts of weight. Neither group experienced any significant
      change in methacholine responsiveness (p = 0.57). Patients who completed the 6
      month weight loss program experienced improvements in respiratory health status,
      irrespective of weight loss. CONCLUSION: We concluded that weight loss can
      improve lung function in obese women, however, the improvements appear to be
      independent of changes in airway reactivity.

PMID- 15189921
TI  - Reference values for arterial blood gases in the elderly.
AB  - OBJECTIVES: We present reference values for arterial blood gas measurements for
      persons > 70 years old. At the same time, we wish to examine how different
      criteria for exclusion from the reference sample with regard to previous smoking
      and various comorbidities might influence reference values. METHODS: After first
      screening a random sample of the general elderly population by postal
      questionnaire, we selected 146 men and women without respiratory disease,
      significant dyspnea, symptomatic heart disease or hypertension, or current smoker
      status. Arterial blood samples were drawn from subjects while in the supine
      position. RESULTS: The mean (SD; lower limit of normal) PaO(2) and arterial
      oxygen saturation (SaO(2)) for men was 77.0 mm Hg (9.1; 62.0) and 95.3% (1.4;
      93.0), respectively, and for women was 73.5 mm Hg (8.4; 59.6) and 94.8% (1.7;
      92.0). Mean (SD; upper limit of normal) PaCO(2) was 39.4 mm Hg (3.3; 44.8) for
      both sexes. None of the blood gas variables were associated with age, smoking
      history, or presence of various comorbidities. CONCLUSIONS: The reference values
      for PaO(2) and SaO(2) in elderly persons are sex specific but age independent. Ex
      smokers and persons with nonpulmonary comorbidities who do not have significant
      respiratory symptoms need not be excluded from the reference sample for arterial
      blood gases.

PMID- 15189922
TI  - Membrane and capillary blood components of diffusion capacity of the lung for
      carbon monoxide in pulmonary sarcoidosis: relation to exercise gas exchange.
AB  - BACKGROUND: Resting pulmonary diffusing capacity of the lung for carbon monoxide
      (DLCO) is known to be the best predictor of arterial desaturation during exercise
      in patients with sarcoidosis. However, the relative contribution of each of the
      two components of DLCO-alveolar membrane diffusing capacity (Dm) and pulmonary
      capillary blood volume (Vc)-remains unclear. STUDY OBJECTIVES: To evaluate which
      component is responsible for the decrease of resting DLCO in patients with
      sarcoidosis, and to determine which resting pulmonary function test, including Dm
      and Vc, is the best predictor of gas exchange abnormalities during submaximal
      exercise. DESIGN: Prospective analysis of patients referred to our department of
      respiratory medicine. PATIENTS: Twenty four patients with pulmonary sarcoidosis
      were separated into two groups according to chest radiographic findings: group 1,
      stages 2 and 3 (n = 15); group 2, stage 4 (n = 9). All the patients completed
      pulmonary function tests (flows, volumes, single-breath DLCO, transfer
      coefficient [Ka], Dm, Vc) and submaximal exercise (two steady-state levels of
      mild and moderate exercise corresponding respectively to a target oxygen
      consumption of approximately 10 to 15 mL/min/kg). RESULTS: DLCO was reduced in
      the two groups (group 1, 63 +/- 16% of predicted; group 2, 64 +/- 16% of
      predicted). Dm was severely decreased (group 1, 58 +/- 24% of predicted; group 2,
      51 +/- 15% of predicted), whereas Vc was unchanged or only mildly decreased
      (group 1, 81 +/- 18% of predicted; group 2, 85 +/- 28% of predicted). Whatever
      the group of patients and the exercise level, Dm and DLCO were the strongest
      predictors (p < 0.001) of gas exchange abnormalities. Ka or volumes were weak
      predictors, and Vc or flows were not related with exercise gas exchange.
      CONCLUSIONS: This study demonstrates that a decrease in Dm mostly accounts for
      resting DLCO reduction, and that Dm as well as DLCO are highly predictive of gas
      exchange abnormalities at exercise in patients with sarcoidosis.

PMID- 15189923
TI  - Influence of immersion in water on muscle function and breathing pattern in
      patients with severe diaphragm weakness.
AB  - STUDY OBJECTIVE: Dyspnea is a common symptom in patients with diaphragm weakness
      or paralysis. In particular, dyspnea may be aggravated by immersion. We
      hypothesized that immersion to the neck in water would decrease vital capacity
      and consequently increase the demand/capacity ratio of the respiratory muscles.
      DESIGN: Case series study. SUBJECTS: Seven patients with profound diaphragm
      weakness or paralysis proven by phrenic nerve stimulation, and seven normal
      control subjects. INTERVENTION AND MEASUREMENTS: We measured land-based and water
      based spirometry, breathing pattern, and mouth occlusion pressures. RESULTS: We
      found that the patients could preserve minute ventilation despite a fall in vital
      capacity from a mean of 2.3 to 1.3 L, but this required an increased respiratory
      rate (RR) [21.4 to 26.7 breaths/min, p = 0.018]. We used mouth occlusion pressure
      100 ms after the start of inspiration (P(0.1)) as an estimation of the drive to
      breath; P(0.1) increased from 1.4 to 3.9 cm H(2)O (p = 0.018) without significant
      change in tidal volume. CONCLUSIONS: Relative to control subjects, patients with
      diaphragm weakness have augmented drive to breathe in order to attempt to defend
      gas exchange. This conclusion is implied by the presevered minute ventilation
      with immersion, the augmented RR, and elevated P(0.1) relative to maximum static
      inspiratory pressure.

PMID- 15189924
TI  - Effect of heliox breathing on dynamic hyperinflation in COPD patients.
AB  - BACKGROUND: and objective: Patients with COPD exhibit increased inspiratory work
      and dyspnea due to dynamic hyperinflation caused by expiratory flow limitation.
      Helium-oxygen mixtures (ie, heliox) have been used in treating these patients on
      the assumption that, by lowering airway resistance, they might be beneficial.
      METHODS: In 22 patients with COPD, the presence of expiratory flow limitation was
      assessed with patients in the sitting and supine positions using the negative
      expiratory pressure technique, and the effects of heliox (80% He, 20% O2) on
      breathing pattern, expiratory flow limitation, and dynamic hyperinflation,
      evaluated from the change in inspiratory capacity (IC), were measured at rest and
      were compared with those due to inhaled salbutamol. RESULTS: During air
      breathing, 13 patients experienced flow limitation while in the sitting position
      and 18 experienced flow limitation while in the supine position. Neither heliox
      nor salbutamol therapy changed the breathing pattern in any of the patients,
      regardless of posture and the presence or absence of expiratory flow limitation.
      However, in both positions IC increased significantly in most flow-limited
      patients after bronchodilator administration, but not after heliox
      administration. CONCLUSIONS: Since heliox had no effect on dynamic
      hyperinflation, the use of this gas mixture, which is costly and cumbersome, does
      not appear to be beneficial in stable patients with COPD breathing at rest.

PMID- 15189925
TI  - Lung density measurements in spontaneous pneumothorax demonstrate airtrapping.
AB  - PURPOSE: Idiopathic spontaneous pneumothorax (SP) is the result of leakage of air
      from the lung parenchyma through a ruptured visceral pleura into the pleural
      cavity. This rupture is thought to be caused by an increased pressure difference
      between parenchymal airspace and pleural cavity. We hypothesize that rather
      peripheral airway inflammation leads to obstruction with check valve phenomena
      and by that to airtrapping in the lung parenchyma, which precedes spontaneous
      pneumothorax. SETTING: University hospital. MATERIALS AND METHODS: Forty-one
      matched healthy volunteers (21 smokers and 20 nonsmokers), and 41 patients with
      SP (21 patients with and 20 patients without bullae) underwent spirometrically
      controlled high-resolution CT density measurements with automatic contour tracing
      at 10% and at 90% of vital capacity. RESULTS: Patients with SP showed lower mean
      lung density (MLD) values and higher percentages of Hounsfield units (HU) below -
      900 HU (pixel index [PI]) compared to the healthy volunteers on expiratory scans.
      This enhanced airtrapping phenomenon is seen in both the SP lung (MLD, p = 002;
      PI, p = 0.01) and the contralateral lung (MLD, p = 0.009; PI, p = 0.05) compared
      to the control subjects. The difference with control subjects is independent of
      smoking behavior and bullae. CONCLUSIONS: Peripheral airway obstruction with
      airtrapping was found, and it is supposed to play an important role in the
      pathogenesis of spontaneous pneumothorax.

PMID- 15189926
TI  - Obstructive sleep apnea syndrome, sleepiness, and quality of life.
AB  - OBJECTIVE: To evaluate the addition of short arousals of > 3 s on indexes of
      sleep-disordered breathing (SDB) and subjective sleepiness in patients with
      obstructive sleep apnea (OSA), and to evaluate the quality of life and reported
      difficulty driving with arousal index and indexes of SDB. METHOD: Data was
      collected from a general clinical evaluation, and evaluations using the Epworth
      sleepiness scale (ESS), the sleep disorders questionnaire, the Beck depression
      inventory (BDI), the Medical Outcomes Study 36-item short form health survey (SF
      36), a questionnaire on driving difficulties and accidents, and polysomnography.
      RESULTS: A total of 135 male subjects (mean [+/- SD] age, 52 +/- 12.1 years; mean
      body mass index [BMI], 27.8 +/- 5.6 kg/m(2); mean apnea-hypopnea index [AHI],
      48.7 +/- 26.8 events per hour) were studied. Of these subjects, 70.4%
      acknowledged having driven while sleepy. ESS scores correlated significantly with
      the arousal index and AHI, and negatively with the lowest arterial oxygen
      saturation. The "physical functioning," "general health," and "role physical"
      subscales of the SF-36 correlated with the arousal index. No significant
      correlation was seen in multiple regression analyses after adjusting for age and
      BMI, using "reports of sleepiness while driving" as the dependent variable.
      CONCLUSION: Several subjective complaints and subscales of the SF-36 correlated
      significantly with a frequency of SDB-related arousal of > 3 s. Patients
      perceived that an organic health problem had been impairing their quality of life
      more than an emotional problem, despite elevated scores on the BDI. However, if
      sleepiness while driving was common in OSA patients, it was not significant. Many
      clinical and polysomnographic variables may be considered as possible independent
      variables in the regression analysis. Other unrelated factors have a greater
      impact. To relate sleepiness while driving only to the usually studied variables
      in OSA patients is an oversimplification.

PMID- 15189927
TI  - Cardiac troponin T in obstructive sleep apnea.
AB  - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with nocturnal
      angina and ST-segment depression, which are relieved by treatment with continuous
      positive airway pressure (CPAP). We tested the hypothesis that severe nocturnal
      hypoxia in patients with OSA causes myocyte necrosis as evidenced by increases in
      cardiac troponin T. DESIGN: Prospective cohort study. SETTING: Cardiovascular
      physiology and sleep research laboratory. PARTICIPANTS: Fifteen male volunteers
      with coronary artery disease (CAD) and moderate or severe OSA (apnea-hypopnea
      index [AHI] > 15). MEASUREMENTS AND RESULTS: Polysomnography and measurement of
      serum cardiac troponin T before sleep, after 4 h of untreated OSA, and in the
      morning after 4 h of treatment with CPAP. The mean AHI for the group was 41 (SD
      16), and the mean oxygen saturation nadir during sleep was 83% (SD 8%). All
      measurements of cardiac troponin T were < 0.010 ng/mL. CONCLUSIONS: Despite the
      fact that some patients with OSA may experience nocturnal ischemia, this study
      shows that patients with severe OSA and coexisting CAD do not have nightly
      episodes of myocardial injury detectable by the current-generation cardiac
      troponin T assay.

PMID- 15189928
TI  - Acidification of distal esophagus and sleep-related breathing disturbances.
AB  - STUDY OBJECTIVES: To investigate whether distal esophageal acidification occurs
      during sleep in patients suspected of sleep-disordered breathing, and whether
      such acidification is related to respiratory abnormalities. DESIGN AND PATIENTS:
      Fourteen middle-aged, snoring men all complaining of daytime sleepiness and
      suspected of having obstructive sleep apnea. SETTING: Sleep laboratory, Pulmonary
      Department, Landspitali University Hospital, Reykjavik, Iceland. MEASUREMENTS AND
      RESULTS: Each patient underwent full nocturnal polysomnography testing, which
      included continuous monitoring of esophageal pressure (Pes) and pH. We identified
      all pH events, which were defined as a reduction in esophageal pH of >/= 1.0.
      During each pH event, the respiratory recordings where examined for the presence
      of apneas or hypopneas, and Pes was recorded. The data were analyzed to determine
      the possible relationships between pH events and respiratory events, and between
      changes in pH and changes in Pes. We found that there were more respiratory
      events than pH events. The mean (+/- SD) number of apneas and hypopneas per hour
      of sleep was 33 +/- 22, whereas the mean number of pH events per hour of sleep
      was 7 +/- 6. Overall, 81% of all pH events were associated with respiratory
      events. Correlation analysis did not reveal any significant relationship between
      pH events and the magnitude of Pes or apnea-hypopnea index. CONCLUSIONS: Episodes
      of esophageal acidification are common in patients with sleep apnea, and are
      usually associated with respiratory and pressure events. However, changes in pH
      were independent of the magnitude of the Pes.

PMID- 15189929
TI  - Corrected QT dispersion and cardiac sympathetic function in patients with
      obstructive sleep apnea-hypopnea syndrome.
AB  - STUDY OBJECTIVES: Hypoxemia increases corrected QT dispersion (QTcD), which is
      the difference between the maximum and minimum QT intervals and is a strong risk
      factor for cardiovascular mortality. The aim of this study was to investigate the
      QTcD in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), and the
      relationship between the QTcD and (123)I-metaiodobenzylguanidine (MIBG) cardiac
      imaging, which reflects cardiac sympathetic activity. SETTING: A university
      hospital. PATIENTS: Forty-eight OSAHS patients without cardiac diseases (mean [+/
      SD] age, 45.9 +/- 10.8 years; apnea-hypopnea index [AHI] 51.9 +/- 18.5 events
      per hour) who underwent polysomnography before treatment and on the first night
      of nasal continuous positive airway pressure (nCPAP) treatment. METHODS: Before
      and after nCPAP treatment was started, we measured the QTcD with computer
      software, before, during, and after sleep, as well as the washout rate of the
      MIBG administered for cardiac imaging. As a control, QTcD was also measured in
      the morning from 26 healthy subjects. RESULTS: Before treatment, the mean QTcD
      during sleep (65.0 +/- 14.6 ms) was greater than that before sleep (57.0 +/- 13.5
      ms; p < 0.0001). Meanwhile, after 1 night of nCPAP therapy, the QTcD during sleep
      (50.6 +/- 11.4 ms) decreased from that before treatment (p < 0.0001) and was
      smaller than the QTcD before sleep (56.2 +/- 13.3 ms; p = 0.003). Before
      treatment, the QTcD during sleep correlated with the AHI (r = 0.38; p = 0.009)
      and the percentage of time that SaO(2) was < 90% (SaO(2) < 90% time) [r = 0.34; p
      = 0.018]. The QTcD did not correlate with the body mass index or the washout rate
      of MIBG. However, the washout rate of MIBG correlated with the AHI and the SaO(2)
      < 90% time. CONCLUSIONS: Nocturnal QTcD is increased in OSAHS patients but is
      decreased by nCPAP therapy independently of cardiac sympathetic function.

PMID- 15189930
TI  - Evaluation of intravascular hemolysis with erythrocyte creatine in patients with
      cardiac valve prostheses.
AB  - STUDY OBJECTIVES: To detect intravascular hemolysis in patients with cardiac
      valve prostheses. Erythrocyte creatine, a marker of erythrocyte age that
      increases with shortening erythrocyte survival, was evaluated with other
      hemolytic markers and hemodynamic parameters. DESIGN: Prospective study. PATIENTS
      AND MEASUREMENTS: Erythrocyte creatine was enzymatically assayed in 33 patients
      with prosthetic valves, including 15 patients with aortic valve replacement, 13
      patients with mitral valve replacement, and 5 patients with double-valve (aortic
      and mitral) replacement, and 33 control subjects. Blood flow velocity and
      valvular regurgitation were determined by Doppler echocardiography. Other
      hemolytic markers (lactate dehydrogenase [LDH], reticulocyte count, and
      haptoglobin) and cardiac muscle markers (myoglobin and myosin light chain 1) were
      also measured. RESULTS: Erythrocyte creatine and LDH levels were significantly
      higher (p < 0.0001) and the haptoglobin level was lower (p < 0.0001) in patients
      with a prosthetic valve as compared with control subjects. However, there were no
      significant differences in these markers between those with (n = 17) and without
      (n = 16) regurgitation. Patients with high erythrocyte creatine levels (> 1.8
      micro mol/g hemoglobin) exhibited significantly higher total peak flow velocity
      (sum of peak flow velocities at mitral and aortic valves) than those with normal
      erythrocyte creatine levels (p = 0.006). Erythrocyte creatine had a significant
      correlation with total peak flow velocity (r = 0.64, p < 0.0001), but LDH and
      haptoglobin had no significant correlation with total peak flow velocity.
      Patients with high LDH levels (> 460 IU/L) showed significantly higher myoglobin
      (p = 0.008) and myosin light chain 1 (p = 0.02) than those with normal LDH
      levels, whereas erythrocyte creatine was not related to cardiac muscle markers.
      CONCLUSIONS: Erythrocyte creatine is a quantitative and reliable marker for
      intravascular hemolysis in patients with prosthetic valves. Mild hemolysis is
      ascribable to valvular flow velocity rather than regurgitation.

PMID- 15189931
TI  - Feasibility of routine pulmonary arterial impedance measurements in pulmonary
      hypertension.
AB  - OBJECTIVES: Right ventricular (RV) afterload is best described by a pulmonary
      arterial impedance (PVZ) spectrum, which integrates pulmonary vascular resistance
      (PVR), elastance, and wave reflection. We evaluated the feasibility of PVZ
      determinations in patients with pulmonary arterial hypertension (PAH) during
      routine right heart catheterization and Doppler echocardiography. DESIGN:
      Prospective study. SETTING: Academic hospital. PATIENTS: Twenty-two patients with
      PAH. INTERVENTIONS: Right heart catheterization with a fluid-filled Swan-Ganz
      catheter, Doppler echocardiography, and administration of inhaled nitric oxide
      (NO) [10 to 20 ppm; 17 patients], maximum tolerated dose of IV epoprostenol
      (average, 8.5 ng/kg/min; 5 patients), and IV dobutamine (8 micro g/kg/min; 8
      patients). MEASUREMENTS AND RESULTS: PVZ was calculated from the spectral
      analysis of synchronized pulmonary artery pressure (Ppa) and flow waves. The mean
      (+/- SE) Ppa was 63 +/- 3 mm Hg, and the mean PVR was 16 +/- 2 Wood units. The
      PVZ spectrum was markedly shifted to higher than normal pressures and
      frequencies, with a mean 0-Hz impedance (Z(0)) of 1,506 +/- 138 dyne. s. cm(-5),
      and a mean characteristic impedance (Zc) of 124 +/- 11 dyne. s. cm(-5), which are
      in keeping with data from previous studies. Inhaled NO levels decreased Ppa, PVR,
      Z(0), and Zc without a change in cardiac output. Epoprostenol administration did
      not affect Ppa, increased cardiac output, and decreased Z(0) and Zc. Dobutamine
      administration increased cardiac output and Ppa, and decreased PVR and Z(0),
      without changing Zc. CONCLUSIONS: The determination of PVZ to quantify RV
      afterload is feasible during routine right heart catheterization and Doppler
      echocardiography. The measurement is sensitive to pharmacologic interventions.

PMID- 15189932
TI  - Preoperative atrial size predicts the success of radiofrequency maze procedure
      for permanent atrial fibrillation in patients undergoing concomitant valvular
      surgery.
AB  - BACKGROUND: The radiofrequency (RF) maze procedure can effectively restore sinus
      rhythm and atrial transport function in the majority of patients with permanent
      atrial fibrillation (AF) and mitral valve disease. No previous study has
      described a cutoff value of preoperative atrial size determined by the
      discriminant analysis in predicting the success of sinus conversion by the RF
      maze procedure for permanent AF in patients with mitral valve disease. METHODS
      AND RESULTS: This study included 81 patients with permanent AF and mitral valve
      disease who underwent the RF maze IV procedure while undergoing concomitant
      valvular operations. There was one surgical death (1.2%). Another patient died of
      acute necrotizing pancreatitis 13 months later. Two patients (2.5%) developed
      sick sinus syndrome and received transvenous permanent pacemaker implantation. In
      the remaining 77 patients, there were 38 men and 39 women, with a mean (+/- SD)
      age of 51 +/- 11 years. At a mean follow-up time of 38 months, 65 patients
      (84.4%) had persistent sinus conversion that had been accomplished by the RF maze
      procedure (group 1), and 12 patients (15.6%) did not regain sinus rhythm (group
      2). We evaluated the preoperative variables between the two groups. Univariate
      analysis demonstrated that the preoperative left atrial area and the left atrial
      diameter of group 1 patients were significantly smaller than those of group 2
      patients. Group 1 had significantly fewer patients associated with tricuspid
      valve disease than did group 2. By multiple stepwise logistic regression
      analysis, only the preoperative left atrial area was an independent determinant
      of sinus conversion by the RF maze procedure (odds ratio, 0.961; 95% confidence
      interval, 0.935 to 0.988; p < 0.005). Linear discriminant analysis demonstrated
      that the sensitivity and specificity of the cutoff value of 56.25 cm(2) of the
      preoperative left atrial area in predicting the sinus conversion by the RF maze
      procedure were 50.0% and 86.2%, respectively, and the positive and negative
      predictive values were 40.0% and 90.3%, respectively. CONCLUSION: The
      preoperative left atrial area is an independent determinant of sinus conversion
      by the RF maze procedure for patients with permanent AF and mitral valve disease.

PMID- 15189933
TI  - Levofloxacin efficacy in the treatment of community-acquired legionellosis.
AB  - BACKGROUND: Although fluoroquinolones possess excellent in vitro activity against
      Legionella, few large-scale clinical trials have examined their efficacy in the
      treatment of Legionnaires disease. Even fewer studies have applied rigorous
      criteria for diagnosis of community-acquired Legionnaires disease, including
      culture of respiratory secretions on selective media. METHODS: Data from six
      clinical trials encompassing 1,997 total patients have been analyzed to determine
      the efficacy of levofloxacin (500 mg qd or 750 mg qd) in treating patients with
      community-acquired pneumonia (CAP) due to Legionella. RESULTS: Of the 1,997 total
      patients with CAP from the clinical trials, 75 patients had infection with a
      Legionella species. Demographics showed a large portion of these patients were <
      55 years of age and nonsmokers. More than 90% of mild-to-moderate and severe
      cases of Legionella infection resolved clinically at the posttherapy visit, 2 to
      14 days after treatment termination. No deaths were reported for any patient with
      Legionnaires disease treated with levofloxacin during the studies. CONCLUSIONS:
      Levofloxacin was efficacious at both 500 mg for 7 to 14 days and 750 mg for 5
      days. Legionnaires disease is not associated only with smokers, the elderly, and
      the immunosuppressed, but also has the potential to affect a broader demographic
      range of the general population than previously thought.

PMID- 15189934
TI  - Treatment costs of community-acquired pneumonia in an employed population.
AB  - BACKGROUND: Community-acquired pneumonia (CAP) is a serious clinical problem,
      causing hospitalization in about 20% of cases and death in up to 16% of
      hospitalized patients. Work-loss cost estimates indicate that the treatment of
      CAP also has a large economic impact. The purpose of this study was to assess the
      medical and prescription drug (treatment) costs of managing CAP in an employed
      population. METHOD: The costs of CAP were determined from an administrative
      claims database covering the years 1996 to 1998 for an employed population and
      their dependents [65 years of age (100,000 population)]. Treatment costs for
      managing both inpatient and outpatient cases of CAP were calculated from payments
      by the health plan. RESULTS: A total of 7,249 episodes of CAP among 6,415
      individuals were identified. The hospitalization rate was 19.6%, and the
      mortality rate for those hospitalized was 9.1%. Patients requiring
      hospitalization were older and had more comorbid conditions. The mean (+/- SD)
      treatment cost for an inpatient episode of CAP (including all inpatient and
      outpatient medical care) was $10,227 +/- 15,342. The costs for inpatients who
      died during hospitalization (mean cost, $15,822 +/- 26,541) were higher than for
      episodes in which patients were discharged from the hospital alive (mean cost,
      $9,595 +/- 13,641). The mean treatment cost for an outpatient episode of CAP was
      $466 +/- 1,038. CONCLUSIONS: The treatment cost of managing CAP in this employed
      population was higher than previously estimated. It is estimated that the annual
      cost of treating CAP in the United States is $12.2 billion.

PMID- 15189935
TI  - Regional deposition of aerosolized interferon-gamma in pulmonary tuberculosis.
AB  - STUDY OBJECTIVES: Aerosol interferon-gamma (IFN-gamma) is a potential
      immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous
      investigations demonstrated conversion of sputum smears in five patients with
      multidrug-resistant TB after 12 treatments over 1 month, and induction of
      signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The
      objective of the current study was to evaluate particle size and deposition
      pattern in patients with TB receiving aerosol IFN-gamma treatment. DESIGN:
      Particle size was determined with a cascade impactor, and deposition of IFN-gamma
      mixed with (99m)Tc-labeled human serum albumin was assessed using a gamma camera.
      Local levels of IFN-gamma were measured in BAL using enzyme-linked immunosorbent
      assays. Study patients/intervention: Fourteen patients with pulmonary TB received
      IFN-gamma aerosol (500 micro g) for 12 treatments in addition to
      antimycobacterial therapy with BAL before and after IFN-gamma aerosol treatment.
      Eight patients with minimal-to-moderate parenchymal involvement underwent
      deposition studies. Deposited (99m)Tc-labeled IFN-gamma aerosol was partitioned
      between upper airways and lungs using attenuation correction measurements.
      (133)Xe equilibrium scanning, (133)Xe washout, and (99m)Tc- macroaggregate
      injection defined regional lung volume, ventilation, and perfusion. RESULTS:
      Upper airway deposition was significant often exceeding lung deposition (53.9 +/-
      7.09 micro g vs 35.8 +/- 2.73 micro g, respectively [mean +/- SE]). IFN-gamma
      levels measured in BAL fluid were significantly increased with aerosol treatment
      (0.83 +/- 0.43 micro g before vs 24.76 +/- 8.71 micro g after, p </= 0.017), and
      IFN-gamma levels correlated with regional deposition of IFN-gamma aerosol (r =
      0.823). Four-quadrant analysis of regional lung deposition best correlated with
      regional perfusion (r = 0.422, p = 0.013) with penetration of aerosol into areas
      of obvious radiographic infiltration on chest radiograph. CONCLUSIONS: Aerosol
      therapy with IFN-gamma in patients with pulmonary TB is widely distributed and
      results in significant enhancement of IFN-gamma levels in the lower respiratory
      tract. In patients without lung destruction, IFN-gamma aerosol may be an adjuvant
      to enhance the local immune response.

PMID- 15189936
TI  - Vascular endothelial growth factor levels in active pulmonary tuberculosis.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) is a mediator with potent
      angiogenic, mitogenic, and vascular permeability-enhancing activities that are
      specific for endothelial cells. Intense angiogenesis has been found in active
      pulmonary tuberculosis lesions. OBJECTIVES: To determine whether active pulmonary
      tuberculosis is associated with increased serum levels of VEGF compared with
      inactive tuberculosis and VEGF levels in healthy subjects, and to assess the
      changes in serum VEGF levels before and after therapy. DESIGN: Prospective
      clinical study. SETTING: Chest clinic of a university hospital, Eskisehir,
      Turkey. PATIENTS AND MEASUREMENTS: Serum VEGF levels of 44 patients with active
      pulmonary tuberculosis, 24 patients with inactive pulmonary tuberculosis, and 20
      healthy subjects were determined. RESULTS: VEGF levels were increased in active
      pulmonary tuberculosis patients (mean [+/- SD] VEGF level, 598.03 +/- 298.25
      pg/mL) compared to both inactive pulmonary tuberculosis patients (mean VEGF
      level, 296.98 +/- 115.31 pg/mL) and control subjects (mean VEGF level, 339.67 +/-
      74.65 pg/mL). The increase in VEGF level observed in patients with active
      tuberculosis was statistically significant when compared with levels in two other
      groups (p < 0.001 for both). Serum VEGF levels were statistically different
      before treatment and after treatment in 10 patients who were observed from
      diagnosis to the end of treatment (p < 0.01). CONCLUSIONS: Increased serum VEGF
      levels may be an indicator of active pulmonary tuberculosis, since levels were
      higher in patients with active pulmonary tuberculosis and were lower after
      successful treatment. The role of VEGF-mediated angiogenesis in the pathogenesis
      and progression of pulmonary tuberculosis lesions should be further elucidated.

PMID- 15189937
TI  - Increased arteriovenous carboxyhemoglobin differences in patients with
      inflammatory pulmonary diseases.
AB  - PURPOSE: Exhaled carbon monoxide and arterial blood carboxyhemoglobin
      concentrations increase in inflammatory pulmonary diseases. The present study was
      undertaken to elucidate whether arteriovenous carboxyhemoglobin (a-vHb-CO)
      concentration differences are also useful to define the site of inflammation,
      either in the lung or organs other than the lung. MATERIALS AND METHODS: We
      examined concentrations of carboxyhemoglobin in both arterial and peripheral
      venous blood and exhaled carbon monoxide in patients with acute pulmonary
      inflammation including bronchial asthma (n = 18) and pneumonia (n = 33), and
      those in patients with extrapulmonary inflammatory diseases, including acute
      pyelonephritis (n = 28) and active rheumatoid arthritis (n = 16). RESULTS: The
      values of carboxyhemoglobin in both arterial and peripheral venous blood were
      significantly higher in patients with pulmonary and extrapulmonary inflammation
      compared with those in control subjects (n = 22). Furthermore, a-vHb-CO
      differences in patients with inflammatory pulmonary diseases were higher than
      those in patients with acute pyelonephritis and patients with rheumatoid
      arthritis, and than those in control subjects. The a-vHb-CO differences
      correlated with the WBC count of peripheral venous blood in patients with
      pneumonia. In patients with bronchial asthma, the a-vHb-CO differences inversely
      correlated with FEV(1), although they did not correlate with WBC count of
      peripheral venous blood. The a-vHb-CO differences in patients with acute
      pyelonephritis were higher than those in patients with active rheumatoid
      arthritis. CONCLUSION: The present study suggests that a-vHb-CO differences may
      be a useful means to define the site of inflammation, either in the lung or
      organs other than the lung, in patients with a fever of unknown origin. The large
      a-vHb-CO differences may be caused by carbon monoxide production in pulmonary
      inflammation.

PMID- 15189938
TI  - Combined corticosteroid and cyclophosphamide therapy does not alter survival in
      idiopathic pulmonary fibrosis.
AB  - STUDY OBJECTIVES: Treatment of patients with idiopathic pulmonary fibrosis (IPF)
      conventionally includes corticosteroids and cytotoxic agents. No study to date
      has adequately evaluated the benefits of this approach. This study
      retrospectively compared combination corticosteroid and cyclophosphamide therapy
      in a large population of patients who meet the current consensus definition of
      IPF. DESIGN: Patients were identified retrospectively and treatment addressed on
      an intention-to-treat basis. Treated and untreated patients were matched by age
      and percentage of predicted FVC (FVC%) at the time of the initial visit. SETTING:
      Two academic tertiary referral centers. PATIENTS OR PARTICIPANTS: The diagnosis
      of IPF was based on current consensus criteria. A total of 164 patients (82
      treated and 82 untreated) were included. INTERVENTIONS: Treatment consisted of
      combined corticosteroid and cyclophosphamide therapy using a standardized
      protocol. MEASUREMENTS AND RESULTS: There was no difference in age, FVC%, gender,
      or smoking status between groups. No survival difference was found between
      patients who were treated (median survival, 1,431 days) or untreated (median
      survival, 1,665 days) [p = 0.58]. The lack of treatment effect persisted when
      only those patients with a diagnosis by surgical biopsy (n = 24) or FVC% >/= 60
      (n = 107) were analyzed. CONCLUSIONS: Our data suggest that combined
      corticosteroid and cyclophosphamide therapy has no impact on survival in patients
      with IPF. This finding supports the evolving concept that chronic inflammation
      plays a minimal role in the progression of IPF and reinforces the importance of
      careful consideration of the risks and benefits of such therapies prior to their
      institution.

PMID- 15189939
TI  - Relationship between a history of antecedent cancer and the probability of
      malignancy for a solitary pulmonary nodule.
AB  - STUDY OBJECTIVES: To determine the probability of malignancy for a solitary
      pulmonary nodule (SPN) as a function of cancer history. SETTING AND DESIGN:
      Patients who had undergone resection of SPNs at Brigham and Women's Hospital
      between August 1989 and October 1998 were analyzed. The cohort was split into the
      following three groups: no history of cancer; history of lung cancer; and history
      of extrapulmonary malignancy. The histology of the SPN was determined after
      excision. Logistic regression was used to evaluate the effect of covariates on
      the probability of malignancy. MEASUREMENTS AND RESULTS: A total of 1,104
      patients (55% women; median age, 64 years; age range, 17 to 88 years) underwent
      removal of 353 benign lesions (32%), 638 non-small cell lung cancers (NSCLCs)
      [58%], and 113 metastases (10%). Antecedent cancer history was significantly
      associated with final diagnosis (p < 0.0001), with SPNs being malignant in 63% of
      patients with no previous cancer, 82% of those with a history of lung cancer
      (NSCLC, 80%; metastases, 2%), and 79% of patients with history of extrapulmonary
      cancer (NSCLC, 41%; metastases, 38%). There was no difference in the cause of
      SPNs between patients with a history of a single cancer and those with a history
      of multiple cancers. The probability of a benign cause ranged between 62% for
      nodules < 1 cm to 17% when nodules were > 3 cm, if the patient had no history of
      cancer (p < 0.0001). The probability of an SPN being benign was cut in half if
      there was a history of cancer. Among patients with previous extrapulmonary
      malignancy, age, smoking history, and histology were predictors of diagnosis (p <
      0.0001). These variables were used to construct a clinical score to predict the
      probability of an SPN being a NSCLC or metastasis in these patients. CONCLUSIONS:
      A history of cancer is an important predictor of the probability of malignancy in
      new SPNs. Metastases from previous cancer account for almost half of SPNs seen
      among patients in this subgroup. Diagnosis depends on the histology of previous
      malignancies, smoking history, age, and size of the SPN.

PMID- 15189940
TI  - Evolution of the postoperative pericardial effusion after day 15: the problem of
      the late tamponade.
AB  - STUDY OBJECTIVES: To evaluate, through clinical and transthoracic
      echocardiography (TTE) follow-up, the natural history of persistent pericardial
      effusion (PE) after postoperative day 15 in patients who were given and were not
      given anticoagulant therapy. DESIGN AND PATIENTS: We retrospectively studied a
      cohort of 1,277 patients who were hospitalized between May 1997 and May 1999 in
      our center a mean (+/- SD) time period of 15 +/- 3 days after undergoing coronary
      artery bypass graft (CABG) surgery (856 patients) or valve replacement (VR)
      surgery (421 patients). MEASUREMENTS: TTE was performed on mean (+/- SD)
      postoperative day 20 +/- 1 (TTE(1)) and postoperative day 30 +/- 2 (TTE(2)). PE
      severity was classified on a scale from grade 1 to grade 4. RESULTS: On
      postoperative day 20 +/- 1, PE was present in 22% of the 1,277 patients and was
      more frequent after patients underwent CABG surgery than after undergoing VR
      surgery (25% vs 17%, respectively; p < 0.01). On postoperative day 30 +/- 2, the
      overall incidence of late tamponade in patients with PE was 4%. The incidence
      increased with the severity grade of PE at TTE(1) (p < 0.001). The negative
      predictive value of a severity grade < 2 at TTE(1) for late tamponade was 100%.
      Late tamponade incidence was higher after VR surgery than after CABG surgery (11%
      vs 2%, respectively; p < 0.01), and was higher in patients who had received
      anticoagulation therapy than in those who had not (8% vs 2%, respectively; p <
      0.05). CONCLUSION: Persisting PE is common after postoperative day 15 and is more
      frequent after undergoing CABG surgery than after undergoing VR surgery. The
      incidence of late tamponade is usually underestimated, and it increases with the
      presence of VR, anticoagulation therapy, and/or higher postoperative TTE severity
      grade. Our data suggest that only patients with a PE severity grade of >/= 2 (<
      10% of patients) require TTE follow-up after postoperative day 20.

PMID- 15189941
TI  - Effect of lung volume reduction surgery on diaphragmatic neuromechanical coupling
      at 2 years.
AB  - STUDY OBJECTIVES: We previously reported that patients with emphysema show an
      increase in diaphragmatic neuromechanical coupling at 3 months after lung volume
      reduction surgery. Diaphragmatic neuromechanical coupling was quantified as the
      quotient of tidal volume (normalized to total lung capacity) to tidal change in
      transdiaphragmatic pressure (normalized to maximal transdiaphragmatic pressure).
      As such, neuromechanical coupling estimates the fraction of diaphragmatic
      capacity used to generate tidal breathing. The present investigation was
      conducted to determine whether benefit is maintained at 2 years. SUBJECTS:
      Fifteen patients with severe COPD, 8 of whom completed the 2-year study. METHODS:
      Lung volumes, exercise capacity (6-min walking distance), diaphragmatic function
      (maximal transdiaphragmatic pressure and twitch transdiaphragmatic pressure
      elicited by phrenic nerve stimulation), and diaphragmatic neuromechanical
      coupling were recorded before surgery, and at 3 months and 2 years after surgery.
      RESULTS: Two years after surgery, lung volumes deteriorated to preoperative
      values, but patients showed persistent improvements in 6-min walking distance (p
      < 0.05). Three months after surgery, maximal transdiaphragmatic pressure (p <
      0.05), twitch transdiaphragmatic pressure (p < 0.01), and diaphragmatic
      neuromechanical coupling (p < 0.01) had increased over preoperative values. The
      improvements in neuromechanical coupling resulted from improvements in
      diaphragmatic strength and, to a lesser extent, from a decrease in
      transdiaphragmatic pressure required to maintain tidal breathing. The change in
      respiratory muscle function at 2 years varied among patients: diaphragmatic
      contractility was > 10% of preoperative value in half of the patients who
      concluded our study, and neuromechanical coupling was > 10% of preoperative value
      in three fourths of the patients who concluded our study. Patients who maintained
      their gains in neuromechanical coupling also maintained their gains in 6-min
      walking distance. CONCLUSION: Patients undergoing lung volume reduction surgery
      can maintain early gains in neuromechanical coupling and exercise capacity 2
      years later.

PMID- 15189942
TI  - Neurological complications after coronary artery bypass grafting related to the
      performance of cardiopulmonary bypass.
AB  - STUDY OBJECTIVES: Neurologic disorders belong among the most serious
      complications of cardiac surgery. We tested the hypothesis that combinations of
      hemodynamic events from apparently normal cardiopulmonary bypass (CPB) procedures
      are related to the development of postoperative neurologic complications and
      affect the impact of common clinical risk factors. DESIGN: Retrospective study.
      SETTING: Cardiothoracic surgery department in a university hospital. METHODS AND
      PATIENTS: A multivariate statistical procedure (ie, cluster analysis) was applied
      to a data set of automatically recorded perfusions from 1,395 patients who had
      undergone coronary artery bypass grafting. One-way analysis of variance was used
      to select five parameters with the strongest significant correlation to
      postoperative neurologic complications for further cluster analysis. The
      dependencies in the clusters were tested against common clinical risk factors. To
      our knowledge, this is the first study of its kind. RESULTS: The following five
      parameters emerged for cluster analysis: mean arterial pressure (MAP); dispersion
      of MAP; dispersion of systemic vascular resistance; dispersion of arterial pulse
      pressure; and the maximum value of mixed venous saturation. Using these
      parameters, we found four clusters that were significantly different by CPB
      performance (first cluster, 389 patients; second cluster, 431 patients; third
      cluster; and fourth cluster, 229 patients). The frequency of postoperative
      neurologic complications was 0.3% in the first cluster and increased to 3.9% in
      the fourth cluster. Importantly, the impact of common clinical risk factors for
      postoperative neurologic complications was affected by the performance of the CPB
      procedure. For example, the frequency of neurologic complications among patients
      with cerebrovascular disease in their medical history was 22% in the fourth
      cluster, whereas it was zero in the second cluster. CONCLUSIONS: This study shows
      that apparently normal CPB procedures affect the impact of common clinical risk
      factors on postoperative neurologic complications. Patients who underwent CPB
      procedures with large fluctuations in hemodynamic parameters particularly showed
      an increased risk for the development of postoperative neurologic complications.

PMID- 15189943
TI  - Extended evaluation of recombinant human activated protein C United States Trial
      (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa
      (activated) in severe sepsis.
AB  - STUDY OBJECTIVE: To gather additional 28-day all-cause mortality and safety data
      among adult patients with severe sepsis who were treated with drotrecogin alfa
      (activated). DESIGN: Prospective, single-arm, multicenter clinical trial.
      SETTING: Eighty-five study sites in the United States and two in Puerto Rico.
      PARTICIPANTS: Adult patients (273 patients) with a diagnosis of severe sepsis,
      which was defined as a systemic inflammatory response due to acute infection and
      one or more sepsis-induced organ dysfunctions present for </= 48 h, as in the
      recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis
      (PROWESS) trial. INTERVENTIONS: Drotrecogin alfa (activated) [Xigris; Eli Lilly
      and Company; Indianapolis, IN], 24 micro g/kg/h, as a continuous IV infusion for
      a duration of 96 +/- 1 h. MEASUREMENTS AND RESULTS: The primary end point was all
      cause mortality, which was assessed 28 days after the start of the infusion of
      drotrecogin alfa (activated). Serious bleeding was monitored to day 28.
      Comparisons of mortality were made to treatment groups from two double-blind,
      placebo-controlled clinical trials (PROWESS United States and the Secretory
      Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly
      defined patient populations from the United States. For the 273 adult patients
      enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This
      mortality rate was 6% lower than that observed in the placebo groups in the
      PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of
      the group treated with drotrecogin alfa (activated) in the PROWESS US trial
      (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended
      Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE
      US) [0.35%]. Serious bleeding events during the infusion period occurred in 11
      patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa
      (activated) treatment group. CONCLUSIONS: Despite the limitations associated with
      comparisons across trials, this study provides confirmatory evidence of the
      efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS
      trial.

PMID- 15189944
TI  - Treatment of acute exacerbations of chronic respiratory failure: integrated use
      of negative pressure ventilation and noninvasive positive pressure ventilation.
AB  - STUDY OBJECTIVES: Acute respiratory failure (ARF) can be treated with either
      invasive mechanical ventilation (IMV) or noninvasive mechanical ventilation
      (NIMV), which can spare the complications of artificial airways. To evaluate the
      efficacy of an integrated approach using negative pressure ventilation (NPV) with
      iron lung and noninvasive positive pressure ventilation (NPPV), we performed a
      prospective study in a group of patients admitted to our respiratory ICU (RICU)
      for ARF due to exacerbation of chronic respiratory failure (CRF). SETTING: RICU
      at "R. Silvestrini" Hospital in Perugia, Italy. PATIENTS AND METHODS: One hundred
      fifty-two consecutive patients were included in the study and treated with iron
      lung as first choice or, when contraindicated or not tolerated, with NPPV using a
      nasal or facial mask. After 2 h of noninvasive mechanical ventilation (NIMV), the
      patients were reevaluated; in case of clinical deterioration, patients receiving
      NPV were switched to NPPV. When NPPV as a first or second line of treatment
      failed the patients were intubated. MEASUREMENTS AND RESULTS: One hundred fifty
      two patients received NIMV, 97 with iron lung as the first choice of treatment,
      and 55 with NPPV. Six patients treated with NPV were switched to NPPV during the
      first 2 h of treatment. Twenty-five patients required IMV. The success rate of
      the integrated use of NIMV (NPV plus NPPV) was 81.6%, compared to that of NPV
      (83.5%) and NPPV (70.5%). Twenty-one patients (13.8%) required tracheostomy; the
      duration of hospital stay was significantly lower in patients treated with NIMV
      only. Thirty patients required mechanical ventilation at home. Few severe
      complications were observed in patients receiving IMV. CONCLUSIONS: The
      integrated use of two NIMV techniques is effective in patients with acute
      exacerbation of CRF. In most cases intubation and tracheostomy were avoided, thus
      reducing the complication rate of mechanical ventilation.

PMID- 15189945
TI  - An educational intervention to reduce ventilator-associated pneumonia in an
      integrated health system: a comparison of effects.
AB  - STUDY OBJECTIVES: To determine whether an educational initiative could decrease
      rates of ventilator-associated pneumonia in a regional health-care system.
      SETTING: Two teaching hospitals (one adult, one pediatric) and two community
      hospitals in an integrated health system. DESIGN: Preintervention and
      postintervention observational study. PATIENTS: Patients admitted to the four
      participating hospitals between January 1, 1999, and June 30, 2002, who acquired
      ventilator-associated pneumonia. INTERVENTION: An educational program for
      respiratory care practitioners and ICU nurses emphasizing correct practices for
      the prevention of ventilator-associated pneumonia. The program included a self
      study module on risk factors for, and strategies to prevent, ventilator
      associated pneumonia and education-based in-services. Fact sheets and posters
      reinforcing the information were posted throughout the ICU and respiratory care
      departments. MEASUREMENTS AND RESULTS: Completion rates for the module were
      calculated by job title at each hospital. Rates of ventilator-associated
      pneumonia per 1,000 ventilator days were calculated for all hospitals combined
      and for each hospital separately. Overall 635 of 792 ICU nurses (80.1%) and 215
      of 239 respiratory therapists (89.9%) completed the study module. There were 874
      episodes of ventilator-associated pneumonia at the four hospitals during the 3.5
      year study period out of 129,527 ventilator days. Ventilator-associated pneumonia
      rates for all four hospitals combined dropped by 46%, from 8.75/1,000 ventilator
      days in the year prior to the intervention to 4.74/1,000 ventilator days in the
      18 months following the intervention (p < 0.001). Statistically significant
      decreased rates were observed at the pediatric hospital and at two of the three
      adult hospitals. No change in rates was seen at the community hospital with the
      lowest rate of study module completion among respiratory therapists (56%).
      CONCLUSIONS: Educational interventions can be associated with decreased rates of
      ventilator-associated pneumonia in the ICU setting. The involvement of
      respiratory therapy staff in addition to ICU nurses is important for the success
      of educational programs aimed at the prevention of ventilator-associated
      pneumonia.

PMID- 15189946
TI  - Association between the TNF-2 allele and a better survival in cardiogenic shock.
AB  - STUDY OBJECTIVES: Tumor necrosis factor (TNF)-alpha has been implicated in the
      pathophysiology of heart failure. We explored a possible association between TNF
      alpha, interleukin (IL)-6, IL-10, transforming growth factor (TGF)-beta, and
      interferon (IFN)-gamma cytokine polymorphisms, their in vivo production, and
      mortality from cardiogenic shock. DESIGN: Prospective, observational study.
      SETTING: Thirty-one bed, university, medicosurgical department of intensive care.
      PATIENTS: Thirty-three adult patients with cardiogenic shock of recent (< 4 h)
      onset. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: TNF-alpha, IL-6, IL-10, TGF
      beta1, and IFN-gamma plasma levels were measured by enzyme-linked immunosorbent
      assay. Polymorphisms of TNF-alpha within the promoter at position -308a-->g, IL-6
      within the promoter at position -174c-->g, IL-10 within the promoter at position 
      1082a-->g/-819t-->c and -819t-->c/-592a-->c, TGF-beta1 at codon 10t-->c and codon
      25c-->g, and IFN-gamma at intron 1 at position + 874t-->a were studied. The 33
      patients had a mean (+/- SD) age of 64 +/- 17 years and a mean simplified acute
      physiology score II of 62.3 +/- 15.3. Twenty-three patients (70%) died in the
      ICU, including 21 of 26 patients (81%) in the TNF-1 group but only 2 of 7
      patients (29%) in the TNF-2 group (p = 0.016). There were no significant
      differences in median plasma TNF-alpha levels between the TNF-1 and the TNF-2
      groups, but TGF-beta1 levels were higher in the survivors than in the
      nonsurvivors (median, 866 pg/mL; range, 384 to 1,966 pg/mL; vs median, 454 pg/mL;
      range, 167 to 1,266 pg/mL, respectively; p = 0.02). There were no significant
      differences in TNF-2 polymorphism between the patients with cardiogenic shock and
      a group of healthy control subjects (7 of 33 patients vs 13 of 48 subjects,
      respectively; p = 0.61), but IFN-gamma polymorphism was less common in the
      cardiogenic shock group (p = 0.034). CONCLUSIONS: Patients with the TNF-2 allele
      have no greater risk of cardiogenic shock but a better survival rate when it
      develops. Different genetic factors appear to influence the risk of development
      of, and outcome from, cardiogenic shock.

PMID- 15189947
TI  - Serum levels of the apoptosis-associated molecules, tumor necrosis factor
      alpha/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis.
AB  - STUDY OBJECTIVE: s: Numerous reports suggest that apoptosis may play an important
      role in the sepsis syndrome. The objective of the present study was to examine
      the levels of molecules associated with apoptosis belonging to the tumor necrosis
      factor (TNF)-alpha/TNF type-I receptor (TNFRI) and Fas ligand (FasL)/Fas receptor
      (Fas) pathways in patients with sepsis. PATIENTS AND METHODS: Twenty-two patients
      with sepsis (14 patients with severe sepsis and 8 patients with sepsis), and 6
      healthy volunteers were evaluated. Sequential analysis of the serum levels of TNF
      alpha, TNFRI, FasL, and Fas were performed in these patients using enzyme-linked
      immunosorbent assays. RESULTS: Detectable levels of TNF-alpha were found in only
      8 of 14 patients with severe sepsis. Patients with severe sepsis and sepsis had
      similarly increased levels of FasL, compared with healthy individuals (p < 0.05).
      Higher levels of TNFRI and Fas were found in patients with severe sepsis than in
      patients with sepsis and healthy volunteers (p < 0.001 and p < 0.01,
      respectively). Fas levels were also higher in patients who died than in those who
      survived (p < 0.01). A direct relationship was found between serum levels of
      TNFRI and Fas, and multiorgan dysfunction (sequential organ failure assessment
      score) [p < 0.0001]. CONCLUSIONS: These results suggest that the TNF-alpha/TNFRI
      and FasL/Fas systems may be involved in the pathogenesis of sepsis. Serum levels
      of the death-receptors, TNFRI and Fas, could serve as potential markers of the
      severity of human sepsis.

PMID- 15189948
TI  - Prolonged nitric oxide inhalation fails to regress hypoxic vascular remodeling in
      rat lung.
AB  - STUDY OBJECTIVE: The purpose of present study was to investigate whether long
      term nitric oxide (NO) inhalation during the recovery in air might improve the
      regression of chronic hypoxic pulmonary hypertension (PH) and vascular changes.
      MATERIALS AND METHODS: The rats were exposed to 10 ppm of NO in air for 10 days
      (n = 12) and 30 days (n = 4), or 40 ppm of NO in air for 10 days (n = 6) and 30
      days (n = 12) following 10 days of hypobaric hypoxia (380 mm Hg, 10% oxygen). For
      each NO group, air control rats following hypoxic exposure were studied at the
      same time (n = 13, 11, 9, and 11, respectively). Normal air rats (n = 6) without
      hypoxic exposure and rats (n = 7) following 10 days of hypoxic exposure were used
      as normal and chronic hypoxic control groups, respectively. Muscularization of
      normally nonmuscular peripheral arteries and medial hypertrophy of normally
      muscular arteries were assessed by light microscopy. An additional 16 rats were
      used to investigate the recovery of pulmonary artery pressure with (n = 8) and
      without NO inhalation (n = 8) after 10 days of hypobaric hypoxia. RESULTS: Long
      term hypoxia-induced PH, right ventricular hypertrophy (RVH), and hypertensive
      pulmonary vascular changes, each of which regressed partly after recovery in room
      air. There were no differences among rats with and without NO during each
      recovery period in RVH, medial wall thickness of muscular artery, and the
      percentages of muscularized arteries at the alveolar wall and duct levels.
      Continuous inhaled 40 ppm NO decreased pulmonary artery pressure from 40.1 +/-
      1.1 to 29.9 +/- 3.8 mm Hg (mean +/- SE) [n = 8], which was not different in the
      rats without NO inhalation (n = 8). Urine nitrate level was higher in rats that
      had inhaled NO. CONCLUSION: Continuous NO inhalation showed no effect on
      regression of pulmonary vascular remodeling in chronic hypoxic PH after returning
      to room air.

PMID- 15189949
TI  - Attenuation of reperfusion-induced systemic inflammation by preconditioning with
      nitric oxide in an in situ porcine model of normothermic lung ischemia.
AB  - STUDY OBJECTIVES: Inhalation of nitric oxide (NO) can ameliorate pulmonary
      ischemia/reperfusion (I/R) injury of the lung in several experimental models, but
      toxic effects of NO were also reported. Here we investigate whether NO inhalation
      for a short period prior to surgery is sufficient to prevent symptoms of lung I/R
      injury, especially the inflammatory response. DESIGN: Using an in situ porcine
      lung model, normothermic left lung ischemia was maintained for 90 min, followed
      by a 5-h reperfusion period (group 1, n = 7). In group 2 (n = 6), I/R was
      preceded by inhalation of NO (10 min, 15 ppm). Animals in group 3 (n = 7)
      underwent sham surgery without NO inhalation or ischemia. MEASUREMENTS:
      Oxygenation and hemodynamic parameters were measured as indicators of lung
      functional impairment. Plasma levels of interleukin (IL)-1beta, IL-6, and
      transforming growth factor (TGF)-beta1 were determined throughout the I/R
      maneuver. In addition, tissue macrophages were analyzed by lectin binding.
      RESULTS: Symptoms of I/R injury (pulmonary hypertension and decreased
      oxygenation) in group 1 animals were attenuated by NO inhalation. The reperfusion
      induced increases of the levels of IL-1beta and IL-6 in plasma were reduced by NO
      pretreatment. A peak of TGF-beta1 immediately after NO administration was
      observed in group 2, but not in groups 1 and 3. There was no significant effect
      of NO on tissue macrophages. CONCLUSION: NO inhalation for a short period prior
      to lung I/R is sufficient to protect against pulmonary hypertension, impaired
      oxygenation, and the inflammatory response of pulmonary I/R injury.

PMID- 15189950
TI  - Increasing renal blood flow: low-dose dopamine or medium-dose norepinephrine.
AB  - BACKGROUND AND OBJECTIVES: Many clinicians believe that low-dose dopamine (LDD)
      [2 micro g/kg/min] increases renal blood flow (RBF) and medium-dose
      norepinephrine (MD-NE) [0.4 micro g/kg/min] decreases RBF. They also believe that
      MD-NE might induce mesenteric and/or coronary ischemia. In fact, the effects of
      these drugs on renal and vital organ blood flow are poorly understood. The aim of
      this study was to compare the effects of 6 h of IV LDD and MD-NE infusion on
      mammalian renal, coronary, mesenteric, and sagittal blood flow. DESIGN:
      Randomized, controlled, experimental animal study. SETTING: Animal laboratory of
      tertiary physiology institute. SUBJECTS: Seven Merino cross sheep were studied.
      MEASUREMENTS AND RESULTS: We performed a staged insertion of transit-time flow
      probes around ascending aorta, sagittal sinus and circumflex coronary, superior
      mesenteric, and left renal arteries. We then randomized these animal with long
      term embedded flow probes to either 6 h of placebo (saline solution) or drugs (MD
      NE at 0.4 micro g/kg/min or LDD at 2 micro g/kg/min), and performed continuous
      measurement of systemic pressures, cardiac output (CO), and flow to vital organs.
      We also sampled blood and urine for the measurement of lactate, creatinine, and
      creatinine clearances at preset intervals. RESULTS: Compared to placebo, LDD did
      not affect systemic hemodynamics. However, it increased mean RBF by 20% (267.3 +/
      87.6 mL/min vs 222.0 +/- 74.4 mL/min, p = 0.028) without a detectable effect on
      other vital regional circulations. MD-NE, however, increased mean arterial
      pressure (101.0 +/- 8.3 mL/min vs 84.2 +/- 5.2 mL/min, p = 0.018) [mean +/- SD]
      and CO (4.93 +/- 1.45 L/min vs 3.81 +/- 0.57 L/min, p = 0.028). It also increased
      coronary blood flow (36.0 +/- 15.7 mL/min vs 23.0 +/- 10.7 mL/min, p = 0.018) and
      RBF (286.5 +/- 79.0 mL/min vs 222.0 +/- 74.4 mL/min, p = 0.018). MD-NE had no
      detectable effect on mesenteric or sagittal sinus flow. LDD infusion increased
      urine output, but did not change creatinine clearance. MD-NE infusion increased
      urine output significantly more than LDD but not creatinine clearance.
      CONCLUSIONS: Both LDD (2 micro g/kg/min) and MD-NE (0.4 micro g/kg/min) increased
      RBF and urine output. However, the effect of MD-NE was more pronounced. LDD did
      not affect other vital organ flows, but MD-NE increased coronary blood flow
      without any changes in mesenteric and sagittal sinus blood flow.

PMID- 15189951
TI  - Talc and silver nitrate induce systemic inflammatory effects during the acute
      phase of experimental pleurodesis in rabbits.
AB  - STUDY OBJECTIVE: s: To determine whether talc (TL) and silver nitrate (SN), two
      effective pleurodesis agents, induce a systemic inflammatory response in the
      acute phase of experimental pleurodesis in rabbits. DESIGN: Samples of blood and
      pleural fluid were collected after 6, 24, and 48 h from rabbits injected
      intrapleurally with 3 mL saline solution, TL (400 mg/kg), or 0.5% SN, and were
      assayed for WBC count, percentage of neutrophils, and levels of lactate
      dehydrogenase (LDH), interleukin (IL)-8, and vascular endothelial growth factor
      (VEGF). The pleural liquid production was compared in the three different groups.
      A sample of blood collected from animals preinjection was used as the control.
      RESULTS: At 6 h after pleural injection, the mean blood WBC count and percentage
      of neutrophils were significantly elevated in the TL group, whereas the mean LDH
      and IL-8 levels were significantly increased in the SN group. VEGF was
      undetectable in the preinjection serum and saline solution-injected animals, but
      was increased in the serum after the pleural injection of both TL and SN to a
      comparable degree. SN elicited a more intense acute pleural inflammation reaction
      than did TL, with higher WBC count and IL-8 levels found in the pleural fluid,
      mainly within the first 6 h. LDH and VEGF levels, and pleural liquid production
      were also higher for SN, and they increased with time. CONCLUSIONS: In the acute
      phase of pleural injection, TL induced a transient increase in blood WBC count
      and percentage of neutrophils, while SN induced increases in blood LDH and IL-8
      levels. Both TL and SN induced significant increases in blood VEGF levels. SN
      induced an earlier and more intense acute pleural inflammation than TL. Pleural
      liquid VEGF levels were higher after SN injection and increased, as did pleural
      liquid production. These findings suggest that the intrapleural injection of TL
      and SN produce a systemic inflammatory response that may have a role in the
      pathogenesis of fever and ARDS, which occur with pleurodesis.

PMID- 15189952
TI  - Identification of spontaneous feline idiopathic pulmonary fibrosis: morphology
      and ultrastructural evidence for a type II pneumocyte defect.
AB  - STUDY OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a poorly understood
      chronic respiratory disease of humans, which has no correlate in other animals.
      Understanding the role that inflammation, alveolar epithelial cells, and
      myofibroblasts play in the progression of the disease is controversial, and
      hampered by the lack of an animal model. We have identified spontaneous IPF in
      domestic cats and hypothesized that this newly identified disease shares the
      pathology of human IPF; further, this work provides data suggesting that the
      disease is related to a defect in type II pneumocyte biology. SETTING AND
      SUBJECTS: Chronic respiratory disease with pathology consistent with usual
      interstitial pneumonia (UIP) spontaneously developed in 16 domestic cats.
      RESULTS: The histopathology of feline IPF consisted of the following: (1)
      interstitial fibrosis with fibroblast/myofibroblast foci, (2) honeycombing with
      alveolar epithelial metaplasia and type II pneumocyte hyperplasia, and (3)
      alveolar interstitial smooth-muscle metaplasia. Interstitial inflammation was not
      a prominent feature of the disease. alpha-Smooth muscle actin-positive
      myofibroblasts were prominent in myofibroblast foci, beneath honeycomb and
      hyperplastic epithelium, and in alveolar septa away from the remodeling. Feline
      IPF type II pneumocyte ultrastructure is similar to a heritable form of human
      IPF, with abnormal cytoplasmic lamellar body-like inclusions. CONCLUSIONS: We
      conclude the following: (1) chronic respiratory disease with clinical and
      pathology features of UIP/IPF occurs in the domestic cat; (2) as in human IPF,
      the type II pneumocyte and myofibroblasts are important cellular constituents of
      feline IPF; and (3) type II cell ultrastructure suggests feline IPF is a defect
      in the type II pneumocyte.

PMID- 15189953
TI  - A new safe and stable spiral wire needle for thoracoscopic resection of lung
      nodules.
AB  - BACKGROUND: To show the safety and stability of a spiral wire needle (Somatex;
      Rietzneuendorf, Germany) in the detection and subsequent thoracoscopic resection
      of subpleural and/or small nodules of the lung. METHODS: Under local anesthesia
      and CT control, 13 patients underwent the positioning of a spiral wire needle
      into the lung, with the spiral located close to or inside the nodule to be
      resected. Then the patients underwent video-assisted thoracoscopic surgery
      resection of the nodules with only two thoracoscopic accesses. RESULTS: All the
      nodules were identified due to the precise location of the spiral wire needle.
      The presence of a stable spiral wire inside the parenchyma has allowed us to put
      under tension the overlying parenchyma, which had previously been excluded from
      ventilation. The external traction on the needle facilitates the detection of the
      nodule and simplifies thoracoscopic resection with a stapler. With this new tool,
      we have always reached an adequate diagnosis and observed no cases of dislodgment
      of the needle during the traction maneuvers, nor cases of conversion from
      thoracoscopy to thoracotomy. CONCLUSIONS: Although our initial experience is
      limited, the use of this spiral wire needle has been shown to be extremely
      advantageous in identifying subpleural and/or small nodules of the lung, even
      sparing the classic third thoracoscopic access for their resection. The presence
      of a wire needle with a spiral terminal portion (which is placed firmly inside
      the lung parenchyma) is very useful for the thoracoscopic resection of pulmonary
      nodules.

PMID- 15189954
TI  - Seeking a home for a PET, part 1: Defining the appropriate place for positron
      emission tomography imaging in the diagnosis of pulmonary nodules or masses.
AB  - There is a growing experience with positron emission tomography (PET) in patients
      with pulmonary nodules or masses. As PET imaging becomes more widely available,
      it is important to thoughtfully define when application of this technology is
      warranted. Review of the literature to date suggests that PET imaging for
      diagnosis of pulmonary lesions is most useful in patients who have a low or
      intermediate risk of lung cancer as determined by an evaluation of symptoms, risk
      factors, and radiographic appearance. There is little role for PET in diagnosis
      in patients with a very low or a high risk of lung cancer, and there is little
      role in patients with lesions < 1 cm in diameter, or lesions suspected to be an
      infection, a bronchioloalveolar carcinoma, or a typical carcinoid tumor.

PMID- 15189955
TI  - Seeking a home for a PET, part 2: Defining the appropriate place for positron
      emission tomography imaging in the staging of patients with suspected lung
      cancer.
AB  - In patients who have a high likelihood of having lung cancer, there is little
      role for positron emission tomography (PET) imaging for diagnosis of the primary
      lesion. The primary impact of PET imaging is in extrathoracic staging, but it
      should not replace a clinical evaluation by a physician experienced in lung
      cancer. PET imaging is most useful for confirmation of the presumed extrathoracic
      stage in patients with intermediate stages of lung cancer. The role of PET
      imaging is limited in patients with strong clinical signs of metastatic disease,
      or in patients with a clinical stage I lung cancer and a negative clinical
      evaluation. With regard to intrathoracic staging, PET imaging has a definite role
      in communities in which mediastinoscopy is not available, whereas the impact is
      limited in institutions in which invasive mediastinal staging is available. The
      data suggest that a positive PET result in the mediastinum should be confirmed by
      biopsy. A mediastinoscopy is also reasonable in patients with clinical stage III
      lung cancer who have no mediastinal PET uptake. It is unclear and controversial
      whether a biopsy is needed in patients with clinical stage II lung cancer who
      have no PET uptake in the mediastinum.

PMID- 15189956
TI  - Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta
      analysis.
AB  - BACKGROUND: beta-Adrenergic agonists exert physiologic effects that are the
      opposite of those of beta-blockers. beta-Blockers are known to reduce morbidity
      and mortality in patients with cardiac disease. beta(2)-Agonist use in patients
      with obstructive airway disease has been associated with an increased risk for
      myocardial infarction, congestive heart failure, cardiac arrest, and acute
      cardiac death. OBJECTIVES: To assess the cardiovascular safety of beta(2)-agonist
      use in patients with obstructive airway disease, defined as asthma or COPD.
      METHODS: A meta-analysis of randomized placebo-controlled trials of beta(2)
      agonist treatment in patients with obstructive airway disease was performed, to
      evaluate the short-term effect on heart rate and potassium concentrations, and
      the long-term effect on adverse cardiovascular events. Longer duration trials
      were included in the analysis if they reported at least one adverse event.
      Adverse events included sinus and ventricular tachycardia, syncope, atrial
      fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or
      sudden death. RESULTS: Thirteen single-dose trials and 20 longer duration trials
      were included in the study. A single dose of beta(2)-agonist increased the heart
      rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced
      the potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54), compared to
      placebo. For trials lasting from 3 days to 1 year, beta(2)-agonist treatment
      significantly increased the risk for a cardiovascular event (relative risk [RR],
      2.54; 95% CI, 1.59 to 4.05) compared to placebo. The RR for sinus tachycardia
      alone was 3.06 (95% CI, 1.70 to 5.50), and for all other events it was 1.66 (95%
      CI, 0.76 to 3.6). CONCLUSION: beta(2)-Agonist use in patients with obstructive
      airway disease increases the risk for adverse cardiovascular events. The
      initiation of treatment increases heart rate and reduces potassium concentrations
      compared to placebo. It could be through these mechanisms, and other effects of
      beta-adrenergic stimulation, that beta(2)-agonists may precipitate ischemia,
      congestive heart failure, arrhythmias, and sudden death.

PMID- 15189957
TI  - A 50-year-old man with skin lesions and multiple pulmonary nodules.

PMID- 15189958
TI  - Effect of ozone exposure on airway responses to inhaled allergen in asthmatic
      subjects.
AB  - BACKGROUND: Controlled human exposure studies have produced conflicting results
      regarding the effect of ozone on the early bronchoconstrictor response to inhaled
      allergen in specifically sensitized asthmatic subjects. Spirometric parameters do
      not necessarily reflect the airway inflammatory effects of inhaled ozone or
      allergen. OBJECTIVE: This study was designed to investigate whether exposure to
      ozone enhances the late airway inflammatory response, as well as the early
      bronchoconstrictor response, to inhaled house dust mite allergen in sensitized
      asthmatic subjects. DESIGN: Randomized, counter-balanced, cross-over study.
      SETTING: Human exposure laboratory. METHODS: Fourteen subjects were exposed to
      0.2 ppm O(3) or filtered air, on separate days, for 1 h during exercise. After
      each exposure, the subjects were challenged with doubling doses of
      Dermatophagoides farinae (DF) allergen (provocative concentration of DF causing a
      15% decrease in FEV(1) [PC(15)]). At 6 h after allergen challenge, bronchoscopy
      with BAL, proximal airway lavage (PAL), and endobronchial biopsy were performed.
      The second exposure/allergen challenge/bronchoscopy sequence was performed at
      least 4 weeks after the first sequence. RESULTS: No significant difference in
      cellular or biochemical markers of the late inflammatory response after allergen
      was found between the ozone and air exposures (although a trend toward increased
      neutrophils was noted after ozone exposure in the PAL fluid, p = 0.06). For the
      group as a whole, no significant difference in PC(15) was demonstrated after
      ozone exposure compared to air exposure. However, subjects with the greatest
      ozone-induced decrements in FEV(1) tended to have lower PC(15) values after ozone
      exposure. CONCLUSION: Exposure to a relatively low-level concentration of ozone
      does not enhance the late inflammatory or early bronchoconstrictor response to
      inhaled antigen in most allergic asthmatic subjects. Our results do suggest,
      however, that a subgroup of asthmatics may acquire increased sensitivity to
      aeroallergens after exposure to ozone.

PMID- 15189959
TI  - Work-related asthma-like symptoms among florists.
AB  - OBJECTIVES: In this study, we evaluated the prevalence of work-related asthma
      like symptoms and possible risk factors among florists in Turkey. METHODS: We
      collected questionnaire data from 128 florists, and investigated occupational
      history and respiratory, ocular, dermal, and nasal symptoms. We evaluated
      pulmonary function tests with spirometry and atopy by using the skin-prick test.
      Possible risk factors were analyzed by age-adjusted, smoking-adjusted, and gender
      adjusted logistic regression models comparing symptomatic and asymptomatic
      individuals. RESULTS: The prevalence of work-related asthma-like symptoms was
      14.1% (18 patients). We observed excess risk with a high work intensity (odds
      ratio [OR], 7.3; 95% confidence interval [CI], 1.1 to 51.8) and long work
      duration (OR, 5.1; 95% CI, 1.2 to 21.6). Florists with work-related asthma-like
      symptoms were 5.9 times more likely (95% CI, 1.4 to 24.3) to have a positive skin
      test response to a flower mix allergen. We also observed an excess risk for work
      related asthma-like symptoms among those with allergic rhinitis (OR, 13.2; 95%
      CI, 3.1 to 56.4) and conjunctivitis (OR, 8.4; 95% CI, 2.4 to 29.2). CONCLUSION:
      The most prominent risk factors in florists were work intensity, work duration,
      and specific atopy.

PMID- 15189960
TI  - A 44-year-old man with suspected exacerbation of COPD and atrial fibrillation.

PMID- 15189961
TI  - Severe acute respiratory syndrome complicated by spontaneous pneumothorax.
AB  - Severe acute respiratory syndrome (SARS) presents an unprecedented diagnostic and
      therapeutic challenge to clinicians. Despite recent progress in identifying and
      analyzing the coronavirus that is responsible for it, few reports have addressed
      the clinical complications of SARS. The present study was a two-center
      retrospective cohort study. All patients in the study had SARS, were managed in
      the two major Hong Kong hospitals (ie, Prince of Wales Hospital and United
      Christian Hospital), and had developed spontaneous pneumothorax during their
      hospitalization between March 10, 2003, and April 28, 2003. Spontaneous
      pneumothorax was reported in 6 of 356 SARS patients who were treated at the two
      hospitals during the period. This represents an incidence of 1.7%. None of the
      six patients had a history of smoking or pulmonary disease. The rate of admission
      to the ICU was 66.7% and the crude mortality rate was 33.3% in this group of
      patients. There was a trend for the mean neutrophil count in these patients to be
      higher than in previously reported cohorts of comparable SARS patients (14.5 x
      10(9) vs 4.6 x 10(9) neutrophils per liter, respectively). Conservative measures
      like tube thoracostomy or observation alone offered satisfactory initial
      symptomatic management in five of six patients. Spontaneous pneumothorax is a
      specific and potentially life-threatening complication in SARS patients. Patients
      with extensive lung injury, as indicated by severe clinical courses, and in
      particular high neutrophil counts, appear to be most at risk. The benefits of
      surgical management must be balanced against the potential risks to health-care
      workers.

PMID- 15189962
TI  - Enhanced alveolar clearance with chest percussion therapy and positional changes
      during whole-lung lavage for alveolar proteinosis.
AB  - Pulmonary alveolar proteinosis has traditionally been treated with whole-lung
      lavage (WLL). The literature describes a variety of techniques used in performing
      the WLL, including mechanical vs manual chest percussion, use of prone
      positioning, and variances in lavage volume. We have quantified and compared the
      effective alveolar clearance for each component of the lavage by measuring the
      dry weight of material in the lavage effluent. We measured this in five patients
      who underwent six consecutive WLLs at the University of Pittsburgh Medical
      Center. We performed the lavage in the following three stages: stage I, passive
      drainage; stage II, assisted clearance; and stage III, positional clearance.
      Aliquots of lavage effluent were centrifuged to determine the dry weight of
      material present in sequentially recorded bottles within each stage. At the
      initiation of each augmentation, there was a statistically significant
      improvement in the clearance of material (stage II, p = 0.009; stage III, p =
      0.012). Furthermore, we show that lipoproteinaceous material is present in the
      lavage effluent in all stages of latter portions of the lavage. The effective
      removal of material would be expected to have an impact on the physiologic and
      clinical response to WLL. This finding emphasizes the importance of performing an
      adequate and standardized lavage.

PMID- 15189963
TI  - Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis.
AB  - BACKGROUND: Talc pleurodesis is widely performed for the management of persistent
      pneumothorax or pleural effusion, particularly malignant effusions. However,
      there are very few data characterizing fluorodeoxyglucose (FDG)-positron emission
      tomography (PET) and CT findings after treatment. METHODS: We retrospectively
      evaluated the FDG-PET and CT studies of nine patients who underwent talc
      pleurodesis for the treatment of malignant pleural effusions or persistent air
      leak. RESULTS: FDG-PET studies were performed on average 22 months after talc
      pleurodesis, and the mean CT follow-up period was 25 months. There was moderate
      to-intense plaque-like or focal nodular-increased FDG uptake in the pleura on PET
      with mean standardized uptake value of 5.4 (SEM, 1.2; range, 2.0 to 16.3). The
      FDG uptake was either diffuse (two patients) or focal (seven patients), and most
      commonly occurred in the posterior costophrenic angles (five patients), followed
      by the apical regions (three patients), anterior costophrenic angle (one
      patient), and the anterior chest wall (one patient). On CT, high-density areas of
      pleural thickening or nodularity (mean, 230 Hounsfield units [HU]; SEM, 23 HU;
      range, 140 to 380 HU) corresponded to regions of increased FDG uptake. These
      pleural foci had an average thickness of 1.2 cm and measured up to 8.2 cm (mean,
      7.1 cm) in length. Rounded pleural nodules were as large as 3.1 cm (mean, 1.5
      cm). CONCLUSIONS: Talc pleurodesis produces increased FDG uptake on PET and high
      density areas of pleural thickening on CT that remain unchanged on serial
      imaging. When PET detects increased uptake in the pleural space, correlation with
      CT is recommended to detect the presence of pleural thickening of increased
      attenuation that suggests talc deposits rather than tumor.

PMID- 15189964
TI  - Further insights into the prothrombotic state in mitral stenosis and atrial
      flutter.

PMID- 15189965
TI  - Adenotonsillectomy and sleep apnea in children.

PMID- 15189966
TI  - Statin, inflammation, and sepsis.

PMID- 15189967
TI  - Diagnosing pleural tuberculosis.

PMID- 15189968
TI  - Informed consent.

PMID- 15189969
TI  - PET scanning in thymic neuroendocrine tumors.

PMID- 15189970
TI  - Withdrawal of treatment in the ISOLDE study.

PMID- 15189971
TI  - Blood and starch in cardiac surgery.

PMID- 15189972
TI  - Unresolved questions with the use of linezolid vs vancomycin for nosocomial
      pneumonia.

PMID- 15189975
TI  - Abnormal glucose homeostasis due to chronic hyperresistinemia.
AB  - Resistin is an adipocyte-secreted protein that circulates at increased levels in
      obesity. Acute administration of resistin impairs glucose tolerance, but the
      effects of chronic hyperresistinemia have not been established. Here we describe
      the generation and characterization of transgenic mice that have high circulating
      levels of resistin in the setting of normal weight. Fasted blood glucose was
      higher in resistin-transgenic mice than in their nontransgenic littermates, and
      glucose tolerance was impaired in the hyperresistinemic mice. Metabolic studies
      in the setting of a hyperinsulinemic-euglycemic clamp protocol revealed that
      chronically hyperresistinemic mice have elevated glucose production. This
      increase in glucose production may be partly explained by increased expression of
      hepatic phosphoenolpyruvate carboxykinase. Thus, chronic hyperresistinemia
      impairs normal glucose metabolism.

PMID- 15189979
TI  - Evidence that hsp90 is involved in the altered interactions of Acanthamoeba
      castellanii variants with bacteria.
AB  - There are many similarities between the interactions of environmental protozoa
      with pathogenic bacterial species and those observed in mammalian macrophages.
      Since single-celled protozoa predate mammalian hosts, it is likely that
      interactions in environmental biofilms have selected for many of the bacterial
      virulence mechanisms responsible for human disease. In order to better understand
      bacterial-phagocyte interactions, we developed a selection for Acanthamoeba
      castellanii variants that are more resistant to killing by bacterial pathogens.
      We identified four amoebal clones that display decreased phagocytosis of bacteria
      but no difference in uptake of latex beads compared to wild-type amoebae. These
      amoebal variants display differences in cellular morphology, partial resistance
      to killing by bacteria, more bactericidal activity, and higher frequencies of
      lysosome fusion with the bacterial vacuole. Three proteins are present at lower
      levels in these variants than in wild-type amoebae, and matrix-assisted laser
      desorption ionization-time of flight mass spectrometry allowed identification of
      two of them as actin and hsp90. We found that specific inhibitors of hsp90
      produce a similar phenotypic effect in macrophages. These data suggest that hsp90
      plays a role in phagocytic and, possibly, bactericidal pathways that affect
      interactions of phagocytic cells with bacteria.

PMID- 15189980
TI  - Novel promoter sequence required for manganese regulation of manganese peroxidase
      isozyme 1 gene expression in Phanerochaete chrysosporium.
AB  - Manganese peroxidase (MnP) is a major, extracellular component of the lignin
      degrading system produced by the wood-rotting basidiomycetous fungus
      Phanerochaete chrysosporium. The transcription of MnP-encoding genes (mnps) in P.
      chrysosporium occurs as a secondary metabolic event, triggered by nutrient
      nitrogen limitation. In addition, mnp expression occurs only under Mn2+
      supplementation. Using a reporter system based on the enhanced green fluorescent
      protein gene (egfp), we have characterized the P. chrysosporium mnp1 promoter by
      examining the effects of deletion, replacement, and translocation mutations on
      mnp1 promoter-directed egfp expression. The 1,528-bp mnp1 promoter fragment
      drives egfp expression only under Mn2+-sufficient, nitrogen-limiting conditions,
      as required for endogenous MnP production. However, deletion of a 48-bp fragment,
      residing 521 bp upstream of the translation start codon in the mnp1 promoter, or
      replacement of this fragment with an unrelated sequence resulted in egfp
      expression under nitrogen limitation, both in the absence and presence of
      exogenous Mn2+. Translocation of the 48-bp fragment to a site 120 bp downstream
      of its original location resulted in Mn2+-dependent egfp expression under
      conditions similar to those observed with the wild-type mnp1 promoter. These
      results suggest that the 48-bp fragment contains at least one Mn2+-responsive cis
      element. Additional promoter-deletion experiments suggested that the Mn2+
      element(s) is located within the 33-bp sequence at the 3' end of the 48-bp
      fragment. This is the first promoter sequence containing a Mn2+-responsive
      element(s) to be characterized in any eukaryotic organism.

PMID- 15189981
TI  - The deletion of the succinate dehydrogenase gene KlSDH1 in Kluyveromyces lactis
      does not lead to respiratory deficiency.
AB  - We have isolated a Kluyveromyces lactis mutant unable to grow on all respiratory
      carbon sources with the exception of lactate. Functional complementation of this
      mutant led to the isolation of KlSDH1, the gene encoding the flavoprotein subunit
      of the succinate dehydrogenase (SDH) complex, which is essential for the aerobic
      utilization of carbon sources. Despite the high sequence conservation of the SDH
      genes in Saccharomyces cerevisiae and K. lactis, they do not have the same
      relevance in the metabolism of the two yeasts. In fact, unlike SDH1, KlSDH1 was
      highly expressed under both fermentative and nonfermentative conditions. In
      addition to this, but in contrast with S. cerevisiae, K. lactis strains lacking
      KlSDH1 were still able to grow in the presence of lactate. In these mutants,
      oxygen consumption was one-eighth that of the wild type in the presence of
      lactate and was normal with glucose and ethanol, indicating that the respiratory
      chain was fully functional. Northern analysis suggested that alternative
      pathway(s), which involves pyruvate decarboxylase and the glyoxylate cycle, could
      overcome the absence of SDH and allow (i) lactate utilization and (ii) the
      accumulation of succinate instead of ethanol during growth on glucose.

PMID- 15189982
TI  - The signal from the initiation of meiotic recombination to the first division of
      meiosis.
AB  - Two of the unique events that occur in meiosis are high levels of genetic
      recombination and the reductional division. Our previous work demonstrated that
      the REC102, REC104, REC114, and RAD50 genes, required to initiate meiotic
      recombination in Saccharomyces cerevisiae, are needed for the proper timing of
      the first meiotic (MI) division. If these genes are absent, the MI division
      actually begins at an earlier time. This paper demonstrates that the meiotic
      recombination genes MER2/REC107, SPO11, and MRE2 and the synaptonemal complex
      genes HOP1 and RED1 are also required for the normal delay of the MI division. A
      rec103/ski8 mutant starts the MI division at the same time as in wild-type cells.
      Our data indicate no obvious correlation between the timing of premeiotic S phase
      and the timing of the first division in Rec- mutants. Cells with rec102 or rec104
      mutations form MI spindles before wild-type cells, suggesting that the initiation
      signal acts prior to spindle formation. Neither RAD9 nor RAD24 is needed to
      transduce the signal, which delays the first division. The timing of the MI
      division in RAD24 mutants indicates that the pachytene checkpoint is not active
      in Rec+ cells and suggests that the coordination between recombination and the MI
      division in wild-type cells may occur primarily due to the initiation signal.
      Finally, at least one of the targets of the recombination initiation signal is
      the NDT80 gene, a transcriptional regulator of middle meiotic gene expression
      required for the first division.

PMID- 15189983
TI  - Suppressors of an adenylate cyclase deletion in the fission yeast
      Schizosaccharomyces pombe.
AB  - Schizosaccharomyces pombe utilizes two opposing signaling pathways to sense and
      respond to its nutritional environment. Glucose detection triggers a cyclic AMP
      signal to activate protein kinase A (PKA), while glucose or nitrogen starvation
      activates the Spc1/Sty1 stress-activated protein kinase (SAPK). One process
      controlled by these pathways is fbp1+ transcription, which is glucose repressed.
      In this study, we isolated strains carrying mutations that reduce high-level
      fbp1+ transcription conferred by the loss of adenylate cyclase (git2delta),
      including both wis1- (SAPK kinase) and spc1- (SAPK) mutants. While characterizing
      the git2delta suppressor strains, we found that the git2delta parental strains
      are KCl sensitive, though not osmotically sensitive. Of 102 git2delta suppressor
      strains, 17 strains display KCl-resistant growth and comprise a single linkage
      group, carrying mutations in the cgs1+ PKA regulatory subunit gene. Surprisingly,
      some of these mutants are mostly wild type for mating and stationary-phase
      viability, unlike the previously characterized cgs1-1 mutant, while showing a
      significant defect in fbp1-lacZ expression. Thus, certain cgs1- mutant alleles
      dramatically affect some PKA-regulated processes while having little effect on
      others. We demonstrate that the PKA and SAPK pathways regulate both cgs1+ and
      pka1+ transcription, providing a mechanism for cross talk between these two
      antagonistically acting pathways and feedback regulation of the PKA pathway.
      Finally, strains defective in both the PKA and SAPK pathways display
      transcriptional regulation of cgs1+ and pka1+, suggesting the presence of a third
      glucose-responsive signaling pathway.

PMID- 15189984
TI  - SYM1 is the stress-induced Saccharomyces cerevisiae ortholog of the mammalian
      kidney disease gene Mpv17 and is required for ethanol metabolism and tolerance
      during heat shock.
AB  - Organisms rapidly adapt to severe environmental stress by inducing the expression
      of a wide array of heat shock proteins as part of a larger cellular response
      program. We have used a genomics approach to identify novel heat shock-induced
      genes in Saccharomyces cerevisiae. The uncharacterized open reading frame (ORF)
      YLR251W was found to be required for both metabolism and tolerance of ethanol
      during heat shock. YLR251W has significant homology to the mammalian peroxisomal
      membrane protein Mpv17, and Mpv17(-/-) mice exhibit age-onset glomerulosclerosis,
      deafness, hypertension, and, ultimately, death by renal failure. Expression of
      Mpv17 in ylr251wdelta cells complements the 37 degrees C ethanol growth defect,
      suggesting that these proteins are functional orthologs. We have therefore
      renamed ORF YLR251W as SYM1 (for "stress-inducible yeast Mpv17"). In contrast to
      the peroxisomal localization of Mpv17, we find that Sym1 is an integral membrane
      protein of the inner mitochondrial membrane. In addition, transcriptional
      profiling of sym1delta cells uncovered changes in gene expression, including
      dysregulation of a number of ethanol-repressed genes, exclusively at 37 degrees C
      relative to wild-type results. Together, these data suggest an important
      metabolic role for Sym1 in mitochondrial function during heat shock. Furthermore,
      this study establishes Sym1 as a potential model for understanding the role of
      Mpv17 in kidney disease and cardiovascular biology.

PMID- 15189985
TI  - The Kip3-like kinesin KipB moves along microtubules and determines spindle
      position during synchronized mitoses in Aspergillus nidulans hyphae.
AB  - Kinesins are motor proteins which are classified into 11 different families. We
      identified 11 kinesin-like proteins in the genome of the filamentous fungus
      Aspergillus nidulans. Relatedness analyses based on the motor domains grouped
      them into nine families. In this paper, we characterize KipB as a member of the
      Kip3 family of microtubule depolymerases. The closest homologues of KipB are
      Saccharomyces cerevisiae Kip3 and Schizosaccharomyces pombe Klp5 and Klp6, but
      sequence similarities outside the motor domain are very low. A disruption of kipB
      demonstrated that it is not essential for vegetative growth. kipB mutant strains
      were resistant to high concentrations of the microtubule-destabilizing drug
      benomyl, suggesting that KipB destabilizes microtubules. kipB mutations caused a
      failure of spindle positioning in the cell, a delay in mitotic progression, an
      increased number of bent mitotic spindles, and a decrease in the depolymerization
      of cytoplasmic microtubules during interphase and mitosis. Meiosis and ascospore
      formation were not affected. Disruption of the kipB gene was synthetically lethal
      in combination with the temperature-sensitive mitotic kinesin motor mutation
      bimC4, suggesting an important but redundant role of KipB in mitosis. KipB
      localized to cytoplasmic, astral, and mitotic microtubules in a discontinuous
      pattern, and spots of green fluorescent protein moved along microtubules toward
      the plus ends.

PMID- 15189986
TI  - RasC plays a role in transduction of temporal gradient information in the cyclic
      AMP wave of Dictyostelium discoideum.
AB  - To define the role that RasC plays in motility and chemotaxis, the behavior of a
      rasC null mutant, rasC-, in buffer and in response to the individual spatial,
      temporal, and concentration components of a natural cyclic AMP (cAMP) wave was
      analyzed by using computer-assisted two-dimensional and three-dimensional motion
      analysis systems. These quantitative studies revealed that rasC- cells
      translocate at the same velocity and exhibit chemotaxis up spatial gradients of
      cAMP with the same efficiency as control cells. However, rasC- cells exhibit
      defects in maintaining anterior-posterior polarity along the substratum and a
      single anterior pseudopod when translocating in buffer in the absence of an
      attractant. rasC- cells also exhibit defects in their responses to both the
      increasing and decreasing temporal gradients of cAMP in the front and the back of
      a wave. These defects result in the inability of rasC- cells to exhibit
      chemotaxis in a natural wave of cAMP. The inability to respond normally to
      temporal gradients of cAMP results in defects in the organization of the
      cytoskeleton, most notably in the failure of both F actin and myosin II to exit
      the cortex in response to the decreasing temporal gradient of cAMP in the back of
      the wave. While the behavioral defect in the front of the wave is similar to that
      of the myoA-/myoF- myosin I double mutant, the behavioral and cytoskeletal
      defects in the back of the wave are similar to those of the S13A myosin II
      regulatory light-chain phosphorylation mutant. Expression array data support the
      premise that the behavioral defects exhibited by the rasC- mutant are the
      immediate result of the absence of RasC function.

PMID- 15189987
TI  - Multiple functionally redundant signals mediate targeting to the apicoplast in
      the apicomplexan parasite Toxoplasma gondii.
AB  - Most species of the protozoan phylum Apicomplexa harbor an endosymbiotic
      organelle--the apicoplast--acquired when an ancestral parasite engulfed a
      eukaryotic plastid-containing alga. Several hundred proteins are encoded in the
      parasite nucleus and are posttranslationally targeted to the apicoplast by a
      distinctive bipartite signal. The N-terminal 20 to 30 amino acids of nucleus
      encoded apicoplast targeted proteins function as a classical signal sequence,
      mediating entry into the secretory pathway. Cleavage of the signal sequence
      exposes a transit peptide of variable length (50 to 200 amino acids) that is
      required for directing proteins to the apicoplast. Although these peptides are
      enriched in basic amino acids, their structural and functional characteristics
      are not well understood, which hampers the identification of apicoplast proteins
      that may constitute novel chemotherapeutic targets. To identify functional
      domains for a model apicoplast transit peptide, we generated more than 80
      deletions and mutations throughout the transit peptide of Toxoplasma gondii
      ferredoxin NADP+ reductase (TgFNR) and examined the ability of these altered
      transit peptides to mediate proper targeting and processing of a fluorescent
      protein reporter. These studies revealed the presence of numerous functional
      domains. Processing can take place at multiple sites in the protein sequence and
      may occur outside of the apicoplast lumen. The TgFNR transit peptide contains at
      least two independent and functionally redundant targeting signals, each of which
      contains a subdomain that is required for release from or proper sorting within
      the endoplasmic reticulum. Certain deletion constructs traffic to multiple
      locations, including the apicoplast periphery, the rhoptries, and the
      parasitophorous vacuole, suggesting a common thread for targeting to these
      specialized compartments.

PMID- 15189988
TI  - Lipid raft polarization contributes to hyphal growth in Candida albicans.
AB  - The polarization of sterol- and sphingolipid-enriched domains (lipid rafts) has
      been linked to morphogenesis and cell movement in diverse cell types. In the
      yeast Saccharomyces cerevisiae, a dramatic polarization of sterol-rich domains to
      the shmoo tip was observed in pheromone-induced cells (M. Bagnat and K. Simons,
      Proc. Natl. Acad. Sci. USA 99:14183-14188, 2002). We therefore examined whether
      plasma membrane lipid polarization contributes to the ability of the fungal
      pathogen Candida albicans to grow in a highly polarized manner to form hyphae.
      Interestingly, staining with filipin revealed that membrane sterols were highly
      polarized to the leading edge of growth during all stages of hyphal growth.
      Budding and pseudohyphal cells did not display polarized staining. Filipin
      staining was also enriched at septation sites in hyphae, where colocalization
      with septin proteins was observed, suggesting a role for the septins in forming a
      boundary domain. Actin appeared to play a role in sterol polarization and hyphal
      morphogenesis in that both were disrupted by low concentrations of latrunculin A
      that did not prevent budding. Furthermore, blocking either sphingolipid
      biosynthesis with myriocin or sterol biosynthesis with ketoconazole resulted in a
      loss of ergosterol polarization and caused abnormal hyphal morphogenesis,
      suggesting that lipid rafts are involved. Since hyphal growth is required for the
      full virulence of C. albicans, these results suggest that membrane polarization
      may contribute to the pathogenesis of this organism.

PMID- 15189989
TI  - Homing endonucleases encoded by germ line-limited genes in Tetrahymena
      thermophila have APETELA2 DNA binding domains.
AB  - Three insertion elements were previously found in a family of germ line-limited
      mobile elements, the Tlr elements, in the ciliate Tetrahymena. Each of the
      insertions contains an open reading frame (ORF). Sequence analysis of the deduced
      proteins encoded by the elements suggests that they are homing endonucleases. The
      genes are designated TIE1-1, TIE2-1, and TIE3-1 for Tetrahymena insertion-homing
      endonuclease. The endonuclease motif occupies the amino terminal half of each TIE
      protein. The C-terminal regions of the proteins are similar to the APETELA2 DNA
      binding domain of plant transcription factors. The TIE1 and TIE3 elements belong
      to families of repeated sequences in the germ line micronuclear genome.
      Comparison of the genes and the deduced proteins they encode suggests that there
      are at least two distinct families of homing endonuclease genes, each of which
      appears to be preferentially associated with a specific region of the Tlr
      elements. The TIE1 and TIE3 elements and their cognates undergo programmed
      elimination from the developing somatic macronucleus of Tetrahymena. The possible
      role of homing endonuclease-like genes in the DNA breakage step in
      developmentally programmed DNA elimination in Tetrahymena is discussed.

PMID- 15189990
TI  - Hph1p and Hph2p, novel components of calcineurin-mediated stress responses in
      Saccharomyces cerevisiae.
AB  - Calcineurin is a Ca2+- and calmodulin-dependent protein phosphatase that plays a
      key role in animal and yeast physiology. In the yeast Saccharomyces cerevisiae,
      calcineurin is required for survival during several environmental stresses,
      including high concentrations of Na+, Li+, and Mn2+ ions and alkaline pH. One
      role of calcineurin under these conditions is to activate gene expression through
      its regulation of the Crz1p transcription factor. We have identified Hph1p as a
      novel substrate of calcineurin. HPH1 (YOR324C) and its homolog HPH2 (YAL028W)
      encode tail-anchored integral membrane proteins that interact with each other in
      the yeast two-hybrid assay and colocalize to the endoplasmic reticulum. Hph1p and
      Hph2p serve redundant roles in promoting growth under conditions of high
      salinity, alkaline pH, and cell wall stress. Calcineurin modifies the
      distribution of Hph1p within the endoplasmic reticulum and is required for full
      Hph1p activity in vivo. Furthermore, calcineurin directly dephosphorylates Hph1p
      and interacts with it through a sequence motif in Hph1p, PVIAVN. This motif is
      related to calcineurin docking sites in other substrates, such as NFAT and Crz1p,
      and is required for regulation of Hph1p by calcineurin. In contrast, Hph2p
      neither interacts with nor is dephosphorylated by calcineurin. Ca2+-induced Crz1p
      mediated transcription is unaffected in hph1delta hph2delta mutants, and genetic
      analyses indicate that HPH1/HPH2 and CRZ1 act in distinct pathways downstream of
      calcineurin. Thus, Hph1p and Hph2p are components of a novel Ca2+- and
      calcineurin-regulated response required to promote growth under conditions of
      high Na+, alkaline pH, and cell wall stress.

PMID- 15189991
TI  - Genome-wide single-nucleotide polymorphism map for Candida albicans.
AB  - Single-nucleotide polymorphisms (SNPs) are essential tools for studying a variety
      of organismal properties and processes, such as recombination, chromosomal
      dynamics, and genome rearrangement. This paper describes the development of a
      genome-wide SNP map for Candida albicans to study mitotic recombination and
      chromosome loss. C. albicans is a diploid yeast which propagates primarily by
      clonal mitotic division. It is the leading fungal pathogen that causes infections
      in humans, ranging from mild superficial lesions in healthy individuals to
      severe, life-threatening diseases in patients with suppressed immune systems. The
      SNP map contains 150 marker sequences comprising 561 SNPs and 9 insertions
      deletions. Of the 561 SNPs, 437 were transition events while 126 were
      transversion events, yielding a transition-to-transversion ratio of 3:1, as
      expected for a neutral accumulation of mutations. The average SNP frequency for
      our data set was 1 SNP per 83 bp. The map has one marker placed every 111 kb, on
      average, across the 16-Mb genome. For marker sequences located partially or
      completely within coding regions, most contained one or more nonsynonymous
      substitutions. Using the SNP markers, we identified a loss of heterozygosity over
      large chromosomal fragments in strains of C. albicans that are frequently used
      for gene manipulation experiments. The SNP map will be useful for understanding
      the role of heterozygosity and genome rearrangement in the response of C.
      albicans to host environments.

PMID- 15189992
TI  - Inducible defense mechanism against nitric oxide in Candida albicans.
AB  - The yeast Candida albicans is an opportunistic pathogen that threatens patients
      with compromised immune systems. Immune cell defenses against C. albicans are
      complex but typically involve the production of reactive oxygen species and
      nitrogen radicals such as nitric oxide (NO) that damage the yeast or inhibit its
      growth. Whether Candida defends itself against NO and the molecules responsible
      for this defense have yet to be determined. The defense against NO in various
      bacteria and the yeast Saccharomyces cerevisiae involves an NO-scavenging
      flavohemoglobin. The C. albicans genome contains three genes encoding
      flavohemoglobin-related proteins, CaYHB1, CaYHB4, and CaYHB5. To assess their
      roles in NO metabolism, we constructed strains lacking each of these genes and
      demonstrated that just one, CaYHB1, is responsible for NO consumption and
      detoxification. In C. albicans, NO metabolic activity and CaYHB1 mRNA levels are
      rapidly induced by NO and NO-generating agents. Loss of CaYHB1 increases the
      sensitivity of C. albicans to NO-mediated growth inhibition. In mice, infections
      with Candida strains lacking CaYHB1 still resulted in lethality, but virulence
      was decreased compared to that in wild-type strains. Thus, C. albicans possesses
      a rapid, specific, and highly inducible NO defense mechanism involving one of
      three putative flavohemoglobin genes.

PMID- 15189993
TI  - Cdc42p GTPase regulates the budded-to-hyphal-form transition and expression of
      hypha-specific transcripts in Candida albicans.
AB  - The yeast Candida albicans is a major opportunistic pathogen of immunocompromised
      individuals. It can grow in several distinct morphological states, including
      budded and hyphal forms, and the ability to make the dynamic transition between
      these forms is strongly correlated with virulence. Recent studies implicating the
      Cdc42p GTPase in hypha formation relied on cdc42 mutations that affected the
      mitotic functions of the protein, thereby precluding any substantive conclusions
      about the specific role of Cdc42p in the budded-to-hypha-form transition and
      virulence. Therefore, we took advantage of several Saccharomyces cerevisiae cdc42
      mutants that separated Cdc42p's mitotic functions away from its role in
      filamentous growth. The homologous cdc42-S26I, cdc42-E100G, and cdc42-S158T
      mutations in C. albicans Cdc42p caused a dramatic defect in the budded-to-hypha
      form transition in response to various hypha-inducing signals without affecting
      normal budded growth, strongly supporting the conclusion that Cdc42p has an
      integral function in orchestrating the morphological transition in C. albicans.
      In addition, the cdc42-S26I and cdc42-E100G mutants demonstrated a reduced
      ability to damage endothelial cells, a process that is strongly correlated to
      virulence. The three mutants also had reduced expression of several hypha
      specific genes, including those under the regulation of the Efg1p transcription
      factor. These data indicate that Cdc42p-dependent signaling pathways regulate the
      budded-to-hypha-form transition and the expression of hypha-specific genes.

PMID- 15189994
TI  - Functional unit of the RNA polymerase II C-terminal domain lies within
      heptapeptide pairs.
AB  - Unlike all other RNA polymerases, the largest subunit (RPB1) of eukaryotic DNA
      dependent RNA polymerase II (RNAP II) has a C-terminal domain (CTD) comprising
      tandemly repeated heptapeptides with the consensus sequence Y-S-P-T-S-P-S. The
      tandem structure, heptad consensus, and most key functions of the CTD are
      conserved between yeast and mammals. In fact, all metazoans, fungi, and green
      plants examined to date, as well as the nearest protistan relatives of these
      multicellular groups, contain a tandemly repeated CTD. In contrast, the RNAP II
      largest subunits from many other eukaryotic organisms have a highly degenerate C
      terminus or show no semblance of the CTD whatsoever. The reasons for intense
      stabilizing selection on CTD structure in certain eukaryotes, and its apparent
      absence in others, are unknown. Here we demonstrate, through in vivo genetic
      complementation, that the essential functional unit of the yeast CTD is contained
      within pairs of heptapeptides. Insertion of a single alanine residue between
      diheptads has little phenotypic effect, while increasing the distance between
      diheptads produces a mostly quantitative effect on yeast cell growth. We further
      explore structural constraints on the CTD within an evolutionary context and
      propose selective mechanisms that could maintain a global tandem structure across
      hundreds of millions of years of eukaryotic evolution.

PMID- 15189995
TI  - Candida albicans Rim13p, a protease required for Rim101p processing at acidic and
      alkaline pHs.
AB  - Candida albicans is an important commensal of mucosal surfaces that is also an
      opportunistic pathogen. This organism colonizes a wide range of host sites that
      differ in pH; thus, it must respond appropriately to this environmental stress to
      survive. The ability to respond to neutral-to-alkaline pHs is governed in part by
      the RIM101 signal transduction pathway. Here we describe the analysis of C.
      albicans Rim13p, a homolog of the Rim13p/PalB calpain-like protease member of the
      RIM101/pacC pathway from Saccharomyces cerevisiae and Aspergillus nidulans,
      respectively. RIM13, like other members of the RIM101 pathway, is required for
      alkaline pH-induced filamentation and growth under extreme alkaline conditions.
      Further, our studies suggest that the RIM101 pathway promotes pH-independent
      responses, including resistance to high concentrations of lithium and to the drug
      hygromycin B. RIM13 encodes a calpain-like protease, and we found that Rim101p
      undergoes a Rim13p-dependent C-terminal proteolytic processing event at neutral
      to-alkaline pHs, similar to that reported for S. cerevisiae Rim101p and A.
      nidulans PacC. However, we present evidence that suggests that C. albicans
      Rim101p undergoes a novel processing event at acidic pHs that has not been
      reported in either S. cerevisiae or A. nidulans. Thus, our results provide a
      framework to understand how the C. albicans Rim101p processing pathway promotes
      alkaline pH-independent processes.

PMID- 15189996
TI  - Novel chimeric spermidine synthase-saccharopine dehydrogenase gene (SPE3-LYS9) in
      the human pathogen Cryptococcus neoformans.
AB  - The Cryptococcus neoformans LYS9 gene (encoding saccharopine dehydrogenase) was
      cloned and found to be part of an evolutionarily conserved chimera with SPE3
      (encoding spermidine synthase). spe3-lys9, spe3-LYS9, and SPE3-lys9 mutants were
      constructed, and these were auxotrophic for lysine and spermidine, spermidine,
      and lysine, respectively. Thus, SPE3-LYS9 encodes functional spermidine synthase
      and saccharopine dehydrogenase gene products. In contrast to Saccharomyces
      cerevisiae spe3 mutants, the polyamine auxotrophy of C. neoformans spe3-LYS9
      mutants was not satisfied by spermine. In vitro phenotypes of spe3-LYS9 mutants
      included reduced capsule and melanin production and growth rate, while SPE3-lys9
      mutants grew slowly at 30 degrees C, were temperature sensitive in rich medium,
      and died upon lysine starvation. Consistent with the importance of saccharopine
      dehydrogenase and spermidine synthase in vitro, spe3-lys9 mutants were avirulent
      and unable to survive in vivo and both functions individually contributed to
      virulence. SPE3-LYS9 mRNA levels showed little evidence of being influenced by
      exogenous spermidine or lysine or starvation for spermidine or lysine; thus, any
      regulation is likely to be posttranscriptional. Expression in S. cerevisiae of
      the full-length C. neoformans SPE3-LYS9 cDNA complemented a lys9 mutant but not a
      spe3 mutant. However, expression in S. cerevisiae of a truncated gene product,
      consisting of only C. neoformans SPE3, complemented a spe3 mutant, suggesting
      possible modes of regulation. Therefore, we identified and describe a novel
      chimeric SPE3-LYS9 gene, which may link spermidine and lysine biosynthesis in C.
      neoformans.

PMID- 15189997
TI  - Hemoglobin regulates expression of an activator of mating-type locus alpha genes
      in Candida albicans.
AB  - Phenotypic switching from the white to the opaque phase is a necessary step for
      mating in the pathogenic fungus Candida albicans. Suppressing switching during
      vascular dissemination of the organism may be advantageous, because opaque cells
      are more susceptible to host defenses. A repressor of white-opaque switching,
      HBR1 (hemoglobin response gene 1), was identified based on its specific induction
      following growth in the presence of exogenous hemoglobin. Deletion of a single
      HBR1 allele allowed opaque phase switching and mating competence, accompanied by
      a lack of detectable MTL alpha1 and alpha2 gene expression and enhanced MTLa1
      gene expression. Conversely, overexpression of Hbr1p or exposure to hemoglobin
      increased MTLalpha gene expression. The a1/alpha2 repressed target gene CAG1 was
      derepressed in the same mutant in a hemoglobin-sensitive manner. Regulation of
      CAG1 by hemoglobin required an intact MTLa1 gene. Several additional Mtlp targets
      were perturbed in HBR1 mutants in a manner consistent with commitment to an a
      mating phenotype, including YEL007w, MFalpha, HST6, and RAM2. Therefore, Hbr1 is
      part of a host factor-regulated signaling pathway that controls white-opaque
      switching and mating in the absence of allelic deletion at the MTL locus.

PMID- 15189999
TI  - Sequence elements necessary for transcriptional activation of BAD1 in the yeast
      phase of Blastomyces dermatitidis.
AB  - Blastomyces dermatitidis is a dimorphic fungal pathogen that converts from
      mycelia or conidia to a host-adapted yeast morphotype upon infection. Conversion
      to the yeast form is accompanied by the production of the virulence factor BAD1.
      Yeast-phase-specific expression of BAD1 is transcriptionally regulated, and its
      promoter shares homology with that of the yeast-phase-specific gene YPS3 of
      Histoplasma capsulatum. Serial truncations of the BAD1 upstream region were fused
      to the lacZ reporter to define functional areas in the promoter. Examination of
      PBAD1-lacZ fusions in B. dermatitidis indicated that BAD1 transcription is
      upregulated in the yeast phase. The 63-nucleotide box A region conserved in the
      YPS3 upstream region was shown to be an essential component of the minimal BAD1
      promoter. A matched PYPS3-lacZ construct indicated that this same region was
      needed for minimal YPS3 promoter activity in B. dermatitidis transformants.
      Reporter activity in H. capsulatum transformants similarly showed a requirement
      for box A in the minimal BAD1 promoter. Several putative transcription factor
      binding sites were identified within box A of BAD1. Replacement of two of these
      predicted sites within box A--a cAMP responsive element and a Myb binding site-
      sharply reduced transcriptional activity, indicating that these regions are
      critical in dictating the yeast-phase-specific expression of this crucial
      virulence determinant of B. dermatitidis.

PMID- 15189998
TI  - RBR1, a novel pH-regulated cell wall gene of Candida albicans, is repressed by
      RIM101 and activated by NRG1.
AB  - The transcription factor Rim101p of Candida albicans has been shown to play a
      major role in pH-dependent gene regulation. Rim101p is involved in cell wall
      biosynthesis, since it regulates PHR1 and PHR2, two almost functionally redundant
      cell wall glycosidases important for adaptation to either neutral or acidic
      habitats within the human host. To identify additional cell wall components
      regulated by Rim101p, we performed transcriptional profiling with a cell wall
      specific DNA microarray. We showed that Rim101p contributes to the activation of
      known hypha-specific genes such as HWP1 and RBT1 but is also required for
      repression of the previously uncharacterized potential cell wall genes RBR1,
      RBR2, and RBR3. Further characterization of RBR1 revealed that it encodes a small
      glycosylphosphatidyl inositol protein that is expressed under acidic conditions
      predominantly at low temperature. Deletion of the gene resulted in a
      filamentation defect at low pH. Most interestingly, NRG1, a transcriptional
      repressor of hyphal growth in C. albicans, was required for RBR1 expression. The
      apparently activating effect of NRG1 observed in this study has not been
      described before. In addition, we showed that expression of NRG1 is not only
      temperature but also pH dependent.

PMID- 15190000
TI  - Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine
      kinase in Dictyostelium discoideum results in a selective increase in sensitivity
      to platinum-based chemotherapy drugs.
AB  - The efficacy of the chemotherapy drug cisplatin is often limited due to
      resistance of the tumors to the drug, and increasing the potency of cisplatin
      without increasing its concentration could prove beneficial. A previously
      characterized Dictyostelium discoideum mutant with increased resistance to
      cisplatin was defective in the gene encoding sphingosine-1-phosphate (S-1-P)
      lyase, which catalyzes the breakdown of S-1-P, an important regulatory molecule
      in cell function and development and in the regulation of cell fate. We
      hypothesized that the increased resistance to cisplatin was due to an elevation
      of S-1-P and predicted that lowering levels of S-1-P should increase sensitivity
      to the drug. We generated three strains that stably overexpress different levels
      of the S-1-P lyase. The overexpressor strains have reduced growth rate and,
      confirming the hypothesis, showed an expression-dependent increase in sensitivity
      to cisplatin. Consistently, treating the cells with D-erythro-N,N,
      dimethylsphingosine, a known inhibitor of sphingosine kinase, increased the
      sensitivity of mutant and parent cells to cisplatin, while addition of exogenous
      S-1-P or 8-Br-cyclic AMP made the cells more resistant to cisplatin. The
      increased sensitivity of the overexpressors to cisplatin was also observed with
      the cisplatin analog carboplatin. In contrast, the response to doxorubicin, 5
      flurouracil, or etoposide was unaffected, indicating that the involvement of the
      sphingolipid metabolic pathway in modulating the response to cisplatin is not
      part of a global genotoxic stress response. The augmented sensitivity to
      cisplatin appears to be the result of an intracellular signaling function of S-1
      P, because D. discoideum does not appear to have endothelial differentiation
      growth (EDG/S1P) receptors. Overall, the results show that modulation of the
      sphingolipid pathway at multiple points can result in increased sensitivity to
      cisplatin and has the potential for increasing the clinical usefulness of this
      important drug.

PMID- 15190001
TI  - The Gbeta-subunit-encoding gene bpp1 controls cyclic-AMP signaling in Ustilago
      maydis.
AB  - In the phytopathogenic fungus Ustilago maydis, fusion of haploid cells is a
      prerequisite for infection. This process is controlled by a pheromone-receptor
      system. The receptors belong to the seven-transmembrane class that are coupled to
      heterotrimeric G proteins. Of four Galpha subunits in U. maydis, only gpa3 has a
      function during mating and cyclic AMP (cAMP) signaling. Activation of the cAMP
      cascade induces pheromone gene expression; however, it does not lead to the
      induction of conjugation tubes seen after pheromone stimulation. To investigate
      the possibility that a Gbeta subunit participates in pheromone signaling, we
      isolated the single beta subunit gene, bpp1, from U. maydis. bpp1 deletion
      mutants grew filamentously and showed attenuated pheromone gene expression,
      phenotypes associated with deltagpa3 strains. In addition, a constitutively
      active allele of gpa3 suppressed the phenotype of the bpp1 deletion strains. We
      suggest that Bpp1 and Gpa3 are components of the same heterotrimeric G protein
      acting on adenylyl cyclase. Interestingly, while deltagpa3 strains are impaired
      in pathogenicity, deltabpp1 mutants are able to induce plant tumors. This could
      indicate that Gpa3 operates independently of Bpp1 during pathogenic development.

PMID- 15190003
TI  - Engineering of an artificial glycosylation pathway blocked in core
      oligosaccharide assembly in the yeast Pichia pastoris: production of complex
      humanized glycoproteins with terminal galactose.
AB  - A significant percentage of eukaryotic proteins contain posttranslational
      modifications, including glycosylation, which are required for biological
      function. However, the understanding of the structure-function relationships of N
      glycans has lagged significantly due to the microheterogeneity of glycosylation
      in mammalian produced proteins. Recently we reported on the cellular engineering
      of yeast to replicate human N-glycosylation for the production of glycoproteins.
      Here we report the engineering of an artificial glycosylation pathway in Pichia
      pastoris blocked in dolichol oligosaccharide assembly. The PpALG3 gene encoding
      Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol mannosyltransferase was deleted in a strain that
      was previously engineered to produce hybrid GlcNAcMan(5)GlcNAc(2) human N
      glycans. Employing this approach, combined with the use of combinatorial genetic
      libraries, we engineered P. pastoris strains that synthesize complex
      GlcNAc(2)Man(3)GlcNAc(2) N-glycans with striking homogeneity. Furthermore,
      through expression of a Golgi-localized fusion protein comprising UDP-glucose 4
      epimerase and beta-1,4-galactosyl transferase activities we demonstrate that this
      structure is a substrate for highly efficient in vivo galactose addition. Taken
      together, these data demonstrate that the artificial in vivo glycoengineering of
      yeast represents a major advance in the production of glycoproteins and will
      emerge as a practical tool to systematically elucidate the structure-function
      relationship of N-glycans.

PMID- 15190004
TI  - NMR spectroscopic and molecular modeling investigations of the trans-sialidase
      from Trypanosoma cruzi.
AB  - Nuclear magnetic resonance (NMR) spectroscopy was used to investigate the
      transfer of sialic acid from a range of sialic acid donor compounds to acceptor
      molecules, catalyzed by Trypanosoma cruzi trans-sialidase (TcTS). We demonstrate
      here that NMR spectroscopy is a powerful tool to monitor the trans-sialidase
      enzyme reaction for a variety of donor and acceptor molecules. The hydrolysis or
      transfer reactions that are catalyzed by TcTS were also investigated using a
      range of N-acetylneuraminosyl-based donor substrates and asialo acceptor
      molecules. These studies showed that the synthetic N-acetylneuraminosyl donor 4
      methylumbelliferyl alpha-d-N-acetylneuraminide (MUN) is hydrolyzed by the enzyme
      approximately 3-5 times faster than either the disaccharide
      Neu5Acalpha(2,3)Galbeta1Me or the trisaccharide Neu5Acalpha(2,3)Lacbeta1Me. In
      the transfer reaction, we show that Neu5Acalpha(2,3)Lacbeta1Me is the most
      favorable substrate for TcTS and is a better substrate than the naturally
      occurring N-acetylneuraminosyl donor alpha1-acid glycoprotein. In the case of MUN
      as the donor molecule, the transfer of Neu5Ac to different acceptors is
      significantly slower than when other N-acetylneuraminosyl donors are used. We
      hypothesize that when MUN is bound by the enzyme, the orientation and steric bulk
      of the umbelliferyl aglycon moiety may restrict the access for the correct
      positioning of an acceptor molecule. AutoDock studies support our hypothesis and
      show that the umbelliferyl aglycon moiety undergoes a strong pi-stacking
      interaction with Trp-312. The binding properties of TcTS towards acceptor
      (lactose) and donor substrate (Neu5Ac) molecules have also been investigated
      using saturation transfer difference (STD) NMR experiments. These experiments,
      taken together with other published data, have clearly demonstrated that lactose
      in the absence of other coligands does not bind to the TcTS active site or other
      binding domains. However, in the presence of the sialic acid donor, lactose (an
      asialo acceptor) was observed by NMR spectroscopy to interact with the enzyme's
      active site. The association of the asialo acceptor with the active site is an
      absolute requirement for the transfer reaction to proceed.

PMID- 15190002
TI  - The circadian RNA-binding protein CHLAMY 1 represents a novel type heteromer of
      RNA recognition motif and lysine homology domain-containing subunits.
AB  - The RNA-binding protein CHLAMY 1 from Chlamydomonas reinhardtii binds
      specifically to UG> or =7 repeat sequences situated in the 3' untranslated
      regions of several mRNAs. Its binding activity is controlled by the circadian
      clock. The biochemical purification and characterization of CHLAMY 1 revealed a
      novel type of RNA-binding protein. It includes two different subunits (named C1
      and C3), whose interaction appears necessary for RNA binding. One of them (C3)
      belongs to the proteins of the CELF (CUG-BP-ETR-3-like factors) family and thus
      bears three RNA recognition motif domains. The other is composed of three lysine
      homology domains and a protein-protein interaction domain (WW). The subunits C1
      and C3 have theoretical molecular masses of 45 and 52 kDa, respectively, and are
      present in nearly equal amounts during the circadian cycle. At the beginning of
      the subjective night, both can be found in protein complexes of 100 to 160 kDa.
      However, during subjective day when binding activity of CHLAMY 1 is low, the C1
      subunit in addition is present in a high-molecular-mass protein complex of more
      than 680 kDa. These data indicate posttranslational control of the circadian
      binding activity of CHLAMY 1. Notably, the C3 subunit shows significant homology
      to the rat CUG-binding protein 2. Anti-C3 antibodies can recognize the rat
      homologue, which can also be found in a protein complex in this vertebrate.

PMID- 15190005
TI  - The mannose receptor fails to enhance processing and presentation of a
      glycoprotein antigen in transfected fibroblasts.
AB  - One function proposed for the mannose receptor found on dendritic cells as well
      as on macrophages and hepatic endothelial cells is in enhancing uptake and
      processing of glycoprotein antigens for presentation by major histocompatibility
      complex (MHC) class II molecules. In this study, a direct assessment of the
      possible role of the mannose receptor in this process was made in the absence of
      other endocytic receptors that can internalize glycoproteins. Presentation of
      RNase A and B peptides was compared in transfected fibroblasts coexpressing the
      mannose receptor and MHC class II molecules. RNase B bears a high-mannose
      oligosaccharide and is a ligand for the mannose receptor, whereas RNase A is not
      glycosylated and is taken up by pinocytosis. Incubation of RNase A or B with the
      transfected cells resulted in identical stimulation of ribonuclease-specific T
      cells, indicating that endocytosis of the glycosylated protein by the mannose
      receptor does not enhance presentation of this antigen. The postulated role of
      the mannose receptor in presentation of glycoprotein-derived antigen is
      reevaluated in light of these results.

PMID- 15190006
TI  - Processing enzyme glucosidase II: proposed catalytic residues and developmental
      regulation during the ontogeny of the mouse mammary gland.
AB  - Following the action of glucosidase I to clip the terminal alpha1,2-linked
      glucose, glucosidase II sequentially cleaves the two inner alpha1,3-linked
      glucose residues from the Glcalpha1,2Glcalpha1,3Glcalpha1,3Man(9)GlcNAc(2)
      oligosaccharide of the incipient glycoprotein as it undergoes folding and
      maturation. Glucosidase II belongs to family 31 glycosidases. These enzymes act
      by the acid-base catalytic mechanism. The cDNA of the wild-type and several
      mutant forms of the fusion protein of the enzyme in which mutations were
      introduced in the conserved motif D(564)MNE(567) were expressed in Sf9 cells, and
      the proteins were purified on Ni-NTA matrix. The catalytic activity of the
      purified proteins was determined with radioactive Glc(2)Man(9)GlcNAc(2)
      substrate. The results show that the aspartate and glutamate within the
      D(564)MNE(567) motif can serve for catalysis, most likely as the acid-base pair
      within the active site of the enzyme. The developmental regulation of glucosidase
      II was studied during the ontogeny of the mouse mammary gland for its growth and
      differentiation. The mRNA of both alpha and beta subunits of the enzyme,
      immunoreactive alpha and beta subunits, and enzyme activity were measured over
      the complete developmental cycle. The changes in all the parameters were
      consistent with similar fluctuations with several other enzymes of the N
      glycosylation machinery reported earlier, reaching a three- to fourfold increase
      over the basal level in the virgin gland at the peak of lactation. Altogether it
      appears that there is a coordinated regulation of the enzymes involved in protein
      N-glycosylation during the development of the mouse mammary gland.

PMID- 15190007
TI  - Purification and characterization of 9-O-acetylated sialoglycoproteins from
      leukemic cells and their potential as immunological tool for monitoring childhood
      acute lymphoblastic leukemia.
AB  - Sialic acids as terminal residues of oligosaccharide chains play crucial roles in
      several cellular recognition events. Exploiting the selective affinity of
      Achatinin-H toward N-acetyl-9-O-acetylneuraminic acid-alpha2-6-GalNAc, we have
      demonstrated the presence of 9-O-acetylated sialoglycoproteins (Neu5,9Ac(2)-GPs)
      on lymphoblasts of 70 children with acute lymphoblastic leukemia (ALL) and on
      leukemic cell lines by fluorimetric HPLC and flow cytometric analysis. This study
      aims to assess the structural aspect of the glycotope of Neu5,9Ac(2)-GPs(ALL) and
      to evaluate whether these disease-specific molecules can be used to monitor the
      clinical outcome of ALL. The Neu5,9Ac(2)-GPs(ALL) were affinity-purified, and
      three distinct leukemia-specific molecular determinants (135, 120, and 90 kDa)
      were demonstrated by SDS-PAGE, western blotting, and isoelectric focusing. The
      carbohydrate epitope of Neu5,9Ac(2)-GPs(ALL) was confirmed by using synthetic
      sialic acid analogs. The enhanced presence of anti-Neu5,9Ac(2)-GP(ALL) antibody
      in ALL patients prompted us to develop an antigen-ELISA using purified
      Neu5,9Ac(2)-GPs(ALL) as coating antigens. Purified antigen was able to detect
      leukemia-specific antibodies at presentation of disease, which gradually
      decreased with treatment. Longitudinal monitoring of 18 patients revealed that in
      the early phase of the treatment patients with lower anti-Neu5,9Ac(2)-GPs showed
      a better prognosis. Minimal cross-reactivity was observed in other hematological
      disorders (n = 50) like chronic myeloid leukemia, acute myelogenous leukemia,
      chronic lymphocytic leukemia, and non-Hodgkin's lymphoma as well as normal
      healthy individuals (n = 21). This study demonstrated the potential of purified
      Neu5,9Ac(2)-GPs(ALL) as an alternate tool for detection of anti-Neu5,9Ac(2)-GP
      antibodies to be helpful for diagnosis and monitoring of childhood ALL patients.

PMID- 15190008
TI  - Production of a complement inhibitor possessing sialyl Lewis X moieties by in
      vitro glycosylation technology.
AB  - Recombinant soluble human complement receptor type 1 (sCR1) is a highly
      glycosylated glycoprotein intended for use as a drug to treat ischemia
      reperfusion injury and other complement-mediated diseases and injuries. sCR1
      sLe(x) produced in the FT-VI-expressing mutant CHO cell line LEC11 exists as a
      heterogeneous mixture of glycoforms, a fraction of which include structures with
      one or more antennae terminated by the sialyl Lewis X (sLe(x)) [Neu5Acalpha2
      3Galbeta1-4(Fucalpha1-3)GlcNAc]) epitope. Such multivalent presentation of sLe(x)
      was shown previously to effectively target sCR1 to activated endothelial cells
      expressing E-selectin. Here, we describe the use of the soluble, recombinant
      alpha2-3 sialyltransferase ST3Gal-III and the alpha1-3 fucosyltransferase FT-VI
      in vitro to introduce sLe(x) moieties onto the N-glycan chains of sCR1
      overexpressed in standard CHO cell lines. The product (sCR1-S/F) of these in
      vitro enzymatic glycan remodeling reactions performed at the 10-g scale has
      approximately 14 N-glycan chains per sCR1 molecule, comprised of biantennary
      (90%), triantennary (8.5%), and tetraantennary (1.5%) structures, nearly all of
      whose antennae terminate with sLe(x) moieties. sCR1-S/F retained complement
      inhibitory activity and, in comparison with sCR1-sLe(x) produced in the LEC11
      cell line, contained twice the number of sLe(x) moieties per mole glycoprotein,
      exhibited a twofold increase in area under the intravenous clearance curve in a
      rat pharmacokinetic model, and exhibited a 10-fold increase in affinity for E
      selectin in an in vitro binding assay. These results demonstrate that in vitro
      glycosylation of the sCR1 drug product reduces heterogeneity of the glycan
      profile, improves pharmacokinetics, and enhances carbohydrate-mediated binding to
      E-selectin.

PMID- 15190009
TI  - Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional
      activator in rod photoreceptors.
AB  - NR2E3, a photoreceptor-specific orphan nuclear receptor, is believed to play a
      pivotal role in the differentiation of photoreceptors. Mutations in the human
      NR2E3 gene and its mouse ortholog are associated with enhanced S-cones and
      retinal degeneration. In order to gain insights into the NR2E3 function, we
      performed temporal and spatial expression analysis, yeast two-hybrid screening,
      promoter activity assays and co-immunoprecipitation studies. The Nr2e3 expression
      was localized preferentially to the rod, and not to the cone, photoreceptor
      nuclei in rodent retina. The yeast two-hybrid screening of a retinal cDNA
      library, using NR2E3 as the bait, identified another orphan nuclear receptor
      NR1D1 (Rev-erbalpha). The interaction of NR2E3 with NR1D1 was confirmed by
      glutathione S-transferase pulldown and co-immunoprecipitation experiments. In
      transient transfection studies using HEK 293 cells, both NR2E3 and NR1D1
      activated the promoters of rod phototransduction genes synergistically with
      neural retina leucine zipper (NRL) and cone-rod homeobox (CRX). All four
      proteins, NR2E3, NR1D1, NRL and CRX, could be co-immunoprecipitated from the
      bovine retinal nuclear extract, suggesting their existence in a multi-protein
      transcriptional regulatory complex in vivo. Our results demonstrate that NR2E3 is
      involved in regulating the expression of rod photoreceptor-specific genes and
      support its proposed role in transcriptional regulatory network(s) during rod
      differentiation.

PMID- 15190010
TI  - Full-length dystrophin expression in half of the heart cells ameliorates beta
      isoproterenol-induced cardiomyopathy in mdx mice.
AB  - Gene therapy holds great promise for curing Duchenne muscular dystrophy (DMD),
      the most common fatal inherited childhood muscle disease. Success of DMD gene
      therapy depends upon functional improvement in both skeletal and cardiac muscle.
      Numerous gene transfer studies have been performed to correct skeletal muscle
      pathology, yet little is known about cardiomyopathy gene therapy. Since complete
      transduction of the entire heart is an impractical goal, it becomes critical to
      determine the minimal level of correction needed for successful DMD
      cardiomyopathy gene therapy. To address this question, we generated heterozygous
      mice that persistently expressed the full-length dystrophin gene in 50% of the
      cardiomyocytes of mdx mice, a model for DMD. We questioned whether dystrophin
      expression in half of the heart cells was sufficient to prevent stress-induced
      cardiomyopathy. Heart function of mdx mouse is normal in the absence of external
      stress. To determine the therapeutic effect, we challenged 3-month-old mice with
      beta-isoproterenol. Cardiomyocyte sarcolemma integrity was significantly impaired
      in mdx but not in heterozygous and C57Bl/10 mice. Importantly, in vivo closed
      chest hemodynamic assays revealed normal left ventricular function in beta
      isoproterenol-stimulated heterozygous mice. Since the expression profile in the
      heterozygous mice mimicked viral transduction, we conclude that gene therapy
      correction in 50% of the heart cells may be sufficient to treat cardiomyopathy in
      mdx mice. This finding may also apply to the gene therapy of other inherited
      cardiomyopathies.

PMID- 15190011
TI  - Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease
      like phenotypes in transgenic mice.
AB  - Huntington's disease (HD) results from the expansion of a glutamine repeat near
      the N-terminus of huntingtin (htt). At post-mortem, neurons in the central
      nervous system of patients have been found to accumulate N-terminal fragments of
      mutant htt in nuclear and cytoplasmic inclusions. This pathology has been
      reproduced in transgenic mice expressing the first 171 amino acids of htt with 82
      glutamines along with losses of motoric function, hypoactivity and abbreviated
      life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to
      the pathogenesis of disease have not been clarified. To examine whether
      pathogenic processes in the nucleus disproportionately contribute to disease
      features in vivo, we fused a nuclear localization signal (NLS) derived from
      atrophin-1 to the N-terminus of an N171-82Q construct. Two lines of mice (lines
      8A and 61) that were identified expressed NLS-N171-82Q at comparable levels and
      developed phenotypes identical to our previously described HD-N171-82Q mice.
      Western blot and immunohistochemical analyses revealed that NLS-N171-82Q
      fragments accumulate in nuclear, but not cytoplasmic, compartments. These data
      suggest that disruption of nuclear processes may account for many of the disease
      phenotypes displayed in the mouse models generated by expressing mutant N
      terminal fragments of htt.

PMID- 15190013
TI  - Variation of gene-based SNPs and linkage disequilibrium patterns in the human
      genome.
AB  - A principal goal in human genetics is to provide the tools necessary to enable
      genome-wide association studies. Extensive information on the distribution of
      gene-based single-nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD)
      patterns across the genome is required in order to choose markers for efficient
      implementation of this approach. To obtain such information, we have genotyped a
      large Japanese cohort for SNPs identified by systematic resequencing of more than
      14 000 autosomal genes. Analysis of these data led to the conclusion that the
      Japanese population contains approximately 130 000 common autosomal gene
      haplotypes (frequency >0.05), of which more than 35% are identified in the
      present study. We also examined allele frequencies and LD patterns according to
      the position of variants within genes, and their distribution across the genome.
      We found lower allele variability at exonic SNP sites (both non-synonymous and
      synonymous) compared with non-exonic SNP sites, and greater average LD between
      SNPs within exons of the same gene compared with other SNP combinations, both of
      which could be signals of selection. LD was correlated with the recombination
      rate per physical distance as estimated from the meiotic map, but the strength of
      the relationship varied considerably in different regions of the genome. Unique
      LD patterns, characterized by frequent instances of high LD between non-adjacent
      SNPs punctuated by blocks of low LD, were found in a 7 Mb region on chromosome 6p
      that includes the MHC (major histocompatibility complex) locus and many non-MHC
      genes. These results demonstrate the complexity that must be taken into account
      when considering SNP variability and LD patterns, while also providing tools
      necessary for implementation of efficient genome-wide association studies.

PMID- 15190012
TI  - Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome
      mouse models by altering Tbx1 dosage.
AB  - Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de
      novo hemizygous 22q11.2 deletions and is characterized by malformations
      attributed to abnormal development of the pharyngeal arches and pouches. The main
      physical findings include aortic arch and outflow tract heart defects, thymus
      gland hypoplasia or aplasia and craniofacial anomalies. The disorder varies
      greatly in expressivity; while some patients are mildly affected with learning
      disabilities and subtle craniofacial malformations, others die soon after birth
      with major cardiovascular defects and thymus gland aplasia. In addition to the
      main clinical features, many other findings are associated with the disorder such
      as chronic otitis media and hypocalcemia. Tbx1, a gene encoding a T-box
      transcription factor, which is hemizygously deleted on chromosome 22q11.2, was
      found to be a strong candidate for the equivalent of human VCFS/DGS in mice. Mice
      hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes
      had severe malformations in the affected structures; neither precisely modeling
      the syndrome. Interestingly, bacterial artificial chromosome (BAC) transgenic
      mice overexpressing human TBX1 and three other transgenes, had similar
      malformations as VCFS/DGS patients. By employing genetic complementation studies,
      we demonstrate that altered TBX1 dosage and not overexpression of the other
      transgenes is responsible for most of the defects in the BAC transgenic mice.
      Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a Tbx1
      dose dependent manner, thus providing a molecular basis for the pathogenesis and
      varied expressivity of the syndrome.

PMID- 15190014
TI  - Transgenic mouse models support HCR as an effector gene in the PSORS1 locus.
AB  - Genetic susceptibility for psoriasis is regulated to the greatest extent by the
      PSORS1 locus. Three psoriasis-associated susceptibility alleles have been
      identified within it, namely, HLACw6, HCR*WWCC and CDSN*5, but strong linkage
      disequilibrium between them has made it difficult to distinguish their individual
      genetic effects, and animal models to study their effects are not known. To study
      the function of HCR, we engineered transgenic mice with either a non-risk allele
      of HCR or the HCR*WWCC risk allele under the control of the cytokeratin-14
      promoter. These choices were motivated by the apparently dominant effect of
      PSORS1 on psoriasis susceptibility and the physiological expression of HCR in
      basal keratinocytes. Transgenic mice appeared phenotypically normal and
      histologically their skin was indistinguishable from wild-type mice. Expression
      studies using Affymetrix arrays suggested that the HCR risk allele has specific
      functional consequences relevant to the pathogenesis of psoriasis. Comparison of
      gene expression changes between non-risk and risk allele mice revealed
      similarities to previous observations in human psoriatic skin, including
      upregulation of cytokeratins 6, 16 and 17 in risk allele mice. We also observed
      changes in the expression of genes associated with terminal differentiation and
      formation of the cornified cell envelope. Our results support the concept that
      HCR may constitute an essential gene in the PSORS1 locus. These observations are
      also compatible with a model that a susceptibility gene for psoriasis induces
      changes that are contributory but not sufficient by itself to produce the
      clinical phenotype.

PMID- 15190015
TI  - Short communication: seasonal onset of menopause?
AB  - BACKGROUND: Seasonal variations of reproductive functions in wild mammals are
      well known. Similar but blunted seasonal trends have also been described for
      humans. METHODS: We performed a questionnaire-based study of 149 patients that
      was designed to search for environmental influence on symptom presentation among
      patients attending an open menopause service. RESULTS: The evaluated data show a
      conspicuous seasonality in cessation of menstrual bleeding, with a higher peak
      after the vernal (spring) equinox and a lower one after the autumn equinox.
      CONCLUSIONS: Of the several environmental factors considered in this study, the
      sequence of seasons seems to affect most obviously the process leading to the
      loss of menstrual cycling. The triggering factor(s) eliciting the onset of the
      menopausal process and the mediators involved, however, need further analysis.

PMID- 15190016
TI  - On the frequency of intercourse around ovulation: evidence for biological
      influences.
AB  - BACKGROUND: Intercourse in mammals is often coordinated with ovulation, for
      example through fluctuations in libido or by the acceleration of ovulation with
      intercourse. Such coordination has not been established in humans. We explored
      this possibility by examining patterns of sexual intercourse in relation to
      ovulation. METHODS: Sixty-eight sexually active North Carolina women with either
      an intrauterine device or tubal ligation provided data for up to three menstrual
      cycles. These women collected daily urine specimens and kept daily diaries of
      intercourse and menstrual bleeding. Major estrogen and progesterone metabolites
      excreted in urine were used to identify the day of ovulation. The fertile days of
      the cycle were defined as the 6 consecutive days ending with ovulation. Women
      contributed a total of 171 ovulatory cycles. Menstrual bleeding days were
      excluded from analysis. RESULTS: The frequency of intercourse rose during the
      follicular phase, peaking at ovulation and declining abruptly thereafter. The 6
      consecutive days with most frequent intercourse corresponded with the 6 fertile
      days of the menstrual cycle. Intercourse was 24% more frequent during the 6
      fertile days than during the remaining non-bleeding days (P < 0.001).
      CONCLUSIONS: There apparently are biological factors that promote intercourse
      during a woman's 6 fertile days.

PMID- 15190017
TI  - Detection of VIM-5 metallo-beta-lactamase in a Pseudomonas aeruginosa clinical
      isolate from Turkey.

PMID- 15190018
TI  - Rapid alternative methods for detection of rifampicin resistance in Mycobacterium
      tuberculosis.
AB  - OBJECTIVE: To study the performance of three rapid low cost methods for the
      detection of rifampicin resistance. METHODS: A panel of 20 coded Mycobacterium
      tuberculosis strains was tested blindly by the low cost methods: nitrate
      reductase, MTT and resazurin assays, and compared with the results obtained with
      the gold standard methods: the proportion method on Lowenstein-Jensen medium and
      the BACTEC TB 460 system. We have also tested two commercial tests: MGIT and INNO
      LiPA Rif.TB kit. RESULTS: Complete agreement was observed among all methods.
      CONCLUSION: These three simple methods might become inexpensive alternative
      procedures for rapid detection of rifampicin resistance in low-resource
      countries.

PMID- 15190019
TI  - Non-nucleoside inhibitors of the HCV polymerase.
AB  - Chronic hepatitis C virus (HCV) infection is the leading cause of chronic liver
      disease. Current therapy using pegylated interferon-alpha with ribavirin is
      poorly tolerated and confers an overall sustained virological response around
      56%. Compounds exhibiting an improved safety profile with similar or enhanced
      antiviral properties may represent future treatment options. Several drug
      discovery programmes are ongoing to directly target the viral enzymes involved in
      HCV replication. Recent clinical success using a peptidomimetic inhibitor of the
      viral serine protease has demonstrated proof-of-concept for the use of direct
      antiviral agents in reducing viral load. The RNA-dependent RNA polymerase (RdRp)
      of HCV is also required for viral RNA replication and thus represents an
      attractive drug discovery target. Preclinical characterization of several non
      nucleoside inhibitors (NNIs) of the HCV RdRp have been described, including a
      promising series of benzothiadiazine derivatives which have been shown to
      efficiently block viral RNA synthesis in HCV replicon cell systems. Herein, the
      antiviral activity, mode of action, resistance profiling and therapeutic
      potential of the benzothiadiazine class of compounds for clinical development are
      explored.

PMID- 15190020
TI  - Identification of Pseudomonas aeruginosa FtsZ peptide inhibitors as a tool for
      development of novel antimicrobials.

PMID- 15190021
TI  - Phenotypic and molecular characterization of macrolide and streptogramin
      resistance in Streptococcus mitis from neutropenic patients.
AB  - OBJECTIVES: To determine the prevalence of macrolide and streptogramin resistance
      in Streptococcus mitis isolates from neutropenic patients and to identify
      mechanisms of macrolide and streptogramin resistance in resistant isolates.
      METHODS: MICs of erythromycin, spiramycin, lincomycin and pristinamycin were
      determined for S. mitis isolates. Macrolide-resistance genes were characterized
      by PCR and ribosomal mutations by sequencing. RESULTS: A total of 169 S. mitis
      isolates were recovered from 66 patients at the Tunisian Bone Marrow Transplant
      Centre. Of these, 120 (70%) were non-susceptible to erythromycin and one was
      resistant to pristinamycin; 48.5% of isolates had an MLSB phenotype with cross
      resistance between erythromycin, spiramycin and lincomycin, 4% had a dissociated
      MLSB phenotype with resistance to erythromycin and spiramycin but apparent
      susceptibility to lincomycin and 47.5% displayed the M phenotype. Resistance
      determinants were characterized in 33 isolates. Ten of 14 isolates with the cross
      MLSB resistance contained an ermB-like gene and four a combination of ermB- and
      mefA-like genes. Four of the five isolates with a dissociated MLSB phenotype
      contained ermB-like and one a combination of ermB- and mefA-like genes. All the
      14 isolates with an M phenotype contained mefA-like genes. The pristinamycin
      resistant strain had G105 and A108 substitutions in the conserved C terminus of
      the L22 ribosomal protein. CONCLUSIONS: The prevalence of macrolide resistance is
      high in S. mitis from neutropenic patients and is due to the spread of ermB- or
      mefA-like genes alone or combined. Resistance to streptogramins is rare and in
      this case associated with ribosomal mutation.

PMID- 15190022
TI  - Macrolide activities beyond their antimicrobial effects: macrolides in diffuse
      panbronchiolitis and cystic fibrosis.
AB  - Diffuse panbronchiolitis (DPB) is a pulmonary disease characterized by chronic
      inflammation of the bronchioles and chronic infiltration of inflammatory cells in
      the lungs. DPB has several features in common with cystic fibrosis (CF). Clinical
      trials in patients with DPB or CF suggest a potential role for maintenance (long
      term and low-dose) macrolide therapy in the treatment of these chronic pulmonary
      conditions. Indeed, these studies demonstrate improved clinical and physiological
      states with macrolide therapy. The beneficial effects of long-term low-dose
      macrolides are not related to their antimicrobial properties, since levels of
      macrolides with low-dose treatment are too low to have sufficient antimicrobial
      effects. Data indicate that macrolides may have immunomodulatory activities: (1)
      in vitro and ex vivo studies clearly show that macrolides can influence cytokine
      production by several cell types; (2) furthermore, macrolides can alter
      polymorphonuclear cell functions in vitro and ex vivo. Although immunomodulation
      may serve as one explanation for the beneficial effects of macrolides in patients
      with chronic pulmonary inflammation, the effect of low-dose macrolide therapy on
      biofilm-formation may form a second explanation for the positive effects of long
      term low-dose macrolide therapy. In the present paper, the clinical trials on
      maintenance macrolide therapy in patients with DPB or CF are reviewed. This is
      followed by a discussion on the immunomodulating effects of macrolides, and the
      effects of macrolides on biofilm formation.

PMID- 15190023
TI  - Substitution of threonine-1351 in the multidrug transporter Cdr1p of Candida
      albicans results in hypersusceptibility to antifungal agents and threonine-1351
      is essential for synergic effects of calcineurin inhibitor FK520.
AB  - OBJECTIVES: Functional characterization of a mutant Candida albicans drug
      resistance protein (Cdr1p) by overexpression in Saccharomyces cerevisiae.
      METHODS: We overexpressed green fluorescent protein-tagged Cdr1p in S. cerevisiae
      AD1-8u- host and introduced a point mutation to substitute T1351 with F in Cdr1p.
      The cells expressing T1351F mutant Cdr1p were analysed for their functional
      activity using minimum inhibitory concentration, spot assay, and fluconazole
      efflux. The binding activity of photoaffinity analogues 8-azidoATP,
      iodoarylazidoprazosin and azidopine to the mutant T1351F Cdr1p was also
      characterized. RESULTS: The T1351F mutant Cdr1p-expressing cells were susceptible
      to anisomycin, cycloheximide, fluconazole, miconazole and nystatin. The mutant
      protein was expressed to the same level as that of native Cdr1p in S. cerevisiae
      cells and was properly localized to the cell surface. There was also no
      difference between the mutant variant and the native protein's ability to bind a
      photoaffinity analogue of ATP, 8-azidoATP, or the radiolabelled photoaffinity
      agents iodoarylazidoprazosin and azidopine. However, the substitution of T1351
      resulted in considerable reduction in its ability to export fluorescent substrate
      rhodamine 6G. The synergy between calcineurin inhibitors FK520 and azoles was
      abrogated in cells expressing the T1351F mutant variant of Cdr1p. CONCLUSIONS:
      The results from this study suggest that the T1351 in the predicted transmembrane
      domain (TMD) 11 of Cdr1p is not only important for drug-substrate transport but
      also has a role in governing synergy of FK520.

PMID- 15190024
TI  - Genetic relatedness between human and animal polymorphic blaTEM genes strengthens
      zoonotic potential among uropathogenic Escherichia coli strains.

PMID- 15190025
TI  - Treatment of meningeal coccidioidomycosis with caspofungin.

PMID- 15190026
TI  - The in vitro activity of a new fluoroquinolone, ABT-492, against recent clinical
      isolates of Chlamydia pneumoniae.

PMID- 15190027
TI  - Ultrastructure of Streptococcus pneumoniae after exposure to xylitol.
AB  - OBJECTIVES: Xylitol is a sugar alcohol which reduces the growth of Streptococcus
      pneumoniae and the adherence of pneumococci and Haemophilus influenzae to
      nasopharyngeal cells. Xylitol prevents acute otitis media but does not decrease
      nasopharyngeal carriage of pneumococci. We hypothesized that xylitol could affect
      the surface structures of viable pneumococci, which would further explain the
      mechanism of action of xylitol in preventing acute otitis media. METHODS: We
      exposed five strains of pneumococci to 0.5%-5% xylitol, 5% glucose, 5% fructose
      and 5% sorbitol or control medium (brain heart infusion) for 0.5-2 h and examined
      the ultrastructure of bacteria by electron microscopy. RESULTS: The cell wall of
      pneumococci became more diffuse, the polysaccharide capsule became ragged and the
      proportion of damaged pneumococci increased after exposure to xylitol for 2 h,
      but not after exposure to other sugars or control medium. The phenotype of all
      pneumococcal strains was opaque before xylitol exposure and became almost
      transparent both in xylitol and in control medium during the experiment.
      CONCLUSIONS: This study demonstrates further that xylitol has a harmful effect on
      pneumococci. The observed changes in the polysaccharide capsule and the cell wall
      of pneumococci could affect the adherence and virulence of pneumococci,
      explaining the good clinical efficacy of xylitol in the prevention of acute
      otitis media.

PMID- 15190028
TI  - The glycopeptide vancomycin does not enhance toll-like receptor 2 (TLR2)
      activation by Streptococcus pneumoniae.
AB  - OBJECTIVES: The exposure of Streptococcus pneumoniae to cell-wall-active
      antibiotics in vivo and in vitro results in the release of bacterial components
      that can induce proinflammatory activation of human cells via toll-like receptor
      2 (TLR2). The aim of this study was to compare the activation of human TLR2
      pathways after exposure of S. pneumoniae to faropenem, cefotaxime and vancomycin.
      MATERIALS AND METHODS: Streptococcus pneumoniae D39 was exposed to cefotaxime,
      faropenem or vancomycin for 6 h during lag or early log phase growth. IL-8
      promoter activity of HeLa cells was measured using a dual luciferase reporter
      plasmid system. HeLa cells were transfected with an expression vector containing
      TLR2/CD14, or empty vector/CD14 and IL-8 promoter activity was measured using
      luminescence. Cells were stimulated with antibiotic-treated bacteria, untreated
      bacteria or medium-only controls. RESULTS: Lag phase S. pneumoniae treated at sub
      MIC (1/8 MIC) cefotaxime or faropenem induced 11-fold and 8-fold increases,
      respectively, in TLR2-mediated IL-8 promoter activity when compared with
      untreated bacteria. Early log MIC cefotaxime or faropenem-treated bacteria also
      enhanced TLR2 activation by 3-fold and 4-fold, respectively, when compared with
      untreated bacteria. Vancomycin treatment had no effect on TLR2 induction at any
      growth stage or MIC ratio tested. CONCLUSIONS: beta-Lactam antibiotics induce
      surface changes and release of cell wall structures from bacteria that are
      proinflammatory via TLR2, but the glycopeptide vancomycin does not.

PMID- 15190029
TI  - The first characterization of extended-spectrum beta-lactamase-producing
      Salmonella in Japan.

PMID- 15190030
TI  - Antibiotic usage in intensive care units: a pharmaco-epidemiological multicentre
      study.
AB  - OBJECTIVES: To prospectively assess the use of antibiotics in ICUs. PATIENTS AND
      METHODS: A total of 979 critically ill patients over 14 years of age were
      recruited in 43 Italian ICUs. For each patient, admission and discharge
      characteristics, information on the drugs administered, use of antibiotic
      susceptibility tests (ASTs), presence and severity of sepsis were collected daily
      until discharge or for a maximum of 21 days. RESULTS: Most patients with sepsis
      (99%) received antibiotics, and in almost all (93%) the treatment was started
      empirically, with broad-spectrum antibiotics. ASTs followed the onset of
      empirical treatment in 93% of cases. De-escalation was carried out in 16
      patients, while in 37.6% of cases an antibiotic had to be changed or added.
      Antibiotic prophylaxis in surgical patients involved widespread use of drug
      combinations (31% of cases) and lasted 3 days on average. In non-surgical
      patients antibiotic prophylaxis lasted 4.6 days and in 42% a third-generation
      cephalosporin was used. CONCLUSIONS: We found an appropriate approach to the
      therapeutic use of antibiotics: early empirical onset with broad-spectrum
      antimicrobial, followed by ASTs in order to target the therapy. However, in more
      than one-third of the cases the first-line choice was inappropriate. As regards
      prophylaxis, both surgical and non-surgical patients tended to have excessive
      duration of treatment, with widespread use of antibiotic combinations, too often
      involving a third-generation cephalosporin or carbapenem. This indicates a wide
      gap between clinical guidelines and clinical practice that calls for close
      assessment.

PMID- 15190031
TI  - Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary
      pathogens including bactericidal action and preliminary in vitro methods
      evaluations.
AB  - OBJECTIVES: To investigate the potency of doripenem, a broad-spectrum carbapenem
      characterized by a wider spectrum of activity combining antimicrobial and
      bactericidal features of imipenem and meropenem. METHODS: This parenteral
      compound was studied against recent clinical isolates (2001-2002) from a
      worldwide organism collection. A total of 902 strains were susceptibility tested
      by reference methods against doripenem and six to 28 comparators including
      ertapenem, imipenem and meropenem. The organisms tested included:
      Enterobacteriaceae (281 strains), Acinetobacter spp. (33), Pseudomonas aeruginosa
      (35), Stenotrophomonas maltophilia (36), other non-fermenters (22), Haemophilus
      influenzae (61), Moraxella catarrhalis (33), oxacillin-susceptible staphylococci
      (39), enterococci (84), streptococci (163), various anaerobes (98), and other
      Gram-positive species such as Corynebacterium and Bacillus spp. (17). RESULTS:
      Against Enterobacteriaceae, the average doripenem MIC90 was 0.03 mg/L (range, <
      or =0.015-0.25 mg/L). Doripenem was two- to 16-fold more potent than imipenem and
      comparable to ertapenem and meropenem; all doripenem MIC values with enteric
      bacilli were < or =4 mg/L. Doripenem was active against Aeromonas (MIC50, 0.03
      mg/L), Bacillus spp. (MIC50, 0.03 mg/L) and all tested anaerobic species (MIC
      range, < or =0.015-4 mg/L), but was less active against S. maltophilia (MIC90,
      >32 mg/L) and Enterococcus faecium (MIC90, >32 mg/L) among the enterococcal
      species. Time-dependent bactericidal action was observed for doripenem and broth
      MIC results were slightly greater when compared to agar MIC results. In pilot
      testing, the optimal doripenem disc concentration was 10 microg, identical to
      standardized reagents for other clinically available carbapenems. CONCLUSIONS:
      Doripenem appears to be a potent carbapenem with a spectrum resembling currently
      marketed antipseudomonal carbapenems, but with greater activity when tested
      against some non-fermentative bacillary strains. Continued evaluation of
      doripenem against isolates resistant to other beta-lactams appears to be
      warranted.

PMID- 15190032
TI  - Recurrent hepatitis C virus infection after liver transplantation: natural
      course, therapeutic approach and possible mechanisms of viral control.
AB  - End-stage liver disease associated with hepatitis C virus (HCV) infection has
      become the leading indication for liver transplantation worldwide. The new
      transplant liver is infected in nearly all patients, but the disease progression
      is highly variable. Although short-term survival appears to be similar to that in
      other causes of liver failure, progression to HCV-related cirrhosis is estimated
      to reach 20-30% at 5 year follow-up. Identification of factors that influence
      disease progression is important to optimize results of current treatment. This
      review summarizes the natural history, therapeutic options and future therapeutic
      strategies aimed at the induction and reinforcement of an adequate virus-specific
      CD4+ T cell response.

PMID- 15190033
TI  - Metronidazole resistance in Bacteroides spp. carrying nim genes and the selection
      of slow-growing metronidazole-resistant mutants.
AB  - OBJECTIVES: Human clinical isolates of Bacteroides spp. originating from patients
      in the UK were investigated for the presence of metronidazole resistance
      determinants (nim genes) and their presence was related to the MIC of
      metronidazole for the isolates. METHODS: Isolates were screened for
      susceptibility to a metronidazole disc and had their MIC determined by the Etest
      method. They were investigated for the presence of nim genes by PCR. An
      experiment to determine the effect of prolonged exposure to metronidazole was
      applied to nim-positive isolates with MICs below the therapeutic breakpoint.
      RESULTS: Fifty of 206 isolates (24%) were found to possess nim genes and these
      had MICs of metronidazole ranging from 1.5 to >256 mg/L with 24 (11.6%) above the
      therapeutic breakpoint of 16 mg/L. The remaining 26 nim-gene-positive isolates
      had MICs that were still below the therapeutic breakpoint, ranging from 1.5 to
      6.0 mg/L. nim genes were not found in 156 (76%) isolates, and all but seven of
      these were susceptible to a 5 microg disc of metronidazole. Ten members of the
      group for which the MICs were below the therapeutic level were found to have slow
      growing sub-populations with metronidazole MICs ranging from 8.0 to >256 mg/L
      that became evident after prolonged exposure to metronidazole in vitro. This
      resistance selection process was sometimes reversible after passage in the
      absence of metronidazole; however, seven of the 10 slow-growing mutants converted
      to stable high-level resistance (MIC >256 mg/L). CONCLUSIONS: Although the
      presence of nim genes per se does not always equate to therapeutic resistance,
      and other metronidazole resistance mechanisms may exist, this study has shown
      that prolonged exposure of nim-gene-carrying Bacteroides spp. to metronidazole
      can select for therapeutic resistance.

PMID- 15190034
TI  - Effects of duplicate and screening isolates on surveillance of community and
      hospital antibiotic resistance.
AB  - OBJECTIVES: To investigate common contentions that duplicate and screening
      isolates consistently show marked excess resistance, and that inclusion of such
      isolates significantly distorts regional resistance estimates. METHODS: Two Welsh
      surveys of antibiotic resistance for routine diagnostic isolates were analysed,
      comprising 309,129 isolates of six common community pathogens and 85,061 ward
      isolates of 11 common hospital pathogens. Duplicate isolates were defined as
      isolates from the same patient of the same pathogen with an indistinguishable
      susceptibility pattern, excluding the initial isolate. Significance was assessed
      from 95% confidence limits of the difference between resistance estimates.
      RESULTS: Duplicate isolates comprised approximately 20% of total isolates. For
      the 195 antibiotic-pathogen combinations investigated, differences in resistance
      between duplicate and non-duplicate isolates were statistically significant for
      93. Only 54 combinations showed significantly increased resistance amongst
      duplicates, and only 30 of these showed a difference >5%. Comparisons of de
      duplicated with un-de-duplicated regional resistance estimates showed significant
      differences for only 18 of 195 antibiotic-pathogen combinations; none were
      sufficient to alter judgement on clinical use. Screening isolates produced little
      disturbance of resistance estimates for Staphylococcus aureus, with the exception
      of flucloxacillin resistance, where inclusion of screening and duplicate isolates
      resulted in an increase of 4.4% for both community and hospital resistance
      estimates. CONCLUSIONS: The contentions were incorrect for these regional
      surveys. However, the proportion (and so effects) of screening and duplicate
      isolates may be greater in surveys of units with frequent repetitive sampling
      practice (burns, ITU, cystic fibrosis), or pathogens subjected to unusually
      intensive infection control sampling.

PMID- 15190035
TI  - Type II topoisomerase mutations in Bacillus anthracis associated with high-level
      fluoroquinolone resistance.
AB  - OBJECTIVES: To identify and characterize the mechanisms of high-level
      fluoroquinolone resistance in two strains of Bacillus anthracis following serial
      passage in increasing concentrations of fluoroquinolones. METHODS:
      Fluoroquinolone-resistant isolates of the Sterne and Russian Anthrax Vaccine STi
      strains were obtained following serial passage in the presence of increasing
      concentrations of four different fluoroquinolones. The quinolone-resistance
      determining regions of the type II topoisomerase genes from the resistant strains
      were amplified by PCR and characterized by DNA sequence analysis. The MICs in the
      presence and absence of reserpine were determined using broth microdilution as a
      means of detecting active efflux. RESULTS: Single and double amino acid
      substitutions in the GyrA (Ser-85-Leu; Glu-89-Arg/Gly/Lys) and GrlA (Ser-81-Tyr;
      Val-96-Ala; Asn-70-Lys) were most common. A single amino acid substitution in
      GyrB (Asp-430-Asn) was also identified. Efflux only applied to isolates selected
      for by either levofloxacin or ofloxacin. CONCLUSIONS: Specific amino acid
      substitutions in the type II topoisomerase enzymes significantly contributed to
      the development of high-level fluoroquinolone resistance in B. anthracis.
      However, notable differences between the strains and the drugs tested were
      identified including the role of efflux and the numbers and types of mutations
      identified.

PMID- 15190037
TI  - Successful treatment of Acinetobacter meningitis with intrathecal polymyxin E.

PMID- 15190036
TI  - Application of microdialysis to cancellous bone tissue for measurement of
      gentamicin levels.
AB  - OBJECTIVES: Knowledge concerning the distribution of antibiotics in bone tissue
      is valuable for pharmacokinetic and clinical use. Unfortunately, appropriate
      techniques are difficult to apply. We introduced microdialysis catheters to
      cancellous bone tissue for the investigation of gentamicin levels and compared
      the pharmacokinetics measured with values obtained from bone samples. METHODS:
      After two microdialysis catheters had been inserted into cancellous bone, eight
      pigs received an intravenous bolus of 240 mg of gentamicin. Microdialysates and
      bone samples were obtained over a period of 6 h and drug concentrations were
      measured. RESULTS: The area under the curves of the two microdialysates and bone
      samples were 1569, 1721 and 1533 mg.min/L (ANOVA, P=0.81). Reproducibility of the
      measurements from the microdialysates was defined as the mean ratio of
      AUC6/catheter no. 1/AUC6/catheter no. 2. This ratio was 1.02. CONCLUSIONS:
      Microdialysis is a suitable, relatively non-invasive and reproducible technique
      for dynamic and quantitative measurement of gentamicin levels in experimental
      research.

PMID- 15190038
TI  - Inhibition of TNF-alpha production in THP-1 macrophages by glatiramer acetate
      does not alter their susceptibility to infection by Listeria monocytogenes and
      does not impair the efficacy of ampicillin or moxifloxacin against intracellular
      bacteria.

PMID- 15190039
TI  - In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin
      and its metabolites.
AB  - OBJECTIVES: To investigate the in vitro activity of Extractum liquiritiae (EL),
      glycyrrhizic acid (GL), glycyrrhetinic acid (GA) and a novel lipophilic
      derivative of glycyrrhetinic acid monoglucuronide (GAMG), acetylated GAMG
      (aGAMG), against 29 Helicobacter pylori strains. METHODS: The MIC of each
      compound was determined by the agar dilution method, and the killing kinetics
      were monitored in brain heart infusion broth ( approximately 10(6)-10(7) cfu/mL)
      at 0, 4, 24, 48, 72 and 96 h. RESULTS: GA was the most potent compound (MIC(50
      /90), 50/100 mg/L), inhibiting 79.3% of the strains at MIC < or =50 mg/L.
      Clarithromycin-resistant strains were susceptible at 12.5 and 25 mg/L, and
      metronidazole-resistant strains at 25-50 and at 200 mg/L. The MIC distribution
      (mg/L) of aGAMG was < or =6.25 (29.2%), 50 (4.2%), 100-200 (12.5%) and > or =400
      (54.1%). EL and GL were less active (MICs >400 mg/L). GA exhibited rapid,
      concentration and strain-dependent bactericidal activity. CONCLUSIONS: The potent
      in vitro activity of GA against H. pylori provides a further explanation for its
      beneficial effect on peptic ulcers. Its effectiveness against clarithromycin
      resistant strains provides hope that it can form the basis for an alternative
      therapeutic agent against H. pylori.

PMID- 15190040
TI  - Long-term dissemination of an OXA-40 carbapenemase-producing Acinetobacter
      baumannii clone in the Iberian Peninsula.
AB  - OBJECTIVE: The main objectives of this study were to assess the clonal
      relatedness of Acinetobacter baumannii carbapenem-resistant isolates recovered
      from the Iberian Peninsula and to investigate the production of carbapenemases.
      METHODS: One hundred and sixty-two imipenem-resistant A. baumannii isolates were
      collected from 1998 to 2003 in three Portuguese university hospitals. An imipenem
      resistant isolate (988FFP strain) recovered in 1995 from a smaller hospital unit,
      was also included, as well as an OXA-40-producing A. baumannii Spanish strain
      (SM28). Susceptibility tests were carried out by disc diffusion and Etest
      methods. DNA fingerprints were obtained by PFGE of ApaI-digested chromosomal DNA.
      Carbapenemase activity was determined by a bioassay and spectrophotometry. The
      detection of the blaOXA-40 gene was conducted through PCR analysis, cloning and
      nucleotide sequencing. RESULTS: All the isolates presented a similar multi
      resistance pattern, including imipenem (MIC >32 mg/L). The Iberian isolates
      showed an identical PFGE pattern with minor band variations, including isolate
      988FFP collected in 1995. PCR results revealed a blaOXA-type gene in 65 isolates
      and nucleotide sequence analysis revealed the presence of the blaOXA-40 gene in
      seven representative Portuguese isolates from the various geographically
      dispersed hospitals. CONCLUSIONS: Our results indicate that a multi-resistant
      epidemic clone of A. baumannii, carrying blaOXA-40, is disseminated in the
      Iberian Peninsula, persisting in Portugal since 1995.

PMID- 15190041
TI  - ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities
      to prevent the selection of resistant Staphylococcus aureus in an in vitro
      dynamic model.
AB  - OBJECTIVE: To compare the kinetics of killing/regrowth of differentially
      susceptible clinical isolates of Staphylococcus aureus exposed to ABT492 and
      levofloxacin and to explore their relative abilities to prevent the selection of
      resistant mutants. METHODS: Three clinical isolates of S. aureus--including two
      ciprofloxacin-susceptible S. aureus, 201 and 480--and a ciprofloxacin-resistant
      S. aureus 866, were exposed to clinically achievable ratios of area under the
      curve (AUC) to MIC in a dynamic model that simulated human pharmacokinetics of
      ABT492 (400 mg) and levofloxacin (500 mg) as a single dose. In addition, S.
      aureus 201 was exposed to single and multiple doses of ABT492 and levofloxacin
      (both once daily for 3 days) over wide ranges of 24 h AUC/MIC (AUC24/MIC)
      including clinically achievable AUC24/MIC ratios. RESULTS: With each isolate,
      ABT492 at clinically achievable AUC/MICs produced greater anti-staphylococcal
      effects than levofloxacin. Areas between the control growth and the time--kill
      curves (ABBC in single dose simulations and the sum of ABBCs determined after the
      first, second and third dosing in multiple dose simulations--ABBC(1+2+3)) were
      higher with ABT492 than levofloxacin. Moreover, at comparable AUC/MICs and
      AUC24/MICs, the maximal reductions in the starting inoculum of ABT492-exposed S.
      aureus were more pronounced than with levofloxacin. Loss in susceptibility of S.
      aureus 201 exposed to ABT492 or levofloxacin depended on the simulated AUC24/MIC.
      Although the maximal increase in MIC (MICfinal) related to its initial value
      (MICinitial) was seen at a higher AUC24/MIC ratio of ABT492 (120 h) than
      levofloxacin (50 h), similar AUC24/MICs (240 and 200 h, respectively) were
      protective against the selection of resistant S. aureus. These threshold values
      are readily achievable with 400 mg ABT492 (AUC24/MIC 870 h) but not with 500 mg
      levofloxacin (AUC24/MIC 70 h). CONCLUSION: Overall, these findings predict
      greater efficacy of clinically achievable AUC/MIC (or AUC24/MIC) of ABT492 both
      in terms of the anti-staphylococcal effect and prevention of the selection of
      resistant mutants.

PMID- 15190042
TI  - Diet as a risk factor for cholesterol gallstone disease.
AB  - Cholesterol gallstone disease is a common condition in western populations. The
      etiology is multifactorial with interaction of genetic and environmental factors.
      Obesity, aging, estrogen treatment, pregnancy and diabetes are consistently
      associated to a higher risk. A number of dietary factors have been involved in
      the pathogenesis of cholelithiasis. In this article we summarize several studies
      that have evaluated the role of diet as a potential risk factor for gallstone
      formation, including energy intake, cholesterol, fatty acids, fiber,
      carbohydrates, vitamins and minerals, and alcohol intake. Consumption of simple
      sugars and saturated fat has been mostly associated to a higher risk, while fiber
      intake and moderate consumption of alcohol, consistently reduce the risk. The
      association between cholesterol intake and gallstone disease has been variable in
      different studies. The effects of other dietary factors are less conclusive;
      additional studies are therefore necessary to clarify their relevance in the
      pathogenesis of gallstone disease. Recent discoveries of the role of orphan
      nuclear receptors in the regulation of fatty acid and hepatic cholesterol
      metabolism and excretion open new perspectives for a better understanding of the
      role of dietary constituents on cholesterol gallstone formation. KEY TEACHING
      POINTS: The etiology of cholesterol gallstone disease is multifactorial with
      interaction between genome and environment. It has been postulated that dietary
      constituents are important determinants for the formation of lithogenic bile.
      Intake of high energy, simple sugar and saturated fat favors gallstone formation.
      Fiber and moderate consumption of alcohol reduce the risk. The role of orphan
      nuclear receptors in the regulation of hepatic cholesterol metabolism and
      excretion open new leads for understanding the role of dietary constituents on
      cholesterol gallstone formation.

PMID- 15190043
TI  - Flavonoid-rich dark chocolate improves endothelial function and increases plasma
      epicatechin concentrations in healthy adults.
AB  - BACKGROUND: Dark chocolate derived from the plant (Theobroma cacao) is a rich
      source of flavonoids. Cardioprotective effects including antioxidant properties,
      inhibition of platelet activity, and activation of endothelial nitric oxide
      synthase have been ascribed to the cocoa flavonoids. OBJECTIVE: To investigate
      the effects of flavonoid-rich dark chocolate on endothelial function, measures of
      oxidative stress, blood lipids, and blood pressure in healthy adult subjects.
      DESIGN: The study was a randomized, double-blind, placebo-controlled design
      conducted over a 2 week period in 21 healthy adult subjects. Subjects were
      randomly assigned to daily intake of high-flavonoid (213 mg procyanidins, 46 mg
      epicatechin) or low-flavonoid dark chocolate bars (46 g, 1.6 oz). RESULTS: High
      flavonoid chocolate consumption improved endothelium-dependent flow-mediated
      dilation (FMD) of the brachial artery (mean change = 1.3 +/- 0.7%) as compared to
      low-flavonoid chocolate consumption (mean change = -0.96 +/- 0.5%) (p = 0.024).
      No significant differences were noted in the resistance to LDL oxidation, total
      antioxidant capacity, 8-isoprostanes, blood pressure, lipid parameters, body
      weight or body mass index (BMI) between the two groups. Plasma epicatechin
      concentrations were markedly increased at 2 weeks in the high-flavonoid group
      (204.4 +/- 18.5 nmol/L, p < or = 0.001) but not in the low-flavonoid group (17.5
      +/- 9 nmol/L, p = 0.99). CONCLUSION: Flavonoid-rich dark chocolate improves
      endothelial function and is associated with an increase in plasma epicatechin
      concentrations in healthy adults. No changes in oxidative stress measures, lipid
      profiles, blood pressure, body weight or BMI were seen.

PMID- 15190044
TI  - Supplementation with mixed fruit and vegetable juice concentrates increased serum
      antioxidants and folate in healthy adults.
AB  - OBJECTIVE: Epidemiological studies have shown that low plasma levels of
      antioxidant micronutrients, which are commonly found in fruit and vegetables, are
      associated with increased risk for diseases such as heart disease, cancer,
      metabolic disorders and the like. The aim of this study was to monitor the
      dietary habits of a group of healthy, middle-aged, men and women and to assess
      the effect of supplementation with a natural phytonutrient preparation from
      fruits and vegetables, on plasma levels of various antioxidant micronutrients and
      oxidative stress assessed by measuring 8-oxodGuo (8-oxo-7,8-dihydro-2'
      deoxyguanosine) in urine. METHODS: The study followed a double-blind randomized
      cross-over design involving 59 healthy men and women (40-60 years of age). The
      supplement or a placebo was given to two groups for a total period of 14 weeks
      (crossover week 7). Blood levels of beta-carotene, vitamin C, vitamin E, selenium
      and folate were measured at 0, 7 and 14 weeks. Fruit and vegetable consumption
      was monitored by means of a retrospective food frequency questionnaire at week 0,
      7 and 14. Urinary 8-oxodGuo was also determined at these time points. RESULTS:
      Significant increases in blood nutrient levels after active supplementation were
      observed for beta-carotene, vitamin C, vitamin E, selenium and folate. Ranges
      measured, after supplementation, often fell into those associated with a reduced
      risk for disease. Our data suggests that, although generally health conscious,
      participants still fell short of the recommended five portions of fruit and
      vegetables per day. No significant group changes were noted for 8-oxodGuo
      concentration in urine. CONCLUSION: Supplementation with mixed fruit and
      vegetable juice concentrates effectively increased plasma levels of important
      antioxidant nutrients and folate.

PMID- 15190045
TI  - Dual energy X-ray absorptiometry measurements in small subjects: conditions
      affecting clinical measurements.
AB  - OBJECTIVE: To document the clinical and experimental situations that may affect
      DXA measurements in small subjects. METHODS: 49 piglets (886g to 21100g) had
      measurements with either of two pencil beam densitometers (QDR 1000W and QDR 2000
      Plus, Hologic Inc, Waltham, MA) using commercial infant (IWB) and adult whole
      body (AWB) software v5.71p and v5.71 respectively. AWB scans were analyzed with
      three additional software versions. 35 infants (2115 to 11564g) had IWB
      measurements. RESULTS: DXA measurements of total weight, bone mineral content,
      bone area, bone mineral density, fat and lean mass from IWB scans (all piglets)
      and from AWB scans (piglets >12 kg) were highly reproducible (p < 0.001). A
      statistically significant change occurred in at least one of the DXA measurements
      from the use of different platforms, variations in the amount and placement of
      covering (e.g., blanket), placement of the external calibration standard,
      presence of radiographic contrast material, presence of movement artifact,
      delivery of an intravenous fluid bolus prior to scanning or improper delineation
      of external calibration standard during analysis. Additionally, results varied
      amongst different versions of software as well as between IWB and AWB softwares.
      CONCLUSION: In small subjects, consistency in the DXA techniques is paramount for
      valid and meaningful comparison of DXA data in bone mass and body composition.

PMID- 15190046
TI  - Efficacy of a transforming growth factor beta 2 containing nutritional support
      formula in a murine model of inflammatory bowel disease.
AB  - OBJECTIVE: Dietary, environmental and genetic events may influence host
      susceptibility to inflammatory bowel diseases (IBD). Transforming growth factor
      beta 2 (TGF-beta 2), a multifunctional polypeptide (cytokine) present in human
      and bovine milk, plays a critical role in the development of tolerance, the
      prevention of autoimmunity, and in anti-inflammatory responses. TGF-beta 2 is a
      potent inhibitor of intestinal epithelial cell (IEC) growth and stimulates IEC
      differentiation. The objective of this study was to determine whether a diet
      containing TGF-beta 2 modulates intestinal injury and immune responses in an
      Interleukin-10 knockout (IL-10-/-) mouse model of IBD. METHODS: Five-week-old IL
      10-/- mice (in BALB/c background) reared in our transgenic facility were fed
      either an enteral diet (Diet-A) containing TGF-beta 2 or a control enteral diet
      (Diet-B) not rich in TGF-beta 2. Mice were weighed weekly, monitored for illness
      and euthanized after eight weeks on the diet. RESULTS: Final weights were 28 +/-
      1.2 g (58.2% gain) for Diet-A mice and 23 +/- 1.6 g (32.9% gain) for Diet-B mice
      (p = 0.0194). The hematocrits were 48.3% for Diet-A compared to 42% for Diet-B
      mice (p = 0.0021). Mice on Diet-A had significantly lower serum TNF-alpha
      concentrations. Forty-four percent of mice on Diet-B developed severe diarrhea
      and rectal prolapse compared with none on Diet-A. Evaluation of intestinal
      pathology (score 0-4) revealed that animals fed Diet-A had a score of 2.1 +/- 0.4
      compared to 3.2 +/- 0.36 in the Diet-B group (p = 0.040). The acute phase
      protein, serum amyloid A (SAA), was 3.8 times higher in the Diet-B group (p =
      0.0038). CONCLUSIONS: IL-10-/- mice fed a TGF-beta 2 containing diet gained more
      weight, did not develop diarrhea or prolapse, had lower pathological scores, and
      lower SAAs. These data further support the use of TGF-beta 2 containing enteral
      diets as one mode of therapy for Crohn's disease.

PMID- 15190047
TI  - The influence of nutritional status on complications after major intraabdominal
      surgery.
AB  - OBJECTIVE: Currently most nutritional assessment techniques are based on their
      ability to predict clinical outcomes. However, the validity of any of these
      techniques to truly measure "nutritional risk" has not been proved. We have
      therefore prospectively assessed the prognostic value of two nutritional
      assessment techniques and nonnutritional factors in determining outcome after
      major abdominal surgery. METHODS: At admission and discharge, 100 patients
      undergoing major abdominal surgery were assessed on the following items:
      Subjective Global Assessment, Nutritional Risk Index, anthropometric
      measurements, serum total protein, serum albumin, lymphocyte count, total serum
      cholesterol. Patients were monitored for postoperative complications until death
      or discharge. RESULTS: At admission, 44% of the patients were malnourished
      according to the Subjective Global Assessment, while 61% of the patients were
      malnourished according to the Nutritional Risk Index. At discharge, these numbers
      were 67% and 82%, respectively. Higher death rates were found in the malnourished
      groups. The risk of complication was increased in malnourished patients with both
      assessment techniques. The odds ratios for the association between malnutrition
      and complications varied between 1.926 and 9.854 with both assessments. The
      presence of cancer in the patient was predictive for complication. CONCLUSIONS:
      Malnutrition is a marker of bad outcomes. Both Subjective Global Assessment and
      Nutritional Risk Index nutrition tests are predictive for malnutrition and
      postoperative complications in patients undergoing major abdominal surgery.

PMID- 15190048
TI  - Alpha and gamma tocopherols in cerebrospinal fluid and serum from older, male,
      human subjects.
AB  - OBJECTIVE: The major forms of vitamin E in human physiological fluids are alpha
      and gamma tocopherols which exhibit different biological activities under a
      variety of assay conditions. The goal of this study was to obtain indirect
      information about the transport of tocopherols across the blood/spinal fluid
      barrier by comparing the concentrations of alpha and gamma tocopherols in serum
      and cerebrospinal fluid (CSF). METHODS: CSF and serum samples were obtained
      simultaneously from 28 human, male subjects excluding those with known pathology
      during the performance of spinal anesthesia procedures. The samples were
      centrifuged and frozen, and analyzed for tocopherols by HPLC with electrochemical
      detection. RESULTS: The concentrations of alpha and gamma tocopherols in CSF
      correlated significantly with their respective concentrations in serum. This
      would be expected since these nutrients have to be supplied by diet to serum
      followed by transport to the brain. The ratios of alpha to gamma tocopherols in
      the CSF and serum were highly correlated. High concentrations of alpha in serum
      tended to suppress gamma in both serum and CSF. CONCLUSIONS: These data suggest
      that the processes involved in the entry of tocopherol from blood to the CSF do
      not discriminate between the alpha and gamma tocopherols. In contrast, alpha
      tocopherol is highly preferred during the packaging of plasma lipoproteins by the
      liver. Our data also suggest that alpha and gamma tocopherols will be available
      to the human brain via transport from blood.

PMID- 15190049
TI  - Micronutrient deficiencies as predisposing factors for hypertension in lacto
      vegetarian Indian adults.
AB  - OBJECTIVE: With the increasing knowledge about the antioxidant potential of many
      micronutrients such as zinc and vitamin C, their roles in oxidative stress
      related health disorders have been postulated. This study therefore investigated
      low micronutrient status as a predisposing factor for hypertension in a
      traditionally lacto-vegetarian population like Indians. METHODS: Micronutrient
      profile was assessed in 109 hypertensives with age-gender-socio-economic status
      matched 115 healthy normotensives (30-58 years of age). Food intakes were
      estimated through a semi-quantitative food frequency questionnaire. Nutrient
      intakes were then evaluated by previous estimates of cooked foods from our
      laboratory. Systolic and diastolic blood pressure (SBP, DBP), age, weight,
      height, waist and hip circumference, occupation, physical activity, smoking
      habits were recorded. Fasting blood samples were analyzed for hemoglobin, serum
      level of glucose, triglycerides, total cholesterol, HDL, ceruloplasmin, plasma
      level of ascorbic acid, folic acid, retinol, erythrocyte glutathione reductase
      activity coefficient (EGRAC) and erythrocyte membrane zinc. RESULTS: There were
      no significant differences between protein, fat intakes of normal and
      hypertensive individuals, though intakes of men were higher than those of women
      (p < 0.05). Intakes of omega-6 fatty acids were higher (p = 0.08) and omega-3
      fatty acids were lower in hypertensive men than normotensive men (p = 0.04).
      Gender differences were also significant for micronutrient intakes except vitamin
      C and beta-carotene. Intakes of potassium, copper, folic acid and vitamin C were
      significantly lower in hypertensive individuals than in normotenisves. No
      significant association was found between occupation or activity level and
      hypertension (p > 0.2) in these subjects. Conditional logistic regression
      analysis indicated that intakes of vitamin C, folic acid and zinc were associated
      with 18% (OR = 1.18, 95% CI:1.08, 1.26), 51% (OR = 1.51, 95% CI 0.94, 2.1) higher
      odds for hypertension, and 3% lower odds for hypertension (OR = 0.97, 95% CI
      0.92, 1.01), respectively. Mean plasma vitamin C and folic acid were
      significantly higher (p < 0.01), and serum ceruloplasmin and erythrocyte membrane
      zinc were marginally higher (p = 0.07) in normal than hypertensive subjects. In
      multivariate linear regression analyses, plasma vitamin C, serum ceruloplasmin
      and erythrocyte membrane zinc were negatively associated with SBP (p = 0.00001)
      and plasma vitamin C was negatively associated with DBP (p = 0.0001). CONCLUSION:
      Low dietary intakes of vitamin C, folic acid and zinc emerged as the possible
      risk factors for hypertension. Further, lower levels of plasma vitamin C,
      erythrocyte membrane zinc and ceruloplasmin were found to be the putative
      intermediary biomarkers in pathogenesis of hypertension.

PMID- 15190050
TI  - Decreasing, null and increasing effects of eight popular types of ginseng on
      acute postprandial glycemic indices in healthy humans: the role of ginsenosides.
AB  - BACKGROUND: It is unclear whether other ginseng sources can replicate the
      glycemic-lowering efficacy observed previously with American ginseng and whether
      ginsenosides are mediators. We assessed the effect of eight popular ginseng types
      on postprandial plasma glucose (PG) and insulin (PI) indices, linking effects to
      ginsenoside profiles. METHODS: Using a double-blind, randomized, multiple
      crossover design, 12 healthy participants (gender: 6M:6F, age: 34 +/- 3 y, BMI:
      25.8 +/- 1.2 kg/m(2)) received 10 3g treatments: American, American-wild, Asian,
      Asian-red, Vietnamese-wild, Siberian, Japanese-rhizome, and Sanchi ginsengs and
      two placebos. Each treatment was given 40-minutes before a 75g-oral-glucose
      tolerance-test (75g-OGTT) with blood drawn at -40, 0, 15, 30, 45, 60, 90, 120
      minutes. HPLC-UV analysis quantified seven principal ginsenosides. RESULTS: Two
      factor analysis showed the main effects of ginseng-type and time were significant
      for PG and PI, with an interaction for PG (p < 0.05). Subsequent one-factor
      analysis showed an effect of ginseng-type on 90-min-PG and 90-min-PI (p < 0.05).
      This was reflected in effects on peak-PG, area under the curve (AUC)-PG and AUC
      PI (p < 0.05). But the effect on 90-min-PI and AUC-PI were significant (p < 0.05)
      only in overweight participants (BMI > 25 kg/m(2), n = 6). Planned comparisons
      with placebo showed a tendency for American ginseng and Vietnamese ginseng to
      lower 90-min-PG (p < 0.06), while Asian ginseng raised peak-PG and AUC-PG,
      American-wild ginseng raised 120-min-PG, and Siberian ginseng raised 90-min-PG,
      120-min-PG, and AUC-PG (p < 0.05). Stepwise-multiple-regression assessed the
      protopanaxadiol:protopanaxatriol (PPD:PPT)-ginsenoside ratio as the sole
      predictor (p < 0.05) for 90-min-PG (beta = -0.43, r(2) = 0.072), AUC-PG (beta = 
      0.25, r(2) = 0.06), 90-min-PI (beta = -0.26, r(2) = 0.065), AUC-PI (beta = -0.20,
      r(2) = 0.04). CONCLUSIONS: Ginseng has variable glycemic effects, in which the
      PPD:PPT-ginsenoside ratio might be involved. But the low variance explained
      suggests the involvement of other unmeasured ginsenoside or non-ginsenoside
      components.

PMID- 15190051
TI  - Malnutrition and dysfunctional mother-child feeding interactions: clinical
      assessment and research implications.
AB  - OBJECTIVES: To evaluate the effects of age and the presence of feeding
      pathologies on the relational modes during meals in a sample of mother-child
      pairs (n = 333), comparing groups of children in the first three years of life
      with normal development (ND-group, n = 211) and clinical groups of children who
      presented a diagnosis of feeding disorder and failure to thrive (FD-group, n =
      122), and to show an association between specific symptomatic characteristics of
      the mother, of the child and the dysfunctional modes of their relationship during
      meals in a subgroup of mother-child pairs (n = 50), selected at random from the
      total clinical sample and paired with a control group chosen for this study.
      METHODS: All mother-child pairs in the sample were observed in twenty-minute
      video-recordings during a meal, using the procedure of the Feeding Scale in the
      Italian version. A subgroup of mothers, selected at random from the total
      clinical sample, and paired with a control group, were given two self-reporting
      instruments for the evaluation of their psychological symptom status: the Eating
      Attitude Test and the Symptom Checklist-90-Revised, as well as two instruments
      for the evaluation of the infant temperament and emotional/behavioral
      functioning: the Baby and Toddler Behavior Questionnaires (from 1 to 18 months)
      and the Child Behavior Checklist 1-1/2--5 (from 18 to 36 months). RESULTS:
      Analysis of variance showed that the FD-group present interactional dysfunctional
      patterns during feeding and raise higher scores in symptomatic characteristics
      both of the mother and of the child, compared to ND-group. A set of correlation
      analyses (Pearson coefficients) showed an association among specific symptomatic
      characteristics of the mothers (dysfunctional eating attitudes, anxiety,
      depression, hostility), of their children (in particular, anxiety/depression,
      somatic complaints and aggressive behavior) and of their dysfunctional relational
      modes during feeding (p < 0.05). CONCLUSIONS: Our study confirms that analysis of
      the individual characteristics of the child, of the mother and of their
      relationship during the development of feeding patterns in the first three years
      of the child's life is extremely important in the clinical assessment of early
      feeding disorders, in order to establish a valid diagnostic methodology and
      formulate strategies for targeted and effective intervention. Furthermore, the
      results emphasize the clinical utility of our research in early identification of
      infants and toddlers at risk for feeding problems.

PMID- 15190053
TI  - The gene controlling marijuana psychoactivity: molecular cloning and heterologous
      expression of Delta1-tetrahydrocannabinolic acid synthase from Cannabis sativa L.
AB  - Delta(1)-tetrahydrocannabinolic acid (THCA) synthase is the enzyme that catalyzes
      oxidative cyclization of cannabigerolic acid into THCA, the precursor of Delta(1)
      tetrahydrocannabinol. We cloned a novel cDNA (GenBank trade mark accession number
      AB057805) encoding THCA synthase by reverse transcription and polymerase chain
      reactions from rapidly expanding leaves of Cannabis sativa. This gene consists of
      a 1635-nucleotide open reading frame, encoding a 545-amino acid polypeptide of
      which the first 28 amino acid residues constitute the signal peptide. The
      predicted molecular weight of the 517-amino acid mature polypeptide is 58,597 Da.
      Interestingly, the deduced amino acid sequence exhibited high homology to
      berberine bridge enzyme from Eschscholtzia californica, which is involved in
      alkaloid biosynthesis. The liquid culture of transgenic tobacco hairy roots
      harboring the cDNA produced THCA upon feeding of cannabigerolic acid,
      demonstrating unequivocally that this gene encodes an active THCA synthase.
      Overexpression of the recombinant THCA synthase was achieved using a baculovirus
      insect expression system. The purified recombinant enzyme contained covalently
      attached FAD cofactor at a molar ratio of FAD to protein of 1:1. The mutant
      enzyme constructed by changing His-114 of the wild-type enzyme to Ala-114
      exhibited neither absorption characteristics of flavoproteins nor THCA synthase
      activity. Thus, we concluded that the FAD binding residue is His-114 and that the
      THCA synthase reaction is FAD-dependent. This is the first report on molecular
      characterization of an enzyme specific to cannabinoid biosynthesis.

PMID- 15190052
TI  - The impact of vitamins and/or mineral supplementation on blood pressure in type 2
      diabetes.
AB  - OBJECTIVE: The present study designed to assess the effect of Mg+Zn, vitamin C+E,
      and combination of these micronutrients on blood pressure in type 2 diabetic
      patients. MATERIALS AND METHODS: In a randomized, double-blind, placebo
      controlled clinical trial, 69 type 2 diabetic patients were randomly divided into
      four groups, each group receiving one of the following daily supplement for three
      months; group M: 200 mg Mg and 30 mg Zn (n = 16), group V: 200 mg vitamin C and
      150 mg vitamin E (n = 18), group MV: minerals plus vitamins (n = 17), group P:
      placebo (n = 18). Blood pressure was measured at the beginning and at the end of
      the trial. Treatment effects were analyzed by general linear modeling. RESULTS:
      Results indicate that after three months of supplementation levels of systolic,
      diastolic and mean blood pressure decreased significantly in the MV group by 8
      mmHg (122 +/- 16 vs. 130 +/- 19 mmHg), 6 mmHg (77 +/- 9 vs. 83 +/- 11 mmHg), and
      7 mmHg (92 +/- 9 vs. 99 +/- 13 mmHg), respectively (p < 0.05). Also combination
      of vitamin and mineral supplementation had significantly effects in increasing
      serum potassium (p < 0.05) and in decreasing serum malondialdehyde (p < 0.05).
      There was no significant change in the levels of these parameters in the other
      three groups. CONCLUSION: The results of the present study indicated that in type
      2 diabetic patients a combination of vitamins and minerals, rather than vitamin C
      and E or Mg and Zn, might decrease blood pressure.

PMID- 15190054
TI  - Structure-based analysis of the metal-dependent mechanism of H-N-H endonucleases.
AB  - Controversy surrounds the metal-dependent mechanism of H-N-H endonucleases,
      enzymes involved in a variety of biological functions, including intron homing
      and DNA repair. To address this issue we determined the crystal structures for
      complexes of the H-N-H motif containing bacterial toxin colicin E9 with Zn(2+),
      Zn(2+).DNA, and Mg(2+).DNA. The structures show that the rigid V-shaped
      architecture of the active site does not undergo any major conformational changes
      on binding to the minor groove of DNA and that the same interactions are made to
      the nucleic acid regardless of which metal ion is bound to the enzyme. The
      scissile phosphate contacts the single metal ion of the motif through distortion
      of the DNA brought about by the insertion of the Arg-96-Glu-100 salt bridge into
      the minor groove and a network of contacts to the DNA phosphate backbone that
      straddle the metal site. The Mg(2+)-bound structure reveals an unusual
      coordination scheme involving two H-N-H histidine residues, His-102 and His-127.
      The mechanism of DNA cleavage is likely related to that of other single metal ion
      dependent endonucleases, such as I-PpoI and Vvn, although in these enzymes the
      single alkaline earth metal ion is coordinated by oxygen-bearing amino acids. The
      structures also provide a rationale as to why H-N-H endonucleases are inactive in
      the presence of Zn(2+) but active with other transition metal ions such as
      Ni(2+). This is because of coordination of the Zn(2+) ion through a third
      histidine, His-131. "Active" transition metal ions are those that bind more
      weakly to the H-N-H motif because of the disengagement of His-131, which we
      suggest allows a water molecule to complete the catalytic cycle.

PMID- 15190055
TI  - A pattern recognition serine proteinase triggers the prophenoloxidase activation
      cascade in the tobacco hornworm, Manduca sexta.
AB  - A serine proteinase cascade in insect hemolymph mediates prophenoloxidase
      activation, a defense mechanism against pathogen or parasite infection. Little is
      known regarding its initiating proteinase or how this enzyme is activated in
      response to invading microorganisms. We have isolated from the tobacco hornworm,
      Manduca sexta, a cDNA encoding a modular protein designated hemolymph proteinase
      14 (HP14). It contains five low density lipoprotein receptor class A repeats, a
      Sushi domain, a unique Cys-rich region, and a proteinase-catalytic domain. The
      HP14 mRNA exists in fat body and hemocytes of the naive larvae, and its level
      increases significantly at 24 h after a bacterial challenge. We expressed proHP14
      with a carboxyl-terminal hexahistidine tag in a baculovirus/insect cell system
      and detected the recombinant protein in two forms. The 87-kDa protein was
      primarily intracellular, whereas the 75-kDa form was present in the medium.
      Interaction with peptidoglycan resulted in proteolytic processing of the purified
      zymogen and generation of an amidase activity. Supplementation of hemolymph with
      proHP14 greatly enhanced prophenoloxidase activation in response to Micrococcus
      luteus. These data suggest that proHP14 is a pattern recognition protein that
      binds to bacteria and autoactivates and triggers the prophenoloxidase activation
      system in the hemolymph of M. sexta.

PMID- 15190056
TI  - Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the
      signaling of selected Galphaq-coupled protein receptors.
AB  - 5-Hydroxytryptamine 2A (5-HT(2A)) serotonin receptors are important for a variety
      of functions including vascular smooth muscle contraction, platelet aggregation,
      and the modulation of perception, cognition, and emotion. In a search for 5
      HT(2A) receptor-interacting proteins, we discovered that caveolin-1 (Cav-1), a
      scaffolding protein enriched in caveolae, complexes with 5-HT(2A) receptors in a
      number of cell types including C6 glioma cells, transfected HEK-293 cells, and
      rat brain synaptic membrane preparations. To address the functional significance
      of this interaction, we performed RNA interference-mediated knockdown of Cav-1 in
      C6 glioma cells, a cell type that endogenously expresses both 5-HT(2A) receptors
      and Cav-1. We discovered that the in vitro knockdown of Cav-1 in C6 glioma cells
      nearly abolished 5-HT(2A) receptor-mediated signal transduction as measured by
      calcium flux assays. RNA interference-mediated knockdown of Cav-1 also greatly
      attenuated endogenous Galpha(q)-coupled P2Y purinergic receptor-mediated
      signaling without altering the signaling of PAR-1 thrombin receptors. Cav-1
      appeared to modulate 5-HT(2A) signaling by facilitating the interaction of 5
      HT(2A) receptors with Galpha(q). These studies provide compelling evidence for a
      prominent role of Cav-1 in regulating the functional activity of not only 5
      HT(2A) serotonin receptors but also selected Galpha(q)-coupled receptors.

PMID- 15190057
TI  - Lipopolysaccharide and double-stranded RNA up-regulate toll-like receptor 2
      independently of myeloid differentiation factor 88.
AB  - Toll-like receptor 2 (TLR2) is a signaling receptor for a variety of microbial
      products, including bacterial lipoproteins and peptidoglycan, and is central in
      initiating immune responses toward Gram-positive bacteria, spirochetes, and
      mycobacteria. The mechanisms behind regulation of TLR2 protein expression are
      still not well understood. By using a newly developed monoclonal antibody against
      mouse TLR2, we detected TLR2 protein expression on macrophages, neutrophils, and
      dendritic cells. Endogenous macrophage TLR2 localized mostly to the cell
      membrane, with particular accumulation around phagosomes containing zymosan.
      Treatment of macrophages with the TLR2 antibody diminished cellular response to
      lipoproteins and down-regulated membrane TLR2. Marked up-regulation of surface
      TLR2 was observed on macrophages in response to whole bacteria, lipoproteins,
      lipopolysaccharide, poly(I-C) (double-stranded RNA), R848, and CpG DNA, and this
      up-regulation appeared to be a very sensitive marker for the presence of
      microbial products. Up-regulation of TLR2 in response to stimuli correlated with
      an increased response to secondary lipoprotein exposure following a low
      concentration of primary lipoprotein challenge. By comparison, exposure to a
      larger primary challenge induced a hyporeactive state. Most interestingly,
      lipopolysaccharide- and double-stranded RNA-induced up-regulation of surface TLR2
      in macrophages was found to be MyD88-independent, whereas the up-regulation in
      response to lipoproteins, R848, and CpG DNA was absent in MyD88-deficient cells.
      We conclude that complex mechanisms regulate expression and signaling via TLR2.
      Up-regulation of TLR2 in the presence of low, yet clinically relevant amounts of
      microbial products may be an important mechanism by which the immune system
      boosts its response to a beginning infection.

PMID- 15190058
TI  - Promotion of hyperphosphorylation by frontotemporal dementia tau mutations.
AB  - Mutations in the tau gene are known to cosegregate with the disease in
      frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).
      However, the molecular mechanism by which these mutations might lead to the
      disease is not understood. Here, we show that four of the FTDP-17 tau mutations,
      R406W, V337M, G272V, and P301L, result in tau proteins that are more favorable
      substrates for phosphorylation by brain protein kinases than the wild-type,
      largest four-repeat protein tau4L and tau4L more than tau3L. In general, at all
      the sites studied, mutant tau proteins were phosphorylated faster and to a higher
      extent than tau4L and tau4L > tau3L. The most dramatic difference found was in
      the rate and level of phosphorylation of tau4L(R406W) at positions Ser-396, Ser
      400, Thr-403, and Ser-404. Phosphorylation of this mutant tau was 12 times faster
      and 400% greater at Ser-396 and less than 30% at Ser-400, Thr-403, and Ser-404
      than phosphorylation of tau4L. The mutated tau proteins polymerized into
      filaments when 4-6 mol of phosphate per mol of tau were incorporated, whereas
      wild-type tau required approximately 10 mol of phosphate per mol of protein to
      self-assemble. Mutated and wild-type tau proteins were able to sequester normal
      tau upon incorporation of approximately 4 mol of phosphate per mol of protein,
      which was achieved at as early as 30 min of phosphorylation in the case of mutant
      tau proteins. These findings taken together suggest that the mutations in tau
      might cause neurodegeneration by making the protein a more favorable substrate
      for hyperphosphorylation.

PMID- 15190059
TI  - Prolonging the action of protein and peptide drugs by a novel approach of
      reversible polyethylene glycol modification.
AB  - Polyethylene glycol (PEG)-conjugated therapeutic peptides/proteins have been
      shown to exhibit clinical properties superior to those of their corresponding
      unmodified parent molecules. However, the desirable pharmacological features
      gained by protein PEGylation become irrelevant if conjugates are inactivated or
      cannot reach their target tissues. Here we describe the design and synthesis of
      MAL-FMS-OSU. This bifunctional agent enables PEG chains to be linked to peptides
      and proteins through a slowly hydrolysable chemical bond. PEG-FMS-peptide/protein
      conjugates thus formed undergo spontaneous hydrolysis at a slow rate upon
      incubation at pH 8.5, 37 degrees C with a t(1/2) value of 8-14 +/- 2 h,
      generating the unmodified parent molecule. The validity of this approach was
      studied with exendin-4 and human growth hormone. A single subcutaneous
      administration of PEG(40,000)-FMS-exendin-4 facilitated a prolonged and stable
      reduction in glucose levels in mice (t(1/2) = 30 +/- 2 h) and exceeded the effect
      obtained by the same dose of the native hormone by 7-8 times.

PMID- 15190060
TI  - Differential protein expression analysis of Leishmania major reveals novel roles
      for methionine adenosyltransferase and S-adenosylmethionine in methotrexate
      resistance.
AB  - Leishmania is a trypanosomatid parasite causing serious disease and displaying
      resistance to various drugs. Here, we present comparative proteomic analyses of
      Leishmania major parasites that have been either shocked with or selected in
      vitro for high level resistance to the model antifolate drug methotrexate.
      Numerous differentially expressed proteins were identified by these experiments.
      Some were associated with the stress response, whereas others were found to be
      overexpressed due to genetic linkage to primary resistance mediators present on
      DNA amplicons. Several proteins not previously associated with resistance were
      also identified. The role of one of these, methionine adenosyltransferase, was
      confirmed by gene transfection and metabolite analysis. After a single exposure
      to low levels of methotrexate, L. major methionine adenosyltransferase
      transfectants could grow at high concentrations of the drug. Methotrexate
      resistance was also correlated to increased cellular S-adenosylmethionine levels.
      The folate and S-adenosylmethionine regeneration pathways are intimately
      connected, which may provide a basis for this novel resistance phenotype. This
      thorough comparative proteomic analysis highlights the variety of responses
      required for drug resistance to be achieved.

PMID- 15190061
TI  - Regulated production of a peroxisome proliferator-activated receptor-gamma ligand
      during an early phase of adipocyte differentiation in 3T3-L1 adipocytes.
AB  - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear hormone
      receptor that is critical for adipogenesis and insulin sensitivity. Ligands for
      PPARgamma include some polyunsaturated fatty acids and prostanoids and the
      synthetic high affinity antidiabetic agents thiazolidinediones. However, the
      identity of a biologically relevant endogenous PPARgamma ligand is unknown, and
      limited insight exists into the factors that may regulate production of
      endogenous PPARgamma ligands during adipocyte development. To address this
      question, we created a line of 3T3-L1 preadipocytes that carry a beta
      galactosidase-based PPARgamma ligand-sensing vector system. In this system,
      induction of adipogenesis resulted in elevated beta-galactosidase activity that
      signifies activation of PPARgamma via its ligand-binding domain (LBD) and
      suggests generation and/or accumulation of a ligand moiety. The putative
      endogenous ligand appeared early in adipogenesis in response to increases in
      cAMP, accumulated in the medium, and dissipated later in adipogenesis.
      Organically extracted and high pressure liquid chromatography-fractionated
      conditioned media from differentiating cells, but not from mature adipocytes,
      were enriched in this activity. One or more components within the organic extract
      activated PPARgamma through interaction with its LBD, induced lipid accumulation
      in 3T3-L1 cells as efficiently as the differentiation mixture, and competed for
      binding of rosiglitazone to the LBD of PPARgamma. The active species appears to
      be different from other PPARgamma ligands identified previously. Our findings
      suggest that a novel biologically relevant PPARgamma ligand is transiently
      produced in 3T3-L1 cells during adipogenesis.

PMID- 15190062
TI  - Paramecium bursaria chlorella virus-1 encodes an unusual arginine decarboxylase
      that is a close homolog of eukaryotic ornithine decarboxylases.
AB  - Paramecium bursaria chlorella virus (PBCV-1) is a large double-stranded DNA virus
      that infects chlorella-like green algae. The virus encodes a homolog of
      eukaryotic ornithine decarboxylase (ODC) that was previously demonstrated to be
      capable of decarboxylating l-ornithine. However, the active site of this enzyme
      contains a key amino acid substitution (Glu for Asp) of a residue that interacts
      with the delta-amino group of ornithine analogs in the x-ray structures of ODC.
      To determine whether this active-site change affects substrate specificity,
      kinetic analysis of the PBCV-1 decarboxylase (PBCV-1 DC) on three basic amino
      acids was undertaken. The k(cat)/K(m) for l-arginine is 550-fold higher than for
      either l-ornithine or l-lysine, which were decarboxylated with similar
      efficiency. In addition, alpha-difluoromethylarginine was a more potent inhibitor
      of the enzyme than alpha-difluoromethylornithine. Mass spectrometric analysis
      demonstrated that inactivation was consistent with the formation of a covalent
      adduct at Cys(347). These data demonstrate that PBCV-1 DC should be reclassified
      as an arginine decarboxylase. The eukaryotic ODCs, as well as PBCV-1 DC, are only
      distantly related to the bacterial and plant arginine decarboxylases from their
      common beta/alpha-fold class; thus, the finding that PBCV-1 DC prefers l-arginine
      to l-ornithine was unexpected based on evolutionary analysis. Mutational analysis
      was carried out to determine whether the Asp-to-Glu substitution at position 296
      (position 332 in Trypanosoma brucei ODC) conferred the change in substrate
      specificity. This residue was found to be an important determinant of substrate
      binding for both l-arginine and l-ornithine, but it is not sufficient to encode
      the change in substrate preference.

PMID- 15190063
TI  - Inhibition of TATA binding protein dimerization by RNA polymerase III
      transcription initiation factor Brf1.
AB  - The Brf1 subunit of TFIIIB plays an important role in recruiting the TATA-binding
      protein (TBP) to the up-stream region of genes transcribed by RNA polymerase III.
      When TBP is not bound to promoters, it sequesters its DNA binding domain through
      dimerization. Promoter assembly factors therefore might be required to dissociate
      TBP into productively binding monomers. Here we show that Saccharomyces
      cerevisiae Brf1 induces TBP dimers to dissociate. The high affinity TBP binding
      domain of Brf1 is not sufficient to promote TBP dimer dissociation but in
      addition requires the TFIIB homology domain of Brf1. A model is proposed to
      explain how two distinct functional domains of Brf1 work in concert to dissociate
      TBP into monomers.

PMID- 15190064
TI  - A novel mechanism for the inhibition of hyaluronan biosynthesis by 4
      methylumbelliferone.
AB  - Specific inhibitors of hyaluronan (HA) biosynthesis can be valuable therapeutic
      agents to prevent cancer invasion and metastasis. We have found previously that 4
      methylumbelliferone (MU) inhibits HA synthesis in human skin fibroblasts and in
      group C Streptococcus. In this paper, the inhibition mechanism in mammalian cells
      was investigated using rat 3Y1 fibroblasts stably expressing HA synthase (HAS) 2.
      Exposure of the transfectants to the inhibitor resulted in significant reduction
      of HA biosynthesis and matrix formation. The evaluation of HAS transcripts and
      analysis of cell-free HA synthesis demonstrated the post-transcriptional
      suppression of HAS activity by MU. Most interesting, the post-transcriptional
      suppression of HAS activity was also observed using p-nitrophenol, a well known
      substrate for UDP-glucuronyltransferases (UGT). We investigated whether the
      inhibition was exerted by the glucuronidation of MU using both high pressure
      liquid chromatography and TLC analyses. The production of MU-glucuronic acid
      (GlcUA) was consistent with the inhibition of HA synthesis in HAS transfectants.
      MU-GlcUA was also detected at a similar level in control cells, suggesting that
      the glucuronidation was mediated by an endogenous UGT. Elevated levels of UGT
      significantly enhanced the inhibitory effects of MU. In contrast, the inhibition
      by MU was diminished to the control level when an excess of UDP-GlcUA was added
      to the cell-free HA synthesis system. We propose a novel mechanism for the MU
      mediated inhibition of HA synthesis involving the glucuronidation of MU by
      endogenous UGT resulting in a depletion of UDP-GlcUA.

PMID- 15190065
TI  - Genetic, biochemical, and transcriptional responses of Saccharomyces cerevisiae
      to the novel immunomodulator FTY720 largely mimic those of the natural
      sphingolipid phytosphingosine.
AB  - Sphingolipids are signaling molecules that influence diverse cellular functions
      from control of the cell cycle to degradation of plasma membrane proteins. The
      synthetic sphingolipid-like compound FTY720 is an immunomodulating agent in
      clinical trials for transplant graft maintenance. In this report, we compare the
      effects of the natural yeast sphingolipid phytosphingosine with FTY720 in
      Saccharomyces cerevisiae. We show that the multicopy suppressor genes that induce
      growth resistance to FTY720 also confer resistance to growth-inhibitory
      concentrations of phytosphingosine. In addition, mutants for ubiquitination
      pathway proteins are shown to be resistant to the growth-inhibiting effect of
      both FTY720 and phytosphingosine. We observe fewer similarities between
      sphingosine and FTY720 than between FTY720 and phytosphingosine as revealed by
      genetic studies. Yeast cells lacking the specific sphingosine kinase LCB4 are
      sensitive to phytosphingosine and FTY720 but resistant to sphingosine, suggesting
      that FTY720 and phytosphingosine have a more related mechanism of action. Gene
      expression profile comparisons of sensitive and resistant yeast cells exposed to
      FTY720 and phytosphingosine highlight a number of similarities. In response to
      treatment with these compounds, approximately 77% of the genes that are regulated
      >2-fold by FTY720 also respond to phytosphingosine in the same direction in the
      parent strain. In addition, a close inspection of TAT1 and TAT2 transporters
      following exposure to phytosphingosine indicates that TAT1 protein is degraded in
      a similar fashion upon treatment with FTY720 and phytosphingosine. There were
      differences, however, with respect to the TAT2 protein level and the expression
      profiles of a subset of genes. The genetic, transcriptional, and biochemical data
      together indicate that FTY720 and phytosphingosine influence similar pathways in
      yeast cells. These findings offer further insights into the physiological
      pathways influenced by these compounds in all eukaryotic cells and help us to
      understand the therapeutic consequences of FTY720 in humans.

PMID- 15190066
TI  - Lipid rafts in higher plant cells: purification and characterization of Triton X
      100-insoluble microdomains from tobacco plasma membrane.
AB  - A large body of evidence from the past decade supports the existence of
      functional microdomains in membranes of animal and yeast cells, which play
      important roles in protein sorting, signal transduction, or infection by
      pathogens. They are based on the dynamic clustering of sphingolipids and
      cholesterol or ergosterol and are characterized by their insolubility, at low
      temperature, in nonionic detergents. Here we show that similar microdomains also
      exist in plant plasma membrane isolated from both tobacco leaves and BY2 cells.
      Tobacco lipid rafts were found to be greatly enriched in a sphingolipid,
      identified as glycosylceramide, as well as in a mixture of stigmasterol,
      sitosterol, 24-methylcholesterol, and cholesterol. Phospho- and
      glycoglycerolipids of the plasma membrane were largely excluded from lipid rafts.
      Membrane proteins were separated by one- and two-dimensional gel electrophoresis
      and identified by tandem mass spectrometry or use of specific antibody. The data
      clearly indicate that tobacco microdomains are able to recruit a specific set of
      the plasma membrane proteins and exclude others. We demonstrate the recruitment
      of the NADPH oxidase after elicitation by cryptogein and the presence of the
      small G protein NtRac5, a negative regulator of NADPH oxidase, in lipid rafts.

PMID- 15190067
TI  - The tumor suppressor adenomatous polyposis coli and caudal related homeodomain
      protein regulate expression of retinol dehydrogenase L.
AB  - Development of normal colon epithelial cells proceeds through a systematic
      differentiation of cells that emerge from stem cells within the base of colon
      crypts. Genetic mutations in the adenomatous polyposis coli (APC) gene are
      thought to cause colon adenoma and carcinoma formation by enhancing colonocyte
      proliferation and impairing differentiation. We currently have a limited
      understanding of the cellular mechanisms that promote colonocyte differentiation.
      Herein, we present evidence supporting a lack of retinoic acid biosynthesis as a
      mechanism contributing to the development of colon adenomas and carcinomas.
      Microarray and reverse transcriptase-PCR analyses revealed reduced expression of
      two retinoid biosynthesis genes: retinol dehydrogenase 5 (RDH5) and retinol
      dehydrogenase L (RDHL) in colon adenomas and carcinomas as compared with normal
      colon. Consistent with the adenoma and carcinomas samples, seven colon carcinoma
      cell lines also lacked expression of RDH5 and RDHL. Assessment of RDH enzymatic
      activity within these seven cell lines showed poor conversion of retinol into
      retinoic acid when compared with normal cells such as normal human mammary
      epithelial cells. Reintroduction of wild type APC into an APC-deficient colon
      carcinoma cell line (HT29) resulted in increased expression of RDHL without
      affecting RDH5. APC-mediated induction of RDHL was paralleled by increased
      production of retinoic acid. Investigations into the mechanism responsible for
      APC induction of RDHL indicated that beta-catenin fails to repress RDHL. The
      colon-specific transcription factor CDX2, however, activated an RDHL promoter
      construct and induced endogenous RDHL. Finally, the induction of RDHL by APC
      appears dependent on the presence of CDX2. We propose a novel role for APC and
      CDX2 in controlling retinoic acid biosynthesis and in promoting a retinoid
      induced program of colonocyte differentiation.

PMID- 15190068
TI  - A protein sequestering system reveals control of cellular programs by the
      transcriptional coactivator HCF-1.
AB  - The mammalian transcriptional coactivator HCF-1 is a critical component of the
      multiprotein herpes simplex virus immediate early gene enhancer core complex. The
      protein has also been implicated in basic cellular processes such as cell-cycle
      progression, transcriptional coactivation, and mRNA processing. Functions have
      been attributed to HCF-1 primarily from analyses of protein-protein interactions
      and from the cell-cycle-arrested phenotype of an HCF-1 temperature-sensitive
      mutant. However, neither the mechanisms involved nor specific cellular
      transcriptional targets have been identified. As the protein is essential for
      cell viability and proliferation, a genetic system was developed to specifically
      sequester the nuclear factor in the cell cytoplasm in a regulated manner. This
      approach exhibits no significant cell toxicity yet clearly demonstrates the
      requirement of available nuclear HCF-1 for herpes simplex virus immediate early
      gene expression during productive infection. Additionally, cellular
      transcriptional events were identified that contribute to understanding the
      functions ascribed to the protein and implicate the protein in events that impact
      the regulation of critical cellular processes.

PMID- 15190069
TI  - Site-specific loading of an MCM protein complex in a DNA replication initiation
      zone upstream of the c-MYC gene in the HeLa cell cycle.
AB  - The MCM proteins participate in an orderly association, beginning with the origin
      recognition complex, that culminates in the initiation of chromosomal DNA
      replication. Among these, MCM proteins 4, 6, and 7 constitute a subcomplex that
      reportedly possesses DNA helicase activity. Little is known about DNA sequences
      initially bound by these MCM proteins or about their cell cycle distribution in
      the chromatin. We have determined the locations of certain MCM and associated
      proteins by chromatin immunoprecipitation (ChIP) in a zone of initiation of DNA
      replication upstream of the c-MYC gene in the HeLa cell cycle. MCM7 and its clamp
      loading partner Cdc6 are highly specifically colocalized by ChIP and re-ChIP in
      G(1) and early S on a 198-bp segment located near the center of the initiation
      zone. ChIP and Re-ChIP colocalizes MCM7 and ORC1 to the same segment specifically
      in late G(1). MCM proteins 6 and 7 can be coimmunoprecipitated throughout the
      cell cycle, whereas MCM4 is reduced in the complex in late S and G(2),
      reappearing upon mitosis. MCM7 is not visualized by immunohistochemistry on
      metaphase chromosomes. MCM7 is recruited to multiple sites in chromatin in S and
      G(2), at which time it is not detected with ORC1. The rate of dissemination is
      surprisingly slow and is unlikely to be simply attributed to progression with
      replication forks. Results indicate sequence-specific loading of MCM proteins
      onto DNA in late G(1) followed by a recruitment to multiple sites in chromatin
      subsequent to replication.

PMID- 15190070
TI  - DNA-protein kinase catalytic subunit-interacting protein KIP binds telomerase by
      interacting with human telomerase reverse transcriptase.
AB  - Telomere homeostasis, a process that is essential for continued cell
      proliferation and genomic stability, is regulated by endogenous telomerase and a
      collection of associated proteins. In this paper, a protein called KIP
      (previously reported as a protein that binds specifically to DNA-dependent
      protein kinase), has been identified as a telomerase-regulating activity based on
      the following pieces of evidence. First, complexes between KIP and the catalytic
      subunit of telomerase (hTERT) were identified using the yeast two-hybrid
      technique. Second, antibodies specific to KIP immunoprecipitate human telomerase
      in cell-free extracts. Third, immunolocalization experiments demonstrate that KIP
      is a nuclear protein that co-localizes with hTERT in cells. Fourth, KIP binds to
      hTERT both in vitro and in vivo in the absence of human telomerase RNA or
      telomeric DNA, thus defining the catalytic subunit of telomerase as the site of
      physical interaction. Fifth, co-immunoprecipitation experiments suggest that KIP
      hTERT complexes form readily in cells and that overexpression of KIP in
      telomerase-positive cells increases endogenous telomerase activity. Finally,
      continued overexpression of KIP (60 population doublings) resulted in cells with
      elongated telomeres; thus, KIP directly or indirectly stimulates telomerase
      activity through hTERT and contributes to telomere lengthening. The collective
      data in this paper suggest that KIP plays a positive role in telomere length
      maintenance and/or regulation and may represent a novel target for anti-cancer
      drug development.

PMID- 15190071
TI  - Solution structure and antibody binding studies of the envelope protein domain
      III from the New York strain of West Nile virus.
AB  - The solution structure of domain III from the New York West Nile virus strain 385
      99 (WN-rED3) has been determined by NMR methods. The West Nile domain III
      structure is a beta-barrel structure formed from seven anti-parallel beta-strands
      in two beta-sheets. One anti-parallel beta-sheet consists of beta-strands beta1
      (Phe(299)-Asp(307)), beta2 (Val(313)-Tyr(319)), beta4 (Arg(354)-Leu(355)), and
      beta5 (Lys(370)-Glu(376)) arranged so that beta2 is flanked on either side by
      beta1 and beta5. The short beta4 flanks the end of the remaining side of beta5.
      The remaining anti-parallel beta-sheet is formed from strands beta3 (Ile(340)
      Val(343)), beta6 (Gly(380)-Arg(388)), and beta7 (Gln(391)-Lys(399)) arranged with
      beta6 at the center. Residues implicated in antigenic differences between
      different West Nile virus strains (and other flaviviruses) and neutralization are
      located on the outer surface of the protein. Characterization of the binding of
      monoclonal antibodies to WN-rED3 mutants, which were identified through
      neutralization escape experiments, indicate that antibody neutralization directly
      correlates with binding affinities. These studies provide an insight into
      theoretical virus-receptor interaction points, structure of immunogenic
      determinants, and potential targets for antiviral agents against West Nile virus
      and highlight differences between West Nile virus and other flavivirus structures
      that may represent critical determinants of virulence.

PMID- 15190072
TI  - Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth
      factor receptor-2 activation supports osteoblast differentiation.
AB  - Fibroblast growth factors (FGFs) play an important regulatory role in skeletal
      development and bone formation. However, the FGF signaling mechanisms controlling
      osteoblast function are poorly understood. Here, we identified a role for the Src
      family members Lyn and Fyn in osteoblast differentiation promoted by constitutive
      activation of FGF receptor-2 (FGFR2). We show that the overactive FGFR2 S252W
      mutation induced decreased Src family kinase tyrosine phosphorylation and
      activity associated with decreased Lyn and Fyn protein expression in human
      osteoblasts. Pharmacological stimulation of Src family kinases or transfection
      with Lyn or Fyn vectors repressed alkaline phosphatase (ALP) up-regulation
      induced by overactive FGFR2. Inhibition of proteasome activity restored normal
      Lyn and Fyn expression and ALP activity in FGFR2 mutant osteoblasts.
      Immunoprecipitation studies showed that Lyn, Fyn, and FGFR2 interacted with the
      ubiquitin ligase c-Cbl and ubiquitin. Transfection with c-Cbl in which the RING
      finger was disrupted or with c-Cbl with a point mutation that abolishes the
      binding ability of the Cbl phosphotyrosine-binding domain restored Src kinase
      activity and Lyn, Fyn, and FGFR2 levels and reduced ALP up-regulation in mutant
      osteoblasts. Thus, constitutive FGFR2 activation induces c-Cbl-dependent Lyn and
      Fyn proteasome degradation, resulting in reduced Lyn and Fyn kinase activity,
      increased ALP expression, and FGFR2 down-regulation. This reveals a common Cbl
      mediated negative feedback mechanism controlling Lyn, Fyn, and FGFR2 degradation
      in response to overactive FGFR2 and indicates a role for Cbl-dependent down
      regulation of Lyn and Fyn in osteoblast differentiation induced by constitutive
      FGFR2 activation.

PMID- 15190073
TI  - Metallothionein-III prevents gamma-ray-induced 8-oxoguanine accumulation in
      normal and hOGG1-depleted cells.
AB  - Metallothioneins (MT) play an important biological role in preventing oxidative
      damage to cells. We have previously demonstrated that the efficiency of the
      protective effect of MT-III against the DNA degradation from oxidative damage was
      much higher than that of MT-I/II. As an extension of the latter investigation,
      this study aimed to assess the ability of MT-III to suppress 8-oxoguanine (8
      oxoG), which is one of the major base lesions formed after an oxidative attack to
      DNA and the mutant frequency of the HPRT gene in human fibroblast GM00637 cells
      upon exposure to gamma-rays. We found that human MT-III expression decreased the
      level of 8-oxoG and mutation frequency in the gamma-irradiated cells. Using an 8
      oxoguanine DNA glycosylase (OGG1)-specific siRNAs, we also found that MT-III
      expression resulted in the suppression of the gamma-radiation-induced 8-oxoG
      accumulation and mutation in the OGG1-depleted cells. Moreover, the down
      regulation of MT in human neuroblastoma SKNSH cells induced by MT-specific siRNA
      led to a significant increase in the 8-oxoG level, after exposure to gamma
      irradiation. These results suggest that under the conditions of gamma-ray
      oxidative stress, MT-III prevents the gamma-radiation-induced 8-oxoG accumulation
      and mutation in normal and hOGG1-depleted cells, and this suppression might, at
      least in part, contribute to the anticarcinogenic and neuroprotective role of MT
      III.

PMID- 15190074
TI  - Reverse gyrase recruitment to DNA after UV light irradiation in Sulfolobus
      solfataricus.
AB  - Induction of DNA damage triggers a complex biological response concerning not
      only repair systems but also virtually every cell function. DNA topoisomerases
      regulate the level of DNA supercoiling in all DNA transactions. Reverse gyrase is
      a peculiar DNA topoisomerase, specific to hyperthermophilic microorganisms, which
      contains a helicase and a topoisomerase IA domain that has the unique ability to
      introduce positive supercoiling into DNA molecules. We show here that reverse
      gyrase of the archaean Sulfolobus solfataricus is mobilized to DNA in vivo after
      UV irradiation. The enzyme, either purified or in cell extracts, forms stable
      covalent complexes with UV-damaged DNA in vitro. We also show that the reverse
      gyrase translocation to DNA in vivo and the stabilization of covalent complexes
      in vitro are specific effects of UV light irradiation and do not occur with the
      intercalating agent actinomycin D. Our results suggest that reverse gyrase might
      participate, directly or indirectly, in the cell response to UV light-induced DNA
      damage. This is the first direct evidence of the recruitment of a topoisomerase
      IA enzyme to DNA after the induction of DNA damage. The interaction between
      helicase and topoisomerase activities has been previously proposed to facilitate
      aspects of DNA replication or recombination in both Bacteria and Eukarya. Our
      results suggest a general role of the association of such activities in
      maintaining genome integrity and a mutual effect of DNA topology and repair.

PMID- 15190075
TI  - Wnt10b inhibits development of white and brown adipose tissues.
AB  - Wnt is a family of secreted signaling proteins that regulate diverse
      developmental processes. Activation of canonical Wnt signaling by Wnt10b inhibits
      differentiation of preadipocytes in vitro. To determine whether Wnt signaling
      blocks adipogenesis in vivo, we created transgenic mice in which Wnt10b is
      expressed from the FABP4 promoter. Expression of Wnt10b in adipose impairs
      development of this tissue throughout the body, with a decline of approximately
      50% in total body fat and a reduction of approximately 60% in weight of
      epididymal and perirenal depots. FABP4-Wnt10b mice resist accumulation of adipose
      tissue when fed a high fat diet. Furthermore, transgenic mice are more glucose
      tolerant and insulin-sensitive than wild type mice. Expression of Wnt10b from the
      FABP4 promoter also blocks development of brown adipose tissue. Interscapular
      tissue of FABP4-Wnt10b mice has the visual appearance of white adipose tissue but
      expresses neither brown (e.g. uncoupling protein 1) nor white adipocyte markers.
      Transgenic mice are unable to maintain a core body temperature when placed in a
      cold environment, providing further evidence that Wnt10b inhibits development of
      brown adipose tissue. Although food intake is not altered in FABP4-Wnt10b mice,
      oxygen consumption is decreased. Thus, FABP4-Wnt10b mice on a chow diet gain more
      weight than controls, largely because of an increase in weight of skin. In
      summary, inhibition by Wnt10b of white and brown adipose tissue development
      results in lean mice without lipodystrophic diabetes.

PMID- 15190077
TI  - Peroxisome proliferator-activated receptor gamma activation can regulate beta
      catenin levels via a proteasome-mediated and adenomatous polyposis coli
      independent pathway.
AB  - The transcription factor peroxisome proliferator-activated receptor gamma
      (PPARgamma) belongs to the family of nuclear hormone receptors and consists of
      two isotypes, PPARgamma1 and PPARgamma2. Our earlier studies have shown that
      troglitazone (TZD)-mediated activation of PPARgamma2 in hepatocytes inhibits
      growth and attenuates cyclin D1 transcription via modulating CREB levels. Because
      this process of growth inhibition was also associated with an inhibition of beta
      catenin expression at a post-translational level, our aim was to elucidate the
      mechanism involved. beta-Catenin is a multifunctional protein, which can regulate
      cell-cell adhesion by interacting with E-cadherin and other cellular processes
      via regulating target gene transcription in association with TCF/LEF
      transcription factors. Two adenomatous polyposis coli (APC)-dependent proteasomal
      degradation pathways, one involving glycogen synthase kinase 3beta (GSK3beta) and
      the other involving p53-Siah-1, degrade excess beta-catenin in normal cells. Our
      immunofluorescence and Western blot studies indicated a TZD-dependent decrease in
      cytoplasmic and membrane-bound beta-catenin, indicating no increase in its
      membrane translocation. This was associated with a reduction in E-cadherin
      expression. PPARgamma2 activation inhibited GSK3beta kinase activity, and
      pharmacological inhibition of GSK3beta activity was unable to restore beta
      catenin expression following PPARgamma2 activation. Additionally, this beta
      catenin degradation pathway was operative in cells, with inactivating mutations
      of both APC and p53. Inhibition of the proteasomal pathway inhibited PPARgamma2
      mediated degradation of beta-catenin, and incubation with TZD increased
      ubiquitination of beta-catenin. We conclude that PPARgamma2-mediated suppression
      of beta-catenin levels involves a novel APC/GSK3beta/p53-independent
      ubiquitination-mediated proteasomal degradation pathway.

PMID- 15190076
TI  - The direct peroxisome proliferator-activated receptor target fasting-induced
      adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated
      protein that is increased by fenofibrate treatment.
AB  - The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously
      identified as a novel adipocytokine that was up-regulated by fasting, by
      peroxisome proliferator-activated receptor agonists, and by hypoxia. To further
      characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and
      adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA
      was up-regulated by peroxisome proliferator-activated receptor alpha (PPARalpha)
      and PPARbeta/delta agonists in rat and human hepatoma cell lines and by PPARgamma
      and PPARbeta/delta agonists in mouse and human adipocytes. Transactivation,
      chromatin immunoprecipitation, and gel shift experiments identified a functional
      PPAR response element within intron 3 of the FIAF gene. At the protein level, in
      human and mouse blood plasma, FIAF was found to be present both as the native
      protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was
      associated with the production of truncated FIAF, whereas in human white adipose
      tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly,
      truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent
      PPARalpha agonist, markedly increased plasma levels of truncated FIAF, but not
      native FIAF, in humans. Levels of both truncated and native FIAF showed marked
      interindividual variation but were not associated with body mass index and were
      not influenced by prolonged semistarvation. Together, these data suggest that
      FIAF, similar to other adipocytokines such as adiponectin, may partially exert
      its function via a truncated form.

PMID- 15190078
TI  - Regulation of murine cytochrome c oxidase Vb gene expression during myogenesis:
      YY-1 and heterogeneous nuclear ribonucleoprotein D-like protein (JKTBP1)
      reciprocally regulate transcription activity by physical interaction with the
      BERF-1/ZBP-89 factor.
AB  - A transcription suppressor element (sequence -481 to -320) containing a G-rich
      motif (designated GTG) and a newly identified CAT-rich motif (designated CATR)
      was previously shown to modulate expression of the mouse cytochrome c oxidase Vb
      gene during myogenesis. Here, we show that the GTG element is critical for
      transcription activation in both undifferentiated and differentiated myocytes.
      Mutations of the CATR motif abolished transcription repression in myoblasts while
      limiting transcription activation in differentiated myotubes, suggesting
      contrasting functional attributes of this DNA motif at different stages of
      myogenesis. Results show that the activity of the transcription suppressor motif
      is modulated by an orchestrated interplay between ubiquitous transcription
      factors: ZBP-89, YY-1, and a member of the heterogeneous nuclear
      ribonucleoprotein D-like protein (also known as JKTBP1) family. In
      undifferentiated muscle cells, GTG motif-bound ZBP-89 physically and functionally
      interacted with CATR motif-bound YY-1 to mediate transcription repression. In
      differentiated myotubes, heterogeneous nuclear ribonucleoprotein D-like
      protein/JKTBP1 bound to the CATR motif exclusive of YY-1 and interacted with ZBP
      89 in attenuating repressor activity, leading to transcription activation. Our
      results show a novel mechanism of protein factor switching in transcription
      regulation of the cytochrome c oxidase Vb gene during myogenesis.

PMID- 15190079
TI  - B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions of polo
      like kinase 1.
AB  - Phosphoprotein profiling by Kinetworks trade mark analysis of M-phase-arrested
      HeLa cells by nocodazole treatment revealed that a novel mitosis-specific
      phosphorylation event occurred in the nucleolar protein B23/nucleophosmin at a
      conserved Ser-4 residue. Consistent with the resemblance of the Ser-4
      phosphorylation site to the Polo-like kinase 1 (Plk1) consensus recognition
      sequence, inhibition of Plk1 by a kinase-defective mutation (K82M) abrogated B23
      Ser-4 phosphorylation, whereas activation of Plk1 by a constitutively active
      mutation (T210D) enhanced its phosphorylation following in vivo transfection and
      in vitro phosphorylation assays. Depletion of endogenous Plk1 by RNA interference
      abolished B23 Ser-4 phosphorylation. The physical interaction of Plk1 and B23 was
      further demonstrated by their co-immunoprecipitation and glutathione S
      transferase fusion protein pull-down assays. Interference of Ser-4
      phosphorylation of B23 induced multiple mitotic defects in HeLa cells, including
      aberrant numbers of centrosomes, elongation and fragmentation of nuclei, and
      incomplete cytokinesis. The phenotypes of B23 mutants are reminiscent of a subset
      of those described previously in Plk1 mutants. Our findings provide insights into
      the biochemical mechanism underlying the role of Plk1 in mitosis regulation
      through the identification of Ser-4 in B23 as a major physiological substrate of
      Plk1.

PMID- 15190080
TI  - G protein-coupled receptor-mediated phosphorylation of the activation loop of
      protein kinase D: dependence on plasma membrane translocation and protein kinase
      Cepsilon.
AB  - Protein kinase D (PKD) is a serine/threonine protein kinase activated by G
      protein-coupled receptor (GPCR) agonists through an incompletely characterized
      mechanism that includes its reversible plasma membrane translocation and
      activation loop phosphorylation via a protein kinase C (PKC)-dependent pathway.
      To gain a better understanding of the mechanism regulating the activation of PKD
      in response to GPCR stimulation, we investigated the role of its rapid plasma
      membrane translocation on its activation loop phosphorylation and identified the
      endogenous PKC isozyme that mediates that event in vivo. We had found that the
      activation loop of a PKD mutant, with reduced affinity for diacylglycerol and
      phorbol esters, was only phosphorylated upon its plasma membrane association. We
      also found that the activation loop phosphorylation and rapid plasma membrane
      dissociation of PKD were inhibited either by preventing the plasma membrane
      translocation of PKCepsilon, through abolition of its interaction with receptor
      for activated C kinase, or by suppressing the expression of PKCepsilon via
      specific small interfering RNAs. Thus, this study demonstrates that the plasma
      membrane translocation of PKD, in response to GPCR stimulation, is necessary for
      the PKCepsilon-mediated phosphorylation of the activation loop of PKD and that
      this event requires the translocation of both kinases to the plasma membrane.
      Based on these and previous results, we propose a model of GPCR-mediated PKD
      regulation that integrates its changes in distribution, catalytic activity, and
      multisite phosphorylation.

PMID- 15190081
TI  - Basic calcium phosphate crystals activate p44/42 MAPK signal transduction pathway
      via protein kinase Cmicro in human fibroblasts.
AB  - Although basic calcium phosphate (BCP) crystals are common in osteoarthritis, the
      crystal-induced signal transduction pathways in human fibroblasts have not been
      fully comprehended. We have previously demonstrated that the induction of matrix
      metalloproteinases (MMP) 1 and 3 by BCP crystals follows both the calcium
      dependent protein kinase C (PKC) pathway and the calcium-independent p44/42
      mitogen-activated protein kinase (p44/42 MAPK) pathway. Although we showed that
      the calcium-dependent PKC pathway was characterized by calcium-dependent
      PKCalpha, here we show that the calcium-independent p44/42 MAPK pathway is
      mediated by calcium-independent PKCmicro. Inhibition of PKCmicro synthesis and
      activity by antisense oligodeoxynucleotides and H-89 (N-(2-[p
      bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide), respectively, results in
      the inhibition of p44/42 MAPK activation, thus demonstrating that p44/42 MAPK
      activity is dependent upon PKCmicro. Reverse transcription-polymerase chain
      reaction and Western blotting also show that inhibition of PKCmicro results in
      the inhibition of MMP-1 and MMP-3 mRNA and protein expression as a result of
      p44/42 MAPK inhibition. These results now lead us to the conclusion that BCP
      crystal activation of human fibroblasts follows two pathways: 1) the calcium
      dependent PKC pathway characterized by PKCalpha and 2) the calcium-independent
      p44/42 MAPK pathway mediated by PKCmicro, which operate independently leading to
      an increase in mitogenesis and MMP synthesis and ultimately complementing each
      other for the efficient regulation of cellular responses to BCP crystal
      stimulation of human fibroblasts.

PMID- 15190082
TI  - Comparative proteomics of Cannabis sativa plant tissues.
AB  - Comparative proteomics of leaves, flowers, and glands of Cannabis sativa have
      been used to identify specific tissue-expressed proteins. These tissues have
      significantly different levels of cannabinoids. Cannabinoids accumulate primarily
      in the glands but can also be found in flowers and leaves. Proteins extracted
      from glands, flowers, and leaves were separated using two-dimensional gel
      electrophoresis. Over 800 protein spots were reproducibly resolved in the two
      dimensional gels from leaves and flowers. The patterns of the gels were different
      and little correlation among the proteins could be observed. Some proteins that
      were only expressed in flowers were chosen for identification by matrix-assisted
      laser desorption/ionization time-of-flight mass spectrometry and peptide mass
      fingerprint database searching. Flower and gland proteomes were also compared,
      with the finding that less then half of the proteins expressed in flowers were
      also expressed in glands. Some selected gland protein spots were identified:
      F1D9.26-unknown prot. (Arabidopsis thaliana), phospholipase D beta 1 isoform 1a
      (Gossypium hirsutum), and PG1 (Hordeum vulgare). Western blotting was employed to
      identify a polyketide synthase, an enzyme believed to be involved in cannabinoid
      biosynthesis, resulting in detection of a single protein.

PMID- 15190083
TI  - Quantitative real-time polymerase chain reaction: methodical analysis and
      mathematical model.
AB  - Real-time polymerase chain reaction was established for 16 genes using the
      LightCycler system to evaluate gene expression in human hepatocytes. During the
      experiments a large set of data has been obtained. These data have now been
      evaluated with respect to template stability, accuracy of melting curve analysis,
      and reproducibility. In addition, the statistical evaluation of the efficiencies
      of all 16 polymerase chain reactions led to a new mathematical model. To examine
      template stability, the degradation of mRNA and cDNA was determined at different
      temperatures. Surprisingly, cDNA, which was obtained by first-strand synthesis,
      appeared to degrade significantly faster than the respective mRNA. Melting curve
      analysis is a fast and sensitive method to check for polymerase chain reaction
      specificity. However, we show that two transcription variants of the glutathione
      S-transferase 1 gene, with over 100 bp length difference, could not be
      distinguished by this method. Furthermore, an equation was set up describing the
      correlation between polymerase chain reaction efficiency and crossing point. This
      equation can be used to estimate the number of template molecules without having
      a standard of known concentration. Finally, experimental reproducibility of the
      real-time polymerase chain reaction was defined.

PMID- 15190084
TI  - Integration of surface plasmon resonance with mass spectrometry: automated ligand
      fishing and sample preparation for MALDI MS using a Biacore 3000 biosensor.
AB  - Integrating surface plasmon resonance analysis with mass spectrometry allows
      detection and characterization of molecular interactions to be complemented with
      identification of interaction partners. We have developed a procedure for Biacore
      3000 that automatically performs all steps from ligand fishing and recovery to
      sample preparation for matrix-assisted laser desorption/ionization (MALDI) mass
      spectrometry including on-target digestion. In the model system used in this
      study a signal transduction protein, calmodulin, was selectively captured from
      brain extract by one of its interaction partners immobilized on a sensor chip.
      The bound material was eluted, deposited directly onto a MALDI target, and
      analyzed by mass spectrometry both as an intact protein and after on-target
      tryptic digestion. The procedure with direct deposition of recovered material on
      the MALDI target reduces sample losses and, in combination with automatic sample
      processing, increases the throughput of surface plasmon resonance mass
      spectrometry analysis.

PMID- 15190085
TI  - Characterization of protein glycosylation using chip-based infusion
      nanoelectrospray linear ion trap tandem mass spectrometry.
AB  - Mass spectrometry (MS) has the potential to revolutionize structural glycobiology
      and help in the understanding of how post-translation events such as
      glycosylation affect protein activities. Several approaches to determine the
      structure of glycopeptides have been used successfully including fast atom
      bombardment, matrix-assisted laser desorption ionization, and electrospray
      ionization with a wide variety of mass analyzers. However, the identification of
      glycopeptides in a complex mixture still remains a challenge. The source of this
      challenge is primarily due to the poor ionization efficiency and rapid
      degradation of glycopeptides. In this report we describe the use of a chip-based
      infusion nanoelectrospray ionization technique in combination with a recently
      developed linear ion trap for identification and characterization of
      glycosylation in complex mixtures. Two standard synthetic glycans were analyzed
      using multiple-stage fragmentation analysis in both positive and negative
      ionization modes. In addition, the high mannose type N-glycosylation in
      ribonuclease B (RNase B) was used to map the glycosylation site and obtain the
      glycan structures. We were able to map the glycosylation site and obtain the
      glycan structures in RNase B in a single analysis. The results reported here
      demonstrate that the fully automated chip-based nanoelectrospray linear ion trap
      platform is a valuable system for oligosaccharide analyses due to the unique
      MS/MS and MS(n) capability of the linear ion trap and the extended analysis time
      provided by the ionization technique.

PMID- 15190086
TI  - Improved 2D nano-LC/MS for proteomics applications: a comparative analysis using
      yeast proteome.
AB  - The most commonly used method for protein identification with two-dimensional
      (2D) online liquid chromatography-mass spectrometry (LC/MS) involves the elution
      of digest peptides from a strong cation exchange column by an injected salt step
      gradient of increasing salt concentration followed by reversed phase separation.
      However, in this approach ion exchange chromatography does not perform to its
      fullest extent, primarily because the injected volume of salt solution is not
      optimized to the SCX column. To improve the performance of strong cation exchange
      chromatography, we developed a new method for 2D online nano-LC/MS that replaces
      the injected salt step gradient with an optimized semicontinuous pumped salt
      gradient. The viability of this method is demonstrated in the results of a
      comparative analysis of a complex tryptic digest of the yeast proteome using the
      injected salt solution method and the semicontinuous pump salt method. The
      semicontinuous pump salt method compares favorably with the commonly used
      injection method and also with an offline 2D-LC method.

PMID- 15190087
TI  - Role of superior colliculus in adaptive eye-head coordination during gaze shifts.
AB  - The goal of this study was to determine which aspects of adaptive eye-head
      coordination are implemented upstream or downstream from the motor output layers
      of the superior colliculus (SC). Two monkeys were trained to perform head-free
      gaze shifts while looking through a 10 degrees aperture in opaque, head-fixed
      goggles. This training produced context-dependent alterations in eye-head
      coordination, including a coordinated pattern of saccade-vestibuloocular reflex
      (VOR) eye movements that caused eye position to converge toward the aperture, and
      an increased contribution of head movement to the gaze shift. One would expect
      the adaptations that were implemented downstream from the SC to be preserved in
      gaze shifts evoked by SC stimulation. To test this, we analyzed gaze shifts
      evoked from 19 SC sites in monkey 1 and 38 sites in monkey 2, both with and
      without goggles. We found no evidence that the goggle paradigm altered the basic
      gaze position-dependent spatial coding of the evoked movements (i.e., gaze was
      still coded in an eye-centered frame). However, several aspects of the context
      dependent coordination strategy were preserved during stimulation, including the
      adaptive convergence of final eye position toward the goggles aperture, and the
      position-dependent patterns of eye and head movement required to achieve this.
      For example, when initial eye position was offset from the learned aperture
      location at the time of stimulation, a coordinated saccade-VOR eye movement drove
      it back to the original aperture, and the head compensated to preserve gaze
      kinematics. Some adapted amplitude-velocity relationships in eye, gaze, and head
      movement also may have been preserved. In contrast, context-dependent changes in
      overall eye and head contribution to gaze amplitude were not preserved during SC
      stimulation. We conclude that 1) the motor output command from the SC to the
      brain stem can be adapted to produce different position-dependent coordination
      strategies for different behavioral contexts, particularly for eye-in-head
      position, but 2) these brain stem coordination mechanisms implement only the
      default (normal) level of head amplitude contribution to the gaze shift. We
      propose that a parallel cortical drive, absent during SC stimulation, is required
      to adjust the overall head contribution for different behavioral contexts.

PMID- 15190088
TI  - Prism adaptation during walking generalizes to reaching and requires the
      cerebellum.
AB  - Adaptation of arm movements to laterally displacing prism glasses is usually
      highly specific to body part and movement type and is known to require the
      cerebellum. Here, we show that prism adaptation of walking trajectory generalizes
      to reaching (a different behavior involving a different body part) and that this
      adaptation requires the cerebellum. In experiment 1, healthy control subjects
      adapted to prisms during either reaching or walking and were tested for
      generalization to the other movement type. We recorded lateral deviations in
      finger endpoint position and walking direction to measure negative aftereffects
      and generalization. Results showed that generalization of prism adaptation is
      asymmetric: walking generalizes extensively to reaching, but reaching does not
      generalize to walking. In experiment 2, we compared the performance of cerebellar
      subjects versus healthy controls during the prism walking adaptation. We measured
      rates of adaptation, aftereffects, and generalization. Cerebellar subjects had
      reduced adaptation magnitudes, slowed adaptation rates, decreased negative
      aftereffects, and poor generalization. Based on these experiments, we propose
      that prism adaptation during whole body movements through space invokes a more
      general system for visuomotor remapping, involving recalibration of higher-order,
      effector-independent brain regions. In contrast, prism adaptation during isolated
      movements of the limbs is probably recalibrated by effector-specific mechanisms.
      The cerebellum is an essential component in the network for both types of prism
      adaptation.

PMID- 15190089
TI  - Adrenergic signaling plays a critical role in the maintenance of waking and in
      the regulation of REM sleep.
AB  - Many experiments have suggested that the adrenergic system is important for
      arousal and the regulation of sleep/wake states. Electrophysiological studies
      have found strong correlations between the firing of adrenergic neurons and
      arousal state. Lesions of adrenergic neurons have been reported to cause changes
      in sleep/wake regulation, although findings have been variable and sometimes
      transient. To more specifically address the role of adrenergic signaling in
      sleep/wake regulation, we performed electroencephalographic and electromyographic
      recordings in mice with a targeted disruption of the gene for dopamine beta
      hydroxylase, the enzyme that converts dopamine to norepinephrine. These mice are
      unable to synthesize the endogenous adrenergic ligands norepinephrine and
      epinephrine. The mutant mice sleep approximately 2 h more each day. The decrease
      in waking is due to a considerable decrease in the duration of waking bouts in
      spite of an increase in the number of waking bouts and transitions from sleep to
      waking. In contrast, the amount of rapid-eye-movement (REM) sleep is only half
      that in control mice due to a decrease in the number and duration of REM sleep
      bouts. Delta power is selectively increased in the mutant mice, and there is much
      less variation in non-REM sleep delta power over 24 h. After 6 h of total sleep
      deprivation during the first half of the light period, there is no rebound
      recovery of sleep time in the mutant mice. These results provide genetic evidence
      that adrenergic signaling acts to maintain waking and is important for the
      regulation of REM sleep and possibly sleep homeostasis.

PMID- 15190091
TI  - Bayesian integration in force estimation.
AB  - When we interact with objects in the world, the forces we exert are finely tuned
      to the dynamics of the situation. As our sensors do not provide perfect knowledge
      about the environment, a key problem is how to estimate the appropriate forces.
      Two sources of information can be used to generate such an estimate: sensory
      inputs about the object and knowledge about previously experienced objects,
      termed prior information. Bayesian integration defines the way in which these two
      sources of information should be combined to produce an optimal estimate. To
      investigate whether subjects use such a strategy in force estimation, we designed
      a novel sensorimotor estimation task. We controlled the distribution of forces
      experienced over the course of an experiment thereby defining the prior. We show
      that subjects integrate sensory information with their prior experience to
      generate an estimate. Moreover, subjects could learn different prior
      distributions. These results suggest that the CNS uses Bayesian models when
      estimating force requirements.

PMID- 15190090
TI  - The spinal GABAergic system is a strong modulator of burst frequency in the
      lamprey locomotor network.
AB  - The spinal network coordinating locomotion is comprised of a core of glutamate
      and glycine interneurons. This network is modulated by several transmitter
      systems including spinal GABA interneurons. The purpose of this study is to
      explore the contribution of GABAergic neurons to the regulation of locomotor
      burst frequency in the lamprey model. Using gabazine, a competitive GABAA
      antagonist more specific than bicuculline, the goal was to provide a detailed
      analysis of the influence of an endogenous activation of GABAA receptors on
      fictive locomotion, as well as their possible interaction with GABAB and
      involvement of GABAC receptors. During N-methyl-D-aspartate (NMDA)-induced
      fictive locomotion (ventral root recordings in the isolated spinal cord),
      gabazine (0.1-100 microM) significantly increased the burst rate up to twofold,
      without changes in regularity or "burst quality." Gabazine had a proportionately
      greater effect at higher initial burst rates. Picrotoxin (1-7.5 microM), a less
      selective GABAA antagonist, also produced a pronounced increase in frequency, but
      at higher concentrations, the rhythm deteriorated, likely due to the unspecific
      effects on glycine receptors. The selective GABAB antagonist CGP55845 also
      increased the frequency, and this effect was markedly enhanced when combined with
      the GABAA antagonist gabazine. The GABAC antagonist (1,2,5,6-tetrahydropyridine-4
      yl)methylphosphinic acid (TPMPA) had no effect on locomotor bursting. Thus the
      spinal GABA system does play a prominent role in burst frequency regulation in
      that it reduces the burst frequency by < or =50%, presumably due to presynaptic
      and soma-dendritic effects documented previously. It is not required for burst
      generation, but acts as a powerful modulator.

PMID- 15190092
TI  - Influence of lateral connections on the structure of cortical maps.
AB  - Maps of ocular dominance and orientation in primary visual cortex have a highly
      characteristic structure. The factors that determine this structure are still
      largely unknown. In particular, it is unclear how short-range excitatory and
      inhibitory connections between nearby neurons influence structure both within and
      between maps. Using a generalized version of a well-known computational model of
      visual cortical map development, we show that the number of excitatory and
      inhibitory oscillations in this interaction function critically influences map
      structure. Specifically, we demonstrate that functions that oscillate more than
      once do not produce maps closely resembling those seen biologically. This
      strongly suggests that local lateral connections in visual cortex oscillate only
      once and have the form of a Mexican hat.

PMID- 15190093
TI  - Dissociation of morphological and physiological changes associated with long-term
      memory in aplysia.
AB  - Neurite outgrowth is a process commonly thought to contribute to long-term
      learning by formation of new synaptic contacts. The behavioral effects of long
      term sensitization training in Aplysia were restricted to the trained side of the
      animal as were changes in strength of the sensorimotor synapse. In contrast,
      training produced varicosity formation on both sides of the animal. Appositions
      with follower neurons, however, were enhanced only on the trained side. The
      dissociation of structural and functional correlates suggests that key regulatory
      steps are downstream from outgrowth, possibly in the targeting of new processes
      and activation of new synapses.

PMID- 15190094
TI  - Effect of eye position on saccades and neuronal responses to acoustic stimuli in
      the superior colliculus of the behaving cat.
AB  - We examined the motor error hypothesis of visual and auditory interaction in the
      superior colliculus (SC), first tested by Jay and Sparks in the monkey. We
      trained cats to direct their eyes to the location of acoustic sources and studied
      the effects of eye position on both the ability of cats to localize sounds and
      the auditory responses of SC neurons with the head restrained. Sound localization
      accuracy was generally not affected by initial eye position, i.e., accuracy was
      not proportionally affected by the deviation of the eyes from the primary
      position at the time of stimulus presentation, showing that eye position is taken
      into account when orienting to acoustic targets. The responses of most single SC
      neurons to acoustic stimuli in the intact cat were modulated by eye position in
      the direction consistent with the predictions of the "motor error" hypothesis,
      but the shift accounted for only two-thirds of the initial deviation of the eyes.
      However, when the average horizontal sound localization error, which was
      approximately 35% of the target amplitude, was taken into account, the magnitude
      of the horizontal shifts in the SC auditory receptive fields matched the observed
      behavior. The modulation by eye position was not due to concomitant movements of
      the external ears, as confirmed by recordings carried out after immobilizing the
      pinnae of one cat. However, the pattern of modulation after pinnae immobilization
      was inconsistent with the observations in the intact cat, suggesting that, in the
      intact animal, information about the position of the pinnae may be taken into
      account.

PMID- 15190095
TI  - Hyperthermia modulates respiratory pacemaker bursting properties.
AB  - Most mammals modulate respiratory frequency (RF) to dissipate heat (e.g.,
      panting) and avoid heat stroke during hyperthermic conditions. Respiratory neural
      network activity recorded in an isolated brain stem-slice preparation of mice
      exhibits a similar RF modulation in response to hyperthermia; fictive eupneic
      frequency increases while inspiratory network activity amplitude and duration are
      significantly reduced. Here, we study the effects of hyperthermia on the activity
      of synaptically isolated respiratory pacemakers to examine the possibility that
      these changes may account for the hyperthermic RF modulation of the respiratory
      network. During heating, modulation of the bursting frequency of synaptically
      isolated pacemakers paralleled that of population bursting recorded from the
      intact network, whereas nonpacemaker neurons were unaffected, suggesting that
      pacemaker bursting may account for the temperature-enhanced RF observed at the
      network level. Some respiratory neurons that were tonically active at hypothermic
      conditions exhibited pacemaker properties at approximately the normal body
      temperature of eutherian mammals (36.81 +/- 1.17 degrees C; mean +/- SD) and
      continued to burst at 40 degrees C. At elevated temperatures (40 degrees C),
      there was an enhancement of the depolarizing drive potential in synaptically
      isolated pacemakers, while the amplitude of integrated population activity
      declined. Isolated pacemaker bursting ceased at 41-42 degrees C (n = 5), which
      corresponds to temperatures at which hyperthermic-apnea typically occurs in vivo.
      We conclude that pacemaker properties may play an important role in the
      hyperthermic frequency modulation and apnea, while network effects may play
      important roles in generating other aspects of the hyperthermic response, such as
      the decreased amplitude of ventral respiratory group activity during
      hyperthermia.

PMID- 15190096
TI  - Slow afterhyperpolarization governs the development of NMDA receptor-dependent
      afterdepolarization in CA1 pyramidal neurons during synaptic stimulation.
AB  - CA1 pyramidal neurons from animals that have acquired a hippocampus-dependent
      task show a reduced slow postburst afterhyperpolarization (sAHP). To understand
      the functional significance of this change, we examined and characterized the
      sAHP activated by different patterns of synaptic stimuli and its impact on
      postsynaptic signal integration. Whole cell current-clamp recordings were
      performed on rat CA1 pyramidal neurons, and trains of stratum radiatum stimuli
      varying in duration, frequency, and intensity were used to activate the AHP. At 
      68 mV, a short train of subthreshold stimuli (20-150 Hz) generated only the
      medium AHP. In contrast, just two suprathreshold stimuli >50 Hz triggered a
      prominent sAHP sensitive to bath-applications of isoproterenol, carbachol, or
      intracellularly applied BAPTA, suggesting that the underlying current is the Ca2+
      activated K+ current, the sIAHP. The sAHP magnitude was positively related to
      stimulus train duration and frequency, consistent with its dependence on
      intracellular Ca2+ accumulation for activation. About 20% of neurons recorded did
      not have a sAHP. In response to high-frequency suprathreshold stimuli, these
      neurons developed a pronounced afterdepolarization (ADP) and multiple action
      potential firing. The ADP magnitude increased with successive stimuli and was
      positively related to stimulus intensity and frequency. It was sensitive to bath
      applications of thapsigargin and nitrendipine, and abolished by d-AP5, indicating
      that it is supported by intracellular Ca2+ release, the L-type Ca2+ influx, and N
      methyl-D-aspartate (NMDA) receptor-mediated influx. In the presence of D-AP5, we
      were unable to trigger an ADP with maximal stimulus intensity. Pharmacologically
      eliminating the sAHP allowed neurons to develop an ADP with the original stimulus
      train. We propose that the slow AHP acts to facilitate Mg2+ re-block of the
      activated NMDA receptors, thereby reducing temporal summation and preventing an
      NMDA receptor-dependent ADP during intense synaptic events. Neuromodulation of
      the sAHP may thus affect information throughput and regulate NMDA receptor
      mediated plasticity.

PMID- 15190097
TI  - Gaze affects pointing toward remembered visual targets after a self-initiated
      step.
AB  - We have investigated pointing movements toward remembered targets after an
      intervening self-generated body movement. We tested to what extent visual
      information about the environment or finger position is used in updating target
      position relative to the body after a step and whether gaze plays a role in the
      accuracy of the pointing movement. Subjects were tested in three visual
      conditions: complete darkness (DARK), complete darkness with visual feedback of
      the finger (FINGER), and with vision of a well-defined environment and with
      feedback of the finger (FRAME). Pointing accuracy was rather poor in the FINGER
      and DARK conditions, which did not provide vision of the environment. Constant
      pointing errors were mainly in the direction of the step and ranged from about 10
      to 20 cm. Differences between binocular fixation and target position were often
      related to the step size and direction. At the beginning of the trial, when the
      target was visible, fixation was on target. After target extinction, fixation
      moved away from the target relative to the subject. The variability in the
      pointing positions appeared to be related to the variable errors in fixation, and
      the co-variance increases during the delay period after the step, reaching a
      highly significant value at the time of pointing. The significant co-variance
      between fixation position and pointing is not the result of a mutual dependence
      on the step, since we corrected for any direct contributions of the step in both
      signals. We conclude that the co-variance between fixation and pointing position
      reflects 1) a common command signal for gaze and arm movements and 2) an effect
      of fixation on pointing accuracy at the time of pointing.

PMID- 15190098
TI  - Current- and voltage-clamp recordings and computer simulations of Kenyon cells in
      the honeybee.
AB  - The mushroom body of the insect brain is an important locus for olfactory
      information processing and associative learning. The present study investigated
      the biophysical properties of Kenyon cells, which form the mushroom body. Current
      and voltage-clamp analyses were performed on cultured Kenyon cells from
      honeybees. Current-clamp analyses indicated that Kenyon cells did not spike
      spontaneously in vitro. However, spikes could be elicited by current injection in
      approximately 85% of the cells. Of the cells that produced spikes during a 1-s
      depolarizing current pulse, approximately 60% exhibited repetitive spiking,
      whereas the remaining approximately 40% fired a single spike. Cells that spiked
      repetitively showed little frequency adaptation. However, spikes consistently
      became broader and smaller during repetitive activity. Voltage-clamp analyses
      characterized a fast transient Na+ current (INa), a delayed rectifier K+ current
      (IK,V), and a fast transient K+ current (IK,A). Using the neurosimulator SNNAP, a
      Hodgkin-Huxley-type model was developed and used to investigate the roles of the
      different currents during spiking. The model led to the prediction of a slow
      transient outward current (IK,ST) that was subsequently identified by
      reevaluating the voltage-clamp data. Simulations indicated that the primary
      currents that underlie spiking are INa and IK,V, whereas IK,A and IK,ST primarily
      determined the responsiveness of the model to stimuli such as constant or
      oscillatory injections of current.

PMID- 15190099
TI  - Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic
      and motor deficits in experimental parkinsonism.
AB  - The NMDA receptor complex represents a key molecular element in the pathogenesis
      of long-term synaptic changes and motor abnormalities in Parkinson's disease
      (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density
      (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)
      denervated striata. These effects are accompanied by an increase in striatal
      levels of alphaCa2+-calmodulin-dependent protein kinase II (alphaCaMKII)
      autophosphorylation, along with a higher recruitment of activated alphaCaMKII to
      the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal
      slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3
      benzazepine hydrochloride, but not with l-sulpiride, mimicked the effect of DA
      denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic
      plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as
      well as assembly and anchoring of the kinase to the NMDA receptor complex,
      intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4
      chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4
      methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory
      peptide II is able to reverse both the alterations in corticostriatal synaptic
      plasticity and the deficits in spontaneous motor behavior that are found in an
      animal model of PD. The same beneficial effects are produced by a regimen of l
      3,4-dihydroxyphenylalanine (L-DOPA) treatment, which is able to normalize
      alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII
      autophosphorylation plays a causal role in the alterations of striatal plasticity
      and motor behavior that follow DA denervation. Normalization of CaMKII activity
      may be an important underlying mechanism of the therapeutic action of L-DOPA in
      PD.

PMID- 15190100
TI  - Microdomains for dopamine volume neurotransmission in primate prefrontal cortex.
AB  - The explicit yet enigmatic involvement of dopamine in cortical physiology is in
      part volumetric (beyond the synapse), as is apparently the action of neuroleptics
      targeting dopamine receptors. The notion that nonsynaptic neuronal membranes
      would translate extracellular dopamine into receptor-specific spatiotemporal
      downstream signaling, similar to the chemical synapse, is intriguing. Here, we
      report that dopamine D5 (but not D1 or D2) receptors in the perisomatic plasma
      membrane of prefrontal cortical neurons form discrete and exclusively
      extrasynaptic microdomains with inositol 1,4,5-trisphosphate-gated calcium stores
      of subsurface cisterns and mitochondria. These findings introduce a novel
      dopaminoceptive substratum in the brain and a unique D5 receptor-specific
      signaling paradigm.

PMID- 15190102
TI  - Identification of a tetramerization domain in the C terminus of the vanilloid
      receptor.
AB  - TRPV1 (transient receptor potential vanilloid receptor subtype 1) is a member of
      the TRP channel family gated by vanilloids, protons, and heat. Structurally,
      TRPV1 appears to be a tetramer formed by the assembly of four identical subunits
      around a central aqueous pore. The molecular determinants that govern its subunit
      oligomerization remain elusive. Here, we report the identification of a segment
      comprising 684Glu-721Arg (referred to as the TRP-like domain) in the C terminus
      of TRPV1 as an association domain (AD) of the protein. Purified recombinant C
      terminus of TRPV1 (TRPV1-C) formed discrete and stable multimers in vitro. Yeast
      two-hybrid and pull-down assays showed that self-association of the TRPV1-C is
      blocked when segment 684Glu-721Arg is deleted. Biochemical and immunological
      analysis indicate that removal of the AD from full-length TRPV1 monomers blocks
      the formation of stable heteromeric assemblies with wild-type TRPV1 subunits.
      Deletion of the AD in a poreless TRPV1 subunit suppressed its robust dominant
      negative phenotype. Together, these findings are consistent with the tenet that
      the TRP-like domain in TRPV1 is a molecular determinant of the tetramerization of
      receptor subunits into functional channels. Our observations suggest that the
      homologous TRP domain in the TRP protein family may function as a general,
      evolutionary conserved AD involved in subunit multimerization.

PMID- 15190101
TI  - Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of
      calcium-dependent afterhyperpolarization currents.
AB  - Action potentials in many central neurons are followed by a prolonged
      afterhyperpolarization (AHP) that influences firing frequency and affects
      neuronal integration. In hippocampal CA1 pyramidal neurons, the current ascribed
      to the AHP (IAHP) has three kinetic components. The IfastAHP is predominantly
      attributable to voltage-dependent K+ channels, whereas Ca2+-dependent and voltage
      independent K+channels contribute to the ImediumAHP (ImAHP) and IslowAHP (IsAHP).
      Apamin, which selectively suppresses a component of the mAHP, increases neuronal
      excitability and facilitates the induction of synaptic plasticity at Schaffer
      collateral synapses and hippocampal-dependent learning. The Ca2+-dependent
      components of the AHP have been attributed to the activity of small conductance
      Ca2+-activated K+ (SK) channels. Examination of transgenic mice, each lacking one
      of the three SK channel genes expressed in the CNS, reveals that mice without the
      SK2 subunit completely lack the apamin-sensitive component of the ImAHP in CA1
      neurons, whereas the IsAHP is not different in any of the SK transgenic mice. In
      each of the transgenic lines, the expression levels of the remaining SK genes are
      not changed. The results demonstrate that only SK2 channels are necessary for the
      ImAHP, and none of the SK channels underlie the IsAHP.

PMID- 15190103
TI  - Estrogen and androgen protection of human neurons against intracellular amyloid
      beta1-42 toxicity through heat shock protein 70.
AB  - Intracellular amyloidbeta peptide (iAbeta1-42) accumulates in the Alzheimer's
      disease brain before plaque and tangle formation (Gouras et al., 2000) and is
      extremely toxic to human neurons (Zhang et al., 2002). Here, we investigated
      whether androgen and estrogen could prevent iAbeta1-4) toxicity, because both
      these hormones have a wide range of neuroprotective actions. At physiological
      concentrations, 17-beta-estradiol, testosterone, and methyl testosterone reduce
      iAbeta1-42-induced cell death by 50% in neurons treated after the injection and
      by 80-90% in neurons treated 1 hr before the injection. The neuroprotective
      action of the hormones is mediated by receptors, because the estrogen receptor
      (ER) antagonist tamoxifen and the androgen receptor (AR) antagonist flutamide
      completely block the estrogen- and androgen-mediated neuroprotection,
      respectively. Transcriptional activity is required for the neuroprotective
      action, because dominant negative forms of the receptors that block the
      transcriptional activity of the ER and AR prevent estrogen- and androgen-mediated
      neuroprotection. Proteomics followed by Western blot analyses identified
      increased levels of heat shock protein 70 (Hsp70) in testosterone- and estrogen
      treated human neurons. Comicroinjection of Hsp70 with the iAbeta1-42 blocks the
      toxicity of iAbeta1-42. We conclude that estrogen and androgens protect human
      neurons against iAbeta1-42 toxicity by increasing the levels of Hsp70 in the
      neurons.

PMID- 15190104
TI  - Involvement of the intracellular ion channel CLIC1 in microglia-mediated beta
      amyloid-induced neurotoxicity.
AB  - It is widely believed that the inflammatory events mediated by microglial
      activation contribute to several neurodegenerative processes. Alzheimer's
      disease, for example, is characterized by an accumulation of beta-amyloid protein
      (Abeta) in neuritic plaques that are infiltrated by reactive microglia and
      astrocytes. Although Abeta and its fragment 25-35 exert a direct toxic effect on
      neurons, they also activate microglia. Microglial activation is accompanied by
      morphological changes, cell proliferation, and release of various cytokines and
      growth factors. A number of scientific reports suggest that the increased
      proliferation of microglial cells is dependent on ionic membrane currents and in
      particular on chloride conductances. An unusual chloride ion channel known to be
      associated with macrophage activation is the chloride intracellular channel-1
      (CLIC1). Here we show that Abeta stimulation of neonatal rat microglia
      specifically leads to the increase in CLIC1 protein and to the functional
      expression of CLIC1 chloride conductance, both barely detectable on the plasma
      membrane of quiescent cells. CLIC1 protein expression in microglia increases
      after 24 hr of incubation with Abeta, simultaneously with the production of
      reactive nitrogen intermediates and of tumor necrosis factor-alpha (TNF-alpha).
      We demonstrate that reducing CLIC1 chloride conductance by a specific blocker
      [IAA-94 (R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden
      5yl)-oxy] acetic acid)] prevents neuronal apoptosis in neurons cocultured with
      Abeta-treated microglia. Furthermore, we show that small interfering RNAs used to
      knock down CLIC1 expression prevent TNF-alpha release induced by Abeta
      stimulation. These results provide a direct link between Abeta-induced microglial
      activation and CLIC1 functional expression.

PMID- 15190105
TI  - Catechol-o-methyltransferase inhibition improves set-shifting performance and
      elevates stimulated dopamine release in the rat prefrontal cortex.
AB  - The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene
      affects activity of the enzyme and influences performance and efficiency of the
      prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is
      implicated, the underlying mechanisms remain elusive because studies of the role
      of COMT in PFC function are sparse. This study investigated the effect of
      tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set
      shifting, which is dependent on catecholamines and the medial PFC (mPFC).
      Additionally, we investigated the effect of tolcapone on extracellular
      catecholamines in the mPFC using microdialysis in awake rats. Tolcapone
      significantly and specifically improved extradimensional (ED) set shifting.
      Tolcapone did not affect basal extracellular catecholamines, but significantly
      potentiated the increase in extracellular dopamine (DA) elicited by either local
      administration of the depolarizing agent potassium chloride or systemic
      administration of the antipsychotic agent clozapine. Although extracellular
      norepinephrine (NE) was also elevated by local depolarization and clozapine, the
      increase was not enhanced by tolcapone. We conclude that COMT activity
      specifically affects ED set shifting and is a significant modulator of mPFC DA
      but not NE under conditions of increased catecholaminergic transmission. These
      data suggest that the links between COMT activity and PFC function can be modeled
      in rats and may be specifically mediated by DA. The interaction between clozapine
      and tolcapone may have implications for the treatment of schizophrenia.

PMID- 15190106
TI  - Hypocretinergic control of spinal cord motoneurons.
AB  - Hypocretinergic (orexinergic) neurons in the lateral hypothalamus project to
      motor columns in the lumbar spinal cord. Consequently, we sought to determine
      whether the hypocretinergic system modulates the electrical activity of
      motoneurons. Using in vivo intracellular recording techniques, we examined the
      response of spinal motoneurons in the cat to electrical stimulation of the
      lateral hypothalamus. In addition, we examined the membrane potential response to
      orthodromic stimulation and intracellular current injection before and after both
      hypothalamic stimulation and the juxtacellular application of hypocretin-1. It
      was found that (1) hypothalamic stimulation produced a complex sequence of
      depolarizing- hyperpolarizing potentials in spinal motoneurons; (2) the
      depolarizing potentials decreased in amplitude after the application of SB
      334867, a hypocretin type 1 receptor antagonist; (3) the EPSP induced by dorsal
      root stimulation was not affected by the application of SB-334867; (4)
      subthreshold stimulation of dorsal roots and intracellular depolarizing current
      steps produced spike potentials when applied in concert to stimulation of the
      hypothalamus or after the local application of hypocretin-1; (5) the
      juxtacellular application of hypocretin-1 induced motoneuron depolarization and,
      frequently, high-frequency discharge; (6) hypocretin-1 produced a significant
      decrease in rheobase (36%), membrane time constant (16.4%), and the equalizing
      time constant (23.3%); (7) in a small number of motoneurons, hypocretin-1
      produced an increase in the synaptic noise; and (8) the input resistance was not
      affected after hypocretin-1. The juxtacellular application of vehicle (saline)
      and denatured hypocretin-1 did not produce changes in the preceding
      electrophysiological properties. We conclude that hypothalamic hypocretinergic
      neurons are capable of modulating the activity of lumbar motoneurons through
      presynaptic and postsynaptic mechanisms. The lack of hypocretin-induced
      facilitation of motoneurons may be a critical component of the pathophysiology of
      cataplexy.

PMID- 15190107
TI  - Day-night changes in downstream regulatory element antagonist modulator/potassium
      channel interacting protein activity contribute to circadian gene expression in
      pineal gland.
AB  - The molecular mechanisms controlling the oscillatory synthesis of melatonin in
      rat pineal gland involve the rhythmic expression of several genes including
      arylalkylamine N-acetyltransferase (AA-NAT), inducible cAMP early repressor
      (ICER), and Fos-related antigen-2 (fra-2). Here we show that the calcium sensors
      downstream regulatory element antagonist modulator/potassium channel interacting
      protein (DREAM/KChIP)-3 and KChIP-1, -2 and -4 bind to downstream regulatory
      element (DRE) sites located in the regulatory regions of these genes and repress
      basal and induced transcription from ICER, fra-2 or AA-NAT promoters.
      Importantly, we demonstrate that the endogenous binding activity to DRE sites
      shows day-night oscillations in rat pineal gland and retina but not in the
      cerebellum. The peak of DRE binding activity occurs during the day period of the
      circadian cycle, coinciding with the lowest levels of fra-2, ICER, and AA-NAT
      transcripts. We show that a rapid clearance of DRE binding activity during the
      entry in the night period is related to changes at the posttranscriptional level
      of DREAM/KChIP. The circadian pattern of DREAM/KChIP activity is maintained under
      constant darkness, indicating that an endogenous clock controls DREAM/KChIP
      function. Our data suggest involvement of the family of DREAM repressors in the
      regulation of rhythmically expressed genes engaged in circadian rhythms.

PMID- 15190108
TI  - Rapid prefrontal-hippocampal habituation to novel events.
AB  - Unexpected novel events generate an orienting response that plays an important
      role in some forms of learning and memory. The orienting response involuntarily
      captures attention and rapidly habituates as events become familiarized. Although
      evidence from patients with focal lesions and scalp and intracranial event
      related brain potential recordings supports the involvement of a distributed
      neural network involving association cortex and the limbic system in novelty
      detection, the key neural substrates and temporal dynamics have not been defined.
      While subjects performed a bi-field visual-selective attention task with random
      novel stimuli embedded in either attended or unattended visual fields, we
      measured rapid changes of regional blood oxygenation level-dependent (BOLD)
      signal to target and novel stimuli using single-trial analysis of event-related
      functional magnetic resonance imaging with a 4T scanner. Habituation was
      quantified by serial BOLD signal changes during the first 10 novel stimuli for
      each subject. Novel stimuli activated the bilateral superior/middle frontal
      gyrus, temporal-parietal junction, superior parietal lobe, cingulate gyrus,
      hippocampus, and fusiform gyrus. The superior/middle frontal gyrus and
      hippocampus showed significant reduction of BOLD signal during the first few
      novel stimuli, whereas the signals in the fusiform and cingulate gyrus were
      constant. Prefrontal and hippocampal responses to attended and unattended novel
      stimuli were comparably habituated. These results, and previous data from lesion
      studies, support the view that prefrontal and hippocampal regions are involved in
      rapid automatic detection and habituation to unexpected environmental events and
      are key elements of the orienting response in humans.

PMID- 15190109
TI  - TRPM8 activation by menthol, icilin, and cold is differentially modulated by
      intracellular pH.
AB  - TRPM8 is a nonselective cation channel activated by cold and the cooling
      compounds menthol and icilin (Peier et al., 2002). Here, we have used
      electrophysiology and the calcium-sensitive dye Fura-2 to study the effect of pH
      and interactions between temperature, pH, and the two chemical agonists menthol
      and icilin on TRPM8 expressed in Chinese hamster ovary cells. Menthol, icilin,
      and cold all evoked stimulus-dependent [Ca2+]i responses in standard
      physiological solutions of pH 7.3. Increasing the extracellular [H+] from pH 7.3
      to approximately pH 6 abolished responses to icilin and cold stimulation but did
      not affect responses to menthol. Icilin concentration-response curves were
      significantly shifted to the right when pH was lowered from 7.3 to 6.9, whereas
      those with menthol were unaltered in solutions of pH 6.1. When cells were exposed
      to solutions in the range of pH 8.1-6.5, the temperature threshold for activation
      was elevated at higher pH and depressed at lower pH. Superfusing cells with a low
      subactivating concentration of icilin or menthol elevated the threshold for cold
      activation at pH 7.4, but cooling failed to evoke [Ca2+]i responses at pH 6 in
      the presence of either agonist. In voltage-clamp experiments in which the
      intracellular pH was buffered to different levels, acidification reduced the
      current amplitude of icilin responses and shifted the threshold for cold
      activation to lower values with half-maximal inhibition at pH 7.2 and pH 7.6. The
      results demonstrate that the activation of TRPM8 by icilin and cold, but not
      menthol, is modulated by intracellular pH in the physiological range.
      Furthermore, our data suggest that activation by icilin and cold involve a
      different mechanism to activation by menthol.

PMID- 15190110
TI  - Identification of sympathetic premotor neurons in medullary raphe regions
      mediating fever and other thermoregulatory functions.
AB  - Sympathetic premotor neurons directly control sympathetic preganglionic neurons
      (SPNs) in the intermediolateral cell column (IML) of the thoracic spinal cord,
      and many of these premotor neurons are localized in the medulla oblongata. The
      rostral ventrolateral medulla contains premotor neurons controlling the
      cardiovascular conditions, whereas rostral medullary raphe regions are a
      candidate source of sympathetic premotor neurons for thermoregulatory functions.
      Here, we show that these medullary raphe regions contain putative glutamatergic
      neurons and that these neurons directly control thermoregulatory SPNs. Neurons
      expressing vesicular glutamate transporter 3 (VGLUT3) were distributed in the rat
      medullary raphe regions, including the raphe magnus and rostral raphe pallidus
      nuclei, and mostly lacked serotonin immunoreactivity. These VGLUT3-positive
      neurons expressed Fos in response to cold exposure or to central administration
      of prostaglandin E2, a pyrogenic mediator. Transneuronal retrograde labeling
      after inoculation of pseudorabies virus into the interscapular brown adipose
      tissue (BAT) or the tail indicated that those VGLUT3-expressing medullary raphe
      neurons innervated these thermoregulatory effector organs multisynaptically
      through SPNs of specific thoracic segments, and microinjection of glutamate into
      the IML of the BAT-controlling segments produced BAT thermogenesis. An
      anterograde tracing study further showed a direct projection of those VGLUT3
      expressing medullary raphe neurons to the dendrites of SPNs. Furthermore, intra
      IML application of glutamate receptor antagonists blocked BAT thermogenesis
      triggered by disinhibition of the medullary raphe regions. The present results
      suggest that VGLUT3-expressing neurons in the medullary raphe regions constitute
      excitatory neurons that could be categorized as a novel group of sympathetic
      premotor neurons for thermoregulatory functions, including fever.

PMID- 15190112
TI  - Somatotopy and attentional modulation of the human parietal and opercular
      regions.
AB  - The somatotopical organization of the postcentral gyrus is well known, but less
      is known about the somatotopical organization of area 2, the somatosensory
      association areas in the postparietal cortex, and the parietal operculum. The
      extent to which these areas are modulated by attention is also poorly understood.
      For these reasons, we measured the BOLD signal when rectangular parallelepipeds
      of varying shape were presented to the immobile right hand or right foot of 10
      subjects either discriminating these or just being stimulated. Activation areas
      in each subject were mapped against cytoarchitectural probability maps of area 2,
      IP1, and IP2 along the intraparietal sulcus and the parietal opercular areas OP1
      OP4. In area 2, the somatotopical representation of the hand and foot were
      distinctly separate, whereas there was considerable overlap in IP1 and no clear
      evidence of separate representations in OP1, OP4, and IP2. The overlap of hand
      and foot representations increased in the following order: area 3a, 3b, 1, 2,
      IP1, OP4, IP2, and OP1. There were significant foot representations but no hand
      representations in right (ipsilateral) areas 3a, 3b, and 1. Shape discrimination
      using the foot as opposed to stimulation enhanced the signal in OP4 bilaterally,
      whereas discrimination with the hand enhanced the signal bilaterally in area 2,
      IP1, and IP2. These results indicate that somatosensory areas in humans are
      arranged from strong somatotopy into no somatotopy in the following order: 3a,
      3b, 1, 2, IP1, OP4, IP2, and OP1. Higher order areas such as IP1, IP2, and OP4
      showed task-related attentional enhancement.

PMID- 15190111
TI  - Regulation of synaptic strength and AMPA receptor subunit composition by PICK1.
AB  - PICK1 (protein interacting with C kinase-1) regulates the surface expression of
      the AMPA receptor (AMPAR) GluR2 subunit, however, the functional consequences of
      this interaction are not well understood. Previous work has suggested that PICK1
      promotes the internalization of AMPARs. However, we found that when PICK1 is
      virally expressed in the CA1 region of hippocampal slices, it causes an increase
      in AMPAR-mediated EPSC amplitude. This effect is associated with increased AMPAR
      rectification and sensitivity to polyamine toxin. These effects are blocked by
      PKC or calcium/calmodulin-dependent protein kinase II inhibitors, indicating that
      the virally expressed PICK1 signals through an endogenous kinase cascade. In
      contrast, blockade of interactions with GluR2 at the N-ethylmaleimide-sensitive
      factor site did not cause a change in subunit composition, suggesting that the
      effects of PICK1 are not simply a nonspecific consequence of removing AMPARs from
      the surface. Immunocytochemical and biochemical analyses in dissociated cultured
      hippocampal neurons show that PICK1 causes a decrease in endogenous GluR2 surface
      expression but no change in GluR1 surface levels. To address the physiological
      role of PICK1, we virally expressed C-terminal GluR2 peptides. Blockade of
      endogenous PICK1 PDZ (postsynaptic density-95/Discs large/zona occludens-1)
      domain interactions produced opposite effects on synaptic strength and AMPAR
      rectification to those observed with PICK1 expression. This demonstrates that
      AMPAR subunit composition is physiologically regulated through a mechanism
      involving PICK1 PDZ domain interactions. These findings suggest that PICK1 acts
      to downregulate the GluR2 content of AMPARs at hippocampal CA1 synapses, thereby
      increasing synaptic strength at resting membrane potentials.

PMID- 15190113
TI  - Dominant-negative calcium channel suppression by truncated constructs involves a
      kinase implicated in the unfolded protein response.
AB  - Expression of the calcium channel Ca(V)2.2 is markedly suppressed by coexpression
      with truncated constructs of Ca(V)2.2. Furthermore, a two-domain construct of
      Ca(V)2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca(V)2.1
      currents. We have now determined the specificity of this effect, identified a
      potential mechanism, and have shown that such constructs also inhibit endogenous
      calcium currents when transfected into neuronal cell lines. Suppression of
      calcium channel expression requires interaction between truncated and full-length
      channels, because there is inter-subfamily specificity. Although there is marked
      cross-suppression within the Ca(V)2 calcium channel family, there is no cross
      suppression between Ca(V)2 and Ca(V)3 channels. The mechanism involves activation
      of a component of the unfolded protein response, the endoplasmic reticulum
      resident RNA-dependent kinase (PERK), because it is inhibited by expression of
      dominant-negative constructs of this kinase. Activation of PERK has been shown
      previously to cause translational arrest, which has the potential to result in a
      generalized effect on protein synthesis. In agreement with this, coexpression of
      the truncated domain I of Ca(V)2.2, together with full-length Ca(V)2.2, reduced
      the level not only of Ca(V)2.2 protein but also the coexpressed alpha2delta-2.
      Thapsigargin, which globally activates the unfolded protein response, very
      markedly suppressed Ca(V)2.2 currents and also reduced the expression level of
      both Ca(V)2.2 and alpha2delta-2 protein. We propose that voltage-gated calcium
      channels represent a class of difficult-to-fold transmembrane proteins, in this
      case misfolding is induced by interaction with a truncated cognate Ca(V) channel.
      This may represent a mechanism of pathology in episodic ataxia-2.

PMID- 15190114
TI  - Locus ceruleus control of state-dependent gene expression.
AB  - Wakefulness and sleep are accompanied by changes in behavior and neural activity,
      as well as by the upregulation of different functional categories of genes.
      However, the mechanisms responsible for such state-dependent changes in gene
      expression are unknown. Here we investigate to what extent state-dependent
      changes in gene expression depend on the central noradrenergic (NA) system, which
      is active in wakefulness and reduces its firing during sleep. We measured the
      levels of approximately 5000 transcripts expressed in the cerebral cortex of
      control rats and in rats pretreated with DSP-4 [N-(2-chloroethyl)-N-ethyl-2
      bromobenzylamine], a neurotoxin that removes the noradrenergic innervation of the
      cortex. We found that NA depletion reduces the expression of approximately 20% of
      known wakefulness-related transcripts. Most of these transcripts are involved in
      synaptic plasticity and in the cellular response to stress. In contrast, NA
      depletion increased the expression of the sleep-related gene encoding the
      translation elongation factor 2. These results indicate that the activity of the
      central NA system during wakefulness modulates neuronal transcription to favor
      synaptic potentiation and counteract cellular stress, whereas its inactivity
      during sleep may play a permissive role to enhance brain protein synthesis.

PMID- 15190115
TI  - Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A
      autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in
      the nucleus raphe dorsalis of rat.
AB  - Because 5-HT1A receptors located on the soma dendrites of serotonin (5-HT)
      neurons normally mediate an inhibition of 5-HT firing and release, the
      desensitization of these autoreceptors is essential for obtaining an enhancement
      of 5-HT transmission after treatment with 5-HT reuptake inhibitors (SSRIs). We
      have demonstrated previously, using immunoelectron microscopy with specific 5
      HT1A antibodies, that an internalization of 5-HT1A autoreceptors is associated
      with their desensitization in rats given a single dose of the 5-HT1A receptor
      agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Here, we examined the subcellular
      distribution of 5-HT1A receptors in dendrites from nucleus raphe dorsalis (NRD)
      (autoreceptors) and hippocampus (heteroreceptors) after acute treatment with the
      antidepressant SSRI, fluoxetine (10 mg/kg, i.p.). In parallel experiments, the
      kinetics of in vivo binding of the 5-HT1A positron emission tomography
      radioligand 4,2-(methoxyphenyl)-1-[2-(N-2-pyridinyl)-p
      fluorobenzamido]ethylpiperazine ([18F]MPPF) was measured in these two brain
      regions by means of stereotaxically implanted beta microprobes. One hour after
      treatment, there was a 36% decrease in 5-HT1A immunogold labeling of the plasma
      membrane of NRD dendrites, and a concomitant increase in their cytoplasmic
      labeling, without any change in hippocampal dendrites. In vivo binding of
      [18F]MPPF was reduced by 35% in NRD and unchanged in hippocampus. Both effects
      were blocked by pretreatment with the 5-HT1A receptor antagonist (N-[2-[4-(2
      methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide) (1
      mg/kg, i.p.). In brain sections of NRD and hippocampus, [18F]MPPF
      autoradiographic labeling did not differ between fluoxetine- and saline-treated
      rats. These immunocytochemical results confirmed that internalization of 5-HT1A
      autoreceptors may account for their desensitization, and the microprobe results
      suggest that this prerequisite for antidepressant treatment efficacy could be
      amenable to brain imaging in humans.

PMID- 15190116
TI  - Using a hybrid neural system to reveal regulation of neuronal network activity by
      an intrinsic current.
AB  - The generation of rhythmic patterns by neuronal networks is a complex phenomenon,
      relying on the interaction of numerous intrinsic and synaptic currents, as well
      as modulatory agents. To investigate the functional contribution of an individual
      ionic current to rhythmic pattern generation in a network, we constructed a
      hybrid system composed of a silicon model neuron and a heart interneuron from the
      heartbeat timing network of the medicinal leech. When the model neuron and a
      heart interneuron are connected by inhibitory synapses, they produce rhythmic
      activity similar to that observed in the heartbeat network. We focused our
      studies on investigating the functional role of the hyperpolarization-activated
      inward current (I(h)) on the rhythmic bursts produced by the network. By
      introducing changes in both the model and the heart interneuron, we showed that
      I(h) determines both the period of rhythmic bursts and the balance of activity
      between the two sides of the network, because the amount and the
      activation/deactivation time constant of I(h) determines the length of time that
      a neuron spends in the inhibited phase of its burst cycle. Moreover, we
      demonstrated that the model neuron is an effective replacement for a heart
      interneuron and that changes made in the model can accurately mimic similar
      changes made in the living system. Finally, we used a previously developed
      mathematical model (Hill et al. 2001) of two mutually inhibitory interneurons to
      corroborate these findings. Our results demonstrated that this hybrid system
      technique is advantageous for investigating neuronal properties that are
      inaccessible with traditional techniques.

PMID- 15190117
TI  - Neurogenic effect of beta-amyloid peptide in the development of neural stem
      cells.
AB  - The adult mammalian brain contains neural stem cells (NSCs) with self-renewal and
      multilineage potential in the hippocampus and subventricular zone. However,
      neurogenesis from these areas does not compensate for neuronal loss in age
      related neurodegenerative disorders such as Alzheimer's disease (AD). To test
      whether an impairment of neurogenesis could contribute to the pathogenesis of AD,
      we examined the effects of amyloid-beta peptide (Abeta) on the survival and
      neuronal differentiation of cultured NSCs from striatum and hippocampus. We show
      that Abeta peptide does not impair the neurogenic rate in NSC progeny, but that
      it increases the total number of neurons in vitro in a dose-dependent manner. The
      neurogenic effect of Abeta peptide is not dependent on soluble factors released
      from the NSC progeny. Neurogenesis is induced by Abeta42 and not Abeta40 or Abeta
      25-35, and the activity appears to be a property of Abeta oligomers and not
      fibrils. These results suggest that Abeta may have positive as well as
      deleterious actions, and that a knowledge of the mechanisms involved in the
      former could be valuable in exploiting the regenerative and plastic potential of
      the brain in preventing and treating Alzheimer's disease.

PMID- 15190119
TI  - Desmoplakin is required for microvascular tube formation in culture.
AB  - Desmoplakin (DP) is a key component of cellular adhesion junctions known as
      desmosomes; however, recent investigations have revealed a novel location for DP
      in junctions separate from desmosomes termed complexus adherens junctions. These
      junctions are found at contact sites between endothelial cells that line
      capillaries. Few studies have focused on the function of DP in de novo capillary
      formation (vasculogenesis) and branching (angiogenesis) during tumorigenesis,
      embryonic development, cardiovascular development or wound healing. Only recently
      have investigations begun to determine the effect the loss of DP has on
      capillaries during embryogenesis (i.e. in DP-/- mice). Evidence shows that the
      loss of desmoplakin in vivo results in leaky capillaries and/or capillary
      malformation. Consequently, the goal of this study was to determine the function
      of DP in complexus adherens junctions during capillary formation. To accomplish
      this goal, we used siRNA technology to knock down desmoplakin expression in
      endothelial cells before they were induced to form microvascular tubes on
      matrigel. DP siRNA treated cells sent out filopodia and came in close contact
      with each other when plated onto matrigel; however, in most cases they failed to
      form tubes as compared with control endothelial cells. Interestingly, after siRNA
      degradation, endothelial cells were then capable of forming microvascular tubes.
      In depth analyses into the function of DP in capillary formation were not
      previously possible because the tools and experimental approaches only recently
      have become available (i.e. siRNA). Consequently, fully understanding the role of
      desmoplakin in capillary formation may lead to a novel approach for inhibiting
      vasculo- and angiogenesis in tumor formation.

PMID- 15190118
TI  - Espins are multifunctional actin cytoskeletal regulatory proteins in the
      microvilli of chemosensory and mechanosensory cells.
AB  - Espins are associated with the parallel actin bundles of hair cell stereocilia
      and are the target of mutations that cause deafness and vestibular dysfunction in
      mice and humans. Here, we report that espins are also concentrated in the
      microvilli of a number of other sensory cells: vomeronasal organ sensory neurons,
      solitary chemoreceptor cells, taste cells, and Merkel cells. Moreover, we show
      that hair cells and these other sensory cells contain novel espin isoforms that
      arise from a different transcriptional start site and differ significantly from
      other espin isoforms in their complement of ligand-binding activities and their
      effects on actin polymerization. The novel espin isoforms of sensory cells
      bundled actin filaments with high affinity in a Ca(2+)-resistant manner, bound
      actin monomer via a WASP (Wiskott-Aldrich syndrome protein) homology 2 domain,
      bound profilin via a single proline-rich peptide, and caused a dramatic
      elongation of microvillus-type parallel actin bundles in transfected epithelial
      cells. In addition, the novel espin isoforms of sensory cells differed from other
      espin isoforms in that they potently inhibited actin polymerization in vitro, did
      not bind the Src homology 3 domain of the adapter protein insulin receptor
      substrate p53, and did not bind the acidic, signaling phospholipid
      phosphatidylinositol 4,5-bisphosphate. Thus, the espins constitute a family of
      multifunctional actin cytoskeletal regulatory proteins with the potential to
      differentially influence the organization, dimensions, dynamics, and signaling
      capabilities of the actin filament-rich, microvillus-type specializations that
      mediate sensory transduction in various mechanosensory and chemosensory cells.

PMID- 15190120
TI  - Rab11 regulates the recycling and lysosome targeting of beta2-adrenergic
      receptors.
AB  - The pericentriolar recycling endosome (RE) may be an alternative compartment
      through which some beta2-adrenergic receptors (beta2ARs) recycle from early
      endosomes to the cell surface during prolonged exposure to agonist. For the
      transferrin receptor, CXCR2, and the M4-muscarinic acetylcholine receptor,
      trafficking through the RE and receptor recycling is regulated by the small
      GTPase rab11. The precise role of the RE and rab11 in regulating the cellular
      trafficking of the beta2AR is not understood. We therefore monitored trafficking
      of beta2ARs in HEK293 cells following the modulation of rab11 activity.
      Expression of a rab11 mutant deficient in GTP binding (as a fusion between
      enhanced green fluorescent protein (EGFP) and the rab11S25N mutant) significantly
      slowed receptor recycling to the cell surface from dispersed transferrin-positive
      peripheral vesicles following a brief exposure to agonist. The agonist was
      applied at a time when receptors have undergone only one or two rounds of
      endocytosis and recycling. In cells overexpressing wild-type rab11, beta2ARs
      localized to a rab11-positive compartment and the rate of beta2AR recycling to
      the cell surface was reduced, but only after prolonged exposure to agonist and
      multiple rounds of receptor endocytosis and recycling. This effect was associated
      with impaired beta2AR trafficking to lysosomes and receptor proteolysis, whereas
      the sorting of low-density lipoprotein from transferrin-positive vesicles to late
      endosomes and lysosomes was not affected. These data highlight a pivotal role for
      rab11 in regulating the traffic of a G protein-coupled receptor at the level of
      the RE, where modulation of rab11 activity dictates the balance between receptor
      recycling and downregulation during prolonged exposure to agonist.

PMID- 15190121
TI  - Synaptotagmin V and IX isoforms control Ca2+ -dependent insulin exocytosis.
AB  - Synaptotagmin (Syt) is involved in Ca2+ -regulated secretion and has been
      suggested to serve as a general Ca2+ sensor on the membrane of secretory vesicles
      in neuronal cells. Insulin exocytosis from the pancreatic beta-cell is an example
      of a Ca2+ -dependent secretory process. Previous studies have yielded conflicting
      results as to which Syt isoform is present on the secretory granules in the
      native beta-cell. Here we show by western blotting and RT-PCR analysis, the
      presence of both Syt V and Syt IX in rat pancreatic islets and in the clonal beta
      cell line INS-1E. The subcellular distribution of the two Syt isoforms was
      assessed by confocal microscopy and by sedimentation in a continuous sucrose
      density gradient in INS-1E cells. These experiments show that both proteins
      colocalize with insulin-containing secretory granules but are absent from
      synaptic-like microvesicles. Further immunofluorescence studies performed in
      primary pancreatic endocrine cells revealed that Syt V is present in glucagon
      secreting alpha-cells, whereas Syt IX is associated with insulin granules in beta
      cells. Transient overexpression of Syt V and Syt IX did not alter exocytosis in
      INS-1E cells. Finally, reduction of the expression of both Syt isoforms by RNA
      interference did not change basal secretion. Remarkably, hormone release in
      response to glucose was selectively and strongly reduced, indicating that Syt V
      and Syt IX are directly involved in the Ca2+ -dependent stimulation of
      exocytosis.

PMID- 15190122
TI  - In vitro internalization, intracellular transport, and clearance of an anti-CD11a
      antibody (Raptiva) by human T-cells.
AB  - Efalizumab (Raptiva) is a humanized CD11a-specific monoclonal antibody that was
      recently approved for the treatment of moderate to severe psoriasis. In psoriasis
      patients, the rate of efalizumab clearance from serum is related to T-cell
      surface expression of CD11a, suggesting a receptor-mediated clearance model for
      efalizumab (Bauer et al., 1999). However, limited experimental data are available
      to explain how the interaction with CD11a results in the systemic clearance of
      efalizumab. The following studies were designed to test the hypothesis that one
      mechanism of anti-CD11a antibody clearance is mediated in part by cellular
      internalization. This was tested in vitro using purified mouse and human T-cells
      as a model to study the cellular uptake and clearance of anti-CD11a antibodies.
      Data from these studies suggest that anti-CD11a antibodies are internalized by
      purified T-cells. Upon internalization, the antibodies appeared to be targeted to
      lysosomes and were cleared from within the cells in a time-dependent manner.
      CD11a-mediated internalization and lysosomal targeting of efalizumab may
      constitute one pathway by which this antibody is cleared in vivo.

PMID- 15190123
TI  - Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians:
      demonstration of phenotypic null alleles.
AB  - The human microsomal cytochrome P450, CYP2B6, is involved in the
      biotransformation of several clinically important drugs. By complete sequence
      analysis of the human CYP2B6 gene coding regions in selected Caucasian DNA
      samples, we identified the five novel missense mutations 62A>T (Q21L in exon 1),
      136A>G (M46V in exon 1), 12820G>A (G99E in exon 2), 13076G>A (R140Q in exon 3),
      and 21388T>A (I391N in exon 8). The recently described but functionally
      uncharacterized variant 13072A>G (K139E) was also observed. Haplotype analysis
      indicated the presence of at least six novel alleles that code for the protein
      variants CYP2B6.10 (Q21L, R22C), CYP2B6.11 (M46V), CYP2B6.12 (G99E), CYP2B6.13
      (K139E, Q172H, K262R), CYP2B6.14 (R140Q), and CYP2B6.15 (I391N). Heterologous
      expression in COS-1 cells revealed comparable levels of CYP2B6 apoprotein and
      bupropion hydroxylase activity for CYP2B6.1 (wild type) and CYP2B6.10, whereas
      all other variants exhibited reduced expression and/or function. The three amino
      acid changes M46V, G99E, and I391N resulted in almost unmeasurable (M46V) or
      undetectable (G99E and I391N) enzyme activity, despite the presence of residual
      protein. The K139E change led to completely abolished protein expression; as a
      consequence, no function was detected. Expression in insect cells by recombinant
      baculoviruses confirmed these results and demonstrated the virtual absence of
      incorporated heme in these protein variants. The collective allele frequency of
      the four very low or null activity variants M46V, G99E, K139E, and I391N was 2.6%
      in a Caucasian study population. These data provide further insight into the
      genetic variability of CYP2B6 and demonstrate the existence of phenotypic null
      alleles in this gene.

PMID- 15190124
TI  - Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]:
      a potent xanthine oxidoreductase inhibitor with hepatic excretion.
AB  - Y-700 (1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid)
      is a newly synthesized inhibitor of xanthine oxidoreductase (XOR). Steady-state
      kinetics with the bovine milk enzyme indicated a mixed type inhibition with K(i)
      and K(i) ' values of 0.6 and 3.2 nM, respectively. Titration experiments showed
      that Y-700 bound tightly both to the active sulfo-form and to the inactive
      desulfo-form of the enzyme with K(d) values of 0.9 and 2.8 nM, respectively. X
      ray crystallographic analysis of the enzyme-inhibitor complex revealed that Y-700
      closely interacts with the channel leading to the molybdenum-pterin active site
      but does not directly coordinate to the molybdenum ion. In oxonate-treated rats,
      orally administered Y-700 (1-10 mg/kg) dose dependently lowered plasma urate
      levels. At a dose of 10 mg/kg, the hypouricemic action of Y-700 was more potent
      and of longer duration than that of 4-hydroxypyrazolo(3,4-d)pyrimidine, whereas
      its action was approximately equivalent to that of 2-(3-cyano-4-isobutoxyphenyl)
      4-methyl-5-thiazolecarboxylic acid, a nonpurine inhibitor of XOR. In normal rats,
      orally administered Y-700 (0.3-3 mg/kg) dose dependently reduced the urinary
      excretion of urate and allantoin, accompanied by an increase in the excretion of
      hypoxanthine and xanthine. Y-700 (1 mg/kg) was absorbed rapidly by the oral route
      with high bioavailability (84.1%). Y-700 was hardly excreted via the kidneys but
      was mainly cleared via the liver. These results suggest that Y-700 will be a
      promising candidate for the treatment of hyperuricemia and other diseases in
      which XOR may be involved.

PMID- 15190125
TI  - The bile acid tauroursodeoxycholic acid modulates phosphorylation and
      translocation of bad via phosphatidylinositol 3-kinase in glutamate-induced
      apoptosis of rat cortical neurons.
AB  - Neurotoxicity associated with increased glutamate release results in cell death
      through both necrotic and apoptotic processes. In addition, tauroursodeoxycholic
      acid (TUDCA), an endogenous bile acid, is a strong modulator of apoptosis in
      several cell types. The aims of this study were to test the hypothesis that TUDCA
      reduces the apoptotic threshold induced by glutamate in rat cortical neurons and
      examine potential transduction pathways involved in both apoptotic signaling and
      neuroprotection by TUDCA. The results demonstrated that exposure of cortical
      neurons to glutamate induced cytochrome c release and caspase activation, as well
      as morphologic changes of apoptosis. These events were associated with down
      regulation of antiapoptotic members of the Bcl-2 family, Bcl-2 and Bcl-x(L), and
      dephosphorylation of the serine/threonine protein kinase Akt. Pretreatment with
      TUDCA significantly reduced glutamate-induced apoptosis of rat cortical neurons.
      In addition, TUDCA induced marked phosphorylation and translocation of Bad from
      mitochondria to the cytosol. Moreover, inhibition of the phosphatidylinositol 3
      kinase (PI3K) survival pathway abrogated the protective effects of TUDCA,
      including phosphorylation and translocation of Bad. In conclusion, TUDCA appears
      to modulate glutamate-induced neuronal apoptosis, in part, by activating a PI3K
      dependent Bad signaling pathway. These data suggest that TUDCA may be beneficial
      in treating neurodegenerative disorders in which increased glutamate levels
      contribute to the pathogenesis of the disease.

PMID- 15190126
TI  - Genomic DNA as a cohybridization standard for mammalian microarray measurements.
AB  - A persistent design problem for ratiometric microarray studies is selecting the
      'denominator' RNA cohybridization standard. The ideal standard should be readily
      available, inexpensive, invariant over time and from laboratory to laboratory,
      and should represent all genes with a uniform signal. RNA references (both
      commercial 'universal' and experiment--specific types), fall short of these
      goals. We show here that mouse genomic DNA is a reliable microarray
      cohybridization standard which can meet these criteria. Genomic DNA was superior
      in universality of coverage (>98% of genes from a 16,000 feature mouse 70mer
      microarray) to the Stratagene Universal Mouse Reference RNA standard. Ratios for
      genes in very low abundance in the Stratagene standard were more unstable with
      the Stratagene standard than with genomic DNA. Genes with mid-range, and
      therefore presumably optimal RNA denominator values, showed comparable
      reproducibility with both standards. Inferred ratios made between two different
      experimental RNAs using a genomic DNA standard were found to correlate well with
      companion, directly measured ratios (Spearman correlation coefficient = 0.98).
      The advantage in array feature coverage of genomic DNA will likely increase as
      newer generation microarrays include genes which are expressed exclusively in
      minor tissue or developmental domains that are not represented in mixed tissue
      RNA standards.

PMID- 15190127
TI  - African Haplogroup L mtDNA sequences show violations of clock-like evolution.
AB  - A set of 96 complete mtDNA sequences that belong to the three major African
      haplogroups (L1, L2, and L3) was analyzed to determine if mtDNA has evolved as a
      molecular clock. Likelihood ratio tests (LRTs) were carried out with each of the
      haplogroups and with combined haplogroup sequence sets. Evolution has not been
      clock-like, neither for the coding region nor for the control region, in combined
      sets of African haplogroup L mtDNA sequences. In tests of individual haplogroups,
      L2 mtDNAs showed violations of a molecular clock under all conditions and in both
      the control and coding regions. In contrast, haplogroup L1 and L3 sequences, both
      for the coding and control regions, show clock-like evolution. In clock tests of
      individual L2 subclades, the L2a sequences showed a marked violation of clock
      like evolution within the coding region. In addition, the L2a and L2c branch
      lengths of both the coding and control regions were shorter relative to those of
      the L2b and L2d sequences, a result that indicates lower levels of sequence
      divergence. Reduced median network analyses of the L2a sequences indicated the
      occurrence of marked homoplasy at multiple sites in the control region. After
      exclusion of the L2a and L2c sequences, African mtDNA coding region evolution has
      not significantly departed from a molecular clock, despite the results of
      neutrality tests that indicate the mitochondrial coding region has evolved under
      nonneutral conditions. In contrast, control region evolution is clock-like only
      at the haplogroup level, and it thus appears to have evolved essentially
      independently from the coding region. The results of the clock tests, the network
      analyses, and the branch length comparisons all caution against the use of simple
      mtDNA clocks.

PMID- 15190128
TI  - Variation of female and male lineages in sub-Saharan populations: the importance
      of sociocultural factors.
AB  - In this paper, we present a study of genetic variation in sub-Saharan Africa,
      which is based on published and unpublished data on fast-evolving (hypervariable
      region 1 of mitochondrial DNA and six microsatellites of Y chromosome) and slow
      evolving (haplogroup frequencies) polymorphisms of mtDNA and Y chromosome. Our
      study reveals a striking difference in the genetic structure of food-producer
      (Bantu and Sudanic speakers) and hunter-gatherer populations (Pygmies, Kung, and
      Hadza). In fact, the ratio of mtDNA to Y-chromosome Nupsilon is substantially
      higher in food producers than in hunter-gatherers as determined by fast-evolving
      polymorphisms (1.76 versus 0.11). This finding indicates that the two population
      groups differ substantially in female and male migration rate and/or effective
      size. The difference also persists when linguistically homogeneous populations
      are used and outlier populations are eliminated (1.78 vs 0.19) or when the
      jacknife procedure is applied to a paired population data set (1.32 to 7.84
      versus 0.14 to 0.66). The higher ratio of mtDNA to Y-chromosome Nnu in food
      producers than in hunter-gatherers is further confirmed by the use of slow
      evolving polymorphisms (1.59 to 7.91 versus 0.12 to 0.35). To explain these
      results, we propose a model that integrates demographic and genetic aspects and
      incorporates ethnographic knowledge. In such a model, the asymmetric gene flow,
      polyginy, and patrilocality play an important role in differentiating the genetic
      structure of sub-Saharan populations. The existence of an asymmetric gene flow is
      supported by the phylogeographic features of mtDNA and Y-chromosome haplogroups
      found in the two population groups. The role of polyginy and patrilocality is
      sustained by the evidence of a differential pressure of genetic drift and gene
      flow on maternal and paternal lineages of food producers and hunter-gatherers
      that is revealed through the analysis of mitochondrial and Y-chromosomal
      intrapopulational variation.

PMID- 15190129
TI  - Modeling the impact of DNA methylation on the evolution of BRCA1 in mammals.
AB  - The modified base 5-methylcytosine ((m)C) plays an important functional role in
      the biology of mammals as an epigenetic modification and appears to exert a
      striking impact on the molecular evolution of mammal genomes. The collective
      epigenetic functions of (m)C revolve around its effect on gene transcription,
      while the influence of this modified base on the evolution of mammal genomes
      derives from the greatly elevated spontaneous mutation rate of (m)C to T. In
      mammals, (m)C occurs at the dinucleotides CpG, CpA, and CpT. As a step toward a
      comprehensive statistical examination of the role of (m)C in mammal molecular
      evolution, we have developed novel Markov models of codon substitution that
      incorporate dinucleotide-level terms relevant to (m)C mutation. We apply these
      models to two data sets of aligned BRCA1 exon 11 sequences from bats and
      primates. In all cases, terms specific to mutations that affect the dinucleotides
      CpG, CpA, and CpT significantly improved model fit. For the CpG-specific terms,
      both transition and transversion substitution rates were elevated. These rates
      differed between the data sets. Bats exhibited a lower relative rate of
      substitutions at CpG-containing codons. Transition substitutions were
      significantly less than 1 at CpA-containing codons but greater than 1 at CpT
      containing codons. The inclusion of interaction terms in the codon models to
      represent possible confounding with the effect of natural selection were
      supported for codons that contained CpG and CpT, but not CpA. From the results,
      we infer that mutation of (m)C is a probable factor that affects BRCA1 codons
      containing the dinucleotide CpG, a possible factor for CpA-containing codons, and
      an unlikely factor that affects CpT-containing codons. The confounding of
      estimated terms with the effect of natural selection indicate this confounding
      must be addressed for comparisons between different coding and noncoding regions.

PMID- 15190130
TI  - Merlin, a new superfamily of DNA transposons identified in diverse animal genomes
      and related to bacterial IS1016 insertion sequences.
AB  - Several new families of DNA transposons were identified by computer-assisted
      searches in a wide range of animal species that includes nematodes, flat worms,
      mosquitoes, sea squirt, zebrafish, and humans. Many of these elements have coding
      capacity for transposases, which are related to each other and to those encoded
      by the IS1016 group of bacterial insertion sequences. Although these transposases
      display a motif similar to the DDE motif found in many transposases and
      integrases, they cannot be directly allied to any of the previously described
      eukaryotic transposases. Other common features of the new eukaryotic and
      bacterial transposons include similarities in their terminal inverted repeats and
      8-bp or 9-bp target-site duplications. Together, these data indicate that these
      elements belong to a new superfamily of DNA transposons, called Merlin/IS1016,
      which is common in many eubacterial and animal genomes. We also present evidence
      that these transposons have been recently active in several animal species. This
      evidence is particularly strong in the parasitic blood fluke Schistosoma mansoni,
      in which Merlin is also the first described DNA transposon family.

PMID- 15190131
TI  - Recognition of DNA by omega protein from the broad-host range Streptococcus
      pyogenes plasmid pSM19035: analysis of binding to operator DNA with one to four
      heptad repeats.
AB  - pSM19035-encoded omega protein forms a dimer (omega2) that binds to a set of 7-bp
      repeats with sequence 5'-NATCACN-3'. Upon binding to its cognate sites, omega2
      regulates transcription of genes required for copy number control and stable
      inheritance of plasmids, and promotes accurate plasmid segregation. Protein
      omega2 binds poorly to one heptad but the affinity to DNA increases with two and
      more unspaced heptads in direct or inverted orientation. DNA titration of
      increasing numbers of heptads with omega2, monitored by circular dichroism
      measurements, indicates the binding of one omega2 to one heptad (omega2:heptad
      stoichiometry of 1:1). Spacing of two directly or inversely oriented heptads by 1
      to 7 bp reduces the affinity of the protein for its cognate target site. The
      binding affinity of omega2 for two directly repeated heptads was severely reduced
      if one of the base pairs of the core 5'-ATCAC-3' sequence of one of the heptads
      was individually substituted by any other base pair. Hydroxyl radical
      footprinting shows a protection pattern at the 5'-ATCAC-3' core. These data
      suggest that each heptad defines an operator half-site and that tight binding of
      the symmetric omega2 to the central 5'-TCA-3' core of symmetric or asymmetric
      targets (differently oriented heptads) is probably achieved by structural changes
      of DNA and/or protein or both.

PMID- 15190132
TI  - Analysis of the LAGLIDADG interface of the monomeric homing endonuclease I-DmoI.
AB  - The general structural fold of the LAGLIDADG endonuclease family consists of two
      similar alpha/beta domains (alphabetabetaalphabetabetaalpha) that assemble either
      as homodimers or monomers with the domains related by pseudo-two-fold symmetry.
      At the center of this symmetry is the closely packed LAGLIDADG two-helix bundle
      that forms the main inter- or intra-molecular contact region between the domains
      of single- or double-motif proteins, respectively. In this work, we further
      examine the role of the LAGLIDADG residues involved in the helix-helix
      interaction. The interchangeability of the LAGLIDADG helix interaction was
      explored by grafting interfacial residues from the homodimeric I-CreI into the
      corresponding positions in the monomeric I-DmoI. The resulting LAGLIDADG exchange
      mutant is partially active, preferring to nick dsDNA rather than making the
      customary double-strand break. A series of partial revertants within the mutated
      LAGLIDADG region are shown to restore cleavage activity to varying degrees
      resulting in one I-DmoI mutant that is more active than wild-type I-DmoI. The
      phenotype of some of these mutants was reconciled on the basis of similarity to
      the GxxxG helix interaction found in transmembrane proteins. Additionally, a
      split variant of I-DmoI was created, demonstrating that the LAGLIDADG helices of
      I-DmoI are capable of forming and maintaining the protein-protein interface in
      trans to create an active heterodimer.

PMID- 15190134
TI  - Coming to America--international medical graduates in the United States.

PMID- 15190133
TI  - Altered DNA binding specificity of Arnt by selection of partner bHLH-PAS
      proteins.
AB  - The Ah receptor (AhR) and HLF are transcription factors involved in xenobiotic
      metabolism and hypoxic response, respectively. AhR and HLF heterodimerize with
      Arnt as the common partner, and bind to asymmetric E-boxes termed XRE and HRE,
      respectively. In order to investigate nucleotide preference of the heterodimers,
      reporter plasmids with oligonucleotides for XREs or HREs with systematic
      mutations were constructed and their activity was determined. Comparison of the
      activity revealed that DNA length and nucleotide preference recognized by Arnt
      subunit in the two heterodimers were largely different between XRE and HRE. We
      expressed AhR-Arnt and HLF-Arnt in Escherichia coli and used them for DNA
      binding. The dissociation constant of HLF-Arnt-HRE was 10.4 +/- 1.6 nM.
      Competition activity of mutated XREs or HREs with wild type was consistent with
      their transcription activity. Bending of XRE and HRE induced by binding of the
      relevant heterodimers was observed with stronger bending of XRE than of HRE. By
      deletional and mutational analyses, an alanine and three arginine (Ala 8, Arg 9,
      Arg 11 and Arg 12) residues in the basic sequence of HLF were found to be
      indispensable for the transcriptional activity.

PMID- 15190135
TI  - Cardiovascular disease in non-Western countries.

PMID- 15190136
TI  - A factorial trial of six interventions for the prevention of postoperative nausea
      and vomiting.
AB  - BACKGROUND: Untreated, one third of patients who undergo surgery will have
      postoperative nausea and vomiting. Although many trials have been conducted, the
      relative benefits of prophylactic antiemetic interventions given alone or in
      combination remain unknown. METHODS: We enrolled 5199 patients at high risk for
      postoperative nausea and vomiting in a randomized, controlled trial of factorial
      design that was powered to evaluate interactions among as many as three
      antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of
      64 possible combinations of six prophylactic interventions: 4 mg of ondansetron
      or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of
      droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or
      nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly
      assigned with respect to the first four interventions. The primary outcome was
      nausea and vomiting within 24 hours after surgery, which was evaluated blindly.
      RESULTS: Ondansetron, dexamethasone, and droperidol each reduced the risk of
      postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk
      by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these
      agents (i.e., total intravenous anesthesia) was thus similar to that observed
      with each of the antiemetics. All the interventions acted independently of one
      another and independently of the patients' baseline risk. Consequently, the
      relative risks associated with the combined interventions could be estimated by
      multiplying the relative risks associated with each intervention. Absolute risk
      reduction, though, was a critical function of patients' baseline risk.
      CONCLUSIONS: Because antiemetic interventions are similarly effective and act
      independently, the safest or least expensive should be used first. Prophylaxis is
      rarely warranted in low-risk patients, moderate-risk patients may benefit from a
      single intervention, and multiple interventions should be reserved for high-risk
      patients.

PMID- 15190137
TI  - Noninvasive positive-pressure ventilation for respiratory failure after
      extubation.
AB  - BACKGROUND: The need for reintubation after extubation and discontinuation of
      mechanical ventilation is not uncommon and is associated with increased
      mortality. Noninvasive positive-pressure ventilation has been suggested as a
      promising therapy for patients with respiratory failure after extubation, but a
      single-center, randomized trial recently found no benefit. We conducted a
      multicenter, randomized trial to evaluate the effect of noninvasive positive
      pressure ventilation on mortality in this clinical setting. METHODS: Patients in
      37 centers in eight countries who were electively extubated after at least 48
      hours of mechanical ventilation and who had respiratory failure within the
      subsequent 48 hours were randomly assigned to either noninvasive positive
      pressure ventilation by face mask or standard medical therapy. RESULTS: A total
      of 221 patients with similar baseline characteristics had been randomly assigned
      to either noninvasive ventilation (114 patients) or standard medical therapy (107
      patients) when the trial was stopped early, after an interim analysis. There was
      no difference between the noninvasive-ventilation group and the standard-therapy
      group in the need for reintubation (rate of reintubation, 48 percent in both
      groups; relative risk in the noninvasive-ventilation group, 0.99; 95 percent
      confidence interval, 0.76 to 1.30). The rate of death in the intensive care unit
      was higher in the noninvasive-ventilation group than in the standard-therapy
      group (25 percent vs. 14 percent; relative risk, 1.78; 95 percent confidence
      interval, 1.03 to 3.20; P=0.048), and the median time from respiratory failure to
      reintubation was longer in the noninvasive-ventilation group (12 hours vs. 2
      hours 30 minutes, P=0.02). CONCLUSIONS: Noninvasive positive-pressure ventilation
      does not prevent the need for reintubation or reduce mortality in unselected
      patients who have respiratory failure after extubation.

PMID- 15190138
TI  - Quantification of plasma Epstein-Barr virus DNA in patients with advanced
      nasopharyngeal carcinoma.
AB  - BACKGROUND: We investigated the clinical significance of plasma concentrations of
      Epstein-Barr virus (EBV) DNA in patients with advanced nasopharyngeal carcinoma.
      METHODS: Ninety-nine patients with biopsy-proven stage III or IV nasopharyngeal
      carcinoma and no evidence of metastasis (M0) received 10 weekly chemotherapy
      treatments followed by radiotherapy. Plasma samples from the patients were
      subjected to a real-time quantitative polymerase-chain-reaction assay. EBV
      genotypes of paired samples from plasma and primary tumor were compared. RESULTS:
      Plasma EBV DNA was detectable before treatment in 94 of the 99 patients, but not
      in 40 healthy controls or 20 cured patients. The median concentrations of plasma
      EBV DNA were 681 copies per milliliter among 25 patients with stage III disease,
      1703 copies per milliliter among 74 patients with stage IV disease, and 291,940
      copies per milliliter among 19 control patients with distant metastasis
      (P<0.001). Patients with relapse had a significantly higher plasma EBV DNA
      concentration before treatment than those who did not have a relapse (median,
      3035 vs. 1202 copies per milliliter; P=0.02). The consistent genotyping of EBV
      DNA between paired samples of plasma and primary tumor suggested that the
      circulating cell-free EBV DNA may originate from the primary tumor. Unlike the
      rebound of plasma EBV DNA concentrations in the patients who had a relapse, the
      plasma EBV DNA concentration was persistently low or undetectable in patients
      with a complete clinical remission. Overall survival (P<0.001) and relapse-free
      survival (P=0.02) were significantly lower among patients with pretreatment
      plasma EBV DNA concentrations of at least 1500 copies per milliliter than among
      those with concentrations of less than 1500 copies per milliliter. Patients with
      persistently detectable plasma EBV DNA had significantly worse overall survival
      (P<0.001) and relapse-free survival (P<0.001) than patients with undetectable EBV
      DNA one week after the completion of radiotherapy. CONCLUSIONS: Quantification of
      plasma EBV DNA is useful for monitoring patients with nasopharyngeal carcinoma
      and predicting the outcome of treatment.

PMID- 15190139
TI  - A trial of three antiretroviral regimens in HIV-1-infected children.
AB  - BACKGROUND: Depletion of CD4 T-cell counts or progression of human
      immunodeficiency virus (HIV) disease occurs rapidly in children, but few data
      address the efficacy of aggressive therapy for HIV-infected children. METHODS: We
      evaluated the safety, tolerability, and activity of three regimens of
      antiretroviral therapy in a multicenter, open-label, phase 1-2 trial. Children
      infected with HIV type 1 (HIV-1) were stratified at entry according to age--three
      months or younger (early therapy) or older than three months (delayed therapy)-
      and assigned sequentially to one of three regimens. Children continued to receive
      treatment for up to 200 weeks if the plasma HIV-1 RNA level was less than 1000
      copies per milliliter by 16 weeks. RESULTS: Plasma HIV-1 RNA levels fell from a
      median of 5.3 log copies per milliliter (range, 3.3 to 6.4 log copies per
      milliliter) at baseline to less than 1000 copies per milliliter at 16 weeks in 32
      of 52 infants (62 percent). Plasma HIV-1 RNA levels were below 400 copies per
      milliliter at 48 weeks in 26 infants (50 percent) and at 200 weeks in 23 infants
      (44 percent). An intention-to-treat analysis revealed that significantly more
      children who received stavudine, lamivudine, nevirapine, and nelfinavir had
      plasma HIV-1 RNA levels of less than 400 copies per milliliter at 48 weeks (83
      percent) and 200 weeks (72 percent) than children who received reverse
      transcriptase inhibitors alone (P=0.001 and P=0.01, respectively). Fewer infants
      in the delayed-therapy group than in the early-therapy group (30 percent vs. 60
      percent) had plasma HIV-1 RNA levels of less than 400 copies per milliliter at
      200 weeks (P=0.03). Treatment-associated adverse effects were infrequent.
      CONCLUSIONS: In this phase 1-2 trial involving HIV-1-infected children, an age of
      three months or younger at the initiation of therapy and treatment with
      stavudine, lamivudine, nevirapine, and nelfinavir were associated with improved
      long-term viral suppression. Larger, randomized trials are required to define the
      optimal time to initiate therapy and the optimal regimen for these infants.

PMID- 15190140
TI  - Tumors of the endolymphatic sac in von Hippel-Lindau disease.

PMID- 15190141
TI  - Pneumocystis pneumonia.

PMID- 15190142
TI  - Images in clinical medicine. Cicatricial pemphigoid.

PMID- 15190143
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 18-2004. A 61-year-old man with rectal bleeding and a 2-cm mass
      in the rectum.

PMID- 15190144
TI  - Prevention of postoperative nausea and vomiting--a multimodal solution to a
      persistent problem.

PMID- 15190145
TI  - Noninvasive ventilation--don't push too hard.

PMID- 15190146
TI  - Erythropoietin for neurologic protection and diabetic neuropathy.

PMID- 15190147
TI  - Sequential therapies for proliferative lupus nephritis.

PMID- 15190148
TI  - Purine-rich foods and the risk of gout in men.

PMID- 15190149
TI  - Pulmonary hypertension as a risk factor for death in patients with sickle cell
      disease.

PMID- 15190150
TI  - Cellulitis.

PMID- 15190151
TI  - Thrombocytosis.

PMID- 15190152
TI  - Diabetic retinopathy.

PMID- 15190154
TI  - Tuberculosis transmission from a patient with skin lesions and a negative sputum
      smear.

PMID- 15190153
TI  - LMO2 and gene therapy for severe combined immunodeficiency.

PMID- 15190155
TI  - Images in clinical medicine. Dislocation of the lenses.

PMID- 15190156
TI  - Revalidation.

PMID- 15190157
TI  - Appraisal standards in occupational medicine.
AB  - Following a series of serious misdemeanours by British doctors, the General
      Medical Council (GMC) has introduced a system of re-licensing called
      'revalidation'. Annual medical appraisal forms an important cornerstone of the
      proposed system, but specific guidance is lacking on the content of appraisal for
      occupational physicians, and the kinds of evidence that they might bring to
      critical reviews of performance. Two educational bodies, the Revalidation
      Committee of the Faculty of Occupational Medicine, Royal College of Physicians
      and the Education Panel of the Society of Occupational Medicine, have jointly
      developed a set of recommendations on appraisal to further the process. In this
      paper we summarize the background and present the guidelines promulgated by the
      Faculty and the Society.

PMID- 15190158
TI  - Incidence of occupational skin conditions in a food manufacturing company:
      results of a health surveillance programme.
AB  - BACKGROUND: The food industry has been associated with a high risk of work
      related skin problems. Aim To examine the incidence of work-related skin
      conditions and the likely causative agents in a single large food company.
      METHOD: Analysis of a health surveillance programme, conducted over a 7 year
      period, in a food company with 21 000 employees working in diverse manufacturing
      processes. RESULTS: The mean incidence of skin conditions, taking all of the
      different food manufacturing operations together, was 1310 per million employees
      per annum. The mean incidence was greatest in the manufacturing sector whose
      operations involved chilled or frozen product (3180 per million employees per
      annum). Most of the cases reported (184/192 = 96%) were due to primary irritant
      dermatitis. The two commonest suspected causes of the dermatitis were contact
      with ingredients and hand washing. Taken together, these factors accounted for
      58% of all cases. Although the wearing of gloves is often considered necessary to
      prevent dermatitis from exposure to ingredients and to lessen the need for hand
      washing, this factor itself was responsible for 9% of all cases. CONCLUSION:
      Analysis of a company health surveillance scheme showed the average incidence of
      work-related skin problems to be lower than previously reported in the food
      industry.

PMID- 15190159
TI  - Management of hepatitis B immunizations and blood exposure incidents in primary
      care.
AB  - AIM: To investigate how well primary care health care workers, with no access to
      an occupational health service (OHS), have managed their hepatitis B
      immunizations and blood exposure incidents, compared with National Health Service
      Trust staff, with access to an OHS. METHOD: A questionnaire was sent to 78
      general practitioners (GPs), 93 general practice nurses, 81 NHS Trust consultants
      and 88 NHS Trust community nurses, in the Airedale area of West Yorkshire in June
      2001. RESULTS: The response rate was 80%. GPs were significantly less likely than
      consultants to have received a hepatitis B booster vaccination after their
      primary course (57 versus 80%, P < 0.009) and significantly less likely to have
      had their blood anti-HBs test checked after their last vaccination (74 versus
      94%, P < 0.011). General practice nurses were significantly less likely to fill
      in a blood exposure incident form after an injury than community nurses (56
      versus 91%, P < 0.006). Overall, the group with access to an OHS was
      significantly more likely to have received a hepatitis B booster (P < 0.036),
      have had a blood anti-HBs test after last vaccination (P < 0.010) and to have
      filled in a blood exposure incident form after last blood exposure (P < 0.033),
      than the group without access to an OHS. CONCLUSION: Any future OHS with
      responsibility for primary care, should consider calling in all GPs and general
      practice nurses for a review of their hepatitis immunity and for education
      regarding the management of blood exposure incidents.

PMID- 15190160
TI  - Assessment of the potential effects of population changes in attitudes, awareness
      and beliefs on self-reporting of occupational ill-health.
AB  - BACKGROUND: It is important to take account of the effects of population changes
      in attitudes, awareness and beliefs when interpreting temporal trends in self
      reported occupational ill-health. Aim To assess how changes in population
      attitudes, awareness and beliefs have influenced trends in the self-reporting of
      occupational and other types of ill-health. METHOD: A review of relevant
      literature was carried out. The criterion for inclusion was that papers must be
      based on empirical evidence; theoretical discussion papers were included only
      where empirical examples were included. RESULTS: Several examples were identified
      where raised awareness of a health problem following intended or unintended
      publicity was followed by an increase in self-reports of this problem. The
      magnitude of the increase varied widely according to the situation. One example
      was identified where self-reports decreased following a publicity programme
      designed to prevent the occurrence and worsening of the problem in the
      population. Potential mechanisms identified as influencing changes in self
      reporting of ill-health following raised awareness included changes in
      symptom/illness management, perception of symptoms, tolerance of symptoms,
      recognition and diagnosis of illness, attribution of illness; social desirability
      and legitimacy and recall. CONCLUSION: The effects of changes in population
      attitudes, awareness and beliefs on trends in self-reports of occupational and
      other illness are difficult to predict for any given situation.

PMID- 15190161
TI  - Analysing and interpreting routinely collected data on sharps injuries in
      assessing preventative actions.
AB  - BACKGROUND: Sharps injuries (SI) occur frequently in hospitals and are a risk for
      exposure to bloodborne pathogens. During the 1990s, the safety service of a
      university general hospital introduced, in collaboration with the occupational
      health service, specific measures to reduce the number of SI. AIM: The aim of
      this study was to assess the occurrence and evolution of SI during this period
      and to evaluate the effectiveness of the preventative measures taken, making use
      of routinely collected data. METHOD: In a retrospective study, we analysed the
      number of SI recorded from 1990 to 1997. The study population was all employees
      at risk of SI. Because the introduction of intensive preventative measures dates
      from 1996, an effect on the incidence of SI can be expected from 1996. To assess
      this effect, mean incidence rates for 1990-1995 and for 1996-1997 were compared.
      RESULTS: In the study period, a total of 4230 SI were recorded. The global SI
      incidence rate decreased from 33.4 SI per 100 occupied beds per year in 1990-1995
      to 30.1 in 1996-1997 (P < 0.01). In the same period, among nurses a decrease in
      incidence rate from 17.2 to 12.7 SI per 100 person-years was noted (P < 0.0001)
      and for the hotel service from 4.8 to 3.7 (not significant). CONCLUSION: Although
      this study has various restraints, these results suggest that intensive
      preventative actions, in combination with technological advances, may have
      contributed to a drop of 67 SI cases per year.

PMID- 15190162
TI  - Do stressful life events cause type 1 diabetes?
AB  - BACKGROUND: The link between psychological stresses and deteriorating diabetes
      control is well known. However, people who develop type 1 diabetes sometimes
      ascribe the onset of diabetes to a recent stressful event. AIMS: To perform a
      systematic review of the literature to assess whether stressful life events can
      cause type 1 diabetes. METHOD: Electronic and manual literature search using
      appropriate key words. RESULTS: Older literature provides anecdotal links between
      stressful life events and diabetes. The difficulty in interpreting these papers
      is the small numbers under study and the lack of distinction between type 1 and
      type 2 diabetes. More recent studies, in particular from Scandinavia, demonstrate
      that there is no link between either the number or the severity of life events in
      the year up to the diagnosis and the onset of the condition. CONCLUSION: Given
      the progress in understanding the molecular biology of diabetes, the concept that
      stress causes type 1 diabetes is no longer plausible. There is no evidence from
      large well-controlled trials that type 1 diabetes is caused by stressful life
      events.

PMID- 15190163
TI  - Mortality in an Australian cohort of textile workers.
AB  - BACKGROUND: Workers in the textile industry may be exposed to textile dusts, a
      wide range of chemicals and electromagnetic radiation. AIM: To investigate the
      risk of mortality in a cohort of textile workers and examine whether specific
      occupational exposures were associated with mortality. METHOD: Data on members
      and former members of a textile industry union were extracted from membership
      cards and matched with the National Death Index to obtain date and cause of
      death. Exposure to 31 different substances was assessed using a specifically
      designed job exposure matrix that consisted of profiles of exposures in 11
      occupational titles. These profiles were modified according to individual
      circumstances. Standardized mortality ratios (SMRs) were computed comparing the
      cohort to the Australian population and Mantel-Haenszel estimates of the rate
      ratios were computed comparing exposed with unexposed for each of the substances.
      RESULTS: There were 113 deaths in the cohort of 7684 workers. Male and female
      textile workers had similar risks of death from any cause, cancer or
      cardiovascular disease to the general Australian population. Male workers had an
      increased risk of death from injury (SMR = 157, 95% confidence interval 113-213).
      There were no statistically significant increases in risk with particular
      occupational exposures. CONCLUSION: Male textile workers are at higher risk of
      death from injury.

PMID- 15190164
TI  - Mortality in the Polish small-scale fishing industry.
AB  - BACKGROUND: The fishing industry has a high occupational mortality. AIM: To
      investigate the cause of mortality amongst Polish small-scale fishermen during a
      40 year period. METHOD: The retrospective data from three independent sources on
      deaths in the Polish small-scale fishing industry were analysed. RESULTS: A total
      of 177 deaths were identified, with an average annual mortality rate of 89 per
      100 000 employees per year. The death rate was significantly higher in boats <13
      m in length. In 96% of cases, death was due to external (non-medical) causes,
      while 60% were related to sea catastrophes, often involving multiple vessels.
      Alcohol was implicated in 45% of deaths where autopsy was carried out.
      CONCLUSION: The Polish small-scale fishing industry has a high mortality rate
      which varies significantly by type of vessel and use of alcohol may be a
      significant contributory factor.

PMID- 15190165
TI  - Effectiveness of therapy with iloprost in hand-arm vibration syndrome.
AB  - AIM: To evaluate the efficacy and tolerance of therapy with iloprost in hand-arm
      vibration syndrome. METHODS: We describe a clinical case of a male aged 53 years,
      who was a heavy smoker for 30 years and a mason working with vibrating tools
      since 1962. He presented with a history of 10 years of attacks of vasospasm,
      functional impairment and digital ulceration. He was diagnosed as having hand-arm
      vibration syndrome vascular stage 4 on the Stockholm Workshop 1986 Scale. Besides
      suspension from work and abstention from smoking, we began intravenous infusion
      of iloprost for 6 h in cycles of 3-6 consecutive days, arriving at a dose of 1.5
      2.0 ng/kg/min. RESULTS: After eight cycles, he reported significant symptomatic
      and functional improvement. Iloprost was seen to be efficacious: the trophic skin
      lesions disappeared and his microcirculatory perfusion tests improved. There were
      no significant side effects. CONCLUSIONS: We suggest that the use of iloprost in
      the treatment of the most advanced stages of vascular hand-arm vibration syndrome
      warrants further study

PMID- 15190168
TI  - The group discussion--a therapeutic modality of the occupational health service?

PMID- 15190166
TI  - Chronic overexposure to cadmium fumes associated with IgA mesangial
      glomerulonephritis.
AB  - BACKGROUND: Cadmium is a metal used in the zinc, copper and steel industries, and
      in the manufacture of electric batteries and solar cells. Acute cadmium poisoning
      is characterized by irritation of the respiratory tract, while in chronic
      poisoning the main target organ is the renal tubule. AIMS: We report a patient
      with chronic work overexposure to cadmium, who presented a IgA mesangial
      glomerulonephritis with no respiratory or renal tubule involvement. Case report A
      39-year-old patient was referred to our hospital for evaluation of a glomerular
      nephropathy. For the past 12 years he had worked as a welder, using cadmium
      electrodes. The patient had no respiratory symptoms and the chest X-ray was
      normal. Tests showed a proteinuria of 2 g in 24 h with microhaematuria [150 red
      blood cells/high power field (rbc/hpf)], with preservation of the renal function
      (creatinine clearance of 137 ml/min). The concentrations of cadmium in blood and
      urine were 45 micro g/l and 25 micro g/g creatinine, and an environmental study
      showed that levels of cadmium in the workplace were 52 micro g/m(3). A renal
      biopsy showed an IgA mesangial glomerulonephritis. The patient ceased to work
      with cadmium, and 1 year later cadmium levels had decreased and renal function
      was found to be stable. CONCLUSIONS: IgA mesangial glomerulonephritis is a
      disease of unknown aetiology which has been associated with other diseases.
      Chronic overexposure to cadmium may contribute to the development of this
      nephrophathy.

PMID- 15190169
TI  - UK worker representatives' views on the causes of stress in the workplace.

PMID- 15190170
TI  - Symptoms are not disorders, and dissatisfaction is not ergonomics.

PMID- 15190173
TI  - Prevalence of back pain assessed with a description of the associated factors.

PMID- 15190175
TI  - Counterattack.

PMID- 15190176
TI  - Inside insulin signaling, communication is key to long life.
AB  - In a recent Nature paper, Tatar and colleagues show that inhibition of
      insulin/insulin-like growth factor (IGF) signaling specifically in the adipose
      tissue of Drosophila melanogaster retards organismal aging, increases resistance
      to oxidative stress, augments lipid deposition, and restricts insulin signaling
      in peripheral tissues by a cell-non-autonomous mechanism. Consistent with recent
      work in the worm, these results suggest that insulin/IGF signaling itself may
      mediate communication among various tissues to influence organismal longevity.

PMID- 15190177
TI  - Neurodegeneration in normal brain aging and disease.
AB  - Normal "healthy" aging is defined as aging without disease. Many aged people do
      not exhibit symptoms of disease and lead normal lives, but nonetheless display
      pathological changes that are characteristic of Alzheimer's disease (AD),
      Parkinson's disease (PD), dementia with Lewy bodies (DLB), and/or cerebrovascular
      disease (CVD). These changes are restricted to distinct brain regions and might
      represent preclinical stages of these disorders. This Perspective discusses
      arguments in favor of and against the hypothesis that pathological changes
      related to AD, PD, DLB, and CVD in the brains of nondemented elderly people
      represent early stages of these diseases rather than healthy aging. We conclude
      that early pathological disease-related changes do indeed constitute the
      beginning of AD, PD, DLB, and CVD rather than normal concomitants of aging, even
      in the absence of any clinical symptoms. Aging is, therefore, a major risk factor
      for these diseases but does not necessarily lead to age-related diseases.

PMID- 15190178
TI  - Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas
      associated death domain-like IL-1 beta-converting enzyme inhibitory protein
      (vFLIP).
AB  - The Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus
      8) has been linked to KS and primary effusion lymphoma (PEL) in immunocompromised
      individuals. We report that PEL cell lines have constitutive active alternative
      NF-kappa B pathway and demonstrate high-level expression of NF-kappa B2/p100
      precursor and its processed subunit p52. To elucidate the mechanism of activation
      of the alternative NF-kappa B pathway in PEL cells, we have investigated the role
      of KSHV-encoded viral Fas-associated death domain-like IL- beta 1-converting
      enzyme inhibitory protein (vFLIP) K13. We demonstrate that stable expression of
      K13, but not other FLIPs, in a variety of cell lines constitutively up-regulates
      p100/NF-kappa B2 expression and leads to its processing into the p52 subunit. K13
      induced up-regulation and processing of p100 critically depends on the I kappa B
      kinase (IKK)alpha/IKK1 subunit of the IKK complex, whereas IKK beta/IKK2,
      receptor-interacting protein, and NF-kappa B-inducing kinase are dispensable for
      this process. Silencing of endogenous K13 expression by siRNA inhibits p100
      processing and cellular proliferation. Our results demonstrate for the first
      time, to our knowledge, that KSHV vFLIP K13 is required for the growth and
      proliferation of PEL cells and alternative NF-kappa B pathway plays a key role in
      this process. Therapeutic agents targeting the alternative NF-kappa B pathway may
      have a role in the treatment of KSHV-associated lymphomas.

PMID- 15190179
TI  - Involvement of Notch signaling in hippocampal synaptic plasticity.
AB  - During development of the nervous system, the fate of stem cells is regulated by
      a cell surface receptor called Notch. Notch is also present in the adult
      mammalian brain; however, because Notch null mice die during embryonic
      development, it has proven difficult to determine the functions of Notch. Here,
      we used Notch antisense transgenic mice that develop and reproduce normally, but
      exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in
      synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term
      potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in
      normal mice and corrects the defect in LTP in Notch antisense transgenic mice.
      Levels of basal and stimulation-induced NF-kappa B activity were significantly
      decreased in mice with reduced Notch levels. These findings suggest an important
      role for Notch signaling in a form of synaptic plasticity known to be associated
      with learning and memory processes.

PMID- 15190180
TI  - Synthesis of (-)-longithorone A: using organic synthesis to probe a proposed
      biosynthesis.
AB  - We present a full report of our enantioselective synthesis of (-)-longithorone A
      (1). The synthesis was designed to test the feasibility of the biosynthetic
      proposal for 1 put forward by Schmitz involving intermolecular and transannular
      Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if
      the biosynthesis does involve these two Diels-Alder reactions, the intermolecular
      Diels-Alder reaction likely occurs before the transannular cycloaddition. The
      intermolecular Diels-Alder precursors, [12]-paracyclophanes 38, 49, 59, and 60,
      were prepared atropselectively, providing examples of ene-yne metathesis
      macrocyclization. The 1,3-disubstituted dienes produced from the
      macrocyclizations represent a previously unreported substitution pattern for
      intramolecular ene-yne metathesis. Protected benzylic hydroxyl stereocenters were
      used as removable atropisomer control elements and were installed by using a
      highly enantioselective vinylzinc addition to electron-rich benzaldehydes 26 and
      27.

PMID- 15190181
TI  - Sorting inhibitors (Sortins): Chemical compounds to study vacuolar sorting in
      Arabidopsis.
AB  - Chemical genomics is an interdisciplinary approach that unites the power of
      chemical screens and genomics strategies to dissect biological processes such as
      endomembrane trafficking. We have taken advantage of the evolutionary
      conservation between plants and Saccharomyces cerevisiae to identify such
      chemicals. Using S. cerevisiae, we screened a library of diverse chemical
      structures for compounds that induce the secretion of carboxypeptidase Y, which
      is normally targeted to the vacuole. Among 4,800 chemicals screened, 14
      compounds, termed sorting inhibitors (Sortins), were identified that stimulated
      secretion in yeast. In Arabidopsis seedlings, application of Sortin1 and -2 led
      to reversible defects in vacuole biogenesis and root development. Sortin1 was
      found to redirect the vacuolar destination of plant carboxypeptidase Y and other
      proteins in Arabidopsis suspension cells and cause these proteins to be secreted.
      Sortin1 treatment of whole Arabidopsis seedlings also resulted in
      carboxypeptidase Y secretion, indicating that the drug has a similar mode of
      action in cells and intact plants. We have demonstrated that screening of a
      simple eukaryote, in which vacuolar biogenesis is not essential, can be a
      powerful tool to find chemicals that interfere with vacuolar delivery of proteins
      in plants, where vacuole biogenesis is essential. Our studies were done by using
      a sublethal dose of Sortin1, demonstrating the powerful ability of the chemical
      to control the induced phenotype in a manner that would be difficult to achieve
      using conventional genetics.

PMID- 15190184
TI  - Post-translational modifications of proteins: implications for aging, antigen
      recognition, and autoimmunity.
AB  - Proteins are complex organic molecules susceptible to numerous post-translational
      modifications occurring spontaneously during aging or as a consequence of
      physiologic or pathologic processes. Antigenicity and interactions of proteins
      with components of the immune system may be profoundly affected by post
      translational modifications. Thus, modified self-antigens may be absent (not
      tolerated) during early T-cell selection and trigger reactions by the immune
      system as they arise later in life. In turn, this may play a role in the
      initiation and pathogenesis of autoimmune diseases. This Review article presents
      an overview of protein modifications that have been shown to affect antigenicity
      and presentation of protein antigens in autoimmune diseases. The relevance of
      these observations is discussed, and the implications for future prophylactic and
      therapeutic interventions are outlined.

PMID- 15190185
TI  - Does Makeham make sense?
AB  - Numerical modeling was used to explore the behavior of ideal cohorts obeying the
      Gompertz-Makeham (GM) law of mortality (-dn/dt 1/n(t) = C + lambda egammat)
      supplemented with the Strehler-Mildvan (SM) correlation (ln lambda = A - Bgamma)
      and to show how changes in the age-independent parameter C will produce an
      apparent SM correlation if C is ignored in mortality data treatment as in the
      case of the so-called longitudinal gompertzian analysis of historical changes in
      human mortality patterns. The essential difference between the Makeham term C and
      Gompertz term lambda e(gammat) has been suggested to be not that the latter is
      age-dependent whereas the former is not, but that C comprises the contributions
      of inherently irresistible stresses to mortality, whereas lambda e(gammat)
      comprises the contributions of resistible stresses and shows how changes in the
      resistance to them are translated into changes in mortality. This assumption was
      used to show by modeling how the transition of stresses from irresistible to
      resistible may result in decreased late survivorship as the cost of increased
      early survivorship, in line with the antagonistic pleiotropy theory of aging. On
      the whole, the modeling suggests that the GM equation is not only a mathematical
      tool for treatment of mortality data but that it also has a fundamental
      biological significance, and its Makeham term C should not be ignored in any
      analysis of mortality data.

PMID- 15190182
TI  - Detailed analysis of gene expression during development of T cell lineages in the
      thymus.
AB  - The genetic mechanisms that promote lineage commitment and eliminate autoreactive
      cells in the thymus are not well understood. To better understand this process,
      we have identified and quantitated transcripts in the two major thymocyte
      lineages by using serial analysis of gene expression. Approximately 25 genes
      displayed almost complete segregation to one or the other T cell lineage.
      Commitment to the CD4 lineage was marked by up-regulation of genes associated
      with increased survival and chaperone function followed by expression of genes
      that regulate nucleosome remodeling and T cell receptor signaling.
      Differentiation within the CD8 lineage, on the other hand, was marked by up
      regulation of genes that regulate lymphocyte homing, followed by quenching of
      genes that inhibit apoptosis. Definition of differential gene expression during
      development of the two major thymocyte lineages will allow insight into
      mechanisms of T cell development after positive and negative selection.

PMID- 15190183
TI  - High urea and NaCl carbonylate proteins in renal cells in culture and in vivo,
      and high urea causes 8-oxoguanine lesions in their DNA.
AB  - Urea and NaCl are elevated in the renal inner medulla. We now find that a high
      concentration of urea or NaCl increases reactive oxygen species (ROS) in mouse
      renal inner medullary (mIMCD3) cells in culture. Previously, high NaCl, but not
      high urea, was found to cause DNA double-strand breaks. We now tested whether
      high urea or NaCl causes oxidative damage to DNA or cellular proteins. We find
      that high urea increases mIMCD3 cell DNA single-strand breaks and 8-oxoguanine
      lesions. High NaCl does not cause detectable 8-oxoguanine lesions. High urea or
      NaCl also greatly increases carbonylation of proteins in mIMCD3 cells.
      Carbonylation occurs within 5 min and with as little as 5 mM urea, a normal
      plasma level. It increases as urea is raised over the range in uremia. A high
      raffinose level increases ROS and carbonylation. High sorbitol and glycerol
      levels do not increase ROS or carbonylation. Carbonyl content is high in mouse
      renal inner medullas where interstitial NaCl and urea concentrations are normally
      high. There, numerous proteins are carbonylated, and carbonylation occurs in both
      collecting ducts and thin limbs. CONCLUSIONS: (i) Oxidative stress, associated
      with high urea, causes 8-oxoguanine DNA lesions in mIMCD3 cell DNA. (ii) High
      urea or NaCl carbonylates proteins in mIMCD3 cells and in renal inner medullary
      cells in vivo. (iii) In mIMCD3 cells a normal plasma concentration of urea causes
      carbonylation, and carbonylation increases over the uremic range of urea
      concentration, indicating that urea can contribute directly to the carbonylation
      found in uremia.

PMID- 15190186
TI  - Association between low self-rated health and heterozygosity for -110A > C
      polymorphism in the promoter region of HSP70-1 in aged Danish twins.
AB  - We have studied the possible association between the -110A > C polymorphism in
      the promoter region of one of the heat shock protein genes HSP70-1 with human
      longevity in a cohort of aged Danish twins. This cohort includes individuals aged
      between 70 and 91 years (mean = 75.6 years), who are categorized according to the
      presence or absence of various diseases and according to the various, age-related
      parameters for which a genetic component has already been defined. Four hundred
      DNA samples from the cohort were genotyped using real-time PCR. Aging phenotypes
      (diseases, physical and cognitive functioning) were compared with regard to
      genotype. Of all the aging phenotypes studied, self-rated health and relative
      self-rated health, which represent an individual's overall sense of physical well
      being and which have been shown to be both predictors of survival at older ages
      and better indicators of future survival than objectively measured health status,
      were associated with the polymorphism. An association was found between low self
      rated health and heterozygosity for -110A > C polymorphism in the promoter region
      of HSP70-1 in aged Danish twins.

PMID- 15190187
TI  - Age-dependent dietary regulation of glucocorticoid receptors in the liver of
      mice.
AB  - Dietary restriction (DR) increases the resistance to different stresses, retards
      various age-related diseases and extends life span in a variety of animals. Here
      we have investigated the effect of DR (alternate days of feeding for 3 months) on
      glucocorticoid receptors (GRs) in the liver of adult (5 months) and old (20
      months) male mice. A significant decrease was observed in the level of receptors
      in old mice (25%) as compared to the adult ones. DR subjected mice of both age
      groups showed a marked increase in the GR concentration (37% in adult and 31% in
      old mice) as compared to the ad libitum (AL) fed mice, whereas the affinity
      remained the same in both groups of animals at both ages. Scatchard analyses and
      the protein slot blot experiment confirmed the increase in the receptor level in
      AL and DR fed animals for both age groups. The magnitude of heat and salt
      activation of GR was higher in the adult mice as compared to the old mice who
      were fed AL. DR, however, significantly increased (40%) the magnitude of
      activation of GR in the older mice as compared to the AL fed animals, whereas no
      such change was observed in the adult animals. Further, DNase I digestion and
      extraction of nuclear bound GR-complexes showed a higher degree of extraction in
      adult animals (57%-59%) as compared to the old (31%-33%) animals. Mice subjected
      to DR revealed no significant change at either age. These findings indicate that
      DR regulates GR in an age-dependent manner and that it may allow animals to
      better adapt to metabolic regulation in older ages.

PMID- 15190189
TI  - Increased catalase activity in mouse cell mutants resistant to paraquat.
AB  - Paraquat is widely used as a generator of superoxide radicals in a cell. First it
      was shown to immediately induce premature senescence in normal human fibroblasts.
      To assess its defense mechanisms, we characterized three paraquat-resistant
      mutants from mouse FM3A cells, MPQR40-1 and MPQR40-3 isolated by a single-step
      selection after mutagenesis, and SPQR100-6 isolated spontaneously. All exhibited
      six to eight times more resistance to paraquat than the parental line. In cell
      cell hybrids, their phenotypes were recessive, co-dominant, or dominant,
      respectively. Biochemical characterization revealed that activity and mRNA level
      for catalase were increased in all of the mutants. In MPQR40-3 that showed the
      highest degree of paraquat resistance, total SOD activity and mRNA level for
      Cu/Zn-SOD were also increased. These results suggest that catalase plays a major
      role in paraquat resistance in mouse FM3A cells.

PMID- 15190188
TI  - The contribution by mitochondrially induced oxidative damage to aging in
      Drosophila melanogaster.
AB  - Strains of Drosophila melanogaster have been generated that vary in the
      mitochondrial genome and have a common nuclear genome. Tetracycline was used to
      cure the strains of the endocommensal bacteria, Wolbachia, which is transmitted
      maternally. Variation in the tetracycline responsive agent contributed
      substantially to variation in longevity and production of metabolic oxidants.
      Changes in diurnal cycle of activity have been investigated: such changes should
      be responsive to metabolism-related damage because of the role of the very active
      neurons, retinal cells and muscle. The metabolic oxidant model predicts that
      longevity and production of metabolic oxidants should be negatively correlated,
      and that deterioration of behavior with age and metabolic oxidant production
      should be positively correlated. Only the first prediction was verified: rate of
      change in behavior correlated with metabolic oxidants, consistent with a role of
      metabolic oxidants in this age-related change. However, the data indicates a role
      for mitochondria in determination longevity, other than by production of
      metabolic oxidants.

PMID- 15190190
TI  - After the genome--the phenome?
AB  - What next? The Human Genome Project signifies complexity rather than
      simplification in the relationship between genotype and phenotype. Genotypes are
      embedded in genomes. Individuality in phenotypes is embedded in components of the
      phenome (transcriptome, metabolome, proteome, etc.). The phenome, its layers, and
      its nodes, links and networks, require elucidation; there is a need for a Human
      Phenome Project (Freimer and Sabatti 2003). Biology has largely been a reductive
      science in the recent past; integrative biology lies ahead. Clinician-scientists
      (including human biochemical geneticists) will be recognized as key participants
      in the 'medical' Phenome Project as it reveals components of individuality, and
      their contributions, in simple or combinatorial fashion, to Mendelian and complex
      traits; better ways to treat 'genetic disease' will be by-products of the
      project. Although the Word is common to all, most men live as if each had a
      private wisdom of his own.Herakleitos

PMID- 15190191
TI  - Retrotransposon-derived elements in the mammalian genome: a potential source of
      disease.
AB  - The plethora of genomic information gathered by the sequencing of the human and
      mouse genomes has paved the way for a new era of genetics. While in the past we
      focused mainly on the small percentage of DNA that codes for proteins, we can now
      concentrate on the remainder, i.e. the noncoding sequences that interrupt and
      separate genes. This portion of the genome is made up, in most part, of
      repetitive DNA sequences including DNA transposons, long terminal repeat (LTR)
      retrotransposons, LINEs (long interspersed nuclear elements) and SINEs (short
      interspersed nuclear elements). Some of these elements are transcriptionally
      active and can transpose or retrotranspose around the genome, resulting in
      insertional mutagenesis that can cause disease. In these cases, insertions have
      occurred in the coding sequence. However, recent evidence suggests that the main
      effect of these elements is their ability to influence transcription of
      neighbouring genes. The elements themselves contain promoters that can initiate
      transcription of flanking genomic DNA. Furthermore, they are susceptible to
      epigenetic silencing, which is often stochastic and incomplete, resulting in
      complex patterns of transcription. This review discusses some diseases in both
      human and mouse that are caused by these repetitive elements.

PMID- 15190192
TI  - The genetics and pathophysiology of diabetes mellitus type II.
AB  - Type II diabetes is a common, complex and heterogeneous group of disorders of
      growing public health concern. Paradoxically, rare monogenic forms of diabetes
      mellitus have been the most informative regarding diabetes pathophysiology to
      date. We discuss disappointing results of genetic approaches thus far,
      emphasizing the genetic heterogeneity underlying the common phenotypic endpoint
      of elevated blood glucose level and the phenotypic misclassification in large
      studies resulting from this admixture and from the obligatory use of
      epidemiological or clinical surrogate measures. We suggest that novel approaches
      that take explicit account of the phenotypic, environmental and genetic
      complexities of type II diabetes are needed and discuss some principles that
      might underlie such approaches.

PMID- 15190193
TI  - Mitochondrial disorders: prevalence, myths and advances.
AB  - Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are renowned for
      their variability in clinical features and genetic causes. This makes it
      difficult to determine their true prevalence, but recent studies have documented
      a minimum birth prevalence of 13.1/100000 or 1/7634 for oxidative phosphorylation
      disorders with onset at any age. This clearly remains an underestimate but it
      indicates that oxidative phosphorylation disorders can be regarded as the most
      common group of inborn errors of metabolism. Pathogenic mutations causing human
      oxidative phosphorylation disorders have now been identified in more than 30 of
      the 37 mitochondrial DNA genes and in more than 30 nuclear genes. Most of the
      nuclear gene defects cause autosomal recessive diseases, but autosomal dominant
      and X-linked disorders also occur. It is likely that at least another 30, and
      perhaps over 100, nuclear-encoded oxidative phosphorylation disorders await
      identification. Oxidative phosphorylation genetics are complex and there appear
      to be a number of common misconceptions about mitochondrial DNA mutations that
      may impede optimal investigation and management of patients. In our experience,
      mitochondrial DNA mutations are not a negligible cause of OXPHOS disorders in
      children but account for 20-25% of cases. Similarly, a family history suggesting
      maternal inheritance is the exception rather than the norm for children with
      mitochondrial DNA mutations, many of whom have de novo mutations. Only some
      mitochondrial DNA mutations disappear from cultured cells, so deficient enzyme
      activity in fibroblasts does not imply the presence of a nuclear defect. Finally,
      it is still widely thought that there are very few reproductive options that can
      be offered to women at risk of transmitting a mitochondrial DNA mutation. While a
      cautious approach is needed, there is now a consensus that prenatal diagnosis
      should be offered to some women, particularly those at lower recurrence risk.
      Preimplantation genetic diagnosis can also be an option.

PMID- 15190194
TI  - Protein substitutes for PKU: what's new?
AB  - Protein substitutes are an essential component in the management of
      phenylketonuria. A series of studies at Birmingham Children's Hospital have
      investigated their optimal dosage, timing and practical administration as well as
      the efficacy and tolerance of novel protein substitutes. The key findings are as
      follows. (1). Lower dosages of protein substitute (1.2 g/kg per day of protein
      equivalent) adversely affect blood phenylalanine control in children aged 1-10
      years. (2). There is wide variability in 24 h blood phenylalanine concentrations.
      (3). Adjusting protein substitute timing during daytime does not reduce blood
      phenylalanine variability. (4). Repeated 4 h administration of protein substitute
      throughout 24 h markedly reduces phenylalanine variability and leads to lower
      phenylalanine concentrations. (5). The new, concentrated, low-volume protein
      substitutes and amino acid tablet preparations are efficacious and well tolerated
      by patients. (6). Administration of protein substitute as a gel or paste has
      reduced difficulties with administration of protein substitute in children. These
      findings are important in rationalizing treatment strategies, improving patient
      compliance and overall in improving blood phenylalanine control.

PMID- 15190195
TI  - Hepatocyte transplantation for inborn errors of metabolism.
AB  - Liver transplantation for inborn errors of metabolism has proved effective in
      some (mostly liver-associated) inborn errors of metabolism. Significant morbidity
      and mortality rates have been extensively reported due to disease recurrence or
      to complications of the immunosuppressive regimen. On the basis of clinical
      trials in animals as well as in humans, the use of isolated hepatocytes offers a
      unique opportunity for treating inborn errors of metabolism. The state of art of
      the technique applied to this field is reviewed here and related practical
      problems are examined. No final conclusions can be drawn, but further insight
      into the use of alternative sources of cells, including stem/progenitor cells
      associated with cryobiology and immunological research, will offer new
      opportunities for cell therapy for inborn errors of metabolism in the near
      future.

PMID- 15190197
TI  - Treatment of lysosomal storage disorders: cell therapy and gene therapy.
AB  - Most lysosomal storage diseases have central nervous system (CNS) involvement. No
      effective treatment is available at present. We investigated the usefulness of
      brain-directed gene therapy and cell therapy using mouse models of lysosomal
      storage diseases. For gene therapy to the CNS, a recombinant adenovirus encoding
      beta-galactocerebrosidase gene was injected into the cerebral ventricle of
      neonatal twitcher mice, a murine model of Krabbe disease. Improvements in
      neurological symptoms and a prolonged lifespan were observed. Brain activity of
      beta-galactocerebrosidase was increased significantly and the concentration of a
      cytotoxic metabolite, psychosine, was decreased. Pathological observations of the
      brain were also improved in treated twitcher mice. For cell therapy to the CNS, a
      neural stem cell line derived from human fetal brain was genetically engineered
      to overexpress beta-glucuronidase and transplanted into the cerebral ventricles
      of neonatal MPS VII mice, a model of beta-glucuronidase deficiency. Transplanted
      human neural stem cells were found to integrate and migrate in the host brain and
      to produce large amounts of beta-glucuronidase. Brain contents of the substrate
      of beta-glucuronidase were reduced and widespread clearing of lysosomal storage
      was observed in treated MPS VII mice. These data suggest that brain-directed
      gene/cell therapy may be useful in the treatment of neurological alterations in
      lysosomal storage diseases.

PMID- 15190196
TI  - Enzyme replacement and enhancement therapies for lysosomal diseases.
AB  - Although first suggested by de Duve in 1964, enzyme replacement therapy (ERT) for
      lysosomal storage diseases did not become a reality until the early 1990s when
      its safety and effectiveness were demonstrated in type 1 Gaucher disease. Today,
      ERT is a reality for Gaucher disease, Fabry disease and mucopolysaccharidosis
      type I (MPS I), and clinical trials with recombinant human enzymes are ongoing in
      Pompe disease, MPS II and MPS VI, and are about to begin in Neimann-Pick B
      disease. In addition to ERT, enzyme enhancement therapy (EET) offers a novel
      therapeutic strategy to increase the residual function of mutant proteins. EET
      employs small molecules as 'pharmacological chaperones' to rescue misfolded
      and/or unstable mutant enzymes or proteins that have residual function. EET also
      offers the possibility of treating neurodegenerative lysosomal disorders since
      these small therapeutic molecules may cross the blood-brain barrier. The current
      status of ERT and the prospects for EET for lysosomal storage diseases are
      reviewed.

PMID- 15190198
TI  - p53 Regulation: a family affair.
AB  - The p53 protein averts tumor formation by preventing the proliferation of damaged
      cells. The presence of functional p53 is critical for efficient and proper
      cellular responses to a variety of stress conditions. Interestingly, p63 and p73,
      which are the homologous ancestors of p53, retain a broader set of activities
      than their progeny, particularly during early embryonic development. The link of
      these homologues to cancer and their effect on p53 tumor suppression is only
      beginning to be unravelled. The tight regulation of p53 is governed by the Mdm2
      E3 ligase, but also by at least two other E3 ligases. Recent findings suggest
      fine-tuning of p53 regulation through changes in the ratio of p53 and Mdm2. This
      regulation of p53 is modulated by the Mdm2 homologue, Mdmx. Genetic studies
      reveal the critical role Mdmx plays in p53 regulation, although the mode of
      action is yet to be fully explored. The relief of p53 from this tight regulation
      is imperative in order for it to respond to stress signals. An intriguing player
      in this process is the prolyl isomerase Pin1, which induces a conformational
      change in p53, and more recently identified, also in p73, in response to DNA
      damage. This complex network of regulation emerges as a family affair. This
      wealth of knowledge has been translated into the development of novel anti-cancer
      strategies based on the p53 status in the cancer cell.

PMID- 15190199
TI  - Reprogramming RelA.
AB  - The diversity of activators and targets of the NF-kappaB transcription factor
      family demands that there be regulatory mechanisms in place to control the
      specificity with which genes under their control are induced. In part this can be
      achieved through selective induction of different NF-kappaB subunits and through
      co-operative interactions with heterologous DNA-binding proteins and co
      activators. Recent work from our laboratory indicates another critical mechanism
      regulating NF-kappaB. We find that the RelA(p65) NF-kappaB subunit does not
      always function as an inducer of gene expression, but under certain circumstances
      can be programmed to actively repress these same target genes. This repressor
      form of NF-kappaB appears to be induced by distinct, atypical pathways of
      activation and also through the action of some tumor suppressors. The
      identification of these pathways not only allows a reinterpretation of NF-kappaB
      function in normal cells and during tumorigenesis but could also have
      implications for both traditional and NF-kappaB based cancer therapy.

PMID- 15190200
TI  - Sex chromosomes and male functions: where do new genes go?
AB  - The position of a gene in the genome may have important consequences for its
      function. Therefore, when a new duplicate gene arises, its location may be
      critical in determining its fate. Our recent work in humans, mouse, and
      Drosophila provided a test by studying the patterns of duplication in sex
      chromosome evolution. We revealed a bias in the generation and recruitment of new
      gene copies involving the X chromosome that has been shaped largely by selection
      for male germline functions. The gene movement patterns we observed reflect an
      ongoing process as some of the new genes are very young while others were present
      before the divergence of humans and mouse. This suggests a continuing
      redistribution of male-related genes to achieve a more efficient allocation of
      male functions. This notion should be further tested in organisms employing other
      sex determination systems or in organisms differing in germline sex chromosome
      inactivation. It is likely that the selective forces that were detected in these
      studies are also acting on other types of duplicate genes. As a result, future
      work elucidating sex chromosome differentiation by other mutational mechanisms
      will shed light on this important process.

PMID- 15190201
TI  - Don't skip the G1 phase: how APC/CCdh1 keeps SCFSKP2 in check.
AB  - By keeping the levels of Skp2 and Cks1 low during G(1) progression, APC/C(Cdh1)
      prevents unscheduled degradation of SCF(Skp2) substrates and premature entry into
      S phase. Thus, APC/C(Cdh1), a ubiquitin ligase involved in mitotic exit and
      maintenance of G(0)/G(1) phase, directly controls SCF(Skp2), a ubiquitin ligase
      involved in the regulation of S phase entry.

PMID- 15190202
TI  - Cdc14p/FEAR pathway controls segregation of nucleolus in S. cerevisiae by
      facilitating condensin targeting to rDNA chromatin in anaphase.
AB  - The condensin complex is the chief molecular machine of mitotic chromosome
      condensation. Nucleolar concentration of condensin in mitosis was previously
      shown to correlate with proficiency of rDNA condensation and segregation. To
      uncover the mechanisms facilitating this targeting we conducted a screen for
      mutants that impair mitotic condensin congression to the nucleolus. Mutants in
      the cdc14, esp1 and cdc5 genes, which encode FEAR-network components, showed the
      most prominent defects in mitotic condensin localization. We established that
      Cdc14p activity released by the FEAR pathway was required for proper condensin-to
      rDNA targeting in anaphase. The MEN pathway was dispensable for condensin-to-rDNA
      targeting, however MEN-mediated release of Cdc14p later in anaphase allowed for
      proper, albeit delayed, condensin targeting to rDNA and successful segregation of
      nucleolus in the slk19 FEAR mutant. Although condensin was physically dislodged
      from rDNA in the cdc14 mutant, it was properly assembled, phosphorylated and
      chromatin-bound, suggesting that condensin was mis-targeted but active. This
      study identifies a novel pathway promoting condensin targeting to a specific
      chromosomal address, the rDNA locus.

PMID- 15190203
TI  - Human ninein is a centrosomal autoantigen recognized by CREST patient sera and
      plays a regulatory role in microtubule nucleation.
AB  - Centrosome is the major microtubule organizing center in mammalian cells that
      plays a critical role in a variety of cellular events by the microtubule arrays
      emanating from it. Despite its significance, the molecular mechanisms underlying
      the structure and function of the centrosome are still not clear. Herein we
      describe the identification of three isotypes of human ninein by expression
      library screening with autoimmune sera from CREST patients. All three ninein
      isotypes exhibit centrosomal localization throughout the cell cycle when GFP
      tagged fusion proteins are expressed transiently in mammalian cells. Construction
      of serial deletions of GFP-tagged ninein reveals that a stretch of three leucine
      zippers with a flanking sequence is required and sufficient for centrosomal
      targeting. Overexpression of ninein results in mislocalization of gamma-tubulin,
      recruiting it to ectopic (noncentrosomal) ninein-containing sites which are not
      active in nucleating microtubules. In these cells, nucleation of microtubules
      from the centrosome is also inhibited. These results thus suggest a regulatory
      role for ninein in microtubule nucleation.

PMID- 15190204
TI  - ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the
      absence of DNA damage.
AB  - The ATR and Chk1 kinases are essential to maintain genomic integrity. ATR, with
      Claspin and the Rad9-Rad1-Hus1 complex, activates Chk1 after DNA damage. Chk1
      mediated phosphorylation of the Cdc25A phosphatase is required for the mammalian
      S-phase checkpoint. Here, we show that during physiological S phase the
      regulation of the Chk1-Cdc25A pathway depends on ATR, Claspin, Rad9, and Hus1.
      Human cells with chemically or genetically ablated ATR showed inhibition of Chk1
      dependent phosphorylation of Cdc25A, and they accumulated Cdc25A without external
      DNA damage. Furthermore, siRNA-mediated depletion of Claspin, Rad9 and Hus1 also
      stabilized Cdc25A. ATR ablation also inhibited the activatory phosphorylation of
      Chk1 on serine 345. Thus, the ATR-Chk1-Cdc25A pathway represents an integral part
      of physiological S-phase progression, and interference with this mechanism
      undermines viability of somatic mammalian cells. DNA damage further activates and
      switches this pathway from its constitutively operating "surveillance mode"
      compatible with DNA replication into an "emergency" checkpoint response.

PMID- 15190205
TI  - Stopped for repairs: a new role for nutrient sensing pathways?
AB  - In order to prevent division of damaged chromosomes, cells activate a checkpoint
      to inhibit mitotic progression in order to repair the damaged DNA. Upon detection
      of DNA damage two downstream checkpoint kinases, Chk1 and Rad53, are activated by
      the sensor kinase, Mec1, to block the metaphase to anaphase transition and
      mitotic exit, respectively. Recent data from studies with budding yeast suggested
      that the DNA damage checkpoint also enlists the cAMP dependent protein kinase
      (PKA) pathway, which is an integral part of the nutrient sensing mechanism in
      budding yeast, to inhibit mitosis in response to DNA damage. Genetic and
      biochemical evidence suggested that the PKA pathway contributes to the inhibition
      of mitotic progression by mediating the phosphorylation of the APC specificity
      factor Cdc20. Phosphorylation of Cdc20 assists the activity of the checkpoint
      pathways in the inhibition of the degradation of mitotic inhibitors securin,
      Pds1, and the B type cyclin, Clb2, in order to block anaphase and mitotic exit.
      Cdc20 was phosphorylated following DNA damage in a PKA and Mec1 dependent manner,
      suggesting PKA activation is dependent on Mec1. Here we discuss possible
      mechanisms for how PKA activity could be regulated in response to DNA damage and
      we will also address the implication of these results in evaluating current
      cancer treatments.

PMID- 15190206
TI  - Life, death and E2F: linking proliferation control and DNA damage signaling via
      E2F1.
AB  - Proper regulation of cellular proliferation is critical for normal development
      and cancer prevention. Most, if not all, cancer cells contain mutations in the
      Rb/E2F pathway, which controls cellular proliferation. Inactivation of the
      retinoblastoma (Rb) family of proteins can occur through Rb loss, mutation, or
      inactivation by cellular or viral oncoproteins leading to unrestrained
      proliferation and, often times, results in apoptosis. The loss of growth control
      occurs primarily by derepression and activation of the E2F transcription factors.
      E2F1 in particular, serves as the primary link between loss of Rb function and
      activation of p53-dependent apoptosis. E2F1 function is crucial for responding to
      loss of proper Rb-mediated growth control to activate p53 and the apoptotic
      program. Recently, we described the requirement for the DNA damage response
      proteins Atm, Nbs1, and Chk2 in the E2F1 apoptosis pathway. These findings
      suggest that there may be a more intimate relationship between the apoptosis
      pathways resulting from loss of proper Rb-mediated growth control and apoptosis
      resulting from the accumulation of DNA damage.

PMID- 15190207
TI  - Induction of transcription by p21Waf1/Cip1/Sdi1: role of NFkappaB and effect of
      non-steroidal anti-inflammatory drugs.
AB  - p21(Waf1/Cip1/Sdi1) is the primary mediator of cell cycle arrest in response to
      different forms of stress and in the programs of senescence and differentiation.
      p21 interacts with many regulatory proteins and has broad effects on cellular
      gene expression. p21 was previously shown to stimulate NFkappaB transcriptional
      activity through its effect on the p300/CBP transcription cofactor family. p21
      expression in human cells increases mRNA levels of different genes, some of which
      have been implicated in carcinogenesis and age-related diseases. Here we report
      that p21 expression stimulates promoters of six p21-responsive human genes and
      the cytomegalovirus promoter, as well as an artificial promoter containing
      NFkappaB response elements. The IkappaBalpha super-repressor blocked the effect
      of p21 on all but one of the promoters, and the response to p21 was abrogated by
      the mutagenesis of an NFkappaB element. p21 inducibility of all the tested
      promoters and of the endogenous p21-responsive genes was strongly inhibited by
      adenoviral E1A protein and its deletion mutants that bind p300/CBP but not p21 or
      Rb. Sulindac and some other non-steroidal anti-inflammatory drugs that inhibit
      NFkappaB decrease the effects of p21 on the responsive promoters and endogenous
      genes. These findings suggest the feasibility of developing agents that will
      counteract p21-mediated induction of disease-associated genes.

PMID- 15190208
TI  - A new look at Rho GTPases in cell cycle: role in kinetochore-microtubule
      attachment.
AB  - Rho GTPases including Rho, Rac and Cdc42 are involved in cell morphogenesis by
      inducing specific types of actin cytoskeleton and alignment and stabilization of
      microtubules. Previous studies suggest that they also regulate cell cycle
      progression; Rho, Rac and Cdc42 regulate the G(1)-S progression and Rho controls
      cytokinesis. However, a role of Rho GTPases in nuclear division has not been
      definitely shown. We have recently found that Cdc42 and its downstream effector
      mDia3 are involved in bi-orientation and stabilization of spindle microtubules
      attachment to kinetochores and regulate chromosome alignment and segregation.
      Here, we discuss how this is coordinated with other events in mitosis,
      particularly, with the action of Rho in cytokinesis and how attachment of
      microtubules to kinetochores is achieved and stabilized. We also discuss
      redundancy of dc42 and Cdc42-related GTPase(s) and potential mechanisms of
      chromosome instability in cancer.

PMID- 15190210
TI  - Chromatin turn ons and turn offs of ribosomal RNA genes.
AB  - Eukaryotes have hundreds (sometimes thousands) of ribosomal RNA (rRNA) genes
      whose transcription by RNA polymerase I helps establish the proliferative ability
      of cells by dictating the pace of ribosome production and protein synthesis.
      Interestingly, only a subset of the total rRNA gene pool is active at any one
      time, making rRNA genes attractive for understanding the dynamic balance between
      gene silencing and activation. However, the fact that rRNA genes are essentially
      identical in sequence in a pure species has been an obstacle to telling apart the
      active and inactive genes. Nature has provided one solution to this conundrum in
      the form of the epigenetic phenomenon, nucleolar dominance: the transcriptional
      silencing of one parental set of rRNA genes in a genetic hybrid. Parental genes
      in hybrids typically differ in sequence as well as expression, allowing a
      definition of the chromatin modifications of rRNA genes in the on and off states
      in vivo. By exploiting nucleolar dominance in plants, we recently showed that
      concerted changes in DNA methylation and histone methylation comprise an
      epigenetic switch that turns rRNA genes on and off. Independent studies using
      mouse and human cells have led to similar conclusions, implicating chromatin
      modifications as important components of the regulatory networks that control the
      effective dosage of active rRNA genes.

PMID- 15190211
TI  - Dynamic balancing of the dual nature of HIF-1alpha for cell survival.
AB  - In hypoxic cells, HIF-1alpha escapes from oxygen-dependent proteolysis and binds
      to the hypoxia-responsive element (HRE) for transcriptional activation of target
      genes involved in angiogenesis and glycolysis. We recently demonstrated that the
      G(1) checkpoint gene p21(cip1)is activated by HIF-1alpha with a novel mechanism
      that involves the HIF-1alpha PAS domains to displace Myc binding from p21(cip1)
      promoter. This HIF-1alpha-Myc pathway may account for up- and down-regulation of
      other hypoxia-responsive genes that lack the HRE. Moreover, the role of HIF
      1alpha in cell cycle control indicates a dual, yet seemingly conflicting, nature
      of HIF-1alpha: promoting cell growth and arrest in concomitance. We speculate
      that a dynamic balance between the two processes is achieved by a "stop-and-go"
      strategy to maintain cell growth and survival. Tumor cells may adopt such scheme
      to evade the killing by chemotherapeutic agents.

PMID- 15190212
TI  - Does cancer solve an optimization problem?
AB  - Many cancers are characterized by a high degree of aneuploidy, which is believed
      to be a result of chromosomal instability (CIN). The precise role of CIN in
      cancer is still the matter of a heated debate. We present a quantitative
      framework for examining the selection pressures acting on populations of cells
      and weigh the "pluses" and "minuses" of CIN from the point of view of a selfish
      cell. We calculate the optimal rate of chromosome loss assuming that cancer is
      initiated by inactivation of a tumor suppressor gene followed by a clonal
      expansion. The resulting rate, p* = 10(-2)per cell division per chromosome, is
      similar to that obtained experimentally by Lengauer et al. (1997). Our analysis
      further suggests that CIN does not arise simply because it allows a faster
      accumulation of carcinogenic mutations. Instead, CIN must arise because of
      alternative reasons, such as environmental factors, epigenetic events, or as a
      direct consequence of a tumor suppressor gene inactivation. The increased
      variability alone is not a sufficient explanation for the presence of CIN in the
      majority of cancers.

PMID- 15190209
TI  - p53 moves to mitochondria: a turn on the path to apoptosis.
AB  - It has been said that no matter which direction cancer research turns, the p53
      tumor suppressor protein comes into view. The widespread role of p53 as a
      suppressor of tumor development is believed to rely on its ability to induce
      programmed cell death in response to stress, either the replicative stress
      associated with uncontrolled cellular proliferation, or the environmental
      stresses that accompany tumor development, such as hypoxia. For some time it has
      been believed that the role of p53 in inducing apoptosis in response to such
      stress was as a master regulator coordinating the expression of other molecules
      whose ultimate role was the execution of the cell. New data, however, suggest
      that p53 itself also has a direct role in accomplishing cell death, at the
      mitochondria.

PMID- 15190213
TI  - Cdc42p, GTP hydrolysis, and the cell's sense of direction.
AB  - The GTPase Cdc42p is essential for polarity establishment in animals and
      fungi.(1) Human Cdc42p can functionally replace yeast Cdc42p,(2) indicating a
      high degree of evolutionary conservation. Current models of Cdc42p action
      generally follow the signaling paradigm established for Ras, in which receptors
      responding to an initiating stimulus cause guanine nucleotide exchange factors
      (GEFs) to trigger GTP-loading of Ras, leading to engagement of downstream
      effectors and ensuing cell proliferation. Key support for the Ras paradigm came
      from the finding that oncogenic forms of Ras, unable to hydrolyze GTP and
      therefore constitutively GTP-bound, mimicked the effect of constitutive signaling
      by the upstream receptors even in the absence of stimuli. Attempts to assess
      whether or not this paradigm is valid for Cdc42p-induced polarization of yeast
      cells have yielded conflicting results.(3-6) Here, we discuss the available
      information on this issue and conclude that unlike Ras signaling, Cdc42p directed
      polarity establishment additionally requires cycling between GTP- and GDP-bound
      forms. We suggest that such cycling is critical for a little-studied "function"
      of Cdc42p: its ability to designate a unique portion of the cell cortex to become
      the polarization site, and to become concentrated at that site.

PMID- 15190214
TI  - Physical and functional interactions between mitotic kinases during
      polyploidization and megakaryocytic differentiation.
AB  - Human Polo-like kinase 3 (Plk3), a protein serine/threonine kinase, is involved
      in the regulation of cell cycle progression at multiple stages. Our previous
      studies revealed that Plk3 is closely associated with centrosomes and plays an
      important role in the regulation of microtubule dynamics. Here we describe the
      physical interaction of Plk3 with Aurora A and BubR1 kinases, and the
      significance of this interaction during terminal differentiation and
      polyploidization of megakaryocytes. Specifically, double immunofluorescence
      staining confirms that Plk3 and Aurora A colocalize to centrosomes or spindle
      poles during essentially all phases of the cell cycle and that BubR1 also
      exhibits spindle pole localization during metaphase. Pull-down assays show that
      Plk3 physically interacts with Aurora A as well as BubR1. Upon treatment with
      phorbol 12-myristate 13-acetate (PMA), human erythroleukemic cells (K562)
      underwent megakaryocytic differentiation characterized by polyploidization and
      expression of mature megakaryocyte surface markers such as CD41. Plk3 protein
      levels were seen to be increased during PMA-induced megakaryocytic
      differentiation of K562 cells, correlating well with the ploidy level in these
      cells. Similarly, Aurora A and its phosphorylated form also increased after PMA
      treatment. In contrast, BubR1 levels were markedly reduced. Taken together, our
      study suggests that Plk3 and Aurora A kinases may lie in the same regulatory
      pathway and that Plk3 and Aurora A as well as BubR1 may play an important role in
      polyploidization and megakaryocytic differentiation.

PMID- 15190215
TI  - The first knockout mouse model of retinoblastoma.
AB  - The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene
      identified in humans (Friend, et al., 1986) and the first tumor suppressor gene
      knocked out by targeted deletion in mice (Jacks, et al., Clarke, et al., Lee, et
      al., 1992). Children with a germline mutation in one of their RB1 alleles are
      likely to experience bilateral multifocal retinoblastoma; however, mice with a
      similar disruption of Rb1 do not develop retinoblastoma. The absence of a knock
      out mouse model of retinoblastoma has slowed the progress toward developing new
      therapies and identifying secondary genetic lesions that occur after disruption
      of the Rb signaling pathway. Several advances have been made, over the past
      several years, in our understanding of the regulation of proliferation during
      retinal development (Zhang, et al., 2004; Dyer J, 2004; Dyer, Cepko, 2001) and we
      have built upon these earlier studies to generate the first nonchimeric knock-out
      mouse model of retinoblastoma. These mice are being used as a preclinical model
      to test new therapies for retinoblastoma and to elucidate the downstream genetic
      events that occur after inactivation of Rb1 or its related family members.

PMID- 15190216
TI  - Reversing drug resistance in vivo.
AB  - Apoptotic defects occur in oncogenesis and contribute to drug resistance. We have
      shown that Bcl-2, Akt, and the translational regulator eIF4E cooperate with Myc
      during lymphomagenesis and are potent inducers of drug resistance. Interestingly,
      lymphomas expressing Akt, but not those expressing Bcl-2 are sensitized to
      chemotherapy-induced apoptosis by the mTOR inhibitor rapamycin, an effect that is
      countered by eIF4E. These results provide in vivo validation for a strategy to
      reverse drug resistance in human cancers and highlight the potential role of
      translational deregulation in oncogenesis and resistance. They also illustrate
      the importance of tailoring cancer therapy based on tumor genotype.

PMID- 15190217
TI  - Clinical nurse leader: moving toward the future.

PMID- 15190218
TI  - Arbitration: a final step in the dispute resolution process.

PMID- 15190219
TI  - Creating a desirable future for nursing, part 2: the issues.

PMID- 15190220
TI  - Asset protection: maintaining and retaining your workforce.

PMID- 15190221
TI  - Improving our image a nurse at a time.

PMID- 15190222
TI  - Navigating in a complex nursing world.
AB  - The recent findings emerging from the new science of complexity are altering our
      view of unpredicted behavior. In many cases, natural laws hidden deep within the
      complex processes of healthcare systems may be exerting a powerful influence over
      our ability to control outcomes. The author explores the concept of complexity
      and how nurse administrators may use these new theories to navigate through an
      increasingly unpredictable world.

PMID- 15190223
TI  - Measuring nurse job satisfaction.
AB  - Using the Index of Work Satisfaction and nurses' comments, a successful method
      has been established to provide nurse-sensitive quality indicator data and
      clarification of work life concerns after restructuring. Findings are being used
      to direct change for acute care nurses in one large regional health authority.
      The authors describe the job satisfaction components and their relationship to
      patient acuity and staff mix.

PMID- 15190224
TI  - Traditional models of care delivery: what have we learned?
AB  - Traditional models of patient care delivery include total patient care and
      functional, team, and primary nursing. These models differ in clinical decision
      making, work allocation, communication, and management, with differing social and
      economic forces driving the choice of model. Studies regarding quality of care,
      cost, and satisfaction for the models provide little evidence for determining
      which model of care is most effective in any given situation. Despite lack of
      evidence, newer models continue to be implemented. This article compares the
      advantages and disadvantages of models, critiques the existing studies, and
      offers recommendations regarding the evidence needed to make informed decisions
      regarding care delivery models.

PMID- 15190225
TI  - Who will be there to nurse? Retention of nurses nearing retirement.
AB  - AIMS: To determine the impact on nursing work-force supply of delaying
      retirement. BACKGROUND DATA: The nursing workforce is aging, and the Baby Boomer
      generation is nearing retirement age. This potential loss of experienced nurses
      is likely to exacerbate current nursing shortages. METHODS: An analysis of loss
      rates of nurses in New South Wales (Australia) is provided using 2 different
      retirement ages--58 and 65 years. Supply numbers were used and then "aged" to
      determine the impact of retirement on workforce numbers. The impact of potential
      retention strategies on the numbers who could be retained were determined if 100%
      of 50- to 55-year-old nurses was retained, 75% of those 56 to 60 years, and 50%
      of those 61 to 65 years. RESULTS: By the year 2004, approximately 4139 nurses
      (registered and enrolled) will be lost through retirement at age 65 years.
      However, retirement at age 58 years sees 7328 lost by 2004. Potentially 2139
      nurses in this age spectrum could be retained if strategies are focused on
      delaying retirement. CONCLUSIONS: Delaying the retirement of nurses could provide
      a significant human resource, not only in terms of absolute numbers but more
      importantly, in terms of experience and expertise. However, retention of this
      portion of the workforce may require different strategies than for younger
      members of the workforce. The needs of this segment of the nursing workforce may
      require nurse administrators to consider different approaches to nursing work and
      work allocation.

PMID- 15190226
TI  - The graduate nurse experience.
AB  - Graduate nurses experience stress transitioning from student to practicing
      professional nurse, moving from a familiar educational environment into the
      workforce, where expectations are to rapidly function as a competent nurse. This
      study identified the stresses and challenges experienced by cohorts of graduate
      nurses working in 6 acute care hospitals, during specific timed data periods, to
      better understand factors that may influence graduate nurse retention. Results
      report graduate nurses do not feel skilled, comfortable, and confident for as
      long as 1 year after being hired, highlighting the need for healthcare
      organizations to provide extended orientation and support programs to facilitate
      successful entry into practice.

PMID- 15190229
TI  - Neuroleptic-induced Tardive Tourette treated with clonazepam: a case report and
      literature review.
AB  - Tardive Tourette syndrome has been reported as a rare complication of neuroleptic
      treatment. This report describes the first case of neuroleptic-induced tardive
      Tourette syndrome in the Latin Americas and supports the successful treatment of
      this disorder with clonazepam. The syndrome developed in a female schizophrenic
      patient who discontinued medication after 8 years of continuous neuroleptic
      therapy. Symptoms were unresponsive to increased doses of typical antipsychotics
      and treatment with an atypical antipsychotic. Significant, sustained improvement
      occurred with clonazepam. In this report all cases of adult-onset tardive
      Tourette are reviewed.

PMID- 15190230
TI  - Acute dystonia during pegylated interferon alpha therapy in a case with chronic
      hepatitis B infection.
AB  - Interferon (IFN) is the most widely prescribed drug of choice for chronic
      hepatitis B infection, which is a common health problem in our country. Therapy
      with IFN-alpha may be associated with a number of neuropsychiatric symptoms, such
      as Parkinsonism, akathisia, seizure, and depressive disorders. In this case
      report, we present clinical and laboratory findings of a case with chronic
      hepatitis B that developed acute dystonia soon after the first dose of pegylated
      interferon alpha. As far as we know, this is the first report in English
      literature indicating such an adverse effect of pegylated interferon alpha.

PMID- 15190231
TI  - Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson
      disease.
AB  - The neuropeptides neurokinin B, neurotensin, and anandamide, the endogenous
      ligands of NK3, NT1, and CB1 receptors respectively, are known to interact with
      brain dopaminergic transmission. This study evaluated the effects of these three
      antagonists of the NK3 (SR 142801), neurotensin (SR 48692), and cannabinoid (SR
      141716) receptors on the severity of motor symptoms and levodopa-induced
      dyskinesias after administration of a single dose of levodopa in 24 patients with
      Parkinson disease. In this exploratory randomized, double-blind, placebo
      controlled study, at the dose used, the drugs tested were well tolerated and
      could not improve parkinsonian motor disability.

PMID- 15190232
TI  - Dopamine transporter gene polymorphism, spect imaging, and levodopa response in
      patients with Parkinson disease.
AB  - OBJECTIVES: To assess the potential association between dopamine transporter
      (DAT) genotype, single photon emission CT (SPECT) measures using [123I]-N-omega
      fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane ([123I]-FP-CIT) of
      striatal dopaminergic function, and oral levodopa response pattern in a cohort of
      patients with Parkinson disease. METHODS: Thirty-six patients at different
      disease stages enrolled in the study. Each patient was examined by [123I]-FP-CIT
      SPECT and a standardized oral levodopa test on 2 separate days in a randomized
      order within 3 weeks. The main outcome variables were the specific-to-nonspecific
      tracer uptake ratio in the contralateral putamen for SPECT analysis; latency,
      duration, and magnitude of the motor effect; and presence of dyskinesias for the
      levodopa test. The variable number of tandem repeat (VNTR) polymorphisms of the
      gene coding for DAT were detected for each patient by standard methods. RESULTS:
      Contralateral putamen [123I]-FP-CIT uptake ratios were similar in the patients
      carrying the 9-copy allele (n=20) of the DAT VNTR compared with 10-repeat
      homozygotes (n=16). No significant difference was found in levodopa main outcome
      variables and dyskinesia incidence between the two groups of patients stratified
      by DAT VNTR polymorphism. CONCLUSIONS: The study did not identify clinically
      relevant in vivo DAT neurochemical function phenotypes or levodopa response
      patterns associated with the DAT polymorphism.

PMID- 15190233
TI  - Variation in the dopaminergic response during the day in Parkinson disease.
AB  - OBJECTIVE: In many parkinsonian patients with fluctuating disease the early
      morning levodopa dose is more effective than the following dose on the same day.
      In this study we investigated whether the poor responsiveness to the early
      afternoon dose of levodopa depends only on peripheral and central levodopa
      pharmacokinetics or also on pharmacodynamic factors. METHODS: Ten parkinsonian
      patients experiencing postprandial drug-resistant off periods received two
      boluses of apomorphine by subcutaneous injection at 8 am and 3 pm on two
      nonconsecutive days. On day 2, therapy was stopped at 11 am. For each bolus we
      determined time to on, duration of the on state, magnitude of benefit, and
      levodopa and apomorphine plasma levels at baseline and immediately after patients
      reached the on state. RESULTS: The mean duration of on phases was significantly
      shorter and the apomorphine plasma level needed to reach the on state was
      significantly higher in the afternoon than in the morning (P<0.01 by paired t
      test). CONCLUSIONS: This study suggest that there is a change in responsiveness
      to dopaminergic stimulation during the day. The less effective dopaminergic
      response in afternoon depends on pharmacodynamic factors and not only on
      peripheral and central levodopa pharmacokinetic.

PMID- 15190234
TI  - Frequency, reasons, and risk factors of entacapone discontinuation in Parkinson
      disease.
AB  - OBJECTIVES: To determine the rate of and identify reasons for discontinuation of
      entacapone treatment in Parkinson disease patients. METHODS: A retrospective
      study design was used, including medical record reviews and telephone call to the
      patient as needed. RESULTS: Two hundred and twenty-two Parkinson disease patients
      were started on entacapone over a period of 3 years. One hundred and twenty-two
      patients (56%) had discontinued the medication by the end of the follow up
      period. Reasons for discontinuation included lack of efficacy (46%), worsening of
      parkinsonian symptoms (28%), worsened cognition (20%), dyskinesia (17%), nausea
      (11%), diarrhea (9%), cost (4%), other side effect (8%), and other, non
      medication related reasons (19%). Presence of wearing off at the time of initial
      treatment and male sex were associated with decreased dropout rates, while the
      presence of orthostatic hypotension increased the likelihood of discontinuation.
      Patient age, disease duration, Hoehn and Yahr stage, Unified Parkinson's Disease
      Rating Scale section II score, presence of dementia, hallucinations, dyskinesias,
      or depression, number of daily L-dopa doses, and concomitant treatment with
      dopamine agonists did not affect dropout rate. CONCLUSIONS: Lack of efficacy
      seems to be the main reason for entacapone discontinuation. Male patients with
      wearing off and no orthostatic hypotension seem to tolerate the medication
      better. Advanced disease stage, presence of cognitive dysfunction, and presence
      of dyskinesia should not necessarily preclude patients from being treated with
      entacapone, when otherwise indicated.

PMID- 15190235
TI  - Effects of gabapentin on the motor response to levodopa: a double-blind, placebo
      controlled, crossover study in patients with complicated Parkinson disease.
AB  - BACKGROUND: Motor fluctuations and dyskinesias affect many parkinsonian patients
      chronically treated with levodopa. Imbalance between gabaergic direct and
      indirect striatopallidal pathways may originate them. Manipulating GABA
      neurotransmission may be effective in the treatment of these patients. Gabapentin
      is an antiepileptic drug that increases the synthesis and release of GABA.
      Previous studies suggest that gabapentin may be useful in Parkinson disease (PD).
      OBJECTIVE: To know the effects of gabapentin on the motor response to levodopa in
      PD patients with motor complications. DESIGN: A randomized double-blind, placebo
      controlled, cross-over trial with four weeks of treatment. SETTING: A tertiary
      referral center. PARTICIPANTS: Twenty subjects with PD and motor fluctuations and
      dyskinesias on stable antiparkinsonian treatment, took gabapentin up to a maximum
      dose of 2.400 mg/d in three doses and placebo. METHODS: Three levodopa challenges
      were performed: at the beginning of the study and at the end of each period of
      treatment (4 weeks). Basal (off) and best (on) motor status were assessed by the
      UPDRS III. Latency to peak effect, magnitude of motor response (difference
      between "on" and "off" scores in the UPDRS III), duration of motor response and
      severity and duration of dyskinesias after each levodopa challenge were assessed.
      Patients' diaries were administered. RESULTS: : Fifteen patients completed the
      study. A significant improvement in the basal UPDRS III resulting in a
      significant reduction in the magnitude of the motor response after gabapentin was
      obtained (P < 0.001). No other changes were observed, either on pharmacological
      parameters or in levodopa-induced dyskinesias. Number of daily hours spent in
      "on," "on with dyskinesias" and "off" also remained unchanged. Tolerance was
      good, dizziness being the most common side effect. CONCLUSION: Gabapentin
      improved parkinsonian symptoms (basal UPDRS III and magnitude of the motor
      response) following levodopa. This improvement was not reflected in the daily
      motor situation of patients. Dyskinesias remained unchanged. Gabapentin was well
      tolerated. Further studies are needed to know the impact of these results in the
      long-term.

PMID- 15190236
TI  - Relationships between total and unbound propofol in plasma and CSF during
      continuous drug infusion.
AB  - BACKGROUND: Propofol is one of the most frequently applied intravenous
      anesthetics. Although it has been used for a long period, its pharmacokinetics,
      especially central nervous system pharmacokinetics, are not fully recognized.
      OBJECTIVE: Investigation of the relationships between total propofol
      concentration in blood, total propofol concentration in cerebrospinal fluid
      (CSF), free propofol concentration in blood, and free anesthetic concentration in
      CSF in patients undergoing elective neurosurgery and anesthetized with propofol.
      METHODS: Eleven patients scheduled for elective intracranial procedures were
      studied. Propofol was applied in the form of target control infusion. During
      anesthesia, fractional doses of fentanyl and cisatracurium were administered as
      necessary. After tracheal intubation the lungs were ventilated to achieve
      normocapnia with an oxygen-air mixture (Fi O2 = 0.33). CSF and blood were taken
      at the moment of intraventricular drainage application. RESULTS: The unbound
      propofol concentration in plasma is 1.12% (SD 0.61%; SEM 0.18%) of the total
      concentration in plasma, and the free propofol concentration in plasma is 71.6%
      (SD 61.0%; SEM 18.4%) of the total CSF propofol concentration. The free
      anesthetic concentration in CSF is 30.9% (SD 15.7%; SEM 4.7%) of the total CSF
      propofol concentration, and 61.8% (SD 34.9%; SEM 10.5%) of the free propofol
      concentration in plasma. CONCLUSION: The relationship between unbound drug
      concentrations in plasma and in CSF determined in this study leads to the
      postulate that propofol is transported from blood to CSF by passive diffusion.

PMID- 15190237
TI  - Citalopram as treatment of depression in patients with epilepsy.
AB  - OBJECTIVES: To assess the safety of citalopram as a treatment of depression in
      patients with epilepsy. METHODS: This is an open, multicentered, uncontrolled
      study. Depressed epileptic patients on antiepileptic drugs (AEDs) took part in
      the study. Patients who had a mild frequency of seizures in the 4 previous months
      underwent treatment with citalopram (20 mg/d) for 4 consecutive months. A change
      in seizure frequency from the baseline was chosen as the primary measure for the
      safety of citalopram and efficacy against depressive symptoms was taken as
      secondary measure. Depression was rated using the Montgomery-Asberg and Zung
      depression rating scales. Clinical assessments were performed at baseline, and at
      2 and 4 months of citalopram therapy. RESULTS: Forty-five patients were enrolled.
      Six patients dropped out of the study early: none of them because of a
      deterioration of seizure frequency. An overall improvement in seizure frequency
      was observed in the 39 patients who completed the study. Plasma AED
      concentrations were unchanged during therapy, and depressive symptoms improved
      markedly. Twenty-two patients complained of adverse effects, mainly headache,
      nausea, dizziness, somnolence, and fatigue. CONCLUSIONS: In this open,
      multicentered, uncontrolled study, 4 months' of treatment with citalopram (20
      mg/d) were associated with an improvement in depressive symptoms and reduction in
      seizure frequency.

PMID- 15190238
TI  - Phyto-oestrogens in the prophylaxis of menstrual migraine.
AB  - BACKGROUND: Falling levels of estrogen is the major provocative factor in
      migraine associated with menstruation. OBJECTIVE: We assessed the efficacy of the
      combination of two phyto-oestrogens, as perimenstrual, prophylactic treatment of
      menstrual migraine and tested their effect on cerebral haemodynamic. SUBJECTS AND
      METHODS: Women with a history of menstrual migraine (i.e., attacks occurring
      exclusively on day 1+/-2 days of menstruation and at no other time of the cycle)
      were included in the study. Eleven women fulfilling the inclusion criteria
      underwent to a 3-month cyclic treatment with 56 mg of genisteine and 20 mg of
      diadzeine per day. Transcranial doppler evaluation (TCD) was performed at
      baseline and after treatment. RESULTS: Among the ten women who completed the
      study the average number of days with migraine during the baseline period
      decreased significantly after 3 months of therapy (P < 0.005). There were no
      major side-effects. Therapy did not affect cerebral blood flow velocities.
      CONCLUSIONS: Phyto-oestrogens appear to be an effective treatment in menstrual
      migraine prophylaxis. This effect seems to be unrelated to cerebral hemodynamic.
      Placebo-controlled trials on larger number of patients are necessary to confirm
      our findings.

PMID- 15190239
TI  - Acetylcholinesterase and its inhibition in Alzheimer disease.
AB  - Until recently, the only established function of acetylcholinesterase (AChE) was
      the termination of cholinergic neurotransmission. Therefore, the use of AChE
      inhibitors to treat symptoms caused by cholinergic imbalances in Alzheimer
      disease (AD) represented a rational approach. However, it is now clear that AChE
      and the cholinergic system may have broader effects in AD. Of particular interest
      may be signal transduction pathways mediated through cholinergic receptors that
      promote nonamyloidogenic amyloid precursor protein processing and decrease tau
      phosphorylation, and the role of AChE in the aggregation of beta-amyloid (Abeta)
      peptide. In addition, the neuronal and nonneuronal cholinergic systems have
      important roles in the modulation of regional cerebral blood flow. These findings
      may modify the overly simplistic cholinergic hypothesis in AD that is limited to
      symptomatic treatment and ignores the potential of cholinergic therapies as
      disease-modifying agents. Chronic increases in AChE activity may exacerbate
      neurodegenerative processes, make clinically relevant levels of AChE inhibition
      more difficult to achieve, and cause the therapeutic value of cholinesterase
      inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear
      to increase AChE activity over the longer term whereas, remarkably, irreversible
      or very slowly reversible ChE-Is do not seem to have this effect. If such
      differences between ChE-Is are shown to have clinical correlates, this may prompt
      reconsideration of the rationale and expectations of some agents in the long-term
      management of AD.

PMID- 15190241
TI  - Methods of suicide among persons aged 10-19 years--United States, 1992-2001.
AB  - In 2001, suicide was the third leading cause of death among persons aged 10-19
      years. The most common method of suicide in this age group was by firearm (49%),
      followed by suffocation (mostly hanging) (38%) and poisoning (7%). During 1992
      2001, although the overall suicide rate among persons aged 10-19 years declined
      from 6.2 to 4.6 per 100,000 population, methods of suicide changed substantially.
      To characterize trends in suicide methods among persons in this age group, CDC
      analyzed data for persons living in the United States during 1992-2001. This
      report summarizes the results of that analysis, which indicated a substantial
      decline in suicides by firearm and an increase in suicides by suffocation in
      persons aged 10-14 and 15-19 years. Beginning in 1997, among persons aged 10-14
      years, suffocation surpassed firearms as the most common suicide method. The
      decline in firearm suicides combined with the increase in suicides by suffocation
      suggests that changes have occurred in suicidal behavior among youths during the
      preceding decade. Public health officials should develop intervention strategies
      that address the challenges posed by these changes, including programs that
      integrate monitoring systems, etiologic research, and comprehensive prevention
      activities.

PMID- 15190240
TI  - Serotonin syndrome associated with tramadol-sertraline coadministration.

PMID- 15190242
TI  - Suicide attempts and physical fighting among high school students--United States,
      2001.
AB  - Violence is a major cause of morbidity and mortality, particularly among youths.
      In the United States, homicide and suicide are the second and third leading
      causes of death, respectively, for persons aged 13-19 years. Although suicide
      commonly is associated with anxiety, depression, and social withdrawal, research
      suggests a link between violent behaviors directed at oneself (i.e., suicidal
      behaviors) and violent behaviors directed at others among adolescents. Certain
      students who engage in extreme forms of violence, such as school shootings,
      exhibit suicidal ideation or behavior before or during the attack. However,
      suicidal behavior also might be associated with involvement in less extreme forms
      of violent behaviors, such as physical fighting, which might be a risk factor for
      more severe forms of violence. To characterize any potential association between
      suicide attempts and fighting, CDC analyzed self-reported 2001 data from a
      nationally representative sample of high school students in the United States.
      The results of that analysis indicated that students who reported attempting
      suicide during the preceding 12 months were nearly four times more likely also to
      have reported fighting than those who reported not attempting suicide. Prevention
      programs that seek to reduce both suicidal and violent behaviors are needed.
      Because prevalence of this association was determined to be highest in the 9th
      grade, these efforts might be most effective if implemented before students reach
      high school.

PMID- 15190243
TI  - School-associated suicides--United States, 1994-1999.
AB  - During 1994-1999, at least 126 students carried out a homicide or suicide that
      was associated with a private or public school in the United States. Although
      previous research has described students who commit school-associated homicides,
      little is known about student victims of suicide. To describe the psychosocial
      and behavioral characteristics of school-associated suicide victims, CDC analyzed
      data from school and police officials. The results of that analysis indicated
      that, among the 126 students who carried out school-associated homicides or
      suicides, 28 (22%) died by suicide, including eight who intentionally injured
      someone else immediately before killing themselves. Two (7%) of the suicide
      victims were reported for fighting and four (14%) for disobedient behavior in the
      year preceding their deaths; none were associated with a gang. However, potential
      indicators of suicide risk such as expressions of suicidal thoughts, recent
      social stressors, and substance use were common among the victims. These findings
      underscore the need for school staff to learn to recognize and respond to chronic
      and situational risk factors for suicide.

PMID- 15190244
TI  - Suicide among Hispanics--United States, 1997-2001.
AB  - By 2020, Hispanics are expected to represent 17% of the U.S. population and to
      surpass all other racial/ethnic minority populations in size. In 1996, the U.S.
      Department of Health and Human Services established the Hispanic Agenda for
      Action initiative; a major goal of this initiative is to identify health problems
      that affect Hispanics. In 2001, although the overall age-adjusted suicide rate
      per 100,000 population among Hispanics was lower than the U.S. national rate
      (10.7), suicide was the third leading cause of death among young (i.e., aged 10
      24 years) Hispanics and the seventh leading cause of years of potential life lost
      before age 75 years. To identify demographic groups at risk for suicide and to
      help guide prevention efforts, CDC analyzed mortality data for 1997-2001. This
      report summarizes the results of that analysis, which indicated that, among
      Hispanics, the largest proportion of suicides occurred among young persons;
      suicide rates were higher among males; and the most common method of suicide was
      by firearms. To reduce the number of suicides, additional prevention strategies
      are needed, including 1) improving methods for collecting data about suicides,
      suicide attempts, and related behaviors; 2) expanding evaluation of prevention
      efforts aimed at reducing suicidal behaviors; and 3) examining how effective
      interventions can be modified for diverse and culturally specific populations.

PMID- 15190245
TI  - Suicide and attempted suicide--China, 1990-2002.
AB  - Suicide is the fifth leading cause of death overall in China and the leading
      cause of death in persons aged 15-34 years. During 1995-1999, approximately
      287,000 persons died each year from suicide, a national rate of 23 per 100,000
      population. In addition, an estimated 2 million suicide attempts occur each year.
      To characterize suicides and attempted suicides in China, analyses were conducted
      of 1) a psychological autopsy study comparing suicides with other injury deaths
      and 2) three studies of attempted suicides. This report summarizes the results of
      these analyses, which indicated that 58% of China's suicides were caused by
      ingesting pesticide, 91% of suicide victims had never visited a mental health
      professional, and 45% of suicide attempts were impulsive acts performed after
      considering suicide for </=10 minutes. To reduce suicides and suicide attempts,
      prevention strategies directed at disrupting patterns of suicidal behavior should
      be implemented in China.

PMID- 15190246
TI  - West Nile virus activity--United States, June 2-8, 2004.
AB  - As of June 8, two states had reported a total of seven human cases of West Nile
      virus (WNV) illness to CDC through ArboNET. Six cases were reported from Arizona
      and one case from New Mexico. Four (57%) of the cases occurred in males; the
      median age of patients was 53 years (range: 22-69 years), and the dates of onset
      of illness ranged from May 9 to June 1.

PMID- 15190247
TI  - Outbreak of Salmonella serotype Enteritidis infections associated with raw
      almonds--United States and Canada, 2003-2004.
AB  - On May 12, 2004, the Oregon State Public Health Laboratory identified a cluster
      of five patients infected with Salmonella enterica serotype Enteritidis (SE)
      isolates that were matched by using two-enzyme pulsed-field gel electrophoresis
      (PFGE). The five patients were from four Oregon counties; their onsets of illness
      occurred during February-April 2004. A subsequent investigation, still ongoing,
      has identified a total of 29 patients in 12 states and Canada with matching SE
      isolates, since at least September 2003. Seven patients have been hospitalized;
      no one has died. Raw almonds distributed throughout the United States and
      internationally have been implicated as the source of the SE infections. As of
      May 21, approximately 13 million pounds of raw almonds had been recalled by the
      producer.

PMID- 15190250
TI  - Metal exposure and common chronic diseases: a guide for the clinician.

PMID- 15190252
TI  - Evidence for dynamically organized modularity in the yeast protein-protein
      interaction network.
AB  - In apparently scale-free protein-protein interaction networks, or 'interactome'
      networks, most proteins interact with few partners, whereas a small but
      significant proportion of proteins, the 'hubs', interact with many partners. Both
      biological and non-biological scale-free networks are particularly resistant to
      random node removal but are extremely sensitive to the targeted removal of hubs.
      A link between the potential scale-free topology of interactome networks and
      genetic robustness seems to exist, because knockouts of yeast genes encoding hubs
      are approximately threefold more likely to confer lethality than those of non
      hubs. Here we investigate how hubs might contribute to robustness and other
      cellular properties for protein-protein interactions dynamically regulated both
      in time and in space. We uncovered two types of hub: 'party' hubs, which interact
      with most of their partners simultaneously, and 'date' hubs, which bind their
      different partners at different times or locations. Both in silico studies of
      network connectivity and genetic interactions described in vivo support a model
      of organized modularity in which date hubs organize the proteome, connecting
      biological processes--or modules--to each other, whereas party hubs function
      inside modules.

PMID- 15190253
TI  - Structural basis of long-term potentiation in single dendritic spines.
AB  - Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity
      dependent structural remodelling that has been proposed to be a cellular basis of
      learning and memory. How structural remodelling supports synaptic plasticity,
      such as long-term potentiation, and whether such plasticity is input-specific at
      the level of the individual spine has remained unknown. We investigated the
      structural basis of long-term potentiation using two-photon photolysis of caged
      glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show
      that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid
      and selective enlargement of stimulated spines that is transient in large
      mushroom spines but persistent in small spines. Spine enlargement is associated
      with an increase in AMPA-receptor-mediated currents at the stimulated synapse and
      is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting
      spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our
      results thus indicate that spines individually follow Hebb's postulate for
      learning. They further suggest that small spines are preferential sites for long
      term potentiation induction, whereas large spines might represent physical traces
      of long-term memory.

PMID- 15190254
TI  - Gene regulation and DNA damage in the ageing human brain.
AB  - The ageing of the human brain is a cause of cognitive decline in the elderly and
      the major risk factor for Alzheimer's disease. The time in life when brain ageing
      begins is undefined. Here we show that transcriptional profiling of the human
      frontal cortex from individuals ranging from 26 to 106 years of age defines a set
      of genes with reduced expression after age 40. These genes play central roles in
      synaptic plasticity, vesicular transport and mitochondrial function. This is
      followed by induction of stress response, antioxidant and DNA repair genes. DNA
      damage is markedly increased in the promoters of genes with reduced expression in
      the aged cortex. Moreover, these gene promoters are selectively damaged by
      oxidative stress in cultured human neurons, and show reduced base-excision DNA
      repair. Thus, DNA damage may reduce the expression of selectively vulnerable
      genes involved in learning, memory and neuronal survival, initiating a programme
      of brain ageing that starts early in adult life.

PMID- 15190255
TI  - Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
AB  - Specific adaptors regulate the activation of initiator caspases; for example,
      FADD and Apaf-1 engage caspases 8 and 9, respectively. The adaptors ASC, Ipaf and
      RIP2 have each been proposed to regulate caspase-1 (also called interleukin (IL)
      1 converting enzyme), which is activated within the 'inflammasome', a complex
      comprising several adaptors. Here we show the impact of ASC-, Ipaf- or RIP2
      deficiency on inflammasome function. ASC was essential for extracellular ATP
      driven activation of caspase-1 in toll-like receptor (TLR)-stimulated
      macrophages. Accordingly, ASC-deficient macrophages exhibited defective
      maturation of IL-1beta and IL-18, and ASC-null mice were resistant to
      lipopolysaccharide-induced endotoxic shock. Furthermore, activation of caspase-1
      in response to an intracellular pathogen (Salmonella typhimurium) was abrogated
      severely in ASC-null macrophages. Unexpectedly, Ipaf-deficient macrophages
      activated caspase-1 in response to TLR plus ATP stimulation but not S.
      typhimurium. Caspase-1 activation was not compromised by loss of RIP2. These data
      show that whereas ASC is key to caspase-1 activation within the inflammasome,
      Ipaf provides a special conduit to the inflammasome for signals triggered by
      intracellular pathogens. Notably, cell death triggered by stimuli that engage
      caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a
      coupling between the inflammatory and cell death pathways.

PMID- 15190256
TI  - Report of 34 patients with clonal chromosomal abnormalities in Philadelphia
      negative cells during imatinib treatment of Philadelphia-positive chronic myeloid
      leukemia.
AB  - Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was
      introduced recently into the therapy of chronic myeloid leukemia (CML). Several
      cases of emergence of clonal chromosomal abnormalities after therapy with
      imatinib have been reported, but their incidence, etiology and prognosis remain
      to be clarified. We report here a large series of 34 CML patients treated with
      imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients
      with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal
      chromosomal abnormalities in Ph-negative cells. Three patients were treated with
      imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and
      monosomy 7 in twelve and seven patients, respectively. In 15 patients,
      fluorescent in situ hybridization with specific probes was performed in materials
      archived before the initiation of imatinib. The Ph-negative clone was related to
      previous therapy in three patients, and represented a minor pre-existing clone
      that expanded after the eradication of Ph-positive cells with imatinib in two
      others. However, in 11 patients, the new clonal chromosomal abnormalities were
      not detected and imatinib may have had a direct effect. No myelodysplasia was
      found in our cohort. With a median follow-up of 24 months, one patient showed CML
      acceleration and two relapsed.

PMID- 15190257
TI  - Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell
      leukemia cells both in vivo and in vitro.
AB  - Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T
      lymphocytes, and regardless of intensive chemotherapy, its mean survival time is
      less than 1 year. Nuclear factor-kappaB (NF-kappaB) activation was reported in
      HTLV-I associated cells, and has been implicated in oncogenesis and resistance to
      anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor,
      bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo.
      Bortezomib could inhibit the degradation of IkappaBalpha in ATL cells, resulting
      in suppression of NF-kappaB and induction of cell death in ATL cells in vitro.
      Susceptibilities to bortezomib were well correlated with NF-kappaB activation,
      suggesting that suppression of the NF-kappaB pathway was implicated in the cell
      death induced by bortezomib. Although the majority of the cell death was
      apoptosis, necrotic cell death was observed in the presence of a caspase
      inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing
      tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective
      against ATL cells in vivo. These studies revealed that bortezomib is highly
      effective against ATL cells in vitro and in vivo by induction of apoptosis, and
      its clinical application might improve the prognosis of patients with this fatal
      disease.

PMID- 15190258
TI  - Imatinib inhibits the activation and proliferation of normal T lymphocytes in
      vitro.
AB  - The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the
      treatment of CML and is increasingly used in the stem cell transplantation (SCT)
      setting. Since ABL-dependent intracellular signaling molecules are involved in T
      cell activation, imatinib may affect T-cell responses in vivo, thus affecting T
      cell function in CML patients, disrupting immune reconstitution after allogeneic
      SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that
      imatinib inhibits PHA-induced proliferation of normal peripheral blood
      mononuclear cells at in vitro concentrations (1-5 micromol/l) representative of
      the pharmacological doses used therapeutically in vivo. The effect is not
      dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation
      was similarly inhibited by imatinib. Dose-dependent inhibition of the
      proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28
      was similarly observed and associated with reduction in IFN-gamma production. The
      inhibitory effect could not be ascribed to an increased rate of apoptosis but the
      expression of activation markers on CD3+ T cells was significantly reduced in the
      presence of imatinib (1-5 micromol/L). Inhibition of T-cell proliferation was
      reversible after removal of the drug from the cultures. Thus, imatinib inhibits T
      cell proliferation in vitro, an effect that is APC-independent, reversible, and
      does not involve apoptosis induction.

PMID- 15190259
TI  - The paternal chromosome 9 and the maternal chromosome 22 are preferentially
      rearranged in chronic myeloid leukaemia.

PMID- 15190260
TI  - Cyclooxygenase-1, but not -2, is upregulated in NB4 leukemic cells and human
      primary promyelocytic blasts during differentiation.
AB  - Cyclooxygenase (COX)-1 or -2 and specific prostaglandin (PG) synthases catalyze
      the formation of various PGs. We investigated the expression and activity of COX
      1 and -2 during granulocyte-oriented maturation induced by all-trans-retinoic
      acid (ATRA) of NB4 cells, originated from a human acute promyelocytic leukemia
      (APL), and in blasts from APL patients. The expression of COX isoenzymes or
      prostaglandin synthases was also investigated in circulating granulocytes and
      human bone marrow. COX-1 was expressed and enzymatically active in NB4 cells and
      primary blasts. COX-1 mRNA and protein were induced by ATRA. COX-1 protein
      increased approximately 2-3.5-fold by culture day 3 in NB4 cells and primary
      blasts, while basal COX-2 expression was very low and unaffected by ATRA. COX-1
      dependent PGE(2) biosynthesis increased during differentiation approx. 5-fold.
      Indomethacin and the selective COX-1 inhibitor SC-560, but not selective COX-2
      inhibition, impaired NB4 differentiation, reducing NADPH-oxidase activity, CD11b
      and CD11c expression. The immunohistochemistry of granulocytes and myeloid
      precursors in the bone marrow showed a large prevalence of COX-1 as compared to
      COX-2. In conclusion, COX-1 is induced during ATRA-dependent maturation and
      appears to contribute to myeloid differentiation both in vitro and ex vivo, and
      COX-1 activity may potentiate the differentiation of human APL.Leukemia (2004)
      18, 1373-1379. doi:10.1038/sj.leu.2403407 Published online 10 June 2004

PMID- 15190261
TI  - Prevalence and control of hypertension in Latvia.
AB  - The analysis of four epidemiological Data bases (Dbases)-randomized populations
      of Latvia (country), Riga (city), Kuldiga (countryside) and Dbase of WHO
      questionnaire 'Hypertension and control' is presented. Extremely high prevalence
      of arterial hypertension (AH) is demonstrated in three samples of population.
      Close relationship between overweight and AH, hypercholesterol and AH in city and
      village population is shown. Our research provides the data about the
      relationship between the prevalence of AH and socioeconomic factors (education,
      income per capita, marital status and occupation) as well. The analyses of blood
      pressure (BP) measurement rate in population reveals it to be unacceptably low.
      Most widely prescribed antihypertensive drugs are diuretics and ACEIs. The
      analysis of drug intake demonstrates the low rate of regular pharmacological
      treatment. An opinion of physicians on drug intake pattern of their patients is
      far from reality. Only 17.5% of hypertensives among those with drug intake have
      their target BP <140/90 mmHg.

PMID- 15190262
TI  - 24-hour blood pressure control: its relevance to cardiovascular outcomes and the
      importance of long-acting antihypertensive drugs.
AB  - This review article outlines the evidence that 24 h blood pressure (BP)
      measurements are particularly important predictors of adverse cardiovascular
      outcome. In turn, there is supportive evidence from a range of studies that 24 h
      BP control should be an integral part of the antihypertensive drug treatment
      strategy. Furthermore, since not all once daily antihypertensive agents can
      provide such 24 h control, there is a requirement for careful drug (and/or
      dosage) selection. Although the clinic (office) BP continues to be the standard
      measurement by which hypertension is diagnosed and treatment monitored, there is
      now clear evidence of the superiority of 24 h BP assessments. Although there are
      not yet prospective, outcome clinical trails which have relied upon 24 h BP
      values there is clear evidence that 24 h BP values correlate much more closely
      than conventional clinic BP values with measurements such as left ventricular
      hypertrophy, cerebral vascular damage (lacunar infarcts), renal damage
      (microalbuminuria) and vascular damage (carotid artery intima media thickness).
      In turn, there is evidence that during drug treatment, when achieved clinic blood
      pressures appear to be comparable, there is improved outcome in those patients
      whose 24 h BP values are significantly lower. Not all antihypertensive drugs are
      equivalent, however, in their abilities to reduce 24 h BP and the clinician needs
      to be aware of possible shortcomings when considering the choice of drug. In this
      respect, intrinsically long-acting agents are best equipped to provide sustained
      and consistent BP control throughout 24 h.

PMID- 15190264
TI  - The microsatellite alleles on chromosome 1 associated with essential hypertension
      and blood pressure levels.
AB  - Essential hypertension (EH) is thought to be a polygenic disease. Several
      candidate genes of this disease have been investigated in studies using
      polymorphic genetic markers, but some studies have failed to show any association
      of EH with these genes. In this experiment, we used microsatellite markers on
      chromosome 1, and performed an association study between EH and control subjects.
      Genomic DNA was amplified with fluorescently labelled primers from the Applied
      Biosystems PRISM linkage mapping set HD-5 comprising 63 highly polymorphic
      microsatellite markers with an average spacing of 4.5 cM. We isolated three loci
      showing significant differences: D1S507, D1S2713 and D1S2842. The P-values of the
      allele with the greatest post hoc contributions in D1S507, D1S2713 and D1S2842
      were 0.0008, 0.0062 and 0.0084, respectively. All these values were significant
      after Bonferroni correction. Furthermore, we found that the three microsatellite
      alleles were associated with the levels of systolic blood pressure. These data
      suggest that there are at least the three susceptibility loci for EH on
      chromosome 1, and that a case-control study using microsatellite markers on
      genomewide basis is a useful method for isolating the susceptibility loci of
      multifactorial disorders.

PMID- 15190263
TI  - Effect of the renin--angiotensin system on the vessel wall: using ACE inhibition
      to improve endothelial function.
AB  - Plasma renin activity and cardiovascular disease (CVD) incidence correlate
      closely in people with hypertension. The effects of angiotensin II (Ang II) on
      blood pressure (BP) are important in hypertensive patients; accumulating data
      suggest that the growth effects of Ang II in the cardiovascular system play a
      critical role in the development of atherosclerosis. Atherosclerosis development
      in hypertensive patients requires fundamental changes in endothelial structure
      and function. Key among the factors that may affect the endothelium is the renin-
      angiotensin--bradykinin system. Ang II, independent of other environmental and
      neurohormonal factors, mediates the vessel wall changes critical for the
      development of atherosclerotic disease. A strong correlation appears to exist
      between Ang II and CVD. Blockade of the renin-angiotensin system has a major
      impact on arterial structure and function independent of BP. Certain angiotensin
      converting enzyme (ACE) inhibitors produce significant improvements in arterial
      compliance, which may yield a reduction in cardiovascular events. Blockade of the
      neurohormonal system may be a critical first-line approach to management of
      hypertension in an effort to prevent or reverse endothelial dysfunction.
      Moreover, the effects of ACE inhibition, in addition to its effect on BP, suggest
      that this therapeutic approach may be appropriate for managing patients at risk
      of CVD who do not yet have hypertension. The ideal antihypertensive agent should
      yield smooth, consistent BP control over the entire 24-hour period, both to avoid
      BP variability that places patients at increased risk of cardiovascular events
      and to offer protection during the vulnerable early morning hours when patients
      are well known to be at high risk.

PMID- 15190265
TI  - cis-Element clustering correlates with dose-dependent pro- and antisignaling
      effects of IL18.
AB  - We examine the effects of IL18 on monocytes by performing microarray experiments
      using cell line KG1. Based on sensitivity to IL18, we identified three
      functionally distinct gene expression clusters (EC). We see little
      proinflammatory gene induction at low IL18 concentrations, but instead observe
      induction of diverse NF kappa B signaling inhibitors. Conversely, intermediate
      concentrations of IL18 induced proinflammatory genes including the activating
      subunits of NF kappa B. At the highest IL18 concentration, we observe a third
      gene cluster containing the proapoptotic Fas gene among others. Clustering of
      IL18-responsive genes based on cis-elements in their promoters agreed well with
      the ECs. We conclude that IL18 produces a dose-dependent transcriptional response
      that can in part be attributed to the composition of cis-elements in the
      promoters of IL18-responsive genes. These results also support a model for
      regulatory mechanisms that prevent spurious immune response due to weak cytokine
      fluctuations and a separate mechanism enabling induction of proinflammatory
      functions by higher levels of cytokine.

PMID- 15190266
TI  - Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene
      cluster: association with knee osteoarthritis.
AB  - The interleukin-1 gene cluster is a key regulator in a number of chronic disease
      processes. We explored the linkage between nine polymorphic loci in the IL1R1
      promoter, eight in the IL1A-IL1B-IL1RN gene complex, and their association with
      osteoarthritis (OA), a common complex disease associated with low-level
      inflammation. Using 195 healthy controls, we identified eight novel polymorphisms
      in the IL1R1 exon 1A region. We found limited LD between IL1R1 and the IL1A-IL1B
      IL1RN cluster, although LD within these two individual groups was high. To test
      association with knee OA, we genotyped 141 patients from Bristol (UK) at the 17
      loci. IL1R1 promoter haplotypes showed no association with disease. However,
      within the IL1A-IL1B-IL1RN complex, we identified a common haplotype conferring a
      four-fold risk of OA (P=0.00043; Pc=0.0043) and one IL1B-IL1RN haplotype
      conferring a four-fold reduced risk (P=0.0036; Pc=0.029). To replicate these
      associations, we subsequently examined 163 knee OA patients from London. Here,
      the effects of the haplotypes were confirmed: the risk IL1A-IL1B-IL1RN haplotype
      conferred a two-fold risk of OA (P=0.02), and the protective IL1B-IL1RN haplotype
      conferred a five-fold reduced risk of OA (P=0.0000008). These results may help to
      explain the genome-wide scan linkage data and functional observations concerning
      association between IL-1 and OA.

PMID- 15190267
TI  - NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease
      patients: evidence for genetic heterogeneity within Europe?
AB  - NOD2/caspase recruitment domain (CARD)15 variants are identified in up to 50% of
      Crohn's disease (CD) patients. Functional variants of toll-like receptor-4 (TLR4)
      and CD14 genes may also be relevant to disease pathophysiology. We aimed to
      assess the contribution of NOD2/CARD15, TLR4 and CD14 variants in Scottish and
      Irish CD patients. In all, 612 patients with well-characterised inflammatory
      bowel disease (252 Scottish CD, 247 Scottish UC, 113 Irish CD) and 304 controls
      were genotyped for variants of NOD2/CARD15 (1007fsinsC, G908R, R702W, P268S),
      TLR4 (A299G) and CD14 (T-159C). Genotype-phenotype analyses were performed.
      Variant 1007fsinsC (P=0.003) and G908R (P=0.008) but not R702W (P=0.269) alleles
      were more prevalent in Scottish CD (4.7, 1.8 and 7.1%, respectively) than
      Scottish control (2.3, 0.3 and 5.4%). CD allelic frequencies were lower than the
      series from Europe (P<0.00001) and North America (P<0.00001) but not Scandinavia
      (P<0.7). Associations were identified with age at diagnosis (P=0.002), ileal
      disease (P<0.02), penetrating disease (P=0.04) and inflammatory joint disease
      (P<0.02). TLR4 and CD14 variants did not differ between CD and controls. In
      conclusion, we present compelling evidence for genetic heterogeneity within
      Europe. These NOD2/CARD15 variants have a minor contribution in Scottish and
      Irish CD patients, consistent with an emerging pattern from Northern Europe.

PMID- 15190268
TI  - Antiphospholipid syndrome.

PMID- 15190269
TI  - Thrombotic thrombocytopenic purpura.

PMID- 15190270
TI  - Idiopathic thrombocytopenic purpura in adults: current issues for pathogenesis,
      diagnosis and management.

PMID- 15190271
TI  - Relations between hemostatic variables, insulin resistance and inflammation.

PMID- 15190272
TI  - Thrombosis and cancer.
AB  - Venous thromboembolism is a common problem in cancer patients. It complicates
      both the surgical management of those with cancer and has been associated with
      varying risk for the development of clinical thromboembolism in patients
      receiving chemotherapy. Unfractionated and low-molecular-weight heparin have been
      validated both in terms of their efficacy and safety, in the prevention of venous
      thromboembolic disease in cancer patients undergoing surgical intervention and
      for the primary treatment and secondary prevention of recurrent venous
      thromboembolism. Beyond their uses in the prevention and treatment of thrombosis,
      low-molecular-weight heparins have recently been shown to prolong survival in
      patients with solid tumour malignancy.

PMID- 15190273
TI  - Treatment of venous thromboembolism: duration and new options.

PMID- 15190274
TI  - Overview of transplant activity in Europe.
AB  - This report summarizes current transplant activity in Europe. It is based on the
      activity survey of the European Group for Blood and Marrow Transplantation
      (EBMT). Introduced in 1990, the survey captures the annual numbers of
      hematopoietic stem cell transplantation (HSCT) by indication, donor type and stem
      cell source from each individual European transplant team. Supplemented by
      demographical data and economical factors, team density and transplant rates can
      be calculated, and the impact of economics on HSCT rates can be assessed. As
      documented in the present analysis, in the year 2002, a total 20 207 HSCT were
      performed on new patients in Europe by 586 teams in 39 countries: 6915 being
      allogeneic and 13 292 autologous HSCT. The main indications for allogeneic HSCT
      were leukemias, lymphoproliferative disorders and non-malignant diseases; main
      indications for autologous HSCT were lymphoproliferative disorders, solid tumors
      and leukemias. The main source of stem cells were peripheral blood (96%) for
      autologous, peripheral blood (62%) and bone marrow (38%) for allogeneic HSCT. On
      the basis of its completeness, the EBMT activity survey presents a rapid
      description of the status quo, assessment of trends and determination of factors
      influencing transplant rates. As such, it provides up-to-date information for
      patients, treating physicians and health-care officials.

PMID- 15190276
TI  - Long-term care after stem-cell transplantation.

PMID- 15190275
TI  - Reduced intensity transplantation: where are we now?

PMID- 15190277
TI  - A European network for AML.

PMID- 15190278
TI  - Developing a European network for adult ALL.

PMID- 15190279
TI  - Choice of empirical therapy and prophylaxis.

PMID- 15190281
TI  - Viral infections: current diagnosis and treatment.

PMID- 15190280
TI  - Fungal infections: current diagnosis and treatment.

PMID- 15190282
TI  - Evolution of microbial safety.

PMID- 15190283
TI  - Haemovigilance procedure in transfusion medicine.

PMID- 15190284
TI  - Safety aspects of blood transfusion and European legislation.

PMID- 15190285
TI  - Immunotherapy with alloreactive natural killer cells in haploidentical
      haematopoietic transplantation.

PMID- 15190286
TI  - Immunotherapy with alloreactive T-cells?

PMID- 15190287
TI  - Immunotherapy of hematological malignancies with dendritic cells.

PMID- 15190288
TI  - Erythropoietin pathophysiology and erythropoietin deficiency anemia.

PMID- 15190289
TI  - Epoetin-induced autoimmune pure red cell aplasia.

PMID- 15190290
TI  - Erythropoietin and erythropoiesis: polycythemias due to disruption of oxygen
      homeostasis.

PMID- 15190291
TI  - Nuclear transplantation, embryonic stem cells and the potential for cell therapy.
AB  - Nuclear transfer experiments in mammals have shown that the nucleus of an adult
      cell has the ability to direct the development of an entire organism, id est its
      genome is totipotent. However, these experiments did not conclusively demonstrate
      that the nuclei of terminally differentiated adult cells remain totipotent. It is
      possible that rare adult stem cells served as donors for the few surviving
      clones. To address this question, we have generated monoclonal mice from
      terminally differentiated lymphocytes that carry a single antigen receptor
      rearrangement in all tissues. Nuclear transfer technology may provide a powerful
      method for obtaining autologous cells for replacement therapy. We have
      demonstrated the feasibility of this concept by combining nuclear transfer with
      gene and cell therapy to treat the immune deficiency of Rag2 mutant mice, thus
      establishing a paradigm for 'therapeutic cloning'. Moreover, we will discuss the
      potential use of nuclear transfer to study the role of reversible genomic
      (epigenetic) modifications during tumorigenesis.

PMID- 15190293
TI  - Chronic myeloproliferative disorders: molecular markers and pathogenesis.

PMID- 15190292
TI  - Molecular basis for stem-cell self-renewal.

PMID- 15190294
TI  - Management of the myeloproliferative disorders : distinguishing data from dogma.

PMID- 15190295
TI  - FIP1L1-PDGFRalpha in hypereosinophilic syndrome and mastocytosis.

PMID- 15190296
TI  - Discovery of novel molecular classification schemes and genes predictive of
      outcome in leukemia.

PMID- 15190297
TI  - Molecular heterogeneity of diffuse large B-cell lymphoma.

PMID- 15190298
TI  - PET scan in the therapeutic strategy.

PMID- 15190299
TI  - Dose intensity or monoclonal antibody in first-line treatment.

PMID- 15190301
TI  - Measuring platelet function?

PMID- 15190300
TI  - Platelet receptor signalling.

PMID- 15190302
TI  - Antiplatelet agents.

PMID- 15190303
TI  - Haemovigilance in the United Kingdom and Europe.

PMID- 15190304
TI  - Intravenous immunoglobulins: too many indications?

PMID- 15190305
TI  - Switching off oncogenic signals in chronic myeloid leukaemia.

PMID- 15190306
TI  - FLT3 tyrosine kinase as a target in acute leukemias.

PMID- 15190307
TI  - Congenital dyserythropoietic anemias.

PMID- 15190308
TI  - Vaso-occlusion in sickle cell anemia: role of interactions between blood cells
      and endothelium.

PMID- 15190309
TI  - Molecular pathology of thalassemia intermedia.

PMID- 15190312
TI  - Precaution versus principles.

PMID- 15190313
TI  - Boosting bioprospects.

PMID- 15190314
TI  - Gene therapists hopeful as trials resume with childhood disease.

PMID- 15190315
TI  - Global fund changes tack on malaria therapy.

PMID- 15190316
TI  - Biotech industry struggles with generics approval.

PMID- 15190317
TI  - Spitzer sues drug giant for deceiving doctors.

PMID- 15190318
TI  - Net losses pose extinction risk for porpoise.

PMID- 15190320
TI  - Nanotech takes small step towards burying 'grey goo'.

PMID- 15190319
TI  - Critics blast 'premature' paper on adult stem cells.

PMID- 15190321
TI  - Futuristic centre under fire from German science council.

PMID- 15190311
TI  - A precision measurement of the mass of the top quark.
AB  - The standard model of particle physics contains parameters--such as particle
      masses--whose origins are still unknown and which cannot be predicted, but whose
      values are constrained through their interactions. In particular, the masses of
      the top quark (M(t)) and W boson (M(W)) constrain the mass of the long
      hypothesized, but thus far not observed, Higgs boson. A precise measurement of
      M(t) can therefore indicate where to look for the Higgs, and indeed whether the
      hypothesis of a standard model Higgs is consistent with experimental data. As top
      quarks are produced in pairs and decay in only about 10(-24) s into various final
      states, reconstructing their masses from their decay products is very
      challenging. Here we report a technique that extracts more information from each
      top-quark event and yields a greatly improved precision (of +/- 5.3 GeV/c2) when
      compared to previous measurements. When our new result is combined with our
      published measurement in a complementary decay mode and with the only other
      measurements available, the new world average for M(t) becomes 178.0 +/- 4.3
      GeV/c2. As a result, the most likely Higgs mass increases from the experimentally
      excluded value of 96 to 117 GeV/c2, which is beyond current experimental
      sensitivity. The upper limit on the Higgs mass at the 95% confidence level is
      raised from 219 to 251 GeV/c2.

PMID- 15190323
TI  - Palaeoclimate: frozen time.

PMID- 15190322
TI  - Fighting AIDS is best use of money, says cost-benefit analysis.

PMID- 15190324
TI  - Natural resources: bioprospects less than golden.

PMID- 15190325
TI  - Small countries receive even less of a fair deal.

PMID- 15190326
TI  - Fair deal: local factors add to price of supplies.

PMID- 15190327
TI  - Fair deal foiled by taxes and exchange rates.

PMID- 15190328
TI  - Isolation is not the answer.

PMID- 15190333
TI  - Causing a commotion.

PMID- 15190334
TI  - Palaeoclimate: a great grand-daddy of ice cores.

PMID- 15190335
TI  - Animal behaviour: eavesdropping on bats.

PMID- 15190336
TI  - Particle physics: from the top...

PMID- 15190339
TI  - Economics: the wealth of nations.

PMID- 15190338
TI  - Interstellar chemistry: molecular nitrogen in space.

PMID- 15190340
TI  - Nanophysics: a step up to self-assembly.

PMID- 15190341
TI  - Molecular medicine: the writing is on the vessel wall.

PMID- 15190343
TI  - Palaeontology: pterosaur embryo from the Early Cretaceous.
AB  - Dinosaur embryos have been discovered all over the world, but so far no pterosaur
      embryos have been reported. Here we describe a Chinese fossil from the Early
      Cretaceous period containing an embryo that is unambiguously a pterosaur. The
      embryonic skeleton, which is exquisitely preserved in its egg, is associated with
      eggshell fragments, wing membranes and skin imprints. This discovery confirms
      that pterosaurs were egg-layers and sheds new light on our understanding of
      pterosaur development.

PMID- 15190344
TI  - Eight glacial cycles from an Antarctic ice core.
AB  - The Antarctic Vostok ice core provided compelling evidence of the nature of
      climate, and of climate feedbacks, over the past 420,000 years. Marine records
      suggest that the amplitude of climate variability was smaller before that time,
      but such records are often poorly resolved. Moreover, it is not possible to infer
      the abundance of greenhouse gases in the atmosphere from marine records. Here we
      report the recovery of a deep ice core from Dome C, Antarctica, that provides a
      climate record for the past 740,000 years. For the four most recent glacial
      cycles, the data agree well with the record from Vostok. The earlier period,
      between 740,000 and 430,000 years ago, was characterized by less pronounced
      warmth in interglacial periods in Antarctica, but a higher proportion of each
      cycle was spent in the warm mode. The transition from glacial to interglacial
      conditions about 430,000 years ago (Termination V) resembles the transition into
      the present interglacial period in terms of the magnitude of change in
      temperatures and greenhouse gases, but there are significant differences in the
      patterns of change. The interglacial stage following Termination V was
      exceptionally long--28,000 years compared to, for example, the 12,000 years
      recorded so far in the present interglacial period. Given the similarities
      between this earlier warm period and today, our results may imply that without
      human intervention, a climate similar to the present one would extend well into
      the future.

PMID- 15190345
TI  - Subtractive proteomic mapping of the endothelial surface in lung and solid
      tumours for tissue-specific therapy.
AB  - The molecular complexity of tissues and the inaccessibility of most cells within
      a tissue limit the discovery of key targets for tissue-specific delivery of
      therapeutic and imaging agents in vivo. Here, we describe a hypothesis-driven,
      systems biology approach to identifying a small subset of proteins induced at the
      tissue-blood interface that are inherently accessible to antibodies injected
      intravenously. We use subcellular fractionation, subtractive proteomics and
      bioinformatics to identify endothelial cell surface proteins exhibiting
      restricted tissue distribution and apparent tissue modulation. Expression
      profiling and gamma-scintigraphic imaging with antibodies establishes two of
      these proteins, aminopeptidase-P and annexin A1, as selective in vivo targets for
      antibodies in lungs and solid tumours, respectively. Radio-immunotherapy to
      annexin A1 destroys tumours and increases animal survival. This analytical
      strategy can map tissue- and disease-specific expression of endothelial cell
      surface proteins to uncover novel accessible targets useful for imaging and
      therapy.

PMID- 15190346
TI  - The interstellar N2 abundance towards HD 124314 from far-ultraviolet
      observations.
AB  - The abundance of interstellar molecular nitrogen (N2) is of considerable
      importance: models of steady-state gas-phase interstellar chemistry, together
      with millimetre-wavelength observations of interstellar N2H+ in dense molecular
      clouds predict that N2 should be the most abundant nitrogen-bearing molecule in
      the interstellar medium. Previous attempts to detect N2 absorption in the far
      ultraviolet or infrared (ice features) have hitherto been unsuccessful. Here we
      report the detection of interstellar N2 at far-ultraviolet wavelengths towards
      the moderately reddened star HD 124314 in the constellation of Centaurus. The N2
      column density is larger than expected from models of diffuse clouds and
      significantly smaller than expected for dense molecular clouds. Moreover, the N2
      abundance does not explain the observed variations in the abundance of atomic
      nitrogen (N I) towards high-column-density sightlines, implying that the models
      of nitrogen chemistry in the interstellar medium are incomplete.

PMID- 15190347
TI  - Energy-transfer pumping of semiconductor nanocrystals using an epitaxial quantum
      well.
AB  - As a result of quantum-confinement effects, the emission colour of semiconductor
      nanocrystals can be modified dramatically by simply changing their size. Such
      spectral tunability, together with large photoluminescence quantum yields and
      high photostability, make nanocrystals attractive for use in a variety of light
      emitting technologies--for example, displays, fluorescence tagging, solid-state
      lighting and lasers. An important limitation for such applications, however, is
      the difficulty of achieving electrical pumping, largely due to the presence of an
      insulating organic capping layer on the nanocrystals. Here, we describe an
      approach for indirect injection of electron-hole pairs (the electron-hole
      radiative recombination gives rise to light emission) into nanocrystals by non
      contact, non-radiative energy transfer from a proximal quantum well that can in
      principle be pumped either electrically or optically. Our theoretical and
      experimental results indicate that this transfer is fast enough to compete with
      electron-hole recombination in the quantum well, and results in greater than 50
      per cent energy-transfer efficiencies in the tested structures. Furthermore, the
      measured energy-transfer rates are sufficiently large to provide pumping in the
      stimulated emission regime, indicating the feasibility of nanocrystal-based
      optical amplifiers and lasers based on this approach.

PMID- 15190348
TI  - High levels of atmospheric carbon dioxide necessary for the termination of global
      glaciation.
AB  - The possibility that the Earth suffered episodes of global glaciation as recently
      as the Neoproterozoic period, between about 900 and 543 million years ago, has
      been widely discussed. Termination of such 'hard snowball Earth' climate states
      has been proposed to proceed from accumulation of carbon dioxide in the
      atmosphere. Many salient aspects of the snowball scenario depend critically on
      the threshold of atmospheric carbon dioxide concentrations needed to trigger
      deglaciation. Here I present simulations with a general circulation model, using
      elevated carbon dioxide levels to estimate this deglaciation threshold. The model
      simulates several phenomena that are expected to be significant in a 'snowball
      Earth' scenario, but which have not been considered in previous studies with less
      sophisticated models, such as a reduction of vertical temperature gradients in
      winter, a reduction in summer tropopause height, the effect of snow cover and a
      reduction in cloud greenhouse effects. In my simulations, the system remains far
      short of deglaciation even at atmospheric carbon dioxide concentrations of 550
      times the present levels (0.2 bar of CO2). I find that at much higher carbon
      dioxide levels, deglaciation is unlikely unless unknown feedback cycles that are
      not captured in the model come into effect.

PMID- 15190349
TI  - Mesozoic origin for West Indian insectivores.
AB  - The highly endangered solenodons, endemic to Cuba (Solenodon cubanus) and
      Hispaniola (S. paradoxus), comprise the only two surviving species of West Indian
      insectivores. Combined gene sequences (13.9 kilobases) from S. paradoxus
      established that solenodons diverged from other eulipotyphlan insectivores 76
      million years ago in the Cretaceous period, which is consistent with vicariance,
      though also compatible with dispersal. A sequence of 1.6 kilobases of
      mitochondrial DNA from S. cubanus indicated a deep divergence of 25 million years
      versus the congeneric S. paradoxus, which is consistent with vicariant origins as
      tectonic forces separated Cuba and Hispaniola. Efforts to prevent extinction of
      the two surviving solenodon species would conserve an entire lineage as old or
      older than many mammalian orders.

PMID- 15190350
TI  - Convergence across biomes to a common rain-use efficiency.
AB  - Water availability limits plant growth and production in almost all terrestrial
      ecosystems. However, biomes differ substantially in sensitivity of aboveground
      net primary production (ANPP) to between-year variation in precipitation. Average
      rain-use efficiency (RUE; ANPP/precipitation) also varies between biomes,
      supposedly because of differences in vegetation structure and/or biogeochemical
      constraints. Here we show that RUE decreases across biomes as mean annual
      precipitation increases. However, during the driest years at each site, there is
      convergence to a common maximum RUE (RUE(max)) that is typical of arid
      ecosystems. RUE(max) was also identified by experimentally altering the degree of
      limitation by water and other resources. Thus, in years when water is most
      limiting, deserts, grasslands and forests all exhibit the same rate of biomass
      production per unit rainfall, despite differences in physiognomy and site-level
      RUE. Global climate models predict increased between-year variability in
      precipitation, more frequent extreme drought events, and changes in temperature.
      Forecasts of future ecosystem behaviour should take into account this convergent
      feature of terrestrial biomes.

PMID- 15190351
TI  - Harmonic-hopping in Wallacea's bats.
AB  - Evolutionary divergence between species is facilitated by ecological shifts, and
      divergence is particularly rapid when such shifts also promote assortative
      mating. Horseshoe bats are a diverse Old World family (Rhinolophidae) that have
      undergone a rapid radiation in the past 5 million years. These insectivorous bats
      use a predominantly pure-tone echolocation call matched to an auditory fovea (an
      over-representation of the pure-tone frequency in the cochlea and inferior
      colliculus) to detect the minute changes in echo amplitude and frequency
      generated when an insect flutters its wings. The emitted signal is the
      accentuated second harmonic of a series in which the fundamental and remaining
      harmonics are filtered out. Here we show that three distinct, sympatric size
      morphs of the large-eared horseshoe bat (Rhinolophus philippinensis) echolocate
      at different harmonics of the same fundamental frequency. These morphs have
      undergone recent genetic divergence, and this process has occurred in parallel
      more than once. We suggest that switching harmonics creates a discontinuity in
      the bats' perception of available prey that can initiate disruptive selection.
      Moreover, because call frequency in horseshoe bats has a dual function in
      resource acquisition and communication, ecological selection on frequency might
      lead to assortative mating and ultimately reproductive isolation and speciation,
      regardless of external barriers to gene flow.

PMID- 15190352
TI  - Echolocation signals reflect niche differentiation in five sympatric congeneric
      bat species.
AB  - Echolocating bats can be divided into guilds according to their preferred habitat
      and foraging behaviour, which coincide with distinct adaptations in wing
      morphology and structure of echolocation signals. Although coarse structuring of
      niche space between different guilds is generally accepted, it is not clear how
      niches differ within guilds, or whether there is fine-grained niche
      differentiation reflected in echolocation signal structure. Using a standardized
      performance test, here we show clutter-dependent differences in prey-capture
      success for bats from five species of European Myotis. These species are
      morphologically similar, sympatric, and all belong to the guild labelled "edge
      space aerial/trawling foragers". We further demonstrate a strong correlation
      between the prey-detection ability of the species and the respective search-call
      bandwidth. Our findings indicate that differences in echolocation signals
      contribute to within-guild niche differentiation. This is the first study
      relating sensory abilities of a set of potentially competing animal species to a
      direct measure of their respective foraging performance, suggesting an important
      role of sensory ecology in the structuring of animal communities.

PMID- 15190353
TI  - Metabolic network analysis of the causes and evolution of enzyme dispensability
      in yeast.
AB  - Under laboratory conditions 80% of yeast genes seem not to be essential for
      viability. This raises the question of what the mechanistic basis for
      dispensability is, and whether it is the result of selection for buffering or an
      incidental side product. Here we analyse these issues using an in silico flux
      model of the yeast metabolic network. The model correctly predicts the knockout
      fitness effects in 88% of the genes studied and in vivo fluxes. Dispensable genes
      might be important, but under conditions not yet examined in the laboratory. Our
      model indicates that this is the dominant explanation for apparent
      dispensability, accounting for 37-68% of dispensable genes, whereas 15-28% of
      them are compensated by a duplicate, and only 4-17% are buffered by metabolic
      network flux reorganization. For over one-half of those not important under
      nutrient-rich conditions, we can predict conditions when they will be important.
      As expected, such condition-specific genes have a more restricted phylogenetic
      distribution. Gene duplicates catalysing the same reaction are not more common
      for indispensable reactions, suggesting that the reason for their retention is
      not to provide compensation. Instead their presence is better explained by
      selection for high enzymatic flux.

PMID- 15190354
TI  - Temporal difference models describe higher-order learning in humans.
AB  - The ability to use environmental stimuli to predict impending harm is critical
      for survival. Such predictions should be available as early as they are reliable.
      In pavlovian conditioning, chains of successively earlier predictors are studied
      in terms of higher-order relationships, and have inspired computational theories
      such as temporal difference learning. However, there is at present no adequate
      neurobiological account of how this learning occurs. Here, in a functional
      magnetic resonance imaging (fMRI) study of higher-order aversive conditioning, we
      describe a key computational strategy that humans use to learn predictions about
      pain. We show that neural activity in the ventral striatum and the anterior
      insula displays a marked correspondence to the signals for sequential learning
      predicted by temporal difference models. This result reveals a flexible aversive
      learning process ideally suited to the changing and uncertain nature of real
      world environments. Taken with existing data on reward learning, our results
      suggest a critical role for the ventral striatum in integrating complex
      appetitive and aversive predictions to coordinate behaviour.

PMID- 15190357
TI  - The power of goodbye.

PMID- 15190358
TI  - Testing new ground.

PMID- 15190355
TI  - Myosin-dependent junction remodelling controls planar cell intercalation and axis
      elongation.
AB  - Shaping a developing organ or embryo relies on the spatial regulation of cell
      division and shape. However, morphogenesis also occurs through changes in cell
      neighbourhood relationships produced by intercalation. Intercalation poses a
      special problem in epithelia because of the adherens junctions, which maintain
      the integrity of the tissue. Here we address the mechanism by which an ordered
      process of cell intercalation directs polarized epithelial morphogenesis during
      germ-band elongation, the developmental elongation of the Drosophila embryo.
      Intercalation progresses because junctions are spatially reorganized in the plane
      of the epithelium following an ordered pattern of disassembly and reassembly. The
      planar remodelling of junctions is not driven by external forces at the tissue
      boundaries but depends on local forces at cell boundaries. Myosin II is
      specifically enriched in disassembling junctions, and its planar polarized
      localization and activity are required for planar junction remodelling and cell
      intercalation. This simple cellular mechanism provides a general model for
      polarized morphogenesis in epithelial organs.

PMID- 15190359
TI  - The 18S rRNA from Odontophrynus americanus 2n and 4n (Amphibia, Anura) reveals
      unusual extra sequences in the variable region V2.
AB  - The nucleotide sequence of the rDNA 18S region isolated from diploid and
      tetraploid species of the amphibian Odontophrynus americanus was determined and
      used to predict the secondary structure of the corresponding 18S rRNA molecules.
      Comparison of the primary and secondary structures for the 2n and 4n species
      confirmed that these species are very closely related. Only three nucleotide
      substitutions were observed, accounting for 99% identity between the 18S
      sequences, whereas several changes were detected by comparison with the Xenopus
      laevis 18S sequence (96% identity). Most changes were located in highly variable
      regions of the molecule. A noticeable feature of the Odontophrynus 18S rRNA was
      the presence of unusual extra sequences in the V2 region, between helices 9 and
      11. These extra sequences do not fit the model for secondary structure predicted
      for vertebrate 18S rRNA.

PMID- 15190360
TI  - Development of microsatellite markers in Fragaria, their use in genetic diversity
      analysis, and their potential for genetic linkage mapping.
AB  - We have developed 21 new microsatellites in the model diploid perennial species
      Fragaria vesca from an enriched genomic library developed using F. vesca
      'Ruegen'. The transferability of the primer pairs to other Fragaria species was
      high; all 31 primer pairs produced amplicons in 3 accessions of the octoploid
      strawberry Fragaria x ananassa, whereas 24 (77%) amplified a product in 7 other
      diploid Fragaria species. We analysed the allelic variation among 15 F. vesca
      accessions using the 21 microsatellites reported here and 10 F. vesca
      microsatellites described previously. The level of polymorphism detected at these
      microsatellite loci was high; five loci were monomorphic. Only two
      microsatellites were required to unambiguously discriminate among the 15 F. vesca
      accessions. A preliminary survey of segregation in an F2 progeny indicates that
      20 of the 26 polymorphic loci (77%) could be mapped.

PMID- 15190361
TI  - Analysis of phylogenetic relationship among five mulberry (Morus) species using
      molecular markers.
AB  - Species identification in mulberry (Morus) continues to be a point of great
      debate among scientists despite the number of criteria such as floral characters,
      wood, and leaf anatomical and biochemical characters used to identify the species
      within this genus. However, no consensus system of classification has emerged.
      Hence, an investigation was undertaken with inter-simple sequence repeat (ISSR)
      and random amplified polymorphic DNA (RAPD) markers to find out the possibility
      of using these DNA markers to confirm the identity of genotypes in a particular
      species. Fifteen ISSR and 15 RAPD primers generated 86% and 78% polymorphism,
      respectively, among 19 mulberry genotypes. The polymorphism among the species
      varied from 50% to 57% in ISSR markers and 31% to 53% in RAPD markers. Similarity
      coefficients were higher among the genotypes of M. latifolia, M. bombycis and M.
      alba. Cluster analyses separated genotypes of M. laevigata and M. indica from
      those of the other species. Population structure analysis of these species
      further showed high genetic differentiation coefficients (GST), high
      heterozygosity between two species (DST), and total heterozygosity among
      populations (Ht) coupled with considerably low gene flow (Nm) when M. laevigata
      was paired with other species. Based on these parameters and the result of
      cluster analysis it is concluded that M. laevigata can be considered as a
      separate species of mulberry, whereas the other four species may be grouped
      together and treated as subspecies.

PMID- 15190362
TI  - EST derived PCR-based markers for functional gene homologues in cotton.
AB  - We investigated the utility of the Gossypium arboreum EST sequences in the
      GenBank database for developing PCR-based markers targeting known-function genes
      in cultivated tetraploid cottons, G. hirsutum and G. barbadense. Four hundred
      sixty-five randomly selected ESTs from this library were subjected to BLASTn
      search against all GenBank databases, of which putative function was assigned to
      93 ESTs based on high nucleotide homology to previously studied genes. PCR
      primers were synthesized for 89 of the known-function ESTs. A total of 57 primer
      pairs amplified G. arboreum genomic DNA, but only 39 amplified in G. hirsutum and
      G. barbadense, suggesting that sequence divergence may be a factor causing non
      amplification for some sites. DNA sequence analysis showed that most primer pairs
      were targeting the expected homologous loci. While the amplified products that
      were of larger size than the corresponding EST sequences contain introns, the
      primer pairs with a smaller amplicon than predicted from the flanking EST
      sequences did not amplify the expected orthologous gene sequences. Among the 39
      primer pairs that amplified tetraploid cotton DNA, 3 detected amplicon size
      polymorphisms and 10 detected polymorphisms after digestion with one of six
      restriction enzymes. Ten of the polymorphic loci were subsequently mapped to an
      anchor RFLP map. Digestion of PCR-amplified sequences offers one means by which
      cotton genes can be mapped to their chromosomal locations more quickly and
      economically than by RFLP analysis.

PMID- 15190363
TI  - QTL affecting soluble carbohydrate concentrations in stored onion bulbs and their
      association with flavor and health-enhancing attributes.
AB  - Onion bulbs accumulate fructans, a type of soluble carbohydrate associated with
      lower rates of colorectal cancers. Higher fructan concentrations in bulbs are
      correlated with higher pungency, longer dormancy, and greater onion-induced
      antiplatelet activity (OIAA). We analyzed replicated field trials of a
      segregating family for types and concentrations of soluble carbohydrates in onion
      bulbs 90 days after harvest. Means were adjusted using dry weight as the
      covariant to reveal highly significant (P < 0.001) differences among parents and
      families for glucose, fructose, sucrose, and the fructans 1-kestose, neokestose,
      and (6G,1)-nystose. Fructan concentrations showed significant (P < 0.05)
      phenotypic correlations with each other and with sucrose, pungency, and OIAA.
      These observations are consistent with the hypothesis that onion bulbs
      accumulating fructans take up or retain less water, concentrating both soluble
      carbohydrates and thiosulfinates responsible for pungency and OIAA. Interval
      mapping of family means from the covariant analyses revealed regions on linkage
      groups A and D significantly (LOD > 2.68) affecting soluble carbohydrate
      concentrations. The enzyme catalyzing the first step of fructan polymerization, 1
      sucrose-sucrose fructosyltransferase (1-SST), mapped independently of these
      genomic regions. One region on linkage group D near an acid-invertase gene was
      significantly (LOD = 3.45) associated with sucrose concentrations. This study
      reveals that the accumulation of sucrose in stored onion bulbs may allow for the
      combination of sweeter flavor with significant OIAA.

PMID- 15190364
TI  - Identification of AFLP makers linked to non-seed shattering locus (sht1) in
      buckwheat and conversion to STS markers for marker-assisted selection.
AB  - Shattering habit in buckwheat has two forms: brittle pedicel and weak pedicel.
      Brittle pedicel is observed in wild buckwheat, but not in cultivated buckwheat.
      Brittle pedicel in buckwheat is produced by two complementary, dominant genes,
      Sht1 and Sht2. The sht1 locus is linked to the S locus; almost all common
      buckwheat cultivars possess the allele sht1. To detect molecular makers linked to
      the sht1 locus, we used amplified fragment-length polymorphism (AFLP) analysis in
      combination with bulked segregant analysis of segregating progeny of a cross
      between a non-brittle common buckwheat and a brittle self-compatible buckwheat
      line. We screened 312 primer combinations and constructed a linkage map around
      the sht1 locus by using 102 F2 plants. Five AFLP markers were linked to the sht1
      locus. Two of these, e54m58/610 and e55m46/320, cosegregated with the sht1 locus
      without recombination. The two AFLP markers were converted to STS markers
      according to the sequence of the AFLPs. The STS markers are useful for marker
      assisted selection of non-brittle pedicel plants and provides a stepping-stone
      for map-based cloning and characterization of the gene encoding non-brittle
      pedicel.

PMID- 15190365
TI  - QTL analysis of quantitative resistance to Phytophthora infestans (late blight)
      in tomato and comparisons with potato.
AB  - Quantitative trait loci (QTLs) for resistance to Phytophthora infestans (late
      blight) were mapped in tomato. Reciprocal backcross populations derived from
      cultivated Lycopersicon esculentum x wild Lycopersicon hirsutum (BC-E, backcross
      to L. esculentum; BC-H, backcross to L. hirsutum) were phenotyped in three types
      of replicated disease assays (detached-leaflet, whole-plant, and field). Linkage
      maps were constructed for each BC population with RFLPs. Resistance QTLs were
      identified on all 12 tomato chromosomes using composite interval mapping. Six
      QTLs in BC-E (lb1a, lb2a, lb3, lb4, lb5b, and lb11b) and two QTLs in BC-H (lb5ab
      and lb6ab) were most consistently detected in replicated experiments or across
      assay methods. Lycopersicon hirsutum alleles conferred resistance at all QTLs
      except lb2a. Resistance QTLs coincided with QTLs for inoculum droplet dispersal
      on leaves, a trait in L. hirsutum that may contribute to resistance, and
      dispersal was mainly associated with leaf resistance. Some P. infestans
      resistance QTLs detected in tomato coincided with chromosomal locations of
      previously mapped R genes and QTLs for resistance to P. infestans in potato,
      suggesting functional conservation of resistance within the Solanaceae.

PMID- 15190366
TI  - Stress-induced expression in wheat of the Arabidopsis thaliana DREB1A gene delays
      water stress symptoms under greenhouse conditions.
AB  - One of the major environmental factors limiting plant productivity is lack of
      water. This is especially true for the major cereals maize, rice, and wheat,
      which demonstrate a range of susceptibility to moisture deficit. Although
      conventional breeding and marker-assisted selection are being used to develop
      varieties more tolerant to water stress, these methods are time and resource
      consuming and germplasm dependent. Genetic engineering is attractive because of
      its potential to improve abiotic stress tolerance more rapidly. Transcription
      factors have been shown to produce multiple phenotypic alterations, many of which
      are involved in stress responses. DREB1A, a transcription factor that recognizes
      dehydration response elements, has been shown in Arabidopsis thaliana to play a
      crucial role in promoting the expression of drought-tolerance genes. In our
      efforts to enhance drought tolerance in wheat, the A. thaliana DREB1A gene was
      placed under control of a stress-inducible promoter from the rd29A gene and
      transferred via biolistic transformation into bread wheat. Plants expressing the
      DREB1A gene demonstrated substantial resistance to water stress in comparison
      with checks under experimental greenhouse conditions, manifested by a 10-day
      delay in wilting when water was withheld.

PMID- 15190367
TI  - Simple sequence repeat diversity in diploid and tetraploid Coffea species.
AB  - Thirty-four fluorescently labeled microsatellite markers were used to assess
      genetic diversity in a set of 30 Coffea accessions from the CENICAFE germplasm
      bank in Colombia. The plant material included one sample per accession of seven
      East African accessions representing five diploid species and 23 wild and
      cultivated tetraploid accessions of Coffea arabica from Africa, Indonesia, and
      South America. More allelic diversity was detected among the five diploid species
      than among the 23 tetraploid genotypes. The diploid species averaged 3.6
      alleles/locus and had an average polymorphism information content (PIC) value of
      0.6, whereas the wild tetraploids averaged 2.5 alleles/locus and had an average
      PIC value of 0.3 and the cultivated tetraploids (C. arabica cultivars) averaged
      1.9 alleles/locus and had an average PIC value of 0.22. Fifty-five percent of the
      alleles found in the wild tetraploids were not shared with cultivated C. arabica
      genotypes, supporting the idea that the wild tetraploid ancestors from Ethiopia
      could be used productively as a source of novel genetic variation to expand the
      gene pool of elite C. arabica germplasm.

PMID- 15190368
TI  - Evaluation of AFLPs for germplasm fingerprinting and assessment of genetic
      diversity in cultivars of tomato (Lycopersicon esculentum L.).
AB  - Cultivated tomato (L. esculentum L.) germplasm exhibits limited genetic variation
      compared with wild Lycopersicon species. Amplified fragment length polymorphism
      (AFLP) markers were used to evaluate genetic variation among 74 cultivars,
      primarily from California, and to fingerprint germplasm to determine if cultivar
      specific patterns could be obtained. All 74 cultivars were genotyped using 26
      AFLP primer combinations; of the 1092 bands scored, 102 AFLP bands (9.3%) were
      polymorphic. Pair-wise genetic similarity coefficients (Jaccard and Nei-Li) were
      calculated. Jaccard coefficients varied from 0.16 to 0.98 among cultivar pairs,
      and 72% of pair-wise comparisons exceeded 0.5. UPGMA (unweighted pair-group
      method with arithmetic averaging) clustering and principle component analysis
      revealed four main clusters, I-IV; most modern hybrid cultivars grouped in II,
      whereas most vintage cultivars grouped in I. Clusters III and IV contained three
      and two cultivars, respectively. Some groups of cultivars closely related by
      pedigree exhibited high bootstrap values, but lower values (<50%) were obtained
      for cluster II and its four subgroups. Unique fingerprints for all 74 cultivars
      were obtained by a minimum of seven AFLP primer pairs, despite inclusion of some
      closely related cultivars. This study demonstrated that AFLP markers are
      effective for obtaining unique fingerprints of, and assessing genetic diversity
      among, tomato cultivars.

PMID- 15190369
TI  - Gypsy-like retrotransposons in Pyrenophora: an abundant and informative class of
      molecular markers.
AB  - This paper describes the development of S-SAP (sequence-specific amplified
      polymorphism) using a primer derived from the LTR (long terminal repeat) of the
      Pyggy retrotransposon isolated from Pyrenophora graminea. Fragments were
      amplified by S-SAP from different Pyrenophora spp., indicating the presence of
      Pyggy-like sequences in these genomes. The bands were highly polymorphic between
      isolates and the number of bands differed by as much as 10-fold between species,
      demonstrating the potential of this method for genetic analysis in fungi. The
      phylogenetic relationship among the isolates as deduced using S-SAP data is
      presented, and shows evidence of genetic exchange between P. graminea and P.
      teres.

PMID- 15190370
TI  - Phylogeny and expression of paralogous and orthologous sulphate transporter genes
      in diploid and hexaploid wheats.
AB  - Twelve genes encoding two closely related subtypes (ST1.1a and ST1.1b) of a
      sulphate transporter have been identified in the diploid wheats Aegilops
      tauschii, Triticum urartu, and Aegilops speltoides, as well as the hexaploid
      Triticum aestivum. Based on phylogenetic comparisons with other plant sulphate
      transporters, the ST1.1a and 1.1b subtypes aligned with group 1 of the plant
      sulphate transporter gene family. The exon-intron structure was conserved within
      the ST1.1a or ST1.1b genes; however, substantial variability in intron sequences
      existed between the two types. The high overall sequence similarity indicated
      that ST1.1b represented a duplication of the ST1.1a gene, which must have
      occurred before the evolution of the ancestral diploid wheat progenitor. In
      contrast with the close relationship of the T. urartu and Ae. tauschii sequences
      to the corresponding A and D genome sequences of T. aestivum, the divergence
      between the Ae. speltoides sequences and the B genome sequences suggested that
      the B genome ST1.1a gene has been modified by recombination. Transcript analysis
      revealed predominant expression of the ST1.1a type and an influence of sulphur
      availability on the level of expression.

PMID- 15190371
TI  - Molecular architecture and rates of DNA substitutions of the mitochondrial
      control region of cracid birds.
AB  - The control region (CR) plays an important role in replication and transcription
      in the mitochondrial genome. Its supposedly high rate of DNA substitution makes
      it a suitable marker for studies of population and closely related species. Three
      domains can be identified in CR, each having its own characteristics regarding
      base composition, pattern of variability and rate of DNA substitution. We
      sequenced the complete CR for 27 cracids, including all 11 genera to characterize
      its molecular organization, describe patterns of DNA substitution along the gene,
      and estimate absolute rates of DNA substitution. Our results show that cracid CR
      organization and patterns of DNA substitution are typical of other birds.
      Conserved blocks C and B, fused CSB2/3, and a putative segment for bidirectional
      replication not usually present in birds were identified in cracids. We also
      suggest a new delimitation for domains to allow better comparisons among CRs at
      different taxonomic ranking. Our estimates of absolute rates of DNA substitution
      show that, in general, CR evolves at a rate slower than that of two protein
      coding genes (CR, 0.14%-0.3%; ND2, 0.37%-0.47%; and cytochrome b, 0.29%-0.35% per
      site per million years within genera). Within CR domains, rates within genera
      ranged from 0.05% to 0.8% per site per million years.

PMID- 15190372
TI  - Heterogeneity of ITS1 sequences in the biting midge Culicoides impunctatus
      (Goetghebuer) suggests a population in Argyll, Scotland, may be genetically
      distinct.
AB  - Ribosomal DNA (rDNA) internal transcribed spacer 1 (ITS1) is a useful genomic
      region for understanding evolutionary and genetic relationships. In the current
      study, variation in ITS1 from eight Culicoides species was analysed by PCR, DNA
      restriction analysis, cloning, and sequencing. ITS1 variants were essentially
      homogenized within a species, as sequences were identical or closely related.
      However, Culicoides impunctatus ITS1 sequences derived from one (Argyll) of five
      populations contained considerable genomic diversity. The secondary structure of
      each ITS1 was computed. The structure aided the production of an accurate
      alignment and the identification of a large indel. A phylogenetic analysis was
      performed. Some of the sequences from the diverse Argyll C. impunctatus
      population were more related to Culicoides imicola, a vector of animal pathogens
      in the Old World, than they were to the other C. impunctatus sequences. Thus, the
      rDNA ITS1 regions of individuals in the Argyll C. impunctatus population were not
      conforming to the general theory of rDNA homogenization through molecular drive.

PMID- 15190373
TI  - DNA-Feulgen cytophotometric determination of genome size for the freshwater
      invading copepod Eurytemora affinis.
AB  - Variation in nuclear DNA content within some eukaryotic species is well
      documented, but causes and consequences of such variation remain unclear. Here we
      report genome size of an estuarine and salt-marsh calanoid copepod, Eurytemora
      affinis, which has recently invaded inland freshwater habitats independently and
      repeatedly in North America, Europe, and Asia. Adults and embryos of E. affinis
      from the St. Lawrence River drainage were examined for somatic cell DNA content
      and the presence or absence of embryonic chromatin diminution, using Feulgen-DNA
      cytophotometry to determine a diploid or 2C genome size of 0.6-0.7 pg DNA/cell.
      The majority of somatic cell nuclei, however, have twice this DNA content (1.3
      pg/nucleus) in all of the adults examined and possibly represent a population of
      cells arrested at the G2 stage of the cell cycle or associated with some degree
      of endopolyploidy. Both suggestions contradict assumptions that DNA replication
      does not occur in adult tissues during the determinate growth characteristic of
      copepods. Absence of germ cell nuclei with markedly elevated DNA values, commonly
      found for species of cyclopoid copepods that show chromatin diminution, indicates
      that E. affinis lacks this trait. The small genome size and presumed absence of
      chromatin diminution increase the potential utility of E. affinis as a model for
      genomic studies on mechanisms of adaptation during freshwater invasions.

PMID- 15190374
TI  - Paradoxical relationship between protein content and nucleolar activity in
      mammalian cardiomyocytes.
AB  - It was recently demonstrated that polyploidization of the avian myocardium is
      associated with a reduction of cardiac aerobic capacity evaluated by the heart
      mass to body mass ratio (heart index). To investigate possible cellular
      correlates of polyploidization, the protein content and nucleolar activity per
      cell and per genome were examined by image cytometry in 21 mammalian species,
      differing in the degree of heart polyploidization and heart index. We found that
      average cardiomyocyte ploidy level correlates negatively with the animal heart
      index (r = -0.75, p < 10(-4)), i.e., the large heart of athletic mammals is
      polyploidized to a lesser degree than the relatively smaller heart of sedentary
      species, which confirms the picture observed in birds. The protein content per
      genome decreased with the elevation of cardiomyocyte ploidy level. This inverse
      correlation was especially pronounced with the removed effect of body mass (r = 
      0.79, p < 10(-4)). Surprisingly, these changes were accompanied by the increase
      of nucleolar activity per genome (r = 0.61, p < 10(-3)). In the two species, for
      which the microarray gene expression data were available (human and mouse), this
      increase was paralleled by the elevated expression of ribosomal protein genes
      (but there was no increase in the expression of tissue-specific genes). Thus, in
      the polyploid cardiomyocytes there is a misbalance between protein content per
      genome and ribosome biogenesis. The reduction of protein content (per genome) of
      polyploid cardio my ocytes should further curtail heart functionality (in
      addition to reduction of heart index), because it is known that cardio myocyte
      protein content consists of more than 90% contractile proteins. This finding
      makes doubtful a widespread notion that polyploidization is necessary for cell
      function. Because somatic polyploidization is associated with stressful
      conditions and impaired energetics, we suppose that additional genomes can serve
      for cell regeneration and as a defense against oxidative damage in the organs
      that work at the limit of their metabolic capacity.

PMID- 15190375
TI  - Diversification within grapevine cultivars goes through chimeric states.
AB  - Vitis vinifera 'Pinot' clones were analysed at 50 microsatellite loci to assess
      intravarietal genetic diversity. When analysing leaf tissue DNAs, polymorphism
      mainly resulted from the appearance of a third allele when two were expected for
      heterozygous loci in a diploid species. The sequencing of the three
      microsatellite alleles at two loci has confirmed their simultaneous presence in
      the leaf tissues. A hypothesis explaining the triallelic profiles at a locus is
      the presence of a periclinal chimera meristem structure, in which genetically
      different cell layers coexist. The periclinal chimeric state of two Vitis
      vinifera 'Pinot gris' clones was confirmed by splitting and analysing the
      genotypes resulting from L1 and L2 cell layers in progeny derived from self
      fertilization, in root tissues, and in plants regenerated from somatic
      embryogenesis. Prevalence of chimerism in polymorphic clones observed in a
      collection of 145 accessions belonging to 'Pinot gris', 'Pinot noir', Pinot
      blanc', 'Pinot meunier', and 'Pinot moure' cultivars was demonstrated. The
      accumulation of somatic mutations and cell layer rearrangements allowed us to
      deduce the relationships between the various genotypes and to open a way for
      understanding the diversification process and the phylogeny in the 'Pinot' group.

PMID- 15190376
TI  - The utility of the nontranscribed spacer of 5S rDNA units grouped into unit
      classes assigned to haplomes - a test on cultivated wheat and wheat progenitors.
AB  - Data is presented on the evolutionary dynamics of non-transcribed spacers (NTSs)
      of 5S rRNA genes in some diploid and polyploid Triticum and Aegilops species.
      FISH experiments with probes representing different unit classes revealed
      presence and (or) absence of these sequences in genomes or separate chromosomes
      of the species. Among the three diploid species only Aegilops speltoides has all
      of the different unit classes in ribosomal clusters as detected by the probes.
      Triticum urartu does not have the long D1 signals and Aegilops tauschii does not
      have the long A1 signals. Both polyploids possess all types of sequences, but
      because of genome rearrangements after polyploidization there is significant
      repatterning of single different rDNA unit classes in chromosomal positions when
      compared with those in diploid progenitors. Additional refined work is needed to
      ascertain if the sequences in the polyploids are mixed or are located in mini
      clusters in close proximity to each other. Mantel tests for association between
      the presence of the FISH signals of the A, B, and D genomes together and
      separately with the unit class data of the material, i.e., the probes used in
      FISH, indicated that all signals were associated with their respective probe
      material, but that there was no association of the unit classes found and the
      signals to each haplome. All combinations of the partial Mantel tests, e.g.,
      between the A and B haplomes while controlling the effect of the all probes
      signals, with correlations ranging from 0.48 to 0.79 were all significant.
      Principal coordinate analysis showed that the signals of most unit class specific
      probes were more or less equally distant except for the long (S1 and short G1
      signals, which were not different, and that the short A1 signals were closely
      related to the former two, whereas the signals of the long G1 were even less
      related.

PMID- 15190377
TI  - Analysis of Drosophila proboscipedia mutant alleles.
AB  - Proboscipedia (PB) is a HOX protein required for adult maxillary palp and
      proboscis formation. To identify domains of PB important for function, 21 pb
      point mutant alleles were sequenced. Twelve pb alleles had DNA sequence changes
      that encode an altered PB protein product. The DNA sequence changes of these 12
      alleles fell into 2 categories: missense alleles that effect the PB homeodomain
      (HD), and nonsense or frameshift alleles that result in C-terminal truncations of
      the PB protein. The phenotypic analysis of the pb homeobox missense alleles
      suggests that the PB HD is required for maxillary palp and proboscis development
      and pb - Sex combs reduced (Scr) genetic interaction. The phenotypic analysis of
      the pb nonsense or frameshift alleles suggests that the C-terminus is an
      important region required for maxillary palp and proboscis development and pb-Scr
      genetic interaction. PB and SCR do not interact directly with one another in a co
      immunoprecipitation assay and in a yeast two-hybrid analysis, which suggests the
      pb-Scr genetic interaction is not mediated by a direct interaction between PB and
      SCR.

PMID- 15190378
TI  - Ancestral genome duplication in rice.
AB  - The recent availability of the pseudochromosome sequences of rice allows for the
      first time the investigation of the extent of intra-genomic duplications on a
      large scale in this agronomically important species. Using a dot-matrix plotter
      as a tool to display pairwise comparisons of ordered predicted coding sequences
      along rice pseudochromosomes, we found that the rice genome contains extensive
      chromosomal duplications accounting for 53% of the available sequences. The size
      of duplicated blocks is considerably larger than previously reported. In the rice
      genome, a duplicated block size of >1 Mb appears to be the rule and not the
      exception. Comparative mapping has shown high genetic colinearity among
      chromosomes of cereals, promoting rice as a model for studying grass genomes.
      Further comparative genome analysis should allow the study of the conservation
      and evolution of these duplication events in other important cereals such as rye,
      barley, and wheat.

PMID- 15190379
TI  - Comment on "AFLP data and the origins of domesticated crops".
AB  - We review some concepts and methods of handling and using DNA fingerprinting in
      phylogenetic analyses related to crop domestication. Particular reference is made
      to AFLP markers and mode and place of einkorn, barley, and tetraploid wheat
      domestication in the Neolithic by human communities in the Fertile Crescent. The
      reconsideration of AFLP databases of domesticated and wild lines demonstrates
      that phylogenetic tree topologies, originally described for the three species,
      match closely the new results obtained by principle coordinate analyse.

PMID- 15190381
TI  - GERD 2003: issues from the past and a consensus for the future.
AB  - Gastroesophageal reflux disease (GERD) has evolved from a scarcely reported,
      little understood disease process just a century ago to a now highly prevalent
      disease with up to 25% of the population complaining of symptoms of reflux.
      Throughout history attempts have been made to delineate the esophagus and related
      pathologies, but it has not been until relatively recently that enough has been
      understood about its screening, diagnosis and treatment to make a substantial
      impact on sufferers. Although the use of antacids and thereafter histamine 2
      receptor antagonists dramatically improved the management of GERD, it was the
      advent of the proton pump inhibitor (PPI) class of drugs that revolutionized
      medical care. Although the relationship of hiatus hernia to reflux was well
      accepted, the modest results of open fundoplication fell into further disregard
      given the efficacy of PPIs. The PPIs are currently the most effective form of
      therapy and are equivalent on a milligram for milligram basis. While currently no
      novel drugs or devices are of proven efficacy for GERD, the development of an
      acid-suppressive agent of equal efficiency to a PPI but with a more rapid onset
      of action and a greater duration of effectiveness would be of particular clinical
      utility for the future.

PMID- 15190382
TI  - The basis of differentiation of PPIs.
AB  - Proton pump inhibitors (PPIs) were initially believed to block acid secretion
      permanently. Evidence that acid secretion returned after administration of the
      compounds led to investigations of the mechanism of this phenomenon. Data showing
      that, after omeprazole administration, acid secretion returned in less time than
      the half-life of the pump suggested that more than only new pump synthesis may
      play a role in acid recovery. In contrast, experiments with pantoprazole revealed
      a much longer time to the return of acid secretion than that seen with
      omeprazole, similar to that predicted from dependence on pump protein turnover.
      These data suggested that differences in the binding sites of the agents could
      explain differences in the time to acid return and shed light on the mechanisms.
      While omeprazole binds at cysteines 813 and 892, only cysteine 813 is involved in
      its inhibitory activity. Pantoprazole also binds at cysteine 813, but
      additionally at cysteine 822. Both of these sites are located in the proton
      transport pathway, though cysteine 822 is found deeper in the membrane domain
      than cysteine 813. Experiments in vitro and in vivo have shown that the reducing
      agent glutathione reverses the acid-inhibitory activity of omeprazole to a much
      greater degree than the activity of pantoprazole, most likely because glutathione
      cannot access cysteine 822. Thus, while the omeprazole-pump binding can be more
      easily reversed, pantoprazole-induced acid inhibition is overcome only by de novo
      pump synthesis. Clinically, this may lead to a longer duration of action and
      therapeutic advantages for pantoprazole. This has also been demonstrated in an
      analysis comparing pantoprazole to both omeprazoles, with pantoprazole showing
      superior relief of nighttime heartburn in patients with GERD.

PMID- 15190383
TI  - Look--but also listen! ReQuest: A new dimension-oriented GERD symptom scale.
AB  - The symptom spectrum of gastroesophageal reflux disease (GERD) is much wider than
      is commonly believed, and in about half the patients endoscopic examination is
      negative. The role of endoscopy to assess response to treatment is therefore much
      reduced in GERD. Assessment of symptoms is becoming increasingly important, so
      different outcome measures are required. The Reflux Questionnaire ReQuest was
      thus designed as a brief, effective and robust method of tracking and quantifying
      GERD symptoms during treatment. It comprises seven dimensions: general well
      being, acid complaints, upper abdominal/stomach complaints, lower
      abdominal/digestive complaints, nausea, sleep disturbances and other complaints.
      In the short version of ReQuest the symptom burden of each dimension is measured
      by its frequency and intensity (except general well-being, for which only the
      intensity was determined). The long version also includes 67 symptom descriptions
      that constitute the dimensions (except general well-being). The rigorous
      validation process included clinical trial evaluation and statistical assessment
      of the findings. Important measures of the instrument, such as internal
      consistency, test/ retest reliability, construct validity and the responsiveness
      to changes during treatment, among others, all fulfilled or exceeded
      requirements, thereby demonstrating the accuracy of the instrument. ReQuest meets
      the criteria set by regulatory authorities and serves as the primary outcome
      measure for symptom assessment in future clinical trials of current and new
      treatments.

PMID- 15190384
TI  - Understanding NSAID-PPI-COX-2 interrelationships.
AB  - Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used to treat arthritis
      but are associated with adverse gastrointestinal events. While the selective COX
      2 inhibitors show fewer gastrointestinal complications than NSAIDs, they may not
      be suitable for all patients and one of them has been associated with serious
      thrombotic cardiovascular events. Furthermore, many arthritis patients are at
      high risk of coronary artery disease and take low-dose aspirin, which is also
      associated with adverse gastrointestinal events. Proton pump inhibitor (PPI)
      therapy has been shown to be effective in reducing the risk of gastrointestinal
      complications in this patient population. Recent randomized clinical trials have
      also shown that pantoprazole therapy is effective in the healing of NSAID-induced
      gastrointestinal damage. Several studies have also demonstrated that pantoprazole
      is effective in preventing the development of gastrointestinal lesions in
      patients with continuous NSAID intake. The use of PPIs in combination with
      nonselective NSAIDs has also been found to be beneficial in patients at high risk
      for rebleeding and reduces the incidence of dyspepsia. Finally, the combination
      of a COX-2 inhibitor with a PPI has shown promise in patients with previous NSAID
      related gastrointestinal complications who are at high risk for reinjury.

PMID- 15190385
TI  - The soluble tumor necrosis factor receptor etanercept: a new strategy for the
      treatment of autoimmune rheumatic disease.
AB  - Rheumatoid arthritis is a severe, debilitating condition for which existing
      therapies are of limited efficacy. In addition, the most common structure of
      treatment for patients with rheumatoid arthritis has recently been called into
      question, and many believe it should be reversed so that stronger treatments are
      administered earlier in the progression of the disease. Pivotal to the changes in
      rheumatoid arthritis treatment is the introduction of the pro-inflammatory tumor
      necrosis factor (TNF) antagonists. Overexpression of cytokines in inflamed joints
      plays an important role in joint inflammation and tissue damage, and the place of
      cytokines in the pathology of rheumatoid arthritis has offered hope that their
      antagonism will reduce symptoms and slow the advancement of the condition. With
      this in mind, etanercept, a fully human soluble TNF receptor fusion protein, was
      developed. The potency of this novel drug in blocking TNF activity has been shown
      in animal models and in clinical trials. The latter have demonstrated a positive
      safety profile and efficacy in reducing pain and the number of tender and swollen
      joints in rheumatoid arthritis patients. The effects of etanercept have also been
      observed soon after administration and have been sustained over several years.
      Etanercept has offered encouragement for those seeking new, more efficacious and
      less toxic methods of treating rheumatoid arthritis in children, adults and the
      elderly. In addition to the treatment of adult and juvenile rheumatoid arthritis,
      etanercept has also demonstrated utility in treating ankylosing spondylitis and
      psoriatic arthritis.

PMID- 15190386
TI  - Adverse effects of new antiepileptic drugs.
AB  - Starting with phenobarbital in the 1900s, it took almost 70-80 years to introduce
      old-generation agents for the treatment of epilepsy. Then, in eleven years, nine
      more new antiepileptic drugs were added to the armamentarium. These drugs produce
      a nearly 40-50% decrease in seizure incidence in refractory patients, but few
      patients have been able to achieve complete freedom from seizures. So the search
      for more effective drugs with minimal adverse effect profiles will continue.
      Although the new antiepileptic drugs do not demonstrate a superior efficacy
      compared to the older ones, they do offer some advantages in terms of
      tolerability, fewer drug interactions and simpler pharmacokinetics. However, our
      knowledge concerning their safety profiles can not yet be considered adequate due
      to the relatively short time these drugs have been on the market and to the
      limited number of patients exposed to them. The fact that the serious side
      effects of felbamate and vigabatrine appeared late after marketing should be
      taken as an important lesson because it implies the potential for unknown side
      effects at any time during treatment. Antiepileptic drug treatment should begin
      with diagnosis of the seizure and epileptic syndrome, followed by selection of
      the drug most appropriate for treatment of the individual patient, and continued
      with monitoring of not only the seizures but the adverse effect profile as well.

PMID- 15190387
TI  - Solifenacin: treatment of overactive bladder.
AB  - An investigational muscarinic antagonist, solifenacin is indicated in the
      treatment of overactive bladder. Solifenacin works to decrease bladder activity
      by inhibiting contraction of the smooth muscle wall surrounding the bladder.
      Micturition normally occurs following stimulation of acetylcholine muscarinic M3
      receptors within the detrusor muscle wall. As a potent and selective muscarinic
      receptor antagonist, solifenacin acts specifically at the M3 receptor site.
      Initial data have shown solifenacin to be more bladder-selective than its
      predecessors. It is this selective mode of action that gives solifenacin the
      potential to limit commonly experienced anticholinergic side effects. These
      developments could translate into higher patient compliance with the potential
      for better long-term results. Solifenacin has been shown to have a favorable
      risk/benefit ratio. At a once-daily oral dose of 5 mg/day, clinical data have
      shown solifenacin to be effective in reducing the symptoms of overactive bladder,
      with an incidence of dry mouth comparable to that associated with placebo.
      Results from phase I, II and III clinical trials have shown solifenacin to have a
      promising efficacy and safety profile for the treatment of overactive bladder.
      Comparative clinical trials are now needed to determine whether these initial
      results can prove solifenacin to be more beneficial than other commonly
      administered antimuscarinics.

PMID- 15190388
TI  - Role of dopamine D3 receptors in the addictive properties of ethanol.
AB  - After the cloning of the dopamine D(1) and D(2) receptors (1-3), several
      additional dopamine receptors were identified. These new subtypes included the
      D(3) and D(4) receptors, which are similar to D(2), and the D(5) receptor, which
      is similar to D(1) (4-6). Although most studies have focused on the role of
      dopamine D(1) and D(2) receptors in mediating the addictive liability of drugs,
      the lack of selective pharmacological tools has significantly hampered this
      particular field of research. In contrast, recent studies using selective
      competitive antagonists have shown that the dopamine D(3) receptor is involved in
      drug-seeking behavior. The present review is intended to highlight a new,
      promising area in alcohol research that focuses on the role of the dopamine D(3)
      receptor in the addictive properties of ethanol.

PMID- 15190389
TI  - Omalizumab: an effective anti-IgE treatment for allergic asthma and rhinitis.
AB  - IgE plays a crucial role in the pathophysiology of asthma and allergic rhinitis.
      Omalizumab is a humanized anti-IgE monoclonal antibody that binds to free IgE and
      prevents its binding to specific receptors on the surface of cells, thus
      preventing the release of immune mediators. Treatment with omalizumab in patients
      with asthma or allergic rhinitis results in a rapid and pronounced decrease in
      serum IgE levels that is correlated with an improvement in the severity of
      symptoms and in the quality of life of patients. Omalizumab has a good safety
      profile, with only mild to intermediate drug-related adverse events.

PMID- 15190393
TI  - Clinical presentation and prevalence of spontaneous bacterial peritonitis in
      patients with cryptogenic cirrhosis and features of metabolic syndrome.
AB  - BACKGROUND: Nonalcoholic steatohepatitis (NASH) may progress to cirrhosis. The
      prevalence and clinical relevance that spontaneous bacterial peritonitis may have
      in complicating ascites due to NASH-related cirrhosis have yet to be defined.
      METHODS: Among 611 cases of cirrhosis-associated ascites, 45 patients with
      cryptogenic cirrhosis were retrospectively identified. Of these, 36 patients and
      a control group of subjects with viral- associated ascites were followed up and
      compared in a case control study. Information on the onset of ascites, with or
      without spontaneous bacterial peritonitis, history of risk factors for
      multimetabolic syndrome, and serological and ascitic laboratory data were
      compared between groups. RESULTS: Spontaneous bacterial peritonitis occurred
      significantly more often in patients with cryptogenic cirrhosis than in equally
      symptomatic viral controls. The prevalence of obesity, diabetes and spontaneous
      bacterial peritonitis was significantly higher in patients with cryptogenic
      cirrhosis. Although liver function was similar in both groups, cryptogenic
      cirrhosis patients had lower aminotransferase levels. Multivariate analysis
      identified diabetes, juvenile obesity and spontaneous bacterial peritonitis as
      independent factors associated with ascites due to cryptogenic cirrhosis.
      CONCLUSIONS: Features suggestive of NASH are more frequently observed in patients
      with ascites and cryptogenic cirrhosis than in age- and sex-matched ascitic
      patients with well-defined viral etiology. Ascites may be a presenting symptom of
      NASH-related cirrhosis, and affected patients have a twofold greater risk of
      spontaneous bacterial peritonitis.

PMID- 15190394
TI  - Effects of Helicobacter pylori water extract on expression of endothelial
      adhesion molecules.
AB  - The present study investigated whether Helicobacter pylori water extract induces
      the upregulation of intercellular adhesion molecule-1, vascular cell adhesion
      molecule-1 and E-selectin on human umbilical vein endothelial cells, using an
      ELISA. The nature of the substances mediating this upregulation was also
      analyzed. H pylori water extract derived from type strain (NCTC 11637)
      significantly upregulated intercellular adhesion molecule-1, vascular cell
      adhesion molecule-1 and E-selectin to the same extent as interleukin-1.
      Treatments with extracts from clinical strains showed no significant increases in
      expression of these adhesion molecules. In a fractionation study, approximately 7
      kDa fraction showed peak activity. This activity was tolerant to heating and
      trypsin digestion. These results indicate that H pylori water extract contains
      water-soluble, low-molecular, nonprotein substances which induce upregulation of
      adhesion molecules on human umbilical vein endothelial cells, suggesting that
      products of H pylori may elicit gastric mucosal inflammation by promoting
      expression of endothelial adhesion molecules.

PMID- 15190395
TI  - Hemochromatosis patients as voluntary blood donors.
AB  - The present study was designed to investigate hemochromatosis patients'
      suitability as blood donors as well as their perceptions and experience with the
      current public donation system. Participants were gathered from a list of current
      hemochromatosis patients (n=120) and members of the Canadian Hemochromatosis
      Society (n=1000). Of the 1120 surveys mailed out to these groups, 801 surveys
      were returned completed. The sample respondents had a mean age of 57.44 years
      (SD=12.73; range 19 to 87 years), and 57% were men. It was found that 20% (160)
      of the respondents have donated blood since their diagnosis; however, only 12% of
      the respondents indicated that they use voluntary blood donation as a means of
      maintaining their iron levels. Forty per cent of the respondents indicated that
      they had been refused from voluntary donation. Despite the fact that in May 2001
      the Canadian Blood Services, in collaboration with the Canadian Hemochromatosis
      Society, began a promotion campaign to encourage hemochromatosis patients to
      become voluntary blood donors, the present study found that 15% of the
      respondents reported having been refused from the voluntary blood donation
      service due to the diagnosis of hemochromatosis. With respect to quality of life,
      it was found that individuals who donate blood were generally healthier with
      respect to physical functioning and bodily pain, however, these findings may
      indicate that hemochromatosis patients who are healthier are better able to
      donate at public blood banks, rather than that voluntary blood donation has an
      effect on the donors' physical functioning over phlebotomy clinic users. These
      study findings suggest that although there may be other medical factors limiting
      individuals from donating, hemochromatosis patients are interested in being
      voluntary blood donors and this potential resource is currently under-used.

PMID- 15190396
TI  - Injection of botulinum toxin A to the upper esophageal sphincter for
      oropharyngeal dysphagia in two patients with inclusion body myositis.
AB  - Inclusion body myositis (IBM) is a progressive degenerative skeletal muscle
      disease leading to weakening and atrophy of both proximal and distal muscles.
      Dysphagia is reported in up to 86% of IBM patients. Surgical cricopharyngeal
      myotomy may be effective for cricopharyngeal dysphagia and there is one published
      report that botulinum toxin A, injected into the cricopharyngeus muscle using a
      hypopharyngoscope under general anesthesia, relieved IBM-associated dysphagia.
      This report presents the first documentation of botulinum toxin A injection into
      the upper esophageal sphincter using a flexible esophagogastroduodenoscope under
      conscious sedation, to reduce upper esophageal sphincter pressure and
      successfully alleviate oropharyngeal dysphagia in two IBM patients.

PMID- 15190397
TI  - Routine second look endoscopy: ineffective, costly and potentially misleading.
AB  - Despite the best medical and endoscopic efforts, some patients with nonvariceal
      upper gastrointestinal bleeding suffer recurrences. Because high risk stigmata
      (visible vessels, active bleeders and adherent clots) often persist despite
      apparently successful initial hemostasis and have a variable natural history, it
      would seem reasonable to at least consider a routine second look endoscopy.
      However, a review of the literature revealed six randomized trials that, in
      aggregate, do not support such a strategy. In fact, a second look does not appear
      to be effective and is associated with an increased number of procedures,
      treatment sessions and possibly retreatment-related complications. In addition,
      the cointerventions in these trials are already out of date and the potential
      absolute risk reductions are low when a second look is used with intravenous
      proton pump inhibitors and/or the application of endoscopic hemoclips or
      combination endoscopic therapy. Finally, the Forrest classification may provide
      dangerously misleading estimates of prognosis because it is being used out of
      context. This review critically analyzes routine second look endoscopy.

PMID- 15190399
TI  - Antineoplastic effects of 5-aminosalicylates and potential cancer preventive role
      in inflammatory bowel disease.

PMID- 15190398
TI  - Bacterial infections in cirrhosis.
AB  - Hospitalized patients with cirrhosis are at increased risk of developing
      bacterial infections, the most common being spontaneous bacterial peritonitis
      (SBP) and urinary tract infections. Independent predictors of the development of
      bacterial infections in hospitalized cirrhotic patients are poor liver synthetic
      function and admission for gastrointestinal hemorrhage. Short term (seven-day)
      prophylaxis with norfloxacin reduces the rate of infections and improves survival
      and should therefore be administered to all patients with cirrhosis and variceal
      hemorrhage. Cirrhotic patients who develop abdominal pain, tenderness, fever,
      renal failure or hepatic encephalopathy should undergo diagnostic paracentesis,
      and those who meet the criterion for SBP (eg, an ascites neutrophil count greater
      than 250/mm3) should receive antibiotics, preferably a third-generation
      cephalosporin. In addition to antibiotic therapy, albumin infusions have been
      shown to reduce the risk of renal failure and mortality in patients with SBP,
      particularly in those with renal dysfunction and hyperbilirubinemia at the time
      of diagnosis. Patients who recover from an episode of SBP should be given long
      term prophylaxis with norfloxacin and should be assessed for liver
      transplantation.

PMID- 15190400
TI  - The perfect way to predict the severity of acute pancreatitis: the search
      continues.

PMID- 15190401
TI  - Finally...real utility scores for hepatitis C patients!

PMID- 15190405
TI  - [A christmas gift].

PMID- 15190403
TI  - Canadian Cardiovascular Society Consensus Conference 2002: Management of heart
      disease in the elderly patient.
AB  - Cardiovascular disease is a major health issue for the elderly patient. Many
      diagnostic, therapeutic and ethical issues are specific for the the older adult
      with heart disease. The Canadian Cardiovascular Society 2002 Consensus Conference
      provides recommendations for the most frequently encountered cardiac problems in
      the elderly patient. A common theme of the recommendations is the need to apply
      the best evidence based medicine together with an assessment of frailty,
      comorbidity and quality of life. A major goal of the conference was to identify
      treatments that are not optimally used in the older patient.

PMID- 15190406
TI  - [Ross procedure - how to minimize the effects of learning curve].
AB  - The introduction of new procedures in surgery usually implies the costs of the so
      called learning curve. However patients should not suffer the negative effects of
      surgeon's learning curves. We report our results with the first 15 Ross
      procedures, a single surgeon and institution experience, and how it was possible
      to build a safe learning curve without major consequences for the patients. We
      emphasize the need for a continuous program of surgical performance assessment
      throughout the learning curve period, as was demonstrated in our series.

PMID- 15190407
TI  - [Pulmonary arterio-venous fistula: a clinical report].
AB  - A 44 years old female was admitted with previous history of several cerebral
      vascular accident (CVA). A transthoracic echocardiogram showed a patent foramen
      ovale (PFO) that was closed, under extracorporeal circulation. The patient
      remained free of symptoms for ten years. In the year 2003 she was admitted to our
      hospital with paresthesias of the left arm. The clinical evaluation led to the
      diagnosis of arteriovenous fistula (AVF) of the lung. In November 2003, the
      patient underwent right inferior lobectomy. This is a rare association of PFO
      with AVF fistula of the lung with a delayed diagnosis. The differential
      diagnosis, the surgical treatment and the most frequent complications of this
      pathology are reported and discussed.

PMID- 15190408
TI  - [Systemic vasculitis].
AB  - This paper is dedicated to a general and synthetic review of a large and
      heterogeneous group of diseases, entitled "Systemic Vasculites". Despite its
      rarity in clinical practice, they can be severe and even fatal, if a proper
      diagnosis and adequate treatment is not made. Among the several classifications,
      we have adopted the Chapel Hill classification based on its pathogenesis. As they
      are multiple entities, we will describe only the essential clinical aspects of
      the diverse vasculitis, including the diagnostic criteria of the American College
      of Rheumatology, which are very sensitive and specific. We will conclude with a
      note on the global strategy of treatment of each entity.

PMID- 15190409
TI  - [Isolated obstructive lesions of the cervical common carotid: clinical and
      surgical aspects].
AB  - Isolated lesions of the extra-thoracic common carotid arteries are unusual in
      clinical practice. Contrarily to the well known lesions of carotid bifurcation,
      its natural history is poorly understood and indications for surgical management
      are not well defined. In this paper, seven patients with isolated lesions of the
      common carotid arteries are reported, being two symptomatic (TIA's). Patients
      underwent successful surgical management. The main features of clinical
      presentation, diagnosis and surgical management are presented and discussed

PMID- 15190410
TI  - [Surgical management of Takayasu's arteritis with extensive vascular involvement
      and bilateral renal artery stenosis].
AB  - Proximal renal artery stenosis, in association with stenoses and/or aneurysms of
      aorta and its branches, suggests a Takayasu's disease and is an important,
      treatable cause of hypertension in young people. A 29-year-old black woman
      presents with systodiastolic hypertension and suprasternal and abdominal bruits.
      An aortography disclosed multiple aneurysms and stenosis of the aorta and its
      main branches, and bilateral stenosis of renal arteries. The patient underwent an
      unusual and well-succeeded surgical procedure consisting in the creation of a
      "ventral aorta", a bypass from the ascending aorta down to the aortic
      bifurcation, and revascularization of both kidneys. Takayasu's disease frequently
      courses with extensive involvement of vasculature and bilateral renal stenosis.
      Renovascular hypertension is a major complication, contributing to the high
      mortality of this disease. Renal revascularization plays an important role in the
      modification of the natural history of Takayasu's disease and is essential for
      long-term survival and prevention of ischaemic renal failure.

PMID- 15190411
TI  - [Images in medicine: cocaine-induced peripheral vascular lesions].

PMID- 15190412
TI  - [Grawitz tumor with invasion of the inferior vena cava and right atrium: surgical
      management with a multidisciplinary team].
AB  - In this paper, the clinical condition of a 56 year old male patient is reported,
      with the diagnosis of renal cell carcinoma, complicated by a tumoral thrombus,
      extended from the renal vein into the vena cava and right atrium, who underwent
      surgical treatment. The operation consisted in the radical nephrectomy associated
      to the vena caval thrombectomy, under extracorporeal circulation, utilizing a
      multidisciplinary team composed by urologists, vascular and cardio-thoracic
      surgeons. The main features related to the diagnosis and surgical management of
      this case are described and discussed, according to data taken from the most
      recent publications of the literature on the subject.

PMID- 15190414
TI  - Leukemia-like syndrome in Balb/c mice infected with the lymphotropic gamma
      herpesvirus MHV-Sumava: an analogy to EBV infection.
AB  - Based on our previous observation that primary infection with the murine gamma
      herpesvirus (MHV) isolate Sumava (MHV-SU) undergoes a lymphoproliferative phase
      resembling to Epstein-Barr virus (EBV) induced infectious mononucleosis (IM), we
      evaluated white blood cell (WBC) counts at late stages following MHV-SU
      infection. In consequence of intranasal inoculation with MHV-SU a leukemia-like
      syndrome in Balb/c mice developed. The syndrome in question was accompanied with
      significant splenomegaly; in the peripheral blood leukocytosis (from 8 x 10(4) to
      5 x 10(5) leukocytes/microl) and a high percentage of atypical lymphocytes (60
      80%) was found. Presented results are bringing further evidence for
      lymphoproliferative effect of MHV and point at analogic course of MHV-SU and EBV
      infections.

PMID- 15190413
TI  - [Mycotic rupture of the reno-external iliac artery anastomosi following kidney
      transplantation].
AB  - Two clinical cases of an unusual complication of the renal transplantation are
      reported, consisting in the infection of the arterial wall by fungi of the
      species Candida Albicans and Aspergillus, which caused acute ruptures of the
      external iliac artery and hypovolemic shock. The main features of the
      pathogenesis of the infection, its diagnosis, management and prevention are
      subjected to analysis and discussion.

PMID- 15190415
TI  - Amplification and overexpression of HER-2/neu in invasive ductal carcinomas of
      the pancreas and pancreatic intraepithelial neoplasms and the relationship to the
      expression of p21(WAF1/CIP1).
AB  - Overexpression of HER-2/neu was described in pancreatic intraepithelial neoplasia
      (PanIN) and in invasive ductal adenocarcinoma of pancreas in a variable
      proportion of cases. The effects of HER-2/neu overexpression on mitogenic
      signalling and cell cycle progression were studied in breast luminal epithelial
      cells and mitogen activated protein kinase-dependent induction of p21(WAF1/CIP1)
      was found to be necessary for G1 phase progression. Overexpression of
      p21(WAF1/CIP1) was described as an early event in the development of PanIN by
      Biankin et al. (2001) and this finding was supported by our previous study that,
      moreover, did not confirm the possible role of activating K-ras mutations in the
      induction of p21(WAF1/CIP1) overexpression. Relationship between p21(WAF1/CIP1)
      expression and HER-2/neu status in PanIN lesions and ductal adenocarcinoma of the
      pancreas was investigated in our study. Expression levels of p21(WAF1/CIP1) and
      HER-2/neu were examined imunohistochemically and the amplification of HER-2/neu
      gene was evaluated by fluorescence in situ hybridisation in HER-2/neu
      overexpressing adenocarcinomas. Fourty nine pancreatic resection specimens from
      patients with invasive adenocarcinoma were included into the study. A large
      spectrum of PanIN lesions adjacent to the structures of infiltrating
      adenocarcinoma was also examined. The possible role of HER-2/neu in an induction
      of p21(WAF1/CIP1) overexpression was not confirmed and p21(WAF1/CIP1)
      overexpression seems to be HER-2/neu independent in pancreatic ductal
      adenocarcinoma according to our results. Increasing levels of HER-2/neu
      expression were demonstrated in pancreatic intraepithelial neoplasia and in
      18.75% of pancreatic adenocarcinoma. The only 2 from 9 HER-2/neu overexpressing
      adenocarcinomas showed the amplification of HER-2/neu gene. Based on these
      results, the overexpression of HER-2/neu in pancreatic adenocarcinoma seems to be
      a result of increased transcription rather than gene amplification. Therefore HER
      2/neu represents a good target for therapy of pancreatic adenocarcinoma only in
      isolated cases.

PMID- 15190416
TI  - Proto-oncogene c-myc in uterine cervix carcinogenesis.
AB  - The biological behaviour of precancerous and early stages of uterine cervix
      carcinoma is not always easily predictable. It is important therefore to identify
      new biological markers which could more reliably predict the evolution of the
      disease or provide important therapeutic targets. To establish the role of the
      proto-oncogene c-myc in uterine cervix tumorigenesis, we examined 96 tissue
      samples of different degrees of cervical intraepithelial neoplasia (CIN1-CIN 3),
      in situ (CIS) or invasive squamous cell carcinoma (ISCC) and control cases.
      Indirect immunohistochemical techniques were used to detect the c-myc expression.
      Significantly higher levels of Myc protein were found in keratinocytes of high
      grade dysplasias in comparison to low-grade dysplasias and control cases. There
      was no difference between low-grade CIN and a control group of patients. The same
      significant changes between above mentioned groups were seen in surrounding
      stromal cells (fibrocytes, fibroblasts, some endothelial cells and lymphocytes).
      We confirm that expression of c-Myc protein is increased not only in uterine
      cervix cancer but also in the premalignant lesions. Problem for discussion seems
      there for whether increased Myc expression in stromal cells might create a more
      tumor promoting microenvironment which may support the growth and proliferation
      of transformed cells.

PMID- 15190417
TI  - Telomerase as a diagnostic and predictive marker in colorectal carcinoma.
AB  - In a search for molecular markers providing both informative diagnostics of
      malignant disease, and rational stratification of a therapeutic strategy to
      achieve optimal response in a given patient, we examined the possibility of using
      telomerase for this purpose in colorectal cancer. Telomerase, a ribonucleoprotein
      enzyme complex catalysing synthesis of chromosome ends (telomeres), has been
      known as an almost universal tumor marker but its predictive value has been found
      in only a limited number of malignant tumor types. Telomerase activity and
      expression of its catalytic subunit hTERT was determined in 82 surgical specimens
      from 41 patients (a sample of tumor tissue and of adjacent morphologically normal
      tissue was obtained from each patient). Telomerase activity was present in tumor
      samples from 34 (83%) patients, reaching an average value of 47.6 telomerase
      units (T.U.), while adjacent tissue specimens were either negative (in 25 (61%)
      patients), or slightly positive (in 16 (39%) patients) showing 1.5 T.U. on
      average. In tumor samples from patients without lymphatic node metastases (pN0),
      an average of 37.1 T.U was found. In contrast, in tumor samples from patients
      with lymphatic node involvement (pN1 or pN2) the average activity was
      significantly higher (60.2 T.U., p<0.05). In patients with distant metastases a
      tendency towards higher telomerase activity, although lacking statistical
      significance, could be observed. Among patients that obtained chemotherapy with 5
      fluoruracil, those with low telomerase activity showed a tendency to
      chemosensitivity. Expression of hTERT was detected not only in samples showing
      telomerase activity, but also in a considerable portion of telomerase-negative
      samples either from the tumor or the adjacent normal tissue. We demonstrate that
      some of these apparent discrepancies may be attributed to differential splicing
      of hTERT mRNA. We conclude that TRAP assay for telomerase activity is more
      informative than the common testing for hTERT expression. Telomerase activity is
      useful both as a diagnostic as well as a predictive factor in colorectal cancer.

PMID- 15190418
TI  - Antigen modulation followed by quantitative flow cytometry of B-chronic
      lymphocytic leukemia cells after treatment.
AB  - Presented study analyzed the immunophenotypic characteristics and antigen density
      of peripheral blood (PB) and bone marrow (BM) cells of 23 patients with B-chronic
      lymphocytic leukemia (B-CLL) and 10 control subjects using flow cytometry. The
      patients were subclassified into two groups. Group I formed 13 patients with B
      CLL at the time of diagnosis and group II 10 patients with B-CLL after the
      therapy but not in remission. For definition of B-CLL cells we used immunological
      marker analysis of surface markers characteristic for B-CLL pattern: CD5, CD19,
      CD20, CD23 and HLA DR and enumeration of fluorescence intensity of these markers
      given by molecular equivalent of soluble fluorochrome--MESF. In group II of B-CLL
      patients, who were already treated, in PB and BM somehow lower MESF values for
      CD19, CD20 and CD23 markers and higher MESF values for CD5 marker (in PB and BM)
      than in group I patients have been detected. The MESF level of HLA DR marker was
      little higher in group II than in group I B-CLL patients. However in PB and BM
      the percentage expression of HLA DR and CD19 markers in both patients groups was
      approximately the same. The values of HLA DR, CD19, CD20, CD23 and CD5 markers (%
      expression and MESF values) in both patients groups with B-CLL were significantly
      higher versus controls (p<0.001 resp. p<0.01) even in PB and BM. In conclusion,
      in our study we observed that the patients with B-CLL after therapy (group II)
      had similar or a little smaller (except CD5) but nonsignificantly decreased
      expression level of markers characteristic for B-CLL, but the MESF values of some
      of them (CD19, CD23) were significantly (p<0.05) decreased when compared with
      untreated B-CLL patients (group I). The determination of antigen density (MESF
      values) may be an important marker to characterize the leukemic cells. Our
      results showed that chemotherapy did not influence in a significant level the
      antigen modulation of B-CLL cells, however, could influence MESF values of some
      characteristic markers. Quantitative analysis of some markers in B-CLL cells
      seems to offer valuable information concerning possible influence of some
      chemotherapeutics on antigen equipment of leukemic cells.

PMID- 15190419
TI  - Predictive value of SCC-Ag, CYFRA 21-1 and selected acute phase proteins in
      radiotherapy of pharyngeal and laryngeal cancer. A preliminary report.
AB  - The diagnostic sensitivity and specificity of tumor markers in head and neck
      cancers is not satisfactory. It is a stimulus for search of other biochemical
      indicators, among others determinations of acute phase proteins, helpful in head
      and neck cancers diagnostics and prognosis. In a group of 33 patients with
      squamous cell carcinoma of the pharynx and larynx (T1-4 N0-3 M0) CYFRA 21-1, SCC
      Ag and acute phase proteins such as prealbumin, albumin, alpha-1 acid
      glycoprotein, alpha-1 antytrypsin, transferrin, ceruloplasmin and C-reactive
      protein (CRP) determinations were performed before radiotherapy. Significantly
      greater area under ROC curve for CYFRA 21-1 than for SCC-Ag was found. In T3-4
      group, significantly lower albumin and higher AAG and CRP concentrations in
      comparison with T1-2 patients were observed. Multivariate analysis revealed that
      apart from tumor stage, elevated concentrations of SCC-Ag and/or CRP are
      independent unfavorable prognostic factors.

PMID- 15190420
TI  - Allogeneic peripheral blood stem cell transplantations in children--a single
      center experience.
AB  - We analyzed 30 peripheral blood stem cell transplantations (PBSCT) from 25 human
      leukocyte antigen (HLA) matched sibling donors (MSD) and 4 HLA-matched unrelated
      donors (MUD) in 29 patients, done between November 1996 and March 2003. Patients
      aged 3 to 17 years underwent allogeneic PBSCT for malignant (16 patients) and non
      malignant (13 patients) diseases. Sibling donors aged 3 to 23 years were given
      granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/day for 4 to 5 days.
      All but one of the 29 donors underwent one single leukapheresis for stem cell
      collection. The patients received a median of 4.2 x 10(6) CD34+ cells/kg of body
      weight, they all engrafted after a median of 13.5 days (range 10-25 days). Acute
      graft-versus-host disease (GVHD) grade II to IV developed in 11 of 26 MSD
      transplants and in all 4 patients after MUD PBSCT. Eleven of 27 evaluable
      patients experienced chronic GVHD. After a median follow-up of 662 days, 20 out
      of 29 patients (69%) are alive, three of them need systemic immunosuppression for
      chronic GVHD. Six patients experienced relapse of their underlying malignant
      disease, one of them still alive in complete remission. Two patients died of
      grade IV acute GVHD and two others due to an opportunistic infection. Based upon
      our experience, PBSCT is a feasible and safe method for both pediatric donors and
      patients. It is associated with rapid engraftment, no greater incidence of acute
      but a higher incidence of chronic GVHD as compared to bone marrow transplantation
      (BMT) and therefore suitable mainly for children suffering from malignant
      diseases.

PMID- 15190421
TI  - Differential diagnosis of benign tumors and tumor-like lesions in the spine. Own
      cases and review of the literature.
AB  - Although benign tumors and tumor-like lesions of the spine are shown in every
      orthopedic teaching book, it is often surprising how little attention is paid to
      the differential diagnosis and diagnostic investigations, respectively, since
      surgical treatment and postoperative control depends on exact diagnosis.
      Clinically the importance of this fact can not be over-emphasized. The most
      common complaint is pain, either local or radicular in nature. Bone deviations
      are diagnosed radiologically. Different types of benign bone tumors and tumor
      like lesions of the spine including osteochondroma, osteoblastoma, osteoid
      osteoma, aneurysmal bone cyst, eosinophilic granuloma, hemangioma, and giant cell
      tumor, their appearance relation to the age and location in the spine were
      reviewed and the common histologic subtypes described. Clinical, laboratory and
      histopathologic findings, radiologic inclusive MRT and scintigraphic features are
      evaluated. Diagnostic investigations including the invasive techniques of CT
      guided needle biopsy, Yamshidi needle biopsy and costotransversectomy for biopsy
      are shown. Treatment including radiation, chemotherapy and the surgical procedure
      as well as the postoperative treatment of patients with benign tumors and tumor
      like lesions of the spine are discussed.

PMID- 15190422
TI  - Combined effect of sodium selenite and campthotecin on cervical carcinoma cells.
AB  - The effects of selenite, campthotecin and their combination were investigated in
      cervical carcinoma cell line Hep-2 HeLa during 24h. The measured parameters
      included morphological changes, proliferation, oxidative stress, mitochondrial
      status, caspase-3 activation and nuclear fragmentation. Selenite at all but
      lowest concentrations inhibited cell growth and proliferation and induced cell
      death characterized by membrane blebbing, oxidative stress and mitochondrial
      damage, occurring in the absence of caspase-3 activation and nuclear
      fragmentation. Campthotecin at all concentrations induced gradual apoptosis
      including all measured morphological and molecular parameters with exception of
      oxidative stress. A combination of selenite and campthotecin induced both
      antagonistic and synergistic effects on cervical carcinoma cells. While low
      selenium concentration slightly reduced cytotoxicity and proapoptotic effects of
      campthotecin, moderate and higher concentrations of selenium enhanced them,
      changing simultaneously apoptosis into more necrosis-like death. These results
      show importance of selenium as a potential modulator and enhancer of campthotecin
      based anticancer therapy in nonovarian malignancies.

PMID- 15190423
TI  - Lung cancer risk among nonsmoking women in relation to diet and physical
      activity.
AB  - To investigate the relationship between diet, physical activity, and the risk of
      lung cancer among female nonsmokers, and to compare it with female smokers in the
      same population, we conducted a case-control study. Data collected by personal
      interviews from 419 cases and 1593 controls were analyzed using unconditional
      logistic regression. As expected, among 130 nonsmoking cases, adenocarcinoma was
      the predominant cell type (49.2%), followed by squamous cell (20.2%) and small
      cell cancers (10.5%). The corresponding figures for 289 smoking cases were 29.3%,
      27.5%, and 28.2%, respectively. Excess lung cancer risk was associated with
      consumption of red meat among nonsmokers (OR=2.20, 95%CI 1.07--4.51). Protective
      effects were observed for vegetables (OR=0.61, 95%CI 0.39--0.96), apples
      (OR=0.67, 95%CI 0.48--0.95), milk/dairy products (OR=0.54, 95%CI 0.32--0.93),
      coffee (OR=0.56, 95%CI 0.34--0.91), and wine (OR=0.69, 95%CI 0.49--0.98) among
      smokers only, and for black tea (OR=0.67, 95%CI 0.46--0.99) among nonsmokers
      only. An inverse association with risk emerged for physical exercise (or sport,
      walking), among smokers only. Some items of diet and physical activity appear to
      be important factors contributing to variation in lung cancer risk among women in
      the Czech Republic, however, their effects in nonsmokers may differ from those in
      smokers.

PMID- 15190424
TI  - Small area variations of cancer mortality in Hong Kong--the roles of health care
      and socio-economic status.
AB  - Variations of cancer incidence and cancer mortality across small areas in Hong
      Kong were explored and attempt made to link them to socio-economic differences.
      The entire Hong Kong population during the period 1984-88 was divided into 65
      small areas. The geographic distributions of incidence and mortality for ten most
      frequent sites of cancers (6 male and 4 female) were analyzed by separating the
      systematic variance from the random variance. A Poisson regression model was
      fitted for each cancer using the standardized incidence ratio (SIR) as a
      covariate for mortality. The geographic variations in SIR for the individual
      cancers were, in turn, analyzed similarly using a socio-economic score as the
      covariate. We found a statistically significant systematic variance in mortality
      for all six male cancers and three of the four female cancers studied. More than
      50% of the systematic variance of mortality for nine cancers could be explained
      by the geographic variations in incidence, suggesting that other factors, like
      the provision and/or outcomes of health care services, played a minor role. There
      were statistically significant systematic variances in SIR for all male and
      female cancers. The socio-economic score accounted for over 50% of the systematic
      variance for three cancer sites. This study illustrated an approach to explore
      underlying explanations for the geographic variations of disease incidence and
      mortality. As more aggregate exposure data become available at the small area
      level, this type of ecological analysis would help in delineating the
      contributions of various factors and guide investigators in their search for the
      etiology background of diseases.

PMID- 15190425
TI  - Extended pneumonectomy for non small cell lung cancer--should we still do it?
AB  - The aim of the study was to assess the early and late results of extended
      pneumonectomies in lung cancer patients with T3 and T4 disease. Between Jan. 1995
      and Dec. 1999--445 pneumonectomies were performed in patients with lung cancer.
      In 37 patients without preoperative N2 involvement a standard pneumonectomy was
      extended to include the following additional resections: chest wall (10),
      pericardium (9), diaphragm (5), VCS (3), descending aorta (2), left atrium (5),
      esophagus (1) and tracheal bifurcation (2). The effect of various factors on
      general mortality and morbidity was analyzed with the use of binary logistic
      regression. There were two early postoperative deaths (6.8%). Major complications
      occurred in 10 patients (29%). Overall survival rates at 1, 2, and 3 years were
      43, 30 and 24%, respectively. The survival rates for the subgroup with chest
      involvement only were 50, 42 and 30%, respectively. Eight patients survived
      beyond the 36 month follow-up. The only factor significantly affecting mortality
      was incomplete resection, as revealed by postoperative microscopic examination
      (R1, p<0.05). Extended operations are justified by a relatively low mortality
      rate and low number of severe postoperative complications, specially in patients
      with chest wall involvement only. The result of this treatment predominantly
      depends upon the completeness of the resection.

PMID- 15190426
TI  - How the implementation of an in-vivo dosimetry protocol improved the dose
      delivery accuracy in head and neck radiotherapy.
AB  - Doses were measured in-vivo at the entrance using semiconductor detectors for
      patients with head and neck tumors. Regular measurements started on January 1st
      and continued till June 30th, 2001. Then the evaluation of the discrepancies
      between the measured and calculated doses was made, and it resulted in the
      changes in the protocol of in-vivo dosimetry made effective by February 1st,
      2002. The collection of the measurements was censored by January 30th 2003. The
      number of patients in the two groups was 285 (1st) and 407 (2nd), respectively.
      The results exhibited the not-Gaussian distribution of the measured doses in both
      groups. The average number of dose checks per patient increased from 4.9 to 6.0
      (1st vs. 2nd group). The mean relative difference between the measured and
      calculated doses was: -1.5% vs. -0.5%, whereas the standard deviation (1 SD)
      decreased from 6.1% to 5.6%. The Mann-Whitney U test detected a significant
      difference between the 1st and the 2nd group (p=0.00000), which justified the
      conclusion that the changes implemented in the protocol improved dose delivery
      accuracy and reproducibility of irradiation.

PMID- 15190427
TI  - [Limiting factors of exercise capacity in patients with COPD].
AB  - Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and
      mortality worldwide. Moderate to severe COPD patients demonstrate severe
      impairments in exercise performance in daily activities, significantly affecting
      their quality of life. There are several causes for this limitation found in
      literature: air-flow limitation, lung hyperinflation, respiratory and peripheral
      muscles weakness, among others. In this study we intended to identify the
      potentially relevant factors that influence exercise performance in a group of
      moderate to severe COPD patients. We studied 24 male patients, 64,13 + 8,46 years
      old (46-83 years), FEV1: 46,96 + 12,99% predicted, FRC: 144,71 + 26,86%
      predicted, DLCO: 69,88 + 16,49 % predicted, PaO2: 78,25 + 7,82 mmHg, PaCO2: 40,78
      + 4,28 mmHg. Patients performed an incremental symptom-limited cycle exercise. We
      correlated rest and exercise lung function parameters with peak oxygen uptake,
      maximal work rate and time span to exertion. The main contributors to exercise
      limitation were gas exchange abnormalities, ventilatory limitation and smaller
      values of body mass index. Rest lung hyperinflation didn't correlate with
      exercise performance. Dynamic exercise hyperinflation contributed greatly to
      exercise intolerance, through progressive restriction to tidal volume expansion
      necessary to deal with increasing exercise metabolic demands. Rest lung function
      parameters didn't correlate with exercise performance, stressing the importance
      of cardio-pulmonary exercise testing in the detection of exercise limitation
      factors in each patient. The identification of exercise limitation factors will
      certainly contribute to towards defining the best therapeutic approach in COPD
      patients.

PMID- 15190428
TI  - [Suberosis and bird fancier's disease: comparative study of radiological,
      functional and bronchoalveolar characteristics profile].
AB  - Extrinsic Allergic Alveolitis (EAA) is an immunologically mediated interstitial
      lung disease that may result from repeated inhalation of many different
      environmental agents. Heterogeneity of the clinical presentation and
      bronchoalveolar lavage profiles has been described, possibly related to different
      occupational exposures. The aim of our study was to compare bronchoalveolar
      lavage fluid (BALF), clinical, functional and radiological characteristics of the
      two most frequent forms of EAA seen in our practice: Suberosis and Bird Fancier's
      Disease (BFD). We included 81 patients with Suberosis, with a mean age of 38.8+/
      11.3 years and a mean exposure of 20.0 +/- 10.5 years and 32 patients with BFD,
      with a mean age of 46.3+/-11.8 years and mean exposure of 10.5 +/- 1.0 years.
      Patients with BFD had more acute forms, while subacute and chronic presentations
      predominated in Suberosis. Restrictive defect was the most frequent pattern of
      lung function impairment, and more severe in BFD. Ground glass opacities were the
      most frequent pattern in high-resolution computed tomography. A normal chest x
      ray was more frequently seen in Suberosis. Both types of EAA had lymphocytic
      alveolitis in BALF: Suberosis - 6.6 +/- 5.7 x 105 ml-1 cells, 58.8 +/- 18.9%
      lymphocytes; bird fancier's disease - 9.0 +/- 6.5 x 105 ml-1 cells, 61.7 +/-
      22.2% lymphocytes. Although BALF CD8+ lymphocytes predominated in both diseases,
      the proportion of CD4+ and CD4/CD8 ratios were significantly higher in Bird
      Fancier's Disease (Suberosis: 0.47 +/- 0.33 versus BFD: 1.1 +/- 1.5; p <0.005).
      Moreover, BALF cellularity and mast cell counts were also significantly higher in
      BFD. In conclusion, Suberosis and bird fancier's disease are EAA with different
      clinical and laboratory profiles, suggesting that despite their
      pathophysiological similarities, different antigenic exposures may cause
      different immune and inflammatory response dynamics in the lung.

PMID- 15190429
TI  - The lung parenchyma in low frequency noise exposed Wistar rats.
AB  - Previous studies of low frequency noise (LFN) ( pound 500 Hz, including
      infrasound) exposed Wistar rat trachea and lung show that LFN induces
      irreversible lesions in the rodent respiratory system. Most notable was the
      behavior of the tracheal brush cell (BC) where fused microvilli were frequently
      captured in scanning electron microscopy. This study focuses on the alvoelar BC
      in LFN-exposed and control rat populations. Ten Wistar rats were exposed to 2160
      hours of continuous LFN, then kept 1 week in silence before sacrifice. Another
      10, age-matched rats were kept in continuous silence. All were fed standard rat
      food, and had unrestrained access to water (treated in accordance with
      86/609/CE). Lung parenchyma fragments were excised and processed for scanning
      electron microscopy. In the non-exposed, alveolar walls were thin, and wall
      structure was well defined. In the LFN-exposed, walls were thickened and wall
      structure was almost effaced. Macrophages were found in the non-exposed
      specimens, but were not so frequent in the LFN-exposed. Both vein and artery
      walls were thickened. In the parenchyma of the exposed rats, an increase in type
      II pneumocytes was observed, and their microvilli were dramatically altered in
      terms of cell-surface distribution, sprouting direction, and amount. Unidentified
      black holes eruptin from the cell surface were observed. In the alveoli, 2
      different types of BC's were observed: external and interstitial. In the exposed
      rats, microvilli of both types of BC were fused. These results confirm that LFN
      exposure can impinge on the entire respiratory system of living organisms.

PMID- 15190430
TI  - [Transient fever after fiberoptic bronchoscopy--a prospective study].
AB  - INTRODUCTION: The Fiberoptic bronchoscopy (BRF) is an essential tool in diagnosis
      and therapy of respiratory diseases. The occurrence of transient fever after BRF
      has been documented in some studies. Its meaning hasn't yet been clarified. AIM:
      Determine the incidence of fever and bacteriemia in the 24 hours after BRF and
      identify its predictive factors. MATERIAL AND METHODS: Ninety one outpatients and
      forty hospitalised patients were prospectively studied in the 24h after BRF to
      assess the appearance of fever (T>38 masculine C) and positive hemocultures.
      Statistical analysis were performed using SPSS and the significance was
      considered when pearson chi2 was < 0,005. RESULTS: Referring outpatients /
      hospitalised patients, 68% / 85% were males, 85% / 52,5% denied previous
      respiratory diseases, mean age was 54 +/- 16,5 years / 59 +/- 15,4 years, 38,5% /
      55% were smokers. Transient fever was observed in 12% / 12,5% patients. Positive
      hemocultures were found in four patients (3 outpatients and 1 hospitalised). None
      hospitalised patients showed radiological changes, in 7,5% cases white blood
      cells count rised >50%. We didn't found statistically significant association
      between appearance of fever after BRF and age, dental caries, smoking habits,
      systemic disease, presence of endoscopic lesions and endoscopic techniques
      performed. CONCLUSION: Transient fever following BRF is a common event and in
      majority of cases is not associated with bacteriemia. No statistical significant
      association was found between fever event and any of the studied factors.

PMID- 15190431
TI  - [Tuberculids].
AB  - Tuberculids represent a form of hypersensitivity reaction to tuberculosis
      antigens released from a distant focus of infection. Most patients are
      characterized by displaying a markedly positive Mantoux skin test and evidence of
      past tuberculosis infection or contacts of patients with tuberculosis. The
      treatment is based on tuberculin desensitizing therapy,antituberculosis drugs and
      corticosteroids.

PMID- 15190432
TI  - [Respiratory epithelia in Wistar rats after 48 hours of continuous exposure to
      low frequency noise].
AB  - Previous studies show that exposure to low frequency noise (LFN) (< or =500 Hz,
      including infrasound) produces irreversible lesions in Wistar rat respiratory
      epithelia. Recovery periods for LFN-induced lesions have thus become an object of
      interest. Changes in the respiratory epithelia of Wistar rats after continuous
      short-term exposure to LFN are described. Twelve rats were exposed to continuous
      LFN for 48 hrs, and 10 age-matched rats were kept in silence. Animals were
      treated in accordance with 86/609/CE. After exposure ceased, two rodents were
      sacrificed immediately, and another two after 6, 12, 24, 48 hrs, and 7 days of
      post-exposure silence. Respiratory epithelial fragments were prepared for light
      and scanning/transmission electron microscopy. Six hours after exposure, intense
      and irregular cellular tumefaction was visible and rosetta structures, formed by
      secretory cells (SC) centered on a brush cell (BC), were identifiable. Cilia were
      shorter and shaggy. BC microvilli tended to group, losing the uniform
      distribution seen in controls. Twelve hours after exposure, cell ballooning was
      still present, BC shape was highly irregular and microvilli were grouped. SC
      microvilli were still shorter than controls. Seven days after exposure, controls
      and exposed were indistinguishable. LFN-induced epithelial lesions seem to be
      reversible if recovery periods are respected.

PMID- 15190433
TI  - [Respiratory epithelia in Wistar rats born in low frequency noise plus varying
      amounts of additional exposure].
AB  - Earlier studies of Wistar rat respiratory epithelia exposed to low frequency
      noise (LFN) (< or =500 Hz, including infrasound) showed that LFN effects trauma
      on the respiratory tract. In rats gestated and born in LFN environments, trauma
      was still treated in accordance with 86/609/EC. Respiratory epithelial fragments
      were prepared for light and scanning/transmission electron microscopy. Group A
      brush cell (BC) microvilli tended to group together; in Group B they were clearly
      clustered together, and in Groups C-F they became fused. Rosetta structures
      (rings of secretory cells centered on a BC) were visible in Groups A-D and
      difficult to identify in Groups E,F. The amount of sheared cilia increased with
      exposure time, as did the images of cellular de-differentiation. LFN exposure
      induces severe trauma on the respiratory epithelial cells in these rats.

PMID- 15190434
TI  - [Localized fibrous tumor of the pleura: analysis of 11 new cases].
AB  - We present a retrospective revision of a pathology, rare in his incidence (5% of
      the pleural tumours) and singular in his characteristics, analyzing the
      presentation forms, surgical treatment and results. The solitary tumours of the
      pleura are a rare entity, whose biological behaviour is not related with
      immunohistochemical characteristics; although considered benign, they present
      sensitive recidivation index and metastization, independently of the volume that
      they present. he surgery is the only available treatment, and complete surgical
      excision is decisive. From August 1995 to January 2003, in the casuistry of the
      Department of Cardiothoracic Surgery in Santa Marta's Hospital, were analyzed all
      the patients with the diagnosis of localized fibrous tumour of the pleura (TFLP).
      In this context, were identified 11 patients with a medium age of 57,54 years
      old, 6 of them females, in which the diagnosis of located fibrous tumour of the
      pleura was established; 6 of the tumours were classified as malignant. All the
      patients were submitted to surgical excision, with different techniques, without
      significant intra-operative mortality or intra-hospital morbidity, despite the
      difficulty of surgery in the most voluminous tumours (one of the tumours weight
      was 2,5 kg). The follow up elapsed between 4 and 84 months (average - 39,4
      months). One patient died 13 months after the surgery, after several crises of
      lung embolism (that began without determinable relationship with the surgery or
      the initial pathology), despite the controlled ambulatory anti-coagulation.

PMID- 15190435
TI  - [Difficulties on diagnosis of ventilator associated pneumonia].
AB  - Ventilator associated pneumonia is associated with high morbidity and mortality.
      It is important a correct diagnosis in way to guide the antibiotic therapy in the
      most appropriate way. However, its diagnosis is difficult, because clinical and
      radiologic features are not specific and approaches to standard diagnosis, that
      allow its confirmation, are very invasive or not very frequent. Protected
      techniques and quantitative cultures have been trying to outline the problem of
      the contamination of the samples obtained by routine methods and to allow the
      distinction between colonization and infection. The author makes a revision on
      the different methods of diagnosis of this clinical entity.

PMID- 15190436
TI  - [Cell granular tumor of the lung--clinical case].
AB  - Lung granular cells tumour is a rare disease, almost always benign, with good
      prognostic after surgical treatment. Although it can present local
      aggressiveness, cases of malignancy have rarely been described. The authors
      describe a case of granular cells tumour of the lung and they make a revision on
      this clinical entity.

PMID- 15190437
TI  - Reference values of fetal ductus venosus, inferior vena cava and hepatic vein
      blood flow velocities and waveform indices during the second and third trimester
      of pregnancy.
AB  - OBJECTIVE: Our objective was to establish reference values for ductus venosus,
      inferior vena cava and hepatic vein flow velocities during ventricular systole (S
      wave) and diastole (D-wave), the lowest forward velocity during atrial
      contraction (a-wave), the intensity-weighted mean flow velocity (Vmean) and
      different calculated indices. METHODS: Venous flow velocity waveforms were
      obtained from 329 singleton pregnancies at 20-42 weeks of gestation by pulsed
      wave color Doppler. Reference values were constructed by means of a quadratic
      regression model after logarithmic transformation of original data. RESULTS: With
      advancing gestational age the peak velocity index for the vein (PVIV) and
      pulsatility index for the vein (PIV) decreased whereas blood flow velocities
      increased. Blood flow velocities were highest in the ductus venosus and lowest in
      the right hepatic vein. Values for PVIV and PIV were highest in the hepatic vein
      and lowest in the ductus venosus. During atrial contraction there was a blood
      flow towards the fetal heart in the ductus venosus, whereas in the inferior vena
      cava and in the hepatic vein blood flow was either in the opposite from the fetal
      heart (reverse flow), or there was absent flow (zero flow) or flow was towards
      the fetal heart (positive flow). CONCLUSIONS: The reference ranges and calculated
      velocities established in this study may be utilized in studies dealing with the
      role of ductus venosus and inferior vena cava blood flow in fetuses with
      chromosomal abnormalities or congenital heart disease as well as hypoxic
      conditions. We speculate, that the reduction in PVIV and PIV with advancing
      gestational age may reflect a decrease in cardiac afterload as a result of
      maturation of diastolic ventricular function.

PMID- 15190438
TI  - Swiss recommendations for the management of genital herpes and herpes simplex
      virus infection of the neonate.
AB  - Genital herpes is being recognised as a medical problem of increasing importance.
      Diagnosis and management are complex. The present recommendations have been
      established by a multidisciplinary panel of specialists and endorsed by all Swiss
      medical societies involved in the medical care of such patients. The aim is to
      improve the care of affected patients, to reduce horizontal and vertical
      transmission and to diminish the psychosocial burden.

PMID- 15190439
TI  - Relationship between various measures of bone mineral density and vertebral
      fractures in cardiac transplant recipients.
AB  - BACKGROUND: The incidence rates of osteoporosis and fractures are increased after
      cardiac transplantation. METHODS: We performed a cross-sectional analysis of
      cardiac transplant recipients in a late post-transplantation period (4.4 [2.5]
      years after cardiac transplantation, n = 27). We measured bone mineral density
      (BMD) by DXA at the hip and lumbar spine and by quantitative ultrasound (QUS) at
      the calcaneus. Vertebral fracture (vfx) prevalence was analysed by anterior
      posterior and lateral radiographs of the thoracic and lumbar spine. RESULTS:
      Overall, vfx were present in 13 of 27 patients (48.2%, n = 51 vfx). Vfx were
      observed in 1 out of 5 patients with normal DXA results, 7 out of 14 osteopenic
      and 5 out of 8 osteoporotic cardiac transplant recipients. BMD at the femoral
      neck and more prominently at Ward's triangle were significantly lower in vfx
      patients compared to patients without vfx, with adjusted mean values (95% CI) of
      0.804 [0.750-0.859] vs. 0.915 [0.860-0.969] g/cm2 and 0.573 [0.501-0.646] vs.
      0.766 [0.697-0.836] g/cm2, respectively. CONCLUSIONS: These findings suggest an
      association between DXA measurements of the hip with vertebral fractures in a
      late post-transplantation period and thus extend knowledge from previous reports
      on cardiac transplant recipients studied earlier after CTX. In particular, our
      data pinpoint a potentially interesting role for BMD at Ward's triangle.

PMID- 15190440
TI  - Mycobacterium bohemicum--a cause of paediatric cervical lymphadenitis.
AB  - We report on two toddlers suffering from Mycobacterium bohemicum lymphadenitis.
      Acid-fast bacilli were cultured from submandibular lymph nodes and identified by
      molecular methods as Mycobacterium bohemicum. Surgical treatment was successful
      and complemented by oral treatment with clarithromycin and rifampicin.

PMID- 15190441
TI  - An unusual cause of transient small bowel thickening.

PMID- 15190442
TI  - [What is the future of gastroenterological endoscopy?].

PMID- 15190444
TI  - Endoscopic measurement of Barrett's esophagus length is unreliable - a
      prospective comparative biopsy study.
AB  - BACKGROUND AND AIMS: Endoscopic assessment of the length and area of Barrett's
      esophagus (BE) has become crucial in assessing its spontaneous course as well as
      any effect of pharmacological or endoscopic treatment. Little, however, is known
      about the extent to which the endoscopic assessment of BE length and area
      correlates with the histopathological confirmation of BE epithelium. PATIENTS AND
      METHODS: 75 consecutive patients (mean age 60 years; 58 men, 17 women) were
      included in a prospective study on the basis of the endoscopic suspicion of BE.
      BE was endoscopically defined as gastric-type epithelium between the proximal
      cardiac folds and the Z line, on moderate air insufflation. Stepwise four
      quadrant biopsies (4QB) were then taken, beginning at the proximal cardiac folds
      and then every 2 cm up to the Z line. RESULTS: Among the 75 study patients, BE
      was histologically verified in 57 cases (group 1) and not confirmed in any of the
      endoscopic biopsy samples in 18 cases (group 2). In group 1, the mean difference
      between the endoscopic and histological assessment of BE length was + 1 cm (range
      0 - 5 cm); when determining the BE area histologically from 4QB the mean
      difference to the endoscopic determination was + 36 % (range 0 - 93 %). These
      differences were independent of the presence and degree of hiatal hernia or the
      presence of long or short BE. CONCLUSIONS: In the majority of patients, there is
      only a moderate correlation between the endoscopic and the histological extent of
      BE. However, we also found a substantial individual variability in endoscopic
      histological correlation; therefore studies on the effects of treatment on BE
      must consider both the endoscopic and histopathological BE lengths.

PMID- 15190445
TI  - [Video capsule endoscopy in a group of networked users: effective and cost
      saving].
AB  - BACKGROUND: At present extensive application of video capsule endoscopy (VCE) as
      the most innovative diagnostic tool for small bowel diseases is limited by its
      high costs. The present study describes the first experience in the mobile use of
      VCE in a cooperation of associated gastroenterology departments in different
      hospitals. METHODS: The VCE device was bought by a centrally located hospital. In
      the case of a need for VCE elsewhere the mobile equipment was brought to the
      respective hospital. The examination was done on site by local physicians, who
      additionally were responsible for the procedure itself. The evaluation of the VCE
      pictures was carried out exclusively by the Ophysicians of the central hospital.
      RESULTS: Within 15 months VCE was performed in 40 patients (19 male, 21 female;
      age 61 +/- 14 years). Ten examinations were performed in the central hospital, 30
      in the associated gastroenterology departments of other hospitals. Indications
      for VCE were obscure GI bleeding (65 %), chronic diarrhea and Crohn's disease
      (17.5 %) or suspected small bowel neoplasms (17.5 %). Clinically relevant
      pathological abnormalities were detected in 62.5 % of the patients, mainly
      ulcerations and erosions. Complications were non-spontaneous capsule passage in
      one patient. Compared to a single hospital, the multicenter use of VCE increased
      the frequency of investigations four times and reduced expenses to almost 30 %.
      CONCLUSIONS: The mobile use of VCE makes this innovative technique available for
      every patient while remaining in his local gastroenterology department.
      Additionally, this concept accelerates amortization and improves the quality of
      evaluation by focusing experience.

PMID- 15190446
TI  - [Splenic trauma--a rare complication during colonoscopy].
AB  - The less frequent complications of colonoscopy include pneumothorax,
      pneumoperitoneum, emphysema of the retroperitoneum or of the subcutis, septicemia
      and injuries of visceral organs (mainly the spleen). Since the mid 1970 s more
      than 30 splenic injuries during colonoscopy have been described. Any cause of
      increased splenocolic adhesions (inflammatory bowel disease, pancreatitis or
      prior abdominal surgery) might be a predisposing factor for splenic injury during
      colonoscopy. Other contributing factors are techniques that result in a strong
      torsion of the spleno-colic ligament. Patients with left shoulder and abdominal
      pain, hypotension, and a drop in hemoglobin without rectal bleeding after
      colonoscopy should be suspected to have splenic injury. Many physicians are not
      aware of splenic injuries as a potential complication of colonoscopy. Therefore
      the diagnosis of splenic injury during colonoscopy is often described in the
      literature as delayed (hours until 10 days). Since a colonoscopic splenic injury
      can be fatal, this exceedindly rare event must be considered when a patient shows
      the above-mentioned symptoms and no signs of colon perforation.

PMID- 15190447
TI  - [Pancreatic tail tumor as an unusual first manifestation of Wegener's disease].
AB  - A fifty-year-old, previously healthy woman presented with abdominal pain and
      weight loss. Diagnostic work-up revealed a mass in the tail of the pancreas with
      the appearance of a pancreatic carcinoma. Partial pancreatectomy was performed.
      Postoperatively, the patient's kidney function deteriorated. Pathohistological
      examination of the resected tissue showed a granulomatous vasculitis but no
      maligant tumor. Renal biopsy revealed a rapid progressive glomerulonephritis.
      Positive C-ANCA screening confirmed the diagnosis of Wegener's disease and an
      immunosuppressive therapy was established. This case demonstrates the difficult
      management of a potentially benign pancreatic mass, as reliable discrimination
      from pancreatic adenocarcinoma is not always possible.

PMID- 15190448
TI  - [Neuroendocrine tumours of the gastrointestinal tract].
AB  - Gastrointestinal neuroendocrine tumours are classified as functioning or non
      functioning according to the presence or absence of a clinically evident
      hypersecretion syndrome. In foregut tumours the presence of autonomous hormone
      secretion and the respective hypersecretion syndrome indicate functionality.
      Abdominal ultrasound (US), computed tomography (CT), magnetic resonance
      tomography (MRT) and somatostatin receptor scintigraphy (SRS) are used for
      localisation of the primary tumour and metastasis. Invasive procedures such as
      endoscopic US, intraoperative US or intraoperative duodenal transillumination are
      useful to localise small (< 1 cm) tumours. For localised tumours surgery is the
      first line treatment. In metastatic disease symptomatic therapy, biotherapy and
      chemotherapy are available. Cytoreductive therapy such as embolisation,
      chemoembolisation, thermo- or cryotherapy, or radio-receptor therapy are
      additional options. The first symptom of most neuroendocrine midgut tumours is
      abdominal pain. An increased chromogranin-A plasma concentration or 5
      hydroxyindoleacetic acid 24-h urinary excretion indicates the neuroendocrine
      origin of the tumour or the possibility of a carcinoid syndrome, respectively.
      Surgical therapy prolongs survival but is rarely curative. Biotherapy is
      effective as symptomatic therapy. However, its cytoreductive potency is low.
      Chemotherapy is less effective in midgut tumours compared to foregut tumours.
      Cytoreductive strategies (chemoembolisation, thermo- or cryotherapy,
      cytoreductive surgery) and radio-receptor therapy may offer new therapeutic
      options. However, their definitive value has yet to be defined.

PMID- 15190449
TI  - [Management of chemotherapy induced diarrhea].
AB  - Chemotherapy-induced diarrhea (CID) became first apparent during clinical studies
      on the combination of 5-FU with leucovorin and, furthermore, with irinotecan in
      the treatment of metastatic colorectal carcinoma. Bowel dysfunctions, such as
      diarrhea and constipation, can be a disturbing side effect in chemotherapy that
      may result not only in significant physical and emotional distress for the
      patients and care givers, but also in diminished therapeutic efficacy due to dose
      limitations and treatment interruptions. Besides leucocytopenia, granulocytopenia
      and thrombocytopenia, CID is considered one of the main dose-limiting toxicities
      associated with chemotherapy agents, especially in treatment regimens for
      colorectal cancer and can even be life-threatening. Early recognition and
      treatment can prevent the morbidity and mortality associated with CID. The most
      commonly used assessment tool is the National Cancer Institute Common Toxicity
      Criteria for Grading the Severity of Diarrhea. In this review, we will
      concentrate on the modern management of CID. Traditional pharmacological
      management of CID has included mainly non-specific agents. For patients who are
      refractory to non-specific therapy, there are more sophisticated, specific
      therapeutic agents available.

PMID- 15190452
TI  - Retrieval of a dislocated plastic stent from the ductus hepaticus Dexter using a
      new balloon system.

PMID- 15190453
TI  - [Rudolf Schindler (1888--1968)--"father" of gastroscopy].
AB  - Rudolf Schindler was born in Berlin and achieved his international reputation
      with the textbook "Lehrbuch und Atlas der Gastroskopie", written in Munich. This
      was the first book containing excellent endoscopic pictures. He was the first to
      report on more than four hundred gastroscopies performed without complications.
      1928 to 1932, he developed the first semi-flexible gastroscope together with the
      technical designer Georg Wolf from Berlin. This became the lasting standard for
      about twenty-five years. In 1934, Schindler emigrated to Chicago after being
      released as a Nazi prisoner. In 1937, he was awarded the gold medal for his
      research on gastritis by the American Medical Association. He became the leading
      person among American gastroscopists for many years and, in 1941, the first
      president of the American Gastroscopic Club. After 1943 he moved to California to
      work and live. He also received awards from the American Societies for
      Gastroscopy and Gastrointestinal Endoscopy in 1953 and 1962. He spent his last
      years in Munich. His honorary titles of father, architect or super salesman of
      gastroscopy describe the spectrum of his personality. He was an endoscopist with
      outstanding technical and diagnostic skills and knew particularly how to deal
      with patients, how to develop endoscopes as well as being a highly qualified
      teacher, author and scientist. He also had many hobbies, in particular playing
      and conducting music perfectly.

PMID- 15190456
TI  - [German Society for Neurogastroenterology and Motility e.V.-- summary of yearly
      meeting 2004].

PMID- 15190457
TI  - Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2:
      a population-based study.
AB  - Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is characterized
      by tumors on the vestibular branch of the VIII cranial nerve, but other types of
      nervous system tumors usually occur as well. Genotype-phenotype correlations are
      well documented for overall NF2 disease severity but have not been definitively
      evaluated for specific types of non-VIII nerve tumors. We evaluated genotype
      phenotype correlations for various types of non-VIII nerve tumors in 406 patients
      from the population-based United Kingdom NF2 registry, using regression models
      with the additional covariates of current age and type of treatment center
      (specialty or nonspecialty). The models also permitted consideration of
      intrafamilial correlation. We found statistically significant genotype-phenotype
      correlations for intracranial meningiomas, spinal tumors, and peripheral nerve
      tumors. People with constitutional NF2 missense mutations, splice-site mutations,
      large deletions, or somatic mosaicism had significantly fewer tumors than did
      people with constitutional nonsense or frameshift NF2 mutations. In addition,
      there were significant intrafamilial correlations for intracranial meningiomas
      and spinal tumors, after adjustment for the type of constitutional NF2 mutation.
      The type of constitutional NF2 mutation is an important determinant of the number
      of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve
      tumors.

PMID- 15190458
TI  - [Monsters].

PMID- 15190459
TI  - [Absence].

PMID- 15190460
TI  - [Phosphatidylserine receptor and clearance of apoptotic cells].

PMID- 15190461
TI  - [TREM, new receptors mediating innate immunity].

PMID- 15190463
TI  - [Yeast and humans].

PMID- 15190462
TI  - [ZAP 70, a kinase indispensible for T lymphocyte activation, implicated in
      autoimmunity].

PMID- 15190464
TI  - [Child survival: a global health challenge].

PMID- 15190465
TI  - [The VKOR target for warfarin identified].

PMID- 15190466
TI  - [Cellular and scrapie prion proteins: which is the more toxic isoform?].

PMID- 15190467
TI  - [Mediterranean purple indirubins: a source of GSK-3 inhibitors].

PMID- 15190468
TI  - [Stem cells to repair neurosensory deafness?].

PMID- 15190469
TI  - [How to use the paradigm of ischemic preconditioning to protect the heart?].
AB  - Ischemic preconditioning affords the most powerful protection to a heart
      submitted to a prolonged ischemia-reperfusion. During the past decade, a huge
      amount of work allowed to better understand the features of this protective
      effect as well as the molecular mechanisms. Ischemic preconditioning reduces
      infarct size and improves functional recovery; its effects on arrhythmias remain
      debated. Triggering of the protection involves cell surface receptors that
      activate pro-survival pathways including protein kinase C, PI3-kinase, possibly
      Akt and ERK1/2, whose downstream targets remain to be determined. Much attention
      has been recently focused on the role of mitochondrial K(+)ATP channels and the
      permeability transition pore that seem to play a major role in the progression
      toward irreversible cellular injury. Based on these experimental studies attempts
      have been made to transfer preconditioning from bench to bedside. Human
      experimental models of ischemic preconditioning have been set up, including
      cardiac surgery, coronary angioplasty or treadmill exercise, to perform
      pathophysiological studies. Yet, protecting the heart of CAD (coronary artery
      disease) patients requires a pharmacological approach. The IONA trial has been an
      example of the clinical utility of preconditioning. It helped to demonstrate that
      chronic administration of nicorandil, a K(+)ATP opener that mimics ischemic
      preconditioning in experimental preparations, improves the cardiovascular
      prognosis in CAD patients. Recent experimental studies appear further
      encouraging. It appears that "postconditioning" the heart (i.e. performing brief
      episodes of ischemia-reperfusion at the time of reperfusion) is as protective as
      preconditioning. In other words, a therapeutic intervention performed as late as
      at the time of reflow can still significantly limit infarct size. Further work is
      needed to determine whether this may be transferred to the clinical practice.

PMID- 15190470
TI  - [Establishment and expression of embryonic axes: comparisons between different
      model organisms].
AB  - In an accompanying article (C. Sardet et al. m/s 2004; 20 : 414-423) we reviewed
      determinants of polarity in early development and the mechanisms which regulate
      their localization and expression. Such determinants have for the moment been
      identified in only a few species: the insect Drosophila melanogaster, the worm
      Caenorhabditis elegans, the frog Xenopus laevis and the ascidians Ciona
      intestinalis and Holocynthia roretzi. Although oogenesis, fertilization, and cell
      divisions in these embryos differ considerably, with respect to early polarities
      certain common themes emerge, such as the importance of cortical mRNAs, the PAR
      polarity proteins, and reorganizations mediated by the cytoskeleton. Here we
      highlight similarities and differences in axis establishment between these
      species, describing them in a chronological order from oocyte to gastrula, and
      add two more classical model organisms, sea urchin and mouse, to complete the
      comparisons depicted in the form of a Poster which can be downloaded from the
      site http://biodev.obs-vlfr.fr/biomarcell.

PMID- 15190471
TI  - [Cell polarity and actin mRNA localization].
AB  - In many species, intracellular mRNA localization is linked to cell polarity. In
      many cases however, mRNAs become localized as a result of a pre-existing cell
      polarity, and they do not modify it. Remarkably, in the case beta actin mRNA in
      vertebrate, it has been shown that the transport and localization of this RNA is
      required for the establishment and maintenance of cell polarity. This occurs in
      fibroblasts, but, very interestingly, in immature neurons as well. This review
      will describe the functions and mechanisms of actin mRNA localization.

PMID- 15190472
TI  - [Neuronal background two-P-domain potassium channels: molecular and functional
      aspects].
AB  - Background K+ conductances are a major determinant of membrane resting potential
      and input resistance, two key components of neuronal excitability. Background
      channels have been cloned and form a K+ channel family structurally different
      from Kv, KCa and Kir channels. These channels with 2P domains (K2P channels) are
      voltage- and time-independent. They are relatively insensitive to classical
      potassium channels blockers such as TEA, 4-AP, Ba2+ and Cs+. TASK and TREK
      subunits are widely expressed in the nervous system. Open at rest, these channels
      mainly contribute to the resting potential of somatic motoneurons, brainstem
      respiratory and chemoreceptor neurones, and cerebellar granule cells. K2P
      channels are regulated by numerous physical and chemical stimuli including
      extracellular and intracellular pH, temperature, hypoxia, pressure, bioactive
      lipids, and neurotransmitters. The regulation of these background K+ channels
      profoundly alters the neuronal excitability. For example, in Aplysia, regulation
      of a background potassium conductance by neurotransmitters is involved in
      synaptic modulation, a simple and primitive form of learning. The recent
      discovery that clinical compounds such as volatile anaesthetics and other
      neuroprotective agents including riluzole and unsaturated fatty acids activate
      K2P channels suggest that neuronal background K+ channels are attractive targets
      for the development of new drugs.

PMID- 15190473
TI  - [Patch-clamp techniques].

PMID- 15190474
TI  - [Shear and signal transduction in the endothelial cell].
AB  - Blood vessels are permanently subjected to mechanical forces in the form of
      stretch and shear stress. Any alterations in the hemodynamic environment
      invariably produce transformations in the vessel wall that will aim to
      accommodate the new conditions and to ultimately restore basal levels of
      mechanical forces. Many receptors, present on the surface of endothelial cells,
      allow vessels to detect subtle changes in shear stress. Inside the cells,
      cytoskeletal proteins transmit and modulate the tension between integrins, focal
      adhesion sites, and the extracellular matrix. Besides inducing structural
      modifications, mechanical forces lead to changes in the ionic composition of
      cells, mediated by ion channels, stimulate various membrane receptors, and induce
      complex biochemical cascades. Many intracellular pathways such as the MAP kinase
      cascade are activated by shear stress and initiate via sequential
      phosphorylations the activation of transcription factors and subsequent gene
      expression. Thus, by purely local mechanisms, blood vessels are capable of true
      autonomic regulation which enables them to adapt to their mechanical environment.

PMID- 15190475
TI  - [Mechanotransduction of hemodynamic forces regulates organogenesis].
AB  - Endothelial cells (EC) of the vertebrate cardiovascular system (CVS) are bona
      fide, yet enigmatic mechanoreceptors. When cultured in vitro and exposed to fluid
      forces, EC modify their physiological behaviour at the structural, metabolical
      and gene expression levels in response to the mechanical stimulus. However, as a
      direct consequence of the hypoxic bias (and often the lethality) that results
      from blocking blood flow in most animal systems, the in vivo role of EC
      mechanosensation (ECMS) remains poorly understood. The zebrafish has recently
      emerged as an alternative genetic model for the study of vertebrate development.
      Its striking ability to survive until larval stages in the absence of blood
      circulation circumveys the usual caveats that are inherent to CVS research, and
      offers the exciting opportunity to dissect the function of ECMS in vivo. Two
      groups have already uncovered an essential role for ECMS in zebrafish
      organogenesis, particularly in heart morphogenesis. In embryos in which
      intracardiac blood flow is genetically or physically compromised, several
      features of the normally developing heart, including valve formation, are
      specifically disrupted. In addition, impressive imaging studies of zebrafish
      hemodynamics demonstrate that the shear stress exerted upon the cardiac
      endothelium is largely in the range of the stimulus that in vitro activates
      cytoskelettal remodeling and gene expression changes in EC. Hence the cardiac
      phenotypes observed in vivo may indeed directly result from a lack of ECMS
      dependent EC activity. These data shed first light on the role of ECMS in vivo.
      Notably, they also suggest that a number of human congenital cardiomyopathies may
      arise through abnormal fetal hemodynamics and/or EC sensory activity. Finally,
      these discoveries reinforce the too often neglected role of epigenetic factors
      (in this case, fluid forces) in the regulation of animal development.

PMID- 15190476
TI  - [Genetic susceptibility to prostate cancer].
AB  - Prostate cancer is the most frequent malignant tumor among men over 50 years old.
      Its incidence varies according to countries and ethnic group. Known risk factors
      are race and positive family history of the disease. Familial aggregation (at
      least 2 cases in the family) is observed in about 20% of cases and an hereditary
      form of prostate cancer in 5%. This proportion increases with younger age at
      diagnosis. Six putative loci are already identified but undoubtedly, others will
      be found in forthcoming studies. The genetic heterogeneity observed in hereditary
      prostate cancer reflects variety of origins of the studied families. In some
      families, aggregation of prostate cancer and other cancers suggests the
      involvement of common predisposing genes. In other familial and in sporadic
      cases, the genetic component should be polygenic: prostate cancer wouldn't result
      to segregation of a major gene mutations transmitted according to a monogenic
      inheritance, but rather to sharing of alleles at many loci, each contributing to
      a small increase in cancer risk. Indeed, several genetic polymorphism were
      associated with an increased risk of developing prostate cancer and could explain
      the variations of prostate cancer incidence observed between populations.

PMID- 15190477
TI  - [MUC genes: mucin or not mucin? That is the question].
AB  - Mucins are macromolecules lying the cells in contact with external environment
      and protect the epithelium against constant attacks such as digestive fluids,
      microorganisms, pollutants, and toxins. Mucins are the main components of mucus
      and are synthesized and secreted by specialized cells of the epithelium (goblet
      cells, cells of mucous glands) or non mucin-secreting cells. Human mucin genes
      show common features: large size of their mRNAs, large nucleotide tandem repeat
      domains, complex expression both at tissular and cellular level. Since 1987, 21
      MUC symbols have been used to designate genes encoding O-glycoproteins containing
      tandem repeat domains rich in serine, threonine and proline. Some of these genes
      encode true mucins while others encode non mucin adhesion O-glycoproteins. In
      this paper, we propose a classification based on sequence similarities and
      expression areas. Two main families can be distinguished: secreted mucins or gel
      forming mucins (MUC2, MUC5AC, MUC5B, MUC6), and membrane-bound mucins (MUC1,
      MUC3, MUC4, MUC12, MUC17). Muc-deficient mice will provide important models in
      the study of functional relationships between these two mucin families.

PMID- 15190478
TI  - [TBP, a universal transcription factor?].
AB  - The TATA binding protein (TBP) is a subunit of several macromolecular complexes
      required for transcription by the three nuclear RNA polymerases. This observation
      led to the idea that TBP is a "universal" transcription factor. The discovery of
      three TBP-related factors and a macromolecular complex which lacks TBP but can
      support RNA polymerase II transcription in vitro has led to a reappraisal of the
      universal character of TBP. Several in vivo studies have rather shown that TBP
      plays a specific role in the activation of a subset of cellular genes controlling
      the cell cycle. In mammals, the aminoterminal region of TBP plays a highly
      selective role in the maternal immunotolerance of pregnancy.

PMID- 15190479
TI  - [Tight junctions, a platform regulating cell proliferation and polarity].
AB  - Tight junctions (TJ) are specialized plasma membrane microdomains that encircle
      the apical pole of each epithelial and endothelial cell, separating apical from
      basolateral side. They form an intercellular diffusion barrier (or gate)
      regulating the passage of ions, water, and various macromolecules through the
      paracellular spaces, and a fence restricting the apical/basolateral diffusion of
      membrane proteins and lipids. This latter function is deeply involved in cancer
      cell biology, in terms of loss of cell polarity. Several TJ proteins are involved
      in organizing signal transduction at TJ. For example, the interaction of TJ
      protein ZO-1 (zonula occludens 1) with the transcription factor ZONAB (ZO-1
      associated nucleic acid protein) is important in the regulation of expression of
      the proto-oncogene Erb-2 as well as epithelial proliferation/differentiation.
      Recent studies indicate that different proteins involved in membrane trafficking
      are associated with tight junctions. Among these proteins are the small G
      proteins of the Rab family that regulate specific membrane transport events in
      both endocytic and exocytic pathways. Rab proteins may coordinate the recruitment
      of protein complexes necessary for the establishment-maintenance of cell
      polarity. Based on the studies reviewed here, tight junctions emerge as a
      platform used to coordinate and regulate cell polarity, and
      proliferation/differentiation.

PMID- 15190480
TI  - [Concepts and therapeutic perspectives of proteomics].
AB  - The present paper aims at clarifying some important aspects of proteomics, i.e.
      the large scale analysis of proteins. To this purpose, the main types of
      proteomic analyses are presented, i.e. those aiming at determining expression
      levels and those aiming at unravelling protein-protein interactions networks.
      Their performances and limitations are outlined, as well as their potential
      applications in biomedicine, to give an reasoned view of the current state of the
      art.

PMID- 15190481
TI  - [The HIV/AIDS epidemic in sub-Saharan Africa].
AB  - Knowledge useful to the fight against HIV/AIDS in sub-Saharan Africa cannot be
      extrapolated to those coming from industrialized countries. The aim of this
      article is to review specificities of the African epidemy, in terms of
      epidiomolgy, natural history, validated therapeutic interventions, and unexplored
      questions. Far from being without effective tools and research tracks to fight
      against this plague which decimates a continent, one is above all confronted with
      a deficit of both mobilization and means.

PMID- 15190482
TI  - [Harm reduction policy related to drug use: the needles exchange programs].
AB  - In several developed countries, needles exchange programs (NEPs) are a key
      preventive tool in harm reduction policy related to drug use. Many studies about
      NEP show it reduces HIV infections related to syringes sharing when part of
      others preventive actions. NEPs seem to have no impact on HCV transmission.
      Furthermore, young drug users, who are at high risk for HIV and HCV infections,
      are not attending NEPs very often. Trying to maintain high accessibility to
      sterile syringes, efforts must be stressed on hard-to-reach populations such as
      young injection drug users (IDU), focusing on their social network. Emphasis must
      also be put on prevention of unsafe sexual intercourse, often related to syringe
      sharing, which must be more prevented. Finally, design of assessment studies
      should be improved.

PMID- 15190483
TI  - [Ups and downs of therapeutic cloning].

PMID- 15190485
TI  - Sentinel lymph node technique for breast cancer: radiation safety issues.
AB  - The radiation safety issues in the application of radioguided sentinel lymph node
      (SLN) biopsy are discussed, particularly the effective dose (ED) for patients
      undergoing lymphoscintigraphy by taking into account both the internal emission
      and the external transmission dose. The quantitative result can be compared with
      other common radiological examinations. Whole body and finger doses of surgical
      and pathology staff were determined by direct measurement using high-sensitivity
      thermoluminescent dosimeters (TLDs) and compared with the annual dose limits
      recommended by the International Commission on Radiological Protection (ICRP).
      These dosimetric observations for personnel also provide reference information to
      implement guidelines for the safe handling, storage, and transport of radioactive
      specimens at all stages of the radioguided surgery effort in order to maintain
      good work practices while dealing with unsealed radioactive substances.

PMID- 15190486
TI  - European studies on breast lymphatic mapping.
AB  - Sentinel lymph node (SLN) biopsy is rapidly emerging as a minimally invasive
      alternative to standard axillary dissection for nodal staging in breast cancer.
      So far only data from case-control trials are available documenting SLN biopsy to
      be highly predictive of axillary node status, with a false-negative rate of less
      than 5%. The procedure has the potential to identify those patients most likely
      to be helped by axillary dissection (ie, those with positive nodes) and to spare
      node-negative patients, who cannot benefit, from the morbidity of an operation.
      No data exist from randomized trials focusing on the oncologic safety of the SLN
      biopsy alone or the expected reduced postoperative morbidity. Therefore, results
      from randomized trials validating SLN biopsy in breast cancer are required before
      accepting the procedure as the standard of care. This review discusses the
      European multicenter randomized trials addressing the pros and cons of SLN
      dissection, either as a surrogate for conventional axillary dissection or to
      examine aspects of the procedure itself. The trials identified are the ALMANAC
      trial (Axillary Lymphatic Mapping Against Nodal Axillary Clearance); the AMAROS
      EORTC trial (After Mapping of the Axilla: Radiotherapy or Surgery); the KiSS
      study (German Clinical Interdisciplinary Sentinel Study); the Milan trial
      (European Institute of Oncology); the Fransenod study (French Randomised Sentinel
      Node Study); and the IBCSG 23-01 trial (International Breast Cancer Study Group
      Trial 23-01).

PMID- 15190487
TI  - Missed micrometastatic disease in breast cancer.
AB  - In the era of sentinel lymph node (SLN) biopsy for breast cancer, ultrastaging by
      enhanced pathologic techniques (serial sections and/or immunohistochemical [IHC]
      staining) has become logistically feasible for the first time. Retrospective
      studies suggest that SLN (and bone marrow) micrometastases detected by these
      methods are prognostically significant, but controversy still surrounds the
      significance of micrometastases detected only by IHC, and especially of isolated
      tumor cells. This heterogeneity among micrometastases may confound the
      interpretation of current prospective clinical trials that aim to determine their
      significance. A major challenge for future investigations will be to determine if
      SLN and bone marrow micrometastases represent similar or distinct biologic
      phenomena, and whether this distinction will have any implications for treatment.

PMID- 15190488
TI  - Worldwide experience with lymphatic mapping for invasive breast cancer.
AB  - Lymphatic mapping and sentinel lymph node (SLN) biopsy have changed the standard
      of surgical care for women with invasive breast cancer. The rate of successful
      axillary SLN identification varies from 90% to 99%. Recurrence rates after a
      negative SLN biopsy have been remarkably low. Internal mammary node drainage has
      been noted in 8% to 22% of cases, but whether to harvest these extra-axillary
      sites of drainage remains controversial. Because of the low morbidity associated
      with the lymphatic mapping procedure, all women with invasive breast cancer
      should be considered as candidates for this more accurate staging technique.

PMID- 15190489
TI  - Controversial topics in breast lymphatic mapping.
AB  - As a result of increased accuracy of staging and decreased patient morbidity,
      lymphatic mapping and sentinel lymph node (SLN) biopsy for breast cancer has
      enjoyed a rapid acceptance into clinical practice. Despite the use of lymphatic
      mapping techniques to obtain nodal staging information, many controversies
      remain. We have attempted to highlight the major controversies in this report.

PMID- 15190490
TI  - Training and mentoring surgeons in lymphatic mapping.
AB  - Intraoperative lymphatic mapping and selective lymphadenectomy for solid
      malignancies is a novel technique, having been introduced into surgical practice
      in the last 12 years. Dissemination of this technique among surgeons has followed
      a course similar to that found with the introduction of new laparoscopic
      techniques. A case series from a leading institution forms the core of the
      surgical literature for the new operation and is followed by additional case
      series, which offer technical refinements. Distinct from the laparoscopic
      techniques, however, sentinel node methodology offers a proficiency assessment
      through completion lymphadenectomy. Several completed clinical trials using
      sentinel lymph node technology have afforded a means for training and mentoring
      surgeons to perform the procedure. These multi-institutional studies and
      mentoring programs represent an initial step towards development of a more
      structured framework to evaluate new surgical procedures.

PMID- 15190491
TI  - Nuclear medicine aspects of melanoma and breast lymphatic mapping.
AB  - A successful sentinel lymph node biopsy (SLNB) procedure in melanoma or breast
      cancer patients requires an accurate map of the pattern of lymphatic drainage
      from the primary site. Lymphoscintigraphy (LS) can provide such a map in each
      patient. This requires an understanding of lymphatic physiology, an appropriate
      small particle radiocolloid, high resolution collimators, and imaging protocols
      that detect all sentinel nodes (SNs) in every patient regardless of their
      location. The SN is not always found in the nearest node field and is best
      defined as "any lymph node receiving direct lymphatic drainage from a primary
      tumor site." Patterns of lymphatic drainage from the skin are not clinically
      predictable and unexpected drainage has been found from the skin of the back to
      SNs in the triangular intermuscular space or through the posterior body wall to
      SNs in the paraaortic, paravertebral, and retroperitoneal areas. Drainage from
      the head and neck is to unexpected nodes in 30% of patients. Upper limb drainage
      can be to SNs above the axilla. Interval nodes are not uncommon as SNs,
      especially on the trunk. Lymphatic drainage may involve SNs in multiple node
      fields and drainage across the midline of the body is quite common. In the
      breast, although 94% of patients have a SN in the ipsilateral axilla, 46% also
      have SNs outside the axilla, especially in the internal mammary chain (40%).
      Failure to biopsy all SNs in each patient thus has the potential to understage a
      significant number of patients with breast cancer. Micrometastatic disease can be
      present in any SN regardless of its location, and for the SLNB technique to be
      accurate a biopsy most be performed on all true SNs in every patient. LS is an
      important first step to ensure this goal is achieved.

PMID- 15190492
TI  - Teaching points on lymphatic mapping for melanoma from the Sydney Melanoma Unit.
AB  - If incorrect or misleading information is obtained from a sentinel node (SN)
      biopsy procedure for melanoma, inappropriate management decisions may be made,
      and the patient's outcome compromised as a result. As well, misleading prognostic
      indications may be provided to the patient. It is therefore important to
      correctly identify all SNs in every patient and to remove them all for
      examination. To reduce the likelihood of error, a high-quality preoperative
      lymphoscintigraphy (LSG) is the first prerequisite. The surgical procedure must
      then be undertaken with great care to remove all of the SNs that have been
      identified by the LSG. This will involve both blue dye mapping and use of a gamma
      probe. A thorough knowledge and understanding of common and uncommon sites at
      which SNs can be located, as outlined here, will not only make the surgery
      simpler and quicker, but will reduce the possibility of error by diminishing the
      risk of overlooking possible locations at which SNs may be found.

PMID- 15190493
TI  - Pathology of the sentinel lymph node in melanoma.
AB  - The success and further evolution of the sentinel lymph node (SLN) concept
      decisively depend on histological techniques. Fundamental standards were agreed
      on by a panel of international experts from various disciplines in 1999 and
      published as "The Augsburg Consensus" in 2000. Conventional histology
      (hematoxylin and eosin [H&E]) has to be supplemented by immunohistochemistry (eg,
      S100 and HMB45) using adequate series of paraffin sections. Melanoma cells in
      SLNs must be carefully differentiated from capsular and trabecular nevocytes,
      from immigrated Langerhans cells, from interdigitating dendritic leukocytes, and
      from nerve sheath cells, which all share S100 positivity in the cytoplasm. The
      micromorphometric S classification is based on the maximum distance of intranodal
      melanoma cells from the interior margin of the SLN capsule. It has proven its
      practicability under routine circumstances, as well as its predictive value
      regarding further nodal and distant metastases as well as overall survival. This
      has to be considered in prospective randomized trials dealing with the issues of
      completion lymphadenectomy and adjuvant therapies of melanoma patients. Reverse
      transcriptase polymerase chain reaction (RT-PCR) techniques, when performed as a
      supplement to histology on the basis of additional paraffin sections, can further
      enhance the diagnostic sensitivity for detecting melanoma cells in SLNs.

PMID- 15190495
TI  - Sentinel lymph node mapping technique in colon cancer.
AB  - Current conventional surgical and pathological techniques substantially
      understage colon cancer. This is evidenced by the fact that a significant subset
      of patients who are stage I and II at the time of colectomy return with distant
      metastases and ultimately succumb to the disease within the next 5 years. The
      identification of more nodes within a specimen and the detailed analysis of lymph
      nodes with advanced pathological techniques such as immunohistochemistry and
      reverse-transcriptase polymerase chain reaction (RT-PCR) can improve the staging
      of colon cancer, but are also associated with tremendous financial, time, and
      labor constraints. Sentinel lymph node (SLN) mapping has provided an avenue of
      staging colon cancer with high success rates and accuracy rates, while
      maintaining cost- and time-effectiveness. The ability to reproduce these results
      is dependent on adherence to the technical details of the procedure, and thereby
      providing the pathologist with the true SLNs, upon which the advanced
      pathological studies can be applied. We report our experience of SLN mapping for
      colon tumors in 209 patients, elaborating on the materials used, technical
      details, pitfalls, and results of the procedure. Our results show a success rate
      of 100% (209/209) and an overall accuracy rate for predicting positive or
      negative metastatic disease of 96.2% (201/209). Nodal metastases were identified
      in 46.2% (85/184) of patients with invasive disease (stage T1 to T4). The SLN was
      the exclusive site of metastases in 38.8% (33/85) of these patients, and the
      nodal disease was detected only as micrometastases in 22.4% (19/85). The skip
      metastases rate (false negatives) was 9.4% (8/85). SLN mapping is a powerful tool
      for accurate staging of colon cancer with a high success rate. The upstaging
      associated with this procedure may reveal disease that might otherwise go
      undetected by conventional surgical and pathological methods. Those patients who
      are upstaged can then benefit from adjuvant chemotherapy, which has been shown to
      improve survival of colon cancer patients with nodal disease by at least 33%.

PMID- 15190494
TI  - National trials involving lymphatic mapping for melanoma: the Multicenter
      Selective Lymphadenectomy Trial, the Sunbelt Melanoma Trial, and the Florida
      Melanoma Trial.
AB  - Radioguided surgery and lymphatic mapping provide more accurate staging and a
      less morbid operation for the patient with malignant melanoma. It has rapidly
      become the standard of care for the nodal staging of this disease. Regional and
      national trials have been designed to address various questions that concern the
      application of this technique. The Multicenter Selective Lymphadenectomy Trial
      (MSLT), being performed by Donald Morton at the John Wayne Cancer Institute, is a
      national trial that will address whether this surgical strategy provides a
      survival benefit for patients. The national, industry-sponsored SunBelt Melanoma
      Trial (SBMT), with Kelly McMasters from the University of Louiville as the
      principle investigator, will determine the role of molecular staging in patients
      who undergo sentinel lymph node (SLN) harvest. In another arm of the study, the
      role of adjuvant interferon alfa (IFN) will be examined in patients with minimal
      disease in the regional basin, those patients with just one microscopically
      positive SLN. Finally, the Florida Melanoma Trial (FMT), with the central office
      and laboratory located at the Lakeland Regional Cancer Center, is a regional,
      industry-sponsored trial that will determine whether all patients with a positive
      SLN need to undergo a complete lymph node dissection (CLND) of the affected
      basin. Clinicians await the results of these three trials to help to determine
      the final role of radioguided surgery in patients with malignant melanoma.

PMID- 15190496
TI  - Lymphatic mapping for staging of head and neck cancer.
AB  - Lymphatic mapping with sentinel lymph node (SLN) biopsy can accurately stage the
      nodal basins in patients with melanoma of the trunk and extremities and has
      become a routine, well-accepted diagnostic method for melanoma at these anatomic
      locations. Melanoma of the head and neck (16% of all cases of melanoma) is
      complex and difficult to manage because of the rich abundant interlacing
      lymphatic drainage patterns, as well as watershed areas, which can lead to
      unusual and unexpected drainage patterns. Radioguided surgery in combination with
      blue dye facilitates localization of the SLN in the head and neck; however, this
      type of radioguided surgery is an evolving technique of some difficulty and thus
      requires careful coordination among the surgeon, nuclear medicine physician, and
      pathologist. Applications of this technique to other sites in the head and neck
      are currently being investigated for conditions including squamous cell carcinoma
      (SCC) of the oral cavity, thyroid cancer, and Merkel cell cancer. More studies of
      patients with head and neck cancer are needed--and technical issues must be
      resolved--before radioguided surgery can be recommended as the standard of care
      for these patients.

PMID- 15190497
TI  - Lymphatic mapping for gynecologic malignancies.
AB  - In gynecologic malignancies, regional lymph node status is a major prognostic
      factor and a decision criterion for adjuvant therapy. This is the basis for
      lymphadenectomy. The sentinel node (SN) procedure has emerged as an alternative
      to systematic lymphadenectomy in various cancers, reducing treatment-related
      morbidity. In melanoma and breast cancer, SN biopsy is the standard procedure for
      determining nodal stage. Use of the SN procedure is also well established in
      vulvar cancer. In small series, combined SN detection based on blue dye and
      radiocolloid was suitable for the evaluation of lymph node status in cervical
      cancer. Although some investigators have reported the feasibility of the SN
      procedure in endometrial cancer, further studies and standardization are required
      before its routine use can be recommended.

PMID- 15190498
TI  - The impact on nodal staging of lymphatic mapping in carcinoma of the colon and
      rectum.
AB  - Although the majority of individuals undergoing apparently curative resection for
      carcinoma of the colon rectum who are found to be without evidence of metastatic
      disease in the regional lymph nodes will remain free of disease, approximately
      20% to 30% of these individuals will develop recurrent disease and die. This may,
      in part, be due to understaging of the disease. For this reason, there has been
      increasing interest in approaches to improving staging of all solid tumors,
      including carcinoma of the colon and rectum. Lymphatic mapping has revolutionized
      the management of patients with cutaneous melanoma and breast cancer and has been
      demonstrated to more accurately stage patients with solid tumors. Our
      investigations as well as others have taken a number of strategies to improving
      the staging of individuals of colorectal cancer patients with apparently node
      negative disease, including the development of a novel ex vivo lymphatic mapping
      technique. This article summarizes our and other investigations into improved
      staging of colorectal cancer with an emphasis on the impact of lymphatic mapping
      on improving the accuracy of staging of apparently node-negative colorectal
      cancer patients.

PMID- 15190499
TI  - Lymphatic mapping for upper gastrointestinal malignancies.
AB  - Recent studies on lymphatic mapping of upper gastrointestinal (GI) malignancies
      have provided new insights with regard to the sentinel node (SN) concept in solid
      tumors. At present, the SN concept seems to be valid not only for breast cancer,
      but also for esophageal and gastric cancers, which have multidirectional and
      complicated lymphatic flows. In addition to the staging merits, individualized
      surgical management has been proposed for upper GI cancer based on the SN
      concept. Gastric cancer is now a suitable target of SN-guided surgery after
      breast cancer because of its anatomical situation. Laparoscopic local resection
      is theoretically feasible for curative treatment of SN-negative early gastric
      cancer. Because SNs in esophageal cancer are multiple and widespread, complete
      sampling of SNs is not a minimally invasive procedure, as it is in breast cancer.
      However, selective and modified lymphadenectomy targeting SNs for clinically N0
      esophageal cancer instead of three-field lymph node dissection should become not
      only feasible but also clinically important. When performing chemoradiotherapy as
      curative treatment for cT1N0 esophageal cancer, lymphoscintigrams revealing the
      distribution of SNs in each individual case are useful to tailor the field of
      irradiation to control occult micrometastases. Although there are several issues
      to be resolved, this novel procedure has the potential to improve quality control
      in upper GI cancer.

PMID- 15190500
TI  - The new staging system for cutaneous melanoma in the era of lymphatic mapping.
AB  - In 2002, the American Joint Committee on Cancer (AJCC) revised the staging system
      for cutaneous melanoma on the basis of a survival analysis of important melanoma
      prognostic factors. Features of the revised system include new strata for primary
      tumor thickness, incorporation of primary tumor ulceration as an important
      staging criterion in both the tumor (T) and node (N) classifications, revision of
      the N classification to reflect the prognostic significance of regional nodal
      tumor burden, and new categories for distant metastatic disease. These changes
      reflect evolving insight into melanoma arising from the results of numerous
      clinical investigations and database analyses. One of the most important recent
      changes in melanoma care is the establishment of lymphatic mapping and sentinel
      lymph node (SLN) biopsy as a highly accurate and minimally morbid technique for
      pathologic regional nodal staging. In this article, the salient features of the
      revised melanoma staging system are examined, with specific attention paid to its
      use in this era of lymphatic mapping and SLN biopsy.

PMID- 15190501
TI  - Sentinel lymph node dissection and the current status of American trials on
      breast lymphatic mapping.
AB  - The current national sentinel lymph node (SLN) clinical trials for breast
      carcinoma address the prognostic and therapeutic utility of SLN dissection (SLND)
      in women with early-stage, clinically node-negative breast cancer. Following
      completion of these studies, overall survival, disease-free survival, morbidity,
      and quality of life of patients will be compared. Surgeon participation is
      crucial to the ongoing success of clinical trials in the field of breast cancer
      surgery.

PMID- 15190509
TI  - Targeting the bone marrow microenvironment in hematologic malignancies.
AB  - Unicellular drug-resistant models have been critical in elucidating intrinsic
      drug-resistant mechanisms; however, these models do not consider resistance
      mechanisms that may be elicited by extrinsic influences such as the tumor
      microenvironment. We propose that specific niches within the tumor
      microenvironment may provide a sanctuary for subpopulations of tumor cells to
      evade or circumvent drug-induced death and that this may represent a form of de
      novo drug resistance. We have found that elements of the bone marrow
      microenvironment, including extracellular matrices and normal stromal elements,
      protect malignant cells, including leukemia and myeloma cells, from drug-induced
      cell death. This extrinsic form of drug resistance may allow cells to survive
      initial drug treatment and thereby acquire a more complex, intrinsic drug
      resistant phenotype. Focusing on this form of de novo drug resistance may
      ultimately prevent the emergence of acquired drug resistance and enhance drug
      therapy for hematologic malignancies.

PMID- 15190510
TI  - Myelodysplastic syndromes: From pathogenesis and prognosis to treatment.
AB  - Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by
      ineffective hematopoiesis resulting in peripheral cytopenia and by increased
      progression to acute myelocytic leukemia (AML). With the exception of allogeneic
      stem cell transplantation, there is generally no curative treatment for these
      disorders. As the contribution of diverse pathologic processes to ineffective
      hematopoiesis in MDS continues to be clarified, promising new avenues for
      treatment are being identified. Agents that interact with newly defined biologic
      targets and that are under investigation include arsenic trioxide, DNA
      methylation inhibitors, farnesyl transferase inhibitors, thalidomide,
      immunomodulating agents, and histone deacetylase inhibitors.

PMID- 15190511
TI  - Targeted therapies in myelodysplastic syndromes: ASH 2003 review.
AB  - The myelodysplastic syndromes (MDS) continue to pose conceptual and practical
      conundrums because of their heterogeneity and therapeutic challenges. They are
      not restricted to the presence of clonal cells that are prone to excessive
      proliferation and premature apoptosis. In MDS the bone marrow microenvironment
      also is abnormal and exhibits an excess of proinflammatory cytokines, especially
      tumor necrosis factor (TNF), neoangiogenesis, and poorly defined immune defects.
      Thalidomide, a drug with anti-TNF, antiangiogenic, and immunomodulatory
      activities, and other agents with anti-TNF effects, such as pentoxifylline,
      etanercept, and infliximab, have produced hematologic improvement in 20% to 40%
      of patients. These agents may provide effective therapy for a subset of lower
      risk MDS patients, even if the drugs target the bone marrow microenvironment
      predominantly. However, in higher-risk MDS patients, especially those with more
      than 10% blasts, it is important to eliminate abnormal cell clones; drugs used
      for this purpose have included arsenic trioxide, topotecan, the farnesyl
      transferase inhibitor tipifarnib, and demethylating agents, such as 5-azacytidine
      and decitabine. To increase the therapeutic index, a combination strategy may be
      preferable for higher-risk MDS patients, in whom the seed (clone) and the soil
      (bone marrow microenvironment) must be targeted simultaneously. The challenge is
      to recognize the subset that is likely to respond to a given drug so that
      patients can be preselected for therapy.

PMID- 15190512
TI  - Recent advances in the management of multiple myeloma.
AB  - Multiple myeloma (MM) is a B-cell malignancy that comprises 10% of all
      hematopoietic cancers. Even with aggressive chemotherapeutic regimens, the
      emergence of chemotherapy-resistant disease remains a notable therapeutic
      challenge, and there is no cure. The recent advances in understanding the
      mechanisms critical for MM cell growth and survival in its microenvironment have
      provided novel therapeutic targets to improve patient outcomes. Based on
      preclinical studies, the novel targeted agents thalidomide and its analogs,
      bortezomib and arsenic trioxide, have been evaluated in phase I and II clinical
      studies in refractory or relapsed MM and have demonstrated significant
      antimyeloma activity. Ongoing studies will further define their usefulness as
      primary therapies at earlier stages of disease. These innovative therapies for MM
      represent a new treatment paradigm, targeting tumor cells and their
      microenvironments to achieve greater tumor cytoreduction and potentially a cure.

PMID- 15190513
TI  - Acute promyelocytic leukemia as a paradigm for targeted therapy.
AB  - Substantial progress has occurred in the treatment of acute promyelocytic
      leukemia (APL) because of improved understanding of the pathophysiology of the
      disease and identification of a molecular target. Novel agents such as all-trans
      retinoic acid (ATRA) (alone or combined with chemotherapy) and, more recently,
      arsenic trioxide have produced complete remission in most patients with newly
      diagnosed APL and/or relapsed or refractory disease, respectively. Use of these
      targeted therapies has resulted in evolution of the disease from one that was
      historically one of the most fatal subtypes of acute myeloid leukemia (AML) to
      one that appears curable in 70% to 80% of patients. The targeted approach to
      treatment of this disease can serve as a paradigm for the treatment of other
      leukemias.

PMID- 15190515
TI  - The chronic myeloproliferative disorders: clonality and clinical heterogeneity.
AB  - The chronic myeloproliferative disorders (MPD), polycythemia vera (PV), chronic
      idiopathic myelofibrosis (IMF), essential thrombocytosis (ET), and chronic
      myelogenous leukemia (CML), are thought to be clonal disorders arising in a
      multipotent hematopoietic progenitor cell. However, establishing the diagnosis of
      an MPD other than CML is problematic due to a lack of clinically applicable
      clonal markers. Furthermore, in some patients, in whom a classical MPD phenotype
      is present, the hematopoietic stem cells appear to be polyclonal, suggesting that
      the chronic MPD other than CML may actually be a genetically heterogeneous group
      of disorders. Furthermore, since the aberrant clone is believed to arise from a
      multipotent hematopoietic stem cell, the non-CML chronic MPD-ET, PV, and IMF
      could be related. Additional unresolved issues regarding the MPD include:
      identification of the multipotent hematopoietic progenitor cell involved, the
      molecular basis for the clinical heterogeneity amongst the individual MPD, the
      clinical significance of clonality in non-CML MPD, and reconciliation of therapy
      with the clonal and clinical heterogeneity of these disorders. Determination of
      clonality has largely been carried out using X chromosome-linked polymorphisms,
      but such studies are limited to women and with increasing patient age are
      compromised by skewing of allelic expression in both neutrophils and T
      lymphocytes, making the results difficult to interpret. X chromosome-linked
      polymorphism studies have indicated that in PV the target stem cell is one that
      gives rise to both lymphoid and myeloid progenitors. Recently, two epigenetic
      markers have been identified in the MPD: impaired expression of the
      thrombopoietin receptor, Mpl, in platelets and megakaryocytes, and overexpression
      in neutrophils of the mRNA of a gene designated polycythemia rubra vera-1 (PRV
      1). The role of these epigenetic abnormalities in the diagnosis of the MPD
      remains to be established. Currently, given the unresolved issues with respect to
      the clinical and clonal heterogeneity of the MPD, treatment needs to be tailored
      individually in patients with an MPD.

PMID- 15190516
TI  - Molecular and biochemical basis for the platelet dysfunction in
      myeloproliferative disorders.
AB  - A large number of platelet abnormalities have been described in patients with
      myeloproliferative disorders (MPDs). Platelet abnormalities include defects in
      receptor expression on the platelet surface, platelet-platelet interactions, and
      platelet activation mechanisms. These platelet defects are demonstrable even in
      patients who are asymptomatic. Both hemorrhagic and thrombotic events occur in
      MPD patients. The mechanisms that underlie the platelet dysfunction in patients
      with MPDs are examined.

PMID- 15190518
TI  - The leukemia controversy in myeloproliferative disorders: is it a natural
      progression of disease, a secondary sequela of therapy, or a combination of both?
AB  - Polycythemia vera (PV) and essential thrombocythemia (ET) may rarely evolve into
      acute leukemia as part of their natural history. Cytogenetic abnormalities and
      the use of alkylating agents can enhance the risk of this transformation.
      Hydroxyurea (HU) has a limited, if any, leukemogenic potential and should be
      considered the current cytotoxic drug for patients at high risk for thrombotic
      complications, ie, those with age above 60 years or previous thrombotic events.
      Interferon-alpha (IFN-alpha) and anagrelide are known not to be leukemogenic and
      might have a role in younger patients. However, no controlled clinical trials of
      efficacy and safety are available for these two drugs and the occurrence of side
      effects may be a limiting factor for their widespread use.

PMID- 15190517
TI  - Propensity for hemorrhage and thrombosis in chronic myeloproliferative disorders.
AB  - Polycythemia vera (PV) and essential thrombocythemia (ET) are two
      myeloproliferative disorders (MPDs) with frequent thrombotic and hemorrhagic
      complications. Thrombosis is often the cause of mortality in PV and ET;
      hemorrhage occurs more commonly in idiopathic myelofibrosis patients, but is
      rarely fatal. Thromboses may occur in arteries or veins. Splanchnic, portal,
      hepatic, and splenic vein thromboses are not uncommon and thrombosis is also
      thought to cause placental vascular insufficiency and fetal wastage during
      pregnancies in MPD patients. These complications may result because of altered
      interactions between platelets, white blood cells, or endothelial cells, due to
      either altered receptor expression, receptor-ligand interactions, or signaling
      events. Age, leukocytosis, increased hematocrit, and a history of thrombotic
      events are risk factors for thrombosis. In determining a link between clonality
      and thrombosis using X-chromosome inactivation patterns in patients with ET,
      those who were polyclonal were less likely to experience thromboses. The search
      for hypercoagulability in these patients led to identification of changes in the
      expression patterns of coagulation proteins from the coagulation cascade.
      Mutations in factor V Leiden were examined and the incidence of mutations did not
      vary between normal and MPD patients. However, mutations in factor V Leiden were
      found to be risk factors for venous thrombotic events. Similarly, presence of a
      prothrombin gene mutation showed a higher risk for venous thromboembolic events.
      Proteolyzed thrombospondin appeared to contribute to hypercoagulability, and
      acquired von Willebrand factor disorder gave rise to hemorrhagic complications.
      These findings provide several potential reasons for thrombotic and hemorrhagic
      complications in MPD patients. Therefore, the best therapy for these patients is
      reduction of their platelet counts to less than 450,000/microL and close
      regulation of their hematocrits. The role of leukocytosis in bleeding or
      hemorrhage in this population remains to be elucidated.

PMID- 15190519
TI  - Treatment paradigms in the management of myeloproliferative disorders.
AB  - Myeloproliferative disorders (MPDs) are chronic conditions that require long-term
      treatment. MPDs have been considered neoplastic disorders that have a propensity
      to transform to acute leukemia or myelodysplastic syndrome. One of the MPDs,
      chronic myeloid leukemia (CML), has the distinct cytogenetic abnormality of the
      Philadelphia chromosome. In CML, transformation to acute leukemia is a common
      occurrence, with the timeline measured in years rather than decades. With the
      other three disorders from this group, polycythemia vera (PV), essential
      thrombocythemia (ET), and idiopathic myelofibrosis (IMF), transformation to acute
      leukemia is less frequently seen and, although variable, can take a longer period
      of time. The choice of therapy used for MPDs may contribute to leukemic
      transformation; chlorambucil, busulfan, and radiophosphorus are all examples of
      therapy that have been shown to be leukemogenic. Several studies have suggested
      the potential leukemogenicity of hydroxyurea (HU), but this remains controversial
      because no randomized studies have been conducted. The two newest agents used for
      MPDs, interferon-alpha and anagrelide, have both been studied for efficacy, but
      their influence on the potential for leukemic transformation has not been well
      studied to date.

PMID- 15190520
TI  - Transplant strategies for idiopathic myelofibrosis.
AB  - Idiopathic myelofibrosis (IMF) is a clonal stem cell disorder and is one of the
      four major myeloproliferative disorders, which include essential thrombocythemia
      (ET), polycythemia vera (PV), and chronic myelogenous leukemia (CML). Patients
      may be asymptomatic at the early stages, but later progress to marrow fibrosis,
      splenomegaly with pancytopenia leading to anemia, and other constitutional
      symptoms. Most of the care available is supportive and only palliates the
      constitutional symptoms. Prognosis for these patients is dependent on karyotype,
      hemoglobin count, and age. Stem cell transplantation is the only curative
      therapy, which results in eradication of the stem cell clone, with the cessation
      of extramedullary hematopoiesis and resolution of marrow fibrosis and its
      sequelae. Stem cell replacement therapy using either autologous or allogeneic
      stem cells has been attempted in small populations of patients with variable
      benefit. A nonmyeloablative approach has shown promise in a very small number of
      patients, but additional investigation is required for the ideal management of
      these patients.

PMID- 15190522
TI  - Mixed cryoglobulinemia: demographic, clinical, and serologic features and
      survival in 231 patients.
AB  - BACKGROUND: Mixed cryoglobulinemia (MC) is a systemic vasculitis secondary to
      circulating immune complex deposition in the small vessels. In the overwhelming
      majority of patients, hepatitis C virus (HCV) infection represents the triggering
      factor of the disease. MC is characterized by multiple organ involvement, mainly
      skin, liver, renal, peripheral nerves, and less frequently by widespread
      vasculitis and cancer. OBJECTIVES: To investigate the demographic, clinical,
      serologic features, and survival in a large series of MC patients. METHODS: The
      study included 231 MC patients recruited between 1972 and 2001 at the
      Rheumatology Unit of the University of Pisa. All patients underwent wide
      clinicoserologic and virologic assessment. Cumulative survival rates were
      computed by the Kaplan-Meier method; moreover, the prognostic relevance of the
      main variables was investigated by Cox model analysis. RESULTS: In 92% of cases,
      the presence of HCV infection was demonstrated (anti-HCV antibody, 92%; HCV RNA,
      90%), whereas hepatitis B virus (HBV) represented the possible causative agent in
      only 1.8% of patients (HBV DNA). Clinically, the MC syndrome followed a
      relatively benign clinical course in over 50% of cases, whereas a moderate-severe
      clinical course was observed in one third of patients whose prognosis was
      severely affected by renal and/or liver failure. In a limited, but significant,
      percentage (15%) of individuals, the disease was complicated by a malignancy, ie,
      B-cell lymphoma, and less frequently by hepatocellular carcinoma, or thyroid
      cancer. The survival study by the Kaplan-Meier method revealed a significantly
      lower cumulative 10th-year survival, calculated from time of diagnosis, in MC
      patients compared with expected death in the age- and sex-matched general
      population. Moreover, significantly lower survival rates were observed in males
      and in subjects with renal involvement. The multivariate analysis by the Cox
      proportional hazard regression model further supported the above findings: an
      increased mortality risk of 98% was observed for male gender (male/female hazard
      ratio, 1.978) and of 197% in patients with, compared with those without, renal
      involvement (hazard ratio, 2.967). At the end of the follow-up, 97 patients were
      deceased, and in 79 of 97 patients, the causes of death were ascertained:
      nephropathy (33%), malignancies (23%), liver involvement (13%), and diffuse
      vasculitis (13%) were the most frequent causes of death. CONCLUSIONS: Careful
      patient monitoring is recommended for a timely diagnosis of life-threatening MC
      complications, mainly nephropathy, widespread vasculitis, and B-cell lymphoma or
      other malignancies.

PMID- 15190523
TI  - The case for hepatitis C arthritis.
AB  - OBJECTIVE: To present the data available supporting the existence of an
      arthropathy associated with hepatitis C infection. METHODS: The MEDLINE database
      was searched for "arthritis" intersecting with "hepatitis C" in addition to the
      authors' investigations and experience on this subject. RESULTS: Arthritis, not
      otherwise explained, has been noted in 2% to 20% of hepatitis C virus (HCV)
      patients. This arthritis is rheumatoid-like in two thirds of the cases and a
      waxing/waning oligoarthritis in the rest. Cryoglobulinemia alone does not explain
      the arthritis, and there is difficulty in differentiating it from rheumatoid
      arthritis. The arthropathy is nonerosive/nondeforming. Whereas nonsteroidal anti
      inflammatory drugs, low-dose corticosteroids, and hydroxychloroquine may be
      helpful, conventional treatment of arthritis may be problematic in the context of
      viral hepatitic arthropathy. Antiviral therapy is most effective, even without
      viral clearance, but rheumatic complications may ensue. CONCLUSIONS: HCV
      arthropathy should be considered in the differential diagnosis of new-onset
      arthritis.

PMID- 15190524
TI  - Relapsing polychondritis, chronic hepatitis C virus infection, and mixed
      cryoglobulemia.
AB  - OBJECTIVE: Review of relapsing polychondritis (RP) and its association to chronic
      hepatitis C virus (HCV) infection and mixed cryoglobulinemia. METHODS: A case of
      RP associated with HCV infection is reported. The English language medical and
      scientific literature was reviewed for RP, hepatitis C, and its relation to other
      connective tissue diseases from February 1966 to January 2003 using MEDLINE.
      RESULTS: RP is an uncommon, multisystem disease of unknown etiology characterized
      by recurrent inflammation of cartilaginous and related tissues, being associated
      with other diseases in 30% to 35% of cases. HCV infection is a systemic illness
      with a propensity to trigger or exacerbate autoimmune disorders: eg, essential
      mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and
      leukocytoclastic and systemic vasculitis. We could find no previous report of an
      association between RP with HCV and mixed cryoglobulinemia. Treatment with
      interferon gamma and ribavirin (IR) not only induced an undetectable viral load,
      but also resolved symptoms of RP. CONCLUSIONS: We report a patient with RP, HCV,
      and mixed cryoglobulinemia. It is unknown if there is a cause-effect or chance
      relationship. Treatment with IR improved the symptoms of RP. It is not known
      whether the effects of IR were directly on the RP or suppressed RP indirectly
      through the actions on the viral load or active hepatitis.

PMID- 15190525
TI  - Th1/Th2 cytokines in patients with systemic lupus erythematosus: is tumor
      necrosis factor alpha protective?
AB  - OBJECTIVES: To determine the circulating levels of Th1 and Th2 cytokines in
      patients with systemic lupus erythematosus (SLE) and to elucidate their
      association with disease activity and autoimmune response. METHODS: We included
      52 patients and 25 healthy controls. Serum levels of tumor necrosis factor (TNF)
      alpha, interferon (IFN) gamma, interleukin (IL)-12p70, IL-10, and IL-4, as well
      as anti-DNA, -Ro, -La, -RNP, and -Sm antibodies were determined by enzyme-linked
      immunosorbent assay. Disease activity was recorded according to the Systemic
      Lupus Erythematosus Disease Activity Index (SLEDAI) and classified as very active
      (SLEDAI > or = 13), moderately active (SLEDAI: 3-12), or inactive (SLEDAI < or =
      2). RESULTS: The mean age of the patients was 34.2 +/- 12.6 years, and the mean
      duration of disease was 4.9 +/- 7.6 years. Twelve patients (23%), 20 patients
      (34.5%), and 20 patients (34.5%) had highly, moderately, and inactive SLE,
      respectively. Levels of IFN-gamma, TNF-alpha, and IL-12 were significantly higher
      in patients than in healthy controls (P <.03), as well as the IL-12/IL-10, IL
      12/IL-4, IFN/IL-10, IFN/IL-4, TNF/IL-10, and TNF/IL-4 ratios (P <.01), suggesting
      a major participation of Th1 over Th2 cytokines. Nevertheless, a direct
      correlation between Th1 (IFN-gamma and TNF-alpha) and Th2 (IL-4 and IL-10)
      cytokines was observed in patients (r >.5, P <.01), indicating a mutual Th1-Th2
      participation. TNF-alpha levels and the TNF/IL-10 ratio were higher in patients
      with inactive disease compared with patients with very active disease and
      controls (P <.04). IL-12 levels and IL-12/IL-4, as well as IL-12/IL-10, ratios
      were higher in patients with very active disease than in those with inactive SLE
      and controls (P <.01). IL-10 levels were associated with anti-DNA, anti-Ro, and
      anti-La response (P <.01). CONCLUSION: Our results suggest that TNF-alpha could
      be a protective factor in SLE patients, whereas IL-12p70 participates in disease
      activity and IL-10 influences the autoimmune response (autoantibody production).

PMID- 15190526
TI  - Pulmonary hemorrhage in systemic lupus erythematosus.
AB  - OBJECTIVE: To determine the clinical features of our systemic lupus erythematosus
      (SLE) patients presenting with pulmonary hemorrhage (PH). METHODS: We reviewed
      the records of all SLE patients who had PH between 1994 and 2001, a total of 22.
      RESULTS: All patients had radiographic infiltrates. The mean drop in hemoglobin
      was 3.2 +/-1.1 g/dL, hemoptysis occurred in 50%, the Dlco was increased in 10 of
      11 patients (91%), and 11 of 14 patients who underwent bronchoscopy had positive
      findings. All received high-dose prednisolone and most also were given pulse
      methylprednisolone (MEP) and cyclophosphamide. All patients required care in the
      intensive/monitored care unit, 14 were intubated, 11 had plasmapheresis, and 8
      died as a result of PH (mortality rate, 36%). SLEDAI and SLAM were able to
      indicate active disease in SLE patients with PH (median SLEDAI, 19 [interquartile
      range, 10 to 24] and mean SLAM, 16.1 +/- 5.8). There was a statistically
      significant increase in the SLEDAI from 1 month prior to PH to the time of PH (P
      =.014), indicating that the patients were having a significant disease flare. The
      median SLEDAI and SLAM scores of patients who died were slightly higher than that
      of survivors. CONCLUSION: PH in SLE patients occurred in those with severe,
      multiorgan involvement, with high SLEDAI scores. A high degree of suspicion
      should be maintained in lupus patients with active disease and unexplained
      infiltrates on chest radiographs and dropping red cell indices, even in the
      absence of hemoptysis. Early aggressive management with high-dose steroids and
      intravenous pulses of cyclophosphamide is advocated and may explain recent trends
      of improved survival. Plasmapheresis may be useful for the acutely ill patient
      who does not respond to the above measures but does not clearly lead to improved
      survival.

PMID- 15190527
TI  - Rationale, design, and methods for a pivotal randomized clinical trial for the
      assessment of a cardiac support device in patients with New York health
      association class III-IV heart failure.
AB  - BACKGROUND: Heart failure remains a progressive disease with incremental
      morbidity and mortality despite optimal medical therapy. A growing body of
      evidence suggests that progressive left ventricular (LV) remodeling is directly
      related to a deterioration in LV performance and untoward clinical outcomes for
      heart failure patients. Preclinical and early phase I clinical studies with the
      CorCap Cardiac Support Device (CSD), a passive cardiac support device that
      prevents cardiac remodeling, have shown that it is safe and is associated with
      improvements in LV structure and function, as well as patient symptomatology.
      METHODS AND RESULTS: The Acorn Pivotal Trial is a pivotal prospective,
      randomized, evaluation of the CorCap CSD in patients with New York Heart
      Association class III-IV heart failure. Patients will be enrolled into one of two
      different strata. Patients who require a mitral valve repair/replacement (MVR)
      will fall into the "MVR stratum" and will be randomized to either treatment (MVR
      surgery plus the CSD) or control (MVR surgery alone). Patients who do not have a
      clinical indication for MVR surgery will fall into the "no-MVR stratum" and will
      also be randomized to either treatment (CSD implant plus optimal medical therapy)
      or control (optimal medical therapy alone). A total of 300 patients (150
      treatment and 150 control) will be enrolled. The primary endpoint of the trial is
      the change in clinical status from baseline to the end of the efficacy phase (1
      year), as determined by a clinical composite score. Patients will be classified
      as improved, worsened, or unchanged based upon patient vital status, the
      occurrence of a major cardiac procedure indicative of heart failure progression,
      and a change in the assessment of New York Heart Association functional class.
      CONCLUSIONS: The Acorn Pivotal Trial will formally test the hypothesis that
      preventing LV remodeling using a passive cardiac support device will favorably
      impact the untoward natural history of heart failure and thus represents an
      important departure from all previous medical and device studies that have been
      reported to date.

PMID- 15190528
TI  - A phase II, double-blind, randomized, placebo-controlled, dose comparative study
      of the efficacy, tolerability, and safety of MCC-135 in subjects with chronic
      heart failure, NYHA class II/III (MCC-135-GO1 study): rationale and design.
AB  - BACKGROUND: Chronic heart failure (CHF) can be caused either by a predominant
      abnormality in systolic function (systolic heart failure) or a predominant
      abnormality in diastolic function (diastolic heart failure). Randomized clinical
      trials have identified a number of pharmaceutical agents that can reduce
      morbidity and mortality in patients with systolic heart failure. Despite
      significant therapeutic advances, systolic heart failure continues to result in
      high rates of morbidity and mortality. In contrast to systolic heart failure, no
      randomized clinical trials have been performed in patients with diastolic heart
      failure. Common to the mechanisms causing both systolic and diastolic heart
      failure are abnormalities in calcium homeostasis. Mitsubishi Pharma Corporation
      has developed a compound (MCC-135, INN; caldaret) whose mechanism of action is
      proposed to be modulation of calcium homeostasis at the sarcoplasmic reticulum
      and cellular membrane. The purpose of this study was to test the safety,
      tolerability, and efficacy of MCC-135 in patients with mild to moderate heart
      failure. METHODS: This was a phase II, multicenter, randomized, double-blind
      study of parallel group design comparing 3 oral dose regimens of MCC-135 (5 mg,
      25 mg, 50 mg, twice daily) with a placebo control. The treatment period was 24
      weeks. A total of 511 patients were recruited from 69 centers in the United
      States and Europe. One hundred and twenty-five patients were recruited in each of
      the 4 treatment groups. Patients in each treatment group were divided into 2
      cohorts: those with an ejection fraction < or = 40%, and those with an ejection
      fraction >40% as determined by core laboratory analysis of echocardiographic
      studies. CONCLUSION: Patient recruitment was completed in September 2002. Patient
      follow-up was completed by February 2003; the results will be available for
      release in 2004.

PMID- 15190529
TI  - Consensus statement: Palliative and supportive care in advanced heart failure.
AB  - BACKGROUND: A consensus conference was convened to define the current state and
      important gaps in knowledge and needed research on "Palliative and Supportive
      Care in Advanced Heart Failure." EVIDENCE: Evidence was drawn from expert opinion
      and from extensive review of the medical literature, evidence-based guidelines,
      and reviews. CONCLUSIONS: The conference identified gaps in current knowledge,
      practice, and research relating to prognostication, symptom management, and
      supportive care for advanced heart failure (HF). Specific conclusions include:
      (1) although supportive care should be integrated throughout treatment of
      patients with advanced HF, data are needed to understand how to best decrease
      physical and psychosocial burdens of advanced HF and to meet patient and family
      needs; (2) prognostication in advanced HF is difficult and data are needed to
      understand which patients will benefit from which interventions and how best to
      counsel patients with advanced HF; (3) research is needed to identify which
      interventions improve quality of life and best achieve the outcomes desired by
      patients and family members; (4) care should be coordinated between sites of
      care, and barriers to evidence-based practice must be addressed programmatically;
      and (5) more research is needed to identify the content and technique of
      communicating prognosis and treatment options with patients with advanced HF;
      physicians caring for patients with advanced HF must develop skills to better
      integrate the patient's preferences into the goals of care.

PMID- 15190530
TI  - Searching for evidence: Refractory questions in advanced heart failure.
AB  - BACKGROUND: Despite ample data from randomized clinical trials (RCTs), the
      management of advanced heart failure (HF) varies greatly. We examined the most
      common refractory questions arising in routine inpatient management of advanced
      HF. METHODS: From the inpatient HF service at 1 hospital, we prospectively
      recorded clinical questions arising for which there were no clear answers
      available about HF management. When possible, patients received angiotensin
      converting enzyme (ACE) inhibitors, beta-blockers, and spironolactone as used in
      RCTs. We identified the topics and frequencies of questions and categorized them
      as Group 1--whether to use a therapy--or Group 2--how to use a therapy. RESULTS:
      During 2 separate months, 318 questions arose among 57 patients. The most common
      topics involved the use of diuretics, potassium, and ACE inhibitors, most often
      about how to titrate diuretics, what targets to use to optimize diuretic therapy,
      and how to select discharge doses of diuretics. Questions of whether to use a
      therapy occurred 73 times, and how to use a therapy, 242 times. RCT data were
      difficult to apply to these questions because little information exists about how
      to combine and titrate HF drugs and how to adjust diuretics. Questions about
      individual drugs arose in patients who fell outside the average RCT entry
      criteria for age, blood pressure, and creatinine. CONCLUSION: Most refractory
      questions focused on how to integrate and adjust therapies within the overall
      medical regimen and how to apply data to patients not represented in RCTs. Future
      studies should evaluate strategies of care for the advanced HF population.

PMID- 15190531
TI  - Remote titration of carvedilol for heart failure patients by advanced practice
      nurses.
AB  - BACKGROUND: beta-blockers (BB) in the treatment of heart failure (HF) are
      frequently underprescribed and underdosed, perhaps because of recommendations for
      office visits at each dose change. In previous work, we demonstrated the
      feasibility of remote telephonically assisted BB titration and found favorable
      effects on morbidity, time to target dose, and low withdrawal rates. In the
      current expanded evaluation, we reasoned that a structured remote telephonic
      titration protocol would achieve outcomes comparable to US Carvedilol Trials in
      regard to optimal dose, titration time, and morbidity. METHODS: Seventy HF
      patients were initiated on BB therapy (carvedilol). Before therapy, patients were
      instructed on BB side effects, pulse taking, and weight monitoring. Patients
      reported weights, vital signs, and symptoms 3 times per week by phone. Advanced
      practice nurses counseled, educated, and reminded patients to increase their dose
      every 2 weeks until target doses were reached. RESULTS: A total of 96% reached a
      therapeutic dose (6.25 mg twice daily). Moreover, 71% of patients reached target
      doses of 25 mg twice weekly in approximately 8 weeks. No HF hospitalizations
      occurred during remote titration. CONCLUSIONS: The use of advanced practice
      nurses, titration protocols, and telemanagement technologies may improve the
      number of HF patients initiated and treated with appropriate doses of BB.

PMID- 15190532
TI  - Quality improvement in heart failure: a simple solution to the beta-blocker
      problem.

PMID- 15190533
TI  - Development and validation of a patient questionnaire to determine New York Heart
      Association classification.
AB  - BACKGROUND: New York Heart Association (NYHA) classification correlates with
      quality of life and is useful in tracking changes in status in clinical trials.
      We explored methods to determine NYHA class in multicenter trials where double
      blind conditions could not be maintained. METHODS AND RESULTS: A questionnaire
      was developed containing 7 major questions based on the standard definitions of
      NYHA classes. The questionnaire was administered to 116 patients with varying
      degrees of heart failure. When comparing NYHA determined by physicians at the
      site to NYHA assigned by 3 independent physician graders, there was an
      approximate 60% concordance. Concordance between independent reviewers was
      approximately 75%. Results of repeat grading of 30 randomly selected
      questionnaires indicated that graders provided the same score 90% of the time.
      Thus, although there were some differences from the site determination of NYHA
      class, the questionnaire had good inter- and intragrader reproducibility. In a
      second group of 103 patients enrolled in an ongoing device-intervention trial, we
      demonstrated that it is feasible to employ the questionnaire in a multicenter
      trial. Finally, NYHA class was correlated with quality of life and peak exercise
      oxygen consumption. CONCLUSIONS: A standardized questionnaire provided an
      approximate 60% concordance in assigning NYHA classification compared to the site
      assessment with approximately 90% reproducibility. This approach may be useful to
      determine NYHA classification within the context of clinical trials where blinded
      conditions are not possible.

PMID- 15190534
TI  - Attenuated respiratory modulation of chemoreflex-mediated sympathoexcitation in
      patients with chronic heart failure.
AB  - BACKGROUND: Enhanced hypercapnic chemoreflex in chronic heart failure could
      modulate sympathetic nerve activity in a different manner depending on the
      severity of heart failure. This study was designed to evaluate the dynamic
      aspects of sympathoexcitation caused by central hypercapnic chemoreflex in
      patients with chronic heart failure. METHODS AND RESULTS: In 21 patients with
      chronic heart failure, wavelet analysis was applied to elucidate the spectral
      components of muscle sympathetic nerve activity (MSNA) and instantaneous
      ventilation during hypercapnic chemoreceptor stimulation. Hypercapnia increased
      MSNA (83+/-8 versus 29+/-9 %, P<.01) and ventilation (209+/-27 versus 190+/-21%,
      P<.05) more in 12 symptomatic patients than in 9 asymptomatic patients. This
      hypercapnic chemoreflex exerted a greater influence on the sympathetic limb than
      on the ventilatory limb in the symptomatic patients. The wavelet analysis
      revealed that the within-breath sympathoinhibition in the symptomatic patients
      was attenuated as compared with that in the asymptomatic patients (0.33+/-0.03
      vs. 0.44+/-0.04, P<.05). CONCLUSIONS: The enhanced chemoreflex sympathetic drive
      and relative attenuation of ventilatory sympathoinhibition could contribute to
      exaggerated sympathoexcitation in patients with heart failure when they are
      exposed to carbon dioxide during exercise or sleep apnea.

PMID- 15190535
TI  - PET abnormalities in patients with nonischemic cardiomyopathy.
AB  - BACKGROUND: The abnormalities in dilated cardiomyopathy (DCM) are generally
      considered diffuse and to affect the left ventricle in a global manner. However,
      regional wall motion abnormalities and metabolic defects may also occur to
      varying, but unclear degrees. QRS width and metabolic defects on positron
      emission tomography (PET) correlate with survival. We sought to ascertain the
      prevalence of regional defects in DCM by multiple imaging modalities and to
      establish the relationship between QRS width and these defects. METHODS: In
      consecutive patients with advanced nonischemic DCM, undergoing cardiac transplant
      evaluation, we reviewed multiple imaging modalities (PET, 2-dimensional
      echocardiography, and radionuclide ventriculography) to quantify the incidence of
      regional metabolic and wall motion abnormalities and correlate them with clinical
      and electrocardiographic parameters. RESULTS: Of 44 patients studied, PET imaging
      revealed scar in 91% of patients, with a mean of 25 +/- 18% of the left ventricle
      involved, predominantly in the distribution of the left anterior descending
      artery. Regional wall motion abnormalities occurred in 51% of patients who
      underwent echocardiography and 59% of patients who underwent nuclear scintigraphy
      (with only 70% concordance). QRS duration on the surface electrocardiogram
      correlated positively with the degree of scarring (r=.52, P=.0007). CONCLUSIONS:
      The presence of scar (matched perfusion and metabolic defects) on PET scanning in
      patients with advanced DCM is not always indicative of coronary disease. Thus
      coronary angiography is usually required to define the etiology of systolic
      dysfunction. The extent of scar correlates with QRS duration. This may have
      implications for the application of cardiac resynchronization therapy.

PMID- 15190536
TI  - Chronic left ventricular failure in the community: Prevalence, prognosis, and
      predictors of the complete clinical recovery with return of cardiac size and
      function to normal in patients undergoing optimal therapy.
AB  - BACKGROUND: Chronic heart failure (CHF) is a progressive process requiring
      complex therapeutic interventions. Recently, several trials documented the
      clinical improvement and regression of left ventricular (LV) remodeling and
      function in patients on optimized CHF treatment. Furthermore, some authors
      reported isolated cases of patients who apparently "healed" from CHF. The aim of
      the present study was to characterize the phenomenon of the normalization in
      clinical status and LV size and function in CHF patients. METHODS AND RESULTS: We
      monitored the clinical and echocardiographic parameters of a large cohort of
      patients with CHF and LV ejection fraction <40% every 6 months for a mean period
      of 17 +/- 9 months. Twenty of 110 study patients (18%) normalized clinical status
      and LV size and ejection fraction at any time (mean time 13 +/- 6 months) during
      the follow up. Such condition, however, was subsequently lost in 11 patients. The
      normalization was predicted by the nonischemic etiology of CHF, arterial
      hypertension, absence of diabetes mellitus, carvedilol therapy, and the dose of
      carvedilol. CONCLUSIONS: The normalization in clinical status and LV size and
      function is not infrequently observed in patients on optimal CHF therapy. It is
      predicted by a set of clinical variables and favored by beta-blocker therapy. At
      medium term, this condition fades in a significant portion of patients.

PMID- 15190537
TI  - Why is depression bad for the failing heart? A review of the mechanistic
      relationship between depression and heart failure.
AB  - BACKGROUND: Depression is 4 to 5 times as common in heart failure (HF) patients
      as in the general population, might confer a higher risk of developing HF, and
      negatively affects prognosis in established HF. METHODS AND RESULTS: A review was
      undertaken via Medline (1966-2003) and PsycINFO (1872-2003) searches using the
      subject headings "depressive disorder" and "heart failure, congestive." Our
      findings suggest that the link between depression and HF may be due to shared
      pathophysiology. Depression may augment catecholamine release, arrhythmias,
      elaboration of proinflammatory cytokines, and platelet activation--processes that
      may influence prognosis in HF. Depression is also associated with a higher risk
      of noncompliance and lower levels of social support, which have been shown to
      worsen prognosis in HF. The impact of pharmacologic or behavioral treatment for
      depression on physiologic parameters or clinical outcomes in HF remains unclear.
      Inherent difficulties in recognition of depression in the setting of HF may
      decrease the likelihood that depressed patients receive the treatment they need.
      CONCLUSIONS: Depression is common in HF, may contribute to the development of HF
      in susceptible populations, and is independently predictive of poor clinical
      outcomes. Pathophysiologic pathways and psychosocial issues that are shared
      between the 2 conditions might explain these observations and represent potential
      therapeutic targets. Vigilant attention to the recognition and treatment of
      depression in HF patients is warranted.

PMID- 15190539
TI  - Proceedings of the Spring 2003 Current Concepts in Joint Replacement meeting. Las
      Vegas, Nevada, USA.

PMID- 15190540
TI  - Arthroscopy before arthroplasty: a con or a comfort?
AB  - The proliferation of arthroscopic procedures in the United States has called into
      question the efficacy of this technique in the presence of degenerative arthritis
      of the knee. Appropriate filters such as a history of mechanical rather than
      inflammatory symptoms, the presence or absence of a joint space on weight-bearing
      radiographs, and the exhaustion of other less invasive measures are not only
      increasingly appropriate, but may soon be mandated by Medicare and other third
      party payers. It is important that orthopedic surgeons lead and modulate this
      debate in the interest of their patients and the quality of their surgeries.

PMID- 15190541
TI  - Proximal tibial osteotomy: where did you go?
AB  - The prevalence of knee osteotomy seems to have diminished. Better total knee
      arthroplasty (TKA) results, greater survival, increased use of unicompartmental
      arthroplasty, and decreased surgeon confidence for osteotomy are likely causes.
      However, continued use of knee osteotomy is encouraged by this author. TKAs are
      not perfect. Furthermore, there is limited long-term durability data for younger,
      active patients. At 40 to 60 years of age at the time of surgery, some patients
      will need prosthetic replacements that must last up to 40 to 60 years. A case is
      made for performing an osteotomy earlier rather than later. Regarding TKA after
      proximal tibial osteotomy, the difficulty and inappropriateness of the standard
      comparisons are clear. Comparison of a virgin primary knee at one point in time,
      with a patient whose situation led to osteotomy surgery 5 to >10 years earlier is
      not a matched comparison. It is proposed that future biologic resurfacing,
      together with computer-and even robotic-methods, as well as other advances in
      biology and technology, will combine to resurrect the performance of knee
      osteotomies.

PMID- 15190542
TI  - Unicompartmental knee arthroplasty: new indications, more complications?
AB  - Despite mixed results with unicompartmental knee arthroplasty (UKA) in the 1970s,
      the UKA was established as a reliable procedure in the low-demand, elderly
      patient. Dependable results up to a decade prompted the idea that UKA may work
      equally well in the younger patient. Expanded indications for UKA are being
      evaluated: might higher failure rates and difficult revisions emerge from
      younger, more active patients?

PMID- 15190543
TI  - Cemented posterior stabilized total knee arthroplasty.
AB  - In the development of modern cemented total knee arthroplasty, the posterior
      stabilized knee prosthesis was designed to substitute for the function of the
      posterior cruciate ligament. Implant designs include the Insall Burstein
      posterior stabilized knee and the Legacy posterior stabilized knee. The primary
      feature of these prostheses is the femoral cam and tibial spine mechanism, which
      prevents posterior tibial subluxation and enhances knee kinematics. Another
      important feature is the relatively conforming round on round articular geometry
      that mitigates edge loading and reduces polyethylene damage. In concert, these
      features have produced a lineage of implants with unsurpassed clinical results,
      predictable kinematics and durability, which have been reproducible and well
      documented.

PMID- 15190544
TI  - The rationale for a total knee implant that confers anteroposterior stability
      throughout range of motion.
AB  - The topic at hand in this series of presentations concerns the design of total
      knee prostheses. This presentation concerns the rationale for an implant to
      confer anteroposterior stability without the need for a central "cam and post"
      mechanism, as is common in posterior cruciate-substituting total knee
      arthroplasty prostheses.

PMID- 15190545
TI  - Mobile-bearing knee arthroplasty: rotation is our salvation!
AB  - Rotating-platform knee arthroplasties have enjoyed an outstanding clinical
      history since their introduction in 1978. Mechanical complications requiring
      further surgery have been identified and include loosening, bearing dislocation,
      bearing wear, and osteolysis. No structural, metallic failures were reported,
      although extreme bearing wear was noted to cause metal surface damage sufficient
      to require revision in isolated cases. Survivorship of primary LCS cemented
      rotating-platform knee arthroplasties using an endpoint of revision of any
      component for any reason was 97.7% at the 20-year interval. Survivorship of
      primary LCS cementless rotating-platform knee arthroplasties using the same
      endpoint was 98.3% at the 18-year interval.

PMID- 15190546
TI  - Why knees fail: lessons learned.
AB  - This article reviews the changing modes of failure in total knee arthroplasty
      over the past decade. Reasons for failure include polyethylene wear, aseptic
      loosening, instability, infection, arthrofibrosis, malalignment, or malposition,
      deficient extensor mechanism, periprosthetic fracture, and isolated patellar
      resurfacing. Awareness of the modes of failure may lower the prevalence of
      failure and aid in developing designs and techniques to better address the
      problems.

PMID- 15190547
TI  - Evaluation of painful total knee arthroplasty.
AB  - Numerous conditions exist that may cause pain following total knee arthroplasty
      (TKA) that can be categorized into articular versus nonarticular etiologies. To
      critically evaluate the painful TKA, the treating physician must perform a
      thorough history and physical examination, as well as both laboratory and
      radiographic testing. Laboratory analysis is directed to differentiate septic
      versus aseptic etiologies of knee pain and commonly includes assessment of white
      blood cell count, erythrocyte sedimentation rate, C-reactive protein, and knee
      aspiration for cell count and cultures. Available radiographic tools include
      plain radiographs, stress views, arthrography, nuclear scanning, ultrasonography,
      and magnetic resonance imaging. In cases of unexplained pain, reoperation is
      unwise and frequently associated with suboptimal results. Periodic repeat
      evaluations are recommended until the etiology of pain is clearly determined.

PMID- 15190548
TI  - Stiffness after total knee arthroplasty.
AB  - Limitation of motion after knee arthroplasty can be the result of a multiplicity
      of factors. Among these are malpositioning of the components, especially in the
      sagittal plane; oversizing at the patellofemoral or tibiofemoral joint spaces;
      retaining posterior osteophytes; and persisting with a tight posterior cruciate
      ligament. Postoperatively, problems with physical therapy likewise can cause
      limitation of both extension and flexion. Specific patient factors also may
      affect the range of motion after surgery. Although most patients achieve a
      postoperative flexion that is highly correlated to that which was present
      preoperatively, factors such as pain, obesity, and deformities of adjacent joints
      may limit such motion.

PMID- 15190549
TI  - Periprosthetic fractures of the knee: puzzle pieces.
AB  - Periprosthetic fractures associated with total knee arthroplasty occur
      intraoperatively or postoperatively. The parameters that determine the treatment
      are stability of the fracture and the implant, site of the fracture, and bone
      quality. Intraoperative fractures, if undisplaced and stable, can be managed by
      protected weight bearing and motion. If displaced, they are treated by internal
      fixation and a stem. Postoperative fractures, if undisplaced and stable, can be
      managed by restricted weight bearing and motion. If the fracture is displaced, in
      association with a stable implant, management is by internal fixation. If the
      fracture is associated with an unstable implant, then a revision with a stemmed
      component must be performed. If there is associated loss of bone stock, then
      augments or structural grafts may be necessary.

PMID- 15190550
TI  - The infected total knee arthroplasty: just when you thought it was over.
AB  - Of the various options available for infected total knee arthroplasties (TKAs), a
      successful primary-exchange revision technique offers decreased morbidity for the
      patient by eliminating a second major surgery and associated hospitalization, and
      substantially reduces the cost associated with this dreaded condition. In 22
      infected TKAs treated by a 1-stage revision and followed for an average of 10.2
      years (range, 1.4-19.6 years), 90.9% were free of recurrent infection. Knee
      scores averaged 79.5, with 85.7% good or excellent results. The physiologic
      classification of the host appeared to influence the outcome of revision. All
      patients in class A or B (20 knees) had successful eradication of their primary
      infection after 1-stage revision; 2 physiologic class C patients developed early
      failure secondary to poor wound healing.

PMID- 15190551
TI  - Bone loss in total knee arthroplasty: graft augment and options.
AB  - The alternatives available for management of bone defects in total knee
      arthroplasty include prosthetic augments, autograft, allograft, and the use of
      bone cement. The selection of the augment technique should be based on the defect
      size, the patient age and life expectancy, and an assessment of the documented
      clinical results of each method. Prosthetic augments will address the vast
      majority of defects. The use of allograft is primarily indicated in the setting
      of major bone loss in revision knee arthroplasty, whereas the use of autograft is
      appropriate in the management of small defects in primary arthroplasty. Bone
      cement can be used for small defects if the stability of the implant is not
      compromised by the defect.

PMID- 15190552
TI  - Case challenges in knee surgery: what would you do?
AB  - This case discussion features knee arthroplasty cases presented to a panel of
      surgeons. The cases were chosen to represent common clinical problems encountered
      in everyday practice.

PMID- 15190553
TI  - Prophylactic use of antibiotic bone cement: an emerging standard--in the
      affirmative.
AB  - Deep infection is a devastating complication following total joint arthroplasty.
      Preclinical testing; randomized; clinical trials; national joint replacement
      data; and our experience indicate that the use of antibiotic-impregnated bone
      cement is a potentially effective strategy in reducing the risk of deep infection
      following both primary and revision total joint arthroplasty. Allergic reactions,
      bacterial resistance, and cost represent barriers to the widespread use of
      antibiotic bone cement.

PMID- 15190554
TI  - Prophylactic use of antibiotic bone cement: an emerging standard--in opposition.
AB  - Antibiotic-loaded bone cement (ABLC) is an effective delivery method of local
      antibiotics. ABLC for treatment should be high dose (>3.6 g per 40 g cement) for
      beads or spacers and 1 to 2 g antibiotic per 40 g cement for prosthesis fixation.
      Multiple antibiotics are required for treatment, with antibiotics being
      individualized according to culture susceptibilities. This approach requires hand
      mixing because there are no commercial high-dose products. ABLC should be low
      dose (< or =1 g per 40 g cement) for prophylaxis purposes. Concerns with toxicity
      and cement mechanical properties are inconsequential with low-dose ABLC.
      Available clinical evidence supports low-dose ABLC for prophylaxis in revisions
      and high-risk primary joints, but concerns of emerging drug-resistant organisms
      probably outweigh routine use of low-dose ABLC in all uncomplicated primary
      arthroplasties.

PMID- 15190555
TI  - Minimally invasive total hip arthroplasty: in the affirmative.
AB  - Hip arthroplasty can be performed through less invasive exposures and achieve
      excellent results. The modification of the posterolateral approach is preferred,
      and in most patients length of skin incision is between 7 and 10 cm. Patient
      selection is important, and those with body mass index below 28 are the most
      suitable patients for these procedures. Custom instrumentation is needed to
      perform these procedures to allow visualization and prevent excessive trauma and
      traction on the soft tissues. Epidural hypotensive anesthesia and a monoblock
      acetabular component has facilitated the procedure significantly. In 2 studies,
      one a randomized trial, blood loss was significantly less and recovery was more
      rapid. Radiographic measurements of cup and stem position and cement technique
      were similar to longer, more traditional approaches. The surgeon should be
      experienced in hip surgery to perform these procedures well and must never
      compromise hip arthroplasty outcome by these less invasive approaches.

PMID- 15190556
TI  - Minimally invasive total hip arthroplasty: in opposition.
AB  - At the Knee Society Winter Meeting in 2003, Seth Greenwald and I debated about
      whether there should be new standards (ie, regulations) applied to the release of
      information to the public on "new developments." I argued for the public's "right
      to know" prior to the publication of peer-reviewed literature. He argued for
      regulatory constraint or "proving by peer-reviewed publication" before alerting
      the public. It is not a contradiction for me to currently argue against the
      public advertising of minimally invasive (MIS) total hip arthroplasty as not yet
      being in the best interest of the public. It is hard to remember a concept that
      has so captured both the public's and the surgical community's fancy as MIS.
      Patients are "demanding" MIS without knowing why. Surgeons are offering it as the
      next best, greatest thing without having developed the skill and experience to
      avoid the surgery's risks. If you put "minimally invasive hip replacement" into
      the Google search engine (http://www.google.com), you get 5,170 matches. If you
      put the same words in PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi),
      referencing the National Library of Medicine database, you get SEVENTEEN; none is
      really a peer-reviewed article. Most are 1 page papers in orthopedics from
      medical education meetings. On the other hand, there are over 6,000 peer-reviewed
      articles on total hip arthroplasty. Dr. Thomas Sculco, my couterpart in this
      debate, wrote an insightful editorial in the American Journal of Orthopedic
      Surgery in which he stated: "Although these procedures have generated incredible
      interest and enthusiasm, I am concerned that they may be performed to the
      detriment of our patients." I couldn't agree with him more. Smaller is not
      necessarily better and, when it is worse, it will be the "smaller" that is held
      accountable.

PMID- 15190557
TI  - Cemented femoral stems: what matters most.
AB  - Since Charnley hip arthroplasty was introduced to North America over 30 years
      ago, the popularity of cemented femoral components has waxed and waned. During
      this time, much has been learned about factors that contribute to cemented stem
      success and failure. The most important factors that influence arthroplasty
      success with a cemented femoral stem are patient selection, intramedullary
      implant geometry, implant surface finish, implant design above the femoral neck
      resection level, and surgical technique.

PMID- 15190558
TI  - Mastering the art of cemented femoral stem fixation.
AB  - Cemented femoral stem fixation is reproducible and provides excellent early
      recovery of hip function in patients 60 to 80 years old. The durability of
      fixation has been evaluated up to 20 years with 90% survivorship. Achieving a
      uniform cement mantle and minimizing polyethylene wear has been shown to reduce
      the incidence of fixation failure. This article describes the senior author's
      (C.S.R.) technique for cemented total hip arthroplasty with particular emphasis
      on the art of cemented femoral stem fixation and his experience with 3 different
      cemented stem designs over 30 years. The results of using this cement technique
      with a modern stem design with a surface roughness of 30 to 40 microinches have
      produced a 95% survivorship at 10- to 20-year follow-up in patients 60 to 80
      years old.

PMID- 15190559
TI  - The role of cemented sockets in 2004: is there one?
AB  - Cement fixation of the acetabular cup in total hip arthroplasty (THA) has evolved
      through multiple generations of cement technology. Whereas cement technology has
      produced improvements in cemented femoral fixation, the cemented socket still
      produces inconsistent results. Even with our current knowledge that cemented cups
      require exposure of cancellous bone, a clean and dry socket, and adequate bony
      coverage of the cup, surgeons such as myself are unable to control radiolucency
      at the bone-cement interface. The technical difficulty of cementing the
      acetabular cup has led to the increasing prevalence of cementless acetabular
      cups. Although cementless fixation has resulted in increased incidence of
      osteolysis, the surgical procedure is less technically demanding, and the long
      term mechanical fixation results have been more consistent. Given the
      experiential learning curve that most orthopedic surgeons face with cemented
      fixation of the acetabular cup component, the role of the cemented socket in THA
      today is limited.

PMID- 15190560
TI  - Are all cementless acetabular components created equal?
AB  - The cementless acetabular components used over the past 2 decades have varied in
      type of ingrowth fixation, supplemental fixation, locking mechanisms, and bearing
      surface. We evaluated 15-year follow-up results from 2 cementless acetabular
      components: the Harris-Galante I (HG; Zimmer, Warsaw, IN) and the PCA (Howmedica,
      Rutherford, NJ), in terms of revision and radiographic loosening. Three of the
      120 HG I acetabular components were revised for wear and osteolysis without
      loosening. Seventeen of the 100 PCA components were revised for aseptic loosening
      (with or without osteolysis). Including those cases revised, 21 PCA acetabular
      components were loose radiographically, and no HG I component was loose. At least
      with these 2 first-generation designs, differences were seen in performance of
      the acetabular component in terms of revision and loosening at 15 years.

PMID- 15190561
TI  - Intraoperative hip fractures: ruining your day.
AB  - The results of treatment of 116 intraoperative femoral fractures were reviewed.
      Excluding calcar and greater trochanter fractures, there were 14 Type I cases
      (Vancouver classification). All healed with cerclage wiring. Three cases of
      vertical fractures of the proximal segment following a subtrochanteric osteotomy
      did not heal and required revision. There were 8 Type II fractures, most being
      minor splits or limited, nondisplaced, vertical fractures. Control was lost in 2
      wired cases, suggesting that Type II fractures should be converted to Type I by
      the use of a long stem, or, if impractical, by supplementary fixation. In 7
      septic cases, a comminuted fracture occurred during implant removal. An
      intramedullary nail and cerclage wires were used, and the patients were left with
      a Girdlestone. The infections were overcome, the fractures healed, and subsequent
      revision was straightforward, because an open channel existed in the femur.

PMID- 15190562
TI  - Neurovascular injury: avoiding catastrophe.
AB  - Major neurovascular injury is the least common, but most distressing,
      complication of total hip arthroplasty (THA). The keys to minimizing the
      incidence of these complications are recognizing patients at risk and knowledge
      of the relevant anatomy. Partial sciatic palsy is the most common nerve injury.
      At least partial recovery can be expected in 70% to 80% of cases, with the
      remainder frequently displaying dissatisfaction with their surgery. Vascular
      injury is most frequently associated with the use of screws for fixation of
      structural grafts, acetabulur components, and protrusio rings or cages. An
      understanding of the acetabular quadrant system is crucial in minimizing these
      potentially catastrophic complications.

PMID- 15190563
TI  - Leg length discrepancy after total hip arthroplasty.
AB  - Restoration of hip biomechanics, including femoral offset and leg length are
      desired goals in performing total hip arthroplasty. Minor leg length
      discrepancies, less than a centimeter, are common after total hip arthroplasty
      and usually well tolerated. However in some patients, even these small
      discrepancies are a source of dissatisfaction. In addition, more significant
      discrepancies can be a risk factor for nerve injury and are a relatively common
      cause of litigation. Although leg length discrepancy cannot be eliminated after
      hip arthroplasty, it can be minimized through a series of steps both
      preoperatively and intraoperatively. These include physical examination to
      determine true and apparent leg length, and radiographic evaluation to both
      assess leg length and to preoperatively template the surgical procedure. Finally,
      the preoperative plan needs to be executed in the operating room using
      appropriate intraoperative cues.

PMID- 15190564
TI  - The dislocating hip: what to do, what to do.
AB  - Dislocation complicates between 1% and 3% of primary total hip arthroplasties
      (THAs) and 7% to 10% of revision procedures. Sixty percent of dislocations occur
      within the first 5 weeks. Closed reduction is successful in 67% of cases. If the
      hip keeps dislocating, revision surgery for instability is successful in only
      about 61% of patients. Many successful techniques have been described to deal
      with recurrent instability, including trochanteric advancement, modular component
      exchange, jumbo femoral heads, a bipolar or tripolar arthroplasty, or a
      constrained acetabular component. This article discusses the results of various
      surgical interventions and presents a treatment algorithm.

PMID- 15190565
TI  - Revision total hip arthroplasty with proximal bone loss.
AB  - The presence of a deficient or mechanically compromised proximal femur represents
      a particular challenge to revision total hip arthroplasty. This article details
      the results of reconstructing these challenging cases using a modular, tapered,
      and distally fixed femoral stem component that allows independent control of
      length, offset, and anteversion of the femur. Mid-term results suggest that
      distal fixation in the presence of a deficient or mechanically compromised femur
      is a reliable solution to these difficult problems.

PMID- 15190566
TI  - Jumbo cup or high hip center: is bigger better?
AB  - A jumbo cup and a high hip center cup placement are 2 options in the revision of
      loose acetabular components associated with bone loss. They allow biologic
      attachment, which is required for long-term fixation. They are easier to use than
      cages. In my personal series of 564 acetabular revisions from 1986 to 2001,
      standard-size porous cups with a high hip center were used in 42 (7%) of the
      cases. Jumbo cups were used in 166 (29%) of the cases. Nineteen percent of the
      jumbo cups also were placed at a high hip center. The majority of these cups were
      placed into combined segmental and cavitary defects. The average follow-up was
      6.1 years. One jumbo cup and 1 high hip center standard cup were revised for
      aseptic loosening (1%). The 5-year and 10-year survival rates for shell revision
      were 95% and 87%, respectively.

PMID- 15190567
TI  - Surgical management of polyethylene wear and pelvic osteolysis with modular
      uncemented acetabular components.
AB  - Osteolysis, usually associated with polyethylene wear, has become one of the most
      prevalent complications associated with total hip arthroplasty inserted without
      cement. Management of osteolysis is challenging because the disorder tends to
      develop silently and surgical intervention can result in complications. In
      addition, long-term outcomes are unknown. We discuss the current knowledge and
      data available on polyethylene wear and pelvic osteolysis with modular uncemented
      acetabular components. We also outline an algorithm for evaluation and treatment
      of patients. In general, we see patients with well-fixed components every 2
      years, and we base follow-up visits after 6 years on predicted polyethylene wear
      rates and the presence or absence of pelvic osteolysis.

PMID- 15190577
TI  - Preparation of highly optically pure homochiral sulfide-containing alcohols via
      oxazaborolidine-catalyzed asymmetric borane reduction of ketones.
AB  - Highly optically pure homochiral 1-(4-alkylthiophenyl) alcohols were prepared
      efficiently and practically via the oxazaborolidine-catalyzed asymmetric borane
      reduction of prochiral ketones in toluene at 25 degrees C. The coordination of
      the sulfur atom in the ketones to the boron atom in the catalyst and borane can
      be inhibited under these reduction conditions.

PMID- 15190578
TI  - Enantioselective transport and liquid-liquid extraction of amino acids as their
      potassium and sodium salts by optically active diaza-18-crown-6 ethers.
AB  - Complexation of amino acids as their sodium and potassium salts by optically
      active diaza crown ethers has been investigated in transport across bulk liquid
      membranes containing the carriers and in extraction experiments. The observed
      enantioselectivity was achieved by (noncovalent) steric and repulsive
      interactions between the side arm of the crown ether and functional group(s) of
      the amino acids. The highest enantioselectivity was observed in the case of
      tryptophan.

PMID- 15190579
TI  - Enantioselective recognition of ammonium perchlorate salts by optically active
      monoaza-15-crown-5 ethers.
AB  - Chiral monoaza-15-crown-5 ethers (1, 2) were prepared from (R)-(-)-2-amino-1
      butanol in high yield. The chiral monoaza-15-crown-5 ethers were purified
      directly as NaClO(4) complexes. Molecular recognition by these chiral monoaza
      crown ethers of (R)- and (S)-PhEtHClO(4) and (R)- and (S)-NapEtHClO(4) as
      characterized by UV-vis spectroscopy. The order of enantiomeric selectivity is
      (R)- > (S)- PhEtHClO(4) and (S)- > (R)-NapEtHClO(4) for 1. In the case of 2 it
      was (R)- > (S)-PhEtHClO(4) and (R)- > (S)- NapEtHClO(4). The cavity of macrocycle
      and steric hindrance of the benzene units appears to play an important role in
      recognition.

PMID- 15190580
TI  - Chiral investigation of midodrine, a long-acting alpha-adrenergic stimulating
      agent.
AB  - Midodrine hydrochloride is a peripheral alpha(1)-adrenoreceptor agonist that
      induces venous and arterial vasoconstriction. Midodrine, after oral or
      intravenous administration, undergoes enzymatic hydrolysis and releases
      deglymidodrine, a pharmacologically active metabolite. Midodrine and
      deglymidodrine have a chiral carbon in the 2-position. To investigate the
      bioactivity of racemates and enantiomers of the drug and metabolite, three
      chromatographic chiral stationary phases, Chiralcel OD-H, Chiralcel OD-R, and
      alpha(1)-AGP, were evaluated for enantiomeric resolution. Good enantioseparation
      of midodrine racemate was obtained using the Chiralcel OD-H column. This
      stationary phase was then used to collect separately the midodrine enantiomers.
      By alkaline hydrolysis of rac-midodrine and each separated enantiomer, rac
      deglymidodrine and its enantiomers were prepared. The control of the enantiomeric
      purity was carried out by alpha(1)-AGP stationary phase, while the hydrolysis of
      rac-midodrine and its enantiomers was controlled by capillary electrophoresis
      using trimethyl-beta-cyclodextrin as chiral selector. The pharmacological
      activity of the two racemates and the two enantiomeric pairs was tested in vitro
      on a strip of rabbit descending thoracic aorta. The tests continued that the
      activity of the drug and metabolite is due only to the (-)-enantiomer because
      neither of the (+)-enantiomers is active.

PMID- 15190581
TI  - Synthesis, complete characterization, and enantioselective electrokinetic
      separation of functionalized ruthenium complex enantiomers.
AB  - Electrokinetic chromatography was employed to separate the enantiomers of two
      novel functionalized ruthenium(II) complexes with different polypyridyl
      coordination spheres. The use of anionic carboxymethyl-beta-cyclodextrin as
      chiral mobile phase additive resulted in maximum efficiency and resolution for
      the enantiomer separation of both transition metal complexes. The syntheses of
      the [4-(3-hydroxypropyl)-4'-methyl-2,2'-bipyridine]-bis(2,2'
      bipyridine)rethenium(II)-bis(tetrafluoroborate) and [4-(3-hydroxypropyl)-4'
      methyl-2,2'-bipyridine]-bis(4,4'-dimethyl-2,2'-bypyridine)ruthenium(II)
      bis(tetrafluoroborate) complexes and their complete characterization by means of
      two-dimensional (1)H and (13)C[(1)H] NMR techniques ((1)H-(1)H COSY and (1)H
      (13)C HMQC) as well as elemental analyses and MALDI-TOFMS are described in
      detail. The functionalized complexes can be used as building blocks for further
      reactions with polymers, biopolymers, surfaces and nanoparticles.

PMID- 15190582
TI  - Probability rule for chiral recognition.
AB  - Molecular Chirality is of central interest in biological studies because
      enantiomeric compounds, while indistinguishable by most inanimate systems, show
      profoundly different properties in biochemical environments. Enantioselective
      separation methods, based on the differential recognition of two optical isomers
      by a chiral selector, have been amply documented. Also, great effort has been
      directed towards a theoretical understanding of the fundamental mechanisms
      underlying the chiral recognition process. Here we report a comprehensive data
      examination of enantio separation measurements for over 72000 chiral selector
      select and pairs from the chiral selection compendium CHIRBASE. The distribution
      of alpha = k'(D)/k'(L) values was found to follow a power law, equivalent to an
      exponential decay for chiral differential free energies. This observation is
      experimentally relevant in terms of the number of different individual or
      combinatorial selectors that need to be screened in order to observe alpha values
      higher than a preset minimum. A string model for enantiorecognition (SMED)
      formalism is proposed to account for this observation on the basis of an extended
      Ogston three-point interaction model. Partially overlapping molecular interaction
      domains are analyzed in terms of a string complementarity model for ligand
      receptor complementarity. The results suggest that chiral selection statistics
      may be interpreted in terms of more general concepts related to biomolecular
      recognition.

PMID- 15190583
TI  - Bioinversion of R-flurbiprofen to S-flurbiprofen at various dose levels in rat,
      mouse, and monkey.
AB  - Information about the potential and extent of bioinversion of chiral drugs in
      laboratory animal species and humans is critical to the interpretation of
      preclinical pharm-tox studies with these drugs. Unlike in the dog, guinea pig,
      and rabbit, in humans the 2-arylpropionic acid (APA) R-flurbiprofen (R-FB)
      undergoes very little bioinversion to S-flurbiprofen. The primary objective of
      this research was to identify laboratory animal species with an R- to S
      bioinversion profile similar to humans. Detailed evaluations of the
      pharmacokinetics parameters of R-flurbiprofen in male and female rats and mice,
      and male nude rats and monkeys demonstrated R- to S-bioinversion of 30% (average)
      in monkeys, 15-24% in mice, and approximately 4% in rats. To date, no laboratory
      animal species has been identified with an R-flurbiprofen bioinversion profile
      identical to humans. However, the rat has a bioinversion profile sufficiently
      similar to humans to be useful for preclinical.

PMID- 15190584
TI  - Recent contributions of electronic circular dichroism to the investigation of
      oligopeptide conformations.
AB  - Recent applications in our laboratories of electronic circular dichroism to the
      study of peptide secondary structures and their changes under external stimuli
      are briefly reviewed. More specifically, this article deals with: 1).
      characterization of a novel peptide conformation; 2). origin of amino acid homo
      chirality on Earth; 3). bend and helical peptides as spacers; and 4). transfer
      and propagation of chirality in peptides.

PMID- 15190585
TI  - Regio- and diastereocontrolled preparative oxidation of methyloctalones by a
      biomimetic porphyrin catalyst.
AB  - Both enantiomers of methyloctalone were oxidized by a biomimetic
      manganese/porphyrin/imidazole catalytic system in order to obtain sufficient
      amounts of various model metabolites. The double bond proved to be less sensitive
      than the ring methylenes. Hydroxylation occurred mainly in the allylic position
      (position 8) and also at positions 7 and 6. In position 8, two diastereomers were
      obtained while in positions 7 and 6 the reaction was diastereospecific. In the
      case of position 8 only the oxidation yielded a keto compound. The efficiency of
      this method for the preparation of functionalized chiral synthons was better than
      it was for biological pathways.

PMID- 15190588
TI  - Obstetric epidurals and chronic adhesive arachnoiditis.

PMID- 15190589
TI  - Dental Informatics & Dental Research: Making the Connection. Proceedings from a
      Conference Sponsored by the University of Pittsburgh Center for Dental
      Informatics. Bethesda, MD, June 12-13, 2003.

PMID- 15190590
TI  - [Functional genomics and its impact on the future medicine].
AB  - The sequencing of the human genome was completed in 2003. These data will affect
      all aspects of biological and medical sciences. Since almost all the genes of the
      genome are known, the diagnosis and therapy of the future is expected to evolve
      towards more personalized and efficient methods. Before these medical
      advancements become applicable, functional genomics must successfully determine
      the cellular role all the genes in the genome. Comprehensive functional studies
      will require suitable animal models. Although many mammalian species are used in
      biological and medical experiments, the mouse emerges as a key model organism in
      studies of human genes. The power of the mouse model system comes from its
      extensive physiological and pathological similarities to humans and from
      technological advancements offered by mouse genetics. Recently, a project called
      ENCODE was launched to accelerate this monumental effort of gene analysis. Once
      gene analysis is completed, the face of medicine will change markedly. The
      greatest impact is expected on the front of individual diagnosis of disease genes
      and personalized treatments of patients.

PMID- 15190591
TI  - [Long-term clinical observation of infants with gastroesophageal reflux].
AB  - The aim of the study was long-term observation of patients with gastroesophageal
      reflux (GER), diagnosed in their infancy, in aspect of spontaneous resolution of
      this disorder. 290 symptomatic infants aged 5 weeks to 11 months (mean--5.8
      months) underwent 24-hour esophageal pH monitoring. In 243 (83.8%) patients,
      abnormal reflux score was observed. After one year of conservative therapy,
      follow-up study by esophageal pH-monitoring has been performed in 136 (46.9%)
      children and still showed pathological GER in 95 (69.8%) subjects. After 2 years,
      45 (15.5%) patients has been investigated--14/45 (31.0%) of them had normal
      reflux score. At the following five-year clinical observation was available group
      of 28/290 (9.6%) patients. In the 2-3 year of their life, 13 of them had resolved
      symptoms and had normal acid reflux parameters, whereas 9 patients still had
      pathological GER. In the following years, basing of results of 24-hour pH
      monitoring, pathological GER persisted: in 7 children in age 4, in 5 subjects in
      age 5 and in 3 children over fifth year of life. Long-term clinical follow-up of
      these children is necessary because of risk of GER complications.

PMID- 15190592
TI  - [Role of interview in diagnosis of gastroesophageal reflux in children].
AB  - THE AIM: Of the study was to establish the most frequent clinical symptoms of
      gastroesophageal reflux (GER) disease in children. MATERIAL AND METHODS: 214
      children aged from 4 months to 15 years with symptoms suggested GER. The medical
      documentation of children was analyzed with regard to results of clinical
      symptoms and 24-hour pH-monitoring. RESULTS: The most frequent symptom in newborn
      was spitting, in children aged 1-3 was vomiting, in children aged 4-15 was
      stomach pain. Amongst children to 3 years recurrent bronchitis was frequent co
      existent disease, in older children duodenitis or/and gastritis. Based on
      positive result of 24-hour pH-monitoring gastroesophageal disease was diagnosed
      in 184 (86%) patients. Preliminary diagnosis of GER based on the medical
      interview with high percentage of positive results of 24-hour pH-monitoring. The
      introduced results prove the medical interview to be still significant part of
      GER diagnosis.

PMID- 15190593
TI  - [Effectiveness of omeprazole therapy in children with gastroesophageal reflux
      diseases(GERD)].
AB  - THE AIM: Of the study was retrospective analysis of omeprazole (Polprazol)
      therapy efficacy in children with GERD. MATERIAL AND METHODS: The analyzed group
      consisted of 78 children with gastroesophageal reflux disease. GERD was detected
      on the base of questionnaire, pH-metry and/or endoscopy. The questionnaire was
      conducted in all patients, 24-hour pH-metric examination in 47% and endoscopy in
      53% children. Than omeprazole therapy was introduced (0.5-1.0 mg/kg daily).
      RESULTS: Before omeprazole therapy rebounding was observed in 94% children,
      heartburn in 84%, vomits in 38% and abdominal pain in 90% children. After 8 weeks
      of therapy analyzed symptoms were significantly reduced--rebounding was observed
      in 31% children, heartburn in 28% vomits in 5% and abdominal pain in 26%
      children. CONCLUSION: Omeprazole therapy is effective in children with
      gastroesophageal reflux disease.

PMID- 15190594
TI  - [Blood vessel imaging before creation of dialysis fistula].
AB  - THE AIM: Of the study was to present own experience in imaging forearm blood
      vessels before creating hemodialysis access. MATERIAL AND METHODS: The studied
      group consisted of 45 hemodialysed patients. Colour duplex sonography (US) was
      performed in 17 patients before creating the first hemodialysis fistula and
      phlebography in 27 patients before creating next fistula. In the first group
      diameter and blood flow parameters in the arteries and deep veins of the upper
      limb were evaluated. In the second group diameter of patients' veins was
      assessed. In patients before creating the first fistula the US examination in
      4/17 cases showed blood vessels, which were insufficient to create fistula. Among
      27 patients who underwent phlebography in 13 cases a stenosis or occlusion was
      demonstrated and in 6 lack of appropriate superficial veins. CONCLUSIONS: Colour
      duplex sonography and phlebography are useful in evaluation of blood vessels
      before creating a vascular access. Phlebography is a method of choice in imaging
      subclavian and brachiocephalic vein.

PMID- 15190595
TI  - [Effect of urinary tract infections in children with chronic renal failure on
      peritoneal dialysis].
AB  - Urinary tract infections (UTI) in children on dialysis treatment are regarded as
      indirect contraindication for kidney transplantation. In medication of UTI it is
      recommended to prescribe antibacterial agent in proper dosage (often in reduced
      amount) and to choose desired drug in selected period of chronic renal failure
      (CRF). THE AIM: of the study was the evaluation of UTI incidence in children and
      adolescents with terminal renal failure on peritoneal dialysis treatment (PD),
      kind of isolated bacterial strains and their current drug-sensitivity. MATERIALS
      AND METHODS: The study included 26 children and young adults (15 girls and 11
      boys) on PD for the period longer than 6 months (mean 2.0+/-1.5 years). The mean
      age of examined children was 13.2+/-4.4 years. Total number of 57 culture
      positive UTI episodes were recorded (30 in girls, 27 in boys)--1-episode/11.1
      patient-month. In examined group UTI most frequently were present in children
      with uncorrected urinary tract malformation (1 episode/7.7 patient-month) and in
      children on immunosuppressive treatment (1 episode/5.7 patient-month). In
      children with cystic kidney disease infections had accidental character.
      CONCLUSIONS: The most frequent occurring pathogen was bacteria Escherichia coli-
      13 (22.8%) and Streptococcus faecalis--13 (22.8%) infections. E. coli strains
      shown sensitivity to second generation of quinolones: ciprofloxacin; third
      generation of cephalosporin: ceftazidime; partial sensitivity to amoxicillin with
      clavulanic acid, aminoglycosides. Streptococcus faecalis strains revealed only
      partial sensitivity to nitrofurantoin, vancomycin, teicoplanin.

PMID- 15190597
TI  - [Silicone and latex urinary catheters cytotoxicity on primary cultured rabbit
      urothelial cells].
AB  - In everyday urological practice, the use of urinary catheters creates problems
      such as epithelial hyperplasia, edema or erosion. THE AIM: of this study is
      estimation of the toxicity of latex and silicone urinary catheters on primary
      cultured rabbit urothelial cells (PRUCC) was compared. MATERIALS AND METHODS:
      Primary cultured rabbit urothelial cells (PRUC) were characterized for their
      proliferation, qualitative evaluation and quantitative measurement of
      cytokeratins. In the first kind of cytotoxic assay included exposition of the
      PRUC cells on liquid extracts of latex and silicone. Cytotoxicity of 1, 5, 10,
      20, 50% dilution and pure extract was evaluated after 24 h. Additionally for 1%
      solution observation was extended up to 3 days. The second cytotoxic assay was
      based on the close contact between the catheter surface and cells. In direct
      contact test, latex and silicon catheters samples covered cultured cells. Trypan
      blue exclusion assay was used to measure cell viability. Cells were counted using
      inverted microscope with camera. RESULTS: 1, 5, 10 and 20% of silicon extracts
      did not affect cell viability while 5% of latex catheter extracts did. There was
      no difference in cytotoxicity when PRUC cells had been exposed to 1% dilutions of
      both silicone and latex catheters extracts after 3-days observation. 50% dilution
      and pure latex and silicone urinary catheters extracts appears to be highly toxic
      on PRUC. Direct contact test confirmed high toxicity of latex and silicone
      catheters on PRUC. CONCLUSIONS: We confirmed latex and silicone on PRUC to be
      very toxic with direct contact. Using extract test the properties of silicone
      seemed to be slightly better. Authors postulate using catheters covered with
      hydrogenic gel in every day urological practice.

PMID- 15190598
TI  - [DNA ploidy and DNA index in aneuploid laryngeal cancer].
AB  - Abnormal cellular DNA content, a hallmark of malignancy, is known to be an
      important prognostic factor in many human solid tumors. In laryngeal tumors
      studies are not as common as in different locations. THE PURPOSE: Of this study
      was to analyze the prognostic value of DNA content in squamous cell carcinoma of
      the larynx and relations between aneuploidy and clinical as well as histological
      features of the tumor. MATERIALS AND METHODS: Sixty-two patients with squamous
      cell carcinoma of the larynx treated in years 1997-2001 on the ENT department of
      the University Hospital in Wroclaw were subject of our study. Flow cytometric DNA
      ploidy, S-phase fraction and index DNA measurements were performed on fresh
      frozen tumor tissues. RESULTS: Results were compared to histological grading and
      TNM category. There was a positive relation between DNA aneuploidy, histological
      grading and with lymph node metastases. This correlation did not reach
      statistical significance. We also noticed low mean values of index DNA in
      advanced tumors (G3, T4, N+). CONCLUSIONS: The results of this study suggest that
      presence of aneuploid cells in laryngeal cancer can be related to lymph node
      metastases and tumor grading. Studies should be continued to prove results on the
      major number of patients.

PMID- 15190599
TI  - [Immunobiomarkers in healthy children from two Polish cities].
AB  - Determination of lymphocyte subpopulation values and immunoglobulin
      concentrations is an important tool in the assessment of immunologic system. The
      only way to establish their reference values in pediatrics is to perform research
      on large populations of healthy children from different age ranges in various
      areas of the world. Such research was conducted within the framework of the
      Central European Study of Air pollution and Respiratory Health (CESAR). It
      involved examination of children 9-11 years old from six countries in Central
      Eastern Europe. We present the results of the Polish section of CESAR and compare
      them to the data provided by different authors from all over the world. Our data
      are relatively numerous: we examined 80 children recruited from primary schools
      in two Polish cities, Swietochlowice and Pszczyna. The values are similar to
      those obtained by other researchers. There is a need to establish an extensive
      and uniform data base of immunobiomarkers for healthy children in different age
      groups.

PMID- 15190600
TI  - [Blood levels of the adhesion molecules ICAM-1 and VCAM-1 in patients with
      chronic myeloid leukemia during remission and exacerbation].
AB  - A change in ICAM-1 and VCAM-1 concentrations is most likely to occur during the
      course of chronic myleoid leukemia (CML). The purpose of our study was to examine
      concentrations of these adhesion molecules in blood plasma, culture supernatant
      and isolated, broken granulocytes in 20 patients (45-65 years old) with CML in
      exacerbation and during the remission of the disease and in 10 healthy control
      subjects. The concentration assay of substances mentioned above was made using
      ready immunoenzymatic sets of ELISA type. The examinations were carried out on
      the cultures of cells stimulated and nonstimulated with mitogen--Neupogen of
      Roche with a the dose of 1 mu/4 ml of culture. Mitogen was added to activate
      granulocytes and to induce blastic transformation. A significant increase in of
      plasma ICAM-1 concentration was found in CML exacerbation and remission. The
      difference between the concentrations of the adhesion molecules with mitogen
      stimulated and nonstimulated cultures were observed. A significant increase in
      ICAM-1 and VCAM-1 concentration could suggest a higher secretory function of
      granulocytes. The values of ICAM-1 were increased in culture supernatants and
      broken granulocytes before and after adding mitogen in comparison to control
      groups. The difference in concentration we observed could be characteristic for
      leukaemic cells.

PMID- 15190601
TI  - [Role of immediate hypersensitivity to airborne allergens in the pathogenesis of
      atopic dermatitis].
AB  - Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with
      hyperproduction of immunoglobulin E directed against common environmental
      allergens. OBJECTIVES: The aim of the study was to evaluate the immediate type of
      immunological reaction indicated by airborne allergens in the pathomechanism of
      atopic dermatitis. MATERIAL AND METHODS: 529 patients with AD aged (0.5-60 years)
      who fulfilled basic Hanifin and Rajka criterias and 60 healthy volunteers in the
      control group were investigated. In order to evaluate IgE-mediated allergy to
      common airborne and alimentary allergens skin prick tests (SPT) were performed
      (26 airborne and 7 basic alimentary allergens) and concentration of serum antigen
      specific IgE (asigE) was measured. RESULTS: Our results indicated airborne
      allergy in case of 405 patients (76.6%) and food allergy only in 67 cases
      (12.7%). In the group of children aged 0.5-4 years food allergy was predominant
      but later on the predominance of airborne allergy was observed. CONCLUSIONS: We
      conclude that airborne allergy plays an important and predominant role in the
      pathomechanism of atopic dermatitis.

PMID- 15190602
TI  - [Diagnostic difficulties in Grave's orbitopathy--case report].
AB  - Graves' orbitopathy is caused by intraorbital inflammatory reaction due to
      autoimmune thyroid disease. In most cases the diagnosis is based on the
      coexistence of typical eye signs and hyperthyroidism symptoms. In presented case,
      the absence of thyroid dysfunction implicated performance of differential
      diagnosis. Among many available diagnostic tools nuclear magnetic resonance seems
      to be the most accurate in confirmation of diagnosis of Graves' orbitopathy.

PMID- 15190603
TI  - [Multiple primary neoplasm without family history--case report].
AB  - The patient without oncologic family history with three primary neoplasms is
      presented in this article. Cancers were diagnosed and successfully treated during
      12 years-long observation time. There were endometrial uterus cancer, breast
      cancer and thyroid cancer in tum.

PMID- 15190604
TI  - [Seminoma metastases as a retroperitoneal space tumor].
AB  - This is a case report of a testicular tumor, probably seminoma, presenting a
      retroperitoneal mass. The patient underwent surgical removal of tumor and the
      possibility of testicular tumor on the basis of histological examination was
      assumed. However, the histological examination of the testicle did not confirm
      the diagnosis of seminoma. The patient did not give consent for adjuvant
      chemotherapy. He has been remaining under clinical follow-up.

PMID- 15190605
TI  - [Severe bilateral hydronephrosis in a 12 years old boy with neurofibromatosis
      type-1].
AB  - The large neurofibromatic tumours developing in head, neck and abdominal cavity
      in children with neurofibromatosis type 1 make a serious clinical problem. In
      this report the case of 12 years old boy with benign abdominal tumor leading from
      nerve roots (S1-S2) is presented. He has been treated for 6 years. The other
      malignant neoplasms, additional congenital defects or neurological dysfunctions
      were not confirmed. The primary resection was not radical and adjuvant therapy
      (chemotherapy, hormonotherapy) was ineffective. Due to the progression and not
      coming to hospital in next 2 years severe obstructive uropathy developed leading
      to complete destruction of the left kidney. Bilateral ureterocutaneostomies were
      performed. Despite of slow tumor grow the patient is stable now. However he needs
      regular calibrations of the right ureterocutaneostomy due to the progressive
      contraction. Further treatment of this case remains open question.

PMID- 15190606
TI  - [Role of the European Scientific Work Group on Influenza in the battle against
      influenza].
AB  - The European Scientific Working group on Influenza (ESWI) was established in
      1992. Its main task is to reduce impact of influenza in Europe by increase of
      awareness about influenza, dangers, methods of its prevention among physicians
      and in the society, stimulation of scientific studies, organizing of conferences,
      including those on the preparedness plans for the next pandemic. Infections, and
      in some cases also deaths, caused in humans by avian influenza viruses A(H5N1) in
      1997 and 2003, A(H9N2) in 1999 and A(H7N7) in 2003 show that the outbreak of the
      next pandemic is a matter of time. Considering the above facts ESWI prepared a
      pilot study to introduce in Poland, Germany and Sweden. The main aim of this
      project is to achieve a better and more effective control of influenza by an
      increase of knowledge about influenza, promoting of vaccinations and new
      antiinfluenza drugs--neuraminidase inhibitors. In Poland project is coordinated
      by the National Influenza Center located at the National Institute of Hygiene,
      Warsaw. This is only one center in Poland and one of 112 similar centers in 83
      countries of the world participating in the international program of influenza
      surveillance in cooperation with WHO, ESWI and European Influenza Surveillance
      Scheme.

PMID- 15190607
TI  - [Connective tissue diseases in childhood].
AB  - The author presented the present classification, clinical course, diagnostic and
      prognostic problems and own remarks in juvenile systemic lupus erythematosus and
      juvenile dermatomyositis.

PMID- 15190608
TI  - [Endoscopic treatment of gastroesophageal reflux disease--new possibilities].
AB  - Gastro-esophageal reflux disease (GERD) is one of the most important problems of
      gastroenterology at present. The symptoms of GERD have negative influence of
      patients' life on a daily basis. The principal aim of reflux disease treatment is
      to eliminate or alleviate the symptoms, to heal tissue damages and to reduce the
      frequency and duration of recurrences. Lifestyle and dietary modification are of
      only limited value in GERD treatment. Proton pump inhibitors (PPI) are the
      mainstay of GERD pharmacotherapy for both initial episode and long-term
      management. Surgical treatment is indicated in: complicated GERD, in patients who
      need high effective dose of medication, young patients who need lifelong PPI,
      patients with big hiatus hernia. Laparoscopic Nissen fundoplication has become
      the operation of choice. Nevertheless patients who have undergone fundoplication
      may experience adverse post operative complication. The useful alternatives in
      the management of GERD may indeed eventually prove the new endoscopic methods of
      minimally invasive treatment which are currently under thorough evaluation. The
      most promising methods of endoscopic treatment of GERD have been discussed:
      radiofrequency ablation (the Streett's procedure), endoscopic gastroplasty,
      endoscopic implantation of biopolymer hydrogel prosthesis.

PMID- 15190610
TI  - [Interleukin 18 as a new immunomodulator of some digestive tract diseases].
AB  - Interleukin 18 has been known since 1989 and since its properties have been
      recognized, an interest in it is constantly growing. IL-18 induces synthesis and
      release of proinflammatory cytokines, chemokines and nitric oxide. Thus, it
      modulates the function of many immunocompetent cells: macrophages, monocytes,
      lymphocytes and granulocytes. In the paper, properties of IL-18 are reviewed and
      its implications for pathogenesis of some gastrointestinal diseases, particularly
      inflammatory bowel diseases, i.e. Crohn Disease and colitis ulcerosa,
      inflammatory liver diseases such as persistent active hepatitis and primary
      biliary cirrhosis and acute pancreatitis are discussed.

PMID- 15190609
TI  - [Biological properties of interleukin 18].
AB  - IL-18 was first described in 1989 and since its properties have been recognized,
      an interest in it is constantly growing. IL-18 induces synthesis and release of
      interferon gamma (IFN-gamma), interleukins 8, 4 and 13, tumor necrosis factor
      alpha (TNF-alpha) and granulocyte/macrophage colony stimulating factor (GM-CSF).
      Thus, it modulates the function of many immunocompetent cells: macrophages,
      monocytes, lymphocytes and granulocytes. Another important feature of IL-18 is
      its ability to induce apoptosis of many cell types by inducing Fas ligand and Fas
      receptor, and granzymes. IL-18 seems to be particularly attractive as a highly
      specific marker of Th1-response and a potential element of complex antitumor
      therapy. In paper, the processes of synthesis, releasing and biological
      properties of IL-18 are reviewed, particularly in the aspects of immunomodulatory
      and antitumor activity.

PMID- 15190611
TI  - [Cancer-related fatigue. II. Causes and management of the problem].
AB  - Fatigue is often related to cancer, and is related to its treatment. Fatigue is
      the most commonly reported side effect of cancer treatment. It differs from
      fatigue induced by other causes, because doesn't decrease after period of rest.
      The fatigue reported by cancer patients is usually described as an unusual,
      excessive, whole-body experience that is disproportionate or unrelated to
      activity or exertion and is not relieved by rest or sleep. Cancer related fatigue
      is multidimensional, subjective experience that has profoundly negative effect on
      patients' quality of life. Fatigue today is the most commonly reported symptom,
      for some patients the most unpleasant symptom, and the most distressing side
      effect in connection with cancer and/or its treatment. The prevalence of fatigue
      in patients receiving anti-cancer treatment has been estimated to be more than 80
      per cent. The fatigue can be pervasive: patients report that fatigue begins with
      treatment, continues during the course of chemotherapy or radiation treatment,
      and declines somewhat--but frequently sustains at a higher-than-baseline rate-
      after treatment is over. It may also persist for several years even in patients
      with no apparent disease. Despite of the prevalence of fatigue and its profoundly
      negative effect on patients quality of life, little is known about the specific
      mechanisms that underline fatigue in cancer patients or how to prevent it and
      treat it effectively.

PMID- 15190612
TI  - [Rectal cancer--review of methods and treatment results].
AB  - Rectal cancer poses a significant worldwide problem. Until the late 19 century
      surgeons were convinced that surgical attempts of treating rectal cancers were
      doomed to failure. Currently, surgery is associated with a poor prognosis, a high
      likelihood of permanent colostomy and a high rate of local recurrence in patients
      with regional disease. Functional changes such as bladder dysfunction and
      impotence remain distressingly common consequences of conventional surgery. An
      important understanding of rectal cancer pathology allied to modern surgical
      techniques such as intestinal stapling guns has led to an increased number of
      sphincter saving operations. The technique of sharp dissection along definable
      planes known as total mesorectal excision (TME) produces the complete resection
      of an intact package of the rectum and surrounding mesorectum, enveloped within
      the visceral pelvic fascia with uninvolved circumferential margins. As a result
      of TME, 5-year survival figures have risen from 45-50% to 78%, local recurrence
      rates have declined from 30% to 5-8%, sphincter preservation has risen by at
      least 20%, and the rates of bladder dysfunction and impotence have declined from
      50-70% to 15%. In some selected cases transanal techniques with or without
      radiotherapy have improved the success of local excision. The value of
      laparoscopic surgery for rectal cancer in terms of cancer outcome can only be
      assessed by large clinical trials with sufficient follow-up.

PMID- 15190613
TI  - [Pathogenesis and morphology of hepatocellular carcinoma].
AB  - Hepatocellular carcinoma (carcinoma hepatocellulare) kills about 1.25 million of
      people a year all over the world and makes 1.5% of all malignant neoplasms. Many
      factors play a role in etiology of hepatocellular cancer; the most important seem
      to be: hepatitis B and C viruses, alcohol and aflatoxin exposure. They all can
      cause hepatic cirrhosis. In present days, however, it is assumed that all
      diseases which lead to hepatic cirrhosis may be complicated by growth of primary
      liver cancer, but degree of risk of its development is various. Hepatocellular
      carcinoma grows in three macroscopic forms: nodular (multifocal), massive
      (unifocal) and diffusely infiltrative. Its varying microscopic pattern has
      resulted in separating four major types: trabecular, pseudoglandular, solid and
      scirrhous. Immunohistochemical analysis of hepatocellular carcinoma plays an
      important role in practical diagnosis. Metastatic tumors of the liver (breast,
      pancreas, kidney and adrenal gland cancers) are more common than primary ones. In
      routine histological examination they may imitate primary hepatic cancer. Precise
      diagnosis is of vital importance for therapy and prognosis.

PMID- 15190614
TI  - [Melanocytic nevi as one of the risk factors of melanoma malignum].
AB  - The paper presents the contemporary view on the melanocytic nevi and their role
      in the pathogenesis of skin malignant melanoma. There is a strong relationship
      between the presence of the melanocytic naevi and the incidence of melanoma
      malignum. Therefore dermatologists should pay close attention to patients from
      the risk group, with many common melanocytic naevi and atypical melanocytic
      naevi, family history of melanoma, bright fair skin, with history of sun burns.
      These patients should be thoroughly and regularly checked up. Examination should
      include photographic surveillance and dermatoscopy and every suspected mole
      should be excised with further histological examination. This kind of procedure
      intensifies the possibility of early recognition of melanoma malignum of the
      skin, which is crucial for successful treatment of this dangerous disease.

PMID- 15190615
TI  - Keep the fun in learning.

PMID- 15190616
TI  - Lessons from Haiti.

PMID- 15190617
TI  - Clinical nurse specialist or nurse practitioner?

PMID- 15190618
TI  - Status and standards of care for older adults.

PMID- 15190619
TI  - Stitch by stitch. An expression of nursing.

PMID- 15190620
TI  - Significant morbidity associated with asthma: a need for increased doctor and
      patient education.

PMID- 15190621
TI  - Prescribing patterns for childhood asthma treatment in general practice.
AB  - The treatment preferences of 109 general practitioners (GPs) for childhood asthma
      were determined. Availability and adherence to clinical practice guidelines (CPG)
      for the treatment of childhood asthma was also assessed. Ninety eight (90%), 60
      (55%) and 33 (30%) GPs considered nocturnal symptoms > 2 times/week, exercise
      induced wheeze and cough respectively as indications for preventer therapy. An
      oral preparation was preferred for relief medication [72 (66%) for 2-5 years, 60
      (55%) for > 5 years]. An inhaled preparation was however preferred for preventer
      medication [60 (55%) for 2-5 years, 85 (78%) for > 5 years]. The oral form was
      more likely prescribed for asthmatic children 2-5 years (p < 0.001).
      Corticosteroids and ketotifen were the commonest inhaled and oral preventer
      treatment prescribed respectively. Only 36(33%) GPs have a CPG copy for
      reference. Children with asthma symptoms that require preventer therapy may not
      always be identified in general practice. The oral route remains important for
      asthma medication especially in young children. The accessibility to the CPG
      among GPs is disappointing.

PMID- 15190622
TI  - Asthma control and prior medical care of patients presenting with acute asthma at
      the emergency department.
AB  - Seventy patients presented with acute asthma at the emergency department of the
      University of Malaya Medical Centre, Kuala Lumpur were recruited over a two-week
      period in July 2001. Fifty-one (73%) patients belonged to the poorly controlled
      group. Fifty-seven (81%) patients were using inhaled salbutamol but 21 (30%) were
      still using oral short acting salbutamol. Only 32 (46%) patients used inhaled
      corticosteroids. In the poorly controlled group, 22 (43.1%) patients were not on
      regular inhaled corticosteroids, 35 (68.6%) were not receiving "add-on"
      medication and 18 (35%) did not have regular follow up. The emergency department
      should implement a protocol for asthma management and follow up to achieve better
      long term patient care.

PMID- 15190623
TI  - Survival of patients surgically treated for lung cancer.
AB  - A study was done on survival of patients surgically treated for lung cancer from
      1995-2001. The average operative rate for 852 patients was 4.8%. In 67 surgically
      treated patients (54M, 13F), the commonest histological type was squamous cell
      carcinoma (52.2%) followed by adenocarcinoma (26.9%). The surgical-pathological
      stage was stage I in 52.2%. Postoperatively, five-year survival was 29%, with a
      median survival of 27 months. Completeness of resection was the foremost
      determinant of survival outcome and stage higher than stage I was an adverse
      prognostic factor. These results indicate that the current outlook for lung
      cancer patients remains poor.

PMID- 15190624
TI  - Risk factors and complications of acute ischaemic stroke patients at Hospital
      Universiti Kebangsaan Malaysia (HUKM).
AB  - In Malaysia, there is limited information on the mortality and morbidity after an
      acute stroke in hospitalised patients. The objective of the study was to identify
      the type, time of onset, and frequency of medical and neurological complications
      following an acute ischaemic stroke. Consecutive patients with acute ischaemic
      stroke who were admitted to Hospital Universiti Kebangsaan Malaysia from June
      2000 to January 2001 were observed. The complication rate was 20.9%. The most
      common individual complication was pneumonia (12.3%), followed by septicaemia
      (11.0%), urinary tract infection (4.3%), and upper gastrointestinal haemorrhage
      (3.7%). The overall mean length of stay was 7.48 days. The independent risk
      factors for complications were diabetes mellitus (OR 2.87; 95%CI 1.06 to 7.78),
      middle cerebral artery (MCA) infarcts (OR 10.0; 95%CI 4.1 to 24.3), and Glasgow
      coma score (GCS) less than 9(OR 3.8; 95%CI 1.03 to 14.3). Infection was the
      commonest complication observed. Patients with diabetes mellitus, poor GCS and
      large MCA infarcts had a higher risk of developing complications.

PMID- 15190625
TI  - What are the clinical factors that affect quality of life in adult asthmatics?
AB  - A study was conducted to determine the clinical factors that affect the quality
      of life in adult asthmatics. As part of their routine follow-up visit, 399
      patients completed the SF-36 quality of life questionnaire, had peak expiratory
      flow rate readings (PEFR) taken and were interviewed to determine current symptom
      severity. The grade of severity of asthma was verified by the consultant
      physician in-charge. The mean age of the patients was 41.8 years and 31.8% of the
      patients were men. Most of the patients were Malay (64.7%), 89% had at least
      secondary level education and the mean duration of asthma was 17.6 years. The
      majority of patients had moderate or severe disease (43.6% and 55.9%
      respectively). For asthmatics with moderate or severe symptoms of chest tightness
      and/or shortness of breath, all domains of SF-36 scored significantly lower than
      those with mild symptoms, with the exception of the domain bodily pain. Patients
      with moderate/severe cough recorded significantly lower scores than those with
      mild cough for all domains except for bodily pain and social functioning. Only
      the physical functioning, role physical, general health and role emotional scores
      were significantly worse in those with a consultant grade of severe asthma
      compared to those with mild/moderate asthma. Patients with PEFR < 80% predicted
      had lower scores for the domains physical functioning, role physical and general
      health than those with PEFR > or = 80% predicted, but the scores for the other
      domains were similar in both groups. Quality of life is significantly impaired in
      adult asthmatics with current respiratory symptoms. However, consultant grade of
      severity of asthma and PEFR readings do not affect quality of life scores as
      much.

PMID- 15190626
TI  - POSSUM--a model for surgical outcome audit in quality care.
AB  - Comparative surgical audit to monitor quality of care should be performed with a
      risk-adjusted scoring system rather than using crude morbidity and mortality
      rates. A validated and widely applied risk adjusted scoring system, P-POSSUM
      (Portsmouth-Physiological and Operative Severity Score for the enUmeration of
      Mortality) methodology, was applied to a prospective series of predominantly
      general surgical patients at the Sarawak General Hospital, Kuching over a six
      months period. The patients were grouped into four risk groups. The observed
      mortality rates were not significantly different from predicted rates, showing
      that the quality of surgical care was at par with typical western series. The
      simplicity and advantages of this scoring system over other auditing tools are
      discussed. The P-POSSUM methodology could form the basis of local comparative
      surgical audit for assessment and maintenance of quality care.

PMID- 15190627
TI  - An audit of upper gastrointestinal bleeding at Seremban Hospital.
AB  - We retrospectively analyzed all patients presenting with upper gastrointestinal
      bleeding to Seremban Hospital over a one-year period. A quarter of the
      oesophagogastro-duodenoscopies (OGD) performed were performed as emergency for
      upper gastrointestinal tract bleeding. Gastric ulcers and duodenal ulcers were
      the two most common findings. Our results suggest that there is a male
      preponderance of 2:1, the Chinese were more likely to be affected and the elderly
      (> 60 years) were at highest risk.

PMID- 15190628
TI  - Disease impact and patient insight--a study on a local population of asthmatics.
AB  - The cornerstone of asthma management is achieving adequate symptom control and
      patient education. We studied in our local population of asthmatic patients how
      well their symptoms were controlled with currently prescribed treatment and their
      insight into the disease and its management. Over a 6-month period, 93 asthmatics
      recruited from two local government health clinics and a state hospital were
      interviewed using a standard questionnaire. Patients were classified into 4
      groups based on the treatment they were on according to Global Initiative for
      Asthma (GINA) treatment guidelines. The number of patients in Step 1 (rescue
      medication alone), Step 2 (1 controller medication), Step 3 (2 controller
      medications) and Step 4 (at least 3 controller medications) were 8, 39, 34 and
      12, respectively. Except for day symptoms in Step 1 group, fewer than 50%
      achieved minimum day or night symptoms and no restriction of daily activities.
      Questions on patient insight were only available for 50 patients. Weather change
      (74%), air pollution (66%) and physical stress (46%) were the three highest
      ranked common asthma triggers. More than half correctly recognized the important
      symptoms of a serious asthma attack but fewer than 15% were familiar with the
      peak flow meter and its use or with the asthma self-management plan. Most
      patients perceived that their treatment had helped reduce disease severity and
      exacerbations. We conclude that symptom control and some aspect of patient
      education are still lacking in our local asthmatics.

PMID- 15190629
TI  - The prevalence of diabetic peripheral neuropathy in an outpatient setting.
AB  - This study was undertaken to clinically estimate the prevalence of diabetic
      peripheral neuropathy amongst patients attending an outpatient clinic and to
      evaluate their risk factors for developing peripheral neuropathy. It was a cross
      sectional study of 134 diabetes mellitus patients who attended the Primary Care
      Clinic, University Hospital, Kuala Lumpur. The patients were interviewed for
      their demographic data, past and present medical/surgical history, social
      history, personal habits and symptoms of peripheral neuropathy. Foot examination
      and clinical neurological tests were conducted and the presence of peripheral
      neuropathy was assessed. The main outcome measures were the Neuropathy Symptom
      Score and the Neuropathy Disability Score. The prevalence of diabetic peripheral
      neuropathy was found to be 50.7%. Peripheral neuropathy was related to the age of
      the patient and the duration of diabetes but did not seem to be significantly
      related to diabetic control. To conclude, there was a high prevalence of
      peripheral neuropathy amongst the diabetics in this study. These patients
      developed peripheral neuropathy at a younger age and shorter duration of diabetes
      compared to a similar study that was done in the UK.

PMID- 15190630
TI  - Clinical presentation of patients with nasopharyngeal carcinoma.
AB  - The poor prognosis for patients with nasopharyngeal carcinoma is principally due
      to its advanced stage at the time of diagnosis. The symptoms and clinical
      findings at presentation of 56 patients with confirmed nasopharyngeal carcinoma
      is described and analysed. Recognising the common modes of presentation is
      essential to diagnose the disease at an early stage.

PMID- 15190631
TI  - Spectrum of malignant lymphoma in Queen Elizabeth Hospital, Sabah.
AB  - Lymphomas, ranked twelve among all cancers world-wide in the 1990s, in which it
      is more prevalent in males compared to females. A previous study on lymphomas in
      East Malaysia for a period of 3 years from 1981-1983 showed that the pattern of
      lymphomas conformed to the general pattern observed in Asia. Current study
      reviews lymphoma cases from the Department of Pathology, Queen Elizabeth
      Hospital, Sabah between 1997 and 1999, with the aim of investigating if the
      spectrum and pattern in Sabah has since changed, a decade later. A total of 91
      confirmed lymphoma cases were phenotyped with a panel of antibodies and
      classified using the new WHO proposed list of lymphoid neoplasms. The 1981-1983
      series was reviewed and cases reclassified accordingly for comparison. There are
      83 (91.2%) NHL and 8 (8.8%) HL cases in this series, a ratio of NHL to HL of 9:1.
      Of the 83 cases of NHL, 66 (79.5%) were confirmed B-cell type, 13 (15.7%) T
      phenotype, 1(1.2%) null cell type and one case unclassified. Diffuse large B-cell
      lymphoma is the most prevalent, (65.1%), followed by Burkitt's lymphoma and
      follicular lymphoma, (10.6%) each. Lymphoma pattern concurs with the previous
      series from Sabah, with higher prevalence of diffuse large cell lymphoma and
      lower incidence of follicular lymphoma and HL, as seen elsewhere in Asia. There
      is an overall increase in the number of cases of NHL in the 1990s. However, the
      proportion of T-NHL is reduced when compared to the series in the 1980s.

PMID- 15190632
TI  - Hypertension and associated cardiovascular risk factors in Kelantan.
AB  - Two thousand five hundred and eight subjects from the state of Kelantan in North
      East Peninsular Malaysia were included in this study to determine the prevalence
      of hypertension and their association with cardiovascular risk factors. The
      overall prevalence of hypertension was 13.9%. There was no difference in the
      prevalence of hypertension between the males and females. The prevalence
      increased with age--the highest being in those above 70-years old. Subjects with
      hypertension also had a higher prevalence of diabetes mellitus (19.0%), obesity
      (39.4%) and hypercholesterolaemia (70.7%) than non-hypertensive subjects. Of the
      hypertensive subjects, 83.3% had 1 other risk factor for cardiovascular disease,
      66.7% had 2 other risk factors and 16.7% had more than 2 risk factors. Other than
      age, body mass index, plasma glucose, total cholesterol and LDL-cholesterol,
      hypertensive subjects also had a higher mean serum urea, creatinine, uric acid
      and triglyceride than non-hypertensive subjects. In conclusion, hypertension is a
      common disease in this area and is associated with multiple risk factors for
      cardiovascular disease. The prevalence is likely to increase in the near future
      with increasing affluence and becoming a major health problem.

PMID- 15190633
TI  - Trabeculectomy outcomes in a Malaysian general hospital.
AB  - A retrospective study was conducted at the Hospital Sultanah Aminah Johor Bahru
      to determine the outcome of trabeculectomy surgeries over a period of 4 years.
      One hundred and two eyes were followed up to a maximum of 63 months (mean 34.2
      months). The 2-year survival rates for plain trabeculectomies, 5-Fluorouracil
      augmented trabeculectomies and Mitomycin-C augmented trabeculectomies were 52.9%,
      27.3% and 60.5% respectively. The commonest complications noted were cataract
      formation (25%) and hyphaema (11%). Mitomycin-C induced complications were rarely
      seen. At last follow-up, 54% of eyes had intraocular pressures below 21 mmHg
      without medication, while 34% of eyes had intraocular pressures below 21 mmHg
      with medication. Vitreous at the trabeculectomy site was a statistically
      significant predictor of operative failure.

PMID- 15190634
TI  - Utilisation of ophthalmic services by foreign nationals in Johor: a review of 452
      patients.
AB  - Between 1st January 1999 and 31st December 2000, 452 foreign nationals were
      treated at the Department of Ophthalmology, Hospital Sultanah Aminah, Johor
      Bahru. Eighty-five percent were male. The peak age range was from 21 to 30 years
      old. The patients were predominantly Indonesians (61%). A history of trauma was
      present in 63% of patients. Eight percent of eyes had severe visual impairment.
      Six patients (1.3%) were blind by WHO standards. Traumatic eye conditions,
      inflammatory/allergic eye conditions and degenerative eye conditions comprised
      66%, 13% and 10% respectively of ocular pathology seen. The commonest ocular
      findings were corneal foreign body, corneal abrasion and subconjunctival
      haemorrhage.

PMID- 15190635
TI  - A study of admission criteria and early management of adult patients with acute
      asthma.
AB  - We studied the admission criteria and first 24-hour management of 62 asthmatic
      patients admitted from Accident and Emergency (A&E) department of a state
      hospital. Data was collected prospectively over a 6-month period from the
      doctors' medical records with reference to recommendations of the Malaysian
      Thoracic Society (MTS) on management of acute asthma. Peak Expiratory Flow Rate
      (PEFR) records were present in only 14.5% of the A&E notes and 54.8% of the ward
      notes. Most of these readings were below 75% of predicted normal values. Over
      half of the patients had records on ability to speak full sentences, and
      respiratory and pulse rates. Based on other records on criteria for life
      threatening features (including arterial blood gases), 42% of patients studied
      had life threatening asthma exacerbations. Most received appropriate treatment as
      recommended by the MTS. We conclude that while most patients were admitted and
      treated appropriately, medical documentation regarding acute asthma assessment
      were inadequate in some.

PMID- 15190636
TI  - Interferon induced glomerular disease in a patient with chronic hepatitis C.
AB  - Chronic hepatitis C manifests with many extrahepatic features including renal
      involvement. However, less commonly, interferon therapy for chronic hepatitis C
      can also result in renal involvement and we describe a case when interferon
      therapy resulted in minimal change glomerulopathy, a form of involvement which,
      carries a good prognosis. Our patient developed nephrotic syndrome while on
      interferon therapy and HCV RNA levels were undetectable at that time. The disease
      showed excellent response to steroid therapy.

PMID- 15190637
TI  - Outpatient treatment of spontaneous pneumothorax using an improved pocket sized
      Heimlich valve.
AB  - We report two patients, who have used Pneumostat to replace the conventional
      underwater seal drainage system for recurrent pneumothorax. Both patients had
      required repeated chest tube insertion for recurrent pneumothorax and needed a
      longer hospital stay. Both patients were able to be discharged with the
      Pneumostat device and were reviewed in outpatient clinic. Both patients had
      optimal clinical improvement and chest X-ray showed no residual pneumothorax.

PMID- 15190638
TI  - Pancreatitis in primary hyperparathyroidism.
AB  - The cause and effect relationship between acute pancreatitis and primary
      hyperparathyroidism (pHPT) still evokes controversy. Our paper reviews the debate
      in the medical literature. In this controversy we add a case of a 49-year old non
      alcoholic man presenting with recurrent attacks of acute pancreatitis. His raised
      serum calcium was realized rather late. Eventually, high intact parathyroid
      hormone levels led to open neck exploration and finding of a solitary parathyroid
      adenoma. Post-surgery, serum calcium returned to normal and abdominal symptoms
      disappeared. The case report and the accompanying literature review support our
      belief, that acute pancreatitis is one of the symptoms of pHPT often caused by a
      parathyroid adenoma and curable by its excision.

PMID- 15190639
TI  - Sengstaken-Blakemore tube to control massive postpartum haemorrhage.
AB  - Massive postpartum haemorrhage after Cesarean section for placenta previa is a
      common occurrence. The bleeding is usually from the placental bed at the lower
      uterine segment. Uterine tamponade has a role in the management of such patients
      especially when fertility is desired. We describe here a case of massive
      postpartum haemorrhage, which was managed, with the use of a Sengstaken-Blakemore
      tube. This allowed us to avoid a hysterectomy for a young primiparous patient.

PMID- 15190640
TI  - Scopulariopsis brevicaulis infection in a patient with acute myeloid leukemia.
AB  - Scopulariopsis brevicaulis is a soil fungus normally associated with
      onychomycosis. It causes subcutaneous infection in immunocompromised patients and
      is rarely isolated from blood. A case of systemic Scopulariopsis brevicaulis
      infection was reported in a patient with acute myeloid leukemia. The patient
      developed persistent fever that did not respond to wide spectrum antibiotics and
      amphotericin B. Scopulariopsis brevicaulis was the only pathogen isolated from
      blood cultures. The fever subsided with itraconazole and there was no recurrence
      of fungal infection with prolonged maintenance of oral itraconazole.

PMID- 15190641
TI  - Penetrating laryngotracheal trauma resulting in vocal cord avulsion.
AB  - Penetrating neck trauma present difficult management issues by virtue of their
      rarity. Undiagnosed laryngotracheal injuries have serious implications,
      especially in the context of multiple trauma, where other injuries overshadow
      that of the laryngotracheal complex. This is a case of a schizophrenic patient
      with multiple self-inflicted cuts on his throat and abdomen. Injuries include
      open, comminuted laryngeal complex lacerations with vocal cord avulsion, as well
      as evisceration of small bowel. Adequate assessment using both direct
      laryngoscopy and rigid endoscopy, coupled with open exploration, allowed optimal
      exposure and fixation of the larynx in the anatomical configuration. The post
      operative outcome of the airway and voice remained satisfactory at follow-up. A
      high index of suspicion coupled with adequate surgical approach allowed
      establishment of a functional larynx.

PMID- 15190642
TI  - Suprahyoid pharyngotomy for base of tongue carcinoma.
AB  - Carcinoma of the tongue remain one of the greatest management challenges for the
      head and neck surgeon because of the adverse effects of treatment on oral and
      pharyngeal function. In early carcinoma of the base of tongue however, the
      prognosis is encouraging and function of swallowing and speech is preserved
      despite surgery. Suprahyoid pharyngotomy is one of the surgical approaches
      advocated for resection of base of tongue tumours with primary anastomosis.

PMID- 15190643
TI  - Bipolar clavicular injury.
AB  - While clavicular injuries are fairly common, bipolar clavicular injuries are not.
      They may involve dislocations at both ends of the clavicle, or a fracture at one
      end and a dislocation at the other. We present two cases; a patient with a
      bipolar clavicular dislocation, and another with a fracture in both medial and
      lateral ends of the clavicle with anterior dislocation of the sternoclavicular
      joint. Both were treated conservatively, with fairly good range of motion and
      return to normal activity.

PMID- 15190644
TI  - Medical negligence suits: risk management.
AB  - Medical negligence suits have become an issue of concern for doctors as well as
      for the health service departments. The main objectives of medical malpractice
      law are to compensate patients who are injured by negligence and to improve the
      quality of medical care. The amount of money and time spent on these cases may
      not be an effective allocation of social resources to minimize patient safety.
      Though physicians generally win more malpractice suits, much time and money are
      spent and results in much stress to those concerned. There are certain
      controllable events in practice that render a physician more or less vulnerable
      to malpractice claims. Attempts by physicians to understand and prevent unwanted
      situations that can lead to litigation is important. The risk factors for medical
      negligence suits are discussed. The practice of good medicine will be the best
      form of risk management.

PMID- 15190645
TI  - Cancer in Malaysia--there is light at the end of the tunnel.

PMID- 15190646
TI  - Open lung biopsy for diffuse parenchymal lung disease in children.
AB  - An open lung biopsy was performed in 12 children with diffuse parenchymal lung
      disease. A definitive histopathological diagnosis was obtained from all
      procedures but determined treatment options in only 10 children (83%). Three
      (25%) children were ventilated for respiratory failure prior to the procedure.
      Four (44%) of the other 9 children required ventilatory support after the
      procedure. Three (25%) children developed post-op pneumothorax that resolved
      fully with chest tube drainage. There were no deaths as a direct result of the
      procedure. Open lung biopsy is useful in providing a definitive diagnosis in
      children with diffuse parenchymal lung disease and determining treatment in the
      majority of cases. The procedure was well-tolerated with minimal complications.

PMID- 15190647
TI  - Morbidity in Alagille syndrome in 6 Malaysian children.
AB  - We retrospectively studied the records of 6 Malaysian children who were diagnosed
      with Alagille Syndrome (AGS) according to this criteria from January 1999 to
      January 2001, at the Institute of Paediatrics, Kuala Lumpur Hospital. Four
      patients (66%) had a positive family history. Thirteen individuals (6 patients
      and 7 relatives) were diagnosed with AGS in these 5 families. Only 6/13 (46%) of
      them presented with liver involvement. All 6 patients presented with typical
      facies and cholestasis (100%). Three (50%) presented with portal hypertension
      (PHT) with synthetic liver dysfunction (1 died), 1/6 (17%) have PHT and normal
      synthetic liver function. Two have cleared their jaundice but have biochemical
      evidence of hepatitis and hepatomegaly, four have congenital heart disease 5/6
      posterior embryotoxon, 2/6 butterfly vertebrae, 4/6 hyperlipidaemia and 4/6
      failure to thrive. One patient has a Jagged-1 gene disruption at the
      translocation breakpoint locus 20p12.3 2n = 46,XX,t(12.20) (q22, p12.3). 5/6
      (83%) are still alive. Two-thirds of our patients developed chronic liver disease
      by 3 years of age. Two-thirds of the index patients have a family history. Only
      46% of individuals in these families have clinical evidence of liver involvement.
      Mortality depends on cardiac/renal disease, end-stage liver failure and
      intercurrent infection.

PMID- 15190648
TI  - Measurement of intima-media thickness of common carotid arteries using ultrasound
      in patients with familial and non-familial hypercholesterolaemia and correlation
      of intima-media thickness to obesity.
AB  - Ultrasonographic measurements of the intima-media thickness (IMT) of common
      carotid arteries (CCA) were taken in 50 patients with familial
      hypercholesterolaemia (FH) and 57 patients with non-familial hypercholesterolemia
      (NFH). The lipid profile, body mass index (BMI) and waist-hip ratio (WHR) of each
      patient were recorded. In FH patients, the IMT was significantly higher in
      overweight and elevated WHR subgroups compared to the normal with significant
      correlations between BMI and WHR to the IMT. In NFH patients, the IMT was
      significantly higher in the elevated WHR compared to the normal subgroup but the
      correlations between either BMI or WHR to IMT were insignificant. These suggest
      that the environmentally modified anthropometric indices may have an effect on
      atherosclerosis in genetically determined hypercholesterolaemia in FH patients.

PMID- 15190649
TI  - Societal risk perception of death among workers in a security company in
      Malaysia.
AB  - How people perceive risk influences their behaviour towards these risks. We do
      not know how workers perceive risk of dying from diseases or accidents. This
      study was conducted among 198 workers of a security company in Malaysia. The
      workers were asked to score on a Likert scale of 1 to 5 the perceived risk of
      death of Malaysians from selected causes of death. The highest perceived risks of
      death were, in order of ranking, motor vehicle accidents, cancer and diabetes
      mellitus whereas according to the certified causes of death in Malaysia the
      highest risks of death among the selected items were cardiovascular disease,
      cancer and stroke. The difference in perception and mortality data needs be
      addressed.

PMID- 15190650
TI  - The prevalence of musculoskeletal problems and risk factors among women assembly
      workers in the semiconductor industry.
AB  - A cross-sectional study to determine work-related musculoskeletal problems and
      ergonomic risk factors was conducted among 529 women semiconductor workers.
      Overall, 83.4% had musculoskeletal symptoms in the last one year. Pain in the
      back (57.8%), lower leg (48.4%) and shoulder (44.8%) were the three most common
      musculoskeletal problems. Significant associations were found between prolonged
      standing and upper and lower leg pain, between prolonged sitting and neck and
      shoulder pain and between prolonged bending and shoulder arm, back and upper leg
      pain. The study therefore showed a clear association between work-related
      musculoskeletal pain and prolonged hours spent in particular postures and
      movements.

PMID- 15190651
TI  - The clinical significance of elevated levels of serum CA 19-9.
AB  - The tumour marker CA19-9 is a sensitive marker for pancreatic, gastric and
      hepatobiliary malignancies. High CA 19-9 level indicates unresectable lesions and
      a poor prognosis. The objective of the study was to determine the significance
      and implications of elevated CA 19-9 levels in the serum. A one-year
      retrospective review of all patients who had CA19-9 measured in our Medical
      Centre was undertaken; 69 patients were found to have CA 19-9 level above the cut
      off value (37 U/ml). Thirty-six patients had malignant and the remaining 33 had
      benign lesions. CA 19-9 was found to be elevated in malignancies of pancreas,
      colorectum, lung, liver and ovary. Benign conditions associated with elevation of
      CA 19-9 included disease of the hepatobiliary system, pneumonia, pleural
      effusion, renal failure and SLE. In two individuals, there was no obvious cause
      for the elevation of this marker. CA 19-9 levels were significantly lower in
      benign than in malignant conditions. In conclusion, elevated CA 19-9 may be found
      in patients with benign as well as malignant disease. Therefore, it is important
      (1) that elevated levels of CA 19-9 are interpreted in the light of the clinical
      presentation of the patient and (2) to be aware of the benign conditions that can
      be associated with increased levels of this marker. With these factors in mind,
      CA 19-9 can be used to assist in the diagnosis of pancreatic cancer and
      assessment of resection adequacy post-operatively.

PMID- 15190653
TI  - The effect of Ramadan fasting on fasting serum glucose in healthy adults.
AB  - The effect of Ramadan fasting on fasting serum glucose (FPG) is still a matter of
      controversy. One hundred and fifteen healthy volunteers fasted for > or = 25 days
      during Ramadan. Blood samples were taken 1 week before Ramadan and on the 14th
      and 28th day of Ramadan. Serum glucose was determined by the glucose oxidase
      method. FPG decreased from 88.4 + 9.0 mg/dl to 62.9 +/- 7.7 mg/dl (p < 0.001).
      Men and women both experienced a significant drop in FPG. Calorie intake
      decreased in all groups (p < 0.001) and was positively correlated with decreasing
      FPG. FPG decreases with Ramadan fasting and has no serious adverse effect on
      fasting adults.

PMID- 15190652
TI  - Prostate biopsies--a retrospective review from the University Malaya Medical
      Center.
AB  - Prostate cancer is not common in south-east asia and in particular there are only
      scarce reports on the characteristics of Malaysian men with prostate cancer. A
      retrospective study where all prostate specimens sent to the pathology department
      during the period 1st January 1996 to 30th June 1998 were reviewed. A total of
      131 prostate specimens were reviewed and these consisted of prostatectomy
      specimens, transurethral resection specimens and trucut biopsy specimens. Only
      114 patients' case notes were evaluated. Data reviewed were age, race, presenting
      symptoms, clinical findings and prostate-specific antigen (PSA) level. Overall
      incidence of carcinoma of the prostate was 19.0%. The incidence of carcinoma of
      the prostate with serum prostate-specific antigen (PSA) of 4.1 to 20.0 ng/ml was
      only 10% and 60.5% of patients had evidence of subclinical histological
      prostatitis. The mean age of men with carcinoma of the prostate was 71.3 years
      and there was no differences in the incidence of carcinoma of the prostate among
      the 3 major ethnic groups (Malays, Chinese and Indian). About three-quarter of
      the patients with carcinoma of the prostate presented with lower urinary tract
      symptoms, a third had haematuria and about a tenth of patients presented with
      urinary retention. The majority of patients presented with metastatic disease
      (66.7%) with a mean PSA of 1476.8 ng/ml. A significant proportion of men with
      prostatic diseases attending the University of Malaya Medical Center had prostate
      cancer (19.0%). A small proportion of men with serum PSA in the range of 4.1 to
      20.0 ng/ml had prostate cancer and this is thought to be due to the background
      histological prostatitis. The majority of patients presented late.

PMID- 15190654
TI  - Respiratory viruses detected in hospitalised paediatric patients with respiratory
      infections.
AB  - Over 200 strains of respiratory viruses cause a variety of human infections
      ranging from common cold to life-threatening pneumonia. Respiratory viruses
      implicated in this study are respiratory syncytial viruses (RSV), adenovirus,
      influenza viruses and parainfluenza viruses. The objective of this study is to
      determine the epidemiology of respiratory viruses in paediatric patients with
      lower respiratory tract infection. The methods used were direct antigen detection
      method, shell vial culture method and conventional tube culture method. The
      samples included in this study are paediatric patients seen in Universiti
      Kebangsaan Malaysia Hospital, Kuala Lumpur with suspected acute viral respiratory
      infection, presenting with acute laryngotracheobronchitis (croup), bronchiolitis
      and pneumonia. Nasopharyngeal aspirates were collected and processed almost
      immediately. A total of 222 specimens were received during February 1999 to
      January 2000 showing a dual peak pattern in the months of April and December. The
      mean age of the patients was 13 months. Pneumonia (77.9%) was the most common
      clinical diagnosis in children with lower respiratory tract infection. This was
      followed by bronchiolitis (19.4%) and croup (27%). Viral aetiologies were
      confirmed in 23.4% of the patients. The most common respiratory virus isolated or
      detected was RSV, followed by parainfluenza viruses, influenza viruses and
      adenovirus.

PMID- 15190655
TI  - Use of complementary medicine amongst diabetic patients in a public primary care
      clinic in Ipoh.
AB  - The use of Complementary Medicine (CM) amongst diabetic patients attending the
      Diabetes/Hypertension, Clinic. Out Patient Department, Ipoh Hospital was studied:
      Forty-three patients were selected by systematic random sampling (1:5) over a one
      week period starting 5/12/01. Data were collected by patient interview, from
      medical records and through a questionnaire. 56% were using CM together with
      conventional therapy. Most commonly used were herbal therapy, homeopathy and
      reflexology. The majority took CM daily with a mean duration of 7 years. Over
      half had subjective relief of pain with increased energy. Patients on CM or
      conventional therapy both showed poorly controlled FBS levels. There is a need to
      assess the effect of these therapies on diabetic outcome.

PMID- 15190656
TI  - Quality of life of the Malaysian general population: results from a postal survey
      using the SF-36.
AB  - Population norms for Health Related Quality of Life using SF-36 are described. A
      national sample was canvassed in 2000 using a self-administered SF-36 in Bahasa
      Malaysia and English. Response rate was 30.6%, with 3072 usable data. Male:
      Female ratio was 1.04 and mean age was 39.8 years. Quality of life was affected
      by age and sex. Older population and women had a poorer quality of life.
      Population norms for Malaysia differed from those of US, Canada and Australia.
      The malaysian general population norm described is useful as reference point for
      studies in Malaysia. Variability in scores by age and sex emphasize the need to
      use appropriate age- or sex-specific normative data.

PMID- 15190657
TI  - Epidemiology of prostate cancer in United Arab Emirates.
AB  - OBJECTIVE: To evaluate the magnitude of prostate cancer in the United Arab
      Emirates (UAE). DESIGN: A descriptive retrospective study. SETTING: Tawam and Al
      Ain Teaching Hospitals, Al-Ain Medical District, UAE. SUBJECTS: Analysis based on
      patient admissions into the main referral teaching hospital, categorizing age,
      nationality groups and type of cancer. All prostate cancer patients, diagnosed
      and treated at Tawam and Al-Ain Hospitals during the period from 1982 to 2000,
      are included in the study and consisted of 84 subjects. RESULTS: The study series
      consisted of 84 patients with the ages ranging from 38 to 81 years with a median
      age of 56 years and a mean and standard deviation of 56.5 +/- 12.5 years. The
      study revealed that majority of the patients (n = 33, 39.2%) were diagnosed
      between 51 to 60 years of age. The majority of our patients were UAE nationals
      (44.0%), followed by patients from neighboring countries i.e. Oman, Yemen, Syria,
      Jordan and Egypt (40.5%). The initial pathological diagnosis was confirmed mainly
      by Trucut Needle Biopsy in the majority of patients (n = 48, 57%), TURP (n = 15,
      18%), Open Prostatectomy (n = 4, 5%) and others i.e. lymph node, bone marrow, and
      pleural biopsies and high PSA (n = 17, 20%). The majority of our patients (77.7%)
      presented with an advanced disease and received hormonal treatment while 16.6%
      received radical radiotherapy and 5.5% had radical prostatectomy. According to
      our analysis the annual incidence of prostate cancer is 4.5/100,000 male
      population. CONCLUSION: The prevalence of prostatic carcinoma in the UAE, like
      other Arabian Gulf and Asian countries, is very low compared to Western Countries
      despite the high intake of calories and consumption of animal fat. However,
      genetics and environmental factors believed to be involved in the complex
      etiology of prostate cancer in UAE are not clear yet, and awaiting investigation.

PMID- 15190658
TI  - Optimal size selection of laryngeal mask airway in Malaysian female adult
      population.
AB  - BACKGROUND: The summary of various studies done looking at size selection of the
      laryngeal mask airway (LMA) in adults is that, selection based on sex is
      appropriate, and that both sizes 4 or 5 are adequate for adult females. However,
      in our local population these sizes may be too large especially the size 5 for
      adult females. OBJECTIVE: To determine the optimal size of LMA in Malaysian
      female adults. METHOD: 135 ASA 1 or 2 adult female patients coming for elective
      surgery, requiring general anaesthesia suitable for LMA insertion were randomised
      into 3 groups to receive either a size 3, 4 or 5 LMA. Optimal size of the LMA was
      assessed based on 4 parameters, the number of attempts at placement, the
      oropharyngeal leak pressure (OLP), fibre optic score and the percentage of the
      vocal cords seen. RESULTS: The 3 groups were demographically similar. There was
      no difference in the 3 groups in terms of number of attempts of placement, OLP
      and fibre-optic score. The percentage of vocal cords seen with the size 3 LMA was
      significantly less than for the size 4 and size 5 (p = 0.009). For the size 5 LMA
      group in 10/45 patients, the size 5 LMA was too big making it incorrectly
      positioned after successful insertion and in another 3/45 patients it was
      difficult to pass the size 5 LMA past the open mouth during insertion. There were
      no such problems with the size 3 or 4 LMA groups. CONCLUSION: The optimal size of
      LMA for the female Malaysian adult is size 4.

PMID- 15190659
TI  - Evaluation with acoustic rhinometry of patients undergoing sinonasal surgery.
AB  - The purpose of this study is to evaluate the use of Acoustic Rhinometry in
      assessing surgical outcomes in sinonasal surgery. This prospective study was
      carried out from January till December 2001. A group of 44 patients who presented
      with nasal obstruction due to various rhinologic abnormality were examined with
      acoustic rhinometry pre and post-operatively. They were examined with acoustic
      rhinometry pre and post decongestion with cocaine and adrenaline. A highly
      significant correlation existed between minimal cross sectional area (MCA) and
      the subjective feeling of nasal problem, pre and post surgery. Thus MCA is a
      valuable parameter to express objectively the nasal patency. The mucovascular
      component of the nasal cavity plays a major role in the nasal patency as
      determined in the pre and post-decongestion acoustic rhinometry measurement.
      Acoustic rhinometry is a good tool to evaluate the nasal patency in cases where
      sinonasal surgery is considered in correcting the abnormality as well as for the
      post-operative evaluation.

PMID- 15190660
TI  - Usefulness of cytological specimens from bronchial brushings and bronchial
      washings in addition to endobronchial biopsies during bronchoscopy for lung
      cancer: 3 years data from a chest clinic in a general hospital.
AB  - A retrospective review of all bronchoscopy cases for investigation of lung cancer
      between January 1997 and December 1999 was done. The cases were included if
      endobronchial mass was visible (Group A) or when there was an abnormal mucosa
      and/or bronchial narrowing in the absence of a mass (Group B). All patients in
      Group A (n = 177) underwent endobronchial biopsy (EB) bronchial brushings (BB)
      and bronchial washings (BW). All cases in Group B underwent transbronchial biopsy
      (TBB), BB and BW. Only a small increase in the positive results for cancer was
      seen when cytology specimens (BB and BW) were added to EB (85.3% vs 88.1%,
      McNemar's P = 0.06) in Group A but there was a significant increase in Group B
      (37.3% vs 54.2%. McNemar's, P = 0.001). Therefore although cytology specimens did
      not significantly add to overall yield of positive results when endobronchial
      lesions were visible, when mass lesions were not visible, cytology specimens
      increased the yield by 16.9%.

PMID- 15190661
TI  - Sexual function outcomes following treatment for lower urinary tract symptoms. A
      one-year study.
AB  - The aim of this study was to assess the effects of treating lower urinary tract
      symptoms (LUTS) on the quality of sexual function in a one-year follow up. A
      total of 116 patients with LUTS received alpha-blocker treatment, 111 patients
      underwent transurethral resection of the prostate (TURP) and 70 patients with
      renal stones, with no or mild symptoms served as a control group. The patients
      were assessed at baseline, three months, six months and twelve months using the
      International Index of Erectile Function (IIEF-15). The surgical group exhibited
      some changes in the domain of IIEF-15. Patients in the medical group showed
      improvement in erectile function and intercourse satisfaction, while orgasmic,
      overall sexual satisfaction and sexual drive were relatively unchanged. In
      contrast, the surgical group suffered retrograde ejaculation and overall sexual
      dissatisfaction after undergoing TURP. TURP has been found to be associated with
      retrograde ejaculation intercourse and overall sexual dissatisfaction.

PMID- 15190662
TI  - Parental perceptions of children's body shapes.
AB  - The aim was to determine the differences in parents' perceptions of boys' and
      girls' body shapes and the explanations for the emphasis on body shape care of
      children. Subjects were low-income parents (n = 158) of preschoolers attending
      preschools in Kuala Lumpur, Malaysia. Parental perceptions of children's body
      shapes were assessed based on their rankings (scale of 1 to 7) of four attributes
      (ideal, healthy, fat and thin) for boy and girl figures. Parental responses to
      five questions on the importance of body shape were also obtained. Parental
      rankings of ideal and healthy body shapes were significantly lower for girls than
      boys (p < 0.001). However, mothers' and fathers' rankings of boys' and girls'
      body shapes were not significantly different. for both boys and girls, parental
      ratings for ideal body shape were significantly lower than for healthy body shape
      (p < 0.001). The majority of parents indicated that children's body shape is
      important for their future health, self enhancement, social interaction and
      career. With the increasing prevalence of body dissatisfaction among Malaysian
      children, these findings contribute to the understanding of parental roles in the
      development of body image and perhaps, in the etiology of body dissatisfaction
      among children.

PMID- 15190663
TI  - Methods used for reconstruction in aggressive bone tumours: an early experience.
AB  - Improvements in the overall treatment of patients with aggressive, large tumours
      involving the bone have made it possible to preserve and salvage limbs instead of
      amputating them. Each patient is unique in his clinical presentation and social
      circumstance. The different reconstructive options available allow us to choose
      the most appropriate method suited to the particular patient and with minimal
      delay, even when resources are limited. The patient and the relatives actively
      participate in the choice. The early experience of the different techniques for
      reconstructing these bone defects at our hospital are presented in this paper.

PMID- 15190664
TI  - Gastric cancer in Malaysia: the need for early diagnosis.
AB  - Gastric cancer is an important cause of death among patients with malignancies in
      Malaysia. Survival of patients with gastric cancer is dependent on the stage at
      which diagnosis is made. We report our experience in dealing with gastric cancer
      in a major Ministry of Health Hospitals in Malaysia. A retrospective review of
      two hundred and fifty consecutive histologically proven gastric adenocarcinoma at
      Hospital Ipoh for the period January 1988 to 1998 was performed. The study
      confirms that gastric cancer is a disease of the elderly and has a male
      preponderance. It is also identifies the Chinese and Indians to be at increased
      risk of gastric cancer when compared to the Malays. The most striking finding in
      this study was the very late stage of disease at time of presentation. Eighty-two
      percent of the patients presented with stage IV disease and curative surgery was
      offered only to a 16% of them. In a substantial number of patients not even a
      palliative procedure was offered. Early detection is the key to improving
      survival in gastric cancer patients. There is an urgent need for clinicians to
      change their approach to the management of the disease. Patients with dyspeptic
      symptoms should be investigated early rather then wait for classical symptoms of
      gastric cancer.

PMID- 15190665
TI  - Choroid plexus carcinoma in an infant.
AB  - Choroid plexus carcinoma is a rare intracranial neoplasm, affecting mainly very
      young children. The commonest site is within the lateral ventricles and the
      prognosis is very poor. We report a seven month old baby boy who presented with
      raised intracranial pressure and seizures. Brain CT scan showed large
      intraventricular mass with calcification and hydrocephalus. Total macroscopic
      resection of the tumour was performed and diagnosis of choroid plexus carcinoma
      was made. However, the patient died 11 days after the tumour excision. The
      histopathology of this rare childhood neoplasm is discussed.

PMID- 15190666
TI  - Barium peritonitis--following barium enema of the proximal colon through a
      colostomy.
AB  - Perforation with extravasation of barium is a rare complication of contrast enema
      examination of the large bowel with a high associated mortality rate. The
      experience of performing a re-laparotomy in a patient previously exposed to
      barium peritonitis is even less common. We describe an elderly male patient with
      a Hartmann's procedure performed a year previously, presenting with peritonitis
      following barium enema evaluation of the proximal colon via an end descending
      colon stoma. Emergency laparotomy, segmental bowel resection and liberal
      peritoneal toilet resulted in a satisfactory outcome. The patient had a
      subsequent successful reversal of his Hartmann's procedure nine months later
      despite the presence of dense barium induced adhesions. This potentially
      preventable iatrogenic complication is discussed in this report, which is
      supplemented by a brief review of the English literature.

PMID- 15190667
TI  - Peritoneal implantation of ureter in a cadaveric kidney transplant recipient.
AB  - We report here a case of a kidney transplant recipient in whom the ureter was
      initially implanted into the peritoneum. Excessive ultrafiltration volume and
      reversal of serum vs dialysate creatinine ratio when the patient was recommenced
      on continuous ambulatory peritoneal dialysis first suggested the diagnosis which
      was subsequently confirmed by a plain abdominal x-ray demonstrating placement of
      ureteric stent in the peritoneum. This rare complication was successfully
      corrected with surgical re-implantation of ureter into the bladder and 5 years
      later, the patient remains well with good graft function.

PMID- 15190668
TI  - Bilateral optic neuritis in pregnancy.
AB  - A 25-year old primigravida at 11-weeks period of amenorrhoea presented with
      bilateral optic neuritis following Varicella Zoster viral (VZV) infection.  She
      was serologically positive for systemic lupus erythematosus but negative for
      virus.  The exact pathogenesis of the patient's severe optic neuritis, adduction
      and neurological deficit was unknown.  The initiation of high dose steroids for
      optic neuritis was a big clinical dilemma in a pregnant patient with viral
      infection.  The patient was treated with high dose steroids  after three days of
      commencement of antiviral treatment.  At 6 months after presentation, her visual
      acuity in the right eye was 6/36 with perception to light in the left.

PMID- 15190669
TI  - Drowning in a child: accidental or neglect?
AB  - We report the case of an infant who was found dead in the toilet of a nursery.
      Examination of the scene revealed an element of neglect in the care of the child.
      Postmortem showed evidence of drowning. Her blood sample showed a toxicologic
      evidence of alcohol exposure.

PMID- 15190670
TI  - A case of severe leptospirosis with pancytopaenia.
AB  - Pancytopaenia is a rare clinical presentation of severe leptospirosis. We would
      like to report a case of severe leptospirosis that progressed to pancytopaenia
      despite initial penicillin therapy. The patient needed a second course of
      antibiotic with doxycycline to improve his persistent symptoms and cytopaenia.
      Persistent pancytopaenia in severe leptospirosis and its management were
      reviewed.

PMID- 15190671
TI  - Acute disseminated encephalomyelitis (ADEM) presenting with seizures secondary to
      anti-tetanus toxin vaccination.
AB  - Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating
      disease of the central nervous system (CNS) that is known to occur spontaneously
      in association with specific and non-specific viral illnesses and after
      vaccination against various pathogens. Although it is often a self-limited
      monophasic illness, the fatality rate is estimated to be as high as 20%, and many
      patients suffer residual neurologic impairment 1. The diagnosis is mainly based
      on clinical and radiological findings. The clinical presentation varies from
      merely, an asymptomatic condition to loss of consciousness, seizures, ataxia,
      optic neuropathy, cranial nerve palsies, and motor dysfunction. MRI of the brain
      is the single most important diagnostic radiological investigation and can
      facilitate early diagnosis and prompt treatment. This case report describes a
      patient with ADEM presenting with only seizures after vaccination with anti
      tetanus toxin.

PMID- 15190672
TI  - Squamous cell carcinoma involving the tibia treated by reimplantation of
      autoclaved resected bone.
AB  - We present an elderly patient with a squamous cell carcinoma over the
      subcutaneous aspect of the leg involving the tibia. En bloc resection of the
      tumour together with a 10 centimetre segment of the tibia was done. The resected
      bone was autoclaved, replaced in its original position and stabilized with bone
      cement and a locked nail. This allowed early ambulation with minimal cost.

PMID- 15190673
TI  - Seoul hantavirus infection mimicking dengue fever.

PMID- 15190674
TI  - Recurrent vaginal candidiasis.
AB  - Recurrent vaginal candidiasis is one of the most common reasons for patients
      visiting their primary care doctors. Majority of the cases are caused by Candida
      albicans. Controlling of risk factors such as diabetes mellitus, used of broad
      spectrum antibiotics, contraceptive pills and steroid therapy helps in managing
      recurrent vaginal candidiasis. Initial 14-day course of oral azoles and followed
      by 6 months maintenance are effective in treating majority of the cases. Failure
      to treat recurrent vaginal candidiasis can lead to various bio-psycho-social
      complications.

PMID- 15190675
TI  - Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases.
AB  - Inflammatory processes associated with the over-production of cytokines,
      particularly of TNF-alpha, accompany numerous neurodegenerative diseases, such as
      Alzheimer's disease, in addition to numerous systemic conditions, exemplified by
      rheumatoid arthritis and erythema nodosum leprosum (ENL). TNF-alpha has been
      validated as a drug target with Remicade and Enbrel available as prescription
      medications. Both, however, are large macromolecules, require injection and have
      limited brain access. The classical drug, thalidomide is being increasingly used
      in the clinical management of a wide spectrum of diseases. As its clinical value
      in treating ENL derives from its TNF-alpha inhibitory activity, thalidomide was
      chosen for structural modification for the discovery of novel and more potent
      isosteric analogues with appropriate lipophilicity to insure high brain
      penetration. TNF-alpha inhibitory activity was evaluated against
      lipopolysacharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in
      cell culture, whose viability was quantified to differentiate reductions in TNF
      alpha secretion from that associated with cellular toxicity. Specific analogues
      potently inhibited TNF-alpha secretion, compared to thalidomide. This involved a
      post-transcriptional mechanism, as they decreased TNF-alpha mRNA stability via
      its 3'-untranslated region (UTR), as determined by luciferase activity in stably
      transfected cells with and without the 3'-UTR of human TNF-alpha.

PMID- 15190676
TI  - Prion disease and Alzheimer's disease: pathogenic overlap.
AB  - Prion diseases are widely recognized for their transmissibility, and it is this
      feature that has been studied most extensively. In recent years, public health
      concerns over the transmission of animal forms of prion disease, such as bovine
      spongiform encephalopathy and chronic wasting disease, to humans has only
      augmented the notion that prion diseases are primarily infectious. Yet within the
      spectrum of human prion diseases, often overlooked is the fact that the
      overwhelming majority of cases are age-dependent sporadic, or inherited
      processes. Closer examination of the pathophysiological processes involved in
      prion disease further indicates a neurodegenerative, rather than infectious
      disease. Indeed, the age requirement, the numerous kindreds carrying point
      mutations in an amyloidogenic protein, the copper binding properties of the
      amyloidogenic protein, the evidence of free radical damage, the presence of
      polymorphisms that influence disease susceptibility, the formation of amyloid
      plaques, and in some cases the presence of neurofibrillary pathology, are
      features common to both prion disease and Alzheimer's disease. Therefore, while
      transmissibility will continue to be a major subject of prion disease research,
      we suspect that further characterization of its pathophysiological mechanisms
      will only substantiate the notion that prion disease is fundamentally a
      neurodegenerative process.

PMID- 15190677
TI  - Genetic aspects of Alzheimer's disease.
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder with a complex etiology
      and pathogenesis. Mutations in presenilin 1 gene (PSEN1), located on chromosome
      14, more rarely in amyloid-beta protein precursor (APP) on chromosome 21, and
      presenilin 2 genes (PSEN2) on chromosome 1, underlie the pathogenesis of most
      cases of familial early onset of AD (EOAD). The genetics of late-onset AD (LOAD)
      have been more enigmatic and the only confirmed risk factor for LOAD remains the
      apolipoprotein E4 allele (ApoE4) on chromosome 19. In this review, we discuss the
      genetics of AD with a focus on the role of the APP and presenilins.

PMID- 15190678
TI  - Tau phosphorylation and assembly.
AB  - Neurofibrillary tangles, one of the aberrant structures found in the brain of
      Alzheimer's disease patients are mainly composed of tau in hyperphosphorylated
      form. Thus, a possible relation between phosphorylation and assembly of tau
      proteins has been analysed. By doing in vitro studies we have observed that in
      certain conditions, where compounds from oxidative stress are present, the
      capacity of tau for self assembly increases upon phosphorylation.

PMID- 15190679
TI  - Neurodegenerative aspects of protein aggregation.
AB  - Protein aggregation and amyloid fibril deposits are characteristic features of
      more than twenty pathologic conditions characterized by plaque deposition in the
      central nervous system. Recent studies point out relationships between protein
      misfolding and numerous serious diseases. Despite different origins (sporadic,
      familial or transmissible), they are sometimes called conformational diseases to
      emphasize aberrant conformations as the putative cause of deposits that precede
      or accompany the clinical manifestation of the disease. Neurological disorders
      such as Alzheimer's disease (AD), Prion disorders (PrD), Parkinson's disease
      (PD), and Huntington's disease (HD) are the most typical examples of protein
      based dementias, characterized by protein conformational transitions (alpha
      helix/random coil to beta-sheet) that cause aggregation followed by
      fibrillization. Although it is very tempting to postulate a common mechanism of
      toxicity based on conformational and structural analogies, it should be noted
      that the factors responsible for conformational transition, oligomerization,
      aggregation, and plaque formation, are still subject of speculation and
      additional data is required to test the amyloid fibril hypothesis.

PMID- 15190680
TI  - Amyloid-beta and tau proteins as biochemical markers of Alzheimer's disease.
AB  - With the development of new therapeutic strategies, and the concept of mild
      cognitive impairment (MCI) as an early stage of Alzheimer's disease (AD), there
      is an increasing need for an early and accurate diagnosis of sporadic AD.
      Therefore, biological markers allowing a positive diagnosis early in the course
      of the disease are highly desirable. The most extensively evaluated markers of
      sporadic AD are amyloid-beta proteins and levels of both total and phosphorylated
      microtubule-associated protein tau. In this study, we review the currently
      available data on the aforementioned markers assessed in the cerebrospinal fluid
      or plasma, alone and in combinations, focusing on their clinical applicability
      including sensitivity in the diagnosis of AD and mild cognitive impairment,
      specificity in discriminating AD from other dementias and correlations with the
      disease progression and apolipoprotein E genotype. We also analyze advantages and
      potential drawbacks of using biomarkers in the laboratory diagnosis of AD.

PMID- 15190681
TI  - Alzheimer's amyloid-beta (A beta) is an essential synaptic protein, not
      neurotoxic junk.
AB  - Despite a decade long universal publication in favor of the view on amyloid-beta
      (A beta) as Alzheimer's disease culprit (solely neurotoxic for neurons and brain
      tissue), current scientific evidence leaves little doubt that A beta serves an
      essential role at synapse and in synaptic structure-functional plasticity that
      underlie learning and memory. Therefore, the change of A beta biology in
      Alzheimer's disease (as well as in a number of other human pathologies, including
      cardiovascular disease, neuromuscular junction disorders, NPC and Down's
      syndrome) may represent a physiological mechanism to compensate for impaired
      brain structure or function. In our own recent study A beta 1-40 rescued long
      term potentiation (LTP, a major model for activity-dependent CNS plasticity),
      while cholesterol synthesis inhibition abolished the restorative action of the A
      beta peptide. This study confirms that A beta protein is a functional player in
      synaptic structure-functional plasticity and in cholesterol neurochemical
      pathways. The article also calls for a need to critically re-evaluate a universal
      belief that transgenic mice with a transgene for amyloid-beta protein precursor
      (A beta PP) are a true model for Alzheimer's type neurodegeneration.

PMID- 15190682
TI  - Sources and mechanisms of cytoplasmic oxidative damage in Alzheimer's disease.
AB  - While evidence supports a pathogenic and proximal role for oxidative stress in
      Alzheimer's disease, the causes and consequences of reactive oxygen species that
      promote oxidative damage have not been directly demonstrated. Co-incident with
      the reduced energy metabolism during the development of the disease, some of the
      key mitochondrial enzymes have shown deficient activity in AD neurons, which may
      lead to increased ROS production. However, we found that oxidative damage occurs
      primarily within the cytoplasm rather than in mitochondria. Given that SOD
      activity is increased in AD mitochondria and that metal ions such as iron and
      copper are enriched in susceptible neurons, we hypothesize that mitochondria, as
      a source, provide hydrogen peroxide, which, as an intermediate, once in the
      cytoplasm, will be converted into highly reactive hydroxyl radicals through
      Fenton reaction in the presence of metal ion and cause damage in cytoplasm.

PMID- 15190683
TI  - The role of metabotropic glutamate receptors in Alzheimer's disease.
AB  - While glutamatergic transmission is severely altered by early degeneration of
      cortico-cortical connections and hippocampal projections in Alzheimer's disease
      (AD), the role of glutamate receptors in the pathogenesis of AD is not yet
      defined clearly. Nonetheless, as reviewed here, the topographical distribution of
      different types of receptors likely contributes to the regional selective nature
      of neuronal degeneration. In particular, metabotropic glutamate receptors (mGluR)
      may contribute the pathogenesis of many neurological conditions and also regulate
      neuronal vulnerability against cytotoxic stress. Thus, we here discuss the
      possible role of mGluR in the pathogenesis of AD based on the results from other
      neurodegenerative diseases that may give us clues to solve the mysterious
      selective neurodegeneration evident in AD.

PMID- 15190684
TI  - Alzheimer's disease and acetylcholine receptors.
AB  - Cholinergic abnormalities, alongside senile plaques, neurofibrillary tangles, and
      extensive neuronal loss, are the major characteristics in Alzheimer's disease
      (AD). Both nicotinic and muscarinic acetylcholine receptors are decreased in AD,
      and it has been shown that the reduction in the number of acetylcholine receptors
      precedes other pathologic changes. Anti-cholinergic drugs induce amnesia, which
      can be reversed by withdrawal of the medication. Inhibition of the down
      regulation of acetylcholine is, therefore, a strategy for the treatment of AD
      because it could augment acetylcholine levels within synaptic clefts. In this
      context, acetylcholinesterase inhibitors, which improve cognitive functions, are
      currently approved for the treatment of AD. Stimulation of acetylcholine
      receptors, nicotinic or muscarinic, is another strategy; some drugs are currently
      under investigation, and reported to be effective. In addition, nicotinic
      stimulation exerts a neuroprotective effect, and reduces the amyloid burden.
      Cholinergic therapy may counter the symptoms and progress of AD.

PMID- 15190685
TI  - Alzheimer's disease and the cell cycle.
AB  - Current views associate the reappearance of cell cycle markers with early events
      in Alzheimer's disease. Even though, the cell cycle was implicated early in the
      study of this disease, only recently has it been associated with selective early
      vulnerability of neurons. The pathological hallmarks of Alzheimer's disease
      namely tau and amyloid have been associated with having effects on or being
      affected by cell cycle progression. Indeed the mitogenic component looms large
      early in the onset of Alzheimer's disease. Although quite a number of markers of
      reentry have been catalogued, the common denominator is abortosis, the
      unalterable march towards neuronal dysfunction, stasis and eventually death. We
      feel that complete understanding of the mechanisms, acting either positively by
      stimulation or through removal of inhibitory signals will provide promising
      molecular targets for pharmacological interventions which have been static for a
      number of years by being relegated to inhibition of the enzyme cholinesterase. In
      our opinion, investigating more proximal mechanisms will provide answers to
      changing the natural course of this illness.

PMID- 15190687
TI  - Dental hygienists and access to oral health care.

PMID- 15190686
TI  - Gonadotropins and Alzheimer's disease: the link between estrogen replacement
      therapy and neuroprotection.
AB  - The search for a definitive gender bias in Alzheimer's disease has resulted in a
      multitude of epidemiological findings that point to a higher prevalence and
      incidence of Alzheimer's disease in women. Due to this reported predisposition of
      women to Alzheimer's disease, the sex steroid estrogen has become the primary
      focus of research in this field, however, inconclusive data regarding estrogen
      replacement therapy has lead some researchers to further investigate the role of
      the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis that have
      been, for the most, part overlooked. The hormones of the HPG axis, such as the
      gonadotropin, (luteinizing hormone and follicle-stimulating hormone), are
      involved in regulating reproductive function via a complex feedback loop. We
      propose that it is in fact the increase in gonadotropin concentrations and not
      the decrease in steroid hormone (e.g., estrogen) production following
      menopause/andropause that results in an increased risk of Alzheimer's disease.
      Furthermore, when the role of gonadotropins is taken into account, the data
      obtained from recent epidemiological studies and randomized trials suggesting the
      ineffectiveness estrogen may indeed be misinterpreted. In this review, we examine
      how hormones of the hypothalamic-pituitary-gonadal axis, in particular the
      gonadotropins, play a central and determining role in modulating the
      susceptibility to and progression of Alzheimer's disease. Based on this, we
      suggest that therapeutic interventions targeted at gonadotropins could both
      prevent disease in those patients currently asymptomatic or halt, and even
      reverse, disease in those currently afflicted.

PMID- 15190688
TI  - Possible replacement for artificial breast implants.

PMID- 15190689
TI  - The mentoring experiences and career satisfaction of dental hygiene program
      directors.
AB  - PURPOSE: The purpose of this study was to describe the relationship between
      career satisfaction and length of the mentoring experiences of dental hygiene
      directors. METHODS: Directors were asked a series of questions (74 items) that
      described their career satisfaction and mentoring experiences during three stages
      of their lives professional student, faculty member, and director. The extent of
      career satisfaction was measured on a five point Likert-type scale. The target
      population consisted of a convenience sample of 235 directors with an active
      Internet mail address (n = 142). An Internet mail questionnaire was sent to these
      directors. The data sample consisted of 72 usable responses (51%). The field test
      was conducted to test for both content and face validity. Cronbach's Alpha was
      used as a measure of internal consistency and an acceptable alpha was determined
      to be 0.60. Data were downloaded from the WEB and manually entered into SPSS 9.
      RESULTS: Results indicated that career satisfaction was positively associated
      with length of the mentor relationship. The relationship between the total length
      of mentoring received as a student, faculty member, and director and the
      perceived level of career satisfaction had a moderate positive association (r =
      0.459). The grand means for career satisfaction and length of mentoring in years,
      were 3.78 (sd = 0.5615, n = 47) and 20.46 (sd = 21.48, n = 45), respectively.
      CONCLUSION: As the length of the mentor experience increased, so did the level of
      career satisfaction, albeit a moderate increase. To enhance career satisfaction,
      mentoring should be initiated in dental hygiene graduate programs, particularly
      for students who aspire to become directors.

PMID- 15190690
TI  - Comparison of plaque removing ability of one standard and two flexible-head
      toothbrushes.
AB  - PURPOSE: This pilot study compared the plaque removing ability of two flexible
      head toothbrushes and one nonflexible-head toothbrush. METHODS: Twenty
      individuals meeting specific criteria participated. Three quadrants on each
      subject were disclosed and scored using the Turesky modification of the Quigley
      Hein plaque index. For consistency, one dental hygienist performed all brushing
      and another performed all indices. Pre- and post-brushing scores were compared
      using t-tests and analysis of variance (ANOVA) to determine differences. RESULTS:
      Differences between pre- and post-brushing scores of all groups were significant
      (p > 0.005). However, no significant differences were detected between mean
      scores of the test toothbrush groups and the control group of the two test
      toothbrush groups, or among the means of all groups. CONCLUSION: No differences
      in plaque removing ability were found between or among the toothbrushes tested.

PMID- 15190691
TI  - The anatomy of evidence-based publications: article summaries and systematic
      reviews. Part I.
AB  - The term evidence-based has become a popular phrase in the title of many
      articles. Some articles discuss the process, whereas others lead readers to
      believe that evidence-based methodology was used in conducting the research or in
      presenting a synthesis of the findings, which may not be the case. The purpose of
      Part I of this two-part report is to define evidence-based decision-making
      (EBDM), discuss the evolution of the evidence based movement, and to describe the
      distinguishing characteristics of evidence-based publications. In doing so,
      articles using an evidence-based format, article summaries found in evidence
      based journals and systematic reviews, such as those published by the Cochrane
      Collaboration, will be presented. Part II reviews the findings from the Cochrane
      Review on manual versus powered toothbrushing for oral health and discusses the
      strengths and weaknesses of systematic reviews.

PMID- 15190692
TI  - Manual versus powered toothbrushes: a summary of the Cochrane Oral Health Group's
      Systematic Review. Part II.
AB  - PURPOSE: A systematic review examining the clinical effectiveness of power versus
      manual toothbrushes was conducted by the Cochrane Collaborations Oral Health
      Group. Their review examined clinical trials conducted through 2001 and used
      international standards to identify, access, evaluate, analyze, and report the
      data. Part I of this series discussed distinguishing characteristics of evidence
      based publications, such as systematic reviews, whereas this report provides a
      summary of the Cochrane Review, its importance to the profession, and discusses
      the strengths and limitations of systematic reviews. METHODS: Search strategies
      to identify published clinical trials on power toothbrushes were developed, and
      manufacturers were contacted for additional published and unpublished
      information. Trials were selected based on pre-established criteria; including
      whether they compared power versus manual toothbrushes used a randomized research
      design tested products in the general population without disabilities, provided
      data on plaque and gingivitis, and were at least 28 days in length. Six reviewers
      independently extracted information in duplicate. Indices for plaque and
      gingivitis levels were expressed as standardized mean differences for data
      distillation. Data distillation was accomplished using a meta-analysis, with a
      mean difference between power and manual toothbrushes as the measure of
      effectiveness. RESULTS: Searches identified 354 trials, of which 29 met inclusion
      criteria. These trials involved 2.547 participants who provided data for meta
      analysis. Results indicated that for both plaque and gingivitis, all types of
      power toothbrushes worked as well as manual toothbrushes, however only the
      rotating oscillating toothbrush consistently provided a statistically significant
      though modest benefit over manual toothbrushes in reducing plaque (7%) and
      gingivitis (17%). None of the battery powered toothbrush studies met the
      inclusion criteria. CONCLUSION: The Cochrane systematic review used international
      standards to examine more than 30 years of published studies. A concern is that
      only one type of electric toothbrush, the rotating oscillating toothbrush
      consistently demonstrated a statistically significant benefit over manual
      toothbrushes, and the majority of studies did not meet the standards for
      inclusion in moving forward it will be important to conduct methodologically
      sound studies demonstrating the ability of power toothbrushes to reduce the
      incidence and prevalence of caries and periodontal disease.

PMID- 15190693
TI  - Sickle cell disease and trait: an increase in trabecular spacing, a case study.
AB  - A case report of a patient with sickle cell disease trait and the
      radiographically evident trabecular bone changes is examined in this article. The
      purpose of this article is to raise awareness in the dental and dental hygiene
      professional community of the treatment and clinical management of patients with
      sickle cell disease (SCD) and sickle cell disease trait (SCD trait). Dentists and
      dental hygienists can provide optimum clinical care for this patient population
      by incorporating appropriate clinical management according to the most recent
      advances in the recognition and treatment of patients with SCD and SCD trait.

PMID- 15190694
TI  - Assessing the informational value of parameter estimates in cognitive models.
AB  - Mathematical models of cognition often contain unknown parameters whose values
      are estimated from the data. A question that generally receives little attention
      is how informative such estimates are. In a maximum likelihood framework,
      standard errors provide a measure of informativeness. Here, a standard error is
      interpreted as the standard deviation of the distribution of parameter estimates
      over multiple samples. A drawback to this interpretation is that the assumptions
      that are required for the maximum likelihood framework are very difficult to test
      and are not always met. However, at least in the cognitive science community, it
      appears to be not well known that standard error calculation also yields
      interpretable intervals outside the typical maximum likelihood framework. We
      describe and motivate this procedure and, in combination with graphical methods,
      apply it to two recent models of categorization: ALCOVE (Kruschke, 1992) and the
      exemplar-based random walk model (Nosofsky & Palmeri, 1997). The applications
      reveal aspects of these models that were not hitherto known and bring a mix of
      bad and good news concerning estimation of these models.

PMID- 15190695
TI  - A computer program for Spearman-Karber and probit analysis of psychometric
      function data.
AB  - PMETRIC is a computer program for the analysis of observed psychometric
      functions. It can estimate the parameters of these functions, using either probit
      analysis (a parametric technique) or the Spearman-Karber method (a nonparametric
      one). For probit analysis, either a maximum likelihood or a minimum chi 2
      criterion may be used for parameter estimation. In addition, standard errors of
      parameter estimates can be estimated via bootstrapping. The program can be used
      to analyze data obtained from either yes-no or m-alternative forced-choice tasks.
      To facilitate the use of PMETRIC in simulation work, an associated program,
      PMETGEN, is provided for the generation of simulated psychometric function data.
      Use of PMETRIC is illustrated with data from a duration discrimination task.

PMID- 15190696
TI  - SPSS and SAS programs for addressing interdependence and basic levels-of-analysis
      issues in psychological data.
AB  - Levels-of-analysis issues arise whenever individual-level data are collected from
      more than one person from the same dyad, family, classroom, work group, or other
      interaction unit. Interdependence in data from individuals in the same
      interaction units also violates the independence-of-observations assumption that
      underlies commonly used statistical tests. This article describes the data
      analysis challenges that are presented by these issues and presents SPSS and SAS
      programs for conducting appropriate analyses. The programs conduct the within-and
      between-analyses described by Dansereau, Alutto, and Yammarino (1984) and the
      dyad-level analyses described by Gonzalez and Griffin (1999) and Griffin and
      Gonzalez (1995). Contrasts with general multilevel modeling procedures are then
      discussed.

PMID- 15190697
TI  - A Matlab function to estimate choice model parameters from paired-comparison
      data.
AB  - Tversky (1972) has proposed a family of models for paired-comparison data that
      generalize the Bradley-Terry-Luce (BTL) model and can, therefore, apply to a
      diversity of situations in which the BTL model is doomed to fail. In this
      article, we present a Matlab function that makes it easy to specify any of these
      general models (EBA, Pretree, or BTL) and to estimate their parameters. The
      program eliminates the time-consuming task of constructing the likelihood
      function by hand for every single model. The usage of the program is illustrated
      by several examples. Features of the algorithm are outlined. The purpose of this
      article is to facilitate the use of probabilistic choice models in the analysis
      of data resulting from paired comparisons.

PMID- 15190699
TI  - Collecting responses through Web page drag and drop.
AB  - This article describes how to collect responses from experimental participants
      using drag and drop on a Web page. In particular, we describe how drag and drop
      can be used in a text search task in which participants read a text and then
      locate and categorize certain elements of the text (e.g., to identify the main
      claim of a persuasive paragraph). Using this technique, participants respond by
      clicking on a text segment and dragging it to a screen field or icon. We have
      successfully used this technique in both the argument element identification
      experiment that we describe here and a tutoring system that we created to teach
      students to identify source characteristics while reading historical texts
      (Britt, Perfetti, Van Dyke, & Gabrys, 2000). The implementation described here
      exploits the capability of recent versions of Microsoft's Internet Explorer Web
      browser to handle embedded XML documents and drag and drop events.

PMID- 15190698
TI  - Using logistic regression to estimate delay-discounting functions.
AB  - The monetary choice questionnaire (MCQ) and similar computer tasks ask preference
      questions in order to ascertain indifference, the perceived equivalence of
      immediate versus larger delayed rewards. Indifference data are then fitted with a
      hyperbolic function, summarizing the decline in perceived value with delay time.
      We present a fitting method that estimates the hyperbolic parameter k directly
      from survey responses. Binary preferences are modeled as a function of time (X2)
      and a transformed reward ratio (X1), yielding logistic regression coefficients
      beta 2 and beta 1. The hyperbolic parameter emerges as k = beta 2/beta 1, where
      the logistic predicted p = .5 (the definition of indifference). The MCQ was
      administered to 1,073 adolescents and was scored using both standard and logistic
      methods. The means for In(k) were similar (standard, -4.53; logistic, -4.51), and
      the results were highly correlated (rho = .973). Simulated MCQ data showed that k
      was unbiased, except where beta 1 > or = -1, indicating a vague survey response.
      Jackknife standard errors provided excellent coverage.

PMID- 15190700
TI  - Escher in color space: individual-differences multidimensional scaling of color
      dissimilarities collected with a gestalt formation task.
AB  - The structure of color perception can be examined by collecting judgments about
      color dissimilarities. In the procedure used here, stimuli are presented three at
      a time on a computer monitor and the spontaneous grouping of most-similar stimuli
      into gestalts provides the dissimilarity comparisons. Analysis with
      multidimensional scaling allows such judgments to be pooled from a number of
      observers without obscuring the variations among them. The anomalous perceptions
      of color-deficient observers produce comparisons that are represented well by a
      geometric model of compressed individual color spaces, with different forms of
      deficiency distinguished by different directions of compression. The geometrical
      model is also capable of accommodating the normal spectrum of variation, so that
      there is greater variation in compression parameters between tests on normal
      subjects than in those between repeated tests on individual subjects. The method
      is sufficiently sensitive and the variations sufficiently large that they are not
      obscured by the use of a range of monitors, even under somewhat loosely
      controlled conditions.

PMID- 15190701
TI  - A vision research apparatus for broad luminance range displays.
AB  - Lightness, the perceived gray shade of a surface, and the perception of self
      luminous surfaces--that is, surfaces that appear to glow--have most often been
      studied with paper displays and computer-generated stimuli presented on CRT
      monitors. Although both methods are often effective, experiments that require a
      wide range of luminance values in the same display are often difficult to conduct
      with paper and computer displays alone. Also, color mode appearance is often an
      issue when surface color perception is the topic of research; CRT monitors are
      essentially light sources themselves and often appear in the luminous mode of
      color appearance. Here, we describe an apparatus in which the target is an
      undetected aperture whose luminance is adjustable. Whereas a typical CRT monitor
      offers a luminance range of about 100:1, much broader luminance ranges are
      possible with the described apparatus. Unlike a CRT monitor, the stimulus
      background will always appear in the surface mode of color perception, and the
      target(s) can appear as either surface colors or luminous colors. Apparatus
      modifications are possible, including the addition of a stereoscope or an
      embedded CRT for creating an adjustable region that is computer controlled.

PMID- 15190702
TI  - The Temporal Automated System for Taste Experiments (TASTE).
AB  - We describe a new, open flow device for presenting taste stimuli to human
      subjects under controlled conditions of timing. The device delivers each stimulus
      as a mist to the participant's tongue through one of 16 nozzles attached to a
      linear slide. Software controls the position of the slide, the duration of the
      stimulus, and the duration of the pre- and poststimulus water rinses and records
      the responses of the participant. Temporal characteristics of this system make it
      especially applicable to studies on the role of attention in taste perception.

PMID- 15190703
TI  - A computer program for measuring body size distortion and body dissatisfaction.
AB  - A computer program is described that measures body size distortion and body
      dissatisfaction. The program is written using Visual Basic development tools and
      will run on any Windows 98 or more current system. The width of a static digital
      image of the participant can be manipulated using three separate psychophysical
      methods. In the method of adjustment, the participant adjusts the image wider or
      thinner to match his or her perceived size. The participants may also be required
      to adjust the image to their ideal size, with the discrepancy between perceived
      and ideal size being used as a measure of body dissatisfaction. In the staircase
      method, participants see an image that is continuously expanding or contracting.
      The participants change the direction of the distortion when the image matches
      their perceived size. In the adaptive probit estimation procedure, participants
      judge whether a static image is distorted too wide or too thin. Analysis of the
      responses permits a determination of the point of subjective equality (PSE) and
      the difference limen (DL) values. The DL reflects the amount of body size
      distortion necessary for the participant to detect the distortion 50% of the
      time. The PSE reflects the participant's subjective judgment of his or her body
      size. These two values are reflective of the sensory and nonsensory components,
      respectively, that contribute to body size judgments.

PMID- 15190704
TI  - A computerized simulation for investigating gambling behavior during roulette
      play.
AB  - The present paper describes a computerized roulette program for the conducting of
      psychological research on gambling behavior. The program was designed to simulate
      an actual roulette game found in casinos and gambling riverboats throughout North
      America. The roulette program collects detailed trial-by-trial data on
      player/participant behavior that can easily be transferred into data analysis and
      graphics programs. This multimedia simulation was designed in the Visual Basic
      programming language, and it is capable of running on any IBM-compatible personal
      computer running the Windows 2000 or higher operating system.

PMID- 15190705
TI  - Touchscreen-enhanced visual learning in rats.
AB  - The efficiency of traditional levers and of modern touchscreen technology for
      training rats on a computerized visual discrimination was studied in a series of
      observations. When compared with a lever-based discrimination procedure, the use
      of touchscreens supported the faster development of signal tracking behavior and
      acquisition of a two-stimulus simultaneous visual discrimination. It did not
      affect the final level of accuracy. Factors related to spatial proximity of the
      responses with the stimuli, sign-tracking, and increased ease of touchscreen
      motor responses were suggested as possible reasons for the touchscreen training
      advantage. This increased efficiency allows large numbers of animals to be tested
      quickly, a necessary requirement for studies involving genetic and physiological
      interventions.

PMID- 15190706
TI  - Implementing communication between Windows PCs and test equipment using RS-232
      and Borland C++ Builder.
AB  - Modern experiments in the behavioral sciences frequently employ several items of
      electronic equipment such as computers, monitoring devices, stimulus presentation
      equipment, and response collection systems. In many cases it would be
      advantageous for these items to communicate directly with each other. Such
      communication may facilitate greater automation of experiments (i.e., reduced
      experimenter influences during the experiment), more precise experiment control
      (i.e., superior timing and synchronization capabilities of electronic devices),
      and greater accuracy of data collection (i.e., reduced ambiguity of participant
      responses). Many electronic experiment devices already provide external
      interfaces through which communication with other devices can be implemented. The
      most common is based on the RS-232 protocol, which is also found in all standard
      PCs. Therefore, Microsoft Windows based computers can be programmed to control
      experiments by communicating directly with electronic experiment devices. We show
      how to implement this RS-232 interconnection between devices and a Windows PC
      using currently available software tools.

PMID- 15190707
TI  - Automatic parsing of parental verbal input.
AB  - To evaluate theoretical proposals regarding the course of child language
      acquisition, researchers often need to rely on the processing of large numbers of
      syntactically parsed utterances, both from children and from their parents.
      Because it is so difficult to do this by hand, there are currently no parsed
      corpora of child language input data. To automate this process, we developed a
      system that combined the MOR tagger, a rule-based parser, and statistical
      disambiguation techniques. The resultant system obtained nearly 80% correct
      parses for the sentences spoken to children. To achieve this level, we had to
      construct a particular processing sequence that minimizes problems caused by the
      coverage/ambiguity tradeoff in parser design. These procedures are particularly
      appropriate for use with the CHILDES database, an international corpus of
      transcripts. The data and programs are now freely available over the Internet.

PMID- 15190708
TI  - Psycholinguistic norms for action photographs in French and their relationships
      with spoken and written latencies.
AB  - A set of 142 photographs of actions (taken from Fiez & Tranel, 1997) was
      standardized in French on name agreement, image agreement, conceptual
      familiarity, visual complexity, imageability, age of acquisition, and duration of
      the depicted actions. Objective word frequency measures were provided for the
      infinitive modal forms of the verbs and for the cumulative frequency of the
      verbal forms associated with the photographs. Statistics on the variables
      collected for action items were provided and compared with the statistics on the
      same variables collected for object items. The relationships between these
      variables were analyzed, and certain comparisons between the current database and
      other similar published databases of pictures of actions are reported. Spoken and
      written naming latencies were also collected for the photographs of actions, and
      multiple regression analyses revealed that name agreement, image agreement, and
      age of acquisition are the major determinants of action naming speed. Finally,
      certain analyses were performed to compare object and action naming times. The
      norms and the spoken and written naming latencies corresponding to the pictures
      are available on the Internet (http://www.psy.univ-bpclermont.fr/~pbonin/pbonin
      eng.html) and should be of great use to researchers interested in the processing
      of actions.

PMID- 15190709
TI  - Predictors of picture naming speed.
AB  - We report the results of a large-scale picture naming experiment in which we
      evaluated the potential contribution of nine theoretically relevant factors to
      naming latencies. The experiment included a large number of items and a large
      sample of participants. In order to make this experiment as similar as possible
      to classic picture naming experiments, participants were familiarized with the
      materials during a training session. Speeded naming latencies were determined by
      a software key on the basis of the digital recording of the responses. The
      effects of various variables on these latencies were assessed with multiple
      regression techniques, using a repeated measures design. The interpretation of
      the observed effects is discussed in relation to previous studies and current
      views on lexical access during speech production.

PMID- 15190710
TI  - MANULEX: a grade-level lexical database from French elementary school readers.
AB  - This article presents MANULEX, a Web-accessible database that provides grade
      level word frequency lists of nonlemmatized and lemmatized words (48,886 and
      23,812 entries, respectively) computed from the 1.9 million words taken from 54
      French elementary school readers. Word frequencies are provided for four levels:
      first grade (G1), second grade (G2), third to fifth grades (G3-5), and all grades
      (G1-5). The frequencies were computed following the methods described by Carroll,
      Davies, and Richman (1971) and Zeno, Ivenz, Millard, and Duvvuri (1995), with
      four statistics at each level (F, overall word frequency; D, index of dispersion
      across the selected readers; U, estimated frequency per million words; and SFI,
      standard frequency index). The database also provides the number of letters in
      the word and syntactic category information. MANULEX is intended to be a useful
      tool for studying language development through the selection of stimuli based on
      precise frequency norms. Researchers in artificial intelligence can also use it
      as a source of information on natural language processing to simulate written
      language acquisition in children. Finally, it may serve an educational purpose by
      providing basic vocabulary lists.

PMID- 15190711
TI  - Cross-serial dependencies in Dutch: testing the influence of NP type on
      processing load.
AB  - We tested the cross-linguistic generalizability of three models of sentence
      processing complexity--Lewis (1996), Gibson (1998, 2000), and Gordon (Gordon,
      Hendrick, & Johnson, 2001; Gordon, Hendrick, & Levine, 2002)--by investigating
      the on-line processing of cross-serial dependencies in Dutch. The number of
      subject-verb relations in a clause was manipulated, as well as type of noun
      phrase (indexical pronouns vs. proper names or full definite NPs). Several of our
      findings diverged from Gibson's model: Processing difficulty at the verbs was not
      affected by the use of proper names versus first- and second-person pronouns; an
      increase at the first verb was seen for full NPs versus pronouns in 3-verb
      constructions, which was predicted by the Gibson model, but is in contrast to
      Lewis's model. These findings are best explained within the framework of
      similarity-based inference models (Gordon et al., 2001; Gordon et al., 2002),
      according to which the number of similar NPs affects processing difficulty at the
      point of retrieval, and not specifically their discourse status or syntactic
      function.

PMID- 15190712
TI  - What plausibly affects plausibility? Concept coherence and distributional word
      coherence as factors influencing plausibility judgments.
AB  - Our goal was to investigate the basis of human plausibility judgements. Previous
      research had suggested that plausibility is affected by two factors: concept
      coherence (the inferences made between parts of a discourse) and word coherence
      (the distributional properties of the words used). In two experiments,
      participants were asked to rate the plausibility of sentence pairs describing
      events. In the first, we manipulated concept coherence by using different
      inference types to link the sentences in a pair (e.g., causal or temporal). In
      the second, we manipulated word coherence by using latent semantic analysis, so
      two sentence pairs describing the same event had different distributional
      properties. The results showed that inference type affects plausibility; sentence
      pairs linked by causal inferences were rated highest, followed by attributal,
      temporal, and unrelated inferences. The distributional manipulations had no
      reliable effect on plausibility ratings. We conclude that the processes involved
      in rating plausibility are based on evaluating concept coherence, not word
      coherence.

PMID- 15190713
TI  - Semantic context influences memory for verbs more than memory for nouns.
AB  - Three experiments revealed that memory for verbs is more dependent on semantic
      context than is memory for nouns. The participants in Experiment 1 were asked to
      remember either nouns or verbs from intransitive sentences. A recognition test
      included verbatim sentences, sentences with an old noun and a new verb, sentences
      with an old verb and a new noun, and entirely new sentences. Memory for verbs was
      significantly better when the verb was presented with the same noun at encoding
      and at retrieval. This contextual effect was much smaller for nouns. Experiments
      2 and 3 replicated this effect and provided evidence that context effects reflect
      facilitation from bringing to mind the same meaning of a verb at encoding and at
      retrieval. Memory for verbs may be more dependent on semantic context because the
      meanings of verbs are more variable across semantic contexts than are the
      meanings of nouns.

PMID- 15190714
TI  - Seriality of phonological encoding in naming objects and reading their names.
AB  - There is a remarkable lack of research bringing together the literatures on oral
      reading and speaking. As concerns phonological encoding, both models of reading
      and speaking assume a process of segmental spellout for words, which is followed
      by serial prosodification in models of speaking (e.g., Levelt, Roelofs, & Meyer,
      1999). Thus, a natural place to merge models of reading and speaking would be at
      the level of segmental spellout. This view predicts similar seriality effects in
      reading and object naming. Experiment 1 showed that the seriality of encoding
      inside a syllable revealed in previous studies of speaking is observed for both
      naming objects and reading their names. Experiment 2 showed that both object
      naming and reading exhibit the seriality of the encoding of successive syllables
      previously observed for speaking. Experiment 3 showed that the seriality is also
      observed when object naming and reading trials are mixed rather than tested
      separately, as in the first two experiments. These results suggest that a serial
      phonological encoding mechanism is shared between naming objects and reading
      their names.

PMID- 15190715
TI  - Advantages and disadvantages of phonological similarity in serial recall and
      serial recognition of nonwords.
AB  - The phonological similarity effect (PSE) was studied with lists of nonwords in
      one task of serial recall and one task of serial recognition. PSE was critically
      affected by the scoring procedure and the type of phonological similarity
      involved, and the effect diverged in several ways from the findings of previous
      studies on words. PSE was absent in serial recall, regardless of scoring
      procedure, when phonologically similar items that shared the midvowel were
      compared with phonologically distinct items. PSE was reversed when serial recall
      and item recall scores of rhyme items and consonant frame items were compared
      with distinct items, but it was present in the position accuracy score of rhyme
      lists. In serial recognition, PSE was absent when rhyme lists were compared with
      distinct lists. Recognition was better for consonant frame lists than for rhyme
      lists, and there was a marginally significant reversal of PSE when consonant
      frame lists were compared with distinct lists. In the view of Fallon, Groves, and
      Tehan's (1999) study and the present study, rhyming improves item recall and
      serial recall but diminishes position accuracy, regardless of lexicality. But
      consonant frame lists with differing midvowels have higher item recall, serial
      recall, and position accuracy scores than do rhyme lists.

PMID- 15190716
TI  - Category-based induction: an effect of conclusion typicality.
AB  - Category-based induction involves the willingness of a thinker to project some
      newly learned property of one or more classes of objects to another class on the
      basis of their shared membership in a common superordinate category. Previous
      research has established that the perceived strength of arguments of the form
      "Class A has Property P; therefore, Class B has Property P" is influenced by the
      similarity of A to B and by the typicality or representativeness of A in a shared
      category, superordinate to both A and B. (The nature of P is also crucial, but we
      do not examine it in this study.) There is, however, no prior evidence that the
      relation between B and the category is influential. Three experiments were
      designed to test whether the typicality of B in the superordinate category also
      has an effect on inductive argument strength. By using multiple regression
      (Experiment 1) and an experimental design (Experiment 3), an effect of conclusion
      typicality was found, so that people are more willing to project properties to
      more typical conclusions. Experiment 2 ruled out conclusion familiarity as a
      potential confounding variable. The results are interpreted in the light of
      current models of category-based induction.

PMID- 15190717
TI  - Perceptual simulation in property verification.
AB  - If people represent concepts with perceptual simulations, two predictions follow
      in the property verification task (e.g., Is face a property of GORILLA?). First,
      perceptual variables such as property size should predict the performance of
      neutral subjects, because these variables determine the ease of processing
      properties in perceptual simulations (i.e., perceptual effort). Second,
      uninstructed neutral subjects should spontaneously construct simulations to
      verify properties and therefore perform similarly to imagery subjects asked
      explicitly to use images (i.e., instructional equivalence). As predicted, neutral
      subjects exhibited both perceptual effort and instructional equivalence,
      consistent with the assumption that they construct perceptual simulations
      spontaneously to verify properties. Notably, however, this pattern occurred only
      when highly associated false properties prevented the use of a word association
      strategy. In other conditions that used unassociated false properties, the
      associative strength between concept and property words became a diagnostic cue
      for true versus false responses, so that associative strength became a better
      predictor of verification than simulation. This pattern indicates that conceptual
      tasks engender mixtures of simulation and word association, and that researchers
      must deter word association strategies when the goal is to assess conceptual
      knowledge.

PMID- 15190718
TI  - Convex hull or crossing avoidance? Solution heuristics in the traveling
      salesperson problem.
AB  - Untrained adults appear to have access to cognitive processes that allow them to
      perform well in the Euclidean version of the traveling salesperson problem (E
      TSP). They do so despite the famous computational intractability of the problem,
      which stems from its combinatorial complexity. A current hypothesis is the
      humans' good performance is based on following a strategy of connecting boundary
      points in order (the convex hull hypothesis). Recently, an alternative has been
      proposed, that performance is governed by a strategy of avoiding crossings. We
      examined the crossing avoidance hypothesis from the perspectives of its capacity
      to explain existing data, its theoretical adequacy, and its ability to explain
      the results of three new experiments. In Experiment 1, effects on the solution
      quality of number of points versus number of interior points were compared. In
      Experiment 2, the distributions of observed paths were compared with those
      predicted from the two hypotheses. In Experiment 3, figural effects were varied
      to induce crossings. The results of the experiments were more consistent with the
      convex hull than with the crossing avoidance hypothesis. Despite its simplicity
      and intuitive appeal, crossing avoidance does not provide a complete alternative
      to the convex hull hypothesis. Further elucidation of human strategies and
      heuristics for optimization problems such as the E-TSP will aid our understanding
      of how cognitive processes have adapted to the demands of combinatorial
      difficulty.

PMID- 15190719
TI  - Use of temporal and spatial information in estimating event completion time.
AB  - In this research, we investigated how students use temporal and spatial
      information to estimate the time to fill a tank. In Experiment 1, we evaluated
      the usefulness of a digital clock to calibrate temporal information and of an
      overflow tank to calibrate spatial information and investigated how component
      skills, such as judging volume, judging time, and performing mental calculations,
      correlate with estimation accuracy. In Experiment 2, we compared the usefulness
      of static and animated displays in order to test the prediction that static
      displays would be more useful when the fill rate remained constant but animated
      displays would be more useful when the fill rate changed. The findings, when
      combined with verbal reports, provide evidence regarding the use of four
      strategies that differ in their perceptual and arithmetic demands.

PMID- 15190720
TI  - Memory for targets in a multilevel simulated environment: evidence for vertical
      asymmetry in spatial memory.
AB  - In two experiments, adult participants explored a symmetrical three-tiered
      computer-simulated building that contained six distinctive objects, two on each
      floor. Following exploration, the objects were removed, and the participants were
      asked to make direction judgments from each floor, indicating the former
      positions of the objects on that floor and on higher and lower floors. Relative
      tilt error scores indicated a bias, in that targets that were higher than the
      test location were judged as consistently lower than their actual positions and
      targets that were lower than the test location were judged as consistently higher
      than their actual positions. Absolute tilt errors revealed an asymmetry, with
      more accurate and less variable tilt errors for judgments directed to lower
      floors than for judgments directed to higher floors. Experiment 3 ruled out an
      account of the findings that does not relate them to spatial memory. The results
      suggest that the superiority of downward over upward spatial judgments,
      previously reported in two-dimensional visual-spatial tasks, extends to
      navigational spatial memory.

PMID- 15190721
TI  - Strategy shift affordance and strategy choice in young and older adults.
AB  - When skill acquisition involves a shift in strategy (such as from rule-based to
      retrieval-based processing), older adults typically shift later in practice than
      young adults do. We observed the shift from scanning-based to memory-based
      processing in a noun pair learning task. Young and older adults were trained in
      conditions in which the relationship between memory load and scanning load was
      manipulated by making the strategy shift more or less beneficial. Older adults in
      a condition with high shift affordance shifted to memory retrieval more fully and
      more rapidly than did older adults in conditions with lower shift affordance.
      Reluctance to rely on memory retrieval was related to metacognitive reports of
      memory confidence. The present study indicates that age differences in skill
      acquisition reflect qualitative age differences in strategy choice in addition to
      quantitative age differences in component task processes.

PMID- 15190722
TI  - Autobiographical memory in two older adults over a twenty-year retention
      interval.
AB  - This article reports on a study of autobiographical memory in two older adults,
      wife and husband, over a retention interval of 20 years. The female participant
      kept a 20-year log of daily events. A sampling of events that varied in
      distinctiveness, from unique, one-of-a-kind events to routine, almost daily
      events, was used to examine cued recall using an incremental scoring system. Each
      event recalled was also rated on phenomenological scales of remembering versus
      knowing, rehearsal, and importance. The strongest effect on recall was the order
      of the cues, with an initial what cue, containing the content of the event,
      proving superior to cues containing who or where elements. When was the most
      effective second cue. The results demonstrate regularity in retention over time
      and highlighted the utility of this approach for understanding the factors that
      influence autobiographical memory performance.

PMID- 15190723
TI  - Effects of multiplication practice on product verification: integrated structures
      model or retrieval-induced forgetting?
AB  - In the integrated structures model of simple multiplication (Manly & Spoehr,
      1999), it is proposed that retrieval of a multiplication fact (e.g., 2 x 7 = ?)
      activates and strengthens operand multiples representations (e.g., 4, 6, 8, etc.;
      14, 21, 28, etc.). In contrast, in the phenomenon of retrieval-induced forgetting
      (RIF; M. C. Anderson, Bjork, & Bjork, 1994), it is suggested that operand
      multiples ought to be suppressed with practice. Participants (N = 72) performed
      40 blocks of practice trials in which they generated answers to a subset of
      simple multiplication problems. We then measured response times and errors in a
      true-false product verification task. Both true and related false equations with
      practiced operand multiples as presented products were solved relatively poorly
      in the verification task. In agreement with RIF, this suggests that operand
      multiples were suppressed, rather than strengthened, during the practice phase.

PMID- 15190724
TI  - Judgment of frequency versus recognition confidence: repetition and recursive
      reminding.
AB  - Judgments of presentation frequency (JOFs) were compared with recognition
      confidence ratings (RCRs) in a single memory experiment. Two differences were
      found: (1) Relative to the effect of exposure duration, frequency had a larger
      effect on JOF than it had on RCR. (2) Replicating a finding by Proctor (1977),
      normalized memory operating characteristic (zMOC) curves for JOF had slopes
      greater than 1.0, whereas those for RCR had slopes of less than 1.0. The slope
      difference was found to be attributable to the first study trial. The results are
      contrary to the hypothesis that a single strength or familiarity dimension
      underlies JOF and RCR. To explain both findings, a new hypothetical basis of JOF
      is proposed. Repetition is assumed to trigger study phase reminding, which, in
      turn, is encoded into memory. Remindings can be recursively embedded, and the
      depth of recursion, recollected at test, is the primary basis of JOF. The
      hypothesis appears consistent with a broad range of JOF findings.

PMID- 15190725
TI  - The neurobiology of pain, affect and hypnosis.
AB  - Recent neuroimaging studies have used hypnotic suggestion to distinguish the
      brain structures most associated with the sensory and affective dimensions of
      pain. This paper reviews studies that delineate the overlapping brain circuits
      involved in the processing of pain and emotions, and their relationship to
      autonomic arousal. Also examined are the replicated findings of reliable changes
      in the activation of specific brain structures and the deactivation of others
      associated with the induction of hypnosis. These differ from those parts of the
      brain involved in response to hypnotic suggestions. It is proposed that the
      activation of a portion of the prefrontal cortex in response to both hypnotic
      suggestions for decreased pain and to positive emotional experience might
      indicate a more general underlying mechanism. Great potential exists for further
      research to clarify the relationships among individual differences in reactivity
      to pain, emotion, and stress, and the possible role of such differences in the
      development of chronic pain.

PMID- 15190726
TI  - Hypnosis and existential psychotherapy with end-stage terminally ill patients.
AB  - Existential Psychological Theory was employed as a conceptual and theoretical
      foundation for the use of hypnotically facilitated therapy in the management of
      intractable pain, nausea, and vomiting in 3 end-stage, terminally ill cancer
      patients. The existential principles of death anxiety, existential isolation, and
      existential meaninglessness were addressed with a combination of classic and
      Ericksonian techniques. The intractable nature of the presenting physical
      symptoms was conceptualized as a possible manifestation of the impact of the
      terminal prognosis. Direct hypnotic suggestions for the management of pain,
      nausea and vomiting were avoided. It was hypothesized that, as the existential
      conflicts associated with the patients' terminal status resolved, the
      physiological symptoms would become responsive to medication. After 6 sessions
      grounded in the principles of Existential Psychotherapy, the intractable status
      of the physical symptomatology remitted, and the patients responded to medical
      management. This paper addresses the usefulness of Existential Psychotherapy in
      hypnotic interventions for mediating somatic and psychosomatic symptomatology.

PMID- 15190728
TI  - Symptom removal: the twentieth century experience.
AB  - The twentieth century hypnosis literature regarding the use of direct symptom
      removal with hypnosis is in strong contrast with that of the nineteenth. It shows
      much ambivalence about the use of symptom removal. Objections, largely based on
      conclusions drawn from psychoanalytic theory, led many twentieth century
      psychotherapists to reject direct symptom removal. However, a certain amount of
      empirical evidence, scattered through the literature, has accumulated during the
      twentieth century to support this rejection. The lack of satisfactory twentieth
      century statistics and of nineteenth century details concerning hypnotic
      interventions that were used, makes it impossible to satisfactorily account for
      the discrepancy in experiences of the nineteenth and twentieth centuries.
      Although therapists did not altogether abandon working directly with symptoms,
      many opted instead for modifying and manipulating them by suggestion instead of
      completely removing them, usually allowing the patient to retain a
      psychodynamically suitable substitute. Here again a lack of adequate statistics
      prevents one from being able to properly appraise the effectiveness of this
      approach which has remained the preferred one for a number of therapists.

PMID- 15190727
TI  - Gene expression and brain plasticity in stroke rehabilitation: a personal memoir
      of mind-body healing dreams.
AB  - In this personal memoir the author describes the progress of his rehabilitation
      from a stroke and the dream manifestations of his mind-body healing. He also
      shares his reminiscences about Erickson's physical difficulties as well as
      Erickson's naturalistic or activity-dependent approach to therapeutic hypnosis
      and rehabilitation and emphasizes what he considers the least understood and most
      under appreciated aspect of Erickson's hypnotherapy--the fact that his patients
      frequently experienced intense emotional experiences as they accessed and
      replayed their traumas in a therapeutic manner. He also speculates about the
      neural mechanisms of his healing from the standpoint of his new neuroscience
      theory which includes the novelty-numinosum-neurogenesis effect.

PMID- 15190729
TI  - Using hypnosis to facilitate resolution of psychogenic excoriations in acne
      excoriee.
AB  - Hypnotic suggestion successfully alleviated the behavioral picking aspect of acne
      excoriee des juenes filles in a pregnant woman who had been picking at the acne
      lesions on her face for 15 years. Acne excoriee is a subset of psychogenic or
      neurotic excoriation. Conventional topical antibiotic treatment was used to treat
      the acne. Compared with other treatments for uncomplicated acne excoriee,
      hypnosis is relatively brief and cost-effective and is non-toxic in pregnancy.

PMID- 15190730
TI  - Self-hypnosis relapse prevention training with chronic drug/alcohol users:
      effects on self-esteem, affect, and relapse.
AB  - This study evaluated the effectiveness of a self-hypnosis protocol with chronic
      drug and alcohol patients in increasing self-esteem, improving affect, and
      preventing relapse against a control, a transtheoretical cognitive-behavioral
      (TCB), and a stress management (attention-placebo) group. Participants were 261
      veterans admitted to Substance Abuse Residential Rehabilitation Treatment
      Programs (SARRTPs). Participants were assessed pre- and postintervention, and at
      7-week follow-up. Relapse rates did not significantly differ across the 4 groups
      at follow-up; 87% of those contacted reported abstinence. At follow-up, the
      participants in the 3 treatment conditions were asked how often they practiced
      the intervention materials provided them. Practicing and minimal-practicing
      participants were compared against the control group for each of the 3
      interventions via MANOVAs/ANOVAs. Results revealed a significant Time by Groups
      interaction for the hypnosis intervention, with individuals who played the self
      hypnosis audiotapes "at least 3 to 5 times a week" at 7-week follow-up reporting
      the highest levels of self-esteem and serenity, and the least anger/impulsivity,
      in comparison to the minimal-practice and control groups. No significant effects
      were found for the transtheoretical or stress management interventions.
      Regression analyses predicted almost two-thirds of the variance of who relapsed
      and who did not in the hypnosis intervention group. Hypnotic susceptibility
      predicted who practiced the self-hypnosis audiotapes. The results suggest that
      hypnosis can be a useful adjunct in helping chronic substance abuse individuals
      with their reported self-esteem, serenity, and anger/impulsivity.

PMID- 15190731
TI  - Hypnosis to facilitate uncomplicated birth.
AB  - Prior research by the author showed that psychosocial factors distinguished
      complicated from uncomplicated birth outcome. The purpose of this study was to
      determine if prenatal hypnosis could facilitate uncomplicated birth. Following a
      psychosocial assessment, 520 pregnant women in their first or second trimester of
      pregnancy were randomized to receiving prenatal hypnosis or attention-only
      groups. The author provided all of the hypnosis in a manner similar to that
      taught by David Cheek. The goal was to reduce fear of birth and parenthood; to
      reduce anxiety; to reduce stress; to identify specific fears that might
      complicate the labor process (addressing them whenever possible); and to prepare
      women for the experience of labor. The attention-only group was matched to a no
      contact comparison group. Women receiving prenatal hypnosis had significantly
      better outcomes than women who did not. Further assessment suggested that
      hypnosis worked by preventing negative emotional factors from leading to an
      complicated birth outcome. Attention only was associated with minimal differences
      in outcome over the no-contact group. The routine prenatal use of hypnosis could
      improve obstetric outcome.

PMID- 15190732
TI  - Reflections on hypnotizability and its impact on successful surgical hypnosis: a
      sole anesthetic for septoplasty.
AB  - While hypnosis has been a significant medical tool through the ages, its use has
      been, at best, capricious. After the development and widespread use of ether,
      hypnosis has been mostly relegated to the role of an adjunct to chemical
      anesthesia. The present paper describes a case where hypnosis was used as the
      sole anesthetic for a septoplasty. The chronology of the surgery, hypnotic
      suggestion and strategies used as well as the clinician's responses are
      described. The paper highlights relevant clinical issues such as the hypnotic
      capacity of the patient, associated hypnotic phenomena, enhancing trance, and
      maximizing the hypnotic capacity by "meeting them where they are."

PMID- 15190733
TI  - Electrophysiological alterations during hypnosis for ego-enhancement: a
      preliminary investigation.
AB  - EEG activity at the midfrontal (Fz) region was recorded during pre- and
      postbaselines, live hypnotic induction, arm levitation and progressive relaxation
      (PNR) deepening, and therapeutic ego-enhancing suggestions among 60 college
      student volunteers, previously screened with the Stanford Hypnotic Susceptibility
      Scale, Form C. Comparisons across conditions for delta, theta, alpha, and beta
      activity were made between low, moderate, high, and very high hypnotizable
      groups. Results indicated (a) significant increases in theta EEGs across the
      hypnosis process with a peak at PNR and a drop in theta thereafter to
      termination, with highs showing significantly more dramatic effects than
      moderates; (b) a similar inverted U-shaped pattern for beta EEGs across hypnosis
      conditions, with very highs significantly higher in beta power than moderates and
      lows, and with highs significantly higher than moderates; (c) general profile
      differences between the highs for theta and the highs and very highs for beta in
      comparison to the moderates and lows, with peak theta and beta power occurring
      during ego-enhancing suggestions for more highly hypnotizable participants; (d) a
      drop in alpha EEGs across the trance process with a return to baseline after
      hypnosis, with moderates showing significantly lower alpha power; and (e) an
      increase in delta power across conditions to PNR and then a decrease to post
      hypnosis baseline, with moderates significantly lower than highs.

PMID- 15190734
TI  - [Pain and the sense of life].

PMID- 15190735
TI  - [Analgesia. "My son cries and screams from pain"].

PMID- 15190736
TI  - [Pain management.A specialty not to be overlooked].

PMID- 15190737
TI  - [Living Group for quality of living of the aged. Living conditions as the
      environment].

PMID- 15190739
TI  - [Nursing matters. Expedition in six areas].

PMID- 15190738
TI  - [The night watch. When night becomes day].

PMID- 15190740
TI  - [Outline of nursing economics. Nurses should all be entirely accessible].

PMID- 15190741
TI  - [The way back].

PMID- 15190742
TI  - [Palliative care. Findings in terminal care].

PMID- 15190743
TI  - [What useless tears].

PMID- 15190744
TI  - [In support of natural nursing. A step essential to maintain one's home].

PMID- 15190746
TI  - [Protocols of the Swiss Nursing Society. Restraint? Excuse us!].

PMID- 15190745
TI  - ["Measures of psychological support are cruel and wrong"].

PMID- 15190747
TI  - [Wounds and scars. Toward harmony in Switzerland].

PMID- 15190748
TI  - [Finding one's own challenge].

PMID- 15190749
TI  - [Was man born to suffer?].

PMID- 15190750
TI  - [Cure for traumatic injury thanks to a new analgesic technique].

PMID- 15190751
TI  - [Gastric pacing in obesity--still not in clinical use].

PMID- 15190752
TI  - [Sugar in food--nutrition or politics? The American sugar industry is offensive,
      children are the target].

PMID- 15190753
TI  - ["Division and disruption of the psychological functions". Schizophrenia in the
      Lakartidningen during 100 years].

PMID- 15190754
TI  - [Regular exercise reduces the climacteric problems].

PMID- 15190755
TI  - [Adverse effects of lithium treatment and safety routines].
AB  - Successful lithium treatment of manic disorders was reported in 1949 by John
      Cade. This marked the beginning of the pharmacological era in psychiatry. In
      spite of the emergence of alternative drugs with antimanic and moodstabilising
      properties, lithium remains the primary long-term treatment for preventing
      relapse of bipolar disorders. Among the adverse effects of lithium treatment are
      unintentional lithium intoxication, nephropathy, hypothyroidism, hypercalcemia,
      hyperparathyroidism, diarrhoea, tremor, weight gain, and effects on the fetus and
      the newborn child. Early detection or prevention of adverse effects, particularly
      lithium intoxication, is vital for safety. Therefore, P-lithium and P-creatinine
      are assessed every 4 months (and pre-lithium) while thyroid and parathyroid
      function, weight, 24 h consumption of liquids (or 24 h urinary output), B
      glucose, and blood pressure are assessed annually (and pre-lithium). Urinary
      concentrating capacity and glomerular filtration rate are always measured after 5
      years of lithium treatment, and always when clinically indicated. Patient
      education and annual reinforcement of his/her knowledge of pertinent aspects of
      the treatment and of risk factors for lithium intoxication are important aspects
      for ensuring safety.

PMID- 15190756
TI  - [Seal finger--a problem among hunters once again].
AB  - Seal finger is an infectious disease unknown to most physicians. It occurs after
      contact with seals, and the symptoms include acute pain, swelling, and, in some
      cases, there is joint involvement. The etiologic agent of Seal finger is now
      believed to be Mycoplasma, and treatment with high dose tetracycline has been
      successful for over 50 years. Seals are after years of protection once again
      hunted in Sweden, and the first case of Seal finger has already occurred.

PMID- 15190757
TI  - [Indwelling catheters in the bladder are often associated with problems.
      Complications are difficult to prevent and alleviate].
AB  - Long-term indwelling catheters are often associated with complications in the
      form of pain, concrement formation, outflow obstruction and symptomatic
      infections. The methods used to alleviate the situation are often ineffective and
      as for chlorhexidine bladder washouts without any effect documented by scientific
      studies. The best way to avoid catheter-associated complications is to, as far as
      possible, avoid long-time use of them.

PMID- 15190758
TI  - [Discussed connection between early exposure to fur animals and risk of allergy].

PMID- 15190759
TI  - [Preoperative cessation of smoking seems to reduce the frequency of
      complications].
AB  - Tobacco smokers suffer from postoperative complications after surgery more often
      than non-smokers. This has been proven in both general, orthopaedic and plastic
      surgery. In recent years, preoperative smoking cessation has been evaluated in
      several studies. It has been shown that smoking cessation four to eight weeks
      prior to surgery significantly reduces wound healing complications. There are
      still some unanswered questions concerning the necessary length of preoperative
      smoking cessation to affect the complication rate. There is also lacking evidence
      on smoking cessation in emergency surgery, and the cost-effectiveness of a
      smoking cessation intervention programme. Therefore, further studies on
      preoperative smoking cessation are needed. Three randomised multi-center trials
      in greater Stockholm are planned to further elucidate these questions.

PMID- 15190760
TI  - [Refractive surgery--evidence-based methods are now available for the correction
      of vision].

PMID- 15190761
TI  - [Poetry breaks the walls. Health care centers and pharmacies should have an
      assortment of poetry books].

PMID- 15190762
TI  - [Can the HSAN live upp to its goals?].

PMID- 15190763
TI  - [The disciplinary board should comment its decisions].

PMID- 15190764
TI  - [What role does the HSAN have in cost development?].

PMID- 15190765
TI  - [A new European concept for prevention of cardiovascular diseases].

PMID- 15190766
TI  - [Human beings are made for physical activity! Physical activity as a cure against
      life style-diseases--a new series in LT].

PMID- 15190767
TI  - [The history of a detail--a study of ST-elevation in ECG].
AB  - ST-elevation in EKG is an important diagnostic sign of acute myocardial
      infarction since more than 80 years. Important clinical decisions such as
      hospitalisation for intensive coronary care and reperfusion of the occluded
      coronary artery by means of thrombolytic drugs or catheter intervention depend on
      this sign. A rapid resolution of a ST-elevation during these therapeutic
      procedures reflects successful reperfusion of the infarct-related coronary
      artery. The definition of ST-elevation is sometimes problematic. Availability of
      the patient's previous EKG from a database facilitates evaluation of ST
      elevations.

PMID- 15190768
TI  - [Different opinions when it comes to research ethics issues concerning patients
      with dementia. A questionnaire study among members of research ethics
      committees].

PMID- 15190771
TI  - [The Lakartidningen 70 years ago: physicians' handwriting a popular subject
      discussed during the years].

PMID- 15190769
TI  - [Only 1 out of 1 000 patients with alcohol dependence problems are reported
      according to the Driver's Licence Act. Physicians estimate to increase the number
      of reports some 70 times with a two-year ignition interlock program].
AB  - This poll, aimed at general practitioners and dependence specialists, shows that
      only one out of 1,000 patients diagnosed alcohol-dependent are reported to the
      county administrative board in accordance with the Swedish Driver's Licence Act.
      The anticipated negative effect on continued doctor-patient contact stands out as
      the predominant obstacle to filing a report. Among general practitioners an
      uncertainty about diagnosing alcohol dependence and alcohol abuse also was an
      important obstacle. Given the opportunity to participate in a two-year alcolock
      programme as an alternative to driver's licence revocation, doctors estimate that
      they would report some 70 times the number of patients. This estimation is
      obviously subject to considerable uncertainty, but does reflect an important
      attitude and an expectation that such a report constitutes a positive move from
      both an individual and a social perspective.

PMID- 15190770
TI  - [Surgical interventions also in primary prevention of stroke caused by
      significant carotid artery stenosis].
AB  - Indications for and the results of carotid endarterectomy in symptomatic and
      asymptomatic carotid artery stenosis are reviewed. The main indication for
      carotid endarterectomy is symptomatic stenosis of a carotid artery with > 70
      percent lumen reduction according to the NASCET method, or > 85 percent lumen
      reduction according to the ECST method. The operation should ideally be performed
      within two weeks after the onset of symptoms. Preliminary results from the ACST
      study, indicating significant beneficial effects of carotid endarterectomy also
      in asymptomatic carotid artery stenosis have been orally presented. Assessment of
      and surgery upon Swedish patients with significant carotid artery stenosis should
      be performed in specialised multidisciplinary "carotid artery centers".
      Endovascular treatment of carotid artery stenosis should at the present stage
      only be performed within clinical trials.

PMID- 15190772
TI  - [Cut one's coat according to one's cloth is physicians' responsibility!].

PMID- 15190773
TI  - [Sick listings should result in demanding resource allocation to specialists].

PMID- 15190774
TI  - [Sick leave certificates--a threat against physicians' ethics and
      responsibility].

PMID- 15190775
TI  - [Stigmatization of persons with mental diseases is a neglected problem].

PMID- 15190777
TI  - [Different brain from the start! Ugh!].

PMID- 15190776
TI  - [A Swedish paradox explained].

PMID- 15190778
TI  - [Nicotine users are included in many trials].

PMID- 15190779
TI  - [Cancer researchers need statistical uncertainty!].

PMID- 15190780
TI  - [Defending confidence intervals].

PMID- 15190781
TI  - [Concerning the classification of Ellen].

PMID- 15190782
TI  - [A neuropsychological perspective to the "sick" Sweden is necessary].

PMID- 15190783
TI  - [The study on the regeneration of skeletal muscles after denervation].
AB  - OBJECTIVE: To study the degeneration and regeneration of skeletal muscle after
      denervation. METHODS: Denervation was carried out in gastrocnemius muscles in 30
      adult BALB/C mice by cutting the sciatic nerve. The gastrocnemius muscles were
      removed at 1, 2, 4, 8, 12, 16 weeks after denervation, respectively. Specimens
      were processed for histological study and immunohistochemical technique. RESULTS:
      Muscle fiber atrophy followed by degerneration and regeneration was observed in
      the early period of denervation. Fusion of the regenerated muscle cells with each
      other followed by degeneration of the cells and growth of fibro-connective tissue
      were observed in the later stage. The expression of myoglobin and actin decreased
      in 1-4 weeks after denervation. The postive expression of the proteins was
      observed in some 8 weeks' cells and in many degenerated 12-14 weeks' muscle
      cells. CONCLUSION: Degeneration and regeneration may coexisted in the denervated
      muscles. The regenerated muscle cells can't fully develop due to the deficit of
      nerve regulation and degenerate again. The regenerated muscle cells will melt
      each other and can't develop to mature muscle fiber in the later stage.

PMID- 15190784
TI  - [Genotoxicity of a new NanoHA-PA66 root filling material in vitro].
AB  - OBJECTIVE: The micronucleus test was applied to evaluate the genotoxicity of a
      new nanocomplex HA-PA66 root filling material in vitro. METHODS: The dulbecco's
      modified eagle media(DMEM) extracts of the powder part and the mixture of the new
      nanomaterial were prepared separately. The V79 cell was used as the test cell and
      the mitomycin C(MMC) as the positive control. The MTT assay was employed in our
      study to evaluate the cytotoxic effect while the number of micronucleus was used
      as the criteria for the detection of genotoxocity. RESULTS: The MTT values in
      test groups and negative group were not significantly different at different
      times (P > 0.05). The number of micronucleus in test groups (powder group: 6.1 +/
      1.1/1,000; complex group: 5.7 +/- 0.6/1,000) was similar to the negative
      control(5.3 +/- 0.8/1,000, P > 0.05), while they were significantly different to
      the positive control(123.9 +/- 8/1,000, P < 0.05). CONCLUSION: The new
      nanocomplex HA-PA66 root filling material showed no detectable cytotoxic and
      genotoxic effects in this study and was proved to be biocompatible.

PMID- 15190785
TI  - [Transfection of human endostatin gene with lipofectamin and the expression of
      hES protein in Tca8113 cell].
AB  - OBJECTIVE: The purpose of this study was to establish transfergeneic Tca8113 cell
      and evaluate the expression of human endostatin (hES) gene in the cell colone in
      vitro. METHODS: To transfect hES gene into Tca8113 cells, lipofectamin was
      complexed with plasmid encoding hES gene, and blasticidin S antibiotic was
      adopted to select Tca8113--hES cell clone. Immunohistochemistry S-P method was
      adopted to detect the expression of hES in the transfergenic Tca8113 cell in
      vitro. RESULTS: Transfected by hES, the transfergenic Tca8113 cells could grow
      and proliferate in RPMI--1640 culture medium containing blasticidin S antibiotic.
      The expression rate of hES reached 100%. CONCLUSION: hES gene can express in hES
      transfected Tca8113 cell in vitro.

PMID- 15190786
TI  - [Gene expression changes of cartilage matrix of condylar cartilage with anterior
      disc displacement].
AB  - OBJECTIVE: To study the gene expression changes in extracellular matrix of
      condylar cartilage following disc anterior displacement of rabbit TMJ. METHODS:
      The right sides of 28 joints in 40 rabbits were subjected to surgical operation
      of disc displacement. The condylar Collagen II and Aggrecan mRNA expression were
      detected by in situ hybridization. RESULTS: Collagen II and Aggrecan mRNA mainly
      expressed in the lower zone of condylar chondrocyte. Aggrecan mRNA decreased
      faster than collagen II following disc displacement, and adjusted to normal
      later. CONCLUSION: Anterior disc displacement leads to alteration of
      extracellurar matrix gene expression in the condylar chondrocyte, which means the
      start of remodeling.

PMID- 15190787
TI  - [Immunohistochemical analysis of dendritic cell in oral squamous cell carcinoma].
AB  - OBJECTIVE: To elucidate the functional status of dendritic cells (DC) in the
      tissue of oral squamous cell carcinoma by analyzing characteristic phenotype of
      them. METHODS: 34 specimens from oral squamous cell carcinoma cases primarily
      treated with surgery were selected as test group. In addition, 30 specimens of
      normal mucosa from oral mucocele cases were used as control. Distribution of DC
      expressing CD1a+, HLA-DR+ and CD83+ in tumor tissue and normal mucous membrane
      was observed by immunohistochemistry. The number of DC expressing the antigens,
      which represented the density of DC infiltrating into tissue, was counted by
      microscope. The density of DC and the rate of DC expressing HLA-DR in oral
      carcinoma group and control were statistically compared. RESULTS: There was no
      CD83+ DC in all cases, but CD1a+ DC was found in all samples. The density of
      CD1a+ DC in tumor tissue was significantly lower than that in normal mucous
      membrane (P < 0.05). HLA-DR antigen expressed on the surface of DC in tumoral
      epithelium of 27-case carcinoma specimens and in normal mucous epithelium of 23
      cases. The rate of HLA-DR positive expression of TIDC had no statistic
      significance between the two groups. CONCLUSION: The lower density of DC
      infiltrating in tumor tissue might reflect the microenviromental immunodeficiency
      of hosts with oral squamous cell carcinoma, and the functional mature of DC might
      be inhibited by the immunosuppressive action of oral squamous cell carcinoma.

PMID- 15190788
TI  - [The correlation between neck lymphy node metastasis and matrixmetalloproteinase
      2 expression at the invasive tumor front of oral squamous cell carcinomas].
AB  - OBJECTIVE: To explore the correlation between neck lymph node metastasis and
      matrix metalloproteinase-2 expression at the invasive tumor front of oral
      squamous cell carcinomas(OSCC). METHODS: Immunohistochemistry LsAB technique was
      used to observe the expression of MMP-2 at the invasive tumor front and center of
      OSCC, and the correlation between the expression of MMP-2 in OSCC and neck lymph
      node metastasis were respectively analyzed by statistics. RESULTS: The results
      demonstrated that MMP-2 existed in all 71 cases, which the expression of MMP-2 at
      the OSCC front was more significant than that of MMP-2 at the OSCC center (P <
      0.01), and related to neck lymph node metastasis (P < 0.05). CONCLUSION: The
      expression of MMP-2 at the OSCC front could be considered as an index of judging
      the present of neck lymph node metastasis of OSCC.

PMID- 15190789
TI  - [In vitro and in vivo study on proliferation of adnoid cystic carcinoma cell
      lines after nm23-h1. Introduction].
AB  - OBJECTIVE: To study the effect of nm23-h1 transfection on proliferation
      characteristics of adnoid carcinoma cell lines in vitro and in vivo. METHODS: In
      vitro ACC-M cell lines were incubated after putative anti-metastatic gene nm23-h1
      was introduced into the cells with the help of G418 selective incubation base.
      The ACC-M cells were transplanted into 10 BALB/C nude mices subcutaneously and
      non-transfected cell lines were taken as control. Immunohisto chemistry and Ki67
      antibody were employed to study the proliferation character of cell crawling
      pieces and paraffin-bedded slice, meanwhile, the solid tumor of both groups were
      prepared for flow cytometry(FCM). RESULTS: Transfected cells grew slower than non
      transfected cells and this trend became more obvious as passages passed on. In
      vitro the expression of Ki67 of transfected cells was little stronger than non
      transfected cells, while the expression of Ki67 in solid slices was almost
      negative in both groups. Transfected cells presented slower growth than non
      transfected cells in the early stage (2 weeks) and 2 weeks later there was no
      obvious difference in size(P > 0.05). FCM value accorded well with the result.
      CONCLUSION: Introduction of nm23-h1 into the ACC-M cell lines may have transient
      inhibitory effects on its proliferation.

PMID- 15190790
TI  - [Effect of phosphorothioate antisense Bcl-xL oligodeoxynucleotides on apoptosis
      and thermosensitivity of BcaCD885 cells].
AB  - OBJECTIVE: To study the effect of phosphorothioate antisense Bcl-xL
      oligodeoxynucleotides on apoptosis and thermosensitivity of BcaCD885 cells.
      METHODS: After phosphorothioate antisense Bcl-xL oligodeoxynucleotides were
      transfected into BcaCD885 cells. The characteristics of apoptotic cells were
      evaluated by morphological observation and TUNEL staining. Apoptotic rate and Bcl
      xL protein expression were analyzed with flow cytometry. The influence of
      phosphorothioate antisense Bcl-xL oligodeoxynucleotides on apoptotic rate of
      BcaCD885 cells induced by hyperthermia with 43 degrees C 40 min was also examined
      through flow cytometry. RESULTS: The BcaCD885 cells transfected with
      phosphorothioate antisense Bcl-xL oligodeoxynucleotides displayed apoptotic
      morphological features. The Bcl-xL protein expression level of these cells was
      down-regulated significantly compared with the controlled group (P < 0.05). The
      apoptotic rate of these cells induced by hyperthermia was increased significantly
      compared with the controlled group (P < 0.05). CONCLUSION: Phosphorothioate
      antisense Bcl-xL oligodeoxynucleotides can induce apoptosis and improve
      thermosensitivity of BcaCD885 cells.

PMID- 15190791
TI  - [Detection of P-glycoprotein and glutathine S-transferase in mucoepidermoid
      carcinoma of salivary gland].
AB  - OBJECTIVE: The aim of this study was to investigate the mechanism(MDR) of
      multidrug resistance(MDR) of mucoepidermoid carcinoma in salivary gland. METHODS:
      40 cases of mucoepidermoid carcinoma in salivary gland were examined the MDR gene
      product P-glycoprotein using a monoclonal antibody JSB-1. And 10 of them were
      also investigated by detecting the expression of GST-pi. All the cases had not
      been accepted any therapy before the samples were collected. RESULTS: 1. Positive
      expression of JSB-1 was observed in 27 of the 40 specimens. The positive
      expression was related not only with clinical stage, but also with
      differentiation degree. 2. The GST-pi positive expression was found in 9 of 10
      cases. There was no significant different between the positive expression of JSB
      1 and GST-pi. CONCLUSION: JSB-1 and GST-pi play an important role in MDR of
      mucoepidermoid carcinoma.

PMID- 15190792
TI  - [The utility of vascularized free peroneal flap in oral maxillofacial
      reconstruction].
AB  - OBJECTIVE: The purpose of this study was to evaluate the advantages and
      disadvantages of vascularized free peroneal flap as a new method for
      reconstruction of oral and maxillofacial defects. METHODS: Twenty-one cases
      received reconstruction of oral and maxillofacial defects with free vascularized
      peroneal flaps in our hospital were studied retrospectively. All of the relevant
      data of operation, such as the cause of the defect, design of the flaps the
      recipient vessels of the recipient and the complications were investigated.
      RESULTS: Twenty cases survived, the average size of the vascularized free
      peroneal flap was 8.5 cm x 5.25 cm. CONCLUSION: It is safe and reliable to use
      free peroneal flap to reconstruct the oral maxillofacial defects.

PMID- 15190793
TI  - [Clinical study of primary branchiogenic carcinoma].
AB  - OBJECTIVE: To analyze the clinical feature and prognosis of primary branchial
      carcinoma. METHODS: The main method of this study was reviewing the clinical
      feature, diagnosis, treatment methods and prognosis of 5 patients suffered from
      primary branchial carcinoma. RESULTS: All of the tumors were excised extensively.
      All of the patients received radical neck dissection and post-operative
      radiotherapy. 3 patients had pathologic evident of metastasis in lymph nodes of
      cervical region. 2 patients died of local recurrence of tumor and metastasis to
      lung. 1 patient died after post-operative 2 years. 2 patients were still alive
      after 5 years' follow-up. CONCLUSION: Primary branchial carcinoma has the very
      similar clinical feature with branchial cyst. The diagnosis should be considered
      if painless mass and swollen lymph nodes were found in upper neck region of
      patients. Rapid frozen pathologic section should be made regularly to make the
      diagnosis clear. The treatment should include extensive excision of tumor and
      radical neck dissection to improve the cure rate and survival rate.

PMID- 15190794
TI  - [Initial clinic research on curved canal preparation by reverse flaring
      technique].
AB  - OBJECTIVE: Curved canal preparation is much difficult in root canal therapy(RCT).
      Step back technique and routine technique are still regular methods in curved
      canal preparation. The purpose of this study was to introduce a new method
      reverse flaring technique, and to investigate its preparation efficiency in
      intermediate-curvature canals. METHODS: 48 cases of lower first molars RCT were
      collected, which were first treated because of pulpitis or apical periodontitis
      in West China College of Stomatology, Sichuan University from Nov. 2001 to Aug.
      2003, mesial canal curvature was intermediate (30 degrees-60 degrees), determined
      by Schineider method. Cases were divided into two groups, in reverse flaring
      technique group, canal preparation in 27 cases were finished by reverse flaring
      technique, 21 cases by step back technique as control. In working length
      determination and fitting master cone stages, cases in two groups which fit full
      working length were recorded, determined by radiograph, and analyzed by chi 2
      test. RESULTS: In working length determination stage, cases which fit full
      working length in reverse flaring technique group were significantly more than
      that of step back technique group (P < 0.05), in fitting master cone stage, cases
      which fit full working length in reverse flaring technique group were also
      significantly more than that of step back technique group(P < 0.05). CONCLUSION:
      In working length determination stage, cases which fit full working length in
      reverse flaring technique group were significantly more than that of step back
      technique group (P < 0.05), in fitting master cone stage, cases which fit full
      working length in reverse flaring technique group were also significantly more
      than that of step back technique group(P < 0.05).

PMID- 15190795
TI  - [Analysis of oral microflora early colonized in infants].
AB  - OBJECTIVE: To observe the dynamic changes of oral microflora early colonized in
      infants. METHODS: The oral swab samples for the study were taken in 1 day, 1, 3,
      6, 9, 12 months after birth from 12 healthy neonates. By choosing suitable
      diluted concentration, the samples were incubated aerobically, facultative
      anaerobically and anaerobically. The strains were identified by observing colony
      characteristics, Gram staining and biochemical tests. RESULTS: S. salivarius was
      the most frequent microflora, followed by S. mitis, S. sanguis, S. gordonii and
      S. mutans occurred in oral cavity after tooth eruption. Veillonella spp. can be
      detected in oral cavity of 1-month-old babies, A. odontolyticus was isolated from
      8.3% infants of more than 3 months old. L. acidophilus maintained the lower
      prevalence in oral cavity of babies. Leptotrichia buccalis and Capnocytophaga
      spp. occurred in oral cavity of some dentate infants. CONCLUSION: S. solivarius
      and S. mitis are predominant species in oral cavity of the infants, Veillonella
      spp. is the first and the most anaerobic species appeared in oral cavity of
      healthy babies. A. odontolyticus is the first actinomyces detected in oral
      cavity. With the increasing months, kind and amount of microflora increase
      dramatically.

PMID- 15190796
TI  - [Rhabdomysarcoma and combined treatment in oral and maxillofacial regions].
AB  - OBJECTIVE: To study the treatment outcome of rhabdomysarcoma(RMS). METHODS: 74
      cases of RMS with definite pathologic diagnosis treated in our department during
      the past 20 years were investigated. The relationship between the therapy and
      prognosis was analyzed. RESULTS: 52 cases among the 74 patients received
      different surgical treatment and post-operative radiotherapy. 22 cases received
      radiotherapy or chemoradiotherapy without surgical treatment. The survival rates
      demonstrated great differences depending on the different clinical stages and
      therapy. CONCLUSION: The combined therapy including radiotherapy after surgical
      treatment may increase 5-year survival rate.

PMID- 15190797
TI  - [Repair of hard cleft palate with absorbable membranes made by poly-DL-lactic
      acid: a feasibility study].
AB  - OBJECTIVE: To investigate the feasibility and clinical results of applying poly
      DL-lactic acid (PDLLA) biomembranes in cleft palate repair. METHODS: 68 cleft
      palate patients were divided into study group and control group. The traditional
      surgical method was used to control group to close the soft cleft palate, and the
      PDLLA biomembrane was used to study group and implanted into the surgical gap
      between the periosteum and bone at the hard palate, and fixed with suture. The
      duration, blood loss at operation, post-operative complication, wound healing and
      recovery were recorded and compared to conventional cleft palate repair. RESULTS:
      Operations were successfully completed on all 34 patients. Wound healing of soft
      palate and uvula was uneventful with no incidence of fistula or dehiscence. The
      primary healing on tissue defect of hard palate occurred in 29 patients,
      secondary healing occurred in 3 patients, permanent fistula between the oral
      cavity and the nasal cavity occurred in only one patients, and 3 patients left
      over fistula on alveolar process. Compared to traditional cleft palate repair,
      blood loss and incidence of fistula on alveolar process were decreased; the
      average surgical time was 89.25 minutes and was not prolonged; and there was no
      significant increase in post-operative complication. CONCLUSION: Hard cleft
      palate repair with PDLLA biomembranes is safe, simple and practical with good
      clinical results and is beneficial to minimize the bad influences towards the
      development and growth for maxilla of cleft palate patients.

PMID- 15190798
TI  - [An outcome analysis of two methods of intra-capsular injection of sodium
      hyaluronate for temporomandibular disorders].
AB  - OBJECTIVE: To analyze the treatment outcome of the two methods of intra-capsular
      injection of temporomandibular joints, the upper capsule alone and both the upper
      and lower capsules, for different subtypes of temporomandibular disorders.
      METHODS: A retrospective cohort study was designed, based on the outpatients and
      the data which were obtained from West China Stomatological Hospital, Sichuan
      University. SPSS10.0 software was used to analyze the data, which were collected
      before the operation and one week after the operation. RESULTS: 294 patients were
      followed up. The group of double capsules injection gained better prospect, not
      only on the mouth-opening but also the pain-cured, especially in two subgroups
      such as the anterior dislocation of disc without reduction and the osteoarthritis
      of TMJ. CONCLUSION: It seems that the double capsules injection of sodium
      hyaluronate for TMD can gain better outcome than the upper capsule injection, but
      a clinical randomized controlled test and a long-term follow-up study of the two
      methods are needed to verify this finding.

PMID- 15190799
TI  - [A study on the center height of clinical crowns for the people with normal
      occlusion in Chengdu area].
AB  - OBJECTIVE: The purpose of this study was to investigate the center height of
      clinical crowns and the difference among individuals, together with the
      regularity of the Spee curve in mandible and compensating curve in maxilla for
      the people with normal occlusion in Chengdu area. METHODS: The data were derived
      from systematically collected people with normal occlusion in Chengdu area,
      including 36 males and 39 females (ranged from 18 to 35 years). The values of
      center height of clinical crowns, the depths of Spee curve and curve formed by
      the center of clinical crowns in mandible were obtained by measurement.
      Afterwards, the distribution of the center height of clinical crowns was
      analyzed, as well as the depth of curve formed by the center of clinical crowns
      in mandible and its correlation with depth of Spee. RESULTS: (1) The distribution
      of the center height of clinical crowns accord with normal distribution and the
      standard deviation was minor(< 0.5 mm); (2) There was no statistical difference
      between male and female for the center height of clinical crowns; (3) The depth
      of curve formed by the center of clinical crowns in mandible and the depths of
      Spee curve showed highly correlation (gamma = 0.986, P < 0.0001). CONCLUSION: (1)
      The difference of the center height in clinical crowns among individuals with
      normal occlusion in Chengdu area was minor; (2) There was no significant
      difference on the center height in clinical crowns between male and female; (3)
      Provide a recommended bracket placement chart suitable for people of Chengdu area
      in clinical practice; (4) The brackets of the pre-adjusted appliance should be
      placed in the center of clinical crowns, despite some adjustment are needed in
      some special circumstances.

PMID- 15190800
TI  - [Construction of eukaryotic expression plasmid pSecTag2B-msBlyS expressing mouse
      soluble B lymphocyte stimulator].
AB  - OBJECTIVE: The purpose of this study was to clone the soluble form of the mouse
      BlyS (msBlyS) and insert it into a eukaryotic expression vector pSecTag2B in
      order to further elucidat the antitumor activity induced by msBlyS expressed by
      the recombined plasmid pSecTag2B-msBlyS. METHODS: Full length cDNA of mouse
      soluble BlyS (msBlyS) was amplified by reverse transcription-PCR from total RNA
      of mouse spleen. The PCR product was ligated directly with linearized vector
      pCR2.1 supplied in the TA cloning kit. The recombined plasmid pCR2.1-msBlyS which
      was selected and identified using blue-white screening method and restriction map
      analysis and the purified original plasmid pSecTag2B were both cut by HindIII and
      EcoR I. The digested fragments were extracted and purified from low-melting
      temperature agarose and ligated by T4DNA ligase. The recombined plasmid pSecTag2B
      msBlyS were isolated and identified by restricted endonuclease cutting and Sanger
      dideoxy DNA sequencing. RESULTS: The sequencing data indicated that inserted
      msBlyS gene had correct DNA sequence and orientation. CONCLUSION: Eukaryotic
      expression vector pSecTag2B. Expressing mouse BlyS have successfully been cloned.
      This will provide us an opportunity to do further research work on BlyS.

PMID- 15190801
TI  - [Effect of para-aminobenzonic acid (PABA) on cell-surface hydrophobicity of
      Streptococcus mutans].
AB  - OBJECTIVE: To study the effect of Para-aminobenzonic acid on cell-surface
      hydrophobicity of Streptococcus mutans. METHODS: Microbial adhesion to
      hydrocarbons (MATH) was used to measure the cell-surface hydrophobicity of
      Streptococcus mutans which grew in modified Carlsson medium with different
      dilutions of PABA. RESULTS: The cell-surface hydrophobicity of Streptococcus
      mutans increased when Carlsson medium contained low dilution of PABA. But
      following the increase of PABA, the cell-surface hydrophobicity decreased.
      CONCLUSION: Para-aminobenzonic acid could inhibit the adherence of Streptococcus
      mutans through changing its cell-surface hydrophobicity.

PMID- 15190802
TI  - [The effect of different fabrication methods and luting cements on post
      retention].
AB  - OBJECTIVE: This study was to compare the retention of posts fabricated by
      different methods and cemented with various cements in order to provide a
      guidance for clinical choice of post fabrication methods and luting cements.
      METHODS: Ninety human maxillary anterior teeth were sectioned by the
      cementoenamel junction and post-holes were prepared. All roots were embedded in
      the center of plastic cylinders and paralleled with the cylinder. All samples
      were divided into 9 groups randomly and equally. Posts fabricated with different
      methods were then cemented with different luting cements. Each sample was placed
      into a specialized jig and mounted on a tensile testing machine with crosshead
      speed of 5 mm/min. Constant tensile force was applied until the post was
      dislodged, and the tensile force required to dislodge the cemented post was
      recorded. RESULTS: The mean retention force of parapost and direct post
      demonstrated significantly higher than that of indirect post did (P < 0.05), but
      there was no significant difference between parapost and direct post(P > 0.05).
      The mean retention of parapost cement demonstrated significantly higher than that
      of ZPC and HY-Bond cement did (P < 0.05), but there was no significant difference
      between ZPC and HY-Bond cement (P > 0.05). CONCLUSION: Different fabrication
      methods and luting cements significantly affect the retention of posts; and there
      exists an interaction between different fabricating methods and luting cements.

PMID- 15190803
TI  - [Expression of p16 and nm23 genes in salivary gland tumors].
AB  - OBJECTIVE: To study the expression of p16 and nm23 genes in salivary gland tumors
      and the relation of P16 and nm23 proteins with fumorigenesis of salivary gland
      tumors. METHODS: Expression of P16 and nm23 proteins was examined by SABC
      immunohistochemical method in 39 cases of paraffin blocks of normal salivary
      gland tissues and salivary gland tumors. RESULTS: P16 and nm23 protein positive
      staining were mainly found in the cytoplasm and cytoblast of all salivary gland
      tissues. Positive rate of P16 protein expression was 76.9% (10/13) and 40.9%
      (9/22) in benign and malignant salivary gland tumors, respectively. There was
      significant difference between P16 protein expression of benign and malignant
      tumors by chi 2 test (P < 0.05). mm23 protein positive staining was found in
      84.6% (11/13) and 45.5% (10/22) of benign and malignant tumors respectively. The
      expression of nm23 protein in benign and malignant tumors was significantly
      different (P < 0.05). There was no correlation of the expression of P16 and nm23
      in salivary gland tumors was found (P > 0.05). CONCLUSION: p16 and nm23 genes may
      play an important role in different sides in salivary gland tumorigenesis and the
      reduce of the expression of p16 and nm23 genes may contribute to the generation
      of malignant salivary gland tumors.

PMID- 15190804
TI  - [The association between Fc gamma receptor IIA gene polymorphism and
      susceptibility to chronic periodontitis in Chinese Han nationality].
AB  - OBJECTIVE: To investigate the association between Fc gamma receptor IIA gene
      polymorphism and susceptibility to chronic periodontitis in Chinese Han
      nationality. METHODS: DNA samples were collected with buccal swabs from 63
      patients with severe chronic periodontitis(CP), 103 patients with mild to
      moderate CP and 80 healthy individuals as control. Polymorphism in Fc gamma
      receptor IIA gene cluster was analyzed with PCR-SSP. The genotype distribution
      and allele frequency among different groups were compared. RESULTS: It was found
      that the frequency of Fc gamma RIIA-R/R131 genotype was significantly higher in
      patients with severe CP (19.05%) compared to that of the healthy controls (P <
      0.0125). CONCLUSION: The Fc gamma RIIA-R/R131 genotype may be one of the
      contributors for the increased susceptibility to severe CP in Chinese Han
      nationality.

PMID- 15190805
TI  - [In vitro cytotoxicity evaluation of comfort denture adhesive].
AB  - OBJECTIVE: The purpose of this study was to evaluate the in vitro cytotoxicity of
      novel Comfort denture adhesive (Comfort-DA), which was developed by the authors,
      to human oral fibroblasts (HOFs). METHODS: A sample of Comfort-DA was prepared
      and extracted in culturing medium to prepare the eluate. Then the eluate was
      diluted by culturing medium to 50% and 75% concentration for the assessment of
      cytotoxicity by tetrazolium bromide (MTT) colorimetric assay. Wells containing
      fresh medium alone were served as control. Cell viability was recorded by optical
      density after culturing in an atmosphere of 5% CO2 and 95% air at 37 degrees C
      for 2, 3 and 4 days, respectively. The viability of HOF cells was evaluated by
      MTT assay to investigate cell proliferation. Optical density (OD) was measured by
      a spectrophotometer at 490 nm. Then evaluating the cytotoxicity grade in test
      groups according to the means of cell proliferation. ANOVA was used to test the
      statistical significance. RESULTS: The statistical analysis of the results of MTT
      cytological assay indicated significant difference (P < 0.05) in OD (indicate
      cell viability) between all concentrations of Comfort-DA and the control at all
      incubation times. The results of cell proliferation percentage also showed that
      the cytotoxicity grade of tested material only displayed "0-2". CONCLUSION: The
      generally favorable in vitro cytotoxicity of the Comfort-DA formulations
      indicates that this product may be an efficacious denture adhesive.

PMID- 15190806
TI  - Assessment of association between consanguinity and fertility in Asian
      populations.
AB  - Although a high proportion of marriages in Asia are consanguineous (i.e.
      contracted between close biological relatives), with some notable exceptions,
      there is a death of demographic and anthropological literature on the association
      between consanguinity and fertility. This paper presents an overview of the
      prevalence of consanguineous marriages in selected South and Southeast Asian
      countries, followed by an assessment of the association between consanguinity and
      fertility. The association between consanguinity and fertility was assessed
      reviewing published literature and analyzing demographic and health survey (DHS)
      data from Pakistan and India. Results of the review of published literature
      showed higher fertility among women in the first-cousin unions compared to those
      married to non-relatives. In the DHS analyses, consanguinity was found to be
      associated with a number of direct and indirect determinants of fertility,
      including lower maternal education, lower maternal age at marriage, lower
      contraceptive use, and rural residence. At the multivariate level, adjusted mean
      fertility was found to be lower among women in the first-cousin unions in the
      Pakistani DHS data, while for the Indian DHS, adjusted mean fertility levels were
      similar in the first-cousin and non-consanguineous marriages. The pathways
      through which consanguinity affects fertility in Asian populations are evaluated
      and discussed.

PMID- 15190807
TI  - Assessment of vaccine wastage during a pulse polio immunization programme in
      India.
AB  - A study to assess the wastage factor of oral polio vaccine (OPV) in the Pulse
      Polio Immunization (PPI) programme of the Government of India was undertaken by
      the Indian Council of Medical Research (ICMR) at approximately 31,000
      immunization booths all over the country. The study was conducted through the
      network of 31 Human Reproduction Research Centres (HRRCs) and other ICMR
      institutes. Wastage at the point of administration of OPV was estimated to be
      14.5% with a wastage factor of 1.17 which is well below the assumed wastage of
      33% and the corresponding wastage factor of 1.5 in the PPI programme. The wastage
      and wastage factor as estimated in the present study were also less than the
      wastage of 25% and the wastage factor of 1.33 recommended by the World Health
      Organization. Minimum wastage (6.3%) at Kanchipuram and maximum wastage (22.1%)
      at Kanpur were observed. Further, the wastage of unopened vials and vials during
      use was also observed following colour changes on the vaccine vial monitor (VVM),
      indicating poor cold-chain maintenance at the immunization site. In total, 13
      booths reported wastage of nine or more unopened vials, whereas 19 booths
      reported wastage of nine or more vials during use because of colour changes on
      VVM. Other reasons for wastage of vaccine were also observed from a sample of
      booths. The technology of introducing VVM on OPV vials for monitoring the cold
      chain proved useful in situations in which mass vaccination programmes such as
      PPI are carried out.

PMID- 15190808
TI  - Application of the capture-recapture method for estimating number of mobile male
      sex workers in a port city of Bangladesh.
AB  - Male sex workers (MSWs) and sex trades are not new in Bangladesh. Current HIV
      interventions for MSWs need to be expanded in the major cities, but the number of
      MSWs needs to be scientifically estimated. Although two-sample capture-recapture
      surveys are suitable for closed populations, this method was here applied to
      indirectly estimate the number of mobile MSWs in a conservative social setting, a
      port city of Bangladesh. Use of the method resulted in an estimation of 248 MSWs
      (95% confidence interval, 246-250) who picked up clients only at open and known
      contact venues. This estimate does not, however, reflect the total number as MSWs
      who worked in unknown hidden venues and could not be reached. Experience suggests
      that the two-sample capture-recapture method is a simple technique for reliably
      estimating an unrecognized population. The limitation of this method can be
      minimized by shortening the time gap between surveys, creating an enabling
      environment to encounter harassment of MSWs, and offering safety to peer-staff.

PMID- 15190809
TI  - Time series analysis of deaths due to diarrhoea in children in Rio de Janeiro,
      Brazil, 1980-1998.
AB  - Diarrhoea is still a considerable public-health problem in developing countries,
      especially among children aged less than five years. The well-known relationship
      between seasonal variation and aetiological agents of diarrhoeal diseases helps
      inform the decisions about the prevention and control measures. The aim of this
      study was to identify the temporal patterns of deaths due to diarrhoea in
      children, aged less than five years, in Rio de Janeiro State from 1980 to 1998.
      The study analyzed data on monthly deaths due to diarrhoea; the data were
      supplied by the Natural Mortality Information System (NMIS, Ministry of Health of
      Brazil). Auto Regressive Integrated Moving Average modelling was applied to the
      data. Using this model, the huge decline and the winter peaks could be
      highlighted, and they may express the predominance of rotavirus as the aetiology
      of diarrhoeal deaths, suggesting that an effective vaccine is the main measure
      for the prevention and control of severe diarrhoea.

PMID- 15190811
TI  - Management of childhood febrile illness prior to clinic attendance in urban
      Nigeria.
AB  - Parents and caregivers often try various treatment modalities for their sick
      children before bringing them to clinic. Many community-based studies have
      documented home and self-treatment practices, often with the aid of patent
      medicine vendors, but less is known about prior treatment behaviour of caregivers
      who actually reach a government clinic. This study, therefore, aimed at
      documenting the treatment provided by caregivers prior to their attendance at a
      public hospital. Beginning in April 1996, a year-long study was conducted among
      1,943 sick children and their caregivers who attended the largest government
      owned paediatric hospital in Lagos, Nigeria. The major complaints mentioned by
      the caregivers included fever, cough, and diarrhoea. Most (89%) caregivers had
      administered some form of medicine to the child prior to the clinic visit, and on
      average, 2.5 medications had been given. Associations were found between major
      complaint and type of medicine given: fevers were associated with antimalarial
      drugs and analgesics (antipyretics), cough was associated with cough syrup and
      analgesics, while diarrhoea was associated with antidiarrhoeal drugs. Although
      one-fifth of the children had received an antibiotic, provision of antibiotics
      was not associated with a particular complaint/illness. Since caregivers appeared
      to use perceived complaints/illnesses as a treatment guide, this can form the
      basis of safer and more appropriate recognition of illness and home management.
      In addition, the information obtained in this study can be used for training
      clinicians to inquire about home management and, thus, for making more informed
      decisions about their own treatment and prescribing practices.

PMID- 15190810
TI  - Relationship between nutritional and psychological status of pregnant adolescents
      and non-adolescents in Brazil.
AB  - This study compared the nutritional and psychological status of 855 pregnant
      adolescents and non-adolescents and assessed their relationships at three
      interviews (gestational age < or = 16 weeks, 20-26 weeks, and 30-36 weeks). The
      instruments used were: anthropometry, state-trait anxiety inventories (STAI),
      general health questionnaire (GHQ), and perceived stress scale (PSS). More
      adolescents were thinner, had higher scores of the trait anxiety inventory (TAI),
      wished to abort their children, and were worried about changes in their bodies
      than non-adolescents. Multiple linear regression analyses (controlling for toxic
      exposure, socioeconomic, demographic and obstetric factors) detected negative
      associations between weight gain in the first interview and distress (GHQ) for
      both the groups of women and weight gain in the second interview and the variable
      "worry about body's change" for the non-adolescent group. The negative
      associations between body mass index and chronic anxiety (TAI) were present in
      the three interviews for non-adolescents. This study detected a relationship
      between the nutritional and the psychological status of pregnant women, although
      there were more associations for non-adolescents.

PMID- 15190812
TI  - Risk factors for diarrhoea and upper respiratory tract infections among children
      in a rural area of Uganda.
AB  - This study explored risk factors associated with diarrhoea and upper respiratory
      tract infections (URTIs) among children in Sembabule district, Uganda. Data were
      collected from 300 women with children aged less than two years using the WHO 30
      cluster sampling technique. The prevalence of diarrhoea among children was 40.3%.
      A child not immunized (odds ratio [OR] 2.8, p < 0.001), absence of latrine in a
      house (OR 1.4, p < 0.03), low knowledge of mixing oral rehydration salts (OR 1.7,
      p < 0.01), garbage thrown anywhere around the house (OR 2.6, p < 0.001), not
      washing hands after using latrine (OR 1.8, p < 0.03), and not washing hands
      before preparing food (OR 1.4, p < 0.04) were risk factors for diarrhoea. The
      prevalence of URTIs among children was 37.4%. A child not immunized (OR 2.4, p <
      0.001), children aged 6-11 months (OR 2.1, p < 0.03), and previous episode of
      diarrhoea (OR 2.5, p < 0.001) were risk factors for URTIs. The results showed
      that low immunization status was an important risk factor for diarrhoea and URTIs
      among children in the study district of Uganda. For 75% of the children, care for
      fever was obtained from drug shops, while 9.2% were taken to health units. This
      is in contrast to diarrhoea cases where 49.5% of children were taken to health
      units for care. To reduce the burden of disease among children in this district,
      an integrated package of immunization services and other childcare programmes
      need to be implemented in addition to improved personal and environmental
      hygiene. There is also a need to design well-focused health-education messages to
      improve treatment-seeking behaviour for childhood diseases.

PMID- 15190813
TI  - Bringing together viewpoints of mothers and health workers to enhance monitoring
      and promotion of growth and development of children: a case study from the
      Republic of Congo.
AB  - In 1996, the Government of the Republic of Congo launched a pilot project to
      improve the child growth and development component of primary healthcare. The
      present study was carried out (i) to explore perceptions and practices of mothers
      and health workers regarding child growth, health, and development, and (ii) to
      design culturally-appropriate tools to enhance their monitoring and promotion.
      The study was carried out in two randomly-selected health centres in Brazzaville.
      Qualitative data collected included 16 focus-group discussions with 174 mothers,
      two focus-group discussions with 18 health workers, and 20 individual interviews
      with paediatricians or psychologists. The health workers reported that the main
      indicator of child growth was weight, while the mothers used broader concepts for
      evaluating growth and development of their toddlers. A strategy encompassing
      anthropometrics, developmental milestones, and acquisition of social skills was
      elaborated to enhance communication between health workers and mothers. A new
      growth chart was designed, and a new calendar of systematic visits, including key
      tasks and messages, was established. However, these new tools derived from the
      formative research still need to be carefully tested.

PMID- 15190814
TI  - Tobacco use among women in Dharan, eastern Nepal.
AB  - The study was undertaken to assess the prevalence and patterns of tobacco use and
      also assess the factors affecting tobacco use among the female population of
      Dharan. A cross-sectional survey of a representative sample of 2,340 female
      participants aged 15 years and above was conducted in Dharan municipality in
      2001. Cluster sampling with probability proportionate to size technique was used.
      Of the 2,340 subjects, 12.9% were cigarette smokers and 14.1% were smokeless
      tobacco users. The smoking habit had a significant relationship with the habit of
      tobacco chewing. About 50% of the smokers had been continuously smoking for more
      than 20 years. Smokers aged 50 years and above were more likely to smoke more
      than 10 cigarettes per day than those at the reproductive age (15-49 years).
      Health problems among females did not have any significant relationship with
      tobacco-chewing, but smokers were nearly twice as likely to suffer from any
      health problem than non-smokers. Gastrointestinal problems were the most common
      complaint among the tobacco users. An effective awareness programme is required
      to discourage the use of tobacco and encourage women to take regular health check
      ups.

PMID- 15190815
TI  - Assessment of obesity, lifestyle, and reproductive health needs of female
      citizens of Al Ain, United Arab Emirates.
AB  - This study was conducted to determine the reproductive and lifestyle
      characteristics in a representative sample (n = 535) of women in Al Ain, United
      Arab Emirates, to guide the development of health programmes for this population
      with rising affluence. A cross-sectional survey was carried out using the
      stratified two-stage sampling technique. Although most women were young, were pre
      menopausal, did not smoke, reported good health status, and 84% (95% confidence
      interval [CI] 81-87%) reported being sufficiently active to meet expert
      recommendations, the prevalence of obesity (defined by body mass index > or = 30)
      was very high (35%; 95% CI 31-39%) and many (28%; 95% CI 24-32%) reported having
      a chronic disease. The prevalence of obesity was associated positively with age
      and negatively with education (p < 0.001 for both). Postmenopausal women had
      significantly more chronic diseases, reported poor health more often, were less
      physically active (p < 0.001 for all), and had a higher percentage of body fat (p
      = 0.002) compared to premenopausal women. Health services should emphasize the
      prevention and treatment of obesity and improving the general health status of
      postmenopausal women.

PMID- 15190816
TI  - Effect of socioeconomic characteristics on age at marriage and total fertility in
      Nepal.
AB  - In societies where childbearing prior to marriage is not socially acceptable,
      postponement of marriage contributes significantly to a reduction in fertility
      level by shortening the total reproductive life of women. This, in turn, reduces
      the number of children a woman is likely to have and has a negative impact on the
      population growth rate of a country. This paper examined the effect of
      socioeconomic characteristics on age at marriage and on total fertility rates in
      Nepal using a household-level dataset. The estimated results showed that an
      increase in age at marriage significantly reduced total fertility of women. An
      increase in the number of children who died had a statistically significant
      effect on total fertility (child replacement effect). The estimation results also
      emphasized the role of female education in reducing total fertility and
      increasing age at marriage. Moreover, female educational effect had a strong
      inter-generational effect on age at marriage, and this effect was stronger than
      the effect of male educational attainment. One implication of these results is
      that from the policy point of view, all other things being equal, governments
      should accord a significant priority to female education and, in particular, a
      higher priority compared to male schooling.

PMID- 15190817
TI  - An outbreak of bacillary dysentery caused by quinolone-resistant Shigella
      dysenteriae type 1 in a northeastern state of India.

PMID- 15190819
TI  - [Advances in gonadal differentiation regulated by SRY].
AB  - Gondadal differentiation is genetically determined in humans. Sex is determined
      when the bipotential embryologic tissues differentiate into testes or ovary. SRY,
      a gene located on the Y chromosome, triggers a complex genetic cascade leading to
      testicular differentiation. However, only a minority of 46, XY sex reversal
      patients can be explained by SRY mutations, suggesting that other genes
      influencing sex determination are to be discovered. Recent studies show that
      testis differentiation requires insulin receptor family function in mice. SRY
      normally requires two distinct NLS-dependent nuclear import pathways to reach
      sufficient levels in the nucleus for gonadal differentiation.

PMID- 15190818
TI  - How much do drug abusers pay for drugs in Bangladesh?

PMID- 15190820
TI  - [Effects of SNP and L-NAME on spermatogenesis in rats].
AB  - OBJECTIVE: To observe the effects of nitric oxide(NO) on the DNA ploidy of germ
      cells and to evaluate the role of NO in modulating spermatogenesis by using SNP,
      a donor of NO and N-nitro-l-arginine-mythel-ester(L-NAME), an inhibitor of nitric
      oxide synthese(NOS) in rats physically in vivo. METHODS: Forty adult male,
      Sprague-Dawley rats (60-70 days) were divided into four groups, and injected
      ultraperitoneally with one of the following agents (once a day, for 12 days):
      SNP, L-NAME and SNP + L-NAME with normal saline. Two hours after the last
      injection the rats were sacrificed. The sera were collected and stored at -70
      degrees C for subsequent hormone assay. The concentration of serum testosterone
      was measured by radioimmunoassay. Serum NOx- (nitrite/nitrate) concentration was
      measured by Greiss method. DNA of spermatogenic cells was detected by flow
      cytometry(FCM), and the percentage of 1c, 2c and 4c germ cells calculated.
      RESULTS: In the SNP treatment group, the serum concentration of NOx- was higher,
      testosterone concentration was lower and the number of 1c cells was smaller
      compared with the control group. However, in rats treated with L-NAME, the
      concentration of NOx- was significantly lower, testosterone concentration was
      higher and the number of 1c cells was larger compared with the control group(P <
      0.01). No changes were observed in the SNP + L-NAME group. CONCLUSION: Enhancing
      ectogenous NO will suppress spermatogenesis while inhibiting NO productive
      pathway will promote it.

PMID- 15190821
TI  - [Restoration of erectile function by reconstructing cavernous nerves with sural
      nerve grafts].
AB  - OBJECTIVE: To investigate the restoration of erectile function by reconstructing
      cavernous nerves with sural nerve grafts. METHODS: Forty-eight male Sprague
      Dawley rats(3-4 m old and 300-400 g) were randomly divided into three groups: the
      sham-operated group (n = 16) underwent pelvic exploration without transection of
      the cavernous nerve; the nerve ablation group (n = 16) had a 5 mm segment of the
      cavernous nerve excised bilaterally; the graft group (n = 16) had a 5 mm segment
      of the cavernous nerve excised bilaterally, followed by immediate microsurgical
      reconstruction with an interposition graft of the sural nerve. The cavernous
      nerves of each group were electrostimulated to determine their potency after 2
      and 4 months. And fluorescent retrograde-transported material Fluoro-Gold(FG) was
      injected into the penis. FG-labeled neuron cells in whole mounts of major pelvic
      ganglions were observed five days after injection. RESULTS: Electrical
      stimulation produced no erection in either the nerve ablation or the graft group,
      but 100% erection in the sham-operated group after 2 months. The numbers of FG
      labeled neurons significantly differed between the nerve ablation group and the
      graft group. After 4 months erection examination showed statistical significance
      in the difference between the graft group and the nerve ablation group(P < 0.05).
      The FG-labeled neurons in the graft group significantly differed from those in
      the ablation (P < 0.05), and almost reached the level of the sham-operated(P <
      0.05). CONCLUSION: Cavernous nerve grafting can successfully restore erectile
      dysfunction in rats after surgical injury.

PMID- 15190822
TI  - [Expression of neuropeptide Y in rat testes and its significance].
AB  - OBJECTIVE: To assay the expression of neuropeptide Y (NPY) in rat testes and to
      investigate the significance of NPY in the regulation of androgen production and
      spermatogenesis. METHODS: NPY mRNA levels in SD rat testes were measured by RT
      PCR semi-quantity with beta-actin as internal control. NPY distribution was
      observed immunohistochemically. RESULTS: NPY gene expressed in the testes,
      showing the strong positive band in the PCR production electrophoresis gel. In
      the immunostaining slides, NPY was found positively expressed in the Leyding cell
      area and around the testicular vessels and tubules, but not in the seminiferous
      tubules. CONCLUSION: There was positive expression of NPY in the rat testes,
      which showed that NPY played a direct role in the regulation of testicular
      function.

PMID- 15190823
TI  - [Effects of prostadyn sabale capsules on chronic prostatitis].
AB  - OBJECTIVE: To study the effects of prostadyn sabale capsules on chronic
      prostatitis (CP). METHODS: One hundred and twenty-five CP cases were divided into
      three categories according to National Institutes of Health (NIH) concensus
      definition and classification of CP:31 of category II. 75 of category IIIA and 19
      of category IIIB. All the cases were treated with prostadyn sabale capsules at
      the dosage of 320 mg twice a day. NIH chronic prostatitis symptom index (NIH
      CPSI), routine examination and culture of expressed prostatic secretions (EPS)
      were prospectively evaluated before and after treatment. RESULTS: The cure rates
      of category II, category IIIA and category IIIB were 25.8%, 16.0%, and 21.1%
      respectively, the general cure rate being 19.2%. The alleviation rate was 63.5%
      and the total effectivity rate was 82.7%. No side effects were observed.
      CONCLUSIONS: Prostadyn sabale capsules have good effects on CP.

PMID- 15190824
TI  - [Effect of castration on restenosis after precutaneous transluminal angioplasty
      in male rats].
AB  - OBJECTIVE: To observe the developing changes of adventitia in restenosis after
      precutaneous transluminal angioplasty(PTA), and investigate the effect of
      androgen on restenosis through contrasting the castrated male rat models and its
      mechanism. METHODS: Models were constructed of castrated male rats and restenosis
      of the common carotid artery, and specimens were collected at the 3rd, 7th, 14th
      and 28th day respectively after modeling. Hematoxylin and eosin staining,
      immunohistochemical staining, and electronic microscopy were performed to observe
      the condition of restenosis. RESULTS: Proliferating cells occurred in adventitia
      first and phenotype of adventitial cells was changed at the 3rd day after PTA.
      The adventitial proliferating index was the highest at the 7th day after PTA, and
      proliferating migration towards intimal was observed. The proliferating cells
      mostly occurred in the middle layer and neointima at the 14th day after PTA. The
      areas of adventitia and neointima were larger and the degrees of restenosis were
      higher in the castrated rats than in the non-castrated ones at different time
      points. Take the 14 d group, the adventitial area was[(3,566 +/- 337) micron2 vs
      (2,751 +/- 401) micron2, P = 0.008], the neointimal area[(3,553 +/- 477) micron2
      vs (2,757 +/- 435) micron2, P = 0.025], the restenosis rate[(76 +/- 2)% vs (60 +/
      8)%, P = 0.005], and the proliferating index [(29 +/- 2)% vs (13 +/- 1)%, P <
      0.001]. CONCLUSION: Adventitial proliferation and migration contribute to
      restenosis after PTA; Androgen in rats can physiologically relieve restenosis,
      probably through intervening in the activation of adventitia.

PMID- 15190825
TI  - [Effects of c-jun on hCG-induced testosterone secretion of rat Leydig cells in
      vitro].
AB  - OBJECTIVE: To investigate the effects of c-jun on hCG-induced testosterone
      secretion in isolated rat Leydig cells by antisense
      oligodeoxynucleotides(ASODNs). METHODS: c-jun ASODNs were used to antagonise the
      effects of c-jun, hCG was used to induce the testosterone secretion of LC
      cultured in vitro and testosterone was measured by radioimmunoassay. RESULTS: The
      testosterone secretion of LC in vitro could be induced by hCG, which was a good
      model for the functional study of LC. c-jun ASODNs decreased the hCG-induced
      testosterone secretion of LC in a dose-dependent manner(P < 0.05). CONCLUSION: It
      is suggested that c-jun proto-oncogene enhances the testosterone secretion of LC.

PMID- 15190826
TI  - [Separation of high-quality sperm by PureSperm centrifugation applied to
      intrauterine insemination cycles].
AB  - OBJECTIVE: To separate high-quality sperm by PureSperm centrifugation applied to
      intrauterine insemination (IUI) cycles. METHODS: We compared the separate results
      after washing the semen with one-layer and two-layer PureSperm gradient
      centrifugation methods and two-layer Percoll gradient centrifugation method, and
      used the recovered high-quality sperm for IUI. RESULTS: The density of the sperm
      washed with one-layer PureSperm centrifugation method was significantly higher
      than that washed with two-layer Percoll and two-layer PureSperm centrifugation
      methods(P < 0.01), but there were no differences in all the results between the
      use of two-layer Percoll and two-layer PureSperm(P > 0.05). No significant
      differences in the motility, teratozoospermia and IUI results were found when the
      three methods were used for sperm preparation(P > 0.05). The percentage of
      morphologically normal sperm was markedly increased, and the non-sperm components
      such as leucocytes, epithelial cells and cellular fragments were significantly
      reduced after washed by the two methods. CONCLUSION: PureSperm centrifugation is
      a safe, efficient and easy method for separating high-quality sperm on
      intrauterine insemination cycles.

PMID- 15190827
TI  - [Clinical significance of six-transmembrane epithelial antigen of the prostate
      expressed in prostatic carcinoma].
AB  - OBJECTIVE: To investigate the relationship between six-transmembrane epithelial
      antigen of the prostate (STEAP) expression and the histologic grading of
      prostatic carcinoma (PCa). METHODS: Different prostatic tissues and non-prostatic
      tumors, 131 cases of PCa, 164 cases of benign prostate hyperplasia (BPH), and 56
      cases of non-prostatic malignancies, were analyzed for the expression of STEAP by
      using STEAP monoclonal antibody and SP immunohistochemical staining. The positive
      area unit (PU) was introduced to describe the intensity of STEAP expression.
      RESULTS: The prostatic tissues of all but 3 cases of PCa and 5 cases of BPH were
      stained positively, while all of the non-prostatic tumors were stained
      negatively. There was a significant negative correlation between the STEAP
      expression and the histologic grading of PCa. CONCLUSION: STEAP can be a
      prognostic marker of PCa and a potential therapeutic target in PCa.

PMID- 15190828
TI  - [Treatment for erectile dysfunction patients with obstructive sleep apnea
      syndrome by nasal continual positive airway pressure].
AB  - OBJECTIVE: To investigate the influence of nasal continual positive airway
      pressure (nCPAP) on the erectile function of erectile dysfunction (ED) patients
      with obstructive sleep apnea syndrome(OSAS). METHODS: Twenty-seven patients with
      ED and OSAS were randomly divided into treatment (n = 15) and control (n = 12)
      groups, the former treated by nCPAP from 22:00 to 6:00 per night for 1 month. And
      the apnea-hypopnea index(AHI), the lowest oxygen saturation (SaO2) and IIEF were
      compared before and after treatment. RESULTS: AHI, the lowest SaO2, erectile
      function and IIEF showed no significant difference before treatment in the two
      groups, but displayed a significant improvement after treatment in the treated
      group compared with the control (P > 0.05), in which no significant changes were
      observed before and after treatment (P > 0.05). CONCLUSION: nCPAP therapy can
      improve the erectile function of ED patients with OSAS.

PMID- 15190829
TI  - [Effect of mifepristone on the expression of chorionic gonadotropin beta subunit
      and collagen type IV in female rhesus monkey decidua and villus at early
      gestation].
AB  - OBJECTIVE: To study the effect of mifepristone on the expression of chorionic
      gonadotropin beta subunit (beta-CG) and collagen type IV in female Rhesus monkey
      decidua and villus during the first trimester of pregnancy. METHODS: Eighteen
      sexually mature female Rhesus monkeys were allowed to cohabitate with their male
      counterparts and diagnosed as being pregnant by B-ultrasound at days 38-45 of the
      menstrual cycle. They were randomly divided into mifepristone treatment group (15
      mg/ml.kg.day, 3 days), control group(no treatment) and CMC-Na treatment
      group(0.5% CMC-Na, 1 ml/kg.day, 3 days). The content and distribution of
      chorionic gonadotropin beta subunit and collagen type IV in the female Rhesus
      monkeys were examined by immunohistochemical technique. RESULTS: Compared with
      the control group, the immunohistochemical reaction intensity of chorionic
      gonadotropin beta subunit in the plasm of stroma cells, glandular epithelial
      cells and decidual cells of decidua, and synctial trophoblast cells of villus
      significantly decreased in the mifepristone treatment group. The positive
      staining of collagen type IV surrounding the epithelial glandular basal membrane,
      decidual cells and blood vessels in decidua and surrounding the synctial
      trophoblast cells in villus were significantly reduced. CONCLUSION: Mifepristone
      may have a strong effect in decreasing the bioactivity of beta-CG in decidua and
      the synthesis of beta-CG in villus, and in accelerating the degradation of
      collagen type IV in decidua and villus.

PMID- 15190830
TI  - [Gleason histologic grading of prostate carcinoma in relation to serum PSA, PSA
      in situ and immunohistochemical expression of 34 beta E12 and P504S].
AB  - OBJECTIVE: To study the Gleason histologic grading of prostate carcinoma in
      relation to the serum prostate-specific antigen (PSA) level and the PSA in situ
      of the tumor, and the immunohistochemical staining of basal cell-specific
      cytokertain(34 beta E12) and alpha-Methylacyl-CoA racemase(P504S) of the tumor.
      METHODS: The serum PSA levels were measured in 40 cases of prostate carcinoma.
      The Gleason histologic grading was based on histopathologic examination of the
      tumors, and the immunohistochemical staining including PSA in situ (35 cases), 34
      beta E12(12 cases) and P504S(10 cases) was examined. RESULTS: The higher the
      Gleason histologic grading of prostate carcinoma, the higher the serum PSA
      level(P < 0.01), and the weaker the positive reaction of the immunohistochemical
      staining of PSA of the tumor(P < 0.05). And the tumor cells displayed positive
      reaction for P504S and negative for 34 beta E12. CONCLUSION: The Gleason
      histologic grading of prostate carcinoma is positively related to the serum PSA
      level and negatively to PSA in situ of the tumor immunohistochemically. It is
      important to use immunohistochemical staining for 34 beta E12 and P504S in the
      pathologic diagnosis of prostate carcinoma.

PMID- 15190831
TI  - [Clinical efficacy of Viagra with behavior therapy against premature
      ejaculation].
AB  - OBJECTIVE: To study the efficacy of Viagra combined with behavior therapy against
      premature ejaculation (PE). METHODS: Sixty PE patients were divided into two
      groups randomly: control group (behavior therapy alone) and the group of Viagra
      combined with behavior therapy. Intra-vaginal ejaculation latency time (IELT) and
      the coitus satisfaction of the patient and the partner were recorded before and
      after treatment. RESULTS: The IELTs of the two groups were 0.80 +/- 0.20 and 0.73
      +/- 0.24 minutes respectively before treatment, and 1.82 +/- 0.54 and 3.63 +/-
      0.55 minutes respectively after treatment. As for IELT and satisfaction degree,
      Viagra produced better result than behavior therapy. CONCLUSION: During this
      clinical trial, Viagra combined with behavior therapy prolonged IELT, which
      suggests that Viagra may be helpful for the treatment of premature ejaculation.

PMID- 15190832
TI  - [Clinical study of zinc for the treatment of chronic bacterial prostatitis].
AB  - OBJECTIVE: To study the efficacy of biological organic zinc in the treatment of
      chronic bacterial prostatitis (CBP). METHODS: Sixty-one CBP patients were
      randomized into two groups: Group A (39 cases) was supplemented with organic zinc
      after routine antibiotic treatment, Group B (22 cases) was given routine
      antibiotic treatment only. NIH-CPIS (including pain, urinary symptoms, quality of
      life) and urodynamic indexes were used to evaluate the efficacy of biological
      organic zinc in the treatment of CBP. RESULTS: The NIH-CPIS (including pain,
      urinary symptoms, quality of life) and the maximum urethra closure pressure
      (MUCP) were markedly decreased after the zinc treatment, compared with the non
      zinc group(P < 0.05). CONCLUSION: It is suggested that biological organic zinc is
      effective for the treatment of CBP.

PMID- 15190833
TI  - [Brachytherapy of 125I implantation for localized prostate cancer (report of 41
      cases)].
AB  - OBJECTIVE: To observe the effect of brachytherapy of 125I implantation on
      localized prostate cancer. METHODS: Two-step technique was engaged in the
      implantation of 125I into the prostate for 41 localized prostate cancer patients.
      The prescription dosage of 125I was 160 Gy. TRUS and C-Arm X-ray were used for
      the confirmation of seeds location in the prostate. RESULTS: Thirty-three
      patients were followed up for 3 to 4 years. Abnormal PSAs were found in 2
      patients by positive biopsy. No patients died in this investigation. The early
      stage complications were urinary irritation symptoms that were severe within 6
      months and disappeared after 1 year. CONCLUSION: Brachytherapy of 125I
      implantation increases long-term tumor-free survival rate, with few long-term
      complications and some short-tern urinary stimulating symptoms.

PMID- 15190834
TI  - [Tolterodine for bladder spasm caused by the indwelling catheter after prostate
      operation].
AB  - OBJECTIVE: To evaluate the efficacy of tolterodine on bladder spasm caused by the
      indwelling catheter after prostate operation. METHODS: Eighty-two patients with
      bladder spasm caused by the indwelling catheter after prostate operation received
      tolterodine (2 mg twice daily), until 24 hours before the removal of the
      catheter. RESULTS: After 24 hours of treatment, bladder spasm was alleviated
      totally in 21 patients (25.6%), partially in 45 (54.9%), and unrelieved in 16
      (19.5%). After 72 hours of treatment, bladder spasm was alleviated totally in 45
      patients (54.9%), partially in 30 (36.6%), and unrelieved in 7 (8.5%). No severe
      adverse events occurred during the treatment. CONCLUSION: The tolterodine therapy
      for patients with bladder spasm caused by the indwelling catheter after prostate
      operations is rapid, effective, persistent and safe.

PMID- 15190835
TI  - [Diagnosis and treatment of tuberculosis in the male genital system].
AB  - OBJECTIVE: To probe into and improve the diagnosis and treatment of tuberculosis
      (TB) in the male genital system. METHODS: Fifteen patients with the male genital
      system TB established by microbiological and pathological examinations were
      retrospectively reviewed. RESULTS: The male genital system TB was diagnosed by
      history, physical examination, semen analysis, TB culture and biopsy. Treatment
      consisted of antituberculous chemotherapy for all the patients before and/or
      after operation, including 5 cases of epididymectomy and 6 cases of orchi
      epididymectomy. CONCLUSION: The male genital system TB tends to be atypical and
      semen polymerase chain reaction of TB (TB-PCR) may provide a new specific means
      for diagnosis in case of clinical suspicion. Surgical approaches should be
      cautiously adopted, especially for young patients.

PMID- 15190836
TI  - [Advances in the research of Peyronie's disease].
AB  - The incidence of Peyronie's disease has continuously increased during the last 30
      years. Because of the better understanding of the basic sciences of the disease,
      earlier diagnosis and improved medical and surgical treatment, currently patients
      with Peyronie's disease have a wider range of therapeutic options and may
      experience a better prognosis, with only few of them in need of prosthesis
      surgery. This paper reviews the pathogenesis, pathology, diagnosis and treatment
      of Peyronie's disease.

PMID- 15190837
TI  - [Prostate stem cell antigen and related cancers].
AB  - Prostate stem cell antigen (PSCA) is a cell surface antigen expressed in normal
      prostate and overexpressed in cancers associated with prostate, bladder and
      pancreas. The sensitivity of PSCA labeling is higher than PSA in prostate cancer.
      PSCA can be used in the preparation of protein vaccine and nucleic acid vaccine.
      Further studies are required to confirm its safety and efficacy as a diagnostic
      means.

PMID- 15190838
TI  - [Present situation in the study of antisperm antibodies].
AB  - Immune factors account for 5%-15% of male infertility. Because of the diversity
      in molecular weight, structure and location, sperm antigens play different roles
      in immune infertility. Antisperm antibodies (AsAb) influence sperm function not
      only by direct action, but also by changing the local microenvironment
      indirectly. This paper reviews the progress in the studies of the implication of
      human sperm antigens, the function, mechanisms, categories and titer of AsAb in
      male infertility.

PMID- 15190839
TI  - [Experimental research on tea saponin ameliorating nonoxynol spermicidal action
      in vitro].
AB  - OBJECTIVE: To study the effect of tea saponin in ameliorating nonoxynol(N-9)
      spermicidal action in vitro. METHODS: According to the improved spermicidal test
      method in vitro recommended by International Planned Parenthood Foundation
      (IPPF), we evaluated the minimum spermicidal concentration of N-9, tea saponin
      and their mixed solution in 20 s and 3 min. RESULTS: The minimum spermicidal
      concentration of N-9 in the mixed solution was (0.13 +/- 0.05) g/L in 20 s and
      (0.05 +/- 0.004) g/L in 3 min, and that of the tea saponin in the mixed solution
      was (2.40 +/- 1.07) g/L in 20 s and (1.27 +/- 0.38) g/L in 3 min, compared with
      the single ingredient N-9 [(0.48 +/- 0.15) g/L in 20 s, (0.34 +/- 0.079 g/L in 3
      min], and tea saponin [(5.78 +/- 1.40) g/L in 20 s, (1.71 +/- 0.176) g/L in 3
      min], P < 0.01. CONCLUSION: Tea saponin can improve N-9 spermicidal action in
      vitro, and tea saponin and nonoxynol have proved of synergic effect.

PMID- 15190840
TI  - [Endoscopic management of chronic frontal sinusitis in the Negev population,
      Israel].
AB  - BACKGROUND: Chronic frontal sinusitis is a relatively common condition, yet one
      with potential for complications. The treatment of chronic frontal sinusitis has
      always been a challenge for the otolaryngologist, and it remains so even in the
      age of endoscopic sinus surgery. Successful treatment is evaluated by both
      subjective (patient history) and objective (radiologic and endoscopic) criteria.
      PURPOSE: This article aims to present our experience in endoscopic surgery for
      chronic frontal sinusitis, with particular focus on the importance of the wide
      opening of the naso-frontal outflow tract, with maximal preservation of the
      mucosa in this area. METHODS: During the period 1999 to 2001, 72 patients at the
      Soroka University Medical Center underwent endoscopic surgery for chronic frontal
      sinusitis. We reviewed the cases of fifty four patients of this group with a
      minimum six months follow-up. Patients who did not return for routine post
      operative visits were excluded from this study. We evaluated and quantified
      subjective measurements including facial pain, nasal respiratory obstruction and
      hyposmia, and objective measurements, based on radiographic studies and
      endoscopic examination. RESULTS: Most patients experienced improvement in all of
      the subjective categories, and particularly in the categories of facial
      pain/headache and nasal respiratory obstruction. Most patients who experienced
      this improvement had suffered from chronic pansinusitis. CONCLUSIONS: The
      endoscopic management of chronic frontal sinus disease is an effective treatment,
      when principles of wide sinus drainage with maximal mucosal preservation are
      observed. Most patients undergoing this type of procedure experience significant
      clinical and radiologic improvement in their condition.

PMID- 15190841
TI  - [Proctalgia Fugax--what's new over the last 100 years?].
AB  - Proctalgia Fugax is a benign, self-limiting disease characterized by episodes of
      intense pain in the anorectal area occurring at infrequent intervals. It is
      common, but most suffers do not seek medical advice. Although its classical
      symptomatology was describe more than a century ago, the etiology is unclear.
      Theories regarding the etiology have centered on alteration in the internal anal
      sphincter function and morphology. For most patients after gathering a detailed
      history, reassurance and warm baths will suffice. In persistent cases therapies
      that induce internal anal sphincter relaxation are the main treatment modalities.

PMID- 15190843
TI  - [Silicone granuloma of the lip].
AB  - Silicone is considered a biocompatible material, and therefore has many
      applications in medicine. It can be used in a liquid form for subcutaneous
      injection, in gel form for implants, and in a solid state for prostheses,
      hemodialysis tubing, etc. The use of injectable liquid silicone for tissue
      augmentation is widespread, but there are many reports of side effects, some
      severe and debilitating such as the granulomatous reaction. We report on a
      patient with an upper lip swelling, who denied having been subjected to any type
      of lip augmentation. An incisional biopsy was taken, and the pathologist reported
      an atypical lyphomatous tumor. The patient was informed that a wide excision of
      the lip was necessary, and then she confessed she underwent silicone injections
      in the past. This is a case of a granulomatous reaction after silicone injection
      in the lip. The article also reviews the literature on the subject.

PMID- 15190842
TI  - [Large loop excision of the transformation zone in Israel--2001].
AB  - BACKGROUND: Large loop excision of the transformation zone (LLETZ) is regarded as
      the treatment of choice in cases of Cervical Intraepithelial Neoplasia (CIN).
      Since the method is easy to learn and the equipment is inexpensive, many
      gynecologists now perform it in the clinic. Concern has been raised regarding the
      use of this procedure with insufficient indication by physicians who have not
      been adequately trained in performing LLETZ. AIM: This article aims to verify
      whether the indications for LLETZ in Israel are similar to those accepted in the
      updated literature and to discuss the need for licensure to perform LLETZ.
      Licensure would limit the use of LLETZ only to professionals specifically trained
      to conduct this procedure. METHOD: A questionnaire was sent to gynecologists,
      heads of obstetrics and gynecology departments as well as managers of public and
      private hospitals, regarding LLETZ performed in 2001. Topics covered in the
      questionnaire included: the number of LLETZ procedures performed, the patient's
      age, pre- and post-operative histopathological diagnosis, complications, follow
      up and recurrence rate. The physicians were asked to complete separate
      questionnaires for each of the clinics in which he or she worked. RESULTS: The
      completed questionnaires comprised of 625 LLETZ procedures in eight public and
      three private colposcopy clinics. The ages of the women ranged from 18 to 70
      years old, with 49% in the 18 to 34 age range. Most women (416) who underwent the
      LLETZ procedure had CIN grades 2 or 3. However, 128 women with CIN 1 were also
      treated. Among this group, 50% were confirmed CIN 1 according to the surgical
      specimen but 43 women had normal epithelium, 20 (15.6%) had high grade CIN (2-3)
      and one had invasive cancer. The most common post-operative short and long-term
      complication was heavy bleeding. Involvement of the surgical specimen borders was
      found in one fifth of the cases. CONCLUSIONS: The finding that about half of the
      women who underwent LLETZ were below the age of 35 years is of particular
      significance since the health insurance agencies in Israel only cover a pap smear
      screening test for women between the ages 35-54, once every three years.
      Therefore, there is an indication to start screening from the age 18. Similar to
      other countries in the world, the main indication to perform LLETZ in Israel is
      CIN 2-3. However, performing LLETZ for CIN 1 in many cases, and administering
      general anesthesia in certain centers, calls for the introduction of licensure
      for performing LLETZ. Involvement of the margins of the specimen in the
      neoplastic process in one fifth of the patients was similar to that reported in
      the literature. The various centers in Israel have different approaches as to the
      required surveillance period for women following LLETZ. It is suggested that
      women with involvement of the surgical specimen margins by CIN should be under
      medical surveillance at colposcopy clinics for a period of at least eight years.

PMID- 15190845
TI  - [Exercise induced hyponatremia].
AB  - A normal water-electrolyte balance is essential for normal function of body
      systems during physical activity. During recent years, awareness of the
      importance of drinking amongst athletes and Israeli Defense Force (IDF) soldiers,
      in particular, has been highlighted. A large number of athletes tend to drink
      prior to, during and after their exercise in order to enhance physical abilities
      and to prevent heat casualties and dehydration. However, excessive water
      consumption combined with sweat induced electrolytes loss during physical
      activity, may cause hyponatremia in extreme cases. Recently, several cases of
      exercise induced hyponatremia were reported in the IDF, resulting from improper
      water consumption. In this article, we describe a clinical case of exercise
      induced hyponatremia in a soldier and a review of the literature, including the
      etiology, clinical characterization and recommended treatment. Moreover, water
      consumption recommendations with regard to physical activity are presented. The
      application of such recommendations may prevent future events of exercise-induced
      hyponatremia.

PMID- 15190844
TI  - [Relief of chronic cervical pain after selective blockade of zygapophyseal
      joint].
AB  - Osteoarthrosis of the zygapophyseal joint (Z-joint) is a potential cause of
      chronic cervical pain. The diagnosis of thirty patients, with pain of more than
      12 months duration and with no history of trauma, was confirmed with intra
      articular fluoroscopy-guided infiltration of anesthetic. The patients were
      subsequently treated with intra-articular corticosteroids (Depo-Medrol 40 mg).
      Visual Analogue Scale was used for evaluation purposes. The mean time for relapse
      of 50 percent of the pre-injection level of pain was 12.47 +/- 1.89 weeks,
      significantly longer than 3 days as reported in patients similarly treated
      following whiplash neck injury. At this point selective blockade of Z-joints may
      be offered as an adjunct for diagnostic and therapeutic purposes for patients
      with chronic neck pain due to facet osteoarthrosis in the ambulatory setup.

PMID- 15190846
TI  - [Knowledge and attitude regarding use of anabolic steroids among youth exercising
      in fitness centers].
AB  - A survey on knowledge and attitudes towards the use of steroids in youth who
      exercise in fitness centers was conducted in a national sample of fitness centers
      in Israel. A total of 528 participants aged 13-18 years completed the
      questionnaire. Fitness centers were chosen by cluster samples. Forty five percent
      of the respondents believe that the use of steroids improves physical fitness and
      41% believe that most well-known athletes use steroids. Ten percent of
      respondents believe that the use of steroids is popular among young people in gym
      centers. Overall, 7% stated that they tended to use steroids and a significantly
      lower percentage were aware of the side effects of steroids. The role of the
      physician is essential to identify the patients at risk, to deliver accurate
      information, to minimize harm and to follow-up. There is also a need for health
      education in schools, fitness centers and the community, concerning the use of
      steroids among young people.

PMID- 15190847
TI  - [Primary care for type 2 diabetes].
AB  - The prevalence of type 2 diabetes is dramatically increasing worldwide and
      expected to double over the next 25 years, reaching epidemic proportions and thus
      incurring a considerable financial burden on the health care system. In order to
      cure the epidemic and minimize expensive complications, a program aimed at
      optimizing metabolic control and improving surveillance and quality assessment
      needs to be developed and implemented nation-wide. Most diabetic patients should
      be treated within the primary care system. In order to meet treatment targets,
      improve metabolic control and avoid complications, the knowledge and skills
      needed to treat this chronic disease should be reinforced by dedicated
      multidisciplinary teams from centers specializing in diabetes care. The
      specialized diabetes clinics should be devoted to both the treatment of
      complicated cases of diabetes, that are not achieving treatment targets in the
      primary care setting, and to the education, updating and empowerment of all
      primary care teams involved in the treatment of patients with diabetes. A local
      framework for shared care should be developed through the combined efforts, of
      the staff of the diabetes center and the primary care physicians and nurses in
      order to secure the shared goals of optimal treatment and prevention of
      complications.

PMID- 15190848
TI  - [Community care of diabetic patients--in the family practice, in specialized
      diabetic clinics or in cooperation?].
AB  - Type 2 diabetes is a common chronic illness with many complications, entailing
      enormous expenditures health services. In the Western world, diabetes is the most
      common cause of amputations of the lower limb, end stage renal failure and
      blindness amongst 18-65 year olds. The care of the diabetic patient is multi
      faceted and the long term compliance of the patient is essential. In the last
      decade there is an ongoing heated debate regarding how treatment and care should
      be provided to diabetics and by whom. "Shared care" between the family physician
      and the specialist diabetes clinic is becoming more popular in an attempt to
      raise standards of care while reducing costs. The aim of the current review is to
      evaluate management modalities of the diabetic patient and its' applications to
      the Israeli health system.

PMID- 15190849
TI  - [Indirect traumatic optic neuropathy--problems and challenges in diagnosis and
      uncertainty in treatment].
AB  - Traumatic optic neuropathy is one of the many facets of head injuries and a major
      cause of devastating permanent visual loss due to head injuries. Indirect
      traumatic optic neuropathy (ITON) occurs when blunt trauma to the forehead
      results in a transmission of force through the cranium to the confined portion of
      the optic nerve within the bony optic canal. The physics of the injuring forces
      that induced anatomical and histological effects on the optic nerve were
      thoroughly studied but the recognition of ITON in the acute stage still poses a
      diagnostic challenge. The accuracy of diagnosis still varies ten-fold among
      different centers. The use of Visual Evoked Potentials (VEP) in the evaluation of
      patients at risk of ITON will improve the diagnostic abilities. The clinical
      course varies between immediate and permanent visual loss of varied severity,
      delayed deterioration and spontaneous recovery. No clinical technique, however,
      proved to provide predictive abilities. None of the current forms of treatment-
      conservative, high dose steroids and surgical decompression of optic nerve, were
      found to be superior, and the patient series are still too small. The reviewers
      recommend establishing a national registry of ITON that will facilitate the
      improvement of the diagnosis and will contribute to the adoption of an evidence
      based therapeutic approach.

PMID- 15190850
TI  - [Q fever pericarditis].
AB  - Q fever is a zoonotic disease caused by Coxiella burnetii--an obligate, gram
      negative, intracellular bacteria. The term Q (Query) was first used because at
      the time the disease was named its etiology was unknown. Q fever is divided into
      acute and chronic infections characterized by different evolution, serological
      profiles and treatment. Pericarditis, as a manifestation of Q fever is rare and
      difficult to diagnose. This is due to the following: firstly, the clinical
      presentation of acute Q fever is pleomorphic, nonspecific and self limited, and
      secondly, the diagnosis relies on the physician's interest and the presence of a
      reliable diagnostic laboratory. The objective of that review is to increase the
      physician's awareness of the clinical presentation of Q fever, to discuss the
      importance of the diagnosis and laboratory tests and to guide the physician as to
      when to provide treatment and the relevant patient population to be treated.

PMID- 15190851
TI  - [Experimental therapeutic modalities for retinitis pigmentosa].
AB  - Retinitis Pigmentosa (RP) is a heterogeneous group of inherited diseases that
      cause retinal degeneration, often leading to blindness. Over the last decade,
      significant insights have been obtained into the mechanisms underlying retinal
      degeneration in RP. This improved understanding of the pathogenesis of RP,
      combined with advances in molecular and cellular biology methods as well as
      electro-optical technologies, have contributed to renewed interest and increasing
      efforts to design novel therapeutic approaches for RP. In the first part of this
      review (Harefuah, April 2003), we summarized recent developments in the fields of
      gene therapy for RP, the use of neurotrophic growth factors, and attempts to
      alter disease progression by vitamins and nutritional modifications. In this
      second part of the review, retinal and retinal pigment epithelium
      transplantation, the potential use of stem cells to replace degenerating retinal
      cells and attempts to develop a retinal prosthesis using electro-optical devices
      are described. The exciting progress made in these various experimental
      directions raises hope that slowing or preventing the progression of retinal
      degeneration in RP patients, and perhaps even partial restoration of visual
      function in RP, is within reach.

PMID- 15190852
TI  - [Budd-Chiari syndrome: updated treatment modalities].
AB  - Budd-Chiari Syndrome (BCS) refers to hepatic venous outflow obstruction,
      resulting in simultaneous occurrence of hepatic congestion and portal
      hypertension, leading to a typical clinical triad consisting of right upper
      quadrant pain, hepatomegaly and ascites. Contrary to Asia and Africa, where BCS
      is caused primarily by an obstructing membranous web, BCS in the western world is
      considered a thrombotic complication of an underlying hypercoagulable state.
      Recognition of the contribution of hypercoagulability as a causative factor in
      BCS, has led to acknowledgement of the importance of anti-coagulant therapy in
      BCS. Indeed, a conservative approach consisting of diuretics and anti-coagulant
      therapy is considered an appropriate treatment strategy for the BCS patient, in
      the absence of significant hepatic insult. However, once disease progression is
      noted, based on clinical symptoms, hepatic laboratory disturbance or histological
      evidence of irreversible hepatic damage, a definite invasive treatment should be
      applied. The specific procedure to be used is dependent upon the extent of
      hepatic insult and the anatomical characteristics of the venous obstruction in
      any individual patient. In the absence of significant hepatic damage, one may
      employ surgical shunting or invasive roentgenic measures, such as TransJugular
      Intrahepatic Porto-Systemic Shunt procedure, for the decompression of the portal
      system. Alternatively, in cases of a single localized obstruction, one may use
      balloon angioplasty with stent insertion. In contrast, upon evidence of
      significant hepatic damage, liver transplantation becomes necessary. To date,
      numerous studies report excellent results regarding the success of liver
      transplantation for patients with advanced BCS disease accompanied by significant
      hepatic damage.

PMID- 15190853
TI  - [An update on probiotics and prebiotics in children].
AB  - This review presents an update on the use of probiotics and prebiotics in
      children. We review the normal flora, and present the possible mechanisms by
      which the probiotic bacteria exert their beneficial effects. We present data from
      multiple studies suggesting that probiotics are effective for the treatment and
      prevention of acute non-bloody infections diarrhea, antibiotic associated
      diarrhea as well as the prevention and treatment of atopic dermatitis and other
      allergic conditions. The safety and future directions of pro- and prebiotic
      treatments are discussed.

PMID- 15190854
TI  - [The establishment of "Ezrath Nashim" Psychiatric Hospital in Jerusalem: selected
      issues].
AB  - This article describes the process of the establishment and early years of
      "Ezrath Nashim" Psychiatric Hospital in Jerusalem. Economic aspects in the
      continuous and daily life of the institution are emphasized, and existential
      difficulties that were involved in its regular management are mentioned. Selected
      issues such as economic difficulties and maintenance of the hospital are
      discussed based on historical documents. The resemblance between the early
      history and the current state of affairs in the mental health field in Israel is
      presented and stressed.

PMID- 15190855
TI  - Interview with Larry L. Mathis, FACHE, consultant, D. Peterson & Associates,
      Houston, Texas. Interview by Kyle L. Grazier.

PMID- 15190856
TI  - From co-opetition to collaboration.

PMID- 15190857
TI  - First the strategy, then the bricks.

PMID- 15190858
TI  - A practice change model for quality improvement in primary care practice.
AB  - Faced with a rapidly changing healthcare environment, primary care practices
      often have to change how they practice medicine. Yet change is difficult, and the
      process by which practice improvement can be understood and facilitated has not
      been well elucidated. Therefore, we developed a model of practice change using
      data from a quality improvement intervention that was successful in creating a
      sustainable practice improvement. A multidisciplinary team evaluated data from
      the Study To Enhance Prevention by Understanding Practice (STEP-UP), a randomized
      clinical trial conducted to improve the delivery of evidence-based preventive
      services in 79 northeastern Ohio practices. The team conducted comparative case
      study analyses of high- and low-improvement practices to identify variables that
      are critical to the change process and to create a conceptual model for the
      change. The model depicts the critical elements for understanding and guiding
      practice change and emphasizes the importance of these elements' evolving
      interrelationships. These elements are (1) motivation of key stakeholders to
      achieve the target for change; (2) instrumental, personal, and interactive
      resources for change; (3) motivators outside the practice, including the larger
      healthcare environment and community; and (4) opportunities for change--that is,
      how key stakeholders understand the change options. Change is influenced by the
      complex interaction of factors inside and outside the practice. Interventions
      that are based on understanding the four key elements and their
      interrelationships can yield sustainable quality improvements in primary care
      practice.

PMID- 15190859
TI  - Keeping patients safe: an analysis of organizational culture and caregiver
      training.
AB  - News headlines and professional publications, such as the Institute of Medicine
      reports, have brought to the attention of both healthcare providers and consumers
      the importance of the issue of patient safety. In this article, we describe the
      study conducted by one hospital to improve patient safety within its culture. The
      study included the development and use of a culture survey tool. Key learnings
      from this survey are presented here as well. The article also states the
      limitations of the study and offers recommendations for further research. The
      work of improving both the culture and processes of healthcare institutions to
      reduce error and promote safety is ongoing. The findings from this study add to
      the growing body of knowledge on successful patient-safety strategies and tools.

PMID- 15190860
TI  - The impact of nursing care and other healthcare attributes on hospitalized
      patient satisfaction and behavioral intentions.
AB  - Healthcare organizations in the United States are struggling to find ways to
      survive in their uncertain and competitive environments. One of the survival
      strategies used by those organizations is to increase patient satisfaction. This
      article presents research on factors that influence hospitalized patients'
      satisfaction and their intention to return to and recommend the hospital. The
      first objective of this study was to find out, using a comprehensive set of
      healthcare attributes, which attributes play a more important role in increasing
      patient satisfaction and behavioral intentions. The second objective was to
      analyze the relative importance of those attributes and the nature of the
      relationships across the values of the attributes. More specifically, this study
      attempted to identify any existing curvilinear relationships among these
      variables. If any curvilinear relationships exist, do they show an increasing or
      a decreasing marginal-utility function? Included in this article is an example,
      featuring a hospital-discharged patient, that explains the importance and
      uniqueness of this curvilinear relationship. This study found that among six
      attributes, nursing care showed the largest parameter estimate for the patient
      satisfaction and behavioral intentions models. Thus, simply improving the nursing
      care attribute seems to be the most effective manner to enhancing patient
      satisfaction and behavioral intentions. However, nursing care also showed a
      diminishing marginal-utility function for both models. To assess the effect of
      this diminishing marginal-utility function, the impact of nursing care was
      computed for each unit of improvement together with other attributes. The finding
      from this study provides information needed to increase patient satisfaction and
      behavioral intentions and should result in more effective and efficient
      healthcare management.

PMID- 15190861
TI  - Getting a return on investment from spending capital dollars on new beds.
AB  - In assessing this bed-purchase process and the resulting return on investment, I
      identified the following critical success factors related to capital investments:
      Evaluation of capital equipment for return on investment from the expense side,
      particularly when looking at use of manpower for critical positions in the
      organization Evaluation of capital equipment for increasing nursing satisfaction,
      a factor in addressing the healthcare worker shortage in today's environment
      Involvement of a representative team to create personal ownership through
      individuals wanting to take care of something they are involved in purchasing
      Spin-off timesaving that can be realized through the adage "form follows
      function" The last factor was found not only in savings of nurse staff time but
      also in pharmacy time because the weight function on the new beds saved
      approximately one hour, allowing for speedier calculation of creatinine clearance
      in antibiotic dosing. Changing my position and perspective was rewarding. The
      persistence of the CNO and the involvement of the employees made the experience
      gratifying on a personal level as well.

PMID- 15190862
TI  - Current awareness in prenatal diagnosis.

PMID- 15190863
TI  - The newest team member?

PMID- 15190864
TI  - Birth can be a hazardous journey: electronic fetal monitoring does not help.

PMID- 15190865
TI  - [Medical standards and guidelines. Making medicine economical].

PMID- 15190866
TI  - [Perinatal anesthesia].

PMID- 15190868
TI  - [171st Congress of the Society of Northwest German Surgeons in Bremen, 12 - 14
      June 2003].

PMID- 15190867
TI  - [Postoperative nausea and vomiting].
AB  - Numerous pathophysiological mechanisms are known to cause nausea or vomiting but
      their role for postoperative nausea and vomiting (PONV) is not quite clear.
      Volatile anesthetics, nitrous oxide and opioids appear to be the most important
      causes for PONV. Female gender, non-smoking and a history of motion sickness and
      PONV are the most important patient specific risk factors. With these risk
      factors an objective risks assessment is achievable as a good rational basis for
      a risk dependent antiemetic approach: When the risk is low, moderate, or high,
      the use of none, a single or a combination of prophylactic antiemetic
      interventions seems to be justified. Performing a total intravenous anesthesia
      (Ti.v.A) with propofol is a reasonable prophylactic approach, but does not solve
      the problem satisfactorily alone if the risk is very high, reducing the risk of
      PONV only by 30%. This is comparable to the reduction rate of antiemetics, such
      as serotonin antagonist, dexamethasone and droperidol. It must be stressed that
      metoclopramide is ineffective. Data from IMPACT indicate that prophylaxis is not
      very effective if the patients risk is low. At a moderate risk the use of Ti.v.A
      or an antiemetic is reasonable and only a (very) high risk justifies the
      combination of several prophylactic antiemetic interventions. For the treatment
      of PONV an antiemetic should be chosen which has not been used prophylactically.
      The necessary doses are usually a quarter of those needed for prophylaxis.

PMID- 15190869
TI  - [Fractures in children. Part 1: Upper extremities].

PMID- 15190870
TI  - [Jural--decisions and background].

PMID- 15190871
TI  - [Discordant anencephaly in dichorionic twins: report of one case].

PMID- 15190872
TI  - [Massive ascites due to Streptococcus acidominimus: report of one case].

PMID- 15190873
TI  - Pre-eclampsia as a 'three stage problem'--a workshop report.

PMID- 15190874
TI  - [Maxillary bone fractures complicated by nasolacrimal canal injury: report of 1
      case].

PMID- 15190875
TI  - [The 44th annual meeting of the Japanese Society of Neurology. Yokohama, Japan.
      May 15-17, 2003. Abstracts].

PMID- 15190876
TI  - Words with multiple meanings.

PMID- 15190877
TI  - Extracting the nerve agent VX from soil.

PMID- 15190878
TI  - MALDI points to origin of anthrax spores.

PMID- 15190880
TI  - The prospects of clay mineral electrodes.

PMID- 15190881
TI  - Optimization of BMD measurements to identify high risk groups for treatment--a
      test analysis.
AB  - INTRODUCTION: The aim of this study was to develop a methodology to optimize the
      role of BMD measurements in a case finding strategy. We studied 2113 women > or =
      75 years of age randomly selected from Sheffield, UK, and adjacent regions.
      Baseline assessment included hip BMD and clinical risk factors. Outcomes included
      death and fracture in women followed for 6723 person-years. MATERIALS AND
      METHODS: Poisson models were used to identify significant risk factors for all
      fractures and for death with and without BMD and the hazard functions were used
      to compute fracture probabilities. Women were categorized by fracture probability
      with and without a BMD assessment. A 10-year fracture probability threshold of
      35% was taken as an intervention threshold. Discordance in categorization of risk
      (i.e., above or below the threshold probability) between assessment with and
      without BMD was examined by logistic regression as probabilities of re
      classification. Age, prior fracture, use of corticosteroids, and low body mass
      index were identified as significant clinical risk factors. RESULTS: A total of
      16.8% of women were classified as high risk based on these clinical risk factors.
      The average BMD in these patients was approximately 1 SD lower than in low-risk
      women; 21.5% of women were designated to be at high risk with the addition of
      BMD. Fifteen percent of all women were reclassified after adding BMD to clinical
      risk factors, most of whom lay near the intervention threshold. When a high
      probability of reclassification was accepted (without a BMD test) for high risk
      to low risk (p1< or = 0.8) and a low probability accepted for low to high risk
      (P2 < or = 0.2), BMD tests would be required in only 21% of the population.
      CONCLUSION: We conclude that the use of clinical risk factors can identify
      elderly women at high fracture risk and that such patients have a low average
      BMD. BMD testing is required, however, in a minority of women--a fraction that
      depends on the probabilities accepted for classification and the thresholds of
      risk chosen. These findings need to be validated in other cohorts at different
      ages and from different regions of the world.

PMID- 15190879
TI  - Top-down proteomics.

PMID- 15190882
TI  - Could crossed wires see the IT programme blow its fuse?

PMID- 15190883
TI  - Royal Devon thinks local as foundation freedom is realised.

PMID- 15190884
TI  - Health education ideas. Read between the lines.

PMID- 15190885
TI  - Jacqueline Geoghegan.

PMID- 15190886
TI  - Osteoblast-like cells from estrogen receptor alpha knockout mice have deficient
      responses to mechanical strain.
AB  - INTRODUCTION: In vivo, bones' osteogenic response to mechanical loading involves
      proliferation of surface osteoblasts. This response is replicated in vitro and
      involves ERK-mediated activation of the estrogen receptor (ER) alpha and
      upregulation of estrogen response element activity. This proliferative response
      can be blocked by selective estrogen receptor modulators and increased by
      transfection of additional ERalpha. MATERIALS AND METHODS: We have now
      investigated the mechanisms of ER involvement in osteoblast-like cells' early
      responses to strain by comparing the responses of primary cultures of these cells
      derived from homozygous ERalpha knockout (ERKO) mice (ERalpha-/-) with those from
      their wildtype (ERalpha+/+) and heterozygous (ERalpha+/-) littermates and from
      ER/beta knockout (BERKO) mice (ERbeta+/+, ERbeta+/-, and ERbeta-/-). RESULTS:
      Whereas ERalpha+/+, ERalpha+/-, ERbeta+/+, and ERbeta-/- cells proliferate in
      response to a single 10-minute period of cyclic strain, ERalpha-/- cells do not.
      Transfection of fully functional, but not mutant, ERalpha rescues the
      proliferative response to strain in these cells. The strain-related response of
      ERalpha-/- cells is also deficient in that they show no increased activity of an
      AP-I driven reporter vector and no strain-related increases in NO production.
      Their strain-related increase in prostacyclin production is retained. They
      proliferate in response to fibroblast growth factor-2 but not insulin-like growth
      factor (IGF)-I or IGF-II, showing the importance of ERalpha in the IGF axis and
      the ability of ERalpha-/- cells to proliferate normally in response to a
      mitogenic stimulus that does not require functional ERalpha. CONCLUSIONS: These
      data indicate ERalpha's obligatory involvement in a number of early responses to
      mechanical strain in osteoblast-like cells, including those that result in
      proliferation. They support the hypothesis that reduction in ERalpha expression
      or activity after estrogen withdrawal results in a less osteogenic response to
      loading. This could be important in the etiology of postmenopausal osteoporosis.

PMID- 15190887
TI  - Aniru Conteh.

PMID- 15190888
TI  - Identification of novel genes of the bone-specific transcription factor Runx2.
AB  - INTRODUCTION: The transcription factor Runx2 is a key regulator of osteoblast
      development and plays a role in chondrocyte maturation. The identification of
      transcriptional target genes of Runx2 may yield insight into how osteoblastic
      differentiation is achieved on a molecular level. MATERIALS AND METHODS: Using a
      differential hybridization technique (selective amplification through biotin and
      restriction-mediated enrichment [SABRE]) and cDNA microarray analysis, 15
      differentially expressed genes were identified using mRNA from C3H 10Tl/2 cells
      with constitutive and inducible overexpression of Runx2. RESULTS AND CONCLUSIONS:
      Among the 15 genes identified, 4 encode the extracellular matrix proteins Ecml,
      Mgp, Fbn5, and Osf-2, three represent the transcription factors Esxl, Osrl, and
      Sox9, whereas others were Ptn, Npdc-1, Higl, and Tem l. The gene for Pttg1ip was
      upregulated in Runx2-expressing cells. Pttg1ip is widely expressed during
      development, but at highest levels in limbs and gonads. The Pttg1ip promoter
      binds Runx2 in a sequence specific manner, and Runx2 is able to transactivate the
      Pttg lip promoter in MC3T3-El cells. Therefore, Pttg1ip is likely tobe a novel
      direct transcriptional target gene of Runx2. In conclusion, the genes identified
      in this study are important candidates for mediating Runx2 induced cellular
      differentiation.

PMID- 15190890
TI  - Keywords in the history of medicine. Bacteria.

PMID- 15190891
TI  - A unique insertion/substitution in helix H1 of the vitamin D receptor ligand
      binding domain in a patient with hereditary 1,25-dihydroxyvitamin D-resistant
      rickets.
AB  - INTRODUCTION: Hereditary vitamin D--resistant rickets (HVDRR) is a genetic
      disorder caused by mutations in the vitamin D receptor (VDR). In this study, we
      examined the VDR in a young boy who exhibited the typical clinical features of
      HVDRR but without alopecia. MATERIALS AND METHODS: The patient's VDR was studied
      using cultured dermal fibroblasts, and the recreated mutant VDR was analyzed in
      transfected cells. RESULTS: The patient's fibroblasts were resistant to 1,25
      dihydroxyvitamin D [1,25(OH)2D3], exhibiting only a slight induction of 24
      hydroxylase gene expression when treated with 1 microM 1,25(OH)2D3 x
      [3H]1,25(OH)2D3 binding was absent in cell extracts from the patient's
      fibroblasts. Sequence analysis of the VDR gene uncovered a unique 5-bp deletion/8
      bp insertion in exon 4. The mutation in helix HI of the ligand-binding domain
      deletes two amino acids (H141 and T142) and inserts three amino acids (L141,
      W142, and A143). In transactivation assays, the recreated mutant VDR was 1000
      fold less active than the wildtype (WT) VDR. In glutathione S-transferase (GST)
      pull-down assays, the mutant VDR bound GST-retinoid X receptor (RXR) weakly in
      the absence of 1,25(OH)2D3; however, the binding did not increase with increasing
      concentrations of ligand. The mutant VDR did not bind to GST-vitamin D receptor
      interacting protein (DRIP) 205 at concentrations up to 1 microM 1,25(OH)2D3. We
      also examined effects of the three individual mutations on VDR transactivation.
      Only the insertion of A143 into the WT VDR disrupted VDR transactivation to the
      same extent observed with the natural mutation. CONCLUSION: We describe a novel
      insertion/substitution mutation in helix Hl of the VDR ligand-binding domain
      (LBD) that abolishes ligand binding and result in the syndrome of HVDRR. This is
      the first time an insertion/substitution has been found as the defect-causing
      HVDRR.

PMID- 15190892
TI  - The impact of cosmetic dermatology on skin care and cosmetics.

PMID- 15190893
TI  - Biochemical and bioengineering analysis of the skin's natural moisturizing
      factors.

PMID- 15190894
TI  - The use of anti-inflammatory actives in cosmetic formulations.

PMID- 15190895
TI  - The fibronectin network during aging: a missing cell connectivity.

PMID- 15190896
TI  - Improving antifungal activity of zinc pyrithione through particle coating
      technology.

PMID- 15190898
TI  - Topical vitamin E: what form and homologue of tocoherol matter?

PMID- 15190897
TI  - Optical characteristics of titanium oxide interference film and the film
      laminated with oxides and their applications for cosmetics.

PMID- 15190899
TI  - Cleansing and release by novel nanogel carriers.

PMID- 15190900
TI  - Advanced histological technology and three-dimensional imaging: a  fruitful
      partnership to visualize the human skin micro-anatomy and changes in cutaneous
      structures.

PMID- 15190901
TI  - [Teleradiology. Document approved by the Directive Council SIRM 18.12.2003].

PMID- 15190902
TI  - Puffy eyes: a multi-factoral cosmetic problem needs a multi-faceted solution.

PMID- 15190903
TI  - Categorical evaluation of the ocular irritancy of cosmetic and consumer products
      by human ocular instillation procedures.

PMID- 15190904
TI  - Mortality trend of hematologic and lymphatic malignancy (lymphoma, multiple
      myeloma and leukemia) in Japan: 1960-2000.

PMID- 15190905
TI  - [Molecular imaging: new frontier in diagnostic imaging].

PMID- 15190906
TI  - In vitro prediction of sunscreens' PFA values.

PMID- 15190907
TI  - Proceedings of the 5th Scientific and Educational Conference of the Polish
      Association for the Study of the Liver. May 10-11, 2002. Ozarow Mazowiecki,
      Poland.

PMID- 15190908
TI  - John Wyclif on body and mind.

PMID- 15190909
TI  - Darwinism, Christianity, and the great visisection debate.

PMID- 15190911
TI  - Modern chemical warfare: a history.

PMID- 15190910
TI  - A case study of the Lash's Bitters company - Advertising changes after the
      Federal Food and Drugs Act of 1906 and the Sherley Amendment of 1912.

PMID- 15190912
TI  - The smell of sleep.

PMID- 15190913
TI  - Abstracts of the 37th Annual Meeting of the Society for Epidemiologic Research.
      Salt Lake City, Utah, USA. June 15-18, 2004.

PMID- 15190914
TI  - Discovery of the anticoagulant drug warfarin.

PMID- 15190915
TI  - Hospital ships of the great war (1914-1918).

PMID- 15190917
TI  - Evolution of drug containers.

PMID- 15190916
TI  - Renal replacement.

PMID- 15190918
TI  - Further additions to the bibliography of Alfred Russel Wallace (1823-1913).
AB  - Twenty-one previously unrecorded published writings by the English naturalist
      Alfred Russel Wallace (1823-1913) are noticed. The writings vary greatly in date,
      size and importance, and include items pertaining both to Wallace's natural
      history as well as social and political interests

PMID- 15190919
TI  - Martin Lister (1639-1712) and fools' gold.
AB  - Seventeenth-century physician Martin Lister is best known for his work in natural
      history and participation in the early Royal Society. However, little attention
      has been focused upon Lister's work in chemistry, the most salient examples being
      his analysis of pyrites or "fools' gold" near mineral springs in the De Fonbibus
      medicatis Angliae Exercitatio of 1684 (Exercises on the healing springs of
      England), his contributions to the Philosophical Transactions in the 1670s and
      1680s, and his unpublished manuscript " A Method for the History of Iron,
      Imperfect." He defined pyrites more specifically as " ironstone marcasites" which
      were "nothing else but a body of iron disguised under a vitriolic varnish";
      "vitriol" referred to iron (II) sulfate which occurred as a weathering product of
      pyrites. This paper demonstrates that an understanding of Lister's work on
      pyrites and vitriol is best attained by placing him in the intellectual context
      of the seventeenth-century chemical debate about minerallogenesis. Lister
      believed that the volatile exhalations of pyrites and its vitriol in the air were
      important in the transformation of matter, and he subscribed to the sixteenth-and
      seventeenth-century theory of witterung (weathering) or ore exhalations as an
      explanation for the formation of minerals. Despite his allegiance to the theories
      of witterung, I will illustrate that Lister made use of his interests in natural
      history to go one step beyond them, postulating that the sulfurous exhalations
      from pyrites were responsible for the heating of hot springs, as well as
      meteorological and geological effects.

PMID- 15190920
TI  - On judgment, impact factor and feelings: what can we learn from the impact
      factor?

PMID- 15190921
TI  - Palaeobiology: Dutch diaries and the demise of the dodo.

PMID- 15190922
TI  - Private long-term care insurance: the Medicaid interaction.
AB  - Does long-term care insurance help purchasers preserve their assets and avoid
      Medicaid? The purpose of this issue brief is to explore the complex interaction
      of Medicaid and private long-term care insurance and highlight the policy
      implications for those who may "fall through the cracks" in their coverage.

PMID- 15190923
TI  - Anchors away: the Food and Drug Administration's use of disgorgement abandons
      legal moorings.

PMID- 15190924
TI  - The First Amendment and federal court deference to the Food and Drug
      Administration: The Times They Are A-Changin'.

PMID- 15190925
TI  - Managing physician financial conflicts of interest in clinical trials conducted
      in the private practice setting.

PMID- 15190926
TI  - Shrinking waters in the safe harbor: has Integra Lifesciences v. Merck turned the
      tide by narrowing available exempted infringing uses?

PMID- 15190927
TI  - Legal strategies to address the misrepresentation of Vermont maple syrup.

PMID- 15190928
TI  - European opposition to exclusive control over predictive breast cancer testing
      and the inherent implications for U.S. patent law and public policy: a case study
      of the Myriad Genetics' BRCA patent controversy.

PMID- 15190929
TI  - Old drugs, new uses: solving a Hatch-Waxman patent predicament.

PMID- 15190930
TI  - Edaravone inhibits acute renal injury and cyst formation in cisplatin-treated rat
      kidney.
AB  - BACKGROUND: Although cis-diamminedichloroplatinum (II) (cisplatin) is an
      effective anticancer agent, its clinical use is highly limited predominantly due
      to its adverse effects on renal functions. The present work examined the
      therapeutic potential of edaravone, a free radical scavenger, for inhibiting
      cisplatin-induced renal injury. METHODS: Edaravone, 3-methyl-1-phenyl-pyrazolin-5
      one, was administrated intravenously at a dose of 30 mg/kg of body weight to male
      Wistar rats (200-220 g). After 30 min, cisplatin was injected intraperitoneally
      at a dose of 5 mg/kg of body weight. At the indicated times after the treatment,
      functions and histological changes of the kidney were analyzed. To test the
      therapeutic potential of edaravone in chemotherapy, its effect on the anticancer
      action of cisplatin was examined in ascites cancer-bearing rats. RESULTS: We
      found that cisplatin rapidly impaired the respiratory function and DNA of
      mitochondria in renal proximal tubules, thereby inducing apoptosis of tubular
      epithelial cells within a few days and chronic renal dysfunction associated with
      multiple cysts one-year after the administration. Administration of edaravone
      inhibited the cisplatin-induced acute injury of mitochondria and their DNA and
      renal epithelial cell apoptosis as well as the occurrence of chronic renal
      dysfunction and multiple cyst formation. The anticancer effect of cisplatin
      remained unaffected by intravenous administrating of edaravone. CONCLUSIONS:
      These results indicate that edaravone may have therapeutic potential for
      inhibiting the acute and chronic injury of the kidney induced by cisplatin.

PMID- 15190932
TI  - Reactions of superoxide radicals with curcumin: probable mechanisms by optical
      spectroscopy and EPR.
AB  - Reactions of superoxide-crown ether complex with curcumin have been studied in
      acetonitrile. Optical absorption spectra showed that curcumin on reaction with
      superoxide forms a blue color intermediate absorbing at 560 nm, which
      subsequently decayed in a few hours with the development of the absorption band
      corresponding to the parent curcumin. The regeneration was 100% at low superoxide
      concentrations (1:1, or 1:2 or 1:3 of curcumin:superoxide) but reduced to 60% at
      high superoxide concentration (>1:5). The regeneration of curcumin is confirmed
      by HPLC analysis. Stopped-flow studies in acetonitrile following either the decay
      of parent curcumin at 420 nm or formation of 560 nm absorption have been used to
      determine the rate constant for the reaction of superoxide with curcumin. EPR
      studies confirmed the disappearance of characteristic superoxide signal in
      presence of curcumin with the formation of new featureless signal with g =
      2.0067. Based on these studies it is concluded that at low superoxide
      concentrations curcumin effectively causes superoxide dismutation without itself
      undergoing any chemical change. At higher concentrations of superoxide, curcumin
      inhibits superoxide activity by reacting with it.

PMID- 15190931
TI  - Reaction of peroxynitrite with hyaluronan and related saccharides.
AB  - The effects of peroxynitrite on hyaluronan has been studied by using an
      integrated spectroscopical approach, namely electron paramagnetic resonance
      (EPR), nuclear magnetic resonance (NMR), and mass spectrometry (MS). The reaction
      has been performed with the polymer, the tetrasaccharide oligomer as well as with
      the monosaccharides N-acetylglucosamine and glucuronic acid. The outcome of the
      presence of molecular oxygen and carbon dioxide has been also evaluated. Although
      1H-NMR and ESI-MS experiments did not revealed peroxynitrite-mediated
      modification of hyaluronan as well as of related saccharides, from spin-trapping
      EPR experiments it was concluded that peroxynitrite induce the formation of C
      centered carbon radicals, most probably by the way of its hydroxyl radical-like
      reactivity. These EPR data support the oxidative pathway involved in the
      degradation of hyaluronan, a probable event in the development and progression of
      rheumatoid arthritis.

PMID- 15190933
TI  - Enhancement of radiation-induced apoptosis by 6-formylpterin.
AB  - Radiation-induced apoptosis and its possible enhancement in the presence of 6
      formylpterin (6-FP), a metabolite of folic acid, were examined in human
      myelomonocytic lymphoma U937 cells. When cells were treated with 6-FP at a
      nontoxic concentration of 300 microM, and then exposed to X-rays at a dose of 10
      Gy, significant enhancement of radiation-induced apoptosis as determined by
      nuclear morphological change, phosphatidylserine (PS) externalization and DNA
      fragmentation were observed. Flow cytometry for the detection of intracellular
      hydrogen peroxide (H2O2) revealed that 6-FP increased the formation of
      intracellular H2O2, which further increased when the cells were irradiated.
      Decrease of mitochondria trans-membrane potential (MMP), release of cytochrome c
      from mitochondria, and activation of caspase-3 were enhanced after the combined
      treatment. Remarkable activation of protein kinase C delta (PKC delta) and its
      translocation from cytosol to mitochondria were detected in combined treatment.
      Increase of intracellular Ca2+ concentrations ([Ca2+]i) was also observed,
      however, neither calpain I nor calpain II could inhibit the apoptosis. In
      addition, c-Jun NH2-terminal kinase (JNK) activation was not enhanced in the
      combined treatment. A protein involved in a caspase-independent apoptosis
      pathway, apoptosis inducing factor (AIF), remained unchanged even 3 h after
      treatment. These results indicate that intracellular H2O2 generated by 6-FP
      enhances radiation-induced apoptosis via the mitochondria-mediated caspase
      dependent pathway, with the active involvement of PKC delta.

PMID- 15190935
TI  - Hydroxyl radical generation caused by the reaction of singlet oxygen with a spin
      trap, DMPO, increases significantly in the presence of biological reductants.
AB  - Photosensitizers newly developed for photodynamic therapy of cancer need to be
      assessed using accurate methods of measuring reactive oxygen species (ROS).
      Little is known about the characteristics of the reaction of singlet oxygen (1O2)
      with spin traps, although this knowledge is necessary in electron spin resonance
      (ESR)/spin trapping. In the present study, we examined the effect of various
      reductants usually present in biological samples on the reaction of 1O2 with 5,5
      dimethyl-1-pyrroline-N-oxide (DMPO). The ESR signal of the hydroxyl radical (*OH)
      adduct of DMPO (DMPO-OH) resulting from 1O2-dependent generation of *OH
      strengthened remarkably in the presence of reduced glutathione (GSH), 6-hydroxy
      2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), ascorbic acid, NADPH, etc.
      A similar increase was observed in the photosensitization of uroporphyrin (UP),
      rose bengal (RB) or methylene blue (MB). Use of 5-(diethoxyphosphoryl)-5-methyl-1
      pyrroline-N-oxide (DEPMPO) as a spin trap significantly lessened the production
      of its *OH adduct (DEPMPO-OH) in the presence of the reductants. The addition of
      DMPO to the DEPMPO-spin trapping system remarkably increased the signal intensity
      of DEPMPO-OH. DMPO-mediated generation of *OH was also confirmed utilizing the
      hydroxylation of salicylic acid (SA). These results suggest that biological
      reductants enhance the ESR signal of DMPO-OH produced by DMPO-mediated generation
      of *OH from 1O2, and that spin trap-mediated *OH generation hardly occurs with
      DEPMPO.

PMID- 15190934
TI  - Application of water-soluble radical initiator, 2,2'-azobis[2-(2-imidazolin-2
      yl)propane] dihydrochloride, to a study of oxidative stress.
AB  - It is essential to generate free radicals at a controled and constant rate for
      specific duration and at specific site to study the dynamics of oxidation and
      also antioxidation. Both hydrophilic and lipophilic azo compounds have been used
      for such purpose. In the present work, the action of 2,2'-azobis[2-(2-imidazolin
      2-yl)propane] dihydrochloride (AIPH) was examined and compared with those of 2,2'
      azobis(2-amidinopropane) dihydrochloride (AAPH) and 2,2'-azobis[2-methyl-N-(2
      hydroxyethyl)-propionamide] (AMHP). The rate constant of free radical formation
      (ek(d)) for AIPH was 2.6 x 10(-6)/s at 37 degrees C in PBS (pH 7.4) solution,
      indicating that AIPH gives 3.8 times more free radicals than AAPH under the same
      conditions. It was found that the dynamics of oxidation and antioxidation induced
      by AIPH can be studied satisfactorily in the oxidation in micelles, LDL and
      erythrocyte suspensions, plasma, and cultured cells. The extent of cell death
      induced by AIPH and AAPH was directly proportional to the total free radicals
      formed. Interestingly, it was found that rats would not drink water containing
      AAPH, but they drank water containing AIPH. The levels of 8-iso-prostaglandin
      F2alpha (8-isoPs), 7-hydroxycholesterol (FCOH), lysophosphatidylcholine in the
      plasma of rats given water containing 50 mM AIPH for 1 month increased compared
      with those of control rats which drank water without AIPH. It may be concluded
      that AIPH is useful for kinetic and mechanistic studies on oxidative stress to
      membranes, lipoproteins, cells, and even animal models.

PMID- 15190936
TI  - Modification of sheep plasma kininogen by free radicals.
AB  - Riboflavin sensitized photodynamic modifications of high molecular weight
      Kininogen (HMWK) isolated from sheep (Avis-arias) plasma leads to inactivation of
      antiproteinase activity and formation of aggregated products. A continued
      disappearance of the inhibitory activity towards papain and formation of high
      molecular weight adducts was observed with increasing concentration of riboflavin
      and varying time periods of incubation reaching a maximum value of over 85% (loss
      in activity). Aggregates resisted dissociation upon heating at 100 degrees C in
      1% SDS. Aggregation and photoinactivation of HMWK was promoted by the
      substitution of H2O for deuterium oxide (D2O), which is known to prolong the life
      span of singlet oxygen, and suppressed by sodium azide a known singlet oxygen
      quencher. Mannitol and thiourea (hydroxyl radical scavenger) did not protect the
      antiproteinase activity of HMWK. Treatment with reducing agent resulted in
      decrease of the aggregated products suggesting the possible involvement of
      disulfide linkages in protein crosslinking. Tryptophan fluorescence was
      completely lost and significant production of dityrosine was detected in
      photoinactivated HMWK aggregates. Changes in the far Ultra violet circular
      dichroism (u.v.c.d.) spectrum of HMWK was indicative of loss of secondary
      structure. Analysis of modifications induced in HMWK by riboflavin reveals that
      the processes proceed via a singlet oxygen mediated pathway. It is concluded that
      the susceptibility of HMWK to oxidation may arise from oxidative modifications by
      reactive oxygen species generated in plasma.

PMID- 15190937
TI  - Involvement of NADPH oxidase-mediated generation of reactive oxygen species in
      the apototic cell death by capsaicin in HepG2 human hepatoma cells.
AB  - Although capsaicin (8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient in a
      variety of red peppers of the genus Capsicum, has been shown to induce apoptotic
      cell death in many cancer cells, the exact mechanism of this action of capsaicin
      is not completely understood. In this study, we investigated the possible
      mediation of the NADPH oxidase-modulated production of reactive oxygen species
      (ROS) in the apoptotic mechanism of capsaicin in HepG2 human hepatoblastoma
      cells. Capsaicin induced apoptotic cell death in a time- and dose-dependent
      manner. Capsaicin at the concentration of inducing apoptosis also markedly
      increased the level of ROS. The capsaicin-induced generation of ROS and apoptosis
      was significantly suppressed by treatment with antioxidants, DPPD and tocopherol.
      In addition, inhibitors of NADPH oxidase, diphenylene iodonium, apocynin and
      neopterine, profoundly blocked the capsaicin-induced ROS generation and
      apoptosis. The expression of Rac1N17, a dominant negative mutant of Rac1, also
      significantly inhibited the capsaicin-induced apoptosis. Activation of nuclear
      factor-kappaB, a transcription factor essentially involved in ROS-induced
      apoptosis, was also observed by treatment with capsaicin. Collectively, these
      results suggest that the NADPH oxidase-mediated generation of ROS may be
      essentially involved in the mechanism of capsaicin-induced apoptosis in HepG2
      cells. These results further suggest that capsaicin may be a valuable agent for
      the therapeutic intervention of human hepatomas.

PMID- 15190938
TI  - Localization of alpha-tocopherol transfer protein in trophoblast, fetal
      capillaries' endothelium and amnion epithelium of human term placenta.
AB  - Vitamin E has been linked to fertility since its discovery in 1922. However, the
      exact mechanism by which alpha-tocopherol allows pregnancy to continue until term
      has remained puzzling over the last 80 years. Alpha-tocopherol transfer protein
      (TTPA) is expressed in liver and in Purkinje cells of the cerebellum. TTPA is
      suggested to be responsible for the transfer of alpha-tocopherol across barrier
      membranes. Ttpa-knockout mice are infertile and show symptoms similar to those
      observed in severe vitamin E deficiency. We thus investigated TTPA expression in
      human placenta and whether clues from its localization in different parts of the
      placenta might be of functional significance. TTPA-mRNA transcripts were
      quantified with a fluorescent 5'-nuclease assay (TaqMan) in five different
      tissues. Placental expression ranged second behind that of liver.
      Immunohistochemistry identified TTPA in the cytosol but also in nuclei of the
      trophoblast and in the endothelium of the fetal capillaries. Expression in
      trophoblast and fetal capillaries' endothelium indicates a role of TTPA in the
      stereoselective transport of RRR-alpha-tocopherol from the maternal to the fetal
      plasma. In amnion epithelial cells, however, TTPA was predominantly located in
      the nuclei. Nuclear localization of the protein may represent a novel function of
      TTPA.

PMID- 15190939
TI  - Activities of the enzymes of hepatic gluconeogenesis in periparturient dairy cows
      with induced fatty liver.
AB  - The objective was to measure the activities of all the enzymes essential for
      hepatic gluconeogenesis in dairy cows with induced fatty liver. We aimed to
      induce severe fatty liver in ten experimental cows by overfeeding them during the
      dry period while seven control cows were maintained on a restricted diet. To
      induce a marked negative energy balance, the experimental cows were deprived of
      feed for 8 h immediately after parturition. In addition, the experimental cows
      were given a restricted amount of diet during the first 5 d of lactation. Liver
      samples were collected 1 week before and 1, 2 and 4 weeks after parturition.
      Before parturition, liver triacylglycerol concentrations did not differ between
      the two groups. After parturition, the experimental cows developed marked fatty
      liver as indicated by a higher level of triacylglycerols in the liver compared
      with the control cows. Before parturition, all gluconeogenic enzymes in the liver
      were lower in experimental cows than in control cows. Phosphoenolpyruvate
      carboxykinase, pyruvate carboxylase and propionyl-CoA carboxylase were
      significantly lower and fructose 1,6-bisphosphatase and glucose 6-phosphatase
      tended to be lower in the experimental cows. The activities of two crucial
      enzymes for gluconeogenesis in ruminants, i.e., phosphoenolpyruvate carboxykinase
      and propionyl-CoA carboxylase, remained low throughout the sampling period post
      partum. Activities of pyruvate carboxylase and glucose 6-phosphatase in the
      experimental cows post partum were upgraded to values similar to those of the
      control cows. The results showed that the capacity for hepatic gluconeogenesis
      before parturition was lower in cows with induced fatty liver than in control
      cows. After parturition, the low activities of crucial gluconeogenic enzymes
      indicated insufficient production of glucose. It is suggested that the low
      gluconeogenic capacity leads successively to low blood glucose concentrations,
      low insulin levels and high rates of mobilization of fatty acid, causing severe
      hepatic lipidosis.

PMID- 15190940
TI  - Hormone-dependent milk protein gene expression in bovine mammary explants from
      biopsies at different stages of pregnancy.
AB  - A method for the collection of mammary biopsies developed previously was refined
      and used to study the endocrine regulation of bovine milk protein gene
      expression. Our surgical biopsy method used real-time ultrasound imaging and
      epidural analgesia to enable recovery of a sufficient quantity of mammary tissue
      from late-pregnant dairy cows for explant culture in vitro. The time of biopsy
      was critical for prolactin-dependent induction of milk protein gene expression in
      mammary explants, as only mammary tissue from cows nearing 30 d prepartum was
      hormone-responsive. This suggests that during the later stages of pregnancy a
      change in the responsiveness of milk protein gene expression to endocrine stimuli
      occurred in preparation for lactation. This may relate to the diminution of a
      putative population of undifferentiated cells that were still responsive to
      prolactin. Alternatively, the metabolic activity of the tissue had increased to
      the level whereby the response of the tissue was no longer assessable using this
      model in vitro.

PMID- 15190941
TI  - Metabolic safety-margins do not differ between cows of high and low genetic merit
      for milk production.
AB  - Three galactopoietic stimuli, frequent milking (4X), bovine somatotrophin (bST)
      and thyroxine (T4) were used in an additive stair-step design to achieve maximum
      output (metabolic capacity) in six peak-lactation cows of high genetic merit (HT)
      and six of low genetic merit (LT). A further six of each merit were untreated
      controls (HC, LC). Milk yield was increased significantly by 4X, increased
      further by the combination of 4X and bST and increased further still and
      significantly by the full combination of 4X, bST and T4. The magnitude of the
      yield response to the sequence of treatments did not differ significantly between
      HT and LT. The yield response to 4X and bST was sustainable without significant
      loss of body weight or body condition score for the 6 weeks during which these
      stimuli were administered. The response to the full combination, which included
      T4, was accompanied by significantly elevated heart rate and significant loss of
      body weight and condition compared with the combination of 4X and bST. As a
      result, treatments were discontinued, on an individual cow basis, before
      completion of this 6-week phase. Time on experiment did not differ between HT and
      LT. The results do not support the commonly held belief that selective breeding
      of dairy cows for high milk production has rendered them markedly more
      susceptible to metabolic disturbances.

PMID- 15190942
TI  - Effect of recombinant cytokines on leucocytes and physiological changes in bovine
      mammary glands during early involution.
AB  - We examined the effects of administering recombinant bovine cytokines to non
      lactating dairy cows and measured mammary gland leucocytes and the involution
      process. After the final milking, groups of cows were given an intramammary
      infusion of cytokine in two quarters. These cytokines were recombinant bovine
      interleukin-2 (rbolL-2) (2 x 10(5) units, n = 6), recombinant bovine granulocyte
      macrophage colony stimulating factor (rboGM-CSF) (500 microg, n = 4) and
      recombinant bovine interleukin-1beta (rbolL-1beta) (10 microg, n = 10). Each
      animal also received an infusion of phosphate-buffered saline (PBS) in the other
      two quarters as controls. The rbolL-2 and rboGM-CSF were produced in a yeast
      expression system, while rbolL-1beta was produced in Escherichia coli. Leucocyte
      numbers, bactericidal activity of leucocytes, and concentrations of citrate and
      lactoferrin in quarter secretion samples were monitored after infusion of
      cytokine or PBS. Infusion of rbolL-2 had minimal effect on leucocyte numbers and
      concentrations of citrate and lactoferrin. Both rboGM-CSF and rbolL-1beta induced
      a rapid increase in the number of neutrophils and macrophages compared with
      control PBS quarters. Concentrations of lactoferrin in secretions were increased
      by rboGM-CSF and rbolL-1beta compared with control PBS quarters. In addition,
      infusion of glands with rbolL-1beta lowered the citrate:lactoferrin molar ratio
      compared with PBS control quarters. The results indicate that intramammary
      infusion of either rboGM-CSF or rbolL-1beta at cessation of milking immediately
      increased the number of phagocytic cells in the gland. These cytokines, in
      particular rbolL-1beta, also increased the rate of mammary gland involution
      during the early dry period.

PMID- 15190943
TI  - Mammary cisternal size, cisternal milk and milk ejection in Murrah buffaloes.
AB  - The internal arrangement of the mammary gland cavity system, cisternal and
      alveolar milk fractions and the characteristics of milk ejection were
      investigated in buffaloes. Twenty-four Murrah buffaloes in three different stages
      of lactation and of two age groups were used. Continuous ultrasound cross
      sections during milk ejection induced by exogenous oxytocin were performed to
      record the latency period of milk ejection. Buffaloes had small cisterns and the
      cavity area in the teat and gland regions were not significantly different (P >
      0.05). The animals had long teat canals (3.1 +/- 0.1 cm), longer in the hind than
      fore quarters. Cisternal milk yield was low (0.17 +/- 0.01 kg) and cisternal
      fraction was only 4.9 +/- 0.1% of the total milk. The cisternal area (cm2) was
      69.6 +/- 4.6, 51.61 +/- 4.8 and 26.01 +/- 4.8 while the cisternal yield (kg) was
      0.32 +/- 0.05, 0.18 +/- 0.05 and 0.05 +/- 0.05 in early, mid and late lactation,
      respectively. A close correlation (r = 0.87, P < 0.05) existed between the
      ultrasound cisternal area and cisternal milk yield. The latency period of induced
      milk ejection was similar to that reported for cows (25 +/- 1 s) and was
      negatively correlated with milk yield (r = -0.75, P < 0.05). Milk ejection
      occurred shortly after elevated oxytocin concentrations were present. Delayed
      milk ejection reported earlier in this species must therefore be due to the
      absence of cisternal milk and delayed oxytocin release. An increase in teat
      length and circumference at milk ejection was also evident in the ultrasound
      cross sections.

PMID- 15190944
TI  - Influence of intramammary infection and non-infection factors on somatic cell
      counts in dairy goats.
AB  - A total of 1304 goat udder halves were sampled monthly during an entire lactation
      (6262 samples) with the aim of identifying factors affecting milk somatic cell
      count (SCC). Bacteriological analyses for identification of mastitis pathogens
      were carried out on all samples and SCC was also determined. All animals were
      examined for infection by caprine arthritis-encephalitis virus (CAEV) using a
      commercial ELISA test kit. Results obtained were arranged in two databases (whole
      lactation average half-udder database and monthly half-udder database) and two
      mixed models were applied. Random effects of half udder nested into flock and
      fixed effects of flock, intramammary infection (IMI) status, number of kids born,
      length of lactation and interaction of parity with IMI status were significant
      for the first database. CAEV infection and its interaction with IMI status was
      not significant. Milk SCC was significantly increased for infected udder halves
      and milk from udder halves infected with minor pathogens had lower SCC than udder
      halves infected with major pathogens. For healthy udder halves, SCC was higher in
      older animals but this effect was not evident in halves with IMI. Multiple birth
      and short-duration lactation were factors associated with elevated milk SCC. The
      second mixed model considered repeated measures in time for consecutive samplings
      throughout lactation (stage of lactation) which was also a significant factor
      with increasing stage of lactation. The influence of all these factors should be
      taken into account in the establishment of more reliable diagnostic SCC
      thresholds for IMI.

PMID- 15190945
TI  - Milk L-lactate concentration is increased during mastitis.
AB  - A study was undertaken in cattle to evaluate changes in milk L-lactate in
      relation to mastitis. A healthy, rear quarter of the udder of each of ten cows in
      mid-lactation was infused with 1000 colony-forming units (cfu) of Streptococcus
      uberis following an afternoon milking. Foremilk samples were taken at each
      milking from control and treated quarters and antibiotic treatment was applied
      following the onset of clinical mastitis or after 72 h. One cow did not become
      infected. Six quarters showed clinical symptoms of mastitis within 24-40 h and
      this was associated with a more than 30-fold increase in milk L-lactate (to 3.3
      mM) and an increase in somatic cell count (SCC) from 4.5 x 10(3) to 1 x 10(7)
      cells/ml. Three cows were subclinical, with cell counts ranging from 1.5 x 10(6)
      to 1 x 10(7) cells/ml. In these animals, milk lactate ranged from 0.7 to 1.5 mM
      in the infected quarters up to 40 h post-infection, compared with less than 0.1
      mM in control quarters. Milk was examined from 137 cows in mid-lactation which
      were known to have mastitis. Foremilk samples were taken aseptically from control
      and infected quarters of cows on commercial farms. Mean milk L-lactate
      concentrations and SCC were 0.14 +/- 0.02 mM and 1.85 +/- 0.3 x 10(5) cells/ml,
      respectively, in control (bacteriologically negative) samples. However, L-lactate
      concentrations exceeded 2.5 mM in the presence of some types of infection, the
      level of the lactate response being closely related to the impact of the
      infection on SCC. L-Lactate concentrations were relatively elevated in milk
      samples taken post partum, declining from 0.8 to 0.14 mM oyer the first few days
      of lactation. In conclusion, milk L-lactate has potential as an indicator of
      clinical and subclinical mastitis in dairy cows.

PMID- 15190946
TI  - DGAT1 polymorphism in Bos indicus and Bos taurus cattle breeds.
AB  - As a result of multiple QTL-mapping projects in recent years, a quantitative
      trait locus for milk fat percentage and milk yield has been described on BTA14.
      Recent reports name the acyl-CoA : diacylglycerol acyltransferase (DGAT1) gene on
      BTA14 as a potential candidate gene, with a nonconservative substitution of
      lysine by alanine (K232A) producing a major effect on milk composition and yield.
      DGAT1K appears to be the ancestral allele and the K232A substitution probably
      occurred after the divergence of the Bos indicus and Bos taurus lineages. These
      findings prompted us to genotype 1748 DNA samples of 38 different Bos taurus and
      Bos indicus cattle breeds from 13 countries on five continents (Europe, Africa,
      Asia, North America and South America), to examine the occurrence of the DGAT1
      polymorphism and characterize the K232A substitution in cattle breeds of
      different origins and selected for different purposes (e.g., beef, dairy and dual
      purpose). Calculating pairwise FST values for pooled subpopulations showed least
      divergence for Bos indicus breeds with high milk fat percentage. Fixation of
      DGAT1A was found in some Bos taurus breeds and fixation of DGAT1K in one Bos
      indicus breed. Breeds of no known organized breeding background from the Near
      East domestication centre of Bos taurus and taurine African N'Dama cattle were
      found to possess intermediate frequencies of DGAT1K. While beef breeds tended to
      harbour higher DGAT1A levels, dairy cattle showed everything from very low levels
      of DGAT1K to unexpectedly high frequencies of this allele.

PMID- 15190947
TI  - High polymorphism in the kappa-casein (CSN3) gene from wild and domestic caprine
      species revealed by DNA sequencing.
AB  - We assessed polymorphisms in exon IV of the kappa-casein gene (CSN3) in ten
      different breeds of domestic goat (Capra hircus) from three continents and in
      three related wild caprine taxa (Capra <ibex> ibex, Capra <ibex> sibirica and
      Capra aegagrus). Thirty-five DNA samples were sequenced within a 558 bp fragment
      of exon IV. Nine polymorphic sites were identified in domestic goat, including
      four new polymorphisms. In addition to four previously described polymorphic
      positions, a total of 13 polymorphisms allowed the identification of 13 DNA
      variants, corresponding to 10 protein variants. Because of conflicting
      nomenclature of these variants, we propose a standardized allele designation.
      CSN3*A, CSN3*B, and CSN3*D were found as widely distributed alleles in European
      goat breeds. Within Capra ibex we identified three variants and showed that the
      sequence of Capra aegagrus is identical to the most common Capra hircus variant,
      consistent with Capra aegagrus being the wild progenitor of domestic goats. A
      dendrogram was drawn to represent the molecular network between the caprine CSN3
      variants.

PMID- 15190948
TI  - The influence of oxidation on proteolysis in raw milk.
AB  - The link between oxidation and increased proteolysis in raw milk was studied. To
      accelerate oxidation, H2O2 (1 mM) was added to raw milk, resulting in enhanced
      proteolysis by up to 11.2% after 24 h incubation at 5 degrees C. Addition of Cu2+
      (10 microM) to milk or exposure of milk to light (60 min) likewise increased
      proteolysis. To explain the mechanism responsible for increased proteolysis as a
      result of oxidation, the effect of lipid oxidation products on plasmin-induced
      proteolysis was tested. Addition of malondialdehyde to skim milk increased the
      formation of gamma-caseins, a proteolysis product from plasmin hydrolysis of beta
      casein. The same observation was made in a model system containing 4.5 g beta
      casein/l sodium tetraborate buffer at pH 8 and plasmin. Addition of a plasmin
      inhibitor blocked the formation of gamma-casein. The results indicate that
      aldehydes accumulated from lipid oxidation can modify beta-casein and thereby
      increase susceptibility of the proteins to proteolysis. Furthermore, the data
      suggest that proteolysis in raw milk may be connected to oxidative processes.

PMID- 15190949
TI  - Bovine milk composition parameters affecting the ethanol stability.
AB  - The objective of the present work was to identify the compositional parameters of
      raw milk that affected ethanol stability at natural pH when natural milk
      conditions were not modified. Heat stability, measured as coagulation time (CT),
      was included in the analysis to verify relation to alcohol test. Statistical
      models were proposed for alcohol and heat (CT) stabilities. Milk samples of good
      hygienic quality from dairy farms were classified in two groups according to
      their alcohol stability. Unstable samples to ethanol (72%, v/v) presented lower
      values of pH, somatic cells count, casein and non-fat-solids relative to ethanol
      stable samples (ethanol at 78%, v/v or more); whereas freezing point, chloride,
      sodium and potassium concentrations were higher in the unstable group. Logistic
      regression and multiple regression were applied to modelling alcohol and heat
      stability behaviour respectively. Chloride, potassium, ionic calcium and somatic
      cell count were included in the alcohol regression model, whereas calcium,
      phosphorous, urea, pH and ionic calcium were part of CT model. Ionic calcium was
      the only measured variable that contributed to both models; however coagulation
      time was noted to be more sensitive to ionic calcium than alcohol. The relation
      between ionic strength and casein was found to contribute to the alcohol model
      but not to the CT model. However, the interaction calcium plus magnesium plus
      phosphorous and casein contributed only to CT model.

PMID- 15190950
TI  - Thermal stability of beta-lactoglobulins A and B: effect of SDS, urea, cysteine
      and N-ethylmaleimide.
AB  - Fourier transform infrared spectroscopy (FTIR) and differential scanning
      calorimetry (DSC) were used to monitor changes in the secondary structure and
      thermal stability of beta-lactoglobulin A and B in the presence of sodium dodecyl
      sulphate (SDS), N-ethylmaleimide (NEM), urea and cysteine. An increase in the
      thermal stabilities of both proteins was noted in the presence of 10 mM-SDS. In
      the presence of 50 mM-SDS, there was extensive denaturation of both variants. In
      general, the beta-strand/beta-sheet regions in the secondary structure of both
      variants were very susceptible to denaturation by SDS and cysteine, suggesting
      that these regions may be held by hydrophobic and disulphide bonds. At ambient
      temperature and physiological pH, a notable difference was observed in the 1636
      and 1627 cm(-1) regions of the FTIR spectra of the two beta-lg variants. The
      results suggest possible differences in the nature of the beta-sheet/beta-strand
      distribution/ content of the two proteins. Urea and NEM at a concentration of 50
      mM, had little effect on the secondary structure and denaturation of both
      variants. New findings are presented which further indicate that although the
      beta-lg B variant showed greater thermal stability than the A variant in all the
      cases studied, its denaturation temperature and secondary structure were affected
      to a greater extent by the protein perturbants than beta-lg A.

PMID- 15190951
TI  - High-level coproduction of the bacteriocins nisin A and lactococcin A by
      Lactococcus lactis.
AB  - In this study, a two-plasmid system for enhanced and consistent biosynthesis of
      the model lactococcal bacteriocin lactococcin A in non-producing Lactococcus
      lactis hosts was developed. The system comprised a plasmid carrying the genes
      lcnA and lciA under the control of the nisin-inducible nisA promoter, and a
      second plasmid harbouring the lcnC and lcnD genes. The introduction of both
      plasmids into two strains containing the nisRK genes required for nisin
      controlled expression, Lc. lactis FI5876 (a nisin A-producer strain) and FI7847,
      resulted in production of extracellular lactococcin A at a higher level than that
      for the parental strain, Lc. lactis WM4. In addition, transformation of the nisin
      producing host with both plasmids led to a high-level production of both
      lactococcal bacteriocins, which may provide a means to exploit their
      complementary properties in cheese ripening.

PMID- 15190952
TI  - Lactobacilli isolated from kefir grains: evidence of the presence of S-layer
      proteins.
AB  - In the present study we report for the first time the presence of S-layer
      proteins in Lactobacillus kefir and Lactobacillus parakefir isolated from kefir
      grains. Soluble whole-cell protein profile obtained either by mechanical
      disruption (X-press) or by a combined treatment with lysozyme and SDS on whole
      cells, showed a significant band of apparent molecular mass of 66-71 kDa as
      measured by SDS-PAGE. The intensity of this band was considerably reduced when
      cells were treated with 5 M-LiCl. The above mentioned proteins were recovered in
      the LiCl extracts. After dialysis and concentration, the proteins extracted were
      able to reassemble in a regular array. Negative staining of these protein
      preparations were analysed by transmission electron microscopy and a
      paracrystalline arrangement was seen. Thin sections of bacteria analysed by
      transmission electron micrographs showed an outermost layer over the bacterial
      cell wall, that was lost after the LiCl treatment. The production of this surface
      structure under different culture conditions was also evaluated. Finally, the
      relationship between the presence of S-layer proteins and surface properties
      (e.g. adhesion to Caco-2 cells, autoaggregation, and hemagglutination) was
      investigated.

PMID- 15190953
TI  - Diversity of lactic acid bacteria isolated from AOC Salers cheese.
AB  - The objective of this work was to describe the diversity of lactic acid bacteria
      in traditional raw milk Salers cheeses at the species and strain levels. The
      characterization of 381 strains isolated during ripening and various strain
      collections was investigated using physiological analysis and molecular
      techniques: Rep-PCR, species and genus specific amplifications and the sequence
      analysis of 16S rDNA for strain typing and taxonomic identification. The strains
      belonged to Lactobacillus plantarum, Lactobacillus paracasei, Lactococcus lactis,
      Lactococcus garviae, Enterococcus faecalis, Enterococcus faecium, Leuconostoc
      mesenteroides, Leuconostoc pseudomesenteroides, Streptococcus salivarius,
      Streptococcus millieri, Streptococcus macedonicus and Pediococcus pentosaceus. A
      wide phenotypic and genomic heterogeneity was observed within the different
      species (Lactobacillus plantarum, Lactobacillus paracasei and Leuconostoc
      mesenteroides) according to the origin and the time of ripening. The natural
      microflora was different from strain collection and each method must be combined
      to identify and characterize natural microflora. This study revealed the low
      selectivity of selective media used for the isolation of different groups of
      lactic acid bacteria except the Facultatively Heterofermentative lactobacilli
      medium selecting mesophile lactobacilli and SB medium selective for Enterococcus.
      The study reveals, for the first time, the microbial lactic acid bacteria
      community of Salers cheese and its diversity. A better knowledge of microbial
      flora will be useful to improve understanding of sensory quality of cheeses.

PMID- 15190955
TI  - How teat canal keratin depends on the length and diameter of the teat canal in
      dairy cows.

PMID- 15190954
TI  - Evaluation of biogenic amines and microbial counts throughout the ripening of
      goat cheeses from pasteurized and raw milk.
AB  - The effect of the hygienic quality of milk on changes in microbial counts and
      biogenic amine content was evaluated during ripening of goat cheeses manufactured
      from pasteurized and raw milks at 1, 14, 30, 60 and 90 d. The original milk,
      rennet, curd and whey were also included in the study. The pH, salt content and
      extent of proteolysis in the cheese were also evaluated. Spermidine and spermine
      were the main amines in raw milk, while they were minor amines in cheeses. Other
      amines increased markedly during ripening, tyramine being the main amine in
      cheese made from raw milk and cadaverine and putrescine in those produced from
      pasteurized milk. Enterobacteriaceae counts decreased during ripening whereas
      those of lactic acid bacteria increased, especially lactobacilli and enterococci.
      Cheese made from raw milk showed higher microbial counts during ripening than
      those made from pasteurized milk, especially for Enterobacteriaceae and
      enterococci, counts being 2 or 3 log units higher. Raw milk cheese showed
      remarkably higher biogenic amines compared with pasteurized milk cheeses.
      Therefore, pasteurization of milk causes a decrease in final biogenic amine
      content of cheese as a result of the reduction of its microbial counts.

PMID- 15190956
TI  - Critical care: you are the future.

PMID- 15190957
TI  - CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial
      with a recombinant chimeric CD14 monoclonal antibody (IC14).
AB  - OBJECTIVE: Binding of bacterial cell wall components to CD14 and co-receptors on
      myeloid cells results in cellular activation and production of proinflammatory
      mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to
      decrease lipopolysaccharide-induced responses in animal and human models of
      endotoxemia. This study was performed to evaluate the safety, pharmacokinetics,
      pharmacodynamics, and clinical pharmacology of IC14 in patients with severe
      sepsis. DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging,
      multiple-center trial. SETTING: Six medical and surgical intensive care units
      located in Germany and The Netherlands. PATIENTS: Forty patients with severe
      sepsis. INTERVENTIONS: IC14 was administered intravenously to eight
      patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily
      for 4 days, or 4 mg/kg on day 1 followed by 2 mg/kg daily for 3 days). A placebo
      group (two patients/cohort) was also included. MEASUREMENTS AND MAIN RESULTS: The
      overall incidence and types of adverse events were similar among treatment
      groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4
      days experienced an anaphylactic reaction after receiving the first dose of study
      drug. IC14 did not induce antibody formation or increase the incidence of
      secondary bacterial infection. A mean IC14 serum concentration of approximately 1
      microg/mL was required to achieve 50% of maximum membrane-bound CD14 receptor
      occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti
      inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and
      acute phase proteins in response to treatment was highly variable by patient and
      IC14 treatment group. CONCLUSIONS: Single and multiple doses of IC14 were
      generally well tolerated and did not induce antibody formation or increase the
      incidence of secondary bacterial infection. The results suggest that CD14
      blockade with IC14 warrants further clinical investigation to determine its
      ability to attenuate the proinflammatory response due to infection.

PMID- 15190958
TI  - Hyperglycemia at admission to the intensive care unit is associated with elevated
      serum concentrations of interleukin-6 and reduced ex vivo secretion of tumor
      necrosis factor-alpha.
AB  - OBJECTIVES: The aim of the study was to investigate the association between
      admission blood glucose concentrations and immune function variables and its
      correlation to mortality rate in patients of a medical intensive care unit.
      DESIGN: Prospective, observational study. SETTING: Medical intensive care unit of
      a university hospital. PATIENTS: Patients were 189 consecutive critically ill
      patients in the medical intensive care unit. INTERVENTIONS: At admission to the
      intensive care unit, serum concentrations of interleukin-6, interleukin-8,
      interleukin-10, and tumor necrosis factor-alpha were measured with immunometric
      assays. Additionally, ex vivo secretion of tumor necrosis factor-alpha after
      stimulation with lipopolysaccharide in a whole blood assay and cytometric human
      leukocyte antigen-DR expression on monocytes were determined in all study
      subjects. Simplified Acute Physiology Score II and Therapeutic Intervention
      Scoring System-28 were calculated for the first day in the intensive care unit.
      MEASUREMENTS AND MAIN RESULTS: The relationships between blood glucose
      concentrations and immunologic variables were analyzed using univariate and
      multivariate statistical methods. Overall, 75 patients (39.7%) presented with
      hyperglycemia. An elevated blood glucose concentration at admission was related
      to an increased risk of mortality in the intensive care unit (odds ratio, 2.6; p
      = .009). At univariate and multivariate analysis, hyperglycemia was associated
      with increased serum concentrations of interleukin-6 (p < .05), a reduced ex vivo
      production of tumor necrosis factor-alpha (p < .01), and a history of diabetes
      mellitus (p < .05), whereas other clinical (including Simplified Acute Physiology
      Score II and Therapeutic Intervention Scoring System-28) and immunologic
      variables were not statistically related to blood glucose. CONCLUSIONS: Our main
      findings show that admission hyperglycemia is statistically related to distinct
      changes of humoral and cellular immune functions. Furthermore, elevated glucose
      concentrations at admission are associated with increased intensive care unit
      mortality rate in a medical intensive care unit. Although these data do not
      explain cause and effect, our results provide a strong rationale for studying the
      immunologic effects of strict glycemic control in the intensive care unit during
      the course of critical illness.

PMID- 15190959
TI  - Association between surfactant protein B + 1580 polymorphism and the risk of
      respiratory failure in adults with community-acquired pneumonia.
AB  - OBJECTIVE: Pulmonary surfactant protein (SP)-B plays a vital role in the
      formation and function of surfactant in the lung. A genetic polymorphism (SP-B +
      1580) is postulated to result in diminished activity of SP-B. The objective was
      to determine whether the SP-B + 1580 CC genotype is associated with an increased
      risk of respiratory failure and ARDS in adults with community-acquired pneumonia.
      DESIGN: Prospective cohort of adults diagnosed with community-acquired pneumonia.
      SETTING: Hospital system. PATIENTS: We enrolled 402 adults > or = 18 yrs of age
      with community-acquired pneumonia; 158 were white, 243 were African American, and
      one was Asian. INTERVENTIONS: Genotypic analysis was performed on DNA isolated
      from whole blood using polymerase chain reaction amplification and DdeI
      restriction enzyme digestion. MEASUREMENTS AND MAIN RESULTS: We recorded the
      requirement for mechanical ventilation, the presence of acute respiratory
      distress syndrome (ARDS) or septic shock, and mortality. Sixty-three patients
      required mechanical ventilation, 12 patients developed ARDS, and 35 patients
      developed septic shock. Genotypic frequencies at the SP-B + 1580 site were T/T
      183 of 402 (0.45), T/C 160 of 402 (0.40), and C/C 59 of 402 (0.15). Of the 59
      patients who were C/C at the SP-B + 1580 site, 21 (0.356) required mechanical
      ventilation, compared with 26 of 160 patients (0.163) who were T/C and 16 of 183
      (0.087) patients who were T/T (p < .001). ARDS developed in five of 59 (0.085)
      patients with the C/C genotype, compared with six of 160 (.038) patients with T/C
      and one of 183 patients with T/T (0.005, p < .009). Septic shock occurred in 12
      of 59 (0.203) patients with the C/C genotype, compared with 13 of 160 (0.081)
      patients with T/C and ten of 183 (0.055) patients with T/T (p < .001). Mortality
      rate was not different between the three genotypes. CONCLUSION: Carriage of the C
      allele at the SP-B + 1580 site is associated with ARDS, septic shock, and the
      need for mechanical ventilation in adults with community-acquired pneumonia.

PMID- 15190960
TI  - Initial pH, base deficit, lactate, anion gap, strong ion difference, and strong
      ion gap predict outcome from major vascular injury.
AB  - OBJECTIVE: This study determines whether acid-base data obtained in the emergency
      department correlate with outcome from major vascular injury. DESIGN:
      Observational, retrospective record review of trauma patients requiring vascular
      repair (torso or extremity, January 1988 to December 1997). Data included age,
      Injury Severity Score, injury mechanism, survival, laboratory profiling,
      calculated anion gap, strong ion difference, and strong ion gap. Patients were
      divided into survivors and nonsurvivors with comparison by Student's t-test;
      significance was assumed for p < or = .05. Multivariate logistic regression was
      used for further analysis of univariate predictors of mortality, and receiver
      operator characteristic curves were generated for mortality from each variable.
      SETTING: Urban level I trauma facility. PATIENTS: Trauma patients requiring
      vascular repair of torso or extremity injury. INTERVENTIONS: None. MEASUREMENTS
      AND MAIN RESULTS: Both nonsurvivors (n = 64) and survivors (n = 218) were similar
      with respect to age (31 +/- 9 vs. 31.5 +/- 10.5, p = 0.15) and injury mechanics
      (81% penetrating in survivors vs. 83% penetrating in nonsurvivors, p = .71). Non
      survivor Injury Severity Score exceeded that of survivors (27.5 +/- 7.8 vs. 12.4
      +/- 9.4, p < .001). Nonsurvivor pH (7.06 +/- 0.15 vs. 7.34 +/- 0.08, p < .001)
      and apparent strong ion difference (31.38 +/- 4.39 vs. 37.53 +/- 3.86, p < .001)
      were significantly lower, whereas nonsurvivor standard base excess (-17.9 +/- 5.1
      vs. -2.9 +/- 4.4 mEq/L, p < .001), lactate (11.1 +/- 3.6 vs. 3.6 +/- 1.5 mmol/L,
      p < .001), anion gap (28.2 +/- 4.1 vs. 15.6 +/- 3.1, p < .001), and strong ion
      gap (10.8 +/- 3.2 vs. 2.4 +/- 1.8, p < .001) were higher. All but one nonsurvivor
      had initial emergency department pH < or = 7.26, standard base excess < or = -7.3
      mEq/L, lactate > or = 5 mmol/L, and strong ion gap > or = 5 mEq/L. All of the
      acid-base descriptors were strongly associated with outcome, but the strong ion
      gap discriminated most strongly with an area under the receiver operator
      characteristic of 0.991 (95% confidence interval, 0.972-0.998). CONCLUSIONS: The
      initial emergency department acid-base variables of pH, base deficit, lactate,
      anion gap, apparent strong ion difference, and strong ion gap discriminate
      survivors from non-survivors of major vascular injury. The strong ion gap is most
      strongly predictive of mortality following major vascular trauma.

PMID- 15190961
TI  - Renal, but not systemic, hemodynamic effects of dopamine are influenced by the
      severity of congestive heart failure.
AB  - OBJECTIVE: To determine whether the short-term systemic and renal hemodynamic
      response to dopamine is influenced by clinical severity of congestive heart
      failure. DESIGN: Effects of increasing doses of dopamine were assessed in
      patients consecutively admitted for acutely decompensated congestive heart
      failure. SETTING: Intensive care unit. PATIENTS: We enrolled 16 congestive heart
      failure patients stratified by clinical severity (New York Heart Association
      [NYHA] class III, n = 8; NYHA class IV, n = 8) and two additional NYHA class III
      patients as controls. INTERVENTIONS: Measurements were carried out throughout
      five 20-min experimental periods: baseline, dopamine infusion at 2, 4, and 6
      microg x kg(-1) x min(-1), and recovery. Controls received a similar amount of
      saline. MEASUREMENTS AND MAIN RESULTS: Systemic and renal hemodynamics were
      determined respectively by right cardiac catheterization and radioisotopes
      (iodine 131-labeled hippuran and iodine 125-labeled iothalamate clearance). The
      peak increase in heart rate and cardiac index occurred at a dopamine dose of 4-6
      microg x kg(-1) x min(-1). The dose-response relation was similar in NYHA classes
      III and IV. Improvement in effective renal plasma flow and glomerular filtration
      rate, peaking at 4 microg x kg(-1) x min(-1), was more rapid and marked in NYHA
      class III than class IV patients, in whom the renal fraction of cardiac output
      failed to increase. The systemic and renal effects of dopamine were independent
      of age. No change occurred in controls. CONCLUSIONS: The dose of dopamine
      producing an optimal improvement of systemic and renal hemodynamics in congestive
      heart failure is higher than usually reported. A greater clinical severity of
      congestive heart failure impairs the renal effects of dopamine, probably through
      a selective loss in renal vasodilating capacity.

PMID- 15190962
TI  - Lung heme oxygenase-1 is elevated in acute respiratory distress syndrome.
AB  - OBJECTIVE: We aimed to quantify concentrations of inducible heme oxygenase (HO)-1
      in the lungs of patients with acute respiratory distress syndrome (ARDS) and to
      investigate its role as a source of ferrous iron and as a signaling agent for
      iron regulation. Control of such processes by heme oxygenase has implications for
      the onset, progression, and resolution of ARDS. DESIGN: Retrospective analysis of
      archived samples. SETTING: Adult intensive care unit of a postgraduate teaching
      hospital. PATIENTS: Patients admitted to the adult intensive care unit who
      fulfilled the American-European Consensus Conference criteria for ARDS.
      INTERVENTIONS: Biochemical and immunohistochemical studies using bronchoalveolar
      lavage fluid or lung tissue were performed in patients with established ARDS and
      in those undergoing lung resection (controls). MEASUREMENTS AND MAIN RESULTS:
      Concentrations of heme oxygenase protein were significantly elevated in lung
      tissue (193.7 +/- 13.27 vs. 81.0 +/- 16.0%, p < .01) and in bronchoalveolar
      lavage fluid (2.4 x 10(5) vs. 1.4 x 10(5) densitometric units, p = .047) taken
      from patients with ARDS compared with controls. Concentrations of heme oxygenase
      protein in bronchoalveolar lavage fluid from patients with ARDS correlated
      positively and significantly with changes in the concentrations of ferritin (r =
      .697, p = .02) and the iron saturation of transferrin (r = .8, p = .014) but
      correlated negatively and significantly with concentrations of bleomycin
      detectable (redox-active) iron (r = -.73, p = .031). Significantly elevated (p <
      .05) concentrations of heme oxygenase staining in cell types expressing this
      protein were detected in patients with ARDS, compared with concentrations in the
      same cells taken from controls undergoing lung resection. CONCLUSIONS: Heme
      oxygenase protein is elevated in the lungs of patients with ARDS and may
      contribute to the changes in iron mobilization, signaling, and regulation seen in
      this condition.

PMID- 15190963
TI  - Effect of interleukin-6 blockade on tissue factor-induced coagulation in human
      endotoxemia.
AB  - OBJECTIVE: Clinical trials show that interleukin (IL)-6 represents a predictive
      marker in human sepsis. Furthermore, IL-6 has been proposed as a candidate
      mediator for endotoxin (lipopolysaccharide)-induced coagulation activation: In a
      primate model, an (alphaIL-6 antibody (alphaIL-6 Ab) almost abolished
      lipopolysaccharide-induced coagulation activation. Therefore, we wished to
      determine if an alphaIL-6 Ab (B-E8) may also attenuate lipopolysaccharide-induced
      activation of coagulation in humans. DESIGN: The study was a randomized, double
      blind, placebo-controlled parallel group trial (n = 12 per group). SETTING:
      University medical center. PATIENTS: Healthy volunteers. INTERVENTIONS: Healthy
      volunteers were randomized to receive either 80 mg of a monoclonal anti-IL-6 Ab
      (B-E8) or placebo intravenously before bolus infusion of 2 ng/kg
      lipopolysaccharide. MEASUREMENTS AND MAIN RESULTS: B-E8 effectively decreased IL
      6 bioactivity as measured by a Bg-bioassay in vitro and concentrations of C
      reactive protein. However, B-E8 did not decrease lipopolysaccharide-induced
      tissue factor-messenger RNA transcription or plasma concentrations of downstream
      coagulation variables (prothrombin fragment 1 + 2, thrombin-antithrombin III
      complexes, and D-dimer concentrations). Similarly, tumor necrosis factor-alpha
      concentrations, fibrinolytic activity (plasmin-antiplasmin complexes),
      endothelial activation (soluble E-selectin), and IL-10 were unaffected.
      CONCLUSION: IL-6 does not appear to mediate early-phase lipopolysaccharide
      induced coagulation activation in humans.

PMID- 15190964
TI  - Evaluation of a standardized order form for the withdrawal of life support in the
      intensive care unit.
AB  - OBJECTIVE: The intensive care unit remains a setting where death is common, and a
      large proportion of these deaths are preceded by withdrawal of life support. We
      describe a quality improvement project implementing and evaluating a "withdrawal
      of life support order form" to improve quality of end-of-life care in the
      intensive care unit. DESIGN: Before-after evaluation. SETTING: County-owned,
      university-operated, tertiary, level I trauma center. SUBJECTS: Subjects were 143
      nurses and 61 physicians. INTERVENTIONS: We conducted a before-after evaluation
      of the order form's implementation. The order form has sections on preparations,
      sedation/analgesia, withdrawal of mechanical ventilation, and the principles of
      life support withdrawal. To evaluate the form, we surveyed intensive care unit
      clinicians regarding satisfaction with the form, measured nurse-assessed quality
      of dying and death with a 14-item survey (scored 0 for worst possible death to
      100 for best possible), and performed chart review to assess narcotic and
      benzodiazepine use and time from ventilator withdrawal to death. MEASUREMENTS AND
      MAIN RESULTS: We surveyed 143 nurses and 61 physicians about satisfaction with
      the form. Among nurses reporting that the form was used (n = 73), most (84%)
      reported that the order form was helpful and they were most satisfied with the
      sedation and mechanical ventilation sections. Almost all physicians found the
      form helpful (95%), and > 70% of physicians found three of the four sections
      helpful (sedation, mechanical ventilation, and preparations). We obtained quality
      of dying and death scores for 41 patient deaths before and 76 deaths after the
      intervention. These scores did not significantly change (mean preintervention
      score, 78.3; mean postintervention score, 74.2; p = .54) before and after the
      intervention. Total doses of narcotics and benzodiazepines increased after
      implementation of the order form in the hour before ventilator withdrawal, the
      hour after ventilator withdrawal, and the hour before death (p < or = .03). There
      was no change in the median time from ventilator withdrawal to death
      (preintervention 37 mins, postintervention 39 mins; p = .49). CONCLUSIONS: Nurses
      and physicians found the withdrawal of life support order form helpful. The order
      form did not improve nurses' assessment of patients' dying experience.
      Medications for sedation increased during the postorder form period without
      evidence of significantly hastening death. Although the order form was helpful to
      clinicians and changed medication delivery, demonstrating clear improvements in
      quality of dying may require larger sample sizes, more sensitive measures, or
      more effective interventions.

PMID- 15190965
TI  - Clinician predictions of intensive care unit mortality.
AB  - OBJECTIVE: Predicting outcomes for critically ill patients is an important aspect
      of discussions with families in the intensive care unit. Our objective was to
      evaluate clinical intensive care unit survival predictions and their consequences
      for mechanically ventilated patients. DESIGN: Prospective cohort study. SETTING:
      Fifteen tertiary care centers. PATIENTS: Consecutive mechanically ventilated
      patients > or = 18 yrs of age with expected intensive care unit stay > or = 72
      hrs. INTERVENTIONS: We recorded baseline characteristics at intensive care unit
      admission. Daily we measured multiple organ dysfunction score (MODS), use of
      advanced life support, patient preferences for life support, and intensivist and
      bedside intensive care unit nurse estimated probability of intensive care unit
      survival. MEASUREMENTS AND MAIN RESULTS: The 851 patients were aged 61.2 (+/-
      17.6, mean + SD) yrs with an Acute Physiology and Chronic Health Evaluation
      (APACHE) II score of 21.7 (+/- 8.6). Three hundred and four patients (35.7%) died
      in the intensive care unit, and 341 (40.1%) were assessed by a physician at least
      once to have a < 10% intensive care unit survival probability. Independent
      predictors of intensive care unit mortality were baseline APACHE II score (hazard
      ratio, 1.16; 95% confidence interval, 1.08-1.24, for a 5-point increase) and
      daily factors such as MODS (hazard ratio, 2.50; 95% confidence interval, 2.06
      3.04, for a 5-point increase), use of inotropes or vasopressors (hazard ratio,
      2.14; 95% confidence interval, 1.66-2.77), dialysis (hazard ratio, 0.51; 95%
      confidence interval, 0.35-0.75), patient preference to limit life support (hazard
      ratio, 10.22; 95% confidence interval, 7.38-14.16), and physician but not nurse
      prediction of < 10% survival. The impact of physician estimates of < 10%
      intensive care unit survival was greater for patients without vs. those with
      preferences to limit life support (p < .001) and for patients with less vs. more
      severe organ dysfunction (p < .001). Mechanical ventilation, inotropes or
      vasopressors, and dialysis were withdrawn more often when physicians predicted <
      10% probability of intensive care unit survival (all ps < .001). CONCLUSIONS:
      Physician estimates of intensive care unit survival < 10% are associated with
      subsequent life support limitation and more powerfully predict intensive care
      unit mortality than illness severity, evolving or resolving organ dysfunction,
      and use of inotropes or vasopressors.

PMID- 15190966
TI  - Hyperoxia exposure impairs surfactant function and metabolism.
AB  - OBJECTIVE: To evaluate the effects of hyperoxia exposure on lung function and the
      endogenous surfactant system in spontaneously breathing adult rats. DESIGN:
      Analysis of the pulmonary surfactant system isolated from adult rats following
      exposure to > 90% oxygen or room air for 48 or 72 hrs. SETTING: A basic science
      research laboratory in a university setting. SUBJECTS: Sixty pathogen-free
      Sprague-Dawley rats. INTERVENTIONS: Exposure to > 90% oxygen for 72 hrs.
      MEASUREMENTS AND MAIN RESULTS: Exposure to > 90% oxygen for 72 hrs resulted in
      significant lung dysfunction and an increase in neutrophils and total protein
      concentrations within the airspace compared with animals exposed to room air or
      48 hrs of 90% oxygen exposure. Total alveolar surfactant and large aggregate pool
      sizes were increased after 72 hrs of hyperoxia compared with the other groups,
      and there was evidence of lipid peroxidation within these large aggregate
      subtractions. The biophysical function of large aggregate isolated from 72-hr
      hyperoxia-exposed animals was also impaired and converted into small aggregate
      forms faster than large aggregate from normoxia-exposed animals when assessed
      using in vitro surface area cycling techniques. CONCLUSIONS: Oxidative stress on
      the endogenous surfactant system may represent an important mechanism
      contributing to the surfactant dysfunction and abnormal surfactant metabolism
      associated with hyperoxia-induced lung injury.

PMID- 15190967
TI  - Mortality rate and length of stay of patients admitted to the intensive care unit
      in July.
AB  - OBJECTIVE: At the beginning of each academic year in July, inexperienced
      residents and fellows begin to care for patients. This inexperience can lead to
      poor patient outcome, especially in patients admitted to the intensive care unit
      (ICU). The objective of this study was to determine the impact of July ICU
      admission on patient outcome. DESIGN: Retrospective, cohort study. SETTING:
      Academic, tertiary medical center. PATIENTS: Patients admitted to the ICU from
      October 1994 through September 2002. INTERVENTIONS: None. MEASUREMENTS AND MAIN
      RESULTS: Demographics, Acute Physiology and Chronic Health Evaluation (APACHE)
      III score and predicted mortality, admission source, admission date, intensity of
      treatment, ICU length of stay (LOS), and hospital mortality of 29,084 patients
      were obtained. The actual and predicted weighted ICU LOS and their ratio were
      calculated. Logistic regression analysis was used to compare the hospital
      mortality rate of patients admitted to the ICU in July with those admitted during
      the rest of the year, with adjustment for potentially confounding variables. The
      patients' mean age was 62.3 +/- 17.6 yrs; 57.3% were male and 95.5% white. Both
      the customized predicted and observed hospital mortality rates of the entire
      cohort were 8.2%. The majority (76.7%) of the patients were discharged home, and
      15.1% were discharged to other facilities. When adjusted for potentially
      confounding variables, ICU admission in July was not associated with higher
      hospital mortality rate compared with any other month. There were no significant
      differences in the discharge location of patients between July and any one of the
      other months. There were no statistically significant differences in the weighted
      ICU LOS ratio between July and any of the other months. CONCLUSIONS: ICU
      admission in July is not associated with increased hospital mortality rate or ICU
      length of stay.

PMID- 15190968
TI  - Diagnostic and prognostic value of procalcitonin in patients with septic shock.
AB  - OBJECTIVE: To determine whether procalcitonin is a reliable diagnostic and
      prognostic marker in septic shock compared with nonseptic shock. DESIGN:
      Prospective controlled trial. SETTING: Intensive care unit of the Avicenne
      Teaching Hospital, Bobigny, France. PATIENTS: All patients admitted to our
      intensive care unit over a 12-month period with clinical evidence of shock.
      INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Echocardiography or pulmonary
      artery flotation catheter measurements were used to assess hemodynamics, and
      multiple specimens were obtained for microbiological studies. Standard criteria
      were used to diagnose septic shock. Serum concentrations of procalcitonin, C
      reactive protein, and lactate were determined on the day of shock onset (day 1)
      and on days 3, 7, and 10. Seventy-five patients were included, 62 in the septic
      shock group and 13 in the cardiogenic shock group. Serum procalcitonin on day 1
      was significantly higher in patients with than without septic shock (median, 14
      [0.3-767] ng/mL vs. 1 [0.5-36] ng/mL, p < .01). A cutoff value of 1 ng/mL had 95%
      sensitivity and 54% specificity for separating patients with and without sepsis.
      C-reactive protein failed to discriminate between these two groups. Among
      patients with sepsis, procalcitonin concentrations were significantly higher in
      those who died than in the survivors, at all four measurement time points
      (median, 16 [0.15-767] ng/mL vs. 6 [0.2-123] ng/mL, p = .045 on day 1; 6.5 [0.3
      135] ng/mL vs. 1.05 [0.11-53] ng/mL, p = .02 on day 10). A cutoff value of 6
      ng/mL on day 1 separated patients who died from those who survived with 87.5%
      sensitivity and 45% specificity. C-reactive protein was not helpful for
      predicting mortality. Serum lactate was a nonspecific prognostic marker.
      CONCLUSIONS: These data indicate that procalcitonin may be a valuable early
      diagnostic and prognostic marker in patients with septic shock.

PMID- 15190969
TI  - Pulmonary injury follows systemic inflammatory reaction in infrarenal aortic
      surgery.
AB  - OBJECTIVE: To investigate whether an inflammatory response occurs in patients
      undergoing infrarenal aortic abdominal aneurysm repair, the localization and
      timing (ischemia and/or reperfusion) of this activation, and finally whether it
      affects postoperative pulmonary function. DESIGN: Prospective, observational
      study. SETTING: Academic referral center in Italy. PATIENTS: We included 12
      patients undergoing infrarenal aortic abdominal aneurysm repair and 12 patients
      undergoing major abdominal surgery. INTERVENTIONS: Timed measurement of gene
      activation (angiotensinogen, angiotensin type 1 receptor, angiotensin-converting
      enzyme, and interleukin-6 genes) in muscle biopsies by reverse transcriptase
      polymerase chain reaction (RT-PCR), and prospective assessment of interleukin-6
      plasma concentration and pulmonary function (Pao2/FIO2 and Pao2/PAO2 ratios).
      MEASUREMENTS AND MAIN RESULTS: After 30 mins of aortic clamping, angiotensinogen,
      angiotensin type 1 receptor, angiotensin-converting enzyme, and interleukin-6
      genes were all overexpressed at RT-PCR studies in quadriceps muscle of patients
      undergoing aortic abdominal aneurysm repair, and the overexpression persisted
      after reperfusion. In situ hybridization and immunohistochemistry revealed that
      the inflammatory response was localized in endothelial cells. A significant
      increase in plasma interleukin-6 concentrations was then detectable at 6 and 12
      hrs after reperfusion in aortic abdominal aneurysm surgery compared with patients
      undergoing abdominal surgery (p < .05). The increase in interleukin-6 plasma
      concentration was then followed (12 and 24 hrs after surgery) by a significant
      reduction of Pao2/ FIO2 and Pao2/PAO2 ratios (p < .05 vs. abdominal surgery).
      CONCLUSIONS: The present study shows that a) during aortic surgery, the genes for
      interleukin-6 and for the components of the local renin-angiotensin system
      (angiotensinogen, angiotensin-converting enzyme, and angiotensin type 1 receptor
      subtype) are activated early in the ischemic muscle, and activation persists
      during reperfusion; b) interleukin-6 plasma concentration increases only in
      patients with tissue ischemia (aortic abdominal aneurysm), whereas no changes are
      detectable in patients with abdominal surgery; and finally c) the occurrence of
      systemic inflammatory reaction with increased interleukin-6 plasma concentrations
      is followed by impaired pulmonary function.

PMID- 15190970
TI  - High-dose exogenous iron following cecal ligation and puncture increases
      mortality rate in mice and is associated with an increase in gut epithelial and
      splenic apoptosis.
AB  - OBJECTIVES: Despite having dysregulated iron metabolism, critically ill patients
      may receive exogenous iron for the treatment of anemia. Iron is associated with
      increased tissue apoptosis and may facilitate bacterial growth. We hypothesized
      that exogenous iron administration given after the onset of sepsis would lead to
      increased mortality rate. To discriminate between elevated cell death and
      bacterial overgrowth as potential mediators of mortality, we examined gut
      epithelial and lymphocyte apoptosis and systemic bacterial counts in animals
      given iron supplementation after the onset of sepsis. DESIGN: Prospective,
      randomized, controlled study. SETTING: Animal laboratory in a university medical
      center. SUBJECTS: Male C57BL/6 mice, 6-10 wks old. INTERVENTIONS: C57BL/6 mice
      were subjected to cecal ligation and puncture (CLP), a well-accepted model of
      intra-abdominal sepsis, followed by daily subcutaneous injections of either 1 mL
      of iron dextran (5 mg/mL) or 0.9% NaCl for a total of five doses. Animals (n =
      78) were followed for survival for 8 days. Separate cohorts (n = 76) were killed
      24 or 48 hrs after cecal ligation and puncture or sham laparotomy and were
      assayed for gut epithelial and splenic apoptosis as well as for quantitative
      blood cultures. MEASUREMENTS AND MAIN RESULTS: Eight-day survival was 7% in
      animals that received iron and 26% in mice that received 0.9% NaCl (p < .005).
      Iron supplementation after cecal ligation and puncture increased apoptosis by
      both active caspase 3 and hematoxylin and eosin staining in both the intestinal
      epithelium and spleen at 24 hrs (p < .05). Iron supplementation after sham
      laparotomy did not cause mortality or elevated apoptosis. Quantitative blood
      cultures revealed no detectable differences between septic animals that received
      iron and those that received 0.9% NaCl. CONCLUSIONS: High-dose iron
      supplementation with iron dextran after the onset of sepsis significantly
      increases mortality rate in this animal model. Iron-induced mortality may be
      mediated by an increase in gut epithelial and splenic apoptosis, whereas severity
      of bacteremia does not appear to play a causative role.

PMID- 15190971
TI  - Differential expression of cytochrome P450 isoforms in the lungs of septic
      animals.
AB  - OBJECTIVE: Sepsis is characterized by an early, hyperdynamic phase and a late,
      hypodynamic phase. Although studies have shown that cytochrome P450 (CYP) plays
      an important role in the regulation of vascular reactivity, alterations of
      vascular CYP isoforms in sepsis remain unknown. Since CYP2C11 and CYP2J4 convert
      arachidonic acid to vasodilative epoxyeicosatrienoic acids, and CYP4A3
      metabolizes arachidonic acid to both epoxyeicosatrienoic acids and
      vasoconstrictive 19,20-hydroxyeicosatetraenoic acid, the aim of this study was to
      examine the expression of these isoforms in sepsis and their association with
      hemodynamic changes. DESIGN: Prospective, controlled, and randomized animal
      study. SETTING: An institute research laboratory. SUBJECTS: Male adult Sprague
      Dawley rats were subjected either to polymicrobial sepsis by cecal ligation and
      puncture or to sham operation followed by the administration of normal saline
      solution (i.e., fluid resuscitation). INTERVENTIONS: At 5 hrs (early sepsis) or
      20 hrs (late sepsis) after cecal ligation and puncture, blood vessel-rich tissues
      (i.e., lungs) were harvested. The expression of CYP isoforms at both messenger
      RNA and protein levels was determined by reverse transcription polymerase chain
      reaction and Western blot analysis (CYP2C11), respectively. Hemodynamic variables
      were measured by radioactive microspheres. MAIN RESULTS: The results indicate
      that the gene expression of CYP2C11 and CYP2J4 was significantly down-regulated
      at 20 hrs after cecal ligation and puncture, whereas the expression of CYP4A3 was
      markedly up-regulated at 5 hrs. The protein concentrations of CYP2C11 also
      decreased significantly at 20 hrs after cecal ligation and puncture. Although
      total peripheral resistance markedly increased, mean arterial pressure did not
      change significantly at 20 hrs after the onset of sepsis. In contrast, cardiac
      output and pulmonary perfusion markedly decreased in late sepsis. CONCLUSIONS:
      Since the up-regulated CYP4A3 is associated with the early, hyperdynamic phase of
      sepsis and the down-regulated CYP2C11 and CYP2J4 are associated with the late,
      hypodynamic phase, vascular CYP isoforms that metabolize arachidonic acid may be
      involved in regulating the cardiovascular response during the progression of
      sepsis.

PMID- 15190972
TI  - Differentiated and dose-related cardiovascular effects of a dual endothelin
      receptor antagonist in endotoxin shock.
AB  - OBJECTIVE: To evaluate the effects of endothelin receptor antagonism on cardiac
      performance in endotoxin shock. DESIGN: Prospective, experimental study. SETTING:
      A university-affiliated research institution. SUBJECTS: Domestic anesthetized
      landrace pigs. INTERVENTIONS: Thirty-seven pigs were anesthetized and subjected
      to echocardiography, coronary sinus catheterization, and monitoring of central
      and regional hemodynamics in order to assess cardiac performance. All animals
      received endotoxin for 5 hrs. Twenty pigs served as endotoxin controls.
      Tezosentan, a dual endothelin-A and -B receptor antagonist, was administered
      during established endotoxemic shock. Seven pigs received an infusion of
      tezosentan of 1 mg x kg(-1) x hr(-1) (tezo1), and an additional ten pigs received
      a higher dose of 10 mg x kg(-1) x hr(-1) (tezo10). MEASUREMENTS AND MAIN RESULTS:
      Endotoxemia evoked a state of shock with pulmonary hypertension and metabolic
      acidosis. A decrease in stroke volume and coronary perfusion pressure as well as
      an increase in troponin I was also noted. Tezosentan administration resulted in a
      significant increase in cardiac index, stroke volume index, left ventricular
      stroke work index, and left ventricular end-diastolic area index. Decreases in
      systemic and pulmonary vascular resistance indexes were also evident after
      intervention. This was achieved without changes in heart rate or systemic
      arterial or pulmonary artery occlusion pressures in tezo, animals compared with
      controls. In addition, metabolic variables were improved by tezosentan. These
      effects were sustained only in the tezo, group. In the higher dosage, tezosentan
      resulted in a deterioration of cardiac performance and 50% mortality rate. The
      endotoxin-induced increase in troponin I was attenuated in the tezo, group
      compared with controls. CONCLUSIONS: In this porcine model of volume
      resuscitated, endotoxemic shock, endothelin-receptor blockade with tezosentan
      improved cardiac performance. However, the effect was not sustained with higher
      doses of tezosentan, possibly due to reduced coronary perfusion pressure. These
      findings show differentiated, dose-dependent effects by dual endothelin receptor
      blockade on endotoxin-induced cardiovascular dysfunction.

PMID- 15190973
TI  - Comparison of aerosol therapy with different perfluorocarbons in surfactant
      depleted animals.
AB  - OBJECTIVE: The study investigates the effectiveness of aerosol treatment on gas
      exchange and pulmonary inflammatory reaction using perfluorocarbons with
      different molecular structure and vapor pressure. DESIGN: Experimental,
      prospective, randomized, controlled study. SETTING: Experimental laboratory at a
      university hospital. SUBJECTS: Twenty anesthetized neonatal piglets assigned to
      four groups. INTERVENTIONS: After establishment of lung injury by bronchoalveolar
      lavage, piglets either received aerosolized FC77 (n = 5), perfluorooctylbromide
      (n = 5), or FC43 (n = 5, 10 mL x kg(-1) x hr(-1) for 2 hrs) or intermittent
      mandatory ventilation (control, n = 5). Thereafter, animals were supported for
      another 6 hrs. MEASUREMENTS AND MAIN RESULTS: Pao2 significantly improved in the
      perfluorocarbon groups compared with control (p < .01). Final Pao2 (mean +/- SEM)
      was FC77, 406 +/- 27 mm Hg; perfluorooctylbromide, 332 +/- 32 mm Hg; FC43, 406 +/
      19 mm Hg; control, 68 +/- 8 mm Hg. Paco2 and mean pulmonary arterial pressure
      were lower in all perfluorocarbon groups compared with control. The ratio of
      terminal dynamic compliance to total compliance was significantly higher in the
      FC77 than in the FC43, perfluorooctylbromide, and control groups. Relative gene
      expression of interleukin-1beta, interleukin-8, P-selectin, E-selectin, and
      intercellular adhesion molecule-1 in lung tissue was determined by TaqMan real
      time polymerase chain reaction normalized to hypoxanthineguanine-phosphoribosyl
      transferase and was shown to be reduced by all perfluorocarbons. CONCLUSIONS:
      Aerosol treatment with all the perfluorocarbons investigated improved gas
      exchange and reduced pulmonary inflammatory reaction independently from molecular
      structure and vapor pressure of the perfluorocarbons. Although differences in
      vapor pressure and molecular structure may account for varying optimal dosing
      strategies, several different perfluorocarbons were shown to be principally
      suitable for aerosol treatment.

PMID- 15190974
TI  - Critical care medicine as a distinct product line with substantial financial
      profitability: the role of business planning.
AB  - OBJECTIVE: As academic health centers face increasing financial pressures, they
      have adopted a more businesslike approach to planning, particularly for discrete
      "product" or clinical service lines. Since critical care typically has been
      viewed as a service provided by a hospital, and not a product line, business
      plans have not historically been developed to expand and promote critical care.
      The major focus when examining the finances of critical care has been cost
      reduction, not business development. We hypothesized that a critical care
      business plan can be developed and analyzed like other more typical product lines
      and that such a critical care product line can be profitable for an institution.
      DESIGN: In-depth analysis of critical care including business planning for
      critical care services. SETTING: Regional academic health center in southern New
      Jersey. SUBJECTS: None. INTERVENTIONS: As part of an overall business planning
      process directed by the Board of Trustees, the critical care product line was
      identified by isolating revenue, expenses, and profitability associated with
      critical care patients. MEASUREMENTS AND MAIN RESULTS: We were able to identify
      the major sources ("value chain") of critical care patients: the emergency room,
      patients who are admitted for other problems but spend time in a critical care
      unit, and patients transferred to our intensive care units from other hospitals.
      The greatest opportunity to expand the product line comes from increasing the
      referrals from other hospitals. A methodology was developed to identify the
      revenue and expenses associated with critical care, based on the analysis of past
      experience. With this model, we were able to demonstrate a positive contribution
      margin of dollar 7 million per year related to patients transferred to the
      institution primarily for critical care services. This can be seen as the profit
      related to the product line segment of critical care. There was an additional
      positive contribution margin of dollar 5.8 million attributed to the critical
      care portion of the hospital stay of patients admitted primarily through other
      product lines or the emergency room. This can be seen as the profit related to
      the "hospital service" segment of critical care. This represented a total
      contribution margin of dollar 12.8 million, approximately 24% of the
      institution's entire contribution margin. This information was subsequently used
      to develop strategic plans to promote this product line. CONCLUSIONS: We were
      able to define the critical care product line, and we were able to demonstrate
      profitability through an analysis of revenue and expenses related to critical
      care services. Our experience suggests that the concept of critical care as a
      product line, in addition to a hospital service, may lead to a useful analysis of
      this new discipline. This plan provided a rational foundation for development of
      the operating and capital budgets for the health system.

PMID- 15190975
TI  - Admission and discharge guidelines for the pediatric patient requiring
      intermediate care.
AB  - During the past three decades, the specialty of pediatric critical care medicine
      has grown rapidly, leading to a number of pediatric intensive care units being
      opened across the country. Many patients who are admitted to the hospital require
      a higher level of care than the routine inpatient general pediatric care, yet not
      to the degree of intensity as pediatric critical care; therefore, an intermediate
      care level has been developed in institutions providing multiple disciplinary
      subspecialty pediatric care. These patients may require frequent monitoring of
      vital signs and nursing interventions but usually do not require invasive
      monitoring. The admission of the pediatric intermediate care patient is guided by
      physiologic parameters depending on the respective organ system involved relative
      to the institution's resources and capacity in caring for a patient in a general
      care environment. This report provides admission and discharge guidelines for
      intermediate pediatric care. Intermediate care promotes greater flexibility in
      patient triage and provides a cost-effective alternative to admission to a
      pediatric intensive care unit. This level of care may enhance the efficiency of
      care and improve the healthcare affordability for patients receiving intermediate
      care.

PMID- 15190976
TI  - Fighting the enemy properly?

PMID- 15190977
TI  - Glucose and the immune system: a victory for Claude Bernard?

PMID- 15190978
TI  - Dying from pneumonia: what gene is the culprit?

PMID- 15190979
TI  - Assessing metabolic acidosis in the intensive care unit: does the method make a
      difference?

PMID- 15190980
TI  - Renal roadblock in managing low output heart failure.

PMID- 15190981
TI  - Improving end-of-life care: targeting what we can.

PMID- 15190982
TI  - Probabilistic thinking and intensive care: a world view.

PMID- 15190983
TI  - Muscling in on systemic inflammatory response syndrome.

PMID- 15190984
TI  - Anemia associated with critical illness: is the erythropoietin receptor a
      culprit?

PMID- 15190985
TI  - Aspiration pneumonia: mixing apples with oranges and tangerines.

PMID- 15190986
TI  - Restriction fragment length polymorphism method in clinical studies.

PMID- 15190987
TI  - Burden of proof.

PMID- 15190988
TI  - Intrapulmonary concentrations of cefepime.

PMID- 15190989
TI  - Modulation of inhibitor kappaB kinase/ nuclear factor kappaB signaling during
      critical illness: a double-edged sword.

PMID- 15190990
TI  - Co2 and lung mechanical or gas exchange function.

PMID- 15190991
TI  - Redefining the ethical and legal foundations of organ procurement.

PMID- 15190992
TI  - Accuracy of respiratory inductive plethysmography in estimating lung volume
      changes.

PMID- 15190993
TI  - Criteria are needed for research in vascular depression.

PMID- 15190994
TI  - The Rowland Universal Dementia Assessment Scale (RUDAS): a multicultural
      cognitive assessment scale.
AB  - OBJECTIVE: To develop and validate a simple method for detecting dementia that is
      valid across cultures, portable and easily administered by primary health care
      clinicians. DESIGN: Culture and Health Advisory Groups were used in Stage 1 to
      develop culturally fair cognitive items. In Stage 2, clinical testing of 42 items
      was conducted in a multicultural sample of consecutive new referrals to the
      geriatric medicine outpatient clinic at Liverpool Hospital, Sydney, Australia (n
      = 166). In Stage 3, the predictive accuracy of items was assessed in a random
      sample of community-dwelling elderly persons stratified by language background
      and cognitive diagnosis and matched for sex and age (n = 90). MEASUREMENTS: A
      research psychologist administered all cognitive items, using interpreters when
      needed. Each patient was comprehensively assessed by one of three geriatricians,
      who ordered relevant investigations, and implemented a standardized assessment of
      cognitive domains. The geriatricians also collected demographic information, and
      administered other functional and cognitive measures. DSM-IV criteria were used
      to assign cognitive diagnoses. Item validity and weights were assessed using
      frequency and logistic regression analyses. Receiver-operating characteristic
      (ROC) curve analysis was used to determine overall predictive accuracy of the
      RUDAS and the best cut-point for detecting cognitive impairment. RESULTS: The 6
      item RUDAS assesses multiple cognitive domains including memory, praxis,
      language, judgement, drawing and body orientation. It appears not to be affected
      by gender, years of education, differential performance factors and preferred
      language. The area under the ROC curve for the RUDAS was 0.94 (95% CI 0.87-0.98).
      At a cut-point of 23 (maximum score of 30), sensitivity and specificity were 89%
      and 98%, respectively. Inter-rater (0.99) and test-retest (0.98) reliabilities
      were very high. CONCLUSIONS: The 6-item RUDAS is portable and tests multiple
      cognitive domains. It is easily interpreted to other languages, and appears to be
      culturally fair. However, further validation is needed in other settings, and in
      longitudinal studies to determine its sensitivity to change in cognitive function
      over time.

PMID- 15190995
TI  - A randomized controlled trial of a specific reminiscence approach to promote the
      well-being of nursing home residents with dementia.
AB  - BACKGROUND: To date, no firm conclusions can be reached regarding the
      effectiveness of reminiscence for dementia. Researchers have emphasized that
      there is an urgent need for more systematic research in the area. OBJECTIVE AND
      METHOD: A single-blinded, parallel-groups (one intervention, one comparison, and
      one no-intervention group) randomized controlled trial (RCT) was adopted to
      investigate whether a specific reminiscence program leads to higher levels of
      psychosocial well-being in nursing home residents with dementia. The intervention
      adopted a life-story approach, while the comparison group provided friendly
      discussions to control for any changes in outcome as a result of social contacts
      and attention. The Social Engagement Scale (SES) and Well-being/Ill-being Scale
      (WIB) were the outcome measures used. The outcomes of the groups were examined
      with reference to the baseline (T0), immediately (T1), and six weeks (T2) after
      intervention. The final sample had 101 subjects (control group: n=30; comparison
      group: n=35; intervention group: n = 36). Using multivariate analysis with
      repeated measures, no significant differences in outcome were found between
      groups at either T1 or T2. Wilcoxon signed rank tests were performed for each
      group comparing outcomes between T1 and T0, T2 and T1, and T2 and T0. Significant
      differences were observed in the intervention group when comparing T1 and T0 WIB
      (p = .014), but not for the other groups. CONCLUSION: Although the intervention
      did not lead to significant differences between the three groups over time, there
      was a significant improvement in psychosocial well-being for the intervention
      group.

PMID- 15190996
TI  - De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI).
AB  - BACKGROUND: There is inadequate information regarding the neuropsychiatric aspect
      of Mild Cognitive Impairment (MCI). OBJECTIVE: To determine the neuropsychiatric
      profile of MCI, and compare this with normal controls and patients with mild
      Alzheimer's Disease (AD). DESIGN: Cross-sectional assessment of psychiatric
      symptoms in subjects that are enrolled in Mayo Clinic's longitudinal study of
      normal aging, MCI and dementia. METHODS AND PARTICIPANTS: The Neuropsychiatric
      Inventory (NPI) was administered to normal control subjects, MCI subjects and
      patients with early AD. Individual NPI domain scores and total NPI scores were
      compared among the three groups after controlling for age, educational status,
      Dementia Rating Scale (DRS) and Mini-Mental State Examination (MMSE) scores.
      Statistical analysis was performed by utilizing ANOVA, chi2 and Fisher's exact
      test. RESULTS: Data were analyzed on 514 normal controls, 54 MCI subjects, and 87
      subjects with mild AD (CDR of 0.5 or 1); females consisted of 60.3%, 53.7% and
      57.5%; and, the average ages (SD) were 77.8 (1.95), 79 (4.6), 80.5 (14.6)
      respectively. ANOVA pair-wise comparison revealed that both MMSE and DRS
      differences among the three groups were significantly different at (p = 0.05).
      The total NPI scores were significantly different (p =0.0001, F = 107.93) among
      the three groups using ANOVA. Pair-wise comparison of individual behavioral
      domain of NPI showed statistically significant differences between MCI and
      normals; and MCI and AD (p = 0.001). Group differences on NPI remained after
      controlling for age and education at p = 0.0375 and p = 0.0050 respectively.
      CONCLUSION: The neuropsychiatric pattern is reminiscent of the clinical,
      neuroimaging and neuropsychological profile of MCI. It gives further credence to
      the view that MCI is indeed the gray zone, with overlap on both ends of the pole.

PMID- 15190997
TI  - Behavioral symptoms and the administration of psychotropic drugs to aged patients
      with dementia in nursing homes and in acute geriatric wards.
AB  - OBJECTIVES: To describe the prevalence of various psychiatric and behavioral
      symptoms among patients with dementia in nursing homes and acute geriatric wards
      and to investigate the administration of psychotropic medications to these
      patients. METHODS: 425 consecutive patients (>70 years) in six acute geriatric
      wards in two city hospitals and seven nursing homes in Helsinki, Finland, were
      assessed with an extensive interview, cognitive tests, and attention tests. Of
      these, 255 were judged to have dementia according to the following information:
      previous dementia diagnoses and their adequacy, results of CT scans, Mini-mental
      State Examination (MMSE) tests, Clinical Dementia Scale (CDR) tests, and DSM-IV
      criteria. Psychiatric and behavioral symptoms were recorded over two weeks for
      each patient. RESULTS: Psychiatric and behavioral symptoms were very common among
      patients with dementia in both settings. In all, 48% presented with psychotic
      symptoms (delusions, visual or auditory hallucinations, misidentifications or
      paranoid symptoms), 43% with depression, 26% agitation, and 26% apathy. Use of
      psychotropic drugs was also common: 87% were on at least one psychotropic drug,
      66% took at least two, 36% at least three, and 11% four or more psychotropic
      drugs. Of the patients with dementia, 42% were on conventional antipsychotics,
      and 34% on anxiolytics despite their known side-effects. Only 13% were on
      atypical antipsychotics and 3% on cholinesterase inhibitors. The use of selective
      serotonin reuptake inhibitors (SSRIs) was common (31%) among the patients. A
      surprising finding was that drugs with anticholinergic effects were also
      frequently (20%) used. CONCLUSION: Both behavioural symptoms and use of
      psychotropic drugs are very common among dementia patients in institutional
      settings. The frequent use of potentially harmful drugs implies a need for
      education among physicians taking care of these patients.

PMID- 15190998
TI  - Does cognitive status modify the relationship between education and mortality?
      Evidence from the Canadian Study of Health and Aging.
AB  - BACKGROUND: There is compelling evidence of an inverse relationship between level
      of education and increased mortality. In contrast to this, one study showed that
      among subjects with Alzheimer's Disease, those with high education are more than
      twice as likely to die earlier; however, this result has proven difficult to
      replicate. We examine the relationship between education and mortality by
      cognitive status, using a large, nationally representative sample of elderly
      people. PATIENTS: A representative sample of 10,263 people, aged 65 or over, from
      the 10 Canadian provinces, participated in the Canadian Study of Health and Aging
      in 1991. METHODS: Information about age, gender, education, and an initial
      screening for cognitive impairment were collected; those who screened positive
      for cognitive impairment were referred for a complete clinical and
      neuropsychological examination, from which cognitive status and clinical severity
      of dementia were assessed. Vital status and date of death were collected at
      follow-up in 1996. The analysis was conducted using survival analysis. RESULTS:
      Cognitive status modifies the relationship between education and mortality. For
      those with no cognitive impairment, an inverse relationship between education and
      mortality exists. Elderly people with cognitive impairment but no dementia, or
      those with dementia, are more likely to die early than the cognitively normal at
      baseline, but no relationship exists between education and mortality.
      INTERPRETATION: These findings do not support previous work that showed a higher
      risk of mortality among highly educated dementia subjects.

PMID- 15190999
TI  - The ECO computerized cognitive battery: collection of normative data using
      elderly New Zealanders.
AB  - BACKGROUND: Computerized testing in the elderly has multiple advantages,
      including increased time-efficiency, a wider range of stimulus options and
      response forms, and increased psychometric reliability. The French-language ECO
      (Examen Cognitif par Ordinateur, Ritchie et al., 1993) computerized cognitive
      battery is investigated in this study. OBJECTIVE: The purpose of the study was to
      yield normative data for an English-language version of the ECO, test the effects
      of age and education on test scores, to observe individual subtest sensitivity to
      cognitive impairment, and to examine participants' receptivity to this form of
      testing. METHOD: A sample of 129 community-dwelling elderly with normal cognitive
      functioning and 56 cognitively impaired older adults living in both independent
      and supported accommodation were tested using the ECO at either their own
      residence or an outpatient facility. RESULTS: Standardized scores for three
      different age bands are given for both impaired and non-impaired groups. Age and
      education effects varied between subtests. A discriminant analysis of subtest
      sensitivity to group prediction is reported using a stepwise regression model.
      CONCLUSION: The English version of the ECO appears to be a sensitive and
      practical cognitive battery that is highly acceptable to older people.

PMID- 15191000
TI  - Efficacy of risperidone for treating patients with behavioral and psychological
      symptoms of dementia.
AB  - BACKGROUND: Large randomized controlled trials have shown that risperidone
      reduces the frequency and severity of behavioral and psychological symptoms of
      dementia (BPSD) in patients with dementia. Since such trials are obliged to use
      very strict inclusion and exclusion criteria, their information about the
      efficacy is limited by the criteria used. Thus, the aim of the present study was
      to investigate the efficacy of risperidone on BPSD in a sample of patients
      routinely treated by their primary care physicians. METHODS: A total of 938
      elderly patients in Austria suffering from BPSD and routinely treated by their
      primary care physicians were included in this open-label prospective study.
      Patients received a flexible dose of risperidone, starting with 0.5 mg daily, for
      at least 6 weeks. Questionnaires were filled in before the start and after 6
      weeks of treatment. RESULTS: Before starting treatment with risperidone, BPSD
      were severe in 36.6% of the patients, moderate in 49.3%, and mild in 14.1%. The
      overall efficacy of risperidone was judged as "excellent" by the general
      practitioners and caregivers in about half the patients. The treatment was judged
      as "not satisfactory" in only a very small proportion (3.3% and 4.3%,
      respectively). According to the physicians' judgement, the tolerability of
      risperidone was "excellent" in 81.5% of the patients and "satisfactory" in 17.8%.
      The tolerability was "not satisfactory" in only 0.7% and only 7.4% of the
      patients reported any adverse event. DISCUSSION: Overall, the results of this
      survey indicate that risperidone is both efficacious and well tolerated for the
      treatment of elderly primary care patients with BPSD.

PMID- 15191001
TI  - Conservative treatment of bladder cancer.

PMID- 15191003
TI  - How should we introduce clinical PET in the UK? The oncologists need to have a
      view.

PMID- 15191002
TI  - A meta-analysis of randomised trials suggests a survival benefit for combined
      radiotherapy and radical cystectomy compared with radical radiotherapy for
      invasive bladder cancer: are these data relevant to modern practice?
AB  - OBJECTIVE: Treatment options for muscle-invasive bladder cancer include radical
      cystectomy or radical radiotherapy, and the prevailing choice varies by country.
      The ideal treatment would be a bladder-preserving therapy without compromising
      survival. The objective of this review was to compare the overall survival after
      radical surgery (cystectomy) with radical radiotherapy in patients with muscle
      invasive cancer. MATERIALS AND METHODS: We searched the Cochrane Controlled
      Trials Register, Medline, EMBASE, Cancerlit, Healthstar and the Database of
      Abstracts of Reviews of Effectiveness. Authors of unpublished data were
      contacted. Randomised trials comparing surgery (alone or with preoperative
      radiotherapy) with radiotherapy were eligible for assessment. Three reviewers
      assessed trial quality based on the Cochrane Guidelines. Data were extracted from
      the text of the article or extrapolated from the Kaplan-Meier plot. The Peto odds
      ratio was determined to compare the overall survival and disease-specific
      survival. Analysis was performed on an intention-to-treat basis and treatment
      actually received. RESULTS: No randomised trials comparing surgery alone with
      radiotherapy alone were identified. Three randomised trials comparing
      preoperative radiotherapy followed by radical cystectomy (surgery) versus radical
      radiotherapy with salvage cystectomy (radical radiotherapy) were eligible for
      assessment. These trials represented a total of 439 patients, 221 randomised to
      surgery and 218 to radical radiotherapy. Three trials were combined for the
      overall survival results, and one was evaluable for the disease-specific survival
      analysis. The mean overall survival (intention-to-treat analysis) at 3 and 5
      years were 45% and 36% for surgery, and 28% and 20% for radiotherapy,
      respectively. Peto odds ratio (95% confidence interval [CI]) analysis
      consistently favoured surgery in terms of overall survival. The results were
      significantly in favour of surgery at 3 years (OR = 1.91, 95% CI 1.30-2.82) and
      at 5 years (OR = 1.85, 95% CI 1.22 -2.82). On a treatment-received basis, the
      results were significantly in favour of surgery at 3 years (OR 1.84, 95% CI 1.17
      2.90) and 5 years (OR 2.17, 95% CI 1.39-3.38) for overall survival, and at 3
      years (OR 1.96, 95% CI 1.06-3.65) for disease-specific survival. CONCLUSIONS: The
      analysis of this review suggests that there is an overall survival benefit with
      combined preoperative radiotherapy plus radical surgery compared with radical
      radiotherapy plus salvage cystectomy in patients with muscle-invasive bladder
      cancer. However, it must be considered that only three trials were included for
      analysis, the patient numbers were small and that many patients did not receive
      the treatment they were randomised to. It must also be noted that many
      improvements in radiotherapy and surgery have taken place since the initiation of
      these trials; therefore, the data may not be readily extrapolated to modern
      practice. Ideally, a new trial comparing modern bladder-sparing therapy with the
      latest surgical approach to this disease is required.

PMID- 15191004
TI  - Positron emission tomography imaging of cell proliferation in oncology.
AB  - Tumour-cell proliferation is a hallmark of the malignant phenotype. Positron
      emission tomography (PET) offers a unique method of imaging biological and
      biochemical changes in vivo. Radiolabelled thymidine and thymidine analogues are
      currently in development as PET tracers. By studying the uptake and kinetics of
      such compounds using PET, a measure of DNA synthesis and hence cell proliferation
      can be obtained. Molecular imaging of cellular proliferation with PET is now
      possible, and has the potential to play an important role in the evaluation of
      efficacy of new anti-cancer agents.

PMID- 15191005
TI  - Localised extranodal lymphoma of the head and neck: the Sheffield Lymphoma Group
      experience (1971-2000).
AB  - AIMS: Over the 30-year period from 1971-2000, 3750 cases of lymphoma were
      referred to the Sheffield Lymphoma Group for investigation and treatment. Of
      these, 580 were extranodal presentations and, of these, 190 (33%) were localised
      to the head and neck region. The aim of this lymphoma database review was to
      evaluate the patient characteristics and survival rates for these patients.
      MATERIALS AND METHODS: The sample included 98 women and 92 men, with a median age
      at presentation of 65 years. RESULTS: The most common site affected was tonsil
      (34%), followed by salivary glands (16%). Other common sites were the thyroid,
      orbit and nasopharynx. The most frequent presenting feature was a swelling or
      mass, with pain, dysphagia and nasal obstruction also comprising large groups.
      All cases were non-Hodgkin's lymphoma. Fifty-five cases were histological grade
      1; 132 were grade 2. Diffuse large B cell was the most common histological
      subtype. The overall 5- and 10-year survival rates were 55% (95% CI 47-62) and
      44%, (95% CI 36-53), respectively, with a median survival of 92 months (95% CI 56
      128). Stage and grade were both found to influence survival. CONCLUSION: This
      data concords with and extends information available from previous studies. More
      detail is now required on specific head and neck sites.

PMID- 15191006
TI  - Primary central nervous system lymphoma with testicular relapse.
AB  - We report the case of a 54-year-old man with primary central nervous system
      lymphoma (PCNSL) who achieved a radiological complete response to high-dose
      methotrexate and 6 months later had a simultaneous local and testicular relapse.

PMID- 15191007
TI  - Any clinical benefit from the use of oncofoetal markers in the management of
      chemotherapy for patients with metastatic colorectal carcinomas?
AB  - AIMS: Computed tomography (CT) is the reference technique for evaluating response
      to chemotherapy. The potential helpfulness of tumour markers is debated.
      MATERIALS AND METHODS: From March 1997 to January 1999, 91 consecutive patients
      receiving chemotherapy for metastatic colorectal carcinoma underwent whole-body
      spiral CT, estimates of anti-carcinoembryonic antigen (CEA) and CA19-9 every 8
      weeks. RESULTS: CEA and CA19-9 levels were above normal in 78 (85.7%) and 61
      (67.5%) patients, respectively. Tumour response evaluation according to the
      RECIST criteria was obtained at 8-week evaluation in 83 (91%) patients. The
      positive predictive values (PPV) for response of a decrease of the marker levels
      were 53.8 for CEA and 41.7 for CA19-9 using a 30% decrease threshold, and
      60/52.2, respectively, using a 50% decrease threshold. Meaningful PPV values (>
      90%) for progression of an increase of the marker levels were only obtained using
      the 200% increase threshold for CEA alone or a combination of CEA and CA 19-9. A
      100% CEA increase between baseline and the 8-week evaluation was correlated to
      overall survival (P = 0.0023). The need for a radiological confirmation of tumour
      progression could be avoided by the systematic dosage of tumour markers at
      baseline and after 8 weeks of treatment only in a sub-population of 13% of the
      patients with a 200% increase of CEA or CA 19-9 at 8 weeks. CONCLUSIONS: CEA, CA
      19-9, or both should be used with caution for tumour response evaluation to
      chemotherapy in addition to CT in metastatic colorectal carcinoma.

PMID- 15191008
TI  - Reactivation of hepatitis C virus after chemotherapy for colon cancer.
AB  - Hepatitis C virus (HCV) infection often goes undiagnosed in asymptomatic
      carriers, but may become clinically relevant during periods of immunosuppression
      or severe illness. We report the clinical course of HCV reactivation in a patient
      receiving chemotherapy for metastatic colon cancer. We also review other reports
      showing the significance of HCV infection in patients being treated with
      chemotherapy.

PMID- 15191009
TI  - Clinical and cellular radiosensitivity in inherited human syndromes.
AB  - AIMS: It has been proposed that in-vitro measurements of radiosensitivity might
      allow individualisation of patient radiotherapy schedules, with concomitant
      increases in the therapeutic ratio between tumours and normal tissues. Most
      predictive assay research on normal tissues to date has been based on the
      radiosensitivity of normal lymphocytes and skin fibroblasts as determined by
      clonogenic cell-survival assays. Studies comparing the radiosensitivity of
      fibroblasts or lymphocytes with acute or late radiation damage have reported
      variable results. METHODS: In this study, we measured the radiosensitivity of
      lymphocytes from three patients displaying clinical radiation hypersensitivity
      who were known or suspected to carry germline mutations in genes that have been
      linked to increased radiosensitivity (a BRCA2 mutation carrier, a patient with
      Bloom's syndrome and a patient with a Fanconi anaemia-like condition), to
      investigate whether there is a correlation between cellular radiosensitivity and
      normal tissue response. RESULTS: We found no association between lymphocyte
      radiosensitivity and the development of adverse radiation reactions in this group
      of patients, as is observed in the paradigm radiosensitivity syndrome, ataxia
      telangiectasia. CONCLUSIONS: Our results, and those of others, show that, at
      present, the evidence is not strong enough to justify routine clinical use of
      clonogenic cell survival assays to predict radiation response.

PMID- 15191010
TI  - Radiotherapy for glioma during pregnancy: fetal dose estimates, risk assessment
      and clinical management.
AB  - Cancer in pregnancy is relatively uncommon, but constitutes a major problem. We
      report the measurement of scatter dose to the fetus and the estimated fetal risk
      from that exposure in an illustrative case of a patient, 20 weeks pregnant, with
      a grade 3 anaplastic astrocytoma. A clinical decision was made to withhold
      radiotherapy, if possible, until after delivery. Sequential magnetic resonance
      imaging (MRI) showed no progression during the pregnancy. In the event, she was
      managed conservatively until the successful completion of her pregnancy. In case
      radiotherapy was required, an estimation of the fetal risk was made. Phantom
      measurements were undertaken to assess the likely fetal dose. Film badges were
      used to estimate the scattered radiation energy. Measurements were made on a
      Varian 600C at 6 MV and Asea Brown Boveri (ABB) accelerator at 8 and 16 MV. Doses
      were measured at 30, 45 and 60 cm from the isocentre; the fetus was assumed to
      lie at about 60 cm and not closer than 45 cm from the isocentre. Estimated doses
      to the position of the fetus were lowest with the 6 MV Varian accelerator. Using
      this machine without additional abdominal shielding, the estimated dose on the
      surface at 45 cm from the tumour volume was 2.2 cGy for a tumour dose of 54 Gy;
      using the ABB accelerator, the dose varied between 49-59 cGy. The energy of
      scattered radiation was in the range 208-688 keV, so that additional shielding
      would be practical to further reduce the fetal dose. The risk of cancer up to the
      age of 15 years attributable to radiation is 1 in 1700 per cGy, of which half
      will be fatal (i.e. 1 in 3300 per cGy). A dose of 2.2 cGy adds a risk of fatal
      cancer by the age 15 years of only 1 in 1500. Because the addition of shielding
      might halve the fetal dose, this risk should be reduced to 1 in 3000. For
      comparison, the overall UK risk of cancer up to the age 15 years is 1 in 650. In
      conclusion, careful choice of linear accelerator for the treatment of a pregnant
      woman and the use of additional shielding is valuable, as this can dramatically
      affect fetal dose.

PMID- 15191011
TI  - Intensity-modulated radiation therapy for children with intraocular
      retinoblastoma: potential sparing of the bony orbit.
AB  - AIMS: We have evaluated the potential for intensity-modulated radiation therapy
      (IMRT) to reduce dose to surrounding normal tissues in children with
      retinoblastoma confined to the globe of the eye. MATERIALS AND METHODS: Treatment
      planning computed tomography (CT) scans from five children were used for
      comparison of four radiotherapy techniques to treat the eye. IMRT, conformal,
      anterior-lateral photon and en face electron plans were generated using the
      Corvus (NOMOS) and PLUNC treatment planning systems. Doses to surrounding
      critical structures were compared after normalisation of target coverage.
      RESULTS: The IMRT treatment technique allowed the greatest sparing of the
      surrounding bony orbit, with an average of 60% of the ipsilateral bony orbit
      treated above 20 Gy and 48% treated above 24 Gy when 45 Gy is prescribed to the
      globe. IMRT techniques reduced dose to the surrounding bony orbit by more than
      one-third compared with anterior-lateral photon and electron techniques, and by
      23% compared with conformal techniques. The application of IMRT also reduced dose
      to other surrounding normal tissues, including the temporal lobe and
      contralateral orbit. CONCLUSION: IMRT shows potential for protecting normal
      tissues in patients requiring external beam radiation therapy for retinoblastoma.

PMID- 15191012
TI  - For purposes of research, palliative care patients should not be considered a
      vulnerable population.

PMID- 15191013
TI  - People at the end of life are a vulnerable research population.

PMID- 15191014
TI  - On the cover. American beech.

PMID- 15191015
TI  - Clinical use of immunoassays in assessing exposure to fungi and potential health
      effects related to fungal exposure.
AB  - OBJECTIVE: To review and summarize current evidence regarding the proper role of
      immunoassays in clinical assessments of exposure to fungi and health effects
      related to fungal exposure. DATA SOURCES: We reviewed relevant scientific
      investigations and previously published reviews concerning this topic. STUDY
      SELECTION: The authors' clinical, laboratory, and public health experiences were
      used to evaluate relevant data for scientific merit. RESULTS: Testing to
      determine the presence of IgE to specific fungi may be a useful component of a
      complete clinical evaluation in the diagnosis of illnesses that can be caused by
      immediate hypersensitivity such as allergic rhinitis and asthma. Detection of IgG
      to specific fungi has been used as a marker of exposure to agents that may cause
      illnesses such as hypersensitivity pneumonitis. However, the ubiquitous nature of
      many fungi and the lack of specificity of fungal antigens limit the usefulness of
      these types of tests in the evaluation of potential building-related illness and
      fungal exposure. Specific serologic tests (such as tests for cryptococcal
      antigen, coccidioidal antibody, and Histoplasma antigen) have been shown to be
      useful in the diagnosis of some fungal infections, but these are the exception
      not the rule. CONCLUSIONS: There is currently not enough scientific evidence to
      support the routine clinical use of immunoassays as a primary means of assessing
      environmental fungal exposure or health effects related to fungal exposure.
      Health care providers who care for persons expressing concerns about the
      relationship of symptoms to potential exposure to fungi are advised to use
      immunoassay results with care and only as an adjunct to a comprehensive approach
      to patient care.

PMID- 15191016
TI  - A 32-year-old man with tuberculosis, fever, and rash.

PMID- 15191018
TI  - Change in prevalence of asthma in Danish children and adolescents.
AB  - BACKGROUND: There is evidence suggesting that the prevalence of asthma has
      increased, especially in industrialized countries. OBJECTIVE: To investigate
      whether the prevalence of asthma in Danish children and adolescents has changed
      during the past 15 years. METHODS: Serial cross-sectional studies of 2 different
      random population samples of children aged 7 to 17 years, living in urban
      Copenhagen, Denmark, were performed 15 years apart. The first cohort was
      investigated in 1986 (n = 527) and the second in 2001 (n = 480). The same methods
      were applied at both occasions. Skin test reactivity was measured using standard
      techniques. Asthma was defined on the basis of questionnaire responses and was
      regarded as nonatopic (intrinsic) if no positive reactions were observed on the
      skin test and as atopic (extrinsic) if at least 1 positive reaction was noted.
      Current asthma was defined as symptoms within the preceding 12 months. RESULTS:
      The prevalence of current asthma increased from 5.3% in 1986 to 11.7% in 2001.
      This was primarily due to an increase in intrinsic asthma, which was 4.2-fold
      (1.5% to 6.4%), compared with extrinsic asthma, which increased only 1.4-fold
      (3.8% to 5.5%). The changes were more pronounced in girls. CONCLUSIONS: The
      prevalence of asthma has increased substantially during the past 15 years. The
      observed striking increase in intrinsic asthma suggests the possibility of a more
      heterogeneous disorder, involving more important factors than atopy. Furthermore,
      our findings suggest that asthma might be shifting toward female predominance in
      childhood.

PMID- 15191017
TI  - Assessment of mood states in patients receiving long-term corticosteroid therapy
      and in controls with patient-rated and clinician-rated scales.
AB  - BACKGROUND: Corticosteroids have been used for many years for inflammatory
      diseases. Mood changes are common during short-term, high-dose, corticosteroid
      therapy. Virtually no data are available on the mood effects of long-term
      corticosteroid therapy. OBJECTIVE: To evaluate mood during corticosteroid therapy
      using standard clinician-rated and patient-rated measures. METHODS: Outpatients
      receiving prednisone therapy (7.5 mg/d for 6 months) and similar controls were
      enrolled. Current mood was evaluated using the Hamilton Rating Scale for
      Depression (HRSD), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating
      Scale (BPRS), Internal State Scale (ISS), and a diagnostic interview. RESULTS:
      Twenty patients and 14 controls were enrolled in the study. Depressive symptom
      severity as evaluated by the HRSD and ISS depression and well-being subscales and
      global psychiatric symptom severity as evaluated by the BPRS and ISS perceived
      conflict subscale were greater in patients receiving prednisone than controls.
      Manic symptom severity as evaluated by the ISS activation subscale but not the
      YMRS was higher in patients receiving prednisone. Twelve (60%) of 20
      corticosteroid-treated patients met diagnostic criteria for a lifetime prednisone
      induced mood disorder. Activation subscale scores did not correlate with YMRS
      scores. Other ISS subscales showed expected correlations with clinician-rated
      assessments. CONCLUSIONS: Mood symptoms and disorders are common in
      corticosteroid-dependent patients. Unlike short-term prednisone therapy, long
      term therapy may be more associated with depressive than manic symptoms based on
      the clinician-rated assessments. The ISS may be more sensitive to mood symptoms
      with prednisone than clinician-rated scales.

PMID- 15191019
TI  - Oral corticosteroid-sparing effects of inhaled corticosteroids in the treatment
      of persistent and acute asthma.
AB  - OBJECTIVE: To review the efficacy and safety of inhaled corticosteroids (ICSs)
      when used to reduce daily oral corticosteroid (OCS) requirements in patients with
      severe persistent asthma and periodic requirements in patients with acute asthma
      exacerbations. DATA SOURCES: Clinical studies of the OCS-sparing effects of ICSs
      were located by searching MEDLINE databases from 1966 onward using the terms
      oral, steroid, and asthma in combination with the generic names for each marketed
      ICS. STUDY SELECTION: Studies reporting on the use of ICSs to reduce OCS
      requirements in patients with persistent and acute asthma are included. RESULTS:
      Clinical study results consistently show that ICSs significantly improve asthma
      control and reduce OCS requirements among adults, children, and infants with
      persistent asthma. A dose reduction or complete discontinuation of use of OCSs is
      possible in most patients without loss of asthma control. ICSs also can control
      asthma during acute asthma exacerbations and reduce the need for short courses of
      OCSs. With many ICSs, the reductions in OCS use are accompanied by recovery of
      hypothalamic-pituitary-adrenal axis function, indicating that the safety of
      asthma therapy is improved when OCS requirements are decreased with ICSs. Of the
      available ICSs that may reduce OCS needs, budesonide appears to be the most
      intensively studied. CONCLUSIONS: ICSs can reduce OCS requirements in adults and
      children with persistent asthma and during acute asthma exacerbations. The
      reduced systemic corticosteroid activity associated with ICS treatment improves
      the overall safety of asthma therapy.

PMID- 15191020
TI  - Asthma hospitalization risk and costs for patients treated with fluticasone
      propionate vs montelukast.
AB  - BACKGROUND: Inhaled corticosteroids have been shown to reduce rates of
      hospitalization and emergency department use compared with leukotriene receptor
      antagonists. OBJECTIVE: To examine differences in the probability of asthma
      related hospitalizations, probability of switching or augmentin, with another
      therapy, and costs for patients treated with fluticasone propionate vs
      montelukast. METHODS: The study involved a 24-month retrospective analysis of
      patients with claims for asthma treatment (primary diagnosis International
      Classification of Disease, Ninth Revision code of 493.xx) between January 1,
      1997, and June 30, 2000, and at least I outpatient pharmaceutical claim for
      fluticasone propionate (44 microg) or montelukast (5 or 10 mg). Univariate and
      multivariate analyses were used to determine the probability of asthma-related
      hospitalizations and switching or augmenting to another therapy, asthma costs,
      and total health care costs. Sensitivity analyses were conducted by replicating
      all of the analyses by age strata (ages 4-17 years and > or = 18 years) and
      varying lengths of follow-up. RESULTS: Patients receiving fluticasone propionate
      had a 62% lower risk of experiencing an asthma-related hospitalization within 1
      year and a 44% lower risk of switching or augmenting to another asthma controller
      medication compared with montelukast. Asthma-related health care expenditures for
      montelukast patients were dollar 339 higher than for fluticasone propionate users
      (P < .001). Overall health care expenditures (asthma and nonasthma) were also
      dollar 1,197 higher in the montelukast group. CONCLUSIONS: Compared with
      montelukast-treated patients, patients treated with low-dose fluticasone
      propionate had a significantly lower risk of experiencing an asthma-related
      hospitalization, a lower risk of switching or augmenting with another controller,
      and significantly lower asthma and total health care costs.

PMID- 15191021
TI  - Effect of reduced exposure on natural rubber latex sensitization in health care
      workers.
AB  - BACKGROUND: Knowledge about the long-term course of allergy or sensitization to
      natural rubber latex (NRL) is insufficient. OBJECTIVE: To investigate the long
      term effect of preventive measures on sensitization variables in health care
      workers who had been diagnosed as having NRL allergy (NRLA) or NRL sensitization
      (NRLS) without clinical symptoms. METHODS: Repeated follow-up investigations,
      skin prick tests, and NRL specific IgE serum antibodies were performed in 88
      health care workers-33 with NRLA and 55 with NRLS. All workers had been
      instructed to avoid NRL exposure. At the workplace, powder-free NRL gloves for
      all other employees were gradually introduced. Re-evaluations were done at 14 +/-
      3.7 (N = 86) and 38 +/- 4.0 (N = 78) months after the first examination. RESULTS:
      At the last follow-up, a loss of skin prick test reactivity to NRL was observed
      in 1 of 29 subjects with NRLA (3.4%) and 16 of 35 with NRLS (45.7%) with previous
      skin test reactions (P < .001). Among those subjects who demonstrated a kU/L
      level (CAP class) equal to or greater than class I to NRL at the initial
      examination, NRL-specific IgE was absent at the last follow-up in 8 (32.0%) of 25
      subjects with NRLA and 14 (38.9%) of 36 with NRLS. At the final examination, we
      could no longer demonstrate sensitization to NRL by any method in 24 (27.3%) of
      88 health care workers. Complete loss of NRL sensitization was less frequent in
      subjects with NRLA than in those with NRLS (1 of 33 or 3.0% vs 23 of 55 or 41.8%;
      P < .001). CONCLUSIONS: Implementation of simple preventive measures lowers
      markers of sensitization to NRL quickly in many health care workers with NRLA or
      NRLS.

PMID- 15191022
TI  - Diminished dendritic cell interleukin 10 production in atopic children.
AB  - BACKGROUND: Diminished interleukin 10 (IL-10) and/or IL-12 production may
      contribute to the pathogenesis of asthma and atopy. Dendritic cells (DCs) produce
      these cytokines and have been implicated in the pathogenesis of these disorders.
      OBJECTIVE: To determine whether DC IL-10 and/or IL-12 production is diminished in
      children aged 6 to 12 years with allergic rhinitis (AR) and with or without
      asthma. METHODS: Monocyte-derived DCs were isolated from 20 subjects without AR
      or asthma (group 1), 20 subjects with AR without asthma (group 2), and 20
      subjects with AR and asthma (group 3). Asthma was defined as a history of
      physician-diagnosed disease, and AR was defined as a positive history and
      positive puncture skin test responses (wheal > or = 5 mm) to relevant inhalant
      allergens. DCs were stimulated with either lipopolysaccharide (LPS) or diluent
      and cultured for 24 hours. Supernatants were assayed for IL-10 and IL-12 levels
      by enzyme-linked immunosorbent assay. RESULTS: DC IL-10 production was diminished
      in groups 2 and 3 compared with group 1. Median LPS-induced IL-10 levels were
      11.0 pg/mL in group 1, 6.1 pg/mL in group 2, and 1.5 pg/mL in group 3. The
      frequencies of subjects with detectable IL-10 levels were 85%, 20%, and 20% in
      groups 1, 2 and 3, respectively. Median LPS-induced IL-12 levels were similar in
      all groups. CONCLUSIONS: These data support the hypothesis that atopic subjects
      have an intrinsic inability to up-regulate DC IL-10 production. Future studies in
      this area could lead to a better understanding of the pathogenesis of atopy.

PMID- 15191023
TI  - Soluble CD14 as a predictor of subsequent development of recurrent wheezing in
      hospitalized young children with respiratory syncytial virus-induced
      bronchiolitis.
AB  - BACKGROUND: Respiratory syncytial virus (RSV) infection in infancy that causes
      severe bronchiolitis had been implicated as potentially responsible for the
      subsequent development of asthma. The CD14 receptor responds to the microbial
      burden in the environment and modulates the development of the allergic
      phenotype. OBJECTIVE: To investigate the relationship between the serum level of
      soluble CD14 (sCD14) in children hospitalized because of RSV-induced
      bronchiolitis and the subsequent development of recurrent wheezing. METHODS:
      Serum levels of sCD14 were measured in 21 children younger than 14 months who
      were hospitalized because of RSV-induced bronchiolitis. The diagnosis of
      significant wheezing was evaluated by recurrent episodes of coughing, wheezing,
      and respiratory distress, which were relieved by inhalation of beta-agonists and
      corticosteroids. RESULTS: Of the 21 children, 19 were followed up for 12 months.
      The mean sCD14 serum level of 14,521 +/- 1,773 pg/mL in the group of 6 children
      who did not exhibit recurrent wheezing was significantly higher than the level of
      11,243 +/- 3,264 pg/mL in the group of 13 children who exhibited significant
      recurrent wheezing (P < .05). The subsequent development of recurrent wheezing
      was not influenced by positive family history of asthma, number of siblings, sex,
      or breast-feeding. CONCLUSION: A follow-up period of 12 months in this small
      pilot group showed that high serum levels of sCD14 modulate the influence of RSV
      on subsequent recurrent episodes of wheezing.

PMID- 15191024
TI  - Lack of type 1 sensitization to laundry detergent enzymes among consumers in the
      Philippines: results of a 2-year study in atopic subjects.
AB  - BACKGROUND: Enzymes have been safely used in laundry products for many years. The
      risk of developing adverse responses to enzymes in laundry detergents among
      consumers in countries where hand laundry predominates is expected to be low.
      OBJECTIVES: To understand how consumers in hand laundry markets used detergent
      products; to show that use of enzyme-containing detergents did not lead to
      sensitization in an atopic population with compromised skin; and to show that
      enzyme detergents did not have an adverse effect on skin condition. METHODS:
      Women in the rural Philippines were chosen since they do hand laundry for several
      hours a day, every day. The skin prick test (SPT) tested for the presence of IgE
      antibody to common aeroallergens and to enzymes in detergent product. Atopic
      women used enzyme-containing laundry bars for hand laundry and personal
      cleansing. They also used enzyme-containing laundry granules for hand laundry.
      All subjects were evaluated by SPT with enzymes over 2 years. Hand and body skin
      conditions were also evaluated. RESULTS: None of the 1,980 subjects screened for
      eligibility into the 2-year study were SPT positive to enzymes, including 655
      women who used enzyme-containing detergent for up to 1 year. None of the subjects
      in the study developed IgE to the enzymes. Enzymes had no adverse effect on skin
      condition or on the development of erosions on the hands. CONCLUSIONS: The 2-year
      study confirms that enzymes are safe for use in laundry products at or below
      levels tested in the study even when used by atopic consumers under extremely
      harsh conditions.

PMID- 15191025
TI  - Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in children with
      human immunodeficiency virus undergoing highly active antiretroviral therapy.
AB  - BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (23PSV) has been
      recommended for children infected with human immunodeficiency virus (HIV);
      however, the efficacy of this vaccination in HIV-infected children undergoing
      highly active antiretroviral therapy (HAART) has not been studied. OBJECTIVE: To
      study the immunogenicity and immunologic protection of 23PSV in HIV-infected
      children after stable HAART. METHODS: Serotype-specific IgG antibodies to 12
      pneumococcal capsular polysaccharides were analyzed before and after 23PSV
      vaccination in 41 HIV-infected children undergoing HAART and compared with 95 HIV
      negative control children. Seropositivity, clinical protection, and additional
      clinical protection from 23PSV were calculated based on serotype specific IgG
      antibody levels and on the known incidence of these serotypes for causing
      invasive disease. RESULTS: Children with HIV infection undergoing HAART developed
      a significant increase in specific IgG levels to Streptococcus pneumoniae after
      23PSV vaccination (0.95 vs 1.84 micro/gmL, P < .001). The HIV-infected children
      with CD4+ cell counts of 25% or higher at the time of vaccination developed a
      higher additional clinical protection gain from 23PSV vaccination than did
      children with a lower percentage of CD4+ cells. CONCLUSIONS: HIV-infected
      children undergoing stable HAART develop a significant immunologic response to
      23PSV, especially those with higher T-cell counts and lower viral loads at the
      time of vaccination.

PMID- 15191026
TI  - Association between CD62 ligand on naive and memory T cells and history of cow's
      milk hypersensitivity in atopic patients.
AB  - BACKGROUND: Both IgE and non-IgE cell-mediated reactions can contribute to the
      immunopathogenesis of food hypersensitivity. OBJECTIVE: To study L-selectin
      expression in naive (CD45RA+) and memory (CD45RO+) T cells in atopic patients
      with a history of cow's milk allergy and CD69 expression. METHODS: We evaluated
      12 children with a history of cow's milk allergy. All 12 children underwent
      clinical history, examination, in vivo skin prick testing to inhalants and milk
      allergen, and in vitro radioallergosorbent testing for milk and total serum IgE
      levels. L-selectin levels on naive and memory T cells from patients and controls
      were analyzed by flow cytometry with fluorochrome-conjugated monoclonal
      antibodies after 4 hours or 7 days of incubation with medium alone, 1 microg/mL
      of pokeweed mitogen, or 50 microg/mL of casein. RESULTS: The percentage of
      CD45RA+ 62L+ cells with casein was 56% +/- 11% vs 38% +/- 7.7% in healthy
      controls (P < .009). The percentage of CD45RO- 62L+ cells was 22% +/- 7.1% vs 39%
      +/- 7.6% in healthy controls (P < .001), whereas the expression of CD62L+ in
      CD45RA+ and CD45RO+ cells decreased 149% +/- 33% vs 540% +/- 36% for healthy
      controls (P < .001) and 89% -+/- 16% vs 402% +/- 103% for healthy controls (P <
      .001), respectively. CONCLUSIONS: The results of the present study demonstrate
      the presence of CD62 ligand on naive and memory T cells, which might serve as a
      predictive marker for atopic dermatitis withother overlapping atopic disorders,
      such as asthma and allergic rhinitis.

PMID- 15191027
TI  - Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme
      inhibitor angioedema.
AB  - BACKGROUND: Angioedema, particularly of the head and neck, is a well-recognized
      adverse effect of angiotensin-converting enzyme (ACE) inhibitors. Most cases
      respond to conventional therapy, including antihistamines and corticosteroids.
      Severe episodes may require epinephrine and intubation. OBJECTIVE: To report the
      case of a patient with ACE inhibitor-induced angioedema treated with fresh frozen
      plasma (FFP). METHODS: The patient is a 43-year-old, white woman who first
      received the ACE inhibitor ramipril in March 2002. After 3 weeks, she developed
      angioedema of her lips and fingers, which resolved with antihistamines,
      corticosteroids, and one dose of epinephrine. A low dose of ramipril was
      restarted 4 days later, which was increased throughout 4 days. In late August
      2002, she developed severe upper lip and tongue edema recalcitrant to
      conventional therapy. Her C1 esterase inhibitor level was normal. RESULTS: After
      4 days of treatment with antihistamines, corticosteroids, epinephrine,
      antileukotrienes, cyclosporine, and intravenous immunoglobulins, the patient's
      tongue swelling continued to recur and became more severe. Two units of
      intravenous FFP was given, with rapid improvement and no further recurrence of
      tongue swelling. CONCLUSIONS: In our patient, FFP was highly successful in the
      treatment of resistant, life-threatening angioedema due to an ACE inhibitor. The
      benefit of FFP in this setting might be due to the effect of kininase II in
      breaking down accumulated bradykinin.

PMID- 15191028
TI  - Rare tracheal chondroid hamartoma masquerading as asthma in a 14-year-old girl.
AB  - BACKGROUND: Tracheal hamartomas are rare in all age groups and have not been
      previously described in adolescence. OBJECTIVE: To report the first case of a
      tracheal chondroid hamartoma presenting as exercise intolerance and wheezing and
      previously misdiagnosed and treated as asthma. METHODS: Symptoms, pulmonary
      function tests, chest x-ray examination, chest computed tomography, and
      histologic examination of the specimen were performed. RESULTS: The pulmonary
      function tests obtained throughout several years revealed progressive decreases
      (approximately 30% of predicted) in peak expiratory flow and forced expiratory
      volume in 1 second (approximately 50% of predicted). The inspiratory and
      expiratory flow-volume curve suggested a fixed central airway obstruction. Both
      the chest x-ray examination and computed tomography revealed an intraluminal
      tracheal tumor that was surgically excised. Histologic examination revealed a
      chondroid hamartoma. CONCLUSIONS: Rare benign primary tracheal tumors, including
      chondroid hamartoma, can present in adolescence with asthma-like symptoms for
      years and should be considered in the differential diagnosis, especially in the
      setting of appropriately abnormal spirometry or when asthma is very difficult to
      control.

PMID- 15191029
TI  - Beta2-adrenoceptor genotypes and diplotypes at positions 16 and 27 in allergic
      rhinitis and asthma.

PMID- 15191030
TI  - Oral tolerance of carboxymethylcellulose in patients with anaphylaxis to
      parenteral carboxymethylcellulose.

PMID- 15191031
TI  - Summary of recommendations for the design of clinical trials and the registration
      of drugs used in the treatment of asthma.
AB  - With new drugs being introduced to treat asthma it is timely to review criteria
      that can be used to assess efficacy in clinical trials. Anti-asthma drugs are
      classified into symptoms-modifying, symptom preventers and disease modifying
      agents. Attention is drawn to the types of experimental evidence required in
      preclinical studies to support further clinical development of a new therapy.
      Clinical trials demand careful selection of patients to maximise the strength of
      the efficacy signal according to the type of trial being designed. While
      provocation tests are useful in suggesting efficacy, negative tests do not
      necessarily indicate lack of anti-asthma activity. Therapeutic trial designs need
      to take account of duration of treatment, dose-response relationships and
      confirmatory trials. Outcome measures include symptoms, lung function, reduction
      in concomitant medication, exacerbations, quality of life and measures of
      inflammation. Interpretation of results need to include the clinical relevance of
      any changes as well as statistical significance. Special consideration needs to
      be given to the evaluation of drugs for acute severe asthma, asthma in children
      and older people, co-morbidity such as rhinitis, and inhaler devices. As with all
      drugs introduced into practice, careful attention needs to be paid to both short-
      and long-term safety.

PMID- 15191032
TI  - Non-infectious and unusual infectious mimics of community-acquired pneumonia.
AB  - Noninfectious or unusual infectious diseases may present with clinical,
      radiological and laboratorial characteristics of community-acquired pneumonia
      (CAP). Usually their presence is only suspected after treatment failure, leading
      to inappropriate interventions, unnecessary costs and risks related to the
      untreated potentially life-threatening disease. The present study aimed to assess
      the noninfectious or unusual infectious diseases that may be misdiagnosed as CAP
      that progresses with treatment failure. Sixteen hospitalized patients with
      presumptive diagnosis of CAP and treatment failure were described. The most
      prevalent symptoms were fever and cough. Radiological pattern of air-space
      disease was observed in 10 (62%) patients. The diagnosis was established by
      autopsy (12%) or invasive procedures (88%), as follows: open lung biopsy (nine),
      flexible fiberoptic bronchoscopy (two), transthoracic fine needle aspiration
      (two) and bone marrow aspiration (one). Eight patients had noninfectious
      diseases: pulmonary embolism, cryptogenic organizing pneumonia, Wegener's
      granulomatosis, hypersensitivity pneumonitis, bronchocentric granulomatosis,
      neoplastic disease and acute leukemia. The unusual infectious diseases were:
      tuberculosis, cryptococcosis, actinomycosis, histoplasmosis and
      paracoccidioidomycosis. Patients with noninfectious or unusual infectious
      diseases may present with symptoms and radiological findings that mimic CAP.
      These diseases should always be suspected in patients who do not respond to
      initial empirical antimicrobial treatment, especially young patients or those
      without comorbidity.

PMID- 15191033
TI  - PDE4 inhibitors in COPD--a more selective approach to treatment.
AB  - Chronic obstructive pulmonary disease (COPD) is a serious and mounting global
      public health problem. Although its pathogenesis is incompletely understood,
      chronic inflammation plays an important part and so new therapies with a novel
      anti-inflammatory mechanism of action may be of benefit in the treatment of COPD.
      Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4
      inhibitors, with an improved therapeutic index compared with the weak, non
      selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by
      poor efficacy and an unfavourable safety and tolerability profile, the selective
      PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in
      improving lung function, decreasing the rate of exacerbations and improving
      quality of life, with proven anti-inflammatory effects in patients with COPD.
      Theophylline is a difficult drug to use clinically, requiring careful titration
      and routine plasma monitoring due to the risk of toxic side effects, such as
      cardiovascular and central nervous system adverse events, with dose adjustments
      required in many patients, including smokers, the elderly and some patients on
      concomitant medications. In contrast, the selective PDE4 inhibitors are
      convenient medications for both patient and physician alike. Hence these agents
      represent a therapeutic advance in the treatment of COPD, due to their novel
      mechanism of action and potent anti-inflammatory effects, coupled with a good
      safety and tolerability profile.

PMID- 15191034
TI  - The development of the first nurse-led bronchoscopy post in the United Kingdom.
AB  - Nurses routinely practice Gastrointestinal endoscopy in the United Kingdom (UK)
      but, to our knowledge, bronchoscopy has never been introduced as a nursing
      discipline. The need for a nurse bronchoscopist was identified within our
      respiratory unit and the post was developed. This process involved: (1) seeking a
      precedent for the role of nurse bronchoscopist, (2) designing an appropriate
      teaching programme, (3) obtaining hospital accreditation for the programme, (4)
      supervising and completing the training, and (5) implementing a nurse-led
      bronchoscopy service. The development phase took approximately 1 year. No
      precedent was found for nurse-led bronchoscopy in the UK or elsewhere. The
      training programme defined minimum entry requirements and was modelled on UK
      nurse GI endoscopy training and the British Thoracic Society bronchoscopy
      guidelines. The role of nurse bronchoscopist was deemed to comply with
      professional codes of nursing practice by the chief nurse and the hospital
      management board authorised a service framework for the post. The first trainee
      completed the programme in January 2003 and has now examined 125 patients
      independently [endobronchial tumour biopsy hit-rate = 95% (95% CI 76-99%)]. The
      post of nurse bronchoscopist has been successfully developed and accredited
      within our hospital.

PMID- 15191035
TI  - Analysis of local T lymphocyte subsets upon stimulation with intravesical BCG: a
      model to study tuberculosis immunity.
AB  - Cell-mediated immune response can control tuberculosis infection. A significant
      role for immune cells like CD4, CD8 and gammadelta T lymphocytes have been
      recognized, but little is known about the kinetics of activation and accumulation
      of these cells in course of Tuberculosis infection in humans. This is due to both
      the difficult to access to human lung and the fact that most subjects are
      examined in different periods of infection which may condition T cell changes. To
      overcome these problems, we have used intravesical BCG (Bacillus Calmette-Guerin)
      treatment for preventing the recurrences of bladder cancer as an in vivo
      experimental model of human tuberculosis infection. 20 male caucasian patients
      with proven bladder superficial transitional cell carcinoma treated with
      transurethral resection followed by six weekly intravesical instillations of BCG
      (T0-T6) were enrolled. Changes in T lymphocyte subsets were assessed by flow
      cytometry in the bladder wash recovered after each BCG instillation. Our study
      shows that the action of BCG appears to be T cell dependent. Lymphocytes increase
      at any new instillation and tend towards the reduction with the suspension of the
      stimulus. BCG induces a massive increase in the proportion of CD4 Th1 subset
      followed by an increase in gammadelta T cells, while no significant variation for
      CD8 and NK cells is found. Our results suggest that BCG infection model
      represents a valid experimental tool to study the immunological events evoked in
      vivo by Mycobacterium tuberculosis in humans at the site of infection.

PMID- 15191036
TI  - Exercise responses during endurance testing at different intensities in patients
      with COPD.
AB  - Endurance time on submaximal exercise tests is a sensitive measure in detecting
      changes after medical intervention and is used as an outcome in clinical trials,
      although there has been little discussion regarding the appropriate intensity.
      Therefore, we investigated whether there were differences in exercise responses
      between endurance tests at high versus moderate intensity, and analyzed which
      test was more appropriate. Thirty-seven patients with chronic obstructive
      pulmonary disease participated in the study. They performed cycle endurance tests
      at high and moderate submaximal workloads representing 80% and 60% of the maximum
      work rate reached on progressive cycle ergometry, respectively. Each type of
      exercise test was performed after inhaling salbutamol 400 microg, ipratropium
      bromide 80 microg or an identical placebo. Endurance time on the 80% endurance
      test was much shorter than on the 60% endurance test. The coefficients of
      variation for the endurance time were lower on the 80% test. Statistically
      significant improvements in the endurance time after bronchodilators in
      comparison to placebo were found only on the 80% test. When using the endurance
      time as an outcome, the high intensity endurance test is preferable to the
      moderate intensity endurance test, as the high intensity test demonstrated
      shorter exercise time, less variability and higher sensitivity.

PMID- 15191037
TI  - Cardiorespiratory response to walk in multiple sclerosis patients.
AB  - To ascertain whether fatigue perception is linked to exertion dyspnea and/or to
      an impaired cardiorespiratory response during walk, 11 patients (8 females, age
      range 21-46 years) with multiple sclerosis (MS) and mild disability underwent the
      6-min walk test. Ten healthy subjects (7 females, age range 25-49 years) were
      studied, as a control group. Patients did not differ from controls in spirometry,
      lung volumes and respiratory muscle strength. There was a significant difference
      in walk distance between patients and controls (P<0.001), but not in dyspnea
      perception. In patients, the walk distance significantly related to disability
      score (P<0.01), but not to fatigue. Compared to controls, patients had a
      significant decrease in oxygen pulse during walk (P<0.05) and a significant
      increase in the ventilatory equivalent of CO2 both at baseline and during walk
      (P<0.05). The relative contribution of both the tidal volume and of the ratio of
      inspiratory to total breathing cycle duration to the increase in minute
      ventilation during walk was significantly less in patients, as compared to
      controls (P<0.05). We conclude that in MS patients with mild disability, fatigue
      and exertion dyspnea are different sensations without any link and a peripheral
      limitation during walk can occur.

PMID- 15191038
TI  - Effect of cigarette smoking on haem-oxygenase expression in alveolar macrophages.
AB  - We investigated the effect of chronic cigarette smoking on the expression of haem
      oxygenase (HO)-1 and HO-2. Normal subjects and asymptomatic young current smokers
      with normal lung function tests underwent bronchoalveolar lavage for recovery of
      macrophages. Reverse transcription/polymerase chain reaction (RT-PCR) analysis
      showed no significant difference in HO-1 and HO-2 mRNA expression between the two
      groups. On the other hand, Western blot analysis showed a significant (P<0.05)
      reduction of HO-2 protein, but not of HO-1, in alveolar macrophages from smokers
      compared to normal. There was no significant differences by immunocytochemistry
      for HO-1 and HO-2 expression between the groups. We concluded that HO-2
      expression is reduced in alveolar macrophages of smokers, possibly due to the
      oxidative stress of cigarette smoke. This may in turn lead to reduced protection
      against further oxidative insults.

PMID- 15191039
TI  - Low initial KCO predicts rapid FEV1 decline in pulmonary
      lymphangioleiomyomatosis.
AB  - Pulmonary lymphangioleiomyomatosis (LAM) is a rare interstitial disorder
      affecting exclusively women, and leading to progressive deterioration of lung
      function. The disease course is highly variable from one patient to another, but
      no clinical predictor of rapid disease progression is currently available. To
      identify clinical variables, which could detect patients at risk for rapid lung
      function decline, we searched for correlations between the rate of forced
      expiratory volume in 1 s (FEV1) decline and clinical features at diagnosis in a
      retrospective series of 31 cases of LAM followed for > or = 1 yr. The mean FEV1
      decline was 106+/-143 ml/yr or 3.4+/-4.6% predicted FEV1/yr. Among clinical
      features at diagnosis, only initial values of carbon monoxide transfer factor
      (TLCO, P = 0.006) and carbon monoxide transfer coefficient (KCO, P = 0.0001) were
      significantly correlated with the rate of FEV1 decline. Lung volumes and
      FEV1/forced vital capacity ratio at diagnosis were not predictive of rapid
      decline. No effect of previous smoking, contraceptive use or pregnancy on FEV1
      decline could be detected. We conclude that low TLCO and KCO at the time of
      diagnosis are the best clinical predictors of rapid FEV1 decline in patients with
      LAM.

PMID- 15191041
TI  - The measurement of exhaled carbon monoxide in healthy smokers and non-smokers.
AB  - The measurement of exhaled carbon monoxide (CO) level may provide an immediate,
      non-invasive method of assessing smoking status. The aims of this study were to
      use a portable CO monitor to compare the exhaled CO levels in established smokers
      and non-smokers. The exhaled CO levels were measured in 322 subjects (243 healthy
      smokers, 55 healthy non-smokers, 24 passive smokers) who applied to healthy stand
      during the spring student activity of Firat University in Elazig. Exhaled CO
      concentration was measured using the EC50 Smokerlyser. The mean exhaled CO level
      was 17.13+/-8.50 parts per million (ppm) for healthy smokers and 3.61+/-2.15 ppm
      for healthy non-smokers, and 5.20+/-3.38 ppm for passive smokers. There were
      significant positive correlation between CO levels and daily cigarette
      consumption, and CO levels and duration of smoking in healthy smokers (r=+0.550,
      P<0.001, r=+0.265, P<0.001, respectively. Spearman's test). When smokers and non
      smokers were looked at as a whole, a cutoff of 6.5 ppm had a sensitivity of 90%
      and specificity of 83%. In conclusion, exhaled CO level provides an easy, an
      immediate way of assessing a subject's smoking status.

PMID- 15191040
TI  - Multiplex PCR for the simultaneous detection of Chlamydia pneumoniae, Mycoplasma
      pneumoniae and Legionella pneumophila in community-acquired pneumonia.
AB  - A multiplex polymerase chain reaction (PCR) was developed for the simultaneous
      detection of Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella
      pneumophila. Oligonucleotide primers for the amplification of the DNA of these
      three organisms were optimized for use in combination in the same reaction. PCR
      products were detected by the Micro-Chip Electrophoresis Analysis System.
      Clinical samples were obtained from 208 community-acquired pneumonia (CAP)
      patients who were participants in a multicenter CAP surveillance study performed
      at seven medical schools and their affiliate hospitals in Japan. No significant
      differences in the sensitivity of each primer set were observed when tested in
      both the multiplex and monoplex PCR assays. Our multiplex PCR was able to
      reliably detect 10 copies/100 microl of each of the three pathogen DNAs. Of the
      panel of 208 samples, 14 of 15 C. pneumoniae, 10 of 10 M. pneumoniae, eight of
      eight L. pneumophila and 165 of 176 negative samples were correctly identified.
      Eleven cases who were the multiplex PCR positive and conventional method negative
      were observed. The PCR findings were of possible significance in at least four of
      these patients. Our multiplex PCR assay could potentially be used as a diagnostic
      and epidemiological tool. Further prospective studies are needed to establish its
      clinical usefulness.

PMID- 15191042
TI  - Risk factors associated with habitual snoring and sleep-disordered breathing in a
      multi-ethnic Asian population: a population-based study.
AB  - INTRODUCTION: There is scant data on the risk factors of sleep-disordered
      breathing (SDB) in the general population in Asian countries. METHODS: Cross
      sectional survey of a random population sample of 2298 adults aged 20-75 years,
      stratified by gender, ethnicity (Chinese, Malay and Indian) and age. An
      interviewer-administered questionnaire was used to elicit responses to questions
      on daytime somnolence and nocturnal events. Three categories of SDB were defined
      for analysis: habitual snoring; apnoeic snoring (SDB I); and apnoeic snoring or
      snoring with diurnal hypersomnia (SDB II). RESULTS: Snoring was reported by 201
      persons (6.8%), SDB-I in 44 (1.9%) and SDB-II in 112 (4.9%) in the sample. The
      adjusted odds ratio (95% C.I.) of association with snoring were: male gender,
      3.79 (2.69-5.33); older age (>60 years old), 2.15 (1.41-3.29); Indian versus
      Chinese, 1.54 (1.05-2.25); family history, 2.21 (1.56-3.12); obesity (BMI>30),
      2.64 (1.62-4.30); neck circumference (>40 cm), 2.57 (1.59-4.11); and cigarette
      smoking, 2.05 (1.21-3.45). The risk factors for SDB were similar to that of
      snoring. CONCLUSION: Population risk factors associated with habitual snoring and
      SDB in Singapore are largely similar to those reported in other populations.
      Differential risks underscore the importance of ethnicity in determining the
      burden of SDB.

PMID- 15191043
TI  - Interstitial lung diseases: characteristics at diagnosis and mortality risk
      assessment.
AB  - As the diagnostic assessment of the different forms of interstitial lung disease
      (ILD) is similar, this study aims to compare age, sex, the functional and broncho
      alveolar lavage fluid (BALF) findings at diagnosis between the different forms of
      ILDs. In addition we want to determine which of these variables determine
      survival. We evaluated 315 patients (176 males and 139 females) in whom the
      diagnosis was made of sarcoidosis (n = 87), ILD due to connective tissue disease
      (n = 56), hypersensitivity pneumonitis (n = 50), idiopathic pulmonary fibrosis
      (IPF) (n = 64), other forms of idiopathic interstitial pneumonia (n = 29) or ILD
      due to an undefined form of fibrosis (n = 29). We analysed the role on outcome of
      type of disease, gender, age at diagnosis, type of cells in BALF, FVC and DLCO.
      In a Kaplan-Meier analysis IPF has the worst outcome in comparison with other
      types of ILDs. A Cox regression analysis showed that type of ILD, FVC, age at
      diagnosis and % of macrophages in BALF predict outcome of patients affected by
      ILD.

PMID- 15191044
TI  - Posterior mediastinal paraganglioma with bilateral adrenal pheochromocytoma.
AB  - Paraganglioma and adrenal pheochromocytoma are tumors of common origin arising
      from chromaffin cells. However, it is extremely rare to find mediastinal
      paraganglioma simultaneously with bilateral adrenal pheochromocytoma. We report a
      53-year-old man who was diagnosed with posterior mediastinal paraganglioma and
      bilateral adrenal pheochromocytoma and who underwent successful excision of the
      posterior mediastinal mass and bilateral total adrenalectomy.

PMID- 15191045
TI  - Ultraviolet radiation and terrestrial ecosystems.

PMID- 15191046
TI  - Ecosystem consequences of enhanced solar ultraviolet radiation: secondary plant
      metabolites as mediators of multiple trophic interactions in terrestrial plant
      communities.
AB  - The potential role of ultraviolet-B (UV-B)-induced secondary plant metabolites as
      mediators of multiple trophic responses in terrestrial ecosystems is considered
      through review of the major classes of secondary metabolites, the pathways for
      their biosynthesis, interactions with primary and secondary consumers and known
      UV effects on their induction. Gross effects of UV-B radiation on plant growth
      and survival under realistic spectral balances in the field have been generally
      lacking, but subtle changes in carbon allocation and partitioning induced by UV
      B, in particular production of secondary metabolites, can affect ecosystem-level
      processes. Secondary metabolites are important in plant-herbivore interactions
      and may affect pathogens. They act as feeding or oviposition deterrents to
      generalists and nonadapted specialists, but adapted specialists are stimulated to
      feed by these same compounds, which they detoxify and often sequester for use
      against their predators. This provides a route for tritrophic effects of enhanced
      UV-B radiation whereby herbivory may be increased while predation on the
      herbivore is simultaneously reduced. It is in this context that secondary
      metabolites may manifest their most important role. They can be the demonstrable
      mechanism establishing cause and effect at higher trophic levels because the
      consequences of their induction can be established at all trophic levels.

PMID- 15191047
TI  - Field testing of biological spectral weighting functions for induction of UV
      absorbing compounds in higher plants.
AB  - Action spectra are typically used as biological spectral weighting functions
      (BSWF) in biological research on the stratospheric ozone depletion issue. Despite
      their critical role in determining the amount of UV supplied in experiments,
      there has been only limited testing of different functions under realistic field
      conditions. Here, we calculate effective radiation according to five published
      BSWF and evaluate the appropriateness of these BSWF in representing the induction
      of UV-absorbing compounds. Experiments were carried out in the field using both
      ultraviolet-B radiation (280-320 nm) supplementation and selective filtering of
      solar UV radiation. For the four species tested, BSWF that extend into the
      ultraviolet-A radiation (320-400 nm) (UV-A) with moderate effectiveness best
      represented the observed results. When compared with the commonly used
      generalized plant response, these BSWF suggest that simulations of ozone
      depletion will require more radiation than in the past experiments. However, they
      imply lower radiation supplements than a new plant growth BSWF that has a greater
      emphasis on UV-A wavelengths.

PMID- 15191048
TI  - UV radiation effects on plant growth and forage quality in a shortgrass steppe
      ecosystems.
AB  - Levels of UV were manipulated in a native shortgrass steppe using open-sided
      structures with tops that either passed or blocked wavelengths shorter than
      approximately 370 nm. Precipitation was controlled to create a drought or a very
      wet year. Subplots were either nondefoliated or defoliated to simulate grazing by
      livestock, which is the primary land use. Plant community productivity and forage
      quality were assessed in response to the two climate change variables (UV,
      precipitation) and grazing stress. Productivity and seasonal standing biomass of
      the dominant grass species were negatively affected by passing versus blocking
      UV, but only in the dry year. Another species was negatively affected by passing
      UV in the wet year, indicating the potential for future shifts in species
      composition. Forage quality for ruminants increased when UV was passed compared
      with blocked, as determined by in vitro digestible dry matter, depending on
      species and precipitation. Nitrogen concentrations and soluble and fiber
      components of vegetation also displayed some UV effects, but they were generally
      small and depended on species, season or amount of precipitation (or all).
      Grazing treatment had large positive effects on current-year productivity only in
      the wet year and some small positive effects on quality in both wet and dry
      years. Interactions between UV and grazing treatment were not observed.

PMID- 15191049
TI  - Personal solar UV exposure measurements employing modified polysulphone with an
      extended dynamic range.
AB  - Polysulphone dosimeters using a simple to use filter have been developed and
      tested to provide an extended dynamic measurement range of personal solar UV
      exposures over an extended period (3 to 6 days). At a Southern Hemisphere
      subtropical site (27.6 degrees S, 151.9 degrees E), the dynamic range of the
      filtered polysulphone allowed measurements of erythemal exposures to
      approximately 100 minimum erythemal dose (MED) for a change in optical absorbance
      at 330 nm (deltaA330) of 0.35. In comparison, unfiltered polysulphone dosimeters
      were exposed to approximately 8 MED for the same deltaA330. The error associated
      with the use of the filtered polysulphone dosimeters is of the order of +/-15%,
      compared with +/-10% of the unfiltered variety. The developed filtered
      polysulphone dosimeter system allowed the measurement of erythemal UV exposures
      over 3 to 6 days at a subtropical site without the need to replace the dosimeters
      because of saturation. The results show that longer-term measurement programs of
      personal solar UV have been made more feasible with the use of these polysulphone
      dosimeters with an extended dynamic range compared with unfiltered polysulphone
      dosimeters.

PMID- 15191050
TI  - Interactive effects of ultraviolet-B radiation and temperature on cotton
      physiology, growth, development and hyperspectral reflectance.
AB  - Current conditions of 2-11 kJ m(-2) day(-1) of UV-B radiation and temperatures of
      >30 degrees C during flowering in cotton cultivated regions are projected to
      increase in the future. A controlled environment study was conducted in sunlit
      growth chambers to determine the effects of UV-B radiation and temperature on
      physiology, growth, development and leaf hyperspectral reflectance of cotton.
      Plants were grown in the growth chambers at three day/night temperatures (24/16
      degrees C, 30/22 degrees C and 36/28 degrees C) and three levels of UV-B
      radiation (0, 7 and 14 kJ m(-2) day(-1)) at each temperature from emergence to 79
      days under optimum nutrient and water conditions. Increases in main stem node
      number and the node of first fruiting branch and decrease in duration to first
      flower bud (square) and flower were recorded with increase in temperature. Main
      effects of temperature and UV-B radiation were significant for net photosynthetic
      rates, stomatal conductance, total chlorophyll and carotenoid concentrations of
      uppermost, fully expanded leaves during squaring and flowering. A significant
      interaction between temperature and UV-B radiation was detected for total biomass
      and its components. The UV-B radiation of 7 kJ m(-2) day(-1) reduced boll yield
      by 68% and 97% at 30/22 degrees C and 36/28 degrees C, respectively, compared
      with yield at 0 kJ m(-2) day(-1) and 30/22 degrees C. No bolls were produced in
      the three temperature treatments under 14 kJ m(-2) day(-1) UV-B radiation. The
      first-order interactions between temperature, UV-B radiation and leaf age were
      significant for leaf reflectance. This study suggests a growth- and process
      related temperature dependence of sensitivity to UV-B radiation.

PMID- 15191051
TI  - Kinetics and mechanism of the vitamin B2-sensitized photooxidation of
      isoproterenol.
AB  - The sensitized photooxidation promoted by daylight-absorbing compounds appears as
      a plausible course to produce the photodegradation of catecholamines. We report
      the kinetics and mechanism of vitamin B2 (riboflavin [Rf])-sensitized
      photooxidation of isoproterenol (Iso), a synthetic sympathomimetic drug
      structurally related to epinephrine, using water as a solvent. A weak dark
      complex Rf-Iso is formed, only detectable at relatively high Iso concentrations
      (>10 mM), with a mean value of 13 +/- 3 M(-1) for the apparent association
      constant. Under aerobic sensitizing conditions (Rf approximately 0.02 mM and Iso
      approximately 0.5 mM) two oxidative mechanisms operate, mediated by singlet
      molecular oxygen (O2(1delta g)) and superoxide radical anion (O2*-). Our analysis
      shows that the main reaction pathway is an electron transfer-mediated quenching
      of Rf excited triplet state (3Rf*) by Iso. It produces the species Iso*+ and Rf*
      . The latter, in a subsequent reaction path, generates O2*-, which is mainly
      responsible for Iso photooxygenation. In a less-important process, energy
      transfer of the 3Rf* to dissolved oxygen generates O2(1delta g). The kinetic
      balance between chemical and physical quenching of O2(1delta g) by Iso indicates
      that the process is largely dominated by the physical, not chemical, interaction.
      The results, which can be extrapolated to an in vivo condition, show the
      susceptibility of Iso to undergo visible light-induced photodegradation in the
      presence of dye sensitizers present in the environment.

PMID- 15191052
TI  - Efficacy of different UV-emitting light sources in the induction of T-cell
      apoptosis.
AB  - Ultraviolet B (UV-B) radiation is a modality widely used for the treatment of
      different skin diseases. One of the major mechanisms of UV-B immunosuppression in
      this treatment modality is thought to be an apoptosis-inducing effect on T cells
      infiltrating the skin. We examined the T-cell apoptosis-induction capacities of
      four different UV light sources, with and without UV filters. The xenon chloride
      (XeCl) laser proved to be the strongest apoptosis inducer. The use of a phtalic
      acid filter eliminated UV radiation almost completely below 300 nm, which
      resulted in a severe decrease in the apoptosis-inducing capacity of different UV
      B sources. Using the results of the measurements with polychromatic UV light
      sources, the wavelength dependence of UV-B light for the induction of T-cell
      apoptosis was also determined. The regression line of the action spectrum
      demonstrated a continuous decrease from 290 to 311 nm. The apoptosis-inducing
      capacity of the XeCl laser was almost four times higher than the calculated value
      according to the action spectrum, which might be attributed to the high
      irradiance of the laser as compared with nonlaser light sources.

PMID- 15191053
TI  - The complex of apomyoglobin with the fluorescent dye coumarin 153.
AB  - Understanding a protein's dielectric response requires both a theoretical model
      and a well-defined experimental system. The former has already been proposed by
      Song (J. Chem. Phys. 116, 9359 [2002]). We suggest that the latter is provided by
      the complex of coumarin 153 (C153) with apomyoglobin (ApoMb). C153 has been
      exhaustively studied and has proven to be an excellent probe of the solvation
      dynamics of polar solvents. Myoglobin is one of the most thoroughly studied
      proteins. Myoglobins from a wide range of species have been subject to X-ray
      structural analysis and site-directed mutagenesis. Here, we demonstrate the
      existence of a robust C153-apomyglobin system by means of molecular dynamics
      simulations, equilibrium binding studies using a Job's plot and capillary
      electrophoresis, circular dichroism and time-resolved fluorescence. The
      reorganization energy of C153 bound to ApoMb is compared with that of C153 in
      bulk solvent using the method of Jordanides et al. (J. Phys. Chem. B 103, 7995
      [1999]).

PMID- 15191054
TI  - Decreased levels of (6-4) photoproduct excision repair in hybrid fish of the
      genus Xiphophorus.
AB  - Selected hybridization in the fish genus Xiphophorus has been used for many years
      to study the genetics of malignant melanoma. Because DNA damage caused by
      ultraviolet radiation is implicated in the etiology of sunlight-induced melanoma,
      the heritability of mechanisms that mitigate DNA damage is a matter of some
      interest. We examined nucleotide excision repair of the two major types of DNA
      damage induced by sunlight; the cyclobutane pyrimidine dimer (CPD) and the
      pyrimidine(6-4)pyrimidone dimer [(6-4)PD]. In most cases, removal of the (6-4)PD
      was more rapid than the CPD, and in many cases, the F1 hybrid showed reduced
      repair efficiency compared with the parental species. These data demonstrate
      reduced function in multienzyme hybrid systems and provide molecular support for
      potential reduced fitness in hybrid fish under conditions of environmental
      stress.

PMID- 15191055
TI  - Biodistribution assessment of a lutetium(III) texaphyrin analogue in tumor
      bearing mice using NIR Fourier-transform Raman spectroscopy.
AB  - The use of near-infrared (NIR)-excited Fourier-transform (FT) Raman spectroscopy
      as a technique for evaluating the extent of photosensitizer localization in tumor
      (human pancreatic adenocarcinomas)-bearing mice has been tested using
      lutetium(III) texaphyrin analogue Lu-T2B2Tex. The complex was injected
      subcutaneously in the form of three injections given during the course of 3 days.
      The kinetics of biodistribution were then followed over a time scale of 1-6 days.
      The NIR-FT-Raman spectra of tissue samples obtained from the xenographic tumor,
      muscle, heart, brain, liver, spleen, kidney and blood were recorded and used to
      identify the presence of Lu-T2B2Tex in these tissues. Five Raman sensitizer
      markers were used to estimate the relative content of Lu-T2B2Tex in tumor at
      various postinjection times. UV-Visible (Vis) absorption spectroscopic detection
      of this sensitizer in tissue extracts was applied as a conventional method. Both
      spectroscopic methods were in good agreement with each other and confirm that Lu
      T2B2Tex localizes well in tumor tissue. Maximal drug content was observed 3 days
      after the final injection. This time delay seems to be optimal for tumor
      irradiation in photodynamic therapy.

PMID- 15191056
TI  - Evaluation of 15 polymerases and phosphorothioate primer modification for
      detection of UV-induced C:G to T:A mutations by allele-specific PCR.
AB  - Allele-specific polymerase chain reaction is based on polymerase extension from
      primers that contain a 3' end base that is complementary to a specific mutation
      and inhibition of extension with wild-type DNA due to a 3' end mismatch. Taq
      polymerase is commonly used for this assay, but because of the high rate of
      nucleotide extension from primer 3' base mismatches documented for Taq
      polymerase, high sensitivity is difficult to achieve. To determine whether other
      polymerases might improve assay sensitivity, 15 polymerases were tested with
      mutation-specific primers for two ultraviolet-induced mutations in the human 5S
      ribosomal RNA genes. Of the 15 polymerases tested, six were capable of
      discriminating these mutations at levels equivalent to or better than Taq
      polymerase. All primers were phosphorothioate modified on the 3' end to block
      removal of the critical 3' mutation-specific base by polymerases containing 3' -
      > 5' exonuclease "proofreading" activity. The effectiveness of phosphorothioate
      modification was measured in mock polymerase chain reaction reactions and a time
      course. All six enzymes containing this exonuclease activity showed some ability
      to digest phosphorothioate-modified primers and could be divided into two groups,
      showing fast and slow digestion kinetics. Of the three enzymes that showed slow
      digestion kinetics, two also showed significantly slower digestion kinetics of
      unmodified primers.

PMID- 15191057
TI  - Mitochondria-derived reactive oxygen species mediate blue light-induced death of
      retinal pigment epithelial cells.
AB  - Throughout the lifetime of an individual, light is focused onto the retina. The
      resulting photooxidative stress can cause acute or chronic retinal damage. The
      pathogenesis of age-related macular degeneration (AMD), the leading cause of
      legal blindness in the developed world, involves oxidative stress and death of
      the retinal pigment epithelium (RPE) followed by death of the overlying
      photoreceptors. Evidence suggests that damage due to exposure to light plays a
      role in AMD and other age-related eye diseases. In this work a system for light
      induced damage and death of the RPE, based on the human ARPE-19 cell line, was
      used. Induction of mitochondria-derived reactive oxygen species (ROS) is shown to
      play a critical role in the death of cells exposed to short-wavelength blue light
      (425 +/- 20 nm). ROS and cell death are blocked either by inhibiting the
      mitochondrial electron transport chain or by mitochondria-specific antioxidants.
      These results show that mitochondria are an important source of toxic oxygen
      radicals in blue light-exposed RPE cells and may indicate new approaches for
      treating AMD using mitochondria-targeted antioxidants.

PMID- 15191059
TI  - Our real protection is our homeland security system--our immune system.

PMID- 15191058
TI  - Torsion potential works in rhodopsin.
AB  - We investigate the role of protein environment of rhodopsin and the
      intramolecular interaction of the chromophore in the cis-trans photoisomerization
      of rhodopsin by means of a newly developed theoretical method. We theoretically
      produce modified rhodopsins in which a force field of arbitrarily chosen part of
      the chromophore or the binding pocket of rhodopsin is altered. We compare the
      equilibrium conformation of the chromophore and the energy stored in the
      chromophore of modified rhodopsins with those of native rhodopsins. This method
      is called site-specific force field switch (SFS). We show that this method is
      most successfully applied to the torsion potential of rhodopsin. Namely, by
      reducing the twisting force constant of the C11=C12 of 11-cis retinal chromophore
      of rhodopsin to zero, we found that the equilibrium value of the twisting angle
      of the C11=C12 bond is twisted in the negative direction down to about -80
      degrees. The relaxation energy obtained by this change amounts to an order of 10
      kcal/mol. In the case that the twisting force constant of the other double bond
      is reduced to zero, no such large twisting of the bond happens. From these
      results we conclude that a certain torsion potential is applied specifically to
      the C11=C12 bond of the chromophore in the ground state of rhodopsin. This
      torsion potential facilitates the bond-specific cis-trans photoisomerization of
      rhodopsin. This kind of the mechanism is consistent with our torsion model
      proposed by us more than a quarter of century ago. The origin of the torsion
      potential is analyzed in detail on the basis of the chromophore structure and
      protein conformation, by applying the SFS method extensively.

PMID- 15191060
TI  - Hygiene hypothesis only a theory.

PMID- 15191062
TI  - Allergy, asthma, and immunology meeting highlights.

PMID- 15191061
TI  - Panel seeks hope in AIDS battle.

PMID- 15191064
TI  - Bouncing back.

PMID- 15191063
TI  - Turning the tables on tumors.

PMID- 15191065
TI  - Smart weapons.

PMID- 15191066
TI  - Smallpox in Saint Paul and Minneapolis, 1924-1925.

PMID- 15191067
TI  - Basic immunology: a primer.
AB  - This article is intended to bring practicing physicians up to date on the current
      state of knowledge regarding the basic components and processes of the immune
      system. It discusses the role of the immune system and the importance of self
      tolerance and describes the main cellular and noncellular entities involved in
      the immune response. It also details immune processes such as the lymphocyte
      selection process leading to self tolerance; antigen processing and presentation;
      cell signaling, activation, and co-stimulation; and the actions of cytokines and
      other signaling molecules.

PMID- 15191068
TI  - Keys to unlocking the mysteries of rheumatic autoimmune disease.
AB  - Autoimmune diseases are thought to affect between 14 million and 22 million
      people in this country. Despite decades of research, the underlying mechanisms of
      disease are poorly understood, diagnosis is often difficult, and therapies that
      minimize systemic side effects are lacking. Major advances in our understanding
      of human genetic variation and remarkable new technologies are paving the way for
      dramatically improving our fundamental knowledge of autoimmune diseases. Gene
      mapping studies have clearly illustrated the complexity of these diseases, which
      appear to involve many genes. Very high-throughput microarray assays that can
      measure the expression levels of thousands of genes simultaneously are revealing
      important insights into key biological pathways that appear to be perturbed in
      autoimmune diseases. We review recent advances in genetic and genomic studies,
      focusing primarily on systemic lupus erythematosus and related rheumatic
      autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis.
      Identification of susceptibility genes and dysregulated biological pathways for
      these diseases is likely to foster development of novel diagnostic and
      therapeutic approaches that are increasingly tailored to the underlying
      pathological mechanisms.

PMID- 15191069
TI  - The immunopathology and genetics of asthma.
AB  - The definition of asthma and its related phenotypes is problematic because
      multiple factors are involved in its development. Asthma is thought to be a
      complex chronic inflammatory disorder of the airways resulting in symptoms of
      coughing, wheezing, and shortness of breath associated with evidence of bronchial
      reversibility and/or hyperreactivity. The ultimate clinical picture involves a
      variety of cellular and noncellular factors and multiple pathways, all of which
      are influenced by genetic and environmental factors. This article provides an
      overview of the characteristics and pathogenesis of asthma and atopy, as well as
      of genetic research underway to determine the major genes likely involved. These
      genes may interact with each other as well as with environmental variables that
      may influence the immune response.

PMID- 15191070
TI  - Adaptive processing bandwidth adjustment for laser Doppler flowmetry.
AB  - A novel laser Doppler flowmetry scheme is reported that adjusts the processing
      bandwidth adaptively to optimise the estimation of flow. To obtain an adequate
      processing bandwidth, the Doppler spectra is first fitted to the Lorentzian
      function, and the bandwidth at half the maximum of the Lorentzian function is
      used as an indicator of the major frequency range of the signal. The processing
      bandwidth is then tuned accordingly, and a frequency-weighted algorithm is
      applied to compute the fluid velocity. To investigate the influence of the
      processing bandwidth, an in vitro experiment was performed. In the experiment,
      the flow rate was controlled at constant velocity in the range from 0 to 18.52 mm
      s(-1), and the fluid velocity indices were calculated using adaptive and fixed
      processing bandwidths, respectively. The results showed that the adaptive
      processing bandwidth adjustment, not only significantly reduced the biological
      zero (9.6% of the case using 100 kHz bandwidth), but also enhanced the
      sensitivity of the laser Doppler measurement (over 20%) and linearly responded to
      a wider velocity range (R2 = 0.979 for velocity from 0 to 18.52 mm s(-1)).

PMID- 15191072
TI  - Classification of cardiac abnormalities using heart rate signals.
AB  - The heart rate is a non-stationary signal, and its variation can contain
      indicators of current disease or warnings about impending cardiac diseases. The
      indicators can be present at all times or can occur at random, during certain
      intervals of the day. However, to study and pinpoint abnormalities in large
      quantities of data collected over several hours is strenuous and time consuming.
      Hence, heart rate variation measurement (instantaneous heart rate against time)
      has become a popular, non-invasive tool for assessing the autonomic nervous
      system. Computer-based analytical tools for the in-depth study and classification
      of data over day-long intervals can be very useful in diagnostics. The paper
      deals with the classification of cardiac rhythms using an artificial neural
      network and fuzzy relationships. The results indicate a high level of efficacy of
      the tools used, with an accuracy level of 80-85%.

PMID- 15191071
TI  - Electro-encephalogram disturbances in different sleep-wake states following
      exposure to high environmental heat.
AB  - In this study, cerebral electrical activity or electro-encephalogram (EEG) was
      studied following exposure to high environmental heat, in three different age
      groups of freely moving rats. Each age group was subdivided into three groups:
      the acute heat stress group, subjected to a single exposure of 4 h at 38 degrees
      C in the biological oxygen demand incubator; the chronic heat stress group,
      exposed for 21 days, for 1 h each day, at 38 degrees C in the incubator; and the
      handling control group. The polygraphic sleep-wake recordings involved
      simultaneous recordings of cortical EEG, electro-oculogram (EOG), and
      electromyogram (EMG), on paper and in digital form on computer hard disk, just
      after the heat exposure for the acute stressed rats and on the 22nd day for the
      chronic stressed rats. The power spectrum was calculated for 2s epochs of the EEG
      signals. Quantitative analyses of EEG (qEEG) showed that, in all three age
      groups, changes in higher-frequency components (beta2) were significant in all
      sleep-wake states following both acute and chronic heat stress conditions. The
      power of beta2 activity in all three age groups after acute heat exposure was
      significantly decreased during slow wave sleep (SWS) (p < 0.05) and rapid eye
      movement sleep (p < 0.05), whereas the reverse was observed in the awake state (p
      < 0.05). Following chronic heat exposure, beta2 activity was found to increase in
      all three sleep-wake stages in all groups of rats (p < 0.01 for SWS in the
      weaning group and p < 0.05 for other data). Thus the study demonstrated that the
      cortical EEG is sensitive to environmental heat, and alterations in EEG
      frequencies in different states of mental consciousness due to high heat can be
      differentiated efficiently by EEG power spectrum analysis.

PMID- 15191073
TI  - Non-invasive computerised detection of acute coronary occlusion.
AB  - The goal of this study was to evaluate the role of a computerised, non-invasive
      ECG method for detecting acute coronary occlusion (ACO). Ninety-five standard ECG
      leads were recorded, before and during ACO, from 18 patients undergoing balloon
      angioplasty. ECG amplitude and derivative parameters were calculated for the ORS,
      ST and T components of the ECG signal, before and during ACO. Results were
      obtained for each lead. Sensitivity of the standard visual ECG analysis for
      detecting ACO was 48%, whereas the percentage of conventional ECG changes during
      baseline was 14%. For the best ECG parameter, the amplitude parameter of the ORS
      component, sensitivity was 82%, and the percentage of parameter changes during
      baseline was 20%. The sensitivity for detecting ACO with five of the six ECG
      parameters studied was greater than that of the standard visual analysis.
      Ischaemic changes were detected in 4.3 +/- 1.6 leads per patient using the
      amplitude parameter of the ORS component, whereas, with the standard visual
      analysis, 2.5 +/- 2.1 leads demonstrated such changes (p<0.001). Results were
      then summarized per patient. The standard visual ECG analysis detected ACO in 15
      of 18 patients (83%), if at least one lead showed ischaemic changes. The
      computerised analysis detected ACO in all 18 patients using the same criterion.
      The sensitivity of the computerised method for detecting ACO in the clinical
      setting of angioplasty was greater than that of the standard visual analysis. It
      is suggested that the computerised method may be useful for detecting myocardial
      ischaemia in other clinical settings of acute myocardial ischaemia.

PMID- 15191074
TI  - Automated detection of transient ST-segment episodes in 24 h electrocardiograms.
AB  - A novel automated system is presented for improved detection of transient
      ischaemic and heart rate-related ST-segment episodes in 'real-world' 24 h
      ambulatory ECG data. Using a combination of traditional time-domain and Karhunen
      Loeve transform-based approaches, the detector derives QRS complex and ST-segment
      morphology feature vectors and, by mimicking human examination of feature-vector
      time series and their trends, tracks the time-varying ST-segment reference level
      owing to clinically unimportant, non-ischaemic causes, such as slow drifts, axis
      shifts and conduction changes. The detector estimates the slowly varying ST
      segment level trend, identifies step changes in the time series and subtracts the
      ST-segment reference level thus obtained from the ST-segment level to obtain the
      ST-segment deviation time series, which are suitable for detection of ST-segment
      episodes. The detector was developed using the Long-term ST database containing
      24 h ambulatory ECG records with human-expert annotated transient ischaemic and
      heart rate-related ST-segment episodes. The average ST episode detection
      sensitivity/positive predictivity obtained when using the annotations of the
      annotation protocol B of the database were 78.9%/80.7%. Evaluation of the
      detector using the European Society of Cardiology ST-T database as a test
      database showed average ST episode detection sensitivity/positive predictivity of
      81.3%/89.2%, which are better performances, comparable with those of the systems
      being developed using the European database.

PMID- 15191076
TI  - Non-invasive monitoring of gingival crevicular fluid for estimation of blood
      glucose level.
AB  - Development of a non-invasive method for measuring the blood glucose level is an
      urgent necessity, and putting such a method into practical use will enable some
      of the physical and mental stress that patients with diabetes have to endure to
      be removed. To realise a non-invasive blood glucose monitor, the gingival
      crevicular fluid (GCF) was measured. A GCF-collecting device was developed that
      was designed to be disposable, biocompatible and small enough to be inserted in
      the gingival crevice for collection of a sub-microlitre sample of GCF. Also, a
      high-sensitivity glucose testing tape incorporated in the device was developed.
      Red laser light in a portable optical device measured the colour density of the
      testing tape. Standard glucose solutions were used to investigate the measurement
      accuracy of the GCF glucose monitor and showed a correlation coefficient of R =
      0.99 (n = 20) between the optical density and the glucose levels. The GCF glucose
      monitor was evaluated on healthy Swedish and Japanese adults (n = 10) and both
      GCF glucose levels (GCFLs) and blood glucose levels (BGLs) were measured in
      conjunction with meal loads. The GCFLs were about 1/10-1/560 lower than the BGLs.
      No difference in the range of GCFLs between the Swedish and the Japanese subjects
      was observed. Therefore it was concluded that physique, body mass index and life
      style, such as dietary habit, did not significantly influence the GCFLs. Further,
      the correlation coefficients of all the subjects were 0.70 and 0.88 with each
      group. It was suggested that GCF could be used as a method of non-invasive blood
      glucose measurement.

PMID- 15191075
TI  - Forward electrical transmission line model of the human arterial system.
AB  - A forward mathematical model of the human arterial system, based on an electrical
      transmission line analogy, has been developed, using a new method for the
      calculation of peripheral impedance. Simulations of the human arterial system
      under normal and stenotic arterial conditions were compared with other published
      simulations, as well as measured clinical data and known clinical quantitative
      and qualitative characteristics: the harmonic arterial input impedance spectrum
      demonstrated a mean error of 0.07-0.1 mmHg.s.cm(-1), compared with equivalent
      simulation and physiological data, respectively; qualitative and quantitative
      variation of blood pressure and flow waveforms along the arterial tree followed
      clinical trends; arterial pulse wave velocities compared favourably with
      physiological data close to the aortic root (-50-20 cm s(-1) difference), but
      there were larger differences in the periphery (149-1192 cm s(-1) difference);
      qualitative as well as quantitative variation of blood flow waveforms with
      progressive stenotic arterial disease, as measured by the pulsatility index,
      demonstrated an error between 2 and 16% in comparison with mean clinical data for
      critical stenosis. Under the given test conditions, the forward model was found
      closely to represent clinically observed haemodynamic characteristics of the
      human arterial system.

PMID- 15191077
TI  - Microprocessor-controlled optical stimulating device to improve the gait of
      patients with Parkinson's disease.
AB  - Different types of visual cue for subjects with Parkinson's disease (PD) produced
      an improvement in gait and helped some of them prevent or overcome freezing
      episodes. The paper describes a portable gait-enabling device (optical
      stimulating glasses (OSGs) that provides, in the peripheral field of view,
      different types of continuous optic flow (backward or forward) and intermittent
      stimuli synchronised with external events. The OSGs are a programmable, stand
      alone, augmented reality system that can be interfaced with a PC for program set
      up. It consists of a pair of non-corrective glasses, equipped with two matrixes
      of 70 micro light emitting diodes, one on each side, controlled by a
      microprocessor. Two foot-switches are used to synchronise optical stimulation
      with specific gait events. A pilot study was carried out on three PD patients and
      three controls, with different types of optic flow during walking along a fixed
      path. The continuous optic flow in the forward direction produced an increase in
      gait velocity in the PD patients (up to + 11% in average), whereas the controls
      had small variations. The stimulation synchronised with the swing phase,
      associated with an attentional strategy, produced a remarkable increase in stride
      length for all subjects. After prolonged testing, the device has shown good
      applicability and technical functionality, it is easily wearable and
      transportable, and it does not interfere with gait.

PMID- 15191078
TI  - Validation of a head-neck computer model for whiplash simulation.
AB  - A head-neck computer model was comprehensively validated over a range of rear
      impact velocities using experiments conducted by the same group of authors in the
      same laboratory. Validations were based on mean +/- 1 standard deviation response
      curves, i.e. corridors. Global head-neck angle, segmental angle and local facet
      joint regional kinematic responses from the model fell within experimental
      corridors. This was true for all impact velocities (1.3, 1.8 and 2.6 m s(-1)).
      The non-physiological S-curvature lasted approximately 100 ms. The present,
      comprehensively validated model can be used to conduct parametric studies and
      investigate the effects of factors such as active sequential and parallel muscle
      contractions, thoracic ramping and local tissue strain responses, as a function
      of cervical level, joint region and impact velocity in whiplash injury
      assessment.

PMID- 15191079
TI  - Biomechanical modelling of orthotic treatment of the scoliotic spine including a
      detailed representation of the brace-torso interface.
AB  - As part of the development of new modelling tools for the simulation and design
      of brace treatment of scoliosis, a finite element model of a brace and its
      interface with the torso was proposed. The model was adapted to represent one
      scoliotic adolescent girl treated with a Boston brace. The 3D geometry was
      acquired using multiview radiographs. The model included the osseo-ligamentous
      structures, thoracic and abdominal soft tissues, brace foam and shell, and brace
      torso interface. The simulations consisted of brace opening to include the
      patient's trunk followed by brace closing. To validate the model, the resulting
      geometry was compared with the real in-brace geometry, and the resulting contact
      reaction forces at the brace-torso interface were compared with the equivalent
      forces calculated from pressure measurements made on the in-brace patient.
      Differences between coronal equivalent and reaction forces were less than 7N.
      However, sagittal reaction forces (47N) were computed on the abdomen, whereas
      negligible equivalent forces were measured. The simulated geometry presented
      partially reduced coronal Cobb angles (1-4 degrees), over-corrected sagittal Cobb
      angles and maximum deformation plane (5 degrees), completely corrected coronal
      shift, and sagittal shift and rib humps that were not corrected. This study
      demonstrated the feasibility of a new approach that represents the load transfer
      from the brace to the spine more realistically than does the direct application
      of forces.

PMID- 15191080
TI  - Analysis of amplitude and frequency variations of essential and Parkinsonian
      tremors.
AB  - Variations in the amplitude and period of essential and Parkinsonian tremors were
      studied. It was found that the variations in frequency (or period) were mostly
      similar to the white noise, with the standard deviation typically less than 10%
      of the mean, whereas the variations in amplitude were much larger, with standard
      deviations greater than 30% of the mean, and so could not be effectively smoothed
      by running means. It is conjectured that variations in frequency reflect the
      stable nature of the neural network that generates the rhythmicity responsible
      for the tremor. The variations in amplitude, however, reflect more the
      fluctuations in the firing of individual neurons in the network. It is further
      discussed that the oscillator behind pathological tremor has a stochastic nature
      and can be characterised as a diffusional process. The latter suggests that it is
      sometimes possible for tremors to be described as chaotic processes on certain
      scales in phase space. It is further discussed how the stochastic nature of
      tremors determines the lack of correlation between different tremulous parts of
      the body.

PMID- 15191081
TI  - Periodical in-situ re-calibration of force platforms: a new method for the robust
      estimation of the calibration matrix.
AB  - The paper provides a new technique based on a least-squares approach for the
      accurate estimation of a force platform calibration matrix using simple manual
      procedures, when the direction of the applied loads cannot be perfectly aligned
      with the axes of the platform. This new procedure can be applied to all force
      platforms and allows the combined application of vertical and horizontal forces,
      both static and time-varying. The robust calibration method includes the angular
      errors in the least-squares parameter vector, thus reducing the bias in the
      estimated calibration matrix parameters. The performance of the robust method was
      compared with the conventional one, using a numerical simulation approach
      starting from a known calibration matrix. With the conventional approach, in
      noiseless conditions, the maximum error due to load misalignment (SD = 3 degrees)
      was 6% for the direct terms and over 10% for the cross-talk terms. With the
      robust method, these errors reduced to zero and were always below 0.4%, even when
      realistic noise was superimposed on the measures. With perfectly aligned loads
      and realistic output noise, the confidence intervals of the calibration matrix
      parameters were very similar for the two methods, demonstrating that the
      increased number of parameters did not affect the reliability of the estimate.

PMID- 15191082
TI  - Electrical admittance method for estimating fluid removal during artificial
      dialysis.
AB  - Because the conductivity of blood changes remarkably during artificial dialysis,
      sometimes by more than 20%, changes in tissue admittance at low frequency are
      caused by changes not only in the extracellular fluid volume but also in blood
      conductivity. Therefore the changes in blood conductance due to artificial
      dialysis must be considered for the estimation of water removal by the admittance
      method. An accurate bio-impedance measurement system was developed. Measurement
      error was less than 1% at low frequency and 10% at high frequency. A new
      electrical bio-admittance method (NAM) was evaluated for the continuous
      measurement of removed fluid volume, using a three parallel-compartment tissue
      model, consisting of intracellular, interstitial and blood compartments, which
      takes into account the blood conductivity change. NAM used the equivalent
      conductivity calculated from the leg admittances of patients, measured at 1 min
      intervals during various artificial dialysis procedures. The actual amount of
      excess water removed by ultra-filtration agreed with the NAM-estimated amount
      within an error of 20%. NAM was also applied to estimate the intra- and
      extracellular fluid changes. The results were consistent with the physiological
      changes known to occur during the various forms of dialysis.

PMID- 15191083
TI  - Estimation of the tissue composition of the tumour mass in neuroblastoma using
      segmented CT images.
AB  - Neuroblastoma is the most common extra-cranial, solid, malignant tumour in
      children. Advances in radiology have made possible the detection and staging of
      the disease. Nevertheless, there is no method available at present that can go
      beyond detection and qualitative analysis, towards quantitative assessment of the
      tissue composition of the primary tumour mass in neuroblastoma. Such quantitative
      analysis could provide important information and serve as a decision-support tool
      to the radiologist and the oncologist, result in better treatment and follow-up
      and even lead to the avoidance of delayed surgery. The problem investigated was
      the improvement of the analysis of the primary tumour mass, in patients with
      neuroblastoma, using X-ray computed tomography (CT) images. A methodology was
      proposed for the estimation of the tissue content of the mass: it comprised a
      Gaussian mixture model for estimation, from segmented CT images, of the tissue
      composition of the primary tumour. To demonstrate the potential of the method,
      the results are presented of its application to ten CT examinations of four
      patients. The method provides quantitative information, and it was observed that
      the tumour in one of the patients reduced from 523 cm3 to 81 cm3 in volume, with
      an increase in calcification from about 20% to about 88% of the tumour volume, in
      response to chemotherapy over a period of five months. Results indicate that the
      proposed technique may be of considerable value in assessing the response to
      therapy of patients with neuroblastoma.

PMID- 15191084
TI  - Segmentation of the fibro-glandular disc in mammograms using Gaussian mixture
      modelling.
AB  - The paper presents a technique for the segmentation of the fibro-glandular disc
      in mammograms based upon a statistical model of breast density. The density
      function of the model was represented by a mixture of up to four weighted
      Gaussians, each one corresponding to a specific density class in the breast. The
      parameters of the model and the number of tissue classes in the breast were
      determined using the expectation-maximisation algorithm and the minimum
      description length method. Grey-level statistics of the pectoral muscle were used
      to determine the tissue categories that are likely to represent the fibro
      glandular disc. The method was applied to 84 medio-lateral oblique mammograms
      from the Mini-MIAS database. The results of the segmented fibro-glandular disc
      were assessed by a radiologist using the original and the segmented images, with
      reference to a ranking table categorising the results of segmentation as: 1:
      excellent; 2: good; 3: average; 4: poor; and 5: complete failure. Of the 84 cases
      analysed, 64.3% were rated as excellent, 16.7% were rated as good, 10.7% were
      rated as average, and 4.7% were rated as poor; only 3.6% of the cases were rated
      as a complete failure with regard to segmentation of the fibro-glandular disc.

PMID- 15191085
TI  - Natural frequency assessment of stability of root keeper magnetic devices.
AB  - The aim of the study was to evaluate the potential for using natural frequency
      (NF) as an indicator for assessing the stability of a magnetic keeper device used
      in prosthodontic treatment. A three-dimensional finite element (FE) model of a
      root keeper-cement-dentine system was established for NF analysis. The model was
      first validated against a series of in vitro experiments. Then, NF values of the
      first vibrational mode of the FE model with various boundary conditions were
      calculated. The in vitro results showed that the measured NF values of the root
      keeper-incisor units decreased significantly (p<0.01) from 9.07 +/- 0.37 to 5.73
      +/- 0.10 kHz when the units were embedded in simulated bony tissue. Results
      obtained from FE simulations demonstrated that the root keeper would fully loosen
      when the constant values of the spring elements were lower than 10(4) N-m(-1).
      Furthermore, a linear increase in the NF values of the model was observed from
      6.16 to 15.52 kHz, when the constant was increased from 10(4) to 10(7) N-m(-1),
      and the values then reached a plateau. The results indicate that the NF value of
      a root keeper has the potential to be used for monitoring the stability of such a
      device.

PMID- 15191086
TI  - Nerve conduction block utilising high-frequency alternating current.
AB  - High-frequency alternating current (AC) waveforms have been shown to produce a
      quickly reversible nerve block in animal models, but the parameters and mechanism
      of this block are not well understood. A frog sciatic nerve/gastrocnemius muscle
      preparation was used to examine the parameters for nerve conduction block in
      vivo, and a computer simulation of the nerve membrane was used to identify the
      mechanism for block. The results indicated that a 100% block of motor activity
      can be accomplished with a variety of waveform parameters, including sinusoidal
      and rectangular waveforms at frequencies from 2 kHz to 20 kHz. A complete and
      reversible block was achieved in 34 out of 34 nerve preparations tested. The most
      efficient waveform for conduction block was a 3-5 kHz constant-current biphasic
      sinusoid, where block could be achieved with stimulus levels as low as 0.01
      microCphase(-1). It was demonstrated that the block was not produced indirectly
      through fatigue. Computer simulation of high-frequency AC demonstrated a steady
      state depolarisation of the nerve membrane, and it is hypothesised that the
      conduction block was due to this tonic depolarisation. The precise relationship
      between the steady-state depolarisation and the conduction block requires further
      analysis. The results of this study demonstrated that high-frequency AC can be
      used to produce a fast-acting, and quickly reversible nerve conduction block that
      may have multiple applications in the treatment of unwanted neural activity.

PMID- 15191087
TI  - Removal of ocular artifacts from electro-encephalogram by adaptive filtering.
AB  - The electro-encephalogram (EEG) is useful for clinical diagnosis and in
      biomedical research. EEG signals, however, especially those recorded from frontal
      channels, often contain strong electro-oculogram (EOG) artifacts produced by eye
      movements. Existing regression-based methods for removing EOG artifacts require
      various procedures for preprocessing and calibration that are inconvenient and
      time-consuming. The paper describes a method for removing ocular artifacts based
      on adaptive filtering. The method uses separately recorded vertical EOG and
      horizontal EOG signals as two reference inputs. Each reference input is first
      processed by a finite impulse response filter of length M (M = 3 in this
      application) and then subtracted from the original EEG. The method is implemented
      by a recursive least-squares algorithm that includes a forgetting factor (lambda
      = 0.9999 in this application) to track the non-stationary portion of the EOG
      signals. Results from experimental data demonstrate that the method is easy to
      implement and stable, converges fast and is suitable for on-line removal of EOG
      artifacts. The first three coefficients (up to M = 3) were significantly larger
      than any remaining coefficients.

PMID- 15191088
TI  - Bellows-less lung system for the human patient simulator.
AB  - A new bellows-less lung simulator utilising a fixed-volume pressure controller to
      simulate spontaneous breathing is presented as an alternative to the traditional
      bellows-driven mechanical lung system in the human patient simulator (HPS). The
      HPS is a fully interactive, life-like simulator used to train medical students
      and anaesthesia residents. The lung simulator simulates carinal pressure, which
      allows for simulation of actively breathing or ventilated patients. In the
      current HPS implementation, breathing is physically simulated with a pair of
      bellows and a computer-controlled piston, but, owing to physical and dynamic
      constraints, the model suffers from a lot of dead space. Furthermore, the set-up
      incorporates several mechanical components that require time-consuming
      calibrations, which drives up manufacturing costs. A bellows-less lung simulator
      has been designed and built which successfully simulates airflow in and out of
      the mouth by controlling the carina pressure. The new system is able to simulate
      tidal volumes between 400 and 500 ml, with flow rates of 4.3-5.71 min(-1) at a
      respiratory rate of 12 breaths per minute. The new design not only matches the
      ventilation performance of the HPS, but also simulates at 60 breaths per minute,
      which the HPS cannot maintain.

PMID- 15191089
TI  - Emotion recognition system using short-term monitoring of physiological signals.
AB  - A physiological signal-based emotion recognition system is reported. The system
      was developed to operate as a user-independent system, based on physiological
      signal databases obtained from multiple subjects. The input signals were
      electrocardiogram, skin temperature variation and electrodermal activity, all of
      which were acquired without much discomfort from the body surface, and can
      reflect the influence of emotion on the autonomic nervous system. The system
      consisted of preprocessing, feature extraction and pattern classification stages.
      Preprocessing and feature extraction methods were devised so that emotion
      specific characteristics could be extracted from short-segment signals. Although
      the features were carefully extracted, their distribution formed a classification
      problem, with large overlap among clusters and large variance within clusters. A
      support vector machine was adopted as a pattern classifier to resolve this
      difficulty. Correct-classification ratios for 50 subjects were 78.4% and 61.8%,
      for the recognition of three and four categories, respectively.

PMID- 15191090
TI  - Coronary angiography using selective catheterization of each coronary artery.

PMID- 15191091
TI  - The existence of radiology is dependent on differences in shades of gray.

PMID- 15191092
TI  - Ultrasound in the diagnosis of developmental dysplasia of the hip (DDH).

PMID- 15191093
TI  - Assessment of hepatic iron content using magnetic resonance imaging.
AB  - Numerous studies over the past decade have shown that magnetic resonance imaging
      (MRI) has great potential for detecting and quantifying the distribution of iron
      in the body. With MRI, tissue iron is indirectly identified by the paramagnetic
      effects of iron on the shortening of water proton MR relaxation times. However,
      these effects are complex and involve a number of factors, such as tissue
      hydration, distribution of iron and water within the tissue, and the amount of
      iron loading within the iron storage molecules. A coherent understanding of how
      these factors influence the MRI signal is still lacking. The dependence on
      experimental conditions, such as magnet field strength, pulse sequences, and data
      acquisition parameters, further complicates iron quantification with MRI. To
      date, there is no generally accepted MRI approach available for clinical
      application. In this review, we first explain the basic MR relaxation mechanisms
      underlying the detection of iron with MRI. We then review the literature on
      empirical MRI studies of hepatic iron. Finally, we summarize the critical issues
      that need to be addressed to develop MRI techniques for non-invasive iron
      detection in the body.

PMID- 15191094
TI  - Fluoroscopically guided percutaneous gastrostomy with modified gastropexy and a
      large-bore balloon-retained catheter in patients with head and neck tumors.
AB  - PURPOSE: To report on fluoroscopically guided percutaneous gastrostomy (FPG)
      using a modified gastropexy technique with the insertion of a large-bore balloon
      retained gastrostomy catheter in patients with head and neck tumors. MATERIAL AND
      METHODS: Thirty-four patients with head and neck tumors underwent a modified
      gastropexy with two T-fasteners followed by the insertion of a 14-F ballooon
      retained catheter through a peel-away introducer. The success rate and the
      complications of the procedures were evaluated at 14 days, 30 days, and 60 days.
      The complications were classified as: major complications that necessitated
      intensive and/or surgical treatment; minor complications that could be treated
      conservatively; and tube-related complications manageable by tube exchange.
      RESULTS: FPG was technically successful in all cases. There were no major
      complications, two minor complications where superficial stoma infection was
      controlled by antibiotics, three minor tube-related complications, all three
      easily managed by catheter replacement via the original tract. CONCLUSION: FPG
      with insertion of a large-bore balloon-retained catheter using a modified
      gastropexy technique is a safe and effective method that creates a feeding access
      for patients with head and neck tumors and esophageal obstruction. Minor
      complications can be managed conservatively. FPG may be a good alternative to
      surgical or percutaneous endoscopic gastrostomy.

PMID- 15191095
TI  - Evaluation of a wavelet-based computer-assisted detection system for identifying
      microcalcifications in digital full-field mammography.
AB  - PURPOSE: To evaluate a new wavelet-based computer-assisted detection (CAD) system
      for detecting and enhancing microcalcifications. MATERIAL AND METHODS: A total of
      280 mammograms acquired by full-field digital mammography (Senographe 2000D; G.E.
      Medical Systems Milwaukee, Wisc., USA) were analyzed with and without a new
      wavelet-based CAD system for detecting and enhancing microcalcifications. The
      mammograms comprised roughly equal numbers of cases from each of the BIRADS
      (Breast Imaging, Reporting and Data System, according to the American College of
      Roentgenology) categories 1-5. Histologic confirmation was available for all of
      the 180 cases assigned BIRADS categories 3-5. Four readers interpreted all 280
      images for suspicious microcalcifications using a scale of 1-5. The readers
      alternately assessed 5 images with and 5 without CAD. In a second reading
      immediately following the first, the readers had to reassess the 280 mammograms.
      The images that had already been interpreted without CAD were now presented with
      CAD and vice versa. The images were interpreted as soft copies on a diagnostic
      mammography workstation (Image Diagnost GmbH, Neufahrn/Munich, Germany). All
      images interpreted with CAD were presented with enhancement of
      microcalcifications by wavelet algorithms and prompting of microcalcifications.
      ROC (receiver operating characteristic) analyses were performed, and image
      interpretation time with and without CAD was measured. RESULTS: The overall time
      for interpretation required by all 4 readers together was 483 min with CAD
      compared to 580 min without CAD. ROC analysis revealed no significant advantage
      of CAD for the individual readers. Readers 3 (0.811/0.817) and 4 (0.799/0.843)
      had a slightly improved AUC (area under the curve) with CAD. Readers 1 and 2 had
      a slightly lower AUC with CAD (0.832 versus 0.861 and 0.818 versus 0.849).
      CONCLUSION: The CAD system significantly (P<0.05, t test) speeded up image
      interpretation with respect to the identification of microcalcifications, while
      the diagnostic quality remained almost identical under the study conditions.

PMID- 15191096
TI  - Stereotactic core needle biopsy in non-palpable breast lesions. What number is
      needed?
AB  - PURPOSE: To investigate whether three stereotactic core needle biopsies (S-CNB)
      in non-palpable breast lesion are enough for accurate preoperative diagnosis.
      MATERIAL AND METHODS: Between September 1994 and December 2000, 523 patients with
      mammographically detected breast lesions and who proceeded to surgery were
      preoperatively stereotactically biopsied with an automated 14-gauge biopsy
      device. Three samples were taken from each lesion irrespective of whether the
      lesion presented as "microcalcifications only", "microcalcifications and a mass",
      or a "mass, architectural distorsion, or stellate lesion without
      microcalcifications". The histopathology was divided into three subgroups:
      diagnostic, atypia (ranging from atypical cells to probably cancer), and non
      diagnostic material. RESULTS: Post-surgical histopathology diagnosed 454 (87%)
      malignant tumors and 69 (13%) benign lesions. Three S-CNB correctly diagnosed the
      malignant tumors in 84% in the subgroup "microcalcifications only". In the
      category "microcalcifications and a mass", the diagnostic accuracy was 97% and in
      the subgroup "mass, architectural distorsion, or stellate lesion without
      microcalcifications" 3 S-CNB resulted in 93% correct diagnostic material. In 19
      of the 454 patients (4%) 1, 2 or all 3 preoperative S-CNB showed atypia. In 20
      patients (4%), all 3 S-CNB were non-diagnostic. Thirteen of these 20 patients had
      "microcalcifications only" and 7 had a mass without microcalcifications.
      CONCLUSION: Three S-CNB were enough for correct diagnosis in "masses,
      architectural distorsions, or stellate lesions without microcalcifications" and
      in "microcalcifications and a mass", but were not sufficient in
      "microcalcifications only".

PMID- 15191097
TI  - Computer-assisted detection as a second reader in symptomatic Asian women with
      palpable breast cancer.
AB  - PURPOSE: To determine the potential role of a computer-assisted detection (CAD)
      algorithm as a second reader for experienced and inexperienced radiologists in
      mammography reading in Asian women. MATERIAL AND METHODS: Two-view mammograms
      performed in 124 consecutive patients who presented with palpable breast cancer
      masses were retrospectively evaluated by two experienced breast radiologists (7
      and 10 years' experience). The original reports of the session radiologists with
      variable experience of reading mammograms (2 to more than 10 years) were also
      evaluated. The number of suspicious masses and microcalcification clusters
      detected in each patient by both groups of radiologists were recorded. The
      radiologists then re-evaluated the films with the CAD system as a second reader.
      Any improvement in the detectability of breast pathology by either the
      experienced radiologists and/or by the session radiologists was then assessed. A
      total of 127 breasts had biopsy-proven carcinoma; 74 breasts had mastectomy
      performed. All the imaging results were correlated with tru-cut biopsy or
      mastectomy histology. RESULTS: With CAD-aided interpretation, there were
      altogether 95 visible masses and 77 suspicious microcalcification clusters in 109
      mammographically detectable cancers correlated with histology results. There was
      a 7.4% (7/95) and 10.4% (8/77) increase in the number of masses and
      microcalcification clusters detected, respectively, by the experienced
      radiologists after application of CAD, whereas the increase was 13.7% (13/95) and
      27.3% (21/77) for detection of masses and microcalcifications by the session
      radiologists, respectively. In 9 patients, a secondary focus detected by CAD was
      confirmed by histology. Three patients had contralateral breast tumors, 1 had a
      satellite invasive tumor while 5 had ductal carcinoma in situ on the same breast.
      Based on the biopsies and 74 mastectomies, the true-positive and false-positive
      detection rate of CAD was 92.6% and 31.8% for detection of carcinomas. The true
      positive and false-positive detection rates were 100% and 58.8% for
      microcalcification clusters. CONCLUSION: The current generation CAD algorithm
      helped to improve the detection rate of carcinomas, calcifications and
      multifocality in Asian breasts.

PMID- 15191098
TI  - Clinical assessment of a radiolucent cushion for mammography.
AB  - PURPOSE: To determine whether use of a radiolucent cushion could significantly
      decrease pain during screening mammography without compromising image quality or
      other technical factors. MATERIAL AND METHODS: 838 patients presenting for
      routine screening mammography were evaluated. The radiolucent cushions were
      placed on the compression surfaces of the mammographic equipment and were used
      while imaging the right breast. No pads were used while imaging the left breast.
      Patient age, hormonal status, compression force, and radiation dose values were
      collected on all patients. Each subject completed a visual analog pain scale
      (VAS) rating the degree of pain experienced with and without the cushions. All
      mammographic images obtained (CC and MLO views) were compared, side by side
      (cushioned versus non-cushioned) by the readers. RESULTS: Use of radiolucent
      cushions reduced pain by 10% or more in 66% (555/838) of women. Patients in this
      "benefited group" experienced an average pain reduction of 53%. No compromise of
      image quality was observed. Compression force and radiation dose values were
      highly correlated between the cushioned and non-cushioned sides. CONCLUSION: Two
      thirds of women experienced a significant reduction of pain when the radiolucent
      cushions were used during mammography. Pain reduction was accomplished without
      any clinically significant change in compression force, radiation dose values, or
      image quality.

PMID- 15191099
TI  - In vitro coronary artery imaging with sixteen-slice helical computed tomography.
AB  - PURPOSE: To determine the benefits of submillimeter coronary computed tomography
      (CT) angiography in vitro. MATERIAL AND METHODS: The coronary arteries of three
      domestic pigs were filled with contrast agent and depicted with clinically
      applicable CT angiography protocols with a slice thickness of 0.63 to 2.5 mm.
      RESULTS: With 2.5 mm slices, only the third-degree coronary artery branches could
      be discerned. With 1.25 mm slices, some fourth-degree branches of the right
      coronary artery could be discerned upon maximum intensity projections. With
      0.63mm slices, fourth-degree coronary artery branches could be discerned in all
      locations. CONCLUSION: The introduction of 16-row detector CT with submillimeter
      z-axis resolution translates into an order-of-magnitude benefit for the depiction
      of coronary artery branches.

PMID- 15191101
TI  - Safety of heparin reversal with protamin and immediate sheath removal after
      coronary angioplasty.
AB  - PURPOSE: To study the safety of giving protamin after coronary angioplasty to
      reverse heparin for immediate removal of the femoral sheath. MATERIAL AND
      METHODS: After successful angioplasty, 100 patients were randomized to receive
      protamin and immediate sheath removal or to the control group with sheath removal
      after 3 h. Patients were followed for 30 days so that groin complications and
      coronary events could be compared. After 6 months, target vessel
      revascularization and death were recorded. RESULTS: The time to mobilization was
      significantly shorter in the protamin group compared to the control group; 6
      versus 19 h. The protamin patients were more satisfied than the control patients,
      in particular during bed rest after compression. Puncture site complications were
      one (2%) and two (4%) pseudoaneurysms in the protamin group and the control
      group, respectively. Early angina and restenosis/reocclusion before 30 days were
      seen in 4 patients in the protamin group and in 1 in the control group. Adverse
      incidents between 30 days and 6 months were the same for both groups. CONCLUSION:
      Protamin reversal improved patient comfort and reduced immobilization time. The
      cardiac safety concern observed requires the antiplatelet agent clopidogrel to be
      given before the procedure.

PMID- 15191100
TI  - High-resolution contrast-enhanced magnetic resonance angiography of the carotid
      arteries using fluoroscopic monitoring of contrast arrival: diagnostic accuracy
      and interobserver variability.
AB  - PURPOSE: To evaluate the diagnostic accuracy of high-resolution contrast-enhanced
      magnetic resonance angiography (CE-MRA) of the supra-aortic arteries using the
      CareBolus technique. Digital subtraction angiography was the standard of
      reference. MATERIAL AND METHODS: Fifty consecutive patients with suspected
      internal carotid artery stenosis underwent CE-MRA and digital subtraction
      angiography. CE-MRA was performed on a 1.5-T superconducting scanner with the
      CareBolus technique. CareBolus combines a nearly real-time 2D-FLASH (fast low
      angle shot) sequence for fluoroscopic triggering and a high-resolution 3D-FLASH
      with elliptical centric view order for the angiographic pulse sequence (6.0/2.16
      ms [TR/TE], 30 degrees flip angle, 30.98 s acquisition time, 0.88 mm effective
      (interpolated) partition thickness and a 160 x 512 matrix). Intra-arterial
      digital subtraction angiography and CE-MRA studies were evaluated independently
      by four blinded readers. Internal carotid artery stenoses were graded according
      to the NASCET criteria. RESULTS: CE-MRA had an accuracy of 92.53%, a sensitivity
      of 95.64%, and a specificity of 90.39% for the identification of carotid artery
      stenoses > or = 70% (grade 3). Image quality for suppression of stationary tissue
      and venous contrast was good, but was reduced in five cases due to patient
      motion. CONCLUSION: The CareBolus technique is a useful non-invasive method for
      high-resolution imaging of the supra-aortic vessels because of its easy
      application and high sensitivity and specificity. Limitations can occur in non
      compliant patients due to motion artifacts during the measurement time.

PMID- 15191102
TI  - Threshold selection in virtual bronchoscopy: phantom study and clinical
      implications.
AB  - PURPOSE: To investigate the effect of the threshold selection on the apparent
      diameter of a virtual bronchus and the virtual wall morphology and to examine the
      parameters that can affect the selection of the appropriate threshold for virtual
      bronchoscopy with single slice computed tomography. MATERIAL AND METHODS: A
      bronchial phantom containing plastic tubes simulating the airways of the
      tracheobronchial tree was constructed. The diameters of the virtual images of
      these tubes were measured using various thresholds for two different materials
      surrounding the tubes: air and water. These measurements were correlated with the
      density in HU of the walls. Furthermore, data from 20 virtual bronchoscopies in
      patients were retrospectively analyzed in the same way. RESULTS: The diameter of
      a virtual bronchus is strongly affected by the selected threshold. The
      appropriate threshold for accurate diameter representation depends on the density
      of the bronchial wall. CONCLUSION: Our results suggest that in clinical practice
      a single threshold value cannot be used for imaging all segments of the
      tracheobronchial tree. While a value of -520 is appropriate for the trachea and
      lobar segments, values down to -720 could be needed on the level of segmental and
      subsegmental bronchi. At these levels, a threshold value about 65 HU more
      negative than the value where the artificial holes appear on the virtual
      bronchial walls could be used.

PMID- 15191103
TI  - Complications associated with percutaneous nephrostomies. A retrospective study.
AB  - PURPOSE: To determine the morbidity and mortality associated with radiologically
      guided percutaneous nephrostomy (PCN). MATERIAL AND METHODS: A retrospective
      analysis of 401 patients treated with 569 PCN over a 5-year period was performed.
      Using the Seldinger technique, the catheters (6-10 F) were placed under
      fluoroscopic, ultrasonographic, or CT guidance. Data on underlying disease,
      complications, subsequent management, and long-term management were collected.
      RESULTS: PCN was successful in 558 of the 569 attempts (98%). There were 22 major
      complications (4%) in 569 procedures, including cardiac arrest, bleeding
      requiring transfusion or embolization, septicemia, hydrothorax or pneumothorax.
      There were 38% minor complications, including urinary tract infection, catheter
      dislodgement, catheter obstruction by debris, urinary leakage, and inflammation
      of the skin at the site of insertion of the percutaneous catheter. Seventy-seven
      (14%) of the procedures were followed by urinary tract infection during the PCN
      treatment. Seventy-nine (14%) catheters slipped out unintentionally. CONCLUSION:
      Percutaneous nephrostomy is a gentle procedure associated with high technical
      success and low morbidity. However, the risk of the procedure has to be weighed
      against the expected benefit.

PMID- 15191104
TI  - Sclerosing stromal tumor of the ovary in pregnancy: clinical, ultrasonography,
      and magnetic resonance imaging findings.
AB  - We report a case of sclerosing stromal tumor of the ovary in a 30-year-old
      pregnant patient presenting with pelvic pain, dysuria, and metrorrhagia. Very few
      reports of sclerosing stromal tumor of the ovary during pregnancy have been
      presented. The purpose of our work is to present the findings at physical
      examination, ultrasonography, magnetic resonance imaging, and histopathology, to
      review the literature regarding this uncommon neoplasm, and to show the
      usefulness of magnetic resonance imaging in the assessment of pelvic masses
      during pregnancy.

PMID- 15191105
TI  - Ultrasound-guided large needle core biopsy of the axilla.
AB  - PURPOSE: To study the diagnostic yield and safety aspects of large needle core
      biopsy of pathologic lesions in the axillary region using a semi-automatic biopsy
      gun. MATERIAL AND METHODS: A series of 21 consecutive large needle core (14G, 2.1
      mm) biopsies of the axilla was evaluated. The biopsies were performed under
      ultrasound guidance with one (n = 13) or two (n = 8) needle passes. The results
      were correlated to the clinical, mammographic, ultrasound and surgical
      histopathologic findings. RESULTS: In 18 patients, specimens large enough for
      diagnosis were retrieved. In two patients the specimens were insufficient and non
      diagnostic. In one patient with a non-malignant yield the result was false
      negative. No neural or vascular injury occurred. CONCLUSION: The procedure might
      be safely employed in the diagnosis of ultrasonographically demonstrable lesions
      of the axilla, whenever specimens larger than those obtainable with a fine needle
      are desired.

PMID- 15191106
TI  - Limitations of quantitative bone-mass measurements using assessments of first
      order statistics of grey-level histograms in plain radiographs.
AB  - PURPOSE: To evaluate the quality assurance of image-processing techniques in
      plain radiographs of skeletal structures. MATERIAL AND METHODS: Twenty-two
      patients were studied, each with one osteolytic metastasis. Accuracy and
      precision of tube voltage and timer were confirmed. The mean value of grey-level
      histograms in plain radiographs (MVGLHs) was assessed. The deviation was
      monitored after five sets of sequential X-rays retaining the same settings for
      each radiograph. RESULTS: Deviation was significantly higher in anatomical areas
      of thorax (21.2%) and abdomen (42.4%), while the consistency of MVGLH for weight
      bearing bones was satisfactory with a maximum deviation of 2.9% (P<0.001, Kruskal
      Wallis test). CONCLUSION: Assessment of MVGLH in plain radiographs is a reliable
      method for the extremities and generally for regions without superimposed movable
      tissues.

PMID- 15191107
TI  - Role of the constructive interference in steady-state sequence in the
      classification of sacral meningeal cysts.
AB  - PURPOSE: To investigate the role of the CISS (constructive interference in steady
      state) sequence in sacral meningeal cysts. MATERIAL AND METHODS: Fourteen
      patients with sacral meningeal cysts were included. Conventional T1W and T2W
      sequences and the CISS sequence (TR/TE = 12.25/5.90) were obtained at 1.5-T. The
      1-mm-thick base images and multiplanar reformatted images of the CISS sequence
      were studied. The sacral meningeal cysts were classified by the CISS sequence in
      accordance with the previously described surgical and histopathological criteria.
      RESULTS: A total of 25 sacral meningeal cysts were identified in the 14 patients.
      The cysts and their contents were visualized by the CISS sequence, and the CISS
      sequence was superior to the T1W and T2W images. Fifteen of the cysts were
      consistent with type I lesions (extradural meningeal cysts without nerve fibers
      inside) and 10 cysts with type II lesions (extradural meningeal cysts with nerve
      fibers inside). There were no type III lesions (intradural meningeal cysts) in
      the sacral region. CONCLUSION: Previous studies have indicated that conventional
      MRI as well as magnetic resonance myelography are inconsistent for a
      classification of sacral meningeal cysts. The CISS sequence with its capability
      to obtain T2W thin slice acquisitions is superior in showing the nerve root
      fibers contained in the cysts, which is essential in the differentiation of type
      I and II cysts. Application of the CISS sequence is recommended in the diagnosis
      of sacral meningeal cysts.

PMID- 15191108
TI  - Dermoid tumor with involvement of the frontal lobes.
AB  - Intraparenchymal location of a dermoid tumor is extremely rare, and there are
      only four reports in the literature. This article presents a patient with a
      dermoid tumor with trilobulated components; an extra-axial component in the basal
      frontal/ethmoidal region, and two intra-axial components located in each frontal
      lobe. In addition, two small fat-density lesions anterior to the component in the
      left frontal lobe were present, probably due to partial intraparenchymal rupture
      of the tumor. The pathogenesis of intra-axial locations is still controversial,
      and this article proposes that in at least some cases intraparenchymal rupture of
      dermoids can cause intra-axial dermoids.

PMID- 15191109
TI  - Magnetic resonance evaluation of cerebral toxoplasmosis in patients with the
      acquired immunodeficiency syndrome.
AB  - PURPOSE: To evaluate and delineate the characteristics of cerebral toxoplasmosis
      lesions using a combination of magnetic resonance (MR) spectroscopy, diffusion,
      and perfusion studies. MATERIAL AND METHODS: A total of 8 patients with 23
      lesions were evaluated on a 1.5-T MR system. Diffusion-weighted imaging (DWI) was
      performed with three 'b' values of 50, 500, and 1000 s/mm2, and the apparent
      diffusion coefficient maps were calculated. The diffusion-weighted appearances
      and the T2-weighted MR appearances of the lesions were compared. MR spectroscopy
      was performed using the point-resolved single-voxel technique with two TE values
      of 135 ms and 270 ms. Perfusion studies were carried out using the dynamic
      contrast-enhanced technique, and the relative cerebral blood volume maps were
      qualitatively and quantitatively analyzed. RESULTS: DWI revealed the majority of
      the lesions as having increased diffusion within their necrotic centers, with the
      ADC ranging from 0.5 to 3.01 (mean +/- SD: 1.49 +/- 0.7). All the lesions
      revealed a predominant lipid peak on MR spectroscopy and were extremely
      hypovascular on perfusion MR studies. CONCLUSION: MR diffusion, spectroscopy, and
      perfusion studies help in characterizing toxoplasmosis lesions and, in most
      cases, can be used in combination to help establish the diagnosis of
      toxoplasmosis.

PMID- 15191110
TI  - Traumatic cervical injuries in ankylosing spondylitis.
AB  - PURPOSE: To demonstrate the importance of magnetic resonance (MR) and computed
      tomography (CT) in the evaluation of cervical traumas in patients suffering from
      ankylosing spondylitis. MATERIAL AND METHODS: Eleven patients with advanced
      ankylosing spondylitis were admitted to neurosurgical treatment after trauma to
      the neck region. All had neurological symptoms and were evaluated with plain X
      ray, CT, and MR. RESULTS: CT with reformation sagittal and coronal plane was
      superior to plain X-ray films in demonstrating fractures and dislocations. MR was
      considered mandatory when evaluating changes in medulla and epidural hematomas,
      which were detected in 4 patients. The clinical outcome was poor in 5 patients
      and good in 6. The poorest outcome was seen in patients with cord contusion and
      epidural hematoma. CONCLUSION: We conclude that plain X-ray is of no greater
      importance in the acute phase of highest value in follow-up evaluation of the
      healing process and final position of the fractured vertebrae. Our protocol in
      the acute phase in traumatized ankylopoetic patients consists of lateral
      conventional X-ray, CT with reformatted images, and MR, the last-mentioned being
      important in detecting epidural hematoma that reduces the clinical outcome
      further if not removed. In our opinion, MR must be part of the radiological
      protocol following neck traumas in all patients with ankylosing spondylitis.

PMID- 15191111
TI  - Comparable ultrasound measurements of ten anatomical specimens of infant hip
      joints by the methods of Graf and Terjesen.
AB  - PURPOSE: To define which sonographic section planes relative to the acetabular
      inlet plane will produce analyzable images with the methods of Graf and Terjesen.
      MATERIAL AND METHODS: Anatomical specimens of infant hip joints were investigated
      in a water bath using the methods of Graf and Terjesen. Acetabular position was
      varied in defined increments with respect to the ultrasound beam. The alpha
      angles and the femoral head coverage (FHC) were measured. RESULTS: To obtain
      images analyzable by the two methods, the ultrasound beam had to intersect with
      the acetabular inlet plane at defined angles. The acetabular notch had to be
      anteriorly rotated from the ultrasound beam plane by at least 20 degrees. Beam
      entry within a 50 degrees sector posterior to the perpendicular on the inlet
      plane resulted in analyzable images. The stepwise multiple linear regression
      analysis showed that alpha angles and FHC were much affected by the coronal-plane
      transducer tilt. CONCLUSION: The fact that caudal tilts of the transducer are
      associated with reduced alpha angles and FHC values should be kept in mind in
      clinical ultrasound investigations. It is recommended that the transducer should
      be put on the greater trochanter perpendicular to the transverse axis of the
      body.

PMID- 15191113
TI  - Doppler examination of the allografted kidney.

PMID- 15191112
TI  - Differential growth rates of the cerebellum and posterior fossa assessed by post
      mortem magnetic resonance imaging of the fetus: implications for the pathogenesis
      of the chiari 2 deformity.
AB  - PURPOSE: To evaluate post mortem magnetic resonance imaging of the fetus to
      provide data on the rate of growth of the cerebellum, bony posterior fossa,
      supratentorial bony compartment and cerebrum. MATERIAL AND METHODS: Twenty
      fetuses subsequently shown to have normal brain and spines on autopsy were
      studied using MRI post mortem. MRI from 20 normal pediatric brain examinations in
      children aged 6 years or younger were studied for comparison. Post mortem MRI was
      performed using a high-resolution fast spin echo technique providing T2 weighted
      images. The area of the cerebellar vermis, posterior fossa, supratentorial skull
      cavity and cerebral hemispheres was measured in the sagittal plane in all cases.
      These measurements were compared over the age ranges studied. RESULTS: We have
      shown that there are differences in the rate of growth and the apparent
      commencement of growth between the structures under study. The cerebellum
      appeared to start its significant growth at 16.5 weeks with a rate of 16 mm2/week
      throughout pregnancy, while the cerebral hemisphere appeared to commence
      significant growth at 13 weeks at a rate of 184 mm2/week throughout pregnancy.
      This is in contrast to the bony posterior fossa, whose growth paralleled the
      supratentorial bony compartment at all ages studied. CONCLUSION: We interpret our
      findings as showing relatively late commencement of cerebellar growth compared to
      the cerebral hemispheres, whereas the growth of the bony posterior fossa appears
      to be in advance and independent of cerebellar growth. Our results support the
      hypothesis that posterior fossa development depends on raised hydrostatic
      pressure in the CSF containing structures of the posterior fossa. When this
      mechanism fails, as in some cases of myelomeningocoele, a small posterior fossa
      is formed which characterizes the Chiari 2 malformation.

PMID- 15191114
TI  - The federal budget--turning the page for public health?

PMID- 15191115
TI  - The need for directly measured health data in Canada.

PMID- 15191116
TI  - Proxy reporting and the increasing prevalence of arthritis in Canada.
AB  - BACKGROUND: Analyses of the 1994/95 to 1998/99 Canadian National Population
      Health Surveys (NPHS) reveal significant, and greater than projected, increases
      in the reported arthritis in the household population aged 15+ years, from 13.4
      to 16.0%. The objectives of this study were to determine whether the increasing
      prevalence of arthritis can be explained by a) changes in the age and sex
      structure of the population, or b) the variation in the proportion of proxy
      respondents and whether proxy reporting affects the overall prevalence estimate.
      METHODS: Overall analyses of 1994/95, 1996/97 and 1998/99 cycles of the NPHS, for
      arthritis or rheumatism reported as a long-term health problem diagnosed by a
      health professional. Stratified analyses, by respondent type, to account for the
      decreasing proportion of proxy respondents over time (33% to 16%). RESULTS:
      Overall age-sex standardized prevalence estimates were similar to crude
      estimates. The crude prevalence of arthritis in proxy respondents was stable
      (approximately 8.5%), whereas in self-respondents it increased from 15.8 to 17.4%
      over the 3 cycles. Adjustment for the lower prevalence in proxy respondents
      increased the estimated overall prevalence of arthritis by at least 1 percentage
      point for each cycle year. The disparity between self- and proxy reporting was
      higher for younger people and females. CONCLUSION: Significant disparity exists
      in age- and sex-specific prevalence estimates between self- and proxy
      respondents. The increase in prevalence of arthritis over time is a result of
      increased reporting by self-respondents. Proxy reporting affects overall
      prevalence. The findings have implications for the use of NPHS data.

PMID- 15191117
TI  - Measured weights in PEI adults reveal higher than expected obesity rates.
AB  - BACKGROUND: The increasing prevalence of obesity and overweight in Canada is a
      significant health concern. Unfortunately, we know very little about the actual
      weight status and associated health risks in our population since most surveys
      use only self-reported body weights and heights and typically do not include a
      measure of body fat distribution. This paper summarizes the findings of the
      Prince Edward Island Nutrition Survey. METHODS: A random sample of 1,995 adults
      aged 18-74 were interviewed in their homes and weights, heights and waist
      circumference measurements were obtained. Relative health risks, population
      proportions and their corresponding 95% confidence intervals were calculated.
      RESULTS: Overall, almost one third of PEI adults are obese (BMI > or = 30). This
      is almost double that reported in the 1995 National Population Health Survey
      using self-reported heights and weights. More women were classified as being very
      severely obese (Class III) than men, but for both men and women there appears to
      be a trend of increased mild obesity with age. Based on BMI and waist
      circumference, over one third of the population is considered to be at high to
      extremely high risk for health problems. CONCLUSION: Self-reported height and
      weight data appear to result in significant underestimation of the problem of
      obesity. Given the serious health consequences associated with this condition, it
      is critical that measured heights and weights be collected in future population
      based surveys to ensure that public health interventions are based on accurate
      prevalence data.

PMID- 15191118
TI  - The relation of body mass index to depressive symptoms.
AB  - OBJECTIVE: Data from the 1995 Nova Scotia Health Survey were analyzed to
      determine the relation between body mass index (BMI) and the risk of depression
      as measured by the Center for Epidemiological Studies Depression Scale (CES-D).
      METHODS: Clinical measures for height and weight and CES-D scores were available
      for 2,482 subjects from an initial sample of 5,578 Nova Scotians stratified
      probabilistically to be representative of age, gender and area of residence. BMIs
      were categorized according to the international standards (BMI 18.5-24.9
      acceptable weight; 25-29.9 overweight; > or = 30 obese). RESULTS: More men than
      women were classified as overweight (43.2% vs. 28.3%) but slightly more women
      than men were obese (25.6% vs. 23.4%). Based on the summary score of the CES-D,
      14.2% were categorized as at risk for depression (> or = 16). Logistic regression
      indicated that lower education (p < 0.001) and income (p < 0.001), and BMI
      category (p < 0.05) were all significantly related to an increased risk of
      depression. The odds ratio for the association between obesity and depression,
      after controlling for education and income, was 1.41 [95% CI = 1.07-1.86].
      DISCUSSION: More studies are needed to ascertain the mechanism by which obesity
      and depression could be related and the significance of this relation for the
      prevention and treatment of both obesity and depression. Given the effects of
      depression, we suggest that health professionals should assess their obese
      patients for risk of depression before embarking on a weight management protocol.

PMID- 15191119
TI  - Thinking locally about pandemic influenza.

PMID- 15191120
TI  - Developing the public health workforce in Canada: a summary of regional workshops
      on workforce education and training.
AB  - The report of the National Advisory Committee on SARS and Public Health
      recommended the need for a national public health human resource strategy and the
      need to identify opportunities for improving training. The recent regional
      workshops reinforced both these recommendations, and the excellent suggestions
      made by the participants will be utilized by the many work groups that will
      endeavour to improve public health system infrastructure in this country.

PMID- 15191121
TI  - Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in a Northern
      Alberta population.
AB  - OBJECTIVE: To describe the demographics and estimate the prevalence of hepatitis
      C virus (HCV) in a cohort of Human Immunodeficiency Virus (HIV) positive patients
      in Northern Alberta. METHODS: A cross-sectional (prevalence) study was performed
      on a cohort of HIV-positive patients. HCV testing was not widely available until
      December 1989, and the more sensitive, second generation immunoassay was not
      available until 1992. To reduce the effect of testing bias, we restricted
      consideration of HCV status to patients first seen January 1, 1992 onward.
      RESULTS: Forty-four percent of patients in the whole cohort were tested for HCV
      (564/1,276) and 62% (505/809) of patients entered since January 1, 1992 were
      tested for HCV. During the period January 1, 1992-December 31, 1999, the
      prevalence of HCV in our cohort of northern Alberta HIV-positive patients was at
      least 37.9% (307/809) and was 60.8% (307/505) among those who were tested for HCV
      in 1992 or later. The mean age of the co-infected group was 33.6 years, 66.1%
      were male, 91.2% were injection drug users (IDUs), 56.8% were Caucasian, and
      40.0% were Aboriginal. A statistically significant difference was found between
      the HCV-negative cohort, the HCV co-infected cohort, and the HCV-untested cohort
      for the following variables: risk behaviour, gender, ethnic status, death,
      occurrence of an AIDS-defining illness (p < 00.0001), and mean baseline CD4 cell
      count (p = 0.002). CONCLUSION: A high proportion of the HIV-infected IDUs was co
      infected with HCV. Compared to the HCV-negative group, the co-infected group
      appears to have had less advanced HIV disease. This is likely a reflection of
      more recent HIV infection in the HCV co-infected group.

PMID- 15191122
TI  - Health status of older Chinese in Canada: findings from the SF-36 health survey.
AB  - BACKGROUND: Despite the fact that the Chinese belong to the largest visible
      minority group in Canada, there is little research findings on their health
      status, particularly the aging adults. This research aimed at bridging the
      knowledge gap by examining the health status of this population and comparing the
      health status between the Chinese aging population and the general aging
      population in Canada. METHODS: Secondary data analysis of data obtained from a
      multi-site study, Health and Well Being of Older Chinese in Canada, and from the
      Medical Outcomes Study 36-item Short Form (SF-36). The SF-36 published scores
      obtained from the same age cohorts in the Canadian Multicentre Osteoporosis Study
      were used for comparison purposes. Independent samples t-tests were used to
      compare the statistical significance of the two groups. RESULTS: Overall, older
      Chinese-Canadians reported better physical health than all older adults in the
      Canadian population. However, the older Chinese in all age and gender groups
      scored lower in the mental component summary (MCS). Despite the age differences,
      Chinese women reported statistically poorer health than the Chinese men in all of
      the 8 health domains. CONCLUSION: The data are useful for forming baselines for
      monitoring the effectiveness of future health interventions for this population.
      Efforts by service providers to address the health needs of older Chinese
      Canadian women, the most vulnerable subgroup in this study, are essential.
      Interventions are also needed to address the poor mental health status in this
      ethnic minority group.

PMID- 15191123
TI  - Canadian mortality rates for liver disease: taking a closer look at ICD coding.

PMID- 15191124
TI  - National Symposium on Immigrant Health in Canada: an overview.

PMID- 15191125
TI  - Setting the stage: reviewing current knowledge on the health of Canadian
      immigrants: what is the evidence and where are the gaps?
AB  - The paper reviews current knowledge on the health of Canadian immigrants,
      examines evidence, and identifies research gaps. The information presented is
      derived from two recent literature reviews. Most literature suggests that
      Canadian immigrants, particularly recent arrivals, enjoy health advantages over
      long-term immigrants and the Canadian-born population in terms of overall health
      status and the prevalence of certain chronic diseases. Immigrants with infectious
      diseases may experience improvements in health over time. Patterns of immigrant
      mental health are less clear. More research is needed on specific health
      problems, how to address determinants of health, and the types of programs and
      services necessary to maintain immigrants in good health over time. Steps must be
      taken to strengthen existing databases and develop new ones.

PMID- 15191126
TI  - Recent research on immigrant health from statistics Canada's population surveys.
AB  - This paper reviews recent research using Statistics Canada data to compare
      immigrant health with that of the Canadian-born. A number of Statistics Canada
      studies have been used for such comparisons, including the National Population
      Health Survey and the Canadian Community Health Survey. Across the range of
      indicators studied, compared to the Canadian-born, immigrants are generally in as
      good or better health, have similar or better health behaviours, and similar or
      less frequent health service use (the "healthy immigrant effect"). These
      indications appear to be strongest among recent and non-European immigrants.
      These studies have established baseline patterns and identified that important
      distinctions exist among immigrant subgroups. Future research on more detailed
      subgroups that uses longitudinal data and cross-culturally validated instruments
      is needed.

PMID- 15191127
TI  - Health, life expectancy, and mortality patterns among immigrant populations in
      the United States.
AB  - BACKGROUND: The US immigrant population has grown considerably in the last three
      decades, from 9.6 million in 1970 to 32.5 million in 2002. However, this
      unprecedented population rise has not been accompanied by increased immigrant
      health monitoring. In this study, we examined the extent to which US- and foreign
      born blacks, whites, Asians, and Hispanics differ in their health, life
      expectancy, and mortality patterns across the life course. METHODS: We used
      National Vital Statistics System (1986-2000) and National Health Interview Survey
      (1992-1995) data to examine nativity differentials in health outcomes. Logistic
      regression and age-adjusted death rates were used to examine differentials.
      RESULTS: Male and female immigrants had, respectively, 3.4 and 2.5 years longer
      life expectancy than the US-born. Compared to their US-born counterparts, black
      immigrant men and women had, respectively, 9.4 and 7.8 years longer life
      expectancy, but Chinese, Japanese, and Filipino immigrants had lower life
      expectancy. Most immigrant groups had lower risks of infant mortality and low
      birthweight than the US-born. Consistent with the acculturation hypothesis,
      immigrants' risks of disability and chronic disease morbidity increased with
      increasing length of residence. Cancer and other chronic disease mortality
      patterns for immigrants and natives varied considerably, with Asian Immigrants
      experiencing substantially higher stomach, liver and cervical cancer mortality
      than the US-born. Immigrants, however, had significantly lower mortality from
      lung, colorectal, breast, prostate and esophageal cancer, cardiovascular disease,
      cirrhosis, diabetes, respiratory diseases, HIV/AIDS, and suicide. INTERPRETATION:
      Migration selectivity, social support, socio-economic, and behavioural
      characteristics may account for health differentials between immigrants and the
      US-born.

PMID- 15191128
TI  - New approaches to immigrant health assessment.
AB  - While immigrant subgroups may present vulnerabilities in terms of health status,
      health service use, and social determinants, comprehensive information on their
      health is lacking. To examine mortality (1980-1998) and health service
      utilization (1985-2002) patterns in Canadian immigrants, a record linkage pan
      Canadian research initiative using immigration and health databases has been
      undertaken. Preliminary results indicate that overall mortality is low among
      Canadian immigrants as compared to the general population for most leading causes
      (thus supporting the notion of "healthy immigrant effect"), with cause-specific
      exceptions. Moreover, results from British Columbia show that overall physician
      visits are low for immigrants, but not for all subgroups. Results from Ontario
      demonstrate a sharp increase in physician claims approximately three months
      following landing. Future analyses will address the short- and long-term health
      outcomes of immigrant subgroups, including less common diseases. Results are
      pertinent to practitioners working with immigrants and can inform immigrant
      health policy.

PMID- 15191129
TI  - National immigration health policy: existing policy, changing needs, and future
      directions.
AB  - Canada has a long history of welcoming immigrants and a longstanding immigration
      policy framework. The historic principles that govern immigration selection and
      processing also include regulatory policies in the area of health. Based on
      historical principles that pre-date Confederation, Canadian immigration health
      policy has remained relatively constant. Policies are based on the identification
      of specific individuals and the exclusion, if appropriate, of the affected
      individuals - an approach that continues today. During the past three decades,
      however, evolutionary changes in the patterns, volume and demography of
      immigration have created situations that may necessitate changes to existing
      policy frameworks. This paper reviews current immigration health policies and
      practices in Canada, describes the nature and impact of existing challenges, and
      proposes some alternatives for future consideration.

PMID- 15191130
TI  - Neighbourhood recent immigration and hospitalization in Toronto, Canada.
AB  - Recent immigrants to Canada tend to initially settle in low-income urban core
      areas. The relationships among immigration, neighbourhood effects and health are
      poorly understood. This study explored the risk of hospitalization in high recent
      immigration areas in Toronto compared to other Toronto neighbourhoods. The study
      used 1996 hospitalization and census data. Regression was used to examine the
      effects of recent immigration on neighbourhood hospitalization rates. Most
      hospitalization categories showed significantly higher rates of admission as the
      proportion of recent immigrants increased. Income was also significantly
      associated with all categories of hospitalization except surgical admissions.
      Average household income was almost 60% lower (dollar 36,122) in the highest
      versus the lowest immigration areas (dollar 82,641) suggesting that, at the
      neighbourhood level, the effects of immigration and income may be difficult to
      disentangle. These findings have important implications for health care planning,
      delivery, and policy.

PMID- 15191131
TI  - Forging alliances to bridge the research-policy gap.
AB  - It is critical that research findings be translated into policy if the research
      is to be beneficial. Researchers can play a role in bridging the research-policy
      gap by participating in the drafting of legislation and regulations, by
      testifying before lawmakers, and by building collaborations with key entities,
      including non-profit and governmental bodies outside of the health arena.
      Advocacy is inherent in the responsibilities of a researcher. A distinction must
      be made between researchers who serve as educators and advocates of change based
      on our current state of knowledge, and "scientific advocates" who rely on science
      only when it supports their political position. It is critical that researchers
      identify appropriate collaborators to bridge the research-policy gap and that the
      communities be involved in this process.

PMID- 15191132
TI  - The impact of cigarette warning labels and smoke-free bylaws on smoking
      cessation: evidence from former smokers.
AB  - BACKGROUND: To effectively address the health burden of tobacco use, tobacco
      control programs must find ways of motivating smokers to quit. The present study
      examined the extent to which former smokers' motivation to quit was influenced by
      two tobacco control policies recently introduced in the Waterloo Region: a local
      smoke-free bylaw and graphic cigarette warning labels. METHODS: A random digit
      dial telephone survey was conducted with 191 former smokers in southwestern
      Ontario, Canada in October 2001. Former smokers who had quit in the previous
      three years rated the factors that influenced their decision to quit and helped
      them to remain abstinent. RESULTS: Thirty-six percent of former smokers cited
      smoke-free policies as a motivation to quit smoking. Former smokers who quit
      following the introduction of a total smoke-free bylaw were 3.06 (CI95 = 1.02
      9.19) times more likely to cite smoking bylaws as a motivation to quit, compared
      to former smokers who quit prior to the bylaw. A total of 31% participants also
      reported that cigarette warning labels had motivated them to quit. Former smokers
      who quit following the introduction of the new graphic warning labels were 2.78
      (CI9 = 1.20-5.94) times more likely to cite the warnings as a quitting influence
      than former smokers who quit prior to their introduction. Finally, 38% of all
      former smokers surveyed reported that smoke-free policies helped them remain
      abstinent and 27% reported that warning labels helped them do so. CONCLUSION:
      More stringent smoke-free and labelling policies were associated with a greater
      impact upon motivations to quit.

PMID- 15191133
TI  - Tobacco industry links to faculties of medicine in Canada.
AB  - BACKGROUND: The tobacco industry uses various strategies to promote itself as a
      socially responsible, ethical industry, including establishing links with health
      institutions and medical research. The purpose of this study was to identify the
      relationships between the tobacco industry and Canadian faculties of medicine,
      specifically research funding and donations from tobacco industry sources, and
      faculty-specific policies regarding the acceptance of tobacco industry funds.
      METHODS: Information about policies and practices regarding research funding and
      donations from 1996-1999 was requested from the 16 Canadian faculties of medicine
      and their parent universities, as part of a larger cross-sectional survey-centred
      study that examined links between the tobacco industry and Canadian universities.
      RESULTS: All 16 faculties of medicine (100%) reported on research funding and
      11/16 (70%) reported on donations from the tobacco industry. Twenty-five percent
      (4/16) of the faculties received research funding from the tobacco industry and
      27% (3/11) received donations. No Canadian medical school had a policy that
      banned tobacco industry research funding or donations. INTERPRETATION: The
      tobacco industry have made donations and given research funding to faculties of
      medicine in Canada. This may present major conflicts of interest that undermine
      public health and have implications for the scientific integrity of the medical
      research enterprise. Faculties of medicine should consider developing policies
      that prohibit tobacco industry research funding and donations, with the intent of
      preventing conflicts and precluding ethical dilemmas arising from links with the
      tobacco industry. They should also encourage parent universities to establish
      similar policies at an institutional level.

PMID- 15191134
TI  - Prevalence of smoking associated with pregnancy in three Southern Ontario Health
      Units.
AB  - OBJECTIVES: The objectives of this study were to determine the prevalence of
      pregnancy-associated smoking among women residing in three Southern Ontario
      Health Units and to examine potential risk factors for smoking during pregnancy,
      using an existing data collection mechanism. METHODS: During May 2001, questions
      about pregnancy-associated smoking were asked during the telephone follow-up of
      postpartum women living in the three health units in Southern Ontario; this
      follow-up is routinely conducted by public health nurses. Sociodemographic data
      were also obtained. Data from 1,134 women were analyzed concerning smoking before
      and after the occurrence of the pregnancy was known, during each trimester, and
      immediately postpartum. RESULTS: The rates of smoking before and after the
      pregnancy was known, in the first, second, and third trimesters, and immediately
      postpartum were 17.8%, 10.4%, 9.6%, 8.7%, 8.1%, and 7.9%, respectively. For all
      six estimates of smoking, Canadian-born women had rates 2.5 to 4 times higher
      than those of women born outside Canada. Age less than 25 years and lower
      educational attainment were also independent risk factors for smoking during
      pregnancy. CONCLUSIONS: The Ontario Tobacco Strategy goal of eliminating smoking
      in pregnancy has not yet been realized. Ongoing smoking cessation programs among
      pregnant women are needed as part of a comprehensive strategy to reduce the
      overall prevalence of smoking. In planning such programs, particular attention
      should be paid to the needs of women who are Canadian-born, have lower
      educational attainment, and are under the age of 25.

PMID- 15191135
TI  - Smoking in Ontario schools: does policy make a difference?
AB  - OBJECTIVE: Studies in other countries have shown that school tobacco control
      policy has potential to prevent smoking uptake in adolescents. Since no Canadian
      research has studied this association, we assessed the statistical link between
      school tobacco policy and smoking status in Ontario elementary and secondary
      schools. METHODS: We conducted secondary analysis of data collected using the
      School Smoking Profile, a cross-sectional, self-report questionnaire. School
      policy variables were formed from five survey items concerning students'
      perceptions of school tobacco control policy. Smoking status was determined
      through self-report measures which had been validated by carbon monoxide testing.
      Logistic regression models used school policy variables to explain smoking status
      in elementary and secondary schools, controlling for school location, school
      size, and student's grade level. RESULTS: The smoking policy variables, rules and
      enforcement, explained smoking status after controlling for other variables. In
      elementary schools, perceptions of stronger enforcement reduced the odds of being
      a smoker (OR = 0.39, CI99 = 0.34-0.44). In secondary schools, enforcement lost
      its protective effect (OR = 1.05, CI99 = 1.00-1.10). In addition, student
      perceptions that rules were strong were indicative of increased smoking in
      secondary schools (OR = 1.32, CI99 = 1.27-1.37). DISCUSSION: Strong enforcement
      of school tobacco control policy appears to be effective in elementary schools
      but is not as helpful in secondary schools. Secondary school policymakers should
      consider modifying their sanctions to avoid alienating smokers.

PMID- 15191136
TI  - [Utilization of preventive dental services by recent immigrants in Quebec].
AB  - OBJECTIVES: Studies conducted in Canada show that recent immigrants tend to under
      utilize preventive services provided by the health care system. The objective of
      our study was to learn whether this phenomenon also applies to dental care.
      METHODS: Our sample was composed of 5,795 women who live in Quebec and are
      between 30 and 44 years old. These women filled out a self-administered
      questionnaire regarding their immigration status and their habits concerning
      dental visits. In our analyses, we compared the use of dental services of recent
      immigrants (10 years or less in Canada), long-term immigrants (more than 10
      years), and non-immigrants (Canadians of origin). RESULTS: 55% of recent
      immigrants are preventive service users compared to 69% of long-term immigrants
      and 76% of non-immigrants. The financial barrier partly explains this result:
      immigrants often have a modest income and rarely benefit from dental coverage.
      However, having private dental insurance does not in itself explain the gap
      between these groups. This suggests that there is a cultural barrier in dental
      services access. CONCLUSIONS: Under-use of preventive services by immigrants is
      not limited to the medical field, it extends to dental services as well. In order
      to facilitate immigrants' adaptation to the health system, we recommend that the
      government provide them with free dental services that respect their culture.

PMID- 15191137
TI  - [Actions against social inequalities of health: tentative explanations for the
      opposition to progress of Quebec public health authorities].

PMID- 15191138
TI  - Angina and socio-economic status in Ontario: how do characteristics of the county
      you live in influence your chance of developing heart disease?
AB  - OBJECTIVE: To assist in the development of community heart health programming and
      policy development, the Central West Health Planning Information Network (CWHPIN)
      was asked by its partners to collaborate in obtaining information that might
      clarify the relationships between socio-economic status (SES) and heart disease
      among residents of Ontario, Canada. The purpose of this component of the project
      was to explore, at the county level, how much of the variation in angina pectoris
      (angina) could be explained by SES variables. STUDY DESIGN: Linear regression
      modeling was used to identify key predictors of angina hospitalization rates in
      counties Ontario-wide. RESULTS: Results of the linear regression modeling showed
      that SES variables (most notably education and occupation) were key predictors of
      angina, even when traditional risk factors (i.e., smoking, etc.) were included in
      the analysis. CONCLUSION: This study demonstrates that, at the county level,
      socio-economic variables such as education and occupation have a significant
      relationship with rates of heart disease at the population level, even when
      including the traditional risk factors in the analysis.

PMID- 15191139
TI  - The Balanced Scorecard: a tool for health policy decision-making.

PMID- 15191140
TI  - Fraction of premature deaths in the Canadian population that were attributable to
      overweight and obesity.

PMID- 15191141
TI  - Surface normal overlap: a computer-aided detection algorithm with application to
      colonic polyps and lung nodules in helical CT.
AB  - We developed a novel computer-aided detection (CAD) algorithm called the surface
      normal overlap method that we applied to colonic polyp detection and lung nodule
      detection in helical computed tomography (CT) images. We demonstrate some of the
      theoretical aspects of this algorithm using a statistical shape model. The
      algorithm was then optimized on simulated CT data and evaluated using a per
      lesion cross-validation on 8 CT colonography datasets and on 8 chest CT datasets.
      It is able to achieve 100% sensitivity for colonic polyps 10 mm and larger at 7.0
      false positives (FPs)/dataset and 90% sensitivity for solid lung nodules 6 mm and
      larger at 5.6 FP/dataset.

PMID- 15191142
TI  - Population-based incremental interactive concept learning for image retrieval by
      stochastic string segmentations.
AB  - We propose a method for concept-based medical image retrieval that is a superset
      of existing semantic-based image retrieval methods. We conceive of a concept as
      an incremental and interactive formalization of the user's conception of an
      object in an image. The premise is that such a concept is closely related to a
      user's specific preferences and subjectivity and, thus, allows to deal with the
      complexity and content-dependency of medical image content. We describe an object
      in terms of multiple continuous boundary features and represent an object concept
      by the stochastic characteristics of an object population. A population-based
      incrementally learning technique, in combination with relevance feedback, is then
      used for concept customization. The user determines the speed and direction of
      concept customization using a single parameter that defines the degree of
      exploration and exploitation of the search space. Images are retrieved from a
      database in a limited number of steps based upon the customized concept. To
      demonstrate our method we have performed concept-based image retrieval on a
      database of 292 digitized X-ray images of cervical vertebrae with a variety of
      abnormalities. The results show that our method produces precise and accurate
      results when doing a direct search. In an open-ended search our method
      efficiently and effectively explores the search space.

PMID- 15191143
TI  - Nonuniform noise propagation by using the ramp filter in fan-beam computed
      tomography.
AB  - It is observed that when the homogeneity property of the ramp filter is used to
      derive a filtered backprojection algorithm in fan-beam tomography, the
      reconstructed images have nonstationary frequency components and nonstationary
      noise. When a short focal-length is used, higher frequency components are
      amplified more at the edge of the image than at the center of the image,
      resulting in higher noise at the edge of the image.

PMID- 15191144
TI  - Image denoising based on multiscale singularity detection for cone beam CT breast
      imaging.
AB  - It was recently reported that the real-time flat panel detector-based cone-beam
      computed tomography (CBCT) breast imaging can help improve the detectability of
      small breast tumors with an X-ray dose comparable to that of the conventional
      mammography. In this paper, an efficient denoising algorithm is proposed to
      further reduce the X-ray exposure level required by a CBCT scan to acquire
      acceptable image quality. The proposed wavelet-based denoising algorithm
      possesses three significant characteristics: 1) wavelet coefficients at each
      scale are classified into two categories: irregular coefficients, and edge
      related and regular coefficients; 2) noise in irregular coefficients is reduced
      as much as possible without producing artifacts to the denoised images; and 3)
      for the edge-related and regular coefficients, if they are at the first
      decomposition level, they are further denoised, otherwise, no modifications are
      made to them so as to obtain good visual quality for diagnosis. By applying the
      proposed denoising algorithm to the filtered projection images, the X-ray
      exposure level necessary for the CBCT scan can be reduced by up to 60% while
      obtaining clinically acceptable image quality. This denoising result indicates
      that in the clinical application of CBCT breast imaging, the patient radiation
      dose can be significantly reduced.

PMID- 15191145
TI  - Robust and objective decomposition and mapping of bifurcating vessels.
AB  - Computational modeling of human arteries has been broadly employed to investigate
      the relationships between geometry, hemodynamics and vascular disease. Recent
      developments in modeling techniques have made it possible to perform such
      analyses on realistic geometries acquired noninvasively and, thus, have opened up
      the possibility to extend the investigation to populations of subjects. However,
      for this to be feasible, novel methods for the comparison of the data obtained
      from large numbers of realistic models in the presence of anatomic variability
      must be developed. In this paper, we present an automatic technique for the
      objective comparison of distributions of geometric and hemodynamic quantities
      over the surface of bifurcating vessels. The method is based on centerlines and
      consists of robustly decomposing the surface into its constituent branches and
      mapping each branch onto a template parametric plane. The application of the
      technique to realistic data demonstrates how similar results are obtained over
      similar geometries, allowing for proper model-to-model comparison. Thanks to the
      computational and differential geometry criteria adopted, the method does not
      depend on user-defined parameters or user interaction, it is flexible with
      respect to the bifurcation geometry and it is readily extendible to more complex
      configurations of interconnecting vessels.

PMID- 15191146
TI  - Sphere-filled organ model for virtual surgery system.
AB  - We have been developing a virtual surgery system that is capable of simulating
      surgical maneuvers on elastic organs. In order to perform such maneuvers, we have
      created a deformable organ model using a sphere-filled method instead of the
      finite element method. This model is suited for real-time simulation and
      quantitative deformation. Furthermore, we have equipped this model with a sense
      of touch and a sense of force by connecting it to a force feedback device.
      However, in the initial stage the model became problematic when faced with
      complicated incisions. Therefore, we modified this model by developing an
      algorithm for organ deformation that performs various, complicated incisions
      while taking into account the effect of gravity. As a result, the sphere-filled
      model allowed our system to respond to various incisions that deform the organ.
      Thus, various physical manipulations that involve pressing, pinching, or incising
      an organ's surface can be performed. Furthermore, the deformation of the internal
      organ structures and changes in organ vasculature can be observed via the
      internal spheres' behavior.

PMID- 15191147
TI  - A Bayesian morphometry algorithm.
AB  - Most methods for structure-function analysis of the brain in medical images are
      usually based on voxel-wise statistical tests performed on registered magnetic
      resonance (MR) images across subjects. A major drawback of such methods is the
      inability to accurately locate regions that manifest nonlinear associations with
      clinical variables. In this paper, we propose Bayesian morphological analysis
      methods, based on a Bayesian-network representation, for the analysis of MR brain
      images. First, we describe how Bayesian networks (BNs) can represent
      probabilistic associations among voxels and clinical (function) variables.
      Second, we present a model-selection framework, which generates a BN that
      captures structure-function relationships from MR brain images and function
      variables. We demonstrate our methods in the context of determining associations
      between regional brain atrophy (as demonstrated on MR images of the brain), and
      functional deficits. We employ two data sets for this evaluation: the first
      contains MR images of 11 subjects, where associations between regional atrophy
      and a functional deficit are almost linear; the second data set contains MR
      images of the ventricles of 84 subjects, where the structure-function association
      is nonlinear. Our methods successfully identify voxel-wise morphological changes
      that are associated with functional deficits in both data sets, whereas standard
      statistical analysis (i.e., t-test and paired t-test) fails in the nonlinear
      association case.

PMID- 15191148
TI  - Sampling and aliasing consequences of quarter-detector offset use in helical CT.
AB  - In this paper, the sampling and aliasing consequences of employing a quarter
      detector-offset (QDO) in helical computed tomography (CT) are analyzed. QDO is
      often used in conventional CT to reduce in-plane aliasing by eliminating data
      redundancies to improve radial sampling. In helical CT, these same redundancies
      are exploited to improve longitudinal sampling and so it might seem ill-advised
      to employ QDO. The relative merit of the two geometries for helical CT is studied
      by conducting a multidimensional sampling analysis of projection-space sampling
      as well as a Fourier crosstalk analysis of crosstalk among the object's Fourier
      basis components. Both a standard fanbeam helical CT geometry and a hypothetical
      parallel-beam CT geometry, which helps illuminate the more complicated fanbeam
      results, are analyzed. Using the sampling analysis, it was found that the use of
      QDO leads to very different spectral tiling than arise when not using QDO.
      However, due to the shape of the essential support of the projection data spectra
      that arises in practice, both configurations lead to very similar or identical
      amounts of spectral overlap. This perspective also predicts the spatially variant
      longitudinal aliasing that has been observed in helical CT. The crosstalk results
      were consistent with those of the multidimensional sampling analysis. Thus, from
      the standpoint of aliasing and crosstalk, no compelling difference is found
      between the two geometries.

PMID- 15191149
TI  - Analytic determination of the resolution-equivalent effective diameter of a
      pinhole collimator.
AB  - To account for photon penetration, the formulas used to calculate the geometric
      resolution of a pinhole collimator use an equivalent diameter d(e) rather than
      the physical diameter of the aperture. The expression commonly used for d(e),
      however, was originally derived to account for penetration in sensitivity
      calculations. In this paper, we show that the concept of equivalent diameter is
      also applicable to resolution calculations, propose angular-dependent expressions
      for d(e) specific to resolution calculations, and discuss the limits of their
      applicability and how they compare to other expressions. Results show that for
      normal incidence Paix's expression for d(e) tends to overestimate the resolution
      equivalent diameter for full-width-at-half-maximum resolution, whereas Anger's is
      a better approximation, but may produce underestimates for submillimeter
      resolution imagers, especially in the case of high-energy photons. For grazing
      incidence, both expressions may result in significant overestimates.

PMID- 15191150
TI  - Differentiation and characterization of rat mammary fibroadenomas and 4T1 mouse
      carcinomas using quantitative ultrasound imaging.
AB  - Scatterer properties like the average effective scatterer diameter and acoustic
      concentration were determined in vivo using a quantitative ultrasound (QUS)
      technique from two tumor phenotypes grown in animal models. These tumor models
      included spontaneously occurring mammary fibroadenomas in rats and transplanted
      4T1 mammary carcinomas in mice. The scatterer properties of average scatterer
      diameter and acoustic concentration were estimated using a Gaussian form factor
      from the backscattered ultrasound measured from both types of tumors. QUS images
      of the tumors were constructed utilizing estimated scatterer properties from
      regions in the tumors. The QUS images showed a clear distinction between the two
      types of tumors and a statistically significant difference existed between their
      estimated scatterer properties. The average scatterer diameter and acoustic
      concentration for the mammary fibroadenomas were estimated to be 105 +/- 25
      microm and -15.6 +/- 5 dB(mm(-3)), respectively. The average scatterer diameter
      and acoustic concentration for the carcinomas was estimated to be 28 +/- 4.6
      microm and 10.6 +/- 6.9 dB(mm(-3)), respectively. The distinctions in the
      scattering properties are clearly seen in the QUS images of the tumors and
      indicate that QUS imaging can be useful in differentiating between different
      types of mammary tumors.

PMID- 15191151
TI  - An interacting multiple model probabilistic data association filter for cavity
      boundary extraction from ultrasound images.
AB  - This paper presents a novel segmentation technique for extracting cavity contours
      from ultrasound images. The problem is first discretized by projecting equispaced
      radii from an arbitrary seed point inside the cavity toward its boundary. The
      distance of the cavity boundary from the seed point is modeled by the trajectory
      of a moving object. The motion of this moving object is assumed to be governed by
      a finite set of dynamical models subject to uncertainty. Candidate edge points
      obtained along each radius include the measurement of the object position and
      some false returns. The modeling approach enables us to use the interacting
      multiple model estimator along with a probabilistic data association filter, for
      contour extraction. The convergence rate of the method is very fast because it
      does not employ any numerical optimization. The robustness and accuracy of the
      method are demonstrated by segmenting contours from a series of ultrasound
      images. The results are validated through comparison with manual segmentations
      performed by an expert. An application of the method in segmenting bone contours
      from computed tomography images is also presented.

PMID- 15191152
TI  - Treatment of rabbit corneal infections with ophthalmic gatifloxacin: a
      concentration dependence study.
AB  - This study was designed to determine the most effective dose of gatifloxacin in
      ophthalmic solution for control of methicillin-resistant Staphylococcus aureus
      (MRSA) corneal infections in rabbits. Rabbits were inoculated by injecting 9300
      colony-forming units of MRSA into the corneal stroma of the eye (n=43). They were
      then randomly assigned to topical administration of saline, ofloxacin 0.3%, or
      gatifloxacin 0.02%, 0.1%, 0.3%, or 0.5% ophthalmic solutions. Infection severity
      48 hours postinoculation was assessed by masked observers using standard scales.
      After treatment completion, viable MRSA in corneal tissue were counted, and
      pathologic examinations of ocular tissues were conducted. Relative to saline,
      treatment with gatifloxacin 0.3% or 0.5% decreased mean infection scores at every
      time point from 16 to 48 hours after inoculation (P < or = .012) and reduced area
      under-the-curve values for infection scores by 50.3% and 54.2%, respectively (P =
      .00005). Rabbits treated with gatifloxacin 0.3% and 0.5% had lower area-under-the
      curve values than those treated with ofloxacin 0.3% (P < or = .039). Viable MRSA
      in corneal tissue after gatifloxacin 0.3% or 0.5% treatment were decreased to
      less than 1% of those found after ofloxacin 0.3% treatment. Gram-positive colony
      formation and abscesses found in saline-treated corneas were distinctly
      alleviated by treatment with gatifloxacin 0.3% or 0.5%. No significant
      differences were observed between treatments with gatifloxacin 0.3% or 0.5%
      ophthalmic formulations and they were equally effective. Topical administration
      of gatifloxacin 0.3% or 0.5% ophthalmic solutions controlled MRSA corneal
      infections in rabbits significantly better than saline or ofloxacin 0.3%.

PMID- 15191153
TI  - Lidocaine intradermal injection--a new approach in tinnitus therapy: preliminary
      report.
AB  - The efficacy of lidocaine in controlling tinnitus is well documented. It can be
      administered intravenously or by transtympanic injection. The first method of
      delivery can produce cardiovascular and central nervous system adverse reactions.
      The transtympanic injection can bring about slight sensorineural hearing loss,
      vertigo, vomiting, and taste disturbances. To improve on results obtained in
      persons with tinnitus, the vasoactive drug lidocaine was delivered by a novel
      intradermal route in 68 patients. The control group, which received intradermal
      saline injection, included 20 patients with tinnitus. As parameters of
      evaluation, the self-evaluation scale of subjective disturbance and tinnitus
      loudness were considered. Significant improvement in level of disturbance and
      tinnitus loudness was observed both in patients with tinnitus intensity less than
      10 dB and in those with tinnitus intensity greater than 10 dB. No significant
      results were observed in the control group. Of particular interest was the
      complete absence of unpleasant complications with intradermal lidocaine.

PMID- 15191154
TI  - Anterior cervical fusion with the PCB cage-plate system.
AB  - Anterior cervical discectomy and fusion, as originally described by Robinson, is
      highly successful in the treatment of neural compression caused by disc material
      or osteophytes. Although the necessity for fusion after anterior cervical
      discectomy is still debated, anterior cervical fusion with interbody bone graft
      and anterior plate implantation is a commonly accepted procedure. In this study,
      preliminary results with a recently developed PCB cervical plate system
      (SCIENT'X, Paris, France), which combines a hollow intradiscal cage with an
      integrated plate, in the management of cervical disc disease are reported.

PMID- 15191155
TI  - Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) improves health
      related quality of life in adults previously receiving inhaled corticosteroids.
AB  - In the treatment of asthma, the conventional measures used to monitor a patient's
      progress and health status do not address the impact of functional impairments
      associated with the disease that may affect the patient's daily life. Unlike
      those measures, health-related quality of life (HRQL) reflects the physical,
      psychological, and social difficulties a patient perceives on a day-to-day basis.
      This study was conducted to determine the effects of once-daily budesonide
      inhalation powder via the Pulmicort Turbuhaler on the HRQL in adult patients with
      asthma previously treated with other inhaled corticosteroids. A total of 184
      patients 18 to 70 years of age who previously received inhaled corticosteroids
      were enrolled in this double-blind, placebo-controlled, parallel-group,
      multicenter study. Patients were randomly assigned to budesonide 400 microg once
      daily or to placebo for 12 weeks. Each patient's HRQL was assessed at
      randomization and at weeks 4 and 12 with the Asthma Quality of Life Questionnaire
      (AQLQ). More patients receiving budesonide than those receiving placebo reported
      statistically significant (P < or = .05) improvements in HRQL at weeks 4 and 12.
      With the exception of the domain pertaining to exposure to environmental stimuli,
      differences from placebo in overall AQLQ scores and individual domain scores were
      clinically important (> or = 0.5 units). In addition, 2.4 patients needed to be
      treated with once-daily budesonide for 1 patient to demonstrate clinically
      important improvement. Budesonide 400 microg administered once daily via the
      Pulmicort Turbuhaler provides statistically significant and clinically important
      HRQL benefit in adult patients with asthma previously receiving inhaled
      corticosteroids.

PMID- 15191156
TI  - Serum IL-8 as a possible marker for determining the status of Helicobacter pylori
      infection in patients with untreated and treated peptic ulcer.
AB  - Failure to eradicate Helicobacter pylori can lead to peptic ulcer recurrence and
      gastric malignancy. Therefore, the objective of this study was to develop a
      noninvasive method for determining whether H. pylori infection was eradicated
      with antibiotic-based triple therapy. A total of 17 patients with duodenal ulcer
      (DU) and 17 with gastric ulcer (GU) were evaluated both before and after
      treatment. Outcomes included serum levels of interleukin-8 (IL-8), pepsinogen I,
      and gastrin, and the Wilcoxon signed rank test was used to test significance.
      Changes in these parameters were also correlated with disease status. In those
      patients where both GU and DU healing occurred as a result of treatment, most
      showed an increase in serum IL-8 and a decrease in serum pepsinogen. Serum
      gastrin levels were not significantly changed in either group. Posttreatment
      increases in serum IL-8 were seen in 15 of 17 (88%) recovered DU patients and 14
      of 17 (82%) recovered GU patients (P<.05 for each). Posttreatment decreases in
      pepsinogen I were found in 15 of 17 DU and 15 of 17 GU patients (P<.05 for each).
      These preliminary findings suggest that an increase in serum IL-8 and possibly a
      decrease in pepsinogen I may be useful in identifying the successful eradication
      of H. pylori infection in patients with peptic ulcer treated with antibiotics. A
      more systematic analysis of these putative diagnostic markers is now warranted.

PMID- 15191157
TI  - Nonsynergistic effects of trimetazidine and selenium combination therapy on renal
      ischemic-reperfusion injury in rats.
AB  - Reactive oxygen species (ROS) have been postulated to play a major role in
      postischemic acute renal injury. Moreover, lipid peroxidation has been described
      as an important pathway of ROS-induced postischemic acute renal failure. To
      evaluate effects of selenium (Se) and trimetazidine (TMZ) on postischemic renal
      failure, renal tissue malondialdehyde (MDA) and superoxide dismutase (SOD)
      concentrations were measured in Wistar rats with ischemic renal failure.
      Treatment groups consisted of rats treated with TMZ (5 mg/kg orally) or Se (30
      microg/kg orally) or TMZ+Se for 15 days. Ischemic groups consisted of rats with
      clamped left renal arteries for 1 hour. Before left renal arterial clamping,
      right nephrectomy was performed; after 24 hours, left nephrectomy was done. The
      animals were divided into 5 groups. Group 1 (n=7) was the nonischemic control
      group without treatment; Group 2 (n=6) was the ischemic control group treated
      with physiologic solution; Group 3 (n=5) received TMZ; Group 4 (n=5) received Se;
      and Group 5 (n=6) received TMZ+Se for 15 days. After TMZ and Se treatment, right
      renal tissue MDA significantly decreased in Groups 3-5 when compared with those
      in Group 1. There was no significant difference between nonischemic and ischemic
      renal tissue MDA in Groups 3, 4, and 5. Postischemic renal tissue SOD levels were
      higher than nonischemic levels in Group 3. In Groups 4 and 5, no significant
      differences were observed between nonischemic and ischemic renal tissue SOD
      levels. Moreover, total scores obtained from histopathologic evaluation of
      ischemic and nonischemic kidney samples in Groups 3, 4, and 5 were similar, but
      these scores in Group 2 were significantly different from those of Groups 3, 4,
      and 5. These results indicate that, under these study conditions, TMZ, Se, and
      TMZ+Se treatments prevent lipid peroxidation in ischemic and nonischemic renal
      tissue. Moreover, these treatments prevent histologic findings of postischemic
      perfusion renal injury.

PMID- 15191158
TI  - Differentiation of human and mouse embryonic stem cells along a hepatocyte
      lineage.
AB  - Embryonic stem (ES) cells may differentiate along a hepatocyte lineage; however,
      currently there are no reports of culture conditions yielding high levels of
      hepatocyte-specific gene expression in these cells. We investigated culture
      conditions for differentiating ES cells into hepatocyte-like cells in vitro.
      Various combinations of culture media, growth and differentiation factors, and
      substratum precoatings were evaluated, and it was determined that a combination
      of Iscove's modified Dulbecco's medium with 20% fetal bovine serum, human
      insulin, dexamethasone. and collagen type I precoating was optimal for directing
      mouse ES cells along a hepatocyte lineage. Treatment of mouse ES cell with the
      optimal condition led to prealbumin gene expression 20% as high, and albumin
      synthesis 7% as high, as in mouse liver. The optimal culture condition also
      induced albumin gene expression in differentiated human ES cells 1% as high as in
      normal human hepatocytes as shown by Western blot analysis, and cells were
      positive for human albumin by immunocytochemistry. In addition, our optimal
      condition led to high levels of albumin gene expression in primary mouse
      hepatocytes after 35 days of culture, levels 10-fold higher than with other
      hepatocyte differentiation media. In conclusion, our optimal condition directed
      both mouse and human ES cells along a hepatocyte lineage. This represents the
      initial step in establishing cell lines that can be employed in cell-based
      therapeutics in humans and for toxicology and pharmacology studies.

PMID- 15191159
TI  - Comparison of bioenergetic activity of primary porcine hepatocytes cultured in
      four different media.
AB  - Primary hepatocytes have extensively been used in biochemical, pharmacological,
      and physiological research. Recently, primary porcine hepatocytes have been
      regarded as the cells of choice for bioartificial liver support systems. The
      optimum culture medium for hepatocytes to be used in such devices has yet to be
      defined. In this study we investigated the effectiveness of four culture media in
      driving energy metabolism of primary porcine hepatocytes. The media selected were
      William's E medium, medium 1640, medium 199, and hepatocyte medium. Cells (3 x
      10(10); viability 87 +/- 6%) were isolated from weanling piglets and seeded on 90
      mm plates in the above media supplemented with antibiotics and hormones at a
      density of 8 x 10(6) viable cells per plate. Using 1H NMR spectroscopy we looked
      at indices of glycolysis, gluconeogenesis. ketogenesis, and ureagenesis on days
      2, 4, and 6 of the experiments (n = 9). We also studied urea and albumin
      synthesis and total P450 content. The examined metabolic pathways of the
      hepatocytes were maintained by all media, although there were statistically
      significant differences between them. All media performed well in glycolysis,
      ureagenesis, and albumin synthesis. William's E medium and medium 199
      outperformed the rest in gluconeogenesis. Medium 199 was best in ketogenesis.
      Overall, medium 199 was the best at driving energy metabolism from its
      constituent substrates and we think that it preferentially should be used in the
      culture of primary porcine hepatocytes.

PMID- 15191160
TI  - Engraftment measurement in human liver tissue after liver cell transplantation by
      short tandem repeats analysis.
AB  - Hepatocyte transplantation has been proposed as a technique for bridging patients
      to whole-organ transplantation, for providing metabolic support during liver
      failure, and for replacing whole-organ transplantation in certain metabolic liver
      diseases. Assessment of hepatocyte engraftment has been difficult to measure, and
      the degree of engraftment needed to correct various liver disorders is still
      unknown. A sensitive, simple, and specific method of monitoring engraftment of
      transplanted hepatocytes for the purpose of bridging human liver failure to
      native regeneration using short tandem repeats (STRs) was evaluated. The
      analytical sensitivity of the test was evaluated using DNA mixing curves and
      established as 0.5% (percentage of donor DNA/ recipient DNA). Sex-matched and
      mismatched cases were included during the validation. The clinical evaluation of
      the assay was performed using liver samples from two patients who underwent
      hepatocyte transplantation. We concluded from this study that the AmpFLSTR
      Profiler Plus PCR Amplification Kit, a well-established technique in forensic
      medicine, is specific, sensitive, and a reproducible assay for measurement of
      engraftment after hepatocyte transplantation in both sex-matched and sex
      mismatched cases.

PMID- 15191161
TI  - Polyvinyl pyrrolidone: a novel cryoprotectant in islet cell cryopreservation.
AB  - The present study was performed on the basis of the hypothesis that the low
      molecular weight (MW) compounds, DMSO and glycerol, permeate the cell and
      interact hydrophobically with intracellular proteins, thereby perturbing the
      cytoskeletal architecture of frozen cells and diminishing islet cell integrity
      and function. Isolated rat islets were cultured overnight (18-24 h) at 37 degrees
      C in RPMI medium supplemented with 10% fetal calf serum and 1% mixture of
      penicillin/streptomycin. Using a programmable temperature controller, samples of
      precounted islets were then frozen under liquid nitrogen, in the presence of
      either 2 M DMSO (MW = 0.078 kDa), 3 M glycerol (MW = 0.092 kDa), 5% polyethylene
      glycol (PEG, MW = 20 kDa), or 10% polyvinylpyrrolidone (PVP, MW = 40 kDa), and
      stored at -80 degrees C for 1 week. Following thawing and overnight (18-24 h)
      culture, intact islet recovery was determined by islet counting after dithizone
      staining. Islet function was assessed by determination of glucose-stimulated
      insulin secretion in perifusion experiments with Krebs-Ringer bicarbonate buffer,
      pH 7.4, containing either basal (3.3 mM) or high (16.7 mM) glucose
      concentrations. The assessment of islet recovery and function of all
      cryopreserved samples was performed only after thawing and overnight culture (18
      24 h) of islets. The mean +/- SEM percent intact islet recovery was higher with
      PVP compared with DMSO (82 +/- 4.6 vs. 62.7 +/- 3.1%, respectively, p < 0.005, n
      = 9). Furthermore, the glucose stimulation index of insulin secretion by islets
      taken from samples frozen with PEG and PVP, after thawing and overnight culture,
      was comparable to that of freshly isolated islets, in contrast to DMSO and
      glycerol. There was no significant difference in intact islet recovery and
      function between samples frozen with PVP and those frozen with PEG. Samples
      frozen with DMSO and glycerol had similar results in islet recovery and function.
      These data show that PVP is a new and potent cryoprotectant for islet cell
      freezing.

PMID- 15191162
TI  - The effects of transforming growth factor-beta2 on dopaminergic graft survival.
AB  - Dopaminergic cell transplantation is a promising therapeutic approach for the
      treatment of Parkinson's disease, the potential of which is limited due to poor
      survival and low dopamine content within engrafted tissue. In this study, the
      ability of transforming growth factor-beta2 (TGF-beta2) to influence transplant
      survival was evaluated. Cell suspensions containing fetal rat ventral
      mesencephalon (VM) cells were incubated prior to surgery with vehicle (DPBS),
      varying concentrations of TGF-beta2 (5-1000 ng/ml), or a pan-specific antibody
      against TGF-beta (1D11, 100 ng/ml). VM cell suspensions (200,000 cells) were
      unilaterally implanted into the striatum of adult Sprague-Dawley rats (n = 5-11
      animals/group). Following a 3-week survival period, small but viable VM grafts
      containing tyrosine hydroxylase-positive (TH+) neurons and fibers were present in
      all animals. Addition of TGF-beta2 resulted in a steep, bell-shaped dose-response
      curve with a significant effect on TH+/dopamine cell survival. At 50 ng/ml TGF
      beta2, the number of surviving dopamine neurons was increased twofold compared
      with controls. Addition of TGF-beta2 or 1D11 did not significantly influence
      graft volume. Further studies, possibly in combination with other neurotrophic
      factors, need to be performed to obtain a greater understanding of the effects of
      TGF-beta on dopamine neurons and fetal VM cell engraftment.

PMID- 15191163
TI  - Neuroprotective effects of encapsulated CNTF-producing cells in a rodent model of
      Huntington's disease are dependent on the proximity of the implant to the
      lesioned striatum.
AB  - Huntington's disease (HD) is a devastating genetic disorder with no effective
      treatments for preventing or lessening the underlying neuronal degeneration.
      Intracerebral delivery of CNTF in animal models of HD has shown considerable
      promise as a means of protecting striatal neurons that would otherwise be
      destined to die. The present study examines whether the neuroprotective effects
      of CNTF require that the delivery be immediately proximal to the lesion site or
      whether protective effects can be exerted when the delivery site is more distal
      to the site of injury. Encapsulated CNTF-producing cells were implanted into the
      lateral ventricle either ipsilateral or contralateral to an intrastriatal
      quinolinic acid (QA) injection. A robust neuroprotective effect was observed only
      in those animals receiving CNTF implants ipsilateral to the QA injection. In
      these animals, the loss of striatal ChAT and GAD activity as well as the
      behavioral impairments that resulted from QA were completely prevented. In
      contrast, no neurochemical or behavioral benefits were produced by implants of
      CNTF-producing cells in the contralateral ventricle. These data continue to
      support the use of cellular delivery of CNTF for HD but caution that delivery
      directly to the striatum may be needed if any clinical benefits are to be seen.

PMID- 15191164
TI  - Liposomal formulations of tacrolimus and rapamycin increase graft survival and
      fiber outgrowth of dopaminergic grafts.
AB  - The immunosuppressive drugs tacrolimus (TAC) and rapamycin (RAPA) have both been
      found to have neuroprotective effects on dopaminergic neurons. The purpose of the
      present study was to investigate whether liposomal formulations of these drugs
      administered directly into the brain improve cell survival and fiber outgrowth.
      Rats with unilateral 6-hydroxydopamine lesions were transplanted with 800,000
      fetal rat ventral mesencephalic cells and randomly divided to one of four groups.
      Group 1 received a transplant containing cells only; group 2 received a cell
      suspension containing 0.68 microM liposomal RAPA (LRAPA); group 3 received a cell
      suspension containing 2.0 microM liposomal TAC (LTAC); and group 4 received a
      cell suspension containing a liposomal formulation of both 0.68 microM RAPA and
      2.0 microM TAC (LRAPATAC). Rats were sacrificed after 6 weeks, and cell survival
      and fiber outgrowth were assessed using tyrosine hydroxylase (TH)
      immunohistochemistry. The animals receiving a cell suspension containing either
      LTAC or LRAPATAC were found to have significantly more surviving TH
      immunoreactive (TH-ir) cells than the control group receiving cells only. The
      group receiving LTAC had significantly longer fibers, the group receiving LRAPA
      had significantly more fibers close to the graft, and the group receiving
      LRAPATAC had significantly more fibers at all distances. This study shows the
      feasibility of using liposomal formulations of neuroimmunophilins directly in the
      brain at the time of implantation to improve graft survival and fiber outgrowth.
      Furthermore, we have shown that the combination of LTAC and LRAPA has a
      synergistic effect. These compounds may play an important role in optimizing
      graft survival and host reinnervation in cell-mediated brain repair strategies
      for the treatment of neurological conditions.

PMID- 15191165
TI  - Reassessment of caspase inhibition to augment grafted dopamine neuron survival.
AB  - One experimental therapy for Parkinson's disease (PD) is the transplantation of
      embryonic ventral mesencephalic tissue. Unfortunately, up to 95% of grafted
      neurons die, many via apoptosis. Activated caspases play a key role in execution
      of the apoptotic pathway; therefore, exposure to caspase inhibitors may provide
      an effective intervention strategy for protection against apoptotic cell death.
      In the present study we examined the efficacy of two different caspase
      inhibitors, caspase-1 inhibitor Ac-YVAD-CMK and caspase-3 inhibitor Ac-DEVD-CMK,
      to augment mesencephalic tyrosine hydroxylase-immunoreactive (TH-ir) neuron
      survival in culture and following implantation into the denervated striatum of
      rats. We report that treatment with Ac-YVAD-CMK provided partial but
      nonsignificant protection for TH-ir neurons against serum withdrawal in
      mesencephalic cultures plated at low density, while neither caspase inhibitor
      promoted TH-ir neuron survival in higher density cultures, simulating graft
      density. We demonstrate that plating procedures (full well vs. microislands) and
      cell density directly affect the degree of insult experienced by TH-ir neurons
      following serum withdrawal. This varying degree of insult directly impacts
      whether caspase inhibition will augment TH-ir neuron survival. Our grafting
      experiments demonstrate that Ac-YVAD-CMK does not augment grafted TH-ir neuron
      survival when added to mesencephalic cell suspensions prior to grafting or to
      mesencephalic reaggregates for 3 days in vitro prior to transplantation. These
      experiments provide further evidence of the failure of these caspase inhibitors
      to augment TH-ir neuron survival. Furthermore, we suggest that cell culture
      paradigms used to model grafting paradigms must more closely approximate the cell
      densities of mesencephalic grafts to effectively screen potential augmentative
      treatments.

PMID- 15191166
TI  - Intracerebral xenotransplantation of GFP mouse bone marrow stromal cells in
      intact and stroke rat brain: graft survival and immunologic response.
AB  - The present study characterized survival and immunologic response of bone marrow
      stromal cells (BMSCs) following transplantation into intact and stroke brains. In
      the first study, intrastriatal transplantation of BMSC (60,000 in 3 microl) or
      vehicle was performed in normal adult Sprague-Dawley male rats that subsequently
      received daily cyclosporin A (CsA, 10 mg/kg, IP in 3 ml) or vehicle (olive oil,
      similar volume) starting on day of surgery up to 3 days posttransplantation.
      Animals were euthanized at 3 or 30 days posttransplantation and brains were
      processed either for green fluorescent protein (GFP) microscopy or flow cytometry
      (FACS). Both GFP epifluorescence and FACS scanning revealed GFP+ BMSCs in both
      groups of transplanted rats with or without CsA, although significantly increased
      (1.6- to 3-fold more) survival of GFP+ BMSCs was observed in the immunosuppressed
      animals. Further histologic examination revealed widespread dispersal of BMSCs
      away from the graft core accompanied by many long outgrowth processes in non-CsA
      transplanted animals, whereas a very dense graft core, with cells expressing only
      sporadic short outgrowth processes, was observed in CsA-transplanted animals.
      There were no detectable GFP+ BMSCs in nontransplanted rats that received CsA or
      vehicle. Immunologic response via FACS analysis revealed a decreased presence of
      cytotoxic cells, characterized by near complete absence of CD8+ cells, and lack
      of activation depicted by low CD69 expression in CsA-treated transplanted
      animals. In contrast, elevated levels of CD8+ cells and increased activation of
      CD69 expression were observed in transplanted animals that received vehicle
      alone. CD4+ helper cells were almost nondetectable in transplanted rats that
      received CsA, but also only minimally elevated in transplanted rats that received
      vehicle. Nontransplanted rats that received either CsA or vehicle displayed very
      minimal detectable levels of all three lymphocyte markers. In the second study, a
      new set of male Sprague-Dawley rats initially received bilateral stereotaxic
      intrastriatal transplantation of BMSCs and 3 days after were subjected to
      unilateral transient occlusion of middle cerebral artery. The animals were
      allowed to survive for 3 days after stroke without CsA immunosuppression.
      Epifluorescence microscopy revealed significantly higher (5-fold more) survival
      of transplanted GFP+ BMSCs in the stroke striatum compared with the intact
      striatum. The majority of the grafts remained within the original dorsal striatal
      transplant site, characterized by no obvious migration in intact striatum, but
      with long-distance migration along the ischemic penumbra in the stroke striatum.
      Moreover, FACS scanning analyses revealed low levels of immunologic response of
      grafted BMSCs in both stroke and intact striata. These results, taken together,
      suggest that xenotransplantation of mouse BMSCs into adult rats is feasible.
      Immunosuppression therapy can enhance xenograft survival and reduce graft-induced
      immunologic response; however, in the acute phase posttransplantation, BMSCs can
      survive in intact and stroke brain, and may even exhibit long-distance migration
      and increased outgrowth processes without immunosuppression.

PMID- 15191167
TI  - Comparison of embryonic stem cell-derived dopamine neuron grafts and fetal
      ventral mesencephalic tissue grafts: morphology and function.
AB  - In this study we compared the function and morphology of two types of neural
      grafts: allografts of fetal ventral mesencephalic (VM) tissue and xenografts of
      embryonic stem cell (ESC)-derived dopamine neurons. Mouse embryonic stem cells
      were cultured and exposed to differentiation factors that induced approximately
      10% of the cells to express a dopaminergic phenotype. These cells were then
      harvested and implanted into the denervated striatum of rats with unilateral
      lesions of the nigrostriatal pathway. Another group of lesioned rats received
      allografts of fetal ventral mesencephalic tissue. While both types of grafts
      yield a similar number of tyrosine hydroxylase (TH)-positive cells, amphetamine
      induced rotational behavior was differentially affected by these grafts:
      rotational behavior was significantly reduced in lesioned rats receiving
      allografts of fetal VM tissue while ESC grafts had slight but insignificant
      effects on rotational scores. Densitometry measures of TH+ fiber outgrowth
      revealed a similar area of reinnervation and a comparable number of TH+ cells for
      ESC graft when compared with VM grafts. These data suggest there are similarities
      and also distinct differences in the manner in which ESC and VM grafts interact
      with the denervated striatum.

PMID- 15191168
TI  - Graft-induced plasticity in the mammalian host CNS.
AB  - In this review we trace back the history of an idea that takes a new approach in
      restorative neurotransplantation by focusing on the "multifaceted dialogue"
      between graft and host and assigns a central role to graft-evoked host
      plasticity. In several experimental examples ranging from the transfer of solid
      fetal tissue grafts into mechanical cortical injuries to deposits of neural stem
      cells into hemisectioned spinal cord. MPTP-damaged substantia nigra or mutant
      cerebella supportive evidence is provided for the hypothesis, that in many CNS
      disorders regeneration of the host CNS can be achieved by taking advantage of the
      inherent capacity of neural grafts to induce protective and restorative
      mechanisms within the host. This principle might once allow us to spare even
      complex circuitry from neurodegeneration.

PMID- 15191169
TI  - A perspective on transplantation therapy and stem cells for Parkinson's disease.

PMID- 15191170
TI  - Albertian errors in head-mounted displays: I. Choice of eye-point location for a
      near- or far-field task visualization.
AB  - A theoretical investigation of rendered depth and angular errors, or Albertian
      errors, linked to natural eye movements in binocular head-mounted displays (HMDs)
      is presented for three possible eye-point locations: the center of the entrance
      pupil, the nodal point, and the center of rotation of the eye. A numerical
      quantification was conducted for both the pupil and the center of rotation of the
      eye under the assumption that the user will operate solely in either the near
      field under an associated instrumentation setting or the far field under a
      different setting. Under these conditions, the eyes are taken to gaze in the
      plane of the stereoscopic images. Across conditions, results show that the center
      of the entrance pupil minimizes rendered angular errors, while the center of
      rotation minimizes rendered position errors. Significantly, this investigation
      quantifies that under proper setting of the HMD and correct choice of the eye
      points, rendered depth and angular errors can be brought to be either negligible
      or within specification of even the most stringent applications in performance of
      tasks in either the near field or the far field.

PMID- 15191171
TI  - First- and second-order information in natural images: a filter-based approach to
      image statistics.
AB  - Previous analyses of natural image statistics have dealt mainly with their
      Fourier power spectra. Here we explore image statistics by examining responses to
      biologically motivated filters that are spatially localized and respond to first
      order (luminance-defined) and second-order (contrast- or texture-defined)
      characteristics. We compare the distribution of natural image responses across
      filter parameters for first- and second-order information. We find that second
      order information in natural scenes shows the same self-similarity previously
      described for first-order information but has substantially less orientational
      anisotropy. The magnitudes of the two kinds of information, as well as their
      mutual unsigned correlation, are much stronger for particular combinations of
      filter parameters in natural images but not in unstructured fractal images having
      the same power spectra.

PMID- 15191172
TI  - Comparison of real and computer-simulated outcomes of LASIK refractive surgery.
AB  - Computer simulations of alternative LASIK ablation patterns were performed for
      corneal elevation maps of 13 real myopic corneas (range of myopia, -2.0 to -11.5
      D). The computationally simulated ablation patterns were designed with biconic
      surfaces (standard Munnerlyn pattern, parabolic pattern, and biconic pattern) or
      with aberrometry measurements (customized pattern). Simulated results were
      compared with real postoperative outcomes. Standard LASIK refractive surgery for
      myopia increased corneal asphericity and spherical aberration. Computations with
      the theoretical Munnerlyn ablation pattern did not increase the corneal
      asphericity and spherical aberration. The theoretical parabolic pattern induced a
      slight increase of asphericity and spherical aberration, explaining only 40% of
      the clinically found increase. The theoretical biconic pattern controlled corneal
      spherical aberration. Computations showed that the theoretical customized pattern
      can correct high-order asymmetric aberrations. Simulations of changes in
      efficiency due to reflection and nonnormal incidence of the laser light showed a
      further increase in corneal asphericity. Consideration of these effects with a
      parabolic pattern accounts for 70% of the clinical increase in asphericity.

PMID- 15191173
TI  - Wideband enhancement of television images for people with visual impairments.
AB  - Wideband enhancement was implemented by detecting visually relevant edge and bar
      features in an image to produce a bipolar contour map. The addition of these
      contours to the original image resulted in increased local contrast of these
      features and an increase in the spatial bandwidth of the image. Testing with
      static television images revealed that visually impaired patients (n = 35) could
      distinguish the enhanced images and preferred them over the original images (and
      degraded images). Most patients preferred a moderate level of wideband
      enhancement, since they preferred natural-looking images and rejected visible
      artifacts of the enhancement. Comparison of the enhanced images with the
      originals revealed that the improvement in the perceived image quality was
      significant for only 22% of the patients. Possible reasons for the limited
      increase in perceived image quality are discussed, and improvements are
      suggested.

PMID- 15191174
TI  - Geometrical effects of positional errors in integral photography.
AB  - The effects of misarrangement of elements (elemental lenses and elemental images)
      that construct three-dimensional (3-D) images in integral photography are
      presented. If the lens arrays of the capturing system and the display system are
      not aligned accurately, positional errors of elements may occur, causing the 3-D
      image to be reconstructed in an incorrect position. The relation between
      positional errors of elements and the reconstructed image is derived. As a
      result, it is shown that a 3-D image is separated by local positional errors and
      blurred by global positional errors. In both local and global positional errors,
      3-D images reconstructed far from the lens array are greatly affected.

PMID- 15191175
TI  - Image formation by use of the geometrical theory of diffraction.
AB  - A deeper understanding of imaging behavior is needed with the widespread adoption
      of optical proximity correction in advanced lithography processes. To gain
      insight into the printing behavior of different mask pattern configurations, we
      derive edge-based and vertex-based image models by combining concepts contained
      in the geometrical theory of diffraction and Hopkins's image model. The models
      are scalar models and apply to planar, perfectly conducting mask objects.

PMID- 15191176
TI  - Imaging of voids by means of a physical-optics-based shape-reconstruction
      algorithm.
AB  - We analyze the performance of a shape-reconstruction algorithm for the retrieval
      of voids starting from the electromagnetic scattered field. Such an algorithm
      exploits the physical optics (PO) approximation to obtain a linear unknown-data
      relationship and performs inversions by means of the singular-value-decomposition
      approach. In the case of voids, in addition to a geometrical optics reflection,
      the presence of the lateral wave phenomenon must be considered. We analyze the
      effect of the presence of lateral waves on the reconstructions. For the sake of
      shape reconstruction, we can regard the PO algorithm as one of assuming the
      electric and magnetic field on the illuminated side as constant in amplitude and
      linear in phase, as far as the dependence on the frequency is concerned.
      Therefore we analyze how much the lateral wave phenomenon impairs such an
      assumption, and we show inversions for both one single and two circular voids,
      for different values of the background permittivity.

PMID- 15191177
TI  - Transmission of an inhomogeneous plane wave through an electrically small
      aperture in a perfectly conducting plane screen.
AB  - Most solutions for electromagnetic diffraction by a circular aperture in a
      perfectly conducting plane screen are for an incident homogeneous (propagating)
      plane wave. When the aperture is electrically small (dimensions small compared to
      the wavelength), the well-known transmission coefficient behaves as the fourth
      power of the diameter/wavelength. We consider the case in which the incident
      field is an inhomogeneous (evanescent) plane wave. Numerical calculations for the
      electrically small circular aperture show that the transmission coefficient for
      an inhomogeneous plane wave can be substantially greater than for a homogeneous
      plane wave at the same frequency. This observation may be helpful in explaining
      the increased transmission recently reported for electrically small apertures in
      plane screens with modifications. The numerical calculations for the electrically
      small aperture are in agreement with results from approximate analytical
      expressions that are based on the equivalent electric and magnetic dipole moments
      for the electrically small complementary disk.

PMID- 15191178
TI  - Effect of finite grating, waveguide width, and end-facet geometry on resonant
      subwavelength grating reflectivity.
AB  - Resonant subwavelength gratings (RSGs) offer narrowband high reflectivity with
      low-reflectivity sidebands. Analysis with the commonly used rigorous coupled-wave
      analysis assumes an RSG with infinite lateral extent and illumination by plane
      waves. This analysis is performed with a finite-difference semivectorial high
      order accurate two-dimensional Helmholtz code that is able to simulate the entire
      finite RSG structure in the dimension of the grating vector. We study the effect
      of finite beam size on RSG reflectivity, resonant wavelength, and spectral
      response width. Independently, we study the effect of a finite RSG by varying the
      waveguide length and number of grating periods while fixing the beam size. We
      show that the placement of the waveguide end facets relative to the termination
      of the grating has a significant effect on the reflectivity and response width.

PMID- 15191179
TI  - Differentiation of globally unpolarized complex random fields.
AB  - Different types of random vector fields can be depolarized in a global sense.
      They can be physically discriminated by probing the statistical invariance when
      they are subject to operations such as a change of the reference frame or the
      introduction of an arbitrary retardance. With use of the observable polarization
      sphere as a visualization tool, a set of measurements is capable of
      discriminating between certain types of globally depolarized light, and we
      discuss the geometric interpretation of the physical invariances.

PMID- 15191180
TI  - Spectral switches of partially coherent light focused by a filter-lens system
      with chromatic aberration.
AB  - It is shown that when partially coherent polychromatic light is focused by a
      filter-lens system with chromatic aberration, a spectral shift exists in the
      focused field, and a spectral switch that is defined as a sharp transition of the
      spectral shift also takes place at some positions of the focused field. The
      influence of the chromatic aberration of the lens, the coherence of the partially
      coherent light in the filter (a circular aperture), the radius of the aperture,
      and the spectral width of the partially coherent light in the aperture on the
      spectral shift and the spectral switch are investigated in detail. The numerical
      results show that these parameters affect the spectral shift and the spectral
      switch significantly. Potential applications of the spectral shift and the
      spectral switch of the partially coherent light are discussed.

PMID- 15191181
TI  - Statistics of partially coherent beams: a numerical analysis.
AB  - We show that by using Monte Carlo simulations, one can study the characteristics
      of beams with adjustable spatial coherence properties that propagate through
      highly scattering media. Moreover, we show that a single simulation is sufficient
      to obtain the intensity distribution at the exit surface of the scattering medium
      for any degree of global coherence of the input beam. The efficient numerical
      procedure correctly reproduces the first- and second-order statistics of the
      intensity distribution obtained after propagation through diffusive media.

PMID- 15191182
TI  - Fast calibration of high-order adaptive optics systems.
AB  - We present a new method of calibrating adaptive optics systems that greatly
      reduces the required calibration time or, equivalently, improves the signal-to
      noise ratio. The method uses an optimized actuation scheme with Hadamard patterns
      and does not scale with the number of actuators for a given noise level in the
      wavefront sensor channels. It is therefore highly desirable for high-order
      systems and/or adaptive secondary systems on a telescope without a Gregorian
      focal plane. In the latter case, the measurement noise is increased by the
      effects of the turbulent atmosphere when one is calibrating on a natural guide
      star.

PMID- 15191183
TI  - Analytic inverse radiative transfer equations for atmospheric and hydrologic
      optics.
AB  - Two new sets of analytical equations are derived with which the albedo of single
      scattering and the coefficients of a Legendre polynomial expansion of the
      scattering phase function can be determined for a source-free, homogeneous plane
      parallel medium uniformly illuminated over the surfaces. The equations,
      essentially linear in the unknowns, require measurements of the radiance in the
      interior of the medium, but no iterative forward-problem calculations are needed.
      Sets of equations for both unpolarized and polarized radiation applications are
      given, as well as a side-by-side comparison with previously known sets of
      analytic inversion equations. Applications of the equations are suggested.

PMID- 15191184
TI  - Lateral photon transport in dense scattering and weakly absorbing media of finite
      thickness: asymptotic analysis of the space-time Green function.
AB  - The asymptotic law for the radial distribution of radiance density from an
      isotropic point source placed in a slab of homogeneous absorbing and scattering
      material is obtained within the framework of diffusion theory. The exponential
      shape of the tail of the resulting Green function has been observed but was not
      theoretically explained until now. We derive formulas for both the steady-state
      and the time-dependent problems. The theoretical results are verified by
      comparison with Monte Carlo simulations.

PMID- 15191185
TI  - Using independent component analysis for material estimation in hyperspectral
      images.
AB  - We develop a method for automated material estimation in hyperspectral images.
      The method models a hyperspectral pixel as a linear mixture of unknown materials.
      The method is particularly useful for applications in which material regions in a
      scene are smaller than one pixel. In contrast to many material estimation
      methods, the new method uses the statistics of large numbers of pixels rather
      than attempting to identify a small number of the purest pixels. The method is
      based on maximizing the independence of material abundances at each pixel. We
      show how independent component analysis algorithms can be adapted for use with
      this problem. We demonstrate properties of the method by application to airborne
      hyperspectral data.

PMID- 15191186
TI  - Fluorescence optical diffusion tomography using multiple-frequency data.
AB  - A method is presented for fluorescence optical diffusion tomography in turbid
      media using multiple-frequency data. The method uses a frequency-domain diffusion
      equation model to reconstruct the fluorescent yield and lifetime by means of a
      Bayesian framework and an efficient, nonlinear optimizer. The method is
      demonstrated by using simulations and laboratory experiments to show that
      reconstruction quality can be improved in certain problems through the use of
      more than one frequency. A broadly applicable mutual information performance
      metric is also presented and used to investigate the advantages of using multiple
      modulation frequencies compared with using only one.

PMID- 15191187
TI  - Information content of the near field: two-dimensional samples.
AB  - Limits on the effective resolution of many optical near-field experiments are
      investigated. The results are applicable to variants of total-internal-reflection
      microscopy (TIRM), photon-scanning-tunneling microscopy (PSTM), and near-field
      scanning-optical microscopy (NSOM) in which the sample is weakly scattering and
      the direction of illumination may be controlled. Analytical expressions for the
      variance of the estimate of the complex susceptibility of an unknown two
      dimensional object as a function of spatial frequency are obtained for Gaussian
      and Poisson noise models, and a model-independent measure is examined. The
      results are used to explore the transition from near-zone to far-zone detection.
      It is demonstrated that the information content of the measurements made at a
      distance of even one wavelength away from the sample is already not much
      different from the information content of the far field.

PMID- 15191188
TI  - Hollow elliptical Gaussian beam and its propagation through aligned and
      misaligned paraxial optical systems.
AB  - A new mathematical model called hollow elliptical Gaussian beam (HEGB) is
      proposed to describe a dark-hollow laser beam with noncircular symmetry in terms
      of a tensor method. The HEGB can be expressed as a superposition of a series of
      elliptical Hermite-Gaussian modes. By using the generalized diffraction integral
      formulas for light passing through paraxial optical systems, analytical
      propagation formulas for HEGBs passing through paraxial aligned and misaligned
      optical systems are obtained through vector integration. As examples of
      applications, evolution properties of the intensity distribution of HEGBs in free
      space propagation were studied. Propagation properties of HEGBs through a
      misaligned thin lens were also studied. The HEGB provides a convenient way to
      describe elliptical dark-hollow laser beams and can be used conveniently to study
      the motion of atoms in a dark-hollow laser beam.

PMID- 15191189
TI  - Finite-difference time-domain calculations of a liquid-crystal-based switchable
      Bragg grating.
AB  - A polymer-wall-confined transmissive switchable liquid crystal grating is
      proposed and investigated by two-dimensional finite-difference time-domain
      optical calculation and liquid-crystal-director calculation, to our knowledge for
      the first time. The results show how to obtain optimized conditions for high
      diffraction efficiency by adjusting the liquid crystal parameters, grating
      geometric structure, and applied voltages. The light propagation direction and
      efficiency can be accurately calculated and visualized concurrently.

PMID- 15191190
TI  - Analysis of strictly bound modes in photonic crystal fibers by use of a source
      model technique.
AB  - We describe a source-model technique for the analysis of the strictly bound modes
      propagating in photonic crystal fibers that have a finite photonic bandgap
      crystal cladding and are surrounded by an air jacket. In this model the field is
      simulated by a superposition of fields of fictitious electric and magnetic
      current filaments, suitably placed near the media interfaces of the fiber. A
      simple point-matching procedure is subsequently used to enforce the continuity
      conditions across the interfaces, leading to a homogeneous matrix equation.
      Nontrivial solutions to this equation yield the mode field patterns and
      propagation constants. As an example, we analyze a hollow-core photonic crystal
      fiber. Symmetry characteristics of the modes are discussed and exploited to
      reduce the computational burden.

PMID- 15191191
TI  - New method for nonparaxial beam propagation.
AB  - A new method for solving the wave equation is presented that is nonparaxial and
      can be applied to wide-angle beam propagation. It shows very good stability
      characteristics in the sense that relatively larger step sizes can be taken. An
      implementation by use of the collocation method is presented in which only simple
      matrix multiplications are involved and no numerical matrix diagonalization or
      inversion is needed. The method is hence faster and is also highly accurate.

PMID- 15191192
TI  - Planar-waveguide integrated spectral comparator.
AB  - A cost-effective yet robust and versatile dual-channel spectral comparator is
      presented. The silica-on-silicon planar-waveguide integrated device includes two
      holographic Bragg-grating reflectors (HBRs) with complementary spectral transfer
      functions. Output comprises projections of input signal spectra onto the
      complementary spectral channels. Spectral comparators may be useful in optical
      code-division multiplexing, optical packet decoding, spectral target recognition,
      and the identification of molecular spectra. HBRs may be considered to be mode
      specific photonic crystals.

PMID- 15191193
TI  - On the optical theory of photoelastic tomography.
AB  - In recent years many authors have considered the possibility of using tomography
      for nondestructive determination of three-dimensional stress fields. A natural
      starting point for this is integrated photoelasticity. The problem is complicated
      since the stress field is a tensor field, and in the general case in integrated
      photoelasticity the relationships between the measurement data and the parameters
      of the stress field are non-linear. To elucidate these relationships, we have
      systematically studied the propagation of polarized light in an inhomogeneous
      birefringent medium. The inverse problem of integrated photoelasticity is
      formulated in the general form, and particular cases in which the polarization
      transformation matrix is exactly determined by integrals of the stress tensor
      components are considered. The possibility of using the Radon inversion for
      approximate determination of the normal stress field in an arbitrary section of
      the test object is outlined.

PMID- 15191194
TI  - Diffraction of cylinders with longitudinal surface structures.
AB  - We present a model to determine the light scattered by a metallic cylinder with
      longitudinal structures when the cylinder is illuminated by a Gaussian light beam
      in oblique incidence. The model is based on an approximate solution to the
      Helmholtz-Kirchhoff integral by means of the stationary-phase method. We have
      studied the variations of the diffraction pattern in terms of the size of the
      defect and other geometrical parameters. The width of the beam and the
      misalignment between the beam and the cylinder have also been considered, as well
      as the optical properties of the surface.

PMID- 15191195
TI  - Transmission of dipole radiation through interfaces and the phenomenon of anti
      critical angles.
AB  - Radiation emitted by an electric dipole consists of traveling and evanescent
      plane waves. Usually, only the traveling waves are observable by a measurement in
      the far field, since the evanescent waves die out over a length of approximately
      a wavelength from the source. We show that when the radiation is passed through
      an interface with a medium with an index of refraction larger than the index of
      refraction of the embedding medium of the dipole, a portion of the evanescent
      waves are converted into traveling waves, and they become observable in the far
      field. The same conclusion holds when the waves pass through a layer of finite
      thickness. Waves that are transmitted under an angle larger than the so-called
      anti-critical angle theta (1) ac are shown to originate in evanescent dipole
      waves. In this fashion, part of the evanescent spectrum of the radiation becomes
      amenable to observation in the far field. We also show that in many situations
      the power in the far field coming from evanescent waves greatly exceeds the power
      originating in traveling waves.

PMID- 15191196
TI  - Hepatopulmonary syndrome: role of nitric oxide and clinical aspects.
AB  - Hepatopulmonary syndrome is defined by oxygenation impairment due to abnormal
      intrapulmonary vascular dilatations in patients with liver disease. The
      implication of enhanced pulmonary production of nitric oxide in the pathogenesis
      of intrapulmonary vascular dilatations has been demonstrated both in murine
      models and in human hepatopulmonary syndrome. The diagnosis of hepatopulmonary
      syndrome in chronic liver disease is of paramount importance, considering the
      fact that severe hypoxemia related to hepatopulmonary syndrome may occur in
      patients with well compensated liver disease and that survival is reduced in
      patients with hepatopulmonary syndrome relative to non hepatopulmonary syndrome
      patients. Priority for liver transplantation, which is presently the only cure,
      has been recently increased in patients with advanced hepatopulmonary syndrome.

PMID- 15191197
TI  - Poor communication between clinicians--poor care for patients!

PMID- 15191198
TI  - Sequential therapy; a new treatment for Helicobacter pylori infection. But is it
      ready for general use?

PMID- 15191199
TI  - How do general practitioners rate their relationship with gastroenterologists?
AB  - BACKGROUND: Relations between general practitioners and the hospital consultants
      are often considered difficult, and occasionally generate conflicts, potentially
      affecting the patient management and healthcare system organisation. These views,
      however, have partly been contradicted by structured surveys and qualitative
      studies. AIMS: We conducted a survey on the general practitioners' opinions
      regarding their relations with the gastroenterological-endoscopy services in
      order to explore current attitudes, any negative aspects and assess scope for
      improvement. SUBJECTS AND METHODS: Structured questionnaires were sent to 221
      general practitioners in the Veneto region of Italy; the questionnaire was based
      on 26 questions concerning their subjective relations with the
      gastroenterologists, expertise in the gastroenterological problems and perceived
      efficiency of gastroenterological services. RESULTS: As many as 106 doctors
      answered the postal questionnaire (mean: 15 per province; range 5-20). Responses
      to the structured questions totalled to 2,339 items, out of which 1,234 (53%)
      presented positive responses, particularly with regard to admissions' management
      and the adequacy of referral reports. Many general practitioners reported of
      their participation in the meetings on gastroenterological problems. Homecare
      referrals were limited in number, even for the patients with tube feeding.
      CONCLUSIONS: Relations between the general practitioners in Veneto and local
      gastroenterological services were generally good, possibly reflecting the well
      developed outreach network. This liaison could be further improved via closer
      interrelations based not only on the patient referrals but also on the
      professional and information exchange to promote successful practice.

PMID- 15191200
TI  - The prolongation of triple therapy for Helicobacter pylori does not allow
      reaching therapeutic outcome of sequential scheme: a prospective, randomised
      study.
AB  - BACKGROUND AND AIM: One-week triple therapy for Helicobacter pylori revealed,
      during these last few years, a decrease in the eradication rate, so that the
      prolongation of its duration has been proposed. A sequential scheme recently
      showed very satisfactory results. We performed a prospective randomised study
      with the aim of either evaluating whether the triple therapy prolongation may
      improve its effectiveness and comparing its outcome with that of sequential
      regimen. PATIENTS AND METHODS: Three hundred and forty-two H. pylori positive
      patients completed the study. They were randomised to receive one of the
      following treatments: (i) a 7-day triple therapy comprising of rabeprazole (20
      mg, b.i.d.) plus clarithromycin (500 mg, b.i.d.) and amoxycillin (1 g, b.i.d.);
      (ii) a 10-day triple therapy comprising the same scheme; (iii) a 10-day
      sequential regimen comprising of rabeprazole (20 mg, b.i.d.) plus amoxycillin (1
      g, b.i.d.) for 5 days followed by rabeprazole (20 mg, b.i.d.) plus clarithromycin
      (500 mg, b.i.d.) and tinidazole (500 mg, b.i.d.) for the next 5 days. Therapeutic
      results were expressed using both intention-to-treat and per protocol analyses
      with 95% confidence intervals. A model of multivariate logistic regression
      analysis was performed using therapeutic outcome as a dependent variable and
      including endoscopic finding, smoking habit, age and sex as candidates for the
      model. RESULTS: Sequential regimen showed a significant gain in the eradication
      rate as compared to the 7-day (P < 0.0001) and the 10-day (P < 0.01) triple
      therapies, respectively. Overall eradication was lower in smokers than in non
      smokers, but the difference remained significant only in the 7-day triple therapy
      (P < 0.01). Additionally, the overall eradication was higher in peptic ulcer than
      dyspepsia (P < 0.01), even if this difference was significant only for both
      triple therapies. CONCLUSIONS: Seven-day triple therapy achieves disappointing
      eradication rates in dyspeptics and smokers. Prolonging triple therapy to 10 days
      does not significantly improve the eradication rate. The novel 10-day sequential
      regimen is more effective and equally tolerated than the 10-day triple therapy.

PMID- 15191201
TI  - Helicobacter pylori infection and increased nitrite synthesis in the stomach.
      Inflammation and atrophy connections.
AB  - BACKGROUND: We have previously shown that the nitrite content in the gastric
      juice of Helicobacter pylori-positive patients is significantly higher than that
      of H. pylori-negative patients and it decreases after eradication of H. pylori.
      AIM: To examine the relationship between the nitric oxide synthesis in the
      gastric lumen and histological findings. METHODS: Eighty-five middle aged
      Japanese patients were studied. Four specimens, each obtained from the greater
      and lesser curvature of antrum and gastric body were processed for the
      determination of histopathological scores using the updated Sydney System.
      Gastric juice was collected endoscopically to determine the concentration of
      nitrite using a modified Griess reaction. RESULTS: There was a significant
      positive correlation between the nitrite and the pH levels (r = 0.81, P < 0.001)
      and between the pH levels and the histopathological scores in the corpus. The
      gastric juice pH and concentration of the nitrite increased in patients with
      histological diagnosis of normal, antral-predominant gastritis, pangastritis and
      corpus-predominant gastritis in due order. CONCLUSIONS: H. pylori infection
      effects nitric oxide synthesis in the gastric lumen which is mainly connected
      with hypoacidity. The gastric juice pH is one of the useful markers for corpus
      dominant gastritis and probably for high-risk group of gastric cancer.

PMID- 15191202
TI  - Searching for coeliac disease in patients with non-alcoholic fatty liver disease.
AB  - BACKGROUND: A non-negligible percentage of patients with non-alcoholic fatty
      liver disease, a leading cause of hepatic progressive disorder related to insulin
      resistance, have no metabolic risk factors, and abnormal intestinal permeability
      has been suggested to be involved in the pathogenesis of the liver damage.
      Coeliac disease, a curable disorder characterised by inflammatory mucosal damage,
      may show hepatic histological features similar to steatohepatitis. Conflicting
      data have been reported on the prevalence of coeliac disease in non-alcoholic
      steatohepatitis. AIM: To search for coeliac disease in a series of patients with
      non-alcoholic fatty liver disease by screening with anti-tissue transglutaminase
      and anti-endomysium antibodies. PATIENTS AND METHODS: Fifty-nine consecutive
      patients with hypertransaminasemia and non-alcoholic fatty liver disease, 38
      (64%) with steatohepatitis. Anti-endomysium antibodies were assayed by indirect
      immunofluorescence, IgA anti-tissue transglutaminase by ELISA. Patients who
      tested positive underwent HLA DQ typing and endoscopy. RESULTS: Tissue
      transglutaminase antibodies were positive in six (10%) patients and anti
      endomysium in two (3.4%); only two (3.4%), positive for both anti-endomysium
      positive and anti-transglutaminase, resulted to have coeliac disease based on
      histological findings. After 6 months of gluten-free diet, liver enzymes
      normalised. CONCLUSIONS: The prevalence of silent coeliac disease is 3.4% in
      patients with non-alcoholic fatty liver. The inclusion of anti-endomysium
      antibodies test in studying patients with non-alcoholic fatty liver and
      persistent biochemical abnormalities has to be taken into account, since
      positivity for tissue transglutaminase antibodies, in the absence of confirmatory
      anti-endomysium antibodies, is not sufficient to perform diagnostic endoscopy.

PMID- 15191203
TI  - Transcriptional downregulation of tight junction protein ZO-1 in active coeliac
      disease is reversed after a gluten-free diet.
AB  - Coeliac disease is an autoimmune enteropathy characterized by an enhanced
      permeability of the intestinal epithelial barrier. In epithelial cells
      paracellular permeability is regulated by intercellular tight junction. The
      cytoplasmic protein ZO-1 interacts directly with F-actin and plays a pivotal role
      in the structural and functional organization of tight junction. AIM: The aim of
      this study was to investigate the expression and localization of ZO-1 in the
      intestinal mucosa of coeliac patients. PATIENTS AND METHODS: Twenty patients with
      active coeliac disease, seven of whom underwent a repeat biopsy following a
      gluten-free diet and 27 control subjects, were studied. In all subjects, three
      biopsies were obtained from distal duodenum during upper gastrointestinal
      endoscopy. ZO-1 protein localization and levels were detected by
      immunofluorescence followed by confocal microscopy analysis and immunoblotting.
      ZO-1 mRNA expression was assessed by RT-PCR. F-actin distribution was also
      investigated. RESULTS: In patients with active coeliac disease, both ZO-1 protein
      levels and mRNA were clearly reduced. Cytoskeletal organization was disrupted
      with F-actin staining concentrated at the subcortical and basal surface regions.
      Abnormalities in ZO-1 expression and actin organization were reversed after a
      gluten-free diet. CONCLUSIONS: In active coeliac disease, ZO-1 protein expression
      is downregulated at the transcriptional level in association with F-actin
      redistribution. These changes are completely reversed after a gluten-free diet
      and could contribute to the increased intestinal paracellular permeability
      observed in this disorder.

PMID- 15191204
TI  - Infliximab heals intestinal inflammatory lesions and restores growth in children
      with Crohn's disease.
AB  - BACKGROUND: Infliximab has recently emerged as an efficacious agent for patients
      with severe Crohn's disease. There are only few studies on the use of infliximab
      in children with Crohn's disease: most of them are retrospective and deal only
      with the clinical response to the drug. AIM: We aimed at assessing the efficacy
      of infliximab in children and adolescents with severe Crohn's disease recruited
      consecutively and followed up prospectively at a single centre. Clinical
      response, intestinal inflammation and growth pattern were evaluated. PATIENTS:
      Eighteen patients entered into the trial (median age: 13 years, range: 6-18).
      They were referred because of severe symptoms with unsatisfactory response to
      conventional drugs. METHODS: All patients received a baseline schedule of three
      intravenous infusions of infliximab (0, 2 and 6 weeks), 5 mg/kg. Paediatric
      Crohn's Disease Activity Index, nutritional and activity serum variables, and
      ileocolonoscopy (with histology) were evaluated before and 8 weeks after
      beginning the therapy. All patients had long-term administration of azathioprine
      (2 mg/kg per day). After the baseline schedule, eight patients had a retreatment
      infusion of infliximab (5 mg/kg) every 8 weeks. Weight and height Z scores were
      measured before starting the baseline infusion programme and after 6 months.
      RESULTS: After 8 weeks of therapy, there was a dramatic improvement in Paediatric
      Crohn's Disease Activity Index, in nutritional and activity blood parameters, as
      well as in endoscopic and histological scores; 10 patients had a clinical
      remission (Paediatric Crohn's Disease Activity Index < or = 10), 12 patients had
      an inflammatory remission (decrease in both endoscopic and histological scores
      for > or = 50% as compared to baseline values). In all patients corticosteroids
      were stopped within 4 weeks after beginning infliximab therapy. After 6 months of
      therapy, Paediatric Crohn's Disease Activity Index was markedly lower than the
      pre-treatment value; however, it was significantly lower in patients on
      retreatment than in those who received only three infusions of infliximab.
      Furthermore, a significant increase in both weight and height Z scores was
      observed 6 months after beginning of the baseline infusion programme. Moreover,
      weight and height gain was significantly higher in patients on retreatment rather
      than in those treated only with three baseline infusions of infliximab. Mild
      infusion reactions controlled by slowing infusion rate were observed in four
      patients. No delayed hypersensitivity-like reactions were seen. CONCLUSIONS: In
      children with severe Crohn's disease, infliximab is a safe and valuable treatment
      in inducing remission, in healing inflammatory lesions of the gut, as documented
      by endoscopy and histology, and in promoting growth. Retreatment infusions of
      infliximab may be suggested in childhood-onset Crohn's disease to maintain
      remission and reverse growth failure.

PMID- 15191205
TI  - Colonic smooth muscle responses in patients with diverticular disease of the
      colon: effect of the NK2 receptor antagonist SR48968.
AB  - BACKGROUND: Little is known about the pathophysiology of diverticular disease.
      AIM: To compare passive and active stress and the response to carbachol of
      colonic smooth muscle specimens from patients with diverticular disease and
      patients with colon cancer. The effect of the NK2 receptor antagonist, SR48968,
      on electrically evoked contractions of circular muscle was also investigated.
      PATIENTS: Sigmoid colon segments were obtained from 16 patients (51-83 years)
      undergoing elective sigmoid resection for diverticular disease and 39 patients
      (50-88 years) undergoing left hemicolectomy for non-obstructive sigmoid colon
      cancer. METHODS: Isometric tension was measured on circular or longitudinal
      taenial muscle. Strips were stretched gradually to Lo (length allowing the
      development of optimal active tension with carbachol) and were also exposed to
      increasing carbachol concentrations. The effects of atropine, tetrodotoxin and
      SR48968 on electrically evoked (supramaximal strength, 0.3 ms, 0.1-10 Hz)
      contractions of circular strips from 8 patients with diverticular disease and 19
      patients with colon cancer were also studied. RESULTS: Both passive and active
      stress in circular muscle strips obtained from patients with diverticular disease
      was higher than in patients with colon cancer (P < 0.05). Electrically evoked
      contractions were significantly reduced by atropine in all preparations and were
      virtually suppressed by combined SR48968 and atropine. Tetrodotoxin suppressed
      electrically evoked contractions only in patients with colon cancer, whereas a
      tetrodotoxin-resistant component was identified in patients with diverticular
      disease. CONCLUSIONS: The changes in both passive and active stress in specimens
      from patients with diverticular disease may reflect circular smooth muscle
      dysfunction. Acetylcholine and tachykinins are the main excitatory
      neurotransmitters mediating electrically evoked contractions in human sigmoid
      colon circular muscle.

PMID- 15191206
TI  - Pancreatic carcinoma with brain metastases: case report and literature review.
AB  - The case of a patient developing multiple brain metastases from carcinoma of the
      exocrine pancreas has been described. A 56-year-old man with stage IV pancreatic
      cancer attained a clinical and radiographic response while receiving the G-FLIP
      chemotherapy regimen (biweekly gemcitabine, irinotecan, 5-fluorouracil,
      leucovorin and cisplatin). After 4 months of therapy, he developed gait imbalance
      and weakness in the right hand. An MRI of the brain showed multiple 1-2 mm
      enhancing nodules in the cerebral hemispheres and pons. A subsequent biopsy
      confirmed that these were pancreatic carcinoma metastases. The patient
      experienced a rapid deterioration in his neurological status and died 3 days
      after brain biopsy. Previously reported cases of brain metastases from pancreatic
      cancer are reviewed.

PMID- 15191207
TI  - Diffuse febrile dermatosis in a patient with active ulcerative colitis under
      treatment with steroids and azathioprine: a case of Sweet's syndrome. Case report
      and review of literature.
AB  - Ulcerative colitis is an inflammatory bowel disease often associated with extra
      intestinal manifestations, such as dermatological disorders. Of these, the most
      frequent are erythema nodosum and pyoderma gangrenosum, the two neutrophilic
      forms of dermatosis. Another is Sweet' s syndrome, which results in a sudden
      eruption of tender, raised erythematous or violaceous plaques/papules or nodules,
      less frequent vesicles, pustules or bullae, involving face, neck, arms and trunk.
      This skin disorder is frequently observed in patients with leukaemia or
      connective tissue diseases, while it is very rare in patients with inflammatory
      bowel disease. The present report deals with the case of a febrile diffuse skin
      eruption in a 53-year-old patient with moderately active ulcerative colitis after
      few days' treatment with steroids and azathioprine. At first, the dermatosis was
      addressed to an idiosyncrasy to azathioprine, which was, therefore, promptly
      discontinued. Histological examination of skin biopsies revealed the presence of
      features typical of a Sweet's syndrome. The eruption gradually improved as well
      as the patient's general condition, until complete regression was achieved
      following steroid treatment.

PMID- 15191208
TI  - Treatment of chronic hepatitis C in naive patients with high-dose interferon
      alpha2a induction therapy and two different ribavirin doses.

PMID- 15191209
TI  - Goodbye old test-tubes! Robot and P.C. rush into the scene.

PMID- 15191210
TI  - Pharmacokinetics of selenium following oral administration selenium preparation
      in rabbits.
AB  - The aim of study was to investigate the bioavailability of selenium after oral
      administration of selenium yeast. As a reference preparation was used sodium
      selenite. The preparations were investigated in rabbits, according to a
      randomized two way crossover design in the fasted state. Each animal was given
      selenium preparation in the form of the single oral dose 0.5 mg Se/kg body
      weight. A washout period of one week separated both treatment periods. The
      selenium concentration was determined in serum spectrofluorometry. The divalent
      equation of one-compartment model was the simplest formula describing the course
      of selenium changes in serum of rabbits and giving the pharmacokinetic
      parameters. Pharmacokinetic variables (mean maximum plasma concentration, mean
      time to reach maximum plasma concentration, and the mean area under the plasma
      concentration-time curve) were not statistically different for the two
      preparations. It can be concluded that the two selenium preparations are likely
      to be bioequivalent.

PMID- 15191211
TI  - Analgesic and anti-inflammatory activities of (-)-o benzyl cubebin, a (-)-cubebin
      derivative, obtained by partial synthesis.
AB  - The anti-inflammatory and antinociceptive effects of the benzylated cubebin
      derivative, obtained by reaction of (-)-cubebin with benzyl bromide, were
      investigated using different animal models. The (-)-o-benzyl cubebin showed a low
      anti-inflammatory effect (16.2%) in relation to cubebin (57%) and indomethacin
      (77%) in the carrageenin-induced paw edema in rats, but on the other hand it was
      more effective (80%) than (-)-cubebin (41%) in inhibiting acetic acid-induced
      writhing in mice, producing dose-response correlation with doses of 10, 20 and 40
      mg/kg, respectively. Moreover, this derivative compound did not show activity in
      both the hot plate and the cell migration test in rats. Overall, the results
      showed that the benzylation of cubebin were efficient in enhancing only its
      analgesic activity.

PMID- 15191213
TI  - Pharma bibliography: Medicinal chemistry.

PMID- 15191212
TI  - Synthesis of novel dihydropyridine, dihydropyrimidine, dithioacetal and chalcone
      derivatives from formylchromones.
AB  - Condensation of 6-Formylfurochromone (4,9-dimethoxy-5-oxo-5H-furo[3,2
      g][1]benzopyran-6-carbaldehyde) 5a and malononitrile without solvent afforded
      (2E)-2-cyano-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]benzopyran-6-yl) acrylamide 8
      at hydrolysis with dilute HCL. 2,6-Diamino-4-(4,9-dimethoxy-5-oxo-5H-furo[3,2
      g]benzopyran-6-yl)-1,4-dihydropyridine-3,5-dicarbonitrile 9 and 6-(2,6-diacetyl
      3,5-dimethylcyclohexa-2,5-dien-1-yl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5
      one 10a,b were synthesized by one-pot cyclocondensation reaction of formyl 5a,
      malononitrile and ammonium acetate/or ammonium hydroxide/or aniline. The reaction
      of formyl 5a, malononitrile/acetylacetone (Thio) urea/guanidine HCL to give 6
      amino-4-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1]benzopyran-6-yl)-2-methylene
      1,2,3,4-tetrahydropyrimidine-5-carbonitrile compounds 11a,b, 6-(2-amino-5,6
      dimethyl-1,4-dihydropyrimidin-4-yl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5
      one 12a,b. Condensation of formylfurochromone 5a with thiol compounds afforded 6
      isopropyl-4-methoxy-9-(methoxy Ia or methyl Ib)-5H-furo[3,2-g][1]benzopyran-5-one
      13a-f; 6-(1,3-dithiolan-2-yl)-4-methoxy-5H-furo[3,2-g]chromen-5-one 14a,b; 7
      hydroxy-6-isopropyl-5-methoxy-2-methyl-4H-benzopyran-4-one 5a-c; 6 hydroxy-7
      [mercapto(methylthio)methyl-8-methoxy-3-methylnaphthalen-1(4H)-one 16,
      respectively. Formylfurochromones 5a-c were reacted with different substituted of
      acetyl compounds (khellinone, 2-acetyl pyrrol, 3-acetyl coumarin, methyl-2
      thienyl ketone and p-aminoacetophenone respectively) to proceed 4-methoxy-9
      (methoxy Ia or methyl Ib)-6-(1E)-3-oxobut-1-enyl]-5H-furo[3,2-g][1]benzopyran-5
      one 17, 5-methoxy-2-methyl-6[(1E)-3-oxobut-1-enyl]-4a,5,8,8a-tetrahydro-4H
      benzopyran-4-one 18a-d, 4,9-dimethoxy-6-[(1E)-3-methoxyprop-1-enyl]-5H-furo[3,2
      g][1]benzopyran-5-one-N-methylene-N-phenylamine-6-(iminomethyl)-4,9-dimethoxy-5H
      furo[3,2-g][1]benzopyran-5-one 19.

PMID- 15191215
TI  - Pharma bibliography: Technology.

PMID- 15191214
TI  - Pharma bibliography: (R&D).

PMID- 15191216
TI  - Relationship of oral lichen planus to hepatitis C virus in southern Taiwan.
AB  - Oral lichen planus (OLP) is a relatively common skin and oral disease that
      manifests as a mucous reaction to a variety of etiologic factors, including
      autoimmune disease, drug reaction, diabetes mellitus (DM), hypertension,
      hepatitis C virus (HCV), urolithiasis, psychogenic factors, and bacterial
      infection. The purpose of this study was to investigate the relationship between
      HCV infection and OLP as there is a high prevalence of HCV infection in Taiwan. A
      total of 1,075 subjects aged at least 15 years participated in the study. The
      total prevalence of OLP was 3% (32/1,075). OLP was significantly associated with
      DM (odds ratio, OR, 3.09) and HCV (OR, 2.05). Atrophic-erosive OLP (13/32) and
      reticular OLP (21/32) were significantly associated with HCV and DM,
      respectively. Logistic regression analysis showed that elevation of alanine
      aminotransferase (ALT) significantly increased the risk of atrophic-erosive OLP.
      We concluded that OLP is significantly associated with HCV and DM in southern
      Taiwan, particularly in HCV patients with elevated serum ALT levels and atrophic
      erosive OLP.

PMID- 15191218
TI  - Perceived enactment of autonomy and related sociodemographic factors among non
      institutionalized elders.
AB  - The purpose of this study was to assess empirical data on the perceived enactment
      of autonomy (PEA), Chinese version, and to explore factors related to PEA among
      non-institutionalized elderly. A purposive sample of 165 subjects older than 65
      years was recruited in Kaohsiung in southern Taiwan. Five subjects failed to
      answer their questionnaires completely; the total effective sample was thus 160.
      Questionnaires and interviews were used to collect data. The structured
      questionnaire consisted of two parts, assessing sociodemographic information and
      the PEA scale, Chinese version. Subjects had a high PEA score (mean, 3.38), with
      the greatest score in individuality (mean, 3.54), followed by self-direction
      (mean, 3.49) and freedom (mean, 3.16). Multiple regression analysis showed that
      the need for assistance in activities of daily living (beta = -0.62), overall
      health status (beta = 0.20), marital status (beta = 0.14), and age (beta = -0.13)
      significantly affected PEA in these elderly subjects and explained 61.9% of the
      total variance of PEA in this population. Based on these results, we provide
      substantive suggestions to practitioners and researchers. Possible future studies
      could expand the sample size using a random sampling method or examine factors
      related to PEA in order to learn more about PEA and apply it to clinical
      practice.

PMID- 15191217
TI  - Relationship between methamphetamine use and risky sexual behavior in
      adolescents.
AB  - Substance abuse and risky sexual behavior have been identified as behaviors that
      can endanger adolescent psychosocial development. This study examined the
      relationship between methamphetamine (MAMP) use and risky sexual behavior in
      adolescents. Risky sexual behavior was compared not only between MAMP users and
      non-users, but also between high-frequency and low-frequency MAMP users. We
      compared the sexual intercourse histories of 85 adolescents formally charged as
      MAMP users with those of 170 gender-matched adolescents with no record of MAMP
      use. MAMP usage characteristics were compared between users who had and those who
      had not experienced sexual intercourse. Previous sexual experience was more
      likely in MAMP users than in non-users. MAMP users were also more likely to have
      had a greater total number of sexual partners and were more likely to have had
      unplanned sex under the influence of alcohol. High-frequency MAMP use was
      associated with increased tendencies to engage in unprotected sex and to use MAMP
      before sexual intercourse. In general, the chance of sexual intercourse increased
      in proportion to frequency of MAMP use. Given the clear link between MAMP use and
      risky sexual behavior, risk-reduction programs directed at teen MAMP users are
      urgently needed.

PMID- 15191219
TI  - Correlates for consistency of contraceptive use among sexually active female
      adolescents.
AB  - This study explored the correlates for consistency of contraceptive use among
      sexually active female adolescents in Kaohsiung County, Taiwan. Overall, 164
      female adolescents who had engaged in sexual behavior within the last 6 months
      and were not pregnant at the time of the study were selected from two vocational
      high schools in Kaohsiung County, Taiwan. An anonymous questionnaire was used to
      measure demographic data, contraceptive attitudes, contraceptive knowledge,
      contraceptive self-efficacy, perception of peers' use of contraceptives, sexual
      history, and contraceptive use. The results showed that 45.7% of subjects had sex
      once or more per week, and that 39.6% of subjects always used contraceptives
      while 15.2% never used contraceptives. Condoms were the most popular
      contraceptives (51.2%) and the withdrawal method was the second most popular
      (23.8%). Stepwise logistic regression showed that higher contraceptive attitudes
      (odds ratio, OR, 1.148) and previous contraceptive education in school (OR,
      3.394) increased the probability of consistently using contraceptives, correctly
      classifying 67.2% of the sample.

PMID- 15191220
TI  - Prevalence of Pediculus capitis infestation among school children of Chinese
      refugees residing in mountanous areas of northern Thailand.
AB  - An epidemiologic survey of Pediculus capitis infestation among Akka aboriginal
      and Han children of Chinese refugees living in mountainous areas at elevations of
      1,100 to 1,400 m in Chiang-Rai Province of northern Thailand was conducted during
      January 2003. Of the 303 children examined, 43 (14.2%) had P. capitis
      infestation. The overall infestation rate for P. capitis in Akka children (29.3%,
      12/41) was significantly higher than that in Han children (11.8%, 31/262; chi2 =
      8.161, p = 0.002). The prevalence in Akka (52.2%, 12/23) and Han girls (19.7%,
      31/157) was higher than that in Akka (0%) and Han boys (0%), respectively (p <
      0.001), and the prevalence was higher in Akka girls than in Han girls (chi2 =
      10.978, p = 0.001). The high prevalence of P. capitis infestation among these
      girls was possibly due to poor environmental hygiene and unavailability of
      sufficient water.

PMID- 15191221
TI  - Development of hyperthyroidism following primary hypothyroidism: a case report.
AB  - Development of hyperthyroidism following primary hypothyroidism is uncommon, and
      only a few documented cases have been reported. Alterations in thyroid
      stimulating hormone receptor antibodies in serum are currently considered to play
      the main role in the pathophysiology, but the exact mechanism is still unknown.
      Here, we report the case of a 60-year-old man with disturbed consciousness due to
      hyponatremia. Thyroid function tests showed primary hypothyroidism with a high
      anti-microsomal antibody titer (1:6,400). The patient experienced weight loss and
      exophthalmos 6 years later. Serum thyroid hormone levels were increased and
      thyroxine treatment was discontinued, but the patient remained thyrotoxic 2
      months later. 131I thyroid uptake was 40.9% at 24 hours, and bilateral thyroid
      lobes were not enlarged with diffuse radioactivity. Six months later, the patient
      was still thyrotoxic and therapy with methimazole 10 mg/day was started. He is
      now taking methimazole and is euthyroid.

PMID- 15191222
TI  - Third ventricle immature teratoma: a case report.
AB  - We present the case of a 1-year-old girl with persistent vomiting who was found
      to have a disproportionately large immature teratoma in the third ventricle.
      Magnetic resonance imaging demonstrated a heterogeneous intracranial mass in the
      third ventricle, with a compressed left cerebral hemisphere and hydrocephalus.
      Bifrontal craniotomy via a transchiasmatic approach achieved total resection of
      the tumor. No significant neurologic deficit was seen except for double vision
      and disturbances in eye movement. Third ventricle immature teratoma, although
      extremely rare, may present as a suprasellar mass lesion and hydrocephalus. The
      prognosis after gross total resection is favorable; however, radiotherapy is
      usually postponed until 36 to 48 months of age in order to avoid complications
      such as stunted growth, endocrine disturbances and neuropsychologic problems.

PMID- 15191223
TI  - Biliary cystadenocarcinoma associated with atrophy of the left hepatic lobe and
      hepatolithiasis mimicking intrahepatic cholangiocarcinoma: a case report.
AB  - Biliary cystadenocarcinoma and its benign counterpart, biliary cystadenoma, are
      rare hepatic cystic tumors arising from the hepatobiliary epithelium. We report
      the case of a 68-year-old Taiwanese woman who presented initially with acute
      cholangitis. A series of imaging studies including abdominal ultrasound,
      computerized tomography, endoscopic retrograde cholangiopancreatography, and
      percutaneous transhepatic cholangiography showed bilateral intrahepatic duct
      (IHD) and common bile duct (CBD) stones with IHD and CBD dilatation, and an ill
      defined tumor within the atrophied left hepatic lobe. The patient underwent
      surgical resection of the tumor and choledocholithotomy. The pathologic diagnosis
      was biliary cystadenocarcinoma. We review this rare disease entity and discuss
      its unusual radiologic features mimicking intrahepatic cholangiocarcinoma.

PMID- 15191224
TI  - Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free
      radical production-DNA damage mechanism?
AB  - Oxygen is toxic to aerobic animals because it is univalently reduced inside cells
      to oxygen free radicals. Studies dealing with the relationship between oxidative
      stress and aging in different vertebrate species and in caloric-restricted
      rodents are discussed in this review. Healthy tissues mainly produce reactive
      oxygen species (ROS) at mitochondria. These ROS can damage cellular lipids,
      proteins and, most importantly, DNA. Although antioxidants help to control this
      oxidative stress in cells in general, they do not decrease the rate of aging,
      because their concentrations are lower in long- than in short-lived animals and
      because increasing antioxidant levels does not increase vertebrate maximum
      longevity. However, long-lived homeothermic vertebrates consistently have lower
      rates of mitochondrial ROS production and lower levels of steady-state oxidative
      damage in their mitochondrial DNA than short-lived ones. Caloric-restricted
      rodents also show lower levels of these two key parameters than controls fed ad
      libitum. The decrease in mitochondrial ROS generation of the restricted animals
      has been recently localized at complex I and the mechanism involved is related to
      the degree of electronic reduction of the complex I ROS generator. Strikingly,
      the same site and mechanism have been found when comparing a long- with a short
      lived animal species. It is suggested that a low rate of mitochondrial ROS
      generation extends lifespan both in long-lived and in caloric-restricted animals
      by determining the rate of oxidative attack and accumulation of somatic mutations
      in mitochondrial DNA.

PMID- 15191225
TI  - The evolution of arthropod limbs.
AB  - Limb morphology across the arthropods is reviewed using external morphological
      and internal anatomical data from both recent and fossil arthropods. Evolutionary
      trends in limb structure are identified primarily by reference to the more
      rigorous of the many existing phylogenetic schemes, but no major new phylogenetic
      inferences are presented. Tagmosis patterns are not considered, although the
      origins and patterns of heteronomy within the postantennulary limb series are
      analysed. The phenomenon of annulation is examined and two basic types of annuli
      are recognised: terminal and intercalary. The annulation of the apical segment of
      a limb results in the formation of terminal flagella, and is typical of primarily
      sensory appendages such as insect and malacostracan antennules and maxillary
      palps of some hexapods. Intercalary annulation, arising by subdivision of
      existing subterminal segments, is common, particularly in the tarsal region of
      arthropodan walking limbs. Differentiating between segments and annuli is
      discussed and is recognised as a limiting factor in the interpretation of
      fossils, which usually lack information on intrinsic musculature, and in the
      construction of groundplans. Rare examples of secondary segmentation, where the
      criteria for distinguishing between segments and annuli fail, are also
      highlighted. The basic crown-group arthropodan limb is identified as tripartite,
      comprising protopodite, telopodite and exopodite, and the basic segmentation
      patterns of each of these parts are hypothesised. Possible criteria are discussed
      that can be used for establishing the boundary between protopodite and telopodite
      in limbs that are uniramous through loss of the exopodite. The subdivision of the
      protopodite, which is typical of the postantennulary limbs of mandibulates, is
      examined. The difficulties resulting from the partial or complete failure of
      expression of articulations within the mandibulate protopodite and subsequent
      incorporation of partial protopodal segments into the body wall, are also
      discussed. The development and homology between the various exites, including
      gills, on the postantennulary limbs of arthropods are considered in some detail,
      and the question of the possible homology between crustacean gills and insect
      wings is critically addressed. The hypothesis that there are only two basic limb
      types in arthropods, antennules and postantennulary limbs, is proposed and its
      apparent contradiction by the transformation of antennules into walking limbs by
      homeotic mutation is discussed with respect to the appropriate level of serial
      homology between these limbs.

PMID- 15191226
TI  - The evolution of learning.
AB  - Most processes or forms of learning have been treated almost as special
      creations, each as an independent process unrelated to others. This review offers
      an evolutionary cladogram linking nearly one hundred forms of learning and
      showing the paths through which they evolved. Many processes have multiple forms.
      There are at least five imprinting processes, eleven varieties of Pavlovian
      conditioning, ten of instrumental conditioning, and eight forms of mimicry and
      imitation. Song learning evolved independently in at least six groups of animals,
      and movement imitation in three (great apes, cetaceans and psittacine birds). The
      cladogram also involves at least eight new processes: abstract concept formation,
      percussive mimicry, cross-modal imitation, apo-conditioning, hybrid conditioning,
      proto-pantomime, prosodic mimicry, and image-mediated learning. At least eight of
      the processes evolved from more than one source. Multiple sources are of course
      consistent with modern evolutionary theory, as seen in some obligate symbionts,
      and gene-swapping organisms. Song learning is believed to have evolved from two
      processes: auditory imprinting and skill learning. Many single words evolved from
      three sources: vocal mimicry, discrimination learning, and abstract concept
      formation.

PMID- 15191227
TI  - Consumer-food systems: why type I functional responses are exclusive to filter
      feeders.
AB  - The functional response of a consumer is the relationship between its consumption
      rate and the abundance of its food. A functional response is said to be of type I
      if consumption rate increases linearly with food abundance up to a threshold
      level at which it remains constant. According to conventional wisdom, such type I
      responses are more frequent among filter feeders than among other consumers.
      However, the validity of this claim has never been tested. We review 814
      functional responses from 235 studies, thereby showing that type I responses are
      not only exceptionally frequent among filter feeders but that they have only been
      reported from these consumers. These findings can be understood by considering
      the conditions that a consumer must fulfil in order to show a type I response.
      First, the handling condition: the consumer must have a negligibly small handling
      time (i.e. the time needed for capturing and eating a food item), or it must be
      able to search for and to capture food while handling other food. Second, the
      satiation condition: unless its gut is completely filled and gut passage time is
      minimal, the consumer must search for food at a maximal rate with maximal effort.
      It thus has to spend much time on foraging (i.e. searching for food and handling
      it). Our functional response review suggests that only filter feeders sometimes
      meet both of these conditions. This suggestion is reasonable because filter
      feeders typically fulfil the handling condition and can meet the satiation
      condition without losing time, for they are, by contrast to non-filter feeders,
      able simultaneously to perform foraging and non-foraging activities, such as
      migration or reproduction.

PMID- 15191228
TI  - Monogamy in marine fishes.
AB  - The formation of long-term pair bonds in marine fish has elicited much empirical
      study. However, the evolutionary mechanisms involved remain contested and
      previous theoretical frameworks developed to explain monogamy in birds and
      mammals are not applicable to many cases of monogamy in marine fish. In this
      review, we summarise all reported occurrences of social monogamy in marine fish,
      which has so far been observed in 18 fish families. We test quantitatively the
      role of ecological and behavioural traits previously suggested to be important
      for the evolution of monogamy and show that monogamous species occur primarily in
      the tropics and are associated with coral reef environments in which territory
      defence and site attachment is facilitated. However, there is little evidence
      that obligately monogamous species are smaller in body size than species that can
      adopt a polygynous mating system. We review the evidence pertaining to six
      hypotheses suggested for the evolution of monogamous pair bonds: (1) biparental
      care, (2) habitat limitation, (3) low population density/low mate
      availability/low mobility, (4) increased reproductive efficiency, (5) territory
      defence, and (6) net benefit of single mate sequestration. We outline predictions
      and associated empirical tests that can distinguish between these hypotheses, and
      assess how generally each hypothesis explains monogamy within and between
      breeding periods for species with different types of territories (i.e. feeding
      only or feeding and breeding). Hypotheses (1) and (2) have limited applicability
      to marine fishes, while hypotheses (3)-(5) have little empirical support beyond
      the species for which they were designed. However, the role of paternal care in
      promoting monogamous pair bonds is not explicit in these hypotheses, yet paternal
      care has been reported in more than 70 monogamous marine fish. We show that
      paternal care may act to increase the likelihood of monogamy in combination with
      each of the proposed hypotheses through decreased benefits to males from
      searching for additional mates or increased advantages to females from
      sequestering a single high-quality mate. Among species defending breeding and
      feeding territories, the benefits, both within and between reproductive periods,
      of sequestering a single high-quality mate (hypothesis 6) appear to be the best
      explanation for socially monogamous pairs. For species without parental care
      (i.e. holding only feeding territories), territory defence (hypothesis 5) in
      combination with the benefits of guarding a large mate (hypothesis 6) could
      potentially explain most instances of monogamy. Empirical studies of marine
      fishes over the past two decades are therefore slowly changing the view of
      monogamy from a mating system imposed upon species by environmental constraints
      to one with direct benefits to both sexes.

PMID- 15191229
TI  - Developmental mechanism and evolutionary origin of vertebrate left/right
      asymmetries.
AB  - The systematically 'handed', or directionally asymmetrical way in which the major
      viscera are packed within the vertebrate body is known as situs. Other less
      obvious vertebrate lateralisations concern cognitive neural function, and include
      the human phenomena of hand-use preference and language-associated cognitive
      partitioning. An overview, rather than an exhaustive scholarly review, is given
      of recent advances in molecular understanding of the mechanism that ensures
      normal development of 'correct' situs. While the asymmetry itself and its
      left/right direction are clearly vertebrate-conserved characters, data available
      from various embryo types are compared in order to assess the likelihood that the
      developmental mechanism is evolutionarily conserved in its entirety. A conserved
      post-gastrular 'phylotypic' stage, with left- and right-specific cascades of key,
      orthologous gene expressions, clearly exists. It now seems probable that earlier
      steps, in which symmetry-breaking information is reliably transduced to trigger
      these cascades on the correct sides, are also conserved at depth although it
      remains unclear exactly how these steps operate. Earlier data indicated that the
      initiation of symmetry-breaking had been transformed, among the different
      vertebrate classes, as drastically as has the anatomy of pre-gastrular
      development itself, but it now seems more likely that this apparent diversity is
      deceptive. Ideas concerning the functional advantages to the vertebrate lifestyle
      of a systematically asymmetrical visceral packing arrangement, while untestable,
      are accepted because they form a plausible adaptationist 'just-so' story.
      Nevertheless, two contrasting beliefs are possible about the evolutionary origins
      of situs. Major recent advances in analysis of its developmental mechanism are
      largely due not to zoologists, comparative anatomists or evolutionary
      systematists, but to molecular geneticists, and these workers have generally
      assumed that the asymmetry is an evolutionary novelty imposed on a true bilateral
      symmetry, at or close to the origin of the vertebrate clade. A major purpose of
      this review is to advocate an alternative view, on the grounds of comparative
      anatomy and molecular systematics together with the comparative study of
      expressions of orthologous genes in different forms. This view is that situs
      represents a co-optation of a pre-existing, evolutionarily ancient non
      bilaterality of the adult form in a vertebrate ancestor. Viewed this way,
      vertebrate or chordate origins are best understood as the novel imposition of an
      adaptively bilateral locomotory-skeletal-neural system, around a retained non
      symmetrical 'visceral' animal. One component of neuro-anatomical asymmetry, the
      habenular/parapineal one that originates in the diencephalon, has recently been
      found (in teleosts) to be initiated from the same 'phylotypic' gene cascade that
      controls situs development. But the function of this particular diencephalic
      asymmetry is currently unclear. Other left-right partitionings of brain function,
      including the much more recently evolved, cerebral cortically located one
      associated with human language and hand-use, may be controlled entirely
      separately from situs even though their directionality has a particular relation
      to it in a majority of individuals. Finally, possible relationships are discussed
      between the vertebrate directional asymmetries and those that occur sporadically
      among protostome bilaterian forms. These may have very different evolutionary and
      molecular bases, such that there may have been constraints, in protostome
      evolution, upon any exploitation of left and right for complex organismic, and
      particularly cognitive neural function.

PMID- 15191230
TI  - Metabolic responses to low temperature in fish muscle.
AB  - For most fish, body temperature is very close to that of the habitat. The
      diversity of thermal habitats exploited by fish as well as their capacity to
      adapt to thermal change makes them excellent organisms in which to examine the
      evolutionary and phenotypic responses to temperature. An extensive literature
      links cold temperatures with enhanced oxidative capacities in fish tissues,
      particularly skeletal muscle. Closer examination of inter-species comparisons
      (i.e. the evolutionary perspective) indicates that the proportion of muscle
      fibres occupied by mitochondria increases at low temperatures, most clearly in
      moderately active demersal species. Isolated muscle mitochondria show no
      compensation of protein-specific rates of substrate oxidation during evolutionary
      adaptation to cold temperatures. During phenotypic cold acclimation,
      mitochondrial volume density increases in oxidative muscle of some species
      (striped bass Morone saxatilis, crucian carp Carassius carassius), but remains
      stable in others (rainbow trout Oncorhynchus mykiss). A role for the
      mitochondrial reticulum in distributing oxygen through the complex architecture
      of skeletal muscle fibres may explain mitochondrial proliferation. In rainbow
      trout, compensatory increases in the protein-specific rates of mitochondrial
      substrate oxidation maintain constant capacities except at winter extremes.
      Changes in mitochondrial properties (membrane phospholipids, enzymatic complement
      and cristae densities) can enhance the oxidative capacity of muscle in the
      absence of changes in mitochondrial volume density. Changes in the unsaturation
      of membrane phospholipids are a direct response to temperature and occur in
      isolated cells. This fundamental response maintains the dynamic phase behaviour
      of the membrane and adjusts the rates of membrane processes. However, these
      adjustments may have deleterious consequences. For fish living at low
      temperatures, the increased polyunsaturation of mitochondrial membranes should
      raise rates of mitochondrial respiration which would in turn enhance the
      formation of reactive oxygen species (ROS), increase proton leak and favour
      peroxidation of these membranes. Minimisation of mitochondrial oxidative
      capacities in organisms living at low temperatures would reduce such damage.

PMID- 15191231
TI  - Enigmas of mammalian gamete form and function.
AB  - The gametes of man and some other Eutheria have been manipulated successfully for
      practical reasons, but many gaps remain in our basic understanding of the way
      that they function. This situation stems not least from a failure to recognize
      the extent to which eutherian spermatozoa and eggs, and elements related to their
      operation, have come to differ from those of other groups. Novel features in the
      male that reflect this include a radical design of the sperm head with the
      acrosome seeming to function primarily in egg-coat binding rather than its lysis,
      a multifaceted post-testicular sperm maturation and an androgen/low-temperature
      regulated system of sperm storage--both tied to the epididymis, a variable male
      accessory sex gland complex, and descent of the testis and epididymis to a
      scrotum. In the female, such novelties are represented in a need for sperm
      capacitation, in an unusual regulation of sperm transport within the oviduct, in
      the cumulus oophorus and character of the zona pellucida around the small egg,
      and in a unique configuration of gamete fusion. The collective evidence now
      suggests that many of these features reflect a new fertilisation strategy or its
      consequences, with most being causally linked. One initial 'domino' in this
      regard appears to be the small yolkless state of the egg and its intolerance for
      polyspermy, as determinants of the unusual mode of oviductal sperm transport and
      possibly the existence and form of the cumulus oophorus. However, a particularly
      influential first 'domino' appears to be the physical character of the eutherian
      zona pellucida. This differs from the egg coats of other animal groups by virtue
      of a resilient elasticity and thickness. These qualities allow this primary and
      often only coat to stretch and so persist during later expansion of the
      blastocyst, usually until close to implantation. At the same time, the
      dimensions, physical character, and particularly the relative protease
      insensitivity of the zona appear to have had profound effects on sperm form and
      function and, more indirectly, on sperm-related events in the male and the female
      tract. Marsupials display some similarities and also some strikingly different
      features, against which the enigmas of the eutherian situation can be evaluated.

PMID- 15191232
TI  - Cellulose microfibril angle in the cell wall of wood fibres.
AB  - The term microfibril angle (MFA) in wood science refers to the angle between the
      direction of the helical windings of cellulose microfibrils in the secondary cell
      wall of fibres and tracheids and the long axis of cell. Technologically, it is
      usually applied to the orientation of cellulose microfibrils in the S2 layer that
      makes up the greatest proportion of the wall thickness, since it is this which
      most affects the physical properties of wood. This review describes the
      organisation of the cellulose component of the secondary wall of fibres and
      tracheids and the various methods that have been used for the measurement of MFA.
      It considers the variation of MFA within the tree and the biological reason for
      the large differences found between juvenile (or core) wood and mature (or outer)
      wood. The ability of the tree to vary MFA in response to environmental stress,
      particularly in reaction wood, is also described. Differences in MFA have a
      profound effect on the properties of wood, in particular its stiffness. The large
      MFA in juvenile wood confers low stiffness and gives the sapling the flexibility
      it needs to survive high winds without breaking. It also means, however, that
      timber containing a high proportion of juvenile wood is unsuitable for use as
      high-grade structural timber. This fact has taken on increasing importance in
      view of the trend in forestry towards short rotation cropping of fast grown
      species. These trees at harvest may contain 50% or more of timber with low
      stiffness and therefore, low economic value. Although they are presently grown
      mainly for pulp, pressure for increased timber production means that ways will be
      sought to improve the quality of their timber by reducing juvenile wood MFA. The
      mechanism by which the orientation of microfibril deposition is controlled is
      still a matter of debate. However, the application of molecular techniques is
      likely to enable modification of this process. The extent to which these
      techniques should be used to improve timber quality by reducing MFA in juvenile
      wood is, however, uncertain, since care must be taken to avoid compromising the
      safety of the tree.

PMID- 15191233
TI  - The new EMTALA regulations--introduction.
AB  - This Introduction provides a broad overview of the new Emergency Medical
      Treatment and Labor Act (EMTALA) regulations and the changes they effected. The
      three Articles that follow discuss various aspects of the regulations in much
      greater detail. Health Lawyers Teleconference: EMTALA Update provides a
      commentary on the regulations from the perspective of representatives of the
      Centers for Medicare & Medicaid Services and the Department of Health and Human
      Services, followed by a critique of the regulations from a practitioner's
      standpoint. EMTALA: Dedicating an Emergency Department Near You analyzes the
      provisions of the regulations in detail and discusses their implications for
      hospitals and their counsel. Finally, The New EMTALA Regulations and the On-Call
      Physician Shortage: In Defense of the Regulations analyzes the on-call provisions
      of the regulations in light of the current shortage of on-call physicians.

PMID- 15191234
TI  - Health lawyers teleconference: EMTALA update.
AB  - On September 16, 2003, the American Health Lawyers Association's (Health Lawyers)
      Regulation, Accreditation, and Payment Practice Group and its Liability Practice
      Group sponsored a teleconference entitled EMTALA: Finally Final Regulations.
      During that Teleconference, Messrs. Barker and Urbanowicz, from the perspective
      of their positions at Centers for Medicare & Medicaid Services and the Department
      of Health and Human Services, gave an informal overview of the Emergency Medical
      Treatment and Labor Act (EMTALA) final regulations that were unveiled a week
      earlier. Ms. Joy critiqued the regulations from the practitioner's standpoint,
      followed by questions from the teleconference off-site participants. This Article
      is a transcript of that teleconference, modified by the addition of endnotes and
      slight editing for publication.

PMID- 15191235
TI  - EMTALA: dedicating an emergency department near you.
AB  - Congress enacted the Emergency Medical Treatment and Labor Act (EMTALA) in 1986
      to prohibit patient dumping. Subsequent to its passage, however, issues
      concerning the application of EMTALA have vexed hospitals, patients, regulators,
      and courts. In an attempt to clarify these issues, the Centers for Medicare &
      Medicaid Services (CMS) recently promulgated new EMTALA regulations. This Article
      reviews the basic requirements of EMTALA and highlights the statutory definitions
      critical to its proper interpretation and application. The article then analyzes
      the impact of the new regulations, particularly in five major areas: where and
      when the statute applies, on-call physician requirements, hospital-owned
      ambulances, managed care, and bioterrorism. It concludes with a discussion of the
      implications of the new regulations for hospitals and their counsel.

PMID- 15191236
TI  - The new EMTALA regulations and the on-call physician shortage: in defense of the
      regulations.
AB  - This Article examines the new Emergency Medical Treatment and Labor Act (EMTALA)
      regulations, focusing on the on-call provisions, in light of the practical
      realities of the on-call physician shortage. It provides an historical account of
      issues surrounding the delivery of emergency care by on-call physicians and the
      legal background of EMTALA insofar as it relates to on-call physicians.
      Ultimately, the author concludes that, although the current shortage of on-call
      physicians has caused hospitals to anticipate EMTALA liability and advocate for
      more specific regulations, a closer look reveals that hospitals' fears are
      overstated. As long as hospitals have proper procedures in place, the new
      regulations will not put them in violation of EMTALA.

PMID- 15191237
TI  - The case against differential diagnosis: Daubert, medical causation testimony,
      and the scientific method.
AB  - For the past decade, federal judges have been obligated to serve as gatekeepers
      and keep scientifically unreliable and irrelevant expert testimony out of the
      courtroom. The exacting evidentiary standards set forth in the landmark Daubert
      decision have had a significant impact on numerous areas of legal dispute. Toxic
      tort litigation, in particular, has been transformed by the standards. This
      Article reviews the Supreme Court's adoption of the scientific method as the
      standard for admissibility of expert testimony. It analyzes how a court's proper
      understanding of the scientific method can guide it in evaluating the different
      types of causation evidence presented in toxic tort litigation, both with respect
      to general and specific causation. Throughout this discussion and in the
      concluding section, the Article reflects the authors' firm's experience as
      national defense counsel in a series of product liability cases involving the
      prescription drug Parlodel, in which these evidentiary issues have been analyzed
      extensively.

PMID- 15191238
TI  - Multijurisdictional practice and the health lawyer: will your practice benefit
      from the new ABA model rules of professional conduct?
AB  - At the end of the twentieth century, bar scholars and regulators were reexamining
      two traditionally improper aspects of legal practice. The first was the
      multidisciplinary practice of law, which would permit lawyers to offer accounting
      and other professional services to their clients, and allow lawyers to share fees
      with non-lawyers. The second was the multijurisdictional practice of law, which
      would permit a lawyer licensed in one jurisdiction to practice law in other
      jurisdiction in which he was not admitted to the bar. Enron and other corporate
      scandals deflated the movement towards multidisciplinary practice, but the
      movement to allow multijurisdictional practice bore some limited, yet important,
      results. This Article argues that the American Bar Association's new Model Rules
      5.5 and 8.5, which broaden the ability of healthcare lawyers to practice outside
      of the states in which they are admitted, are a suitable accommodation to today's
      mode of practice, while still preserving the states' ability to regulate lawyers
      and protect clients.

PMID- 15191239
TI  - Physician/hospital joint ventures in the wake of St. David's: reference material.

PMID- 15191240
TI  - Pharmacist work attitudes reflect a readiness for practice change.

PMID- 15191241
TI  - Patients large and small: role of the pharmacist in veterinary medicine.

PMID- 15191242
TI  - Tablet splitting: evaluating appropriateness for patients.

PMID- 15191243
TI  - Pharmacists' attitudes toward worklife: results from a national survey of
      pharmacists.
AB  - OBJECTIVES: To provide a current profile of pharmacists' attitudes toward
      worklife and determine how demographic, family, and practice variables influence
      work attitudes. DESIGN: Cross-sectional descriptive survey. SETTING: Nationwide
      sample of licensed pharmacists in the United States. PARTICIPANTS: 1,737 actively
      practicing pharmacists. INTERVENTIONS: Mailed survey. MAIN OUTCOME MEASURES:
      Previously validated rating scales were used to measure job satisfaction, job
      stress, work-home conflict, role overload, role ambiguity, and role conflict.
      Family variables included the number and age(s) of children and marital status;
      demographic variables included age, gender, race, years of experience, region,
      and degree; practice variables included setting, position, work status, and work
      activities. RESULTS: Although 67.2% of pharmacists were satisfied with their job,
      more than 68% experienced job stress and role overload, and 48% experienced work
      home conflict. The levels of role ambiguity, role conflict, and job stress were
      significantly higher in chain, mass merchandiser, and hospital settings relative
      to independent settings. Wanting to spend more time in consultation was most
      positively associated with role ambiguity, role overload, and role conflict and
      most negatively associated with job satisfaction. Gender, race, years of
      experience, marital status, and children also affected work attitudes.
      CONCLUSION: Those interested in the quality of worklife of pharmacists need to
      develop and implement realistic methods to decrease the role stress that
      pharmacists continue to face. Unless role stress of pharmacists is lessened, the
      profession may be endangering not only the physical and mental health of its
      current and future practitioners, but possibly compromising patient safety as
      well.

PMID- 15191244
TI  - Evaluation of the Iowa Medicaid pharmaceutical case management program.
AB  - OBJECTIVE: To test the effect of pharmaceutical case management (PCM) on
      medication safety and health care utilization. DESIGN: Prospective cohort design
      with 9-month follow-up period (enrollment from October 1, 2000, through July 1,
      2001, with follow-up through July 1, 2002). SETTING: Iowa Medicaid program.
      PARTICIPANTS: 2,211 noninstitutionalized, continuously eligible Iowa Medicaid
      patients taking four or more chronic medications including at least one agent
      commonly used in at least 1 of 12 specific diseases who were cared for by
      pharmacists in 117 pharmacies. INTERVENTIONS: Reimbursement for PCM services
      (initial patient assessment, written recommendations to physician, follow-up
      assessments and communication of progress and new problems to physician). MAIN
      OUTCOME MEASURES: Use of high-risk medications, Medication Appropriateness Index
      (MAI) score, health care utilization. RESULTS: Pharmacists in 114 pharmacies had
      eligible patients during at least one quarter during the study period; 28
      pharmacies were classified as high intensity based on the number of PCM patients
      they managed. A total of 524 of the eligible patients received 1,599 PCM
      services; 90% of claims were filed by pharmacists, and the remainder by
      physicians. Nearly one half (46.1%) of medications and 92.1% of patients had at
      least one medication problem before PCM. By closeout, the percentage of
      medications with problems decreased in 8 of 10 MAI domains for those who received
      PCM. Compared with baseline, mean MAI score improved significantly from 9.4 to
      8.3 among PCM recipients (P < .001). Percentage of PCM recipients using high-risk
      medications decreased significantly compared with PCM eligibles who did not
      receive the service. In the 28 pharmacies that adopted the new service most
      intensely, patients had a significant decrease in high-risk medication use,
      compared with patients of low-intensity pharmacies (P < .001). No difference was
      observed between PCM recipients and PCM eligibles who did not receive PCM in
      health care utilization or charges, even after including reimbursements for PCM.
      CONCLUSION: Medication safety problems were prevalent in this high-risk
      population. The PCM program improved medication safety during a 9-month follow-up
      period.

PMID- 15191246
TI  - Collaborative working relationships between pharmacists and physicians: an
      exploratory study.
AB  - OBJECTIVES: To determine the degree of collaboration in a limited number of
      pharmacist-physician professional relationships and identify variables important
      in establishing collaboration between pharmacists and physicians. DESIGN: A
      multicase design, using a personal interview and a mailed survey. SETTING: Iowa.
      PARTICIPANTS: Pharmacists in 10 community pharmacies and physicians with whom
      they collaborated. INTERVENTION: Two researchers independently judged the stage
      of collaboration for each case and the level of effect each influence variable
      had on the development of pharmacist-physician collaboration. MAIN OUTCOME
      MEASURES: Using the Collaborative Working Relationship Model, nine indicators of
      collaboration were assessed. In addition, influence variables were studied, which
      included individual, context, and exchange characteristics believed to affect the
      development of collaborative working relationships between pharmacists and
      physicians. RESULTS: A Perrealt-Leigh reliability index of 0.89 was calculated as
      an estimate of interrater reliability of the judgments of nine indicators of
      collaboration. Four pharmacies were rated as having achieved early-stage
      collaboration, while six pharmacies were at late-stage collaboration. A high
      level of joint care activities, care communication, and increased accessibility
      to the physician and to patient information characterized late-stage
      collaboration. Six variables, labeled as discriminating, helped distinguish
      between early-stage collaboration and late-stage collaboration: the development
      of bidirectional communication, caring for mutual patients, the ability to
      identify a win-win opportunity, adding value to the medical practice, physician
      convenience, and movement toward balanced dependence between the pharmacist and
      physician. CONCLUSION: The development of collaboration between pharmacists and
      physicians is influenced by characteristics of exchanges occurring between them.
      Continued study of collaborative working relationships between physicians and
      pharmacists can assist health care practitioners in developing a team-based
      approach to patient care, improving the ability of pharmacists and physicians to
      work together to coordinate patient care.

PMID- 15191245
TI  - Pharmacist care plans and documentation of follow-up before the Iowa
      Pharmaceutical Case Management program.
AB  - OBJECTIVES: To document drug therapy problems and their causes and assess
      pharmacist follow-up of patients with identified drug therapy problems. DESIGN:
      Cross-sectional analysis. SETTING: Iowa. PARTICIPANTS: 160 pharmacists who
      submitted 754 pharmaceutical care plans in an effort to qualify for participation
      in the Iowa Pharmaceutical Case Management program. INTERVENTIONS AND MAIN
      OUTCOME MEASURES: Care plans were assessed for drug therapy problems and causes
      and for documentation of pharmacist follow-up (actual, none, or intent to follow
      up). RESULTS: Pharmacists documented a wide variety of drug therapy problems and
      causes, including adverse drug reactions (20.1% of care plans), need for
      additional drug therapy (18.9%), lack of patient adherence to therapy (16.3%),
      incorrect medication being prescribed (14.1%), and drug dose too high (10.0%).
      Pharmacist follow-up with patients was not optimal, with 31% of care plans
      providing documentation of actual follow-up. Another 42.2% of plans indicated
      that the pharmacist intended to contact the patient for follow-up but either did
      not do so or did not record the intervention. No actual follow-up or intent to
      follow up was recorded in 26.8% of care plans. Pharmacists practicing in
      independent pharmacies followed up with patients more frequently than those in
      other settings (36.4% of care plans, compared with 22.7%, 23.2%, and 28.4% for
      chain, clinic, and franchise pharmacies). Pharmacists were more likely to follow
      up when the identified problem involved drug safety rather than effectiveness
      (36.2% versus 28.3% of care plans). CONCLUSION: Documentation of pharmacist
      follow-up with patients was less than optimal. In addition to identifying drug
      therapy problems and causes, pharmacists must complete the care continuum through
      documentation of patient monitoring and follow-up to transform the philosophy and
      vision of the pharmaceutical care concept into a practice of pharmacy recognized
      and rewarded by patients and payers.

PMID- 15191247
TI  - Counseling Spanish-speaking patients: Atlanta pharmacists' cultural sensitivity,
      use of language-assistance services, and attitudes.
AB  - OBJECTIVE: To document the types of language-assistance services available in
      pharmacies and the perceptions of pharmacists regarding the effectiveness of
      these services, and to measure the attitudes toward counseling Spanish-speaking
      patients and cultural sensitivity of pharmacists. DESIGN: Cross-sectional
      assessment. SETTING: Metropolitan Atlanta, Ga. PARTICIPANTS: Registered Georgia
      pharmacists residing in metropolitan Atlanta. INTERVENTIONS: Mailed survey, with
      repeat mailing 2 weeks later. MAIN OUTCOME MEASURES: 38 survey items measuring
      demographic and practice-site characteristics, types of language-assistance
      services available with an assessment of the effectiveness of each measured on a
      nominal scale, and attitudinal items concerning counseling of Spanish-speaking
      patients and pharmacists' cultural sensitivity using a 5-point Likert-type
      response scale. RESULTS: Of 1,975 questionnaires mailed, 608 were returned, a
      30.8% response rate. Nearly two thirds of the pharmacists had recently counseled
      a Spanish-speaking patient, but only one fourth of those respondents considered
      their interactions effective. Nearly all pharmacists, 88.0%, worked in pharmacies
      with language-assistance services. Of seven types of these services, a mean of
      2.19 were available in pharmacies, and the majority of pharmacists (84.4% or
      more) identifying a service considered it to be effective. The pharmacists were
      neutral about counseling Spanish-speaking patients (mean = 2.94) and indifferent
      toward other cultures (mean = 3.28); however, they agreed they had a
      responsibility to counsel Spanish-speaking patients, and they believed that use
      of language-assistance services would constitute a reasonable effort to counsel
      these patients. CONCLUSION: Pharmacists have an opportunity to address barriers
      to communication with the Spanish-speaking population through use of language
      assistance services and educational measures within the profession.

PMID- 15191248
TI  - Compounding for animal patients: contemporary issues.
AB  - OBJECTIVES: To provide background information relating to the growth observed in
      veterinary compounding, discuss positive contributions made to animal health via
      compounding, present compounding practices that are in the best interest of
      patient care, present documents available to pharmacists to use for guidance when
      practicing veterinary pharmacy, and emphasize the need for education among
      stakeholders on the subject of veterinary compounding. DATA SOURCES: The Animal
      Medicinal Drug Use Clarification Act of 1994, compliance policy guide section
      608.400, the American Veterinary Medical Association Position Statement on
      Compounding and Extralabel Drug Use Algorithm; supporting data from veterinary
      and pharmacy literature documenting the practice of veterinary compounding are
      referenced (SilverPlatter Medline 1966-2002 and International Pharmaceutical
      Abstracts; 1970 through December 2002; no restrictions; search terms, veterinary
      AND compounding). STUDY SELECTION: By the author. DATA EXTRACTION: By the author.
      DATA SYNTHESIS: Requests for compounding of products for veterinary uses are
      common in community pharmacy, and these preparations fill many clinical, dosing,
      and drug-administration needs in the care of companion animals. However, like
      other elements of pharmacy compounding, preparation of veterinary products falls
      into a legally gray area that is the subject of current scrutiny by the U.S. Food
      and Drug Administration (FDA). Pharmacists involved in this practice should keep
      the best interests of the animal in mind; recognize limitations about safety,
      effectiveness, and stability of compounded formulations; and avoid preparing
      products similar in ingredients and purpose as commercially available, FDA
      approved products. Situations in which compounding becomes manufacturing invites
      enforcement action by FDA. The dispensing of compounded products should be based
      on a valid veterinarian-client-patient relationship and comply with federal acts,
      FDA's compounding compliance policy guide, and other such resources. CONCLUSION:
      All pharmacists and pharmacies engaged in any type of veterinary pharmacy
      practice must be aware of the contemporary issues facing their profession. Best
      patient care practices, education, and open communication among stakeholders will
      play a critical role in the practice and future regulation of veterinary
      compounding.

PMID- 15191249
TI  - Using buzz marketing to promote ideas, services, and products.
AB  - OBJECTIVE: To (1) discuss buzz marketing, contrast it with traditional forms of
      promotional communications, and provide guidelines for use and (2) describe a
      successful buzz-marketing program used by Sentara Healthcare to decrease overuse
      and inappropriate use of antibiotic medications. DATA SOURCES: An English
      language-only literature search of ABI Inform, Lexus-Nexus, InfoTrac, and
      university library databases from 1980 to the present using the keywords buzz,
      word of mouth, opinion leader, and thought leader. Articles and books were cross
      referenced for other works of interest. STUDY SELECTION: Performed by the author
      for their contribution to an exploratory analysis of this topic. DATA EXTRACTION:
      Performed by the author. DATA SYNTHESIS: Buzz marketing is an indirect
      communications method that has been used successfully in the promotion of a wide
      variety of products, services, and ideas. By identifying and cultivating nonmedia
      opinion leaders, the technique generates word-of-mouth communications between
      these early adopters of products and services and the early and late majority of
      people who tend to follow their lead. Opinion leaders can be categorized as
      ordinary or extraordinary, technical or social, and specialist or generalist,
      depending on the nature of their communications, expertise, and range of
      knowledge. Buzz marketing is most useful for ideas that are memorable, produce
      small changes in behavior that have big effects over time, and have the potential
      to reach a "tipping point" in terms of momentum among a target population.
      Pharmacists can use buzz marketing for promoting innovative services such as
      pharmaceutical care. A case study is presented on the use of buzz marketing by a
      health system for decreasing antibiotic resistance through lessening of public
      demand for antibiotics and support of physicians in prescribing the agents
      appropriately. CONCLUSION: Buzz marketing is a potent force in the promotion of
      pharmaceuticals and can be used by pharmacists. It works best when patients
      perceive the benefits of innovations. Providing samples and demonstrations of the
      innovation will foster positive perceptions. Innovations also spread better when
      they are compatible with the needs, desires, and preferences of individuals and
      can be adapted to the unique situation of the adopter.

PMID- 15191250
TI  - Disposition of pharmaceutical samples from a private medical clinic.

PMID- 15191251
TI  - Genetic testing: the community pharmacist's perspective.

PMID- 15191252
TI  - Donald Crum Brodie (1908-1994): pharmacy theoretician.

PMID- 15191253
TI  - Albert Benjamin Prescott (1832-1905): pharmacy education's revolutionary spark.

PMID- 15191254
TI  - Influenza vaccine: basis for expanded pharmacy-based immunization services.

PMID- 15191255
TI  - Future challenges to practitioners: pharmacy law and continuing professional
      development.

PMID- 15191256
TI  - Education and support groups for patients with chronic stable angina and their
      families.

PMID- 15191258
TI  - Patient-centered needs assessment: rationale for a psychometric measure for
      assessing needs in heart failure.
AB  - Determining an individual's unique perspective of an illness experience remains a
      challenge for clinicians, administrators, and researchers. A range of concepts
      and psychometric measures have been developed and evaluated to capture this
      information. These include patient satisfaction, quality of life, and utility
      measures. Needs assessment as a tool for evaluating perceptions of health status
      and determining patient satisfaction and treatment plans has been explored in
      oncology. Studies have demonstrated that a high proportion of patients have unmet
      needs in relation to activities of daily living, information sources, and
      comfort. Heart failure (HF), a condition with significant individual and societal
      burden, mirrors the illness of experience of cancer, as individuals process
      issues related to prognosis, treatment regimens, and decreased functional status.
      A needs-based assessment of health status, expectations, and perceptions is
      patient-centered and has the capacity to not only evaluate current health status
      but also plan and project care plans. Needs assessment is a dynamic construct
      rather than a point in time consistent with other assessment modalities, such as
      quality of life. Multidimensional needs assessment allows for planning and
      projection of needs, not only on an individual but also a population basis.
      Implicit in the exploration of needs is an expectation of level of care to be
      provided, from both the provider and recipient of care. In many instances a
      misalignment may exist between services and resources available to the
      individual. This article seeks to provide a theoretical justification for the
      development of a needs assessment instrument for patients with HF and to discuss
      the rationale of this method of assessment to create better alignment and
      resources with patients needs and expectations.

PMID- 15191257
TI  - American Indian women and cardiovascular disease: response behaviors to chest
      pain.
AB  - Cardiovascular disease (CVD) is currently the number one killer of American
      women. Consequently, CVD is a concern for all women, including ethnic women.
      However, little is known about CVD behaviors and responses to CVD symptomology
      among minority women, especially American Indian women. Response behaviors to
      chest pain require important actions. This article examines response behaviors to
      chest pain in a group of American Indian women participants of the Inter-Tribal
      Heart Project. In 1992 to 1994, 866 American Indian women, aged 22 years and
      older, participated in face-to-face interviews to answer survey questions on
      multiple areas related to cardiovascular disease on 3 rural reservations in
      Minnesota and Wisconsin. A secondary data analysis was conducted on selected
      variables including demographic characteristics, healthcare access, rating of
      health status, personal and family history of cardiovascular disease, and action
      in response to crushing chest pain that lasted longer than 15 minutes. Research
      findings report that 68% of women would actively seek healthcare immediately if
      experiencing crushing chest pain that lasted longer than 15 minutes. However, 264
      women (32%) would take a passive action to crushing chest pain, with 23%
      reporting they would sit down and wait until it passed. Analysis revealed women
      reporting a passive response were younger in age (under age 45) and had less
      education (less than a high school education). These findings have implications
      for nurses and other healthcare providers working in rural, geographically
      isolated Indian reservations. How to present CVD education in a culturally
      appropriate manner remains a challenge.

PMID- 15191259
TI  - Commentary: Creative support strategies to improve recovery from cardiac events:
      peer support, lay health advisors, and eHealth.

PMID- 15191260
TI  - Is individual peer support a promising intervention for persons with heart
      failure?
AB  - Peer support has been used effectively in a variety of patient populations, but
      its effectiveness in improving outcomes in persons with chronic heart failure has
      not been explored. We trained 9 persons with heart failure to mentor other heart
      failure patients and tested the effectiveness of this approach in a randomized
      controlled clinical trial. A low proportion (37%) of the eligible population of
      hospitalized patients agreed to participate. At the end of the 3-month trial,
      there was significantly higher heart failure self-care in the intervention group
      (P < .05). The only difference in social support was a significant decline in
      perceived support reciprocity in the intervention group (F = 5.94, P = .004). No
      significant group differences in heart failure readmissions, length of stay, or
      cost were evident at 90-days, although the heart failure readmission rate was 96%
      higher in the intervention group when compared to that in the control group. The
      reasons for low overall enrollment and high readmission rates in the intervention
      group require further study. Including additional self-care education by a
      professional, rather than leaving all the education to the mentor, could
      strengthen the peer support intervention trialed in this study. Small group
      meetings may be less intrusive and more desirable for this patient population.

PMID- 15191261
TI  - Partnerships in mending hearts: nurse and peer intervention for recovering
      cardiac elders.
AB  - As a growing number of older adults recover from cardiac events, volunteer
      programs have emerged to provide low-cost community support to vulnerable elders.
      Although an increasing number of studies have described the beneficial
      relationships between patients and volunteers, little is known about the unique
      partnership between the advanced practice nurse (APN) and the volunteer peer. The
      purpose of this article was to explore the interaction between the APN and the
      peer advisor who provide support for unpartnered elders after myocardial
      infarction or coronary artery bypass grafting. As part of a larger research
      study, "Improving Health Outcomes for Unpartnered Cardiac Elders" (R01-NR05205),
      interactions with peers were recorded by APNs. Essential themes related to
      working with 20 peer advisors emerged from 30 logs. Findings suggest that
      establishing the peer support role, acknowledging abilities, and overcoming
      difficulties are important steps in the relationship. A partnership between
      healthcare professionals and peer advisors enhances social support for vulnerable
      elders recovering from myocardial infarction and coronary artery bypass grafting.

PMID- 15191262
TI  - The impact of lay health advisors on cardiovascular health promotion: using a
      community-based participatory approach.
AB  - Overweight and obesity, lack of exercise, and exposure to tobacco smoke are
      clearly identified behavioral risk factors for cardiovascular disease. These
      problems disproportionately affect some communities. To address these problems
      within one community of underserved Latinos, participatory research methods were
      used to design an outreach program through a collaborative partnership between
      UCLA School of Nursing, Los Angeles County Department of Health Services, and
      members of the target community. Latina lay health advisors (LHAs) (n = 12) from
      the community were recruited and trained to teach 3 classes on healthy nutrition,
      physical activity, and maintaining smoke-free environments. Classes were offered
      in Spanish to adult Latinos recruited through the LHAs' social networks. A
      questionnaire on lifestyle behaviors was completed at baseline and 1 month
      following the last class. Exploratory open-ended questions on successes and
      challenges of applying new knowledge were also asked at follow-up. Results of
      paired t-tests on 256 participants showed significant increases in scores from
      baseline to follow-up in overall lifestyle behaviors and all 3 behavioral subsets
      (nutrition, physical activity, smoke-free behavior). Qualitative findings are
      also presented. Findings support utilizing LHAs as a feasible and effective
      healthcare delivery strategy for cardiovascular community health promotion,
      especially among immigrant populations.

PMID- 15191263
TI  - Supporting cardiac recovery through eHealth technology.
AB  - The Internet continues to evolve as a popular and increasingly vital channel for
      health information and communication among patients, families, and health
      providers. This article provides an overview of published studies that have
      described or tested Internet-based resources and interventions designed to
      support recovery and enhance health outcomes for the cardiac population. Three
      categories of applications are discussed: (1) peer support communities; (2)
      information support through automated, tailored patient education; and (3)
      professionally facilitated education and support programs. The article also
      address key issues such as barriers to innovation adoption, patient literacy, and
      the digital divide that must be overcome for successful integration of such
      interventions into clinical practice. How Internet-based interventions will fit
      with existing conventional programs and clinical practice structures is not yet
      clear. However, evidence that supports use of this new communication channel is
      likely to emerge as more programs are developed and rigorously evaluated.

PMID- 15191264
TI  - eHealth technology and Internet resources: barriers for vulnerable populations.
AB  - Disparities in accessing health information exist for various vulnerable
      populations. Reviewing access issues for those seeking and/or needing health
      information suggests that there are many factors that may inhibit access. These
      include a wide diversity in the education, background, and needs of those seeking
      information, and the distribution of information among many disciplines and
      information sources. The most needy among this group may require extensive,
      multispecialty healthcare and may have particular problems with access, treatment
      adherence, and working within the healthcare system.

PMID- 15191265
TI  - Obesity: focus on prevention and policy.

PMID- 15191266
TI  - A call for research on planned vs. unplanned suicidal behavior.
AB  - Unplanned acts of suicidal behavior involve little preparation or forethought
      whereas planned acts may be carefully conceived and implemented. Planned acts are
      associated with greater depression, hopelessness, and lethality, but there are
      meager data on other factors associated with planning. The prevention of planned
      and unplanned acts may require different strategies, but in either case improved
      knowledge is required to tailor prevention efforts. Improved knowledge can be
      facilitated by the acceleration of validation studies on assessments of planning,
      taking steps to avoid the conflation of assessments of planning with measurements
      of psychopathology such as impulsivity, and the use of controlled research
      designs.

PMID- 15191267
TI  - Describing suicidality: an investigation of qualitative SSF responses.
AB  - Given the incidence and seriousness of suicidality in clinical practice, the need
      for new and better ways to assess suicide risk is clear. While there are many
      published assessment instruments in the literature, survey data suggest that
      these measure are not widely used. One possible explanation is that current
      quantitatively developed assessment instruments may fail to capture something
      essential about the suicidal patient's experience. The current exploratory study
      examined a range of open ended qualitative written responses made by suicidal
      outpatients to five assessment prompts from the Suicide Status Form (SSF)-
      psychological pain, press, perturbation, hopelessness, and self-hate. Two
      different samples of suicidal outpatients seeking treatment, including suicidal
      college students (n = 119) and active duty U.S. Air Force personnel (n = 33),
      provided a wide range of written responses to the five SSF prompts. A qualitative
      coding manual was developed through a step-by-step methodology; two naive coders
      were trained to use the coding system and were able to sort all the patients'
      written responses into the content categories with very high interrater
      reliability (Kappa > .80). Certain written qualitative responses of the patients
      were more frequent than others, both within and across the five SSF constructs.
      Among a range of specific exploratory findings, one general finding was that two
      thirds of the 636 obtained written responses could be reliably categorized under
      four major content headings: relational (22%), role responsibilities (20%), self
      (15%), and unpleasant internal states (10%). Theoretical, research, and clinical
      implications of the methodology and data are discussed.

PMID- 15191268
TI  - Childhood diagnoses and later risk for multiple suicide attempts.
AB  - The relationship between childhood diagnosis, personality psychopathology and
      suicidal behavior in young adulthood was explored in a sample of 327 suicide
      ideators, single attempters, and multiple attempters. Of the total sample, 174
      received at least one childhood diagnosis; the 153 without a diagnosis provided a
      comparison group. Results suggest that a childhood history of an anxiety disorder
      or major depression predispose a person to both later multiple suicide attempts
      and personality psychopathology. Gender was found to play a significant role,
      with females being predisposed to multiple attempts in young adulthood but only
      as a function of childhood anxiety, not major depression. Additionally, childhood
      anxiety disorders were found to predispose to multiple attempts as a function of
      personality psychopathology, with distinctly different paths for males and
      females. Implications are discussed in terms of etiology, prevention, and
      treatment.

PMID- 15191270
TI  - Inequalities in daily variations of deaths from suicide in Lithuania:
      identification of possible risk factors.
AB  - The aim of this study was to analyze daily variations in mortality from suicides
      of Lithuanian urban and rural populations in two different periods of economic
      and political development of the country (1988-1990 and 1998-2000). The highest
      proportion of suicides occurred on Mondays and during the first days after the
      major public holidays, especially in men. Suicide mortality in rural areas was
      significantly higher in comparison to urban; nevertheless, daily variation was
      more marked in urban areas. Developing market economy and rising unemployment did
      not increase daily variation in suicides.

PMID- 15191269
TI  - Perfectionism, cognitive bias, and hopelessness as prospective predictors of
      suicidal ideation.
AB  - Perfectionism, negative cognitive bias, and hopelessness were assessed among
      people hospitalized for depression (N = 121). Hopelessness and suicidal ideation
      were assessed 6 months after discharge. Path analyses indicated that higher
      perfectionism as an inpatient was directly associated with higher suicidal
      ideation 6 months later. Cognitive bias, in contrast, led to greater hopelessness
      6 months later, which in turn led to higher concurrent suicidal ideation.
      Alternative models examined whether hopelessness partially or fully mediated the
      effect of perfectionism, whether hopelessness partially mediated the effect of
      cognitive bias, and whether inpatient depression and suicidal ideation severity
      explained the observed relationships. These alternative models were not
      supported. Perfectionism and negative cognitive bias both uniquely contributed to
      the prospective prediction of suicidal ideation.

PMID- 15191271
TI  - Modernization and the male-female suicide ratio in India 1967-1997: divergence or
      convergence?
AB  - The traditional view that modernization is likely to increase male vulnerability
      to suicide while protecting females from such self-destruction was offered by
      Durkheim (1951). This implies a theory of divergence of suicide rates such that
      the male-female suicide ratio should increase with modernization. Contemporary
      researchers have questioned whether modernization has had such an impact. We
      conducted a time series analysis of male and female suicide data to determine the
      impact on the suicide ratio for India for the years 1967 to 1997. We developed a
      modernization index comprised of urbanization, female literacy, and female work
      participation rates. Moreover, to improve methodological efficacy, we controlled
      for the passage of time. However, we found that there is no significant
      relationship between modernization and the male-female suicide ratio. Our
      conclusion is that using national male-female suicide ratios to determine
      modernization effects may mask significant regional gender and age differences,
      particularly in developing countries such as India.

PMID- 15191272
TI  - Suicidal behavior in urban American Indian adolescents: a comparison with
      reservation youth in a southwestern state.
AB  - The majority of American Indians live off of reservations, yet research on
      suicidal behavior in this population overwhelmingly focuses on reservation
      Indians. This exploratory study interviewed a stratified random sample of 144
      urban and 170 reservation American Indian adolescents to compare rates and
      correlates of suicidal behavior. One fifth of urban youth and one third of
      reservation youth reported lifetime suicidal ideation, although similar numbers
      (14%-18%) reported an attempt. Urban youth had fewer psychosocial problems, and
      in separate multivariate analyses, the groups shared no common correlate of
      attempted suicide. Different approaches to prevention and treatment may be
      warranted for urban Indian youth.

PMID- 15191274
TI  - Self-harmful behaviors in a population-based sample of young adults.
AB  - A birth cohort of 472 women and 494 men aged 26 years was interviewed about a
      range of self-harmful behaviors first and then asked about suicidal intent.
      Lifetime prevalence of self-harm using traditional methods of suicide (ICD
      [International Classification of Diseases] self-harm) was 13%, with 9% of the
      sample describing at least one such episode as "attempted suicide." Other self
      harmful behaviors were common; 14% of women and 33% of men reported self-battery.
      ICD self-harm over the past year was reported by 3%, mostly without suicidal
      intent. ICD self-harm and even lesser behaviors were associated with high odds of
      reporting suicidal ideation. The findings suggest that studies of self-harm
      should include behaviors not necessarily associated with suicidal intent.

PMID- 15191273
TI  - Dimensions of impulsivity and aggression associated with suicide attempts among
      bipolar patients: a preliminary study.
AB  - Impulsivity and hostility are often thought to be interrelated among depressed
      patients with suicidal behavior, but few studies have examined this relationship
      empirically. In this study, we assessed trait impulsivity and hostility among 52
      DSM-IV bipolar subjects with and without histories of suicide attempts.
      Impulsivity and hostility were correlated among attempters (r = .41, p = .03) but
      not non-attempters (r = .22, p = .28). As compared to non-attempters, attempters
      had significantly higher levels of overall hostility, more extensive
      subcomponents of hostility, and a trend toward higher overall impulsivity.
      Associations between lifetime suicide attempts and overall hostility were
      significant while controlling for current depression severity and lifetime
      illness duration. Aggression and impulsivity appear linked among bipolar patients
      with lifetime suicide attempts but may be independent constructs among non
      attempters. The presence of both factors may elevate risk for suicidal behavior.

PMID- 15191275
TI  - Minor self-harm and psychiatric disorder: a population-based study.
AB  - Little is known about the extent to which minor self-harm in the general
      population is associated with psychiatric disorder. A population-based sample of
      980 young adults was interviewed independently about past-year suicidal and self
      harm behavior and thoughts, and psychiatric disorders. Self-harm included self
      harmful behaviors such as self-battery, as well as traditional methods of suicide
      (ICD [International Classification of Diseases] self-harm). All with ICD self
      harm and most with other self-harmful behavior met the criteria for DSM-IV
      disorder. Suicidal/self-harmful thoughts increased the odds for self-harm, even
      in men without psychiatric disorder (odds ratio 4.9, 95% confidence interval 1.3
      17.9). Young adults engaging in even minor self-harm warrant screening for
      psychiatric disorder.

PMID- 15191276
TI  - Warning signs for suicide: everyone's business.

PMID- 15191277
TI  - Physicists are better educated for a career in medical physics if they graduate
      from a specialized medical physics graduate program rather than from a more
      traditional physics graduate program. For the Proposition.

PMID- 15191278
TI  - Physicists are better educated for a career in medical physics if they graduate
      from a specialized medical physics graduate program rather than from a more
      traditional physics graduate program. Against the Proposition.

PMID- 15191279
TI  - A new 2D segmentation method based on dynamic programming applied to computer
      aided detection in mammography.
AB  - Mass segmentation plays a crucial role in computer-aided diagnosis (CAD) systems
      for classification of suspicious regions as normal, benign, or malignant. In this
      article we present a robust and automated segmentation technique--based on
      dynamic programming--to segment mass lesions from surrounding tissue. In
      addition, we propose an efficient algorithm to guarantee resulting contours to be
      closed. The segmentation method based on dynamic programming was quantitatively
      compared with two other automated segmentation methods (region growing and the
      discrete contour model) on a dataset of 1210 masses. For each mass an overlap
      criterion was calculated to determine the similarity with manual segmentation.
      The mean overlap percentage for dynamic programming was 0.69, for the other two
      methods 0.60 and 0.59, respectively. The difference in overlap percentage was
      statistically significant. To study the influence of the segmentation method on
      the performance of a CAD system two additional experiments were carried out. The
      first experiment studied the detection performance of the CAD system for the
      different segmentation methods. Free-response receiver operating characteristics
      analysis showed that the detection performance was nearly identical for the three
      segmentation methods. In the second experiment the ability of the classifier to
      discriminate between malignant and benign lesions was studied. For region based
      evaluation the area Az under the receiver operating characteristics curve was
      0.74 for dynamic programming, 0.72 for the discrete contour model, and 0.67 for
      region growing. The difference in Az values obtained by the dynamic programming
      method and region growing was statistically significant. The differences between
      other methods were not significant.

PMID- 15191280
TI  - An automated procedure for the quality assurance of electron beam output and
      energy.
AB  - In this article, we report on the development of a simple and accurate method for
      quality assurance of electron beam output and energy. Aluminum disks of
      thicknesses d(max) or d50 of the particular electron energy are positioned
      sequentially over a parallel-plate ion chamber and the ratio of the two signals
      is compared to the standard. The positioning of the aluminum disks is carried out
      remotely and automatically to eliminate the necessity of multiple setups. One
      method utilizes the remote control feature of the treatment couch and another
      employs a motor-driven carousel. The superior sensitivity over a commercially
      available energy monitor is illustrated.

PMID- 15191281
TI  - Heterogeneity phantoms for visualization of 3D dose distributions by MRI-based
      polymer gel dosimetry.
AB  - Heterogeneity corrections in dose calculations are necessary for radiation
      therapy treatment plans. Dosimetric measurements of the heterogeneity effects are
      hampered if the detectors are large and their radiological characteristics are
      not equivalent to water. Gel dosimetry can solve these problems. Furthermore, it
      provides three-dimensional (3D) dose distributions. We used a cylindrical phantom
      filled with BANG-3 polymer gel to measure 3D dose distributions in heterogeneous
      media. The phantom has a cavity, in which water-equivalent or bone-like solid
      blocks can be inserted. The irradiated phantom was scanned with an magnetic
      resonance imaging (MRI) scanner. Dose distributions were obtained by calibrating
      the polymer gel for a relationship between the absorbed dose and the spin-spin
      relaxation rate of the magnetic resistance (MR) signal. To study dose
      distributions we had to analyze MR imaging artifacts. This was done in three
      ways: comparison of a measured dose distribution in a simulated homogeneous
      phantom with a reference dose distribution, comparison of a sagittally scanned
      image with a sagittal image reconstructed from axially scanned data, and
      coregistration of MR and computed-tomography images. We found that the MRI
      artifacts cause a geometrical distortion of less than 2 mm and less than 10%
      change in the dose around solid inserts. With these limitations in mind we could
      make some qualitative measurements. Particularly we observed clear differences
      between the measured dose distributions around an air-gap and around bone-like
      material for a 6 MV photon beam. In conclusion, the gel dosimetry has the
      potential to qualitatively characterize the dose distributions near
      heterogeneities in 3D.

PMID- 15191282
TI  - Performance of electronic portal imaging devices (EPIDs) used in radiotherapy:
      image quality and dose measurements.
AB  - The aim of our study was to compare the image and dosimetric quality of two
      different imaging systems. The first one is a fluoroscopic electronic portal
      imaging device (first generation), while the second is based on an amorphous
      silicon flat-panel array (second generation). The parameters describing image
      quality include spatial resolution [modulation transfer function (MTF)], noise
      [noise power spectrum (NPS)], and signal-to-noise transfer [detective quantum
      efficiency (DQE)]. The dosimetric measurements were compared with ionization
      chamber as well as with film measurements. The response of the flat-panel imager
      and the fluoroscopic-optical device was determined performing a two-step Monte
      Carlo simulation. All measurements were performed in a 6 MV linear accelerator
      photon beam. The resolution (MTF) of the fluoroscopic device (f 1/2 = 0.3 mm(-1))
      is larger than of the amorphous silicon based system (f 1/2 = 0.21 mm(-1)), which
      is due to the missing backscattered photons and the smaller pixel size. The noise
      measurements (NPS) show the correlation of neighboring pixels of the amorphous
      silicon electronic portal imaging device, whereas the NPS of the fluoroscopic
      system is frequency independent. At zero spatial frequency the DQE of the flat
      panel imager has a value of 0.008 (0.8%). Due to the minor frequency dependency
      this device may be almost x-ray quantum limited. Monte Carlo simulations verified
      these characteristics. For the fluoroscopic imaging system the DQE at low
      frequencies is about 0.0008 (0.08%) and degrades with higher frequencies. Dose
      measurements with the flat-panel imager revealed that images can only be directly
      converted to portal dose images, if scatter can be neglected. Thus objects
      distant to the detector (e.g., inhomogeneous dose distribution generated by a
      modificator) can be verified dosimetrically, while objects close to a detector
      (e.g., a patient) cannot be verified directly and must be scatter corrected prior
      to verification. This is justified by the response of the flat-panel imaging
      device revealing a strong dependency at low energies.

PMID- 15191283
TI  - An experimental method of determining relative phase-contrast factor for x-ray
      imaging systems.
AB  - The relative phase-contrast factor (RPF) represents a quantitative measure of the
      phase-contrast transfer in x-ray in-line phase-contrast imaging. The larger the
      modulus of RPF(u, v) is, the more the phase-contrast manifests. In this work we
      show how the RPF can be determined by measurements of the focal spot size and x
      ray spectra for a x-ray imaging system with a micro-focus x-ray tube. The results
      show the significant effects of x-ray beam hardening on the visibility of phase
      contrast, and reveal a new dimension in seeking optimal techniques for x-ray
      phase-contrast imaging.

PMID- 15191284
TI  - Monte Carlo modeling of a high-sensitivity MOSFET dosimeter for low- and medium
      energy photon sources.
AB  - Metal-oxide-semiconductor field effect transistor (MOSFET) dosimeters are
      increasingly utilized in radiation therapy and diagnostic radiology. While it is
      difficult to characterize the dosimeter responses for monoenergetic sources by
      experiments, this paper reports a detailed Monte Carlo simulation model of the
      High-Sensitivity MOSFET dosimeter using Monte Carlo N-Particle (MCNP) 4C. A dose
      estimator method was used to calculate the dose in the extremely thin sensitive
      volume. Efforts were made to validate the MCNP model using three experiments: (1)
      comparison of the simulated dose with the measurement of a Cs-137 source, (2)
      comparison of the simulated dose with analytical values, and (3) comparison of
      the simulated energy dependence with theoretical values. Our simulation results
      show that the MOSFET dosimeter has a maximum response at about 40 keV of photon
      energy. The energy dependence curve is also found to agree with the predicted
      value from theory within statistical uncertainties. The angular dependence study
      shows that the MOSFET dosimeter has a higher response (about 8%) when photons
      come from the epoxy side, compared with the kapton side for the Cs-137 source.

PMID- 15191285
TI  - A calibration procedure for beam monitors in a scanned beam of heavy charged
      particles.
AB  - An international code of practice (CoP) for dosimetry based on standards of
      absorbed dose to water has recently been published by the IAEA [Technical Report
      Series No. 398, 2000] (TRS-398). This new CoP includes procedures for proton and
      heavy ion beams as well as all other beam qualities. In particular it defines
      reference conditions to which dose measurements should refer to. For proton and
      ion beams these conditions include dose measurements in the center of all
      possible modulated Bragg peaks. The recommended reference conditions in general
      are used also for the calibration of beam monitors. For a dynamic beam delivery
      system using beam scanning in combination with energy variation, like, e.g., at
      the German carbon ion radiotherapy facility, this calibration procedure is not
      appropriate. We have independently developed a different calibration procedure.
      Similar to the IAEA CoP this procedure is based on the measurement of absorbed
      dose to water. This is translated in terms of fluence which finally results in an
      energy-dependent calibration of the beam monitor in units of particle number per
      monitor unit, which is unique for all treatment fields. In contrast to the IAEA
      CoP, the reference depth is chosen to be very small. The procedure enables an
      accurate and reliable determination of calibration factors. In a second step, the
      calibration is verified by measurements of absorbed dose in various modulated
      Bragg peaks by comparing measured against calculated doses. The agreement between
      measured and calculated doses is usually better than 1% for homogeneous fields
      and the mean deviation for more inhomogeneous treatment fields, as they are used
      for patient treatments, is within 3%. It is proposed that the CoP in general, and
      in particular the IAEA TRS-398 should include explicit recommendations for the
      beam monitor calibration. These recommendations should then distinguish between
      systems using static and dynamic beams.

PMID- 15191286
TI  - Improving radiochromic film's sensitivity by wrapping it with UV phosphor.
AB  - The main advantage of radiochromic-film dosimeters is the coupling of rapid full
      planar-acquisition, high-spatial resolution and dose linearity. Their main
      limitation, however, is their low radiation sensitivity. This precludes their
      application to measuring doses below a few Gy. Radiochromic films are sensitive
      to ultraviolet radiation. In this note the results of exposing radiochromic films
      to x rays through an UV imaging cassette, which converts and amplifies x rays to
      UV radiation, are presented. These results indicate a clear increase (around 50%)
      in radiochromic film's sensitivity to MV x rays (6, 10, and 18 MV) when exposed
      through the UV phosphor.

PMID- 15191287
TI  - Korean adult male voxel model KORMAN segmented from magnetic resonance images.
AB  - A voxel model of Korean adult male, KORMAN, was developed by processing whole
      body magnetic resonance (MR) images of a healthy volunteer who represents an
      approximately average Korean in height and weight. Layer by layer the MR images
      were semi-automatically segmented and indexed using a graphic software and
      digitizer to construct data arrays consisting of 250 x 120 x 170 voxels of a size
      of 2 x 2 x 10 mm3. To assess the utility of the model, some illustrative
      dosimetric calculations were made to obtain organ absorbed doses and effective
      doses to the KORMAN placed in broad parallel photon fields with energies ranging
      from 0.05 to 10 MeV. The results were compared with those based on the medical
      internal radiation dose (MIRD)-type models given in ICRP74. The effective doses
      of ICRP74 were higher than those of KORMAN with percent differences ranging from
      6% (LLAT, 10 MeV) to 30% (PA, 0.05 MeV). Significant differences of more than 40%
      were observed in organ absorbed doses for some organs including bone surface
      (AP), stomach (PA), and testes (LAT) for low photon energy. These are mainly
      caused by difference in trunk thickness between MIRD-type model and KORMAN, and
      differences in organ positions in the body.

PMID- 15191288
TI  - Clinical implementation of intensity-modulated tangential beam irradiation for
      breast cancer.
AB  - A Monte Carlo based intensity-modulated radiation therapy (IMRT) treatment
      planning system has been developed and used for breast treatment. An iterative
      method was used for optimization to generate IMRT plans and a step-and-shoot
      technique was used for beam delivery. The patient setup and incident beam
      directions were the same as those for conventional tangential photon treatment.
      The weights for the opposed beamlets in the two tangential beams were determined
      first by the doses at the depths of the maximum dose at both sides to minimize
      hot spots. The intensity of an individual beamlet pair was then optimized based
      on the dose at the midplane. Fine tuning was made to achieve optimal target dose
      uniformity and to reduce the dose to the heart when necessary. The final dose
      calculations were performed using the Monte Carlo method and the plans were
      verified by phantom measurements. The dose distributions and dose-volume
      histograms of IMRT plans were compared with those of conventional plans that were
      generated using a commercial treatment planning system and recalculated using an
      in-house Monte Carlo system for the first 25 patients. The dose comparisons
      showed that the percentage volume receiving more than 95% of the prescription
      dose (V95) and the percentage volume receiving more than 100% of the prescription
      dose (V100) for the clinical target volume (CTV) of IMRT plans were about the
      same as those of conventional plans. The percentage volume receiving more than
      105% of the prescription dose (V105) for the CTV was reduced from 23.1% to 7.9%
      on average. The percentage volume of the lung receiving more than 20 Gy dose (V20
      Gy) during the entire treatment was reduced by about 10%. The percentage volume
      of the heart receiving more than 30 Gy dose (V30 Gy) is reduced from 3.3% to
      0.3%. Further studies revealed that a less than 5 degrees change in couch angle
      and collimator angle at patient setup had no significant effect on the dose
      coverage of CTV but had significant effect on the dose to the lung and heart. The
      study on the effect of beam spoiler showed that it increased the dose at the
      buildup region by 0- 13% that varies with location. The machine output linearity
      and stability for small monitor unit delivery of Siemens accelerators used for
      this study was checked and found to be suitable for breast IMRT. The total effect
      of variations was calculated to be less than 1% for typical breast treatments.
      The beam delivery time was increased by about 2 min compared with conventional
      tangential treatments. The whole treatment including patient setup and beam
      delivery can be completed in a 15 min slot. The IMRT technique has been proven
      practical for breast treatment clinically. The results showed that tangential
      IMRT improved the dose homogeneity in the breast and reduced the dose to the lung
      and heart.

PMID- 15191289
TI  - Ultrasonic tissue characterization using 2-D spectrum analysis and its
      application in ocular tumor diagnosis.
AB  - We are investigating the utility of a new ultrasonic tissue characterization
      technique, specifically two-dimensional (2-D) spectrum analysis of radio
      frequency backscatter signals, which promises to provide quantitative measures of
      the physical properties of tissue microstructures. Previously successful 1-D
      spectrum analysis is expanded to 2-D to more fully characterize diagnostically
      significant features of biological tissue. Two new spectral functions, radially
      integrated spectral power (RISP) and angularly integrated spectral power (AISP),
      are defined to quantitatively characterize tissue properties. This new approach
      is applied to the diagnosis of in vivo ocular melanomas. Our initial results
      indicate that 2-D spectrum analysis can provide significant new information on
      tissue anisotropy that are not apparent in 1-D spectra. Acoustic scattering
      models are applied to relate the 2-D spectral parameters to the physical
      properties (e.g., size and shape) of biological tissues.

PMID- 15191291
TI  - First proton radiography of an animal patient.
AB  - The purpose of this work is to show the feasibility of proton radiography in
      terms of radiation dose, imaging speed, image quality (density and spatial
      resolution), and image content under clinical conditions. Protons with 214 MeV
      energy can penetrate through most patients and were used for imaging. The
      measured residual range (or energy) of the protons behind the patient was
      subtracted from the range without an object in the beam path and used to create a
      projected image. The image content is therefore proportional to the range that
      protons have lost in the patient. We took proton images of the head of a dog
      after it received proton radiotherapy treatment of a nasal tumor. The spatial
      resolution by measuring for each proton separately its coordinate in front of and
      behind the patient was approximately 1 mm. The acquisition time was on the order
      of several seconds and was limited by the patient table movement. The range
      sensitivity of the images was approximately 0.6 mm, which is good enough to use
      the images for therapy range verification. The dose that the dog received during
      exposure was 0.03 mGy, which is approximately a factor 50-100 smaller than for a
      comparable x-ray image. The potential to obtain quantitative images of proton
      ranges with satisfying spatial and range resolution and low dose to the patient
      suggests that proton radiography should be applied to patients who are under
      proton radiotherapy treatment.

PMID- 15191290
TI  - On the development of consensus values of reference dosimetry parameters for
      interstitial brachytherapy sources.
AB  - The American Association of Physicists in Medicine recommends that the reference
      dose-rate distribution, used for treatment planning for low-energy photon
      brachytherapy sources in routine clinical use, must be based on at least two
      independent determinations: one using experimentally measured dose rates and one
      using Monte Carlo simulation dosimetry techniques. In this work, we present an
      approach for developing consensus dosimetry parameters from various independent
      reference dosimetry studies for interstitial brachytherapy sources. This approach
      is applied to four recently published papers on the dosimetric properties of the
      BrachySeed Model LS-1 125I seed. Consensus values for the dose-rate constant,
      radial dose function, and anisotropy parameters are presented for the LS-1 Model
      125I seed.

PMID- 15191292
TI  - IMRT optimization: variability of solutions and its radiobiological impact.
AB  - We aim at (1) defining and measuring a "complexity" index for the optimization
      process of an intensity modulated radiation therapy treatment plan (IMRT TP), (2)
      devising an efficient approximate optimization strategy, and (3) evaluating the
      impact of the complexity of the optimization process on the radiobiological
      quality of the treatment. In this work, for a prostate therapy case, the IMRT TP
      optimization problem has been formulated in terms of dose-volume constraints. The
      cost function has been minimized in order to achieve the optimal solution, by
      means of an iterative procedure, which is repeated for many initial modulation
      profiles, and for each of them the final optimal solution is recorded. To explore
      the complexity of the space of such solutions we have chosen to minimize the cost
      function with an algorithm that is unable to avoid local minima. The size of the
      (sub)optimal solutions distribution is taken as an indicator of the complexity of
      the optimization problem. The impact of the estimated complexity on the
      probability of success of the therapy is evaluated using radiobiological
      indicators (Poissonian TCP model [S. Webb and A. E. Nahum, Phys. Med. Biol.
      38(6), 653-666 (1993)] and NTCP relative seriality model [Kallman et al., Int. J.
      Radiat. Biol. 62(2), 249-262 (1992)]). We find in the examined prostate case a
      nontrivial distribution of local minima, which has symmetry properties allowing a
      good estimate of near-optimal solutions with a moderate computational load. We
      finally demonstrate that reducing the a priori uncertainty in the optimal
      solution results in a significant improvement of the probability of success of
      the TP, based on TCP and NTCP estimates.

PMID- 15191293
TI  - Scanning-slit photon counting x-ray imaging system using a microchannel plate
      detector.
AB  - An experimental prototype of a novel photon counting x-ray imaging system was
      evaluated. This system is based on an "edge-on" microchannel plate (MCP) detector
      and utilizes scanning slit imaging configuration. The detector is capable of
      photon counting, direct conversion, high spatial resolution, controllable
      physical charge amplification, quantum limited and scatter free operation. The
      detector provides a 60 mm wide field of view (FOV) and its count rate is 200 kHz
      for the entire FOV. The count rate of the current system is limited by the
      position encoding electronics, which has a single input for all events from the
      entire detector, and incorporates a single channel ADC with 1 micros conversion
      time. It is shown that the count rate can potentially be improved to clinically
      acceptable levels using multichannel application specific integrated circuit
      (ASIC) electronics and multi-slit image acquisition geometry. For a typical
      acquisition time used in this study, the image noise was measured to be less than
      the typically acceptable noise level for medical x-ray imaging. It is anticipated
      that the noise level will be also low after the implementation of the ASIC
      electronics. The quantum efficiency of the detector was measured to be 40%-56%
      for an energy range of 50-90 kVp for MCPs used in this study and can be improved
      to > 80% using MCPs with the optimized parameters. Images of resolution and
      anthropomorphic phantoms were acquired at an x-ray tube voltage of 50 kVp. The
      value of contrast transfer function for the detector was measured to be 0.5 at a
      spatial frequency of 5 lp/mm. The intrinsic spatial resolution of the system is
      28 microm FWHM and was limited by the accuracy of the time-to-digital conversion
      of the position encoding electronics. Given the advantages of the edge-on MCP
      detector such as direct conversion and physical charge amplification, it can
      potentially be applied to mammography and chest radiography.

PMID- 15191294
TI  - Distance and angular dependence of intensity ratios in laser-induced
      autofluorescence techniques.
AB  - Laser-induced autofluorescence techniques have the potential to be used for the
      detection of preinvasive human cancer cells. For colorectal and gastrointestinal
      cancer cells, the light is introduced in vivo through endoscopic means and the
      probe tip is brought gently into contact with the tissue under investigation.
      However, it is often assumed that there is no distance or angular dependence in
      the intensity of the light collected from the probes. We performed an in vitro
      experiment in which we showed that there was indeed no angular dependence
      provided the angle of inclination of the probe to normal incidence is small.
      However, we find substantial fluctuation in the intensities of peaks for changing
      distances. These fluctuations can be eliminated by considering the ratio of the
      intensities from two spectral lines.

PMID- 15191295
TI  - Computerized interpretation of breast MRI: investigation of enhancement-variance
      dynamics.
AB  - The advantages of breast MRI using contrast agent Gd-DTPA in the diagnosis of
      breast cancer have been well established. The variation of interpretation
      criteria and absence of interpretation guidelines, however, is a major obstacle
      for applications of MRI in the routine clinical practice of breast imaging. Our
      study aims to increase the objectivity and reproducibility of breast MRI
      interpretation by developing an automated interpretation approach for ultimate
      use in computer-aided diagnosis. The database in this study contains 121 cases:
      77 malignant and 44 benign masses as revealed by biopsy. Images were obtained
      using a T1-weighted 3D spoiled gradient echo sequence. After the acquisition of
      the precontrast series, Gd-DTPA contrast agent was injected intravenously by
      power injection with a dose of 0.2 mmol/kg. Five postcontrast series were then
      taken with a time interval of 60 s. Each series contained 64 coronal slices with
      a matrix of 128 x 256 pixels and an in-plane resolution of 1.25 x 1.25 mm2. Slice
      thickness ranged from 2 to 3 mm depending on breast size. The lesions were
      delineated by an experienced radiologist as well as independently by computer
      using an automatic volume-growing algorithm. Fourteen features that were
      extracted automatically from the lesions could be grouped into three categories
      based on (I) morphology, (II) enhancement kinetics, and (III) time course of
      enhancement-variation over the lesion. A stepwise feature selection procedure was
      employed to select an effective subset of features, which were then combined by
      linear discriminant analysis (LDA) into a discriminant score, related to the
      likelihood of malignancy. The classification performances of individual features
      and the combined discriminant score were evaluated with receiver operating
      characteristic (ROC) analysis. With the radiologist-delineated lesion contours,
      stepwise feature selection yielded four features and an Az value of 0.80 for the
      LDA in leave-one-out cross-validation testing. With the computer-segmented lesion
      volumes, it yielded six features and an Az value of 0.86 for the LDA in the leave
      one-out testing.

PMID- 15191296
TI  - Phantom validation of coregistration of PET and CT for image-guided radiotherapy.
AB  - Radiotherapy treatment planning integrating positron emission tomography (PET)
      and computerized tomography (CT) is rapidly gaining acceptance in the clinical
      setting. Although hybrid systems are available, often the planning CT is acquired
      on a dedicated system separate from the PET scanner. A limiting factor to using
      PET data becomes the accuracy of the CT/PET registration. In this work, we use
      phantom and patient validation to demonstrate a general method for assessing the
      accuracy of CT/PET image registration and apply it to two multi-modality image
      registration programs. An IAEA (International Atomic Energy Association) brain
      phantom and an anthropomorphic head phantom were used. Internal volumes and
      externally mounted fiducial markers were filled with CT contrast and 18F
      fluorodeoxyglucose (FDG). CT, PET emission, and PET transmission images were
      acquired and registered using two different image registration algorithms. CT/PET
      Fusion (GE Medical Systems, Milwaukee, WI) is commercially available and uses a
      semi-automated initial step followed by manual adjustment. Automatic Mutual
      Information-based Registration (AMIR), developed at our institution, is fully
      automated and exhibits no variation between repeated registrations. Registration
      was performed using distinct phantom structures; assessment of accuracy was
      determined from registration of the calculated centroids of a set of fiducial
      markers. By comparing structure-based registration with fiducial-based
      registration, target registration error (TRE) was computed at each point in a
      three-dimensional (3D) grid that spans the image volume. Identical methods were
      also applied to patient data to assess CT/PET registration accuracy. Accuracy was
      calculated as the mean with standard deviation of the TRE for every point in the
      3D grid. Overall TRE values for the IAEA brain phantom are: CT/PET Fusion = 1.71
      +/- 0.62 mm, AMIR = 1.13 +/- 0.53 mm; overall TRE values for the anthropomorphic
      head phantom are: CT/PET Fusion = 1.66 +/- 0.53 mm, AMIR = 1.15 +/- 0.48 mm.
      Precision (repeatability by a single user) measured for CT/PET Fusion: IAEA
      phantom = 1.59 +/- 0.67 mm and anthropomorphic head phantom = 1.63 +/- 0.52 mm.
      (AMIR has exact precision and so no measurements are necessary.) One sample
      patient demonstrated the following accuracy results: CT/PET Fusion = 3.89 +/-
      1.61 mm, AMIR = 2.86 +/- 0.60 mm. Semi-automatic and automatic image registration
      methods may be used to facilitate incorporation of PET data into radiotherapy
      treatment planning in relatively rigid anatomic sites, such as head and neck. The
      overall accuracies in phantom and patient images are < 2 mm and < 4 mm,
      respectively, using either registration algorithm. Registration accuracy may
      decrease, however, as distance from the initial registration points (CT/PET
      fusion) or center of the image (AMIR) increases. Additional information provided
      by PET may improve dose coverage to active tumor subregions and hence tumor
      control. This study shows that the accuracy obtained by image registration with
      these two methods is well suited for image-guided radiotherapy.

PMID- 15191297
TI  - Optical-CT gel-dosimetry. II: Optical artifacts and geometrical distortion.
AB  - There is a clear need for technology that enables accurate, high-resolution,
      three-dimensional (3D) measurement of intricate dose distributions associated
      with modern radiation treatments. A potential candidate has emerged in the form
      of water-equivalent "3D gel dosimetry" utilizing optical-computed-tomography
      (optical-CT). In a previous paper we presented basic physical characterization of
      an in-house prototype optical-CT scanning system. The present paper builds on
      that work by investigating sources of optical artifacts and geometric distortion
      in optical-CT scanning. Improvements in scanner design are described. Correction
      strategies were developed to compensate for reflection and refraction,
      imperfections in the water-bath, signal drift, and other effects. Refraction and
      reflection were identified as the principal factors causing inaccurate
      reconstruction of absolute attenuation coefficients. A correction specific to a
      given flask was developed utilizing prescans of the flask when filled with water
      bath fluid, thereby isolating the refractive and reflective components for that
      flask. Residual artifacts were corrected by fitting a theoretical model to the
      well-behaved portion of these prescans and extrapolating to regions of lost data,
      enabling reconstruction of absolute optical-CT attenuation coefficients to within
      4% of corresponding spectrophotometer values. Needle phantoms are introduced to
      quantify geometric distortion under a range of conditions. Radial distortion of
      reconstructed needle positions was reduced to < 0.3 mm (0.27% of the field of
      view) through adjustment of the water-bath refractive index. Geometric distortion
      in polymer gel due to radiation-induced refractive index changes was found to be
      negligible under the conditions examined. The influence of scattered light on
      reconstructed attenuation coefficients was investigated by repeat optical-CT
      scans while varying the aperture of a scatter-rejecting collimator. Significant
      depression of reconstructed attenuation coefficients was observed, particularly
      under conditions of poor scatter rejection collimation. The general conclusion is
      that the first-generation optical-CT technique can be made insensitive to
      geometrical distortion, but can be susceptible to scatter effects. For accurate
      reconstruction of absolute attenuation coefficients, correction strategies are
      essential.

PMID- 15191298
TI  - Measurement of mesothelioma on thoracic CT scans: a comparison of manual and
      computer-assisted techniques.
AB  - Our purpose in this study was to evaluate the variability of manual mesothelioma
      tumor thickness measurements in computed tomography (CT) scans and to assess the
      relative performance of six computerized measurement algorithms. The CT scans of
      22 patients with malignant pleural mesothelioma were collected. In each scan, an
      initial observer identified up to three sites in each of three CT sections at
      which tumor thickness measurements were to be made. At each site, five observers
      manually measured tumor thickness through a computer interface. Three observers
      repeated these measurements during three separate sessions. Inter- and intra
      observer variability in the manual measurement of tumor thickness was assessed.
      Six automated measurement algorithms were developed based on the geometric
      relationship between a specified measurement site and the automatically extracted
      lung regions. Computer-generated measurements were compared with manual
      measurements. The tumor thickness measurements of different observers were highly
      correlated (r > or = 0.99); however, the 95% limits of agreement for relative
      inter-observer difference spanned a range of 30%. Tumor thickness measurements
      generated by the computer algorithms also correlated highly with the average of
      observer measurements (r > or = 0.93). We have developed computerized techniques
      for the measurement of mesothelioma tumor thickness in CT scans. These techniques
      achieved varying levels of agreement with measurements made by human observers.

PMID- 15191299
TI  - A conceptual design of a beam-shaping assembly for boron neutron capture therapy
      based on deuterium-tritium neutron generators.
AB  - A conceptual design of a beam-shaping assembly for boron neutron capture therapy
      using deuterium-tritium accelerator based neutrons source is developed.
      Calculations based on a simple geometry model for the radiation transport are
      initially performed to estimate the assembly materials and their linear
      dimensions. Afterward, the assembly geometry is produced, optimized and verified.
      In order to perform these calculations the general-purpose MCNP code is used.
      Irradiation time and therapeutic gain are utilized as beam assessment parameters.
      Metallic uranium and manganese are successfully tested for fast-to-epithermal
      neutron moderation. In the present beam-shaping assembly proposal, the
      therapeutic gain is improved by 23% and the accelerator current required for a
      fixed irradiation period is reduced by six times compared to previous proposals
      based on the same D-T reaction.

PMID- 15191300
TI  - Calibration of a scintillation dosemeter for beta rays using an extrapolation
      ionization chamber.
AB  - A scintillation dosemeter is calibrated for 90Sr/90Y beta rays from an ophthalmic
      applicator, using an extrapolation ionization chamber as a reference instrument.
      The calibration factor for the scintillation dosemeter agrees with that given by
      the manufacturer of the dosemeter within ca. 2%. The estimated overall
      uncertainty of the present calibration is ca. 6% (2 sd). A calibrated beta-ray
      ophthalmic applicator can be used as a reference source for further calibrations
      performed in the laboratory or in the hospital.

PMID- 15191301
TI  - Advantage and limitations of weighting factors and weighted dose quantities and
      their units in boron neutron capture therapy.
AB  - Defining the parameters influencing the biological reaction due to absorbed dose
      is a continuous topic of research. The main goal of radiobiological research is
      to translate the measurable dose of ionizing radiation to a quantitative
      expression of biological effect. Mathematical models based on different
      biological approaches (e.g., skin reaction, cell culture) provide some
      estimations that are often misleading and, to some extent, dangerous.
      Conventional radiotherapy is the simplest case because the primary radiation and
      secondary radiation are both low linear energy transfer (LET) radiation and have
      about the same relative biological effectiveness (RBE). Nevertheless, for this
      one-dose-component case, the dose-effect curves are not linear. In fact, the
      total absorbed dose and the absorbed dose per fraction as well as the time
      schedule of the fractionation scheme influence the biological effects.
      Mathematical models such as the linear-quadratic model can only approximate
      biological effects. With regard to biological effects, fast neutron therapy is
      more complex than conventional radiotherapy. Fast neutron beams are always
      contaminated by gamma rays. As a consequence, biological effects are due to two
      components, a high-LET component (neutrons) and a low-LET component (photons). A
      straight transfer of knowledge from conventional radiotherapy to fast neutron
      therapy is, therefore, not possible: RBE depends on the delivered dose and
      several other parameters. For dose reporting, the European protocol for fast
      neutron dosimetry recommends that the total absorbed dose with gamma-ray absorbed
      dose in brackets is stated. However, boron neutron capture therapy (BNCT) is an
      even more complex case, because the total absorbed dose is due to four dose
      components with different LET and RBE. In addition, the terminology and units
      used by the different BNCT groups is confusing: absorbed dose and weighted dose
      are both to be stated in grays and are never "photon equivalent." The ICRU/IAEA
      made proposals, which should be followed by all BNCT groups, to report always the
      four absorbed dose components, boron dose DB, proton dose Dp, gamma-ray dose
      Dgamma, and neutron dose Dn, as well as the sum DT of all components, as total
      absorbed dose, together with the total weighted dose Dw (to be used only for
      internal purposes, indicating the used weighting factors) at all points of
      interest and the treatment conditions.

PMID- 15191302
TI  - Constructal theory of flow architecture of the lungs.
AB  - Here we explain the reasons why we have a bronchial tree with 23 levels
      ofbifurcation. Based on Bejan's Constructal Principle we found that the best
      oxygen access to the alveolar tissues as well as carbon dioxide removal is
      provided by a flow structure composed of ducts with 23 levels of bifurcation
      (bronchial tree) that ends with spaces (alveolar sacs) from where oxygen diffuses
      into the tissues. The model delivers the dimensions of the alveolar sac, the
      total length of the airways, the total alveolar surface area, and the total
      resistance to oxygen transport inthe respiratory tree. A constructal law also
      emerges: the length defined by the ratio of the square of the airway diameter to
      its length is constant for all individuals of the same species and is related to
      the characteristics of the space allocated to the respiratory process and
      determines univocally thebranching level of the respiratory tree.

PMID- 15191303
TI  - Speed and convergence properties of gradient algorithms for optimization of IMRT.
AB  - Gradient algorithms are the most commonly employed search methods in the routine
      optimization of IMRT plans. It is well known that local minima can exist for dose
      volume-based and biology-based objective functions. The purpose of this paper is
      to compare the relative speed of different gradient algorithms, to investigate
      the strategies for accelerating the optimization process, to assess the validity
      of these strategies, and to study the convergence properties of these algorithms
      for dose-volume and biological objective functions. With these aims in mind, we
      implemented Newton's, conjugate gradient (CG), and the steepest decent (SD)
      algorithms for dose-volume- and EUD-based objective functions. Our implementation
      of Newton's algorithm approximates the second derivative matrix (Hessian) by its
      diagonal. The standard SD algorithm and the CG algorithm with "line minimization"
      were also implemented. In addition, we investigated the use of a variation of the
      CG algorithm, called the "scaled conjugate gradient" (SCG) algorithm. To
      accelerate the optimization process, we investigated the validity of the use of a
      "hybrid optimization" strategy, in which approximations to calculated dose
      distributions are used during most of the iterations. Published studies have
      indicated that getting trapped in local minima is not a significant problem. To
      investigate this issue further, we first obtained, by trial and error, and
      starting with uniform intensity distributions, the parameters of the dose-volume-
      or EUD-based objective functions which produced IMRT plans that satisfied the
      clinical requirements. Using the resulting optimized intensity distributions as
      the initial guess, we investigated the possibility of getting trapped in a local
      minimum. For most of the results presented, we used a lung cancer case. To
      illustrate the generality of our methods, the results for a prostate case are
      also presented. For both dose-volume and EUD based objective functions, Newton's
      method far outperforms other algorithms in terms of speed. The SCG algorithm,
      which avoids expensive "line minimization," can speed up the standard CG
      algorithm by at least a factor of 2. For the same initial conditions, all
      algorithms converge essentially to the same plan. However, we demonstrate that
      for any of the algorithms studied, starting with previously optimized intensity
      distributions as the initial guess but for different objective function
      parameters, the solution frequently gets trapped in local minima. We found that
      the initial intensity distribution obtained from IMRT optimization utilizing
      objective function parameters, which favor a specific anatomic structure, would
      lead to a local minimum corresponding to that structure. Our results indicate
      that from among the gradient algorithms tested, Newton's method appears to be the
      fastest by far. Different gradient algorithms have the same convergence
      properties for dose-volume- and EUD-based objective functions. The hybrid dose
      calculation strategy is valid and can significantly accelerate the optimization
      process. The degree of acceleration achieved depends on the type of optimization
      problem being addressed (e.g., IMRT optimization, intensity modulated beam
      configuration optimization, or objective function parameter optimization). Under
      special conditions, gradient algorithms will get trapped in local minima, and
      reoptimization, starting with the results of previous optimization, will lead to
      solutions that are generally not significantly different from the local minimum.

PMID- 15191304
TI  - Experimental evaluation of analytical penumbra calculation model for wobbled
      beams.
AB  - The goal of radiotherapy is not only to apply a high radiation dose to a tumor,
      but also to avoid side effects in the surrounding healthy tissue. Therefore, it
      is important for carbon-ion treatment planning to calculate accurately the
      effects of the lateral penumbra. In this article, for wobbled beams under various
      irradiation conditions, we focus on the lateral penumbras at several aperture
      positions of one side leaf of the multileaf collimator. The penumbras predicted
      by an analytical penumbra calculation model were compared with the measured
      results. The results calculated by the model for various conditions agreed well
      with the experimental ones. In conclusion, we found that the analytical penumbra
      calculation model could predict accurately the measured results for wobbled beams
      and it was useful for carbon-ion treatment planning to apply the model.

PMID- 15191305
TI  - A new smoothing procedure to reduce delivery segments for static MLC-based IMRT
      planning.
AB  - In the application of pixel-based intensity-modulated radiation therapy (IMRT)
      using the step-and-shoot delivery method, one major difficulty is the prolonged
      delivery time. In this study, we present an integrated IMRT planning system that
      involves a simple smoothing method to reduce the complexity of the beam profiles.
      The system consists of three main steps: (a) an inverse planning process based on
      a least-square dose-based cost function; (b) smoothing of the intensity maps; (c)
      reoptimization of the segment weights. Step (a) obtains the best plan with the
      lowest cost value using a simulated annealing optimization algorithm with
      discrete intensity levels. Step (b) takes the intensity maps obtained from (a)
      and reduces the complexity of the maps by smoothing the adjacent beamlet
      intensities. During this process each beamlet is assigned a structure index based
      on anatomical information. A smoothing update is applied to average adjacent
      beamlets with the same index. To control the quality of the plan, a predefined
      clinical protocol is used as an acceptance criterion. The smoothing updates that
      violate the criterion are rejected. After the smoothing process, the segment
      weights are reoptimized in step (c) to further improve the plan quality. Three
      clinical cases were studied using this system: a medulloblastoma, a prostate
      cancer, and an oropharyngeal carcinoma. While the final plans demonstrate a
      degradation of the original plan quality, they still meet the plan acceptance
      criterion. On the other hand, the segment numbers or delivery times are reduced
      by 40%, 20%, and 20% for the three cases, respectively.

PMID- 15191306
TI  - Evaluation of the imaging properties of an amorphous selenium-based flat panel
      detector for digital fluoroscopy.
AB  - The imaging performance of an amorphous selenium (a-Se) flat-panel detector for
      digital fluoroscopy was experimentally evaluated using the spatial frequency
      dependent modulation transfer function (MTF), noise power spectrum (NPS), and
      detective quantum efficiency (DQE). These parameters were investigated at beam
      qualities and exposures within the range typical of gastrointestinal fluoroscopic
      imaging (approximately 0.1 - 10 microR, 75 kV). The investigation does not take
      into consideration the detector cover, which in clinical use will lower the DQE
      measured here by its percent attenuation. The MTF was found to be less than the
      expected aperture response and the NPS was not white which together indicate
      presampling blurring. The cause of this blurring was attributed to charge
      trapping at the interface between two different layers of the a-Se. The effect on
      the DQE was also consistent with presampling blur, which reduces the aliasing in
      the NPS and thereby reduces the spatial frequency dependence of the DQE. (The DQE
      was independent of spatial frequency from 0.12 to 0.73 mm(-1) due to antialiasing
      of the NPS.) Moreover, the first zero of the measured MTF and the aperture
      response appeared at the same spatial frequency (6.66 mm(-1) for a pixel of 150
      microm). Hence, the geometric fill factor (77%) was increased to an effective
      fill factor of 99 +/- 1%. A large scale ( approximately 32 pixels) correlation in
      the noise due to the configuration of the readout electronics caused increased
      noise power in the gate line NPS at low spatial frequency (< 0.1 mm(-1)). The DQE
      (f = 0) was exposure independent over a large range of exposures but became
      exposure dependent at low exposures due to the electronic noise.

PMID- 15191307
TI  - TCP isoeffect analysis using a heterogeneous distribution of radiosensitivity.
AB  - A formula for the alpha/beta ratio is derived using the heterogeneous (population
      averaged) tumor control model. This formula is nearly identical to the formula
      obtained using the homogeneous (individual) tumor control model, but the new
      formula includes extra terms showing that the alpha/beta ratio, the ratio of the
      mean value of a divided by the mean value of beta that would be observed in a
      patient population, explicitly depends on the survival level and heterogeneity.
      The magnitude of this correction is estimated for prostate cancer, and this
      appears to raise the mean value of the ratio estimate by about 20%. The method
      also allows investigation of confidence limits for alpha/beta based on a
      population distribution of radiosensitivity. For a widely heterogeneous
      population, the upper 95% confidence interval for the alpha/beta ratio can be as
      high as 7.3 Gy, even though the population mean is between 2.3 and 2.6 Gy.

PMID- 15191308
TI  - Porous phantoms for PET and SPECT performance evaluation and quality assurance.
AB  - Characterization of PET and SPECT imaging performance often requires phantoms
      with complex radionuclide distributions. For example, lesion detection studies
      use multiple spherical regions of specific target-to-background ratios to
      simulate cancerous lesions. Such complex distributions are typically created
      using phantoms with multiple fillable chambers. However, such phantoms are
      typically difficult and time-consuming to prepare accurately and reproducibly. A
      new approach using a single-chamber phantom with a porous core can overcome these
      difficulties. METHODS: Prototypes of two designs of porous core phantoms were
      produced and evaluated. The "hot spheres" phantom contained a multitude of
      simulated spherical lesions with diameters ranging from 6.35 to 25.4 mm ("multi
      resolution" slice) and with lesion-to-background ratios ranging from 1.6 to 4.4
      ("multi-contrast" slice). The "multi-attenuation" phantom consisted of two
      halves. One half contained a porous core to produce regions of different
      attenuation but uniform activity. The other half mimicked the NEMA-94 design with
      cold inserts of different attenuation. RESULTS: Both phantoms produced the
      expected radionuclide distributions while requiring the preparation of only a
      single radionuclide solution and with much reduced preparation time. In images
      taken on clinical PET and SPECT scanners, the porous core structures were found
      to contribute negligible background noise or artifact. The measured lesion-to
      background ratios from the hot spheres phantom differed slightly from calculated
      values, with the differences attributed mainly to uncertainty in pore diameter.
      The measured attenuation coefficients from the multi-attenuation phantom agreed
      well with expected values. However, it was found that trapped air bubbles due to
      manufacturing defects in the porous core could potentially cause quantitative
      errors. CONCLUSION: The hot spheres and multi-attenuation porous phantoms
      exhibited a wide range of imaging features providing thorough tests of lesion
      detection and of attenuation and scatter correction accuracy. Because the local
      activity concentration is set by the relative volume of radionuclide solution in
      the porous core, the quantitative accuracy is limited mainly by mechanical
      tolerance, and strict quality control during manufacturing is essential.
      Nonetheless, the single-chamber design of the porous core phantoms is inherently
      more reproducible and more practical for routine use compared to conventional
      multi-chamber phantoms.

PMID- 15191310
TI  - Lag measurement in an a-Se active matrix flat-panel imager.
AB  - Lag and residual contrast have been quantified in an amorphous selenium (a-Se)
      active-matrix flat-panel imager (AMFPI) as a function of frame time, kilovoltage
      (kV) and megavoltage (MV) x-ray photon energies and amount of radiation incident
      on the detector. The AMFPI contains a 200 microm thick a-Se layer deposited on a
      thin film transistor (TFT) array of size 8.7 cm x 8.7 cm with an 85-microm pixel
      pitch. For all energies, the lag (signal normalized to the signal due to
      exposure) for the first (n = 1) and second (n = 2) frame after exposure ranges
      from 0.45% to 0.91% and from 0.29% to 0.51%, respectively. The amount of lag was
      determined to be a function of the time after the x-ray exposure irrespective of
      frame time or the magnitude of exposure. The lag for MV photon energies was
      slightly less than that for kV photon energies. The residual contrast for all
      energies studied ranges from 0.41% to 0.75% and from 0.219% to 0.41% for the n =
      1 and n = 2 frames, respectively. These results show that lag and residual
      contrast in kV and MV radiographic applications are always less than 1% for the
      detection system used and only depend on the time after x-ray exposure.

PMID- 15191309
TI  - X-ray scatter correction algorithm for cone beam CT imaging.
AB  - Developing and optimizing an x-ray scatter control and reduction technique is one
      of the major challenges for cone beam computed tomography (CBCT) because CBCT
      will be much less immune to scatter than fan-beam CT. X-ray scatter reduces image
      contrast, increases image noise and introduces reconstruction error into CBCT. To
      reduce scatter interference, a practical algorithm that is based upon the beam
      stop array technique and image sequence processing has been developed on a flat
      panel detector-based CBCT prototype scanner. This paper presents a beam stop
      array-based scatter correction algorithm and the evaluation results through
      phantom studies. The results indicate that the beam stop array-based scatter
      correction algorithm is practical and effective to reduce and correct x-ray
      scatter for a CBCT imaging task.

PMID- 15191311
TI  - Determination of shielding requirements for mammography.
AB  - Shielding requirements for mammography when considerations are to be given to
      attenuation by compression paddle, breast tissue, grid and image receptor
      (intervening materials) has been investigated. By matching of the attenuation and
      hardening properties, comparisons are made between shielding afforded by breast
      tissue materials (water, Lucite and 50%-50% adipose-glandular tissue) and some
      materials considered for shielding diagnostic x-ray beams, namely lead, steel and
      gypsum wallboard. Results show that significant differences exist between the
      thickness required to produce equal attenuation and that required to produce
      equal hardening of a given incident beam. While attenuation equivalent thickness
      produces equal exposure, it does not produce equal hardening. For shielding
      purposes, equivalence in exposure reduction without equivalence in penetrating
      power of an emerging beam does not amount to equivalence in shielding affordable
      by two different materials. Presented are models and results of sample
      calculations of additional shielding requirements apart from that provided by
      intervening materials. The shielding requirements for the integrated beam
      emerging from intervening materials are different from those for the integrated
      beam emerging from materials (lead/steel/gypsum wallboard) with attenuation
      equivalent thicknesses of these intervening materials.

PMID- 15191312
TI  - Dose perturbation induced by radiographic contrast inside brachytherapy balloon
      applicators.
AB  - Phantom measurements and Monte Carlo calculations have been performed for the
      purpose of characterizing the dose perturbation caused by radiographic contrast
      inside the MammoSite breast brachytherapy applicator. Specifically, the dose
      perturbation is quantified as a heterogeneity correction factor (HCF) for various
      balloon radii and contrast concentration levels. The dose perturbation is larger
      for larger balloon radii and higher contrast concentrations. Based on a validated
      Monte Carlo simulation, the calculated HCF values are 0.99 for a 2 cm radius
      balloon and 0.98 for a 3 cm radius balloon at 6% contrast concentration levels,
      and 0.89 and 0.87 for 2 and 3 cm radius balloons, respectively, at 100% contrast
      concentrations. For a typical implanted balloon radius of 2.4 cm, the HCF values
      decrease from 0.99 at 6% contrast concentration to 0.90 at 100% contrast
      concentration. For balloons implanted in patients at our institution, the mean
      HCF is 0.99, corresponding to a dose reduction of approximately 1%. The contrast
      effect results in a systematic reduction in the delivered dose, therefore the
      minimal amount of radiographic contrast necessary should be used.

PMID- 15191313
TI  - Modeling scintillator-photodiodes as detectors for megavoltage CT.
AB  - The use of cadmium tungstate (CdWO4) and cesium iodide [CsI(Tl)] scintillation
      detectors is studied in megavoltage computed tomography (MVCT). A model
      describing the signal acquired from a scintillation detector has been developed
      which contains two steps: (1) the calculation of the energy deposited in the
      crystal due to MeV photons using the EGSnrc Monte Carlo code; and (2) the
      transport of the optical photons generated in the crystal voxels to photodiodes
      using the optical Monte Carlo code DETECT2000. The measured detector signals in
      single CdWO4 and CsI(Tl) scintillation crystals of base 0.275 x 0.8 cm2 and
      heights 0.4, 1, 1.2, 1.6 and 2 cm were, generally, in good agreement with the
      signals calculated with the model. A prototype detector array which contains 8
      CdWO4 crystals, each 0.275 x 0.8 x 1 cm3, in contact with a 16-element array of
      photodiodes was built. The measured attenuation of a Cobalt-60 beam as a function
      of solid water thickness behaves linearly. The frequency dependent modulation
      transfer function [MTF(f)], noise power spectrum [NPS(f)], and detective quantum
      efficiency [DQE(f)] were measured for 1.25 MeV photons (in a Cobalt-60 beam). For
      6 MV photons, only the MTF(f) was measured from a linear accelerator, where large
      pulse-to-pulse fluctuations in the output of the linear accelerator did not allow
      the measurement of the NPS(f). A two-step Monte Carlo simulation was used to
      model the detector's MTF(f), NPS(f) and DQE(f). The DQE(0) of the detector array
      was found to be 26% and 19% for 1.25 MeV and 6 MV photons, respectively. For 1.25
      MeV photons, the maximum discrepancies between the measured and modeled MTF(f),
      relative NPS(f) and the DQE(f) were found to be 1.5%, 1.2%, and 1.9%,
      respectively. For the 6 MV beam, the maximum discrepancy between the modeled and
      the measured MTF(f) was found to be 2.5%. The modeling is sufficiently accurate
      for designing appropriate detectors for MVCT.

PMID- 15191315
TI  - GAFChromic film dosimetry with a flatbed color scanner for Leksell Gamma Knife
      therapy.
AB  - GAFChromic films MD-55-2 have recently been established widely in industrial,
      scientific, and medical applications as radiation dosimeters. We applied these
      films to the dosimetry for Leksell Gamma Knife therapy. We used a flatbed image
      scanner to take digital images of irradiated MD-55-2, and the data were converted
      to Red, Green and Blue pixel values. The absorbed dose, as derived from the
      response curve of the Red pixel value, was consistent with the Leksell Gamma Plan
      dose planning system, for exposures using collimator sizes, 4 mm, 8 mm, and 14
      mm. However, the maximum dose in the exposure of the 18 mm collimator was
      measured to be about 5% smaller than Gamma Plan due to the density effect of the
      compound material in the head phantom.

PMID- 15191314
TI  - Efficient particle transport simulation through beam modulating devices for Monte
      Carlo treatment planning.
AB  - For Monte Carlo treatment planning it is essential to model efficiently patient
      dependent beam modifying devices, e.g., Multi-Leaf Collimators (MLC). Therefore a
      Monte Carlo geometry tracking procedure is presented allowing the simulation of
      photon and electron transport through these devices within short calculation
      time. The tracking procedure is based on elemental regions, on surfaces (mainly
      planes) to separate the regions as well as on bit patterns and bit masks to
      identify the regions. Photon cross sections for photoelectric absorption, Compton
      scattering and pair production as well as electron stopping powers and ranges are
      provided by the Physical Reference Data of the National Institute of Standards
      and Technology (NIST). The tracking procedure is implemented in c + + with object
      oriented design based on c + + class hierarchies and inheritance. Using the
      geometry technique, several MLC models are constructed. Some of them take into
      account tongue-and-groove effects as well as curved leaf ends. The models are
      integrated into the Monte Carlo dose calculation engine XVMC for treatment
      planning. The system is tested by comparing different MLC implementations and by
      verification with measurement.

PMID- 15191316
TI  - A new algorithm for determining collimator angles that favor efficiency in MLC
      based IMRT delivery.
AB  - A new algorithm to determine collimator angles that favor delivery efficiency of
      intensity modulated radiotherapy plans was developed. It was found that the
      number of segments and monitor units (MUs) were largely reduced with the set of
      collimator angles determined with the new algorithm without compromising plan
      quality. The improvement of delivery efficiency using the new algorithm depends
      on the size and shape of the target(s), the number of modulation levels, and the
      type of leaf-sequencing algorithm. In a typical prostate case, when a sweeping
      leaf-sequencer is used for Varian 120 leaf (0.5 x 0.5 cm2 beamlet), 80 leaf (1 x
      1 cm2 beamlet) and Elekta 40 leaf (1 x 1 cm2 beamlet), the number of segments was
      reduced by 42%, 29%, and 5%, respectively. The number of MUs was reduced by 41%,
      35%, and 10%. For the Siemens MLC (IMFAST leaf sequencer, 1 x 1 cm2 beamlet) the
      segment reduction was 32% and the MU reduction was 14%. Comparison of the plans
      using the new and Brahme algorithms, in terms of target conformity index and dose
      volume histogram of the organs at risk, showed that the quality of the plans
      using the new algorithm was uncompromised. Similar results were obtained for a
      set of head and neck treatment plans.

PMID- 15191317
TI  - Fractional scan algorithms for low-dose perfusion CT.
AB  - One of the key considerations in CT perfusion is the X-ray dose received by the
      patient, since cine acquisition mode is typically used in which repeated x-ray
      exposure occurs at the same anatomical location. In this technical note, we
      propose a new approach for dose reduction in which the X-ray tube current is
      maintained and the number of projection views is reduced per gantry rotation. A
      projection interpolation algorithm and an image prediction algorithm are
      developed to address the incompleteness of such projection data. Both algorithms
      utilize a priori knowledge that the contrast-uptake in perfusion images is
      gradual and predictable. As a result, excellent perfusion images can be
      reconstructed at a fraction of the nominal radiation dose.

PMID- 15191318
TI  - Solid-state fluoroscopic imager for high-resolution angiography: parallel
      cascaded linear systems analysis.
AB  - Cascaded linear systems based modeling techniques have been used in the past to
      predict important system parameters that have a direct impact on image quality.
      Such models are also useful in optimizing system parameters to improve image
      quality. In this work, detailed analysis of a solid-state fluoroscopic imaging
      system intended for high-resolution angiography is presented with the use of such
      a model. The imaging system analyzed through this model uses four 8 x 8 cm three
      side buttable interlined charge-coupled devices (CCDs) specifically designed for
      high-resolution angiography and tiled in a seamless fashion to achieve a field of
      view (FOV) of 16 x 16 cm. Larger FOVs can be achieved by tiling more CCDs in a
      similar manner. The system employs a CsI:Tl scintillator coupled to the CCDs by
      straight (nontapering) fiberoptics and can potentially be operated in 78, 156, or
      234 microm pixel pitch modes. The system parameters analyzed through this model
      include presampling modulation transfer function, noise power spectrum, and
      detective quantum efficiency (DQE). The results of the simulations performed
      indicate that DQE(0) in excess of 0.6 is achievable, with the imager operating at
      156 microm pixel pitch, 30 frames/s, and employing a 450-microm-thick CsI:Tl
      scintillator, even at a low fluoroscopic exposure rate of 1 microR/frame.
      Further, at a nominal fluoroscopic exposure rate of 2.5 microR/frame there was no
      noticeable degradation of the DQE even at the 78 microm pixel pitch mode
      suggesting that it is feasible to perform high-resolution angiography hitherto
      unattainable in clinical practice.

PMID- 15191319
TI  - Dosimetric characteristics of the Novoste Beta-Cath 90Sr/Y source trains at
      submillimeter distances.
AB  - Measurements were performed on the 30, 40, and 60 mm 90Sr/Y beta-emitter source
      trains used in the Novoste Beta-Cath system to determine their dosimetric
      characteristics at submillimeter distances and provide the necessary TG-60
      parameters for mapping their dose distributions. These measurements were carried
      out in a Solid Water phantom where MD55-2 Gafchromic films were placed in direct
      contact with a 5 French (F) catheter used for the 30 and 60 mm source trains and
      a 3.5F catheter used for thinner 30 and 40 mm source trains. A data set consisted
      of three pieces of Gafchromic film irradiated for periods of 1.5, 5, and 10
      minutes, respectively. This 3-film irradiation technique provided reliable dose
      data at short, intermediate and long distances from a source train. Three data
      sets per source train were collected in this study. For the 30 mm source train
      with a 5F catheter, data were collected with the source axis at proximal (0.41
      mm) and distal (1.19 mm) positions to the film surface in order to investigate
      dosimetric effects due to the off centering of the source train lumen within the
      catheter. Absolute doses were determined by calibrating the Gafchromic film in a
      high-energy electron beam from a radiotherapy accelerator. The absolute dose
      rates at a distance of 2 mm along the source trains transverse axis were found to
      be within 13.7% of the values provided by Novoste. Radial dose functions were
      within 13% compared to 90Sr/Y source train data constructed from Soares' 90Sr/Y
      single seed data and within 17% and 25% compared to Monte Carlo data by Ye et
      al., and Wang et al., respectively. Discrepancies of 33% and 19% were observed at
      short radial distances (< or = 1 mm) between the Novoste Monte Carlo and the 3.5F
      and 5F catheter measured data, respectively. The source off centering data showed
      higher dose contribution from the source train at its distal rather than proximal
      position. Radial dose function comparisons between the Novoste Monte Carlo and
      the measured data, calculated as a function of radial distance from the
      catheter's center showed good agreement (< or = 10%).

PMID- 15191320
TI  - Prostate brachytherapy seed localization by analysis of multiple projections:
      identifying and addressing the seed overlap problem.
AB  - Intraoperative three-dimensional reconstruction of seed locations during prostate
      brachytherapy for purposes of immediate computation of radiation dosimetry is an
      active area of current investigation, including methods which use multiple
      fluoroscopic projections. A simulation study using seed locations extracted from
      clinical CT data was performed; the result showed that on average one quarter of
      the seeds had a projection image overlapping with other seeds. The average
      percentage of non-overlapping seeds for the prostate implants and seed types
      investigated was 74.5% with a range of 56.9%-92.9%. The distribution of seeds in
      different cluster sizes was analyzed as well as the distribution of pixel counts
      of connected components. A statistical classifier was developed to determine the
      number of seed images in a self-connected component in the segmented images. The
      classifier was tested with simulation data, and the error rate was below 2%. A
      method to determine seed image position is also provided. A modified three-film
      technique was used to reconstruct 3-D seed locations. The algorithm allows
      unequal number of seed images for each projection as input while current methods
      require the same number of seed images detected in all projections. An accuracy
      analysis based on angular and positional uncertainty was performed. The
      reconstruction and seed localization algorithms were tested with simulation data,
      and the mean distance error of the reconstructed results was 0.61 mm. A phantom
      study was performed to validate the seed localization method. Three false
      positive seeds, 4.7% of the total, in the reconstruction result were observed in
      this study.

PMID- 15191321
TI  - Classification of mammographic masses using generalized dynamic fuzzy neural
      networks.
AB  - In this article, computer-aided classification of mammographic masses using
      generalized dynamic fuzzy neural networks (GDFNN) is presented. The texture
      parameters, derived from first-order gradient distribution and gray-level co
      occurrence matrices, were computed from the regions of interest. A total of 343
      images containing 180 benign masses and 163 malignant masses from the Digital
      Database for Screening Mammography were analyzed. A fast approach of
      automatically generating fuzzy rules from training samples was implemented to
      classify tumors. This work is novel in that it alleviates the problem of
      requiring a designer to examine all the input-output relationships of a training
      database in order to obtain the most appropriate structure for the classifier in
      a conventional computer-aided diagnosis. In this approach, not only the
      connection weights can be adjusted, but also the structure can be self-adaptive
      during the learning process. By virtue of the automatic generation of the
      classifier by the GDFNN learning algorithm, the area under the receiver-operating
      characteristic curve, Az, attains 0.868 +/- 0.020, which corresponds to a true
      positive fraction of 95.0% at a false positive fraction of 52.8%. The
      corresponding accuracy is 70.0%, the positive predictive value is 62.0%, and the
      negative predictive value is 91.4%.

PMID- 15191322
TI  - Simulation study for thermal dose optimization in ultrasound surgery of the
      breast.
AB  - In this paper the previously published optimization algorithm for thermal dose
      optimization is tested with numerical simulations. The simulations concern the
      thermal dose optimization in ultrasound surgery of the breast. The optimization
      algorithm is extended by setting the inequality constraint approximations to
      temperature in healthy tissue as well as in tumor region. In addition, the
      simulations are accomplished in realistic 3D geometry with varying thermal
      parameters. Another topic of the paper is to show the potential of the
      hemispherical phased array applicator for ultrasound surgery of the breast. With
      such an applicator larger tissue volumes can be treated with shorter time as
      compared to single element transducers. In simulations the geometrical focus of
      the applicator was placed mechanically in the middle of the treatable region. The
      whole tumor region was then scanned electrically by changing the phase of the
      emitted wave from individual elements. The simulations indicate that a feasible
      treatment plan can be achieved. In simulated cases the desired thermal dose was
      achieved for tumors with diameter from 1.5 to 2.4 cm, depending on the position
      of tumor. The maximum temperature limitations of 45 degrees C in healthy region
      and 80 degrees C in tumor region can be maintained in all simulations.

PMID- 15191323
TI  - A meme's eye view of speech-language pathology.
AB  - In this article, the reason why certain terms, labels, and ideas prevail, whereas
      others fail to gain acceptance, will be considered. Borrowing the concept of
      "meme" from the study of evolution of ideas, it will be clear why language-based
      and phonological disorders have less widespread appeal than, for example,
      auditory processing and sensory integration disorders. Discussion will also
      center on why most speech-language pathologists refer to themselves as speech
      therapists or speech pathologists, and why it is more desirable to have dyslexia
      than to have a reading disability. In a meme's eye view, science and logic do not
      always win out because selection favors ideas (memes) that are easy to
      understand, remember, and copy. An unfortunate consequence of these selection
      forces is that successful memes typically provide superficially plausible answers
      for complex questions.

PMID- 15191324
TI  - Digital data collection and analysis: application for clinical practice.
AB  - Technology for digital speech recording and speech analysis is now readily
      available for all clinicians who use a computer. This article discusses some
      advantages of moving from analog to digital recordings and outlines basic
      recording procedures. The purpose of this article is to familiarize speech
      language pathologists with computerized audio files and the benefits of working
      with those sound files as opposed to using analog recordings. This article
      addresses transcription issues and offers practical examples of various
      functions, such as playback, editing sound files, using waveform displays, and
      extracting utterances. An appendix is provided that describes step-by-step how
      digital recording can be done. It also provides some editing examples and a list
      of useful computer programs for audio editing and speech analyses. In addition,
      this article includes suggestions for clinical uses in both the assessment and
      the treatment of various speech and language diorders.

PMID- 15191325
TI  - School-age follow-up of children with childhood apraxia of speech.
AB  - PURPOSE: The primary aim of this study was to examine differences in
      speech/language and written language skills between children with suspected
      childhood apraxia of speech (CAS) and children with other speech-sound disorders
      at school age. METHOD: Ten children (7 males and 3 females) who were clinically
      diagnosed with CAS (CAS group) were followed from the preschool years (ages 4-6)
      to school age (ages 8-10) and were compared with children with isolated speech
      sound disorders (S group; n = 15) and combined speech-sound and language
      disorders (SL group; n = 14). Assessments included measures of articulation,
      diadochokinetic rates, language, reading, and spelling. RESULTS: At follow-up, 8
      of the children with CAS demonstrated improvement in articulation scores, but all
      10 continued to have difficulties in syllable sequencing, nonsense word
      repetition, and language abilities. The children also exhibited comorbid
      disorders of reading and spelling. Group comparisons revealed that the CAS group
      was similar to the SL group, but not the S group during the preschool years. By
      school age, however, the SL group made more positive changes in language skills
      than the CAS group. CLINICAL IMPLICATIONS: These findings suggest that the
      phenotype for CAS changes with age. Language disorders persist in these children
      despite partial resolution of articulation problems. Children with CAS are also
      at risk for reading and spelling problems.

PMID- 15191326
TI  - Performance of elementary-grade African American students on the Gray Oral
      Reading Tests.
AB  - PURPOSE: African American students perform disproportionately more poorly on
      standardized reading assessments than their majority peers. Poor reading
      performances may be related to test biases inherent in standardized reading
      instruments. The purpose of this investigation was to examine the appropriateness
      of the Gray Oral Reading Tests-Third Edition (GORT-3; Wiederholt & Bryant, 1992)
      for assessing the reading abilities of elementary-grade African American
      students. METHOD: Performances of 65 typically developing African American second
      through fifth graders were examined on the GORT-3. RESULTS: African American
      English (AAE) was produced by most students while reading passages from the GORT
      3 that were written in Standard American English (SAE). A scoring correction for
      AAE resulted in a statistical improvement in the performance distributions, but
      this did not appear to be educationally significant. Measures of total feature
      production predicted reading accuracy and rate, but not comprehension. CLINICAL
      IMPLICATIONS: Findings are discussed in terms of the appropriateness of this
      instrument for use by speech-language pathologists as they contribute to
      curricular and classroom placement decisions in schools with large numbers of
      typically developing African American students.

PMID- 15191327
TI  - Narrative discourse in bilingual children: language and task effects.
AB  - PURPOSE: This study investigated the effect of language on Spanish-English
      bilingual children's production of narrative samples elicited in two ways.
      METHOD: Twelve bilingual (Spanish-English-speaking) children ranging in age from
      4;0 (years;months) to 6;11 who were fluent speakers of English as a second
      language produced two narratives--one elicited by using a wordless picture book
      and another by using a static picture. The children produced stories for each
      task in each language, for a total of four stories. For the book task, the story
      complexities were compared across both languages. Stories were scored for
      complexity of story grammar and the inclusion of specific narrative elements.
      Both stories in each language were further analyzed for productivity (total
      words, number of C-units, and mean length of C-unit). The grammaticality
      (proportion of grammatically acceptable C-units) and the proportion of utterances
      influenced by the nontarget language was compared across each language and story
      task. RESULTS: Children produced narratives of equal complexity for the book task
      regardless of language. However, children used more attempts and initiating
      events in Spanish, while producing more consequences in English. The picture task
      yielded mixed results, and these were not compared quantitatively. There were
      differences in the two task conditions with respect to the children's use of
      Spanish-influenced English and English-influenced Spanish. Although children were
      equally productive in both languages, they used proportionally more Spanish
      influenced utterances in the book task. CLINICAL IMPLICATIONS: The results
      demonstrate the importance of considering the test language when eliciting
      narratives from bilingual children and the type of the narrative task for
      eliciting a productive and complex narrative.

PMID- 15191328
TI  - Speech perception benefits of FM and infrared devices to children with hearing
      aids in a typical classroom.
AB  - Children typically learn in classroom environments that have background noise and
      reverberation that interfere with accurate speech perception. Amplification
      technology can enhance the speech perception of students who are hard of hearing.
      PURPOSE: This study used a single-subject alternating treatments design to
      compare the speech recognition abilities of children who are, hard of hearing
      when they were using hearing aids with each of three frequency modulated (FM) or
      infrared devices. METHOD: Eight 9-12-year-olds with mild to severe hearing loss
      repeated Hearing in Noise Test (HINT) sentence lists under controlled conditions
      in a typical kindergarten classroom with a background noise level of +10 dB
      signal-to-noise (S/N) ratio and 1.1 s reverberation time. Participants listened
      to HINT lists using hearing aids alone and hearing aids in combination with three
      types of S/N-enhancing devices that are currently used in mainstream classrooms:
      (a) FM systems linked to personal hearing aids, (b) infrared sound field systems
      with speakers placed throughout the classroom, and (c) desktop personal sound
      field FM systems. RESULTS: The infrared ceiling sound field system did not
      provide benefit beyond that provided by hearing aids alone. Desktop and personal
      FM systems in combination with personal hearing aids provided substantial
      improvements in speech recognition. CLINICAL IMPLICATIONS: This information can
      assist in making S/N-enhancing device decisions for students using hearing aids.
      In a reverberant and noisy classroom setting, classroom sound field devices are
      not beneficial to speech perception for students with hearing aids, whereas
      either personal FM or desktop sound field systems provide listening benefits.

PMID- 15191329
TI  - Print referencing: an emergent literacy enhancement strategy and its clinical
      applications.
AB  - Print referencing is an evidence-based strategy that may be used by speech
      language pathologists and other early childhood specialists to enhance the
      emergent literacy skills of young children. Print referencing is a strategy
      implemented within the context of adult-child shared storybook reading
      interactions, and specifically refers to the use of verbal and nonverbal cues to
      encourage children's attention to and interactions with print. Print referencing
      increases the metalinguistic focus of storybook reading interactions. When print
      referencing is delivered within the children's zone of proximal development,
      clinicians can foster children's movement from dependent to independent mastery
      of key emergent literacy concepts. This clinical exchange provides suggestions
      for using print referencing as a clinical tool, including a theoretical overview
      of this approach and descriptions of clinical targets.

PMID- 15191330
TI  - Treatment of patients with a pituitary adenoma: one clinician's experience.
AB  - The diagnosis and treatment of a patient with a pituitary adenoma or another type
      of pituitary lesion requires a team approach involving the neurosurgeon,
      endocrinologist, primary care physician, and, in some patients, an
      ophthalmologist and radiation therapist. The diagnosis of excessive pituitary
      hormone secretion and/or loss of pituitary function is based on biochemical
      findings and can usually be confirmed by performing blood tests, except for
      patients with suspected Cushing syndrome. The primary treatment of pituitary
      adenomas is resection, except in patients with a prolactin-producing tumor, who
      are most successfully treated medically with a dopamine agonist. In this article
      the author reviews the principles of diagnosis and treatments and offers
      recommendations for ideal patient care.

PMID- 15191331
TI  - Contemporary management of prolactinomas.
AB  - Prolactin-secreting pituitary adenomas--prolactinomas--are the most common type
      of functional pituitary tumor. Treatment of hyperprolactinemia is indicated
      because of the consequences of infertility, gonadal dysfunction, and
      osteoporosis. Making the correct diagnosis is important because the first line of
      therapy is medical management with dopamine agonists. Medical therapy is
      effective in normalizing prolactin levels in more than 90% of patients, but
      longterm treatment may be required in some patients. Transsphenoidal surgery is
      usually indicated in those patients in whom medical therapy fails or cannot be
      tolerated, or in patients who harbor microprolactinomas. In experienced hands, a
      hormonal and oncological cure can be achieved in more than 90% of patients after
      transsphenoidal removal of microprolactinomas with minimal risks. Thus, surgery
      may be an option for microprolactinomas in a young patient who desires
      restoration of fertility and avoidance of long-term medical therapy. The authors
      review the diagnosis and management of prolactinomas, including medical therapy,
      surgical therapy, and stereotactic radiosurgery.

PMID- 15191332
TI  - Pharmacological approach to the treatment of acromegaly.
AB  - The treatment of patients with persistently active acromegaly has been
      facilitated over the past decade by the advent of highly specific and selective
      pharmacological agents. Somatostatin analogs, derived from the native inhibitory
      hormone somatostatin, are available in extended-duration preparations and are
      effective in reducing serum levels of growth hormone (GH) and insulin-like growth
      factor-I (IGF-I) as well as in improving the adverse clinical effects of
      acromegaly. Cabergoline, an agonist with a specificity for the dopamine D-2
      receptor, has been shown to suppress IGF-I levels and induce tumor shrinkage in
      35 and 50% of patients, respectively. The GH receptor antagonists compete with
      naturally occurring GH for binding with the GH receptor. As such, pegvisomant
      normalizes circulating IGF-I levels in 80 to 90% of patients with acromegaly.
      This last line of therapy should be considered for use in patients in whom
      surgery and medical therapy with somatostatin and/or dopamine agonists are either
      ineffective or poorly tolerated.

PMID- 15191333
TI  - The biochemical investigation of Cushing syndrome.
AB  - Cushing syndrome is an insidious illness that warrants an early diagnosis to
      avoid the effects of prolonged hypercortisolism. The variability in the clinical
      features of the disease and the occasional inconsistencies between different
      biochemical tests performed to identify it render the diagnosis challenging. In
      this paper the author discusses the various biochemical tests that are useful for
      the diagnoses of Cushing syndrome and Cushing disease, with an emphasis on the
      respective sensitivities and specificities of these tests. The measurement of
      evening salivary cortisol and the combined low-dose dexamethasone-corticotropin
      releasing hormone stimulation test have improved overall sensitivity and
      specificity in the evaluation of Cushing syndrome and Cushing disease.

PMID- 15191334
TI  - Stereotactic radiosurgery for Cushing disease.
AB  - The most common cause of Cushing syndrome is Cushing disease, in which
      hypercortisolism is produced by a functional adrenocorticotropic hormone
      producing adenoma of the anterior pituitary gland. The common therapies available
      include microsurgical resection, conventional fractionated radiotherapy, and
      stereotactic radiosurgery (SRS). In this article the authors review the
      indications, results, and complications associated with SRS in the treatment of
      Cushing disease. In as many as 90% of patients SRS results in disease remission,
      which is defined as a normal 24-hour urinary free cortisol level and a normal or
      subnormal morning serum cortisol level. Although in most patients who are
      subsequently cured a marked decrease in the serum cortisol level is demonstrated
      within 3 months after treatment, a biochemical cure may be delayed up to 3 years
      in some cases. Complications following SRS for pituitary adenomas are uncommon,
      particularly in patients with microadenomas, which are most commonly seen in
      Cushing disease. The most common complication is hypopituitarism, which occurs in
      up to 50% of patients with a mean latency period of 5 years. Radiation-induced
      optic neuropathy has been reported in less than 2% of cases and induction of a
      secondary neoplasm in less than 1% of cases. For patients with Cushing disease,
      the rate of endocrinological cure following SRS appears to be similar to that
      attained using microsurgical resection. In contrast to surgery, SRS has the
      benefit of being noninvasive and associated with a very low incidence of diabetes
      insipidus, although hypopituitarism may be more common with SRS. With continued
      follow-up patient reviews and additional experience with SRS, it may become
      possible to make more definitive statements regarding SRS as the initial
      treatment for patients with Cushing disease.

PMID- 15191335
TI  - Pituitary tumor apoplexy: characteristics, treatment, and outcomes.
AB  - Pituitary tumor apoplexy is an uncommon event heralded by abrupt onset of severe
      headache, restriction of visual fields, deterioration of visual acuity, and
      weakness of ocular motility frequently coupled with clinical indications of
      decreased endocrine function. Hemorrhage into or necrosis of a preexisting sellar
      mass, usually a pituitary macroadenoma, produces an expansion of sellar contents.
      Compression of adjacent structures elicits the variable expression of symptoms
      referable to displacement of the optic nerves and chiasm and impingement of the
      third, fourth, and sixth cranial nerves. Damage to or destruction of the anterior
      pituitary leads to multiple acute and/or chronic hormone deficiencies in many
      patients. Medical management may be used in rare cases in which the signs and
      symptoms are mild and restricted to meningismus or ophthalmoplegia deemed to be
      stable. In patients with visual or oculomotor lability or an altered level of
      consciousness, expeditious surgical decompression, accomplished most commonly
      through a transsphenoidal approach, should be performed to save life and vision
      and to optimize the chance of regaining or maintaining pituitary function.

PMID- 15191336
TI  - Pituitary carcinoma: a review of the literature.
AB  - Pituitary carcinomas, defined as distant metastases of a pituitary neoplasm, are
      rare; fewer than 140 reports exist in the English literature. The initial
      presenting pituitary tumor is usually a secreting, invasive macroadenoma, with
      adrenocorticotropic hormone (ACTH)--and prolactin (PRL)--secreting tumors being
      the most common. The latency period between the diagnosis of a pituitary tumor
      and the diagnosis of a pituitary carcinoma is 9.5 years for ACTH-producing
      lesions and 4.7 years for PRL-secreting tumors. Survival after documentation of
      metastatic disease is poor; 66% of patients die within 1 year. Treatment options
      include additional surgery, radiotherapy, and chemotherapy, all of which are
      associated with poor results. Future studies will focus on identifying those
      invasive pituitary tumors most likely to metastasize and treating them
      aggressively before they progress to pituitary carcinomas.

PMID- 15191337
TI  - Metastases to the pituitary gland.
AB  - Only 1% of all pituitary surgeries are performed to treat tumors that have
      metastasized to the pituitary gland; however, in certain cases of malignant
      neoplasms pituitary metastases do occur. Breast and lung cancers are the most
      common diseases that metastasize to the pituitary. Breast cancer metastasizes to
      the pituitary especially frequently, with reported rates ranging between 6 and 8%
      of cases. Most pituitary metastases are asymptomatic, with only 7% reported to be
      symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field
      defects, headache/pain, and ophthalmoplegia are the most commonly reported
      symptoms. Diabetes insipidus is especially common in this population, occurring
      in between 29 and 71% of patients who experience symptoms. Differentiation of
      pituitary metastasis from other pituitary tumors based on neuroimaging alone can
      be difficult, although certain features, such as thickening of the pituitary
      stalk, invasion of the cavernous sinus, and sclerosis of the surrounding sella
      turcica, can indicate metastasis to the pituitary gland. Overall,
      neurohypophysial involvement seems to be most prevalent, but breast metastases
      appear to have an affinity for the adenohypophysis. Differentiating metastasis to
      the pituitary gland from bone metastasis to the skull base, which invades the
      sella turcica, can also be difficult. In metastasis to the pituitary gland,
      surrounding sclerosis in the sella turcica is usually minimal compared with
      metastasis to the skull base. Treatment for these tumors is often multimodal and
      includes surgery, radiation therapy, and chemotherapy. Tumor invasiveness can
      make resection difficult. Although surgical series have not shown any significant
      survival benefits given by tumor resection, the patient's quality of life may be
      improved. Survival among these patients is poor with mean survival rates reported
      to range between 6 and 22 months.

PMID- 15191338
TI  - Hyponatremia in the neurosurgical patient: diagnosis and management.
AB  - Hyponatremia is frequently encountered in patients who have undergone
      neurosurgery for intracranial processes. Making an accurate diagnosis between the
      syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral
      salt wasting (CSW) in patients in whom hyponatremia develops is important because
      treatment differs greatly between the conditions. The SIADH is a volume-expanded
      condition, whereas CSW is a volume-contracted state that involves renal loss of
      sodium. Treatment for patients with SIADH is fluid restriction and treatment for
      patients with CSW is generally salt and water replacement. In this review, the
      authors discuss the differential diagnosis of hyponatremia, distinguish SIADH
      from CSW, and highlight the diagnosis and management of hyponatremia, which is
      commonly encountered in patients who have undergone neurosurgery, specifically
      those with traumatic brain injury, aneurysmal subarachnoid hemorrhage, recent
      transsphenoidal surgery for pituitary tumors, and postoperative cranial vault
      reconstruction for craniosynostosis.

PMID- 15191339
TI  - Syndrome of inappropriate secretion of antidiuretic hormone and hyponatremia
      after spinal surgery.
AB  - Hyponatremia caused by an inappropriately high level of antidiuretic hormone
      secretion after spinal surgery is an uncommon and self-limiting phenomenon that
      resolves within 2 or 3 weeks. During the early postoperative period, the
      patient's urine output and serum level of sodium should be monitored closely to
      prevent possible serious complications of the syndrome of inappropriate secretion
      of antidiuretic hormone. Symptoms vary depending on the severity of the
      hyponatremia and can range from mild headache, muscle cramps, nausea, and
      vomiting to convulsions, coma, and death. Treatment options include fluid
      restriction, oral intake of salt, and hypertonic saline. It is important that
      spine surgeons recognize this phenomenon early and treat it appropriately and
      conservatively to prevent possible serious complications.

PMID- 15191340
TI  - Spinal epidural lipomatosis: a review of its causes and recommendations for
      treatment.
AB  - Spinal epidural lipomatosis is most commonly observed in patients receiving long
      term exogenous steroid therapy, but can also be seen in patients with endogenous
      steroid overproduction, obesity, or idiopathic disease. With this condition,
      there is hypertrophy of the epidural adipose tissue, causing a narrowing of the
      spinal canal and compression of neural structures. A majority of patients will
      present with progressive myelopathy, but radicular symptoms are also common.
      Conservative treatment--weaning from steroids or weight loss--can reverse the
      hypertrophy of the adipose tissue and relieve the neural compression. If
      conservative management fails, surgery with decompressive laminectomy is also
      very successful at improving the patient's neurological symptoms.

PMID- 15191341
TI  - Growth hormone replacement for patients with adult onset growth hormone
      deficiency--what have we learned.
AB  - Growth hormone (GH) deficiency is a condition recognized to occur in individuals
      who have had multiple pituitary hormone deficiencies as a result of pathological
      processes or neurosurgical interventions. The indications, benefits, and risks of
      GH replacement therapy will be reviewed with an emphasis on those patients who
      were adults with the deficiency first emerged. The results of this analysis
      indicate that, although a measurable improvement can be detected in the patient's
      quality of life, body composition, and some cardiovascular parameters, the larger
      questions of long-term benefit and patient selection currently remain unanswered.

PMID- 15191342
TI  - A review of neurophysiological testing.
AB  - The rapid advances in the technology of, and accumulation of pertinent data in,
      electrophysiological testing has increased exponentially in the past decade. This
      is attributable to continued advances in computer technology, biomedical
      engineering, and now the coregistration of the electrophysiological data with
      neuroimaging results. Knowledge of normal function and electrophysiological
      response at rest or on stimulation of the central and peripheral nervous systems
      is important to the neurosurgeon. Only by a basic understanding of normal and
      abnormal recordings may diagnoses and localizations be achieved. Intraspinal and
      intracranial surgical procedures are predicated on nontrauma to the neuraxis.
      This can be accomplished by performing electrophysiological testing to monitor
      the function of the spinal and cranial nerves, spinal cord, brainstem, basal
      ganglia, and cerebrum. If the surgeon cannot delineate critical cortex or
      pathways, he or she will be unable to avoid these areas in the patient.

PMID- 15191343
TI  - Thyroid autoimmunity and miscarriage.
AB  - To ascertain the strength of the association between thyroid autoimmunity and
      miscarriage, we performed a meta-analysis of both case-control and longitudinal
      studies performed since 1990 when this association was first described. A clear
      association between the presence of thyroid antibodies and miscarriage was found
      with an odds ratio (OR) of 2.73 (95 % confidence interval (CI), 2.20-3.40) in
      eight case-control and ten longitudinal (OR, 2.30; 95 % CI, 1.80-2.95) studies.
      This association may be explained by a heightened autoimmune state affecting the
      fetal allograft, of which thyroid antibodies are just a marker. Alternatively,
      the association can be partly explained by the slightly higher age of women with
      antibodies compared with those without (mean+/-S.D. age difference, 0.7+/-1.0
      years; P<0.001). A third possibility is mild thyroid failure, as thyroid
      stimulating hormone (TSH) levels in antibody-positive but euthyroid women are
      higher than in antibody-negative women: difference 0.81+/-0.58 mU/l (P=0.005).
      Randomized clinical trials with l-thyroxine (aiming at TSH values between 0.4 and
      2.0 mU/l) and with selenium (to decrease antibodies against thyroid peroxidase)
      are clearly needed to elucidate further the nature of this association.

PMID- 15191344
TI  - Myocardial contractility and total arterial stiffness in patients with overt
      hyperthyroidism: acute effects of beta1-adrenergic blockade.
AB  - OBJECTIVES: To ascertain whether myocardial contractility and total arterial
      stiffness are significantly altered in human thyrotoxicosis, and to what extent
      they are affected by acute beta(1)-adrenergic blockade. METHODS: Doppler
      echocardiography was used to assess left ventricular (LV) structure and function,
      hemodynamics and total arterial stiffness in untreated overt hyperthyroid
      patients before and 2 h after 5 mg bisoprolol given orally compared with age- and
      sex-matched healthy euthyroid controls. RESULTS: Compared with controls,
      untreated patients (n=20) had a higher heart rate (HR) and LV stroke index (SI),
      which were associated with higher pulse pressure (PP), larger LV end-diastolic
      volume index (EDVI, an index of preload,+11%, P<0.05), marginally increased
      stress-corrected LV midwall fractional shortening (MWS, an index of myocardial
      contractility,+5%; P=0.066), and shorter isovolumic relaxation time (IVRT). These
      changes resulted in a higher cardiac index (CI) and a lower systemic vascular
      resistance (SVR), which were associated with fairly normal mean blood pressure
      (BP) but higher PP/stroke volume (an index of total arterial stiffness,+29%;
      P<0.01). After bisoprolol, compared with controls, the randomly treated patients
      (n=10) had comparable HR but additionally increased SI; PP remained enhanced,
      EDVI was further enlarged (+26%, P<0.001), stress-corrected MWS was substantially
      unchanged, and IVRT remained shorter. Overall, these effects attenuated the high
      output state, which was associated with normalization of PP/stroke volume without
      changes of mean BP. CONCLUSIONS: In human overt hyperthyroidism, myocardial
      contractility does not play a major role in increasing LV performance, which is
      instead predominantly sustained by increased preload with enhanced LV diastolic
      function. In addition, human thyrotoxicosis is associated with increased total
      arterial stiffness despite fairly normal mean BP. In this scenario, acute beta(1)
      adrenergic blockade blunts the cardiovascular hyperkinesia predominantly by
      slowing HR - a process that is associated with normalization of total arterial
      stiffness.

PMID- 15191345
TI  - Clinical, hormonal and magnetic resonance imaging (MRI) predictors of
      transsphenoidal surgery outcome in acromegaly.
AB  - OBJECTIVE: Progress in the treatment of acromegaly with drugs is making it
      necessary to improve the prediction of the outcome of transsphenoidal surgery.
      DESIGN: We evaluated clinical, hormonal and radiologic predictors based on
      magnetic resonance imaging (MRI) of surgical outcome in patients with acromegaly.
      METHODS: This retrospective analysis included 125 consecutive patients
      investigated for acromegaly in a single endocrine unit since the use of MRI
      imaging began (1988). Eighty-three of these patients (50 women) underwent
      transsphenoidal surgery and were investigated before and after surgery in our
      department. A neuroradiologist unaware of the surgical outcome analyzed the
      results of pituitary gland MRI investigations. RESULTS: Surgical remission rates
      were 44%, 43%, 61% and 59% based on mean basal GH concentration under 2.5
      microg/l, GH/oral glucose tolerance test (OGTT) of <1 microg/l, GH/OGTT of <2
      microg/l or IGF-I concentration normal for age and sex respectively. In
      univariate logistic regression analysis with IGF-I concentration used as the
      criterion for cure, young age (P<0.001), high IGF-I concentration before surgery
      (P<0.01), high basal GH concentration before surgery (P<0.02), and high nadir
      GH/OGTT before surgery (P=0.03) were predictors of poor outcome. The following
      results in standardized MRI analysis were associated with a higher probability of
      not being cured: adenoma greater than 15 mm in diameter (P<0.02), infrasellar
      extension (P=0.04), suprasellar extension (P<0.005) and invasive adenoma (0.02)
      according to MRI staging. MRI analysis of the intracavernous extension showed
      that stages above B2 (possible sinus extension with sign of invasion of the space
      below the carotid artery) were associated with a lower probability of
      postoperative normal GH plasma levels (P=0.01). In multivariate analysis, age,
      preoperative hormonal levels and adenoma size remained the major predictors of
      surgical outcome. CONCLUSIONS: This report provides the first evidence that
      detailed MRI analysis of adenoma size, location and potential invasion, together
      with preoperative clinical and hormonal parameters, can be used for the
      prediction of hormonal outcome after transsphenoidal surgery for acromegaly.

PMID- 15191346
TI  - Gene expression of the GH receptor in subcutaneous and intraabdominal fat in
      healthy females: relationship to GH-binding protein.
AB  - OBJECTIVE: Circulating GH-binding protein (GHBP) is produced by proteolytical
      cleavage of the extracellular part of the GH receptor (GHR) and is positively
      correlated to the amount of body fat. To test the hypothesis that adipose tissue
      may contribute to the production of circulating GHBP, we compared gene expression
      of two GHR isoforms in adipose tissue with serum GHBP concentrations in healthy
      females. DESIGN: Twenty-two healthy females undergoing surgery for benign
      gynecological conditions were included in the study. METHODS: During surgery,
      s.c. and intraabdominal fat biopsy samples were taken. Gene expression of the
      full-length GHR and a truncated GHR (GHRtr) was assessed by RT-PCR relative to
      the expression of beta-actin. RESULTS: The full-length GHR was expressed to a
      much higher level than GHRtr in both tissues. The levels of both GHR and GHRtr
      mRNA were similar in intraabdominal and s.c. adipose tissues. Surprisingly,
      concentrations of circulating GHBP were negatively correlated to the levels of
      mRNA transcripts of both the full-length GHR and GHRtr in intraabdominal fat.
      Whole body resistance (as a measure of lean body mass) was positively correlated
      to mRNA levels for both GHRs in intraabdominal fat. CONCLUSIONS: (i) The full
      length GHR is expressed to a much higher level than GHRtr in s.c. as well as
      visceral abdominal fat; (ii) the observation of a significant correlation between
      GHR expression and GHBP levels further emphasizes the link between adipose tissue
      and GHBP; (iii) it remains, however, to be demonstrated whether circulating GHBP
      is produced to a significant degree by adipose tissue.

PMID- 15191347
TI  - Modulation of basal glucose metabolism and insulin sensitivity by growth hormone
      and free fatty acids during short-term fasting.
AB  - BACKGROUND AND AIMS: The metabolic response to fasting involves an increase in
      circulating levels of growth hormone (GH) and free fatty acids, and resistance to
      insulin's actions on glucose metabolism. Stimulation of lipolysis and insulin
      resistance are well-described effects of GH. The present study was designed to
      test the degree to which the insulin antagonistic effects of GH on glucose
      metabolism are mediated through stimulation of lipolysis during fasting. METHODS:
      Seven normal subjects were examined on three occasions during a 40-h fast with
      infusion of somatostatin, insulin and glucagon for the final 18 h: (expt. i) with
      GH replacement, (expt. ii) with GH replacement and antilipolysis with acipimox,
      and (expt. iii) without GH and with antilipolysis. RESULTS: Basal glucose
      turnover was significantly reduced by addition of acipimox (rate of disappearance
      (Rd) glucose (mg/kg/min): 1.91+/-0.08 (expt. i), 1.69+/-0.05 (expt. ii), 1.61+/
      0.08 (expt. iii); P<0.01), whereas insulin-stimulated glucose uptake was
      significantly increased (glucose infusion rate (M-value) (mg/kg/min): 1.66+/-0.22
      (expt. i), 2.47+/-0.10 (expt. ii), 2.00+/-0.31 (expt. iii); P<0.05). Addition of
      GH during inhibition of lipolysis failed to affect basal and insulin-stimulated
      glucose metabolism significantly. CONCLUSION: Thus, the present data provide
      strong evidence that the insulin antagonistic effects of GH on fasting glucose
      metabolism are causally linked to concomitant stimulation of lipolysis.

PMID- 15191348
TI  - 18F-fluorodeoxyglucose positron emission tomography as a diagnostic tool for
      malignancy of adrenocortical tumours? Preliminary results in 13 consecutive
      patients.
AB  - DESIGN: This study is a preliminary report on 18F-fluorodeoxyglucose (18F-FDG)
      uptake for the characterization of hypersecretory or non-hypersecretory
      adrenocortical masses in patients without known neoplastic disease, thereby
      minimizing the presence of adrenal metastases, and without phaeochromocytoma, in
      comparison with computed tomography (CT) scanning and with iodocholesterol
      scintigraphy. METHODS: Thirteen consecutive patients with an adrenal mass
      scheduled to have surgery, underwent hormonal exploration, a CT scan for tumour
      size measurement and an 18F-FDG positron emission tomography scan. Eleven of
      these patients also had unenhanced density measurement at CT scan and
      iodocholesterol scintigraphy. RESULTS: CT-scanned adrenal masses ranged in size
      from 2.2 to 10 cm; attenuation value was <10 Hounsfield units (HUs) in two cases
      and >10 HU in nine. All benign lesions demonstrated iodocholesterol uptake. In
      the case of malignant tumours, results were non-homogeneous: no uptake, uptake
      and non-informative scintigraphy. All patients with an adrenocortical carcinoma
      had positive adrenal 18F-FDG uptake (n=3), one had a liver metastasis with
      positive 18F-FDG uptake, one showed 18F-FDG uptake in an adrenal metastasis from
      an unknown primary kidney tumour. All patients with a benign adrenocortical
      lesion had negative 18F-FDG uptake (n=9). Patients' lesions were hypersecretory
      (n=5), or non-hypersecretory (n=8), regardless of the pathology. CONCLUSION: This
      short preliminary study indicates that 18F-FDG gave a correct classification of
      tissue characterization with accurate identification of malignant lesions, as
      well as the disease stage (metastasis or primary). These promising preliminary
      results on adrenocortical lesions, seldom studied with 18F-FDG, are to be
      confirmed in larger series.

PMID- 15191349
TI  - The prevalence of 4G5G polymorphism of plasminogen activator inhibitor-1 (PAI-1)
      gene in polycystic ovarian syndrome and its association with plasma PAI-1 levels.
AB  - OBJECTIVE: To investigate the prevalence of 4G5G polymorphism of plasminogen
      activator inhibitor-1 (PAI-1) gene in polycystic ovary syndrome (PCOS) and its
      functional significance. DESIGN: Case-control study. METHODS: We studied 98
      patients and 64 controls. Body mass index (BMI) and waist-to-hip (WHR) ratio were
      determined. Blood samples were obtained for DNA analysis. PAI-1 plasma levels,
      serum total testosterone, fasting insulin and fasting glucose were measured and
      the glucose-to-insulin ratio was estimated in all subjects. RESULTS: There was a
      statistically significant difference in the distribution of PAI-1 gene variations
      among the groups. The PCOS group had significantly higher 4G/4G and 4G/5G
      combinations than the control group, whereas there were significantly less 5G/5G.
      Among the PCOS women, 39.8% had the genotype 4G/4G, 39.8% 4G/5G and 20.4% 5G/5G.
      From the control group, 20.3% had genotype 4G/4G, 28.1% 4G/5G and 51.6% 5G/5G. In
      the 4G/4G genotype subgroup 75% were PCOS and 25% were controls, in the 4G/5G
      were 68.42% and 31.58% and in the 5G/5G were 31.58% and 62.26% respectively. The
      population of PCOS women had significantly higher PAI-1 levels, WHR, total
      testosterone, and fasting glucose than the population of controls. CONCLUSIONS:
      1) The genotypic subtypes 4G/4G and 4G/5G, in PCOS, were present with a
      statistically higher frequency compared with controls. 2) PCOS women have higher
      levels of PAI-1 compared with the control group. 3) The presence of the 4G allele
      in PAI-1 promoter region of the gene further increases the PAI-1 levels.

PMID- 15191350
TI  - Quantitave and qualitative changes in vascular endothelial growth factor gene
      expression in glomeruli of patients with type 2 diabetes.
AB  - OBJECTIVE: Vascular endothelial growth factor (VEGF) exists in three main splice
      variants, characterized by 121, 165 and 189 amino acids (VEGF 121, VEGF 165 and
      VEGF 189) and acts via two specific receptors: VEGF-R1 or Flt-1 and VEGF-R2 or
      KDR. VEGF plays an important role in the pathogenesis of diabetic retinopathy.
      This study examined the relationship between VEGF and its isoforms and the
      severity of diabetic nephropathy in type 2 diabetes. DESIGN: We evaluated the
      glomerular gene expression of VEGF and its receptors and studied the
      relationships with renal functional and structural parameters in type 2 diabetic
      patients. METHODS: Glomeruli from 17 kidney biopsies were microdissected; 14 out
      of 17 biopsies were also subjected to electron microscopic morphometric analysis
      to estimate glomerular structural parameters. VEGF mRNA was studied by
      comparative kinetic RT-PCR and real-time RT-PCR in order to identify the three
      different isoforms and to quantify VEGF, VEGF-R1 and VEGF-R2 mRNA levels.
      RESULTS: (i) Glomerular VEGF mRNA levels were inversely related to albumin
      excretion rate (r=-0.66, P=0.004); (ii) both the degree of mesangial and
      mesangial matrix expansion were inversely related to VEGF 165 mRNA levels (r=
      0.73, P=0.005 and r=-0.64, P=0.017), and directly to VEGF 121 mRNA levels
      (r=0.74, P=0.003 and r=0.73, P=0.004); and (iii) VEGF and VEGF-R2 mRNA levels
      were directly related (r=0.62, P=0.033). CONCLUSIONS: These findings suggested
      that quantitative and qualitative changes in VEGF expression are present in type
      2 diabetic patients with nephropathy and might be involved in the pathogenesis
      and progression of diabetic glomerulopathy.

PMID- 15191351
TI  - Cyclin E correlates with malignancy and adverse prognosis in adrenocortical
      tumors.
AB  - OBJECTIVE: In many cases, the prognosis of an adrenocortical tumor cannot be
      determined from pathologic findings alone. We investigated cyclin E levels as a
      potential marker. METHODS: We studied 57 tumors by immunohistochemical staining
      with an anticyclin E antibody. We also evaluated clinical and pathologic factors
      (McFarlane staging and Weiss score) and previously validated genetic markers
      (17p13 loss of heterozygosity, 11p15 uniparental disomy, and overexpression of
      the IGF-II gene) for these tumors. Disease-free survival was estimated in 49
      patients who underwent curative surgery. RESULTS: Cyclin E overproduction (> or
      =5%) was associated with the malignant phenotype and was strongly correlated with
      tumor size (P<0.0001), Weiss score (P<0.0001) and the presence of genetic
      abnormalities in tumors (P<0.001) (nonparametric Wilcoxon test and Fisher's exact
      test). Within a median follow-up of 44.1 months, seven patients exhibited a
      recurrence and two patients died from other causes. Cyclin E overproduction was
      significantly associated with shorter disease-free survival in univariate
      analysis (P=0.016; RR: 7.6), as were histologic grade (Weiss score > or =4;
      P=0.0006; RR: 18), 17p13 LOH (P=0.014, RR: 14.9), 11p15 UPD (P=0.003, RR: 11.8)
      and overexpression of the IGF-II gene (P=0.015, RR: 13.8). CONCLUSION: This study
      shows that cyclin E overproduction is of adverse prognostic significance in
      adrenocortical tumors.

PMID- 15191352
TI  - Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous
      mutation of T3 receptor gene.
AB  - Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually
      inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid
      but can occasionally present with signs and symptoms of thyrotoxicosis or rarely
      with hypothyroidism. Affected individuals are usually heterozygous for mutations
      in the thyroid hormone receptor beta gene (TR-beta). We present a patient with
      RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single
      nucleotide substitution I280S (1123T-->G) was present either on both alleles or
      in a hemizygous form with complete deletion of the second allele. The I280S
      mutation was recently reported in a heterozygous patient. The severe phenotype
      with seriously impaired intellectual development, hyperkinetic behaviour,
      tachycardia, hearing and visual impairment is probably due to the dominant
      negative effect of the I280S mutant protein and the absence of any functional TR
      beta.

PMID- 15191353
TI  - An N-terminal WT1 mutation (P181S) in an XY patient with ambiguous genitalia,
      normal testosterone production, absence of kidney disease and associated heart
      defect: enlarging the phenotypic spectrum of WT1 defects.
AB  - OBJECTIVE: This study reports the clinical and molecular data of an XY patient
      with a very unusual phenotype due to a Wilms' tumor-suppressor (WT1) gene
      mutation. The genotype-phenotype relationship of different WT1 mutations is then
      discussed. PATIENT: The patient presented at birth with micropenis, severe
      hypospadias and cryptorchidism. Normal androgen production and an absence of
      clinical response to a testosterone treatment trial suggested partial androgen
      resistance. Eventually, female sex of rearing was chosen. At the beginning of
      puberty, normal male androgen production occurred, and subsequent gonadectomy did
      not show gonadal dysgenesis. It is notable that the patient, now 20 years of age,
      has not developed kidney disease. In addition to the genital malformation, the
      patient displayed an associated congenital heart defect, consisting of a
      coarctation of the aorta and a patent ductus arteriosis (PDA). RESULTS: No
      mutations were detected in the androgen receptor or 5alpha-reductase genes.
      Direct sequencing of the WT1 gene identified a heterozygous proline to serine
      substitution at position 181 (P181S). The same heterozygous mutation was found in
      the mother. Interestingly, the mother shows no signs of kidney disease at her
      present age of 49. CONCLUSION: This is the first germline missense mutation in
      the N-terminal part of WT1 identified in a patient with the very particular
      phenotype of ambiguous genitalia with absence of gonadal dysgenesis and kidney
      disease. The possible molecular mechanisms leading to the patient's phenotype are
      considered. The high frequency of PDA in newborns and the absence of heart
      abnormalities in XX females carrying the P181S mutation, however, suggest that
      the heart defect was most likely a coincidental association. This case enlarges
      the clinical spectrum of WT1 defects and may provide new insights into the
      complex functions of WT1 in genital and kidney development.

PMID- 15191354
TI  - Transient chylomicronemia preceding the onset of insulin-dependent diabetes in a
      young girl with no humoral markers of islet autoimmunity.
AB  - OBJECTIVE: We investigated the possible causes of diabetes in a young child who
      presented with hyperglycemia associated with severe hypertriglyceridemia (>166
      mmol/l), hypercholesterolemia (>38 mmol/l) and fasting chilomicrons. RESULTS: The
      patient did not have any of the HLA and autoantibody markers typically associated
      with type 1 diabetes. A glucose clamp failed to demonstrate insulin resistance
      (peripheral glucose utilization rate (M)=4.3 mg/kg per min) and there was no
      family history of type 2 diabetes or maturity onset diabetes in youth. Both
      fasting and stimulated C-peptide levels, including those in response to i.v.
      glucagon, were below the limit of detection. This is consistent with loss of beta
      cell function. The family history did not reveal the existence of relatives with
      lipid abnormalities, coronary heart disease, and pancreatitis. We did not find
      any abnormality of plasma apoCII, lipoproteinlipase and hepatic lipase
      activities. The patients had a epsilon3/epsilon3 apoE genotype and she rapidly
      cleared an oral fat load after normalization of plasma lipids. CONCLUSIONS: The
      mild hyperglycemia seems an unlikely explanation for both the severe
      hypertriglyceridemia and chylomicronemia. A more plausible explanation is
      transient lipoproteinlipase deficiency. This rare condition, occasionally
      associated with a high-fat diet, could have caused the rapid and dramatic
      hypertriglyceridemia observed in this patient, which in turn might have led to
      the beta-cell destruction by direct lipid toxicity.

PMID- 15191355
TI  - Multiple neuroendocrine tumors of the pancreas associated with pancreas divisum.
AB  - Pancreas divisum is the most common congenital anomaly of the pancreas,
      characterized by missing fusion of the ventral and dorsal pancreatic duct. It may
      cause pancreatitis, but is rarely associated with malignancy.We report herein for
      the first time the rare association, in a symptomless patient, of multiple
      neuroendocrine tumors of the pancreas with pancreas divisum and a failure of the
      exocrine system. Diagnosis was made incidentally by routine abdominal ultrasound.
      Laboratory examinations and a fine-needle aspiration revealed the neuroendocrine
      nature of the tumor. Spleen-preserving left pancreas resection was performed,
      with evidence of multiple neuroendocrine tumors of the pancreas with the typical
      histological characteristics. Eighteen months later the patient is still free of
      tumor burden.

PMID- 15191356
TI  - Selenium has a protective role in caspase-3-dependent apoptosis induced by H2O2
      in primary cultured pig thyrocytes.
AB  - OBJECTIVE: Hydrogen peroxide (H2O2), necessary for thyroid hormonogenesis, is
      produced at the apical surface of the thyroid follicular epithelium. Excess H2O2
      is potentially cytotoxic and may contribute to the development of hypothyroidism,
      e.g. in severe selenium deficiency. Yet it is unclear how H2O2 contributes to
      thyroid cell death. DESIGN AND METHODS: H2O2-induced apoptosis and necrosis were
      studied in primary cultured pig thyroid cells. Glutathione peroxidase (GPx)
      activity was altered by culture in low serum with or without selenite
      substitution. Apoptosis was evaluated by spectrofluorometric measurement of
      caspase-3-specific substrate cleavage, and by analysis of DNA fragmentation by
      agarose gel electrophoresis. Necrosis was detected by 51Cr release from
      prelabeled cells. RESULTS: Exogenous H2O2 dose-dependently (100-400 micromol/l)
      activated caspase-3 within 3-12 h, and DNA degradation was observed after 24 h.
      The potency of H2O2 to induce apoptosis was low compared with that of
      staurosporine, a strong proapoptotic agent. H2O2-treated cells with reduced GPx
      activity showed increased caspase-3 activation. Incubation of serum-starved cells
      with selenite (10-100 nmol/l) normalized the GPx activity and reduced the
      activation of caspase-3 by H2O2. High H2O2 concentrations (400-800 micromol/l)
      were required to obtain necrosis. The H2O2-induced necrosis was exaggerated by
      both low GPx activity and catalase inhibition. CONCLUSIONS: Cytotoxic effects of
      H2O2 on thyroid cells include caspase-3-dependent apoptosis that occurs at H2O2
      concentrations insufficient to induce necrosis. Selenium deficiency aggravates
      the apoptotic response, probably due to impaired capacity of GPx to degrade H2O2.

PMID- 15191357
TI  - TSH/cAMP up-regulate sarco/endoplasmic reticulum Ca2+-ATPases expression and
      activity in PC Cl3 thyroid cells.
AB  - OBJECTIVE: We recently reported that the sarco/endoplasmic reticulum Ca2+-ATPase
      (SERCA) 2b is the SERCA form preferentially expressed in rat thyroid. Moreover,
      SERCA2b expression dramatically decreases in virally transformed, highly
      tumorigenic, PC Cl3 thyroid cells. These results suggest that, in the thyroid,
      SERCA2b, in addition to its housekeeping role, is linked to differentiation and
      is a regulated gene. We therefore sought to study the effect of TSH, the main
      regulator of thyroid function, on SERCA2b expression and activity. METHODS: PC
      Cl3 cells were hormone starved in low-serum medium and stimulated for long (48 h)
      or short (1, 2 and 4 h) times. SERCA2b expression and activity were evaluated by
      Northern and Western blots, Ca2+-ATPase activity and Ca2+ store content. RESULTS:
      In PC Cl3 cells, SERCA2b mRNA and protein were induced twofold by a 48-h long
      treatment with TSH. Long-term elevation (48 h) of intracellular cAMP levels, by
      forskolin or 8-Br-cAMP, had similar effects on SERCA2b mRNA and protein. We also
      measured Ca2+-ATPase activity and Ca2+ store content. Both long (48 h) and short
      (0.5-1 h) treatments with TSH, forskolin or 8-Br-cAMP induced a marked increase
      of SERCA2b activity. This effect was completely abolished by H89, a specific
      inhibitor of cAMP-dependent protein kinase A (PKA). TSH and 8-Br-cAMP increased
      Ca2+ store content after both long (48 h) and short (1-2 h) treatments.
      CONCLUSIONS: These data suggested that TSH/cAMP acts as an important regulator of
      both SERCA2b expression and activity in the thyroid system, through PKA
      activation.

PMID- 15191358
TI  - PPARgamma inhibits GH synthesis and secretion and increases apoptosis of
      pituitary GH-secreting adenomas.
AB  - OBJECTIVE: The objective of the study was to evaluate the expression and
      functional activity of Peroxisome proliferator-activated receptor (PPAR) gamma in
      pituitary adenomas from 14 consecutive acromegalic patients and to establish its
      role in apoptosis. SUBJECTS AND METHODS: Fourteen consecutive acromegalic
      patients were enrolled in the study. Wistar-Furth rats were used for in vivo
      studies. Expression of PPARgamma was evaluated by RT-PCR and Western blot.
      Apoptosis and cell cycle were assessed by FACS analysis. The effects of PPARgamma
      ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and
      electromobility shift assay. RESULTS: PPARgamma was expressed in all human GH
      secreting adenoma (GH-oma), in normal pituitary tissue samples (39+/-24% and 78+/
      5% of immunostained nuclei respectively; P<0.0002; ANOVA), and in rat GH
      secreting (GH3) cells. A PPRE-containing reporter plasmid transfected into GH3
      cells was activated by ciglitazone or rosiglitazone (TZDs), indicating that
      PPARgamma was functionally active. Treatment of GH3 cells with TZDs increased
      apoptosis in a dose-dependent manner (P=0.0003) and arrested cell proliferation,
      reducing the number of cells in the S-phase (P<0.0001 vs untreated cells). TZDs
      increased the expression of TRAIL, leaving unaffected that of p53 and Bax. TZDs
      reduced GH concentrations in the culture media from 43.7+/-5.4 ng/ml to 2.1+/-0.3
      ng/ml (P<0.0001) and in cell extracts (P<0.004). PPARgamma-RXRalpha heterodimers
      bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 x
      10(6) vs 5.7 x 10(6) transcripts respectively vs untreated cells; P<0.002).
      Subcutaneous GH-oma developed in rats injected with GH3 cells; tumor growth
      increased in placebo-treated rats and to a lesser extent in TZDs-treated animals
      (24.1+/-2.0 g, and 14.8+/-4.2 g respectively, P<0.03). Serum GH concentrations
      were lower in TZDs-treated rats than in controls (871+/-67 ng/ml vs 1.309+/-238
      ng/ml; P<0.05). CONCLUSIONS: The results of this study indicate that PPARgamma
      controls GH transcription and secretion as well as apoptosis and growth of GH
      oma; thus, TZDs have the potential of a useful tool in the complex therapeutic
      management of acromegalic patients.

PMID- 15191359
TI  - Identification of amino-acids in the alpha-subunit first and third loops that are
      crucial for the heterospecific follicle-stimulating hormone activity of equid
      luteinizing hormone/choriogonadotropin.
AB  - OBJECTIVE: To identify amino-acids in the alpha-subunit important for expression
      of heterospecific FSH activity of horse (e) LH/choriogonadotropin (CG) (eLH) and
      donkey (dk) LH/CG (dkLH) (FSH/LH ratio ten times higher for eLH than for dkLH);
      this FSH activity absolutely requires an equid (donkey or horse) alpha-subunit
      combined with an equid beta-LH subunit. DESIGN: Chimeric alpha-subunits
      possessing the first 63 amino-acids of the porcine (p) and the last 33 amino
      acids of the donkey alpha-subunit (alphap-dk) and the inverse (alphadk-p) were
      constructed. Porcine-specific amino-acids were introduced by mutagenesis in
      donkey alpha-subunit at positions 70, 85, 89, 93 and 96 (alphadk5xmut), 18
      (alphadkK18E) or 78 (alphadkI78A). METHODS: These different alpha-subunits were
      co-transfected in COS-7 cells with beta-eLH, beta-dkLH and beta-eFSH. The LH and
      FSH bioactivities of the dimers were then assessed in two heterologous in vitro
      bioassays. RESULTS: alphap-dk or alphadk-p exhibited FSH activity when co
      expressed with beta-eLH but not with beta-dkLH. alphadkK18E or alphadkI78A gave
      hybrids with no FSH activity and important LH activity when expressed with beta
      dkLH. alphadkI78A/betaeLH displayed an FSH/LH ratio as low as that of dkLH.
      However, mutation at 78 in alpha-dk had no effect on FSH bioactivity when co
      expressed with beta-eFSH. CONCLUSIONS: Amino-acids present in both the first two
      thirds and the last third of the alpha-subunit of equid LHs are involved in their
      heterologous biospecificity. Ile alpha78 exerts as strong an influence on it as
      the beta102-103 residues. By contrast, this residue plays no role in the FSH
      specificity of eFSH.

PMID- 15191360
TI  - Resistin promotes 3T3-L1 preadipocyte differentiation.
AB  - OBJECTIVE: To investigate the relationship between resistin (a potential link
      between obesity and type 2 diabetes) and preadipocyte differentiation. DESIGN: A
      rat resistin expression vector was transfected into 3T3-L1 preadipocytes and
      differentiation was compared between normal 3T3-L1 cells, rat resistin
      transfected cells and non-transfected cells grown in conditioned medium taken
      from resistin-expressing cultures. METHODS: The rat resistin gene was inserted
      into the pDual GC and pEFGP-N2 expression vectors for examination of the effects
      of resistin overexpression in 3T3-L1 cells before and after differentiation was
      stimulated with 3-isobutyl-1-methyxanthine (MIX), insulin and dexamethasone
      (DEX). Smaller conserved fragments were inserted into short interference RNA
      (siRNA) expression vectors, for examination of the effect of targeted resistin
      inhibition on differentiation of resistin-overexpressing 3T3-L1 cells. RESULTS:
      Prior to stimulation, the resistin-transfected 3T3-L1 cells contained many more
      small lipid droplets than did non-transfected 3T3-L1 cells. Following
      stimulation, differentiation in the resistin-transfected 3T3-L1 cells was
      dramatically promoted, especially in the early stages. Stimulation of
      differentiation was also observed in non-transfected 3T3-L1 cells grown in
      resistin protein-containing conditioned medium. The expression of adipocyte
      differentiation-associated markers such as CCAAT enhancer binding protein
      (C/EBPalpha), retinoid X receptor (RXRalpha) and lipoprotein lipase (LPL) was
      upregulated in resistin-overexpressing cells, whereas expression of preadipocyte
      factor-1 (Pref-1), an inhibitor of preadipocyte differentiation, was
      downregulated. In addition, expression of two of the three tested siRNAs
      inhibited the adipoconversion process, providing further evidence that resistin
      promotes the differentiation of preadipocytes to adipocytes. CONCLUSION: Resistin
      can promote preadipocyte differentiation. Based on this, we propose that resistin
      may be an important candidate mediator of obesity-induced insulin resistance.

PMID- 15191361
TI  - Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are
      diminished in leptin-signalling-deficient ZDF rats.
AB  - OBJECTIVE: The aim was to investigate the possible interactions of the two
      peripheral hormones, leptin and ghrelin, that regulate the energy balance in
      opposite directions. METHODS: Leptin-receptor mutated Zucker diabetic fatty (ZDF)
      and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin
      (50 mg/kg p.o.) for 18 days, and the effects on body weight, food intake and body
      composition were investigated. The level of expression of anabolic and catabolic
      neuropeptides and their receptors in the hypothalamic area were analysed by in
      situ hybridization. RESULTS: Tabimorelin treatment induced hyperphagia and
      adiposity (increased total fat mass and gain in body weight) in lean control
      rats, while these parameters were not increased in ZDF rats. Treatment with
      tabimorelin of lean control rats increased hypothalamic mRNA expression of the
      anabolic neuropeptide Y (NPY) mRNA and decreased hypothalamic expression of the
      catabolic peptide pro-opiomelanocortin (POMC) mRNA. In ZDF rats, the expression
      of POMC mRNA was not affected by treatment with tabimorelin, whereas NPY mRNA
      expression was increased in the hypothalamic arcuate nucleus. CONCLUSION: This
      shows that tabimorelin-induced adiposity and hyperphagia in lean control rats are
      correlated with increased hypothalamic NPY mRNA and decreased POMC mRNA
      expression. The elimination of tabimorelin-induced adiposity and hyperphagia in
      ZDF rats may be due to lack of POMC mRNA downregulation. In conclusion, we
      suggest that ghrelin-receptor ligands exert their adipogenic and orexigenic
      effects via hypothalamic mechanisms that are dependent on intact leptin-receptor
      signalling.

PMID- 15191362
TI  - Glucocorticoid-dependent stimulation of adiposity and appetite by a ghrelin
      mimetic in the rat.
AB  - OBJECTIVE: Chronic administration of GH secretagogues (GHSs) induces a state of
      positive energy balance in rodents by a GH-independent mechanism. Here we sought
      to determine to what extent the GHS effects to increase food intake and increase
      fat accumulation are glucocorticoid-dependent. DESIGN: The effects of twice-daily
      s.c. injections of GH-releasing peptide-6 (GHRP-6) (250 microg/kg) for 2 weeks on
      body weight, food intake and fat pad weight were determined in both
      adrenalectomised (ADX) rats (with or without basal corticosterone replacement)
      and adrenal-intact rats. RESULTS: All GHS-injected rats had a significantly
      increased body weight at the end of 2 weeks of treatment compared with saline
      controls. However, increased fat accumulation was only seen in adrenal-intact
      rats, with a 15% increase in s.c. inguinal (P<0.05 vs saline controls) and 20%
      increase in visceral mesenteric (P<0.05) fat pad weights following GHS treatment.
      The increased body weight observed in ADX rats following GHS treatment was not
      due to increased fat mass or increased weight of other organs measured. Food
      intake was increased for up to 7 h following a single injection of GHRP-6 in both
      the adrenal-intact (P<0.01) and corticosterone-replacement groups (P<0.05). This
      stimulating effect on food intake was not observed at any time point in the ADX
      rats without corticosterone replacement. CONCLUSION: These data suggest that GHS
      induced body weight gain is glucocorticoid-independent. However, basal levels of
      glucocorticoids are permissive for the GHS-induced increase in food intake whilst
      activation of the hypothalamo-pituitary-adrenal axis appears to contribute to the
      GHS-induced accumulation of fat mass.

PMID- 15191363
TI  - Short-term secretory regulation of the active form of ghrelin and total ghrelin
      during an oral glucose tolerance test in patients with anorexia nervosa.

PMID- 15191364
TI  - Short-term use of continuous positive airway pressure ameliorates glomerular
      hyperfiltration in patients with obstructive sleep apnoea syndrome.
AB  - Patients with OSAS (obstructive sleep apnoea syndrome) demonstrate renal signs
      such as proteinuria, glomerular hypertrophy and focal glomerular sclerosis. We
      performed a clinical study to investigate the glomerular function in OSAS
      patients and the short-term effect of CPAP (continuous positive airway pressure)
      on it. OSAS patients underwent a sodium thiosulphate and p-aminohippurate double
      clearance test, polysomnography and ambulatory blood pressure monitoring before
      and a week after the induction of CPAP. Twenty-seven consecutive patients (24
      males) with moderate-to-severe OSAS admitted to our hospital for the induction of
      CPAP, and 32 healthy donors for renal transplantation as controls participated in
      the study. Before treatment, the glomerular filtration rate, estimated by the
      sodium thiosulphate clearance test, was within normal range, and the renal plasma
      flow was significantly lower than normal in the OSAS patients, thus the FF
      (filtration fraction) value was much higher than normal. FF before CPAP was not
      significantly correlated with age, body mass index or blood pressure; however,
      indices of increased hypoxaemia correlated with increased FF values.
      Polysomnographic variables after CPAP showed significant improvements in all
      patients, and only the nocturnal blood pressures were slightly lower than before
      CPAP. In 21 patients who underwent the clearance test after CPAP, FF
      significantly decreased from 0.26 +/- 0.04 to 0.23 +/- 0.03 (P < 0.001). OSAS
      patients were generally in a glomerular-hyperfiltrating condition that appeared
      to cause the renal findings associated with OSAS. CPAP might prevent nephropathy
      by ameliorating the glomerular hyperfiltration in OSAS patients.

PMID- 15191365
TI  - Proceedings of the 7th Clinicopathological Conference on Renal Allograft
      Pathology. July 12, 2003, Tokyo, Japan.

PMID- 15191366
TI  - Histological analysis of late renal allografts of antidonor antibody positive
      patients with C4d deposits in peritubular capillaries.
AB  - The association of humoral immunity with late renal allograft dysfunction has
      recently been recognized, and many reports have revealed C4d deposits in
      peritubular capillaries (C4d in PTC), and the presence of serum antidonor HLA
      antibody in patients suffering from graft dysfunction, long time after
      transplantation. In this study, morphological changes in renal allograft biopsies
      more than 1 year after transplantation in 14 patients with C4d in PTC and serum
      antidonor antibody were investigated for the presence of chronic rejection (CR).
      In addition to the light microscope study, an electron microscope study was done
      to evaluate the multilayering of the peritubular capillary basement membrane
      (MLPTC). Histologically, only seven of 14 patients met the criteria of CR, and
      71.4% (5/7) of CR patients had episodes of acute humoral rejection (AHR),
      coexisting with acute tubulointerstitial rejection. Peritubular capillaritis was
      observed in all patients, although it differed in severity. Transplant
      glomerulitis and interstitial inflammation were also observed in many patients:
      71.4% (10/14) and 92.9% (13/14) respectively. MLPTC was observed in 12 patients
      (85.7%), but the severity of the MLPTC did not reflect the severity of
      peritubular capillaritis or any other histological features. The long-term
      outcomes of the patients CR, especially those with episodes of AHR, were poor,
      and two of them lost their graft functions. On the other hand, patients without
      CR had relatively favourable outcomes. In conclusion, we confirmed the diverse
      morphological changes of late renal allografts, which cannot be categorized as
      chronic humoral rejection (CHR), and such patients who do not have typical
      morphological changes such as CHR, should be followed-up on a long-term basis in
      order to clarify the significance of C4d on PTC in late renal allografts.

PMID- 15191367
TI  - C4d and/or immunoglobulins deposition in peritubular capillaries in perioperative
      graft biopsies in ABO-incompatible renal transplantation.
AB  - We evaluated 0 h and/or 1 h graft biopsy specimens from 14 recipients in ABO
      incompatible renal transplantation using immunofluorescence for C4d, IgG, and
      IgM. All 0 h biopsy specimens revealed negative C4d, IgG, and IgM deposition in
      peritubular capillaries (PTC). In contrast, 8 of 14 1 h biopsy specimens revealed
      a positive C4d deposition in PTC. Eight specimens revealed positive IgM staining
      and seven of them had both C4d and IgM depositions. Three specimens had C4d, IgM,
      and IgG depositions in PTC. Three of eight patients with C4d deposition and two
      of six patients without C4d deposition in the 1 h biopsy group suffered from
      acute rejection within 1 month of transplantation. These findings suggest that
      complement fragments and immunoglobulin deposition in PTC in ABO-incompatible
      renal grafts can start soon after reperfusion, although acute rejection may or
      may not develop.

PMID- 15191368
TI  - Pathological study on the relationship between C4d, CD59 and C5b-9 in acute renal
      allograft rejection.
AB  - In order to evaluate the activation or inhibition of the later phases of
      classical complement cascade in renal allograft presenting with acute rejection,
      particularly with C4d deposition on the peritubular capillary (PTC), we observed
      the expression of CD59 and C5b-9 on the PTC. Subjective cases were divided into
      two groups, an acute rejection group, of 4 males and 6 females, and a normal
      donor group, of 5 males and 5 females. Renal biopsies were performed at the onset
      of acute rejection and at the transplant operation, before reperfusion. C4d
      deposition on PTC was found in three of 10 cases (30%) with biopsy proven acute
      rejection, whereas CD59 on PTC was positively expressed in all of the rejection
      cases. Although C5b-9 was not observed on PTC in the acute rejection group, it
      was intensively deposited on the tubular basement membrane (TBM) in five cases,
      including the three with positive C4d on PTC. In the normal donor group, CD59 on
      PTC was intensively observed, whereas C5b-9 was weakly expressed on TBM. CD59, a
      complement regulatory factor, works as an inhibitory factor against the formation
      of C5b-9, a membrane attack complex. From our data, we noted the dissociation
      between the depositions of C4d and C5b-9 on PTC. The substantially expressed CD59
      on PTC may affect this dissociation between C4d and C5b-9 on PTC. The intensive
      deposition of C5b-9 on TBM in acute rejection cases may suggest an independent
      immunological injury attacking tubular cells.

PMID- 15191369
TI  - Histopathological evaluation of 0-h biopsy specimens of donor kidney procured by
      laparoscopic donor nephrectomy.
AB  - We evaluated the histopathology of donor kidneys procured by laparoscopic donor
      nephrectomy (LDN), by examining allograft biopsy specimens obtained immediately
      after donor nephrectomy (0-h biopsies). MATERIALS AND METHODS: LDN was performed
      on 65 donors between December 1999 and November 2002, in our institution. Their
      mean age was 56 years, and there were 19 males and 46 females. Hand-assisted LDN
      (HALDN) was used in 10 cases and retroperitoneal LDN (RPLDN) in 55 cases.
      Allograft biopsy of all 65 kidneys was performed immediately after LDN (0-h
      biopsy), and the biopsy specimens were used in this study. All specimens were
      routinely examined by light and immunofluorescence microscopy. The 43 donors who
      underwent traditional open donor nephrectomy (ODN) between January 2001 and June
      2001 served as controls. RESULTS: There was no significant difference in the rate
      of glomerular sclerosis and moderate interstitial fibrosis with tubular atrophy,
      the severity of arteriosclerosis, and the severity of arteriolar hyalinosis among
      the specimens from kidneys removed by the three different methods: HALDN, RPLDN,
      and ODN. Prominent and characteristic histopathological changes which are not
      usually seen in 0-h biopsy specimens of kidneys obtained by traditional ODN were
      'subcapsular cortical damage (SCCD) with capsular lesions (CL)'. The SCCD with CL
      changes included a subcapsular degeneration and necrosis of tubular cells and a
      congestion of glomerular and peritubular capillaries (SCCD) associated with
      haemorrhage and fibrin deposits in the renal capsule (CL). In this study, such
      characteristic 'SCCD with CL' findings were observed in 35 specimens (54%). The
      damage was much milder in donor kidneys procured by RPLDN than by HALDN.
      CONCLUSION: SCCD with CL occurred in donor kidneys procured by LDN, which may be
      due to a compression of the renal parenchyma and veins. RPLDN may be better
      method for donor nephrectomy.

PMID- 15191370
TI  - Comparison of histopathological characteristics of allograft biopsy between
      responder and non-responder to antiproteinuric effect of angiotensin-converting
      enzyme inhibitor (ACEI).
AB  - Angiotensin-converting enzyme inhibitor (ACEI) has become recognized as agents
      that have renoprotective effects in the treatment of progressive renal diseases
      including post-transplant kidneys. Previously we demonstrated the safety and
      effectiveness of ACEI treatment on the hypertensive proteinuric post-transplant
      patients (N = 10) who had been followed up for 12 months. However, not all
      patients show good response in urinary protein reduction. We aimed to analyse the
      histopathological factor(s) affecting the responsiveness of proteinuria to ACEI
      treatment. Fourteen post-transplant patients with proteinuria who were treated
      with ACEI and underwent allograft biopsy were analysed. Eight patients showed 50%
      or more reduction in proteinuria (responder). The other 6 patients showed less (<
      50%) reduction in proteinuria (non-responder). There was no difference in
      clinical characteristics (BP, renal function, donor age, recipient body mass
      index), dietary sodium or protein intake, and diuretic use between the two
      groups. As a histopathological characteristic, glomerular size in responder group
      was significantly larger than that in non-responder group. This suggests that the
      large glomerular size at least partly contributes to the responsiveness in
      urinary protein reduction to ACEI treatment in kidney allograft recipients with
      proteinuria.

PMID- 15191371
TI  - Clinicopathological study of vesicoureteral reflux (VUR)-associated
      pyelonephritis in renal transplantation.
AB  - We retrospectively studied the occurrence of vesicoureteral reflux (VUR)
      associated pyelonephritis using renal biopsies obtained from the transplanted
      kidneys, and correlated the histological changes with clinical parameters. Out of
      a total of 131 renal biopsies performed between 1990 and 2001 on renal transplant
      patients at the department of Urology of Nagasaki University Graduate School of
      Biomedical Sciences, 12 patients showed pyuria more than twice in a single year.
      Seven of these 12 patients were available for determining VUR by voiding
      cystourethrography (VCUG). Cystoureterography demonstrated VUR in three of seven
      studied patients with pyuria. A histopathological examination revealed dilatation
      of both proximal and distal tubules in renal biopsies of transplant patients with
      VUR, compared to renal biopsies of transplant patients without VUR, or non
      transplanted patients with thin membrane disease. One of the patients with VUR
      showed advanced features of chronic pyelonephritis in four consecutive biopsies
      at different time points, suggesting a late stage of reflux nephropathy in the
      transplanted kidney. We conclude from our study that the occurrence of VUR
      related pyelonephritis may be one of the important long-term complications in the
      survival of renal allografts.

PMID- 15191372
TI  - BK virus nephropathy in a patient with ABO-incompatible renal transplantation.
AB  - A 43-year-old woman with end-stage renal disease originating from IgA nephropathy
      entered chronic haemodialysis therapy. She then received an ABO-incompatible
      living related renal transplantation. Initial immunosuppression consisted of
      azathioprine, methylprednisolone and tacrolimus. At 155 days after
      transplantation, the azathioprine was changed to mycophenolate mofetil for
      continuous graft dysfunction. Furthermore, a total of three courses of anti
      rejection therapy was given. At 665 days after transplantation, diagnosis of BK
      virus nephropathy was made by immunohistochemical analysis and viral DNA assay.
      Therefore the immunosuppression therapy was reduced for graft dysfunction. All
      five renal biopsy specimens were examined retrospectively in order to determine
      when the BK virus nephropathy had developed. The expressions of SV40 large T
      antigens were detected from the third (117 days) to the fifth (665 days)
      biopsies, with increasing numbers of SV40 large T antigen positive cells. In
      addition, many cells contained inclusion bodies which were already present in the
      urinary sediment for 3 months post-transplantation. Although it is difficult to
      make a diagnosis of early stage of BKVN, we have to consider with caution if
      urinary cells with inclusion body are seen. Awareness of BKVN at the earliest
      opportunity is important in order to avoid over-immunosuppression.

PMID- 15191373
TI  - An autopsy case of bacterial septic shock 12 years following ABO-incompatible
      renal transplantation.
AB  - We report the case of an ABO-incompatible kidney transplant recipient who died
      suddenly following a good transplant course of 12 years. For 10 years after
      transplantation, the graft function had been stable (s-Cr: 1.0-1.5 mg/dL),
      although chronic hepatitis C had developed, with elevation of transaminase. In
      the 11th year, he was admitted into the hospital with low-grade fever and general
      fatigue. Jaundice and anaemia progressed, and he died 2 months after admission.
      The autopsy diagnosis was: (1) post-renal transplantation state, (2) phlegmonous
      enterocolitis with septic infarction, (3) cellulitis and necrotic myositis, and
      (4) sepsis. The transplanted kidney graft showed well-preserved glomeruli and
      tubules, corresponding to chronic allograft nephropathy (CAN) grade Iota (ci1,
      ct1, cv1), according to the Banff classification. The pathological changes
      observed in this long-surviving ABO-incompatible kidney graft were similar to
      those of an ABO-compatible graft, although its degree was milder.

PMID- 15191374
TI  - A case of plasmacytic hyperplasia arising in a kidney allograft salvaged with
      immunosuppression reduction alone.
AB  - Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication
      of organ transplantation. Plasmacytic hyperplasia (PH) is thought of as the
      mildest form of PTLD; however, a graftectomy is necessary in most situations. We
      experienced an interesting case of PH arising in a kidney allograft, which could
      be relieved with a reduction in immunosuppression. A 27-year-old female underwent
      a living-related kidney transplantation. A 3-month non-episode protocol biopsy
      unexpectedly showed the devastating appearance of polymorphic plasma cell
      infiltration into the graft intersitium, compatible with PH. The PH was located
      in the graft by radiographic examinations. The infiltration of plasma cell
      disappeared completely on the 6-month graft biopsy specimen following
      immunosuppression reduction and the graft is functioning, although it was damaged
      by a subsequent acute rejection. Our present case indicates that some PTLD can be
      completely cured with a reduction in immunosuppression alone. The diagnostic
      modality for the evaluation of PTLD cell extinction is necessary to maintain
      graft function with adequate immunosuppression thereafter.

PMID- 15191375
TI  - Different clinicopathological courses of two recipients of kidneys retrieved from
      the same non-heart beating donor.
AB  - We report the clinicopathological courses of two recipients of kidneys retrieved
      from the same non-heart beating donor (NHBD). A 52-year-old man received a renal
      transplant from an NHBD. The donor was a 66-year-old woman who died of
      subarachnoid haemorrhage. The recipient was immunosuppressed by basiliximab,
      tacrolimus (TAC), mycophenolate mofetil (MMF), methyl prednisolone (MP), and
      antilymphocyte globulin (ALG). On post-operative day (POD) 21, haemodialysis
      therapy was withdrawn, however, their serum creatinine (s-Cr) level failed to
      improve. Four transplant biopsies were performed (1 h and POD 46, 74, and 114).
      The biopsy showed tubular degeneration but no evidence of TAC nephrotoxicity. The
      last biopsy after discontinuation of TAC demonstrated acute rejection of
      borderline grade. The s-Cr level at discharge was 5.0 mg/dL. The contra-lateral
      kidney was transplanted into a 31-year-old female and showed early functioning,
      with an s-Cr level at discharge of 1.8 mg/dL. Biopsy examination on POD 38 showed
      a recovery of tubular degeneration. The causes of delayed graft function and
      persistently high level of s-Cr in Case 1 remain unclear. Various factors,
      including donor-related factors, recipient-related factors, TAC nephrotoxicity,
      acute rejection, and urinary tract infection could all be associated with this
      condition.

PMID- 15191376
TI  - Fusarium fungaemia in immunocompromised patients.
AB  - Fusarium spp. cause infections only rarely in immunologically competent hosts,
      but disseminated infection may occur in severely immunocompromised patients.
      Symptoms of disseminated infection are persistent fever, despite broad-spectrum
      antibacterial and antifungal treatment, associated with skin lesions, most
      commonly on the extremities, in 60-80% of patients. A mortality rate of 50-75%
      has been reported for patients with disseminated fusariosis. Despite treatment
      failures, amphotericin B remains the preferred drug, in part because of lack of
      alternatives. Voriconazole is a promising new agent, but more clinical experience
      is required.

PMID- 15191377
TI  - Optimal use of antibiotic resistance surveillance systems.
AB  - Increasing concern about the emergence of resistance in clinically important
      pathogens has led to the establishment of a number of surveillance programmes to
      monitor the true extent of resistance at the local, regional and national levels.
      Although some programmes have been operating for several years, their true
      usefulness is only now being realised. This review describes some of the major
      surveillance initiatives and the way in which the data have been used in a number
      of different settings. In the hospital, surveillance data have been used to
      monitor local antibiograms and determine infection control strategies and
      antibiotic usage policies. In the community, surveillance data have been used to
      monitor public health threats, such as infectious disease outbreaks involving
      resistant pathogens and the effects of bioterrorism countermeasures, by following
      the effects of prophylactic use of different antibiotics on resistance.
      Initially, the pharmaceutical industry sponsored surveillance programmes to
      monitor the susceptibility of clinical isolates to marketed products. However, in
      the era of burgeoning resistance, many developers of antimicrobial agents find
      surveillance data useful for defining new drug discovery and development
      strategies, in that they assist with the identification of new medical needs,
      allow modelling of future resistance trends, and identify high-profile isolates
      for screening the activity of new agents. Many companies now conduct pre-launch
      surveillance of new products to benchmark activity so that changes in resistance
      can be monitored following clinical use. Surveillance data also represent an
      integral component of regulatory submissions for new agents and, together with
      clinical trial data, are used to determine breakpoints. It is clear that
      antibiotic resistance surveillance systems will continue to provide valuable data
      to health care providers, university researchers, pharmaceutical companies, and
      government and regulatory agencies.

PMID- 15191378
TI  - Once-daily oral gatifloxacin vs three-times-daily co-amoxiclav in the treatment
      of patients with community-acquired pneumonia.
AB  - A double-blind, double-dummy, multicentre, multinational, parallel-group study
      was designed to establish proof of equivalence between oral gatifloxacin and oral
      co-amoxiclav in the treatment of 462 patients with mild-to-moderate community
      acquired pneumonia. Eligible patients were randomised equally to either
      gatifloxacin 400 mg once-daily plus matching placebo for 5-10 days, or
      amoxycillin 500 mg + clavulanic acid 125 mg three-times-daily for 5-10 days. The
      primary efficacy endpoint was clinical response (clinical cure plus improvement)
      at the end of treatment. Overall, a successful clinical response was achieved in
      86.8% of gatifloxacin-treated patients, compared with 81.6% of those receiving co
      amoxiclav, while corresponding rates of bacteriological efficacy (eradication
      plus presumed eradication) were 83.1% and 78.7%, respectively. The safety and
      tolerability profile of gatifloxacin was comparable to that of co-amoxiclav, with
      adverse gastrointestinal events, e.g., diarrhoea and nausea, being the most
      common treatment-related adverse events in both groups. The study showed no
      evidence of gatifloxacin-induced phototoxicity, musculoskeletal disorders, or
      hepatic and renal problems. Overall, this study showed that gatifloxacin was
      equivalent clinically to a standard course of co-amoxiclav in patients with
      community-acquired pneumonia, and that gatifloxacin was safe and well-tolerated.

PMID- 15191379
TI  - Antimicrobial susceptibility to levofloxacin and other antibacterial agents among
      common respiratory pathogens-a Brazilian perspective from the GLOBAL Surveillance
      Initiative 2001-2002.
AB  - The GLOBAL (Global Landscape On Bactericidal Activity of Levofloxacin)
      Surveillance programme monitored antimicrobial susceptibility patterns of the key
      respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae and
      Moraxella catarrhalis collected in Brazil during 1997-1998, 1999-2000 and 2001
      2002. Penicillin and azithromycin resistance among S. pneumoniae strains
      increased from 1997-1998, reaching 7.9% and 9.5%, respectively, in 2001-2002.
      Although decreasing by 4.9% since the previous study, trimethoprim
      sulphamethoxazole resistance remained high at 33.7%. Concurrent resistance to
      penicillin, azithromycin and trimethoprim-sulphamethoxazole was seen in 2.9% of
      the S. pneumoniae isolates collected. Levofloxacin remained extremely active
      against S. pneumoniae, with 0.3% resistance reported in 1997-1998 and 0%
      resistance in 1999-2000 and 2001-2002. beta-Lactamase production in H. influenzae
      was > 10% in all three studies, with correspondingly high rates of ampicillin
      resistance. Trimethoprim-sulphamethoxazole was the least active agent tested
      against H. influenzae, with resistance rates of > 40% recorded in all three
      studies. All H. influenzae isolates were susceptible to cefuroxime, ceftriaxone,
      azithromycin and levofloxacin. Of the M. catarrhalis isolates, 98.0% in 1997
      1998, 98.0% in 1999-2000 and 81.8% in 2001-2002 were beta-lactamase-positive. The
      continued high prevalence of antimicrobial resistance in Brazil underscores the
      importance of current surveillance initiatives. Levofloxacin, a fluoroquinolone
      prescribed widely for respiratory tract infections, continued to show potent
      activity against key respiratory pathogens.

PMID- 15191380
TI  - Albendazole as an alternative therapeutic agent for childhood giardiasis in
      Turkey.
AB  - The efficacy of albendazole for the treatment of giardiasis has been indicated by
      previous in-vitro and in-vivo studies. In order to compare the therapeutic
      efficacy of albendazole and metronidazole, 107 Giardia-positive children (aged 3
      15 years), diagnosed by three consecutive positive stool examinations, were
      enrolled in the study. Of these children, 52 were given a single daily dose of
      albendazole 10 mg/kg for 5 days, and 55 were given metronidazole 20 mg/kg daily
      in three doses for 7 days. Parasite eradication was achieved in 47 (90.4%) of 52
      children treated with albendazole and 49 (89.1%) of 55 children treated with
      metronidazole (p > 0.05). These results suggest that albendazole is an effective
      treatment option for childhood giardiasis.

PMID- 15191381
TI  - Performance of focus ELISA tests for herpes simplex virus type 1 (HSV-1) and HSV
      2 antibodies among women in ten diverse geographical locations.
AB  - To determine the sensitivity and specificity of Focus HerpeSelect ELISAs, sera or
      plasma samples from women aged 18-55 years were collected in ten cities from
      eight countries and tested by HerpeSelect HSV-1 ELISA (Focus-HSV-1) and by
      HerpeSelect HSV-2 ELISA (Focus-HSV-2). Sera with Focus-HSV-2-positive results
      were retested; 94% of the 3617 samples retested were positive. A subset of sera
      from each site was then selected, based on the HSV-2 results, and tested by
      Western blot (WB). The sensitivity and specificity were determined with samples
      from ten sites (n = 967) for Focus-HSV-1 and from seven sites (n = 675) for Focus
      HSV-2. Focus-HSV-1 and WB results were concordant (both negative or both
      positive) for 97% of samples, with 99% sensitivity and 77% specificity. Specimens
      from Songkla, Thailand had 84% concordance with WB results for HSV-1, while three
      other sites had 100% concordance. Concordance of Focus-HSV-2 and WB was 92%, with
      97% sensitivity and 89% specificity. Ibadan, Nigeria had 78% concordance. Focus
      HSV-2 sensitivity and specificity in sites other than Ibadan were 97% and 93%,
      respectively. Raising the positive cut-off index value for HSV-2 from 1.1 to 3.5
      yielded a sensitivity of 90% and a specificity of 96%. A sensitivity of 90% and a
      specificity of 98% were achieved for sites other than Nigeria with the higher cut
      off. In summary, the sensitivity and specificity of the Focus-HSV-1 and Focus-HSV
      2 tests varied by site. Performance data generated in one area may not be
      applicable to other populations.

PMID- 15191382
TI  - Acute hepatitis B virus infection in Turkey: epidemiology and genotype
      distribution.
AB  - The aim of this study was to investigate the prevalence of hepatitis B virus
      (HBV) genotypes in Turkey. Epidemiological and clinical data for 158 patients
      with acute HBV infection from 22 medical centres in the period February 2001 to
      February 2002 were collected prospectively. HBV genotyping was based on analysis
      of restriction fragment length polymorphisms and nested PCR. There were 59 female
      and 99 male patients, with a mean age of 34.2 +/- 15.6 years. The most common
      probable transmission route was blood contact in 63 (41.1%) cases, but was
      unknown in 78 (49.4%) cases. The mean alanine aminotransferase level was 1718 +/-
      1089 IU/L. Four of the 158 patients (2.5%) died because of fulminant hepatitis.
      One year after discharge, 11 (10.6%) of 103 cases were positive for hepatitis B
      surface antigen (HBsAg) and 80 (77.7%) were positive for anti-HBsAg. Genotype
      determination was unsuccessful in 11 cases because of a negative PCR; genotype D
      was found in the remaining 147 cases. The results suggested that acute HBV
      infection constitutes a significant health problem in Turkey and that genotype D
      is predominant.

PMID- 15191383
TI  - Bloodstream infection surveillance in a cancer centre: a prospective look at
      clinical microbiology aspects.
AB  - A prospective clinical and microbiological surveillance study was conducted
      during a 26-month period to evaluate consecutive malignancy or post-bone marrow
      transplant patients with positive blood cultures. The study included 859 episodes
      of bloodstream infection (BSI) in 719 patients. There were 6.9 BSI episodes/1000
      patient-days. Overall mortality was 25%. The median age of patients was 43 years,
      with 71% of episodes occurring in patients aged > 18 years. Patients with
      underlying haematology malignancies accounted for 38.2% of the episodes. An
      indwelling central vein catheter was present in 61% of episodes. BSI origin was
      unknown in 27% of episodes, associated with other sites in 49.6%, and catheter
      related in 23.4%. There were 638 concomitant infection sites, of which the most
      common were pulmonary (28.4%), urinary tract (14.8%), and non-surgical skin or
      soft tissue (9.7%). In total, 1039 microorganisms were isolated within 48 h of
      the first blood culture, of which Gram-negative bacilli accounted for 56%. Among
      Klebsiella pneumoniae and Escherichia coli isolates, 37.8% and 8.9%,
      respectively, produced extended-spectrum beta-lactamases. High rates of
      ceftazidime resistance were detected among Acinetobacter spp. (40%) and
      Enterobacter spp. (51.2%). E. coli and K. pneumoniae were isolated frequently
      from haematology patients, and Enterobacter spp. from solid tumour patients. E.
      coli, K. pneumoniae and Pseudomonas aeruginosa were isolated more often from
      neutropenic than from non-neutropenic patients. Oxacillin resistance was detected
      in 18.7% of Staphylococcus aureus isolates. It was concluded that continuous
      multidisciplinary surveillance of BSI is warranted in this high-risk group of
      patients in order to develop strategies for antimicrobial resistance control and
      treatment of infectious complications.

PMID- 15191384
TI  - Potential risk factors for infection with Candida spp. in critically ill
      patients.
AB  - The incidence, risk factors and prognostic factors for candidal infection were
      determined in a prospective study of 280 infected patients. Thirty-one (11%)
      patients were infected with Candida spp., sub-divided into 18 (58%) with C.
      albicans, and 13 (42%) with non-albicans spp. (six C. glabrata, three C.
      parapsilosis, and one each of C. krusei, C. tropicalis, C. guilliermondii and C.
      lusitaniae). Infection with Candida spp. was always associated with concurrent
      bacterial infection. By univariate logistic regression analysis, the degree of
      morbidity and the duration of mechanical ventilation were independent predictive
      factors for death, but infection with Candida spp., was not. Factors associated
      with Candida spp. infection were the degree of morbidity, intensive care unit
      length of stay, alterations of immune response, and the number of medical devices
      involved. By multivariate logistic regression analysis, the only independent risk
      factor for candidal infection was intensive care unit length of stay.

PMID- 15191385
TI  - Infective endocarditis in Greece: a changing profile. Epidemiological,
      microbiological and therapeutic data.
AB  - The epidemiology, and clinical and microbiological spectrum, of infective
      endocarditis (IE) in Greece was analysed in a prospective 4-year study in a
      tertiary hospital and a heart surgery centre in Athens. In total, 101 cases of IE
      (71 men, 30 women, aged 54.4 +/- 17.1 years) were studied, with a follow-up
      period of 3 months. Seventy-seven cases were definite and 24 possible; 59
      involved native valves (native valve endocarditis; NVE), 31 prosthetic valves
      (prosthetic valve endocarditis; PVE), of which nine were early and 22 late, and
      11 permanent pacemakers (pacemaker endocarditis; PME). There was a predominant
      involvement of aortic (48/101) and mitral (40/101) valves. Seven patients had
      rheumatic valvular disease, two had mitral valve prolapse, and eight had a
      previous history of IE. Thirteen and six patients had undergone dental and
      endoscopic procedures, respectively. In 13 patients, intravenous catheters were
      used within the 3 months before diagnosis of IE. There were three intravenous
      drug users among the patients. Staphylococcus aureus was the most important
      pathogen, isolated in 22% of cases, followed by viridans streptococci (19%) and
      coagulase-negative staphylococci (16%). Enterococcus spp. were responsible for
      3%, HACEK group for 2%, and fungi for 6% of cases. Viridans streptococci were the
      leading cause of NVE (29%), Staphylococcus epidermidis of PVE (16%), and S.
      aureus of PME (54.5%). Six of 22 S. aureus and ten of 16 S. epidermidis isolates
      were methicillin-resistant. Surgical intervention, including total pacemaker
      removal, was performed in 51.5% of patients. Overall mortality was 16%, but was
      29% with PVE, and was significantly higher with medical than with combined
      surgical and medical therapy (24.5% vs. 8%). Compared with previous studies,
      there were changing trends in the epidemiology, microbiology, treatment and
      prognosis of IE in Greece.

PMID- 15191386
TI  - Diversity of Listeria monocytogenes isolates of human and food origin studied by
      serotyping, automated ribotyping and pulsed-field gel electrophoresis.
AB  - Automated ribotyping, pulsed-field gel electrophoresis (PFGE) and serotyping were
      evaluated for the epidemiological study of isolates of Listeria monocytogenes
      collected in Finland in 1997-1999 from human blood (n = 116) and the food
      industry (n = 72). The isolates divided into six serotypes, 23 EcoRI ribotypes,
      54 AscI PFGE types, and 57 final subtypes if all results were combined. The
      discrimination index of ribotyping was lower (0.873) than that of PFGE (0.946).
      Two final subtypes dominated among human isolates, and identical subtypes were
      also found among food industry isolates. All PFGE types were serotype-specific,
      whereas two ribotypes included isolates of two serotypes. Isolates of serotype
      3a, involved in an outbreak in Finland in 1999, matched one of these ribotypes,
      which also included some food industry isolates of serotype 1/2a. Ribotyping with
      EcoRI would not have been sufficient to define the outbreak in Finland caused by
      serotype 3a isolates. Although ribotyping is applicable as the first method in
      outbreak situations, human and food isolates with identical ribotypes should be
      investigated further by PFGE.

PMID- 15191387
TI  - Detection of virulence factors in alpha-haemolytic Escherichia coli strains
      isolated from various clinical materials.
AB  - In total, 201 alpha-haemolytic Escherichia coli isolates from various clinical
      materials (urine samples and vaginal and rectal swabs) were examined by PCR for
      the presence of genes for the virulence factors alpha-haemolysin (hly), cytotoxic
      necrotising factor type 1 (cnf1), P-fimbriae (pap), S/F1C-fimbriae (sfa/foc),
      aerobactin (aer) and afimbrial adhesin (afaI). Among vaginal isolates, 96% were
      positive for cnf1, compared with 80% of urine strains (p 0.02) and 63% of rectal
      strains (p 0.0001). Similarly, sfa/foc-specific DNA sequences were found in 97%
      of vaginal isolates compared with 75% of rectal strains (p 0.004). The afa1 and
      aer genes were associated more with rectal alpha-haemolytic E. coli strains than
      with extra-intestinal isolates. The results suggested that CNF1 and/or S/F1C
      fimbriae contribute to colonisation and persistence of alpha-haemolytic E. coli
      strains in the vaginal environment.

PMID- 15191388
TI  - Prevalence of the sat, set and sen genes among diverse serotypes of Shigella
      flexneri strains isolated from patients with acute diarrhoea.
AB  - New virulence factors associated with the genus Shigella have been described
      recently. These comprise enterotoxins ShET-1 and ShET-2, encoded by the set and
      sen genes, respectively, and the secreted autotransporter toxin Sat, encoded by
      the sat gene. The present study aimed to determine the prevalence of genes
      encoding these toxins among a collection of Shigella flexneri clinical isolates
      belonging to different serotypes. While the set gene was detected only in S.
      flexneri serotypes 2a and 2b, the sen and sat genes were present in diverse
      serotypes of S. flexneri.

PMID- 15191390
TI  - Detection of bacterial DNA in cardiac vegetations by PCR after the completion of
      antimicrobial treatment for endocarditis.
AB  - PCR with broad-range primers for prokaryotic 16S rRNA genes was used to identify
      bacterial DNA in tissue from patients undergoing valve replacements following a
      previous episode of infective endocarditis (IE). Of eight valves investigated,
      bacterial DNA was detected in three from patients for whom IE had been treated by
      antibiotic therapy 5, 12 and 18 months previously. The demonstration of bacterial
      DNA within resected heart valves suggests either recurrence of infection,
      treatment failure or the persistence of bacterial debris within the cardiac
      vegetation. There may also be implications for routine use of PCR in the
      diagnosis of infection.

PMID- 15191389
TI  - A family outbreak of haemolytic uraemic syndrome and haemorrhagic colitis caused
      by verocytotoxigenic Escherichia coli O157 from unpasteurised cow's milk in
      Slovakia.
AB  - This report describes a family outbreak of verocytotoxigenic Escherichia coli
      O157 (VTEC) infection, involving nine persons from one extended family, which
      occurred in eastern Slovakia. Three children suffered from haemolytic uraemic
      syndrome, two children had bloody diarrhoea, and four adults were asymptomatic
      carriers. Fourteen sorbitol-non-fermenting E. coli O157 isolates harbouring the
      vtx2, eae and ehxA genes were obtained. Verocytotoxin 2 activity was demonstrated
      in all 14 isolates. After epidemiological surveillance, the source of infection
      was identified as unpasteurised cow's milk.

PMID- 15191391
TI  - Colistin efficacy in an experimental model of Acinetobacter baumannii
      endocarditis.
AB  - The in-vivo activity of colistin was evaluated in an experimental rabbit model of
      Acinetobacter baumannii endocarditis with a strain susceptible to colistin and
      intermediate to imipenem. Compared to a control group, colistin was effective (p
      < 0.05) in bacterial clearance from blood and in the sterilisation of blood
      cultures, but was not effective in clearing A. baumannii from vegetations. Thus,
      although colistin may be effective in treating bacteraemia caused by susceptible
      strains of A. baumannii, it may not be a suitable treatment for endocarditis,
      perhaps because of poor penetration into vegetations and a low C(max)/MIC ratio
      in tissue.

PMID- 15191392
TI  - Exposure to Burkholderia pseudomallei induces cell-mediated immunity in healthy
      individuals.
AB  - Melioidosis is an emerging tropical infection caused by the intracellular
      bacterium Burkholderia pseudomallei, and is associated with high mortality rates.
      Previous studies investigating the prevalence of melioidosis have based
      conclusions on serological evidence. However, cell-mediated immunity is more
      relevant for protection against an intracellular pathogen such as B.
      pseudomallei. This is the first demonstration that exposure to B. pseudomallei
      may lead to the formation of specific antibodies and the development of cell
      mediated immunity in a healthy individual.

PMID- 15191393
TI  - CD4 T-lymphocyte subset counts in HIV-seropositive patients during the course of
      community-acquired pneumonia caused by Streptococcus pneumoniae.
AB  - Total lymphocyte counts, CD4 T-lymphocyte counts and CD4/CD8 ratios were measured
      in 30 anti-retroviral-naive HIV-seropositive patients upon hospital admission for
      acute community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae, and
      again 1 month after resolution of infection. There was a significant depression
      of the total lymphocyte count (p < 0.005) and CD4 T-lymphocyte count (p < 0.001)
      in the acute stage of CAP caused by S. pneumoniae, with a subsequent increase in
      90% (27/30) of cases after resolution of the infection. There was no significant
      difference in the CD4/CD8 T-lymphocyte ratio on admission compared with 1 month
      later (p 0.9).

PMID- 15191394
TI  - Simplified sunflower (Helianthus annuus) seed agar for differentiation of Candida
      dubliniensis from Candida albicans.
AB  - This study evaluated sunflower (Helianthus annuus) seed agar (SSA) for
      differentiation of Candida dubliniensis from Candida albicans on the basis of
      colony characteristics and chlamydospore production. Simplified SSA without
      creatinine and KH(2)PO(4) was also used. On both media, C. dubliniensis isolates
      (n = 25) developed rough colonies and formed abundant chlamydospores after
      incubation for 24-48 h at 28 degrees C, while C. albicans isolates (n = 53)
      showed smooth colonies with no evidence of chlamydospore formation. Cryptococcus
      neoformans isolates (n = 10) formed brown colonies on both media. Simplified SSA
      offers a simple and inexpensive tool for presumptive differentiation of C.
      dubliniensis from C. albicans in clinical microbiology laboratories.

PMID- 15191398
TI  - Nanomolar level of ouabain increases intracellular calcium to produce nitric
      oxide in rat aortic endothelial cells.
AB  - Changes in [Ca(2+)](i) across the cell membrane and/or the sarcoplasmic reticulum
      regulate endothelial nitric oxide (NO) synthase activity. In the present study,
      we investigated the effect of ouabain, a specific inhibitor of Na(+)/K(+)-ATPase,
      on NO release and [Ca(2+)](i) movements in cultured rat aortic endothelial cells
      (RAEC) by monitoring NO production continuously using an NO-specific real-time
      sensor and by measuring the change in [Ca(2+)](i) using a fluorescence
      microscopic imaging technique with high-speed wavelength switching. The t((1/2))
      (half-time of the decline of [Ca(2+)](i) to basal levels after stimulation with
      10 micro mol/L bradykinin) was used as an index of [Ca(2+)](i) extrusion. A very
      low concentration of ouabain (10 nmol/L) did not increase the peak of NO
      production, but decreased the decay of NO release and, accordingly, increased
      integral NO production by the maximal dose-response concentration induced by
      bradykinin. The same dose of ouabain affected [Ca(2+)](i) movements across the
      cell membrane and/or sarcoplasmic reticulum induced by bradykinin with a time
      course similar to that of NO release. Moreover, the t((1/2)) was significantly
      increased. Pretreatment of RAEC with Na(+)-free solution, an inhibitor of the
      Na(+)/Ca(2+) exchanger, and nickel chloride hexahydrate prevented the effects
      induced by bradykinin and ouabain. These observations using real-time recording
      indicate that a small amount of ouabain contributes to the bradykinin-stimulated
      increase of NO production through inhibition of plasma membrane Na(+)/K(+)-ATPase
      activity and an increase in intracellular Na(+) concentrations. The membrane was
      then depolarized, leading to a decline in the bradykinin-stimulated increase in
      [Ca(2+)](i) by forward mode Na(+)/Ca(2+) exchange to prolong the Ca(2+) signal
      time. From these results, we suggest that nanomolar levels of ouabain modulate
      [Ca(2+)](i) movements and NO production in RAEC.

PMID- 15191399
TI  - Inhibition of the dopamine system in rat amygdala attenuates the picrotoxin
      induced locomoter hyperactivity and hypertension.
AB  - The aim of the present study was to investigate whether picrotoxin-induced
      locomotor hyperactivity and hypertension can be inhibited by dopaminergic
      inhibition in rat amygdala. Locomotor activity was detected using a modularized
      infrared light matrix system in freely moving rats. In anaesthetized rats, blood
      pressure was measured while dopamine release was detected using in vivo
      voltammetry with carbon fibre electrodes. Systemic administration of picrotoxin
      (1-4 mg/kg) increased both locomotor activity (including horizontal motion,
      vertical motion and total distance travelled) and the number of turnings (both
      clockwise and anticlockwise), but inhibited postural freezing. The locomotor
      hyperactivity induced by systemic administration of picrotoxin was mimicked by
      direct injection of a small dose (1-3 micro g in 1.0 micro L) of picrotoxin into
      the amygdala. In vivo voltammetry data revealed that systemic administration of
      picrotoxin increased the release of dopamine in the amygdala of rat brain
      accompanied by hypertension. Local injection of kainic acid into the paramedian
      reticular nucleus (PRN) of the medulla oblongata decreased both the spontaneous
      release of dopamine in the amygdala and spontaneous levels of locomotor activity
      in rats. Furthermore, the picrotoxin-induced locomotor hyperactivity,
      hypertension and increased amygdaloid dopamine release were all suppressed
      following chemical stimulation of the PRN with kainic acid. Blockade of dopamine
      receptors with systemic or intra-amygdaloid injection of haloperidol (a dopamine
      receptor antagonist) significantly attenuated the picrotoxin-induced locomotor
      hyperactivity and hypertension. These results demonstrate that picrotoxin-induced
      hyperactivity and hypertension involve an increase in amygdaloid dopamine
      transmission that can be modulated by ascending projections from the PRN in the
      medulla oblongata.

PMID- 15191400
TI  - Auranofin increases apoptosis and ischaemia-reperfusion injury in the rat
      isolated heart.
AB  - Auranofin, an antirheumatic gold compound, is an inhibitor of selenocysteine
      enzymes, such as thioredoxin reductase and glutathione peroxidase. These enzymes
      play an important role in protecting cardiac tissue from oxidative stress
      generated during ischaemia-reperfusion. Auranofin (100 mg/kg) was administered to
      rats and their hearts were subjected to an in vitro model of ischaemia
      reperfusion. The activity of thioredoxin reductase and glutathione peroxidase was
      determined in liver and heart tissues in an attempt to correlate enzymatic
      activity with heart recovery after ischaemia-reperfusion. There was significantly
      less thioredoxin reductase activity in rat liver extracts, whereas the level of
      glutathione activity remained unchanged, demonstrating that the dose of auranofin
      used was able to selectively inhibit one of these enzyme systems. Rats
      administered auranofin displayed significantly impaired recovery from ischaemic
      insult. The end diastolic pressure was increased, whereas the rate pressure
      product was significantly decreased. The level of postischaemic apoptosis was
      also assessed by examining caspase-3 activity in tissue homogenates. Auranofin
      significantly increased the degree of postischaemic apoptosis, leading to poor
      postischaemic recovery.

PMID- 15191401
TI  - Cytochromes P450 are differently expressed in normal and varicose human saphenous
      veins: linkage with varicosis.
AB  - The expression of cytochrome P450 (CYP) enzymes and cyclo-oxygenases (COX) was
      investigated in human saphenous veins by reverse transcription-polymerase chain
      reaction analysis. Non-varicose veins were obtained from patients undergoing
      aortocoronary bypass grafting, whereas varicose veins were obtained from patients
      undergoing stripping removal of varicose saphenous veins. In non-varicose veins,
      CYP1B1, CYP2C, CYP2E1 and CYP4A11 were detected, whereas CYP2J2, CYP3A5, COX-1
      and COX-2 were detected almost exclusively in varicose veins. CYP4F2 was not
      detectable. Except for CYP4A11, the levels of individual CYP mRNA were higher in
      varicose veins than in control veins. Smooth muscle cell volume, determined by a
      colour image-analysis system, was increased approximately 1.5-fold in varicose
      veins. Because CYPs and COXs produce various vasoactive compounds, increased
      expression of these enzymes could be involved in the impairment of vascular tone
      and may contribute to varicose pathology. Then, CYP or COX modulators may be
      potentially active in the treatment of chronic venous insufficiency.

PMID- 15191402
TI  - Chronic decrease in flow contributes to heart failure-induced endothelial
      dysfunction in rats.
AB  - Chronic heart failure (CHF) impairs endothelium-dependent, nitric oxide (NO)
      mediated dilation. This decreased dilation may be partly secondary to the chronic
      decrease in blood flow, but this hypothesis has not yet been tested. Thus, we
      assessed whether a localized, chronic increase in blood flow in vivo reverses
      endothelial dysfunction of small arteries in rats with CHF. Two months after
      coronary artery ligation or sham surgery, second-order side branches of the
      superior mesenteric artery were ligated in order to obtain persistently elevated
      blood flow (HF) in the adjacent first-order side branch compared with normal
      vessels (NF). One month later, responses to acetylcholine and flow-mediated
      vasodilatation (FMD) were assessed in vitro in an arteriograph. Chronic heart
      failure induced a decrease in mesenteric blood flow (374 +/- 25 and 305 +/- 27
      micro L/min for sham and CHF, respectively; P < 0.05). Neither CHF nor the
      chronic increase in flow affected the responses to acetylcholine. Chronic heart
      failure decreased FMD (maximal response in sham and control 34 +/- 6 and 13 +/-
      4%, respectively; P < 0.05). Chronic increases in blood flow did not modify FMD
      in sham, but restored FMD in CHF rats (28 +/- 4%; P < 0.05 vs CHF NF). The
      restored response was abolished by an inhibitor of NO synthesis (N(G)-nitro-l
      arginine). Chronic heart failure did not affect the abundance of mesenteric
      endothelial NO synthase (eNOS) mRNA. A chronic increase in flow significantly
      increased the abundance of eNOS mRNA in sham rats, but only moderately and non
      significantly in CHF rats. Thus, endothelial dysfunction of small arteries in CHF
      appears to be largely the consequence of the chronic decrease in flow.

PMID- 15191403
TI  - Effect of magnesium on mechanical properties of pressurized mesenteric small
      arteries from old and adult rats.
AB  - The purpose of the present study was to determine the effects of magnesium (Mg)
      on the mechanical properties of resistance arteries in adult and old rats.
      Studies were performed in adult (17 weeks) and old (104 weeks) male Wistar rats.
      The vasodilatory response and the passive mechanical properties of the wall of
      isolated perfused and pressurized arterial segments of mesenteric small arteries
      were investigated after Mg and verapamil application, both known for their
      calcium antagonistic properties. Mesenteric resistance arteries from old rats
      exhibited an outward hypertrophic remodelling, with enlargment of the lumen,
      thickening of the media and enlarged media cross-sectional area. The vasodilatory
      response induced by the application of increasing extracellular concentrations of
      Mg and verapamil was significantly smaller in preconstricted mesenteric arteries
      of old rats than in those of adult rats. Incremental distensibility in response
      to increasing intravascular pressures did not change. However, the stress-strain
      curve was shifted to the left in pressurized mesenteric arteries from old rats,
      indicating arterial wall stiffness. Verapamil (3 micro mol/L) did not modify the
      stress-strain curves in either adult or aged rats. However, Mg (4.8 mmol/L)
      significantly shifted the curve to the right in mesenteric arteries from adult
      rats and, to a greater degree, in those from old rats. Although Mg-induced
      vasodilatation is impaired in aged rats, increased Mg concentration improved the
      mechanics of pressurized mesenteric resistance arteries. The fact that Mg
      decreases arterial stiffness in arteries from old rats suggests that Mg has a
      beneficial effect on age-related changes to the vascular wall.

PMID- 15191404
TI  - Sensitive thyroid-stimulating antibody assay with high concentrations of
      polyethylene glycol for the diagnosis of Graves' disease.
AB  - The aim of the present study was to determine the usefulness of a newly developed
      thyroid-stimulating antibody (TSAb) assay. We developed a highly sensitive TSAb
      (sTSAb) assay with 22.5% polyethylene glycol-precipitated crude IgG. The thyroid
      stimulating hormone (TSH) receptor antibody (TRAb) causes Graves' disease and
      TRAb has been measured as TSH-binding inhibitor immunoglobulin (TBII) and thyroid
      stimulating antibody (TSAb). The TSAb stimulates the thyroid glands and causes
      hyperthyroidism. In addition to investigating the usefulness of the newly
      developed sTSAb assay, we also investigated the frequencies of positive TRAb in
      thyrotoxic patients with subacute thyroiditis, painless thyroiditis or a solitary
      toxic nodule. We studied 700 untreated Graves' patients with hyperthyroidism and
      923 normal controls. We also studied thyrotoxic patients with subacute
      thyroiditis, painless thyroiditis or a solitary toxic nodule. Conventional TSAb
      (cTSAb) and sTSAb were measured as TSAb, whereas porcine TBII (pTBII) and human
      recombinant TBII (hTBII) were measured as TBII. Levels of cTSAb and sTSAb were
      determined in 923 normal controls and 629 untreated Graves' patients and cTSAb
      and sTSAb were found to be normally distributed in normal controls, but not in
      untreated Graves' patients. Receiver operating characteristic (ROC) curve
      analysis demonstrated that cTSAb and sTSAb had high sensitivity and specificity
      for Graves' disease. Of the patients investigated, 96.5% of untreated Graves'
      patients were positive for sTSAb and/or pTBII. Some untreated Graves' patients
      who were negative for cTSAb were positive for sTSAb. Paired determinations of
      cTSAb and sTSAb were performed in 146 untreated Graves' patients. A positive
      correlation was found between cTSAb and sTSAb. Titres of sTSAb were higher than
      those of cTSAb and sTSAb had high sensitivity. Of the 35 untreated Graves'
      hyperthyroid patients who were negative for cTSAb, 18 (51%) were positive for
      sTSAb. Of the 36 untreated Graves' patients who were negative for hTBII, nine
      (25%) were positive for sTSAb. Some untreated Graves' patients who were negative
      for cTSAb were positive for sTSAb and some who were negative for hTBII and pTBII
      were positive for sTSAb. 5. Some thyrotoxic patients with subacute thyroiditis or
      painless thyroiditis were positive for TRAb. However, the frequency of TRAb
      positive patients was low in this group. None of the patients with a solitary
      toxic nodule was positive for TRAb. In conclusion, sTSAb had higher sensitivity
      than cTSAb. Graves' patients who were cTSAb negative and hTBII negative could be
      sTSAb positive. The sTSAb indicates TSAb activity, but pTBII and hTBII do not
      necessarily do so. We recommended that the sTSAb is used in Graves' patients.

PMID- 15191406
TI  - Administration of exogenous tissue plasminogen activator reduces oedema in mice
      lacking the tissue plasminogen activator gene.
AB  - It has recently become apparent that tissue plasminogen activator (tPA) modulates
      inflammation in diseases such as rheumatoid arthritis (RA) and acute respiratory
      distress syndrome (ARDS). We have shown previously that tPA has anti-inflammatory
      activity in in vivo models of oedema or inflammation. The present study
      investigated the ability of exogenous recombinant tPA (rtPA) to reduce
      carrageenan-mediated oedema in mice lacking the tPA gene, testing the hypothesis
      that rtPA treatment may be beneficial in diseases such as RA and ARDS in which
      there is a paucity of endogenous tPA. Knockout mice deficient in the tPA gene and
      matching wild-type mice received an intraplantar injection (25 micro L) of
      carrageenan (1.5%, w/v) following either vehicle (sterile water for injection) or
      tPA (12 mg/kg). Footpad oedema was measured, an oedema index was calculated and
      tissue myeloperoxidase (MPO) activity was determined. Mean oedema indices were
      higher in untreated tPA (-/-) mice than untreated wild-type mice. Pretreatment
      with rtPA in either tPA (-/-) or wild-type mice reduced the mean measured peak
      footpad oedema index by 63 and 48%, respectively. Tissue MPO activity was not
      different between treatment groups. We conclude that exogenous rtPA has the
      ability to reduce acute oedema without altering neutrophil infiltration into the
      site of injury in both tPA (-/-) and wild-type mice and that endogenous tPA may
      participate in the inflammatory process, as evidenced by higher oedema indices in
      untreated tPA (-/-) mice. These data provide support for the potential clinical
      utility of exogenous rtPA in the treatment of inflammatory diseases, such as RA
      and ARDS, in which there is a paucity of tPA.

PMID- 15191405
TI  - Protection against kainate neurotoxicity by pyrrolidine dithiocarbamate.
AB  - The effect of pyrrolidine dithiocarbamate (PDTC) on kainate (KA)-induced
      neurotoxicity was examined in Sprague-Dawley rats. At 10 mg/kg, i.p., KA produced
      seizures accompanied by neuronal loss in the hippocampus and increased levels of
      malondialdehyde (MDA) and protein carbonyl. Pretreatment with PDTC (100 or 200
      mg/kg, p.o., every 12 h x 5) blocked KA-induced neurotoxicities (seizures,
      increases in MDA and protein carbonyl and neuronal losses) in a dose-dependent
      manner. These effects were counteracted by the adenosine A(1) receptor antagonist
      8-cyclopentyl-1,3-dimethylxanthine (25 or 50 micro g/kg, i.p.), but not by the
      A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1
      mg/kg, i.p.) or the A(2B) receptor antagonist alloxazine (1.5 or 3.0 mg/kg,
      i.p.). Our results suggest that the anticonvulsant and neuroprotective effects of
      PDTC are mediated, at least in part, via adenosine A(1) receptor stimulation.

PMID- 15191407
TI  - Hyperhomocysteinaemia-induced atrial remodelling in hypertensive rats.
AB  - Studies from our laboratory and others indicate that, in addition to its
      purported atherothrombotic effects, hyperhomocysteinaemia (Hhe) is a powerful
      stimulus for ventricular remodelling, dysfunction and clinical heart failure.
      Because changes in atrial structure and function can impact on cardiac function
      in progressive ventricular remodelling and dysfunction, we conducted experiments
      to examine structural and functional remodelling of the atria in the
      hyperhomocysteinaemic hypertensive rat, a previously described model of
      ventricular diastolic dysfunction. Atrial muscle preparations were isolated from
      hearts of spontaneously hypertensive rats that were fed control, intermediate Hhe
      inducing or severe Hhe-inducing diet for 10 weeks. Atrial developed tension,
      +dT/dt(max) and -dT/dt(max) were found to increase in parallel with levels of Hhe
      and ventricular diastolic dysfunction. Post-rest developed tension and the
      maximum developed tension observed in the presence of isoproterenol were also
      increased significantly in both Hhe groups compared with control. These results
      indicate that Hhe increases both basal and maximal contractile function in atrial
      muscle. Atrial structural remodelling was characterized by increased interstitial
      fibrosis in both Hhe groups. These data suggest that Hhe-associated changes in
      atrial structure and function may act to maintain ventricular filling in Hhe
      induced diastolic dysfunction.

PMID- 15191408
TI  - Brief exposure to ethanol augments vascular contractility in human chorionic
      plate arteries.
AB  - Heavy alcohol consumption has been known as a risk factor for hypertension,
      although the mechanism by which alcohol intake causes hypertension remains
      elusive. We tested the hypothesis that brief exposure to ethanol augments
      vascular contractility through the stress response in human chorionic plate
      arteries. Human chorionic plate arteries were mounted in organ baths and exposed
      to 5% ethanol for 15, 30 or 45 min. Brief exposure for 45 min, but not 15 min,
      not only augmented contractility to KCl and 5-hydroxytryptamine 5 h after the end
      of exposure, but also increased the expression of heat shock protein (HSP) 70 in
      the tissues. Reverse transcription-polymerase chain reaction showed gradual
      increases of hsp70 mRNA expression, but not heat shock cognate 70 (hsc70),
      hsp90alpha or glucose regulatory protein 78 (grp78) mRNA expression, in an
      exposure time-dependent manner 3 h after the end of exposure. These results
      indicate that ethanol augments vascular contractility through the stress
      response.

PMID- 15191409
TI  - Dose-dependent effect of captopril on aortic reactivity of streptozotocin
      diabetic rats.
AB  - Diabetes mellitus is a primary risk factor for cardiovascular disorders.
      Strategies that interrupt the renin-angiotensin system have been known to reduce
      cardiovascular disease. The present study was performed to investigate the effect
      of sub-chronic administration of captopril on the aortic reactivity of
      streptozotocin-diabetic rats. Streptozotocin-diabetic rats received captopril (30
      and 50 mg/kg per day) for 2 months. Contractile responses to phenylephrine (PE)
      and relaxation responses to acetylcholine (ACh) and isosorbide dinitrate (ISD)
      were obtained from aortic rings. Concentration-response curves from captopril
      treated diabetic rats to PE were attenuated compared with vehicle (Saline)
      treated diabetic rats, especially at a dose of 50 mg/kg captopril. In addition,
      endothelium-dependent relaxation responses induced by ACh were significantly
      higher in captopril-treated diabetic rats compared with diabetic rats. The
      endothelium-independent relaxation responses for ISD were found not to be
      significantly different among the groups. Therefore, sub-chronic treatment of
      diabetic rats with captopril in a dose-dependent manner could prevent the
      functional changes in vascular reactivity in diabetic rats.

PMID- 15191410
TI  - Effects of rilmenidine on proximal tubular fluid absorption in rats.
AB  - The antihypertensive agent rilmenidine has threefold higher affinity for I(1)
      imidazoline receptors compared with alpha(2)-adrenoceptors and acts on the
      central nervous system by reducing sympathetic activity and in the kidney by
      inhibiting Na(+)/H(+) exchange activity. In the present study, we examined: (i)
      the effects of luminal and peritubular administration of rilmenidine on fluid
      absorption in superficial proximal tubules; and (ii) the nature of the receptors
      involved in mediating the action of this drug in the presence of specific
      antagonists (efaroxan, idazoxan and 2-methoxy-idazoxan). Studies were performed
      in anaesthetized Sprague-Dawley rats using shrinking split-drop micropuncture.
      Luminal administration of rilmenidine (10(-5) and 10(-13) mol/L) inhibited
      proximal tubular fluid absorption. Peritubular rilmenidine at 10(-12) and 10(-13)
      mol/L also inhibited fluid uptake, whereas rilmenidine at 10(-11) mol/L had a
      significant stimulatory action. In the presence of the I(2) > I(1)/alpha(2)
      adrenoceptor antagonist idazoxan (10(-5) mol/L), luminal rilmenidine (10(-5)
      mol/L) stimulated fluid absorption. Stimulation of fluid uptake was also observed
      when rilmenidine (10(-5) mol/L) and the I(1) imidazoline receptor antagonist
      efaroxan (10(-5) mol/L) were added together in the luminal fluid. Luminal
      administration of the selective alpha(2)-adrenoceptor antagonist 2-methoxy
      idazoxan (10(-5) mol/L) resulted in significant attenuation of the inhibitory
      action of luminal rilmenidine (10(-5) mol/L). This indicates that both I(1)
      imidazoline receptors and alpha(2)-adrenoceptors are involved in the luminal
      actions of rilmenidine. The effects of luminal and peritubular administration of
      alpha-methylnoradrenaline (an alpha(2)-adrenoceptor agonist) were compared with
      those of rilmenidine. Luminal alpha-methylnoradrenaline, at higher concentrations
      (10(-7) and 10(-5) mol/L), inhibited fluid absorption, as was seen with
      peritubular rilmenidine, but, in contrast with rilmenidine, no stimulatory action
      was observed. Peritubular alpha-methylnoradrenaline inhibited fluid uptake at
      higher concentrations (10(-5) and 10(-7) mol/L), whereas rilmenidine at these
      concentrations had no effect. The differences in the concentration-dependent
      responses for rilmenidine and alpha-methylnoradrenaline indicate that both
      imidazoline receptors and alpha(2)-adrenoceptors are involved in the actions of
      these compounds on proximal fluid uptake.

PMID- 15191411
TI  - Effects of fluvastatin on endothelium-derived hyperpolarizing factor- and nitric
      oxide-mediated relaxations in arteries of hypertensive rats.
AB  - Endothelial cells release endothelium-derived hyperpolarizing factor (EDHF), as
      well as nitric oxide (NO). It has recently been suggested that 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve NO
      mediated endothelial function, partially independently of their cholesterol
      lowering effects. It is, however, unclear whether statins improve EDHF-mediated
      responses. Eight-month-old stroke-prone spontaneously hypertensive rats (SHRSP)
      were treated with fluvastatin (10 mg/kg per day) for 1 month. Age-matched,
      normotensive Wistar Kyoto (WKY) rats served as controls. Both EDHF- and NO
      mediated relaxations were impaired in SHRSP compared with WKY rats. Fluvastatin
      treatment did not affect blood pressure and serum total cholesterol. The
      acetylcholine (ACh)-induced, EDHF-mediated hyperpolarization in mesenteric
      arteries did not significantly differ between fluvastatin-treated SHRSP and
      untreated SHRSP and the responses in both groups were significantly smaller
      compared with those of WKY rats. Endothelium-derived hyperpolarizing factor
      mediated relaxations, as assessed by the relaxation to ACh in mesenteric arteries
      contracted with noradrenaline in the presence of N(G)-nitro-l-arginine and
      indomethacin, were virtually absent and similar in both SHRSP groups. In
      contrast, NO-mediated relaxation, as assessed by the relaxation in response to
      ACh in rings contracted with 77 mmol/L KCl, was improved in fluvastatin-treated
      SHRSP compared with untreated SHRSP (maximum relaxation in control and
      fluvastatin groups 42.0 +/- 5.2 and 61.2 +/- 3.8%, respectively; P < 0.05).
      Hyperpolarization and relaxation in response to levcromakalim, an ATP-sensitive
      K(+) channel opener, were similar between the two SHRSP groups. These findings
      suggest that fluvastatin improves NO-mediated relaxation, but not EDHF-mediated
      hyperpolarization and relaxation, in SHRSP. Thus, the beneficial effects of the
      statin on endothelial function may be mainly ascribed to an improvement in the NO
      pathway, but not EDHF.

PMID- 15191412
TI  - Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a
      reductase inhibitor, on cardiac myocytes through protein kinase C activation.
AB  - Pleiotropic effects of statins, which are independent of lipid lowering, have
      been reported. In the present study, we examined the effect of a statin on
      apoptosis of adult rat cultured cardiac myocytes. We used the protein kinase C
      (PKC) inhibitors staurosporine (1 micro mol/L), chelerythrine (10 micro mol/L)
      and rottlerin (5 micro mol/L) to induce myocyte apoptosis. The effect of
      atorvastatin (10(-7) g/mL), a statin, on myocyte apoptosis induced by these PKC
      inhibitors was examined. All these PKC inhibitors markedly increased the
      percentage of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin
      nick end-labeling (TUNEL)-positive myocytes. This increase was significantly
      suppressed by atorvastatin treatment. Both chelerythrine and rottlerin induced
      subcellular translocation of PKCdelta and elevated caspase-3 activity in
      myocytes. The changes in the subcellular distribution of PKCdelta and caspase-3
      activity induced by these PKC inhibitors were suppressed by atorvastatin
      treatment. The results of the present study suggest that the inhibitory effect of
      atorvastatin on apoptosis of adult rat cardiac myocytes induced by the PKC
      inhibitors is through activation of PKCdelta pathway.

PMID- 15191413
TI  - A novel inexpensive murine model of oral chronic digitalization.
AB  - A novel inexpensive murine model of oral administration of digitoxin (100 micro
      g/kg per day) added to routine chow is described. Serum digitoxin levels achieved
      after oral (n = 5; 116 +/- 14 ng/mL) and subcutaneous (n = 5; 124 +/- 11 ng/mL)
      administration were similar. A significant increase in the maximal left
      ventricular pressure rise of treated (n = 9) compared with control (n = 6) rats
      (dP/dt: 8956 +/- 233 vs 7980 +/- 234 mmHg/s, respectively; P = 0.01)
      characterized the positive inotropic action of digitoxin. In addition, no
      differences were observed in treated compared with control rats with regard to
      the electrocardiogram and systolic and diastolic left ventricular pressures.

PMID- 15191415
TI  - Activation of renal calcium and water excretion by novel physiological and
      pharmacological activators of the calcium-sensing receptor.
AB  - Activated Ca(2+)-sensing receptors (CaR) play key roles in the regulation of
      whole-body calcium metabolism by inhibiting the secretion of the key calcitropic
      hormone parathyroid hormone and promoting urinary calcium excretion. We have now
      examined the effects of intravenous administration of novel calcium receptor
      activators on renal function in anaesthetized female Wistar rats. The type II
      calcimimetic NPS R-467 and the CaR-active amino acids l-Phe and l-Ala, which act
      at distinct binding sites on the receptor, all activated urinary flow rate,
      calcium and osmolar excretion and suppressed urinary osmolality. The effects of l
      Phe and NPS R-467 on urine flow rate and calcium excretion were stereoselective,
      consistent with the idea that these effects were mediated by calcium-sensing
      receptors. However, d-Phe also suppressed urinary osmolality and promoted osmolar
      excretion, possibly by exceeding the transport maximum in the proximal tubule.
      The data indicate that novel activators of CaR, including l-amino acids at
      physiologically relevant serum concentrations, play a significant role in the
      regulation of urinary calcium and water excretion.

PMID- 15191416
TI  - Molecular changes in proximal tubule function in diabetes mellitus.
AB  - Diabetic kidney disease is initially associated with hypertension and increased
      urinary albumin excretion. The hypertension is mediated by enhanced volume
      expansion due to enhanced salt and water retention by the kidney. The increased
      urinary albumin is not only due to increased glomerular leak, but also to a
      decrease in albumin reabsorption by the proximal tubule. The precise molecular
      mechanisms underlying these two phenomena and whether there is any link between
      the increase in Na(+) retention and proteinuria remain unresolved. There is
      significant evidence to suggest that increased Na(+) retention by the proximal
      tubule Na(+)/H(+) exchanger isoform 3 (NHE3) can play a role in some forms of
      hypertension. Increased NHE3 activity in models of diabetes mellitus may explain,
      in part, the enhanced salt retention observed in patients with diabetic kidney
      disease. The NHE3 also plays a role in receptor-mediated albumin uptake in the
      proximal tubule. The uptake of albumin requires the assembly of a macromolecular
      complex that is thought to include the megalin/cubulin receptor, NHE3, the
      vacuolar type H(+)-ATPase (v-H(+)-ATPase), the Cl(-) channel ClC-5 and
      interactions with the actin cytoskeleton. The NHE3 seems to exist in two
      functionally distinct membrane domains, one involved with Na(+) reabsorption and
      the other involved in albumin uptake. The present review focuses on the evidence
      derived from in vivo studies, as well as complementary studies in cell culture
      models, for a dual role of NHE3 in both Na(+) retention and albumin uptake. We
      suggest a possible mechanism by which disruption of the proximal tubule albumin
      uptake mechanism in diabetes mellitus may lead to both increased Na(+) retention
      and proteinuria.

PMID- 15191417
TI  - Differential neural control of glomerular ultrafiltration.
AB  - The renal nerves constrict the renal vasculature, causing decreases in renal
      blood flow (RBF) and glomerular filtration rate (GFR). Whether renal
      haemodynamics are influenced by changes in renal nerve activity within the
      physiological range is a matter of debate. We have identified two morphologically
      distinct populations of nerves within the kidney, which are differentially
      distributed to the renal afferent and efferent arterioles. Type I nerves almost
      exclusively innervate the afferent arteriole whereas type II nerves are
      distributed equally on the afferent and efferent arterioles. We have also
      demonstrated that type II nerves are immunoreactive for neuropeptide Y, whereas
      type I nerves are not. This led us to hypothesize that, in the kidney, distinct
      populations of nerves innervate specific effector tissues and that these nerves
      may be selectively activated, setting the basis for the differential neural
      control of GFR. In physiological studies, we demonstrated that differential
      changes in glomerular capillary pressure occurred in response to graded reflex
      activation of the renal nerves, compatible with our hypothesis. Thus, sympathetic
      outflow may be capable of selectively increasing or decreasing glomerular
      capillary pressure and, hence, GFR by differentially activating separate
      populations of renal nerves. This has important implications for our
      understanding of the neural control of body fluid balance in health and disease.

PMID- 15191418
TI  - Neural control of renal medullary perfusion.
AB  - There is strong evidence that the renal medullary circulation plays a key role in
      long-term blood pressure control. This, and evidence implicating sympathetic
      overactivity in development of hypertension, provides the need for understanding
      how sympathetic nerves affect medullary blood flow (MBF). The precise vascular
      elements that regulate MBF under physiological conditions are unknown, but likely
      include the outer medullary portions of descending vasa recta and afferent and
      efferent arterioles of juxtamedullary glomeruli, all of which receive dense
      sympathetic innervation. Many early studies of the impact of sympathetic drive on
      MBF were flawed, both because of the methods used for measuring MBF and because
      single and often intense neural stimuli were tested. Recent studies have
      established that MBF is less sensitive than cortical blood flow (CBF) to
      electrical renal nerve stimulation, particularly at low stimulus intensities.
      Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic
      nerve activity within the physiological range in all but the most extreme cases.
      Multiple mechanisms appear to operate in concert to blunt the impact of
      sympathetic drive on MBF, including counter-regulatory roles of nitric oxide and
      perhaps even paradoxical angiotensin II-induced vasodilatation. Regional
      differences in the geometry of glomerular arterioles are also likely to
      predispose MBF to be less sensitive than CBF to any given vasoconstrictor
      stimulus. Failure of these mechanisms would promote reductions in MBF in response
      to physiological activation of the renal nerves, which could, in turn, lead to
      salt and water retention and hypertension.

PMID- 15191419
TI  - Childhood injury prevention advice: a survey of health professionals responses to
      common scenarios.
AB  - AIM: To determine the responses of health professionals when asked at what age a
      child could safely engage in a number of common activities and scenarios.
      METHODS: Eleven scenarios reflecting everyday activities were adapted from the
      BBC book Play it Safe. Questionnaires were completed by a convenience sample of
      health professionals. Respondents were asked to give the minimum age they felt a
      child could safely engage in each of the activities. The literature was searched
      for an evidential basis for answers to the activities and scenarios posed.
      RESULTS: A total of 215 questionnaires were completed. For all questions there
      was a spread in responses of at least 9 years. Recommended answers were found in
      the literature for six of the scenarios, however, in only four of these was this
      confirmed to have an evidential basis. Fifty-four per cent of responses were at
      least 2 or more years from these recommended answers. DISCUSSION: Injury
      prevention advice needs to be consistent and, where possible, evidentially based.
      Health professionals often need to rely on their own opinions to provide advice.
      This survey shows opinions vary and highlights the need for evidence-based
      guidelines for parents and professionals.

PMID- 15191420
TI  - Variation in how mothers, health visitors and general practitioners use the
      personal child health record.
AB  - BACKGROUND: In the UK, a national personal child health record (PCHR) with local
      adaptations is in widespread use. Previous studies report that parents find the
      PCHR useful and that health visitors use it more than other health professionals.
      This study was carried out in Nottingham, where the local PCHR is similar to the
      national PCHR. OBJECTIVES: To explore variation in use of the PCHR made by
      mothers with differing social characteristics, to compare heath visitors' and
      general practitioners' (GPs') use of the PCHR, and to compare health visitors'
      and GPs' perceptions of the PCHR with those of mothers for whose children they
      provide care. METHODS: Questionnaires to 534 parents registered with 28 general
      practices and interviews with a health visitor and GP at each practice. A score
      per mother for perceived usefulness of the PCHR was developed from the
      questionnaire, and variation in the score was investigated by linear regression
      adjusted for clustering. RESULTS: Four hundred and one (75%) questionnaires were
      returned. Three hundred and twenty-five (82%) mothers thought the PCHR was very
      good or good. Higher scores for usage of the PCHR were significantly associated
      with teenage and first-time mothers, but no association was found with mother's
      social class, education or being a single parent. There was no association
      between variation in the score and practice, health visitor or GP
      characteristics. Mothers, health visitors and GPs reported that mothers took the
      PCHR to baby clinic more frequently than when seeing their GP, and that health
      visitors wrote in the PCHR more frequently than GPs. Eighteen (67%) health
      visitors and 20 (71%) GPs said they had difficulty recording information in the
      PCHR. CONCLUSION: The PCHR is used by most mothers and is important for providing
      health promotion material to all families with young children. It may be
      particularly useful for first-time and teenage mothers.

PMID- 15191421
TI  - The needs of physically disabled young people during transition to adult
      services.
AB  - OBJECTIVES: The needs and provisions for health service and housing adaptation of
      a cohort of school leavers with physical disabilities in two inner city London
      health districts are described in this cross-sectional study. METHODS: Fourteen
      young people were assessed by two consultant community paediatricians during
      their last year at school, using a structured proforma that includes the British
      Association of Community Child Health standards of functional levels. RESULTS:
      Great difficulty was encountered in identifying the subjects, partly because of
      inadequate information systems. Only 16 were identified out of over 12 000 school
      leavers. Important discrepancies were found between the needs assessed and the
      services provided. For the total sample, the need for 49 potential referrals to
      adult specialist services was identified, but 17 were not made as such services
      did not exist, in contrast to what had been available within paediatric services.
      Adult physiotherapy and occupational therapy services were particularly under
      provided for young people with physical disabilities. Only a minority were
      eligible for housing adaptations. CONCLUSIONS: Suggestions are made for
      improvements in information systems, the transition process, revised provision of
      services and closer involvement of general practitioners.

PMID- 15191422
TI  - How great is the risk of abuse in infants born to drug-using mothers?
AB  - This prospective, cohort study reports early child protection and surveillance
      process markers for children born to self-proclaimed drug-using mothers.
      BACKGROUND: A strong association is reported between maternal drug use and child
      abuse in North American studies. There are no systematic data describing this
      association for the UK population. Given the heterogeneous nature of drug
      cultures and associated behaviour it is difficult to generalize from US data to
      the UK population. METHODS: The study group consisted of all women referred to a
      hospital-based antenatal clinic for pregnant drug users. Infants of non-drug
      users were matched for social class and gestational age. At 18 months the Bristol
      and surrounding area child protection registers and child health surveillance
      records were searched. Infants were coded as to whether they were the subject of
      an enquiry, case conference, registration, registration with subsequent
      deregistration, or taken into care. RESULTS: There were 68 infants of drug users
      and 127 infants of non-drug users. Most (81%) of drug users were heroin and/or
      methadone users; half were using/had used intravenously. Child health
      surveillance uptake for both groups is lower than that reported for the Avon
      population as a whole during the study period, consistent with the relatively
      deprived populations represented. There is no statistically significant
      difference between the drug users and non-drug users. The overall risk of child
      protection proceedings was higher in children of drug users than in children of
      non-drug users. However, closer inspection of the data shows most of the excess
      risk is explained by the small group taken into care and the much larger group
      for whom the concerns were relatively shortlived as shown by their subsequent
      deregistration during the study period. CONCLUSIONS: Maternal drug use does not
      necessarily lead to unacceptable standards of parenting. More UK-based research
      is needed to inform the risk assessment process for child protection.

PMID- 15191423
TI  - Experience of Turkish parents about their infants' teething.
AB  - AIM: To evaluate Turkish parents' experience about their infants' teething; which
      symptoms they have seen and attributed to teething and how they have acted to
      manage these symptoms. METHODS: A questionnaire form was applied by face-to-face
      interview to 335 families who have children less than 18 months of age and have
      at least one tooth. They were asked questions to clarify the eruption time and
      sequence of primary teeth of their infants and whether their infants had some
      symptoms they attributed to teething. RESULTS: The mean eruption time of the
      primary teeth was 7.4 +/- 2.0 months, with a range of 3-17 months. Teeth eruption
      time was found similar in both genders. Teeth eruption time of the term and
      preterm infants was similar. (P > 0.05). The first tooth erupted was the lower
      central incisor in the 288 infants (86.0%) and upper central incisor in 44
      infants (13.1%). Most of the families (98.8%) reported that their children had
      suffered from at least one of the symptoms that were mentioned in the
      questionnaire. The most commonly reported symptom was increase in biting,
      followed by irritability and fever. Of the children who were taken to a health
      care centre, in 78.8% the symptoms were attributed to teething and in 7.1% a
      bacterial infection was found and antibiotics were prescribed. CONCLUSION: When
      an infant at teething age has some symptoms, they may be attributed to teething
      but other possible causes must be ruled out first.

PMID- 15191424
TI  - Relevance of the pH probe in sleep study analysis in infants.
AB  - BACKGROUND: To establish the relationship between sleep apnoea and gastro
      oesophageal reflux in infants and describe the clinical, demographic and pHmetric
      profile and the characteristic of the sleep polysomnography with a pH probe.
      METHODS: A total of 102 consecutive patients were evaluated. Parents were
      requested to fill out a questionnaire about symptoms and previous therapy. Gastro
      oesophageal reflux was considered abnormal when the percentage of time with pH
      less than 4 was higher than 4% of total sleep time. RESULTS: A total of 102
      infants were enrolled, 53% males. Seventy-four per cent of the infants were full
      term babies. At the moment of the polysomnography, the mean age of the sample was
      2.6 months. Suspicion of apnoea was the most common clinical diagnosis prior to
      the study. Only two infants have abnormal electroencephalogram. Mild gastro
      oesophageal reflux was seen in 37 (36%) infants, while 22 (21.5%) did not have
      any reflux episode, and the remaining 43 (42%) infants had reflux index in the
      pathologic range. Only one patient had an unequivocal temporal relationship
      between acid oesophageal reflux and respiratory pause with oxygen desaturation.
      DISCUSSION: Infants with history of apnoea or acute life threatening event
      frequently had gastro-oesophageal reflux episodes which did not correlated with
      respiratory events, suggesting that gastro-oesophageal reflux and apnoea often
      occur in the same infant as two separate events.

PMID- 15191425
TI  - Implications for the development of children in over 11 hours of centre-based
      care.
AB  - BACKGROUND: With increasing numbers of women joining the evening/night-time and
      extended-hour workforce, there is a need for quality childcare during these
      hours. This project, conducted in Japan, sought to compare the effects of
      expanded childcare on the development and adaptation of 648 young children after
      2 years in care. METHOD: All parents in 41 governmentally licensed child care
      facilities in Japan completed a survey on the child-rearing environment at home,
      their feelings of self-efficacy, and the presence of support for childcare to
      provide a baseline of information. Two years later, 648 of these parents were
      surveyed again. Childcare professionals evaluated the development of children at
      both times. RESULTS AND DISCUSSION: The results of multiple regression analysis
      indicate that factors in the home environment, not length of centre-based care,
      explained developmental risks 2 years later.

PMID- 15191426
TI  - The expression of pain in infants with developmental delays.
AB  - OBJECTIVE: To explore how infants with developmental delays express pain, we
      analysed facial expressions of infants receiving their routine immunization at
      around 4-6 months developmental age. The sample included eight infants with
      developmental disabilities (mean developmental age 4.8 months) and 30 typically
      developing infants (mean age 4 months). The Maximally Discriminative Facial
      Movement Coding system was used to code infant facial expressions during
      immunization. RESULTS: The pain expression was by far the most common of all
      facial expressions following immunization for both groups of infants. Those with
      disabilities produced significantly fewer discrete high-intensity expressions of
      pain, and significantly more blended expressions than typically developing
      infants. Expressions of fear, sadness and anger were relatively infrequent in
      both groups. Infants with disabilities used their upper face less often than
      typically developing infants, and their mid face was uncodeable more often.
      CONCLUSION: Infants with developmental delays were likely to show pain in facial
      expressions less clearly than typically developing infants. It is important for
      health care professionals to be aware that this may be the case when considering
      the administration of analgesia for such children.

PMID- 15191427
TI  - Child day care risks of common infectious diseases revisited.
AB  - BACKGROUND: The increased risk of common infectious diseases associated with
      child day care attendance may vary by age, health plan and parent educational
      level. This study determined quantitatively the risk of diarrhoeal illness and
      upper respiratory infection (URI) among day-care children in comparison with home
      care children. It examined the extent of risks in day-care children under
      different conditions of three age groups, enrolled in two health plans, and from
      families of two levels of education. METHODS: The study subjects were recruited
      through two health plans: a Health Maintenance Organization (HMO) and the
      Medicaid program in Columbia, South Carolina of the USA. The sample was collected
      using a household survey of children, aged 5 years or younger. The participants
      were contacted bimonthly for 18 months with 435 attending out-of-home day care
      facilities and 753 being cared for at home. The potential confounding factors of
      family characteristics were controlled in examining the odds ratios for day care
      effect on common infections in children under different conditions. RESULTS: In
      general, risks of diarrhoeal illness and URI in day-care children are greater
      than in home-care children. Children younger than 1.5 years of age attending day
      care and covered by the Medicaid program are at the greatest risk. The difference
      in risks between day-care and home-care children, however, is reduced to an
      insignificant level for children older than 1.5 years of age and for children
      covered by the HMO health plan. Among day-care children, those who are covered by
      the Medicaid program are at a significantly higher risk than those who are
      covered by the HMO health plan. CONCLUSIONS: Although day-care children in
      general suffer a greater risk of common infectious diseases, the extent of day
      care effect on risks of diarrhoeal illness and URI varies significantly by age
      and type of health insurance plan.

PMID- 15191428
TI  - Body weight perception among Bahraini adolescents.
AB  - BACKGROUND: This study examines the relationship between actual weight status and
      perceptions of body weight in Bahraini adolescents. The study also investigates
      the adolescents' perceptions of parents' and peers' opinions of weight. METHODS:
      A cross-sectional survey of 447 Bahraini male and female adolescents aged 12-17
      years was conducted. Weight and height were measured and body mass index (BMI)
      was calculated. A short questionnaire was used to obtain their attitudes towards
      their weight status, as well as the attitudes of their parents and friends. The
      nine figure silhouettes illustration was used to measure perception of ideal body
      image and how it compares with their current body weight. RESULTS: The results
      revealed a significant discrepancy between adolescents' perception of body weight
      and actual BMI. There was a tendency for teenagers to underestimate their weight
      status, which was especially noteworthy among the overweight and obese. More than
      half of the girls and about one-third of the boys expressed discontent with their
      current body weight. One-third (33.5%) and 26.6% of the adolescents thought that
      their parents and their peers, respectively, would consider them to be overweight
      or obese. The percentage of adolescents who reported parental or peer
      underestimation was higher among those classified as overweight or obese than it
      was among those who were of normal weight. CONCLUSION: The study shows the
      existence of a distorted body image as reflected by failure of many overweight or
      obese adolescents to perceive themselves as such. Among Bahraini adolescents
      weight-related beliefs and attitudes exist at two ends of the spectrum: a
      tolerance of obesity at one end and an exaggerated concern for its occurrence at
      the other.

PMID- 15191429
TI  - Ethical issues in social research: difficulties encountered gaining access to
      children in hospital for research.
AB  - BACKGROUND: This paper recounts the difficulties experienced when the authors
      sought access to children in hospital for social research interviews. These were
      part of a 2-year study, funded by the Joseph Rowntree Foundation, aiming to
      explore the numbers, circumstances and experiences of children who spend
      prolonged periods in health care settings. METHODS: As the intention was to carry
      out 'guided conversations' with 24 young people in various different NHS
      locations, permission to do so was sought from a multi-site research ethics
      committee (MREC), and from several local research ethics committees (LRECs).
      Agreement was then necessary from NHS trusts, which were asked to nominate a
      liaison person to help identify and recruit children to the study. Consent was
      also required from individual parents and children. A series of unexpected delays
      encountered during this process are discussed in some detail. Eventually a sample
      of 15 children was achieved. DISCUSSION: The second part of the paper locates
      this experience within a wider context, noting that similar difficulties gaining
      access to children in NHS settings have recently been reported by other social
      researchers. Several possible reasons for this trend are identified and
      discussed. These relate to the role of MRECs and LRECs in screening social
      research proposals, recently implemented legislation about data protection,
      heightened concerns within the NHS about confidentiality and consent, and
      increasing awareness of the risk of child abuse in health care settings.
      CONCLUSION: Finally, some suggestions for facilitating the access process are
      discussed. They include the sensitive and appropriate application of research
      governance frameworks to social research - including studies within health care
      settings. Ethical considerations and adequate protection of children are vital
      but, the authors argue, wherever possible children themselves should be
      encouraged to decide whether or not to participate in research. In addition,
      unnecessarily complex access procedures may adversely affect research outcomes.

PMID- 15191430
TI  - Maternal distress, child behaviour, and disclosure of psychosocial concerns to a
      paediatrician.
AB  - BACKGROUND: Despite the availability of effective screening measures, primary
      care providers continue to fail to identify and manage many children with
      psychosocial problems. One of the best predictors of identification by a primary
      care physician is whether mothers disclose concerns about their child's
      psychosocial functioning to their child's physician. This study examined if
      maternal distress and child behaviour predicted whether mothers had and discussed
      concerns about their child's behaviour and emotions with paediatricians. METHODS:
      Participants were 138 mothers who accompanied their 4-12-year-old children to a
      health supervision visit at an urban teaching hospital. Mothers completed a
      demographic questionnaire, the Pediatric Symptom Checklist, the Beck Depression
      Inventory, and an exit questionnaire. Results Logistic regression correctly
      classified 97.3% of mothers who did not disclose child problems. Only 34.5% of
      mothers who did disclose were correctly classified. CONCLUSIONS: The results
      supported the hypothesis that mothers' psychosocial functioning is significantly
      related to concern about child behaviour and disclosure of concerns to the
      paediatrician. The inability of child behaviour and maternal functioning to
      predict which mothers were concerned and disclosed concerns supports the
      hypothesis that disclosure and identification of psychosocial problems in primary
      care is complex and requires a multifactor model.

PMID- 15191439
TI  - William Smellie's obstetrical forceps.

PMID- 15191440
TI  - Medical professionalism and continuing professional development for medical
      specialists.
AB  - The present paper briefly describes a growing trend in continuing professional
      development (CPD) for medical practitioners, examines some recent published
      contributions related to professionalism in medicine and describes the
      theoretical platform of a CPD framework based on medical professionalism that has
      been developed for use in a variety of medical specialties. The work arises from
      a project funded by The Commonwealth Department of Health and Ageing and
      conducted by the Royal Australian and New Zealand College of Obstetricians and
      Gynaecologists on behalf of the Committee of Presidents of Medical Colleges.
      Overall, the aim of the project was to design and develop a framework that can be
      considered 'best practice' in the field of medical specialist CPD, and which
      could be applicable to a wide variety of medical specialties and practice
      environments. The project was informed by available literature in areas such as
      the ways in which medical practitioners learn and the effectiveness of CPD, as
      well as consultations with a variety of stakeholders in the health-care field,
      including medical boards, medical defence organisations, health complaints
      organisations, specialist medical colleges and practising specialists.
      Overwhelmingly, the primary purpose of specialists participating in ongoing CPD
      was, according to the project consultations conducted, the maintenance,
      development and improvement of skills that enable consumers of healthcare to be
      confident of the level of care that they receive. Coupled with the need to
      recognise CPD as contributing to the wider context of professional practice, the
      resulting framework is underpinned by a theoretical platform based on the concept
      of medical professionalism. It is this theoretical platform, which articulates
      the nature of and responsibilities associated with the practice of specialist
      medicine, that enables a CPD framework to be constructed that can accommodate a
      wide range of specialist disciplines and practice settings, while also framing
      ongoing education expectations from the viewpoint of a range of stakeholders,
      rather than a single perspective; that of practitioners themselves.

PMID- 15191441
TI  - Diagnostic radiography in pregnancy: risks and reality.
AB  - BACKGROUND: The use of X-rays, computed tomography scanning and nuclear medicine
      imaging in the pregnant woman is a source of great anxiety for the patient, her
      family and the treating doctor. METHODS: A literature review of appropriate
      databases, articles and relevant institutional protocols was performed. Data was
      sought regarding any adverse effects of diagnostic radiation in pregnancy, fetal
      absorbed dose of diagnostic radiation and how the timing of exposure and form of
      administration might influence these effects. RESULTS: The estimated radiation
      dose for a fetus from background sources as well as medical imaging was
      identified. Most diagnostic radiation procedures will lead to a fetal absorbed
      dose of less than 1 mGy for imaging beyond the abdomen/pelvis and less than 10
      mGy for direct or nuclear medicine imaging. Potential adverse outcomes related to
      radiation exposure during pregnancy include teratogenicity, genetic damage,
      intrauterine death and increased risk of malignancy. The only adverse effect
      statistically proven at the dose levels associated with diagnostic radiation
      procedures is a very small increase in childhood malignancy, with an estimated
      increase of one additional cancer death per 1700 10 mGy exposures. The important
      exception was the risk to the fetal thyroid from radioiodine exposure after 12
      weeks' gestation. CONCLUSION: In practice, diagnostic radiography during
      pregnancy not involving direct abdominal/pelvic high dosage, is not associated
      with any significant adverse events. Counselling of pregnant women who require
      diagnostic radiographic procedures as well as those inadvertently exposed should
      be based on the available human data with an emphasis on the minimal impact of
      such procedures.

PMID- 15191442
TI  - HIV and pregnancy in Australia.
AB  - It is estimated there are over 19 million women worldwide living with HIV
      infection. In Australia the total number of notified cases of HIV in women has
      been gradually increasing (the estimated number of women newly diagnosed with HIV
      infection was 78 in 2000 and 94 in 2001). Management of women in pregnancy and
      strategies to reduce perinatal transmission is critical, but differ significantly
      according to resource availability. The current review examines the best
      available scientific evidence and current guidelines for optimal management of
      HIV-infected women contemplating pregnancy in Australia.

PMID- 15191443
TI  - Prospective evaluation of a first trimester screening program for Down syndrome
      and other chromosomal abnormalities using maternal age, nuchal translucency and
      biochemistry in an Australian population.
AB  - BACKGROUND: A combination of maternal age and ultrasound assessment of the nuchal
      translucency (NT) has been used in the first trimester to screen for chromosomal
      abnormality. In the United Kingdom, the addition of NT screening was shown to be
      beneficial. AIMS: To report the sensitivity of combined first trimester
      biochemistry and ultrasound screening for Down syndrome in an Australian private
      practice specialising in obstetric ultrasound. METHODS: A prospective study in a
      private obstetric ultrasound practice. Over 22 months, 2121 patients were
      screened and data was analysed for sensitivity (detection) and false positive
      rates for all chromosome abnormalities. RESULTS: There were 17 chromosomal
      abnormalities, five of which were Down syndrome. Using maternal age alone or age
      and biochemistry, four of the Down syndrome cases were detected for a 29 and 19%
      false positive rate, respectively. Using age and NT or age, NT and biochemistry,
      all the Down syndrome cases were detected, for a false positive rate of 5.7 and
      7.2%, respectively. The difference in detection rates for Down syndrome or other
      chromosomal abnormalities, using the four screening methods, did not reach
      statistical significance. However, the false positive rates in screening methods
      without ultrasound to assess the NT was significantly higher (P < 0.01).
      CONCLUSIONS: A combination of maternal age, NT and maternal serum biochemistry
      gives a high detection rate for both trisomy 21 and other chromosomal
      abnormalities. Down syndrome screening using either maternal age alone or age in
      combination with first trimester biochemistry conferred screen positive rates
      significantly higher than when combined with NT.

PMID- 15191444
TI  - Is placenta accreta catching up with us?
AB  - BACKGROUND: Concomitant with the increase in Caesarean birth over the past three
      decades there has been an apparent rise in the incidence of placenta accreta and
      its variants. The sequelae of an increase in the occurrence of abnormal
      placentation is the enhanced potential for severe maternal morbidity. AIM: To
      determine the contempory demographics of placenta accreta over a 5-year period in
      a tertiary level teaching hospital. METHODS: A retrospective review of all cases
      of placenta accreta and variants during the period of 1998-2002. Individual
      charts review followed case ascertainment via the hospital obstetric database.
      RESULTS: Thirty-two women with placenta accreta (or variant) were identified.
      Median maternal age was 34 years, with a median parity of 2.5. Seventy-eight
      percent of cases had had at least one prior Caesarean birth, and 88% of cases
      were associated with placenta praevia. Pre-delivery ultrasonography was performed
      in all cases, providing diagnostic sensitivity of 63% and specificity of 43% with
      a predictive value of 76%. Hysterectomy was performed in 91% of cases with median
      intraoperative blood loss of 3000 mL. There were no maternal deaths in the
      current series. CONCLUSION: A strong association between placenta accreta,
      placenta praevia and prior Caesarean birth has been demonstrated. As there is the
      potential for significant maternal morbidity the risk of placenta accreta needs
      to be recognised and women at risk should be considered for delivery at an
      institution with appropriate expertise and resources in managing this condition.

PMID- 15191446
TI  - Maternal and neonatal outcomes in 54 triplet pregnancies managed in an Australian
      tertiary centre.
AB  - BACKGROUND: To provide current data on maternal and neonatal outcomes in triplet
      pregnancies in an Australian population. METHODS: Retrospective case note review
      of all triplet pregnancies managed within a single Australian tertiary centre.
      RESULTS: Fifty-four sets of triplets were managed from January 1996 to October
      2002. A total of 59% resulted from the use of assisted reproductive technologies.
      The median gestation at delivery was 32.5 weeks (range: 21-36 weeks); 14%
      delivered prior to 28 weeks and 43% delivered before 32 weeks. Preterm labour and
      preterm rupture of membranes were the most common antenatal complications
      occurring in 57 and 22% of pregnancies, respectively. A total of 93% of
      pregnancies were delivered by Caesarean section and 37% of mothers experienced at
      least one post-partum complication. A total of 96% of neonates were liveborn,
      with a median birthweight of 1644 g (range: 165-2888 g). The two most common
      neonatal complications were jaundice and hypoglycaemia in 52 and 43% of liveborn
      neonates, respectively. A total of 28% of neonates were below the 10th centile
      for gestational age and sex. A total of 8% of neonates demonstrated congenital
      anomalies. The perinatal mortality at a gestational age of 20-24 weeks was 100%,
      22% at 25-28 weeks and zero for those babies born at 29 weeks or beyond.
      CONCLUSION: Assisted reproductive technologies contribute significantly to the
      incidence of triplet pregnancies. Gestational age at delivery and perinatal
      mortality is comparable to published international data. Triplets born in a
      tertiary centre beyond 28 weeks gestation have a very favourable prognosis in the
      newborn period.

PMID- 15191445
TI  - Hysterectomy for gynaecological cancer: a follow-up study of subjective and
      objective outcome.
AB  - AIMS: To evaluate morbidity and subjective outcome associated with hysterectomy
      either with or without pelvic or pelvic and para-aortic lymphadenectomy for
      gynaecological cancer. METHODS: Ninety-nine patients who underwent hysterectomy
      with lymphadenectomy (n = 38) or simple hysterectomy (n = 61) for ovarian,
      endometrial and cervical cancer in Turku University Hospital, Turku, Finland,
      were followed-up prospectively to determine the incidence of complications during
      a 1-year period after operation. Subjective outcomes were assessed using two
      questionnaires, 6 weeks and 1 year after operation. Hospital records of the
      patients were reviewed up to 6 years after operation. RESULTS: During their
      hospital stay 58% of patients in the hysterectomy with lymphadenectomy group and
      56% in the simple hysterectomy group experienced some type of complication.
      Serious complications occurred in four patients (10.5%) in the former group and
      in two patients (3.3%) in the latter group. In the study population overall, the
      incidence of subjective complaints increased from 18% of respondents 6 weeks
      after operation to 55% 1 year after operation. Most patients (95 and 92%,
      respectively) remained satisfied with the operation at both times of evaluation.
      CONCLUSIONS: More than half of the patients experienced morbidity related to
      surgical treatment for gynaecological cancer. The incidence of complications and
      subjective complaints were unaffected by the type of operation.

PMID- 15191447
TI  - Cervical surveillance as an alternative to elective cervical cerclage for
      pregnancy management of suspected cervical incompetence.
AB  - OBJECTIVE: The aim of the present study was to compare the outcome of pregnancies
      among patients with suspected cervical incompetence treated either by elective
      cervical cerclage or an alternative management program involving cervical
      surveillance. DESIGN, SETTING AND METHODS: A prospective cohort study was
      performed in two groups of patients at risk of cervical incompetence with
      singleton gestations attending the Royal Women's Hospital, Melbourne, Australia,
      from 1996 to 2000. The first group was managed by their obstetric carers with an
      elective cerclage, while the second group was managed conservatively as part of a
      cervical surveillance program offered to patients attending the Department of
      Perinatal Medicine for pregnancy care. This program consists of weekly visits
      from 16 weeks' gestation and involves alternating transvaginal ultrasound
      assessment of cervical morphometry with cervico-vaginal bacteriology and fetal
      fibronectin swabs. Empiric insertion of a cerclage is undertaken when there is
      evidence of significant cervical shortening (cervical canal <2.5 cm in length at
      </=24 weeks). RESULTS: A total of 135 patients were identified for the study.
      Ninety-seven patients had an elective cervical cerclage inserted. Thirty-eight
      patients were followed through the cervical surveillance program. Twelve (32%) of
      the surveillance patients had a cerclage inserted at a mean gestational age of
      20.6 weeks. There were no statistically significant differences between the
      groups in terms of maternal demographics or risk assessment scoring. One out of
      38 (2.6%) patients of the surveillance group and 18/97 (18.6%) of the elective
      cerclage group delivered before 30 weeks' gestation (P = 0.034). CONCLUSIONS: Our
      study suggests that by only inserting a cerclage when indicated on the basis of
      ultrasound assessment of cervical morphometry, the number of cerclages required
      can be reduced while the perinatal outcome is significantly improved.

PMID- 15191448
TI  - People who influence women's decisions and preferred sources of information about
      prenatal testing for birth defects.
AB  - BACKGROUND: More than half of Victorian pregnant women are undergoing prenatal
      testing for birth defects, although little is known about the factors that are
      influencing their decisions. AIMS: To examine whom women perceived as influencing
      their decision about prenatal testing for birth defects, with whom they would
      have liked to talk more, and what sources of information they preferred. METHODS:
      A total of 737 pregnant women aged 37 years and over, who either had or had not
      undergone prenatal testing (screening and/or diagnosis) completed a questionnaire
      in 18 hospitals throughout Victoria. RESULTS: Over 90% reported that they
      themselves had a strong influence on their decision, and 70% reported their
      partner as strongly influencing their decision. Approximately 30% of women who
      had both screening and diagnosis and more than 20% of women who had no prenatal
      testing, would like to have discussed prenatal testing with women who had
      previously had testing. Face-to-face counselling with a doctor or counsellor was
      the preferred source of information, followed by a pamphlet as the second choice.
      CONCLUSIONS: Given that both tested and untested women felt so strongly that they
      were responsible for their own decisions about prenatal testing, it is unlikely
      that universal acceptance and uptake will occur, even in this group of women of
      advanced maternal age. A support network of women who have already had testing
      could supplement existing sources of support. However, there continues to be a
      need for face-to-face sessions with a doctor or counsellor in combination with
      printed material.

PMID- 15191449
TI  - Prostitution and other cofactors in preinvasive and invasive lesions of the
      cervix.
AB  - OBJECTIVE: To examine risk factors for preinvasive and invasive lesions of the
      cervix in Venezuelan female sex workers (FSW). METHODS: A total of 438 FSW were
      analysed. Each FSW had their clinical history recorded, a gynaecological
      examination, a Pap smear and a colposcopic examination of the cervix. A cervical
      biopsy was taken under colposcopic guidance when there was an abnormal
      epithelium. The statistical methods used were Student's t-test, chi(2) test and
      logistic regression. RESULTS: The sex workers' mean age was 32.1 +/- 7.9 years
      old (mean +/- standard deviation). The age of the first sexual intercourse
      activity for the FSW was 15.9 +/- 2.1 years. Sixty-four of the 84 women (76.2%)
      who had cervical biopsies had preinvasive and invasive lesions; 41 (9.4%) had
      cervical intra-epithelial neoplasia (CIN) 1, 12 (2.7%) had CIN 2, eight (1.8%)
      had CIN 3, two (0.5%) had microinvasive carcinoma, and one (0.2%) had invasive
      carcinoma. Forty of these 64 women (62.5%) with preinvasive or invasive lesions
      had a concurrent histological diagnosis of human papilloma virus (HPV) infection
      (P < 0.0001). The FSW with cervical pathology were younger (P < 0.05) and had
      their first sexual intercourse earlier (P < 0.02) than FSW with no pathology. Two
      hundred and seventy-six (63%) of the FSW were current smokers, and 47 of these
      women (17.6%) had cervical pathology (P < 0.03). CONCLUSIONS: First sexual
      experience before 20 years of age, cigarette smoking and HPV infection were high
      risk factors for preinvasive and invasive lesions of the cervix in Venezuelan
      FSW.

PMID- 15191450
TI  - Early repair of episiotomy dehiscence.
AB  - We retrospectively reviewed the medical records of our hospital between 1 March
      2001 and 1 March 2003 for patients with episiotomy dehiscence. In the study
      period, there were 37 patients with episiotomy dehiscence. While 12 of the
      patients with episiotomy dehiscence were allowed to heal by secondary intention,
      25 patients underwent early repair. All the episiotomies were mediolateral.
      Infection was the obvious cause of dehiscence in the majority (25 out of 37) of
      the women. The average time from recognition of dehiscence to discharge from
      hospital was 5.6 +/- 2.8 days for the patients with early repair of episiotomy
      dehiscence and 5.8 +/- 2.4 days in patients allowed to heal by secondary
      intention. Patients were seen 2 weeks after being discharged. Among the patients
      treated by early repair, three patients had a superficial separation of skin
      edges. Healing was complete in the rest of the patients with early repair of
      episiotomy dehiscence. We concluded that with adequate preoperative care,
      primarily wound cleansing and intravenous antibiotics, early repair of episiotomy
      dehiscence is safe and effective.

PMID- 15191451
TI  - Levonorgestrel-releasing intrauterine system for treating menstrual disorders: a
      patient satisfaction questionnaire.
AB  - AIMS: To establish the continuation and satisfaction rates and the reasons for
      removal of the levonorgestrel-releasing intrauterine system (LNG-IUS) in
      Palmerston North Hospital (PNH), New Zealand. SAMPLE AND SETTING: All women (120)
      who had a LNG-IUS inserted at PNH between June 1998 and June 2002 were included
      in the study. METHODS: A survey questionnaire regarding bleeding patterns, side
      effects and satisfaction rates relating to the device as well as reasons for
      premature removal, current treatment for dysfunctional uterine bleeding (DUB) and
      contraception was sent to all 120 women. Seventy-eight of the 85 women who
      received the questionnaire (91%) responded to it. Thirty-five women were lost to
      follow-up and the overall response rate was 65%. RESULTS: The LNG-IUS was
      prematurely removed from nine women and expulsion occurred in one case. The
      overall continuation rate was 87%. No women had LNG-IUS removed as a result of
      hormonal side-effects except for bleeding abnormalities. The overall satisfaction
      rate was 76%. CONCLUSION: Levonorgestrel-releasing intrauterine system is a well
      accepted and efficacious therapy for heavy menstrual bleeding. These satisfaction
      and premature removal rates compare favourably with international figures. The
      response rate to the questionnaire was reasonably high given the highly mobile
      nature of the studied population.

PMID- 15191452
TI  - Women with low-grade abnormalities on Pap smear should be referred for
      colposcopy.
AB  - AIM: To assess cytological, colposcopic and histological outcomes in women
      referred to a teaching hospital dysplasia clinic with low-grade changes on
      screening Pap smear. METHODS: Analysis of a computerised database. RESULTS:
      Repeating the Pap test was of little value. Fifteen percent of women with low
      grade changes on the referral smear had biopsy proven high-grade change. There
      was little difference in biopsy proven high-grade change in women referred with
      an 'abnormal smear of uncertain significance' (23%) or 'an abnormal smear of
      uncertain significance-possible high-grade change' (24%). CONCLUSIONS: Given
      these findings and the current medico-legal climate, immediate referral of women
      with low-grade changes on routine cytology is indicated, and seems a safer option
      than the more conservative approach of a repeat smear in 6 or 12 months. Further
      study of the usefulness of separating smears of uncertain significance into high
      grade and low-grade categories is warranted. Consumer input into recommendations
      for management of Pap smear abnormalities is required.

PMID- 15191453
TI  - Two cases of heterotopic cornual pregnancy with initially missed diagnosis.

PMID- 15191454
TI  - Triple pregnancy: intrauterine and bilateral tubal ectopic pregnancies.

PMID- 15191455
TI  - Pregnancy from intracytoplasmic injection of a frozen-thawed oocyte.

PMID- 15191456
TI  - Ischaemic stroke associated with ovarian hyperstimulation syndrome and factor V
      Leiden mutation.

PMID- 15191457
TI  - Spontaneous bilateral chronic and acute tubal ectopic pregnancies following
      methotrexate treatment.

PMID- 15191459
TI  - Laparoscopic unwinding and cyst aspiration of an ovarian torsion in spontaneous
      ovarian hyperstimulation syndrome associated with a singleton pregnancy.

PMID- 15191458
TI  - Carcinoma of uterine cervix primarily presenting as carcinomatous meningitis: a
      case report.

PMID- 15191460
TI  - Relapse of non-Hodgkin's lymphoma confined to the corpus uteri.

PMID- 15191461
TI  - Re: Complex long-term eating disorder, Bartter's syndrome and pregnancy: a rare
      combination.

PMID- 15191463
TI  - Reply to article by King et al.

PMID- 15191465
TI  - Re: Gestational diabetes. What happens post-partum?

PMID- 15191466
TI  - People with colorectal cancer: can we help them do better?

PMID- 15191467
TI  - Access to breast-conserving treatment: are surgeons responsible?

PMID- 15191468
TI  - Variations in procedure rates: a need for population-based surgical research.

PMID- 15191469
TI  - Colorectal cancer patterns of care in the Western Sydney and Wentworth Area
      Health Services.
AB  - INTRODUCTION: Colorectal cancer is a leading cause of morbidity and mortality in
      Australia. Recent clinical trials show that the recurrence of colorectal cancer
      decreases with chemotherapy and/or radiotherapy in advanced disease. The present
      study aimed to document the patterns of care by the type of treatment, document
      the preoperative investigations and provide results to the Area Health Services.
      METHODS: A prospective data collection was initiated in May 1994 and ended in May
      1996 in the Western Sydney and Wentworth Area Health Services of New South Wales.
      Deaths and recurrences were followed up until July 2002. RESULTS: There were 253
      colon cancers, 107 rectal cancers and 10 patients with tumours in both the colon
      and rectum. Forty-one surgeons performed 299 curative procedures with 78% of them
      performing one to four procedures annually. One hundred and twenty-two patients
      had non-fatal complications and six (2%) died postoperatively. Twenty-eight per
      cent of rectal cancer patients underwent abdomino-perineal resection and 56%
      underwent low anterior resection. Forty-five per cent of rectal cancer patients
      and 51% of colon cancer patients who were potentially eligible received
      appropriate adjuvant therapy. Ninety-one per cent of patients who received
      chemotherapy had no or mild toxicity. By the end of follow-up period, 30% of
      rectal cancer patients and 24% of colon cancer patients had developed recurrence.
      At last follow up, 197 patients had died. Median overall survival from time of
      diagnosis was 73 months. Overall 5-year survival for colonic and rectal cancers
      was 50% and 57%, respectively. For the 299 patients who had curative procedures,
      the 5-year survival was 63% and 62% for colonic and rectal cancers, respectively.
      CONCLUSION: Colorectal cancer patients who were eligible for and received
      adjuvant therapy had significantly better survival. Rectal cancer patients whose
      tumours only required low anterior resection had a better survival than those who
      needed an abdomino-perineal resection. High-volume surgeons have less
      postoperative complications than low-volume surgeons. The high proportion of late
      presentations seen in colon cancer patients supports the need for screening to
      improve early detection.

PMID- 15191470
TI  - Unequal access to breast-conserving surgery in Western Australia 1982-2000.
AB  - BACKGROUND: The purpose of the present study was to examine the effects of
      demographic, locational and social disadvantage and the possession of private
      health insurance in Western Australia on the likelihood of women with breast
      cancer receiving breast-conserving surgery rather than mastectomy. METHODS: The
      WA Record Linkage Project was used to extract all hospital morbidity, cancer and
      death records of women with breast cancer in Western Australia from 1982 to 2000
      inclusive. Comparisons between those receiving breast-conserving surgery and
      mastectomy were made after adjustment for covariates in logistic regression.
      RESULTS: Younger women, especially those aged less than 60 years, and those with
      less comorbidity were more likely to receive breast-conserving surgery (BCS). In
      lower socio-economic groups, women were less likely to receive BCS (OR 0.73; 95%
      CI 0.60-0.90). Women resident in rural areas tended to receive less BCS than
      those from metropolitan areas (OR 0.84; 95% CI 0.55-1.29). Women treated in a
      rural hospital had a reduced likelihood of BCS (OR 0.74; 95% CI 0.61-0.89).
      Treatment in a private hospital reduced the likelihood of BCS (OR 0.70; 95% CI
      0.54-0.90), while women with private health insurance were much more likely to
      receive BCS (OR 1.39; 95% CI 1.08-1.79). CONCLUSION: Several factors were found
      to affect the likelihood of women with breast cancer receiving breast-conserving
      surgery, in particular, women from disadvantaged backgrounds were significantly
      less likely to receive breast-conserving surgery than those from more privileged
      groups.

PMID- 15191471
TI  - Complications of intercostal catheter insertion using EMST techniques for chest
      trauma.
AB  - BACKGROUND: The purpose of the present study was to determine the complication
      rates associated with intercostal catheter insertion (ICI) performed using Early
      Management of Severe Trauma (EMST) guidelines on trauma patients admitted through
      The Alfred Trauma Centre. METHODS: The Alfred Trauma Registry identified
      demographic and clinical data for patients who underwent ICI in the Alfred
      hospital following admission for trauma. The medical histories were subsequently
      reviewed for complications resulting from ICI. RESULTS: There were 211 ICI
      performed on 173 trauma patients at The Alfred Trauma Centre between July 2001
      and June 2002. The mean injury severity score was 34. Mean age was 38 (range 15
      82 years), with 77% of the patients being men. Chest injury was the result of
      blunt trauma in 90.2% and penetrating trauma in 9.8%. ICI occurred in the Trauma
      Centre (84%), operating theatre (6%), intensive care unit (9%) and in the general
      ward (1%). Eighty per cent of patients had a unilateral ICI. The indications for
      ICI were pneumothorax (45.7%), haemothorax (15.0%), haemopneumothorax (28.3%) and
      tension pneumothorax (7.5%). There were no insertional and 11 (5.2%) positional
      complications. The infection rate was 2.4% comprising two superficial and three
      deep (empyema thoraces) infections. No statistically significant association was
      found between infective complications and age, injury severity score (ISS),
      haemothorax, penetrating trauma, prehospital needle thoracostomy and time to ICI.
      There was no mortality arising from ICI complications. CONCLUSION: Intercostal
      catheter insertion for chest trauma performed in accordance with EMST guidelines
      has a low complication rate. Prehospital prophylactic chest decompression for
      ventilated patients with chest trauma, using a lateral rather than an anterior
      approach, may decrease the incidence of untreated tension pneumothorax.

PMID- 15191472
TI  - Developing Australia's first statewide trauma registry: what are the lessons?
AB  - Trauma registries, like disease registries, provide an important analysis tool to
      assess the management of patient care. Trauma registries are well established and
      relatively common in the USA and have been used to change legislation, promote
      trauma prevention and to evaluate trauma system effectiveness. In Australia, the
      first truly statewide trauma registry was established in Victoria in 2001 with an
      estimated capture of 1700 major trauma cases annually. The Victorian State Trauma
      Registry, managed by the Victorian State Trauma Outcomes Registry and Monitoring
      (VSTORM) group, was established in response to a ministerial review of trauma and
      emergency services undertaken in 1997 to advise the Victorian Government on a
      best practice model of trauma service provision that was responsive to the
      particular needs of critically ill trauma patients. This taskforce recommended
      the establishment of a new system of care for major trauma patients in Victoria
      and a statewide trauma registry to monitor this new system. The development of
      the Victorian state trauma registry has shown that there are certain issues that
      must be resolved for successful implementation of any system-wide registry. This
      paper describes the issues faced by VSTORM in developing, implementing and
      maintaining a statewide trauma registry.

PMID- 15191473
TI  - Laparoscopic adrenalectomy for phaeochromocytoma: with caution.
AB  - INTRODUCTION: Laparoscopic adrenalectomy is well described and many series
      include patients with phaeochromocytoma. Our aim was to establish whether
      laparoscopic adrenalectomy for phaeochromocytoma was a safe and feasible
      technique at our institution. METHODS: Patients requiring adrenalectomy were
      entered into a prospective database that included patient details, operative
      data, hormone excretion, tumour size, hospital stay and complications. All
      operations were performed under the supervision of a single surgeon. Analysis was
      performed for those patients with a diagnosis of phaeochromocytoma. RESULTS: Of
      60 patients having laparoscopic adrenal surgery, 18 had phaeochromocytoma as the
      indication. Seventeen (89%) of 19 tumours in these 18 patients were successfully
      removed laparoscopically. Median operative time was 180 min (range 130-300 min)
      and this was significantly longer compared with other adrenal pathology. The
      median tumour size was 6 cm which was significantly larger than other adrenal
      tumours. Seven (38%) patients developed complications and median postoperative
      inpatient stay was 5 days (range 3-8 days). CONCLUSIONS: The postoperative stay
      was equivalent to other laparoscopic series and laparoscopic removal was
      successful in 89%. The laparoscopic approach to the adrenal gland in
      phaeochromocytoma is safe and effective treatment.

PMID- 15191475
TI  - Antireflux anastomosis following oesophagectomy.
AB  - BACKGROUND: Reflux of duodeno-gastric fluid is a significant problem after
      oesophagectomy with gastric conduit reconstruction. It can impact considerably
      upon the patient's quality of life and can induce oesophagitis and Barrett's
      metaplasia in the remnant oesophagus. AIM: The aim of the present study was to
      describe the use of a modified fundoplication in controlling reflux after
      oesophagectomy. METHODS: Patients undergoing subtotal oesophagectomy at the Royal
      Adelaide Hospital were identified. Clinical and operative details were obtained
      from hospital records. All patients had an end oesophagus to side stomach
      anastomosis. Two cohorts were identified - one with a standard anastomosis only
      and the other in whom a modified fundoplication had been added. A structured
      phone interview was used to assess reflux in the two groups with a minimum of 6
      months follow up. The interviewer was blinded to the operative details. RESULTS:
      The operative technique is described. A total of 44 patients were assessed, 33
      having the fundoplication type anastomosis and 11 the standard anastomosis.
      Operative morbidity was not different between the groups. Symptoms of reflux were
      better controlled in patients with the fundoplication anastomosis than in
      patients with a standard anastomosis. Of those with a fundoplication, 14 of 33
      patients (42%) were asymptomatic with respect to reflux compared to only one of
      11 patients (9%) in the standard anastomosis group. Only four of the 33 patients
      (12%) with a fundoplication anastomosis had symptoms of severe reflux while seven
      of the 11 patients (63%) with a standard anastomosis had severe reflux symptoms.
      CONCLUSIONS: This initial evaluation of a modified fundoplication as an
      antireflux manoeuvre after oesophagectomy suggests that the technique is
      effective in controlling post-oesophagectomy reflux in the majority of patients.
      It is simple to perform and may have benefits in improving quality of life and
      preventing oesophagitis and metaplastic changes in the remnant oesophagus. A more
      detailed prospective study of the technique is warranted.

PMID- 15191477
TI  - Surgical masks: operative field contamination following visor-to-visor contact.
AB  - BACKGROUND: Clashing of surgical visor masks frequently occurs when two surgeons
      bend over an operative field simultaneously; however, it is unknown whether this
      results in contamination. The purpose of the present study was to determine the
      potential for operative field contamination following surgical visor-mask
      clashes. The nature of bacterial contamination was also assessed. METHODS: Thirty
      sham operative procedures were performed under normal operating conditions for a
      specified time period. The number of surgical visor mask clashes during each
      procedure was determined by randomization (0, 1, 2, 3, 4 or 6 clashes). All
      procedures were performed over a standard blood agar plate array. The degree of
      bacterial contamination was assessed by counting c.f.u. that developed after 24 h
      of incubation. Bacterial types were also determined. RESULTS: Surgical visor mask
      clashes resulted in increased contamination of the operative field; however, this
      was found to be independent of the number of clashes. 95% of pathogens were
      coagulase negative Staphylococcus species. Other bacteria included Micrococcus
      species, Bacillus species, Corynebacterium species, various Gram negative bacilli
      and Staphylococcus aureus (< 1%). CONCLUSION: Surgical visor mask clashes
      increase the risk of bacterial contamination of the operative field.

PMID- 15191478
TI  - Horner's syndrome in association with thyroid and parathyroid disease.
AB  - BACKGROUND: Injury to the cervical sympathetic chain and its consequence,
      Horner's syndrome, as a result of thyroid pathology or surgical intervention is
      an uncommon complication. The purpose of the present study was to examine the
      experience of one endocrine surgical unit with pre and postoperative Horner's
      syndrome. METHODS: This is a retrospective case series. The study group comprised
      all patients undergoing thyroid and parathyroid surgery at Royal North Shore
      Hospital from January 2000 to October 2003 who were identified as having either
      pre or postoperative Horner's syndrome. Patient demographics, operation
      performed, underlying pathology and outcomes were evaluated. RESULTS: There were
      nine cases of Horner's syndrome recorded from a total of 2208 thyroid and
      parathyroid operations undertaken: three with preoperative Horner's, an incidence
      of 0.14%, six with postoperative Horner's, an incidence of 0.27%. Patients ranged
      in age from 22 to 87 years. Two of the three preoperative cases were related to
      benign pathology, the remaining case having anaplastic carcinoma. Five of the six
      postoperative cases were related to thyroid malignancy with lymph node
      dissection; one case was associated with benign parathyroid pathology.
      CONCLUSIONS: Cervical sympathetic chain injury is a rare complication of surgery
      for thyroid and parathyroid conditions. The presence of preoperative Horner's
      does not necessarily indicate an underlying malignancy.

PMID- 15191479
TI  - Effect of total hip arthroplasty on recreational and sporting activity.
AB  - BACKGROUND: Common concerns of patients undergoing total hip arthroplasty are
      whether they can continue with certain recreational and sporting activities or
      even commence new ones after the procedure. The present paper describes
      preoperative and postoperative activities, the numbers participating and the time
      to resume these activities. METHODS: Between 1 and 2 years after total hip
      arthroplasty, 216 patients, who had undergone a total of 235 arthroplasties, were
      surveyed by postal questionnaire to ascertain how the arthroplasty had affected
      their recreational and sporting ability. Their preoperative and postoperative
      activity along with the time to resume was recorded. A general hip score and
      estimate of physical activity was also collected. RESULTS: The number of patients
      participating in sport increased from 188 preoperatively to 196 postoperatively.
      Patients stated that the surgery had a beneficial effect on their performance of
      sporting activities although the number of sporting events decreased. By
      multiplying individuals by the number of sports they participated in, there were
      434 occurrences of sport preoperatively giving a mean for the group of 1.9 sports
      per patient. Postoperatively this had reduced to 382, giving a mean of 1.7. Five
      sports showed a significant change for individual patients from pre to
      postoperation. Those which showed an increase were exercise walking, where 38
      patients (16.8%) who did not walk before surgery took up walking afterwards (P <
      0.0001) and aqua aerobics, where 15 took up this activity postoperatively for the
      first time (P = 0.002). There were three sports which decreased significantly
      from pre to postoperation. They were, golf where 13 out of 39 (P = 0.005), tennis
      13 out of 14 (P = 0.01) and jogging where six out of seven (P = 0.01) patients
      stopped participating. CONCLUSION: This study has shown that patients are
      adopting lower impact activities to participate in after total hip arthroplasty.
      The total number of patients performing a sport increases postoperatively but the
      total amount of sport played decreases. These data will help to counsel patients.

PMID- 15191480
TI  - Surgical management of thoracic outlet syndrome: a 10-year experience.
AB  - BACKGROUND: Thoracic Outlet Syndrome (TOS) refers to compression of the
      neurovascular structures in the region between the scalene muscles and the first
      rib, or by anatomical abnormalities such as cervical rib, fibrous bands and other
      variations in the scalene musculature. METHODS: Our experience with 63
      consecutive operations for TOS, over a period of 10 years, has been reviewed.
      Preoperative symptoms and signs, investigations, surgery done, complications and
      the outcome of surgery are analysed. RESULTS: A total of 60 patients underwent 63
      operations for decompression of TOS. All the 63 first ribs, were excised by the
      transaxillary approach. In seven patients (16%), a combined transaxillary and
      supraclavicular approach was used. There was no operative mortality in this
      series. The operative complications included pneumothorax in four patients
      (6.3%), which was treated by insertion of chest drain, and lower brachial plexus
      neuropraxia in two patients (3%), which improved with conservative management.
      The mean duration of postoperative hospital stay was 3.6 days. At 12 months
      following surgery, 56 patients (93%) had complete or partial relief of symptoms
      and only four patients (6.6%) had no relief of symptoms. CONCLUSION: The results
      of the present study confirm that transaxillary excision of the first rib is a
      surgical procedure associated with very low morbidity and excellent relief of
      symptoms. It can therefore be offered as an early option for patients with
      thoracic outlet syndrome. It may be combined with the supraclavicular approach if
      exposure of the subclavian artery is required for vascular reconstruction.

PMID- 15191481
TI  - Venous thromboembolism prophylaxis for surgical patients in an Asian hospital.
AB  - BACKGROUND: Venous thromboembolism (VTE) is increasingly recognized as a
      significant postoperative complication in Asian hospitals. Recommendations have
      been published for VTE prophylaxis. We conducted a prospective survey of the risk
      profile and measures used for VTE prophylaxis in elective surgical patients in
      our hospital. METHODS: All patients who underwent elective general or orthopaedic
      surgery over a 4-week period were included. Information collected included
      demographic data, presence of risk factors, type and duration of surgery,
      perioperative use of VTE prophylaxis and any diagnosis of deep vein thrombosis or
      pulmonary embolism during the current admission as well as in any readmissions in
      the 6 weeks after discharge. The patients were classified based on their age,
      risk factors and type of surgery into low, moderate, high or highest risk and the
      prophylactic measures they received compared with published recommendations.
      RESULTS: Two hundred and twenty-six patients underwent 227 elective surgeries
      over the 4-week period. There were 7 low, 16 moderate, 45 high and 55 highest
      risk patients. One hundred and three patients could not be classified.
      Postoperative prophylactic measures were omitted in 93.8%, 81.8% and 31.5% of
      patients in moderate, high and highest risk groups, respectively. One patient
      developed clinical deep vein thrombosis preoperatively and one postoperatively.
      There were no cases of pulmonary embolism. CONCLUSIONS: VTE prophylaxis is
      underutilized in our survey. Further studies are required to identify the reasons
      for omission and to develop hospital specific protocols to increase appropriate
      use of prophylaxis.

PMID- 15191482
TI  - Emergency sclerotherapy for control of acute oesophageal variceal bleeding using
      3% aqueous phenol: a 15-year experience.
AB  - BACKGROUND: The purpose of the present study was to compare the efficacy of
      emergency endoscopic variceal sclerotherapy (EVS) using 3% aqueous phenol as an
      initial procedure to control acute oesophageal variceal bleed. METHODS: One
      hundred and ninety-five consecutive patients presenting with acute variceal bleed
      were included in the study. Protocol based endoscopic sclerotherapy and
      management of bleeding oesophageal varices was done. Immediate cessation of
      bleeding, re-bleeding within the first 72 h, success of first injection, final
      success of EVS, short-term mortality, influence of aetiology of portal
      hypertension and severity of liver disease on these results were studied.
      RESULTS: Immediate cessation of bleeding was obtained in 191 out of 195 patients
      (97.9%). Twenty-seven (13.8%) patients re-bled within 72 h. On re-injection final
      success of EVS was 87.2% (170/195 patients). There was no significant difference
      between final success rate in cirrhotic versus non-cirrhotic patients (103/118
      (87.3%) vs. 67/77 (87%)). Success of first sclerotherapy session was
      significantly higher than that of second sclerotherapy session. Surgical rescue
      was required in 25 (12.8%) patients. Mortality was 3.6%. Failure of EVS and
      mortality was significantly higher in Child's C group (P = 0.04, Relative risk =
      0.5, confidence interval 0.22-1.16). CONCLUSION: EVS remains an effective and
      cost effective modality of treatment to control acute variceal bleeding
      irrespective of aetiology of portal hypertension provided strict protocol based
      management is followed. With timely surgical rescue for the failures, the overall
      mortality can be reduced to less than 5%.

PMID- 15191483
TI  - Patient preference for bra or binder after breast surgery.
AB  - BACKGROUND: No data are currently available to assess the relative merits of
      breast binder or bra following breast surgery. METHODS: A randomized controlled
      study was undertaken to compare a breast binder with a bra postoperatively for
      patients undergoing lumpectomies, partial mastectomies and total mastectomies.
      RESULTS: Fifty-eight patients were included in the study. Six different
      parameters were compared and the bra was found better on all criteria; a small
      group of patients who initially used a binder and then, for a second procedure,
      used a bra, found the bra more comfortable. CONCLUSION: Postoperative discomfort
      can be decreased by using a well-fitting bra rather than a breast binder.

PMID- 15191484
TI  - Methicillin-resistant Staphylococcus aureus and beyond: what's new in the world
      of the golden staph?
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) continues to plague our
      hospitals. With the appearance of isolates that are resistant to vancomycin, now,
      more than ever, we must direct our efforts to controlling its development and
      spread. New antimicrobials have become available for treatment, but may only be a
      short-term answer. Our efforts towards control must be directed towards infection
      control measures such as improved hand hygiene with user-friendly products, such
      as alcohol-based hand disinfectants. Intranasal mupirocin may have a place in
      prevention of surgical site infection, although this role has not yet been
      clearly defined. Other areas where MRSA control may be effected include prudent
      controlled use of antibiotics, including surgical prophylaxis.

PMID- 15191485
TI  - Indications for operative management of abdominal aortic aneurysms.
AB  - The increasing incidence of abdominal aortic aneurysms, along with the more
      frequent use of screening techniques, has resulted in greater numbers of patients
      with small abdominal aortic aneurysms. The questions of frequency of surveillance
      and timing of intervention are the two most controversial issues faced by
      surgeons dealing with this condition. Most management decisions are based on the
      size of the aneurysm but other factors must also be considered. This review makes
      recommendations on the management of small abdominal aortic aneurysms according
      to the current available evidence.

PMID- 15191487
TI  - Cancer: communicating in the team game.
AB  - There is increasing evidence that effective communication is a critical means by
      which surgeons can assist their patients to achieve the best outcomes. This paper
      examines the processes and outcomes of effective communication by surgeons in
      cancer teams, and includes: (i). strategies that promote collaborative
      relationships with patients and lead to more effective treatment; (ii).
      strategies to improve multidisciplinary team performance; and (iii). methods to
      minimize the risk of error and litigation. The experience of a cancer diagnosis
      involves radical changes in patients' lives, somewhat akin to suddenly finding
      yourself in the middle of a rugby scrum for the first time. The analogy of rugby
      throws fresh light on such critical factors in communication as prematch
      preparation, orientation to the game and the team, a good kick off, sizing up the
      opposition, creative plays and optimizing teamwork to promote quality of life and
      survival.

PMID- 15191488
TI  - Novel in-line multielectrode radiofrequency ablation considerably reduces blood
      loss during liver resection in an animal model.
AB  - INTRODUCTION: Liver resection is widely used in the treatment of primary and
      secondary liver tumours. One of several important factors associated with
      mortality both in cirrhotic and non-cirrhotic patients after liver resection is
      operative blood loss. We evaluated the use of a prototype radiofrequency ablation
      probe to treat the transection plane prior to liver resection in the sheep model.
      METHODS: In-line radiofrequency ablation (RFA) was performed on the liver using a
      prototype device consisting of 11 electrodes mounted on a 8-cm base. The RITA
      1500 generator was used for power delivery. Ultrasonic aspirator (UA) and clamp
      resection were performed on the liver of sheep with and without in-line RFA. The
      blood loss was measured by weighing swabs. RESULTS: A total of 26 liver
      resections were performed. The mean (SD) blood loss with UA resection was 0.032 g
      (0.011) versus 0.005 (0.005) g without and with prior in-line RFA, respectively
      (P = 0.001). The mean (SD) blood loss with clamp resection was 0.087 (0.10) g
      versus 0.01 (0.008) without and with in-line RFA, respectively (P = 0.155).
      CONCLUSION: In-line RFA makes liver resection easier with minimal blood loss and
      may make cirrhotic liver resection easier with minimal blood loss. This is likely
      to improve the operative safety of liver resection.

PMID- 15191489
TI  - Arterial flow induces changes in venous endothelium which are modified by calcium
      channel blockers.
AB  - INTRODUCTION: Adaptation of saphenous vein to arterial flow may be critical to
      the results of bypass. The present paper summarizes work recently presented as a
      Hunterian Lecture. Work includes in vitro investigation of the response of
      saphenous vein endothelium to arterial flow and assessment of its clinical
      importance using a cohort of patients undergoing vein bypass surgery. METHODS:
      Freshly excised human saphenous vein segments were placed in an in vitro flow
      circuit to simulate arterial and venous flow conditions. Changes in the
      endothelial expression of proteins were assessed using a combination of
      immunohistochemistry and Western blotting. The role of ion channels in the
      changes seen induced by arterial flow in the saphenous vein endothelium was
      assessed by addition of ion channel blocking medication to the medium perfusing
      vein segments. A cohort of patients undergoing vein bypass surgery were followed
      to assess graft patency and the influence of prescribed medication on its
      outcome. RESULTS: After arterial flow conditions, the staining area for the
      endothelial adhesin ICAM-1 and nitric oxide synthase were increased, while that
      of the anticoagulant protein thrombomodulin was decreased. The concentration of
      the important stimulant of the clotting cascade tissue factor was unaffected by
      arterial flow. These changes were modulated by the addition of ion channel
      blocking drugs to the vein perfusate. In particular, nifedipine abolished the
      reduction in thrombomodulin, but increased the amount of tissue factor. In a
      series of 236 patients undergoing primary infra-inguinal vein grafts,
      prescription of calcium channel blocker was associated with improved primary
      patency. CONCLUSIONS: Important changes in the venous endothelium are induced by
      arterial flow. Ion channel blocking drugs have the potential to modulate these
      responses.

PMID- 15191490
TI  - Dorsal lumbotomy incision in paediatric pyeloplasty.
AB  - BACKGROUND: The purpose of the present study was to comprehensively assess the
      results of surgical management of pelvi-ureteric junction (PUJ) obstruction using
      lumbotomy as the surgical approach. METHODS: Records of 36 consecutive patients
      with unilateral PUJ obstruction who underwent pyeloplasty in the last 5 years
      were reviewed retrospectively. The investigations included renal function tests,
      ultrasound and serial renal diuretic scans. A micturating cystourethrogram was
      also done whenever indicated. A dismembered pyeloplasty via lumbotomy was the
      only surgical approach considered. Thirteen patients had a right pyeloplasty
      while 23 had a left pyeloplasty. Mean age at diagnosis was 57 months in 31
      patients while five were antenatally diagnosed (range 1 month-12 years). Age at
      surgery ranged from 1 month to 12 years with a mean of 59.9 months. Nine children
      underwent surgery in infancy. Six patients had a preoperative percutaneous
      nephrostomy (PCN) placement, five for poorly functioning kidneys (less than 10%
      split renal function) and one for oliguria. Records were reviewed for age at
      diagnosis, age at surgery, duration of surgery, preoperative and postoperative
      split renal function. RESULTS: The follow-up period in the present study ranged
      from 9 months to 68 months with a mean of 44.9 months. Mean duration of surgery
      was 78 min of the group as a whole but in PCN patients it was significantly more
      (100 min vs 71.3 min). Fourteen patients had an improvement in split renal
      function noticed at 3 and 6 months postoperatively, 17 patients had no change
      while one patient had a deterioration of split renal function. Four patients had
      a solitary functioning kidney and in all of these glomerular filtration rate
      improved postoperatively. Hospital stay was on the average 7.45 days with a range
      of 6-10 days. However, when a double-J (D-J) stent was used across the
      anastomosis and the uretero-vesical junction (transrenal D-J stenting), the mean
      stay was reduced to 3 days. All patients returned to full oral feeds by
      postoperative day 1. No incidences of wound related problems were encountered.
      CONCLUSIONS: Pyeloplasty results in predictably good outcome in paediatric PUJ
      obstruction whenever indicated. The lumbotomy approach avoids muscle cutting,
      thereby minimizing complications related to wound and assisting with faster
      recovery. Keeping a double-J (D-J) stent across the anastomosis and the uretero
      vesical junction (transrenal D-J stenting) reduces hospital stay.

PMID- 15191491
TI  - Complicated small bowel diverticular disease.

PMID- 15191492
TI  - Vocal cord paralysis, synkinesis and vocal fold motion impairment.

PMID- 15191493
TI  - Can trainees do something completely different?

PMID- 15191494
TI  - Evidence-based medicine.

PMID- 15191495
TI  - Management of contrast extravasation injury of the forearm during computed
      tomography.

PMID- 15191496
TI  - Oesophageal phytobezoar causing acute dysphagia: a complication of gastric
      bezoar.

PMID- 15191497
TI  - Case of duodenal haematoma treated with ultrasound guided drainage.
AB  - Duodenal haematoma usually occurs secondary to blunt abdominal trauma(1),
      although more recently it has been recognized as a complication of endoscopic
      duodenal biopsy(2). The two established management strategies are to treat
      conservatively until resolution of the haematoma occurs or to surgically evacuate
      the haematoma. We present a case of duodenal haematoma that was successfully
      treated by ultrasound guided drainage when no improvement occurred with
      conservative treatment.

PMID- 15191498
TI  - Mesenteric Castleman's disease in childhood.

PMID- 15191499
TI  - New method of abdominoplasty for morbidly obese patients.
AB  - INTRODUCTION: We report two cases of morbidly obese patients with huge infected
      abdominal aprons who underwent apronectomies at Alice Springs Hospital, Northern
      Territory, Australia. We describe a novel technique which to date has not been
      described in the available literature. Patients afflicted by morbid obesity with
      large aprons can be incapacitated by immobility as well as suffer from recurrent
      infections. Apronectomy in this situation can be difficult because of the heavy
      weight of the apron. METHOD: This technique involves the use of a small crane and
      large orthopaedic K-nails. Two K-nails were inserted into the apron and attached
      to a small crane. This facilitated the elevation and manipulation of the apron
      during surgical dissection. The abdominal tissue removed from the female and male
      weighed 30 kg and 64 kg, respectively. The wounds were closed primarily and
      drained by three large bore suction drains. RESULTS: The female patient had a
      largely uneventful postoperative course with a minor wound infection that
      resolved with conservative treatment. The other patient required a more
      protracted course of antibiotics for his more severe infection. Mobility was
      markedly improved in both individuals. CONCLUSION: This novel technique can be
      used successfully for severely morbidly obese individuals and can significantly
      reduce the surgeon's and assistants' difficulty in manipulating and handling a
      heavy apron during dissection.

PMID- 15191500
TI  - Airway fire during tracheostomy.

PMID- 15191503
TI  - The evolution to stool DNA testing for colorectal cancer.
AB  - Despite a variety of screening strategies and recent trends showing death rate
      stabilization, colorectal cancer still remains the second leading cause of
      overall cancer death. Current screening tools suffer from performance
      limitations, low patient acceptability, and marginal reliable access within the
      health care system. Noninvasive strategies present the lowest risk with the
      highest potential for patient satisfaction. However, serious implementation
      barriers exist requiring consistent programmatic screening, strict patient
      adherence, and poor sensitivity for adenomas. Colonoscopy remains an invasive
      screening test with the best sensitivity and specificity, but faces large
      financial costs, manpower requirements, patient access and adherence. Development
      of advanced molecular techniques identifying altered DNA markers in exfoliated
      colonocytes signify early or precancerous growth. Stool-based DNA testing
      provides an entirely noninvasive population-based screening strategy which
      patients can perform easier than faecal occult blood testing (FOBT). Large-scale
      prospective randomized control trials currently pending should help characterize
      accurate test performance, screening intervals, cost-effectiveness, direct
      comparison to FOBT and analysis of patient adherence. As tumour development
      pathways and potential target genes are further elucidated, refinements in multi
      assay stool-based DNA testing portend enhanced test characteristics to detect and
      treat this genetically heterogeneous disease.

PMID- 15191504
TI  - Irritable bowel syndrome - an evidence-based approach to diagnosis.
AB  - Irritable bowel syndrome (IBS) represents one of the most common reasons for
      primary care visits and consultation with a gastroenterologist. It is
      characterized by abdominal discomfort, bloating and disturbed defecation in the
      absence of any identifiable physical, radiologic or laboratory abnormalities
      indicative of organic gastrointestinal disease. IBS is a costly disorder,
      responsible for significant direct and indirect costs to patients and society.
      Much of the cost attributed to IBS arises from the time and resources used to
      establish the diagnosis. Historically IBS has been viewed by many as a diagnosis
      of exclusion rather than as a primary diagnosis, and many patients with typical
      symptoms will undergo an extensive array of diagnostic tests and procedures prior
      to the eventual diagnosis of IBS. Recent reviews addressing the management of
      such patients have cast doubt on the necessity for this degree of testing.
      Current best evidence does not support the routine use of blood tests, stool
      studies, breath tests, abdominal imaging or lower endoscopy in order to exclude
      organic gastrointestinal disease in patients with typical IBS symptoms without
      alarm features. Serological testing for celiac sprue in this population may
      eventually prove useful but validation of studies indicating an increased
      prevalence of this disease in patients with suspected IBS is needed. The
      development and refinement of symptom-based criteria defining the clinical
      syndrome of IBS has greatly facilitated the diagnosis of this condition, which
      can be confidently diagnosed through the identification of typical symptoms,
      normal physical examination and the exclusion of alarm features. The presence of
      alarm features or persistent non-response to symptom-directed therapies should
      prompt a more detailed diagnostic evaluation dictated by the patient's
      predominant symptoms.

PMID- 15191505
TI  - Patient-physician discordance about benefits and risks in gastroenterology
      decision-making.
AB  - AIMS: To illustrate the characteristics of situations in gastroenterology when
      patients and physicians harbour different perspectives of medical costs and
      benefits, and how such different perspectives affect the outcome of medical
      decision-making. METHODS: Two exemplary scenarios are presented, in which
      threshold analysis yields different results depending on the varying values
      assigned to identical medical events. The occurrence of varying values is
      subsequently phrased in economical terms of varying utility functions that
      characterize patient vs. physician behaviour. RESULTS: Safety and therapy are the
      two major preferences that determine patient and physician utility functions.
      Patients and physicians make medical decisions based on two different utility
      functions. In comparison with their patients, gastroenterologists are more
      concerned with safety and inclined to spend more health care resources on safety
      than therapy because safety and the occurrence of medical complications affect
      their own professional status. In trying to maximize their own utility,
      gastroenterologists tend to spend more resources on safety than the patient
      him/herself might have spent given a free choice of management options.
      CONCLUSIONS: In instances of potential complications associated with risky
      medical interventions, patients may receive less medical therapy in exchange for
      more procedural safety.

PMID- 15191506
TI  - The length of newly diagnosed Barrett's oesophagus and prior use of acid
      suppressive therapy.
AB  - BACKGROUND: The length of Barrett's oesophagus seems to correlate well with
      indicators of severe gastro-oesophageal reflux disease. However, it remains
      unknown whether prior acid suppressive therapy affects the length of newly
      diagnosed Barrett's oesophagus. METHODS: A retrospective analysis of a well
      characterized large cohort of patients with Barrett's oesophagus diagnosed
      between 1981 and 2000. AIM: To compare the length of Barrett's oesophagus between
      patients who received acid suppressive therapy prior to their diagnosis to those
      who did not receive such therapy. Pharmacy records were obtained from Department
      of the Veterans Affairs computerized records and prospectively collected research
      records. We further examined the association between prior use of acid
      suppressive therapy and the length of Barrett's oesophagus in correlation
      analyses, as well as multivariate linear regression analyses while adjusting for
      differences in year of diagnosis, age, gender, ethnicity, and the presence of
      intestinal metaplasia of the gastric cardia. Results : There were 340 patients
      with Barrett's oesophagus first diagnosed between 1981 and 2000. The average
      length of Barrett's oesophagus at the time of first diagnosis was 4.4 cm (range:
      0.5-16). Of all patients, 139 (41%) had prior use of histamine-2 receptor
      antagonists, or proton-pump inhibitors (41 used both), and 201 (59%) used neither
      prior to the diagnosis of Barrett's oesophagus. The mean length of Barrett's
      oesophagus was significantly shorter in patients with prior use of proton-pump
      inhibitors (3.4 cm) or proton-pump inhibitors and histamine-2 receptor
      antagonists (3.1 cm) when compared to those with none of these medications (4.8
      cm). In the multivariate linear regression model, the prior use of proton-pump
      inhibitors or either proton-pump inhibitors or histamine-2 receptor antagonists
      was an independent predictor of shorter length of Barrett's oesophagus (P =
      0.0396). CONCLUSIONS: The use of acid suppressive therapy among patients is
      associated with a reduction in the eventual length of newly diagnosed Barrett's
      oesophagus with gastro-oesophageal reflux disease. This finding is independent of
      the year of diagnosis or demographic features of patients. Further studies are
      required to confirm this finding.

PMID- 15191507
TI  - Influence of a lipase inhibitor on gastric sensitivity and accommodation to an
      orally ingested meal.
AB  - BACKGROUND: Intraduodenal administration of lipids, through lipid digestion and
      release of cholecystokinin (CCK), induces viscero-visceral reflexes that affect
      gastric tone and sensitivity. It is unclear whether the same mechanisms control
      gastric function after an orally ingested meal. AIM: To evaluate the effect of
      orlistat, a selective lipase inhibitor, on gastric response to an orally
      administered meal. METHODS: Eighteen healthy volunteers participated in this
      study. They were treated for 5 days with orlistat (120 mg) or placebo t.d.s. in a
      double-blind randomized crossover design. During treatment, all subjects
      underwent a gastric barostat study, measurement of plasma CCK levels and a
      satiety drinking test. RESULTS: Although CCK plasma levels were significantly
      decreased, pre-treatment with orlistat failed to affect gastric compliance (72 +/
      6 mL/mm Hg and 64 +/- 6 mL/mm Hg, NS), gastric sensitivity (discomfort threshold
      12.2 +/- 0.6 mm Hg vs. 10.9 +/- 0.6 mm Hg above minimal distending pressure, NS)
      or gastric accommodation (172 +/- 41 mL vs. 206 +/- 49 mL, NS) to an orally
      ingested meal. Furthermore, orlistat pre-treatment had no significant effect on
      the amount of calories ingested during a satiety drinking test (1329 +/- 88 kcal
      vs. 1217 +/- 115 kcal, NS). CONCLUSION: Administration of a lipase inhibitor does
      not affect gastric compliance, sensitivity to distension and accommodation to an
      orally ingested meal, and does not influence meal-induced satiety.

PMID- 15191508
TI  - Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease.
AB  - BACKGROUND: 6-Thioguanine-nucleotides seem to be the active metabolites of
      thiopurine therapy, and their monitoring has been considered a useful tool for
      optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine)
      therapy results in much higher levels of 6-thioguanine-nucleotide levels when
      compared with azathioprine or mercaptopurine. AIM: To elucidate the influence of
      6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under
      tioguanine on efficacy and toxicity in Crohn's disease. METHODS: 6-Thioguanine
      nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly
      in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were
      related to efficacy and toxicity. RESULTS: 6-Thioguanine-nucleotide levels rose
      very high [median 1241 pmol/8 x 10(8) red blood cells (range 313-1853)].
      Methylated 6-thioguanine-nucleotide levels were detected in all patients [491
      pmol/8 x 10(8) red blood cells (154-1775)]. 6-Thioguanine-nucleotide and
      methylated 6-thioguanine-nucleotide concentrations correlated significantly (r =
      0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14)
      did not differ significantly from non-remitters (n = 12) [6-thioguanine
      nucleotide: 1077 (599-2160) vs. 1210 (534-4665); methylated 6-thioguanine
      nucleotide: 510 (214-1222) vs. 421 (145-1284)]. One patient with intermediate
      thiopurine S-methyltransferase activity experienced bone marrow toxicity upon
      dose escalation parallel with excessively high thioguanine-nucleotide levels.
      CONCLUSIONS: 6-Thioguanine-nucleotide as well as methylated 6-thioguanine
      nucleotide levels under tioguanine therapy were not related to efficacy. This
      suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool
      to predict response to thiopurines.

PMID- 15191509
TI  - The safe threshold for gluten contamination in gluten-free products. Can trace
      amounts be accepted in the treatment of coeliac disease?
AB  - BACKGROUND: Gluten contamination in gluten-free products cannot totally be
      avoided. The safe threshold for gluten remains obscure. AIM: The purpose was to
      estimate a reasonable limit for residual gluten, based on current literature and
      measurement of gluten in gluten-free products on the market. METHODS: The gluten
      content of 59 naturally gluten-free and 24 wheat starch-based gluten-free
      products were analysed by enzyme-linked immunosorbent assay. The daily intake of
      flours was calculated in 76 adults on gluten-free diet, and the intake compared
      with mucosal histology. RESULTS: A number of both naturally gluten-free (13 of
      59) and wheat starch-based gluten-free (11 of 24) products contained gluten from
      20 to 200 ppm (=mg/kg). The median daily flour consumption was 80 g (range: 10
      300). Within these limits, the long-term mucosal recovery was good. CONCLUSIONS:
      The threshold for gluten-contamination can safely be set at 100 ppm. Provided
      that the daily flour intake is even 300 g, a level of 100 ppm results in 30 mg of
      gluten intake. This has been shown to be safe, when correlated to histology, in
      clinical and challenge studies. The level can be achieved by the industry, and
      does not make the diet too cumbersome.

PMID- 15191510
TI  - Carditis in patients with gastro-oesophageal reflux disease: results of a
      controlled study based on both endoscopy and 24-h oesophageal pH monitoring.
AB  - BACKGROUND: There are conflicting reports on the role of gastro-oesophageal
      reflux disease (GERD) and Helicobacter pylori infection in the aetiology of
      carditis. AIM: The role of reflux and H. pylori infection in causing carditis was
      assessed in 113 consecutive patients with GERD and in 25 controls. METHODS: All
      subjects underwent endoscopy and pH test and carditis was diagnosed on biopsies
      taken across the squamocolumnar junction. Helicobacter pylori was assessed by
      histology and rapid urease test. GERD was diagnosed by endoscopic oesophagitis or
      abnormal pH test. RESULTS: Carditis was detected in 53 of 71 GERD patients and in
      15 of 20 controls. Among patients, 18 showed absent, 39 mild and 14 marked cardia
      inflammation and their H. pylori infection rates were 17, 23 and 57%,
      respectively (P < 0.025). Most patients with carditis (68%) lacked H. pylori
      infection. pH-metry was abnormal in 15 of 18 patients with normal cardia, 33 of
      39 with mild carditis and 12 of 14 with marked inflammation. CONCLUSIONS:
      Carditis is a frequent finding in GERD and controls. Mild, non-active carditis is
      frequent in GERD patients. Marked inflammation is associated with both H. pylori
      and abnormal pH testing. Thus, both GERD and H. pylori infection may play a role
      in inducing carditis.

PMID- 15191511
TI  - Cholestatic pruritus - the role of cutaneous mast cells and nerves.
AB  - BACKGROUND: The pathogenesis of pruritus in cholestatic liver disease is poorly
      understood. Cutaneous mast cells and nerves are thought to contribute to pruritus
      in several dermatological diseases. AIM: To determine if cutaneous mast cell
      density, neural density and mast cell-neural interaction are increased in
      patients with pruritus and cholestatic liver disease. METHODS: Skin biopsy
      specimens from (i). patients with pruritus due to cholestatic liver disease
      (CLDP+; n = 6), (ii). patients with chronic liver disease without pruritus (CLDP
      ; n = 5), and (iii). healthy controls (n = 6) were studied. Biopsies were dual
      stained immunohistochemically for mast cells and nerves. RESULTS: Mast cell
      density in the control group was not significantly different from that in CLDP+
      group or from that in the CLDP- group. Similarly neural density was not
      significantly different between groups when assessed either in terms of total
      nerve area, or in terms of the number of neural elements seen. The frequency of
      mast cell-nerve contact was not significantly different between groups.
      CONCLUSIONS: These findings suggest that mast cells, nerves or interaction
      between the two may not contribute to cholestatic pruritus. Therefore, therapies
      targeted at cutaneous mast cells or nerves are unlikely to be of benefit.

PMID- 15191512
TI  - Comparison of transarterial chemoembolization and percutaneous acetic acid
      injection as the primary loco-regional therapy for unresectable hepatocellular
      carcinoma: a prospective survey.
AB  - BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous acetic acid
      injection (PAI) are effective loco-regional therapies for hepatocellular
      carcinoma (HCC). AIM: To compare the therapeutic efficacy of TACE vs. PAI for
      unresectable HCC. METHODS: A total of 310 patients with unresectable HCCs (size
      <or=6 cm) undergoing TACE (n = 195) or PAI (n = 115) were studied prospectively.
      Overall and progression-free survivals were measured endpoints. RESULTS: The
      overall survival was not significantly different between the two groups (P =
      0.508). Among 129 patients with large (3.1-6 cm) HCCs, the overall survival was
      significantly better for the TACE group (P = 0.018). Cox multivariate analysis
      showed that Child-Pugh B [relative risk (RR): 4.2, 95% confidence interval (CI):
      2.3-7.7, P < 0.001] and PAI therapy (RR: 1.4, 95%: 1.0-1.9, P = 0.057) were poor
      prognostic predictors; the progression-free survival was also significantly
      better in the TACE group (P = 0.038). Among 181 patients with small (<or=3 cm)
      HCCs, there was no significant difference of overall survival (P = 0.265) or
      progression-free survival (P = 0.146) between the two groups; Child-Pugh B was
      the only prognostic factor predicting a decreased survival (RR: 2.8, 95% CI: 1.7
      4.8, P < 0.001). CONCLUSIONS: Patients with large HCC undergoing TACE tend to
      have a more favourable long-term outcome. For small HCC, either TACE or PAI
      therapy could be recommended as the primary treatment modality.

PMID- 15191513
TI  - Chronic gastritis with expression of inducible nitric oxide synthase is
      associated with high expression of interleukin-6 and hypergastrinaemia.
AB  - BACKGROUND AND AIMS: High levels of inducible nitric oxide synthase and
      nitrotyrosine in Helicobacter pylori-infected gastric mucosa may contribute to
      development of gastric cancer. We investigated the relation between expression of
      inducible nitric oxide synthase and proinflammatory cytokines in gastric mucosa
      and serum markers of gastritis. METHODS: The study included 103 patients with H.
      pylori infection. We examined levels of interleukin-1beta, interleukin-6 and
      interleukin-8 by enzyme-linked immunosorbent assay and evaluated expression of
      inducible nitric oxide synthase and nitrotyrosine by immunohistochemical
      staining. Furthermore, we assessed serum levels of pepsinogens, gastrin, anti
      parietal cell antibody, nitrite and nitrate, as markers of gastritis. RESULTS:
      Thirty-seven of 103 (35.6%) gastric mucosa specimens showed simultaneous
      expression of inducible nitric oxide synthase and nitrotyrosine. In these
      patients (inducible nitric oxide synthase-positive group), the serum level of
      gastrin was significantly higher than that of the inducible nitric oxide synthase
      negative group (509.5 +/- 141.5 pg/mL vs. 210.0 +/- 227.2 pg/mL; P < 0.01),
      whereas there were no significant differences in serum levels of pepsinogen, anti
      parietal cell antibody, and nitrate and nitrite or in scores of histological
      gastritis. Interleukin-6 levels were significantly higher in the inducible nitric
      oxide synthase-positive group than in the inducible nitric oxide synthase
      negative group (25.9 +/- 7.0 pg/mg protein vs. 10.6 +/- 4.9 pg/mg protein; P <
      0.05). CONCLUSIONS: Inducible nitric oxide synthase-producing gastritis was
      correlated with high levels of interleukin-6. Patients with hypergastrinaemia
      should be carefully followed on a long-term basis to ensure that the development
      of any malignancy is detected early.

PMID- 15191515
TI  - 'Guidelines' or marketing for non-steroidal anti-inflammatory drug and proton
      pump inhibitor use?

PMID- 15191514
TI  - The importance of the level of metronidazole resistance for the success of
      Helicobacter pylori eradication.
AB  - AIMS: To evaluate the role of antibiotic susceptibility for the treatment outcome
      of proton pump inhibitor-dependent and independent Helicobacter pylori
      eradication regimens. METHODS: In a placebo-controlled clinical study of peptic
      ulcer patients with H. pylori infection, patients were randomized to receive
      lansoprazole, clarithromycin and tinidazole twice-daily, clarithromycin and
      tinidazole once-daily with lansoprazole or with placebo. Helicobacter pylori
      status was assessed by culture and antibiotic susceptibility by E-test minimal
      inhibitory concentration (MIC) in 205 clinical isolates. RESULTS: Primary
      resistance to clarithromycin and metronidazole was 1 and 76%, respectively. In
      metronidazole susceptible strains eradication rates were similar at > 90% for all
      treatment groups (P = 0.49). With low-level metronidazole resistance (4 microg/mL
      < MIC < 256 microg/mL), eradication rates were similar at >75% (P = 0.80). The
      major difference was found at high-level metronidazole resistance (MIC >or= 256
      microg/mL) with 95%, 58% and 21% eradication in the lansoprazole, clarithromycin
      and tinidazole twice-daily, lansoprazole, clarithromycin and tinidazole once
      daily and placebo, clarithromycin and tinidazole once-daily groups, respectively
      (P < 0.001). CONCLUSION: In the absence of antibiotic resistance, a once-daily
      therapy of only clarithromycin and tinidazole can achieve a high rate of H.
      pylori eradication. Such a combination could offer a simpler and cheaper
      treatment option for developing countries. The standard, twice-daily proton pump
      inhibitor-based triple therapy was shown to be efficient in H. pylori eradication
      even in the presence of high-level metronidazole resistance.

PMID- 15191517
TI  - The role of galectins in the initiation, amplification and resolution of the
      inflammatory response.
AB  - Inflammation involves the sequential activation of signalling pathways leading to
      the production of both pro-inflammatory and anti-inflammatory mediators.
      Galectins constitute a family of structurally related beta-galactoside-binding
      proteins, which are defined by their affinity for poly-N-acetyllactosamine
      enriched glycoconjugates and sequence similarities in the carbohydrate
      recognition domain. By crosslinking specific glycoconjugates, different members
      of the galectin family behave as pro-inflammatory or anti-inflammatory agents,
      acting at different levels of acute and chronic inflammatory responses. Recent
      studies highlighted immunomodulatory roles for galectins in vivo in several
      experimental models of chronic inflammation, suggesting that these carbohydrate
      binding proteins may be potential targets for the design of a novel generation of
      anti-inflammatory agents. In this study, we review recent advances on the role of
      galectins in the initiation, amplification and resolution of the inflammatory
      response. In particular, we examine the influence of individual members of this
      family in regulating cell adhesion, migration, chemotaxis, antigen presentation,
      immune cell activation and apoptosis. From a better understanding of the
      molecular basis of galectin-induced immune regulation, we may become able to
      exploit the potential of these sugar-binding proteins and their glycoligands as
      suitable therapeutic agents in acute and chronic inflammatory disorders.

PMID- 15191518
TI  - Donor-specific sensitization by cadaveric venous allografts used for arterial
      reconstruction in peripheral arterial occlusive vascular disease.
AB  - The use of allogeneic venous grafts from postmortal organ donors allows for the
      reconstruction of critically affected arteries in patients with peripheral
      occlusive vascular disease. We were interested to determine the prevalence and
      specificity of anti-HLA antibodies in patients after allogeneic vein
      transplantation. Anti-HLA class I and II alloantibodies were analyzed by
      flowcytometric analysis using color-coded microbeads coated with HLA antigens
      including recombinant single antigens. Nine out of 10 patients involving 12
      venous allografts were positive for anti-HLA alloantibodies. All antibody
      positive patients carried both anti-HLA class I and II alloantibodies. Anti-donor
      HLA specificity of the anti-HLA alloantibodies was seen in seven out of nine
      patients for anti-class I antibodies and in eight out of nine patients for anti
      HLA class II antibodies. A high rate of donor-specific allosensitization was seen
      after allogeneic venous transplantation. In conclusion, allosensitization not
      only includes a humoral response against the constitutively expressed class I
      antigens but also extends to class II antigens.

PMID- 15191519
TI  - Chagas' disease susceptibility/resistance: linkage disequilibrium analysis
      suggests epistasis between major histocompatibility complex and interleukin-10.
AB  - Association between the major histocompatibility complex (MHC) and the
      susceptibility/resistance to acquire Chagas' disease has been largely
      demonstrated. To study the role of candidate genes in this
      susceptibility/resistance to Chagas, we designed a population-genetic-based case
      control approach (chagasic n = 104 and controls n = 60) and tested the presence
      of genotype and linkage disequilibrium on microsatellite loci establishing
      specific landmarks for the MHC, interleukin (IL)-2, IL-2Rbeta chain, IL-4, IL-10,
      and natural resistance-associated mactophage protein 1 (NRAMP1). After
      demonstrating no genetic stratification among cases and controls (F(st) were not
      different from 0), we found significant allelic differences among chagasic
      patients and controls at microsatellite locus D6S291 (MHC) and at the
      microsatellite pointing out the IL-10. At the MHC, we found significant
      differences between patients and controls in Hardy-Weinberg equilibrium-expected
      genotype proportions. Additionally, MHC II-locus-inferred haplotypes in chagasic
      patients exhibited strong significant departures from the expected proportions
      predicted by the second Mendelian law. The linkage disequilibrium pattern at MHC
      involves a region of approximately 10 cM. These results replicate previous
      analyses and suggest that presence of epistasis between MHC with humoral systems,
      such as IL-10, could be underlying the susceptibility/resistance to Chagas'
      disease.

PMID- 15191520
TI  - Involvement of the major histocompatibility complex region in the genetic
      regulation of circulating CD8 T-cell numbers in humans.
AB  - Variability in T-lymphocyte numbers is partially explained by a genetic
      regulation. From studies in animal models, it is known that the Major
      Histocompatibility Complex (MHC) is involved in this regulation. In humans, this
      has not been shown yet. The objective of the present study was to test the
      hypothesis that genes in the MHC region influence the regulation of T-lymphocyte
      numbers. Two approaches were used. Association studies between T-cell counts
      (CD4(+) and CD8(+)) or total lymphocyte counts and HLA class I alleles (A and B)
      or mutations in the HFE (C282Y and H63D), the hemochromatosis gene, in an
      unrelated population (n = 264). A second approach was a sibpair correlation
      analysis of the same T-cell counts in relation to HLA-HFE haplotypes in subjects
      belonging to 48 hemochromatosis families (n = 456 sibpairs). In the normal
      population, results showed a strong statistically significant association of the
      HLA-A*01 with high numbers of CD8(+) T cells and a less powerful association with
      the HLA-A*24 with low numbers of CD8(+) T cells. Sibpair correlations revealed
      the most significant correlation for CD8(+) T-cell numbers for sibpairs with HLA
      HFE-identical haplotypes. This was not observed for CD4(+) T cells. These results
      show that the MHC region is involved in the genetic regulation of CD8(+) T-cell
      numbers in humans. Identification of genes responsible for this control may have
      important biological and clinical implications.

PMID- 15191521
TI  - Transforming growth factor-beta1 gene polymorphism modifies the histological and
      clinical manifestations in Japanese patients with IgA nephropathy.
AB  - Transforming growth factor (TGF)-beta1, a multifunctional cytokine, which
      regulates proliferation and differentiation of a variety of cell types, has the
      central role in the development and progression of renal injury in both animal
      models and human. Although it has been suggested that genetic variations in the
      TGF-beta1 gene are associated with the activity of the gene product, their
      clinical significance in glomerular disease is unknown. We investigated whether
      the polymorphisms of C-509T and T869C in TGF-beta1 account for interindividual
      variation in manifestations of IgA nephropathy (IgAN) using 626 Japanese subjects
      including 329 patients with histologically proven IgAN and 297 healthy controls
      with normal urinalysis. The frequencies of genotypes, alleles, and major
      haplotypes were similar between the patients and controls. The C-509T and T869C
      polymorphisms were in tight linkage disequilibrium, and the major haplotypes were
      C-C and T-T, which accounted for more than 95% of the total. In patients with 
      509CC and in those with the 869CC, urinary protein excretion was higher than in
      those with other genotypes, whereas no difference in other clinical
      manifestations was noted. Moreover, patients with -509CC and those with 869CC
      genotypes presented with a significant higher score of mesangial cell
      proliferation than in those with other genotypes. These results suggest that TGF
      beta1 gene polymorphisms are specifically associated with heavy proteinuria and
      mesangial cell proliferation in Japanese patients with IgAN, although they do not
      confer susceptibility to this disease.

PMID- 15191522
TI  - A psoriasis vulgaris protective gene maps close to the HLA-C locus on the EH18.2
      extended haplotype.
AB  - We determined the molecular haplotypes of the HLA-A, HLA-C and HLA-B loci and the
      MHC class I-B-related (MIB) microsatellite in 179 unrelated psoriatic patients
      (72 familial cases) and in 120 controls. The HLA-A*3002-Cw*0501-B*1801-MIB1
      haplotype showed a strong negative association with psoriasis vulgaris (PV) and
      in particular with familial PV, revealing the presence of a PV-protective gene.
      Analysis of association and linkage disequilibrium of the single alleles and the
      various two-three-four-locus segments of this haplotype indicated the presence of
      a protective gene telomeric to the HLA-C locus. This finding was confirmed in 13
      informative multiplex PV families, in which at least one parent carried the
      EH18.2 haplotype. In two families, an affected sibling presented HLA-A/C
      recombination on the EH18.2 haplotype. A study of 12 polymorphic microsatellites
      in all members of the informative families, 145 PV patients, 120 controls and 32
      EH18.2 homozygous healthy individuals demonstrated that the protection conferred
      by the EH18.2 haplotype lies within a 170 kb interval between the C143 and C244
      loci, most probably in a 60 kb segment between the C132 and C244 loci.

PMID- 15191523
TI  - HLA-B and HLA-C alleles and haplotypes in the Dravidian tribal populations of
      southern India.
AB  - The Dravidians are believed to be the earliest inhabitants of India. Their
      subsequent migration and admixture with invading racial groups has been of
      scientific interest for population geneticists. In the present study, seven
      highly endogamous and extremely isolated colonies of Dravidian tribal populations
      (n = 105) from Kerala in South India were analysed and compared with random non
      tribal Dravidian (RND) samples (n = 78) of southern India using the polymerase
      chain reaction with sequence-specific primer method for HLA-B and HLA-C typing.
      The tribal group comprises Adiya, Kanikkar, Kattunaikka, Kuruma, Kurichiya,
      Malapandaram and Paniya, while the RND group includes Malayalam-speaking
      individuals from various non-tribal castes of Kerala selected randomly. Some of
      the most frequent HLA-B alleles in the RND population were similar to the North
      Indian population and included B*07, B*61 (B*40), B*44, B*51, B*35 and B*52.
      Although B*61 was the most frequent allele in our total study population, the
      frequency fluctuated in individual populations. HLA-Cw*14 was one of the most
      frequent alleles while HLA-Cw*17 was totally absent in all populations studied.
      The haplotype B*61-Cw*14 was present in all the study groups except in Kurichiya,
      and the haplotype B*51-Cw*14 was only absent in Kattunaikka. Phylogenetic tree
      and correspondence analysis indicate that all the Dravidian tribal communities
      group together as a separate cluster, while the RND group of individuals from
      South India lie close to the North Indian population. This suggests that the RND
      population of South India might have a crypto-Dravidian origin, while the smaller
      Dravidian tribal communities have a distinct Dravidian origin.

PMID- 15191524
TI  - Association between human leukocyte antigen-G genotype and success of in vitro
      fertilization and pregnancy outcome.
AB  - To determine if a 14-bp deletion/insertion polymorphism in the 3'-untranslated
      region of exon 8 of the gene encoding human leukocyte antigen (HLA)-G in a
      homozygous form is associated with repeated, unsuccessful in vitro fertilization
      (IVF) treatments, and with increased risk of recurrent spontaneous abortions
      (RSA), 29 white women undergoing IVF treatments, 61 RSA women and 93 fertile
      controls were HLA-G genotype. The HLA-G genotype, homozygous for the presence of
      the 14 bp sequence in exon 8, was significantly associated with reduced fertility
      with respect to unsuccessful IVF treatments and increased risk of recurrent
      miscarriage (combined P < 0.01). The 14-bp insertion/deletion polymorphism is
      associated with differences in HLA-G mRNA alternative splicing and levels of HLA
      G. This might affect a possible immunomodulatory role of HLA-G expression in both
      the mother and foetus during implantation and pregnancy.

PMID- 15191525
TI  - Analysis of the monocyte chemoattractant protein 1 -2518 promoter polymorphism in
      patients with multiple sclerosis.
AB  - Cytokines and chemokines like the proinflammatory chemokine,
      monocytechemoattractant protein 1 (MCP-1) are important for the recruitment of
      inflammatory cells into multiple sclerosis (MS) lesions. Recently, a nucleotide
      substitution from adenosine to guanosine (A-->G) at position -2518 of the MCP-1
      promoter was shown to be associated with increased MCP-1 expression. We analysed
      MCP-1 genotypes in 634 MS patients and 405 healthy controls. The allelic
      frequencies were comparable between both groups. No correlation was found between
      genotype and disease course, disease severity or age of disease onset. Although
      statistically no+ significant mRNA expression and MCP-1 secretion were elevated
      in patients carrying the mutant allele. Thus, our data could not reveal any
      association between the MCP-1 -2518 polymorphism and susceptibility to or
      clinical disease course of MS.

PMID- 15191526
TI  - A novel major histocompatibility complex class I-related chain allele.
AB  - We report the identification of a novel major histocompatibility complex class I
      related chain (MICB) allele, provisionally designated as MICB-0114 pending the
      WHO Nomenclature Classification for the MICB locus. This new allele is identical
      to MICB-0103101v except for a single mutation of G to A in exon 4 that translates
      into an amino acid substitution from glutamic acid to lysine.

PMID- 15191527
TI  - An HLA-A*2607 variant (A*260702) independently identified in two unrelated French
      families.
AB  - Abstract In this report, we describe the identification of a new variant of the
      A*2607 allele, named A*260702. This variant was detected independently in two
      unrelated potential bone marrow donors living in two different regions of France.
      Molecular typing and mono-allelic sequencing revealed that this allele differs
      from the original A*2607 allele by a single-nucleotide substitution in codon 56
      (GGG --> GGT). This nucleotide change does not affect the amino acid sequence,
      both triplets coding for a glycine.

PMID- 15191528
TI  - Identification of a novel allele HLA-A*1113 in a Japanese donor.
AB  - Anew HLA-A*11 allele, A*1113, was identified in a healthy Japanese female. She
      was typed as HLA-A11?, A2, B46, B67, Cw1, Cw7 (Bw6) with unusual serological
      reactivity of A11, suggesting possible presence of a new A*11 allele. The novel
      A*1113 allele was identified by haplotypic group-specific allele amplification
      using A*11 allele-specific primer pairs and sequence-based typing. The A*1113
      allele differs from A*11011 by one nucleotide substitution in exon 3 at position
      503 (A --> G) which causes an amino acid change in the alfa2 domain at residue
      144 (lysine : K --> arginine : R), thus resulting in the unusual serological
      reactivity.

PMID- 15191530
TI  - A novel human leucocyte antigen-DRB1 genotyping method based on multiplex primer
      extension reactions.
AB  - We have developed and validated a semi-automated fluorescent method of genotyping
      human leucocyte antigen (HLA)-DRB1 alleles, HLA-DRB1*01-16, by multiplex primer
      extension reactions. This method is based on the extension of a primer that
      anneals immediately adjacent to the single-nucleotide polymorphism with
      fluorescent dideoxynucleotide triphosphates (minisequencing), followed by
      analysis on an ABI Prism 3700 capillary electrophoresis instrument. The validity
      of the method was confirmed by genotyping 261 individuals using both this method
      and polymerase chain reaction with sequence-specific primer (PCR-SSP) or
      sequencing and by demonstrating Mendelian inheritance of HLA-DRB1 alleles in
      families. Our method provides a rapid means of performing high-throughput HLA
      DRB1 genotyping using only two PCR reactions followed by four multiplex primer
      extension reactions and PCR-SSP for some allele groups. In this article, we
      describe the method and discuss its advantages and limitations.

PMID- 15191529
TI  - HLA allele frequency and clinical outcome in Italian patients with cutaneous
      melanoma.
AB  - The current study focuses the analysis on the possible relationship between HLA
      allele frequency and clinical outcome of melanoma in a population of 382 Italian
      patients, as compared with 203 ethnically matched controls. In a 3-year follow-up
      study, results showed significant differences between groups of patients selected
      according to clinical stage, histology, and progression of the disease. A*01
      seems to be correlated with a less aggressive variant of the disease, whereas
      DRB1*01-DQB1*0501 seems to be associated with metastatic progression of melanoma.
      Moreover, a negative association with B*13, B*44, as well as with DRB1*04
      DQB1*0302 was found. A multivariate logistic regression model showed HLA-DRB1*04
      to behave as an independent favorable prognostic marker of melanoma in our
      population (OR = 2.34, CI = 1.15-4.74).

PMID- 15191531
TI  - Identification of a novel HLA-B*55 variant (B*5513) from a Korean family.
AB  - The novel allele, B*5513, was identified from three siblings of a Korean family.
      Direct DNA sequencing analysis revealed that B*5513 differed from B*5502 by a
      single-nucleotide substitution at codon 116 (TTA-->TTC) resulting in an amino
      acid change from leucine to phenylalanine. This substitution altered serologic
      reactivity of the B55 molecule to B22-specific alloantisera.

PMID- 15191532
TI  - Identification of two novel HLA-DRB1 alleles, DRB1*0903 and DRB1*1145.
AB  - Two new HLA-DRB1 alleles were identified by sequencing-based typing in the oral
      submucous fibrosis and buccal cancer patients of Taiwan. They have been
      officially named HLA-DRB1*0903 and DRB1*1145 by the World Health Organization
      Nomenclature Committee. The complete exon 2 sequence of DRB1*0903 was identical
      to that of the DRB1*090102 but differed by nucleotides of position 207-210 and
      216 (AGAC, C replacing GCGG, and G). The DRB1*1145 was identical to the
      DRB1*110101 except for three nucleotide substitutions at codon 199, 220, and 221
      (A, CT replacing T, and GC). Two complete exon 2 sequences of those new alleles
      had been deposited in the EMBL Sequence Database under accession number AY465114
      and AY465115, respectively.

PMID- 15191533
TI  - Identification of a novel HLA-DRB1 allele (DRB1*1147)* by sequence-based typing
      in eight siblings.
AB  - We report here a novel DRB1 allele (DRB1*1147) identified by sequence-based
      typing. The DRB1*1147 allele was detected during routine human leukocyte antigen
      (HLA)-typing of a patient and his family prior to bone marrow transplantation.
      This allele was found in the patient and his two sisters and five brothers. The
      new allele is identical to DRB1*110601 at exon 2 except for a single-nucleotide
      substitution at codon 37 (TAC-->TCC), changing the encoded tyrosine to serine.

PMID- 15191534
TI  - Nomenclature for factors of the HLA system, update February 2004.

PMID- 15191535
TI  - Nomenclature for factors of the HLA system, update March 2004.

PMID- 15191536
TI  - Regulation of human sebaceous glands.

PMID- 15191537
TI  - Regulation of involucrin gene expression.
AB  - The epidermis is a dynamic renewing structure that provides life-sustaining
      protection from the environment. The major cell type of the epidermis, the
      epidermal keratinocyte, undergoes a carefully choreographed program of
      differentiation. Alteration of these events results in a variety of debilitating
      and life-threatening diseases. Understanding how this process is regulated is an
      important current goal in biology. In this review, we summarize the literature
      regarding regulation of involucrin, an important marker gene that serves as a
      model for understanding the mechanisms that regulate the differentiation process.
      Current knowledge describing the role of transcription factors and signaling
      cascades in regulating involucrin gene expression are presented. These studies
      describe a signaling cascade that includes the novel protein kinase C isoforms,
      Ras, MEKK1, MEK3, and a p38delta-extracellular signal regulated kinase 1/2
      complex. This cascade regulates activator protein one, Sp1, and CCATT/enhancer
      binding protein transcription factor DNA binding to two discrete involucrin
      promoter regions, the distal- and proximal-regulatory regions, to regulate
      involucrin gene expression.

PMID- 15191538
TI  - S100 proteins in the epidermis.
AB  - The S100 proteins comprise a family of 21 low molecular weight (9-13 kDa)
      proteins that are characterized by the presence of two calcium-binding EF-hand
      motifs. Fourteen S100 protein genes are located within the epidermal
      differentiation complex on human chromosome 1q21 and 13 S100 proteins (S100A2,
      S100A3, S100A4, S100A6, S100A7, S100A8, S100A9, S100A10, S100A11, S100A12,
      S100A15, S100B, and S100P) are expressed in normal and/or diseased epidermis.
      S100 proteins exist in cells as anti-parallel hetero- and homodimers and upon
      calcium binding interact with target proteins to regulate cell function. S100
      proteins are of interest as mediators of calcium-associated signal transduction
      and undergo changes in subcellular distribution in response to extracellular
      stimuli. They also function as chemotactic agents and may play a role in the
      pathogenesis of epidermal disease, as selected S100 proteins are markedly
      overexpressed in psoriasis, wound healing, skin cancer, inflammation, cellular
      stress, and other epidermal states.

PMID- 15191539
TI  - Macrophage-stimulating protein promotes hair growth ex vivo and induces anagen
      from telogen stage hair follicles in vivo.
AB  - Hepatocyte growth factor (HGF) is a promoter of hair follicle growth. We examined
      another HGF family member, macrophage-stimulating protein (MSP), for its hair
      follicle-modulating properties. Western blotting revealed presence of mature MSP
      in cultured human dermal papilla (DP) cells and bulbar dermal sheath (DS) cells,
      but not non-bulbar DS cells. Immunohistology demonstrated expression of MSP
      receptor RON in the outer and inner root sheaths, hair matrix cells, DP, and
      bulbar DS whereas non-follicular epithelium and some cells of the sweat glands
      exhibited low-level receptor expression. Human hair follicles exposed in vitro
      for 8 d to 0.1, 1, 10, and 100 ng per mL MSP all yielded a mean net increase in
      hair follicle length in excess of the mean baseline growth observed in controls.
      MSP was incubated with agarose beads and injected subcutaneously into mice all 70
      d old when a uniform telogen state in dorsal skin was apparent. All eight mice
      receiving 1 microg MSP, and four of eight receiving 100 ng MSP showed induction
      of anagen hair growth at the site of bead implantation by 16 d whereas eight mice
      implanted with saline incubated beads had no hair growth. The data identify MSP
      as a modulator of hair growth.

PMID- 15191541
TI  - Divergent beliefs about psoriasis are associated with increased psychological
      distress.
AB  - The psychological adjustment of patients with psoriasis has been studied
      extensively. By comparison, no research has focused on their partners. We
      examined illness representations of psoriasis held by patients and their
      partners, and investigated whether divergent beliefs were associated with
      psychological distress. Fifty-eight patients with chronic plaque psoriasis and
      their partners completed a range of psychological assessments including beliefs
      about the condition, anxiety, depression, and worry. Patients also completed a
      self-assessment of psoriasis severity. Patients with psoriasis had significantly
      higher levels of anxiety, depression, and worry than their partners (t's > 2.53,
      p's < .05). Multiple regression analysis indicated that divergence in patients'
      and partners' beliefs about emotional impact of psoriasis and chronicity of
      timeline accounted for a statistically significant (21.3%) proportion of the
      variance in depression for partners. Differences in views on the consequences of
      having psoriasis and the cyclical nature of the condition were also significantly
      associated with increased levels of worry in partners. Dissimilarity in
      particular aspects of illness representations are associated with increased
      psychological distress in particular for the partners of patients with psoriasis.
      The results illustrate the importance of concordance between patients' and
      partners' models of illness in relation to adjustment, and highlight the need to
      consider and collaborate with both patients and their partners in managing this
      challenging condition.

PMID- 15191540
TI  - The effect of LXR activators on AP-1 proteins in keratinocytes.
AB  - Oxysterols, via activation of liver X receptor (LXR), regulate keratinocyte
      differentiation by stimulating transglutaminase cross-linking of several
      constituent proteins leading to the formation of the cornified envelope. We
      previously reported that oxysterols increase the expression of one of these cross
      linked proteins, involucrin, and that this effect can be abolished by mutations
      of the distal activator protein (AP)-1 response element in the involucrin
      promoter. Furthermore, oxysterols increase AP-1 binding in an electrophoretic gel
      mobility shift assay and increase the expression of an AP-1 reporter. In this
      study, we describe the individual components of the AP-1 complex that are
      involved in the oxysterol-mediated AP-1 activation and stimulation of
      keratinocyte differentiation. We identified Fra-1 within the AP-1 DNA binding
      complex by supershift analysis of nuclear extracts from oxysterol-treated,
      cultured keratinocytes and confirmed that oxysterol treatment increased the
      levels of Fra-1 by western blot analysis. Additionally, on Western and Northern
      analysis, oxysterol treatment increased two other AP-1 proteins, Jun-D and c-Fos,
      whereas Fra-2, Jun-B, and c-Jun were not changed. Similar alterations in AP-1
      proteins occurred when 25-OH-cholesterol or non-steroidal LXR agonists (GW3965,
      TO-901317) were used. These results indicate that oxysterols induce specific AP-1
      proteins, thereby activating involucrin, one of the genes required for epidermal
      differentiation.

PMID- 15191543
TI  - Genetic association between an AACC insertion in the 3'UTR of the stratum corneum
      chymotryptic enzyme gene and atopic dermatitis.
AB  - Atopic dermatitis is a disease with an impaired skin barrier that affects 15%-20%
      of children. In the normal epidermis, the stratum corneum chymotryptic enzyme
      (SCCE) thought to play a central role in desquamation by cleaving proteins of the
      stratum corneum (e.g., corneodesmosin and plakoglobin). Genetic variations within
      the SCCE gene could be associated with dysregulation of SCCE activity leading to
      an abnormal skin barrier. We screened the SCCE gene for variations and performed
      a case-control study on 103 atopic dermatitis patients and 261 matched controls.
      16 synonymous single nucleotide polymorphisms (SNPs) have been identified and a 4
      bp (AACC) insertion has been found in the 3'UTR. We performed an association
      study of the SCCE AACC insertion in the 3'UTR, and found a significant trend
      between the AACC allele with the two insertions and disease in the overall data
      set [odds ratio (OR)=2.31; p=0.0007]. The AACC insertion in the SCCE gene may
      result in a change to SCCE activity within the skin barrier. These findings
      suggest that SCCE could have an important role in the development of atopic
      dermatitis.

PMID- 15191542
TI  - Systemic absorption of the sunscreens benzophenone-3, octyl-methoxycinnamate, and
      3-(4-methyl-benzylidene) camphor after whole-body topical application and
      reproductive hormone levels in humans.
AB  - Recent in vitro and animal studies have reported estrogen-like activity of
      chemicals used in sunscreen preparations. We investigated whether the three
      sunscreens benzophenone-3 (BP-3), octyl-methoxycinnamate (OMC), and 3-(4
      methylbenzylidene) camphor (4-MBC) were absorbed and influenced endogenous
      reproductive hormone levels in humans after topical application. In this 2-wk
      single-blinded study 32 healthy volunteers, 15 young males and 17 postmenopausal
      females, were assigned to daily whole-body topical application of 2 mg per cm(2)
      of basic cream formulation without (week 1) and with (week 2) the three
      sunscreens at 10% (wt/wt) of each. Maximum plasma concentrations were 200 ng per
      mL BP-3, 20 ng per mL 4-MBC, and 10 ng per mL OMC for females and 300 ng per mL
      BP-3, 20 ng per mL 4-MBC, and 20 ng per mL OMC for men. All three sunscreens were
      detectable in urine. The reproductive hormones FSH, LH were unchanged but minor
      differences in testosterone levels were observed between the 2 wk. A minor
      difference in serum estradiol and inhibin B levels were observed in men only.
      These differences in hormone levels were not related to sunscreen exposure.

PMID- 15191544
TI  - Hailey-Hailey disease: identification of novel mutations in ATP2C1 and effect of
      missense mutation A528P on protein expression levels.
AB  - ATP2C1, encoding the human secretory pathway Ca(2+)-ATPase (hSPCA1), was recently
      identified as the defective gene in Hailey-Hailey disease (HHD), an autosomal
      dominant skin disorder characterized by abnormal keratinocyte adhesion in the
      suprabasal layers of the epidermis. In this study, we used denaturing high
      performance liquid chromatography to screen all 28 exons and flanking intron
      boundaries of ATP2C1 for mutations in 9 HHD patients. Nine different mutations
      were identified. Five of these mutations, including one nonsense, one deletion,
      two splice-site, and one missense mutation, have not been previously reported.
      Recently, functional analysis of a series of site-specific mutants, designed to
      mimic missense mutations found in ATP2C1, uncovered specific defects in Ca(2+)
      and/or Mn(2+) transport and protein expression in mutant hSPCA1 polypeptides. In
      order to investigate the molecular and physiological basis of HHD in the patient
      carrying missense mutation A528P, located in the putative nucleotide binding
      domain of the molecule, site-directed mutagenesis was employed to introduce this
      mutation into the wild-type ATP2C1 (hSPCA1) sequence. Functional analyses of HHD
      mutant A528P demonstrated a low level of protein expression, despite normal
      levels of mRNA and correct targeting to the Golgi, suggesting instability or
      abnormal folding of the mutated hSPCA1 polypeptides. Analogous to conclusions
      drawn from our previous studies, these results further support the theory of
      haploinsufficiency as a prevalent mechanism for the dominant inheritance of HHD,
      by suggesting that the level of hSPCA1 in epidermal cells is critical.

PMID- 15191545
TI  - Reproduction of Langerin/CD207 traffic and Birbeck granule formation in a human
      cell line model.
AB  - Birbeck granules (BG) are organelles specific to Langerhans cells (LCs), which
      form where the C-type lectin Langerin accumulates. Their function remains obscure
      due to morphologic and dynamic alterations induced by maturation of isolated LC.
      In this study, we attempted to reconstitute Langerin traffic and BG formation in
      the endosomal pathway of a human melanoma cell line. In the selected Langerin
      transfected cell line, M10-22E, Langerin is distributed between the early
      recycling endosomal compartment and the plasma membrane, as in LC. Whereas mainly
      concentrated in membranes related to the Rab11(+) endosomal recycling compartment
      at the steady state, Langerin also recycles in M10-22E cells and drives BG
      biogenesis in the endosomal recycling compartment. Interruption of endocytosis or
      recycling induces redistribution of intracellular Langerin with an associated
      alteration in BG location and morphology. We have, therefore, generated a stable,
      Langerin-transfected cell line in which Langerin traffic and distribution and BG
      morphology replicate that seen in freshly isolated LC. This practical model can
      now be used to further delineate the nature and function of BG.

PMID- 15191546
TI  - Identification and characterization of an alternatively spliced isoform of mouse
      Langerin/CD207.
AB  - The mouse homologue of human Langerin (CD207), a novel Langerhans cells (LC)
      restricted C-type lectin that likely participates in antigen recognition and
      uptake, has been recently identified. In this study, we isolated the mouse
      Langerin cDNA from murine fetal skin-derived dendritic cells (FSDDC) by
      subtractive cloning and rapid amplification of cDNA ends (RACE). An alternatively
      spliced variant of mouse Langerin that lacked the extracellular neck domain
      (DeltaE3Langerin) was detected in RNA derived from FSDDC and epidermal LC by RT
      PCR. In vitro-generated FSDDC and epidermal LC expressed both full-length and
      DeltaE3Langerin mRNA, but tissue expression was not restricted to skin. Mouse
      Langerin protein isoforms were readily detected in fibroblasts transfected with
      cDNAs encoding epitope-tagged Langerin and DeltaE3Langerin. Recombinant
      DeltaE3Langerin protein localized with transferrin-containing compartments in
      transfected fibroblasts. Full-length mouse Langerin-bound mannan, whereas
      DeltaE3Langerin and soluble bacterial recombinant Langerin protein lacking the
      neck domain did not. Fibroblasts transfected with mouse Langerin cDNA contained
      typical Birbeck granules (BG) and cored tubules, whereas DeltaE3Langerin cDNA did
      not induce BG or cored tubule formation in transfected fibroblasts.
      Developmentally regulated expression of Langerin isoforms provides a mechanism by
      which Langerin involvement in antigen uptake and processing could be regulated.

PMID- 15191547
TI  - Diabetes prolongs the inflammatory response to a bacterial stimulus through
      cytokine dysregulation.
AB  - Diabetes has been identified as an important risk factor for infection. But
      relatively little is known about how diabetes alters the inflammatory response to
      bacteria. The objective of this study was to investigate how diabetes affects
      host-bacteria interactions by focusing on the inflammatory response in a
      connective tissue setting. Diabetic (db/db) and control (db/+) mice were
      inoculated with Porphyromonas gingivalis, a pathogen associated with bite wounds
      and periodontal disease. The response was measured histologically or by the
      expression of inflammatory cytokines. By quantitative histologic analysis, there
      was little difference between the diabetic and control mice on day 1. On day 3,
      however, the inflammatory infiltrate had subsided in the control group, whereas
      it had not in the diabetic group (p<0.05). Similar results were noted at the
      molecular level by the persistent expression of tumor necrosis factor-alpha (TNF
      alpha) and the chemokines MCP-1 and MIP-2. The importance of TNF in this process
      was demonstrated by reversal of the prolonged chemokine expression by specific
      inhibition of TNF with Enbrel. These results indicate that cytokine dysregulation
      associated with prolonged TNF expression represents a mechanism through which
      bacteria may induce a more damaging inflammatory response in diabetic
      individuals.

PMID- 15191548
TI  - Identification of autoantigens in psoriatic plaques using expression cloning.
AB  - To search for autoantigens in psoriatic plaques, we screened cDNA libraries of
      plaque epidermis with psoriatic serum samples. This approach has been highly
      successful in identifying tumor antigens, but has not been widely applied to
      autoimmune disease. We identified 11 autoantigens including three with prominent
      reactivity and plausible disease relevance. These are keratin 13 (K13),
      heterogeneous nuclear ribonucleoprotein-A1 (hnRNP-A1), and a previously
      uncharacterized protein, FLJ00294. Serum antibody screening for these
      demonstrated reactivity in 40%, 38%, and 27% of psoriasis patients, respectively.
      Most positive samples reacted with all three, and we found that this was due to
      cross-reactivity among them. Enzyme-linked immunospot assay (ELISPOT) analysis of
      psoriatic peripheral blood T cells confirmed that these autoantigens are also
      recognized by T cells. This demonstrates that this is a feasible method to
      identify autoantigens in an autoimmune target tissue, and suggests that these
      antigens warrant further study in psoriasis. Furthermore, but peripheral blood of
      normal controls reacted to these autoantigens with essentially the same
      frequencies as patients, suggesting that psoriatics may have not only an immune
      system which is capable of reacting to certain autoantigens, but also to a skin
      immunoregulatory alteration which allows this normal reactivity to develop into
      abnormal inflammation.

PMID- 15191549
TI  - Characterization of the progressive skin disease and inflammatory cell infiltrate
      in mice with inhibited NF-kappaB signaling.
AB  - A growth inhibitory role in skin development for the NF-kappaB proteins has been
      established in recent years. We have previously shown that inhibition of NF
      kappaB by overexpression of degradation-resistant IkappaB-alpha in the skin
      results in the development of squamous cell carcinomas (SCC). In this paper, we
      characterize the progressive skin disease leading to cancer development in mice
      with inhibited NF-kappaB signaling in the skin. Increased proliferation and a
      strong inflammatory response were evident in transgenic skin. A mixed
      inflammatory cell infiltrate dominated by polymorphonuclear leukocytes was
      observed in concurrence with an upregulation of the proinflammatory cytokine
      tumor necrosis factor-alpha. This genetically engineered mouse mutation may be a
      useful tool to test the efficacy of cytokine therapies for SCC in the future.

PMID- 15191550
TI  - Induction of GVHD-like skin disease by passively transferred CD8(+) T-cell
      receptor transgenic T cells into keratin 14-ovalbumin transgenic mice.
AB  - To understand the mechanisms involved in immunological tolerance to skin
      associated antigens, we have developed transgenic (Tg) mice that express a model
      self-antigen, membrane-bound chicken ovalbumin (OVA), under the control of a
      keratin 14 (K14) promoter. K14-mOVA Tg mice express OVA mRNA in the epidermis,
      and appear normal. K14-mOVA Tg mice failed to mount T cell and delayed type
      hypersensitivity reactions to OVA, suggesting that the Tg mice were tolerant to
      OVA. Skin dendritic cells, including Langerhans cells, may contribute to the
      tolerance induction because migratory skin DC derived from K14-mOVA efficiently
      activated CD8(+) T cells from OVA-specific T-cell receptor (Va2/Vb5) Tg (OT-I)
      mice. OT-I cells expanded and accumulated in skin-draining lymph nodes after
      intravenous injected into K14-mOVA mice and exhibited activation markers. Graft
      versus-host disease-like skin lesions appeared in K14-mOVA mice by day 7 after
      injection of OT-I cells. These studies demonstrate that K14-mOVA Tg mice are
      susceptible to an autoimmunelike skin disease induced by passively transferred
      naive CD8(+) OVA T-cell receptor Tg T cells, and serve as a good model for
      understanding self-tolerance and for the investigation of the pathogenesis,
      treatment and potential prevention of cell-mediated autoimmune reactions in skin.

PMID- 15191551
TI  - Human skin mast cells express H2 and H4, but not H3 receptors.
AB  - Mast cells generate and release histamine during anaphylactic reactions, and
      there is pharmacological evidence that histamine regulates this process via
      specific receptors. Therefore, we examined human leukemic (HMC-1) and normal skin
      mast cells for the expression of all four currently known histamine receptors.
      Both cell types expressed H2 and H4 receptors at mRNA and protein levels, whereas
      H3 receptor specific mRNA and receptor protein was undetectable. Similarly,
      immunohistochemistry of cutaneous tissue showed an absence of H3 receptor in
      these cells. Despite transcription of mRNA, H1 receptor protein was only
      moderately expressed in HMC-1 cells and was virtually absent in skin mast cells.
      Furthermore, only H1, H2, and H4 receptors were detectable by Western blot
      analysis of HMC-1 cells. Radiolabeled histamine binding was strongly inhibited
      only by H2 (ranitidine)- and H3/H4 (FUB 108)-specific antagonists. Histamine
      induced increase of cAMP was inhibited by the H2 receptor antagonist famotidine,
      whereas induction of IP3 was not observed, making signaling via the H1 receptor
      unlikely. These data show that human mast cells constitutively express primarily
      H2 and H4 receptors and that H2 receptors are functionally linked to cellular
      processes. They provide new insights into the mechanisms that govern auto- and
      paracrine histamine-induced mast cell functions.

PMID- 15191552
TI  - The interleukin-6 cytokine system regulates epidermal permeability barrier
      homeostasis.
AB  - Interleukin-6 (IL-6) is involved in the growth and differentiation of numerous
      cell types. In the skin it is produced primarily by keratinocytes. The
      transcription factor STAT3 is activated by cytokines of the IL-6 family. In this
      study, we examined the involvement of IL-6, soluble IL-6-receptor, and STAT3 in
      epidermal barrier repair after injury to the stratum corneum by tape-stripping.
      After barrier disruption in wild-type mice we found an increased immunostaining
      of IL-6 and IL-6R on epidermal keratinocytes at 15 min to 5 h after treatment.
      The increase in IL-6 and IL-6R was confirmed by western blotting using epidermal
      homogenates and was partially prevented by occlusion immediately after barrier
      disruption. In IL-6-deficient mice, epidermal barrier repair was reduced at 3-24
      h after treatment. Topical application of IL-6 or Hyper-IL-6, a complex of IL-6
      linked to the soluble IL-6 receptor, enhanced epidermal barrier repair in wild
      type mice. Application of the fusion protein gp130-FC, a specific inhibitor of
      the agonist IL-6/sIL-6 receptor complex, delayed barrier repair in wild, but not
      in IL-6-deficient mice. STAT3 tyrosine phosphorylation was induced after barrier
      disruption in wild-type, but markedly reduced in IL-6-deficient mice. Our results
      indicate that the IL-6 cytokine system, particularly transsignalling via the
      soluble IL-6R, is critically involved in barrier repair after skin injury.

PMID- 15191553
TI  - The neuronal nitric oxide synthase is upregulated in mouse skin repair and in
      response to epidermal growth factor in human HaCaT keratinocytes.
AB  - Expression of nNOS mRNA was found in normal human and mouse skin tissue. Upon
      wounding, we observed a rapid downregulation of nNOS mRNA and protein in wounds
      of mice; however, when repair continued, nNOS mRNA was strongly upregulated and
      nNOS protein expression peaked at late stages of healing. Immunohistochemistry
      revealed wound keratinocytes as the cellular source of nNOS. In line with the in
      vivo situation, we found a basal expression of nNOS in the human keratinocyte
      cell line HaCaT. A marked stimulation of nNOS expression in the cells was
      achieved with epidermal growth factor receptor (EGFR) ligands such as epidermal
      growth factor (EGF), heparin-binding EGF, transforming growth factor-alpha and
      two alternate splicing forms of the neuregulin gene. EGF-induced induction of
      nNOS was completely inhibited by the specific EGFR antagonist PD153035 and by the
      EGFR and Janus kinase 2/3 inhibitor AG490. Activation of EGFR might contribute to
      the observed upregulation of nNOS also in skin repair, as we found a spatial and
      temporal correlation of phosphorylated EGFR (Y1173) with nNOS expression at the
      wound site. Thus, in addition to the inducible- and endothelial-type NOS
      isoforms, also nNOS expression is regulated in the process of cutaneous wound
      repair.

PMID- 15191554
TI  - Functional consequences of a neutral pH in neonatal rat stratum corneum.
AB  - At birth, neonatal stratum corneum (SC) pH is close to neutral but acidifies with
      maturation, which can be ascribed, in part, to secretory phospholipase A(2) and
      sodium/hydrogen antiporter 1 (NHE1) activities. Here we assessed the functional
      consequences of a neutral SC pH in a newborn rat model. While basal
      transepidermal water loss rates are near normal, barrier recovery (BR) rates
      after acute barrier disruption were delayed in newborn animals. The abnormality
      in barrier homeostasis could be improved by topical applications of an acidic
      buffer, indicating that barrier abnormality is primarily due to high SC pH. The
      delay in BR correlated with incompletely processed lamellar membranes and
      decreased activity of beta-glucocerebrosidase. Inhibition of NHE1 delayed BR
      after acute barrier perturbation. SC integrity was abnormal in newborn animals.
      Electron microscopy demonstrated decreased corneodesmosomes (CD) in newborn
      animals with decreased expression of desmoglein 1 and corneodesmosin. Serine
      protease activation appears to be responsible for CD degradation in newborn
      animals, because serine protease activity is increased in the SC and it can be
      reduced by acidification of the SC. The delay in acidification of neonatal SC
      results in abnormalities in permeability barrier homeostasis and SC integrity and
      are likely due to pH-induced modulations in enzyme activity.

PMID- 15191556
TI  - Use of RT-PCR and DNA microarrays to characterize RNA recovered by non-invasive
      tape harvesting of normal and inflamed skin.
AB  - We describe a non-invasive approach for recovering RNA from the surface of skin
      via a simple tape stripping procedure that permits a direct quantitative and
      qualitative assessment of pathologic and physiologic biomarkers. Using semi
      quantitative RT-PCR we show that tape-harvested RNA is comparable in quality and
      utility to RNA recovered by biopsy. It is likely that tape-harvested RNA is
      derived from epidermal cells residing close to the surface and includes adnexal
      structures and present data showing that tape and biopsy likely recover different
      cell populations. We report the successful amplification of tape-harvested RNA
      for hybridization to DNA microarrays. These experiments showed no significant
      gene expression level differences between replicate sites on a subject and
      minimal differences between a male and female subject. We also compared the array
      generated RNA profiles between normal and 24 h 1% SLS-occluded skin and observed
      that SLS treatment resulted in statistically significant changes in the
      expression levels of more than 1,700 genes. These data establish the utility of
      tape harvesting as a non-invasive method for capturing RNA from human skin and
      support the hypothesis that tape harvesting is an efficient method for sampling
      the epidermis and identifying select differentially regulated epidermal
      biomarkers.

PMID- 15191555
TI  - Insulin-like growth factor-II regulates the expression of vascular endothelial
      growth factor by the human keratinocyte cell line HaCaT.
AB  - Psoriasis is a chronic, relapsing skin disease characterized by enhanced
      angiogenesis. The pathogenetic process resulting in hypervascularity remains to
      be further investigated. It has been reported that a potent angiogenic factor,
      vascular endothelial growth factor (VEGF) is overexpressed in psoriatic epidermis
      and that the level of insulin-like growth factor II (IGF-II) is significantly
      elevated in the tissue fluid and serum of the psoriatic lesion. We considered the
      possibility that IGF-II might function as a paracrine inducer of VEGF. Here, we
      demonstrated that exposure of HaCaT keratinocytes to IGF-II induced both mRNA and
      protein expression of VEGF through the MAP kinase (extracellular signal-regulated
      kinase (ERK2) pathway. Particularly, we determined that phosphorylation of ERK2
      but not p38 and JNK1/2 was activated by IGF-II in a time-dependent manner.
      Additionally, we found that IGF-II treatment induced the expression of MDM2
      through the MAP kinase pathway. Moreover, the increase of MDM2 resulted in
      decreased levels of p53 followed by increased expression of HIF-1alpha and VEGF.
      Taken together, these results suggest that IGF-II enhances the expression of VEGF
      in HaCaT cells by increasing HIF-1alpha levels.

PMID- 15191557
TI  - Penetration profile of microspheres in follicular targeting of terminal hair
      follicles.
AB  - The transfollicular administration of pharmacologically active molecules is of
      current therapeutic interest, mainly with regard to delivery to specific sites of
      the hair follicle (HF) and the reduction of hepatic metabolism and systemic
      toxicity. HF are privileged pathways for specific molecules depending on
      formulations, which enter faster into these shunts than through the stratum
      corneum. The aim was to optimize the delivery of fluorescent microspheres into
      the HF, thereby, developing a standardized protocol for follicular targeting with
      microspheres. The number of HF showing penetration, as well as the depth of
      penetration, was determined. Freshly excised skin samples with terminal HF were
      divided into groups, with or without prior treatment with cyanoacrylate skin
      surface stripping-technique (CSSS). Thereafter microspheres at a size of 0.75-6.0
      microm were applied according to the developed standardized protocol. Skin
      biopsies were obtained, shock-frozen, and sectioned in 5 microm slices. We
      demonstrated a selective penetration route of the microspheres into the HF.
      Optimal microsphere size proved to be approximately 1.5 microm, with a 55% rate
      of all HF, and with a maximum penetration depth of >2300 microm. Without previous
      CSSS treatment of the skin, the transfollicular microsphere penetration was below
      27% with a maximum penetration depth of 1000 microm. Thus, the basis for
      follicular targeting of essential structures containing stem cells for
      keratinocytes, melanocytes, and mast cells has been laid.

PMID- 15191558
TI  - BRAF point mutations in primary melanoma show different prevalences by subtype.
AB  - To elucidate the biological significance of activating mutations of BRAF in human
      malignant tumors, we performed a mutation analysis using 43 cell lines
      established from tumors that had developed in several kinds of human organs.
      Because the same V599E point mutation was observed in three of six melanoma cell
      lines and no such mutations were observed in other types of cancers, we focused
      further on melanoma, performed mutation analyses of NRAS, KRAS, CTNNB1, and
      p16/p14(ARF) in these cell lines, and found one NRAS mutation and three
      p16/p14(ARF) mutations. We further searched for mutations of BRAF and NRAS in 35
      primary sporadic melanomas from 35 Japanese patients and detected the V599E BRAF
      point mutation in only nine (26%) of them. Significant differences in mutation
      frequency were observed among four histological subtypes; four (50%) of eight
      superficially spreading melanoma and five (33%) of 15 acral lentiginous melanoma
      had the mutation, whereas none of 12 other types (six nodular melanoma, five
      lentigo melanoma, and one mucosal melanoma) had it. The BRAF mutation was
      observed frequently even in small lesions, indicating that activation of this
      gene may be one of the early events in the pathogenesis of some melanomas.

PMID- 15191559
TI  - beta-Endorphin as a regulator of human hair follicle melanocyte biology.
AB  - The pro-opiomelanocortin (POMC)-derived peptides, alpha-melanocyte-stimulating
      hormone, and adrenocorticotropic hormone, are important mediators of human skin
      pigmentation via action at the melanocortin-1 receptor. Recent data suggests that
      such a regulatory role also exists for the endogenous opiate, beta-endorphin
      (beta-END). A role for this beta-END in the regulation of follicular
      pigmentation, however, has not been determined. This study was designed to
      examine the involvement of the beta-END/mu-opiate receptor system in human
      follicular melanocyte biology. We employed RT-PCR, and immunohisto/cytochemistry
      and immunoelectron microscopy using beta-END and mu-opiate receptor specific
      antibodies and a functional role for beta-END was assessed by direct stimulation
      with the peptide. This study has demonstrated that human hair follicle
      melanocytes (HFM) express mRNA for the mu-opiate receptor and POMC. Furthermore,
      beta-END and its high affinity mu-opiate receptor are expressed at the protein
      level in glycoprotein100-positive follicular melanocytes and as a function of
      their anatomic location and differentiation status during the hair growth cycle.
      Functional studies revealed that beta-END is a modifier of HFM phenotype via its
      ability to upregulate melanogenesis, dendricity, and proliferation. These
      findings suggest a new regulatory role for beta-END in human HFM biology,
      providing a new research direction into the fundamental regulation of human hair
      pigmentation.

PMID- 15191560
TI  - Intradermal nociceptin elicits itch-associated responses through leukotriene B(4)
      in mice.
AB  - Nociceptin, the endogenous peptide ligand for opioid receptor like-1 (ORL1)
      receptor, has been implicated in the inflammation and pain in the skin. We
      examined whether nociceptin is a pruritogen in mice. Intradermal injections of
      nociceptin (1-100 nmol per site) concentration dependently increased scratching
      in ICR mice; the effect started within 1 min, peaked at 10-20 min, and almost
      subsided by 30 min. The nociceptin action was absent in ORL1 receptor-deficient
      (ORL1(-/-)) mice. Systemic, but not local, treatment with naloxone significantly
      inhibited scratching induced by nociceptin. The action of nociceptin was
      inhibited by the leukotriene B(4) receptor antagonist ONO-4057 and azelastine,
      which inhibits the action and production of leukotriene B(4) in the skin.
      Prepronociceptin and ORL1 receptor mRNAs were substantially expressed in the
      skin, whereas their expression levels were very low in the dorsal root ganglia.
      In the skin, nociceptin- and ORL1 receptor-like immunoreactivities were localized
      in the epidermis. Administration of nociceptin to primary cultures of
      keratinocytes from ICR and C57BL/6 (ORL1(+/+)) mice, but not ORL1(-/-) mice,
      produced leukotriene B(4). The results suggest that nociceptin acts on ORL1
      receptor on the keratinocytes to produce leukotriene B(4), which induces itch
      associated responses in mice.

PMID- 15191561
TI  - Decreased neutrophil skin infiltration after UVB exposure in patients with
      polymorphous light eruption.
AB  - UV radiation, in particular UVB, suppresses the skin immune response. In patients
      with polymorphous light eruption (PLE) the skin immune response seems activated
      after UV exposure. Typical PLE skin lesions can occur as early as several hours
      after UV exposure. In healthy volunteers, neutrophils infiltrate the skin shortly
      after UV exposure. The kinetics and mechanisms of neutrophil infiltration in the
      skin of PLE patients after UVB exposure was studied. Skin biopsies at 0, 3, 6,
      and 18 h were taken from five PLE patients and six healthy controls after
      irradiation with three minimal erythema dose UVB. Furthermore, neutrophils were
      isolated from blood of five PLE patients and six healthy controls to test their
      chemotactic activity. Immunohistochemical analysis showed a significant decreased
      neutrophil infiltration in PLE skin after UVB irradiation compared with healthy
      controls (p<0.05). In both healthy controls and PLE patients, after UVB
      irradiation, ICAM-1 and E-selectin expression on endothelial cells increased at 6
      h after irradiation. Blood neutrophil chemotactic response towards IL-8 and C5a,
      as well as the expression of cell surface markers involved in adhesion and
      chemotaxis, was not different between PLE patients and healthy controls. In
      conclusion, PLE is marked by a decreased skin infiltration of neutrophils after
      UVB irradiation, possibly leading to a diminished neutrophil-induced suppression.

PMID- 15191562
TI  - AKT status controls susceptibility of malignant keratinocytes to the early
      activated and UVB-induced apoptotic pathway.
AB  - In previous work, we have described an early-activated and ultraviolet B (UVB)
      induced apoptotic pathway in human keratinocytes, which can be completely
      inhibited by AKT activation. We now compared this response of primary human
      keratinocytes with the response of two p53-mutated squamous cell carcinoma (SCC)
      derived cell lines (A431 and A253) to an apoptotic UVB dose. In these cell lines,
      both the basal AKT phosphorylation status and the apoptotic response to UVB
      diverged strongly from the response of healthy primary keratinocytes. Even more,
      a remarkable correlation was found between the two. Although a constitutive dual
      phosphorylation of AKT rendered the A253 SCC cell line completely resistant to
      the early-activated and UVB-induced apoptotic pathway, deficient T308
      phosphorylation of AKT in the SCC cell line A431 led to a greatly augmented
      sensitivity to the early-activated, UVB-induced apoptotic pathway. These results
      indicate that the preservation of a healthy AKT pathway is essential for a wild
      type UVB-induced apoptotic response in skin, and suggest that AKT-mediated
      dysregulation of the early-activated apoptotic response to UVB is an important
      event in the oncogenic transformation of keratinocytes.

PMID- 15191563
TI  - Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6,
      and MALT1 gene loci in primary cutaneous B-cell lymphomas.
AB  - Chromosomal translocations affecting the IGH locus and various oncogene loci are
      recurrent in many types of systemic B-cell lymphomas. Hardly any data exist,
      however, on such translocations in primary cutaneous B-cell lymphomas (PCBCL).
      Here, a series of 29 PCBCL was investigated by interphase fluorescence in situ
      hybridization with probes for the IGH, MYC, BCL6, and MLT1 loci. None of the six
      follicle center cell lymphomas and nine marginal zone lymphomas showed evidence
      for any translocation affecting these loci. In contrast, 11 of 14 large B-cell
      lymphomas of the leg harbored breakpoints in at least one of the loci.
      Translocations involving the MYC locus were detected in six cases, five of them
      derived from a MYC/IGH juxtaposition and one from a translocation involving a non
      IG gene partner. Rearrangements of the BCL6 locus were detected in five B-cell
      lymphomas of the leg, and involved IGH (two cases), IGL (one case), and non-IG
      genes (two cases). This study shows that large B-cell lymphomas of the leg
      display a pattern of chromosomal translocations similar to their systemic
      counterparts whereas primary cutaneous follicle center cell lymphomas and
      marginal zone lymphomas lack these typical chromosomal translocations.

PMID- 15191564
TI  - XPA gene-deficient, SCF-transgenic mice with epidermal melanin are resistant to
      UV-induced carcinogenesis.
AB  - Photobiologic investigations have been performed using animals without epidermal
      melanocytes. We developed xeroderma pigmentosum group A gene-deficient (XPA (-/
      )), stem cell factor transgenic (SCF-Tg) mice, which one defective in nucleotide
      excision repair and have epidermal melanocytes, and investigated protective
      effects of epidermal melanin against UV-induced injuries. When irradiated to UVB,
      XPA (-/-) mice developed greatly enhanced responses including acute inflammation,
      cyclobutane pyrimidine dimer (CPD) formation, keratinocyte apoptosis, depletion
      of Langerhans cells and immunosuppression of contact hypersensitivity, but XPA (
      /-), SCF-Tg mice showed much less responses to the same dose of UVB. XPA (-/-),
      SCF-Tg mice did not develop skin cancers after repeated exposures to UVB for 30
      wk at a total dose of 72 J per cm(2), which induced a significant number of
      tumors even in wild-type, XPA (+/+) mice, and was lethal dose for XPA (-/-) mice.
      Dimethylbenz (alpha) anthracence (DMBA) induces DNA damages, which require XPA
      protein to be repaired. Topical application of DMBA produced a significant
      inflammation, CPD formation, apoptosis, immunosuppression, and skin cancers in
      XPA (-/-), SCF-Tg mice as well as XPA (-/-) mice. These findings indicate that
      epidermal melanin has a high ability to protect DNA damage by UVB radiation, and
      thereby, prevent UV-induced inflammation, immunosuppression, and carcinogenesis.

PMID- 15191565
TI  - Exogenous Smad3 accelerates wound healing in a rabbit dermal ulcer model.
AB  - Exogenous administration of transforming growth factor-beta (TGF-beta) improves
      wound healing by affecting cellular and molecular events involved in tissue
      repair. But mice with a deficiency of a key TGF-beta signaling intermediate,
      Smad3, paradoxically showed accelerated cutanenous wound healing, suggesting that
      endogenous Smad3 had inhibitory effect on cutaneous wound healing. Here we
      investigated the effect of exogenous expression of Smad3 in dermal fibroblasts on
      cutaneous wound healing. Subcutaneous injection of adenovirus-containing Smad3
      complementary DNA (AdCMV-Smad3) targeting mainly dermal fibroblasts accelerated
      tissue repair following full-thickness dermal round wounds in rabbit ear as
      judged by the size of granulation tissue area, number of capillaries, and re
      epithelialization rate of the wounds. Expressions of alpha-smooth muscle actin
      (alpha-SMA), vascular endothelial growth factor (VEGF), and fibroblast growth
      factor receptor were upregulated in the wounded area injected with AdCMV-Smad3.
      Consistent with the in vivo findings, overexpression of Smad3 induced alpha-SMA,
      VEGF, and TGF-beta1 expression and augmented chemotactic response in cultured
      dermal fibroblasts. Therefore, exogenous administration of Smad3 targeting dermal
      fibroblasts accelerated tissue repair in a rabbit dermal ulcer model by affecting
      fibroblast responses associated with wound healing. The results suggest that
      Smad3, when overexpressed in dermal fibroblasts, can promote wound healing.

PMID- 15191566
TI  - UVA radiation induces suppression of perforin-granule release from CD8(hi+)
      cytotoxic T lymphocytes ex vivo.

PMID- 15191567
TI  - A multigene family of inactivated cysteine proteases in Sarcoptes scabiei.

PMID- 15191568
TI  - FPRL1 receptor agonist peptides prevent etoposide-induced alopecia in neonatal
      rats.

PMID- 15191569
TI  - Human melanocytes do not express EGF receptors.

PMID- 15191570
TI  - A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families
      with autosomal recessive hypotrichosis.

PMID- 15191577
TI  - If it's not the hamburgers, it's the sunscreens.

PMID- 15191578
TI  - Polymorphic light eruption: does a neutrophil defect contribute to the
      pathogenesis?

PMID- 15191580
TI  - Alcohol consumption and periodontal disease. The Third National Health and
      Nutrition Examination Survey.
AB  - OBJECTIVE: This study was carried out to evaluate the effect of alcohol
      consumption on the severity of periodontal disease. MATERIAL AND METHODS: This
      cross-sectional study employed 13,198 subjects of the Third National Health and
      Nutrition Examination Survey (NHANES III) aged 20 and older who have at least six
      natural teeth. Alcohol intake was represented both as a continuous variable and
      dichotomized using 5, 10, 15, and 20 drinks/week as cut-points. Periodontal
      disease was represented by clinical attachment loss (CAL) and was assessed both
      as a continuous variable and dichotomized as <1.5 mm and >/=1.5 mm. Independent
      effect of alcohol on CAL was assessed by weighted multiple linear and logistic
      regression analyses adjusting simultaneously for the effects of age, gender,
      race, education, income, smoking, diet, diabetes, gingival bleeding, number of
      remaining teeth. RESULTS: There was a significant linear relationship between
      number of drinks per week and log CAL (p=0.0001). Odds ratios for the risk of
      attachment loss using 5, 10, 15, and 20 drinks/week as cut-points were 1.22 [1.02
      1.47], 1.39 [1.13-1.71], 1.54 [1.22-1.93], and 1.67 [1.25-2.23], respectively.
      CONCLUSION: Alcohol consumption may be associated with increased severity of CAL
      in a dose-dependent fashion. Prospective studies and studies of mechanism are
      needed to confirm the role of alcohol as a risk factor for periodontal disease.

PMID- 15191581
TI  - Some risk factors for periodontal bone loss in 50-year-old individuals. A 10-year
      cohort study.
AB  - OBJECTIVE: The aim of this 10-year prospective study of 50-year-old individuals
      was to analyze the incidence of periodontal bone loss and potential risk factors
      for periodontal bone loss. METHODS: The subject sample was generated from an
      epidemiological survey performed in 1988 of subjects living in the County of
      Varmland, Sweden. A randomized sample of 15% of the 50-year-old inhabitants in
      the county was drawn. At the 10-year follow-up in 1998, 320 (75%) of the 449
      individuals examined at baseline were available for re-examination, out of which
      4 had become edentulous. Full-mouth clinical and radiographic examinations and
      questionnaire surveys were performed in 1988 and 1998. Two hundred and ninety
      five individuals (69%) had complete data for inclusion in the analysis of
      radiographic bone changes over 10 years. Non-parametric tests, correlations and
      stepwise multiple regression models were used for statistical analysis of the
      data. RESULTS: The mean alveolar bone level (ABL) in 1988 was 2.2 mm (0.05) and a
      further 0.4 mm (0.57) (p=0.000) was lost over the 10 years. Eight percent of the
      subject sample showed no loss, while 5% experienced a mean bone loss of >/=1 mm.
      Smoking was found to be the strongest individual risk predictor (RR=3.2; 95% CI
      2.03-5.15). When including as smokers only those individuals who had continued
      with the habit during the entire 10-year follow-up period, the relative risk was
      slightly increased (3.6; 95% CI 2.32-5.57). Subjects who had quit smoking before
      the baseline examination did not demonstrate a significantly increased risk for
      disease progression (RR=1.3; 95% CI 0.57-2.96). Stepwise multiple regression
      analysis revealed that smoking, % approximal sites with probing pocket depth >/=4
      mm, number of teeth and systemic disease were significant explanatory factors for
      10-year ABL loss (R(2)=0.12). For never smokers, statistically significant
      predictors were number of teeth, mean ABL, % periodontally healthy approximal
      sites and educational level (R(2)=0.20). CONCLUSION: The inclusion of smokers in
      risk analysis for periodontal diseases may obstruct the possibility to detect
      other true risk factors and risk indicators.

PMID- 15191582
TI  - Critical soft tissue parameters of the zygomatic implant.
AB  - AIM: Zygomatic implants have been introduced for the rehabilitation of patients
      with severe bone defects of the maxilla. The soft tissue aspects of the palatal
      emergence situation have not been described yet. The aim of this study was to
      evaluate the incidence and clinical impact of possible periimplant alterations of
      zygomatic implants. MATERIALS AND METHODS: From 1998 to 2001 all patients with
      zygomatic implants were included into this study (24 patients, 37 zygomatic
      implants). One implant was lost in the loading phase giving a survival rate of
      97%. Fourteen patients with 20 zygomatic implants fulfilled the inclusion
      criteria and were all available for the recall examination. Thirteen zygomatic
      implants were inserted in cases of severe maxillary atrophy, seven in cases of
      tumour-resection of the maxilla. Clinical examination and microbial analysis
      using a DNA probe was performed. The implants had a mean time in situ of 598 days
      (min: 326, max: 914). RESULTS: Colonisation with periodontal pathogens was found
      at four of the 20 implants. A positive microbiologic result of the periimplant
      pocket and the maximum pocket probing depth were not statistically related. Nine
      of the 20 implants showed bleeding on probing, four of these had positive
      microbiologic results. At sites without bleeding on probing only negative
      microbiologic samples were found (p=0.026). The mean palatal and mesial probing
      depth was 1 mm deeper than at the vestibular and distal aspect. Thus at nine out
      of the 20 implants both, bleeding on probing and pocket probing depth >/=5 mm
      indicated soft tissue problems resulting in a success rate of only 55%. The
      patient's history (tumor versus atrophy) or smoking habits seemed not to have
      influence the situation. CONCLUSION: These soft tissue problems should be taken
      into account if zygomatic implants are considered as an alternative therapy
      option in the maxilla.

PMID- 15191583
TI  - Effects of experimental gingivitis on crevicular PGE2 in a split mouth trial.
AB  - OBJECTIVE: The study aimed to analyse the effects of experimental gingivitis on
      crevicular prostaglandin E(2) (PGE(2)). An increase of PGE(2) was expected.
      METHODS: Fourteen medical students refrained for 28 days from any oral hygiene
      procedures in two antagonistic quadrants while they maintained close to perfect
      oral hygiene in the remaining quadrants. Crevicular fluid samples were taken at
      baseline and at days 7, 14, 21 and 28 of experimental gingivitis both from
      quadrants with and without oral hygiene. PGE(2)-concentrations (ng/ml) and
      absolute levels (pg/sample) were analysed for quadrants with and without oral
      hygiene. RESULTS: Comparison of quadrants with and without oral hygiene by
      repeated measures anova revealed no effects of experimental gingivitis both on
      crevicular PGE(2)-concentrations and absolute levels. CONCLUSION: The study does
      not support the notion that experimental gingivitis induces an increase of
      crevicular PGE(2). The data are discussed in the context of other studies on
      PGE(2) concentrations in gingivitis. Close inspection of these studies reveals no
      clear evidence for an increase of local PGE(2) in gingivitis.

PMID- 15191584
TI  - Impact of tongue cleansers on microbial load and taste.
AB  - OBJECTIVES: Tongue cleaning has been advocated to improve oral malodor and to
      reduce reinfection of periodontal niches by eliminating tongue coating and/or
      reducing putrefaction by bacteria. MATERIAL AND METHODS: This cross-over, single
      blind study on periodontitis-free, non-smoking, subjects with habitual oral
      hygiene (n=16), evaluated the effect of tongue cleaning (with either plastic
      scraper or nylon multi-tufted toothbrush), on the microbial load of the tongue
      dorsum (anterior and posterior of the sulcus terminalis), the extent of tongue
      coating, and taste sensation for bitter, sweet, salt, and sour. Both devices had
      been used twice daily for 2 weeks (toothbrush three forward-backward movements
      along the linea mediana and for each longitudinal third of the tongue; two
      strokes with the scraper along the linea mediana and along the borders of the
      tongue). RESULTS: Two weeks of tongue brushing or scraping resulted in only
      negligible reductions in aerobic and anaerobic bacteria on the tongue (reductions
      <0.5 log). The amount of tongue coating, however, decreased significantly
      (p<0.05), with both devices. The taste sensation improved after 2 weeks of tongue
      cleaning, especially with the scraper (significant improvements for quinine and
      sodium chloride). CONCLUSION: Tongue cleaning improves taste sensation and seems
      to reduce the substrata for putrefaction, rather than the bacterial load.

PMID- 15191585
TI  - Lactoferrin and other markers from gingival crevicular fluid and saliva before
      and after periodontal treatment.
AB  - OBJECTIVES: The aim of the study was to verify (i) if crevicular fluid defence
      variables reflect the changes after surgical periodontal treatment and (ii) if
      they are in correspondence with changes of these variables in the unstimulated
      and stimulated whole saliva. MATERIAL AND METHODS: For 12 male and 13 female
      volunteers with chronic periodontitis lactoferrin concentration as well as the
      lysozyme and peroxidase activities were determined in crevicular fluid as well as
      in unstimulated and stimulated saliva before and 14 days after surgical
      periodontal treatment by a minimal invasive flap technique. RESULTS: The
      lactoferrin concentrations decreased significantly in the crevicular fluid
      eluting solution from 1.63 to 1.23 mg/l reflecting a decrease in the total amount
      collected, in unstimulated saliva from 10.54 to 8.96 mg/l, and in stimulated
      saliva from 9.00 to 7.11 mg/l after treatment. No significant change could be
      found for lysozyme. Peroxidase activity was significantly reduced from 269.06 to
      186.15 U/l only in the crevicular fluid. CONCLUSION: The results of this study
      suggest that (i) the defence factor lactoferrin is suitable for monitoring of
      periodontal treatment results and (ii) changes of the lactoferrin concentration
      in crevicular fluid are related with significant changes in unstimulated and
      stimulated saliva.

PMID- 15191586
TI  - Local and systemic total antioxidant capacity in periodontitis and health.
AB  - BACKGROUND: The involvement of reactive oxygen species (ROS) in periodontal
      pathology is unclear but will be modulated by in vivo antioxidant defence
      systems. The aim of this cross-sectional study was to determine both local
      (saliva and gingival crevicular fluid (GCF) and peripheral (plasma and serum)
      antioxidant capacity in periodontal health and disease. MATERIALS AND METHODS:
      Twenty non-smoking volunteers with chronic periodontitis were sampled together
      with twenty age- and sex-matched, non-smoking controls. After overnight fasting,
      saliva (whole unstimulated and stimulated) and blood were collected. Total
      antioxidant capacity (TAOC) was determined using a previously reported enhanced
      chemiluminescence method. RESULTS: GCF antioxidant concentration was
      significantly lower (p<0.001) in periodontitis subjects compared to healthy
      controls. Although mean levels of peripheral and salivary TAOC were also lower in
      periodontitis the difference was only significant for plasma (p<0.05). Healthy
      subjects' GCF antioxidant concentration was significantly greater than paired
      serum or plasma (p<0.001). Data stratified for gender did not alter the findings
      and a male bias was revealed in all clinical samples except GCF. CONCLUSIONS:
      These findings suggest that the antioxidant capacity of GCF is both qualitatively
      and quantitatively distinct from that of saliva, plasma and serum. Whether
      changes in the GCF compartment in periodontitis reflect predisposition to or the
      results of ROS-mediated damage remains unclear. Reduced plasma total antioxidant
      defence could result from low-grade systemic inflammation induced by the host
      response to periodontal bacteria, or may be an innate feature of periodontitis
      patients.

PMID- 15191587
TI  - Mandibular overdentures supported by two Branemark, IMZ or ITI implants: a 5-year
      prospective study.
AB  - OBJECTIVES: The aim of this prospective comparative study was to evaluate the
      survival rate and the condition of the peri-implant tissues of the IMZ implant
      system (two-stage cylindertype), the Branemark implant system (two-stage
      screwtype) and the ITI implant system (one-stage screwtype) supporting a
      mandibular overdenture during a 5-year follow-up period. MATERIAL AND METHODS:
      Three groups of 30 edentulous patients were treated with two endosseous implants
      in the interforaminal region of the mandible. Clinical and radiographic
      parameters were evaluated immediately after completion of the prosthetic
      treatment and after 1, 2, 3, 4 and 5 years of functional loading. RESULTS: The
      five-year survival rate is 98.3% for the IMZ group, 98.3% for the Bra group and
      100% for the ITI group. Mean scores on indices for plaque, calculus, gingiva and
      bleeding were very low at all evaluation periods. Mean marginal bone loss over a
      period of 5 years, was 1.4 mm for the IMZ group, 0.7 mm for the Bra group and 0.9
      mm for the ITI group. CONCLUSION: It is concluded that two implants placed in the
      interforaminal region, connected with a bar, supply a proper base for the support
      of a mandibular overdenture in the edentulous patient. After 5 years no
      clinically relevant and statistically significant radiographic changes had
      developed between the three implant systems.

PMID- 15191588
TI  - Changes in transforming growth factor-beta1 in gingival crevicular fluid
      following periodontal surgery.
AB  - OBJECTIVES: Growth factors play a major part in wound healing, including in the
      periodontium. However, the presence of growth factors in gingival crevicular
      fluid (GCF) in humans during periodontal wound healing has not yet been
      determined. Our hypothesis is that such factors are present in GCF and that
      changes in their levels might be of value as a prognostic marker of wound-healing
      activity and therapeutic progress following periodontal surgery. The aim of this
      study was therefore to measure transforming growth factor-beta1 (TGF-beta1) in
      GCF collected from sites that have undergone guided tissue regeneration (GTR) and
      conventional flap (CF) surgery and to compare these with GCF collected from
      unaffected healthy sites. MATERIALS AND METHODS: GCF samples were collected,
      using filter paper strips, at baseline (pre-surgical) and then at intervals up to
      26 weeks from 16 patients undergoing GTR and from 11 patients undergoing CF
      surgery. After elution and acid treatment, TGF-beta1 levels were measured by
      ELISA. RESULTS: Treatment of periodontal defect sites significantly reduced the
      mean probing pocket depth (PPD) and improved the mean lifetime cumulative
      attachment loss (LCAL). Average GCF volumes also significantly increased at all
      sites at 2 weeks post-surgery and thereafter declined to baseline levels, except
      at the GTR test sites that were still elevated at 7 weeks. TGF-beta1 could be
      detected in almost all GCF samples, and 2 weeks after surgery, the average levels
      increased two-fold at the surgically treated but not at the control sites, which
      remained unchanged. CONCLUSION: TGF-beta1 is readily detectable in GCF and
      increases transiently following periodontal surgery. This suggests that changes
      in the levels of this growth factor in GCF might be useful for monitoring the
      progress of periodontal repair and regeneration.

PMID- 15191589
TI  - Histologic evaluation of demineralized freeze-dried bone allografts in barrier
      membrane covered periodontal fenestration wounds and ectopic sites in dogs.
AB  - BACKGROUND/AIM: The aim of this study was to investigate healing responses to
      demineralized freeze-dried bone powder allografts in standardized periodontal
      fenestration defects, compared with subcutaneous wounds in a dog model. METHODS:
      Circular periodontal fenestration defects were created buccally at all four
      canines in 14 mongrel dogs. Each site received one of the following underneath a
      barrier membrane: (a) ethylene oxide (EO)-sterilized demineralized freeze-dried
      bone allografts (DFDBA), (b) heat-treated DFDBA, (c) non-sterilized DFDBA and (d)
      ungrafted control. Twelve of the 14 dogs had three subcutaneous chest wall
      pouches created and one of the three DFDBA materials placed in each. The animals
      were necropsied at 4 weeks. Histologic sections were prepared through the center
      of the fenestration sites in an apico-coronal direction. Quantitative analysis
      using computer-assisted imaging technique was performed. Subcutaneous implants
      were evaluated histologically and quantified for associated inflammatory cell
      infiltrate. RESULTS: Fenestration defects healed by partial osseous fill and
      cementum regeneration with formation of a periodontal ligament. The graft
      particles generally appeared isolated from the site of osteogenesis and covered
      by cementum-like substance. Graft particles incorporated into newly formed bone
      at a distance from the root surface was the exception. No statistically
      significant differences in new bone formation were observed between treatment
      groups within animals, but significant inter-animal variation was found (p<0.01).
      Quantities of retained graft particles were limited, and without cellular
      resorption. A bone augmentation effect was associated with the barrier in the
      majority of sites. No bone formation was evident at the subcutaneous sites where
      graft particles displayed distinctly modified surface zones and multinucleated
      giant cell resorption. Significantly more inflammatory infiltrate was associated
      with EO-sterilized grafts compared with heat-treated grafts (p=0.05). CONCLUSION:
      Implantation of DFDBA neither enhanced osseous healing in periodontal
      fenestration defects, nor resulted in ectopic bone induction. DFDBA particles
      implanted in either periodontal fenestration or subcutaneous wounds evoked
      distinctly different healing responses.

PMID- 15191590
TI  - Five-year results following treatment of intrabony defects with enamel matrix
      proteins and guided tissue regeneration.
AB  - BACKGROUND: Treatment with enamel matrix proteins (EMD) or guided tissue
      regeneration (GTR) has been shown to enhance periodontal regeneration. However,
      until now there are limited data on the long-term results following these
      treatment modalities. AIM: The aim of the present clinical study was to present
      the 5-year results following treatment of intrabony defects with EMD, GTR,
      combination of EMD and GTR, and open flap debridement (OFD). MATERIAL AND
      METHODS: Forty-two patients, each of whom displayed one intrabony defect of a
      probing depth of at least 6 mm, were randomly treated with one of the four
      treatment modalities. The following parameters were evaluated prior to surgery,
      at 1 year and at 5 years after: plaque index, gingival index, bleeding on
      probing, probing pocket depth (PPD), gingival recession, and clinical attachment
      level (CAL). No statistically significant differences in any of the parameters
      were observed at baseline between the four groups. RESULTS: The sites treated
      with EMD demonstrated a mean CAL gain of 3.4+/-1.1 mm (p<0.001) and of 2.9+/-1.6
      mm (p<0.001) at 1 and 5 years, respectively. The sites treated with GTR showed a
      mean CAL gain of 3.2+/-0.8 (p<0.001) at 1 year and of 2.7+/-0.9 mm (p<0.001) at 5
      years. The mean CAL gain at sites treated with EMD+GTR was 3.0+/-1.0 mm (p<0.001)
      and 2.6+/-0.7 mm (p<0.001) at 1 and 5 years, respectively. The sites treated with
      OFD demonstrated a mean CAL gain of 1.6+/-1.0 mm (p<0.001) at 1 year and 1.3+/
      1.2 mm (p<0.001) at 5 years. At 1 year, the only statistically significant
      difference between the four different treatments was found in terms of PPD
      reduction and CAL gain between EMD and OFD (p<0.05). However, at 5 years there
      were no statistically significant differences in any of the investigated
      parameters between the four different treatments. CONCLUSION: Within the limits
      of the present study, it may be concluded that the short-term clinical results
      following treatment with EMD, GTR, EMD+GTR, and OFD can be maintained over a
      period of 5 years.

PMID- 15191591
TI  - Tooth loss during maintenance following periodontal treatment in a periodontal
      practice in Norway.
AB  - BACKGROUND: Periodontal therapy coupled with careful maintenance has been shown
      to be effective in maintaining periodontal health; however, a small number of
      teeth are still lost because of progressive periodontitis. AIM: To investigate
      factors associated with tooth loss due to periodontal reasons during maintenance
      following periodontal treatment in patients in a Norwegian specialist periodontal
      practice. The study also examined how initial prognosis related to actual outcome
      as measured by periodontal tooth loss. METHODS: Hundred consecutive patients (68
      females, 32 males) who had comprehensive periodontal treatment and attended for
      9.8 (SD: 0.7), range: 9-11 years of maintenance care, were studied. All teeth
      classified as being lost due to periodontal disease over the period were
      identified. RESULTS: Only 36 (1.5%) of the 2436 teeth present at baseline were
      subsequently lost due to periodontal disease. There were 26 patients who lost at
      least one tooth. Logistic regression analysis showed that tooth loss was
      significantly related to male gender (p=0.049; adjusted odds ratio: 2.8;
      confidence interval (c.i.): 1.0-8.1), older age, i.e.>60 years (p=0.012; adjusted
      odds ratio: 4.0; c.i.: 1.3-12.0) and smoking (p=0.019; adjusted odds ratio: 4.2;
      c.i.: 1.4-13.8). The majority 27 (75%) of the teeth lost due to periodontal
      disease had been assigned an uncertain, poor or hopeless initial prognosis;
      however, nine teeth (25%) lost had been assigned a good prognosis at baseline.
      The prognosis for 202 teeth was judged to have worsened over the period of the
      study. CONCLUSION: Compliance with maintenance following periodontal treatment
      was associated with very low levels of tooth loss in a referral practice in rural
      Norway. Male gender, older age (>60 years) and smoking were predictors of tooth
      loss due to progressive periodontitis.

PMID- 15191593
TI  - Plasma antibody levels in periodontitis patients and controls.
AB  - BACKGROUND: A major aspect of the adaptive host response in periodontitis is the
      production of antibodies. Several risk and susceptibility factors for
      periodontitis, including smoking, age and composition of the subgingival
      microflora, have also been suggested to influence antibody production. AIM: The
      present study was conducted to investigate plasma levels of immunoglobulin (Ig)
      G, A and M antibodies in periodontitis patients of Caucasian European heritage in
      relation to disease severity, smoking, diagnosis and prevalence of
      periodontopathogens. METHODS: In this study, 29 patients with severe
      periodontitis, 51 with moderate periodontitis and 55 controls without periodontal
      destruction were enrolled. From the total of 80 patients, 18 were diagnosed with
      aggressive periodontitis and 62 with chronic periodontitis. Total IgG, IgA and
      IgM as well as IgG isotypes were analyzed in plasma samples. RESULTS: Levels of
      total IgG, IgA and IgM were not different between patients and controls; however,
      in periodontitis, higher levels of IgG1 and IgG2 were observed. Smoking appeared
      to be significantly and inversely related to antibody levels in periodontitis, in
      particular for total IgG and IgG2. The absence of an elevated total IgG and IgG2
      in smoking patients was irrespective of severity, prevalence of periodontal
      pathogens and diagnosis. The elevation of total IgG and IgG1 and IgG2 in non
      smoker periodontitis patients was observed in patients with moderate
      periodontitis and even greater in patients with severe periodontitis, but was
      independent whether patients were infected with Actinobacillus
      actinomycetemcomitans or Porphyromonas gingivalis and independent of diagnosis.
      Clinically, it was observed that patients who smoked had more periodontal bone
      loss; the current findings on antibody levels may be one of several mechanisms
      related to more extensive periodontal breakdown in smoker patients. CONCLUSION:
      The current study shows that non-smoker periodontitis patients have higher levels
      of total IgG and IgG2 than smoker periodontitis patients.

PMID- 15191592
TI  - Plasminogen activators and plasminogen activator inhibitors in gingival
      crevicular fluid of cyclosporin A-treated patients.
AB  - BACKGROUND: The plasminogen activator (PA) system plays many roles in the
      inflammatory process and tissue remodelling and repair and is considered to play
      a significant role in periodontal tissue destruction and healing. The aim of this
      study was to evaluate the role of the PA system in cyclosporin A (CsA)-induced
      gingival overgrowth in renal transplant patients. METHODS: Eighteen renal
      transplant patients exhibiting moderate to severe CsA-induced gingival
      overgrowth, 10 other renal transplant patients receiving CsA therapy but showing
      no sign of CsA-induced gingival overgrowth (CsA-H), 16 chronic gingivitis
      patients (CG) and 16 systemically and periodontally healthy control subjects (H)
      were included in the study. Gingival crevicular fluid (GCF) samples were obtained
      from four randomly selected sites in each subject with the exception of the CsA
      induced gingival overgrowth group, where four GCF samples were harvested from
      sites with severe overgrowth (CsA GO+) and from four sites without any gingival
      overgrowth (CsA GO-). The GCF levels of albumin, tissue-type plasminogen
      activator (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen
      activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) were
      analysed by enzyme-linked immunosorbent assay. The results were tested for
      statistical differences. RESULTS: In CsA GO+ sites t-PA levels were significantly
      elevated in comparison with gingivitis and healthy sites, while PAI-2 levels in
      these sites showed statistically significant differences only with CsA-H and
      gingivitis sites (p<0.05). The levels of t-PA and PAI-2 were significantly higher
      in CsA GO- sites compared with those of CsA-H, gingivitis and healthy sites
      (p<0.05). The levels of u-PA and PAI-1 failed to show significant differences
      between the study groups. CONCLUSIONS: The findings of the present study indicate
      alterations in GCF t-PA and PAI-2 levels in CsA-induced gingival overgrowth and
      might suggest involvement of the plasminogen activating system in the
      pathogenesis of this side-effect of CsA therapy. However, to what extent these
      molecules contribute to the pathogenesis of CsA-induced gingival overgrowth
      remains to be determined.

PMID- 15191594
TI  - Quantification of dental plaque on lingual tooth surfaces using image analysis:
      reliability and validation.
AB  - AIM: The aim of this study was to increase the versatility and further validate
      the method reported by Smith et al. (2001) by testing the reliability of plaque
      measurement against two well-known dental plaque quantification methodologies
      using image analysis in a clinical trial. METHOD: The teeth of 40 subjects were
      disclosed before digital images of the labial and lingual surfaces of their upper
      and lower incisors were acquired. The amount of plaque present was quantified
      using a modification of the method described by Smith et al. (2001). The method
      was modified for obtaining images of the lingual surfaces by incorporating the
      use of orthodontic occlusal mirrors and 5-mm pieces of moistened blue
      articulating paper used to enable calibration. Plaque measurements were made from
      320 upper and lower anterior teeth from the 40 subjects by two operators. Fliess'
      coefficient of reliability was used to assess intra- and inter-operator
      reliability and the independent sample t test was used to assess statistical
      significance between test and control groups after checking the data for
      normality. For validation, measurements were recorded using the Turesky et al.
      (1970) (modification of the Quigley & Hein (1962) plaque index and the Addy et
      al. (1983) plaque area index. The results were compared with the image analysis
      method using Pearson's correlation coefficient. RESULTS: The results for
      reliability were within Fliess' range of "excellent" for both intra-operator
      repeatability and inter-operator reproducibility. Pearson's correlation
      coefficients showed highly significant values indicating the close similarity
      between all three methods. CONCLUSIONS: This method for the measurement of dental
      plaque on lingual surfaces of anterior teeth proved reliable. The combined
      results from the labial and lingual surfaces of anterior teeth using image
      analysis produced trial conclusions comparable with the alternate plaque
      quantification methods used, with less clinician time and further producing a
      permanent database of images for future use.

PMID- 15191595
TI  - The relationship between tomato intake and congestive heart failure risk in
      periodontitis subjects.
AB  - BACKGROUND: The objective of this study was to investigate the relationship
      between monthly tomato consumption (MTC) and serum lycopene (sLyco) levels, and a
      self-reported history of congestive heart failure (CHF) in individuals with
      periodontitis using data available in the Third National Health and Nutrition
      Examination Survey (NHANES III). METHODS: Adult participants in NHANES III were
      used in this study. Zero to thirty three percent of sites with a periodontal
      attachment loss (PAL) of >3 mm was considered a healthy periodontium, while
      greater than >33% of sites with PAL of >3 mm as periodontitis. The outcome
      variable was the self-reported history of CHF. MTC and sLyco levels were
      categorized into quartiles. Data was analyzed by Kruskal-Wallis, anova and
      multivariate analyses using SPSS(R). p<0.05 was used to reject the null
      hypothesis. RESULTS: Individuals with periodontitis showed a dose-response
      relationship between dietary MTC and self-reported CHF risk; moderate MTC (risk
      ratio (RR), 3.15; 95% confidence interval (CI), 1.03-9.67), low MTC (RR, 3.31;
      95% CI, 1.33-8.24) (p<0.05) and very low MTC (RR, 5.10; 95% CI, 1.67-15.57)
      (p<0.01), adjusting for confounders of both diseases (periodontitis and CHF). The
      moderate sLyco level-healthy periodontium group showed a significant decrease in
      CHF risk (RR, 0.25; 95% CI, 0.07-0.84) (p<0.05), adjusting for confounders.
      Significant inverse dose-response relationships were seen between sLyco and C
      reactive protein, and MTC and white blood cell count in periodontitis subjects,
      respectively (p<0.05). MTC was correlated with sLyco concentration (r=-0.018,
      p<0.05), adjusting for confounders abolished that significance. CONCLUSIONS: A
      relationship exists between periodontitis and CHF risk, and high MTC appears to
      affect this relationship in a positive direction in periodontitis subjects.

PMID- 15191597
TI  - Aggressive periodontitis - what exactly is it?

PMID- 15191596
TI  - Post-transplant lymphoproliferative disorders presenting as gingival overgrowth
      in patients immunosuppressed with ciclosporin. A report of two cases.
AB  - BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) can occur in
      patients maintained on immunosuppressive therapy following transplantation. This
      paper describes two cases of PTLD occurring in gingival tissues, in patients
      receiving ciclosporin following cardiac transplantation. TREATMENT: The lesions
      were localised to gingival tissues, mimicking ciclosporin-induced gingival
      overgrowth. They were removed surgically and the ciclosporin dose reduced to help
      prevent recurrence. CONCLUSION: The importance of histopathological examination
      of all tissue removed during routine gingivectomy procedures for ciclosporin
      induced gingival overgrowth is highlighted.

PMID- 15191598
TI  - What is the role of the librarian in 21st century healthcare?

PMID- 15191599
TI  - The information needs and information seeking behaviour of family doctors.
AB  - AIMS: To explore the information needs and information seeking behaviour of
      family doctors, identifying any differences in attitudes and behaviours deriving
      from membership of a training practice and investigating the impact of a practice
      librarian. METHODS: A case study of general practitioners (GPs) in Aylesbury Vale
      incorporated a quantitative study of use of the medical library, and two
      qualitative techniques, in-depth interviews and group discussions. RESULTS: A
      total of 58 GPs, almost three quarters of those in the Vale, participated; 19 via
      individual interviews and a further 39 via two group discussions. Family doctors
      are prompted to seek information by needs arising from a combination of
      professional responsibilities and personal characteristics. A need for problem
      orientated information, related to the care of individual patients, was the
      predominant factor that prompted these GPs to seek information. Personal
      collections remain the preferred information resource; electronic sources rank
      second. The study demonstrated low use of the medical library. However, both
      vocational training and the employment of a practice librarian impacted on
      library use. CONCLUSIONS: The study illuminates the information needs and
      preferences of GPs and illustrates the contribution that librarians may make at
      practice level, indicating the importance of outreach work.

PMID- 15191600
TI  - The informationist in Australia: a feasibility study.
AB  - OBJECTIVES: A clinical informationist could provide the best available published
      evidence in response to clinicians' questions identified during the process of
      care. This study sought to assess the feasibility of an informationist service
      and to propose a model for its delivery in an Australian teaching hospital.
      Whilst similar services are increasing in the UK, with a long history in the USA,
      this is the first Australian study in an acute public hospital. METHODS: The
      views of 40/49 (82%) medical staff at the Daw Park Repatriation General Hospital,
      South Australia were canvassed using a questionnaire designed to address key
      issues relating to a proposed service. RESULTS: Doctors were receptive to its
      potential benefits, perceived it as relevant and likely to be used, and were
      interested in a pilot. They typically indicated a required response time of 24 h.
      They expressed limited concerns other than a likely high workload for such a
      service, and reported currently searching infrequently for evidence in response
      to clinical questions, citing time issues and unavailability of computers as
      current key barriers to pursuing clinical questions. CONCLUSIONS: An
      informationist service is feasible. Results suggest that a pilot could be run in
      an area of acute medicine where questions about therapy and diagnosis are likely
      to proliferate, and the informationist should attend consultant ward rounds and
      clinical meetings, aiming to provide a response within 24 h.

PMID- 15191601
TI  - Information overload within the health care system: a literature review.
AB  - There is a widespread view held by health clinicians that their work
      effectiveness is impaired by 'information overload.' Building upon a previous
      work by Wilson, a review of the literature was undertaken to look for the
      evidence of this. It was found that the literature, particularly in the context
      of the clinical environment, was limited. This review explores the diverse
      overarching theories of information overload, effects of the phenomenon that are
      perceived to occur and proposed solutions to this problem. Many of the papers
      noted an information explosion but only three authors explicitly attempted to
      measure both the quantity and the complexity of this information. It was also
      found that the typology of the information studied was severely limited with most
      studies exploring information such as guidelines, access to journals, research
      findings and other knowledge intensive areas. Solutions proposed seem to
      concentrate on technological means rather than exploring the use of humans either
      in management of information or as a step in the filtering process.

PMID- 15191602
TI  - Semantics and the medical web: a review of barriers and breakthroughs in
      effective healthcare query.
AB  - This paper provides an overview of the research into current medical vocabularies
      and their impact on searching the Web for health information. The Web provides
      growing opportunities for laypersons to gain knowledge about specific health
      conditions, though research to date has been incomplete. Many studies have
      examined aspects of controlled medical vocabularies. Other studies have examined
      aspects of medical Web searching vocabularies. In this context, there is a
      growing need to examine more closely laypersons' Web queries using controlled
      medical vocabularies that were designed to serve the needs of medical
      professionals. It may be the case that the average consumer of Web health
      services is not able to use correct medical terminology, and may not be able to
      choose analogous or synonymous terms from a search result list. Our review
      suggests a growing need for studies to examine the current applicability of
      controlled medical vocabularies as well as alternatives to semantic query by Web
      search engine users.

PMID- 15191604
TI  - Publishing trends in medical journal literature: the views of medical staff in an
      NHS teaching hospital in the United Kingdom.

PMID- 15191603
TI  - Do primary care teams have easy access to information in GP training practices?

PMID- 15191605
TI  - Library student placements in the health sector: a positive experience at
      Liverpool John Moores University, United Kingdom.

PMID- 15191606
TI  - E-health centre: a web-based tool to empower patients to become proactive
      customers.

PMID- 15191607
TI  - Rave reviews?

PMID- 15191608
TI  - Learning and teaching.

PMID- 15191610
TI  - Leslie Morton 1907-2004.

PMID- 15191611
TI  - Readiness to change physical activity and dietary practices and willingness to
      consult healthcare providers.
AB  - BACKGROUND: Complementary or discrepant stages of change for multiple risk
      behaviors can guide the development of effective risk reduction interventions for
      multiple risk factors. The objectives of this study were to assess readiness to
      change physical activity and dietary practices and the relationships among
      readiness scores for physical activity and dietary practices. In an underserved
      population, the readiness scores were analyzed in relationship to the patient's
      interest in communicating with healthcare providers about health behavior change.
      Healthcare providers are important contributors in promoting behavior change in
      community health centers. METHODS: Patients completed questionnaires about
      communicating with healthcare providers and readiness to change physical
      activity, intake of fruits and vegetables, dietary fat, calories and weight
      management. Frequency distributions, correlations, and analysis of variance were
      computed. RESULTS: Readiness to change physical activity was not related to
      readiness to change dietary practices. Readiness to change fruit and vegetable
      intake and readiness to change dietary fat intake were significantly related.
      Readiness to change and interest in communicating with healthcare providers were
      significantly related for physical activity but not for dietary practices.
      CONCLUSIONS: Readiness to change behavior and interest in talking to healthcare
      providers were distinct dimensions; for physical activity, the dimensions were
      congruent and for dietary practices, the dimensions were unrelated. Readiness to
      change physical activity and dietary practices were not related (discrepant
      stages of readiness). Therefore, among underserved populations, sequential rather
      than simultaneous interventions may be appropriate when intervening on multiple
      risk behaviors, particularly physical activity and dietary practices.

PMID- 15191612
TI  - ARTs in action in non-human primates: introduction to workshop proceedings.

PMID- 15191613
TI  - Lipopolysaccharide induces nitric oxide synthase expression and platelet
      activating factor increases nitric oxide production in human fetal membranes in
      culture.
AB  - BACKGROUND: Platelet-activating factor and nitric oxide may be involved in the
      initiation of human labour as inflammatory mediators. The aim of this study was
      to test whether platelet-activating factor and lipopolysaccharide were able to
      induce nitric oxide synthase expression and stimulate the production of nitric
      oxide in human fetal membrane explants in culture. METHODS: Fetal membranes were
      collected from Caesarean sections at term. RNA was extracted from membranes and
      subjected to a qualitative RT-PCR to assess the baseline expression of iNOS.
      Discs of fetal membranes were cultured for 24 hours in the presence of platelet
      activating factor at a dose range of 0.1 nanomolar--1 micomolar or 1 microgram/ml
      lipopolysaccharide. Nitric oxide production was measured via nitrite ions in the
      culture medium and mRNA for iNOS was detected by RT-PCR. RESULTS: Culturing the
      membrane discs in medium containing serum induced nitric oxide synthase
      expression and platelet-activating factor significantly stimulated the production
      of nitric oxide under these conditions. When cultured without serum inducible
      nitric oxide synthase expression was induced by lipopolysaccharide, but not by
      platelet-activating factor. CONCLUSION: Platelet-activating factor may have a
      role in the initiation of labour, at term or preterm, via the increased local
      production of nitric oxide as an inflammatory mediator. In this model of
      intrauterine infection, lipopolysaccharide was found to induce iNOS expression by
      fetal membranes, and this mechanism could be involved in preterm labour.

PMID- 15191614
TI  - Subsidized sales of insecticide-treated nets in Afghan refugee camps demonstrate
      the feasibility of a transition from humanitarian aid towards sustainability.
AB  - BACKGROUND: Introducing sustainability and self-reliance is essential in chronic
      humanitarian emergencies before financial assistance is phased out. In Pakistan
      based Afghan refugee camps, this was attempted through shifting from indoor
      residual spraying (IRS) to the subsidized sale of insecticide-treated nets (ITNs)
      for prevention of malaria and anthroponotic cutaneous leishmaniasis (ACL). Here
      we outline the strategy and document the progress to provide guidance for
      replication of similar approaches in other chronic refugee situations. METHODS:
      The operational monitoring data presented were collected through: (i) two surveys
      of knowledge, attitude and practice (KAP); (ii) routine sales reporting of health
      care providers; (iii) records completed during field visits; and (iv) registers
      used during annual re-treatment campaigns. RESULTS: From 2000 until 2003,
      subsidized ITN sales expanded from 17 to 44 camps. Based on 2003 sales records,
      maximum coverage from subsidized sales exceeded 50% in 13 camps and 20% in an
      additional 14 camps. Free annual treatment campaigns showed that many refugees
      were in possession of non-programme nets, which were either locally-made or had
      leaked from an ITN programme in Afghanistan. Estimated re-treatment coverage of
      sold and existing nets through annual campaigns exceeded 43% in all camps and was
      above 70% in the majority. CONCLUSION: Subsidized sales of ITNs have effectively
      introduced the components of sustainability and self-reliance to the prevention
      of malaria and ACL in Afghan refugee camps. Similar approaches should be
      investigated in other chronic refugee situations to discourage expectations of
      continuing humanitarian donations that cannot be fulfilled.

PMID- 15191615
TI  - Miniaturized fluorescent RNA dot blot method for rapid quantitation of gene
      expression.
AB  - BACKGROUND: RNA dot blot hybridization is a commonly used technique for gene
      expression assays. However, membrane based RNA dot/slot blot hybridization is
      time consuming, requires large amounts of RNA, and is less suited for parallel
      assays of more than one gene at a time. Here, we describe a glass-slide based
      miniaturized RNA dot blot (RNA array) procedure for rapid and parallel gene
      expression analysis using fluorescently labeled probes. RESULTS: RNA arrays were
      prepared by simple manual spotting of RNA onto amino-silane coated microarray
      glass slides, and used for two-color fluorescent hybridization with specific
      probes labeled with Cy3 and 18S ribosomal RNA house-keeping gene probe labeled
      with Cy5 fluorescent dyes. After hybridization, arrays were scanned on a
      fluorescent microarray scanner and images analyzed using microarray image
      analysis software. We demonstrate that this method gives comparable results to
      Northern blot analysis, and enables high throughput quantification of transcripts
      from nanogram quantities of total RNA in hundreds of samples. CONCLUSION: RNA
      array on glass slide and detection by fluorescently labeled probes can be used
      for rapid and parallel gene expression analysis. The method is particularly well
      suited for gene expression assays that involve quantitation of many transcripts
      in large numbers of samples.

PMID- 15191616
TI  - Is amiodarone a safe antiarrhythmic to use in supraventricular tachyarrhythmias
      after lung cancer surgery?
AB  - BACKGROUND: Supraventricular arrhythmias after thoracotomy for pulmonary
      resections are well documented. There has been considerable interest in their
      incidence, nature, predictability from preoperative assessment and treatment. The
      purpose of this study is to define prevalence, type, risk factors for post
      thoracotomy supraventricular arrhythmias and to assess the efficacy of amiodarone
      as an antiarrhythmic drug. METHODS: The records of 250 patients undergoing
      pulmonary resection for lung cancer during last two years were followed up in
      this prospective study with particular attention to possible risk factors
      (gender, age, extent and side of resection, diabetes mellitus, hypertension,
      tobacco smoking, beta-blocker ingestion). Patients underwent biopsy only were
      excluded. Once onset of supraventricular arrhythmia was monitored or documented
      in the electrocardiogram, intravenous infusion of amiodarone was started with a
      loading dose of 5 mg/kg in 30 minutes and a maintenance dose of 15 mg/kg until
      remission of it. RESULTS: Forty-three episodes (21.6%) of supraventricular
      arrhythmias were documented with atrial fibrillation being the most common
      (88.3%). Rhythm disturbances were most likely to develop on the second
      postoperative day. Pneumonectomy, lobectomy and age >65 years were the
      statistically significant factors. The overall postoperative mortality was 3.2%
      and 2.3% for the patients with postoperative supraventricular arrhythmias. In
      none of the cases did supraventricular arrhythmia cause cardiac failure leading
      to death. Sinus rhythm was achieved with amiodarone in 37 out of 43 patients
      (86%). Electrical cardioversion was necessary for 6 patients who were
      hemodynamically unstable. The most common amiodarone-related complication was
      bradycardia (13.5%). CONCLUSIONS: Postoperative supraventricular arrhythmias are
      a common complication in elderly patients undergoing lung resection surgery
      (especially pneumonectomy or lobectomy). Amiodarone is both safe and effective in
      establishing sinus rhythm.

PMID- 15191617
TI  - Three year naturalistic outcome study of panic disorder patients treated with
      paroxetine.
AB  - BACKGROUND: This naturalistic open label follow-up study had three objectives: 1)
      To observe the course of illness in Panic Disorder patients receiving long-term
      versus intermediate-term paroxetine treatment, 2) To compare the relapse rates
      and side-effect profile after long-term paroxetine treatment between patients
      with Panic Disorder and Panic Disorder with Agoraphobia, 3) To observe
      paroxetine's tolerability over a 24 month period. METHODS: 143 patients with
      panic disorder (PD), with or without agoraphobia, successfully finished a short
      term (ie 12 week) trial of paroxetine treatment. All patients then continued to
      receive paroxetine maintenance therapy for a total of 12 months. At the end of
      this period, 72 of the patients chose to discontinue paroxetine pharmacotherapy
      and agreed to be monitored throughout a one year discontinuation follow-up phase.
      The remaining 71 patients continued on paroxetine for an additional 12 months and
      then were monitored, as in the first group, for another year while medication
      free. The primary limitation of our study is that the subgroups of patients
      receiving 12 versus 24 months of maintenance paroxetine therapy were selected
      according to individual patient preference and therefore were not assigned in a
      randomized manner. RESULTS: Only 21 of 143 patients (14%) relapsed during the one
      year medication discontinuation follow-up phase. There were no significant
      differences in relapse rates between the patients who received intermediate-term
      (up to 12 months) paroxetine and those who chose the long-term course (24 month
      paroxetine treatment). 43 patients (30.1%) reported sexual dysfunction. The
      patients exhibited an average weight gain of 5.06 kg. All patients who eventually
      relapsed demonstrated significantly greater weight increase (7.3 kg) during the
      treatment phase. CONCLUSIONS: The extension of paroxetine maintenance treatment
      from 12 to 24 months did not seem to further decrease the risk of relapse after
      medication discontinuation. Twenty-four month paroxetine treatment is accompanied
      by sexual side effects and weight gain similar to those observed in twelve month
      treatment.

PMID- 15191619
TI  - Implementing a public web based GIS service for feedback of surveillance data on
      communicable diseases in Sweden.
AB  - BACKGROUND: Surveillance data allow for analysis, providing public health
      officials and policy-makers with a basis for long-term priorities and timely
      information on possible outbreaks for rapid response (data for action). In this
      article we describe the considerations and technology behind a newly introduced
      public web tool in Sweden for easy retrieval of county and national surveillance
      data on communicable diseases. METHODS: The web service was designed to
      automatically present updated surveillance statistics of some 50 statutory
      notifiable diseases notified to the Swedish Institute for Infectious Disease
      Control (SMI). The surveillance data is based on clinical notifications from the
      physician having treated the patient and laboratory notifications, merged into
      cases using a unique personal identification number issued to all Swedish
      residents. The web service use notification data from 1997 onwards, stored in a
      relational database at the SMI. RESULTS: The web service presents surveillance
      data to the user in various ways; tabulated data containing yearly and monthly
      disease data per county, age and sex distribution, interactive maps illustrating
      the total number of cases and the incidence per county and time period, graphs
      showing the total number of cases per week and graphs illustrating trends in the
      disease data. The system design encompasses the database (storing the data), the
      web server (holding the web service) and an in-the-middle computer (to ensure
      good security standards). CONCLUSIONS: The web service has provided the health
      community, the media, and the public with easy access to both timely and detailed
      surveillance data presented in various forms. Since it was introduced in May
      2003, the system has been accessed more than 1,000,000 times, by more than 10,000
      different viewers (over 12.600 unique IP-numbers).

PMID- 15191618
TI  - Magnetic resonance spectroscopy of normal appearing white matter in early
      relapsing-remitting multiple sclerosis: correlations between disability and
      spectroscopy.
AB  - BACKGROUND: What currently appears to be irreversible axonal loss in normal
      appearing white matter, measured by proton magnetic resonance spectroscopy is of
      great interest in the study of Multiple Sclerosis. Our aim is to determine the
      axonal damage in normal appearing white matter measured by magnetic resonance
      spectroscopy and to correlate this with the functional disability measured by
      Multiple Sclerosis Functional Composite scale, Neurological Rating Scale,
      Ambulation Index scale, and Expanded Disability Scale Score. METHODS: Thirty one
      patients (9 male and 22 female) with relapsing remitting Multiple Sclerosis and a
      Kurtzke Expanded Disability Scale Score of 0-5.5 were recruited from four
      hospitals in Andalusia, Spain and included in the study. Magnetic resonance
      spectroscopy scans and neurological disability assessments were performed the
      same day. RESULTS: A statistically significant correlation was found (r = -0.38 p
      < 0.05) between disability (measured by Expanded Disability Scale Score) and N
      Acetyl Aspartate (NAA/Cr ratio) levels in normal appearing white matter in these
      patients. No correlation was found between the NAA/Cr ratio and disability
      measured by any of the other disability assessment scales. CONCLUSIONS: There is
      correlation between disability (measured by Expanded Disability Scale Score) and
      the NAA/Cr ratio in normal appearing white matter. The lack of correlation
      between the NAA/Cr ratio and the Multiple Sclerosis Functional Composite score
      indicates that the Multiple Sclerosis Functional Composite is not able to measure
      irreversible disability and would be more useful as a marker in stages where
      axonal damage is not a predominant factor.

PMID- 15191620
TI  - Associative nitrogen fixation, C4 photosynthesis, and the evolution of
      spittlebugs (Hemiptera: Cercopidae) as major pests of neotropical sugarcane and
      forage grasses.
AB  - Neotropical grass-feeding spittlebugs of several genera are important pests of
      pasture grasses from the southeastern USA to northern Argentina, and of sugarcane
      from southern Mexico to southern Brazil, causing estimated reductions of up to
      70% in yield and estimated monetary losses of 840-2100 million US dollars
      annually. With few exceptions, the species badly damaged by these spittlebugs are
      introduced C4 grasses that exhibit associative nitrogen fixation. This study
      synthesizes evidence that the pest status of many tropical and subtropical grass
      feeding spittlebugs is linked to associative N-fixation in their C4 hosts.
      Recognition that associative N-fixation is a major factor in spittlebug host
      preferences should deepen understanding of spittlebug agricultural ecology and
      facilitate efforts to combat spittlebug pests. In particular, spittlebugs should
      be susceptible to manipulation of xylem transport solutes. However, reduction of
      nitrate fertilizer rates, increase in ammonium fertilizer rates, or enhancement
      of associative N-fixation as a consequence of genetic engineering could make
      hosts more susceptible to spittlebug attack. Because of their predilection for C4
      grasses, spittlebugs present a clear counterexample to the hypothesis that
      herbivores prefer C3 plants to C4 plants. Finally, it appears that declines in
      atmospheric carbon dioxide levels during recent geological history promoted the
      proliferation of C4 grasses. This, compounded by human agricultural activities,
      has driven an ecological and evolutionary radiation of grass-feeding spittlebugs
      that presents continuing opportunities for the evolution of spittlebug pests.

PMID- 15191621
TI  - Key premises, a guide to Aedes aegypti (Diptera: Culicidae) surveillance and
      control.
AB  - The population densities of Aedes aegypti Linneaus in four towns in Trinidad were
      studied using standard house-to-house inspections of all water-holding containers
      to determine whether persistently positive containers and premises existed over a
      three-month period in the wet season, from May to July 2002. From a total of 1503
      houses inspected, 223 were positive with 41 persistently positive over the three
      month period and classified as 'key premises'. The definition of the term key
      premises is described and the rationale for its utilization discussed. A total of
      24,439 containers was inspected from Santa Margarita (6407), Mt Lambert (5709),
      St Augustine (5384) and Curepe (6939) of which 1.3% or 334 containers were
      positive for A. aegypti larvae and pupae. A total of 16,507 immatures of A.
      aegypti were retrieved from these containers which comprised 17 container types
      but when these were ranked according to productivity levels, only water drums
      (average 53.5%), buckets (22.2%), tubs and basins (8.0%), water tanks (5.4%),
      brick holes (4.2%) and tyres (2.0%) were significant (P < 0.001) producers. The
      role that key premises play in the introduction and re-infestation of A. aegypti
      free communities is described and illustrated. These results suggest that A.
      aegypti control programmes could be more cost effective and sustainable by
      concentrating efforts on key premises and key containers to control mosquito
      densities and Dengue transmission while reducing manpower needs and insecticide
      use.

PMID- 15191622
TI  - Staphylinidae and Carabidae overwintering in wheat and sown wildflower areas of
      different age.
AB  - Species richness and abundance of staphylinid and carabid beetles overwintering
      in winter wheat fields and 1- to 3-year-old wildflower areas were investigated
      during 2000/2001 on 16 study sites in Switzerland. Abundance and species richness
      of overwintering staphylinids significantly increased with successional age of
      the wildflower areas and were always higher in older wildflower areas than in
      winter wheat. A similar but less distinct pattern was observed for the abundance
      and species richness of carabid beetles. The influence of habitat parameters
      (vegetation cover, fine sand content, organic matter, pH, soil pore volume,
      surrounding landscape structure, habitat area) on the staphylinid and carabid
      assemblages based on the number of individuals per species and site was analysed
      using canonical correspondence analysis. Vegetation cover was the most
      significant parameter significantly characterizing both staphylinid and carabid
      assemblages. The amount of vegetation cover explained 15.7% of the variance, fine
      sand content accounted for 13.3% and surrounding landscape structure for 10.9% of
      the variance in the staphylinid assemblage. In the carabid assemblage, vegetation
      cover was the only significant factor, explaining 24.7% of the variance. This
      study showed for the first time that the significance of wildflower areas as a
      reservoir for hibernation for generalist predatory beetles increases with
      progressing successional age.

PMID- 15191623
TI  - Diet breadth and its relationship with genetic diversity and differentiation: the
      case of southern beech aphids (Hemiptera: Aphididae).
AB  - Herbivorous insect species with narrow diet breadth are expected to be more prone
      to genetic differentiation than insect species with a wider diet breadth.
      However, a generalist can behave as a local specialist if a single host-plant
      species is locally available, while a specialist can eventually behave as a
      generalist if its preferred host is not available. These problems can be
      addressed by comparing closely related species differing in diet breadth with
      overlapping distributions of insect and host populations. In this work, diet
      breadth, genetic diversity and population differentiation of congeneric aphid
      species from southern beech forests in Chile were compared. While at the species
      level no major differences in genetic diversity were found, a general trend
      towards higher genetic diversity as diet breadth increased was apparent. The
      aphid species with wider diet breadth, Neuquenaphis edwardsi (Laing), showed the
      highest genetic diversity, while the specialist Neuquenaphis staryi Quednau &
      Remaudiere showed the lowest. These differences were less distinct when the
      comparisons were made in the same locality and over the same host. Comparison of
      allopatric populations indicates that genetic differentiation was higher for the
      specialists, Neuquenaphis similis Hille Ris Lambers and N. staryi, than for the
      generalist N. edwardsi. Over the same host at different locations, genetic
      differentiation among populations of N. edwardsi was higher than among
      populations of N. similis. The results support the assumption that specialists
      should show more pronounced genetic structuring than generalists, although the
      geographical distribution of host plants may be playing an important role.

PMID- 15191624
TI  - Allozyme markers to help define the South American origins of Microctonus
      hyperodae (Hymenoptera: Braconidae) established in New Zealand for biological
      control of Argentine stem weevil.
AB  - The thelytokous parasitoid, Microctonus hyperodae Loan, was collected from eight
      South American locations and introduced to New Zealand in 1991 for biological
      control of Argentine stem weevil, Listronotus bonariensis (Kuschel) (Coleoptera:
      Curculionidae). Parasitoids from each population were released in equal numbers
      at each New Zealand site to give them the same opportunities to establish.
      Population markers have been sought to identify the South American geographic
      populations that have become most successful in New Zealand. These would assist
      in determining the importance of concepts such as climate matching and host
      parasitoid coevolution to the establishment of natural enemies in new regions for
      biological control. Vertical polyacrylamide electrophoresis was used to survey 16
      enzymes and ten calcium binding proteins, and this paper reports variation at
      three putative loci. Malate dehydrogenase, a dihydrolipoamide dehydrogenase
      isozyme and a calcium binding protein exhibited clear genetic variation, each
      with two alleles. All M. hyperodae isofemale lines from east of the Andes
      mountains shared one genotype, all but one from west of the Andes shared another,
      while a population from within the Andes contained both genotypes. This variation
      was highly congruent with previously described morphometric variation. At two
      loci, the maintenance of heterozygotes, and the absence of homozygotes, within
      isofemale lines suggested M. hyperodae thelytoky is apomictic.

PMID- 15191625
TI  - How does a carabid predator find aggregations of slugs in the field?
      Electroantennograms and behavioural assays suggest chemical cues.
AB  - Field studies suggest that the generalist carabid predator and scavenger
      Pterostichus melanarius Illiger aggregates to patches with a higher density of
      slug prey. The mechanisms behind such aggregation are unknown. Experiments were
      conducted to test the hypothesis that they are responding to chemical cues.
      Electroantennograms (EAGs) showed no response by P. melanarius antennae to live,
      nematode-infected, injured or freshly killed slugs, but a strong response to dead
      slugs that had been allowed to decay for up to 48 h. Such a response would enable
      the beetles to find carrion in the field and may also, as dead prey are likely to
      be spatially correlated with live ones, provide a mechanism by which P.
      melanarius finds patches with a higher density of live slugs. Subsequent video
      analyses of P. melanarius responses to patches of slug mucus within arenas showed
      that beetles with intact antennae could detect these patches because they spent
      more time, and moved greater distances, within them and increased their rate of
      turning. Thus, at close range, P. melanarius used their antennae to detect slug
      mucus and hence, by implication, live slugs. The apparent contradiction between
      EAG data and behavioural experiments is discussed. Together these result confirm
      that P. melanariusdoes respond to chemical cues from its slug prey in ways that
      could lead to aggregation in areas of higher slug density in the field.

PMID- 15191626
TI  - An updated list of the ticks of Ghana and an assessment of the distribution of
      the ticks of Ghanaian wild mammals in different vegetation zones.
AB  - Twenty one species of ticks belonging to five genera of the family Ixodidae
      (Order Acari, sub-order Ixodida) - Amblyomma, Haemaphysalis, Hyalomma, Ixodes and
      Rhipicephalus (including the sub-genus Rhipicephalus (Boophilus)) - were
      collected from 1260 mammals, representing 29 species, 14 families and 6 orders,
      in four vegetation zones in Ghana during the period 1971-1978. Four other species
      were collected from humans in 1977. In all, eight species appeared to be new
      records for Ghana: Amblyomma tholloni Neumann; Dermacentor circumguttatus
      Neumann; Haemaphysalis houyi Nuttall & Warburton; Ixodes loveridgei Arthur;
      Ixodes oldi Nuttall; Ixodes vanidicus Schultze; Rhipicephalus complanatus
      Neumann; Rhipicephalus cuspidatus Neumann. The updated list of tick species in
      Ghana given here includes 41 species of ixodid ticks and four species of argasid
      ticks. Most species have been found in neighbouring regions of West Africa but 56
      of the 121 different combinations of ixodid tick species and host species found
      in the collection described here have not apparently been reported before. The
      new combinations recorded here bring the total number of different combinations
      of ixodid tick species and mammalian host species now reported in Ghana to 151.
      The tick species found on wild mammals in Ghana mostly differed from those
      reported from domestic stock by other authors. The data showed that different
      tick species occurred in different vegetation zones and that most species
      displayed a pronounced preference for certain groups of related host species.
      Some tick species were found in the savanna feeding mainly on large bovids and/or
      suids; others were found in forests feeding mainly on small bovids, large rodents
      or small carnivores.

PMID- 15191627
TI  - Multi-trophic level interactions in a cassava-maize mixed cropping system in the
      humid tropics of West Africa.
AB  - Multi-trophic level interactions in a mixed crop, involving cassava and maize,
      were studied in derived-savanna in Benin, West Africa. Two trials were planted,
      one during the short rainy season two months before onset of the dry season and
      one during the long rainy season in spring. Key pests under study on maize were
      the noctuid Sesamia calamistis Hampson and the pyralids Eldana saccharina Walker
      and Mussidia nigrivenella Ragonot, and on cassava, the exotic mealybug,
      Phenacoccus manihoti Matile-Ferrero and its encyrtid parasitoid Apoanagyrus
      lopezi De Santis. Both crops received insecticide treatments to assess the crop
      loss by a pest species. On maize, intercropping with cassava reduced egg and
      immature numbers of S. calamistis by 67 and 83%, respectively, as a result of
      reduced host finding by the ovipositing adult moth and of higher egg parasitism
      by Telenomus spp. Both trials showed similar effects on maize yields: on
      insecticide-treated maize, intercropping with cassava reduced maize yields by 9
      16%, while on untreated maize the net effect of reduced pest density and
      increased plant competition resulted in zero yield differences; yield losses were
      lower in inter- compared to monocropped maize. For cassava, cropping system had
      no effect on parasitism by A. lopezi. Yield differences between mono- and
      intercropped cassava depended on time of harvest: they were large at the
      beginning and zero at final harvest. Land equivalent ratios were mostly > 1.5
      indicating that a maize/cassava mixed crop, protected or unprotected,
      considerably increased the productivity per unit area of land.

PMID- 15191629
TI  - Effectiveness of the defence mechanism of the turnip sawfly, Athalia rosae
      (Hymenoptera: Tenthredinidae), against predation by lizards.
AB  - The turnip sawfly, Athalia rosae Linnaeus, is a pest on cruciferous crops. Larvae
      sequester secondary plant compounds, namely glucosinolates, in their haemolymph.
      When attacked, their integument is easily disrupted and a droplet of haemolymph
      is exuded ('easy bleeding'). This has been shown to be an effective, chemical
      based, defence against invertebrate predators. The efficiency of this proposed
      defence was tested against a vertebrate predator, using groups of the iguanid
      lizard Anolis carolinensis Voigt as a model predator. Caterpillars of Pieris
      rapae Linnaeus and Pieris brassicae Linnaeus served as control prey species that
      do not sequester glucosinolates. Lizards attacked far fewer sawfly larvae than
      pierid caterpillars. Several of the sawfly larvae were rejected after an initial
      attack, demonstrating unpalatability to the lizards, while the Pieris larvae were
      not rejected. However, P. rapae larvae topically treated with extracts of
      haemolymph of A. rosae had no deterrent effect on the lizards and no avoidance
      learning occurred over a period of two weeks. Adult sawflies do not easy bleed
      but have glucosinolates carried over from the larval stage. Lizards attacked them
      at a higher rate than larvae and they were never rejected. The results suggest
      that for the defensive effectiveness of the pest sawfly species against
      vertebrates the chemical cue is not necessarily sufficient. Movement and colour
      may be important additional factors triggering the behaviour of vertebrate
      predators.

PMID- 15191628
TI  - Biological and chemical assays of pyrethroids in cattle dung.
AB  - Bioassays were developed in Zimbabwe to measure pyrethroid in cattle dung. These
      and chemical assays then estimated concentrations in dung from treated oxen and
      elucidated risks to dung fauna. Laboratory bioassays with adult beetles
      (Histeridae and Scarabaeinae, including Copris, Digitonthophagus, Onitis and
      Sisyphus spp.) and muscoid larvae (Musca lusoria Wiedemann) indicated that the
      LC50 of pyrethroids, as ppm in the wet weight, averaged 0.04 for deltamethrin
      pour-on, 0.25 for deltamethrin dip, 0.22 for alphacypermthrin pour-on, 0.10 for
      cyfluthrin pour-on, 0.23 for cypermethrin dip and 0.63 for flumethrin dip. Field
      bioassays involved artificial dung pats of 800 g, deployed in woodland and
      inspected after 24 h to record insects dead and alive. Beetles were most abundant
      in the wet season. Muscoid larvae were less seasonal. The LC50 of insecticides in
      the field confirmed laboratory indications. Adult Diptera (muscoids and Sgifidae)
      were not repelled or killed until the deltamethrin concentration reached 10 ppm.
      Pat dispersal by dung fauna and termites (Microtermes spp.) was halved by
      deltamethrin at 0.1-1 ppm. Scavenging of dead beetles by ants was greatest with
      small beetles (< 15 mm long) uncontaminated with insecticide. Dips and pour-ons
      of deltamethrin on cattle gave residues of about 0.01-0.1 ppm in dung produced in
      the fortnight after application. About 1.6% of the deltamethrin applied was
      transferred to dung. Deltamethrin and alphacypermethrin in dung showed no
      detectable degradation in 64 days. Contamination levels threaten populations of
      slow-breeding beetles.

PMID- 15191630
TI  - Enhanced blood feeding of Anopheles mosquitoes (Diptera: Culicidae) through
      membranes with applied host odour.

PMID- 15191631
TI  - Focusing on inflammation in the treatment of atherosclerosis.
AB  - Modern-day treatment of atherosclerosis has arisen primarily from an
      understanding of the epidemiology of the disease rather than its pathophysiology,
      in that risk factors have traditionally been targeted. Now that the pivotal role
      of inflammation in the process of atherosclerosis is recognized, it is noteworthy
      to evaluate the effect of modern therapies on this facet of the disease. This
      article first reviews the role of inflammation in the pathophysiology of
      atherosclerosis, and then explores potential mechanisms by which modern-day
      therapies can modify this inflammation.

PMID- 15191632
TI  - Cardiovascular pharmacotherapeutic considerations during pregnancy and lactation.
AB  - Cardiovascular drugs are often used in pregnancy for the treatment of maternal
      and fetal conditions. Mothers could also require continued postpartum drug
      therapy. Most cardiovascular drugs taken by pregnant women can cross the placenta
      and therefore expose the developing embryo and fetus to their pharmacologic and
      teratogenic effects. These effects are influenced by the intrinsic
      pharmacokinetic properties of a given drug as well as by the complex
      physiological changes occurring during pregnancy. Many drugs are also transferred
      into human milk and therefore can potentially have adverse effects on the nursing
      infant. This 2-part article summarizes some of the available literature
      concerning the risks and benefits of using various cardiovascular drugs and drug
      classes during pregnancy and lactation. Included in the discussion are cardiac
      glycosides, antiarrhythmic drugs, drugs used to treat both acute and chronic
      hypertension, cholesterol-lowering agents, anticoagulants, thrombolytics, and
      antiplatelet drugs.

PMID- 15191633
TI  - Two-to-one atrioventricular block: where is the block?

PMID- 15191634
TI  - Lyme carditis: restitutio ad integrum documented by cardiac magnetic resonance
      imaging.
AB  - Lyme disease is a tickborne illness that could cause, weeks to months later,
      complications involving the joints, central nervous system, and cardiovascular
      system. We report a case of cardiac manifestation with transitory higher degree
      atrioventricular block and dysfunction of the left ventricle. Complete resolution
      without signs of myocardial scar is demonstrated by cardiac magnetic resonance
      imaging.

PMID- 15191636
TI  - Disease management and clinical outcomes: summer 2001.

PMID- 15191635
TI  - Pulmonary thromboembolism superimposed on a congenital ventricular septal defect
      in a 50-year-old man inhaled nitric oxide and sildenafil to the rescue.
AB  - We report the combined use of inhaled nitric oxide (iNO) and sildenafil to
      selectively lower pulmonary vascular resistance (PVR) and reverse right-to-left
      shunt flow across a congenital ventricular septal defect (VSD) in a 50-year-old
      man. The patient developed right-to-left shunt flow with profound hypoxia because
      of an acute pulmonary embolism superimposed on underlying pulmonary hypertension.
      The dramatic improvement in oxygenation and PVR with sildenafil plus iNO has been
      sustained with sildenafil monotherapy. To our knowledge, use of this combination
      therapy in patients with decompensated pulmonary arterial hypertension (PAH) and
      a predisposition to right-to-left shunting has not been previously reported.

PMID- 15191637
TI  - Congenital and acquired long QT syndrome. Current concepts and management.
AB  - Congenital long QT syndrome (LQTS) is a rare but potentially lethal disease,
      characterized by prolongation of QT interval, recurrent syncope, and sudden
      death. In the pregenomic era (1959-1991), sympathetic imbalance was thought to be
      responsible for this disease. Since 1991 (postgenomic era), 7 LQTS genes have
      been discovered and more than 300 mutations have been identified to account for
      approximately 70% of patients affected. Despite the advancement in molecular
      genetic knowledge, diagnosis of congenital LQTS is still based on
      electrocardiographic and clinical characteristics. Beta-blockers remain the
      mainstay treatment. For high-risk patients, the implantable cardioverter
      defibrillator (ICD) offer an effective therapeutic option to reduce mortality.
      Gene-based specific therapy is still preliminary. Further studies are required to
      investigate new strategies for targeting the defective genes or mutant channels.
      For acquired LQTS, it is generally believed that the main issue is the blockade
      of the slow component of the delayed rectifier K+ current (IKr). These IKr
      blockers have a "reverse frequency-dependent" effect on the QTc interval and
      increase the dispersion in repolarization. In the presence of risk factors such
      as female gender, slow heart rate, and hypokalemia, these IKr blockers have a
      high propensity to induce torsades de pointes. For patients with a history of
      drug-induced LQTS, care must be taken to avoid further exposure to QT-prolonging
      drugs or conditions. Molecular genetic analysis could be useful to unravel
      subclinical mutations or polymorphisms. Physicians not only need to be aware of
      the pharmacodynamic and pharmacokinetic interactions of various important drugs,
      but also need to update their knowledge.

PMID- 15191639
TI  - Temporal organization of "internal speech" as a basis for cerebellar modulation
      of cognitive functions.
AB  - The sequencing of smooth and rhythmically "sculptured" words and phrases at a
      speaker's habitual speech rate (4 Hz to 6 Hz) critically depends on the
      cerebellum. Besides overt performance, the cerebellum also seems to organize the
      syllabic structure of "auditory verbal imagery" or "internal speech"--that is, a
      prearticulatory but otherwise fully elaborated and temporally organized
      representation of verbal utterances. As a consequence, cerebellar disorders may
      compromise cognitive operations that involve a speech code, such as verbal
      working memory, or disrupt cognitive processes that encompass linguistic
      mediation. Besides the temporal organization of syllable strings at a
      prearticulatory level, cerebellar patients are impaired in speech perception
      tasks requiring the encoding of durational parameters of the acoustic signal. The
      hemodynamic responses associated with these two aspects of verbal-acoustic
      communication--internal speech and speech perception--were found to be organized
      along the rostro-caudal direction within paravermal aspects of the superior right
      cerebellar hemisphere. Those areas of the right cerebellar hemisphere thus might
      provide a common platform for the computation of temporal aspects of verbal
      utterances in the domains of both speech production and perception.

PMID- 15191640
TI  - The neurobiology of conditioned and unconditioned fear: a neurobehavioral system
      analysis of the amygdala.
AB  - A neurobehavioral system approach to conditioned and unconditioned fear is
      presented. By employing reproducible fear behaviors in Pavlovian conditioning and
      unconditioned fear paradigms, it has been possible to delineate some differences
      in neural circuitry and cellular biology for conditioned and unconditioned fear.
      It is suggested that the basolateral complex of the amygdala and the central
      nucleus of the amygdala are part of the neural circuitry for fear conditioning
      but not for unconditioned fear to a predator odor. Furthermore, changes in
      expression of the transcription factor early growth response gene 1 in the
      lateral nucleus of the amygdala are shown to be important for contextual fear
      conditioning but not for unconditioned fear to a predator odor. In addition, data
      suggest that although conditioning to a synthetic predator odor,
      trimethylthiazoline, has been difficult to demonstrate, conditioning can occur by
      modifying by the environment. Finally, the relevance of the animal studies to
      human anxiety disorders is discussed.

PMID- 15191638
TI  - Developmental changes in the neural mechanisms of eyeblink conditioning.
AB  - Eyeblink conditioning has been used as a model system for examining the ontogeny
      of associative learning and its neural basis in rodents. Associative eyeblink
      conditioning emerges between postnatal days (P) 17 and 24 in rats.
      Neurophysiological studies in infant rats during eyeblink conditioning revealed
      developmental changes in the activity of cerebellar neurons that correspond to
      the ontogenetic emergence of eyeblink conditioning. The developmental changes in
      cerebellar neuronal activity suggest that the ontogeny of eyeblink conditioning
      is related to changes in learning mechanisms rather than motor performance
      mechanisms. Additional neurophysiological and neuroanatomical studies
      demonstrated that the developmental changes in neuronal activity in the
      cerebellum are due to developmental changes in interactions between the
      cerebellum and its inputs, the inferior olive and pontine nuclei. Developmental
      changes in cerebellar inputs and regulation of its inputs affect the induction of
      learning-related plasticity, thereby affecting the rate and magnitude of
      conditioning.

PMID- 15191641
TI  - Schizophrenia and the stroop effect.
AB  - Conflict between irrelevant words and relevant colors in the Stroop task creates
      interference, long considered a measure of how well individuals focus attention.
      In the traditional card version of the Stroop task, schizophrenia patients
      exhibit increased interference, consistent with the distractibility they exhibit
      in everyday life. In contrast, on other versions of the Stroop task they show
      augmented facilitation (faster responding to congruent than to neutral trials).
      We suggest that schizophrenia patients possess adequate attentional resources to
      avoid interference when each letter string is presented individually but face
      difficulty when delays are imposed and multiple attentional demands appear.
      Although psychiatric symptomatology may contribute to different patterns of
      performance, there is no evidence that medication modulates this.

PMID- 15191644
TI  - The use of 3-D cultures for high-throughput screening: the multicellular spheroid
      model.
AB  - Over the past few years, establishment and adaptation of cell-based assays for
      drug development and testing has become an important topic in high-throughput
      screening (HTS). Most new assays are designed to rapidly detect specific cellular
      effects reflecting action at various targets. However, although more complex than
      cell-free biochemical test systems, HTS assays using monolayer or suspension
      cultures still reflect a highly artificial cellular environment and may thus have
      limited predictive value for the clinical efficacy of a compound. Today's
      strategies for drug discovery and development, be they hypothesis free or
      mechanism based, require facile, HTS-amenable test systems that mimic the human
      tissue environment with increasing accuracy in order to optimize preclinical and
      preanimal selection of the most active molecules from a large pool of potential
      effectors, for example, against solid tumors. Indeed, it is recognized that 3
      dimensional cell culture systems better reflect the in vivo behavior of most cell
      types. However, these 3-D test systems have not yet been incorporated into
      mainstream drug development operations. This article addresses the relevance and
      potential of 3-D in vitro systems for drug development, with a focus on screening
      for novel antitumor drugs. Examples of 3-D cell models used in cancer research
      are given, and the advantages and limitations of these systems of intermediate
      complexity are discussed in comparison with both 2-D culture and in vivo models.
      The most commonly used 3-D cell culture systems, multicellular spheroids, are
      emphasized due to their advantages and potential for rapid development as HTS
      systems. Thus, multicellular tumor spheroids are an ideal basis for the next step
      in creating HTS assays, which are predictive of in vivo antitumor efficacy.

PMID- 15191645
TI  - High-throughput siRNA-based functional target validation.
AB  - The drug discovery process pursued by major pharmaceutical companies for many
      years starts with target identification followed by high-throughput screening
      (HTS) with the goal of identifying lead compounds. To accomplish this goal,
      significant resources are invested into automation of the screening process or
      HTS. Robotic systems capable of handling thousands of data points per day are
      implemented across the pharmaceutical sector. Many of these systems are amenable
      to handling cell-based screening protocols as well. On the other hand, as
      companies strive to develop innovative products based on novel mechanisms of
      action(s), one of the current bottlenecks of the industry is the target
      validation process. Traditionally, bioinformatics and HTS groups operate
      separately at different stages of the drug discovery process. The authors
      describe the convergence and integration of HTS and bioinformatics to perform
      high-throughput target functional identification and validation. As an example of
      this approach, they initiated a project with a functional cell-based screen for a
      biological process of interest using libraries of small interfering RNA (siRNA)
      molecules. In this protocol, siRNAs function as potent gene-specific inhibitors.
      siRNA-mediated knockdown of the target genes is confirmed by TaqMan analysis, and
      genes with impacts on biological functions of interest are selected for further
      analysis. Once the genes are confirmed and further validated, they may be used
      for HTS to yield lead compounds.

PMID- 15191646
TI  - Multiplexing fluorescence polarization assays to increase information content per
      screen: applications for screening steroid hormone receptors.
AB  - As the push to reduce cost per well in high-throughput screening reaches the
      practical limitations of liquid handling, future cost savings will likely arise
      from an increase in information content per well. One strategy to increase
      information content is to perform discreet assays against multiple targets in a
      single well. In such assays, reagent usage and liquid handling steps do not scale
      up in direct proportion to the increase in information content, providing for a
      simple method to increase data points per screen without further reductions in
      assay volume. The authors have used tracers incorporating the spectrally distinct
      fluorophores fluorescein and TAMRA to develop a high-throughput assay to identify
      selective estrogen receptor alpha or progesterone receptor ligands. Selectivity
      is assessed immediately in this assay, with no requirement for separate follow-up
      screening to determine selectivity. This methodology is easily adaptable to other
      target classes.

PMID- 15191647
TI  - Affinity capillary electrophoresis for the screening of novel antimicrobial
      targets.
AB  - The increasing number of multiantibiotic-resistant organisms, including
      methicillin-resistant Staphylococcus aureus (MRSA), requires the development of
      novel chemotherapies that are structurally distinct and exempt from current
      resistance mechanisms. Bioinformatics data mining of microbial genomes has
      revealed numerous previously unexploited essential open reading frames (ORFs) of
      unknown biochemical function. The potential of these proteins as screening
      targets is not readily apparent because most screening technologies rely on
      knowledge of biological function. To address this problem, the authors employed
      affinity capillary electrophoresis (ACE) to identify antimicrobial compounds that
      bound the novel target YihA. Screening a small-molecule library of 44,000
      compounds initially identified 115 binders, of which 76% were confirmed.
      Furthermore, the ACE assay distinguished diverse compounds that possessed drug
      like properties and antimicrobial activity against drug-resistant clinical
      isolates. These data validate ACE as a valuable tool for the fast, efficient
      detection of specific binding molecules that possess biological activity.

PMID- 15191649
TI  - Development of a BRET2 screening assay using beta-arrestin 2 mutants.
AB  - This study has focused on enhancing the signal generated from the interaction
      between a G-protein-coupled receptor (GPCR) and beta-arrestin 2 (beta-arr2),
      measured by the bioluminescence resonance energy transfer (BRET(2)) technology.
      Both class A (beta(2)-adrenergic receptor [beta(2)-AR]) and class B (neurokinin
      type 1 receptor [NK1-R]) GPCRs, classified based on their internalization
      characteristics, have been analyzed. It was evaluated whether the BRET(2) signal
      can be enhanced by using (1) beta-arr2 phosphorylation-independent mutant (beta
      arr2 R169E) and (2) beta-arr2 mutants deficient in their ability to interact with
      the components of the clathrin-coated vesicles (beta-arr2 R393E, R395E and beta
      arr2 373 stop). For the class B receptor, there was no major difference in the
      agonist-promoted BRET(2) signal when comparing results obtained with wild-type
      (wt) and mutant beta-arr2. However, with the class A receptor, a more than 2-fold
      increase in the BRET(2) signal was observed with beta-arr2 mutants lacking the AP
      2 or both AP-2 and clathrin binding sites. This set of data suggests that the
      inability of these beta-arr2 mutants to interact with the components of the
      clathrin-coated vesicle probably prevents their rapid dissociation from the
      receptor, thus yielding an increased and more stable BRET(2) signal. The beta
      arr2 R393E, R395E mutant also enhanced the signal window with other members of
      the GPCR family (neuropeptide Y type 2 receptor [NPY2-R] and TG1019 receptor) and
      was successfully applied in full-plate BRET(2)-based agonist and antagonist
      screening assays.

PMID- 15191648
TI  - Development of a fluorescence polarization bead-based coupled assay to target
      different activity/conformation states of a protein kinase.
AB  - Most of the protein kinase inhibitors being developed are directed toward the
      adenosine triphosphate (ATP) binding site that is highly conserved in many
      kinases. A major issue with these inhibitors is the specificity for a given
      kinase. Structure determination of several kinases has shown that protein kinases
      adopt distinct conformations in their inactive state, in contrast to their
      strikingly similar conformations in their active states. Hence, alternative assay
      formats that can identify compounds targeting the inactive form of a protein
      kinase are desirable. The authors describe the development and optimization of an
      Immobilized Metal Assay for Phosphochemicals (IMAP)-based couple d assay using
      PDK1 and inactive Akt-2 enzymes. PDK1 phosphorylates Akt-2 at Thr 309 in the
      catalytic domain, leading to enzymatic activation. Activation of Akt by PDK1 is
      measured by quantitating the phosphorylation of Akt-specific substrate peptide
      using the IMAP assay format. This IMAP-coupled assay has been formatted in a 384
      well microplate format with a Z' of 0.73 suitable for high-throughput screening.
      This assay was evaluated by screening the biologically active sample set LOPAC
      trade mark and validated with the protein kinase C inhibitor staurosporine. The
      IC(50) value generated was comparable to the value obtained by the radioactive
      (33)P-gamma-ATP flashplate transfer assay. This coupled assay has the potential
      to identify compounds that target the inactive form of Akt and prevent its
      activation by PDK1, in addition to finding inhibitors of PDK1 and activated Akt
      enzymes.

PMID- 15191650
TI  - Development of a high-throughput plate-based chemiluminescent transcription
      factor assay.
AB  - Transcription factors are DNA-binding proteins that regulate the expression of
      specific genes by controlling transcription initiation. Two families of
      transcription factors, NFkappaB and AP-1, play pivotal roles in controlling
      important cellular processes ranging from normal cell growth and differentiation
      to apoptosis and cancer. Identifying changes in the DNA-binding activity of these
      factors is essential to understanding the regulation of these processes. We have
      developed a high-throughput DNA-based ELISA capable of monitoring activated
      levels of NFkappaB (p50 and p65) and AP-1 (c-Jun and c-Fos). This
      chemiluminescent assay utilizes a 96-well plate format, eliminating the
      throughput challenges imposed by traditional gel shift assays and exceeding the
      sensitivity and dynamic range of standard colorimetric detection systems. The
      sensitivity of this assay enables distinction between subtle as well as dramatic
      differences in the DNA-binding activity of these factors that result from the
      treatment of cells with various inhibitors or activating agents.

PMID- 15191651
TI  - A miniaturized column chromatography method for measuring receptor-mediated
      inositol phosphate accumulation.
AB  - Inositol phosphates (IPs), such as 1,4,5-inositol-trisphosphate (IP(3)), comprise
      a ubiquitous intracellular signaling cascade initiated in response to G protein
      coupled receptor-mediated activation of phospholipase C. Classical methods for
      measuring intracellular accumulation of these molecules include time-consuming
      high-performance liquid chromatography (HPLC) separation or large-volume, gravity
      fed anion-exchange column chromatography. More recent approaches, such as radio
      receptor and AlphaScreen assays, offer higher throughput. However, these
      techniques rely on measurement of IP(3) itself, rather than its accumulation with
      other downstream IPs, and often suffer from poor signal-to-noise ratios due to
      the transient nature of IP(3). The authors have developed a miniaturized, anion
      exchange chromatography method for measuring inositol phosphate accumulation in
      cells that takes advantage of signal amplification achieved through measuring
      IP(3) and downstream IPs. This assay uses centrifugation of 96-well-formatted
      anion-exchange mini-columns for the isolation of radiolabeled inositol phosphates
      from cell extracts, followed by low-background dry-scintillation counting. This
      improved assay method measures receptor-mediated IP accumulation with signal-to
      noise and pharmacological values comparable to the classical large-volume, column
      based methods. Assay validation data for recombinant muscarinic receptor 1,
      galanin receptor 2, and rat astrocyte metabotropic glutamate receptor 5 are
      presented. This miniaturized protocol reduces reagent usage and assay time as
      compared to large-column methods and is compatible with standard 96-well
      scintillation counters.

PMID- 15191652
TI  - High-throughput screening: searching for higher productivity.

PMID- 15191656
TI  - [Sonographically guided percutaneous "air-cooled" microwave coagulation in live
      pig liver: an experimental study].
AB  - BACKGROUND & OBJECTIVE: Sonographically guided percutaneous microwave coagulation
      therapy has been widely used as an effective minimal invasive therapy for small
      liver cancer. However, high temperature of the shaft of the electrode blocks the
      advance of microwave coagulation in the treatment of liver cancer. The present
      study was conducted to investigate the prospect of the newly developed microwave
      coagulation equipment with "air-cooled" electrode in the treatment of liver
      cancer. METHODS: Six Pigs underwent hepatic coagulation at 60 W for 10 minutes,
      60 W for 20 minutes, 80 W for 10 minutes, and 80 W for 20 minutes under US-guided
      percutaneous microwave coagulation using the "air-cooled" microwave coagulation
      equipment-ECO-100 Advanced Type. RESULTS: The experiment showed that the lesion
      size of microwave coagulation in single irradiation could be significantly
      enlarged when increasing the power output and exposure duration without the worry
      of high temperature of the shaft of the electrode. Microwave coagulation using
      the "air-cooled" electrode produced a necrosis volume of 4.0 cmx4.3 cm at 80 W
      for 10 minutes, 4.7 cmx5.2 cm at 80 W for 20 minutes. The "air-cooled" microwave
      coagulation did not leave a trail in the coagulation area. CONCLUSION: The
      technique of "air-cooled" electrode can decrease the temperature of the shaft of
      the electrode. The effectiveness could be improved through increasing the power
      output and exposure duration

PMID- 15191657
TI  - [Identification of colorectal cancer using proteomic patterns in serum].
AB  - BACKGROUND & OBJECTIVE: At present there is no serological parameter with high
      sensitivity and specificity to diagnose colorectal cancer. This study aimed at
      establishing a serum protein fingerprinting technique coupled with a pattern
      matching algorithm to distinguish colorectal cancer from benign colorectal
      diseases and healthy people. METHODS: Preliminary group and test group were both
      random selected serum samples, which each comprises 73 cases of colorectal
      cancer, 31 healthy people, and 16 cases of benign colorectal diseases. The sera
      of the test group was combined with the surface of the IMAC3 proteinchip. Then
      reading data of surface enhanced laser desorption/ionization- time of flight-mass
      spectrometry (SELDI-TOF-MS) was analyzed by Biomarker Wizard software and
      Biomarker pattern software to get a classification rule of tree, which is
      standard configuration that can distinguish the sera of colorectal cancer
      patients from the sera of benign colorectal disease patients and healthy people,
      and the standard was approved test validity by double-blindly in the test group.
      RESULTS: At the key M/Z values of 4 467 Da, 8 131 Da, 8 939 Da, 9 192 Da, 9 134
      Da, 8 221 Da, 5 928 Da, 8 324 Da, 11 732 Da, protein contents of the three
      classes in preliminary group are obviously different by the software analysis.
      And the classification rule of tree was discovered, and corresponding correct
      ratio was 98.33% (118/120), corresponding sensitivity was 97.26% (71/73) and
      corresponding specificity was 100% (47/47); after double-blind examining the test
      group with that rule, the corresponding correct ratio was 96.77% (116/120),the
      corresponding sensitivity was 95.89% (70/73) and the corresponding specificity
      was 97.87%(46/47). CONCLUSION: Via comparative proteomics research in the sera of
      colorectal cancer patients and benign colorectal disease patients and healthy
      people, the group of protein was obviously different in pathological process in
      discovering colorectal cancer.

PMID- 15191658
TI  - [Experimental research of targeting hTERT gene inhibited in hepatocellular
      carcinoma therapy by RNA interference].
AB  - BACKGROUND & OBJECTIVE: RNA interference (RNAi) is a new gene blocking technology
      that silences target gene at post-transcription level induced by the small
      interference RNA (siRNA). RNAi has been demonstrated great prospect in gene
      functional research and gene therapy areas. Nowadays, RNAi has been reported to
      be used to inhibit the expression of endogenous genes including cyclophilin,
      GAPDH, p53, and c-myc; and there were some progresses in the therapy of the
      diseases caused by AIDS and hepatitis viruses with RNAi. However, hTERT gene,
      which was highly expressed in hepatocellular carcinoma and other malignant
      neoplasm, has not been researched by RNAi. In present research, we utilized RNAi
      to inhibit hTERT gene expression in vitro and in vivo, investigated the
      feasibility and specificity of gene therapy for hepatocellular carcinoma.
      METHODS: Small interference RNAs homologous to hTERT gene were designed,pTZU6+1
      shRNA-hTERT vector was constructed and transfected into hepatocellular carcinoma
      SMMC-7721 cells and transplanted SMMC-7721 tumor in nude mice to induce RNAi. The
      changes of hTERT gene expression and tumor cell proliferation in both siRNA
      treatment groups and control group were determined by flow cytometry, reverse
      transcription polymerase chain reaction (RT-PCR), immunochemistry in vitro and in
      vivo. RESULTS: The expression of hTERT had been obviously inhibited by RNAi in
      vitro. The inhibition rate of cell growth was 37.5% after pTZU6+1-shRNA-hTERT
      vector was transfected to hepatocellular carcinoma SMMC-7721 cells; the phase of
      cell cycle indicated the reduction of S phase, while G(1)/G(0) phase increased.
      The mRNA level of hTERT decreased from 99.4% to 53.1%, its protein expression
      reduced from 86.3% to 46.6%. The tumor size reduced after treated with pTZU6+1
      shRNA-hTERT vector in vivo; hTERT mRNA level decreased from 99.1% to 76.2%, and
      its protein expression decreased from 87.2% to 61.8% in siRNA treatment group. In
      contrast, there were no changes in control groups in vitro and in vivo.
      CONCLUSION: RNAi inhibits the hTERT gene expression and proliferation of
      hepatocellular carcinoma SMMC-7721 cells with specificity, and is a possible new
      approach for neoplasm gene therapy.

PMID- 15191659
TI  - [Re-expression of p16 gene in myeloma cell line U266 by arsenic trioxide].
AB  - BACKGROUND & OBJECTIVE: DNA methylation status regulates gene expression and is
      associated with oncogenesis. Demethylation of DNA has been proposed as a possible
      new strategy for cancer prophylaxis and treatment. S-adenosylmethionine is
      required as methyl donor for both arsenic metabolism and DNA methylation. The
      present study was designed to explore the possibility and mechanism of re
      expression of the silenced p16 gene in human myeloma cell line U266 cells by
      arsenic trioxide (As2O3). METHODS: The U266 cell line in which the p16 gene is
      silenced due to hypermethylation was treated with different concentration of
      As2O3. The PCR technique combined with HpaII and its isoschizomer MspI was used
      to assess p16 gene methylation status. The mRNA expression levels of p16 and DNA
      methyltransferases (DNMTs) genes were determined with RT-PCR technique. Western
      blot was performed for P16 protein expression analysis. RESULTS: (1)The
      characteristic hypermethylation with losing expression of p16 gene in U266 cells
      was confirmed. After agarose gel electrophoresis, the genomic DNA digested with
      MspI showed a "smear" pattern, however the HpaII digested DNA showed a strong
      single band. There was no PCR amplified product of p16 gene when MspI digested
      DNA was used as the templates, whereas a 340 bp p16 gene product was found in
      HpaII digested DNA sample as the undigested DNA was amplified. Also, neither p16
      mRNA nor P16 protein was detectable when assessed with RT-PCR and Western blot,
      respectively. (2)When the genomic DNA from cells treated with (0.5-2.0)
      micromol/L As2O3 was digested with HpaII and then analyzed by electrophoresis, a
      "smear" pattern was observed. The 340 bp product could not be amplified if such
      digested DNA was used as PCR templates. Detectable expression of both p16 mRNA
      and P16 protein was found in the cells treated with 1.0 micromol/L and 2.0
      micromol/L As2O3. (3)Expression levels of DNMT 3A and 3B mRNA were increased in
      the treated cells and were dependent on As2O3 concentration, however no
      significant difference was found between each two groups (P >0.05). CONCLUSION:
      As2O3 could induce p16 gene re-expression in human myeloma cell line U266 through
      DNA demethylation.

PMID- 15191660
TI  - [Arsenic trioxide induced cell apoptosis by mitochondria dependent pathway in KB
      and KBv200 cells].
AB  - BACKGROUND & OBJECTIVE: Arsenic trioxide (As2O3) is a new drug used to treat the
      patients with solid tumor,but the mechanism is still unclear. This study was
      designed to investigate the effect of mitochondrial dependent pathway in
      apoptosis induced by arsenic trioxide in multidrug resistant KBv200 cells and
      their parental sensitive KB cells. METHODS: The cytotoxic effect of As2O3 on KB
      and KBv200 cells was measured by MTT assay. KB and KBv200 cells were treated
      respectively with As2O3 for 12, 24, 48 hours. Cell apoptosis was determined by
      Annexin V FITC staining. Mitochondrial membrane potential was labeled by DiOC6
      and examined by flow cytometry. RESULTS: Arsenic trioxide showed the inhibition
      of KB and KBv200 cells proliferation in vitro. The IC(50)s of As2O3 to KB and
      KBv200 cells were (0.22+/-0.02)microg/ml and (0.20+/-0.01)microg/ml,
      respectively. As2O3 induced cell apoptosis in time- dependent manner. The
      apoptosis rates were 20.2%+/-3.1% and 52.2%+/-11.0% for KB cells and 15.8%+/-1.3%
      and 36.4%+/-5.9% for KBv200 cells under 2.5 microg/ml As2O3 treating 24 h and 48
      h, respectively. The levels of mitochondrial membrane potential were
      concentration-dependently decreased after treating with arsenic trioxide for 12,
      24, and 48 hours. CONCLUSION: The decrease of mitochondrial membrane potential
      maybe plays an important role in apoptosis induced by As2O3.

PMID- 15191661
TI  - [Synergism of c-myc and p16 in oral squamous cell carcinoma].
AB  - BACKGROUND & OBJECTIVE: The study on the protein expression of c-myc and p16 in
      oral squamous cell carcinoma (OSCC) has been reported, and a few researches
      involved in their gene amplification and mRNA expression in OSCC, however, the
      synergism of c-myc and p16 in OSCC in multiple levels is still unclear. This
      study aims to probe the synergism of c-myc and p16 in OSCC in gene amplification,
      mRNA expression, and protein expression levels. METHODS: The gene amplification,
      expression of mRNA, and protein of c-myc and p16 in 30 cases of OSCC were
      determined by in situ hybridization and immunohistochemical techniques. RESULTS:
      The amplification rate of c-myc was 63.3%, but no amplification of p16 was found
      in OSCC. The mRNA expression rates of c-myc and p16 were 83.3% and 93.3%, and
      their protein expression rates were 60.0% and 86.7%, respectively. The
      correlation analysis showed that there was significant correlativity between p16
      and c-myc both in mRNA expression (r=0.676 5, P=4.055 6E-05) and in protein
      expression (r=0.564 2, P=0.001 2). CONCLUSION: The gene amplification and
      overexpression of c-myc plays an important role in the tumorigenesis and
      development of OSCC. There is certain internal relationship between p16 and c-myc
      expression in OSCC.

PMID- 15191662
TI  - [p33(ING1b) enhances chemosensitivity of osteosarcoma cell U2OS to etoposide].
AB  - BACKGROUND & OBJECTIVE: As a new tumor suppressor gene, ING1 shared many
      biological functions with p53, such as cell cycle arrest, DNA repair, apoptosis,
      and chemosensitivity. The aim of this study was to investigate the effect of
      p33(ING1b) on chemosensitivity of osteosarcoma cells and its mechanism. METHODS:
      p33(ING1b) was overexpressed in osteosarcoma cell line U2OS through transient
      transfection. After transfection, U2OS cells were treated with etoposide for 24
      hours, then cell growth inhibitory rates were detected by trypan blue exclusion
      assay, and apoptosis was assessed using flow cytometry analysis and fluorescent
      microscopy. Furthermore, the protein expression of p53, p21(WAF1), MDM2 and Bax
      were determined by Western blot analysis. RESULTS: After transient transfection
      with p33(ING1b) vector for 24 hours, U2OS cells were treated with 20 microg/ml VP
      16 for 24 hours. The results showed that the cell growth inhibitory rates
      strongly increased [(63.1+/-5.1)%], and etoposide- induced apoptosis was
      increased(62.7%). Ectopic overexpression of p33(ING1b) increased the protein
      expression of p53 and strongly enhanced the expression of endogenous p21(WAF1)
      and Bax. Moreover, after transfection and treatment with 20 microg/ml VP-16, the
      protein expression of p53, p21(WAF1), and Bax strongly increased compared with
      other groups. The protein expression of MDM2 showed no significant difference.
      CONCLUSION: These observations suggest that p33(ING1b) up-regulates p53 protein,
      and cooperate with p53 in stimulating expression of p21(WAF1) and Bax gene, thus
      to enhance etoposide-induced apoptosis via p53-dependent pathways.

PMID- 15191663
TI  - [Effect of p73 gene on chemosensitivity of human lung adenocarcinoma cells
      H1299].
AB  - BACKGROUND & OBJECTIVE: Recent studies have shown that wild-type p53 gene can
      enhance the chemosensitivity of the majority of non-small cell lung cancers. p73
      gene and its homologue p53 gene have significant sequence and functional
      similarities. This study was designed to investigate the effect of p73 gene on
      chemosensitivity of human lung adenocarcinoma cells H1299. METHODS: The pcDNA3-HA
      p73alpha plasmid were transferred into in vitro cultured human lung
      adenocarcinoma cell line H1299 with Dosper. The p73alpha positive cells which
      were resistant to G418 were selected out. The expression of exogenous P73alpha
      protein were examined by Western blot analysis. MTT assay were used to analyze
      the response of transfected cells to cisplatin (cDDP),adriamycin (ADM). The drug
      induced apoptosis of transfected cells was measured by flow cytometry and TUNEL
      technique. The biological behavior changes of the cells were observed by colony
      formation assay. RESULTS: The transfected lung adenocarcinoma cell line H1299
      overexpressed P73alpha protein stably. MTT assay showed that the IC(50) values
      for cDDP and ADM were reduced to approximate 86.2% and 99.2% in the transfected
      cells compared with the untransfected cells, respectively. The low concentration
      of chemotherapeutic drugs (1.25 micromol/L cDDP or 0.05 micromol/L ADM) without
      inhibition essentially suppressed the growth of the transfected cells markedly.
      The cDDP-induced apoptosis rate increased from 10.1% to 38.4%(P< 0.01). The ADM
      induced apoptosis rate increased from 12.1% to 49.3%(P< 0.01). Colony-formation
      assays showed that the colony number in transfected cells was decreased
      significantly by chemotherapeutic drugs compared with parental cells(P< 0.01).
      The sensitive enhancement ratios for cDDP or ADM were 1.8 and 2.6, respectively.
      CONCLUSION: p73 gene was capable of enhancing the sensitivity of H1299 cells to
      chemotherapeutic drugs such as cDDP and ADM, and the increased sensitivity was
      associated with the induction of apoptosis undepend p53 gene. It suggests the
      possibility of using p73 gene combined with anticancer agents to improve the
      effectiveness of chemotherapy.

PMID- 15191664
TI  - Association between Nm23-H1 gene expression and metastasis of ovarian carcinoma.
AB  - BACKGROUND & OBJECTIVE: Metastasis is the leading cause of treatment failure and
      death of ovarian cancer. However, The molecular mechanisms associated with
      acquisition of metastatic ability in ovarian cancer are poorly understood. This
      study aimed at selecting the ovarian carcinoma cell lines with high frequency
      metastasis and studing the association between nm23-H1 gene expression in the
      model of ovarian carcinoma cells so as to provide the evidence for systematical
      experimental studying and clinical practice. METHODS: Each ovarian cancer cell
      line was transplanted subcutaneously into the flank of nude mice, and the
      metastatic behavior was evaluated by counting the number of lung tumor foci at
      different time. The metastatic tumors were cultured in vitro, then established
      substrain and transplanted subcutaneously three times. The mRNA and protein level
      of nm23 in 8 human ovarian cancer cell lines were examined. RESULTS: Four cell
      lines have high frequency metastatic potentiality. The subpopulation of cells
      with high frequency metastasis could be screened by injection several times. The
      expression of nm23 mRNA and protein in human ovarian cancer cells is inversely
      related to metastatic behavior in experimental animals (r=0.96, P=0.0001).
      CONCLUSION: The difference of metastatic potential, which was determined by
      genetic and molecular levels, was significant among different type of cell lines
      and subtypes. The expression of nm23 mRNA and protein in human ovarian carcinomas
      were correlated closely with the reduced metastatic behavior in experimental
      animals and may serve as a sensitive prognostic indicator of ovarian cancer.

PMID- 15191665
TI  - [Analysis of survivin expression in subtypes of lymphoma].
AB  - BACKGROUND & OBJECTIVE: It is difficult to diagnose and classify lymphoma in
      clinical pathology. This study was designed to examine the expression of
      survivin, an important anti-apoptosis gene, in subtypes of lymphoma,and to
      investigate its value in classification of lymphoma. METHODS: Biopsies from 83
      cases of lymphoma and 5 cases of lymph node reactive proliferation were collected
      from the First Affiliated Hospital and Cancer Center of Sun Yat-sen University
      from January 2001 to June 2003. Reverse transcription- polymerase chain reaction
      (RT-PCR) and immunohistochemical staining were performed to determine the mRNA
      and protein expression of survivin. In addition, the survivin expression in four
      tumor cell lines (K562, HL60, Raji, and Jurkat cell line) were also determined by
      RT-PCR and immunohistochemical staining. Semi-quantity assay was used to evaluate
      the quantity of survivin protein and mRNA expression in subtypes of lymphoma.
      RESULTS: Protein expression of survivin was high and strong in diffuse large B
      cell lymphoma (DLBL) (87.2%,34/39), Burkitt lymphoma (BL) (100%,2/2), and
      lymphoblastic lymphoma (LBL) (85.7%,6/7), while their expression were lower and
      weaker in follicular lymphoma (FL)(22.2%), extranodal marginal zone B-cell
      lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (33.3%), and
      marginal zone lymphoma (MZL)(40.0%). There exist a significant difference between
      the higher expression group (DLBL, BL, and LBL) and lower one (FL, MZL, and MALT)
      in expression of survivin. Chi-square test,Chi(2)=24.77,P< 0.01. Furthermore,
      survivin protein expression level in older patients (media age: 57-year old) with
      DLBL was higher than that in younger patients (media age: 41-year old). Almost
      all of Reed-Sternberg cells (R-S cells) in Hodgkin's lymphoma (HL) showed
      strongly positive expression of survivin. The protein expression of survivin was
      positively correlated with mRNA (r=0.627 0,P< 0.01). CONCLUSION: The expression
      level of survivin mRNA and protein shows significant difference in subtypes of
      lymphoma,and it might be act as a biomarker to classify the subtypes of lymphoma.

PMID- 15191666
TI  - [Expression of PTEN, Cx43, and VEGF in hepatocellular carcinoma].
AB  - BACKGROUND & OBJECTIVE: Previous studies showed that expression of phosphatase
      and tensin homology deleted on chromosome ten (PTEN), gap junction protein
      connexin 43 (Cx43) and vascular endothelial growth factor (VEGF) may play an
      important role in tumor occurrence and progression. This study was designed to
      investigate the relationship among the protein expression of PTEN, Cx43, and VEGF
      in carcinogenesis and progression of hepatocellular carcinoma. METHODS: The
      expression of PTEN, Cx43 and VEGF were determined in 47 cases of HCC by
      streptavidin peroxidase immunohistochemistry. RESULTS: In the hepatocellular
      carcinoma, the total positive rates of PTEN, Cx43 and VEGF were 76.4%, 42.6%, and
      70.2%, respectively. With progression of tumor course, PTEN and Cx43 positive
      rates decreased (P< 0.05), but the VEGF positive rate significantly increased
      (P=0.001). In comparison with the group of intrahepatic vascular embolism, PTEN
      positive rate increased apparently in the group without intrahepatic vascular
      embolism (P=0.006). Cx43 positive rate was lower in the group with cirrhosis
      background than that in the group without cirrhosis background (Chi(2)=4.713 5,
      P=0.03). No significant difference of PTEN positive rate was observed in tumor
      size, differentiation degree in cancerous tissue and cirrhosis background, Cx43
      positive rate in tumor size, differentiation degree in cancerous tissue and
      intrahepatic vascular embolism, VEGF positive rate in tumor size, differentiation
      degree in cancerous tissue, cirrhosis background and intrahepatic vascular
      embolism. Correlation analysis revealed that PTEN positive rate was positively
      correlated with Cx43 positive rate (Cramer's V=0.394 9, P=0.023), negatively
      correlated with VEGF positive rate (Cramer's V=0.393 7,P=0.024), but no
      significant association was observed between Cx43 positive rate and VEGF positive
      rate (Cramer's V=0.307 2, P=0.064). CONCLUSION: The aberrant expression of PTEN,
      Cx43, and VEGF may play a role in occurrence, progression, and intrahepatic
      metastasis of the hepatocellular carcinoma. Determining the expression of PTEN,
      Cx43, and VEGF may contribute to synthetically evaluating the biological behavior
      of hepatocellular carcinoma.

PMID- 15191667
TI  - [Development and characterization of a gemcitabine-resistant variant of human
      lung adenocarcinoma cell line A549].
AB  - BACKGROUND & OBJECTIVE: Gemcitabine (2',2-difluorodeo- xycytide) has antitumor
      activity in both experimental and clinical treatment of solid tumors. Although
      resistance to gemcitabine in ovarian cancer cell line and erythroleukemic cell
      line was described, there was no report on the lung cancer resistant variant. In
      order to elucidate the mechanism by which gemcitabine induce resistance in lung
      cancer, we have established the resistance to gemcitabine in human lung
      adenocarcinoma cell line A549 and described the characteristics of its resistant
      variant. METHODS: Resistance to gemcitabine was established by exposing A549
      cells to increasing concentration of gemcitabine, which was designated as A549
      Gem. The IC(50) and resistance index(RI) were tested by MTT assay and colony
      formation test. The growth curve and cell cycle of A549 and A549-Gem were
      compared. The cross-resistance profile of A549-Gem was also tested. RESULTS: The
      IC(50) increased from 6.56+/-1.19 micromol/L in A549 to 921.09+/-225.27
      micromol/L in A549-Gem as tested by MTT assay at 72h exposure, the RI was 140.52
      (P=0.019 5). The RI of colony formation test was 132.95. Double time of A549 and
      A549-Gem were 29.7 h and 36.4 h, respectively, as evaluated by the growth curve.
      A549-Gem was cross-resistant to vincristine and etoposide(54.38-fold and 6.18
      fold)(P< 0.01), but not to adriamycin, cisplatin, cytarabine, and paclitaxel.
      CONCLUSION: A549-Gem, the gemcitabine resistant phenotype, is stable and suitable
      for the study of gemcitabine resistance in lung cancer. A549-Gem is cross
      resistant to vincristine and etoposide, but not resistant to adriamycin,
      cisplatin, cytarabine and paclitaxel.

PMID- 15191668
TI  - [Expression of cytochrome P450 enzymes in human nasopharyngeal carcinoma and non
      cancerous nasopharynx tissue].
AB  - BACKGROUND & OBJECTIVE: The etiology of nasopharyngeal carcinoma (NPC) is
      associated with environmental and hereditary factors. Xenobiotics from
      environment must be activated to derive carcinogens. Several cytochrome P450
      (CYP450) metabolic enzymes participate to the activation of pre-carcinogens, and
      the genetic polymorphism of those genes is associated with metabolic polymorphism
      and susceptibility to cancer. We performed a preliminary investigation on the
      xenobiotics metabolism of human nasopharynx by determining the expression of
      CYP450 genes in NPC and non-cancerous nasopharynx tissues. METHODS: The following
      two methods were used: (1)A cDNA library from the mixed RNA sample of seven non
      cancerous nasopharynx tissues was generated, followed by clone sequencing and
      bioinformatics analysis. (2)RNA of 14 NPC and 8 non-cancerous nasopharynx tissues
      were reversely transcribed, and the expression of CYP450 genes in those samples
      was determined by PCR amplification. RESULTS: Eight ESTs of CYP450 genes
      including CYP1B1, CYP2F1, CYP2J2, CYP4B1, CYP4F12, CYP5A(TBXAS1), CYP20A1, and
      CYP51A1 were detected in non-cancerous nasopharynx cDNA library, among these
      CYP4B1 exhibited the highest expression level with 16 copies of ESTs. Positive
      expression of fourteen CYP450 genes including CYP1A1, CYP1B1, CYP2A6, CYP2A13,
      CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP2F1, CYP3A4, CYP3A5, CYP3A7, and
      CYP4B1 were detected by RT-PCR, among these, CYP1B1, CYP2B6, and CYP4B1 had also
      been detected in the cDNA library. A total of 19 CYP450 genes expression were
      detected in NPC and non-cancerous nasopharynx tissues, and the expression levels
      of CYP1B1, CYP2C8, CYP2C9, CYP2D6, CYP3A5, and CYP4B1 were higher than those of
      the other genes. CONCLUSION: The expression of a great number of CYP450 genes was
      detected in human nasopharynx, some of which might participate to the activation
      of pre-carcinogen in human nasopharynx. Contribution of these genes to the risk
      of NPC needs further investigation.

PMID- 15191669
TI  - [Reconstructing or pulling down tongue-base in surgical treatment of laryngeal
      cancer].
AB  - BACKGROUND & OBJECTIVE: The surgical treatment of laryngeal cancer, especially
      for the supraglottic cancer, usually involve the management of tongue-base, which
      is important in the rebuilding laryngeal function. There was no simple and
      effective method to repair tongue-base previously, which was removed for the
      greater part when invaded by advanced laryngeal cancer. As a result, many cases
      could not regain the satisfactory laryngeal function. And only several published
      reports focused on the efficacy of rebuilding laryngeal function by means of
      tongue-base flap. In order to develop a simple and reliable method to rebuild the
      laryngeal function, the management of tongue base in surgical treatment of
      laryngeal cancer was explored. METHODS: After the laryngeal carcinoma or the
      involved tongue-base was removed, according to the extent of surgical defect,
      sternohyoid myofascial flap was used to reconstruct the tongue-base, or the
      tongue-base was selected to rebuild the laryngeal function when greater part of
      it was preserved. RESULTS: Out of the 32 cases with partial laryngectomy, 26
      cases were decannulated with a decannulation rate of 81.3%, all the cases
      regained speaking functions except 4 cases undergone total laryngectomy. All the
      cases resumed normal diet, none presented complication of accidental aspiration.
      The 3-year and 5-year survival rates were 81.3% and 65.6%, respectively.
      CONCLUSION: Reconstructing or pulling down the tongue-base is highly effective in
      rebuilding satisfactory laryngeal function, which is easily and simply performed
      with less damage and complications, appropriate for surgical treatment of
      laryngeal cancer.

PMID- 15191670
TI  - [Value of radiotherapy and chemotherapy after SEMS implantation operation in
      patients with malignant esophageal stricture].
AB  - BACKGROUND & OBJECTIVE: Owing to the lack of a systematic comparative study, it
      still remains a controversial issue whether a patient with malignant esophageal
      tumor causing dysphagia should receive radiotherapy or/and chemotherapy after the
      SEMS (self-expanding esophageal metal stents) implantation operation. The present
      paper aims at a careful study of this field. METHODS: A total of 283 specimens
      were divided into two groups, namely, the group merely receiving the SEMS
      implantation operation (Group 1, n=91) and the group receiving a combined
      treatment of the SEMS implantation operation followed by radiotherapy /and
      chemotherapy (Group 2, n=192). The survival time of the patients in the two
      different groups was compared and the factors associated with the survival time
      were analyzed by means of Cox regression method. RESULTS: The survival time of
      the patients in group 2 was apparently much longer than that of the patients in
      group 1 (499.27+/-239.7 days and 312.81+/-192.77 days, respectively, P< 0.0001).
      The factors associated with the survival time included the choice of treatment
      method, incidence of distant metastasis and lymph node metastasis, formation of
      esophageal fistula and the location of diseased area. Among them the relative
      risk of treatment method is the highest. CONCLUSION: A combined treatment of SEMS
      implantation operation followed by radiotherapy and chemotherapy is significantly
      associated with the effect of treatment and will undoubtedly prolong the life of
      the patients with malignant esophageal tumor causing dysphagia.

PMID- 15191671
TI  - [Clinical study of 22 cases of primary gastrointestinal lymphoma].
AB  - BACKGROUND & OBJECTIVE: Primary gastrointestinal lymphoma (PGIL) is extranodal
      non-Hodgkin's lymphoma (NHL) that originates from extra-nodal tissue of
      gastrointestinal (GI) tract and has specific clinical and pathological features.
      This study was to report the clinical and pathological features as well as the
      treatment outcome of this disease. METHODS: The clinical data of 22 cases of PGIL
      admitted and treated from January 1994 to June 2000 in the First Hospital of
      Xi'an Jiaotong University were analyzed retrospectively. The diagnosis was
      confirmed histologically. RESULTS: All the patients were followed up for more
      than 3 years; among them 13 patients were followed up to 5 years. The 3-year and
      5-year survival rates were 45.5% (10/22) and 38.5% (5/13), respectively. The
      survival rates decreased with the progression of the clinical stage. Low-grade
      marginal zone derived mucosa-associated lymphoid tissue lymphoma (MALT) showed a
      better prognosis than other pathological types. Of the 16 patients who received
      treatment attained complete remission (CR), the 3-year and 5-year survival rates
      were 62.5% (10/16) and 45.5% (5/11), respectively, whereas the 3-year and 5-year
      survival rates of the 6 non-controlled patients were 0 and 0. Among the twelve
      cases treated with surgery alone, the 3-year and 5-year survival rates were 33.3%
      (4/12) and 10% (1/10), respectively. For those receiving surgery combined with
      chemotherapy and radiotherapy (5 cases received adjuvant chemotherapy after
      surgery, and 1 patient received abdominal irradiation after the surgery), the 3
      year and 5-year survival rates were 83.3% (5/6) and 66.7% (2/3), respectively.
      CONCLUSION: The prognosis of PGIL is related to control of the primary disease.

PMID- 15191672
TI  - [Evaluation for degree of malignancy and prognosis of patients with brain glioma
      using 99Tcm-MIBI brain SPECT].
AB  - BACKGROUND & OBJECTIVE: It is important and useful to evaluate the degree of
      malignancy for therapeutic scheme and prognosis evaluation. Traditional imaging
      methods such as CT and MRI play the important role in distinguishing glioma, but
      sometimes it was still difficult to diagnose accurately only having the aid of
      these anatomic information. Stereotaxic needle biopsy is an invasive method and
      indicates only local pathologic change, sometimes the error of sample collection
      will result in inaccurate grading. 18F-FDG PET can reflect the glucose metabolic
      rate of tumor directly and is thought as the most useful method, but the cost is
      too high so that it cannot be used widely at present. This study measured
      (99)Tc(m)-MIBI uptake in the patients with different pathological types using
      (99)Tc(m)-MIBI brain scan and evaluated the malignant degree of astrocytoma and
      its prognosis. METHODS: Fifty-two patients with glioma and 15 collators were
      retrospectively analyzed. (99)Tc(m)-MIBI was injected into each patient via elbow
      vein. SPECT was performed 20 min(early phase) and 2 h (delayed phase) after
      injection. (1)Diagnostic indices such as sensitivity, specificity, and accuracy
      were calculated. (2) The tumor to non-tumor ratios (T/N) were calculated
      according to ROI and compared between groups of different malignancy grading by t
      test. (3) The survival time (by means of mean survival time, MST) after (99)Tc(m)
      MIBI brain SPECT was follow-up surveyed. According to T/N ratios, the patients
      were divided into four groups. The MST was compared between four groups by t
      test. RESULTS: (1) Among 52 cases of glioma, 44 showed positive and 2 collators
      showed false-positive on (99)Tc(m)-MIBI SPECT and the sensitivity, specificity,
      and accuracy were 84.6%, 86.7%, and 85.1%,respectively. (2) On early phase and
      delayed phase,when T/N ratio was compared, there was no significant difference
      between grade-I astrocytoma and grade-II astrocytoma (P >0.05), nor was between
      patients with ependymocytomas and patients with oligodendrogliomas (P >0.05).
      There was significantly different between every other two groups (P<
      0.001),showing the higher the malignancy of astrocytoma,the more the T/N ratio.
      (3)Comparison of MST indicated that the more the T/N ratio, the shorter the MST.
      MST in group with T/NT ratio of 1.2-2.0 was significantly longer than that in
      group with T/NT ratio of 4.1-(t=5.412,P< 0.001) and that in group with T/N ratio
      of 3.1-4.0(t=4.418,P< 0.001). MST in group of 2.1-3.0 was significantly longer
      than that in group of 4.1-(t=3.382, 0.002< P< 0.005) and that in group of 3.1-4.0
      (t=2.389,0.02< P< 0.05). MST showed no significant difference between the group
      of 1.2-2.0 and the group of 2.1-3.0 (t=1.691,P >0.05), nor did between the group
      of 3.1-4.0 and group of 4.1-(t=1.629,P >0.05). CONCLUSION: As a noninvasive
      technique, (99)Tc(m)-MIBI brain SPECT is effective to diagnose brain glioma and
      distinguish its malignancy degree. This method, by monitoring the T/N ratio
      closely, is useful to discriminate tumor viability and determine the prognosis of
      patients.

PMID- 15191673
TI  - [Relationship between expression of survivin and prognosis in human laryngeal
      squamous cell carcinoma].
AB  - BACKGROUND & OBJECTIVE: A novel inhibitor of apoptosis Survivin has recently been
      found in many common human cancers but not in normal tissues. Its potential
      distribution in human laryngeal squamous cell carcinoma (HLSCC) and its
      implication for inhibition of apoptosis were not yet very clear. This study was
      designed to investigate the expression of survivin and the probabilities of using
      it as a new indicator of the prognosis of HLSCC. METHODS: HLSCC samples from 71
      patients treated in Department of Otorhinolaryngology, Second Affiliated Hospital
      of Sun Yat-sen University between 1995 and 1998 were analyzed for survivin
      expression by immunohistochemistry method. The patients were followed-up for long
      term and the relationship between survivin expression and clinical data including
      age, gender, classification, clinical type, pathological type, lymph node
      metastasis, distant metastasis, and prognosis were analyzed using software
      SPSS11.0. RESULTS: The expression rate was 50.7% (36/71) in all 71 cases. The
      expression rate was 81.8% (9/11) in the cases with lymph nodes metastasis, which
      was higher than that in the cases without lymph nodes metastasis (45%, 27/60),
      with significant difference (P=0.025). Univariate analysis revealed that
      classification,type and survivin expression were significantly related to the
      prognosis of HLSCC. P value were 0.0001, 0.009, and 0.0008, respectively.
      Multivariate analysis demonstrated that the patients with positive survivin had
      significant shorter survival (63.5 months) than those with negative survivin
      (84.0 months) (P=0.006) except the effect of classification and type on the
      prognosis of HLSCC. CONCLUSION: Survivin expressed in HLSCC especially in the
      cases with lymph nodes metastasis. Its expression may related to the prognosis of
      HLSCC.

PMID- 15191674
TI  - [Expression of survivin in different stages of carcinogenesis and progression of
      breast cancer].
AB  - BACKGROUND & OBJECTIVE: Survivin is one of the newly identified apoptosis
      inhibitor; it can block the cell apoptosis by inhibiting the function of the
      enzyme caspase-3 and caspase-7. Present studies indicate that survivin is
      overexpressed in malignant tumor. This current study was designed to investigate
      the effects of survivin in tumorigenesis and progression of breast carcinoma
      through observing the expression of survivin in the tissue of normal mammary,
      cystic hyperplasia mammary, atypical hyperplasia mammary and breast carcinoma.
      METHODS: The expression of survivin in the tissue of normal mammary (96 cases),
      cystic hyperplasia mammary (56 cases), atypical hyperplasia mammary (12 cases),
      and breast carcinoma (119 cases) were evaluated by SP immunohistochemistry. The
      relationship between survivin expression and the pathologically biological
      features of breast cancer was assessed. RESULTS: The positive rates of survivin
      were 4.2%(4/96),5.4% (3/56),42.7% (5/12), and 72.3%(86/119)in the tissue of
      normal mammary, cystic hyperplasia mammary, atypical hyperplasia mammary, and
      breast carcinoma, respectively. The positive rates in the last two groups were
      higher than those in the former two groups (P< 0.005). Survivin was more
      expressed in the infiltrative nonspecial breast carcinoma (82.0%, 73/89) than in
      the special and early stage infiltrative breast carcinoma (37.5%,3/8)(P< 0.05).
      Expression of survivin was correlated with lymph node metastasis although the
      difference is not significant (P >0.05). CONCLUSION: Overexpression of survivin
      is common in tumorigenesis and progression of breast carcinoma. Altered
      expression of survivin may contribute to tumorigenesis and progression of breast
      carcinoma by inhibiting cell apoptosis, its overexpression indicates worse
      prognosis.

PMID- 15191675
TI  - [Changes of serum total PSA and free PSA in patients with prostate carcinoma and
      benign prostate hyperplasia].
AB  - BACKGROUND & OBJECTIVE: Total prostate-specific antigen (TPSA) is considered the
      best marker in diagnosis of carcinoma of prostate (Pca), and FPSA (free prostate
      specific antigen)/TPSA can improve its specificity in diagnosis of PCa. This
      study was designed to compare the level of serum TPSA and FPSA/TPSA between PCa
      and benign prostate hyperplasia (BPH) patients, providing reference for diagnosis
      of PCa. METHODS: Values of serum TPSA and FPSA of 66 BPH cases, 29 BPH with acute
      urinary retention (AUR) cases, 22 PCa cases were determined by enzyme linked
      immunosorbent assay (ELISA). The differences of serum TPSA and FPSA/TPSA of the
      three groups were compared and analyzed. RESULTS: There were significant
      differences of serum TPSA concentration among the three groups (P< 0.05), when
      the serum TPSA in the patients with BPH, BPH and AUR, PCa were 4.1+/-1.39
      microg/L, 15.5+/-3.34 microg/L, 55+/-13.5 microg/L, respectively. Serum TPSA
      concentration overlapped in the three groups especially in AUR group when the
      TPSA level in the three groups were less than 4.0 microg/L, 4.0-10.0 microg/L,
      and more than 10.0 microg/L. There was no significant difference between BPH
      group and AUR group when the FPSA/ TPSA of BPH group was 0.32+/-0.13, AUR group
      was 0.30+/-0.09 (P >0.05). However, there were significant differences between
      BPH and Pca group, between AUR and PCa group when the FPSA/TPSA of Pca group was
      0.11+/-0.05 (P< 0.05). FPSA/TPSA level also overlapped in these three groups when
      FPSA/TPSA level was less than 0.15, 0.15-0.25, and more than 0.25. CONCLUSIONS:
      The serum TPSA and the level of FPSA/TPSA overlapped in these three groups. They
      can only be regarded clinically as reference index.

PMID- 15191676
TI  - [Association of uPA and uPAR expression with invasive behaviors of urinary
      transitional cell carcinoma].
AB  - BACKGROUND & OBJECTIVE: Urokinase-type plasminogen activator (uPA)/its receptor
      (uPAR), serine protease system, plays a key role in the degradation of
      extracellular matrix and basement membranes, and intensifying the tumor invasion.
      The study was designed to investigate the expression of uPA and uPAR in urinary
      transitional cell carcinoma. The correlation between their expression and tumor
      invasion was evaluated. METHODS: The expression and localization of uPA and uPAR
      were examined among 50 cases of renal pelvic and ureter carcinoma and 40 cases of
      bladder cancer using the PicTure(TM) current type of immunohistochemical two-step
      method. RESULTS: The normal pelvic, ureter, and bladder did not express uPA and
      uPAR. The positive expression of uPA and uPAR were concentrated in tumor tissues
      compared with that in the adjacent tissues. The positive rates of uPA and uPAR
      expressed the tissues were 33.33% and 50.00% in G1 grade; 88.47% and 96.15% in G3
      grade; 37.50% and 50.00% in Ta-T1 tissues; 100.0% and 100.0% in T4 tissues,
      respectively. The positive rates of uPA and uPAR expression in tumor tissues with
      higher grade and stage were obviously increased (P< 0.05); meanwhile, there were
      close correlation between uPA and uPAR (rs=0.979). CONCLUSION: The co-expression
      of uPA and uPAR was one of the characteristics of urinary transitional cell
      carcinoma and significantly correlated with tumor stage and grade.

PMID- 15191677
TI  - [Expression of IGF-I and IGF-IR in bladder cancer].
AB  - BACKGROUND & OBJECTIVE: Insulin-like growth factors (IGF) is one of polypeptide
      growth factors that stimulate proliferation, survival, and differentiation in
      many cell types; their signal pathways implicate development and progression of
      many kinds of malignant tumor, while less study were undergone on the roles of
      IGF-I and IGF-IR in bladder cancer genesis. This study was designed to
      investigate the expression of IGF-I and IGF-IR and proliferation cell nuclear
      antigen (PCNA) in human normal and carcinomatous bladder cancer, and to explore
      the mechanism of IGF-I and IGF-IR in cellular proliferation and tumorigenesis of
      bladder cancer. METHODS: Immunohistochemical methods were adopted to examine
      expression of IGF-I, IGF-IR, and PCNA in 88 cases with bladder cancer and 12
      cases with normal bladder tissues. The relationship of expression of IGF-I and
      IGF-IR with various clinicopathological parameters and PCNA were analyzed.
      RESULTS: The protein expression rates of IGF-I and IGF-IR in bladder cancer were
      73.9% and 59.1%, significantly higher than 33.3% and 16.7% in normal tissues,
      respectively(P< 0.05). Both two protein expression were association with PCNA
      indexes in bladder cancer (P< 0.05). There were close relationship among IGF-I
      expression and tumor recurrence (P< 0.05), IGF-IR and tumor grade, stage and
      recurrence (P< 0.05). CONCLUSION: Abnormality of IGF-I-IGF-IR autocrine loop play
      an important role in development and progression of bladder cancer by promoting
      abnormal cellular proliferation. IGF-IR may be a marker for evaluating tumor
      biological behaviors.

PMID- 15191678
TI  - [Significance and expression of insulin-like growth factor 1 and IGF binding
      protein 3 in serum of patients with lung cancer].
AB  - BACKGROUND & OBJECTIVE: Insulin-like growth factors (IGFs) can strongly stimulate
      the proliferation of a variety of cancer cells, including lung cancer cells. This
      study was to discuss the possible role of IGFs in lung cancer development. We
      examined the expression level of IGF(1) and IGF-binding protein 3 (IGFBP(3)) in
      plasma of the patients with lung cancer and control subjects, and the relation of
      its level with clinical characteristics and biological behaviors of lung cancer
      was elucidated. METHODS: Seventy-eight cases with lung cancer (A group), 35 with
      benign pulmonary disease (B group), and 14 healthy controls (C group) were
      included in this study. Serum IGF(1) and IGFBP(3) levels were measured with
      radioimmunoassay (RIA) and immunoradiometricassay (IRMA), respectively. RESULTS:
      Serum IGF(1) level and IGF(1)/IGFBP(3) ratio in A group [X+/-S,(570.67+/-185.80)
      microg/L,(0.23+/-0.16)] were significantly higher compared with those of B
      group[(466.53+/-142.42) microg/L,(0.14+/-7.12E-02)] and those of C group
      [(427.66+/-141.19) microg/L,(0.12+/-8.2E-02)]. But there was no significance
      difference (P=0.060) in IGFBP(3) levels between A group [(3133.60+/-1110.30)
      microg/L], B group [(3694.46+/-1534.03) microg/L], and C group [(4024.67+/
      1373.31) microg/L], and there was no significance in the expression of IGF(1) and
      IGFBP(3) between B group and C group (P >0.05). For the cases with lung cancer in
      pre-chemotherapy, the serum IGF(1) level was higher in patients with lymphoid
      node metastasis, and IGFBP(3) level of them was significantly lower than those
      without metastasis(P< 0.05). Serum IGFBP(3) levels were lowest in the patients
      with bone metastases [(1933.14+/-715.21) microg/L, P< 0.05]. Fourteen post
      chemotherapy patients showed a lower IGF(1) [(480.29+/-117.93)microg/L] than
      those in pre-chemotherapy[(661.76+/-153.54)microg/L](P< 0.05),whereas IGFBP(3)
      level was in inverse to IGF(1). CONCLUSION: These results suggested that IGF(1)
      and IGFBP(3) play important roles in the growth of lung cancer. Serum examination
      of them may have potential clinical value.

PMID- 15191680
TI  - [Influence of vacuum bag on direct measurement of depth for isocentric posterior
      oblique field].
AB  - BACKGROUND & OBJECTIVE: In order to improve quality assurance (QA) and quality
      control (QC) of radiotherapy, individualized vacuum bag is used in the
      localization of radiation treatment, gradually becoming one of the important
      steps for the QA and QC in the many departments of radiation oncology. It is
      controversial whether localization with vacuum bags under the simulator
      influences the precision of direct measurement for tumor depth in the isocentric
      posterior oblique field in the patients with thoracic and abdominal tumors. This
      study was designed to explore the influence of vacuum bag on the direct
      measurement METHODS: Twenty-nine patients with thoracic and abdominal carcinoma
      who had to need isocentric irradiation in the supine position were immobilized
      using vacuum bag. The irradiation depths of 45 posterior oblique fields were
      determined by CT-simulator and conventional simulator, respectively; then the
      absolute value for the difference of both depths was regarded as error value.
      RESULTS: There were 37 fields (82.2%) with error value of smaller than 5 mm; 8
      fields (17.8%), more than 5 mm. In the latter, 5 field were belonged to be
      repositioned in the phase II of radiotherapy because of light leaking air into
      the vacuum bag in the phase I of radiotherapy. CONCLUSION: Vacuum bag has a
      slight influence on direct measurement for depths of isocentric posterior oblique
      field.

PMID- 15191679
TI  - [Effect of IL-6/sIL-6R on ex vivo expansion of human cord blood derived CD34+
      cells].
AB  - BACKGROUND & OBJECTIVE: Hematopoietic stem cells (HSC) have the ability of
      regeneration, differentiation, and reconstructing hematopoietic function, and it
      is widely used in many fields such as hematopoietic stem cell transplantation,
      immune therapy, gene therapy and so on. Human cord blood (CB) is abundant of HSC.
      But a single collection of CB has only a limited amount of HCS and cannot fit the
      clinical and research use. Thus ex vivo expansion of human CB derived HSC is
      important. We know that there are some cytokines, which can synergize for
      enhancing the expansion of CB derived CD34(+) cells in vitro. Currently, some
      experiments have discovered that IL-6/sIL-6R or its chimera can enhance the ex
      vivo expansion of CD34(+)gp130+IL-6R- subpopulation. This study was designed to
      observe the effect of IL-6/sIL-6R on the ex vivo expansion of human CB derived
      CD34(+) cells, and explore the optimal cytokine combinations. METHODS: Human CB
      derived CD34(+) cells were isolated by Mini MACS and cultured in ex vivo liquid
      media in the presence of different cytokine cocktails for 7 or 14 days. After
      cultured on the seventh or the fourteenth day, the total number of the cultured
      cells were counted, the ratio of the CD34(+) cell were assayed by flow cytometry
      (FCM) and the number of it were calculated, and CFU-GM were cultured, then the
      effects of different cytokine combinations on the ex vivo expansion of CD34(+)
      cells were compared. In line with the different cytokine cocktails, our
      experiment divided into five groups: (A) control,(B) SCF,(C) IL-6/sIL-6R+SCF,(D)
      IL-6/sIL-6R+SCF+FL,and (E) SCF+FL. RESULTS: After cultured in vitro for 7 or 14
      days, (1) the number of CD34(+) cells descended apparently in groups A and B; (2)
      the number of nucleated cells and CD34(+) cells after cultural on the seventh or
      the fourteenth day increased 7.1+/-2.4 folds, 39.0+/-14.0 folds; 1.8+/-0.7 folds,
      4.8+/-2.4 folds, respectively in group C; 16.5+/-5.7 folds, 110.0+/-28.0 folds;
      3.5+/-1.5 folds, 10.2+/-4.2 folds in Group D; 17.3+/-3.8 folds, 104.0+/-21.0
      folds; 3.6+/-2.1folds, 8.4+/-3.5 folds in Group E. The expansion effects of group
      C, D, and E were all superior to the group A or B (P< 0.01). The expansion
      effects of group D and E were superior to group C (P< 0.01). But there was no
      difference between group D and E (P >0.05); (3) Adding the concentration of sIL
      6R to 400 ng/ml, the number of nucleated and CD34(+) cells increased 24.0+/-4.8
      folds and 5.6+/-1.2 folds in group D after cultured for seven days superior to
      group E (P< 0.05). CONCLUSION: IL-6/sIL-6R, SCF, FL can synergize for enhancing
      the ex vivo expansion of human CB derived CD34(+) cells. But this synergetic
      effect depends on the concentration of sIL-6R.

PMID- 15191681
TI  - [Radiotherapy of tumor patients implanted with permanent cardiac pacemaker: 4
      cases report].
AB  - BACKGROUND & OBJECTIVE: The amount of patients implanted with permanent cardiac
      pacemaker is increasing, among whom some tumor patients require radiotherapy.
      This retrospective study summarized experience of the radiotherapy of tumor
      patients implanted with the permanent cardiac pacemaker and evaluated the results
      of the radiotherapy. METHODS: Four patients (2 male, 2 female; age range 70-81
      years) implanted with permanent cardiac pacemaker were studied. Among them, 3 had
      third-degree atria ventricular block (AVB) and were implanted with VVI
      pacemakers, and 1 sick sinus syndrome (SSS), and was implanted with DDDR
      packmaker. Pathological study proved 1 esophageal carcinoma, 1 non-Hodgkin's
      lymphoma, 1 non-small cell lung carcinoma, and 1 nasopharyngeal carcinoma. 60Co
      or 6-8 MV linear accelerator 40-70 Gy were used to irradiate, while the dynamic
      electrocardiogram was monitored through the radiation period. RESULTS: All 4
      patients completed the radiotherapy. 3 cases gained PR and 1 case gained SD; 3
      patients received continuous chemotherapy, 1 patient received a second
      radiotherapy. The monitor of dynamic electrocardiogram enunciation for 10 months
      revealed good function of the cardiac pacemakers. CONCLUSION: With proper choice
      of irradiation energy and dose, according to irradiation field including the
      pacemaker and contents or not, 4 tumor patients implanted with permanent cardiac
      pacemaker could tolerate radiotherapy well, and the cardiac pacemaker could
      function normally.

PMID- 15191682
TI  - [Study on MGMT assay and tumor individual predictable chemotherapy].
AB  - How to predict and surmount the cell resistance in tumor chemotherapy is a prompt
      problem. We have observed that there were close correlation among O6
      Methylguanine-DNA methyltransferase (MGMT) enzyme activity, protein expression
      and cell resistance to alkylating agents especially to nitrosourea anti-tumor
      compounds by a series of experiments including cell survival, xenografts in nude
      mice, tumor patient biopsy and molecule biology assay. We found that those tumors
      with high MGMT activity and abundance of MGMT protein were resistant to
      alkylating agents killing effect, while those with low MGMT activity and little
      MGMT protein were sensitive to alkylating anti-tumor drugs. We proposed a new
      tactics for tumor predictable chemotherapy treated with alkylating agents based
      on MGMT protein detection. By means of preparing MGMT monoclone antibody, we have
      succeeded in developing MGMT immunohistochemistry diagnostic kit.

PMID- 15191683
TI  - Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.
AB  - OBJECTIVES: To determine the role of autoantibody tests for autoimmune diseases
      in children with newly diagnosed type 1 diabetes mellitus. DATA SOURCES: MEDLINE,
      EMBASE and the Cochrane Library. Citation lists of included studies were scanned
      and relevant professional and patient websites reviewed. Laboratories and
      manufacturers were contacted to identify ongoing or unpublished research. REVIEW
      METHODS: Following scoping searches on thyroid and coeliac autoantibodies, a
      systematic review of autoantibody tests for diagnosis of coeliac disease was
      carried out. Studies were included where cohorts of untreated patients with
      unknown disease status were included, all patients had undergone the reference
      test (biopsy) and antibody tests, and sensitivity and specificity were reported
      or calculable. Selected studies were then evaluated against a quality checklist.
      Summary statistics of diagnostic accuracy, i.e. sensitivity, specificity,
      positive and negative likelihood ratios and diagnostic odds ratios, were
      calculated for all studies. A decision analytic model was developed to evaluate
      the cost utility of screening for coeliac disease at diagnosis of diabetes.
      RESULTS: All antibody tests for diagnosis of coeliac disease showed reasonably
      good diagnostic test accuracy. Studies reported variable measures of test
      accuracy, which may be due to aspects of study quality, differences in the tests
      and their execution in the laboratories, different populations and reference
      standards. The decision analytic model indicated screening for coeliac disease at
      diagnosis of diabetes was cost-effective. Sensitivity analyses exploring
      variations in the cost and disutility of gluten-free diet, the utilities attached
      to treated and untreated coeliac disease and the decrease in life expectancy
      associated with treated and untreated coeliac disease did substantially affect
      the cost-effectiveness of the screening strategies considered. CONCLUSIONS: In
      terms of test accuracy in testing for coeliac disease, immunoglobulin A (IgA)
      anti-endomysium is the most accurate test. If an enzyme-linked immunoassay test
      was required, which may be more suitable for screening purposes as it can be semi
      automated, testing for IgA tissue transglutaminase is likely to be most accurate.
      The decision analytic model shows that the most accurate tests combined with
      confirmatory biopsy are the most cost-effective, whilst combinations of tests add
      little or no further value. There is limited information regarding test accuracy
      in screening populations with diabetes, and there is some uncertainty over
      whether the test characteristics would remain the same. Further research is
      required regarding the role of screening in silent coeliac disease and regarding
      long-term outcomes and complications of untreated coeliac disease.

PMID- 15191684
TI  - Rationale for treating pruritus complicating chronic liver disease with opiate
      antagonists.

PMID- 15191685
TI  - Therapy for painful chronic pancreatitis.

PMID- 15191687
TI  - Interventional endoscopic ultrasound in pancreatic disease.
AB  - The use of endoscopic ultrasound (EUS) in pancreatic disease is rapidly evolving
      as the field moves from a primarily diagnostic role to one of therapeutic
      intervention. Therapeutic EUS includes techniques such as the celiac block and
      transmural pseudocyst drainage. Newer techniques include EUS-guided fine-needle
      injection therapy in which a variety of agents are being investigated for the
      treatment of pancreatic cancer. Novel EUS-guided techniques are being devised to
      drain and alleviate pancreaticobiliary and gastroduodenal obstruction.

PMID- 15191686
TI  - Acute pancreatitis and organ failure: pathophysiology, natural history, and
      management strategies.
AB  - Acute pancreatitis is a common condition that carries a significant risk of
      morbidity and mortality. It is characterized by intra-acinar cell activation of
      digestive enzymes and a subsequent systemic inflammatory response governed by the
      release of proinflammatory cytokines. In 80% of patients the disease runs a self
      limiting course, but in the rest, pancreatic necrosis and systemic organ failure
      carry a mortality rate of up to 40%. The key to management is early
      identification of the patients liable to have a severe attack and require
      treatment in a high-dependency or critical-care setting by a specialist team. In
      gallstone-induced pancreatitis, early removal of ductal calculi by endoscopic
      sphincterotomy is indicated. The use of prophylactic antibiotics to prevent the
      infection of pancreatic necrosis remains controversial, but once established,
      infected necrosis must be removed. Although a number of techniques to accomplish
      this end have been described, minimally invasive techniques are gaining in
      popularity.

PMID- 15191691
TI  - The droperidol debacle.

PMID- 15191690
TI  - Now that fecal elastase is available in the United States, should clinicians
      start using it?
AB  - Fecal elastase-1 estimation is an alternative fecal enzyme test for the detection
      of exocrine pancreatic insufficiency, which, in contrast to chymotrypsin
      estimation, uses monoclonal antibodies against human pancreatic elastase and is
      thus unaffected by simultaneous pancreatic enzyme replacement therapy. Similar to
      other indirect pancreatic function tests, it has a high sensitivity rate for
      detecting severe functional impairment of the gland. However, the two major
      problems for the clinician--namely diagnosing mild to moderate exocrine
      pancreatic insufficiency or chronic pancreatitis and differentiating pancreatic
      from nonpancreatic steatorrhea or diarrhea--cannot be solved by pancreatic
      elastase-1 determination. The test cannot be used in non-formed stool (ie,
      diarrhea) unless the stool is lyophilized. All in all, this new test does not
      seem to be the gold standard for pancreatic function that we have been waiting
      for.

PMID- 15191688
TI  - The pathology of ductal-type pancreatic carcinomas and pancreatic intraepithelial
      neoplasia: insights for clinicians.
AB  - The phenotypic classification of pancreatic neoplasms is based on their cellular
      lineage. Thus, tumors with a ductal, acinar, and endocrine phenotype can be
      distinguished. Most pancreatic neoplasms show a ductal phenotype and can be
      classified as ductal adenocarcinomas. Less common tumors with a ductal phenotype
      are the variants of ductal adenocarcinoma, intraductal papillary mucinous
      neoplasm (including colloid carcinoma), mucinous cystic neoplasm, medullary
      carcinoma, and other rare tumors. Ductal adenocarcinomas most likely develop from
      ductal proliferative lesions arising in the pancreatic duct system. A recently
      adopted classification system for these lesions distinguishes between three
      grades of pancreatic intraepithelial neoplasia (PanIN). Molecular studies have
      revealed that PanIN-2 and PanIN-3 lesions represent a distinct step toward
      invasive carcinoma.

PMID- 15191689
TI  - Novel therapies for pancreatic adenocarcinoma.
AB  - Despite advances in our understanding of the molecular and genetic basis of
      pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the
      standard chemotherapy for pancreatic cancer, offers modest improvement of tumor
      related symptoms and marginal advantage of survival. New approaches, alone and in
      combination with gemcitabine, are being developed to combat this cancer. In this
      article we review the current status of investigations into several classes of
      agents: matrix metalloproteinase inhibitors; farnesyl transferase inhibitors;
      epidermal growth factor receptor inhibitors, including monoclonal antibodies and
      tyrosine kinase inhibitors; cyclooxygenase-2 inhibitors, and others. The
      scientific rationale, mechanism of action, and clinical trial data for these
      novel agents are discussed.

PMID- 15191693
TI  - Intestinal dysmotility and its relationship to sphincter of Oddi dysfunction.
AB  - Sphincter of Oddi dysfunction (SOD) is a clinical entity that presents with pain
      as the predominant symptom, and patients may require invasive procedures for its
      proper diagnosis. Those with abnormal sphincter of Oddi manometry (SOM) are
      commonly treated with endoscopic ablation of the sphincter. The results of such
      therapy vary and depend on the type of SOD. In the past several years, evidence
      has emerged of an association between SOD, intestinal dysmotility, and visceral
      hyperalgesia. This article reviews the evidence supporting such an association.

PMID- 15191694
TI  - Genetic analysis of cholesterol gallstone formation: searching for Lith
      (gallstone) genes.
AB  - The genetics of cholesterol cholelithiasis is complex because a number of
      interacting genes regulate biliary cholesterol homeostasis. Quantitative trait
      locus (QTL) analysis is a powerful method for identifying primary rate-limiting
      genetic defects and discriminating them from secondary downstream lithogenic
      effects caused by mutations of the primary genes. The subsequent positional
      cloning of such genes responsible for QTLs may lead to the discovery of
      pathophysiologic functions of Lith (gallstone) genes. In this review, we present
      a map of candidate genes for Lith genes that may determine gallstone
      susceptibility in mice. The physical-chemical, pathophysiologic, and genetic
      studies of Lith genes in bile, liver, gallbladder, and intestine will be crucial
      for elucidating the genetic mechanisms of cholesterol gallstone disease in mice
      and in humans. Because exceptionally close homology exists between mouse and
      human genomes, the orthologous human LITH genes can often be recognized after
      mouse genes are identified.

PMID- 15191696
TI  - Normal sphincter of oddi motor function.
AB  - With the introduction of endoscopic retrograde cholangiopancreatography (ERCP)
      manometry, the characteristics of sphincter of Oddi (SO) motor activity have been
      described. SO manometry is the only available method to measure SO motor activity
      directly and is usually performed at the time of ERCP. SO manometry is considered
      to be the gold standard for evaluating patients for sphincter dysfunction. This
      review reports the technique of SO manometry and normal values for SO manometry.
      SO motility is characterized by prominent phasic contractions superimposed on a
      tonic pressure. Elevated basal SO pressure is the most consistent and reliable
      criteria to diagnose SO dysfunction. Basal pressures obtained from the biliary
      sphincter are similar to the basal pressure obtained from the pancreatic
      sphincter. Abnormal SO manometric values are shown. Factors that influence SO
      pressures, and interpretation of SO manometric tracing are discussed. The most
      common and serious complication of SO manometry is post-manometry pancreatitis.
      In healthy volunteers with normal sphincter function, pancreatitis is almost
      never seen. However, in patients with SO dysfunction, the incidence of
      pancreatitis is high. The use of new nonperfused microtransducers may reduce this
      complication.

PMID- 15191695
TI  - Smooth muscle function and dysfunction in gallbladder disease.
AB  - The gallbladder epithelium and smooth muscle layer are exposed to concentrated
      biliary solutes, including cholesterol and potentially toxic hydrophobic bile
      salts, which are able to influence muscle contraction. Physiologically,
      gallbladder tone is regulated by spontaneous muscle activity, hormones, and
      neurotransmitters released into the muscle from intrinsic neurons and extrinsic
      sympathetic nerves. Methods to explore gallbladder smooth muscle function in
      vitro include cholecystokinin (CCK) receptor-binding studies and contractility
      studies. In human and animal models, studies have focused on cellular and
      molecular events in health and disease, and in vitro findings mirror in vivo
      events. The interplay between contraction and relaxation of the gallbladder
      muscularis leads in vivo to appropriate gallbladder emptying and refilling during
      fasting and postprandially. Defective smooth muscle contractility and/or
      relaxation are found in cholesterol stone-containing gallbladders, featuring a
      type of gallbladder leiomyopathy; defects of CCKA receptors and signal
      transduction may coexist with abnormal responses to oxidative stress and
      inflammatory mediators. Abnormal smooth musculature contractility, impaired
      gallbladder motility, and increased stasis are key factors in the pathogenesis of
      cholesterol gallstones.

PMID- 15191697
TI  - Endoscopic papillotomy, syn. sphincterotomy: results from the past two years.
AB  - Endoscopic papillotomy, introduced in 1973, is now an established endoscopic
      procedure for treatment of various diseases of the papilla, bile duct, and
      pancreas. This article describes the use of this technique, the various
      instruments that can be employed, the instances in which it is indicated, and its
      associated complications and risks. Alternative treatments are also summarized.

PMID- 15191698
TI  - Randomized clinical stroke trials in 2003.
AB  - Randomized clinical stroke trials published during 2003 dealt with what impact
      treatment of stroke risk factors have on reducing future strokes. Treatment of
      hypertension and hyperlipidemia, and atrial fibrillation with a new
      anticoagulant, were confirmed to be beneficial. Treatment with female hormones
      was not beneficial. A potentially important study indicated that donepezil is a
      useful treatment for dementia in people who have had strokes.

PMID- 15191699
TI  - Cardiovascular risk factors and Alzheimer's disease.
AB  - Alzheimer's disease is a devastating condition that is increasing in prevalence.
      No known prevention or cure exists for Alzheimer's disease. Cardiovascular risk
      factors are prevalent and increase in the elderly, and there have been
      conflicting reports of associations between modifiable cardiovascular risk
      factors and Alzheimer's disease. The mechanisms for these associations are
      uncertain, but they are likely to be the result of a combination of direct and
      cerebrovascular disease-related mechanisms. From this standpoint, diabetes and
      hyperinsulinemia seem to have the strongest evidence from laboratory, clinical,
      and epidemiologic studies. Studies have also indicated that hypertension,
      hyperlipidemia, hyperhomocysteinemia, and smoking are potentially important risk
      factors for Alzheimer's disease.

PMID- 15191701
TI  - Systemic blood pressure and stroke outcome and recurrence.
AB  - Although it is clear that hypertension is a primary cause of stroke, there has
      been recent controversy about blood pressure management after stroke. Recent
      studies indicate that lowering systemic blood pressure after stroke does reduce
      the risk of recurrent stroke or vascular events, but other studies provide
      evidence that blood pressure should not be lowered in the first week after stroke
      onset. Additional investigations have provided preliminary evidence that raising
      blood pressure in the first few days after stroke may improve outcome in
      selective patients. However, other studies have recorded benefit of lowering
      blood pressure in some patients at the acute stage, whereas still others have
      identified patients in whom lowering blood pressure even later after stroke may
      be more harmful than beneficial. The remaining challenge is to identify efficient
      measures for determining when to lower blood pressure in each case of ischemic
      stroke.

PMID- 15191700
TI  - Applications of diffusion/perfusion magnetic resonance imaging in experimental
      and clinical aspects of stroke.
AB  - The acute evaluation of stroke patients has undergone dramatic advances in the
      recent past. The increasing availability of novel magnetic resonance imaging
      (MRI) techniques, such as diffusion and perfusion MRI, provides a plethora of
      information to clinicians evaluating patients suspected of having an acute
      stroke. This review focuses on recent advances with experimental and clinical
      applications of perfusion and diffusion imaging and their utility in identifying
      potentially salvageable ischemic tissue in rat stroke model and stroke patients.

PMID- 15191702
TI  - Novel features of nitric oxide, endothelial nitric oxide synthase, and
      atherosclerosis.
AB  - There is a complex pathophysiologic scenario involving nitric oxide (NO),
      endothelial nitric oxide synthase (eNOS), and the development of atherosclerosis
      and unstable atheroma. Endothelial damage induced by atherosclerosis leads to the
      reduction in bioactivity of ENOS with subsequent impaired release of NO. An
      important mechanism is local enhanced degradation of NO by increased generation
      of reactive oxygen species and other free radicals, with subsequent cascade of
      oxidation-sensitive mechanisms in the arterial wall. Novel molecular approaches
      have resulted in the development of new strains of mice lacking eNOS. These
      experimental models will help to understand how to implement NO-based therapies
      against atherosclerosis. L-arginine, the precursor of NO, has demonstrated
      beneficial effects in atherosclerosis and disturbed shear stress. The target or
      goal for new drugs should be the complete restoration of NO-mediated signaling
      pathways in atherosclerotic arteries.

PMID- 15191703
TI  - Therapeutic time window of thrombolytic therapy following 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 hours after symptom onset. Treatment beyond the
      3-hour 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 hours after stroke. It seems reasonable to apply improved selection
      criteria that would allow one to differentiate patients with a relevant
      indication for thrombolytic therapy from those who do not have one. We present an
      overview of a diagnostic approach to acute stroke management that allows the
      clinician to individualize patient management based on pathophysiologic reasoning
      and not rigid time windows established by randomized controlled trials.
      Therefore, this review concentrates on giving the reader an integrated knowledge
      of the current status of thrombolytic therapy in stroke and then develops a
      treatment algorithm based on pathophysiologic information rendered by a
      multiparametric stroke magnetic resonance imaging protocol.

PMID- 15191704
TI  - Small molecule activators of the heat shock response and neuroprotection from
      stroke.
AB  - Various cellular defense pathways are mobilized in response to stress that serve
      to limit potential damage to organelles and biochemical pathways that would
      disrupt normal cellular function or trigger cell death. Strategies utilized by
      cells subjected to various forms of stress include the activation of
      detoxification systems that act to eliminate the primary damaging molecules,
      remove damaged cellular macromolecules, or restore organelle and macromolecule
      function in cases where loss of activity is generated by reversible modifications
      or alterations in conformation (ie, misfolding). Central to many intracellular
      defense mechanisms that operate to limit damage to protein function are molecular
      chaperones of the heat shock protein (HSP) family. This review briefly discusses
      the molecular mechanisms that are thought to dictate the well-established
      neuroprotective effects of HSPs and highlight the recent attempts to use
      pharmacologic approaches to activate this important cellular defense pathway.

PMID- 15191705
TI  - Erythropoietin (epoetin) as a protective factor for the brain.
AB  - Erythropoietin (EPO) has been viewed traditionally as a hematopoietic cytokine.
      Emerging evidence now exists supporting a physiologic role for EPO within the
      nervous system. EPO is expressed in the developing central nervous system and is
      capable of regulating the production of neuronal progenitor cells. There are
      numerous preclinical studies demonstrating a neuroprotective potential for EPO in
      a variety of disorders of both the central and peripheral nervous systems. A
      small pilot study in patients with acute ischemic stroke has recently been
      completed and the results are encouraging. Its mechanism of action is
      multifactorial but probably related to its ability to act as an antiapoptotic
      agent. Its widespread use clinically for the treatment of anemias has given us
      the experience and knowledge of its safety and pharmacokinetics. EPO is thus an
      ideal compound to study for the potential treatment of a variety of neurologic
      disorders.

PMID- 15191706
TI  - Implications of silent strokes.
AB  - "Silent strokes" or "subclinical strokes" refer to incidental findings of strokes
      on neuroimaging studies, such as computed tomography or magnetic resonance
      imaging/diffusion-weighted imaging, that are asymptomatic. These include lacunar
      and other ischemic strokes and minor hemorrhages, particularly in "silent areas"
      of the brain, but also include leukoaraiosis due to small vessel pathology of a
      variety of origins. Clinicians need to appreciate their significance because with
      certain conditions, such as atrial fibrillation and significant carotid stenosis,
      follow-up of these patients shows an increased incidence of strokes, impaired
      cognitive function, and dementia. These serious consequences of subclinical
      strokes require the clinician to be vigilant and institute preventive strategies
      to avert these untoward outcomes.

PMID- 15191707
TI  - Robotics and other devices in the treatment of patients recovering from stroke.
AB  - Stroke is the leading cause of permanent disability in the United States despite
      advances in prevention and novel interventional treatments. Randomized controlled
      studies have demonstrated the effectiveness of specialized post-stroke
      rehabilitation units, but administrative orders have severely limited the length
      of stay, so novel approaches to the treatment of recovery need to be tested in
      outpatients. Although the mechanisms of stroke recovery depend on multiple
      factors, a number of techniques that concentrate on enhanced exercise of the
      paralyzed limb have demonstrated effectiveness in reducing the motor impairment.
      For example, interactive robotic devices are new tools for therapists to deliver
      enhanced sensorimotor training for the paralyzed upper limb, which can
      potentially improve patient outcome and increase their productivity. New data
      support the idea that for some post-stroke patients and for some aspects of
      training-induced recovery, timing of the training may be less important than the
      quality and intensity of the training. The positive outcome that resulted in the
      interactive robotic trials contrasts with the failure to find a beneficial result
      in trials that used a noninteractive device that delivered continuous passive
      motion only. New pilot data from novel devices to move the wrist demonstrate
      benefit and suggest that successive improvement of the function of the arm
      progressing to the distal muscles may eventually lead to significant disability
      reduction. These data from robotic trials continue to contribute to the emerging
      scientific basis of neuro-rehabilitation.

PMID- 15191708
TI  - Headache and the risk of stroke.
AB  - Several studies have suggested that migraine is a risk factor for stroke. The
      association between migraine and the risk of stroke has been observed most often
      among premenopausal women but also in some studies among men. The association may
      be stronger among women who smoke and among women using oral contraceptives
      compared with nonsmokers and nonusers. Classic migraine with aura may be a more
      powerful predictor of stroke than common migraine without aura. Findings of a
      recent population-based study suggest that subclinical brain lesions are more
      common among migraine patients, particularly among those with aura, than among
      the control subjects. Two cohort studies have shown that chronic non-specific
      headache also is related to increased stroke risk. The effect of treatment of
      migraine and other types of headache on the risk of stroke is not known. Even
      though the relative risk of stroke may be fairly high among migraine patients,
      the absolute risk is usually low due to low baseline risk among young people.

PMID- 15191709
TI  - Estrogen affects the differentiation and function of splenic monocyte-derived
      dendritic cells from normal rats.
AB  - AIM: To explore the mechanism resulting in the preventive effect of estrogen on
      experimental autoimmune encephalomyelitis (EAE), which is an animal model for
      multiple sclerosis (MS), and examine if estrogen can affect the immune response
      in EAE at dendritic cell (DC) level. METHODS: Flow cytometry was used to reveal
      the surface marker expression. 3H-thymidine incorporation was applied to examine
      the cellular proliferation. Levels of anti-myelin basic protein (MBP)(68-86)
      antibody and cytokines were determined by enzyme-linked immunospot and ELISA,
      respectively. RESULTS: 17beta-estradiol (E2) could dose-dependently accelerate
      the differentiation process of DCs by up-regulating CD11c, B7-2 and CD40
      expressions, but exert no effect on its antigen presentation ability. MBP
      specific T cells cocultured with E2-treated DCs (E2-DC) produced more IL-10 and
      less IFN-gamma in the supernatant than those without E2 pretreatment (ctr-DC). In
      contrast to ctr-DC, E2-DC, if injected i.v. into EAE rats on day 5 post
      immunization, could initiate antigen nonspecific hyper-responsivity in T cells in
      terms of enhanced proliferation and cytokine secretion of mononuclear cells in
      LN, but suppressed antibody secretion from splenocytes. CONCLUSION: These results
      suggest that estrogen can affect the differentiation and function of DCs, which
      leads T cells switching to Th2 secretion. This may account partly for the
      protective effect of estrogen on EAE.

PMID- 15191710
TI  - [Expression of CTLA4-EGFP fusion protein in K562 cells and its subcellular
      localization].
AB  - AIM: To construct a eukaryotic expression vector for cytotoxic T lymphocyte
      antigen-4 (CTLA4) gene fused with enhanced green fluorescent protein(EGFP) gene
      and to analyze the expression and subcellular localization of the fusion protein
      in K562 cells. METHODS: The human CTLA4 gene was cloned by RT-PCR and was then
      inserted into plasmid pEGFP-N1 to construct the expression vector for CTLA4-EGFP
      fusion gene. The expression and subcellular localization of the fusion protein in
      transfected K562 cells were analyzed by flow cytometry and confocal microscopy,
      respectively. RESULTS: The cDNA of CTLA4 gene was cloned from human peripheral
      blood cells. The expression vector for CTLA4-EGFP fusion gene was constructed by
      PCR through introducing a Kozak sequence before the initiation site and deleting
      the stop codon. Flow cytometry analysis revealed that the proportion of both
      CTLA4+ and EGFP+ K562 cells was 16% at 24 h after the transfection. Confocal
      microscopy observation showed that the expressed fusion protein was mainly
      distributed in the intracellular compartments and had small part on the cell
      membrane. In contrast, only EGFP expression could be detected in K562 cells
      transfected with empty vector with diffuse distribution in the cells. Moreover,
      the expression level of the fusion protein on the cells increased to 29% after
      stimulation with phorbol ester and ionomycin. In addition, the fusion protein
      inside the cells tended to move towards and fused with the cell membrane.
      CONCLUSION: The expression vector for CTLA4-EGFP fusion gene has been constructed
      successfully and expressed in K562 cells. The expressed fusion protein has
      similar subcellular localization and transport characteristics to native CTLA4 in
      activated T cells.

PMID- 15191711
TI  - [Activation of mouse macrophages by the alkali-extracted polysaccharide from
      spore of Ganoderma lucidum].
AB  - AIM: To investigate the activation of mouse macrophages by the alkali-extracted
      polysaccharides from the spore of Ganoderma lucidum (LZSBS). METHODS: The mouse
      macrophages cultured in-vitro were stimulated by LZSBS. IL-1beta and TNF-alpha in
      the culture supernatants were detected by ELISA. NO production was detected by
      Griess assay. The percentage of phagocytosis of latex beads by mouse macrophages
      was counted under microscope. RESULTS: The mouse macrophages stimulated by LZSBS
      increased in volume and darkened in appearance under phase-contrast microscope.
      LZSBS-activated mouse macrophages secreted IL-1beta and TNF-alpha produced a
      large amount of NO. The percentage of phagocytosis of latex beads by mouse
      macrophages was also significantly increased in the presence of LZSBS.
      CONCLUSION: LZSBS can activate markedly the mouse macrophages.

PMID- 15191712
TI  - [Hepatocellular carcinoma associated antigen HCA520, a novel Ca2+-binding
      protein].
AB  - AIM: To analyze the binding activity of the hepatocellular carcinoma associated
      antigen HCA520 to Ca2+. METHODS: The HCA520 gene was gained by PCR. Then, it was
      cloned into the prokaryotic expression vector pGEX-4T-3. The GST-HCA520 fusion
      gene was induced to express in E. coli and the expressed product was purified via
      GST-agarose affinity resin. The fusion protein was confirmed by Western blot
      analysis. The Ca2+ binding capability of the fusion protein was analyzed by dot
      blot. RESULTS: The GST-HCA520 fusion gene was constructed and the protein was
      successfully expressed and purified, which was identified by DNA sequencing and
      Western blot respectively. The fusion protein could bind to Ca2+ depend on
      dosages. CONCLUSION: HCA520, a novel hepatocellular carcinoma associated antigen,
      is a novel Ca2+ binding protein.

PMID- 15191713
TI  - [Expression of RhoC in gastric cancer cell lines and construction and
      identification of RhoC-specific siRNA expression vector].
AB  - AIM: To study the expression of RhoC in human gastric cancer cell lines and to
      construct and identify the RhoC-specific siRNA expressing vector. METHODS: The
      expression of RhoC in human gastric cancer cell lines was detected by Western
      blot. According to the computer aided design(CAD),RhoC-specific siRNA gene was
      synthesized and cloned into the expression vector mU6pro. The constructed RhoC
      siRNA was transiently transfected into high-metastatic gastric cancer cell line
      AGS and the inhibition effect of RhoC-siRNA on expression of RhoC in AGS cells
      was detected using Western blot. RESULTS: The expression level of RhoC was up
      regulated in high metastatic cells lines. Double enzyme digestion analysis and
      DNA sequencing confirmed that the RhoC-specific siRNA expression vector was
      constructed successfully. RhoC expression in AGS cells was specifically
      suppressed after transfection of RhoC-siRNA. CONCLUSION: The RhoC-specific siRNA
      expression vector has been successfully constructed, which may provide a novel
      applicable strategy for gene therapy of gastric cancer.

PMID- 15191714
TI  - [The relationship of p53 and the cytotoxicity mediated by TM-TNF-alpha and S-TNF
      alpha].
AB  - AIM: To explore the relationship of p53 and the cytotoxicity mediated by TM-TNF
      alpha and S-TNF-alpha. METHODS: P53 mutation in tumor cell was detected by PCR
      SSCP. Wide type p53 expression plasmid was transfected to tumor cells with mutant
      p53 gene, while the mutant type p53 plasmid to tumor cell with wide type p53
      gene.Then,the effects of transfection on the cytotoxicity of two types of TNF
      were detected. RESULTS: Mutation in the p53 gene were found in most of tumor
      cells (Raji, HL-60, K562) which were resistant to S-TNF-alpha. The tumor cells
      transfected with wild type p53 plasmid were more sensitive to S-TNF-alpha while
      the tumor cells transfected with mutant type p53 plasmid were less sensitive to S
      TNF-alpha. But the cytotoxicity of TM-TNF-alpha was not affected by the
      transfection. CONCLUSION: The cytotoxicity mediated by TM-TNF-alpha is not
      dependent on wide type p53, which may account for the broader tumorcidal spectrum
      of TM-TNF-alpha than that of S-TNF-alpha.

PMID- 15191715
TI  - [Construction and expression of anti-human integrin alphavbeta3 scFv].
AB  - AIM: To construct single chain antibody (scFv) gene of mAb E10 against human
      integrin alphavbeta3. METHODS: The VH and VL genes were amplified from hybridoma
      cells secreting mAb E10 by RT-PCR and connected with the use of linker (Gly4Ser)3
      to assemble scFv gene. The scFv gene was cloned into prokaryotic expression
      vector pTIG-TRX and expressed in E. coli BL21 (DE3). RESULTS: SDS-PAGE analysis
      showed the expressed recombinant protein with relative molecular mass (Mr) being
      31,000. Western blot confirmed that the protein was labeled with His6. scFv
      protein was expressed as soluble protein under the condition of a small amount of
      IPTG induction and culture at lower temperature. The purity of the protein
      purified through Ni-NTA agarose metal affinity resin column was over 91%. The
      purified protein could bind to the human integrin alphavbeta3 by ELISA
      confirmation. CONCLUSION: scFv against human integrin alphavbeta3 has been
      successfully constructed and expressed,which lays the foundation for further
      clinical research.

PMID- 15191716
TI  - [Construction of eukaryotic vector and expression of chimeric antibody against rh
      bFGF].
AB  - AIM: To express a human-mouse chimeric antibody against rh-bFGF antigen in
      eukaryotic cells. METHODS: The VL and VH genes were amplified and cloned from the
      hybridoma 1F11 secreting anti-rh-bFGF mouse monoclonal antibody (mAb) and the CL
      and CH genes were amplified and cloned from the plasmid pMDHC and pMDLC. They
      were inserted into eukaryotic expression vectors after sequencing. The
      recombinant plasmids were then transformed into CHO-dhfr- cells for expression.
      The humanization and antigen specificity of expressed products were identified by
      indirect ELISA. The relative molecular mass (Mr) of expressed products was
      determined by SDS-PAGE. RESULTS: The cloned antibody genes were identified to be
      functional by sequencing. The chimeric antibody could be detected in the culture
      supernatant of transformed CHO cells. The humanization and specificity of the
      chimeric antibody to rh-bFGF were confirmed by ELISA. CONCLUSION: The mouse-human
      chimeric antibody against rh-bFGF has been expressed successfully in eukaryotic
      cells, which lays the foundation for its further clinical research.

PMID- 15191717
TI  - [Expression of Lagurus ZP3 fusion protein in prokaryotic cells and preparation of
      its antiserum].
AB  - AIM: To express and purify Lugurus zone pellucida 3 (LZP3) in prokaryotic cells
      and to prepare the LZP3-specific rabbit antiserum. METHODS: The core fragment of
      LZP3 gene was cloned into plasmid pGEX-4T-1 containing glutathione s-transferase
      (GST) fusion protein gene. Following restriction enzyme digestion analysis and
      sequencing, pGEX-4T-LZP3 was transformed into E. coli BL21(DE3). GST-LZP3 fusion
      protein was expressed under IPTG induction and further purified with Glutathione
      Sepharose 4B. Then the purified GST-LZP3 fusion protein was used to immunize New
      Zealand rabbits. LZP3-specific rabbit antiserum was identified by ELISA and
      Western blot. RESULTS: GST-LZP3 fusion protein was overexpressed and its LZP3
      specific antiserum was obtained. CONCLUSION: The successful expression of GST
      LZP3 fusion protein in E.coli and the preparation of LZP3-specific rabbit
      antiserum will be valuable for the study on birth control of Lagurus.

PMID- 15191718
TI  - [The expression of truncated YggG protein and preparation of its polyclonal
      antibody].
AB  - AIM: To express truncated YggG protein (TYP) in Escherichia coli and to prepare
      anti-TYPE antibody. METHODS: Truncated yggg gene was amplified by PCR from the
      plasmid containing full length yggg gene and was cloned into the expression
      vector pDH2. The expression of TYP was achieved by thermal induction. Antiserum
      was prepared by immunizing rabbit with TYP,The titer and specificity of
      polyclonal antibody were detected by Western blot. RESULTS: Thin-layer scan
      analysis showed that TYP accounted for about 37.1% of total bacterial protein.
      The antiserum was about 1:2,000 in titier and highly specific. Full-length rggG
      protein could also be recognized by the antiserum. CONCLUSION: The TYP was highly
      expressed, and specific anti-TYP antiserum was prepared successfully.

PMID- 15191719
TI  - [Preparation and characterization of rabbit antibody against gastric cancer
      related protein GCRG213].
AB  - AIM: To prepare the rabbit antibody against gastric cancer-related protein
      GCRG213. METHODS: The thioredoxin/GCRG213 fusion protein was expressed in E.
      coli. The rabbit antibody against GCRG213 was obtained by immunizing a rabbit
      with the purified GCRG213 protein. The titer and specificity of the antibody was
      determined by ELISA and Western-blot, respectively. RESULTS: The
      thioredoxin/GCRG213 fusion protein with relative molecular mass (Mr) of 29,400
      was overexpressed in E. coli. The purity of expressed product directly purified
      from a denaturing polyacrylamide gel was about 100%. The rabbit antibody against
      GCRG213 was obtained. The ELISA titer of antiserum against GCRG213 was about
      1:256,000. Western blot analysis showed that the antiserum could bind to the
      expressed fusion protein specifically. CONCLUSION: The rabbit antibody against
      GCRG213 has been successfully prepared, which lays the foundation for further
      studying the biological function and the possible role of the GCRG213 in the
      development of gastric carcinoma.

PMID- 15191720
TI  - [Antibody production and its neutralization of Abeta42's cytoxicity in BALB/c
      mice induced by Abeta42 and its subunit vaccines].
AB  - AIM: To explore the production of anti-Abeta42 antibody after immunization with
      Abeta42 and its subunit peptide vaccines. METHODS: Seventy five male BALB/c with
      the age of 6 weeks were randomly divided into 5 groups, namely, control group,
      Abeta42 group, Abeta(36-42) group, Abeta(1-15)group and F Abeta(1-15) group. The
      BALB/c mice were immunized four times with PBS+MF59 adjuvant, Abeta42+MF59,
      Abeta(36-42)+heptalysine (MAP)+MF59, Abeta(1-15)+MAP+MF59 and Abeta(1
      15)+MAP+Freud's adjuvant, respectively. The titers of specific antibodies in sera
      and supernatants of brain tissue homogenates from the immunized mice in every
      group were detected by indirect ELISA. After Abeta42, Abeta(36-42), Abeta(1-15)
      and F Abeta(1-15) were co-cultured together with cultured PC12 cells for 7 days,
      the cytotoxicity of the 3 antigen peptides to PC12 cells were determined by MTT
      colorimetry. In addition, after immune sera from each group were added to culture
      medium containing 20 mg/L Abeta42 and co-cultured with PC12 cells for 7 days, the
      survival rate of PC12 cells were examined by MTT assay. RESULTS: The production
      of anti-Abeta42 antibodies was detected in sera of each experimental group after
      the second time immunization, and the titer of antibody rose with the increase of
      immunizing times. In addition, the anti-Abeta42 antibody with low titer was also
      detected in supernatants of brain tissue homogenates. The Abeta42 could reduce
      the survival rate of PC12 cells, whereas Abeta(36-42) and Abeta(1-15) had no
      obvious effect on survival rate of PC12 cells. After immune sera from 4
      experimental groups and Abeta42 were co-cultured with PC12 cells, their survival
      rate was found improved. CONCLUSION: Combination of Abeta42 and its subunit
      (Abeta(36-42) and Abeta(1-15)) vaccines with MF59 adjuvant can induce BALB/c mice
      to produce anti-Abeta42 antibody. The antibody may neutralize the cytotoxicity of
      Abeta42.

PMID- 15191721
TI  - [Preparation and characterization of anti-human IL-15 monoclonal antibody].
AB  - AIM: To prepare monoclonal antibody (mAb) against human interleukin-15 (hIL-15)
      and identify its characterization. METHODS: The GST-IL-15 was extracted from the
      gene-engineering bacteria E. coli and identified by SDS-PAGE. The gel strip
      containing GST-IL-15 was cut off to immunize BALB/c mice. The splenocytes of
      immunized mice were fused with Sp2/0 myeloma cells by a routine method and the
      hybridomas were selected in HAT medium. The hybridoma cells secreting specific
      antibody were detected by ELISA and cloned by limiting dilution. The stability of
      the obtained hybridoma cells and the specificity of anti-hIL-15 mAb the hybridoma
      cells secreted were identified. In addition, the New Zealand rabbits were
      immunized with the rhIL-15 inclusion body protein (rhIL-15IBP) to prepare the
      polyclonal antibody (pAb) against hIL-15. A sandwich ELISA was established with
      the anti-IL-15 mAb and pAb as coating and sandwich antibodies, respectively, to
      detect hIL-15. RESULTS: One hybridoma cell line which could stably secrete
      specific mAb was obtained. A sandwich ELISA for detecting rhIL-15 protein was
      established and its sensitivity was as low as 10 microg/L. CONCLUSION: The anti
      hIL-15 mAb was prepared successfully. A sandwich ELISA for the detection of hIL
      15 was established.

PMID- 15191722
TI  - [Preparation and characterization of monoclonal antibody against N-terminal
      domain of polycystin 1].
AB  - AIM: To prepare and identify monoclonal antibody (mAb) against N-terminal domain
      of polycystin 1. METHODS: Total RNA was extracted from kidney tissue of a healthy
      man. Gene sequence encoding polycystin 1 N-terminal domain was amplified by one
      step RT-PCR. The target gene was inserted into prokaryotic expression vector
      pQE30 and transformed into competent cells E. coli M15. The fusion protein was
      expressed under IPTG induction and purified by affinity chromatography. The
      purified fusion protein was then used to immunize BALB/c mice. The splenocytes
      from immunized mice were fused with myeloma cells Sp2/0 by PEG 4000 mediator
      method and the hybridomas were selected in HAT medium. The hybridoma clones
      secreting mAb against polycystin 1 amino-terminal domain were detected by ELISA
      and cloned by limiting dilution. The specificity of mAb against polycystin 1 N
      terminal domain was verified by ELISA and Western blot. RESULTS: cDNA encoding
      polycystin 1 extracellular region was obtained. Fusion protein of polycystin 1 N
      terminal domain were expressed in pQE30 expression system. The relative molecular
      masses (Mr) of the two fusion proteins were 19,800 and 18,900, respectively. One
      hybridoma cell 7B1 secreting specific mAb was obtained. Western blot analysis
      showed that the mAb reacted strongly and specifically to polycystin 1 N-terminal
      domain. CONCLUSION: polycystin 1 N-terminal fusion proteins have been expressed
      in E.coli M15. Anti-fusion protein mAb with antigen-binding activity has been
      prepared successfully.

PMID- 15191723
TI  - [Preparation of monoclonal antibody against sulfadiazine and development of an
      ELISA kit].
AB  - AIM: To prepare monoclonal antibody (mAb) against sulfadiazine (SD) and develop
      an ELISA kit for rapidly detecting residual SD in different kinds of samples.
      METHODS: BALB/c mice were immunized with the conjugate of SD and BSA, and then
      anti-SD mAb was prepared by hybridoma technique. The purified ascitic mAb and HRP
      labeled SD were used to establish a competitive ELISA for detection of SD in
      samples. RESULTS: 5 hybridoma cell lines secreting anti-SD mAbs 1A1, 1B8, 1E4,
      2C1 and 3D9 were obtained. 1A1, 1B8 and 1E4 belonged to IgG1, while 2C1 and 3D9
      belonged to IgG2. The I50 and theoretical minimum detectable amount of the kit
      was 9.3 microg/L and 0.6 microg/L, respectively. The recovery rates of the kit
      for SD in different kinds of samples were higher than 60%. The cross-reaction
      rate of the kit for other sulfanilamide drugs was lower than 3%. CONCLUSION: 5
      mAbs against SD have been prepared successfully and possess high titer and
      specificity. The development of an ELISA kit for rapidly detecting SD can meet
      the needs of detection of SD in different samples.

PMID- 15191724
TI  - [Cloning and expression of human IL-1R II gene].
AB  - AIM: To clone human IL-1R II cDNA and construct its recombinant retrovirus vector
      so as to explore its role in IL-1R II related diseases. METHODS: Human IL-1R II
      cDNA was amplified by RT-PCR from peripheral blood mononuclear cells (PBMCs) and
      inserted into the vector PET22b to construct recombinant vector PET22b-IL-R II.
      The recombinant was transfected into E. coli BL21 and expressed under IPTG
      induction. Expressed products were detected by Western blot. In addition, human
      IL-1R-II cDNA was subcloned into retrovirus vector LZRSPBMN and transfected into
      293 cells by calcium phosphate precipitation. IL-1R II expression was detected by
      immunohistochemical staining. RESULTS: IL-1R II cDNA with 1,203 bp was amplified
      by RT-PCR from human PBMCs. The recombinant of this cDNA could be expressed in E.
      coli,which was confirmed by Western blot results. Immunohistochemistry detection
      showed IL-1R II protein was expressed in 293 cells. CONCLUSION: Human IL-1R II
      gene was cloned successfully. PET22b-IL-1R II and LZR-IL-1R II were constructed
      and the recombinant protein IL-1R II was expressed in E.coli BL21. The results
      reported herein lay the foundation for further research on the role of IL-1R II
      in certain diseases.

PMID- 15191725
TI  - [Experimental study on the effect of VEGF165 antisense RNA on human squamous cell
      carcinoma of esophagus].
AB  - AIM: To investigate the effect of antisense RNA against vascular endothelial
      growth factor 165 (VEGF165) on human esophagus squamous cell carcinoma cell line
      EC109. METHODS: Eukaryotic expression vector for VEGF165 antisense RNA was
      constructed and identified. Recombinant plasmid was transfected into EC109 cells
      and the transfected EC109 cells were inoculated subcutaneously to nude mice. The
      biological characteristics and tumorigenicity of transfected EC109 cells were
      observed by in situ hybridization, laser confocal microscope, transmission
      electron microscopy and flow cytometry. RESULTS: The eukaryotic expression vector
      pCEP-AVEGF165 was successfully constructed and expressed in transfected EC109
      cells. The rate of VEGF165 expression dropped by 75% in transfected cells. The
      morphology and cell cycle of transfected EC109 cells were not affected by the
      antisense RNA, but the tumorigenicity and angiogenesis of transfected EC109 cells
      were greatly reduced in nude mice. The volume of tumors in pCEP-AVEGF165
      transfected group, empty vector transfected group and control group were (820+/
      112.5) mm3, (7 930+/-1 035) mm3 and (7 850+/-950) mm3, respectively. The
      microvessel density of the three groups were (8.5+/-1.2)/mm2, (44.3+/-9.4)/mm2
      and (46.4+/-12.6)/mm2, respectively. CONCLUSION: The angiogenesis and
      tumorigenicity of human esophageal squamous cell carcinoma were effectively
      inhibited by VEGF165 antisense RNA, which may be applied to treat solid tumor in
      the future.

PMID- 15191726
TI  - [Expression and its significance of b-FGF in human benign prostatic hyperplasia
      and prostatic carcinoma tissues].
AB  - AIM: To investigate the clinical significance of basic fibroblast growth factor
      (b-FGF) in human benign prostatic hyperplasia (BPH) and prostatic carcinoma
      (Pca). METHODS: b-FGF expressions were examined by RNA dot blot hybridization and
      immunohistochemical staining in prostate tissues from 40 normal cases (NP), 38
      BPH and 36 Pca. RESULTS: The expressions of b-FGF in BPH and Pca tissues were
      significantly higher than those in normal prostate tissues (P < 0.01). There was
      no significant correlation between the increased expression of b-FGF and the
      graduation of BPH, pathologic grading as well as clinical stages of Pca.
      CONCLUSION: b-FGF may be secreted from BPH and Pca tissues themselves, which is
      closely involved in the genesis and development of BPH and Pca.

PMID- 15191727
TI  - [Prokaryotic expression of human calcyclin-binding protein and preparation of
      mouse polyclonal antibody against hCacyBP].
AB  - AIM: To express hCacyBP in E.coli and prepare mouse polyclonal antibody against
      hCacyBP so as to study tissue distribution of hCacyBP and evaluate its role
      during formation of multidrug resistance to gastric cancer. METHODS: hCacyBP gene
      was subcloned into an expression vector pET28a, and then the recombinant vector
      was transformed into E. coli BL21. The recombinant protein was expressed in BL21
      under IPTG induction. Using purified hCacyBP as immunogen, mouse polyclonal
      antibody against hCacyBP was prepared. hCacyBP was detected by Western blot in 10
      kinds of rabbit tissues. Expression and distribution of hCacyBP in SGC7901/VCR
      and SGC7901 cells were detected by Western blot and immunohistochemical staining.
      RESULTS: hCacyBP was successfully expressed in E. coli. The Western blot analysis
      showed that hCacyBP was expressed in all 10 kinds of rabbit tissues, but
      expression of brain and liver tissues were higher as compared with other tissues.
      Expression and distribution of hCacyBP in both SGC7901/VCR and SGC7901 cells had
      no significant difference. CONCLUSION: CacyBP expressed widespreadly in varied
      tissues. Polyclonal antibody against hCacyBP that we prepared has high
      specificity, which provides a powerful tool for studying the function of hCacyBP.

PMID- 15191728
TI  - [Establishment of mouse melanoma B16 cell lines co-expressing MAGE-1 and EGFP].
AB  - AIM: To construct the melanoma antigen-1(MAGE-1) eukaryotic expression plasmid
      and express MAGE-1 in mouse melanoma B16 cells. METHODS: The MAGE-1 gene was
      amplified by PCR and cloned into the eukaryotic expression vector pIRES2-EGFP to
      construct the pIRES2-EGFP-MAGE-1 plasmid. The plasmid was transfected into the
      B16 cells. The EGFP expression was detected under fluoroscent microscope and the
      MAGE-1 expression was detected by immunohistochemistry staining. RESULTS: The
      eukaryotic expression vector pIRES2-EGFP-MAGE-1 was constructed and transfected
      successfully into B16 cells, and the EGFP and MAGE-1 genes were co-expressed in
      the B16 cells. CONCLUSION: A mouse melanoma cell line B16 co-expressing MAGE-1
      and EGFP genes has been established successfully, which lays the foundation for
      the research on application of MAGE-1 in the tumor immunotherapy.

PMID- 15191729
TI  - [Role of nitric oxide--NF-kappaB signaling pathway in differentiation of human
      naive T lymphocytes into Th1/Th2 cells].
AB  - AIM: To explore the role of nitric oxide (NO)--NF-kappaB signaling pathway in the
      differentiation of human naive T lymphocytes into Th1/Th2 cells. METHODS: Human
      naive T lymphocytes were isolated from umbilical blood. Various concentrations of
      NO donor sodium nitroprusside (SNP), NO inhibitor NAME and NF-kappaB inhibitor
      PDTC were added to the culture medium to induce the differentiation of naive T
      cells towards Th1/Th2 cells. The expressions of intracellular cytokine IFN-gamma
      and IL-4 were detected by flow cytometry. RESULTS: The treatment of SNP, NAME and
      PDTC made no difference on the percentage of cells expressing IFN-gamma (Th1) or
      IL-4 (Th2) in comparison with that of the control group (P < 0.05). CONCLUSION:
      Signaling pathway of NO--NF-kappaB had no effect on differentiation of human
      naive T lymphocytes into Th1 and Th2 cells. The role of NO--NF-kappaB signaling
      pathway in the regulation of types 1 and 2 cytokines may occur mainly at the
      level of mature Th cells.

PMID- 15191730
TI  - [Changes of intercellular adhesion molecule-1 and E-selectin levels in plasma of
      uremic patients treated with maintaining hemodialysis].
AB  - AIM: To detect the levels of ICAM-1 and E-selectin in plasmas from uremic
      patients treated by means of maintaining hemodialysis (MHD) and explore the
      pathological mechanism of atherosclerosis in MHD patients. METHODS: The levels of
      ICAM-1 and E-selectin in plasmas from the 105 MHD patients and 25 healthy persons
      (control group) were detected by dual antibody sandwich ELISA. The cervical
      atherosclerosis of the patients was examined by type B ultrasonography.
      Simultaneously, the blood pressures of the patients and control group were taken
      and recorded, as well as the biochemical criterions in their blood were detected.
      RESULTS: (1) The plasma levels of ICAM-1 and E-selectin in MHD patients were
      significantly higher than those in the control group, respectively (P < 0.01),
      and in MHD group the above indexes in patients with cervical atherosclerosis were
      significantly higher than those without cervical atherosclerosis (P < 0.01,P <
      0.05). (2) In MHD group, the plasma ICAM-1 level was positively correlated with E
      selectin and triglycerides (TG) levels(r = 0.62 and 0.60, respectively), and with
      the diastolic pressure(r = 0.41,P < 0.05). CONCLUSION: The impairment of vascular
      endothelial function was obvious in uremic patients with MHD. The changes of ICAM
      1 and E-selectin could be accepted as biochemical criterions of vascular
      endothelial injury. The two adhesion molecules have close relationship with
      atherosclerosis in MHD patients.

PMID- 15191731
TI  - [Defect of TCR-mediated signal pathway of T cells in IDDM patients].
AB  - AIM: To study the mechanism responsible for alteration of T cell response in IDDM
      patients. METHODS: T cells from peripheral blood of IDDM patients were activated
      by anti-TCR antibodies. The level of TCR-mediated signaling pathway was analyzed.
      RESULTS: T cells from IDDM patients responded weakly to anti-TCR antibody-induced
      proliferation, as compared with T cells from normal subjects (P < 0.05). The
      defect could be partially remedied by the addition of rIL-2, while the anti-CD28
      antibody stimulation did not restore the proliferative response of anti-TCR
      induced cells from IDDM patients (P = 0.03). CONCLUSION: Unresponsiveness of the
      T cells from IDDM patients to anti-TCR antibody may result from a defect in the
      signaling pathway, the CD28 co-stimulation-signaling pathway is normal. Defect in
      the TCR signaling pathway increases the sensitivity of T cells from IDDM patients
      to apoptosis or anergy.

PMID- 15191732
TI  - [Immunophenotyping of peripheral blood leukemic cells by multi-parameter
      cytometry].
AB  - AIM: To explore the clinical application and significance of CD45/SCC gating
      strategy of multi-parameter cytometry and tricolor fluorescence-labeled
      monoclonal antibodies in immunophenotyping of peripheral blood leukocytes in
      leukemia. METHODS: Peripheral blood leukocytes were stained with CD45 combined
      with a panel of monoclonal antibodies to different lineage markers. CD45/SSC dot
      plot was formed and leukemic cell colony, once displayed, was gated for
      immunophenotyping. RESULTS: 144 patients with acute leukemia and 51 with chronic
      leukemia were enrolled. Distinguishable leukemic cell colony was found in 137 out
      of 144 specimens. 66 patients were immunologically classified as ALL and 67 as
      AML. 4 patients were unable to be classified immunophenotypically. 27 AL patients
      coexpressed markers of another cell lineage (20%). Immunophenotypic features of
      different types of leukemia were described. It is a common phenomenon that AL of
      one lineage coexpressed markers of another lineage. CONCLUSION: An accurate
      immunophenotyping of leukemia can be realised when leukemic cell colony is
      displayed and analyzed by CD45/SCC pattern and gating strategy, which is
      important for clinical treatment and prognosis judgment.

PMID- 15191733
TI  - [Extraction and purification of non-receptor type PTKs-Syk].
AB  - AIM: To extract and purify Syk protein from Sf21 cells transfected by Syk gene.
      METHODS: Sf21 cells were transfected with recombinant syk gene. After 48 h of
      incubation at 28 degrees Celsius, the transfected cells were collected and
      sonicated with Sonfier sonicator on ice. Filtered cell extract was loaded onto a
      Reactive Yellow-3 resin column and Toyopearl AF-Heparin-650 M column
      respectively. The characters of Syk protein in the fractions were identified by
      SDS-PAGE, Western blotting and IEF. RESULTS: 225 mg of protein containing Syk
      were obtained from Sf21 cells (2.5 x 10(9))extract. There were two subpopulations
      in the elution of Reactive Yellow-3 resin column with the same relative molecular
      mass (Mr) 72 x 10(3). The two subpopulations were then applied on Toyopearl AF
      Heparin-650 M column and two pure proteins were obtained. The results of SDS
      PAGE, Western blotting, and IEF showed the two proteins having the same relative
      molecular mass (72 x 10(3)), corresponding to Syk, but with different pI.
      CONCLUSION: The yield of Syk was 8 mg from 2.5 billion cells and the purity was >
      95%. The two purified Syk proteins have the same Mr and different pI. The
      purified Syk protein can be applied to study Syk's mechanism, produce anti-Syk
      antibody and invent Syk diagnosis kit, etc.

PMID- 15191734
TI  - [The effect of polyporus umbellatus polysaccharide on the immunosuppression
      property of culture supernatant of S180 cells].
AB  - AIM: To investigate the effect of polyporus umbellatus polysaccharide (PUPS) on
      the immunosuppression property of tumor cell line S180 culture supernatant.
      METHODS: The inhibitory effects of the culture supernatant of S180 cells in the
      presence or absence of PUPS on the ConA-induced mouse splenocyte proliferation,
      IL-2 production, killer activity and the reactivity of CTLL-2 cells to IL-2 were
      detected by MTT colorimetry. The effect of the culture supernatant on the IL
      2Ralpha expression on murine splenocytes was detected by flow cytometry. RESULTS:
      The culture supernatant of S180 cells could strongly inhibit immunity in terms of
      the above five indexes, while PUPS could reverse the immunosuppression.
      CONCLUSION: PUPS can offset the immunosuppression of the supernatant from S180
      cell culture, which may be mediated by down-regulating the synthesis and/or
      secretion of immunosuppressive substance by S180 cells.

PMID- 15191735
TI  - [The effects of two TCM prescriptions, Tonifying Kidney and Strengthening Vital
      Energy, on NF-kappaB activing in aged mouse T cells].
AB  - AIM: The aim of the present study was to explore the immunologic mechanism of
      delaying senescence by Strengthening Vital Energy(SVE), Tonifying Kidney (TK) and
      combined TK and SVE. METHODS: Mice of 20 months were used as senescence model.
      The effects of the prescriptions on anti-CD3 antibody-induced NF-kappaB activity
      and the expression of NF-kappaB in T cells from aged mice were analyzed by
      electrophoretic mobility shift assay (EMSA) and Western blot, respectively.
      RESULTS: NF-kappaB activity in anti-CD3 antibody-induced T cells from the aged
      mice was lower than that from young ones. The three prescriptions raised the
      activity of NF-kappaB in the T cells from the aged mice to certain extent.
      Combined TK and SVE had no influence on p65 and p50 subunits expressions.
      CONCLUSION: The increased NF-kappaB activity may be one of mechanisms underlying
      the improvement of immune response in aged mice by Chinese medicines.

PMID- 15191736
TI  - [Construction of human phage-displayed scFv library and selection of the ScFv
      against rabies virus].
AB  - AIM: To construct a human phage displayed single chain Fv antibody (scFv) library
      and screen specific scFv against rabies virus. METHODS: Using a phage-display
      technique, IgVH and IgVL genes were cloned from peripheral blood lymphocytes from
      three donors immunized with the WISTAR PM strain vaccine. Genes encoding scFv
      fragments were constructed by random linkage of VH gene and VL gene by SOE PCR,
      and then the constructed scFv genes were cloned into phagemid vector and
      transfected into E. coli TG1. The recombinant phages were screened by four rounds
      of panning with rabies virus vaccine. The positive recombinant phages were
      sequenced and antigen-binding activity of recombinant scFv was detected by
      competition ELISA. RESULTS: A human phage-displayed scFv library with about 7 x
      10(8) sink size was constructed. A new human scFv was selected, which bound
      specifically to rabies virus and had higher affinity. CONCLUSION: The results lay
      a solid foundation for preparation of human engineering antibody to rabies virus
      reported herein with higher affinity.

PMID- 15191737
TI  - The eight-cysteine motif, a versatile structure in plant proteins.
AB  - A number of protein sequences deduced from the molecular analysis of plant cDNA
      or genomic libraries can be grouped in relation to a defined number of cysteine
      residues located in distinct positions of their sequences. This is the case for a
      group of around 500 polypeptides from different species that contain a small
      domain (less than 100 amino acids residues) displaying a pattern of eight
      cysteines in a specific order. The plant sequences containing this motif belong
      to proteins having different functions, ranging from storage, protection, enzyme
      inhibition and lipid transfer, to cell wall structure. The eight-cysteine motif
      (8CM) appears to be a structural scaffold of conserved helical regions connected
      by variable loops, as observed by three-dimensional structure analysis. It is
      proposed that the cysteine residues would form a network of disulfide bridges
      necessary, for the maintenance of the tertiary structure of the molecule together
      with the central helical core, while the variable loops would provide the
      sequences required for the specific functions of the proteins.

PMID- 15191738
TI  - Real-time PCR monitoring of fungal development in Arabidopsis thaliana infected
      by Alternaria brassicicola and Botrytis cinerea.
AB  - Reliable methods for disease severity assessment are of crucial importance in the
      study of plant pathogen interactions, either for disease diagnostic on the field
      or to assess phenotypical differences in plants or pathogen strains. Currently,
      most of the assays used in fungal disease diagnostic rely on visual assessment of
      the symptoms, lesion diameter measurement or spore counting. However, these tests
      are tedious and often cannot discriminate between slightly different levels of
      resistance. Besides, they are not well suited to assess fungal development in the
      early phases of the infection, before macroscopical symptoms are visible or
      before sporulation. We describe here a pathogenicity assay based on the relative
      quantification of fungal and plant DNA in infected Arabidopsis thaliana leaves by
      means of real-time quantitative PCR. We show that it allows to monitor
      quantitatively the growth of the fungi Alternaria brassicicola and Botrytis
      cinerea in a sensitive and reliable way. Although highly sensitive, this test
      also exhibits a high robustness, which is crucial to significantly discriminate
      between lines displaying slightly different levels of resistance. Therefore, it
      allows to assess fungal development from the very first stages of infection and
      provides a fast and very practical alternative to currently described assays for
      phenotyping either plant mutant lines or fungal strains.

PMID- 15191739
TI  - Biochemical characterization of a high-palmitoleic acid Helianthus annuus mutant.
AB  - In the present work we carried out analytical and biochemical studies on a new
      high-n-7 monounsaturated fatty acid sunflower (Helianthus annuus L.) mutant. This
      new line, which has been selected by classical methods of breeding and
      mutagenesis, shows contents of unusual acyl chains up to 20% (12% of 16:1DELTA9,
      5% of 16:2delta9,12 and 6% of 18:1delta11), whereas those fatty acids are found
      in negligible amounts in common sunflower cultivars. This characterization
      involved in vivo incubations with radiolabeled acetate and measurement of the
      last enzymes involved in the intraplastidial de novo fatty acid synthesis: beta
      ketoacyl-ACP synthase II, stearoyl-ACP desaturase (EC 1.14.19.2) and acyl-ACP
      thioesterases (EC 3.1.2.14). Results indicated that the high-palmitoleic acid
      phenotype was associated with a concerted reduction in the fatty acid synthase II
      activity with respect to the control lines and an increase of stearoyl-ACP
      desaturase activity with respect to the high-palmitate mutant line.

PMID- 15191740
TI  - Larvicidal Cry proteins from Bacillus thuringiensis are released in root exudates
      of transgenic B. thuringiensis corn, potato, and rice but not of B. thuringiensis
      canola, cotton, and tobacco.
AB  - Larvicidal proteins encoded by cry genes from Bacillus thuringiensis were
      released in root exudates from transgenic B. thuringiensis corn, rice, and potato
      but not from B. thuringiensis canola, cotton, and tobacco. Nonsterile soil and
      sterile hydroponic solution in which B. thuringiensis corn, rice, or potato had
      been grown were immunologically positive for the presence of the Cry proteins;
      from B. thuringiensis corn and rice, the soil and solution were toxic to the
      larva of the tobacco hornworm (Manduca sexta), and from potato, to the larva of
      the Colorado potato beetle (Leptinotarsa decemlineata), representative
      lepidoptera and coleoptera, respectively. No toxin was detected immunologically
      or by larvicidal assay in soil or hydroponic solution in which B. thuringiensis
      canola, cotton, or tobacco, as well as all near-isogenic non-B. thuringiensis
      plant counterparts or no plants, had been grown. All plant species had the
      cauliflower mosaic virus (CaMV) 35S promoter, except rice, which had the
      ubiquitin promoter from maize. The reasons for the differences between species in
      the exudation from roots of the toxins are not known. The released toxins
      persisted in soil as the result of their binding on surface-active particles
      (e.g. clay minerals, humic substances), which reduced their biodegradation. The
      release of the toxins in root exudates could enhance the control of target insect
      pests, constitute a hazard to nontarget organisms, and/or increase the selection
      of toxin-resistant target insects.

PMID- 15191741
TI  - Xyloglucan-cellulose interaction depends on the sidechains and molecular weight
      of xyloglucan.
AB  - Recent papers have brought evidence against the hypothesis that the fucosyl
      branching of primary wall xyloglucans (Xg) are responsible for their higher
      capacity of binding to cellulose. Reinforcement of this questioning has been
      obtained in this work where we show that the binding capacity was improved when
      the molecular weight (MW) of the Xg polymers is decreased by enzymatic
      hydrolysis. Moreover, the enthalpy changes associated with the adsorption process
      between Xg and cellulose is similar for Xgs with similar MW (but differing in the
      fine structure such as the presence/absence of fucose). On the basis of these
      results, we suggest that the fine structure and MW of Xg determines the energy
      and amount of binding to cellulose, respectively. Thus, the occurrence of
      different fine structural domains of Xg (e.g. the presence of fucose and the
      distribution of galactoses) might have several different functions in the wall.
      Besides the structural function in primary wall, these results might have impact
      on the packing features of storage Xg in seed cotyledons, since the MW and
      absence of fucose could also be associated with the self-association capacity.

PMID- 15191742
TI  - Photosynthetic pigment composition and photosystem II photochemistry of wheat
      ears.
AB  - The characteristics of pigment composition and photosystem II (PSII)
      photochemistry in the flag leaf and ear parts of wheat (Triticum aestivum L.)
      grown in the field was compared. At the early stage of flowering, awns and the
      flag leaf showed the highest values in the maximal efficiency of PSII
      photochemistry (Fv/Fm), actual PSII efficiency (phi(PSII)), photochemical
      quenching (qP), and the efficiency of excitation capture by open PSII centres
      (Fv/F'm), followed by glumes, lemmas, and paleae, respectively except that no
      differences in F'v/F'm were observed among glumes, leamms, and paleae. With
      progressing grain filling, there was a change in the photosynthetic pigment
      stoichiometry. In the ear parts, neoxanthin and antheraxanthin decreased equally
      with chlorophyll levels. Lutein and zeaxanthin decreased less than chlorophyll
      levels while beta-carotene and violaxanthin decreased faster than chlorophyll
      levels. No big differences in pigment composition were observed among different
      ear parts. For the flag leaf, neoxanthin and beta-carotene decreased
      concomitantly with chlorophyll, whereas lutein and xanthophyll cycle pigment were
      less affected, leading to increases in lutein/chlorophyll and xanthophyll cycle
      pigment/chlorophyll ratios. Fv/Fm, phi(PSII), qP, and F'v/F'm decreased gradually
      in the flag leaf and ear parts but to different extents. The largest changes were
      observed in awns, followed by the lemmas of floret 2, the lemmas of floret 1,
      glumes, and the flag leaf, respectively. The results suggest that during grain
      filling, a down-regulation of PSII associated with an increase of the de
      epoxidation state of the xanthophyll cycle carotenoids occurred in the flag leaf
      but not in the ear parts.

PMID- 15191743
TI  - Enhancement of photosynthetic O2 evolution in Chlorella vulgaris under high light
      and increased CO2 concentration as a sign of acclimation to phosphate deficiency.
AB  - The photosynthetic oxygen evolution of Chlorella vulgaris (Beijer.) cells taken
      from phosphate-deficient (-P) and control cultures was measured during 8 days of
      culture growth. Under inorganic carbon concentration (50 microM) in the measuring
      cell suspension and irradiance (150 micromol m(-2) s(-1)), the same as during
      culture growth, there were no marked differences in the photosynthetic O2
      evolution rate between the -P cells and the controls. The much slower growth of 
      P cultures indicated that the utilization of absorbed photosynthetically active
      radiation (PAR) in the CO2 assimilation and biomass production were in -P cells
      less efficient than in the controls. Alga cells under the phosphorus stress
      utilized more of the absorbed PAR in the nitrate reduction than the control
      cells. However, under conditions of more efficient CO2 supply (inorganic carbon
      concentration 150 microM, introducing of exogenous carbonic anhydrase to the
      measuring cell suspension) and under increased irradiance (500 micromol m(-2) s(
      1)), the photosynthetic O2 evolution in -P cells reached a higher rate than in
      the controls. The results suggest that in -P cells the restricted CO2
      availability limits the total photosynthetic process. But under conditions more
      favorable for the CO2 uptake and under high irradiance, the -P cells may reveal a
      higher photosynthetic oxygen evolution rate than the controls. It is concluded
      that an increased potential activity of the photosynthetic light energy
      absorption and conversion in the C. vulgaris cells from -P cultures is a sign of
      acclimation to phosphorus stress by a sun-type like adaptation response of the
      photosynthetic apparatus.

PMID- 15191744
TI  - Photoperiod and temperature effects on in vitro growth and flowering of P.
      pusilla, an epiphytic orchid.
AB  - Psygmorchis pusilla Dodson and Dressler, an epiphytic orchid, has been shown to
      be an interesting model to study in vitro flower formation. In the present study,
      the effects of photoperiod and temperature on vegetative and reproductive
      development were investigated. Although photoperiod had limited effects on leaf
      number, an etiolating process was verified in darkness and a higher growth was
      detected under long days. A positive relationship was observed between long days
      and floral spike formation. However, plant incubation under 20 h photoperiod or
      longer days negatively affected floral bud development, inhibiting anthesis and
      reducing flower longevity. Higher soluble sugar and starch levels were detected
      in plants cultivated under long days, while chlorophyll and carotenoids contents
      were negatively affected under these conditions. Plants showed great sensitivity
      to temperature variations; 27 degrees C being the most adequate for growth, leaf
      and floral spike formation. Temperatures of 22 and 32 degrees C were not
      appropriate for in vitro development of P. pusilla.

PMID- 15191745
TI  - 2S storage protein gene of Douglas-fir: characterization and activity of promoter
      in transgenic tobacco seeds.
AB  - To date a few sequences regulating expression of conifer seed-specific genes have
      been reported. To characterize Douglas-fir (Pseudotsuga menziesii [Mirb] Franco)
      2S albumin storage protein genes, a genomic DNA sequence containing upstream
      promoter sequences was isolated by screening a Douglas-fir genomic library.
      Sequence analysis of the Douglas-fir gPm2S1 promoter revealed the presence of RY
      repeated elements (GCATGC), and multiple E-box motifs (CANNTG) and ACGT-core
      elements, features characteristic of 2S storage protein genes in angiosperms.
      When fused to the GUS reporter gene, the 1.16 kb Douglas-fir 2S promoter sequence
      was sufficient to direct transient expression in both developing Douglas-fir
      embryos and maternally derived haploid megagametophytes. Analysis of this
      promoter construct in transgenic tobacco showed that expression was restricted to
      embryo and endosperm in developing seeds and was not detected in vegetative
      tissues of two-week-old seedlings. These results strongly suggest that both
      structural and regulatory elements as well as upstream signaling components
      controlling the expression of 2S albumin genes are highly conserved during
      evolution.

PMID- 15191746
TI  - Rapid transmission of oxidative and nitrosative stress signals from roots to
      shoots in Arabidopsis.
AB  - Protein kinases play a central role in signal transduction pathways in
      eukaryotes. A highly conserved group of kinases, termed mitogen-activated-protein
      kinases (MAPKs) was shown to mediate many diverse stress responses. In plants,
      MAPKs were shown to function in resistance responses to many biotic and abiotic
      stresses. Here, we show that exposure of Arabidopsis roots to hydrogen peroxide
      or to nitric oxide resulted in rapid activation of protein kinases in the shoots
      that exhibited MAPK properties. The same pattern of kinases was induced by direct
      injection of these compounds into leaves, indicating accurate long-distance
      transmission of H2O2 and NO signals. These results are important for the
      understanding of redox signal transmission from the rhizosphere throughout the
      plant.

PMID- 15191747
TI  - Ergosterol elicits oxidative burst in tobacco cells via phospholipase A2 and
      protein kinase C signal pathway.
AB  - Ergosterol, a typical fungal sterol, induced in tobacco (Nicotiana tabacum L. cv.
      Xanthi) suspension cells the synthesis of reactive oxygen species and
      alkalization of the external medium that are dependent on the mobilization of
      calcium from internal stores. We used specific inhibitors to elucidate the signal
      pathway triggered by ergosterol compared with cryptogein, a proteinaceous
      elicitor of Phytophthora cryptogea. Herbimycin A and genistein, inhibitors of
      tyrosine protein kinases, had no effect on the oxidative burst and pH changes
      induced by both elicitors. Similarly, H-89, an inhibitor of protein kinase A, had
      no effect on the induction of these defense reactions. However, the response to
      both elicitors was completely blocked by NPC-15437, a specific inhibitor of
      animal protein kinase C (PKC). The responses induced by cryptogein but not those
      induced by ergosterol were inhibited by U73122 and neomycin, inhibitors of
      phospholipase C (PLC). On the other hand, the activity of phospholipase A2 (PLA2)
      measured using a fluorogenic substrate was stimulated by ergosterol and not by
      cholesterol and cryptogein. A specific inhibitor of PLA2, arachidonic acid
      trifluoromethyl ketone (AACOCF3), inhibited the pathway stimulated by ergosterol
      but not that induced by cryptogein. These results suggest that the cryptogein
      induced signal pathway leading to the oxidative burst and DeltapH changes
      includes PLC and PKC, whereas this response induced by ergosterol includes PLA2
      and PKC.

PMID- 15191748
TI  - Isolation and functional assessment of a tomato proteinase inhibitor II gene.
AB  - A genomic clone encoding a serine proteinase inhibitor II, designated as TPI-2,
      was isolated from tomato (Lycopersicon esculentum Mill.) seedling. It consisted
      of a 990 bp upstream regulatory region and a 680 bp transcription region
      containing an intron. As shown by northern hybridization, mechanical injury
      activated its expression in roots, stems and leaves, and so did exogenous
      hormones jasmonic acid (JA) and alpha-Linolenic acid (LA), though abscisic acid
      (ABA) and NaCl failed to induce its expression. Salicylic acid (SA) was found to
      inhibit the inducing effect of LA but not those of mechanical injury and JA. As
      demonstrated experimentally, TPI-2 could be expressed effectively in tobacco
      cells and the protein products showed insecticidal activity.

PMID- 15191749
TI  - Spread of oxidative damage and antioxidative response through cell layers of
      tobacco callus after UV-C treatment.
AB  - Tobacco (Nicotiana tabacum L. cv. Petit Havana) callus cultures were exposed to
      UV-C high dose pulse-treatment (254 nm, 50 kJ m(-2), 1 h-treatment). After 6, 24
      and 48 h from the end of the treatment, calli were cut transversally in two
      layers and oxidative damage (malondialdehyde [MDA] and hydrogen peroxide), non
      enzymatic (radical scavenging antioxidants [RSA] and polyamines) and enzymatic
      antioxidants (ascorbate peroxidase [APX, EC 1.11.1.11], glutathione reductase
      [GR, EC 1.6.4.2], catalase [CAT, EC 1.11.1.6] and guaiacol peroxidase [GPX, EC
      1.11.1.7]) were evaluated. At each time-point data referred to UV-C treated calli
      were compared to data of untreated ones (control). Despite of a strong increase
      of H2O2 content, a slight cellular damage was observed in both upper and lower
      layers 24 and 48 h after UV-C treatment. An activation first of non-enzymatic
      antioxidants and then of enzymatic antioxidants was detected in UV-C treated
      calli. In particular, RSA and putrescine (PUT) accumulated 6 h after UV-C
      treatment while APX, GR and GPX enzyme activities increased 24 h after UV-C
      irradiation. Catalase activity did not change. UV-C-induced oxidative stress and
      antioxidative response were observed also in cell layers not directly exposed to
      UV irradiation, indicating that a stress signal was transmitted to the whole mass
      of callus.

PMID- 15191750
TI  - Differential expression of 10 sweetpotato peroxidase genes in response to
      bacterial pathogen, Pectobacterium chrysanthemi.
AB  - To understand the function of each peroxidase (POD, EC 1.11.1.7) in terms of
      biotic stress, changes in POD specific activity and expression of 10 POD genes
      were investigated in four cultivars of sweetpotato (Ipomoea batatas) after
      infection with Pectobacterium chrysanthemi. POD specific activity (units mg(-1)
      protein) increased from 16 h after inoculation (HAI) in three varieties. POD
      activities of two cultivars, Shinwhangmi and White Star, reached a maximum level
      at 24 HAI by about three times compared to mock treatment (MT), and then
      decreased, whereas those of Zami and Yulmi continuously increased until 36 HAI.
      Native gel analysis revealed that one POD isoenzyme with a high electrophoretic
      mobility significantly increased in response to pathogen infection in all
      cultivars. Additionally, 10 POD genes displayed differential expression patterns
      upon bacterial infection by northern analysis. Several POD genes such as swpa2,
      swpa3, swpa4, swpa5, swpb1 were induced upon bacterial infection, but other genes
      were not. Particularly, swpa4 gene was markedly expressed in response to
      bacterial infection in four different cultivars, suggesting that this gene has a
      stress-inducible promoter. These results indicate that some specific POD
      isoenzymes are involved in defense in relation to pathogenesis of P. chrysanthemi
      in sweetpotato plants.

PMID- 15191751
TI  - Optimization of the primary collimator settings for fractionated IMRT
      stereotactic radiotherapy.
AB  - Advances in field-shaping techniques for stereotactic radiosurgery/radiotherapy
      have allowed dynamic adjustment of field shape with gantry rotation (dynamic
      conformal arc) in an effort to minimize dose to critical structures. Recent work
      evaluated the potential for increased sparing of dose to normal tissues when the
      primary collimator setting is optimized to only the size necessary to cover the
      largest shape of the dynamic micro multi leaf field. Intensity-modulated
      radiotherapy (IMRT) is now a treatment option for patients receiving stereotactic
      radiotherapy treatments. This multisegmentation of the dose delivered through
      multiple fixed treatment fields provides for delivery of uniform dose to the
      tumor volume while allowing sparing of critical structures, particularly for
      patients whose tumor volumes are less suited for rotational treatment. For these
      segmented fields, the total number of monitor units (MUs) delivered may be much
      greater than the number of MUs required if dose delivery occurred through an
      unmodulated treatment field. As a result, undesired dose delivered, as leakage
      through the leaves to tissues outside the area of interest, will be
      proportionally increased. This work will evaluate the role of optimization of the
      primary collimator setting for these IMRT treatment fields, and compare these
      results to treatment fields where the primary collimator settings have not been
      optimized.

PMID- 15191752
TI  - Heterogeneous planning for homogeneous protocols.
AB  - Clinical trials often require homogeneous treatment plans. Many institutions,
      however, have begun using heterogeneous plans. Is it possible to satisfy the
      requirements of such a protocol while achieving the superior accuracy of
      heterogeneous treatment planning? At the University of Texas M. D. Anderson
      Cancer Center, we currently use conformal treatment planning with heterogeneities
      for thoracic cancers. This paper describes a procedure that has been developed to
      satisfy the requirements of a homogeneous protocol, such as RTOG 98-01 (A Phase
      III Study of Amifostine mucosal protection), while maintaining accuracy in
      treatment planning.

PMID- 15191753
TI  - New equations for matching a low neck field to oblique upper neck fields with
      collimator rotation in a 3-field monoisocentric setup for head-and-neck cancers.
AB  - With a monoisocentric 3-field technique for treating head-and-neck cancer,
      collimator rotation may be needed for the upper lateral fields to avoid cephalad
      positioned shoulders or to avoid unnecessary arytenoid irradiation while
      maintaining more anterior coverage. For patients with unilateral lymphadenopathy,
      lateral oblique-opposed boost fields can be used to encompass the primary tumor
      and ipsilateral lymph nodes without junctioning through gross disease. When
      initial collimated lateral fields are also rotated with a gantry angle to produce
      oblique boost fields, however, the resulting matchline with a low anterior neck
      (LAN) boost field is no longer nondivergent. This can be corrected by manual
      adjustment of collimator and gantry angles for the LAN field using 3D treatment
      planning software. The goal of this study was to derive mathematical formulas to
      simplify this process. We used a transformation matrix to define formulas that
      could predict the appropriate modifications to the LAN boost field. Output from
      the formulas was (1) visually tested within 3D treatment planning software and
      (2) verified using a solid water head-and-neck phantom and radiographic film
      dosimetry to confirm that a nondivergent matchline was obtained in several
      clinical scenarios. When evaluated with 3D treatment planning software, the
      formulas accurately predicted the appropriate gantry and collimator angles of the
      LAN boost field for a variety of possible beam combinations. When evaluated with
      film dosimetry, the formulas were shown to accurately predict the appropriate
      gantry and collimator angles of the LAN boost field to within the +/- 2 mm/1
      degrees tolerance specifications of the linear accelerator and acceptable for
      routine clinical use. The presented formulas are simple and geometrically
      precise. They predict the necessary manipulations of the LAN boost field to
      maintain a geometrically precise matchline, as verified by 3D treatment planning
      software, phantom dosimetry, and actual patient setups.

PMID- 15191754
TI  - The utilization of a 3-dimensional noncoplanar treatment plan to avoid pacemaker
      complications.
AB  - Treatment planning of thoracic patients having upper lobe lesions and a pacemaker
      presents quite a challenge. It is necessary to avoid the pacemaker as well as
      other critical structures in order to deliver the prescribed dose for local
      control. This case demonstrates the utilization of noncoplanar beams and
      asymmetric fields to limit the radiation dose to the pacemaker. The dose to the
      pacemaker was quantified by the information represented in the dose-volume
      histogram (DVH) of the computerized tomography (CT)-based treatment plan. The
      delivered dose was verified utilizing thermoluminescent dosimeters (TLDs) placed
      on the patient. Measurements of the daily dose from all of the treatment fields
      to include the open jaws during portal imaging were taken to sum the total
      possible dose the pacemaker may receive. The allowable dose to the pacemaker is
      dependent upon individual manufacturers. It was found that with proper treatment
      planning and appropriate precautions, a patient is able to receive full
      prescribed dose with no risks of interfering with the pacemaker function.

PMID- 15191755
TI  - 3D naming system.
AB  - Technology now allows vast amounts of information to be shared among individuals
      and applications with great speed. The need for nomenclature that is conducive
      for clear and accurate communication is critical. This is especially true in
      medicine, and radiation oncology in particular, where miscommunication can cause
      significant harm to patients. Frequent sharing of radiation treatment information
      occurs not only between members within a department, but also between different
      treatment centers. Physicians share techniques with each other at conferences, in
      publications, and over the phone. Retrospective investigation may be done
      evaluating various treatment courses. Descriptions of treatment beams are perhaps
      the most commonly shared information about a patient's course of treatment in
      radiation oncology. This paper highlights the advantages of using a 3D naming
      system to identify treatment beams with unique names.

PMID- 15191756
TI  - Dosage along the matchline between upper head-and-neck IMRT fields and
      conventional supraclavicular fields.
AB  - There is concern about dose along the matchline when upper head-and-neck fields
      are treated with IMRT and the lower (supraclavicular) field is treated with a
      conventional fixed beam. An anatomical phantom was scanned and planned with IMRT
      upper head-and-neck fields and a fixed-beam supraclavicular field. The plans were
      fused and dose was calculated to points along the matchline. These doses were
      compared with thermolaminescent dosimetry measurements in the phantom, as the
      phantom was treated according to the plans.

PMID- 15191757
TI  - A comparative study of surface dose and dose distribution for intact breast
      following irradiation with field-in-field technique vs. the use of conventional
      wedges.
AB  - Dose to the contalateral breast is a traditional concern with the use of wedges
      in breast irradiation. A solution is to treat using field-in-field technique
      (segmental dose), which also provides a more uniform dose distribution to the
      irradiated volume. In this experiment, an anatomical phantom was scanned,
      planned, and treated using 3 different treatment techniques. Thermoluminescent
      dosimetry was used for verification and to measure skin surface dose on both
      breasts.

PMID- 15191758
TI  - Comparison of three brachytherapy gynecological intercavitary treatment planning
      systems.
AB  - In preparation to change treatment planning systems for gynecological
      intracavitary insertion dosimetry, 3 patients were planned on 3 systems. The GE
      Target II, BrachyVision, and ADAC Pinnacle were the systems used. The dose
      distributions to several points of interest were calculated and compared. We
      analyzed the data sets to assess the differences and found that they were
      insignificant, mostly due to human error during digitization and calculation
      rounding.

PMID- 15191759
TI  - Linearity and uniformity response as an indicator of performance for Agfa ADC
      MD10 computed radiography plates.
AB  - Computed radiography (CR) plates are currently used in radiation therapy clinics
      to acquire digital radiographic images for the purpose of verifying the treatment
      field size, shape, and location. Each CR plate may be used numerous times, and
      the use of these digital images allows for easy storage and retrieval of patient
      data. Over prolonged repeat exposures of the CR plates, however, the image
      quality begins to degrade, making it increasingly more difficult for the
      therapists and physicians to determine where one anatomical structure begins, and
      the other ends. The purpose of this project was to analyze and compare the
      linearity and uniformity responses of new CR plates, versus CR plates that have
      been used clinically for a period of 2 years, and determine whether linearity or
      uniformity response may be used as an indicator of image quality degradation. To
      determine this, 44 old Agfa MD10 CR plates and 56 new Agfa MD10 CR plates were
      tested. When comparing the results of the uniformity test, we found both the old
      and the new plates varied from approximately 0.5% to 3.2%. When comparing the
      results of the linearity test, we found that the correlation coefficient, R(2),
      for both the old and the new plates varied from approximately 0.996 to 0.998,
      with the mean values being 0.9972 and 0.9979, respectively. We concluded that
      linearity and uniformity response cannot be used as an effective method for the
      evaluation of CR plate performance. Additional research is currently underway to
      evaluate various other methods of assessing CR plate performance.

PMID- 15191760
TI  - A retrospective analysis to determine if the timing of H&D curve production has a
      clinically significant effect on the percent difference in agreement of isodose
      delivery for film-based IMRT QA.
AB  - The current practice of film-based intensity-modulated radiation therapy (IMRT)
      quality assurance (QA) involves exposing the QA phantom and subsequently exposing
      a series of small fields to produce an H&D curve. Both of these procedures
      currently are completed on the same day. To avoid the need to produce several H&D
      curves, our current practice is to accumulate at least 10 IMRT cases to perform
      the QA deliveries concurrently, thereby requiring that we only expose a single
      film to provide an H&D curve to be utilized for all 10 cases. Our current
      standard requires that the IMRT QA be completed prior to the first treatment
      delivery. This standard precludes the facilitation of the possible accumulation
      of IMRT cases, thereby mandating that we expose many more films for H&D curves.
      This project will investigate the possibility of applying H&D curves exposed on
      different days than the IMRT QA. We will determine the percent difference between
      IMRT QA isodose agreement with planned isodose delivery, given that the H&D curve
      was performed concurrently VS. the IMRT QA isodose agreement with planned isodose
      delivery with several different H&D curves taken on random dates. This analysis
      will be performed using the RIT software. The goal of the project is to determine
      if the timing of H&D curve production has a clinically significant effect on the
      percent difference in agreement of isodose delivery for IMRT QA. We will not be
      recommending the parameters that will define clinical significance but rather
      report the effect for individual discernment.

PMID- 15191761
TI  - Comparison of two treatment techniques for breast irradiation including internal
      mammary nodes.
AB  - Techniques to treat breast cancer inclusive of the internal mammary lymph node
      chain (IMC) vary. This study compared a presently accepted technique implemented
      at the Radiation Oncology Department at Barnes-Jewish Hospital/Washington
      University School of Medicine (BJ/WU) to a proposed technique for irradiation of
      breast tissue and the IMC. The present technique consists of parallel-opposed
      breast tangential beams in combination with photon and electron IMC fields angled
      along the chest wall. The proposed method involves a wide medial tangent field
      covering the IMC, with an angled electron IMC field for a portion of the
      treatment regimen and an opposed lateral breast-only tangent. This technique uses
      a multileaf collimation (MLC) reduction to treat the IMC aspect following the
      wide medial tangent, to supplement the IMC to a tumorcidal dose. These techniques
      were compared by reviewing isodoses with subsequent isodensity confirmation.
      Computerized tomography imaging sets of patients with various body types (chest
      wall, small and large breasts) for left-sided tumors were planned using a three
      dimensional treatment planning system (FOCUS, Computerized Medical Systems). The
      plans were evaluated by comparing irradiated heart and lung volumes and the
      respective dose distribution at the IMC field/medial tangent junction. Specific
      treatment aids and photon/electron energies were employed to produce desirable
      isodose distributions, with a dose prescription of 4680-cGy total dose. The
      efficiency of the radiation treatments itself was also evaluated. The proposed
      technique decreases treatment time by eliminating an additional IMC field that
      involves repositioning and placement of a block. Phantom-based film isodensity
      measurements were evaluated to validate the calculated dosimetry for these
      techniques.

PMID- 15191762
TI  - IMRT for the treatment of prostate cancer: a comparison of a forward-planned
      technique and an inverse-planned technique utilizing a dose gradient method.
AB  - Radiation therapy has been a major treatment option for patients with prostate
      cancer with documented efficacy over the last 30 years. Recent research has shown
      a correlation between improved local control, disease-free survival, and overall
      survival and dose delivered. Excessive dose to the rectum is one of the leading
      causes of morbidity in the treatment of prostate cancer. The RTOG and others have
      suggested dose limitations based on various treatment parameters. Intensity
      modulated radiation therapy (IMRT) is becoming more widely used, with the goal of
      improving dose coverage while limiting morbidity. In an effort to evaluate our
      inverse-planning technique relative to our forward-planned technique based on
      rectal dose, 2 plans were generated on 10 patients. One plan was generated with 9
      field forward planning, using 2 posterior obliques to decrease dose to the
      rectum. The other plan utilized inverse IMRTplanning. To evaluate dose to the
      rectum, we compared the dose gradient from the posterior edge of the prostate
      across the anterior third of the rectal wall. This gradient, which is not part of
      the IMRT planning objectives, proved useful in assessing plan differences, and
      led to new dose objectives for certain IMRT plans.

PMID- 15191763
TI  - The PLUNC 3D treatment planning system: a dynamic alternative to commercially
      available systems.
AB  - Three-dimensional (3D) treatment planning is an integral step in the treatment of
      various cancers when radiation is prescribed as either the primary or adjunctive
      modality, especially when the gross tumor volume lies in a difficult to reach
      area or is proximal to critical bodily structures. Today, 3D systems have made it
      possible to more precisely localize tumors in order to treat a higher ratio of
      cancer cells to normal tissue. Over the past 15 years, these systems have evolved
      into complex tools that utilize powerful computational algorithms that offer
      diverse functional capabilities, while simultaneously attempting to maintain a
      user-friendly quality. A major disadvantage of commercial systems is that users
      do not have access to the programming source code, resulting in significantly
      limited clinical and technological flexibility. As an alternative, in-house
      systems such as Plan-UNC (PLUNC) offer optimal flexibility that is vital to
      research institutions and important to treatment facilities. Despite this
      weakness, commercially available systems have become the norm because their
      commissioning time is significantly less and because many facilities do not have
      computer experts on-site.

PMID- 15191764
TI  - The potential influence of cell protectors for dose escalation in cancer therapy:
      an analysis of amifostine.
AB  - The attempt to increase the therapeutic ratio in an effort to improve survival or
      quality of life is the goal of modern cancer therapy. It is commonly accepted
      that local and systemic tumor control would increase if the dose intensity of
      antineoplastic drugs, radiation therapy, or the combination were increased.
      Radiation dose escalation using intensity-modulated radiation therapy (IMRT),
      accelerated or hypofractionated radiation schemes, and multidrug chemotherapy
      regimens are being used to try to increase tumor kill while inflicting minimal
      injury to normal tissue. Modern chemoradiation techniques have led to improved
      local regional control and increased cure rates, but the potentially severe and
      debilitating adverse effects of the therapies prevent them from reaching the
      ultimate goal of curing the disease while leaving the patient with a good quality
      of life. Cell protectants such as amifostine function by reducing the effects of
      therapy on normal cells while maintaining tumor sensitivity to the therapy. In
      various studies, amifostine has been analyzed and appears to be a potentially
      powerful adjuvant to current cancer therapy. Administering amifostine may allow
      dose escalation with less or equal risk to surrounding normal tissues. This could
      improve therapeutic efficacy, survival, and quality of life for cancer patients.

PMID- 15191765
TI  - [We love so much... plastic surgery].

PMID- 15191766
TI  - [A "small" legend. of "Annales de Chirurgie Plastique Esthetique"].

PMID- 15191767
TI  - Stem cells in unstable angina: the dynamic duo.

PMID- 15191768
TI  - Time is muscle in primary PCI: the strength of the evidence grows.

PMID- 15191769
TI  - Circulating endothelial progenitor cells in patients with unstable angina:
      association with systemic inflammation.
AB  - BACKGROUND: Endothelial progenitor cells (EPC) are present in peripheral blood
      and can develop a functional endothelial phenotype. The number and function of
      circulating EPCs are altered in atherosclerosis, diabetes, and after myocardial
      infarction and EPCs have been shown to promote postnatal angiogenesis and
      vasculogenesis. We investigated the number and adhesive properties of EPCs from
      patients with unstable angina and no evidence of cardiac necrosis. METHODS AND
      RESULTS: Patients were selected with unstable angina (n=29) and no evidence of
      cardiac necrosis, and controls with stable angina (n=12) and atherosclerotic risk
      factors, medication use, and coronary vessel involvement similar to patients.
      Circulating EPC numbers were determined by colony-forming unit assay and their
      adhesive properties were evaluated by EPC capacity to bind immobilised
      fibronectin. High-sensitivity C-reactive protein (hsCRP) was determined in all
      patients. Circulating EPCs were significantly increased in patients with unstable
      as compared with stable angina (24.5+/-2.6 vs. 13.3+/-2.9, respectively). Seven
      unstable angina patients followed up for 3 months after clinical stabilisation
      exhibited a reduction of close to 50% in circulating EPC numbers. The adhesive
      capacity of EPCs from patients with unstable and stable angina did not differ. A
      positive correlation was found between systemic CRP levels and circulating EPC
      numbers, but not their adhesive capacity. CONCLUSION: Patients with unstable
      angina and no evidence of cardiac necrosis exhibited increased circulating EPCs.
      Systemic inflammation, in addition to recognised growth factors, could play a
      role in the peripheral mobilisation of EPCs in patients with anginal syndromes.

PMID- 15191770
TI  - Time-to-treatment significantly affects the extent of ST-segment resolution and
      myocardial blush in patients with acute myocardial infarction treated by primary
      angioplasty.
AB  - AIMS: The prognostic role of time-to-treatment in primary angioplasty is still a
      matter of debate. The aim of our study was to evaluate the relationship between
      time-to-treatment and myocardial perfusion in patients with ST-segment-elevation
      myocardial infarction (STEMI) treated by primary angioplasty. METHODS AND
      RESULTS: Our study population consisted of 1072 patients with STEMI treated by
      primary angioplasty from 1997 to 2001. Myocardial perfusion was evaluated by
      using ST-segment resolution and myocardial blush grade. Time-to-treatment was
      defined as the time from symptom-onset to the first balloon inflation. Time-to
      treatment was significantly associated with the extent of ST-segment resolution,
      myocardial blush grade, enzymatic infarct size, and 1-year mortality. After
      adjustment for baseline confounding factors, time-to-treatment was still
      associated with impaired ST-segment resolution (adjusted OR [95% CI]=1.01 [1.01
      1.02], p<0.001) and myocardial blush (adjusted OR [95% CI]=1.01 [1.01-1.02],
      p<0.0001). CONCLUSIONS: This study shows that in patients with STEMI treated by
      primary angioplasty prolonged ischaemic time is associated with impaired
      myocardial perfusion, larger infarct size, and higher 1-year mortality.
      Therefore, all efforts should be made to shorten ischaemic time as much as
      possible to achieve better myocardial perfusion and myocardial salvage in primary
      angioplasty for STEMI.

PMID- 15191771
TI  - Risk of decompression illness among 230 divers in relation to the presence and
      size of patent foramen ovale.
AB  - BACKGROUND: The risk of developing decompression illness (DCI) in divers with a
      patent foramen ovale (PFO) has not been directly determined so far; neither has
      it been assessed in relation to the PFO's size. METHODS: In 230 scuba divers (age
      39+/-8 years), contrast trans-oesophageal echocardiography (TEE) was performed
      for the detection and size grading (0-3) of PFO. Prior to TEE, the study
      individuals answered a detailed questionnaire about their health status and about
      their diving habits and accidents. For inclusion into the study, > or =200 dives
      and strict adherence to decompression tables were required. RESULTS: Sixty-three
      divers (27%) had a PFO. Overall, the absolute risk of suffering a DCI event was
      2.5 per 10(4) dives. There were 18 divers (29%) with, and 10 divers (6%) without,
      PFO who had experienced > or =1 major DCI events P=0.016. In the group with PFO,
      the incidence per 10(4) dives of a major DCI, a DCI lasting longer than 24 h and
      of being treated in a decompression chamber amounted to 5.1 (median 0,
      interquartile range [IQR] 0-10.0), 1.9 (median 0, IQR 0-4.0) and 3.6 (median 0,
      IQR 0-9.8), respectively and was 4.8-12.9-fold higher than in the group without
      PFO (P<0.001). The risk of suffering a major DCI, of a DCI lasting longer than 24
      h and of being treated by recompression increased with rising PFO size.
      CONCLUSION: The presence of a PFO is related to a low absolute risk of suffering
      five major DCI events per 10(4) dives, the odds of which is five times as high as
      in divers without PFO. The risk of suffering a major DCI parallels PFO size.

PMID- 15191773
TI  - Pre-procedural plasma levels of C-reactive protein and interleukin-6 do not
      predict late coronary angiographic restenosis after elective stenting.
AB  - AIMS: Inflammatory markers may serve as an important prognostic predictor in
      patients with coronary heart diseases. In patients undergoing coronary
      interventions, it has been shown that baseline C-reactive protein (CRP) could
      predict late clinical restenosis. Only a few small studies have examined the
      possible relationship with angiographic restenosis. In patients with stable
      angina pectoris,we examined whether baseline CRP and IL-6 predict late coronary
      angiographic restenosis after stenting. METHODS AND RESULTS: Pre-procedural
      plasma levels of CRP and IL-6 were measured in 216 patients with stable angina
      pectoris undergoing elective coronary stenting. Angiographic follow-up was
      performed in all patients at 6 months. Baseline CRP levels were 6.15 +/- 0.78
      mg/L versus 5.24 +/- 1.17 mg/L in the patent and restenosis groups, respectively
      (P=0.64). IL-6 levels were 0.46 +/- 0.03 ng/L versus 0.40 +/- 0.07 ng/L in the
      patent and restenosis groups, respectively (P=0.50). CRP levels were obtained
      again at the time of angiographic follow-up and were found to be similar in both
      groups (2.89 +/- 0.29 mg/L versus 2.61 +/- 0.63 mg/L, P=0.72). Moreover, in a sub
      group of 43 patients, serial blood samples were obtained at several time points
      after the procedure up to 6 months. Both CRP and IL-6 plasma levels increased
      significantly in response to the procedure. CRP levels peaked at 3 days (11.27 +/
      1.53 mg/L versus 4.26 +/- 0.72 mg/L at baseline, P<0.0001). IL-6 levels reached
      maximum values after 24 h (1.08 +/- 0.14 ng/L versus 0.53 +/- 0.08 ng/L at
      baseline, P<0.0001). However, in this sub-group of patients, neither peak CRP nor
      IL-6 levels were found to predict late angiographic restenosis. CONCLUSIONS:
      Coronary stenting is associated with transient increases in both CRP and IL-6
      levels. However, pre-procedural CRP and IL-6 levels do not predict late coronary
      angiographic restenosis.

PMID- 15191772
TI  - Haemoglobin predicts survival in patients with chronic heart failure: a substudy
      of the ELITE II trial.
AB  - AIMS: The correction of anaemia in chronic heart failure (CHF) has been suggested
      to be associated with an improvement in symptoms and cardiac function. We aimed
      to investigate the relationship between the concentration of haemoglobin and
      survival in CHF. METHODS AND RESULTS: We analysed haemoglobin concentrations in
      3044 patients recruited in the Evaluation of Losartan In The Elderly (ELITE II)
      trial. Patients of mean age 71.5 +/- 6.8 years (+/-SD) and New York Heart
      Association (NYHA) class 2.5 +/- 0.6 were enrolled from June 1997 to May 1998 and
      followed-up for survival (range 1-780 days, median 551). In univariate analysis,
      age, NYHA class, serum creatinine, left ventricular ejection fraction (all
      P<0.0001) and sex (P=0.046) all predicted survival. Haemoglobin as a continuous
      variable for all patients was not a significant prognostic marker (P=0.26).
      However, sub-dividing patients according to 1.0 g/dL increments of haemoglobin
      revealed that the survival relationship was non-linear. The results from the
      polynomial regression suggest that the optimal interval is a symmetric one
      centred around 14.5 g/dL. This was independent of age, sex, NYHA class, left
      ventricular ejection fraction, creatinine, co-existing chronic obstructive
      pulmonary disease and treatment allocation (P<0.001). There was a minor fall in
      plasma haemoglobin at the 12-month follow-up (mean change for all patients 0.3 +/
      2.2 g/dL, P<0.0001), with no difference between captopril and losartan groups
      (P>0.3). CONCLUSION: Haemoglobin is an independent predictor of mortality in CHF
      patients, with anaemic and polycythaemic patients having the worst survival.

PMID- 15191774
TI  - Risks and benefits of optimised medical and revascularisation therapy in elderly
      patients with angina--on-treatment analysis of the TIME trial.
AB  - AIM: To assess treatment effects of optimised medical therapy and PCI or CABG
      surgery on one-year outcome in patients 75 years old with chronic angina. METHODS
      AND RESULTS: On-treatment analysis of the TIME data: all re-vascularised patients
      (REVASC n=174: 112 randomised to revascularisation and 62 to drugs with late
      revascularisation) were compared to all patients on continued drug therapy (MED
      n=127: 86 randomised to drugs and 41 to revascularisation only). Baseline
      characteristics of both groups were similar (age 80 +/- 4 years). Risk of death
      at one year (adjusted hazard ratio (HR)=1.31; 95%-CI: 0.58-2.99; P=0.52) and of
      death/infarction (adjusted hazard RATIO=1.77; 95%-CI 0.91-3.41; P=0.09) were
      comparable between REVASC and MED patients. Furthermore, the risk of death within
      30 days was even slightly lower among REVASC patients (unadjusted hazard
      RATIO=0.73; 95%-CI: 0.21-2.53; P=0.98). Overall, REVASC patients had greater
      improvements in symptoms and well-being than MED patients (P<0.01). Surgical
      patients had similar mortality rates as angioplasty patients, but they also had
      greater symptomatic improvements (P<0.01). CONCLUSION: Treated medically, elderly
      patients with chronic angina have a similarly high 30-day and one-year mortality
      as patients of the same age being re-vascularised; however, they can expect lower
      improvements in symptoms and well being.

PMID- 15191775
TI  - Accuracy of thin-slice computed tomography in the detection of coronary stenoses.
AB  - AIM: Our aim was to investigate the accuracy of multislice spiral computed
      tomography (MSCT) in the detection of significant (>50%) coronary stenosis using
      a scanner equipped for 16 x 0.625 mm collimation. METHODS: In 64 patients (59
      male, mean age 58 +/- 5 years) with suspected coronary artery disease, MSCT (GE
      Light Speed-16, collimation: 16 x 0.625 mm) was performed 20 +/- 5 days before
      coronary angiography (CAG). Only angiographic segments >1.5 mm were considered
      for analysis. RESULTS: In all patients, MSCT was carried out without
      complications. Three patients were excluded from the analysis. Of 729
      angiographic segments, 613 (84%) were judged evaluable by MSCT. Considering only
      the segments judged evaluable, the sensitivity was 89%, specificity 98%, positive
      predictive value 90%, and negative predictive value 98%. Including all segments
      in the analysis (evaluable and nonevaluable), sensitivity was 78%. CONCLUSIONS:
      Using a scanner with a collimation of 16 x 0.625 mm, our study confirms the
      potential role of MSCT in the detection of significant coronary stenosis with a
      sensitivity of 89% and a very high specificity (98%). Exclusion criteria and less
      than full evaluability of the coronary arteries must still be considered
      limitations of the method.

PMID- 15191776
TI  - Haemostatic/inflammatory markers predict 10-year risk of IHD at least as well as
      lipids: the Caerphilly collaborative studies.
AB  - AIMS: We compare the predictive values of plasma lipids (total and HDL
      cholesterol, triglycerides) and three haemostatic/inflammatory risk markers for
      subsequent ischaemic heart disease (IHD). METHODS AND RESULTS: Two UK populations
      totalling 4860 men were screened for evidence of IHD between 1979 and 1983. Men
      were followed over 10 years and validated coronary events were recorded. Risk
      estimates were made using relative odds, receiver operating characteristic (ROC)
      curves and deciles of risk. Regression dilution effects were also examined. By 10
      years, 525 men had a coronary event (fatal, non-fatal or silent myocardial
      infarction, MI). Two alternative multivariate models were compared - a lipid
      model (total, HDL-cholesterol, triglyceride) and a haemostatic/inflammatory model
      (fibrinogen, viscosity and white cell count). 'Correction' for regression
      dilution increased relative odds for most risk factors. In the distribution of
      predicted risk, using established risk factors in conjunction with either lipid
      or haemostatic/inflammatory factors, the deciles of risk analysis showed that the
      observed 10-year risk of IHD was 34-35% in men in the top tenth, compared to 2-3%
      in the lowest tenth of the distribution. CONCLUSION: At the 10 years' follow-up,
      major, haemostatic/inflammatory risk factors showed a graded relationship to
      incident IHD that was at least as strong as that given by plasma lipids.
      Haemostatic/inflammatory factors provide possible additional targets for
      intervention.

PMID- 15191777
TI  - Outcome of patients after surgical closure of ventricular septal defect at young
      age: longitudinal follow-up of 22-34 years.
AB  - BACKGROUND: Long-term survival and clinical outcome after surgical closure of a
      VSD is poorly documented. Such data are important for the future perspectives,
      medical care, employability, and insurability of these patients. METHODS: 176
      consecutive patients underwent surgical closure of an isolated VSD between 1968
      and 1980 in our hospital. A systematic follow-up study was performed in 1990 and
      again in 2001. FINDINGS: Late survival was poorer than in the general population.
      Pulmonary hypertension and right ventricular hypertrophy were present in the 4
      patients who died suddenly, late after operation. During follow-up no new
      pulmonary hypertension became manifest. Re-operations were necessary in 6%. Some
      patients (4%) developed sinus node disease late after repair, requiring pacemaker
      implantation. At last follow-up (91 survivors) 92% of the patients were in NYHA
      class I. Pulmonary hypertension was found in 4%, and aorta insufficiency in 16%.
      Patients experienced difficulties when applying for insurance. CONCLUSION: Among
      patients with surgically repaired VSDs, late results were good, although some
      late sudden deaths occurred in the patients with pulmonary hypertension.
      Furthermore, some patients developed sinus node disease late after repair,
      requiring pacemaker implantation. Employability is good, but pregnancy and
      insurance matters need further attention.

PMID- 15191778
TI  - Limited thoracotomy as a second choice alternative to transvenous implant for
      cardiac resynchronisation therapy delivery.
AB  - AIMS: Left ventricular (LV) pacing via transvenous implantation has an overall
      success rate ranging from 88% to 92%. The aim of this study was to assess whether
      LV pacing via limited thoracotomy would be feasible and safe when used on a
      routine basis for those cases in which standard transvenous procedures proved to
      be ineffective or unsatisfactory. METHODS AND RESULTS: We enrolled 33 patients (8
      females, 65+/-10 years) who experienced a transvenous implantation failure. All
      patients underwent a limited thoracotomy and an epicardial lead was implanted.
      The procedure time was 51+/-28 min. No surgical or post-operative complications
      occurred and optimal lateral position was achieved for all patients. In the 12
      months follow-up period, 5 patients died from refractory heart failure, the
      remaining patients did not experience complications. At implant, the mean pacing
      threshold was 1.3+/-0.7 V, bi-ventricular pacing impedance was 476+/-201 Omega
      and R-wave amplitude was 15.0+/-6.1 mV. No significant differences were found in
      any of the electrical parameters between baseline and follow-up. Significant
      improvement was observed in functional and echocardiographic parameters.
      CONCLUSION: Our results suggest that a combined approach to cardiac
      resynchronisation therapy delivery, including a transvenous attempt followed by a
      back up thoracotomic procedure, could potentially guarantee the success.

PMID- 15191779
TI  - Severe bradyarrhythmias in patients with sleep apnoea: the effect of continuous
      positive airway pressure treatment: a long-term evaluation using an insertable
      loop recorder.
AB  - AIM: In this new era of insertable loop recorders, we studied obstructive sleep
      apnoea-hypopnoea syndrome (OSAHS) patients in order to evaluate their arrhythmias
      and the beneficial effect of Continuous Positive Airway Pressure treatment
      (CPAP), over a long-term period. METHODS AND RESULTS: We enrolled 23 patients (16
      men, 50 +/- 11 years) with moderate and severe OSAHS. In all patients, an
      insertable loop recorder capable of monitoring the heart rhythm for 16 months was
      implanted. Cardiac pauses >3 s and bradycardic episodes <40 bpm during a 2-month
      period before, and for 14 months after, the CPAP application, were noted. In each
      period, the patients underwent two 24-h Holter recordings. Before treatment, 11
      patients (47%) revealed severe cardiac rhythm disturbances, mostly nocturnal.
      Holter recordings showed disturbances in only 3 (13%) patients (P=0.039), those
      in whom the insertable loop device had recorded frequent episodes. Eight weeks
      after the initiation of treatment, the total number of the recorded episodes
      tended to decrease while, during the last 6 months of the follow-up, no episodes
      were recorded. CONCLUSION: Approximately half of OSAHS patients evidence severe
      cardiac rhythm disturbances, which are significantly reduced by CPAP. Holter
      recordings seem unable to precisely describe the incidence of severe brady
      arrhythmias and the effect of treatment.

PMID- 15191780
TI  - Terminology for high-risk and vulnerable coronary artery plaques. Report of a
      meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece.
AB  - A group of investigators met for two days in Santorini, Greece, to discuss
      progress in the field of identification and treatment of high risk/vulnerable
      atherosclerotic plaques and patients. Many differences in the manner in which
      terms are being utilized were noted. It was recognized that increased
      understanding of the pathophysiology of coronary thrombosis and onset of acute
      coronary syndromes has created the need for agreement on nomenclature. The
      participants spent considerable time discussing the topic and reached agreement
      on their own usage of the terms as described below. It is the hope that this
      usage might be of value to the larger community of scientists working in this
      field, and that widespread adoption of a common nomenclature would accelerate
      progress in the prevention of acute coronary events.

PMID- 15191781
TI  - B-type natriuretic peptide serum levels in acute heart failure.

PMID- 15191783
TI  - Atrial remodeling in persistent atrial fibrillation: the potential role of
      aldosterone.

PMID- 15191785
TI  - Veterinary drug delivery: Part VI.

PMID- 15191786
TI  - Sustained release veterinary parenteral products.
AB  - Controlled release parenteral dosage forms have application in veterinary
      medicine. Systems that minimize the need for repeated injections while achieving
      therapeutic effects for extended periods offer benefits that make commercial
      development of these products desirable. While some products have already found
      commercial success, others will result from application of new controlled release
      technologies. This review highlights the formulation and technology challenges in
      developing some of these controlled release technologies into products. Further,
      examples of application of controlled release technologies in the veterinary
      field are discussed.

PMID- 15191787
TI  - Current status and potential application of ISCOMs in veterinary medicine.
AB  - The immune stimulating complex (ISCOM) is a 40 nm nanoparticle used as a delivery
      system for vaccine antigens, targeting the immune system both after parenteral
      and mucosal administration. The ISCOM is made up of saponin, lipids and antigen
      usually held together by hydrophobic interaction between these three components.
      The compulsory elements to form the ISCOM structure are cholesterol and saponin.
      When the antigen is omitted the ISCOM-MATRIX is formed. There are a number of
      saponins that can form ISCOMs, and many other substances (including antigens,
      targeting and immuno-modulating molecules) can be incorporated into the ISCOM
      provided they are hydrophobic or rendered to be hydrophobic. Thus, it is possible
      to create ISCOM particles with different properties. After parenteral
      immunisation of the ISCOM, the T cell response is first detected in the draining
      lymph node. Subsequently, the T cell response is localised to the spleen, while
      the B cell response is first found both in the draining lymph nodes and in the
      spleen. Up to 50 days later, the majority of the antibody producing cells is
      found in the bone marrow (BM). In contrast, antigens that have been adjuvanted in
      an oil emulsion, limit the T cell response to the draining lymph nodes while the
      B cell response is found in the draining lymph nodes and spleen, but not in the
      BM. The ISCOM efficiently evokes CD8+, MHC class 1 restricted T cell response.
      The deposit of antigens both to the endosomal vesicles and to the cytosol of
      antigen presenting cells (APCs) explains why both T helper cells (vesicles) and
      cytotoxic T lymphocytes (cytosol) are efficiently induced by ISCOMs. The T helper
      (Th) cell response is balanced in the sense that both Th1 and Th2 cells are
      induced. Prominent IL-12 production by cells in the innate system is a
      characteristic reaction induced by ISCOMs, promoting the development of a strong
      Th1 response. After mucosal administration by the intranasal or the intestinal
      routes, the ISCOM induces strong specific mucosal IgA responses in local and
      remote mucosal surfaces. Also T cell responses are evoked by the mucosal
      administration. A large number of experimental ISCOM vaccines have been tested
      and protection has been induced against a number of pathogens in various species
      including chronic and persistent infections exemplified by human immune
      deficiency virus 1 (HIV-1), and 2 (HIV-2) and simian immune deficiency virus
      (SIV) in primates, and various herpes virus infections in several species. In
      contrast to a conventional rabies virus vaccine the ISCOM rabies formulation
      protected mice after exposure to the virulent virus. Recently, experimental ISCOM
      vaccines were shown to efficiently induce immune response in newborns of murine
      and bovine species in the presence of maternal antibodies, while conventional
      vaccines have failed. ISCOM vaccines are on the market for horses and cattle and
      several other ISCOM vaccines are under development. Since the ISCOM and the ISCOM
      MATRIX can be blended with live attenuated vaccine antigens without hampering the
      proliferation of the live vaccine antigens, it opens the possibility to use the
      ISCOM adjuvant system in a mixture of live and killed vaccine antigens.

PMID- 15191788
TI  - Companion animal physiology and dosage form performance.
AB  - Among the most critical parameters for any drug candidate are tolerability, dose,
      solubility and permeability. For controlled release formulations,
      gastrointestinal transit is an added hurdle. While we might assume that
      intestinal transit is independent of the drug candidate, the relative importance
      of gastrointestinal transit time (GITT) depends directly on the other parameters.
      For example, a formulation of a drug with low solubility (LS) and/or low
      permeability (LP) characteristics might provide the required systemic
      concentrations when administered with food, but not if administered on an empty
      stomach. In the LS case, the drug may require the solubilizing effects of
      increased fluid and bile salts that accompany the meal. Likewise, a controlled
      release formulation of a drug with a region of preferred absorption may empty
      from the fasted stomach and move beyond the region before drug release is
      complete. Companion animals (e.g. cats and dogs) differ from humans and each
      other with respect to GITT, food effects, eating habit influences, breed and size
      variability, gastric pH, intestinal enzymes, GI permeability and absorption
      regions. This review examines how the anatomy and physiology of companion animals
      relates to the performance of orally administered immediate and controlled
      release formulations. Examples are presented of techniques used to predict the
      dose and acceptable solubility of drug candidates, and the performance of
      formulations in companion animals.

PMID- 15191789
TI  - Oral delivery of medications to companion animals: palatability considerations.
AB  - There is an increased need for highly palatable solid oral dosage forms for
      companion animals, which are voluntarily accepted by the dog or cat, either from
      a feeding bowl or from the outstretched hand of the pet owner. Such dosage forms
      represent an emerging trend in companion animal formulations with major impact on
      medical needs such as convenience and compliance, particularly for chronically
      administered medications, and on marketing needs such as product differentiation.
      This review focuses on the science of taste, food and flavor preferences of dogs
      and cats, and palatability testing, in the context of applying these principles
      to the development of an oral palatable tablet for companion animals.

PMID- 15191790
TI  - Issues and challenges in developing ruminal drug delivery systems.
AB  - Ruminants have a specialised digestive system that contains anaerobic bacteria
      and protozoa capable of digesting the cellulosic materials that are so common in
      plant materials. In addition, their distinct digestive system can change the
      metabolism and mode of action of some nutrients, medicines or other bioactive
      materials when delivered orally or may provide opportunities for alternative oral
      dosing strategies. In particular, there is interest in administering a relatively
      large depot of some drugs into the rumen, which then provides for a prolonged and
      sustained release of small quantities of these drugs over time. Any strategy to
      develop a new ruminal drug delivery system must take into account the
      characteristics of the digestive system of ruminants and its specific bioactive
      application. For example, in the case of products to control parasitic
      infections, the development of the host's immunity against the nematodes, which
      can be acquired during the pasture season, must be considered; likewise, where
      pharmacologically active materials are used to manipulate a particular metabolic
      or biochemical process, one must always be aware of interactions with other
      processes, which might eventuate. This article reviews the necessary concepts,
      the issues and the challenges to construct ruminal drug delivery systems.

PMID- 15191791
TI  - Membrane transporter/receptor-targeted prodrug design: strategies for human and
      veterinary drug development.
AB  - The bioavailability of drugs is often severely limited due to the presence of
      biological barriers in the form of epithelial tight junctions, efflux proteins
      and enzymatic degradation. Physicochemical properties, such as lipophilicity,
      molecular weight, charge, etc., also play key roles in determining the permeation
      properties of drug candidates. As a result, many potential drug candidates may be
      dropped from the initial screening portfolio. Prodrug derivatization targeting
      transporters and receptors expressed on mammalian cells holds tremendous
      potential. Enhanced cellular delivery can significantly improve drug absorption.
      Such approaches of drug targeting and delivery have been the subject of intense
      research. Various prodrugs have been designed that demonstrate enhanced
      bioavailability and tissue specificity. This approach is equally applicable to
      human and veterinary pharmaceuticals since most of the transporters and receptors
      expressed by human tissues are also expressed in animals. This review highlights
      studies conducted on the use of transporters and receptors in an effort to
      improve drug bioavailability and to develop targeted drug delivery systems.

PMID- 15191792
TI  - Biodegradable polymers and their potential use in parenteral veterinary drug
      delivery systems.
AB  - Biodegradable polymers have been extensively studied for numerous drug delivery
      systems for human health purposes. The ever-increasing value of animals to human
      society allows the application of pharmaceutical developments in the veterinary
      field from those developed in human medicine. Although many similarities between
      the human and animal health industries exist there are also notable differences.
      This paper provides an insight into the animal health market with regard to the
      challenges and special considerations associated with veterinary drug delivery.
      It also gives an overview of biodegradable polymers that are used or have been
      tested in the veterinary field. The purpose of this paper is to highlight some
      recent developments in this area and to investigate the directions in which
      veterinary pharmaceutics is heading. In particular, examples of existing
      biodegradable veterinary drug delivery systems are presented together with
      applications including intravaginal devices, injectables and implantable systems.

PMID- 15191793
TI  - Potential applications of chitosan in veterinary medicine.
AB  - Chitosan is a partially deacetylated polymer obtained from the alkaline
      deacetylation of chitin which is a glucose-based unbranched polysaccharide widely
      distributed in nature as the principal component of exoskeletons of crustaceans
      and insects as well as of cell walls of some bacteria and fungi. Chitosan
      exhibits a variety of physicochemical and biological properties resulting in
      numerous applications in fields such as waste and water treatment, agriculture,
      fabric and textiles, cosmetics, nutritional enhancement, and food processing. In
      addition to its lack of toxicity and allergenicity, and its biocompatibility,
      biodegradability and bioactivity make it a very attractive substance for diverse
      applications as a biomaterial in pharmaceutical and medical fields, where it has
      been used for systemic and local delivery of drugs and vaccines. It also has
      bioactive properties in its own right. This paper reviews current veterinary
      applications for chitosan including wound healing, bone regeneration, analgesic
      and antimicrobial effects. It also discusses the potential application of
      chitosan to drug and vaccine delivery in veterinary species. Given the
      restrictions imposed by financial and animal restraint considerations, especially
      in farming applications, the veterinary drug delivery areas most likely to
      benefit from chitosan are the delivery of chemotherapeutics such as antibiotics,
      antiparasitics, anaesthetics, painkillers and growth promotants to mucosal
      epithelium for absorption for local or systemic activity, and the delivery of
      immunomodulatory agents to the mucosal associated lymphoid tissue for induction
      or modulation of local immune responses. The properties of chitosan expected to
      enhance these functions are discussed, and the future research directions in this
      field are indicated.

PMID- 15191794
TI  - Issues and challenges in developing long-acting veterinary antibiotic
      formulations.
AB  - Antibiotics are an important class of therapeutic agents, which are used for the
      treatment of bacterial infectious diseases in a variety of animal species.
      Antibiotic therapy varies from treatment period to administration routes,
      depending on the animal species or the type of the disease being treated. Despite
      the fact that there are a wide variety of commercially available antibiotics,
      difficulties and problems associated with the administration of antibiotics to
      animals still exist. Thus, there is a great need and tremendous opportunity to
      develop long-acting antibiotic formulations for veterinary applications. In this
      review article, common approaches used to develop long-acting antibiotic
      formulations are summarized. The challenges and issues related to the development
      of these long-acting formulations are also discussed.

PMID- 15191795
TI  - Antimicrobial drug delivery in food animals and microbial food safety concerns:
      an overview of in vitro and in vivo factors potentially affecting the animal gut
      microflora.
AB  - This review provides an overview of considerations particular to the delivery of
      antimicrobial agents to food animals. Antimicrobial drugs are used in food
      animals for a variety of purposes. These drugs may have therapeutic effects
      against disease agents, or may cause changes in the structure and/or function of
      systems within the target animal. Routes of administration, quantity, duration,
      and potency of an antimicrobial drug are all important factors affecting their
      action(s) and success. Not only might targeted pathogens be affected, but also
      bacteria residing in (or on) the treated food animals, especially in the
      intestines (gastrointestinal tract microflora). Resistance to antimicrobial
      agents can occur through a number of mechanisms. The extent to which resistance
      develops is greatly affected by the amount of drug [or its metabolite(s)] a
      bacterium is exposed to, the duration of exposure, and the interaction between an
      individual antimicrobial agent and a particular bacterium. The impact of
      antimicrobial agents on the emergence of resistance in vitro and in vivo may not
      readily correlate.

PMID- 15191797
TI  - Reciprocal changes of CD44 and GAP-43 expression in the dentate gyrus inner
      molecular layer after status epilepticus in mice.
AB  - Mossy fiber sprouting (MFS), a common feature of human temporal lobe epilepsy and
      many epilepsy animal models, contributes to hippocampal hyperexcitability. The
      molecular events responsible for MFS are not well understood, although the growth
      associated protein GAP-43 has been implicated in rats. Here, we focus on the
      hyaluronan receptor CD44, which is involved in routing of retinal axons during
      development and is upregulated after injury in many tissues including brain.
      After pilocarpine-induced status epilepticus (SE) in mice most hilar neurons died
      and neuropeptide Y (NPY) immunoreactivity appeared in the dentate inner molecular
      layer (IML) after 10-31 days indicative of MFS. Strong CD44 immunoreactivity
      appeared in the IML 3 days after pilocarpine, then declined over the next 4
      weeks. Conversely, GAP-43 immunoreactivity was decreased in the IML at 3-10 days
      after pilocarpine-induced SE. After SE induced by repeated kainate injections,
      mice did not show any hilar cell loss or changes in CD44 or GAP-43 expression in
      the IML, and MFS was absent at 20-35 days. Thus, after SE in mice, early loss of
      GAP-43 and strong CD44 induction in the IML correlated with hilar cell loss and
      subsequent MFS. CD44 is one of the earliest proteins upregulated in the IML and
      coincides with early sprouting of mossy fibers, although its function is still
      unknown. We hypothesize that CD44 is involved in the response to axon terminal
      degeneration and/or neuronal reorganization preceding MFS.

PMID- 15191798
TI  - Repair of the entorhino-hippocampal projection in vitro.
AB  - The repair of axonal projections and the reconstruction of neuronal circuits
      after CNS lesions or during neurodegenerative disease are major challenges in
      restorative neuroscience. We have explored the potential of transplanted immature
      neurons to repair a specific axonal projection in an entorhino-hippocampal slice
      culture model system. When slices of immature entorhinal cortex (EC) from tau-GFP
      transgenic mice were cultured next to slices from postnatal hippocampus, an
      axonal projection from the E18 embryonic entorhinal cortex to the dentate gyrus
      of the postnatal hippocampus developed, which was similar to that observed in
      control cultures. Even more immature neuronal precursors in slices from E15
      developing cerebral cortex differentiated and established an axonal projection to
      the hippocampal slice. This projection terminated specifically in the outer
      molecular layer of the dentate gyrus, the normal target area of the entorhino
      hippocampal projection. When embryonic tissue from the presumptive brainstem area
      was used, there was still a subpopulation of fibers with a specific termination
      in the outer molecular layer, but few specific fibers were found in cocultures
      with embryonic midbrain. Our results show that very immature cortical neurons are
      potentially able to form an entorhino-hippocampal projection that terminates in a
      correct lamina-specific fashion in the dentate gyrus. These findings support the
      idea that immature neuronal precursor cells could be used for the reconstruction
      of specific neuronal circuits.

PMID- 15191799
TI  - Induction of HIF1alpha but not HIF2alpha in motoneurons after ventral funiculus
      axotomy-implication in neuronal survival strategies.
AB  - Spinal cord injury is frequently associated with local tissue hypoxia. As
      neuronal cells are susceptible to damage caused by low oxygen levels, hypoxia
      induced activation of tissue-protective factors could represent an endogenous
      mechanism for neuron survival following injury. We studied in vivo, in a rat
      model of intraspinal axotomy of motoneurons, the cell- and time-dependent
      regulation of the hypoxia-inducible transcription factors (HIFs), HIF1alpha and
      HIF2alpha, as well as one of their target genes, vascular endothelial growth
      factor (VEGF). VEGF is a potent hypoxia-regulated angiogenic growth factor with
      recently discovered neuroprotective and neurotrophic activities. While neither
      HIF1alpha, HIF2alpha, nor VEGF mRNA were detected in noninjured motoneurons, we
      found a strong induction of HIF1alpha, but not HIF2alpha mRNA in axotomized
      motoneurons. HIF1alpha expression peaked at about 7 days after injury. Moreover,
      we found increased VEGF mRNA and protein expression around and within the scar
      but also within motoneurons, peaking around 3 days after axotomy. In addition,
      increased survival of cultured motoneurons after treatment with VEGF could also
      be shown. We conclude that axotomized motoneurons in this model respond to injury
      by specific induction of HIF1alpha and VEGF expression that may provide an
      endogenous mechanism with the potential to promote motoneuron survival after
      injury.

PMID- 15191800
TI  - Partial recovery after treatment of chronic paraplegia in rat.
AB  - While acute spinal cord injury has been the object of intensive research, chronic
      spinal cord injury has received less attention although most clinical cases of
      spinal cord injury become chronic. We attempted to surgically "repair" chronic
      and acute spinal cord injury in a complete transection rat model using a multiple
      peripheral nerve grafting protocol. The lesion extent was assessed by magnetic
      resonance imaging (MRI) before the repair procedure. Rats were treated
      immediately after injury or at 2, 4, or 8 months postinjury. Standard behavioral
      methods were used to evaluate functional recovery. Two novel tests, the Bipedal
      Test and the Head-scratch test, were also employed to evaluate hindpaw
      positioning, interlimb coordination, and stepping rhythmicity, and to indicate
      rostrocaudal pathway regeneration. MRI helped guide the treatment procedure that
      was applied to animals with chronic injury. Treated animals demonstrated
      significant motor recovery. Axonal regeneration resultant to treatment was
      demonstrated histologically. The results suggest that not only acute but also
      chronic total paraplegia can be reversed to a moderate degree in rats with regard
      to hindlimb motor function.

PMID- 15191801
TI  - Insulin as an in vivo growth factor.
AB  - Insulin peptide has been identified to promote regeneration of axons in culture
      and in some in vivo model systems. Such actions have been linked to direct
      actions of insulin, or to cross occupation of closely linked IGF-1 receptors. In
      this work, we examined insulin support of peripheral nerve regenerative events in
      mice. Systemic insulin administration accelerated the reinnervation of foot
      interosseous endplates by motor axons after sciatic nerve transection and
      enhanced recovery of functional mouse hindpaw function. Similarly, insulin
      accelerated the regeneration-related maturation of myelinated fibers regrowing
      beyond a sciatic nerve crush injury. That such benefits might occur through
      direct signaling on axons was supported by immunohistochemical studies of
      expression with an antibody directed to the beta insulin receptor (IR) subunit.
      The proportion of sensory neurons expressing IRbeta increased ipsilateral to a
      similar sciatic crush injury in the L4 and L5 dorsal root ganglia. Insulin
      receptors, although widely expressed in axons, were also preferentially and
      intensely expressed on axons regrowing just beyond a peripheral nerve crush
      injury zone. The findings indicate that insulin imparts a substantial impact on
      regenerating peripheral nerve axons through upregulation of its expression
      following injury. Although the findings do not exclude insulin coactivating IGF-1
      receptors during regeneration, its own receptors are present and available for
      action on injured nerves.

PMID- 15191802
TI  - Transgenic mice overexpressing amyloid beta protein are an incomplete model of
      Alzheimer disease.
AB  - We compared lesions in elderly transgenic (tg) mice carrying the Swedish double
      mutation KM670/671NL with lesions in Alzheimer disease (AD) by histochemical and
      immunohistochemical techniques. Highly similar staining for beta-amyloid protein
      (Abeta) was observed in AD and the mouse models. The abundant amyloid deposits in
      tg mice were in a consolidated state as revealed by strong Congo red
      birefringence. In both tg mice and AD, amyloid deposits were ApoE-positive and
      were surrounded by activated astrocytes. However, Bielschowsky silver staining
      and immunostaining with tau antibodies revealed no neurofibrillary tangles (NFTs)
      in the mice as opposed to abundant NFTs in AD. The microglial pattern was also
      distinctly different. Tg mice had only weakly activated microglia, which
      expressed low levels of the complement receptor CD11b. They were gathered around
      the periphery of the deposits. In contrast, AD lesions had strongly activated
      microglia, which expressed high levels of CD11b. They were associated with the
      plaque core. Immunostaining for complement proteins was weak in tg mice but very
      strong in AD deposits. We conclude that the weak inflammatory response and
      absence of NFTs indicate that tg mice are only a limited model of AD. Therapeutic
      strategies for the treatment of AD based on tg mouse models that overexpress
      Abeta may be limited in their application.

PMID- 15191803
TI  - The ability of grafted human sympathetic neurons to synthesize and store
      dopamine: a potential mechanism for the clinical effect of sympathetic neuron
      autografts in patients with Parkinson's disease.
AB  - We have investigated the potential of autologous sympathetic neurons as a donor
      for cell therapy of Parkinson's disease (PD). Our recent study demonstrated that
      sympathetic neuron autografts increase the duration of levodopa-induced "on"
      periods with consequent reduction in the percent time spent in "off" phase. We
      also found that human sympathetic neurons grown in culture have the ability to
      convert exogenous levodopa to dopamine and to store the synthesized dopamine.
      This may explain the clinically observed prolongation in the duration of levodopa
      effects. To further analyze the mechanism for the graft-mediated effect, the
      present study investigated the metabolic function of human sympathetic ganglionic
      neurons xenografted into the dopamine (DA)-denervated striatum of rats by
      monitoring striatal levels of DA and its primary metabolite, 3,4
      dihydroxyphenylacetic acid (DOPAC), after systemic administration of levodopa. We
      also explored whether the graft-mediated effect above may last in four PD
      patients who had been given the grafts and followed for 12-36 months
      postgrafting. Clinical evaluations showed that an increase in the duration of
      levodopa-induced "on" phase is detected during a follow-up period of 12-36 months
      postgrafting in all the four patients tested. Accordingly, the percent time spent
      in "off" phase exhibited a 30-40% reduction as compared to the pregrafting
      values. The animal experiment showed that a significant increase in striatal DA
      levels is noted after systemic levodopa treatment, and that the DA levels remain
      high for longer periods of time in the grafted rats than in control animals. When
      given reserpine pretreatment, the levodopa-induced rise of striatal DA levels was
      significantly attenuated with concomitant increase in DOPAC levels. Histological
      examinations demonstrated that the grafts contain some tyrosine hydroxylase (TH)
      positive cells. These cells were also found to express aromatic-l-amino acid
      decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT), both of which
      are important molecules for the synthesis and the storage of DA, respectively.
      These results indicate that grafted sympathetic neurons can provide a site for
      both the conversion of exogenous levodopa to DA and the storage of the
      synthesized DA in the DA-denervated striatum, explaining a mechanism by which
      sympathetic neuron autografts can increase the duration of levodopa-induced "on"
      phase in PD patients.

PMID- 15191804
TI  - Radial glial cells, proliferating periventricular cells, and microglia might
      contribute to successful structural repair in the cerebral cortex of the lizard
      Gallotia galloti.
AB  - Reptiles are the only amniotic vertebrates known to be capable of spontaneous
      regeneration of the central nervous system (CNS). In this study, we analyzed the
      reactive changes of glial cells in response to a unilateral physical lesion in
      the cerebral cortex of the lizard Gallotia galloti, at 1, 3, 15, 30, 120, and 240
      days postlesion. The glial cell markers glial fibrillary acidic protein (GFAP),
      glutamine synthetase (GS), S100 protein, and tomato lectin, as well as
      proliferating cell nuclear antigen (PCNA) were used to evaluate glial changes
      occurring because of cortical lesions. A transitory and unilateral upregulation
      of GFAP and GS in reactive radial glial cells were observed from 15 to 120 days
      postlesion. In addition, reactive lectin-positive macrophage/microglia were
      observed from 1 to 120 days postlesion, whereas the expression of S100 protein
      remained unchanged throughout the examined postlesion period. The matricial zones
      closest to the lesion site, the sulcus lateralis (SL) and the sulcus
      septomedialis (SSM), showed significantly increased numbers of dividing cells at
      30 days postlesion. At 240 days postlesion, the staining pattern for PCNA, GFAP,
      GS, and tomato lectin in the lesion site became similar to that observed in
      unlesioned controls. In addition, ultrastructural data of the lesioned cortex at
      240 days postlesion indicated a structural repair process. We conclude that
      restoration of the glial framework and generation of new neurons and glial cells
      in the ventricular wall play a key role in the successful structural repair of
      the cerebral cortex of the adult lizard.

PMID- 15191805
TI  - Catecholamine release in human skin--a microdialysis study.
AB  - Dermal microdialysis might be a promising tool to investigate properties of
      sympathetic neurons in the skin as investigation of peripheral noradrenergic
      neurons in humans usually relies on highly variable vasoconstrictor reflexes or
      on indirect measurements like skin temperature recordings. To evaluate this
      technique, 21 experiments were performed in 15 healthy subjects with four
      intracutaneous microdialysis fibers (diameter, 200 microm; cutoff, 5 kDa) at
      hands or feet. After 60 min, saline perfusion tyramine at concentrations of 0.195
      to 200 microg/ml was applied for 15 min followed by a 15-min saline perfusion
      again. Catecholamine concentrations were detected through high-performance liquid
      chromatography with electrochemical detection. Control experiments were performed
      in human skin homogenates with and without tyramine incubation. In vivo,
      norepinephrine (NE) concentration increased from 36.3 +/- 10.2 pg/ml to 84.4 +/-
      18.4 pg/ml (P < 0.001) during stimulation with tyramine, dialysate dopamine (DA)
      concentration increased from 105.2 +/- 36.5 pg/ml to 7162.4 +/- 3972.4 pg/ml (P <
      0.001). Both tyramine-induced NE and DA release were dose-dependent (NE: r =
      0.438, P < 0.05; DA: r = 0.894, P < 0.001). In skin homogenates, tyramine
      incubation led to a significant increase of DA concentrations (387.0 +/- 34.8
      pg/ml, controls: 13.2 +/- 2.4 pg/ml; P < 0.05), while NE and epinephrine levels
      remained unchanged. In conclusion, our experiments show that dermal microdialysis
      is capable of locally measuring catecholamines in human skin. This offers the
      opportunity to investigate the function of the peripheral sympathetic nervous
      system. Additional to non-enzymatic oxidation, DA increase probably reflects
      metabolic degradation of tyramine by non-neuronal pathways and therefore does not
      reflect local sympathetic innervation.

PMID- 15191806
TI  - Protease-activated receptor-1 in human brain: localization and functional
      expression in astrocytes.
AB  - Protease-activated receptor-1 (PAR1) is a G-protein coupled receptor that is
      proteolytically activated by blood-derived serine proteases. Although PAR1 is
      best known for its role in coagulation and hemostasis, recent findings
      demonstrate that PAR1 activation has actions in the central nervous system (CNS)
      apart from its role in the vasculature. Rodent studies have demonstrated that
      PAR1 is expressed throughout the brain on neurons and astrocytes. PAR1 activation
      in vitro and in vivo appears to influence neurodegeneration and neuroprotection
      in animal models of stroke and brain injury. Because of increasing evidence that
      PAR1 has important and diverse roles in the CNS, we explored the protein
      localization and function of PAR1 in human brain. PAR1 is most intensely
      expressed in astrocytes of white and gray matter and moderately expressed in
      neurons. PAR1 and GFAP co-localization demonstrates that PAR1 is expressed on the
      cell body and on astrocytic endfeet that invest capillaries. PAR1 activation in
      the U178MG human glioblastoma cell line increased PI hydrolysis and intracellular
      Ca(2+), indicating that PAR1 is functional in human glial-derived tumor cells.
      Primary cultures of human astrocytes and human glioblastoma cells respond to PAR1
      activation by increasing intracellular Ca(2+). Together, these results
      demonstrate that PAR1 is expressed in human brain and functional in glial tumors
      and cultures derived from it. Because serine proteases may enter brain tissue and
      activate PAR1 when the blood brain barrier (BBB) breaks down, pharmacological
      manipulation of PAR1 signaling may provide a potential therapeutic target for
      neuroprotection in human neurological disorders.

PMID- 15191807
TI  - VEGF disrupts the neonatal blood-brain barrier and increases life span after non
      ablative BMT in a murine model of congenital neurodegeneration caused by a
      lysosomal enzyme deficiency.
AB  - The course of certain congenital neurodegenerative diseases like lysosomal
      storage diseases (LSDs) begins shortly after birth and can progress quickly.
      Ideally, therapeutic interventions for LSDs, which include bone marrow
      transplantation (BMT), recombinant enzyme replacement, or systemic viral-mediated
      gene therapy, should be initiated at birth. However, the blood-brain barrier
      (BBB) remains an obstacle to effective therapy even when these strategies are
      initiated at birth. We studied whether VEGF, an endothelial cell mitogen and
      permeability factor, can open the BBB in newborn mice for therapeutic purposes.
      Intravenous (IV) administration of VEGF at birth increased BBB permeability
      within 2 h. The increased permeability persisted for at least 24 h, became
      undetectable 48 h after injection, and was restricted to newborns. Systemic VEGF
      treatment before BMT or administration of recombinant lentivirus resulted in
      increased numbers of both donor cells and virus-transduced cells, respectively,
      in the recipient brain. Administration of VEGF before BMT in newborn mice with a
      neurodegenerative LSD, globoid-cell leukodystrophy, resulted in a significant
      increase in life span compared to affected animals that were injected with saline
      before BMT.

PMID- 15191808
TI  - NGF message and protein distribution in the injured rat spinal cord.
AB  - Nerve growth factor (NGF) content of the spinal cord is increased after cord
      injury. NGF can cause central sprouting of sensory fibers after spinal cord
      injury (SCI), leading to autonomic dysfunction and pain. NGF also can promote the
      death of oligodendroglia after SCI. Knowing the source of intraspinal NGF would
      benefit strategies for minimizing abnormal plasticity and cell death after SCI.
      We identified these sources, using RNA in situ hybridization to detect NGF mRNA
      and double-labeling immunocytochemistry for NGF and cell-marking antigens. In
      uninjured and sham-injured rats, we identified NGF mRNA in leptomeningeal cells
      and in neurons in the intermediate grey matter, whereas NGF protein was observed
      only in leptomeningeal cells. At 3-7 days after transection or clip-compression
      SCI, NGF mRNA and protein were expressed in the lesion and throughout the
      intermediate grey matter and white matter rostral and caudal to the injury site.
      Transection-SCI was used to permit comparisons to previous studies; clip
      compression injury was used as a more clinically relevant model. mRNA and protein
      in adjacent sections were expressed in ramified microglia, astrocytes,
      intermediate grey neurons, pial cells, and leptomeningeal and Schwann cells in
      the lateral white matter and the lesion site. Rounded macrophages in the lesion
      were immunoreactive (Ir) for NGF, but the cells expressing NGF mRNA were not in
      the same areas of the lesion and were not stained by a macrophage marker. Our
      data demonstrate that glia, neurons, meningeal cells and Schwann cells but not
      macrophages contribute to the increased intraspinal NGF after SCI.

PMID- 15191809
TI  - Selective blockade of D(3) dopamine receptors enhances the anti-parkinsonian
      properties of ropinirole and levodopa in the MPTP-lesioned primate.
AB  - To date, the lack of highly selective antagonists at the dopamine D(3) receptor
      has hampered clarification of their involvement in the actions of currently used
      therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084,
      displays greater than 100-fold selectivity as an antagonist for D(3) versus D(2)
      receptors and all other sites tested. S33084 was administered to 1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed
      with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest,
      but significant, anti-parkinsonian effect without provoking dyskinesia. At low
      D(3)-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to
      different extents and in qualitatively different ways, the anti-parkinsonian
      actions of both ropinirole and levodopa. At these doses, S33084 did not
      significantly modify levodopa-induced or ropinirole-induced dyskinesia. These
      data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or
      pro-dyskinetic actions via D(3) receptor stimulation. Indeed, stimulation of D(3)
      receptors may be detrimental to the anti-parkinsonian properties of D(2)/D(3)
      agonists. Selectivity for stimulation of D(2), over D(3), receptors may therefore
      be a beneficial property of dopamine receptor agonists in management of motor
      symptoms of Parkinson's disease patients with established dyskinesia.

PMID- 15191810
TI  - Differential effect of anterior cingulate cortex lesion on mechanical
      hypersensitivity and escape/avoidance behavior in an animal model of neuropathic
      pain.
AB  - Various limbic system structures have been implicated in processing noxious
      information. One such structure is the anterior cingulate cortex (ACC), a region
      that is thought to modulate higher order processing of noxious input related to
      the affective/motivational component of pain. The present experiment examined the
      involvement of the ACC in higher order pain processing by measuring paw
      withdrawal threshold and escape/avoidance responses in the L5 spinal nerve
      ligation model of neuropathic pain before and following electrolytic lesion of
      the ACC. In the place/escape avoidance paradigm, the afflicted paw is
      mechanically stimulated when the animal is in the preferred dark area of the
      chamber and the contralateral paw is stimulated when the animal is in the light
      area. Escape/avoidance was defined as a shift from the preferred dark area to an
      increase of time spent in the light area of the chamber. Animals with L5 ligation
      had significantly lower mechanical paw withdrawal threshold (hypersensitivity)
      and enhanced escape/avoidance behavior. ACC lesion in animals with L5 ligation
      did not alter mechanical hypersensitivity, but did significantly decrease
      escape/avoidance behavior. Anxiety, as measured using the light-enhanced startle
      paradigm, was not altered by ACC lesion. These results highlight the utility of
      novel behavioral test paradigms and provide additional support for the role of
      the ACC in higher order processing of noxious information, suggesting that ACC
      lesions selectively decrease negative affect associated with neuropathy-induced
      hypersensitivity.

PMID- 15191812
TI  - Tat-calpastatin fusion proteins transduce primary rat cortical neurons but do not
      inhibit cellular calpain activity.
AB  - Excessive activation of calpains (calcium-activated neutral proteases) is
      observed following spinal cord contusion injury, traumatic brain injury, stroke,
      and in neurodegenerative disorders including Alzheimer's disease. Calpain
      inhibition represents an attractive therapeutic target, but current calpain
      inhibitors possess relatively weak potency, poor specificity, and in many cases,
      limited cellular and blood-brain barrier permeability. We developed novel calpain
      inhibitors consisting of the endogenous inhibitor, calpastatin or its inhibitory
      domain I, fused to the protein transduction domain of the HIV trans-activator
      (Tat) protein (Tat(47-57)). The Tat-calpastatin fusion proteins were potent
      calpain inhibitors in a cell-free activity assay, but did not inhibit cellular
      calpain activity in primary rat cortical neurons when applied exogenously at
      concentrations up to 5 microM. The fusion proteins were able to transduce
      neurons, but were localized within endosome-like structures. A similar endosomal
      uptake was observed for Tat-GFP. Together, the results suggest that endosomal
      uptake of the Tat-calpastatin prevents its interaction with calpain in other
      cellular compartments. Endosomal uptake of proteins fused to the Tat protein
      transduction domain severely limits the applications of this methodology.

PMID- 15191811
TI  - Contribution of degeneration of motor and sensory fibers to pain behavior and the
      changes in neurotrophic factors in rat dorsal root ganglion.
AB  - To elucidate the role of the degeneration of motor and sensory fibers in
      neuropathic pain, we examined the pain-related behaviors and the changes of brain
      derived neurotrophic factor (BDNF) in the L4/5 dorsal root ganglion (DRG) and the
      spinal cord after L5 ventral rhizotomy. L5 ventral rhizotomy, producing a
      selective lesion of motor fibers, produced thermal hyperalgesia and increased
      BDNF expression in tyrosine kinase A-containing small- and medium-sized neurons
      in the L5 DRG and their central terminations within the spinal cord, but not in
      the L4 DRG. Furthermore, L5 ventral rhizotomy up-regulated nerve growth factor
      (NGF) protein in small to medium diameter neurons in the L5 DRG and also in ED-1
      positive cells in the L5 spinal nerve, suggesting that NGF synthesized in the
      degenerative fibers is transported to the L5 DRG and increases BDNF synthesis. On
      the other hand, L5 ganglionectomy, producing a selective lesion of sensory
      fibers, produced heat hypersensitivity and an increase in BDNF and NGF in the L4
      DRG. These data indicate that degeneration of L5 sensory fibers distal to the
      DRG, but not motor fibers, might influence the neighboring L4 nerve fibers and
      induce neurotrophin changes in the L4 DRG. We suggest that these changes of
      neurotrophins in the intact primary afferents of neighboring nerves may be one of
      many complex mechanisms, which can explain the abnormal pain behaviors after
      nerve injury. The ventral rhizotomy and ganglionectomy models may be useful to
      investigate the pathophysiological mechanisms of neuropathic pain after Wallerian
      degeneration in motor or sensory or mixed nerve.

PMID- 15191813
TI  - MRI of peripheral nerve degeneration and regeneration: correlation with
      electrophysiology and histology.
AB  - Acute axonal nerve lesions cause a hyperintense signal on T2-weighted (T2-w)
      magnetic resonance imaging (MRI) at the nerve lesion site and distal to it. The
      aim of this experimental study was to investigate the spatiotemporal evolution
      and resolution of MR nerve signal changes following denervation and
      reinnervation, and to relate these findings to electrophysiology and histology.
      The proximal sciatic nerve of adult rats was ligated by a tight suture that was
      removed 1 week later to induce complete axotomy and nerve regeneration upon
      release. Serial electromyography (EMG) and motor nerve conduction studies were
      performed parallel to MRI at multiple points of time. Moreover, sciatic nerves
      were taken for quantitative histological evaluation. Nerve hyperintensity on T2-w
      MRI was present distal to the lesion at thigh level 24 h after denervation
      preceding the occurrence of spontaneous activity on EMG by 24 h. After 48 h, the
      entire sciatic nerve and its branches showed an increased signal down to the
      level of the lower leg. The increased nerve signal regressed with a proximo
      distal gradient beginning from week 2 after onset of nerve regeneration in the
      thigh. On EMG, the first reinnervation potentials were detected at that time at
      the respective level. Compound muscle action potential (CMAP) in the foot muscle
      fully recovered 12 weeks after onset of nerve regeneration, that is, 2 weeks
      after resolution of the hyperintensity along the entire nerve on MRI. Histology
      revealed axonal degeneration in the acute phase and later nerve oedema parallel
      to the increased nerve signal on MRI. MR signal alterations occur as early as 24
      h after an axonal nerve lesion and correlate with nerve fiber degeneration and
      later with nerve oedema on histology. MR findings in denervation and
      reinnervation parallel the electrophysiological changes. Thus, MRI is a promising
      diagnostic tool for the early detection of acute axonal nerve lesions and
      monitoring of nerve regeneration.

PMID- 15191814
TI  - Modulation of IL-1 beta gene expression by lipid peroxidation inhibition after
      kainic acid-induced rat brain injury.
AB  - Brain injury was induced by intraperitoneal administration of kainic acid (KA, 10
      mg/kg). Animals were randomized to receive either IRFI 042 (20 mg/kg i.p.), a
      lipid peroxidation inhibitor, or its vehicle (NaCl 0.9% DMSO 10% 1 ml/kg i.p.) 30
      min before KA administration. A first set of animals was sacrificed 6 h after KA
      injection to measure malondialdehyde (MDA) content, glutathione-reduced (GSH)
      levels and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the
      hippocampus. A second set of animals was sacrificed 48 h after KA administration
      for histological analysis. All animals were observed for monitoring the
      behavioral sequelae and for evaluating latency of convulsions. Sham brain injury
      rats were used as controls. Intraperitoneal administration of IRFI 042
      significantly decreased brain MDA (cortex: KA + vehicle = 0.285 +/- 0.04 nmol/mg
      protein; KA + IRFI 042 = 0.156 +/- 0.02 nmol/mg protein, P < 0.005; hippocampus:
      KA + vehicle = 0.350 +/- 0.03 nmol/mg protein; KA + IRFI 042 = 0.17 +/- 0.04
      nmol/mg protein, P < 0.005), prevented the brain loss of GSH in both cortex (KA +
      vehicle = 7.81 +/- 1 micromol/g protein; KA + IRFI 042 = 12.1 +/- 1 micromol/g
      protein; P < 0.005) and hippocampus (KA + vehicle = 5 +/- 0.8 micromol/g protein;
      KA + IRFI 042 = 9.4 +/- 1.8 micromol/g protein; P < 0.005), reduced both brain IL
      1beta mRNA expression and oedema, and increased latency of convulsions.
      Histological analysis showed a reduction of cell damage in IRFI 042-treated
      samples. The present data indicate that lipid peroxidation inhibition reduces IL
      1beta gene expression and protects against kainic acid-induced brain damage.

PMID- 15191815
TI  - Wallerian degeneration after crush or chronic constriction injury of rodent
      sciatic nerve is associated with a depletion of endoneurial interleukin-10
      protein.
AB  - We used enzyme-linked immunoassay (ELISA), immunohistochemistry (IHC), and
      quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to
      determine whether interleukin (IL)-10 protein is changed after unilateral crush
      or chronic constriction injury (CCI) of mouse or rat sciatic nerve and whether IL
      10 protein and mRNA are differentially regulated. In the mouse sciatic nerve, IL
      10 protein declined rapidly to 10-20% of baseline early after crush or CCI, while
      the IL10 mRNA was up-regulated with a maximum on Days 1 and 3. In the rat sciatic
      nerve, IL-10 protein was significantly reduced on Day 3 after CCI, and IL-10 mRNA
      was up-regulated in both models. These results suggest that changes of the local
      cytokine network during wallerian degeneration include an early deficiency of the
      antiinflammatory cytokine IL-10 despite up-regulation at the mRNA level.

PMID- 15191816
TI  - Give and take.

PMID- 15191817
TI  - Composite tissue allotransplantation--a new era in plastic surgery?
AB  - Composite tissue allotransplantation (CTA) holds great potential for
      reconstructive surgery. The recent hand transplants have made this a clinical
      reality. However, concerns about CTA have divided the medical community. The
      current transplants require life-long immunosuppression, which could place the
      recipients at risk of serious complications. In addition despite potent
      immunosuppression, chronic rejection may still negate any early favourable
      results. This article will outline the clinical experience of CTA, the major
      problems of the technique and the potential solutions to these problems.

PMID- 15191818
TI  - The arterial vascularisation of the abdominal wall with special regard to the
      umbilicus.
AB  - AIM: In order to prevent wound healing problems around the transposed umbilicus
      following abdominoplasty, we investigated the arterial vascularisation of the
      abdominal wall with special regard to the umbilicus. The aim was to optimise the
      planning of the umbilical stalk and flap design. METHOD: The inferior and
      superior epigastric arteries of 12 cadavers (mean age 83 years) were injected
      with barium-sulphate, lead-mennige and gelatine. The abdominal walls were
      resected en bloc and X-ray photographs were taken by conventional and
      mammographic technique. RESULTS: The radiographic examination showed that the
      main trunks of the epigastric vessels follow an "hour-glass" or "rhomboid"
      pattern around the centromedial umbilicus. Each main trunk splits into two
      obligate branches one medial and one lateral. The anastomosis between the
      inferior and superior epigastric artery is located above the umbilicus. The
      umbilicus is nourished by separate axial vessels originating from the inferior
      epigastric artery. It was also shown that the inferior intercostal arteries
      anastomose with the branches of the inferior and superior epigastric artery.
      CONCLUSION: Dividing the abdominal wall into four quadrants around the central
      umbilicus, the lateral areas of the lower quadrants show the weakest
      vascularisation by the inferior epigastric artery. This fact may cause healing
      problems after surgery in this area. The axial vascularisation of the umbilicus
      makes any torsion or traction a potential hazard to the umbilical flap during
      abdominoplasty especially by re-siting the umbilicus. The anatomical study showed
      clearly the benefit of preparing a broad base fat layer with a generous diameter
      of incision line around the umbilicus.

PMID- 15191819
TI  - Changes in the local morphology of the rectus abdominis muscle following the DIEP
      flap: an ultrasonographic study.
AB  - This study was undertaken to assess the changes in the local morphology of the
      rectus abdominis muscle following intramuscular dissection of the deep inferior
      epigastric artery perforators after harvesting of the deep inferior epigastric
      perforator (DIEP) flap. While the DIEP provides the well-known advantage of use
      of the lower abdominal tissue with preservation of the integrity of the abdominal
      wall musculature, postoperative problems such as abdominal asymmetry, bulges and
      reduced flexion capacity have been found. These changes may be due to rectus
      abdominis muscle damage from ischemia or denervation. We used ultrasonography to
      assess the changes in rectus abdominis muscle thickness and contractility,
      preoperatively, 1-month and 1-year postoperatively. The study group consisted of
      17 rectus abdominis muscles in 14 patients subjected to intramuscular dissection
      of perforators. The control group consisted of 11 intact rectus abdominis muscles
      in 11 patients who had undergone unilateral DIEP flap elevation, the dissected
      muscles being part of the study group. We found that the resting muscle thickness
      in the study group was, significantly increased at 1-month postoperatively,
      resolving by 1-year follow-up. As these changes were not seen in the control
      group, the increased muscle thickness is attributed to postoperative oedema that
      resolves with time. All muscles in the study and control groups retained
      contractility showing no evidence of muscle denervation. Our date demonstrates
      that intramuscular dissection of perforator vessels in the DIEP flap leads to
      minimal changes in the local morphology and contractility of the rectus abdominis
      muscle.

PMID- 15191820
TI  - Immediate vulvar and vaginal reconstruction using the gluteal-fold flap: long
      term results.
AB  - The gluteal-fold flap was used to reconstruct vulvar and posterior vaginal wall
      defects in 40 patients. This is a fasciocutaneous, islanded flap based on the
      internal pudendal artery and vein perforators. The flap is robust and has the
      advantage of being away from the pathway of carcinoma spread. In addition it has
      minimal donor-site morbidity as the scar is hidden in a natural crease.

PMID- 15191821
TI  - Large thoracolumbar meningomyelocele defects: incidence and clinical experiences
      with different modalities of latissimus dorsi musculocutaneus flap.
AB  - In this study, we report a series of large thoracolumbar meningomyelocele (MMS)
      defects. The total incidence per 1000 live birth is 0.6, the male incidence per
      1000 live birth is 0.56, and the female incidence per 1000 live birth is 0.47.
      The study was conducted on 23 infants, all suffered from large thoracolumbar MMC
      defects, and our treatment techniques are modifications of procedures previously
      described. The timing of surgery ranged between 2 and 5 days after birth, and the
      follow-up was ranged between 3 and 7 years. Different modalities were used for
      reconstruction: bilateral proximally based skin island, muscle pedicle latissimus
      dorsi (LD), myocutaneous flap (seven patients), bilateral bipedicled LD,
      myocutaneous flaps (nine patients), and distally based skin island, muscle
      pedicle LD, myocutaneous flaps (seven patients). All the patients tolerated
      procedures smoothly, and because LD muscle may be important for mobility in a
      potentially paraplegic wheelchair-bound patient, the author presents some
      modifications in order to preserve the muscle function. Criteria for flap
      selection will be discussed.

PMID- 15191822
TI  - Trans-nasal endo-assisted pharyngoplasty: a cadaver study.
AB  - A possible new technique of endoscopic pharyngoplasty is described and has been
      developed in cadavers. The trans-nasal route is used for endoscopic visualisation
      of the velopharyngeal sphincter. Hynes pharyngoplasty is performed using both
      trans-oral and trans-nasal routes. This approach allows better visualisation and
      performance of the Hynes pharyngoplasty at the desired level, "high" in the
      nasopharynx, without splitting the soft palate.

PMID- 15191823
TI  - Effects of human amniotic fluid on cartilage regeneration from free perichondrial
      grafts in rabbits.
AB  - After the chondrogenic potential of free grafts of perichondrium was shown in
      several experimental studies, perichondrium has been used to reconstruct
      cartilage tissue in various clinical situations. This study investigates the
      effects of human amniotic fluid on neochondrogenesis from free perichondrial
      grafts in a rabbit model. Since this fluid contains high concentrations of
      hyaluronic acid, hyaluronic acid-stimulating activator, growth factors, and
      extracellular matrix precursors during the second trimester, it may have a
      stimulating effect on neochondrogenesis. Perichondrial grafts, measuring 20 x 20
      mm2 were obtained from the ears of 144 New Zealand young rabbits and were sutured
      over the paravertebral muscles. The rabbits were randomly divided into three
      groups with 48 rabbits per group. In group 1, 0.3 ml human amniotic fluid, and in
      group 2, 0.3 ml saline were injected underneath the perichondrial grafts. Group 3
      formed the control group in which no treatment was given. Histologically,
      neochondrogenesis was evaluated in terms of cellular form and graft thickness at
      2, 4, 6, and 8 weeks after surgery. In group 1, the mature cartilage was
      generated quickly and the cartilage plate in this group was significantly thick
      and extensive when compared with groups 2 and 3 at 8 weeks ( p<0.05 ANOVA). In
      conclusion, our study shows that human amniotic fluid enhances neochondrogenesis
      from free perichondrial grafts. The rich content of hyaluronic acid and growth
      factors possibly participate in this result.

PMID- 15191824
TI  - The stromal reaction in basal cell carcinomas. A prerequisite for tumour
      progression and treatment strategy.
AB  - Specimens of basal cell carcinomas collected from 28 patients were classified
      into three groups: superficial, nodular, and infiltrative, according to their
      microarchitecture. The specimens were then subjected to histological
      characterization by means of a biotinylated hyaluronan-binding probe (HABP). By
      using Ki-67 and PCNA the proliferative activity of the BCC tumours was evaluated
      with immunohistological techniques. In superficial BCC the tumour islands
      displayed moderate hyaluronan (HA) staining. Feeble proliferation, denoted by
      modest mitotic activity and weak Ki-67 and PCNA immunoreactivity, occurred within
      the tumour islands. The surrounding connective tissue resembled normal skin, and
      no differentiated tumour stroma was observed. In nodular BCC, the HA staining of
      the tumour strands was weak to moderate, denoting increased proliferative
      activity. The differentiated surrounding tumour stroma stained strongly for HA.
      Tumour islands of infiltrative BCC stained weakly to moderately to HA and
      evidenced intense proliferation. The intensely HA-stained tumour stroma ended
      abruptly and the adjacent areas were almost devoid of HA. This study showed that
      the proliferative activity of BCC cells is associated with increased expression
      of HA in the tumour stroma. Modification of tumour-associated connective tissue
      indicates a close relationship between the tumour cells and the adjacent matrix.
      In particular, in infiltrative BCC, such alterations include degeneration and
      possible modification and remodelling of the surrounding extracellular matrix.
      These processes involving areas of probable importance for tumour progression,
      should be considered when deciding the extent of intended surgical resection.

PMID- 15191825
TI  - Psychiatric morbidity in a regional plastic surgery centre--one-year review with
      a proposed categorisation.
AB  - Few studies describe the incidence and nature of psychiatric morbidity in plastic
      surgery patients. We undertook a review of all referrals from the Plastic Surgery
      Service to the Psychological Medicine Service over a 1-year period (January
      December 2001). Standardised socio-demographic information, nature and cause of
      injury/defect, surgical intervention, surgical outcome, psychiatric diagnosis and
      psychiatric follow-up were determined. The majority of patients referred had a
      significant existing psychiatric illness, had made a suicide/parasuicide attempt,
      or were burns patients. There was a high rate of referral of plastic surgery
      inpatients. Liaison with plastic surgery staff to allow rapid identification and
      early management of psychiatric morbidity is an important role for psychological
      medicine. We outline a defined categorisation of common contexts in which
      psychiatric morbidity may present to plastic surgery services.

PMID- 15191826
TI  - Re-evaluating selection criteria for local anaesthesia in day surgery.
AB  - Day surgery is an increasing element of surgical practice, particularly in
      plastic surgery. A large proportion of work is undertaken using local anaesthesia
      in the elderly who have associated co-morbidity. At present no national
      guidelines exist for the use of local anaesthesia in day surgery. This study
      aimed to examine the relationship between patient selection and complications, in
      order to identify those who should be excluded from local anaesthetic day surgery
      treatment. A retrospective analysis of patients undergoing local anaesthetic
      plastic surgical procedures over a 10-month period identified 328 operative
      episodes. There were 37 complications, two of which required admission 5 days
      post surgery for treatment of wound infection. The remaining complications were
      treated on an outpatient basis. An increased level of complication was seen in
      males with elevated systolic blood pressure and with the use of full thickness
      skin grafts in reconstruction. Age, smoking, ASA grade, and medication that
      altered coagulation (aspirin, warfarin and steroids) were not associated with
      increased complication levels. We conclude that local anaesthetic plastic
      surgical procedures are associated with a very low level of risk, and are
      suitable for those patients traditionally regarded as unsuitable for general
      anaesthetic day surgery.

PMID- 15191827
TI  - Posterior tibialis transfer for foot-drop due to leprosy: a case with 40 years
      follow up.
AB  - A 56-year-old male was transferred to our centre because of a relapse of leprosy
      neuritis in the hands. We found that the patient had received a posterior
      tibialis tendon transfer for correction of his left dropped foot 40 years
      previously. On examination active dorsiflexion of the left ankle joint was close
      to 0 degrees with grade 4 power of dorsiflexion, and the plantar flexion was
      about 35 degrees. Walking gait was almost normal. There were some scars on the
      plantar surface of the left metatarsal area; but with the continuous use of a
      soft dressing pad under the middle part of the sole, plantar ulceration has been
      avoided for many years even with active daily activities of the patient. The
      patient is very satisfied with the operative results.

PMID- 15191828
TI  - Intense pulsed light therapy in the management of hereditary benign
      telangiectasia.
AB  - Hereditary benign telangiectasia is an idiopathic condition that causes
      considerable cosmetic embarrassment but has eluded successful treatment due to
      its extensive nature. We report a case of hereditary benign telangiectasia of the
      lower limbs in which the challenge of treating an extensive vascular lesion is
      met by using an Intense pulsed light (IPL) source.

PMID- 15191829
TI  - Severe haemorrhage in neurofibromatoma: a lesson.
AB  - Neurofibromatosis is a relatively common inherited disease of the nervous system,
      with a frequency of almost 1 in 3000. It is associated with a wide range of
      vascular abnormalities. A 62-year-old man with neurofibromatosis presented to us
      with a sacral haematoma. This was due to spontaneous rupture of a pre-existing
      neurofibromata. Upon admission the patient was in hypovolaemic shock and required
      aggressive resuscitation prior to surgery. Haemorrhage following trauma or
      spontaneous rupture is an uncommon complication of neurofibromatosis. The
      management is discussed with emphasis on the cause and control of bleeding from
      these lesions.

PMID- 15191831
TI  - An unusual complication of penile piercing: a report and literature review.
AB  - Body piercing has been practiced for many centuries and is thought to have its
      origins in the Hindu religion. As traditional ear piercings have given way to
      more adventurous anatomical sites, so too have the associated complications of
      these practices. We present the case of a 35 year old man who presented 12 months
      after a penile piercing with an extensive fistula of the glans penis resembling
      an acquired glanular hypospadius.

PMID- 15191830
TI  - Reduction mammaplasty in granular cell tumour of the breast.
AB  - Granular cell tumour of the breast is a rare peripheral nerve tumour. A case in a
      34-year-old woman is reported. The clinical and histological differentiation from
      invasive malignant neoplasm and the surgical management are discussed. Core
      needle biopsy preoperatively is able to establish the definite diagnosis and help
      to avoid surgical overtreatment.

PMID- 15191832
TI  - Osteofasciocutaneous flap based on the dorsal ulnar artery. A new option for
      reconstruction of composite hand defects.
AB  - Since the initial description of the dorsal ulnar artery fasciocutaneous flap by
      Becker and Gilbert in 1988 many modifications have been introduced to allow more
      versatility to the flap. The authors describe the dissection technique of an
      osteofasciocutaneous flap based on the dorsal ulnar artery and present a clinical
      case where this flap has been used to reconstruct a bone defect of the fifth
      metacarpal. Up to one third of the outer cortex of a long bone is supplied by the
      periosteal arterioles. This permits the inclusion of a small amount of ulnar
      cortical bone in the dorsal ulnar flap to reconstruct compound defects of the
      hand. The essential precaution is not to disrupt the continuity formed by the
      posterior border of the ulna, the periosteum, bony attachments of the flexor
      carpi ulnaris and extensor carpi ulnaris muscles, fascia and the skin. This flap
      allows the transposition of optimal soft tissue coverage to the hand with
      vascularised bone preserving the main arteries to the hand.

PMID- 15191833
TI  - Letter to the Editor: Management of aplasia cutis congenita in a non-scalp
      location.

PMID- 15191835
TI  - Research options for plastic surgical trainees.

PMID- 15191836
TI  - Skin sparing mastectomy using the Wise pattern: protecting the T-junction with a
      dermal pedicle.

PMID- 15191837
TI  - Painless steroid injections for hypertrophic scars and keloids.

PMID- 15191838
TI  - Issues arising from the presentation of synchronous cutaneous malignant melanoma
      and sentinel node biopsies: a case report and discussion.

PMID- 15191839
TI  - Subunits of the cheek: an algorithm for the reconstruction of partial-thickness
      defects.

PMID- 15191841
TI  - Low-cost, single-use breast sizing for augmentation mammaplasty.

PMID- 15191840
TI  - Hypafix removal.

PMID- 15191842
TI  - Breast reconstruction by the free transverse gracilis (TUG) flap.

PMID- 15191843
TI  - The VAC dressing--a cautionary tale.

PMID- 15191844
TI  - [When a surgical procedure loses its adjective "laparoscopic". A slow semantic
      evolution, scientifically justified].

PMID- 15191845
TI  - [Breast reconstruction after mastectomy for breast cancer: which reconstructive
      surgical procedure should be retained?].
AB  - Post-mastectomy breast reconstruction represents a surgical option that may
      improve psychosocial outcome without modifying patients' survival. Psychosocial
      impact of used surgical technique and moment of realization of breast
      reconstruction remains unclear. However, complications are negatively related to
      patients' satisfaction. There is no guideline for BR indications. Therefore, a
      review of clinical and cosmetic outcomes of different breast reconstruction
      modalities was necessary. It permitted to propose a shared decision-making
      algorithm for the choice of moment and technique of BR according to the presence
      of radiotherapy that appears to be the main risk factor of clinical outcome of
      breast reconstruction. It also disclosed some limits in information reliability
      about clinical outcome of particular associations of breast reconstruction and
      radiotherapy. Proportion of women pursuing breast reconstruction, and
      particularly immediate breast reconstruction, is rising. Clinical surveys
      assessing relation between radiotherapy and clinical and psychosocial outcome of
      breast reconstruction are urgently expected.

PMID- 15191846
TI  - [Self expanding metallic stent in the management of malignant colonic
      obstruction].
AB  - INTRODUCTION: Fifteen to thirty percent of colonic cancers are diagnosed at acute
      colic obstruction stage. In this situation surgery is associated with a high
      morbi-mortality. The self-expandable metallic stents (SEM) have two objectives:
      (a) resolution of the obstructive to allow secondary planified radical surgical
      procedure; (b) palliative in the event of advanced disease. PATIENTS AND METHODS:
      From May 2001 to December 2002, 11 patients, mean age 75 +/- 8 years, presenting
      with acute colic obstruction were initially treated by SEM placed by endoscopy.
      Four patients were classified score ASA 4. Ten patients had a colonic cancer, and
      a patient presented a peritoneal carcinomatosis from an ovarian carcinoma.
      Overall five patients had a carcinomatosis. Stenosis, mean length 4 +/- 3 cm,
      were located on the left colon. In five patients the SEM was proposed as a
      palliative treatment. RESULTS: Successfully placement of SEM was obtained in 10
      (91%) patient without perforation. Three complications (bleeding, reobstruction,
      migration) were observed. Clinical success (colonic decompression within 96 h
      without endoscopic or surgical reintervention) was observed in nine out of ten
      (90%) patients. Six patients had a SEM with curative attempt allowing (i) colonic
      resection (9 +/- 2 days) without stomy (one postoperative death) in five
      patients; (ii) a colo-colic derivation for diffuse carcinomatosis discovered
      peroperatively. A diverting colostomy was carried out in two of the four patients
      (j6, j30) (reobstruction, migration) for whom the SEM had been proposed as
      palliative treatment. CONCLUSIONS: This study confirms that SEM and surgery are
      not competitive but complementary techniques. When the SEM is placed with
      curative attempt, it allows resolution of the obstructive syndrome and secondary
      planified radical surgical procedure under better conditions. The results
      observed in the palliative SEM group suggested to reconsider this indication.

PMID- 15191847
TI  - [Transperineal repair of rectocele with prosthetic mesh. A prospective study].
AB  - PURPOSE: To assess the long term results of a transperineal repair of rectocele
      with a prosthetic mesh and the criteria for selecting the patients. METHODS:
      Twenty-five consecutive patients (median age: 60 years) with a symptom-giving
      rectocele have been operated upon. Indication for surgery was: an obstructed
      defecation (N = 22); a fecal incontinence (N = 1); a pelvic heaviness with
      dyspareunia (N = 1) or a severe rectal syndrome (N = 1). Patients were evaluated
      by physical examination and, preoperatively, by defecography and anorectal
      manometry. The rectovaginal septum was repaired, through a perineal approach,
      with an absorbable (N = 5) or non absorbable (N = 20) prosthetic mesh. Long term
      results were assessed after a median follow-up of 45 (range 12-120) months by
      physical examination and a standardized questionnaire. The presence of the
      following three symptoms was evaluated: feeling of incomplete emptying, prolonged
      and unsuccessful straining at stool, digital assistance. Outcome was considered
      as successful when none of these symptoms were present, as good when minor
      emptying difficulties persisted, as moderate when emptying difficulties were
      associated with straining, as a failure when the symptomatic triad was unchanged.
      A general satisfaction score was established. RESULTS: All the patients had the
      defect of the rectovaginal septum corrected. Four patients had a low residual
      rectocele associated, in two cases, with a rectal prolapse subsequently treated
      by a Delorme's operation. Outcome in patients complaining of obstructed
      defecation was considered excellent or good in 80% of patients, moderate in 9%
      and poor in 9%. Subjective scoring showed a significantly better result in cases
      of success. Among 11 incontinent patients, seven (63.5%) improved or regained
      full continence. Dyspareunia in three cases was corrected. Age, parity, digital
      assistance, previous gynecologic surgery, use of laxatives, size of rectocele,
      type of mesh, anatomical result of repair had no significant prognostic value. On
      the other hand, in patients with obstructed defecation, clinical and manometric
      signs of anal hyperactivity of the pelvic floor or anismus (N = 4) were
      significantly related to a poor result (P < 0.001). CONCLUSION: Surgical repair
      with a prosthetic mesh is an efficient therapy in patients with obstructed
      defecation and/or incontinence caused by a rectocele. Clinical and defecographic
      parameters have no influence on outcome. Preoperative manometric data may help in
      selecting patients. In case of anal hyperactivity or anismus, given the risk of
      functional failure, behavioral retraining must be considered as first-line
      treatment.

PMID- 15191848
TI  - [Metastatic renal cell carcinoma to the thyroid gland: report of seven cases and
      review of the literature].
AB  - PURPOSE: The aim of this study was to retrospectively report clinical
      manifestations, type of treatment, survival rate of thyroid metastases from renal
      carcinoma. PATIENTS AND METHODS: Seven patients were retrospectively collected
      from files of different Burgundy's hospitals. All renal and thyroid gland
      specimens were controlled by the anatomopathologist. RESULTS: Tumors occurred in
      four women and three men (mean age: 66 years). Symptoms were generally a solitary
      mass. The metastatic tumor to the thyroid gland was the initial presentation of
      renal carcinoma in one case. In the other cases, patients had documented previous
      evidence of renal carcinoma as remotely 8.1 years before the thyroid metastases.
      Thyroglobulin immunohistochemistry was always negative in the foci of metastatic
      renal carcinoma. All patients had surgical resection of there metastasis. The
      majority of patients died with disseminated malignancies (mean: 38.1 months after
      there thyroid resection). Three patients are still alive, one after a
      complementary pancreatic resection for a secondary pancreatic metastasis and one
      other with cervical and mediastinal lymph node recurrence. CONCLUSIONS: Surgical
      treatment of the metastatic disease is suggested, as this may prolonged patient
      survival.

PMID- 15191849
TI  - [Reoperation for persistent or recurrent primary hyperparathyroidism. Seventy
      seven cases among 1888 operated patients].
AB  - AIMS: To analyse the results of re-operations for persistent (p) or recurrent (r)
      primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: From 1965 throughout
      2001, 1888 patients were operated on for PHPT. The cure rate after initial
      surgery was 97.6%. Seventy-seven (4.1%) were reoperated for p PHPT (n = 54) or r
      PHPT (n = 23). Thirty-two out of 77 (41%) had been primarily operated elsewhere.
      In 15 cases (20%) PHPT was genetically determined. The re-operation was
      undertaken on average 40.7 months after initial surgery (1 day-190 months).
      RESULTS: Two out of 77 were cases of familial hypocalciuric hypercalcaemia. Among
      the 75 patients reoperated for true PHPT, 23 (31%) had uniglandular disease (UGD)
      and 52 (69%) had multiglandular disease (MGD). There were two cases of recurrent
      parathyroid carcinoma. Overall 97 pathological glands were resected, 37% being
      orthotopic and 63% heterotopic. The re-operation was performed by a cervical
      approach in 80%, by a mediastinal approach in 15%, whereas 5% involved excision
      of antebrachial implants. In 96% of cases the parathyroid glands were in the
      cervical position. Among the preoperative localisations studies the sensitivity
      of scintigraphy utilising 2-methoxyisobutyl-isonitril (MIBI) was 61%. Utilising
      both MIBI and cervical ultrasound the sensitivity was 64%. Sixty-eight out of 75
      (91%) were cured of their hypercalcaemia, but at the cost of permanent
      hypoparathyroidism in 9% of cases. No sporadic adenoma appears to have been
      missed. The seven failures after re-operation (9%) involved five cases of MGD, of
      which four were sporadic, two cases of carcinoma and one case of
      parathyreomatosis. 39 patients (51%) had more than four parathyroid glands and in
      22/39 cases at least one supernumerary gland was pathological. CONCLUSION: The re
      operations for PHPT were essentially due to MGD that was either sporadic or
      genetically determined. Often the offending supernumerary gland was not detected
      by imaging studies. Avoiding failures entails an initial bilateral cervicotomy
      with thymic exploration after MIBI scintigraphy to exclude a mediastinal focus.

PMID- 15191850
TI  - [Unruptured ectopic pregnancy: which therapeutic options?].

PMID- 15191851
TI  - [Gastric trichobezoar: one case report].
AB  - The gastric trichobezoar is a rare disease in which diagnosis is easy in case of
      evocative context. Its treatment is not standardized. The authors report the case
      of a 9 year old girl, known to have trichophagy, presenting with a large
      epigastric mass. Upper endoscopy made the diagnosis of a trichobezoar. Surgical
      extraction was performed through gastrotomy, without complications. Psychiatric
      follow-up was recommended.

PMID- 15191852
TI  - [Aberrant pancreas: report of five cases].
AB  - We herein report five cases of heterotopic pancreas localized on common bile
      duct, gastric antrum, duodenum (two cases including one with cystic dystrophy),
      and jejunum. The choledocal localization was revealed by jaundice. The duodenal
      localization with cystic, diagnosed by endoscopic ultrasound, was revealed by
      onsets of acute pancreatitis. All localizations were treated by resection:
      antrectomy, bowel resection, and pancreaticoduodenectomy. Postoperative course
      was uneventful. Review of the literature shows that, even in uncomplicated cases,
      resection is usually performed.

PMID- 15191853
TI  - [Encapsulating peritonitis disclosing primary melanoma of the small intestine: a
      case report].
AB  - Encapsulating peritonitis is a chronic peritonitis leading to the constitution of
      the thick white nacred fibrosis membrane. It is a rare affection. Its
      physiopathology is poorly elucidated. Diagnosis is usually at operation. We
      report an unpublished case of a 36-year-old patient, admitted for an abdominal
      mass. The different investigations demonstrated small bowel tumor with entrapped
      ileal and jejunal loops within a capsule. Diagnosis was made at the time of
      operation by discovering an encapsulating peritonitis caused by a primary
      malignant melanoma of the small bowel, which is an exceptional affection.

PMID- 15191854
TI  - [Endovenous therapy for varicose veins of the lower extremities].
AB  - Endovenous treatment for varicose veins of the lower extremities is an old
      technique. New technologies such as radiofrequency and laser have revived its
      indications. Thermal energy which is delivered to the vein wall results in a
      fibrous retraction and eventually complete obstruction of the vessel.

PMID- 15191856
TI  - Utility of axillary ultrasound examination to select breast cancer patients
      suited for optimal sentinel node biopsy.
AB  - BACKGROUND: Because sentinel node (SN) biopsy (SNB) is known to produce false
      negative results, we examined the usefulness of axillary ultrasound (AUS) in
      selecting patients suitable for optimal SNB. METHODS: A positive AUS finding
      (positive AUS) was defined as an echo pattern of a homogeneously hypoechoic SN
      without an echo-rich center, indicating massive to extensive nodal involvement.
      The identification of SNs was performed, and complete axillary dissection was
      carried out. RESULTS: A total of 262 women were enrolled into the study (T1
      disease = 94; T2 disease = 145; and T3 disease = 23). The incidence of positive
      AUS increased with increasing size of breast tumor (P <0.0001). The overall
      identification and false-negative rates were 88.2% and 10.8%, respectively.
      However, when limited to AUS-negative patients, SNs were identified in 205 of 208
      patients (98.6%), and the false-negative rate was 1.7%. CONCLUSIONS: AUS should
      be included in the preoperative procedure for the selection of breast cancer
      patients suitable for SNB.

PMID- 15191855
TI  - Mastectomy and concomitant sentinel lymph node biopsy for invasive breast cancer.
AB  - BACKGROUND: Although sentinel lymph node biopsy (SNLB) has become a standard
      ancillary to breast conservation, there remains a hesitancy to perform SLNB
      concomitant with mastectomy primarily because of concerns regarding reoperation
      for a positive SLN. METHODS: A retrospective review of 51 patients who underwent
      SLN biopsy concomitantly with mastectomy for invasive breast cancer was
      performed. In addition, a survey was sent to surgical oncologists who routinely
      perform SLNB in conjunction with mastectomy. RESULTS: The SLN was identified in
      98% of patients, and an average of 2.4 SLNs/patient were removed. The SLN was
      positive in 14 patients (27%). Ten patients underwent axillary lymph node
      dissection as a second procedure; an average of 15.4 +/- 6 nodes were cleared,
      and there were no complications. Although techniques vary greatly among surgeons,
      the majority believe that a subsequent ALND procedure does not carry additional
      risk of morbidity. CONCLUSIONS: Mastectomy and concomitant SLNB is a safe option
      for well-selected breast cancer patients. Results appear acceptable using a
      variety of techniques. Patients with a positive SLN can safely undergo completion
      axillary lymph node dissections. This includes patients who have undergone
      immediate reconstruction, but proper planning is needed to minimize potential
      risks.

PMID- 15191857
TI  - Sentinel lymph node biopsy performed under local anesthesia is feasible.
AB  - BACKGROUND: A sentinel lymph node (SLN) biopsy in breast cancer patients,
      performed under local anesthesia (LA), could have advantages such as more
      efficient use of operating room time and pathologist time. It also provides a
      histologic diagnosis before definitive breast surgery is undertaken. The aim of
      this study was to assess feasibility by comparing the results of SLN procedures
      performed under LA versus general anesthesia (GA). METHODS: The SLN procedure was
      performed in 50 consecutive outpatients and 167 inpatients with clinical T1-2N0
      breast cancer while they were under LA and GA, respectively. The SLN detection
      rate, a comparison of mapped and harvested SLNs, was compared for both groups.
      The duration of the SLN biopsies performed under LA was also measured. RESULTS:
      For both groups a median of 2 SLNs/patient were harvested. The detection rate was
      1.00 for the LA group and 0.99 for the GA group. The learning curve for SLN
      procedures under LA showed a decrease in duration for the consecutive months (not
      significant). CONCLUSIONS: SLN biopsy can be safely and adequately performed with
      the patient under LA. It allows early diagnosis of the lymph node status,
      acquired on an outpatient basis, with minimal discomfort to the patient. The
      learning curve demonstrated that the LA procedure can quickly be mastered if the
      surgeon is experienced in performing SLN biopsies.

PMID- 15191858
TI  - Medical malpractice and cancer of the skin.
AB  - BACKGROUND: A litigation crisis exists in this country, and it may be better
      understood through analysis of lawsuits. Verdict summary analysis has been used
      for this purpose. METHODS: Ninety-nine jury verdict reviews from 1986 to 2001
      were obtained from a computerized database. Reviews compiled data on defendants,
      plaintiffs, allegations of wrongdoing, cancer cell types, sites, outcomes, and
      case summaries. Data was entered into a spreadsheet for analysis. RESULTS:
      Failure to diagnose was alleged in 54%; of these, 48% alleged biopsies were
      inappropriately omitted. Allegations were highest for failure to diagnose in
      dermatologists and general practice physicians, for misdiagnosis in pathologists,
      and for complications in surgeons. Young patients and those with poor outcomes
      received more and larger awards. Trauma appears to have support for a role in
      causation of skin cancer in some courts. CONCLUSIONS: The study of skin cancer
      suits may help develop risk management and prevention strategies.

PMID- 15191859
TI  - A senior elective designed to prepare medical students for surgical residency.
AB  - BACKGROUND: The transition from medical student to surgery internship can be
      stressful. The goal of this project was to design, implement, and evaluate a 1
      month long elective course that would meet the majority of the American College
      of Surgeons Graduate Medical Education Committee prerequisites for graduate
      surgical education METHODS: The major elements of the curriculum included faculty
      and resident-facilitated case-based sessions and cadaver dissections. In
      addition, the students participated in skills laboratory experiences, Intensive
      Care Unit rounds, and mock interviews and clinical pages. The students took a
      knowledge pretest and post-test that was compared with the performance of 8
      surgical interns on the same examination. RESULTS: The highest rated elements of
      the course were those that provided hands-on experience or practical knowledge.
      The post-test knowledge examination scores were significantly higher than pretest
      scores and surgical intern scores. CONCLUSIONS: It was possible to develop a 1
      month senior medical student elective course that provided students with the
      essential prerequisites believed to be essential for all surgical interns.

PMID- 15191860
TI  - How medical students define surgical mentors.
AB  - BACKGROUND: Current literature does not define ideal qualities of surgical
      mentors. We sought to define mentoring qualities desired by medical students in
      attending and resident surgeons. METHODS: We conducted a survey asking third-year
      medical students to identify the best attending surgeon and resident surgeon
      mentors during their surgical clerkship and to explain their selections. Comments
      were systematically evaluated using content analysis. RESULTS: The survey
      response rate was 94.8%. Attending surgeon mentors were described by 84 students;
      70 students described resident surgeon mentors. Students most frequently
      described the "teacher" role for attending surgeons. For resident surgeon
      mentors, students most often ranked the "person" role. Students prioritized
      characteristics or attributes within roles differently for attending and resident
      surgeon mentors. CONCLUSIONS: Medical students' expectations of attending and
      resident surgeon mentors differ. Emphasis on behaviors consonant with identified
      characteristics may improve mentoring of medical students by surgeons and
      increase interest in surgical careers.

PMID- 15191861
TI  - How do general surgery replacement residents match up with those recruited
      through the National Resident Matching Program?
AB  - BACKGROUND: Although the scope and patterns of attrition of general surgery
      residents have been reported, no study has examined the residents who replaced
      them. The purpose of this study was to assess the quality of replacement
      residents (RRs). METHODS: A questionnaire asked program directors (PDs) about the
      prevalence, characteristics, and disposition of RRs in general surgery residency
      programs from 2001 to 2002. RESULTS: PDs from 169 programs (67%) responded, and
      109 (64%) of these programs had RRs. Of 244 RRs (7%), 18 (7%) were postgraduate
      year (PGY)-1 residents; 64 (26%) were PGY-2 residents; 77 (32%) were PGY-3
      residents; 52 (21%) were PGY-4 residents; and 33 (14%) were PGY-5 residents. RRs
      averaged 1.9 years in their programs. One hundred seventy-five (72%) came from
      outside the current institution, and 142 had (58%) graduated from U.S. medical
      schools. PDs judged RRs to be superior (20%), comparable (55%), or inferior (25%)
      to their peers. Neither internal recruitment nor United States medical school
      graduation predicted performance. Disposition included promotion and graduation
      (88%), leaving the program voluntarily (5%), repeating the year (4%), and
      dismissal (3%). Successful RR performance occurred in 71% of RRs. CONCLUSIONS:
      Typically, RRs were U.S. medical school graduates, were recruited from outside
      the institution, and have performed satisfactorily.

PMID- 15191862
TI  - Port site metastases.
AB  - BACKGROUND: Concerns about port site metastases have limited the application of
      minimally invasive surgery for intra-abdominal malignancies. The purpose of this
      review article was to summarize the current literature regarding port site
      metastases. METHODS: A Medline search identified >100 articles in English
      published during the last 15 years regarding the history, incidence, etiology,
      and prevention of port site metastases. These articles were reviewed and are
      summarized. RESULTS: The incidence of port site metastases, initially thought to
      be as high as 21%, is now thought to be closer to the incidence of wound
      metastases after open surgery. Multiple etiologic factors have been studied
      including direct wound contamination, surgical technique, effects of carbon
      dioxide pneumoperitoneum, and changes in host immune response. Various preventive
      measures have been proposed. CONCLUSIONS: Port site metastases are a well
      documented and devastating complication after laparoscopic resection of intra
      abdominal malignancies. Although the etiology is not yet understood, a number of
      factors are contributory. All efforts should be made to prevent port site
      metastases.

PMID- 15191863
TI  - Resource utilization and its management in splenic trauma.
AB  - BACKGROUND: This study compared resource utilization and its management for
      splenic injury at 2 level-I trauma centers and a pediatric referral center with
      other facilities in a state currently developing a trauma system. METHODS:
      Management strategy, length of stay, and total charges for children were compared
      among the pediatric referral center, trauma centers, and other facilities. Adult
      management, length of stay, and total charges were compared between trauma
      centers and other facilities. RESULTS: Nonoperative management was more frequent
      in children at the pediatric referral center than trauma centers or other
      facilities and was more common in adults at trauma centers than at other
      facilities. Mean length of stay and total charges for children were significantly
      greater at the pediatric referral center and trauma centers than at other
      facilities and for adults at trauma centers than at other facilities. Facility
      type was associated with length of stay and total charges when injury type and
      severity were controlled. CONCLUSIONS: Nonoperative management of splenic injury
      is more common at trauma centers, and splenic trauma management may be more
      costly at trauma centers.

PMID- 15191865
TI  - Technical factors in the creation of a "floppy" Nissen fundoplication.
AB  - The original description of "floppy" Nissen fundoplication was that of an open
      procedure involving a large esophageal bougie, complete fundic mobilization,
      ligation of the short gastric vessels, and placement of a finger or a dilator
      under the completed fundoplication to assure laxity. A maneuver equivalent to the
      latter step during laparoscopic Nissen fundoplication has not been described. The
      consensus in the literature appears to be that the element of a fundoplication
      that defines it as floppy is complete mobilization of the fundus. We report an
      intraoperative maneuver that assures the fundoplication has adequate laxity. We
      also discuss several other maneuvers to assure proper formation of the
      fundoplication and to minimize side effects such as long-term dysphagia.

PMID- 15191864
TI  - Laparoscopic splenectomy for idiopathic thrombocytopenic purpura.
AB  - BACKGROUND: Laparoscopic splenectomy (LS) has become the treatment of choice for
      patients with idiopathic thrombocytopenic purpura (ITP) who do not respond to
      medical treatment. Long-term follow-up data of LS for ITP are scarce. METHODS:
      From May 1997 to December 2002, we performed 67 LS for patients with ITP. Data
      were assessed retrospectively. RESULTS: LS was successfully attempted in all 67
      patients. There was no surgical mortality. Three postoperative complications (5%)
      were encountered. The mean operative time decreased significantly from 176.2
      minutes in the first 41 cases to 125.2 minutes in the last 26 cases. The mean
      postoperative hospital stay was 3.2 days. Accessory spleens were found in 3
      patients (5%) during the LS. The mean follow-up interval was 23.3 months. The
      initial response to LS was 83%, and overall remission of ITP was 74%. The
      preoperative effect of steroid therapy had no significant influence on
      postoperative remission rate. More significant indicators of LS effectiveness
      were either an immediate postoperative platelet count surge or an immediate
      postoperative platelet count >or=100000/microL. CONCLUSIONS: LS can be performed
      safely with a satisfactory remission rate for patients with ITP who do not
      respond to medical treatment. Our results indicated that an immediate
      postoperative platelet count surge and/or an immediate postoperative platelet
      count >or=100000/microL were positive predictors of long-term remission after LS
      for ITP.

PMID- 15191866
TI  - Postoperative functional evaluation of jejunal interposition with or without a
      pouch after a total gastrectomy for gastric cancer.
AB  - BACKGROUND: The objective of this study was to compare the motility of a gastric
      substitute after jejunal interposition without a pouch and jejunal interposition
      with a pouch and to evaluate the relationship of both methods with nutritional
      outcome. METHODS: Twelve patients with gastric cancer treated by total
      gastrectomy and reconstruction with jejunal interposition without a pouch (J-I)
      and 14 patients treated by total gastrectomy and reconstruction with jejunal
      interposition with a pouch (J-P) were investigated in regard to the motor
      activity of the interposed jejunum and changes in body weight and dietary intake.
      RESULTS: Phase III of the interposed jejunum without a pouch was observed over a
      3-month follow-up, but phase III of the interposed jejunum with a pouch was not
      observed in any patient within 3 months of surgery. In the fed state, the motor
      activity of the interposed jejunum without a pouch increased significantly in
      patients within 12 months of follow-up, but in the interposed jejunum with a
      pouch, it did not. The amount of food consumed by the J-I group was significantly
      greater than that consumed by the J-P group. CONCLUSIONS: This study demonstrates
      that the interposed jejunum with a pouch shows marked disturbances from the motor
      pattern of a normal jejunum during the fasting and fed states. These motor
      abnormalities may be responsible for insufficient food intake of the J-P group.

PMID- 15191867
TI  - Outcome of paraaortic node-positive pancreatic head and bile duct adenocarcinoma.
AB  - BACKGROUND: This retrospective study aimed to identify the clinicopathologic
      features and surgical results of paraaortic node-positive periampullary
      adenocarcinoma. METHODS: Between 1995 and 1999, 101 patients underwent
      pancreatectomy with regional and paraaortic lymphadenectomy. Fifteen (15%)
      patients had histologically proven paraaortic lymph node disease. RESULTS: The 15
      patients included 9 (26%) of 34 patients with pancreatic head carcinoma and 6
      (17%) of 36 patients with bile duct adenocarcinoma. All 15 patients had locally
      advanced tumor invading adjacent structures. The 1-, 2-, and 3-year survival
      rates were 33%, 27%, and 0%, with median survival of 12 months (range 3 to 33).
      In patients with pancreatic head carcinoma or bile duct adenocarcinoma, survival
      curve for those without paraaortic lymph node metastasis was significantly better
      than that for those with involved paraaortic lymph nodes (P = 0.0033 or P =
      0.0149). CONCLUSIONS: When the paraaortic lymph nodes obtained from sampling
      biopsy are histologically positive, radical pancreatectomy with extended
      lymphatic and soft tissue clearance should be abandoned owing to poor outcome.

PMID- 15191868
TI  - Demonstration of a pancreaticopleural fistula with magnetic resonance
      cholangiopancreatography.

PMID- 15191869
TI  - A new reconstruction method for preventing delayed gastric emptying after pylorus
      preserving pancreatoduodenectomy.
AB  - BACKGROUND: With the aim of preventing delayed gastric emptying after pylorus
      preserving pancreatoduodenectomy (PPPD), we devised a new reconstruction method
      in which the pancreas and the bile duct are anastomosed to the proximal jejunum
      brought through the transverse mesocolon, and the duodenum is antecolically
      anastomosed to the jejunum below the mesocolon. The right gastric artery is
      divided in order to place the stomach, the duodenum, and the jejunum in a
      straight line. METHODS: Thirty patients underwent PPPD with the new
      reconstruction method (n = 12) or the conventional method (all anastomoses
      performed retrocolically; n = 18). Early and late complications were compared
      between the two groups. RESULTS: Delayed gastric emptying occurred respectively
      in 1 patient (8%) and 13 patients (72%) operated on by the new and conventional
      method (P <0.001). The incidences of other complications did not differ
      significantly between the two groups. CONCLUSIONS: The new reconstruction method
      may prevent delayed gastric emptying after PPPD.

PMID- 15191870
TI  - Laparoscopic cholecystectomy in geriatric patients.
AB  - BACKGROUND: The results and advantages of laparoscopic cholecystectomy in the
      geriatric population have received minimal attention. Several early reports
      related high conversion rates complications and mortality. This case series
      review is focused on the results of laparoscopic cholecystectomy in the geriatric
      population in a private practice environment. METHODS: The records of all
      patients undergoing cholecystectomy by the author over the past 12 years were
      reviewed. The entire series consists of 248 patients in whom 239 procedures were
      completed laparoscopically, with 9 patients converted to an open cholecystectomy.
      This report identifies 82 patients who were aged 65 years or older at the time of
      the laparoscopic cholecystectomy. The results of this series are reported in
      three progressive geriatric age groups: 65 to 74, 75 to 84, and 85 to 95 years.
      RESULTS: All 82 geriatric patients reported from this series were symptomatic
      from their gallbladder disease. A majority of all patients in all age groups were
      female. Gallstones were present in 77 patients, and 5 patients had a gallbladder
      ejection fraction of less than 35%. In this series of laparoscopic
      cholecystectomy, 26.8% had an emergent procedure for acute cholecystitis and the
      remainder had an elective or semielective procedure for symptomatic
      cholecystitis. The majority of patients between the ages of 65 and 84 years had
      elective procedures whereas the majority of patients over age 85 had an emergent
      procedure. There were 2 deaths. The first death (age 86 years) was from extensive
      metastatic cancer from the gallbladder, and the second patient (age 91 years)
      died of sepsis and multiple system organ failure. Each patient in this entire
      series had an attempt at laparoscopic removal of the gallbladder. The conversion
      rate was 3.6% in the entire series of 248 patients and also 3.6% in the geriatric
      series. Ninety-one percent of the patients in this geriatric series were
      discharged home after only 24 to 48 hours of postoperative observation.
      CONCLUSIONS: Laparoscopic cholecystectomy is a safe procedure in the geriatric
      population. The procedure should be recommended for all geriatric patients who
      have symptomatic cholecystitis before the development of acute cholecystitis or
      severe fibrosis with dense adhesions from chronic cholecystitis.

PMID- 15191872
TI  - Are there any prognostic factors for small intestinal stromal tumors?
AB  - BACKGROUND: Stromal tumors of the digestive tract, or gastrointestinal stromal
      tumors (GIST), originate from an intestinal mesenchymal precursor cell. Criteria
      that predict the outcome of small intestinal stromal tumors (SIST) after surgical
      resection are not clearly established. The aim of the study was to define
      prognostic criteria for SIST. METHODS: All c-kit positive SIST treated in our
      center over a 10-year period were reviewed. RESULTS: Eighteen patients with SIST
      treated by surgical resection were included. Overall actuarial 5-year survival
      was 74% (median follow-up of 69 months). We developed a panel of five criteria
      (tumor size, mitotic rate, proliferation index, presence of necrosis, and
      invasion of mucosa or adjacent structures) that permitted distinction between low
      and high malignant potential SIST. Presence of any four of these five criteria
      defined a high malignant potential SIST, and was associated with disease
      recurrence and poor prognosis after surgical resection (P <0.01). Patients with
      low malignant potential SIST had a 5-year survival of 92%, compared with 0% for
      high malignant potential SIST (P <0.01). CONCLUSIONS: This study demonstrates
      that a panel of morphologic factors can reliably distinguish between low and high
      malignant potential SIST. Although patients with low malignant potential SIST
      have an excellent prognosis after surgical resection, the role of adjuvant
      treatment for high malignant potential SIST remains to be defined.

PMID- 15191871
TI  - Five years' world experience with nonpenetrating clips for vascular anastomoses.
AB  - BACKGROUND: A new sutureless technique has been introduced clinically to
      facilitate the process of vascular reconstruction and improve patency. The Vessel
      Closure System (VCS) is nonpenetrating, creates an elastomeric everted
      anastomosis, and is easily and reproducibly applied. The objective of this report
      is to review the published world experience that has accrued regarding these
      clips with attention to the assets, liabilities, and pitfalls associated with the
      new technology. DATA SOURCES: Medline search and manual cross-referencing were
      performed, after which 61 original articles were identified on the use of VCS
      clips for vascular anastomoses. RESULTS: Advantages of the clips compared with
      sutures include the technical ease of application, the reduced anastomotic time,
      the superior hemodynamics, and the improved healing pattern of the anastomosis.
      Disadvantages include the potential problems in atherosclerotic vessels, lack of
      prospective randomized long-term follow-up, and initial costs. The best clinical
      results have been achieved in microvascular repair, as well as with vascular
      access and transplantation surgery. CONCLUSIONS: The VCS clip technology has
      become an accepted vascular anastomosing technique, which in future could lead to
      the use of clips as a standard approach and the use of sutures only in case of
      severe atherosclerosis and other circumstances in which vessel edges are
      difficult to evert.

PMID- 15191873
TI  - Effects of timing of thoracoscopic surgery for primary spontaneous pneumothorax
      on prognosis and costs.
AB  - BACKGROUND: Primary spontaneous pneumothorax recurs frequently. Timing of video
      assisted thoracoscopic surgery to prevent recurrence is controversial and long
      term costs remain inconclusive. METHODS: We constructed a Markov model to assess
      the effect of different timings for surgery on health status, costs, and cost
      effectiveness from the payers' perspective in Japan. RESULTS: During 1-year
      follow-up, the proportions of patients who underwent surgery after the first and
      second drainage were 46% and 36%, respectively. Average 1-year cost for surgery
      at the first episode was highest (U.S. dollars 6556), followed by the second
      (U.S. dollars 2988) and the third (U.S. dollars 2532). Incremental cost for
      surgery at the first episode compared with the second and that at the second
      episode compared with the third were U.S. dollars 30564 and U.S. dollars 29915
      per quality-adjusted life year, respectively. Sensitivity analyses showed utility
      and length of hospital stay for surgery have the strongest effect on incremental
      cost. CONCLUSIONS: Thoracoscopic surgery at the first episode significantly
      increased costs, but could be acceptable from a cost-effectiveness perspective.

PMID- 15191874
TI  - Howship-Romberg sign caused by an obturator granuloma.

PMID- 15191875
TI  - Circulating heat-shock protein 70 is associated with postoperative infection and
      organ dysfunction after liver resection.
AB  - BACKGROUND: Although extracellular heat-shock protein 70 (Hsp70) potentially
      mediates an inflammatory response, the association of circulating Hsp70 with
      complications after surgery is poorly understood. METHODS: Perioperative plasma
      concentrations of Hsp70 and interleukin-6 were measured by immunoassays in 64
      consecutive patients undergoing liver resection. RESULTS: Plasma concentrations
      of Hsp70 and interleukin-6 showed a striking increase immediately after surgery,
      and on postoperative day 1. The Hsp70 levels correlated significantly with
      operation time, hepatic ischemia time, postoperative alanine aminotransferase
      levels, and maximum interleukin-6 levels (P <0.01). The Hsp70 and interleukin-6
      concentrations were associated significantly with postoperative infection (P
      <0.05); Hsp70 concentrations and blood loss but not interleukin-6 were associated
      significantly with postoperative organ dysfunction (P <0.05) in multivariate
      analyses. CONCLUSIONS: These results suggest that circulating Hsp70 and IL-6
      potentially play a pivotal role in pathophysiology of postoperative infection,
      and that circulating Hsp70 and blood loss may represent a prognostic marker for
      postoperative organ dysfunction.

PMID- 15191876
TI  - Caustic burns of rectum and colon in emergencies.
AB  - BACKGROUND: Because of their rarity, chemical burns of rectum and colon have been
      poorly studied. This clinical report studies the epidemiologic, diagnostic, and
      therapeutic features of rectal and colonic burns after enema with caustics.
      METHODS: This is a retrospective clinical report of a personal series of 21
      patients admitted in our hospital from January 1990 to January 2000 for an acute
      chemical colitis after enema. RESULTS: Inpatient prevalence: 0.04%. Mean age:
      29.7 +/- 12 years (range 17 to 19). Sex ratio: 16 female and 5 male.
      Circumstances: suicide (n = 14), abortion (n = 3), murder (n = 3), mistake (n =
      1). Responsible caustic: sulphuric acid (n = 12), chlorhydric acid (n = 5),
      potash (n = 2), unknown acid (n = 1), plant decoction (n = 1). Injected quantity:
      50 to 250 mL. Ten patients suffered light damage and had an early favorable
      course under medical treatment, 8 of them had a secondary rectal-sigmoid
      stenosis. Eleven patients presented with severe necrotic damage, of difficult and
      often delayed diagnosis based on an enduring symptomatology without clear
      peritoneal syndrome. Upon surgery, necrotic damage spread on rectum and sigmoid
      colon (n = 2), up to the transverse colon (n = 4), to the right colonic angle (n
      = 3), to the right colon (n = 2); once a 10 cm long necrosis of the ileum was
      associated (n = 1); only 1 patient had a colonic perforation. Performed surgery:
      11 resections of necrotic colon and proximal colostomy (Hartman operation).
      Mortality: 6 patients. Morbidity: 3 of 5 patients. CONCLUSIONS: Chemical burns of
      rectum and colon produced by strong acid or basic products are necrotizing
      lesions whose gravity is often hidden by the absence of peritoneal inflammation
      signs, thus mortality is high. Only early surgery is likely to improve the poor
      prognosis of severe chemical damage of the rectum and colon.

PMID- 15191877
TI  - Some considerations for management of choledochal cysts.
AB  - BACKGROUND: There are five types of choledochal cysts, which are anomalies that
      involve intrahepatic or extrahepatic bile ducts, or both. These lesions are found
      most frequently in patients who are Asian, female, infants but are recognized
      with increasing frequency in adults. METHODS: We have managed 16 patients with
      this anomaly. One patient was Asian, and 1 was a child. There were 3 males and 13
      females. The mean age was 29 years. There were 9 type I, 1 type II, 1 type III, 4
      type IV, and 1 type V cysts. Resection of cysts and hepatico Roux-en-Y
      jejunostomy were performed in 9 patients for type I cysts.
      Pancreaticoduodenectomy was performed for a type I and a type IV cyst. The
      extrahepatic portion of a type IV cyst along with a segment of liver was resected
      in 1 patient. Operation was terminated on 1 patient with a type IV cyst because
      of extensive involvement of the intrahepatic ducts. She will undergo liver
      transplantation. The type II cyst was resected. No surgery was performed on a
      type III and type V cyst. Four of these patients were previously treated
      unsuccessfully by internal drainage procedures. RESULTS: There was no mortality.
      Morbidity was limited to a patient who previously underwent incomplete resection
      of a cyst and a cyst Roux-Y jejununostomy. No cholangiocarcinoma has been
      encountered in our patients after a mean follow-up of 5.5 years from the time of
      initial discovery of the choledochal cyst. CONCLUSIONS: Management of choledochal
      cysts is successful after their complete removal. Partial cyst resection and
      internal drainage is less satisfactory because of occasional pancreatitis,
      cholangitis, and cholangiocarcinoma. Resection of the intrahepatic and
      intrapancreatic portions of the cysts reduces the risk of cancer even though this
      risk is low after incomplete cyst excision. Biliary continuity after cyst
      resection is best established by Roux-Y hepaticojejunostomy.

PMID- 15191878
TI  - Linear staplers in pancreatic surgery.

PMID- 15191879
TI  - Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and
      autocrine regulation.
AB  - The phenotypic features of liver sinusoidal endothelial cells (SEC), open
      fenestrae in sieve plates and lack of a basement membrane, are lost with
      capillarization. The current study examines localization of CD31 as a marker for
      the dedifferentiated, nonfenestrated SEC and examines regulation of SEC phenotype
      in vitro. CD31 localization in SEC was examined by confocal microscopy and
      immunogold-scanning electron microscopy. SEC cultured for 1 day express CD31 in
      the cytoplasm, whereas after 3 days, CD31 is also expressed on cell-cell
      junctions. Immunogold-scanning electron microscopy confirmed the absence of CD31
      surface expression on fenestrated SEC 1 day after isolation and demonstrated the
      appearance of CD31 surface expression on SEC that had lost fenestration after 3
      days in culture. SEC isolated from fibrotic liver do show increased expression of
      CD31 on the cell surface. Coculture with either hepatocytes or stellate cells
      prevents CD31 surface expression, and this effect does not require heterotypic
      contact. The paracrine effect of hepatocytes or stellate cells on SEC phenotype
      is abolished with anti-VEGF antibody and is reproduced by addition of VEGF to SEC
      cultured alone. VEGF stimulates SEC production of nitric oxide. NG-nitro-L
      arginine methyl ester blocked the paracrine effect of hepatocytes or stellate
      cells on SEC phenotype and blocked the ability of VEGF to preserve the phenotype
      of SEC cultured alone. In conclusion, surface expression of CD31 is a marker of a
      dedifferentiated, nonfenestrated SEC. The VEGF-mediated paracrine effect of
      hepatocytes or stellate cells on maintenance of SEC phenotype requires autocrine
      production of nitric oxide by SEC.

PMID- 15191880
TI  - Epithelial cell spreading induced by hepatocyte growth factor influences paxillin
      protein synthesis and posttranslational modification.
AB  - Superficial wounds in the gastrointestinal tract rapidly reseal by coordinated
      epithelial cell migration facilitated by cytokines such as hepatocyte growth
      factor (HGF)/scatter factor released in the wound vicinity. However, the
      mechanisms by which HGF promotes physiological and pathophysiologic epithelial
      migration are incompletely understood. Using in vitro models of polarized T84 and
      Caco-2 intestinal epithelia, we report that HGF promoted epithelial spreading and
      RhoA GTPase activation in a time-dependent manner. Inducible expression of
      enhanced green fluorescent protein-tagged dominant-negative RhoA significantly
      attenuated HGF-induced spreading. HGF expanded a zone of partially flattened
      cells behind the wound edge containing basal F-actin fibers aligned in the
      direction of spreading. Concomitantly, plaques positive for the focal adhesion
      protein paxillin were enhanced. HGF induced an increase in the translation of
      paxillin and, to a lesser extent, beta1-integrin. This was independent of cell
      matrix adhesion through beta1-integrin. Subcellular fractionation revealed
      increased cosedimentation of paxillin with plasma membrane-containing fractions
      following HGF stimulation, without corresponding enhancements in paxillin
      coassociation with beta1 integrin or actin. Tyrosine phosphorylation of paxillin
      was reduced by HGF and was sensitive to the Src kinase inhibitor PP2. With these
      taken together, we propose that HGF upregulates a free cytosolic pool of paxillin
      that is unaffiliated with either the cytoskeleton or focal cell-matrix contacts.
      Thus early spreading responses to HGF may partly relate to increased paxillin
      availability for incorporation into, and turnover within, dynamic
      cytoskeletal/membrane complexes whose rapid and transient adhesion to the matrix
      drives migration.

PMID- 15191881
TI  - Stimulation of small intestinal burst activity in the postprandial state
      differentially affects lipid and glucose absorption in healthy adult humans.
AB  - Small intestinal motor activity is important for the optimal digestion and
      absorption of nutrients. These motor responses to feeding are frequently abnormal
      during critical illness, with the persistence of migrating bursts of contractions
      during enteral feeding. Whether this disturbance influences nutrient absorption
      is not known. In this study, the effects of small intestinal burst activity on
      lipid and glucose absorption were evaluated in 10 healthy human adults (6 males,
      4 females, 19-47 yr). Upper gastrointestinal manometry was recorded for 6 h
      during and shortly after a 20-min intravenous infusion of either erythromycin (1
      mg/kg), to stimulate burst activity, or saline (0.9%) in a double-blind
      randomized fashion. Simultaneously with the start of the intravenous infusion, 60
      ml liquid feed mixed with 200 microl 13C-triolein and 2 g 3-O-methylglucose (3
      OMG) was infused intraduodenally for 30 min. Absorption of lipid and glucose was
      assessed using the [13C]triolein breath test and plasma concentrations of 3-OMG,
      respectively. Infusion of erythromycin was followed by a more rapid onset of
      burst activity following commencement of the duodenal infusion compared with
      saline (30 +/- 6.1 vs. 58 +/- 10.7 min; P < 0.05). Erythromycin was associated
      with a slower recovery of 13CO2 (P < 0.01). A positive correlation existed
      between the time to onset of burst activity and 13CO2 recovery (P < 0.001).
      Erythromycin had no effect on 3-OMG absorption. In conclusion, stimulation of
      small intestinal burst activity reduces the rate of lipid absorption but not
      glucose absorption in healthy human adults.

PMID- 15191882
TI  - Quantitative hepatic phosphorus-31 magnetic resonance spectroscopy in compensated
      and decompensated cirrhosis.
AB  - Few studies have examined the physiological/biochemical status of hepatocytes in
      patients with compensated and decompensated cirrhosis in situ. Phosphorus-31
      magnetic resonance spectroscopy ((31)P MRS) is a noninvasive technique that
      permits direct assessments of tissue bioenergetics and phospholipid metabolism.
      Quantitative (31)P MRS was employed to document differences in the hepatic
      metabolite concentrations among patients with compensated and decompensated
      cirrhosis as well as healthy controls. All MRS examinations were performed on a
      1.5-T General Electric Signa whole body scanner. The concentration of hepatic
      phosphorylated metabolites among patients with compensated cirrhosis (n = 7) was
      similar to that among healthy controls (n = 8). However, patients with
      decompensated cirrhosis (n = 6) had significantly lower levels of hepatic ATP
      compared with patients with compensated cirrhosis and healthy controls (P < 0.02
      and P < 0.009, respectively) and a higher phosphomonoester/phosphodiester ratio
      than controls (P < 0.003). The results of this study indicate that metabolic
      disturbances in hepatic energy and phospholipid metabolism exist in patients with
      decompensated cirrhosis that are not present in patients with compensated
      cirrhosis or healthy controls. These findings provide new insights into the
      pathophysiology of hepatic decompensation.

PMID- 15191883
TI  - In vivo muscle amino acid transport involves two distinct processes.
AB  - We have tested the hypothesis that transit through the interstitial fluid, rather
      than across cell membranes, is rate limiting for amino acid uptake from blood
      into muscle in human subjects. To quantify muscle transmembrane transport of
      naturally occurring amino acids, we developed a novel 4-pool model that
      distinguishes between the interstitial and intracellular fluid compartments.
      Transport kinetics of phenylalanine, leucine, lysine, and alanine were quantified
      using tracers labeled with stable isotopes. The results indicate that
      interstitial fluid is a functional compartment insofar as amino acid kinetics are
      concerned. In the case of leucine and alanine, transit between blood and
      interstitial fluid was potentially rate limiting for muscle amino acid uptake and
      release in the postabsorptive state. For example, in the case of leucine, the
      rate of transport between blood and interstitial fluid compared with the
      corresponding rate between interstitial fluid and muscle was 247 +/- 36 vs. 610
      +/- 95 nmol.min(-1).100 ml leg(-1), respectively (P < 0.05). Our results are
      consistent with the process of diffusion governing transit from blood to
      interstitial fluid without selectivity, and of specific amino acid transport
      systems with varying degrees of efficiency governing transit from interstitial
      fluid to muscle. These results imply that changes in factors that affect the
      transit of amino acids from blood through interstitial fluid, such as muscle
      blood flow or edema, could play a major role in controlling the rate of muscle
      amino acid uptake.

PMID- 15191884
TI  - Differential regulation of fatty acid trapping in mouse adipose tissue and muscle
      by ASP.
AB  - Acylation-stimulating protein (ASP) is a lipogenic hormone secreted by white
      adipose tissue (WAT). Male C3 knockout (KO; C3(-/-)) ASP-deficient mice have
      delayed postprandial triglyceride (TG) clearance and reduced WAT mass. The
      objective of this study was to examine the mechanism(s) by which ASP deficiency
      induces differences in postprandial TG clearance and body composition in male KO
      mice. Except for increased (3)H-labeled nonesterified fatty acid (NEFA) trapping
      in brown adipose tissue (BAT) of KO mice (P = 0.02), there were no intrinsic
      tissue differences between wild-type (WT) and KO mice in (3)H-NEFA or
      [(14)C]glucose oxidation, TG synthesis or lipolysis in WAT, muscle, or liver.
      There were no differences in WAT or skeletal muscle hydrolysis, uptake, and
      storage of [(3)H]triolein substrate [in situ lipoprotein lipase (LPL) activity].
      ASP, however, increased in situ LPL activity in WAT (+64.8%, P = 0.02) but
      decreased it in muscle (-35.0%, P = 0.0002). In addition, after prelabeling WAT
      with [(3)H]oleate and [(14)C]glucose, ASP increased (3)H-lipid retention,
      [(3)H]TG synthesis, and [(3)H]TG-to-[(14)C]TG ratio, whereas it decreased (3)H
      NEFA release, indicating increased NEFA trapping in WAT. Conversely, in muscle,
      ASP induced effects opposite to those in WAT and increased lipolysis, indicating
      reduced NEFA trapping within muscle by ASP (P < 0.05 for all parameters). In
      conclusion, novel data in this study suggest that 1) there is little intrinsic
      difference between KO and WT tissue in the parameters examined and 2) ASP
      differentially regulates in situ LPL activity and NEFA trapping in WAT and
      skeletal muscle, which may promote optimal insulin sensitivity in vivo.

PMID- 15191885
TI  - Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6
      gene: absence of development of age-related obesity.
AB  - Obesity-related insulin resistance may be caused by adipokines such as IL-6,
      which is known to be elevated with the insulin resistance syndrome. A previous
      study reported that IL-6 knockout mice (IL-6(-/-)) developed maturity onset
      obesity, with disturbed carbohydrate and lipid metabolism, and increased leptin
      levels. Because IL-6 is associated with insulin resistance, one might have
      expected IL-6(-/-) mice to be more insulin sensitive. We examined body weights of
      growing and older IL-6(-/-) mice and found them to be similar to wild-type (IL
      6(+/+)) mice. Dual-energy X-ray absorptiometry analysis at 3 and 14 mo revealed
      no differences in body composition. There were no differences in fasting blood
      insulin and glucose or in triglycerides. To further characterize these mice, we
      fed 11-mo-old IL-6(-/-) and IL-6(+/+) mice a high- (HF)- or low-fat diet for 14
      wk, followed by insulin (ITT) and glucose tolerance tests (GTT). An ITT showed
      insulin resistance in the HF animals but no difference due to genotype. In the
      GTT, IL-6(-/-) mice demonstrated elevated postinjection glucose levels by 60%
      compared with IL-6(+/+) but only in the HF group. Although IL-6(-/-) mice gained
      weight and white adipose tissue (WAT) with the HF diet, they gained less weight
      than the IL-6(+/+) mice. Total lipoprotein lipase activity in WAT, muscle, and
      postheparin plasma was unchanged in the IL-6 (-/-) mice compared with IL-6(+/+)
      mice. There were no differences in plasma leptin or TNF-alpha due to genotype.
      Plasma adiponectin was approximately 53% higher (71.7 +/- 14.1 microg/ml) in IL
      6(-/-) mice than in IL-6(+/+) mice but only in the HF group. Thus these data show
      that IL-6(-/-) mice do not demonstrate obesity, fasting hyperglycemia, or
      abnormal lipid metabolism, although HF IL-6(-/-) mice demonstrate elevated
      glucose after a GTT.

PMID- 15191886
TI  - Regulation of myocardial function by histidine-rich, calcium-binding protein.
AB  - Impaired sarcoplasmic reticulum (SR) Ca release has been suggested to contribute
      to the depressed cardiac function in heart failure. The release of Ca from the SR
      may be regulated by the ryanodine receptor, triadin, junctin, calsequestrin, and
      a histidine-rich, Ca-binding protein (HRC). We observed that the levels of HRC
      were reduced in animal models and human heart failure. To gain insight into the
      physiological function of HRC, we infected adult rat cardiac myocytes with a
      recombinant adenovirus that contains the full-length mouse HRC cDNA.
      Overexpression (1.7-fold) of HRC in adult rat cardiomyocytes was associated with
      increased SR Ca load (28%) but decreased SR Ca-induced Ca release (37%),
      resulting in impaired Ca cycling and depressed fractional shortening (36%) as
      well as depressed rates of shortening (38%) and relengthening (33%). Furthermore,
      the depressed basal contractile and Ca kinetic parameters in the HRC-infected
      myocytes remained significantly depressed even after maximal isoproterenol
      stimulation. Interestingly, HRC overexpresssion was accompanied by increased
      protein levels of junctin (1.4-fold) and triadin (1.8-fold), whereas the protein
      levels of ryanodine receptor, calsequestrin, phospholamban, and
      sarco(endo)plasmic reticulum Ca-ATPase remained unaltered. Collectively, these
      data indicate that alterations in expression levels of HRC are associated with
      impaired cardiac SR Ca homeostasis and contractile function.

PMID- 15191887
TI  - Physiological significance of troponin T binding domains in striated muscle
      tropomyosin.
AB  - Striated muscle tropomyosin (TM) plays an essential role in sarcomeric
      contraction and relaxation through its regulated movement on the thin filament.
      Previous work in our laboratory established that alpha- and beta-TM isoforms
      elicit physiological differences in sarcomeric performance. To address the
      significance of isoform-specific troponin T binding regions in TM, in this
      present work we replaced alpha-TM amino acids 175-190 and 258-284 with the beta
      TM regions and expressed this chimeric protein in the hearts of transgenic mice.
      Hearts that express this chimeric protein exhibit significant decreases in rates
      of contraction and relaxation when assessed by ex vivo work-performing cardiac
      analyses. There are increases in time to peak pressure and in half-time to
      relaxation. These hearts respond appropriately to beta-adrenergic stimulation but
      do not attain control rates of contraction or relaxation. With increased
      expression of the transgene, 70% of the mice die by 5 mo of age without
      exhibiting gross pathological changes in the heart. Myofilaments from these mice
      have no differences in Ca(2+) sensitivity of percent maximum force, but there is
      a decrease in maximum tension development. Our data are the first to demonstrate
      that the troponin T binding regions of specific TM isoforms can alter sarcomeric
      performance without changing the Ca(2+) sensitivity of the myofilaments.

PMID- 15191888
TI  - Sphingosine kinase-1 mediates TNF-alpha-induced MCP-1 gene expression in
      endothelial cells: upregulation by oscillatory flow.
AB  - Atherosclerosis is a focal inflammatory disease and preferentially occurs in
      areas of low fluid shear stress and oscillatory flow, whereas the risk of
      atherosclerosis is decreased in regions of high fluid shear stress and steady
      laminar flow. Sphingosine kinase-1 (SphK1) catalyzes the conversion of
      sphingosine to sphingosine-1 phosphate (S1P), a sphingolipid metabolite that
      plays important roles in angiogenesis, inflammation, and cell growth. In the
      present study, we demonstrated that exposure of human aortic endothelial cells to
      oscillatory flow (shear stress, +/-5 dyn/cm(2) for 48 h) resulted in a marked
      increase in SphK1 mRNA levels compared with endothelial cells kept in static
      culture. In contrast, laminar flow (shear stress, 20 dyn/cm(2) for 48 h)
      decreased SphK1 mRNA levels. We further investigated the role of SphK1 in TNF
      alpha-induced expression of inflammatory genes, such as monocyte chemoattractant
      protein-1 (MCP-1) and VCAM-1 by using small interfering RNA (siRNA) specifically
      for SphK1. Treatment of endothelial cells with SphK1 siRNA suppressed TNF-alpha
      induced increase in MCP-1 mRNA levels, MCP-1 protein secretion, and activation of
      p38 MAPK. SphK1 siRNA also inhibited TNF-alpha-induced cell surface expression of
      VCAM-1, but not ICAM-1, protein. Exposure of endothelial cells to S1P led to an
      increase in MCP-1 protein secretion and MCP-1 mRNA levels and activation of NF
      kappaB-mediated transcriptional activity. Treatment of endothelial cells with the
      p38 MAPK inhibitor SB-203580 suppressed S1P-induced MCP-1 protein secretion.
      These data suggest that SphK1 mediates TNF-alpha-induced MCP-1 gene expression
      through a p38 MAPK-dependent pathway and may participate in oscillatory flow
      mediated proinflammatory signaling pathway in the vasculature.

PMID- 15191889
TI  - Prevention of diminished parasympathetic control of the heart in experimental
      heart failure.
AB  - Decreased synaptic transmission in parasympathetic ganglia contributes to
      abnormal parasympathetic function in heart failure (HF). Because nicotinic ACh
      receptors (nAChR) mediate synaptic transmission at the ganglion and upregulate in
      response to chronic exposure to agonist in vitro, we tested the hypothesis that
      repeated exposures of ganglionic neurons to a nAChR agonist can prevent a loss of
      parasympathetic control in HF. Two sets of experiments were performed. In set 1,
      unpaced control dogs and dogs undergoing pacing-induced HF were treated with a
      repeated intravenous nicotinic agonist during the development of HF. Under
      conditions of sympathetic blockade, R-R responses to a bolus injection of 200
      microg 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; nicotinic agonist) were
      found to be increased five times over the untreated group after 6 wk. In
      experimental set 2, dogs treated with weekly DMPP injections and in HF were
      anesthetized and underwent electrical stimulation of the right vagus nerve, which
      showed sinus cycle length responses >10 times that of controls (P < 0.05).
      Complete ganglionic blockade with hexamethonium abolished all responses,
      confirming that synaptic transmission was mediated entirely by nAChRs in both
      controls and HF. Despite decreased ganglionic function leading to reduced
      parasympathetic control of the heart in HF, repeated exposure with a nicotinic
      agonist during the development of HF results in not only preserved but also
      supranormal effects of parasympathetic stimulation on the sinus node.

PMID- 15191890
TI  - Bmx, a member of the Tec family of nonreceptor tyrosine kinases, is a novel
      participant in pharmacological cardioprotection.
AB  - Previous studies have indicated that PKC-epsilon is a central regulator of
      protective signal transduction in the heart. However, the signaling modules
      through which PKC-epsilon exerts its protective effects have only begun to be
      understood. We have identified a novel participant in the PKC-epsilon signaling
      system in cardioprotection, the nonreceptor tyrosine kinase Bmx. Functional
      proteomic analyses of PKC-epsilon signaling complexes identified Bmx as a member
      of these complexes. Subsequent studies in rabbits have indicated that Bmx is
      activated by nitric oxide (NO) in the heart, concomitant with the late phase of
      NO donor-induced protection, and provide the first analysis of Bmx
      expression/distribution in the setting of cardioprotection. In addition,
      increased expression of Bmx induced by NO donors was blocked by the same
      mechanism that blocked cardioprotection: inhibition of PKC with chelerythrine.
      These findings indicate that a novel type of PKC-tyrosine kinase module
      (involving Bmx) is formed in the heart and may be involved in pharmacological
      cardioprotection by NO donors.

PMID- 15191891
TI  - The permissive role of endothelial NO in CO-induced cerebrovascular dilation.
AB  - Carbon monoxide (CO) and nitric oxide (NO) are important paracrine messengers in
      the newborn cerebrovasculature that may act as comessengers. Here, we
      investigated the role of NO in CO-mediated dilations in the newborn
      cerebrovasculature. Arteriolar branches of the middle cerebral artery (100-200
      microm) were isolated from 3- to 7-day-old piglets and cannulated at each end in
      a superfusion chamber, and intravascular pressure was elevated to 30 mmHg, which
      resulted in the development of myogenic tone. Endothelium removal abolished
      dilations of pressurized pial arterioles to bradykinin and to the CO-releasing
      molecule Mn(2)(CO)(10) [dimanganese decacarbonyl (DMDC)] but not dilations to
      isoproterenol. With endothelium intact, N(omega)-nitro-l-arginine (l-NNA), 1H
      [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), or tetraethylammonium chloride
      (TEA(+)), inhibitors of NO synthase (NOS), guanylyl cyclase, and large
      conductance Ca(2+)-activated K(+) (K(Ca)) channels, respectively, also blocked
      dilation induced by DMDC. After inhibition of NOS, a constant concentration of
      sodium nitroprusside (SNP), a NO donor that only dilated the vessel 6%, returned
      dilation to DMDC. The stable cGMP analog 8-bromo-cGMP also restored dilation to
      DMDC in endothelium-intact, l-NNA-treated, or endothelium-denuded arterioles, and
      this effect was blocked by TEA(+). Similarly, in the continued presence of ODQ, 8
      bromo-cGMP restored DMDC-induced dilations. These findings suggest that
      endothelium-derived NO stimulates guanylyl cyclase in vascular smooth muscle
      cells and, thereby, permits CO to cause dilation by activating K(Ca) channels.
      Such a requirement for NO could explain the endothelium dependency of CO-induced
      dilation in piglet pial arterioles.

PMID- 15191892
TI  - Hypotension and bradycardia during caloric restriction in mice are independent of
      salt balance and do not require ANP receptor.
AB  - We hypothesized that caloric restriction (CR)-induced hypotension would correlate
      with increased sodium excretion through an atrial natriuretic peptide (ANP)
      dependent mechanism. To test this hypothesis, the cardiovascular parameters of
      c57/Bl mice were measured with radiotelemetry while urine was collected. The 23-h
      mean blood pressure (BP) dropped from 108.6 +/- 1.8 to 92.7 +/- 2.4 mmHg, and 23
      h heart rate dropped from 624 +/- 5 to 426 +/- 13 beats/min over 7 days of CR at
      29 degrees C. Contrary to our hypothesis, urine sodium excretion decreased by 55%
      by day 7 of CR. Consistent with decreased sodium excretion was the drop in plasma
      ANP (from 82.4 +/- 4.3 to 68.0 +/- 5.8 pg/ml). To explore the possibility that CR
      lowers BP through an ANP receptor-dependent mechanism that is independent of its
      effect on sodium retention, we measured the cardiovascular parameters of mice
      deficient in the ANP receptor (NPR1(-/-)) or the ANP clearance receptor (NPR3(-/
      )). Mean BP fell from 117.1 +/- 3.9 to 108.0 +/- 4.7 mmHg in the NPR1(-/-) mice
      and from 87.0 +/- 2.4 to 78.4 +/- 1.7 mmHg in the NPR3(-/-) mice during CR. These
      data indicate that the hypotension induced by CR does not depend on increased
      sodium excretion. Rather, it appears that the mouse responds to the low BP
      induced by CR with an increase in sodium reabsorption. Furthermore, circulating
      ANP levels and data from NPR1(-/-) and NPR3(-/-) mice suggest that the ANP
      pathway may not be involved in the cardiovascular response to CR.

PMID- 15191894
TI  - Upregulation of corin gene expression in hypertrophic cardiomyocytes and failing
      myocardium.
AB  - High levels of plasma atrial natriuretic peptides (ANP) are associated with
      pathological conditions such as congestive heart failure (CHF). Recently, we have
      identified a cardiac serine protease, corin, that is the pro-ANP convertase. In
      this study, we examined the regulation of corin gene expression in cultured
      hypertrophic cardiomyocytes and in the left ventricular (LV) myocardium of a rat
      model of heart failure. Quantitative RT-PCR analysis showed that both corin and
      ANP mRNA levels were significantly increased in phenylephrine (PE)-stimulated rat
      neonatal cardiomyocytes in culture. The increase in corin mRNA correlated closely
      with the increase in cell size and ANP mRNA expression in the PE-treated cells (r
      = 0.95, P < 0.01; r = 0.92, P < 0.01, respectively). The PE-treated
      cardiomyocytes had an increased activity in converting recombinant human pro-ANP
      to biologically active ANP, as determined by a pro-ANP processing assay and a
      cell-based cGMP assay. In a rat model of heart failure induced by ligation of the
      left coronary artery, corin mRNA expression in the noninfarcted LV myocardium was
      significantly higher than that of control heart tissues from sham-operated
      animals, when examined by Northern blot analysis and RT-PCR at 8 wk. These
      results indicate that the corin gene is upregulated in hypertrophic
      cardiomyocytes and failing myocardium. Increased corin expression may contribute
      to elevation of ANP in the setting of cardiac hypertrophy and heart failure.

PMID- 15191893
TI  - Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats.
AB  - Hydrogen sulfide (H2S) has been shown recently to function as an important
      gasotransmitter. The present study investigated the vascular effects of H2S, both
      exogenously applied and endogenously generated, on resistance mesenteric arteries
      of rats and the underlying mechanisms. Both H2S and NaHS evoked concentration
      dependent relaxation of in vitro perfused rat mesenteric artery beds (MAB). The
      sensitivity of MAB to H2S (EC50, 25.2 +/- 3.6 microM) was about fivefold higher
      than that of rat aortic tissues. Removal of endothelium or coapplication of
      charybdotoxin and apamin to endothelium-intact MAB significantly reduced the
      vasorelaxation effects of H2S. The H2S-induced relaxation of MAB was partially
      mediated by ATP-sensitive K+ (KATP) channel activity in vascular smooth muscle
      cells. Pinacidil (EC50, 1.7 +/- 0.1 microM, n=6) mimicked, but glibenclamide (10
      microM, n=6) suppressed, the vasorelaxant effect of H2S. KATP channel currents in
      isolated mesenteric artery smooth muscle cells were significantly augmented by
      H2S. L-cysteine, a substrate of cystathionine-gamma-lyase (CSE), at 1 mM
      increased endogenous H2S production by sixfold in rat mesenteric artery tissues
      and decreased contractility of MAB. DL-propargylglycine (a blocker of CSE) at 10
      microM abolished L-cysteine-dependent increase in H2S production and relaxation
      of MAB. Our results demonstrated a tissue-specific relaxant response of
      resistance arteries to H2S. The stimulation of KATP channels in vascular smooth
      muscle cells and charybdotoxin/apamin-sensitive K+ channels in vascular
      endothelium by H2S represents important cellular mechanisms for H2S effect on
      MAB. Our study also demonstrated that endogenous CSE can generate sufficient H2S
      from exogenous L-cysteine to cause vasodilation. Future studies are merited to
      investigate direct contribution of endogenous H2S to regulation of vascular tone.

PMID- 15191895
TI  - Oxygen distribution in microcirculation after arginine vasopressin-induced
      arteriolar vasoconstriction.
AB  - The microvascular distribution of oxygen was studied in the arterioles and
      venules of the awake hamster window chamber preparation to determine the
      contribution of vascular smooth muscle contraction to oxygen consumption of the
      microvascular wall during arginine vasopressin (AVP)-induced vasoconstriction.
      AVP was infused intravenously at the clinical dosage (0.0001 IU.kg(-1).min(-1))
      and caused a significant arteriolar constriction, decreased microvascular flow
      and functional capillary density, and a substantial rise in arteriolar vessel
      wall transmural Po(2) difference. AVP caused tissue Po(2) to be significantly
      lowered from 25.4 +/- 7.4 to 7.2 +/- 5.8 mmHg; however, total oxygen extraction
      by the microcirculation increased by 25%. The increased extraction, lowered
      tissue Po(2), and increased wall oxygen concentration gradient are compatible
      with the hypothesis that vasoconstriction significantly increases vessel wall
      oxygen consumption, which in this model appears to constitute an important oxygen
      consuming compartment. This conclusion was supported by the finding that the
      small percentage of the vessels that dilated in these experiments had a vessel
      wall oxygen gradient that was smaller than control and which was not determined
      by changes in tissue Po(2). These findings show that AVP administration, which
      reduces oxygen supply by vasoconstriction, may further impair tissue oxygenation
      by the additional oxygen consumption of the microcirculation.

PMID- 15191896
TI  - Moderate severity heart failure does not involve a downregulation of myocardial
      fatty acid oxidation.
AB  - Recent human and animal studies have demonstrated that in severe end-stage heart
      failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype,
      characterized by downregulation of free fatty acid (FFA) oxidation and an
      enhancement of glucose oxidation. The goal of this study was to examine
      myocardial substrate metabolism in a model of moderate coronary microembolization
      induced HF. We hypothesized that during well-compensated HF, FFA oxidation would
      predominate as opposed to a more fetal metabolic phenotype of greater glucose
      oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n
      = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction =
      28%) by infusing three isotopic tracers ([9,10-(3)H]oleate, [U-(14)C]glucose, and
      [1-(13)C]lactate) in anesthetized open-chest animals. There were no differences
      in myocardial substrate metabolism between the two groups. The total activity of
      pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation
      (and hence glucose and lactate oxidation) was not affected by HF. We did not
      observe any difference in the activity of carnitine palmitoyl transferase I (CPT
      I) and its sensitivity to inhibition by malonyl-CoA between groups; however,
      malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo
      inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be
      explained by changes in the Michaelis-Menten constant and maximal velocity for
      malonyl-CoA decarboxylase because neither were affected by HF. These results
      support the concept that there is no decrease in fatty acid oxidation during
      compensated HF and that the downregulation of fatty acid oxidation enzymes and
      the switch to carbohydrate oxidation observed in end-stage HF is only a late
      stage phenomenon.

PMID- 15191897
TI  - Influence of increased central venous pressure on baroreflex control of
      sympathetic activity in humans.
AB  - Volume expansion often ameliorates symptoms of orthostatic intolerance; however,
      the influence of this increased volume on integrated baroreflex control of
      vascular sympathetic activity is unknown. We tested whether acute increases in
      central venous pressure (CVP) diminished subsequent responsiveness of muscle
      sympathetic nerve activity (MSNA) to rapid changes in arterial pressure. We
      studied healthy humans under three separate conditions: control, acute 10 degrees
      head-down tilt (HDT), and saline infusion (SAL). In each condition, heart rate,
      arterial pressure, CVP, and peroneal MSNA were measured during 5 min of rest and
      then during rapid changes in arterial pressure induced by sequential boluses of
      nitroprusside and phenylephrine (modified Oxford technique). Sensitivities of
      integrated baroreflex control of MSNA and heart rate were assessed as the slopes
      of the linear portions of the MSNA-diastolic blood pressure and R-R interval
      systolic pressure relations, respectively. CVP increased approximately 2 mmHg in
      both SAL and HDT conditions. Resting heart rate and mean arterial pressure were
      not different among trials. Sensitivity of baroreflex control of MSNA was
      decreased in both SAL and HDT condition, respectively: -3.1 +/- 0.6 and -3.3 +/-
      1.0 versus -5.0 +/- 0.6 units.beat(-1).mmHg(-1) (P < 0.05 for SAL and HDT vs.
      control). Sensitivity of baroreflex control of the heart was not different among
      conditions. Our results indicate that small increases in CVP decrease the
      sensitivity of integrated baroreflex control of sympathetic nerve activity in
      healthy humans.

PMID- 15191898
TI  - Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin-D on the
      electrophysiology of perfused mouse hearts.
AB  - Chemical uncouplers diacetyl monoxime (DAM) and cytochalasin D (cyto-D) are used
      to abolish cardiac contractions in optical studies, yet alter intracellular
      Ca(2+) concentration ([Ca(2+)](i)) handling and vulnerability to arrhythmias in a
      species-dependent manner. The effects of uncouplers were investigated in perfused
      mouse hearts labeled with rhod-2/AM or 4-[beta-[2-(di-n-butylamino)-6
      naphthyl]vinyl]pyridinium (di-4-ANEPPS) to map [Ca(2+)](i) transients (emission
      wavelength = 585 +/- 20 nm) and action potentials (APs) (emission wavelength >
      610 nm; excitation wavelength = 530 +/- 20 nm). Confocal images showed that rhod
      2 is primarily in the cytosol. DAM (15 mM) and cyto-D (5 microM) increased AP
      durations (APD(75) = 20.0 +/- 3 to 46.6 +/- 5 ms and 39.9 +/- 8 ms, respectively,
      n = 4) and refractory periods (45.14 +/- 12.1 to 82.5 +/- 3.5 ms and 78 +/- 4.24
      ms, respectively). Cyto-D reduced conduction velocity by 20% within 5 min and DAM
      by 10% gradually in 1 h (n = 5 each). Uncouplers did not alter the direction and
      gradient of repolarization, which progressed from apex to base in 15 +/- 3 ms.
      Peak systolic [Ca(2+)](i) increased with cyto-D from 743 +/- 47 (n = 8) to 944 +/
      17 nM (n = 3, P = 0.01) but decreased with DAM to 398 +/- 44 nM (n = 3, P <
      0.01). Diastolic [Ca(2+)](i) was higher with cyto-D (544 +/- 80 nM, n = 3) and
      lower with DAM (224 +/- 31, n = 3) compared with controls (257 +/- 30 nM, n = 3).
      DAM prolonged [Ca(2+)](i) transients at 75% recovery (54.3 +/- 5 to 83.6 +/- 1.9
      ms), whereas cyto-D had no effect (58.6 +/- 1.2 ms; n = 3). Burst pacing
      routinely elicited long-lasting ventricular tachycardia but not fibrillation.
      Uncouplers flattened the slope of AP restitution kinetic curves and blocked
      ventricular tachycardia induced by burst pacing.

PMID- 15191899
TI  - Microvascular PO2 during extreme hemodilution with hemoglobin site specifically
      PEGylated at Cys-93(beta) in hamster window chamber.
AB  - The oxygen transport capacity of nonhypertensive polyethylene glycol (PEG)
      conjugated hemoglobin solutions were investigated in the hamster chamber window
      model. Microvascular measurements were made to determine oxygen delivery in
      conditions of extreme hemodilution [hematocrit (Hct) 11%]. Two isovolemic
      hemodilution steps were performed with a 6% Dextran 70 (70-kDa molecular mass)
      plasma expander until Hct was 35% of control. Isovolemic blood volume exchange
      was continued using two surface-modified PEGylated hemoglobins (P5K2, P(50) =
      8.6, and P10K2, P(50) = 8.3; P(50) is the hemoglobin Po(2) corresponding to its
      50% oxygen saturation) until Hct was 11%. P5K2 and P10K2 are PEG-conjugated
      hemoglobins that maintain most of the hemoglobin allosteric properties and have a
      cooperativity index of n = 2.2. The effects of these molecular solutions were
      compared with those obtained in a previous study using MP4, a PEG-modified
      hemoglobin whose P(50) was 5.4 and cooperativity was 1.2 (Tsai et al., Am J
      Physiol Heart Circ Physiol 285: H1411-H1419, 2003). Tissue oxygen levels were
      higher after P5K2 (7.0 +/- 2.5 mmHg) and P10K2 (6.3 +/- 2.3 mmHg) versus MP4 (1.7
      +/- 0.5 mmHg) or the nonoxygen carrier Dextran 70 (1.3 +/- 1.2 mmHg).
      Microvascular oxygen delivery was higher after P5K2 and P10K2 (2.22 and 2.34 ml
      O(2)/dl blood) compared with MP4 (1.41 ml O(2)/dl blood) or Dextran 70 (0.90 ml
      O(2)/dl blood); however, all these values were lower than control (7.42 ml
      O(2)/dl blood). The total hemoglobin in blood was similar in all cases;
      therefore, the improvement in tissue Po(2) and oxygen delivery appears to be due
      to the increased cooperativity of the new molecules.

PMID- 15191900
TI  - Do fever and anapyrexia exist? Analysis of set point-based definitions.
AB  - Fever and anapyrexia are the most studied thermoregulatory responses. They are
      defined as a body temperature (T(b)) increase and decrease, respectively,
      occurring because of a shift in the set point (SP) and characterized by active
      defense of the new T(b). Although models of T(b) control with a single SP
      (whether obvious or hidden) have been criticized, the SP-based definitions have
      remained unchallenged. In this article, the SP-based definitions of fever and
      anapyrexia were subjected to two tests. In test 1, they were compared with
      experimental data on changes in thresholds for activation of different
      thermoeffectors. Changes in thresholds were found compatible with an SP increase
      in some (but not all) cases of fever. In all cases of what is called anapyrexia,
      its mechanism (dissociation of thresholds of different effectors) was found
      incompatible with a decrease in a single SP. In test 2, experimental data on the
      dependence of T(b) on ambient temperature (T(a)) were analyzed. It was found that
      the febrile level of T(b) is defended in some (but not all) cases. However,
      strong dependence on T(a) was found in all cases of anapyrexia, which agrees with
      threshold dissociation but not with a decrease of the SP. It is concluded that
      fever (as defined) has only limited experimental support, whereas anapyrexia (as
      defined) does not exist. Two solutions are offered. A palliative is to accept
      that SP-based terms (anapyrexia, cryexia, regulated hypothermia, and such) are
      inadequate and should be abandoned. A radical solution is to transform all
      definitions based on comparing T(b) with the SP into definitions based on
      balancing active and passive processes of T(b) control.

PMID- 15191901
TI  - Impact of periconceptional nutrition on maternal and fetal leptin and fetal
      adiposity in singleton and twin pregnancies.
AB  - It has been proposed that maternal nutrient restriction may alter the functional
      development of the adipocyte and the synthesis and secretion of the adipocyte
      derived hormone, leptin, before birth. We have investigated the effects of
      restricted periconceptional undernutrition and/or restricted gestational
      nutrition on fetal plasma leptin concentrations and fetal adiposity in late
      gestation. There was no effect of either restricted periconceptional or
      gestational nutrition on maternal or fetal plasma leptin concentrations in
      singleton or twin pregnancies during late gestation. In ewes carrying twins, but
      not singletons, maternal plasma leptin concentrations in late gestation were
      directly related to the change in ewe weight that occurred during the 60 days
      before mating [maternal leptin = 0.9 (change in ewe weight) + 7.8; r = 0.6, P <
      0.05]. In twin, but not singleton, pregnancies, there was also a significant
      relationship between maternal and fetal leptin concentrations (maternal leptin =
      0.5 fetal leptin + 4.2, r = 0.63, P < 0.005). The relative mass of perirenal fat
      was also significantly increased in twin fetal sheep in the control-restricted
      group (6.0 +/- 0.5) compared with the other nutritional groups (control-control:
      4.1 +/- 0.4; restricted-restricted: 4.4 +/- 0.4; restricted-control: 4.3 +/-
      0.3). In conclusion, the impact of maternal undernutrition on maternal plasma
      leptin concentrations during late gestation is dependent on fetal number.
      Furthermore, we have found that there is an increased fetal adiposity in the
      twins of ewes that experienced restricted nutrition throughout gestation, and
      this may be important in the programming of postnatal adiposity.

PMID- 15191902
TI  - Regenerative capacity of the dystrophic (mdx) diaphragm after induced injury.
AB  - Duchenne muscular dystrophy is characterized by myofiber necrosis, muscle
      replacement by connective tissue, and crippling weakness. Although the mdx mouse
      also lacks dystrophin, most muscles show little myofiber loss or functional
      impairment. An exception is the mdx diaphragm, which is phenotypically similar to
      the human disease. Here we tested the hypothesis that the mdx diaphragm has a
      defective regenerative response to necrotic injury, which could account for its
      severe phenotype. Massive necrosis was induced in mdx and wild-type (C57BL10)
      mouse diaphragms in vivo by topical application of notexin, which destroys mature
      myofibers while leaving myogenic precursor satellite cells intact. At 4 h after
      acute exposure to notexin, >90% of diaphragm myofibers in both wild-type and mdx
      mice demonstrated pathological sarcolemmal leakiness, and there was a complete
      loss of isometric force-generating capacity. Both groups of mice showed strong
      expression of embryonic myosin within the diaphragm at 5 days, which was largely
      extinguished by 20 days after injury. At 60 days postinjury, wild-type diaphragms
      exhibited a persistent loss ( approximately 25%) of isometric force-generating
      capacity, associated with a trend toward increased connective tissue
      infiltration. In contrast, mdx diaphragms achieved complete functional recovery
      of force generation to noninjured values, and there was no increase in muscle
      connective tissue over baseline. These data argue against any loss of intrinsic
      regenerative capacity within the mdx diaphragm, despite characteristic features
      of major dystrophic pathology being present. Our findings support the concept
      that significant latent regenerative capacity resides within dystrophic muscles,
      which could potentially be exploited for therapeutic purposes.

PMID- 15191903
TI  - Standing up to the challenge of standing: a siphon does not support cerebral
      blood flow in humans.
AB  - Model studies have been advanced to suggest both that a siphon does and does not
      support cerebral blood flow in an upright position. If a siphon is established
      with the head raised, it would mean that internal jugular pressure reflects right
      atrium pressure minus the hydrostatic difference from the brain. This study
      measured spinal fluid pressure in the upright position, the pressure and the
      ultrasound-determined size of the internal jugular vein in the supine and sitting
      positions, and the internal jugular venous pressure during seated exercise. When
      the head was elevated approximately 25 cm above the level of the heart, internal
      jugular venous pressure decreased from 9.5 (SD 2.8) to 0.2 (SD 1.0) mmHg [n = 15;
      values are means (SD); P < 0.01]. Similarly, central venous pressure decreased
      from 6.2 (SD 1.8) to 0.6 (SD 2.6) mmHg (P < 0.05). No apparent lumen was detected
      in any of the 31 left or right internal veins imaged at 40 degrees head-up tilt,
      and submaximal (n = 7) and maximal exercise (n = 4) did not significantly affect
      internal jugular venous pressure. While seven subjects were sitting up, spinal
      fluid pressure at the lumbar level was 26 (SD 4) mmHg corresponding to 0.1 (SD
      4.1) mmHg at the base of the brain. These results demonstrate that both for
      venous outflow from the brain and for spinal fluid, the prevailing pressure
      approaches zero at the base of the brain when humans are upright, which negates
      that a siphon supports cerebral blood flow.

PMID- 15191904
TI  - Predominant postglomerular vascular resistance response to reflex renal
      sympathetic nerve activation during ANG II clamp in rabbits.
AB  - We have shown previously that a moderate reflex increase in renal sympathetic
      nerve activity (RSNA) elevated glomerular capillary pressure, whereas a more
      severe increase in RSNA decreased glomerular capillary pressure. This suggested
      that the nerves innervating the glomerular afferent and efferent arterioles could
      be selectively activated, allowing differential control of glomerular capillary
      pressure. A caveat to this conclusion was that intrarenal actions of neurally
      stimulated ANG II might have contributed to the increase in postglomerular
      resistance. This has now been investigated. Anesthetized rabbits were prepared
      for renal micropuncture and RSNA recording. One group (ANG II clamp) received an
      infusion of an angiotensin-converting enzyme inhibitor (enalaprilat, 2 mg/kg
      bolus plus 2 mg.kg(-1).h(-1)) plus ANG II ( approximately 20 ng.kg(-1).min(-1)),
      the other vehicle. Measurements were made before (room air) and during 14% O(2).
      Renal blood flow decreased less during ANG II clamp compared with vehicle [9 +/-
      1% vs. 20 +/- 4%, interaction term (P(GT)) < 0.05], despite a similar increase in
      RSNA in response to 14% O(2) in the two groups. Arterial pressure and glomerular
      filtration rate were unaffected by 14% O(2) in both groups. Glomerular capillary
      pressure increased from 33 +/- 1 to 37 +/- 1 mmHg during ANG II clamp and from 33
      +/- 2 to 35 +/- 1 mmHg in the vehicle group before and during 14% O(2),
      respectively (P(GT) < 0.05). During ANG II clamp, postglomerular vascular
      resistance was still increased in response to RSNA during 14% O(2), demonstrating
      that the action of the renal nerves on the postglomerular vasculature was
      independent of the renin-angiotensin system. This further supports our hypothesis
      that increases in RSNA can selectively control pre- and postglomerular vascular
      resistance and therefore glomerular ultrafiltration.

PMID- 15191905
TI  - Top-down control analysis of the effect of temperature on ectotherm oxidative
      phosphorylation.
AB  - Top-down control and elasticity analysis was conducted on mitochondria isolated
      from the midgut of the tobacco hornworm (Manduca sexta) to assess how temperature
      affects oxidative phosphorylation in a eurythermic ectotherm. Oxygen consumption
      and protonmotive force (measured as membrane potential in the presence of
      nigericin) were monitored at 15, 25, and 35 degrees C. State 4 respiration
      displayed a Q(10) of 2.4-2.7 when measured over two temperature ranges (15-25
      degrees C and 25-35 degrees C). In state 3, the Q(10)s for respiration were 2.0
      and 1.7 for the lower and higher temperature ranges, respectively. The kinetic
      responses (oxygen consumption) of the substrate oxidation system, proton leak,
      and phosphorylation system increased as temperature rose, although the proton
      leak and substrate oxidation system showed the greatest thermal sensitivity.
      Whereas there were temperature-induced changes in the activities of the oxidative
      phosphorylation subsystems, there was no change in the state 4 membrane potential
      and little change in the state 3 membrane potential. Top-down control analysis
      revealed that control over respiration did not change with temperature. In state
      4, control of respiration was shared nearly equally by the proton leak and the
      substrate oxidation system, whereas in state 3 the substrate oxidation system
      exerted over 90% of the control over respiration. The proton leak and
      phosphorylation system account for <10% of the temperature-induced change in the
      state 3 respiration rate. Therefore, when the temperature is changed, the state 3
      respiration rate is altered primarily because of temperature's effect on the
      substrate oxidation system.

PMID- 15191906
TI  - Fetal heart rate variability and brain stem injury after asphyxia in preterm
      fetal sheep.
AB  - This study was undertaken to determine the mechanisms mediating changes in fetal
      heart rate variability (FHRV) during and after exposure to asphyxia in the
      premature fetus. Preterm fetal sheep at 0.6 of gestation (91 +/- 1 days, term is
      147 days) were exposed to either sham occlusion (n = 10) or to complete umbilical
      cord occlusion for either 20 (n = 7) or 30 min (n = 10). Cord occlusion led to a
      transient increase in FHRV with abrupt body movements that resolved after 5 min.
      In the 30 min group there was a marked increase in FHRV in the final 10 min of
      occlusion related to abnormal atrial activity. After reperfusion, FHRV in both
      study groups was initially suppressed and progressively increased to baseline
      levels over the first 4 h of recovery. In the 20 min group this improvement was
      associated with return of normal EEG activity and movements. In contrast, in the
      30 min group the EEG was abnormal with epileptiform activity superimposed on a
      suppressed background, which was associated with abnormal fetal movements. As the
      epileptiform activity resolved, FHRV fell and became suppressed for the remainder
      of the study. Histological assessment after 72 h demonstrated severe brain stem
      injury in the 30 min group but not in the 20 min group. In conclusion, during
      early recovery from asphyxia, epileptiform activity and associated abnormal fetal
      movements related to evolving neural injury can cause a confounding transient
      increase in FHRV, which mimics the normal pattern of recovery. However, chronic
      suppression of FHRV was a strong predictor of severe brain stem injury.

PMID- 15191907
TI  - Activation of the systemic and adipose renin-angiotensin system in rats with diet
      induced obesity and hypertension.
AB  - In obesity-related hypertension, activation of the renin-angiotensin system (RAS)
      has been reported despite marked fluid volume expansion. Adipose tissue expresses
      components of the RAS and is markedly expanded in obesity. This study evaluated
      changes in components of the adipose and systemic RAS in diet-induced obese
      hypertensive rats. RAS was quantified in adipose tissue and compared with primary
      sources for the circulating RAS. Male Sprague-Dawley rats were fed either a low
      fat (LF; 11% kcal as fat) or moderately high-fat (32% kcal as fat) diet for 11
      wk. After 8 wk, rats fed the moderately high-fat diet segregated into obesity
      prone (OP) and obesity-resistant (OR) groups based on their body weight gain
      (body weight: OR, 566 +/- 10; OP, 702 +/- 20 g; P < 0.05). Mean arterial blood
      pressure was increased in OP rats (LF: 97 +/- 2; OR: 97 +/- 2; OP: 105 +/- 1
      mmHg; P < 0.05). Quantification of mRNA expression by real-time PCR demonstrated
      a selective increase (2-fold) in angiotensinogen gene expression in
      retroperitoneal adipose tissue from OP vs. OR and LF rats. Similarly, plasma
      angiotensinogen concentration was increased in OP rats (LF: 390 +/- 48; OR: 355
      +/- 24; OP: 530 +/- 22 ng/ml; P < 0.05). In contrast, other components of the RAS
      were not altered in OP rats. Marked increases in the plasma concentrations of
      angiotensin peptides were observed in OP rats (angiotensin II: LF: 95 +/- 31; OR:
      59 +/- 20; OP: 295 +/- 118 pg/ml; P < 0.05). These results demonstrate increased
      activity of the adipose and systemic RAS in obesity-related hypertension.

PMID- 15191908
TI  - 5-HT3 receptors participate in CCK-induced suppression of food intake by delaying
      gastric emptying.
AB  - Serotonin type 3 (5-HT(3)) receptors have been shown to participate in the
      negative-feedback control of food intake. We previously reported that
      cholecystokinin (CCK)-induced suppression of food intake is partly mediated
      through 5-HT(3) receptors when rats were tested on a preferred liquid diet, but
      whether such an effect occurs when they are tested on a solid maintenance diet is
      unknown. In the present study, we examined the effects of ondansetron, a
      selective 5-HT(3) antagonist, on CCK-induced suppression of solid chow intake.
      Intraperitoneal administration of ondansetron significantly attenuated 30- and 60
      min CCK-induced reduction of food intake, with suppression being completely
      reversed by 120 min. It is not known whether 5-HT(3) receptors directly mediate
      CCK-induced satiation or whether their participation depends on CCK acting as
      part of a feedback cascade to inhibit ongoing intake. Because CCK-induced
      inhibition of sham feeding does not depend on additive gastric/postgastric
      feedback signals, we examined the ability of ondansetron to reverse CCK-induced
      satiation in sham-feeding rats. Ondansetron did not attenuate reduction of sham
      feeding by CCK, suggesting that ondansetron does not directly antagonize CCK
      satiation signals. CCK suppresses real feeding through a delay in gastric
      emptying. Ondansetron could attenuate CCK-induced reduction of food intake by
      reversing CCK-induced inhibition of gastric emptying. We found that blockade of 5
      HT(3) receptors attenuates CCK-induced inhibition of gastric emptying of a solid
      meal, as well as saline and glucose loads. We conclude that 5-HT(3) receptors
      mediate CCK-induced satiation through indirect mechanisms as part of a feedback
      cascade involving inhibition of gastric emptying.

PMID- 15191909
TI  - Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of
      acclimatization to 4,100 m and in high-altitude Aymara natives.
AB  - We aimed to test effects of altitude acclimatization on pulmonary gas exchange at
      maximal exercise. Six lowlanders were studied at sea level, in acute hypoxia
      (AH), and after 2 and 8 wk of acclimatization to 4,100 m (2W and 8W) and compared
      with Aymara high-altitude natives residing at this altitude. As expected,
      alveolar Po2 was reduced during AH but increased gradually during acclimatization
      (61 +/- 0.7, 69 +/- 0.9, and 72 +/- 1.4 mmHg in AH, 2W, and 8W, respectively),
      reaching values significantly higher than in Aymaras (67 +/- 0.6 mmHg). Arterial
      Po2 (PaO2) also decreased during exercise in AH but increased significantly with
      acclimatization (51 +/- 1.1, 58 +/- 1.7, and 62 +/- 1.6 mmHg in AH, 2W, and 8W,
      respectively). PaO2 in lowlanders reached levels that were not different from
      those in high-altitude natives (66 +/- 1.2 mmHg). Arterial O2 saturation (SaO2)
      decreased during maximum exercise compared with rest in AH and after 2W and 8W:
      73.3 +/- 1.4, 76.9 +/- 1.7, and 79.3 +/- 1.6%, respectively. After 8W, SaO2 in
      lowlanders was not significantly different from that in Aymaras (82.7 +/- 1%). An
      improved pulmonary gas exchange with acclimatization was evidenced by a decreased
      ventilatory equivalent of O2 after 8W: 59 +/- 4, 58 +/- 4, and 52 +/- 4 l x min x
      l O2(-1), respectively. The ventilatory equivalent of O2 reached levels not
      different from that of Aymaras (51 +/- 3 l x min x l O2(-1)). However, increases
      in exercise alveolar Po2 and PaO2 with acclimatization had no net effect on
      alveolar-arterial Po2 difference in lowlanders (10 +/- 1.3, 11 +/- 1.5, and 10 +/
      2.1 mmHg in AH, 2W, and 8W, respectively), which remained significantly higher
      than in Aymaras (1 +/- 1.4 mmHg). In conclusion, lowlanders substantially improve
      pulmonary gas exchange with acclimatization, but even acclimatization for 8 wk is
      insufficient to achieve levels reached by high-altitude natives.

PMID- 15191910
TI  - Modulation of deltaF508 cystic fibrosis transmembrane regulator trafficking and
      function with 4-phenylbutyrate and flavonoids.
AB  - Over 70% of patients with cystic fibrosis have the DeltaF508 mutation. This
      protein is a partially functional chloride (Cl-) channel that is prematurely
      degraded in the endoplasmic reticulum. Specific members of the flavonoid class of
      compounds have been shown to increase Cl- conductance of wild-type and DeltaF508
      cystic fibrosis transmembrane regulator (CFTR). Although flavonoid effects on
      CFTR processing are unknown, evidence of effects on heat shock proteins,
      specifically those that have been shown to interact with CFTR, led us to believe
      that there would be an effect on CFTR processing through modulation of CFTR
      chaperone interactions. We sought to determine (i) the effect of apigenin,
      genistein, kaempferol, and quercetin on CFTR processing in IB3-1 cells
      (F508/W1282X) and (ii) whether sequential treatment with 4-phenylbutyrate (4-PBA)
      to increase CFTR processing and flavonoid to directly stimulate CFTR would
      increase Cl- conductance. Our results show no significant effect on CFTR
      processing as measured by immunoblotting with 1 microM or 5 microM of apigenin,
      genistein, kaempferol, or quercetin. However, despite no effect on CFTR
      processing as determined by immunoblot, immunofluorescence demonstrated a
      favorable change in the intracellular distribution of CFTR with 24 h treatments
      of apigenin, kaempferol, and genistein. Furthermore, we observed an increase in
      Cl- conductance as measured by Cl- efflux in cells that were treated for 24 h
      with 4-PBA and then assayed with forskolin and 1 microM or 5 microM genistein,
      and also with cells treated for 24 h with either 4-PBA, 5 microM apigenin, or 1
      microM quercetin. Thus, a combination of chronic treatment with 4-PBA or select
      flavonoids, followed by acute flavonoid exposure, may be beneficial in cystic
      fibrosis.

PMID- 15191911
TI  - Inflammatory time course after quartz instillation: role of tumor necrosis factor
      alpha and particle surface.
AB  - Inflammation has been suggested as the key factor in the development of quartz
      induced fibrosis and carcinogenesis, and particle surface properties are argued
      as an important characteristic responsible for these pathologic alterations. To
      evaluate the effect of surface modification on acute and subchronic inflammation,
      female Wistar rats were intratracheally instilled with 2 mg native quartz, or
      quartz coated either with polyvinyl-pyridine-N-oxide or with aluminium lactate.
      Various markers of lung toxicity, inflammation, and oxidative stress were found
      to be enhanced at 3, 7, 21, and 90 d after instillation of native quartz. Quartz
      treated animals also showed enhanced immunostaining of nuclear factor-kappaB (NF
      kappaB) in alveolar macrophages and lung epithelium, as well as reduced
      IkappaBalpha levels in whole lung homogenate. Both surface modifications were
      found to inhibit most of the effects as observed with native quartz. NF-kappaB
      activation was also observed in vitro in rat lung epithelial cells following
      treatment with lavage fluid from quartz-treated animals, as well as with
      conditioned medium of quartz-treated macrophages, and these effects appeared to
      be at least partly tumor necrosis factor-alpha-independent. In conclusion, the
      persistent subchronic inflammatory lung response after quartz exposure appears to
      be particle surface-driven and is associated with NF-kappaB activation in both
      alveolar macrophages and the lung epithelium.

PMID- 15191912
TI  - Activation of airway epithelial cells by toll-like receptor agonists.
AB  - Toll-like receptors (TLR) play an important role in pathogen recognition and
      innate immunity. We investigated the presence and function of TLRs in the BEAS-2B
      airway epithelial cell line and primary bronchial epithelial cells. Standard real
      time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and Taqman
      RT-PCR revealed that BEAS-2B cells express mRNA for TLR1-10. Several TLR ligands
      were tested for their ability to activate gene expression in BEAS-2B cells using
      limited microarray analyses focusing on genes of the chemokine and chemokine
      receptor family, cytokines, and signaling pathways. While the TLR3 ligand double
      stranded RNA was the most effective epithelial activator, clear responses to
      flagellin, lipopolysaccharide, CpG, peptidoglycan, and zymosan were also
      observed. RT-PCR and/or enzyme-linked immunosorbent assay were used to confirm
      results obtained with microarrays for five of the induced genes: interleukin-8,
      serum amyloid A, TLR3, macrophage inflammatory protein-3alpha, and granulocyte
      macrophage colony-stimulating factor. Stimulation of epithelial cells with double
      stranded RNA induced levels of interleukin-8 exceeding 20 ng/ml and levels of
      serum amyloid A exceeding 80 ng/ml. Double-stranded RNA, lipopolysaccharide,
      zymosan A, and flagellin also induced expression of macrophage inflammatory
      protein-3alpha and granulocyte-macrophage colony-stimulating factor, which may
      facilitate immature dendritic cell migration and maturation. These results
      suggest that airway epithelial cells express several TLRs and that they are
      functionally active. Epithelial expression of TLRs may be of importance in
      inflammation and immunity in the airways in response to inhaled pathogens.

PMID- 15191913
TI  - Elastase mediates the release of growth factors from lung in vivo.
AB  - Uncontrolled elastase activity is involved in the development of several types of
      lung disease. Previous reports demonstrated that growth factors are liberated
      from pulmonary matrix storage sites by elastase; however, release of these
      entities in vivo is not well defined. In the present study, we investigated the
      release of fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta
      (TGF-beta), after intratracheal instillation of porcine pancreatic elastase into
      mice. We found that elastase promoted a time-dependent release of FGF-2 and TGF
      beta1 from the lung into bronchoalveolar lavage (BAL) fluid. A large fraction of
      the TGF-beta1 in BAL fluid was in the active form (approximately 60%), suggesting
      that elastase might participate in the activation of TGF-beta1 from its latent
      form. Analysis of the levels of FGF-2 and TGF-beta1 in mouse blood indicated that
      the growth factors in BAL fluid were not entirely derived from blood. Moreover,
      elastase treatment of pulmonary fibroblasts cultures caused the release of TGF
      beta1, suggesting that the TGF-beta1 in BAL fluid could have come from lung
      cells/matrix. Additional in vitro studies also indicated that TGF-beta1 plays a
      role in upregulating elastin mRNA levels. These data suggest that elastase
      releases growth factors from lung that participate in elastolytic injury
      responses.

PMID- 15191914
TI  - Expression and functions of the duodenal peptide secretin and its receptor in
      human lung.
AB  - The physiological role of the duodenal peptide secretin is as a potent stimulant
      of electrolyte and water movement in pancreatic and biliary epithelium, via
      activation of G protein-coupled secretin receptors (hSCTR). However, the
      distribution and potential function of hSCTR in human lung has not previously
      been addressed. Using real-time quantitative reverse transcriptase-polymerase
      chain reaction profiling, in situ hybridization, and immunohistochemistry, we
      demonstrated that the hSCTR is abundantly expressed within the distal regions of
      human lung (tertiary bronchus and parenchyma), with negligible expression
      detected in more proximal regions (trachea, primary, and secondary bronchus).
      Expression was observed predominantly on the basolateral membrane of the
      bronchial epithelial layer, with some expression also observed in bronchial
      smooth muscle. In primary cultures of human tertiary bronchial epithelial cells,
      secretin was demonstrated to potently stimulate channel-mediated Cl- efflux in a
      concentration-dependent manner. Secretin was also shown to cause concentration
      dependent relaxation of human tertiary bronchial smooth muscle. In summary, these
      data demonstrate that secretin receptors are present in human lung, and that
      activation of these receptors with human secretin potently stimulates
      concentration-dependent Cl- efflux from bronchial epithelial cells and
      bronchorelaxation.

PMID- 15191916
TI  - Molecular regulation of interleukin-13 and monocyte chemoattractant protein-1
      expression in human mast cells by interleukin-1beta.
AB  - Mast cells play pivotal roles in immunoglobulin (Ig) E-mediated airway
      inflammation, expressing interleukin (IL)-13 and monocyte chemoattractant protein
      1 (MCP-1), which in turn regulate IgE synthesis and/or inflammatory cell
      recruitment. The molecular effects of IL-1beta on cytokine expression by human
      mast cells (HMC) have not been studied well. In this report, we provide evidence
      that human umbilical cord blood-derived mast cells (CBDMC) and HMC-1 cells
      express the type 1 receptor for IL-1. We also demonstrate that IL-1beta and tumor
      necrosis factor-alpha are able to induce, individually or additively, dose
      dependent expression of IL-13 and MCP-1 in these cells. The induction of IL-13
      and MCP-1 gene expression by IL-1beta was accompanied by the activation of IL-1
      receptor-associated kinase and translocation of the transcription factor, nuclear
      factor (NF) kappaB into the nucleus. Accordingly, Bay-11 7082, an inhibitor of NF
      kappaB activation, inhibited IL-1beta-induced IL-13 and MCP-1 expression. IL
      1beta also induced IL-13 promoter activity while enhancing the stability of IL-13
      messenger RNA transcripts. Dexamethasone, a glucocorticoid, inhibited IL-1beta
      induced nuclear translocation of NF-kappaB and also the secretion of IL-13 from
      mast cells. Our data suggest that IL-1beta can serve as a pivotal costimulus of
      inflammatory cytokine synthesis in human mast cells, and this may be partly
      mediated by IL-1 receptor-binding and subsequent signaling via nuclear
      translocation of NF-kappaB. Because IL-1beta is a ubiquitously expressed
      cytokine, these findings have important implications for non-IgE-mediated
      signaling in airway mast cells as well as for innate immunity and airway
      inflammatory responses, such as observed in extrinsic and intrinsic asthma.

PMID- 15191915
TI  - Mucin is produced by clara cells in the proximal airways of antigen-challenged
      mice.
AB  - Airway mucus hypersecretion is a prominent feature of many obstructive lung
      diseases. We thus determined the ontogeny and exocytic phenotype of mouse airway
      mucous cells. In naive mice, ciliated (approximately 40%) and nonciliated
      (approximately 60%) epithelial cells line the airways, and > 95% of the
      nonciliated cells are Clara cells that contain Clara cell secretory protein
      (CCSP). Mucous cells comprise < 5% of the nonciliated cells. After sensitization
      and a single aerosol antigen challenge, alcian blue-periodic acid Schiff's
      positive mucous cell numbers increase dramatically, appearing 6 h after challenge
      (21% of nonciliated/nonbasal cells), peaking from Days 1-7 (99%), and persisting
      at Day 28 (65%). Throughout the induction and resolution of mucous metaplasia,
      ciliated and Clara cell numbers identified immunohistochemically change only
      slightly. Intracellular mucin content peaks at Day 7, and mucin expression is
      limited specifically to a Clara cell subset in airway generations 2-4 that
      continue to express CCSP. Functionally, Clara cells are secretory cells that
      express the regulated exocytic marker Rab3D and, in antigen-challenged mice,
      rapidly secrete mucin in response to inhaled ATP in a dose-dependent manner.
      Thus, Clara cells show great plasticity in structure and secretory products, yet
      have molecular and functional continuity in their identity as specialized apical
      secretory cells.

PMID- 15191917
TI  - Src kinase mediates angiotensin II-dependent increase in pulmonary endothelial
      nitric oxide synthase.
AB  - We have previously demonstrated that angiotensin II (Ang II) stimulates nitric
      oxide (NO) production in bovine pulmonary artery endothelial cells (BPAECs) by
      increasing NO synthase (NOS) expression via the type 2 receptor. The purpose of
      this study was to identify the Ang II-dependent signaling pathway that mediates
      this increase in endothelial NOS (eNOS). The Ang II-dependent increase in eNOS
      expression is prevented when BPAECs are pretreated with the tyrosine kinase
      inhibitors, herbimycin A and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4
      D]pyrimidine, which also blocked Ang II-dependent mitogen-activated protein
      kinase (MAPK) kinase/extracellular-regulated protein kinase (MEK)-1 and MAPK
      phosphorylation, suggesting that Src is upstream of MAPK in this pathway.
      Transfection of BPAECs with an Src dominant negative mutant cDNA prevented the
      Ang II-dependent Src activation and increase in eNOS protein expression. PD98059,
      a MEK-1 inhibitor, prevented the Ang II-dependent phosphorylation of
      extracellular-regulated protein kinases 1 and 2 and increase in eNOS expression.
      Neither AG1478, an epidermal growth factor receptor kinase inhibitor, nor AG1295,
      a platelet derived growth factor receptor kinase inhibitor, had any effect on Ang
      II-stimulated Src activity, MAPK activation, or eNOS expression. Pertussis toxin
      prevented the Ang II-dependent increase in Src activity, MAPK activation, and
      eNOS expression. These data suggest that Ang II stimulates Src tyrosine kinase
      via a pertussis toxin-sensitive pathway, which in turn activates the MAPK
      pathway, resulting in increased eNOS protein expression in BPAECs.

PMID- 15191918
TI  - Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual
      interstitial pneumonia.
AB  - Chemokines are increased and may exert effects on both inflammatory and
      remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we
      examined the concomitant expression of inflammatory CC chemotactic cytokines or
      chemokines and their corresponding receptors in surgical lung biopsies obtained
      at the time of disease diagnosis and pulmonary fibroblasts grown from these
      biopsies. By gene array analysis, upper and lower lobe biopsies and primary
      fibroblast lines from patients with usual interstitial pneumonia (UIP),
      nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial
      lung disease, but not patients without IIP, exhibited CCL7 gene expression.
      TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed
      at significantly higher levels in UIP lung biopsies compared with biopsies from
      patients with nonspecific interstitial pneumonia, respiratory bronchiolitis
      interstitial lung disease, and from patients without IIP. Higher levels of CCL7
      were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts,
      and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP
      fibroblasts. Together, these data suggest that CCL7 is highly expressed in
      biopsies and pulmonary fibroblast lines obtained from patients with UIP relative
      to patients with other IIP and patients without IIP, and that this CC chemokine
      may have a major role in the progression of fibrosis in this IIP patient group.

PMID- 15191919
TI  - Human immunodeficiency virus and the prevalence of undiagnosed tuberculosis in
      African gold miners.
AB  - We hypothesized that rapid presentation may be a general feature of tuberculosis
      (TB) associated with human immunodeficiency virus (HIV) that limits the impact of
      HIV on the point prevalence of TB. To investigate this, we performed a cross
      sectional HIV and TB disease survey with retrospective and prospective follow-up.
      HIV prevalence among 1,773 systematically recruited miners was 27%. TB incidence
      was much more strongly HIV associated (incidence rate ratio, 5.5; 95% confidence
      interval [CI], 3.5-8.6) than the point prevalence of undiagnosed TB disease (odds
      ratio, 1.7; 95% CI, 0.9-3.3). For smear-positive TB, 7 of 9 (78%) prevalent cases
      were HIV negative, and point prevalence was nonsignificantly lower in miners who
      were HIV positive (odds ratio, 0.8; 95% CI, 0.1-4.2). The calculated mean
      duration of smear positivity before diagnosis (point prevalence/incidence) was
      substantially shorter for HIV-positive than HIV-negative TB patients (0.17 and
      1.15 years, respectively; ratio, 0.15; 95% CI, 0.00-0.73). HIV has considerably
      less impact on the point prevalence of TB disease than on TB incidence, probably
      because rapid disease progression increases presentation and case-finding rates.
      The difference in mean duration of smear positivity was particularly marked and,
      if generalizable, will have major implications for TB control prospects in high
      HIV prevalence areas.

PMID- 15191920
TI  - Fullerene derivatives protect against oxidative stress in murine macrophage line
      cells and ischemia-reperfused lungs.

PMID- 15191921
TI  - 20-HETE or EETs: which arachidonic acid metabolite regulates proximal tubule
      transporters and contributes to pressure natriuresis?

PMID- 15191922
TI  - Leptin: the "skinny" on torpor.

PMID- 15191923
TI  - Investigating sleep homeostasis using an unusual instability.

PMID- 15191924
TI  - Mutant mice: sleep starved and chronologically clueless.

PMID- 15191925
TI  - Fullerene derivatives protect against oxidative stress in RAW 264.7 cells and
      ischemia-reperfused lungs.
AB  - Fullerene derivatives have often been used as effective scavengers for reactive
      oxygen species (ROS). This study was designed to test whether polyhydroxylated
      fullerene derivatives [C(60)(OH)(7+/-2)] protect against oxidative stress in
      cultured RAW 264.7 cells and ischemia-reperfused (IR) lungs. In RAW 264.7 cells,
      sodium nitroprusside (SNP, 1 mM) and H(2)O(2) (400 microM) caused a marked (90%)
      decrease in cell viability, and this decrease was dose dependently reversed by
      pretreatment with C(60)(OH)(7+/-2) (10-50 microM). The increase in ROS production
      induced by SNP and H(2)O(2) was significantly suppressed by C(60)(OH)(7+/-2).
      Also, the decrease in mitochondrial membrane potential induced by SNP and
      H(2)O(2) was significantly reversed by C(60)(OH)(7+/-2). However, high
      concentration of C(60)(OH)(7+/-2) (1 and 1.5 mM) lead to cell death (apoptosis or
      necrosis). In the isolated rat lung, the increases in pulmonary artery pressure
      and capillary filtration pressure induced by SNP during IR were reversed
      significantly by C(60)(OH)(7+/-2) (10 mg/kg). These results indicate that
      polyhydroxylated fullerene derivatives C(60)(OH)(7+/-2) at low concentrations
      protect against oxidative stress in RAW 264.7 cells and IR lungs.

PMID- 15191926
TI  - Reduced leptin concentrations are permissive for display of torpor in Siberian
      hamsters.
AB  - A photoperiod with a short photophase induces a winterlike phenotype in Siberian
      hamsters that includes a progressive decrease in food intake and body mass and
      reproductive organ regression, as well as reversible hypothermia in the form of
      short-duration torpor. Torpor substantially reduces energy utilization and is not
      initiated until body mass, fat stores, and serum leptin concentrations are at
      their nadir. Because photoperiod-dependent torpor is delayed until fat reserves
      are lowest, leptin concentrations may be a permissive factor for torpor onset.
      This conjecture was tested by implanting osmotic minipumps into Siberian hamsters
      manifesting spontaneous torpor; the animals received a constant release of leptin
      or vehicle for 14 days. Exogenous leptin treatment eliminated torpor in a
      significant proportion of treated hamsters, whereas treatment with the vehicle
      did not. Similarly, endogenous serum leptin concentrations were markedly reduced
      in all animals undergoing daily torpor. Although simply reducing leptin
      concentrations below a threshold value is not sufficient for torpor initiation,
      reduced leptin concentrations nevertheless appear necessary for its occurrence.
      It is proposed that drastically reduced leptin concentrations provide a
      "starvation signal" to an as yet unidentified central mechanism mediating torpor
      initiation.

PMID- 15191927
TI  - Mitochondrial ATP measurements.

PMID- 15191928
TI  - Parental exposure to polycyclic aromatic hydrocarbons and the risk of childhood
      brain tumors: The SEARCH International Childhood Brain Tumor Study.
AB  - Experimental evidence suggests that parental exposure to polycyclic aromatic
      hydrocarbons (PAH), which occurs primarily through tobacco smoke, occupational
      exposure, and air pollution, could increase the risk of cancer during childhood.
      Population-based case-control studies carried out in seven countries as part of
      the SEARCH Program compared data for 1,218 cases of childhood brain tumors and
      2,223 controls (1976-1994). Parental occupational exposure to PAH during the 5
      year period before birth was estimated with a job exposure matrix. Risk estimates
      were adjusted for child's age, sex, and study center. Paternal preconceptional
      occupational exposure to PAH was associated with increased risks of all childhood
      brain tumors (odds ratio (OR) = 1.3, 95% confidence interval: 1.1, 1.6) and
      astroglial tumors (OR = 1.4, 95% confidence interval: 1.1, 1.7). However, there
      was no trend of increasing risk with predicted level of exposure. Paternal
      smoking alone (OR = 1.4) was also associated with the risk of astroglial tumors
      in comparison with nonsmoking, non-occupationally-exposed fathers. Risks for
      paternal occupational exposure were higher, with (OR = 1.6) or without (OR = 1.7)
      smoking. Maternal occupational exposure to PAH before conception or during
      pregnancy was rare, and this exposure was not associated with any type of
      childhood brain tumor. This large study supports the hypothesis that paternal
      preconceptional exposure to PAH increases the risk of brain tumors in humans.

PMID- 15191929
TI  - Mortality from solid cancers among workers in formaldehyde industries.
AB  - In industrial workers, formaldehyde exposure has been associated with cancer of
      the nasal cavities, nasopharynx, prostate, lung, and pancreas; however, these
      associations are inconsistent and remain controversial. Animals exposed to
      formaldehyde show excesses of nasal cancer. In an extended follow-up of a large
      cohort of formaldehyde-exposed workers, the authors evaluated mortality from
      solid cancers (1,921 deaths) among 25,619 workers (865,708 person-years) employed
      in 10 US formaldehyde-producing or -using facilities through 1994. Exposure
      assessment included quantitative estimates of formaldehyde exposure. Standardized
      mortality ratios and relative risks were calculated. Compared with that for the
      US population, mortality from solid cancers was significantly lower than expected
      among subjects exposed and nonexposed to formaldehyde (standardized mortality
      ratios = 0.91 and 0.78, respectively). Relative risks for nasopharyngeal cancer
      (nine deaths) increased with average exposure intensity, cumulative exposure,
      highest peak exposure, and duration of exposure to formaldehyde (p-trend = 0.066,
      0.025, <0.001, and 0.147, respectively). Formaldehyde exposure did not appear to
      be associated with lung (744 deaths), pancreas (93 deaths), or brain (62 deaths)
      cancer. Although relative risks for prostate cancer (145 deaths) were elevated
      for some measures of formaldehyde exposure, the trend was inconsistent. In this
      cohort of formaldehyde-industry workers, some evidence was found of an exposure
      response relation with mortality from nasopharyngeal cancer (based on small
      numbers) but not for cancers of the pancreas, brain, lung, or prostate.

PMID- 15191930
TI  - Case-control study of use of nonsteroidal antiinflammatory drugs and glioblastoma
      multiforme.
AB  - Evidence from epidemiologic and experimental studies suggests that use of
      nonsteroidal antiinflammatory drugs (NSAIDs) reduces risk of colon and breast
      cancer. The association between use of aspirin and other NSAIDs and risk of adult
      glioblastoma multiforme (GBM) was evaluated among 236 incident GBM cases and 401
      population-based controls frequency-matched on age, gender, and ethnicity from
      the San Francisco Bay Area Adult Glioma Study. Cases (or proxies) and controls
      were interviewed in person between May 1997 and August 2000. Cases with self
      reported GBM reported less use of at least 600 pills of all types of NSAIDs
      combined during the 10-year prediagnostic period than did controls (odds ratio
      (OR) = 0.53, 95% confidence interval (CI): 0.3, 0.8). Findings were consistent
      for aspirin (OR = 0.51, 95% CI: 0.3, 0.8), ibuprofen (OR = 0.41, 95% CI: 0.2,
      0.8), and naproxen/other NSAIDs (OR = 0.34, 95% CI: 0.1, 0.8). GBM cases also
      reported less use of acetaminophen than did controls (OR = 0.51, 95% CI: 0.3,
      1.0). Eliminating participants who initiated NSAID use within 2 years of
      diagnosis yielded similar results. These findings show an inverse association
      between NSAID use and GBM. Further studies are warranted to determine whether
      NSAIDs might be effective in the inhibition of GBM development or progression.

PMID- 15191931
TI  - Abdominal obesity and respiratory function in men and women in the EPIC-Norfolk
      Study, United Kingdom.
AB  - Poor respiratory function and obesity are associated with all-cause and
      cardiovascular disease mortality. Obese persons may also have impaired lung
      function, but the mechanism is unclear. The authors investigated the relation
      between abdominal pattern of obesity and respiratory function in the European
      Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk) cohort
      in Norfolk, United Kingdom. This analysis included 9,674 men and 11,876 women
      aged 45-79 years with no known preexisting serious illness who had complete
      anthropometric and respiratory function measures obtained at a health visit
      between 1993 and 1997. Waist:hip ratio was used to assess abdominal obesity, and
      forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC),
      obtained by spirometry, were used to assess respiratory function. Both FEV1 and
      FVC were linearly and inversely related across the entire range of waist:hip
      ratio in both men and women. This relation persisted after adjustment for age,
      body mass index, cigarette smoking, social class, physical activity index,
      prevalent bronchitis/emphysema, and prevalent asthma. The association remained
      significant among nonobese nonsmokers without preexisting respiratory disease. In
      the general adult population, abdominal fat deposition may play a role in the
      impairment of respiratory function among the abdominally obese.

PMID- 15191932
TI  - Changes in body weight and body fat distribution as risk factors for clinical
      diabetes in US men.
AB  - Although previous studies have linked obesity to diabetes, the risks associated
      with weight gain or changes in body fat distribution have not been fully
      elucidated. The authors therefore prospectively examined the relations between
      changes in body weight and body fat distribution (1986-1996) and the subsequent
      risk of diabetes (1996-2000) among 22,171 men in the Health Professionals Follow
      up Study. Weight gain was monotonically related to risk, and for every kilogram
      of weight gained, risk increased by 7.3%. A gain in abdominal fat was positively
      associated with risk, independent of the risk associated with weight change.
      Compared with men who had a stable waist, men who increased waist circumference
      by 14.6 cm or more had 1.7 (95% confidence interval: 1.0, 2.8) times the risk of
      diabetes after controlling for weight gain. In contrast, men who lost more than
      4.1 cm in hip girth had 1.5 (95% confidence interval: 1.0, 2.3) times the risk of
      diabetes compared with men with stable hip circumference. Fifty-six percent of
      the cases of diabetes in this cohort could be attributed to weight gain greater
      than 7 kg, and 20 percent of the cases could be attributed to a waist gain
      exceeding 2.5 cm. Our findings underscore the critical importance of maintaining
      weight and waist to reduce the risk of diabetes.

PMID- 15191933
TI  - Diabetes mellitus as a predictor of cancer mortality in a large cohort of US
      adults.
AB  - Several studies have suggested that diabetes mellitus may alter the risk of
      developing a variety of cancers, and the associations are biologically plausible.
      To learn more about the relation between diabetes and cancer mortality, the
      authors examined associations with selected cancers in a large, prospective US
      cohort of 467,922 men and 588,321 women who had no reported history of cancer at
      enrollment in 1982. After 16 years of mortality follow-up, diabetes was
      significantly associated with fatal colon cancer in men (multivariate relative
      risk (RR) = 1.20, 95% confidence interval (CI): 1.06, 1.37) and women (RR = 1.24,
      95% CI: 1.07, 1.43) and with pancreatic cancer in men (RR = 1.48, 95% CI: 1.27,
      1.73) and women (RR = 1.44, 95% CI: 1.21, 1.72). For men, diabetes was
      significantly associated with liver cancer (RR = 2.19, 95% CI: 1.76, 2.72) and
      bladder cancer (RR = 1.43, 95% CI: 1.14, 1.80). In addition, diabetes was
      significantly associated with breast cancer in women (RR = 1.27, 95% CI: 1.11,
      1.45). These associations were not explained by high body mass. Our findings
      suggest that diabetes is an independent predictor of mortality from cancer of the
      colon, pancreas, female breast, and, in men, of the liver and bladder.

PMID- 15191934
TI  - Population effects on individual systolic blood pressure: a multilevel analysis
      of the World Health Organization MONICA Project.
AB  - Individuals from the same population share a number of contextual circumstances
      that may condition a common level of blood pressure over and above individual
      characteristics. Understanding this population effect is relevant for both
      etiologic research and prevention strategies. Using multilevel regression
      analyses, the authors quantified the extent to which individual differences in
      systolic blood pressure (SBP) could be attributed to the population level. They
      also investigated possible cross-level interactions between the population in
      which a person lived and pharmacological (antihypertensive medication) and
      nonpharmacological (body mass index) effects on individual SBP. They analyzed
      data on 23,796 men and 24,986 women aged 35-64 years from 39 worldwide Monitoring
      of Trends and Determinants in Cardiovascular Disease (MONICA) study populations
      participating in the final survey of this World Health Organization project (1989
      1997). SBP was positively associated with low educational achievement, high body
      mass index, and use of antihypertensive medication and, for women, was negatively
      associated with smoking. About 7-8% of all SBP differences between subjects were
      attributed to the population level. However, this population effect was
      particularly strong (i.e., 20%) in antihypertensive medication users and
      overweight women. This empirical evidence of a population effect on individual
      SBP emphasizes the importance of developing population-wide strategies to reduce
      individual risk of hypertension.

PMID- 15191935
TI  - Religiosity and the earliest stages of adolescent drug involvement in seven
      countries of Latin America.
AB  - To investigate the role of religiosity in the earliest stages of drug
      involvement, the authors studied recent-onset occurrence of first chances to try
      a drug and first actual drug use, expressed as a function of religious practice
      behaviors, levels of religious devotion, and religious affiliation. Based upon
      standardized questionnaire assessments of nationally representative samples of
      school-attending youths drawn in Panama, the five Spanish heritage countries of
      Central America, and the Dominican Republic (n = 12,797), the 1999-2000 study
      estimates indicate that higher levels of religious practice are inversely
      associated with the earliest stages of tobacco and cannabis experiences (i.e.,
      the first chance to try and the first actual use) but not so for alcohol. To
      illustrate, for each unit increase in levels of religious practice behaviors,
      there was an associated reduced occurrence of the first chance to try tobacco
      (odds ratio = 0.76, 95% confidence interval: 0.62, 0.94). Occurrence of first
      actual use of tobacco and cannabis was not associated with levels of religious
      practice behaviors among youths exposed to the opportunity to try these drugs. As
      such, these behaviors apparently have not strengthened resistance. Rather,
      autarcesis may be at work, functioning to shield youths from drug exposure
      opportunities.

PMID- 15191936
TI  - Lifestyle and demographic factors in relation to vasomotor symptoms: baseline
      results from the Study of Women's Health Across the Nation.
AB  - Results of recent trials highlight the risks of hormone therapy, increasing the
      importance of identifying preventive lifestyle factors related to menopausal
      symptoms. The authors examined the relation of such factors to vasomotor symptoms
      in the multiethnic sample of 3,302 women, aged 42-52 years at baseline (1995
      1997), in the Study of Women's Health Across the Nation (SWAN). All lifestyle
      factors and symptoms were self-reported. Serum hormone and gonadotropin
      concentrations were measured once in days 2-7 of the menstrual cycle. After
      adjustment for covariates using multiple logistic regression, significantly more
      African-American and Hispanic and fewer Chinese and Japanese than Caucasian women
      reported vasomotor symptoms. Fewer women with postgraduate education reported
      vasomotor symptoms. Passive exposure to smoke, but not active smoking, higher
      body mass index, premenstrual symptoms, perceived stress, and age were also
      significantly associated with vasomotor symptoms, although a dose-response
      relation with hours of smoke exposure was not observed. No dietary nutrients were
      significantly associated with vasomotor symptoms. These cross-sectional findings
      require further longitudinal exploration to identify lifestyle changes for women
      that may help prevent vasomotor symptoms.

PMID- 15191937
TI  - Re: "Use of electric bedding devices and risk of breast cancer in African
      American women".

PMID- 15191938
TI  - Re: "Sense of coherence and mortality in men and women in the EPIC-Norfolk United
      Kingdom prospective cohort study".

PMID- 15191939
TI  - Proteolysis of the pericellular matrix: a novel element determining cell survival
      and death in the pathogenesis of plaque erosion and rupture.
AB  - The 2 major general concepts about the cell biology of atherogenesis, growth of
      smooth muscle cells, and lipid accumulation in macrophages, ie, foam cell
      formation, have not been able to satisfactorily explain the genesis of acute
      coronary syndromes. Rather, the basic pathology behind the acute atherothrombotic
      events relates to erosion and rupture of unstable coronary plaques. At the
      cellular level, we now understand that a switch from cellular growth to cellular
      death, notably apoptosis, could be involved in turning at least some types of
      atherosclerotic plaques unstable. Because intimal cells require a proper matrix
      environment for normal function and survival, the vulnerability of an
      atherosclerotic plaque may critically depend on the integrity of the pericellular
      matrix of the plaque cells. In vitro studies have revealed that plaque
      infiltrating inflammatory cells, such as macrophages, T-lymphocytes, and mast
      cells, by secreting a variety of proteases capable of degrading pericellular
      matrix components, induce death of endothelial cells and smooth muscle cells, and
      so provide a mechanistic explanation for inflammation-dependent plaque erosion
      and rupture. Thus, a novel link between inflammation and acute coronary syndromes
      is emerging. For a more explicit understanding of the role of proteases released
      by inflammatory cells in the conversion of a clinically silent plaque into a
      dangerous and potentially killing plaque, animal models of plaque erosion and
      rupture need to be established.

PMID- 15191940
TI  - Smoking cessation rapidly increases circulating progenitor cells in peripheral
      blood in chronic smokers.
AB  - OBJECTIVE: Circulating endothelial progenitor cells (EPCs) contribute to
      postnatal angiogenesis. The number of circulating EPCs has an inverse correlation
      with coronary risk scores. However, the effect of smoking on the number of
      circulating EPCs is not well-known. METHODS AND RESULTS: We examined the effects
      of chronic smoking and of smoking cessation on EPC levels. Circulating EPCs were
      quantified by flow cytometry as CD45lowCD34+CD133+ (progenitor cells [PCs]) or
      CD45lowCD34+CD133+VEGFR2+ (EPCs) in 14 nonsmokers and in 15 smokers. All smokers
      quit smoking. Eight quit smoking with nicotine patch and 7 without nicotine
      patch. PC/EPC levels were inversely correlated with the number of cigarettes
      smoked. Circulating PCs/EPCs increased rapidly after cessation (P<0.0001) and
      decreased again after resumption of smoking to the level similar to that before
      cessation (P=0.0031). The magnitude of increase in EPCs was greater in light
      smokers than in heavy smokers. CONCLUSIONS: The number of circulating PCs/EPCs
      was reduced in chronic smokers. Smoking cessation led to a rapid restoration of
      PC/EPC levels. The recovery of EPC levels was greater in light smokers than in
      heavy smokers. The decreased number of circulating EPCs would make smokers
      susceptible to cardiovascular disease, and even short-time cessation of smoking
      may be an effective means to reduce cardiovascular risk.

PMID- 15191941
TI  - Matrix metalloproteinase-9 genotype influences large artery stiffness through
      effects on aortic gene and protein expression.
AB  - OBJECTIVE: Because large artery stiffening contributes to myocardial ischemia,
      its determinants are of relevance as potential risk markers. This study examined
      whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated
      with large artery stiffening and aortic MMP-9 gene and protein expression.
      METHODS AND RESULTS: MMP-9 genotype (C-1562T promoter polymorphism) was
      determined in 84 patients (73 male) with angiographically defined coronary artery
      disease (CAD). Carotid applanation tonometry was used to assess central blood
      pressures and, with Doppler velocimetry, to assess aortic stiffness (input and
      characteristic impedance). Gene expression real-time polymerase chain reaction
      (RT-PCR) and protein levels (Western blotting) were assessed in relation to
      genotype in aortic samples from a separate population. T-allele carriers (C/T and
      T/T) had stiffer large arteries (higher input and characteristic impedance) and
      higher carotid pulse and systolic blood pressure (all P<0.05) than C/C
      homozygotes. In aortic samples, gene expression was 5-fold higher and active
      protein levels were >2-fold higher in T-allele carriers. CONCLUSIONS: Because the
      T allele was associated with greater MMP-9 mRNA and protein levels, the greater
      large artery stiffness in T-allele carriers may be secondary to excessive
      degradation of the arterial elastic matrix. The consequent higher pulse pressure
      may increase susceptibility to myocardial ischemia.

PMID- 15191942
TI  - Microbial dustiness and particle release of different biofuels.
AB  - Exposure to organic dust originating from biofuels can cause adverse health
      effects. In the present study we have assessed the dustiness in terms of
      microbial components and particles of various biofuels by using a rotating drum
      as a dust generator. Microbial components from straw, wood chips, wood pellets
      and wood briquettes were quantified by several methods. Excellent correlations (r
      >/= 0.85, P < 0.0001) were found: between lipopolysaccharide (LPS) (as determined
      by 3-hydroxy fatty acid analysis) and endotoxin (as determined by a Limulus
      test), cultivable bacteria, total number of bacteria and muramic acid; between
      endotoxin and cultivable bacteria, total number of bacteria and muramic acid;
      between total number of bacteria and muramic acid; between cultivable fungi and
      total number of fungi. Straw was dustier than the other biofuels in terms of
      actinomycetes, bacteria, muramic acid, endotoxin, LPS, particle mass and number
      of particles. One of the wood chips studied and the straws had comparatively high
      dustiness in terms of fungi, while both wood pellets and wood briquettes had
      comparatively low dustiness in terms of all microbial components. An initially
      high particle generation rate of straw and wood chips decreased over time whereas
      the particle generation rate of wood briquettes and wood pellets increased during
      a 5 min rotation period. Particles of non-microbial origin may be the determining
      factor for the health risk in handling briquettes and pellets. Straw dust
      contained significantly more microorganisms per particle than did wood chip dust,
      probably because bacteria were most abundant in straw dust. The concentrations of
      endotoxin and fungi were high in wood and straw dust; dust from one of the straws
      contained 3610 EU/mg and dust from one of the chips contained 7.3 x 10(6) fungal
      spores/mg. An exposure to 3 mg of straw or wood chips dust/m(3) (the Swedish and
      Danish OEL of unspecific inhalable dust) could cause exposures to endotoxin and
      fungi higher than levels were health symptoms are seen to develop. The very
      different levels of dustiness in terms of particles and microbial components of
      different biofuels shows that dustiness is an important health-relevant factor to
      consider when choosing among biofuels and when designing worksites for handling
      of biofuels.

PMID- 15191943
TI  - Emission of hexanal and carbon monoxide from storage of wood pellets, a potential
      occupational and domestic health hazard.
AB  - OBJECTIVES: The objective of the present study was to investigate and describe
      the emissions of volatile compounds, particularly hexanal and carbon monoxide,
      from large- and small-scale storage of wood pellets. METHODS: Air sampling was
      performed with Fourier transform infrared spectroscopy and adsorbent sampling in
      pellet warehouses, domestic storage rooms, lumber kiln dryers and experimental
      set-ups. Literature studies were included to describe the formation of hexanal
      and carbon monoxide and the toxicology of hexanal. RESULTS: A arithmetic mean
      aldehyde level of 111 +/- 32 mg/m(3) was found in one warehouse, with a peak
      reading of 156 mg/m(3) [correction]. A maximum aldehyde reading of 457 mg/m(3)
      was recorded at the surface of a pellet pile. Hexanal (70-80% w/w) and pentanal
      (10-15% w/w) dominated, but acetone (83 +/- 24 mg/m(3)), methanol (18 +/- 7
      mg/m(3)) and carbon monoxide (56 +/- 4 mg/m(3)) were also found. The emissions in
      a domestic storage room varied with the ambient temperature and peaked after 2
      months storage in the midst of the warm season. Aldehyde levels of 98 +/- 4
      mg/m(3) and carbon monoxide levels of 123 +/- 10 mg/m(3) were recorded inside
      such storage rooms. Elevated levels of hexanal (0.084 mg/m(3)) were recorded
      inside domestic housing and 6 mg/m(3) in a room adjacent to a poorly sealed
      storage area. Experimental laboratory studies confirmed the findings of the field
      studies. A field study of the emissions from industrial lumber drying also showed
      the formation of aldehydes and carbon monoxide. CONCLUSIONS: High levels of
      hexanal and carbon monoxide were strongly associated with storage of wood pellets
      and may constitute an occupational and domestic health hazard. The results from
      lumber drying show that the emissions of hexanal and carbon monoxide are not
      limited to wood pellets but are caused by general degradation processes of wood,
      facilitated by drying at elevated temperature. Emission of carbon monoxide from
      wood materials at low temperatures (<100 degrees C) has not previously been
      reported in the literature. We postulate that carbon monoxide is formed due to
      autoxidative degradation of fats and fatty acids. A toxicological literature
      survey showed that the available scientific information on hexanal is
      insufficient to determine the potential risks to health. However, the data
      presented in this paper seem sufficient to undertake preventive measures to
      reduce exposure to hexanal.

PMID- 15191944
TI  - Performance of personal inhalable aerosol samplers in very slowly moving air when
      facing the aerosol source.
AB  - While personal aerosol samplers have been characterized primarily based on wind
      tunnel tests conducted at relatively high wind speeds, modern indoor occupational
      environments are usually represented by very slow moving air. Recent surveys
      suggest that elevated levels of occupational exposure to inhalable airborne
      particles are typically observed when the worker, operating in the vicinity of
      the dust source, faces the source. Thus, the first objective of this study was to
      design and test a new, low cost experimental protocol for measuring the sampling
      efficiency of personal inhalable aerosol samplers in the vicinity of the aerosol
      source when the samplers operate in very slowly moving air. In this system, an
      aerosol generator, which is located in the centre of a room-sized non-ventilated
      chamber, continuously rotates and omnidirectionally disperses test particles of a
      specific size. The test and reference samplers are equally distributed around the
      source at the same distance from the centre and operate in parallel (in most of
      our experiments, the total number of simultaneously operating samplers was 15).
      Radial aerosol transport is driven by turbulent diffusion and some natural
      convection. For each specific particle size and the sampler, the aerosol mass
      concentration is measured by weighing the collection filter. The second objective
      was to utilize the new protocol to evaluate three widely used aerosol samplers:
      the IOM Personal Inhalable Sampler, the Button Personal Inhalable Aerosol Sampler
      and the 25 mm Millipore filter holder (closed-face C25 cassette). The sampling
      efficiencies of each instrument were measured with six particle fractions,
      ranging from 6.9 to 76.9 micro m in their mass median aerodynamic diameter. The
      Button Sampler efficiency data demonstrated a good agreement with the standard
      inhalable convention and especially with the low air movement inhalabilty curve.
      The 25 mm filter holder was found to considerably under-sample the particles
      larger than 10 micro m; its efficiency did not exceed 7% for particles of 40-100
      micro m. The IOM Sampler facing the source was found to over-sample compared with
      the data obtained previously with a slowly rotating, freely suspended sampler in
      a low air movement environment. It was also found that the particle wall
      deposition in the IOM metallic cartridge was rather significant and particle size
      dependent. For each sampler (IOM, Button and C25) the precision was characterized
      through the relative standard deviation (RSD) of the aerosol concentration
      obtained with identical samplers in a specific experiment. The average RSD was
      14% for the IOM Sampler, 11% for the Button Sampler and 35% for the 25 mm filter
      cassette. A separate set of experiments, performed with the Simplified Torso
      showed that in very slowly moving air a personal sampler can be adequately
      evaluated even when it is not attached to a body but freely suspended (confirming
      the data reported previously).

PMID- 15191945
TI  - Platelet-associated CD154 in immune thrombocytopenic purpura.
AB  - CD40-ligand (CD154) is expressed on activated CD4+ T lymphocytes and is essential
      for the T cell-dependent activation of B lymphocytes. CD154 is also expressed at
      the activated platelet surface. In this study, we show that platelet-associated
      CD154 is increased in immune thrombocytopenic purpura (ITP), a disease
      characterized by an autoimmune response against proteins of the platelet
      membrane. CD154 and its messenger RNA were also present in increased amounts in
      the megakaryocytes of patients with ITP. We found that platelet-associated CD154
      is competent to induce the CD40-dependent proliferation of B lymphocytes, and we
      observed an in vitro CD154-dependent production of antibodies to the GPIIb/IIIa
      complex (integrin alphaIIbbeta3) when platelets and peripheral blood B
      lymphocytes from ITP patients with circulating anti-GPIIb/IIIa antibody were
      cultured together. Therefore, platelet-associated CD154 expression is increased
      in ITP and is able to drive the activation of autoreactive B lymphocytes in this
      disease.

PMID- 15191946
TI  - New anticoagulants.
AB  - Anticoagulants are pivotal agents for prevention and treatment of thromboembolic
      disorders. Limitations of existing anticoagulants, vitamin K antagonist and
      heparins, have led to the development of newer anticoagulant therapies. These
      anticoagulants have been designed to target specific coagulation enzymes or steps
      in the coagulation pathway. New anticoagulants that are under evaluation in
      clinical trials include: (1) inhibitors of the factor VIIa/tissue factor pathway;
      (2) factor Xa inhibitors, both indirect and direct; (3) activated protein C and
      soluble thrombomodulin; and (4) direct thrombin inhibitors. Although most of
      these are parenteral agents, several of the direct inhibitors of factor Xa and
      thrombin are orally active. Clinical development of these therapies often starts
      with studies in the prevention of venous thrombosis before evaluation for other
      indications, such as prevention of cardioembolism in patients with atrial
      fibrillation or prosthetic heart valves. At present, the greatest clinical need
      is for an oral anticoagulant to replace warfarin for long-term prevention and
      treatment of patients with venous and arterial thrombosis. Ximelagatran, an oral
      direct thrombin inhibitor, is the first of a series of promising new agents that
      might fulfill this need. Large phase 3 trials evaluating ximelagatran for the
      secondary prevention of venous thromboembolism and prevention of cardioembolic
      events in patients with atrial fibrillation have been completed.

PMID- 15191947
TI  - The homozygous FcgammaRIIIa-158V genotype is a risk factor for heparin-induced
      thrombocytopenia in patients with antibodies to heparin-platelet factor 4
      complexes.
AB  - We hypothesized that Fcgamma receptor IIIa (FcgammaRIIIa), a polymorphic receptor
      for the Fc portion of immunoglobulin G (IgG) other than FcgammaRIIa, was involved
      in heparin-induced thrombocytopenia (HIT). FcgammaRIIa-131 and FcgammaRIIIa-158
      genotypes were determined in 102 patients with definite HIT and in 2 control
      groups of patients treated by heparin (86 subjects without detectable antibodies
      [Abs] to heparin-platelet factor 4 [H/PF4], Ab(-) group; 84 patients with Abs to
      H/PF4 without HIT, Ab(+) group). There were no significant differences in
      genotype distribution or allele frequencies between the 3 groups for FcgammaRIIa
      131H/R polymorphism. In contrast, FcgammaRIIIa-158V homozygotes were more
      frequent in the HIT group than in the Ab(+) group (P = .02), a difference that
      was more pronounced in patients with high levels of anti-H/PF4 Abs (P = .01).
      Since anti-H/PF4 Abs are mainly IgG1 and IgG3, clearance of sensitized platelets
      may be increased in patients homozygous for the FcgammaRIIIa-158V allotype, thus
      contributing to the development of thrombocytopenia.

PMID- 15191948
TI  - In a model of tumor dormancy, long-term persistent leukemic cells have increased
      B7-H1 and B7.1 expression and resist CTL-mediated lysis.
AB  - In tumor dormancy, tumor cells persist in the host over a long period of time but
      do not grow. We investigated in the DA1-3b mouse model of acute myeloid leukemia
      how leukemic cells could persist for months in spite of an effective antileukemic
      immune response. Mice were immunized with irradiated interleukin 12 (IL12)- or
      CD154-transduced DA1-3b cells, challenged with wild-type DA1-3b cells, and
      randomly killed during 1-year follow-up. Quantification of residual disease 1
      year after challenge showed that persistent leukemic cells represented less than
      0.02% of spleen cells in most animals. These residual cells were still able to
      kill naive hosts, even when isolated after 1 year of persistence. Persistent
      leukemic cells were more resistant to specific cytotoxic T-cell (CTL)-mediated
      killing and had enhanced B7-H1 and B7.1 expression proportional to the time they
      had persisted in the host. Blocking B7-H1 or B7.1/cytotoxic T-lymphocyte
      associated antigen (CTLA-4) interaction enhanced CTL-mediated killing of the
      persistent cells, and blocking B7-H1, B7.1, or CTLA-4 in vivo prolonged survival
      of naive mice injected with persistent leukemic cells. Thus, escape of leukemic
      cells from tumor immunity via overexpression of B7-H1 or B7.1 might represent a
      new mechanism of tumor dormancy in acute leukemia.

PMID- 15191949
TI  - Adult bone marrow-derived cells recruited during angiogenesis comprise precursors
      for periendothelial vascular mural cells.
AB  - Bone marrow (BM)-derived cells are thought to participate in the growth of blood
      vessels during postnatal vascular regeneration and tumor growth, a process
      previously attributed to stem and precursor cells differentiating to endothelial
      cells. We used multichannel laser scanning confocal microscopy of whole-mounted
      tissues to study angiogenesis in chimeric mice created by reconstituting C57BL
      mice with genetically marked syngeneic BM. We show that BM-derived endothelial
      cells do not significantly contribute to tumor- or cytokine-induced
      neoangiogenesis. Instead, BM-derived periendothelial vascular mural cells were
      persistently detected at sites of tumor- or vascular endothelial growth factor
      induced angiogenesis. Subpopulations of these cells expressed the pericyte
      specific NG2 proteoglycan, or the hematopoietic markers CD11b and CD45, but did
      not detectably express the smooth muscle markers smooth muscle alpha-actin or
      desmin. Thus, the major contribution of the BM to angiogenic processes is not
      endothelial, but may come from progenitors for periendothelial vascular mural and
      hematopoietic effector cells.

PMID- 15191950
TI  - Human blood IgM "memory" B cells are circulating splenic marginal zone B cells
      harboring a prediversified immunoglobulin repertoire.
AB  - The human peripheral B-cell compartment displays a large population of
      immunoglobulin M-positive, immunoglobulin D-positive CD27(+)
      (IgM(+)IgD(+)CD27(+)) "memory" B cells carrying a mutated immunoglobulin
      receptor. By means of phenotypic analysis, complementarity-determining region 3
      (CDR3) spectratyping during a T-independent response, and gene-expression
      profiling of the different blood and splenic B-cell subsets, we show here that
      blood IgM(+)IgD(+)CD27(+) cells correspond to circulating splenic marginal zone B
      cells. Furthermore, analysis of this peripheral subset in healthy children
      younger than 2 years shows that these B cells develop and mutate their
      immunoglobulin receptor during ontogeny, prior to their differentiation into T
      independent antigen-responsive cells. It is therefore proposed that these
      IgM(+)IgD(+)CD27(+) B cells provide the splenic marginal zone with a diversified
      and protective preimmune repertoire in charge of the responses against
      encapsulated bacteria.

PMID- 15191951
TI  - Chemokine receptor-mediated delivery directs self-tumor antigen efficiently into
      the class II processing pathway in vitro and induces protective immunity in vivo.
AB  - Nonimmunogenic antigens can be efficiently rendered immunogenic by targeting them
      to antigen-presenting cells via differentially expressed chemokine receptors. For
      example, self-tumor or HIV antigens genetically fused with proinflammatory
      chemoattractants elicit potent immune responses and protective antitumor immunity
      in mice. Herein we demonstrate that the mechanism by which chemokine fusions
      elicit responses is efficient uptake, processing, and presentation of antigens
      via the major histocompatibility complex class II pathway. Experiments with
      inhibitors of intracellular trafficking suggest that chemoattractant fusion
      proteins, but not antigen alone, were processed and presented through early/late
      endosomal and Golgi compartments and stimulated antigen-specific CD4+ T cells
      both in vitro and in vivo. Chemokine fusion also facilitated the presentation of
      antigen by dendritic cells to an autologous human tumor-specific CD4+ T-cell
      line. Taking advantage of chemokine redundancy, viral chemokine fusions were
      equally potent in inducing protective immunity in vivo, providing a possible
      strategy to circumvent hypothetical, vaccine-induced antihost chemokine
      autoimmunity, for example, by use of viral chemoattractants in humans.

PMID- 15191953
TI  - Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia
      in first complete remission: a retrospective study of the European Group for
      Blood and Marrow Transplantation (EBMT).
AB  - Acute megakaryoblastic leukemia (M7 AML) is a highly aggressive disease. We
      evaluated outcomes in 57 children (11 with Down syndrome) and 69 adults with M7
      AML after first complete remission (CR1) following autologous or HLA-identical
      allogeneic transplantation. Characteristics of the recipients of autologous
      transplants (38 children, 37 adults) were, respectively: median age, 1.7 and 46
      years; non-total body irradiation (non-TBI) conditioning regimen, 97% and 70%;
      bone marrow as stem cell source, 74% and 43%. Characteristics of the recipients
      of allogeneic transplants (19 children, 32 adults) were, respectively: median
      age, 2.8 and 37 years; non-TBI regimen, 63% and 42%; bone marrow as stem cell
      source, 95% and 69%. Autologous transplantation benefited children more; the
      relapse rate was high in adults. Results for autologous transplantation were
      (children and adults, respectively): engraftment, 90% and 100%; 3-year treatment
      related mortality (TRM) rate, 3% and 8%; relapse rate, 45% and 64%; leukemia-free
      survival (LFS) rate, 52% and 27%; overall survival (OS) rate, 61% and 30%. After
      allogeneic transplantation, TRM was fairly low in children and adults, and
      relapse rates were lower than after autologous transplantation. Results for
      allogeneic transplantation were, respectively: engraftment, 95% and 90%; TRM, 0%
      and 26%; relapse rate, 34% and 28%; LFS, 66% and 46%; OS, 82% and 43%). We
      conclude that M7 AML patients in CR1 (except children with Down syndrome, who
      already have better outcomes) can benefit from transplantation.

PMID- 15191952
TI  - Impact of HLA class I and class II high-resolution matching on outcomes of
      unrelated donor bone marrow transplantation: HLA-C mismatching is associated with
      a strong adverse effect on transplantation outcome.
AB  - Outcome of unrelated donor marrow transplantation is influenced by donor
      recipient matching for HLA. Prior studies assessing the effects of mismatches at
      specific HLA loci have yielded conflicting results. The importance of high
      resolution matching for all HLA loci has also not been established. We therefore
      examined the effects of HLA matching (low or high resolution or both) on
      engraftment, graft-versus-host disease (GVHD), and mortality in 1874 donor
      recipient pairs retrospectively typed at high resolution for HLA-A, -B, -C, 
      DRB1, -DQ, and -DP. Mismatches at HLA-A, -B, -C, and -DRB1 each had similar
      adverse effects on mortality. Only HLA-A mismatches demonstrated significant
      adverse effects on GVHD. These adverse effects on outcome were more evident in
      transplants with low-resolution versus only high-resolution mismatches.
      Mismatches for HLA-DQ or -DP did not significantly affect outcome. When high
      resolution mismatches at HLA-A, -B, -C, and -DRB1 were considered together,
      adverse effects on survival and GVHD were observed. We therefore conclude that
      matching for HLA-C should be incorporated into algorithms for unrelated donor
      selection. High-resolution mismatches at HLA-A, -B, -C, and -DRB1 adversely
      affect outcome, but less so than low-resolution mismatches. When clinical
      circumstances allow, high-resolution class I typing may help optimize donor
      selection and improve outcome.

PMID- 15191954
TI  - Whole body magnetic resonance imaging.

PMID- 15191955
TI  - Eradicating H pylori.

PMID- 15191956
TI  - Choice and equity: lessons from long term care.

PMID- 15191957
TI  - A firm foundation for senior house officers.

PMID- 15191958
TI  - Tackling the next influenza pandemic.

PMID- 15191959
TI  - Doctor charged with misconduct over murder claim.

PMID- 15191962
TI  - Report shows strong sex differences in teenage health behaviour.

PMID- 15191963
TI  - GlaxoSmithKline faces US lawsuit over concealment of trial results.

PMID- 15191966
TI  - Homeless families in England report high levels of depression.

PMID- 15191969
TI  - Doctors demand national screening for chlamydia.

PMID- 15191970
TI  - West Nile infections are occurring early in North America.

PMID- 15191971
TI  - Smoking habits of ethnic groups lead to higher risk of heart disease.

PMID- 15191972
TI  - US judge says ban on partial birth abortion is unconstitutional.

PMID- 15191973
TI  - Greek authorities probe illegal clinical studies on elderly people.

PMID- 15191975
TI  - Charity suspends work in Afghanistan after five staff are killed.

PMID- 15191976
TI  - Pain control often neglected in war areas.

PMID- 15191977
TI  - Social class and elective caesareans in the English NHS.

PMID- 15191978
TI  - Nose bleeds associated with use of risperidone.

PMID- 15191979
TI  - Kidney stones.

PMID- 15191981
TI  - Nalbuphine and slow release morphine.

PMID- 15191982
TI  - ABC of burns: pathophysiology and types of burns.

PMID- 15191983
TI  - Chemotherapy for cancer patients who present late.

PMID- 15191985
TI  - Reaching beyond the white middle classes.

PMID- 15191986
TI  - Data protection, informed consent, and research: Data Protection Act does not bar
      medical research.

PMID- 15191987
TI  - Sharing electronic health records: confidentiality is big issue.

PMID- 15191988
TI  - Data protection, informed consent, and research: Interpretation of legislation
      should reflect patients' views.

PMID- 15191989
TI  - Managing nocturia: nocturia is a symptom, not a diagnosis.

PMID- 15191990
TI  - Managing nocturia: article is removed from clinical practice.

PMID- 15191991
TI  - Hypocalcaemia after intravenous bisphosphonate: lesson to be learnt.

PMID- 15191992
TI  - Hypocalcaemia after intravenous bisphosphonate: read the product information
      first.

PMID- 15191993
TI  - Hypocalcaemia after intravenous bisphosphonate: adjuvant bisphosphonate is not
      currently accepted practice.

PMID- 15191994
TI  - Hospital management of self harm in adults in England: study contains important
      data not reported in the paper.

PMID- 15191995
TI  - Am I breaking the law again?

PMID- 15191996
TI  - Balancing mammography's benefits and harms.

PMID- 15191997
TI  - Patient-centered communication.

PMID- 15192001
TI  - Editorial: Cardiovascular medicine and Moore's Law.

PMID- 15192002
TI  - Anaesthetic implications of grown-up congenital heart disease.

PMID- 15192003
TI  - Opioids for non-cancer pain.

PMID- 15192004
TI  - Infective complications of thoracic epidural.

PMID- 15192005
TI  - Spectral entropy--what has it to do with anaesthesia, and the EEG?

PMID- 15192006
TI  - Surgical critical care--a rose by any other name.

PMID- 15192007
TI  - Protective ventilation of patients with acute respiratory distress syndrome.

PMID- 15192008
TI  - Cardiovascular stability during inhalational anaesthesia in morbidly obese
      patients: which is better, sevoflurane or desflurane?

PMID- 15192009
TI  - Potential role for sildenafil in the management of perioperative pulmonary
      hypertension and right ventricular dysfunction after cardiac surgery.

PMID- 15192011
TI  - Correlation maps allow neuronal electrical properties to be predicted from single
      cell gene expression profiles in rat neocortex.
AB  - The computational power of the neocortex arises from interactions of multiple
      neurons, which display a wide range of electrical properties. The gene expression
      profiles underlying this phenotypic diversity are unknown. To explore this
      relationship, we combined whole-cell electrical recordings with single-cell
      multiplex RT-PCR of rat (p13-16) neocortical neurons to obtain cDNA libraries of
      26 ion channels (including voltage activated potassium channels, Kv1.1/2/4/6,
      Kvbeta1/2, Kv2.1/2, Kv3.1/2/3/4, Kv4.2/3; sodium/potassium permeable
      hyperpolarization activated channels, HCN1/2/3/4; the calcium activated potassium
      channel, SK2; voltage activated calcium channels, Caalpha1A/B/G/I, Cabeta1/3/4),
      three calcium binding proteins (calbindin, parvalbumin and calretinin) and GAPDH.
      We found a previously unreported clustering of ion channel genes around the three
      calcium-binding proteins. We further determined that cells similar in their
      expression patterns were also similar in their electrical properties. Subsequent
      regression modeling with statistical resampling yielded a set of coefficients
      that reliably predicted electrical properties from the expression profile of
      individual neurons. This is the first report of a consistent relationship between
      the co-expression of a large profile of ion channel and calcium binding protein
      genes and the electrical phenotype of individual neocortical neurons.

PMID- 15192010
TI  - Where bottom-up meets top-down: neuronal interactions during perception and
      imagery.
AB  - Functional magnetic resonance imaging (fMRI) studies have identified category
      selective regions in ventral occipito-temporal cortex that respond preferentially
      to faces and other objects. The extent to which these patterns of activation are
      modulated by bottom-up or top-down mechanisms is currently unknown. We combined
      fMRI and dynamic causal modelling to investigate neuronal interactions between
      occipito-temporal, parietal and frontal regions, during visual perception and
      visual imagery of faces, houses and chairs. Our results indicate that, during
      visual perception, category-selective patterns of activation in extrastriate
      cortex are mediated by content-sensitive forward connections from early visual
      areas. In contrast, during visual imagery, category-selective activation is
      mediated by content-sensitive backward connections from prefrontal cortex.
      Additionally, we report content-unrelated connectivity between parietal cortex
      and the category-selective regions, during both perception and imagery. Thus, our
      investigation revealed that neuronal interactions between occipito-temporal,
      parietal and frontal regions are task- and stimulus-dependent. Sensory
      representations of faces and objects are mediated by bottom-up mechanisms arising
      in early visual areas and top-down mechanisms arising in prefrontal cortex,
      during perception and imagery respectively. Additionally non-selective, top-down
      processes, originating in superior parietal areas, contribute to the generation
      of mental images, regardless of their content, and their maintenance in the
      'mind's eye'.

PMID- 15192012
TI  - Environmental control of the survival and differentiation of dentate granule
      neurons.
AB  - Dentate granule cells (DGCs) and their microcircuits have been implicated in
      hippocampus-dependent memory encoding and epileptogenesis. Little is known about
      how the proper maturation of DGCs is determined by their intrinsic programs or
      external factors during development. In order to explore this, we dispersed
      premature DGCs on living hippocampal slices. Here we report that the survival and
      network formation of DGCs are supported by local cues present in the dentate
      gyrus ex vivo. The density of surviving DGCs was almost uniform throughout the
      host slices 12 h after implantation but gradually became heterogenous across
      substrata, with the cells engrafted onto the stratum granulosum scoring the
      highest rate of survival. The mossy fiber axons arising from DGCs growing on this
      substratum were properly guided towards CA3, whereas other misplaced DGCs
      exhibited heterotopic axon projection. In particular, about half of the axons
      originating from the hilus were misguided into the molecular layer, which
      resembles the supragranular mossy fiber sprouting seen in epileptic disorders.
      These results suggest that local environmental factors influence the cell
      adhesion, neurite polarization and axon guidance of DGCs.

PMID- 15192013
TI  - Gender- and age-related distinctions for the in vivo prooxidant state in Fanconi
      anaemia patients.
AB  - Some selected oxidative stress parameters were measured in 56 Fanconi anaemia
      (FA) patients (42 untransplanted and 14 transplanted), 54 FA heterozygotes
      (parents) and 173 controls. Untransplanted FA patients showed a highly
      significant increase in leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) (P =
      0.00003) and a borderline increase (P = 0.076) in urinary levels of 8-OHdG versus
      child controls. These increases were more pronounced in female FA patients (P =
      0.00005 for leukocyte 8-OHdG and P = 0.021 for urinary 8-OHdG). Female FA
      patients also displayed a highly significant excess of spontaneous chromosomal
      breaks versus male patients (P = 0.00026), in the same female:male ratio (
      approximately 1.4) as detected for both leukocyte and urine 8-OHdG levels. Plasma
      methylglyoxal (MGlx) levels were increased in untransplanted FA patients versus
      child controls (P = 0.032). The increases in leukocyte and urinary 8-OHdG and in
      MGlx levels were detected in young FA patients (< or =15 years), whereas patients
      aged 16-29 years failed to display any differences versus controls in the same
      age group. A significant increase in oxidized:reduced glutathione (GSSG:GSH)
      ratio was observed (P = 0.046) in the FA patients aged < or =15 years, whereas
      those aged 16-29 years, both untransplanted and transplanted, displayed a
      decrease (P = 0.06) in the GSSG:GSH ratio versus the controls of the respective
      age groups. No significant changes were detected in plasma levels of vitamin C,
      vitamin E or uric acid. Transplanted FA patients showed lesser alterations in
      leukocyte 8-OHdG and in GSSG:GSH ratio versus untransplanted patients. The
      parents of FA patients displayed a significant increase in plasma MGlx levels (P
      = 0.0014) versus adult controls. The results suggest a gender- and age-related
      modulation of oxidative stress in FA patients. The observed increase in urinary 8
      OHdG in untransplanted FA patients suggests a proficient removal of oxidized DNA
      bases.

PMID- 15192014
TI  - Insufficient p65 phosphorylation at S536 specifically contributes to the lack of
      NF-kappaB activation and transformation in resistant JB6 cells.
AB  - NF-kappaB activation is required for TNF-alpha-induced transformation of JB6
      mouse epidermal cells. Deficient activation of p65 contributes to the lack of NF
      kappaB activation in transformation-resistant (P-) cells. We hypothesized that
      the differential NF-kappaB activation involves differential p65 phosphorylation
      arising from enzyme activity differences. Here we show that TNF-alpha induces
      greater ERK-dependent p65 phosphorylation at S536 in transformation sensitive
      (P+) cells than in P- cells. Our results establish that limited ERK content
      contributes to a low IkappaB kinase (IKKbeta) level, in turn resulting in
      insufficient p65 phosphorylation at S536 upon TNF-alpha stimulation in P- cells.
      Phosphorylation of p65 at S536 appears to play a role in TNF-alpha-induced p65
      DNA binding and recruitment of p300 to the p65 complex as well as in release of
      p65 bound to HDAC1 and 3. Blocking p65 phosphorylation at S536, but not at S276
      or S529, abolishes p65 transactivational activity. Over-expression of p65 but not
      p65 phosphorylation mutant (S536A) in transformation-resistant P- cells renders
      these cells sensitive to TNF-alpha-induced transformation. Over-expression of p65
      phosphorylation mimics p65-S536D or p65-S536E in P- cells and also rescues the
      transformation response. These findings provide direct evidence that
      phosphorylation of p65 at S536 is required for TNF-alpha-induced NF-kappaB
      activation in the JB6 transformation model. The lack of NF-kappaB activation seen
      in P- cells can be attributed to an insufficient level of p65 phosphorylation on
      S536 that arises from insufficient IKKbeta that in turn arises from insufficient
      ERK. Thus, p65 phosphorylation at S536 offers a potential molecular target for
      cancer prevention.

PMID- 15192015
TI  - Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC
      induced phosphorylation of ATF2 in JB6 cells.
AB  - Activating transcription factor 2 (ATF2) has been shown to regulate gene
      expression in the cellular response to environmental stresses such as ultraviolet
      (UV) irradiation. However, the signal transduction mechanism of ATF2 activation
      by UV is not as yet completely understood. In the present study, we provide
      evidence showing that UVC-stimulated phosphorylation of ATF2 (Thr71) was to
      varying degrees prevented by a dominant negative mutant of p38beta kinase, c-Jun
      N-terminal kinase 1 (JNK1) or extracellular signal-regulated kinase 2 (ERK2). The
      phosphorylation was also suppressed by PD98059, an MEK inhibitor, or H89, a
      potent inhibitor of mitogen- and stress-activated protein kinase 1 (MSK1), and a
      C- or N-terminal 'kinase-dead' mutant of MSK1 (MSK1-Cd or MSK1-Nd). Furthermore,
      co- immunoprecipitation experiments revealed a potential intracellular signaling
      complex consisting of ATF2 and ERKs and/or MSK1. In vitro kinase assays revealed
      that ERK1, ERK2 and MSK1, like p38 kinase and JNK2, directly phosphorylate ATF2
      at Thr71, but addition of RSK2 or Akt1 had almost no effect. Active kinase
      immunoprecipitated by an MSK1, ERKs or p38 antibody from an extract of JB6 cells
      irradiated by UVC can directly phosphorylate ATF2 at Thr71, suggesting UVC
      induces a direct phosphorylation of ATF2 by ERKs or MSK1. Overall, our results
      reveal that MSK1 and ERKs, like p38 kinase and JNKs, are required for ATF2
      phosphorylation (Thr71) in the UVC response.

PMID- 15192016
TI  - Glutathione pathway genes and lung cancer risk in young and old populations.
AB  - Multiple enzymes with overlapping functions and shared substrates in the
      glutathione (GSH) metabolic pathway have been associated with host susceptibility
      to tobacco smoke carcinogens and in lung cancer etiology. However, few studies
      have investigated the differing and interacting roles of GSH pathway enzymes with
      tobacco smoke exposure on lung cancer risk in young (<50 years of age) and old
      (>80 years of age) populations. Between 1997 and 2001, 237 primary lung cancer
      patients (170 young, 67 old) and 234 controls (165 young, 69 old) were enrolled
      at the Mayo Clinic. Using PCR amplification of genomic DNA, polymorphic markers
      for gammaGCS, GPX1, GSTP1 (I105V and A114V), GSTM1 and GSTT1 were genotyped.
      Recursive partitioning and logistic regression models were used to build binary
      classification trees and to estimate odds ratios (OR) and 95% confidence
      intervals for each splitting factor. For the young age group, cigarette smoking
      had the greatest association with lung cancer (OR = 3.3). For never smokers, the
      dividing factors of recursive partitioning were GSTT1 (OR = 1.7), GPX1 (OR = 0.6)
      and GSTM1 (OR = 4.3). For the old age group, smoking had the greatest association
      with lung cancer (OR = 3.6). For smokers, the dividing factors were GPX1 (OR =
      3.3) and GSTP1 (I105V) (OR = 4.1). Results from logistic regression analyses
      supported the results from RPART models. GSH pathway genes are associated with
      lung cancer development in young and old populations through differing
      interactions with cigarette smoking and family history. Carefully evaluating
      multiple levels of gene-environment and gene-gene interactions is critical in
      assessing lung cancer risk.

PMID- 15192017
TI  - Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of
      azoxymethane-treated rats.
AB  - Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly
      inhibit development of azoxymethane (AOM)-induced rat colon tumors. Little,
      however, is known about the inhibitory mechanisms. We have demonstrated recently
      that lactoferrin enhances the expression of a member of the tumor necrosis factor
      receptor family, Fas, in the colon mucosa during both early and late stages of
      carcinogenesis. Thus, Fas could be involved in bovine lactoferrin-mediated
      inhibition of tumor development. To investigate this possibility, we studied the
      influence of bovine lactoferrin on Fas-mediated apoptosis with regard to
      expression of Fas, activation of caspase-8 and caspase-3, and DNA fragmentation
      in the colon mucosa of AOM-treated rats. Western blot analysis demonstrated a
      >2.5-fold increase in Fas protein expression, as well as elevation of the active
      forms of both caspase-8 and caspase-3. Immunohistochemical analysis revealed Fas
      positive cells and apoptotic cells preferentially within the proximal colon
      region, clearly at the site of bovine lactoferrin-mediated tumor inhibition.
      These results suggest that apoptosis caused by elevated expression of Fas is
      involved in chemoprevention by lactoferrin of colon carcinogenesis.

PMID- 15192018
TI  - Avian precardiac endoderm/mesoderm induces cardiac myocyte differentiation in
      murine embryonic stem cells.
AB  - The ability to regenerate damaged myocardium with tissue derived from embryonic
      stem (ES) cells is currently undergoing extensive investigation. As a
      prerequisite to transplantation therapy, strategies must be developed to induce
      ES cells to the cardiac phenotype. Toward this end, cues from mechanisms of
      embryonic induction have been exploited, based on previous findings that anterior
      lateral endoderm (precardiac endoderm) from gastrulation-stage chick embryos
      potently induces cardiac myocyte differentiation in both precardiac and
      nonprecardiac mesoderm. Hypothesizing that avian precardiac endoderm acting as
      feeder/inducer cells would induce high percentage conversion of murine ES (mES)
      cells into cardiac myocytes, it was observed that the majority (approximately
      65%) of cocultured ES cell-derived embryoid bodies (EBs) were enriched in cardiac
      myocytes and exhibited rhythmic contractions. By contrast, mouse EBs cultured
      alone, or on feeder layers of mouse embryonic fibroblasts or avian nonprecardiac
      posterior endoderm, contained only 7% to 16% cardiac myocytes while exhibiting a
      relatively low incidence (<10%) of beating. When mES cells were cocultured with a
      bilayer of explanted precardiac endoderm/mesoderm, the incidence of rhythmically
      contractile EBs increased to 100%. To verify that the rhythmically contractile
      cells were derived from murine ES cells, cell-free medium conditioned by avian
      precardiac endoderm/mesoderm was used to induce myocyte differentiation in a mES
      cell-line containing a nuclear LacZ reporter marker gene under control of the
      cardiac-specific alpha-myosin heavy chain promoter, resulting in rhythmic
      contractility in 92% of EBs in which the majority of cells (average=86%) were
      identified as cardiac myocytes. The inductive efficacy of medium conditioned by
      avian precardiac endoderm/mesoderm may provide an opportunity to biochemically
      define factors that induce cardiac myocyte differentiation in ES cells. The full
      text of this article is available online at http://circres.ahajournals.org.

PMID- 15192019
TI  - Endothelial PAS domain protein 1 gene promotes angiogenesis through the
      transactivation of both vascular endothelial growth factor and its receptor, Flt
      1.
AB  - Endothelial PAS domain protein 1 (EPAS1) is a basic-helix-loop-helix/PAS domain
      transcription factor that is expressed preferentially in vascular endothelial
      cells. EPAS1 shares high homology with hypoxia-inducible factor-1alpha (HIF
      1alpha) and is reported to transactivate vascular endothelial growth factor
      (VEGF), fetal liver kinase-1 (Flk-1), and Tie2 promoters. In this study, we
      analyzed the role of EPAS1 in the process of angiogenesis. Using microarray
      technology, we looked for target genes regulated by EPAS1 in vascular endothelial
      cells. A total of 130 genes were upregulated by EPAS1, including fms-like
      tyrosine kinase-1 (Flt-1). Reporter analysis using human Flt-1 promoter and gel
      mobility shift assays showed that the heterodimer of EPAS1 and aryl hydrocarbon
      receptor nuclear translocator binds directly to HIF-1-binding site upstream of
      Flt-1 promoter and transactivates it. Small interfering RNA targeted to EPAS1 but
      not HIF-1alpha attenuated desferrioxamine-induced Flt-1 mRNA expression, thus
      EPAS1 is thought to play an essential role in hypoxic induction of Flt-1 gene.
      Furthermore, using mouse wound healing models, we demonstrated that adenovirus
      mediated delivery of EPAS1 gene significantly induced the expression of VEGF, Flt
      1, Flk-1, and Tie2 mRNA at the wound site and promoted mature angiogenesis. The
      proportion of the number of mural cells in newly formed vessels was significantly
      higher in EPAS1-treated wound area than VEGF-treated area. In conclusion, EPAS1
      promotes Flt-1 gene expression and induces mRNA expression of VEGF, Flk-1, and
      Tie2, leading to enhancement of mature angiogenesis in vivo. Thus, EPAS1 may
      contribute to the construction of mature vessels by modulating the coordinated
      expressions of VEGF, Flt-1, Flk-1, and Tie2.

PMID- 15192020
TI  - Signal transducer and activator of transcription 3 is required for myocardial
      capillary growth, control of interstitial matrix deposition, and heart protection
      from ischemic injury.
AB  - The transcription factor signal transducer and activator of transcription 3
      (STAT3) participates in a wide variety of physiological processes and directs
      seemingly contradictory responses such as proliferation and apoptosis. To
      elucidate its role in the heart, we generated mice harboring a cardiomyocyte
      restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3
      deficient mice developed reduced myocardial capillary density and increased
      interstitial fibrosis within the first 4 postnatal months, followed by dilated
      cardiomyopathy with impaired cardiac function and premature death. Conditioned
      medium from STAT3-deficient cardiomyocytes inhibited endothelial cell
      proliferation and increased fibroblast proliferation, suggesting the presence of
      paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3
      deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion
      injury and infarction with increased cardiac apoptosis, increased infarct sizes,
      and reduced cardiac function and survival. Our study establishes a novel role for
      STAT3 in controlling paracrine circuits in the heart essential for postnatal
      capillary vasculature maintenance, interstitial matrix deposition balance, and
      protection from ischemic injury and heart failure.

PMID- 15192021
TI  - Paradoxical cAMP-induced lung endothelial hyperpermeability revealed by
      Pseudomonas aeruginosa ExoY.
AB  - Mammalian transmembrane adenylyl cyclases synthesize a restricted plasmalemmal
      cAMP pool that is intensely endothelial barrier protective. Bacteria have devised
      mechanisms of transferring eukaryotic factor-dependent adenylyl cyclases into
      mammalian cells. Pseudomonas aeruginosa ExoY is one such enzyme that catalyzes
      cytosolic cAMP synthesis, with unknown function. Pseudomonas aeruginosa
      genetically modified to introduce only the ExoY toxin elevated cAMP 800-fold in
      pulmonary microvascular endothelial cells over 4 hours, whereas a catalytically
      deficient (ExoY(K81M)) strain did not increase cAMP. ExoY-derived cAMP was
      localized to a cytosolic microdomain not regulated by phosphodiesterase activity.
      In contrast to the barrier-enhancing actions of plasmalemmal cAMP, the ExoY
      cytosolic cAMP pool induced endothelial gap formation and increased the
      filtration coefficient in the isolated perfused lung. These findings collectively
      illustrate a previously unrecognized mechanism of hyperpermeability induced by
      rises in cytosolic cAMP.

PMID- 15192022
TI  - Electrical propagation in synthetic ventricular myocyte strands from germline
      connexin43 knockout mice.
AB  - To characterize the role of connexin43 (Cx43) as a determinant of cardiac
      propagation, we synthesized strands and pairs of ventricular myocytes from
      germline Cx43-/- mice. The amount of Cx43, Cx45, and Cx40 in gap junctions was
      analyzed by immunohistochemistry and confocal microscopy. Intercellular
      electrical conductance, gj, was measured by the dual-voltage clamp technique
      (DVC), and electrical propagation was assessed by multisite optical mapping of
      transmembrane potential using a voltage-sensitive dye. Compared with wild-type
      (Cx43+/+) strands, immunoreactive signal for Cx43 was reduced by 46% in Cx43+/-
      strands and was absent in Cx43-/- strands. Cx45 signal was reduced by 46% in
      Cx43+/- strands and to the limit of detection in Cx43-/- strands, but total Cx45
      protein levels measured in immunoblots of whole cell homogenates were equivalent
      in all genotypes. Cx40 was detected in 2% of myocytes. Intercellular conductance,
      gj, was reduced by 32% in Cx43+/- cell pairs and by 96% in Cx43-/- cell pairs.
      The symmetrical dependence of gj on transjunctional voltage and properties of
      single-channel recordings indicated that Cx45 was the only remaining connexin in
      Cx43-/- cells. Propagation in Cx43-/- strands was very slow (2.1 cm/s versus 52
      cm/s in Cx43+/+) and highly discontinuous, with simultaneous excitation within
      and long conduction delays (2 to 3 ms) between individual cells. Propagation was
      abolished by 1 mmol/L heptanol, indicating residual junctional coupling. In
      summary, knockout of Cx43 in ventricular myocytes leads to very slow conduction
      dependent on the presence of Cx45. Electrical field effect transmission does not
      contribute to propagation in synthetic strands.

PMID- 15192023
TI  - Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor
      1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of
      prolyl hydroxylases.
AB  - The vasodilator hydralazine, used clinically in cardiovascular therapy, relaxes
      arterial smooth muscle by inhibiting accumulation of intracellular free Ca2+ via
      an unidentified primary target. Collagen prolyl hydroxylase is a known target of
      hydralazine. We therefore investigated whether inhibition of other members of
      this enzyme family, namely the hypoxia-inducible factor (HIF)-regulating O2
      dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel
      mechanism of action. Hydralazine induced rapid and transient expression of HIF
      1alpha and downstream targets of HIF (endothelin-1, adrenomedullin, haem
      oxygenase 1, and vascular endothelial growth factor [VEGF]) in endothelial and
      smooth muscle cells and induced endothelial cell-specific proliferation.
      Hydralazine dose-dependently inhibited PHD activity and induced nonhydroxylated
      HIF-1alpha, evidence for HIF stabilization specifically by inhibition of PHD
      enzyme activity. In vivo, hydralazine induced HIF-1alpha and VEGF protein in
      tissue extracts and elevated plasma VEGF levels. In sponge angiogenesis assays,
      hydralazine increased stromal cell infiltration and blood vessel density versus
      control animals. Thus, hydralazine activates the HIF pathway through inhibition
      of PHD activity and initiates a pro-angiogenic phenotype. This represents a novel
      mechanism of action for hydralazine and presents HIF as a potential target for
      treatment of ischemic disease.

PMID- 15192024
TI  - Apolipoprotein D and platelet-derived growth factor-BB synergism mediates
      vascular smooth muscle cell migration.
AB  - We identified apolipoprotein (apo)D in a search for proteins upregulated in a
      posttranscriptional manner similar to fibronectin in motile smooth muscle cells
      (SMCs). To address the function of apoD in SMCs, we cloned a partial apoD cDNA
      from ovine aortic (Ao) SMCs using RT-PCR. We documented a 2.5-fold increase in
      apoD protein but no increase in apoD mRNA in Ao SMCs 48 hours after a multiwound
      migration assay (P<0.01). Confocal microscopy revealed prominent perinuclear and
      trailing edge expression of apoD in migrating SMCs but not in the confluent
      monolayer. Stimulation of Ao SMCs with 10 ng/mL platelet-derived growth factor
      (PDGF)-BB increased apoD protein expression (P<0.05). Moreover, PDGF-BB
      stimulated migration of human pulmonary artery SMCs was suppressed by knock-down
      of apoD using RNAi. Stable overexpression of apoD in Ao SMCs cultured in 10%
      fetal bovine serum promoted random migration by 62% compared with vector
      transfected cells (P<0.01). Overexpression of apoD or addition of exogenous apoD
      to a rat aortic SMC line (A10) stimulated their migration in response to a
      subthreshold dose of PDGF-BB (P<0.05). This was unrelated to increased
      phosphorylation of ERK1/2 or of phospholipase C-gamma1, but correlated with
      enhanced Rac1 activation. This study shows that apoD can be expressed or taken up
      by SMCs and can regulate their motility in response to growth factors.

PMID- 15192025
TI  - Hypertension caused by angiotensin II infusion involves increased superoxide
      production in the central nervous system.
AB  - Hypertension caused by angiotensin II (Ang II) infusion is associated with
      oxidative stress in the peripheral vasculature and kidney. The role of redox
      mechanisms in the central nervous system (CNS), a tissue known to be pivotal in
      Ang II-dependent hypertension, has not been investigated. We recently identified
      superoxide (O2*-) in the brain as a key signaling intermediate in the transient
      pressor response elicited by acute injection of Ang II directly into the CNS.
      Here we tested the hypothesis that hypertension caused by chronic systemic
      infusion of Ang II is mediated by a central neurogenic mechanism involving O2*-.
      Infusion of Ang II (600 ng x kg(-1) x min(-1)) over a 2-week period in mice
      caused a gradually developing hypertension that was correlated with marked
      elevations in O2*- production specifically in the subfornical organ (SFO), a
      brain region lying outside the blood-brain barrier and known to be a primary
      sensor for blood-borne Ang II. Adenoviral-mediated delivery of cytoplasmically
      targeted superoxide dismutase (SOD) selectively to this site prevented the
      hypertension and the increased O2*- production, whereas gene transfer of SOD
      targeted to the extracellular matrix had no effect. These data suggest that
      increased intracellular O2*- production in the SFO is critical in the development
      of Ang II-induced hypertension.

PMID- 15192026
TI  - Differential modulation of L-type Ca2+ current by SR Ca2+ release at the T
      tubules and surface membrane of rat ventricular myocytes.
AB  - We have characterized modulation of ICa by Ca2+ at the t-tubules (ie, in control
      cells) and surface sarcolemma (ie, in detubulated cells) of cardiac ventricular
      myocytes, using the whole-cell patch clamp technique to record ICa. ICa
      inactivation was significantly slower in detubulated cells than in control cells
      (27.1+/-7.8 ms, n=22, versus 16.4+/-7.9 ms, n=22; P<0.05). In atrial myocytes,
      which lack t-tubules, ICa inactivation was not changed by the treatment used to
      produce detubulation. In the presence of ryanodine or BAPTA, or when Ba2+ was
      used as the charge carrier, the rate of inactivation was not significantly
      different in control and detubulated cells. Frequency-dependent facilitation
      occurred in control cells but not in detubulated cells, and was abolished by
      ryanodine. These results suggest that Ca2+ released from the SR has a greater
      effect on ICa in the t-tubules than at the surface sarcolemma. This does not
      appear to be due to differences in local Ca2+ release from the SR, because the
      gain of Ca2+ release was not significantly different in control and detubulated
      cells. These data suggest that the t-tubules are a key site for the regulation of
      transsarcolemmal Ca2+ flux by Ca2+ release from the SR; this could play a role in
      altered Ca2+ homeostasis in pathological conditions. The full text of this
      article is available online at http://circres.ahajournals.org.

PMID- 15192027
TI  - Endothelial nitric oxide synthase regulates microlymphatic flow via collecting
      lymphatics.
AB  - Functional interactions between the initial and collecting lymphatics, as well as
      the molecular players involved, remain elusive. In this study, we assessed the
      influence of nitric oxide (NO) on lymphatic fluid velocity and flow, using a
      mouse tail model that permits intravital microscopy and microlymphangiography. We
      found that NO synthase (NOS) inhibition decreased lymphatic fluid velocity in the
      initial lymphatics, without any effect on their morphology. Using the same model,
      we found a similar effect in eNOS-/- mice and in mice treated with a selective
      endothelial NOS (eNOS) inhibitor. Next, we uncoupled the superficial initial
      lymphatics from the deeper collecting lymphatics by ligating the latter and found
      that lymphatic fluid velocity in NOS-inhibited mice became equal to that in
      control animals. Surprisingly, lymphatic fluid velocity was significantly
      increased after ligating the collecting lymphatics, and there was a concomitant
      increase in injection rate and mean lymphatic vessel diameter. Our results
      provide the first in vivo evidence that eNOS affects function of the whole
      microlymphatic system and that it is regulated via the collecting lymphatics.

PMID- 15192028
TI  - Prospective analysis of discordant results between biochemical markers and biopsy
      in patients with chronic hepatitis C.
AB  - BACKGROUND: The FibroTest and ActiTest are noninvasive biochemical markers of
      liver injury that are intended for use as alternatives to liver biopsy in
      patients with chronic hepatitis C. The aims of this study were to assess the
      quality of biopsy and the prevalence of discordances between biopsy and markers,
      to identify factors associated with discordances, and to attribute these
      discordances to either markers or biopsy failure. METHODS: Fibrosis stage and
      activity grade were prospectively assessed on the same day by a liver biopsy and
      by markers. On the basis of risk factors for failure and independent endpoints,
      discordance was classified as being attributable to biopsy or to markers.
      RESULTS: Only 74 of 537 patients (14%) had a biopsy size > or =25 mm. Discordance
      was observed in 154 of 537 patients (29%), including 16% for fibrosis staging and
      17% for activity grading. Steatosis, an inflammatory profile, and biopsy size
      were associated with discordance. Discordance was attributable to failure of
      markers in 13 patients (2.4%) and to biopsy failure in 97 (18%; P <0.001 vs
      Fibrotest and Actitest), and was nonattributable in 44 patients (8.2%). The most
      frequent failures attributable to markers were false negatives (1.3%)
      attributable to inflammation. The most frequent failures attributable to biopsy
      were false negatives of activity grading (10.1%) and of fibrosis staging (4.5%),
      both associated with smaller biopsy size and steatosis. False positives of
      fibrosis staging (3.5%) were associated with fragmented biopsies. CONCLUSION: In
      this series, the size of liver biopsy is adequate in only a minor proportion
      (approximately 14%) of patients with chronic hepatitis C. When biopsy and marker
      results are discordant, a reason can be identified in more than two-thirds of
      cases and, in those cases, biopsy failure is >7 times more common than diagnostic
      failure of markers.

PMID- 15192029
TI  - Direct nonisotopic assay of 3-methylglutaconyl-CoA hydratase in cultured human
      skin fibroblasts to specifically identify patients with 3-methylglutaconic
      aciduria type I.

PMID- 15192030
TI  - Denaturing HPLC profiling of the ABCA4 gene for reliable detection of allelic
      variations.
AB  - BACKGROUND: Mutations in the retina-specific ABC transporter (ABCA4) gene have
      been associated with several forms of macular degenerations. Because the high
      complexity of the molecular genotype makes scanning of the ABCA4 gene cumbersome,
      we describe here the first use of denaturing HPLC (DHPLC) to screen for ABCA4
      mutations. METHODS: Temperature conditions were designed for all 50 exons based
      on effective separation of 83 samples carrying 86 sequence variations and 19
      mutagenized controls. For validation, samples from 23 previously characterized
      Stargardt patients were subjected to DHPLC profiling. Subsequently, samples from
      a cohort of 30 patients affected by various forms of macular degeneration were
      subjected to DHPLC scanning under the same conditions. RESULTS: DHPLC profiling
      not only identified all 132 sequence alterations previously detected by double
      gradient denaturing gradient gel electrophoresis but also identified 5 sequence
      alterations that this approach had missed. Moreover, DHPLC scanning of an
      additional panel of 30 previously untested patients led to the identification of
      26 different mutations and 29 polymorphisms, accounting for 203 sequence
      variations on 29 of the 30 patients screened. In total, the DHPLC approach
      allowed us to identify 16 mutations that had never been reported before.
      CONCLUSIONS: These results provide strong support for the use of DHPLC for
      molecular characterization of the ABCA4 gene.

PMID- 15192031
TI  - Lithium monitoring by reverse iontophoresis in vivo.
AB  - BACKGROUND: We investigated reverse transdermal iontophoresis as an alternative,
      noninvasive method for lithium monitoring in vivo. The objectives of such an
      approach would be to facilitate compliance with treatment and to improve the
      quality of life for bipolar patients. METHODS: We studied 23 bipolar or schizo
      affective patients. Over a 2-h period, we extracted lithium and other cations
      across intact skin by application of an electric current (0.8 mA) and quantified
      the concentrations by ion chromatography. A blood sample provided comparative
      reference values for the drug and other electrolytes. RESULTS: Lithium, sodium,
      potassium, and calcium were efficiently extracted by iontophoresis. Lithium
      extraction fluxes were proportional to the corresponding serum concentrations,
      whereas sodium, potassium, and calcium extraction fluxes were relatively
      constant, consistent with their stable concentrations in blood. Normalization of
      the lithium extraction flux with that of sodium, which acted as an "internal
      standard", permitted calibration of the monitoring procedure without the need for
      a blood measurement. This conclusion was tested retrospectively by dividing the
      patients into two groups. The reverse iontophoretic extraction data from the
      first subset (a) established the proportionality between lithium iontophoresis
      (or the relative electrotransport of lithium and sodium) and (b) predicted
      lithium blood concentrations in the second subset of patients. The predictive
      ability was very good, with the internal standard concept providing substantial
      benefit. CONCLUSIONS: Reverse iontophoresis appears to offer a novel and accurate
      method for lithium monitoring.

PMID- 15192032
TI  - Extraction and amplification of genomic DNA from human blood on nanoporous
      aluminum oxide membranes.

PMID- 15192033
TI  - Only our patients know for sure.

PMID- 15192034
TI  - Defining "culprit mechanisms" in arrhythmogenic cardiac remodeling.

PMID- 15192035
TI  - Connecting the cells: vascular differentiation via homeobox genes and
      extracellular matrix in the distal lung.

PMID- 15192036
TI  - Caveolae and caveolins in the cardiovascular system.
AB  - Caveolae and the caveolae coat proteins, caveolins, are putatively implicated in
      many cellular processes, including transcytosis of macromolecules, cholesterol
      transport, and signal transduction. Recent insights into the physiological and
      pathophysiological roles of these organelles and the caveolins from genetically
      modified mice suggest that they may be profoundly important for postnatal
      cardiovascular function, including endothelial barrier function, regulation of
      nitric oxide synthesis, cholesterol metabolism, and cardiac function.

PMID- 15192037
TI  - Biology of cardiac arrhythmias: ion channel protein trafficking.
AB  - The mechanisms underlying normal and abnormal cardiac rhythms are complex and
      incompletely understood. Through the study of uncommon inheritable arrhythmia
      syndromes, including the long QT and Brugada syndromes, new insights are
      emerging. At the cellular and tissue levels, we now recognize that ion channel
      current is the sum of biophysical (gating, permeation), biochemical
      (phosphorylation, etc), and biogenic (biosynthesis, processing, trafficking, and
      degradation) properties. This review focuses on how heart cells process ion
      channel proteins and how this protein trafficking may be altered in some cardiac
      arrhythmia diseases. In this review, we honor Dr Harry A. Fozzard, a modern
      pioneer in cardiac arrhythmias, cell biology, and molecular electrophysiology. As
      a scientist and physician, his writings and mentorship have served to foster a
      generation of investigators who continue to bring this complex field toward
      greater scientific understanding and impact on humankind.

PMID- 15192038
TI  - Blockage of VEGF-induced angiogenesis by preventing VEGF secretion.
AB  - Vascular endothelial growth factor (VEGF)/vascular permeability factor is one of
      the most frequently expressed angiogenic factors in several pathological tissues.
      Development of VEGF antagonists has become an important approach in the treatment
      of angiogenesis-dependent diseases. Here we describe a novel anti-VEGF strategy
      by preventing the secretion of VEGF. We utilize the fact that placenta growth
      factor (PlGF)-1, a member of the VEGF family lacking detectable angiogenic
      activity, preferentially forms intracellular heterodimers with VEGF in cells
      coexpressing both factors. We constructed a retroviral vector containing human
      PlGF-1 or VEGF with a C-terminal KDEL sequence, which is a mammalian retention
      signal for the endoplasmic reticulum. Transduction of murine Lewis lung carcinoma
      cells with the retro-hPlGF-1-KDEL construct almost completely abrogated tumor
      growth. Consistent with the dramatic antitumor effect, most mouse VEGF molecules
      remained as intracellular mVEGF/hPlGF-1 heterodimers, and only a negligible
      amount of mVEGF homodimers were secreted. As a result, in hPlGF-1-KDEL-expressing
      tumors, blood vessels remained at very low numbers and lacked branching and
      capillary networks. Gene transfer of a hVEGF-KDEL construct into tumor cells
      likewise produced a dramatic antitumor effect. Thus, our study provides a novel
      antiangiogenic approach by preventing the secretion of VEGF.

PMID- 15192039
TI  - Regulation of adrenomedullin gene transcription and degradation by the c-myc
      gene.
AB  - Adrenomedullin, a vasodilatory peptide originally isolated from pheochromocytoma,
      is known to regulate cell growth, apoptosis, and migration. Overexpression of the
      c-myc oncogene has been shown to suppress the mouse adrenomedullin gene via the
      initiator element. We investigated whether c-myc regulates rat and human
      adrenomedullin genes because there appears to be no initiator elements in their
      promoter regions. Transactivation of the human adrenomedullin gene by c-myc was
      demonstrated using a luciferase reporter construct containing an upstream
      sequence. Using a panel of isogenic rat fibroblast cell lines with differential c
      myc expression obtained by targeted homologous recombination, we found markedly
      elevated adrenomedullin transcript levels in cells stably overexpressing c-myc
      but a minimal decrease in two independent cell lines containing a homozygous null
      deletion of c-myc. Degradation of adrenomedullin mRNA was enhanced by a c-myc
      transgene, resulting in a relatively reserved increase in cellular secretion of
      adrenomedullin-like immunoreactivity. These results indicate that c-myc
      transactivates rat and human adrenomedullin genes and accelerates the degradation
      rate of adrenomedullin mRNA. However, c-myc is not essential for basal expression
      of the adrenomedullin gene.

PMID- 15192041
TI  - Regulation of luteal cell big stanniocalcin production and secretion.
AB  - In mammals, the ovaries have the highest levels of stanniocalcin (STC) gene
      expression, most or all of which is confined to androgen-producing thecal
      interstitial cells (TICs). Ovarian TICs also synthesize a different STC that
      consists of three high molecular weight species collectively known as big STC.
      Upon release in response to LH stimulation, TIC-derived big STC is sequestered
      locally by target cells, particularly steroidogenic cells of the corpus luteum,
      via a receptor-mediated process. Although there is little or no STC gene
      expression in luteal cells in the in vivo setting, this report describes how the
      gene is turned on, STC mRNA becomes readily detectable, and big STC is secreted
      when bovine luteal cells are cultured in vitro. STC gene expression and secretion
      were both positively regulated by activation of the adenylate cyclase/protein
      kinase A signaling pathway (forskolin and 8-bromo-cAMP). However, prostaglandin
      E2 was the only natural luteal cell ligand capable of replicating the effects of
      forskolin and 8-bromo-cAMP (LH had no consistent effect). Sex steroids such as
      17beta-estradiol, androstenedione, and progesterone significantly decreased
      luteal cell STC expression and secretion. However, only androstenedione was
      capable of reducing STC production and secretion to undetectable levels. This
      report is the first to show that once removed from their normal context within
      the ovary, luteal cells are capable of synthesizing and secreting big STC. It is
      also the first to delineate the regulatory mechanisms involved in STC production
      and secretion by luteal cells. These results therefore suggest that under certain
      physiological conditions, the corpus luteum could very well serve as a source of
      STC production.

PMID- 15192040
TI  - Stimulation of insulin-like growth factor (IGF) binding protein-3 synthesis by
      IGF-I and transforming growth factor-alpha is mediated by both
      phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways in
      mammary epithelial cells.
AB  - IGF binding protein (IGFBP)-3 is an important regulator of mammary epithelial
      cell (MEC) growth and can enhance the ability of both IGF-I and epidermal growth
      factor ligands such as TGFalpha to stimulate MEC proliferation. Here we
      investigate the role of the phosphatidylinositol-3 kinase (PI3K) and MAPK
      pathways in the regulation of IGFBP-3 expression by IGF-I and TGFalpha in bovine
      MECs. Both growth factors stimulated DNA synthesis, although IGF-I was the
      stronger mitogen. IGF-I and TGFalpha also stimulated IGFBP-3 mRNA and protein
      levels. TGFalpha stimulated rapid, transient activation of Akt that was maximal
      at 5 min and diminished by 15 min. In contrast, IGF-I-induced Akt activation was
      maximal between 15 and 90 min and was sustained for 6 h. Although ERK 1/2 was
      maximally stimulated by TGFalpha between 5 and 15 min, IGF-I did not stimulate
      discernible activation of ERK 1/2. In addition, TGFalpha but not IGF-I induced
      rapid phosphorylation of Shc, whereas only IGF-I activated insulin receptor
      substrate-1. Pretreatment with the PI3K inhibitor LY294002 or knockdown of p85
      with small interfering RNA inhibited IGF-I or TGFalpha-stimulated IGFBP-3
      expression. Similarly, MAPK kinase-1 inhibitors PD98059 and U0126 each abolished
      TGFalpha-stimulated increases in IGFBP-3 mRNA levels. In contrast to TGFalpha,
      IGF-I retained the ability to partially increase IGFBP-3 mRNA levels in the
      presence of MAPK kinase-1 inhibitors, indicating that IGF-I may activate
      alternative substrates of the PI3K pathway that are involved in IGFBP-3
      regulation. In conclusion, stimulation of IGFBP-3 mRNA levels by mitogens is
      regulated through both the PI3K and MAPK pathways in bovine MECs.

PMID- 15192042
TI  - Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid
      cancer: biological effects of HGF in thyroid cancer cells depend on Met
      expression levels.
AB  - Met, the receptor for hepatocyte growth factor (HGF), is overexpressed in
      approximately 90% papillary thyroid carcinomas. To investigate the role of the
      HGF-Met system in these tumors, we examined HGF and Met expression in a variety
      of primary cultures, normal or malignant thyroid cells, and tissue specimens and
      analyzed the different HGF effects (promotion of mitogenesis, branching
      morphogenesis, and cell motility and invasion). In cancer specimens, HGF was
      produced at high levels by tumor stromal cells, and Met was constitutively
      phosphorylated in malignant cells. No HGF production was found in a panel of
      malignant thyroid cancer cells. Biological effects of HGF were examined in
      papillary cancer cell cultures with either high or low Met expression. High-Met
      cells were more sensitive to the growth effect of HGF (ED50 = 3-5 ng/ml and 10-15
      ng/ml in high- or low-Met cells, respectively). Moreover, only high-Met cells
      underwent branching morphogenesis in response to HGF. In contrast, high-Met cells
      showed a reduced migration. Met down-regulation by small interfering RNAs
      resulted in enhanced cell migration and abrogation of branching morphogenesis in
      response to HGF. Conversely, Met overexpression impaired cell migration while
      favoring branching morphogenesis and cell adherence to substrate. These data
      suggest that both Met and HGF are overexpressed in papillary thyroid carcinomas,
      that Met is frequently activated in these carcinomas and may favor tumor growth,
      and that the abundance of Met expression may differently regulate cell growth,
      morphogenesis, and migration in response to HGF.

PMID- 15192043
TI  - Characterization of the bone morphogenetic protein (BMP) system in human
      pulmonary arterial smooth muscle cells isolated from a sporadic case of primary
      pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like
      kinase-6) in the mitotic action.
AB  - The functional involvement of bone morphogenetic protein (BMP) system in primary
      pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role
      of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary
      arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH
      patient bearing no mutations in BMPR2 gene. A striking increase in the levels of
      ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6
      transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of
      pphPASMCs, which was opposite to their suppressive effects on the mitosis of the
      control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas
      these did not affect control PASMCs. The presence of BMP signaling machinery in
      pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad
      reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed
      that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling
      of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced
      DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2
      stimulation. Although Id-1 response was not stimulated by BMP-2 in control
      PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the
      Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38
      MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the
      mitotic action is in part MAPK dependent. Thus, the BMP system is strongly
      involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of
      Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary
      arteries in PPH.

PMID- 15192044
TI  - Intracerebroventricular infusion of glucose, insulin, and the adenosine
      monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D
      ribofuranoside, controls muscle glycogen synthesis.
AB  - The AMP-activated kinase has been proposed to be an important intracellular
      energy sensor because the enzyme controls lipid and glucose oxidation. In the
      corresponding knockout mice, insulin-stimulated muscle glycogen synthesis and
      glucose tolerance are reduced. In addition, these mice excrete catecholamines in
      excess, suggesting that the central and autonomic nervous systems are impaired.
      Indeed, in the brain, fuel sensor mechanisms have been described, and recently,
      evidence has shown that the AMP-activated kinase could control food intake. We
      show in this study that the intracerebroventricular infusion of 5-aminoimidazole
      4-carboxamide-1-beta-D-ribofuranoside (AICAR), a pharmacological AMP-activated
      kinase activator, increased insulin-stimulated muscle glycogen synthesis and
      insulin sensitivity during a hyperinsulinemic clamp. Similarly, we infused AICAR
      in the brain of fasted mice, i.e. when insulinemia was low, and showed that
      muscle glycogen synthesis was also increased. We then studied the effect of a
      cerebral infusion of the peripheral signals, i.e. insulin and glucose, known to
      be detected by the brain. The cerebral infusion of insulin increased muscle
      glycogen synthesis. This effect was blunted by the coinfusion of glucose, which
      induced insulin resistance. Importantly, the cerebral injections of AICAR,
      insulin, and glucose were associated with variations in the phosphorylation state
      of the AMP-activated kinase in the hypothalamus. In conclusion, our data showed
      for the first time that 1) the brain is sensitive to insulin and glucose for the
      regulation of muscle glycogen synthesis; and 2) the cerebral infusion of AICAR
      enhances insulin sensitivity. Although the above mechanisms are correlated with
      the regulation of AMP-activated kinase, the direct involvement of the enzyme in
      the mechanism remains to be demonstrated.

PMID- 15192045
TI  - Characteristics and thyroid state-dependent regulation of iodothyronine
      deiodinases in pigs.
AB  - Three iodothyronine deiodinases (D1, D2, and D3) regulate local and systemic
      availability of thyroid hormone. D1 and D2 activate the prohormone T4 to the
      thyromimetic T3, and D3 inactivates T4 and T3 to rT3 and 3,3'-diiodothyronine,
      respectively. The expression of the three deiodinases is tightly regulated with
      regard to developmental stage and cell type to provide fine tuning of T3 supply
      to target cells. Most studies regarding distribution and regulation of
      deiodinases have been carried out in rodents. However, in different respects,
      rodents do not seem to be the optimal experimental model for human thyroid
      hormone physiology. For instance, D2 expression has been observed in human
      thyroid and skeletal muscle but not in these tissues in rodents. In this study,
      we have explored the pig as an alternative model. Porcine D1, D2, and D3 were
      cloned by RT-PCR, and their catalytic properties were shown to be virtually
      identical to those reported for human and rodent deiodinases. The tissue
      distribution of deiodinases was studied in normal pigs and in pigs made
      hypothyroid by methimazole treatment or in pigs made hyperthyroid by T4
      treatment. D1 activity in liver and kidney was increased in T4-treated pigs. D2
      activities in cerebrum and pituitary were decreased after T4 treatment and
      strongly increased after methimazole treatment. Remarkably, D2 activity in
      thyroid and skeletal muscle was induced in hypothyroid pigs. Significant
      expression of D3 was observed in cerebrum and was positively regulated by thyroid
      state. In conclusion, the pig appears to be a valuable model for human thyroid
      hormone physiology. The expression of D2 activity in thyroid and skeletal muscle
      is of particular interest for studies on the importance of this enzyme in
      (hypothyroid) humans.

PMID- 15192047
TI  - Differential effects of transforming growth factor-beta1 on cellular
      proliferation in the developing prostate.
AB  - TGFbeta1 plays an important role in the growth of the prostate and has been
      reported to stimulate or inhibit the proliferation of prostatic epithelia. We
      show here that Tgfbeta1, Tgfbeta2, and Tgfbeta3 mRNA expression correlated with
      developmental growth of the prostate. Recombinant TGFbeta1 inhibited the growth
      of the prostate when added to cultures of ventral prostate (VP) organs grown in
      vitro. Interestingly, TGFbeta1 had contrasting effects on cellular proliferation;
      it stimulated proliferation at the periphery of the organs (distal to urethra),
      but inhibited proliferation in the center of the organs (proximal to urethra). We
      speculate that differential effects on proliferation may be determined by the
      level of cellular differentiation, because cells at the periphery are
      undifferentiated whereas those in the center are more highly differentiated.
      TGFbeta1 also stimulated branching morphogenesis at growing ductal tips at the
      perimeter of the VP. To investigate potential mechanisms of TGFbeta1 action, we
      examined the three-dimensional distribution of smooth muscle in prostatic organs
      after treatment with TGFbeta1. TGFbeta1 showed a significant effect on the
      distribution of smooth muscle within VPs, which may mediate part of its effect on
      proliferation. Finally, we addressed how testosterone and TGFbeta1 might affect
      gene expression in our developmental system. Testosterone repressed the
      expression of Tgfbeta2 mRNA in the prostate, whereas TGFbeta1 showed a modest
      repression of fibroblast growth factor-10 mRNA. It appeared that the effects of
      these factors were more pronounced in a model of prostatic mesenchyme devoid of
      epithelia than in prostatic organs (containing epithelia).

PMID- 15192046
TI  - Differential activation of epidermal growth factor (EGF) receptor downstream
      signaling pathways by betacellulin and EGF.
AB  - To determine the downstream signaling pathways regulated by betacellulin (BTC) in
      comparison with epidermal growth factor (EGF), we used Chinese hamster ovary
      cells overexpressing the human EGF receptor (ErbB1/EGFR). The overall time
      dependent activation of EGFR autophosphorylation was identical in cells treated
      with 1 nm BTC or 1.5 nm EGF. Analysis of site-specific EGFR phosphorylation
      demonstrated that the BTC and EGF tyrosine phosphorylation of Y1086 was not
      significantly different. In contrast, the autophosphorylation of Y1173 was
      markedly reduced in BTC-stimulated cells, compared with EGF stimulation that
      directly correlated with a reduced BTC stimulation of Shc tyrosine
      phosphorylation, Ras, and Raf-1 activation. On the other hand, Y1068
      phosphorylation was significantly increased after BTC stimulation, compared with
      EGF in parallel with a greater extent of Erk phosphorylation. Expression of a
      dominant interfering MEK kinase 1 (MEKK1) and Y1068F EGFR more efficiently
      blocked the enhanced Erk activation by BTC, compared with EGF. Interestingly BTC
      had a greater inhibitory effect on apoptosis, compared with EGF, and expression
      of Y1068F EGFR abolished this enhanced inhibitory effect. Together, these data
      indicated that although BTC and EGF share overlapping signaling properties, the
      ability of BTC to enhance Erk activation occurs independent of Ras. The increased
      BTC activation results from a greater extent of Y1068 EGFR tyrosine
      phosphorylation and subsequent increased recruitment of the Grb2-MEKK1 complex to
      the plasma membrane, compared with EGF stimulation. The increased Erk activation
      by BTC associated with antiapoptotic function.

PMID- 15192048
TI  - Insulin attenuates the systemic inflammatory response in endotoxemic rats.
AB  - Insulin decreases the mortality and prevents the incidence of infection and
      sepsis in critically ill patients. The molecular and cellular mechanisms by which
      insulin improves survival have not been defined. The purpose of the present study
      was to determine the effect of insulin on the inflammatory reaction during
      endotoxemia. Endotoxemic rats were randomly divided into two groups to receive
      either saline or insulin. The effects of insulin on hepatic signal transcription
      factor mRNA expression, proinflammatory and antiinflammatory cytokine mRNA and
      protein concentration were determined. Insulin administration did not change
      glucose or electrolyte levels, but significantly decreased proinflammatory signal
      transcription factors [CCAAT/enhancer-binding protein-beta, signal transducer and
      activator of transcription-3 and-5, RANTES (regulated on activation, normal T
      cell expressed and secreted)] and cytokine expression in the liver and serum
      levels of IL-1beta, IL-6, macrophage inflammatory factor, and TNFalpha. Insulin
      administration further decreased high mobility group 1 protein in the serum
      compared with controls. In addition, insulin increased antiinflammatory cytokine
      expression in the liver; serum levels of IL-2, IL-4, and IL-10; and hepatic
      suppressor of cytokine signaling-3 mRNA expression. Insulin modulates the
      inflammatory response by decreasing the proinflammatory and increasing the
      antiinflammatory cascade. Because glucose and electrolyte levels did not differ
      between insulin-treated patients and controls, we hypothesize that the effects
      are direct antiinflammatory mechanisms of insulin, rather than indirect, through
      modulation of glucose or electrolyte metabolism.

PMID- 15192050
TI  - Sexual partner reductions explain human immunodeficiency virus declines in
      Uganda: comparative analyses of HIV and behavioural data in Uganda, Kenya,
      Malawi, and Zambia.

PMID- 15192049
TI  - Conjugative transfer of the virulence gene, esp, among isolates of Enterococcus
      faecium and Enterococcus faecalis.
AB  - OBJECTIVES: The enterococcal surface protein gene, esp, is a major putative
      pathogenicity marker in clinical isolates of Enterococcus faecium and
      Enterococcus faecalis. This study demonstrates in vitro conjugative transfer of
      the esp gene among E. faecium and E. faecalis. MATERIALS AND METHODS:
      Enterococcal isolates from clinical samples, positive for esp, were mated on
      filters with enterococcal recipients. Transconjugants were checked for transfer
      of antibiotic resistance determinants and co-mobilization of the esp gene. They
      were also characterized by PCR and plasmid profiling/PFGE typing including
      Southern hybridizations with labelled esp probes. Transfer as triggered by
      excision was tested using Taqman PCR. RESULTS: Two of five E. faecalis and five
      of nine E. faecium transferred antibiotic resistance determinants into a
      recipient. Of the transconjugants analysed by PCR for acquisition of esp, only
      isolates from two E. faecalis and a single E. faecium mating were positive. In
      the donor strains, the esp gene was located on the chromosome. Molecular analysis
      revealed a plasmid localization of esp in the E. faecium transconjugant and
      chromosome-to-chromosome transfer in E. faecalis. CONCLUSION: The esp gene is
      transferable by conjugation among enterococcal isolates.

PMID- 15192051
TI  - Age-related thymic involution is mediated by Fas on thymic epithelial cells.
AB  - Age-related thymic involution, which is linked to senescence of the immune
      system, was found to be mediated by the death receptor Fas. The thymus of aged
      Fas(-/-) mice exhibited an intact structure and the normal differentiation of
      thymocytes. Both thymocytes and thymic epithelial cells (TECs) were sensitive to
      Fas-mediated apoptosis, and in vivo stimulation of wild-type thymocytes with anti
      CD3 mAb was shown to induce apoptosis in TECs in a Fas-dependent manner. In
      addition, thymopoiesis continued uninterrupted in aged Fas(-/-) mice that had
      been lethally irradiated and reconstituted with bone marrow cells derived from
      wild-type mice, while age-related thymic involution was observed in irradiated
      wild-type mice reconstituted with bone marrow cells from either Fas(-/-) or wild
      type mice. The results indicate that Fas on TECs plays a key role in age-related
      thymic involution.

PMID- 15192052
TI  - CpG oligodeoxynucleotides enhance FcgammaRI-mediated cross presentation by
      dendritic cells.
AB  - Dendritic cells (DC) can trigger naive CD8(+) T cell responses by their capacity
      to cross-present exogenous antigens via the major histocompatibility complex
      class I pathway. The myeloid class I IgG receptor, FcgammaRI (CD64), is expressed
      on DC, and in vivo targeting of antigens to FcgammaRI induces strong humoral and
      cellular immune responses. We studied the capacity of human FcgammaRI
      (hFcgammaRI) to facilitate DC-mediated cross presentation and T cell activation,
      and assessed the effect of CpG oligodeoxynucleotides on this process. We
      generated hFcgammaRI expressing immature DC from hFcgammaRI transgenic and
      immature DC from non-transgenic mice. Antigens were targeted to Fcgamma receptors
      as ovalbumin immune complexes, or selectively to hFcgammaRI via ovalbumin-CD64
      mAb fusion proteins. Co-incubation of immature DC with CpG ODN led to markedly
      increased MHC class I presentation of FcgammaR-targeted antigens. When OVA was
      selectively targeted to hFcgammaRI, few differences were observed between Tg and
      NTg DC. However, upon co-incubation with CpG ODN, hFcgammaRI-triggered cross
      presentation was enhanced. These results document the capacity of hFcgammaRI on
      DC to trigger cross presentation via MHC class I upon co-culture with CpG ODN.

PMID- 15192053
TI  - Diagnosis and management of the infertile couple: missing information.
AB  - Missing information about reproductive processes is an important barrier to
      conception and live birth among infertile couples. In vitro and genetic
      techniques have been informative, but not enough is known about potential defects
      in fertilization, implantation and early embryo development to define explicit
      infertility diagnoses and direct specific treatment. Study of gamete quality is
      needed because endocrine and ultrasound measurements in the female cannot
      determine oocyte quality and semen analysis in the male is a limited predictor of
      fertilizing ability. Also, more study would help in understanding the conditions
      in the Fallopian tube and elsewhere that foster fertilization and embryo
      development. Research in related subjects is also needed: after many years of
      enquiry, there exists little or no evidence to determine how and if endometriosis
      causes subfertility. In contrast, the recently described impact of smoking in
      males is large, clinically important and possibly reversible. Missing information
      limits the choice of specific treatment, puts a ceiling on the overall prognosis,
      increases the likelihood of persistent infertility and forms a barrier to
      understanding the broader meanings of success in the management of infertility.

PMID- 15192054
TI  - Hormones and breast cancer.
AB  - The incidence of breast cancer in women varies with age, mammary gland mass and
      exposure to endogenous and exogenous hormones. Age is the single most important
      factor and if, as projected, 32% of women will be aged >60 years by 2050, world
      breast cancer incidence will exceed the current 10(6) per year. Hormonal
      influences that affect growth of the mammary gland increase the risk of breast
      cancer; for example earlier menarche and later menopause. Childbearing protects
      against later development of breast cancer, and breastfeeding further decreases
      the risk. The breast cancer risk declines more with increasing total duration of
      breastfeeding. Exposure to hormonal contraceptives has been evaluated in a
      combined reanalysis of data from 51 epidemiological studies. There is a small
      transient increase in the relative risk of breast cancer among users of oral
      contraceptives but, since use typically occurs at young ages when breast cancer
      is relatively rare, such an increase would have little effect on overall
      incidence rates. In contrast, exposure to menopause hormone treatment occurs when
      the baseline risk of breast cancer is higher, and epidemiological studies and
      randomized controlled trials consistently find an increase in breast cancer risk
      with exposure to combined estrogen and progestogen. Women with a family history
      of breast cancer in first degree relatives have an increased risk of breast
      cancer but there is no evidence to suggest that this differs according to a
      woman's use of oral contraceptives or menopause hormone treatment. Selective
      estrogen receptor modulators are useful in the treatment and/or prevention of
      breast cancer depending on the specific agonist or antagonist effects on estrogen
      target tissues.

PMID- 15192055
TI  - Ectoplasmic specialization, a testis-specific cell-cell actin-based adherens
      junction type: is this a potential target for male contraceptive development?
AB  - The seminiferous tubule of the mammalian testis is largely composed of Sertoli
      and germ cells, which coordinate with Leydig cells in the interstitium and
      perform two major physiological functions, namely spermatogenesis and
      steroidogenesis respectively. Each tubule is morphologically divided into (i) the
      seminiferous epithelium composing Sertoli and germ cells, and (ii) the basement
      membrane (a modified form of extracellular matrix); underneath this lies the
      collagen fibril network, the myoid cell layer, and the lymphatic vessel, which
      collectively constitute the tunica propia. In the seminiferous epithelium, of
      rodent testes each type A1 spermatogonium (diploid, 2n) differentiates into 256
      elongated spermatids (haploid, 1n) during spermatogenesis. Additionally,
      developing germ cells must migrate progressively from the basal to the luminal
      edge of the adluminal compartment so that fully developed spermatids can be
      released into the lumen at spermiation. Without this timely event of cell
      movement, spermatogenesis cannot reach completion and infertility will result.
      Yet developing round elongating/elongated spermatids must remain attached to the
      epithelium via a specialized Sertoli-germ cell actin-based adherens junction (AJ)
      type known as ectoplasmic specialization (ES), which is crucial not only for cell
      attachment but also for spermatid movement and orientation in the epithelium.
      However, the biochemical composition and molecular architecture of the protein
      complexes that constitute the ES have only recently been studied. Furthermore,
      the signalling pathways that regulate ES dynamics are virtually unknown. This
      review highlights recent advances in these two areas of research. It is expected
      that, if adequately expanded, these studies should yield new insights into the
      development of novel contraceptives targeted to perturb ES function in the
      testis. The potential to specifically target the ES may also mean that
      contraceptive action could be achieved without perturbing the hypothalamic
      pituitary-testicular axis.

PMID- 15192056
TI  - Mechanisms of action of mifepristone and levonorgestrel when used for emergency
      contraception.
AB  - An emergency contraceptive method is used after coitus but before pregnancy
      occurs. The use of emergency contraception is largely under-utilized worldwide.
      One of the main barriers to widespread use is concern about the mechanism of
      action. Recently, treatment with either 10 mg mifepristone or 1.5 mg of
      levonorgestrel has emerged as the most effective hormonal method for emergency
      contraception with very low side-effects. However, the knowledge of the mechanism
      of action of mifepristone and levonorgestrel in humans, when used for
      contraceptive purposes and especially for emergency contraception, remains
      incomplete. The objective of this review is to summarize available data on the
      effects of mifepristone and levonorgestrel on female reproductive functions
      relevant to the emergency use of the compounds. When summarized, available data
      from studies in humans indicate that the contraceptive effects of both
      levonorgestrel and mifepristone, when used in single low doses for emergency
      contraception, involve either blockade or delay of ovulation, due to either
      prevention or delay of the LH surge, rather than to inhibition of implantation.

PMID- 15192057
TI  - Infertility in the third millennium: implications for the individual, family and
      society: condensed meeting report from the Bertarelli Foundation's second global
      conference.
AB  - Primary infertility is a key issue in the developed world, while the developing
      world has high rates of secondary infertility. The impact of HIV/AIDS on
      fertility is insufficiently explored. One of the most important barriers to
      access to infertility treatment is cost; at the same time the role of social and
      cultural factors in restricting access should not be underestimated. IVF has
      become the standard therapy for female infertility, and ICSI for infertility of
      the male partner. However, the use of these therapies should not be initiated
      without a thorough investigation and, whenever possible, individual diagnosis of
      the underlying causes of infertility. Multiple gestation remains one of the most
      challenging and controversial issues in the treatment of infertility. Current IVF
      practices are often blamed for this; in this respect, attention should also be
      focused on the role of ovarian stimulation in ovulation induction. National
      guidelines and national registries for assisted reproductive technology (ART) are
      becoming more widespread and are expected to play an important role in promoting
      best practice in ART in the future.

PMID- 15192058
TI  - Overall prognosis with current treatment of infertility.
AB  - Few reports provide pregnancy or birth rates for large groups of infertile
      couples having a comprehensive range of treatments. This model utilizes published
      evidence about diagnosis, treatment, the duration of treatment and the proportion
      of couples receiving treatment. Assisted reproduction technology treatment (ART)
      utilization was set arbitrarily at three levels: 3, 10 or 50% of the couples that
      had no live birth after conventional treatment. For each diagnosis and treatment
      the model estimated total live births, singleton live births and multiple live
      births per 10,000 couples. The overall live birth rate with non-ART treatment
      would be 37%, involving 3,725 live births, of which 3,478 (93%) would be
      singleton and 247 (7%) would be multiple. With ART utilization at 3, 10 and 50%
      of couples with persistent infertility in each diagnostic category, live birth
      rates were 39, 43 and 47% respectively, with 8, 10 and 12% multiple births. The
      corresponding utilization of ART would be 244, 813 and 1481 ART cycles per 10(6)
      population per annum. Typical management of infertility would fall short of 50%
      live births even with extensive utilization of ART. Underlying unknown
      untreatable factors remain barriers to greater overall success in the treatment
      of infertility.

PMID- 15192059
TI  - Reproductive functions of the ageing male.
AB  - Delayed childbearing is a common phenomenon in industrialized countries. This
      review focuses on age-associated alterations of male fertility and genetic risks.
      Semen volume, sperm motility and sperm morphology decrease with age, whereas the
      data concerning sperm concentration are conflicting. The age-related changes of
      semen parameters reflect the histological modifications which are found to
      varying degrees in individual testes. Men aged >40 years contribute to reduced
      fertility and fecundity of a couple, especially when the female partner is also
      of advanced age. Because relatively few children are born to older fathers and
      genetic diseases are rare, there is little statistical power supporting an
      association of genetic diseases in the offspring with advancing paternal age.
      Nevertheless, autosomal dominant diseases and some diseases of complex aetiology,
      such as schizophrenia, are associated with advancing paternal age. The single
      point mutations in sperm which are responsible for achondroplasia and Apert's
      syndrome, two autosomal dominant diseases, increase with the man's age. In case
      of Apert's syndrome this increase is believed to be due to a pre-meiotic
      selection of mutant spermatogonia. Although structural chromosome anomalies and
      disomies of certain chromosomes increase in sperm with the man's age, paternal
      age is, with the exception of trisomy 21, not associated with numerical or de
      novo structural chromosomal aberrations in newborns. However, even if the genetic
      risk for progeny from older fathers is slightly increased, the risk to the
      individual is low.

PMID- 15192060
TI  - Are routine breast and pelvic examinations necessary for women starting combined
      oral contraception?
AB  - Millions of women worldwide use combined oral contraception (COC). Most of them
      are in good health and have no contraindications to using any contraceptive
      method. Although extremely safe for the vast majority of women and even though
      the absolute risk of complications is very small, COC is associated with an
      increased relative risk of serious conditions including cardiovascular disease
      and breast and cervical cancer. In many countries, breast and pelvic examinations
      are routinely undertaken annually for all women using hormonal contraception.
      Breast and pelvic examination have low detection rates for abnormality and may
      yield clinically irrelevant results, causing anxiety and inconvenience to the
      patient for no obvious gain. There is no good evidence to support routine breast
      or pelvic examination either for women starting hormonal contraception or for
      monitoring long-term use.

PMID- 15192061
TI  - Surrogate end-points or primary outcomes in clinical trials in women with
      polycystic ovary syndrome?
AB  - There are multiple surrogate variables in polycystic ovary syndrome (PCOS),
      including biometric and biochemical parameters. The number of surrogate variables
      and their poor validity in relationship to primary clinical end-points pose major
      problems to conducting a trial in women with PCOS. The aim of this review is to
      discuss the use of surrogate variables compared with primary clinical end-points
      in women with PCOS. Arguably the best documented correlation between a surrogate
      variable and a primary clinical end-point is that between ovulation and pregnancy
      in women with PCOS. Good correlation has been noted between the increase in
      ovulation frequency with clomiphene citrate and the chance of pregnancy in women
      with PCOS. However, ovulation cannot be equated with pregnancy, as a host of
      other factors may affect the true outcome of interest: a healthy liveborn child.
      Pregnancy and an improvement in hirsutism are clinical end-points that have been
      successfully studied in past and ongoing clinical trials in women with PCOS. Many
      other clinical end-points, such as endometrial cancer and cardiovascular disease,
      are rare in premenopausal women with PCOS, and may not be suitable as the primary
      outcome of clinical studies. Future multicentre trials in women with PCOS should
      focus on primary clinical end-points.

PMID- 15192062
TI  - How can the genetic risks of embryo donation be minimized? Proposed guidelines of
      the French Federation of CECOS (Centre d'Etude et de Conservation des Oeufs et du
      Sperme).
AB  - Embryo donation is now an acceptable practice which offers new possibilities to
      many infertile couples wishing to procreate. In France, embryo donation, like
      gamete donation, is controlled by law, but its application has been poorly
      developed because too many questions remained unsolved and because of the lack of
      practical guidelines. Here we report the results of the debate which took place
      within the Genetics Commission of the French Federation of CECOS and the proposed
      recommendations which followed, emphasizing the genetic background to be
      considered for embryo donation.

PMID- 15192063
TI  - Studies on the membrane integrity of human sperm treated with a new injectable
      male contraceptive.
AB  - BACKGROUND: The aim of this study was to evaluate the integrity of sperm surface
      characteristics in the presence of a new male contraceptive, RISUG [1 mg styrene
      maleic anhydride (SMA)/100 microl dimethylsulphoxide (DMSO) in 1 ml sperm
      solution]. METHODS: Progressively motile human sperm were treated in vitro with
      RISUG. The cells were analysed for the release of 5'-nucleotidase (5'-NT) (a
      plasma membrane marker) using 3 mmol/l 5'-AMP and 3 mmol/l beta-glycerophosphate
      as substrates. Hyaluronidase (an acrosomal membrane marker) was analysed using
      hyaluronic acid as a substrate. The contents of free and total acrosin, and %
      proacrosin (all acrosome markers) were assayed using 0.5 mmol/l alpha-N-benzoyl-L
      arginine ethylester (BAEE). RESULTS: RISUG caused almost complete disintegration
      of the plasma membrane leading to significant (P < 0.0001) release of 5'-NT into
      the surrounding media. Complete dissolution of the acrosome with concomitant
      vesiculation of the membrane system, as judged from the loss of hyaluronidase,
      was observed. Total acrosin content in the sperm was also reduced to almost 10%,
      and proacrosin dropped to 13.2% in the presence of RISUG in comparison to 90.2%
      in control (P < 0.0001), indicating dispersion of acrosomal contents. CONCLUSION:
      Under in vitro conditions, RISUG, at a concentration of 1 mg SMA dissolved in 100
      microl of DMSO, caused significant damage to the acrosome and its contents,
      indicating loss of functional ability of sperm.

PMID- 15192064
TI  - Monozygotic twinning associated with day 5 embryo transfer in pregnancies
      conceived after IVF.
AB  - BACKGROUND: This study examines the association between day of embryo transfer
      and monozygotic (MZ) twinning. METHODS: We used a population-based sample of
      108,36 IVF/embryo transfer procedures in which the patients oocytes' were freshly
      fertilized (non-frozen; non-donor) and 39,98 resultant pregnancies from US
      clinics in 1999 and 2000. Cases were pregnancies for which the number of fetal
      hearts observed on ultrasound exceeded the number of embryos transferred. These
      pregnancies were considered to contain at least one set of MZ twins. A total of
      226 MZ pregnancies were compared with two control groups: 23,880 singleton
      pregnancies (one fetal heart) and 15,092 other multiple-gestation pregnancies (>
      or = 2 fetal hearts but the number of fetal hearts on ultrasound was less than or
      equal to the number of embryos transferred). RESULTS: Cases of presumed MZ
      multiple-gestation pregnancies were more likely to have had a day 5 embryo
      transfer compared with day 3 embryo transfers than singleton pregnancies
      [adjusted odds ratio (AOR) = 3.92, 95% confidence interval (CI) = 2.97-5.17] or
      other multiple-gestation pregnancies (AOR = 3.91, 95% CI = 2.96-5.17) conceived
      with IVF/embryo transfer. CONCLUSIONS: Day 5 embryo transfer may be associated
      with increased MZ twinning.

PMID- 15192065
TI  - Misoprostol versus curettage in women with early pregnancy failure after initial
      expectant management: a randomized trial.
AB  - BACKGROUND: Little is known about the effectiveness of misoprostol treatment in
      women with early pregnancy failure who have been managed expectantly. We
      therefore performed a randomized trial on this subject. METHODS: Women with early
      pregnancy failure, who had been managed expectantly for at least 1 week, were
      assigned randomly (using a computer-generated list) to receive either vaginal
      misoprostol 800 microg or curettage. If, after 24 h, there had not been complete
      evacuation, a further 800 microg of misoprostol was administered. In the absence
      of complete evacuation after > days, curettage was performed. The primary end
      point was the complete evacuation of the products of conception, with secondary
      end-points being the occurrence of side effects, pain intensity, need for
      analgesics, and intensity and duration of bleeding. RESULTS: In the misoprostol
      group, 47% (37/79) required curettage due to incomplete evacuation. After 1 week,
      evacuation was complete in 85% (67 out of 79) of the misoprostol group and 93%
      (70 out of 75) of the curettage group. Severity of pain, bleeding and emergency
      evacuation was higher in the misoprostol group. The complication rate was 0% for
      misoprostol and 4% for curettage. CONCLUSIONS: Curettage is superior to
      misoprostol in the evacuation of early pregnancy failure after failed expectant
      management. However, misoprostol could be clinically useful since it reduces the
      need for curettage by half and has a lower complication rate, at the expense of
      increased pain, vaginal bleeding and emergency evacuation.

PMID- 15192066
TI  - Evidence of parthenogenetic origin of ovarian teratoma: case report.
AB  - This case report represents one of the few documented cases of parthenote embryo
      retrieval from an IVF patient with a history of ovarian teratomas. A 29-year-old
      woman presented at our centre with a history of primary infertility for 6 years
      due to male factor. She had undergone left oophorectomy 4 years before due to an
      ovarian teratoma. An ultrasound scan performed during basal evaluation revealed
      two complex images in the right ovary suggesting teratomas, measuring 2.5 x 2.4
      and 1.7 x 1.3 cm. A significant extent of sonographically normal ovarian
      parenchyma was present, and the patient underwent the long leuprolide acetate
      protocol of ovarian stimulation with recombinant FSH for an IVF-ICSI cycle. She
      had 13 metaphase II (MII), four metaphase I (MI), two germinal vesicle (GV)
      oocytes and one 4-cell embryo retrieved. Eight out of nine injected oocytes were
      fertilized normally while one was unfertilized. Embryo transfer was carried out
      72 h after retrieval. The 4-cell (parthenote) embryo recovered at oocyte
      retrieval continued to cleave in culture, developing into a 7-cell embryo by the
      next day. The embryo was morphologically normal, presenting an evident nucleus in
      each blastomere. Fluorescent in situ hybridization (FISH) returned two signals
      for the X chromosome in each blastomere that was analysed. Of the eight normally
      fertilized embryos, three were transferred, resulting in a normal singleton
      pregnancy and the birth of a healthy baby.

PMID- 15192067
TI  - Correlation between endometrial histology, microvascular density and calibre,
      matrix metalloproteinase-3 and bleeding pattern in women using a levonorgestrel
      releasing intrauterine system.
AB  - BACKGROUND: The main reason for discontinuation of the levonorgestrel-releasing
      intrauterine system (LNG-IUS) is unpredictable bleeding pattern. METHODS: The
      objective of the study was to evaluate the endometrial histology, microvascular
      density and calibre, and the quantification of matrix metalloproteinase (MMP-3)
      in long-term users of LNG-IUS, with and without bleeding. Endometrial biopsies
      were obtained from 58 healthy women, 29 who maintained some degree of endometrial
      bleeding and 29 who were amenorrhoeic. RESULTS: In the histological analysis, the
      majority of samples displayed a progestin-modified appearance. The major
      glandular diameter and the perimeter were significantly greater in the group of
      women with amenorrhoea. A significantly higher number of leukocytes was found in
      the group with bleeding (P = 0.014). No significant correlation was observed
      between the microvascular density or calibre and the bleeding pattern. MMP-3
      showed a significantly higher number of reactive cells (P = 0.005) in the group
      who maintained some degree of bleeding. CONCLUSIONS: Women using LNG-IUS who
      maintained endometrial bleeding during its use presented a higher number of
      leukocytes and MMP-3 in the endometrium when compared to women using LNG-IUS who
      became amenorrhoeic. However, the results did not provide evidence for
      microvascular pattern changes.

PMID- 15192068
TI  - Sonographic assessment of non-malignant ovarian cysts: does sonohistology exist?
AB  - BACKGROUND: Transvaginal ultrasound (TVU) is feasible and accurate in the
      differentiation between non-malignant and malignant ovarian abnormalities.
      However, despite the clinical relevance, the accuracy of TVU in the
      differentiation between the many different non-malignant cysts is unknown.
      METHODS: Between 1992 and 2002, all women who had surgery at our centre because
      of a non-malignant ovarian cyst were included prospectively in this study. The
      sonographic characteristics as well as the expected histological diagnosis (the
      'sonohistological diagnosis') were evaluated pre-operatively. This diagnosis was
      compared with the histopathological diagnosis, and diagnostic parameters [with
      95% confidence interval (CI)] of the sonohistological diagnosis were calculated.
      Logistic models, with the sonographic characteristics as variables, were
      constructed for each histopathological diagnosis. RESULTS: A total of 406 women
      were included consecutively. The overall diagnostic accuracy of the
      sonohistological diagnosis was 60% (95% CI 0.56-0.65). Only in cases of simple
      ovarian cysts did the diagnostic accuracy of the respective logistic model exceed
      that of the sonohistological diagnosis (0.88 versus 0.81, P < 0.01). The
      diagnostic accuracy of the sonohistological diagnosis for endometriotic and
      dermoid ovarian cysts was significantly better compared with the respective
      logistic model (0.84 versus 0.71, P < 0.01 and 0.87 versus 0.82, P = 0.03,
      respectively). CONCLUSION: In approximately half of the non-malignant ovarian
      cysts, TVU is capable of distinguishing between the different histopathological
      diagnoses of non-malignant ovarian masses. Only in the diagnosis of simple
      ovarian cysts might use of the logistic models be helpful.

PMID- 15192069
TI  - Detectable levels of interleukin-18 in uterine luminal secretions at oocyte
      retrieval predict failure of the embryo transfer.
AB  - BACKGROUND: Most implantation failures after successful in vitro fertilization
      embryo transfer (IVF-ET) result from inadequate uterine receptivity. There is
      currently no way to predict this receptivity. METHODS: We investigated whether
      the detection of interleukin-(IL)18 by ELISA in uterine luminal secretions might
      predict implantation failure. Secretions of 133 patients enrolled in our IVF-ET
      program were sampled by uterine flushing immediately before oocyte retrieval. We
      assessed the following outcomes: pregnancy rate, multiple pregnancy rate, and
      implantation rate per embryo transferred. RESULTS: Interleukin-18 was detected in
      the flushing fluid of 38 patients (28.6%). Although the two groups were
      comparable for all other characteristics (age, etiology, ovarian reserve, number
      of embryos transferred, quality of embryos), all outcome variables differed
      significantly. The pregnancy rate was 37.9% in the IL-18 - ve group and 15% in
      the IL-18 + ve group, the multiple pregnancy rate 27.7% and 0%, and the
      implantation rate per embryo transferred 19.4% and 6.7% (all comparisons,
      P=0.02). Only embryos meeting good quality criteria were transferred to 65
      patients: 50 IL-18 - ve and 15 IL-18 + ve. The pregnancy rate was 51% for the IL
      18 - ve group and 20% for the IL-18 + ve group, the multiple pregnancy rate 36%
      and 0.0%, respectively, and the implantation rate 29% and 8.3% (P = 0.02).
      CONCLUSION: This non-invasive and simple method predicted inadequate uterine
      receptivity, independent of embryo quality.

PMID- 15192071
TI  - Influence of the time interval between embryo catheter loading and discharging on
      the success of IVF.
AB  - BACKGROUND: To ascertain the influence of the duration of the 'interval loading
      discharging embryos' (ILDE) on the results of embryo transfer. METHODS: The
      population under study consisted of 450 consecutive fresh embryo transfers. ILDE
      was measured in all transfers. Pregnancy and implantation rates were analyzed.
      RESULTS: Conceptional cycles had a lower (mean +/- SD) ILDE than non conceptional
      cycles (53.5 +/- 43.6 s vs 63.7 +/- 49.3). When only easy transfers--defined as
      those not requiring cervical tenaculum--were considered, similar differences were
      observed. The following pregnancy rates were obtained according ILDE duration:
      38.9% (ILDE < 30 s), 33.2% (ILDE 31-60), 31.6% (ILDE 61-120) and 19.1% (ILDE >
      120) (P < 0.05). When only easy transfers were considered, similar results were
      obtained: 40.0%, 33.3%, 32.0% and 19.4%, respectively. Similar results were
      observed regarding implantation rates regarding the whole population (21.2%,
      15.4%, 15.9% and 9.4%, respectively; P < 0.01) as well as when only easy
      transfers were considered. CONCLUSIONS: ILDE duration is a prognostic factor of
      pregnancy rate and of implantation rate in IVF. The longer the ILDE duration, the
      lower the pregnancy and implantation rates. The decrease in pregnancy and
      implantation rates is gradual until an ILDE of 120 s, and decreases sharply
      afterwards. It is recommended to speed up the embryo transfer process, wherever
      possible. ILDE > 120 s carries a poor prognosis and should, when possible, be
      avoided.

PMID- 15192070
TI  - Two new prediction rules for spontaneous pregnancy leading to live birth among
      subfertile couples, based on the synthesis of three previous models.
AB  - BACKGROUND: Several models have been published for the prediction of spontaneous
      pregnancy among subfertile patients. The aim of this study was to broaden the
      empirical basis for these predictions by making a synthesis of three previously
      published models. METHODS: We used the original data from the studies of Eimers
      et al. (1994), Collins et al. (1995) and Snick et al. (1997) on couples
      consulting for various forms of subfertility. We developed a so-called three
      sample synthesis model for predicting spontaneous conception leading to live
      birth within 1 year after intake based on the three data sets. The predictors
      used are duration of subfertility, women's age, primary or secondary infertility,
      percentage of motile sperm, and whether the couple was referred by a general
      practitioner or by a gynaecologist (referral status). The performance of this
      model was assessed according to a 'jack-knife' analysis. Because the post-coital
      test (PCT) was not assessed in one of the samples, a synthesis model including
      the PCT was based on two samples only. RESULTS: The ability of the synthesis
      models to distinguish between women who became pregnant and those who did not was
      comparable to the ability of the one-sample models when applied in the other
      samples. The reliability of the predictions by the three-sample synthesis model
      was somewhat better. Predictions improved considerably by including the PCT.
      CONCLUSIONS: The synthesis models performed better and had a broader empirical
      basis than the original models. They are therefore better suitable for
      application in other centres.

PMID- 15192072
TI  - Recombinant human LH supplementation during GnRH antagonist administration in
      IVF/ICSI cycles: a prospective randomized study.
AB  - BACKGROUND: When administered in the late follicular phase to prevent an LH
      surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be
      detrimental for assisted reproductive technology cycle outcome. Therefore, a
      prospective study was designed to assess the effects of recombinant human (r)LH
      supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The
      protocol consisted of cycle programming with oral contraceptive pill, ovarian
      stimulation with rFSH and flexible administration of a single dose of cetrorelix
      (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed
      envelopes or according to woman's birth date) to receive (n = 114) or not (n =
      104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG
      injection. RESULTS: The only significant difference was a higher serum peak E2
      level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P <
      0.001) whereas the numbers of oocytes and embryos as well as the delivery rate
      (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were
      similar in both groups. CONCLUSIONS: These results show that in an unselected
      group of patients, there is no evident benefit to supplement GnRH antagonist
      treated cycles with rLH.

PMID- 15192073
TI  - What is the most relevant standard of success in assisted reproduction? Should
      BESST really be the primary endpoint for assisted reproduction?
AB  - A major problem in IVF procedures is a high rate of induced iatrogenic
      complications including multiple gestations. Until now, transfer of at least
      three embryos followed by the subsequent elective reduction of triplet or higher
      order gestations to twins, single embryo transfer (SET) with cryopreservation of
      the remaining embryos, as well as the application of SET in unstimulated cycles,
      serves to illustrate the diversity characterizing the worldwide effort of
      achievement of pregnancy that aims to avoid possible complications. The BESST
      (birth emphasizing a successful singleton at term) endpoint constitutes an
      interesting parameter imposing the safety of SET. However, the observed success
      rate (11.1%) requires elucidation of the specific pattern of endometrial
      behaviour around the implantation window as well as its involvement in the
      further support of gestation. Consequently, research has to focus primarily on
      the improvement of technical parameters to achieve an acceptable success rate
      during the IVF procedures as compared with spontaneous gestations.

PMID- 15192074
TI  - Evidence for the notch signaling pathway on the role of estrogen in angiogenesis.
AB  - We have investigated the molecular mechanisms involved in 17 beta-estradiol
      induced angiogenic pathway. We show here that 17 beta-estradiol promoted a 6-fold
      increase in Jagged1 expression and an 8-fold increase in Notch1 expression by
      cDNA arrays in breast cancer MCF7 cells. Interestingly, Jagged1 was abrogated by
      incubation with the estrogen antagonist, ICI182,780. A similar up-regulation of
      both Notch1 receptor and Jagged1 ligand was found in endothelial cells.
      Additionally, imperfect estrogen-responsive elements were found in the 5'
      untranslated region of Notch1 and Jagged1 genes. Treatment with 17 beta-estradiol
      also led to an activation of Notch signaling in MCF7 cells expressing Notch1
      reporter gene or by promoting Jagged1-induced Notch signaling in coculture
      assays. Inoculation of MCF7 cells in 17 beta-estradiol-treated nude mice resulted
      in up-regulation of Notch1 expression as well as increased number of tumor
      microvessels in comparison to placebo-treated mice. Notch1-expressing endothelial
      cell cultures formed cord-like structures on Matrigel in contrast to cells
      expressing a dominant-negative form of Notch1, emphasizing the relevance of
      Notch1 pathway in vessel assembly. Finally, Notch1-expressing MCF7 cells up
      regulated hypoxia-inducible factor 1 alpha gene, a well-known angiogenic factor
      that clustered with Notch1 gene. This study implicates Notch signaling in the
      cross talk between 17 beta-estradiol and angiogenesis.

PMID- 15192075
TI  - New naturally occurring missense mutations of the human mineralocorticoid
      receptor disclose important residues involved in dynamic interactions with
      deoxyribonucleic acid, intracellular trafficking, and ligand binding.
AB  - We have investigated the functional consequences of three naturally occurring
      amino acid substitutions of the human mineralocorticoid receptor (hMR). These
      mutations are located in the DNA-binding domain and the ligand-binding domain
      (LBD) and are associated with autosomal dominant or sporadic type I
      pseudohypoaldosteronism. All mutant receptors bound specifically to
      glucocorticoid-responsive elements but presented modified transcriptional
      properties. The DNA-binding domain mutant G633R, which possesses a normal
      affinity for a glucocorticoid-responsive element, displayed altered interaction
      with, and a reduced dissociation rate from, DNA. Its intracellular localization
      in the absence of hormone was predominantly nuclear in comparison with
      predominant cytoplasmic location of hMR. Hormone-dependent nuclear cluster
      formation was comparable to wild-type hMR. These results and the three
      dimensional modeling of the interaction of R633 with DNA suggest that altered
      interaction dynamics with DNA as well as modified intracellular localization may
      be responsible for submaximal transcriptional potency of hMR. Two LBD mutations,
      Q776R and L979P, were also investigated. Our data confirm the fundamental role of
      amino acid Q776 for anchoring the C3 ketone group of steroids in the ligand
      binding pocket. Analysis of LBD conformation of mutant P979 demonstrates the
      relevance of hydrophobic interactions in the extreme C-terminal tail of the hMR
      for the correct ligand-binding competent state of the receptor. Our data
      underline the importance of studying naturally occurring mutants to identify
      crucial residues involved in hMR function.

PMID- 15192076
TI  - Ovarian follicle development requires Smad3.
AB  - Smad3 is an important mediator of the TGF beta signaling pathway. Interestingly,
      Smad3-deficient (Smad3-/-) mice have reduced fertility compared with wild-type
      (WT) mice. To better understand the molecular mechanisms underlying the reduced
      fertility in Smad3-/- animals, this work tested the hypothesis that Smad3
      deficiency interferes with three critical aspects of folliculogenesis: growth,
      atresia, and differentiation. Growth was assessed by comparing the size of
      follicles, expression of proliferating cell nuclear antigen, and expression of
      cell cycle genes in Smad3-/- and WT mice. Atresia was assessed by comparing the
      incidence of atresia and expression of bcl-2 genes involved in cell death and
      cell survival in Smad3-/- and WT mice. Differentiation was assessed by comparing
      the expression of FSH receptor (FSHR), estrogen receptor (ER) alpha, ER beta, and
      inhibin alpha-, beta(A)-, and beta(B)-subunits in Smad3-/- and WT mice. Because
      growth, atresia, and differentiation are regulated by hormones, estradiol, FSH,
      and LH levels were compared in Smad3-/- and WT mice. Moreover, because
      alterations in folliculogenesis can affect the ability of mice to ovulate, the
      number of corpora lutea and ovulated eggs in response to gonadotropin treatments
      were compared in Smad3-/- and WT animals. The results indicate that Smad3
      deficiency slows follicle growth, which is characterized by small follicle
      diameters, low levels of proliferating cell nuclear antigen, and low expression
      of cell cycle genes (cyclin-dependent kinase 4 and cyclin D2). Smad3 deficiency
      also causes atretic follicles, degenerated oocytes, and low expression of bcl-2.
      Furthermore, Smad3 deficiency affects follicular differentiation as evidenced by
      decreased expression of ER beta, increased expression of ER alpha, and decreased
      expression of inhibin alpha-subunits. Smad3 deficiency causes low estradiol and
      high FSH levels. Finally, Smad3-/- ovaries have no corpora lutea, and they do not
      ovulate after ovulatory induction with exogenous gonadotropins. Collectively,
      these data provide the first evidence that reduced fertility in Smad3-/- mice is
      due to impaired folliculogenesis, associated with altered expression of genes
      that control cell cycle progression, cell survival, and cell differentiation. The
      findings that Smad3-/- follicles have impaired growth, increased atresia, and
      altered differentiation in the presence of high FSH levels, normal expression of
      FSHR, and lower expression of cyclin D2, suggest a possible interaction between
      Smad3 and FSH signaling downstream of FSHR in the mouse ovary.

PMID- 15192077
TI  - Stability of A+U-rich element binding factor 1 (AUF1)-binding messenger
      ribonucleic acid correlates with the subcellular relocalization of AUF1 in the
      rat uterus upon estrogen treatment.
AB  - The nucleocytoplasmic shuttling protein, A+U-rich element binding factor 1
      (AUF1), is one of the RNA-binding proteins that specifically bind adenylate
      uridylate rich elements (AREs) in mRNA 3'-untranslated regions (UTRs), and acts
      as a regulator of ARE-mediated mRNA degradation in the cytoplasm. We previously
      reported that in the female rat uterus, the levels of specific AUF1 isoform mRNAs
      (p40/p45) were increased by 17 beta-estradiol (E2) treatment. Therefore, we
      examined the role of AUF1 in the regulation of E2-mediated mRNA turnover in the
      rat uterus. We identified ABIN2 and Ier2/pip92 mRNAs as candidate targets of AUF1
      in the rat uterus. We found that AUF1-binding elements were present in the 3'-UTR
      of both mRNAs and that the 3'-UTRs functioned as mRNA turnover regulatory
      elements. In the ovariectomized rat uterus, the nucleocytoplasmic localization of
      AUF1p40/p37 isoform proteins was regulated by E2. We also found that cytoplasmic
      AUF1-bound mRNA levels changed coincidentally with the cytoplasmic levels of
      AUF1p40/p37. Finally, we confirmed that the subcellular localization of AUF1p40
      controlled the stability of target mRNAs in vitro, such that cytoplasmically
      localized AUF1p40 led to marked mRNA stabilization, whereas nuclear-localized
      AUF1p40 stabilized target mRNA only slightly. These results suggested that E2
      inducible ARE-containing gene transcripts are regulated, at least in part, via
      mRNA stabilization through the nucleocytoplasmic relocalization of AUF1.

PMID- 15192078
TI  - Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit
      intrauterine growth retardation associated with embryonic and perinatal
      lethality.
AB  - Leucine-rich repeat-containing, G protein-coupled receptors (LGRs) belong to the
      largest mammalian superfamily of proteins with seven-transmembrane domains. LGRs
      can be divided into three subgroups based on their unique domain arrangement.
      Although two subgroups have been found to be receptors for glycoprotein hormones
      and relaxin-related ligands, respectively, the third LGR subgroup, consisting of
      LGR4-6, are orphan receptors with unknown physiological roles. To elucidate the
      functions of this subgroup of LGRs, LGR4 null mice were generated using a
      secretory trap approach to delete the majority of the LGR4 gene after the
      insertion of a beta-galactosidase reporter gene immediately after exon 1. Tissues
      expressing LGR4 were analyzed based on histochemical staining of the transgene
      driven by the endogenous LGR4 promoter. LGR4 was widely expressed in kidney,
      adrenal gland, stomach, intestine, heart, bone/cartilage, and other tissues. The
      expression of LGR4 in these tissues was further confirmed by immunohistochemical
      studies in wild-type animals. Analysis of the viability of 250 newborn animals
      suggested a skewed inheritance pattern, indicating that only 40% of the expected
      LGR4 null mice were born. For the LGR4 null mice viable at birth, most of them
      died within 2 d. Furthermore, the LGR4 null mice showed intrauterine growth
      retardation as reflected by a 14% decrease in body weight at birth, together with
      30% and 40% decreases in kidney and liver weights, respectively. The present
      findings demonstrate the widespread expression of LGR4, and an essential role of
      LGR4 for embryonic growth, as well as kidney and liver development. The observed
      pre- and postnatal lethality of LGR4 null mice illustrates the importance of the
      LGR4 signaling system for the survival and growth of animals during the perinatal
      stage.

PMID- 15192079
TI  - Plasticity of the ecdysone receptor DNA binding domain.
AB  - Ecdysteroids coordinate molting and metamorphosis in insects via a heterodimer of
      two nuclear receptors, the ecdysone receptor (EcR) and the ultraspiracle (Usp)
      protein. Here we show how the DNA-recognition alpha-helix and the T box region of
      the EcR DNA-binding domain (EcRDBD) contribute to the specific interaction with
      the natural response element and to the stabilization of the EcRDBD molecule. The
      data indicate a remarkable mutational tolerance with respect to the DNA-binding
      function of the EcRDBD. This is particularly manifested in the heterocomplexes
      formed between the EcRDBD mutants and the wild-type Usp DNA-binding domain
      (UspDBD). Circular dichroism (CD) spectra and protein unfolding experiments
      indicate that, in contrast to the UspDBD, the EcRDBD is characterized by a lower
      alpha-helix content and a lower stability. As such, the EcRDBD appears to be an
      intrinsically unstructured protein-like molecule with a high degree of
      intramolecular plasticity. Because recently published crystal structures indicate
      that the ligand binding domain of the EcR is also characterized by the extreme
      adaptability, we suggest that plasticity of the EcR domains may be a key factor
      that allows a single EcR molecule to mediate diverse biological effects.

PMID- 15192080
TI  - Small ubiquitin-like modifier 1 (SUMO-1) modification of the synergy control
      motif of Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) regulates
      synergistic transcription between Ad4BP/SF-1 and Sox9.
AB  - An orphan nuclear receptor, Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF
      1), is essential for the development and function of steroidogenic tissues. To
      examine the transcriptional regulation of Ad4BP/SF-1, two-hybrid screening was
      performed, and the sumoylation [conjugation of a small ubiqutin-like modifier
      (SUMO-1)] components Ubc9, protein inhibitor of activated STAT 1 (PIAS1), and
      protein inhibitor of activated STAT 3 (PIAS3) were isolated. Cultured cell and in
      vitro studies revealed that Ad4BP/SF-1 is sumoylated at K119 and K194. Because
      K194 lies within the synergy control (SC) motif defined to repress synergistic
      transcription from promoters containing multiple binding sites, correlation
      between the functions of the SC motif and sumoylation was investigated. The K194R
      mutant of Ad4BP/SF-1, which cannot be sumoylated, showed enhanced synergistic
      transcription from a promoter containing multiple Ad4/SF-1 sites, suggesting that
      sumoylation is necessary for repression of transcriptional synergy through the SC
      motif. It has been established that the Mullerian inhibiting substance gene is
      transcribed predominantly under the control of Ad4BP/SF-1 and, moreover, its
      transcription is regulated synergistically with Sox9, Gata4, and Wt1.
      Interestingly, it was found that all of these factors are sumoylated, and these
      sumoylation sites occur within SC motifs. Based on the observation that SC motif
      mutants of Ad4BP/SF-1 and Sox9 resulted in the enhancement of their synergistic
      transcription, it was concluded that the SC motif regulates synergistic
      transcription even between distinct types of transcription factors. Considering
      that both mutants cannot be sumoylated, it is likely that sumoylation is
      implicated in this regulation. Because it was revealed with an in vitro
      sumoylated Ad4BP/SF-1 that DNA binding activity and interaction with Sox9 were
      unaffected, sumoylation may regulate transcription through affecting selective
      and cooperative interaction among factors constituting transcriptional complexes.

PMID- 15192081
TI  - The role of uncoupling protein 1 in the metabolism and adiposity of RII beta
      protein kinase A-deficient mice.
AB  - Mice lacking the RII beta regulatory subunit of protein kinase A exhibit a 50%
      reduction in white adipose tissue stores compared with wild-type littermates and
      are resistant to diet-induced obesity. RII beta(-/-) mice also have an increase
      in resting oxygen consumption along with a 4-fold increase in the brown adipose
      specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined
      the basis for UCP1 induction and tested the hypothesis that the induced levels of
      UCP1 in RII beta null mice are essential for the lean phenotype. The induction of
      UCP1 occurred at the protein but not the mRNA level and correlated with an
      increase in mitochondria in brown adipose tissue. Mice lacking both RII beta and
      UCP1 (RII beta(-/-)/Ucp1(-/-)) were created, and the key parameters of metabolism
      and body composition were studied. We discovered that RII beta(-/-) mice exhibit
      nocturnal hyperactivity in addition to the increased oxygen consumption at rest.
      Disruption of UCP1 in RII beta(-/-) mice reduced basal oxygen consumption but did
      not prevent the nocturnal hyperactivity. The double knockout animals also
      retained the lean phenotype of the RII beta null mice, demonstrating that
      induction of UCP1 and increased resting oxygen consumption is not the cause of
      leanness in the RII beta mutant mice.

PMID- 15192082
TI  - Cathepsin D processes human prolactin into multiple 16K-like N-terminal
      fragments: study of their antiangiogenic properties and physiological relevance.
AB  - 16K prolactin (PRL) is the name given to the 16-kDa N-terminal fragment obtained
      by proteolysis of rat PRL by tissue extracts or cell lysates, in which cathepsin
      D was identified as the candidate protease. Based on its antiangiogenic activity,
      16K PRL is potentially a physiological inhibitor of tumor growth. Full-length
      human PRL (hPRL) was reported to be resistant to cathepsin D, suggesting that
      antiangiogenic 16K PRL may be physiologically irrelevant in humans. In this
      study, we show that hPRL can be cleaved by cathepsin D or mammary cell extracts
      under the same conditions as described earlier for rat PRL, although with lower
      efficiency. In contrast to the rat hormone, hPRL proteolysis generates three 16K
      like fragments, which were identified by N-terminal sequencing and mass
      spectrometry as corresponding to amino acids 1-132 (15 kDa), 1-147 (16.5 kDa),
      and 1-150 (17 kDa). Biochemical and mutagenetic studies showed that the species
      specific digestion pattern is due to subtle differences in primary and tertiary
      structures of rat and human hormones. The antiangiogenic activity of N-terminal
      hPRL fragments was assessed by the inhibition of growth factor-induced thymidine
      uptake and MAPK activation in bovine umbilical endothelial cells. Finally, an N
      terminal hPRL fragment comigrating with the proteolytic 17-kDa fragment was
      identified in human pituitary adenomas, suggesting that the physiological
      relevance of antiangiogenic N-terminal hPRL fragments needs to be reevaluated in
      humans.

PMID- 15192083
TI  - Simultaneous alpha2B- and beta2-adrenoceptor activation sensitizes the alpha2B
      adrenoceptor for agonist-induced down-regulation.
AB  - We recently reported that alpha(2A)-adrenoceptor (AR) desensitization and down
      regulation occurs after 24-h treatment with epinephrine (EPI) (0.3 microM) in
      BE(2)-C cells that express both alpha(2)- and beta(2)-ARs. The same concentration
      of norepinephrine (NE) has no effect. The effect of EPI is prevented by beta(2)
      AR blockade and is associated with an increase in G protein-coupled receptor
      kinase 3 (GRK3) expression. Because differences in agonist-induced down
      regulation of the alpha(2A)-versus alpha(2B)-ARs have been reported, the present
      study examines the effects of simultaneous activation of alpha(2B)- and beta(2)
      ARs on alpha(2B)-AR number and signaling. We studied NG108 cells that naturally
      express alpha(2B)-ARs, and BN17 cells, NG108 cells transfected to express the
      human beta(2)-AR. In NG108 cells, alpha(2B)-AR desensitization and down
      regulation require treatment with 20 microM EPI or NE; GRK expression was not
      changed. In BN17 cells expressing beta(2)-ARs, the threshold EPI concentration
      for alpha(2B)-AR desensitization and down-regulation was reduced to 0.3 microM;
      10 microM NE was required for the same effect. Furthermore, 24-h EPI or NE
      treatments that produced desensitization also resulted in a selective 2-fold up
      regulation of GRK3; GRK2 was unchanged. The beta-AR antagonist alprenolol (1
      microM) and GRK3 antisense (but not sense) DNA blocked 0.3 microM EPI- and 10
      microM NE-induced desensitization and down-regulation of the alpha(2B)-AR as well
      as GRK3 up-regulation. In conclusion, simultaneous activation of alpha(2B)- and
      beta(2)-ARs results in a 67-fold decrease in the threshold concentration of EPI
      required for alpha(2B)-AR down-regulation. This lower threshold for down
      regulation is associated with alpha(2B)- and beta(2)-AR dependent up-regulation
      of GRK3 expression.

PMID- 15192084
TI  - Disposition kinetics of propranolol isomers in the perfused rat liver.
AB  - The aim of this study was to define the determinants of the linear hepatic
      disposition kinetics of propranolol optical isomers using a perfused rat liver.
      Monensin was used to abolish the lysosomal proton gradient to allow an estimation
      of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were
      used for independent estimates of microsomal binding and intrinsic clearance.
      Hepatic extraction and mean transit time were determined from outflow
      concentration profiles using a nonparametric method. Kinetic parameters were
      derived from a physiologically based pharmacokinetic model. Modeling showed an
      approximate 34-fold decrease in ion trapping following monensin treatment. The
      observed model-derived ion trapping was similar to estimated theoretical values.
      No differences in ion-trapping values was found between R(+)- and S(-)
      propranolol. Hepatic propranolol extraction was sensitive to changes in liver
      perfusate flow, permeability-surface area product, and intrinsic clearance. Ion
      trapping, microsomal and nonspecific binding, and distribution of unbound
      propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of
      propranolol in the liver, respectively. It is concluded that the physiologically
      more active S()-propranolol differs from the R(+)-isomer in higher permeability
      surface area product, intrinsic clearance, and intracellular binding site values.

PMID- 15192085
TI  - Memantine improves spatial learning in a transgenic mouse model of Alzheimer's
      disease.
AB  - Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate
      receptor antagonist, has been shown to improve learning and memory in several
      pharmacological models of Alzheimer's disease (AD). In the present study, the
      effect of memantine on locomotor activity, social behavior, and spatial learning
      was assessed in a transgenic mouse model of AD. Eight-month-old male C57BL/6J
      mice carrying mutated human APP and PS1 genes (APP/PS1) and their nontransgenic
      (NT) litter mates were administered a therapeutic dose of memantine (30 mg/kg/day
      p.o.) for 2 to 3 weeks. At this age, APP/PS1 mice show elevated levels of beta
      amyloid peptides in several brain regions. APP/PS1 mice exhibited less
      exploratory rearing and increased aggressive behavior compared with NT mice. In
      the water maze test for spatial learning, APP/PS1 mice had longer escape
      latencies to both hidden and visible platforms, but they did not differ from NT
      mice in their swimming speed. Memantine significantly improved the acquisition of
      the water maze in APP/PS1 mice without affecting swimming speed. Memantine did
      not affect either locomotor activity or aggressive behavior in either genotype.
      These data indicate that memantine improves hippocampus-based spatial learning in
      a transgenic mouse model of AD without producing nonspecific effects on
      locomotion/exploratory activity.

PMID- 15192086
TI  - ydaG and ydbA of Lactococcus lactis encode a heterodimeric ATP-binding cassette
      type multidrug transporter.
AB  - Multidrug resistance (MDR)-type transporters mediate the active extrusion of
      structurally and functionally dissimilar compounds from the cells, thereby
      rendering cells resistant to a range of drugs. The ydaG and ydbA genes of
      Lactococcus lactis encode two ATP-binding cassette half-transporters, which both
      share homology with MDR proteins such as LmrA from L. lactis or the mammalian P
      glycoprotein. The ydaG/ydbA genes were cloned and expressed separately and
      jointly in L. lactis using the nisin-inducible system. When both proteins are co
      expressed, several structurally dissimilar drugs such as ethidium, daunomycin,
      and BCECF-AM are extruded from the cell. YdaG and YdbA could be co-purified as a
      stable heterodimer. ATPase activity was found to be associated with the YdaG/YdbA
      heterodimer only and not with the individual subunits. Both the ydaG and ydbA
      genes are up-regulated in multidrug-resistant L. lactis strains selected for
      growth in the presence of a variety of toxic compounds. This is the first
      demonstration of a functional heterodimeric ATP-binding cassette-type MDR
      transporter.

PMID- 15192087
TI  - Selection of cysteine protease inhibitor-resistant malaria parasites is
      accompanied by amplification of falcipain genes and alteration in inhibitor
      transport.
AB  - Cysteine protease inhibitors are being studied as possible new antimalarial
      agents. To evaluate the potential for resistance to these compounds, we subjected
      chloroquine-resistant (W2 strain) Plasmodium falciparum to increasing
      concentrations of a vinyl sulfone cysteine protease inhibitor. After incubation
      with 1-200 nm morpholine urea-leucine-homophenylalanine-phenyl vinyl sulfone over
      approximately 8 months, highly resistant parasites ( approximately 100-fold
      increases in IC(50)) were selected. The vinyl sulfone-resistant parasites were
      also resistant to related peptidyl inhibitors, but had only modest (
      approximately 2-fold) decreases in sensitivity to other cysteine protease
      inhibitors. Compared with the parental strain, resistant parasites showed no
      changes in multiplication rates, but elevations in cysteine protease activity,
      falcipain-2 and falcipain-3 copy numbers, transcription of falcipain genes, and
      levels of these target proteases in trophozoites. Resistant parasites grown in
      the absence of the vinyl sulfone for 12 weeks showed partial reversion, with
      increased inhibitor sensitivity and apparent decreases in copy numbers of
      falcipain-2 and falcipain-3. The sequences of falcipain-1, falcipain-2, and
      falcipain-3 were identical in sensitive and resistant parasites. The accumulation
      of a vinyl sulfone inhibitor was decreased approximately 9-fold in resistant
      parasites. In summary, parasites resistant to a cysteine protease inhibitor were
      selected, although the acquisition of high level resistance required extended
      exposure to the inhibitor and this resistance was somewhat unstable. Resistance
      was specific for the type of protease inhibitor used for the selection and
      appeared to be mediated both by alterations in inhibitor transport and by a
      previously unidentified mechanism in P. falciparum, the amplification of genes
      encoding targets of enzyme inhibitors.

PMID- 15192088
TI  - Differential activation of Smads in HeLa and SiHa cells that differ in their
      response to transforming growth factor-beta.
AB  - We assessed the responsiveness of six human cervical cancer cell lines to
      transforming growth factor (TGF)-beta with p3TP-lux reporter assay and found that
      HeLa and SiHa cells were highly responsive to TGF-beta. However, when pSBE4
      BV/Luc reporter with four Smad binding elements was used, only the SiHa, not the
      HeLa, cells showed Smad activation. Smad DNA binding activity was relatively more
      in SiHa than in HeLa cells upon TGF-beta treatment, and the active complex
      contained Smad 2 and Smad 4. In 3-(4,5-dimethylthiazol-2-yl)-2,5
      diphenyltetrazolium bromide assays, HeLa cells treated with 5 ng/ml of TGF-beta
      for 24 h showed proliferation, whereas SiHa cells showed growth inhibition under
      the same conditions. TGF-beta treatment resulted in G(0)/G(1) arrest with a
      reduction in S-phase only in SiHa cells. A chemical inhibitor of Smad activation
      (SB203580) blocked the growth inhibitory effect of TGF-beta in SiHa, whereas the
      proliferative response in HeLa was unaffected. TGF-beta-induced translocation of
      phospho-Smad 2 was relatively less in HeLa than in SiHa cells. MAPK activation
      occurred within 5 min and persisted up to 15 min upon TGF-beta treatment in HeLa
      but was negligible in SiHa cells. TGF-beta activated JNK in HeLa, but SiHa cells
      showed a down-regulation of its activity. When an inhibitor of MAPK (U0126) was
      used, the TGF-beta-mediated proliferative response in HeLa cells was completely
      abolished. SB203580 did not affect MAPK activation induced by TGF-beta in HeLa
      cells. We report for the first time an activation, presumably independent of Smad
      activation, of TGF-beta-dependent MAPK within 5 min of treatment that resulted in
      cell cycle progression in a cervical adenocarcinoma cell line, HeLa.

PMID- 15192089
TI  - Regulation of insulin signaling through reversible oxidation of the protein
      tyrosine phosphatases TC45 and PTP1B.
AB  - Many studies have illustrated that the production of reactive oxygen species
      (ROS) is important for optimal tyrosine phosphorylation and signaling in response
      to diverse stimuli. Protein-tyrosine phosphatases (PTPs), which are important
      regulators of signal transduction, are exquisitely sensitive to inhibition after
      generation of ROS, and reversible oxidation is becoming recognized as a general
      physiological mechanism for regulation of PTP function. Thus, production of ROS
      facilitates a tyrosine phosphorylation-dependent cellular signaling response by
      transiently inactivating those PTPs that normally suppress the signal. In this
      study, we have explored the importance of reversible PTP oxidation in the
      signaling response to insulin. Using a modified ingel PTP assay, we show that
      stimulation of cells with insulin resulted in the rapid and transient oxidation
      and inhibition of two distinct PTPs, which we have identified as PTP1B and TC45,
      the 45-kDa spliced variant of the T cell protein-tyrosine phosphatase. We
      investigated further the role of TC45 as a regulator of insulin signaling by
      combining RNA interference and the use of substrate-trapping mutants. We have
      shown that TC45 is an inhibitor of insulin signaling, recognizing the beta
      subunit of the insulin receptor as a substrate. The data also suggest that this
      strategy, using ligand-induced oxidation to tag specific PTPs and using
      interference RNA and substrate-trapping mutants to illustrate their role as
      regulators of particular signal transduction pathways, may be applied broadly
      across the PTP family to explore function.

PMID- 15192090
TI  - Ca2+-selective transient receptor potential V channel architecture and function
      require a specific ankyrin repeat.
AB  - Transient receptor potential (TRP) proteins form cation-conducting ion channels
      with currently 28 known genes encoding TRP channel monomers in mammals. These
      monomers are thought to coassemble to form homo- or heterotetrameric channels,
      but the signals governing their assembly are unknown. Within the TRPV subgroup,
      TRPV5 and TRPV6 show exclusive calcium selectivity and play an important role in
      calcium uptake. To identify signals that mediate assembly of functional TRPV6, we
      screened domains for self-association using co-immunoprecipitation, sucrose
      gradient centrifugation, bacterial two-hybrid assays, and patch clamp analysis.
      Of the two identified interaction domains within the N-terminal region, we showed
      that the first domain encompassing the third ankyrin repeat is the stringent
      requirement for physical assembly of TRPV6 subunits and when transferred to an
      unrelated protein enables its interaction with TRPV6. Deletion of this repeat or
      mutation of critical residues within this repeat rendered nonfunctional channels
      that do not co-immunoprecipitate or form tetramers. Suppression of dominant
      negative inhibitors of TRPV6-specific currents was achieved by deletion of
      ankyrin (ANK) 3. We propose that the third ANK repeat initiates a molecular
      zippering process that proceeds past the fifth ANK repeat and creates an
      intracellular anchor that is necessary for functional subunit assembly.

PMID- 15192091
TI  - Argininosuccinate synthetase is reversibly inactivated by S-nitrosylation in
      vitro and in vivo.
AB  - Prior studies have demonstrated that the substrate for NO synthesis, l-arginine,
      can be regenerated from the NOS co-product l-citrulline. This requires the
      sequential action of two enzymes, argininosuccinate synthetase (AS) and
      argininosuccinate lyase (AL). AS activity has been shown to be rate-limiting for
      high output NO synthesis by immunostimulant-activated cells and represents a
      potential site for metabolic control of NO synthesis. We now demonstrate that NO
      mediates reversible S-nitrosylation and inactivation of AS in vitro and in
      lipopolysaccharide-treated cells and mice. Using a novel mass spectrometry-based
      method, we show that Cys-132 in human AS is the sole target for S-nitrosylation
      among five Cys residues. Mutagenesis studies confirm that S-nitrosylation of Cys
      132 is both necessary and sufficient for the inhibition of AS by NO donors. S
      nitroso-AS content is regulated by cellular glutathione levels and selectively
      influences NO production when citrulline is provided to cells as a protosubstrate
      of NOS but not when l-arginine is provided. A phylogenetic comparison of AS
      sequences suggests that Cys-132 evolved as a site for post-translational
      regulation of activity in the AS in NOS-expressing species, endowing NO with the
      capacity to limit its own synthesis by restricting arginine availability.

PMID- 15192092
TI  - SUMO modification of repression domains modulates function of nuclear receptor
      5A1 (steroidogenic factor-1).
AB  - Steroidogenic factor 1 (SF-1 or NR5A1), is a Ftz-F1 member of the nuclear
      receptor superfamily that plays essential roles in endocrine development,
      steroidogenesis, and gonad differentiation. We investigated modifications that
      control SF-1 function and found that SF-1 could be conjugated by SUMO-1 both in
      vitro and in vivo. SF-1 was modified predominantly at Lys(194) and much less at
      Lys(119) when free SUMO-1 was supplied. Mutations of Lys(194) and Lys(119)
      enhanced transcriptional activity of SF-1, although the DNA binding activity of
      SF-1 was not affected. Sequences around Lys(194) and Lys(119) both repressed
      transcription intrinsically. The Lys(194) motif repressed transcription more
      efficiently than the Lys(119) domain, consistent with its ability to be a better
      substrate for SUMO conjugation. Thus, SUMO modification of SF-1 correlates with
      transcriptional repression. Wild-type but not conjugation-deficient SF-1 was
      localized at the nuclear speckles together with SUMO-1. Thus, SUMO-1 conjugation
      could also target SF-1 into nuclear speckles. Collectively, these results suggest
      that SUMO modification at the repression domains targets SF-1 to nuclear
      speckles; this could be an important mechanism by which SF-1 is regulated.

PMID- 15192093
TI  - Identification of domain structures in the propeptide of corin essential for the
      processing of proatrial natriuretic peptide.
AB  - Corin is a type II transmembrane serine protease and functions as the proatrial
      natriuretic peptide (pro-ANP) convertase in the heart. In the extracellular
      region of corin, there are two frizzled-like cysteine-rich domains, eight low
      density lipoprotein receptor (LDLR) repeats, a macrophage scavenger receptor-like
      domain, and a trypsin-like protease domain at the C terminus. To examine the
      functional importance of the domain structures in the propeptide of corin for pro
      ANP processing, we constructed a soluble corin, EKshortCorin, that consists of
      only the protease domain and contains an enterokinase (EK) recognition sequence
      at the conserved activation cleavage site. After being activated by EK,
      EKshortCorin exhibited catalytic activity toward chromogenic substrates but
      failed to cleave pro-ANP, indicating that certain domain structures in the
      propeptide are required for pro-ANP processing. We then constructed a series of
      corin deletion mutants and studied their functions in pro-ANP processing.
      Compared with that of the full-length corin, a corin mutant lacking frizzled 1
      domain exhibited approximately 40% activity, whereas corin mutants lacking single
      LDLR repeat 1, 2, 3, or 4 had approximately 49, approximately 12, approximately
      53, and approximately 77% activity, respectively. We also made corin mutants with
      a single mutation at a conserved Asp residue that coordinates Ca(2+)-binding in
      LDLR repeats 1, 2, 3, or 4 (D300Y, D336Y, D373Y, and D410Y) and showed that these
      mutants had approximately 25, approximately 11, approximately 16, and
      approximately 82% pro-ANP processing activity, respectively. Our results indicate
      that frizzled 1 domain and LDLR repeats 1-4 are important structural elements for
      corin to recognize its physiological substrate, pro-ANP.

PMID- 15192094
TI  - Genome-wide analysis of ARS (autonomously replicating sequence) binding factor 1
      (Abf1p)-mediated transcriptional regulation in Saccharomyces cerevisiae.
AB  - Autonomously replicating sequence-binding factor-1 (Abf1p) is an essential
      sequence-specific transcription factor in Saccharomyces cerevisiae that
      participates in multiple nuclear events including DNA replication, transcription
      activation, and gene silencing. Numerous gene-specific analyses have implicated
      Abf1p in the transcriptional control of genes involved in a diverse range of
      cellular functions, leading to the notion that Abf1p acts as a global
      transcriptional regulator. Here we report findings from a genome-wide comparison
      of the gene expression profiles in the wild-type and abf1-1 temperature-sensitive
      mutant. The study identifies a total of 86 Abf1p-regulated genes (1.4% of the
      genome) of which 50 are activated and 36 are repressed by Abf1p. Interestingly,
      Abf1p binds to its own promoter in vivo and strongly represses its own
      transcription, suggesting a potential negative regulatory loop in Abf1p-mediated
      gene regulation. A comparison of our microarray data with the available databases
      reveals a significant overlap of genes regulated by Abf1p and those by several
      general transcription factors such as Mot1p and TAFs (TATA-binding protein
      associated factors). Different mutant alleles of abf1 affect Abf1p-mediated
      transcription in a gene-dependent manner. Furthermore, Abf1p in vivo is
      associated with the promoter region of most Abf1p-activated but not with that of
      most Abf1p-repressed genes. Taken together, these results strongly suggest
      distinct underlying mechanisms by which Abf1p regulates gene expression.

PMID- 15192095
TI  - The topography of transmembrane segment six is altered during the catalytic cycle
      of P-glycoprotein.
AB  - Structural evidence has demonstrated that P-glycoprotein (P-gp) undergoes
      considerable conformational changes during catalysis, and these alterations are
      important in drug interaction. Knowledge of which regions in P-gp undergo
      conformational alterations will provide vital information to elucidate the
      locations of drug binding sites and the mechanism of coupling. A number of
      investigations have implicated transmembrane segment six (TM6) in drug-P-gp
      interactions, and a cysteine-scanning mutagenesis approach was directed to this
      segment. Introduction of cysteine residues into TM6 did not disturb basal or drug
      stimulated ATPase activity per se. Under basal conditions the hydrophobic probe
      coumarin maleimide readily labeled all introduced cysteine residues, whereas the
      hydrophilic fluorescein maleimide only labeled residue Cys-343. The amphiphilic
      BODIPY-maleimide displayed a more complex labeling profile. The extent of
      labeling with coumarin maleimide did not vary during the catalytic cycle, whereas
      fluorescein maleimide labeling of F343C was lost after nucleotide binding or
      hydrolysis. BODIPY-maleimide labeling was markedly altered during the catalytic
      cycle and indicated that the adenosine 5'-(beta,gamma-imino)triphosphate-bound
      and ADP/vanadate-trapped intermediates were conformationally distinct. Our data
      are reconciled with a recent atomic scale model of P-gp and are consistent with a
      tilting of TM6 in response to nucleotide binding and ATP hydrolysis.

PMID- 15192097
TI  - In vitro assembly of the characteristic chromatin organization at the yeast PHO5
      promoter by a replication-independent extract system.
AB  - An extensive set of analyses of the yeast PHO5 gene, mostly performed in vivo,
      has made this gene a model for the role of chromatin structure in gene
      regulation. In the repressed state, the PHO5 promoter shows a characteristic
      chromatin organization with four positioned nucleosomes and a short
      hypersensitive site. So far the basis for this nucleosome positioning has
      remained unresolved. We have therefore decided to complement the in vivo studies
      by an in vitro approach. As a first step, we have asked whether the
      characteristic PHO5 promoter chromatin structure depends on the cellular context
      including replication or higher order nuclear chromatin organization or whether
      it can be reconstituted in vitro in a cell-free system. To this end we have
      established an in vitro chromatin assembly system based on yeast extracts. It is
      capable of generating extensive regular nucleosomal arrays with physiological
      spacing. Assembly requires supplementation with exogenous histones and is
      dependent on energy leading to chromatin with dynamic properties due to ATP
      dependent activities of the extract. Using the PHO5 promoter sequence as template
      in this replication independent system, we obtain a nucleosomal pattern over the
      PHO5 promoter region that is very similar to the in vivo pattern of the repressed
      state. This shows that the chromatin structure at the PHO5 promoter represents a
      self-organizing system in cell-free yeast extracts and provides a promising
      substrate for in vitro studies with a direct in vivo correlate.

PMID- 15192096
TI  - Action of Pasteurella multocida toxin depends on the helical domain of Galphaq.
AB  - Pasteurella multocida produces a 146-kDa protein toxin (PMT), which activates
      multiple cellular signal transduction pathways, resulting in the activation of
      phospholipase Cbeta, RhoA, Jun kinase, and extracellular signal-regulated kinase.
      Using Galpha(q)/Galpha(11) -deficient cells, it was shown that the PMT-induced
      pleiotropic effects are mediated by Galpha(q) but not by the highly related
      Galpha(11) protein (Zywietz, A., Gohla, A., Schmelz, M., Schultz, G., and
      Offermanns, S. (2001) J. Biol. Chem. 276, 3840-3845). Here we studied the
      molecular basis of the unique specificity of PMT to distinguish between Galpha(q)
      and/or Galpha(11). Infection of Galpha(q) -deficient cells with retrovirus
      encoding Galpha(q) caused reconstitution of PMT-induced activation of
      phospholipase Cbeta, whereas Galpha(11) -encoding virus did not reconstitute PMT
      activity. Chimeras between Galpha(q) and/or Galpha(11) revealed that a peptide
      region of Galpha(q), covering amino acid residues 105-113, is essential for the
      action of PMT to activate phospholipase Cbeta. Exchange of glutamine 105 or
      asparagine 109 of Galpha(11), which are located in the all-helical domain of the
      Galpha subunit, with the equally positioned histidines of Galpha(q), renders
      Galpha(11) capable of transmission PMT-induced phospholipase Cbeta activation.
      The data indicate that the all-helical domain of Galpha(q) is essential for the
      action of PMT and suggest an essential functional role of this domain in signal
      transduction via G(q) proteins.

PMID- 15192098
TI  - Structure and stability of the non-covalent swapped dimer of bovine seminal
      ribonuclease: an enzyme tailored to evade ribonuclease protein inhibitor.
AB  - A growing number of pancreatic-type ribonucleases (RNases) present cytotoxic
      activity against malignant cells. The cytoxicity of these enzymes is related to
      their resistance to the ribonuclease protein inhibitor (RI). In particular,
      bovine seminal ribonuclease (BS-RNase) is toxic to tumor cells both in vitro and
      in vivo. BS-RNase is a covalent dimer with two intersubunit disulfide bridges
      between Cys(31) of one chain and Cys(32) of the second and vice versa. The native
      enzyme is an equilibrium mixture of two isomers, MxM and M=M. In the former the
      two subunits swap their N-terminal helices. The cytotoxic action is a peculiar
      property of MxM. In the reducing environment of cytosol, M=M dissociates into
      monomers, which are strongly inhibited by RI, whereas MxM remains as a non
      covalent dimer (NCD), which evades RI. We have solved the crystal structure of
      NCD, carboxyamidomethylated at residues Cys(31) and Cys(32) (NCD-CAM), in a
      complex with 2'-deoxycitidylyl(3'-5')-2'-deoxyadenosine. The molecule reveals a
      quaternary structural organization much closer to MxM than to other N-terminal
      swapped non-covalent dimeric forms of RNases. Model building of the complexes
      between these non-covalent dimers and RI reveals that NCD-CAM is the only dimer
      equipped with a quaternary organization capable of interfering seriously with the
      binding of the inhibitor. Moreover, a detailed comparative structural analysis of
      the dimers has highlighted the residues, which are mostly important in driving
      the quaternary structure toward that found in NCD-CAM.

PMID- 15192100
TI  - The interaction of protein kinase C isozymes alpha, iota, and theta with the
      cytoplasmic domain of L-selectin is modulated by phosphorylation of the receptor.
AB  - The leukocyte adhesion molecule L-selectin has an important role in the initial
      steps of leukocyte extravasation during inflammation and lymphocyte homing. Its
      cytoplasmic domain is involved in signal transduction after L-selectin cross
      linking and in the regulation of receptor binding activity in response to
      intracellular signals. However, the signaling events occurring at the level of
      the receptor are largely unknown. This study therefore addressed the question of
      whether protein kinases associate with the cytoplasmic domain of the receptor and
      mediate its phosphorylation. Using a glutathione S-transferase fusion protein of
      the L-selectin cytoplasmic domain, we isolated a kinase activity from cellular
      extracts of the human leukemic Jurkat T-cell line that phosphorylated L-selectin
      on serine residues. This kinase showed characteristics of the protein kinase C
      (PKC) family. Moreover, the Ca(2+)-independent PKC isozymes theta and iota were
      found associated with the cytoplasmic domain of L-selectin. Pseudosubstrate
      inhibitors of these isozymes abolished phosphorylation of the cytoplasmic domain,
      demonstrating that these kinases are responsible for the phosphorylation.
      Analysis of proteins specifically bound to the phosphorylated cytoplasmic tail of
      L-selectin revealed that PKCalpha and -theta are strongly associated with the
      phosphorylated cytoplasmic domain of L-selectin. Binding of these isozymes to L
      selectin was also found in intact cells after phorbol ester treatment inducing
      serine phosphorylation of the receptor. Furthermore, stimulation of Jurkat T
      cells by CD3 cross-linking induced association of PKCalpha and -theta with L
      selectin, indicating a role of these kinases in the regulation of L-selectin
      through the T-cell receptor complex. The phosphorylation-regulated association of
      PKC isozymes with the cytoplasmic domain of L-selectin indicates an important
      role of this kinase family in L-selectin signal transduction.

PMID- 15192099
TI  - The family 11 carbohydrate-binding module of Clostridium thermocellum Lic26A
      Cel5E accommodates beta-1,4- and beta-1,3-1,4-mixed linked glucans at a single
      binding site.
AB  - Modular glycoside hydrolases that attack recalcitrant polymers generally contain
      noncatalytic carbohydrate-binding modules (CBMs), which play a critical role in
      the action of these enzymes by localizing the appended catalytic domains onto the
      surface of insoluble polysaccharide substrates. Type B CBMs, which recognize
      single polysaccharide chains, display ligand specificities that are consistent
      with the substrates hydrolyzed by the associated catalytic domains. In enzymes
      that contain multiple catalytic domains with distinct substrate specificities, it
      is unclear how these different activities influence the evolution of the ligand
      recognition profile of the appended CBM. To address this issue, we have
      characterized the properties of a family 11 CBM (CtCBM11) in Clostridium
      thermocellum Lic26A-Cel5E, an enzyme that contains GH5 and GH26 catalytic domains
      that display beta-1,4- and beta-1,3-1,4-mixed linked endoglucanase activity,
      respectively. Here we show that CtCBM11 binds to both beta-1,4- and beta-1,3-1,4
      mixed linked glucans, displaying K(a) values of 1.9 x 10(5), 4.4 x 10(4), and 2 x
      10(3) m(-1) for Glc-beta1,4-Glc-beta1,4-Glc-beta1,3-Glc, Glc-beta1,4-Glc-beta1,4
      Glc-beta1,4-Glc, and Glc-beta1,3-Glc-beta1,4-Glc-beta1,3-Glc, respectively,
      demonstrating that CBMs can display a preference for mixed linked glucans. To
      determine whether these ligands are accommodated in the same or diverse sites in
      CtCBM11, the crystal structure of the protein was solved to a resolution of 1.98
      A. The protein displays a beta-sandwich with a concave side that forms a
      potential binding cleft. Site-directed mutagenesis revealed that Tyr(22),
      Tyr(53), and Tyr(129), located in the putative binding cleft, play a central role
      in the recognition of all the ligands recognized by the protein. We propose,
      therefore, that CtCBM11 contains a single ligand-binding site that displays
      affinity for both beta-1,4- and beta-1,3-1,4-mixed linked glucans.

PMID- 15192103
TI  - Principles of mimicking and engineering the self-organized structure of hard
      tissues.
AB  - The mechanism of the formation of a self-aligned hydroxyapatite (HAP)
      nanocrystallite structure was examined. It is found that the highly ordered HAP
      nanocrystallite assembly is attributed to the so-called self-(homo)epitaxial
      nucleation and growth. On the other hand, according to this mechanism, a high
      supersaturation will give rise to a random assembly of HAP crystallites. The
      effects of ions, biosubstrate, and supersaturation on the micro/nanostructure
      correlation between substrate and biominerals as well as their implications in
      hard tissue formation were examined. Surprisingly, some biomolecules are found to
      be able to suppress the supersaturation-driven interfacial structure mismatch and
      hence promote the well aligned HAP pattern formation.

PMID- 15192102
TI  - Sphingosine 1-phosphate cross-activates the Smad signaling cascade and mimics
      transforming growth factor-beta-induced cell responses.
AB  - Exposure of renal mesangial cells to sphingosine 1-phosphate (S1P) leads to a
      rapid and transient activation of the mitogen- and stress-activated protein
      kinases but also the protein kinase B. Here, we show that S1P also induces
      phosphorylation of Smad proteins, which are members of the transforming growth
      factor-beta (TGF-beta) signaling device. However, Smad phosphorylation occurred
      more slowly with a maximal effect after 20-30 min of S1P stimulation when
      compared with the rapid activation of the MAPKs. Interestingly, Smad
      phosphorylation is increased by pertussis toxin, which is in contrast to the
      complete inhibition of S1P-induced MAPK phosphorylation by pertussis toxin. TGF
      beta is a potent anti-inflammatory cytokine, which in mesangial cells attenuates
      the expression of (i) inducible nitricoxide synthase (iNOS) caused by interleukin
      (IL)-1beta, (ii) secreted phospholipase A(2) (sPLA(2)), and (iii) matrix
      metalloproteinase-9 (MMP-9). These gene products are also down-regulated by S1P
      in a concentration-dependent manner. Furthermore, the expression of connective
      tissue growth factor is enhanced by both TGF-beta(2) and S1P. These effects of
      S1P are not mediated by the MAPK cascade as neither pertussis toxin nor the MAPK
      cascade inhibitor U0126 are able to reverse this inhibition. Overexpression of
      the inhibitory Smad-7 or down-regulation of co-Smad-4 lead to a reversal of the
      blocking effect of S1P on IL-1beta-induced NO release. Moreover, down-regulating
      the TGF-beta receptor type II by the siRNA technique or antagonizing the S1P(3)
      receptor subtype with suramin abrogates S1P-stimulated Smad phosphorylation. In
      summary, our data show that S1P trans-activates the TGF-beta receptor and
      triggers activation of Smads followed by activation of connective tissue growth
      factor gene transcription and inhibition of IL-1beta-induced expression of iNOS,
      sPLA(2), and MMP-9.

PMID- 15192101
TI  - Cathepsin V, a novel and potent elastolytic activity expressed in activated
      macrophages.
AB  - Atherosclerosis is characterized by a thickening and loss of elasticity of the
      arterial wall. Loss of elasticity has been attributed to the degradation of the
      arterial elastin matrix. Cathepsins K and S are papain-like cysteine proteases
      with known elastolytic activities, and both enzymes have been identified in
      macrophages present in plaque areas of diseased blood vessels. Here we
      demonstrate that macrophages express a third elastolytic cysteine protease,
      cathepsin V, which exhibits the most potent elastase activity yet described among
      human proteases and that cathepsin V is present in atherosclerotic plaque
      specimens. Approximately 60% of the total elastolytic activity of macrophages can
      be attributed to cysteine proteases with cathepsins V, K, and S contributing
      equally. From this 60%, two-thirds occur extracellularly and one-third
      intracellularly with the latter credited to cathepsin V. Ubiquitously expressed
      glycosaminoglycans (GAGs) such as chondroitin sulfate specifically inhibit the
      elastolytic activities of cathepsins V and K via the formation of specific
      cathepsin-GAG complexes. In contrast, cathepsin S, which does not form complexes
      with chondroitin sulfate is not inhibited; thus suggesting a specific regulation
      of elastolytic activities of cathepsins by GAGs. Because the GAG content is
      reduced in atherosclerotic plaques, an increase of cathepsins V and K activities
      may accelerate the destruction of the elastin matrix in diseased arteries.

PMID- 15192104
TI  - Functional characterization of the Saccharomyces cerevisiae VHS3 gene: a
      regulatory subunit of the Ppz1 protein phosphatase with novel, phosphatase
      unrelated functions.
AB  - The yeast gene VHS3 (YOR054c) has been recently identified as a multicopy
      suppressor of the G(1)/S cell cycle blockade of a conditional sit4 and hal3
      mutant. Vhs3 is structurally related to Hal3, a negative regulatory subunit of
      the Ser/Thr protein phosphatase Ppz1 important for cell integrity, salt
      tolerance, and cell cycle control. Phenotypic analyses using vhs3 mutants and
      overexpressing strains clearly show that Vhs3 has functions reminiscent to those
      of Hal3 and contrary to those of Ppz1. Mutation of Vhs3 His(459), equivalent to
      the supposedly functionally relevant His(90) in the plant homolog AtHal3a, did
      not affect Vhs3 functions mentioned above. Similarly to Hal3, Vhs3 binds in vivo
      to the C-terminal catalytic moiety of Ppz1 and inhibits in vitro its phosphatase
      activity. Therefore, our results indicate that Vhs3 plays a role as an inhibitory
      subunit of Ppz1. We have found that the vhs3 and hal3 mutations are synthetically
      lethal. Remarkably, lethality is not suppressed by deletion of PPZ1, PPZ2, or
      both phosphatase genes, indicating that it is not because of an excess of Ppz
      phosphatase activity. Furthermore, a Vhs3 version carrying the H459A mutation did
      not rescue the synthetically lethal phenotype. A conditional vhs3 tetO:HAL3
      double mutant displays, in the presence of doxycycline, a flocculation phenotype
      that is dependent on the presence of Flo8 and Flo11. These results indicate that,
      besides its role as Ppz1 inhibitory subunit, Vhs3 (and probably Hal3) might have
      important Ppz-independent functions.

PMID- 15192105
TI  - Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G
      protein-coupled form of the receptor and sequesters G protein.
AB  - Accurate characterization of the molecular mechanisms of the action of ligands is
      an extremely important issue for their appropriate research, pharmacological, and
      therapeutic uses. In view of this fact, the aim of the present work was to
      investigate the mechanisms involved in the actions of mepyramine at the guinea
      pig H(1) receptor stably expressed in Chinese hamster ovary cells. We found that
      mepyramine is able to decrease the basal constitutive activity of the guinea pig
      H(1) receptor, to bind with high affinity to a G(q/11) protein-coupled form of
      the receptor and to promote a G protein-coupled inactive state of the H(1)
      receptor that interferes with the G(q/11)-mediated signaling of the endogenously
      expressed ATP receptor, as predicted by the Cubic Ternary Complex Model of
      receptor occupancy. The effect of mepyramine on ATP-induced signaling was
      specifically neutralized by Galpha(11) overexpression, indicating that mepyramine
      is able to reduce G protein availability for other non-related receptors
      associated with the same signaling pathway. Finally, we found a loss of
      mepyramine efficacy in decreasing basal levels of intracellular calcium at high
      Galpha(11) expression levels, which can be theoretically explained in terms of
      high H(1) receptor constitutive activity. The whole of the present work sheds new
      light on H(1) receptor pharmacology and the mechanisms H(1) receptor inverse
      agonists could use to exert their observed negative efficacy.

PMID- 15192106
TI  - Mycobacterium tuberculosis antigen 85A and 85C structures confirm binding
      orientation and conserved substrate specificity.
AB  - The maintenance of the highly hydrophobic cell wall is central to the survival of
      Mycobacterium tuberculosis within its host environment. The antigen 85 proteins
      (85A, 85B, and 85C) of M. tuberculosis help maintain the integrity of the cell
      wall 1) by catalyzing the transfer of mycolic acids to the cell wall
      arabinogalactan and 2) through the synthesis of trehalose dimycolate (cord
      factor). Additionally, these secreted proteins allow for rapid invasion of
      alveolar macrophages via direct interactions between the host immune system and
      the invading bacillus. Here we describe two crystal structures: the structure of
      antigen 85C co-crystallized with octylthioglucoside as substrate, resolved to 2.0
      A, and the crystal structure of antigen 85A, which was solved at a resolution of
      2.7 A. The structure of 85C with the substrate analog identifies residues
      directly involved in substrate binding. Elucidation of the antigen 85A structure,
      the last of the three antigen 85 homologs to be solved, shows that the active
      sites of the three antigen 85 proteins are virtually identical, indicating that
      these share the same substrate. However, in contrast to the high level of
      conservation within the substrate-binding site and the active site, surface
      residues disparate from the active site are quite variable, indicating that three
      antigen 85 enzymes are needed to evade the host immune system.

PMID- 15192107
TI  - Identification of a novel endocytic recycling signal in the D1 dopamine receptor.
AB  - A critical event determining the functional consequences of G protein-coupled
      receptor (GPCR) endocytosis is the molecular sorting of internalized receptors
      between divergent recycling and degradative membrane pathways. The D1 dopamine
      receptor recycles rapidly and efficiently to the plasma membrane after agonist
      induced endocytosis and is remarkably resistant to proteolytic down-regulation.
      Whereas the mechanism mediating agonist-induced endocytosis of D1 receptors has
      been investigated in some detail, little is known about how receptors are sorted
      after endocytosis. We have identified a sequence present in the carboxyl-terminal
      cytoplasmic domain of the human D1 dopamine receptor that is specifically
      required for the efficient recycling of endocytosed receptors back to the plasma
      membrane. This sequence is distinct from previously identified membrane
      trafficking signals and is located in a proximal portion of the carboxyl-terminal
      cytoplasmic domain, in contrast to previously identified GPCR recycling signals
      present at the distal tip. Nevertheless, fusion of this sequence to the carboxyl
      terminus of a chimeric mutant delta opioid neuropeptide receptor is sufficient to
      re-route internalized receptors from lysosomal to recycling membrane pathways,
      defining this sequence as a bona fide endocytic recycling signal that can
      function in both proximal and distal locations. These results identify a novel
      sorting signal controlling the endocytic trafficking itinerary of a
      physiologically important dopamine receptor, provide the first example of such a
      sorting signal functioning in a proximal portion of the carboxyl-terminal
      cytoplasmic domain, and suggest the existence of a diverse array of sorting
      signals in the GPCR superfamily that mediate subtype-specific regulation of
      receptors via endocytic membrane trafficking.

PMID- 15192108
TI  - Specific residues in plasmatocyte-spreading peptide are required for receptor
      binding and functional antagonism of insect immune cells.
AB  - Plasmatocyte-spreading peptide (PSP) is a 23-amino acid cytokine that activates a
      class of insect immune cells called plasmatocytes. PSP consists of two regions:
      an unstructured N terminus (1-6) and a highly structured core (7-23). Prior
      studies identified specific residues in both the structured and unstructured
      regions required for biological activity. Most important for function were Arg13,
      Phe3, Cys7, Cys19, and the N-terminal amine of Glu1. Here we have built on these
      results by conducting cell binding and functional antagonism studies. Alanine
      replacement of Met12 (M12A) resulted in a peptide with biological activity
      indistinguishable from PSP. Competitive binding experiments using unlabeled and
      125I-M12A generated an IC50 of 0.71 nm and indicated that unlabeled M12A, at
      concentrations > or =100 nm, completely blocked binding of label to hemocytes. We
      then tested the ability of other peptide mutants to displace 125I-M12A at a
      concentration of 100 nm. In the structured core, we found that Cys7 and Cys19
      were essential for cell binding and functional antagonism, but these effects were
      likely because of the importance of these residues for maintaining the tertiary
      structure of PSP. Arg13, in contrast, was also essential for binding and activity
      but is not required for maintenance of structure. In the unstructured N-terminal
      region, deletion of the phenyl group from Phe3 yielded a peptide that reduced
      binding of 125I-M12A 326-fold. This and all other mutants of Phe3 we bioassayed
      were unable to antagonize PSP. Deletion of Glu1 in contrast had almost no effect
      on binding and was a strong functional antagonist. Experiments using a
      photoaffinity analog indicated that PSP binds to a single 190-kDa protein.

PMID- 15192109
TI  - An important functional role of the N terminus domain of type VI adenylyl cyclase
      in Galphai-mediated inhibition.
AB  - We show herein that removal of the first 86 amino acids (aa) of the N terminus
      (designated N) of type VI adenylyl cyclase (ACVI) caused the resultant ACVI
      mutant (ACVI-DeltaA87) to be more greatly inhibited by a Galpha(i)-coupled
      receptor or activated Galpha(i) protein. Moreover, in vitro binding of the full
      length N and C1a domain (designated C1a), which interacts with Galpha(i), was
      detected. A truncated N terminus (aa 1-86) also interacted with C1a, suggesting
      that the C1a-interacting region is located within aa 1-86. Mutation analyses
      further revealed that N might interact with C1a in the region (aa 434-505) where
      Galpha(i) is bound. Mutations of two residues (Leu-472 and Val-476) located in
      this N-binding region of C1a suppressed the interaction between recombinant N and
      C1a and markedly reduced Galpha(i)-mediated inhibition of ACVI-DeltaA87. Further
      biochemical analyses of the effect of internal mutations of Leu-472/Val-476 on
      Galpha(i)-mediated inhibition of wild-type ACVI and ACVI-DeltaA87 suggested that
      N modulates the Galpha(i)-mediated inhibition of ACVI via binding to C1a when the
      level of Galpha(i) is low (i.e. around the IC(50) value) and that a more
      complicated interfering mode results when the level of Galpha(i) is high (i.e.
      approximately 10- to 20-fold of the IC(50) value). Collectively, data presented
      herein suggest a novel function of the N terminus of ACVI in Galpha(i)-mediated
      regulation.

PMID- 15192110
TI  - Involvement of the late secretory pathway in actin regulation and mRNA transport
      in yeast.
AB  - Both the delivery of secretory vesicles and asymmetric distribution of mRNA to
      the bud are dependent upon the actin cytoskeleton in yeast. Here we examined
      whether components of the exocytic apparatus play a role in mRNA transport. By
      screening secretion mutants in situ and in vivo, we found that all had an altered
      pattern of ASH1 mRNA localization. These included alleles of CDC42 and RHO3
      (cdc42-6 and rho3-V51) thought to regulate specifically the fusion of secretory
      vesicles but were found to affect strongly the cytoskeleton as well. Most
      interestingly, mutations in late secretion-related genes not directly involved in
      actin regulation also showed substantial alterations in ASH1 mRNA distribution.
      These included mutations in genes encoding components of the exocyst (SEC10 and
      SEC15), SNARE regulatory proteins (SEC1, SEC4, and SRO7), SNAREs (SEC9 and
      SSO1/2), and proteins involved in Golgi export (PIK1 and YPT31/32). Importantly,
      prominent defects in the actin cytoskeleton were observed in all of these
      strains, thus implicating a known causal relationship between the deregulation of
      actin and the inhibition of mRNA transport. Our novel observations suggest that
      vesicular transport regulates the actin cytoskeleton in yeast (and not just vice
      versa) leading to subsequent defects in mRNA transport and localization.

PMID- 15192111
TI  - Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1
      receptor signaling induced 3T3-L1 adipocyte differentiation.
AB  - During 3T3-L1 preadipocyte differentiation induction, the insulin-stimulated
      insulin-like growth factor-1 (IGF-1) receptor signal is responsible for the
      induction of adipocyte differentiation. Treatment with inhibitors of
      phosphatidylinositol 3-kinase, LY294002 or wortmannin, leads to the complete
      blockade of adipocyte differentiation in 3T3-L1 preadipocytes. Of the three
      factors (1-methyl-3-isobutylxanthine, dexamethasone, and insulin) inducing 3T3-L1
      preadipocyte differentiation, only insulin was able to activate the
      phosphatidylinositol 3-kinase-protein kinase B/Akt signal cascade. In 3T3-L1
      preadipocytes, protein kinase B/Akt 1 RNA interference not only suppressed the
      expression of protein kinase B/Akt 1 but also blocked hormone-induced adipocyte
      differentiation. In these protein kinase B/Akt 1 RNA interference cells, the
      signal molecules upstream of protein kinase B/Akt 1, such as IGF-1 receptor and
      insulin receptor substrate-1, were normally activated by insulin stimulation,
      whereas insulin-stimulated phosphorylation of forkhead transcription factor
      (FKHR), which is a downstream molecule of PKB/Akt 1, was blocked. Thus, protein
      kinase B/Akt 1 is an important signal mediator in IGF-1 receptor signal cascade
      for inducing adipocyte differentiation.

PMID- 15192112
TI  - Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated
      protein kinases in different forms of apoptotic neuronal death.
AB  - The stress-activated protein kinases c-Jun-activated kinase (JNK) and p38 are
      implicated in neuronal apoptosis. Early studies in cell lines suggested a
      requirement for both in the apoptosis induced by withdrawal of nerve growth
      factor. However, studies in neuronal cells typically implicate JNK but not p38 in
      apoptosis. In some cases, p38 is implicated, but the role of JNK is undefined. It
      remains unclear whether p38 and JNK have differing roles dependent on cell type,
      apoptotic stimulus, or mechanism of cell death or whether they are redundant and
      each sufficient to induce identical forms of cell death. We investigate the
      relative roles of these protein kinases in different death mechanisms in a single
      system, cultured cerebellar granule neurons. Apoptosis induced by withdrawal of
      trophic support and glutamate are mechanistically different in terms of caspase
      activation, DNA fragmentation profile, chromatin morphology, and dependence on de
      novo gene expression. Caspase-independent apoptosis induced by glutamate is
      accompanied by strong activation of p38, and dominant negatives and inhibitors of
      the p38 pathway prevent this apoptosis. In contrast, withdrawal of trophic
      support induces caspase-dependent death accompanied by JNK-dependent
      phosphorylation of c-Jun, and inhibition of JNK is sufficient to prevent the
      death induced by withdrawal of trophic support. Inhibition of p38 does not block
      withdrawal of trophic support-induced death, nor does inhibition of JNK block
      glutamate-induced death. We propose that mechanistically different forms of
      apoptosis have differing requirements for p38 and JNK activities in neurons and
      demonstrate that only inhibition of the appropriate kinase will prevent neurons
      from undergoing apoptosis.

PMID- 15192113
TI  - ADAMTS7B, the full-length product of the ADAMTS7 gene, is a chondroitin sulfate
      proteoglycan containing a mucin domain.
AB  - We have characterized ADAMTS7B, the authentic full-length protein product of the
      ADAMTS7 gene. ADAMTS7B has a domain organization similar to that of ADAMTS12,
      with a total of eight thrombospondin type 1 repeats in its ancillary domain. Of
      these, seven are arranged in two distinct clusters that are separated by a mucin
      domain. Unique to the ADAMTS family, ADAMTS7B is modified by attachment of the
      glycosaminoglycan chondroitin sulfate within the mucin domain, thus rendering it
      a proteoglycan. Glycosaminoglycan addition has potentially important implications
      for ADAMTS7B cellular localization and for substrate recognition. Although not an
      integral membrane protein, ADAMTS7B is retained near the cell surface of HEK293F
      cells via interactions involving both the ancillary domain and the prodomain.
      ADAMTS7B undergoes removal of the prodomain by a multistep furin-dependent
      mechanism. At least part of the final processing event, i.e. cleavage following
      Arg(220) (mouse sequence annotation), occurs at the cell surface. ADAMTS7B is an
      active metalloproteinase as shown by its ability to cleave alpha(2)
      macroglobulin, but it does not cleave specific peptide bonds in versican and
      aggrecan attacked by ADAMTS proteases. Together with ADAMTS12, whose primary
      structure also predicts a mucin domain, ADAMTS7B constitutes a unique subgroup of
      the ADAMTS family.

PMID- 15192114
TI  - Positive role of the mammalian TBPIP/HOP2 protein in DMC1-mediated homologous
      pairing.
AB  - In meiosis, homologous recombination preferentially occurs between homologous
      chromosomes rather than between sister chromatids, which is opposite to the bias
      of mitotic recombinational repair. The TBPIP/HOP2 protein is a factor that
      ensures the proper pairing of homologous chromosomes during meiosis. In the
      present study, we found that the purified mouse TBPIP/HOP2 protein stimulated
      homologous pairing catalyzed by the meiotic DMC1 recombinase in vitro. In
      contrast, TBPIP/HOP2 did not stimulate homologous pairing by RAD51, which is
      another homologous pairing protein acting in both meiotic and mitotic
      recombination. The positive effect of TBPIP/HOP2 in the DMC1-mediated homologous
      pairing was only observed when TBPIP/HOP2 first binds to double-stranded DNA, not
      to single-stranded DNA, before the initiation of the homologous pairing reaction.
      Deletion analyses revealed that the C-terminal basic region of TBPIP/HOP2 is
      required for efficient DNA binding and is also essential for its homologous
      pairing stimulation activity. Therefore, these results suggest that TBPIP/HOP2
      directly binds to DNA and functions as an activator for DMC1 during the
      homologous pairing step in meiosis.

PMID- 15192115
TI  - pH microdomains in oligodendrocytes.
AB  - Oligodendrocytes (OLs) are cells that produce myelin in the central nervous
      system. Here we use ratiometric pH indicator dye to analyze intracellular pH in
      OLs in culture. The results reveal alkaline microdomains, which predominate in
      the perikaryon and proximal dendrites, and acidic microdomains, which predominate
      in distal dendrites. Spatial nonuniformity of pH is generated by differential
      subcellular distribution of Na(+)/H(+) exchanger (NHE), which is localized in a
      punctate distribution in the perikaryon and proximal processes, Na(+)/HCO(3)(-)
      cotransporter (NBC), which is localized in a punctate distribution in distal
      dendrites, and carbonic anhydrase isotype II (CAII), which is colocalized with
      either NHE or NBC. Inhibition of NHE activity by amiloride inhibits regeneration
      of alkaline microdomains after cytoplasmic acidification, whereas the inhibition
      of CAII activity with ethoxyzolamide inhibits acidification of dendrites.
      Fluorescence correlation spectroscopy analysis of CAII microinjected into OLs
      reveals freely diffusing protein throughout the cell as well as protein
      associated predominantly with NHE in the perikaryon and predominantly with NBC in
      the dendrites. Alkaline and acidic microdomains could be generated by transport
      metabolons consisting of CAII associated with NHE or NBC, respectively. This
      study provides the first evidence for pH microdomains in cells and describes a
      mechanism for how they are generated.

PMID- 15192116
TI  - Evidence for multiple pathways in the assembly of the Escherichia coli maltose
      transport complex.
AB  - We used the maltose transport complex MalFGK2 of the Escherichia coli cytoplasmic
      membrane as a model for the study of the assembly of hetero-oligomeric membrane
      protein complexes. Analysis of other membrane protein complexes has led to a
      general model in which a unique, ordered pathway is followed from subunit
      monomers to a final oligomeric structure. In contrast, the studies reported here
      point to a fundamentally different mode for assembly of this transporter. Using
      co-immunoprecipitation and quantification of interacting partners, we found that
      all subunits of the maltose transport complex efficiently form heteromeric
      complexes in vivo. The pairwise complexes were stable over time, suggesting that
      they all represent assembly intermediates for the final MalFGK2 transporter.
      These results indicate that several paths can lead to assembly of this oligomer.
      We also characterized MalF and MalG mutants that caused reduced association
      between some or all of the subunits of the complex with this assay. The mutant
      analysis highlights some important motifs for subunit contacts and suggests that
      the promiscuous interactions between these Mal proteins contribute to the
      efficiency of complex assembly. The behaviors of the wild type and mutant
      proteins in the co-immunoprecipitations support a model of multiple assembly
      pathways for this complex.

PMID- 15192117
TI  - KpnI restriction endonuclease and methyltransferase exhibit contrasting mode of
      sequence recognition.
AB  - The molecular basis of the interaction of KpnI restriction endonuclease (REase)
      and the corresponding methyltransferase (MTase) at their cognate recognition
      sequence is investigated using a range of footprinting techniques. DNase I
      protection analysis with the REase reveals the protection of a 14-18 bp region
      encompassing the hexanucleotide recognition sequence. The MTase, in contrast,
      protects a larger region. KpnI REase contacts two adjacent guanine residues and
      the single adenine residue in both the strands within the recognition sequence 5'
      GGTACC-3', inferred by dimethylsulfate (DMS) protection, interference and missing
      nucleotide interference analysis. In contrast, KpnI MTase does not show elaborate
      base-specific contacts. Ethylation interference analysis also showed the
      differential interaction of REase and MTase with phosphate groups of three
      adjacent bases on both strands within the recognition sequence. The single
      thymine residue within the sequence is hyper- reactive to the permanganate
      oxidation, consistent with MTase-induced base flipping. The REase on the other
      hand does not show any major DNA distortion. The results demonstrate that the
      differences in the molecular interaction pattern of the two proteins at the same
      recognition sequence reflect the contrasting chemistry of DNA cleavage and
      methylation catalyzed by these two dissimilar enzymes, working in combination as
      constituents of a cellular defense strategy.

PMID- 15192121
TI  - Nucleosomes bind fibroblast growth factor-2 for increased angiogenesis in vitro
      and in vivo.
AB  - Solid tumors often display sites of necrosis near regions of angiogenesis in
      vivo. As tumor cell necrosis would result in the release of nucleosomes into the
      extracellular environment, we explored the potential role of nucleosomes in the
      promotion of angiogenesis. Data indicate that nucleosomes acted similar to
      heparin and bound to several heparin-binding, proangiogenic factors [i.e.,
      fibroblast growth factor (FGF)-1, FGF-2, vascular endothelial growth factor, and
      transforming growth factor-beta1]. Nucleosomes modestly enhanced FGF-2 growth of
      human umbilical vein endothelial cells when grown in restricted media as well as
      increased human umbilical vein endothelial cell migration and primitive blood
      vessel tube formation in vitro. On s.c. injection in mice, nucleosomes aided FGF
      2 in promoting angiogenesis. These results suggest that nucleosomes released from
      dying tumor cells aid in the formation of blood vessels and may provide a novel
      means by which tumor cells increase angiogenesis.

PMID- 15192120
TI  - Human tissue kallikreins: physiologic roles and applications in cancer.
AB  - Tissue kallikreins are members of the S1 family (clan SA) of trypsin-like serine
      proteases and are present in at least six mammalian orders. In humans, tissue
      kallikreins (hK) are encoded by 15 structurally similar, steroid hormone
      regulated genes (KLK) that colocalize to chromosome 19q13.4, representing the
      largest cluster of contiguous protease genes in the entire genome. hKs are widely
      expressed in diverse tissues and implicated in a range of normal physiologic
      functions from the regulation of blood pressure and electrolyte balance to tissue
      remodeling, prohormone processing, neural plasticity, and skin desquamation.
      Several lines of evidence suggest that hKs may be involved in cascade reactions
      and that cross-talk may exist with proteases of other catalytic classes. The
      proteolytic activity of hKs is regulated in several ways including zymogen
      activation, endogenous inhibitors, such as serpins, and via internal
      (auto)cleavage leading to inactivation. Dysregulated hK expression is associated
      with multiple diseases, primarily cancer. As a consequence, many kallikreins, in
      addition to hK3/PSA, have been identified as promising diagnostic and/or
      prognostic biomarkers for several cancer types, including ovarian, breast, and
      prostate. Recent data also suggest that hKs may be causally involved in
      carcinogenesis, particularly in tumor metastasis and invasion, and, thus, may
      represent attractive drug targets to consider for therapeutic intervention.

PMID- 15192122
TI  - Detecting cervical cancer by quantitative promoter hypermethylation assay on
      cervical scrapings: a feasibility study.
AB  - Current morphology-based cervical cancer screening is associated with significant
      false-positive and false-negative results. Tumor suppressor gene hypermethylation
      is frequently present in cervical cancer. It is unknown whether a cervical
      scraping reflects the methylation status of the underlying epithelium, and it is
      therefore unclear whether quantitative hypermethylation specific PCR (QMSP) on
      cervical scrapings could be used as a future screening method augmenting the
      current approach. Cervical scrapings and paired fresh frozen cervical tissue
      samples were obtained from 53 cervical cancer patients and 45 controls. All
      scrapings were morphologically scored and analyzed with QMSP for the genes APC,
      DAPK, MGMT, and GSTP1. To adjust for DNA input, hypermethylation ratios were
      calculated against DNA levels of a reference gene. Hypermethylation ratios of
      paired fresh frozen tissue samples and scrapings of cervical cancer patients and
      controls were strongly related (Spearman correlation coefficient, 0.80 for APC,
      0.98 for DAPK, and 0.83 for MGMT; P < 0.001). More cervical cancer patients than
      controls were DAPK positive (P < 0.001). When cutoff levels for ratios were
      defined to be above the highest ratio observed in controls, QMSP in cervical
      scrapings identified 32 (67%) of 48 cervical cancer patients. This feasibility
      study demonstrates that QMSP on cervical scrapings holds promise as a new
      diagnostic tool for cervical cancer. The addition of more genes specifically
      methylated in cervical cancer will further improve the assay.

PMID- 15192124
TI  - HMG-I/Y is a c-Jun/activator protein-1 target gene and is necessary for c-Jun
      induced anchorage-independent growth in Rat1a cells.
AB  - The transcription complex activator protein-1 (AP-1) plays a role in a diverse
      number of cellular processes including proliferation, differentiation, and
      apoptosis. To identify AP-1-responsive target genes, we used a doxycycline
      inducible c-Jun system in Rat1a cells. The HMG-I/Y chromatin binding protein was
      found to be up-regulated by c-Jun. Following induction of c-Jun expression, Rat1a
      cells under nonadherent growth conditions have sustained HMG-I/Y mRNA expression
      and 2-fold higher protein than uninduced cells. HMG-I/Y promoter reporter assays
      show that HMG-I/Y promoter activity increases in the presence of c-Jun
      expression, and gel mobility shift assays demonstrate that induced c-Jun binds to
      an AP-1 consensus site at position -1,091 in the HMG-I/Y promoter. Suppression of
      HMG-I/Y expression by its antisense sequence significantly reduces the ability of
      c-Jun-overexpressing Rat1a cells to grow in an anchorage-independent fashion. HMG
      I/Y transforms Rat1a cells (although the colonies are smaller than that observed
      for the cells overexpressing c-Jun). Taken together, these results suggest that
      HMG-I/Y is a direct transcriptional target of c-Jun necessary for c-Jun-induced
      anchorage-independent growth in Rat1a cells.

PMID- 15192123
TI  - Constitutive and DNA damage inducible activation of pig3 and MDM2 genes by tumor
      derived p53 mutant C277Y.
AB  - The p53 gene is compromised in most human cancers by point mutation. Evidence is
      accumulating that these alterations frequently do not result in a complete loss
      of the sequence-specific transcriptional regulatory function of p53. Here, we
      describe the transcriptional activity of the p53 mutant C277Y isolated from a
      Ewing's sarcoma with high constitutive pig3 expression. Transient transfection of
      this mutant into a p53 null cell line resulted in activation not only of the pig3
      but also of the MDM2 gene compatible with the presence of constitutively
      expressed MDM2 transcripts initiated from the P2 promoter in the p53-C277Y
      hemizygous Ewing's sarcoma cell line. Expression of endogenous pig3 and MDM2
      genes was further enhanced on irradiation of this cell line. Here, suppression of
      p53-C277Y by RNAi reduced pig3 promoter activity, RNA, and protein expression.
      Reporter gene assays revealed that the potential of p53-C277Y to up-regulate MDM2
      expression was similar to wild-type p53, whereas activation of the pig3 promoter
      was at least 5-fold increased over wild-type p53. The pentanucleotide
      microsatellite sequence present in exon 1 of the pig3 gene was found to be
      responsible for p53-C277Y-mediated activation. In concordance with a role of PIG3
      protein for cell death, we showed residual apoptotic activity of p53-C277Y to
      which the described Ewing's sarcoma cell line was found to be resistant. p53
      C277Y has previously been reported to bind to DNA with altered sequence
      specificity and to be unable to activate generic p53 target genes in yeast-based
      functional assays. Our results, therefore, show that a p53 mutant may behave
      differently when tested in its authentic cellular context.

PMID- 15192126
TI  - Application of dialysis and transplant registries to clinical practice: the
      Lombardy Registry.
AB  - BACKGROUND: Data collected from registries provide a useful source of information
      for clinical practice. Therefore, several regional and national registries of end
      stage renal disease (ESRD) patients have been established. The Lombardy Registry
      of Dialysis and Transplantation (RLDT) was established in 1982, with
      participation of all 44 dialysis units that were present at that time within the
      region. METHODS: Demographic and clinical data on ESRD patients are collected
      yearly. We present here the results of some of the analyses that have been
      performed on RLDT data since it was started. RESULTS: Briefly, data on
      epidemiology of ESRD, cardiovascular disease, patterns of care and patients'
      outcomes have been considered. Comparisons with international registries have
      also been performed. CONCLUSIONS: This analysis shows how data collected from a
      homogeneous patient population receiving similar patterns of care provide precise
      information on that population. A clear example is provided by the similar
      results obtained in the comparison of high-flux vs low-flux membranes in a
      randomized control trial, the HEMO study, and in an analysis of RLDT data.
      Therefore, analysis of data collected by registries represents an important tool
      to improve clinical practice and possibly patients' outcomes.

PMID- 15192127
TI  - Introduction: last decade's important changes in renal transplantation.

PMID- 15192128
TI  - Causes of death and mortality risk factors.
AB  - BACKGROUND: Patient death continues to be a leading cause of renal transplant
      failure. This mortality is mainly due to cardiovascular, infectious and tumoural
      diseases. The aim of our study was to analyse the evolution of the mortality and
      its causes after renal transplantation (RT). METHODS: We studied 3365 adult renal
      transplant recipients, surviving at least 1 year, and transplanted in Spain in
      the years 1990, 1994 and 1998. Risk factors for all-cause and specific-cause
      mortality were analysed employing simple and multivariate Cox regression.
      RESULTS: 300 patients (8.9%) died after the first post-transplantation year. The
      follow-up was shorter (maximum 2.5 years) in recipients transplanted in 1998.
      When we consider an identical follow-up (2.5 years) for all patients, we did not
      find statistical differences in mortality rates or its causes, in the three
      analysed periods. Cardiovascular diseases (CVDs) and neoplasia were the most
      frequent causes of death. Mortality was higher for males and patients > 60 years.
      Renal function, evaluated by creatinine level or proteinuria range at 3 months
      and its increase in the first year post-transplantation were significant factors
      associated with high risk for cardiovascular and infectious death. CONCLUSIONS:
      During the last decade, in Spain, the mortality after RT (2.5 years follow-up)
      remains stable. Recipient age (> 60 years), male gender and renal function in the
      first year were associated with higher risk of death, especially for CVD.

PMID- 15192129
TI  - The impact of donor age on the results of renal transplantation.
AB  - BACKGROUND: The use of elderly donors is becoming more frequent. An increase in
      the donor's age is associated with a greater incidence of delayed graft function
      (DGF), chronic allograft nephropathy (CAN) and worse graft survival. Poor renal
      graft function is a risk factor for cardiovascular (CV) complications and,
      finally, for mortality of the patients. METHODS: A total of 3365 adult patients
      transplanted in 1990 (n = 824), 1994 (n = 1075) and 1998 (n = 1466) with a
      functioning graft after the first year were included. The impact of donor age on
      renal function, DGF, acute rejection and other clinical factors was evaluated
      according to two donor and recipient age categories: young (< 60 years old) and
      elderly (> or =60 years old). Additionally, donor age was categorized by decades
      for the analysis of patient and graft survival, acute rejection and CV mortality.
      RESULTS: Donor mean age significantly increased during the three transplantation
      periods. A total of 478 out of 3365 donors were older than 60 years. Elderly
      donors showed an increased risk of DGF (38.9 vs 28.8%) and CAN (56.8 vs 46.2%).
      Mean serum creatinine at 3 and 12 months and proteinuria were significantly
      higher in the old donor group. Incidence and severity of acute rejection were
      similar in both groups. Graft and patient survival were significantly lower in
      the old donor group. Also, risk of mortality due to CV events was also
      significantly higher. A linear increase in risk of graft loss, patient death or
      CV mortality was observed when donor age was divided into 10 year increase
      subsets. CONCLUSIONS: Donor age is a strong predictor of CAN and graft loss.
      Patient survival is also affected by donor age, particularly by a higher risk of
      CV mortality.

PMID- 15192130
TI  - Recipient age as a determinant factor of patient and graft survival.
AB  - BACKGROUND: Age of renal transplants has been related to death, alloimmune
      response and graft outcome. We reviewed the influence of patient age on
      transplant outcome in three cohorts of patients transplanted in Spain during the
      1990 s. METHODS: Patient age was categorized into four groups (I, 18-40; II, 41
      50; III, 51-60; and IV, > 60 years). Risks factors for acute rejection were
      evaluated by logistic regression adjusting for transplant centre and
      transplantation year, while a Cox proportional hazard model was employed for
      analysing patient and graft survival. RESULTS: Older patients had a higher death
      rate (I, 3.5%; II, 7.7%; III, 13.2%; and IV, 16.9%; P<0.001), but a lower
      standardized mortality index (I, 7.6; II, 7.0; III, 5.8; and IV, 4.1; P =
      0.0019). Older patients had the lowest risk of acute rejection [odds ratio (OR)
      0.79 and 95% confidence interval (CI) 0.66-0.97 for group II; OR 0.75 and 95% CI
      0.62-0.91 for group III; OR 0.43 and 95% CI 0.33-0.56 for group IV). Death
      censored graft survival was poorer in patients older than 60 years (relative risk
      1.40; 95% CI 1.09-1.80), but this result was not explained by any combination of
      patient age with donor age, delayed graft function or immunosuppression.
      CONCLUSIONS: Patient age is a main determinant of transplant outcome. Although
      death rate is higher for older patients, standardized mortality was not. Thus,
      the efforts to reduce mortality should be also implemented in younger patients.
      Old patients have a low risk of acute rejection but a poorer death-censored graft
      survival. This last result was not explained by any controlled variable in our
      study.

PMID- 15192131
TI  - A disproportionately greater body weight of the recipient in regards to the donor
      causes chronic graft nephropathy. A study of paired kidneys.
AB  - BACKGROUND: Chronic graft nephropathy is the most frequent cause of long-term
      renal transplant loss. Although immunological causes participate in its
      pathogenesis, other non-immunological factors such as hyperfiltration due to
      reduced renal mass have been proposed as causal factors of chronic renal graft
      nephropathy. AIM: This study aimed to assess the effect of weight disproportion
      between the donor and recipient in the development of chronic renal graft
      nephropathy. METHODS: Three weight categories for donors and recipients were
      established: < 50, 50-75 and > 75 kg. Three groups were distinguished according
      to the three possible weight combinations between donor and recipient: donor
      weight (DW)>recipient weight (RW) (N = 133), DW = RW (N = 255) and DW<RW (N =
      80). For the study of paired kidneys from the same donor, a multiple Cox
      regression model was applied to observe the influence of the weight differences
      between donor and recipient and other variables on the long-term graft and
      patient survival, and on the level of serum creatinine, proteinuria and arterial
      hypertension at 3 months after transplantation. RESULTS: Graft survival at 10
      years was significantly lower in the DW<RW group vs the DW = RW and DW>RW groups.
      In addition, the DW<RW group developed higher proteinuria even by 3 months of
      evolution. Donor and recipient age, acute rejection and type of immunosuppressive
      treatment were also independent risk factors to develop chronic nephropathy in
      this study of paired kidneys. CONCLUSIONS: Weight disproportion between donor and
      recipient, unfavourable to the recipient, is a risk factor for the development of
      chronic graft nephropathy. Matching the body weights between the donor and
      recipient is obligatory to prevent chronic rejection.

PMID- 15192132
TI  - Non-heart beating donors.
AB  - BACKGROUND: Several groups have demonstrated that non-heart beating donation is a
      viable source of organs for transplantation. However, the theoretically worse
      graft function and survival of the kidneys obtained from non-heart beating donors
      (NHBDs) is still a matter of debate that has led to consider them as marginal
      donors for kidney transplantation. METHODS: In this report, we compare the
      outcome and course of 83 kidney transplants from NHBDs with those corresponding
      to 3177 adult cadaveric heart beating donor (HBD) transplants performed over the
      same period in our country. Graft and patient survival were estimated by means of
      Kaplan-Meier analysis. In addition, groups were compared using Cox proportional
      regression. RESULTS: The delayed graft function (DGF) rate was higher on NHBD
      transplants than in HBD kidneys (58.8 vs 28.9%, P<0.0001). However, in 1998,
      where the highest number of NHBD transplants was performed, graft function
      estimated by serum creatinine levels at 3 months and 1 year, was significantly
      better in the NHBD transplant group (1.42+/-0.45 vs 1.66+/-0.66 and 1.45+/-0.59
      vs 1.62+/-0.64, respectively, P = 0.01 and 0.07). Graft survival at 2 years was
      97%, 95% at 4 years and 84% at 6 years for NHBDs and 97, 90 and 84%,
      respectively, for HBDs. Interestingly, DGF was a risk factor for worse graft
      survival in HBDs but not on NHBDs. CONCLUSIONS: We conclude that, in our study,
      both graft function and graft survival of NHBD kidney transplants are at least
      similar to those from HBD transplants. Therefore, NHBDs should be considered as a
      viable source of non-marginal kidneys for transplant.

PMID- 15192133
TI  - The influence of delayed graft function.
AB  - We study the incidence of delayed graft function (DGF) in a group of 3365 renal
      transplant recipient patients from various Spanish centres, its clinical
      consequences, and the evolution in time (transplants performed in 1990, 1994 and
      1998) of the factors that determine its presence. The incidence of DGF remained
      constant in the 3 years studied (30.4, 30.8 and 29.2%, respectively) when
      contrasting the following factors involved in the establishment of DGF were
      studied: body mass of recipient, donor age, non-heart beating donation, type of
      replacement treatment in the pre-transplant period, time of vascular anastomosis
      and time of cold ischaemia. DGF was not associated with graft or patient
      survival. In the transplants performed with elderly donors, the cold ischaemia
      time was associated with greater incidence of DGF, and the latter with less
      survival of the graft when censored for death. The presence of DGF was
      significantly associated with acute rejection, cytomegalovirus infection, worse
      renal function and arterial hypertension at 3 months post-transplantation. In
      conclusion, the incidence of DGF remained stable in our patients over the years
      studied and, although not directly, it can affect graft survival as it is
      associated with acute rejection, arterial hypertension and worse renal graft
      function. A shortening of ischaemia times may reduce the incidence of DGF and
      improve transplant results.

PMID- 15192134
TI  - Acute rejection and late renal transplant failure: risk factors and prognosis.
AB  - BACKGROUND: Acute rejection episodes are a major determinant of renal allograft
      survival, and the improvement of the transplantation results in the last two
      decades is largely due to a progressive decrease in the incidence of acute
      rejection. These results are explained by the incorporation of new
      immunosuppressive agents since the introduction of cyclosporine. Because the
      detrimental effect of acute rejection on graft survival is not limited to the
      early post-transplant period, we have focused on the impact of acute rejection
      episodes on late transplant failure in patients with the graft functioning 1 year
      after transplantation. METHODS: We have retrospectively analysed in 3365 renal
      transplants performed in adults in Spain during 1990, 1994 and 1998 the incidence
      and severity of the acute rejection episodes, their risk factors, and their
      influence on graft and patient survival. RESULTS: The incidence of rejection
      episodes in the whole series was 32.5%, decreasing in 1998 (25.1%) compared with
      the previous years (38%) (P<0.0001). Corticoid-resistant rejection episodes also
      decreased from 8% in 1990 and 1994 to 3.4% in 1998 (P<0.0001). Multivariate
      analysis showed that patients < 60 years old (P<0.0001), sensitized recipients (P
      = 0.038), patients with delayed graft function (P<0.0001), cytomegalovirus
      infection (P = 0.0060), and those transplanted in 1990 or 1994 (P<0.0001) had an
      increased incidence of rejection episodes. In the univariate analysis, induction
      treatment with antilymphocyte globulines or OKT3 (P = 0.0002), and traumatic
      donor death (P = 0.042) were associated with a lower incidence of acute
      rejection. In the univariate analysis of the transplants performed in 1998,
      addressed to evaluate the effect of the new immunosuppressive agents, treatment
      with mycophenolate mofetil (P<0.0001) or tacrolimus (P = 0.0067), but not with
      anti-IL2 antibodies reduced the incidence of acute rejection. Patients with
      rejection episodes had an increased risk of late graft failure (Cox proportional
      hazards model, P<0.0001), which was homogeneous in the three periods analysed,
      with no effect on patient survival (P = 0.13). CONCLUSIONS: Despite a decreased
      incidence and severity of acute rejections in 1998, compared with the previous
      years, acute rejection still remains a powerful risk factor for late transplant
      failure.

PMID- 15192136
TI  - Proteinuria: a new marker of long-term graft and patient survival in kidney
      transplantation.
AB  - BACKGROUND: Proteinuria developing after renal transplantation is associated with
      increased renal failure. Moreover, proteinuria in the general population has been
      shown to be associated with morbidity and mortality due to cardiovascular
      disease, which is the main cause of death in renal transplant patients. The
      purpose of the present study was to investigate whether persistent proteinuria
      following renal transplantation was associated with a worse patient and graft
      survival. METHODS: We analysed kidney recipients included in the Spanish Chronic
      Allograft Nephropathy Study (n = 3365). Proteinuria at 1 year post
      transplantation was analysed as a categorical variable (< 0.5, 0.5-1, > 1 g/day).
      RESULTS: Post-transplant proteinuria at 1 year was detected in 15.3% of patients.
      Graft survival in proteinuric patients was significantly lower as compared with
      patients without proteinuria and the survival was worse with increasing amounts
      of proteinuria. In the groups with proteinuria, renal graft function at the time
      of the analysis was worse than in the group without proteinuria. Patient survival
      was lower in patients with proteinuria although there was no difference between
      the two groups of proteinuric patients. The main cause of death was vascular
      disease in all groups of patients but especially in proteinuric patients. The
      relative risk of graft failure and patient death was higher in proteinuric
      patients: graft failure [0.5-1 g/day: 2.33 (1.79-3.01, P<0.0001); > 1 g/day: 3.46
      (2.73-4.39, P<0.0001)], patient death [0.5-1 g/day: 2.05 (1.39-3.01, P = 0.0002);
      > 1 g/day: 2.3 (1.55-3.39, P<0.0001)]. CONCLUSIONS: Proteinuria, as in native
      kidney disease, is an excellent marker of poor long-term allograft prognosis and
      is an independent risk factor for total and cardiovascular mortality in the renal
      transplant population.

PMID- 15192135
TI  - Early post-transplant renal allograft function between 1990 and 1998 in Spain.
AB  - BACKGROUND: The last decade has witnessed a sustained improvement of renal
      allograft survival that is partly explained by a better preservation of renal
      allograft function. This study describes time-dependent modifications of serum
      creatinine (SCr) during the first year after transplantation in the last decade
      in Spain and characterizes the predictive value of SCr on death-censored graft
      survival. METHODS: A total of 3365 adult patients transplanted in 1990 (n = 824),
      1994 (n = 1075) and 1998 (n = 1466) with a functioning graft after the first year
      were included. Renal function deterioration during the first year was expressed
      as the difference between SCr at 1 year and SCr at 3 months. RESULTS: Despite the
      projected renal allograft half-life, estimation was significantly higher in 1998
      than in 1990 (17.7 vs 15.4 years, P = 0.007), the SCr levels at 3 months were
      significantly lower in 1990 (1.59+/-0.64) than in 1998 (1.65+/-0.66). While SCr
      tended to worsen during the first year in 1990 (0.05+/-0.64) it improved in 1998
      (-0.003+/-0.48), P = 0.0001. The following variables were significantly
      associated with SCr at 3 months: donor age and sex, cause of death, recipient
      sex, time on dialysis, cold ischaemia time, delayed graft function, acute
      rejection, cytomegalovirus infection and reintervention for any reason. Renal
      function deterioration during the first year was associated with the presence of
      acute rejection and hepatitis C virus antibodies in the recipient. CONCLUSIONS:
      Despite poorer renal function at 3 months in 1998 than in 1990, renal allograft
      survival has improved in Spain between 1990 and 1998. This result is partly
      explained by a slower deterioration of renal function during the first year of
      follow-up.

PMID- 15192137
TI  - Effect of the immunosuppressive treatment on long-term renal graft survival.
AB  - BACKGROUND: Although new immunosuppressive agents have improved the results of
      renal transplants (RTs), long-term graft loss remains high. We evaluated the
      impact of different immunosuppressive regimens on patient and graft survival.
      METHODS: Data from 3365 patients receiving cadaver RTs in Spain during the years
      1990, 1994 and 1998 were retrospectively analysed. All data were entered into a
      specially designed database. Graft and patient survival rates were estimated by
      the Cox regression method and results expressed as percentage survival. A maximum
      likelihood estimate of the projected graft half-life (median value) was
      calculated by Weibull regression. RESULTS: In 1990 graft and patient survival
      differed significantly from the other treatment years (P = 0.0006 and P = 0.0101,
      respectively). The risk of graft loss was significantly higher for cyclosporine
      (CsA), prednisone (P) and azathioprine (Az) than for CsA + P, which in turn was
      higher than for CsA + P plus polyclonal antibodies [antilymphocyte globulin
      (ALG)/antithymocyte globulin (ATG)]. Risk of patient death was also significantly
      higher for CsA + P + Az than for CsA + P. No significant differences between
      treatment groups were found in graft and patient survival for 1994 and 1998. The
      projected median graft life for patients with the most used immunosuppressive
      regimen for each year was 12.9 years for CsA + P + Az and 15.6 years for CsA + P
      plus mycophenolate mofetil (MMF). CONCLUSIONS: Triple therapy with Az in 1990 and
      1994 and with MMF in 1998 were the most frequently used immunosuppressive
      regimens in the Spanish kidney transplant population. The best results were seen
      after induction therapy with polyclonal antibodies.

PMID- 15192138
TI  - Impact of diabetes mellitus on kidney transplant recipients in Spain.
AB  - BACKGROUND: The increasing prevalence of pre-existing diabetes mellitus (DM) and
      especially the incidence of post-transplant diabetes mellitus (PTDM) is a
      disturbing tendency with far-reaching health and cost implications. We assessed
      the factors associated with PTDM and the impact of either condition on death
      censored graft and patient survival. METHODS: We studied 3365 adult kidney
      allograft recipients transplanted in 1990, 1994 and 1998, whose graft was
      functioning after 1 year of follow-up. Three groups were considered: Group I (DM;
      N = 156), Group II (PTDM; N = 251) and Group III (non-diabetic; N = 2958).
      RESULTS: Group I patients had been dialysed for shorter periods and received
      angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blockers
      (ARB) therapy more frequently during follow-up than the other groups (P<0.001).
      Mean age, body weight and body mass index (BMI) were greater in Group II patients
      than the other groups (P<0.001). Group II showed lower rejection rates than Group
      III (P<0.01). Risk factors for developing PTDM were recipient age > 60 years (OR
      = 2.24; P<0.001), female recipient (OR = 1.5; P<0.005), recipient weight > 65 kg
      (OR = 1.77; P<0.002), BMI > 25 kg/m(2) (OR = 1.6; P<0.04) or > 30 kg/m(2) (OR =
      2.92; P<0.005), and tacrolimus-based therapy (OR = 1.48; P<0.05). Of note, the
      use of Sandimmune vs Neoral had a protective effect (OR = 0.7; P<0.01). Using
      Cox's proportional hazards analysis, DM correlated with reduced death-censored
      graft survival (RR = 1.68; 95% CI = 1.14-2.47; P<0.008), while PTDM correlated
      with reduced patient survival (RR = 1.55; 95% CI = 1.05-2.27; P<0.02).
      CONCLUSIONS: One year after transplantation, DM was associated with a decrease in
      death-censored graft survival, while PTDM was an independent negative predictor
      of patient survival after kidney transplantation. New strategies to improve
      outcome are needed.

PMID- 15192139
TI  - Epidemiology of arterial hypertension in renal transplant patients: changes over
      the last decade.
AB  - BACKGROUND: Arterial hypertension is a common clinical problem in renal
      transplantation, with important consequences on graft and patient survival.
      PATIENTS AND METHODS: A total of 3365 adult patients transplanted in 1990 (N =
      824), 1994 (N = 1075) and 1998 (N = 1466) with a functioning graft after the
      first year were included. In this study, arterial hypertension was defined as
      systolic blood pressure (SBP) > or =140 mmHg and/or diastolic blood pressure
      (DBP) > or =90 mmHg and/or treatment with antihypertensive drugs. The use of
      angiotensin converting enzyme (ACE) inhibitors or angiotensin II (ATII) receptor
      blockers during the first year was recorded. RESULTS: The prevalence of
      hypertension showed a progressive and significant increase during follow-up after
      renal transplantation in the three periods analysed, although SBP and DBP were
      lower in patients who underwent transplantation in 1998. The presence of arterial
      hypertension at 1 year was significantly associated with recipient gender (male),
      donor age (< 60 years), immunosuppressive therapy (cyclosporine), serum
      creatinine and year of transplantation. Arterial hypertension was not associated
      with graft survival and cardiovascular mortality. The prevalence and severity of
      hypertension was significantly lower in patients treated with tacrolimus vs
      cyclosporine. The use of ACE inhibitors or ATII receptor blockers has increased
      in the recent years. CONCLUSIONS: Arterial hypertension remained a common problem
      in renal transplantation, although in recent years the intensity of the control
      seems satisfactory. The use of ACE inhibitors or ATII receptor blockers has
      increased significantly in the last years.

PMID- 15192140
TI  - The effects of hyperlipidaemia on graft and patient outcome in renal
      transplantation.
AB  - Hyperlipidaemia is a frequent complication after renal transplantation. As to
      whether total cholesterol (TC) and triglyceride levels are risk factors for
      cardiovascular disease and graft survival is controversial. The prevalence of
      hypercholesterolaemia in the transplanted population in Spain has increased over
      the years, going from 38.8% in 1990 to 48% in 1998. In contrast, the prevalence
      of hypertriglyceridaemia being approximately 20%, has not shown any significant
      variation. Transplant recipients with high cholesterol were characterized by
      increased age, lower proportion of males, higher mean body mass index, lower
      proportion of HCV antibodies, reduced time on dialysis and diabetes. Patients
      with high cholesterol were more frequently treated with cyclosporine + MMF +
      prednisone and less frequently treated with tacrolimus + MMF + prednisone.
      Hypertriglyceridaemia was more frequent in patients treated with cyclosporine +
      MMF + prednisone, and these patients showed significantly higher creatinine
      plasma levels at 1 year and were more frequently treated with lipid-lowering
      agents. Hypertriglyceridaemia at 3 months after transplantation is associated
      with worse graft survival (RR 1.078; CI 1.07-1.143; P = 0.011) and greater
      cardiovascular mortality (RR 1.265; CI 1.20-1.428; P = 0.0002), while treatment
      with statins has a protective effect on the graft survival (RR 0.64; CI 0.512
      0.888; P = 0.0051). In conclusion, in the renal transplant population in Spain,
      hypertriglyceridaemia rather than hypercholesterolaemia, may exert a deleterious
      effect on graft and patient survival.

PMID- 15192141
TI  - The influence of hepatitis B and hepatitis C virus infection in the recipient on
      late renal allograft failure.
AB  - BACKGROUND: Chronic liver disease is one of the most important complications
      after renal transplantation. Hepatitis B and mainly hepatitis C are the more
      frequent causes of liver disease. Although there are controversial results, in
      some series, hepatitis B and hepatitis C are associated with lower graft and
      patient survival. PATIENTS AND METHODS: A total of 3365 adult patients who
      received a renal transplant in 1990 (N = 824), 1994 (N = 1075) and 1998 (N =
      1466) with a functioning graft after the first year were included. Fifty-one
      (2.1%) with positive HbsAg were diagnosed with hepatitis B at transplantation;
      488 (16.9%) presented positive anti-hepatitis C antibodies and were diagnosed
      with hepatitis C virus (HCV) infection and 25 patients (0.8%) were diagnosed with
      concomitant hepatitis B virus (HBV) and HVC infection. Demographic,
      immunosuppression, survival figures and post-transplant and follow-up data of
      these patients and negative HBV and HVC patients were recorded. RESULTS: The
      overall prevalence of HBV in the recipients was 2.1%. Patient survival was lower
      and liver disease was the main cause of death in HBV-positive patients. However,
      in the multivariate analysis the presence of positive HbsAg did not have an
      independent risk factor for graft loss and patient death. This finding was
      similar in patients with concomitant HBV and HVC infection. Graft and patient
      survival were lower in HCV-positive patients and liver disease was the main cause
      of death. Interestingly, proteinuria and serum creatinine were risk factors for
      graft loss and patient death. Fortunately, prevalence of HCV in the recipients
      significantly decreased from 29% in 1990 to 10% in 1998. CONCLUSIONS: In the last
      decade in Spain, HBV infection in the recipients, showing an overall prevalence
      approximately 2%, did not influence graft and patient survival. However, HCV
      infection in the recipient was associated with lower graft and patient survival,
      although the prevalence of HCV clearly decreased from 29% in 1990 to 10% in 1998.

PMID- 15192142
TI  - Impact of the new drugs in the cost of maintenance immunosuppression of renal
      transplantation. Is it justified?
AB  - BACKGROUND: The new immunosuppressive drugs control acute rejection better, and
      have potentially short-term economic advantages. However, their long-term cost
      effectiveness must still be determined. The Spanish study of chronic transplant
      nephropathy provides data that facilitates the assessment of the economic
      importance of maintenance immunosuppression (MI). METHODS: We determined the
      frequency of use of the different MI drugs and their combinations in three renal
      transplantation cohorts performed in 1990, 1994 and 1998 (total: 3279), and their
      evolution over time. Based on the real costs found in a medium-sized service in
      our country at the end of 2000, the mean annual costs of MI drugs were
      calculated. We performed a multivariate analysis of graft survival in the 1998
      cohort. RESULTS: In 1990 and 1994, cyclosporine (CsA) with or without
      azathioprine (AZA) was used almost exclusively as the initial MI drug. In 1998,
      76% received mycophenolate mofetil (MMF) and 20% tacrolimus (TAC). During their
      follow-up, a growing number of patients from the 1990 and 1994 groups were
      converted to MMF (12 and 17%) and TAC (4 and 8%), while the treatment of those
      from 1998 remained stable. Using prices from the year 2000, the mean cost of the
      MI at the end of the first year in 1998 (5380) was almost double that of 1994
      (2902) and 1990 (2855). In these two groups, the mean cost remained stable until
      1996; afterwards, it increased in both, more rapidly in the 1994 (24.8%) than in
      the 1990 (17.3%) group, although it remained significantly inferior to that of
      1998. Correction for the evolution of the drug prices and the peseta purchasing
      value lessened these changes in an important way. The new regimens allowed for
      the withdrawal of steroids in a greater proportion of cases; TAC was associated
      with a less frequent use of lipid-lowering drugs and antihypertensive drugs. In
      the whole patient group, the regimens with MMF and/or TAC showed a tendency to
      greater mean life of the organs, but without reaching statistical significance in
      the multivariate analysis of patients in 1998. CONCLUSIONS: The introduction of
      new drugs in the MI applied in Spain has had an important economic impact since
      1996. Their cost-effectiveness is still pending confirmation in our country.

PMID- 15192143
TI  - Formation of a central supramolecular activation cluster is not required for
      activation of naive CD8+ T cells.
AB  - Although both naive and effector T lymphocytes interact with antigen-expressing
      cells, the functional outcome of these interactions is distinct. Naive CD8(+) T
      cells are activated to proliferate and differentiate into effector cytolytic T
      lymphocytes (CTL), whereas CTL interact with specific targets, such as tumor
      cells, to induce apoptotic death. We recently observed that several molecules
      linked to actin cytoskeleton dynamics were up-regulated in effector vs. naive
      CD8(+) T cells, leading us to investigate whether T cell differentiation is
      accompanied by changes in actin-dependent processes. We observed that both naive
      and effector CD8(+) T cells underwent T cell receptor capping and formed stable
      conjugates with antigen-specific antigen-presenting cells. However, the
      characteristics of the immunological synapse were distinct. Whereas accumulation
      of signaling molecules at the T cell/antigen-presenting cell contact site was
      detectable in both naive and effector CD8(+) T cells, only effector cells
      developed a central supramolecular activation cluster as defined by punctate
      focusing of PKC theta, phospho-PKC theta, and phospho-ZAP70. Extended kinetics,
      CD28 costimulation, and high-affinity antigenic peptide did not promote PKC theta
      focusing in naive cells. Nonetheless, naive CD8(+) T cells polarized the
      microtubule organizing center, produced IL-2, proliferated, and differentiated
      into effector cells. Our results suggest that the formation of a central
      supramolecular activation cluster is not required for activation of naive CD8(+)
      T cells and support the notion that one role of an organized immune synapse is
      directed delivery of effector function.

PMID- 15192144
TI  - Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion:
      Implications for inflammatory processes.
AB  - Blocking the activity of IL-1 beta has entered the clinical arena of treating
      autoimmune diseases. However, a successful outcome of this approach requires a
      clear definition of the mechanisms controlling IL-1 beta release. These are still
      unclear as IL-1 beta, lacking a secretory signal peptide, follows a nonclassical
      pathway of secretion. Here, we analyze the molecular mechanism(s) undergoing IL-1
      beta processing and release in human monocytes and provide a unifying model for
      the regulated secretion of the cytokine. Our data show that in a first step, pro
      caspase-1 and endotoxin-induced pro-IL-1 beta are targeted in part to specialized
      secretory lysosomes, where they colocalize with other lysosomal proteins.
      Externalization of mature IL-1 beta and caspase-1 together with lysosomal
      proteins is then facilitated by extracellular ATP. ATP triggers the efflux of
      K(+) from the cell, followed by Ca(2+) influx and activation of three
      phospholipases: phosphatidylcholine-specific phospholipase C and calcium
      independent and -dependent phospholipase A(2). Whereas calcium-independent
      phospholipase A(2) is involved in processing, phosphatidylcholine-specific
      phospholipase C and calcium-dependent phospholipase A(2) are required for
      secretion. Dissection of the events that follow ATP triggering allowed to
      demonstrate that K(+) efflux is responsible for phosphatidylcholine-specific
      phospholipase C induction, which in turn allows the rise in intracellular free
      calcium concentration required for activation of phospholipase A(2). This
      activation is ultimately responsible for lysosome exocytosis and IL-1 beta
      secretion.

PMID- 15192145
TI  - Population effects of growth hormone transgenic coho salmon depend on food
      availability and genotype by environment interactions.
AB  - Environmental risk assessment of genetically modified organisms requires
      determination of their fitness and invasiveness relative to conspecifics and
      other ecosystem members. Cultured growth hormone transgenic coho salmon
      (Oncorhynchus kisutch) have enhanced feeding capacity and growth, which can
      result in large enhancements in body size (>7-fold) relative to nontransgenic
      salmon, but in nature, the ability to compete for available food is a key factor
      determining survival fitness and invasiveness of a genotype. When transgenic and
      nontransgenic salmon were cohabitated and competed for different levels of food,
      transgenic salmon consistently outgrew nontransgenic fish and could affect the
      growth of nontransgenic cohorts except when food availability was high. When food
      abundance was low, dominant individuals emerged, invariably transgenic, that
      directed strong agonistic and cannibalistic behavior to cohorts and dominated the
      acquisition of limited food resources. When food availability was low, all groups
      containing transgenic salmon experienced population crashes or complete
      extinctions, whereas groups containing only nontransgenic salmon had good (72.0
      +/- 4.3% SE) survival, and their population biomass continued to increase. Thus,
      effects of growth hormone transgenic salmon on experimental populations were
      primarily mediated by an interaction between food availability and population
      structure. These data, while indicative of forces which may act on natural
      populations, also underscore the importance of genotype by environment
      interactions in influencing risk assessment data for genetically modified
      organisms and suggest that, for species such as salmon which are derived from
      large complex ecosystems, considerable caution is warranted in applying data from
      individual studies.

PMID- 15192146
TI  - Diversity Arrays Technology (DArT) for whole-genome profiling of barley.
AB  - Diversity Arrays Technology (DArT) can detect and type DNA variation at several
      hundred genomic loci in parallel without relying on sequence information. Here we
      show that it can be effectively applied to genetic mapping and diversity analyses
      of barley, a species with a 5,000-Mbp genome. We tested several complexity
      reduction methods and selected two that generated the most polymorphic genomic
      representations. Arrays containing individual fragments from these
      representations generated DArT fingerprints with a genotype call rate of 98.0%
      and a scoring reproducibility of at least 99.8%. The fingerprints grouped barley
      lines according to known genetic relationships. To validate the Mendelian
      behavior of DArT markers, we constructed a genetic map for a cross between
      cultivars Steptoe and Morex. Nearly all polymorphic array features could be
      incorporated into one of seven linkage groups (98.8%). The resulting map
      comprised approximately 385 unique DArT markers and spanned 1,137 centimorgans. A
      comparison with the restriction fragment length polymorphism-based framework map
      indicated that the quality of the DArT map was equivalent, if not superior, to
      that of the framework map. These results highlight the potential of DArT as a
      generic technique for genome profiling in the context of molecular breeding and
      genomics.

PMID- 15192147
TI  - A unified approach to polyene macrolides: synthesis of candidin and nystatin
      polyols.
AB  - Polyene macrolide antibiotics are naturally occurring antifungal agents. Members
      of this class include amphotericin B, which has been used widely to treat
      systemic fungal infections. A general synthetic strategy has been devised to
      prepare polyol chains associated with the polyene macrolides. Cyanohydrin
      acetonide alkylations were used to assemble the carbon skeleton, and a simple
      modification of the strategy allowed an advanced intermediate to be converted to
      either the candidin polyol or the nystatin polyol. The candidin polyol was
      further elaborated to a protected candidin aglycone. This strategy will be
      applicable to other members of the polyene macrolide natural products.

PMID- 15192148
TI  - Identification of an outer membrane protein required for the transport of
      lipopolysaccharide to the bacterial cell surface.
AB  - Lipopolysaccharide (LPS), also known as endotoxin due to its severe
      pathophysiological effects in infected subjects, is an essential component of the
      outer membrane (OM) of most Gram-negative bacteria. LPS is synthesized in the
      bacterial inner membrane, a process that is now well understood. In contrast, the
      mechanism of its transport to the outer leaflet of the OM has remained enigmatic.
      We demonstrate here that the OM protein, known as increased membrane permeability
      (Imp) or organic solvent tolerance protein, is involved in this process. An Imp
      deficient mutant of Neisseria meningitidis was viable and produced severely
      reduced amounts of LPS. The limited amount of LPS that was still produced was not
      accessible to LPS-modifying enzymes expressed in the OM or added to the
      extracellular medium. We conclude therefore that Imp mediates the transport of
      LPS to the cell surface. The role of Imp in LPS biogenesis and its high
      conservation among Gram-negative bacteria make it an excellent target for the
      development of novel antibacterial compounds.

PMID- 15192149
TI  - CD154 is a negative regulator of autoaggressive CD8+ T cells in type 1 diabetes.
AB  - TNF/CD80 mice, a CD8(+) T cell-mediated model for type 1 diabetes, transgenically
      express tumor necrosis factor alpha (TNF-alpha) and the costimulatory molecule
      CD80 in their pancreatic islets. Here we show that these molecules bypass the
      need for CD40-CD154 costimulatory interactions in activation of CD8(+) T cells,
      allowing us to determine the role of CD40-CD154 signals in regulation of
      autoaggressive CD8(+) T cells after their in vivo priming. TNF/CD80 CD154
      deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not.
      This finding correlates with the decreased numbers of CD4(+)CD25(+) T regulatory
      (T(R)) cells in the islets and pancreatic lymph nodes, in comparison to disease
      protected CD154-sufficient mice. Administration of a CD40 agonistic antibody
      induces a systemic and tissue-specific increase in T(R) cells. However, this
      increase fails to delay diabetes development in the absence of CD154. Adoptive
      transfer studies show that CD8(+) T cells from TNF/CD80 CD154-deficient, but not
      CD154-sufficient, mice are resistant to regulation in vivo. This study provides
      evidence that CD40-transduced signals initiate T(R) cell increase in vivo and
      that CD154-transduced signals sensitize autoaggressive CD8(+) T cells to
      suppression.

PMID- 15192150
TI  - The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-,
      transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes.
AB  - The antimicrobial peptide hepcidin appears to play a central role in the
      regulation of iron homeostasis. In intact animals, iron overload or the injection
      of lipopolysaccharide (LPS) stimulates transcription of HAMP, the gene that
      encodes hepcidin. In isolated hepatocytes, IL-6, an inflammatory cytokine the
      production of which is stimulated by LPS, up-regulates transcription of hepcidin.
      In contrast, iron has no stimulatory effect on hepcidin expression in isolated
      hepatocytes. There is apparently a signaling pathway, activated by iron, that is
      present in the intact animal but not in isolated hepatocytes. Studies in humans
      and mice have shown that this iron-dependent pathway requires the presence of
      Hfe, hemojuvelin, and probably transferrin receptor 2 (tfr-2). To determine
      whether activation of hepcidin transcription by IL-6 also requires Hfe and tfr-2,
      we have studied mice homozygous for targeted disruption of HFE, beta(2)
      microglobulin, and for a truncating mutation of TFR-2. We show that these mutant
      mice react normally to injection of endotoxin and that their isolated hepatocytes
      react normally to IL-6. This indicates that the signaling pathway activated by IL
      6 does not require either Hfe or tfr-2. Mice with disruption of the gene encoding
      IL-6 seem to have a blunted response to LPS, but the statistical significance of
      the small response documented is borderline. It is therefore not clear whether
      LPS stimulates secretion of cytokines other than IL-6 that may stimulate hepcidin
      transcription.

PMID- 15192151
TI  - Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype
      1, is anxiogenic and antidepressive in the mouse model.
AB  - Two subtypes of the corticotropin-releasing factor (CRF) receptor, CRF(1) and
      CRF(2), differentially modulate brain functions such as anxiety and memory. To
      facilitate the analysis of their differential involvement, we developed a CRF(1)
      specific peptidic agonist by synthesis of chimeric peptides derived from
      human/rat CRF, ovine CRF (oCRF), and sauvagine (Svg). High affinity to the CRF
      binding protein was prevented by introduction of glutamic acid in the binding
      site of the ligand. The resulting chimeric peptide, [Glu(21),Ala(40)][Svg(1
      12)]x[human/rat CRF(14-30)]x[Svg(30-40)], named cortagine, was analyzed
      pharmacologically in cell culture by using human embryonic kidney-293 cells
      transfected with cDNA coding for CRF(1) or CRF(2), in autoradiographic
      experiments, and in behavior experiments using male C57BL/6J mice for its
      modulatory action on anxiety- and depression-like behaviors with the elevated
      plus-maze test and the forced swim test (FST), respectively. We observed that
      cortagine was more selective than oCRF, frequently used as CRF(1)-specific
      agonist, in stimulating the transfected cells to release cAMP. Cortagine's
      specificity was demonstrated in autoradiographic experiments by its selective
      binding to CRF(1) of brain sections of the mouse. After injection into the brain
      ventricles, it enhanced anxiety-like behavior on the elevated plus-maze at a
      lower dose than oCRF. Whereas at high doses, oCRF injected into the lateral
      intermediate septum containing predominantly CRF(2) increased anxiety-like
      behavior as CRF(2)-specific agonists do, cortagine did not. In contrast to its
      anxiogenic actions, cortagine reduced significantly the immobility time in the
      FST as described for antidepressive drugs. Thus, cortagine combines anxiogenic
      properties with antidepressive effects in the FST.

PMID- 15192152
TI  - Herpes simplex virus protein kinase US3 activates and functionally overlaps
      protein kinase A to block apoptosis.
AB  - Herpes simplex virus 1 encodes at least four genes whose functions include
      blocking apoptosis induced by exogenous agents (e.g., sorbitol, Fas ligand, and
      BAD protein) or replication-incompetent mutants (e.g., the d120 mutant lacking
      both copies of the alpha 4 gene). U(S)3, one of these four genes, encodes a
      serine-threonine kinase that has been demonstrated to block apoptosis induced by
      proapoptotic cellular proteins or by the d120 mutant. The amino acid context of
      serine-threonine phosphorylated by U(S)3 is similar to that of the cAMP-dependent
      protein kinase PKA. We report that (i) the pattern of proteins phosphorylated by
      U(S)3 in transduced cells or in cells infected with WT virus overlaps that of
      phosphoproteins targeted by PKA, (ii) activation of PKA blocks apoptosis induced
      by d120 mutant or by BAD protein independently of U(S)3, (iii) U(S)3 protein
      kinase phosphorylates peptides containing the serine or threonine targeted by PKA
      including that present in the regulatory type II alpha subunit of PKA, and (iv)
      in WT virus-infected cells the regulatory type II alpha subunit is phosphorylated
      in a U(S)3-dependent manner. We conclude that a major determinant of the
      antiapoptotic activity of the U(S)3 protein kinase is the phosphorylation of PKA
      substrates by either or both enzymes.

PMID- 15192154
TI  - Long-lived Drosophila with overexpressed dFOXO in adult fat body.
AB  - Reduced activity of the insulin/insulin-like growth factor signaling (IIS)
      pathway increases life-span in diverse organisms. We investigated the timing of
      the effect of reduced IIS on life-span and the role of a potential target tissue,
      the fat body. We overexpressed dFOXO, a downstream effector of IIS, in the adult
      Drosophila fat body, which increased life-span and reduced fecundity of females
      but had no effect on male life-span. The role of FOXO transcription factors and
      the adipose tissue are therefore evolutionarily conserved in the regulation of
      aging, and reduction of IIS in the adult is sufficient to mediate its effects on
      life-span and fecundity.

PMID- 15192155
TI  - Discovery of a compact radio component in the center of supernova 1986J.
AB  - Very-long-baseline interferometry observations have revealed a bright, compact
      radio component near the center of the expanding shell of supernova 1986J. The
      component, not present in earlier images, has an inverted radio spectrum
      different from that of the shell. Such an inversion has not been seen in the
      spectrum of any other supernova. The new component is likely radio emission
      associated either with accretion onto a black hole or with the nebula formed
      around an energetic young neutron star in the center of SN 1986J, which would
      directly link either a black hole or a neutron star to a modern supernova.

PMID- 15192153
TI  - Suppression of tumorigenesis by the p53 target PUMA.
AB  - The p53 tumor suppressor regulates diverse antiproliferative processes such that
      cells acquiring p53 mutations have impaired cell-cycle checkpoints, senescence,
      apoptosis, and genomic stability. Here, we use stable RNA interference to examine
      the role of PUMA, a p53 target gene and proapoptotic member of the Bcl2 family,
      in p53-mediated tumor suppression. PUMA short hairpin RNAs (shRNAs) efficiently
      suppressed PUMA expression and p53-dependent apoptosis but did not impair
      nonapoptotic functions of p53. Like p53 shRNAs, PUMA shRNAs promoted oncogenic
      transformation of primary murine fibroblasts by the E1A/ras oncogene combination
      and dramatically accelerated myc-induced lymphomagenesis without disrupting p53
      dependent cell-cycle arrest. However, the ability of PUMA to execute p53 tumor
      suppressor functions was variable because, in contrast to p53 shRNAs, PUMA shRNAs
      were unable to cooperate with oncogenic ras in transformation. These results
      demonstrate that the p53 effector functions involved in tumor suppression are
      context dependent and, in some settings, depend heavily on the expression of a
      single proapoptotic effector. Additionally, they demonstrate the utility of RNA
      interference for evaluating putative tumor suppressor genes in vivo.

PMID- 15192156
TI  - Force microscopy with light-atom probes.
AB  - The charge distribution in atoms with closed electron shells is spherically
      symmetric, whereas atoms with partially filled shells can form covalent bonds
      with pointed lobes of increased charge density. Covalent bonding in the bulk can
      also affect surface atoms, leading to four tiny humps spaced by less than 100
      picometers in the charge density of adatoms on a (001) tungsten surface. We
      imaged these charge distributions by means of atomic force microscopy with the
      use of a light-atom probe (a graphite atom), which directly measured high-order
      force derivatives of its interaction with a tungsten tip. This process revealed
      features with a lateral distance of only 77 picometers.

PMID- 15192157
TI  - Implications of Harold Shipman for general practice.
AB  - Harold Shipman was an English general practitioner who murdered at least 215 of
      his patients between 1974 and 1998. A public inquiry is underway, but general
      practitioners and all doctors also need to consider the implications for their
      profession. The aim of this paper is to stimulate debate. Issues identified as
      important to consider include: trust between doctors; attitudes towards failing
      systems such as cremation certification; acceptance of the duty of
      accountability; ensuring patients can have reasonable confidence in their
      doctors; commitment to preventing such a case occurring again; and relationships
      with patients. It is argued that restricting debate to methods to detect doctors
      who murder would limit the opportunity to improve medical practice and would
      constitute a failure to fulfil the duty owed by doctors to Shipman's victims and
      their families.

PMID- 15192162
TI  - Diagnosing pulmonary embolism.
AB  - Objective testing for pulmonary embolism is necessary, because clinical
      assessment alone is unreliable and the consequences of misdiagnosis are serious.
      No single test has ideal properties (100% sensitivity and specificity, no risk,
      low cost). Pulmonary angiography is regarded as the final arbiter but is ill
      suited for diagnosing a disease present in only a third of patients in whom it is
      suspected. Some tests are good for confirmation and some for exclusion of
      embolism; others are able to do both but are often non-diagnostic. For optimal
      efficiency, choice of the initial test should be guided by clinical assessment of
      the likelihood of embolism and by patient characteristics that may influence test
      accuracy. Standardised clinical estimates can be used to give a pre-test
      probability to assess, after appropriate objective testing, the post-test
      probability of embolism. Multidetector computed tomography can replace both
      scintigraphy and angiography for the exclusion and diagnosis of this disease and
      should now be considered the central imaging investigation in suspected pulmonary
      embolism.

PMID- 15192163
TI  - Evolving immunotherapeutic strategies in bladder and renal cancer.
AB  - For patients with urological cancers, immunotherapy is currently a treatment
      option for metastatic renal cell carcinoma, and those with "high risk"
      superficial bladder cancers. In this review, our current understanding of tumour
      immune escape is discussed. The principles and role of current immunotherapies
      for these tumours are described, and new areas of immunotherapeutic promise are
      highlighted.

PMID- 15192165
TI  - Activity analysis of telemedicine in the UK.
AB  - BACKGROUND: Telemedicine is a new way of delivering health care to people,
      particularly in remote areas. The UK has experienced a surge of telematic
      projects in recent years. However, there is little information available in the
      literature regarding the past and present of telemedicine in the UK. OBJECTIVES:
      To evaluate the state of telemedicine in the UK. METHODS: All the projects that
      took place in UK since 1991 were considered for the study and evaluated according
      to the population and area served. RESULTS: A total of 216 projects were
      identified. The number of projects was highest in England (172). Emergency
      medicine, medical specialties, and educational projects received most
      consideration (9.7% each). With the exception of Wales, the number of projects
      increased steadily with time. The projects, when correlated in accordance with
      the area (per 10 000 sq km) and population (per million), were found to be
      highest in England (49.5%) and Northern Ireland (36.2%) respectively. No
      dedicated educational project took place in Scotland, Northern Ireland, and
      Wales. CONCLUSIONS: The UK embraced telemedicine in the early 1990s and the
      overall growth had been steady. Scotland, in spite of being the most likely
      beneficiary in UK, has lagged behind in telemedicine schemes and merits more
      projects. The issue of tele-education needs urgent review. Multisite trials and a
      combined approach involving the government, health professionals, technologists,
      and patients' representatives would facilitate such developments and help widen
      the application of telemedicine.

PMID- 15192164
TI  - Lemierre's syndrome: more than a historical curiosa.
AB  - Lemierre's syndrome is a severe illness caused by the anaerobic bacterium,
      Fusobacterium necrophorum which typically occurs in healthy teenagers and young
      adults. The infection originates in the throat and spreads via a septic
      thrombophlebitis of the tonsillar vein and internal jugular vein. The ensuing
      bacteraemia is complicated by septic emboli to a range of sites such as lung,
      joints, and bones. Although rare, there is evidence of a resurgence in the
      condition in recent years, possibly associated with reduced use of antibiotic
      therapy for sore throats. The typical clinical picture is characteristic but many
      clinicians are unaware of the condition and diagnosis is often delayed with
      potentially fatal consequences.

PMID- 15192166
TI  - Clues for the differential diagnosis of hypersensitivity pneumonitis as an
      expectant variant of diffuse parenchymal lung disease.
AB  - Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis, a type
      of diffuse parenchymal lung disease (DPLD), is an immunologically mediated
      pulmonary disease induced by inhalation of various antigens. As data on the
      frequency of hypersensitivity pneumonitis are lacking in Turkey, a retrospective
      analyses was performed in 43 patients with DPLD, followed up over seven years.
      The objective was to discover cases fulfilling the diagnostic criteria for
      hypersensitivity pneumonitis, to determine the frequency and/or the new
      characteristics of the disease, and to pick up clues for differentiating it from
      other DPLDs. The four subjects with hypersensitivity pneumonitis (9%) who lived
      in an urban area were studied in detail. The most common symptoms were dry cough
      and dyspnoea. According to the symptom duration, clinical features, radiological
      and pathological findings, three were diagnosed with chronic and one with
      subacute hypersensitivity pneumonitis. Patients with hypersensitivity pneumonitis
      and those with DPLD were compared by means of age, sex, smoking status, symptom
      duration, haematology, erythrocyte sedimentation rate, peripheral cell count,
      spirometric parameters, blood gases, and diffusion capacity. No statistically
      significant difference was detected in these parameters except for forced
      expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). In
      conclusion, patients with a history of antigen exposure, with mild symptoms such
      as dry cough and dyspnoea, and who have diffuse interstitial lung involvement on
      radiology should be carefully evaluated for hypersensitivity pneumonitis.
      Moreover, among other DPLDs, stable FEV(1) or FVC values may be the clues for
      establishing the diagnosis of hypersensitivity pneumonitis. However, further
      studies are needed in larger series of patients.

PMID- 15192168
TI  - Clinical presentation of acute chest syndrome in sickle cell disease.
AB  - In this study the records of 45 patients with sickle cell disease involved in 63
      presentations of acute chest syndrome at the Princess Margaret Hospital in
      Nassau, the Bahamas, between 1997 and 2001 were examined. Patients were divided
      into three groups on the basis of age (<13 years, 13-18 years, >/=19 years) with
      a view to assessing clinical presentation. The incidence of symptoms, physical
      signs, and laboratory findings were enumerated and significant differences
      between age groups determined. The data were analysed using analysis of variance,
      t test, and chi(2) test and compared with existing knowledge on the subject. This
      study proposed to evaluate the clinical presentation of acute chest syndrome with
      emphasis on historical and physical findings, and to encourage the physician to
      maintain a high index of suspicion for the condition in susceptible patients. It
      was found that presentation varied significantly with age groups, children
      presenting most classically with fever and cough and adults, with chest pain. The
      13-18 age group emerged as the group which presented most frequently with the
      typical symptoms of chest infection, thus potentially making diagnosis easier. Of
      note, the most frequent finding was a normal examination, while the second
      commonest physical finding was crepitations on auscultation of the chest.

PMID- 15192169
TI  - The Medical Society of London.
AB  - The Medical Society of London was founded in 1773 by the Quaker physician and
      philanthropist, Dr John Coakley Lettsom, who was convinced that a combined
      membership of physicians, surgeons, and apothecaries would prove productive. His
      revolutionary idea met with success and the Society has provided a forum for all
      branches of the medical profession for the last 231 years. Situated at the heart
      of London's medical community at Lettsom House, Chandos Street, near Cavendish
      Square, this is the oldest medical society in the United Kingdom.

PMID- 15192170
TI  - Bullosis diabeticorum.

PMID- 15192171
TI  - A novel multimedia tool to improve bedside teaching of cardiac auscultation.
AB  - Training in cardiac auscultation is a core element of undergraduate teaching but
      recent studies have documented a remarkable decline in auscultatory skills.
      Therefore there is an interest in new ways to teach cardiac auscultation. In
      analogy to phonocardiography, an electronic system for simultaneous auscultation
      and visualisation of murmurs was sought. For this purpose, an electronic
      stethoscope was linked to a laptop computer and software created to visualise
      auscultatory findings. In a preliminary trial in undergraduate students, this
      approach greatly facilitated teaching. Amalgamating traditional phonocardiography
      with a multimedia approach, this system represents a novel tool for bedside
      teaching of cardiac auscultation.

PMID- 15192172
TI  - Genital condylomata in a patient receiving infliximab for Crohn's disease.
AB  - Infliximab is a monoclonal antibody against tumour necrosis factor-alpha. Recent
      studies have shown that it is effective in treating patients with refractory
      Crohn's disease and in those with Crohn's fistulae. Though this drug is found to
      be safe in clinical trials, sporadic reports of serious complications have been
      recorded in the literature. The case of a patient who developed profuse genital
      warts after infliximab treatment is reported. The literature is reviewed and
      information is presented on side effects and complications as a result of
      infliximab therapy.

PMID- 15192173
TI  - Rocking bed and prolonged independence from nocturnal non-invasive ventilation in
      neurogenic respiratory failure associated with limb weakness.
AB  - A 40 year old mother of three with autosomal dominant scapuloperoneal muscular
      dystrophy presented with severe neurogenic respiratory failure requiring
      nocturnal non-invasive ventilation (NIV). Because of the development of profound
      proximal muscular weakness as a consequence of the progressive nature of her
      neurological disease, she eventually was unable to apply and remove the facial
      interface to set up her NIV circuit. She therefore became dependent on her
      children and carers to start and stop NIV during the night. A rocking bed was
      successfully employed as an alternative to nocturnal NIV. Ventilation was
      facilitated by the passive movement of the diaphragm as a consequence of the
      movement of the abdominal contents under the effect of gravity. Benefit was
      demonstrated objectively by pulse oximetry and subjectively by the improvement in
      the patient's symptomatology and continued independence at night. The ease of use
      of a rocking bed should be borne in mind when the necessity for nocturnal
      ventilatory support in neuromuscular disease results in the potential loss of
      independence for a patient.

PMID- 15192174
TI  - Endoscopic view of a gall stone impacted in the duodenum.

PMID- 15192175
TI  - Dramatic levodopa responsiveness of dystonia in a sporadic case of
      spinocerebellar ataxia type 3.
AB  - A genetically confirmed case of spinocerebellar ataxia type 3 (SCA 3), presenting
      with disabling foot dystonia, peripheral neuropathy, and minimal cerebellar signs
      is reported. The dystonia improved dramatically with levodopa treatment in the
      absence of additional parkinsonian feature. A trial of levodopa for dystonia in
      SCA 3 may be of therapeutic benefit, at least in the initial stage of the
      disease.

PMID- 15192176
TI  - Myocarditis as a prognostic indicator in systemic lupus erythematosus.
AB  - Lupus myocarditis is a life threatening complication of systemic lupus
      erythematosus (SLE). A case of left ventricular failure secondary to myocarditis
      occurring in a patient with SLE is reported. Despite resolution of the cardiac
      failure with pulsed cyclophosphamide and steroids, she eventually died of non
      cardiac complications 18 months later. The literature is also reviewed.

PMID- 15192177
TI  - A peculiar rash and red eye.

PMID- 15192178
TI  - Left pleural effusion in a woman with coronary artery by-pass grafting.

PMID- 15192184
TI  - Climate change and climate science.

PMID- 15192179
TI  - A painful swollen hand.

PMID- 15192185
TI  - Antidepressants and children. Buried data can be hazardous to a company's health.

PMID- 15192186
TI  - Immunology. Unexpectedly, ancient molecule tied to asthma.

PMID- 15192187
TI  - Agbiotech. Report says India needs stronger, independent regulatory body.

PMID- 15192188
TI  - Astronomy. Spitzer Telescope weighs and dates a primeval galaxy.

PMID- 15192189
TI  - Particle physics. Top quark tips the scale for a heavier Higgs boson.

PMID- 15192190
TI  - Astronomy. Giant black holes shed their dusty veils.

PMID- 15192191
TI  - Education research. Meager evaluations make it hard to find out what works.

PMID- 15192192
TI  - Roger Payne profile. A toxic odyssey.

PMID- 15192194
TI  - Astronomy. Aliens in the neighborhood?

PMID- 15192193
TI  - Astronomy. Astronomers shine a light upon dim nearby stars.

PMID- 15192195
TI  - The Biology of Genomes meeting. The case of the disappearing DNA hotspots.

PMID- 15192196
TI  - The Biology of Genomes meeting. Disposable DNA puzzles researchers.

PMID- 15192197
TI  - The Biology of Genomes meeting. Surveys reveal vast numbers of genes.

PMID- 15192198
TI  - Fish in deep-water coral habitats.

PMID- 15192199
TI  - Starting a global scientific journal.

PMID- 15192200
TI  - Hog picture doesn't tell whole story.

PMID- 15192201
TI  - A new beginning.

PMID- 15192202
TI  - Predicting protein structures accurately.

PMID- 15192203
TI  - Building on the IGY anniversary.

PMID- 15192204
TI  - Geology. Building for earthquakes.

PMID- 15192205
TI  - Behavior. Can a dog learn a word?

PMID- 15192206
TI  - Materials science. Fundamental size limits in ferroelectricity.

PMID- 15192207
TI  - Developmental biology. A linker histone restricts muscle development.

PMID- 15192208
TI  - Paleoclimate. Do I hear a million?

PMID- 15192209
TI  - Developmental biology. Hox genes in the limb: a play in two acts.

PMID- 15192211
TI  - Soil and trouble.

PMID- 15192212
TI  - Wounding Earth's fragile skin.

PMID- 15192213
TI  - From Alaska to Yucatan, a long-awaited soil survey takes shape.

PMID- 15192214
TI  - Defrosting the carbon freezer of the north.

PMID- 15192215
TI  - The secret life of fungi.

PMID- 15192216
TI  - Soil carbon sequestration impacts on global climate change and food security.
AB  - The carbon sink capacity of the world's agricultural and degraded soils is 50 to
      66% of the historic carbon loss of 42 to 78 gigatons of carbon. The rate of soil
      organic carbon sequestration with adoption of recommended technologies depends on
      soil texture and structure, rainfall, temperature, farming system, and soil
      management. Strategies to increase the soil carbon pool include soil restoration
      and woodland regeneration, no-till farming, cover crops, nutrient management,
      manuring and sludge application, improved grazing, water conservation and
      harvesting, efficient irrigation, agroforestry practices, and growing energy
      crops on spare lands. An increase of 1 ton of soil carbon pool of degraded
      cropland soils may increase crop yield by 20 to 40 kilograms per hectare (kg/ha)
      for wheat, 10 to 20 kg/ha for maize, and 0.5 to 1 kg/ha for cowpeas. As well as
      enhancing food security, carbon sequestration has the potential to offset fossil
      fuel emissions by 0.4 to 1.2 gigatons of carbon per year, or 5 to 15% of the
      global fossil-fuel emissions.

PMID- 15192217
TI  - Breaking the sod: humankind, history, and soil.
AB  - For most of history, few things have mattered more to human communities than
      their relations with soil, because soil provided most of their food and
      nutrients. Accordingly, some of the earliest written documents were agricultural
      manuals intended to organize, preserve, and impart soil knowledge. Indeed,
      ancient civilizations often worshipped the soil as the foundry of life itself.
      For the past century or two, nothing has mattered more for soils than their
      relations with human communities, because human action inadvertently ratcheted up
      rates of soil erosion and, both intentionally and unintentionally, rerouted
      nutrient flows.

PMID- 15192218
TI  - Ecological linkages between aboveground and belowground biota.
AB  - All terrestrial ecosystems consist of aboveground and belowground components that
      interact to influence community- and ecosystem-level processes and properties.
      Here we show how these components are closely interlinked at the community level,
      reinforced by a greater degree of specificity between plants and soil organisms
      than has been previously supposed. As such, aboveground and belowground
      communities can be powerful mutual drivers, with both positive and negative
      feedbacks. A combined aboveground-belowground approach to community and ecosystem
      ecology is enhancing our understanding of the regulation and functional
      significance of biodiversity and of the environmental impacts of human-induced
      global change phenomena.

PMID- 15192220
TI  - Early precision compound machine from ancient China.

PMID- 15192219
TI  - Interactions and self-organization in the soil-microbe complex.
AB  - Soil is the most complicated biomaterial on the planet. As with any material, the
      physical habitat is of prime importance in determining and regulating biological
      activity. However, until recently the opaque nature of soil has meant that any
      interrogation of its interior architecture has been relatively rudimentary,
      restricted to simple qualitative expressions of the physical heterogeneity that
      fail to relate to any specific function. However, new techniques and insights
      into the biophysical and biochemical processes of this inner space are leading to
      the developments of theoretical frameworks and experimental approaches that will
      allow us to sustainably manage Earth's most important resource. We introduce the
      concept that the soil-microbe system is self-organized and suggest new priorities
      for research based on an integrative approach that combines biochemistry and
      biophysics.

PMID- 15192221
TI  - Phospholipid metabolism regulated by a transcription factor sensing phosphatidic
      acid.
AB  - Cells regulate the biophysical properties of their membranes by coordinated
      synthesis of different classes of lipids. Here, we identified a highly dynamic
      feedback mechanism by which the budding yeast Saccharomyces cerevisiae can
      regulate phospholipid biosynthesis. Phosphatidic acid on the endoplasmic
      reticulum directly bound to the soluble transcriptional repressor Opi1p to
      maintain it as inactive outside the nucleus. After the addition of the lipid
      precursor inositol, this phosphatidic acid was rapidly consumed, releasing Opi1p
      from the endoplasmic reticulum and allowing its nuclear translocation and
      repression of target genes. Thus, phosphatidic acid appears to be both an
      essential ubiquitous metabolic intermediate and a signaling lipid.

PMID- 15192222
TI  - Femtotesla magnetic field measurement with magnetoresistive sensors.
AB  - The measurement of magnetic fields in the femtotesla (fT, 10(-15) tesla) range is
      important for applications such as magnetometry, quantum computing, solid-state
      nuclear magnetic resonance, and magnetoencephalography. The only sensors capable
      of detecting these very small fields have been based on low-temperature
      superconducting quantum interference devices operating at 4.2 kelvin. We present
      a magnetic field sensor that combines a superconducting flux-to-field transformer
      with a low-noise giant magnetoresistive sensor. The sensor can be operated up to
      77 kelvin. Our small-size prototype provides the capability of measuring 32 fT.

PMID- 15192223
TI  - Ferroelectricity in ultrathin perovskite films.
AB  - Understanding the suppression of ferroelectricity in perovskite thin films is a
      fundamental issue that has remained unresolved for decades. We report a
      synchrotron x-ray study of lead titanate as a function of temperature and film
      thickness for films as thin as a single unit cell. At room temperature, the
      ferroelectric phase is stable for thicknesses down to 3 unit cells (1.2
      nanometers). Our results imply that no thickness limit is imposed on practical
      devices by an intrinsic ferroelectric size effect.

PMID- 15192225
TI  - Iron isotope fractionation and the oxygen fugacity of the mantle.
AB  - The oxygen fugacity of the mantle exerts a fundamental influence on mantle
      melting, volatile speciation, and the development of the atmosphere. However, its
      evolution through time is poorly understood. Changes in mantle oxidation state
      should be reflected in the Fe3+/Fe2+ of mantle minerals, and hence in stable iron
      isotope fractionation. Here it is shown that there are substantial (1.7 per mil)
      systematic variations in the iron isotope compositions (delta57/54Fe) of mantle
      spinels. Spinel delta57/54Fe values correlate with relative oxygen fugacity,
      Fe3+/sigmaFe, and chromium number, and provide a proxy of changes in mantle
      oxidation state, melting, and volatile recycling.

PMID- 15192224
TI  - Oxoiron(IV) in chloroperoxidase compound II is basic: implications for P450
      chemistry.
AB  - With the use of x-ray absorption spectroscopy, we have found that the Fe-O bond
      in chloroperoxidase compound II (CPO-II) is much longer than expected for an
      oxoiron(IV) (ferryl) unit; notably, the experimentally determined bond length of
      1.82(1) A accords closely with density functional calculations on a protonated
      ferryl (Fe(IV)-OH, 1.81 A). The basicity of the CPO-II ferryl [pKa > 8.2 (where
      Ka is the acid dissociation constant)] is attributable to strong electron
      donation by the axial thiolate. We suggest that the CPO-II protonated ferryl is a
      good model for the rebound intermediate in the P450 oxygenation cycle;with
      elevated pKa values after one-electron reduction, thiolate-ligated ferryl
      radicals are competent to oxygenate saturated hydrocarbons at potentials that can
      be tolerated by folded polypeptide hosts.

PMID- 15192226
TI  - New Zealand maritime glaciation: millennial-scale southern climate change since
      3.9 Ma.
AB  - Ocean Drilling Program Site 1119 is ideally located to intercept discharges of
      sediment from the mid-latitude glaciers of the New Zealand Southern Alps. The
      natural gamma ray signal from the site's sediment core contains a history of the
      South Island mountain ice cap since 3.9 million years ago (Ma). The younger
      record, to 0.37 Ma, resembles the climatic history of Antarctica as manifested by
      the Vostok ice core. Beyond, and back to the late Pliocene, the record may serve
      as a proxy for both mid-latitude and Antarctic polar plateau air temperature. The
      gamma ray signal, which is atmospheric, also resembles the ocean climate history
      represented by oxygen isotope time series.

PMID- 15192227
TI  - Seawater sulfur isotope fluctuations in the Cretaceous.
AB  - The exogenic sulfur cycle is tightly coupled with the carbon and oxygen cycles,
      and therefore a central component of Earth's biogeochemistry. Here we present a
      high-resolution record of the sulfur isotopic composition of seawater sulfate for
      the Cretaceous. The general enrichment of isotopically light sulfur that
      prevailed during the Cretaceous may have been due to increased volcanic and
      hydrothermal activity. Two excursions toward isotopically lighter sulfur
      represent periods of lower rates of pyrite burial, implying a shift in the
      location of organic carbon burial to terrestrial or open-ocean settings. The
      concurrent changes in seawater sulfur and inorganic carbon isotopic compositions
      imply short-term variability in atmospheric oxygen partial pressure.

PMID- 15192228
TI  - Soils, agriculture, and society in precontact Hawai'i.
AB  - Before European contact, Hawai'i supported large human populations in complex
      societies that were based on multiple pathways of intensive agriculture. We show
      that soils within a long-abandoned 60-square-kilometer dryland agricultural
      complex are substantially richer in bases and phosphorus than are those just
      outside it, and that this enrichment predated the establishment of intensive
      agriculture. Climate and soil fertility combined to constrain large dryland
      agricultural systems and the societies they supported to well-defined portions of
      just the younger islands within the Hawaiian archipelago; societies on the older
      islands were based on irrigated wetland agriculture. Similar processes may have
      influenced the dynamics of agricultural intensification across the tropics.

PMID- 15192229
TI  - A dual role for Hox genes in limb anterior-posterior asymmetry.
AB  - Anterior-to-posterior patterning, the process whereby our digits are differently
      shaped, is a key aspect of limb development. It depends on the localized
      expression in posterior limb bud of Sonic hedgehog (Shh) and the morphogenetic
      potential of its diffusing product. By using an inversion of and a large
      deficiency in the mouse HoxD cluster, we found that a perturbation in the early
      collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a loss of
      asymmetry. Ectopic Hox gene expression triggered abnormal Shh transcription,
      which in turn induced symmetrical expression of Hox genes in digits, thereby
      generating double posterior limbs. We conclude that early posterior restriction
      of Hox gene products sets up an anterior-posterior prepattern, which determines
      the localized activation of Shh. This signal is subsequently translated into
      digit morphological asymmetry by promoting the late expression of Hoxd genes, two
      collinear processes relying on opposite genomic topographies, upstream and
      downstream Shh signaling.

PMID- 15192230
TI  - Phosphoryl transfer and calcium ion occlusion in the calcium pump.
AB  - A tight coupling between adenosine triphosphate (ATP) hydrolysis and vectorial
      ion transport has to be maintained by ATP-consuming ion pumps. We report two
      crystal structures of Ca2+-bound sarco(endo)plasmic reticulum Ca2+-adenosine
      triphosphatase (SERCA) at 2.6 and 2.9 angstrom resolution in complex with (i) a
      nonhydrolyzable ATP analog [adenosine (beta-gamma methylene)-triphosphate] and
      (ii) adenosine diphosphate plus aluminum fluoride. SERCA reacts with ATP by an
      associative mechanism mediated by two Mg2+ ions to form an aspartyl
      phosphorylated intermediate state (Ca2-E1 approximately P). The conformational
      changes that accompany the reaction with ATP pull the transmembrane helices 1 and
      2 and close a cytosolic entrance for Ca2+, thereby preventing backflow before
      Ca2+ is released on the other side of the membrane.

PMID- 15192231
TI  - MSX1 cooperates with histone H1b for inhibition of transcription and myogenesis.
AB  - During embryogenesis, differentiation of skeletal muscle is regulated by
      transcription factors that include members of the Msx homeoprotein family. By
      investigating Msx1 function in repression of myogenic gene expression, we
      identified a physical interaction between Msx1 and H1b, a specific isoform of
      mouse histone H1. We found that Msx1 and H1b bind to a key regulatory element of
      MyoD, a central regulator of skeletal muscle differentiation, where they induce
      repressed chromatin. Moreover, Msx1 and H1b cooperate to inhibit muscle
      differentiation in cell culture and in Xenopus animal caps. Our findings define a
      previously unknown function for "linker" histones in gene-specific
      transcriptional regulation.

PMID- 15192232
TI  - Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway
      activation.
AB  - Chitin is a surface component of parasites and insects, and chitinases are
      induced in lower life forms during infections with these agents. Although chitin
      itself does not exist in humans, chitinases are present in the human genome. We
      show here that acidic mammalian chitinase (AMCase) is induced via a T helper-2
      (Th2)-specific, interleukin-13 (IL-13)-mediated pathway in epithelial cells and
      macrophages in an aeroallergen asthma model and expressed in exaggerated
      quantities in human asthma. AMCase neutralization ameliorated Th2 inflammation
      and airway hyperresponsiveness, in part by inhibiting IL-13 pathway activation
      and chemokine induction. AMCase may thus be an important mediator of IL-13
      induced responses in Th2-dominated disorders such as asthma.

PMID- 15192233
TI  - Word learning in a domestic dog: evidence for "fast mapping".
AB  - During speech acquisition, children form quick and rough hypotheses about the
      meaning of a new word after only a single exposure-a process dubbed "fast
      mapping." Here we provide evidence that a border collie, Rico, is able to fast
      map. Rico knew the labels of over 200 different items. He inferred the names of
      novel items by exclusion learning and correctly retrieved those items right away
      as well as 4 weeks after the initial exposure. Fast mapping thus appears to be
      mediated by general learning and memory mechanisms also found in other animals
      and not by a language acquisition device that is special to humans.

PMID- 15192236
TI  - Homocysteine, vitamin B6, and endothelial dysfunction in circulatory disorders.

PMID- 15192238
TI  - Cerebral ischemia, matrix metalloproteinases, and TNF-alpha: MMP inhibitors may
      act not exclusively by reducing MMP activity.

PMID- 15192239
TI  - Stroke risk after transient ischemic attack in a population-based setting.
AB  - BACKGROUND AND PURPOSE: Stroke risk after transient ischemic attack (TIA) has not
      been examined in an ethnically diverse population-based community setting. The
      purpose of this study was to identify stroke risk among TIA patients in a
      population-based cerebrovascular disease surveillance project. METHODS: The Brain
      Attack Surveillance in Corpus Christi (BASIC) Project prospectively ascertains
      stroke and TIA cases in a geographically isolated Southeast Texas County. The
      community is approximately half Mexican American and half nonHispanic white.
      Cases are validated by board-certified neurologists using source documentation.
      Cumulative risk for stroke after TIA was determined using Kaplan-Meier estimates.
      Cox proportional hazards regression was used to test for associations between
      stroke risk after TIA and demographics, symptoms, risk factors, and history of
      stroke/TIA. RESULTS: BASIC identified 612 TIA cases between January 1, 2000, and
      December 31, 2002; 60.9% were female and 48.0% were Mexican American. Median age
      was 73.8 years. Stroke risk within 2 days, 7 days, 30 days, 90 days, and 12
      months was 1.64%, 1.97%, 3.15%, 4.03%, and 7.27%, respectively. Stroke risk was
      not influenced by ethnicity, symptoms, or risk factors. CONCLUSIONS: Using a
      population-based design, we found that early stroke risk after TIA was less than
      previously reported in this bi-ethnic population of Mexican Americans and
      nonHispanic whites. Approximately half of the 90-day stroke risk after TIA
      occurred within 2 days.

PMID- 15192240
TI  - Ethnic disparities in risk factors for stroke: what are the implications?

PMID- 15192242
TI  - Infiltrating macrophages as in vivo targets for intravenous gene delivery in
      cerebral infarction.
AB  - BACKGROUND AND PURPOSE: Gene therapy may show promise for stroke patients, but
      invasive techniques such as intraventricular or intracerebral injection of
      therapeutic genes may have limited applicability. The purpose of this study is to
      develop systemic gene therapy using macrophages infiltrating the infarct to
      deliver and express the gene. METHODS: After permanent middle cerebral artery
      occlusion in rats, an enhanced green fluorescent protein (EGFP) plasmid conjugate
      in liposomes was injected via the femoral vein. We also constructed a bicistronic
      plasmid vector for fibroblast growth factor-2 (FGF-2) as well as EGFP,
      administering it in other rats with middle cerebral artery occlusion. RESULTS:
      EGFP expression in normal brain was absent but was strong in macrophages
      accumulating along the infarct border. FGF-2 protein production was induced in
      macrophages along the infarct border after injection of bicistronic FGF-2 and
      EGFP plasmid vector; this stimulated proliferation of neural progenitors in the
      subventricular zone in the ischemic hemisphere compared with control plasmid
      vectors (61.7+/-5.2 versus 42.2+/-5.5 cells per mm2, n=4 each, P<0.01).
      CONCLUSIONS: Systemic gene transfer by liposome to macrophages infiltrating an
      infarct may prove useful for gene therapy in stroke.

PMID- 15192241
TI  - Insular cortical ischemia is independently associated with acute stress
      hyperglycemia.
AB  - BACKGROUND AND PURPOSE: Acute poststroke hyperglycemia has been associated with
      larger infarct volumes and a cortical location, regardless of diabetes status.
      Stress hyperglycemia has been attributed to activation of the hypothalamic
      pituitary-adrenal axis but never a specific cortical location. We tested the
      hypothesis that damage to the insular cortex, a site with autonomic connectivity,
      results in hyperglycemia reflecting sympathoadrenal dysregulation. METHODS:
      Diffusion-weighted MRI, glycosylated hemoglobin (HbA1c), and blood glucose
      measurements were obtained in 31 patients within 24 hours of ischemic stroke
      onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and
      involvement of the insular cortex was assessed on T2-weighted images. RESULTS:
      Median admission glucose was significantly higher in patients with insular
      cortical ischemia (8.6 mmol/L; n=14) compared with those without (6.5 mmol/L;
      n=17; P=0.006). Multivariate linear regression demonstrated that insular cortical
      ischemia was a significant independent predictor of glucose level (P=0.001), as
      was pre-existing diabetes mellitus (P=0.008). After controlling for the effect of
      insular cortical ischemia, DWI lesion volume was not associated with higher
      glucose levels (P=0.849). There was no association between HbA1c and glucose
      level (P=0.737). CONCLUSIONS: Despite the small sample size, insular cortical
      ischemia appeared to be associated with the production of poststroke
      hyperglycemia. This relationship is independent of pre-existing glycemic status
      and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1
      aspect of a more generalized acute stress response. Future studies of poststroke
      hyperglycemia should account for the effect of insular cortical ischemia.

PMID- 15192243
TI  - Basilar artery vasospasm and delayed posterior circulation ischemia after
      aneurysmal subarachnoid hemorrhage.
AB  - BACKGROUND AND PURPOSE: The clinical and hemodynamic impacts of basilar artery
      (BA) vasospasm (VS) after aneurysmal subarachnoid hemorrhage (SAH) are ill
      defined. The purpose of the present study was to evaluate the relationship
      between BA-VS and regional cerebral blood flow (rCBF) with posterior circulation
      after aneurysmal SAH. METHODS: Daily transcranial Doppler (TCD) measurements of
      posterior and anterior circulation arteries were conducted in 162 patients with
      aneurysmal SAH. rCBF to the brain stem (BS) and other brain territories was
      assessed by multiple single-photon emission computed tomography with (99m)Tc
      ethyl cysteinate dimer single-photon emission computed tomography (ECD-SPECT)
      imaging during the course of VS. RESULTS: SPECT imaging showed delayed BS
      hypoperfusion in 29 patients (17.9%). Of them, 23 patients (79.3%) were found to
      have BA-VS. Patients with very high BA flow velocities (FVs; >115 cm/s) had a 50%
      chance of developing delayed BS ischemia. BA-VS was found at a higher rate in
      patients who experienced reduced rCBF in the cerebellum (56.3%), thalamic nuclei
      (68.4%), and occipital lobe (81.8%). Although patients with delayed BS
      hypoperfusion did not present with a higher clinical grade, their clinical
      outcome was significantly worse (Glasgow Outcome Score after 30 days 2.48+/-1.16
      versus 3.3+/-1.27; P=0.001). CONCLUSIONS: These findings suggest for the first
      time that BA-VS after aneurysmal SAH is associated with hypoperfusion to BS and
      other posterior circulation territories. The risk for delayed BS ischemia
      increased significantly when TCD BA-FVs were >115 cm/s.

PMID- 15192244
TI  - Cognitive functioning in preclinical vascular dementia: a 6-year follow-up.
AB  - BACKGROUND AND PURPOSE: Recent studies have shown that cognitive deficits are
      present during the years preceding a diagnosis of vascular dementia (VaD). The
      aims of this study were to (1) extend previous research by examining whether
      cognitive deficits are already present 6 years before diagnosis, and (2) examine
      the strength of the association between cognitive performance and a future VaD
      diagnosis after controlling for previous vascular disorders. METHODS: Subjects
      from a population-based study of very old persons (> or =75) were examined with a
      test of global cognitive functioning (the Mini-Mental State Examination [MMSE])
      at 3 occasions over a 6-year period. The study sample was nondemented the first 2
      measurement times. On the last occasion, 22 individuals were diagnosed with VaD,
      and 450 persons remained nondemented. RESULTS: The preclinical VaD group showed
      no MMSE deficits 6 years before diagnosis (P>0.10) compared with the controls.
      However, 3 years before diagnosis, poor cognitive performance was significantly
      associated with forthcoming VaD after controlling for demographic factors and
      prior vascular disorders (odds ratio, 2.55; 95% CI, 1.67 to 3.89). CONCLUSIONS:
      This study extends previous findings on preclinical cognitive deficits in VaD and
      suggests that cognitive measures can be useful in the process of recognizing
      individuals at risk for developing VaD to initiate early treatment.

PMID- 15192245
TI  - Contribution of susceptibility-weighted imaging to acute stroke assessment.
AB  - BACKGROUND: Susceptibility-weighted (SW) MRI provides insight into the
      pathophysiology of acute stroke. We report on the use of SW imaging (SWI)
      sequences in clinical practice and highlight the future applications. SUMMARY OF
      REVIEW: SWI exploits the magnetic susceptibility effects generated by local
      inhomogeneities of the magnetic field. The paramagnetic properties of
      deoxyhemoglobin support signal changes related to acute hemorrhage and the
      intravascular spontaneous blood oxygen level dependent (BOLD) effect. SWI allows
      the early detection of acute hemorrhage within 6 hours after symptom onset. SWI
      may also identify previous microbleeds in acute ischemia; however, the impact of
      these findings on thrombolytic therapy safety has not been definitely
      established. The diagnosis of arterial occlusion is usually performed by magnetic
      resonance angiography. SWI allows intravascular clot detection at the acute
      stage.Substantial experimental data suggest that spontaneous BOLD contrast may
      improve tissue viability assessment. The ratio of oxyhemoglobin to
      deoxyhemoglobin, measured by MRI in the capillary and venous compartments,
      reflects the oxygen extraction fraction (OEF) and the cerebral metabolic rate of
      oxygen. The combination of magnetic resonance (MR)-measured OEF and cerebral
      blood flow, via perfusion studies, may provide information about tissue
      viability. CONCLUSIONS: SWI offers a spectrum of current clinical applications
      and may improve our knowledge of the pathophysiology of acute stroke.

PMID- 15192246
TI  - Soluble thrombomodulin and brain infarction: case-control and prospective study.
AB  - BACKGROUND AND PURPOSE: Increased soluble thrombomodulin (sTM) concentration has
      been associated with recurrent coronary events, whereas in one prospective study
      it predicted fewer first-ever coronary events. One study found no relationship
      between brain infarction (BI) and sTM levels. Among all subjects of the Etude du
      Profil Genetique de l'Infarctus Cerebral (GENIC) cohort and those free of
      previous vascular history, we investigated the relationship between sTM level and
      BI risk, and among cases, its relationship with BI prognosis. METHODS: Patients
      with BI (n=492) were consecutively recruited from 12 centers. Hospital controls
      without a history of stroke (n=492) were individually matched for age, sex, and
      center. Blood samples were collected after hospitalization. Determination of sTM
      levels was centralized in a single laboratory. RESULTS: Soluble TM concentration
      significantly increased with age and hypertensive status, but was similar in
      cases and controls. With analyses restricted to 278 pairs of subjects with no
      previous vascular history, sTM concentration >59.6 microg/L (second and third
      tertiles compared with the first) was associated with fewer first-ever BI
      (adjusted odds ratio of 0.56 (95% CI, 0.35 to 0.89; P=0.014). Among the cases,
      increased sTM concentration was associated with a higher death rate after a
      median follow-up of 5.2 (1.4 to 6.4) years. The adjusted hazard ratio per 1 SD of
      sTM concentration increase (34.2 microg/L) was 1.19 (95% CI, 1.02 to 1.39;
      P=0.028). CONCLUSIONS: Increased sTM concentration may be protective against BI
      in subjects with no previous vascular disease, whereas it may predict a fatal
      outcome in patients who have already had a BI. Consequently, sTM levels should be
      interpreted according to vascular history.

PMID- 15192247
TI  - Diagnostic impact of transcranial color-coded real-time sonography with echo
      contrast agents for hyperperfusion syndrome after carotid endarterectomy.
AB  - BACKGROUND AND PURPOSE: The purpose of the present study was to evaluate
      availability of transcranial color-coded real-time sonography (TCCS) to detect
      hyperperfusion after carotid endarterectomy (CEA). METHODS: This prospective
      study included 105 consecutive patients who underwent CEA for severe carotid
      stenosis. TCCS with echo contrast agents was performed serially to evaluate flow
      velocity of the middle cerebral artery (MCA). Regional cerebral blood flow (rCBF)
      and vasodilatory capacity of the MCA territory were evaluated using single-photon
      emission computed tomography. We compared the changes in MCA flow velocity with
      rCBF. RESULTS: Using echo contrast agents, we could evaluate the MCA flow in 95
      (90%) of 105 patients. Twelve patients showed hyperperfusion syndrome. Changes in
      the MCA mean flow velocity (MFV) before and 4 days after CEA were significantly
      correlated with those in rCBF (r=0.48; P<0.0001). An increase of >50% in MCA MFV
      was observed within 4 days after CEA in all 12 patients with hyperperfusion
      syndrome. Multivariate analysis revealed that reduced vasodilatory capacity (odds
      ratio, 0.14; 95% CI, 0.04 to 0.46) was an independent risk factor for a 1.5-fold
      increase in the MFV of MCA ipsilateral to CEA. CONCLUSIONS: Findings of a 1.5
      fold increase in the MCA MFV can accurately identify those patients with high
      risk of developing post-CEA hyperperfusion syndrome. TCCS with echo contrast
      agents is available for the evaluation of hyperperfusion after CEA.

PMID- 15192248
TI  - Underestimation of the early risk of recurrent stroke: evidence of the need for a
      standard definition.
AB  - BACKGROUND: There is considerable variation in the definitions used for recurrent
      stroke. Most epidemiological studies exclude events within the first 28 days (eg,
      Monitoring Trends and Determinants in Cardiovascular Disease [MONICA]) or events
      within 21 days in the same territory as the presenting event (eg, most stroke
      incidence studies). However, recurrence is most common during this early period
      and these restrictive definitions could underestimate the benefits of early
      prevention. METHODS: We determined the 90-day risk of recurrence after incident
      ischemic stroke in 2 population-based cohorts (Oxford Vascular Study [OXVASC] and
      Oxfordshire Community Stroke Project [OCSP]) with the 3 most common definitions:
      any stroke > or =24 hours after the incident event excluding early deterioration
      not caused by a stroke (definition A); as above, but excluding any stroke within
      21 days in the same territory as the incident event (definition B); and any
      stroke > or =28 days after the incident event (definition C). RESULTS: 657
      patients had 93 recurrent strokes between 24 hours and 90 days after the incident
      event. The 90-day recurrence risks (95% CI) using definition A were 14.5% (11.5
      to 17.5) in the OCSP and 18.3% (10.8 to 25.8) in the OXVASC. The equivalent risks
      using definitions B and C were 8.3% (5.9 to 10.8) and 4.8% (2.8 to 6.7),
      respectively, in the OCSP and 7.0% (1.6 to 12.4) and 5.9% (1.0 to 10.9) in the
      OXVASC. The definition A risk of recurrence was particularly high after partial
      anterior (22.9%,17.5 to 28.2) and posterior (19.5%,13.0 to 25.9) circulation
      strokes. CONCLUSIONS: The 3 most widely used definitions of recurrent stroke
      yield markedly different 90-day risks. We suggest that, where possible,
      definition A be adopted as the standard to avoid underestimation of risk and to
      allow valid comparison of different studies.

PMID- 15192249
TI  - Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylene
      tetrahydrofolate reductase mutation in cerebral venous thrombosis.
AB  - BACKGROUND AND PURPOSE: Elevated plasma levels of homocysteine are associated
      with an increased risk of deep-vein thrombosis. Through a case-control study, we
      examined the potential association among homocysteine, folate and vitamin B12
      levels, and the common C677-->T mutation in the methylene tetrahydrofolate
      reductase (MTHFR) gene in patients with cerebral venous thrombosis (CVT).
      METHODS: Forty-five patients with CVT and 90 control subjects were studied.
      Plasma levels of homocysteine (fasting and after methionine load), folate, and
      vitamin B12 were measured. Genotyping of the MTHFR gene was also performed. The
      estimated risk of CVT associated with hyperhomocysteinemia, low vitamin levels,
      and MTHFR mutation were expressed as odds ratio (OR) and its 95% CI (crude and
      after adjusting by other independent variables). RESULTS: The adjusted OR for CVT
      associated with high (>90th percentile) fasting levels of homocysteine was 4.6
      (1.6 to 12.8). The association between low plasma folate values (<10th
      percentile) and presence of CVT was 3.5 (1.2 to 10.0) after adjustment for
      confounding factors. There was a higher frequency of MTHFR mutation in patients
      with CVT (22% versus 10%), but it was not statistically significant (P=0.098).
      Patients with MTHFR mutation and low folate levels presented the highest
      homocysteine levels. CONCLUSIONS: High plasma concentrations of homocysteine and
      low plasma folate levels were associated with an increased risk of CVT in this
      population in which low socioeconomic conditions and deficient nutritional status
      may contribute to its relatively high incidence.

PMID- 15192250
TI  - Short-term effects of practice with trunk restraint on reaching movements in
      patients with chronic stroke: a controlled trial.
AB  - BACKGROUND AND PURPOSE: In prehension tasks with objects placed within arm's
      reach, patients with hemiparesis caused by stroke use excessive trunk movement to
      compensate for arm motor impairments. Compensatory trunk movements may improve
      motor function in the short term but may limit arm recovery in the long term.
      Previous studies showed that restriction of trunk movements during reach-to-grasp
      movements results in immediate increases in active arm joint ranges and
      improvement in interjoint coordination. To evaluate the potential of this
      technique as a therapeutic intervention, we compared the effects of short-term
      reach-to-grasp training (60-trial training session) with and without physical
      trunk restraint on arm movement patterns in patients with chronic hemiparesis.
      METHODS: A total of 28 patients with hemiparesis were assigned to 2 groups: 1
      group practiced reach-to-grasp movements during which compensatory movement of
      the trunk was prevented by a harness (trunk restraint), and the second group
      practiced the same task while verbally instructed not to move the trunk
      (control). Kinematics of reaching and grasping an object placed within arm's
      length were recorded before, immediately after, and 24 hours after training.
      RESULTS: The trunk restraint group used more elbow extension, less anterior trunk
      displacement, and had better interjoint coordination than the control group after
      training, and range of motion was maintained 24 hours later in only the trunk
      restraint group. CONCLUSIONS: Restriction of compensatory trunk movements during
      practice may lead to greater improvements in reach-to-grasp movements in patients
      with chronic stroke than practice alone, and longer-term effects of this
      intervention should be evaluated.

PMID- 15192251
TI  - Ethnic differences in risk factors for ischemic stroke: a European case-control
      study.
AB  - BACKGROUND AND PURPOSE: The aim is to estimate the relative risk and population
      attributable risk (PAR) of risk factors for ischemic stroke by ethnic group.
      METHODS: In this case-control study, cases of first ischemic stroke were taken
      from the South London Stroke Register and controls from a cross-sectional
      prevalence survey covering the same area. PAR was determined for each risk factor
      by ethnic group. Multivariable analysis was used to examine the association
      between risk factors and ischemic stroke across all ethnic groups. RESULTS: 664
      cases and 716 controls aged 45 to 74 years were included, with ethnicity of white
      78%:42%, black Caribbean 16%:43%, and black African 6%:15%, respectively. For the
      white group, high PAR was found for ischemic heart disease (IHD) on ECG (56% [95%
      CI, 49% to 62%]), obesity (49% [95% CI, 40% to 56%]), hypertension (HT) (38% [95%
      CI, 29% to 46%]), smoking (31% [95% CI, 19% to 41%]), transient ischemic attack
      (TIA) (23% [95% CI, 19% to 27%]), and atrial fibrillation (AF) (16% [95% CI, 10%
      to 21%]). In the black Caribbean compared with the white group, PAR was higher
      for HT (46% [95% CI, 21% to 63%]) and diabetes mellitus (DM) (29% [95% CI, 14% to
      42%]), and lower for current smoking (18% [95% CI, 1% to 32%]) and AF (10% [95%
      CI, 0% to 18%]). In the black African group HT had a higher PAR (59% [95% CI, 91%
      to 82%]) than the other groups. PAR for AF (11% [95% CI, -11% to 29%]), obesity
      (30% [95% CI, -20% to 60%]), and DM (4% [95% CI, -25% to 26%]) was low compared
      with the other groups. In multivariable analysis, risk factors associated with
      ischemic stroke included TIA, AF, IHD on ECG, smoking, excess alcohol, obesity,
      HT, and DM. CONCLUSIONS: In the first European case-control study examining risk
      factors for ischemic stroke in black Caribbean and African populations, some
      differences were demonstrated in the impact of risk factors between these groups.
      It may be important to address such differences when developing stroke
      preventative strategies.

PMID- 15192252
TI  - Racial and ethnic disparities in cardiovascular risk factors among stroke
      survivors: United States 1999 to 2001.
AB  - BACKGROUND AND PURPOSE: Stroke mortality is higher among US blacks than it is
      among US whites. Few studies have examined racial and ethnic differences in the
      prevalence of cardiovascular disease (CVD) risk factors among stroke survivors,
      especially among Hispanics. METHODS: Data are from 96 501 persons aged 18 years
      or older who participated in the 1999, 2000, or 2001 National Health Interview
      Survey, a continuous annual household-based survey of the US population.
      Participants reported a history of stroke, hypertension, diabetes, myocardial
      infarction, and coronary heart disease. Other CVD risk factors were current
      smoking, overweight/obese, inadequate physical activity, and binge drinking.
      RESULTS: Stroke was reported by 2.8% of blacks, 1.3% of Hispanics, and 2.2% of
      whites. Among 2265 stroke survivors, blacks were 1.65-times more likely (95% CI,
      1.55 to 1.75) and Hispanics were 0.73-times less likely (95% CI, 0.69 to 0.78)
      than whites to report hypertension. Hispanics and blacks were more likely than
      whites to report diabetes (P<0.05). Hispanics and blacks were less likely than
      whites to report total coronary heart disease (P<0.05). Overweight was 1.63-times
      higher among blacks (95% CI, 1.55 to 1.73) and 1.36-times higher (95% CI, 1.30 to
      1.44) among Hispanics than whites. Blacks were 1.82-times more likely (95% CI,
      1.71 to 1.94) and Hispanics 2.09-times more likely (95% CI, 1.98 to 2.22) than
      whites to report inadequate levels of physical activity. Binge drinking and
      smoking were less common among Hispanics and Blacks than among whites (P<0.05).
      CONCLUSIONS: Racial and ethnic disparities exist in stroke prevalence and CVD
      risk behaviors and medical history. Targeted secondary prevention will be
      important in reducing disparities among Hispanic and black stroke survivors.

PMID- 15192255
TI  - Preventing congenital rubella infection in the European Region of WHO: 2010
      target.
AB  - The World Health Organisation (WHO) Regional Office for Europe has recently
      published a strategic plan and surveillance guidelines for measles and congenital
      rubella infection. The strategy prioritizes measles control activities but
      encourages the introduction of rubella vaccine when measles vaccine coverage has
      reached >90 %; although, many western European countries with suboptimal measles
      vaccine coverage are already using the combined measles, mumps and rubella (MMR)
      vaccine. Women in these countries may have an especially high risk of having an
      infant with congenital rubella syndrome. WHO is seeking to improve the
      surveillance for rubella and congenital rubella syndrome as a means to obtain
      better information on the burden of these diseases and engage policy decision
      makers in the need to support the WHO European Region's strategies for rubella.

PMID- 15192256
TI  - Serological surveillance of rubella in Europe: European Sero-Epidemiology Network
      (ESEN2).
AB  - Serological surveillance is an important resource to evaluate vaccine programmes,
      especially for diseases such as rubella, where a sub-optimal programme can lead
      to an increase in morbidity. A coordinated vaccine policy in Europe is needed and
      the aim of the European Sero-Epidemiology Network (ESEN2) is to standardise
      serological surveillance in 22 countries for eight diseases, including rubella.

PMID- 15192257
TI  - A large rubella outbreak, Romania--2003.
AB  - Romania experienced a large rubella outbreak in 2002-03, with more than 115,000
      reported cases nationwide, and an incidence of 531 reported cases per 100,000
      population. The incidence was highest in children of school age. The cohorts of
      adolescent girls vaccinated in 1998 and 2002 (when a rubella-containing vaccine
      was available) had significantly lower incidence rates (p<0.001) compared with
      those in boys in the same age groups who were not vaccinated. In 2003, of the 150
      suspected congenital rubella syndrome (CRS) cases reported, seven (4.6%) were
      confirmed by positive rubella IgM antibodies. In the absence of available rubella
      containing vaccine for outbreak control, an outbreak response plan to improve the
      detection of cases and to limit rubella virus transmission was developed. The
      following activities were conducted: surveillance of pregnant women with
      suspected rubella or history of exposure to rubella virus was implemented, with
      follow up of pregnancy outcomes; surveillance for CRS was strengthened; existing
      infection control guidelines to prevent disease transmission within healthcare
      facilities were reinforced; and a communication plan was developed. In May 2004,
      Romania is introducing measles, mumps and rubella (MMR) vaccine for routine
      vaccination of children aged 12 to 15 months, while continuing vaccination of
      girls in the 8th grade of school (13-14 years of age) with rubella-only vaccine.

PMID- 15192258
TI  - Rubella in Denmark.
AB  - An average of 20,000 rubella cases were recorded annually in Denmark until 1987.
      In 1989, however, only 1006 cases were reported, and the true current incidence
      of rubella infection in Denmark is unknown but considered to be very low and <1
      per 100,000 population. The significant decrease in the incidence of rubella
      mirrors the success of vaccination of rubella seronegative women of childbearing
      age, which was initiated in Denmark in 1980. From 1982 and onwards the national
      health security scheme also refunded vaccination of children and the MMR vaccine
      was introduced in the Danish child-hood vaccination program in 1987. The low
      incidence has been sustainable due to these interventions, and since 1994
      congenital rubella syndrome and rubella in pregnancy have been listed as
      notifiable infectious diseases in Denmark. Nevertheless, in order to meet the WHO
      goal of control of rubella in the Region, the introduction of mandatory reporting
      of all laboratory diagnosed rubella cases is now being considered.

PMID- 15192259
TI  - Epidemiology of rubella in Finland.
AB  - Before rubella vaccination programmes began, rubella infection was prevalent in
      Finnish children. The disease occurred as epidemics at intervals of a few years.
      Rubella infection was most often contracted between the ages of 2 and 12 years.
      Vaccinations specifically aimed at eradicating rubella were begun with
      monocomponent vaccine in the mid-1970s, and the measles, mumps and rubella (MMR)
      vaccination programme with two injections got underway in 1982. A clear reduction
      in rubella cases was evident a few years after the launch of the MMR programme.
      Owing to a sufficiently high vaccination coverage (>95% since 1987), circulation
      of the indigenous rubella virus in the Finnish population ceased in the late
      1990s. Some rubella cases have been imported to Finland since elimination, but
      they have not caused any secondary cases. This shows unambiguously that
      protection against rubella continues to be effective, although our cohort studies
      imply that the vaccine induced antibody levels do decrease with time. The MMR
      programme has also eliminated congenital rubella syndrome (CRS) from the country.
      The last CRS case was recorded in 1986. As a result of the high coverage two dose
      MMR vaccination programme, rubella was successfully eliminated from Finland. How
      long the acquired protection will last remains to be seen.

PMID- 15192260
TI  - Rubella control in France.
AB  - In the pre-vaccination era, rubella was regarded as only a mild exanthematous
      acute viral infection of children. The devastating effects of the disease were
      first identified in the early 1940s by an Australian ophthalmologist, and further
      confirmed during the 1962-65 rubella pandemic in Europe and the United States.
      They result from the transmission of the virus by infected pregnant women to
      their fetus. The resulting congenital rubella syndrome (CRS) comprises a lengthy
      list of abnormalities. The most common ones are deafness, ocular and cardiac
      defects and mental retardation. The objective of rubella vaccination, to which
      France has subscribed, is the elimination of CRS.

PMID- 15192261
TI  - Epidemiology of rubella and congenital rubella syndrome in Greece, 1994-2003.
AB  - In 1993, there was a large epidemic of rubella and congenital rubella syndrome
      (CRS) in Greece. The epidemiology of rubella and CRS after 1993 is described in
      this paper using information from surveillance data and published studies and
      reports. The incidence of rubella fell sharply after 1993, but a smaller outbreak
      occurred in 1999, mainly in young adults, and four CRS cases (4.0 per 100,000
      live births) were recorded. A very high proportion of the child population in
      Greece are currently vaccinated for rubella, while teenagers are inadequately
      covered (60-80% in different studies). A substantial proportion of women of
      childbearing age are susceptible to rubella (10-20% in urban areas). This could
      lead to local or more extended outbreaks. This situation shows that a
      comprehensive preventive policy should be implemented.

PMID- 15192262
TI  - Rubella control in Italy.
AB  - In Italy, rubella vaccination has been recommended since 1972 for pre-adolescent
      girls, and since the early 1990s for all children in the second year of life.
      Nevertheless, coverage in children from 12 to 24 months of age is suboptimal
      (i.e., 56% in 1998, 78% in 2003), with wide variations among regions. As a
      result, rubella is still circulating in Italy, and in 1996 the percentage of
      women susceptible to rubella between 15 and 39 years of age was >5%. Congenital
      rubella syndrome (CRS) was a notifiable disease between 1987 and 1991, with a
      range of 8-76 cases reported annually. Since 1992, national incidence data are no
      longer available, but local reports show that CRS cases are still occurring.
      Nationwide, coordinated and uniform actions are needed to control CRS
      effectively. For this reason, the National Plan for the Elimination of Measles
      and of Congenital Rubella has recently been launched. This plan includes
      strategies aimed at increasing MMR vaccination coverage in children and specific
      control measures for congenital rubella control, i.e., improving the vaccination
      of susceptible women of childbearing age, and reintroducing national surveillance
      of CRS.

PMID- 15192263
TI  - New features of rubella in Spain: the evidence of an outbreak.
AB  - In most of western Europe the rubella vaccine coverage is high. However, prior to
      the introduction of the vaccine in Latin America, rubella susceptibility in women
      of childbearing age was 10-25%. Forty one (93%) countries in Latin America have
      adopted the rubella vaccine since 2002. The adult immigrant population in Spain
      constitutes a group of susceptibles. In February 2003, the Madrid Community
      Measles Elimination Plan detected an increase in rubella notifications in women
      who had been born in Latin America. A descriptive study was undertaken to
      characterise the outbreak. A confirmed case was a person with fever or rash and a
      positive IgM serology, and living in Madrid, between 1 December 2002 and 31 March
      2003. The secondary attack rate (SAR) per household was calculated. A total of 19
      cases of rubella were identified, 15 were confirmed and 4 were probable cases.
      Fourteen (73.7%) cases were women at childbearing age. The mean age was 25.1
      years. One pregnancy was diagnosed with a voluntary termination. Eleven (57.9%)
      cases were from Ecuador. The mean time of residence in Spain was 41 months. None
      of the cases or the 54 (78.3%) household contacts had been vaccinated against
      rubella. The SAR was 9.1%. This study showed the spread of rubella in the
      susceptible Latin American Community that is resident in Madrid. The
      interventions proposed were a vaccination programme towards immigrants, a health
      education campaign to prevent congenital rubella, and a health professional
      training programme case management.

PMID- 15192264
TI  - Rubella in England, Scotland and Wales.
AB  - Rubella vaccine was offered to schoolgirls in the United Kingdom (UK) from 1970,
      with antenatal testing and postpartum vaccination for susceptible women
      introduced during the 1970s. Mass vaccination with MMR of children aged 12-15
      months was introduced in 1988; schoolgirl vaccination was discontinued in 1996
      and replaced by a second dose of MMR for pre-school children; postpartum
      vaccination of susceptible women identified through antenatal testing continues.
      Rubella was made a notifiable disease in 1988, and is monitored through clinical
      and laboratory reports; data are available on rubella associated terminations and
      congenital rubella syndrome(CRS) births, rubella susceptibility in population
      subgroups, and vaccine uptake. Reported cases of CRS declined from about 50 a
      year 1971-75 to just over 20 a year 1986-90, and rubella associated terminations
      from an average of 750 to 50 a year. About 40 infants with CRS have been reported
      since 1991; about a third of their mothers were infected abroad, most in their
      country of origin (imported infections), a third were born abroad but acquired
      infection in the UK, and a third were UK-born. Women living in the UK who were
      born abroad have much higher rubella susceptibility rates than UK-born women.
      Although there is currently very little rubella infection circulating, uptake of
      MMR has dropped by over 10% since 1995. If rubella starts to circulate again,
      immigrant women will be at increased risk of acquiring infection in pregnancy.

PMID- 15192266
TI  - Adenovirus-encoded hammerhead ribozyme to PDGF A-chain mRNA inhibits neointima
      formation after arterial injury.
AB  - To develop a strategy for gene therapy of restenosis following coronary
      angioplasty, we examined the effects of a recombinant adenovirus vector encoding
      a hammerhead ribozyme specific for rat platelet-derived growth factor (PDGF) A
      chain mRNA (Ad. Ribozyme) and a control recombinant adenovirus vector encoding
      the Escherichia coli LacZ gene (Ad.LacZ) on neointima formation in rat carotid
      artery after balloon injury. Ad. Ribozyme (10(8) PFU/ml) markedly reduced the
      increased expression of PDGF A-chain mRNA and protein. Ad. Ribozyme significantly
      decreased the intima/media ratio (68%) of the injured artery, whereas Ad.LacZ had
      no effect on the intima/media ratio. Most carotid arteries developed thrombi by
      14 days after balloon injury, whereas Ad. Ribozyme completely inhibited thrombus
      formation. Expression of thromboxane A2 (TXA2) receptor mRNA was significantly
      increased after balloon injury. Ad. Ribozyme significantly decreased the levels
      of TXA2 receptor. Expression of prostaglandin I2 (PGI2) synthase mRNA was
      significantly decreased after balloon injury. Ad. Ribozyme significantly
      increased levels of PGI2 synthase mRNA after balloon injury. The observation that
      adenovirus-encoded ribozyme to PDGF A-chain inhibits neointima formation may
      serve as a novel strategy to prevent restenosis after coronary angioplasty.
      Inhibition of growth factors by genetic approaches may yield new insights into
      the mechanisms underlying responses to vascular injury and lead to new
      therapeutic applications.

PMID- 15192265
TI  - Human apo-lactoferrin enhances angiogenesis mediated by vascular endothelial
      growth factor A in vivo.
AB  - BACKGROUND: Lactoferrin, LF, a multifunctional iron- and heparin-binding protein,
      present in exocrine body secretions and leukocytes, is remarkably resistant to
      proteolysis. Ingested bovine iron-unsaturated LF, apo-bLF, suppresses VEGF-A
      mediated angiogenesis in a previously described rat mesentery angiogenesis assay,
      possibly explaining, at least in part, its established anticancer effect in rats
      and mice. METHODS: Using the same experimental system, we have now studied the
      effect of (i) ingested human apo-LF, apo-hLF, on angiogenesis mediated by VEGF-A
      and bFGF, (ii) ingested human iron-saturated LF, holo-hLF, on VEGF-A-mediated
      angiogenesis and (iii) subcutaneous continuously infused apo-hLF on VEGF-A
      mediated angiogenesis. RESULTS: Ingested holo-hLF did not affect VEGF-A-mediated
      angiogenesis. Ingested apo-hLF (from one and the same batch) significantly
      enhanced VEGF-A-mediated angiogenesis but did not affect bFGF-mediated
      angiogenesis. Moreover, subcutaneously infused apo-hLF also significantly
      stimulated VEGF-A-mediated angiogenesis. CONCLUSION: Taken together, the data
      suggest that apo-hLF exerts a specific proangiogenic effect in VEGF-A-mediated
      angiogenesis. Clearly, human and bovine apo-LF exert opposite effects on VEGF-A
      induced angiogenesis. Differences in molecular features between human and bovine
      LFs of possible significance for the outcome are discussed. In hypoxia,
      compensatory collateral circulation is mediated primarily by VEGF-A. We
      hypothesize that systemically administered apo-hLF may promote collateral blood
      vessel formation at hypoxic sites in normal tissue, thus counteracting ischemia
      and infarction.

PMID- 15192267
TI  - Contrasting effects of urokinase and tissue-type plasminogen activators on
      neointima formation and vessel remodelling after arterial injury.
AB  - Urokinase-type plasminogen activator (uPA) has been implicated in neointima
      formation and arterial lumen narrowing after angioplasty. To determine the
      specificity of the action of uPA on vessel remodelling after arterial injury we
      compared the effects of the recombinant urokinase- and tissue-type plasminogen
      activators on vessel morphology, cell migration and proliferation. We used a
      standard model of the balloon catheter injury of the rat carotid artery followed
      by the periadventitial application to the injured vessel of the one of the
      recombinant PAs or recombinant alpha(2)-antiplasmin (alpha-AP) in pluronic gel
      with further immunohistochemistry and morphometry. The perivascular application
      of alpha-AP immediately after injury attenuated the healing response,
      significantly reducing neointima size and neointimal SMC numbers. The
      periadventitial application to the injured artery of recombinant uPA stimulated
      neointima formation as well as cell proliferation and migration in vivo and
      induced greater reductions in lumen size than injury alone. In contrast,
      recombinant tissue-type plasminogen activator reduced the number of neointimal
      smooth muscle cells and the neointimal area and increased both the lumen area and
      the area encompassed by the external elastic laminae after balloon catheter
      injury of the rat carotid artery. In the meantime both PAs nearly doubled medial
      and adventitial SMC numbers in the vessels. We conclude that the ability to
      stimulate neointima formation and inward arterial remodelling is a specific
      property for urokinase plasminogen activator that could not be mimicked by tissue
      type plasminogen activator.

PMID- 15192268
TI  - Role of the Rhoa/Rho kinase system in flow-related remodeling of rat mesenteric
      small arteries in vivo.
AB  - In small arteries, a chronic blood flow reduction leads to inward hypotrophic
      remodeling, while a chronic blood flow elevation induces outward hypertrophic
      remodeling. The RhoA/Rho kinase system was shown to be modulated by shear stress,
      and to be involved in other kinds of vascular remodeling. The aim of this study
      was to investigate the role of RhoA/Rho kinase in flow-related small artery
      remodeling. Rat mesenteric small arteries were subjected to flow-modifying
      surgery. After 1, 2, 4, 16, and 32 days, the animals were sacrificed and small
      arteries were harvested. Messenger RNA was isolated and amplified. Using cDNA
      microarray analysis, the differential expression of >14,000 genes was analyzed,
      part of which was confirmed by RT-PCR. In vivo treatment with fasudil (3
      mg/kg/day s.c.) was used to test the effect of Rho kinase inhibition. The main
      findings are that: (1) blood flow alteration modified the expression of
      approximately 5% of the genes by >2-fold, (2) flow reduction downregulated many
      RhoA-related cytoskeletal markers of smooth muscle cell phenotype, (3) many RhoA
      related genes were rapidly (<1 day) regulated and (4) fasudil treatment
      potentiated the inward hypotrophic remodeling in response to chronically reduced
      flow. These results indicate the importance of the RhoA/Rho kinase system in flow
      related small artery remodeling.

PMID- 15192269
TI  - Sustained low alanine aminotransferase levels can predict the survival for 10
      years without hepatocellular carcinoma development in patients with hepatitis C
      virus-associated liver cirrhosis of child stage A.
AB  - An analysis was performed of the patients with hepatitis C virus-associated liver
      cirrhosis (HCV-LC) who never developed hepatocellular carcinoma (HCC) for 10
      years after the histological diagnosis of LC. Seventy-four consecutive HCV-LC
      patients of Child stage A were observed for >10 years prospectively for the
      development of HCC with frequent ultrasonography and magnetic resonance imaging
      or computed tomography. Of the 63 patients who fulfilled the study, 48 patients
      were treated and 15 were nontreated because of their stable state. They were
      subdivided into three groups according to their serum alanine aminotransferase
      (ALT) levels: the high ALT group comprised of 23 patients whose annual average
      serum ALT level was persistently high (>/=80 IU); the low ALT group comprised of
      28 patients whose annual average serum ALT level was persistently low (<80 IU),
      and the unclassified ALT group comprised of 12 patients. In the low ALT group, as
      high as 71.4% of patients had never developed HCC for 10 years, in contrast to
      only 17.4% in the high ALT group (p < 0.001). In the 30 patients who never
      developed HCC for 10 years, 20 patients belonged to the low ALT group, in
      contrast to only 4 belonging to the high ALT group. Sustained low ALT levels were
      important to survive for 10 years without developing HCC in the HCV-LC patients
      of Child stage A.

PMID- 15192270
TI  - Molecular epidemiology of porcine H3N2 influenza A viruses isolated in Germany
      between 1982 and 2001.
AB  - We examined influenza virus strains of the subtype H3N2 from outbreaks of
      respiratory diseases in swine herds in Germany. Four different clusters can be
      distinguished when comparing parts of the HA1 gene from porcine H3N2 isolates
      analyzed between 1982 and 2001. Comparison between these clusters reveals a bp
      homology of less than 90%. In contrast, the homology within the clusters is
      between 93.7 and 100%. Each of these clusters was confined to a specific time
      period. For the NA gene an additional cluster is formed by the porcine H1N2
      isolate. The findings that different subtypes and drift variants are circulating
      in the German pig population explain the emergence of new influenza virus
      variants and the need for continued surveillance of swine.

PMID- 15192271
TI  - Internalization and propagation of the dengue virus in human hepatoma (HepG2)
      cells.
AB  - OBJECTIVES: This study sought to undertake a comparative analysis of the
      internalization and propagation of all four dengue serotypes in a single cell
      line of human liver origin, HepG2. METHODS: Virus production after infection was
      determined by the plaque assay technique. Internalization profiles were
      determined by incubating virus and cells on ice and then raising the temperature
      for various times. The contribution of extracellular matrix components to
      internalization was determined by pretreatment of cells with either trypsin or
      heparinase III. RESULTS: HepG2 cells were able to support the propagation of all
      four serotypes with mature viruses being produced by 12 h for dengue serotype 4
      and by 17-18 h for the remaining serotypes. Virus internalization showed a
      plateau for serotypes 1, 2 and 4 entry while serotype 3 showed a constant
      increase in internalization for up to 5 h. Pretreatment of HepG2 cells with
      heparinase III or trypsin both resulted in a reduction in viral production, with
      the smallest effect being noted for dengue serotype 3. CONCLUSION: These results
      suggest that the interaction between the dengue virus and liver cells is a
      complex one that requires both protein and nonprotein elements, and has a
      significant serotype/strain element.

PMID- 15192272
TI  - Stromal cell-derived factor (SDF) 1-3'A polymorphism may play a role in
      resistance to HIV-1 infection in seronegative high-risk Thais.
AB  - OBJECTIVE: It is known that a 32-bp-deleted CCR5 mutant (CCR5-Delta32) plays a
      critical role in resistance to human immunodeficiency virus type 1 (HIV-1)
      infection. We became aware of a number of seronegative patients at high risk of
      HIV-1 infections. Since CCR-Delta32 is not found in Thais, we examined the role
      of stromal cell-derived factor (SDF) 1-3'A polymorphism in resistance to HIV-1 in
      seronegative Thai prostitutes at high risk. METHODS: We determined CCR5-Delta32
      by PCR, SDF1-3'A by RFLP, and plasma SDF-1 level by sandwich ELISA. RESULTS: We
      did not find any CCR-Delta32 mutant in 432 subjects. In our SDF1-3'A genotyping,
      we found allelic frequencies of 0.406, 0.199, and 0.289 in HIV-1-seronegative
      prostitutes at high risk, HIV-1-seropositive patients, and normal blood donors,
      respectively. There was a significant difference in the allelic frequencies of
      SDF1-3'A between HIV-1-seronegative prostitutes at high risk and HIV-1
      seropositive patients (p < 0.005). Striking differences were seen in homozygotes
      (SDF1-3A/3A); 20.3% in HIV-1-seronegative patients at high risk compared with
      2.5% in HIV-1-seropositive patients. In addition, we showed that the plasma SDF1
      level in the HIV-1-seronegative prostitutes at high risk was twice that found in
      normal blood donors (p = 0.005), and even higher than that of HIV-1-seropositive
      patients (p = 0.002). CONCLUSIONS: The finding is relevant as regards the fact
      that SDF1-3'A polymorphism induces an increase of SDF1 chemokine production, in
      which it competes with HIV-1 in binding to CXCR4 receptor, and in turn inhibits
      HIV-1 infection. The SDF1-3'A-mediated resistant mechanism in Thais differs from
      that of CCR5-Delta32-mediated resistance in Caucasians. This study provides the
      first evidence for SDF-3'A polymorphism in resistance to HIV-1 infection in
      Thais, and may represent the resistant mechanism in the extremely rare CCR5
      Delta32 mutant of other ethnic groups such as Africans and Japanese.

PMID- 15192273
TI  - Establishing the reactivity of monoclonal antibodies against porcine endogenous
      retrovirus envelope protein.
AB  - Xenotransplantation of pig organs may be associated with a risk of transmission
      of microorganisms. Porcine endogenous retroviruses (PERV) are of particular
      concern since in vitro experiments have demonstrated that human cells are
      susceptible to such microorganisms. To monitor the transmission of PERV, highly
      sensitive and specific immunoassays must be developed for clinical surveillance.
      This report describes the production, preliminary characterization and
      application of a monoclonal antibody (mAb) against a recombinant PERV envelope
      (Env) protein. The generated mAb was tested using recombinant PERV Env protein
      expressed in Escherichia coli, purified PERV virus particles and human 293 cell
      line infected with PERV. PERV-translated proteins of 15, 70 and 85 kD were
      recognized specifically using PERV-8E10 mAb and Western blotting. No cross
      reactivity was demonstrated with exogenous viral protein (HIV, HTLV and MuLV).
      Moreover, PERV-8E10 mAb can be applied to localize PERV proteins using an
      immunoperoxidase assay. This work reveals that recombinant PERV Env protein and
      mAb may be effective in detecting antibodies against PERV in xenotransplanted
      patients, or for butchers who have extensive contact with pigs.

PMID- 15192274
TI  - A comparison of the exponential decay slope between PEG-IFN alfa-2b/ribavirin and
      IFN alfa-2b/ribavirin combination therapy in patients with chronic hepatitis C
      genotype 1b infection and a high viral load.
AB  - OBJECTIVES: A high virological response rate can often be shown to be obtained
      with PEG-IFN alpha-2b and ribavirin combination therapy in chronic hepatitis C
      patients. Viral dynamics have been utilized for the evaluation of antiviral
      effects, especially the exponential second decay slope, which represents the
      elimination of infected cells. METHODS: Forty-nine patients were randomly
      assigned to the IFN alpha-2b group (n = 26) or the PEG-IFN alpha-2b group (n =
      23). Ribavirin was administered equally to both groups. Measuring the serum
      concentration of HCVRNA, the exponential viral decay during phase 1 and 2 was
      calculated. RESULTS: The exponential decay slope in phase 2 during the first 2
      weeks was greater in the IFN alpha-2b group than in the PEG-IFN alpha-2b group;
      however, from weeks 3 to 4, it was greater in the PEG-IFN alpha-2b group than in
      the IFN alpha-2b group. Interestingly, in the PEG-IFN alpha-2b group, the
      exponential decay slope was greater from weeks 3 to 4 after initiating
      combination therapy than during the weeks 1-2 (p < 0.01), despite administration
      of the same PEG-IFN alpha-2b dose (1.5 microg/kg once weekly). CONCLUSIONS: In
      PEG-IFN alpha-2b and ribavirin combination therapy, elimination of infected cells
      may be pronounced following an increase in serum ribavirin concentration in
      chronic hepatitis C patients with genotype 1b infection and a high viral load.

PMID- 15192275
TI  - Inhibition of Borna disease virus-mediated cell fusion by monoclonal antibodies
      directed against the viral glycoprotein.
AB  - Borna disease virus-infected Vero cells express on their surface the major viral
      glycoprotein which mediates cell fusion after low pH treatment. This fusion event
      can be inhibited by monoclonal antibodies (mAbs) generated from chronically BDV
      infected rats boosted with a recombinant vaccinia virus expressing the gp94
      glycoprotein of BDV. Analysis of mAbs suggests specificity for the 43-kD C
      terminal furin cleavage product of gp94 and provides evidence for the recognition
      of a conformational epitope. The results confirm and extend earlier findings on
      the presence of the gp43 protein on the surface of BDV-infected cells and its
      specific role in cell fusion.

PMID- 15192276
TI  - CCR5 promoter polymorphism influences the interferon response of patients with
      chronic hepatitis C in Japan.
AB  - OBJECTIVE: Chemokines and chemokine receptors play important roles in the
      pathogenesis of chronic hepatitis C. Here, we explore the influence of genetic
      polymorphisms of chemokine and chemokine receptors such as regulated upon
      activation and T cell secreted (RANTES), CC chemokine receptor 5 (CCR5) and CCR2
      on the outcome of interferon (IFN) monotherapy. METHODS: In a cohort of 105
      patients with chronic hepatitis C as well as in 50 sustained responders and 55
      nonresponders the presence of polymorphisms such as CCR5-Delta32, CCR5 59029G/A,
      CCR2 V64I and RANTES -403G/C was determined. RESULTS: Gender, age, liver
      histological staging, pretreatment ALT levels, total dose of IFN and frequencies
      of polymorphisms (CCR2 V64I and RANTES -403G/C) did not significantly differ
      between the two groups. A low viral load, hepatitis C virus (HCV) serotype 2 and
      CCR5 59029G/G were significantly associated with a higher probability of a
      sustained response (p < 0.01, p < 0.05, p < 0.05, respectively). Multiple
      logistic regression analysis showed that a low viral load, HCV serotype 2 and
      CCR5 59029G/G were independently associated with a sustained response [odds ratio
      3.980 (1.647-9.621), p = 0.002; 3.584 (1.439-8.924), p = 0.006; 3.638 (1.163
      11.379), p = 0.026, respectively]. CONCLUSION: These findings indicate that CCR5
      59029 is a host genetic factor that is associated with responses to IFN therapy
      among Japanese patients with chronic hepatitis C.

PMID- 15192277
TI  - Hyperghrelinemia is a common feature of Prader-Willi syndrome and pituitary stalk
      interruption: a pathophysiological hypothesis.
AB  - BACKGROUND: Elevated plasma ghrelin levels have recently been reported in adults
      and children with Prader-Willi syndrome (PWS). The aim of the study is to
      investigate the relationship between obesity, growth hormone (GH) deficiency
      (GHD) and ghrelinemia in PWS and to examine whether hyperghrelinemia is specific
      to PWS. METHODS: We measured fasting ghrelinemia in children with PWS, idiopathic
      GHD (iGHD), obese children, controls and in 6 children presenting another
      congenital syndrome associated with GHD: pituitary stalk interruption (PSI).
      RESULTS: Children with PWS exhibited significantly higher ghrelin levels (995
      pg/ml (801/1,099, median 1st/3rd quartile)) than iGHD (517 pg/ml (392/775)),
      obese (396 pg/ml (145/610)) and control (605 ng/ml (413/753)) children. Similar
      to PWS hyperghrelinemia was found in PSI children (1,029 pg/ml (705/1,151)), and
      was not modified by GH treatment. CONCLUSION: We conclude that hyperghrelinemia
      in PWS and PSI is not related to GH secretion. We hypothesize that a major site
      of ghrelin action is at the hypothalamic level and that a 'ghrelin resistance'
      syndrome may be present in these patients, primarily due to a hypothalamic
      defect. Combined alterations such as impaired serotonin receptor regulation
      associated with abnormal ghrelin responsiveness are probably responsible for
      obesity in PWS.

PMID- 15192278
TI  - A novel permutation testing method implicates sixteen nicotinic acetylcholine
      receptor genes as risk factors for smoking in schizophrenia families.
AB  - Smoking is a common correlate of schizophrenia, which leads to medical morbidity.
      Although twin and adoption studies have consistently implicated genes in the
      etiology of both smoking and schizophrenia, finding genes has been difficult.
      Several authors have suggested that clinical or neurobiological features
      associated with schizophrenia, such as smoking, might improve the ability to
      detect schizophrenia susceptibility genes by identifying genes related to the
      etiology of that feature. The objective of this study is to assess evidence for
      linkage of sixteen nicotinic acetylcholine receptor genes and smoking in
      schizophrenia families, using data from the NIMH Genetics Initiative for
      schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior
      to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2,
      with a smoking trait in schizophrenia families. The significance of the group of
      candidate genes, in addition to each individual candidate gene, was assessed
      using permutation testing, which adjusted for multiple comparisons. The group of
      genes showed significant linkage to the smoking trait after adjusting for
      multiple comparisons through permutation testing (p = 0.039). In addition, two of
      the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2,
      p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1,
      p = 0.076). The significance of the complex hypothesis, involving sixteen genes,
      implicates the nicotinic system in smoking for schizophrenic families. Individual
      gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this
      involvement. Such findings help prioritize genes for future case control studies.
      In addition, we provide a novel permutation method that is useful in future
      analyses involving a single hypothesis, with multiple candidate genes.

PMID- 15192279
TI  - Class I and II HLA genes are associated with susceptibility and age at onset in
      Finnish families with type 1 diabetes.
AB  - OBJECTIVES: We explored the properties of the long-term survivor model (LTS) in
      the genetic association studies and studied allelic and haplotypic associations
      between the age at onset and partially latent susceptibility of type 1 diabetes
      (T1DM) and Human Leucocyte Antigen (HLA) A, B and DR loci. METHODS: The authors
      applied the long-term survivor model (LTS) for sibships collected in a population
      based registry during a calendar time period. The method uses sibs that could not
      become probands and includes the proband's age at onset during the recruitment
      period. Association between the candidate gene and the partially latent
      susceptibility is modeled with logistic regression and the age at onset with a
      two-parameter gamma distribution, where a scale parameter depends on the
      candidate genotypes. We also performed a simulation study of nuclear families to
      compare the power of the likelihood ratio tests of the genetic association based
      on the LTS model with those obtained using family-based association method (FBAT)
      and bias of the case-pseudo control design. In addition, we analysed allele and
      haplotype associations between HLA A, B and DR loci (IDDM1) with T1DM, using
      population-based ascertainment of 705 sibships with complete HLA information.
      RESULTS: A simulation study showed that the estimates of the genetic association
      using an ascertainment-corrected LTS model are virtually unbiased and that the
      relative risk estimates obtained from case-pseudo control design (TDT) are
      negatively biased. In the analysis of the Finnish T1DM families we found that
      only B62 (p < 0.05) is positively significantly associated with susceptibility
      after adjusting for the haplotype effects. Five alleles were significantly
      associated with age at onset (B8 and DR3, p < 0.01; A2, B60 and DR6, p < 0.05).
      No significant three-locus haplotype associations with the susceptibility were
      found, but A3B18DR4 (p < 0.001) haplotype was associated with older age at onset
      than average. CONCLUSIONS: Estimates of genetic relative risk obtained from the
      case-pseudo control design are negatively biased and the prospective LTS model is
      an appropriate choice, when there are non-susceptible subjects in the population
      with variable age at onset. Based on the analysis of T1DM, we conclude that there
      are gene(s) in the HLA region that are associated with susceptibility and/or age
      at onset of T1DM, and this should be taken into account in future studies.

PMID- 15192280
TI  - Familial aggregation and genome-wide linkage analysis of carotid artery plaque:
      the NHLBI family heart study.
AB  - OBJECTIVE: To evaluate familial and genetic influences on carotid artery plaque,
      a qualitative marker of the systemic burden of atherosclerosis. METHODS: The
      design was a cross-sectional study of 2,223 members of 525 randomly-ascertained
      families and 2,514 members of 589 high coronary heart disease (CHD) risk families
      from 4 U.S. communities. RESULTS: The prevalence of plaque was 33, 36, and 47%,
      respectively, among probands with 0, 1, and 2 or more first-degree relatives with
      a history of CHD. There was evidence of sibling aggregation of plaque in random
      families (OR = 1.89; 95% CI: 1.44, 2.48), but associations were substantially
      attenuated when adjusted for major cardiovascular disease risk factors. A genome
      scan with 420 microsatellite markers revealed no regions of significant or
      suggestive linkage for plaque in 342 affected sibling pairs, although suggestive
      linkage (LOD score: 2.43) was found on chromosome 2p11.2 (D2S1790) in pairs aged
      55 years or younger. Other markers with nominal evidence for linkage (p < 0.05)
      were found on chromosomes 2p25, 2q24-q32, 6q21-q23, 7p12-p21, 7q11-q21, 8q24,
      12q12-q13, 18p11, 21q21 and Xp11, Xq12, and Xq24. CONCLUSIONS: There was modest
      familial aggregation of carotid artery plaque, but a genome-wide scan indicated
      no regions of significant or suggestive linkage.

PMID- 15192281
TI  - A new method for computing the multipoint posterior probability of linkage.
AB  - The posterior probability of linkage (PPL) is a Bayesian statistic which directly
      measures the probability of linkage between a trait locus and a marker (in the 2
      point case) or a genomic region (in the multipoint case). It has several
      benefits, including ease of interpretation, the ability to incorporate prior
      genomic information, and a mathematically rigorous and robust procedure for
      accumulating linkage information across multiple heterogeneous datasets. To date,
      the majority of work on the PPL has focused on the development of the 2-point
      statistic, with only preliminary attempts at the development of an equivalent
      multipoint version. In this paper we present a new way of computing of the
      multipoint PPL. This new version imputes to each genomic point an estimate of the
      2-point PPL we would have obtained from a fully informative marker giving similar
      evidence for linkage. This version, which we call the imputed PPL, is shown to be
      superior to previously developed versions.

PMID- 15192282
TI  - Using lod scores to detect sex differences in male-female recombination
      fractions.
AB  - Human recombination fraction (RF) can differ between males and females, but
      investigators do not always know which disease genes are located in genomic areas
      of large RF sex differences. Knowledge of RF sex differences contributes to our
      understanding of basic biology and can increase the power of a linkage study,
      improve gene localization, and provide clues to possible imprinting. One way to
      detect these differences is to use lod scores. In this study we focused on
      detecting RF sex differences and answered the following questions, in both phase
      known and phase-unknown matings: (1) How large a sample size is needed to detect
      a RF sex difference? (2) What are "optimal" proportions of paternally vs.
      maternally informative matings? (3) Does ascertaining nonoptimal proportions of
      paternally or maternally informative matings lead to ascertainment bias? Our
      results were as follows: (1) We calculated expected lod scores (ELODs) under two
      different conditions: "unconstrained," allowing sex-specific RF parameters
      (theta(female), theta(male)); and "constrained," requiring theta(female) =
      theta(male). We then examined the DeltaELOD (identical with difference between
      maximized constrained and unconstrained ELODs) and calculated minimum sample
      sizes required to achieve statistically significant DeltaELODs. For large RF sex
      differences, samples as small as 10 to 20 fully informative matings can achieve
      statistical significance. We give general sample size guidelines for detecting RF
      differences in informative phase-known and phase-unknown matings. (2) We defined
      p as the proportion of paternally informative matings in the dataset; and the
      optimal proportion p(circ) as that value of p that maximizes DeltaELOD. We
      determined that, surprisingly, p(circ) does not necessarily equal (1/2), although
      it does fall between approximately 0.4 and 0.6 in most situations. (3) We showed
      that if p in a sample deviates from its optimal value, no bias is introduced
      (asymptotically) to the maximum likelihood estimates of theta(female) and
      theta(male), even though ELOD is reduced (see point 2). This fact is important
      because often investigators cannot control the proportions of paternally and
      maternally informative families. In conclusion, it is possible to reliably detect
      sex differences in recombination fraction.

PMID- 15192283
TI  - A modified revisited Haseman-Elston method to further improve power.
AB  - The original and revisited Haseman-Elston methods are simple robust methods to
      detect linkage, but neither is uniformly optimal in terms of power. In this
      report, we propose a simple modification of the revisited Haseman-Elston method
      that retains the simplicity and robustness properties, but increases its power.
      We demonstrate theoretically that the modification can be more powerful than the
      optimally weighted Haseman-Elston method when the sibship mean can be correctly
      specified. We then examine the properties of this modification by simulation when
      the sibship mean is replaced by its best linear unbiased predictor. The
      simulation results indicate that this modification maintains good control over
      type I error, even in the case of larger sibships, and that the empirical power
      of this modification is similar to that of the optimally weighted Haseman-Elston
      method in most cases.

PMID- 15192284
TI  - Adenosine deaminase activity and its isoenzyme pattern in women with recurrent
      spontaneous abortions.
AB  - Normal pregnancy is characterized by suppressed cell-mediated immunity. Adenosine
      deaminase (ADA) is a purine metabolic enzyme enriched in trophoblast cells of the
      placenta. It is an early marker of trophoblast cell differentiation. Also, the
      activation of ADA gene expression in the placenta is crucial and essential for
      proper fetal development. The activity of ADA shows changes in diseases
      characterized by the alteration of cell-mediated immunity. The purpose of this
      study was to assess the possible role of the alteration of cell-mediated immunity
      in women with recurrent spontaneous abortions (RSA) as a cause of changes in tADA
      activity, and also to evaluate the extent of the contribution of ADA1 and ADA2 to
      changes of tADA activity in serum and peripheral blood lymphocytes (PBLs). We
      measured in serum and in PBLs activities of tADA, ADA1 and ADA2 of 25 married
      women with RSA (group A) and of 28 healthy non-pregnant women (group B).
      According to our results in women with RSA, mean serum tADA, ADA1 and ADA2
      activities were significantly higher than those of non-pregnant women (p < 0.001,
      p < 0.05 and p < 0.05 respectively). In women with RSA, mean PBLs tADA, ADA1 and
      ADA2 activities were significantly higher than those of non-pregnant women (p <
      0.001, p < 0.05 and p < 0.05 respectively). The findings of this study show a
      marked increase of serum and PBLs ADA activities, which is derived from an
      increase of ADA2 and ADA1 activity in women with RSA. These changes reflect cell
      mediated immunological changes.

PMID- 15192285
TI  - Pharmacokinetics of natural progesterone vaginal suppository.
AB  - Natural and synthetic progesterone have been used to treat luteal insufficiency,
      premenstrual syndrome, and in infertile patients. The transvaginal route has
      advantages, such as lack of local pain, avoidance of first-pass hepatic
      metabolism, rapid absorption, high bioavailability and local endometrial effect.
      The aim of this study was to evaluate the pharmacokinetic of natural progesterone
      administered as vaginal suppositories of 25, 50 or 100 mg. Thirty-five healthy
      ovulating patients, 31.54 +/- 1.29 (mean +/- SEM) years old, in the follicular
      phase of the menstrual cycle (between days 7 and 10) participated in the study.
      They were separated in three groups and received vaginal suppositories containing
      either 25, 50 or 100 mg of natural progesterone. Progesterone serum concentration
      reached maximal levels within 2 or 3 h after the administration and was similar
      for the three groups (7.27 +/- 2.8 ng/ml; 8.84 +/- 3.14 ng/ml; 9.82 +/- 9.8
      ng/ml, respectively). This study demonstrated that vaginally administered
      progesterone could reach levels that are similar to those obtained in ovulatory
      and luteal phases. The progesterone regimen for adequate endometrial protection
      and in vitro fertilization (IVF) programs still remains to be studied.

PMID- 15192286
TI  - 'Quick course' neoadjuvant chemotherapy with cisplatin, bleomycin and vincristine
      in advanced cervical cancer.
AB  - To evaluate the response and safety of 'quick course' neoadjuvant chemotherapy,
      30 patients with advanced squamous cell carcinoma of cervix were given cisplatin,
      bleomycin, and vincristine weekly for 3 courses. The response was evaluated by
      subjective parameters and by standard response criteria. In addition to the
      marked improvement in symptoms, the overall objective response was 60% with a
      complete pathological response of 6.6%. Tumor volume decreased significantly
      (p=0.002) after chemotherapy. Patients with stage IB and 27% (3 of 11) of
      patients with stage II disease who became technically stage IB (stage reduction)
      after chemotherapy underwent surgery. Radiotherapy was given to the remaining
      patients. All patients tolerated the chemotherapy.

PMID- 15192287
TI  - Chromosomal translocation t(10;11)(q26;q13) in a woman with combined pituitary
      hormone deficiency.
AB  - We describe the case of a girl with combined pituitary hormone deficiency (CPHD)
      carrying a balanced chromosomal translocation t(10;11)(q26;q13) with paternal
      transmission. Her father, with no apparent physical abnormalities, had the
      karyotype: 46, XY, t(10;11)(q26;q13). CPHD denotes impaired production of growth
      hormone (GH) and one or more of the other five anterior pituitary-derived
      hormones. Pit-1 gene and Prop-1 gene mutations and deletions have been reported
      being responsible for CPHD. Although our patient had a t(10;11) (q26q13) paternal
      chromosomal translocation, the phenotype was similar to that found in humans with
      different Pit-1 or Prop-1 gene alterations. Interestingly, the patient's father
      had the same translocation without phenotypic effects. In conclusion, we describe
      panhypopituitarism in a woman with a paternally transmitted translation, which
      appears to be phenotypically expressed only in females.

PMID- 15192288
TI  - Reappraisal of in utero stem cell transplantation based on long-term results.
AB  - The therapeutic field of in utero transplantation of stem cells, into human
      fetuses, has developed since 1988 with the hope of improved probability of
      engraftment and tolerance, due to immune immaturity of the host. Fifteen years
      later, it is possible to evaluate the results that we and others have obtained in
      the treatment of several fetal diseases. Seven fetal patients have been treated
      in Lyon: In 2 cases, pregnancy termination was induced by the in utero injection;
      in the 5 other cases, engraftment was obtained and repeatedly documented with
      presence of donor HLA antigens and/or Y chromosome in recipients. In the 2
      patients with combined immunodeficiency disease, a sustained reconstitution of
      immunity was obtained as a result of the transplant but other complications
      occurred thereafter. In patients with thalassemia major, Niemann-Pick disease or
      hemophilia, a very partial and very transitory benefit was only obtained.
      Approximately 33 other patients with immunodeficiencies, hemoglobinopathies or
      inborn errors of metabolism have been treated worldwide, over the last 13 years,
      with a comparable method, using parental or fetal stem cells transplanted in
      utero. Successful treatment has usually been recorded in immunodeficiencies, and
      insufficient results have been obtained in the other cases. This form of
      treatment can therefore be recommended after prenatal diagnosis of combined
      immunodeficiency but additional research is required to improve the degree of
      engraftment, the lack of resistance of the host and the 'space' available for
      hematopoiesis in the other conditions.

PMID- 15192289
TI  - The results of cytogenetic analysis with regard to intracytoplasmic sperm
      injection in males, females and fetuses.
AB  - OBJECTIVES: To determine the incidence of chromosome abnormalities among couples
      for whom intracytoplasmic sperm injection (ICSI) treatment was indicated and
      fetuses conceived through the ICSI procedure. METHODS: All cytogenetic results
      were evaluated retrospectively. Patients undergoing ICSI (n = 508) were
      classified according to the referring indications as: (1) males with severe
      infertility (87 azoospermia and 34 oligoasthenoteratozoospermia, OAT), (2) prior
      to ICSI (56 males and 61 females), and (3) following an unsuccessful ICSI
      procedure (132 males and 138 females). Fetuses conceived through ICSI (n = 475)
      were also classified into 4 groups according to the additional risk factors for
      chromosome abnormalities: ICSI (n = 185), ICSI + advanced maternal age (AMA, n =
      215), ICSI + positive triple test result (TT, n = 50), and ICSI + abnormal
      ultrasound findings (USG, n = 25). RESULTS: An abnormal karyotype was found in
      31.03% of males with azoospermia and 14.71% of males with OAT, in 3.57% of males
      and 1.64% of females in the group prior to ICSI, and in 5.30 and 5.07%,
      respectively, in the group following unsuccessful ICSI treatment. Gonosomal
      aneuploidies were predominant in males with azoospermia and autosomal
      rearrangements in males with OAT, while low-level sex chromosome mosaicism was
      found in females. The overall frequency of chromosome abnormalities in fetuses
      was 4.42% and varied in the different groups from 1.62% in ICSI, 2.79% in ICSI +
      AMA, 10.0% in ICSI + TT to 28.0% in ICSI + USG. The frequencies of the different
      types of chromosome abnormalities were as follows: balanced 1.05%, unbalanced
      3.37%, familial 0.84%, de novo 3.37%, autosomal 3.58%, gonosomal 0.84%, numerical
      1.89%, structural abnormalities 2.53%, and mosaicism 1.26%. CONCLUSION: Our
      results indicate that cytogenetic investigations of the ICSI parents and fetuses
      are essential for the families, genetic counselors and also reproductive centers.
      In fetal karyotyping, de novo structural chromosome abnormalities and mosaicism
      should be taken into consideration.

PMID- 15192290
TI  - Sonographic prognostic factors in prenatal diagnosis of SCT.
AB  - OBJECTIVE: A subset of fetuses with sacrococcygeal teratomas (SCT) develops
      hydrops caused by high-output heart failure. Identification of fetuses at risk
      for hydrops is important because surgical intervention may reverse the
      pathophysiology of the disease. The aim of this study was to evaluate sonographic
      prognostic factors regarding tumor morphology and vascularity associated with the
      development of hydrops in utero. METHODS: Over a 10-year period, we identified 7
      fetuses with SCT diagnosed antenatally and managed at the University of Mainz. We
      retrospectively reviewed the charts of mothers and infants and recorded data on
      prenatal diagnosis, tumor size and localization, perinatal management, neonatal
      care, and fetal outcome. RESULTS: The diagnosis of SCT was made in all cases by
      ultrasound. The median gestational age at the time of initial diagnosis was 23
      weeks. In 3 cases, signs of fetal heart failure were detected by ultrasound.
      Pathological blood flow in the venous system was further noted in 2 cases. One
      fetus developed hydrops. The mean gestational age at delivery was 35 weeks,
      depending on the presence or absence of maternal or fetal complications. Six
      infants were delivered by cesarean section, and 1 by vaginal delivery. After
      fetal stabilization, surgery was performed in 5 of 7 cases. Inadequate
      ventilation secondary to prematurity was a contributing factor to death in 1
      fetus. One fetal intrauterine death occurred at 27 weeks of gestation.
      CONCLUSION: Pregnancies with antenatally diagnosed fetal SCT necessitate frequent
      monitoring to ensure the detection of fetal/maternal complications by ultrasound
      and Doppler ultrasound. The most important prognostic criteria were cardiomegaly,
      fetal hydrops, and increased preload indexes of the fetal venous system as sign
      of fetal heart failure. Many studies show that the occurrence of pulsations in
      the umbilical vein of a hydropic fetus correlates with a poor fetal outcome. The
      decision on the optimal time of delivery should therefore be made by a
      multidisciplinary team of specialists.

PMID- 15192291
TI  - Reduction of pleural effusion by OK-432 in a fetus complicated with congenital
      hydrothorax.
AB  - A 29-year-old, primiparous woman was referred to our hospital at 21 weeks of
      gestation because of right pleural effusion in the fetus shown by routine
      ultrasonographic examination. Cytology revealed abundant lymphocytes, suggesting
      chylothorax. We removed the pleural effusion and injected OK-432 into the chest
      cavity at 24 and 25 weeks of gestation. Pleural effusion declined and an adhesion
      between the lung surface and the pleural membrane seemed to form. At 33 weeks of
      gestation, a female infant was born by cesarean section (1,090 g and Apgar score
      6/8). Although she demonstrated slight retraction and tachypnea, management could
      be achieved by administration of oxygen alone without mechanical ventilation.
      Later, the baby was diagnosed as suffering from the Cornelia de Lange syndrome
      with characteristic features. OK-432 injections could thus prevent complications
      of chylothorax and hypoplastic lungs, without injury to either the baby or the
      mother.

PMID- 15192292
TI  - Fetal akinesia deformation sequence presenting with increased nuchal translucency
      in the first trimester of pregnancy.
AB  - Prenatal sonographic diagnosis of fetal akinesia deformation sequence (FADS) is
      usually achieved during the second and third trimester of pregnancy and relies on
      the demonstration of contractures of multiple joints, paucity of fetal movements
      and nuchal edema or generalized hydrops. We present the early diagnosis of FADS
      in a 13-week fetus presenting with nuchal translucency thickness (NT) of 5.1 mm,
      bilateral talipes and fixed flexion deformity of the fingers and wrists. We also
      review cases of this condition diagnosed during the first trimester and discuss
      the role of increased NT in the early diagnosis of FADS even in cases without
      previous history of an affected child.

PMID- 15192293
TI  - Obstetric prognosis after placental abruption.
AB  - OBJECTIVE: To assess obstetric outcome in women with a history of placental
      abruption. METHODS: We utilised the population-based birth registry data of
      Kuopio University Hospital to investigate pregnancy outcome in 59 women with
      prior placental abruption. The general obstetric population was used as a
      reference group in logistic regression analysis. RESULTS: Recurrent placental
      abruption and associated adverse neonatal outcome occurred in 11.9% (7:59) of the
      women. If the disease did not recur, a history of placental abruption had no
      significant effects on birth weight, fetal distress or prematurity rate, whereas
      the incidence of pre-eclampsia was found to be increased. CONCLUSIONS: Women in
      whom placental abruption does not recur have a good outcome in their subsequent
      delivery, almost comparable to that in the general obstetric population. However,
      the recurrence rate of 11.9% is high (OR: 16.9, 95% CI: 8.2-34.9) when compared
      with the background incidence of placental abruption (0.7%).

PMID- 15192294
TI  - Dandy-Walker malformation: a review of 78 cases diagnosed by prenatal sonography.
AB  - OBJECTIVE: The purpose of this study was to determine the associated
      abnormalities and clinical outcomes of fetuses with Dandy-Walker malformations.
      METHODS: Sonograms and medical reports of 78 cases were reviewed and information
      regarding each outcome was collected from autopsy records, hospital charts and
      specialists caring for the surviving infants. RESULTS: We identified 64 fetuses
      with classic Dandy-Walker malformation (DW) and 14 fetuses with Dandy-Walker
      variant (DWV). A high proportion (44.8%) of the parents were consanguineous. The
      spectrum and proportion of central nervous system (67.1 vs. 71.4%; p = 1.0) and
      other malformations (43.7 vs. 64.2%; p = 0.57) associated with DW and DWV were
      similar. Chromosome abnormalities were found in 9 of the 51 (17.6%) fetuses that
      underwent karyotype analysis. Only 4 of 64 (6.2%) DW and 3 of 14 (21.4%) DWV
      infants survived (p 0.14), and all surviving infants with DW or DWV had
      neurological disorders. CONCLUSIONS: DW and DWV cases show so many similarities
      that a clear-cut distinction is difficult. There was no significant difference in
      the spectrum of associated anomalies and postnatal prognosis between DW and DWV
      cases.

PMID- 15192295
TI  - Importance of ductus venosus Doppler assessment for fetal outcome in cases of
      intrauterine growth restriction.
AB  - OBJECTIVE: The measurement and evaluation of ductus venosus (DV) blood flow
      velocity waveform in high-risk pregnancies has been studied intensively in recent
      years in order to find a more intermediate signal of fetal compromise. Our
      objective was to study the fetal outcome of pregnancies with intrauterine growth
      retardation (IUGR) and normal pulsatility of DV compared to an IUGR group with
      increased DV pulsatility. METHODS: The outcome of 42 fetuses before 32 weeks of
      gestational age without chromosomal or structural aberrations was analyzed. All
      fetuses showed IUGR <5th percentile based on placental insufficiency diagnosed by
      pathologic RI >90th percentile of both maternal uterine arteries. One group (30
      fetuses; mean weight 730 g/SD 190 g; mean gestational age 197 days/SD 12 days)
      showed normal, the other (12 fetuses, mean weight 675 g/SD 179 g; mean
      gestational age 198 days/SD 12 days) reduced, but neither absent nor reverse DV
      flow during atrial contraction. All 42 fetuses were delivered by cesarean section
      because of severe variable or prolonged decelerations. We measured blood flow
      velocities of the DV in every fetus on an average 3.7 days (range 1-5 days)
      before cesarean section. Fetal outcome was determined by Apgar scores after 5 and
      10 min, arterial pH and base excess; neonatal morbidity was recorded by intensive
      follow-up. RESULTS: There were no significant differences of pH, umbilical artery
      base excess, Apgar scores and severe neonatal complications between the two
      groups. CONCLUSIONS: Our own data show no correlation between increased
      pulsatility in the DV (without absent or reverse flow during atrial contraction)
      and fetal outcome before 32 gestational weeks, even in cases of severe growth
      restriction based on placental insufficiency. Therefore in these cases reduced DV
      flow during atrial contraction should cautiously be interpreted regarding
      obstetrical decisions.

PMID- 15192296
TI  - Prenatal diagnosis of a fetus affected with Down syndrome and deletion 1p36
      syndrome by fluorescence in situ hybridization and spectral karyotyping.
AB  - OBJECTIVE: A fetus having partial trisomy of the distal part of chromosome 21q
      due to a de novo translocation is reported here. METHOD: A 29-year-old woman
      received amniocentesis at 18 weeks of gestation because of abnormal ultrasound
      findings including bilateral choroid plexus cysts, atrioventricular septal
      defects, rocker-bottom feet, and possible hydrocephalus. RESULTS: Cytogenetic
      analysis revealed 46,XY, add(1)(p36.3), in which an additional material of
      unknown origin was attached to one of the terminal short arms of chromosome 1.
      Parental blood studies showed normal karyotypes in both parents. Spectral
      karyotyping was then performed and the origin of the additional material locating
      at chromosome 1p was found to be from chromosome 21. Conventional fluorescence in
      situ hybridization analysis was also used and confirmed the spectral karyotyping
      findings by use of a chromosome 21 specific painting probe, a locus specific
      probe localized within bands 21q22.13-q22.2 and a 21q subtelomeric probe. A
      hidden Down syndrome caused by a de novo translocation in this fetus was
      therefore diagnosed and the karyotype was designated as 46,XY,
      der(1)t(1;21)(p36.3;q22.1).ish der(1)(WCP21+, LSI 21+, 1pTEL-, 21q TEL+) de novo.
      Clinical features of the 1p36 deletion syndrome are also reviewed and may
      contribute to some features of this fetus. Termination of pregnancy was performed
      at 20 weeks of gestation. CONCLUSION: To our knowledge, our case appears to be
      the first to have partial monosomy 1p and partial trisomy 21q caused by de novo
      translocation being diagnosed prenatally.

PMID- 15192298
TI  - Gender does matter in perinatal medicine.
AB  - OBJECTIVE: To investigate complications and outcome of pregnancies with male and
      female fetuses. METHODS: A population-based study comparing all singleton
      deliveries between the years 1988 and 1999 was performed. We compared pregnancies
      with male vs. female fetuses. Patients with a previous cesarean section (CS) were
      excluded from the study. Statistical analyses with the Mantel-Haenszel technique
      and multiple logistic regression models were performed to control for
      confounders. RESULTS: During the study period there were 55,891 deliveries of
      male and 53,104 deliveries of female neonates. Patients carrying male fetuses had
      higher rates of gestational diabetes mellitus (OR = 1.1; 95% CI 1.01-1.12; p =
      0.012), fetal macrosomia (OR = 2.0; 95% CI 1.8-2.1; p < 0.001), failure to
      progress during the first and second stages of labor (OR = 1.2; 95% CI 1.1-1.3; p
      < 0.001 and OR = 1.4; 95% CI 1.3-1.5; p < 0.001, respectively), cord prolapse (OR
      = 1.3; 95% CI 1.1-1.6; p = 0.014), nuchal cord (OR = 1.2; 95% CI 1.1-1.2; p <
      0.001) and true umbilical cord knots (OR = 1.5; 95% CI 1.3-1.7; p < 0.001).
      Higher rates of CS were found among male compared with female neonates (8.7 vs.
      7.9%; OR = 1.1; 95% CI 1.06-1.16; p < 0.001). Using three multivariate logistic
      regression models and controlling for birth weight and gestational age, male
      gender was significantly associated with non-reassuring fetal heart rate patterns
      (OR = 1.5; 95% CI 1.4-1.6; p < 0.001), low Apgar scores at 5 min (OR = 1.5; 95%
      CI 1.3-1.8; p < 0.001) and CS (OR = 1.2; 95%CI 1.2-1.3; p < 0.001). Controlling
      for possible confounders like gestational diabetes, cord prolapse, failed
      induction, nonprogressive labor, fetal macrosomia, nuchal cord and true umbilical
      cord knots using the Mantel-Haenszel technique did not change the significant
      association between male gender and CS. CONCLUSION: Male gender is an independent
      risk factor for adverse pregnancy outcome.

PMID- 15192297
TI  - Preterm deliveries among women with MacDonald cerclage performed due to cervical
      incompetence.
AB  - OBJECTIVE: The study was aimed to assess the impact of obstetric risk factors for
      preterm delivery among women with MacDonald cerclage performed due to cervical
      incompetence. STUDY DESIGN: A cohort study was conducted including all patients
      with MacDonald cerclage performed at 12-14 weeks gestation due to cervical
      incompetence (n = 793). Deliveries occurred between the years 1988 and 2002 in a
      University Medical Center. A multiple linear regression model was used to assess
      the impact of maternal characteristics as well as pregnancy complications on the
      length of pregnancy. RESULTS: The following factors were found to be associated
      with preterm delivery among these patients, in the univariate analysis:
      nulliparity, fertility treatments, severe preeclampsia, second-trimester
      bleeding, premature rupture of membranes (PROM), chorioamnionitis and placental
      abruption. Using a multiple linear regression model, with backward elimination,
      the impact of these variables on the length of pregnancy was assessed (R(2) =
      0.33, p < 0.001). The mean gestational age at birth among patients without risk
      factors was 38.1. Second-trimester bleeding reduced gestational age by 6.4 weeks,
      chorioamnionitis by 5.6 weeks, placental abruption by 5.1 weeks, PROM by 3.2
      weeks and severe preeclampsia by 2.4 weeks. CONCLUSIONS: Second-trimester
      bleeding, chorioamnionitis, placental abruption, PROM and severe preeclampsia are
      ominous signs for preterm delivery among patients with MacDonald cerclage
      performed due to cervical incompetence.

PMID- 15192299
TI  - Antenatal necrotic injury in severe twin-to-twin transfusion syndrome. A case and
      review.
AB  - A case of twin-to-twin transfusion syndrome (TTTS) was associated with ischemic
      injury of the left leg of the recipient twin. Five reduction amniocenteses were
      performed between 17 6/7 and 23 3/7 weeks followed by fetoscopic laser ablation
      of chorioangiopagus vessels at 23 6/7 weeks of gestation. Anatomic assessment of
      the affected limb indicated timing of the injury at 19 4/7 weeks gestational age.
      The published literature suggests that ischemic fetal injuries in severe TTTS are
      associated with blood hyperviscosity in the affected twin.

PMID- 15192300
TI  - Congenital laryngeal cyst: benefits of prenatal diagnosis and multidisciplinary
      perinatal management.
AB  - Congenital laryngeal cysts are rare and can cause upper airway obstruction if
      they are misdiagnosed. We describe a case of large vallecular cyst diagnosed at
      33 weeks of gestation. The purpose of an early diagnosis is to establish a
      careful perinatal management. If the airway is compromised, a multidisciplinary
      medical team is necessary to perform emergency immediate tracheostomy. Elective
      delivery should be always carried out in a tertiary referral center.

PMID- 15192301
TI  - Non-immune hydrops and superior vena cava syndrome due to diaphragmatic hernia in
      one twin.
AB  - BACKGROUND: In a monochorionic twin gestation, hydrops in one fetus often results
      from placental transfusion, accompanied by intrauterine growth restriction (IUGR)
      of the non-hydropic fetus. CASE: A 35-year-old G11P9 presented with hydrops and
      IUGR of one of a monochorionic-diamniotic gestation. Extensive testing failed to
      reveal etiology for hydrops. The patient was delivered at 30 weeks gestation
      after non-reassuring fetal monitoring. The hydropic baby could not be adequately
      ventilated and expired in the early post-partum period. A diagnosis of superior
      vena cava syndrome and pulmonary hypoplasia secondary to right-sided congenital
      diaphragmatic hernia (CDH) was made neonatally. CONCLUSION: Right-sided CDH can
      be difficult to diagnose by sonography at times because of the echogenic
      similarity of liver and lung, and may be suspected from signs of pericardial
      effusion and ascites.

PMID- 15192302
TI  - Prospective evaluation of uterine artery flow velocity waveforms at 12-14 and 22
      24 weeks of gestation in relation to pregnancy outcome and birth weight.
AB  - OBJECTIVE: Uterine artery flow velocity was prospectively assessed using Doppler
      ultrasound at 12-14 and 22-24 weeks of gestation in the prediction of subsequent
      complications related to uteroplacental insufficiency: preeclampsia, pregnancy
      induced hypertension, fetal growth restriction, fetal death and placental
      abruption, and to elucidate its relationship with birth weight. METHODS: Uterine
      artery Doppler assessment was obtained during routine ultrasound screening in 263
      unselected women. Flow velocity waveforms were coded according to the number of
      notches present at each scanning, respectively: none (0, 0), uni-/bilateral
      notches that disappeared (1, 0) or (2, 0), uni-/bilateral notches that persisted
      unilaterally (1, 1) or (2, 1), and persistent bilateral notches (2, 2). RESULTS:
      Complete outcome data was obtained for 243 (92.4%) women. Of these women, 55
      (22.6%) and 84 (34.6%) women had uni- and bilateral notches, respectively, at 12
      14 weeks' gestation; 14 (5.8%) and 21 (8.6%) patients had uni- and bilateral
      notches, respectively, at 22-24 weeks' gestation. Analysis of complication rates
      for the four groups showed that they increased with notch persistence (5.7, 13.5,
      57.1 and 76.2%), while the corresponding mean birth weight declined (3,273,
      3,180, 2,698 and 2,418 g). CONCLUSION: The absence or early disappearance of
      uterine artery notches is associated with fewer complications related to
      uteroplacental insufficiency and normal birth weight, whereas their late and
      partial disappearance or bilateral persistence tends to compromise the prognosis.

PMID- 15192303
TI  - Impact of improved survival of very low-birth-weight infants on incidence and
      severity of bronchopulmonary dysplasia.
AB  - BACKGROUND: It has been suggested that improved survival of very low birth weight
      (VLBW) infants may have resulted in increased numbers of patients with
      bronchopulmonary dysplasia (BPD). GOAL: To determine the impact of changes in
      mortality on the incidence and/or severity of BPD in three different time periods
      with distinct respiratory support strategies. METHODS: Retrospective single
      center cohort study of VLBW infants: Cohort A (1986-1990): pre-surfactant era,
      use of conventional intermittent mandatory ventilation (IMV); cohort B (1993
      1994): use of synthetic surfactant, nasopharyngeal continuous positive airway
      pressure (CPAP) and conventional IMV; cohort C (2000-2001): use of natural
      surfactant, early nasal prong CPAP, synchronized IMV with tidal volume monitoring
      and high frequency oscillatory ventilation (HFOV). BPD was classified as mild,
      moderate or severe according to Jobe and Bancalari. RESULTS: The median
      gestational ages and birth weights were 28 3/7 weeks and 1,120 g for cohort A (n
      = 97), 30 0/7 weeks and 1,340 g for cohort B (n = 100), and 29 1/7 weeks and
      1,200 g for cohort C (n = 135). The use of partial or complete courses of
      antenatal corticosteroids (ANC) increased over time (58%, 72%, and 82%, p =
      0.003). There was a 50% reduction of mortality between each time period with
      mortality rates of 30%, 14% and 7% in cohorts A, B and C, respectively (p <
      0.001). The overall incidence of BPD was 26% in the pre-surfactant era, 11%
      during the mid-1990s and 19% in the most recent time period (r = -0.05, p =
      0.36). Moderate and severe forms of BPD decreased over time and were seen in 11%
      in cohort A, 3% in cohort B and 2% in cohort C (p = 0.008). CONCLUSION: Changes
      in neonatal care of VLBW infants, including increased use of ANC and modified
      respiratory support strategies, have resulted in dramatically improved survival
      rates over the past 15 years without increasing moderate to severe pulmonary
      morbidity.

PMID- 15192304
TI  - Safety and tolerability of high-dose angiotensin receptor blocker therapy in
      patients with chronic kidney disease: a pilot study.
AB  - BACKGROUND: The progression of renal disease is ameliorated by drugs that inhibit
      the renin-angiotensin system (RAS). The doses used to slow the progression of
      renal disease may not completely suppress the RAS for 24 h and may explain why
      some patients do not obtain optimal renoprotective benefits from therapy. This
      pilot study was initiated to determine the safety and tolerability of using
      higher doses, than currently approved by the Food and Drug Administration, for
      the angiotensin-receptor blocker (ARB) candesartan cilexetil in patients with
      chronic kidney disease. We hypothesized that higher doses will be safe and well
      tolerated. Consequently, this should be a viable strategy for larger clinical
      trials evaluating the preservation of renal function. METHODS: Twelve patients
      (10 males; age = 57 +/- 14 years) with a history of diabetic or non-diabetic
      chronic kidney disease were enrolled in an 8-week open-label trial. Patients
      received candesartan titrated to a targeted dosage of 160 mg/day (5 times above
      the currently approved maximum dose) and remained at that dosage for the
      subsequent 4 weeks. The safety and tolerability of the higher doses were
      determined by measures of blood pressure, serum creatinine and potassium.
      RESULTS: Candesartan was well tolerated with no serious drug-related adverse
      events reported. Serum creatinine concentrations throughout the study were not
      different (p > 0.05) from baseline levels (2.0 +/- 0.5 mg/dl). Plasma potassium
      concentrations at 160 mg/day candesartan (4.9 +/- 0.7 mEq/l) were similar (p >
      0.05) to those at baseline (4.8 +/- 0.5 mEq/l). CONCLUSIONS: The results of this
      pilot study suggest that supramaximal doses of ARBs are safe and well tolerated
      in patients with chronic kidney disease, while reducing both blood pressure and
      proteinuria. This study demonstrates the need to further investigate the optimal
      dosing strategy for ARBs in reducing the progression of renal disease.

PMID- 15192305
TI  - Expression of placental growth factor gene in lung cancer.
AB  - Differences in the gene expression profiles in small cell lung cancers (SCLC) and
      non-small cell lung cancers (NSCLC) may explain their different clinical
      characteristics. The aims of this study were (1) to identify genes differentially
      expressed in SCLC and NSCLC using mRNA differential display, and (2) to determine
      the clinical relevance of such genes in lung cancer. RNA differential display
      using three SCLC and six non-SCLC cell lines was used to identify a
      differentially expressed gene. Differential expression of the gene was confirmed
      in additional lung cancer cell lines using RT-PCR. Immunohistochemical staining
      for the gene product was performed on paraffin-embedded tissue from lung cancer
      patients. We examined the relationship between the expression of the gene and
      clinical parameters, including disease stage, response to treatment and survival
      time. The placental growth factor (PGF) gene was identified as preferentially
      expressed in SCLC compared with NSCLC cell lines using mRNA differential display.
      Further analysis of 45 lung cancer cell lines using RT-PCR showed that the
      placental growth factor (PGF) gene was expressed in nine of 13 SCLC cell lines
      (69%) and five of 32 NSCLC cell lines (15.6%) (p < 0.001, Fisher's exact test).
      Immunohistochemistry using anti-PGF antibody on the paraffin blocks from lung
      cancer patients showed that PGF expression was significantly higher in SCLC than
      NSCLC tissue sections (32 vs. 5.6%, p = 0.041, Fisher's exact test). Expression
      of PGF protein did not correlate with disease stage, response to treatment or
      survival time in SCLC patients. The present study suggests there is higher
      expression of PGF in SCLC compared to NSCLC. It may be that higher expression of
      the angiogenic factor PGF contributes to differences between the progression of
      SCLC and NSCLC, especially in regard to the nature of SCLC metastasis.

PMID- 15192306
TI  - Specificity rescue and affinity maturation of a low-affinity IgM antibody against
      pro-gastrin-releasing peptide using phage display and DNA shuffling.
AB  - The objectives of the present study were to use phage display to rescue the
      specificity of an IgM antibody and by the use of DNA shuffling to construct a
      sublibrary from which mutants with higher affinity could be selected. As a test
      system, a hybridoma cell line producing low-affinity IgM against recombinant pro
      gastrin-releasing peptide (ProGRP) was chosen as starting material for
      construction of a single-chain Fv (scFv) phage library. One clone, pGRP5,
      demonstrating affinity for the antigen, was selected for the study. Random
      mutations were introduced into the scFv sequence by DNA shuffling, and mutants
      with raised affinity were selected by biopanning against recombinant ProGRP.
      Clones with affinities improved by approximately two orders of magnitude were
      selected after the first round of DNA shuffling. An additional 8- to 9-fold rise
      in affinity was demonstrated in mutants after the second round of mutagenesis.
      Sequence analysis demonstrated changes primarily in the complementarity
      determining region (CDR) H1, CDR L1 and CDR H3 as compared to the original clone.
      Thus, by the use of phage display in combination with DNA shuffling, the
      specificity of an IgM antibody was rescued and the affinity was raised almost
      three orders of magnitude.

PMID- 15192307
TI  - Monocyte chemoattractant protein-1 serum levels in patients with breast cancer.
AB  - The chemokine monocyte chemoattractant protein (MCP)-1 is thought to be involved
      in breast carcinogenesis. We evaluated MCP-1 serum levels in patients with breast
      cancer (n = 135), ductal carcinoma in situ (DCIS) I-III (n = 30), benign breast
      lesions (n = 143) and in healthy women (n = 27). We determined the value of MCP-1
      serum levels as a differentiation marker between malignant, preinvasive and
      benign breast diseases and as a predictive marker for the biological phenotype of
      breast carcinoma. Median (range) MCP-1 serum levels in patients with breast
      cancer, DCIS I-III, benign breast lesions and healthy women were 200 (57-692)
      pg/ml, 194 (58-525) pg/ml, 174 (39-529) pg/ml and 175 (67-425) pg/ml,
      respectively. No differences were ascertained between the patient groups. In
      patients with breast cancer, increased MCP-1 serum levels were correlated with
      advanced tumor stage (p = 0.04) and lymph node involvement (p = 0.04). We were
      not able to establish MCP-1 as a differentiation marker between malignant and
      benign breast diseases. Our data might indicate that MCP-1 influences breast
      carcinogenesis by facilitating tumor growth and metastatic spread, thus altering
      the biological phenotype of the disease.

PMID- 15192308
TI  - The free monomeric beta subunit of human chorionic gonadotrophin (hCG beta) and
      the recently identified homodimeric beta-beta subunit (hCG beta beta) both have
      autocrine growth effects.
AB  - The ectopic production of free hCG beta is a common phenomenon in epithelial
      tumours, a phenomenon originally believed to have no biological significance.
      However, it is now apparent that hCG beta may significantly effect tumour
      development by increasing cell populations through inhibition of apoptosis. The
      recently identified hCG beta beta homodimer, with topological similarities to
      cystine knot growth factors, has been suggested to be the responsible mediator of
      these novel tumourigenic responses. In this study we isolated hCG beta monomer
      from hCG beta beta homodimer using size exclusion chromatography and confirmed
      the separation by Western blotting. Using a tetrazolium bromide incorporation
      cell number quantification assay (MTT), we measured the growth effects of
      separated hCG beta fractions corresponding to monomeric (hCG beta) and dimeric
      (hCG beta beta) forms on the hCG beta responding cell line T24. Maximal increases
      in cell number corresponded to the elution peak of dimeric and monomeric hCG
      beta. In conclusion, it would appear that the recently observed hCG beta beta
      homodimer is no more bioactive than its monomeric counterpart, in stimulating
      bladder cancer cell growth. This strengthens the proposition that hCG beta may
      exert its antiapoptotic effects by antagonistic inhibition of other cystine knot
      growth factor receptors and not by a specific receptor-mediated homodimeric
      interaction as seen for its topological counterparts TGF, PDGF-B and NGF.

PMID- 15192309
TI  - Profiling of proteolytic activities secreted by cancer cells using phage display
      substrate technology.
AB  - Although the cellular steps required for metastasis are similar for all cancer
      cells, proteases involved in this process and their expression levels vary
      greatly between different cancer types. Thus, the identification of these
      proteolytic activities represents a crucial issue in the understanding of cancer
      development. Until now, phage display substrate technology has been successfully
      employed for the characterization of purified proteases but was never used with a
      mix of proteases. In the present work, we report an easy protocol to identify
      multiple proteolytic activities secreted by cancer cells. We selected substrates
      from a phage display library of high diversity using secreted media of three
      established prostate cancer cell lines (DU-145, LNCaP and PC-3) with variable
      degrees of invasive capability. Some of these selected peptide substrates were
      hydrolyzed by the secreted proteins of all three prostatic cancer cell lines,
      demonstrating similarities in their proteolytic activities. On the other hand, a
      few substrates were cancer cell specific, indicating differences in the
      phenotypes of protease expression in prostate cancer. This work reports for the
      first time the selection of substrates from a mix of proteases using phage
      display technology and opens a new avenue for the direct identification of
      proteolytic activities for tumor extracts.

PMID- 15192310
TI  - Immunofluorometric assay for the metastasis-related protein S100A4: release of
      S100A4 from normal blood cells prohibits the use of S100A4 as a tumor marker in
      plasma and serum.
AB  - The metastasis-related protein S100A4 is released from tumor cells, and since it
      is highly expressed in colorectal cancer (CRC), it could be a potential tumor
      marker in plasma or serum. Monoclonal antibodies (MAbs) were raised against human
      recombinant S100A4 and shown to detect native and recombinant antigen with high
      sensitivity and specificity. Using two MAbs, an immunofluorometric assay (IFMA)
      was established to detect S100A4 in clinical samples with high sensitivity and
      precision. S100A4 in plasma and serum from patients with CRC was highly
      influenced by sample hemolysis. Both red blood cells and mononuclear cells were
      found to contain S100A4, possibly contributing to the measured levels in serum
      and plasma. Since even very low-level hemolysis influenced the results, a
      potential contribution from an S100A4-expressing tumor could not be discerned,
      indicating that S100A4 is not suitable as a plasma or serum tumor marker for CRC.
      The antibodies and the IFMA may still be useful for research purposes.

PMID- 15192311
TI  - Genes related to growth regulation, DNA repair and apoptosis in an oestrogen
      receptor-negative (MDA-231) versus an oestrogen receptor-positive (MCF-7) breast
      tumour cell line.
AB  - The molecular mechanism(s) behind the development of endocrine resistance in
      breast cancer remains controversial. Here, we compare the capability of oestrogen
      receptor (ER)-negative cells (MDA-231) versus ER-positive tamoxifen-sensitive
      cells (MCF-7) to handle DNA repair, transmit signals from damaged DNA, initiate
      cell death via apoptosis, and then to control transmitted signals from the cell
      cycle and to synthesize growth factors and receptors. Genes related to these
      events were studied by cDNA micro-array. Normal human breast cells (H2F) and
      human lymphoblastoid tumour cells (CEM) were used as controls. Of the 18 genes
      investigated, 10 genes showed differences in their expression between the cell
      types. The ER-negative cells showed higher expressions of BRCA1, BRCA2, cdc2,
      cyclin B1, cyclin D1, cyclin E, IGFBP-3, TGF-alpha, TGF beta 2 and a lower
      expression of TGF beta R1. No differences in the expressions of bax, bcl-2, p53,
      p21 and GADD45 were found between the two cell lines. We found that the ER
      negative cells were characterized by: (1) a stimulated expression of growth
      factors and cell cycle regulation compounds, (2) improved DNA repair capacity,
      but (3) no change in DNA damage signals and apoptotic pathways. Improved DNA
      repair capacity of ER-negative cells would have a growth advantage over ER
      positive tumours when receiving antitumour therapy.

PMID- 15192312
TI  - Intravasation-related metastatic factors in colorectal cancer.
AB  - Alterations in adhesion molecules, angiogenesis, and matrix metalloproteinases
      have been associated with metastasis and intravasation. The present study
      investigated the role of these metastatic factors in the context of primary
      colorectal tumor. Intravasated colorectal epithelial cells were detected by an RT
      PCR assay, and the expression of E-cadherin, alpha-catenin, or beta-catenin as
      well as the vascularity of tumor were assessed by immunohistochemical staining.
      Activity of matrix metalloproteinase was assessed by gelatin zymography. The
      tumor venous blood was positive for guanylyl cyclase C (GCC) mRNA expression in
      40 of 68 patients, but alteration in expression of E-cadherin, alpha-catenin, or
      beta-catenin was not significantly associated with the presence of colorectal
      epithelial cells in paired portal venous blood. Further, matrix metalloproteinase
      activity did not correlate with the presence of intravasated colorectal
      epithelial cells. Multivariate analysis demonstrated that the only factor
      associated with intravasated colorectal tumor cells was the vascularity of the
      tumor. Thus, metastasis of colon cancer may result from passive entry into the
      circulation secondary to angiogenic factors and does not appear to involve other
      metastatic factors studied in our experiments.

PMID- 15192313
TI  - Pro-gastrin-releasing peptide in patients with benign and malignant diseases.
AB  - The specificity and sensitivity of pro-gastrin-releasing peptide (ProGRP) was
      evaluated in 37 healthy subjects, 197 patients with benign diseases and 310
      patients with malignant diseases of different origins. Abnormal ProGRP serum
      levels (>50 pg/ml) were found in 10% of the patients with benign diseases and in
      26.1% of the patients with active cancer. None of the healthy subjects had
      abnormal ProGRP levels. The benign disease with the highest ProGRP concentration
      was renal failure, with abnormal values in 51.6% of the patients studied.
      Excluding patients with renal failure or patients with creatinine levels greater
      than 1.5 mg/dl, raised ProGRP values (<80 ng/ml) were found in 2.5% (4/160) of
      patients with benign diseases and in 4.9% of patients with active malignancies
      other than lung cancer or neuroendocrine tumors (<110 ng/ml). Abnormal ProGRP
      serum levels were found in 26.2% of patients with non-small cell lung cancer
      (NSCLC) (mean 40.5 +/- 35.4 pg/ml) and in 76.8% of patients with small cell lung
      cancer (SCLC) (mean 694 +/- 1,776 pg/ml) (p < 0.001). ProGRP serum levels >300
      pg/ml were only found in SCLC patients (41.4%). ProGRP results were related to
      tumor extension in SCLC (sensitivity in limited disease 58.3%, in extensive
      disease 95.5%) but not in NSCLC. In summary, renal failure is the most frequent
      source of false-positive results with ProGRP, and this marker is useful in the
      histological differential diagnosis of lung cancer.

PMID- 15192314
TI  - Differential expression patterns of the insulin-like growth factor 2 gene in
      human colorectal cancer.
AB  - Tumour development and metastasis are associated with altered gene expression
      profiles. The aim of this study was to identify the transcriptional differences
      in normal, tumour and metastatic tissue. We used oligonucleotide arrays to
      identify differential expression patterns of insulin-like growth factor 2 (IGF 2)
      between 139 primary colorectal tumour specimens and 42 tumour-adjacent mucosa
      specimens from colorectal cancer (CRC) patients. The expression levels of the IGF
      2 gene were significantly increased in primary tumours compared with adjacent
      mucosae. This was concordant with our real-time RT-PCR quantification of 48
      matched tumour mucosa samples. IGF 2 expression levels were also measured by RT
      PCR quantitative analysis in 18 liver metastases and 10 normal tissues from
      patients without cancer. The mRNA levels were significantly under-expressed in
      liver metastases compared with either colorectal tumours or adjacent normal
      mucosae. The non- malignant normal tissue expressed significantly lower IGF 2
      levels than adjacent normal tissue, and this was not due to a field effect
      originating from the tumour. In addition, our microarray data demonstrated that
      IGF 2 expression was down-regulated in sporadic microsatellite instability (MSI
      H) CRC and parallels under-expression of hMLH1 and IGF 2 receptor genes in these
      patients. We conclude that IGF 2 plays an important role in CRC development.
      Also, individuals with loss of genomic imprinting (LOI) causing over-expression
      of IGF 2 may be at greater risk of developing CRC. However, this LOI may be
      reversed in MSI-H patients.

PMID- 15192315
TI  - Characterization of monoclonal antibodies directed against squamous cell
      carcinoma antigens: report of the TD-10 Workshop.
AB  - Thirteen monoclonal antibodies directed against squamous cell carcinoma antigens
      (SCCA1 and SCCA2) were obtained from five international collaborating
      laboratories participating in the ISOBM TD-10 Workshop. Native and recombinant
      forms of SCCA were used in a wide variety of approaches to determine the
      reactivity and specificity of these antibodies. Based on reactivity, the
      antibodies could be divided into three groups: the SCCA1-reactive group
      containing those that reacted only with recombinant SCCA1 (rSCCA1) and native
      SCCA1 (nSCCA1) antigens, the SCCA2-reactive group containing those that reacted
      only with recombinant SCCA2 (rSCCA2), and the pan-reactive group containing those
      antibodies that reacted with rSCCA1, nSCCA1, and rSCCA2. Binding to
      radioiodinated rSCCA1 showed that all reactive antibodies were of a high affinity
      (K(d) <2 x 10(-9) mol/l). Binding to labelled rSCCA2 demonstrated that five
      antibodies were of a high affinity (K(d) <2 x 10(-9) mol/l). Antibody reactivity
      on Western blots was tested with nonreduced and reduced native and recombinant
      SCCA1 and SCCA2. In general, these findings showed that reduction had little
      effect on binding to SCCA1, but often a strong effect on the binding to SCCA2.
      Binding of antibodies to rSCCA1 and rSCCA2 in complexes with cathepsin L and G,
      respectively, was used to assist in the localization of epitope regions in enzyme
      complexed SCCA. Cross-inhibition experiments showed that SCCA1-reactive
      antibodies represent two different epitope groups, and this is supported by their
      ability to make SCCA1-specific assays by combining antibodies from the two
      epitope groups. The SCCA2-reactive group represents two related antibodies and
      one unique as seen in cross-inhibition, but they do not form successful assay
      combinations. Classification of the pan-reactive antibodies is more difficult, as
      some epitope groups differ when results from rSCCA1 are compared with rSCCA2 as
      the target. However, two antibodies are outstanding, SCC107 and SCC113, as they
      are high-affinity antibodies which react equally well with free and protease
      complexes of SCCA1 and SCCA2. The precise location of epitopes was further
      studied using sequential overlapping peptides and homology modelling. The
      findings from this workshop strongly indicate that the recombinant antigens
      (rSCCA1 and rSCCA2) are very similar in epitope structure to the native
      counterparts in saliva, and squamous epithelium from normal and cancer tissues.
      Therefore, it is reasonable to conclude that the specificities found are reliable
      and have application for antibody measurement of all forms of squamous cell
      carcinoma in serum except SCCA2 in complex with its protease.

PMID- 15192317
TI  - The latent structure of Wallerstein's Scales of Psychological Capacities.
AB  - BACKGROUND: Wallerstein's Scales of Psychological Capacities (SPC) is a fairly
      new measure of psychological change, developed to meet the need for an instrument
      which can be used by clinicians and researchers from different psychotherapy
      directions and schools. This study examined whether Blatt's theory of 2 different
      types of psychopathology can be used to interpret the latent structure of the
      SPC. SAMPLING AND METHODS: Data from 224 individuals with mild to severe
      psychopathology were factor analyzed. RESULTS: A 2-factor solution was
      meaningfully interpreted from Blatt's theory, and the factors were used for
      computing summary scales. The scales had adequate reliabilities and discriminated
      well between different classifications according to DSM-III-R. Patients with
      depressive or anxiety disorder had more problems with issues concerning self
      definition compared to patients with cluster B personality disorder. CONCLUSION:
      The findings supported the assumption that the concept of psychological capacity
      is based on an integrative model of the mind, and that the SPC can be a useful
      tool for clinicians and researchers in understanding psychological problems and
      resources in patients with various psychiatric disorders. A weakness of the study
      was that reliability data for DSM diagnoses were not gathered. Moreover, the
      group of patients with depressive or anxiety disorder was small.

PMID- 15192316
TI  - Engineering antibodies for clinical applications in cancer.
AB  - The 'magic bullet' concept predicted over a century ago that antibodies would be
      used to target cancer therapy. Since then initial problems that were related to
      specificity, purity and immungenicity of antibody-based reagents have slowly been
      overcome due to developments in technology and increased knowledge. As a result,
      antibodies are in use for many clinical applications and now comprise the second
      largest category of medicines in clinical development after vaccines. For
      antibody-based cancer therapeutics the last 20 years have met with an explosion
      of knowledge about the biology of the disease and potential targets as well as
      new technology which allows cloning and manipulation of multifunctional antibody
      based molecules. However, the focus still remains on developing therapeutics that
      will have potential for treating cancer in people and this is efficiently
      assessed in mechanistic clinical trials that feed back to the laboratory for
      further development. This review illustrates the mechanistic approach to making
      new molecules for antibody imaging and therapy of cancer. It is illustrated by
      examples of radioimmunotherapy and antibody-directed enzyme prodrug therapy
      developed by the authors.

PMID- 15192318
TI  - Magical ideation -- defense mechanism or neuropathology? A study with multiple
      sclerosis patients.
AB  - BACKGROUND: The major psychological stress factor in multiple sclerosis (MS) is
      loss of control of life. In MS patients with impaired cognition, magical ideation
      might be a characteristic way of thinking. Proof for this may be the high
      frequency of alternative treatments used by individuals with MS. The study
      investigates whether the level of magical ideation in MS patients is higher
      compared to healthy control subjects and, in case of positive confirmation, with
      which somatic and psychological features it is associated. Moreover, it is aimed
      to discuss the modalities of magical ideation in general. SAMPLING AND METHODS: A
      German version of the Magical Ideation Scale was validated with a group of 69
      healthy subjects. Ninety-four MS patients were additionally assessed with the
      Dissociative Experience Scale, the Symptom-Check-List-90-Revised and 5
      neuropsychological tests. RESULTS: The Magical Ideation Scale did not reveal a
      significant difference between MS patients and healthy controls (p = 0.968).
      Among the MS patients, magical ideation shows a correlation neither with age nor
      with disability, but a positive correlation (p = 0.007; r = 0.329) with the grade
      of neuropsychological deficiency. Among the psychological parameters, the highest
      positive correlation with magical ideation was found in dissociation (p = 0.000;
      r = 0.520). DISCUSSION: Magical ideation, sharing common features with
      dissociation, can be viewed as an early defense mechanism when perceiving a loss
      of control of life, particularly in early stages of MS. In late stages, when
      developing neuropsychological deficits, it may occur as a substitute for
      cognitive coping. The data may encourage clinicians to identify magical ideation.
      In young and previously diagnosed patients, it is important to acknowledge
      helplessness and support a rather rational way of coping. Training cognitive
      skills could be crucial to prevent older patients from losing touch with reality.
      More generally, the occurrence of a significant amount of magical ideation is
      discussed both as a psychological and a neurophysiologic regression of thinking.

PMID- 15192319
TI  - Psychosocial factors and sexual dysfunctions: a descriptive study in Turkish
      males.
AB  - The study of human sexuality has dramatically changed in the last decade. The
      conceptualization of sexual dysfunction developed in the West is now mushrooming
      in different parts of the world and there is a dearth of research on
      characteristics of patients seeking treatment for sexual dysfunction in non
      Western countries. This paper describes the demographic characteristics, related
      factors, and clinical symptomatology of 40 male patients with various sexual
      dysfunctions attending the psychiatric out-patient clinic of Cukurova University,
      Turkey. Turkey's population is predominantly Muslim and the country unites Europe
      and Asia, showing the cultural characteristics of both continents. Our results
      suggest that the patterns of manifestation are similar to those reported
      elsewhere with the exception of premarital patterns of sexuality.

PMID- 15192320
TI  - Delusion of test-tube pregnancy in a sexually abused girl.
AB  - We report the case of a patient who presented with catatonic features and
      delusion of test-tube pregnancy in the background of previous sexual abuse. The
      reported case illustrates the importance of contemporary themes in the evolution
      of psychopathology.

PMID- 15192321
TI  - Subpressor dose asymmetric dimethylarginine modulates renal function in humans
      through nitric oxide synthase inhibition.
AB  - Increased blood concentrations of the endogenous nitric oxide (NO) synthase
      inhibitor asymmetric dimethylarginine (ADMA) have been linked to high blood
      pressure and to cardiovascular mortality. We evaluated the effects of a
      subpressor ADMA dose on NO production, renal hemodynamics, sodium handling and
      active renin and noradrenalin plasma concentrations in 12 healthy subjects (age
      26 +/- 1 year) using a double-blind placebo-controlled study design. Infusion of
      ADMA caused a significant decrease in plasma cyclic guanosine monophosphate
      (cGMP) levels, i.e. the second messenger of NO (from 6.1 +/- 0.4 to 4.3 +/- 0.3
      pmol/l; p < 0.05). In parallel, effective renal plasma flow (ERPF) decreased
      while renovascular resistance (RVR) increased significantly (ERPF from 667 +/- 9
      to 603 +/- 10 ml/min/1.73 m2; RVR from 79 +/- 2 to 91 +/- 2 ml/min/mm Hg; both p
      < 0.05 vs. baseline). Infusion of placebo did not cause significant changes in
      plasma cGMP levels, ERPF and RVR (cGMP from 5.7 +/- 0.5 to 5.9 +/- 0.6 pmol/l;
      ERPF from 665 +/- 12 to 662 +/- 11 ml/min/1.73 m2; RVR from 79 +/- 2 to 78 +/- 2
      ml/min/mm Hg; all non-significant). Moreover, urinary sodium excretion was
      significantly lower with infusion of ADMA as compared with placebo infusion (128
      +/- 8 vs. 152 +/- 7 micromol/min; p < 0.05). In contrast, blood pressure, active
      renin and noradrenalin plasma concentrations did not change significantly with
      either infusion protocol. Acute infusion of a subpressor ADMA dose modulates
      several aspects of renal function in humans without affecting the activity of the
      renin-angiotensin and sympathetic system. Whether chronic (intrarenal) NO
      synthase inhibition in individuals with increased ADMA blood levels may cause
      persistent renal vasoconstriction and sodium retention must be evaluated.

PMID- 15192322
TI  - Modulation of phagocyte apoptosis by bacterial pathogens.
AB  - Phagocytic leukocytes such as neutrophils and macrophages are essential for the
      innate immune response against invading bacteria. Binding and ingestion of
      bacteria by these host cells triggers potent anti-microbial activity, including
      production of reactive oxygen species. Although phagocytes are highly adept at
      destroying bacteria, modulation of leukocyte apoptosis or cell death by bacteria
      has emerged as a mechanism of pathogenesis. Whereas induction of macrophage
      apoptosis by pathogens may adversely affect the host immune response to
      infection, acceleration of neutrophil apoptosis following phagocytic interaction
      with bacteria appears essential for the resolution of infection. This idea is
      supported by the finding that some bacterial pathogens alter normal phagocytosis
      induced neutrophil apoptosis to survive and cause disease. This review summarizes
      what is currently known about modulation of phagocyte apoptosis by bacteria and
      describes a paradigm whereby bacteria-induced neutrophil apoptosis plays a role
      in the resolution of infection.

PMID- 15192323
TI  - APP induces neuronal apoptosis through APP-BP1-mediated downregulation of beta
      catenin.
AB  - Alzheimer's disease (AD) is a neurodegenerative disease associated with
      progressive dementia. This mini-review focuses on how the amyloid precursor
      protein (APP) plays a central role in AD and Down syndrome as the regulator of
      the APP-BP1/hUba3 activated neddylation pathway. It is argued that the
      physiological function of APP is to downregulate the level of beta-catenin.
      However, this APP function is abnormally amplified in patients with familial AD
      (FAD) mutations in APP and presenilins, resulting in the hyperactivation of
      neddylation and the decrease of beta-catenin below a threshold level. Evidence in
      the literature is summarized to show that dysfunction of APP in downregulating
      beta-catenin may underlie the mechanism of neuronal death in AD and Down
      syndrome.

PMID- 15192324
TI  - Caspase-9 regulation: an update.
AB  - The complex sequence of events leading to apoptotic cell death is governed by an
      elaborate regulatory scheme involving the actions of both initiator and
      executioner proteases. Among the most intensively studied of the initiator
      caspases is caspase-9, an essential throughput element in the so-called intrinsic
      or mitochondrially gated pathway of apoptosis. Previous reviews have described
      the proteolytic processing and activation of this protease in much detail; here
      we provide an update on caspase-9 regulation. A comprehensive description of the
      intra- and intermolecular events involved in modulating protein expression and
      activity are presented. Particular emphasis is placed on the role alternative
      splicing plays in the expression of functionally divergent protein isoforms, as
      well as, the participation of specific post-translational events in regulating
      caspase-9 activity. Such discrete modulation in reported activity characterizes,
      not only the pivotal role of this protease in the final commitment process
      itself, but also emphasizes the more general interplay that exists between
      mutually opposing cytotoxic and cytoprotective influences in maintaining cellular
      homeostasis.

PMID- 15192325
TI  - Characterization of 4-O-methyl-ascochlorin-induced apoptosis in comparison with
      typical apoptotic inducers in human leukemia cell lines.
AB  - Apoptosis can be induced by various stimuli such as the ligands of death
      receptors, chemotherapeutic drugs and irradiation. It is generally believed that
      chemotherapeutic drugs induce mitochondrial damage, cytochrome c release and
      activation of caspase-9, leading to apoptosis. Here, we found that an isoprenoid
      antibiotic, 4-O-methyl ascochlorin, significantly induces typical apoptotic
      events in Jurkat cells including the degradation of poly (ADP-ribose) polymerase,
      DNA fragmentation, activation of caspase-3, -9 and -8, and cytochrome c release
      from mitochondria. Similar to Fas stimulation, 4-O-methyl ascochlorin but not
      staurosporine, cycloheximide and actinomycin D, induced apoptosis in SKW6.4
      cells, in which apoptosis is strongly dependent on death-inducing signaling
      complex. Bcl-2 overexpression in Jurkat cells completely suppressed the
      apoptosis, but procaspase-9 processing was partially induced. A caspase-8
      inhibitor, IETD-fmk, effectively suppressed poly (ADP-ribose) polymerase cleavage
      and cytochrome c release. However, 4-O-methyl ascochlorin induced apoptosis in
      Jurkat cells deficient of caspase-8 or Fas-associated death domain protein. These
      results suggest that 4-O-methyl ascochlorin induces apoptosis through the
      mechanism distinct from conventional apoptosis inducers.

PMID- 15192326
TI  - Apoptosis induction by the natural product cancer chemopreventive agent deguelin
      is mediated through the inhibition of mitochondrial bioenergetics.
AB  - Deguelin exhibits chemopreventive properties in animal carcinogenesis models. The
      mechanism underpinning the chemopreventive effects of deguelin has not been fully
      elucidated. However, it has been suggested that this agent reduces ornithine
      decarboxylase activity, and perhaps the activity of other signaling intermediates
      associated with tumorigenesis, by inhibiting mitochondrial bioenergetics. We
      sought to determine if deguelin could trigger apoptosis by inhibiting
      mitochondrial bioenergetics. Therefore, we compared and contrasted the effects of
      deguelin on cells from two human cutaneous squamous cell carcinoma cell lines
      (parental cells) and their respiration-deficient clones lacking mitochondrial DNA
      (rho0). While deguelin promoted marked apoptosis in the parental cells in a dose-
      and time-dependent manner, it failed to do so in the rho0 clones. Furthermore,
      short-term exposure to deguelin diminished oxygen consumption by the parental
      cells and promoted mitochondrial permeability transition as evidenced by the
      dissipation of mitochondrial inner transmembrane potential, reactive oxygen
      species production, cardiolipin peroxidation, caspase activation, and
      mitochondrial swelling. Mitochondrial permeability transition was not observed in
      the rho0 clones exposed to deguelin. These results demonstrate that deguelin
      induces apoptosis in skin cancer cells by inhibiting mitochondrial bioenergetics
      and provide a novel mechanism for the putative anticancer activity of this agent.

PMID- 15192327
TI  - Potentiation of UVB-induced apoptosis by novel phytosphingosine derivative,
      tetraacetyl phytosphingosine in HaCaT cell and mouse skin.
AB  - Inappropriate apoptosis results in the epidermal hyperplasia as in psoriasis and
      UVB irradiation has been successfully used to treat this kind of skin disorders.
      Previously, we reported that the novel phytosphingosine derivative, tetraacetyl
      phytosphingosine (TAPS) induced apoptosis in HaCaT cells. This study examined the
      effect of UVB irradiation and/or TAPS on the induction of apoptosis in HaCaT. 10
      mJ/cm2 of UVB irradiation or 10 microM of TAPS alone exhibited weak cytotoxicity
      but co-treatment of UVB and TAPS synergistically enhanced the cytotoxicity and
      apoptosis in HaCaT. The cells treated with UVB and TAPS showed much higher levels
      of cleaved caspase-3, -8, -9 and Bax than with UVB or TAPS alone, whereas Bcl-2
      level was decreased by co-administration of UVB and TAPS. In hairless mice, co
      treatment of UVB and TAPS synergistically increased apoptosis, as shown in the
      HaCaT co-treated with UVB and TAPS. Furthermore, UVB irradiation caused an
      increase of apoptotic cells in the epidermis and the TAPS-treated mice showed an
      increase of apoptotic cells in the dermis as well as in the epidermis. These
      results suggest that the TAPS co-treatment synergistically increases the level of
      UVB-induced apoptosis via caspase activation by regulating the level of pro
      apoptotic Bax and anti-apoptotic Bcl-2.

PMID- 15192328
TI  - Identification of deficient mitochondrial signaling in apoptosis resistant
      leukemia cells by flow cytometric analysis of intracellular cytochrome c, caspase
      3 and apoptosis.
AB  - Deficient activation of apoptosis signaling pathways may be responsible for
      treatment failure of malignant diseases. In primary leukemia samples the
      detection of deficient mitochondrial apoptosis signaling would enable
      identification of chemo-resistant cells. To investigate the key events of
      apoptosis at the mitochondrial level, we developed a flow cytometric method for
      simultaneous detection of mitochondrial cytochrome c release and caspase-3
      processing using conformation sensitive monoclonal antibodies. This method proved
      to identify deficient mitochondrial apoptosis signaling in leukemia cells
      overexpressing Bcl-2 by a pattern of apoptosis resistance, deficient cytochrome c
      reduction and partial processing of caspase-3. In primary leukemia cells,
      reduction of cytochrome c and caspase-3 activation was induced by treatment with
      anticancer drugs in vitro. In leukemia cells of a patient with resistant disease,
      a pattern of deficient apoptosis signaling as in Bcl-2 transfected cells was
      observed, suggesting that deficient mitochondrial signaling contributed to the
      clinical phenotype of drug resistance in this patient. Flow cytometric analysis
      of mitochondrial apoptosis signaling may provide a useful tool for the prediction
      of drug resistance and treatment failure in primary leukemia.

PMID- 15192330
TI  - LUCA-15/RBM5, a putative tumour suppressor, enhances multiple receptor-initiated
      death signals.
AB  - LUCA-15/RBM5 is a putative tumour suppressor. The gene encodes a number of
      alternative RNA splice variants with differing abilities to either enhance or
      suppress apoptosis, and it is likely that this ability to modulate apoptosis is
      central to the putative tumour suppressor activity of LUCA-15. This report
      demonstrates for the first time that expression from the LUCA-15 locus modulates
      apoptosis triggered by the death-inducing ligand TRAIL. Using Jurkat T
      lymphoblastic leukemia cells, LUCA-15 expression was shown to enhance not only
      TRAIL but TNF-alpha- and Fas-mediated apoptosis. LUCA-15, therefore, has the
      ability to lower the apoptotic threshold of multiple receptor-initiated death
      inducing signals. Of note, sensitisation of the Jurkat cells to TRAIL was shown
      to depend on new protein synthesis, since no enhancement of apoptosis was
      observed when cells were exposed to both TRAIL and the protein synthesis
      inhibitor cycloheximide. This result suggests that LUCA-15 does not act
      independently to regulate apoptosis, but modulates a process that requires
      additional, newly synthesized protein. These results may explain the putative
      role of LUCA-15 as a tumour suppressor, suggesting that lack of functional LUCA
      15 could provide the means by which malignant T cells escape receptor-initiated
      apoptotic signals.

PMID- 15192329
TI  - LPS-induced apoptosis is dependent upon mitochondrial dysfunction.
AB  - Bacterial infection induces apoptotic cell death in human monoblastic U937 cells
      that have been pretreated with interferon gamma (U937IFN). Apoptosis occurs in a
      manner that is independent of bacterial virulence proteins. In the present study,
      we show that lipopolysaccharide (LPS), a membrane constituent of gram-negative
      bacteria, also induces apoptosis in U937IFN cells. LPS treatment led to the
      appearance of characteristic markers of apoptosis such as nuclear fragmentation
      and activation of caspases. While the caspase inhibitor Z-VAD-fmk prevented LPS
      induced apoptosis as judged by its inhibition of nuclear fragmentation, it failed
      to inhibit cytochrome c release and loss of mitochondrial membrane potential.
      Transfection of peptides containing the BH4 (Bcl-2 homology 4) domain derived
      from the anti-apoptotic protein Bcl-XL blocked LPS-induced nuclear fragmentation
      and the limited digestion of PARP. These results suggest that LPS does not
      require caspase activation to induce mitochondrial dysfunction and that
      mitochondria play a crucial role in the regulation of LPS-mediated apoptosis in
      U937IFN cells.

PMID- 15192331
TI  - Involvement of MIP-2 and CXCR2 in neutrophil infiltration following injection of
      late apoptotic cells into the peritoneal cavity.
AB  - Apoptotic cells are cleared by phagocytes, such as macrophages, as soon as they
      appear in vivo. If apoptosis occurs acutely, however, macrophages may be
      outnumbered by apoptotic cells, which causes late apoptosis. We previously showed
      that injection of late apoptotic cells into the peritoneal cavity led to
      transient infiltration of neutrophils. In this study, we examined the involvement
      of MIP-2 and CXCR2 in the neutrophil infiltration. We first produced a
      recombinant MIP-2 protein, and a fusion protein between CXCR2 and GST in E. coli,
      and then generated anti-MIP-2 antibodies and anti-CXCR2 antibodies in rabbits. We
      then confirmed their specificity by Western blotting analysis and flow cytometry.
      Injection of late apoptotic cells, such as P388 cells treated with etoposide for
      24 hours and CTLL-2 cells cultured in IL-2-free medium for 28 hours, induced
      neutrophil infiltration into the peritoneal cavity, as expected. The antibodies,
      but not control antibodies against GST, suppressed the neutrophil infiltration to
      the level caused by injection of normal (viable) cells, suggesting that MIP-2 and
      CXCR2 are mainly involved in the neutrophil infiltration caused by late apoptotic
      cells.

PMID- 15192332
TI  - Phosphatidylserine exposure during early primary necrosis (oncosis) in JB6 cells
      as evidenced by immunogold labeling technique.
AB  - Apoptotic cell death is characterized by the early exposure of phosphatidylserine
      (PS) at the outer surface of the plasma membrane. The aim of the present study
      was to examine whether PS exposure also occurs during oncosis (early primary
      necrosis) and to localize PS at the subcellular level, applying a pre-embedding
      immunogold labeling technique with biotin conjugated annexin V. The issue was
      addressed by using caspase-8 deficient, Bcl-2 overexpressing JB6 cells, which die
      by oncosis when stimulated with synthetic dsRNA. We observed by fluorescence
      microscopy that oncotic cells with preserved plasma membrane integrity showed PS
      exposure (annexin+/propidium iodide-). The data was confirmed on the
      ultrastructural level and PS was localized in oncosis at the outer leaflet of the
      continuous plasma membrane with preserved trilamellar structure. In postoncotic
      necrotic cells the immunogold labels were found on the plasma membrane and on the
      intracellular membranes of the cells, which underwent plasma membrane disruption.
      In conclusion, this study reveals that PS externalization occurs not only in
      apoptosis but also in oncosis at least in our cell model system.

PMID- 15192333
TI  - GRP94 reduces cell death in SH-SY5Y cells perturbated calcium homeostasis.
AB  - The endoplasmic reticulum (ER) resident-94 kDa glucose-regulated protein (GRP94),
      plays a pivotal role in cell death due to ER stress. In our study expression of
      GRP94 was increased in human neuroblastoma SH-SY5Y cells due to exposure to
      calcium ionophore A23187. A23187-mediated cell death was associated with
      activation of the major cysteine proteases, caspase-3 and calpain. Pretreatment
      with adenovirus-mediated antisense GRP94 (AdGRP94AS) reduced viability of SH-SY5Y
      cells subjected to A23187 treatment compared with wild type cells or cells with
      adenovirus-mediated overexpression of GRP94 (AdGRP94S). These results indicated
      that suppression of GRP94 is associated with accelerated cell death. Moreover,
      expression of GRP94 suppressed A23187-induced cell death and stabilized calcium
      homeostasis.

PMID- 15192334
TI  - An immunohistochemical study of the gastrointestinal endocrine cells in the ddY
      mice.
AB  - The distributions and frequencies of some endocrine cells in the gastrointestinal
      (GI) tract of ddY mice were studied with immunohistochemical method using 7 types
      of antisera against bovine chromogranin (BCG), serotonin, gastrin,
      cholecystokinin (CCK)-8, somatostatin, glucagon and human pancreatic polypeptide
      (HPP). All of 7 types of immunoreactive (IR) cells were identified. Most of IR
      cells in the intestinal portion were generally spherical or spindle in shape
      (open typed cell) while cells showing round in shape (close typed cell) were
      found in the intestinal gland and stomach regions occasionally. Their relative
      frequencies were varied according to each portion of GI tract. BCG-IR cells were
      demonstrated throughout whole GI tract except for the cecum and they were most
      predominant in the fundus and pylorus. Serotonin-IR cells were detected
      throughout whole GI tract and they were most predominant cell types in this
      species of mice. Gastrin-IR cells were restricted to the pylorus and CCK-8-IR
      cells were demonstrated in the pylorus, duodenum and jejunum with numerous
      frequencies in the pylorus. Somatostatin-IR cells were detected throughout whole
      GI tract except for the cecum and rectum and they showed more numerous
      frequencies in the stomach regions. In addition, glucagon-IR cells were
      restricted to the fundus, duodenum and jejunum with rare frequencies, and HPP-IR
      cells were restricted to the rectum only with rare frequency. In conclusion, some
      strain-dependent unique distributional patterns of gastrointestinal endocrine
      cells were found in GI tract of ddY mice.

PMID- 15192335
TI  - Pharmacokinetics, tissue residue and plasma protein binding of ofloxacin in
      goats.
AB  - Ofloxacin was administered to six male goats intravenously (5 mg/kg) to determine
      its kinetic behavior, tissue residue, in vitro plasma protein binding and to
      compute a rational dosage regimen. The concentration of ofloxacin in plasma and
      tissue samples collected at prescheduled time were estimated by using HPLC. The
      pharmacokinetic parameters were determined by non-compartmental model and plasma
      protein binding was estimated by equilibrium dialysis technique. The therapeutic
      concentration (> or =0.5 microg/ml) was maintained up to 36 h and the initial
      concentration at 2.5 min (14.76 +/- 0.47 microg/ml) declined to 0.05 +/- 0.03
      microg/ml at 96 h with a secondary peak (0.64 +/- 0.15 microg/ml) at 24 h. The
      mean AUC, AUMC, t1/2, MRT, Cl and Vd were calculated to be 58.94 +/- 19.43 microg
      x h/ml, 1539.57 +/- 724.69 microg x h2/ml, 15.58 +/- 1.87 h, 22.46 +/- 2.71 h,
      135.60 +/- 31.12 ml/h/kg and 2.85 +/- 0.74 L/kg respectively. Significantly high
      concentration of drug was detected in different tissues after 24 h of intravenous
      dosing of 5 mg/kg, at 24 h interval for 5 days. The in vitro plasma protein
      binding of ofloxacin was found to be 15.28 +/- 0.94%. Based on these kinetic
      parameters, a loading dose of 5 mg/kg followed by the maintenance dose of 3 mg/kg
      at 24 h dosing interval by intravenous route is recommended.

PMID- 15192336
TI  - Comparative studies on pheno- and genotypic properties of Staphylococcus aureus
      isolated from bovine subclinical mastitis in central Java in Indonesia and Hesse
      in Germany.
AB  - In the present study, 35 Staphylococcal strain isolated from milk samples of 16
      cows from eight farms of three different geographic locations in Central Java,
      Indonesia, and from milk samples of 19 cows from 19 farms of different geographic
      locations in Hesse, Germany, were compared pheno- and genotypically. On the basis
      of cultural and biochemical properties as well as by amplification of the 23S
      rRNA specific to Staphylococcus aureus, all isolates could be identified as S.
      aureus. In addition, all S. aureus isolates harboured the genes clfA and coa
      encoding staphylococcal clumping factor and coagulase, and the gene segments
      encoding the immunoglobulin G binding region and the X-region of protein A gene
      spa. By PCR amplification, the genes seb, seg, seh, and sei was observed for the
      S. aureus cultures isolated in Central Java, Indonesia and the genes sec, sed,
      seg, seh, sei, sej and tst for the S. aureus cultures isolated in Hesse, Germany.
      None of the S. aureus of both origins harboured the genes sea, see, eta and etb.
      All isolates were additionally positive for the genes nuc, fnbA, hla, and set1.
      The gene hlb was found for 6 cultures from Central Java, Indonesia and 16
      cultures from Hesse, Germany. However, the gene fnbB and the gene segments cnaA
      and cnaB were not present among the strains isolated in Central Java, Indonesia
      and rare among the strains isolated in Hesse, Germany. It was of interest that
      most of the S. aureus isolated in Central Java, Indonesia harboured the gene cap5
      and most of the strains isolated in Hesse, Germany the gene cap8. The phenotypic
      and genotypic results of the present study might help to understand the
      distribution of prevalent S. aureus clones among bovine mastitis isolates of both
      countries and might help to control S. aureus infections in dairy herds.

PMID- 15192337
TI  - Comparative antibody response of five recombinant antigens in related to
      bacterial shedding levels and development of serological diagnosis based on 35
      kDa antigen for Mycobacterium avium subsp. paratuberculosis.
AB  - Eighty-five complex (85A, 85B and 85C), 35-kDa and superoxide dismutase (SOD)
      were cloned, expressed and purified as antigens in an enzyme-linked immunosorbent
      assay (ELISA) to compare the serological reactivity of cows with different
      shedding levels of Mycobacterium avium subsp. paratuberculosis (MPT). Antibody
      responses to all recombinant antigens positively increased depending on shedding
      levels. In particular, antibody responses to the 35 kDa were higher than those to
      the others in all shedder groups. Also, the mean of O. D. values among Ag 85
      complex, 85B showed slightly higher response than others with high sensitivity
      and specificity in all shedder groups. In receiver operating characteristic (ROC)
      curve analysis, the result of 35 kDa ELISA yielded an area under the curve value
      of 0.945 (95% confidence interval = 0.895. 0.996), which indicated that this 35
      kDa is more accurate indicator of MPT infection than other antigens. At the cut
      off point recommended by the ROC curve analysis, the sensitivity and specificity
      of 35 kDa ELISA were higher than those of other antigens with 93.3% and 86.4%,
      respectively. Finally, a commercially available ELISA kit was used to clarify 200
      positive and 200 negative sera. We then re-tested these serum samples with our
      ELISA test using the 35-kDa antigens. 35 kDa ELISA and commercial kit showed
      almost similar results in ROC curve analysis even though two of positive sera in
      commercial kit were negative in 35 kDa ELISA. The sera, which showed difference
      in the comparison with commercial ELISA kit, they also did not react with 35 kDa
      in Western blot. These results suggest that a 35-kDa based ELISA can be useful
      for detecting MPT infection.

PMID- 15192338
TI  - Escherichia coli O157:H7 adherence to HEp-2 cells is implicated with curli
      expression and outer membrane integrity.
AB  - Escherichia coli (E. coli) has ability to express thin aggregative fimbriae,
      known as curli, on the cell surface. Previously, a few example of curli
      expression in serogroup O157:H7 of enterohemorrhagic E. coli (EHEC) were
      reported, compared to other E. coli groups. However, significance of curliation
      in the EHEC pathobiology has not been described well in the literature. A highly
      curliated O157:H7 strain was used in this study in order to elucidate role of
      curliation in EHEC adherence to cultured HEp-2 cells. The expression of curli in
      the EHEC isolate was consistent with strong positive indication of Congo-red (CR)
      binding and formation of clumps in the bottom of the tube containing Luria
      Bertani (LB) broth when cultured overnight at 37 degrees C. A few CR-binding
      negative (CR-) colonies occurred spontaneously within the population of CR+
      isolate. The CR+ EHEC showed massive aggregative adhesion pattern, whereas the
      spontaneous CR- strain showed typical localized adherence on HEp-2 cells.
      Electron microscopy confirmed highly curliated bacteria in the CR+ EHEC sample.
      Interestingly, the curliation disappeared in a msbB1 and msbB2 double mutant
      derived from the CR+ EHEC. These results suggest that the compromised outer
      membrane integrity caused by msbB mutations may abrogate curli production in the
      CR+ EHEC harbouring penta-acylated lipid A structure in their outer membrane.

PMID- 15192339
TI  - Biophysical characterization of Japanese encephalitis virus (KV1899) isolated
      from pigs in Korea.
AB  - A virus strain, showing cytopathic effect in Vero cell, was isolated from plasma
      of a fattening pig in Gyeonggi province, Korea in October 1999. The evaluation of
      physicochemical/biological properties of the isolate showed that the virus,
      KV1899, inoculated suckling mouse showed paralysis and died within 7 days post
      inoculation, the mouse brain suspension had hemagglutinating activity with goose
      RBC. Pathogenicity of isolate was carried out by intracranial and intraperitoneal
      inoculation of 3-4 weeks mice. The mice inoculated with isolate showed 10(4.5)
      LD50/ 0.03 ml and 10(3.0) LD50/0.5 ml according to the inoculation route. The
      isolate was identified as RNA and enveloped virus using IUDR and chloroform
      sensitivity test. The virus particles within the infected Vero cell were measured
      to be 40-50 nm in size by electron microscopy. The isolate was further
      characterized by immuno-fluorescence assay using Japanese encephalitis virus
      (JEV) specific monoclonal antibodies. Reverse transcription polymerase chain
      reaction (RT-PCR) revealed the presence of JE specific conserved sequences in
      this isolate. The artificially inoculated pigs had HI titer of 320 to 2,560
      against JEV at 14 to 42 days post inoculation. We confirmed this isolate as
      Japanese encephalitis virus. It was the second isolation of JEV in pigs in Korea.

PMID- 15192340
TI  - B6C3F1 mice exposed to ozone with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1
      butanone and/or dibutyl phthalate showed toxicities through alterations of NF
      kappaB, AP-1, Nrf2, and osteopontin.
AB  - Toxic effects of ozone, 4-(N-methyl-N-nitrosamino)-1-(3- pyridyl)-1-butanone
      (NNK), and/or dibutyl phthalate (DBP) were examined through NF-kappaB, AP-1,
      Nrf2, and osteopontin (OPN) in lungs and livers of B6C3F1 mice. Electrophoretic
      mobility shift assay (EMSA) indicated that mice treated with combination of
      toxicants induced high NF-kappaB activities. Expression levels of p105, p65, and
      p50 proteins increased in all treated mice, whereas IkB activity was inhibited in
      NNK-, DBP-, and combination-treated ones. All treated mice except ozone-treated
      one showed high AP-1 binding activities. Expression levels of c-fos, c-jun, junB,
      jun D, Nrf2, and OPN proteins increased in all treated mice. Additive
      interactions were frequently noted from two-toxicant combination mice compared to
      ozone-treated one. These results indicate treatment of mixture of toxicants
      increased toxicity through NF-kappaB, AP-1, Nrf2, and OPN. Our data could be
      applied to the elucidation of mechanism as well as the risk assessment of mixture
      induced toxicity.

PMID- 15192341
TI  - Two-dimensional gel electrophoresis and immunoblot analysis of Neospora caninum
      tachyzoites.
AB  - Identification of expressed protein profiles and antigenic determination are some
      of the most challenging aspects of proteomics. Two-dimensional gel
      electrophoresis (2-DE) combined with immunoblot analysis were employed to study
      the N. caninum proteome. Protein sample preparation was carried out by first
      conducting sonication, followed by adding lysis buffer containing 7M urea plus 2M
      thiourea to the purified tachyzoites in order to complete disruption. A total of
      335 differentially expressed protein spots were detected using pH 4-7 IPG strip
      (7 cm) that were run in a 56 kVh isoelectric focusing (IEF) system. Of the spots
      analyzed, 64 were identified as antigenic spots on immunoblot profile. Major
      antigenic spots appeared at 65 kDa (pI 5.2-5.3), 51 kDa (pI 5.5), 38 kDa (pI
      5.1), 33 kDa (pI 4.4), 29 kDa (pI 5.6) and 15.5 kDa (pI 5.0) were observed to be
      significantly distinct compared to the rest of the antigenic spots. The results
      indicate that combination of 2-DE and immunoblotting methods were thought as very
      useful tools in defining both proteins and antigens of N. caninum tachyzoites.
      Additionally, present 2-DE profiles may be valuable in further proteomic
      approaches and study of the pathogen.

PMID- 15192342
TI  - Idiopathic canine polyarteritis in control beagle dogs from toxicity studies.
AB  - It is sometimes difficult to assess the relevance of polyarteritis with treatment
      related lesions in dog toxicity studies, as number of dogs used in a toxicity
      study is small and the lesions are similar to those seen in spontaneous diseases.
      This report is intended to establish a general profile of idiopathic canine
      polyarteritis in beagle dogs. Data from a total of 40 dog studies including 4-,
      13- or 52- weeks studies conducted between 1990 and 2003 at Huntingdon Life
      Sciences, UK, were collected and analysed. There was no death by this disease and
      also no prominent clinical signs related to this disease. Histologically, males
      tended to develop polyarteritis more frequently than in females and epididymis is
      the most probable tissues, followed by thymus and heart. Dogs in two studies
      showed higher incidences of these lesions, whereas animals in the other studies
      did not exhibited, suggesting that genetic predilection plays an important role
      in this disease.

PMID- 15192343
TI  - Effect of intratesticular injection of xylazine/ketamine combination on canine
      castration.
AB  - This study was performed to compare the effect of intratesticular (IT) injection
      of xylazine/ketamine combination for canine castration with those of
      intramuscular (IM) or intravenous (IV) injection. Xylazine and ketamine was
      administered simultaneously via intratesticularly (IT group), intramuscularly (IM
      group) or intravenously (IV group) at doses of 2 and 10 mg/kg, respectively. Pain
      response at the time of injection, mean induction time, mean arousal time, mean
      walking time and cardiopulmonary function during anesthesia were monitored after
      the xylazine and ketamine administration. In IV and IM groups, heart rates were
      significantly decreased 30 and 45 min after xylazine and ketamine administration,
      respectively (p < 0.05). Respiratory rates were significantly decreased in the IV
      group (p < 0.05). In the IT group, there was no significant changes in heart and
      respiratory rates. The occurrence of cardiac arrhythmias was less severe in IT
      group compared with those in IM and IV groups. The route of administration did
      not affect rectal temperature. Mean induction time was significantly (p < 0.05)
      longer in IT group than in IM and IV groups. On the contrary, mean arousal time
      and mean walking time were shortened in IT group. Clinical signs related to pain
      response at the time of injection and vomiting were less observed in IT group
      than in IM group, and head shaking was less shown in IT group than in IM and IV
      groups during recovery period. These results indicated that intratesticular
      injection of xylazine/ketamine for castration has several advantages such as less
      inhibition of cardiopulmonary function and fast recovery from anesthesia without
      severe complications, and would be an effective anesthetic method for castration
      in small animal practice.

PMID- 15192344
TI  - Radiographic diagnosis of diaphragmatic hernia: review of 60 cases in dogs and
      cats.
AB  - Sixty cases of diaphragmatic hernia in dogs and cats were radiologically reviewed
      and categorized by their characteristic radiographic signs. Any particular
      predilection for age, sex, or breed was not observed. Liver, stomach and small
      intestine were more commonly herniated. At least two radiographs, at different
      angles, were required for a valid diagnosis, because some radiographic signs were
      not visible in a single radiographic view and more clearly detectable in two
      radiographic views. In addition to previously reported radiographic signs for
      diaphragmatic hernia, we found that the location of the stomach axis and the
      displacement of tracheal and bronchial segments were also useful radiographic
      signs.

PMID- 15192345
TI  - Quantification of mitral regurgitation using proximal isovelocity surface area
      method in dogs.
AB  - The present study was performed to determine the accuracy and reproducibility of
      calculating the mitral regurgitant orifice area with the proximal isovelocity
      surface area (PISA) method in dogs with experimental mitral regurgitation and in
      canine patients with chronic mitral insufficiency and to evaluate the effect of
      general anesthesia on mitral regurgitation. Eight adult, Beagle dogs for
      experimental mitral regurgitation and 11 small breed dogs with spontaneous mitral
      regurgitation were used. In 8 Beagle dogs, mild mitral regurgitation was created
      by disrupting mitral chordae or leaflets. Effective regurgitant orifice (ERO)
      area was measured by the PISA method and compared with the measurements
      simultaneously obtained by quantitative Doppler echocardiography 4 weeks after
      creation of mitral regurgitation. The same procedure was performed in 11 patients
      with isolated mitral regurgitation and in 8 Beagle dogs under two different
      protocols of general anesthesia. ERO and regurgitant stroke volume (RSV) by the
      PISA method correlated well with values by the quantitative Doppler technique
      with a small error in experimental dogs (r = 0.914 and r = 0.839) and 11 patients
      (r = 0.990 and r = 0.996). The isoflurane anesthetic echocardiography
      demonstrated a significant decrease of RSV, and there was no significant change
      in fractional shortening (FS), ERO area, LV end-diastolic and LV end-systolic
      volume. ERO area showed increasing tendency after ketamine-xylazine
      administration, but not statistically significant. RSV, LV end-systolic and LV
      end-diastolic volume increased significantly (p < 0.01), whereas FS significantly
      decreased (p < 0.01). The PISA method is accurate and reproducible in
      experimental mitral regurgitation model and in a clinical setting. ERO area is
      considered and preferred as a hemodynamic-nondependent factor than other
      traditional measurements.

PMID- 15192346
TI  - Canine biphasic synovial sarcoma: case report and immunohistochemical
      characterization.
AB  - The clinical, radiological and pathologic features of a biphasic synovial sarcoma
      in the left elbow joint of a two-year-old male Rottweiler are presented. The
      tumor showed positive immunoreactivity for vimentin, Epithelial Membrane Antigen
      (EMA), p53 and PCNA, while it was negative for the cytokeratin used, S-100, Rb
      and p21. Immunohistochemistry for EMA allowed the identification of epithelioid
      components of synovial sarcoma, and may, therefore, contribute in establishing a
      diagnosis of biphasic synovial sarcoma. Intratumoral variation in PCNA
      immunoreactivity was minimal, indicating that the various tumor components
      proliferate at more or less similar rates. Overall, the characterized
      immunohistochemical profile for canine synovial sarcoma, not defined previously,
      may provide clues to the histogenesis of the phenotypically mesenchymal and
      epithelial elements of the tumor, and may be of value in the differential
      diagnosis of challenging cases, decreasing the risk of under- and mis-diagnosis.
      Although more cases need to be studied to determine whether there is a consistent
      pattern of immunostaining in canine synovial sarcoma, its potential significance
      is discussed in relation to the histogenesis, molecular pathology and
      differential diagnosis of canine synovial sarcoma.

PMID- 15192347
TI  - Gastrointestinal impaction by Parascaris equorum in a Thoroughbred foal in Jeju,
      Korea.
AB  - A weanling Thoroughbred foal was admitted to Equine Hospital, Korea Racing
      Association with signs of colic. On admission the foal was sweating profusely,
      appeared anxious and exhibiting signs suggestive of abdominal pain. Clinical
      examination revealed: tachycardia (90 beats/min), tachypnea (50 breaths/min) and
      congested and slightly cyanotic mucous membranes. No intestinal sounds were
      auscultated in all 4 abdominal quadrants. Rectal palpation identified concurrent
      cecum and large colon impactions. Treatment consisted of intravenous
      administration of a balanced electrolyte solution, nasogastric siphonage and
      administration of analgesics. Nasogastric reflux contained ascarids. This
      treatment failed to alleviate the signs of colic. The foal died 3 hours later
      following discharge because the owner didn't want laparatomy because of economic
      constraints. Prior to admission this foal had not received any prophylactic
      anthelmintic treatment. In necropsy, there were masses of ascarids accumulation
      in the stomach, small intestine and large intestine. The outcome of this report
      is to describe the first diagnosed case of gastrointestinal impaction by P.
      equorum in a Thoroughbred foal in South Korea and indicates the importance of
      regular anthelmintic treatment.

PMID- 15192348
TI  - Asthma update.
AB  - This article reviews the latest treatment of asthma and incorporates recent
      changes in asthma management.

PMID- 15192350
TI  - Systemic lupus erythematosus.
AB  - Systemic lupus erythematosus is a challenging diagnosis. This article provides an
      overview of this disorder and what nurses need to know to provide care to
      patients with this potentially life-threatening disorder.

PMID- 15192352
TI  - Recognizing and treating methemoglobinemia: a rare but dangerous complication of
      topical anesthetic or nitrate overdose.
AB  - Methemoglobinemia is a rare but dangerous complication of topical anesthetic
      overdose administration or exposure to nitrate-containing substances in the
      hospital or community. Paradoxically, although the patient may present with
      cyanosis with low oxygen saturation levels, they will not respond to oxygen
      therapy. Treatment is slow intravenous administration of a titrated dose of
      methylene blue. Adult and pediatric critical care nurses and respiratory
      therapists, operating room and procedure/diagnostic center nurses, short-stay or
      outpatient surgery center staff, and adult and pediatric emergency department
      nurses and respiratory therapists need to be aware of this potentially fatal
      condition.

PMID- 15192354
TI  - Enhanced external counterpulsation: bringing the concept of the intraaortic
      balloon pump to the outpatient setting.
AB  - Enhanced external counterpulsation can now be used in patients with congestive
      heart failure. As our population ages, we will see more patients with this
      challenging diagnosis. The authors discuss this exciting treatment.

PMID- 15192355
TI  - The intimacy of dying: a personal reflection.
AB  - Nurses are often involved in patient care at the patient's end of life. The
      author describes how a nurse's actions can make a positive difference in one
      person's life, and in one person's death. Using all of the skills and gifts that
      nurses have to preserve life is a privilege and a challenge; using all of the
      skills and gifts nurses have to provide a respectful, dignified, peaceful, and
      even intimate death, is an equal privilege and challenge.

PMID- 15192356
TI  - Innovative solutions in critical care units: extravasation guidelines.
AB  - The increasing complexity and acuity of the patient population at a southwest
      United States medical center was a catalyst in updating, revising, and
      distributing a current extravasation guideline document to caregivers. The
      guidelines provide information on initial treatment for nurses and the process
      for documentation and tracking of extravasations. The authors describe how a
      synthesis of the Nursing and Pharmacy partnership at Banner Good Samaritan
      Medical Center resulted in the creation of current extravasation guidelines for
      the facility.

PMID- 15192357
TI  - Rights of patients.
AB  - As we all know, patients have certain rights. However, because we are so busy in
      today's healthcare climate we may not always be aware of these rights. This
      article will present a brief overview of the rights of patients.

PMID- 15192358
TI  - Self-care resources and activity as predictors of quality of life in persons
      after myocardial infarction.
AB  - An ex post facto correlational study was conducted to examine predictors of
      quality of life in persons 3 to 6 months after a myocardial infarction. Self-care
      resources, self-care knowledge (needs), activity level, and selected demographic
      variables were examined as predictor variables. A convenience sample of 86
      subjects with a mean age of 61 years, was recruited for participation in this
      study. The study that explained 35% of the variance in quality of life included
      self-care resources available, activity level, and self-care needs. Modeling and
      Role Modeling Paradigm provided a useful explanation of how self-care resources
      and self-care knowledge can be applied to persons recovering from myocardial
      infarction.

PMID- 15192363
TI  - Holistic care: treatment and interventions for hypovolemic shock secondary to
      hemorrhage.
AB  - Hypovolemic shock can be a life-threatening condition. This article uses a case
      study to present the diagnostic criteria and the medical and nursing management
      of a patient with hypovolemic shock.

PMID- 15192365
TI  - Injury in women who are raped: what every critical care nurse needs to know.
AB  - Sexual assault is considered the silent, violent epidemic. However, many critical
      care nurses are unaware of the injury patterns that may indicate that their
      patient has been sexually assaulted. In addition, critical care nurses are often
      uncertain how to proceed when caring for someone with a suspected sexual assault.
      This article provides both background information about sexual assault and
      guidance to critical care nurses on how to manage this difficult situation.

PMID- 15192368
TI  - Bariatric implications of critical care nursing.
AB  - The delivery of optimum nursing care to morbidly obese patients in critical care
      presents unique challenges in critical thinking, planning, and teamwork. The
      purpose of this article is to review the special needs of this patient population
      and to provide a template to guide proactive nursing care planning in critical
      care settings.

PMID- 15192367
TI  - Update on transplant pharmacology: sirolimus.
AB  - Rapamune (Sirolimus), the latest immunosuppressant agent for solid organ
      transplants, is prescribed for induction therapy, refractory rejection, steroid
      withdrawal, and combination therapy. As the use of this agent increases among
      various transplant populations, it is essential for critical care nurses to be
      cognizant of the indications, pharmacodynamics, current research findings, side
      effects, and implications. This knowledge will ultimately improve patient
      education and outcomes in this ever-growing field of nursing.

PMID- 15192369
TI  - Implementing a family presence protocol option.
AB  - Families' needs of patients being resuscitated in critical care areas are
      frequently not a high priority for the healthcare team. However, recent research
      suggests family member presence during life-saving efforts may help families cope
      with the devastating outcomes of unsuccessful resuscitation. This article
      provides the rationale and process for implementing a family presence option
      during resuscitation.

PMID- 15192371
TI  - End-of-life education in undergraduate nursing curricula.
AB  - Americans are increasingly dying in hospitals. The provision of end-of-life care
      is essential to providing a death with dignity. However, this is not taught in
      many schools of nursing. The purpose of this article is to discuss the importance
      of including this important content in nursing curricula.

PMID- 15192373
TI  - Cognitive deficits following cardiac surgery: a brief review of the literature.
AB  - Cognitive deficits are far too common after cardiac surgery and are believed to
      be related to the use of cardiopulmonary bypass. This article presents a brief
      review of the literature related to this topic.

PMID- 15192377
TI  - A closing word: what every nurse should know about malpractice.

PMID- 15192437
TI  - Lipolytic PPAR activation: new insights into the intersection of triglycerides
      and inflammation?
AB  - PURPOSE OF REVIEW: To examine connections between triglyceride metabolism and
      inflammation, especially as they relate to transcriptional regulation through
      peroxisomal proliferator activated receptors activation. RECENT FINDINGS:
      Peroxisomal proliferator activated receptors, members of the steroid hormone
      nuclear receptor family, have been of particular interest as a mechanism through
      which different dietary components might control gene expression. Extensive prior
      work has defined the central role peroxisomal proliferator activated receptors
      play in many key metabolic responses, including glucose control and lipid
      metabolism. Emerging evidence suggests peroxisomal proliferator activated
      receptor activation may limit inflammation and atherosclerosis. The demonstration
      that certain fatty acids can activate peroxisomal proliferator activated
      receptors belies the potential link between nutritional components and
      peroxisomal proliferator activated receptor responses. Interest in this
      connection had been heightened by recent evidence that lipolysis in certain
      situations can both generate peroxisomal proliferator activated receptor ligands
      and limit some known inflammatory responses. SUMMARY: Lipolytic peroxisomal
      proliferator activated receptor activation suggests new ways in which to
      reconsider triglycerides and the distal consequences of their metabolism,
      including the possible effects on inflammation and atherosclerosis.

PMID- 15192438
TI  - Roles of peroxisome proliferator-activated receptor delta in skeletal muscle
      function and adaptation.
AB  - PURPOSE OF THE REVIEW: Peroxisome proliferator-activated receptors mediate the
      transcriptional effects of fatty acids and fatty acid metabolites and regulate
      many physiological functions including development and metabolism. The roles of
      peroxisome proliferator-activated receptor alpha and gamma isotypes have been
      well established, while the functions of the third member of the family,
      peroxisome proliferator-activated receptor delta, remained unclear until very
      recently. This review focuses on the physiological functions of the nuclear
      receptor and especially on its roles in the control of fatty acid metabolism.
      RECENT FINDINGS: We review very recent data demonstrating that peroxisome
      proliferator-activated receptor delta plays a central role in the regulation of
      fatty acid oxidation in several tissues, such as skeletal muscle and adipose
      tissue, and also that the nuclear receptor is involved in cholesterol metabolism.
      SUMMARY: Use of potent and specific peroxisome proliferator-activated receptor
      delta agonists and appropriate transgenic animal models revealed the importance
      of this nuclear receptor in regulation of fatty acid catabolism in skeletal
      muscle and other tissues. It also indicated the potential of peroxisome
      proliferator-activated receptor delta as a therapeutic target in pathologies such
      as metabolic syndrome. However, the effects of peroxisome proliferator-activated
      receptor delta activation in atherosclerosis and the control of cell
      proliferation remain to be established.

PMID- 15192439
TI  - Gene expression in humans with diabetes and prediabetes: what have we learned
      about diabetes pathophysiology?
AB  - PURPOSE OF REVIEW: Type 2 diabetes mellitus is characterized by insulin
      resistance and pancreatic beta-cell dysfunction. In high-risk individuals, the
      earliest detectable abnormality is insulin resistance in skeletal muscle.
      Impaired insulin-mediated signaling, gene expression, and glycogen synthesis, and
      the accumulation of intramyocellular triglycerides have all been linked with
      insulin resistance, but no specific defect responsible for insulin resistance and
      diabetes mellitus has been identified in humans. However, recent analyses of gene
      expression patterns in muscle tissue from metabolically characterized humans have
      highlighted new genes and pathways potentially important in the pathogenesis of
      diabetes mellitus. This review will summarize these data and highlight the
      potential importance of oxidative metabolism in diabetes pathophysiology. RECENT
      FINDINGS: Genomic analysis of skeletal muscle samples from patients with diabetes
      mellitus has revealed the reduced expression of genes encoding key enzymes in
      oxidative metabolism and mitochondrial function. Moreover, the same pattern of
      gene expression is also observed in insulin resistant 'prediabetic' individuals
      with normal glucose tolerance. Many of the genes dysregulated in both diabetes
      and 'prediabetes' are regulated by the transcription factor nuclear respiratory
      factor-1 and the peroxisome proliferator-activated receptor gamma co-activator 1.
      These data suggest a potential role for both genetic and environmental factors to
      modify the risk of diabetes by modifying the expression or activity of these
      transcriptional regulators. SUMMARY: Nuclear respiratory factor and peroxisome
      proliferator activated receptor gamma co-activator-1-dependent oxidative
      metabolic pathways may play a central, and potentially primary, role in the
      pathogenesis of type 2 diabetes. Additional studies will be required to identify
      upstream genetic and environmental determinants of this expression phenotype.

PMID- 15192440
TI  - The role of the peroxisome proliferator-activated receptor alpha pathway in
      pathological remodeling of the diabetic heart.
AB  - PURPOSE OF REVIEW: Cardiovascular disease is exceptionally prevalent in patients
      with diabetes mellitus, which is an emerging pandemic. Unfortunately, the
      pathogenesis of diabetic myocardial disease is still poorly understood. RECENT
      FINDINGS: Evidence has emerged that perturbed cardiac energy metabolism
      (excessive dependence on fatty acid utilization and diminished carbohydrate
      metabolism) plays a role in the development of myocardial dysfunction in
      diabetes. In support of this, transgenic mice with cardiac-specific activation of
      the peroxisome proliferator-activated receptor alpha, a nuclear receptor
      transcription factor that enhances the expression of myriad genes controlling
      cellular fatty acid utilization, exhibit several classic signatures of the
      diabetic heart. In particular, the hearts of these mice display: increased
      import, oxidation, and storage of fatty acids; strong counter-regulatory
      inhibition of glucose import and oxidation; and cardiomyopathic remodeling and
      dysfunction. A high-fat diet exacerbates the cardiomyopathic phenotype in
      peroxisome proliferator-activated receptor alpha transgenic mice in a completely
      reversible manner. The dysfunctional phenotype and its resolution correlates with
      levels of several potential toxic mediators, including triglycerides, ceramide,
      and reactive oxygen species. These findings contrast with several studies
      demonstrating beneficial effects of peroxisome proliferator-activated receptor
      alpha ligands in the treatment of type 2 diabetes. SUMMARY: Such studies provide
      a rationale for greater emphasis on serum lipid-lowering strategies and the
      control of dietary fat content in the treatment of diabetic cardiomyopathy.
      Moreover, the use of peroxisome proliferator-activated receptor alpha activators
      or related compounds as therapeutic agents will require rigorous evaluation of
      the effects on cardiac function in the diabetic patient.

PMID- 15192441
TI  - PPAR trilogy from metabolism to cancer.
AB  - PURPOSE OF REVIEW: This review highlights recent advances related to malignancies
      in the field of peroxisome proliferator-activated receptors (PPARs). It also
      discusses the implications of cancer research and therapy. RECENT FINDINGS: In
      the last few years, genetic evidence has implicated the PPARs, specifically
      PPARgamma and PPARbeta/delta, in tumorigenesis. Also, new insights into the
      regulation of the nuclear hormone receptors have emerged. SUMMARY: Exciting
      research in PPAR biology has established these nuclear factors as key regulators
      of metabolism and energy homeostasis. Evidence indicates that PPARs can also
      affect the pathogenesis and development of tumors. However, the type of effects
      observed thus far appears to depend on the experimental context. As a result, the
      findings are generating much debate, as PPAR agonists are widespread targets in
      the treatment of metabolic disorders such as diabetes and dyslipidemia. Here, we
      summarize the most recent advances in this field, outline the conflicting reports
      and discuss their overall implications in cancer research.

PMID- 15192444
TI  - Chronic hypoxia: common traits between chronic obstructive pulmonary disease and
      altitude.
AB  - PURPOSE OF REVIEW: Loss of body mass and exercise intolerance are common findings
      in chronic obstructive pulmonary disease and are often difficult to reverse
      despite optimal nutritional intake. Similar findings have been reported in
      healthy individuals during high-altitude exposure. The role of hypoxia in
      modulating metabolism has been largely investigated in vitro and in animal
      studies. More fragmentary is the knowledge regarding hypoxia effects on in-vivo
      human metabolism. This paper reviews recent literature regarding the effects of
      chronic exposure to hypoxia on metabolism, particularly comparing chronic
      obstructive pulmonary disease patients with humans exposed to high altitude.
      RECENT FINDINGS: Hypoxia has important metabolic effects. Many oxygen-sensitive
      regulatory mechanisms work through hypoxia inducible factor 1, and recent
      literature regarding the hypoxic stimulus and its pathological implications deals
      largely with hypoxia inducible factor 1-related findings. Hypoxia inducible
      factor 1 is pivotal in the adaptation to chronic hypoxia: it induces gene
      expression for fructose-2-6-biphosphatase, an enzyme switching glucose metabolism
      towards glycolysis, allowing energy production in anaerobic conditions. Hypoxia
      inducible factor 1 is also involved in the development of anorexia because it
      induces the promoter of the leptin gene. Particularly important for future
      therapeutic implications are findings related to hypoxia inducible factor 1
      polymorphism and interaction with other molecules, especially estrogens, in the
      clinical evolution of disease. SUMMARY: Malnutrition is a worsening factor in
      chronic obstructive pulmonary disease. Similarities between chronic obstructive
      pulmonary disease and altitude exposure point to the importance of hypoxia in
      this regard. A better understanding of the underlying mechanisms will help to
      find alternative therapeutic approaches.

PMID- 15192443
TI  - Muscle tissue changes with aging.
AB  - PURPOSE OF REVIEW: This review article focuses on the changes that occur in
      muscle with age, specifically the involuntary loss of muscle mass, strength and
      function, termed sarcopenia. Particular emphasis is given to the metabolic
      alterations that characterize sarcopenia, and to the potentially treatable causes
      of this condition, including age-related endocrine and nutritional changes, and
      inactivity. RECENT FINDINGS: Recent data reported include those regarding the
      potential role of insulin resistance in the development of sarcopenia, the
      potential role of androgens and growth hormone in the treatment of this
      condition, the usefulness of exercise including both resistance and aerobic
      training to improve muscle growth and function, and, finally, the possible use of
      nutritional manipulations to improve muscle mass. SUMMARY: Sarcopenia is likely a
      multifactorial condition that impairs physical function and predisposes to
      disability. It may be prevented or treated with lifestyle interventions and
      pharmacological treatment. Further long-term investigations are needed, however,
      to ascertain what type and combinations of interventions are the most efficacious
      in improving muscle mass and function in older people.

PMID- 15192446
TI  - Cancer anorexia-cachexia syndrome: cytokines and neuropeptides.
AB  - PURPOSE OF REVIEW: Cancer anorexia-cachexia syndrome is observed in 80% of
      patients in the advanced stages of cancer and is a strong independent risk factor
      for mortality. Numerous cytokines produced by tumor and immune cells, interacting
      with the neuropeptidergic system, mediate the cachectic effect of cancer. Since
      there is currently no effective pharmacological treatment and the anorexia
      cachexia syndrome continues to be defined biochemically, we review the role of
      cytokines and neuropeptides in this process. RECENT FINDINGS: Currently data
      suggest that cancer anorexia-cachexia syndrome results from a multifactorial
      process involving many mediators, including hormones (e.g. leptin), neuropeptides
      (e.g. neuropeptide Y, melanocortin, melanin-concentrating hormone and orexin) and
      cytokines (e.g. interleukin 1, interleukin 6, tumor necrosis factor alpha and
      interferon gamma). It is likely that close interrelation among these mediators
      exists in the hypothalamus, decreasing food intake and leading to cachexia.
      SUMMARY: In the pathogenesis of cancer anorexia, cytokines play a pivotal role
      influencing the imbalance of orexigenic and anorexigenic circuits that regulate
      the homeostatic loop of body-weight regulation, leading to cachexia. Interfering
      pharmacologically with cytokine expression or neural transduction of cytokine
      signals can be an effective therapeutic strategy in anorectic patients before
      they develop cancer anorexia-cachexia syndrome.

PMID- 15192445
TI  - Interleukin-1beta system in anorectic catabolic tumor-bearing rats.
AB  - PURPOSE OF REVIEW: The onset of cancer anorexia and the accompanying neurological
      symptoms and signs involve the general influence of cytokines on the brain. Using
      methylcholanthrene to induce tumors in Fischer 344 rats, we measured various
      specific components of the cytokine-induced anorectic reaction, including: (1) IL
      1beta system components (ligand, signaling receptor, receptor accessory proteins,
      and receptor antagonist); (2) TNF-alpha; (3) TGF-beta1; and (4) IFN-gamma in the
      tumor tissue, the liver and the brain. RECENT FINDINGS: The data show that IL
      1beta, TNF-alpha and IFN-gamma messenger RNA were detected in the tumor tissue of
      anorectic tumor-bearing rats. In brain regions, anorexia is associated with the
      upregulation of IL-1beta and its receptor mRNA. All other mRNA remained unchanged
      in the brain regions examined. SUMMARY: This suggests that IL-1beta and its
      receptor may play a significant role in this model of cancer-associated anorexia.
      In vivo, the characterization of cytokine components in the brain may provide
      data for potential pharmacological interventions to ameliorate the anorexia of
      disease.

PMID- 15192447
TI  - Muscle wastage in chronic heart failure, between apoptosis, catabolism and
      altered anabolism: a chimaeric view of inflammation?
AB  - PURPOSE OF THE REVIEW: The mechanisms involved in determining skeletal muscle
      wastage and cachexia in heart failure are complex and not unequivocal. There are
      however three different mechanisms that are in some way related to each other and
      play a very important role. These are inflammation, the catabolic/anabolic
      imbalance and apoptosis. We have tried to link these pathophysiological processes
      with the aim of giving a holistic view. RECENT FINDINGS: Recent experiments have
      demonstrated that a major determinant of muscle atrophy in congestive heart
      failure is apoptosis of skeletal myocytes. Apoptosis is triggered by tumour
      necrosis factor alpha and its second messenger sphingosine. The source of tumour
      necrosis factor alpha has to be searched for in inflammation, which may have its
      origin in the bowel, in the heart, in peripheral hypoxic tissues or in
      neurohormonal activation. It has also been shown that the growth hormone/insulin
      like growth factor 1 axis regulates contractile protein synthesis (transition
      from slow to fast fibres) and apoptosis, through calcineurin, FK506-FK506-binding
      protein, mitogen-activated protein kinase and nuclear factor kappaB. Tumour
      necrosis factor alpha also intervenes in this interplay by activating nuclear
      factor kappaB. SUMMARY: According to these new pathophysiological insights, some
      strategies aiming to prevent or revert congestive heart failure myopathy with
      pharmacological interventions blocking inflammation, tumour necrosis factor alpha
      and apoptosis have been proposed. Future perspectives are based on stem cell
      implantation, transcription and gene therapy, for instance by overexpression of
      insulin-like growth factor 1.

PMID- 15192448
TI  - Signaling pathways weigh in on decisions to make or break skeletal muscle.
AB  - PURPOSE OF REVIEW: Regulation of muscle size is essential for proper development
      and homeostasis of adult musculature. This regulation is mediated in large part
      by signal transduction pathways that promote the synthesis or breakdown of
      skeletal muscle. PI(3)K/Akt, myostatin and NF-kappaB represent three such
      pathways that will be the focus of this review. RECENT FINDINGS: Recent reports
      solidify the requirement of the PI(3)K/Akt pathway in the regulation of muscle
      hypertrophy. In response to IGF-1, Akt activates downstream effectors, mTOR and
      p70S6K to stimulate protein synthesis thereby increasing the cytoplasmic
      compartment in muscle fibers. Tsc2 was also identified as a novel Akt target,
      whose phosphorylation and inactivation by Akt may lead to an increase in cell
      size. The mechanisms by which myostatin functions in muscle wasting was recently
      explored using in-vitro assays of myogenesis. Myostatin was found to repress
      myogenesis by inhibiting the synthesis and activity of MyoD. Paradoxically,
      myostatin expression is itself regulated by MyoD binding to the myostatin
      promoter. The NF-kappaB transcription factor also functions as a negative
      regulator of myogenesis by inhibiting MyoD. Chronic activation of NF-kappaB has
      been associated with muscle wasting, but the mechanisms by which this regulation
      occurs remain for the most part unknown. SUMMARY: Recent cell culture and animal
      studies have provided insight on the mechanisms by which Akt, myostatin, and NF
      kappaB signaling pathways regulate muscle size. Clinical intervention to boost
      Akt signaling or modulate myostatin and NF-kappaB activities may prove useful in
      diseases associated with chronic muscle wasting.

PMID- 15192449
TI  - Role of myostatin in metabolism.
AB  - PURPOSE OF REVIEW: To review papers on myostatin published in 2003 and early
      2004. Myostatin is a negative regulator of skeletal muscle mass produced in this
      tissue. Inactivating mutations of the myostatin gene or interaction of myostatin
      protein with follistatin and other inhibitory proteins induce a hypermuscular
      phenotype in cattle and mice; this is assumed to result from inhibition of muscle
      cell proliferation and DNA and protein synthesis (antianabolic effects).
      Myostatin also controls muscle mass in other animals, and appears to affect
      adipose tissue mass. RECENT FINDINGS: New protein interactions inhibiting
      myostatin that lead to double muscling, as well as the induction of
      hypermuscularity with myostatin antibodies, or the generation of a myostatin
      conditional knockout mouse, have been reported. Conversely, a transgenic mouse
      over-expressing myostatin and exhibiting reduced muscle mass in a gender-specific
      process has been obtained. In addition, novel inactivating mutations in the
      myostatin gene and genetic loci regulating myostatin effects, and the
      characterization of the myostatin gene and its effects on metabolism in fish and
      chicken have been described. Finally, the regulation of myostatin levels by
      growth hormone, glucorticoids, anabolic agents, nutritional status and exercise,
      the characterization of myostatin signaling pathways, and the clarification of
      myostatin effects on cell replication and differentiation, are other important
      recent findings. SUMMARY: These studies suggest that proteins and drugs that
      inactivate myostatin, or interfere with its binding to its receptor, may be
      useful for the therapy of wasting and degenerative muscle diseases and for the
      food industry. Other promising approaches may derive from new insights into the
      biochemical cascade that mediates myostatin effects, and into the role of
      myostatin in the regulation of fat metabolism and of heart and muscle
      regeneration after injury.

PMID- 15192450
TI  - Therapy of muscle wasting in cancer: what is the future?
AB  - PURPOSE OF REVIEW: The aim of the present review is to provide insights into the
      future therapeutic approaches to cancer-related muscle wasting that flow from the
      progressive knowledge of mechanisms regulating muscle mass in health and disease.
      RECENT FINDINGS: Cancer cachexia is a severely debilitating and life-threatening
      paraneoplastic syndrome accounting for approximately 20% of cancer deaths. The
      prominent clinical feature of cancer cachexia is the progressive loss of muscle
      mass, which is substantially not reversible with any of the currently available
      nutritional, metabolic or pharmacological approaches. Cancer cachexia has long
      been considered a late event in the natural history of cancer patients, thus
      condemning them to merely palliative interventions. The accumulating evidence
      that the metabolic and molecular derangements ultimately leading to muscle
      wasting are operating early after tumour onset, even when weight loss is minimal
      or absent, is strengthening the view that cancer cachexia should be considered an
      early phenomenon. SUMMARY: Currently, despite scientific and economic efforts,
      the therapy of cancer-related muscle wasting has a poor success rate. Present
      knowledge of the intracellular mechanisms involved in muscle homeoastasis is
      prompting continuous research aimed at developing more effective and selective
      therapeutic tools for the prevention and treatment of muscle loss in cancer.

PMID- 15192451
TI  - How are we going to understand (dys)regulation of glucose metabolism?

PMID- 15192452
TI  - Gut-derived signaling molecules and vagal afferents in the control of glucose and
      energy homeostasis.
AB  - PURPOSE OF REVIEW: The control of glucose and energy homeostasis, including
      feeding behaviour, is tightly regulated by gut-derived peptidic and nonpeptidic
      endocrine mediators, autonomic nervous signals, as well as nutrients such as
      glucose. We will review recent findings on the role of the gastrointestinal tract
      innervation and of portal vein glucose sensors; we will review selected data on
      the action of gastrointestinally released hormones. RECENT FINDINGS: The
      involvement of mechanosensory vagal afferents in postprandial meal termination
      has been clarified using mouse models with selective impairments of genes
      required for development of mechanosensory fibres. These activate central
      glucogen-like peptide-1/glucogen-like peptide-2 containing ascending pathways
      linking the visceroceptive brainstem neurons to hypothalamic nuclei. Mucosal
      terminals comprise the chemosensory vagal afferents responsive to postprandially
      released gastrointestinal hormones. The mechanism by which the hepatoportal
      glucose sensor stimulates glucose utilization by muscles was demonstrated, using
      genetically modified mice, to be insulin-independent but to require GLUT4 and AMP
      kinase. This sensor is a key site of glucogen-like peptide-1 action and plays a
      critical role in triggering first phase insulin secretion. PeptideYY and ghrelin
      target intracerebral receptors as they are bidirectionally transported across the
      blood brain barrier. The anorectic functions of peripherally released peptideYY
      may however be mediated both via vagal afferents and intracerebral Y2 receptors
      in the brainstem and arcuate nucleus. SUMMARY: These recent findings demonstrate
      that the use of improved anatomical and physiological techniques and animal
      models with targeted gene modifications lead to an improved understanding of the
      complex role of gastrointestinal signals in the control of energy homeostasis.

PMID- 15192453
TI  - The gastrointestinal tract and glucose tolerance.
AB  - PURPOSE OF REVIEW: The development of incretin hormones and incretin analogues
      for the therapy of diabetes highlights the importance of the gastrointestinal
      tract in the maintenance of glucose tolerance. RECENT FINDINGS: The review
      focuses on recent information on the role of incretins and their breakdown
      products on insulin secretion, gastric emptying, and satiety. The importance of
      gastric emptying and its absorptive potential as well as of dietary composition
      on gastric emptying and glucose tolerance is highlighted. The concept of a portal
      glucose sensor in humans has been the subject of some controversy but has been
      recently revisited. SUMMARY: The gastrointestinal tract plays an important part
      in glucose tolerance. In this review we have examined how factors altering
      gastric emptying, insulin secretion in response to meal ingestion, and gastric
      emptying contribute to the maintenance and deterioration of glucose tolerance.

PMID- 15192455
TI  - Current world literature. Genes and nutrition.

PMID- 15192454
TI  - Carbohydrate and weight control: where do we stand?
AB  - PURPOSE OF THE REVIEW: The Atkins diet has been criticized and vilified by much
      of the scientific community since it was proposed 30 years ago, because it
      challenged nutritional recommendations and dietary guidelines for a healthy diet.
      However, in spite of such recommendations the prevalence of obesity continues to
      rise. The present review evaluates recent scientific evidence and attempts to
      reach consensus on the confusion of weight-reducing diets. RECENT FINDINGS: Many
      dietary macronutrient paradigms have been proposed for the treatment of obesity.
      Since obesity in its dynamic phase is the result of energy intake exceeding
      energy expenditure, intuitively to lose weight energy intake should be less than
      energy expenditure, and one might expect that the macronutrient composition of
      the diet would have very little, if any, effect. However, short- and long-term
      therapies with low-carbohydrate or high-protein diets appear to offer advantages
      over conventional weight-loss regimens for weight loss, body composition and
      cardiovascular risk factors. SUMMARY: Low-carbohydrate, Atkins-type diets have
      been demonstrated to have positive effects on weight loss and biomarkers of
      cardiovascular risk, which has prompted some researchers to question the validity
      of present-day dietary guidelines. Although evidence is accumulating in their
      favour, the safety and efficacy of low-carbohydrate, high-protein diets needs
      further long-term verification.

PMID- 15192463
TI  - Comparative evaluation of Tc-99m-heat-denatured RBC and Tc-99m-anti-D IgG
      opsonized RBC spleen planar and SPECT scintigraphy in the detection of accessory
      spleen in postsplenectomy patients with chronic idiopathic thrombocytopenic
      purpura.
AB  - OBJECTIVE: Radionuclide imaging specific for functioning splenic tissue is
      considered the method of choice to detect an accessory spleen in patients of
      chronic idiopathic thrombocytopenia purpura (ITP), who present with relapse after
      splenectomy. Radioimmunospleen scintigraphy with Tc-99m-labeled autologous RBC
      opsonized with anti-D IgG (RIS) is claimed to be more sensitive and specific than
      Tc-99m heat-denatured RBC spleen scintigraphy (HDRS) in the detection of an
      accessory spleen. We compared the efficacy of RIS with HDRBC for the detection of
      accessory spleens METHODS: A total of 45 patients (male:female = 17:28, age
      range: 6-58 years) who presented with relapse of ITP after splenectomy underwent
      scintigraphy with both methods. An average of 3 years had passed since surgery.
      All patients were imaged by a dual-head gamma camera with high-resolution
      collimators; planar static images and SPECT of abdomen were acquired. RESULTS:
      Accessory spleens were detected in 31% (14 of 45) of patients, 6 had 1 each and 8
      had more than 1 (including 1 patient who had 13 accessory spleens). Both methods
      were concordant in all the patients. There was no difference in the scintigraphic
      picture (planar and SPECT) or in the size and number of accessory spleens
      detected. CONCLUSION: Tc-99m-labeled anti-D IgG opsonized autologous RBC spleen
      scintigraphy provides no additional diagnostic information over heat-denatured
      RBC spleen scintigraphy. Heat-denatured RBC scintigraphy thus remains the
      procedure of choice in the detection of accessory spleens.

PMID- 15192464
TI  - Supranormal renal function in unilateral hydronephrotic kidney can be avoided.
AB  - INTRODUCTION: There are reports and controversy in the literature of supranormal
      (defined as >55%) differential renal function (DRF) in the hydronephrotic kidney
      in children with unilateral hydronephrosis. It is not confirmed whether
      supranormal DRF is an artifact or a true finding. In patients in whom the
      relative renal function deteriorates, relief of obstruction becomes surgically
      necessary and if this artifact can be removed. Supranormal function in an
      obstructed kidney is confusing and there is no consensus on how to manage these
      patients. There is no agreement if this is a true entity or an artifact. We
      wanted to address this issue by reporting our experience. METHODS: We reviewed
      all the consecutive cases from August 2000 to October 2001 who were studied in
      our center with the diagnosis of unilateral renal obstruction for confirmation or
      evaluation of DRF. All patients had MAG-3 studies that were interpreted by
      experienced nuclear medicine physicians. The DRF were measured within the first
      to second minute of the MAG-3 injection. Regions of interest were drawn by the
      imaging software and the images were corrected for background counts by drawing
      regions of interest 2 pixels away from the edge of the renal cortex. RESULTS:
      Fifty-seven patients were confirmed to be obstructed unilaterally; 41 (72%)
      patients had obstructive lesions in the left kidney and 16 (28%) in the right
      kidney. There was no case of supranormal DRF in the obstructed kidneys in our
      study. CONCLUSION: The supranormal renal function, as noted in some reports in
      the literature, was not seen in any patients at our institution. We believe that
      this entity is an artifact and can be avoided by using MAG-3 and projecting
      regions of interest by computer software; we plan to start analyzing multiple
      algorithms in phantoms with different ROI selection for background analysis.

PMID- 15192465
TI  - Retroperitoneal malignant peripheral nerve sheath tumor: evaluation with serial
      FDG-PET.
AB  - Retroperitoneal malignant peripheral nerve sheath tumor (MPNST), a rare type of
      neurogenic tumor, was diagnosed in a 14-year-old girl with a history of
      neurofibromatosis type 1 (NF1). Immunochemistry demonstrated spindle cells
      positive for S-100 protein. The patient had multiple tumor recurrences and she
      was evaluated with serial F-18 fluorodeoxyglucose (FDG) positron emission
      tomography (PET). A tumor in the right iliac wing showed increased FDG uptake on
      PET. FDG-PET played an important role in therapy planning and subsequent follow
      up. This case emphasizes the important role FDG-PET could play in the staging,
      restaging, and posttherapy follow up of MPNST.

PMID- 15192466
TI  - Clinicians' perceptions of the value of ventilation-perfusion scans.
AB  - RATIONALE: The goal of this investigation was to understand clinicians'
      perceptions of the probability of pulmonary embolism as a function of V/Q scan
      results of normal, low, intermediate, and high probability. METHODS: A
      questionnaire was developed and distributed to 429 clinicians at a single
      academic medical center. The response rate was 44% (188 of 429). The questions
      included level of training, specialty, probability of PE given 1 of the 4 V/Q
      scan results, and estimations of the charges for V/Q scanning and pulmonary
      angiography, and estimations of the risks of pulmonary angiography. RESULTS: The
      medians and ranges for the probability of pulmonary embolism given a normal, low,
      intermediate, and high probability V/Q scan result were 2.5% (0-30), 12.5% (0.5
      52.5), 41.25% (5-75), and 85% (5-100), respectively. Eleven percent (21 of 188)
      of the respondents listed the probability of PE in patients with a low
      probability V/Q scan as being 5% or less, and 33% (62 of 188) listed the
      probability of PE given an intermediate probability scan as 50% or greater. The
      majority correctly identified the rate of serious complications of pulmonary
      arteriography, but many respondents underestimated the charge for V/Q scans and
      pulmonary arteriography. CONCLUSIONS: A substantial minority of clinicians do not
      understand the probability of pulmonary embolism in patients with low and
      intermediate probability ventilation-perfusion scans. More quantitative reporting
      of results is recommended. This could be particularly important because VQ scans
      are used less frequently but are still needed in certain clinical situations.

PMID- 15192467
TI  - False-positive PET scan in a patient with lipoid pneumonia simulating lung
      cancer.
AB  - PURPOSE: Lipoid pneumonia usually presents with alveolar infiltrates or as a
      nonresolving process. We report a case of lipoid pneumonia that presented as a
      solitary pulmonary nodule and had a high standard uptake value on PET scan,
      thereby mimicking a malignant process. This case highlights the presence of false
      positive PET imaging in a patient with lipoid pneumonia and Mycobacterium
      chelonae infection. MATERIALS AND METHODS: The patient was examined using CT
      scanning. The nodule was further investigated with a PET scan using F-18 FDG and
      the standard uptake value was determined. RESULTS: Histopathology following
      removal of the nodule confirmed the diagnosis of lipoid pneumonia, and the
      bronchoalveolar lavage (BAL) was reported as M. chelonae, a rapidly growing
      mycobacterium (RGM). CONCLUSION: Lipoid pneumonia can present as a PET-positive
      lung nodule and should be considered in the differential diagnosis and workup of
      a solitary pulmonary nodule.

PMID- 15192468
TI  - Iatrogenic artifacts on whole-body F-18 FDG PET imaging.
AB  - PURPOSE: Whole-body F-18 FDG PET images frequently show artifacts related to
      medical and surgical interventions. We present some of the common artifact
      patterns in this atlas article. MATERIALS AND METHODS: We studied whole-body F-18
      FDG PET images of 30 adult patients (17 males and 13 females). Of these, 9
      patients had lymphoma, 7 had colon cancer, 6 had lung cancer, 3 had lung nodules,
      2 each had breast and bladder cancer, and 1 patient had brain cancer. All
      patients had a history of some surgical or medical intervention for malignant or
      some other associated disease. RESULTS: PET images of 8 patients showed artifacts
      related to implanted prostheses and ports and 9 patients showed artifacts related
      to percutaneous insertion or opening of catheters, tubes, and stomas. Six
      patients had artifacts from previous surgery, 3 from previous radiation therapy,
      3 from previous chemotherapy, and 1 from changes in glucose metabolism.
      CONCLUSIONS: Medical and surgical interventions can give rise to artifacts on
      whole-body F-18 FDG PET images. The possibilities and patterns of these artifacts
      should be kept in mind while reporting these studies.

PMID- 15192469
TI  - Lymphoscintigraphy and radionuclide venography in chylothorax.

PMID- 15192470
TI  - FDG PET manifestation of lobular panniculitis.

PMID- 15192471
TI  - Colon cancer metastasis to the adrenal gland demonstrated with FDG PET/CT.

PMID- 15192472
TI  - Transmogrification of lung: a rare entity of bullous emphysema assessed by
      perfusion scintigraphy.

PMID- 15192474
TI  - Hodgkin disease in the sinonasal region detected by FDG PET.

PMID- 15192473
TI  - Crescent-shaped Tc-99m MDP accumulation in the bladder.

PMID- 15192475
TI  - Detection of finger clubbing and primary lung tumor on Tc-99 MDP bone
      scintigraphy in a patient with a scaphoid fracture.

PMID- 15192476
TI  - F-18 fluorodeoxyglucose positron emission tomography in an anorectal fistula with
      actinomycosis.

PMID- 15192477
TI  - Tc-99m MDP uptake in a soft tissue hematoma of the chest wall.

PMID- 15192478
TI  - Bilateral symmetrical Ollier disease and Tc-99m MDP bone scintigraphy.

PMID- 15192479
TI  - Current readings in nuclear medicine.

PMID- 15192480
TI  - An unusual cause of nonhealing wounds.

PMID- 15192481
TI  - More on pressure ulcers in long-term care.

PMID- 15192491
TI  - The use of telemedicine in the management of diabetes-related foot ulceration: a
      pilot study.
AB  - OBJECTIVE: To determine if the management of forefoot ulcerations through
      telemedicine is medically equivalent to ulcer care at a diabetes foot program.
      DESIGN: Nonrandomized comparison of forefoot ulcer healing rates. SETTING: The
      Louisiana State University Health Sciences Center Diabetes Foot Program, Baton
      Rouge, LA, and Lallie Kemp Medical Center, Independence, LA. PARTICIPANTS: Twenty
      consecutive patients with diabetes were treated for neuropathic forefoot
      ulcerations via telemedicine consultation and 120 consecutive patients with
      diabetes were treated face-to-face at a diabetes foot program. INTERVENTIONS:
      Management of forefoot ulcers by a certified wound care nurse trained in the use
      of a staged management approach algorithm and alternative off-loading methods,
      supported by real-time interactive telemedicine consultation. MAIN OUTCOME
      VARIABLES: Forefoot ulcer healing time in days, percentage of wounds healed in 12
      weeks, and healing time ratio (adjusted for age, gender, ulcer duration,
      location, size, crossover, and grade). RESULTS: No differences were found between
      the telemedicine and diabetes foot program groups in the average forefoot ulcer
      healing time (43.2 + 29.3 vs. and 45.5 + 43.4 days, P =.828), the percent of
      forefoot ulcers healed in 12 weeks (75 % vs. 81%, P =.546) and the adjusted
      healing time ratio (1.40 vs 1.00, P =.104). CONCLUSION: These data appear to
      support the effectiveness of real-time interactive telemedicine consultation in
      the management of diabetes-related forefoot ulceration.

PMID- 15192490
TI  - Incidence and risk factors associated with pressure ulcers among patients with
      HIV infection.
AB  - OBJECTIVE: To assess the incidence of and risk factors for pressure ulcers among
      patients with advanced human immunodeficiency virus type 1 (HIV-1) infection.
      DESIGN: Multicenter trial that included 1258 consecutive patients infected with
      HIV-1 who had 1815 admissions to 16 acute care infectious disease units in Italy.
      METHODS: Data were collected for demographic, clinical, immunologic, and
      virologic parameters. The chi-square test was used to compare categorical
      variables, and the Student t test was used for continuous variables. Univariate
      analysis was performed to examine possible risk factors for pressure ulcers by
      computing odds ratios; a multiple logistic regression model was used to obtain
      adjusted estimates of odds ratios while accounting for all possible risk factors.
      RESULTS: The incidence of pressure ulcers was 2.31 per 100 admissions, 3.33 per
      100 patients, and 1.06 per 1000 patient days. All stages of pressure ulcers were
      represented in the sample: 7 Stage I (15.9%), 24 Stage II (54.5%), 8 Stage III
      (18.2%), and 5 Stage IV (11.4%). Multivariate analyses showed that being female,
      length of hospitalization, and clinical markers of HIV infection were
      independently associated with pressure ulcers. Mortality rates were 50% among
      patients with pressure ulcers and 7.2% among patients without pressure ulcers (P
      <.0001), with an attributable mortality rate of 42.8% and an odds ratio of 12.96
      (95% confidence interval 6.99-24.22). CONCLUSIONS: A higher incidence of pressure
      ulcers was found in patients infected with HIV-1 when compared with noninfected
      patients. Because a longer hospitalization may increase the risk of developing a
      pressure ulcer, practitioners should be aware of the clinical conditions that may
      prolong a patient's hospital stay. Aggressive preventive strategies should be
      implemented to decrease the complications associated with pressure ulcers among
      patients infected with HIV-1.

PMID- 15192494
TI  - Moist dressings: bridging the gap between research and practice.

PMID- 15192492
TI  - Arterial insufficiency and ulceration: diagnosis and treatment options.
AB  - PURPOSE: To provide physicians and nurses with an overview of the
      pathophysiology, assessment, diagnosis, and treatment of arterial insufficiency
      and ulceration. TARGET AUDIENCE: This continuing education activity is intended
      for physicians and nurses with an interest in managing patients with arterial
      insufficiency and ulceration. OBJECTIVES: After reading the article and taking
      the test, the participant will be able to: 1. Describe the anatomy and physiology
      of the lower extremity arterial system and the pathophysiology of arterial
      ulcers. 2. Describe the assessment and diagnosis of arterial insufficiency and
      ulceration. 3. Identify treatment options and teaching considerations for
      patients with arterial insufficiency and ulceration.

PMID- 15192495
TI  - The never-ending saga: Changes to wound care payment systems.

PMID- 15192496
TI  - Pressure ulcer prevention: a total disconnect.

PMID- 15192498
TI  - Public reporting of healthcare data: new arenas.

PMID- 15192497
TI  - Diagnosing ulcerative skin eruptions.

PMID- 15192499
TI  - Managing forces of change: commission for case manager certification looks to the
      future.

PMID- 15192500
TI  - Today's hospital-based case manager: how one hospital integrated/adopted
      evidenced-based medicine using InterQual criteria.
AB  - This is the first in an intermittent series highlighting different types of
      clinical decision support tools utilized by case managers and others involved in
      strategic healthcare management.

PMID- 15192501
TI  - Social service needs and case management implications for individuals accessing a
      faith-based suburban homeless shelter.
AB  - The purpose of this study was to identify social service needs and case
      management implications for homeless and marginally housed individuals accessing
      services at a suburban faith-based agency. The overall goal for the study was to
      provide data from the perspectives and experiences of clients that could be used
      to develop and/or revise services to more fully facilitate clients' movement
      toward self-sufficiency. The study used an exploratory qualitative design. Study
      participants consisted of 38 men and women currently using agency services who
      participated in one of four focus group sessions. Thematic analysis of the
      content of the audiotapes of the group sessions revealed that the overarching
      issue for participants was the ability to obtain and maintain employment. Related
      to this issue were six themes: job readiness and support; self-esteem issues;
      substance use and treatment; communications; women's issues; and transportation.
      Based on these client-generated themes, a multi-level case management program is
      presented.

PMID- 15192503
TI  - Home health compare: Web site offers critical information to consumers,
      professionals.
AB  - The Centers for Medicare & Medicaid Services, a federal agency of the U.S.
      Department of Health and Human Services, has released new data about the quality
      of care provided by Medicare-certified home health agencies as part of an
      expanding initiative to continue to improve the home care services that are
      provided to millions of Americans. The initiative combines information about the
      quality of care provided by individual home health agencies-for use by consumers,
      their families, and healthcare professionals-with important resources to assist
      home health agencies working to improve quality of care. This article provides an
      overview of that initiative, and discusses information available on the Home
      Health Compare Web site that case managers and discharge planners will find
      useful for helping patients and their families select a home health agency.

PMID- 15192504
TI  - Case management and the chronic care model: a multidisciplinary role.
AB  - The core functions of case management, assessment, planning, linking, monitoring,
      advocacy, and outreach assume a new perspective in the context of systems that
      have adopted the Chronic Care Model. This article considers case management
      through the experience of three systems that have implemented the Chronic Care
      Model. A movement toward condition neutral case management, focused on care that
      is more wholly patient centric, is also examined.

PMID- 15192505
TI  - Documentation: a guide for case managers.

PMID- 15192506
TI  - AAOHN and CMSA develop joint position paper on HIPAA and confidentiality.

PMID- 15192507
TI  - When quality management meets case management.

PMID- 15192508
TI  - History and uses of BOTOX (botulinum toxin type A).

PMID- 15192513
TI  - [What criteria predict the severity of an exacerbation?].

PMID- 15192512
TI  - [Pathophysiology of exacerbations].

PMID- 15192514
TI  - [Contribution of cohort studies on exacerbations and their management].

PMID- 15192515
TI  - [Exacerbations of CODP: consequences in terms of morbidity and mortality].

PMID- 15192517
TI  - [Risk management and radiology].

PMID- 15192518
TI  - [Imaging of complications of Meckel diverticulum].
AB  - Meckel's diverticulum is a persistent embryonic remnant occurring in 2% of the
      general population. As an "ileal appendix", it is usually clinically silent and
      only discovered at the time of complications: inflammation, hemorrhage,
      obstruction, tumor. The preoperative diagnosis is rarely made because of the non
      specific nature of the symptomatology and only about 10% of complicated cases are
      diagnosed at imaging. Complications from Meckel's diverticulum should always be
      considered in patients presenting with an acute abdomen, especially in young
      adults.

PMID- 15192519
TI  - [Basic principles of diffusion tensor MR tractography].
AB  - Diffusion tensor MR tractography allows in vivo depiction of anatomical bundles
      composing the white matter of the brain and of spinal cord. Diffusion MRI uses
      the effects of heterogeneous water molecule movement to determine for each pixel
      the main axis and magnitude of local anisotropy. Tractography exploits these data
      to reconstruct the tridimensional geometry of the bundles providing neurologists
      with precise information about white matter tract architecture involvement by
      various pathologies. In this paper, the basic principles of molecular diffusion
      and the subsequent diffusion tensor that describes its geometrical and
      quantitative characteristics will be reviewed, in particular within bundles of
      white matter. Then main principles of diffusion tensor MR imaging and
      tractography will be presented.

PMID- 15192520
TI  - [Diffusion tensor MR imaging of the brain. Clinical applications].
AB  - Diffusion tensor MR imaging is a technique that provides details on tIssue
      microstructure and organization well beyond the usual image resolution. With
      diffusion tensor MR imaging, diffusion anisotropy can be quantified and subtle
      white matter changes not normally seen on conventional MRI can be detected. The
      purpose of this article is to review the current applications of diffusion tensor
      MR imaging for the study of the brain, including normal aging, Alzheimer's
      disease, neuropsychiatric disorders, strokes, multiple sclerosis, brain tumors
      and intractable seizures.

PMID- 15192521
TI  - [Peritoneal lymphoma].

PMID- 15192522
TI  - [Diagnosis and quantification of hepatic fibrosis with diffusion weighted MR
      imaging: preliminary results].
AB  - PURPOSE: Diagnosis and quantification of hepatic fibrosis are especially
      important in patients with chronic liver disease. Liver biopsy remains the gold
      standard for diagnosis of cirrhosis but has several limitations. The purpose of
      this study was to determine the usefulness of diffusion-weighted MR imaging, for
      the diagnosis of cirrhosis and quantification of hepatic fibrosis, and to define
      the best sequence parameters for this evaluation. METHODS AND MATERIALS:
      Diffusion-weighted imaging using a 1.5 T MR unit was performed in 14 healthy
      volunteers and 13 cirrhotic patients. Sets of 8 images with different b values
      (200, 400, 600, and 800 sec/mm2) and different TR (3500 and 5000 ms) were
      acquired with breath-holding. Apparent diffusion coefficients (ADCs) were
      calculated. Correlation between Child-Pugh scores, serum hyaluronate
      concentrations and ADCs were performed. RESULTS: ADCs were significantly lower in
      cirrhotic patients (2,055 10-3) compared to controls (2,915 10-3) (p<0.05) when
      the b value was 200 s/mm2 and the TR was 5000 ms. Significant correlations were
      observed between Child-Pugh scores and ADCs (p<0.05), and between serum
      hyaluronate concentrations and ADCs (p<0.05), when the b value was 400 sec/mm2
      and the TR was 5000 ms. CONCLUSION: Our preliminary study showed that the
      measurement of ADCs has good potential for diagnosis and quantification of
      hepatic fibrosis, especially when using b values of 200 sec/mm2 and 400 sec/mm2.

PMID- 15192523
TI  - [Detection of liver metastases in colorectal cancer on chemotherapy. Comparative
      study between MRI with teslascan and computed tomography with intravenous
      contrast media].
AB  - OBJECTIVE: To compare MRI of the liver with mangafodipir trisodium (MnDPDP) and
      computed tomography with intravenous contrast media in the follow-up of liver
      metastases in patient on chemotherapy for colorectal carcinoma. MATERIALS AND
      METHODS: This was a prospective study with patients on chemotherapy for liver
      metastases from colorectal cancer. Patients underwent both contrast-enhanced
      helical CT using 2 cc/kg contrast at 3 cc/sec and mangafodipir trisodium-enhanced
      MR imaging at 1.5 T using 2-3 cc/min contrast at 5 micro mol/kg within a two week
      interval. Two experienced radiologists independently reviewed all scans in a
      blinded fashion and recorded image quality as well as presence and number of
      liver lesions. Statistical analysis was performed using the wilcoxon signed rank
      test. RESULTS: All examinations were of good quality. A total of 71 lesions were
      detected at CT, with 69 lesions consistent with metastases and 2 lesions
      consistent with cysts. A total of 98 lesions were detected at MRI, with 97
      consistent with metastases and 1 lesion consistent with a cyst. T1 weighted
      images with MnDPDP significantly detected two additional lesions compared to CT
      (p<0.05). No significant difference was demonstrated between T1 weighted images
      without MnDPDP and CT or between T2 weighted images and CT. CONCLUSION: Magnetic
      resonance imaging with MnDPDP is significantly more sensitive than unenhanced MRI
      and helical CT for the follow-up of liver lesions.

PMID- 15192524
TI  - [MRI and arrhythmogenic right ventricular dysplasia (ARVD). Retrospective
      evaluation of 50 patients].
AB  - PURPOSE: To retrospectively evaluate the contribution of MRI to the diagnosis of
      arrhythmogenic right ventricular dysplasia (ARVD). PATIENTS AND METHODS: Thirty
      two men and 18 women (mean age: 48.7 years) were imaged using gated spin echo
      scans and short axis cine MR. References were McKenna criteria (gold standard),
      and also what we called "strong presumption" which may correspond to early or
      localized patterns, but correspond to negative McKenna scores. RESULTS: One
      patient was claustrophobic; another one was lost to follow-up. In reference to
      McKenna score, diagnosis of ARVD was established in 12 patients (2 of whom had
      familial dilated biventricular cardiomyopathy with rhythmic expression).
      Sensitivity, specificity, positive predictive value, negative predictive value
      and prevalence were respectively: 75%, 75%, 50%, 90% and 25%. Using "strong
      presumption" criteria, we observed 14 true positives (with sensitivity of 82%,
      specificity of 87%, PPV of 78%, NPV of 90% and prevalence of 35%). CONCLUSION: In
      our group, MRI was always performed before angiography. In our series, right
      ventricular wall T1W hyperintensity was the most frequent finding.

PMID- 15192525
TI  - [Doppler ultrasound and aortic regurgitation. Evaluation of the sensitivity and
      specificity of Doppler findings].
AB  - PURPOSE: The purpose of this study was to determine the sensitivity and
      specificity of arterial Doppler findings of aortic regurgitation to assess if the
      amplitude of changes of Doppler tracings can accurately quantify the degree of
      regurgitation. PATIENTS AND METHODS: We analysed and compared the arterial
      Doppler tracings and echocardiograms of 250 patients. RESULTS: Even if the
      obvious pitfall of vascular stenoses is avoided, the global sensitivity of
      arterial Doppler findings for aortic regurgitation remains weak (30%). However,
      our study demonstrates that it can reach 100% if only significant AR (> or =2/4)
      is taken into account. Since the clear false-positive cases have been carefully
      excluded from the very start, the specificity of the classical criteria already
      proves excellent (above 95%). It will reach perfection if additional simple
      criteria gathered from the data mentioned in this study are considered.
      Quantifying precisely the degree of aortic regurgitation on the basis of arterial
      Doppler tracings is impossible. Nevertheless, we show that it is easy to identify
      significant AR (> or =2/4) that should be further assessed with echocardiography.
      CONCLUSION: Arterial Doppler sonography is unable to detect all cases of aortic
      regurgitation but those that are overlooked are not significant (1/4). If AR
      signs happen to be detected by arterial Doppler, the amplitude of the leak cannot
      be accurately determined based on tracing analysis. Yet, simple criteria will
      indicate whether it is important enough (> or =2/4) to require complementary
      echocardiogram, with well documented accuracy for morphological and hemodynamic
      evaluation.

PMID- 15192526
TI  - [Subacute combined degeneration of the spinal cord: contribution of MRI].
AB  - The authors report a case of subacute combined degeneration of the
      cervicothoracic spinal cord involving the dorsal and lateral spinal columns,
      extending to the brainstem, due to cobalamin deficiency in an elderly patient.
      Symptoms of this subacute myelopathy are potentially reversible with early
      diagnosis. Presenting symptoms of this myelopathy, involvement of the lateral
      columns and brainstem have rarely been documented by magnetic resonance imaging
      (MRI) studies. MRI showed increased T2-weighted signal in the spinal cord. The
      patient's background and history and the posterior location of the abnormalities
      increased the specificity of MRI, and the resolution of clinical symptoms with
      vitamin supplementation confirmed the diagnosis.

PMID- 15192527
TI  - [Necrolytic cutaneous erythema and pancreatic tumour: the glucagonoma].
AB  - Glucagonoma is a rare neuroendocrine neoplasm. Characteristics are clinical
      (necrolytic migratory erythema, weight loss), biological (diabetes) and
      radiological (pancreatic tumor). The Authors report a case of glucagonoma that
      also secreted insulin.

PMID- 15192528
TI  - [Gastro-epiploic lymphangioma. A case report].
AB  - The authors report a case of a gastro-epiploic lymphangioma in a 29-year-old male
      patient presenting with epigastric cramps. Physical examination was normal.
      Ultrasound and abdominal CT-scan showed a cystic mass under the left lobe of the
      liver containing fine septations and extending to the lesser sac. At surgery, a
      large cystic mass was found, situated around the celiac trunk. It was adherent to
      the lesser curvature of the stomach and posterior surface of the antrum and
      extended to the lesser sac. Excision of the mass and antrectomy were performed.
      Histologic examination was consistent with a diagnosis of cystic lymphangioma.

PMID- 15192529
TI  - [What is your diagnosis? Foreign bodies].

PMID- 15192530
TI  - [Usefulness of ultrasound in infantile cortical hyperostosis].

PMID- 15192532
TI  - [Value of the antibody cocktail anti p63 + anti p504s for the diagnosis of
      prostatic cancer].
AB  - Numerous lesions of the prostate, such as atrophy, adenomatous atypical
      hyperplasia (adenosis) or PIN can be misdiagnosed with prostatic cancer, and
      confused with ASAP, leading to perform additional biopsies. In such lesions, the
      pathologist can perform an immunohistochemical study with the anti-high molecular
      weight cytokeratin antibody CK903 (34bE12), which confirms the absence of basal
      cells and supports the diagnosis of prostatic cancer. AIM OF THE STUDY: To
      compare markers of basal cells (cytokeratin 5/6, p63) and the marker of prostatic
      carcinomatous glands (p504s) or alpha methylacyl-CoA racemase (AMACR). MATERIAL
      AND METHODS: Retrospective study of 44 cases of paraffin-embedded prostatic
      specimens (36 biopsies, 4 PER, 1 adenomectomy and 3 radical prostatectomies),
      consisting in 20 cases of prostatic carcinomas (2 intraductal, 12 Gleason 6
      (3+3), 4 Gleason 7 (4+3), 2 Gleason 8 (4+4)), 11 ASAP, 9 PIN (2 low grade, 7 high
      grade (2 isolated)), and 10 benign lesions (8 atrophy, 1 atypical adenomatous
      hyperplasia and 1 case of clear cell cribriform hyperplasia). All cases were
      tested with antibodies to CK 5/6, and with a cocktail to p63 and p504s, after
      heat antigenic retrieval on NEXES Ventana processor. RESULTS: Basal cells of
      normal prostatic glands stained with CK5/6 and p63 in 91,3% and 100% of cases,
      independently from the fixation procedure (Bouin or Formalin). Carcinomas had a
      p63-/p504s+ profile, PIN were p63+/p504s+, and benign lesions were p63+/p504s-.
      We observed an increase in sensitivity: p63/p504s (100%), CK5/6 (80%), p63 (90%),
      p504s (95%), and specificity: p53/p504s (90%), CK5/6 (87.5%), p63 (90.5%), p504s
      (90.9%). CONCLUSION: Our results show that the use of a cocktail to p63/p504s is
      more specific than the use of CK5/6 alone this technique supports a diagnosis of
      prostatic cancer in 40% of cases previously considered as ASAP.

PMID- 15192534
TI  - [Miscellaneous benign lesions of the bladder and the urinary tract].
AB  - Miscellaneous benign lesions of the bladder are composed of morphologic aspects
      of the urothelial mucosa. They are epithelial lesions (von Brunn nests,
      glandularis cystitis, nephrogenic adenoma, polypoid cystitis and epidermoid
      metaplasia), myofibroblastic proliferations and heterotopias (endometriosis,
      endocervicosis, endosalpingiosis and ectopic prostatic tissue). Etiology,
      morphologic aspects and differential diagnosis are discussed.

PMID- 15192535
TI  - [Neurotoxicity and neuroprotection, two aspects of microglial activation in human
      immunodeficiency virus (HIV) infection].
AB  - Microglial cells and macrophages are the only cells within the central nervous
      system, in which productive HIV infection has been unquestionably demonstrated.
      Those cells play a key role in the origin of the neuronal dysfunction underlying
      HIV-related cognitive disorders. The neurotoxicity of the cells is both direct,
      related to HIV proteins, and indirect, through the release by activated
      macrophages and microglial cells (AMM) of multiple neurotoxic factors. The
      mechanisms of neuronal damage, the final irreversible stage of which is neuronal
      apoptosis, are only partly understood but appear to involve oxidative stress and
      glutamate-receptor mediated toxicity. On the other hand, recent experimental in
      vitro and in vivo studies, and neuropathological studies in HIV infected patients
      at different stages of the disease, tend to show that AMM express excitatory
      amino acid transporters (EAAT) suggesting that in addition to their neurotoxic
      properties, they also have a neuroprotective role by clearing extra-cellular
      glutamate and producing antioxidant glutathione. This neuroprotective role could
      counteract, at least in the early stages of the disease, the neurotoxicity of AMM
      explaining the discrepancy between the conspicuous microglial activation at that
      stage and the absence of cognitive disorder, neuronal loss and neuronal
      apoptosis. It could also explain the regression of the cognitive disorders in
      some patients who received highly active antiretroviral treatment.

PMID- 15192536
TI  - [Late metastasis after a testicular Sertoli cell tumour].
AB  - The diagnosis of Sertoli cell tumors is sometimes difficult and can be improved
      using anti inhibin immunohistochemistry. It is also difficult to establish the
      prognostic of Sertoli cell tumors. In our observation a high Mib 1 rate (20%)
      could have be taken in account to decide a better survey or/and a
      lymphadenectomy, which could have avoided lymph node metastasis in our patient,
      which was discovered ten years after orchidectomy.

PMID- 15192537
TI  - [Localised bronchi amyloidosis: a case report].
AB  - Localised pulmonary amyloidosis is exceptional. Tracheobronchial symptoms are the
      most frequent. We report a case of a 68 year-old man complaining of cough and
      breathlessness. Bronchoscopy showed a submucosal infiltration with stenosis of
      left upper and lower bronchi. Multiples biopsy were performed and concluded to
      amyloidosis of AL type. Our objective is to describe the anatomopathologic
      aspects of localised pulmonary amyloidosis and to discuss its pathogeny.

PMID- 15192538
TI  - [Mixed tumor or myoepithelioma of the skin? Histologic and immunohistochemical
      features].
AB  - Mixed tumor, first reported in the parotid gland, is formed from the
      proliferation of epithelial and myoepithelial cells in a mesenchymatous stroma.
      We report the case of a woman hospitalized for a subcutaneous nodule of the
      thigh, characterized by a fast increased in size in 8 months. Microscopic
      analysis showed a proliferation of grouped and isolated spindle cells, without
      atypia or mitotic features. Few tubular features were noted. Stroma was
      hyalinized or myxoid. Neoplastic cells displayed immunohistochemical positivity
      with smooth muscle actin, keratin and S-100 protein. This neoplasm appeared
      mesenchymatous. The diagnosis was mixed tumor with a predominant myoepithelial
      component. This case underlines the difficulties encountered in defining this
      neoplasm. Some authors consider that myoepithelioma is a monophasic variant of
      mixed tumor; others consider that myoepithelioma is different from mixed tumor
      because its is more aggressive prognosis. The evolution of our case suggests that
      a myoepithelial differentiation should be a ma of poor prognosis.

PMID- 15192539
TI  - [An unusual lesion of the mediastinum: angiomatosis or diffuse hemangioma].
AB  - Angiomatosis are rare benign vascular lesions representing almost 4% of vascular
      tumours in children and adolescent. These lesions occur in soft tissue and are
      clinically extensive, covering large parts of the body in a continuous pattern.
      Limbs are classically involved. The incidence is high in childhood and
      adolescence. The authors report an original case of angiomatosis or diffuse
      haemangioma located in the anterosuperior part of the mediastinum in a 17 year
      old girl. The patient consulted for increasing dyspnoea starting two years
      earlier. At medical imaging, calcified tumoral mass measuring 60 mm situated in
      the anterosuperior mediastinum was objectivated. The mass did not involve bony
      nor chondral structure. Teratoma or thymoma was suspected. At operation the whole
      tumor was resected with adherent pericardium. At histological examination, the
      lesion showed the presence of vascular structures inside fibro muscular and fatty
      tissue mixed with multiple nerve sections. In the lesion, venous walls were
      remarkably thick and sometimes picked or surrounded by multiple micro vessels. A
      Hamartomatous or proliferative origin may be discussed. The multiple components
      supports a hamartomatous origin, especially because of the unexpected presence of
      nervous elements. A proliferative process trapping preexisting vascular and
      nervous elements may be also considered. Furthermore, the lesion may represent a
      diffuse mesenchymatous proliferation as suggested by the presence of adipose
      tissue or glomic cells. Additional studies based on cytogenetics could surely
      improve the understanding of this lesion.

PMID- 15192540
TI  - [Papillary tumor of the gallbladder: the clear cells carcinoma].
AB  - Clear cell carcinoma has been described in numerous anatomic sites. Renal
      location is the most frequent. The occurrence in the gallbladder is exceptional.
      We report the case of a 71-Year-old woman who presented with sub-acute
      angiocrolitis. Computer tomographic scan revealed a polypoid mass close to the
      neck of the gallbladder; there was no renal lesion. Histological analysis of the
      gallbladder showed a primitive clear cell carcinoma with a papillary pattern
      associated with carcinoma in situ. Immunohistochemical study confirmed the
      primitive character of the tumor, characterized by an expression of KL-1, EMA and
      ACE and an absence of vimentin, CD 10 and CD15. Clear cell carcinomas of the
      gallbladder are uncommon neoplasms which could only be diagnosed on clinical,
      histological and immunohistochemical arguments.

PMID- 15192541
TI  - [Parasellar paraganglioma: a case report].
AB  - A 66-Year-old man presented with diplopia, headache and dizziness. Magnetic
      resonance imaging showed a right intrasphenoidal paracavernous mass. A biopsy was
      performed by endonasal route in the lesion which appeared to be part of the
      hypophyseal fossa. Histological examination revealed a highly cellular tumoral
      proliferation, with a variable architecture, of which chief cells were
      immunoreactive for neuroendocrine markers and spindle-shaped cells positive for
      PS 100. Morphological features were consistent with the diagnosis of
      paraganglioma. Our observation is the first case of this rare tumor reported in
      the French literature.

PMID- 15192543
TI  - [Metastasis and pulmonary pseudo-tumors].

PMID- 15192544
TI  - [Pap smear and endometrial tumor].

PMID- 15192545
TI  - [Pulmonary calcified micronodules].

PMID- 15192546
TI  - [An exceptional cause of intestinal ischemic necrosis].

PMID- 15192550
TI  - Medical examiners, coroners, and biologic terrorism: a guidebook for surveillance
      and case management.
AB  - Medical examiners and coroners (ME/Cs) are essential public health partners for
      terrorism preparedness and response. These medicolegal investigators support both
      public health and public safety functions and investigate deaths that are sudden,
      suspicious, violent, unattended, and unexplained. Medicolegal autopsies are
      essential for making organism-specific diagnoses in deaths caused by biologic
      terrorism. This report has been created to 1) help public health officials
      understand the role of ME/Cs in biologic terrorism surveillance and response
      efforts and 2) provide ME/Cs with the detailed information required to build
      capacity for biologic terrorism preparedness in a public health context. This
      report provides background information regarding biologic terrorism, possible
      biologic agents, and the consequent clinicopathologic diseases, autopsy
      procedures, and diagnostic tests as well as a description of biosafety risks and
      standards for autopsy precautions. ME/Cs' vital role in terrorism surveillance
      requires consistent standards for collecting, analyzing, and disseminating data.
      Familiarity with the operational, jurisdictional, and evidentiary concerns
      involving biologic terrorism-related death investigation is critical to both
      ME/Cs and public health authorities. Managing terrorism-associated fatalities can
      be expensive and can overwhelm the existing capacity of ME/Cs. This report
      describes federal resources for funding and reimbursement for ME/C preparedness
      and response activities and the limited support capacity of the federal Disaster
      Mortuary Operational Response Team. Standards for communication are critical in
      responding to any emergency situation. This report, which is a joint
      collaboration between CDC and the National Association of Medical Examiners
      (NAME), describes the relationship between ME/Cs and public health departments,
      emergency management agencies, emergency operations centers, and the Incident
      Command System.

PMID- 15192547
TI  - [Guidelines for the macroscopic studies of surgically resected lung specimens.
      Proposal for a anatomo-pathologic standardized form for the examination of
      pulmonary cancer].
AB  - We present practice guidelines for the examination of lung specimens removed for
      cancer, and pulmonary biopsies performed for interstitial lung diseases. In
      addition, we propose a standardized form for the reporting of lung cancer. This
      approach takes place in looking for better quality and should facilitate the use
      of the morphologic data, particularly in multicentric studies.

PMID- 15192551
TI  - Presidential address: Time, our vanishing commodity, and a prescription for
      rescue.

PMID- 15192552
TI  - Predicting aneurysm enlargement in patients with persistent type II endoleaks.
AB  - OBJECTIVE: The clinical significance of type II endoleaks is not well understood.
      Some evidence, however, indicates that some type II endoleaks might result in
      aneurysm enlargement and rupture. To identify factors that might contribute to
      aneurysm expansion, we analyzed the influence of several variables on aneurysm
      growth in patients with persistent type II endoleaks after endovascular aortic
      aneurysm repair (EVAR). METHODS: In a series of 348 EVARs performed during a 10
      year period, 32 patients (9.2%) developed type II endoleaks that persisted for
      more than 6 months. Variables analyzed included those defined by the reporting
      standards for EVAR (SVS/AAVS) as well as other endoleak characteristics.
      Univariate, receiver operating characteristic curve, and Cox regression analyses
      were used to determine the association between variables and aneurysm
      enlargement. RESULTS: The median follow-up period was 26.5 months (range, 6-88
      months). Thirteen patients (41%) had aneurysm enlargement by 5 mm or more (median
      increase in diameter, 10 mm), whereas 19 (59%) had stable or shrinking aneurysm
      diameter. Univariate and Cox regression analyses identified the maximum diameter
      of the endoleak cavity, ie, the size of the nidus as defined on contrast computed
      tomography scan, as a significant predictor for aneurysm enlargement (relative
      risk, 1.12; 95% confidence interval, 1.04-1.19; P =.001). The median size of the
      nidus was 23 mm (range, 13-40 mm) in patients with aneurysm enlargement and 8 mm
      (range, 5-25 mm) in those without expansion (Mann-Whitney U test, P <.001).
      Moreover, receiver operating characteristic curve and Cox regression analyses
      showed that a maximum nidus diameter greater than 15 mm was particularly
      associated with an increased risk of aneurysm enlargement (relative risk, 11.1;
      95% confidence interval, 1.4-85.8; P =.02). Other risk factors including gender,
      smoking history, hypertension, need of anticoagulation, aneurysm diameter, type
      of endograft used, and number or type of collateral vessels were not significant
      predictors of aneurysm enlargement. CONCLUSIONS: In patients with persistent type
      II endoleaks after EVAR, the maximum diameter of the endoleak cavity or nidus is
      an important predictor of aneurysm growth and might indicate the need for more
      aggressive surveillance as well as earlier treatment.

PMID- 15192553
TI  - Thoracovisceral segment aneurysm repair after previous infrarenal abdominal
      aortic aneurysm surgery.
AB  - OBJECTIVE: Repair of thoracovisceral aortic aneurysms (TVAA) after previous open
      repair of an infrarenal abdominal aortic aneurysm (AAA) poses significant
      challenges. We sought to better characterize such recurrent aneurysms and to
      evaluate their operative outcome. METHODS: We reviewed the records and
      radiographs of 49 patients who underwent repair of TVAAs between 1988 and 2002
      after previous repair of an AAA. Visceral artery reconstructions were completed
      with combinations of beveled anastomoses, inclusion patches, and side arm grafts.
      In 14 patients visceral endarterectomy was required to treat associated occlusive
      disease. Sixteen patients had cerebrospinal fluid drainage, and 10 patients had
      distal perfusion during cross-clamping. RESULTS: Patient mean age was 72 years,
      and 80% were men. Fifty-one percent of patients had symptomatic disease, and
      average TVAA diameter was 6.2 cm. Mean time between AAA and TVAA repair was 77
      months. Twenty-six percent of aneurysms were restricted to the lower visceral
      aortic segment, 35% extended to the diaphragm, another 35% extended to the distal
      or middle thoracic aorta, and 4% involved the entire remaining visceral and
      thoracic aorta. The 30-day operative mortality rate was 4.1% in patients with
      nonruptured aneurysms and 50% in patients with ruptured aneurysms, for an overall
      mortality rate of 8.2%. Fifteen patients (30.6%) had major morbidity, including
      paresis in two patients and dialysis-dependent renal failure in five patients. At
      late follow-up, three patients required further aortic operations to treat
      additional aneurysms, and four patients had fatal aortic ruptures. Two-year and 5
      year cumulative survival rates were 61% (+/-7.5%) and 37% (+/-7.8%),
      respectively. At univariate analysis, operative blood loss was the sole
      significant predictor of major morbidity (P <.023), and rupture (P <.030, P
      <.0001) and aneurysm extent (P <.0007, P <.0001) correlated with both operative
      death and long-term survival. Only aneurysm extent (P <.010, relative risk 37.3)
      remained a significant predictor of long-term survival at multivariate analysis.
      CONCLUSION: Elective repair of TVAAs after previous AAA repair can be performed
      with an acceptable level of operative mortality, though with considerable
      operative morbidity. Limited long-term survival mandates careful patient
      selection, and the high mortality associated with ruptured TVAA underscores the
      need for post-AAA surveillance.

PMID- 15192554
TI  - Popliteal artery aneurysms: a comparison of outcomes in elective versus emergent
      repair.
AB  - OBJECTIVE: The purpose of this study was to assess and compare outcomes of
      elective versus emergent operative repair of popliteal artery aneurysms. DESIGN:
      A retrospective analysis of a prospectively recorded vascular surgery database
      from June 1992 to December 2002 was performed with chart review. Main outcome
      measures Patient survival, limb salvage, and graft patency were evaluated.
      RESULTS: Fifty-one popliteal artery aneurysms were repaired in 39 patients, all
      male and ranging in age from 18 to 87 years (mean 67.1). Mean follow-up was 47.8
      months. Repair was elective in 37 (72.5%) and emergent in 14 (27.5%) limbs, 13
      with acute ischemia and one with aneurysm rupture. Thrombolytic therapy was
      utilized in four ischemic limbs with no suitable bypass target vessel identified
      on initial arteriogram. Outflow vessels included the popliteal artery in 22
      (43.1%) and infrapopliteal vessels in 29 (56.9%) limbs. Cardiac morbidity and 30
      day mortality rates were 0%. Overall primary patency, secondary patency, limb
      salvage, and actuarial survival were 95.6%, 100%, 98.0%, and 98.0% at 1 year and
      85.1%, 96.9%, 98.0%, and 83.8% at 5 years, respectively. Bypass graft redo or
      revision was performed for stenosis in one and occlusion in four limbs. Two
      amputations were performed at 6 days and 63.6 months after initial aneurysm
      repair. No difference was noted between elective and emergent groups with regard
      to patency, limb salvage, or survival (P >.26), and no association between the
      number of identified target vessels and limb salvage or patency was demonstrated
      (P =.12). CONCLUSION: In our experience, the outcome of the popliteal artery
      aneurysm repair was comparable in the emergent and elective settings. Aggressive
      tibial reconstruction plays a crucial role in the treatment of popliteal artery
      aneurysms, especially in those presenting with acute limb ischemia. Thrombolytic
      therapy is infrequently required in the acute setting, although it may be useful
      in patients with no identifiable outflow target vessel on initial arteriogram.

PMID- 15192555
TI  - Statin therapy is associated with improved patency of autogenous infrainguinal
      bypass grafts.
AB  - OBJECTIVE: HMG-CoA reductase inhibitors (statins) broadly reduce cardiovascular
      events, effects that are only partly related to cholesterol lowering. Recent
      studies suggest important anti-inflammatory and antiproliferative properties of
      these drugs. The purpose of this study was to determine the influence of statin
      therapy on graft patency after autogenous infrainguinal arterial reconstructions.
      METHODS: A retrospective analysis of consecutive patients (1999-2001) who
      underwent primary autogenous infrainguinal reconstructions with a single segment
      of greater saphenous vein was performed. Patients were categorized according to
      concurrent use of a statin. Graft lesions (identified by duplex surveillance) and
      interventions were tabulated. Comparisons between groups were made by using the
      Fisher exact test for categorical variables and the Student t test for continuous
      variables. Patency, limb salvage, and survival were compared by log rank test. A
      stepwise Cox proportional hazards analysis was then employed to ascertain the
      relative importance of factors influencing graft patency. RESULTS: A total of 172
      patients underwent 189 primary autogenous infrainguinal arterial reconstructions
      (94 statin, 95 control) during the study period. The groups were well matched for
      age, indication, and atherosclerotic risk factors. Procedures were performed
      primarily for limb salvage (92%), with 65% to an infrapopliteal target.
      Perioperative mortality (2.6%) and major morbidity (3.2%) were not different
      between groups. There was no difference in primary patency (74% +/- 5% vs 69% +/-
      6%; P =.25), limb salvage (92% +/- 3% vs 90% +/- 4%; P =.37), or survival (69% +/
      5% vs 63% +/- 5%; P =.20) at 2 years. However, patients on statins had higher
      primary-revised (94% +/- 2% vs 83% +/- 5%; P <.02) and secondary (97% +/- 2% vs
      87% +/- 4%; P <.02) graft patency rates at 2 years. Of all factors studied by
      univariate analysis, only statin use was associated with improved secondary
      patency (P =.03) at 2 years. This was confirmed by multivariate analysis. The
      risk of graft failure was 3.2-fold higher (95% confidence interval, 1.04-10.04)
      for the control group. Perioperative cholesterol levels (available in 47% of
      patients) were not statistically different between groups. CONCLUSIONS: Statin
      therapy is associated with improved graft patency after infrainguinal bypass
      grafting with saphenous vein.

PMID- 15192556
TI  - Long-term results of peripheral arterial disease rehabilitation.
AB  - PURPOSE: Although the Peripheral Arterial Disease Rehabilitation Program (PADRx)
      improves walking ability and quality of life over brief periods of follow-up, the
      long-term durability of results has not been established. This study examined
      functional status, walking ability, and quality of life in patients several
      months after completion of a 12-week PADRx. METHODS: Patients who completed a
      PADRx were eligible for participation. A Medical Outcomes Study 36-Item Short
      Form (SF-36), Walking Impairment Questionnaire (WIQ), and physical activity
      questionnaire were administered by telephone. A progressive treadmill test was
      performed on-site. RESULTS: Of 63 eligible patients, 14 were lost to follow-up,
      11 refused participation, and four died. Thirty-four patients had completed PADRx
      20 to 80 months previously (mean, 48.2 +/- 13.7 months), and completed the phone
      survey. Fifteen patients reported exercising a minimum of 60 min/wk for 3 months
      (EX group), and 19 had not exercised in the preceding 3 months (SED group). Self
      reported SF-36 values were significantly different between the EX and SED groups
      for Physical Function (43.3 +/- 8.2 vs 34.2 +/- 7.8), Role-Physical Function
      (41.2 +/- 7.7 vs 32.8 +/- 9.2), and Bodily Pain (46.9 +/- 8.8 vs 38.9 +/- 7.1),
      as well as the Physical Composite (43.5 +/- 6.5 vs 34.0 vs 5.8) domains of the SF
      36. Similarly the WIQ demonstrated significant differences in Walking Distance
      (46.8 +/- 36.2 vs 7.8 +/- 9.4), Walking Speed (47.5 +/- 32.6 vs 14.5 +/- 13.9),
      and Stair Climbing (60.6 +/- 36.6 vs 37.1 +/- 27.6), favoring the EX group.
      Sixteen patients, equally distributed between the EX and SED groups, completed
      the progressive treadmill test. Both groups had experienced improvement (P <.05)
      in claudication pain time and maximal walking time after completing the 12-week
      supervised program. The EX group maintained increased claudication pain time of
      121% and maximum walking time of 109% over baseline, whereas the SED group values
      had returned to baseline (P <.05). CONCLUSIONS: Patients with claudication
      realize symptomatic and functional improvement with supervised exercise programs.
      Those who continue to exercise will potentially maintain these benefits and
      experience improved health-related quality of life.

PMID- 15192557
TI  - Early results of carotid stent placement for treatment of extracranial carotid
      bifurcation occlusive disease.
AB  - OBJECTIVE: The purpose of this study was to review the initial results of carotid
      artery angioplasty with stenting (CAS) performed by vascular surgeons to treat
      bifurcation occlusive disease. Most patients were selected for CAS if they had
      indications for endarterectomy (CEA) but were considered at high risk for
      surgery. METHODS: Since December 2000, 74 carotid arteries in 69 patients
      underwent CAS, with distal balloon embolization protection in 96%. Mean patient
      age was 72 years; 82% of patients were men. Indications for CAS included
      asymptomatic disease (62%), transient ischemic attack (TIA; 23%), and
      cerebrovascular accident (15%). Mean internal carotid artery diameter stenosis
      was 82%. CAS was chosen over CEA because of cardiac (49%) or pulmonary (4%)
      comorbid conditions, hostile neck (25%), distal extent of disease (6%), and
      contralateral cranial nerve injury (1%). CAS was performed in 15% patients who
      were good surgical candidates, because of patient preference. Pathologic
      conditions were primary atherosclerosis (81%), recurrent carotid stenosis (18%),
      and dissection (1%). Procedures were transfemoral in 95% of cases and
      transcarotid in 5%. In 30% of cases the contralateral carotid artery had 80% or
      greater stenosis or was completely occluded. RESULTS: Technical success was
      achieved in 96% of cases. There were no deaths, no major strokes, one minor
      stroke (National Institutes of Health Stroke Scale, 3), and one TIA (neurologic
      event rate, 2.6%). The single minor stroke resolved completely by 1 month. One
      patient (1.3%) had a perioperative myocardial infarction. Transient neurologic
      changes occurred in 8% of patients during the protection balloon inflation, and
      all resolved with deflation. Bradyarrhythmia requiring pharmacologic treatment
      occurred in 14% of patients. At mean follow-up of 6 months there have been two
      instances of recurrent stenosis greater than 50% as noted at duplex scanning.
      During the same period, 266 carotid CEAs were performed, with a neurologic event
      rate of 0.8% (major stroke, 0.4%; no minor strokes; TIA, 0.4%) and a myocardial
      infarction rate of 3%. Combined stroke and death rate was 1.3% in patients who
      underwent CAS and 0.5% in patients who underwent CEA. CONCLUSION: CAS with
      cerebral protection can be performed safely in patients at high surgical risk,
      with low perioperative morbidity and mortality. The durability of the procedure
      must be determined with longer follow-up.

PMID- 15192558
TI  - Understanding trends in inpatient surgical volume: vascular interventions, 1980
      2000.
AB  - OBJECTIVE: To help understand past and future trends in vascular intervention, we
      examined changes in the rate of utilization, patient demographics, and length of
      stay from 1980 to 2000. METHODS: We reviewed the ICD-9 codes for all vascular
      procedures using the National Hospital Discharge Survey of non-federal United
      States hospitals (1980-2000). RESULTS: The number of vascular procedures
      performed in this country increased from 412,557 in 1980 to 801,537 in 2000 (per
      capita increase of >50%). This increase was most evident in elderly patients (>75
      years, 67% per capita increase in discharges). Long hospital stays (> or =7 days)
      for vascular procedures fell 41%, and short hospital stays (<24 hours) increased
      15% over the period of study. The frequency of abdominal aortic aneurysm repairs
      remained relatively constant. Except for an interval in the late 1980s, and a
      minor decrease from 1997 to 2000, the frequency of carotid endartarectomy rose
      dramatically (69%). Lower extremity revascularizations increased steadily until
      1990 but then declined 12%. From 1995 to 2000, there was a 27% per capita
      decrease in the number of renal-mesenteric operations. Correspondingly, over the
      past 5 years there has been a 979% growth in the number of
      percutaneous/endovascular interventions. Despite a substantial number of
      interventions for lower extremity vascular disease, there was a concomitant
      increase in the number of major and minor amputations. CONCLUSION: Interventions
      for vascular disease have increased dramatically, with a major shift toward less
      invasive treatments, particularly for the renal and mesenteric vessels and the
      lower extremities. These trends in procedural use suggest that vascular surgeons
      need to embrace catheter-based approaches if they want to remain leaders in the
      treatment of peripheral vascular diseases.

PMID- 15192559
TI  - Zenith AAA endovascular graft: intermediate-term results of the US multicenter
      trial.
AB  - PURPOSE: The intent of this study was to assess the safety and effectiveness of
      the Zenith AAA Endovascular Graft compared with conventional aneurysm repair.
      MATERIAL AND METHODS: The study was conducted in a prospective, multicenter,
      nonrandomized, concurrent control manner. Physiologically similar patients with
      infrarenal abdominal aortic aneurysms (AAAs) underwent either open surgery or
      repair with the Zenith AAA Endovascular Graft. Separate analyses of
      physiologically challenged patients were performed. Follow-up was conducted at
      hospital discharge and at 1, 6, and 12 months (endovascular repair group) or 1
      and 12 months (open surgical repair group). Evaluation included computed
      tomography, abdominal radiography, laboratory tests, and physical examination.
      Mortality (AAA-related and overall), morbidity, in-hospital recovery, renal
      function, and secondary interventions were assessed. Patients in the endovascular
      repair group were evaluated for change in aneurysm size, endoleak, graft
      migration, conversion, rupture, and device integrity. Statistical analyses were
      performed with the Kaplan-Meier method, Blackwelder test, propensity score
      assessment, two-sample t test, Yates-corrected Pearson chi(2) test, and Fisher
      exact test. RESULTS: Conventional open surgery was used in 80 patients, and 200
      patients underwent repair with the Zenith AAA Endovascular Graft. Technical
      success was accomplished in 98.8% of patients in the open repair group and 99.5%
      in the endovascular repair group. Patients in the endovascular repair group had
      fewer significant adverse events within 30 days (80% vs 57%; P <.001). All-cause
      mortality was similar (endovascular, 3.5%; open surgery, 3.8%). Aneurysm-related
      mortality was higher with conventional surgery at 12 months (3.8% vs 0.5%; P
      =.04). In-hospital recovery and procedural measures were better for endovascular
      repair in all categories (P <.001). The incidence of endoleak was 17% at 30 days,
      7.4% at 12 months, and 5.4% at 24 months. Aneurysm shrinkage (>5 mm) was noted in
      more than two thirds of patients at 12 months and three fourths of patients at 24
      months. Renal dysfunction rate did not differ between groups. Migration (>5 mm)
      was detected in four (2%) patients through 12 months; none was greater than 10 mm
      or associated with adverse events through 24 months. Three conversions were
      performed within 12 months, one because of aneurysm rupture. Secondary procedures
      were more common in the endovascular group (11% vs 2.5%; P =.03). In total, 351
      patients had endografts implanted, and 6 patients were noted to have barb
      separations through 12-month follow-up. No stent fractures were noted.
      CONCLUSIONS: The Zenith AAA Endovascular Graft is safe and effective for
      treatment of infrarenal AAAs. The high likelihood of decrease in aneurysm size
      provides evidence that treatment of aneurysms with this device reverses the
      natural history of aneurysmal disease. The importance of long-term follow-up is
      underscored by the small but defined incidence of barb separation and the
      potential for unforeseen failure modes.

PMID- 15192560
TI  - Analysis of renal function after aneurysm repair with a device using suprarenal
      fixation (Zenith AAA Endovascular Graft) in contrast to open surgical repair.
AB  - PURPOSE: This study was undertaken to assess the effect on renal function of open
      surgery and endovascular abdominal aortic aneurysm (AAA) repair with suprarenal
      fixation with the Zenith device. METHODS: Data for 279 patients with similar
      preoperative comorbid conditions were prospectively analyzed after AAA repair.
      One hundred ninety-nine patients underwent endografting with the Zenith AAA
      Endovascular Graft, which incorporates suprarenal fixation (Zenith standard risk
      group, ZSR), and 80 patients underwent open surgery (standard surgical risk
      group, SSR). Endovascular repair was also performed in 100 patients considered
      poor candidates for open repair (Zenith high risk group, ZHR). Serum creatinine
      concentration (SCr) and anatomic defects were assessed before the procedure,
      before discharge, and at 1, 6, 12, and 24 months in all patients who underwent
      endovascular repair, and before the procedure and at 1 and 12 months in patients
      who underwent open surgical repair (only SCr was measured before discharge).
      Renal function was also analyzed, with a creatinine clearance calculation
      (Cockcraft-Gault). Renal insufficiency was defined as an increase in SCr greater
      than 30% from a preoperative baseline value, any SCr concentration in excess of
      2.0 mg/dL, or any need for dialysis. Cumulative renal infarction and arterial
      occlusion rates were calculated with computed tomographic, ultrasonographic, and
      angiographic data, and reported as cumulative values. RESULTS: Despite the
      initially superior renal function in the ZSR group at the pre-discharge
      evaluation (P =.01), there were no differences at 12 months with respect to rise
      in SCr greater than 30% (ZSR, 16%, vs SSR, 12%; P =.67), SCr rise greater than
      2.0 mg/dL (ZSR, 2.5%, vs SSR, 3.4%; P =.66), incidence of renal artery occlusion
      (ZSR, 1%, vs SSR, 1.4%; P >.99), or infarction (ZSR, 1.5%, vs SSR, 1.4%; P >.99).
      Only one patient in each group required hemodialysis. Of note, both groups of
      patients demonstrated a reduction in creatinine clearance over 12 months, which
      then stabilized or improved by 24 months for ZSR patients. CONCLUSIONS: Renal
      dysfunction occurs in a subset of patients regardless of type of repair (open or
      endovascular with suprarenal fixation). The cause of renal dysfunction after open
      or endovascular repair with a suprarenal stent is probably multifactorial. The
      observed dysfunction occurs in a small number of patients, and the effect in the
      endovascular group (no data for the surgical group at 24 months) appears to be
      transient. The initial dysfunction, apparent in both groups over 12 months of
      follow-up, stabilizes or improves at 12 to 24 months.

PMID- 15192562
TI  - Late abdominal aortic aneurysm enlargement after endovascular repair with the
      Excluder device.
AB  - OBJECTIVES: Behavior of the abdominal aortic aneurysm (AAA) sac after
      endovascular abdominal aortic aneurysm repair (EVAR) is graft-dependent. The
      Excluder endograft has been associated with less sac regression than some other
      stent grafts. Long-term follow-up has not been reported. METHODS: Between May
      1999 and July 2002, 50 patients underwent EVAR with the Excluder bifurcated
      endoprosthesis. These patients were followed up prospectively with computed
      tomography (CT) at 1, 6, and 12 months and yearly thereafter. One immediate
      conversion to open surgery and three deaths occurred within 6 months. One
      additional patient was lost to follow-up. The remaining 45 patients, 35 men and
      10 women, were followed up for at least 1 year, and form the basis for this
      report. Their mean age was 73 +/- 5.5 years. The minor axis diameter at the
      largest area of the AAA on CT examination was compared with the baseline
      measurement at 1 month and to the smallest size previously recorded during follow
      up. Change in sac size of 5 mm or greater was considered significant. Mean follow
      up was 2.7 +/- 1.2 years (range, 1-4 years). Nominal variables were compared with
      the chi(2) test, and continuous variables with the Student t test. RESULTS: A
      significant decrease in average AAA sac diameter was observed at 6-month, 1-year,
      and 2-year follow-up. These differences were lost by the 3-year evaluation,
      because of delayed sac growth (n = 9) and re-expansion of once shrunken aneurysms
      (n = 3). The probability of freedom from sac growth or re-expansion at 4 years
      was only 43%. At last follow-up, sac expansion occurred in the absence of active
      endoleak in nine patients. Type II endoleak was associated with sac expansion in
      three patients (P =.003), resulting in one conversion to open surgery after the 4
      year follow-up. No graft migrations, AAA ruptures, or aneurysm-related deaths
      were noted. CONCLUSIONS: Late aneurysm sac growth or re-expansion after EVAR with
      the Excluder device is common, even in the absence of endoleak. Although the
      incidence of important clinical sequelae is low at this point, the incidence of
      aneurysm expansion should be taken into consideration during the risk-benefit
      assessment before EVAR repair with the Excluder device.

PMID- 15192561
TI  - Intra-aneurysm sac pressure measurements after endovascular aneurysm repair:
      differences between shrinking, unchanged, and expanding aneurysms with and
      without endoleaks.
AB  - OBJECTIVE: Our objective was to study intra-aneurysm pressure after endovascular
      aneurysm repair (EVAR) in shrinking, unchanged, and expanding abdominal aortic
      aneurysms (AAAs) with and without endoleaks. METHODS: Direct intra-aneurysm sac
      pressure measurement (DISP) by percutaneous translumbar puncture of the AAA under
      fluoroscopic guidance was performed 46 times during the follow-up of 37 patients
      (30 men; median age, 73 years [range, 58-82 years]; AAA diameter: median, 60 mm
      [range, 48-84 mm]). Three patients were included in two different groups because
      DISP was performed more than once with different indications. Tip-pressure
      sensors mounted on 0.014-inch guidewires were used for simultaneous measurement
      of systemic and AAA sac pressures. Mean pressure index (MPI) was calculated as
      the percentage of mean intra-aneurysm pressure relative to the simultaneous mean
      intra-aortic pressure. RESULTS: Median MPI was 19% in shrinking (11 patients),
      30% in unchanged (10 patients), and 59% in expanding (9 patients) aneurysms
      without endoleaks. Pulse pressure was also higher in expanding (10 mm Hg)
      compared with shrinking (2 mm Hg; P <.0001) AAAs. Four of the nine patients with
      expanding AAAs underwent five repeated DISPs later in the follow-up, and MPIs
      were consistently elevated. Seven of the 10 patients with unchanged AAAs without
      endoleaks underwent further computed tomography follow-up after DISP; 2 expanded
      (MPI, 47%-63%), 4 shrank (MPI, 21%-30%), and 1 remained unchanged (MPI, 14%).
      Type II endoleaks (6 patients, 7 DISPs) were associated with wide range of MPI
      (22%-92%). Successful endoleak embolization (n = 4) resulted in pressure
      reduction. CONCLUSIONS: Intra-aneurysm sac pressure measurement is an important
      adjunctive for EVAR evaluation, possibly allowing early detection of failures.
      High pressure is associated with AAA expansion and low pressure with shrinkage.
      Type II endoleaks can be responsible for AAA pressurization, and successful
      embolization appears to result in pressure reduction.

PMID- 15192565
TI  - Anatomic characteristics of ruptured abdominal aortic aneurysm on conventional CT
      scans: Implications for rupture risk.
AB  - OBJECTIVE: The purpose of this study was to analyze anatomic characteristics of
      patients with ruptured abdominal aortic aneurysms (AAAs), with conventional two
      dimensional computed tomography (CT), including comparison with control subjects
      matched for age, gender, and size. METHODS: Records were reviewed to identify all
      CT scans obtained at Dartmouth-Hitchcock Medical Center or referring hospitals
      before emergency AAA repair performed because of rupture or acute severe pain
      (RUP group). CT scans obtained before elective AAA repair (ELEC group) were
      reviewed for age and gender match with patients in the RUP group. More than 40
      variables were measured on each CT scan. Aneurysm diameter matching was achieved
      by consecutively deleting the largest RUP scan and the smallest ELEC scan to
      prevent bias. RESULTS: CT scans were analyzed for 259 patients with AAAs: 122 RUP
      and 137 ELEC. Patients were well matched for age, gender, and other demographic
      variables or risk factors. Maximum AAA diameter was significantly different in
      comparisons of all patients (RUP, 6.5 +/- 2 cm vs ELEC, 5.6 +/- 1 cm; P <.0001),
      and mean diameter of ruptured AAAs was 5 mm smaller in female patients (6.1 +/- 2
      cm vs 6.6 +/- 2 cm; P =.007). Two hundred patients were matched for diameter,
      gender, and age (100 from each group; maximum AAA diameter, 6.0 +/- 1 cm vs 6.0
      +/- 1 cm). Analysis of diameter-matched AAAs indicated that most variables were
      statistically similar in the two groups, including infrarenal neck length (17 +/-
      1 mm vs 19 +/- 1 mm; P =.3), maximum thrombus thickness (25 +/- 1 mm vs 23 +/- 1
      mm, P =.4), and indices of body habitus, such as [(maximum AAA diameter)/(normal
      suprarenal aorta diameter)] or [(maximum AAA diameter)/(L3 transverse diameter)].
      Multivariate analysis controlling for gender indicated that the most significant
      variables for rupture were aortic tortuosity (odds ratio [OR] 3.3, indicating
      greater risk with no or mild tortuosity), diameter asymmetry (OR, 3.2 for a 1-cm
      difference in major-minor axis), and current smoking (OR, 2.7, with the greater
      risk in current smokers). CONCLUSIONS: When matched for age, gender, and
      diameter, ruptured AAAs tend to be less tortuous, yet have greater cross
      sectional diameter asymmetry. On conventional two-dimensional CT axial sections,
      it appears that when diameter asymmetry is associated with low aortic tortuosity,
      the larger diameter on axial sections more accurately reflects rupture risk, and
      when diameter asymmetry is associated with moderate or severe aortic tortuosity,
      the smaller diameter on axial sections more accurately reflects rupture risk.
      Current smoking is significantly associated with rupture, even when controlling
      for gender and AAA anatomy.

PMID- 15192566
TI  - Survival after ruptured abdominal aortic aneurysm: effect of patient, surgeon,
      and hospital factors.
AB  - OBJECTIVE: The purpose of this study was to determine the effects of patient,
      surgeon, and hospital factors on survival after repair of ruptured abdominal
      aortic aneurysm (AAA) and to compare them with risk factors for survival after
      elective AAA repair. It was hypothesized that patients operated on by high-volume
      surgeons with subspecialty training would have better outcomes, which might argue
      for regionalization of AAA surgery. METHODS: In this population-based
      retrospective cohort study, surgeon billing and administrative data were used to
      identify all patients who had undergone AAA repair between April 1, 1992, and
      March 31, 2001, in Ontario, Canada. Demographic information was collected for
      each patient, as well as numerous variables related to the surgeons and
      hospitals. RESULTS: There were 2601 patients with ruptured AAA repair, with an
      average 30-day mortality rate of 40.8%. Significant independent predictors of
      lower survival were older age, female gender, lower patient income quintile,
      performance of surgery at night or on weekends, repair in larger cities, surgeons
      with lower annual volume of ruptured AAA operations, and surgeons without
      vascular or cardiothoracic fellowship training. There were 13,701 patients with
      elective AAA repair, with an average 30-day mortality rate of 4.5%. Significant
      independent predictors of lower survival were similar, except gender was not
      significant, but the Charlson Comorbidity Index was. When the hazard ratios
      associated with predictive factors were compared, surgeon factors appeared to be
      more important in ruptured AAA repair, and patient factors appeared more
      important in elective AAA repair. CONCLUSION: For elective AAA repair, and even
      more so for ruptured AAA repair, high-volume surgeons with subspecialty training
      conferred a significant survival benefit for patients. Although this would seem
      to argue in favor of regionalization, decisions should await a more complete
      understanding of the relationship between transfer time, delay in treatment, and
      outcome.

PMID- 15192567
TI  - Long-term survival and temporal trends in patient and surgeon factors after
      elective and ruptured abdominal aortic aneurysm surgery.
AB  - OBJECTIVE: Records for all patients in Ontario who underwent elective repair of
      abdominal aortic aneurysms (AAAs) or repair of ruptured AAAs between 1993 and
      1999 were studied to determine whether the profile of surgeons or patients
      changed and to determine whether postoperative mortality changed over time. The
      secondary objective was to describe long-term survival after AAA surgery.
      METHODS: A population-based retrospective cohort was assembled from
      administrative data. Surgeon billing records were used to identify operations
      performed between 1993 and 1999. Chi(2) and linear regression analyses were used
      to determine whether variables changed over time. Kaplan-Meier survival curves
      were used to estimate long-term survival. RESULTS: For patients undergoing
      elective AAA repair, average annual surgeon volume (P <.0001) and proportion of
      patients operated on by vascular surgeons (P =.02) increased over the study
      period; similar trends were noted for patients undergoing repair of ruptured
      AAAs. Surgeon volume was clearly correlated with mortality after both elective
      AAA repair and repair of ruptured AAAs; however, the benefit of this effect was
      modest beyond a surgeon volume of 6 to 10 ruptured AAA repairs per year or 20 to
      30 elective AAA repairs per year. No change in crude 30-day mortality (4.5% for
      elective AAA repair and 40.4% for repair of ruptured AAAs) was noted during the
      study. CONCLUSION: Despite the finding that surgery to repair ruptured AAAs and
      elective repair of AAAs is being increasingly performed by high-volume vascular
      surgeons, there was no change in early mortality between 1993 and 1999. This may
      have been because average surgeon volume was already relatively high at the
      beginning of the study period, which translated into only modest benefit to
      further increases in surgeon volume.

PMID- 15192568
TI  - Invasive treatment of chronic limb ischemia according to the Lower Extremity
      Grading System (LEGS) score: a 6-month report.
AB  - BACKGROUND: The invasive treatment of chronic lower extremity peripheral arterial
      disease (PAD) has become inconsistent. To standardize treatment at our
      institution, the Lower Extremity Grading System (LEGS) score was devised, based
      on arteriographic findings, symptoms, functional status, comorbid conditions, and
      technical factors. The scoring system was used to direct the invasive treatment
      approach in patients with lower extremity PAD. The purpose of this study was to
      prospectively assess outcomes of invasive treatment of lower extremity ischemia
      as directed by LEGS. METHODS: From March 2002 through December 2002, 332 limbs in
      227 patients with indications for intervention were scored and treated according
      to the LEGS score and followed for 6 months. Of the 227 patients, 66.1% were
      male; median age was 65 years. Diabetes mellitus was present in 44.9% of
      patients, claudication in 48.5%, and limb-threatening ischemia in 51.5%. Results
      of treatment as directed by LEGS were judged with the treatment outcome measures
      of reconstruction patency, limb salvage, mortality, change in ambulatory status,
      change in independent living status, and change in the short-form health survey
      (SF-36). RESULTS: Of 332 limbs, 61.5% with a score of 10 to 19 underwent
      endovascular therapy; 34% with a score of 0 to 9 underwent open
      revascularization; and 4.5% with a score greater than 20 underwent primary limb
      amputation. Interventions for the entire cohort as directed by LEGS resulted in 6
      month primary reconstruction patency of 82.4%; secondary reconstruction patency,
      92.6%; limb salvage, 90%; survival, 89.1%; maintenance of ambulatory status,
      85.6%; maintenance of independent living, 88.4%; and statistically significant
      improvement in health assessment, regardless of treatment type, as determined
      with the SF-36. There was no statistically significant variability when comparing
      results according to treatment (open surgery, 0-9 vs endovascular therapy, 10-19)
      or smaller score group categories (0-5, 6-9, 10-13, 14-19). CONCLUSIONS: At 6
      months, treatment as directed by LEGS score resulted in acceptable outcomes. This
      project is the first reported prospectively confirmed standardization tool for
      treatment of lower extremity PAD, and, pending independent confirmation by
      others, provides a comparative baseline against which other standardization
      efforts can be measured.

PMID- 15192569
TI  - Early results with use of gracilis muscle flap coverage of infected groin wounds
      after vascular surgery.
AB  - INTRODUCTION: Management of a nonhealing femoral wound after vascular surgery can
      pose a challenging problem, particularly when there is prosthetic material
      involved. We prefer to use pedicled gracilis muscle flaps (PGMFs) to cover
      problematic groin wounds when more conventional management is not possible.
      METHODS: We describe the technique for using PGMFs to provide groin coverage,
      report a summary of our short-term and long-term results, and describe why we
      prefer this reconstructive technique. RESULTS: Twenty PGMFs were placed in 18
      patients to treat nonhealing and infected groin wounds. Exposed prosthetic
      vascular reconstructions were covered with the PGMF in 14 wounds, and in situ
      autogenous vascular reconstructions were covered in four. Seven wound infections
      were polymicrobial, 10 had a single gram-positive organism, and one had a single
      gram-negative organism. Pseudomonas cultured out in four wounds, and Candida in
      one wound. Two patients had a virulent combination of methicillin-resistant
      Staphylococcus aureus and vancomycin-resistant enterococcus. Complete healing was
      initially achieved in all wounds, and no patient died within 30 days of surgery.
      Two PGMFs failed, at 2 weeks and 2 months, respectively, one from tension on the
      flap pedicle and one from acute inflow occlusion. Underlying prosthetic
      reconstruction was salvaged in 12 of 14 wounds; the remaining wounds with
      autogenous reconstructions or exposed femoral vessels all closed successfully. At
      a mean follow-up of 40 +/- 10 months there were no recurrent groin infections.
      Seven patients died, at 2.5, 3, 8, 12, 14, 22, and 28 months, respectively.
      CONCLUSION: PGMF transposition is an effective option to cover infected or
      exposed femoral vessels or salvage prosthetic graft material in the groin. In
      appropriately selected patients, when complete graft removal and extra-anatomic
      bypass is not an acceptable option, gracilis muscle flap coverage is a viable
      alternative. The technique is relatively simple, and morbidity from PGMF harvest
      is minimal.

PMID- 15192571
TI  - Effect of lignocaine injection in carotid sinus on baroreceptor sensitivity
      during carotid endarterectomy.
AB  - OBJECTIVES: This study was undertaken to test the hypothesis that there is a
      neural basis for baroreceptor deterioration during carotid endarterectomy (CEA),
      by investigating intraoperative hemodynamic changes induced by intraluminal
      carotid stretch stimulation, before and after application of local anesthetic to
      the adventitial layer of the carotid sinus region. METHODS: This was a
      prospective study of 20 patients undergoing elective CEA. During CEA, before
      removal of the atheroma, intraluminal stretch simulation of the carotid
      baroreceptors (rub test) was performed before and after injection of 1%
      lignocaine into adventitial tissue of the artery in the region of the carotid
      sinus. Continuous measurements of mean arterial blood pressure (MAP),
      electrocardiographic r-r intervals (R-R), heart rate, cardiac vagal tone, and
      carotid sinus baroreflex were recorded to determine alterations in baroreceptor
      function. RESULTS: Rub test before injection of lignocaine was associated with a
      decrease in MAP and heart rate and an increase in R-R, cardiac vagal tone, and
      carotid baroreflex response, indicating a functioning baroreflex. After
      lignocaine injection and repetition of the rub test, no significant change was
      seen in MAP, heart rate, R-R, cardiac vagal tone, or carotid baroreflex response,
      indicating a nonfunctioning baroreflex. Comparing the peak responses to the rub
      test stimulus before and after lignocaine injection showed significant
      differences for all variables (P <.05), with carotid baroreflex response and
      heart rate being highly significant (P <.0005). CONCLUSIONS: The baroreflex
      response to intraluminal stretch stimulation of the carotid sinus area is
      operational in patients undergoing CEA, and this response is abolished by
      infiltration of local anesthetic into the periadventitial tissue around the
      carotid sinus.

PMID- 15192570
TI  - Neuropathic pain after femoropopliteal bypass surgery.
AB  - OBJECTIVE: This retrospective study was performed to investigate prolonged
      postoperative pain in the area of the proximal or distal scar or the bypass
      tunnel after femoropopliteal bypass surgery to treat symptomatic peripheral
      arterial disease. PATIENTS AND METHODS: Ninety-three patients with peripheral
      arterial disease who underwent femoropopliteal bypass surgery between January
      2000 and December 2002 were included in the study. The short-form McGill Pain
      Questionnaire was used to score pain. Ultrasound examination of the soft tissue
      around the graft was performed to exclude other pathologic conditions responsible
      for pain, such as inflammatory processes, perigraft reactions, swollen lymph
      nodes, and hematomas. RESULTS: Pain in at least one scar existed in 22 patients
      on average 13.9 +/- 9.8 months after surgery. In 10 patients pain existed
      simultaneously along the inguinal scar and the above-knee or below-knee scar.
      Pain along the bypass tunnel was experienced by seven patients. Most patients had
      mild to moderate pain. The mean numeric ranking score of pain severity in
      patients with pain was 4.2 +/- 2.3. The occurrence of prolonged postoperative
      pain was not associated with age, gender, diabetes, indication for surgery,
      material or type of bypass, number of preceding operations, or postoperative
      wound complications. Only follow-up time after femoropopliteal bypass surgery
      tended to be lower in patients with pain compared with those without pain.
      CONCLUSION: Prolonged postoperative neuropathic pain along the distal and
      proximal incision or the bypass tunnel exists in one fourth of patients after
      femoropopliteal bypass surgery. Patients should be informed of this kind of
      complication before surgery. The results of our study justify further
      investigations of the origin and treatment of this pain, to find effective
      methods to reduce the incidence of prolonged postoperative pain after
      femoropopliteal bypass surgery.

PMID- 15192572
TI  - Perioperative stress response to carotid endarterectomy: the impact of anesthetic
      modality.
AB  - OBJECTIVE: Surgery for extracranial carotid artery disease has been challenged by
      carotid angioplasty stenting because the latter is less invasive and avoids
      surgical trauma. In fact, the magnitude of the perioperative stress response
      evoked by carotid endarterectomy (CEA) has never been evaluated. Our aim was to
      determine the degree of surgical trauma caused by CEA and to define differences
      related to the use of locoregional or general anesthesia. METHODS: We
      prospectively studied 113 consecutive CEAs performed on 109 patients admitted at
      a community institutional center. Patients were stratified for demographics and
      risk factors and operated on under locoregional (LA) or general anesthesia (GA)
      depending on both the surgeon preference and patient's compliance. Selective
      carotid shunting was performed for patients who manifested neurologic deficits
      under LA or had stump pressure values </=30 mm Hg under GA. Markers of the stress
      response, including cortisol, adrenocorticotropic hormone, prolactin, and C
      reactive protein, were measured intraoperatively, before and after carotid artery
      cross-clamping (CACC), and postoperatively up to the third day after surgery.
      Hemodynamic variability was assessed during surgery and for 24 hours
      postoperatively. Operative times were also measured. Surgeons were considered as
      independent variables for stress response. Statistics were run by means of
      nonparametric tests and univariate and multivariate analysis with a linear
      regression model. RESULTS: CEA was performed under GA in 63 cases (55.8%) and
      under LA in 50 (44.2%). The two groups were comparable in terms of demographics
      and risk factors. Intraoperatively, cortisol and adrenocorticotropic hormone
      levels were significantly higher in the LA group (both P <.001). CACC increased
      the intraoperative cortisol levels in both the GA (P =.019) and the LA groups (P
      =.006). However, in patients who underwent carotid shunting, this effect was
      abolished (GA group, P =.779; LA group, P = 1.0). During the early postoperative
      period there was no difference between the two groups. On postoperative day 1 the
      stress response was abolished in both groups. Prolactin levels increased
      intraoperatively in both the LA and GA groups and returned within preoperative
      values on postoperative day 1. Prolactin levels were higher in the GA group (P
      =.003 intraoperatively and P <.001 postoperatively). C-reactive protein
      significantly increased in both GA and LA groups on postoperative days 1 and 2
      and started to decrease on day 3 with no differences between the two groups at
      any time. Hemodynamic variability and considered risk factors including
      individual surgeon were not significant variables. Gender-related differences
      were found only in prolactin secretion. The length of surgery had an impact for
      procedures that lasted >120 minutes. Three patients experienced an intraoperative
      neurologic event and had higher post-CACC cortisol values as compared to
      asymptomatic patients. CONCLUSIONS: Intraoperative surgical stress was higher
      under LA and was blunted by carotid shunting under both LA and GA. Within 2 hours
      after surgery the anesthetic modality no longer had any impact on surgical
      trauma. The stress response to CEA, regardless of the type of anesthesia, was
      abolished within 24 hours. Intraoperative stress response, namely
      hypercortisolemia, directly correlated with subclinical and clinical cerebral
      hypoperfusion/ischemia during CACC. Hence, attenuation of the stress response to
      CEA might decrease the incidence of cerebral ischemic events.

PMID- 15192573
TI  - Interpretation of three-dimensional structure from two-dimensional endovascular
      images: implications for educators in vascular surgery.
AB  - PURPOSE: Endovascular therapy has had a major effect on vascular surgery;
      surgeons perform tasks in three dimensions (3D) while viewing two-dimensional
      (2D) displays. This fundamental change in how surgeons perform operations has
      educational implications related to learning curves and patient safety. We
      studied the effects of experience, training, and visual-spatial ability on 3D
      perception of 2D angiographic images of abdominal aortic aneurysms (AAA).
      METHODS: A novel computer-based method was developed to produce 3D depth maps
      based on subjects' interpretations of 2D images. Seven experts (certified
      vascular surgeons) and 20 novices (medical or surgical trainees) were presented
      with a 2D AAA angiographic image. With software specifically designed for this
      study, a depth map representing each subject's 3D interpretation of the 2D
      angiogram was produced. The novices were then randomized into a control group and
      a treatment group, who received a 5-minute AAA anatomy educational session. All
      subjects repeated the exercise on a second AAA image. Finally, all novices were
      given tests of visual-spatial ability, including the Surface Development Test and
      the Mental Rotations Test. Comparisons between experts and novices were made with
      depth map comparison, a subject's perception of overall object contour. RESULTS:
      The depth maps were significantly different (depth map comparison, P <.001)
      between the expert and both novice groups for the first image. After the
      educational intervention, the control group and the treatment group exhibited
      significantly different depth maps (depth map comparison, P <.001), with
      treatment group depth maps more similar to those of the expert group. There were
      no significant correlations between the visual-spatial tests and the novice depth
      map comparison with the expert group. CONCLUSIONS: This is the first study to
      examine perception of endovascular images in an educational context. Perception
      of overall surface contour of 3D structures from 2D angiographic images is
      affected by experience and training. With application of methods of vision
      science to an important problem in surgery, this research represents a first step
      in understanding the nature of visual perceptual processes involved in execution
      of an increasingly common clinical task. These results have implications for
      understanding and studying the endovascular learning curve. CLINICAL RELEVANCE:
      This research represents a unique collaboration in an effort to understand and
      solve one of the greatest problems facing surgical educators and surgeons. This
      research uses applied tools in vision science to understand the perceptual
      constraints involved in minimally invasive surgery. Specifically, we examined the
      mental three-dimensional maps experts use when viewing two-dimensional displays.
      Furthermore, we compared experts with novices in an effort to assist surgical
      trainees.

PMID- 15192574
TI  - Continuous periaortic infusion improves doxycycline efficacy in experimental
      aortic aneurysms.
AB  - OBJECTIVE: We created a novel continuous infusion system to evaluate the efficacy
      of juxta-aortic doxycycline delivery as a transitional step toward developing
      hybrid drug/device treatment strategies for abdominal aortic aneurysm (AAA)
      disease. METHODS: Controlled comparison of treatment outcomes was studied in
      animal models with molecular and morphologic tissue analysis in a collaboration
      between university and corporate research laboratories. Rat AAAs were created via
      porcine pancreatic elastase (PPE) infusion and grouped and analyzed by subsequent
      treatment status (either doxycycline in vehicle or vehicle alone) and drug
      delivery method (continuous infusion via periaortic delivery system [PDS] or
      twice-daily subcutaneous injection). The main outcome measures were AAA diameter
      via direct measurement, medial elastin lamellar preservation via light
      microscopy, mural smooth muscle cell (SMC) proliferation and SMC and macrophage
      density via immunostaining and counting, expression of matrix metalloproteinases
      2, 9, and 14 and tissue inhibitors of metalloproteinases 1 and 2 via real-time
      reverse transcriptase-polymerase chain reaction, and enzymatic activity via
      substrate zymography. Serum drug levels were analyzed via liquid
      chromatography/mass spectroscopy. RESULTS: PDS (1.5 mg/kg/day) and subcutaneous
      (60 mg/kg/day) delivery methods caused comparable reductions in AAA diameter
      during the period of 14 days after PPE infusion. PDS rats gained more weight
      during the postoperative period (P <.001), possibly as a result of reduced serum
      drug levels and systemic toxicity. Doxycycline treatment reduced AAA macrophage
      infiltration and SMC proliferation significantly. Despite reduced diameter,
      circumferential elastic lamellar preservation was not apparent in doxycycline
      treated AAAs. CONCLUSIONS: Continuous periaortic infusion lowers the effective
      doxycycline dose for experimental AAA limitation. Alternative biologic inhibition
      strategies might also be amenable to direct intra-aortic or juxta-aortic
      delivery. Periaortic infusion might improve the clinical outcome of minimally
      invasive AAA treatment strategies. Clinical relevance Aneurysm remodeling may
      continue after successful endovascular AAA exclusion. Continued proteolytic
      activity within the aneurysm wall potentiates late graft migration and failure.
      The doxycycline infusion system developed in these experiments may serve as a
      prototype for adjuvant treatment modalities that complement endovascular AAA
      exclusion. Local delivery of doxycycline or other agents active in AAA disease,
      either continuously or at selected intervals after graft implantation, may
      stabilize the wall and aid in maintaining aneurysm exclusion. Alternative
      delivery methods could include passive diffusion from either the graft material
      itself or treatment reservoirs incorporated into endografts. Given the recognized
      limitations of current technologies, adjuvant biologic therapies have the
      potential to improve long-term patient outcome significantly after endovascular
      exclusion.

PMID- 15192575
TI  - Small-caliber heparin-coated ePTFE grafts reduce platelet deposition and
      neointimal hyperplasia in a baboon model.
AB  - PURPOSE: Intimal hyperplasia and graft thrombosis are major causes of graft
      failure. Heparin prolongs graft patency and inhibits neointimal hyperplasia in
      animal models. The purpose of this study was to evaluate the effect of a heparin
      coated expanded polytetrafluoroethylene (ePTFE) graft on platelet deposition and
      anastomotic neointimal hyperplasia after aortoiliac bypass grafting in a baboon
      model. METHODS: Heparin-coated ePTFE grafts (4-mm diameter) were incorporated
      into exteriorized femoral arteriovenous shunts placed in five baboons. Platelet
      deposition was analyzed by measuring the accumulation of indium 111-labeled
      platelets on the grafts, with dynamic scintillation camera imaging. Eight adult
      male baboons (mean weight, 9.3 kg) underwent bilateral aortoiliac bypass grafting
      with ePTFE grafts (4-mm internal diameter). In each animal a heparin-coated ePTFE
      graft was placed in one aortoiliac artery, and an uncoated graft, which served as
      the control, was placed in the contralateral aortoiliac artery. All grafts were
      harvested at 4 weeks, and were analyzed quantitatively for neointimal hyperplasia
      at graft-vessel anastomoses. RESULTS: Early platelet deposition on heparin-coated
      grafts after 1 to 4 hours of ex vivo circuitry was significantly reduced. All the
      harvested aortoiliac grafts were patent at 4 weeks. There was a significant
      reduction in neointimal area at both proximal (0.26 +/- 0.11 mm(2)) and distal
      (0.29 +/- 0.14 mm(2)) anastomoses in the heparin-coated grafts, compared with
      proximal (0.56 +/- 0.18 mm(2)) and distal (0.63 +/- 0.21 mm(2)) anastomoses in
      the untreated control grafts (P <.05). In addition, neointimal cell proliferation
      assayed with bromodeoxyuridine (BrdU) incorporation was reduced in the graft
      neointima (3.47% +/- 0.43%) in heparin-coated grafts compared with the graft
      neointima (6.21% +/- 0.59%) in untreated control grafts (P <.05). CONCLUSIONS:
      Small-caliber heparin-coated ePTFE grafts significantly reduce platelet
      deposition and anastomotic neointimal hyperplasia and cell proliferation, without
      measurable side effects, in baboons. Surface coating with heparin in small
      caliber ePTFE grafts is useful for improving prosthetic bypass graft patency.
      CLINICAL RELEVANCE: An autologous vein graft is the ideal bypass conduit in
      peripheral arterial reconstruction; however, many patients who undergo bypass
      grafting do not have adequate or available autologous vein graft. As a result
      surgeons often must rely on prosthetic grafts as an alternative conduit in
      arterial bypass procedures. Clinical outcomes with prosthetic grafts in
      peripheral arterial reconstruction are generally inferior to those with
      autologous vein bypass grafts, in part because of anastomotic neointimal
      hyperplasia. This study evaluated the effect of small-caliber heparin-coated
      expandable polytetrafluoroethylene (ePTFE) grafts in aortoiliac reconstruction in
      a baboon model. The study found that heparin-coated ePTFE grafts resulted in less
      intimal hyperplasia and less platelet deposition after implantation, compared
      with noncoated control ePTFE grafts.

PMID- 15192576
TI  - Hypertension-induced venous valve remodeling.
AB  - INTRODUCTION: In human beings, chronic venous insufficiency is linked to venous
      hypertension. This in turn is associated with venous valve incompetence. This
      study was designed to test the hypothesis that venous hypertension serves to
      initiate a process that results in the venous valve and venous wall damage
      observed in venous insufficiency. Material and methods Acute venous hypertension
      was produced by creation of an arteriovenous (AV) fistula between the femoral
      artery and vein in Wistar rats. At specified intervals pressure in the veins was
      recorded. The proximal valve containing saphenous vein was exposed, and reflux
      was measured from reverse blood flow through the first proximal valve. The vein
      was excised, valve parameters were measured, a portion was taken for morphologic
      investigation, and the remaining specimen was frozen in liquid nitrogen for
      investigation of leukocyte infiltration, expression of adhesion molecules, matrix
      metalloproteinase (MMP) levels, and apoptotic markers. Contralateral
      nonpressurized saphenous veins were used as control specimens. RESULTS: The
      saphenous and femoral veins were immediately distended by pulsatile blood flow
      from the arterial system. Pressure was significantly increased from 11 +/- 2 mm
      Hg to 94 +/- 9 mm Hg. At 2 days no reflux was detected in the saphenous veins. At
      1 week, one of four rats exhibited reflux; at 2 weeks, two of four rats had
      reflux; and at 3 weeks, three of four rats showed reflux. Contralateral saphenous
      veins were uniformly competent. Compared with control specimens, the veins were
      dilated; leaflet length and leaflet width were significantly reduced.
      Granulocytes, monocytes, and macrophages were identified in all regions of the
      vein wall, and the number was increased by the presence of the AV fistula. The
      number of T-lymphocytes was increased, and B-lymphocytes were present. P-selectin
      was upregulated in the saphenous vein walls, as was intercellular adhesion
      molecules. MMP-2 and MMP-9 expression in the veins was not enhanced. In the
      nuclear factor kappabeta family, Ikappabeta was not increased in any hypertensive
      veins. The number of apoptotic cells in the vein wall was increased in the
      presence of the AV fistula. CONCLUSION: This study indicates that acute venous
      hypertension is accompanied by significant venous distention and some valve
      damage as early as 3 weeks after fistula creation. There is development of
      inflammatory markers, with leukocyte infiltration and increased adhesion molecule
      expression. We could not detect significant enhancement of MMP levels or nuclear
      transcription factors. It is uncertain whether this lack of evidence may be
      partially due to enhanced apoptosis in venous valves and vein walls. A detailed
      definition of the inflammatory reaction produced by venous hypertension should be
      the subject of further study. Clinical relevance Saphenous vein valves when
      observed at the time of vein stripping show deformities of shortening, scarring,
      and tearing. The current model of induced venous hypertension demonstrates early
      venous valve changes similar to those observed in human beings and links them to
      a venous hypertension-induced inflammatory reaction. Thus the model could be
      useful in pharmacologic testing to prevent or treat venous insufficiency and for
      defining the fundamental mechanisms that cause varicose veins.

PMID- 15192577
TI  - Management of carotid injuries in a hostile neck using endovascular grafts.
AB  - Pseudoaneurysms and iatrogenic injuries of the extracranial carotid artery are
      not common but represent unique operative challenges with associated high
      morbidity and mortality. We report two cases in which a Wallgraft was used via
      percutaneous femoral access to treat such injuries. In the first, a 6-cm carotid
      pseudoaneurysm was successfully excluded by coil embolization of the external
      carotid artery and stent grafting across the carotid bifurcation. In the second
      case, an endovascular graft was used to treat an intraoperative common carotid
      injury in a re-operated, radiated neck. These cases demonstrate the utility of
      endovascular graft treatment of emergent carotid injuries.

PMID- 15192578
TI  - Acute lower extremity ischemia in a 7-year-old boy: an unusual case of popliteal
      entrapment syndrome.
AB  - Popliteal artery entrapment syndrome is a rare cause of acute limb ischemia that
      most commonly is seen in young adults. The most significant complications
      associated with popliteal entrapment include aneurysm formation and acute
      thrombosis. This case presents the youngest patient ever reported with this
      syndrome and highlights the advantages of multimodal treatment including
      thrombolysis, popliteal aneurysm resection, and revascularization. Although a
      significant body of literature exists on popliteal entrapment syndrome in
      teenagers and young adults, it has not been reported previously in a patient
      younger than 11 years. Limb salvage was achieved in this patient with a
      combination of endovascular and surgical techniques.

PMID- 15192579
TI  - Aortitis and bilateral ureteral obstruction after endovascular repair of
      abdominal aortic aneurysm.
AB  - A bifurcated stent graft was used to treat an asymptomatic 5.4-cm abdominal
      aortic aneurysm in a 76-year-old man. No endoleaks or inflammatory changes were
      seen on the 1-month follow-up computed tomography scan. Five months later the
      patient had acute renal failure and ureteral obstruction secondary to significant
      inflammatory changes in the aneurysm wall. After bilateral ureteral stenting,
      conservative treatment included tamoxifen and steroid therapy. The patient
      remains symptom-free, and at 2-year follow-up a computed tomography scan
      demonstrated decreased inflammation and shrinkage of the excluded abdominal
      aortic aneurysm.

PMID- 15192580
TI  - Surgical resection of a large recurrent pelvic arteriovenous malformation using
      deep hypothermic circulatory arrest.
AB  - Transcatheter embolization has emerged as the treatment of choice for pelvic
      arteriovenous malformations (AVMs), because surgical resection may be difficult
      and is associated with a high recurrence rate. We report a patient with a large
      recurrent pelvic AVM in whom transcatheter embolization was not feasible. This
      patient underwent surgical resection of the AVM, which was accomplished with deep
      hypothermic circulatory arrest. Early postoperative angiography demonstrated a
      small amount of residual AVM, which was successfully embolized with microcoils.
      Follow-up magnetic resonance angiography at 2 months showed no residual AVM. In
      cases where surgical resection of an extensive AVM is required, deep hypothermic
      circulatory arrest offers the distinct advantages of performing the resection in
      a bloodless field and enabling adequate visualization of important adjacent
      structures.

PMID- 15192581
TI  - Cystic adventitial disease of the popliteal artery.

PMID- 15192582
TI  - Caution in signing nondisclosure contracts.

PMID- 15192583
TI  - Ethics of boutique medical practice.

PMID- 15192592
TI  - Regarding "Use of abdominal aortic endovascular prostheses in France from 1999 to
      2001".

PMID- 15192608
TI  - Influencing career decisions in pediatrics.

PMID- 15192609
TI  - Perfecting practice guidelines.

PMID- 15192610
TI  - Site of care for the treatment of cystic fibrosis exacerbations: does it matter?

PMID- 15192611
TI  - In search of the optimal therapy for congenital hypothyroidism.

PMID- 15192612
TI  - Traumatic intracranial injuries can be clinically silent.

PMID- 15192613
TI  - Decreasing overuse of therapies in the treatment of bronchiolitis by
      incorporating evidence at the point of care.
AB  - OBJECTIVE: To describe the effect of evidence-based point-of-care algorithms and
      rules, based on guideline recommendations, on the overuse of therapies for
      bronchiolitis. Study design Pre-postintervention for infants <1 year of age
      admitted with a first-time episode of bronchiolitis. Data collected for guideline
      eligible patients discharged between January 15, 2002, and March 27, 2002, were
      compared with data collected for guideline-eligible patients discharged from the
      hospital with a diagnosis of bronchiolitis during the same time period in the
      first 5 years after the original guideline implementation (1997 to 2001). The
      primary outcome of interest was use of bronchodilator therapy. Secondary outcomes
      included use of guideline order sets, resource utilization, length of stay, and
      readmission. RESULTS: A total of 256 patients from 2002 were compared with 1272
      historic patients. In 2002, the odds of receiving any bronchodilator, more than
      1, more than 2, and more than 4 bronchodilators were all significantly less than
      predicted by the 1997 to 2001 year-to-year trend. The odds of receiving a
      nasopharyngeal wash for respiratory syncytial virus and a chest radiography
      (OR=0.680, CL=0.476, 0.973) were also significantly lower than what was predicted
      from use trends of previous years. CONCLUSIONS: Evidence-based point-of-care
      instruments can have a significant effect on unwarranted treatment variation.

PMID- 15192614
TI  - The impact of treatment of pulmonary exacerbations on the health-related quality
      of life of patients with cystic fibrosis: does hospitalization make a difference?
AB  - OBJECTIVES: To investigate the impact of pulmonary exacerbations on the health
      related quality of life (HRQOL) of patients with cystic fibrosis (CF) and to
      elucidate factors that are associated with changes in HRQOL post-exacerbation.
      STUDY DESIGN: Participants completed questionnaires at a pre-exacerbation visit,
      at the beginning of the exacerbation, and at the post-exacerbation visit. To
      measure HRQOL, we used the Child Health Questionnaire-Parent Form (PF-50) and the
      Medical Outcomes Study Short Form-36 (SF-36). We examined demographic, clinical,
      and treatment-related predictor variables for association with change in Physical
      Summary (PhS) and Psychosocial Summary (PsS) HRQOL scores after an exacerbation.
      RESULTS: We collected data from 48 subjects. Patients experiencing exacerbations
      who were treated as outpatients had a mean (SD) age of 19.5 (12.7) years and a
      mean pre-exacerbation forced expiratory volume in 1 second (FEV(1)) of 70% (36%)
      of predicted; 53% were female. Patients treated as inpatients had a mean age of
      14.6 (5.5) years and a mean FEV(1) of 56% (24%); 56% were female. In univariate
      analyses, exacerbations were associated with a statistically significant decrease
      in FEV(1) (-10.0%) and PhS scores (-4.5 points). PsS scores did not significantly
      change with exacerbations (-0.7 points). In multivariable analyses examining
      change between pre-exacerbation and post-exacerbation visits, no variables were
      significantly associated with change in PhS scores. However, not being
      hospitalized for the exacerbation was associated with deterioration in PsS
      scores, and being hospitalized was associated with improvement in PsS scores
      (beta coefficient: 9.4; P <.01) by the post-exacerbation visit. Results were
      similar from the exacerbation to the post-exacerbation visit. CONCLUSION: In
      patients with CF, on average, pulmonary exacerbations affect physical HRQOL more
      than psychosocial HRQOL. Being hospitalized for exacerbations is associated with
      improvement in psychosocial HRQOL after exacerbations, whereas not being
      hospitalized is associated with deterioration.

PMID- 15192615
TI  - Occult head trauma in young suspected victims of physical abuse.
AB  - OBJECTIVES: To determine the frequency of neuroimaging and ophthalmology consults
      in children evaluated for physical abuse without neurologic symptoms and the
      diagnostic yield of these studies. STUDY DESIGN: Records of neurologically
      asymptomatic patients younger than 48 months evaluated with a skeletal survey at
      two academic medical centers were reviewed for frequency of CT or MRI and
      ophthalmology consults, the results of these tests, and factors associated with
      given evaluations. Factors associated with positive findings during evaluation
      were also analyzed. RESULTS: Fifty-one patients had a skeletal survey and no
      clinical signs of intracranial injury. Seventy-five percent of patients had CT or
      MRI; 69% had formal evaluation for retinal hemorrhages. Twenty-nine percent had
      evidence of intracranial injury without neurologic symptoms. Age less than 12
      months was the only factor significantly associated with neuroimaging (90% vs
      55%, P=.004). Sex, race, insurance, and having an unrelated male caretaker were
      not significantly associated with performance of neuroimaging or findings of
      intracranial injury. CONCLUSIONS: Age less than 1 year was the only significant
      factor associated with the diagnostic evaluation. Neither retinal hemorrhage nor
      historic factors were sensitive markers for abnormalities found by neuroimaging.
      Clinicians should have a low threshold for neuroimaging when physical abuse is
      suspected in a young child.

PMID- 15192616
TI  - Relation of per capita income and gross domestic product to the supply and
      distribution of pediatricians in the United States.
AB  - OBJECTIVE: To describe the number and distribution of pediatricians per child
      nationally and on a state-by-state basis relative to the economic conditions
      within each state. STUDY DESIGN: Real inflation-adjusted gross domestic product
      (GDP) per capita (1996 dollars) was plotted against the number of all active
      physicians and pediatricians in the United States for all years data were
      available. GDP was then compared with the active number of pediatric medical
      physicians per child 0 to 14 years of age. RESULTS: The number of pediatricians
      per 100000 children has more than doubled, from 49.8 to 106.2. Since 1929, the
      growth in the total number of physicians per capita in the United States has
      followed a linear relation (r(2)=0.977) with per capita national GDP. This
      relation is consistent with that specifically for all pediatricians as well
      (r(2)=0.980) for the years in which data are available (1963 to 2000). There is
      an extremely uneven distribution of pediatricians. Income differences only
      partially explain this maldistribution. CONCLUSIONS: There has been a marked
      increase in the number of pediatricians relative to the number of children in the
      United States, correlating strongly with the rise in per capita GDP. However,
      there has been a furthering of their uneven distribution across the United
      States.

PMID- 15192617
TI  - Outcome after pediatric liver transplantation impact of living donor
      transplantation on cost.
AB  - OBJECTIVE: To compare the direct health care cost of living donor liver
      transplantation (LDLT) with that of cadaver donor liver transplantation (CDLT) in
      children and identify predictors of cost. STUDY DESIGN: All 16 children who
      underwent LDLT from January 1997 through January 2002 at Cincinnati Children's
      Hospital Medical Center comprised the study population. They were matched for
      age, diagnosis, and nutritional status with 31 children who received CDLT during
      the same era. A historic cohort analysis was performed. RESULTS: There was no
      difference in the 1-year mortality rates between both groups. Costs associated
      with graft retrieval contributed 15.3% and 31% of the initial transplant cost for
      LDLT and CDLT, respectively. Mean cost of care in the first year was 60.3% higher
      for LDLT than CDLT (P=.01). Multivariate analysis identified biliary
      complications and insurance status as predictors of cost for initial
      transplantation (R(2)=0.57), whereas biliary complications and pediatric end
      stage liver disease scores were identified as predictors of cost of care in the
      first year after transplantation (R(2)=0.77). CONCLUSIONS: The comprehensive cost
      of LDLT in the first year after transplantation is higher than cadaveric
      transplantation. This must be balanced against the time spent and care needs of
      patients on the waiting list.

PMID- 15192618
TI  - Suppression of adrenal function in children with acute lymphoblastic leukemia
      following induction therapy with corticosteroid and other cytotoxic agents.
AB  - OBJECTIVE: To evaluate adrenal function in children with acute lymphoblastic
      leukemia (ALL) after induction therapy with corticosteroid and other cytotoxic
      agents. Study design Children with ALL (N=24) were treated with prednisolone (40
      mg/m(2) per day) for 28 days during the induction phase followed by 1 week of
      oral dexamethasone every 4 weeks. A low-dose (1 microg) adrenocorticotropin
      (ACTH) test was performed 2 weeks after discontinuation of prednisolone; it was
      repeated 2 weeks later and then every 4 weeks in patients with adrenal
      suppression until normal response was achieved. RESULTS: Adrenal suppression was
      found in 46% of patients at 2 weeks after discontinuation of prednisolone; it
      persisted in 38%, 29%, and 13% of patients through 4 weeks, 8 weeks, and 20
      weeks, respectively. Adrenal suppression appeared to last significantly longer in
      children aged >or=5 years than in children aged <5 years. Four children developed
      febrile neutropenia; all belonged to the adrenal suppressed group and were unable
      to mount an adequate adrenal response to the stress. CONCLUSIONS: About 50% of
      children with ALL developed adrenal suppression 2 weeks after a 4-week induction
      therapy with prednisolone. The suppression could persist through 20 weeks and may
      hinder an adequate adrenal response during acute febrile illness.

PMID- 15192620
TI  - Psychological adjustment in children and adults with congenital adrenal
      hyperplasia.
AB  - OBJECTIVE: To determine psychological health in individuals with one form of
      intersexuality, congenital adrenal hyperplasia (CAH), and its relation to
      characteristics of the disease and treatment. STUDY DESIGN: Participants (ages 3
      31 years) included 72 females and 42 males with CAH, and unaffected relatives (44
      females and 69 males). Psychological adjustment was assessed with parent-reports
      on the Child Behavior Checklist (CBCL) and subject self-reports on the Self-Image
      Questionnaire for Young Adolescents (SIQYA) or the Multidimensional Personality
      Questionnaire (MPQ). Information about disease characteristics and genital
      surgery was obtained from medical records. RESULTS: There were no significant
      differences between females with CAH and unaffected females on any measure.
      Psychological adjustment was not significantly associated with genital
      virilization or age at genital surgery. Males with CAH were not significantly
      different from unaffected males in childhood, but they showed more negative
      affect at older ages. CONCLUSIONS: Psychological adjustment is not compromised in
      females with virilized genitalia who are treated early in life and reared as
      females. Adjustment does not appear to depend on the characteristics of the
      disease or its treatment, but sample size and restricted range limit
      generalizability about adjustment-disease associations.

PMID- 15192621
TI  - Cognition and behavior at school entry in children with congenital hypothyroidism
      treated early with high-dose levothyroxine.
AB  - OBJECTIVE: To document cognition and behavior at school entry in these patients.
      Study design Eighteen children with congenital hypothyroidism (CH; 9 severe and 9
      moderate, based on a surface of the knee epiphyses at diagnosis<or >or=0.05
      cm(2)) treated from a median of 14 days with a median of 12.0 microg/kg per day
      of levothyroxine were evaluated at 5 years, 9 months, with the McCarthy Scale and
      the Questionnaire for Evaluation of Social Behavior, as were 40 control children.
      RESULTS: The global IQs at 5 years, 9 months, were similar: medians (range) were
      102 (87 to 133), 102 (84 to 135), and 115 (88 to 136) (not significant) for
      severe CH, moderate CH, and control children, respectively. The behavioral scores
      of CH children were within the normal range. However, the number of times when
      plasma TSH was >6.0 mIU/L during treatment was correlated positively with anxiety
      (P=.02) and inattention (P=.05), whereas the number of times TSH was <0.8 mIU/L
      was correlated with lower verbal scores (P=.05). CONCLUSIONS: Children with
      severe CH treated early with a high dose of levothyroxine have normal global
      development and behavior at school entry.

PMID- 15192622
TI  - Growth hormone and body composition in children younger than 2 years with Prader
      Willi syndrome.
AB  - OBJECTIVES: To assess body composition of infants with Prader-Willi syndrome
      (PWS) by using deuterium dilution and investigating the efficacy of early
      institution of growth hormone (GH) therapy in increasing lean mass (LM) and
      preventing massive obesity. STUDY DESIGN: One group of 11 children with PWS <2
      years before and during 30-month GH therapy (GH group) was compared with 6
      infants administered only coenzyme Q(10) for 1 year (Q10 group). LM adjusted for
      height (LM(Ht)) and relative fat mass (%FM(Age)) standard deviation scores (SDS)
      were calculated from data of 95 healthy children. RESULTS: Initially, LM(Ht) of
      all patients was below the normal average. LM(Ht) decreased by -0.46 +/- 0.3 SD
      (P=.03) per year in the Q10 group but rose by 0.25 +/- 0.3 SD (P=.02) per year
      during GH therapy, normalizing after 30 months (-0.70 +/- 1.0 SD). Despite low to
      normal weight for height (WfH), %FM(Age) was above the normal average (GH group,
      31.0% +/- 4.5%, Q10 group, 32.4% +/- 9.5%). In the Q10 infants, %FM(Age)
      increased by 0.71 +/- 0.7 SD per year, whereas in the GH group, %FM(Age) remained
      more stable up to 30 months. CONCLUSIONS: Diminished LM(Ht) found in infants with
      PWS further declines during the early years. Early institution of GH therapy
      lifts LM(Ht) into the normal range and delays fat tissue accumulation.

PMID- 15192623
TI  - Long-term clinical outcome of infants with mild and moderate fetal pyelectasis:
      validation of neonatal ultrasound as a screening tool to detect significant
      nephrouropathies.
AB  - OBJECTIVE: To assess the long-term outcome of infants with mild and moderate
      fetal pyelectasis and to determine the predictive value of neonatal ultrasound
      imaging in identifying significant nephrouropathies. STUDY DESIGN: This
      prospective study included 213 infants with antenatal mild to moderate
      pyelectasis who were followed for up to 2 years. Postnatal renal ultrasound
      examinations were performed at day 5 and months 1, 3, 6, 12 and 24 after birth.
      Voiding cystourethrography was performed in all infants. RESULTS: Normal or
      nonsignificant findings were diagnosed in 130 of 213 (61%) infants. Significant
      nephrouropathies were diagnosed in 83 of 213 (39%) infants. The sensitivity,
      specificity, positive predictive value, and negative predictive value of two
      successive neonatal renal ultrasound examinations performed at day 5 and 1 month
      to predict significant nephrouropathies were 96%, 76%, 72%, and 97%,
      respectively. In 102 of 213 (48%) infants with normal neonatal renal ultrasound
      scans, we later found only three of 102 (3%) cases with significant
      nephrouropathies. CONCLUSIONS: We found in a population of infants with mild to
      moderate fetal pyelectasis a 39% incidence of significant nephrouropathies.
      Ultrasound is an excellent screening tool with high sensitivity and negative
      predictive value that allows avoidance of unjustified medical follow-up in
      patients with two normal neonatal ultrasound scans.

PMID- 15192624
TI  - Severe obesity associated with cardiovascular deconditioning, high prevalence of
      cardiovascular risk factors, diabetes mellitus/hyperinsulinemia, and respiratory
      compromise.
AB  - OBJECTIVE: To determine the extent and severity of obesity-related
      cardiorespiratory morbidity in children with body mass index (BMI) >or=40
      kg/m(2). STUDY DESIGN: Cross-sectional analysis of a cohort comprised of 48 boys
      and girls aged 8 to 17 years with BMI >or=40 kg/m(2). Cardiorespiratory fitness
      (graded cycle exercise test), left ventricular (LV) mass (echocardiography),
      blood pressure, fasting lipid profile, fasting insulin, fasting glucose, HbA1c,
      and pulmonary function (spirometry and sleep studies) were measured. RESULTS: The
      cohort averaged 14.2 +/- 2 years of age with mean BMI of 45.5 kg/m(2). Only 2
      patients had normal fitness; 37 of 48 had peak oxygen consumption <20 mL
      O(2)/minute. Hypertension was present in 10 of 48 patients. Mean lipid values
      were: triglycerides 103 +/- 48 mg/dL, HDL cholesterol 41 +/- 10 mg/dL, and LDL
      cholesterol 108 +/- 26 mg/dL. Type II diabetes mellitus was diagnosed in 6
      patients. Mean fasting insulin was 31 +/- 19 microU/mL. Asthma treatment, small
      airways disease by pulmonary function testing, or both were present in 35 of 48
      patients; upper airway obstruction was present in 7 patients. LV hypertrophy was
      present in 8 patients, with a mean LV mass of 43 +/- 11 g/m(2.7). CONCLUSIONS:
      Children and adolescents with BMI >or=40 kg/m(2) have substantial
      cardiorespiratory morbidity including severe physical deconditioning.

PMID- 15192626
TI  - Lifestyle factors and the development of bone mass and bone strength in young
      women.
AB  - OBJECTIVE: To evaluate the contributions of adolescent calcium intake, oral
      contraceptive use, and exercise on bone mass and bone strength.Study design
      Eighty white women participated in 10 years of the Penn State Young Women's
      Health Study, a longitudinal study of community participants. We measured bone
      mineral mass (g), density (BMD, g/cm(2)), and body composition from dual energy x
      ray absorptiometry and estimated proximal femur section modulus (bone bending
      strength). Calcium intake was determined from 45 days of prospective food records
      at regular intervals between the ages of 12 and 22 years. Exercise history and
      oral contraceptive use were assessed by questionnaire. RESULTS: Daily calcium
      intakes between the ages of 12 and 22 years ranged from 500 to 1900 mg/d and were
      not significantly associated with bone gain or bone strength. Oral contraceptive
      use during adolescence was not correlated with bone or body composition
      measurements. Femoral neck BMD did not change from 17 to 22 years of age, but
      section modulus increased 3% (P <.05). Only exercise during adolescence was
      significantly associated with increased BMD and bone bending strength.
      CONCLUSIONS: Adolescent lifestyle patterns can influence young adult bone
      strength. Our data suggest that exercise is the predominant lifestyle determinant
      of bone strength for this cohort.

PMID- 15192625
TI  - Lack of accuracy of continuous glucose sensors in healthy, nondiabetic children:
      results of the Diabetes Research in Children Network (DirecNet) accuracy study.
AB  - OBJECTIVE: The workup of hypoglycemia requires frequent glucose sampling. We
      designed these studies to determine if the Continuous Glucose Monitoring System
      (CGMS) and the GlucoWatch G2 Biographer (GW2B) are sufficiently accurate to use
      in nondiabetic children. Study design Fifteen healthy children (aged 9-17 years,
      11 boys) wore a GW2B and a CGMS during a 24-hour period, and reference serum
      glucose was measured hourly during the day and half-hourly overnight. RESULTS:
      Compared with the reference glucose, the median absolute difference in
      concentrations measured by the GW2B (487 pairs) was 13 mg/dL, and the difference
      measured by the CGMS was 17 mg/dL (668 pairs), with 30% and 42% of values using
      the GW2B and CGMS, respectively, deviating >20 mg/dL from the reference value.
      The GW2B reported values <60 mg/dL in 73% of subjects, the CGMS in 60% of
      subjects. In none of these episodes was serum glucose truly low. Spurious high
      glucose concentrations also were observed with the sensors. The mean reference
      glucose was lowest at 5 am (89 mg/dL) and highest at 11:30 pm (106 mg/dL) during
      the 24-hour period. CONCLUSIONS: Neither the CGMS nor the GW2B is accurate enough
      to establish population standards of the glycemic profile of healthy children and
      cannot be recommended in the workup of hypoglycemia in nondiabetic youth.

PMID- 15192627
TI  - Cholesterol supplementation does not improve developmental progress in Smith
      Lemli-Opitz syndrome.
AB  - OBJECTIVE: Smith-Lemli-Opitz syndrome (SLOS) results in multiple malformations,
      growth deficiency, and mental retardation. Cholesterol supplementation has been
      used for several years to treat symptoms of SLOS. We assessed the developmental
      progress of children and adolescents with SLOS over a 6-year period. STUDY
      DESIGN: Patients with SLOS (n=14) received continuous cholesterol supplementation
      as part of a longitudinal study. Assessment of their developmental progress in
      the areas of cognitive, motor, and adaptive skills occurred every 6 to 12 months.
      The progress of each subject over time and the progress of the group as a whole
      were analyzed by using a repeated-measures design and multiple t tests. RESULTS:
      Developmental quotients did not improve over time for children with SLOS
      receiving cholesterol. In addition, baseline cholesterol levels, rather than age
      when supplementation began or increase in cholesterol levels, best predicted
      developmental outcome. CONCLUSIONS: These results suggest that cholesterol
      supplementation in its current form does not improve the developmental progress
      of children and adolescents with SLOS.

PMID- 15192628
TI  - Growth of pediatric intensive care units in the United States from 1995 to 2001.
AB  - OBJECTIVE: To describe the growth and distribution of pediatric intensive care
      unit (PICU) beds in the United States from 1995 to 2001 and the characteristics
      of PICUs in 2001. STUDY DESIGN: This was a cross-sectional survey of PICUs in
      1995 to 1996 and 2001 to 2002. RESULTS: There were 306 general PICUs in the
      United States in 1995 and 349 in 2001 (13.7% growth). In both survey periods,
      approximately half of the PICUs had <or=8 beds. The largest growth (34.4%) was in
      PICUs with >or=15 beds. There were 3899 PICU beds in 2001 (23.9% increase from
      1995), with a mean number of PICU beds per pediatric population (age <18 years)
      of 1/18542 in the United States (17.5% increase from 1995). There was an increase
      in the number of annual admissions, occupancy rate, length of stay, percentage
      intubated, mortality rate, and number of intensivists per PICU with increasing
      bed size. In 2001, 94% of PICUs had a pediatric intensivist on staff, and these
      specialists were in-house at night in 17% of all PICUs and in 30% of PICUs with
      >or=15 beds. CONCLUSIONS: The number of PICU beds is growing more rapidly than
      the rate of pediatric population growth. The impetus for this growth is unclear.

PMID- 15192629
TI  - Rehospitalization in the first year of life among infants with bronchopulmonary
      dysplasia.
AB  - OBJECTIVE: To describe rates and identify risk factors for rehospitalization
      during the first year of life among infants with bronchopulmonary dysplasia
      (BPD). STUDY DESIGN: This was a retrospective cohort study of infants born at a
      gestational age (GA) <33 weeks, between 1995 and 1999. BPD was defined as
      requirement of supplemental oxygen and/or mechanical ventilation at 36 weeks'
      corrected GA. The outcome was rehospitalization for any reason before first
      birthday. RESULTS: In the first year of life, 118 of 238 (49%) infants with BPD
      were rehospitalized, more than twice the rate of rehospitalization of the non-BPD
      population, which was 309 of 1359 (23%) (P=<.0001). No measured factor
      discriminated between those infants with BPD who were and were not
      rehospitalized, even when only rehospitalizations for respiratory diagnoses were
      considered. CONCLUSIONS: Among premature infants, BPD substantially increases the
      risk of rehospitalization during the first year of life. Neither demographic nor
      physiologic factors predicted rehospitalization among the infants with BPD. Other
      factors, such as air quality of home environment, passive smoking exposure,
      respiratory syncytial virus prophylaxis, breast-feeding status, and/or parenting
      and primary care management styles, should be examined in future studies.

PMID- 15192630
TI  - Early surfactant for neonates with mild to moderate respiratory distress
      syndrome: a multicenter, randomized trial.
AB  - OBJECTIVE: We studied the efficacy and safety of electively providing surfactant
      to preterm infants with mild to moderate respiratory distress syndrome (RDS) not
      requiring mechanical ventilation. STUDY DESIGN: A 5-center, randomized clinical
      trial was performed on 132 infants with RDS, birth weight >or=1250 grams,
      gestational age <or=36 weeks, postnatal age 4 to 24 hours, Fio(2) >or=40% for
      >or=1 hour, and no immediate need for intubation. Infants were randomly assigned
      to intubation, surfactant (Survanta, Ross Laboratories, Columbus, Ohio)
      administration, and expedited extubation (n=65) or expectant management (n=67)
      with subsequent intubation and surfactant treatment as clinically indicated. The
      primary outcome was duration of mechanical ventilation. RESULTS: Infants in the
      surfactant group had a median duration of mechanical ventilation of 2.2 hours
      compared with 0.0 hours for control infants, since only 29 of 67 control infants
      required mechanical ventilation (P=.001). Surfactant-treated infants were less
      likely to require subsequent mechanical ventilation for worsening respiratory
      disease (26% vs 43%, relative risk=0.60; 95% CI, 0.37, 0.99). There were no
      differences in secondary outcomes (duration of nasal continuous positive airway
      pressure, oxygen therapy, hospital stay, or adverse outcomes). CONCLUSIONS:
      Routine elective intubation for administration of surfactant to preterm infants
      >or=1250 grams with mild to moderate RDS is not recommended.

PMID- 15192631
TI  - Surfactant administration acutely affects cerebral and systemic hemodynamics and
      gas exchange in very-low-birth-weight infants.
AB  - OBJECTIVES: To determine whether surfactant administration affects cerebral and
      systemic hemodynamics and gas exchange in very low birth weight infants and to
      determine the predominant factor influencing changes in mean cerebral blood flow
      velocity (mCBFv) after surfactant instillation. STUDY DESIGN: Fourteen very low
      birth weight infants with respiratory distress syndrome had continuous monitoring
      of mCBFv, Paco(2), mean arterial blood pressure (MABP), and Pao(2) before,
      during, and after the second dose of surfactant. Peak values and relative changes
      of the 4 variables for 45 minutes after surfactant were calculated. Logistic
      regression was used to determine the predominant factor influencing changes in
      mCBFv after surfactant. RESULTS: Birth weight was 832 +/- 162 grams and
      gestational age was 25.7 +/- 1.5 weeks. The time from birth to monitoring was 6.9
      +/- 1.0 hours. Mean CBFv increased 75.7% +/- 51.6% after surfactant and peaked at
      14.4 +/- 5.9 minutes. Paco(2) was highly associated (OR=107.3, P <.0001) with
      mCBFv; as Paco(2) increased, mCBFv increased. In contrast, MABP (OR=6.7, P=.047)
      had less impact on mCBFv. Pao(2) was not associated with mCBFv. CONCLUSIONS: The
      increases in mCBFv after surfactant administration were predominantly due to
      increases in Paco(2) and not changes in MABP.

PMID- 15192634
TI  - Enterobacter sakazakii is a rare cause of neonatal septicemia or meningitis in
      VLBW infants.
AB  - To determine the rates of Enterobacter sakazakii (ES) infections among very low
      birth weight infants, culture data from the National Institute of Child Health
      and Human Development Neonatal Research Network were reviewed. Only one case of
      ES sepsis was identified among 10660 neonates. These data suggest that outside of
      the epidemic situation, ES is very rare in very low birth weight infants.

PMID- 15192635
TI  - When body temperature changes, does rectal temperature lag?
AB  - By using temporal artery and rectal thermometers, we followed temperatures in 45
      febrile (>38.5 degrees C) infants given an antipyretic drug. Sixty and 90 minutes
      after drug administration, temporal artery temperatures had decreased
      significantly more than rectal temperatures. When body arterial temperature
      changes rapidly, changes in rectal temperature may lag.

PMID- 15192633
TI  - Ultrasound abnormalities preceding cerebral palsy in high-risk preterm infants.
AB  - OBJECTIVE: To assess sequential high-resolution cranial ultrasound (US) in high
      risk preterm infants to predict cerebral palsy (CP). STUDY DESIGN: Preterm
      infants were prospectively studied (n=2139), 1636 <or=32 weeks gestational age
      (GA) (group A) and 503 with a GA of 33 to 36 weeks (group B). US was performed
      once a week until discharge and at 40 weeks postmenstrual age (PMA), using a 7.5
      MHz transducer. Grade III and IV hemorrhage, cystic periventricular leukomalacia
      (c-PVL), and focal infarction were considered major US abnormalities. A diagnosis
      of CP was made at a minimum age of 24 months. RESULTS: Seventy-six (5%) of the
      1460 survivors in group A developed CP. US abnormalities were present in 70 of 76
      (92%) infants, being major in 58 (83%) and minor in 12 (17%). In 29% of the CP
      cases with major US abnormalities, cysts were first detected beyond day 28. A
      further 6 infants without US abnormalities developed CP, and 3 of these infants
      developed ataxic CP. Twenty-nine (6%) of the 469 survivors in group B developed
      CP. US abnormalities were present in 28 of 29 (96%) infants, being major in 25
      (89%) and minor in 3 (11%). One infant without US abnormalities developed CP.
      Considering the major US abnormalities, a specificity of 95% and 99% and a
      sensitivity of 76% and 86% were found for group A and B, respectively. The
      positive predictive value was 48% in group A and 83% in group B. CONCLUSION:
      Seventy-nine percent of our CP cases had major US abnormalities. To detect c-PVL,
      the most predictive US marker for CP, sequential scans with a 7.5-MHz transducer
      are required.

PMID- 15192636
TI  - Mild variant of nonketotic hyperglycinemia with typical neonatal presentations:
      mutational and in vitro expression analyses in two patients.
AB  - In neonatal-onset nonketotic hyperglycinemia, severe psychomotor retardation is
      the expected uniform outcome. We report two patients with typical neonatal
      presentation who showed far better developmental outcomes. The in vitro
      expression analysis of the identified GLDC mutations revealed considerable
      residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even
      in neonatal-onset nonketotic hyperglycinemia.

PMID- 15192637
TI  - Birth prevalence of homocystinuria.
AB  - Serious complications of homocystinuria caused by cystathionine beta-synthase
      deficiency can be prevented by early intervention. We determined the prevalence
      of 6 specific mutations in 1133 newborn blood samples. Our results suggest that
      homocystinuria is more common than previously reported. Newborn screening for
      homocystinuria through mutation detection should be further considered.

PMID- 15192639
TI  - Gastric polyps as a cause of vomiting.

PMID- 15192649
TI  - Plasma homocysteine levels in living kidney donors before and after
      uninephrectomy.
AB  - An increased prevalence of hyperhomocysteinemia has been observed among patients
      with end-stage renal disease, and numerous studies have demonstrated that kidney
      function is one of the most important determinants of plasma total homocysteine
      (tHcy) concentration. In an effort to understand the mechanism of
      hyperhomocysteinemia in renal disease, we chose, as our model, living kidney
      donors who had undergone uninephrectomy. We studied 10 living kidney donors and
      measured fasting plasma tHcy, plasma creatinine, folate, vitamins B(12) and B(6),
      and high-sensitivity C-reactive protein (hsCRP) 24 hours before nephrectomy and 2
      days, 6 weeks, and 6 months after nephrectomy compared to the values 24 hours
      before nephrectomy. Mean fasting tHcy and creatinine concentrations were
      significantly higher in donors 2 days, 6 weeks and 6 months after nephrectomy
      they were 24 hours before nephrectomy. Both the increases in tHcy levels 2 days
      after nephrectomy and subsequent decreases 6 weeks and 6 months after are
      paralleled by the changes in plasma creatinine values, although neither returned
      to its presurgery value. Decreases in tHcy are significantly correlated with
      decreases in creatinine values. The B vitamins were unchanged, and the hsCRP
      level was increased 2 days after surgery but had returned to the baseline level
      after 6 weeks. We conclude that tHcy and creatinine levels parallel each other
      after uninephrectomy and that the gradual decrease in tHcy is accounted for by
      hypertrophy of the remaining kidney. Our results, the first to be obtained from
      living kidney donors, support the hypothesis that renal metabolism of tHcy is the
      mechanism responsible for the correlation between renal function and plasma tHcy
      level.

PMID- 15192648
TI  - Metal contents of liver parenchyma after percutaneous ethanol injection or
      radiofrequency ablation in patients with hepatocellular carcinoma before and
      after trientine hydrochloride therapy.
AB  - We administered trientine hydrochloride, a drug used in the treatment of Wilson's
      disease, to patients with hepatocellular carcinoma after radical treatment with
      percutaneous ethanol injection or radiofrequency ablation, and examined its
      effect on the reduction of liver-tissue copper content. We enrolled 24 patients
      with 3 or fewer primary lesions of Child class A or B hepatocellular carcinoma
      with diameters of 3 cm or less who had undergone radical treatment with
      percutaneous ethanol injection or radiofrequency ablation. Trientine
      hydrochloride was orally administered in a single daily dose of 250 mg to 12
      patients before a meal (at fasting, group 1) or at a total daily dosage of 750
      mg, divided into 3 doses, to 12 patients (group 2). This study was a randomized
      between-groups comparative study of 12 weeks' duration. We used the particle
      induced x-ray-emission method to determine liver-tissue mineral content. Urine
      copper and serum mineral levels were also measured, and transaminase levels were
      examined. Liver-tissue copper content decreased significantly, to 160.1 microg/g
      dry weight, after treatment, compared with the pretreatment level of 306.8
      microg/g dry weight (P <.05). We detected no significant difference in iron or
      zinc content before and after treatment. The copper content was significantly
      reduced after treatment in both groups (P <.05). The urine copper level was
      significantly increased after 1 week of treatment but decreased thereafter. Serum
      copper levels were significantly reduced after treatment (P <.01). We detected no
      significant difference in transaminase level before and after treatment. Iron
      deficiency anemia in 1 patient after 12 weeks' treatment was the only adverse
      reaction, and it was improved by the administration of an iron product. We noted
      no other overt adverse reactions. In patients with hepatocellular carcinoma,
      trientine hydrochloride therapy may significantly reduce copper content in liver
      tissue.

PMID- 15192650
TI  - Tissue preparation for gene expression profiling of colorectal carcinoma: three
      alternatives to laser microdissection with preamplification.
AB  - Colorectal-carcinoma specimens are heterogeneous and include areas of
      nonmalignant mucosal and connective tissue. For those study designs in which
      laser microdissection and RNA preamplification are impracticable, the optimal
      yield of genuine cancer RNA is a key factor in gene-expression analysis. In this
      study we compared alternative methods of tissue purification. Three contiguous
      0.5-cm(3) samples taken from an advanced primary adenocarcinoma of the sigmoid
      colon were processed immediately after surgery with the use of the following
      methods: (1) cryotomy after manual dissection (CMD), (2) microscopically assisted
      manual dissection (MAMD), and (3) tumor-cell isolation with the use of Ber-EP4
      antibodies and Dynabeads (Dynal Biotech GmbH, Hamburg, Germany; technique
      abbreviated as DB). We generated gene-expression profiles with the use of
      GeneChip technology (Affymetrix, Santa Clara, Calif) and recorded preparation
      times, costs, and RNA quantity and quality. CMD took 60 minutes, MAMD 180
      minutes, and DB 90 minutes to isolate 22, 8, and 23 microg of RNA, respectively.
      Expenses for materials amounted to 41, 23, and 91 US dollars for CMD, MAMD, and
      DB, respectively. The 3'/5' ratio, as determined with the GeneChips, for
      GAPDH/beta-actin was 1.01:1.03 for CMD, 1.13:1.28 for MAMD, 1.43:1.68 for DB, K
      ras, APC, smad 2, transforming growth factor-beta, and p53 were marked as present
      in all cases, with the exception of APC, which was graded as marginal on DB. The
      correlation values of gene-expression profiles were 91% (CMD/DB), 93% (CMD/MAMD),
      and 97% (DB/MAMD). All 3 methods provided enough RNA, of sufficient quality, for
      gene-expression microarray analysis in colorectal carcinoma. Cross-methodologic
      analyses of array data should not be performed uncritically.

PMID- 15192651
TI  - Effects of dichloroacetate and ubiquinone infusions on glycolysis activity and
      thermal sensitivity during sepsis.
AB  - Energy-metabolism disturbances during sepsis are characterized by enhanced
      glycolytic fluxes and reduced mitochondrial respiration. However, it is not known
      whether these abnormalities are the result of a specific mitochondrial
      alteration, decreased pyruvate dehydrogenase (PDH) complex activity, depletion of
      ubiquinone (CoQ(10); electron donor for the mitochondrial complex III), or all 3.
      In this study we sought to specify metabolism disturbances in a murine model of
      sepsis, using either a PDH-activator infusion (dichloroacetate, DCA) or CoQ(10)
      supplementation. After anesthesia, Sprague-Dawley rats received intravenous
      saline solution (control; n = 5), DCA (n = 5; 20 mg/100 g), or CoQ(10) (n = 5; 1
      mg/100 g), before the induction of sepsis. Increased plasma lactate levels and
      increased muscle glucose content were observed after 4 hours in the control
      group. In the DCA group, a decrease in the muscle content of lactate (P <.05) and
      an increase in muscle glucose content (P <.05) were observed at 4 hours, but no
      lactatemia variation was noted. In the CoQ(10) group, only increased plasma
      lactate levels were observed. Increased muscle glycolysis fluxes were observed
      after 4 hours in the control group, but to a slighter degree in both the DCA and
      CoQ(10) groups. Only DCA restored a normal temperature sensitivity in the
      hyperthermia range, but we noted no differences in survival time. In conclusion,
      only DCA infusion restores normal glycolysis function.

PMID- 15192653
TI  - Urinary test use for cancer screening: an underestimated health economics
      pitfall?

PMID- 15192652
TI  - Role of complement receptors 1 and 2 (CD35 and CD21), C3, C4, and C5 in survival
      by mice of Staphylococcus aureus bacteremia.
AB  - Complement-mediated opsonization and phagocytosis of encapsulated serotype 5
      Staphylococcus aureus are essential to host defense. We describe the effects of
      complement depletion and deficiencies of C4, C5, and complement receptors 1 and 2
      on mouse survival after intravenous exposure to S aureus. Depletion of complement
      proteins in C57BL/6 mice with the use of cobra-venom factor decreased survival
      compared with that of controls after the induction of bacteremia with mucoid (90%
      mortality), encapsulated (73%), and unencapsulated (59%) S aureus strains. In
      this model complement is even more important in the control of infection with
      encapsulated S aureus (80% of clinical isolates) than in the control of infection
      by unencapsulated strains. C4-deficient mice demonstrated similar mortality from
      bacteremia caused by encapsulated S aureus compared with controls, suggesting
      that in the unimmunized animal the alternative complement pathway contributes
      more to control of bacteremia caused by encapsulated S aureus than the classical
      complement pathway or mannan-binding lectin pathway. C5-deficient mice (B10.D2
      H2(d) H2-T18(c) Hc(0)/oSnJ) showed similar mortality when subjected to bacteremia
      caused by encapsulated S aureus compared with C5-sufficient (B10.D2-Hc(1) H2(d)
      H2-T18(c)/nSnJ) mice, suggesting that in this model the anaphylatoxin C5a and the
      late complement cascade are not critical to survival of bacteremia induced with
      the use of these strains. However, C5-deficient mice depleted of C3 with the use
      of cobra-venom factor had 60% decreased survival compared with untreated C5
      deficient mice with bacteremia induced by encapsulated S aureus, suggesting that
      in this model C3 is more critical than C5 in controlling S aureus bacteremia.
      Complement receptor 1 (CD35) is the primary receptor for the opsonin C3b. Mice
      deficient in CD35/CD21 showed a 67% decrease in survival compared with normal
      mice, suggesting that CD35/CD21 is of major importance in the control of S aureus
      induced bacteremia.

PMID- 15192654
TI  - Reference value of younger people's erythrocyte sedimentation rate and altitude.

PMID- 15192657
TI  - Geriatric Emergency Nurse Education (GENE) course premieres in September.

PMID- 15192672
TI  - A 12-year-old boy with multiple bruises and a dislocated knee but no reported
      injury.

PMID- 15192673
TI  - The experience of trauma resuscitation in the emergency department: themes from
      seven patients.
AB  - PURPOSE: Little is known about the patients' experience of trauma resuscitation
      in the emergency department. Therefore, the purpose of this study was to
      determine (1) patients' perspectives of the experience of trauma resuscitation in
      the emergency department; (2) if patients have perceptions of vulnerability
      during trauma resuscitation in the emergency department; and (3) if there are
      factors that influence the patients' experience. METHODS: A qualitative study of
      7 patients using interpretive phenomenology was conducted in a Level I lead
      trauma hospital in Ontario, Canada. Inclusion criteria included age >/=18 years;
      trauma code initiated in the emergency department; Glasgow Coma Scale score
      >/=13; Revised Trauma Score >/=10; and physically and cognitively capable of
      participating in an interview in English. The sample included 4 men and 3 women.
      One-on-one semistructured tape-recorded interviews were conducted on the in
      patient Trauma Unit between day 2 and 7 after trauma resuscitation. Follow-up
      interviews were conducted 7 to 12 months after the initial interview. RESULTS:
      Four themes were revealed in the data analysis: "I remember," "I was scared," "I
      felt safe," and "I will be okay." The findings revealed that initial perceptions
      of vulnerability subsided as a sense of feeling safe became prominent. System
      factors, such as a clearly identifiable trauma team leader, and caring behaviors,
      such as touch and tone of voice, were important and contributed to the overall
      belief that it was a positive experience. CONCLUSION: Both system factors and
      nursing interventions were important in contributing to the patients' feelings of
      being safe during trauma resuscitation in the emergency department. The fact that
      pain was felt or that family was not present, for example, seemed less important
      to patients than the perception that they were in capable hands and believed they
      were "safe."

PMID- 15192676
TI  - A strategy to manage overcrowding: development of an ED holding area.

PMID- 15192675
TI  - Humanitarian aid to Iraqi civilians during the war: a US nurse's role.

PMID- 15192674
TI  - Undiagnosed hypertension in the ED setting--an unrecognized opportunity by
      emergency nurses.
AB  - INTRODUCTION: Hypertension is often undiagnosed, untreated, undertreated, and
      poorly controlled. Many patients use the emergency department as their primary
      source of health care, and the emergency department represents an opportunity to
      identify undiagnosed hypertension. We sought to (1) identify the prevalence of
      elevated blood pressures in low-acuity patients and (2) describe the existing
      practice of reassessment, treatment, and referral of abnormal vital signs in
      these patients. METHODS: We conducted a retrospective study of 88 ED patients at
      an academic medical center. All patients meeting Emergency Severity Index level 4
      or 5 criteria (low acuity) were eligible. The following variables were recorded:
      triage level, medical history and medications, disposition, and all blood
      pressures. The investigators independently reviewed and reached consensus
      regarding the following outcome variables: the need for and actual treatment of
      elevated blood pressure, and the need for and referral for blood pressure recheck
      after discharge. RESULTS: Thirty-seven patients (45%) had hypertension by
      definition on arrival. Systolic hypertension was more common. Ten of the patients
      (27%) with elevated blood pressures had documented rechecks prior to discharge in
      the emergency department, and only one patient was referred for follow-up. Twenty
      seven out of 37 low-acuity patients (73%) who presented with elevated blood
      pressures had no documentation of the blood pressure being rechecked and no
      documentation of the patient being referred. CONCLUSION: Our data suggest that
      important opportunities for education and follow-up of hypertension are being
      missed.

PMID- 15192678
TI  - Emergency management of patients with implanted pain control devices.

PMID- 15192680
TI  - The danger with neuromuscular blocking agents.

PMID- 15192679
TI  - Insulin pumps in the emergency department.

PMID- 15192681
TI  - Emergency medical service--mass gathering action plans.

PMID- 15192682
TI  - Routine ED screening of the alcohol-impaired driver: ask the questions!

PMID- 15192684
TI  - Preparing ED nurses to use the Canadian Triage and Acuity Scale with Web-based
      learning.

PMID- 15192685
TI  - A 34-year-old woman with fever, tachycardia, vomiting, and hemiparesis.

PMID- 15192686
TI  - Overview and helpful hints for caring for the ED patient with Asperger's
      syndrome.

PMID- 15192688
TI  - Isn't an alcohol- or drug-addicted adolescent worth a penny? Self-funding
      programs can make a difference.

PMID- 15192689
TI  - Bladder trauma: a review.

PMID- 15192687
TI  - Acetaminophen toxicity.

PMID- 15192690
TI  - A 39-year-old woman with nausea, vomiting, and abdominal pain during flu season.

PMID- 15192691
TI  - Electrocardiographic arrhythmia risk testing.
AB  - Among the most compelling challenges facing cardiologists today is identification
      of which patients are at highest risk for sudden death. Automatic implantable
      cardioverter-defibrillators are now indicated in many of these patients, yet the
      role of noninvasive risk stratification in classifying patients at high risk is
      not well defined. The purpose of this review is to evaluate the various
      electrocardiographic (ECG) techniques that appear to have potential in assessment
      of risk for arrhythmia. The resting ECG (premature ventricular contractions, QRS
      duration, damage scores, QT dispersion, and ST segment and T wave abnormalities),
      T wave alternans, late potentials identified on signal-averaged ECGs, and heart
      rate variability are explored. Unequivocal evidence to support the widespread use
      of any single noninvasive technique is lacking; further research in this area is
      needed. It is likely that a combination of risk evaluation techniques will have
      the greatest predictive power in enabling identification of patients most likely
      to benefit from device therapy.

PMID- 15192692
TI  - Specifying colours for colour vision testing using computer graphics.
AB  - AIMS: This paper describes a novel test of colour vision using a standard
      personal computer, which is simple and reliable to perform. METHODS: Twenty
      healthy individuals with normal colour vision and 10 healthy individuals with a
      red/green colour defect were tested binocularly at 13 selected points in the CIE
      (Commission International d'Eclairage, 1931) chromaticity triangle, representing
      the gamut of a computer monitor, where the x, y coordinates of the primary colour
      phosphors were known. RESULTS: The mean results from individuals with normal
      colour vision were compared to those with defective colour vision. Of the 13
      points tested, five demonstrated consistently high sensitivity in detecting
      colour defects. CONCLUSION: The test may provide a convenient method for
      classifying colour vision abnormalities.

PMID- 15192693
TI  - The pressure phosphene tonometer--a clinical evaluation.
AB  - AIMS: Pressure phosphene tonometry is said to assess intraocular pressure by
      inducing a pressure phosphene. This study compared the results of this relatively
      new technique with Goldmann applanation tonometry. METHODS: A total of 100
      patients (196 readings) in a general ophthalmology clinic at Dunedin Hospital who
      consented to take part in this study were randomised to receive by different
      examiners either pressure phosphene tonometry by a Proview eye pressure monitor
      (Bausch & Lomb Inc., Tampa, FL, USA) or Goldmann tonometry first. There was no
      communication between the examiners regarding results. RESULTS: Of the 196
      attempted readings, pressure phosphene tonometer readings were only able to be
      obtained for 136 eyes (69%) compared to all 196 (100%) eyes with the Goldmann
      tonometer. The mean IOPs were 18.5 mmHg using the pressure phosphene tonometer
      and 16.0 mmHg using the Goldmann tonometer. The mean difference was +2.43 mmHg
      (95% confidence interval: 10.37 mmHg below to 15.22 mmHg above Goldmann
      readings). CONCLUSION: This study found that 31% of patients could not perceive a
      pressure phosphene using the Proview eye pressure monitor. Data obtained from
      those who could perceive the phosphene indicated that large discrepancies between
      pressure phosphene tonometry and Goldmann tonometry were common.

PMID- 15192694
TI  - Atypical manifestation of neurofibromatosis type 2 in a boy.

PMID- 15192695
TI  - Risk factors for progressive visual field loss in primary open angle glaucoma.
AB  - PURPOSE: The aim of this study was to evaluate routine ophthalmic data to
      identify clinically useful risk factors for progressive visual field loss in
      patients with primary open-angle glaucoma (POAG) already receiving intraocular
      pressure-lowering treatments. METHODS: A retrospective cohort study design was
      used. Routine ophthalmic data for all subjects were obtained from case records
      with the knowledge that baseline clinical data had been collected in a
      standardised manner. Progression was defined according to the AGIS visual field
      defect scoring system. Variables evaluated as candidate risk factors for
      progression were assessed by survival analysis. Factors exerting a significant
      effect on survival were subsequently tested in a Cox proportional hazards model.
      RESULTS: A cohort of 108 eligible POAG patients was followed over an average of
      3.6 years, with an average visual field intertest interval of 8 months. The
      incidence rate of progressive loss among the cohort was 5.4 cases per 100 person
      years. Increasing age was found to be independently associated with a small but
      significantly increased risk of glaucomatous visual field defect progression
      (hazard ratio 1.07, P=0.022), and a borderline association was also demonstrated
      with being male (hazard ratio 2.76, P=0.057). CONCLUSIONS: This retrospective
      investigation has provided preliminary information on factors associated with
      increased risk of progressive glaucomatous visual field loss that may inform
      clinical care strategies. Lack of concordance with other studies suggests that
      further prospective investigations are needed if risk stratification strategies
      are to be employed in caring for patients with chronic open-angle glaucoma.

PMID- 15192696
TI  - Ocular perforation during peribular injection: reply.

PMID- 15192698
TI  - Efficient production of germline transgenic chickens using lentiviral vectors.
AB  - An effective method for genetic modification of chickens has yet to be developed.
      An efficient technology, enabling production of transgenic birds at high
      frequency and with reliable expression of transgenes, will have many
      applications, both in basic research and in biotechnology. We investigated the
      efficiency with which lentiviral vectors could transduce the chicken germ line
      and examined the expression of introduced reporter transgenes. Ten founder
      cockerels transmitted the vector to between 4% and 45% of their offspring and
      stable transmission to the G2 generation was demonstrated. Analysis of expression
      of reporter gene constructs in several transgenic lines showed a conserved
      expression profile between individuals that was maintained after transmission
      through the germ line. These data demonstrate that lentiviral vectors can be used
      to generate transgenic lines with an efficiency in the order of 100-fold higher
      than any previously published method, with no detectable silencing of transgene
      expression between generations.

PMID- 15192697
TI  - Pharmacological-based translational induction of transgene expression in
      mammalian cells.
AB  - In the quest for the development of pharmacological switches that control gene
      expression, no system has been reported that regulates at the translational
      level. To permit small-molecule control of transgene translation, we have
      constructed a farnesyl transferase inhibitor-responsive translation initiation
      factor. This artificial protein is a three-component chimaera consisting of the
      ribosome recruitment core of the eIF4G1 eukaryotic translation initiation factor,
      the RNA-binding domain of the R17 bacteriophage coat protein and the plasma
      membrane localization CAAX motif of farnesylated H-Ras. This membrane-delocalized
      translation factor is inactive unless liberated in the cytosol. Farnesyl
      transferase inhibitor FTI-277 prevents the membrane association of the CAAX motif
      and thus increases the cytoplasmic levels of the eIF4G fusion protein, which is
      then capable of inducing translation of the second cistron of a bicistronic
      messenger RNA containing an R17-binding site in its intercistronic space. Such
      direct translational control by farnesyl transferase inhibitors provides a system
      for fast, graded and reversible regulation of transgene expression.

PMID- 15192699
TI  - Histone variant H2ABbd confers lower stability to the nucleosome.
AB  - The histone H2ABbd is a novel histone variant of H2A with a totally unknown
      function. We have investigated the behaviour of the H2ABbd nucleosomes.
      Nucleosomes were reconstituted with recombinant histone H2ABbd and changes in
      their conformations at different salt concentrations were studied by analytical
      centrifugation. The data are in agreement with H2ABbd being less tightly bound
      compared with conventional H2A in the nucleosome. In addition, stable cell lines
      expressing either green fluorescent protein (GFP)-H2A or GFP-H2ABbd were
      established and the mobility of both fusions was measured by fluorescence
      recovery after photobleaching. We show that GFP-H2ABbd exchanges much more
      rapidly than GFP-H2A within the nucleosome. The reported data are compatible with
      a lower stability of the variant H2ABbd nucleosome compared with the conventional
      H2A particle.

PMID- 15192700
TI  - Differential input by Ste5 scaffold and Msg5 phosphatase route a MAPK cascade to
      multiple outcomes.
AB  - Pathway specificity is poorly understood for mitogen-activated protein kinase
      (MAPK) cascades that control different outputs in response to different stimuli.
      In yeast, it is not known how the same MAPK cascade activates Kss1 MAPK to
      promote invasive growth (IG) and proliferation, and both Fus3 and Kss1 MAPKs to
      promote mating. Previous work has suggested that the Kss1 MAPK cascade is
      activated independently of the mating G protein (Ste4)-scaffold (Ste5) system
      during IG. Here we demonstrate that Ste4 and Ste5 activate Kss1 during IG and in
      response to multiple stimuli including butanol. Ste5 activates Kss1 by generating
      a pool of active MAPKKK (Ste11), whereas additional scaffolding is needed to
      activate Fus3. Scaffold-independent activation of Kss1 can occur at multiple
      steps in the pathway, whereas Fus3 is strictly dependent on the scaffold. Pathway
      specificity is linked to Kss1 immunity to a MAPK phosphatase that constitutively
      inhibits basal activation of Fus3 and blocks activation of the mating pathway.
      These findings reveal the versatility of scaffolds and how a single MAPK cascade
      mediates different outputs.

PMID- 15192702
TI  - DNA damage checkpoint kinase Chk2 triggers replicative senescence.
AB  - Telomere shortening in normal human cells causes replicative senescence, a p53
      dependent growth arrest state, which is thought to represent an innate defence
      against tumour progression. However, although it has been postulated that
      critical telomere loss generates a 'DNA damage' signal, the signalling pathway(s)
      that alerts cells to short dysfunctional telomeres remains only partially
      defined. We show that senescence in human fibroblasts is associated with focal
      accumulation of gamma-H2AX and phosphorylation of Chk2, known mediators of the
      ataxia-telangiectasia mutated regulated signalling pathway activated by DNA
      double-strand breaks. Both these responses increased in cells grown beyond
      senescence through inactivation of p53 and pRb, indicating that they are driven
      by continued cell division and not a consequence of senescence. gamma-H2AX
      (though not Chk2) was shown to associate directly with telomeric DNA.
      Furthermore, inactivation of Chk2 in human fibroblasts led to a fall in p21(waf1)
      expression and an extension of proliferative lifespan, consistent with failure to
      activate p53. Thus, Chk2 forms an essential component of a common pathway
      signalling cell cycle arrest in response to both telomere erosion and DNA damage.

PMID- 15192701
TI  - PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation:
      effects of FAD mutations.
AB  - Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by
      activating its downstream effector Akt kinase. Here we show that PS1, a protein
      involved in familial Alzheimer's disease (FAD), promotes cell survival by
      activating the PI3K/Akt cell survival signaling. This function of PS1 is
      unaffected by gamma-secretase inhibitors. Pharmacological and genetic evidence
      indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms
      complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association.
      Furthermore, conditions that inhibit this association prevent the PS1-induced
      PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by
      promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1
      promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3),
      suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated
      in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the
      PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau
      overphosphorylation at AD-related residues. Our data raise the possibility that
      PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling
      pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this
      pathway.

PMID- 15192703
TI  - A new alpha-helical extension promotes RNA binding by the dsRBD of Rnt1p RNAse
      III.
AB  - Rnt1 endoribonuclease, the yeast homolog of RNAse III, plays an important role in
      the maturation of a diverse set of RNAs. The enzymatic activity requires a
      conserved catalytic domain, while RNA binding requires the double-stranded RNA
      binding domain (dsRBD) at the C-terminus of the protein. While bacterial RNAse
      III enzymes cleave double-stranded RNA, Rnt1p specifically cleaves RNAs that
      possess short irregular stem-loops containing 12-14 base pairs interrupted by
      internal loops and bulges and capped by conserved AGNN tetraloops. Consistent
      with this substrate specificity, the isolated Rnt1p dsRBD and the 30-40 amino
      acids that follow bind to AGNN-containing stem-loops preferentially in vitro. In
      order to understand how Rnt1p recognizes its cognate processing sites, we have
      defined its minimal RNA-binding domain and determined its structure by solution
      NMR spectroscopy and X-ray crystallography. We observe a new carboxy-terminal
      helix following a canonical dsRBD structure. Removal of this helix reduces
      binding to Rnt1p substrates. The results suggest that this helix allows the Rnt1p
      dsRBD to bind to short RNA stem-loops by modulating the conformation of helix
      alpha1, a key RNA-recognition element of the dsRBD.

PMID- 15192704
TI  - Biochemical analysis of TREX complex recruitment to intronless and intron
      containing yeast genes.
AB  - The TREX complex is involved in both transcription elongation and mRNA export and
      is recruited to nascent transcription complexes. We have examined Yra1p, Sub2p
      and Hpr1p recruitment to nine genes of varying lengths and transcription
      frequencies. All three proteins increase from the 5' to the 3' ends of the four
      intronless genes examined. A modified chromatin immunoprecipitation assay that
      includes an RNase step indicates that Sub2p is bound to nascent RNA, Yra1p is
      associated with both RNA and DNA, and Hpr1p is associated with DNA. Although
      Hpr1p is recruited similarly to both intronless and intron-containing genes, low
      Yra1p and Sub2p levels are present on a subset of intron-containing genes. The
      residual Yra1p and Sub2p recruitment is less RNA-associated, and this correlates
      with high levels of U1 SnRNP on these genes. These experiments support a model in
      which TREX is recruited via the transcription machinery and then Yra1p and Sub2p
      are transferred to the nascent RNA. On some intron-containing genes, retention
      and/or transfer of Yra1p and Sub2p to nascent RNA are inhibited.

PMID- 15192705
TI  - Interactions between UvrA and UvrB: the role of UvrB's domain 2 in nucleotide
      excision repair.
AB  - Nucleotide excision repair (NER) is a highly conserved DNA repair mechanism
      present in all kingdoms of life. UvrB is a central component of the bacterial NER
      system, participating in damage recognition, strand excision and repair
      synthesis. None of the three presently available crystal structures of UvrB has
      defined the structure of domain 2, which is critical for the interaction with
      UvrA. We have solved the crystal structure of the UvrB Y96A variant, which
      reveals a new fold for domain 2 and identifies highly conserved residues located
      on its surface. These residues are restricted to the face of UvrB important for
      DNA binding and may be critical for the interaction of UvrB with UvrA. We have
      mutated these residues to study their role in the incision reaction, formation of
      the pre-incision complex, destabilization of short duplex regions in DNA, binding
      to UvrA and ATP hydrolysis. Based on the structural and biochemical data, we
      conclude that domain 2 is required for a productive UvrA-UvrB interaction, which
      is a pre-requisite for all subsequent steps in nucleotide excision repair.

PMID- 15192706
TI  - Biogenesis of PSI involves a cascade of translational autoregulation in the
      chloroplast of Chlamydomonas.
AB  - Photosystem I comprises 13 subunits in Chlamydomonas reinhardtii, four of which
      the major reaction center I subunits PsaA and PsaB, PsaC and PsaJ-are chloroplast
      genome-encoded. We demonstrate that PSI biogenesis involves an assembly-governed
      regulation of synthesis of the major chloroplast-encoded subunits where the
      presence of PsaB is required to observe significant rates of PsaA synthesis and
      the presence of PsaA is required to observe significant rates of PsaC synthesis.
      Using chimeric genes expressed in the chloroplast, we show that these regulatory
      processes correspond to autoregulation of translation for PsaA and PsaC. The
      downregulation of translation occurs at some early stage since it arises from the
      interaction between unassembled PsaA and PsaC polypeptides and 5' untranslated
      regions of psaA and psaC mRNAs, respectively. These assembly-dependent
      autoregulations of translation represent two new instances of a control by
      epistasy of synthesis process that turns out to be a general feature of protein
      expression in the chloroplast of C. reinhardtii.

PMID- 15192707
TI  - PKD1/PKCmu promotes alphavbeta3 integrin recycling and delivery to nascent focal
      adhesions.
AB  - To identify kinases that regulate integrin recycling, we have immunoprecipitated
      alphavbeta3 integrin from NIH 3T3 fibroblasts in the presence and absence of
      primaquine (a drug that inhibits receptor recycling and leads to accumulation of
      integrins in endosomes) and screened for co-precipitating kinases. Primaquine
      strongly promoted association of alphavbeta3 integrin with PKD1, and fluorescence
      microscopy indicated that integrin and PKD1 associate at a vesicular compartment
      that is downstream of a Rab4-dependent transport step. PKD1 association was
      mediated by the C-terminal region of the beta3 integrin cytodomain, and mutants
      of beta3 that were unable to recruit PKD1 did not recycle in a PDGF-dependent
      fashion. Furthermore, suppression of endogenous PKD1 levels by RNAi, or
      overexpression of catalytically inactive PKD1 inhibited PDGF-dependent recycling
      of alphavbeta3 from early endosomes to the plasma membrane and blocked
      recruitment of alphavbeta3 to newly formed focal adhesions during cell spreading.
      These data indicate that PKD1 influences cell migration by directing vesicular
      transport of the alphavbeta3 integrin heterodimer.

PMID- 15192709
TI  - Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an
      adenovirus overexpressing dominant-negative FANCA.
AB  - Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow
      failure and cellular hypersensitivity to crosslinking agents, including
      cisplatin. Here, we studied the use of the FA pathway as a possible target for
      cancer gene therapy with the aim to sensitize tumor cells for cisplatin by
      interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast
      derived tumors were grown subcutaneously in scid mice and treated with two
      different concentrations of cisplatin. As predicted, the antitumor response was
      considerably improved in FA tumors. An adenoviral vector encoding a dominant
      negative form of FANCA, FANCA600DN, was generated that interfered with endogenous
      FANCA-FANCG interaction resulting in the disruption of the FA pathway as
      illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines,
      including non-small-cell lung cancer cells, could be sensitized approximately two
      to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase
      upon enhanced infection efficiency. In conclusion, targeting the FA pathway may
      provide a novel strategy for the sensitization of solid tumors for cisplatin and,
      in addition, provides a tool for examining the role of the FA pathway in
      determining chemoresistance in different tumor types.

PMID- 15192708
TI  - Negative feedback loop in T-cell activation through MAPK-catalyzed threonine
      phosphorylation of LAT.
AB  - Mitogen-activated protein kinase (MAPK) cascades are involved in a variety of
      cellular responses including proliferation, differentiation, and apoptosis. We
      have developed an expression screening method to detect in vivo substrates of
      MAPKs in mammalian cells, and identified a membrane protein, linker for
      activation of T cells (LAT), as an MAPK target. LAT, an adapter protein essential
      for T-cell signaling, is phosphorylated at its Thr 155 by ERK in response to T
      cell receptor stimulation. Thr 155 phosphorylation reduces the ability of LAT to
      recruit PLCgamma1 and SLP76, leading to attenuation of subsequent downstream
      events such as [Ca2+]i mobilization and activation of the ERK pathway. Our data
      reveal a new role for MAPKs in a negative feedback loop in T-cell activation via
      threonine phosphorylation of LAT.

PMID- 15192712
TI  - Student debt dilemma.

PMID- 15192711
TI  - Conscious sedation.

PMID- 15192713
TI  - Bug busting.

PMID- 15192714
TI  - Digitally aware dentists.

PMID- 15192715
TI  - Do cycle helmets work?

PMID- 15192725
TI  - Research in primary dental care part 3: Designing your study.
AB  - Earlier articles in this series identified the importance of stating a clear
      research question as the first step in conducting research in primary dental
      care. The study design seeks to answer the research question. This article
      describes different types of study design and their application. A framework of
      the steps involved in designing each type of study are described, together with
      the situations in which they could be used. Useful resources and sources of
      information are provided.

PMID- 15192726
TI  - Orthodontic and prosthodontic treatment of ectodermal dysplasia--a case report.
AB  - In addition to its other symptoms, ectodermal dysplasia causes anodontia and
      hypodontia intraorally. Partial or total anodontia results in some loss of
      function, such as chewing, and affects aesthetics. Prosthodontic rehabilitation
      can be accomplished with fixed, overdenture, complete, or implant-retained
      prostheses. For rehabilitation, it is crucial to know the age, number and
      condition of present teeth, and the state of growth of the patient. A 10-year-old
      male patient who visited our clinic was treated by a multi-disciplinary team of
      surgeons, orthodontists, and prosthodontists. An overdenture was planned, and an
      implant-supported prosthesis was considered for when the patient had finished
      growing. A clasp retained over the denture was planned for prosthetic
      rehabilitation after considering his growth and the number and condition of his
      present teeth.

PMID- 15192734
TI  - Modulation of dental anxiety--the role of past experiences, psychopathologic
      traits and individual attachment patterns.
AB  - OBJECTIVE: To evaluate factors affecting modulation of dental anxiety among
      adults. METHODS: A total of 183 adult members of a closed communal society
      (Kibbutz), who have been treated since childhood only by the dentists employed in
      their community, were investigated concerning their past and present dental
      anxiety, evaluation of their past and present dentists, psychopathologic symptoms
      and individual pattern of attachment. RESULTS: The best predictor of subjects'
      evaluation of their present dental anxiety was the scale of anxiety as recorded
      by the SCL-90R questionnaire. The best predictors of the decrease in subjects'
      dental anxiety over time were the evaluation of their past and present dentists
      and the secure and avoidant patterns of attachment. Patterns of attachment
      (avoidant and ambivalent) were the best predictors of subjects' evaluation of
      their present dentist. CONCLUSIONS: While psychopathologic traits are involved in
      subjects' present dental anxiety, pattern of attachment may have a dominant
      affect as to whether anxiety persists throughout life or can be modulated through
      a corrective emotional experience.

PMID- 15192735
TI  - Puncture resistance and stiffness of nitrile and latex dental examination gloves.
AB  - OBJECTIVE: The aim of the current study was to assess the puncture resistance and
      stiffness of nitrile and latex dental examination gloves. METHODS: Puncture
      resistance was measured by employing an adapted version of ASTM F1342-91 using
      both a 316 stainless steel puncture probe (0.8 mm diameter) and a dental
      injection needle (0.45 mm diameter) interfaced to a tensile testing apparatus.
      Glove specimens (12 cm length, 1.5 cm breadth) were removed for modulus (M100)
      evaluation by assessing the force required to elongate the specimen to 100% of
      the original length. Glove samples were also aged to investigate whether puncture
      resistance and M100 values varied with aging at 70 degrees C for 7 days in an air
      circulating oven. RESULTS: The nitrile glove types were assessed to have
      significantly higher puncture resistance compared with the latex glove type when
      the steel puncture probe was the pentrometer when using the one way analysis of
      variance (ANOVA) at the 95% significance level. Interestingly the puncture
      resistance for the latex glove type was significantly higher (P < 0.001) when a
      dental injection needle was used as the pentrometer compared with the nitrile
      glove types. The M100 values were significantly higher for the nitrile glove
      types for which the stiffness increased when the gloves were aged (P < 0.001).
      CONCLUSIONS: The higher stiffness values resulted in increased puncture
      resistance when the nitrile glove specimens were aged irrespective of the
      pentrometer type. However, the ability of latex to re-seal itself on puncture may
      be beneficial when considering the protection potential of each glove type
      against breaches in cross infection. For clinicians that have experienced an
      adverse reaction to natural latex gloves, the results of the current study
      indicate that nitrile gloves are available at reasonable cost and offer the
      clinician comparable resistance to puncture with latex gloves.

PMID- 15192736
TI  - Patterns of antifungal prescribing in general dental practice.
AB  - OBJECTIVE: To examine the current practice of antifungal prescribing by GDPs in
      the United Kingdom. Design A postal questionnaire circulated to a random
      selection of 400 dentists. OUTCOME MEASURES: The questionnaires were analysed and
      the responses expressed as absolute and relative frequencies. RESULTS: Responses
      to the questionnaire were received from 297 (74.3%) GDPs. Nystatin was the most
      popular choice of antifungal agent that GDPs would use, followed by miconazole,
      amphotericin B and fluconazole. The likelihood of use of miconazole was
      positively linked to recent date of graduation. Lack of knowledge regarding
      contraindications and problems with azole antibiotics was found in a significant
      minority of practitioners (36%). CONCLUSIONS: The present study indicates that
      azole antifungal agents (especially miconazole) are becoming more widely used by
      GDPs, but that knowledge regarding potential problems with their use is sub
      optimal. Nystatin remains the most popular choice of antifungal agent.

PMID- 15192751
TI  - Focus Awards 2003.

PMID- 15192754
TI  - Using C. elegans to screen for targets of ethanol and behavior-altering drugs.
AB  - Caenorhabditis elegans is an attractive model system for determining the targets
      of neuroactive compounds. Genetic screens in C. elegans provide a relatively
      unbiased approach to the identification of genes that are essential for
      behavioral effects of drugs and neuroactive compounds such as alcohol. Much work
      in vertebrate systems has identified multiple potential targets of ethanol but
      which, if any, of those candidates are responsible for the behavioral effects of
      alcohol is uncertain. Here we provide detailed methodology for a genetic screen
      for mutants of C. elegans that are resistant to the depressive effects of ethanol
      on locomotion and for the subsequent behavioral analysis of those mutants. The
      methods we describe should also be applicable for use in screening for mutants
      that are resistant or hypersensitive to many neuroactive compounds and for
      identifying the molecular targets or biochemical pathways mediating drug
      responses.

PMID- 15192755
TI  - Expression and purification of recombinant vesicular glutamate transporter VGLUT1
      using PC12 cells and High Five insect cells.
AB  - In synaptic vesicles, the estimated concentration of the excitatory amino acid
      glutamate is 100-150 mM. It was recently discovered that VGLUT1, previously
      characterized as an inorganic phosphate transporter (BNPI) with 9-11 predicted
      transmembrane spanning domains, is capable of transporting glutamate. The
      expression and His-tag based purification of recombinant VGLUT1 from PC12 cells
      and High Five insect cells is described. Significantly better virus and protein
      expression was obtained using High Five rather than Sf9 insect cells. PC12 cell
      expressed VGLUT1 is functional but not the Baculovirus expressed protein. The
      lack of functionality of the Baculovirus expressed VGLUT1 is discussed. The data
      indicate that VGLUT1 readily oligomerizes/dimerizes. The data are discussed in
      the context of developing this system further in order to reconstitute vesicular
      glutamate uptake in vitro using lipid-detergent vesicles.

PMID- 15192757
TI  - Technology: mechanical ventilation strategy versus tactics.

PMID- 15192756
TI  - [Chronic functional constipation. Which supplementary fiber to choose?].

PMID- 15192758
TI  - [Reflux esophagitis in infants: current knowledge and future challenges].

PMID- 15192759
TI  - [Childhood obesity--towards effectiveness].
AB  - OBJECTIVE: To review therapeutic approaches to childhood obesity and also its
      diagnosis and prevention. SOURCES OF DATA: Searches were performed of scientific
      papers held on the MEDLINE, Ovid, Highwire and Scielo databases. Keywords
      utilized were: "childhood", "obesity" and a variety of combinations of this term
      with "treatment", "prevention" and "consequence". The search returned papers
      including review articles, observational studies, clinical trials and consensus
      statements. Bibliographical references in these articles were also investigated
      if it was perceived that they were relevant. Data was collected from 1998 to
      2003. SUMMARY OF THE FINDINGS: While a number of different Brazilian prevalence
      studies were found, few gave details of the results of educational programs in
      our country. CONCLUSIONS: Childhood obesity must be prevented through
      prescriptive diets from birth throughout childhood. Educational programs that
      might be applicable to primary health care or schools should receive further
      study.

PMID- 15192760
TI  - [The effect of soy polysaccharide fiber on fecal weight and humidity in growing
      rats].
AB  - OBJECTIVE: To compare the effect of soy polysaccharide on fecal weight and
      humidity in growing rats in relation to cellulose and a Soy formula without
      dietary fiber. METHODS: Twelve, 21-day-old, Wistar male rats, were distributed
      into three groups and fed AIN-93G ration with varying amounts of dietary fiber:
      Polysaccharide Group, 5% fiber in the form of soy polysaccharide; Soy Formula
      Group, 5% soy formula without fiber; and Cellulose Group, 5% fiber in cellulose
      form. Feces were collected for three 72-hour periods beginning on days 7, 17 and
      27. They were weighed while humid and then dried at 105 degrees C until a
      constant weight. The humidity was calculated using the formula [(humid fecal
      weight - dry fecal weight)/humid fecal weight] X 100. RESULTS: The total humid
      fecal weight for Polysaccharide, Soy Formula and Cellulose groups was: 17.372
      /+4.743 g; 6.045-/+0.619 g; and 16.012-/+2.600 g, (p = 0.001), respectively.
      There was no statistically significant difference between the Cellulose and
      Polysaccharide groups, but a statistically significant difference was observed
      between theses two groups and the soy formula group. Values for dry weight, in
      the same order, were: 6.463-/+1.177 g; 2.909-/+0.277 g; and 10.068-/+1.085 g, (p
      < 0.001), with a statistically significant difference between each of the groups.
      CONCLUSION: Animals that received soy formula presented lower humid and dried
      fecal weight than the other two groups, while the soy polysaccharide caused
      higher fecal humidity than did cellulose, probably due to greater fermentation.

PMID- 15192761
TI  - [The impact of mechanical ventilation strategies that minimize atelectrauma in an
      experimental model of acute lung injury].
AB  - OBJECTIVE: To evaluate whether ventilation strategies that target alveolar
      stabilization and prevention of atelectrauma would be associated with more
      favorable physiologic outcomes in a combined model of acute lung injury. METHODS:
      Thirty-nine rabbits were instrumented and ventilated with FiO(2) of 1.0. Combined
      lung injury was induced by an infusion of lipopolysaccharide and tracheal saline
      lavage. Animals were randomized to receive conventional ventilation with tidal
      volume of 10 ml/kg, PEEP of 4 cm H(2)O; conventional ventilation with surfactant
      (Infasurf, 3 mg/kg IT); partial liquid ventilation (18 ml/kg of perflubron IT);
      or high-frequency oscillatory ventilation with mean airway pressure of 14 cm
      H(2)O and frequency of 4 Hz. Uninjured ventilated animals served as controls.
      Conventional ventilation with surfactant, partial liquid ventilation and control
      groups were ventilated with settings identical to the conventional ventilation
      group. Animals were studied for 4 hours, during which serial blood gas
      measurements were obtained. After sacrifice, lungs were harvested for injury
      grading by a microscopic lung injury score and measurement of 4-hydroxy-nonenal,
      a marker of lipid peroxidation. RESULTS: Conventional ventilation resulted in
      hypoxia and greater evidence of lung injury. Animals treated with partial liquid
      ventilation, high-frequency oscillatory ventilation or conventional ventilation
      with surfactant had adequate oxygenation, but conventional ventilation with
      surfactant resulted in higher lung injury scores and increased pulmonary
      oxidative damage. CONCLUSION: Strategies that minimize atelectrauma (partial
      liquid ventilation and high-frequency oscillatory ventilation) are associated
      with adequate oxygenation and attenuated lung injury. Surfactant improves
      oxygenation in comparison to conventional ventilation alone but resulted in
      increased injury, presumably because the inadequately low PEEP was insufficient
      to stabilize the alveoli during expiration.

PMID- 15192762
TI  - [Diagnosis of reflux esophagitis in infants: histology of the distal esophagus
      must complement upper gastrointestinal endoscopy].
AB  - OBJECTIVE: The aim of this study was to validate the endoscopic findings against
      histologic features of the distal esophageal mucosa for the diagnosis of reflux
      esophagitis in infants. METHODS: The data records of 167 patients (88 M; 79F)
      aged 38-364 days, referred for investigation of reflux esophagitis, between
      January 1995 and December 2000 were retrospectively reviewed. The association
      between nominal (presence or absence of esophagitis) and ordinal (grades of
      esophagitis) variables was analyzed through a correlation between the results of
      endoscopic findings and histology. RESULTS: Endoscopy when compared with
      histologic analysis had a sensitivity of 45%; specificity of 71%; positive and
      negative predictive value of 89% and 21% respectively; and accuracy of 50%.
      Additionally, this study demonstrated that there was a poor correlation between
      endoscopic and histologic findings when endoscopy was normal or when endoscopic
      grade I esophagitis was observed (p = 0.10). Normal esophageal appearance failed
      to identify 79.2% of patients with histologic esophagitis. Conversely, amongst
      patients with endoscopic grade I esophagitis, 12.1% had normal histology.
      CONCLUSIONS: We concluded that whilst endoscopy had a specificity of 71%, it did
      not attain an acceptable range of sensitivity (45%) to justify performing an
      endoscopy without biopsy, as many true cases of esophagitis would not be
      detected; and that the presence of grade I (non-erosive) esophagitis at endoscopy
      did not increase the value of the test in predicting histologic abnormality.

PMID- 15192763
TI  - [Sensitization to inhalant and food allergens in Brazilian atopic children by in
      vitro total and specific IgE assay. Allergy Project--PROAL].
AB  - OBJECTIVE: To determine the frequency of sensitization to inhalant and food
      allergens in children seen at Brazilian allergy services. PATIENTS AND METHODS:
      Total and specific IgE serum levels to inhalant and food allergens (RAST, UniCAP 
      Pharmacia) were measured in 457 children accompanied in pediatric allergy
      services and in 62 control children age matched. RAST equal or higher than class
      1 was considered as positive (R+). RESULTS: Frequency of R+ was significantly
      higher among atopics (361/457, 79%) when compared to controls (16/62, 25.8%).
      There were no differences according to gender. The frequency of R+ to all
      allergens evaluated was higher among atopics when compared to controls.
      Significantly higher total IgE serum levels were observed among the atopics with
      R+ in comparison to those with R-. The frequency of R+ to main inhalant allergens
      were: D. pteronyssinus = 66.7% x 14.5% (p < 0.05), D. farinae = 64.5% x 17.8% (p
      < 0.05), B. tropicalis = 55.2% x 19.4% (p < 0.05), cockroach = 32.8% x 9.7% (p <
      0.05), and cat = 12% x 8.1%. In relation to food allergens we observed: fish =
      29.5% x 11.3% (p < 0.05), egg = 24.4% x 4.8% (p < 0.05), cow's milk = 23.1% x
      3.2% (p < 0.05), wheat = 20% x 8.1% (p < 0.05), peanuts = 14% x 4.8% (p < 0.05),
      soy = 11.8% x 4.8% (p < 0.05), and corn = 10.6% x 4.8% (p < 0.05). With respect
      of age, food allergen sensitization predominates in young children whereas the
      inverse occurs with inhalant allergens. CONCLUSIONS: There was a predominant
      frequency of sensitization to inhalant allergens, mainly house dust mites in the
      evaluated patients. Food allergens were also responsible for a significant
      proportion of sensitization, mainly in infants.

PMID- 15192764
TI  - [The impact of malnutrition on idiopathic dilated cardiomyopathy in children].
AB  - OBJECTIVE: To analyze the prognostic value of malnutrition in children with
      idiopathic dilated cardiomyopathy. METHODS: This is a retrospective study of 165
      patients with idiopathic dilated cardiomyopathy, diagnosed from September 1979 to
      March 2003. It analyzed the following variables: gender, age, previous viral
      illness in the preceding 3 months, functional class according to the New York
      Heart Association (NYHA), evaluation of nutritional status (normal vs.
      malnutrition), percentile and standard deviation (z index) of weight. Weight was
      measured 744 times during the first 72 months, 93 during the first month.
      Statistical analysis was performed by Chi Squared, Student t test and analysis of
      variance for repeated measures (ANOVA). Ninety-five percent confidence intervals
      (CI95) and odds ratios (OR) were calculated. An alpha value of 0.05 and beta of
      0.80 were used. RESULTS: Mean age at presentation was 2.2+/-3.2 years with higher
      incidence in those younger than 2 years (75.8%-CI95 = 68.5% to 82.1%) (p <
      0.0001). NYHA classes III and IV were observed in 81.2% (CI95 = 74.4% to 86.9%)
      (p < 0.0001) and all 40 deaths were this group (p = 0.0008). At presentation,
      myocarditis occurred in 39.4% (CI95 = 31.9% to 47.3%) (p = 0.0001) and a high
      level of association between myocarditis and previous viral illness was observed
      (p = 0.0005) (OR = 3.15-CI95 = 1.55 to 6.44). Malnutrition at presentation did
      not influence death (p = 0.10), however progressive malnutrition was a marker for
      death (p = 0.02) (OR = 3.21-CI95 = 1.04 to 9.95). No significant differences
      weight percentiles (p = 0.15) or in z scores (p = 0.14) were observed. Observed
      mean weight percentiles (34.9+/-32.6 vs. 8.6+/-16.0) (p < 0.0001) and z scores (
      0.62+/-1.43 vs. -2.02+/-1.12) (p < 0.0001) during the study period were greater
      among survivors. ANOVA demonstrated significant differences in weight percentile
      progression (p = 0.0417) and z scores (p = 0.0005) from the first month onwards.
      CONCLUSION: The evaluation of nutritional status is easy to perform, it does not
      imply additional costs and should become routine for children with chronic heart
      failure.

PMID- 15192765
TI  - [Phadiatop in the diagnosis of respiratory allergy in children: Allergy Project-
      PROAL].
AB  - OBJECTIVES: To evaluate the positivity of Phadiatop in children from several
      Brazilian pediatric allergology centers and to compare its results with the
      presence of serum specific IgE to inhalant and food allergens. PATIENTS AND
      METHOD: Phadiatop and serum specific IgE levels (RAST) to inhalant and food
      allergens (UniCAP - Pharmacia) were measured in 457 children from several
      pediatric allergy centers and in a non-allergic control group (n = 62),
      distributed across five age groups. RESULTS: Phadiatop was positive in 305 atopic
      children (67.6%) and in 25.8% of controls (p < 0.001). Among atopic children the
      distribution of positive test varied according to age: 7.9% (24/305) among under
      2 year-olds, 15.4% (47/305) in 2 to 3 year-olds, 22.0% (67/305) in 3 to 4 year
      olds, 19.3% (59/305) in 4 to 5 year-olds and 35.4% (108/305) in 5 to 12 year
      olds. No concordance between food allergens and Phadiatop was observed. Analysis
      of the relationship between positive inhaled allergen RASTs and positive
      Phadiatop showed best indices with house dust mites (D. pteronyssinus, D. farinae
      and Blomia tropicalis). CONCLUSIONS: Phadiatop is a useful tool for diagnosing
      domestic mite allergy.

PMID- 15192766
TI  - [Neuroradiological investigation in patients with idiopathic growth hormone
      deficiency].
AB  - OBJECTIVE: The aim of this study was to analyze the type and frequency of cranial
      computed tomography and magnetic resonance imaging anomalies in patients with
      idiopathic growth hormone deficiency, and also to investigate the possible
      relationship between neuroradiological images and the presence of isolated growth
      hormone or multiple pituitary hormone deficiency. METHODS: Magnetic resonance and
      computed tomography images were obtained for 37 patients with idiopathic growth
      hormone deficiency. The patients were divided into two groups: patients with
      isolated growth hormone (group A) and patients with multiple pituitary hormone
      deficiencies (group B). RESULTS: Computed tomography was normal in 25 (68%), and
      abnormal in 12 (32%) patients. We observed empty sella in 50%, partially empty
      sella in 17% and anterior pituitary hypoplasia in 33% patients. MRI studies
      revealed normal findings in the hypothalamus-pituitary area in 17 (46%) and
      abnormal in 20 (54%) patients. We did not observed differences in the frequency
      of computed tomography alterations when groups A and B were compared (p = 0.55).
      With magnetic resonance imaging we observed, empty sella in 10%, partially empty
      sella in 15% and anterior pituitary hypoplasia in 75% patients. Among those
      patients whose magnetic resonance images were altered, the posterior lobe of the
      pituitary gland was identified in an abnormal position in 70%, and the
      hypophyseal stalk was thin or interrupted in 60%. The patients from group B
      presented a higher frequency of magnetic resonance imaging anomalies (90%) when
      compared to group A (10%), p = 0.03. There was disagreement between the two
      methods in 43% of cases, but we didn't observe a difference in the frequency of
      alterations when computed tomography was compared with magnetic resonance imaging
      (p = 0.06). CONCLUSIONS: The most frequent defects observed using magnetic
      resonance imaging are anterior pituitary hypoplasia and ectopic posterior
      pituitary lobe. The association of glandular hypoplasia with other magnetic
      resonance imaging abnormalities can suggest the presence of multiple anterior
      pituitary deficiencies.

PMID- 15192767
TI  - Factors associated with iron deficiency anemia in Brazilian preschool children.
AB  - OBJECTIVE: To examine the determining factors of anemia and iron deficiency in
      children attending two day care centers in the town of Pontal, southeast of
      Brazil. METHODS: Cross-sectional study was conducted in 192 children aged 12 to
      72 months. Personal data (age, sex, use of medicinal iron supplements, duration
      of breast-feeding, type of delivery, prenatal care, weight, and height), and
      socioeconomic data (number of co-inhabitants, parental schooling, and per capita
      family income) were obtained and evaluated together with hemoglobin, serum
      transferrin receptor, ferritin, and iron deficiency anemia. RESULTS: Age was the
      variable that most affected iron nutritional status, with higher hemoglobin
      values, lower transferrin receptor concentrations, higher ferritin values and
      lower iron deficiency anemia being detected with increasing age. The other
      studied variables did not show any correlation with iron nutritional status.
      CONCLUSION: The obtained data suggest that control strategies for this preschool
      population should be especially directed at younger children.

PMID- 15192768
TI  - [The impact of a breastfeeding promotion program at a health center].
AB  - OBJECTIVES: To determine the impact on breastfeeding sustained beyond two months
      of the "Seventeen Steps" breastfeeding maintenance program consisting of
      seventeen strategies used to promote, support and protect breastfeeding and
      implemented for ten months at a medical center. METHODS: Nonrandomized clinical
      trial, involving 147 children born between 01/01/99 and 31/12/2001, who had
      attended their first medical appointment before two months; 67 children who had
      passed through the traditional program were studied retrospectively and 80 that
      had the "17 steps" applied to them were studied prospectively. Maximum follow up
      period was ten months. The program's impact on breastfeeding was evaluated
      through survival analysis techniques. The survival curves were described by the
      Kaplan Meier method and compared with the log-rank test. The Cox regression model
      was used for covariate adjustment. The initial group comparison was done through
      the t, Kruskal-Wallis and Chi-squared tests. The significance level adopted was
      5%. RESULTS: Adjusting for mother-child covariates, a significant difference was
      observed in breastfeeding duration between the two groups (p = 0.047). The
      relative risk of interrupting breastfeeding for the "17 steps" group was RR =
      0.54 (95CI = 0.30-0.99), indicating that there was an 85% greater risk that
      children on the traditional program would be weaned before completing a year than
      there was that children on the "17 steps" program would be. CONCLUSION: The
      program had a positive impact on the duration of breastfeeding from two to twelve
      months of age.

PMID- 15192769
TI  - [Exclusive breastfeeding at the point of discharge of high-risk newborns at a
      Neonatal Intensive Care Unit and the factors associated with this practice].
AB  - OBJECTIVE: To study the rate of exclusive breastfeeding at the moment of hospital
      discharge of newborns admitted to a neonatal Intensive Care Unit and to analyze
      potential risk factors. METHODS: Four hundred and ninety-five medical records
      were studied, pertaining to neonates born between 1998 and 1999, admitted to a
      neonatal intensive care unit, before and after the implementation of the Baby
      Friendly Hospital Initiative policies. Babies born during the Baby Friendly
      Hospital Initiative transition period and outside the Maternity ward were
      excluded from the study, as were children or mothers who were transferred from
      the institution, abandoned children and also mothers unfit to breastfeed. Risk
      factors for non-exclusive breast-feeding at discharge were studied. Odds ratio
      and 95% confidence intervals were calculated using multivariate logistic
      regression. RESULTS: The exclusive breastfeeding rate increased from 36% at
      discharge (before the Baby Friendly Hospital Initiative) to 54.7% (after BFHI).
      The independent risk factors associated with non-exclusive breastfeeding were the
      use of enteral feeding (OR = 3.01), ante-natal consultations < 6 (OR = 2.75),
      relactation use (OR = 2.66), birth weight < 2,500 g (OR = 2.64) and being born
      during the period before Baby Friendly policies were implemented (OR = 2.75).
      CONCLUSION: This research shows the potential efficiency of adopting Baby
      Friendly policies to increase the chance of successful breastfeeding at the point
      of discharge for high-risk newborns.

PMID- 15192770
TI  - [Marcus Gunn Phenomenon: differential diagnosis of palpebral ptoses in children].
AB  - OBJECTIVE: The aim of this paper is to review existing literature on the subject
      and to report on and discuss a case of Marcus Gunn Phenomenon. DESCRIPTION: A
      five year-old female, otherwise a healthy patient, while still a few months old,
      was seen by a pediatrician who detected a disorder of the right eye, initially
      believed to be strabismus, at a follow-up childcare consultation. Several
      ophthalmologists failed to establish a precise diagnosis. After a pediatric
      ophthalmologist had examined the child at four years of age, a diagnosis of
      Marcus Gunn Phenomenon, otherwise known as jaw-winking phenomenon, was confirmed.
      Apart from this anomaly, physical, ophthalmological, and neurological
      examinations were normal. Since ptosis was mild and no association with
      strabismus, amblyopia or other conditions was established, no surgical procedures
      were necessary. COMMENTS: This report is an alert to pediatricians regarding the
      presence of this largely unknown phenomenon, making it possible for pediatricians
      to identify the phenomenon, refer the patient to an ophthalmologist, and
      establish differential diagnosis from other, more severe forms of ptosis,
      requiring more aggressive treatment.

PMID- 15192771
TI  - Protein kinase C and myocardial calcium handling during ischemia and reperfusion:
      lessons learned using Rhod-2 spectrofluorometry.
AB  - OBJECTIVE: We sought to assess myocardial Ca (2+) handling and excitation
      contraction coupling in surgically relevant models of ischemia-reperfusion injury
      and to clarify the importance of protein kinase C (PKC) for cardioprotection.
      METHODS: Experimentally, surgical ischemia and reperfusion can only be mimicked
      in intact perfused heart models. We introduced the long-wavelength fluorescent Ca
      (2+) indicator Rhod-2 for real-time recording of cytosolic Ca (2+) transients in
      Langendorff-perfused rabbit, rat, and mouse hearts, and utilized it to study the
      impact of PKC on myocardial Ca (2+) handling during ischemia and reperfusion.
      RESULTS: We first established that the dissociation constant for Rhod-2 and Ca
      (2+) must be adjusted to account for changes in pH and temperature during
      ischemia and reperfusion. Based on this method, we determined the time-course and
      extent of cytosolic Ca (2+) accumulation during myocardial ischemia, which is
      associated with translocation of the PKC isoforms alpha and epsilon between the
      cytosolic and particulate compartments in cardiomyocytes. The PKC translocation
      is mediated by activation of phosphatidyl-inositol-specific phospholipase C (PI
      PLC), and represents a cardioprotective mechanism. Finally, we studied the
      mechanism of action of PKC and found that it both limits the accumulation of
      cytosolic Ca (2+) during reperfusion and attenuates contractile protein Ca (2+)
      sensitivity via phosphorylation of troponin I. CONCLUSIONS: Rhod-2
      spectrofluorometry is a valuable tool for assessment of cytosolic Ca (2+) in
      surgically relevant experimental models and can aid the development of more
      effective methods for myocardial protection.

PMID- 15192772
TI  - Brain natriuretic peptide (BNP) in patients undergoing coronary artery bypass
      grafting.
AB  - BACKGROUND: This study was designed to examine plasma concentrations of BNP and
      its relation to hemodynamic parameters in patients (pts.) with coronary artery
      disease (CAD) undergoing coronary artery bypass grafting (CABG). METHODS: 21 pts.
      with CAD undergoing CABG were examined. The pts. were divided into two groups.
      Group I: normal left ventricular function (LVF); Group II: reduced LVF. Pre-,
      intra- and postoperative BNP and hemodynamic parameters were measured. The
      perioperative administration of inotropic drugs was documented. RESULTS: In both
      groups postoperative BNP increased to a peak 24 h postoperatively; although BNP
      concentrations were high 24 h postoperatively hemodynamic parameters were
      improved in both groups. In Group I the BNP peak did not correlate with any
      hemodynamic parameter nor with the use of inotropic drugs. In Group II the BNP
      peak was inversely correlated with CO and CI and positively correlated with the
      PCWP. There was no correlation with inotropic support. CONCLUSION: Postoperative
      peak of BNP after 24 h does not reflect a state of acute perioperative heart
      failure or myocardial damage. These results suggest that the gene expression,
      metabolism and biological activity of BNP may be altered after extracorporeal
      circulation. Further studies are warranted to reveal the actual triggers for BNP
      increase early after CABG.

PMID- 15192773
TI  - Correction of congenital heart defects in Jehovah's Witness children.
AB  - Between August 1989 and July 2003 14 Jehovah's Witness children with congenital
      heart defects (CHD) aged under 14 years (median 2.9 years) and with a median
      weight of 14 kg underwent 16 operations with cardiopulmonary bypass (CPB). Five
      children had been operated on previously between one to three times.
      Preoperatively, 7 children were prepared with oral iron supplementation and 10
      received erythropoietin. Mean hemoglobin (Hb) at admission was 14.4 g/dl (range
      10.9 - 19.2). The cardiopulmonary bypass (CPB) circuit was modified to reduce
      total priming volume. High doses of aprotinin were administered. The modified
      ultrafiltration (MUF) circuit, used in 7 patients, was parallel to the ECC
      circuit with continuous circulation of the blood through a small shunt between
      the arterial and venous lines. Operations performed consisted of VSD closure (3
      pts.), ASD closure (3 pts.), Fontan operation (2 pts.), and complete AV canal
      correction, aortic commissurotomy, Ross operation, Glenn shunt, cor triatriatum
      correction, MV reconstruction combined with left outflow tract stenosis
      resection, correction of absent pulmonary valve syndrome, and correction of
      tetralogy of Fallot in one patient each. There were no deaths. Mean duration of
      CPB was 192 min and mean aortic cross-clamp time 40 min. The Hb value at the end
      of the operation was 4.9 - 14.5 g/dl (mean 9.6) and at discharge it was 7.1 -
      14.5 g/dl (mean 15.5). No blood or blood products were used in any patient.
      CONCLUSION: Bloodless cardiac surgery with and without CPB can be safely
      performed in Jehovah's Witness infants and children.

PMID- 15192774
TI  - Intermittent aortic cross-clamping for isolated CABG can save lives and money:
      experience with 15307 patients.
AB  - BACKGROUND: The ideal myocardial protection during isolated CABG is still a
      matter of debate. Cardioplegia versus intermittent aortic cross-clamping (IACC)
      are the main opponents; the following article shows that IACC can be safe,
      efficient and might be cheaper than cardioplegia. METHODS: Demographics and co
      morbidities of 15307 CABG only patients consecutively operated on between January
      1993 and October 2001 in the Heart Center in Bad Oeynhausen were assessed by the
      German Quality Assurance data set and risk-stratified using the EuroSCORE.
      Outcome (30-day or in-hospital mortality) was compared to the expected EuroSCORE
      estimation. RESULTS: Expected mortality was 3.25 %, observed mortality was 1.3 %,
      being significantly lower in the low, medium as well as high risk patients
      subgroup. Complication rates increased steadily with expected mortality rates.
      Stroke and myocardial infarction rates for patients with peripheral vessel
      disease were not higher than in comparable studies. More than 1000000 EUR were
      saved by lower cardioplegia bills. CONCLUSION: Myocardial protection with
      intermittent aortic cross-clamping for isolated CABG can be safe, effective, and
      economically advantageous when compared to cardioplegic solutions.

PMID- 15192775
TI  - CABG and bone marrow stem cell transplantation after myocardial infarction.
AB  - OBJECTIVE: Bone marrow-derived adult stem cells may be able to regenerate
      infarcted myocardium. We initiated a phase-I study of autologous stem cell
      transplantation in patients undergoing coronary artery bypass grafting. METHODS:
      Inclusion criteria were: acute myocardial infarction > 10 days ago; presence of a
      distinct area of infarcted and akinetic myocardium; CABG indicated to treat
      ischemia of other LV wall areas. Stem cells were isolated from bone marrow using
      a ferrite-conjugated AC133 antibody, and were injected in the infarct border zone
      during the CABG operation. RESULTS: To date, 12 patients were treated without
      major complications. There is no evidence of new ventricular arrhythmia or
      neoplasia. Scintigraphic imaging demonstrated significantly improved local
      perfusion in the stem cell-treated infarct area. LV dimensions (LVEDV 140 +/- 38
      ml vs. 124 +/- 30 ml, p = 0.004, paired t-test) and LV ejection fraction (39.7 +/
      9 % vs. 48.7 +/- 6 %, p = 0.007) have improved. CONCLUSIONS: Bone marrow stem
      cell transplantation for myocardial regeneration can be safely performed in
      humans. There is evidence of improved revascularization and contractility of
      infarct areas, but controlled studies are needed to clearly determine the
      clinical benefit.

PMID- 15192776
TI  - Psychological care and vocational reintegration of patients with coronary artery
      disease after open heart surgery.

PMID- 15192778
TI  - Excision of the coronary orifices in arterial switch operation: "O" like
      obstructive and "U" like unobstructive?
AB  - BACKGROUND: Stenoses of the neo-pulmonary artery (NPA) may complicate follow-up
      of the arterial switch operation (ASO). It is unknown whether the type of patch
      covering the coronary excision defects ("O"- or "U"-shaped) might influence this
      complication. METHODS: Echocardiographically and invasively measured NPA pressure
      gradients were evaluated retrospectively in 95 children after ASO. Median follow
      up was 5.8 years. Defects had been covered with pericardial patches: O/O and U/U
      (left/right) 34 x each, and 27 x in mixed combinations. The frequency of NPA
      stenoses requiring re-interventions was registered. RESULTS: Median of the peak
      instantaneous echocardiographic pressure gradient was 23 mmHg (interquartile
      range, IQR: 16 - 49, n = 34) in O/O, and 19 mmHg (IQR: 13 - 23, n = 34) in U/U; p
      < 0.034, t-test. Invasively measured gradients were 49 mmHg (IQR: 17 - 65, n =
      12) in O/O, and 12 mmHg (IQR: 7-21, n = 28) in U/U; p < 0.001. One child per O/O-
      and U/U-group underwent balloon angioplasty of the neo-pulmonary root. Five
      children of the O/O-group had to undergo repeat surgery, whereas only one child
      in the U/U-group required repeat surgery ( p < 0.34). CONCLUSIONS: The
      preferential type of covering the NPA coronary excision sites in ASO should be U
      shaped.

PMID- 15192777
TI  - First experience with rapamycin-based immunosuppression to improve kidney
      function after heart transplantation.
AB  - This study was designed to gain initial experience with rapamycin in thoracic
      organ transplant recipients with severely compromised kidney function, i.e. to
      see whether and how kidney function will improve with a rapamycin-based
      immunosuppressive protocol. METHODS: Twelve heart transplant patients were
      included into the study (serum creatinine > 2.5 mg/dL), with an average time
      after transplantation of more than 4 years. The calcineurin inhibitor
      (cyclosporine A = 9, tacrolimus = 3) was reduced by 50 %, and rapamycin added to
      reach a target level of 8 - 12 ng/dL. Azathioprine was halted, corticosteroid
      treatment remained unchanged. RESULTS: After implementing the rapamycin-based
      immunosuppression kidney function improved in all patients within one week. Serum
      creatinine dropped from 3.1 +/- 0.6 mg/dL to 2.7 +/- 0.5 mg/dL ( p = 0.0004),
      creatinine clearance increased from 30.4 +/- 11 mL/min to 40.8 +/- 10.5 mL/min (
      p = 0.003). This improvement continued until 3 months after the conversion ( p =
      0.032). Thereafter, no statistically significant changes were noted up to 6
      months posttransplant ( p = 0.41). Serum cyclosporine levels dropped from 180 +/-
      40 ng/mL to 132 +/- 46 ng/mL on average ( p = 0.002). Side-effects occurred in 4
      patients and were all related to a rapamycin level exceeding 12 ng/mL.
      CONCLUSIONS: We conclude that transplant patients with impaired kidney function
      will have an immediate benefit from partially replacing calcineurin inhibitors by
      rapamycin.

PMID- 15192779
TI  - Warm or cold ischemia in animal models of lung ischemia-reperfusion injury: is
      there a difference?

PMID- 15192780
TI  - Surgical outcome of combined pulmonary and atrial resection for lung cancer.
AB  - OBJECTIVES: The study was carried out to assess the short and long-term outcome
      of patients with non-small cell lung cancer infiltrating the left atrium treated
      by surgery. METHODS: We retrospectively collected the hospital files of twenty
      three consecutive patients operated on between 1982 and 2001 in two units of
      Thoracic Surgery. Four patients received an induction regimen. Fourteen right
      pneumonectomies, 8 left pneumonectomies and 1 right inferior lobectomy were
      performed. No cardiopulmonary bypass was employed. RESULTS: In all patients the
      diagnosis of T4 atrial invasion was confirmed by pathological examination. A
      complete resection was achieved in nineteen patients (83%). With respect to nodal
      staging, there were 13 N0, 5 N1 and 4 N2 cases, respectively. Two deaths occurred
      during the one month postoperative period (9%). Three patients had postoperative
      atrial fibrillation. Two other patients had postpneumonectomy empyema without
      bronchopleural fistula and recovered, one after thoracoscopic debridement and the
      second after open window thoracostomy. Follow-up was completed on September 2002;
      only one patient was lost to follow-up. Median survival, excluding the
      perioperative mortality, was 20 months (range 4 - 62 months). The survival rate,
      calculated with the Kaplan-Meier method, was estimated as 63% at 1 year, 2 % at 3
      years and 10% at 5 years. Using a Cox model analysis, lymph node stage and
      completeness of resection were not independent prognostic factors. CONCLUSIONS:
      In cases of NSCLC with left atrial invasion complete resection is technically
      feasible in most instances without cardiopulmonary bypass. The acceptable
      operative risk and the encouraging long-term survival observed in this series
      suggest that NSCLC invading the left atrium should not be systematically
      considered as a definitive contraindication to surgery.

PMID- 15192781
TI  - Supraclavicular approach without thoracotomy for posterior mediastinal tumor.
AB  - Using a right-sided supraclavicular approach, we operated on a 15-year-old girl
      with a posterior mediastinal neurogenic tumor and von Recklinghausen's disease.
      The encapsulated 95 x 65 x 40 mm neurofibroma was removed safely and completely
      without thoracotomy. No peripheral neurologic defect such as Horner's syndrome,
      paralysis of accessory nerve, or palsy of the right upper extremity was observed
      after operation. The postoperative course was uneventful and the patient was
      discharged on the third postoperative day with no symptoms. Today, various
      adaptations of video-assisted thoracic surgery are frequently utilized for many
      lesions. However, more direct, safer, and less invasive approaches should be
      selected based on local anatomy, such as the supraclavicular approach without
      thoracotomy that we utilized.

PMID- 15192782
TI  - Unusual complications after rewarming for deep accidental hypothermia.
AB  - Deep accidental hypothermia is an uncommon pathology. Successful management has
      been reported in isolated cases, but the majority of patients die from
      complications after rewarming. We report on a patient with deep accidental
      hypothermia after a mountaineering accident. He was successfully rewarmed with
      cardiopulmonary bypass, but presented several complications which led to death.
      These complications included the patient developing acute peritonitis and
      necrotizing fasciitis, which represent, to our knowledge, complications that have
      never been associated with deep accidental hypothermia before.

PMID- 15192783
TI  - Surgery for aortic arch thrombosis.
AB  - A localized thrombus involving the ascending aorta and arch rarely occurs in the
      absence of an underlying etiology such as chest trauma, atherosclerosis, a
      hypercoagulable state or instrumentation. A review of the literature between 1966
      - 2003 yielded 38 reported cases of localized aortic arch thrombi, 21 of which
      were treated by surgical excision of the thrombus using different approaches. In
      this communication, we describe this clinical entity, with its diagnosis and
      management. The technical details that are important to ensure the safe conduct
      of the procedure are discussed.

PMID- 15192785
TI  - The epidemiology of cholangiocarcinoma.
AB  - The incidence rates of cholangiocarcinoma (CC) vary greatly among different areas
      of the world, and this variation is related to distribution of risk factors.
      Intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC)
      have different epidemiological features. Recent data show that the incidence and
      mortality rates of ICC have been increasing in several areas around the world. On
      the other hand, the incidence and mortality rates of ECC have been decreasing.
      For example, in the United States, the age-adjusted incidence rates of ICC
      increased by 165% from 0.32 per 100,000 in 1975 to 1979 to 0.85 per 100,000 in
      1995 to 1999, whereas ECC declined by 14%. In the meantime, there has been very
      little improvement in long-term survival, which remains dismal (3.5%). Men are
      affected 1.5 times more than women are, and Asians are affected almost 2 times
      more than whites and blacks. There are few well-established risk factors for CC,
      including primary sclerosing cholangitis, liver fluke infestations,
      hepatolithiasis, Thorotrast exposure, and choledochal cysts. None of these risk
      factors can explain the recent increasing trends of ICC in the United States.
      Some data, however, point to a potential role for chronic liver disease,
      hepatitis C, and probably hepatitis B infections in the development of ICC.

PMID- 15192786
TI  - The molecular pathogenesis of cholangiocarcinoma.
AB  - Cholangiocarcinoma is rising in clinical importance because of increasing
      incidence, poor prognosis, and suboptimal response to therapy. Recent
      investigations into the underlying molecular mechanisms involved in
      cholangiocarcinogenesis and tumor growth have contributed greatly to our
      understanding of this disease. To review this topic, we discuss the molecular
      mechanisms in sections reflecting the unique features that allow cancer cells to
      develop and maintain a growth advantage. Through a better understanding of these
      mechanisms, improved and more specific diagnostic, therapeutic, and preventative
      strategies may be developed and hopefully improve the outcome of this devastating
      disease.

PMID- 15192787
TI  - Serum and bile markers for cholangiocarcinoma.
AB  - Surgery remains the only curative treatment option for cholangiocarcinoma (CC).
      Currently, both early identification of CC in affected individuals at high risk
      and accurate diagnosis of unexplained biliary strictures are problematic.
      However, growing insights into biochemical and molecular mechanisms underlying
      biliary carcinogenesis have suggested serum and bile markers for the diagnosis of
      CC. These tools include tumor antigens or products (e.g., carbohydrate antigen
      [CA] 19-9), cytokines (e.g., interleukin-6), metabolic products (e.g., lactate),
      proteases (e.g., trypsinogen-2), regulatory peptides (e.g., pancreatic
      polypeptide), and (epi-)genetic lesions (e.g., K- ras and p53 mutations, p16
      (INK4a) or p14 (ARF) promoter hypermethylation). In this article we discuss these
      new potential tumor markers for the diagnosis of CC.

PMID- 15192788
TI  - Magnetic resonance imaging of cholangiocarcinoma.
AB  - Cholangiocarcinoma arises from the bile ducts and is the most common primary
      malignancy of the biliary tree. Cholangiocarcinoma is classified according to its
      growth pattern: mass-forming, periductal-infiltrating, or intraductal-growing
      type. The majority of cholangiocarcinomas occur at the common hepatic duct (CHD)
      and its bifurcation, also referred to as Klatskin's tumor, but they also can
      occur in more peripheral branches within the hepatic parenchyma. Microscopically,
      cholangiocarcinoma represents an adenocarcinoma with a glandular appearance
      arising from the epithelium of the bile ducts. On magnetic resonance (MR) images,
      cholangiocarcinomas appear hypointense on T1-weighted images, and hyperintense on
      T2-weighted images. Central hypointensity can be seen on T2-weighted images and
      correspond to fibrosis. On dynamic MR images, cholangiocarcinomas show moderate
      peripheral enhancement followed by progressive and concentric filling in the
      tumor with contrast material. Pooling of contrast within the tumor on delayed MR
      images is suggestive of peripheral cholangiocarcinoma. The role of MR imaging in
      hilar cholangiocarcinoma is to confirm/reach a diagnosis and to assess
      resectability. Hilar cholangiocarcinoma shows the same signal intensity pattern
      of peripheral tumors both on T1- and T2-weighted images. On magnetic resonance
      cholangiopancreatography (MRCP) images, hilar cholangiocarcinoma appears as a
      moderately irregular thickening of the bile duct wall (>/=5 mm) with symmetric
      upstream dilation of the intrahepatic bile ducts. The aim of preoperative
      investigation in Klatskin tumors typically requires the evaluation of the level
      of biliary obstruction, the intrahepatic tumor spread, and the vascular
      involvement; it also needs to show any atrophy-hypertrophy complex. Because of
      its intrinsic high tissue contrast and multiplanar capability, MR imaging and
      MRCP are able to detect and preoperatively assess patients with
      cholangiocarcinoma, investigating all involved structures such as bile ducts,
      vessels and hepatic parenchyma. The main reason for surgical/imaging discrepancy
      is represented by the microscopic diffusion along the mucosa and in the
      perineural space.

PMID- 15192789
TI  - Endoscopic management of cholangiocarcinoma.
AB  - Cholangiocarcinoma (CCA) is an uncommon malignant tumor arising from the biliary
      epithelium. The incidence increases with age and usually affects individuals in
      their 6th or 7th decade of life. Those patients with underlying risk factors such
      as primary sclerosing cholangitis (PSC) and choledochal cysts generally present 2
      decades earlier. Most patients clinically present with painless jaundice;
      however, other common symptoms include pruritus, weight loss, and abdominal pain.
      Although surgical resection offers the only hope for cure, most patients are
      found to have unresectable disease on initial presentation and have an extremely
      grim prognosis. This has led to an emphasis on the role of palliative care, with
      relief of biliary obstruction, in the management of these patients. Surgical
      bypass was once the primary means of palliation of jaundice in patients with
      unresectable cholangiocarcinoma but in the last 2 decades has been superseded by
      less invasive and less morbid nonsurgical procedures such as endoscopic and
      percutaneous biliary stent placement. Newer modalities of palliation such as
      endoscopic delivery of photodynamic therapy and high-intensity ultrasound therapy
      are emerging nonsurgical modalities that may result in improved survival and may
      play a future role as an adjunctive therapy to surgical resection.

PMID- 15192790
TI  - Photodynamic therapy for cholangiocarcinoma.
AB  - The prognosis of perihilar cholangiocarcinoma (CC) is limited by tumor spread
      along the biliary tree leading to refractory obstructive cholestasis,
      cholangitis, and liver failure. Palliation with biliary endoprostheses yields
      median survival times between 4 and 6 months for nonresectable CC. Tumor ablation
      with photodynamic therapy (PDT) combined with biliary stenting reduces
      cholestasis and significantly improves median survival time to 11.5 to 16.2
      months. PDT with porfimer and laser light of 630 nm provides tumoricidal tissue
      penetration to a depth of only 4 to 4.5 mm that does not eradicate most tumors.
      Time to progression lasts approximately 6 months; in other words, PDT is required
      twice annually. PDT costs less and enhances quality of life and survival time as
      compared with chemotherapy for metastatic colon cancer. These data suggest that
      PDT should be offered as part of the palliative treatment of CC in hepatobiliary
      referral centers.

PMID- 15192791
TI  - Surgical management of cholangiocarcinoma.
AB  - Biliary tract cancer affects approximately 7500 Americans each year. Tumors
      arising from the gallbladder are the most common; those of bile duct origin, or
      cholangiocarcinoma, are less frequently encountered, constituting approximately
      2% of all reported cancers. Although cholangiocarcinoma can arise anywhere within
      the biliary tree, tumors involving the biliary confluence (i.e., hilar
      cholangiocarcinoma) represent the majority, accounting for 40 to 60% of all
      cases. Twenty to 30% of cholangiocarcinomas originate in the lower bile duct, and
      approximately 10% arise within the intrahepatic biliary tree and will present as
      an intrahepatic mass. Complete resection remains the most effective and only
      potentially curative therapy for cholangiocarcinoma. For all patients with
      intrahepatic cholangiocarcinoma and nearly all patients with hilar tumors,
      complete resection requires a major partial hepatectomy. Distal
      cholangiocarcinomas, on the other hand, are treated like all periampullary
      malignancies and typically require pancreaticoduodenectomy. Most patients with
      cholangiocarcinoma present with advanced disease that is not amenable to surgical
      treatment, and even with a complete resection, recurrence rates are high.
      Adjuvant therapy (chemotherapy and radiation therapy) has not been shown clearly
      to reduce recurrence risk.

PMID- 15192793
TI  - Invasive colloid carcinoma arising from intraductal papillary neoplasm in a 50
      year-old woman with primary sclerosing cholangitis.

PMID- 15192792
TI  - Liver transplantation for unresectable perihilar cholangiocarcinoma.
AB  - Patients with unresectable, stage I and II perihilar cholangiocarcinoma were
      treated with neoadjuvant external beam irradiation, brachytherapy, and 5
      fluorouracil and/or oral capecitabine prior to liver transplantation. Fifty-six
      patients underwent treatment between 1993 and 2003. Four patients died and 4 had
      disease progression prior to completion of neoadjuvant therapy. Forty-eight
      patients underwent operative staging and 14 had findings precluding
      transplantation. Twenty-eight patients underwent transplantation and 6 patients
      are awaiting transplantation. Three patients died from perioperative
      complications, and 4 developed recurrent disease 22 to 63 months after
      transplantation. Actuarial patient survival was 54% at 5 years for all 56
      patients, 64% for 48 operatively staged patients, and 84% for 34 patients with
      negative staging operations. Actuarial survival was 88% at 1 year and 82 % 5
      years after transplantation. Neoadjuvant chemoradiotherapy with liver
      transplantation achieves excellent results for patients with localized, regional
      lymph node negative, hilar cholangiocarcinoma.

PMID- 15192794
TI  - HBV viral kinetics and clinical management: key issues and current perspectives.
      Proceedings of a scientific and clinical expert panel meeting. Chicago, Illinois,
      USA, October 18, 2003.

PMID- 15192795
TI  - Molecular virology of hepatitis B virus.
AB  - Hepatitis B virus (HBV) has evolved a unique life cycle that results in the
      production of enormous viral loads during active replication without actually
      killing the infected cell directly. Because HBV uses reverse transcription to
      copy its DNA genome, mutant viral genomes emerge frequently. Particular selection
      pressures, both endogenous (host immune clearance) and exogenous (vaccines and
      antiviral drugs), readily select out these escape mutants. Which particular viral
      mutations or combination of mutations directly affect the clinical outcome of
      infection are not known. Further studies are clearly needed to identify the
      pathogenic basis and clinical sequelae arising from the selection of these
      mutants.

PMID- 15192796
TI  - Hepatitis B virus kinetics and mathematical modeling.
AB  - In this article, we review modeling and interpretation of kinetics data obtained
      from patients with chronic hepatitis B virus infection that has been treated with
      lamivudine, adefovir dipivoxil, and lamivudine plus famciclovir combination
      therapy.

PMID- 15192797
TI  - The natural history of chronic hepatitis B virus infection.
AB  - Three stages of chronic hepatitis B virus (HBV) infection are recognized: the
      immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis
      B carrier phase. Active liver disease is most often found in persons with
      elevated aminotransferase levels and HBV DNA levels >10(5) copies/mL. Possible
      risk factors for developing liver disease include older age, male gender,
      presence of hepatitis B e antigen (HBeAg), HBV genotype, mutations in the precore
      and core promoter regions of the viral genome, and coinfection with hepatitis D
      (delta) virus. All persons chronically infected with HBV should be followed every
      6 to 12 months with aminotransferase levels. Those with elevated levels should be
      tested for HBeAg and its antibody (anti-HBe) as well as HBV DNA levels to
      determine if they are in need of further evaluation with a liver biopsy and are
      candidates for antiviral therapy. Future research will help clarify the outcome
      of chronic HBV infection.

PMID- 15192799
TI  - Clinical trial results and treatment resistance with lamivudine in hepatitis B.
AB  - Lamivudine is an effective first-line therapy for chronic hepatitis B virus (HBV)
      infection, accomplishing the goals of viral suppression, normalization of alanine
      aminotransferase (ALT) levels, histological improvement, and seroconversion. In
      the lamivudine clinical trials, up to 32% of patients positive for hepatitis B e
      antigen (HBeAg) lost HBeAg after 1 year of treatment, and approximately 18%
      achieved HBeAg seroconversion. ALT levels greater than five times the upper limit
      of normal increased the likelihood of HBeAg loss. The rates of seroconversion and
      resistance both increase with the length of treatment. In HBeAg-negative
      patients, two thirds showed response after 6 to 12 months of therapy, but this
      response diminished over time despite continued treatment, largely due to the
      emergence of resistance. Resistance is present in nearly 70% of patients at 5
      years. Resistance reverses prior biochemical, virological, and histological gains
      and can lead to progressive liver failure. Careful patient selection is
      important, therefore, to maximize the potential for a treatment response under
      limited therapy.

PMID- 15192798
TI  - Overview of treatment of hepatitis B: key approaches and clinical challenges.
AB  - The development of nucleoside analogues has been a major advance in the treatment
      of hepatitis B; however, prolonged monotherapy is associated with drug
      resistance. Currently, no data in humans indicate that a combination of
      nucleoside analogues leads to enhanced efficacy. New nucleoside analogues with
      greater inhibitory effects on hepatitis B virus (HBV) replication being developed
      could prove to be more effective or less likely to be associated with viral
      resistance. Interferon still has a role to play in the management of chronic HBV
      infection. Recent data indicate that the response to interferon may be determined
      in part by differences in genotype. From a theoretical perspective, a combination
      of pegylated interferon with one or more nucleosides could induce a higher rate
      of virological response. Additional studies are needed to further address these
      issues.

PMID- 15192800
TI  - Treatment of patients with chronic hepatitis B with adefovir dipivoxil.
AB  - Adefovir dipivoxil, a nucleotide analog of adenosine monophosphate, is an
      antiviral agent that suppresses hepatitis B virus (HBV) replication through
      inhibition of DNA polymerase and by chain termination. To determine the
      effectiveness of adefovir, three populations of patients with chronic hepatitis B
      patients were studied: hepatitis B e antigen (HBeAg)-positive patients, HBeAg
      negative patients, and patients with lamivudine-resistant tyrosine-methionine
      asparate-aspartate (YMDD) mutants. All three groups of patients were treated for
      48 weeks with adefovir 10 mg/d, and significant reduction in serum HBV DNA and
      normalization of serum alanine aminotransferase (ALT) were noted. Significant
      improvement in liver histology was noted in HBeAg-positive and in HBeAg-negative
      patients. Significant HBeAg loss and HBeAg seroconversion rates were noted in
      HBeAg-positive patients and in lamivudine-resistant patients. No major drug
      related side effects were noted. Adefovir 10 mg/d orally is safe and effective
      for treatment of chronic hepatitis B.

PMID- 15192801
TI  - Treatment with interferons (including pegylated interferons) in patients with
      hepatitis B.
AB  - Studies of 4 to 6 months of treatment with interferon for hepatitis B e antigen
      (HBeAg)-positive chronic hepatitis B virus (HBV) infection have shown clearance
      of HBeAg to be higher in treated patients than it is in controls by approximately
      25%. These results are considerably better than those with antiviral agents.
      Therefore, the recent European Association for the Study of the Liver (EASL)
      Consensus Committee recommended the use of interferon alpha for this condition.
      Treatment with pegylated interferons in several trials has shown better results
      still. Lamivudine in combination with interferon, however, did not improve the
      results at 6 months after the end of therapy. In HBeAg-negative chronic HBV
      infection, pegylated interferon alpha is superior to lamivudine, and, again,
      combination with lamivudine does not improve the results. Side effects in all
      studies have been tolerable. Thus, these observations in chronic HBV infection,
      whether HBeAg-positive or HBeAg-negative, suggest an important, even primary,
      role for pegylated interferon therapy.

PMID- 15192802
TI  - Management of hepatitis B in liver transplantation patients.
AB  - The success of orthotopic liver transplantation for patients with hepatitis B
      virus (HBV) disease has been compromised by reinfection. Prophylaxis has
      dramatically lowered the rate of reinfection and increased patient survival. Long
      term treatment with hepatitis B immunoglobulin (HBIg), although expensive, is
      effective. New antiviral nucleoside analogs have also been evaluated. In patients
      with cirrhosis and replicative HBV infection, lamivudine before transplantation
      and in combination with HBIg post transplantation reduces reinfection, but the
      rate of resistance mutation is rather high, reaching 25% at 2 years. Adefovir has
      been used as a rescue therapy and prior to transplantation in lamivudine
      resistant patients, significantly improving liver function and reducing HBV DNA
      levels. Patients with active viral replication should receive preoperative
      antiviral therapy with lamivudine. HBIg therapy may be discontinued in selected
      patients after transplantation, albeit with caution, because low levels of HBV
      DNA have persisted. Antiviral therapy has improved the prognosis after graft
      infection.

PMID- 15192803
TI  - HBV infection in patients with end-stage renal disease.
AB  - Controlling the spread of hepatitis B virus (HBV) infection in dialysis units has
      been one of major triumphs in the management of end-stage renal disease. However,
      HBV incidence and prevalence rates remain high in dialysis patients in less
      developed countries, and HBV within dialysis units continues to spread in the
      industrialized world. Overall response rates to HBV vaccination are lower in
      dialysis patients than in the nondialysis population. Lamivudine is effective in
      the treatment of HBV infection in the dialysis setting. Presence of hepatitis B
      surface antigen (HbsAg) has a negative impact on patient survival after renal
      transplantation. Several issues remain unanswered with regard to the management
      of HBV infection in dialysis patients, including the management of lamivudine
      resistance and the optimal timing and duration of antiviral therapy. Liver biopsy
      prior to renal transplantation is crucial in order to identify and exclude
      patients with advanced fibrosis or even cirrhosis.

PMID- 15192804
TI  - Practical management of chronic hepatitis B infection.
AB  - Chronic hepatitis B virus (HBV) infection is a complex disease. In recent years,
      there has been a marked increase in new knowledge regarding its virology,
      epidemiology, and natural history. In addition, more sensitive molecular
      diagnostic tests and relatively effective therapies for many individuals with
      chronic HBV infection have been developed and are available to practicing
      physicians. On the other hand, the influx of new immigrants from HBV hyperendemic
      areas such as the Asia-Pacific region, Indochina, and Eastern Europe has
      increased the demand for management of HBV infection in these populations.
      Physicians thus need to be able to identify persons at risk for hepatitis B and
      to evaluate and monitor them appropriately. Counseling on precautions to prevent
      transmission of HBV is also important for patients, as is education regarding the
      natural course of HBV infection and patient prognosis. Clinicians need to balance
      the treatment options carefully for their patients. This article provides up-to
      date information on management of HBV infection for practicing physicians.

PMID- 15192805
TI  - New treatment of chronic hepatitis B.
AB  - Currently approved treatments for chronic hepatitis B are limited by low rates of
      sustained response, side effects, or drug resistance. Thus, new treatments that
      have more potent antiviral effects, less toxicity, and minimal or no risk of
      resistance are needed. This article will focus on new antiviral agents that are
      being evaluated in clinical trials.

PMID- 15192815
TI  - [Mutational analysis of three Chinese pedigrees with adrenoleukodystrophy].
AB  - OBJECTIVE: To identify the mutational genotype of three Chinese families with X
      linked adrenoleukodystrophy (X-ALD: MIM#300100). METHODS: Total RNA was extracted
      from the peripheral blood leukocytes of patients 1, 2 and the mother of patient
      3, using RNA blood Mini kit (QIAGEN). After reverse transcription, cDNA was
      amplified in four overlapping segments. The PCR products were purified and
      directly sequenced. To confirm the mutations, the genomic DNA was isolated from
      the patients and their family members using DNA blood isolation kit (MO-BIO) and
      analyzed by PCR-restrictive digestion or amplification refractory mutation
      system. RESULTS: Three distinct mutations were detected in the ABCD1 gene of the
      three pedigrees. A mutation of CCC-->CGC was detected at codon 534 of the ABCD1
      gene from patient 1, resulting in the arginine for proline substitution. A change
      of GGG-->AGG was found at codon 266 of the second patient's gene, accompanied
      with the replacement of glycine by arginine. A mutation of CGC-->GGC was found at
      codon 617 in one ABCD1 allele of the third patient's mother, leading to the
      glycine for arginine substitution. The three mutations were confirmed through
      restriction analysis or amplification refractory mutation system. CONCLUSION:
      Three ABCD1 gene missense mutations were detected in three unrelated Chinese
      families with X-linked adrenoleukodystrophy, one of which, the mutation (P534R),
      is novel in Chinese with ALD, and the other two G266R and R617G mutations, have
      been reported outside China.

PMID- 15192806
TI  - Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6)
      cause Pelizaeus-Merzbacher-like disease.
AB  - The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD)
      and Pelizaeus-Merzbacher-like disease (PMLD) are characterized by nystagmus,
      progressive spasticity, and ataxia. In a consanguineous family with PMLD, we
      performed a genomewide linkage scan using the GeneChip Mapping EA 10K Array
      (Affymetrix) and detected a single gene locus on chromosome 1q41-q42. This region
      harbors the GJA12 gene, which encodes gap junction protein alpha 12 (or connexin
      46.6). Gap junction proteins assemble into intercellular channels through which
      signaling ions and small molecules are exchanged. GJA12 is highly expressed in
      oligodendrocytes, and, therefore, it serves as an excellent candidate for
      hypomyelination in PMLD. In three of six families with PMLD, we detected five
      different GJA12 mutations, including missense, nonsense, and frameshift
      mutations. We thereby confirm previous assumptions that PMLD is genetically
      heterogeneous. Although the murine Gja12 ortholog is not expressed in sciatic
      nerve, we did detect GJA12 transcripts in human sciatic and sural nerve tissue by
      reverse-transcriptase polymerase chain reaction. These results are in accordance
      with the electrophysiological finding of reduced motor and sensory nerve
      conduction velocities in patients with PMLD, which argues for a demyelinating
      neuropathy. In this study, we demonstrate that GJA12 plays a key role in central
      myelination and is involved in peripheral myelination in humans.

PMID- 15192817
TI  - [Study on the mechanism of oocyte aneuploidy formation by multicolor fluorescence
      in situ hybridization].
AB  - OBJECTIVE: To investigate the mechanism of oocyte aneuploidy formation. METHODS:
      The unfertilized oocytes were fixed 1-3 days after oocyte retrieval. Multicolor
      fluorescence in situ hybridization (M-FISH) was performed according to the Vysis
      protocol to check the chromosome status in oocytes by using centromeric
      enumerator probes for chromosomes 16, 18 and locus-specific probes for
      chromosomes 13, 21 and 22. RESULTS: 47% oocytes were found to be normal, while 53
      % oocytes were abnormal. Nondisjunction was found in 22(18%) oocytes, unbalanced
      predivision of chromatids in 15(12%) oocytes, balanced predivision of chromatids
      in 45(36%) oocytes. The balanced predivision rate in oocytes aged in vitro>24h
      was much higher than that in oocytes aged in vitro<or=24h (P<0.01). CONCLUSION:
      Both nondisjunction, balanced and unbalanced predivision of chromatids are
      involved in the oocyte aneuploidy formation. Balanced predivision is related to
      the time in culture.

PMID- 15192816
TI  - [Fine mapping of Smith-Fineman-Myers syndrome and exclusion of GPC3, GPCR2  MST4
      and GLUD2 as candidate genes].
AB  - OBJECTIVE: Smith-Fineman-Myers syndrome (SFMS) is an X-linked mental retardation
      syndrome. The authors had ascertained a large Chinese family with SFMS from
      Shandong and had mapped the disease locus to an interval of 19.8 Mb on Xq25
      flanked by markers DXS8064 and DXS8050. Further investigation suggested that SFMS
      exhibited locus heterogeneity. In this study for facilitating the identification
      of the gene responsible for SFMS, the additional markers were analyzed to narrow
      down the candidate region, and four candidate genes (GPC3, MST4,GPCR2 and GLUD2)
      were chosen and screened for disease-causing mutation. METHODS: PCR and
      denaturing polyacrylamide gel electrophoresis were used to genotype 13 new
      polymorphic markers distributed within the candidate region. Mutation detection
      was accomplished by sequencing the exons and intron-exon junctions of the
      candidate genes. RESULTS: By analyzing 13 additional polymorphic markers, SFMS
      candidate region can be reduced to an interval of 10.18 Mb bounded by XSTR3 and
      XSTR4, and no disease-causing mutation was identified in the coding regions of
      four candidate genes. CONCLUSION: GPCR2  GPC3, MST4 and GLUD2 were excluded as
      pathogenic genes for SFMS. The refined SFMS locus will assist in the
      identification and characterization of other candidate genes for SFMS.

PMID- 15192818
TI  - [Mutation analysis of ganglioside-induced differentiation associated protein-1
      gene in Chinese Charcot-Marie-Tooth disease].
AB  - OBJECTIVE: To study the mutation feature of ganglioside-induced differentiation
      associated protein-1 (GDAP1) gene in Chinese Charcot-Marie-Tooth disease(CMT)
      patients. METHODS: Mutation analysis was carried out by use of polymerase chain
      reaction-single strand conformation polymorphism(PCR-SSCP) combined with DNA
      direct sequencing of the six exons and their flanking regions of GDAP1 gene in
      twenty-three CMT patients, including 8 probands of autosomal recessive CMT
      families and 15 sporadic patients. RESULTS: A compound heterozygous mutation
      A533G and A767G were unveiled in one autosomal recessive CMT kindred. The
      homozygous and heterozygous T507G were common SNPs in Chinese population.
      CONCLUSION: A533G and A767G of GDAP1 gene were new mutations firstly reported.

PMID- 15192820
TI  - [Two base deletion of the alpha (1,2) fucosyltransferase gene responsible for
      para-Bombay phenotype].
AB  - OBJECTIVE: To probe into the molecular genetics basis for para-Bombay phenotype.
      METHODS: Red blood cell phenotype of the proband was characterized by serological
      techniques. Exons 6 and 7 of ABO gene, the entire coding region of alpha(1,2)
      fucosyltransferase (FUT1) gene and FUT2 gene were amplified by polymerase chain
      reaction (PCR) from genomic DNA of the proband respectively. The PCR products
      were excised and purified from agarose gels and were directly sequenced. RESULTS:
      AG at 547-552 deletion homozygous allele was found in the proband, which caused a
      reading frame shift and a premature stop codon. Parents of proband were
      heterozygous carriers. CONCLUSION: Two base deletion at position 547-552 of alpha
      (1,2) fucosyltransferase gene may cause para-Bombay phenotype.

PMID- 15192819
TI  - [Mutation detection of PKD2 gene in Chinese by denaturing high-performance liquid
      chromatograph].
AB  - OBJECTIVE: To detect the mutations of autosomal dominant polycystic kidney
      disease gene 2(PKD2)in Chinese. METHODS: The white blood cell genomic DNA from
      patients of 94 Chinese autosomal dominant polycystic kidney disease(ADPKD)
      pedigrees was isolated and amplified by polymerase chain reaction(PCR). The PCR
      products were analyzed by denaturing high-performance liquid
      chromatography(DHPLC). The samples with abnormal profiles were sequenced.
      RESULTS: Eight mutations were identified, including 2 nonsense mutations, 2
      deletion mutations,1 insertion mutation and 3 missense mutations. Two nonsense
      mutations occurred in exon 5(1249C-->T) and exon 13(2407C-->T),both resulted in a
      stop codon. The insertion was in exon 2(636-637 ins T),and the deletion mutations
      were in exons 12(2348-2351 del AGAA) and 13(2401 delete A),resulting in the
      reading frame shift. Three missense mutations were in exons 1(G568-->A),4(C964-
      >T),and 5(G1168-->A), which caused amino acid changes (190Ala-->Thr,322Arg-
      >Trp,390Gly-->Ser). CONCLUSION: The method of DHPLC was used in detecting
      mutations successfully and 8 mutations in PKD2 were identified. It will be useful
      in the molecular diagnosis of ADPKD in advance of the cysts formation and birth.

PMID- 15192821
TI  - [New polymorphism (IVS3-20 T-->C) of the parkin gene associated with the early
      onset Parkinson's disease in Chinese].
AB  - OBJECTIVE: To investigate the association between a new polymorphism (IVS3-20 T>C
      GenBank accession number: AY463003) in intro 3 of the parkin gene and the risk
      for Parkinson's disease (PD) in Chinese, particularly the relation between this
      polymorphism and the age of onset of PD patients. METHODS: PD was diagnosed
      according to the criteria of Core Assessment Program for Intracerebral
      Transplantations(CAPIT). All patients and controls were examined by two
      neurologists and were of the Han ethnic background. Polymerase chain reaction
      (PCR), denaturing high performance liquid chromatography (DHPLC) and sequencing
      were used to determine the genotype of each subject. RESULTS: A total of 312 PD
      patients (including 99 early-onset PD patients and 213 late-onset PD patients)
      and 236 controls were studied. The C/C homozygote was not found in this study.
      Chi-square analysis revealed that the frequencies of the C allele and T/C
      genotype were higher in total PD group but were not statistically different from
      those of the control group (P=0.6350 and 0.6331, respectively). After being
      stratified by age of onset, the frequency of T/C genotype was significantly
      higher (OR=3.52, 95%CI  0.97-13.13) in PD group with an onset age at or below 45
      years old (7.07%), compared with that in the control group (2.12%). Similarly, C
      allele was much higher (OR=3.42, 95%CI  0.96-12.57, P=0.0276) in the early-onset
      PD group (3.90%) than that in the control group (1.06%). The linear trend
      analysis showed that both the T/C genotype and C allele increased significantly
      in the PD group with the increase of the onset age [chi-square(trend of
      Genotypes)=4.414, P=0.036; chi-square(trend of Alleles)=4.344, P=0.037]. On the
      other hand, there was no difference in the frequencies of allele and genotype
      between the late-onset PD patients and controls. CONCLUSION: The above results
      suggest that the parkin IVS3-20 T>C polymorphism might be a genetic risk factor
      for early-onset PD in Chinese.

PMID- 15192822
TI  - [Carrier detection of Duchenne/Becker muscular dystrophy in Chinese families by
      microsatellite analysis].
AB  - OBJECTIVE: To screen and detect the female carriers from the DMD/BMD family
      members for prenatal or preimplantation genetic diagnosis. METHODS: For the
      detection of DMD/BMD carriers from 27 family members in 4 families, PCR to five
      microsatellite markers(located in 5' terminus and intron 44, 45, 49, 50) and
      analysis of the short tandem repeat(STR) sequence polymorphism with the use of
      genescan were implemented. RESULTS: Six of the 17 female members were obligate
      DMD gene carriers according to the haplotype analysis of the results of the
      genescan, which conformed with the pedigree analysis. Besides, the authors
      detected five carriers and five normal females in these families with the use of
      the haplotype analysis only. The most polymorphic locus was STR 49, and the least
      was STR 50. CONCLUSION: The STR haploid linkage analysis using (CA)n repeats
      within the human dystrophin gene is a rapid,accurate, objective method and is
      well suited for routine use in clinical laboratories engaged in DMD/BMD linkage
      analysis for the detection of carrier.

PMID- 15192823
TI  - [Additive effects of the variants in the beta(3)-adrenergic receptor and
      uncoupling protein-2 genes on obesity in Chinese].
AB  - OBJECTIVE: To investigate the additive effects of uncoupling protein 2 (UCP2)
      gene Ala55Val variation and ADR beta(3) gene Trp64Arg variation on the obesity in
      Chinese Han population. METHODS: The UCP2 gene Ala55Val variation and ADR beta(3)
      gene Trp64Arg variation were examined by polymerase chain reaction-restriction
      fragment length polymorphism(PCR-RFLP) in 119 obese subject with mean BMI (27.9+/
      2.98)kg/m(2) and in 177 control subjects with mean BMI(21.9+/-1.9)kg/m(2). The
      additive effects of the two gene mutations were analyzed. RESULTS: (1) The
      frequency of ADR beta(3) gene Trp64Arg variation in obese subjects was not
      significantly different from that in control subjects. In control subjects, the
      Trp64Arg variation carriers had higher fasting glucose level and 2-hour-post
      prandial glucose level than did non-carriers. (2) The frequency of homozygote of
      UCP2 gene Ala55Val variation in obese subjects was higher than that in the
      control subjects (OR=3.71, P=0.001). In control subjects the Ala55Val variation
      carriers had higher BMI. (3) When there was only UCP2 gene or ADR beta(3) gene
      mutation, the frequency of gene mutation in obese subjects was not significantly
      different from that in control subjects (P>0.05). But when there were
      simultaneously two gene mutations, the frequency of gene mutations was higher in
      obese subjects than in control subjects (OR=2.57, P=0.009). (4) The genotype
      carriers with Val/Val+ Trp/Arg were the greatest relation to obese obesity
      (OR=8.58, P=0.002). CONCLUSION: The homozygote of UCP2 gene Ala55Val mutation
      increases the risk of obesity. Though the UCP2 gene mutation alone or the ADR
      beta(3) gene mutation alone is not associated with obesity, the possible additive
      effects of the two micro-genes increase the occurring of obesity.

PMID- 15192824
TI  - [Polymorphism and multiplex amplification of 3 X-chromosome specific short tandem
      repeat loci].
AB  - OBJECTIVE: To devise a multiplex PCR system of three X-chromosome specific short
      tandem repeat (X-STR) loci and study the genetic polymorphism. METHODS: DXS6799,
      DXS6804 and DXS6854 were amplified simultaneously using a multiplex system and
      were typed by polyacrylamide gel electrophoresis and silver staining. RESULTS: A
      total of 262 male and 255 female individuals from Guangdong Han population were
      tested; each locus showed 7 alleles. 73 haplotypes were detected in the male
      individuals. The haplotype diversity reached 0.9674. CONCLUSION: The 3 X-STR
      multiplex system is relatively abundant in polymorphic information for forensic
      identification and paternity testing.

PMID- 15192825
TI  - [The mutation scanning of KCNQ1 gene for 31 long QT syndrome families].
AB  - OBJECTIVE: To search for the mutations of potassium voltage-gated channel, KQT
      like subfamily member 1(KCNQ1) gene in 31 Chinese long QT syndrome(LQTS)
      families. METHODS: Due to the genetic heterogeneity, the genotype of patients was
      first predicted based on the spectrum of ST-T-wave patterns on ECG. Ten of 31
      probands were considered as LQT1. Then the mutation of KCNQ1 gene was screened by
      the polymerase chain reaction and single strand conformation polymorphism (PCR
      SSCP) technique combined with DNA sequencing in all members of these 10 families.
      To avoid omitting some LQT1 patients without typical characteristics and also to
      do methodological comparison, the mutations of KCNQ1 gene on 16 exons were
      screened by PCR and direct DNA sequencing in the rest 21 non-LQT1 probands only.
      Co-segregation analysis was carried out after the finding of an abnormal
      sequence. In case that the abnormality existed in patients only, the test of such
      exon was performed in 50 irrelevant normal individuals. RESULTS: Two missense
      mutations and three single nucleotide polymorphisms (SNPs) were found in the LQT1
      predicted families. The two mutations were S277L (1 family) and G306V (1 family)
      in exon 5 and were not reported previously. Three polymorphisms were 435C-->T (7
      families), 1632C-->A (1 family), and IVS1+9 C-->G (3 families). Only a splice
      mutation IVS1+5G-->A (2 families) and a polymorphism IVS10+18C-->T (1 family)
      were found in the non-LQT1 predicted probands. All three mutations were localized
      within the functional domain of KCNQ1 and were co-segregated with the disease,
      and were not found in 50 normal individuals. CONCLUSION: Two novel missense
      mutations, 1 splice mutation and four SNPs on KCNQ1 gene were found in the 31
      LQTS families. Combined with ECG-based genotype prediction, PCR-SSCP could find
      most mutations on KCNQ1 and be a simple and economic method for screening LQTS.

PMID- 15192826
TI  - [Study on STK15 gene abnormality and centrosomal amplification in laryngeal
      carcinoma].
AB  - OBJECTIVE: To investigate STK15 gene abnormality and centrosomal amplification in
      laryngeal carcinoma. METHODS: STK15 gene mRNA expressional level was tested in 62
      cases of laryngeal squamous cell carcinoma and laryngeal squamous cell carcinoma
      cell line Hep-2 by reverse transcription-polymerase chain reaction(RT-PCR); the
      mutation of STK15 gene exon 6 and exon 7 in the same tissues and cells was
      detected by PCR-single strand conformation polymorphism. Immunofluorescent
      antibodies were used to test centrosomal amplification in Hep-2 cell line as an
      example. RESULTS: STK15 gene overexpressed in 39 cases of laryngeal carcinoma
      (63%) and Hep-2 cell line. No mutation was found in exon 6 and exon 7 of STK15
      gene in the above tissues and cells. Centrosomal amplification was apparent in
      Hep-2 cell line. The number of centrosome in a single cell changed from 1 to 7,
      and Hep-2 cells with amplified centrosomes (more than 2 in one cell) were 11%
      23%. CONCLUSION: STK15 gene overexpression and centrosomal amplification were
      first found in human laryngeal squamous cell carcinoma, which indicated that
      STK15 gene overexpression leading to centrosomal amplification might occur in the
      early stage of human laryngeal carcinogenesis and be one of the key mechanisms
      for the occurrence of laryngeal carcinoma.

PMID- 15192827
TI  - [Application of the Bgl II-Bln I dosage test to gene diagnosis of
      facioscapulohumeral muscular dystrophy 1A gene].
AB  - OBJECTIVE: To increase the sensitivity and specificity of conventional gene
      diagnosis of facioscapulohumeral muscular dystrophy 1A(FSHD1A) by analyzing the
      distribution of translocation between chromosomes 4q35 and 10q26 in suspected
      FSHD cases. METHODS: The Bgl II- Bln I dosage test was performed to detect
      translocation between chromosomes 4q35 and 10q26 in 7 cases of presymptomatic
      FSHD patients showing positive result in gene diagnosis and 5 cases of sporadic
      FSHD patients showing negative result in gene diagnosis. DNA samples were
      digested with Bgl II and Bln I, followed by agrose gel electrophoresis. Probe
      p13E-11 was labeled with alpha-(32) P dCTP, followed by Southern hybridization.
      Then the ratio between the chromosomes 4 and 10 derived signal intensities was
      judged and hence was made known whether there was interchromosomal translocation
      between chromosomes 4 and 10. RESULTS: The Bgl II-Bln I dosage test revealed a
      translocation from chromosome 4q35 to 10q26 in one presymptomatic FSHD patient,
      thus indicating the result of gene diagnosis for her might be false positive.
      There was one translocation from chromosome 10q26 to 4q35 detected in one
      sporadic FSHD patient, indicating the result of gene diagnosis for her might be
      false negative. There were no translocations between chromosomes 4 and 10 in the
      other 10 cases. CONCLUSION: The Bgl II-Bln I dosage test can detect the
      translocation between chromosomes 4q35 and 10q26. It can improve the accuracy of
      the conventional method for gene diagnosis of FSHD1A.

PMID- 15192828
TI  - [Structural characterization of 5' flanking regulatory region of DNA repair gene
      Rad51].
AB  - OBJECTIVE: To clarify the regulatory elements of Rad51 gene in its 5'flanking
      region. METHODS: Various constructs were obtained by cloning different DNA
      fragments into pGL3 reporter vector. These constructs were then introduced into
      osteosarcoma cell line U2-OS by calcium phosphate method for transient expression
      of reporter gene, and luciferase activities were measured by luciferase assay.
      RESULTS: Cells transfected with pGL3 constructs containing fragment -964 to +1430
      and -733 to +1430 showed high luciferase activities. Obvious elevation of
      luciferase activities was also observed in cells transfected with pGL3 constructs
      containing four shorter derivative fragments -964 to -412, -746 to -412, -651 to 
      412 and -536 to -412. The highest luciferase activities were measured in
      transfected cells with plasmids containing fragment -964 to -412, and the lowest
      were in transfected cells with plasmids containing fragment -536 to -412.
      Luciferase activities in transfected cells with plasmids containing fragment -651
      to -412 were higher than that in transfected cells with plasmids containing
      fragment -746 to -412. CONCLUSION: It is believable that the basic transcription
      promoting element (promoter) for Rad51 gene resides between -536 to -412, and two
      transcription-enhancing elements (enhancer) or binding sites of positive
      transcription factors reside between -651 to -536 and -964 to -746, whereas one
      transcription-inhibiting element (silencer) or binding site of negative
      transcription factor may reside between -746 to -651.

PMID- 15192830
TI  - [Progress in the research of aneuploidy genesis].
AB  - Aneuploidy is an important point at issue in human reproductive biology,
      accounting for both a major proportion of miscarriages and various congenital
      malformation syndromes among newborns. Despite its high incidence and severe
      clinical consequences, very little is known about how aneuploidy originates in
      human. On the other hand, remarkable progress has been made in the research of
      meiosis. The failure of any process in meiosis can result in chromosome mal
      disjunction. The alteration in recombination and the premature separation of
      sister chromatids are two important processes on which more intensive researches
      have been done. In addition, mtDNA mutation and sexual dimorphism in aneuploidy
      genesis have also attracted more and more researchers' attention.

PMID- 15192829
TI  - [Relationship of variation 3057 G-->A of exon 20 of leptin receptor gene to lipid
      metabolism and fat distribution of children with obesity].
AB  - OBJECTIVE: To assess the relationship of the variation of exon 20 of leptin
      receptor (LEPR) gene to the lipid metabolism and fat distribution of the children
      with obesity. METHODS: Polymerase chain reaction-restriction fragment length
      polymorphism(RFLP) and polyacrylamide gel electrophoresis were used to analyze
      the variation of exon 20 of the LEPR gene of the obesity group(72 obesity
      children) and the control group(60 healthy children). At the same time, all
      childrens' serum triglyceride(TG),total cholesterol(TC),high density lipoprotein
      cholesterol(HDL-C), low density lipoprotein cholesterol(LDL-C), height and weight
      were measured, and their body mass index(BMI) and fat percent(%fat) were
      calculated. RESULTS: Three genotypes of exon 20 of LEPR gene were detected in
      this study. Compared with the control, the frequency of gene variation at 3057
      nucleotide G-->A transversion was higher(P<0.05). The concentration of serum TG
      and the BMI and %fat of the A/A genotype obesity children were higher than those
      of the G/G genotype ones(P<0.01) but the level of serum HDL of the A/A children
      were lower than that of the G/G children (P<0.01). As to the G/A genotype
      children, only their serum TG level was higher than that of the G/G genotype
      ones(P<0.05). CONCLUSION: The above findings indicated there were polymorphisms
      in the children with obesity, and those polymorphisms might remarkably affect
      their lipid metabolism and fat distribution.

PMID- 15192831
TI  - [Study on mutations of exon 12 of the PAH gene in 127 phenylketonuria patients].
AB  - OBJECTIVE: To obtain the mutation spectrum of exon 12 of the phenylalanine
      hydroxylase(PAH) gene. METHODS: The samples from 127 patients with
      phenylketonuria(PKU) were studied by polymerase chain reaction(PCR)-single strand
      conformation polymorphism(SSCP)  PCR-denaturing gradient gel
      electrophoresis(DGGE) and direct DNA sequencing. RESULTS: Four heterozygous
      mutations including R413P  S411X  R408W  R408Q in 10 of 127 patients were
      identified by DNA sequencing. The frequencies of R413P  S411X  R408W  R408Q
      mutation were 2.76%, 0.39%, 0.39% and 0.39%, respectively. The S411X mutation in
      Chinese was first reported. Only 2 cases with R413P mutation were detected by
      SSCP. DGGE analysis showed that 10 cases displayed 3 kinds of abnormal
      electrophoretic bands. There were no obvious differences in the frequency of
      R413P mutation between northern and southern Chinese with PKU, and between
      classical PKU and hyperphenylalaninemia. CONCLUSION: DGGE is more sensitive than
      SSCP in screening the mutations of exon 12 of the PAH gene. DGGE combined with
      DNA sequencing can be used to define all the mutations of exon 12 of the PAH
      gene. These results indicate the similarity in the frequency of R413P mutation
      between northern and southern patients.

PMID- 15192832
TI  - [New mutations of the 12th exon of CCM1 gene in Chinese patients with
      intracranial cavernous angiomas].
AB  - OBJECTIVE: To study the effect of CCM1 gene mutations in Chinese patients with
      intracranial cavernous angiomas(ICCA). METHODS: Twenty-one ICCA patients
      confirmed by pathology after operations in hospital from June 2002 to Feb.2003
      and 15 healthy individuals as contrast were recruited. The peripheral venous
      blood samples of all the individuals were collected, and then DNA was extracted
      from the blood samples followed by amplification of exon 12 and some of its
      intron sequence using PCR. After purification, the PCR products were directly
      sequenced by ABI PRISM377 sequencing instrument. RESULTS: Three mutations of CCM1
      gene were found in 5 patients and reported firstly. There existed a missense
      mutation of 1172C-->T in exon 12 in 5 patients, which led the No.391 amino acid
      of KRIT1 protein, serine, to phenyalanine. There existed a missense mutation of
      1160A-->C in one patient, which led the No.387 amino acid, glutamine, to proline.
      Another mutation was an intronic mutation of IVS12-4C-->T in 4 patients. In
      contrast no mutations were found. CONCLUSION: The authors firstly report that
      mutations of CCM1 gene in exon 12 also exist in Chinese ICCA patients and those
      mutations are related with the occurring of ICCA.

PMID- 15192834
TI  - [Detection of a new mutation (G1253T) of iduronate-2-sulfatase gene for the
      patient with mucopolysaccharidosis type II].
AB  - OBJECTIVE: To identify the mutations of iduronate-2-sulfatase (IDS) gene in
      mucopolysaccharidosis type II patients. METHODS: PCR-SSCP analysis was applied to
      detect the common mutations in the exons 2, 3, 5, 7, 8, 9 in IDS-gene of the
      patient. DNA sequencing and PCR-RFLP were applied to analyze the mutation
      detected by PCR-SSCP. RESULTS: A new mutation(1253G-->T) of exon 7 of the IDS
      gene was found by PCR-SSCP and DNA sequencing in the patient, The PCR-restriction
      enzyme digestion showed that enzyme digestion location appeared in the patient
      and his mother, which verified the results of sequencing analysis. CONCLUSION:
      The mutation of patient with MPSII could be detected effectively and quickly by
      the applications of PCR-SSCP, DNA sequencing and PCR-restriction enzyme digestion
      analysis, and the new mutation thus detected is necessary for the prenatal
      diagnosis of the pedigree.

PMID- 15192833
TI  - [A cytogenetic and molecular genetic study on microdeletion of AZF region on Y
      chromosome].
AB  - OBJECTIVE: To study the morphology of Y chromosome and microdeletion of the
      correlated specific azoospermia factor(AZF) region on Y chromosome in cases of
      azoospermia and to identify the genetic diagnosis made for male infertility
      patients. METHODS: Peripheral blood samples were taken from two patients with
      azoospermia, and then were examined by use of G banding, C banding cytogenetic
      analysis and multiplex polymerase chain reaction (PCR) microdeletion analysis.
      RESULTS: The karyotypes of the two cases were 45, X, -Y, -22,
      +der(Y)t(Y;22)(q11.2;q11.2) and 46, XY, del(Y)(q11.2) respectively. In 12
      sequence-tagged sites(STS) of AZFa, AZFb, AZFd, AZFc, only one was detected in
      the first case and two were detected in the other case. CONCLUSION: The
      cytogenetic analysis and the detection of AZF microdeletion on Y chromosome are
      essential to the final genetic diagnosis to be made for male infertility
      patients.

PMID- 15192835
TI  - [Long QT syndrome gene diagnosis by haplotype analysis].
AB  - OBJECTIVE: Three long QT syndrome(LQTS) pedigrees were brought together for
      genetic diagnosis by using short tandem repeat(STR) markers. METHODS: Genomic DNA
      was extracted from blood samples. STR markers (D7S1824, D7S2439, D7S483, D3S1298,
      D3S1767, D3S3521) in or spanning the HERG and SCN5A gene were amplified; the
      haplotype analysis for LQTS was performed. RESULTS: Clinical diagnosis showed
      that 15 are LQTS patients (3 died) and 11 are probable patients. Linkage analysis
      showed that LQTS patients are linked with the SCN5A gene in family 1, HERG is
      linked with the disease in family 2 and 3. Fourteen gene carriers were
      identified, 2 patients and 7 probable patients were excluded. CONCLUSION: Linkage
      analysis using STR markers can serve as useful tool for presymptomatic diagnosis.

PMID- 15192836
TI  - [Association between the polymorphism of beta-fibrinogen gene -455G/A and
      ischemic stroke].
AB  - OBJECTIVE: To study the association between the variation of beta fibrinogen gene
      promoter -455G/A and ischemic stroke. METHODS: Eighty-six hypertensive patients
      with ischemic stroke (stroke group) and 85 hypertensive patients without ischemic
      stroke (hypertensive group) were randomly selected from the in patients, and 90
      healthy persons(control group) were recruited for this study. Polymerase chain
      reaction with restrictive enzyme Hae III (PCR-restriction fragment length
      polymorphism method) was employed to analyze the polymorphism of beta-fibrinogen
      gene promoter -455G/A. Plasma fibrinogen levels were measured with prothrombin
      time (PT) assay. RESULTS: A(-455) allele frequencies of the stroke group (0.22)
      was significantly higher than that of the control group and the hypertensive
      group (0.11, 0.13, chi-square=8.3 P<0.05). The genotype exhibited significant
      difference among the 3 groups; G/A and A/A were more commonly seen in the stroke
      group(chi-square=10.03,P<0.05). The mean fibrinogen level of the stroke
      group(4.82+/-0.26 g/L) was significantly higher than that of the control group
      and the hypertensive group(4.37+/-0.19, 5.50+/-0.20, F=5.98 P<0.01) In both
      stroke group and hypertensive group, the plasma fibrinogen levels in patients
      with -455G/G were significantly lower than those in patients with -455G/A, and 
      455A/A but the difference was not significant among the 3 genotypes in the
      control group. CONCLUSION: Plasma fibrinogen level could be affected by the beta
      fibrinogen gene -455G/A polymorphism. And A(-455) allele may be an independent
      risk factor for ischemic stroke.

PMID- 15192837
TI  - [Methylation and expression analysis of p16(INK4a) and RB genes in meningiomas].
AB  - OBJECTIVE: To investigate the methylation of p16(INK4a) and RB gene, and the
      expression of p16(INK4a) in meningiomas. METHODS: Methylation-specific polymerase
      chain reaction (MSP) was used to detect the methylation of p16(INK4a) and RB in
      50 cases of meningiomas, and immunostaining was performed to analyze the protein
      expression of p16(INK4a) in 25 of those cases. RESULTS: No methylation was found
      in the benign meningiomas, whereas methylation of p16(INK4a)or RB occurred in
      6(37.5%) cases of grade II tumors and 4(28.6%) cases of grade III tumors, and
      among these cases, an atypical meningioma showed methylation of both genes.
      Thirteen cases showed p16(INK4a) positive expression, but none of them was
      methylated. CONCLUSION: The methylation of p16(INK4a) or RB is related with the
      tumorigenesis and progression of atypical and anaplastic meningiomas, and a
      probable mechanism is that methylation causes the loss of expression and leads to
      dysfuncation of the p16(INK4a)/cyclin D1/CDK4/RB pathway.

PMID- 15192838
TI  - [Association of angiotensinogen gene M235T variant with hypertrophic
      cardiomyopathy].
AB  - OBJECTIVE: To evaluate the influence of the angiotensinogen(AGT) gene M235T
      variant on the prevalence and severity of hypertrophic cardiomyopathy(HCM).
      METHODS: The authors conducted a case-control study on 152 subjects, including 72
      HCM patients and 80 normal controls. Polymerase chain reaction(PCR) combined with
      restriction fragment length polymorphism(RFLP) was used to detect the M235T
      variant of AGT gene. Interventricular septum thickness, left ventricular
      posterior wall thickness and apical wall thickness were measured by means of M
      mode echocardiography under two-dimensional guidance in the parasternal long-axis
      plane and apical two- and four-chamber views. RESULTS: (1) The genotype
      distributions of AGT gene in both groups were in agreement with Hardy-Weinberg
      equilibrium. (2) The genotype distributions of the M235T variant differed
      significantly in HCM patients and controls(chi-square=6.090  P<0.05). The
      frequencies of TT genotype and T235 allele in HCM patients were higher than did
      the patients in controls(TT genotype  0.63 vs 0.45  OR=2.037  95%CI  1.064-7.899 
      P<0.05  T235 allele  0.78 vs 0.64  OR=1.990  95%CI  1.197-3.308  P<0.01). (3)The
      patients with the TT genotype had significantly greater mean left ventricular
      maximal wall thickness than did the patients with the MM and MT genotypes
      [(19.1+/-4.8) mm vs(15.3+/-2.6)mm and(16.2+/-5.1)mm  F=4.261  P<0.05].
      CONCLUSION: The variant M235T of the AGT gene is significantly associated with
      HCM in this population. The genotype TT or allele T might be a genetic risk
      factor for the development and extent of hypertrophy in HCM patients.

PMID- 15192839
TI  - [The relationship of angiotensin I-converting enzyme gene polymorphism with
      diabetic retinopathy and diabetes myocardial infarction].
AB  - OBJECTIVE: To investigate the relationship of angiotensin I-converting enzyme
      (ACE) gene polymorphism to diabetic retinopathy and diabetes myocardial
      infarction. METHODS: ACE insertion/deletion(I/D) polymorphism was determined by
      PCR. RESULTS: No evidence showed that ACE gene was associated with diabetic
      retinopathy. By comparison of the type 2 diabetes patients with myocardial
      infarction versus those without-myocardial infarction, it was found that the
      frequencies of homozygote DD (41.2% versus 33.2%) and of allele D (64.7% versus
      55.0%) increased remarkably; the difference was statistically significant
      (P<0.05). CONCLUSION: Allele D(RR=1.50) and genotype DD(RR=1.33) seemed to be a
      genetic risk factor for type 2 diabetes myocardial infarction.

PMID- 15192841
TI  - [Study on mixed lineage leukemia gene rearrangement in AML-M4/M5 by interphase
      fluorescence in situ hybridization].
AB  - OBJECTIVE: To explore the value of fluorescence in situ hybridization (FISH) in
      the detection of mixed lineage leukemia (MLL) rearrangement and to assess the
      incidence and prognostic significance of MLL gene rearrangement in AML-M4/M5.
      METHODS: Bone marrow chromosome preparation of 23 cases of acute myeloid
      leukemia(AML) consisting of 19 cases with M5 and 4 cases with M4 was made using
      direct method or short-term culture. Karyotypic analysis was carried out by R
      banding technique. Dig labeled 11q23 probe which spans the breakpoint cluster
      region in MLL was used to detect the MLL rearrangement in the above 23 cases.
      RESULTS: R-banding karyotyping analysis revealed 11q23 translocation in 7 cases,
      while FISH analysis detected MLL rearrangement in 12 cases including the above 7
      cases. CONCLUSION: Interphase FISH was more sensitive in detecting the MLL
      rearrangement in AML-M4/M5, compared with the conventional cytogenetic method.
      MLL rearrangement is highly related to AML-M4/M5; it is an indication of poor
      prognosis.

PMID- 15192840
TI  - [Alleles of HLA class II DRB1 of patients with essential hypertension in Yunnan
      Hans].
AB  - OBJECTIVE: To investigate the association between the alleles of human leukocyte
      antigens (HLA)-DRB1 and essential hypertension (EH) in the Hans living in Yunnan
      of China. METHODS: The alleles of HLA-DRB1 were typed by polymerase chain
      reaction-sequence specific primers (PCR-SSP) technique in samples from 83
      patients with essential hypertension and 91 healthy controls. All of the
      subjects, their grandparents and grand-grandparents are Hans living in Yunnan of
      China. RESULTS: The frequency of DRB1*1501/2 in the EH patients (0.219) was
      significantly higher than that in the controls(0.060), chi quare=18.331, P<0.01.
      Relative risk (RR) was 4.46, and etiologic factor (EF) was 0.34. The frequency of
      DRB1*0901 significantly decreased in the group of patients with EH in comparison
      to the controls (0.081 versus 0.192)  chi-square=8.704  P<0.05. RR was 0.41 and
      prevention factor(PF) was 0.19. CONCLUSION: HLA-DRB1*1501/2 is associated with
      the susceptibility to essential hypertension in the Yunnan Hans of China.
      DRB1*0901 may protect one from the disease.

PMID- 15192842
TI  - [Study on the association between the polymorphism of HLA-DQA1 alleles and type 2
      diabetes in Yunnan Han nationality].
AB  - OBJECTIVE: To investigate the association between the polymorphism of HLA-DQA1
      alleles and type 2 diabetes mellitus in Yunnan Hans. METHODS: Polymerase chain
      reaction-sequence specific primers(PCR-SSP) genotyping method was conducted in
      108 Han patients with type 2 diabetes and 56 ethnically matched controls from the
      same area of Yunnan Province. RESULTS: HLA-DQA1*0301(RR=3.092, P<0.01) and
      DQA1*0501 (RR=3.257, P<0.05) allelic frequencies in type 2 diabetic patients were
      significantly higher than those in non-diabetic control subjects respectively.
      HLA-DQA1*0401 (RR=0.371, P<0.01) allelic frequencies in patients were
      significantly decreased, compared with controls; HLA-DQA1*0302 (RR=3.356, P<0.01)
      allelic frequencies in patients with type 2 diabetic nephropathy were
      significantly increased. CONCLUSION: HLA-DQA1*0301 and DQA1*0501 are susceptible
      genes of type 2 diabetes in Yunnan Han nationality; in reverse, HLA-DQA1*0401 is
      a resistant gene. HLA-DQA1*0302 is a susceptible gene of type 2 diabetic
      nephropathy.

PMID- 15192844
TI  - [Genetic polymorphisms of short tandem repeat loci D3S1358, D13S317, D5S818 from
      Nongqu Mongolia].
AB  - OBJECTIVE: To understand the allele structure and genetic polymorphism at
      D3S1358, D13S317, D5S818 short tandem repeats (STRs) loci in Nongqu Mongolian of
      China, and to construct a preliminary database. METHODS: The allele frequencies
      of the three STRs loci in 291 unrelated individuals from Nongqu Mongolian were
      analyzed by polymerase chain reaction and polyacrylamide gel electrophoresis.
      RESULTS: Six, ten, and eight alleles were observed at D3S1358, D13S317, D5S818,
      respectively, and all 3 loci met Hardy-Weinberg equilibrium. The statistical
      analysis of 3 STR loci showed the heterozygosity >or=0.7332, the polymorphic
      information content >or=0.6884; the combined discrimination power and the
      probabilities of paternity exclusion were 0.9991 and 0.9806 respectively.
      CONCLUSION: All three of the loci in this study were found to have high
      heterozygosity and polymorphic information content, so they could provide useful
      markers for genetic purposes. These results could serve as valuable data to
      enrich the Mongolian genetic database and play an important role in Chinese
      population genetic application.

PMID- 15192843
TI  - [The polymorphism distributions of MICA and MICB microsatellite in Guangdong Han
      population].
AB  - OBJECTIVE: To investigate the genetic polymorphism of microsatellite in the exon
      5 of MICA gene and the intron 1 of MICB gene in Guangdong Han population.
      METHODS: One hundred and six samples of Guangdong Han population were genotyped
      by polymerase chain reaction and fluorescent technique (6-FAM). Gene frequency,
      power of discrimination, expected heterozygosity, polymorphism information
      content and probability of paternity exclusion were calculated. RESULTS: The
      genotype distributions of MICA and MICB microsatellite met Hardy-Weinberg
      equilibrium. MICA A5 was the most common allele (0.2877), whereas A4 was the
      least popular one (0.1321). The genotype distribution frequencies of A5-5.1
      (14.15%) and A5-5 (10.38%) are high. MICB CA14 was the most common allele
      (0.3255), and CA19,28 was the least popular one (0.0047). CA27 was not observed.
      The genotype distribution frequency of CA14-CA14(14.15%) is high. CONCLUSION: The
      microsatellite of the exon 5 of MICA gene and the intron 1 of MICB gene could be
      used as the genetic markers of Chinese population in the studies of anthropology,
      linkage analysis of genetic disease genes, individual identification and
      paternity test in forensic medicine.

PMID- 15192845
TI  - [Extrinsic allergic alveolitis].

PMID- 15192846
TI  - The embryo rescue debate.

PMID- 15192847
TI  - Washington Insider: Congressional impasse on human cloning.

PMID- 15192848
TI  - Coercing conscience: the effort to mandate abortion as a standard of care.

PMID- 15192850
TI  - Vaccines and the right of conscience.

PMID- 15192849
TI  - Law and public policy to protect health-care rights of conscience.

PMID- 15192851
TI  - Do anovulants and IUDs kill early human embryos? A question of conscience.

PMID- 15192853
TI  - Pro-life nurses and cooperation in abortion: ordinary care or extraordinary
      intervention?

PMID- 15192852
TI  - Catholic hospitals and modern culture: a challenging relationship.

PMID- 15192854
TI  - Compliance with contraceptive insurance mandates: licit or illicit cooperation in
      evil?

PMID- 15192855
TI  - Catholic Charities of Sacramento, Inc. v. California Department of Managed
      Health, petitioners brief on the merits.

PMID- 15192856
TI  - Globalization and the culture of life consensus statement: international
      colloquium of Catholic bioethics institutes.

PMID- 15192857
TI  - Linking economics and risk assessment.
AB  - Benefit-cost analysis relies heavily upon risk assessment. The extent to which
      benefits can be quantitatively included in an economic analysis is frequently
      determined by risk assessment methods. Therefore, interdisciplinary collaboration
      between economists and experts in risk assessment-related disciplines is critical
      to further development of quantitative human health benefits analysis. To further
      lay the groundwork for such collaborations, this article reviews the economic
      foundations of benefit-cost analysis, identifies implications of incorporating
      this approach into risk assessment, and suggests future cooperation between
      economists and risk assessors.

PMID- 15192858
TI  - The Acute Exposure Guideline Level (AEGL) program: applications of
      physiologically based pharmacokinetic modeling.
AB  - The primary aim of the Acute Exposure Guideline Level (AEGL) program is to
      develop scientifically credible limits for once-in-a-lifetime or rare acute
      inhalation exposures to high-priority, hazardous chemicals. The program was
      developed because of the need of communities for information on hazardous
      chemicals to assist in emergency planning, notification, and response, as well as
      the training of emergency response personnel. AEGLs are applicable to the general
      population, including children, the elderly, and other potentially susceptible
      subpopulations. AEGLs are the airborne concentrations of chemicals above which a
      person could experience notable discomfort or irritation (AEGL-1); serious, long
      lasting health effects (AEGL-2); and life-threatening effects or death (AEGL-3).
      AEGLs are determined for five exposure periods (10 and 30 min and 1, 4, and 8 h).
      Physiologically based pharmacokinetic (PBPK) models can be very useful in the
      interspecies and time scaling often required here. PBPK models are used for the
      current article to predict AEGLs for trichlorethylene (TCE), based on the time
      course of TCE in the blood and/or brain of rats and humans. These AEGLs are
      compared to values obtained by standard time-scaling methods. Comprehensive
      toxicity assessment documents for each chemical under consideration are prepared
      by the National Advisory Committee for AEGLs, a panel comprised of
      representatives of federal, state, and local governmental agencies, as well as
      industry and private-sector organizations. The documents are developed according
      to National Research Council (NRC) guidelines and must be reviewed by the NRC
      Subcommittee on Acute Exposure Guideline Levels before becoming final. AEGLs for
      18 chemicals have been published, and it is anticipated that 40 to 50 chemicals
      will be evaluated annually.

PMID- 15192859
TI  - Noninvasive biomonitoring approaches to determine dosimetry and risk following
      acute chemical exposure: analysis of lead or organophosphate insecticide in
      saliva.
AB  - There is a need to develop approaches for assessing risk associated with acute
      exposures to a broad range of metals and chemical agents and to rapidly determine
      the potential implications to human health. Noninvasive biomonitoring approaches
      are being developed using reliable portable analytical systems to quantitate
      dosimetry utilizing readily obtainable body fluids, such as saliva. Saliva has
      been used to evaluate a broad range of biomarkers, drugs, and environmental
      contaminants, including heavy metals and pesticides. To advance the application
      of noninvasive biomonitoring a microfluidic/electrochemical device has also been
      developed for the analysis of lead (Pb), using square-wave anodic stripping
      voltametry. The system demonstrates a linear response over a broad concentration
      range (1-2000 ppb) and is capable of quantitating saliva Pb in rats orally
      administered acute doses of Pb acetate. Appropriate pharmacokinetic analyses have
      been used to quantitate systemic dosimetry based on determination of saliva Pb
      concentrations. In addition, saliva has recently been used to quantitate
      dosimetry following exposure to the organophosphate insecticide chlorpyrifos in a
      rodent model system by measuring the major metabolite, trichloropyridinol, and
      saliva cholinesterase inhibition following acute exposures. These results suggest
      that technology developed for noninvasive biomonitoring can provide a sensitive
      and portable analytical tool capable of assessing exposure and risk in real-time.
      By coupling these noninvasive technologies with pharmacokinetic modeling it is
      feasible to rapidly quantitate acute exposure to a broad range of chemical
      agents. In summary, it is envisioned that once fully developed, these monitoring
      and modeling approaches will be useful for evaluating acute exposure and health
      risk.

PMID- 15192860
TI  - Predictive population dose-response assessment for Cryptosporidium parvum:
      infection endpoint.
AB  - Data validation of safe doses of pathogens in drinking water consistent with
      public health goals is not possible due to the number of subjects that would be
      needed at each dose. Because of this problem, together with the difficulty in
      extrapolating pathogenic response between species, and the ability of microbes to
      adapt rapidly, confidence-level-dependent assessments of Cryptosporidium parvum
      dose-response have been developed. However, these results, even on a relative
      basis, are dependent on confidence level, and the lack of scientific basis for
      this choice hampers efforts to set water quality standards. Therefore, a
      predictive Bayesian dose-response assessment method was proposed previously. In
      this article, a hierarchical predictive population dose-response Bayesian
      assessment for C. parvum is presented for the infection endpoint. Available data
      on the infectivity of three isolates of C. parvum, genotype C, were adjusted for
      sensitive and antibody-positive subpopulations not proportionately represented in
      the data, by bootstrap analysis. The diverse mean infectivities of the isolates
      were used to obtain a predictive distribution for population infectivity, used in
      turn to obtain the predictive population dose-response function. The predictive
      result is a distribution of unconditional probability of infection, based on
      available dose-response information. Information includes theoretical and
      empirical evidence for the conditional beta-Poisson parametric dose-response
      function. Results indicate that a dose of 6 x 10(-6) oocysts per exposure
      corresponds to 10(-4) infections per capita year. An allowable dose corresponding
      to goals of the SWTR should be increased over this value to reflect the illness
      endpoint, while potentially being reduced to account for secondary transmission
      among hosts if important for gastroenteritis in developed countries.

PMID- 15192862
TI  - Assessing biomarker use in risk assessment--a survey of practitioners.
AB  - Advances in molecular epidemiology and mechanistic toxicology have provided
      increased opportunities for incorporating biomarkers in the human health risk
      assessment process. For years, the published literature has lauded the concept of
      incorporating biomarkers into risk assessments as a means to reduce uncertainty
      in estimating health risk. For all the potential benefits, one would think that
      markers of effective dose, markers of early biological effects, and markers of
      human susceptibility are frequently selected as the basis for quantitative human
      health risk assessments. For this article, we sought to determine the degree to
      which this evolution in risk assessment has come to pass. The extent to which
      biomarkers are being used in current human health risk assessment was determined
      through an informal survey of leading risk assessment practitioners. Case studies
      highlighting the evolution of risk assessment methods to include biomarkers are
      also described. The goal of this review was to enhance the implementation of
      biomarker technology in risk assessment by (1) highlighting successes in
      biomarker implementation, (2) identifying key barriers to overcome, and (3)
      describing evolutions in risk assessment methods.

PMID- 15192861
TI  - Discerning strain effects in microbial dose-response data.
AB  - In order to estimate the risk or probability of adverse events in risk
      assessment, it is necessary to identify the important variables that contribute
      to the risk and provide descriptions of distributions of these variables for well
      defined populations. One component of modeling dose response that can create
      uncertainty is the inherent genetic variability among pathogenic bacteria. For
      many microbial risk assessments, the "default" assumption used for dose response
      does not account for strain or serotype variability in pathogenicity and
      virulence, other than perhaps, recognizing the existence of avirulent strains.
      However, an examination of data sets from human clinical trials in which
      Salmonella spp. and Campylobacter jejuni strains were administered reveals
      significant strain differences. This article discusses the evidence for strain
      variability and concludes that more biologically based alternatives are necessary
      to replace the default assumptions commonly used in microbial risk assessment,
      specifically regarding strain variability.

PMID- 15192863
TI  - Military deployment human exposure assessment: urine total and isotopic uranium
      sampling results.
AB  - Currently the Department of Defense (DoD) does not use exposure biomarkers to
      measure service members' exposure to environmental chemicals. Blood and urine
      exposure biomarkers for volatile organic compounds (VOC), selected heavy metals,
      depleted uranium (DU), and chemical warfare agents are currently available but
      have not been field tested or validated by the DoD in military deployments as a
      tool to document exposures. The Military Deployment Human Exposure Assessment
      Study, a prospective cohort of 46 soldiers deployed to Bosnia, was designed to
      field test blood and urine exposure biomarkers as a mechanism to document
      exposures to these chemicals during military deployments. Blood and urine were
      collected before, during, and after deployment. Standard questionnaire,
      environmental, and occupational monitoring data collection methods were conducted
      for comparison to the exposure biomarker results. This article compares and
      reports the pre-, during, and postdeployment urine total and isotopic uranium
      measurements and compares them to perceived exposures captured on questionnaire,
      to environmental data collected by the United Nations Environmental Program in
      Bosnia, and to standard U.S. urine uranium reference levels (CDC, 2003).
      Additionally, the questionnaire and environmental and occupational measurements
      are reported. The results of the study indicate that exposure biomarkers may be a
      valuable tool to the DoD in exposure and risk assessment with regard to
      environmental and occupational exposures to uranium.

PMID- 15192864
TI  - Biomarkers of exposure in community settings.
AB  - Biomonitoring is a valuable tool for assessing human exposures to chemical
      contaminants in the environment. Biomonitoring tests can be divided into
      biomarkers of exposure, effect, and susceptibility. In studies of community
      exposure to an environmental contaminant, biomarkers of exposure are most often
      used. The ideal biomarker should be sensitive, specific, biologically relevant,
      practical, inexpensive, and available. Seldom does a biomarker meet all of these
      criteria--most biomarkers represent a compromise of these criteria. In designing
      a community exposure study, consideration should also be given to the selection
      of the test population, the practicality of collecting biological samples,
      temporal or seasonal variations in exposure, the availability of background
      comparison ranges, and interpretation of the test results. Biomonitoring tests
      provide unequivocal evidence of exposure, but they do not typically identify the
      source of exposure. Furthermore, rarely do the test results predict a health
      outcome. For many chemicals, testing must be conducted soon after exposure has
      occurred. In spite of these limitations, the use of biomonitoring is finding
      wider application in many scientific disciplines. Recent advances in analytical
      techniques are expanding the utility of biomarker testing in public health
      investigations.

PMID- 15192865
TI  - Promotion of noise-induced hearing loss by chemical contaminants.
AB  - Recent studies have underscored the ability of a wide range of chemical agents to
      potentate noise-induced hearing loss. Given the ubiquitous nature of noise
      exposure particularly in many work settings, the high rate of noise-induced
      hearing loss, the limited degree to which auditory function can recover following
      damage to the inner ear, and the disparate chemical structures that appear
      capable of impairing hearing, this issue appears to have great public health
      significance. A compendium of chemicals known to potentiate noise induced hearing
      loss is presented along with a hypothesis that might explain at least one basis
      for potentiation of noise-induced hearing loss by certain chemical toxicants. The
      use of benchmark dose analysis to undertake a risk assessment for promotion of
      noise-induced hearing loss by both carbon monoxide and hydrogen cyanide is
      described.

PMID- 15192866
TI  - Component-based and whole-mixture techniques for addressing the toxicity of
      drinking-water disinfection by-product mixtures.
AB  - Chemical disinfection of water is of direct public health benefit as it results
      in decreased water-borne illness. The chemicals used to disinfect water react
      with naturally occurring organic matter, bromide, and iodide in the source water,
      resulting in the formation of disinfection by-products (DBPs). Despite the
      identification of several hundred DBPs, more than 50% of the mass of total
      organic halide formed during chlorination remains unidentified. The toxic
      contribution of the DBPs that are formed and present but not yet chemically
      identified, the unidentified fraction, has been largely unexplored. A better
      understanding of the potential for adverse human health consequences associated
      with exposure to the DBPs present in drinking water will be gained by integration
      of knowledge on the toxicity of individual DBPs; simple, defined DBP mixtures;
      complex, environmentally realistic DBP mixtures with partial chemical
      characterization; and the unidentified fraction.

PMID- 15192867
TI  - A feasibility study of cumulative risk assessment methods for drinking water
      disinfection by-product mixtures.
AB  - Humans are exposed daily to complex mixtures of chemicals, including drinking
      water disinfection by-products (DBPs) via oral, dermal, and inhalation routes.
      Some positive epidemiological and toxicological studies suggest reproductive and
      developmental effects and cancer are associated with consumption of chlorinated
      drinking water. Thus, the U.S. Environmental Protection Agency (EPA) conducted
      research to examine the feasibility of evaluating simultaneous exposures to
      multiple DBPs via all three exposure routes. A cumulative risk assessment
      approach was developed for DBP mixtures by combining exposure modeling and
      physiologically based pharmacokinetic modeling results with a new mixtures risk
      assessment method, the cumulative relative potency factors (CRPF) approach.
      Internal doses were estimated for an adult female and an adult male, each of
      reproductive age, and for a child (age 6 yr) inclusive of oral, dermal, and
      inhalation exposures. Estimates of the daily internal doses were made for 13
      major DBPs, accounting for activity patterns that affect the amount of human
      contact time with drinking water (e.g., tap water consumed, time spent
      showering), building characteristics (e.g., household air volumes), and
      physicochemical properties of the DBPs (e.g., inhalation rates, skin permeability
      rates, blood: air partition coefficients). A novel cumulative risk assessment
      method, the CRPF approach, is advanced that integrates the principles of dose
      addition and response addition to produce multiple-route, chemical mixture risk
      estimates using total absorbed doses. Research needs to improve this approach are
      presented.

PMID- 15192868
TI  - Bottom-up and top-down integration of human and ecological risk assessment.
AB  - The World Health Organization has published a framework for integrating human
      health and ecological risk assessments, and many others have argued for greater
      integration of health and environmental concerns in assessments. However, those
      who argue for integration do not agree on the expected benefits. This article
      provides a conceptual organization of the rationale for integration. The bottom
      up line of argument begins with the premise that the mechanisms of transport,
      fate, exposure, and effects of chemicals on humans and nonhuman organisms are
      largely common. Therefore, integrated assessment should be more efficient and
      should employ the highest quality of science. The top-down line of argument
      begins with the premise that humans are organisms that reside in ecosystems.
      Therefore, changes in the environment imply changes in human health and welfare.
      These include changes in the many services of nature that contribute to human
      health, such as air and water purification, sentinel functions, and provision of
      recreation and food supplies. They also include the direct health benefits that
      have been associated with exposure of humans to plants, animals, and natural
      ecosystems. Integration should proceed from both the top and bottom.

PMID- 15192869
TI  - The importance of marine foods to a near-urban first nation community in coastal
      British Columbia, Canada: toward a risk-benefit assessment.
AB  - There is increasing concern that some subsistence-oriented consumer groups may be
      exposed to elevated levels of persistent organic pollutants (POPs) through the
      consumption of certain traditional foods, including fish and other aquatic
      resources. Exposure to POPs has been associated with adverse health effects
      including immunotoxicity, endocrine disruption, and altered development in
      moderate to highly exposed humans and wildlife. The Sencoten (Saanich) First
      Nation consists of approximately 1900 people inhabiting communities in a near
      urban setting in coastal British Columbia, Canada. A survey was conducted to
      document the relative importance of traditional foods in the diet of the Sencoten
      people, as a basis for the future assessment of exposure to, and risks associated
      with, environmental contaminants in such a diet. Salmon represented 42% of the
      total marine meals, but at least 24 other marine species were also consumed. Our
      study suggests that traditional marine foods remain very important to the social
      and economic well-being of the Sencoten, despite their proximity to an urban
      center. This information will be of value to those interested in nutritional,
      cultural, and health issues concerning subsistence-oriented First Nations
      peoples, and provides an important first step in risk assessment.

PMID- 15192871
TI  - Induced plant signaling and its implications for environmental sensing.
AB  - The sophisticated chemical responses of plants to environmental stimuli have
      profound implications for the development of remote sensing systems. Recent
      advances in the investigation of these responses have demonstrated that plants
      can be developed as reliable reporters of numerous environmental stimuli
      including soil and water conditions, light levels, temperature, mechanical
      damage, insect feeding, exposure to pathogens--including those that affect
      animals and humans--and exposure to airborne chemicals. Researchers are just
      beginning to understand the full range of plant phenotypic responses to these and
      other stimuli. These responses often have measurable physiological and molecular
      components that are readily observed. Other responses (e.g., internal biochemical
      changes) are less readily assayed, although sensing devices are being developed.
      Plant volatile emission "signatures" are particularly promising modes of plant
      reporting that can provide highly specific information regarding a diverse range
      of environmental variables on short time scales, but new approaches are needed
      for sensing these responses remotely. Modern molecular techniques promise to
      allow us to refine plant sensing and reporting, greatly enhancing the potential
      utility of plants as "sentinels." Continued basic research aimed at
      characterizing the physiological, biochemical, and molecular responses of plants
      to environmental stimuli (including airborne chemicals, insects and pathogenic
      microbes) are essential to achieving that promise.

PMID- 15192870
TI  - Sensitivity of the neuronal network biosensor to environmental threats.
AB  - It is widely acknowledged that there is a critical need for broad-spectrum
      environmental threat detection. While cells/tissue-based biosensors have been
      discussed for many years as a means of meeting this critical need, these kinds of
      systems have met with logistic concerns, in particular with regard to stability.
      Our group has been working with cultured neuronal networks, which have the
      capacity to respond to a wide range of neuroactive compounds and are sufficiently
      robust to be shipped to end users. The basis of operation involves extracellular
      recording using thin-film microelectrode arrays where spontaneous bioelectrical
      activity, that is, spike firing, can be monitored in a noninvasive manner
      conducive for potentially long-term measurements. This work describes the current
      status of our efforts for the fabrication of a portable biosensor that
      incorporates cultured neuronal networks grown over standardized microelectrode
      arrays. Based on our protocol for aqueous phase sample introduction under
      constant flow conditions, minimal variation in mean spike rate is observed,
      consistent with temporal stability, such that changes of > 10% are readily
      distinguished. To demonstrate the capability of this system, changes are reported
      in mean spike rate and network synchronization resulting from exposure to
      different model environmental threats, cadmium and strychnine. The sensitivity of
      this assay approach and implications of the experimental findings for
      environmental threat detection are discussed.

PMID- 15192872
TI  - An evaluation of neurobehavioral tests used to assess the neurodevelopmental
      effects of early ammonium perchlorate exposure.
AB  - Perchlorate is an anion known to interfere with normal production of thyroid
      hormones that are integrally involved in the development of the central nervous
      system and neurobehavioral capacities. Given the identification of drinking water
      contamination with perchlorate, there are efforts to investigate the effects of
      exposure in developing fetuses and children in order to guide the establishment
      of regulatory standards. Systematic neurobehavioral investigations in animal
      models have been completed to evaluate neurodevelopmental consequences of
      exposures at different concentrations in drinking water. However, these
      investigations have not directly addressed the public concern for increased
      incidences of childhood attention deficit disorders, autism, and lowered IQs of
      children in areas with known contamination. Although epidemiological data suggest
      there is not a relationship between drinking-water perchlorate exposure and these
      childhood disorders, it may be prudent to use animal models to systematically
      assess the potential for such problems. Given the behavioral complexity of these
      problems, an appropriate evaluation will require the use of nontraditional
      neurobehavioral tests such as operant conditioning tasks of varying levels of
      complexity, and juvenile rat play. Such tests will provide a more direct
      evaluation of the potential for attention deficits, autism, and lowered IQ scores
      related to thyroid hormone disruption due to early perchlorate exposure.

PMID- 15192873
TI  - Patient care. Shhh, quiet please!
AB  - Silence is golden--and critical to patient recovery. But nurses at the Mayo
      Clinic found that it is hard to come by. Administrators at Mayo and elsewhere are
      working to reduce the noise.

PMID- 15192874
TI  - Finance. Booking losses.

PMID- 15192875
TI  - Technology. IT comes together.
AB  - After years of decentralizing IT systems, large health networks are bringing back
      office functions under one roof hoping for economies of scale.

PMID- 15192876
TI  - Technology. Beyond bar codes.
AB  - Just as the Food and Drug Administration orders the use of bar codes on most
      prescription drugs and blood products meant for transfusion, there is a push for
      an even more potent technology--radio frequency identification.

PMID- 15192877
TI  - Technology. Sold, to the e-bidder.

PMID- 15192878
TI  - The more things change.

PMID- 15192879
TI  - The patient room.
AB  - Of all the advances that hospitals are making in the delivery of care, nowhere is
      the impact felt more drastically than in the patient room. Even as room decor
      grows cozier and more home-like, dazzling new technology is bringing the future
      directly to the bedside, giving clinicians the power to monitor patients more
      carefully and giving patients more control over their own experience. Creating
      flexible, comforting rooms that can accommodate ever-changing technology, that
      encourage loved ones to spend more time with patients, and that allow staff to
      work more efficiently is a challenge for hospital planners, one that they are
      confronting with ingenuity and finesse.

PMID- 15192880
TI  - Patient-friendly billing.
AB  - A project to redesign hospital and physician bills is picking up steam as
      providers realize the benefits for financial and operational performance, and for
      patient satisfaction.

PMID- 15192881
TI  - Complexity made simple. Interview by David Ollier Weber.
AB  - In a preview of his keynote address at July's Health Forum and AHA Summit,
      Petzinger describes how--as in nature--everything in an organization is
      interconnected and why recognizing that fact can lead to real solutions to all
      sorts of problems.

PMID- 15192882
TI  - Infotech. Cyber security. Health care learns to share scares and solutions.
AB  - Health care information technology leaders and others are coming together to
      share scary experiences and develop best practices to guard against crippling
      computer viruses, scheming hackers and other cyber threats.

PMID- 15192883
TI  - HIV/AIDS patients feel they get less respect than other hospital patients.

PMID- 15192884
TI  - History lesson? Community benefit programs were developed in the 1980s, but not
      adopted. Will this time be different?

PMID- 15192885
TI  - Bridging a widening gap. The call for capital grows more urgent.

PMID- 15192886
TI  - Capital and IT.

PMID- 15192887
TI  - Better access to capital.

PMID- 15192888
TI  - What you can do. Five initiatives to undertake now to expand sources of capital.

PMID- 15192889
TI  - 2002-based national population projections for the United Kingdom and constituent
      countries.
AB  - The 2002-based national population projections, carried out by the Government
      Actuary in consultation with the Registrars General, show the population of the
      United Kingdom rising from 59.2 million in 2002 to nearly 65 million by 2031.
      Longer-term projections suggest the population will peak around 2050 at over 65
      million and then gradually start to fall. The population will become gradually
      older with the median age expected to rise from 38.2 years in 2002 to 43.3 years
      by 2031. In 2002, there were around 850 thousand (8 per cent) more children aged
      under 16, than people of state pensionable age. However, from 2007, the
      population of pensionable age is projected to exceed the number of children.

PMID- 15192890
TI  - The 2011 Census: a proposed design for England and Wales.
AB  - This article sets out the proposed design for a 2011 Census in England and Wales,
      as part of the ONS's proposed future population statistics system. The design
      draws on experiences from the 2001 Census and changes in available technology,
      and takes account of the many comments received from respondents to a Discussion
      Paper published in October 2003 and of views expressed at a joint ONS/RSS
      Conference on 11-12 November 2003. The article highlights the statistical and
      operational strategic aims for the 2011 Census, the major changes proposed from
      the 2001 approach, and gives an indication of the benefits and risks. It is
      important to note that this design remains a proposal at present, the elements of
      which will be subject to further research building on comments received during
      consultation and a detailed testing programme over the coming years.

PMID- 15192891
TI  - Living arrangements among older people: an overview of trends in Europe and the
      USA.
AB  - This article compares the trends in living arrangements of older people in
      several European countries and in the United States. Trends and cross-country
      variability in several factors that could account for these cross-national
      differences, including marital status, fertility, labour force participation and
      attitudes, are also examined. In most countries the proportion of older people
      living alone increased substantially between 1970 and 1990. However the increase
      in living alone stabilised or even declined between 1990 and 2000 in most of the
      countries analysed indicating a possible reversal in the trend. Increases in
      proportions of older women who are married and reductions in the proportions
      childless may partially explain this. Considerable variability in both trends and
      levels of older people's living arrangements was seen especially between north
      western and southern European countries. These variations mirrored contrasts in
      attitudes towards residential care and parent-child coresidence between the
      countries.

PMID- 15192892
TI  - What level of marketing commitment does it take to gain market share?

PMID- 15192893
TI  - Hospitals find ways to fight rising bad debt.

PMID- 15192894
TI  - What Medicare Prescription Drug Act '03 means to hospitals.

PMID- 15192896
TI  - Comments on watercraft-related drownings.

PMID- 15192895
TI  - Is online-only health care a viable possibility? Limits are clear.

PMID- 15192897
TI  - Firearm homicide and firearm suicide: opposite but equal.
AB  - OBJECTIVE: Homicide and suicide are intentional acts of violence that
      disproportionately involve firearms. Much more effort has been devoted to the
      ecological study of homicide; methods that have been developed to better
      understand and subsequently prevent homicide may be applicable to suicide. The
      purpose of the present study was to compare the occurrence of firearm homicide
      and firearm suicide using routine activity theory as a framework for analysis.
      METHODS: Detailed mortality data pertaining to decedents, their neighborhoods,
      and use of firearms were collected from 1994 to 1998 for the counties containing
      and surrounding three small to medium-sized U.S. cities. Data from a total of 468
      neighborhoods that collectively experienced 1,025 intentional deaths from
      firearms (396 firearm homicides and 629 firearm suicides) were analyzed. RESULTS:
      Firearm homicide was consistently associated with out-of-home, nighttime activity
      in neighborhoods where many people were likely to be coming and going. In an
      opposite-but-equal fashion, firearm suicide was consistently associated with in
      home, daytime activity in out-of-the-way neighborhoods. CONCLUSIONS: Firearm
      homicide and firearm suicide were found to be consistently associated with
      markers of routine activity in all three cities, albeit in an opposite-but-equal
      manner. Because firearm suicides very often occur as lonely events in lonely
      neighborhoods, they may go under-noticed relative to firearm homicides. More
      awareness and additional public health studies of firearm suicide, in tandem with
      firearm homicide, should be pursued to better identify individuals and
      neighborhoods that are at greatest risk of experiencing each event.

PMID- 15192899
TI  - Development of guidelines on nonoccupational HIV postexposure prophylaxis for the
      state of Rhode Island.
AB  - The Brown University AIDS Program and the Rhode Island Department of Health
      joined with health care practitioners, researchers, and representatives of
      community-based health, social service, and advocacy organizations to create
      comprehensive guidelines on nonoccupational HIV postexposure prophylaxis for the
      state of Rhode Island. These guidelines offer health care practitioners detailed
      advice on the evaluation and management of blood or body fluid exposures outside
      the health care setting, e.g., through sexual assault, consensual sex, injecting
      drug use, or needlestick injuries. In these circumstances, HIV postexposure
      prophylaxis serves those for whom primary prevention measures have failed or were
      impractical or impossible. The guidelines represent the end product of
      coordination among private and public, academic and nonacademic, clinician and
      layperson groups committed to decreasing the incidence of HIV infections in the
      state of Rhode Island. The guidelines serve as both a resource for health care
      practitioners and a means of educating them on this method of HIV prevention.

PMID- 15192898
TI  - State efforts to measure the health care safety net.
AB  - This article describes the role states could play in a national effort to measure
      and monitor the public health safety net. The authors developed a data collection
      framework using information from five states on two components of the safety net:
      structure and demand. Because states are the primary vehicle for access
      expansions and programs to care for the poor, the authors suggest that they be
      the primary coordinating mechanism for data collection on the safety net. Because
      the necessary mechanisms for more uniform standards or criteria to evaluate state
      data collection activities and capacity remain undeveloped, they recommend using
      existing data to begin building state capacity to measure and monitor the safety
      net.

PMID- 15192900
TI  - An innovative blood lead screening program for Indian children.
AB  - There is little information on the lead levels of Indian children nationally. In
      the late 1990s, members of the Chippewa and Cree tribes living on the Rocky Boy
      Reservation near Box Elder, Montana, were concerned about environmental pollution
      and how it might be affecting the health of their children. With financial
      assistance from the Environmental Protection Agency, the tribes designed and
      implemented an innovative lead screening program for young children. Because most
      children on the reservation participated in WIC and Head Start, those programs
      were used to identify and screen close to 100% of young children on the
      reservation. The average blood lead level for children ages 1-5 on the Rocky Boy
      reservation was 2.4 micrograms/dL, which is not significantly different from that
      of children of the same age nationally. The project showed that Indian families
      will participate readily in screening programs that may improve their children's
      health.

PMID- 15192902
TI  - Impact of health insurance status on vaccination coverage in children 19-35
      months old, United States, 1993-1996.
AB  - OBJECTIVES: To show how health insurance (privately and publicly insured, insured
      and uninsured) relates to vaccination coverage in children 19-35 months old, and
      how this can be used to better target public health interventions. METHODS: The
      National Health Interview Survey (NHIS) gathers information on the health and
      health care of the U.S. non-institutionalized population through household
      interviews. The authors combined immunization and health insurance supplements
      from the 1993 through 1996 NHIS, and classified children 19-35 months old by
      their immunization and insurance status. Results were compared using both
      bivariate and multivariate analyses, and the backwards stepwise selection method
      was used to build multivariate logistic regression models. RESULTS: Uninsured
      children tended to have lower vaccination coverage than those who had insurance,
      either private or public. Among those with insurance, publicly insured children
      had lower vaccination coverage than privately insured children. Backwards
      stepwise regression retained insurance status, metropolitan statistical area, and
      education of responsible adult family member as major predictors of immunization.
      Factors considered but not retained in the final model included child
      race/ethnicity, family poverty index, and region of country. CONCLUSIONS:
      Insurance status was a critical predictor of vaccination coverage for children
      ages 19-35 months. After controlling for confounders, the uninsured were about
      24% less likely to receive all recommended shots than the insured and, among the
      insured, those with public insurance were about 24% less likely to receive all
      recommended vaccines than those with private insurance.

PMID- 15192901
TI  - Risk factors for delay in age-appropriate vaccination.
AB  - OBJECTIVE: To estimate the risk factors of children experiencing delay in age
      appropriate vaccination using a nationally representative population of children,
      and to compare risk factors for vaccination delay with those based on up-to-date
      vaccination status models. METHODS: The authors compared predictors of delay in
      age-appropriate vaccination with those for children who were not up-to-date,
      using a nationally representative sample of children from five years of pooled
      data (1992-1996) from the National Health Interview Survey (NHIS) Immunization
      Supplement. Duration of delay was calculated for the DTP4, Polio3, MMR1 doses and
      4:3:1 series using age-appropriate vaccination standards; up-to-date status
      (i.e., whether or not a dose was received) was also determined. Adjusted odds
      ratios were estimated using multivariate logistic regression for models of
      vaccination delay and up-to-date vaccination status. RESULTS: Absence of a two
      parent household, large family size, parental education, Medicaid enrollment,
      absence of a usual provider, no insurance coverage, and households without a
      telephone were significantly related to increased odds of a child experiencing
      vaccination delay (p < or = 0.05). CONCLUSIONS: Many of the risk factors observed
      in models of vaccination delay were not found to be significant in risk models
      based upon up-to-date status. Consequently, risk models of delays in age
      appropriate vaccination may foster identification of children at increased risk
      for inadequate vaccination. Populations at increased risk of inadequate
      vaccination can be more clearly identified through risk models of delays in age
      appropriate vaccination.

PMID- 15192904
TI  - Occurrence of low birthweight and preterm delivery among California infants
      before and after compulsory food fortification with folic acid.
AB  - OBJECTIVES: Studies suggest that folic acid intake influences the occurrence of
      low birthweight and preterm delivery. Since 1998, there has been compulsory
      fortification of flour and other grains with folic acid in the U.S. The objective
      of this study was to investigate the frequencies of low birthweight and preterm
      delivery after mandatory folic acid fortification among approximately six million
      California births. METHODS: The authors investigated prevalences of low
      birthweight and preterm delivery before and after compulsory fortification among
      5,916,630 singleton California live births that occurred from January 1990
      through December 2000. RESULTS: The unadjusted prevalences of very low
      birthweight, low birthweight, and preterm delivery did not substantially vary
      across birth years. That is, substantial decreased prevalences during the
      fortification period relative to the period preceding it were not observed.
      However, analyses that simultaneously adjusted for maternal age, parity,
      race/ethnicity, education, year of birth, and fortification period revealed the
      following relative risk ratios (RR) and 95% confidence intervals (CI): RR = 0.91,
      CI 0.88, 0.94 for very low birthweight, RR = 0.94; 95% CI 0.93, 0.96 for low
      birthweight, and RR = 0.96; 95% CI 0.94, 0.97 for preterm delivery. CONCLUSION:
      Findings indicate small reductions in prevalences of these outcomes associated
      with the timing of fortification of the U.S. food supply.

PMID- 15192903
TI  - Vaccine coverage levels after implementation of a middle school vaccination
      requirement, Florida, 1997-2000.
AB  - OBJECTIVE: Little information is available about the effectiveness of school
      entry vaccination requirements at the middle school level. This study examined
      coverage levels among students entering seventh grade in Florida following
      implementation of a school entry vaccination requirement in 1997. METHODS: The
      authors analyzed county-specific vaccination coverage levels (three doses of
      hepatitis B vaccine, a second dose of measles, mumps, and rubella [MMR] vaccine,
      and a booster dose of tetanus and diphtheria toxoids [Td]) among students
      entering public and private schools in Florida from 1997 through 2000. In 1998, a
      survey of all county health departments was conducted, and the resulting data
      were linked to county-specific vaccination rates. RESULTS: During the 1997-1998
      school year, the first year the requirement went into effect, at school entry
      121,219 seventh-grade students (61.8%) were fully vaccinated, 72,275 seventh
      grade students (36.9%) lacked one or more doses of vaccine but were considered in
      process, 1,817 were non-compliant (0.9%), and 763 had medical or religious
      exemptions (0.4%). In the 2000-2001 school year, the proportions of students
      reported fully vaccinated at school entry had increased to 66%. Most of this
      change was related to an increase in hepatitis B coverage. There was a
      significant inverse relationship between the proportion of students fully
      vaccinated and the size of the county's seventh grade population. CONCLUSIONS:
      The seventh grade vaccination entry requirement was associated with sustained
      high levels of vaccination coverage. Passing a school entry vaccination
      requirement appears may be sufficient to increase coverage, but other strategies
      may be required to achieve full immunization of middle school students.

PMID- 15192905
TI  - Prostate cancer incidence and mortality rates and trends in the United States and
      Canada.
AB  - OBJECTIVE: The purpose of this study was to compare prostate cancer incidence and
      mortality trends between the United States and Canada over a period of
      approximately 30 years. METHODS: Prostate cancer incident cases were chosen from
      the National Cancer Institute's Surveillance Epidemiology and End Results (SEER)
      Program to estimate rates for the United States white males and from the Canadian
      Cancer Registry for Canadian men. National vital statistics data were used for
      prostate cancer mortality rates for both countries, and age-adjusted and age
      specific incidence and mortality rates were calculated. Joinpoint analysis was
      used to identify significant changes in trends over time. RESULTS: Canada and the
      U.S. experienced 3.0% and 2.5% growth in age-adjusted incidence from 1969-90 and
      1973-85, respectively. U.S. rates accelerated in the mid- to late 1980s. Similar
      patterns occurred in Canada with a one-year lag. Annual age-adjusted mortality
      rates in Canada were increasing 1.4% per year from 1977-93 then fell 2.7% per
      year from 1993-99. In the U.S., annual age-adjusted mortality rates for white
      males increased 0.7% from 1969-1987 and 3.0% from 1987-91, then decreased 1.2%
      and 4.5% during the 1991-94 and 1994-99 periods, respectively. CONCLUSIONS:
      Recent incidence patterns observed between the U.S. and Canada suggest a strong
      relationship to prostate-specific antigen (PSA) test use. Clinical trials are
      required to determine any effects of PSA test use on prostate cancer and overall
      mortality.

PMID- 15192906
TI  - Multiple-race mortality data for California, 2000-2001.
AB  - OBJECTIVES: To examine mortality rates and quality of race reporting for multiple
      race individuals in California using the new multiple-race data available on the
      death certificate. METHODS: Death date were drawn from California vital
      statistics for 2000 and 2001. Denominator data were drawn from the 2000 census
      Modified Race Data Summary File. The authors calculated mortality rates and
      relative standard errors for multiple-race individuals as a whole and by county,
      and for the three largest reported multiple-race groups (African American and
      white, American Indian/Alaska Native and white, and Asian and white). RESULTS:
      Decedents reported to be of more than one race were disproportionately young,
      Hispanic, male, and never-married. Age-adjusted mortality rates for multiple-race
      groups were approximately one-sixth as high as rates for single-race individuals.
      There was substantial variability in rates for multiple-race decedents according
      to county of residence. CONCLUSIONS: Mortality rates for multiple-race people
      were implausibly low, and death certificates for multiple-race individuals were
      geographically clustered. Race reporting on death certificates will need to be
      improved before accurate death rates can be calculated for those of multiple
      races.

PMID- 15192907
TI  - Bridging between two standards for collecting information on race and ethnicity:
      an application to Census 2000 and vital rates.
AB  - OBJECTIVES: The 2000 Census, which provides denominators used in calculating
      vital statistics and other rates, allowed multiple-race responses. Many other
      data systems that provide numerators used in calculating rates collect only
      single-race data. Bridging is needed to make the numerators and denominators
      comparable. This report describes and evaluates the method used by the National
      Center for Health Statistics to bridge multiple-race responses obtained from
      Census 2000 to single-race categories, creating single-race population estimates
      that are available to the public. METHODS: The authors fitted logistic regression
      models to multiple-race data from the National Health Interview Survey (NHIS) for
      1997-2000. These fitted models, and two bridging methods previously suggested by
      the Office of Management and Budget, were applied to the public-use Census
      Modified Race Data Summary file to create single-race population estimates for
      the U.S. The authors also compared death rates for single-race groups calculated
      using these three approaches. RESULTS: Parameter estimates differed between the
      NHIS models for the multiple-race groups. For example, as the percentage of
      multiple-race respondents in a county increased, the likelihood of stating black
      as a primary race increased among black/white respondents but decreased among
      American Indian or Alaska Native/black respondents. The inclusion of county-level
      contextual variables in the regression models as well as the underlying
      demographic differences across states led to variation in allocation percentages;
      for example, the allocation of black/white respondents to single-race white
      ranged from nearly zero to more than 50% across states. Death rates calculated
      using bridging via the NHIS models were similar to those calculated using other
      methods, except for the American Indian/Alaska Native group, which included a
      large proportion of multiple-race reporters. CONCLUSION: Many data systems do not
      currently allow multiple-race reporting. When such data systems are used with
      Census counts to produce race-specific rates, bridging methods that incorporate
      geographic and demographic factors may lead to better rates than methods that do
      not consider such factors.

PMID- 15192908
TI  - Lessons of history? Anti-malaria strategies of the International Health Board and
      the Rockefeller Foundation from the 1920s to the era of DDT.

PMID- 15192909
TI  - HIPAA's implications for public health policy and practice: guidance from the
      CDC.

PMID- 15192910
TI  - MNA pursues litigation against Ottawa County to protect jail nurses.

PMID- 15192912
TI  - Healthy Michigan 2010 status report shows room for improvement.

PMID- 15192911
TI  - Developing union leaders.

PMID- 15192913
TI  - Let's get moving, Grand Traverse women! (and spouses, kids, neighbors, pets...).

PMID- 15192915
TI  - Great expectations.

PMID- 15192914
TI  - New childcare allowance raises funding question.

PMID- 15192916
TI  - Helping people who self-harm.

PMID- 15192917
TI  - Treating children with ADHD.

PMID- 15192918
TI  - Understanding the implications of over the counter statin sales.
AB  - Coronary heart disease (CHD) is the UK's biggest killer. While recommending that
      all patients can benefit from lifestyle interventions, the current guidelines
      focus pharmacological management on those at high risk. An over the counter (OTC)
      statin would enable people with moderate (10-15 per cent) CHD risk to take
      preventive action. Pharmacists would be able to recommend OTC simvastatin to
      those at moderate risk by following a simple pharmacy protocol to assess a
      person's risk. A regime of 10 mg simvastatin daily would have a significant
      impact on both the low-density lipoprotein cholesterol (LDL-C) level and the CHD
      risk of those at moderate risk. Cholesterol testing would not be mandatory but
      would be available in pharmacy to enable people to monitor their progress.

PMID- 15192919
TI  - What you need to know about ... pneumothorax.

PMID- 15192920
TI  - Understanding the nursing role in patients who have cataract.

PMID- 15192921
TI  - The detection and prevention of depression in older people.
AB  - Nurses are well placed to detect and prevent depression in older people,
      especially at times of critical life changes, such as the move to a care home.
      This best practice statement forms a major part of a national practice
      development initiative aimed at developing evidenced-based practice in nursing
      older people. It aims to demonstrate how nurses can begin to work with older
      people and their families to provide support and prevent the normal responses to
      loss and grief from turning into clinical depression.

PMID- 15192922
TI  - Using decision trees to aid decision-making in nursing.
AB  - This article discusses judgement and decision-making in nursing. It outlines an
      approach to analysing clinical problems known as decision analysis. It suggests
      decision analysis can be a useful technique for nurses to assist them with
      decision-making in practice.

PMID- 15192923
TI  - An RCT into calculating insulin start dose in type 2 diabetes.
AB  - AIMS: This trial compares to methods used to find the insulin dose when starting
      insulin in people with type 2 diabetes in whom maximal tolerated oral
      hypoglycaemic agents have failed to control glycaemia. One method of initiating
      insulin (based on height, weight, and fasting blood plasma glucose and insulin
      resistance) was compared with a conventional method of initiating 10 units of
      isophane insulin twice daily. METHOD: Sixty subjects were randomised to
      calculated (CALC) or conventional (C). Follow-up was at three, six and 12 months
      with diabetes specialist nurse (DSN) support. The outcomes that were compared
      were glycated haemoglobin levels (HbA1c), hypoglycaemia, weight gain, insulin
      dose, quality of life, treatment satisfaction, blood pressure, and frequency of
      DSN contact. RESULTS: HbA1c levels values were reduced significantly in the CALC
      group during the first three months after starting insulin (p = 0.0001) and
      improved by one per cent overall during 12 months (p = 0.03). No difference was
      found in rates of hypoglycaemia, blood pressure, quality of life, and treatment
      satisfaction. Weight gain was seen in both groups but was significantly higher in
      the CALC group. People in the CALC group needed significantly less DSN time (p =
      0.01). CONCLUSIONS: HbA1c target values were achieved more quickly and with less
      DSN contact using the CALC method. The difference in weight gain with the CALC
      method needs further investigation.

PMID- 15192924
TI  - It's an ill pill.

PMID- 15192925
TI  - A leap in the dark.

PMID- 15192926
TI  - Safety in numbers.

PMID- 15192927
TI  - Crossing the line.

PMID- 15192928
TI  - Talking cure.

PMID- 15192929
TI  - Welfare writes.

PMID- 15192930
TI  - Just Margaret.

PMID- 15192931
TI  - Geographies of exclusion.

PMID- 15192932
TI  - Knowing what to do.

PMID- 15192933
TI  - All you need to know?

PMID- 15192934
TI  - Shared experience.

PMID- 15192935
TI  - Loose nuts.

PMID- 15192936
TI  - Mandated collaboration: the case of the forensic MOU.
AB  - The management and support of forensic clients is an area of interest to both
      clinicians and policy makers. Collaboration between hospital and community
      service providers is required and in some instances, mandated. This article
      reviews some of the literature about collaboration and examines selected
      experiences in the mental health field using a case study method. The case study
      examines the process of mandated collaboration in the development of the forensic
      MOU (memorandum of understanding), which involved CMHA Metro Toronto, and three
      general hospital ACT (assertive community treatment) teams and the Law and Mental
      Health Program at the Centre for Addiction Mental Health. The article offers
      observations on the extent to which collaboration is an emergent process that is
      responsive to its particular environment and explores power dynamics and how
      trust and flexibility affect outcomes in a positive or negative sense.

PMID- 15192937
TI  - 1933-2003: lessons from 70 years of experience with mental health, capacity and
      consent legislation in Ontario.

PMID- 15192938
TI  - Mental health nursing and clinical supervision.

PMID- 15192939
TI  - Queensland's Mental Health Court: the first 12 months.

PMID- 15192940
TI  - Investigating the quality of psychiatric care: the New Zealand experience.

PMID- 15192941
TI  - Perspective. Senate GOP plan: cut red tape, focus on individuals.

PMID- 15192942
TI  - Fine needle aspiration cytology of endocrine neoplasms of the pancreas.
      Morphologic and immunocytochemical findings in 20 cases.
AB  - OBJECTIVE: To analyze the role of fine needle aspiration (FNA) cytology in the
      preoperative diagnosis of pancreatic endocrine neoplasms. METHODS: Cytologic and
      histologic diagnoses of pancreatic endocrine tumors were reviewed. A total of 20
      FNA cytologic procedures from 20 patients were selected. A false positive case, a
      retroperitoneal paraganglioma, was also reviewed. Two groups of patients were
      established: (1) those in whom a surgical biopsy with an immunohistochemical
      study was available (n = 13), and (2) those with a pancreatic tumor in which the
      diagnosis was confirmed by immunocytochemical studies (n = 7). In 13 cases the
      pancreatic tumor was aspirated, while in 7, liver metastases were studied. The
      immunoexpression of chromogranin and synaptophysin was evaluated in alcohol-fixed
      smears from 12 and 11 cases, respectively. RESULTS: One false negative and 1
      false positive diagnosis were present. In the remaining 19 cases a cytologic
      diagnosis of pancreatic endocrine tumor was given. Main cytologic features were:
      (1) a prominent cellular dissociation with many single cells and small, poorly
      cohesive groups; (2) intermediate to large size cells with ill-defined cytoplasm,
      naked or eccentric nuclei, and frequent binucleation; and (3) variable nuclear
      pleomorphism with the characteristic finely granular distribution of the
      chromatin. Immunocytochemical evidence of endocrine differentiation (chromogranin
      or synaptophysin) was present in the 12 cases analyzed. CONCLUSION: FNA cytology
      offers the possibility of a precise preoperative, noninvasive diagnosis of
      pancreatic endocrine tumors. Cytologic features differ considerably from those of
      pancreatic adenocarcinoma, allowing differentiation from nonfunctioning endocrine
      neoplasms. In difficult cases immunocytologic studies are very helpful.

PMID- 15192943
TI  - Myoepithelioma of the salivary glands. Fine needle aspiration biopsy findings.
AB  - OBJECTIVE: To evaluate the cytologic findings and pitfalls in the diagnosis of
      myoepithelioma of the salivary glands. STUDY DESIGN: Smears from 7 cases of
      myoepithelioma of the salivary glands, 3 plasmacytoid, 2 spindle and 2 mixed
      types, all histologically confirmed, were evaluated with special attention to
      cytologic features that may be helpful for the diagnosis. RESULTS: A correct
      cytologic diagnosis was not made in any of the cases. Three were diagnosed as
      plasmacytomas or cellular pleomorphic adenomas, 2 as benign spindle cell tumors
      and 2 as cellular pleomorphic adenomas. Mitoses and marked pleomorphism were
      absent. Nuclear striations were noted frequently. CONCLUSION: Diagnosis of
      myoepithelioma was difficult on fine needle aspiration smears. Nuclear striations
      (zebra lines) were noted in 5 cases. This finding is not reported in previously
      published papers.

PMID- 15192944
TI  - Cytomorphologic spectrum of carcinoma ex pleomorphic adenoma.
AB  - OBJECTIVE: To delineate the cytomorphologic features of carcinoma ex pleomorphic
      adenoma (CPA) and identify the diagnostic pitfalls. STUDY DESIGN: Smears of 14
      cases suspected as CPA on fine needle aspiration over a period of 15 years were
      reviewed. Cytohistologic correlation was done in 10 cases. RESULTS: All cases had
      a salivary gland mass of 1-16 years' duration, with a rapid increase in size in
      10 cases. Epithelial cells predominated over stroma in 11 of 14 cases. Group I
      showed unequivocal malignant cells admixed with benign epithelial and stromal
      components of pleomorphic adenoma (PA), which were considered diagnostic of CPA
      on review. The cytologic differential diagnosis in these cases included
      mucoepidermoid carcinoma, carcinosarcoma and metastatic adenocarcinoma. Group II
      comprised 7 cases suspected to be cellular PA with atypia or CPA. These showed
      mild to moderate degrees of pleomorphism, absence of unequivocal malignant cells,
      and a variable proportion of benign epithelial and stromal components. Four of
      them were histologically confirmed as CPA. CONCLUSION: Sampling error is an
      important cause of diagnostic pitfalls. Correlation with clinical data is
      essential in diagnosis of CPA on cytology. In a proper clinical setting,
      extensive fine needle aspiration sampling should be done initially. Any degree of
      nuclear atypia in PA should be documented, alerting the clinician and
      histopathologist to the possibility of CPA.

PMID- 15192945
TI  - Cytologic features of granulosa cell tumors in fluids and fine needle aspiration
      specimens.
AB  - OBJECTIVE: To describe the cytologic features of granulosa cell tumors in fluids
      and fine needle aspiration specimens, with histologic confirmation. STUDY DESIGN:
      Histologically confirmed granulosa cell tumors, 6 adult type and 1 juvenile type,
      were identified. All patients had local recurrences or metastases. Eleven
      specimens from 7 patients, including cytologic samples, cell blocks and
      histology, were reviewed. Inhibin immunostaining was performed on cell blocks to
      aid identification of this group of tumors in the cytologic and histologic
      samples. RESULTS: The patients were 22-72 years old. Sites included ovary and
      peritoneum; there were pelvic recurrences and metastatic lesions in the spleen,
      liver, perirectum and cervical lymph node. Cytologic features of adult granulosa
      cell tumors included 3-dimensional clusters, resettes loose monolayers and
      individual cells. Other features were Call-Exner bodies, vacuolated cytoplasm,
      exuberant capillaries associated with papillarylike fronds, a second population
      of elongated theca cells, and prominent or rare nuclear grooves. In juvenile
      granulosa cell tumor the features observed were monolayers, loosely cohesive
      sheets, single cells, occasional larger pleomorphic cells with nuclear clefting
      and nuclear protrusions, vacuolated cytoplasm, finely granular chromatin and
      frequent mitoses. The overall cytologic and histologic correlation was good.
      Inhibin was focally positive in one peritoneal fluid, correlating with the focal
      pattern of staining seen on histology. CONCLUSION: A definitive cytologic
      diagnosis of granulosa cell tumor can be made based on the above criteria.
      Aggressive tumors are discohesive and show pleomorphism and nuclear protrusions.
      Inhibin stain may be helpful in identifying granulosa cell tumors in cell block
      specimens.

PMID- 15192946
TI  - Role of unstained smears in determining sample adequacy.
AB  - OBJECTIVE: To determine adequacy with air-dried, unstained smears. STUDY DESIGN:
      The study was conducted on a total of 70 cases. The cases were divided into 2
      groups. Group I consisted of all 70 and was analyzed by a consultant, observer A.
      Group II consisted of 41 cases from group I. In addition to observer A, a junior
      resident with 3 months' experience in pathology (observer B), analyzed the slides
      independently. The results were compared with those on stained smears. RESULTS:
      When correlated with stained smears, in group I, 55 of 58 (94.8%) cases were
      reported as adequate, and 11 of 12 cases (91.7%) were labeled inadequate. All
      were proven correct. In group II, stained smears confirmed that 33 of 35 (94.3%)
      were labeled adequate by observer A and 33 of 36 (91.7%) by observer B. Stained
      smears did not confirm 1 of 6 (16.6%) cases labeled inadequate by observer A and
      1 of 5 (20%) cases by observer B. CONCLUSION: Unstained smear examination is an
      effective technique for determining adequacy. An inexperienced practitioner can
      perform it as well.

PMID- 15192948
TI  - Utility of repeat fine needle aspiration in acute suppurative lesions. Follow-up
      of 263 cases.
AB  - OBJECTIVE: To determine the clinical value of repeat fine needle aspiration (FNA)
      as a follow-up strategy in the management of patients in India, clinically
      suspected of having tuberculosis (TB) but showing a cytologic picture of acute
      suppuration. STUDY DESIGN: Repeat aspirates from 263 patients presenting with
      lymph node or soft tissue masses were analyzed. The previous FNA of these cases
      had shown acute inflammatory exudate but no epithelioid granuloma or acid-fast
      bacilli (AFB). RESULTS: The repeat FNA helped to detect 55% additional cases of
      TB within a period of 8 weeks; 67% of them were diagnosed in the second and third
      weeks. Diagnostic yield rose to 59% after the third FNA. AFB were detected in 34
      (13.3%) cases that showed a low bacterial load. In addition, nontubercular
      lesions, such as epidermal inclusion cyst (4), cysticercosis (3), sialadenitis
      (2) and metastatic carcinoma (8), were diagnosed. CONCLUSION: All cases showing
      acute suppuration without granulomas or AFB on the first FNA should be
      reevaluated by follow-up FNA and staining for AFB. This will enhance the
      diagnostic yield of tuberculosis in developing countries, where molecular
      diagnostics are too costly or unavailable. This procedure is cost effective as
      compared to biopsy and culture. In addition to tuberculosis, many unexpected
      nontubercular lesions may also be unmasked. Repeat FNA reduces sampling and
      screening errors, improves sensitivity and helps to study the evolution of
      epithelioid granulomas.

PMID- 15192947
TI  - Papillary thyroid carcinoma and its variants in fine needle aspiration smears. A
      cytomorphologic study with special reference to tall cell variant.
AB  - OBJECTIVE: To study the fine needle aspiration (FNA) cytologic features of
      papillary thyroid carcinoma (PTC) with special reference to its tall cell variant
      (TCV), which is the most aggressive of the variants. STUDY DESIGN: Fifty-four PTC
      cases were classified into variants, and the frequency of well-known morphologic
      criteria was determined. Four parameters were quantitatively analyzed based on a
      study of 200 consecutive neoplastic follicular cells: shape of cells, color of
      cytoplasm, intranuclear cytoplasmic inclusion (INCI) and nuclear grooves.
      RESULTS: The PTC cases included 6 TCV (> or = 30% tall cells), 8 cases with a
      significant tall cell component (sig. TCC) having 10-29% tall cells, 17 usual
      variant (UV), 17 follicular variant (FV) and 6 miscellaneous variants. TCV
      differed significantly from UV and FV in having a higher tall cell count, higher
      count of cells with reddish cytoplasm and INCI, and higher frequency of cases
      with lymphocytic infiltration. PTC (with significant tall cell component [TCC])
      differed significantly from TCV with regard to tall cell count and lymphocytic
      infiltration, from UV with respect to tall cell count and monolayered sheets, and
      from FV with respect to tall cells, INCI, grooved nuclei, acinar formation, fire
      flare appearance and giant cells. CONCLUSION: TCV was cytologically distinct from
      other variants. The biologic behavior of PTC cases with significant TCC, which
      morphologically seem to be a group intermediate between TCV on the one hand and
      UV and FV on the other, however, needs to be carefully monitored.

PMID- 15192949
TI  - Methodologic aspects of evaluating brush samples from biliary strictures by
      cytology and DNA flow cytometry.
AB  - OBJECTIVE: To present a method of increasing the cell yield from brush samples of
      the biliary tree for measurement of DNA content by flow cytometry (FCM). STUDY
      DESIGN: One hundred eight cell specimens from 86 patients were studied by FCM for
      DNA ploidy and cell cycle composition. All specimens were cytologically
      classified into benign, suspicious for malignancy and malignant. Two methods for
      preparation of the cell material were compared. RESULTS: Enzymatic treatment of
      formalin-fixed brushes for release of cell nuclei was superior to mechanical
      removal of the cells. The fraction of samples not possible to assess was reduced
      from 27% to 4%, and good quality histograms increased from 21% to 62%. Aneuploidy
      was detected in 7% of benign and 57% of suspicious malignant samples. Using DNA
      analysis in addition to cytology as a diagnostic marker for cancer, the
      sensitivity increased from 12% to 31%. CONCLUSION: FCM of cells from biliary
      strictures can be used routinely as an adjunct to cytology for DNA analysis.

PMID- 15192950
TI  - Population-based cervical screening with a 5-year interval in The Netherlands.
      Stabilization of the incidence of squamous cell carcinoma and its precursor
      lesions in the screened population.
AB  - OBJECTIVE: To evaluate the outcome of population-based cervical screening at 5
      year intervals. STUDY DESIGN: Results from the west region of the Netherlands
      (population 2 million) were used. The 1995-2000 round was compared with the first
      2 years of the second (2001-2002). All results were prospectively collected in a
      central database. Positive cytologies and histoscores per 1,000 screened for
      preinvasive squamous cervical intraepithelial neoplasia (CIN) lesions and
      invasive squamous cell carcinoma were calculated. RESULTS: In the first round,
      378,081 women were screened; in the second round, 100,561 women were screened. In
      both rounds the youngest screenees had the highest cytoscores. Cytoscores in the
      first round did not differ significantly from those in the second. The histoscore
      for CIN 1 and 2 was 1.42 per 1,000 in the first round and 1.18 per 1,000 (NS, P <
      .01) in the second. The histoscore for CIN 3 was 2.07 per 1,000 in the first
      round and 2.13 per 1,000 (NS, P < .01) in the second. Histoscores for invasive
      squamous cell carcinoma remained virtually the same (0.16 per 1,000 in the first,
      0.14 per 1,000 in the second round). CONCLUSION: Population-based screening at 5
      year intervals in the Netherlands may result in stabilization of positive
      cytology and of the incidence of CIN and (histologic) invasive squamous cell
      carcinoma. The program seems more cost effective than that of 2 decades ago, with
      a screening interval of 3 years.

PMID- 15192951
TI  - Bethesda 2001. Impact on the reporting of gynecologic cytology.
AB  - OBJECTIVE: To examine the impact of implementing Bethesda 2001 in one laboratory.
      STUDY DESIGN: A computer search identified all cervicovaginal specimens evaluated
      between July 2001 and June 2002. Bethesda 2001 was implemented on January 1,
      2002. The rates of specimen adequacy and the frequency of each diagnostic
      category 6 months before and 6 months after the implementation of Bethesda 2001
      were compared. RESULTS: A total of 21,332 cervicovaginal specimens were evaluated
      during the study period. During the first 6 months, 10,695 specimens were
      examined; 40% were liquid-based preparations. During the next 6 months, 10,367
      specimens were examined; 60% were liquid-based preparations. Prior to the
      implementation of Bethesda 2001, the percentages of each category were as
      follows: 74.99% within normal limits, 7.10% reactive/reparative cellular changes
      (R/R), 10.29% atypical squamous cells (ASC), 0.24% atypical glandular cells
      (AGC), 3.45% low grade squamous intraepithelial lesion (LSIL), 3.44% high grade
      squamous intraepithelial lesion (HSIL) and 0.73% unsatisfactory. In addition,
      19.00% were classified as "satisfactory but limited by" (SBLB). Following the
      implementation of Bethesda 2001, the percentages of each category were as
      follows: 80.09% negative for intraepithelial lesion and malignancy including
      6.94% with the qualifier R/R, 10.32% ASC, 0.27% AGC, 4.54% LSIL, 3.44% HSIL and
      0.81% unsatisfactory. In addition, 17.40% were satisfactory with a quality
      indicator (SAT with QI). The incidence of reporting benign endometrial cells in
      patients over age 40 was the same for both periods. There was a significant
      decrease in the percentage of specimens classified as SAT with QI when compared
      to that of specimens classified as SBLB. A statistically significant increase in
      the percentage of specimens was noted in the category LSIL (P < or = .001) and
      satisfactory (.005) after implementing Bethesda 2001. No significant changes were
      noted in other categories. CONCLUSION: Our laboratory experienced some changes in
      the laboratory statistics of reporting gynecologic cytology after the
      implementation of Bethesda 2001. Continuous monitoring of reporting trends is
      indicated to clearly understand the impact of Bethesda 2001 on laboratory
      statistics.

PMID- 15192952
TI  - False positive diagnosis in conventional and liquid-based cervical specimens.
AB  - OBJECTIVE: To examine conventional and liquid-based cervical smears falsely
      diagnosed as malignant at our institution and to investigate, through cytologic
      histologic correlation, factors influencing false positive diagnoses. STUDY
      DESIGN: Cervical cytologic diagnoses of malignancy from May 1, 1995, to April 30,
      2001, were retrieved through a computer search. A retrospective review of
      hospital records and pathology reports was performed. Cases identified as false
      positives were reviewed and correlated with histologic follow-up specimens.
      RESULTS: A group of 68 patients with malignancy reported on cervical smears and
      with histologic follow-up was identified. Conventional smears numbered 32 (47%);
      the remaining 36 (53%) were liquid-based samples. Of the total, 7 false positive
      cases (10.3%) were identified in 4 conventional and 3 liquid-based preparations.
      Cytologic diagnosis in these cases was squamous cell carcinoma in 5 and
      adenocarcinoma in 2. On histologic follow-up, all 7 patients were ultimately
      found to have high grade squamous intraepithelial lesions (HSILs) without
      invasion. Review of the original slides confirmed most, or all, of the following
      features in all cases: major cellular pleomorphism, extensive cytoplasmic
      keratinization, intense nuclear pyknosis, background necrosis and severe atrophy.
      CONCLUSION: There was no significant difference in rates of false positive
      diagnoses between conventional (12.5%) and liquid-based (8.3%) samples. The chief
      reason for overdiagnosis in this series was the capacity of HSIL to exfoliate
      cells mimicking invasive malignancy, particularly when keratinized and especially
      in an atrophic milieu. The other cause of false positivity was superimposition of
      inflammation and atypical reparative change on a background of HSIL, which then
      suggested invasion.

PMID- 15192953
TI  - Glandular lesions of the cervix on thin-layer Pap tests. Validity of cytologic
      criteria used in identifying significant lesions.
AB  - OBJECTIVE: To determine the cytologic features that are most helpful in
      characterizing significant glandular lesions of the cervix observed on the
      ThinPrep (TP) Pap test (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) and to
      compare these features with those published for conventional smears. STUDY
      DESIGN: Thirty-nine TP preparations with cytologic evidence of glandular lesions
      of the cervix and histologic and/or clinical correlation were studied. These
      lesions included (1) 11 cases of benign/reactive conditions; (2) 10 cases of
      adenocarcinoma in situ (AIS), of which 1 had both AIS and carcinoma in situ; (3)
      1 case of invasive adenocarcinoma; (4) 15 cases of squamous intraepithelial
      lesions and squamous cell carcinoma, including 4 with glandular involvement, and
      (5) 2 cases of adenosquamous cell carcinoma. These cases were reviewed by the
      first author without knowledge of the histologic diagnosis. Twenty-five
      previously published cytologic criteria were used to evaluate glandular cells on
      TP slides. Statistical analysis was performed using Fisher's exact test to
      determine the significance of the features studied. RESULTS: All glandular
      lesions had cytologic features on TP similar to those previously described on
      conventional smears. However, TP slides demonstrated enhanced nuclear features
      but less-preserved architectural patterns. Reactive lesions showed minimal
      overlapping without hyperchromasia or mitotic figures and with normal
      nuclear/cytoplasmic ratios. AIS and invasive adenocarcinoma cases had similar
      features. Increased cellularity and overcrowding were prominent, whereas
      feathering, rosettes and cell strips were present but subtle. CONCLUSION:
      Glandular lesions of the cervix on TP slides shared many of the characteristic
      features reported for conventional smears. However, nuclear details were more
      pronounced in TP slides, while architectural patterns, although present, were
      relatively subtle.

PMID- 15192954
TI  - Postoperative bladder washing cytology after transurethral resection. Can it
      predict the recurrence of urothelial carcinoma?
AB  - OBJECTIVE: To assess the ability of postoperative bladder washing cytology,
      performed immediately after transurethral resection of mostly stage Ta or T1
      papillary urothelial carcinoma, to predict early recurrence. STUDY DESIGN: In a 1
      year period, preoperative and postoperative bladder washing cytology specimens
      were sampled from patients undergoing transurethral resections in which all
      visible tumor was removed. There were 38 resections in 32 patients. RESULTS:
      Postoperative cytology was satisfactory in 35 of 38 cases and positive in 17
      (49%) after a mean of 6.9 months. Follow-up of these 35 transurethral resections
      disclosed a 15/17 (88%) recurrence rate after positive cytology and a 4/18 (22%)
      recurrence rate after negative cytology (P < .001). Postoperative cytology
      demonstrated a sensitivity for recurrence of 79%, specificity of 88%, positive
      predictive value of 88% and negative predictive value of 77%. In contrast, tumor
      in the transurethral resection specimen had a positive predictive value of 54%
      for recurrence, and its grade and stage were inferior to cytology in predicting
      recurrence. CONCLUSION: Postoperative bladder washing cytology is a useful
      adjunct to the management of papillary urothelial carcinoma. A positive result,
      signifying residual tumor, should encourage prompt follow-up and possibly repeat
      transurethral resection.

PMID- 15192955
TI  - Indian file pattern of adenocarcinoma cells in effusions.
AB  - OBJECTIVE: To determine the prevalence of the Indian file pattern of
      adenocarcinoma cells in malignant serous effusions. STUDY DESIGN: Twenty-five
      malignant and 10 benign effusion samples were selected. Clinical data, including
      the sites of the primary neoplasms, were noted. The presence or absence of Indian
      file arrangement of carcinoma cells and other patterns were recorded. RESULTS:
      Seven of the 25 positive cases showed Indian file arrangement, whereas none of
      the negative cases did. Their number did not show any correlation with the type
      and site of the primary neoplasms. In most of the 7 cases other patterns, such as
      3-dimensional balls and papillations, were also present. CONCLUSION: Cells in
      Indian file in serous effusions are strongly suggestive of metastatic carcinoma.
      They are not specific to any particular site of the primary adenocarcinoma.

PMID- 15192956
TI  - Spindle cell malignant melanoma metastatic to the breast from a pigmented lesion
      on the back. A case report.
AB  - BACKGROUND: Tumors metastatic to the breast are quite unusual (1.2% of all
      tumors). Malignant melanoma is an exception and is one of the principal
      metastasizing tumors, described mainly as a primary tumor. There are 5 different
      cytologic patterns; the spindled pattern is very uncommon, more difficult to
      diagnose and can be confused with a wide range of sarcomatous lesions.
      Nevertheless, there are some cytologic features that allow differentiation from
      similar tumors. CASE: A 30-year-old woman presented with a firm, deep, nontender
      mass in the upper outer quadrant of the right breast. Fine needle aspiration
      cytology was performed, and the aspiration smears showed spindle-shaped
      neoplastic cells arranged singly or in clusters with marked nuclear atypia.
      Melanin pigment was sometimes seen in the cytoplasm of some cells. Pathologic
      study of the breast tumor corroborated the diagnosis, and later study revealed
      lymph node metastases and relapse in the breast area and on a scar on the back.
      Two years earlier, biopsy of a pigmented lesion on the back was diagnosed as a
      cellular blue nevus. CONCLUSION: The cytologic features of spindle cell melanoma
      are distinctive. The presence of atypical fusiform cells with elongated
      cytoplasm; enlarged nuclei, some of them binucleated or multinucleated; prominent
      nucleoli; intranuclear cytoplasmic inclusions; and melanin pigment can help to
      diagnose these unusual metastases to the breast. This case was the first of
      malignant metastatic melanoma with the spindled pattern in which the diagnosis
      was made by fine needle aspiration cytology.

PMID- 15192957
TI  - Fine needle aspiration cytology of primary epithelioid sarcoma. A report of 2
      cases.
AB  - BACKGROUND: Epithelioid sarcoma is a rare soft part tumor, the cytologic features
      of which have not been fully elucidated to date. We describe the cytologic
      features in 2 cases of primary epithelioid sarcoma with samples obtained by fine
      needle aspiration (FNA). CASES: Case 1 was a 50-year-old male who complained of a
      small mass in his left palm. Case 2 was a 56-year-old female who presented with a
      mass on the medial aspect of her right forearm. Preoperative FNA smears in both
      cases showed loose, aggregated and isolated tumor cells that were round to
      polygonal, with eccentrically located nuclei, against a background of
      inflammation and necrosis. The tumor cells showed moderate atypia, irregularity
      in size and many mitoses. In case 1 a presumptive diagnosis of epithelioid
      sarcoma was made by FNA cytology, while in case 2, FNA cytology revealed a high
      grade sarcoma with abundant matrix mimicking osteoids, difficult to differentiate
      from an extraskeletal osteosarcoma. CONCLUSION: Epithelioid sarcoma may be
      difficult to differentiate from an extraskeletal osteosarcoma in cases with
      abundant hyalinized collagen on FNA cytology.

PMID- 15192958
TI  - Cytologic features of chordoid meningioma. A case report.
AB  - BACKGROUND: Chordoid meningioma is a rare subtype of meningioma characterized by
      myxoid matrices deposited among epithelioid or vacuolated tumor cells and
      infiltrates of inflammatory cells, and its cytologic features have rarely been
      reported. CASE: A 57-year-old man with a history of headache and visual
      disturbance presented with a tumor in the suprasellar region. Intraoperative
      touch smear cytology of the tumor disclosed a cord-like arrangement of polygonal
      tumor cells occasionally containing intranuclear inclusions. Furthermore,
      periodic acid-Schiff-positive, mucinous matrices were deposited among the tumor
      cells. Also, infiltrates of lymphocytes and plasma cells were noted. Histologic,
      immunohistochemical and ultrastructural examination confirmed the diagnosis of
      chordoid meningioma. CONCLUSION: Intraoperative smear cytology in a case of
      chordoid meningioma showed distinctive cytologic features suggestive of the
      histologic patterns. The cytologic features, together with a histologic
      examination, are useful for its diagnosis.

PMID- 15192959
TI  - Cytologic features of solitary fibrous tumor of the parotid gland. A case report.
AB  - BACKGROUND: Solitary fibrous tumor (SFT) is a rare neoplasm that most commonly
      involves the pleura but is increasingly recognized at other locations, including
      lung, liver, thyroid and parotid glands, with only a few reports describing its
      cytologic features. CASE: The fine needle aspiration biopsy (FNAB) features of an
      SFT located in the left parotid gland of a 34-year-old woman were compared to the
      histologic and immunohistochemical aspects of the lesion. CONCLUSION: This case
      confirms that SFT has distinct cytomorphologic features and that FNAB can be
      helpful in its diagnosis.

PMID- 15192961
TI  - Intravascular lymphomatosis of the brain. Report of a case using an
      intraoperative cytologic preparation.
AB  - BACKGROUND: Intravascular lymphomatosis (IVL) of the brain is a rare non
      Hodgkin's lymphoma characterized by proliferation of tumor cells in the lumina of
      blood vessels. Although an intraoperative cytologic examination of the brain is
      routinely done, the cytologic features of IVL are rarely encountered by
      pathologists. We report a case of IVL diagnosed by an intraoperative cytology
      preparation. CASE: A 62-year-old woman presented with a seizure and fever.
      Computed tomography and magnetic resonance imaging of the brain were insufficient
      to establish a diagnosis but suggested a cerebral infarction, so a stereotactic
      brain biopsy was performed. On an intraoperative cytologic examination, a few
      small and medium-sized vessels were filled with tumor cells showing atypical,
      pleomorphic, large nuclei. Immunohistochemical staining using paraffin-embedded
      tissue revealed intraluminal tumor cells expressing leukocyte common antigen and
      CD20 but not CD3. CONCLUSION: This disease must be considered one of the
      diagnostic possibilities in any patient with rapidly progressive dementia and
      cerebral infarction. Increased awareness of this disease and intraoperative early
      diagnosis are important for its successful management.

PMID- 15192960
TI  - Cytologic diagnosis of suppurative cholecystitis due to Candida albicans and
      actinomyces. A report of 2 cases.
AB  - BACKGROUND: Cholecystitis is a common inflammatory disease of the gallbladder.
      Actinomycosis and candidiasis of the gallbladder are uncommon causes of acute
      cholecystitis. There has been no previous report on the cytologic diagnosis of
      actinomycosis and candidiasis from aspirated gallbladder bile intraoperatively.
      CASES: Purulent bile was intraoperatively aspirated from the gallbladder of 71
      year-old Indian and a 30-year-old Australian woman. The specimens were sent for
      cytologic examination. The first case revealed sulphur granules characteristic of
      Actinomyces spp. The second case showed budding spores and pseudohyphae of
      Candida spp. Pure colonies of Candida albicans grew from the bile culture.
      CONCLUSION: Actinomycosis and candidiasis rarely cause acute suppurative
      cholecystitis. Initial diagnosis can be made by cytologic examination of the
      aspirated purulent bile intraoperatively.

PMID- 15192962
TI  - Hemophagocytic histiocytosis diagnosed by fine needle aspiration cytology of the
      spleen. A case report.
AB  - BACKGROUND: Hemophagocytic histiocytosis (HPS) is an idiopathic, familial or
      secondary syndrome characterized by mature histiocytes causing intensive
      erythrophagocytosis. CASE: A 2-month-old male suffering from autoimmune hemolytic
      anemia, fever, jaundice and hepatosplenomegalia underwent fine needle aspiration
      cytology of the spleen. Aspiration was performed using a 23-gauge, short needle
      with a subcostal approach. The smear showed a monomorphous cell population of
      mature histiocytes with marginal nuclei and wide, well-defined cytoplasm. The
      cytoplasm was microvaculated and often contained > or = 1 erythrocytes and
      occasional lymphocytes. Immunostaining performed on cytospin samples showed
      diffuse positivity for alpha-1-antichymotrypsin and S-100. Differential diagnosis
      with malignant histiocytosis, Langerhans histiocytosis and sinus histiocytosis
      with massive lymphadenopathy was established. HPS was diagnosed because of the
      cytologic and immunocytochemical features and clinical data. CONCLUSION: HPS may
      be diagnosed using fine needle aspiration of the spleen when other biopsy samples
      have been unsuccessful. Cytologic, diagnosis of HPS should always be considered
      in a specific clinical setting, because early treatment can often save the
      patient's life.

PMID- 15192963
TI  - Marginal zone B-cell lymphoma of the parotid gland associated with epithelioid
      granulomas. Report of a case with fine needle aspiration.
AB  - BACKGROUND: Although granulomas can occur in association with malignant
      neoplasms, including some subtypes of lymphoma, they have been described rarely
      in marginal zone B-cell lymphoma (MZCL). To our knowledge, the cytologic features
      of this association have not been documented. We present the cytologic findings
      with fine needle aspiration cytology (FNAC) of an unusual case of MZCL with
      concomitant granulomas. CASE: An 82-year-old male presented with a mass in the
      left parotid gland. The lesion was evaluated by FNAC. The smears showed syncytial
      aggregates of epithelioid histiocytes intermixed with small and medium-sized
      lymphoid cells containing round to irregular-shaped nuclei and small nucleoli.
      Some of these cells had a greater amount of cytoplasm and frequently had a
      plasmacytoid appearance. The lesion was removed, and histopathologic study showed
      MZCL associated with extensive nonnecrotizing granulomas. CONCLUSION:
      Granulomatous reactions can be seen in rare cases of MZCL. However, the cytologic
      features of the lymphoid infiltrate can suggest the possibility of MZCL in the
      clinical setting of FNAC performed from an extranodal location, such as the
      parotid gland.

PMID- 15192964
TI  - Human herpesvirus 8 in primary effusion lymphoma in an HIV-seronegative male. A
      case report.
AB  - BACKGROUND: AIDS-related body cavity-based lymphoma, or primary effusion lymphoma
      (PEL), is a distinct clinicopathologic entity that occurs predominantly in
      immunosuppressed patients infected with human herpesvirus 8 (HHV-8), also known
      as Kaposi's sarcoma-associated herpesvirus. Although it rarely occurs in human
      immunodeficiency virus (HIV)-negative patients, we report such a case here. CASE:
      A 74-year-old male, who was HIV and Epstein-Barr virus (EBV) negative, was
      admitted to the hospital with dyspnea and chest pain. Chest radiography and
      computed tomography showed right pleural effusion. Cytologic analysis of the
      pleural effusion revealed a high grade lymphoma with round nuclei, prominent
      nucleoli and abundant cytoplasm. Polymerase chain reaction performed on the
      pleural effusion was positive for HHV-8 and negative for EBV. On molecular
      studies, the immunoglobulin heavy and kappa light chains were rearranged. Flow
      cytometry revealed a hyperploid fraction with DNA index of 1.29 expressing CD30.
      Immunostaining for HHV-8 from a cell block was positive. Electron microscopy
      revealed lymphomalike cells, many in various stages of apoptosis, with large
      nucleoli and clusters of viruslike particles in the nucleoplasm. CONCLUSION: A
      firm diagnosis of PEL can be established by the examination of cells from the
      lymphomatous effusion by a combination of cytology, molecular genetics,
      phenotypic features, immunostaining and electron microscopy. To our knowledge,
      this is the first case in which immunostaining for anti-HHV-8 monoclonal
      antibodies was used to support the diagnosis.

PMID- 15192965
TI  - Cribriform-morular variant of papillary thyroid carcinoma. Report of a case
      showing morules with peculiar nuclear clearing.
AB  - BACKGROUND: There have been only 4 reported cases of cribriform-morular variant
      of papillary thyroid carcinoma (CMVPTC) with cytologic findings from fine needle
      aspiration. In these reports, the cytologic findings do not fully reflect the
      histologic characteristics of this entity. We report a case of CMVPTC in which a
      cribriform pattern without colloid and epithelial morules with peculiar nuclear
      clearing (PNC) were present in smears, thus fulfilling the criteria for a
      cytologic diagnosis of CMVPTC. Protein truncation tests for APC molecule
      abnormality indicated the presence of germline mutation in the patient's APC
      gene. CASE: A 30-year-old woman had multiple thyroid tumors. Aspiration cytology
      revealed a large number of round to spindle-shaped atypical-cells showing sheet
      like, cribriform, follicular, whorl-like and solid, 3-dimensional arrangements.
      The cribriform and follicular arrangements did not contain colloid in the lumen.
      The powdery chromatin pattern characteristic of papillary carcinoma was not
      observed, but there were scattered intranuclear cytoplasmic pseudoinclusions and
      grooved nuclei. The nuclei of the atypical cells presenting in the whorl
      formations showed enlargement, thickened nuclear membranes and entirely clear
      contents, consistent with PNC. Hyalinelike necrotic cells were also observed in
      the cell clusters or in the background. Histologic and immunohistochemical
      findings were typical of CMVPTC. CONCLUSION: The cribriform pattern without
      colloid, fascicular or whorl formation of spindle cells, and morules with PNC are
      identifiable on cytologic smears and are sufficiently distinctive to allow a
      cytologic diagnosis of CMVPTC.

PMID- 15192966
TI  - Asymptomatic intrathyroidal parathyroid adenoma. Report of a case with a
      cytologic differential diagnosis including thyroid neoplasms.
AB  - BACKGROUND: Intrathyroidal parathyroid neoplasms (IPNs) are uncommon tumors with
      an indolent clinical course. When asymptomatic, they can be incorrectly diagnosed
      as thyroid neoplasms on fine needle aspiration biopsy (FNAB), leading to
      inappropriate surgical treatment. CASE: A case of unsuspected IPN occurred in
      which the cytologic picture mimicked that of a thyroid neoplasm. The histologic
      specimen of the total thyroidectomy showed 2 adjacent intrathyroidal nodules
      morphologically and immunohistochemically corresponding to a parathyroid adenoma.
      CONCLUSION: The incidence of IPN remains controversial, especially in
      asymptomatic patients. On FNAB it is a possible cause of inappropriate surgery
      for a suspicious thyroid neoplasm (follicular or medullary carcinoma).
      Immunostaining for parathormone on the cytologic smear is valuable in
      establishing the correct preoperative diagnosis when the morphologic features are
      strongly suggestive of IPN.

PMID- 15192967
TI  - Diagnosis of thymolipoma with fine needle aspiration biopsy. Report of a case
      initially misdiagnosed as liposarcoma.
AB  - BACKGROUND: Thymolipomas are the most outstanding mesenchymal mediastinal tumors
      although they represent only a small percentage of thymic neoplasms. Their
      histogenesis remains unsolved, and they are usually benign. Fine needle
      aspiration biopsy (FNAB) has become the method of choice for the study of
      mediastinal tumors, including thymolipomas. Making the correct diagnosis depends
      on the availability of all thymic and lipomatous components as well as on the
      correct application of a differential diagnosis with other lipomatous tumors.
      CASE: A 24-year-old woman had a 3-month history of coughing with sputum, fever,
      asthenia, adynamia, headaches and anemia. Physical examination revealed a
      bilateral pulmonary condensation syndrome. Imaging studies showed a well-defined,
      large mass occupying both hemithoraxes and the mediastinum. FNAB revealed an
      admixture of atypical adipocytes, nonneoplasic lymphoid tissue and capillaries
      with prominent endothelium. An initial diagnosis of well-differentiated
      liposarcoma was made. A 2.8-kg, encapsulated, yellowish gray mediastinal tumor
      was surgically removed. Mature adipose tissue intermingled with abundant thymic
      tissue containing numerous Hassall's corpuscles were seen histologically.
      Immunohistochemical markers for thymic epithelium, lymphoid tissue and adipocytes
      were all positive. Thymolipoma was the final diagnosis. The anemia subsided with
      resection of the tumor, and the patient was disease free 2.5 years after surgery.
      CONCLUSION: To the best of our knowledge, this is the second report of a
      thymolipoma studied with FNAB. The criteria for the differential diagnosis
      between thymolipomas and other lipomatous tumours should be kept in mind.

PMID- 15192969
TI  - Tissue concentration and preservation of morphology in bloody aspirates.

PMID- 15192968
TI  - Squash smear findings of spherical amyloid in pituitary prolactinoma. A case
      report.
AB  - BACKGROUND: Pituitary prolactinoma containing spherical amyloid is rare. Squash
      smear findings of spherical amyloid in pituitary prolactinoma are characteristic.
      CASE: A 25-year-old woman presented with a pituitary tumor. The intraoperative
      squash smear showed abundant, homogeneous, eosinophilic material with multiple
      prominent striations. The scattered atypical cells in the periphery contained an
      irregular, bizarre nucleus; coarse chromatin; occasional prominent nucleoli; rare
      cytoplasm; and prolactin immunoreactivity. CONCLUSION: The characteristic squash
      smear findings should be helpful in the diagnosis of this rare tumor.

PMID- 15192970
TI  - Cytologic features of paratesticular adenomatoid tumor.

PMID- 15192971
TI  - Observation of epithelial atypia associated with intranuclear inclusions in
      ovarian endometriosis.

PMID- 15192972
TI  - Metastatic pulmonary urothelial carcinoma of the renal pelvis with an unusual
      presentation.

PMID- 15192973
TI  - A modified rapid Papanicolaou stain for imprint smears.

PMID- 15192974
TI  - Carcinoma in situ of the fallopian tube presenting as a positive Pap smear.

PMID- 15192975
TI  - Metastatic granulosa cell tumor: diagnosis by fine needle aspiration.

PMID- 15192977
TI  - Cytologic features of papillary cystadenoma of the epididymis associated with
      hydrocele.

PMID- 15192976
TI  - Benefits of the conventional Papanicolaou smear.

PMID- 15192978
TI  - Effusion cytology of pleural mesothelioma, epithelial type, with extreme
      cytoplasmic vacuolization.

PMID- 15192979
TI  - Cysticercosis diagnosed by fine needle aspiration cytology.

PMID- 15192980
TI  - Early bar code ruling helps reduce medication errors.

PMID- 15192981
TI  - Factors that impact the transfer and retention of best practices for reducing
      error in hospitals.
AB  - Recent research and theory in organizational learning literature advances seven
      propositions that illuminate the nature and complexities of transferring and
      retaining best practices for reducing error and increasing patient safety in U.S.
      and Canadian hospitals.

PMID- 15192982
TI  - Nurse productivity measures for the 21st century.
AB  - The concept and measurement of nurses' productivity ranges from traditional
      economic interpretation of nurses as labor costs to human capital theory
      interpretation of nurses as intellectual capital assets.

PMID- 15192983
TI  - Nurse staffing patterns and quality of care in nursing homes.
AB  - Using the structure-process-outcome framework and the resource-based view of the
      firm, this study considers both direct and indirect effects of registered nurse
      staffing patterns on the quality of patient care outcomes. Consistent with
      theory, registered nurse staffing patterns were found to affect quality of
      patient care both directly and indirectly through their positive effect on the
      processes of delivering care.

PMID- 15192984
TI  - Building legitimacy and the early growth of health networks for the uninsured.
AB  - An integrated system of health care for serving the uninsured population of one
      community was followed from formation through early growth. Funding was provided
      through the Health Resources Services Administration's Community Access Program
      to bring together a diverse set of health care providers to form a collaborative
      network managed by a central administrative entity. Legitimacy building was
      critical for explaining how the network evolved and the effectiveness of the
      network in sustaining itself and building a patient base. Based on the study's
      results, conclusions are drawn that contribute to theory on network legitimacy in
      health care. In addition, lessons learned are offered that may help other
      communities address the health needs of the uninsured through collaborative
      health care networks.

PMID- 15192985
TI  - How does the culture of medical group practices influence the types of programs
      used to assure quality of care?
AB  - OBJECTIVE: It is widely acknowledged that the culture of medical group practices
      greatly influences the quality of care, but little is known about how cultures
      are translated into specific types of programs focused on quality. This study
      explores this issue by assessing the influence of the organizational culture on
      these types of programs in medical group practices in the upper Midwest. DESIGN
      AND METHODS: Data were obtained from two surveys of medical group practices. The
      first survey was designed to assess the culture of the practice using a nine
      dimension instrument developed previously. The second survey was designed to
      obtain organizational structure data including the programs identified by the
      literature as important to the quality of care in medical practices. Completed
      surveys were obtained from eighty-eight medical groups. The relationship of the
      group practice culture to structural programs focused on quality of care was
      analyzed using logistic regression equations. RESULTS: Several interesting
      patterns emerged. As expected, practices with a strong information culture favor
      electronic data systems and formal programs that provide comparative or evidence
      based data to enhance their clinical practices. However, those with a quality
      centered culture appear to prefer patient satisfaction surveys to assess the
      quality of their care, while practices that are more business-oriented rely on
      bureaucratic strategies such as benchmarking and physician profiling. Cultures
      that emphasize the autonomy of physician practice were negatively (but not at a
      statistically significant level) associated with all the programs studied.
      Practices with a highly collegial culture appear to rely on informal peer review
      mechanisms to assure quality rather than any of the structural programs included
      in this analysis. CONCLUSION: This study suggests that the types of quality
      programs that group practices develop differ according to their cultures.
      Consequently, it is important for practice administrators and medical directors
      to develop quality assurance programs that fit their cultures if they are to gain
      buy-in by their clinicians. Future research should assess the effect of culture
      structure fit on quality and safety outcomes.

PMID- 15192986
TI  - Strategic group stability: evidence from the health care industry.
AB  - To better understand strategic group stability and the associated mobility
      barriers concept, we surveyed health care administrators on their reasons for
      remaining in their current strategic group. We offer administrators' responses to
      the strategic group stability (mobility barrier) question. Decision-makers may be
      unaware of these cognitive biases (e.g., group-level world-view and resource
      similarity) and may not recognize the extent to which they are reducing their
      strategic alternatives.

PMID- 15192987
TI  - Predictors of lawsuit activity against nursing homes in Hillsborough County,
      Florida.
AB  - The objective of this study is to examine the litigation experience of twenty
      eight nursing homes in Hillsborough County, Florida. Primary data were collected
      from Hillsborough County Circuit Court's Clerk's Recording Computer System about
      lawsuit activity from 1996 to 2000 and linked to the Centers for Medicare and
      Medicaid Services Online Survey, Certification, and Reporting system. We found
      that registered nurse levels, size, and being part of a chain or system impacted
      litigation in Hillsborough County.

PMID- 15192989
TI  - Is the term "patient" overused?

PMID- 15192988
TI  - Sustainable network advantages: a game theoretic approach to community-based
      health care coalitions.
AB  - Health care organizations often enter into a cooperative arrangement to create
      safety-net programs and coordinate care. Maintaining effective cooperation in
      such alliances poses special problems that can be examined using network analysis
      and explained in game theory terms. A mental health coalition case study is
      presented using network analysis and game theory interpretations. Had a positive
      sum game approach been applied to the coalition's initial design, its subsequent
      suboptimal performance might have been averted. The application of network
      analysis plus a game theoretic paradigm has significant implications for
      improving both the design and the coordination of such coalitions.

PMID- 15192990
TI  - Nursing leadership. Serving those who serve others.
AB  - Because of the current and projected continuance of an acute nursing shortage,
      increased attention is being focused on the workplace environment. This article
      encourages nursing leadership to examine the feasibility of implementing a
      servant-leadership model as a possible methodology for securing and retaining
      current and future nursing staff.

PMID- 15192992
TI  - Work status congruence, work outcomes, and psychologic well-being.
AB  - This study investigated work status congruence, work outcomes, and psychologic
      well-being among nursing staff. Data were collected from 744 hospital-based
      nurses using anonymous questionnaires. Nurses indicated whether they were
      currently working full-time or part-time and whether they preferred to work full
      time or part-time. Two work status groups--congruent and incongruent--were then
      compared. Nursing staff having congruent work status were generally more
      satisfied and reported higher levels of psychologic well-being.

PMID- 15192991
TI  - The measurement of performance in a physical therapy clinical program. A ROI
      approach.
AB  - This research presents the development and implementation of a measurement model
      that yields the return on investment (ROI) in a physical therapy clinical
      program. A performance measurement model was constructed, which determined the
      ROI of a clinical program in physical therapy using revenue, patient outcomes,
      staff productivity, costs, and patient satisfaction. Implementation used archival
      data for 2 groups of patients in a back and neck rehabilitation program. An
      expert panel was formed to review the model. Based on the results, ROI provided a
      more comprehensive tool to measure performance than traditional evaluation
      measures. ROI appears beneficial, making it a useful tool for health care
      professionals to measure the performance of PT clinical programs.

PMID- 15192993
TI  - Leaders who create change and those who manage it. How leaders limit success.
AB  - There is no formula for either leading or managing change. Every organization and
      leader is unique. Leading change, however, is more art than science. Managing
      change is more science than art. Leading change is not simply a matter of a
      leader's style or personality; it is a leader's philosophy of how to generate and
      mobilize the total resources of an organization to enable it to be its best.
      Managing change, on the other hand, is focused on maintaining stability in an
      organization and containing the effects of unwanted and unexpected change.
      Leaders set the limits of success in their organizations by how they manage
      change. The different approaches of 2 leaders who have created change to correct
      problems in our health care delivery system are discussed.

PMID- 15192994
TI  - The benefits of a work-at-home program.
AB  - Working from home offers the employee and the organization many benefits. The
      organization can use telework to recruit and retain valuable employees. The
      organization can also save money on work space and boost morale and loyalty.
      Employees enjoy the flexibility and convenience that telework offers. Teleworking
      is popular in the general business world and can be adapted to some jobs in the
      health care field. Managers must look throughout their organization to see what
      jobs can be accomplished either partially or completely at home.

PMID- 15192995
TI  - Indicators of a healthy and sustainable community. The Central Florida
      experience.
AB  - The society, economy, and health and well-being of residents in the Central
      Florida region create a holistic perspective of a healthy community. This article
      discusses the important role health care organizations play in developing and
      creating healthy communities. It also discusses the responsibility health care
      providers in the Central Florida region have to the communities they serve using
      this broad-based approach to a healthy community. A history is presented showing
      how a local initiative to develop a healthier community led to the development of
      several healthy community indicators for the Central Florida region. The article
      delineates how the indicators reflect the health and long-term viability of the 7
      counties comprising the Central Florida region. A number of public policy
      implications and the role of the region's health care system in furthering these
      indicators are presented for the broadly defined categories of crime, education,
      the local economy, and transporation.

PMID- 15192996
TI  - Applied game theory for the hospital manager. Three case studies.
AB  - This article reviews the more complex aspects of game theory than those presented
      in a recent HCM article. Following a basic overview of terminology and simplified
      examples, case studies are presented to show the hospital manager how game theory
      is a useful modeling strategy for predicting human interactions and the potential
      outcomes of certain decisions, especially economic ones. Understanding game
      theory provides the manager with an understanding of basic and advanced
      strategies that can be utilized to competitive advantage in the health care
      market (thus giving it applicability at the manager's clinical level of decision
      making), as well as grasping the "larger picture" of health care decision making
      at high levels, such as in professional societies and government.

PMID- 15192997
TI  - The looming health care crisis. Fact or myth?
AB  - Health care literature succinctly describes the challenges faced by hospitals
      today: shortages of skilled workers, escalating costs, government regulations,
      shortfalls in revenue, and similar concerns. To assess the relative importance
      that hospitals attach to these challenges, as perceived by hospital HR managers,
      a nationwide survey of 400 randomly selected HR managers was conducted. These HR
      directors were asked to rank-order various hospital concerns, assess the success
      their employers have achieved in dealing with such problems, and predict the
      difficulty of recruiting and retaining qualified workers in various job
      categories throughout this decade. In contrast to hospital CEOs, who regard
      financial concerns as their top priority, hospital HR managers rank shortages of
      skilled workers first. These HR managers anticipate continued difficulty in
      recruiting and retaining RNs, pharmacists, anesthetists, and some therapists and
      technicians throughout this decade.

PMID- 15192998
TI  - Strengthening organizational commitment. Understanding the concept as a basis for
      creating effective workforce retention strategies.
AB  - One of the most significant challenges facing any health care leader today is
      that of building commitment among followers. The last decade, with its tumultuous
      changes in our organizations, left many employees emotionally detached from their
      workplace. Mistrust, increasing cynicism, escalating financial pressures, and
      continuing challenges adversely impact our workforce's organizational commitment.
      The author explores the concept of commitment, which can serve as a basis for
      developing practical effective retention strategies.

PMID- 15192999
TI  - Interpersonal skills. What they are, how to improve them, and how to apply them.
AB  - Interpersonal skills are those essential skills involved in dealing with and
      relating to other people largely on a one-on-one basis. The interpersonal
      communication behavior of many people suggests they assume to have the ability to
      communicate effectively, which they do not possess and which they take for
      granted. One must work conscientiously to develop interpersonal competence by
      doing the right things at all times and doing them repeatedly until they become
      ingrained. As with any human skills, interpersonal skills can be improved through
      conscious effort. Successful interpersonal communication involves shaping the
      behavior of others, often while countering their shaping behavior. To have a
      chance of being successful, every interpersonal contact must have an objective
      and every effort must be made to avoid creating win-lose transactions whenever
      possible.

PMID- 15193000
TI  - Options for sustaining school-based health centers.
AB  - Several methods exist for financing and sustaining operations of school-based
      health centers (SBHCs). Promising sources of funds include private grants,
      federal grants, and state funding. Recently, federal regulation changes mandated
      that federal funding specifically for SBHCs go only to SBHCs affiliated with a
      Federally Qualified Health Center (FQHC). Becoming a FQHC allows a SBHC to bill
      Medicaid at a higher rate, be notified about federal grants, and access the
      federal drug-pricing program. However, FQHCs must bill for services, including a
      sliding-fee scale based on ability to pay; develop a governance board with a
      majority of consumer members; provide a set of designated primary care services;
      and serve all people regardless of ability to pay. Private grants impose fewer
      restrictions and usually provide start-up and demonstration funds for specific
      program needs. Such funds are generally time limited, so new programs need to be
      incorporated into the operational budget of the center. State funding proves
      relatively stable, but fiscal challenges in some states made these funds less
      available. Using a variety of funding sources will enable ongoing provision of
      health care to students. Overall, SBHCs should consider infrastructure
      development that allows a variety of funding options, including formalizing
      existing partnership commitments, engaging in a needs assessment and strategic
      planning process, developing the infrastructure for FQHC status, and implementing
      a billing system for client services.

PMID- 15193001
TI  - Physical activity, dietary practices, and other health behaviors of at-risk youth
      attending alternative high schools.
AB  - This study assessed the interest of alternative high school staff in intervention
      research on students' eating and physical activity habits and the feasibility of
      conducting such research in alternative school settings. A two-phase descriptive
      design incorporated both quantitative and qualitative methods. In fall/winter
      2001-2002, alternative high school administrators in Minnesota were surveyed
      (response rate = 83%; n = 130/157). During summer 2002, one-on-one,
      semistructured interviews were conducted with key school personnel (n = 15) from
      urban and suburban schools. Findings indicated few schools had been invited to
      participate in research on nutrition (11%) and physical activity (7%). However,
      more than 80% of administrators reported interest in their students participating
      in such research. Most schools offered health and PE classes and had access to
      indoor gym facilities and outdoor play areas. While most schools offered a school
      lunch program, participation was low, cold lunches were common, and food often
      was unappealing. Beverage and snack vending machines were common. Overall, the
      physical environment of most alternative schools did not support physical
      activity and healthy eating as normative behavior. Interest in interventions on
      physical inactivity, unhealthy dietary practices, and other priority health-risk
      behavior common in students attending alternative schools was high among teachers
      and administrators. Results suggest research in alternative high schools is
      feasible and successful implementation and evaluation of programs possible.

PMID- 15193002
TI  - Mental health services at selected private schools.
AB  - Private schools educate a significant percentage of US children and adolescents.
      Private schools, particularly where students reside during the academic year,
      assume responsibility for the health and well-being of their students. Children
      and adolescents experience mental health problems at a predictable rate, and
      private schools need a mechanism for addressing their students' mental health
      needs. Understanding that need requires data to guide the services and programs a
      school may put in place. Having data helps inform those services, and comparative
      data from other schools provides feedback and perspective. This project surveyed
      type and frequency of mental health problems experienced by students who received
      a formal evaluation at 11 private schools in Connecticut during academic year
      2001-2002.

PMID- 15193003
TI  - The relationship between school health councils and school health policies and
      programs in US schools.
AB  - This study analyzed data from the School Health Policies and Programs Study
      (SHPPS) 2000 to examine the relationship between school health councils and
      selected school health policies and programs. SHPPS 2000 collected data from
      faculty and staff in a nationally representative sample of schools. About two
      thirds (65.7%) of US schools have school health councils. Schools with councils
      were significantly more likely than schools without councils to report policies
      and programs related to health services, mental health and social services,
      faculty and staff health promotion, and family and community involvement. Schools
      with councils were as likely as schools without councils to report policies and
      programs related to health education, physical education, and food service.
      Although school health councils are associated with the presence of some key
      school health policies and programs, a council does not guarantee a school will
      have all important school health policies and programs in place.

PMID- 15193005
TI  - Self-evaluated competencies of school nurses in Korea.

PMID- 15193004
TI  - Correlates of body mass index, weight goals, and weight-management practices
      among adolescents.
AB  - The study examined associations among physical activity, cigarette smoking, body
      mass index, perceptions of body weight, weight-management goals, and weight
      management behaviors of public high school adolescents. The CDC Youth Risk
      Behavior Survey provided a cross-sectional sample (n = 3,089) of public high
      school students in South Carolina. Logistic regression models were constructed
      separately for four race-gender groups. Adjusted odds ratios and 95% confidence
      intervals were calculated to determine the magnitude of associations. Based on
      self-reported height and weight, 13% of students were overweight, while 15% were
      at risk for becoming overweight. However, 42% of students were trying to lose
      weight, and 22% were trying to maintain current weight. Female students were less
      likely than male students to be overweight, but more likely to be attempting to
      lose weight. Extreme weight control practices were reported by 27% of the sample.
      Among Black females trying to lose weight, positive associations were observed
      for strengthening exercises (OR = 1.55), but that relationship was associated
      inversely in Black males (OR = .600). Among White females, attempted weight loss
      was associated with strengthening exercises (OR = 1.72) and cigarette smoking (OR
      = 1.54). For White males, attempted weight loss was associated positively with
      vigorous exercise (OR = 1.41) and inversely related to moderate exercise (OR =
      .617). Effective weight-management practices for adolescents should focus on
      appropriate eating behaviors, physical activity, and low-fat/calorie diets.
      Multicomponent weight management interventions should be conducted within a
      coordinated school health framework.

PMID- 15193006
TI  - My journey through the specialty recognition process with the American Dental
      Association.

PMID- 15193007
TI  - Assessing dental caries prevalence in African-American youth and adults.
AB  - It has been well documented that dental caries affect millions of children in the
      USA with the majority experiencing decay by the late teens. This is especially
      true for low-income minorities. The objective of this descriptive study was to
      determine dental caries prevalence in a sample of low-income African-American
      youth and adults. A total of 1034 individuals were examined. They were divided
      into two age groups: youth, 9-19 years and adults, 20-39 years. Females comprised
      approximately 65 percent (64.5) of the study group. The DMFT Index was used to
      determine caries prevalence in this study population. The DMFT findings showed
      that approximately 73 percent (72.9 percent) of the youth had either decayed,
      missing or filled teeth. Male youth had slightly higher DMFT mean scores than
      female youth: male mean = 7.93, standard error = 0.77, female mean = 7.52,
      standard error = 0.36; however, as females reached adulthood their DMFT scores
      increased substantially, mean = 15.18, standard error = 0.36. Caries prevalence
      was much lower in male adults, DMFT, mean = 7.22, standard error of 0.33. The
      decayed component for female adults mean score was 6.81, a slight increase over
      adult males, mean = 6.58. Although there were few filled teeth in both age
      groups, female adults had slightly more filled teeth than male adults, females
      mean = 2.91 vs. males; however, adult males experienced slightly more missing
      teeth, mean = 5.62 as compared to adult females, mean = 5.46. n = 2.20. Both
      female and male adults had an increase in missing teeth. As age increased there
      was a significant correlation among decayed, missing and filled teeth as tested
      by Analysis of Variance (ANOVA), p < 0.01. A significant correlation was found
      between filled teeth by sex, p < .005. We conclude that caries prevalence was
      higher in female and male youth, but dental caries increased more rapidly in
      females as they reached adulthood.

PMID- 15193008
TI  - Complicated comprehensive reconstruction: report of a case.
AB  - This patient presented an interesting problem surgically from the standpoint of
      placement of implants immediately following removal of periodontally involved
      teeth at which time it was necessary to completely debride the alveoli. A 20-year
      history of smoking mitigated the prognosis in this particular case. Prophylactic
      antibiotics were used perioperatively, and his healing was uneventful. The
      prosthetic rehabilitation also details a specific technique to reproduce superior
      anterior esthetics to retain virtually the same appearance in the final implant
      retained fixed bridge. The case also demonstrates the efficacy of immediate
      implant placement and augmentation of the maxilla for adequate prosthetic
      management.

PMID- 15193010
TI  - Alcoholism and the elderly.

PMID- 15193009
TI  - Common drugs of abuse--Part II.
AB  - Drug abuse affects a significant number of individuals of all ages. Health care
      practitioners must be knowledgeable about both the physiological effects of such
      drugs and the impact of drug-seeking behavior on their patients.

PMID- 15193011
TI  - Not enough healthcare in jails: worse than capital punishment?

PMID- 15193012
TI  - Gray power.

PMID- 15193013
TI  - HIV and the elderly.

PMID- 15193014
TI  - A person's right to active or passive euthanasia.

PMID- 15193015
TI  - The Baby Boom generation and health insurance.

PMID- 15193016
TI  - The change in values that drives the nursing shortage.
AB  - In the 21st century we are eagerly trying to recruit candidates into the nursing
      profession in order to provide safe care to patients and address the national
      nursing shortage. There are fewer and fewer individuals who retain the value of
      helping others for purely altruistic reasons. It is only when a recruitment and
      retention plan is tied to the values and motivators of the modern employee that
      health care agencies can hope to address the shortages in staffing. Providing
      motivation for a nursing care giving role which is physically difficult,
      psychologically draining, and frequently demanding time beyond the 8 hours of a
      shift, requires a consideration of the values held by 21st century adults.
      Nevertheless, when values held by the modern day job seeker are considered
      enticing strategies can be designed and can lead to job satisfaction and
      stability among employees. As employees realize that LPNs fill vital roles in the
      health care team and can assist in responding to RN vacancies, it is essential
      that employers of LPNs be fully cognizant of values that are prevalent in our
      society and respond to these values in terms of agency recruitment and retention
      policy.

PMID- 15193017
TI  - The effects of angina from the caregiver's perspective.

PMID- 15193018
TI  - Patient care and reprocessed single-use devices-- is there a balance?

PMID- 15193019
TI  - "Code blue".

PMID- 15193020
TI  - Integrating the principles of evidence-based practice: prognosis and the
      metabolic syndrome.
AB  - Current health care trends and pressures have strained clinical decision making
      and practice patterns of practitioners. Evidence-based practice has evolved in
      response to these trends. Evidence-based practice requires providers to be
      proficient in statistical analysis and critique of the evidence. This article
      uses a hypothetical patient's prognostic concerns to depict a practitioner's
      integration of the principles of evidence-based practice as she considers
      clinical practice guidelines, expert opinion, and a prognostic study relative to
      her patient's prognosis. Statistical measures evident in a prognostic study, such
      as absolute risk, baseline risk, relative risk, survival curves, and hazard
      ratios are defined.

PMID- 15193021
TI  - Stress urinary incontinence in women.
AB  - PURPOSE: To review and synthesize existing knowledge about the epidemiology,
      pathophysiology, evaluation, and management of stress urinary incontinence in
      women. DATA SOURCE: Selected scientific literature. CONCLUSIONS: Stress urinary
      incontinence is more than merely a symptom. Instead, it is a clinically relevant
      disease with adverse psychosocial and physical consequences. Evaluation begins
      with active screening and is followed by individualized assessment when urinary
      leakage is detected. IMPLICATIONS FOR PRACTICE: Traditional treatment modalities,
      including pelvic muscle rehabilitation, focus on behavioral strategies to reduce
      urine loss, and surgical correction of anatomic defects is completed in selected
      cases. Pharmacotherapeutic options have been limited, but one compound is
      undergoing clinical trials to determine whether it is a safe and effective
      alternative for the treatment of stress urinary incontinence.

PMID- 15193022
TI  - Industry-sponsored weight loss programs: description, cost, and effectiveness.
AB  - PURPOSE: To describe three commercial weight loss programs (Jenny Craig, LA
      Weight Loss, and Weight Watchers), including efficacy data when available, and to
      provide clinicians with information for patient counseling. DATA SOURCES:
      Personal interviews, journal articles, and Web site information. CONCLUSIONS:
      Commercial weight loss programs provide weight loss services. Benefits are
      experience, planned menus, and psychological support. Limitations are cost, sales
      promotions that encourage on-the-spot commitment to prepaid contracts, and the
      cost of program food and additional vitamins. IMPLICATIONS FOR PRACTICE: Weight
      loss is a necessary goal for many patients. Clinicians are mandated to provide
      counseling regarding weight loss.

PMID- 15193023
TI  - Nurse practitioners' behavior regarding teaching testicular self-examination.
AB  - PURPOSE: To test a model derived from the theory of reasoned action and to
      determine the behavior of nurse practitioners (NPs) regarding teaching testicular
      self-examination (TSE). DATA SOURCES: A cross-sectional, explanatory design was
      used to survey a random sample of 1,490 members of the American Academy of Nurse
      Practitioners. CONCLUSIONS: NPs had positive attitudes toward teaching TSE and
      were engaged in such teaching. They perceived that other NPs, physicians, and
      patients also value TSE teaching. The theoretical model was supported.
      IMPLICATIONS FOR PRACTICE: The results have implications for research, practice,
      and education. The theory was shown to be useful as a framework for the study of
      NP behavior. The results highlight the importance of including strategies to
      promote positive values as components of nurse preparation. For practice, patient
      adherence to illness detection activities may be fostered by positive attitude,
      perception that significant others also value these activities, and belief that
      failure to do so may result in personal loss.

PMID- 15193024
TI  - Oligodendroglial tumors: refinement of candidate regions on chromosome arm 1p and
      correlation of 1p/19q status with survival.
AB  - Loss of heterozygosity (LOH) on the chromosome arms 1p and 19q is frequent in
      oligodendroglial tumors and has been correlated with chemosensitivity and good
      prognosis in anaplastic oligodendrogliomas. The oligodendroglioma-associated
      tumor suppressor genes on 1p and 19q are as yet unknown. To narrow down candidate
      regions on 1p, we investigated oligodendroglial tumors from 89 patients for LOH
      at up to 30 polymorphic loci on 1p. In addition, all tumors were studied for LOH
      at 7 loci on 19q. Combined LOH on 1p and 19q was detected in 20 (83%) of 24
      oligodendrogliomas, 15(63%) of 24 anaplastic oligodendrogliomas, 10 (56%) of 18
      oligoastrocytomas, and 12 (52%) of 23 anaplastic oligoastrocytomas. Five tumors
      demonstrated partial deletions on 1p, which allowed to define 3 distinct
      candidate regions at 1p36.31-pter distal to D1S2633, 1p36.22-p36.31 between
      D1S489 and D1S2642, and 1p34.2-p36.1 between D1S2743 and D1S482, respectively. No
      partial deletions were detected on 19q. Combined LOH on 1p and 19q was associated
      with prolonged time to progression (TTP), longer overall survival (OS), and a
      higher 5-year survival rate. Depending on the presence or absence of combined LOH
      on 1p and 19q, patients with anaplastic oligodendroglial tumors treated with
      adjuvant radio- and/or chemotherapy showed a median TTP of 86 months versus 39
      months, a median OS of 91 months versus 46 months, and a 5-year survival rate of
      80% versus 36%, respectively. Similarly, LOH on 1p and 19q was associated with
      longer survival in patients with low-grade oligodendroglial tumors (TTP: 57
      months versus 47 months; OS: 172 months versus 105 months; 5-year survival rate:
      92% versus 70%). Thus, our results refine the location of putative
      oligodendroglioma suppressor genes on 1p and support the significance of LOH on
      1p and 19q as a favorable prognostic marker.

PMID- 15193025
TI  - Predominant expression of mutant EGFR (EGFRvIII) is rare in primary
      glioblastomas.
AB  - EGFR amplification is a frequent genetic alteration in primary (de novo)
      glioblastomas, and is often associated with structural alterations. Most common
      is variant III (EGFRvIII), which results from a non-random 801 bp in-frame
      deletion of exons 2 to 7 of the EGFR gene. We assessed amplification and
      overexpression of EGFRvIII and wild-type EGFR in 30 glioblastoma biopsies.
      Immunohistochemically, EGFR overexpression was observed in 20 (67%) of 30
      glioblastomas. Eight (27%) cases also showed immunoreactivity to an EGFRvIII
      antibody. In 6 of these cases, the pattern of EGFR and EGFRvIII overexpression
      was compared in serial sections: In 4 cases, areas with immunoreactivity to
      EGFRvIII largely coincided with wild-type EGFR expression. In the other 2 cases,
      the areas immunoreactive to EGFRvIII were significantly less extensive than EGFR
      positive areas. To assess whether EGFRvIII is predominantly amplified in tumors
      with concurrent wild-type EGFR amplification, we carried our real-time
      quantitative PCR using 2 sets of primers located in exon 2 and intron 15 of the
      EGFR gene. A > 5-fold ratio of relative copy numbers between intron 15 (present
      both in wild-type EGFR and EGFRvIII) and exon 2 (present only in wild-type EGFR,
      but missing in EGFRvIII) suggested predominant amplification of EGFRvIII in only
      3 (10%) of 30 glioblastomas. The observation that intratumoral wild-type EGFR
      overexpression is often more extensive and that predominant amplification of
      EGFRvIII is a rare event would limit the effectiveness of therapeutic approaches
      based on selective targeting of EGFRvIII.

PMID- 15193026
TI  - Early-onset dementia with Lewy bodies.
AB  - The clinical and neuropathological characteristics of an atypical form of
      dementia with Lewy bodies (DLB) are described. The proband experienced
      difficulties in her school performance at 13 years of age. Neurological
      examination revealed cognitive dysfunction, dysarthria, parkinsonism and
      myoclonus. By age 14 years, the symptoms had worsened markedly and the proband
      died at age 15 years. On neuropathological examination, the brain was severely
      atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as
      Lewy neurites, were present throughout the cerebral cortex and subcortical
      nuclel; vacuolar changes were seen in the upper layers of the neocortex and
      severe neuronal loss and gliosis were evident in the cerebral cortex and
      substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for
      alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and
      granular material and isolated filaments were decorated by alpha-synuclein
      antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative
      results. The etiology of this atypical form of DLB is unknown, since there was no
      family history and since sequencing of the exonic regions of alpha-Synuclein,
      beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and
      Neurofilament-M failed to reveal a pathogenic mutation. This study provides
      further evidence of the clinical and pathological heterogeneity of DLB.

PMID- 15193027
TI  - Mechanisms and time course of neuronal degeneration in experimental autoimmune
      encephalomyelitis.
AB  - Neuronal and axonal damage is considered to be the main cause for long-term
      disability in multiple sclerosis. We analyzed the mechanism and kinetics of
      neuronal cell death in experimental autoimmune encephalomyelitis (EAE) induced by
      myelin oligodendrocyte glycoprotein (MOG) by combining an electrophysiological in
      vivo assessment of the optic pathway with the investigation of retinal ganglion
      cell (RGC) counts. In accordance with our previous findings in this animal model,
      neuritis of the optic nerve (ON) leads to apoptotic RGC death. By further
      investigating the time course of RGC apoptosis in the present study, we found
      that neuronal cell death together with decreased visual acuity values occurred
      before the onset of clinical symptoms. Simultaneously with the time course of RGC
      apoptosis, we found a down-regulation of phospho-Akt as well as a shift in the
      relation of 2 proteins of the Bcl-2 family, Bax and Bcl-2, towards a more
      proapoptotic ratio in these cells. Comparing the kinetics and mechanisms of RGC
      death during MOG-EAE with those following complete surgical transection of the
      ON, we found significant agreement. We hypothesize that the main reason for RGC
      loss in MOG-EAE is the inflammatory attack but RGC death also occurs
      independently of histopathological ON changes.

PMID- 15193028
TI  - CGH pattern of esthesioneuroblastoma and their metastases.
AB  - Comparative genomic hybridization (CGH) was used to screen 22
      esthesioneuroblastomas (ENB) from 12 patients including 12 primary tumors and 10
      metastasis/recurrent lesions for chromosomal imbalances being the most extensive
      study so far. The analysis revealed a characteristic pattern consisting of
      deletions on chromosomes 3p and overrepresentations on 17q in up to 100% of
      cases. Other important alterations being detectable in more than 80% of cases
      were deletions on 1p, 3p/q, 9p, 10p/q along with overrepresentation on 17p13, 20p
      and 22q. Particularly striking was the pattern for chromosomes 3, 10 and 17q and
      20 being affected almost exclusively by deletions or overrepresentations,
      respectively. Pronounced overrepresentations suggestive for high copy
      amplifications were seen on 1p34, 1q23-q31, 7p21, 7q31, 9p23-p24, 17q11-q22,
      17q24-q25, 19, 20p, 20q13 and 22q13. Comparing tumor pairs from the same patient
      revealed a high concordance indicating clonality and confirming the genetic
      homogeneity of the tumor entity. The analysis of metastatic/recurrent lesions
      indicated a higher percentage of pronounced alterations, e.g., high copy DNA
      gains at 1q34-qter, 7q11, 9p23-p24, 9q34, 13q33-q34, 16p13.3, 16p11, 16q23-q24
      and 17p13. The analysis furthermore suggested specific alterations, e.g.,
      deletions of chromosome 11 and gains of 1p to be associated with metastasis
      formation and/or worse prognosis. Our results indicate that ENB is a distinct
      entity and provides criteria for its genetic distinction from other small round
      cell tumor types.

PMID- 15193029
TI  - Detection of ectopic B-cell follicles with germinal centers in the meninges of
      patients with secondary progressive multiple sclerosis.
AB  - Multiple sclerosis (MS) is characterized by synthesis of oligoclonal
      immunoglobulins and the presence of B-cell clonal expansions in the central
      nervous system (CNS). Because ectopic lymphoid tissue generated at sites of
      chronic inflammation is thought to be important in sustaining immunopathological
      processes, we have investigated whether structures resembling lymphoid follicles
      could be identified in the CNS of MS patients. Sections from post-mortem MS
      brains and spinal cords were screened using immunohistochemistry for the presence
      of CD20+ B-cells, CD3+ T-cells, CD138+ plasma cells and CD21+, CD35+ follicular
      dendritic cells, and for the expression of lymphoid chemokines (CXCL 13, CCL21)
      and peripheral node addressin (PNAd). Lymphoid follicle-like structures
      containing B-cells, T-cells and plasma cells, and a network of follicular
      dendritic cells producing CXCL13 were observed in the cerebral meninges of 2 out
      of 3 patients with secondary progressive MS, but not in relapsing remitting and
      primary progressive MS. We also show that proliferating B-cells are present in
      intrameningeal follicles, a finding which is suggestive of germinal center
      formation. No follicle-like structures were detected in parenchymal lesions. The
      formation of ectopic lymphoid follicies in the meninges of patients with MS could
      represent a critical step in maintaining humoral autoimmunity and in disease
      exacerbation.

PMID- 15193031
TI  - Moderate and severe traumatic brain injury: epidemiologic, imaging and
      neuropathologic perspectives.
AB  - This article examines 3 contexts in which moderate or severe traumatic brain
      injury can be approached. The epidemiologic background of moderate and severe
      traumatic brain injury is presented, with particular attention paid to new
      findings from the study of a national hospital inpatient database. We review
      aspects of neuroimaging and how new imaging modalities can reveal fine detail
      about traumatic brain injury. Finally we examine the current state of
      neuropathologic evaluation of, and recent developments in, understanding of the
      neural disruptions that occur following traumatic brain injury, together with
      cellular reactions to these disruptions.

PMID- 15193030
TI  - Comparison of ethanol versus formalin fixation on preservation of histology and
      RNA in laser capture microdissected brain tissues.
AB  - Although RNA can be retrieved from formalin-fixed, paraffin-embedded (FFPE)
      tissues, the yield is low, and the RNA is fragmented. Recent advances in gene
      expression profiling underscore the importance of identifying a fixative that
      preserves histology and mRNA. We demonstrated that, for immersion fixation of
      brains, 70% ethanol is superior to formalin for mRNA preservation. RNA yield from
      ethanol-fixed tissues was 70% of the yield from fresh frozen specimens, but only
      a negligible quantity was recovered from formalin-fixed tissues. RNA from ethanol
      fixed brains showed integrity comparable to RNA from fresh frozen tissues, and RT
      PCR using RNA from ethanol-fixed tissues was consistently successful. RNA from
      FFPE tissues composed of low-molecular weight fragments, and their use in RT-PCR
      failed repeatedly. The yield and quality of RNA from ethanol-fixed brains were
      unaffected after immersion at 4 degrees C for 2 weeks. In a blinded comparison to
      FFPE tissues, ethanol-fixed specimens were judged to show comparable histology
      and superior immunostaining. After laser capture microdissection (LCM), we failed
      to recover mRNA from FFPE tissues but retrieved mRNA from ethanol-fixed tissues
      for RT-PCR and cDNA microarray analysis. We conclude that 70% ethanol preserves
      RNA integrity and is suitable for expression profiling of brain tissues by LCM
      and cDNA microarray.

PMID- 15193032
TI  - Nitric oxide in traumatic brain injury.
AB  - Nitric oxide (NO) is a gaseous chemical messenger which has functions in the
      brain in a variety of broad physiological processes, including control of
      cerebral blood flow, interneuronal communications, synaptic plasticity, memory
      formation, receptor functions, intracellular signal transmission, and release of
      neurotransmitters. As might be expected from the numerous and complex roles that
      NO normally has, it can have both beneficial and detrimental effects in disease
      states, including traumatic brain injury. There are two periods of time after
      injury when NO accumulates in the brain, immediately after injury and then again
      several hours-days later. The initial immediate peak in NO after injury is
      probably due to the activity of endothelial NOS and neuronal NOS. Pre-injury
      treatment with 7-nitroindazole, which probably inhibits this immediate increase
      in NO by neuronal NOS, is effective in improving neurological outcome in some
      models of traumatic brain injury (TBI). After the initial peak in NO, there can
      be a period of relative deficiency in NO. This period of low NO levels is
      associated with a low cerebral blood flow (CBF). Administration of L-arginine at
      this early time improves CBF, and outcome in many models. The late peak in NO
      after traumatic injury is probably due primarily to the activity of inducible
      NOS. Inhibition of inducible NOS has neuroprotective effects in most models.

PMID- 15193034
TI  - Regional heterogeneity of post-traumatic brain metabolism as studied by
      microdialysis, magnetic resonance spectroscopy and positron emission tomography.

PMID- 15193033
TI  - Biomarkers of proteolytic damage following traumatic brain injury.
AB  - The history of numerous failed clinical trials designed to identify therapeutic
      agents to assist in improving outcomes after traumatic brain injury points to the
      critical importance of understanding biochemical markers of injury. Such
      biomarkers should be readily accessible, provide information specific to the
      pathologic disruptions occurring in the central nervous system, and allow
      improved monitoring of the progression of secondary damage. Additionally, these
      biomarkers should may provide investigators a window on the individual patient's
      response to treatment, and should contribute to prediction of outcome. Most
      research on this topic to date has focused on neuronspecific enolase (NSE) and S
      100 proteins but these have not proven to be satisfactory for a variety of
      reasons. A different approach is provided by the study of 2 important proteases,
      caspase-3 and calpain. This paper reports the current state of knowledge
      concerning caspase and calpain as specific markers of TBI, and discusses all
      spectrin, a principal substrate for both caspase and calpain, as well as initial
      findings regarding neurofilament 68 protein (NF-68).

PMID- 15193035
TI  - Cell death mechanisms following traumatic brain injury.
AB  - Neuronal and glial cell death and traumatic axonal injury contribute to the
      overall pathology of traumatic brain injury (TBI) in both humans and animals. In
      both head-injured humans and following experimental brain injury, dying neural
      cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and
      necrotic neurons have been identified within contusions in the acute post
      traumatic period, and in regions remote from the site of impact in the days and
      weeks after trauma, while degenerating oligodendrocytes and astrocytes have been
      observed within injured white matter tracts. We review and compare the regional
      and temporal patterns of apoptotic and necrotic cell death following TBI and the
      possible mechanisms underlying trauma-induced cell death. While excitatory amino
      acids, increases in intracellular calcium and free radicals can all cause cells
      to undergo apoptosis, in vitro studies have determined that neural cells can
      undergo apoptosis via many other pathways. It is generally accepted that a shift
      in the balance between pro- and anti-apoptotic protein factors towards the
      expression of proteins that promote death may be one mechanism underlying
      apoptotic cell death. The effect of TBI on cellular expression of survival
      promoting-proteins such as Bcl-2, Bcl-xL, and extracellular signal-regulated
      kinases, and death-inducing proteins such as Bax, c-Jun N-terminal kinase, tumor
      suppressor gene, p53, and the calpain and caspase families of proteases are
      reviewed. In light of pharmacologic strategies that have been devised to reduce
      the extent of apoptotic cell death in animal models of TBI, our review also
      considers whether apoptosis may serve a protective role in the injured brain.
      Together, these observations suggest that cell death mechanisms may be
      representative of a continuum between apoptotic and necrotic pathways.

PMID- 15193036
TI  - Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma.

PMID- 15193037
TI  - October 2003: a 59-year-old woman with sudden onset of diplopia. Listerial
      rhombencephalitis.

PMID- 15193038
TI  - November 2003: neonatal female with congenital brain tumor. Congenital
      gemistocytic astrocytoma.

PMID- 15193039
TI  - December 2003: a 70-year-old woman with a recurrent meningeal mass. Recurrent
      meningioma with rhabdomyosarcomatous differentiation.

PMID- 15193040
TI  - [Seasonal features of the time course of changes in the aggregated state of the
      causative agent of plague in the organism of Citellophilus tesquorum altaicus
      (Siphonaptera)].
AB  - The data of experiments made in a Tuva natural plague focus with the main vector
      of the flea C. lesquorum altaicus during different seasons are analyzed.
      Ectoparasites were infected with the plague microbial strain typical for the
      focus and fed on natural nourishment, such as long-tailed sousliks. An analysis
      indicated that estimation of the parameter "the proportion of infected insects
      containing the causative agent at the aggregated state" is of greater informative
      value than is the recording of only sporadic gizzard "blocks". In experiments on
      fleas of a breeding of the current year, the conglomerates of the causative agent
      of plague were more frequently observed in males. All things being equal, the
      greatest efficiency of transmission of the microbe to the carriers of infection
      and the highest block formation in the fleas were observed in summer. The
      proportion of specimens with microbial conglomerates drastically increased in
      autumn during the preparation of the body of imagoes for hibernation. At this
      state, the microbe survived in the organism of a dormant carrier during winter.
      In spring, in the imagoes infected during the previous season, bacterial
      conglomerates were observed during the first feeds ten times more frequently than
      those in the insects of a breeding and infection of the current year.

PMID- 15193041
TI  - [Epidemiology of Ixodes tick-borne borreliosis in the north of the Volga-Viatka
      region].
AB  - Among the territories of the Volga-Vyatka Region of Russia, the Kirov Region is
      characterized by the highest incidence of Ixodes tick-borne borreliosis. Its
      incidence rates ranged from 10.5 to 48.6 per 100,000 inhabitants. The average
      long-term regional rate was 8 times as high as the federal one. The bulk of cases
      was notified in the central regional districts referred to as a southern taiga
      subarea. The infection with the borreliae I. persulcatus and I. ricinus was 21
      29%. Urban inhabitants infected for domestic reasons were prevalent among those
      who had been ill. Patients aged above 40 years accounted for 64.5%. There was an
      increase in the proportion of patients referring for medical care for the bites
      being stuck. Cases of mixed infections (Ixodes tick-borne borreliosis and tick
      borne encephalitis) came to be more frequently detected; these constituted about
      a third of all tick-borne infections.

PMID- 15193043
TI  - [Epidemiology and clinical aspects of central European (western) tick-borne
      encephalitis in the Brest region of the Republic of Belarus].
AB  - The paper presents the results of epidemiological and clinical studies of the
      peaks of tick-borne encephalitis (TBE) in the Belovezhskaya Pushcha region in
      1993-2001. The findings confirm the concept worked out by Byelorussian
      researchers on nosological differences in the western and eastern subtypes of
      TBE.

PMID- 15193042
TI  - [New evidence for the detection of ehrlichia and anaplasma in ixodes ticks in
      Russia and Kazakhstan].
AB  - Polymerase chain reaction and sequence analysis were used to screen Ehrlichia and
      Anaplasma DNA in 900 specimens of Ixodes ticks of four genera (Dermacetor,
      Haemaphysalis, Ixodes, and Hyalomma) collected on 14 administrative territories
      of Russia and Kazakhstan. Anaplasma phagocytophilia DNA was detected and
      identified in Ixodes persulcatus ticks gathered in the Altai and Primorye
      Territories. Ehrlichia muris DNA was genotyped in the I. persulcatus ticks
      collected in the Tyumen, Omsk, and Novosibirsk Regions and the Altai Territory.
      Examining the Haemaphysalis concinna collected in the Primorye Territory revealed
      A. bovis DNA. The I. persulcatus ticks gathered in the Omsk Region were found to
      have "Ehrlichia-like "Schotti variant" DNA, Studying the ticks of the genera
      Dermatocentor and Hyalomma gathered in Russia and Kazakhstan failed to detect the
      representatives of the genera Anaplasma and Ehrlichia. The detection of A.
      phagocytophilia DNA in the I. persulcatus ticks in the Altai and Primorye
      territories and the serological verification of cases of human granulocytic
      anaplasmosis among patients with tick-borne infections in these territories lead
      to the conclusion that there are natural loci of this disease in West Siberia and
      the Far East of Russia.

PMID- 15193044
TI  - [The mammalian fauna in the Republic of Guinea as reservoirs and vectors of the
      pathogens of natural and focal infections].

PMID- 15193045
TI  - [Prevalence and diagnosis of lambliasis in Perm region].
AB  - The prevalence and its specific features of Lamblia invasion in children in some
      districts of the Perm Region, which differ in the nonstandard quality of drinking
      water samples are described. For the specific diagnosis of giardiasis, a
      serological study of the population was made by enzyme immunoassay determining
      specific Lamblia antibodies in the serum. The authors proposed a questionnaire
      that may suspect giardiasis in a child. The data obtained from the questionnaire
      study correlate with the positive results of enzyme immunoassay in 47.5% of
      cases. The clinical picture of Lamblia invasion in the examinees corresponds to
      the data available in the literature on the course of giardiasis.

PMID- 15193046
TI  - [Epidemiology of parasitic diseases in the Mordovian Republic in 1999-2002].

PMID- 15193047
TI  - [Prediction of malaria spread in Russia in the first quarter of the 21st
      century].
AB  - The paper presents a prediction of changes in the potential areas of tertian
      malaria till 2025. It shows that possible climatic changes whose main features
      are an increase in average annual temperatures do not imply a uniform expansion
      of areas for parasitic infections. The regional and seasonal trends of
      temperature changes in Russia (both established for the 20th century and
      predicted for the early 21st century) will both expand the area in its one part
      and reduce in its another part. Overall, the changes caused by climatic factors
      in the potential area of human malaria in Russia in the first quarter of the 21st
      century will not lead to a drastically aggravated malaria epidemiological
      situation.

PMID- 15193049
TI  - [Assessment of malaria control in the Republic of Tadjikistan in 1998-2000].

PMID- 15193048
TI  - [Trichinosis in the Republic of Buriatiia].
AB  - Patient P. aged 8 years complained of temperature elevation up to 39 degrees,
      which being noted within 5-6 days. He had also facial edema. After two days of
      the disease, vesiculopapular eruption appeared on the abdomen, upper and lower
      extremities, arthralgia, and myalgia. The Parasitological Laboratory, Central
      State Epidemiological Surveillance Station, Republic of Buryatia, confirmed the
      diagnosis by serological blood assay. Patient M. had pains of sweating, weakness,
      and myalgia. He fell ill when the temperature increased up to 40 degrees, there
      was facial edema; following 2 days, bright pink eruption appeared on the abdomen,
      dorsal chest. Eruption disappeared in its own following 2-3 days. The diagnosis
      of trichinosis was serologically verified.

PMID- 15193050
TI  - [Epidemiology of parasitic diseases in Ukraine and the measures of the diseases
      prevention].

PMID- 15193052
TI  - [Natural and focal diseases and the tasks of the state sanitary-and
      epidemiological service in the Ul'ianovsk region for their prevention].

PMID- 15193051
TI  - [Morbidity and detection rates of cryptosporidiosis in the Zhitomir region].

PMID- 15193053
TI  - [Splenic rupture in tropical malaria].
AB  - The authors have observed splenic rupture in patients mainly with P. vivax
      malaria in 0.37% of cases. A rare case of splenic rupture in topical P.
      falciparum malaria is described. The patient underwent splenectomy. He was
      discharged from hospital after his recovery.

PMID- 15193054
TI  - [Diagnosis of hemorrhagic fever with renal syndrome and bacterial endocarditis].

PMID- 15193055
TI  - [Notification of cases of dirofilariasis in the Gomel region].

PMID- 15193056
TI  - [Dirofilariasis in the Volgograd region--a new disease in the region].
AB  - Due to the availability of factors whose reasons have not been studied so far for
      this area. Volgograd and Volgograd Region should be recognized to be a
      dirofilariasis-endemic zone. The lack of an actual system of prevention, as well
      as other objective and subjective factors are responsible for constantly
      increasing numbers of ill human beings and animals. The disease awaits further
      thorough studies to reveal the causes of this disease in the area; to elaborate a
      package of preventive measures, and to improve methods of diagnosis, surgical and
      medical treatments.

PMID- 15193057
TI  - [A case of dirofilariasis in the town of Magnitogorsk of the Cheliabinsk region].
AB  - A local case of dirofilariasis was first reported in a 70-year-old female in
      Magnitogorsk, Chelyabinsk Region, in November 2002. The primary diagnosis is
      atheroma of the skin of the forehead. A round mass having a smooth surface and
      slightly solid gray-whitish walls was surgically excised, which yielded a mobile
      rolled nematode measuring 7 cm in length and 0.8 mm in width. The parasitological
      diagnosis is an immature Dirofilaria repense female. It has been found that the
      female has neither dogs nor cats in her flat and she had not been left
      Mangitogorsk for approximately 18 years. A histological examination of the
      fibrotic capsule around the parasite revealed inflammation in the inner layer of
      the capsule, which was regarded as proliferative and having no signs of a
      granulomatous process. Fragments of cuticles of a round helminth having a well
      defined alimentary tube was found. To encode the case, the authors have used
      Category B74.8 "Other types of filarisis (dirofilariasis)" of the first class,
      ICD-10.

PMID- 15193058
TI  - [Pharyngoesophageal stenosis following surgery and radiotherapy in patients with
      advanced laryngeal cancer].
AB  - OBJECTIVE: Our objectives were to 1) know the frequency of pharyngoesophageal
      stenosis in patients with clinical stage III transglottic laryngeal cancer (LCa
      Stage III) post-surgery and radiotherapy, and to 2) describe clinical,
      radiologic, and endoscopic characteristics of pharyngeal-esophageal stenoses and
      response to dilations. MATERIALS AND METHODS: We conducted a series of
      consecutive cases from 1997-2000 at the National Cancer Institute (INCan) in
      Mexico City and included patients with transglottic (LCa Stage III) post-surgery
      and -radiotherapy. We evaluated dysphagia and stenosis (length, diameter, and
      localization) by radiology and endoscopy before and after surgery and
      radiotherapy. Statistical method was descriptive. RESULTS: Sixty five of 197
      cases (33%) with laryngeal cancer were transglottic and 52 (26.3%) were clinical
      stage III. Patients were treated with total laryngectomy and pharyngo-esophageal
      "Y" stent and post-operative radiotherapy with average 7,000 cGy total dose.
      Thirteen patients (25%) presented pharyngo-esophageal stenosis. There was no pre
      operative dysphagia; dysphagia was present in five patients post-surgery and in
      all after radiotherapy. In all cases, stenoses were simple and were treated with
      Savary Guillard-guided endoscopic dilation with an average of five sessions. Five
      of 13 patients (38.5%) had persistent dysphagia: two due to fibrosis, two due to
      loco-regional recurrences, and one due to recurrence in pharyngo-esophageal
      closure. CONCLUSIONS: A total of 197 cases of laryngeal cancer were present
      during this period; 33% were transglottic, the majority in clinical stage III.
      Global frequency of stenosis was 25%; all cases were simple. Endoscopic dilations
      were useful in absence of fibrosis, extrinsic compression, and tumor recurrence.

PMID- 15193060
TI  - [Diagnostic value of limited research in patients with irritable bowel syndrome].
AB  - BACKGROUND: It is a common practice in irritable bowel syndrome (IBS) patients,
      to perform multiple diagnostic tests to rule out organic diseases. However, its
      usefulness has not yet been evaluated in Mexico. OBJECTIVES: a) To know frequency
      of an abnormal test; b) to know prevalence of organic diseases, and c) to
      identify subgroups with high risk of organic disease among IBS patients. METHODS:
      IBS patients (Rome II) were evaluated by using limited investigation that
      include: a) complete blood cell count, erytrocyte sedimentation rate, fecal
      examination for ova and parasites, fecal occult blood test, and serum
      thyroidstimulating hormone in all patients; b) colonic visualization with
      colonoscopy, barium enema, and/or flexible sigmoidoscopy in all patients > or =
      45 years, and c) left colon and rectum biopsies with diarrhea patients of all
      ages. Organic disease was diagnosed by compatible signs and symptoms, abnormal
      test, confirmatory test, and other specialists opinion. RESULTS: Three hundred
      ten with IBS patients were included (77% women, mean age 41.6 years). One hundred
      ninety nine had patients at least one abnormal test (64%) and organic disease was
      diagnosed in 88 subjects (28%). Diarrhea and mixed-habit patients more had
      organic disease than constipated patients (OR 3.55). No cases of neoplasia were
      detected. CONCLUSIONS: Among IBS patients in whom limited investigation was
      performed, 64% of patients had one abnormal test and 28% had an organic disease.
      Diarrhea and mixed-habit patients have more risk of organic disease than
      constipated patients.

PMID- 15193059
TI  - [Diagnostic usefulness of the Carlsson-Dent questionnaire in gastroesophageal
      reflux disease (GERD)].
AB  - BACKGROUND: Diagnosis of GERD is based on presence of symptoms (heartburn)
      associated to abnormal esophageal acid exposure or esophageal erosions determined
      by 24-hr pH monitoring and/or endoscopy, respectively. Different instruments have
      been evaluated in order to diagnose GERD without invasive studies. Carlsson-Dent
      questionnaire (CDQ), validated among European patients, have shown good
      sensitivity and positive predictive values for detection of GERD. Diagnostic
      usefulness of the CDQ in Mexican patients is unknown. OBJECTIVE: To evaluate
      usefulness of CDQ among patients with erosive GERD (EG) and non-erosive GERD
      (NERD). PATIENTS AND METHODS: Consecutive patients with heartburn at least twice
      per week during the last three months and previous endoscopy were included. All
      patients answered a self-administered Spanish version of the CDQ, previously
      evaluated for its content validity and easy application. A score of > or = 4 was
      considered as positive for GERD. All patients underwent 24-hr pH esophageal
      monitoring to determine the presence of pathologic reflux (% time pH < 4, > 4.2),
      as well as the symptom index (SI). Questionnaire's sensitivity (S), specificity
      (E), positive and negative predictive values (PPV, NPV) were calculated using 24
      hr pH monitoring and endoscopic oesophagitis as gold-standard tests. RESULTS: A
      total of 125 patients were evaluated, 81 women (65%) and 44 men (35%) with an age
      of 47.9 (21-83). Eighty-six patients (69%) had NERD and 39 (31%) EG. Among
      patients with NERD, 28 (32%) had abnormal pH study, 10 (12%) had normal pH study
      with positive SI (> 50%), and 48 (65%) had normal pH study with negative SI. Most
      common symptom was a burning feeling rising from the stomach or lower chest up
      towards the neck (classic definition of heartburn) in 53%, noncardiac chest pain
      in 14%, and nausea in 5%. In 44 patients (35%) the main discomfort occurred
      within 2 hours of taking food, and in 77% it worsed with larger meals and food
      rich in fat, as well as in 77% after taking spicy food. One hundred and seven
      patients (86%) scored > or = 4 on CDQ and there was no significantly difference
      between CDQ score among groups. CDQ's sensitivity compared to pH monitoring was
      89%, and PPV 55%. When compared to endoscopic findings, sensitivity was 94% and
      PPV 90. There was strong and significative correlation between esophageal acid
      exposure and higher CDQ's scores. CONCLUSIONS: CDQ in Spanish is an useful
      instrument for detection of GERD, and its score correlates with the degree of
      esophageal acid exposure.

PMID- 15193061
TI  - [Perception of symptoms with minimal reductions of esophageal pH in patients with
      erosive and non-erosive GERD].
AB  - BACKGROUND: Patients with gastrointestinal reflux disease GERD perceive < 5% of
      acid reflux episodes, independently of GERD type. The role of minimal changes on
      esophageal pH (1 or 2 units) on development of symptoms is unknown. OBJECTIVE: To
      evaluate symptom perception and its relationship with minimal changes on
      esophageal pH in patients with erosive and non-erosive GERD (NERD). PATIENTS AND
      METHODS: We evaluated consecutive patients with symptomatic GERD. All patients
      had endoscopy in the previous 8 weeks. All patients underwent 24-h esophageal pH
      monitoring. Abnormal pH-metry was defined as % time of pH < 4 > 4.2. Symptom
      index (SI) was considered positive when > or = 50. We also calculated SI at pH 5
      and pH 6. Patients with GERD were classified into three groups: 1) abnormal pH
      and negative SI. For statistical analysis, we used the test-Student, chi 2, and
      ANOVA test. P < 0.05 was considered statistically significant. RESULTS: We
      evaluated 120 patients, 79 (66%) females and 41 (34%) males with mean age of 47.8
      years (range 21-83 years). Eighty three (69%) patients had NERD and 37 (31%),
      erosive esophagitis (EE). Seventy two patients (87%) with NERD and 36 (97%) with
      erosive GERD developed symptoms during the study. NERD patients had mean of 69
      reflux episodes compared with 184 of patients with EE. Perception of reflux
      symptoms was significantly higher in the group with EE (3.4 vs. 1.02 p < 0.0001).
      Among patients with NERD, 33% had abnormal pH-metry and 67%, a normal test. Of
      these patients, nine (16%) had normal pH test and positive SI, and 47 (83%)
      normal pH test and negative SI. There was no difference in symptom perception
      among the three groups. Patients with NERD and abnormal pH had similar SI
      patients with EE; 4% of patients with normal pH and negative SI at pH 4 had
      positive SI when calculated at pH 5, and 68% when SI was calculated at pH 6.
      CONCLUSIONS: The majority of acid reflux episodes are not perceived and this
      phenomenon is independent of erosive or non-erosive GERD. Patients with erosive
      esophagitis had significantly higher esophageal acid exposure than patients with
      NERD. Minimal changes in esophageal pH (1 or 2 pH units) increases SI in patients
      with GERD, especially in those with normal esophageal acid exposure.

PMID- 15193062
TI  - [Portal biliopathy].
AB  - Portal biliopathy is a rare condition that is usually not diagnosed. It is
      associated with presence of varix around bile duct with concomitant ischemic
      damage and structural alterations of bile duct wall; this produces obstructive
      phenomena. There are scarce reports on the literature this entity. In the present
      paper, we report two cases in which obstruction of extrahepatic bile duct was
      associated with cholecystitis with well-documented extrahepatic portal
      hypertension. Both cases were managed with cholecystectomy and endoscopic
      placement of endoprothesis. Treatment of portal biliopathy should be adjusted to
      the individual patient's characteristics. It is focused on the one hand on
      management of portal hypertension and on the other hand to management of
      obstructive jaundice. When cholecistitis is found, cholecistectomy should to be
      performed. If the patient develops concomitant gastrointestinal bleeding due to
      portal hypertension, management of the problem could require surgical
      devascularization, shunting procedures, or endoscopic variceal ligature.

PMID- 15193064
TI  - [Report of activities of the Directive Board 2002-2003 of the Mexican Association
      of Gastroenterology. Veracruz, Ver., November 18, 2003].

PMID- 15193065
TI  - [Speech for the Presidency office of the Mexican Association of Gastroenterology
      2004].

PMID- 15193063
TI  - [Appendicitis following esophagogastroduodenal study: report of a case].
AB  - Retention of barium within appendix following a gastrointestinal tract study may
      predispose in rare instances to narrowing of appendiceal lumen, thus contributing
      to development of acute appendicitis. We present the case of a 42-year-old woman
      in whom this sequence of events was recognized who presented with clinical signs
      of acute appendicitis 9 days after barium swallow test was performed. Patients
      must be informed increased chance for development of appendicitis in these cases
      and be instructed to recognize early symptoms. Surgical treatment is reserved for
      symptomatic patients and prophylactic appendectomy is not reccommended.

PMID- 15193067
TI  - The stress response to environmental change in captive cheetahs (Acinonyx
      jubatus).
AB  - The captive North American cheetah (Acinonyx jubatus) population is not self
      sustaining because of high prevalences of unusual diseases and poor reproductive
      success. Cheetahs are commonly moved between zoos for breeding purposes to
      maintain genetic diversity within the captive population, and movement may
      exacerbate infertility and disease. Fecal corticoids were analyzed by
      radioimmunoassay to measure the stress response of cheetahs to movement between
      facilities. Fecal samples were collected from 15 cheetahs for 14 days before
      movement and for at least 30 days after movement. For each cheetah, premovement
      fecal corticoid concentrations were used to determine baseline and then compared
      with trends in postmovement concentrations. In general, postmovement corticoid
      concentrations either increased (n = 8), did not change (n = 2), or decreased (n
      = 5). Although individual animal differences occurred, corticoid concentrations
      increased for most animals moved on-exhibit and decreased in animals moved off
      exhibit. Animals moving on-exhibit had an 18-times greater risk of having
      corticoids elevated more than two standard deviations above baseline for 30 days
      after movement compared with animals that moved off-exhibit. In addition, greater
      day-to-day variation in corticoids occurred in animals moved on-exhibit. In
      general, animals with initially low baseline corticoid concentrations had a
      greater postmovement corticoid response than cheetahs with initially high
      baseline levels. These results indicate that some cheetahs have a prolonged
      stress response when moved between facilities, and the magnitude and character of
      this response is influenced by the exhibit environment.

PMID- 15193066
TI  - Oral, nasal, and cutaneous eosinophilic granulomas in the black rhinoceros
      (Diceros bicornis): a lesion distinct from superficial necrolytic dermatitis.
AB  - Oral, nasal, and cutaneous lesions resembling eosinophilic granulomas (EGs) were
      observed in eight captive black rhinoceroses (Diceros bicornis). Oral lesions
      were observed in all affected animals and occurred most often behind the
      prehensile lip. The typical clinical history of affected animals included oral
      bleeding or epistaxis from multilobulated, fungating, proliferative masses with
      areas of ulceration. Histologically, lesions were characterized by prominent
      infiltrates of eosinophils and rare foci of collagen degeneration on a background
      of marked submucosal or dermal neovascularization. Mucosal or epidermal
      hyperplasia was also present sometimes in association with distinctive epithelial
      degenerative changes consistent with superficial necrolytic dermatopathy of black
      rhinoceroses. Lesions of EG and superficial necrolytic dermatopathy were
      interpreted as being concurrently manifested in these cases. EG lesions
      spontaneously resolved over periods of 30 days-7 mo and were recurrent in three
      animals. Lesions were responsive to treatment with corticosteroids or to local
      cryotherapy with liquid nitrogen. Two animals treated with systemic
      corticosteroids died of disseminated fungal infections, emphasizing that
      corticosteroids should be used cautiously in black rhinoceroses.

PMID- 15193068
TI  - Treatment with omeprazole, metronidazole, and amoxicillin in captive South
      African cheetahs (Acinonyx jubatus) with spiral bacteria infection and gastritis.
AB  - Six captive cheetahs (Acinonyx jubatus) with severe gastritis diagnosed by
      gastric endoscopy and mucosal histopathology were treated with omeprazole,
      metronidazole, and amoxicillin for 3 wk. Endoscopic biopsies were performed
      before therapy, immediately after treatment, and 3, 7, and 19 mo after treatment.
      Macroscopic appearance of the stomach, histologic scoring of gastric
      inflammation, and the presence or absence of spiral bacteria were recorded.
      Spiral bacteria were absent histologically immediately after treatment but
      reappeared in endoscopic biopsies by 3 mo after treatment. Gastritis scores
      fluctuated widely during the trial but improved in five of six cheetahs by 3 mo
      after treatment. By 19 mo after treatment, scores were close to the pretreatment
      scores. Therapy with omeprazole, amoxicillin, and metronidazole was associated
      with temporary improvement in the degree and distribution of gastritis in some
      cheetahs with gastritis, suggesting that treatment may be warranted once severe
      gastric inflammation has been diagnosed.

PMID- 15193069
TI  - Physiologic manifestations of stress from capture and restraint of free-ranging
      male African green monkeys (Cercopithecus aethiops).
AB  - Adrenal gland weights, stomach mucosal lesions, and morning serum cortisol and
      prolactin levels were measured in 15 juvenile and adult male African green
      monkeys (Cercopithecus aethiops) that were shot by a hunter, euthanized after 24
      hr of captivity, or euthanized after 45 days of captivity and intermittent blood
      sampling. Hormone levels were measured in seven additional males that had been in
      captivity for 7 mo. Mean serum cortisol concentrations were significantly lower
      in free-ranging wild monkeys at the time they were shot than in the monkeys after
      1 day in captivity. Cortisol concentrations were significantly higher in wild
      caught monkeys on the day after capture than they were in the same animals after
      18 and 26 days of captivity. Cortisol concentrations were also significantly
      higher in the wild-caught monkeys 18 days after capture than in the laboratory
      habituated monkeys in captivity for 7 mo. Mean prolactin concentration was
      significantly lower in the wild-caught monkeys on day 2 after capture, and the
      levels increased gradually to 45 days in captivity and was highest in monkeys
      that had been captive for 7 mo.

PMID- 15193070
TI  - Prevalence of Mycoplasma agassizii and Chelonian herpesvirus in captive tortoises
      (Testudo sp.) in the United Kingdom.
AB  - During the months of April to August in 1999 and 2002, oral swabs were collected
      from 146 tortoises (Testudo sp.) in private collections in the United Kingdom and
      tested by polymerase chain reaction (PCR) for the presence of Mycoplasma
      agassizii and Chelonian herpesvirus (ChHV). The presence of M. agassizii was
      confirmed by restriction digestion of the PCR product. A 307-bp fragment of the
      ChHV UL5 homologue gene was sequenced and found to show most similarity to equine
      herpesvirus type 1. A prevalence of 15.8 and 8.2% was found for M. agassizii and
      ChHV, respectively. Comparison of the carriage of both M. agassizii and ChHV in
      different species of tortoises correlated the presence of M. agassizii with
      Testudo horsfieldii and ChHV with Testudo marginata and Testudo graeca iberia. An
      association of ChHV with stomatitis was also found. Mixed infections with both
      agents were detected. The findings further demonstrate this pathogen-tortoise
      association and the cross transmission of these infections if different tortoise
      species are housed together.

PMID- 15193071
TI  - Serum lipid concentrations in six canid and four ursid species in four zoos.
AB  - Serum lipid levels were measured in healthy captive wild canids and ursids, and
      the values were compared with previously published data. Serum lipid levels were
      evaluated in blood samples collected from eight African wild dogs (Lycaon
      pictus), three arctic foxes (Alopex lagopus), nine gray wolves (Canis lupus),
      four maned wolves (Chrysocyon brachyurus), two Mexican wolves (Canis lupus
      baleiyi), nine red wolves (Canis rufus), two brown bears (Ursus arctos), six
      polar bears (Ursus maritimus), six spectacled bears (Tremarctos ornatus), and
      five sun bears (Ursus malayanus). Samples were analyzed for total cholesterol,
      triacylglycerides, high-density lipoprotein-cholesterol, and low-density
      lipoprotein-cholesterol. Although the results showed a great variation among
      species, circulating lipids appeared especially high, sometimes extremely so, in
      the spectacled bears, polar bears, sun bears, and maned wolves compared with all
      other species sampled. The study provides a substantial basis for comparing lipid
      levels in presumed healthy animals and indicates a need for controlled study of
      the effects of diet on circulating lipid levels.

PMID- 15193073
TI  - Three novel herpesviruses associated with stomatitis in Sudan plated lizards
      (Gerrhosaurus major) and a black-lined plated lizard (Gerrhosaurus
      nigrolineatus).
AB  - Glossal stomatitis was observed in a Sudan plated lizard (Gerrhosaurus major)
      with severe dyspnea. On necropsy, intranuclear inclusion bodies were seen in the
      periglottal lingual epithelium. Labial stomatitis was seen in a second Sudan
      plated lizard and a black-lined plated lizard (G. nigrolineatus). Degenerate
      polymerase chain reaction (PCR) primers targeting a conserved region of
      herpesvirus DNA-dependent DNA polymerase gene were used to amplify products from
      lesions from each lizard. Nucleotide sequencing of the PCR products showed that
      the sequence from each lizard was unique. Phylogenetic and comparative sequence
      analyses suggest that these viruses are novel members of the subfamily
      Alphaherpesvirinae, and they are here termed gerrhosaurid herpesviruses 1-3.
      Results of our analyses suggest that the genus Gerrhosaurus can be infected by
      these novel herpesviruses.

PMID- 15193072
TI  - Clinical evaluation of the oral iron chelator deferiprone for the potential
      treatment of iron overload in bird species.
AB  - The clinical use of oral Fe chelators for the treatment of Fe-storage disease in
      birds requires evaluation. In this study, the efficacy of the Fe chelator
      deferiprone in reducing hepatic Fe stores, its effects on hematologic,
      biochemical, and plasma Fe parameters, and its potential toxicity during a 30-day
      treatment period were investigated in a controlled setting using two model
      species, the white leghorn chicken (Gallus gallus f. domestica) and the domestic
      pigeon (Columba livia). A second phase of the study investigated deferiprone
      related Fe elimination in the excreta. Deferiprone, administered orally at a
      dosage of 50 mg/kg twice daily to birds that had been experimentally Fe loaded,
      significantly reduced hepatic Fe concentrations compared with levels in Fe-loaded
      and non-Fe-loaded controls. There were no significant alterations in routine
      clinical hematologic or biochemical parameters, although decreased transferrin
      saturation was noted in both species. Side effects associated with deferiprone
      administration were decreased weight gain and significant decreases in plasma Zn
      concentrations. No mortalities occurred in the pigeons, but there were three
      deaths in the deferiprone-treated group of Fe-loaded chickens, most likely
      associated with acute reduction of Fe required for normal enzymatic processes.
      Histologic changes associated with deferiprone treatment were not noted.
      Deferiprone caused a dose-dependent increase of Fe in the excreta at oral dosages
      of 50 and 75 mg/kg once daily in both species. Deferiprone is a promising, orally
      active Fe chelator for the treatment of Fe overload in birds, although its
      potential side effects need to be considered.

PMID- 15193074
TI  - Vaccination of Egyptian fruit bats (Rousettus aegyptiacus) with monovalent
      inactivated rabies vaccine.
AB  - Twenty-six captive, adult Egyptian fruit bats (Rousettus aegyptiacus) were tested
      for the presence of rabies virus neutralizing antibodies (RVNA) using a rapid
      fluorescent focus inhibition test before and after vaccination. The bats were
      randomly assigned into three treatment groups: group A (n = 10) bats each
      received one 0.1-ml dose of monovalent inactivated rabies vaccine, group B (n =
      10) bats each received two 0.1-ml doses of vaccine given 30 days apart, and group
      C (n = 6) bats remained unvaccinated. Plasma was collected from all bats before
      vaccination and on days 14, 30, 60, and 360. All bats were seronegative before
      vaccination, and all unvaccinated animals remained negative throughout the study.
      Rabies virus neutralization titers remained above 0.5 IU/ml from day 30 through
      day 360 for both vaccinated groups. Group B had significantly higher titers on
      day 60. This study demonstrated a measurable humoral immune response after
      vaccination with an inactivated rabies vaccine, with two doses producing a higher
      level of RVNA. This study confirms the feasibility of a rabies vaccination
      program for Egyptian fruit bats.

PMID- 15193075
TI  - Survey for Haemoproteus spp., Trichomonas gallinae, Chlamydophila psittaci, and
      Salmonella spp. in Galapagos Islands columbiformes.
AB  - Endemic free-ranging Galapagos doves (Zenaida galapagoensis) and introduced rock
      doves (Columba livia) were surveyed in several islands of the Galapagos
      archipelago to establish sample prevalence of hemoparasites, Trichomonas
      gallinae, Chlamydophila psittaci, and Salmonella species. A Haemoproteus sp., the
      only hemoparasite identified, was found in 89% of the Galapagos doves sampled but
      not in the rock doves. Trichomonas gallinae was detected by polymerase chain
      reaction in 44% of rock doves from San Cristobal but in none of the Galapagos
      doves. Chlamydophila psittaci was detected from cloacal swabs in 6% of the
      Galapagos doves but in none of the rock doves sampled. All positive cases of C.
      psittaci occurred on Espanola, where the crude sample prevalence was 24%. A
      polymerase chain reaction-based Salmonella test failed to show evidence of this
      organism from any birds sampled.

PMID- 15193076
TI  - Reversible anesthesia of captive California sea lions (Zalophus californianus)
      with medetomidine, midazolam, butorphanol, and isoflurane.
AB  - Two adult California sea lions (Zalophus californianus) were effectively
      anesthetized 13 times with medetomidine (0.010-0.013 mg/kg), midazolam (0.2-0.26
      mg/kg), and butorphanol (0.2-0.4 mg/kg) by i.m. hand or pole syringe injection.
      For each anesthetic event, atropine (0.02 mg/kg, i.m.) was administered 6-20 min
      after initial injections, and oxygen administration via face mask or nasal
      insufflation began at the same time. Light anesthesia was induced in 8-22 min and
      lasted 13-78 min. During eight of the procedures, isoflurane (0.5-2.0%) was
      administered via face mask or endotracheal tube for an additional 30-120 min to
      facilitate longer procedures or surgery. Anesthesia was antagonized with
      atipamezole (0.05-0.06 mg/kg) and naltrexone (0.1 mg/kg) in seven events, with
      the addition of flumazenil (0.0002-0.002 mg/kg) in six events. The antagonists
      were administered by i.m. injection 42-149 min after administration of the
      induction agents. All sea lions recovered to mild sedation within 4-17 min after
      administration of the antagonists.

PMID- 15193078
TI  - Tibiotarsal fracture repair in a bald eagle (Haliaeetus leucocephalus) using an
      interlocking nail.
AB  - A 14-yr-old, 5.13-kg bald eagle (Haliaeetus leucocephalus) was hit by a car and
      presented to the Michigan State University Small Animal Clinic with an open,
      grade II, transverse, midshaft, Winquist-Hansen type-II-comminuted left
      tibiotarsal fracture. The fracture was reduced and fixation established with a
      4.7-mm-diameter, 112-mm-long, four-hole veterinary intramedullary interlocking
      nail maintained in position by single 2-mm transcortical screws placed in the
      main proximal and distal fragments. The bird was weight bearing on the bandaged
      limb 48 hr postoperatively. Radiographs obtained 4 wk postoperatively revealed
      bridging callus over three of four cortices. The bird was released after 5 mo of
      rehabilitation.

PMID- 15193077
TI  - Control of musth in an Asian elephant bull (Elephas maximus) using leuprolide
      acetate.
AB  - The results of long-term administration of leuprolide acetate (LA) depot in a 52
      yr-old Asian elephant bull (Elephas maximus) for control of musth are presented.
      Twelve injections were administered for 6 yr during our interpretation of early
      musth or "premusth." Intervals between musth periods during the study varied from
      2 to 34 mo. Blood samples, drawn weekly, were assayed for serum testosterone
      concentrations; mean levels were 11.78 +/- 1.97 nmol/L throughout the first 26 mo
      of the study, 7.28 +/- 1.28 nmol/L during the following 21 mo, and 0.45 +/- 0.035
      nmol/L in the last 34 mo of this study. Early musth signs ceased within 3 days of
      drug administration after 10 of 12 injections. The mean serum testosterone
      concentrations were significantly decreased by the last 34 mo of the study. The
      results suggest leuprolide is a suitable alternative for controlling or
      preventing (or both) musth in captive Asian elephants, although permanent
      reproductive effects may occur. Zoos and wildlife conservation institutions could
      benefit from the use of LA in Asian elephants to increase the male availability
      in captivity, consequently ensuring genetic diversity and the perpetuation of the
      species.

PMID- 15193079
TI  - Thyroid cystadenoma, colloid goiter, and hypothyroidism in an American black bear
      (Ursus americanus).
AB  - A 178-kg, 14-yr-old captive female American black bear (Ursus americanus) was
      examined because of lethargy, inappetance, obesity, and alopecia. Serum chemistry
      and complete blood count values were within normal limits. Based on serum levels
      for total thyroxine (T4), free T4 by equilibrium dialysis (fT4ED), and canine
      thyroid-stimulating hormone concentrations, using assays validated for domestic
      dogs, hypothyroidism was diagnosed presumptively, and therapy with levothyroxine
      sodium (0.022 mg/kg p.o. b.i.d.) was initiated. Haircoat, body weight, appetite,
      and activity level improved within 30 days. The levothyroxine dose was decreased
      twice (to 0.018 mg/kg p.o. b.i.d. and then to 0.011 mg/kg p.o. b.i.d.) during the
      course of treatment based on monitoring of serum T4 and fT4ED concentrations.
      After euthanasia for severe refractory lameness, postmortem examination revealed
      bilateral thyroid lobe enlargement and a fluid-filled cyst within the right lobe.
      Histologically, colloid goiter was present in both lobes, and a follicular
      cystadenoma had replaced one third of the cranial pole of the right lobe. The
      goiter and cystadenoma likely contributed to the hypothyroid condition in this
      bear and fT4ED was a more sensitive indicator of hypothyroidism than was T4. The
      recommended canine dosage of levothyroxine may be too high for the treatment of
      hypothyroidism in American black bears; 0.011 mg/kg p.o. b.i.d. may be a more
      appropriate dosage.

PMID- 15193080
TI  - A Pasteurella-like bacterium associated with pneumonia in captive
      megachiropterans.
AB  - A novel Pasteurella-like organism was recovered postmortem from lung tissue of
      two captive Wahlberg's epauleted fruit bats (Epomophorus wahlbergi), with severe,
      unilateral pneumonia. The bats had been recently shipped and died shortly after
      release from a 30-day quarantine. One presented with clinical signs of anorexia
      and lethargy before death; the other died without prior clinical symptoms. The
      same Pasteurella-like organism was recovered antemortem from subcutaneous
      abscesses in two captive little golden mantled flying foxes (Pteropus pumilus)
      housed with additional E. wahlbergi. The organism was also cultured on tracheal
      wash from one Malaysian flying fox (Pteropus vampyrus) and another E. wahlbergi,
      both demonstrating clinical signs of pneumonia. All recovered isolates appeared
      morphologically and biochemically similar to the initial isolates and were
      further characterized as either a Pasteurella or Actinobacillus organism on the
      basis of biochemical and cellular fatty acid profiles. Screening of the current
      collection using pharyngeal swabs isolated this organism from 12 of 15 E.
      wahlbergi, two of three P. vampyrus, one of 26 island flying foxes (Pteropus
      hypomelanus), and one of nine Rodrigues fruit bats (Pteropus rodricensis). The
      organism was not identified in pharyngeal culture from eight Indian flying foxes
      (Pteropus giganteus), nine Egyptian fruit bats (Rousettus aegypticus), or an
      additional 16 P. pumilus.

PMID- 15193081
TI  - An outbreak of chlamydiosis in captive blue-fronted Amazon parrots (Amazona
      aestiva) in Brazil.
AB  - Fifty-eight blue-fronted Amazon parrot (Amazona aestiva) nestlings, recovered
      from the illegal trade, became ill at a wildlife rehabilitation center in Sao
      Paulo State, Brazil. Clinical signs observed were nonspecific, and the mortality
      rate was 96.5% despite initial treatment with norfloxacin. Postmortem
      examinations were performed on 10 birds. Liver and spleen smears showed
      structures suggestive of Chlamydophila psittaci in four cases. Diagnosis was
      confirmed by seminested polymerase chain reaction on tissue samples. Other birds
      from the same location showed no clinical signs of the disease, although high
      complement fixation titers to C. psittaci were found in 10 adult psittacines. All
      birds in the facility were treated with doxycycline. The two surviving nestlings
      did not recover after two doxycycline treatments and were euthanatized. The high
      mortality rate observed in this outbreak was attributed to poor conditions of
      husbandry and delays in the diagnosis and treatment of the disease. After
      diagnosis, improved control measures for chlamydiosis were instituted.

PMID- 15193082
TI  - Congenital neuropathy and dilution of feather melanin in nestlings of urban
      breeding northern goshawks (Accipiter gentilis).
AB  - A pair of northern goshawks (Accipiter gentilis) breeding in a public park in the
      city center of Hamburg, Germany, raised 12 healthy and five aberrant offspring
      between 1996 and 2000. Aberrant nestlings (three males and two females) had pale
      silver-blue plumage and displayed severe locomotor disorders.
      Histopathologically, the defects were characterized by adendritic feather
      melanocytes and mild degeneration of the cerebellar white matter. Epidemiologic
      results were suggestive of a hereditary autosomal recessive defect, which may
      have originated from close inbreeding during the foundation of Hamburg's urban
      population of northern goshawks.

PMID- 15193083
TI  - A vasectomy technique for Egyptian fruit bats (Rousettus aegyptiacus).
AB  - Bats in captivity reproduce well and contraceptive techniques are needed. In
      initial attempts at vasectomy using a prescrotal approach, it was difficult to
      identify the mesoductus deferens. The technique described here uses a scrotal
      approach with exteriorization of the testis, followed by identification and
      ligation of the mesoductus deferens. Nine Egyptian fruit bats (Rousettus
      aegyptiacus) underwent vasectomy for this study. No postoperative complications
      were seen (n = 18 testes), but some of the testes (5/18, 27%), which previously
      moved freely from the scrotum to the abdominal cavity, were still adhered to the
      scrotal sac 14 mo postoperatively. This technique appears safe, is fast, and is
      relatively easy to perform.

PMID- 15193084
TI  - Fibrosarcoma of the brood pouch in an aquarium-reared lined seahorse (Hippocampus
      erectus).
AB  - An adult, male, captive lined seahorse (Hippocampus erectus) was presented with
      weight loss, anorexia, and brood pouch distention. Initial treatments included
      manual expression of the brood pouch followed by saline flushes and enrofloxacin
      infusions. Radiographs and physical examination identified a nodular swelling in
      the brood pouch wall. The mass was excised, but the seahorse died. Necropsy and
      histopathology revealed a malignant mesenchymal tumor with a collagenous stroma,
      and a brood pouch fibrosarcoma was diagnosed.

PMID- 15193085
TI  - Bilateral phacofragmentation in a New Zealand fur seal (Arctocephalus forsteri).
AB  - Ophthalmic examination under anesthesia of a 5-yr-old, captive, male New Zealand
      fur seal (Arctocephalus forsteri) with reduced visual capacity revealed bilateral
      cataracts. Surgical extraction of the lenses was performed by phacofragmentation.
      Preoperative mydriasis was unsuccessful using common topical mydriatic agents.
      Intraoperative intracameral epinephrine 1:10,000 produced minimal pupillary
      dilation, but excellent dilation was achieved with intracameral epinephrine at
      1:1,000. Postoperative uveitis was controlled with oral prednisolone.
      Postoperative complications included generalized corneal edema persisting for
      approximately 1 wk and corneal ulceration caused by the lateral canthotomy
      sutures. Vision was restored in both eyes.

PMID- 15193086
TI  - Systemic toxoplasmosis in a five-month-old beaver, (Castor canadensis).
AB  - A 5-mo-old orphan beaver, Castor canadensis, died of severe systemic
      toxoplasmosis during rehabilitation. Histologic lesions included
      lymphohistiocytic encephalitis, myocarditis, and interstitial pneumonia with
      multinucleated cells. Intracytoplasmic cysts containing tachyzoites and
      bradyzoites identified as Toxoplasma gondii by immunohisto-chemistry were present
      in macrophages, type-II pneumocytes, and endothelial cells. Immunohistochemistry
      using a polyclonal morbillivirus antibody and transmission electron microscopy of
      lung revealed no evidence of concurrent paramyxoviral infection, as commonly
      found in carnivores with toxoplasmosis. Toxoplasmosis may affect young beavers in
      rehabilitation and zoological settings.

PMID- 15193087
TI  - Assessment of ultrasound imaging as a noninvasive measure of blubber thickness in
      pinnipeds.
AB  - Portable ultrasound imaging was examined as a noninvasive measure of skin
      including blubber thickness in captive subadult Steller sea lions (Eumetopias
      jubatus) and adult harbor seals (Phoca vitulina). This method was validated
      through comparison with blubber biopsy. Ultrasound images provided depth
      measurements that were accurate to 99.8% of the actual. This method allowed clear
      images of the epidermis, dermis, and blubber layer to be rapidly obtained, with
      minimal animal restraint, and allowed differentiation of phocid and otariid
      blubber structure.

PMID- 15193088
TI  - Environmental engineering education for developing countries: framework for the
      future.
AB  - This paper presents the existing philosophy, approach, criteria and delivery of
      environmental engineering education (E3) for developing countries. In general,
      environmental engineering is being taught in almost all major universities in
      developing countries, mostly under civil engineering degree programmes. There is
      an urgent need to address specific inputs that are particularly important for
      developing countries with respect to the reality of urbanisation and
      industrialisation. The main component of E3 in the near future will remain on
      basic sanitation in most developing countries, with special emphasis on the
      consumer-demand approach. In order to substantially overcome environmental
      problems in developing countries, E3 should include integrated urban water
      management, sustainable sanitation, appropriate technology, cleaner production,
      wastewater minimisation and financial framework.

PMID- 15193089
TI  - International evaluation of current and future requirements for environmental
      engineering education.
AB  - The field of environmental engineering is developing as a result of changing
      environmental requirements. In response, environmental engineering education (E3)
      needs to ensure that it provides students with the necessary tools to address
      these challenges. In this paper the current status and future development of E3
      is evaluated based on a questionnaire sent to universities and potential
      employers of E3 graduates. With increasing demands on environmental quality, the
      complexity of environmental engineering problems to be solved can be expected to
      increase. To find solutions environmental engineers will need to work in
      interdisciplinary teams. Based on the questionnaire there was a broad agreement
      that the best way to prepare students for these future challenges is to provide
      them with a fundamental education in basic sciences and related engineering
      fields. Many exciting developments in the environmental engineering profession
      will be located at the interface between engineering, science, and society.
      Aspects of all three areas need to be included in E3 and the student needs to be
      exposed to the tensions associated with linking the three.

PMID- 15193090
TI  - Environmental education for all engineers.
AB  - Environmental engineering education at universities is a rapidly changing field
      globally. Traditionally it has resided in the civil engineering program
      addressing water and wastewater quality, treatment, design and regulatory issues.
      In recent years environmental engineering has become a much broader field
      encompassing water, wastewater, soil pollution, air pollution, risk assessment,
      ecosystems, human health, toxicology, sustainable development, regulatory aspects
      and much more. The need to introduce environmental engineering/green
      engineering/pollution prevention/design for the environment concepts to
      undergraduate engineering students has become recognized to be increasingly
      important. This need is being driven in part through the US Engineering
      Accreditation Commission Accreditation Board for Engineering and Technology
      criteria 2000. Thus there has been a major shift in environmental engineering
      education and it no longer resides only within the civil engineering discipline.
      This paper focuses on the development of innovative curricula for a brand new
      engineering program at Rowan University that integrates environmental education
      for all engineers. A common course known as "engineering clinic" was developed
      for all engineering students throughout their eight semesters of engineering
      education. One of the clinic goals is to integrate engineering design and the
      environment. The program, in its seventh year, indicates successful
      implementation of environmental education in all four engineering disciplines in
      their course work and clinics.

PMID- 15193091
TI  - The HOCS paradigm shift from disciplinary knowledge (LOCS)--to interdisciplinary
      evaluative, system thinking (HOCS): what should it take in science-technology
      environment-society oriented courses, curricula and assessment?
AB  - Given the current world state of affairs, striving for sustainability and the
      consequent paradigm shift: growth-to-sustainable development, correction-to
      prevention and options selection-to-options generation: the corresponding
      paradigm shift in science-technology-environment-society (STES) education is
      unavoidable. Accordingly, the essence of the current reform in STES education,
      worldwide, is a purposed effort to develop students' higher-order cognitive
      skills (HOCS) capability; i.e., question-asking, critical system thinking,
      decision making and problem solving, at the expense of the "delivery" of lower
      order cognitive skills (LOCS)-oriented knowledge. This means a paradigm shift
      from the contemporary prevalent LOCS algorithmic teaching to HOCS evaluative
      learning and HOCS-promoting courses, curricula, teaching strategies and
      assessment methodologies, leading, hopefully to evaluative thinking and transfer.
      Following the formulation of selected relevant axioms, major paradigm shift in
      STES research and education for sustainability have been identified. The
      consequent shift, in the STES context, from disciplinary to inter- and
      transdisciplinary learning, in science technology and environmental engineering
      education is discussed, followed by selected examples of successfully implemented
      HOCS-promoting courses, and assessment methodologies. It is argued, that
      transferable "HOCS learning" for sustainability can and should be done.

PMID- 15193092
TI  - Systems analysis in environmental engineering: how far should we go?
AB  - Systems analysis is identified as a unifying topic of environmental engineering.
      Based on a questionnaire sent out to peers and based on the experience with an
      advanced systems analysis course the possible content and association of the
      content with bachelor and master's programs is discussed. At the bachelor's level
      it is concluded that an array of topics should be introduced more in an inductive
      way, going along with the discussion of examples. At the master's level it is
      suggested that a substantial course, which systematically introduces a broad
      variety of systems analysis tools, is provided. Such a course should go along
      with the introduction of a simulation tool, which supports application of systems
      analysis methods.

PMID- 15193093
TI  - Ever deeper and wider: incorporating sustainability into a practitioner oriented
      engineering curriculum.
AB  - Whilst valuable debates about how best to plan, promote, and evaluate sustainable
      futures for our communities are conducted by governments and NGOs at global
      gatherings, there is an equal, and possibly more pressing, need to inspire and
      equip engineering graduates with the means to design and implement the required
      solutions. However, incorporation of sustainability as a subject into existing
      syllabi is problematic, primarily because of the need for students to acquire
      both holistic and context specific skills. This contribution first considers the
      reasons why we should be concerned with the integration of sustainability
      concepts into graduate and post-graduate curricula. We then go on to discuss the
      significance of cross-disciplinary thinking and skills as a key element of
      sustainability relevant knowledge. Finally, we report the design and deployment,
      within a water engineering degree course, of a post-graduate module in "Process
      design for sustainability". The implications of our experiences for the theory
      and practice of engineering education are examined and suggestions made
      concerning best practice.

PMID- 15193094
TI  - Membrane-based gas transfer: an environmental engineering laboratory.
AB  - We propose an educational experience in which students design a membrane gas
      transfer reactor, construct a bench-scale version in the laboratory, and employ
      the reactor to measure mass transfer coefficients. The membrane reactor is useful
      for teaching mass transfer principles because the mass transfer interface is well
      defined and easily observed. The system can be modeled successfully using
      straightforward mathematics. The reactor can be designed and constructed by
      students, using the mathematical model as a basis, providing insight into the
      physical meaning of model parameters. The proposed membrane system can be readily
      operated to obtain data that can be employed to develop or modify existing mass
      transfer correlations. This can provide students with significant insight into
      the development of mass transfer correlations and how the constants in such
      correlations are typically determined. These features help promote a deeper
      understanding of mass transfer principles.

PMID- 15193095
TI  - Evaluation of air pollution modelling tools as environmental engineering
      courseware.
AB  - The study of phenomena related to the dispersion of pollutants usually takes
      advantage of the use of mathematical models based on the description of the
      different processes involved. This educational approach is especially important
      in air pollution dispersion, when the processes follow a non-linear behaviour so
      it is difficult to understand the relationships between inputs and outputs, and
      in a 3D context where it becomes hard to analyze alphanumeric results. In this
      work, three different software tools, as computer solvers for typical air
      pollution dispersion phenomena, are presented. Each software tool developed to be
      implemented on PCs, follows approaches that represent three generations of
      programming languages (Fortran 77, VisualBasic and Java), applied over three
      different environments: MS-DOS, MS-Windows and the world wide web. The software
      tools were tested by students of environmental engineering (undergraduate) and
      chemical engineering (postgraduate), in order to evaluate the ability of these
      software tools to improve both theoretical and practical knowledge of the air
      pollution dispersion problem, and the impact of the different environment in the
      learning process in terms of content, ease of use and visualization of results.

PMID- 15193096
TI  - Computer-aided tutorials and tests for use in distance learning.
AB  - Compared to the traditional on-campus students, remote students in distance
      education courses find it more difficult to develop problem-solving skills. In
      this paper, we propose the use of computer-aided tutorials and tests (CATTs) as
      convenient tools for remote students to practice and improve problem-solving and
      test taking skills at their own pace. Example of CATTs developed with Authorware
      software for use in distance education is presented.

PMID- 15193097
TI  - The ACCEND program: a combined BS and MS program in environmental engineering
      that includes co-operative work experience.
AB  - Environmental engineering education has rapidly expanded in recent years and new
      teaching methods are needed. Many professionals and educators believe that a MS
      degree in environmental engineering should be the minimum in order to practice
      the profession, along with practical training. This paper describes an innovative
      program being offered at the University of Cincinnati that combines an integrated
      BS in civil engineering and an MS in environmental engineering with extensive
      practical co-operative education (co-op) experience, all within a five-year
      period. The program includes distance learning opportunities during the co-op
      periods. The result is a well-trained graduate who will receive higher pay and
      more challenging career opportunities, and who will have developed
      professionalism and maturity beyond that from traditional engineering programs.

PMID- 15193098
TI  - Environmental management master's programme in Kazakhstan: development and
      operation.
AB  - The paper looks at the origins of the environmental management master's programme
      in Kazakhstan course and its development over the 7 years for which it has
      operated. It considers the difficulties of teaching, in particular issues
      covering the diverse range of topics covered, the need for staff training and
      development and how this has been approached, and the need to gain financial aid
      to support the students. Details are given of how students are selected, the
      range of backgrounds and geographical regions from which they come, and the types
      of employment they take on graduation. In total 110 students have benefited from
      the course which has proved an attractive alternative to overseas study.

PMID- 15193099
TI  - Environmental management master's programme in Kazakhstan: course structure and
      content.
AB  - The paper briefly considers changes in the higher education system in Kazahkstan
      since the break-up of the former Soviet Union. At that time master's programmes
      did not exist and there was no unified system for their introduction. The one
      year environmental management course described was the first of its type and was
      set up with special permission from the Ministry of Education and Science,
      Republic of Kazakhstan to run on an experimental basis. The course differs
      significantly from other programmes and, under regulations introduced by the
      ministry in 2001, it is difficult to see how a broad-based programme aimed at
      introducing graduates from a variety of backgrounds to environmental issues could
      be achieved within a one-year period. The permission to run the course is
      periodically reviewed, however, and has been extended due to the excellent
      results. The course structure and the philosophy behind it are presented along
      with some of its history. The aim is not to produce specialists in any one area
      of environmental management, technology or engineering, but individuals with a
      broad foundation to build on as their professional careers progress.

PMID- 15193100
TI  - Environmental engineering education in Spain.
AB  - There is a growing demand for engineers and technologists who show
      multidisciplinary expertise to deal with environmental issues. As a result of
      this demand, most countries are adapting their old university programs on
      environmental engineering education. In Spain an official environmental
      engineering degree does not yet exist, but the Council of Universities is working
      to present a proposal, based on Bologna agreement concepts. The paper summarizes
      not only the future perspectives of environmental engineering education in Spain,
      but also the evolution of the approach during the last decades, which includes
      the role of the private initiative, the environmental sciences degree, and the
      intensification in different traditional engineering degrees. Finally, the paper
      briefly details and compares the syllabus developed in the only four Spanish
      universities where environmental engineering is offered as a non-official post
      graduate course lasting two years.

PMID- 15193101
TI  - Some aspects of the environmental labour market in five European countries and
      conclusions with respect to environmental curricula.
AB  - The environmental labour market in the Czech Republic, Germany, Italy, Sweden and
      the Netherlands was evaluated by analysing up to 120 job advertisements in each
      country. The conditions and requirements were grouped into 11 categories showing
      clear similarities and differences between the five countries. Further evaluation
      of the data gives evidence that the private sector plays a significant role for
      technical environmental professionals in Europe. As a central task, conclusions
      regarding degree and knowledge requirements, respectively, and the importance of
      a variety of skills are drawn. Suggestions are made how the findings can be
      accounted for in environmental curricula. Furthermore the role of networks for
      the graduates' entry into the labour market is emphasized.

PMID- 15193102
TI  - Environmental engineering education at Ghent University, Flanders (Belgium).
AB  - Since the 1980s, environmental engineering education has been a rapidly growing
      discipline in many universities. This paper discusses the history, the current
      status and the near future of environmental engineering education at Ghent
      University. This university, with about 50% of the Flemish university
      environmental engineering students, can be considered as representative for the
      situation in Flanders, Belgium. In contrast to many other universities,
      environmental engineering education at Ghent University does not have its
      historical roots in civil engineering, but has been developed from the curricula
      organized by the former Faculty of Agricultural Sciences. As part of a
      reorganisation of the education and research activities at this faculty, a
      curriculum leading to the degree of "bio-engineer in environmental technology"
      was established in 1991. This curriculum covers a 5-year study and is constructed
      around 8 main components. Exchange of students with other European universities,
      e.g. within the Socrates framework, has become a prominent aspect of student life
      and education. This paper also briefly describes the employment opportunities of
      graduated bio-engineers in environmental technology. Finally, the current
      implementation of the bachelor's-master's structure, leading to a "master of
      science in environmental technology" degree is summarized.

PMID- 15193103
TI  - EEE in changing times: new B/M study programs, increasing specialization and
      interdisciplinarity for fewer students.
AB  - Scope and organisational aspects of environmental engineering education in
      Germany as part of civil engineering are described. The structure of conventional
      diploma courses is compared with study programs structured in bachelor and
      master's courses. The current discussion and first steps of reorganisation in
      Germany are outlined. Intensifying interdisciplinarity and internationalisation,
      limited resources and increasing specialisation of research work together with a
      decreasing number of students are identified as future challenges to be met by
      innovative study programs. Cooperation in education between EE programs and
      networking of universities--together with enhanced student mobility--seem to be
      promising and necessary to achieve high quality and efficient EE education.

PMID- 15193104
TI  - Case study: a decade of changes in a small environmental engineering graduate
      program.
AB  - For a small graduate program in environmental engineering in a rural state in the
      US, it is important for the program curriculum to stay in the mainstream. While
      resident student enrollment is approaching a steady level, international student
      enrollment increases steadily, this is due in part to the out-of-state tuition
      waiver provided to the students. Part-time students are a significant part of the
      program, these students have special needs that are different from traditional
      full-time students that must be taken into consideration in program planning. A
      small program provides an attentive atmosphere for students' learning, but it
      also has problems that a larger program would not encounter, such as
      competitiveness, personal conflicts, program identity, etc. Despite success in
      the past, the program is likely to merge with other related programs in the
      university during times of budget restrictions.

PMID- 15193105
TI  - European higher education space: where do we go from here?
AB  - The Declaration of Bologna and subsequent documents have drastically changed the
      European university panorama and the future role of universities as providers of
      continuous education for a lifelong learning. There will be a convergence not
      only in academic titles, but also in the way we see university education. The
      previous EEE symposium gave some clues on the approaches taken by different
      European countries: organization of EE studies, integration of graduates into the
      market, and interaction with professional bodies. Bologna's outcomes were sold in
      Spain as a change into an American (USA) model, which, as any other model, has
      advantages and drawbacks. This paper deals with an open reflection on the future
      of university studies in Europe.

PMID- 15193106
TI  - Planar chromatography.

PMID- 15193107
TI  - Solid-state nuclear magnetic resonance.

PMID- 15193109
TI  - Electrochemical sensors.

PMID- 15193108
TI  - Fiber-optic chemical sensors and biosensors.

PMID- 15193110
TI  - Thermal analysis.

PMID- 15193111
TI  - Atomic spectroscopy.

PMID- 15193112
TI  - Environmental mass spectrometry: emerging contaminants and current issues.

PMID- 15193113
TI  - Chemometrics.

PMID- 15193114
TI  - Micro total analysis systems. Recent developments.

PMID- 15193115
TI  - Gas chromatography.

PMID- 15193117
TI  - Mass spectrometry of synthetic polymers.

PMID- 15193116
TI  - Inductively coupled plasma mass spectrometry.

PMID- 15193118
TI  - Scanning probe microscopy.

PMID- 15193119
TI  - X-ray spectrometry.

PMID- 15193120
TI  - Photosynthetic units of phototrophic organisms.
AB  - Photoautotrophic organisms play a key role in the biosphere of the Earth,
      converting solar energy of the 350-1000 nm range into biochemically available
      form. In contemporary aquatic and terrestrial ecosystems, the dominating groups
      are the oxygen evolving cyanobacteria, algae, and higher plants. Anoxygenic
      phototrophic microorganisms occupy mainly ecological niches with extreme
      environmental conditions. Despite diverse evolution of all these taxonomic
      groups, their photosynthetic apparatus has a similar molecular design and
      identical principles of operation. This review covers recent data about features
      of the structural and functional organization of pigment-protein complexes of the
      basic types of photosynthetic units in prokaryotes and eukaryotes. A
      correspondence between the optical properties of various photosynthetic units and
      the natural light conditions is discussed.

PMID- 15193121
TI  - Analysis of the cell cycle and a method employing synchronized cells for study of
      protein expression at various stages of the cell cycle.
AB  - Study of protein expression during the cell cycle requires preparation of pure
      fractions of cells at various phases of the cell cycle. This was achieved by the
      development of methods for cell synchronization. Successful cell synchronization
      requires knowledge of the duration of all phases of the cell cycle. So, in the
      present review these interrelated problems are considered together. The first
      part of this review deals with basic methods employed for analysis of duration of
      cell cycle phases. The second summarizes data on treatments used for cell
      synchronization. Methods for calculation of percent of cells at various stages of
      the cell cycle in fractions of synchronized cells are considered in the third
      part. The fourth part of this review deals with a method of study of protein
      expression during the cell cycle by means of immunoblotting of synchronized cell
      fractions. In the Appendix, basic principles are illustrated with practical
      examples of analysis of the cell cycle, synchronization, and study of expression
      of some proteins at various stages of the cell cycle using synchronized XL2
      (Xenopus laevis) cells.

PMID- 15193122
TI  - Change in contents of biologically active sphingolipids modulating cell growth
      and survival in hepatoma 27 compared to rat liver.
AB  - The contents of bioactive sphingolipids (sphingomyelin, ceramide, glucosyl- and
      lactosylceramides, gangliosides) were studied in rat hepatoma 27 and rat liver.
      The amounts of sphingomyelin, ceramide, and glucosyl- and lactosylceramides were
      about twofold and that of gangliosides was about 3.5-fold increased in the tumor
      compared to normal tissue. Since sphingomyelin promotes angiogenesis, glucosyl-
      and lactosylceramides stimulate proliferation, gangliosides inhibit apoptosis,
      but ceramides suppress proliferation and stimulate apoptosis, it is obvious that
      the balance of these effectors in hepatoma 27 moves with the tumor growth.

PMID- 15193123
TI  - Structural investigations and identification of the extracellular bacteriolytic
      endopeptidase L1 from Lysobacter sp. XL1.
AB  - The N-terminal amino acid sequence (23 amino acid residues) and the amino acid
      composition of the extracellular bacteriolytic enzyme L1 of 21 kD from the
      bacterium Lysobacter sp. XL1 have been determined. The enzyme was hydrolyzed by
      trypsin, the resulting peptides were isolated, and their primary structures were
      determined. A high extent of homology (92%) of the N-terminal amino acid sequence
      and the primary structure of isolated peptides of the enzyme L1 (62 amino acid
      residues or 31% of protein sequence) to the corresponding sites of alpha-lytic
      proteinases (EC 3.4.21.12) of Lysobacter enzymogenes and Achromobacter lyticus
      was found. These data allowed identification of the endopeptidase L1 of
      Lysobacter sp. XL1 as alpha-lytic proteinase EC 3.4.21.12.

PMID- 15193124
TI  - Physicochemical properties and amino acid sequence of sheep brain galectin-1.
AB  - A beta-galactoside-specific soluble 14-kD lectin from sheep brain was isolated,
      sequenced, and compared with similar galectins from other species. Percent
      identities of amino acid sequence and the carbohydrate recognition domain (CRD)
      revealed that the isolated galectin shares all the absolutely preserved and
      critical residues of the mammalian galectin-1 subfamily. The isolated sheep brain
      galectin (SBG) showed more than 90% amino acid sequence (92%) and carbohydrate
      recognition domain identity (96%) with human brain galectin-1. Conformational
      changes were found induced by interaction of the protein with its specific
      disaccharide and oxidizing agent (hydrogen peroxide). Upon oxidation a drastic
      change in the environment of aromatic residues and conformation of the galectin
      was observed with the loss of hemagglutination activity, while no significant
      change was observed upon addition of D-lactose (Gal(beta1-4)Glc) in the far-UV
      and near-UV spectra, suggesting no significant modification in the secondary as
      well as tertiary structures of sheep brain galectin. But the functional integrity
      of the CRD is found to be affected in the presence of oxidizing agent, indicating
      intramolecular disulfide bonds and requirement of complete polypeptide chain for
      functional integrity of the carbohydrate recognition domain.

PMID- 15193125
TI  - Expression of neutral glycosphingolipids in cytokine-stimulated human endothelial
      cells.
AB  - We compared immunohistochemical distribution of glycosphingolipids
      globotriosylceramide (GbOse(3)Cer) and globotetraosylceramide (GbOse(4)Cer) with
      that of E-selectin on human umbilical vein endothelial cells (HUVEC) stimulated
      with tumor necrosis factor (TNF)-alpha. HUVECs activated by TNF-alpha were
      characterized by the highest expression of E-selectin and greatest adhesion of HL
      60 cells as well compared to stimulation with interleukin-1beta or
      lipopolysaccharide. HUVECs activated by TNF-alpha also stained intensely with
      globoside antibodies, especially with the GbOse(3)Cer-directed one, staining
      being redistributed in a concentration-dependent manner. These results indicate
      the possible role of GbOse(3)Cer and GbOse(4)Cer in immune effector mechanisms of
      endothelium such as adhesion.

PMID- 15193126
TI  - Protection of rat myocardium by coenzyme Q during oxidative stress induced by
      hydrogen peroxide.
AB  - Ubiquinone Q(10) (coenzyme Q) is an important component of the mitochondrial
      electron transport chain and an antioxidant. The purpose of this work was to find
      out whether an increase in the level of coenzyme Q in the heart changes its
      maximal working capacity and resistance to oxidative stress. Male Wistar rats
      were treated with coenzyme Q (10 mg/kg body weight per day) for six weeks, and
      this increased its content in the myocardium by 63%. The myocardial content of
      malonic dialdehyde and activities of key antioxidant enzymes were unchanged,
      except nearly 2.5-fold decrease in the activity of superoxide dismutase. The
      maximal working capacity of the isolated isovolumic heart did not change, but
      under conditions of oxidative stress induced by 45-min infusion of hydrogen
      peroxide (70 micro M) into coronary vessels the contractile function of these
      hearts decreased significantly more slowly. This was associated with less
      pronounced lesions in the ultrastructure of cardiomyocytes and lesser disorders
      in the oxidative metabolism of mitochondria that suggested increased antioxidant
      protection of the myocardium.

PMID- 15193127
TI  - Significance of codon usage and irregularities of rare codon distribution in
      genes for expression of BspLU11III methyltransferases.
AB  - Genes of adenine-specific DNA-methyltransferase M.BspLU11IIIa and cytosine
      specific DNA-methyltransferase M.BspLU11IIIb of the type IIG BspLU11III
      restriction-modification system from the thermophilic strain Bacillus sp. LU11
      were expressed in E. coli. They contain a large number of codons that are rare in
      E. coli and are characterized by equal values of codon adaptation index (CAI) and
      expression level measure (E(g)). Rare codons are either diffused (M.BspLU11IIIa)
      or located in clusters (M.BspLU11IIIb). The expression level of the cytosine
      specific DNA-methyltransferase was increased by a factor of 7.3 and that of
      adenine-specific DNA only by a factor of 1.25 after introduction of the plasmid
      pRARE supplying tRNA genes for six rare codons in E. coli. It can be assumed that
      the plasmid supplying minor tRNAs can strongly increase the expression level of
      only genes with cluster distribution of rare codons. Using heparin-Sepharose and
      phosphocellulose chromatography and gel filtration on Sephadex G-75 both DNA
      methyltransferases were isolated as electrophoretically homogeneous proteins
      (according to the results of SDS-PAGE).

PMID- 15193128
TI  - Comparative analysis of different typing methods for Helicobacter pylori clinical
      isolates.
AB  - The goal of the present work was to compare different techniques of molecular
      typing using as an example clinical isolates of Helicobacter pylori obtained from
      patients in different regions of Russia. DNA-macroarray genome scanning using
      individual genes was employed to set up our basic classification of isolates that
      did or did not contain pathogenicity islands. In parallel, DNA of the same
      isolates was used in the conventional random amplified polymorphic DNA (RAPD) PCR
      analysis, and the isolates were also genotyped (cagA, vacA, iceA, and babA
      status) and their proteomic maps were obtained by means of unidimensional SDS
      polyacrylamide gel electrophoresis (1D-SDS-PAGE) coupled with identification
      using peptide mass fingerprinting by MALDI-TOF mass spectrometry. A statistically
      significant correlation (coefficient of correlation r = 0.25, p = 0.005) was
      observed between the results of genome scanning and 1D-SDS-PAGE. No correlation
      was found between RAPD-PCR typing and genome scanning.

PMID- 15193129
TI  - Cellulase complex of the fungus Chrysosporium lucknowense: isolation and
      characterization of endoglucanases and cellobiohydrolases.
AB  - Using different chromatographic techniques, eight cellulolytic enzymes were
      isolated from the culture broth of a mutant strain of Chrysosporium lucknowense:
      six endoglucanases (EG: 25 kD, pI 4.0; 28 kD, pI 5.7; 44 kD, pI 6.0; 47 kD, pI
      5.7; 51 kD, pI 4.8; 60 kD, pI 3.7) and two cellobiohydrolases (CBH I, 65 kD, pI
      4.5; CBH II, 42 kD, pI 4.2). Some of the isolated cellulases were classified into
      known families of glycoside hydrolases: Cel6A (CBH II), Cel7A (CBH I), Cel12A
      (EG28), Cel45A (EG25). It was shown that EG44 and EG51 are two different forms of
      one enzyme. EG44 seems to be a catalytic module of an intact EG51 without a
      cellulose-binding module. All the enzymes had pH optimum of activity in the
      acidic range (at pH 4.5-6.0), whereas EG25 and EG47 retained 55-60% of the
      maximum activity at pH 8.5. Substrate specificity of the purified cellulases
      against carboxymethylcellulose (CMC), beta-glucan, Avicel, xylan, xyloglucan,
      laminarin, and p-nitrophenyl-beta-D-cellobioside was studied. EG44 and EG51 were
      characterized by the highest CMCase activity (59 and 52 U/mg protein). EG28 had
      the lowest CMCase activity (11 U/mg) amongst the endoglucanases; however, this
      enzyme displayed the highest activity against beta-glucan (125 U/mg). Only EG51
      and CBH I were characterized by high adsorption ability on Avicel cellulose (98
      99%). Kinetics of Avicel hydrolysis by the isolated cellulases in the presence of
      purified beta-glucosidase from Aspergillus japonicus was studied. The hydrolytic
      efficiency of cellulases (estimated as glucose yield after a 7-day reaction)
      decreased in the following order: CBH I, EG60, CBH II, EG51, EG47, EG25, EG28,
      EG44.

PMID- 15193130
TI  - Inter-subunit cross-linking suppressed the dynamic oligomeric dissociation of
      Mycobacterium tuberculosis Hsp16.3 and reduced its chaperone activity.
AB  - Small heat shock proteins (sHsps) usually exist as dynamic oligomers and
      oligomeric dissociation was believed to be a prerequisite for their chaperone
      activities. The truth of this hypothesis was verified in our present study on
      Hsp16.3, one member of sHsps from Mycobacterium tuberculosis, mainly by utilizing
      chemical cross-linking. Analysis using size exclusion chromatography demonstrated
      that the heat-induced oligomeric dissociation of Hsp16.3 was severely blocked due
      to highly efficient inter-subunit cross-linkages generated by chemical cross
      linking, as well as its chaperone activity being reduced. Further analysis by non
      denaturing pore gradient polyacrylamide gel electrophoresis and fluorescence
      spectrometry revealed that the dynamic oligomeric dissociation/reassociation
      process of Hsp16.3 at room temperature was suppressed by inter-subunit cross
      linkages, accompanied by significantly decreased exposure of hydrophobic surfaces
      that are usually hidden in oligomers. These findings supported the hypothesis
      that substrate-binding sites of sHsps are exposed presumably by dissociation of
      larger oligomers into smaller active oligomers, and therefore such a dissociation
      process could be adjusted to modulate chaperone activities.

PMID- 15193131
TI  - Poly(ADP-ribose) polymerase-1 inhibits strand-displacement synthesis of DNA
      catalyzed by DNA polymerase beta.
AB  - Poly(ADP-ribose) polymerase-1 (PARP-1), a eucaryotic nuclear DNA-binding protein
      that is activated by breaks in DNA chains, may be involved in the base excision
      repair (BER) because DNAs containing single-stranded gaps and breaks are
      intermediates of BER. The effect of PARP-1 on the DNA synthesis catalyzed in
      vitro by DNA polymerase beta (pol beta) was studied using analogs of DNA
      substrates produced during BER and imitating intermediates of the short patch and
      long patch subpathways of BER. Oligonucleotide duplexes of 34 bp that contained a
      mononucleotide gap or a single-strand break with tetrahydrofuran phosphate or
      phosphate at the 5;-end of the downstream oligonucleotide were taken as DNA
      substrates. The efficiency of DNA synthesis was determined at various ratios of
      pol beta and PARP-1. The efficiency of gap filling was decreased in the presence
      of PARP-1, but strand-displacement DNA synthesis was inhibited significantly
      stronger, which seemed to be due to competition between PARP-1 and pol beta for
      DNA. In the presence of NAD+ and single-strand breaks in DNA, PARP-1 catalyzes
      the synthesis of poly(ADP-ribose) covalently attached to the enzyme, and this
      automodification is thought to provide for dissociation of PARP-1 from DNA. The
      effect of PARP-1 automodification on inhibition of DNA synthesis was studied, and
      efficiency of mononucleotide gap filling was shown to be restored, but strand
      displacement synthesis did not revert to the level observed in the absence of
      PARP-1. PARP-1 is suggested to regulate the interaction between pol beta and DNA,
      in particular, via its own automodification.

PMID- 15193132
TI  - Interaction of oxoferrylmyoglobin and dinitrosyl-iron complexes.
AB  - It is shown that dinitrosyl-iron complexes (DNIC) with glutathione can reduce
      oxoferrylmyoglobin forming on interaction of tert-butyl hydroperoxide and
      metmyoglobin. A rapid decrease in the DNIC concentration was observed under the
      conditions of production of tert-butyl free radicals; however, destruction of
      DNIC in the presence of oxoferrylmyoglobin alone was negligible. It is
      demonstrated that DNIC reduces oxoferrylmyoglobin more than an order more
      efficiently than S-nitrosoglutathione and glutathione. DNIC also inhibits
      formation of the thiyl radicals of glutathione in a medium containing
      metmyoglobin and tert-butyl hydroperoxide. A mechanism of the antioxidant action
      of DNIC based on regeneration of the nitrosyl complexes from the products of
      their interaction with oxoferrylheme is proposed.

PMID- 15193133
TI  - Initial stages of low-temperature induction of cabbage cold shock protein gene
      csp5.
AB  - Some stages of low-temperature signal transduction causing appropriate cold
      stress response in plants are considered. The effects of Ca2+ chelators, Ca2+
      channel blockers, and protein kinase inhibitors on protoplasts and plants of
      cabbage suggest that the initial stages of cold signal transduction are the
      change in membrane fluidity followed by the activation of calcium channels and
      elevation of Ca2+ influx into the cytoplasm. Increased concentration of Ca2+ in
      cytoplasm activates calcium-dependent protein kinase most likely participating in
      induction of transcription factors necessary for the expression of cold-regulated
      genes, in particular csp5. The protein kinase inhibitors staurosporine and
      wortmannin insignificantly repress the expression of csp5.

PMID- 15193134
TI  - NADH oxidation by mitochondria from the thermogenic plant Arum orientale.
AB  - The enzyme content of the mitochondrial respiratory chain was investigated in the
      heat-producing plant Arum orientale. It is shown that mitochondria isolated from
      thermogenic tissues of this plant (with respect to non-thermogenic tissues of A.
      orientale or to Zea mays) demonstrate significantly elevated levels of activities
      of two non-coupled NADH dehydrogenases oxidizing intramitochondrial and
      cytoplasmic NADH pools. It is postulated that operation of a completely non
      coupled respiratory chain consisting of non-coupled NADH:quinone oxidoreductases
      and cyanide-resistant alternative quinol-oxidase is the main mechanism of heat
      production in thermogenic plants.

PMID- 15193136
TI  - Chemokine receptor-directed agents as novel anti-HIV-1 therapies.
AB  - Historically, therapeutic benefit in the treatment of human immunodeficiency
      virus infection (HIV-1) infection has been best achieved by targeting viral
      proteins like HIV protease involved in viral replication rather than host cell
      proteins, like CD4, which facilitate the process of viral infection. Two
      discoveries in 1996 presented a novel opportunity to redress this issue: 1) the
      understanding that heptahelical G-protein coupled chemokine receptors on the
      surface of T cells and macrophages functioned together with CD4 to mediate viral
      entry, and 2) the observation that CD4 positive T cells from individuals
      homozygous for the CCR5 delta 32 null allele were resistant to infection by
      macrophage-tropic strains of the virus in vitro and in vivo. Since that time,
      data demonstrating that selective blockade of two chemokine receptors, CCR5 and
      CXCR4, by small molecule chemokine receptor antagonists or receptor-directed
      biologics could robustly inhibit the infection of human peripheral blood
      mononuclear cells (PBMCs) by macrophage-tropic and T-cell line tropic strains
      respectively in vitro has validated this potential approach to therapy. Early
      clinical trial data now also confirms that these types of agents will have anti
      viral activity in some HIV-1 infected individuals; however to date, dose limiting
      off-target activities have prohibited a full test of their potential clinical
      value. It also remains to be seen how these types of agents will fare in synergy
      with existing HIV-1 targeted antivirals, or those currently in development.

PMID- 15193137
TI  - Biochemical and mechanistic basis for the activity of nucleoside analogue
      inhibitors of HIV reverse transcriptase.
AB  - HIV encodes an RNA directed DNA polymerase (reverse transcriptase, RT) that is an
      essential enzyme in the viral replication cycle. This enzyme catalyzes the
      synthesis of double stranded proviral DNA from single stranded genomic RNA via a
      bireactant-biproduct mechanism. The functional enzyme purified from virus
      particles is a complex consisting of two polypeptides of molecular weight 66,000
      and 51,000. Two of the four classes of currently approved anti-HIV drugs, the
      nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside
      reverse transcriptase inhibitors (NNRTIs), act by inhibiting this enzyme. In this
      review each step of DNA synthesis catalyzed by the RT is described and the
      mechanism of inhibition of catalysis and termination of DNA synthesis by NRTIs is
      detailed. The individual steps in the catalytic cycle and the effects that the
      NRTIs have on them have been examined using transient kinetic analysis. The
      impact of stereoisomerism and resistance mutations on the rate of NRTI
      triphosphate incorporation (k(pol)), binding in the catalytic complex (K(d)) and
      the overall efficiency of incorporation (k(pol)/K(d)) are summarized for
      lamivudine, coviracil and zalcitabine. The results provide insight into the
      molecular forces and structural features that make these molecules effective
      inhibitors.

PMID- 15193138
TI  - Recent advances in the development of next generation non-nucleoside reverse
      transcriptase inhibitors.
AB  - Since their discovery, non-nucleoside reverse transcriptase inhibitors (NNRTIs)
      have become one of the cornerstones of highly active anti-retroviral therapy
      (HAART). Currently, three NNRTI agents, efavirenz, nevirapine and delavirdine are
      commercially available. Efavirenz and nevirapine, used in combination with
      nucleoside reverse transcriptase inhibitors (NRTIs), provide durable regimens
      with efficacy comparable to protease inhibitor (PI) containing therapies. When
      virological failure occurs following treatment with an NNRTI, the resistance
      mutations can confer reduced sensitivity to the entire agent class. Therefore,
      the strategy for the development of next generation NNRTIs has been to focus on
      compounds which have improved potencies against the clinically relevant viral
      mutants. Agents with improved virological profiles and which maintain the ease of
      administration and favorable safety profiles of the current agents should find
      use in anti-retroviral naive patients as well as in components of salvage
      regimens in the anti-retroviral experienced patient. This review summarizes the
      recent developments with compounds in clinical trials as of January 2002 as well
      as to summarize information on new agents appearing in the primary and patent
      literature between January 2001 and December 2002.

PMID- 15193139
TI  - HIV-1 integrase inhibitors: a decade of research and two drugs in clinical trial.
AB  - AIDS is currently treated with a combination therapy of reverse transcriptase and
      protease inhibitors. Recently, the FDA approved a drug targeting HIV-1 entry into
      cells. There are currently no FDA approved drugs targeting HIV-1 integrase,
      though many scientists and drug companies are actively in pursuit of clinically
      useful integrase inhibitors. The objective of this review is to provide an update
      on integrase inhibitors reported in the last two years, including two novel
      inhibitors in early clinical trials, recently developed hydroxylated aromatics,
      natural products, peptide, antibody and oligonucleotide inhibitors. Additionally,
      the proposed mechanism of diketo acid inhibition is reviewed.

PMID- 15193140
TI  - Peptidomimetic inhibitors of HIV protease.
AB  - There are currently (July, 2002) six protease inhibitors approved for the
      treatment of HIV infection, each of which can be classified as peptidomimetic in
      structure. These agents, when used in combination with other antiretroviral
      agents, produce a sustained decrease in viral load, often to levels below the
      limits of quantifiable detection, and a significant reconstitution of the immune
      system. Therapeutic regimens containing one or more HIV protease inhibitors thus
      provide a highly effective method for disease management. The important role of
      protease inhibitors in HIV therapy, combined with numerous challenges remaining
      in HIV treatment, have resulted in a continued effort both to optimize regimens
      using the existing agents and to identify new protease inhibitors that may
      provide unique properties. This review will provide an overview of the discovery
      and clinical trials of the currently approved HIV protease inhibitors, followed
      by an examination of important aspects of therapy, such as pharmacokinetic
      enhancement, resistance and side effects. A description of new peptidomimetic
      compounds currently being investigated in the clinic and in preclinical discovery
      will follow.

PMID- 15193141
TI  - Non-peptidic HIV protease inhibitors.
AB  - The past decade has seen many exciting achievements and advances in the treatment
      of HIV infection. One of the key components in this ever-evolving remedial
      strategy has been medicinally efficacious enzymatic inhibitors targeting the
      essential viral aspartyl protease. While the use of currently approved HIV
      protease inhibitors in concert with drugs that target the reverse transcriptase
      has dramatically ameliorated the disease state for many individuals, highly
      structured dosing regimens accompanied by adverse side-effect profiles have led
      to a significant level of patient non-compliance. In addition, the development of
      and selection for resistant mutants have limited the long-term therapeutic
      outlook of the current protease inhibitors. The need for complementary agents in
      this salutary class addressing these challenges and opportunities is vividly
      clear. To this end, much attention and focus has been placed on cyclic, non
      peptidic protease inhibitors, exemplified by dihydropyrones and ureas, and their
      possible future role in this medicinal campaign. The strategies to their design
      as well as their biological, pharmacokinetic and resistance profiles, and their
      clinical application will be discussed.

PMID- 15193143
TI  - Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase
      control the balance between retinol storage and degradation.
AB  - Vitamin A homoeostasis requires the gene encoding cellular retinol-binding
      protein-1 (Crbp1) which stimulates conversion of retinol into retinyl esters that
      serve as a storage form of vitamin A. The gene encoding alcohol dehydrogenase-1
      (Adh1) greatly facilitates degradative metabolism of excess retinol into retinoic
      acid to protect against toxic effects of high dietary vitamin A. Crbp1-/-/Adh1-/-
      double mutant mice were generated to explore whether the stimulatory effect of
      CRBP1 on retinyl ester formation is due to limitation of retinol oxidation by
      ADH1, and whether ADH1 limits retinyl ester formation by opposing CRBP1. Compared
      with wild-type mice, liver retinyl ester levels were greatly reduced in Crbp1-/-
      mice, but Adh1-/- mice exhibited a significant increase in liver retinyl esters.
      Importantly, relatively normal liver retinyl ester levels were restored in Crbp1
      /-/Adh1-/- mice. During vitamin A deficiency, the additional loss of Adh1
      completely prevented the excessive loss of liver retinyl esters observed in Crbp1
      /- mice for the first 5 weeks of deficiency and greatly minimized this loss for
      up to 13 weeks. Crbp1-/- mice also exhibited increased metabolism of a dose of
      retinol into retinoic acid, and this increased metabolism was not observed in
      Crbp1-/-/Adh1-/- mice. Our findings suggest that opposing actions of CRBP1 and
      ADH1 enable a large fraction of liver retinol to remain esterified due to CRBP1
      action, while continuously allowing some retinol to be oxidized to retinoic acid
      by ADH1 for degradative retinoid turnover under any dietary vitamin A conditions.

PMID- 15193142
TI  - PTEN function: how normal cells control it and tumour cells lose it.
AB  - The PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour
      suppressor is a PI (phosphoinositide) 3-phosphatase that can inhibit cellular
      proliferation, survival and growth by inactivating PI 3-kinase-dependent
      signalling. It also suppresses cellular motility through mechanisms that may be
      partially independent of phosphatase activity. PTEN is one of the most commonly
      lost tumour suppressors in human cancer, and its deregulation is also implicated
      in several other diseases. Here we discuss recent developments in our
      understanding of how the cellular activity of PTEN is regulated, and the closely
      related question of how this activity is lost in tumours. Cellular PTEN function
      appears to be regulated by controlling both the expression of the enzyme and also
      its activity through mechanisms including oxidation and phosphorylation-based
      control of non-substrate membrane binding. Therefore mutation of PTEN in tumours
      disrupts not only the catalytic function of PTEN, but also its regulatory
      aspects. However, although mutation of PTEN is uncommon in many human tumour
      types, loss of PTEN expression seems to be more frequent. It is currently unclear
      how these tumours lose PTEN expression in the absence of mutation, and while some
      data implicate other potential tumour suppressors and oncogenes in this process,
      this area seems likely to be a key focus of future research.

PMID- 15193145
TI  - Metabolic cleavage of cell-penetrating peptides in contact with epithelial
      models: human calcitonin (hCT)-derived peptides, Tat(47-57) and penetratin(43
      58).
AB  - We assessed the metabolic degradation kinetics and cleavage patterns of some
      selected CPP (cell-penetrating peptides) after incubation with confluent
      epithelial models. Synthesis of N-terminal CF [5(6)-carboxyfluorescein]-labelled
      CPP, namely hCT (human calcitonin)-derived sequences, Tat(47-57) and
      penetratin(43-58), was through Fmoc (fluoren-9-ylmethoxycarbonyl) chemistry.
      Metabolic degradation kinetics of the tested CPP in contact with three cell
      cultured epithelial models, MDCK (Madin-Darby canine kidney), Calu-3 and TR146,
      was evaluated by reversed-phase HPLC. Identification of the resulting metabolites
      of CF-hCT(9-32) was through reversed-phase HPLC fractionation and peak allocation
      by MALDI-TOF-MS (matrix-assisted laser-desorption ionization-time-of-flight mass
      spectrometry) or direct MALDI-TOF-MS of incubates. Levels of proteolytic activity
      varied highly between the investigated epithelial models and the CPP. The Calu-3
      model exhibited the highest proteolytic activity. The patterns of metabolic
      cleavage of hCT(9-32) were similar in all three models. Initial cleavage of this
      peptide occurred at the N-terminal domain, possibly by endopeptidase activity
      yielding both the N- and the C-terminal counterparts. Further metabolic
      degradation was by aminopeptidase, endopeptidase and/or carboxypeptidase
      activities. In conclusion, when in contact with epithelial models, the studied
      CPP were subject to efficient metabolism, a prerequisite of cargo release on the
      one hand, but with potential for premature cleavage and loss of the cargo as well
      on the other. The results, particularly on hCT(9-32), may be used as a template
      to suggest structural modifications towards improved CPP performance.

PMID- 15193144
TI  - DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated
      transcription regulation of the circadian gene mPer1.
AB  - DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding
      transcription factors and exhibit a circadian expression pattern. Recently, both
      proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g.
      mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It
      was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved
      by binding to E-box elements and interacting with Bmal1. In the present study, we
      report that E-box binding rather than Bmal1 interaction is responsible for the
      observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly
      repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no
      repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed
      the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant
      with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the
      Clock/Bmal1-induced activation, providing direct evidence that DNA binding,
      rather than Bmal1 interactions, is responsible for the repression on the mPer1
      promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of
      mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2
      showed that this factor interacts with Sp1. These findings suggest that DEC
      proteins regulate the expression of mPer1 through E-box binding and Sp1
      interaction. Alterations on circadian systems are increasingly recognized as
      important risk factors for disease initiation and progression, and the expression
      of Dec genes is rapidly induced by environmental stimuli and is highly increased
      in tumour tissues. Therefore de-regulated expression of DEC genes probably alters
      normal circadian rhythms and contributes significantly to the pathogenesis of
      many diseases including cancer.

PMID- 15193146
TI  - Delta-catenin/NPRAP (neural plakophilin-related armadillo repeat protein)
      interacts with and activates sphingosine kinase 1.
AB  - Sphingosine kinase (SPHK) is a key enzyme catalysing the formation of sphingosine
      1-phosphate (SPP), a lipid messenger that is implicated in the regulation of a
      wide variety of important cellular events acting through intracellular, as well
      as extracellular, mechanisms. However, the molecular mechanism of intracellular
      actions of SPP remains unclear. Here, we have identified delta-catenin/NPRAP
      (neural plakophilin-related armadillo repeat protein) as a potential binding
      partner for SPHK1 by yeast two-hybrid screening. From co-immunoprecipitation
      analyses, the C-terminal portion of delta-catenin/NPRAP containing the seventh to
      tenth armadillo repeats was found to be required for interaction with SPHK1.
      Endogenous delta-catenin/NPRAP was co-localized with endogenous SPHK1 and
      transfected delta-catenin/NPRAP was co-localized with transfected SPHK1 in
      dissociated rat hippocampal neurons. MDCK (Madin-Darby canine kidney) cells
      stably expressing delta-catenin/NPRAP contained elevated levels of intracellular
      SPP. In a purified system delta-catenin/NPRAP stimulated SPHK1 in a dose
      dependent manner. Furthermore, delta-catenin/NPRAP-induced increased cell
      motility in MDCK cells was completely inhibited by dimethylsphingosine, a
      specific inhibitor of SPHK1. These results strongly suggest that at least some of
      delta-catenin/NPRAP functions, including increased cell motility, are mediated by
      an SPHK-SPP signalling pathway.

PMID- 15193147
TI  - Intracellular ceramide synthesis and protein kinase Czeta activation play an
      essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle
      cells.
AB  - Non-esterified fatty acids (NEFAs) have been implicated in the pathogenesis of
      skeletal muscle insulin resistance that may develop, in part, as a consequence of
      a direct inhibitory effect on early insulin signalling events. Here we report
      work investigating the mechanism by which palmitate (a saturated free fatty acid)
      inhibits insulin action in rat L6 myotubes. Palmitate suppressed the insulin
      induced plasma membrane recruitment and phosphorylation of protein kinase B (PKB)
      and this was associated with a loss in insulin-stimulated glucose transport. The
      inhibition in PKB was not due to a loss in insulin receptor substrate (IRS)1
      tyrosine phosphorylation, IRS-1/p85 (phosphoinositide 3-kinase) association or
      suppression in phosphatidyl 3,4,5 triphosphate synthesis, but was attributable to
      an elevated intracellular synthesis of ceramide (6-fold) from palmitate and a
      concomitant activation of protein kinase PKCzeta (5-fold). Inhibitors of serine
      palmitoyl transferase suppressed the intracellular synthesis of ceramide from
      palmitate, prevented PKCzeta activation, and antagonized the inhibition in PKB
      recruitment/phosphorylation and the loss in insulin-stimulated glucose transport
      elicited by the NEFA. Inhibiting the palmitate-induced activation of PKCzeta with
      Ro 31.8220, also prevented the loss in the insulin-dependent phosphorylation of
      PKB caused by palmitate. These findings indicate that intracellular ceramide
      synthesis and PKCzeta activation are important aspects of the mechanism by which
      palmitate desensitizes L6 muscle cells to insulin.

PMID- 15193148
TI  - Identification of phospholipase B from Dictyostelium discoideum reveals a new
      lipase family present in mammals, flies and nematodes, but not yeast.
AB  - The social amoeba Dictyostelium discoideum exhibits high activities of
      phospholipase and lysophospholipase [Ferber, Munder, Fischer and Gerisch (1970)
      Eur. J. Biochem. 14, 253-257]. We assayed Dictyostelium lysates to demonstrate
      the presence of a highly active phospholipase B (PLB) enzyme that removed both
      fatty-acid chains from phosphatidylcholine and produced the water-soluble
      glycerophosphorylcholine. We purified the PLB activity from Dictyostelium cytosol
      using standard agarose media (size exclusion and ion exchange), and combined this
      with an affinity purification step using myristoylated ARF1 (ADP-ribosylation
      factor 1), a protein which has a single fatty acid at its N-terminus. Two
      proteins co-purified (48 kDa and 65 kDa), and the 48 kDa protein was digested
      with trypsin, peptide fragments were separated by reverse-phase chromatography,
      and the resultant peptides were sequenced by Edman degradation. From the peptide
      sequences obtained, database searches revealed a gene which encodes a protein of
      65 kDa with unknown function. The 48 kDa protein therefore appears to be a
      fragment of the full-length 65 kDa product. Expression of the gene in Escherichia
      coli confirmed that it encodes a PLB. Characterization of its substrate
      specificity indicated that, in addition to phosphatidylcholine deacylation, the
      enzyme also hydrolysed phosphatidylinositol and phosphatidylethanolamine. The PLB
      identified in the present study is not related to existing PLBs found in
      bacteria, fungi or mammals. There are, however, genes similar to Dictyostelium
      PLB in mammals, flies, worms and Giardia, but not in yeast. We therefore have
      identified a novel family of intracellular PLBs.

PMID- 15193149
TI  - Polarized fibronectin secretion induced by adenosine regulates bacterial
      epithelial interaction in human intestinal epithelial cells.
AB  - Fibronectin (FN) is a multifunctional protein that plays important roles in many
      biological processes including cell adhesion and migration, wound healing and
      inflammation. Cellular FNs are produced by a wide variety of cell types including
      epithelial cells, which secrete them and often organize them into extensive
      extracellular matrices at their basal surface. However, regulation of FN
      synthesis and the polarity of FN secretion by intestinal epithelial cells have
      not been investigated. In the present study we investigated the role of
      adenosine, whose levels are up-regulated during inflammation, in modulating FN
      synthesis, the polarity of FN secretion and the downstream effects of the
      secreted FN. Polarized monolayers of T84 cells were used as an intestinal
      epithelial model. Adenosine added to either the apical or basolateral aspect of
      the cells led to a time- and dose-dependent accumulation of FN in the culture
      supernatants, polarized to the apical compartment and reached maximal levels 24 h
      after apical or basolateral addition of adenosine. Confocal microscopy confirmed
      that FN localized to the apical domain of model intestinal epithelial cells
      stimulated with apical or basolateral adenosine. The induction of FN was
      significantly down-regulated in response to the adenosine receptor antagonist
      alloxazine and was inhibited by cycloheximide. Moreover, adenosine increased FN
      promoter activity (3.5-fold compared with unstimulated controls) indicating that
      FN induction is, in part, transcriptionally regulated. Interestingly, we
      demonstrated that adenosine, as well as apical FN, significantly enhanced the
      adherence and invasion of Salmonella typhimurium into cultured epithelial cells.
      In summary, we have shown for the first time that FN, a classic extracellular
      matrix protein, is secreted into the apical compartment of epithelial cells in
      response to adenosine. FN may be a critical host factor that modulates adherence
      and invasion of bacteria, thus playing a key role in mucosal immune responses
      during inflammation.

PMID- 15193150
TI  - Noradrenaline represses PPAR (peroxisome-proliferator-activated receptor) gamma2
      gene expression in brown adipocytes: intracellular signalling and effects on
      PPARgamma2 and PPARgamma1 protein levels.
AB  - PPAR (peroxisome-proliferator-activated receptor) gamma is expressed in brown and
      white adipose tissues and is involved in the control of differentiation and
      proliferation. Noradrenaline stimulates brown pre-adipocyte proliferation and
      brown adipocyte differentiation. The aim of the present study was thus to
      investigate the influence of noradrenaline on PPARgamma gene expression in brown
      adipocytes. In primary cultures of brown adipocytes, PPARgamma2 mRNA levels were
      20-fold higher than PPARgamma1 mRNA levels. PPARgamma expression occurred during
      both the proliferation and the differentiation phases, with the highest mRNA
      levels being found at the time of transition between the phases. PPARgamma2 mRNA
      levels were downregulated by noradrenaline treatment (EC50, 0.1 microM) in both
      proliferative and differentiating cells, with a lagtime of 1 h and lasting up to
      4 h, after which expression gradually recovered. The down-regulation was beta
      adrenoceptor-induced and intracellularly mediated via cAMP and protein kinase A;
      the signalling pathway did not involve phosphoinositide 3-kinase, Src, p38
      mitogen-activated protein kinase or extracellular-signal-regulated kinases 1 and
      2. Treatment of the cells with the protein synthesis inhibitor cycloheximide not
      only abolished the noradrenaline-induced down-regulation of PPARgamma2 mRNA, but
      also in itself induced PPARgamma2 hyperexpression. The down-regulation was
      probably the result of suppression of transcription. The down-regulation of
      PPARgamma2 mRNA resulted in similar down-regulation of PPARgamma2 and
      phosphoPPARgamma2 protein levels. Remarkably, the level of PPARgamma1 protein was
      similar to that of PPARgamma2 (despite almost no PPARgamma1 mRNA), and the down
      regulation by noradrenaline demonstrated similar kinetics to that of PPARgamma2;
      thus PPARgamma1 was apparently translated from the PPARgamma2 template. It is
      suggested that beta-adrenergic stimulation via cAMP and protein kinase A
      represses PPARgamma gene expression, leading to reduction of PPARgamma2 mRNA
      levels, which is then reflected in down-regulated levels of PPARgamma2,
      phosphoPPARgamma2 and PPARgamma1.

PMID- 15193151
TI  - Phase I clinical study of anti-apoptosis protein, survivin-derived peptide
      vaccine therapy for patients with advanced or recurrent colorectal cancer.
AB  - Survivin is a member of the inhibitor of apoptosis protein (IAP) family
      containing a single baculovirus IAP repeat domain. It is expressed during fetal
      development but becomes undetectable in terminally differentiated normal adult
      tissues. We previously reported that survivin and its splicing variant survivin
      2B was expressed abundantly in various types of tumor tissues as well as tumor
      cell lines and was suitable as a target antigen for active-specific anti-cancer
      immunization. Subsequently, we identified an HLA-A24-restricted antigenic
      peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes
      (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of
      survivin-2B peptide vaccination in patients with advanced or recurrent colorectal
      cancer expressing survivin. Vaccinations with survivin-2B peptide were given
      subcutaneously six times at 14-day intervals. Of 15 patients who finished
      receiving the vaccination schedule, three suffered slight toxicities, including
      anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe
      adverse events were observed in any patient. In 6 patients, tumor marker levels
      (CEA and CA19-9) decreased transiently during the period of vaccination. Slight
      reduction of the tumor volume was observed in one patient, which was considered a
      minor responder. No changes were noted in three patients while the remaining
      eleven patients experienced tumor progression. Analysis of peripheral blood
      lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase
      in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4
      vaccinations. This phase I clinical study indicates that survivin-2B peptide
      based vaccination is safe and should be further considered for potential immune
      and clinical efficacy in HLA-A24-expression patients with colorectal cancer.

PMID- 15193152
TI  - Highlights on endoglin (CD105): from basic findings towards clinical applications
      in human cancer.
AB  - Antibody targeting of tumor-associated vasculature is a promising therapeutic
      approach in human cancer; however, a specific cell membrane marker for
      endothelial cells of tumor vasculature has not been discovered yet. Endoglin
      (CD105) is a cell-surface glycoprotein most recently identified as an optimal
      indicator of proliferation of human endothelial cells. The finding that CD105 is
      over-expressed on vascular endothelium in angiogenetic tissues has prompted
      several pre-clinical studies designed to get a deeper understanding on the role
      of CD105 in angiogenesis, and to evaluate the most appropriate clinical
      setting(s) to utilize CD105 as a therapeutic target. In this review, the
      foreseeable clinical applications of CD105 in human cancer are discussed.

PMID- 15193153
TI  - The recombinant adeno-associated virus vector (rAAV2)-mediated apolipoprotein B
      mRNA-specific hammerhead ribozyme: a self-complementary AAV2 vector improves the
      gene expression.
AB  - BACKGROUND: In humans, overproduction of apolipoprotein B (apoB) is positively
      associated with premature coronary artery diseases. To reduce the levels of apoB
      mRNA, we have designed an apoB mRNA-specific hammerhead ribozyme targeted at
      nucleotide sequences GUA6679 (RB15) mediated by adenovirus, which efficiently
      cleaves and decreases apoB mRNA by 80% in mouse liver and attenuates the
      hyperlipidemic condition. In the current study, we used an adeno-associated virus
      vector, serotype 2 (AAV2) and a self-complementary AAV2 vector (scAAV2) to
      demonstrate the effect of long-term tissue-specific gene expression of RB15 on
      the regulation apoB mRNA in vivo. METHODS: We constructed a hammerhead ribozyme
      RB15 driven by a liver-specific transthyretin (TTR) promoter using an AAV2 vector
      (rAAV2-TTR-RB15). HepG2 cells and hyperlipidemic mice deficient in both the low
      density lipoprotein receptor and the apoB mRNA editing enzyme genes (LDLR-/
      Apobec1-/-; LDb) were transduced with rAAV2-TTR-RB15 and a control vector rAAV
      TTR-RB15-mutant (inactive ribozyme). The effects of ribozyme RB15 on apoB
      metabolism and atherosclerosis development were determined in LDb mice at 5-month
      after transduction. A self-complementary AAV2 vector expressing ribozyme RB15
      (scAAV2-TTR-RB15) was also engineered and used to transduce HepG2 cells. Studies
      were designed to compare the gene expression efficiency between rAAV2-TTR-RB15
      and scAAV2-TTR-RB15. RESULTS: The effect of ribozyme RB15 RNA on reducing apoB
      mRNA levels in HepG2 cells was observed only on day-7 after rAAV2-TTR-RB15
      transduction. And, at 5-month after rAAV2-TTR-RB15 treatment, the apoB mRNA
      levels in LDb mice were significantly decreased by 43%, compared to LDb mice
      treated with control vector rAAV2-TTR-RB15-mutant. Moreover, both the rAAV2-TTR
      RB15 viral DNA and ribozyme RB15 RNA were still detectable in mice livers at 5
      month after treatment. However, this rAAV2-TTR-RB15 vector mediated a prolonged
      but low level of ribozyme RB15 gene expression in the mice livers, which did not
      produce the therapeutic effects on alteration the lipid levels or the inhibition
      of atherosclerosis development. In contrast, the ribozyme RB15 RNA mediated by
      scAAV2-TTR-RB15 vector was expressed immediately at day-1 after transduction in
      HepG2 cells. The apoB mRNA levels were decreased 47% (p = 0.001), compared to the
      control vector scAAV2-TTR-RB15-mutant. CONCLUSION: This study provided evidence
      that the rAAV2 single-strand vector mediated a prolonged but not efficient
      transduction in mouse liver. However, the scAAV2 double-strand vector mediated a
      rapid and efficient gene expression in liver cells. This strategy using scAAV2
      vectors represents a better approach to express small molecules such as ribozyme.

PMID- 15193154
TI  - Altered expression of hypothetical proteins in hippocampus of transgenic mice
      overexpressing human Cu/Zn-superoxide dismutase 1.
AB  - BACKGROUND: Cu/Zn-superoxide dismutase 1 (SOD1), encoded on chromosome 21, is a
      key enzyme in the metabolism of reactive oxygen species (ROS) and
      pathogenetically relevant for several disease states including Down syndrome (DS;
      trisomy 21). Systematically studying protein expression in human brain and animal
      models of DS we decided to carry out "protein hunting" for hypothetical proteins,
      i.e. proteins that have been predicted based upon nucleic sequences only, in a
      transgenic mouse model overexpressing human SOD1. RESULTS: We applied a
      proteomics approach using two-dimensional electrophoresis (2-DE) with in-gel
      digestion of spots followed by mass spectrometric (matrix-assisted laser
      desorption/ionization-time of flight) identification and quantification of
      hypothetical proteins using specific software. Hippocampi of wild type,
      hemizygous and homozygous SOD1 transgenic mice (SOD1-TGs) were analysed.We
      identified fourteen hypothetical proteins in mouse hippocampus. Of these,
      expression levels of 2610008O03Rik protein (Q9D0K2) and 4632432E04Rik protein
      (Q9D358) were significantly decreased (P < 0.05 and 0.001) and hypothetical
      protein (Q99KP6) was significantly increased (P < 0.05) in hippocampus of SOD1
      TGs as compared with non-transgenic mice. CONCLUSIONS: The biological meaning of
      aberrant expression of these proteins may be impairment of metabolism, signaling
      and transcription machinery in SOD1-TGs brain that in turn may help to explain
      deterioration of these systems in DS brain.

PMID- 15193155
TI  - Deteriorating health satisfaction among immigrants from Eastern Europe to
      Germany.
AB  - BACKGROUND: Migrants from Eastern Europe constitute more than 5% of Germany's
      population. Since population health in their countries of origin is poor their
      health status upon arrival may be worse than that of the native-born German
      population (hypothesis H1). As a minority, they may be socio-economically
      disadvantaged (H2), and their health status may deteriorate quickly (H3).
      METHODS: We compared data from 1995 and 2000 for immigrants from Eastern Europe
      (n = 353) and a random sample of age-matched Germans (n = 2, 824) from the German
      Socioeconomic Panel. We tested H1-3 using health satisfaction, as a proxy for
      health status, and socioeconomic indicators. We compared changes over time within
      groups, and between immigrants and Germans. We assessed effects of socio-economic
      status and being a migrant on declining health satisfaction in a regression
      model. RESULTS: In 1995, immigrants under 55 years had a significantly higher
      health satisfaction than Germans. Above age 54, health satisfaction did not
      differ. By 2000, immigrants' health satisfaction had declined to German levels.
      Whereas in 1995 immigrants had a significantly lower SES, differences five years
      later had declined. In the regression model, immigrant status was much stronger
      associated with declining health satisfaction than low SES. CONCLUSION: In
      contrast to H1, younger immigrants had an initial health advantage. Immigrants
      were initially socio-economically disadvantaged (H2), but their SES improved over
      time. The decrease in health satisfaction was much steeper in immigrants and this
      was not associated with differences in SES (H3). Immigrants from Eastern Europe
      have a high risk of deteriorating health, in spite of socio-economic
      improvements.

PMID- 15193156
TI  - Homology building as a means to define antigenic epitopes on dihydrofolate
      reductase (DHFR) from Plasmodium falciparum.
AB  - BACKGROUND: The aim of this study was to develop site-specific antibodies as a
      tool to capture Plasmodium falciparum-dihydrofolate reductase (Pf-DHFR) from
      blood samples from P. falciparum infected individuals in order to detect, in a
      sandwich ELISA, structural alterations due to point mutations in the gene coding
      for Pf-DHFR. Furthermore, we wanted to study the potential use of homology models
      in general and of Pf-DHFR in particular in predicting antigenic malarial surface
      epitopes. METHODS: A homology model of Pf-DHFR domain was employed to define an
      epitope for the development of site-specific antibodies against Pf-DHFR. The
      homology model suggested an exposed loop encompassing amino acid residues 64-100.
      A synthetic peptide of 37-mers whose sequence corresponded to the sequence of
      amino acid residues 64-100 of Pf-DHFR was synthesized and used to immunize mice
      for antibodies. Additionally, polyclonal antibodies recognizing a recombinant
      DHFR enzyme were produced in rabbits. RESULTS AND CONCLUSIONS: Serum from mice
      immunized with the 37-mer showed strong reactivity against both the immunizing
      peptide, recombinant DHFR and a preparation of crude antigen from P. falciparum
      infected red blood cells. Five monoclonal antibodies were obtained, one of which
      showed reactivity towards crude antigen prepared from P. falciparum infected red
      cells. Western blot analysis revealed that both the polyclonal and monoclonal
      antibodies recognized Pf-DHFR. Our study provides insight into the potential use
      of homology models in general and of Pf-DHFR in particular in predicting
      antigenic malarial surface epitopes.

PMID- 15193157
TI  - Availability and structure of primary medical care services and population health
      and health care indicators in England.
AB  - BACKGROUND: It has been proposed that greater availability of primary medical
      care practitioners (GPs) contributes to better population health. We evaluated
      whether measures of the supply and structure of primary medical services are
      associated with health and health care indicators after adjusting for
      confounding. METHODS: Data for the supply and structure of primary medical
      services and the characteristics of registered patients were analysed for 99
      health authorities in England in 1999. Health and health care indicators as
      dependent variables included standardised mortality ratios (SMR), standardised
      hospital admission rates, and conceptions under the age of 18 years. Linear
      regression analyses were adjusted for Townsend score, proportion of ethnic
      minorities and proportion of social class IV/ V. RESULTS: Higher proportions of
      registered rural patients and patients >/= 75 years were associated with lower
      Townsend deprivation scores, with larger partnership sizes and with better health
      outcomes. A unit increase in partnership size was associated with a 4.2 (95%
      confidence interval 1.7 to 6.7) unit decrease in SMR for all-cause mortality at
      15-64 years (P = 0.001). A 10% increase in single-handed practices was associated
      with a 1.5 (0.2 to 2.9) unit increase in SMR (P = 0.027). After additional
      adjustment for percent of rural and elderly patients, partnership size and
      proportion of single-handed practices, GP supply was not associated with SMR (
      2.8, -6.9 to 1.3, P = 0.183). CONCLUSIONS: After adjusting for confounding with
      health needs of populations, mortality is weakly associated with the degree of
      organisation of practices as represented by the partnership size but not with the
      supply of GPs.

PMID- 15193158
TI  - Nutrient-stimulated insulin secretion in mouse islets is critically dependent on
      intracellular pH.
AB  - BACKGROUND: Many mechanistic steps underlying nutrient-stimulated insulin
      secretion (NSIS) are poorly understood. The influence of intracellular pH (pHi)
      on insulin secretion is widely documented, and can be used as an investigative
      tool. This study demonstrates previously unknown effects of pHi-alteration on
      insulin secretion in mouse islets, which may be utilized to correct defects in
      insulin secretion. METHODS: Different components of insulin secretion in mouse
      islets were monitored in the presence and absence of forced changes in pHi. The
      parameters measured included time-dependent potentiation of insulin secretion by
      glucose, and direct insulin secretion by different mitochondrial and non
      mitochondrial secretagogues. Islet pHi was altered using amiloride, removal of
      medium Cl-, and changing medium pH. Resulting changes in islet pHi were monitored
      by confocal microscopy using a pH-sensitive fluorescent indicator. To investigate
      the underlying mechanisms of the effects of pHi-alteration, cellular NAD(P)H
      levels were measured using two-photon excitation microscopy (TPEM). Data were
      analyzed using Student's t test. RESULTS: Time-dependent potentiation, a function
      normally absent in mouse islets, can be unmasked by a forced decrease in pHi. The
      optimal range of pHi for NSIS is 6.4-6.8. Bringing islet pHi to this range
      enhances insulin secretion by all mitochondrial fuels tested, reverses the
      inhibition of glucose-stimulated insulin secretion (GSIS) by mitochondrial
      inhibitors, and is associated with increased levels of cellular NAD(P)H.
      CONCLUSIONS: Pharmacological alteration of pHi is a potential means to correct
      the secretory defect in non-insulin dependent diabetes mellitus (NIDDM), since
      forcing islet pHi to the optimal range enhances NSIS and induces secretory
      functions that are normally absent.

PMID- 15193159
TI  - Factors associated with in-hospital mortality following intracerebral hemorrhage:
      a three-year study in Tehran, Iran.
AB  - BACKGROUND: Primary intracerebral hemorrhage (ICH) is one of the common vascular
      insults with a relatively high rate of mortality. The aim of the current study
      was to determine the mortality rate and to evaluate the influence of various
      factors on the mortality of patients with intracerebral hemorrhage (ICH).
      Demographic characteristics along with clinical features and neuroimaging
      information on 122 patients with primary ICH admitted to Sina Hospital between
      1999-2002 were assessed by multivariate analysis. RESULTS: Of 122 patients
      diagnosed with intracerebral hemorrhage, 70 were men and 52 were women. Sixty
      nine percent of subjects were between 60 to 80 years of age. A history of
      hypertension was the primary cause in 67.2% of participants and it was found more
      frequent compared to other cardiovascular risk factors such as a history of
      ischemic heart disease (17.2%), diabetes mellitus (18%) and cigarette smoking
      (13.1%). The overall mortality rate among ICH patients admitted to the hospital
      was 46.7%. About one third of the deaths occurred within the first two days after
      brain injury. Factor independently associated with in-hospital mortality were
      Glasgow Coma Scale (GCS) score (</= 8), diabetes mellitus disease, volume of
      hematoma and and intraventricular hematoma. CONCLUSION: Higher rate of mortality
      were observed during the first two weeks of hospitalization following ICH.
      Neuroimaging features along with GCS score can help the clinicians in developing
      their prognosis.

PMID- 15193160
TI  - Smoking behaviour, knowledge and attitudes among Family Medicine physicians and
      nurses in Bosnia and Herzegovina.
AB  - BACKGROUND: Smoking rates among the general population in Bosnia and Herzegovina
      are extremely high, and national campaigns to lower smoking rates have not yet
      begun. As part of future activities of the Queen's University Family Medicine
      Development Program in the Balkans Region, technical assistance may be provided
      to Bosnia and Herzegovina to develop of national tobacco control strategies. This
      assistance may focus on training doctors and nurses on smoking cessation
      strategies with a view to helping their patients to stop smoking. Given this
      important role that health professionals have, data is needed on smoking rates as
      well as on smoking behaviour among doctors and nurses in Bosnia and Herzegovina.
      This study therefore seeks to determine the smoking rates and behaviour of family
      medicine physicians and nurses in Bosnia and Herzegovina and to determine how
      well prepared they feel with respect to counselling their patients on smoking
      cessation strategies. METHODS: The WHO Global Health Professional Survey, a self
      administered questionnaire, was distributed to physicians and nurses in 19 Family
      Medicine Teaching Centres in Bosnia and Herzegovina in June 2002. Smoking rates
      and behaviour, as well as information on knowledge and attitudes regarding
      smoking were determined for both physicians and nurses. RESULTS: Of the 273
      physicians and nurses currently working in Family Medicine Teaching Centres, 209
      (77%) completed the questionnaire. Approximately 45% of those surveyed currently
      smoke, where 51% of nurses smoked, compared to 40% of physicians. With respect to
      knowledge and attitudes, all respondents agreed that smoking is harmful to one's
      health. However, "ever" smokers, compared to "never" smokers, were less likely to
      agree that health professionals who smoke were less likely to advise patients to
      quit smoking than non-smoking health professionals. Less than half of physicians
      and nurses had received formal training in smoking cessations strategies, but
      about two thirds of health professionals felt very or somewhat prepared to
      counsel their patients on how to quit smoking. CONCLUSIONS: Our study indicates
      that almost half of Family Medicine health professionals in Bosnia and
      Herzegovina are smokers. This indicates a severe public health problem throughout
      the country. Steps need to be taken at a national level to address the fight
      against tobacco.

PMID- 15193161
TI  - The phosphatidylserine receptor from Hydra is a nuclear protein with potential
      Fe(II) dependent oxygenase activity.
AB  - BACKGROUND: Apoptotic cell death plays an essential part in embryogenesis,
      development and maintenance of tissue homeostasis in metazoan animals. The
      culmination of apoptosis in vivo is the phagocytosis of cellular corpses. One
      morphological characteristic of cells undergoing apoptosis is loss of plasma
      membrane phospholipid asymmetry and exposure of phosphatidylserine on the outer
      leaflet. Surface exposure of phosphatidylserine is recognised by a specific
      receptor (phosphatidylserine receptor, PSR) and is required for phagocytosis of
      apoptotic cells by macrophages and fibroblasts. RESULTS: We have cloned the PSR
      receptor from Hydra in order to investigate its function in this early metazoan.
      Bioinformatic analysis of the Hydra PSR protein structure revealed the presence
      of three nuclear localisation signals, an AT-hook like DNA binding motif and a
      putative 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase activity. All of
      these features are conserved from human PSR to Hydra PSR. Expression of GFP
      tagged Hydra PSR in hydra cells revealed clear nuclear localisation. Deletion of
      one of the three NLS sequences strongly diminished nuclear localisation of the
      protein. Membrane localisation was never detected. CONCLUSIONS: Our results
      suggest that Hydra PSR is a nuclear 2-oxoglutarate (2OG)-and Fe(II)-dependent
      oxygenase. This is in contrast with the proposed function of Hydra PSR as a cell
      surface receptor involved in the recognition of apoptotic cells displaying
      phosphatidylserine on their surface. The conservation of the protein from Hydra
      to human infers that our results also apply to PSR from higher animals.

PMID- 15193162
TI  - Twin research, and its multiple births and expressions: a short, personal voyage
      through its scope, history, and organization.
AB  - The notion of twins and twinning involves a multiplicity of meanings and contexts
      that altogether encompass an unexpectedly wide and significant part of human
      experience, culture, and endeavor. This cultural polysemy is, to some extent,
      also an attribute of twin research, which has structured itself around a
      multiplicity of scientific areas of enquiry, and across time, throughout a
      multiplicity of births and rebirths, periodically declining and resurging as a
      phoenix from its ashes. What is proposed is a short voyage through this polysemy
      and phoenixity of twinning and twin research, and through the structuring process
      that has accompanied its developments, international scope, and organization. No
      claim to completeness, but an attempt to dig into personal memory and experience,
      and share some recollections of the main steps of the process, and particularly
      the evolution of the journal, the society, the international meetings, and their
      role in supporting the area's persistence and continuous revivals and adaptations
      until today.

PMID- 15193163
TI  - The danish twin registry: past and present.
AB  - The Danish Twin Registry was established formally in 1954 and thus celebrates its
      50th anniversary in 2004. Here we give an account of its founding and the early
      years, and a brief summary of more recent progress.

PMID- 15193164
TI  - Familial monozygotic twinning: report of an extended multi-generation family.
AB  - Thirteen sets of monozygotic (MZ) twins from an extended multi-generation family
      are reported. Zygosity was determined by interviewing families for overall
      physical similarity and by assessment of facial photographs. A hypothetical gene
      was traced back five generations to a common grandfather. Familial monozygotic
      twinning in this pedigree is compatible with autosomal dominant inheritance with
      reduced penetrance. Other plausible mechanisms of inheritance are discussed.

PMID- 15193165
TI  - The risk of birth defects in dichorionic twins conceived by assisted reproductive
      technology.
AB  - The purpose of this study was to examine whether dichorionic twins conceived by
      assisted reproductive technology (ART; intracytoplasmic sperm injection [ICSI],
      in vitro fertilization [IVF], gamete-intrafallopian tube transfer [GIFT]) have a
      higher risk of birth defects compared to dichorionic twins conceived naturally.
      We reviewed the medical records of 406 mothers with dichorionic twin pregnancies,
      who received continuous antenatal care from < or = 20 weeks of gestation and gave
      birth to infants after > or = 24 weeks of gestation in our institute. Birth
      defects were diagnosed at the time of hospital discharge according to the
      International Classification of Diseases, 10th Revision. Occurrence of birth
      defects was compared between twins conceived by ART and those conceived naturally
      using logistic regression analysis. Overall, 51 of 812 infants (51/812 = 6.2%)
      had birth defects. The incidence of birth defects in ART-conceived twins was
      significantly higher than that of naturally conceived twins with an odds ratio of
      6.9 (95% confidence interval [CI] 2.1, 22.5), 3.7 (95% CI 1.2, 12.0), and 4.3
      (95% CI 1.4, 14.3) for ICSI, IVF, and GIFT, respectively. The higher frequency of
      birth defects in ART-conceived twins was still significant after adjusting for
      higher maternal age in the ART group, with an adjusted odds ratio of 6.7 (95% CI
      2.1, 21.9), 3.6 (95% CI 1.1, 11.5), and 3.7 (95% CI 1.2-11.8) for ICSI, IVF, and
      GIFT, respectively. Dichorionic twins conceived by ART, compared to dichorionic
      twins conceived naturally, had a much higher risk for birth defects diagnosed at
      hospital discharge.

PMID- 15193166
TI  - Zygosity misclassification of twins at birth in Japan.
AB  - Though twinning rates have been rapidly increasing in Japan, the problem of
      zygosity misclassification at birth has been paid little attention. By analyzing
      four independent samples, the authors found that at a constant rate about 25-30%
      of monozygotic twins were misclassified as dizygotic twins at birth. This
      percentage is in very good accordance with that of monozygotic twins having
      dizygous placenta. Generally the obstetricians informed twins' parents about
      their children's zygosity. The number of placentas, as informed by obstetricians,
      was very strongly associated with zygosity. Concluding, even now many monozygotic
      twins in Japan may be misclassified as dizygotic at birth by obstetricians based
      solely on the number of placenta.

PMID- 15193167
TI  - Trends in triplet stillbirth rates in Japan, 1975-1998.
AB  - Stillbirth rates of triplet births in the whole of Japan were analyzed using
      vital statistics from 1975 to 1998. Stillbirths were registered at 12 weeks
      gestation or later. The stillbirth rate was significantly higher in like- than in
      unlike-sex triplets for 1975-1998. During the 23-year period the stillbirth rate
      decreased from 342 to 49 per 1000 total births for like-sex and from 195 to 54
      for unlike-sex triplets. The decrease in the stillbirth rate in the 23- year
      period was greater in both like- and unlike-sex triplets than in singleton and
      twin births. Risk factors for stillbirth in triplets were like-sex, youngest or
      oldest maternal age groups, shorter gestational age and lower birthweight. It is
      recommended that the optimum period to give birth for triplet pregnancies is 34
      35 weeks of gestation for Japanese women.

PMID- 15193168
TI  - Otitis media: genetic factors and sex differences.
AB  - Although genetic factors are recognised as major contributors to otitis media,
      the presence of sex differences in heritability needs clarification. The aim of
      this study was to estimate the relative contribution of genetic and environmental
      effects in otitis media liability with particular focus on sex differences. Data
      from a cohort of Norwegian twins born between 1967 and 1979 with repeated
      measures on recurrent childhood otitis media were analysed. Altogether the sample
      included 4247 twin pairs. The tetrachoric correlations for monozygotic twins were
      .71 and .65 for males and females respectively. In dizygotic twins the
      correlations were .35 and .25 for males and females, respectively, and was.34 in
      opposite sexed pairs. The contribution of genetic and environmental effects was
      analyzed using structural equation modeling. The best fitting model showed that
      additive genetic effects explained 72% and 61% of the variance in males and
      females, respectively. The remaining variance was attributed to individual
      environmental effects. A model specifying equal heritability estimates for males
      and females yielded an almost equivalent fit. We found substantial genetic
      effects for liability to otitis media. There is no evidence that different sets
      of genes influence liability in males and females, but there may be sex
      differences in the relative importance of genetic effects.

PMID- 15193169
TI  - The contribution of risk factors to blood pressure heritability estimates in
      young adults: the East flanders prospective twin study.
AB  - The heritability of blood pressure estimated in previous studies may be
      confounded by the influence of potential blood pressure risk factors. We applied
      the classical twin design to estimate the contribution of these covariates to
      blood pressure heritability. The study consisted of 173 dizygotic and 251
      monozygotic twin pairs aged 18-34 years, randomly selected from the East Flanders
      Prospective Twin Survey. In a standardized examination, blood pressure and
      anthropometry was measured, a questionnaire was completed, and a fasting blood
      sample was taken. In univariate and bivariate modeling, diastolic and systolic
      heritability were estimated both unadjusted and adjusted for potential risk
      factors. Also, covariate interaction was modeled. Bivariate analysis gave
      heritability estimates of 0.63 (95%CI 0.55-0.59), 0.74 (95%CI: 0.68-0.79), and
      0.78 (95%CI: 0.70-0.84) for diastolic, systolic, and cross-trait heritability,
      respectively. The remaining variances could be attributed to unique environmental
      influences. These heritability estimates did not change substantially in
      univariate analyses or after adjustment for risk factors. A sex-limitation model
      showed that the heritability estimates for women were significantly higher than
      for men, but the same genetic factors were operating across sexes. Sex and
      cigarette smoking appeared to be statistically significant interaction terms. The
      heritability of blood pressure is relatively high in young adults. Potential risk
      factors of blood pressure do not appear to confound the heritability estimates.
      However, gene by sex by smoking interaction is indicated.

PMID- 15193170
TI  - Genetic covariation of pelvic organ and elbow mobility in twins and their
      sisters.
AB  - A range of environmental risk factors, with childbirth the most notable, have
      been associated with the development of pelvic organ prolapse and urinary
      incontinence. However, indications of genetic influence (positive family
      histories, ethnic differences) have prompted research into the heritability of
      measures of pelvic organ descent and joint mobility, which have also been
      associated with prolapse and incontinence. Genes appear to influence about half
      of the variation in these measures and, furthermore, the pelvic organ measures
      are associated with elbow hyperextension at a phenotypic level (r approximately
      .2). We examined these measures in young, nulligravid women to determine if their
      association is due to a common genetic source. Data were collected from 178
      Caucasian female co-twins and non-twin sisters, 50 of whom returned to be
      retested, which allowed reliability to be estimated and unreliable variance to be
      isolated in the multivariate analyses. Structural equation modeling was used to
      estimate genetic associations between latent elbow and bladder mobility factors
      for which heritabilities were estimated to be 0.80 and 0.64 respectively. The
      association between these factors appeared to be mediated by common genes
      (genetic r = .48, non-shared environmental r = -.06), with genes influencing
      latent elbow mobility accounting for 14% of the variation in latent bladder
      mobility. We speculate that genes influencing connective tissue structure may
      underlie this association.

PMID- 15193172
TI  - Causal models of reading disability: a twin study.
AB  - The genetic and environmental relationships among measures of phoneme awareness,
      naming speed, Intelligence Quotient (IQ), and reading performance were
      investigated in 623 identical and fraternal twin pairs tested in the Colorado
      Learning Disabilities Research Center. A Cholesky decomposition analysis of these
      measures provided evidence supporting the double deficit hypothesis that
      difficulties in phonological processing and naming speed both contribute to
      reading disability. Additionally, the model revealed marginally significant
      genetic and significant non-shared environmental relationships between IQ and
      reading independent of naming speed and phoneme awareness. Thus a more complete
      causal model of reading disability should include IQ as well as measures of
      phonological processing and naming speed.

PMID- 15193171
TI  - Genetic and environmental influences on the relationship between aggression and
      hyperactivity-impulsivity as rated by teachers and parents.
AB  - This study examined genetic and environmental contributions to the covariance
      between aggression and hyperactivity-impulsivity as rated by twins' teachers and
      parents. Sex-differences in these genetic and environmental contributions and
      rater bias/sibling interaction effects were of interest as well. Part of an
      ongoing nation-wide twin-family study of behavioral development and health
      habits, the sample consisted of 1636 Finnish twin pairs ascertained from five
      consecutive and complete twin birth cohorts. Data were collected at ages 11-12,
      using teacher and parental rating forms of the Multidimensional Peer Nomination
      Inventory. Bivariate analyses were performed using structural equation modeling
      allowing sex-limitation effects. Results show that, in addition to significant
      genetic and environmental influences specific to each behavior, aggression and
      hyperactivity-impulsivity share common genetic and environmental etiology.
      Results provide evidence that both genetic and environmental factors are
      important in creating the observed correlation between aggression and
      hyperactivity-impulsivity.

PMID- 15193173
TI  - A longitudinal genetic study of vocabulary knowledge in adults.
AB  - Vocabulary test scores were obtained from a total of 997 adults, all twins or a
      sibling of twins in this study. Some (N = 217) individuals were tested twice,
      around 6 years apart. Heritability varied from 50% at the first test occasion to
      63% at the second test occasion. The correlation of scores across time was.74.
      Structural equation modelling showed that stability in vocabulary knowledge over
      time can largely (around 76%) be explained by genetic factors. Part of the non
      shared environmental variance was stable over time also. Any influence from
      shared environmental factors could not be detected. Results were similar for the
      two sexes, except that males generally outperformed females. Results were also
      similar for two age cohorts, except that the older cohort generally outperformed
      the younger cohort.

PMID- 15193174
TI  - Implications of absence of measurement invariance for detecting sex limitation
      and genotype by environment interaction.
AB  - Using univariate sum scores in genetic studies of twin data is common practice.
      This practice precludes an investigation of the measurement model relating the
      individual items to an underlying factor. Absence of measurement invariance
      across a grouping variable such as gender or environmental exposure refers to
      group differences with respect to the measurement model. It is shown that a
      decomposition of a sum score into genetic and environmental variance components
      leads to path coefficients of the additive genetic factor that are biased
      differentially across groups if individual items are non-invariant. The arising
      group differences in path coefficients are identical to what is known as "scalar
      sex limitation" when gender is the grouping variable, or as "gene by environment
      interaction" when environmental exposure is the grouping variable. In both cases
      the interpretation would be in terms of a group-specific effect size of the
      genetic factor. This interpretation may be incorrect if individual items are non
      invariant.

PMID- 15193175
TI  - Alternate parameterization for scalar and non-scalar sex-limitation models in Mx.
AB  - The purpose of this article is to present alternative parameterizations of scalar
      and non-scalar sexlimitation models in the Mx matrix algebra program (Neale et
      al., 2002). These models are designed for use with extended pedigrees and take
      advantage of the dynamic treatment of covariates within Mx. Example scripts are
      provided.

PMID- 15193176
TI  - [Antibiotic resistance and molecular epidemiology of Shigella spp. in
      northeastern Argentina].
AB  - OBJECTIVES: To evaluate the antibiotic resistance of strains of Shigella spp.
      isolated from feces samples from northeastern Argentina and to characterize the
      strains in terms of their molecular epidemiology. METHODS: We studied 132
      isolates of Shigella spp. obtained from feces samples from 132 patients with
      diarrhea who were seen at various private and public laboratories in the
      Argentine provinces of Chaco and Corrientes during the period of 1998 to 2002.
      Each strain was characterized according to its serotype, its resistance to 13
      individual or combination antibiotics, and its sensitivity to pyocins. With 52
      strains selected in relation to their antimicrobial susceptibility profiles we
      conducted plasmid profile analysis using alkaline lysis, and the repetitive
      extragenic palindromic sequences were determined by amplifying repetitive DNA
      segments using polymerase chain reaction. The chi-square test was used to compare
      proportions, with a level of statistical significance of 0.05. RESULTS: Shigella
      flexneri was the most common species (78%), followed by S. sonnei (22%). In
      general, the resistance of S. flexneri to the antibiotics studied was greater
      than that of S. sonnei, and this difference was statistically significant (P <
      0.001) for ampicillin, tetracycline, chloramphenicol, and the combination of
      ampicillin and sulbactam. The S. flexneri strains also showed multiple resistance
      more often than S. sonnei strains (84.5% vs. 31.0%; P < 0.001). The strains
      isolated from S. flexneri were grouped into five pyocin types, three plasmid
      profiles, and five patterns of repetitive palindromic sequences. The strains of
      S. sonnei formed three pyocin types, two plasmid profiles, and three patterns of
      repetitive palindromic sequences. CONCLUSIONS: Given that the Shigella species
      that were studied showed a high level of resistance to the most frequently used
      antibiotics, surveillance activities should be implemented in order to detect and
      control the appearance of new resistant strains. Applying epidemiological typing
      techniques can provide more precise information about the distribution and
      evolution of resistant strains of circulating microorganisms.

PMID- 15193177
TI  - Peer and sibling substance use: predictors of substance use among adolescents in
      Mexico.
AB  - OBJECTIVE: To examine the extent to which peer drug use and sibling drug use
      predict alcohol abuse/dependence disorder status and the use of drugs other than
      alcohol among school-based youth in Mexico. METHODS: Data were collected on 1 203
      middle and high school students in northern Mexico in May 1998. Participation was
      voluntary, and responses were confidential. Logistic regression analyses
      estimated the association that peer drug use and that sibling drug use had with
      alcohol abuse/dependence diagnosis and the lifetime use of drugs other than
      alcohol. RESULTS: Students who had siblings or peers who used alcohol and other
      drugs were more likely to meet the standard alcohol abuse/dependence criteria
      defined by the Diagnostic and Statistical Manual of Mental Disorders Fourth
      Edition (DSM-IV), and were more likely to have used drugs other than alcohol.
      Controlling for potentially important confounders, we found that adolescents with
      the highest level of peer substance use were eight times as likely to meet
      alcohol abuse/dependence criteria and four times as likely to use other drugs.
      Youth who had siblings who used drugs were about twice as likely to meet alcohol
      abuse/dependence criteria and about 2.5 times as likely to use drugs other than
      alcohol when compared to youth with no sibling substance use. CONCLUSIONS:
      Consistent with extant findings among youth in the United States of America, peer
      and sibling substance use are major risk factors for substance use among school
      based youth in Mexico. Students in Mexico may benefit from prevention strategies
      found to be effective among students in the United States.

PMID- 15193178
TI  - [Mortality due to infectious and parasitic diseases in the elderly in Brazil].
AB  - OBJECTIVE: To describe the mortality due to infectious and parasitic diseases in
      persons over 65 years of age in all of Brazil and in individual states and to
      study the association between that mortality due to these causes and specific
      socioeconomic variables over the period from 1980 to 1995. METHODS: Data were
      obtained from Brazil's national Mortality Information System. Standardized
      mortality rates were calculated for tuberculosis, Chagas' disease, and sepsis.
      The relative contribution of these causes of death to overall mortality was also
      calculated. The study also analyzed the relationship between mortality rates and
      gender and the following socioeconomic variables: per capita gross domestic
      product; number of hospital beds per inhabitant; proportion of the total
      population living in urban areas; number of benefits provided per capita by the
      social welfare system; number of deaths reported for every 100 hospitalizations;
      and life expectancy at birth. A normal multiple linear regression model was used
      for this analysis. RESULTS: There were no significant changes in the proportion
      of deaths due to infectious and parasitic diseases in the elderly population
      during the period studied, regardless of sex. However, for both men and women
      there was a sizeable decrease in the impact of tuberculosis and Chagas' disease,
      while that of sepsis appeared to increase. According to the results of the
      ecological analysis, socioeconomic indicators had little power to explain the
      differences in mortality patterns seen in the different states of the country.
      CONCLUSIONS: Our results suggest that policies to prevent and control infectious
      and parasitic diseases among the elderly in Brazil have stagnated. Given this
      situation and the progressive increase in the elderly population, mortality due
      to infectious and parasitic diseases is not likely to decrease in this age group,
      at least in the near future.

PMID- 15193179
TI  - Antenatal voluntary counseling and testing for HIV in Barbados. Success and
      barriers to implementation.
AB  - OBJECTIVE: To determine the success of voluntary counseling and testing (VCT) for
      HIV and to identify the barriers to implementation when VCT is offered as a
      package integrated with antenatal care. METHODS: In this descriptive study we
      investigated antenatal VCT and HIV testing in all post-parturient women at the
      Queen Elizabeth Hospital, Bridgetown, Barbados, who gave birth between April and
      September 2002. Data were collected retrospectively from the antenatal care
      record and by recall during one-on-one interview. RESULTS: Of 1 342 women
      surveyed, 954 (71.1%) received antenatal counseling and were offered an HIV test.
      Of the 954 women offered HIV test after counseling, 914 (95.8%) agreed to have
      the test. Among the women surveyed, 1 106 (82.4%) had a documented HIV test, 914
      (85.7%) were tested after documented pretest counseling, and another 192 (14.3%)
      were tested without documented pretest counseling. Overall, 822 of the 1 342
      women surveyed (61.2%) had a documented HIV test result in their antenatal case
      record at the time of delivery. Of the 1 106 women who had a documented HIV test,
      the test results were unavailable at the time of delivery in only 284 (21.2%).
      Among the reasons for unavailability of a documented HIV test result, the most
      common (45.0%) was that no test was done, followed by unclear documentation of
      the result. CONCLUSIONS: Twenty-nine percent of surveyed women failed to receive
      antenatal VCT and this is a cause of concern, for both the high coverage and good
      quality counseling are key to the overall success and cost effectiveness of the
      VCT program. Fourteen percent of the women surveyed who did not receive VCT were
      tested for HIV, a situation that is undesirable because some women may be tested
      without understanding the full implication of this policy, and as a result the
      overall impact of VCT may be reduced.

PMID- 15193180
TI  - [Efficacy and safety of a vaccine against human leptospirosis in Cuba].
AB  - OBJECTIVES: To evaluate the efficacy of vax-SPIRAL, a Cuban vaccine against
      leptospirosis, and to provide additional information concerning the safety of
      this vaccine (which was developed by Cuba's Finlay Institute). METHODS: This
      phase III efficacy trial of vax-SPIRAL was controlled, randomized, and double
      blind. The control vaccine used for the trial was Heberbiovac-HB (Heber Biotec,
      Cuba), a recombinant hepatitis B vaccine. The randomization unit for allocating
      persons to the study group or the control group were 523 family physician offices
      in the selected municipalities. The study covered the entire population of males
      and females from 20 to 64 years old who voluntarily agreed to participate, from
      the municipalities of Ranchuelo, Quemado, Santo Domingo, Encrucijada, Corralillo,
      Cifuentes, and Camajuani, which are in the province of Villa Clara, in the
      central region of Cuba. The vaccinations were given in the physicians' offices
      between February and July 1998, with an interval of 6 weeks between the two
      doses. The follow-up period was 12 months. A case was considered positive if a
      person who had received the two doses of the vaccine became ill with
      leptospirosis more than 21 days after receiving the second dose, with the
      diagnosis confirmed through serological and microbiological methods. We
      calculated the efficacy of the vaccine and the relative risk of becoming ill with
      leptospirosis after the vaccination. For the safety study, two persons were
      chosen at random from among the individuals vaccinated at the office of each
      physician participating in the study. Follow-up of local and systemic adverse
      reactions was carried out by the family physicians during the seven days after
      the application of each dose. The level of statistical significance was set at
      0.05. RESULTS: A total of 101 832 persons were vaccinated, with 50 354 of them
      (49.4%) receiving the leptospirosis vaccine and 51 478 of them (50.6%) receiving
      the control vaccine. The efficacy of the vax-SPIRAL vaccine was 78.1% (95%
      confidence interval (CI): 59.2% to 88.3%), and the relative risk of becoming ill
      with leptospirosis after receiving the leptospirosis vaccine was 0.22 (95% CI:
      0.12 to 0.41). General discomfort was the most frequent systemic adverse
      reaction, and mild spontaneous pain at the injection site was the most frequent
      local effect. The local and systemic adverse reactions were both more frequent in
      the study group than in the control group (P = 0.003). There were no serious
      adverse events. CONCLUSION: The vax-SPIRAL vaccine proved to be safe and
      efficacious for leptospirosis control. The vaccine is recommended for use in
      preventing this disease among groups at risk of contracting it.

PMID- 15193181
TI  - [Fluoride mouth-rinsing to prevent dental caries in a Brazilian municipality with
      fluoridated drinking water].
AB  - OBJECTIVE: To compare the prevalence of dental caries in two groups of
      schoolchildren: (1) schoolchildren participating in a weekly 0.2% sodium fluoride
      mouth-rinsing program and (2) schoolchildren not participating in the program.
      METHODS: This cross-sectional study was conducted in the city (municipality) of
      Londrina, in the state of Parana, Brazil; the city has fluoridated drinking
      water. We examined 367 12-year-old children: 190 participants in the weekly mouth
      rinsing program (51.8%) and 177 nonparticipants (48.2%). The prevalence of caries
      was determined based on the scores for decayed, missing, and filled teeth and for
      decayed, missing, and filled surfaces. The examinations were performed by three
      examiners, with nearly perfect agreement in their diagnosis of caries (kappa =
      0.90). The dependent variable was dental caries. The independent variables were:
      participation or nonparticipation in the mouth-rinsing program, attending a
      private school or a public school, frequency of tooth-brushing, amount of
      toothpaste used, consumption of sweets between meals, and visits to the dentist.
      RESULTS: The decayed, missing, and filled teeth score (mean and standard
      deviation) at 12 years of age was 0.85 +/- 0.059 overall, 1.0 +/- 0.058 for
      program participants, and 0.70 +/- 0.060 for nonparticipants. The decayed,
      missing, and filled surfaces score (mean and standard deviation) was 1.16 +/-
      0.017, with it ranging from a low of 0.34 in one private school to a high of 1.66
      in one public school. Bivariate analysis showed an association between caries (P
      < 0.05) and the following variables: attending a public school, participating in
      the mouth-rinsing program, and consuming sweets between meals more than once a
      day. In the multivariate analysis, attending a public school (P = 0.0004) and
      consuming sweets (P = 0.001) remained associated with the presence of caries.
      CONCLUSIONS: The weekly mouth-rinsing program was not associated with a decreased
      prevalence of caries, in either the public schools or the private schools.
      However, additional research is needed to assess the cost-effectiveness of
      fluoride mouthrinsing programs in populations with a higher prevalence of caries.
      Given the caries prevalence that we found in the schoolchildren whom we studied,
      the resources allocated to the fluoride mouth-rinsing program for them should
      probably be used to pay for other health-promotion activities with them.

PMID- 15193184
TI  - The obesity epidemic in the Americas: making healthy choices the easiest choices.

PMID- 15193182
TI  - Overweight and aerobic fitness in children in the United States/Mexico border
      region.
AB  - OBJECTIVE: To study overweight and aerobic fitness among children in the third
      and fourth grades of elementary schools in a city in the United States of America
      (El Paso, Texas) and a city in Mexico (Chihuahua, Chihuahua) that are on or near
      the border between those two countries, and to compare the results from those two
      cities with earlier findings for other children in the United States. METHODS: We
      followed the El Paso children (427 boys and 385 girls, 93% of them of Mexican
      descent) from third to fourth grade and assessed the change in their body mass
      index (BMI). In the city of Chihuahua we cross-sectionally measured the BMI of a
      sample of third grade children (221 boys and 237 girls) and a sample of fourth
      grade children (268 boys and 215 girls). BMI and triceps skinfolds were measured
      for all the children studied in the two cities. BMI was used to assess risk for
      overweight (at least the 85th percentile BMI for age and gender) and overweight
      (at least the 95th percentile BMI for age and gender) in all the children. The
      distance that El Paso children ran in nine minutes was used to assess their
      aerobic fitness (aerobic fitness was not measured in the Chihuahua children). The
      data from El Paso were collected in 1999, 2000, and 2001, and the Chihuahua data
      were collected in 2000 and 2001. RESULTS: In the El Paso boys, overweight
      significantly increased in the one year from third grade to fourth grade, from
      22% to 28%, while risk for overweight significantly increased, from 37% to 44%.
      In the El Paso girls, risk for overweight significantly increased over the same
      one-year period, from 29% to 37%. The El Paso boys and girls were significantly
      less fit when compared to samples of children from throughout the United States.
      Third and fourth grade children from Chihuahua had similar rates of risk for
      overweight and of overweight when compared to the children from the same grades
      in El Paso. CONCLUSIONS: Children in both El Paso and Chihuahua were more
      overweight than were non-Hispanic white children throughout the United States. In
      addition, the children in El Paso were less aerobically fit than were non
      Hispanic white children and than were other Mexican-American children in the
      United States. These results clearly show that efforts should be made in the
      border regions of both Mexico and the United States to develop physical activity
      and nutrition programs to help stem rising rates of overweight.

PMID- 15193185
TI  - [Emerging and reemerging diseases: a health problem in the Americas].
AB  - In the Region of the Americas the emerging and reemerging infectious diseases
      that had the greatest impact on health, in terms of their incidence and the
      number of deaths that they caused during the five-year period of 1999-2003, were:
      malaria, yellow fever, dengue hemorrhagic fever, AIDS, anthrax, and SARS, as well
      as infection by hantavirus and by West Nile virus. The appearance of epidemics of
      emerging and reemerging diseases is related to biological, social, and economic
      factors. Growth in international trade, the movement of large numbers of people
      across national borders, the variability and genetic adaptability of the
      causative microorganisms, and inefficiencies in public health systems help to
      spread infections and epidemics. To avoid or reduce the serious effects of these
      epidemics, countries should give priority in their national agendas to
      surveillance of emerging and reemerging diseases and should implement a set of
      measures to combat the diseases. The most important of these measures is to
      develop a strategy that is based on early warning and rapid response mechanisms,
      with personnel and laboratories as well as communications networks that link
      laboratories with health service providers. This strategy should be backed by
      priority funding and adequate policies.

PMID- 15193186
TI  - [Preparatory guidelines for local health services on how to respond to new cases
      of severe acute respiratory syndrome (SARS)].
AB  - The Centers for Disease Control and Prevention (CDC) of the United States of
      America recently issued a set of guidelines on how different community health
      services should prepare for and respond to the reemergence of severe acute
      respiratory syndrome (SARS). This document summarizes the recommendations of the
      CDC for basic health services. Disease surveillance in communities and hospitals
      should be performed in light of existing information on risk factors,
      particularly those related to geographic dissemination patterns and to documented
      transmission of SARS-CoV, the coronavirus that causes SARS. As long as no cases
      of person-to-person disease transmission are reported anywhere in the world,
      efforts should be aimed at early detection and notification of cases and of
      groups of people who are in contact with one another and who have severe
      respiratory infections of undetermined cause, such as pneumonia, which could
      signal the reemergence of SARS. If cases of transmission of SARS-CoV have been
      reported, the aim should be to immediately identify and notify any cases detected
      in order to take appropriate diagnostic and therapeutic measures and to
      facilitate outbreak control. The reach of surveillance and reporting activities
      in specific communities should depend on how widely the disease has spread, both
      in the community and in local health services. Physicians and public health
      workers should be familiar with ways to detect SARS cases early, as well as with
      existing norms for reporting any cases detected.

PMID- 15193187
TI  - Psychology and psychotherapy. Introduction.

PMID- 15193188
TI  - Part I: conversation between A.S. Byatt and Stephen Frosh. A.S. Byatt interviewed
      by Stephen Frosh.

PMID- 15193189
TI  - '...the depth to which the root reaches, just beyond the constrictions'.

PMID- 15193190
TI  - Part II: conversation between Nick Hornby and Simon Thomas. Nick Hornby
      interviewed by Simon Thomas.

PMID- 15193191
TI  - Commentary: echoes of the ordinary.

PMID- 15193192
TI  - Part III: conversation between Pat Barker and Caroline Garland. Pat Barker
      interviewed by Caroline Garland.

PMID- 15193193
TI  - Commentary: threading some beads.

PMID- 15193194
TI  - The description of concerns.
AB  - This article seeks to provide a rationale, and review a strategy, for descriptive
      assessment in routine clinical practice. The basis of the rationale is a
      distinction drawn between assessment priorities in research and clinical work. It
      is argued that if clinical work is to take account of the broad coverage and
      specificity of patients' self-reported difficulties, initial assessments need to
      sample content, rather than measure constructs. Personalized problem lists
      provide a strategy for sampling content, when adopted by clinicians with
      systematic description in mind. The article reviews the use of Shapiro's Personal
      Questionnaires (PQs) to achieve this. The results of a literature search suggest
      a decline in their use, particularly for systematic description. Three proposals
      are made to revive it: first, a focus on 'concerns'; secondly, the pursuit of
      alternative interview coverage; and thirdly, the treating of assessment as a
      process rather than an event. The main purposes of the strategy for clinical
      practice - outcome assessment and clinical formulation - are illustrated. The
      concluding discussion raises the wider implications of descriptive assessment for
      the use of ordinary language, the application of descriptive hypotheses, the
      status given to idiographic variables, and the adoption of an inductive strategy.

PMID- 15193196
TI  - 'The vehicle of success': theoretical and empirical perspectives on the
      therapeutic alliance in psychotherapy and psychiatry.
AB  - The importance of the 'therapeutic alliance' has long been recognized in
      psychotherapeutic theory and research, but is also increasingly researched in
      psychiatry. This paper examines the clinical and empirical literature on the
      alliance and asks, first, whether the concept is unrecognizably distorted when it
      travels from the psychoanalytic context to other therapies and to psychiatry, or
      when translated into research instruments; and, second, how we are to understand
      the apparent anomaly whereby its proponents have defined it as a 'vehicle' for
      treatment rather than curative, whereas quantitative research increasingly
      associates it with outcome. This paper reviews the evolution of the concept in
      clinical theory, traces the development of empirical research on the subject and
      considers its use in psychiatry. It argues that the empirical research
      misleadingly suggests a curative paradigm, and that it may be unable to
      illuminate some of the clinical controversies, although its implications for
      theory demand consideration. It argues for the retention of the alliance concept
      in psychiatry distinct from the broader spectrum of the 'relationship'. Finally,
      it argues that the debate about the concept's curative properties may,
      paradoxically, be more pressing within psychotherapy than psychiatry, and
      endorses calls for more theoretically driven empirical research into the
      alliance.

PMID- 15193195
TI  - A model of narrative development: implications for understanding psychopathology
      and guiding therapy.
AB  - Story-telling is one of the psyche's basic functions. All of us organize our
      experience in the form of narratives in order to give meaning to events, make
      forecasts about how situations will evolve, guide our actions in relationships
      and make our self-experience coherent. Here we present a theoretical model which
      starts out from the hypothesis that, when they are created, the narratives we
      continuously relate to ourselves and others do not have a pre-existing form. We
      propose a model for understanding the way each organizational level is formed in
      the mind, and works and interacts with other levels; and what psychological
      disorders could affect it, ranging from the basic, where there are simple
      aggregates of mental images, to the more complex, where there are true and proper
      stories, in which the characters of the internal scenario interact with each
      other. According to our model, it is possible to hypothesize the existence of:
      (1) a pre-narrative level, and (2) a proto-narrative level, followed by three
      extended narrative levels: (3) a procedural unconscious narrative level, (4) a
      conscious propositional narrative level, and (5) a verbal interactive narrative
      level. Our hypothesis is based on: (1) a review of various theories from
      different fields of research; and (2) illustrative clinical material obtained by
      recording psychotherapy sessions with severely personality-disordered patients.

PMID- 15193197
TI  - The importance of ethnic similarity in the therapist-patient dyad among
      Surinamese migrants in Dutch mental health care.
AB  - Empirical evidence is equivocal on whether ethnic matching in the therapist
      patient dyad is preferred by ethnic minority patients and whether it leads to
      treatment satisfaction. The aim of this study was to establish the importance of
      ethnic similarity in mental health care among Surinamese migrants in the
      Netherlands. A convenience sample of Surinamese out-patients in community mental
      health care (N = 96) was interviewed. Data were analysed using logistic
      multivariate techniques. The majority of the Surinamese out-patients (in
      particular recently residing participants) rated ethnic matching as relevant; a
      considerable minority considered compassion and expertise to be more relevant
      than ethnic background. Most out-patients reported to be satisfied with the
      services, especially females and respondents treated by an ethnically similar
      therapist. Ethnic similarity in the patient-therapist dyad is a strong predictor
      for satisfaction with mental health care services. However, although it is
      preferred by many, ethnic matching per se is no must - empathy, expertise and
      world view sharing are reported to be of considerable importance as well.

PMID- 15193198
TI  - Double jeopardy: hormone therapy on trial again.

PMID- 15193199
TI  - The resurgence of Chlamydia trachomatis.
AB  - The objective of the review is to alert reproductive-care providers to the
      unexpected resurgence of Chlamydia infections and to new findings related to
      complications associated with Chlamydia infection. Data sources consisted of
      national and local guidelines and literature searches of MEDLINE with the heading
      Chlamydia infections 2002 and 2003. The complications of Chlamydia infections are
      considered to be longterm, and may include debilitating pain, infertility, tubal
      pregnancy, cancer, and HIV infection. Only a strong disease-management response
      from reproductive-care providers, using new diagnostic techniques and simpler
      treatment regimens, as well as a strong public health reaction, will be effective
      to limit the scourges of Chlamydia infection in the female population.

PMID- 15193200
TI  - Availability of hormone replacement therapy products in Canada.
AB  - OBJECTIVES: To determine the availability in Canada of different types of hormone
      replacement therapy (HRT) products, and to compare the availability of HRT
      products in Canada to their availability in other countries. METHODS: A
      systematic review was conducted of the availability of products indicated for
      treatment of menopausal symptoms in Canada, the United States (US), the United
      Kingdom (UK), Sweden, and Australia. Products indicated for the treatment of
      menopausal symptoms were determined for each country by using on-line drug
      product databases. Products administered by injection and androgen products,
      unless combined with estrogens, were excluded from the analysis. RESULTS: There
      were 111 different brands identified in the 5 countries examined, with Canada
      having the lowest number of brands and active ingredients (28 and 22,
      respectively) compared to the other countries (Sweden and UK at 67 and 47 brands
      and 39 and 40 active ingredients, respectively). Not available in Canada are 34
      active ingredients (either alone or in combination products) and 5 different
      types of formulations of HRT. There was a significant difference between the
      number of combination brand products available in Canada and in the UK (5 versus
      29, P <.001, respectively). CONCLUSIONS: Canadian women have comparatively few
      options available to them for the management of menopausal symptoms. The wide
      range of HRT products available in other developed countries provides
      alternatives for managing side

PMID- 15193201
TI  - Cerclage for the short cervix demonstrated by transvaginal ultrasound: current
      practice and opinion.
AB  - OBJECTIVES: (1) To elucidate the views of obstetricians with respect to the use
      of transvaginal ultrasound in general, and, specifically, for determining
      cervical length, and the conditions under which obstetricians would employ
      cervical cerclage based on a sonographically revealed shortened cervix; and (2)
      to determine the possibility of a randomized controlled trial on the use of
      cervical cerclage in this situation. METHODS: A 7-item questionnaire in French
      and English was designed and pretested. Questionnaires were mailed to 1421
      physicians identified in the Canadian Medical Directory as practising
      obstetricians/gynaecologists in Canada. Returned questionnaires were scanned into
      an Access database for simple descriptive analyses. RESULTS: Responses were
      received from 766 physicians. Of these 766 respondents, 604 physicians indicated
      they continued to practise obstetrics and supplied information that was usable in
      the analysis. The majority of the 604 respondents (85.6%) reported that they
      would recommend transvaginal ultrasound only in pregnant women with 1 or more
      risk factors for preterm birth. Respondents were most likely to recommend a
      cerclage, and least unsure of their decision to do so, if the gestational age was
      less than 23 weeks, the cervical length was less than 1 cm, and additional risk
      factors for preterm birth were present. As gestational age and cervical length
      increased, respondents were less likely to recommend cerclage and more unsure of
      their decision to do so. The pattern of responses was similar for singleton and
      multiple pregnancies. The McDonald technique was favoured over the Shirodkar
      technique by 70.4% of the respondents who performed cervical cerclage procedures.
      Adjunctive antibiotics were used with cerclage by 52.5% and adjunctive tocolytics
      were employed by 37.4%. The majority (68.8%) of the respondents who performed
      cervical cerclage procedures stated that they would participate in a randomized
      controlled trial on the effectiveness of cerclage for a sonographically revealed
      short cervix. CONCLUSION: In the case of a short cervix determined by ultrasound,
      there is significant uncertainty surrounding the decision whether to place a
      cerclage and considerable variation in the clinical practice on its placement. In
      the absence of good evidence to guide clinical practice, a randomized controlled
      trial is being planned.

PMID- 15193202
TI  - An association of chorionicity with preterm twin birth.
AB  - OBJECTIVE: To assess the risk factors for preterm birth in twin pregnancies,
      particularly monochorionicity. METHODS: A cohort study of 767 sets of twins, each
      twin weighing more than 500 g, born between January 1, 1992, and December 31,
      2001, at St. Joseph's Health Care in London, Ontario. Statistical analysis was
      performed using forward stepwise logistic regression models, with gestational age
      at birth less than 28 or 32 weeks as the outcome. RESULTS: Polyhydramnios and
      chorioamnionitis were significant risk factors for preterm birth prior to 28 or
      32 weeks' gestation. Monochorionicity was a risk factor for preterm birth prior
      to 32 weeks' gestation. Past term birth and maternal age over 30 years were
      associated with reduced risk for preterm birth. CONCLUSION: Monochorionic
      placentation is a significant risk factor for preterm twin birth.

PMID- 15193203
TI  - Women's views regarding participation in a proposed randomized controlled trial
      of twin delivery.
AB  - OBJECTIVE: To determine the views of women regarding participation in a proposed
      multicentre randomized controlled trial comparing planned vaginal birth to
      planned Caesarean delivery for twins at 32 or more weeks' gestation, in which the
      first twin (twin A) is presenting as a vertex. METHODS: Pregnant women with a
      known twin gestation were recruited from 2 hospital centres. Written information
      was provided about the proposed Twin Birth Study, and the women were then
      requested to complete a questionnaire to determine their views regarding
      participation in the proposed trial. RESULTS: Of the 64 women recruited for the
      study, 31 (48%) indicated they would be willing to consider participating in the
      proposed trial (95% CI, 37-60%), 14 (22%) were unsure about trial participation
      (95% CI, 13-33%), and 19 (30%) indicated they would not be willing to participate
      in the proposed study (95% CI, 20-42%). The most common reason for agreement to
      participation was altruism (n = 28). Those who responded "not sure" wished to
      speak with their partner (n = 5) or their doctor (n = 8) before deciding on
      participation. Of those who indicated they would not participate in the proposed
      trial, 12 (63%) indicated they preferred to have a vaginal birth, and 7 (37%)
      preferred to have a Caesarean section. CONCLUSIONS: Almost half the women in our
      sample were agreeable to considering their participation in a randomized trial
      that will compare planned vaginal birth to planned Caesarean section for twins at
      32 or more weeks' gestation with twin A presenting as a vertex. Altruism was the
      most common reason for agreeing to participate, whereas preference for a specific
      mode of delivery was the most common reason for declining participation.

PMID- 15193204
TI  - The 2002 Canadian Contraception Study: part 1.
AB  - OBJECTIVES: To investigate the contraception and sexual health-related awareness,
      attitudes, and practices of a representative sample of Canadian women of
      childbearing age. METHODS: A self-report survey was mailed to a national sample
      of 3345 women, aged 15 to 44 years, who were members of a pre-recruited market
      research panel. Survey questions and methodology were similar to 3 previous
      Canadian Contraception Studies, allowing for description of current patterns of
      behaviours and beliefs and comparison of trends over time. RESULTS: Of 3345 women
      contacted, 1582 returned completed surveys, for a response rate of 47.3%.
      Responses were weighted to represent Canadian women by region, age, and marital
      status on the basis of current census data. Eighty-six percent of women sampled
      had ever had sexual intercourse and 78% were currently sexually active. Women's
      familiarity with oral contraceptives and condoms as methods of contraception was
      high (96% and 93%, respectively), but familiarity with other methods was much
      lower (sterilization, 62%; withdrawal, 59%; the morning-after pill, 57%;
      intrauterine devices, 50%; depot [injectable] medroxyprogesterone acetate, 38%).
      A very favourable opinion was held by 63% of respondents concerning oral
      contraceptives, by 38% concerning condoms, and by 39% and 28% concerning male and
      female sterilization, respectively. Among respondents who have ever had sexual
      intercourse, the most frequently used current methods were oral contraceptives
      (32%), condoms (21%), male sterilization (15%), female sterilization (8%), and
      withdrawal (6%). Nine percent of these respondents reported using no method of
      contraception at all. The currently reported rate of female sterilization is the
      lowest ever recorded in Canada. Survey results show that adherence to
      contraceptive methods is a challenge for many women and their partners, and that
      risk of sexually transmitted disease is an ongoing concern. CONCLUSION: This
      study provides a wide-ranging examination of contraception awareness, beliefs,
      and use among Canadian women that may provide guidance for clinical and public
      health practice. Part 1 of this report describes the methodology of the 2002
      Canadian Contraception Study and the overall results of this study; Part 2
      considers results pertaining specifically to adolescent women and women in their
      later reproductive years, reports on indicators of women's sexual function and
      reproductive health history, describes approaches to addressing challenges in
      contraception counselling, and presents data concerning trends in Canadian
      women's awareness and use of contraception over the past 2 decades.

PMID- 15193206
TI  - Preeclampsia as a cause of pancreatitis: a case report.
AB  - BACKGROUND: Pancreatitis is an uncommon but well-described entity in pregnancy
      and labour, with most cases attributable to biliary disease. Preeclampsia is not
      an established cause of pancreatitis. CASE: A 29-year-old woman with preeclampsia
      and adverse features at 33 weeks' gestation developed pancreatitis during her
      labour induction. Investigations ruled out known etiologies of pancreatitis. The
      woman was monitored clinically, biochemically, and radiologically, and underwent
      a Caesarean delivery of a healthy infant. Both the pancreatitis and preeclampsia
      resolved rapidly postpartum. Given her benign clinical picture, no specific
      therapeutic intervention was deemed necessary for the pancreatitis, and she was
      discharged 5 days postpartum. CONCLUSION: The clinical course and investigations
      of this woman suggest that preeclampsia should be considered as a cause of
      pancreatitis.

PMID- 15193205
TI  - Isolated gastroschisis in successive siblings: a case report and review of the
      literature.
AB  - BACKGROUND: Although gastroschisis occurring in siblings is rare, a number of
      cases have been reported. A variety of inheritance patterns and embryologic
      explanations have previously been suggested. Young maternal age appears to be a
      consistent risk factor. CASE: At age 17 years, Melanie (pseudonym) presented at
      36 weeks' gestation and delivered a boy affected by gastroschisis. This condition
      had not been noted at a 13-week prenatal ultrasound. At age 18 years, Melanie
      delivered a second son with gastroschisis. There was no history of gastroschisis
      or other congenital anomaly in either parent's family. Melanie denied the use of
      alcohol, cigarettes, street drugs, and medications. She has since delivered 2
      healthy children. CONCLUSION: There is a need for preconception counselling for
      women who have experienced a pregnancy complicated by gastroschisis, to discuss
      the low but possible risk of recurrence. Early ultrasound may allow for detection
      or reassurance.

PMID- 15193207
TI  - School-based and school-linked sexual health education and promotion in Canada.

PMID- 15193208
TI  - Development and validation of methods for assessing the quality of diagnostic
      accuracy studies.
AB  - OBJECTIVES: To develop a quality assessment tool which will be used in systematic
      reviews to assess the quality of primary studies of diagnostic accuracy. DATA
      SOURCES: Electronic databases including MEDLINE, EMBASE, BIOSIS and the
      methodological databases of both CRD and the Cochrane Collaboration. REVIEW
      METHODS: Three systematic reviews were conducted to provide an evidence base for
      the development of the quality assessment tool. A Delphi procedure was used to
      develop the quality assessment tool and the information provided by the reviews
      was incorporated into this. A panel of nine experts in the area of diagnostic
      accuracy studies took part in the Delphi procedure to agree on the items to be
      included in the tool. Panel members were also asked to provide feedback on
      various other items and whether they would like to see the development of
      additional topic and design specific items. The Delphi procedure produced the
      quality assessment tool, named the QUADAS tool, which consisted of 14 items. A
      background document was produced describing each item included in the tool and
      how each of the items should be scored. RESULTS: The reviews produced 28 possible
      items for inclusion in the quality assessment tool. It was found that the sources
      of bias supported by the most empirical evidence were variation by clinical and
      demographic subgroups, disease prevalence/severity, partial verification bias,
      clinical review bias and observer/instrument variation. There was also some
      evidence of bias for the effects of distorted selection of participants, absent
      or inappropriate reference standard, differential verification bias and review
      bias. The evidence for the effects of other sources of bias was insufficient to
      draw conclusions. The third review found that only one item, the avoidance of
      review bias, was included in more than 75% of tools. Spectrum composition,
      population recruitment, absent or inappropriate reference standard and
      verification bias were each included in 50-75% of tools. Other items were
      included in less than 50% of tools. The second review found that the quality
      assessment tool should have the potential to be discussed narratively, reported
      in a tabular summary, used as recommendations for future research, used to
      conduct sensitivity or regression analyses and used as criteria for inclusion in
      the review or a primary analysis. This suggested that some distinction is needed
      between high- and low-quality studies. Component analysis was considered the best
      approach to incorporate quality into systematic reviews of diagnostic studies and
      this was taken into consideration when developing the tool. CONCLUSIONS: This
      project produced an evidence-based quality assessment tool to be used in
      systematic reviews of diagnostic accuracy studies. Through the various stages of
      the project the current lack of such a tool and the need for a systematically
      developed validated tool were demonstrated. Further work to validate the tool
      continues beyond the scope of this project. The further development of the tool
      by the addition of design- and topic-specific criteria is proposed.

PMID- 15193209
TI  - Newer hypnotic drugs for the short-term management of insomnia: a systematic
      review and economic evaluation.
AB  - OBJECTIVES: To assess the clinical and cost-effectiveness of zaleplon, zolpidem
      and zopiclone (Z-drugs) compared with benzodiazepines. DATA SOURCES: Electronic
      databases, reference lists of retrieved articles and pharmaceutical company
      submissions. REVIEW METHODS: Randomised controlled trials (RCTs) that compared
      either benzodiazepines to the Z-drugs or any two of the non-benzodiazepine drugs
      in patients with insomnia were included in the review. Data on the following
      outcome measures were considered: sleep onset latency, total sleep duration,
      number of awakenings, quality of sleep, adverse effects and rebound insomnia. A
      search was also undertaken for any study designs that evaluated issues related to
      adverse events (e.g. dependency and withdrawal symptoms). Full economic
      evaluations that compared two or more options and considered both costs and
      consequences including cost-effectiveness, cost-utility analysis or cost-benefit
      analysis undertaken in the context of high-quality RCTs were considered for
      inclusion in the review. RESULTS: Twenty-four studies, involving a total study
      population of 3909 patients, met the inclusion criteria. These included 17
      studies comparing a Z-drug with a benzodiazepine and seven comparing a Z-drug
      with another Z-drug. The diversity of possible comparisons and the range of
      outcome measures in the review may be confusing. Outcomes were rarely
      standardised and, even when reported, differed in interpretation. In addition,
      variations in assessment and variety in the level of information provided make
      study comparisons difficult. As a result, meta-analysis has been possible on only
      a small number of outcomes. However, some broad conclusions might be reached
      based on the limited data provided. The existing published economic literature in
      this area is very limited. No relevant economic evaluations were identified for
      inclusion in the review. The industry submissions did not include detailed
      evidence of cost-effectiveness. Given the lack of robust clinical evidence, no
      economic model describing the costs and benefits of the newer hypnotic drugs for
      insomnia was developed. The systematic review provided in this report suggests
      that an agnostic approach to cost-effectiveness is required at this stage. In the
      short-term, no systematic evidence is available concerning significant outcome
      variations between either the different classes of drugs or between individual
      drugs within each class. Within this short-term horizon, the one element that
      does vary significantly is the acquisition cost of the individual drugs.
      CONCLUSIONS: The short-acting drugs seem equally effective and safe with minor
      differences that may lead a prescriber to favour one over another in different
      patients. There is no evidence that one is more cost-effective than any other.
      Analysis of the additional costs to the NHS, depending on the rate of change from
      benzodiazepine prescriptions to Z-drug prescriptions, at current levels of
      hypnotic prescribing, range from GBP2 million to GBP17 million per year. There
      are clear research needs in this area; in particular, none of the existing trials
      adequately compare these medications. It is suggested that further consideration
      should be given to a formal trial to allow head-to-head comparison of some of the
      key drugs in a double-blind RCT lasting at least 2 weeks, and of sufficient size
      to draw reasonable conclusions. We would also recommend that any such trial
      should include a placebo arm. It should also collect good-quality data around
      sleep outcomes and in particular quality of life and daytime drowsiness. We do
      not believe that any formal study of risk of dependency is feasible at present.
      Finally, the management of long-term insomnia is suggested for further
      investigation: considering the frequency of this symptom and its recurring
      course, the short-term trial of medication and lack of long-term follow-up
      undermine attempts to develop evidence-based guidelines for the use of hypnotics
      in this condition, or indeed for its whole management.

PMID- 15193210
TI  - Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids
      in trauma patients.
AB  - OBJECTIVES: To systematically review the evidence on the effectiveness (in terms
      of mortality and morbidity) of prehospital intravenous (i.v.) fluid replacement,
      compared with no i.v. fluid replacement or delayed fluid replacement, in trauma
      patients with no head injury who have haemorrhage-induced hypotension due to
      trauma. DATA SOURCES: Electronic databases, relevant websites, handsearching,
      expert contacts. REVIEW METHODS: Search strategies were defined to identify
      randomised controlled trials (RCTs) and previous systematic reviews relating to
      the use of i.v. fluids in a prehospital (or other) setting compared to no fluids
      or delayed fluids. Inclusion and exclusion criteria were applied to identified
      studies, and key quality criteria of included studies were checked. Data were
      extracted independently by two reviewers. Economic evaluations were also
      systematically sought and appraised. RESULTS: Four relevant RCTs were identified,
      three of which were poorly designed and/or conducted. One good-quality RCT
      suggested that i.v. fluids may be harmful in patients with penetrating injuries.
      No evidence was found on the relative effectiveness of i.v. fluids in patients
      with blunt versus penetrating trauma. No reliable evidence was found from
      systematic reviews to suggest that a particular type of fluid is more beneficial
      compared to another type, although there was a trend favouring crystalloids over
      colloids. The relative costs of using i.v. fluids versus not using them were
      found to be very similar and changes in the use of fluids would therefore have no
      cost consequences for the ambulance service. A more detailed cost-effectiveness
      analysis would require further information on the relative consequences
      (mortality, morbidity) of different resuscitation strategies. CONCLUSIONS: The
      review found no evidence to suggest that prehospital i.v. fluid resuscitation is
      beneficial, and some evidence that it may be harmful. This evidence is however
      not conclusive, particularly for blunt trauma. A UK Consensus Statement, and to a
      lesser extent the UK Joint Royal Colleges Ambulance Liaison Committee guidelines
      represent a more cautious approach to fluid management than previously advocated
      and are therefore consistent with the limited evidence base. Further research is
      required on hypotensive (cautious) resuscitation versus delayed or no fluid
      replacement, particularly in blunt trauma. There is also a need for an
      improvement in the quality of data collection and analysis of routinely collected
      ambulance call-out data.

PMID- 15193211
TI  - [The cloning, expression, purification and identification of SARS virus S2 gene
      and study on its immunological characteristics].
AB  - AIM: To express S2 protein of SARS virus fused with Trx and then detect its
      reactivity to the sera from convalescent SARS patients. METHODS: The Trx-S2
      fusion protein was expressed in E.coli. After purification, the Trx-S2 fusion
      protein was detected by Western blot with 6 serum samples of convalescent SARS
      patients and 6 serum samples of healthy donors. RESULTS: According to the SDS
      PAGE analysis, the relative molecular mass (M(r)) of the Trx-S2 fusion protein is
      about 76 x 10(3). The fusion protein could react with all the sera from
      convalescent SARS patients but not with the sera from healthy donors. CONCLUSION:
      The Trx-S2 fusion protein provides a basis for the research on its role in the
      course of SARS virus infection of host cells and preparation of recombinant
      vaccine against SARS virus.

PMID- 15193212
TI  - [Correlation between point mutation frequency of MBL gene exon I and plasma MBL
      concentration in healthy Mongolians].
AB  - AIM: To investigate the point mutation at codon 54 of mannose binding lectin
      (MBL) gene, detect the plasma MBL level, and analyze the correlation between the
      gene mutation frequency and plasma MBL concentration. METHODS: A method for
      detecting MBL gene point mutation (PCR-RFLP) was established with self-designed
      primers according to MBL genomic sequence. The plasma MBL concentration was
      detected by MBL Oliger ELISA kit. RESULTS: The PCR-RFLP for detecting the point
      mutation at codon 54 of MBL gene was established. Frequency of point mutation at
      codon 54 of MBL gene in healthy Mongolians was 0.18. The plasma MBL concentration
      was (2.53+/-1.96)mg/L. There was negative correlation between plasma MBL
      concentration and MBL gene mutation frequency in Mongolians (r = -0.641).
      CONCLUSION: The established method of PCR-RFLP was proved to have high
      specificity, excellent reproducibility and high sensitivity. The relationship
      between frequency of mutation at codon 54 of MBL gene and the plasma MBL
      concentration in healthy Mongolians is negatively correlated.

PMID- 15193213
TI  - [In-vitro refolding and biotinylation of soluble HLA-A2-peptide complex].
AB  - AIM: To refold and biotinylate HLA-A2-peptide complex in-vitro. METHODS: The BirA
      substrate peptide (BSP) containing H chain of HLA-A2 and beta(2m) were expressed
      highly as insoluble aggregates in E.coli, and then the two subunits were refolded
      to form an HLA-A2-peptide complex by dilution method in the presence of an
      antigenic peptide (NH(2)-CLGGLLTMV-COOH of EB virus latent membrane protein 2A
      LMP2A). Then the BirA enzyme was used to biotinylate the refolded complex. The
      refolded and biotinylated products were detected by ELISA and Western blot with
      mAb W6/32 and rabbit anti-human beta(2m) antibody and streptavidin. RESULTS: The
      refolded complex was composed of H chain aggregate, HLA-A2-peptide complex and
      beta(2m). Both HLA-A2-peptide complex and the H chain aggregate could be
      biotinylated. CONCLUSION: The refolding and biotinylation of HLA-A2-peptide
      complex were successfully performed and the products were confirmed by our
      practical immunological method. This study laid the foundation for the
      preparation of HLA-peptide tetramer and artificial antigen presenting cells.

PMID- 15193214
TI  - [Inhibitory effect of hDAF displayed on yeast cells on deposition of complement
      on the yeast cells].
AB  - AIM: To investigate whether the hDAF displayed on the surface of yeast cells can
      inhibit the deposition of C5b-9. METHODS: After treatment with normal human
      serum, deposition of human complement C5b-9 and DAF expression on yeast cells
      EBY100 were analyzed by flow cytometry. RESULTS: Yeast cells EBY100 could
      activate the complement molecules in human serum and lead to the deposition of
      C5b-9, while the deposition of C5b-9 on the surface of yeast cells with hDAF
      could significantly reduce the deposition of C5b-9. CONCLUSION: hDAF displayed on
      the surface of yeast cells can fold correctly and exhibit activity of
      complement's inhibition.

PMID- 15193215
TI  - [Study on the immunogenicity of HIV-1 gag vaccine].
AB  - AIM: To detect the immunogenicity of HIV-1 gag DNA vaccine. METHODS: The serum
      antibody titers of the immunized mice were detected by ELISA. The numbers of
      spleen's CD4(+) and CD8(+) T cells were analyzed by the fluorescent antibody
      staining and the cytotoxic activity was determined by lactate dehydrogenase (LDH)
      release assay. RESULTS: The titers of the serum antibodies and the numbers and
      cytotoxic activity of spleen's T lymphocyte subsets had significant differences
      (P<0.05 and P<0.01, respectively) between pVAXGAG and pVAX1 vaccinated groups.
      CONCLUSION: HIV-1 DNA vaccine plasmid pVAXGAG could elicit both the specific
      humoral and cellular immunities in BALB/c mice.

PMID- 15193216
TI  - [Construction and expression of adeno-associated virus vectors of Smad 6 and Smad
      7 genes in human renal tubule epithelial cells].
AB  - AIM: To construct the adeno-associated virus(AAV) vectors of Smad 6 and Smad 7
      genes and observe their expressions in human renal tubule epithelial cells.
      METHODS: The plasmids pcDNA3-Smad 6/flag and pcDNA3-Smad 7/flag were digested
      with BamH I and Xho I. Then the Smad 6/flag and Smad 7/flag gene fragments were
      cloned into plasmid pAAV-MCS, respectively to construct the recombinant pAAV-Smad
      6/flag and pAAV-Smad 7/flag plasmids. The recombinant expression plasmid or pAAV
      LacZ plasmid were co-transfected into the HEK 293 cells with pHelper and pAAV-RC
      by calcium-phosphate precipitation method. Recombinant AAV-2 viral particles were
      prepared from infected HEK293 cells and then were used to infect human renal
      tubule epithelial cells (HKCs), The expressions of Smad 6 and Smad 7 in HKCs were
      demonstrated by immunocytochemical staining. RESULTS: The recombinant AAV vectors
      of Smad 6 or Smad 7 genes were constructed and expressed in the HKCs
      successfully. CONCLUSION: These results indicate that AAV can deliver Smad 6 and
      Smad 7 genes to renal cells in-vitro, suggesting the recombinant AAV can be used
      for gene therapy of renal fibrosis.

PMID- 15193217
TI  - [Construction and expression of a fusion protein containing extracellular domain
      of human Jagged1 and Fc fragment of human IgG1].
AB  - AIM: To construct a eukaryotic expression vector containing the extracellular
      domain of human Jagged1 and Fc fragment of human IgG1 fusion gene and to express
      the hJagged1(ext)-Fc fusion protein in mammalian cells. METHODS: The
      extracellular domain of human Jagged1 gene was cloned from normal human bone
      marrow cells. In order to obtain hJagged1(ext)-Fc fusion gene, the extracellular
      domain of Jagged1 gene was inserted into pBluescript-sk II-hc gamma 1, and then
      the fusion gene was inserted into pEF-BOSneo to get the eukaryotic expression
      vector pEF-BOSneo-hJagged1(ext)-Fc. The recombination plasmid was transiently
      transfected into COS7 cells and the expression of the fusion protein was
      identified by RT-PCR, immunofluorescent assay and sandwich ELISA. RESULTS: The
      extracellular domain of human Jagged1 gene was effectively amplified. The DNA
      sequencing result showed that the constructed plasmid containing hJagged1(ext)-Fc
      fusion gene was the same as designed. The fusion protein was successfully
      expressed in mammalian cells. CONCLUSION: The hJagged1(ext) gene has been
      successfully cloned and expressed, which provides a new fusion protein for
      further experiments, for example, the Jagged1(ext)-Fc fusion protein can be used
      as a new stimulator for proliferation of hematopoietic stem/progenitor cells in
      vitro.

PMID- 15193218
TI  - [Experimental study on immune responses induced in mice by gp120 gene vaccine of
      Chinese HIV-1 strain].
AB  - AIM: To construct the gp120 DNA vaccine of Chinese HIV-1 strain and evaluate the
      immune responses induced with it in BALB/c mice. METHODS: The recombinant
      expression vector pVAX1-GP120 was constructed by inserting HIV gp120 gene into
      the eukaryotic expression vector pVAX1 and confirmed with EcoR I/Pst I and DNA
      sequencing. BALB/c mice were immunized with pVAX1-GP120 and pVAX1 respectively.
      The levels of serum anti-HIV antibody and IFN-gamma of the immunized mice were
      detected by ELISA. The proliferation of splenocytes was determined by MTT
      colorimetry and the specific cytotoxic T lymphocytes (CTLs) response by LDH
      assay. RESULTS: Restriction enzymes digestion analysis and DNA sequencing results
      revealed that the pVAX1-GP120 had been constructed successfully. The titer of
      anti-HIV antibody and the IFN-gamma level in mice immunized with the pVAX1-GP120
      were higher than those in mice immunized with pVAX1 respectively (P<0.01). As
      compared with mice immunized with pVAX1 alone, the cytotoxic activity of specific
      CTLs and antigen-specific lymphoproliferative responses in mice immunized with
      pVAX1-GP120 were significantly enhanced (P<0.01). CONCLUSION: Specific cellular
      and humoral immune responses in mice can be induced with gp120 gene vaccine of
      Chinese HIV-1 strain, which lays the foundation for further development of
      therapeutic HIV vaccine against HIV-1 infection.

PMID- 15193219
TI  - [Effects of TGF beta 1 on the cell cycle of irradiated human lung fibroblasts and
      its signal transduction mechanism].
AB  - AIM: To investigate the effects of TGF beta 1 on the proliferative activity and
      cell cycle of normal and gamma ray-irradiated human lung fibroblasts (HLFs).
      METHODS: HLFs were cultured and irradiated with 3Gy gamma rays and then
      stimulated by TGF beta 1 at 0.01, 0.1, 1 and 10 microg/L. The proliferative
      activity and cell cycle were detected by MTT colorimetry and FACS. Furthermore,
      the expressions of signal proteins Smad3/4 in HLFs were observed by
      immunohistochemical staining and FACS. RESULTS: TGF beta 1 of 10 microg/L could
      promote the proliferation of HLFs, with the number of cells in S phase increased.
      It also could enhance the expression of Smad3 protein and promote the nuclear
      translocation of Smad4 protein. CONCLUSION: A given dose of TGF beta 1 can
      promote the proliferation of gamma rays-irradiated HLFs by regulating their cell
      cycle in which the activation of Smad pathway may play a role.

PMID- 15193220
TI  - [Expression of human growth hormone gene in mice and its effect on concentration
      of murine serum cytokines].
AB  - AIM: To explore the effects of high level human growth hormone(GH) on immune
      function. METHODS: The eukarytic expression plasmid containing hGH gene was
      constructed and then was injected into musculi quadriceps femoris of mice. 5th,
      15th and 25th day after injection, the murine sera were collected and the levels
      of hGH, IL-2, IFN-gamma and TNF-alpha were detected by ELISA. RESULTS: hGH cDNA
      was correctly cloned into pcDNA3. COS-1 cells transfected with the recombinant
      plasmid secreted high level of active hGH. The concentration of hGH in the sera
      of mice receiving the plasmid was obviously higher than that of control group.
      However, the concentrations of IL-2, IFN-gamma and TNF-alpha had no significant
      variation in comparison with those of control group. CONCLUSION: High level GH
      has no marked effect on secretion of IL-2, IFN-gamma and TNF-alpha.

PMID- 15193221
TI  - [The effect of copolymer-1 on the apoptosis and the IL-6R expression of the
      retinal ganglion cells in chronic elevated intraocular pressure rat model].
AB  - AIM: To observe the effect of autoimmune response induced by copolymer-1 (COP-1)
      on apoptosis of retinal ganglion cells (RGCs) and IL-6R expression on the RGCs in
      chronic elevated intraocular pressure (EIOP) rat models. METHODS: Thirty SD rats
      were randomly divided into 3 groups, namely normal control group, mock-immunized
      EIOP group and COP-1-immunized EIOP group. Cauterization of episcleral vein was
      used to set up rat's EIOP model. The normal control rats were not immunized,
      whereas the rats in the other two groups were immunized via i.p injection with
      normal saline and COP-1 at hindfeet, respectively. The expression of the IL-6R on
      RGCs was detected by immunohistochemical staining. The apoptosis of the RGCs was
      examined by TUNEL staining. RESULTS: The number of the apoptotic RGCs in the COP
      1- immunized EIOP group was notably lower than that in mock-immunized EIOP group
      (P<0.05). IL-6R were expressed on RGCs in all 3 groups, and expression level of
      IL-6R increased in the following order: normal control group, mock-immunized EIOP
      group and COP-1-immunized EIOP group (P<0.05). CONCLUSION: The autoimmune
      response induced by COP-1 protects the RGCs from apoptosis under the condition of
      chronic EIOP and results in increased IL-6R expression on RGCs. These results
      suggest that increased IL-6R expression on RGCs induced by COP-1 immunization
      with the protection of neurons resulted from autoimmune response is related.

PMID- 15193222
TI  - [The effects of culture supernatant of human GRC-1 cells transfected with PF4
      cDNA on the VEGF expression and the growth of ECV304 cells].
AB  - AIM: To construct the eukaryotic expression vector pcDNA3-PF4-SS, and to detect
      the effects of the culture supernatant of transfected GRC-1 cells on the VEGF
      expression in transfected GRC-1 cells and the growth of ECV304 cells. METHODS:
      The eukaryotic expression vector pcDNA3-PF4-SS was constructed and identified
      with Bgl II/BamH I digestion. The pcDNA3-PF4-SS was transfected stably into GRC-1
      cells with lipofectamine mediation. The VEGF expression in transfected GRC-1
      cells was detected by immunohistochemical staining, and the effect of the culture
      supernatant of transfected GRC-1 cells on ECV304 cells was detected by MTT
      colorimetry. RESULTS: Restrictive enzyme (Bgl II/BamH I)digestion analysis showed
      that the recombinant expression vector pcDNA3-PF4-SS had been constructed
      successfully. RT-PCR detection proved that hPF4 cDNA had been transfected into
      GRC-1 cells. The result of immunohistochemical staining showed that the VEGF
      expression could be seen in the cytoplasm and on cytomembrane of GRC-1 cells
      transfected with pcDNA3-PF4-SS, but the expression obviously weakened as
      comparison with that before transfection. Cell counting and MTT colorimetry
      manifested that the culture supernatant of transfected GRC-1 cells could inhibit
      markedly growth of ECV304 cells. CONCLUSION: The eukaryotic expression vector
      pcDNA3-PF4-SS has been constructed successfully, and stably transfected into the
      GRC-1 cells. The culture supernatant of transfected GRC-1 cells has obviously
      inhibitory effect on the growth of ECV304 cells and the VEGF expression in the
      GRC-1 cells, which lays some foundation for exploring the mechanism for anti
      tumor growth and developing tumor vaccine for kidney neoplasms.

PMID- 15193223
TI  - [Acceleration of mixed lymphocyte reaction by HCV C-Fc gene-transferred murine
      dendritic cells].
AB  - AIM: To observe the metergasis of murine dendritic cells (DCs) transfected with
      HCV C-Fc gene through electroporation. METHODS: Mononucleocytes isolated from
      murine bone marrow were co-cultured with rmGM-CSF and rm-IL-4 for 7 days.
      Morphological characteristics of the cultured cells were observed under scan
      electron-microscope (SEM) and the expression of DEC205 on the cells was detected
      by FACS. DCs derived from the culture were transfected with plasmids containing
      HCV C-Fc gene. HCV C-Fc level in the transfected cells was detected by indirect
      immunofluorescence assay. MLR was studied with DCs and T cells. RESULTS:
      Following 7-day culture, a large number of cells with typical characteristics of
      DC were observed. The HCV C-Fc level in the transfected DCs was higher. MLR was
      stimulated markedly by DCs transfected with HCV C-Fc gene in comparison with the
      control group. CONCLUSION: A large number of DCs could be generated from murine
      bone marrow mononucleocyte cultures supplemented with GM-CSF and IL-4 for 1 week.
      The function of DCs transfected with pcDNA3HCV C-Fc was enhanced in MLR.

PMID- 15193225
TI  - [Expression of MAGE-1 and MAGE-3 genes in gastric cancer and gastric biopsy
      tissues and its clinical significance].
AB  - AIM: To detect the expression of melanoma antigen-1 and -3 genes (MAGE-1 and MAGE
      3) and explore its significance in immunotherapeutic application. METHODS: The
      expression of MAGE-1 and MAGE-3 in gastric cancer, para-tumorous normal mucosa,
      and gastric biopsy tissues were detected by RT-PCR. The target genes in RT-PCR
      product were verified by means of DNA sequencing. RESULTS: MAGE-1 expression was
      positive in 26 out of 36 (72.22%) cases of gastric cancer, MAGE-3 positive in 25
      out of 36(69.44%), and both MAGE-1 and MAGE-3 positive in 19 out of 36 (52.78%).
      Positive expression rates of MAGE-1, MAGE-3 and both MAGE-1 and MAGE-3 were
      47.22%, 44.44% and 30.55%, respectively in para-tumorous normal mucosa, while
      29.73%, 27.03% and 8.1% in gastric biopsy tissues The positive rates of MAGE-1
      and MAGE-3 gene expressions in tumor tissues was significant higher than those
      its parallelism mucosae and biopsy tissues from chronic gastritis. The
      expressions of MAGE-1 and MAGE-3 genes in tumor tissues were relevant to intruded
      depth and the differentiated degree of tumor cells (P<0.05). CONCLUSION: MAGE-1
      and MAGE-3 protein may be used as targets molecules of immunotherapy for gastric
      cancer and indexes for follow-up study of chronic gastritis as well.

PMID- 15193224
TI  - [Experimental research using human bone marrow mesenchymal stem cells as the seed
      cells for bone and cartilage tissue engineering].
AB  - AIM: To investigate the feasibility of human bone marrow mesenchymal stem
      cells(hMSCs) as the seed cells for bone and cartilage tissue engineering.
      METHODS: Purified hMSCs were cultured in-vitro and induced to differentiate into
      osteoblasts and chondrocytes. Cellular morphologies were observed under inverted
      and electron microscopes. The specific markers of the osteoblasts and
      chondrocytes were detected by histochemical staining, immunohistochemical
      staining, and RT-PCR. RESULTS: After the hMSCs were passaged for 15 generations,
      the choractenistic morphology and cell surface antigens of hMSCs remained
      unchanged. The level of alkaline phosphatase(ALP) in the culture supernatant of
      the osteoinduction groups was higher than those in the control groups (P<0.05).
      The morphology of the cells in the osteoinduction and chondroinduction groups
      changed from spindle-shaped cells into polygon-shaped cells. A large number of
      the dilated rough endoplasmic reticulua, Golgi apparatus and mitochondria could
      be seen under transmission electron microscope. Calcium deposition was detected
      on the surfaces of the hMSCs after osteoinduction. Collagen(COL)-like processes
      were detected under scanning electron microscope. The staining of the ALP,
      calcium nudis, COL-I and osteocalcin(OC) were positive, and expressions of the
      COL-I and OC mRNAs were detected after osteoinduction. The expression of COL-II
      was detected by immunohistochemical staining and RT-PCR and a lot of the
      metachromatic-staining matrix around the cells was observed with toluidine blue
      staining after chondroinduction. CONCLUSION: hMSCs from human bone marrow can be
      purified, expanded and differentiated into osteoblasts and chondrocytes in-vitro,
      providing an alternative source for bone and cartilage tissue engineering.

PMID- 15193226
TI  - [Role of Akt/NF-kappa B signal transduction pathway in murine glomerular
      mesangial cell proliferation induced by immune complex].
AB  - AIM: To explore whether immune complex (IC) can directly induce glomerular
      mesangial cells(MCs) proliferation and the role of Akt/NF-kappa B signal pathway
      in the proliferation. METHODS: The mice were divided into control, stimulation
      and oligodeoxynucleotide(ODN) groups. In ODN group, MCs isolated from mice were
      transfected with Akt1 sense, mismatched or antisense ODN for 8 h, respectively,
      by using lipofectin, control and stimulation groups were incubated with
      lipofectin for 8 h. Then stimulation and ODN groups were incubated with
      aggregated IgG(AIgG)(a standard IC model), while the control group with monomeric
      IgG. MTT colorimetry was used to detect MCs proliferation. Distribution of MCs in
      cell cycle was analyzed by flow cytometry. Cyclin D1 mRNA and its protein
      expression were determined by RT-PCR and Western blot, respectively.The activity
      of NF-kappa B in MCs was determined by EMSA. RESULTS: AIgG activated NF-kappa B,
      upregulated cyclin D1 mRNA and its protein expression, and induced majority of
      MCs to enter S-phase in cell cycle. Akt1 antisense ODN specifically decreased
      AIgG-induced NF-kappa B activation, cyclin D1 mRNA and its protein expression,
      and then inhibited MCs to progress to S-phase and cell proliferation. Sense ODN
      and mismatched ODN had no such effects. CONCLUSION: IC can directly stimulate MCs
      proliferation through Akt/NF-kappa B signal pathway, suggesting that NF-kappa B
      probably be a useful molecule for targeted therapy in IC-mediated MC
      overproliferation.

PMID- 15193227
TI  - [Study on the attenuation of graft versus host disease by methoxy polyethylene
      glycol modification of donor lymphocytes].
AB  - AIM: To find out why mPEG modification of donor's lymphocytes can attenuate the
      occurrence of graft versus host disease(GVHD), but not affect the hemopoietic
      reconstitution of stem/progenitor cells after transplanting the mPEG-modified
      mononuclear cells from human cord blood into the SCID mice. METHODS: The
      followings were observed: (1) Changes of CD4(+) and CD8(+) T cells and the ratio
      of CD4(+)/CD8(+) T cells were examined by flow cytometry before and after
      mononuclear cells from human cord blood were modified with mPEG. (2) The
      difference in forming the CFU-GM in-vitro between the mPEG modified
      stem/progenitor cell group and non-modified cell group was observed. (3) The time
      of appearance of GVHD and the survival of the SCID mice were observed after the
      pre- and post-modification mononuclear cells were transplanted. (4) The number of
      humanized CD45(+) cells in the mouse's bone marrow was detected about 7 weeks
      after transplantation. RESULTS: (1) mPEG nearly completely covered up the CD4 and
      CD8 antigens on T cells, while the number of CFU-GM did not show any obvious
      change between the modified and non-modified cell groups. (2) GVHD appeared later
      in the modified mononuclear cell group than in the non-modified group, and the
      survival rate was elevated in the modified group than in the non-modified group.
      (3) Humanized CD45 cells were found in mouse's bone marrow at the 47th day after
      transplantation of both mPEG-modified and non-modified mononuclear cells.
      CONCLUSION: After CD4 and CD8 antigens were covered up with mPEG, the graft's
      immune response against host was weakened, but the proliferation and
      differentiation of transplanted hemopoietic stem/progenitor cells were not
      affected.

PMID- 15193228
TI  - [Study on T cell subsets and their activated molecules from the convalescent SARS
      patients during two follow-up surveys].
AB  - AIM: To explore the changes of peripheral blood T cell subsets and their
      activated molecules in convalescent SARS patients. METHODS: In two follow-up
      surveys of the SARS patients discharged from our hospital, the changes of CD3(+),
      CD4(+), CD8(+), CD8(+) CD28(+), CD8(+) CD28(-), CD3(+) CD25(+), CD3(+) CD69(+),
      CD3(+) HLA-DR(+)T cells and the ratio of CD4(+)/CD8(+) T cells in peripheral
      blood of SARS patients treated unitedly with Chinese and Western medicines were
      detected by flow cytometry. RESULTS: In two follow-up surveys, the percentages of
      CD3(+), CD4(+), CD8(+) CD28(+) T cells and the ratio of CD4(+)/CD8(+) T cells
      were remarkably lower than those of normal values(P<0.05), while the percentage
      of CD8(+) CD28 (-) T cells was higher(P<0.01). As for the percentages of CD3(+),
      CD8(+), CD4(+)/CD8(+), CD3(+) CD25(+), CD3(+) CD69(+) and CD3(+) HLA-DR(+) T
      cells, there was marked difference between 1st and 2nd follow-up results, but for
      other molecules there was no notable difference. CONCLUSION: The convalescent
      SARS patients' immune function gradually recovers, and the effect of SARS virus
      on activation of T cells gradually disappears.

PMID- 15193229
TI  - [A HLA-A2-restricted-CTL epitope variation at the N-terminal of HCV helicase and
      the immune response of CTLs].
AB  - AIM: To investigate a HLA-A2-restricted CTL epitope variation at the N terminal
      of hepatitis C virus (HCV) helicase and the proliferative response of cytotoxic T
      lymphocytes (CTLs) to this epitope. METHODS: Two patients infected with HCV were
      followed up for 7 years. Blood samples taken at the first year and the fifth year
      were used for viral RNA extraction. Using RT-PCR, the N terminal gene of helicase
      region was amplified from the extracted RNA. The amplified segments were
      subcloned and sequenced to assess the epitope variation. A HLA-A2-restricted CTL
      epitope peptide was synthesized according to the sequencing result. HLA types of
      the two patients were determined by serological method. The peripheral blood
      lymphocytes were separated from the two patients at 7th year after infection and
      cultured with the synthetic CTL epitope peptide to assess the CTL's proliferative
      response. RESULTS: In the HLA-A2(+) individual, there was an amber mutation at
      the first amino acid of the epitope in the first year after infection, but the
      amber mutation disappeared after 5 years. However, in the HLA-A2(-) individual,
      the epitope had neither variation nor amber mutation in 5 years after infection.
      7 years after HCV infection, T lymphocytes from both individuals had no
      proliferative response to the epitope peptide. CONCLUSION: The amber mutation of
      the epitope at N terminal of helicase may be associated with viral immune escape.
      CTLs have no response to the epitope peptide in the N terminal of HCV helicase in
      the later stage of chronic HCV infection.

PMID- 15193230
TI  - [Expression and activation of MAPK pathway signaling molecules in human breast
      cancer cell lines].
AB  - AIM: To detect the expression and status of extracellular regulatory kinase 1 and
      2 (ERK1/2) and its upstream kinase MEK1/2 proteins in four breast cancer cell
      lines MCF-7, Bcap-37, SK-BR-3 and T47D and study the effects of cyclophosphamide
      and epirubicin on the growth of the cell lines and on the expression and status
      of the signaling molecules. METHODS: Western blot was used to examine the
      expression and status of MEK1/2 and ERK1/2 proteins in these cells and the
      effects of these two drugs on them. The effects of the two drugs on the
      proliferation of these breast cancer cell lines were detected by MTT colorimetry.
      RESULTS: The levels of expression and phosphorylation of MEK1/2 and ERK1/2
      proteins in four breast cancer cell lines increased notably as compared with
      those in MCF-10 cells. Both drugs could inhibit the proliferation of breast
      cancer cells. And the levels of expression and phosphorylation of MEK1/2 and
      ERK1/2 proteins in breast cancer cell lines treated with the drugs were markedly
      lower than those in untreated breast cancer cells. CONCLUSION: Overexpression and
      phosphorylation of MEK and ERK may play an important role in the generation and
      development of human breast cancer. The inhibitory effect of cyclophosphamide and
      epirubicin on proliferation of the breast cancer cells may be by means of
      inhibiting expression and phosphorylation of MEK and ERK.

PMID- 15193231
TI  - [The cytokine secretion of peripheral blood mononucleocytes from patients
      infected with HCV].
AB  - AIM: To detect the levels of cytokines secreted by PBMC from patients infected
      with HCV after culture for 72 hours in-vitro, so as to reflect the immune state
      of the HCV-infected patients. METHODS: The levels of cytokines in the culture
      supernatant of PBMCs were detected by ELISA. RESULTS: (1)Compared with the
      cytokine level of normal control, the levels of IFN-gamma, TNF-alpha, and IL-10
      of HCV patients notably increased while IL-2, IL-4, and IL-12 were not detected
      in the culture supernatant of PBMCs from both normal control and HCV patients
      after culture for 72 hours. (2)There was no statistic difference in secretion of
      cytokines among the patients with mild, and moderate chronic hepatitis, and
      compensated or uncompensated cirrhosis. CONCLUSION: (1)PMBCs from the HCV
      infected patients tend to secret Th2 type cytokines. (2)Lack of the IL-2
      secretion from PBMCs of HCV patients may account for the immune escape of HCV.

PMID- 15193232
TI  - [The influence of TLSFJM on the proportion of Th1/Th2-like cell subsets].
AB  - AIM: To explore the influence of TLSF(JM) on the proportion of alloantigen
      activated Th1 and Th2-like cell subsets. METHODS: TLSF(JM) or IL-4 was added to
      mixed lymocyte reaction(MLR) system. The influence of TLSF(JM) on the proportion
      of Th1 and Th2-like cell subsets was analyzed by intracellular immunofluorescence
      staining and FACS. RESULTS: In the TLSF(JM) group, the proportion of IFN-gamma(+)
      cells differentiated from activated lymphoblast descended from 49.8% to 43.1%, IL
      4(+) cells from 75.4% to 43.7% and IL-6(+) cells from 67.8% to 52.6%. The similar
      tendency was also observed in the unactivated small lymphocytes. CONCLUSION:
      TLSF(JM) can inhibit both the Th1 and Th2-like cell subsets, but mainly inhibit
      the Th2-like cell subset, thereby reducing the proportion of Th2-like cell
      subsets.

PMID- 15193234
TI  - [Cloning and expression of the extracellular domain of calcium-activated chloride
      channel in mouse airway goblet cells].
AB  - AIM: To clone and express the extracellular domain of murine calcium-activated
      chloride channel (mCLCA3) in airway goblet cell of mouse. METHODS: According to
      the gene sequence of mCLCA3 the PCR primers for N-terminal, middle and C-terminal
      extracellular domains were designed. Using recombinant plasmid pcDNA3.1(-)/mCLCA3
      as template, the DNAs coding for the three extracellular domains were amplified.
      And then the DNAs encoding N-terminal and C-terminal extracellular domains were
      inserted into expression vector pRSET-A, while the middle extracellular domain
      DNA was inserted into pGEX-T1. E.coli. BL21(DE3) were transformed with the three
      recombinant plasmids, respectively, and were induced with IPTG for expression.
      RESULTS: DNA sequencing showed that the cloned DNAs encoding extracellular
      domains were identical with those in GenBank (GenBank accession No. NM-017474 ).
      The 3 domains were expressed in E.coli and most of the expressed products existed
      in the form of inclusion body. CONCLUSION: The expression of three extracellular
      domains of mCLCA3 lays the foundation for further preparing anti-mCLCA3 antibody
      and exploring the mechanism of modulation of mCLCA3.

PMID- 15193233
TI  - [The isolation and expansion of gamma delta T cells in peripheral blood and
      bronchoalveolar lavage fluid].
AB  - AIM: To explore the method of selective culture of gamma delta T cells in
      peripheral blood and bronchoalveolar lavage fluid(BALF) for obtaining pure gamma
      delta T cell subset. METHODS: A novel attack-panning method for selectively
      culturing gamma delta T cells was set up. The peripheral blood mononuclear cells
      (PBMCs) and BALF were isolated by Ficoll-hypaque density gradient centrifugation
      (n=10). alpha beta T cells in PBMCs were depleted by complement-dependent
      cytotoxicity(CDC) after the monocytes/macrophages were removed by adherence. The
      gamma delta T cells in PBMCs were cultivated selectively using anti-TCR gamma
      delta monoclonal antibody and IL-2. The proliferation of gamma delta T cells were
      observed by plotting growth curve. The purity of gamma delta T cells were
      detected by flow cytometry and immunohistochemistry. RESULTS: Stimulated by anti
      TCR gamma delta mAb and IL-2, gamma delta T cells of peripheral blood and BALF
      could proliferate for a few days. The purity of gamma delta T cells obtained by
      Attack-panning method was 81%-99%. CONCLUSION: The attack-panning method can get
      pure gamma delta T cells from peripheral blood and BALF.

PMID- 15193235
TI  - [Construction and identification of recombinant adenovirus vector containing Tet
      on adjustable NT3 and BDNF genes].
AB  - AIM: To construct Tetracycline(tet) inducible recombinant adenovirus vectors
      containing human neurotrophin 3(NT3) and brain-derived neurotrophic factor(BDNF)
      genes, respectively and perform PCR and restrictive enzyme digestion analysis.
      METHODS: Full length NT3 and BDNF cDNAs were subcloned into pIND vector, followed
      by being cloned into pTRE-shuttle2 vector. The NT3 and BDNF gene fragments
      resulted from the pTRE-shuttle2-NT3 and pTRE-shuttle2-BDNF digested with I-Ceu I
      and PI-Sce I were linked to the linear adeno-X virus DNA. The recombinant
      adenovirus vectors were confirmed by PCR and restriction enzyme digestion
      analysis. RESULTS: The PCR identification showed that a given band with 312 bp,
      and predictive fragments proved by restriction enzyme digestion analysis were
      exhibited. All the above results indicated that human NT3 and BDNF genes had been
      connected with pAdeno-X vectors correctly. CONCLUSION: Tet inducible recombinant
      adenovirus vector of Human NT3 and BDNF genes have been constructed successfully,
      which upon packaged in HEK293 cells, will be used to introduce the target genes
      into Schwann's cells in-vitro or in-vivo.

PMID- 15193236
TI  - [Purification of colorectal cancer-associated antigen by immuno-affinity
      chromatography].
AB  - AIM: To purify and characterize the colorectal cancer-associated antigen from
      cultured colorectal cancer cells. METHODS: The colorectal cancer cell lines that
      highly expressed the associated antigen were selected by flow cytometry with five
      specific monoclonal antibodies (mAbs) CYL1-5. Western blot was used to determine
      the binding ability of five mAbs to the associated antigens released from
      colorectal cells lysed with single or triplex-detergent, respectively. The mAb
      with highest binding ability was employed as the ligand for the immuno-affinity
      chromatography. The antigens purified through immuno-affinity chromatography were
      identified by Western blot. RESULTS: The associated antigens were highly
      expressed on the colorectal cancer cell lines Hce-8693. The binding ability of
      mAb CYL-2 to the antigen was higher than that of CYL-1, CYL-3-5. The purified
      associated antigen binding to mAb CYL-2 was a heterodimer composed of two
      subunits with relative molecular mass (M(r)) of 60 x 10(3) and 70 x 10(3),
      respectively. CONCLUSION: The purified associated-antigen binding to mAb CYL-2
      was obtained from the colorectal cancer cell line Hce-8693 through immuno
      affinity chromatography with mAb CYL-2.

PMID- 15193237
TI  - [Prediction of T-cell epitopes from schistosoma japonicum 28 kDa glutathione-S
      transferase and identification of their Th1 type T-cell epitopes].
AB  - AIM: To predict T-cell epitopes of recombinant schistosoma japonicum 28 kDa
      glutathione-S-transferase(GST) with software and identify the Th1 type T-cell
      epitopes by experiments. METHODS: T-cell epitopes of recombinant schistosoma
      japonicum 28kDa GST were predicted with software and several epitopic candidates
      were screened from them according to their scores. Some of the epitopic
      candidates were synthesized and the other epitope peptides fused with
      thioredoxin(Trx) were expressed in E.coli BL21(DE3) and purified by Ni(+) column
      affinity chromatography. C57BL/6 (H-2(b)) mice's were immunized via peritoneal
      infection with ultraviolet ray irradiated-cercariae and then boosted with
      recombinant schistosoma japonicum 28 kDa GST. The immunized mice splenocytes were
      prepared, cultured and stimulated with synthesized epitope peptides and epitope
      peptide fusion proteins, respectively. Stimulation activity of synthesized
      epitope peptides and epitope peptides fusion proteins were assayed by lymphocyte
      proliferation assay. Levels of IFN-gamma and IL-2 were measured by ELISA. CD4(+)
      T cells and T cells secreting IFN-gamma and IL-4 were detected by flow cytometry.
      RESULTS: Epitope P6(73-86aa) among 9 epitopic candidates could generate the
      strongest stimulation effect on splenocytes, stimulate secretion of higher levels
      of IFN-gamma and IL-2, and induce more IFN-gamma(+) and IL-4 (+) T cells.
      CONCLUSION: The recombinant 28 kDa GST possesses functional Th1 type T-cell
      epitope.

PMID- 15193239
TI  - [Preparation and the anti-tumor activity of mutant Staphylococcal enterotoxin B].
AB  - AIM: To prepare mutant Staphylococcal enterotoxin B(SEB) and observe its anti
      tumor activity. METHODS: The expressed mutant SEB-K172E in inclusion body was
      denatured and renatured, and then isolated and purified. The anti-tumor activity
      of the mutant SEB-K172E was compared with wild-type SEB. RESULTS: Renaturation
      and purification method of the mutant SEB-K172E was developed. The anti-tumor
      activity of acquired mutant protein was ten times higher than that of wild-type
      SEB. CONCLUSION: The anti-tumor activity of the mutant SEB-K172E is much higher
      than that of wild-type SEB, suggesting that the mutant SEB-K172E may become a
      potential anti-tumor drug.

PMID- 15193238
TI  - [Preliminary study on regulable DNA vaccines against Plasmodium falciparum].
AB  - AIM: To construct regulable DNA vaccine against Plasmodium falciparum by using
      tetracycline(Tet) regulable system. METHODS: Eukaryotic expression vectors pTL
      8/apical membrane antigen 1 (AMA-1) (tTA) and pTL-8/AMA-1(rtTA) gene which
      express trans-activator (tTA) or reverse trans-activator(rtTA), respectively, and
      AMA-1 gene of Plasmodium falciparum were constructed. BALB/c mice were immunized
      with these plasmids and doxycycline (dox) was administered to regulate the
      expression of AMA-1. For some mice immunized with pTL-8/AMA-1(rtTA), pUHS6-1, a
      plasmid containing trans-silencer (tTS) to suppress basal expression of AMA-1
      from pTL-8/AMA-1(rtTA), was injected into these mice together with pTL-8/AMA
      1(rtTA). The sera of the mice were isolated at 2,4,6 and 8 weeks post
      immunization and the antibodies specific to AMA-1 were measured by ELISA.
      RESULTS: pTL-8/AMA-1 and pTL-8/AMA-1(rtTA) were constructed successfully. The
      mice immunized by pTL-8/AMA-1(tTA) with dox or by pTL-8/AMA-1(rtTA) without dox
      (at these conditions, AMA-1 was expressed at basal level)developed significant
      antibodies against AMA-1. Mice immunized by pTL-8/AMA-1(rtTA) and pUHS6-1 without
      dox did not develop significantly antibodies against AMA-1. In contrast, the mice
      immunized by pTL-8/AMA-1(rtTA) and pUHS6-1 with dox produced high level of
      antibodies. CONCLUSION: pTL-8/AMA-1(rtTA) combined with pUHS6-1 is a good
      regulable DNA vaccine candidate against Plasmodium falciparum.

PMID- 15193240
TI  - [Construction of expression vector for human-mouse chimeric antibody and
      expression of an antibody against human HER2].
AB  - AIM: To construct universal eukaryotic expression vector for expressing human
      mouse chimeric antibody and have application in expression of PCR-obtained mouse
      variable region gene fragments in the form of human-mouse chimeric antibody, for
      the purpose of clinical therapy. METHODS: By using human Tac antigen signal
      peptide and kappa chain and gamma 1 heavy chain gene fragments of human Ig, we
      constructed a versatile expression vector for human-mouse chimeric antibody and
      used it to transfect cultured 293T cells. The expressed product was detected
      using RT-PCR, FACS and ELISA. RESULTS: An expression vector for PCR-derived V
      genes of mouse Ig as human-mouse chimeric antibody was constructed. The V(L) and
      V(H) genes encoding mouse anti-human HER2 antibody were amplified with primers
      designed for this expression system, and an expression vector for chimeric
      antibody against human HER2 was constructed. By transfection of 293T cells, we
      demonstrated that a chimeric antibody was produced and secreted to the culture
      medium. CONCLUSION: This expression system is useful for antibody engineering for
      it provides a simple way to express chimeric antibody from V genes of mouse
      antibody obtained by PCR.

PMID- 15193241
TI  - [Detection of LOS-specific antibody-secreting cells by ELISPOT assay].
AB  - AIM: To detect dynamically the response of specific antibody-secreting cells
      elicited by a detoxified-lipooligosaccharide-cross-reactive mutant (dLOS-CRM) of
      diphtheria toxin conjugate vaccine for Moraxella catarrhalis (M.cat). METHODS:
      BALB/c mice were intranasally immunized with dLOS-CRM conjugate vaccine. The
      specific antibody-secreting cells responding to LOS of M. cat in different
      inductive and effective sites, including nasally associated lymphoid tissues
      (NALT), spleen, cervical lymph nodes (CLN), nasal passages (NP), lungs and
      Peyer's patches (PP) were detected by an enzyme-linked immunospot assay
      (ELISPOT). The levels of LOS-specific antibodies IgA, IgG and IgM in serum, nasal
      flush fluid, alveolar douche fluid, saliva and fecal extract were also detected
      by ELISA. RESULTS: Intranasal immunization with dLOS-CRM plus cholera toxin
      induced a significantly dose-dependent enhancement of immune response. LOS
      specific antibody (IgA,IgG or IgM)-secreting cells were found in NALT, spleens,
      CLN, NP, lungs and PP with most LOS-specific IgA antibody-secreting cells located
      in nasal passages, and next, NALT and lungs. It was correlated well with the
      level of LOS-specific IgA, IgG or IgM antibody titers in nasal flush fluid,
      alveolar douche fluid, saliva, serum and fecal extract. CONCLUSION: dLOS-CRM can
      induce specific mucosal and systemic humoral immune response through intranasal
      immunization. ELISPOT assay is quick, sensitive, specific, and would be a very
      useful tool to analyze dynamically the mechanism of single antibody-secreting
      cell response.

PMID- 15193242
TI  - [Preparation and characterization of monoclonal antibodies against human plasmin
      alpha 2-antiplasmin complexes].
AB  - AIM: To prepare monoclonal antibodies (mAbs) against human plasmin-alpha(2)
      antiplasmin complexes (PAP). METHODS: BALB/c mice were immunized with PAP
      purified from human fresh plasma. The splenocytes of immunized mice were fused
      with Sp2/0 cells and the cultural supernatants of hybridoma cells were screened
      by indirect ELISA with equimolar plasminogen, alpha(2)-antiplasmin and PAP as
      immobilized antigen, respectively. The specificity and affinity of mAbs in
      ascitic fluids were characterized by Western blot and ELISA, respectively.
      RESULTS: Among the 24 specific mAbs obtained, 7 were directly against neoantigens
      (new emerging epitopes that were different from PAP precursor plasminogen and
      alpha(2)-antiplasmin, which are formed during PAP generation), 16 against plasmin
      domain and 1 against modified alpha(2)-antiplasmin in PAP molecule. Titers of all
      the mAbs to PAP were from 2 x 10(-4) to 1 x 10(-8), and 4 of them could strongly
      recognize PAP or plasminogen (K(d) from 5.62 x 10(-9) to 3.58 x 10(-11) mol/L).
      CONCLUSION: The mAbs against PAP neoantigens with high affinity was acquired
      successfully, which provided a tool for determination of plasma levels of PAP
      without interferences from plasminogen and alpha(2)-antiplasmin and for research
      on fibrinolytic status in-vitro.

PMID- 15193245
TI  - Positron emission tomography scan findings of autoimmune lymphoproliferative
      syndrome.

PMID- 15193243
TI  - [Preparation and characterization of monoclonal antibody against Clostridium
      difficile toxin A].
AB  - AIM: To prepare monoclonal antibodies (mAbs) against Clostridium difficile toxin
      A and identify their properties. METHODS: BALB/c mice were immunized with
      C.difficile toxin A. The splenocytes from immunized mice were fused with myeloma
      cells Sp2/0. The hybridoma cells were screened by indirect ELISA and limiting
      dilution method. The titer and relative affinity of ascitic mAbs were determined
      by ELISA. Specificity of mAbs was analyzed by Western blot. RESULTS: Six
      hybridoma cell lines (2H7, 3E9, 4B5, 5C10, 6G8 and 8A1) secreting mAbs against
      C.difficile toxin A were obtained. The Ig classes and subclasses of mAbs 2H7, 3E9
      and 6G8 were IgM, mAbs 4B5 and 8A1 were IgG1, and mAb 5C10 was IgG2a. All 6 mAbs
      had no neutralization activity. Epitope recognized by 5 mAbs(2H7, 4B5, 5C10, 6G8
      and 8A1) differed from that by mAb 3E9. Relative affinities of mAbs 8A1 and 4B5
      were all above 10(5), and those of other 4 mAbs were 10(4). Western blot analysis
      no-denatured PAGE showed that all 6 mAbs reacted to C.difficile toxin A with M(r)
      being 55 x 10(4), and under the condition of denatured SDS-PAGE, Western blot
      analysis showed that all 6 mAbs reacted to subunits of C.difficile toxin A with
      M(r) being 5 x 10(4)-24 x 10(4). CONCLUSION: Six mAbs against C.difficile toxin A
      with high titers were obtained successfully with satisfactory specificity and
      relative affinity, which will be useful for detection of C.difficile toxin A.

PMID- 15193246
TI  - The role of 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission
      tomography/computed tomography in monitoring the immunosuppressive therapy
      response of inflammatory myofibroblastic tumor.
AB  - PURPOSE: To compare the pre and post treatment 2-deoxy-2-[(18)F]fluoro-D-glucose
      (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging
      findings of an inflammatory myofibroblastic tumor (IMT) with its clinical
      response to immunosuppressive therapy. PROCEDURE: Forty-nine-year-old female
      presented with dyspnea, chest pain, and weight loss and underwent an FDG-PET/CT
      scan before and after mediastinal biopsy and treatment with dexamethasone and
      thalidomide. RESULTS: FDG-PET/CT scan demonstrated a hypermetabolic mediastinal
      mass. The biopsy of the lesion was consistent with IMT. Following
      immunosuppressive therapy, the patient's clinical findings resolved, and PET/CT
      showed a significant decrease in the FDG uptake and the size of the mass.
      CONCLUSION: Pre-treatment imaging features and post-treatment imaging
      characteristics of IMT correlate with clinical findings and suggest that FDG
      PET/CT may be useful as an adjunct to clinical evaluation in monitoring of
      immunosuppressive therapy of IMT.

PMID- 15193247
TI  - Intravascular probe for detection of vulnerable plaque.
AB  - PURPOSE: Coronary angiography defines geometry of lumen of artery. However,
      perhaps 70% of heart attacks occur when minimally obstructive thin capped
      fibroatheroma rupture, causing thrombus and arterial occlusion. We have developed
      an intravascular imaging detector to identify vulnerable coronary artery plaque.
      PROCEDURE: Detector measures beta or conversion electron emissions from plaque
      binding radiotracers. Detector assembly fits into a 2-mm diameter catheter and
      overcomes technical constraints of size, sensitivity, and conformance to
      intravascular environment. RESULTS: Device was tested by stepping test point
      sources past detector to verify function. System resolution is 6.7 mm and
      sensitivity is 400 cps/microCi one mm from detector. CONCLUSION: This prototype
      is a first step in imaging of labeled vulnerable plaque in coronary arteries.
      This type of system may assist in development of targeted and cost effective
      therapies to lower incidence of acute coronary artery diseases (CAD) such as
      unstable angina, acute myocardial infarction, and sudden cardiac death.

PMID- 15193248
TI  - Quantitation of cell number by a positron emission tomography reporter gene
      strategy.
AB  - PURPOSE: An important potential of positron emission tomography (PET) is the
      capacity for quantitation of cell signals in an anatomic regions of interest.
      However, little is known about the constraints and parameters for using PET
      signal detection to establish cell numbers in regions of interest. In this study,
      we determined the correlation of PET signal to cell number, and characterized the
      cellular limit of detection for PET imaging. PROCEDURES: Cells expressing the
      herpes simplex virus type I thymidine kinase PET reporter gene (HSV1-sr39TK) were
      detected following accumulation of [(18)F]FHBG (9-[4-[(18)F]-fluoro-3
      (hydroxymethyl) butyl]guanine) by microPET scanning and quantitation. RESULTS:
      When cells were cultured with [(18)F]FHBG in vitro, and then transferred to a
      model vascularized site, 73% retention was observed one hour post-transfer. Using
      this information, and the measured attenuation of PET signal in whole mouse
      scans, we assessed the per-cell uptake of [(18)F]FHBG in the vascularized site
      following standard parenteral administration of the substrate. We observed a cell
      number-dependent signal, with a limit of detection calculated as 10(6) cells in a
      region of interest of 0.1 mL volume. Quantitatively similar parameters were
      observed with stably tranfected N2a glioma cells and retrovirally transduced
      primary T lymphocytes. CONCLUSION: These methods and findings provide a strategy
      for quantitation of cellularity using PET imaging that has implications for both
      experimental models and clinical diagnosis.

PMID- 15193249
TI  - Development of a 4-D digital mouse phantom for molecular imaging research.
AB  - PURPOSE: We develop a realistic and flexible 4-D digital mouse phantom and
      investigate its usefulness in molecular imaging research. METHODS: Organ shapes
      were modeled with non-uniform rational B-spline (NURBS) surfaces based on high
      resolution 3-D magnetic resonance microscopy (MRM) data. Cardiac and respiratory
      motions were modeled based on gated magnetic resonance imaging (MRI) data
      obtained from normal mice. Pilot simulation studies in single-photon emission
      computed tomography (SPECT) and X-ray computed tomography (CT) were performed to
      demonstrate the utility of the phantom. RESULTS: NURBS are an efficient and
      flexible way to accurately model the anatomy and cardiac and respiratory motions
      for a realistic 4-D digital mouse phantom. The phantom is capable of producing
      realistic molecular imaging data from which imaging devices and techniques can be
      evaluated. CONCLUSION: The phantom provides a unique and useful tool in molecular
      imaging research. It can be used in the development of new imaging
      instrumentation, image acquisition strategies, and image processing and
      reconstruction methods.

PMID- 15193250
TI  - Myocardial viability in patients with ischemic cardiomyopathy-evaluation by 3-D
      integration of myocardial scintigraphic data--and coronary angiographic data.
AB  - PURPOSE: To determine the prevalence of viable myocardium in patients with
      ischemic cardiomyopathy and, to evaluate the value of three-dimensional (3-D)
      fusion imaging of myocardial scintigraphic and angiographic data to assign
      coronary artery lesions to the corresponding viable and nonviable myocardial
      territory. PROCEDURES: In 105 patients, the combination of perfusion and
      metabolic imaging with (201)thallium ((201)TI) single-photon emission computed
      tomography (SPECT) and 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission
      tomography (PET) determined viability in dysfunctional myocardium. In addition,
      the value of 3-D scintigraphic fusion imaging was assessed in these patients.
      RESULTS: Based on the presence of viable dysfunctional myocardium, 54% of
      patients with ischemic cardiomyopathy may be considered for coronary
      revascularization. In 31 of 105 patients, the 3-D fusion imaging was estimated to
      be helpful in the diagnostic and interpretative process. CONCLUSION: In patients
      with end-stage coronary artery disease scintigraphic imaging is most important in
      the decision-making process. Three-dimensional fusion imaging may add important
      information in approximately 30% of these patients.

PMID- 15193251
TI  - Oncological diagnosis using (11)C-choline-positron emission tomography in
      comparison with 2-deoxy-2-[(18)F] fluoro-D-glucose-positron emission tomography.
AB  - PURPOSE: To assess and compare the usefulness of (11)C-Choline-positron emission
      tomography (PET) with that of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG)-PET for the
      differentiation between benign and malignant in various tumors. MATERIALS AND
      METHODS: We examined 38 consecutive patients with various tumors, including seven
      patients with brain tumors, two with oral cavity tumor, two with esophageal
      cancer, six with lung cancer, 11 with bone tumor, nine with soft tissue tumors,
      and one with myeloma. (11)C-Choline-PET and FDG-PET were performed from five
      minutes and 40 minutes, respectively, after injection of 275-455 MBq tracer.
      Tracer uptakes were evaluated by the standardized uptake value (SUV) and were
      analyzed in according to the pathologic data. RESULTS: (11)C-Choline uptake in
      malignancies (3.9 +/- 1.7, n=24) was significantly higher than that in benign
      lesions (1.7 +/- 1.2, n=14) (P < 0.0001). On the other hand, the FDG uptake in
      malignancies was 4.9 +/- 2.0 (n=24) and was also significantly larger than that
      in benign lesions 1.6 +/- 1.3 (n=14) (P < 0.0001). The (11)C-Choline uptake in
      all the lesions correlated with FDG uptake (r=0.658, P < 0.02, n=38). According
      to the receiver operating characteristic (ROC) analysis, the area under the ROC
      curve for (11)C-Choline-PET was 0.871, and with no significant difference
      compared to FDG-PET with the area of 0.929. CONCLUSIONS: This study demonstrated
      that (11)C-Choline-PET is similar to FDG-PET in differentiation between malignant
      and benign lesion in various tumors.

PMID- 15193252
TI  - Naturally death-resistant precursor cells revealed as the origin of
      retinoblastoma.
AB  - The molecular mechanisms and the cell-of-origin leading to retinoblastoma are not
      well defined. In this issue of Cancer Cell, Bremner and colleagues describe the
      first inheritable model of retinoblastoma, revealing that loss of the pocket
      proteins pRb and p107 deregulates cell cycle exit in retinal precursors. The
      authors show that a subset of these precursors contain an inherent resistance to
      apoptosis, and that while most terminally differentiate, some are likely to
      acquire additional mutations, leading to tumor formation. Thus, this work defines
      the cell-of-origin of retinoblastoma and suggests that mutations giving increased
      proliferative capacity are required for retinoblastoma development.

PMID- 15193253
TI  - The linchpin? Pin1 meets p73.
AB  - A recent paper shows that the peptidyl-prolyl isomerase Pin1 conformationally
      alters p73, promoting its acetylation by p300 in a c-Abl dependent manner. Given
      previous findings with p53, Pin1 may represent a common mediator linking
      proapoptotic cooperative activity of the p53 family members.

PMID- 15193254
TI  - Lost in translation: dysregulation of cap-dependent translation and cancer.
AB  - Activation of the phosphatidylinositol 3' kinase-Akt pathway has long been
      associated with malignant transformation and antiapoptotic signaling. Mutations
      downstream of Akt that activate the TOR kinase are found in tumor-prone
      syndromes, while overexpression of translation initiation complex components,
      such as eIF4E, occurs frequently in human cancer. However, direct roles for TOR
      signaling or eIF4E overexpression, in the genesis of cancer, have been lacking.
      Recent papers, including one by in this issue of Cancer Cell, clearly establish
      that dysregulation of cap-dependent translation confers malignant characteristics
      and induces cancer by suppressing apoptosis, underscoring the potential of
      therapeutics that selectively target the Akt-TOR-eIF4E pathway.

PMID- 15193256
TI  - Focus on endometrial and cervical cancer.

PMID- 15193255
TI  - Tyrosine kinase inhibitors: why does the current process of clinical development
      not apply to them?
AB  - The robust clinical activity of imatinib and trastuzumab for treatment of chronic
      myeloid leukemia, gastrointestinal stromal tumors, and breast cancer has
      demonstrated that blocking pathogenic tyrosine kinases can alter the natural
      history of human tumors. On the other hand, EGF receptor inhibitors have shown
      overall modest activity. The contrast in the development of these agents implies
      that both molecular target dependence and patient selection are essential for the
      successful outcome of this process. We will contrast lessons derived from the
      development of inhibitors of Abl, c-Kit, HER2/neu (erbB2), and EGFR, highlight
      successes and limitations in the field, and propose new approaches for clinical
      development of tyrosine kinase inhibitor therapy.

PMID- 15193257
TI  - Cell-specific effects of RB or RB/p107 loss on retinal development implicate an
      intrinsically death-resistant cell-of-origin in retinoblastoma.
AB  - Retinogenesis involves expansion of pluripotent progenitors, specification of
      postmitotic precursors, and terminal differentiation. Rb or Rb/p107 loss causes
      retinoblastoma in humans or mice, respectively. One model suggests that Rb- or
      Rb/p107-deficient retinal precursors have infinite proliferative capacity but are
      death-prone and must acquire an antiapoptotic mutation. Indeed, we show that
      Rb/p107 loss does not affect progenitor proliferation or precursor specification,
      but perturbs cell cycle exit in all seven retinal precursors. However, three
      precursors survive Rb/p107-loss and stop proliferating following terminal
      differentiation. Tumors arise from precursors that escape this delayed growth
      arrest. Thus, retinoblastoma arises from a precursor that has extended, not
      infinite, proliferative capacity, and is intrinsically death-resistant, not death
      prone. We suggest that additional lesions common in retinoblastoma overcome
      growth arrest, not apoptosis.

PMID- 15193258
TI  - Activation of translation complex eIF4F is essential for the genesis and
      maintenance of the malignant phenotype in human mammary epithelial cells.
AB  - Common human malignancies acquire derangements of the translation initiation
      complex, eIF4F, but their functional significance is unknown. Hypophosphorylated
      4E-BP proteins negatively regulate eIF4F assembly by sequestering its mRNA cap
      binding component eIF4E, whereas hyperphosphorylation abrogates this function. We
      found that breast carcinoma cells harbor increases in the eIF4F constituent
      eIF4GI and hyperphosphorylation of 4E-BP1 which are two alterations that activate
      eIF4F assembly. Ectopic expression of eIF4E in human mammary epithelial cells
      enabled clonal expansion and anchorage-independent growth. Transfer of 4E-BP1
      phosphorylation site mutants into breast carcinoma cells suppressed their
      tumorigenicity, whereas loss of these 4E-BP1 phosphorylation site mutants
      accompanied spontaneous reversion to a malignant phenotype. Thus, eIF4F
      activation is an essential component of the malignant phenotype in breast
      carcinoma.

PMID- 15193259
TI  - Inhibition of HER-kinase activation prevents ERK-mediated degradation of
      PPARgamma.
AB  - R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of
      CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer
      xenograft growth through downregulation of cyclin D1 expression via the PPARgamma
      pathway. PPARgamma protein degradation, observed post-R-etodolac treatment,
      resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively
      regulating PPARgamma function. Negative regulation of PPARgamma was overcome by a
      combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4,
      which demonstrated an additive antitumor effect. We further show that the
      inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit
      PPARgamma protein degradation. This study introduces a novel concept of an in
      vivo crosstalk between the HER-kinase axis and PPARgamma pathways, ultimately
      leading to negative regulation of PPARgamma activity and tumor growth inhibition.

PMID- 15193260
TI  - Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes
      cancerous phenotypes.
AB  - We identified dynein light chain 1 (DLC1) as a physiologic substrate of p21
      activated kinase 1 (Pak1). Pak1-DLC1 interaction plays an essential role in cell
      survival, which depends on Pak1's phosphorylation of DLC1 on Ser88. Pak1
      associates with the complex of DLC1 and BimL, a proapoptotic BH3-only protein,
      and phosphorylates both proteins. Phosphorylation of BimL by Pak1 prevents it
      from interacting with and inactivation of Bcl-2, an antiapoptotic protein.
      Overexpression of DLC1 but not DLC1-Ser88Ala mutant promotes cancerous properties
      of breast cancer cells. DLC1 protein level is elevated in more than 90% of human
      breast tumors. The regulation of cell survival functions by Pak1-DLC1 interaction
      represents a novel mechanism by which a signaling kinase might regulate the
      cancerous phenotypes.

PMID- 15193261
TI  - TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB.
AB  - Activation of the basic-helix-loop-helix (bHLH) gene TAL1 (or SCL) is a frequent
      gain-of-function mutation in T cell acute lymphoblastic leukemia (T-ALL). To
      provide genetic evidence that tal1/scl induces leukemia by interfering with E47
      and HEB, we expressed tal1/scl in an E2A or HEB heterozygous background. These
      mice exhibit disease acceleration and perturbed thymocyte development due to
      repression of E47/HEB target genes. In tal1/scl thymocytes, we find the
      corepressor mSin3A bound to the CD4 enhancer, whereas an E47/HEB/p300 complex is
      detected in wild-type thymocytes. Furthermore, tal1/scl tumors are sensitive to
      pharmacologic inhibition of HDAC and undergo apoptosis. These data demonstrate
      that tal1/scl induces leukemia by repressing E47/HEB and suggest that HDAC
      inhibitors may prove efficacious in T-ALL patients who express TAL1/SCL.

PMID- 15193262
TI  - Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha
      after PKA activation in breast cancer.
AB  - Using a novel approach that detects changes in the conformation of ERalpha, we
      studied the efficacy of anti-estrogens to inactivate ERalpha under different
      experimental conditions. We show that phosphorylation of serine-305 in the hinge
      region of ERalpha by protein kinase A (PKA) induced resistance to tamoxifen.
      Tamoxifen bound but then failed to induce the inactive conformation, invoking
      ERalpha-dependent transactivation instead. PKA activity thus induces a switch
      from antagonistic to agonistic effects of tamoxifen on ERalpha. In clinical
      samples, we found that downregulation of a negative regulator of PKA, PKA
      RIalpha, was associated with tamoxifen resistance prior to treatment. Activation
      of PKA by downregulation of PKA-RIalpha converts tamoxifen from an ERalpha
      inhibitor into a growth stimulator, without any effect on ICI 182780
      (Fulvestrant).

PMID- 15193263
TI  - A two-gene expression ratio predicts clinical outcome in breast cancer patients
      treated with tamoxifen.
AB  - Tamoxifen significantly reduces tumor recurrence in certain patients with early
      stage estrogen receptor-positive breast cancer, but markers predictive of
      treatment failure have not been identified. Here, we generated gene expression
      profiles of hormone receptor-positive primary breast cancers in a set of 60
      patients treated with adjuvant tamoxifen monotherapy. An expression signature
      predictive of disease-free survival was reduced to a two-gene ratio, HOXB13
      versus IL17BR, which outperformed existing biomarkers. Ectopic expression of
      HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro,
      and its expression is increased in both preinvasive and invasive primary breast
      cancer. The HOXB13:IL17BR expression ratio may be useful for identifying patients
      appropriate for alternative therapeutic regimens in early-stage breast cancer.

PMID- 15193264
TI  - Purification and properties of proteinaceous trypsin inhibitors in the skin mucus
      of pufferfish Takifugu pardalis.
AB  - A screening assay for inhibitory activity against trypsin in skin mucus from 29
      species of fishes reveals a wide distribution of trypsin inhibitors in skin mucus
      and relatively high antitryptic activity in pufferfish of the family
      Tetraodontidae. Two trypsin inhibitors termed TPTI 1 and 2 were purified to
      homogeneity from the skin mucus of Takifugu pardalis by salting out, lectin
      affinity, anion exchange FPLC and gel filtration HPLC. Both inhibitors are acidic
      glycoproteins, with an apparent molecular mass of 57 kDa in SDS-PAGE, pI below 4
      and 1.9% reducing sugar for TPTI 1 and with an apparent molecular mass of 47 kDa
      in SDS-PAGE, pI 5.2 and 0.8% reducing sugar for TPTI 2. The inhibitors
      effectively repress the catalytic activity of trypsin and alpha-chymotrypsin, and
      therefore can be classified as serine protease inhibitors. The inhibitory
      constants against trypsin were 4.9x10(-8) M for TPTI 1 and 3.9x10(-8) M for TPTI
      2. Both inhibitors react with trypsin at a molar ratio of 1:1, although TPTI 1
      reversibly inactivates the proteolytic activity of trypsin non-competitively and
      TPTI 2, competitively. The trypsin inhibitors in the skin mucus of T. pardalis
      may function as defense substances to neutralize serine proteases released by
      invasive pathogens.

PMID- 15193265
TI  - Presence of tear lipocalin and other major proteins in lacrimal fluid of rabbits.
AB  - The lipocalins are a highly divergent, ubiquitous family of proteins that
      commonly function in binding lipophilic molecules. Although a specific tear
      lipocalin is a major component of lacrimal fluid and tears in many mammals, there
      has been no definitive identification of such a protein in rabbit tears. The
      goals of this project were to identify the major proteins in rabbit (Oryctolagus
      cuniculus) lacrimal fluid, so as to determine if they include a lipocalin and, if
      such a protein is present, to determine its source. Lacrimal fluid was collected
      from NZW sexually mature female rabbits, and culture medium from rabbit lacrimal
      gland epithelial (acinar) and interstitial cells was isolated. Proteins from
      these fluids were separated by SDS-PAGE electrophoresis and analyzed by
      sequencing the intact proteins and sequencing or mass analysis of fragments
      derived by trypsin digestion. Proteins of approximately 85 and 67 kDa were
      identified as rabbit transferrin and serum albumin, respectively, while
      components of 17 and 7 kDa had N-terminal sequences identical to those of
      lipophilin CL and AL, respectively. BLAST searches of the nr database with the N
      terminal sequence of a protein of 18 kDa did not identify any homologues.
      However, when used to scan the PROSITE database, it was found to contain a
      lipocalin signature sequence. It is closely related to two lipocalins previously
      isolated from rabbit saliva and nasal mucus. Further studies with the N-terminal
      and internal sequences confirmed that the lacrimal protein is a lipocalin that is
      truncated at the N-terminus as compared with other tear lipocalins and is more
      similar to odorant binding proteins from rodents.

PMID- 15193266
TI  - Evidence for 15alpha- and 7alpha-hydroxylase activity in gonadal tissue of the
      early-life stages of sea lampreys, Petromyzon marinus.
AB  - Gonads of premetamorphosing larval (PML), transforming (TL) and newly
      metamorphosed (juvenile) sea lampreys (JL) (Petromyzon marinus) were incubated in
      vitro with tritiated pregnenolone ([(3)H]P(5)), progesterone ([(3)H]P(4)), and
      androstenedione ([(3)H]A(4)) to identify the major products of steroidogenesis in
      early developmental stages. Reverse-phase high-performance liquid chromatography,
      using two mobile phase gradients, was used to separate the radioactive steroid
      metabolites. 7alpha-Hydroxylase activity was evident, based on the loss of
      radioactivity from [(3)H]P(5) labelled at position 7, appearing as tritiated
      water, and on the appearance of radiolabelled 7alpha-hydroxypregnenolone in the
      incubation medium. In addition, there was evidence of the synthesis of 15alpha
      hydroxylated steroids from the three steroid precursors used. For the progestogen
      precursors, one of the major 15alpha -hydroxylated metabolites synthesized by
      both testis and ovarian tissue co-eluted with authentic 15alpha
      hydroxyprogesterone, and for [(3)H]A(4), the product was predominantly
      [(3)H]15alpha-hydroxyandrostenedione. Additional polar steroids were produced,
      some of which co-eluted with authentic 15alpha-hydroxytestosterone and 15alpha
      hydroxyestradiol, whereas others could not be correlated with the authentic
      15alpha- or 15beta-hydroxylated steroids available. Ovarian tissues from PML and
      TL developmental stages synthesized several very non-polar compounds, some of
      which were present as unconjugated compounds, and others only in the conjugated
      fraction. These molecules had retention times consistent with pregnanes, and
      their presence in the incubation medium was therefore indicative of the presence
      of 5alpha-reductase. These metabolites were not present in the incubation medium
      from testis, or the JL ovary, suggesting that there is no expression of 5alpha
      reductase activity in these tissues. Traces of 17beta-estradiol were found in the
      incubation medium from ovarian tissue incubated with P(5), but not following
      incubation with P(4) or A(4). Testosterone was not present in the incubation
      medium from either ovarian or testis fragments incubated with any of the
      substrates used.

PMID- 15193267
TI  - Identification of multiple cytochrome P450 genes belonging to the CYP4 family in
      Xenopus laevis: cDNA cloning of CYP4F42 and CYP4V4.
AB  - In order to obtain cDNA clones coding for CYP4 proteins in frog Xenopus laevis,
      degenerate primers were designed utilizing the conserved sequences of known CYP4s
      and were used to amplify partial cDNA fragments from liver mRNA. Five new CYP
      genes were identified. Three of these genes, XL-1, -2 and -3, were assigned to
      the CYP4T subfamily found previously in fish and amphibians. The other two genes,
      XL-4 and XL-5, were quite similar to CYP4F and CYP4V subfamilies, respectively.
      Subsequently, two full-length cDNA clones corresponding to XL-4 and XL-5 were
      isolated and characterized. The resultant cDNAs, designated as CYP4F42 and
      CYP4V4, had open reading frames encoding proteins of 528 and 520 residues,
      respectively. RT-PCR analysis indicated that the expression of CYP4F42 was
      limited to the liver, kidney, intestine and brain. In contrast, CYP4V4 mRNA was
      expressed ubiquitously.

PMID- 15193268
TI  - Digestive enzyme profiles reveal digestive capacity and potential energy sources
      in fed and starved spiny lobster (Jasus edwardsii) phyllosoma larvae.
AB  - The impact of starvation on the digestive enzyme (protease, trypsin, lipase and
      amylase) activities of Stage I and IV Jasus edwardsii phyllosoma larvae was used
      to identify the nutrients metabolised or conserved during food deprivation,
      highlighting the most critical energy reserves. Protease activities increased
      significantly in both Stages I and IV phyllosoma, suggesting that protein
      catabolism provided energy during food deprivation. Lipase activity decreased
      significantly in starved Stages I and IV larvae indicating that lipid may be
      spared for fuelling later developmental moults. The use of protein, while sparing
      lipid, may provide immediate energy but not at the expense of long-term lipid
      energy stores which are known to be important during their lengthy larval phase.
      The preferential use of protein during short-term periods of starvation suggests
      that particular attention must be given to providing sufficient protein in
      artificial diets at all times. Amylase activity in starved Stage I larvae was
      lower than in fed animals, suggesting that the starved animals are not gaining
      sufficient carbohydrate. However, amylase activity was similar in fed and starved
      Stage IV larvae, possibly due to the catabolism of accumulated glycogen stores
      that were not sufficiently developed in Stage I animals.

PMID- 15193269
TI  - Molecular cloning of hepatic glucose-6-phosphatase catalytic subunit from
      gilthead sea bream (Sparus aurata): response of its mRNA levels and glucokinase
      expression to refeeding and diet composition.
AB  - To examine the relationship between structure and function of glucose-6
      phosphatase (G6Pase) in fish, we undertook molecular cloning and modulation of
      G6Pase expression by starvation and refeeding on diets with different nutrient
      composition in the liver of the carnivorous fish, Sparus aurata. A cDNA encoding
      the full-length G6Pase catalytic subunit from the liver of S. aurata was
      isolated. This cDNA encodes a 350-amino acid protein, with low homology to the
      mammalian G6Pase, although it contains most of the key residues required for
      catalysis. Based on hydrophobicity and membrane structure prediction, we propose
      a model containing nine-transmembrane regions for S. aurata G6Pase. Northern
      blots showed that refeeding after a prolonged starvation rapidly reverses the
      glucose/glucose-6-phosphate substrate cycle flux in the fish liver through
      decreased G6Pase expression and strong glucokinase (GK) induction. The effect of
      refeeding different diets on G6Pase and GK expression, indicated that hepatic
      intermediary metabolism of fish fed diets with low protein/high carbohydrate
      diets is impelled towards utilization of dietary carbohydrates, by means of
      modulation of GK mRNA levels rather than G6Pase expression. These findings
      challenge the role attributed to dysregulation of G6Pase or GK expression in the
      low ability of carnivorous fish to metabolise glucose.

PMID- 15193270
TI  - Penaeus vannamei isotrypsins: purification and characterization.
AB  - Three isotrypsins from digestive gland of Penaeus vannamei were purified and
      characterized by molecular, biochemical and kinetic parameters. Purified
      isotrypsins A, B, and C are glycoproteins with molecular masses between 30.2 and
      32.9 kDa, and, therefore similar to other trypsins. The isoelectric points are
      anionic and different among the three isotrypsins: pH 3.5 for isotrypsin A, pH
      3.0 for isotrypsin B, and pH 4.5 for isotrypsin C. Differences in the NH(2)
      terminal amino acid sequences allowed us to define three different protein
      entities that match isotrypsins previously deduced by cDNA. Isoform C has higher
      physiological efficiency and specific activity, lower K(m), and requires higher
      concentrations of Ca(+2) to reach the same activity as the other two isotrypsins.

PMID- 15193271
TI  - Purification and characterization of methylmalonyl-CoA mutase from a
      photosynthetic coccolithophorid alga, Pleurochrysis carterae.
AB  - Low activity (about 4 mU/mg protein) of 5'-deoxyadenosylcobalamin-dependent
      methylmalonyl-CoA mutase (MCM; EC 5.4.99.2) was found in a cell homogenate of a
      photosynthetic coccolithophorid alga, Pleurochrysis carterae. Most of the enzyme
      occurred as the apo-enzyme, which was labile during purification. The holo
      enzyme, which was converted from the apo-enzyme by incubation with 10 microM 5'
      deoxyadenosylcobalamin at 4 degrees C in the dark, was purified to homogeneity
      and partially characterized. An apparent molecular mass for the enzyme of 150+/-5
      kDa was calculated by Superdex 200 pg gel filtration. SDS-polyacrylamide gel
      electrophoresis of the purified enzyme gave a single protein band with an
      apparent molecular mass of 80+/-5 kDa, indicating that the P. carterae enzyme
      occurs as a homodimer. Some properties of methylmalonyl-CoA mutase from P.
      carterae were studied.

PMID- 15193272
TI  - Purification and characterization of Atlantic salmon (Salmo salar) fibrinogen.
AB  - This study describes a purification protocol of salmon fibrinogen that gives a
      consumable and highly clottable fibrinogen. Some characteristics of salmon and
      human fibrinogen are compared. Fibrinogen was purified from barium sulphate
      adsorbed plasma of Atlantic salmon, using two steps of 25% ammonium sulphate
      precipitation followed by ultrafiltration. The clottability of the purified
      salmon fibrinogen was 91%. The Aalpha chains of salmon fibrinogen were
      heterogeneous with a molecular mass of 90-110 kDa, compared to approximately 67
      kDa of human fibrinogen Aalpha chains. The Bbeta and gamma chains of salmon and
      human fibrinogen had molecular masses of approximately 55 and 50 kDa,
      respectively. Western blotting revealed that polyclonal rabbit anti-human
      fibrinogen antibodies had affinity for the gamma chains of salmon fibrinogen,
      making it possible to study factor XIII activity in purified salmon fibrinogen.
      Cross-linking of either gamma-gamma or gamma-alpha chains was not detected upon
      incubation of the purified fibrinogen with thrombin and calcium alone, but was
      detected when clotting was performed in plasma indicating absence of factor XIII
      activity in the purified product.

PMID- 15193273
TI  - Use of individual polymorphism to validate potential functional markers: case of
      a candidate lectin (BgSel) differentially expressed in susceptible and resistant
      strains of Biomphalaria glabrata.
AB  - BgSel has been identified in Biomphalaria glabrata as a candidate adhesion
      molecule exhibiting both an Ig-like domain and a carbohydrate recognition domain
      showing similarities with the l domain of C-type lectins. As susceptibility or
      resistance of B. glabrata to the trematode Echinostoma caproni correlates with a
      differential hemocytic adhesive behavior, we investigated the expression of BgSel
      in snails selected for their susceptibility or resistance. Semi-quantitative RT
      PCR analysis of BgSel expression revealed that (i) BgSel expression level was
      high in susceptible snails and almost undetectable in resistant snails, and that
      (ii) exposure to the parasite did not affect the expression level of BgSel in
      either strain. In order to validate this apparent association between low levels
      of BgSel expression and resistance, we used Real-Time PCR to characterize the
      relative expression of BgSel in individual snails segregating for
      susceptibility/resistance. Results established that differential expression of
      BgSel represents a functional strain marker, but is not a marker of
      resistance/susceptibility. It is suggested that this correlative approach may be
      a rapid and efficient alternative to complete functional analyses, and may
      facilitate the validation of candidate transcripts potentially identified through
      the numerous differential analyses of animal transcriptomes.

PMID- 15193274
TI  - Fatty acid and lipid class composition in eyes and brain from teleosts and
      elasmobranchs.
AB  - The fatty acid and lipid class composition of the eyes and brain were determined
      for the following species: Atlantic cod (Gadus morhua), saithe (Pollachius
      virens), redfish (Sebastes marinus), Atlantic salmon (Salmo salar), rainbow trout
      (Oncorhynchus mykiss), Portuguese dogfish (Centroscymnus coelolepis), black
      dogfish (Centroscyllium fabricii), and leafscale gulper shark (Centrophorus
      squamosus). Fatty acid analyses of eyes from teleosts in the present study
      indicated that the lean species contained high ratios of docosahexaenoic acid
      (DHA) versus eicosapentaenoic acid (EPA), and high ratios of n-3 fatty acids
      versus n-6 fatty acids, while these ratios were significantly lower for the fatty
      fish species. The lipid class analyses revealed that among both elasmobranchs and
      teleosts, phospholipid was the dominant class of lipids in the eyes of lean
      species, while triacylglycerol was the dominant class of lipids in fatty species.
      Analyses of the fatty acid composition of brains revealed that the deep-sea
      elasmobranchs, Portuguese dogfish, black dogfish, and leafscale gulper shark,
      contained a level of arachidonic acid (AA) that was higher than their level of
      EPA and about fivefold higher than what was found in the brains of teleosts. Such
      high levels of AA are not normally observed in fish brains; rather, they are
      generally observed in brains of higher vertebrates.

PMID- 15193275
TI  - Stage-specific surface chemicals of Plodia interpunctella: 2-acyl-1,3
      cyclohexanediones from larval mandibular glands serve as cuticular lipids.
AB  - Cuticular lipid compositions of all life stages of the stored product moth Plodia
      interpunctella have been determined. Eggs and adults of P. interpunctella have
      cuticular lipids consisting solely of hydrocarbons. The composition of eggs and
      adult females is qualitatively nearly identical with ca. 86 hydrocarbons (11 n
      alkanes, 39 monomethyl alkanes, 19 dimethyl alkanes, 11 trimethyl alkanes and 6
      monoenes) except females lack the 2-methyl alkanes found in eggs. Adult males
      have a hydrocarbon composition qualitatively nearly identical to females with the
      exception that they lack the monoenes. Larval and pupal cuticular lipids are
      dominated by a mixture of ca. 20 previously described 2-acyl-1,3
      cyclohexanediones, with only minute amounts of n-alkanes on the larvae and pupae.
      The 2-acyl-1,3-cyclohexanediones are continuously secreted onto their silk
      webbing and food particles by the paired mandibular glands found in all larvae.
      Extracts from dissected mandibular glands have a qualitatively identical
      composition to larval cuticular extracts. The pupal stage (which does not have
      mandibular glands) is enclosed in a silk cocoon also coated with 2-acyl-1,3
      cyclohexanediones laid down while the wandering stage larvae spin the cocoon. The
      2-acyl-1,3-cyclohexanediones have physical properties which closely mimic those
      of cuticular hydrocarbons, including melting point and boiling point range and
      hydrophobicity. This is the first report of an insect with a life stage that does
      not use conventional cuticular lipids for conservation of water.

PMID- 15193276
TI  - Redifferentiation of human hepatoma cells induced by synthesized coumarin.
AB  - The effects of synthesized 7-OH-4-CH(3)-coumarin on proliferation and
      differentiation of human hepatoma carcinoma cell line, SMMC-7721, were examined.
      Results showed that 7-OH-4-CH(3)-coumarin suppressed the proliferation of the
      SMMC-7721 cells in a dose-dependent manner, with an IC(50) value of 356 +/- 1.8
      .M, while concentrations< or =200 mM could trigger differentiation. After
      treatment with this compound at 100 mM, the growth curve of human hepatoma cells
      decreased markedly. When treated with 50 and 100 mM, the cells' electrophoresis
      rate decreased from 2.2 mm/s/V/cm in the control group to 1.5 and 1.8 mm/s/V/cm,
      respectively, and the alpha-fetoprotein content decreased from 123 ng/mg in the
      control group to 68 and 45 ng/mg, respectively. The microvilli on the surface of
      treated cells were also reduced. All the above indexes related to cell malignancy
      were alleviated significantly. Results showed that 7-OH-4-CH(3)-coumarin could
      reverse human hepatoma cells' malignant phenotypic characteristics and induce
      redifferentiation.

PMID- 15193277
TI  - Acid phosphatase activity in gerbil prostate: comparative study in male and
      female during postnatal development.
AB  - The prostate is present in both male and female mammals. It is composed of
      secretory epithelium, connective stroma, smooth muscle and neuroendocrine cells,
      which are under hormonal regulation. Acid phosphatases catalyze the hydrolysis of
      orthophosphate monoesters. We have compared the expression of acid phosphatases
      in gerbil (Meriones unguiculatus) prostate glands in both sexes using young,
      adult and old animals. Eighteen prostates were isolated, frozen, sectioned,
      fixed, incubated with sodium beta-glycerophosphate sodium, washed with acetate
      buffer solution, treated with ammonium sulfide and counterstained with Methyl
      Green aqueous solution. Ultracytochemical analyses were also conducted. This
      substrate revealed total acid phosphatase activity. The expression of the enzyme
      was heterogeneous, occurring in all ages during postnatal development. The data
      revealed that the female prostate matured before the male prostate. In addition,
      acid phosphatase activity in both sexes was regulated by androgen variation
      concomitant with development.

PMID- 15193278
TI  - Phorbol ester-induced cell death in PC-12 cells overexpressing Bcl-2 is dependent
      on the time at which cells are treated.
AB  - The aim of the present study was to investigate the involvement of PKC in Bcl-2
      protection against serum withdrawal-induced apoptosis in PC-12 cells. Human Bcl-2
      was overexpressed in PC-12 cells and was found to totally inhibit serum
      withdrawal-induced apoptosis. 12-O-tetradecanoylphorbol-13-acetate (TPA) could
      induce cell death in PC-12 cells that overexpressed Bcl-2, implicating protein
      kinase C (PKC) in Bcl-2 protection. However, TPA-induced cell death did not
      involve caspase-3 activation or DNA degradation, suggesting that Bcl-2 was still
      inhibiting these processes and that TPA was mediating cell death either
      downstream of Bcl-2 or via independent signalling pathways. High cytosolic and
      particulate protein levels of PKC delta were correlated with TPA-induced cell
      death suggesting that PKC delta positively regulated this cell death. However,
      substantial down-regulation of PKC by prolonged exposure to TPA did not reduce
      the frequency of TPA-induced cell death, raising the possibility that PKC delta
      did not regulate cell death alone. Surprisingly, TPA-induced cell death was
      dependent on the time at which cells were treated, suggesting that cells were
      changing with time. Supporting this idea, the cytosolic and particulate protein
      levels of PKC delta and were found to change with time, and may account for the
      time-dependent manner in which TPA induced cell death. This is the first report
      to show that sensitivity to drug induced cell death in a cultured cell line
      changes with time. Experimental and theoretical evidence suggests that many
      cellular constituents exhibit temporal variations, oscillations or rhythms due to
      feedback regulation. We believe that investigation of these temporal changes, how
      they alter cell function with time and how they might be manipulated in single
      cells as well as across cellular populations is paramount in furthering our
      understanding of cellular behaviour.

PMID- 15193279
TI  - Hepatocyte growth factor disrupts tight junctions in human breast cancer cells.
AB  - Tight junctions in epithelial cells act as cell-cell adhesion structures and
      govern paracellular permeability. Disruption of these functions can lead to
      dissociation of cancer cells. This study aimed to determine whether HGF, a
      cytokine secreted by stromal cells, is capable of modulating expression and
      function of tight junction molecules in human breast cancer cell lines. HGF
      decreased trans-epithelial resistance and increased paracellular permeability of
      two human breast cancer cell lines, MDA MB 231 and MCF-7. Q-PCR showed that HGF
      modulated the levels of several tight junction molecule (occludin, claudin-1 and 
      5, JAM-1 and -2) mRNA transcripts in MDA MB 231 and MCF-7 cells. Western blotting
      and immunohistochemistry also showed modulation of expression of the tight
      junction molecule, occludin. It is suggested that HGF disrupts tight junction
      function in human breast cancer cells by effecting changes in the expression of
      tight junction molecules at both the mRNA and protein levels. We conclude that
      regulation of tight junctions could be of fundamental importance in the
      prevention of metastasis of breast cancer cells.

PMID- 15193280
TI  - Protection against MPP+ neurotoxicity in cerebellar granule cells by
      antioxidants.
AB  - The neuropathology associated with Parkinson's disease (PD) is thought to involve
      excessive production of free radicals, dopamine autoxidation, defects in
      glutathione peroxidase expression, attenuated levels of reduced glutathione,
      altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial
      complex I activity. While the neurotoxic mechanisms are vastly different for
      excitotoxins and 1-methyl-4-phenylpyridinium ion (MPP(+)), both are thought to
      involve free radical production, compromised mitochondrial activity and excessive
      lipid peroxidation. We show here that the levels of reactive oxygen species (ROS)
      and reactive nitrogen species (RNS) increased significantly after treatment of
      cultured cerebellar granule cells (CGCs) with 50 microM MPP(+). Co-treatment with
      antioxidants such as ascorbate (ASC), catalase, alpha-tocopherol (alpha-TOH),
      coenzyme Q(10) (CoQ(10)) or superoxide dismutase (SOD) rescued the cells from
      MPP(+)-induced death. MPP(+)-induced cell death was also abolished by co
      treatment with nitric oxide synthase (NOS) inhibitors such as 7-nitroindazole (7
      NI), 2-ethyl-2-thiopseudourea hydrobromide (EPTU) or S-methylisothiourea sulphate
      (MPTU). We also tested the protective effects of an iron chelator (deferoxamine
      mesylate, DFx) and a peroxynitrite scavenger (FeTTPS) and the results lend
      further support to the view that the free radical cytotoxicity plays an essential
      role in MPP(+)-induced death in primary cultures of CGC.

PMID- 15193281
TI  - Differentiation-dependent localisation of tissue-type plasminogen activator in
      human bladder urothelium.
AB  - Human bladder urothelium is able to secrete tissue-type plasminogen activator
      (tPA). The aim of our study was to analyse localisation of tPA antigen in
      comparison to differentiation state of cells in samples of histologically normal
      urothelium and non-invasive tumours of the human urinary bladder. Twenty-five
      samples of normal urothelium and 31 non-invasive papillary tumours from 36
      patients were examined. The presence of tPA antigen was evaluated
      immunohistochemically. Differentiation of superficial cells was assessed by the
      presence of urothelial cell differentiation markers, uroplakins (UPs;
      immunohistochemistry) and cell's apical surface architecture (scanning electron
      microscopy). All tissue samples stained anti-tPA positive. In normal urothelium,
      the intensity of anti-tPA staining was the strongest in superficial cells, which
      were well-differentiated. In tumours, all cell layers stained anti-tPA positive.
      The intensity of anti-tPA positive reaction in the upper cell layer correlated
      with the percentage of anti-UP positive superficial cells. Superficial cells
      showed various differentiation states. The localisation of tPA antigen in human
      in vivo tissue is not confined to the well-differentiated superficial cells. Our
      results suggest a positive correlation between tPA secretion and cell
      differentiation.

PMID- 15193282
TI  - Analysis of the contraction of an organelle using its birefringency: the R-fibre
      of the Ceratium (Dinoflagellate) flagellum.
AB  - Some organelles responsible for contraction consist of bundles of 2-4 nm
      filaments called nanofilaments. Such organelles are present in the longitudinal
      flagellum of Ceratium (Dinoflagellate): the R-fibre is the motor system for
      contraction and parallels the axoneme, which is responsible for wave generation.
      We used a highly sensitive polarization microscope developed by one of the
      authors to measure the birefringence of these nanofilament bundles during
      contraction in vivo. Our results show that the R-fibre gives a highly
      birefringent signal, retarding the polarization to much the same extent
      irrespective of the direction of polarization. By rotating the axis of the
      microscope compensator we confirmed that the birefringence is positive,
      suggesting that the bundles run parallel to the longitudinal axis of the
      flagellum. Conversely, when the compensator was rotated contrary to the direction
      of retardation, the bundle appeared dark (except when the organelle was in a
      fully contracted state). Experiments performed on detergent-treated and ATP
      reactivated flagella show that a portion of the flagella regained activity with
      the addition of ATP in the presence of low Ca(2+) concentrations. This
      demonstrates the ability to reactivate flagellar motility after permeabilization
      and that axonemal microtubules were not responsible for the strong flagellar
      birefringence. Combined with complementary data from DIC microscopy of
      demembranated flagella and electron microscopy, these findings have led to the
      development of a model of the R-fibre and a comparison with other types of
      birefringent nanofilament bundles, such as the myoneme of Acantharia.

PMID- 15193283
TI  - Changes in elemental concentrations in LNCaP cells are associated with a
      protective effect of neuropeptides on etoposide-induced apoptosis.
AB  - One of the mechanisms that has been put forward for the development of the
      androgen-resistant status is neuroendocrine differentiation. Neuroendocrine cells
      secrete neuropeptides that may represent one of the possible molecular bases by
      which hormone-dependent prostate cancer cells could escape treatment. LNCaP
      prostate cancer cells were treated with either etoposide or neuropeptides.
      Morphological changes related to apoptosis and cell viability were assessed.
      Changes in intracellular ion content were quantitatively analyzed by electron
      probe X-ray microanalysis. Etoposide treatment consistently induces a decrease in
      K and an increase in Na, which are inhibited by bombesin or calcitonin. The Na/K
      ratio increased markedly after exposure to etoposide, and both bombesin and
      calcitonin blocked this increase. Etoposide also caused changes in the
      intracellular P and S concentrations that to a large extent could be blocked by
      neuropeptides. These results support the hypothesis that neuropeptides confer
      anti-apoptotic capabilities onto non-neuroendocrine cells in close proximity to
      neuroendocrine cells.

PMID- 15193284
TI  - ERK signaling pathway is differentially involved in erythroid differentiation of
      K562 cells depending on time and the inducing agent.
AB  - K562 cells can be induced to differentiate along the erythroid lineage by a
      variety of chemical compounds, including hemin, butyrate, cisplatin and ara-C.
      Differential signaling through MAP kinases has been suggested to be involved in
      this differentiation process. We have investigated the involvement of ERK
      activation/inhibition in hemin-, butyrate-, cisplatin- and ara-C-induced
      erythroid differentiation using the K562 cell line. ERK activity decreased for 2
      4h after administration of either inducing agent. ERK was then activated by hemin
      and cisplatin, while ERK phosphorylation remained decreased during incubation
      with butyrate and ara-C. There was no activation of JNK or p38. The MEK-1
      inhibitors UO126 or PD98059 induced erythroid differentiation in K562 cells and
      acted additively with butyrate. Inhibition of MEK-1 reduced the hemoglobin
      accumulation by hemin and cisplatin; erythroid differentiation by ara-C was
      unchanged. The results suggest that inhibition of signaling through ERK in K562
      cells may be needed to enter the erythroid differentiation process, while after
      initiation both activation and inhibition of signaling through ERK enhance
      erythroid differentiation, which, however, is dependent on the inducing compound.

PMID- 15193285
TI  - Intracellular phenotype of Mycobacterium avium enters macrophages primarily by a
      macropinocytosis-like mechanism and survives in a compartment that differs from
      that with extracellular phenotype.
AB  - Mycobacterium avium uptake by human macrophages differs between the phenotypes of
      bacterium grown in laboratory media (extracellular growth, EG) and bacterium
      grown within macrophages (intracellular growth, IG). Studies in vivo have
      confirmed that, when spreading, pathogenic mycobacteria enter macrophages by a
      complement receptor 3-independent pathway, in contrast to mycobacteria uptake in
      vitro. M. avium, grown in macrophages (IG) for 3 or more days, invade fresh
      macrophages by a macropinocytosis-like mechanism, in contrast to bacteria grown
      in media (EG), confirmed by the inhibitory effect of wortmannin, an inhibitor of
      phosphoinoside-3-kinase, on the uptake of IG, but not EG, by macrophages. The IG
      phenotype was seen in vacuoles with lower pH than those inhabited by the EG
      phenotype. Incubation of macrophages with bafilomycin A1, an inhibitor of vacuole
      acidification, decreased the viability of intracellular IG, but not EG,
      phenotype, suggesting the importance of an acidic environment for the regulation
      of IG genes. In addition, the percentage of vacuoles that incorporate and retain
      LAMP-1 is smaller with EG than with IG bacteria. The formation of M. avium
      macropinosomes was also shown to be independent of microtubules. These data
      suggest that uptake of extracellular fluid is part of M. avium IG phenotype
      uptake by macrophages, and that the IG phenotype inhabits a slightly different
      vacuole than that of EG.

PMID- 15193286
TI  - Sleep-wake architecture in mouse models for Down syndrome.
AB  - Sleep-wake homeostasis is crucial for behavioral performances and memory both in
      the general population and in patients with learning disability, among whom were
      Down syndrome (DS) patients. We investigated, in mouse models of DS, cortical EEG
      and sleep-wake architecture under baseline conditions and after a 4-h sleep
      deprivation (SD). Young hemizygous mice (hSODwt/+) transgenic for the human CuZn
      superoxide dismutase (hSOD1) or for the human amyloid precursor protein
      (HuAPP(695); hAPPwt/+) were obtained on the same FVB/N inbred background.
      Baseline records for slow wave sleep (SWS) and wake (W) parameters were
      unchanged, whereas paradoxical sleep (PS) episode numbers were decreased and PS
      latency increased after lights off in hSODwt/+ mice versus controls. hSODwt/+
      mice did not experience SWS or PS rebounds after SD but EEG activity in the delta
      SWS activity (SWA) was enhanced. hAPPwt/+ mice exhibited no change in PS but an
      increase in W and a decrease in SWS before light transition as well as an
      increase in theta-power in PS and W. After SD, hAPPwt/+ mice exhibited SWS and PS
      rebounds as well as enhancement of SWA. We investigated also the nitrite/nitrate
      levels in all mice and found an increase in the brainstem of hSODwt/+ mice only
      versus control ones. These preliminary data provide useful results to investigate
      other genetically manipulated mice and to better understand the biochemical basis
      of sleep disorders in DS patients.

PMID- 15193287
TI  - TGF-beta promotes survival on mesencephalic dopaminergic neurons in cooperation
      with Shh and FGF-8.
AB  - Impaired neuronal survival is a key event in the development of degenerative
      diseases, such as Parkinson's disease (PD). Here we show that transforming growth
      factor beta (TGF-beta) acts directly on rat E14 midbrain dopaminergic neurons in
      vitro, its survival-promoting effect being not mediated by BDNF, NT-3, or GDNF.
      Treatment with TGF-beta, sonic hedgehog (Shh), or fibroblast growth factor-8
      (FGF8) significantly increased number of tyrosine hydroxylase (TH)-immunoreactive
      neurons after 7 days, whereas application of these factors added together further
      increased number of TH-positive neurons, compared to single-factor treatments.
      Neutralization of endogenous TGF-beta, Shh, or FGF8 significantly reduced number
      of dopaminergic neurons. TGF-beta treatment decreased number of apoptotic cells,
      having no effect on cell proliferation. Neutralization of TGF-beta in vivo during
      chick E6-10 resulted in reduced number of midbrain dopaminergic neurons. The
      results suggest that TGF-beta is required for survival of mesencephalic
      dopaminergic neurons acting in cooperation with Shh and FGF8.

PMID- 15193288
TI  - Proteins released from degenerating neurons are surrogate markers for acute brain
      damage.
AB  - The experimental and clinical study of degenerative brain disorders would benefit
      from new surrogate markers for brain damage. To identify novel candidate markers
      for acute brain injury, we report that rat cortical neurons release over 60
      cytoskeletal and other proteins, as well as their proteolytic fragments into the
      medium during neuronal death. The profiles of released proteins differ for
      necrosis and apoptosis, although a subset of proteins is released generally
      during neurodegeneration. The value of this approach was established by
      immunodetection of the released proteins 14-3-3 zeta and 14-3-3 beta, as well as
      calpain and caspase derivatives of tau and alpha-spectrin in cerebrospinal fluid
      (CSF) following traumatic brain injury (TBI) or transient forebrain ischemia in
      the rat. These results indicate that proteins and their proteolytic fragments
      released from degenerating neurons are cerebrospinal fluid markers for acute
      brain damage and suggest that efflux of proteins from the injured brain may
      reflect underlying mechanisms for neurodegeneration.

PMID- 15193290
TI  - Cutaneous and sympathetic denervation in neonatal rats with a mutation in the
      delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 gene.
AB  - The mutilated-foot rat (mf rat) is an autosomal recessive mutant with
      characteristic digit deformities in adult animals, and this phenotype mimics many
      aspects of human sensory neuropathy. The genetics of mf rats was recently
      elucidated. To understand whether the genotype is responsible for cutaneous
      denervation before clinically overt mutilation in adult mf rats, we investigated
      skin innervation in postnatal day 7 (P7) mf rats and compared the patterns with
      P7 wild-type rats. The mf rat carries a G-->A mutation in the gene encoding the
      delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4).
      In the footpad skin of P7 mf rats, there was a >90% loss of epidermal nerves (0.7
      7.9% of P7 wild-type rats) as indicated by neuronal markers including protein
      gene product 9.5 (PGP 9.5), growth-associated protein 43 (GAP43), calcitonin gene
      related peptide (CGRP), and substance P (SP). The epidermis of hairy skin in hind
      feet was completely denervated in mf rats as well. Compared with an approximately
      80% reduction in the size of dermal nerve fascicles and a parallel loss of nerve
      fibers, the nearly complete absence of epidermal innervation suggests further
      sensory nerve degeneration at the level of nerve terminals in the epidermis. In
      contrast, the loss of epidermal nerves in the abdominal skin of mf rats was less
      extensive than that in the footpad skin of mf rats; CGRP (+) and SP (+) fibers
      were moderately reduced (28.3-56.4% of levels of wild-type rats) with normal
      amounts of PGP 9.5 (+) and GAP43 (+) nerves. Sympathetic innervation as assessed
      by tyrosine hydroxylase immunoreactivity was absent from the footpad and
      abdominal skin of mf rats. In conclusion, there is regional skin denervation with
      diffuse sympathetic denervation in P7 mf rats. These results suggest that the
      mutation in Cct4 underlies cutaneous nerve degeneration in mf rats.

PMID- 15193289
TI  - Innate immune reaction in response to seizures: implications for the
      neuropathology associated with epilepsy.
AB  - In the present study, the expression of pro-inflammatory transcripts was assessed
      across the brain of mice having undertaken pilocarpine-induced seizures.
      Pilocarpine-induced marked neurodegeneration and demyelination in multiple
      regions of the forebrain. The pattern of genes encoding toll-like receptor type 2
      (TLR2) and I kappa B alpha (index of NF-kappa B activation) was associated with
      the neurodegenerating areas, but this was not the case for the mRNA encoding
      other inflammatory proteins. Scattered tumor necrosis factor-alpha (TNF-alpha)
      expressing cells were found across brain, whereas the signals for monocyte
      chemoattractant protein-1 and microsomal prostaglandin mPGES E synthase were
      robust in thalamus and cerebral cortex and weak in the hippocampus and amygdala.
      TLR2 and TNF-alpha transcripts were expressed mainly in microglia/macrophages.
      Cyclooxygenase-2 was induced specifically in the hippocampus and piriform cortex.
      A low increase in interleukin-12 mRNA was detected in the brain, but the signal
      for interferon gamma (IFN-gamma) remained undetectable. Although pro-inflammatory
      markers were induced in a different manner across the CNS, their patterns were
      not characteristic of those caused by other inflammatory challenges, such as
      endotoxin. These data suggest a different mechanism involved in regulating the
      innate immune reaction in response to seizures and could have direct implications
      for the neuropathology associated with epilepsy.

PMID- 15193291
TI  - Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null
      mutant mouse model of infantile neuronal ceroid lipofuscinosis.
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is one of a group of fatal
      hereditary lysosomal storage disorders. Palmitoyl protein thioesterase 1 null
      mutant mice (PPT1-/-) now exist that accurately recapitulate many important
      disease features. The severely affected PPT1-/- mouse CNS exhibited reduced
      volume of both cortical and subcortical regions, but with sparing of the
      cerebellum. Pronounced differences existed in the extent of cortical thinning
      between different regions, due to lamina-specific effects upon neuronal survival.
      A dramatic reduction in cortical and hippocampal interneuron number was also
      evident, with different extents of specific interneuron loss depending upon the
      region and phenotypic marker. These neuronal changes were accompanied by
      widespread astrocytosis and localized microglial activation in restricted
      cortical and subcortical regions. This characterization of PPT1-/- mice not only
      provides defined pathological landmarks for understanding disease pathogenesis,
      but also provides an invaluable resource for subsequently judging the efficacy of
      therapeutic strategies.

PMID- 15193292
TI  - Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage
      material and increases brain mass in a murine model of infantile neuronal ceroid
      lipofuscinosis.
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is the earliest onset form of a
      class of inherited neurodegenerative disease called Batten disease. INCL is
      caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1
      (PPT1). Autofluorescent storage material accumulates in virtually all tissues in
      INCL patients, including the brain, and leads to widespread neuronal loss and
      cortical atrophy. To determine the efficacy of viral-mediated gene therapy, we
      injected a recombinant adeno-associated virus 2 vector encoding human PPT1 (rAAV
      PPT1) intracranially (I.C.) into a murine model of INCL. INCL mice given four
      I.C. injections of rAAV-PPT1 as newborns exhibited PPT1 activity near the
      injection sites and decreased secondary elevations of another lysosomal enzyme.
      In addition, storage material was decreased in cortical, hippocampal, and
      cerebellar neurons, and brain weights and cortical thicknesses were increased.
      These data demonstrate that an adeno-associated virus 2 (AAV2)-mediated gene
      therapy approach may provide some therapeutic benefit for INCL.

PMID- 15193293
TI  - A critical role of Pax6 in alcohol-induced fetal microcephaly.
AB  - Maternal alcohol abuse during pregnancy is one of the leading causes of birth
      defects in humans. Despite extensive studies, the molecular basis is still not
      clear. Here we transiently exposed Xenopus embryos to alcohol and showed that
      alcohol dose-dependently produced microcephaly and growth retardation. Moreover,
      it reduced the expression of several key neural genes (xPax6, xOtx2, xSox3,
      xSox2, and xNCAM), of which xPax6 was most vulnerable. An alcohol concentration
      as low as 0.3% could produce more than 90% reduction of xPax6 expression.
      Consistently, microinjection of xPax6 expression plasmid to Xenopus embryos dose
      dependently rescued alcohol-induced microcephaly and restored the expression of
      xOtx2, xSox3, xSox2, and xNCAM. To test whether reactive oxygen species (ROS) is
      the upstream signal for alcohol-induced microcephaly and xPax6 suppression, we
      overexpressed catalase in Xenopus embryos and found that catalase not only
      decreased alcohol-induced H(2)O(2) formation, but also fully restored Pax6
      expression and reversed microcephaly. In contrast, xPax6 and catalase could only
      provide partial protection against growth retardation. Results from this study
      illustrate for the first time the critical role of H(2)O(2)-mediated Pax6
      suppression in alcohol-induced microcephaly and suggest the presence of
      additional mechanisms for alcohol-induced fetal growth retardation.

PMID- 15193294
TI  - Effects on turning of microinjections into basal ganglia of D(1) and D(2)
      dopamine receptors agonists and the cannabinoid CB(1) antagonist SR141716A in a
      rat Parkinson's model.
AB  - Brain cannabinoid CB(1) receptors are expressed in neural areas that contribute
      to movement such as basal ganglia, where they co-localize with dopamine D(1) and
      D(2) receptors. The objective of the present study was to further study the
      functional role of CB(1) receptors along with D(1) and D(2) dopamine receptors of
      basal ganglia by local injections of SR141716A (CB(1) receptor antagonist), SKF
      38393 (D(1) agonist), and quinpirole (D(2) agonist), in a rat Parkinson's model.
      Turning response after amphetamine was considered as the parkinsonian variable
      for quantifying motor effects of drugs. The findings indicated that, after
      intrastriatal infusions, both D(1) or D(2) dopamine receptor agonists alone
      reduced turning in parkinsonian rats. At the pallidal and subthalamic levels,
      D(1) (not D(2)) receptor stimulation also reduced rotation. Regarding SR141716A
      induced effects, CB(1) antagonism reduced motor asymmetry in parkinsonian rats
      after injections into striatum, globus pallidus, and to a lesser extent,
      subthalamic nucleus. At the level of dorsal striatum, effects of SR141716A were
      mediated through an opposite modulation of D(1) and D(2) dopamine receptor
      function. At the pallidal and subthalamic nucleus levels, motor effects after
      SR14716A are not associated to modulation of D(1) and D(2) receptor function.

PMID- 15193295
TI  - Animal models of depression: olfactory lesions affect amygdala, subventricular
      zone, and aggression.
AB  - Psychiatric or depressed patients show alterations in both olfactory projection
      areas and mucosa. In rodents, ablation of olfactory bulbs causes a depression
      like syndrome, useful to test antidepressant agents. We studied in mice the
      behavioral symptoms and neuroanatomical correlates after mucosal damage or
      ablation of the olfactory bulb. Our results are based on a battery of tests
      exploiting anxious, aggressive, and depressive behavior, on morphological and
      immunohistochemical analysis. We found similar results in both sensory-damaged
      and bulbectomized animals, with a behavioral dissociation concerning different
      forms of aggression. These findings do not support a simple downregulation of
      social interactions in damaged mice. The most prominent modifications in the
      brains of sensory damaged and bulbectomized mice are detected in the
      subventricular zone (SVZ), the source area of neural stem cells, and in the
      content of cAMP-dependent protein kinase within the amygdala, suggesting a
      central role of this structure in the functional modulation of behavior.

PMID- 15193296
TI  - Specific downregulation and mistargeting of the lipid raft-associated protein MAL
      in a glycolipid storage disorder.
AB  - Metachromatic leukodystrophy (MLD) is a lysosomal lipid storage disease caused by
      arylsulfatase A deficiency. In MLD patients the sphingolipid sulfatide
      increasingly accumulates leading to progressive demyelination. We have analysed
      arylsulfatase A-deficient mice, a MLD mouse model, and we show that accumulation
      of sulfatide is not restricted to the lysosomal compartment but also occurs in
      myelin itself. Although, this sulfatide storage did not affect the overall
      composition of most myelin proteins, it specifically caused a severe reduction of
      MAL. This demonstrates a regulatory link between sulfatide accumulation and MAL
      expression and indicates the existence of regulatory mechanisms between lipid and
      myelin protein synthesis in oligodendrocytes. In addition, in cultured renal
      epithelial cells, sulfatide accumulation diverts MAL to the late
      endosomal/lysosomal compartment and thus also affects the intracellular
      distribution of MAL. The specific reduction and mistargeting of MAL protein as a
      reaction to sulfatide overload may contribute to the pathogenic mechanisms in
      metachromatic leukodystrophy.

PMID- 15193297
TI  - IGF-I prevents glutamate-induced motor neuron programmed cell death.
AB  - Insulin-like growth factor I (IGF-I) is currently in clinical trials for
      treatment of amyotrophic lateral sclerosis (ALS), but little is known about how
      it promotes the survival of motor neurons. In the current study, we examined IGF
      I-mediated neuroprotection in an in vitro model of ALS utilizing enriched
      cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I
      receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector
      of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling
      involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is
      elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation
      and caspase-3 cleavage in the spinal cord motor neurons. These effects of
      glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I
      treatment for as little as 30 min eliminated its neuroprotective effect. Finally,
      alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor
      LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors
      together were effective in this regard. These results suggest that the dose and
      timing of IGF-I administration are critical for producing a neuroprotective
      effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote
      the survival of motor neurons. We discuss our results in terms of novel
      strategies for ALS therapy.

PMID- 15193298
TI  - GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit
      hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases.
AB  - Glial cell line-derived neurotrophic factor (GDNF) is a potent survival agent for
      neurons, however, its effect on A beta-evoked neuronal death has not been
      examined. We show that the injection of A beta into New Zealand white rabbit
      brain activates the endoplasmic reticulum (ER) chaperones, grp 78 and grp 94, and
      the transcription factor, gadd 153. These effects correlate with the activation
      of JNK and ERK as well as of microglia and with the phosphorylation of tau
      protein. Treatment with GDNF inhibits the activation of gadd 153, reduces the
      phosphorylation of JNK, abolishes the phosphorylation of ERK, prevents microglial
      activation, greatly reduces apoptotic cells, and does not affect the
      phosphorylation of tau. Our data suggest that the tau hyperphosphorylation and
      apoptosis triggered by A beta are two independent events, and that the
      neuroprotective effect of GDNF against A beta may result either directly by the
      inhibition of ER stress or indirectly through the inhibition of JNK and ERK
      activation.

PMID- 15193299
TI  - Encapsulated GDNF-producing C2C12 cells for Parkinson's disease: a pre-clinical
      study in chronic MPTP-treated baboons.
AB  - Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor
      with restorative effects in a variety of rodent and primate models of Parkinson's
      disease (PD), could be of therapeutic value to PD. In this study, we show that
      intraventricular chronic infusion of low doses of GDNF using encapsulated
      genetically engineered C2C12 cells can exert: (1) transient recovery of motor
      deficits (hypokinesia); (2) significant protection of intrinsic striatal
      dopaminergic function in the immediate vicinity of the site of implantation of
      the capsule in the caudate nucleus, and (3) significant-long-lasting-neurotrophic
      properties at the nigral level with an increase volume of the cell bodies. These
      observations confirm the potent neurorestorative potential of GDNF in PD and the
      safety/efficacy of the encapsulation technology as a means to deliver in situ
      this neurotrophic cytokine even using an intraventricular approach.

PMID- 15193301
TI  - Amyloid precursor protein metabolism is regulated toward alpha-secretase pathway
      by Ginkgo biloba extracts.
AB  - Clinical trials report that Ginkgo biloba extracts (e.g., EGb761) reduce
      cognitive symptoms in age-associated memory impairment and dementia, including
      Alzheimer disease (AD). However, the mechanisms behind their neuroprotective
      ability remain to be fully established. In this study, the effect of EGb761 on
      the amyloid precursor protein (APP) metabolism has been investigated by both in
      vitro and in vivo models. To this aim, alpha-secretase, the enzyme regulating the
      non-amyloidogenic processing of APP and the release of alphaAPPs, the alpha
      secretase metabolite, were studied in superfusates of hippocampal slices after
      EGb761 incubation, and in hippocampi and cortices of EGb761-treated rats. PKC
      translocation state was evaluated as well. EGb761 increases alphaAPPs release
      through a PKC-independent manner. This effect is not accompanied by a
      modification of either APP forms or alpha-secretase expression. Moreover, EGb761
      influence on alphaAPPs release was strictly dependent on treatment dosage. Our
      findings suggest that the benefit of EGb761 reported by previous clinical studies
      is underscored by a specific biological mechanism of this compound on APP
      metabolism, directly affecting the release of the non-amyloidogenic metabolite.
      Additional research will be needed to clearly define the effective clinical
      relevance, thus considering EGb761 as a possible supplementary treatment in
      dementing diseases.

PMID- 15193300
TI  - Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in
      the developing rat brain.
AB  - The developing rodent brain is vulnerable to pharmacological blockade of N-methyl
      d-aspartate (NMDA) receptors which can lead to severe and disseminated apoptotic
      neurodegeneration. Here, we show that systemic administration of the NMDA
      receptor antagonist MK801 to 7-day-old rats leads to impaired activity of
      extracellular signal-regulated kinase 1/2 (ERK1/2) and reduces levels of
      phosphorylated cAMP-responsive element binding protein (CREB) in brain regions
      which display severe apoptotic neurodegeneration. Impaired ERK1/2 and CREB
      activity were temporally paralleled by sustained depletion of neurotrophin
      expression, particularly brain-derived neurotrophic factor (BDNF). BDNF
      supplementation fully prevented MK801-induced neurotoxicity in immature neuronal
      cultures and transgenic constitutive activation of Ras was associated with marked
      protection against MK801-induced apoptotic neuronal death. These data indicate
      that uncoupling of NMDA receptors from the ERK1/2-CREB signaling pathway in vivo
      results in massive apoptotic deletion of neurons in the developing rodent brain.

PMID- 15193302
TI  - Protective potential of experimental autoimmune myasthenia gravis in Lewis rats
      by IL-10-modified dendritic cells.
AB  - Dendritic cells (DC) are usually regarded as antigen-presenting cells (APC)
      involved in T cell activation, but DC also directly or indirectly affect B cell
      function, antibody synthesis and isotype switch. In this study, we explore
      potential of DC-based immunotherapy in ongoing experimental autoimmune myasthenia
      gravis (EAMG) in Lewis rats, which is mediated by anti-acetylcholine receptor
      (AChR) antibodies. Spleen DC were isolated from onset of Lewis rat EAMG on day 39
      post immunization (p.i.), exposed in vitro to IL-10 and then injected
      intraperitoneally into ongoing EAMG Lewis rats at dose of 1 x 10(6) cells/rat on
      day 5 p.i. with AChR + complete Freund's adjuvant. IL-10-modified DC resulted in
      lower clinical scores, less body weight loss, lower numbers of anti-AChR IgG
      antibody-secreting cells and lower affinity of anti-AChR antibodies in rats
      receiving IL-10-modified DC, accompanied with lower expression of CD80 and CD86
      and lower lymphocyte proliferation among lymph node mononuclear cells compared
      with control EAMG rats. Lower levels of IL-10 and IFN-gamma were also found in
      the supernatants of AChR-stimulated lymph node MNC culture in rats receiving IL
      10-modified DC. These results demonstrate that IL-10-modified DC induced hypo
      responsiveness by down-regulating co-stimulatory molecules, and reduced
      production of anti-AChR antibodies possibly by inhibiting IL-10 production.
      Importantly, this procedure that autologous DC from EAMG were adopted to treat
      ongoing EAMG is more close to clinical trial in human, encouraging future
      evaluation in human myasthenia gravis.

PMID- 15193303
TI  - On the neurotoxicity mechanism of leukoaminochrome o-semiquinone radical derived
      from dopamine oxidation: mitochondria damage, necrosis, and hydroxyl radical
      formation.
AB  - Leukoaminochrome o-semiquinone radical is generated during one-electron reduction
      of dopamine oxidation product aminochrome when DT-diaphorase is inhibited.
      Incubation of 100 microM aminochrome with 100 microM dicoumarol, an inhibitor of
      DT-diaphorase during 2 h, induces 56% cell death (P < 0.001) with concomitant
      formation of (i) intracellular hydroperoxides (4.2-fold increase compared to
      control; P < 0.001); (ii) hydroxyl radicals, detected with ESR and spin trapping
      agents (2.4-fold increase when cells were incubated with aminochrome in the
      presence of dicoumarol compared to aminochrome alone); (iii) intracellular edema,
      and cell membrane deterioration determined by transmission electron microscopy;
      (iv) absence of apoptosis, supported by using anexin-V with flow cytometry; (v) a
      strong decrease of mitochondrial membrane potential determined by the fluorescent
      dye 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanineiodide (P
      < 0.01); (vi) swelling and disruption of outer and inner mitochondrial membranes
      determined by transmission electron microscopy. These results support the
      proposed role of leukoaminochrome o-semiquinone radical as neurotoxin in
      Parkinson's disease neurodegeneration and DT-diaphorase as neuroprotective
      enzyme.

PMID- 15193305
TI  - Recent advances in gene structure prediction.
AB  - De novo gene predictors are programs that predict the exon-intron structures of
      genes using the sequences of one or more genomes as their only input. In the past
      two years, dual-genome de novo predictors, which exploit local rates and patterns
      of mutation inferred from alignments between two genomes, have led to significant
      improvements in accuracy. Systems that exploit more than two genomes
      simultaneously have only recently begun to appear and are not yet competitive on
      practical tasks, but offer the greatest hope for near-term improvements. Dual
      genome de novo prediction for compact eukaryotic genomes such as those of
      Arabidopsis thaliana and Caenorhabditis elegans is already quite accurate.
      Although mammalian gene prediction lags behind in accuracy, it is yielding ever
      more useful results. Coupled with significant improvements in pseudogene
      detection methods, which have eliminated many false positives, we have reached
      the point where de novo gene predictions are being used as hypotheses to drive
      experimental annotation via systematic RT-PCR and sequencing.

PMID- 15193306
TI  - The evolving roles of alternative splicing.
AB  - Alternative splicing is now commonly thought to affect more than half of all
      human genes. Recent studies have investigated not only the scope but also the
      biological impact of alternative splicing on a large scale, revealing that its
      role in generating proteome diversity may be augmented by a role in regulation.
      For instance, protein function can be regulated by the removal of interaction or
      localization domains by alternative splicing. Alternative splicing can also
      regulate gene expression by splicing transcripts into unproductive mRNAs targeted
      for degradation. To fully understand the scope of alternative splicing, we must
      also determine how many of the predicted splice variants represent functional
      forms. Comparisons of alternative splicing between human and mouse genes show
      that predominant splice variants are usually conserved, but rare variants are
      less commonly shared. Evolutionary conservation of splicing patterns suggests
      functional importance and provides insight into the evolutionary history of
      alternative splicing.

PMID- 15193307
TI  - Structure and evolution of transcriptional regulatory networks.
AB  - The regulatory interactions between transcription factors and their target genes
      can be conceptualised as a directed graph. At a global level, these regulatory
      networks display a scale-free topology, indicating the presence of regulatory
      hubs. At a local level, substructures such as motifs and modules can be discerned
      in these networks. Despite the general organisational similarity of networks
      across the phylogenetic spectrum, there are interesting qualitative differences
      among the network components, such as the transcription factors. Although the DNA
      binding domains of the transcription factors encoded by a given organism are
      drawn from a small set of ancient conserved superfamilies, their relative
      abundance often shows dramatic variation among different phylogenetic groups.
      Large portions of these networks appear to have evolved through extensive
      duplication of transcription factors and targets, often with inheritance of
      regulatory interactions from the ancestral gene. Interactions are conserved to
      varying degrees among genomes. Insights from the structure and evolution of these
      networks can be translated into predictions and used for engineering of the
      regulatory networks of different organisms.

PMID- 15193308
TI  - Protein interaction networks from yeast to human.
AB  - Protein interaction networks summarize large amounts of protein-protein
      interaction data, both from individual, small-scale experiments and from
      automated high-throughput screens. The past year has seen a flood of new
      experimental data, especially on metazoans, as well as an increasing number of
      analyses designed to reveal aspects of network topology, modularity and
      evolution. As only minimal progress has been made in mapping the human proteome
      using high-throughput screens, the transfer of interaction information within and
      across species has become increasingly important. With more and more
      heterogeneous raw data becoming available, proper data integration and quality
      control have become essential for reliable protein network reconstruction, and
      will be especially important for reconstructing the human protein interaction
      network.

PMID- 15193309
TI  - Metabolic networks: enzyme function and metabolite structure.
AB  - Metabolism is one of the most complex cellular processes. Connections between
      biochemical reactions via substrate and product metabolites create complex
      metabolic networks that may be analyzed using network theory, stoichiometric
      analysis, and information on protein structure/function and metabolite
      properties. These frameworks take into consideration different aspects of enzyme
      chemistry, enzyme structure and metabolite structure, and demonstrate the impact
      of metabolic biochemistry on the systemic properties of metabolism. The
      integration of these approaches and the systematic classification of enzyme
      function and the chemical structure of metabolites will enhance our understanding
      of metabolism, and could improve our ability to predict enzyme function and novel
      metabolic pathways.

PMID- 15193310
TI  - The interplay of fold recognition and experimental structure determination in
      structural genomics.
AB  - Achieving the goals of structural genomics initiatives depends on the outcomes of
      two groups of factors: the number and distribution of experimentally determined
      protein structures, and our ability to assign novel proteins to known structures
      (fold recognition) and use them to build models (modeling). The quality of the
      tools used for fold recognition defines the scope of experimental effort - the
      more distant the templates that can be recognized, the smaller the number of
      proteins that have to be solved. Recent improvements in fold recognition may have
      suggested that the goals of structural genomics initiatives are getting closer.
      However, problems that surfaced during the first few years of active work have
      put many of the early estimates in doubt and new ones are still slow in coming.

PMID- 15193311
TI  - A structural perspective on protein-protein interactions.
AB  - Structures of macromolecular complexes are necessary for a mechanistic
      description of biochemical and cellular processes. They can be solved by
      experimental methods, such as X-ray crystallography, NMR spectroscopy and
      electron microscopy, as well as by computational protein structure prediction,
      docking and bioinformatics. Recent advances and applications of these methods
      emphasize the need for hybrid approaches that combine a variety of data to
      achieve better efficiency, accuracy, resolution and completeness.

PMID- 15193312
TI  - Computational exploration of structural information from cryo-electron tomograms.
AB  - Cryo-electron tomography aims to act as an interface between in vivo cell imaging
      and techniques achieving atomic resolution. This attempt to bridge the resolution
      gap is facilitated by recent software and hardware advances. Information provided
      by atomically resolved macromolecules and molecular interaction data need to be
      put into a common framework in order to create a hybrid multidimensional cellular
      image. A major partner in this enterprise is the development of regularization
      and pattern recognition techniques, which try to identify macromolecular
      complexes as a function of their structural signature in cryo-electron tomograms
      of living cells.

PMID- 15193314
TI  - RNA structure and function in C/D and H/ACA s(no)RNPs.
AB  - From archaea to humans, C/D- and H/ACA-type small ribonucleoprotein particles
      play key roles in crucial RNA processing events. Various such particles are
      required for pre-rRNA cleavage steps and/or for chemical modification of rRNAs,
      spliceosomal small nuclear RNAs, tRNAs and perhaps even mRNAs. Each C/D-type
      particle contains a small RNA possessing conserved C and D, as well as related C'
      and D', sequence motifs, whereas each H/ACA-type particle contains a small RNA
      featuring conserved H and ACA sequence elements. Recently published studies
      highlight the importance of sequence and structural elements of these RNAs in the
      localization, activity and assembly of the ribonucleoprotein particles. A novel
      sequence element, the Cajal body box, found at the apex of stem structures within
      a subset of H/ACA small RNAs, mediates the specific retention of particles
      containing these elements inside nucleoplasmic Cajal bodies. Two highly conserved
      elements, the m1 and m2 boxes, have been identified in the 3' stem of the
      atypical H/ACA snR30/U17 RNAs. These conserved sequence elements are necessary
      for early pre-rRNA cleavage events and consequently for mature 18S rRNA
      production. Finally, convincing evidence has been provided that the conserved C
      and D sequence motifs of C/D-type small RNAs fold into a helix-bulge-helix
      structure, called a kink-turn, that provides a platform for assembly of C/D-type
      ribonucleoprotein particles.

PMID- 15193315
TI  - Riboswitches exert genetic control through metabolite-induced conformational
      change.
AB  - Conserved RNA structures have traditionally been thought of as potential binding
      sites for protein factors and consequently are regarded as fulfilling relatively
      passive albeit important roles in cellular processes. With the discovery of
      riboswitches, RNA no longer takes a backseat to protein when it comes to
      affecting gene expression. Riboswitches bind directly to cellular metabolites
      with exceptional specificity and affinity, and exert control over gene expression
      through ligand-induced conformational changes in RNA structure. Riboswitches now
      represent a widespread mechanism by which cells monitor their metabolic state and
      facilely alter gene expression in response to changing conditions.

PMID- 15193316
TI  - Application of NMR and EPR methods to the study of RNA.
AB  - The application of techniques based on magnetic resonance, specifically electron
      paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR), has provided a
      wealth of new information on RNA structures, as well as insights into the
      dynamics and function of these important biomolecules. NMR spectroscopy is very
      successful for determining the solution structures of small RNA domains, aptamers
      and ribozymes, and exploring their intramolecular dynamics and interactions with
      ligands. EPR-based methods have been used to map local dynamic and structural
      features of RNA, to explore different modes of RNA-ligand interaction, to obtain
      long-range structural restraints and to probe metal-ion-binding sites.

PMID- 15193317
TI  - Simulation and modeling of nucleic acid structure, dynamics and interactions.
AB  - In moving towards the simulation of larger nucleic acid assemblies over longer
      timescales that include more accurate representations of the environment, we are
      nearing the end of an era characterized by single nanosecond molecular dynamics
      simulation of nucleic acids. We are excited by the promise and predictability of
      the modeling methods, yet remain prudently cautious of sampling and force field
      limitations. Highlights include the accurate representation of subtle drug-DNA
      interactions, the detailed study of modified and unusual nucleic acid structures,
      insight into the influence of dynamics on the structure of DNA, and exploration
      of the interaction of solvent and ions with nucleic acids.

PMID- 15193318
TI  - Single-molecule manipulation of nucleic acids.
AB  - During the past decade, local force measurement techniques, such as atomic force
      microscopy and optical tweezers, were used to study the elastic properties and
      mechanically induced structural transitions of nucleic acids at the single
      molecule level. Single-molecule manipulation has also increasingly been used to
      investigate DNA-dependent enzymatic processes, with implications for unfolding
      and modifying DNA, protein-DNA interactions, replication and transcription.
      Compared to classical techniques of molecular biology, single-molecule
      measurements avoid the need to average over a large number of events, and can
      thus potentially provide detailed and complementary information.

PMID- 15193319
TI  - RNA folding and unfolding.
AB  - Single-molecule studies of RNA folding and unfolding are providing impressive
      details of the intermediates that occur and their rates of interconversion. The
      folding and unfolding of RNA are controlled by varying the concentration of
      magnesium ions and measuring fluorescence energy transfer, or by applying force
      to the RNA and measuring the end-to-end distance. The hierarchical nature of RNA
      folding - first secondary structure, then tertiary structure - makes the process
      susceptible to analysis and prediction.

PMID- 15193320
TI  - Atomic force microscopy imaging and pulling of nucleic acids.
AB  - Recent advances in atomic force microscopy (AFM) imaging of nucleic acids include
      the visualization of DNA and RNA incorporated into devices and patterns, and into
      structures based on their sequences or sequence recognition. AFM imaging of
      nuclear structures has contributed to advances in telomere research and to our
      understanding of nucleosome formation. Highlights of force spectroscopy or
      pulling of nucleic acids include the use of DNA as a programmable force sensor,
      and the analysis of RNA flexibility and drug binding to DNA.

PMID- 15193321
TI  - From biofouling to bioremediation: the good, the bad and the vague.

PMID- 15193322
TI  - Detection and enumeration of airborne biocontaminants.
AB  - The sampling and analysis of airborne microorganisms has received attention in
      recent years owing to concerns with mold contamination in indoor environments and
      the threat of bioterrorism. Traditionally, the detection and enumeration of
      airborne microorganisms has been conducted using light microscopy and/or culture
      based methods; however, these analyses are time-consuming, laborious, subjective
      and lack sensitivity and specificity. The use of molecular methods, such as
      quantitative polymerase chain reaction amplification, can enhance monitoring
      strategies by increasing sensitivity and specificity, while decreasing the time
      required for analysis.

PMID- 15193323
TI  - Emerging waterborne pathogens: can we kill them all?
AB  - The rapid emergence of Cryptosporidium parvum and Escherichia coli 0157:H7 have
      created a threat to the drinking water industry and there is a growing need to
      develop a strategy for recognizing potential emerging waterborne pathogens.
      Globalization of trade, changing population demographics and changes in treatment
      technology have been driving factors in the emergence of these new pathogens. An
      understanding of disinfectant action and microbial resistance to treatment
      processes is needed to better identify those pathogens likely to be of greatest
      concern. Recent research on microbial resistance to treatment and disinfection
      demonstrates that the microbial surface structure and composition and the nature
      of the genome are key to determining the potential for waterborne transmission of
      emerging pathogens.

PMID- 15193324
TI  - Biocorrosion: towards understanding interactions between biofilms and metals.
AB  - The term microbially influenced corrosion, or biocorrosion, refers to the
      accelerated deterioration of metals owing to the presence of biofilms on their
      surfaces. The detailed mechanisms of biocorrosion are still poorly understood.
      Recent investigations into biocorrosion have focused on the influence of
      biomineralization processes taking place on metallic surfaces and the impact of
      extracellular enzymes, active within the biofilm matrix, on electrochemical
      reactions at the biofilm-metal interface.

PMID- 15193325
TI  - To BAC or not to BAC: marine ecogenomics.
AB  - Most microbes in the ocean are still resistant to our collective cultivation
      efforts. Environmental microbial genomics provides science with the means for
      accessing and assessing the genomes, diversity, evolution and population dynamics
      of uncultured microorganisms--the ocean's hidden majority.

PMID- 15193326
TI  - Genome analysis of marine photosynthetic microbes and their global role.
AB  - Four recently completed genome projects on marine Cyanobacteria have started the
      age of comparative genomics for marine microbes. Cyanobacteria are a group of
      photoautotrophic bacteria that have traditionally been under-represented in
      studies of complete genome sequences, as have microbes from the marine
      environment in general. The new genome information is of crucial importance to
      understanding their role in oceanic primary production, global carbon cycling and
      functioning of the biosphere. Marine microbes are a still almost untapped
      resource for the identification of novel beneficial metabolites and activities.
      The availability of an increasing number of genome sequences will eventually lead
      to a sustained development of marine biotechnology.

PMID- 15193327
TI  - The soil metagenome--a rich resource for the discovery of novel natural products.
AB  - Soil microorganisms have been the most valuable source of natural products,
      providing industrially important antibiotics and biocatalysts. But, of late, the
      discovery rate of novel biomolecules using traditional cultivation techniques has
      been extremely low, as most soil microorganisms cannot be cultured in this way.
      The development of novel cultivation-dependent and molecular cultivation
      independent approaches has paved the way for a new era of product recovery from
      soil microorganisms. In particular, gene-mining based on the construction and
      screening of complex libraries derived from the soil metagenome provides
      opportunities to fully explore and exploit the enormous genetic and metabolic
      diversity of soil microorganisms. This strategy has already resulted in the
      isolation of novel biocatalysts and bioactive molecules.

PMID- 15193328
TI  - Microbial communities in oil-contaminated seawater.
AB  - Although diverse bacteria capable of degrading petroleum hydrocarbons have been
      isolated and characterized, the vast majority of hydrocarbon-degrading bacteria,
      including anaerobes, could remain undiscovered, as a large fraction of bacteria
      inhabiting marine environments are uncultivable. Using culture-independent rRNA
      approaches, changes in the structure of microbial communities have been analyzed
      in marine environments contaminated by a real oil spill and in micro- or
      mesocosms that mimic such environments. Alcanivorax and Cycloclasticus of the
      gamma-Proteobacteria were identified as two key organisms with major roles in the
      degradation of petroleum hydrocarbons. Alcanivorax is responsible for alkane
      biodegradation, whereas Cycloclasticus degrades various aromatic hydrocarbons.
      This information will be useful to develop in situ bioremediation strategies for
      the clean-up of marine oil spills.

PMID- 15193329
TI  - Genomic and mechanistic insights into the biodegradation of organic pollutants.
AB  - Several new methodologies have enabled recent studies on the microbial
      biodegradation mechanisms of organic pollutants. Culture-independent techniques
      for analysis of the genetic and metabolic potential of natural and model
      microbial communities that degrade organic pollutants have identified new
      metabolic pathways and enzymes for aerobic and anaerobic degradation.
      Furthermore, structural studies of the enzymes involved have revealed the
      specificities and activities of key catabolic enzymes, such as dioxygenases.
      Genome sequencing of several biodegradation-relevant microorganisms have provided
      the first whole-genome insights into the genetic background of the metabolic
      capability and biodegradation versatility of these organisms. Systems biology
      approaches are still in their infancy, but are becoming increasingly helpful to
      unravel, predict and quantify metabolic abilities within particular organisms or
      microbial consortia.

PMID- 15193330
TI  - Phytodegradation of organic compounds.
AB  - The phytodegradation of organic compounds can take place inside the plant or
      within the rhizosphere of the plant. Many different compounds and classes of
      compounds can be removed from the environment by this method, including solvents
      in groundwater, petroleum and aromatic compounds in soils, and volatile compounds
      in the air. Although still a relatively new area of research, there are many
      laboratories studying the underlying science necessary for a wide range of
      applications for plant-based remediation of organic contaminants.

PMID- 15193331
TI  - Biological degradation of cyanide compounds.
AB  - Cyanide compounds are produced as waste products of a number of industrial
      processes and several routes for their removal from the environment are under
      investigation, including the use of biodegradation. The most recent developments
      in this area have come from studies of the hydrolytic and oxidative pathways for
      biodegradation and the conditions that affect their activity. The biodegradation
      of cyanide under anaerobic conditions has also recently demonstrated the
      feasibility for concomitant biogas generation, a possible economic benefit of the
      process. Significant advances have been reported in the use of plants for the
      phytoremediation of cyanide compounds and evidence for the biodegradation of
      thiocyanate and metal-cyanide complexes has become available. Despite these
      advances, however, physical and economic factors still limit the application of
      cyanide biodegradation, as do competing technologies.

PMID- 15193332
TI  - Biotechnology and science policy.

PMID- 15193333
TI  - Science policy and society: the British debate over GM agriculture.
AB  - The outcome of 'GM Nation?'--a public debate on genetic modification and the
      commercial growing of GM crops in Britain--was published in 2003. The objective
      of this public consultation was 'to promote an innovative, effective and
      deliberative programme of debate, against the background of the possible
      commercial production of GM crops in the UK...[and] provide meaningful
      information to Government about the nature and spectrum of the public's views,
      particularly at the grass roots level, to inform decision making'. Complementing
      an independent evaluation of GM Nation?, this article puts the debate into
      context, comments on the legitimacy of this, and similar exercises in public
      consultation, and develops some ideas on the future of public consultation on
      technological innovation.

PMID- 15193334
TI  - A public policy on biotechnology education: what might be relevant and effective?
AB  - The public perception of the life sciences--including biotechnology--has in
      recent years drifted far from the reality. Bringing perception and reality closer
      together requires an open dialogue between science and society based upon a well
      thought-out educational policy and a better mutual understanding between
      scientists and media professionals.

PMID- 15193336
TI  - Biotechnology--a challenge to the patent system.
AB  - Biotechnology inventions raise both moral and technical dilemmas. The patent
      system was developed to protect inventions such as the Spinning Jenny and
      Stevenson's Rocket. This article looks at how this long-established and slow
      moving system is coping with a modern, highly sophisticated and swiftly moving
      field of science. It looks at specific areas of the technology--research tools
      and claims that reach to the products produced using those tools, genes, stem
      cells and bioinformatics. It concludes that the system is having to adapt, but
      that it will cope.

PMID- 15193335
TI  - Bioethics for technology?
AB  - Ethical concerns about biotechnology continue to be debated in the scientific and
      popular press. Ethical considerations have led to the development of frameworks
      within which biotechnology can be developed in socially acceptable and desirable
      ways: through legislation, the development of public-private collaborations, and
      regimes that safeguard consumer choice.

PMID- 15193337
TI  - How should public policy respond to the challenges of modern biotechnology?
AB  - Modern biotechnology has been a topic of public and political debate around the
      world for over 30 years; continuing scientific breakthroughs keep it high on the
      agenda. Policy responses have been diverse, fragmented and incoherent, at levels
      ranging from local regions to agencies of the United Nations, but particularly in
      national administrations and the European Union. Reactions have been ambivalent,
      combining fears about conjectural risks with concern to maintain competitiveness
      and exploit beneficial applications. Adverse public perceptions have become a
      significant influence on policy, in combination with more cynical and self
      interested motives of some of the players in policy debates. Future options, in
      Europe and elsewhere, are constrained by past and continuing mistakes and over
      reactions.

PMID- 15193338
TI  - Facing the possibility of bioterrorism.
AB  - The possibility of bioterrorism has been met by significant financial outlays to
      map out public health responses. These have included comprehensive audits of
      potential agents, as well as exploring mechanisms for counteracting their impact.
      Psychological intervention and communication have been identified as key areas
      requiring further work, as fear of infection could pose a greater strain on
      social resources than the pathogens themselves. Bioterrorism provides a powerful
      metaphor for elite fears of social corrosion from within. Accordingly, a broader
      historical and cultural perspective is required to understand why individuals and
      societies feel so vulnerable to what remain largely speculative scenarios.

PMID- 15193339
TI  - Dementia as a window to the neurology of art.
AB  - Art is an expression of neurological function and how it organizes and interprets
      perception. Recent reports of changes in art performance among patients with
      frontotemporal dementia have provided an unexpected window to the neurology of
      art. They confirm that visual art is predominantly in the right hemisphere and
      suggest a neuroanatomical schema for artistic creativity. The right parietal
      region is critical for the visuospatial prerequisites of art, and the right
      temporal lobe integrates and interprets these percepts. The right temporal lobe
      appears necessary for extracting and exaggerating the essential features of an
      artistic composition. In contrast, the left parietal region and the left temporal
      lobe have inhibitory effects on artistic expression through attention to
      visuospatial detail and semantic labeling, respectively. Frontal-executive
      functions are also required for artistic expression, particularly right
      dorsolateral frontal initiation of a network for novelty-seeking behavior.
      Further study of art in dementia can profitably evaluate this proposed schema for
      the mechanisms of art in the brain.

PMID- 15193340
TI  - A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease.
AB  - Alzheimer's disease (AD) includes etiologically heterogeneous disorders
      characterized by senile or presenile dementia, extracellular amyloid protein
      aggregations containing an insoluble amyloid precursor protein derivative, and
      intracytoplasmic tau protein aggregations. Recent studies also show excess
      neuronal aneuploidy, programmed cell death (PCD), and mitochondrial dysfunction.
      The leading AD molecular paradigm, the "amyloid cascade hypothesis", is based on
      studies of rare autosomal dominant variants and does not specify what initiates
      the common late-onset, sporadic form. We propose for late-onset, sporadic AD a
      "mitochondrial cascade hypothesis" that comprehensively reconciles seemingly
      disparate histopathologic and pathophysiologic features. In our model, the
      inherited, gene-determined make-up of an individual's electron transport chain
      sets basal rates of reactive oxygen species (ROS) production, which determines
      the pace at which acquired mitochondrial damage accumulates. Oxidative
      mitochondrial DNA, RNA, lipid, and protein damage amplifies ROS production and
      triggers three events: (1) a reset response in which cells respond to elevated
      ROS by generating the beta-sheet protein, beta amyloid, which further perturbs
      mitochondrial function, (2) a removal response in which compromised cells are
      purged via PCD mechanisms, and (3) a replace response in which neuronal
      progenitors unsuccessfully attempt to re-enter the cell cycle, with resultant
      aneuploidy, tau phosphorylation, and neurofibrillary tangle formation. In
      addition to defining a role for aging in AD pathogenesis, the mitochondrial
      cascade hypothesis also allows and accounts for histopathologic overlap between
      the sporadic, late-onset and autosomal dominant, early onset forms of the
      disease.

PMID- 15193341
TI  - Biofeedback as a supportive method in weaning long-term ventilated critically ill
      patients.
AB  - Weaning a patient from mechanical ventilation is occasionally a difficult process
      complicated by the patient's emotional state. Anxiety, agitation, depression and
      other emotional disturbances can start a vicious circle between fear of losing
      breath and dyspnea that impairs the process of withdrawing ventilatory support. A
      biocybernetic loop model is suggested that integrates psychological variables
      (e.g., capacity of self-control, self-confidence, sense of self-efficacy) as
      important factors for a successful weaning. The paradigm of biofeedback is
      regarded as a suited approach to strengthen these psychological factors. It means
      the externalization of physiological functions especially of those from the
      autonomous nervous system so that a patient becomes aware of them. In the case of
      the ventilated patient, it is assumed that the transformation of the respiratory
      activities into perceptible (acoustic and visual) signals supports the patient's
      self-controlling behaviour during the weaning process. He gets positive
      reinforcement for his efforts to influence his breathing intentionally and, by
      continuous and immediate information, he regains self-confidence to control his
      somatic functions effectively. The application of biofeedback is mainly described
      in single case studies. They all report a decrease in the respiratory rate and an
      increase in the tidal volume. The need for a controlled study is suggested that
      would answer the question of whether biofeedback is an appropriate psychological
      tool to facilitate the weaning process in mechanically ventilated patients.

PMID- 15193342
TI  - A novel approach to the psychopharmacologic treatment of insomnia in depression.
AB  - BACKGROUND: Depressed patients who respond to anti-depressant drugs but have
      persisting insomnia can be hypothesized as having one foot on the bipolar
      spectrum. In this hypothesis, the insomnia would respond to augmentation of the
      anti-depressants with anti-kindling agents (i.e., anti-convulsant drugs for the
      purposes of this paper) in the same way that many anti-convulsants are effective
      in bipolar disorders as mood-stabilizers from above (anti-manic agents) or below
      (anti-depressants). CASE REPORTS: Cases supporting this augmentation strategy are
      presented. The patients met DSM-IV criteria for recurrent major depression,
      depression with psychotic features, and depression NOS. There was no discernible
      history of mania or hypomania and all had insomnia that did not respond or
      partially responded to anti-depressant drugs singly or in combinations. All
      responded to the addition of anti-convulsant drugs. DISCUSSION: This augmentation
      strategy seems to be an effective treatment for chronic insomnia in depression,
      but controlled studies are needed to quantify and qualify these effects. This
      strategy's effectiveness may be due to the anti-kindling or inhibitory effects of
      anti-convulsant drugs, which are often GABAergic. Since it is becoming clear that
      bipolar spectrum disorders are misdiagnosed as unipolar depression at an alarming
      rate, and since anti-depressants often have deleterious effects on the course of
      bipolar illness, perhaps most depressed patients should be protected with an anti
      convulsant whenever they are started on an anti-depressant.

PMID- 15193343
TI  - Why minocycline can cause systemic lupus - a hypothesis and suggestions for
      therapeutic interventions based on it.
AB  - The tetracycline antibiotic minocycline is widely used in dermatology, but can
      sometimes cause systemic lupus erythematodes, a serious autoimmune disorder. It
      is not known how it does this. However, recent data suggest that minocycline can
      protect cells from apoptosis by inhibition of caspase-dependent and independent
      cell death pathways. Here, it is suggested that this ability of minocycline is
      responsible for the induction of lupus. This idea is based on the recent insight
      that incomplete or failed apoptosis of damaged cells, particularly keratinocytes,
      may be responsible for the development of auto-immunity. The protection against
      apoptosis as conferred by minocyclin may be incomplete, with failed apoptosis and
      development of autoimmunity as a result. Experimental confirmation of the theory
      may be obtained by in vitro experiments using induction of apoptosis in cell
      types known to be affected by lupus. Next, mice that are sensitive to apoptosis
      may be used for in vivo experiments. Novel therapeutic approaches to drug-induced
      lupus may be based on induction of apoptosis; DNA-damaging immunosuppressive
      agents appear particularly useful. Such treatments can be tested in apoptosis
      deficient mice that develop autoimmune disease.

PMID- 15193344
TI  - A similarity function to evaluate the orthodontic condition in patients with
      cleft lip and palate.
AB  - The objective of this work is the modeling of a similarity function adapted to
      the medical environment using the logical-combinatorial approach of pattern
      recognition theory, and its application to compare the orthodontic conditions of
      patients with cleft-primary palate and/or cleft-secondary palate congenital
      malformations. The variables in domains with no a priori algebraic or topological
      structure are objects whose similarity or difference is evaluated by comparison
      criteria functions. The range of these functions is an ordered set normalized
      into the unit interval, and they are designed to allow differentiation and non
      uniform treatment of the object-variables. The analogy between objects is
      formalized as a similarity function that stresses the relations among the
      comparison criteria and evaluates the partial descriptions (partial
      similarity/difference) or total descriptions (total similarity/difference) of the
      objects. For the orthodontic problem we defined a set of 12 variables featuring
      the unilateral/bilateral fissures, the conditions of maxilla, premaxilla,
      mandible and patient's bite. The comparison criteria (logical for malocclusion,
      fuzzy for maxillary collapse unilateral/anteroposterior and for overbite, and
      Boolean for protrusive/retrusive premaxilla conditions) were assigned a relevance
      factor based on the orthodontist accumulated knowledge and experience. The
      modeling of the similarity function and its effectiveness in comparing
      orthodontic conditions in patients are illustrated by the study of four clinical
      cases with different clefts. The results through similarity are close to the
      expected ones. Moreover evaluated at different moments it allows to assess the
      effect of treatment in a single patient, hence providing valuable auxiliary
      criteria for medical decision making as to the patient's rehabilitation. We
      include the potential extension of the methodology to other medical disciplines
      such as speech therapy and reconstructive surgery.

PMID- 15193345
TI  - Post-traumatic inflammatory response: perhaps a succession of phases with a
      nutritional purpose.
AB  - Post-traumatic inflammatory response, whether this be local or systemic, is
      considered to be the succession of three functional phases called nervous, immune
      and endocrine, that could have a nutritional significance. In the nervous phase,
      ischemia-reperfusion, which causes interstitial and cellular edema, is produced.
      Both types of edema could represent an ancestral mechanism to feed the cells by
      diffusion. During the immune phase, the tissues are infiltrated by inflammatory
      cells and bacteria. Then, extracellular digestion, by enzyme release
      (fermentation), and intracellular digestion by phagocytosis could be associated
      with a hypothetical trophic capacity for the neighbouring cells. Finally, in the
      late or endocrine phase nutrition mediated by the blood capillaries is
      established. In these three successive phases the inflammatory response goes on
      from an anaerobic metabolism (ischemia) through a metabolism characterized by a
      defective oxygen use (reperfusion, oxidative burst and heat hyperproduction) to
      an oxidative metabolism (oxidative phosphorilation) with a correct use of oxygen
      to produce usable energy. This type of metabolism is characterized by a large
      production of ATP, which is used to drive specialized multiple cellular
      processes. Since the nervous, immune and endocrine phases of the inflammatory
      response go from ischemia to the development of an oxidative metabolism, It is
      also tempting to speculate on whether the body reproduces the successive stages
      by which life passes from its origin without oxygen until it develops an
      effective, although costly, system for the use of oxygen every time we suffer
      post-traumatic acute inflammation.

PMID- 15193346
TI  - New fetoproteins, as presumptive antigenic inducers of abortions and congenital
      anomalies. Temporal forking of immunological abortions. A working hypothesis.
AB  - In a previous experimental study soluble alloantigens and soluble foreign (not
      recognized by the dam's immune system) transitory antigens in chick embryo have
      been detected. When a chick embryo extract was injected in hens and their eggs
      were incubated, the death or a delay in chick embryo development or congenital
      anomalies were observed. Based on the foregoing, the following working hypothesis
      is established: any fetoprotein not coming into contact with the fetal immune
      system during the central clonal selection period becomes a foreign antigen. If
      it is a female fetus that becomes pregnant at adult age, then passage to the
      maternal circulation or to the decidua of the same foreign fetoprotein from her
      fetus is a candidate to induce a humoral or cell-mediated response. If specific
      IgG or toxic factors of the different cells activated by cell-mediated immunity
      in the mother access the inductive antigen (e.g., an enzyme) in the conceptus,
      there functions may be cancelled or the antigen-carrier cell may undergo lysis.
      This will result in damage to tissues leading to abortion or to a viable but
      morphologically or functionally abnormal offspring. This can occurs with some of
      soluble foreign transitory antigens existents. The soluble alloantigens are
      foreign for the mother because are coded by paternal genes and act of similar
      way.

PMID- 15193347
TI  - Addition of granulocyte-colony stimulating factor (G-CSF) to adjuvant treatment
      may increase survival in patients with operable breast cancer: interaction of G
      CSF with dormant micrometastatic breast cancer cells.
AB  - All cancers are clonal and represent the progeny of a single cell. The unclear
      point is which clonogenic cells within the tumor clone possess tumor-initiating
      cell (T-IC) function and are capable of maintaining tumor growth. Stem cells have
      the ability to divide almost indefinitely. The division can give rise to a new
      stem cell as well as differentiated cells of the tumor. Breast tumors are
      comprised of phenotypically diverse populations of breast cancer cells. Among
      them, the breast cancer stem cell is important for regrowth of tumor and
      metastasis. Granulocyte-colony stimulating factor (G-CSF) stimulates the
      pluripotent stem cell beside neutrophil precursors. Breast cancer stem cells
      which have not been characterized totally may carry the almost identical antigens
      with hematopoietic stem cell. The dose-intense therapies with the addition of G
      CSF in the adjuvant treatment of breast cancer improved clinical outcomes
      significantly. Presence of micrometastasis in bone marrow of the breast cancer
      patients is predictor of relapse free survival and important prognostic factor.
      Actually, breast cancer stem cells in the thousands of micrometastatic cancer
      cells have the capacity to repopulate and metastasise. We hypothesize that G-CSF
      use in adjuvant treatment of breast cancer may activate and repopulate these
      dormant breast cancer stem cells besides its stimulation on blood stem cells. So
      activated breast cancer stem cells become chemosensitive to cell-cycle specific
      various chemotherapeutic agents. Improvement in overall survival in operable
      breast cancer patients having been treated by dose-dense therapies may also be
      explained by this mechanism.

PMID- 15193348
TI  - A putative role for Toxocara species in the aetiology of multiple sclerosis.
AB  - Multiple sclerosis (MS) is a disease of unknown aetiology. The finding of
      monoclonal antibodies in MS has been attributed to various infectious agents.
      Nematodes, such as Toxocara species have not been explored as possible aetiologic
      agents of MS. Some epidemiological studies have found an association between
      exposure to stress and household pets prior to the diagnosis of MS. In a case
      known to the authors, slight malaise and eosinophilia in peripheral blood
      preceded the diagnosis of MS by one year in a middle-aged man who lived in rural
      surroundings with cats in the household. The ubiquitary parasite Toxocara catis
      or canis is prevalent and serum antibodies are found regularly in populations
      examined. It is able to develop into the larval stage in human beings. The
      hypothesis presented here is that MS could be initiated by such infections in
      previously unexposed subjects under conditions of long-term stress.

PMID- 15193349
TI  - Activity-dependent hepatocyte growth factor expression and its role in
      organogenesis and cancer growth suppression.
AB  - Studies by Murphy et al. have shown that neuronal stimulation can activate
      immediate early genes that code for transcription factors. Recent data suggest
      that Ca(2+) elevation in both neuronal cytoplasmic and nuclear compartments is
      responsible for the coupling of synaptic excitation to gene expression.
      Deisseroth et al. suggest that Ca(2+) influx through L-type voltage-sensitive
      Ca(2+) channels (VSCCs) activates cytoplasmic Ca(2+) targets such as calmodulin
      (CaM). The Ca(2+)-CaM complex then translocates to the nucleus leading to Ca(2+)
      and cAMP response element-binding protein (CREB) phosphorylation and gene
      expression. Reports have shown that L-type VSCCs are found on the vagus nerve.
      Other studies have suggested that activation of L-type VSCCs leads to a Ca(2+)
      store-dependent elevation of nuclear [Ca(2+)] that triggers gene expression by
      more direct activation of nuclear Ca(2+)/CaM-dependent protein kinase (CaMK).
      Moreover, nuclear transcription factors such as DREAM are themselves Ca(2+)
      dependent, further supporting the importance of both nuclear and cytoplasmic
      Ca(2+) elevation in regulating gene expression. Our simulation studies suggest
      that intense synaptic stimulation in combination with amplification by release
      from intracellular Ca(2+) stores can produce elevations in nuclear Ca(2+)
      concentration and CaMK phosphorylation leading to CREB phosphorylation and gene
      expression. One of the downstream events would be the production of hepatocyte
      growth factor (HGF). HGF has trophic, repair, therapeutic or mitotic effect on
      kidney, pancreas, spleen, liver, lung, heart and spinal cord. These organs and
      systems' regeneration can be achieved by either upregulation of HGF release from
      the vagus nerve or upregulation of HGF production within the system (spinal
      cord). Conversely, inhibition of HGF release from the vagus nerve can inhibit
      cancer growth. Vagus nerve seems to be the nerve that nature intends to regulate
      organ growth and regeneration, it is very possible that other than HGF and
      injurin, other growth factors could be found in the vagus nerve. Electrical
      depolarization and hyperpolarization of the vagus nerve would be the most natural
      and effective way to induce organ regeneration and suppress cancer growth,
      respectively. A similar pathway seems to exist for different organs as HGF has
      trophic, repair, therapeutic or mitotic effect on different vagally innervated
      organs.

PMID- 15193350
TI  - Molecular basis of the evolution of drug resistance: potential role of the
      transient state during infection/drug treatment.
AB  - Transient period represents the time window between the exposure and response to
      the given stimuli inflicting the stress on the host. However, this time window is
      unlikely to engage in variety of signaling to culminate drastic impact on the
      host cell rather it is evolutionary in its sense implying a slow process. But it
      is reasonable to speculate that most significant signals are initiated at this
      time, and first responder will confer required adaptive features on the host
      cells. This alteration would be followed by amplification of appropriate
      adaptative signals in the successive generation(s), thus conferring the increased
      adaptability to given stress.

PMID- 15193351
TI  - Erythropoietin: a new tool for muscle disorders?
AB  - The main action of erythropoietin (EPO) is to regulate the production of red
      cells. However both experimental evidence and clinical experience suggest that
      erythropoietin has a positive effect on skeletal and cardiac muscle. Mice lacking
      EPO or its receptors suffer from hearth hypoplasia and have a reduced number of
      proliferating cardiac myocytes. EPO receptors are expressed on mouse primary
      satellite cells and in cultured myoblasts, and their stimulation appears to
      enhance proliferation and reduce the differentiation of both cell types. Moreover
      EPO is capable of promoting angiogenesis in muscle cells, which provides an
      additional route to increase oxygen supply to active muscles. In men, the effects
      of EPO on muscle cells are suggested by the illegal use of EPO by agonistic and
      amateur athletes to enhance their performances. In some athletes EPO improved
      their long-duration muscular performances much more than expected on the basis of
      the increment of the blood hemoglobin alone. Our proposal is to investigate the
      effect of EPO treatment in various animal models of muscular dystrophies (MD),
      which are common hereditary primary muscle disorders characterized by muscle
      damage and wasting, to date without any effective treatment. The ability of EPO
      to induce the proliferation of satellite cells in the presence of differentiating
      conditions, typical of the damaged muscle, may represent a tool to expand the
      cellular population competent for muscle repair. This would lengthen the period
      when muscles can be efficiently repaired. In the presence of positive results,
      the possibility could be considered of selecting some of the human forms of MD
      and treating the patients with EPO.

PMID- 15193352
TI  - Vagal nerve stimulation technique: enhancing its efficacy and acceptability by
      augmentation with auto activation and deactivation mode of operation.
AB  - The purpose of this article is to search for an additional modus operandi to
      improve the functioning of currently deployed vagal nerve stimulation (VNS)
      technique that is being used as an adjunctive therapy for intractable epilepsy,
      mainly complex partial seizures (partial onset with secondary generalization).
      The efficacy and success of current VNS technique is variable and limited, which
      can be attributed (to a considerable extent) to its present modi operandi. The
      mechanism of anti-epileptic action of VNS that has been hypothesized in the
      article is found to conform to observations and results in a large number of
      studies including those on VNS itself. Based on this mechanism in controlling
      seizures, the author proposes an additional mode of operation of the VNS device,
      (an auto activation and deactivation mode), designed to work on a feedback
      mechanism, which would deliver VNS as and when the brain requires it to
      abort/arrest the impending focal attack and/or its generalization, thus
      eliminating the limitations associated with the current VNS device. This mode
      should enhance its acceptability, efficacy and success.

PMID- 15193353
TI  - Inhibition of tumor growth by replacing glutathione with N-acetyl-L-cysteine.
AB  - There have been several attempts to prevent the tumor growth and the resulting
      death. However, almost none of the developed methods designed to inhibit tumor
      growth gives a satisfactorily result without deleterious side effects. Some of
      the existing methods employed on prevention of tumor growth and invasion target
      the metabolic differences between normal and tumor cells. The most pronounced
      metabolic differences between normal and tumor cells appear to be in the energy
      generating pathways. The energy generating pathways in normal cells are inter
      regulated and the most developed pathway controls the activity of the least
      developed pathway. Cancer cells do not respond to these regulations and as a
      result energy generating pathways start to operate independently. Among the
      energy generating pathways, the least developed or the most primitive pathway is
      the non-phosphorylating glycolysis. The increased activity of this pathway has
      been suggested to provide the cells with sufficient mitotic activity. It has been
      suggested that in non-phosphorylating glycolysis, glucose is broken down to
      lactate in a manner that requires glutathione. Here, I hypothesize that
      manipulation of intracellular glutathione concentrations as protecting the cells
      form oxidative stress may efficiently inhibit tumor growth. Glutathione is a
      soluble antioxidant and its concentration is high in prenatal tissue and in
      cancer cells. Though its primary function seems to combat against oxidant injury
      and toxic xenobiotics, glutathione is implicated in many other different cellular
      processes including cell proliferation and DNA and RNA synthesis. Another
      function of glutathione relevant to the subject is its involvement in
      detoxification of methylglyoxal, a compound that is generated at high
      concentrations in rapidly proliferating cells possessing an inhibitory activity
      on cell proliferation. Therefore, inhibition of intracellular glutathione
      concentration may negatively impact the tumor cell growth by at least three ways.
      The first is through inhibition of non-phosphorylating glycolysis that provides
      mitotic energy for cells. The second is through the inhibition of methylglyoxal
      metabolism and the third is through the redox regulation of DNA and RNA
      synthesis.

PMID- 15193354
TI  - Towards a unified and interdisciplinary model of ageing.
AB  - Researchers currently disagree about the appropriate biomarkers to monitor when
      measuring the ageing process. The major problem is identifying symptoms that are
      an end in and of themselves, from symptoms that are tied directly to the root
      cause, or causes, of ageing. This is most likely the reason that numerous,
      diverse and plausible theories for ageing co-exist. When young and old nuclei are
      exchanged between cells, the age of the resulting cell correlated with the
      nucleus. This suggests a large role of the nucleus as the target of ageing,
      although the sources of ageing may originate externally. There are three
      processes that occur when eukaryotes age. They are: (1) a progressive and
      patterned alteration of the structure of chromosomes after young adulthood has
      been reached, (2) a progressive and patterned malfunction of the degradation
      systems, and (3) age-altered post-translational modifications of proteins. A
      change in any one of these processes often causes a ripple effect that affects
      the other two processes. This paper begins by stating that the above three
      processes are the appropriate biomarkers of ageing. These three processes are
      coordinated with one another under normal physiological conditions. For example,
      proteasomes and their subunits have been found to regulate excision repair,
      transcription, and the turnover of nuclear/cytoplasmic receptors. The degradation
      system is also responsible for the removal of oxidized histones and other
      factors, which influence chromosome structure. Regulatory post-translational
      modifications at the histone level include methylation, phosphorylation, and
      acetylation. In addition, the above three processes undergo age related changes.
      Some of these modifications represent valid responses by the cell, but many do
      not. The effect of these age-altered macromolecules is perverse and
      unpredictable. For example, the cell's age-compromised degradation allows the
      accumulation of signaling complexes, which no longer match the needs of the cell.
      Age related histone and non-histone post-translational modifications alter both
      chromosome structure and expression. Nuclear pores have been found to slowly
      decrease in number in an age dependent manner. These pores have been found
      associated with the nuclear lamin. Several types of mutations in the lamin A gene
      cause progeria like symptoms. There is a diverse set of mechanisms that cause age
      related post-translational modifications. Previous attempts to find a commonality
      among those modifications have been disappointing. This paper will present a
      possible explanation that involves conformational changes caused by ionic and
      other perturbations in the nucleoplasm.

PMID- 15193355
TI  - Are lethal audiogenic seizures a missing link to the sudden infant death
      syndrome?
AB  - The pathogenesis of human seizure disorders has largely been derived from rodent
      models. A number of rodent and chick strains exhibit a genetic predisposition for
      lethal audiogenic seizures (AGSs) in the first year of life. Consideration is
      warranted that this disorder may be linked to the sudden infant death syndrome
      (SIDS). Factors that carry a strong association with SIDS such as hyperthermia
      and the prone sleeping position would conceivably play a significant role in a
      human AGS syndrome. Importantly, there is data to support the likelihood that
      motor seizure activity may be absent in infants with an AGS syndrome. Rodent AGSs
      may hold important clues to unraveling the mystery of SIDS.

PMID- 15193356
TI  - Xenografts are an achievable breakthrough.
AB  - The objective of this communication is to show that pig-to-human organ
      transplantation could be feasible through genetic engineering. By introducing
      into donor pigs several different tolerance promoting genetic modifications there
      can be a synergistic effect to produce extended tolerance for xenografted organs
      in human recipients. Nuclear-transfer cloning allows production of pigs with
      knockout mutations in the galactose-alpha-1,3-galactosyl transferase gene, in
      principle eliminating hyperacute rejection. Once hyperacute rejection is
      circumvented, long-term tolerance of xenografted organs should be possible
      through a combination of transgenic immunomodulating molecule, bone marrow
      chimerism and short to intermediate term use of immunosuppressive drugs. If
      immunomodulating transgenes are deleterious during pig development, inducible cre
      recombinase excision of stop codons provides a means to delay expression of such
      transgenes until after transplantation. Zoonotic diseases can be circumvented via
      pathogen-free colonies and additional knockout mutations to disable porcine
      endogenous retrovirus and prion disease. Thus, there is now a technical and
      theoretical framework for serious efforts at cross-species transplantation.

PMID- 15193357
TI  - Oxidant free radical initiated chain polymerization of protein and other
      biomolecules and its relationship to diseases.
AB  - We review the evidence for free radical initiated chain polymerization of
      biomolecules. Our hypothesis predicts damaging effects of this chain
      polymerization. Free radical lipid peroxidation could initiate the chain
      polymerization of amyloid peptides and other biomolecules found in Alzheimer's
      disease. Reactions forming polymers present in other neurodegenerative diseases
      could follow the same pathway. Antioxygenic nutrients could protect against free
      radical oxidant damage, thereby delaying or preventing the onset of Alzheimer's
      disease and other neurodegenerative diseases The onset of Alzheimer's disease
      could be delayed if the initiation of free radical chain polymerization were
      inhibited or limited by nutrients that act as chain terminators or provide
      reducing conditions to reduce peroxidized lipids in the brain. Vitamins E and C
      and coenzyme Q are chain terminators. Selenium, sulfur amino acids and vitamin C
      provide reducing conditions.

PMID- 15193358
TI  - Atheroscleritis is a more rational term for the pathological entity currently
      known as atherosclerosis.
AB  - The term "atheroma", a Latin word was first used in 1755 by Albrecht von Halles
      to designate the plaque deposited on the innermost layer of systemic artery
      walls. In 1940, however, Felix Marchand suggested the word "atherosclerosis"
      should be better instead of "atheroma", which is derived from two Greek roots:
      athere means gruel or porridge and sclerosis signifies hardening. It is obviously
      an improvement over the older designation arteriosclerosis. Atherosclerosis is
      still used up to data because it describes the two components of plaque: the
      lipid-filled core of atheroma encased in a shell of sclerosis or fibrosis, which
      presents the feature of atherosclerotic structure. Although atherosclerosis has
      been considered to be multi-factorial disease in which genetic, environmental,
      metabolic factors have been implicated, the gaps remain in our knowledge of the
      etiopathogenesis of atherosclerosis. More recently, there is mounting evidence
      that inflammation plays an important role in the initiation, development as well
      as evolution of atherosclerosis. The data from animals as well as humans
      indicated that an inflammatory process was involved in all stages of
      atherosclerosis appeared in different clinical settings, including atheromatous
      development, plaque rupture, restenotic process. The anti-inflammatory approach
      has been showed as one of the most promising strategies for atherosclerosis, such
      as statin intervention. Based on evidence and in light of the new understanding
      that inflammation is an intrinsic part of the process, we would like to propose a
      further change of nomenclature, call the disease atheroscleritis.

PMID- 15193359
TI  - Treatment with selective serotonin reuptake inhibitors for enhancing wound
      healing.
AB  - Selective serotonin reuptake inhibitors (SSRIs) are well-established medications
      for the treatment of mood disorders including major depression. These agents are
      also known to exhibit potent antiplatelet and endothelium protective effects
      effects. Additionally, SSRIs can exacerbate the development of inflammation, and
      modulate the interleukin and interferon production. All of the above suggest that
      SSRIs therapy could be considered as a potential strategy for the wound healing
      treatment. We summarized some body of the available data on the history of
      serotonin metabolism, mechanism of action of ketanserin, and hypothesize why
      SSRIs may be beneficial in the wound repair natural history. Different
      pathophysiological considerations are also reflected in this review. Finally, we
      suggest that the topical use of SSRIs may represent a promising avenue for future
      strategies affecting wound repair in high-risk patients, especially those with
      diabetes mellitus, venous insufficiency, obesity, and other vascular disorders.

PMID- 15193360
TI  - From plasticity to complexity: a new diagnostic method for psychiatry.
AB  - There is growing dissatisfaction regarding the available diagnostic systems for
      psychiatric disorders (DSM, ICD). Psychiatrists acknowledge that though mental
      disease reflects brain disorders, the descriptive and symptom based nature of
      psychiatric diagnosis bears no relation to brain functions. According to Helmut's
      article published in the October 2003 issue of Science, in the coming decade
      researchers and psychiatrists will be called upon to propose a basis for the
      psychiatric diagnostic system of the future. I propose a new etiology-oriented
      diagnostic system for psychiatry by integrating two recently emerging bodies of
      knowledge, one regarding plasticity and the other involving complex systems.
      Plasticity refers to all brain processes involved in dynamic alterations within
      communicating neuronal ensembles or networks, in the brain. Complexity refers to
      certain formulations from system theories relevant to brain dynamics and
      plasticity. It is proposed to divide plasticity processes into three types based
      on time domains: (1) "developmental plasticity", (2) "tuning plasticity" and (3)
      "fast stabilizing plasticity". Each type of plasticity is related to different
      complexity models achieved by the brain, developmental plasticity is life-long
      brain organization, it is related to state-space configurations molded into brain
      representations internalized via processes such as Hebbian learning. Tuning
      plasticity is related to "matching complexity" a measure of adaptability between
      internal configurations in the brain-system and externally originating event
      stimuli. Fast stabilizing plasticity is related to "neural complexity" a measure
      of neural network integration in the brain. Neural complexity meets the mental
      requirement to extract important features from different sensory inputs and to
      simultaneously generate coherent perceptual and cognitive states, thus balancing
      specialized segregated brain processes with coherent globally integrated whole
      brain activity. Mental disorders can be reconceptualized as disorders of
      plasticity resulting in disturbances of state-space brain configurations,
      matching and neural complexities. Personality disorders result from altered
      internal representations of the psychosocial environment. Depression and anxiety
      have been recently linked to alterations of adaptive neuronal plasticity thus
      reconceptualized as disorders of matching complexity. Finally, psychoses,
      including schizophrenia spectrum disorders, are reconceptualized as disturbances
      of neural complexity resulting in altered fast stabilizing plasticity. The new
      diagnostic system generates testable predictions regarding diagnosis and
      treatments of mental disorders which may be the future of psychiatry.

PMID- 15193361
TI  - Is pigment epithelium-derived factor level in cerebrospinal fluid a promising
      biomarker for early diagnosis of Alzheimer's disease?
AB  - Alzheimer's disease (AD) is the most common cause of dementia in Western
      countries and in Japan. Early diagnosis and treatment is needed to slow down the
      degenerative process and dementia in AD. The main histopathological
      characteristics of AD are senile plaques and neurofibrillary tangles. Based on
      the disease pathology, numerous blood and cerebrospinal fluid (CSF) tests have
      been proposed for early detection of AD. However, there is no definite clinical
      method to determine in which patients with mild cognitive impairment will
      progress to AD with dementia. Since pigment epithelium-derived factor (PEDF) has
      been recently shown to protect various types of cells including neuronal cells
      against oxidative stress- or glutamate-induced injury through its anti-oxidative
      properties, we examined here the expression levels of PEDF in AD's brain. PEDF
      was found to have the strong immunoreactivity in cortical neurons and astrocytes
      in the brains of AD. Further, the distribution of PEDF proteins was good
      concordance with RAGE proteins, one of the receptors for amyloid beta peptides,
      which are involved in neuronal cell death and microglial activation in AD. These
      results suggest that PEDF overexpression may indicate a compensation mechanism to
      fight against neuronal cell injury in AD. Our present observations suggest that
      PEDF in CSF might reflect cerebral PEDF turnover and provide a means for
      monitoring neuronal perturbation induced by oxidative stress in the early stage
      of AD. Clinical use of CSF-PEDF as a biomarker for AD might enable more effective
      diagnosis and treatment of patients with this disorder.

PMID- 15193363
TI  - Attacks of anxiety, panic and frenzy, and their related depression: a hypothesis.
AB  - The hypothesis is that the pathogenesis of attacks of anxiety, panic or frenzy
      (hyperactive disorders) rests on the abnormal activation of the same brain
      controlled survival mechanism, and that the subsequent depression is part of this
      nosological continuum. The acute activation phase would be the counterpart of two
      principal types of reaction to threat and imminent attack: run-for-life or fight
      for-life, sub-served by brain-controlled metabolic activation to make energy
      available for either. The phase of depression that follows would represent the
      recovery phase during which homeostatic controls and metabolism, distorted during
      the acute attacks, are restored to normal. It is further tentatively postulated
      that anxiety and panic attacks may mimic run-for-life responses, whereas attacks
      of frenzy might be homologous to fight-for-life. Both the degree of dys
      homeostasis and the completeness of the return to normality through the
      depression phase would depend on severity, duration and, importantly, spacing of
      the acute attacks. At the limit, severity, long duration and only short
      intermissions between hyperactive attacks may be postulated to result in
      persistence of the depression.

PMID- 15193362
TI  - Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and
      complementary therapy to aerobic exercise.
AB  - Increased shear stress to the endothelium increases activity of endothelial
      nitric oxide synthase (eNOS) with subsequent release of small quantities (nMol)
      of nitric oxide (NO) into the circulation. It occurs during moderate aerobic
      exercise mostly as a result of laminar shear stress and with whole body, periodic
      acceleration as a result of pulsatile shear stress. The latter is administered by
      means of a new, non-invasive, passive exercise device. Moderate exercise has long
      been known to alleviate the symptoms of fibromyalgia and chronic fatigue syndrome
      and in the current study, whole body, periodic acceleration did as well. Since NO
      through action of eNOS has potent anti-inflammatory properties mainly by
      suppressing nuclear factor kappabeta activity, it is hypothesized that both
      diseases have chronic inflammation as their basis. Whole body periodic
      acceleration can be applied separately or supplementary to aerobic exercise in
      the treatment of fibromyalgia and chronic fatigue syndrome.

PMID- 15193364
TI  - Group-theoretic structure in the sequential flow of sensory experiences.
AB  - The hypothesis presented here is that in a given person, the overall
      configuration of sensory variables at any given moment, i.e. everything that the
      person is seeing, hearing, etc., can be treated as belonging to an infinite
      sequence of such momentary configurations, with the sequence being generated by a
      particular mathematical group. The ideas behind this are as follows. If a
      person's various moment-to-moment sensory experiences can all be described within
      the same coordinate system, then they can be treated as objects that sequentially
      transform into one another. If they are also encoded by brain events, then the
      person's own encounters with this encoding, e.g. when participating in brain
      stimulation experiments, amount to instances where a given sensory experience
      inevitably follows other sensory experiences occurring in a specific sequence.
      For example, a person's visual encounters with certain equipment-settings might
      always be followed by a particular visual hallucination. If there exist sequences
      like this for any given momentary sensory experience, then these collectively
      form the person's sensory code, as it would be encountered from the person's own
      perspective. The person's ongoing flow of sensory experiences may then be treated
      as part of the infinite sequence implied by the various code-conserving ways in
      which sensory experiences can flow from one to the next. If this sequence can be
      generated by a finite number of code-conserving segments that transform into each
      other and link together end to end, then a person's full range of sensory
      experiences can be defined in group-theoretic terms.

PMID- 15193366
TI  - Inhibition of protein kinase C might be harmful to diabetic retinopathy.
AB  - Selective loss of retinal pericytes is the earliest histopathological hallmark in
      diabetic retinopathy. Various structural and functional abnormalities in diabetic
      retinas are the consequent of the loss of pericytes. Therefore, elucidating the
      molecular mechanisms for pericyte loss and targeting this characteristics change
      in early diabetic retinopathy may help to slow the development and progression of
      sight-threatening retinopathy in diabetes. Protein kinase C (PKC) inhibition has
      been used in therapeutic trials intended to reduce the incidence of proliferative
      diabetic retinopathy. However, we speculate that it is likely to do more harm
      than good in diabetic retinopathy because PKC inhibition augments pro-apoptotic
      effects of high glucose on cultured retinal pericytes. In the DCCT-Epidemiology
      of Diabetes Interventions and Complications Research, the reduction in the risk
      of progressive retinopathy resulting from intensive therapy in patients with type
      1 diabetes persisted for at least four years, despite increasing hyperglycemia.
      These clinical studies strongly suggest that so-called "hyperglycemic memory"
      causes vascular damage in diabetic retinopathy. Glucose react non-enzymatically
      with the amino groups of proteins to initiate a complex series of rearrangement
      and dehydration reactions to produce a class of irreversibly cross-linked,
      fluorescent moieties, termed advanced glycation end products (AGEs). The
      formation and accumulation of AGEs progress at an extremely accelerated rate in
      diabetic retinas, and these products have been implicated in the pathogenesis of
      loss of pericytes in diabetic retinopathy. The nature of AGEs is most compatible
      with the theory of 'hyperglycemic memory' as well. We hypothesize here that PKC
      inhibition is likely to do harm in diabetic retinopathy, while inhibition of AGE
      formation might be a promising therapeutic strategy for treatment of this
      devastating complication.

PMID- 15193365
TI  - The biochemical basis of the neurobehavioral abnormalities in the Lesch-Nyhan
      syndrome: a hypothesis.
AB  - Lesch-Nyhan syndrome (LNS) is a rare X-recessive disorder that leads to virtually
      complete deficiency of the purine salvage enzyme hypoxanthine-guanine
      phosphoribosyltransferase (HPRT). Partial HPRT deficiency results in uric acid
      overproduction with subsequent hyperuricemia, nephrolithiasis, renal failure and
      gouty arthritis. In contrast, at complete HPRT deficiency, besides overproduction
      of uric acid neurological problems appear including spasticity, choreoathetosis,
      mental retardation, and compulsive self-mutilation. The cause for the uric acid
      overproduction has been clarified, but the connection between the enzyme
      deficiency and the neurological manifestations in LNS remains unclear. A
      hypothesis, which explains this relation, is proposed in the paper. The
      hypothesis has several important points most substantial of which is the
      accelerated biosynthesis of semiessential amino acid histidine that against the
      background of accelerated purine de novo biosynthesis results in 5-aminoimidazole
      4-carboxamideribotide (AICAR) and histamine accumulation. The histamine and AICAR
      were determined to be the compounds that cause the neurobehavioral symptoms of
      LNS for several reasons. First, in the basal ganglia a balance between the direct
      (activating) and the indirect (inhibiting) pathways arising on the basis of the
      antagonistic and reciprocal dopamine-adenosine interactions normally exists. This
      balance can tonically regulate smooth voluntary movements and the activity of the
      thalamus, which, in turn, processes the afferent sensorimotor signals from the
      whole body to the all areas of the cerebral cortex and is concerned to modulate
      mental development and bring sensory information into awareness. Second,
      histamine is known to induce a selective damage in dopaminergic neurons
      inhibiting the direct dopaminergic pathway, which could lead to muscular
      rigidity, and slowness in initiating movements as well as tremor that are
      characteristic of Parkinsonism in LNS. Third, AICAribosid (AICAR breakdown
      product) is a potent adenosine A2a receptor antagonist inhibiting the indirect
      dopamine-adenosinergic pathway and, therefore, could be responsible for the
      choreoathetosis, dystonia and ballismus found in LNS. The excitatory-inhibitory
      disbalance in the basal ganglia could result in inadequate modification of the
      thalamus activity with subsequent mental retardation and symptoms that include
      the patients not being aware for their own bodies that could give rise to self
      mutilation. Finally, a possibility for the creation of a new animal model that
      could exactly match the human LNS is proposed in the paper.

PMID- 15193367
TI  - Should we restrict chloride rather than sodium?
AB  - Low-salt diets have potential for prevention and treatment of hypertension, and
      may also reduce risk for stroke, left ventricular hypertrophy, osteoporosis,
      renal stones, asthma, cataract, gastric pathology, and possibly even senile
      dementia. Nonetheless, the fact that salt restriction evokes certain counter
      regulatory metabolic responses-- increased production of renin and angiotensin
      II, as well as increased sympathetic activity--that are potentially inimical to
      vascular health, has suggested to some observers that salt restriction might not
      be of unalloyed benefit, and might in fact be contraindicated in some "salt
      resistant" subjects. Current epidemiology indicates that lower-salt diets tend to
      reduce coronary risk quite markedly in obese subjects, whereas the impact of such
      diets on leaner subjects (who are less likely to be salt sensitive) is equivocal-
      seemingly consistent with the possibility that salt restriction can exert
      countervailing effects on vascular health. There is considerable evidence that
      sodium chloride, rather than sodium per se, is responsible for the known adverse
      effects of dietary salt. Other non-halide sodium salts, such as sodium citrate or
      bicarbonate, do not raise plasma volume, increase blood pressure, boost urinary
      calcium loss, or promote stroke in stroke-prone rats. Nonetheless, these
      compounds have been shown to blunt the impact of salt restriction on renin,
      angiotensin II, and sympathetic activity in humans. This may rationalize limited
      clinical evidence that organic sodium salts can decrease blood pressure in salt
      restricted hypertensives. Furthermore, organic sodium salts have an alkalinizing
      metabolic impact favorable to bone health. These considerations suggest that
      restricting dietary salt to the extent feasible, while encouraging consumption of
      organic sodium salts in mineral waters, soft drinks, or other nutraceuticals-
      preferably in conjunction with organic potassium salts and taurine--may represent
      a superior strategy for controlling blood pressure, promoting vascular health,
      and preserving bone density. Further clinical studies should determine whether a
      moderately salt-restricted diet supplemented with organic sodium salts has a
      better and more uniform impact on hypertension than salt restriction alone, while
      rodent studies should examine the comparative impact of these regimens on rodents
      prone to vascular disease.

PMID- 15193369
TI  - Temporal variation of autonomic balance and diseases during circadian, seasonal,
      reproductive, and lifespan cycles.
AB  - Many diseases show patterns of temporal variation that remain unexplained. We
      hypothesize that oscillation of autonomic balance over different time intervals
      plays a role in these variations. In the Darwinian struggle, organisms must
      perform various functions related to fitness such as survival, energy
      acquisition, and reproduction in a prioritized fashion. Autonomic systems enable
      differential allocation of effort to various functions under different
      conditions, some of which vary in patterns that are predictable such as
      circadian, menstrual, seasonal, and life cycles. For many species, daytime
      functions such as seeking food and avoiding predators are achieved with
      sympathetic activity while night-time functions such as internal processing are
      achieved with parasympathetic activity. For organisms that maintain thermal
      homeostasis year-round, cooler temperature seasons may demand sympathetic bias to
      drive adaptive thermogenesis. Reproduction may necessitate autonomic shift to
      sympathetic bias during the luteal phase and pregnancy to modulate immune balance
      towards a more tolerant Th2 bias. Many diseases including infectious,
      cardiovascular, inflammatory, pulmonary, metabolic, fertility, oncologic, and
      neurologic conditions also show variation in prevalence over these cycles. The co
      variation of autonomic balance and diseases over time intervals suggests that
      autonomic balance, by its direct effects as well as its indirect effects through
      modulation of T helper immune balance, plays an under-recognized role in
      diseases. The theory is extended to the co-variation of autonomic balance and
      diseases over the lifespan. Termination of organisms during senescence, achieved
      by emergence of autonomic imbalance and other systemic dysfunctions, is explored
      from a Darwinian perspective.

PMID- 15193368
TI  - Medicine without drugs--a new direction for application of nanotechnology.
AB  - A working model of direct computer-organism interaction is described. The model
      is based on the understanding of the ways/modes, by which information is
      transmitted in the living organism. Information is transmitted in an organism by
      different ways. Communication between (among) the streams of different modes of
      information is provided by particular natural mechanisms--transformers and
      interconnectors. The model suggests that the functions of the cells, organs and
      systems of an organism can be monitored, controlled and governed directly by
      means of nano-computers. The application of a computer enables one to provide
      early diagnostics and successful treatment using specifically designed computer
      programs instead of, or in conjunction with, medications or surgery. The computer
      organism interaction is being achieved through an effective engagement and
      interaction of the streams of computer generated information with the streams of
      information naturally transmitted in the organism.

PMID- 15193370
TI  - Menstrual variation of autonomic balance may be a factor in exacerbations of
      certain diseases during the menstrual cycle.
AB  - Exacerbation of certain medical conditions during specific phases of the
      menstrual cycle has long been recognized. Mechanisms of the cyclic variations are
      poorly understood, but are often attributed to fluctuations in reproductive
      hormones. We hypothesize that normal variations in autonomic balance during the
      menstrual cycle, which likely evolved as adaptations for reproduction, may
      contribute to catamenial variations in diseases independent of hormonal
      variations. Emerging evidence suggests that autonomic balance shifts towards
      sympathetic bias during the second half of the menstrual cycle. This shift can be
      seen as an evolutionary adaptation to address the immunologic and physiologic
      demands for successful implantation and gestation. Through direct modulation of
      lymphoid system and activation of the cortisol pathway, sympathetic bias promotes
      a shift to relative T helper (Th)-2-biased immunity which may favor maternal
      tolerance of the embryo by attenuating Th-1-mediated interference of
      implantation. Immune variance during the menstrual cycle has been implicated in
      menstrual fluctuations of many diseases, but until now the immune variance has
      been attributed to female hormonal changes. We propose that shifts in autonomic
      balance independently contribute to fluctuations in diseases by modulating the
      immune system. Still further, we propose that many other diseases fluctuate due
      to the direct nervous system actions of shifts in autonomic balance. Our
      hypothesis portends new therapeutic paradigms based on cyclical modulation of
      autonomic balance to address catamenial variations of medical conditions.

PMID- 15193371
TI  - Immunomodulatory function of seminal catecholamines may be an adaptation for
      reproduction.
AB  - Catecholamines are found at high concentrations in seminal fluid. The exact
      functional significance of seminal catecholamines is unknown. We hypothesize that
      seminal catecholamines perform important immunomodulatory functions that support
      reproductive success. Specifically, we propose that catecholamines contribute to
      a local adaptive shift of T helper (Th) balance to Th2 dominance in the maternal
      reproductive tract to enable the gametes, and possibly the nascent zygote, to
      evade immune surveillance of the female. Our hypothesis suggests that the Th2
      effects of catecholamines are independent of the direct immunomodulatory effects
      of seminal cytokines such as prostaglandin E2 and transforming growth factor
      beta1. Potential immunomodulatory functions of other seminal constituents such as
      aldosterone, oxytocin, vasopressin, and angiotensin remain unexplored and
      represents a topic of future interest. Seminal stress hormones may play a role in
      mating dynamics since alpha males typically live in a state of high hormonal
      stress, Mating with adrenalized alpha males may represent an adaptive Darwinian
      strategy by females to maximize their reproductive fitness.

PMID- 15193372
TI  - Autonomic dysfunction may be an under-recognized cause of female fertility
      disorders.
AB  - Female conditions of impaired fertility comprise a heterogeneous group of
      disorders that are attributed to various anatomic, hormonal and immunologic
      disturbances. We hypothesize that autonomic dysfunction may be a previously
      unrecognized factor in female fertility disorders. Emerging physiologic and
      molecular evidence suggests that autonomic balance varies during normal menstrual
      cycles with a shift to sympathetic bias during the luteal phase. Furthermore,
      many diseases associated with autonomic dysfunction show catamenial variations in
      patterns consistent with a shift to sympathetic bias occurs during the second
      half of normal menstrual cycles. The shift to sympathetic bias during the normal
      luteal phase may be an evolutionary adaptation to address the immunologic and
      physiologic demands for successful implantation and gestation. Through direct
      modulation of the lymphoid system and activation of the cortisol pathway,
      sympathetic bias promotes a shift to relative T helper (Th)-2 biased immunity
      which may favor maternal tolerance of the embryo by attenuating Th-1 mediated
      interference of implantation. Indeed, a growing body of evidence has implicated
      abnormal Th balance in fertility disorders, but the link has been attributed to
      factors other than autonomic function, such as hormonal factors. After
      implantation, maternal sympathetic bias may further support gestation through
      physiologic changes necessary to maintain placental perfusion pressure. We
      propose that insufficient shift to sympathetic bias during the luteal phase,
      which manifests in inadequate shift towards Th-2 bias and down-regulation of Th-1
      function, may be the mechanism of impaired fertility in certain patients. Our
      hypothesis portends new potential methods to treat fertility disorders by
      modulating autonomic balance.

PMID- 15193373
TI  - Parkinson's disease and vegan diet.

PMID- 15193374
TI  - Several possible causes for multiple myeloma including a vaccination in a single
      case study.

PMID- 15193375
TI  - Mucosal immunization against dental caries with plasmid DNA encoding pac gene of
      Streptococcus mutans in rats.
AB  - Salivary secretory immunoglobulin A (S-IgA) antibodies act as the first line of
      defense against dental caries by blocking of adherence of Streptococcus mutans to
      tooth surfaces. This study focused on finding proper mucosal immunization route
      and delivery system to induce higher level of specific anti-S. mutans saliva S
      IgA and inhibit dental caries in animal model. By immunizing rats with an anti
      caries DNA vaccine, pCIA-P, via different mucosal routes, we found that
      intranasal (i.n.) immunization with pCIA-P/bupivacaine DNA complexes elicited the
      highest specific anti-S. mutans saliva S-IgA mucosal antibody responses compared
      with naked DNA and other routes. Correspondingly, rats immunized with pCIA
      P/bupivacaine DNA complex via i.n. displayed the least carious lesions. Our
      findings suggested that DNA vaccination via intranasal immunization with
      bupivacaine delivery system be a promising approach against dental caries.

PMID- 15193376
TI  - The efficacy of electroporated plasmid vaccines correlates with long-term antigen
      production in vivo.
AB  - We sought to determine whether in vivo electroporation might overcome the
      requirement for strong transcriptional promoters in plasmid vaccines. We tested
      plasmid vaccines containing viral promoters that exhibited a broad range of
      transcriptional activities by in vitro assay. In contrast to the in vitro
      observations, no difference in gene expression was measured in vivo 24h following
      injection when the plasmids were introduced via electroporation. Despite the
      similarities in gene expression in vivo, the cellular and humoral responses
      elicited by these plasmid vaccines were dramatically different and correlated
      more closely with the promoter activity measured in vitro. When antigen
      production in vivo was measured over a longer period following injection,
      significant differences in gene expression became apparent after 2-3 days and the
      differences in gene expression at day 7 correlated well with plasmid
      immunogenicity. These studies reconfirm the importance of antigen production for
      effective plasmid vaccination and demonstrate that the duration of gene
      expression should also be considered when designing plasmid vaccines.

PMID- 15193377
TI  - A Salmonella enterica serovar Typhi vaccine expressing Yersinia pestis F1 antigen
      on its surface provides protection against plague in mice.
AB  - A recombinant strain of attenuated Salmonella enterica serovar Typhi surface
      expressing Yersinia pestis F1 antigen was generated by transforming strain
      BRD1116 (aroA aroC htrA) with plasmid pAH34L encoding the Y. pestis caf operon.
      BRD1116/pAH34L was stable in vitro and in vivo. An immunisation regimen of two
      intranasal doses of 1 x 10(8) cfu of BRD1116/pAH34L given intranasally to mice 7
      days apart induced the strongest immune response compared to other regimens and
      protected 13 out of 20 mice from lethal challenge with Y. pestis. Intranasal
      immunisation of mice constitutes a model for oral immunisation with Salmonella
      vaccines in humans. Thus, the results demonstrate that attenuated strains of S.
      enterica serovar Typhi which express Y. pestis F1 antigen may be developed to
      provide an oral vaccine against plague suitable for use in humans.

PMID- 15193378
TI  - Identification and characterization of outer membrane proteins G1a and G1b of
      Moraxella catarrhalis.
AB  - Moraxella catarrhalis is an important cause of otitis media, sinusitis, and lower
      respiratory tract infections in patients with chronic obstructive pulmonary
      disease. The purified outer membrane of M. catarrhalis contains a 29 kDa band,
      previously named outer membrane protein G1 (OMP G1). Polyclonal antiserum to the
      OMP G1 band was used to screen a genomic lambda phage library and the gene for
      OMP G1a was cloned and sequenced. Analysis of outer membrane by isoelectric
      focusing and amino-terminal protein sequence of the 29 kDa band revealed that the
      band is actually two individual proteins designated OMP G1a and OMP G1b. OMP G1a
      is a lipoprotein with an isoelectric point of 4. OMP G1b contains an unblocked
      amino-terminus and has an isoelectric point of 9. Analysis of the sequence of OMP
      G1a and OMP G1b from 25 clinical isolates revealed a high degree of conservation
      among strains. The sequence conservation of OMP G1a and OMP G1b among strains,
      combined with previous observations that OMP G1a and OMP G1b contain epitopes on
      the bacterial surface, indicate that OMP G1a and OMP G1b are potential vaccine
      antigens for M. catarrhalis.

PMID- 15193379
TI  - Immunisation against Helicobacter felis infection protects against the
      development of gastric MALT Lymphoma.
AB  - The formation of mucosa-associated lymphoid tissue (MALT) in response to
      Helicobacter pylori infection is closely associated with the development of
      primary gastric MALT lymphoma. AIM: To examine whether immunisation against
      Helicobacter felis can protect against development of MALT lymphoma. RESULTS: The
      majority of control infected mice demonstrated MALT formation (13/15) and five
      developed lymphoma. Fifteen immunised mice were protected against bacterial
      challenge, of which only five had evidence of MALT formation and none developed
      lymphoma. Interestingly, of the four mice in which immunisation failed, all
      developed MALT and two of these had lymphoma. CONCLUSION: Effective immunisation
      against Helicobacter infection can protect against gastric MALT lymphoma. To our
      knowledge this is the first demonstration of vaccination protecting against a
      bacteria-induced malignancy.

PMID- 15193380
TI  - Generation of tumor-specific cytotoxic T lymphocyte and prolongation of the
      survival of tumor-bearing mice using interleukin-18-secreting fibroblasts loaded
      with an epitope peptide.
AB  - There is currently much interest in generating cytotoxic T lymphocyte (CTL)
      responses against tumor antigens as a therapy for cancer. In this study mouse
      fibroblasts (H-2(b)) were genetically modified to express a costimulatory B7.1
      and a mature interleukin (IL)-18, and then loaded with an ovalbumin (OVA) epitope
      (SIINFEKL, H-2K(b) restricted) as a model antigen, and tested for the induction
      of OVA-specific CTLs in C57BL/6 mice (H-2(b)). The genetically modified
      fibroblasts lacking either IL-18 or B7.1 were also constructed. Immunization with
      the IL-18/B7.1-transfected fibroblasts induced strong cytotoxic activities
      against OVA-expressing EL4 (EG7) tumor cells, but not against other H-2(b) tumor
      cells such as EL4, C1498, and B16F1 cells. The magnitude of the cytotoxic
      response in mice with the IL-18/B7.1-transfected fibroblasts was significantly
      higher than the response in mice immunized with any other cell constructs. CD8(+)
      T cells with OVA-specific cytotoxic activities were predominant in mice immunized
      with the IL-18/B7.1-transfected fibroblasts. Furthermore, treatment with the IL
      18/B7.1-transfected fibroblasts significantly prolonged the survival period of
      EG7 tumor-bearing mice. Anti-tumor CTL immunity by the IL-18/B7.1-transfected
      fibroblasts could be induced without the help of host antigen-presenting cells
      (APCs) and NK1.1(+) cells, whereas partially decreased by the depletion of CD4(+)
      T cells at the inductive stage. These results support the ability of IL-18/B7.1
      gene transfer to enhance the antigen-presenting capacity of fibroblasts for
      inducing antigen-specific CTL response.

PMID- 15193381
TI  - Varicella-zoster virus expressing HSV-2 glycoproteins B and D induces protection
      against HSV-2 challenge.
AB  - A recombinant Oka (ROka) varicella-zoster virus (VZV) vaccine was constructed
      that expresses herpes simplex virus type 2 (HSV-2) glycoproteins B (gB) and D
      (gD). Guinea pigs received one of four inocula: (a). uninfected cells, (b).
      recombinant Oka VZV infected cells, (c). recombinant Oka VZV expressing HSV-2
      gB/gD (ROka-gB2/gD2) infected cells, or (d) heat-inactivated ROka-gB2/gD2
      infected cells. Only animals inoculated with ROka-gB2/gD2 developed high titers
      of neutralizing antibodies to HSV-2. Animals immunized with ROka-gB2/gD2 had
      reduced mortality after intravaginal challenge with HSV-2 compared with animals
      that received ROka or heat-inactivated ROka-gB2/gD2. Animals immunized with ROka
      gB2/gD2 had reduced lesions scores for the first 2 weeks after challenge, and
      reduced shedding of HSV-2 on Days 5 and 7 after challenge, compared to the other
      two groups. These data show that recombinant VZV expressing HSV-2 antigens must
      be infectious to offer significant protection against challenge with HSV-2, and
      that ROka-gB2/gD2 has promise as a candidate HSV-2 vaccine.

PMID- 15193382
TI  - Mucosal (SIgA) and serum (IgG) immunologic responses in young adults following
      intranasal administration of one or two doses of inactivated, trivalent anti
      influenza vaccine.
AB  - Influenza morbidity affects the entire population and has an enormous impact upon
      the economic burden and the health care systems. Available vaccines are often
      unsatisfactory and many individuals are reluctant to receive injections.
      Intranasal immunization is painless, side effect free and may encourage a large
      number of individuals to participate in the vaccination programs. Ninety-two
      students were immunized intranasally once or twice, 21 days apart, with a
      trivalent inactivated whole influenza vaccine during three separate seasons
      (1996/1997, 1997/1998 and 1998/1999) with the recommended seasonal strains. The
      vaccine was well tolerated, without adverse effect and morbidity in the vaccinees
      during the winter season was low. Serum antibody response was determined by the
      hemagglutination inhibition (HI) test and nasal response by the enzyme-linked
      immunoadsorbant assay (ELISA). Following the second dose, mucosal antibody
      response was detected in 48.1-73.3% of immunized subjects. Serum and mucosal
      antibody levels (GMT) increased significantly to all the strains, with the
      exception of A/H3N2 in the mucosal response in 1997/1998. At the end of the
      trial, the percentage of immune subjects was over 93% to A/H1N1 strains, 60-71%
      to A/H3N2 and 64-66% to B/Harbin in 1996/1997 and 1997/1998, and 75-91% following
      one dose in 1998/1999. When serum and mucosal responses were combined, a higher
      percentage of responders was found (60-86%). Repeated vaccination does not seem
      to interfere with serum or mucosal response. The double barrier of mucosal and
      serum antibody may inhibit infection and decrease morbidity when infection
      occurs, thus limiting the spread of influenza in the community.

PMID- 15193383
TI  - An ELISA for putative neutralizing antibodies to hepatitis E virus detects
      antibodies to genotypes 1, 2, 3, and 4.
AB  - Two monoclonal antibodies that neutralize hepatitis E virus (HEV) were used to
      identify a subregion of ORF2 capsid protein spanning amino acids 459-607 as the
      shortest peptide to form the corresponding neutralization epitopes. An enzyme
      linked immunosorbent assay (ELISA) based on a purified recombinant protein
      covering amino acids 458-607 in ORF2 of the Sar-55 strain (genotype 1)
      efficiently detected anti-HEV in non-human primates which had been experimentally
      infected with the four known mammalian genotypes of HEV, respectively. However,
      anti-HEV in these animals did not react with a shorter ORF2 peptide spanning
      amino acids 475-607. The ELISA was highly specific and sensitive when human or
      non-human primate sera were tested in parallel with a previously established
      ELISA based on amino acids 112-607 in ORF2. The antibody titer to peptides 458
      607 in two ORF2-vaccinated rhesus monkeys which had different HEV challenge
      outcomes differed at the time of challenge. Since the ELISA appeared to be
      specific for neutralizing antibodies against HEV, it should be especially useful
      for quantifying the humoral immune response in hepatitis E vaccine trials.

PMID- 15193384
TI  - Codon optimization and ubiquitin conjugation of human immunodeficiency virus-1
      Tat lead to enhanced cell-mediated immune responses.
AB  - The transactivator protein, Tat, is a potential candidate for developing a
      vaccine against human immunodeficiency virus (HIV-1). Since Tat is not
      immunodominant, especially when delivered as a genetic vaccine, we expressed
      codon-optimized subtype-C Tat as a molecular conjugate of ubiquitin, to elicit
      antigen-specific cell-mediated immune responses. Immunization of mice with
      different ubiquitin-Tat constructs elicited a strong cellular, but not a humoral,
      immune response. The combination of codon-optimization and ubiquitin-mediated
      processing of Tat induced a Th-1 type cellular immune response that was
      detectable without in vitro stimulation, suggesting its potential utility for
      destruction of virus-infected cells via CTL-mediated lysis. Preliminary attempts
      at characterizing the immunodominant regions identified a novel T-helper epitope
      within the core domain of Tat.

PMID- 15193385
TI  - Japanese encephalitis subunit vaccine composed of virus-like envelope antigen
      particles purified from serum-free medium of a high-producer J12#26 cell clone.
AB  - A stable cell clone, J12#26, which continuously secretes large amounts of the
      envelope (E) antigen of Japanese encephalitis (JE) virus (J. Virol. 77 (2003)
      8745) was adapted to serum-free medium. The J12#26 antigen possessed
      hemagglutinating activity, as well as the viral E and M proteins. More than 10
      and 1mg of the antigen quantified with the licensed JE vaccine (JE-VAX) as a
      standard by E-ELISA and protein determination, respectively, were recovered from
      500 ml of serum-free medium by membrane ultrafiltration, Sephacryl S-300
      chromatography, sucrose gradient centrifugation and Sephadex G-25 chromatography.
      SDS-PAGE and Western blot analyses confirmed the high yield and purity of the
      J12#26 E antigen, which was comprised of small spherical virus-like particles
      (VLP) of approximately 25 nm in diameter. This antigen induced in mice without
      adjuvant neutralizing antibody (NT Ab) titers, as high as or higher than the
      licensed JE vaccine, and complete protection against challenge with wild-type
      virus. These results suggest that the J12#26 antigen is a promising second
      generation JE subunit vaccine.

PMID- 15193386
TI  - Induction of cytotoxic T lymphocytes following immunization with cationized
      soluble antigen.
AB  - Antigen presentation on major histocompatibility complex (MHC) class I and
      subsequent priming of antigen-specific cytotoxic T lymphocytes (CTLs) are
      essential steps for vaccination but exogenous soluble proteins are conventionally
      taken up by endosomes and presented on MHC class II rather than class I. In this
      study, we demonstrated, for the first time, that ovalbumin (OVA) chemically
      cationized with hexamethylenediamine (HMD) can induce OVA-specific CTLs without
      any adjuvants. Cationization of OVA greatly enhances cellular uptake by antigen
      presenting cells (APCs) through adsorptive endocytosis. Two kinds of Cat-OVAs
      with different cationic charges were evaluated to elicit a CTL response through
      enhanced uptake by APCs and concomitant participation in the class I pathway.
      Cat(20)-OVA, a cationized OVA derivative with more cationic charges, showed
      pronounced induction of the OVA-specific CTL response after subcutaneous
      immunization. The CTL response was comparable with that induced by OVA with CFA.
      In contrast to the CFA formulation that actually produced local tissue damage in
      this study, local damage at the injection sites was not observed with Cat-OVAs.
      Cat(20)-OVA also showed a significant protective effect on the growth of OVA
      expressing E.G7 tumor cells. In conclusion, cationization of soluble antigen is a
      useful and safe vaccination strategy.

PMID- 15193387
TI  - Outer membrane vesicles (OMVs) and detoxified lipooligosaccharide (dLOS) obtained
      from Brazilian prevalent N. meningitidis serogroup B strains protect mice against
      homologous and heterologous meningococcal infection and septic shock.
AB  - Neisseria meningitidis (N. meningitidis) is a serious bacterial pathogen that
      causes life-threatening invasive bacterial infections especially in children
      below 2 years of age, teenagers and young adults. We have investigated the
      protective potential of outer membrane vesicles (OMVs) and detoxified
      lipooligosaccharide (dLOS) obtained from Brazilian prevalent N. meningitidis
      serogroup B strains. Swiss mice were immunized with different combinations of OMV
      and dLOS from N. meningitidis serogroup B strains compared to a reference vaccine
      (VA-MENGOC-BC), Cuba). The OMVs + dLOS from Brazilian prevalent strains induced
      higher bactericidal antibody titers against homologous and heterologous target
      strains and stronger inhibition of thrombocytopenia as compared to the reference
      vaccine. When the challenge was performed with the B strain, all immunogens
      tested showed similar survival rates (80%) significantly higher than the control
      group. Bacterial clearance against the group B strain was comparable for animals
      immunized with the tested immunogen and the reference vaccine. Inclusion of dLOS
      from the B strain with the OMV, induced a similar clearance of C strain bacteria
      as compared to VA-MENGOC-BC. The immunogens, as well as the reference vaccine
      drastically inhibited increases in TNF-alpha and IL-6 plasma levels after
      challenge. In conclusion, the OMV/dLOS formulation obtained from Brazilian
      prevalent strains of N. meningitidis has a remarkable performance protecting mice
      against the lethal effects of meningococcal challenge showing a good potential as
      a vaccine and should be considered for clinical evaluation.

PMID- 15193388
TI  - Long-term memory B-cell responses in recipients of candidate human
      immunodeficiency virus type 1 vaccines.
AB  - The efficacy and practical application of human immunodeficiency virus type 1
      (HIV-1) vaccines may depend in part on the longevity of the immune responses
      generated, particularly those in the memory compartment. Candidate vaccines based
      on the HIV-1 envelope glycoproteins generate binding and neutralizing antibodies
      in humans but there have been no prior studies on the long-term persistence and
      recall of those responses. We evaluated six healthy, HIV non-infected adults who
      had received a combination of recombinant canarypox HIV-1 vaccines boosted by
      gp120 and who had achieved a high serum titer of neutralizing antibody to HIV-1
      MN. These individuals were administered a gp160 boost 4-5 years after their last
      vaccination. Four volunteers had detectable binding and neutralizing antibodies
      at the time of boosting and all six volunteers exhibited a recall binding and
      neutralizing antibody response. The antibodies neutralized multiple T cell line
      adapted (TCLA) strains of virus, including the vaccine strain, but not primary
      isolates. These results demonstrate that memory B-cell responses can last for
      many years following HIV-1 envelope glycoprotein immunization. In principle,
      similar long-term memory may be possible with improved immunogens that generate
      broadly cross-reactive neutralizing antibodies.

PMID- 15193389
TI  - Strong T cell type-1 immune responses to HIV-1 Tat (1-72) protein-coated
      nanoparticles.
AB  - A significant emphasis has been placed on the development of adjuvants and/or
      delivery systems to improve both antibody production and cell-mediated immune
      responses. We previously reported on a novel anionic nanoparticle, which led to
      enhanced humoral and T helper type-1 (Th1) biased immune responses in mice when
      coated with cationized model antigen. Tat (1-72) is a conserved regulatory HIV-1
      protein. It was hypothesized that HIV vaccine strategies employing Tat (1-72) may
      be a promising approach. Although previous reports have suggested that Tat (1-86)
      may be immunosuppressive, it was demonstrated in this present study that Tat (1
      72) was not immunosuppressive when co-administered to mice with ovalbumin (OVA).
      Tat (1-72) was coated on novel anionic nanoparticles. BALB/c mice were immunized
      with Tat (5 microg)-coated nanoparticles (15 microg) by subcutaneous injection on
      days 0 and 14. Antibody and cytokine release were determined on day 28 and
      compared to Tat (5 microg) adjuvanted with Alum (15 microg) as a Th2 control, Tat
      (5 microg) adjuvanted with Lipid A (50 microg) as a Th1 control. Immunization of
      BALB/c mice with Tat-coated nanoparticles resulted in antibody levels (IgG and
      IgM) comparable to those elicited from Tat and Alum. However, Tat-coated
      nanoparticles led to a Th1 biased immune response. The IFN-gamma release from
      splenocytes with Tat-coated nanoparticles was comparable to that from mice
      immunized with Tat and Lipid A, and 3.3-fold greater than that from mice
      immunized with Tat and Alum. These studies warrant further investigation of these
      nanoparticles to enhance both antibody and cellular-based immune responses.

PMID- 15193390
TI  - Induction of autoantibody production but not autoimmune disease in HEL transgenic
      mice vaccinated with HEL in combination with CpG or control
      oligodeoxynucleotides.
AB  - CpG oligodeoxynucleotides (ODN) are synthetic DNA sequences that mimic bacterial
      DNA, and bind to the TLR9 receptor. The cells that express TLR9, B cells and
      dendritic cells, are stimulated by CpG ODN and induce innate and acquired immune
      responses. Because CpG ODN induce antigen-independent immune activation there has
      been much interest in the possibility that they may break self tolerance. To test
      this hypothesis we used a tolerance model with hen egg lysozyme (HEL)-transgenic
      (Tg) mice, anti-HEL Ig-Tg mice and double (Dbl)-Tg mice injected with CpG ODN
      alone or together with HEL self antigen. When cultured in vitro, tolerant B cells
      responded to CpG ODN in a similar way as the non-tolerant Ig-Tg B cells in terms
      of cell proliferation, NFkappaB activation and CD69 expression. Despite these
      potent in vitro stimulatory effects of CpG ODN alone, HEL-Tg mice injected with
      CpG ODN alone, or in combination with low dose antigen (4 microg HEL),
      surprisingly did not produce any detectable anti-HEL Ab. However, HEL-Tg or Dbl
      Tg mice immunized with CpG ODN plus higher doses of self antigen showed strong
      antigen-specific humoral responses. Surprisingly, control non-CpG ODN also had
      partial activity for breaking tolerance and inducing autoantibody production when
      administered in combination with self antigen, though not when used alone.
      Despite the production of high titers of anti-HEL Ab in the immunized HEL-Tg
      mice, no evidence of autoimmune disease was detected. We conclude that
      immunization with CpG or control ODN in the presence of a high dose of exogenous
      self antigen, but not treatment with ODN alone, can break tolerance to self
      antigen without inducing autoimmune disease in this system.

PMID- 15193391
TI  - A plasmid immunization construct encoding urease B of Helicobacter pylori induces
      an antigen-specific antibody response and upregulates the expression of beta
      defensins and IL-10 in the stomachs of immunized mice.
AB  - The objectives of this study were to investigate the efficacy of a prototype DNA
      immunization construct encoding the urease B subunit enzyme of Helicobacter
      pylori (H. pylori) for inducing adaptive and innate immune responses in mice
      immunized via intramuscular or subcutaneous routes and to further explore the
      adjuvant effects of the CpG motifs in the vector. Antibody, cytokine, and beta
      defensin profiles were assessed in the stomachs of immunized animals: experiments
      were terminated 3 months after immunization because there was a significant
      increase in the anti-H. pylori urease B antibody response at Week 6 in mice
      immunized with the urease B construct. A long lasting expression of IL-10 mRNA
      was noted. Furthermore, a marked and sustained increase in the mRNA expression of
      beta-defensins was also observed, particularly beta1. This study demonstrates
      that an H. pylori urease B DNA construct can induce innate as well as adaptive
      immune responses in the stomachs of immunized mice. Upregulation of beta-defensin
      gene expression followed immunization and we believe that this is the first
      report of a DNA vaccine inducing innate anti-microbial responses. Such complex
      molecular interactions that modulate both innate and adaptive immune responses
      may be of critical importance in the control of mucosal pathogens, such as H.
      pylori.

PMID- 15193392
TI  - Enhancement of antigen uptake and antibody production in goldfish (Carassius
      auratus) following bath immunization and ultrasound treatment.
AB  - Ultrasound irradiation and hyperosmotic treatments were compared as facilitators
      of antigen (BSA) penetration through the skin by bath vaccination and as
      enhancers of the antibody response in goldfish. The kinetics of BSA penetration
      and accumulation into the skin, and via it to the blood, and the consequent
      specific stimulation of the humoral immune response, were studied. The main
      findings are: (1). ultrasonic treatment is more effective than hyperosmotic
      treatment in enhancing both antigen transport through the skin and antibody
      production; (2). the requirements for high antigen concentrations, which are
      needed for simple bath immersion, could be reduced five times in presonicated
      fish; and (3). anesthesia, which significantly reduced gill uptake following
      hyperosmotic treatment, had no effect on skin uptake. The importance of these
      finding for mass vaccination of adult fish and larvae is discussed.

PMID- 15193393
TI  - Environmental hazard assessment of Venezuelan equine encephalitis virus vaccine
      candidate strain V3526.
AB  - A hazard assessment of Venezuelan equine encephalitis (VEE) virus sub-types and
      vaccine candidates was performed according to standard risk assessment
      procedures. Data from published literature demonstrates a considerable degree of
      safety of V3526 when compared to TC-83 vaccine, the protective measure that has
      been used to protect laboratory workers for over four decades. V3526 is a new
      recombinant vaccine candidate that is a vastly different product with a
      diminished hazard to public health and the general environment. A weight-of
      evidence (WOE)-based scheme was employed to assign weights for relevance,
      quality, and adequacy of evidence in published literature on medical pathology,
      epidemiology, pre-clinical investigational studies, and environmental studies.
      The results of this assessment indicated that V3526 has a low adverse impact on
      public health and the general environment. Although there are currently no human
      infectivity or pathogenicity data for V3526, existing evidence from published
      experimental animal studies reveals a diminished hazard for environmental
      transmission and distribution. Recently, the US Centers for Disease Control and
      Prevention (CDC) excluded V3526 from select agent requirements set forth under
      the Health and Human Services (HHS) regulations in Title 42 C.F.R. Part 73 and
      the US Department Agriculture (USDA) regulations set forth in Title 7 C.F.R. Part
      331 and Title 9 C.F.R. Part 121. This paper summarizes the background, rationale,
      and hazard analysis used for assessing the environmental hazard of the VEE
      vaccine candidate strain V3526.

PMID- 15193395
TI  - Development of experimental carbohydrate-conjugate vaccines composed of
      Streptococcus pneumoniae capsular polysaccharides and the universal helper T
      lymphocyte epitope (PADRE).
AB  - Experimental carbohydrate-conjugate vaccines composed of the 13 amino acid
      universal Pan HLA-DR Epitope (PADRE) and Streptococcus pneumoniae capsular
      polysaccharides from serotypes 14, 6B and 9V were produced. Simple carbodiimide
      mediated condensation chemistry was used to conjugate the PADRE synthetic peptide
      to the three chemically different capsular polysaccharides in a 1:1 molar ratio.
      The immunogenicity of the PADRE peptide component of the conjugate vaccines was
      confirmed by the induction of PADRE-specific CD4+ helper T cell (HTL) responses
      following immunization of C57BL/6 mice. High titer antibody responses specific
      for polysaccharides of S. pneumoniae serotypes 14, 6B and 9V were induced using
      Complete Freund's Adjuvant (CFA) and alhydrogel Al(OH)3 formulations. The HTL, or
      carrier, effect of the PADRE synthetic peptide was only evident using the PADRE
      polysaccharide conjugates; simple mixtures of the PADRE peptide and
      polysaccharides were essentially nonimmunogenic. The functional or potential
      protective value of the polysaccharide-specific antibodies was measured as a
      function of opsonophagocytic activity for the 6B serotype. High titers of
      opsonophagocytic activity were measured in sera from mice immunized with
      formulations containing both adjuvants. These data demonstrate that the PADRE
      synthetic peptide can induce the HTL responses needed to support the development
      of antibodies specific for bacterial carbohydrates used in conjugate vaccines.

PMID- 15193396
TI  - CEL-1000--a peptide with adjuvant activity for Th1 immune responses.
AB  - CEL-1000 (derG, DGQEEKAGVVSTGLIGGG) is a small immunomodulatory peptide which
      delivers demonstrated protective activity in two infectious disease challenge
      models (HSV and malaria) and an allogenic tumor vaccine model. CEL-1000 and other
      activators (defensin-beta, CpG ODN, and imiquimod) of the innate immune system
      promote IFN-gamma-associated protective responses. CEL-1000 is an improved form
      of peptide G (a peptide from human MHC II beta chain second domain, aa 135-149)
      known to enhance immune responses of other immunogenic peptides. Since defensin
      beta, CpG ODN, and imiquimod have been shown to possess adjuvant activity, we
      investigated the adjuvant effect of peptide G and CEL-1000 as conjugates with HIV
      and malaria peptides. Antibody titers and isotypes were evaluated on serum taken
      from select days following immunization. Results for CEL-1000 and G peptide
      conjugates were compared with results for KLH conjugates of the same HIV peptide
      from the p17 molecule (87-116) referred to as HGP-30. Studies demonstrated that
      comparable titers were seen on day 28, 42, 63, and 77 with either G or KLH-HGP-30
      peptide conjugates. In another study, CEL-1000 conjugates (CEL-1000-HGP-30)
      demonstrated a 4-10-fold higher titer antibody response than seen with several
      other peptide conjugates of the same HGP-30 peptide. Improved adjuvant activity
      of CEL-1000 in peptide conjugates was also demonstrated by a shift in the
      antibody isotypes toward a Th1 response (IgG2a). The IgG2a/IgG1, ratio for G-HGP
      30 HIV or KLH-HGP-30 HIV conjugates were lower than for the CEL-1000-HGP-30 HIV
      conjugate. A similar favoring of the IgG2a/IgG1 ratio was seen for a malaria
      peptide conjugate (CEL-1000-SF/GF) compared to the un-conjugated peptide (SF-GF).
      CEL-1000 also showed adjuvant activity in an allogenic tumor vaccine model. As
      expected for an adjuvant, CEL-1000 or G does not induce detectable self-directed
      or cross reactive antibodies. CEL-1000 is currently being investigated for use as
      an adjuvant with conventional vaccines. It is expected that IgG2a antibodies
      would be preferably generated by CEL-1000 adjuvancy and could enhance in vivo
      clearance of antigens or pathogens.

PMID- 15193397
TI  - Vaccine adjuvant: it makes the difference.
AB  - The use of protein or DNA in vaccination process rather than living or attenuated
      microorganism, aims at the increase of the vaccines safety. However, in these
      cases, the use of adjuvant is frequently required to improve their
      immunogenicity. In this study, we show the importance of the adjuvant in a
      vaccine formulation. Vaccines for tuberculosis provide an instructive example,
      based on the mycobacterial 65 kDa heat shock protein (hsp65). The same antigen
      can elicit completely different patterns of immune response depending on how it
      is administered. Thus, the same antigen might or not protect mice from challenge
      with Mycobacterium tuberculosis, depending on the formulation. These data suggest
      that, despite the name, the adjuvant plays a fundamental role on the vaccination
      process.

PMID- 15193398
TI  - Immunobiology of the Tomatine adjuvant.
AB  - Soluble or sub-unit protein vaccines alone are incapable of generating antigen
      specific cellular immune responses. This failure can be attributed to the manner
      in which the immune system processes antigen; endogenous antigens are cycled
      through the MHC class I pathway to stimulate CD8+ restricted responses and
      exogenous antigens are processed through the MHC class II pathway to generate
      humoral immunity. Traditionally sub-unit vaccines have been formulated with
      adjuvants to enhance immunogenicity, however in the last decade a number of
      adjuvants have been developed that effectively stimulate the generation of both
      humoral and cellular immune responses, although the manner in which they exert
      their effects has not been investigated. Here we describe Tomatine, a
      glycoalkaloid based adjuvant, capable of stimulating potent antigen-specific
      humoral and cellular immune responses that contribute to protection against
      malaria, Francisella tularensis and regression of experimental tumors. Using in
      vivo models we investigated the manner in which cellular immune responses were
      generated by Tomatine. We established that Tomatine did not require either lymph
      node or splenic macrophages to generate cytotoxic T lymphocytes (CTL) and
      delivered soluble protein into a pathway not dependant on the machinery of the
      classical MHC class I pathway. We also observed that at the molecular level
      Tomatine required both CD80 and CD86 costimulation to engender antigen-specific
      cellular immunity.

PMID- 15193399
TI  - Modulation of immune responses with transcutaneously deliverable adjuvants.
AB  - Transcutaneous immunisation is a novel vaccination strategy based on the
      application of antigen together with an adjuvant onto hydrated bare skin. This
      simple and non-invasive immunisation procedure elicits systemic and mucosal
      immune responses and therefore, it provides a viable and cost-effective strategy
      for disease prevention. For the induction of antigen-specific immune responses
      the use of adjuvants is critical. They potentiate and modulate the type of immune
      responses by stimulating the production of cytokines that drive the
      differentiation of T cells towards the Th1 or Th2-phenotype. These cells mediate
      protection against different infectious diseases and therefore, their selective
      induction is important for successful vaccination. In this review we give a brief
      overview of transcutaneously deliverable adjuvants and we discuss how they
      modulate immune responses to topically applied antigens.

PMID- 15193400
TI  - ISCOMATRIX adjuvant: a potent inducer of humoral and cellular immune responses.
AB  - ISCOMATRIX adjuvant is capable of inducing broad and potent humoral and cellular
      immune responses. The components are well defined and the manufacturing process
      is simple and robust. Many vaccines containing the ISCOMATRIX adjuvant have been
      tested in a range of animal models, including human and non-human primates.
      Strong antibody and T cell responses have been induced in these studies. The
      antibody response is often achieved with lesser amounts of antigen than other
      adjuvant systems and the maximal responses have also been reached more quickly.
      Both CD4+ and CD8+ T cell responses are induced with the cytotoxic T lymphocyte
      responses being very long lived. Additionally, ISCOMATRIX adjuvant can be used in
      vaccines for induction of mucosal immune responses. This review provides an
      overview of the immune responses that can be elicited using ISCOMATRIX vaccines
      and the current state of knowledge regarding the mechanism of action of this
      adjuvant.

PMID- 15193401
TI  - Pluronic F127-based systemic vaccine delivery systems.
AB  - We have developed a vaccine delivery system based on the non-ionic block
      copolymer, Pluronic F127 (F127), combined with selected immunomodulators. F127
      based matrices are characterized by a phenomenon known as reverse thermogelation,
      whereby the formulation undergoes a phase transition from liquid to gel upon
      reaching physiological temperatures. Protein antigens (tetanus toxoid (TT),
      diphtheria toxoid (DT) and anthrax recombinant protective antigen (rPA)) were
      formulated with F127 in combination with CpG motifs or chitosan, as examples of
      immunomodulators, and were compared to more traditional adjuvants in mice. IgG
      antibody responses were significantly enhanced by the F127/CpG and F127/chitosan
      combinations compared to antigens mixed with CpGs or chitosan alone. In addition,
      the responses were significantly greater than those elicited by aluminum salts.
      Furthermore, the functional activity of these antibodies was demonstrated using
      either in vivo tetanus toxin challenge or an anthrax lethal toxin neutralization
      assay. These studies suggest that a block-copolymer approach could enhance the
      delivery of a variety of clinically useful antigens in vaccination schemes.

PMID- 15193403
TI  - Bacteriophage lambda is a highly stable DNA vaccine delivery vehicle.
AB  - The stability of whole bacteriophage lambda particles, used as a DNA vaccine
      delivery system has been examined. Phage were found to be highly stable under
      normal storage conditions. In liquid suspension, no decrease in titre was
      observed over a 6-month period at 4 and -70 degrees C, and phage stability was
      unaffected by freeze/thawing. The measured half life of phage in suspension was
      36 days at 20 degrees C, 3.4 days at 37 degrees C and 2.3 days at 42 degrees C.
      Freeze drying of a phage suspension (with or without the stabilizers dry skim
      milk or trehalose) resulted in 5-20% residual viability. Following desiccation
      (with or without stabilizers), measured half lives ranged from 20 to 100 days at
      20 degrees C, 2.6 to 38 days at 37 degrees C, 2.1 to 26 days at 42 degrees C, 7
      to 33 h at 70 degrees C, and 1.3 to 6m at 100 degrees C. In all cases the
      addition of trehalose significantly increased the stability of the desiccated
      phage. When stored at -70 degrees C, desiccated phage appeared to be stable in
      the absence of stabilizers. When phage lambda was diluted into water, a marginal
      loss in titre was observed over a 2-week period. Over a 24 h period, liquid phage
      suspensions were stable within the pH range pH 3-11, therefore oral
      administration of bacteriophage DNA vaccines via drinking water may be possible.

PMID- 15193402
TI  - Characterization of poly(D,L-lactic-co-glycolic acid) based nanoparticulate
      system for enhanced delivery of antigens to dendritic cells.
AB  - Biodegradable nanoparticles made of poly(D,L-lactic acid-co-glycolic acid) (PLGA)
      copolymer were characterized for enhanced delivery of antigens to murine bone
      marrow derived dendritic cells (DCs) in vitro. PLGA nanoparticles were
      efficiently phagocytosed by the DCs (CD11c+, MHC class II+, CD86+) in culture,
      resulting in their intracellular localization. The efficiency of the uptake was
      influenced by the incubation time and nanoparticle concentration. DCs pulsed with
      PLGA nanoparticles containing an immunomodulator, monophosphoryl lipid A (MPLA),
      showed upregulation of surface expression of MHC class II and CD86 molecules.
      Delivery of a cancer-associated antigen (MUC1 mucin peptide: BLP25) and MPLA in
      PLGA nanoparticles was shown to be superior to their delivery in the soluble form
      for activation of naive T cells of normal and MUC1-transgenic mice. These results
      strongly suggest that PLGA nanoparticles provide an efficient vaccine delivery
      system for targeting DCs and the development of DC based cellular vaccines.

PMID- 15193404
TI  - A corn-based delivery system for animal vaccines: an oral transmissible
      gastroenteritis virus vaccine boosts lactogenic immunity in swine.
AB  - Recombinant plant expression systems offer a means to produce large quantities of
      selected antigens for subunit vaccines. Cereals are particularly well-suited
      expression vehicles since the expressed proteins can be stored at relatively high
      concentrations for extended periods of time without degradation and dry seed can
      be formulated into oral vaccines suitable for commercial applications. A subunit
      vaccine candidate directed against porcine transmissible gastroenteritis virus
      and expressed in corn seed has been developed for oral delivery to swine. Here,
      we show that this vaccine, when administered to previously sensitized gilts, can
      boost neutralizing antibody levels in the animals' serum, colostrum and milk.
      Thus, this vaccine candidate is effective at boosting lactogenic immunity and is
      appropriate to pursue through large-scale field trials preceding
      commercialization.

PMID- 15193405
TI  - Optimisation of a lipid based oral delivery system containing A/Panama influenza
      haemagglutinin.
AB  - Vaccine antigens administered by the oral route are often degraded by gastric
      secretions during gastrointestinal transit. This necessitates larger and more
      frequent doses of antigen for vaccination. A delivery system, which overcomes
      this, is a lipid vesicle containing bile salts (bilosome), which prevents antigen
      degradation and enhances mucosal penetration. The effect of bilosome formulation
      modification on vaccine transit efficacy across the mucosa was determined.
      Specific antibody levels were assessed by end-point titre ELISA and the
      subclasses determined. Significant IgG1 titres were induced when the protein
      loading was doubled from 15 to 30 microg (P=0.009) and was equivalent to antigen
      administration by the subcutaneous route. No IgG2a was induced, indicating the
      generation of a TH2 response. Significant mucosal IgA levels were also observed
      with this treatment group (P=0.05).

PMID- 15193406
TI  - In vivo uptake of an experimental microencapsulated diphtheria vaccine following
      sub-cutaneous immunisation.
AB  - Previous studies demonstrated in vitro phagocytosis of poly(lactide-co-glycolide)
      (PLGA) microspheres (MS) by macrophages and dendritic cells and the
      biodistribution of fluorescent PLGA particles following oral or intranasal
      administration. In this study, we report the uptake and biodistribution of sub
      cutaneously administered fluorescent labelled PLGA MS loaded with diphtheria
      toxoid (DT). The cell type and percentage of fluorescent positive cells were
      determined by flow cytometry and confirmed by fluorescent microscopy. Fluorescent
      particles were detected inside cells of the peritoneal flush as early as 10 min
      post-inoculation, predominantly in cells of macrophage morphology. In vivo
      trafficking of PLGA particles following a sub-cutaneous immunisation of mice
      appeared to be governed by macrophages. However, in the first week after
      inoculation, dendritic cells played a significant role in the uptake and
      digestion of the microspheres, thereby triggering the immune response against the
      antigen. Fluorescent PLGA MS were also observed in cells of lymphoid tissues such
      as mesenteric lymph nodes (MLN) and spleen (S). However, microsphere fluorescence
      in lymphoid tissues decreased rapidly, as they were degraded inside the cells,
      thereby enabling the presentation of the antigen to specific cells of the immune
      system. To our knowledge, this is the first time the fate of immunogenic PLGA
      microspheres was studied in vivo following a sub-cutaneous injection route.

PMID- 15193408
TI  - Can oral cholera vaccination play a role in controlling a cholera outbreak?
AB  - Control measures to limit the spread of a cholera outbreak in Pohnpei Island
      (Micronesia), included mass vaccination with the single-dose live-attenuated oral
      cholera vaccine CVD 103-HgR as a potential adjunct measure. The outbreak provided
      a unique opportunity to evaluate the practicality of use and effectiveness of
      this vaccine. Under field conditions encountered in Pohnpei, crude vaccine
      efficacy was estimated at 79.2% (95% CI: 71.9-84.6%) in the target population.
      Retrospective analysis suggests that mass vaccination with oral cholera vaccines
      can be a useful adjunct tool for controlling outbreaks, particularly if
      implemented early in association with other standard control measures.

PMID- 15193407
TI  - An assessment of different DNA delivery systems for protection against
      respiratory syncytial virus infection in the murine model: gene-gun delivery
      induces IgG in the lung.
AB  - Immunization with plasmid DNA (pDNA) has the potential to overcome the
      difficulties of neonatal vaccination that may be required for protection against
      infection with respiratory syncytial virus (RSV); however, little is known about
      optimal delivery modalities. In this pilot study we compared mucosal delivery of
      pDNA encoding RSV F protein encapsulated in poly(DL-lactide-co-glycolide) with
      delivery of pDNA by gene-gun for the induction of immunity in mice. Intra-gastric
      or intra-nasal immunization with various doses of microparticles induced weak low
      levels of RSV-specific serum antibodies in a proportion of mice; in contrast,
      gene-gun vaccination led to protective immunity associated with a humoral
      response. Interestingly, RSV-specific antibody was detected in lung fragment
      cultures following intradermal vaccination with the gene-gun.

PMID- 15193409
TI  - European union regulatory developments for new vaccine adjuvants and delivery
      systems.
AB  - Interest in vaccine adjuvants and new delivery systems has grown rapidly over the
      past few years. New vaccine candidates have emerged, which, because of their poor
      immunogenicity, rely on adjuvants to improve their presentation and targeting and
      to potentiate their protective immune response. Better understandings of the
      mechanisms of action, together with logistic and economical considerations have
      resulted in an explosion of technologies. However, there have been few new
      registered products for human use, and antigens incorporated into
      immunostimulating reconstituted influenza virosomes have only relatively recently
      been licensed in European Union (EU) countries. Influenza vaccine, adjuvanted
      with water in oil emulsion containing squalene (adjuvant MF59C1) is now also
      approved. Although current EU regulations focus on traditional adjuvants, notably
      aluminium and calcium salts, advances have been made in regulatory
      considerations. The European agency for the evaluation of medicinal products,
      through its working parties, is actively drafting guidance on requirements for
      the evaluation of new adjuvants in vaccines. This paper summarises the new
      developments in EU regulatory aspects relevant to adjuvant quality at development
      stages, during the manufacturing process, and at the final bulk stage of adjuvant
      with antigen, and also summarises regulatory expectation regarding safety at pre
      clinical and clinical stages. The paper highlights the regulatory concerns and
      existing bottlenecks that have led to slow approval of new technologies.

PMID- 15193410
TI  - Biosafety aspects of the recombinant live oral Vibrio cholerae vaccine strain CVD
      103-HgR.
AB  - The development of live attenuated vaccines, allowing for the safe and effective
      immunisation at mucosal surfaces, is a strategy of great interest for
      vaccinologists. The main advantage of this approach over conventional parenteral
      vaccines is the induction of strong mucosal immune responses, allowing targeting
      of the pathogen at the initial point of contact with the host. Further advantages
      include the ease of administration, high acceptance by vaccines, and relatively
      low production costs. Finally, well-characterised, safe and immunogenic vaccine
      strains are well suited as vectors for the mucosal delivery of foreign vaccine
      antigens and of DNA vaccines. However, such vaccines, when based on or containing
      genetically modified organisms (GMOs), are facing new and specific regulatory
      hurdles, particularly regarding the potential risks for humans and the
      environment. In this contribution we address selected aspects of the risk
      assessment of live attenuated bacterial vaccines covered in the course of the
      registration of vaccine strain CVD 103-HgR as a recombinant live oral vaccine
      against cholera.

PMID- 15193411
TI  - Protective vaccination against murine visceral leishmaniasis using aldehyde
      containing Quillaja saponaria sapogenins.
AB  - The presence of aldehyde groups at C-23 and C-24 of the triterpen aglycon moiety
      was disclosed in 1H NMR spectra of both the Riedel de Haen saponin (R) (delta
      9.336) and Quillaja saponaria QuilA saponin (delta 9.348). The sign of the C-28
      acylated linked moiety (delta 176) was present in both saponins, while the delta
      171 at C-28 (carboxy group) corresponding to the deacylated saponin, was only
      detected in the QuilA preparation, indicating 50% of hydrolysis of the ester
      moiety, probably due to the storage in aqueous solution. The normoterpen moiety
      was present in both saponins (signals at delta 14-18). The chemical removal of
      saponin glicidic moieties gave rise to their sapogenin fractions. Their 1H NMR
      spectra showed the presence of two signals (delta 9.226 and 9.236) for sapogenin
      R and two signals (delta 9.338 and 9.352) for the QuilA sapogenin. The intensity
      of the signals suggested two conformational isomers of sapogenin R in the ratio
      53% of equatorial aldehyde group to 47% of axial aldehyde group, and two
      conformational isomers of QuilA sapogenin in the ratio 76% of equatorial aldehyde
      group to 24% of axial aldehyde group. The chemical treatment abolished the
      saponin slight in vivo toxicity, reduced their hemolytic potential, did not
      affect their aldehyde contents, but gave rise to an enriched axial aldehyde
      containing sapogenin R with enhanced potential on antibody humoral response (anti
      IgM, IgG, IgG1, IgG2a, IgG2b and IgG3) and to an enriched equatorial aldehyde
      containing QuilA-sapogenin that induced a mainly cellular specific immune
      response (increased intradermal response to leishmanial antigen and IFNgamma sera
      levels) and effective protection against murine infection by L. donovani (77%
      reduction in liver parasitic load). Our results suggest that the Riedel de Haen
      saponin is probably a Quillaja saponaria saponin.

PMID- 15193412
TI  - Development of immunomodulatory six base-length non-CpG motif oligonucleotides
      for cancer vaccination.
AB  - We have previously described a novel family of immunomodulatory synthetic
      oligonucleotides characterized by a phosphodiester backbone, a length of six
      bases and a 5'G3xG23' sequence, where x is A, C, G or T. In the present study, we
      have evaluated whether these 5'G3xG23' oligonucleotides possess additional
      activities essential for adequate cancer vaccination. Immunization for the
      treatment of cancer requires an adjuvant, a source of tumor-associated
      antigen(s), for example apoptotic cancer cells, and a way to overcome the escape
      of tumor cells from the immune system, for example the up-regulation of Fas
      ligand (FasL) on the surface of cancer cells. The results show that
      phosphodiester 5'G3AG23' and 5'G3TG23' oligonucleotides have a direct activity on
      a number of different cancer cells by inducing apoptosis (release of cytochrome
      C, activation of caspase-3, cleavage of poly [ADP-ribose] polymerase, degradation
      of nuclear mitotic apparatus protein and translocation of phophatidylserine at
      the cell surface). In addition, the 5'G3AG23', 5'G3CG23', and 5'G3TG23'
      oligonucleotides were found to down-regulate the levels of FasL on the surface of
      cancer cells. These immunomodulatory phosphodiester six base-length
      oligonucleotides, which are capable of inducing apoptosis in cancer cells as well
      as downregulating the expression of FasL at their cell surface, may have
      application as cancer cell vaccines.

PMID- 15193414
TI  - Synthetic lipopeptide adjuvants and Toll-like receptor 2--structure-activity
      relationships.
AB  - Bacterial lipoproteins and their synthetic analogues (sLP) are strong immune
      modulators of the early host responses after infection. Synthetic lipopeptides
      are strong adjuvants for the adaptive immune system. Lipoproteins and
      lipopeptides induce signalling in immune cells through Toll-like receptor
      TLR2/TLR1 heterodimers. By screening a combinatorial lipohexapeptide amide
      collection in an in vitro IL-8 induction assay, we systematically evaluated the
      potential of 19 proteinogenic amino acids in the peptide moiety of Pam3Cys
      lipopeptides to interact with TLR2. New Pam3Cys-lipopeptides with high activity
      were obtained. Different fatty acids were introduced to investigate the influence
      of the acyl moiety. Lipopeptides with modifications in the core structure of the
      unusual amino acid S-glycerylcysteine were synthesized and tested for IL-8
      induction via TLR2.

PMID- 15193413
TI  - Enhancement of DNA vaccine potency in rhesus macaques by electroporation.
AB  - The potency of an HIV DNA vaccine was enhanced in rhesus macaques by in vivo
      electroporation, as judged by increased onset, magnitude and duration of antibody
      and cell-mediated immune responses against both components of a combination Gag
      and Env vaccine. These data demonstrate the utility of the electroporation
      technology for use in large animals.

PMID- 15193415
TI  - Salivary gland genetic vaccination: a scalable technology for promoting distal
      mucosal immunity and heightened systemic immune responses.
AB  - Use of plasmid DNA for vaccination has been demonstrated quite successfully in
      small rodents. However, some of the many challenges of DNA vaccine development
      are the relatively low performance obtained in larger animals and a generally
      weak mucosal immune response. Vaccination through salivary gland (SG) cannulation
      and delivery of aqueous solutions of DNA is one potential solution. The
      scalability of SG DNA vaccination was tested in multiple animal models; antigen
      specific titers above 10,000 were demonstrated in dogs and rats. Immune responses
      were also present at a variety of mucosal sites. In conclusion, our data
      demonstrate that DNA vaccination to the SG presents a unique and advantageous
      method for eliciting systemic and mucosal immune responses.

PMID- 15193416
TI  - Generation of anti-beta-amyloid antibodies via phage display technology.
AB  - The EFRH sequence, found to be the main anti-aggregating epitope corresponding to
      amino acids 3-6 of beta-amyloid peptide (AbetaP), was displayed on a phage and
      used as an antigen for immunization of mice, guinea pigs and rabbits. The
      generated antibodies recognize the full-length AbetaP (1-40) and exhibit similar
      biological properties to antibodies raised against whole soluble peptide and/or
      fibrillar beta-amyloid. EFRH-phage immunization of a transgenic mouse model of
      Alzheimer's disease evokes antibodies able to dissolve already formed beta
      amyloid plaques, suggesting that they could become a therapeutic approach in
      treatment of the disease.

PMID- 15193417
TI  - Identification and characterization of epsilon-sarcoglycans in the central
      nervous system.
AB  - Alpha-, beta-, gamma-, and delta-sarcoglycans (SGs) are transmembrane
      glycoprotein components of the dystrophin-associated protein (DAP) complex, which
      is critical for the stability of the striated muscle cell membrane. Epsilon-SG
      was found as a homologue of alpha-SG, but unlike other SG members, it is
      ubiquitously expressed in various tissues as well as in striated muscle.
      Moreover, mutations in the epsilon-SG gene cause myoclonus-dystonia, indicating
      the importance of epsilon-SG for the function in the central nervous system. To
      gain insight into the role of epsilon-SG, its expression and subcellular
      distribution in mouse tissues and especially in the mouse brain were
      investigated. Analysis by reverse transcription-polymerase chain reaction showed
      four splice variants of epsilon-SG transcripts in the mouse brain, two of which
      are major transcript forms. One is a conventional form including exon 8 (epsilon
      SG1), and the other is a novel form excluding exon 8 but including a previously
      unknown exon, 11b (epsilon-SG2). Immunoblot analysis using various mouse tissues
      indicated a broad expression pattern for epsilon-SG1, but epsilon-SG2 was
      expressed exclusively in the brain. Therefore, both epsilon-SG isoforms coexist
      in various regions of the brain. Furthermore, these isoforms were found in
      neuronal cells using immunohistochemical analysis. Subcellular fractionation of
      brain homogenates, however, indicated that epsilon-SG1 and epsilon-SG2 are
      relatively enriched in post- and pre-synaptic membrane fractions, respectively.
      These results suggest that the two epsilon-SG isoforms might play different roles
      in synaptic functions of the central nervous system.

PMID- 15193418
TI  - Expression of the secreted FAD-dependent sulfydryl oxidase (QSOX) in the guinea
      pig central nervous system.
AB  - cpQSOx1 is a member of the QSOx family of proteins, expressed in the guinea pig
      (Cavia porcellus) and ortholog of the rat rQSOx1. In this study, in vitro
      experiments were conducted and showed that, as other member of this family,
      cpQSOx1 has a sulfydryl oxidase activity, and is a secreted protein. Then, the
      expression of this enzyme was researched in the guinea pig brain, as very little
      information exists yet on the expression of QSOx family members in the central
      nervous system. By immunohistochemistry, RT-PCR and in situ hybridization,
      cpQSOx1 is synthesized by neurons throughout the whole guinea pig central nervous
      system. Reticular structures as the basal forebrain, reticular thalamic nucleus
      and reticular nuclei of the brainstem contained the densest labeling. These
      results are discussed in terms of putative roles of this protein in synaptic
      strengthening and in redox activities.

PMID- 15193419
TI  - Species differences in brain pre-pro-neurotensin/neuromedin N mRNA distribution:
      the expression pattern in mice resembles more closely that of primates than rats.
AB  - We have used in situ hybridization to determine the distribution of pre-pro
      neurotensin/neuromedin N (NT/N) mRNA in the brain of mice and rats. In rats and
      mice, expression was observed in the lateral septal nucleus, nucleus accumbens,
      medial preoptic area, bed nucleus of the stria terminalis, lateral hypothalamus,
      central amygdaloid nucleus and the subicilum. However, several differences in the
      NT/N mRNA distribution were observed between rats and mice in other brain areas.
      In mice, NT/N expression was detected in the subthalamic nucleus and geniculate
      nucleus, whereas expression was not observed in these brain areas in rats.
      Surprisingly, expression was not observed in mouse mesencephalic dopaminergic
      (mesDA) neurons and the CA1 area of the hippocampus, areas known to contain NT/N
      mRNA in the rat brain. Taken together, these results show that although the brain
      NT/N mRNA distribution largely overlaps in mice and rats, species differences
      exist in specific brain areas in rodents. Moreover, these data indicate that the
      distribution in mice resembles most that of primates than rats.

PMID- 15193420
TI  - Molecular cloning and characterization of the promoter region of the human Phox2b
      gene.
AB  - The closely related homeodomain transcription factors, Phox2a and Phox2b, are
      restrictively expressed in central and peripheral noradrenergic (NA) neurons in
      an overlapping but distinct manner, and critically regulate the differentiation
      and neurotransmitter identity of NA neurons. The structure and function of the
      human Phox2a (hPhox2a) promoter has recently been reported. Towards the long-term
      goal of delineating the regulatory cascade of NA neuron differentiation, we
      isolated a human Phox2b (hPhox2b) genomic clone encompassing approximately 7.8 kb
      of the 5' upstream promoter region, the entire exon-intron structure and 4.5 kb
      of the 3' flanking region. Two transcription start sites are identified to reside
      115 and 110 nucleotides upstream of the start codon, based on both primer
      extension and 5'-rapid amplification of the cDNA ends analyses. In addition,
      transient transfection assays indicate that 1.1 kb or longer upstream sequences
      of the hPhox2b gene may confer cell type-specific gene expression in certain, but
      not all cell lines. The promoter activity of the hPhox2b gene is modestly
      transactivated by forced co-expression of Phox2b and the hPhox2b gene promoter
      contains a high-affinity binding site at -320 to -295 bp. This study provides a
      frame to further elucidate the molecular mechanisms underlying the regulation of
      Phox2a and Phox2b gene expression and its relation to NA differentiation.

PMID- 15193421
TI  - Identification and characterization of an L-type Cav1.2 channel in spiral
      ligament fibrocytes of gerbil inner ear.
AB  - Intracellular free Ca2+ levels are critical to the activity of BK channels in
      inner ear type I spiral ligament fibrocytes. However, the mechanisms for
      regulating intracellular Ca2+ levels in these cells are currently poorly
      understood. Using patch-clamp technique, we have identified a voltage-dependent L
      type Ca2+ channel in type I spiral ligament fibrocytes cultured from gerbil inner
      ear. With 10 mM Ba2+ as the conductive cation, an inwardly rectifying current was
      elicited with little inactivation by membrane depolarization. The voltage
      activation threshold and the half-maximal voltage activation were -40 and -6 mV,
      respectively. This inward whole-cell current reached its peak at around 10 mV of
      membrane potential. The amplitude of the peak current varied among cells ranging
      from 50 to 274 pA with an average of 132.4 +/- 76.2 pA (n = 19); 10(-6) M
      nifedipine significantly inhibited the inward currents by 90.3 +/- 1.2% (n = 11).
      RT-PCR analysis revealed that cultured type I spiral ligament fibrocytes express
      the alpha1C isoform of the L-type Ca2+ channels encoded by the Cav1.2 gene. The
      expression of this channel in gerbil inner ear was confirmed by RT-PCR analysis
      using freshly isolated spiral ligament tissues. The Cav1.2 channel may function
      in conjunction with a previously identified intracellular Ca-ATPase (SERCA) to
      regulate intracellular free Ca2+ levels in type I spiral ligament fibrocytes, and
      thus modulate BK channel activity in these cells.

PMID- 15193422
TI  - Molecular mechanisms regulating cell type specific expression of BMP/RA Inducible
      Neural-specific Protein-1 that suppresses cell cycle progression: roles of
      NRSF/REST and DNA methylation.
AB  - We have recently identified a novel protein family, BMP/RA-Inducible Neural
      specific Protein (BRINP) including BRINP1, 2, 3. Among BRINP family genes, BRINP1
      is most highly and widely expressed in various regions of the mammalian nervous
      system, although its expression is also found in some non-neural tissues and cell
      types at low levels. We have previously suggested that BRINPs are involved in the
      suppression of cell-cycle progression in post-mitotic neuronal cells. In the
      present study, we investigated the transcriptional mechanisms regulating the cell
      type-specific expression of BRINP1. First, bisulfite analysis of the methylation
      status revealed hypermethylation of the CpG island surrounding BRINP1 exon 1 in a
      non-neural cell line, NIH 3T3, which expresses low but detectable levels of
      BRINP1, while methylation levels of the BRINP1 CpG island in either non-neural or
      neural tissues are very low. Treatment of NIH 3T3 cells with a demethylating
      agent, 5-azacytidine, upregulated the expression of BRINP1 remarkably. Then, we
      analyzed the promoter activity of 7 kb region surrounding BRINP1 exon 1 in
      neuronal and non-neuronal cells. Consequently, we found a basic promoter region
      and a non-neural-specific silencing region which contains neuron-restrictive
      silencing element/repressor element 1 (NRSE/RE-1) like element (BRINP1-NRSE).
      Mutation of BRINP1-NRSE recovered the BRINP1 promoter activity in non-neuronal
      cells. Furthermore, proteins in nuclear extract from non-neural cells bound to
      the BRINP1-NRSE. These results strongly suggest that BRINP1-NRSE determines
      neural-specific expression of BRINP1, while hypermethylation of the BRINP1-CpG
      island suppresses BRINP1 expression in NIH 3T3 cells.

PMID- 15193423
TI  - Identification and characterization of novel developmentally regulated neural
      specific proteins, BRINP family.
AB  - Processes of neuronal differentiation involve activation of a set of neuronal
      specific genes and cessation of cell proliferation in postmitotic neurons.
      Previous studies revealed that bone morphogenetic protein (BMP) and retinoic acid
      (RA) play important roles in the differentiation of peripheral sympathetic
      neurons such as the synergistic induction of responsiveness to specific
      neurotrophic factors. In the present study, while trying to clarify the mechanism
      of the BMP/RA-actions, we identified a novel neural-specific protein, BMP/RA
      inducible neural-specific protein-1 (BRINP1) which shows no similarity to other
      known proteins. Subsequently, two homologous proteins, BRINP2 and BRINP3, making
      up the BRINP family, are identified. Individual BRINP genes have distinct
      regulatory mechanisms of expression within the nervous system. In rodent brain,
      BRINP1 is expressed from earlier developmental stage, i.e. E9.5, and widely
      expressed in various neuronal layers and nuclei of the adult animal, while BRINP2
      and BRINP3 were detectable from E11.5 and expressed in rather limited regions in
      a complementary manner. During the course of perinatal development of sympathetic
      neurons, BRINP1 is induced from earlier embryonic stage and further increased
      toward adult stage, while BRINP3 expressed from earlier stage is replaced by
      BRINP2 expression which increases postnatally in accordance with the action of
      BMP2 and RA. Furthermore, when expressed in nonneuronal cells, all three BRINP
      family proteins suppressed the cell cycle progression. Possible physiological
      functions of BRINP family members in the development of the nervous system are
      discussed.

PMID- 15193424
TI  - Roles of adenosine receptors in the regulation of kainic acid-induced neurotoxic
      responses in mice.
AB  - Kainic acid (KA) is a well-known excitatory and neurotoxic substance. In ICR
      mice, morphological damage of hippocampus induced by KA administered
      intracerebroventricularly (i.c.v.) was markedly concentrated on the hippocampal
      CA3 pyramidal neurons. In the present study, the possible role of adenosine
      receptors in hippocampal cell death induced by KA (0.1 microg) administered
      i.c.v. was examined. It has been shown that 3,7-dimethyl-1-propargylxanthine
      (DMPX; A2 adenosine receptors antagonist, 20 microg) reduced KA-induced CA3
      pyramidal cell death. KA dramatically increased the phosphorylated extracellular
      signal-regulated kinase (p-ERK) immunoreactivities (IR) in dentate gyrus (DG) and
      mossy fibers. In addition, c-Jun, c-Fos, Fos-related antigen 1 (Fra-1) and Fos
      related antigen 2 (Fra-2) protein levels were increased in hippocampal area in KA
      injected mice. DMPX attenuated KA-induced p-ERK, c-Jun, Fra-1 and Fra-2 IR.
      However, 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX; A1 adenosine
      receptor antagonist, 20 microg) did not affect KA-induced p-ERK, c-Jun, Fra-1 and
      Fra-2 IR. KA also increased the complement receptor type 3 (OX-42) IR in CA3
      region of hippocampus. DMPX, but not PACPX, blocked KA-induced OX-42 IR. Our
      results suggest that p-ERK and c-Jun may function as important regulators
      responsible for the hippocampal cell death induced by KA administered i.c.v. in
      mice. Activated microglia, which was detected by OX-42 IR, may be related to
      phagocytosis of degenerated neuronal elements by KA excitotoxicity. Furthermore,
      it is implicated that A2, but not A1, adenosine receptors appear to be involved
      in hippocampal CA3 pyramidal cell death induced by KA administered i.c.v. in
      mice.

PMID- 15193425
TI  - Effects of the abused solvent toluene on recombinant P2X receptors expressed in
      HEK293 cells.
AB  - ATP acts as a neurotransmitter in both the peripheral and central nervous systems
      by activating receptors in the P2Y and P2X families. P2Y receptors are coupled to
      intracellular signaling pathways, while P2X receptors contain an integral
      membrane-spanning pore and act as ion channels. Previous studies have established
      that certain abused drugs such as alcohol inhibit P2X receptors. In this study,
      we have examined the sensitivity of both homomeric and heteromeric P2X receptors
      to toluene, a commercial solvent widely used as a drug of abuse. P2X receptors
      were transiently expressed in HEK293 cells, and agonist-gated currents were
      measured using whole-cell patch clamp electrophysiology. Toluene potentiated
      currents in cells expressing homomeric P2X2 or P2X4 subunits when ATP
      concentrations were near or below the EC50 concentration. This potentiation was
      rapid in onset, voltage independent and was readily reversed upon washout of the
      toluene-containing solution. The toluene-induced potentiation of P2X2 currents
      was not altered by lowering the pH of the recording media to 5.5 or by including
      the heavy-metal chelator EDTA in the recording solution. At maximal ATP
      concentrations, toluene did not affect ATP-gated currents in cells expressing
      P2X2 or P2X4 receptors. ATP-gated currents were also markedly potentiated by
      toluene in cells transfected with both P2X4 and P2X6 subunits. In contrast, P2X3
      receptor currents were inhibited by toluene at both low and high ATP
      concentrations. HEK293 cells transfected with both P2X2 and P2X3 subunits showed
      non-desensitizing currents when stimulated with alpha, beta-methylene ATP. In
      these cells, toluene potentiated currents only at sub-maximal concentrations of
      alpha, beta-methylene ATP. The results of this study suggest that the abused
      solvent toluene affects the function of P2X receptors in a subunit-dependent and
      agonist-dependent fashion.

PMID- 15193426
TI  - Characterization and localization of a human serine racemase.
AB  - D-serine is present in the mammalian central nervous system, where it acts as one
      of the co-activators of N-methyl-D aspartate receptors. Synthesis of D-serine is
      catalyzed by the serine racemase enzyme. The current studies report on the
      isolation of a cDNA encoding a human serine racemase (SRR) from the human
      neuronal like cell line, NT2N. The SRR gene was localized on chromosome 17q13.
      The full-length cDNA has 1020 nucleotides which encode for a protein of 340 amino
      acids. The human protein shares 89% sequence identity with the mouse serine
      racemase. Human embryonic kidney 293 cells transiently transfected with this SRR
      gene were able to produce d-serine, indicating that the sequence encodes for an
      active enzyme. In Northern blot analysis the SRR mRNA was expressed in human
      brain, heart, skeletal muscle, kidney and liver tissues. Different splice forms
      of SRR were present in the peripheral tissues. Transcripts of at least three
      different sizes were present in heart and kidney, while in Western blot analysis
      multiple bands of different sizes were observed. Immunohistochemical studies,
      using a polyclonal anti-human serine racemase antibody, revealed a peripheral
      expression of serine racemase protein in human cardiac myocytes and convoluted
      tubules of the kidney. Experiments in non-human primate brain demonstrated the
      localization of SRR in amygdala nuclei, cortex, thalamus and hippocampus. Co
      localization studies in the hippocampus demonstrated the exclusive expression of
      serine racemase in glial cells. The cloning of a functional human serine racemase
      and its expression in central nervous system of primates support a role for D
      serine in neuronal activity. Furthermore, its presence in human periphery such as
      in heart and kidney suggest a potential biological role for D-serine in the
      regulation of N-methyl-D-aspartate (NMDA) receptor activity in these peripheral
      organs as well.

PMID- 15193427
TI  - Phosphohippolin expression in the rat central nervous system.
AB  - The FXYD family is a small single-span membrane protein family; recently, we have
      identified a novel member of this family from the cDNA library of the rat
      hippocampus and named phosphohippolin (Php) (Mol. Br. Res. vol. 86, 2001). The
      deduced amino acid sequence of this novel Php comprises 93 residues with a core
      motif of FXYD and a single transmembrane domain. This indicates that Php belongs
      to FXYD6 subfamily of the seven FXYD subfamilies (FXYD1-7). Php shows a 48.1%
      homology with rat phospholemman (FXYD1), a transmembrane family protein. In this
      study, polyclonal antibodies against the carboxyl-terminal sequence of rat Php
      were raised and purified. The spatial expression of the Php protein was in the
      neuronal fibers of the medial part of lateral habenula nucleus, thalamus,
      hypothalamus, stria terminalis, zona incerta, amygdaloid body and cingulum,
      olfactory bulb, hippocampus, cerebral cortex and cerebellum. A unique Php
      distribution was identified in the cerebellum, with a predominant expression
      pattern in the granule layer of lobules VI-IX of the posterior lobe.
      Developmental studies demonstrated that the highest level of Php expression was
      seen in the postnatal (PN) 3-week-old rat brain, and a significant amount of Php
      still existed in the adult brain. These findings suggest that Php may play an
      important role in the excitability of neurons in the central nervous system
      during postnatal development, as well as those in the adult brain.

PMID- 15193429
TI  - TBP, a polyglutamine tract containing protein, accumulates in Alzheimer's
      disease.
AB  - Alzheimer's disease (AD) is characterised by extra cellular beta-amyloid (betaA)
      deposition, Tau-containing neurofibrillary tangles (NFTs) and progressive
      cortical atrophy. Abnormal protein accumulation is also a common feature of other
      late onset neurodegenerative diseases, including the heritable polyglutamine
      (polyQ) disorders such as Huntington disease (HD) and the spinocerebellar ataxias
      (SCAs). One of this family of disorders, SCA17, is caused by an expansion of a
      polymorphic polyQ repeat in TATA binding protein (TBP), an essential
      transcription factor. Surprisingly, the wild type TBP repeat length ranges from
      25 to 42, and in Caucasian populations the most common allele is 38, a size large
      enough to cause HD if within the huntingtin protein. Wild type length TBP
      accumulates in HD and in at least some of the SCAs, and consequently we
      hypothesised that it may contribute to AD. Here we provide evidence that TBP
      accumulates in AD brain, localising to neurofibrillary tangle structures. A
      proportion of TBP present in AD brain is insoluble; a signature of the polyQ
      diseases. TBP is present differentially between patients and its amount and
      distribution is not directly proportional to that of Tau or beta-amyloid positive
      structures. We present this as evidence for the hypothesis that the accumulation
      or misfolding of this polyQ containing protein may be a contributing factor in
      Alzheimer's disease.

PMID- 15193428
TI  - Nonsteroidal anti-inflammatory drugs increase expression of inducible COX-2
      isoform of cyclooxygenase in spinal cord of rats with adjuvant induced
      inflammation.
AB  - Several lines of evidence have accumulated that release of excitatory amino
      acids, nitric oxide and prostaglandin E2 (PGE2) play a critical role in the
      development of peripheral tactile and thermal hypersensitivity in chronic
      inflammatory pain models. Synthesis of PGE2 is controlled by cyclooxygenase
      (COX), either the COX-1 or COX-2 isoform. COX-2 plays a central role in the
      inflammatory reactions. The relationship between central sensitization of a
      complete Freund's adjuvant (CFA) induced inflammation and expressions of COX-2
      were assessed in a rat model of CFA injection induced inflammation. Moreover, the
      time course of analgesia and spinal COX-2 expression following intrathecal (IT)
      injection with a nonspecific COX inhibitor (ketorolac) and COX-2 inhibitor
      (celecoxib) were determined using Western blot and immunohistochemistry. COX-2
      protein was slightly increased in the lumbosacral spinal cord at 24 h following
      subcutaneous injection of CFA in the plantar surface of the left hindpaw (p >
      0.05). COX-1 was not detected in normal and CFA injection rats. Surprisingly, IT
      ketorolac or celecoxib significantly increased spinal COX-2 levels at 1 h post-IT
      injection (p < 0.05) both in inflamed and non-inflamed rats. Then, spinal COX-2
      levels declined at 3 and 6 h post-IT injection. These results provide strong in
      vivo evidence that COX-2 activity but not level may play a central role in the
      Freund's adjuvant-induced inflammation. However, spinal COX-2 level was
      upregulated following IT ketorolac and celecoxib injection. These data implies
      that suppression of PGE2 activity may induce the expression of spinal COX-2 in
      Freund's adjuvant-induced pain model. Our study concludes that IT administration
      of COX-2 inhibitor or nonspecific COX inhibitor is associated with significant
      short-term increase in spinal COX-2 expression.

PMID- 15193430
TI  - Down-regulated expression of agouti-related protein (AGRP) mRNA in the
      hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice.
AB  - A mutation in the mouse tub gene causes a phenotype characterized by maturity
      onset obesity, blindness and deafness. The role of the intact tubby protein and
      the pathogenesis resulting in the phenotype of tub/tub mice remain largely
      unknown. In this study, we have investigated whether obese tub/tub mice exhibit
      altered expression levels for agouti-related protein (AGRP) or glutamic acid
      decarboxylase-65 (GAD65) in body weight-regulating neurons of the hypothalamic
      arcuate nucleus. In situ hybridization revealed that AGRP, but not GAD65 mRNA
      levels, were significantly lower in obese tub/tub mice as compared to tub/+ mice.
      The lower levels of AGRP mRNA in the arcuate nucleus of tub/tub mice were
      paralleled by lower fluorescence intensity and numbers of AGRP- and neuropeptide
      Y (NPY)-immunoreactive (ir) nerve fibers and terminals in the arcuate,
      ventromedial, dorsomedial hypothalamic nuclei and perifornical and lateral
      hypothalamic areas. No obvious differences in GAD65-ir nerve fibers and terminals
      could be detected. Measurements of daily food intake revealed that tub/tub mice
      displayed progressively higher food consumption as compared to lean tub/+
      littermates over a 15-day observation period. When moved to an unfamiliar
      environment, e.g. a novel cage, daily food intake was initially lower in tub/tub
      mice than in tub/+ mice suggesting that tub/tub mice may be more sensitive to
      psychogenic stress. The results together show that tub/tub mice are hyperphagic
      and exhibit, within the hypothalamic arcuate nucleus, a depressed expression of
      neuropeptides involved in the regulation of feeding behavior.

PMID- 15193431
TI  - Distribution of 5-hydroxytriptamine2C receptor mRNA in rat retina.
AB  - There are several factors that suggest serotonin [5-hydroxytryptamine (5-HT)]
      plays a role as a neurotransmitter/neuromodulator within the retina. The presence
      of mRNAs encoding 5-HT receptors (5-HTR) of the types 5-HT2CR and 5-HT5AR within
      the rat retina was investigated using in situ hybridization of digoxigenin
      labeled probes. The 5HT5AR probe produced no labeling, whereas the 5HT2CR probe
      hybridized in cells scattered in the inner nuclear and ganglion cell layers.
      Thus, the 5HT2CR gene is expressed by retinal neurons, some of which represent
      third-order neurons, either amacrine or ganglion cells. This suggests that 5-HT
      may modulate the outgoing signal from the retina.

PMID- 15193432
TI  - Localization of 20alpha-hydroxysteroid dehydrogenase mRNA in mouse brain by in
      situ hybridization.
AB  - The enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the
      conversion of progesterone into its inactive form, 20alpha-hydroxyprogesterone.
      We studied the expression of 20alpha-HSD mRNA in mouse brain by in situ
      hybridization. 20alpha-HSD mRNA was exclusively found in neurons in cortex and
      hippocampus. In the cortex, the labelled cells were concentrated in the external
      granular layer, the external pyramidal layer and the inner granular layer. In the
      hippocampus, the labelling was mostly located over pyramidal cells of the CA1
      layer. These results suggest that progesterone can be inactivated by 20alpha-HSD
      in some specific brain areas.

PMID- 15193433
TI  - Identification and characterization of NBEAL1, a novel human neurobeachin-like 1
      protein gene from fetal brain, which is up regulated in glioma.
AB  - The Beige and Chediak-Higashi (BEACH) domain is highly conserved in a large
      family of eukaryotic proteins, and is crucial for their functions in vesicle
      trafficking, membrane dynamics and receptor signaling. From a fetal brain cDNA
      library, we isolated a cDNA of 3858 bp encoding a novel human BEACH protein,
      which was named as human neurobeachin-like 1 (NBEAL1) gene. The cDNA had an open
      reading frame (ORF) of 3006 bp encoding a putative 1001 amino acid protein. The
      NBEAL1 gene was located on human chromosome 2q33-2q34 and consisted of 25 exons
      spanning about 73 kb of the human genome. PSORT analysis indicated that the
      NBEAL1 protein contained a vacuolar-targeting motif ILPK, which suggested the
      protein might be located in the cell lysosome. The expression pattern was
      examined by reverse transcription/polymerase chain reaction (RT-PCR), which
      showed that the transcripts were highly expressed in the human brain, kidney,
      prostate, and testis while lowly in the ovary, small intestine, colon and
      peripheral blood leukocyte. In addition, the RT-PCR result of and Northern blot
      showed that the novel gene was highly expressed in the biopsies of different
      grade glioma, especially in that of lower grade ones, which suggested it might be
      correlative with the glioma.

PMID- 15193434
TI  - Overexpressed mutant G93A superoxide dismutase protects calcineurin from
      inactivation.
AB  - Previous studies have claimed that there is a failure of a mutant form of
      superoxide dismutase (mSOD) to protect the protein phosphatase, calcineurin (CN),
      against inactivation in the pathogenesis of amyotrophic lateral sclerosis (ALS),
      as determined in a murine model of ALS resulting from overexpression of mSOD
      (G93A). In contrast to previous studies, we find that mice overexpressing G93A
      mSOD have no statistically significant differences in the expression, or
      activity, of CN. However, CN from G93A mSOD overexpressing mice is significantly
      more protected against inactivation than non-transgenic mice that do not
      overexpress SOD. This reduced inactivation of CN is a consequence of increased
      expression of G93A mSOD. Thus, like wild-type SOD, G93A mSOD protects CN against
      inactivation.

PMID- 15193435
TI  - The role of fluorescence in situ hybridization (FISH) for monitoring hematologic
      malignancies with BCR/ABL or ETO/AML1 rearrangement: a comparative study with
      FISH and G-banding on 919 consecutive specimens of hematologic malignancies.
AB  - Fluorescence in situ hybridization (FISH) can detect minor genetic changes that
      cytogenetic analysis may miss; however, there are few reports on the kinds of
      genetic changes that show large discrepancies between results obtained with FISH
      versus G-banding techniques. To investigate genetic changes that tend to be
      detected with FISH only, we compared the results of cytogenetic study and FISH
      analysis in 919 consecutive specimens from 304 patients with hematologic
      malignancies, covering most of the frequent genetic changes by using 18 types of
      FISH probes. The genetic changes with especially large discrepancy rates at
      diagnosis were del(7q) (20.0%), PML/RARA (17.6%), and trisomy 21 (12.5%) and, at
      follow-up, BCR/ABL (28.2%) and AML1/ETO (24.4%); the latter two showed only small
      discrepancies at diagnosis (4.7 and 4.8%, respectively). The overall discrepancy
      rate was 6.0% at diagnosis and 11.9% at follow-up, indicating generally greater
      discrepancy rates at follow-up. In all but one of the cases with discrepant
      results, G-banding missed the corresponding chromosomal abnormalities revealed
      with FISH. Considered by type of leukemia, the discrepancy rate at follow-up was
      higher in acute biphenoptypic leukemia (38%) and acute lymphoblastic leukemia
      (24.5%) than in acute myelogenous leukemia (10.6%). Given these results, all
      patients with known genetic changes should have FISH analysis in follow-up, for
      an accurate assessment of the likelihood of complete remission or recurrence. If
      this is not practical, then at a minimum FISH analysis should be done in follow
      up for patients with genetic changes of BCR/ABL and AML1/ETO seen at diagnosis.

PMID- 15193436
TI  - Overexpression through amplification of genes in chromosome region 17p11.2
      approximately p12 in high-grade osteosarcoma.
AB  - Osteosarcomas are malignant tumors of the bone that are characterized by complex
      genetic changes, including loss and amplification of chromosome regions. Region
      17p11.2 approximately p12 is frequently found to be amplified in this tumor,
      suggesting the presence of an oncogene (or oncogenes) important in osteosarcoma
      tumorigenesis. We had previously determined amplification profiles for this
      region. Reasoning that amplification of a causative oncogene in a tumor should
      result in increased expression of that gene, we have now determined the
      expression status of genes and expressed sequence tags (ESTs) in 17p11.2
      approximately p12. We constructed a 17p11.2 approximately p12-specific macroarray
      containing 40 genes and 21 ESTs from this region, which was used for expression
      profiling of 11 osteosarcoma samples (9 tumors and 2 cell lines) and of normal
      human osteoblasts. Compared to normal osteoblasts, genes with at least threefold
      increased expression were considered to be overexpressed in the tumor. Genes
      PMP22 and COPS3, EST AA126939 (encoding part of the hypothetical protein
      FLJ20343), and two anonymous ESTs (AA918483 and R02360) were found to be most
      consistently overexpressed after amplification. By real-time reverse
      transcriptase polymerase chain reaction, we could confirm the overexpression
      status of PMP22 and COPS3 but not of FLJ20343. We conclude that PMP22 and COPS3,
      and possibly also the three ESTs, are candidate amplification targets in 17p11.2
      approximately p12 in osteosarcoma.

PMID- 15193437
TI  - Multiple reciprocal translocations in salivary gland mucoepidermoid carcinomas.
AB  - Mucoepidermoid carcinoma, the most common human malignant salivary gland tumor,
      can arise from both major and minor salivary glands, including sites within the
      pulmonary tracheobronchial tree. We performed comparative genomic hybridization
      (CGH) and spectral karyotyping (SKY) on two tumor cell lines: H3118, derived from
      tumor originating in the parotid gland, and H292, from tumor in the lung. In both
      cell lines, CGH showed a partial gain within the short arm of chromosome 7 and
      SKY revealed the presence of the previously reported reciprocal translocation
      t(11;19)(q21;p12). Additional chromosomal rearrangements were found in both cell
      lines, including three more reciprocal translocations in cell line H292 [t(1;16),
      t(6;8)x2] and three other reciprocal translocations in cell line H3118 [t(1;7),
      t(3;15), and t(7;15)]. A review of the literature of other reported cases of
      mucoepidermoid carcinomas analyzed with standard G-banding techniques, as well as
      distinct benign salivary gland tumors, such as pleomorphic adenomas and Warthin
      tumor, confirmed the presence of a karyotype dominated by reciprocal
      translocations. Four chromosomal bands were involved in chromosomal
      translocations in both cell lines: 1q32, 5p15, 7q22, and 15q22. Fluorescence in
      situ hybridization studies showed that the breakpoints in these four bands were
      often within a few megabases of each other. The involvement of similar
      chromosomal bands in breakpoints in these two cell lines suggests that these
      regions may be predisposed or selected for chromosomal rearrangements in this
      tumor type. The presence of multiple reciprocal translocations in both benign and
      malignant salivary gland tumors may also suggest a particular mechanism within
      mucous or serous glands mediating chromosomal rearrangements.

PMID- 15193438
TI  - The genetics of renal oncocytosis: a possible model for neoplastic progression.
AB  - Renal oncocytosis is a rare condition characterized by the presence of numerous
      oncocytomas and oncocytic changes in the renal tubules. Other than oncocytomas
      associated with the Birt-Hogg-Dube (BDH) syndrome, the genetics of oncocytosis is
      not known. Whether oncocytomas and oncocytosis are similar to BDH syndrome, in
      which the tumors diploid (as most oncocytomas are), or show chromosomal losses
      may be significant regarding the observation that in oncocytosis, there
      frequently is morphological evidence of progression to chromophobe carcinoma.
      Here we report on the case of a 69-year old male who underwent a staged procedure
      of partial nephrectomy on the left side and right radical nephrectomy for
      multiple renal tumors. The tumors were studied by routine hematoxylin and eosin
      morphology, immunohistochemistry, cytogenetics, and loss of heterozygosity
      analysis. Both kidneys had numerous oncocytic neoplasms morphologically
      progressing from oncocytomas to hybrid tumors with chromophobe carcinoma. Genetic
      studies demonstrated progression from normal cytogenetics to chromosomal losses
      similar to those in some oncocytomas and in chromophobe carcinomas. The genetics
      of this apparently nonfamilial oncocytoma differs from that of BDH syndrome and
      is characterized by losses involving chromosomes 1, 14, 21, and Y. To our
      knowledge, this is the first report of the genetic and cytogenetic findings in
      oncocytosis not related to BDH syndrome and may suggest a possible model of
      progression from oncocytoma to chromophobe renal cell carcinoma.

PMID- 15193439
TI  - Systematic screening at diagnosis of -5/del(5)(q31), -7, or chromosome 8
      aneuploidy by interphase fluorescence in situ hybridization in 110 acute
      myelocytic leukemia and high-risk myelodysplastic syndrome patients: concordances
      and discrepancies with conventional cytogenetics.
AB  - To assess the contribution of interphase fluorescence in situ hybridization (I
      FISH) toward the detection of recurring unbalanced chromosomal anomalies at
      diagnosis, a systematic screening of -5/del(5)(q31), -7, and chromosome 8
      aneuploidy was performed on 110 patients with acute myelocytic leukemia or high
      risk myelodysplastic syndrome. We searched for monosomy 5/del(5q) by one-color I
      FISH with a probe specific for the 5q31 region and for -7/8 by dual-color I-FISH
      with centromeric probes for chromosomes 7 and 8. Discrepancies between
      conventional cytogenetics (CC) and I-FISH were observed in 8 of the 110 patients
      (7.3%). For -5/del(5)(q31), a discordance was observed in two patients with
      complex abnormalities involving chromosome 5. Whereas no discordance was observed
      for -7, I-FISH detected a trisomy 7 unnoticed by CC in two cases. In six
      patients, I-FISH revealed a chromosome 8 aneuploidy not detected by CC. Our
      results illustrate that, when using this specific set of probes, I-FISH is of
      special interest for the detection of minor clones with chromosome 8 aneuploidy,
      breakpoint assessment, and sequence identification (markers). Also, to avoid
      misinterpretations, I-FISH should not be used alone at disease presentation,
      particularly in cases complex changes that have clearly established prognostic
      significance.

PMID- 15193440
TI  - Gene expression profiles in human mesothelioma cell lines in response to
      interferon-gamma treatment.
AB  - Interferon-gamma (IFN-gamma) has been found to be antiproliferative and
      antitumoral in malignant mesothelioma (MM), but the MM cell response to IFN-gamma
      has not been fully characterized so far. We investigated gene expression profiles
      in human MM cell lines (HMCLs) exposed to IFN-gamma. Four HMCLs showing different
      sensitivities to the antiproliferative effect of IFN-gamma, two of them
      presenting a defect in the JAK/STAT signaling pathway, were treated with 500
      IU/mL of IFN-gamma. Gene expression patterns were studied at 6 and 72 hours after
      exposure to the IFN-gamma, using a cDNA array technique. Six genes were studied
      with real-time reverse transcription-polymerase chain reaction. The gene
      expression profiles in response to IFN-gamma were shown to differ in different
      HMCLs. Numerous genes involved in cell proliferation and cell adhesion were
      regulated by IFN-gamma in JAK/STAT-deficient HMCLs. Genes possibly involved in
      regulation of cell proliferation included CDC2, PLK1, and IGFBP4, as well as
      several genes involved in cell-cell interactions and cell adhesion. The cDNA
      array technique revealed differences in expression pathways, especially those
      involved in cell growth, cell adhesion, and cell proliferation, between IFN-gamma
      resistant and -sensitive MM cell lines. We found that the changes in gene
      expression profiles of HMCLs exposed to IFN-gamma were also related to features
      other than the antiproliferative response.

PMID- 15193441
TI  - Occurrence of a variant Philadelphia translocation, t(10;22), in de novo acute
      megakaryoblastic leukemia.
AB  - Acute megakaryoblastic leukemia (AMegL) in adults is a very rare subtype of acute
      myeloid leukemia (AML) and is characterized by a larger diversity of chromosomal
      abnormalities than the other subtypes, including 3q21q26 changes, aberrations of
      chromosomes 5 and 7, and the t(9;22)(q34;q11). We report the case of a 24-year
      old patient with de novo AMegL and thrombocythemic cell count. Diagnosis was
      established with a bone marrow biopsy, and cytogenetics with G-banding revealed a
      t(10;22), which by FISH, was found to be a variant Philadelphia translocation
      involving chromosome 10q in all 20 metaphases analyzed. We believe that this is
      the first report of de novo AMegL with this chromosomal abnormality, and its
      possible correlation with morphology and thrombocytosis is discussed.

PMID- 15193442
TI  - Deletion 6p23 and add(11)(p15) leading to NUP98 translocation in a case of
      therapy-related atypical chronic myelocytic leukemia transforming to acute
      myelocytic leukemia.
AB  - A NUP98 gene translocation occurring with a del(6p23) and an add(11)(p15) was
      determined in a 61-year-old patient with therapy-related atypical chronic
      myelocytic leukemia after complete remission from acute promyelocytic leukemia
      that eventually underwent clonal evolution and transformed to CD56-positive acute
      myelocytic leukemia (French-American-British classification M0). Precise
      chromosome analysis by G-banding, spectral karyotyping analysis, and dual-color
      fluorescence in situ hybridization showed this abnormality as
      46,XY,del(6)(p23),add(p15). ish del(6)(NUP98
      ,D6Z1+),der(7)(NUP98+,D7Z1+),der(11)(NUP98+,D11Z1). A split signal of NUP98 was
      observed in 68.4% of the 117 cells analyzed, which clearly indicated that the
      NUP98 partially translocated to chromosome 7. However, the potential fusion
      partner of the NUP98 was not HOX family or DEK. The fusion gene has not been
      found by a differential display method. The significance of simultaneously
      combined del(6)(p23), which also has been reported with secondary leukemogenesis,
      has not been elucidated. Additional karyotype abnormalities evolved increasingly,
      and leukocytosis with blasts with more complex karyotypic abnormalities appeared
      5 months later. Careful and continuous analysis of karyotype change clarified the
      process of the clonal evolution after NUP98 translocation. Further investigation
      of molecular characterization of this NUP98 translocation and interaction with
      6p23 abnormalities might be worthwhile for understanding leukemogenesis.

PMID- 15193443
TI  - Myxoinflammatory fibroblastic sarcoma with complex supernumerary ring chromosomes
      composed of chromosome 3 segments.
AB  - Myxoinflammatory fibroblastic sarcoma is a rare, recently described, and
      distinctive low-grade tumor of soft tissue. To our knowledge, there is only one
      previous report on the cytogenetics of this tumor. That case showed complex
      structural abnormalities, including a reciprocal translocation between
      chromosomes 1 and 10 [t(1;10)(p22;q24)] with loss of chromosomes 3 and 13. We
      describe here a second case showing supernumerary ring chromosomes, and a
      derivative chromosome 13, with additional material on the short arm. We conclude
      that the presence of chromosomal abnormalities supports the neoplastic nature of
      this tumor and aids in its diagnosis. Furthermore, we also postulate that the
      finding of ring chromosomes, which have been identified in other low-grade soft
      tissue tumors, may have important prognostic implications regarding the
      aggressiveness of this neoplasm.

PMID- 15193444
TI  - Translocation (8;22) in cold agglutinin disease associated with B-cell lymphoma.
AB  - Cold agglutinin disease (CAD) is a hemolytic anemia due to anti-red cell
      autoantibodies that are reactive at cold temperatures. In the elderly, it may be
      associated with underlying B-cell lymphoma, usually a lympho-plasmacytic lymphoma
      variant. We report a case of CAD in an elderly Indonesian female, which was
      associated with a B-cell lymphoma that showed a histologic appearance consistent
      with large-cell lymphoma. Cytogenetic analysis revealed the presence of trisomies
      3 and 12, which have been reported previously in B-cell lymphoma associated with
      CAD. In addition, a t(8;22) was found in 24 out of 28 metaphases. Translocation
      (8;22) is associated with Burkitt lymphoma or acute lymphoblastic lymphoma,
      French-American-British subtype L3. It has not been previously reported in B-cell
      lymphoma asssociated with CAD, and could represent a blastic transformation of
      the underlying B-cell lymphoma.

PMID- 15193445
TI  - No association between two MLH3 variants (S845G and P844L)and colorectal cancer
      risk.
AB  - Recently we identified a new variant, S845G, in the MLH3 gene in 7 out of 327
      patients suspected of hereditary nonpolyposis colorectal cancer but not
      fulfilling the Amsterdam criteria and in 1 out of 188 control subjects. As this
      variant might play a role in causing sporadic colorectal cancer, we analyzed its
      prevalence in sporadic colorectal cancer patients. We analyzed a small part of
      exon 1 of the MLH3 gene, including the S845G variant, in germline DNA of 467
      white sporadic colorectal cancer patients and 497 white controls. The S845G
      variant was detected in five patients and eight controls; the results thus
      indicate that this variant does not confer an increased colorectal cancer risk.
      Another variant (P844L) was clearly a polymorphism. Three other missense variants
      were rare and the sample size of the study was too small to conclude whether they
      are pathogenic. In conclusion, no association was observed between two MLH3
      variants (P844L and S845G) and colorectal cancer risk.

PMID- 15193446
TI  - Cryptic deletion involving the ATM locus at 11q22.3 approximately q23.1 in B-cell
      chronic lymphocytic leukemia and related disorders.
AB  - B-cell chronic lymphocytic leukemia (B-CLL) follows a heterogeneous clinical
      course, and several biological parameters have been investigated to try to
      predict its clinical outcome. New staging systems including cytogenetics and CD38
      expression as predictive values have been developed. Deletions of 11q22.3
      approximately q23.1 detected at diagnosis in cases of CLL patients have been
      associated with a relatively aggressive disease. This region, which contains the
      ataxia telangiectasia mutated (ATM) locus, may be implicated in the pathogenesis
      of lymphoid malignancies. We developed a set of dual-color specific probes to
      evaluate the ATM deletion by means of fluorescence in situ hybridization (FISH).
      We also used flow cytometry to investigate CD38 expression. Forty-one patients
      with CLL or low-grade B-cell lymphomas were studied at diagnosis or before
      treatment. FISH showed that only three CLL patients had deletions in the 11q23
      locus; all three had progressive disease and were resistant to treatment. These
      data show that our FISH set of probes efficiently detects ATM deletions in CLL.
      No correlation was found between ATM deletions and CD38 expression level. These
      results confirm the prognostic significance of ATM deletions in CLL.

PMID- 15193447
TI  - ETV6/RUNX1 rearrangement in childhood B-precursor acute lymphoblastic leukemia
      with normal karyotypes or without cytogenetic results.
AB  - The ETV6/RUNX1 rearrangement (also known as TEL/AML1) was evaluated in 39
      children with B-precursor acute lymphoblastic leukemia (ALL) who had a normal
      karyotype or lack of mitoses. Forty-one point six percent of patients with normal
      karyotypes and 66.6% of patients without mitoses presented with the ETV6/RUNX1
      rearrangement. In addition to this rearrangement, eight patients showed loss of
      the normal ETV6 allele; of three patients without mitoses, two showed an extra
      signal of the RUNX1 gene and the third showed the fusion gene duplicated and loss
      of the normal ETV6 allele. One patient without the ETV6/RUNX1 rearrangement and
      without mitoses showed two extra signals of the RUNX1 gene.

PMID- 15193448
TI  - A t(1;9)(q23.3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic
      leukemia.
AB  - Recurring chromosome translocations, which are found in leukemia, can result in
      the inappropriate expression of oncogenes or in the formation of chimeric genes
      that code for structurally and functionally abnormal proteins. The chromosomal
      t(1;9)(q23.3 approximately q25;q34) was found in a patient with biphenotypic
      leukemia. Fluorescence in situ hybridization (FISH) analysis revealed that the
      break on chromosome 9 occurred in the ABL1 gene. The breakpoint on chromosome 1
      occurred distal to the PBX1 gene at 1q23.3, as shown by FISH using BAC RP11
      503N16 and RP11-403P14, which flank the PBX1 locus; hence, the ABL1 gene can be
      fused with another gene distal to PBX1 gene.

PMID- 15193450
TI  - Gene silencing by nuclear orphan receptors.
AB  - Nuclear orphan receptors represent a large and diverse subgroup in the nuclear
      receptor superfamily. Although putative ligands for these orphan members remain
      to be identified, some of these receptors possess intrinsic activating,
      inhibitory, or dual regulatory functions in development, differentiation,
      homeostasis, and reproduction. In particular, gene-silencing events elicited by
      chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage
      sensitive sex reversal-adrenal hypoplasia congenita critical region on the X
      chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer
      partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best
      characterized. These orphan receptors are critical in controlling basal
      activities or hormonal responsiveness of numerous target genes. They employ
      multiple and distinct mechanisms to mediate target gene repression. Complex cross
      talk exists between these orphan receptors at their cognate DNA binding elements
      and an array of steroid?nonsteroid hormone receptors, other transcriptional
      activators, coactivators and corepressors, histone modification enzyme complexes,
      and components of basal transcriptional components. Therefore, perturbation
      induced by these orphan receptors at multiple levels, including DNA binding
      activities, receptor homo- or heterodimerization, recruitment of cofactor
      proteins, communication with general transcriptional machinery, and changes at
      histone acetylation status and chromatin structures, may contribute to silencing
      of target gene expression in a specific promoter or cell-type context. Moreover,
      the findings derived from gene-targeting studies have demonstrated the
      significance of these orphan receptors' function in physiologic settings. Thus,
      COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple
      physiologic and biologic functions, including neurogenesis and development of the
      heart and vascular system steroidogenesis and sex determination, gametogenesis
      and embryonic development, and cholesterol?lipid homeostasis.

PMID- 15193449
TI  - Deletion of 5q31 and 7q31 in patients with stable melphalan treated multiple
      myeloma.
AB  - Multiple myeloma represents a malignant proliferation of plasma cells derived
      from a single clone. It is well known that alkylating agents are capable of
      inducing myelodysplastic syndromes (MDS) and acute myelocytic leukemias (AML).
      This risk of both diseases in patients with multiple myeloma has been estimated
      to be 10-20% after 10 years. We aimed to evaluate the time course and the type of
      genetic abnormalities in melphalan-treated patients in the chronic stage of the
      disease. We applied fluorescence in situ hybridization methods with probes to
      5q31 and 7q31 to mononuclear peripheral blood leukocytes of 18 melphalan-treated
      patients and compared the results to those of 8 untreated myeloma patients. We
      found three patients (17%) with a 5q31 deletion in their peripheral white blood
      cells, but no 7q31 deletion. These findings suggest that 5q- occurs before the
      overt development of MDS/AML and raise important concerns regarding long-term
      treatment of myeloma patients with alkylating agents. Also, the performance of
      cytogenetic evaluation should be considered before autologous transplantation.
      The clinical and biological implications of these findings should be evaluated in
      larger clinical and laboratory studies.

PMID- 15193451
TI  - Structure and function of the glucocorticoid receptor ligand binding domain.
AB  - After binding to an activating ligand, such as corticosteroid, the glucocorticoid
      receptor (GR) performs an impressive array of functions ranging from nuclear
      translocation, oligomerization, cofactor/kinase/transcription factor association,
      and DNA binding. One of the central functions of the receptor is to regulate gene
      expression, an activity triggered by ligand binding. In this role, GR acts as an
      adapter molecule by encoding the ligand's message within the structural
      flexibility of the ligand binding domain (LBD). The purpose of this review is to
      discuss the many structural and functional features of the GR LBD in light of
      recent successful biochemical and crystallographic studies. Progress in this area
      of research promises to reveal new strategies and insights allowing for the
      design of novel drugs to treat inflammatory diseases, diabetic conditions,
      steroid resistance, and cancers.

PMID- 15193452
TI  - Nuclear receptor recruitment of histone-modifying enzymes to target gene
      promoters.
AB  - Nuclear receptors (NRs) compose one of the largest known families of eukaryotic
      transcription factors and, as such, serve as a paradigm for understanding the
      fundamental molecular mechanisms of eukaryotic transcriptional regulation. The
      packaging of eukaryotic genomic DNA into a higher ordered chromatin structure,
      which generally acts as a barrier to transcription by inhibiting transcription
      factor accessibility, has a major influence on the mechanisms by which NRs
      activate or repress gene expression. A major breakthrough in the field's
      understanding of these mechanisms comes from the recent identification of NR
      associated coregulatory factors (i.e., coactivators and corepressors). Although
      several of these NR cofactors are involved in chromatin remodeling and
      facilitating the recruitment of the basal transcription machinery, the focus of
      this chapter is on NR coactivators and corepressors that act to covalently modify
      the amino-terminal tails of core histones. These modifications (acetylation,
      methylation, and phosphorylation) are thought to directly affect chromatin
      structure and?or serve as binding surfaces for other coregulatory proteins. This
      chapter presents the most current models for NR recruitment of histone-modifying
      enzymes and then summarizes their functional importance in NR-associated gene
      expression.

PMID- 15193453
TI  - Corepressor recruitment by agonist-bound nuclear receptors.
AB  - Members of the nuclear receptor superfamily are ligand-regulated transcription
      factors that are composed of a series of conserved domains. These receptors are
      targets of a wide range of lipophilic signaling molecules that modulate many
      aspects of physiology and metabolism. Binding of cognate ligands to receptors
      induces a conformational change in the ligand binding domain (LBD) that creates a
      pocket for recruitment of coregulatory proteins, which are essential for ligand
      dependent regulation of transcription. Several coregulatory proteins that
      interact with hormone-bound receptors contain characteristic helical LXXLL
      motifs, known as nuclear receptor (NR) boxes. Generally, ligand binding to
      receptors is associated with activation of transcription, and most of the NR box
      containing proteins characterized to date are coactivators. However, a full
      understanding of the function of hormone-bound receptors must also incorporate
      their recruitment of corepressors. The recent identification of ligand-dependent
      corepressor (LCoR) is a case in point. LCoR contains a single NR box that
      mediates its hormone-dependent interaction with several nuclear receptors. It
      functions as a molecular scaffold that recruits several proteins that function in
      transcriptional repression. Remarkably, although the two proteins share only very
      limited homology, LCoR and another NR box-containing corepressor RIP140 recruit
      similar cofactors implicated in transcriptional repression, suggesting many
      parallels in their mechanisms of action. Corepressors such as LCoR and RIP140 may
      function in negative feedback loops to attenuate hormone-induced transactivation,
      act more transiently as part of a cycle of cofactors recruited to target
      promoters by ligand-bound receptors, or function in hormone-induced target gene
      repression.

PMID- 15193454
TI  - Pharmacology of nuclear receptor-coregulator recognition.
AB  - The nuclear receptor (NR) superfamily comprises approximately 50 members that are
      responsible for regulating a number of physiologic processes in humans, including
      metabolism, homeostasis, and reproduction. Included in the superfamily are the
      receptors for steroids, lipophilic vitamins, bile acids, retinoids, and various
      fatty acids. NRs exert their action as transcription factors that directly bind
      to the promoters of target genes and regulate their rate of transcription. To
      modulate transcription, however, NRs must recruit a number of accessory
      coregulators known as corepressors and coactivators. These coregulators harbor a
      variety of activities, such as the ability to modify chromatin structure,
      interact with basal transcriptional machinery, and modify RNA splicing. Recent
      studies have revealed that the pharmacological characteristics of various NR
      ligands are regulated by their ability to modulate the coregulator interaction
      profile of an NR.

PMID- 15193456
TI  - Corepressor requirement and thyroid hormone receptor function during Xenopus
      development.
AB  - The biologic role of hormonal activation of nuclear receptors is well
      established. Only recently, however, has the biologic significance of repression
      begun to be appreciated. Amphibian metamorphosis is marked by dramatic thyroid
      hormone induced changes, including de novo morphogenesis, tissue remodeling, and
      organ resorption through programmed cell death. These changes involve cascades of
      gene regulation initiated by 3,5,3'-triiodothyronine (T(3)). T(3) functions by
      regulating gene expression through thyroid hormone receptor (TR). TRs are DNA
      binding transcription factors that belong to the steroid hormone receptor
      superfamily. In the absence of a ligand, TRs can repress gene expression by
      recruiting corepressor complexes, whereas liganded TRs recruit coactivator
      complexes for gene activation. Corepressor and coactivator complexes induce
      chromatin remodeling to mediate TR regulation of transcription. The mechanisms of
      TR action permit a dual function for TRs during development. In premetamorphic
      tadpoles, when TRs are expressed and T(3) levels are barely detectable,
      unliganded TRs repress transcription through corepressor recruitment. This TR
      mediated repression of target genes is critical for proper larval development,
      allowing tadpole growth and acquisition of metamorphic competence. In contrast,
      during metamorphosis, endogenous T(3) causes TRs to activate gene expression,
      leading to tadpole transformation. Several results also support a role for
      corepressors during metamorphosis. Corepressor targeted functions, however, are
      still speculative but may again involve TRs. The requirement of active gene
      repression at different stages during amphibian development establishes an
      important biologic role for corepressors.

PMID- 15193455
TI  - Thyroid hormone receptor subtypes and their interaction with steroid receptor
      coactivators.
AB  - Thyroid hormone (TH) is required for normal growth, development, and metabolism
      in metazoans. To influence this broad range of physiologic actions, TH is
      necessarily involved in the regulation of a multitude of genes in virtually every
      tissue. The diversity of gene expression regulation in response to TH is mediated
      through specific intranuclear TH receptors (TRs) and other nuclear coregulators.
      This chapter reviews TRs and nuclear coregulators, specifically coactivators,
      based on in vivo data from knockout (KO) mouse models.

PMID- 15193458
TI  - Vitamin D receptor-DNA interactions.
AB  - The vitamin D receptor (VDR) is a member of the steroid and nuclear hormone
      receptor superfamily of eukaryotic transcription factors and binds target DNA, or
      response elements, as a homodimer or heterodimer with the 9-cis retinoid X
      receptor (RXR). In this chapter, we survey the current understanding of VDR-DNA
      interactions, emphasizing recent structural insights. We highlight the
      stereochemical interactions that dictate DNA binding and hexameric half-site
      sequence affinity as well as the protein-protein interactions that account for
      preferential binding to a direct repeat of half-sites with three base pairs of
      spacer DNA (DR3). In addition, we review alternative response element
      arrangements other than those with DR3. Finally, the chapter discusses the VDR
      DNA binding domain (DBD) and suggests that it violates classical canons because
      it does not heterodimerize with the RXR DBD. This unique behavior of VDR is
      considered in light of recent results demonstrating the formation of VDR DBD-DNA
      and DR3 DBD-DNA complexes with RXR using a mutant VDR protomer.

PMID- 15193457
TI  - Cdc25B as a steroid receptor coactivator.
AB  - The traditional role of the Cdc25 family of dual-specificity phosphatases is to
      activate cyclin-dependent kinases (CDKs) to enable progression through the cell
      cycle. This chapter reports that in addition to its cell cycle role, Cdc25B
      functions as a novel steroid receptor coactivator (SRC). When overexpressed in
      transgenic mammary glands, Cdc25B can up-regulate the expression of two estrogen
      receptor (ER)-target genes: cyclin D1 and Lactoferrin. In addition, when
      coexpressed with ER, Cdc25B can coactivate an ER-dependent reporter in the
      presence of estradiol. The coactivation of Cdc25B can be extended to the
      glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor
      (AR). Because of the respective importance of ER and AR in breast and prostate
      cancer, this chapter focuses on the coactivation of both receptors by Cdc25B. We
      demonstrate that Cdc25B can interact directly with these nuclear receptors,
      recruit and enhance the activity of histone acetyltransferases (HATs), and
      potentiate cell-free transcription independent of its cell cycle regulatory
      function. Furthermore, because Cdc25B is up-regulated in highgrade and poorly
      differentiated prostate tumors, which are likely transiting from the hormone
      dependent to hormone-independent state, we hypothesize that the coactivation of
      AR by Cdc25B may induce genes responsible for this progression. Taken together,
      it is highly conceivable that Cdc25B can promote neoplasia by its two disparate
      functions of (1) coactivation to induce higher levels of expression of steroid
      receptor target genes and (2) its role of activating CDKs to deregulate
      progression of the cell cycle, DNA replication, and mitosis.

PMID- 15193460
TI  - Tools for making correct decisions regarding hormone therapy. part I: background
      and drugs.
AB  - OBJECTIVE: To review existing scientific data related to the biology of estrogen
      in the aging process of women, and to understand the pharmacology, physiology,
      and diversity of sex hormones. DESIGN: A MEDLINE computer search was performed to
      identify relevant articles. RESULT(S): Estrogen and progesterone have been
      prescribed for postmenopausal women over the last 60 years. Various formulations
      have had divergent properties, which are related to dissimilarities in the
      molecule structure, metabolism, plasma carrier, distribution, receptor binding,
      and the specific localizations of the different receptors in the various organs.
      CONCLUSION(S): Extensive data are available on the various characteristics of sex
      hormone formulations, which are related to clinical consequences. The drugs and
      means of application have resulted in fundamental differences in activity, such
      as variance between oral and transdermal applications resulting in different
      forms of liver involvement. This information could assist in understanding why
      certain formulations may either prove harmful or beneficial to specific women.

PMID- 15193461
TI  - Tools for making correct decisions regarding hormone therapy. Part II. Organ
      response and clinical applications.
AB  - OBJECTIVE: To review existing scientific knowledge of the complicated and
      variable behavior and response to hormone therapy (HT) of different organs during
      aging, and to summarize long-term consequences on human health. DESIGN: A MEDLINE
      computer search was performed to identify relevant articles. RESULT(S): Five body
      organs were evaluated. [1]. Physiologic aging of the bone has deleterious
      consequences on women's health and quality of life. Bone fractures could be
      attributed to the combination of estrogen depletion and osteoporosis, mechanisms
      of applied forces, and disturbed brain function, partially reversible by timely
      estrogen administration. [2]. Estrogen seems to have a profound neuroprotective
      effect. As physiologic aging of the brain is an unhealthy phenomenon, possible
      intervention is justified. The therapeutic time window seems crucial. [3]. The
      differentiation between response of a healthy or already damaged organ to sex
      hormones is the key factor to understanding the possible cardioprotective
      effects. [4]. Based on doubling time of tumor cells, intracrinology,
      epidemiological data on breast cancer, and behavior of breast cancer survivors in
      response to estrogen treatment, estrogen seems to be mainly a promoter and even a
      protector of breast cancer survivors. [5]. Colon cancer appears to be an estrogen
      dependent tumor with a wide therapeutic window, as every report regardless of age
      and dose demonstrates protective effects. CONCLUSION(S): Knowledge of each
      organ's response to aging and sex hormone substitutions demonstrates that the
      organs could benefit from properly designed intervention. In the wake of the
      publication of the Women's Health Initiative study, which shocked the medical
      community, we suggest that the results be reevaluated according to the
      aforementioned principles, and that menopausal medicine could play an important
      role.

PMID- 15193462
TI  - High follicle-stimulating hormone levels should not necessarily lead to the
      exclusion of subfertile patients from treatment.
AB  - OBJECTIVE: To determine ongoing pregnancy rates in subfertile patients with
      elevated FSH levels and regular cycles and to assess whether or not it is
      justified to exclude such patients from treatment on the basis of elevated FSH
      levels alone. DESIGN: Retrospective follow-up study. SETTING: Tertiary fertility
      center. PATIENT(S): One hundred twenty-two patients with normal FSH levels <10.0
      IU/L, 126 with FSH between 10.0 and 15.0 IU/L, and 53 with FSH levels >15.0 IU/L,
      all having regular cycles and belonging to a general subfertility population.
      INTERVENTION(S): Follow-up. MAIN OUTCOME MEASURE(S): Overall and treatment
      independent and treatment-dependent ongoing pregnancy rates and time to ongoing
      pregnancy. RESULT(S): Overall ongoing pregnancy rates declined from 65% in the
      normal FSH group to 47%, and 28% in the respective elevated FSH groups. However,
      when adjusting for differences in age and whether or not treatment was applied,
      this declining trend became inconsistent for both treatment-independent and
      treatment-dependent ongoing pregnancy rates. Only when FSH levels exceeded 20
      IU/L was a clear fall in ongoing pregnancy rate observed, independent of age. In
      a Cox regression analysis, FSH seemed significantly associated with the outcome
      time to overall ongoing pregnancy (odds ratio = 0.94, 95% confidence interval,
      0.88-0.99), but after adjusting for age and being on treatment or not this
      significance disappeared (odds ratio = 0.97, 95% confidence interval, 0.91-1.01).
      CONCLUSION(S): The contribution of FSH in the initial evaluation of subfertile
      couples is restricted to counseling patients on the probability of having lower
      chances of conceiving. It does not seem justified to exclude patients with normal
      regular cycles from treatment on the basis of the FSH value alone.

PMID- 15193464
TI  - Diminished ovarian reserve and access to care.
AB  - Critical evaluation of the diminished ovarian reserve literature prognosticates
      an extremely poor prognosis. Clinicians should counsel patients in detail about
      their extremely limited prognosis but not deny access to care.

PMID- 15193463
TI  - Value of the day 3 follicle-stimulating hormone measurement.
AB  - Although elevated day 3 FSH is associated with diminished ovarian reserve, the
      predictive value is low in young women. Its use in this population as an
      exclusion criterion is unjustified.

PMID- 15193465
TI  - Modest follicle-stimulating hormone elevations in younger women: warn but don't
      disqualify.
AB  - Markers of quantitative defects in egg production (low ovarian reserve) have
      often been used to exclude patients from treatment, even when egg quality is apt
      to be satisfactory. Women younger than 38 years of age with modest FSH elevations
      (10-15 or even 20 IU/L) have acceptable pregnancy rates despite their limited
      production of eggs ("quality matters more than quantity") and so should be given
      the opportunity to try IVF.

PMID- 15193467
TI  - The Women's Health Initiative could not have detected cardioprotective effects of
      starting hormone therapy during the menopausal transition.
AB  - The Women's Health Initiative (WHI) randomized controlled trial failed to show
      cardioprotection by estrogen plus progestin treatment of postmenopausal women.
      But by design, the WHI population was 10-fold underpowered to show
      cardioprotection of women starting hormone treatment during the menopausal
      transition. Thus, observational studies that showed cardioprotection in such
      women remain the only applicable clinical guide to this issue. Randomized
      controlled trials are urgently needed to test cardioprotection in women starting
      treatment during the menopausal transition.

PMID- 15193468
TI  - Equivalency of culture media for human in vitro fertilization formulated to have
      the same pH under an atmosphere containing 5% or 6% carbon dioxide.
AB  - Culture media for human in vitro fertilization and early embryonic development
      were modified to maintain similar pH values under an atmosphere containing 5% or
      6% carbon dioxide by adjusting the concentration of sodium bicarbonate. Similar
      results were obtained with both media groups in a mouse embryo assay and in human
      in vitro parameters of fertilization and early development and clinical outcomes.

PMID- 15193469
TI  - Urine vascular endothelial growth factor-A is not a useful marker for
      endometriosis.
AB  - OBJECTIVE: To determine whether urine VEGF is elevated in women with
      endometriosis. DESIGN: Prospective observational study. SETTING: Tertiary care
      government and private hospitals. PATIENT(S): During laparoscopy for pelvic pain
      or infertility, urine was collected and possible endometriosis lesions were
      excised. Of 62 women, 40 had histology-proven endometriosis and 22 had no
      histological proof of the disease. INTERVENTION: None. MAIN OUTCOME MEASURE(S):
      Urine VEGF-A(121, 165) was measured and compared in women with and without biopsy
      proven endometriosis. RESULT(S): Urine VEGF levels corrected for creatinine
      excretion were similar in women with (83.6 +/- 11.3 pg/mg Cr) and without (88.5
      +/- 10.4 pg/mg Cr) endometriosis (P =.77). The frequency distribution of urine
      VEGF measurements for women with and without endometriosis was similar. No
      significant difference was noted in urine VEGF levels when comparing
      endometriosis stages or in those with endometriomas compared to controls. Urine
      VEGF did not vary significantly over the menstrual cycle or between groups by
      cycle phase. No cutoff point discriminated individuals with and without the
      condition. CONCLUSION(S): It is unlikely that urine VEGF-A(121, 165), as measured
      in this study, will be a useful non-invasive marker for endometriosis.

PMID- 15193470
TI  - Evaluation of risk factors associated with endometriosis.
AB  - OBJECTIVE: To investigate the association between several factors such as
      demographics, personal habits, reproductive factors, menstrual characteristics,
      contraception, and clinical profile and the probability of having endometriosis.
      SETTING: Ten clinical institutions in the Montreal area. PATIENT(S): A total of
      2777 subjects who underwent surgery for diagnostic laparoscopy, tubal ligation,
      or hysterectomy between January 1998 and July 2002. Eight hundred ninety subjects
      were classified as cases on the basis of the presence of endometriotic lesions
      found at the time of surgery, whereas 1881 controls had no surgical evidence of
      endometriosis. MAIN OUTCOME MEASURE(S): The association between potential risk
      factors and endometriosis was estimated by Pearson chi(2) and by crude and
      adjusted odds ratios. RESULT(S): Results indicated a positive association between
      endometriosis and education level for subjects who underwent hysterectomy. An
      inverse relation between gravidity and endometriosis was also found within a
      subgroup of subjects who had diagnostic laparoscopy. Furthermore, the proportion
      of uterine leiomyoma was significantly higher in cases compared with in controls,
      among subjects who underwent surgery for diagnostic laparoscopy or hysterectomy
      but not for tubal ligation. CONCLUSION(S): These observations underline the
      importance of taking into account the clinical profile of subjects when
      investigating risk factors for endometriosis.

PMID- 15193471
TI  - An open and randomized study comparing the efficacy of standard danazol and
      modified triptorelin regimens for postoperative disease management of moderate to
      severe endometriosis.
AB  - OBJECTIVE: To compare the efficacy of danazol and triptorelin (Decapeptyl CR,
      Ferring, Kiel, Germany) in the management of moderate and severe endometriosis in
      terms of symptom control and revised American Fertility Society (AFS) score
      reduction, and to evaluate the hormonal profile of patients treated with
      triptorelin every 6 weeks. DESIGN: Open and randomized trial. SETTING: Kwong Wah
      Hospital, a large public hospital in an urban location (Hong Kong). PATIENT(S):
      Forty patients after their first conservative operation for endometriosis, with
      surgical confirmation of revised AFS stage III or IV endometriosis.
      INTERVENTION(S): Postoperative 6 months' therapy of danazol or triptorelin every
      6 weeks, postmedical therapy second-look laparoscopy. MAIN OUTCOME MEASURE(S):
      Symptom control and patients' tolerance during medical therapy, posttherapy
      revised AFS score, hormonal profile during triptorelin therapy. RESULT(S): Pain
      control was similar between danazol and triptorelin therapy. There was less
      breakthrough bleeding with triptorelin. More patients failed to complete the
      whole course of danazol because of its side effects. The revised AFS score at
      second-look laparoscopy did not show a significant difference between the two
      medications. Adequate pituitary suppression was observed with injection of
      triptorelin every 6 weeks. CONCLUSION(S): Lengthening of triptorelin
      administration intervals from 4 weeks to 6 weeks is effective in maintaining a
      hypoestrogenic state. Patients were more compliant with triptorelin than danazol.
      Thus, triptorelin injection every 6 weeks is more cost-effective than
      conventional regimens.

PMID- 15193472
TI  - Immunohistochemical analysis of vascular endothelial growth factor cellular
      expression in ovarian endometriomata.
AB  - OBJECTIVE: To evaluate the expression of vascular endothelial growth factor
      (VEGF) in the cell populations of ovarian endometriomata cyst layers. DESIGN:
      Experimental retrospective study. SETTING: University hospital. PATIENT(S):
      Twenty-eight patients with ovarian endometriomata. INTERVENTION(S): Surgical
      excision of 32 ovarian cysts. MAIN OUTCOME MEASURE(S): Histologic and VEGF
      immunohistochemical analysis of cyst layers. RESULT(S): Though the least
      represented cell types, macrophages exhibited the highest frequency of strong
      immunoreactivity, followed by capsular vessel endothelial and subepithelial
      stromal cells and by epithelial cells and capsular fibroblasts. Endothelia of the
      subepithelial stroma were the least immunoreactive cells. Diffuse VEGF expression
      in epithelial cells was associated with cyst diameters greater than 5.4 cm, and
      high VEGF expression in capsular fibroblasts was associated with bilateral cysts.
      CONCLUSION(S): Angiogenesis plays an active role in ovarian endometriosis,
      especially in the presence of large and bilateral cysts. Expression of VEGF in
      epithelial cells, capsular fibroblasts, and vessels was found to be related,
      suggesting that neoangiogenesis might especially affect the outer cyst wall, thus
      contributing to the fibrosing process of adhesion formation during cyst growth.

PMID- 15193473
TI  - Use of outcomes-based data in reducing high-order multiple pregnancies: the role
      of age, diagnosis, and embryo score.
AB  - OBJECTIVE: To identify high-risk categories for high-order multiple pregnancy
      (HMP) in in vitro fertilization (IVF), establish clinic-specific HMP risk data
      for counseling use, and verify their utility in reducing HMP. DESIGN: Before and
      after intervention study. SETTING: Two IVF programs using the same embryology
      laboratory and IVF protocols. PATIENT(S): All IVF patients undergoing fresh
      embryo transfers. INTERVENTION(S): Use of clinic-specific age, diagnosis, and
      embryo score (ES) risk data in assessing individual HMP risk during informed
      consent. MAIN OUTCOME MEASURE(S): HMP and pregnancy outcomes. RESULT(S): In
      determining clinic-specific high risk categories and developing outcomes-based
      HMP risk data for counseling, the good outcome rate (GR) was defined as the
      percentage of singleton or twin deliveries per cycle and the bad outcome rate
      included no pregnancy or nondelivered pregnancies (miscarriages, multifetal
      reduction) and HMP per cycle. During 1995 to 1999, age <35 years, calculated
      morphologic ES, and donor egg (DE) cycles were factors shown by logistic
      regression to statistically significantly affect the GR. The optimal GRs for DE
      <35 and >or=35 years (donor age), and non-DE cycles <35 years were achieved with
      two (57.7%), three (43.2%), and three (43.2%) embryos transferred, respectively.
      A DE <35 years with >or=3 embryos transferred had the highest risk for HMP. The
      GR correlated (0.91) with the ES according to the formula: GR = 3.3 + 2.0 ES,
      when ES range was between 4 and 26. Clinic-specific risks for HMP based on age,
      diagnosis, and ES were developed and considered while counseling for ET during
      2004. The clinic-specific HMP risk data made for a reduction in the HMP rate of
      90.9% for DE-IVF (11.8% to 1%) and 53.8% for all IVF (9.1% to 4.2%), without
      decreases in clinical pregnancy or delivery rates. Physicians showing the
      greatest decline (64%) in HMP had no reduction in pregnancy or delivery rates.
      CONCLUSION(S): The use of clinic-specific HMP risk data in counseling based on
      age, diagnosis, and ES provided a 53% to 64% reduction in HMP without affecting
      rates of pregnancy or delivery. The clinic-specific ES system correlated closely
      with good outcomes. A standardized ES system may provide useful information for
      counseling during ET informed consent.

PMID- 15193474
TI  - A controlled trial of natural cycle versus microdose gonadotropin-releasing
      hormone analog flare cycles in poor responders undergoing in vitro fertilization.
AB  - OBJECTIVE: To determine the efficacy of natural-cycle IVF compared with
      controlled ovarian hyperstimulation in poor responders. DESIGN: Randomized,
      controlled study. SETTING: Private center for assisted reproduction. PATIENT(S):
      One hundred twenty-nine women who were poor responders in a previous IVF cycle.
      INTERVENTION(S): Fifty-nine women underwent 114 attempts of natural-cycle IVF,
      and 70 women underwent 101 attempts of IVF with controlled ovarian
      hyperstimulation with microdose GnRH analog flare. MAIN OUTCOME MEASURE(S):
      Number of oocytes retrieved, pregnancy rate (PR) per cycle, PR per transfer, and
      implantation rate. RESULT(S): The poor responders treated with natural-cycle IVF
      and those treated with micro-GnRH analog flare showed similar PRs per cycle and
      per transfer. The women treated with natural-cycle IVF showed a statistically
      significant higher implantation rate (14.9%) compared with controls (5.5%). When
      subdivided into three groups according to age (<or=35 years, >or=36-39 years,
      >or=40 years), younger patients had a better PR than the other two groups.
      CONCLUSION(S): In poor responders, natural-cycle IVF is at least as effective as
      controlled ovarian hyperstimulation, especially in younger patients, with a
      better implantation rate.

PMID- 15193475
TI  - Conclusions about the effects on fertilization of time from aspiration to
      incubation and blood in the aspirate depend on the use of appropriate statistical
      techniques.
AB  - OBJECTIVE: To examine the effects of exposure to blood and time from aspiration
      to incubation on oocyte fertilization. DESIGN: Retrospective, cohort study.
      SETTING: Hospital-based IVF practice. PATIENT(S): Eighty-two women undergoing IVF
      procedures. INTERVENTION(S): Patients received a standard gonadotropin protocol
      or a microdose flare protocol. MAIN OUTCOMES MEASURE(S): Logistic regression was
      used to estimate odds of nonfertilization, adjusting for maternal age, time from
      aspiration to incubation, presence of blood in the aspirate, and a time-by-blood
      interaction. Two statistical methods were used: an analysis that assumed oocytes
      were independent and an analysis that adjusted for the lack of independence of
      oocytes within mothers (i.e., cluster-correlated data). RESULT(S): The 82 women
      contributed 1093 oocytes. In a model with blood dicotomized as present or absent,
      and with time elapsed and maternal age categorized into quartiles, both time and
      maternal age were statistically significant when conventional logistic regression
      was used. In analyses that accounted for clustering within mother, retrieval-to
      incubation times more than 4 minutes were associated with an increased risk of
      nonfertilization, but age and blood were not; there was no evidence of an
      interaction between time elapsed and blood. CONCLUSION(S): If appropriate
      statistics are applied, retrieval-to-incubation times more than 4 minutes are
      associated with increased risk of nonfertilization.

PMID- 15193476
TI  - Premenstrual administration of gonadotropin-releasing hormone antagonist
      coordinates early antral follicle sizes and sets up the basis for an innovative
      concept of controlled ovarian hyperstimulation.
AB  - OBJECTIVE: To investigate whether premenstrual administration of a GnRH
      antagonist coordinates early antral follicle sizes during the subsequent
      follicular phase. DESIGN: Prospective, longitudinal study. SETTING: University
      Hospital in France PATIENT(S): Twenty-five women, 50 cycles. INTERVENTION(S): On
      cycle day 2 (control/day 2), women underwent measurements of early antral
      follicles by ultrasound and serum FSH and ovarian hormones. On day 25, they
      received a single cetrorelix acetate administration, 3 mg. On the subsequent day
      2 (premenstrual GnRH antagonist/day 2), participants were re-evaluated as on
      control/day 2. MAIN OUTCOME MEASURE(S): Magnitude of follicular size
      discrepancies. RESULT(S): Follicular diameters (4.1 +/- 0.9 vs. 5.5 +/- 1.0 mm)
      and follicle-to-follicle size differences decreased on premenstrual GnRH
      antagonist/day 2 as compared with control/day 2. Consistently, FSH (4.5 +/- 1.9
      vs. 6.7 +/- 2.4 mIU/mL), E(2) (23 +/- 13 vs. 46 +/- 26 pg/mL), and inhibin B (52
      +/- 30 vs. 76 +/- 33 pg/mL) were lower on GnRH antagonist/day 2 than on
      control/day 2. CONCLUSION(S): Premenstrual GnRH antagonist administration reduces
      diameters and size disparities of early antral follicles on day 2, likely through
      the prevention of luteal FSH elevation and early follicular development. This
      simple, original approach may be used to coordinate multifollicular development
      in controlled ovarian hyperstimulation.

PMID- 15193478
TI  - Disclosure decisions among known and anonymous oocyte donation recipients.
AB  - OBJECTIVE: The purpose of this study was to compare anonymous and known donor
      mothers' demographics, knowledge about the donor, and disclosure attitudes.
      DESIGN: Cross-sectional survey of oocyte donation parents. SETTING: Academic
      medical centers. PATIENT(S): Women having a child through oocyte donation in the
      past 12 years. INTERVENTION(S): Subjects completed a survey regarding their
      oocyte donation experience. MAIN OUTCOME MEASURE(S): Donor characteristics and
      disclosure behavior. RESULT(S): Questionnaires were sent to 524 individuals (262
      couples); 157 (92 women and 65 men) were returned yielding a response rate of
      31.4% (157/500). The average age of the women was 44.7 years and the average age
      of the child was 2.89 years. Seventy women used anonymous donors and 20 women
      used known donors. Significantly more known recipients knew their donors'
      religion, number of children, hobbies, profession, and photograph. Eighty percent
      of both groups told others about using a donor to conceive. Regarding telling the
      child, there were also no significant differences with approximately 10% who have
      told, 49% plan to tell, 31% are not telling, and 10% are unsure. CONCLUSION(S):
      Contrary to conventional wisdom we found no differences in plans to inform the
      child based on the use of a known or an anonymous donor.

PMID- 15193477
TI  - Low-dose aspirin in a short regimen as standard treatment in in vitro
      fertilization: a randomized, prospective study.
AB  - OBJECTIVE: To determine if treatment with low-dose aspirin in a short regimen
      improves the outcome in a nonselected IVF population as compared with no
      treatment. DESIGN: Prospective, randomized study where IVF patients were given
      aspirin or received no treatment. SETTING: IVF clinic. PATIENT(S): The study
      included 1380 consecutive IVF cycles. INTERVENTION(S): Women undergoing IVF were
      randomly assigned to treatment with aspirin 75 mg daily from the day of embryo
      transfer (ET) until pregnancy test or no treatment in an open study. MAIN OUTCOME
      MEASURE(S): Birth rate per ET. RESULT(S): Background characteristics were similar
      in the two groups studied except for a minor difference in number of embryos
      transferred (2.1 vs. 2.0). Birth rate was 27.2% in the aspirin group as compared
      with 23.2% in the nontreated group, giving an odds ratio, adjusted for number of
      embryos transferred, of 1.2 (95% confidence interval, 1.0-1.6). CONCLUSION(S):
      The increased birth rate with aspirin compared with no treatment was significant.
      Given the importance of every birth in IVF, especially when taking into account
      the limited number of IVF cycles that are normally performed in an individual
      woman, any treatment to improve birth rate is important.

PMID- 15193479
TI  - A novel protocol of ovulation induction with delayed gonadotropin-releasing
      hormone antagonist administration combined with high-dose recombinant follicle
      stimulating hormone and clomiphene citrate for poor responders and women over 35
      years.
AB  - OBJECTIVE: To evaluate the efficacy of a novel protocol of ovulation induction
      for poor responders. DESIGN: Prospective, controlled, clinical study. SETTING:
      Research institute's reproductive unit. PATIENT(S): One hundred forty-five
      infertile women, aged 27-39 years, candidates for assisted reproductive
      techniques (ART). INTERVENTION(S): Before undergoing ART, 85 patients received
      clomiphene citrate, high-dose recombinant human FSH, and a delayed, multidose
      GnRH antagonist, whereas 60 patients underwent a standard long protocol. MAIN
      OUTCOME MEASURE(S): Estradiol levels (pg/mL), cancellation rate, oocyte
      retrieval, embryo score, and fertilization and pregnancy rates. RESULT(S):
      Patients undergoing the study protocol obtained lower cancellation rates (4.7%
      vs. 34%) and higher E(2) levels (945.88 +/- 173.2 pg/mL vs. 169.55 +/- 45.07
      pg/mL), oocyte retrieval (5.56 +/- 1.13 vs. 3.36 +/- 1.3), and pregnancy (22.2%
      vs. 15.3%) and implantation rates (13.5% vs. 7.6%) compared with those receiving
      the long protocol. Age negatively correlated with ovarian response in the latter,
      whereas the ovarian outcome results were comparable in younger (<35 yrs) and
      older (>35 yrs) women treated with the study protocol. CONCLUSION(S): The
      proposed protocol of ovulation induction can be usefully administered in poor
      responders as well as in aged woman, probably because the delayed administration
      of GnRH antagonist prevents its adverse effects on ovarian paracrine activity and
      on oocyte maturation.

PMID- 15193480
TI  - A placebo-controlled double-blind randomized trial of the use of combined l
      carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia.
AB  - OBJECTIVE: To determine the efficacy of combined l-carnitine and l-acetyl
      carnitine therapy in infertile males with oligo-astheno-teratozoospermia. DESIGN:
      Placebo-controlled double-blind randomized trial. SETTING: University tertiary
      referral center. PATIENT(S): Sixty infertile patients (aged 20-40 years) with the
      following baseline sperm selection criteria: concentration, 10 to 40 x 10(6)/mL;
      forward motility, <15%; total motility, 10% to 40%; and atypical forms, <80%.
      Fifty-six patients completed the study. INTERVENTION(S): Patients were submitted
      to a combined treatment of l-carnitine (2 g/d) and l-acetyl-carnitine (1 g/d) or
      of placebo; the study design was 2 months' wash-out, 6 months of therapy or of
      placebo, and 2 months' follow-up. MAIN OUTCOME MEASURE(S): Variation in the semen
      parameters that were used for patient selection. RESULT(S): Even though increases
      were seen in all sperm parameters after combined carnitine treatment, the most
      significant improvement in sperm motility (both forward and total) was present in
      patients who had lower initial absolute values of motile sperm (<4 x 10(6)
      forward or <5 x 10(6) total motile spermatozoa per ejaculate). CONCLUSION(S):
      Combined treatment with l-carnitine and l-acetyl-carnitine in a controlled study
      of efficacy was effective in increasing sperm motility, especially in groups with
      lower baseline levels.

PMID- 15193481
TI  - Role of varicocelectomy in men with nonobstructive azoospermia.
AB  - OBJECTIVE: To evaluate the benefits of varicocelectomy in men with nonobstructive
      azoospermia. DESIGN: Retrospective review of effect of prior varicocelectomy on
      sperm retrieval rates in men with nonobstructive azoospermia. Chart review of men
      with nonobstructive azoospermia who underwent microsurgical varicocelectomy to
      determine the effect of the procedure on the need for testicular sperm extraction
      (TESE). SETTING: Tertiary, university-based referral center. PATIENT(S): Men with
      clinical varicoceles and nonobstructive azoospermia. INTERVENTION(S):
      Microsurgical varicocelectomy, TESE. MAIN OUTCOME MEASURE(S): Return of sperm to
      the ejaculate and need for TESE after varicocele repair, ability to find sperm
      using microdissection TESE. RESULT(S): Of 31 men who underwent varicocele repair
      at one institution for documented nonobstructive azoospermia, 7/31 (22%) had
      sperm reported on at least one semen analysis postoperatively. However, only 3/31
      (9.6%) men after varicocele repair had adequate motile sperm in the ejaculate for
      ICSI, without TESE. Sperm retrieval rates for men with varicoceles were not
      affected by a history of prior varicocelectomy. CONCLUSION(S): Men with clinical
      varicoceles that are associated with nonobstructive azoospermia will rarely have
      adequate sperm in the ejaculate after varicocele repair to avoid TESE. A history
      of prior varicocele repair does not appear to affect the chance of sperm
      retrieval by TESE for men with clinical varicoceles and nonobstructive
      azoospermia. The benefits of varicocelectomy in men with nonobstructive
      azoospermia may be less than previously reported.

PMID- 15193482
TI  - Sperm function in workers exposed to N,N-dimethylformamide in the synthetic
      leather industry.
AB  - OBJECTIVE: To determine whether occupational exposure to N,N-dimethylformamide
      (DMF) for men has adverse effects on sperm function. DESIGN: Cross-sectional
      study. SETTING: A synthetic leather factory in Taiwan. PATIENT(S): Twelve DMF
      exposed workers in a synthetic leather factory and 8 socioeconomically matched
      control workers from another non-DMF-exposed manufacturing plant in the vicinity
      were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Breathing-zone
      monitoring of DMF exposure covering the full work shift was implemented on each
      participant. Urine specimens were collected from each worker immediately after
      their work shift in parallel with environmental sampling. Environmental DMF and
      urinary N-methylformamide (NMF) levels were measured by gas chromatograph.
      Analysis of semen samples was performed to measure semen volume, sperm
      concentration, morphology, and motility in accordance with World Health
      Organization criteria. RESULT(S): Both conventional microscopy and computer
      assisted semen analysis showed that sperm motility in DMF-exposed group was
      significantly reduced from that in controls. Motility parameters were related to
      urinary NMF in a dose-response manner but were not related to airborne DMF.
      CONCLUSION(S): Workers occupationally exposed to DMF could be at risk of sperm
      motility perturbation. The responsible toxicant for the alterations of sperm
      function could be the active NMF metabolite instead of DMF, but this conclusion
      warrants a further complete investigation.

PMID- 15193483
TI  - Stereological analysis of the human testis after vasectomy indicates impairment
      of spermatogenic efficiency with increasing obstructive interval.
AB  - OBJECTIVE: To quantify germ cell loss and the extent of testicular fibrosis in
      vasectomized patients of varying obstructive intervals. DESIGN: Retrospective
      study. SETTING: Specialized male reproductive surgery and endocrinology service.
      PATIENT(S): Thirty-four vasectomized patients 1-20 years after surgery and 10
      normal subjects. INTERVENTION(S): Thirty-four testicular biopsies taken at the
      time of vasectomy reversal (vasovasostomy). Control biopsies taken from 10 normal
      men at the time of vasectomy. MAIN OUTCOME MEASURE(S): Stereological assessment
      of testicular germ cell populations and testicular fibrosis. RESULT(S): Vasectomy
      caused a significant decrease in germ cells in the later stages of
      spermatogenesis, with significant reductions in pachytene spermatocytes (by 18%),
      round spermatids (by 40%), elongating spermatids (by 23%), and elongated
      spermatids (by 39%). The loss of spermatids showed a significant relationship
      with obstructive interval. A significant 2.7-fold increase in total (peritubular
      plus interstitial) fibrosis was observed, which showed a positive relationship
      with obstructive interval. Decreased germ cell populations and fibrosis did not
      seem to be related to sperm antibody levels nor to sperm counts obtained up to 2
      years after vasovasostomy. CONCLUSION(S): Vasal obstruction results in
      significant reductions in germ cells in the later stages of spermatogenesis and
      increases in testicular fibrosis, both worsening with an increasing obstructive
      interval. Testicular damage after vasectomy might impact upon the prospects for
      reversal.

PMID- 15193484
TI  - Pregnancy course and outcome after intracytoplasmic sperm injection: a
      controlled, prospective cohort study.
AB  - OBJECTIVE: To determine pregnancy course and major malformation rate after
      intracytoplasmic sperm injection (ICSI). DESIGN: Prospective, controlled,
      multicenter, nationwide German cohort study. SETTING: Tertiary infertility
      centers in Germany. PATIENT(S): Three thousand three hundred seventy-two children
      and fetuses and 8,016 children and fetuses after the 16th week of gestation in
      pregnancies after ICSI and natural conception, respectively. INTERVENTION(S):
      Standardized prospective follow-up. MAIN OUTCOME MEASURE(S): Major malformation
      rate. RESULT(S): The major malformation rate was 8.7% (295/3,372) for the ICSI
      cohort and 6.1% (488/8,016) for the population-based control cohort (relative
      risk, 1.44 [1.25-1.65]). After adjustment for risk factors, the risk declined
      (adjusted odds ratio, 1.24 [95% CI, 1.02-1.50]). Regarding singletons, there was
      a significant difference for birth weight and gestational age, with a higher
      number of preterm and low birth weight children in pregnancies achieved after
      ICSI. CONCLUSION(S): Children who are born after intracytoplasmic sperm injection
      have an increased risk of a major congenital malformation compared with those
      born after spontaneous conception. This risk is mainly due to paternal and
      maternal risk factors, which are more prevalent in couples who use ICSI for
      reproduction. An infertility-linked risk is highly probable for the observed
      findings. A technique-related risk, however, cannot be ruled out.

PMID- 15193485
TI  - Mammographic breast density, hormones, and growth factors during continuous
      combined hormone therapy.
AB  - OBJECTIVE: To study the effect on mammographic breast density of two different
      continuous combined regimens for hormone therapy. DESIGN: Randomized clinical
      study. SETTING: University hospital. PATIENT(S): Postmenopausal women without any
      previous history of breast disorder. INTERVENTION(S): The women received either
      estradiol valerate/dienogest or estradiol/norethisterone acetate. Mammograms and
      venous blood samples were obtained at baseline and after 6 months. MAIN OUTCOME
      MEASURE(S): Change in mammographic breast density. Correlations with levels of
      hormones, growth factors, and binding proteins. RESULT(S): An increase in
      mammographic density was recorded in approximately 50% of the women, and there
      were no differences between treatments. Increased density showed a positive
      correlation with estradiol, estrone, and sex hormone-binding globulin and showed
      a negative association to free T. Among hormonal factors, levels of free T were
      the most important for predicting increased density. CONCLUSION(S): Continuous
      combined hormone therapy with different progestogens has a marked impact on the
      breast.

PMID- 15193487
TI  - Endometrial evaluation with transvaginal ultrasound during hormone therapy: a
      prospective multicenter study.
AB  - OBJECTIVE: To assess the value of endometrial thickness as a marker of
      endometrial abnormality risk during hormone therapy (HT) and to study the
      correlation between abnormal bleeding and abnormal endometrial histology in
      patients with thick endometrium. DESIGN: Prospective multicenter study. SETTING:
      University and general hospitals outpatient centers. PATIENT(S): Postmenopausal
      women (702) on HT. INTERVENTION(S): Biendometrial thickness was measured by
      transvaginal sonography (TVS) between day 5 and day 10 after the last P intake
      and, when present, after the end of the menstrual-like bleeding. MAIN OUTCOME
      MEASURE(S): Hysteroscopy and biopsy were performed within 5 days from TVS on all
      patients with an endometrial thickness >4.5 mm (precision scale 0.5 mm).
      RESULT(S): Endometrial thickness >4.5 mm was observed in 20.5% of patients. One
      hundred sixteen hysteroscopies and biopsies were performed. Hyperplasia, polyps,
      and endocavitary fibroids were detected in 15%, 24%, and 8% of cases,
      respectively. The positive predictive value of TVS examination was 47%.
      Endometrial thickness was the only variable significantly and independently
      associated with histologic abnormalities and endocavitary fibroids. Abnormal
      bleeding occurred in 17.1% of patients. Among 17 patients detected with thick
      endometrium and hyperplasia, 8 cases showed abnormal bleeding. CONCLUSION(S):
      Sonographic endometrial thickness of 4.5 mm provides a sensitive tool to select
      HT patients who might benefit from hysteroscopy and biopsy. Abnormal bleeding is
      not a sensitive sign of hyperplasia in patients with thick endometrium.

PMID- 15193486
TI  - Effect of tibolone on markers of cardiovascular disease risk in postmenopausal
      women undergoing hemodialysis: a pilot study.
AB  - OBJECTIVE: To assess the effect of tibolone on markers of vascular risk in
      postmenopausal women who were receiving hemodialysis. DESIGN: One-year open-label
      study. SETTING: "Zvezdara" University Medical Center, Belgrade, Serbia.
      PATIENT(S): Twenty-eight postmenopausal women undergoing chronic hemodialysis.
      INTERVENTION(S): Fifteen women received tibolone 2.5 mg three times per week; 13
      other women served as controls. MAIN OUTCOME MEASURE(S): Mean arterial pressure
      and weight were measured at baseline and at 6 and 12 months, and blood was
      collected for insulin, total cholesterol, low-density lipoprotein, high-density
      lipoprotein, triglycerides, lipoprotein(a), high-sensitivity C-reactive protein
      (hs-CRP), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and
      markers of renal function. RESULT(S): Mean arterial pressure fell in the tibolone
      but not in the control group at 6 and 12 months versus baseline (mean [SD]: 93
      [15] vs. 105 [11] mmHg and 94 [10] vs. 105 [11] mmHg, respectively). Weight,
      insulin, lipids, lipoprotein(a), hs-CRP, ET-1, VEGF, and renal function remained
      unchanged within each group, but high-density lipoprotein concentrations fell in
      the tibolone group after 12 months (1.2 [0.3] vs. 1.6 [0.6] mmol/L).
      CONCLUSION(S): The effects of tibolone on markers of vascular risk in
      postmenopausal women who are receiving hemodialysis and healthy women appear to
      differ. This should be taken into account when tailoring menopausal therapies to
      the specific requirements of each individual.

PMID- 15193488
TI  - A common interleukin-6 gene promoter polymorphism influences the clinical
      characteristics of women with polycystic ovary syndrome.
AB  - OBJECTIVE: To investigate the association of a common polymorphism of the
      interleukin-6 gene (IL6) promoter with the occurence and the clinical
      characteristics of polycystic ovary syndrome (PCOS). DESIGN: Prospective, case
      control study. SETTING: Academic research institution. PATIENT(S): Sixty-two
      patients with PCOS and 94 healthy controls. INTERVENTION(S): Peripheral venous
      puncture, ultrasonography, oral glucose tolerance test (OGTT), questionnaire.
      MAIN OUTCOME MEASURE(S): Genotype analysis with respect to the common -174 G/C
      polymorphism of the IL6 gene promoter, analysis of testosterone (T),
      androstendione, and sex hormone binding globulin serum levels, and evaluation of
      the OGTT. RESULT(S): Allele frequencies among women with PCOS and controls were
      62.9% and 64.4%, respectively, for the wild-type G allele, and 37.1% and 35.6%,
      respectively, for the mutant C allele. We ascertained a significant association
      between presence of at least one mutant C allele and the clinical characteristics
      of affected women: these women were more likely to present with a body mass index
      >27 kg/m(2), elevated total T serum levels, and a pathological OGTT result.
      CONCLUSION(S): A common polymorphism of the IL6 promoter, although not associated
      with the presence of PCOS, is associated with the clinical characteristics of
      women affected by this condition.

PMID- 15193489
TI  - Differential diagnosis of suspected cervical pregnancy and conservative treatment
      with the combination of laparoscopy-assisted uterine artery ligation and
      hysteroscopic endocervical resection.
AB  - OBJECTIVE: To determine the accuracy of differential diagnosis by team
      consultation of abortion in progression, low-lying implantation/cervicoisthmic
      pregnancy, and cervical pregnancy (CP) in patients referred for suspicion of
      abnormal implantation on the lower segment and cervix of the uterus and to
      determine the efficacy of endoscopic surgery with uterine artery blockade
      followed by cervical evacuation in the treatment of confirmed CP. DESIGN:
      Prospective observational study under multiple-clinic and multiple-hospital
      cooperation. SETTING: Tertiary clinical and academic medical center. PATIENT(S):
      Twenty-seven women with a tentative diagnosis of CP made at their primary
      gynecologists' offices from July 1999 to June 2003. INTERVENTION(S): Second
      opinion ultrasound scanning with transabdominal and transvaginal approach and
      optional color Doppler use. For patients with confirmed CP, a new treatment
      modality with laparoscopy-assisted uterine artery ligation followed by
      hysteroscopic local endocervical resection to remove the ectopic pregnancy was
      employed. For patients with abortion in progression or low-lying
      implantation/cervicoisthmic pregnancy (non-CP) requiring termination, dilatation
      and curettage (D&C) was performed under transabdominal ultrasound guidance. MAIN
      OUTCOME MEASURE(S): Fulfillment of ultrasound-based diagnostic criteria and
      operative course, convalescence, and commencement of menstruation in those
      patients with confirmed CP. RESULT(S): Cervical pregnancy was diagnosed in six
      (22.2%) patients at <or=9-weeks' gestation, and they were all successfully
      treated without the need for adjuvant therapy. The mean operating time was 119
      minutes, and the mean blood loss was 125 mL. Menstruation began a mean of 63 days
      after the treatment. Termination of non-CPs was achieved by a simple D&C.
      CONCLUSION(S): Team consultation minimizes false-positive ultrasound-based
      diagnosis of CP. A single-step combination endoscopic operation is an effective
      uterus-preserving alternative in the management of CP.

PMID- 15193490
TI  - Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha
      gene affect the risk of developing endometriosis in a Japanese population.
AB  - OBJECTIVE: To determine whether polymorphisms in the estrogen receptor (ER) alpha
      and beta genes are associated with endometriosis in a Japanese population.
      DESIGN: Association study. SETTING: University hospital. PATIENT(S): Japanese
      women diagnosed with endometriosis by laparotomy or laparoscopy. INTERVENTION(S):
      Determination of polymorphisms in the ERalpha and ERbeta genes was performed by
      polymerase chain reaction restriction fragment-length polymorphism analysis in
      132 affected women and 182 controls. MAIN OUTCOME MEASURE(S): Frequency and
      distribution of AluI and RsaI polymorphisms in ERbeta gene and of PvuII and XbaI
      polymorphisms in ERalpha gene. RESULT(S): No significant differences in the
      frequency of either AluI and RsaI polymorphisms in the ERbeta gene or of XbaI and
      PvuII polymorphisms in the ERalpha gene were found between endometriosis patients
      and controls. However, a positive association was noted between the AluI
      polymorphism in the ERbeta gene and stage IV endometriosis patients in the
      population studied. CONCLUSION(S): The AluI polymorphism in the ERbeta gene is
      associated with an increased risk of stage IV endometriosis in a Japanese
      population.

PMID- 15193491
TI  - Effect of Tisseel on expression of tissue plasminogen activator and plasminogen
      activator inhibitor-1.
AB  - OBJECTIVE: To examine the effect of fibrin sealant on mRNA expression of factors
      regulating plasminogen activator activity in human peritoneal cells. Plasminogen
      activator activity is thought to play a pivotal role in degradation of the
      proteinaceous mass that develops after surgical procedures. Reduction of
      plasminogen activator activity, as occurs with tissue trauma, results in
      increased postoperative adhesion development. DESIGN: Tissue culture for 6, 12,
      24, and 48 hours. SETTING: University research laboratory. PATIENTS: Source of
      mesothelial cells with fibroblasts. INTERVENTION(S): Measurement of mRNA
      expression of tissue plasminogen activator (t-PA) and plasminogen activator
      inhibitor 1 (PAI-1). MAIN OUTCOME MEASURE(S): Multiplex reverse
      transcriptase/polymerase chain reaction (RT/PCR) was used to determine relative
      change in t-PA and PAI-1 mRNA levels under six conditions: [1]. fibrin sealant
      (Tisseel); [2]. fibrin sealant (Tisseel) two components diluted 1:2; [3]. fibrin
      sealant (Tisseel) sealer protein component reconstituted without aprotinin (a
      protease inhibitor); [4]. fibrin sealant (Tisseel) sealer protein component
      reconstituted without aprotinin, both components diluted 1:2; [5]. fibrin sealant
      (Tisseel) components diluted to physiologic concentrations; and [6] control
      (culture media). RESULTS: The mRNA levels of t-PA and PAI-1 by human peritoneal
      cells were unchanged during 48 hours. In mesothelial cells, the addition of the
      compositions increased t-PA mRNA levels. A selective increase was observed in the
      normal peritoneal fibroblasts at the later time points; similar increases were
      identified in adhesion fibroblast cultures. In mesothelial cells, the more
      concentrated compositions generally increased PAI-1 mRNA above control levels,
      whereas in normal peritoneal fibroblasts PAI-1 levels generally remained
      unchanged. In contrast, in adhesion fibroblasts, PAI-1 levels decreased over time
      with treatment. CONCLUSION(S): Fibrin sealant, in the presence and absence of
      aprotinin, increases both t-PA and PAI-1 expression by human peritoneal cells;
      changes not seen with physiologic concentrations of fibrin sealant. These
      observations suggest that in addition to its ability to help achieve hemostasis,
      fibrin sealant affects the healing process by altering components of the
      plasminogen activator system, which may be of benefit in the reduction of
      postoperative adhesions.

PMID- 15193492
TI  - Gene transfections with p53 and p21 inhibit cell proliferation, collagen type I,
      leukemia inhibitory factor, and tumor necrosis factor-alpha expression in
      leiomyoma cells.
AB  - OBJECTIVE: To transfect the p53 and p21 gene into the leiomyoma cells isolated
      from patients and observe their influence on the cell proliferation, leukemia
      inhibitory factor production, and gene expression of collagen type I as well as
      tumor necrosis factor-alpha (TNF-alpha) of cultured cells. DESIGN: Prospective
      study. SETTING: An assisted reproductive technology (ART) and genetic unit of a
      medical center. PATIENT(S): Leiomyoma cells isolated from leiomyoma tissue of 12
      patients were divided into three groups: [1]. vehicle DNA, [2]. p53 gene, and
      [3]. p21 gene transfections. INTERVENTION(S): The pcDNA3.1 was used as vector to
      carry p53 and p21 genes for transfer. After gene transfection, RNAs of the
      leiomyoma cells were extracted for further analyses of gene expression. MAIN
      OUTCOME MEASURE(S): Relative cell numbers were determined by 3-(4,5
      dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay. The leukemia
      inhibitory factor (LIF) concentration was determined with ELISA. Gene expressions
      of collagen type I and TNF-alpha were detected by reverse transcriptase
      polymerase chain reaction (RT-PCR). Gene expression of glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) was used as an internal control. The cell proliferation,
      LIF production, as well as gene expressions of collagen type I and TNF-alpha in
      each group were compared. RESULTS: Relative cell numbers (%)/LIF production (in
      picograms per milliliter) in each group were: [1]. 100/58, [2]. 71/43, and [3].
      106/65. The ratios of gene expression of collagen type I/TNF-alpha with GAPDH in
      each group were: [1]. 1.64/0.335, [2]. 1.25/0.434, and [3]. 1.77/0.234.
      CONCLUSION(S): Transfection with p53 significantly inhibits proliferation of
      leiomyoma cells and decreases collagen type I gene expression and LIF production.
      The p21 transfection inhibits TNF-alpha gene expression.

PMID- 15193493
TI  - Intraoperative ultrasound during a laparoscopic myomectomy.
AB  - OBJECTIVE: To report a gynecologic use of a laparoscopic ultrasound transducer to
      isolate a myoma for surgical removal. DESIGN: Case report. SETTING: University
      based infertility practice. PATIENT(S): A 44-year-old woman gravida 1 para 1 with
      history of a first trimester miscarriage who desired pregnancy as a participant
      in the donor egg program. INTERVENTION(S): Before she entered the assisted
      reproduction program, a patient was found to have a myoma that was greater than 2
      cm with both intramural and submucosal components. During the laparoscopic
      evaluation, a laparoscopic ultrasound transducer helped identify and properly
      locate the myoma in what otherwise appeared to be a normal uterus. Appropriate
      laparoscopic hysterotomy incision was then made, thereby minimizing uterine
      trauma. MAIN OUTCOME MEASURE(S): Appropriately placed hysterotomy incision and
      successful reconstruction of uterus. RESULT(S): After the successful laparoscopic
      myomectomy, the patient achieved a pregnancy in our donor oocyte program.
      CONCLUSION(S): Laparoscopic intraoperative ultrasound can help gynecologic
      surgeons complete a laparoscopic myomectomy.

PMID- 15193494
TI  - Reproductive outcome after hysteroscopic metroplasty in women with septate uterus
      and otherwise unexplained infertility.
AB  - OBJECTIVE: To evaluate the reproductive outcome of hysteroscopic metroplasty
      performed in women with septate uterus and otherwise unexplained primary
      infertility. DESIGN: Prospective, observational study. SETTING: Tertiary center
      for reproductive medicine. PATIENT(S): Sixty-one patients with uterine septa and
      otherwise unexplained primary infertility. INTERVENTION(S): Hysteroscopic
      division of the uterine septum. MAIN OUTCOME MEASURE(S): Reproductive outcome
      after hysteroscopic metroplasty. RESULT(S): Of 61 women, 25 (41%) conceived
      within 8-14 (mean 11.2) months after hysteroscopic metroplasty. Of these, 18
      (29.5% of the total group) had live births (13 carried to term and 5 had preterm
      deliveries), and 7 (11.5% of the total group) had spontaneous abortions. Cervical
      cerclage was performed in 9 women; only 1 (11.1%) of these patients and 4 (44.4%)
      of the 9 who did not have a cerclage had preterm deliveries. Twelve of the 18
      women (66.6%) who had live births were delivered by cesarean section.
      CONCLUSION(S): Women with uterine septum and otherwise unexplained infertility
      might benefit from hysteroscopic metroplasty.

PMID- 15193495
TI  - Influence of varicocele embolization on the choice of infertility treatment.
AB  - OBJECTIVE: To investigate whether embolization of a varicocele improves semen
      quality and enables use of less-invasive modes of assisted reproductive
      technology (ART) in infertile men with a physically palpable varicocele confirmed
      by phlebography. DESIGN: Retrospective chart review. SETTING: University
      infertility clinic. PATIENT(S): Fifty patients with varicoceles that were treated
      with embolization and 11 patients with untreated varicoceles (control group). In
      both groups the clinical varicoceles had been phlebographically confirmed.
      INTERVENTION(S): Phlebography and embolization. MAIN OUTCOME MEASURE(S): Semen
      characteristics and mode of ART before and after treatment. RESULT(S): Median
      improvements of semen parameters, such as concentration and motility after
      processing, were significantly greater in the embolization group than in the
      untreated group. In the embolization group, semen samples improved to levels
      requiring less-invasive modes of ART in significantly more patients than in the
      untreated group. Deterioration of semen samples, requiring more invasive
      techniques, was significantly more frequent in the untreated group than in the
      embolization group. CONCLUSION(S): Embolization of a varicocele in infertile men
      significantly improved semen, such that much more often a less-invasive form of
      ART than was planned before treatment became feasible. Embolization of a
      varicocele might even prevent further deterioration of semen samples to levels
      requiring more-invasive ART.

PMID- 15193496
TI  - Use of assisted reproductive technologies and anesthesia in a patient with
      primary pulmonary hypertension.
AB  - OBJECTIVE: To report the use of assisted reproductive technologies (ART) in a
      patient with primary pulmonary hypertension. DESIGN: Case report. SETTING:
      University medical center. PATIENT(S): A 28-year-old nulliparous woman with
      primary pulmonary hypertension (PPH) treated with continuous intravenous
      epoprostenol. INTERVENTION(S): Ovarian stimulation, egg retrieval, general
      anesthesia, and pregnancy by surrogate carrier. MAIN OUTCOME MEASURE(S):
      Successful ART cycle(s) in patient with PPH and successful gestational carrier
      pregnancy. RESULT(S): Successful pregnancy by surrogate gestational carrier.
      CONCLUSION(S): Assisted reproductive technologies and a surrogate gestational
      carrier were a successful reproductive option for a patient with primary
      pulmonary hypertension. Ovarian stimulation, oocyte retrieval, and general
      anesthesia are not without risk but were well tolerated in this case.
      Multidisciplinary involvement in the planning and administration of such
      procedures is necessary for optimal outcomes in these patients.

PMID- 15193497
TI  - Sperm tail agenesis in a case of consanguinity.
AB  - OBJECTIVE: To report a case of 100% teratozoospermia in a patient whose family
      history presented a high degree of consanguinity. DESIGN: Case report. SETTING:
      University-based andrology clinic. PATIENT(S): A 27-year-old man undergoing
      infertility evaluation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum
      hormone analysis, standard (World Health Organization) semen quality evaluation,
      sperm ultrastructure, lymphocytic karyotype, and polymerase chain reaction
      screening for Y chromosome microdeletions in peripheral blood. RESULT(S): One
      hundred percent teratozoospermia characterized by shape alterations of the heads
      and tail agenesis on standard morphology evaluation, which was confirmed using
      electron microscopy. CONCLUSION(S): A case of familial infertility in a
      consanguineous patient characterized by morphological abnormalities of
      spermatozoa such as tail agenesis, chromatin subcondensation, and residual
      cytoplasmic droplets.

PMID- 15193498
TI  - Infertility from female circumcision.
AB  - OBJECTIVE: To present a case report of a patient with primary infertility from
      female circumcision, the management of the patient, and a review of the
      literature. DESIGN: Case report and literature review. SETTING: University
      hospital. PATIENT(S): A 31-year-old woman referred for a history of primary
      infertility. INTERVENTION(S): Complete history and physical exam of the patient
      and subsequent deinfibulation. MAIN OUTCOME MEASURE(S): Diagnosis, surgical
      management, and postoperative sexual function and pregnancy. RESULT(S):
      Resolution of dyspareunia, satisfactory postoperative sexual function, and
      pregnancy. CONCLUSION(S): Awareness of this type of female circumcision and
      familiarity with its surgical management may prevent delays and any subsequent
      complications.

PMID- 15193499
TI  - Vaginal perforation during transvaginal ultrasound-guided follicle aspiration in
      a woman undergoing multiple cycles of assisted reproduction.
AB  - OBJECTIVE: To report a case of vaginal perforation during transvaginal ultrasound
      guided follicle aspiration. DESIGN: Case report. SETTING: A university hospital.
      PATIENT(S): A 41-year-old woman who had undergone transvaginal ultrasound-guided
      follicle aspiration five times previously for IVF-embryo transfer.
      INTERVENTION(S): Retrospective evaluation of past medical history and surgical
      treatment. MAIN OUTCOME MEASURE(S): Medical follow-up after surgical repair of
      the perforation. RESULT(S): Simple vaginal perforation with no damage to the
      gastrointestinal or genitourinary systems can be repaired at the time of
      perforation through the vagina. CONCLUSION(S): Perforation of the vagina is a
      possible complication of transvaginal ultrasound-guided follicle aspiration in
      older patients with a history of repeated transvaginal aspiration of follicles,
      particularly when the ovaries are difficult to visualize.

PMID- 15193500
TI  - Elective single blastocyst transfer.
AB  - This report describes our initial experience with elective single blastocyst
      transfer in 19 patients who had a mean age of 36.3 +/- 2.4 years. The ongoing
      pregnancy rate, 53% after the fresh embryo transfer and 68% when thaw cycles are
      included, suggests that single blastocyst transfer has a place in this relatively
      older patient population.

PMID- 15193501
TI  - Influence of the Women's Health Initiative trial on the practice of prophylactic
      oophorectomy and the prescription of estrogen therapy.
AB  - Physicians have become more conservative regarding prophylactic oophorectomy
      after publication of the Women's Health Initiative trial. They are less likely to
      prescribe estrogen therapy for women who have a high risk of coronary heart
      disease and more likely to use nonoral routes for estrogen therapy.

PMID- 15193503
TI  - Effect of tumor necrosis factor-alpha blocker (infliximab) on blastocyst
      development in vitro.
AB  - Infliximab does not have any toxic effects on early cleaving embryos.

PMID- 15193502
TI  - Assisted hatching is associated with a higher ectopic pregnancy rate.
AB  - In a retrospective analysis of 623 clinical pregnancies conceived after IVF, a
      5.4% ectopic pregnancy rate (14/258 clinical pregnancies) was found in cases
      where assisted hatching (AH) was performed compared to 2.2% (8/365) in the group
      without assisted hatching. In view of the widespread use of AH, it may be
      relevant to assess the effect of AH on the incidence of ectopic pregnancy in a
      large multicenter effort.

PMID- 15193504
TI  - Serum estradiol positively predicts outcomes in patients undergoing in vitro
      fertilization.
AB  - In patients undergoing in vitro fertilization, the presence of higher E(2) levels
      at the time of hCG administration predict a greater likelihood of ongoing
      pregnancy.

PMID- 15193505
TI  - Overweight infertile patients have a higher fecundity than normal-weight women
      undergoing controlled ovarian hyperstimulation with intrauterine insemination.
AB  - There is a positive effect of being overweight or obese on the pregnancy rate in
      women undergoing controlled ovarian hyperstimulation with intrauterine
      insemination.

PMID- 15193506
TI  - Effect of androgen levels on in vitro fertilization cycles.
AB  - Serum androgens have a negative correlation with some IVF stimulation parameters.
      Day 3 T levels <or=20 ng/dL are associated with poor IVF success rates.

PMID- 15193508
TI  - The glitter of the correlation coefficient.

PMID- 15193509
TI  - The glitter of the correlation coefficient.

PMID- 15193510
TI  - An appropriate endpoint--cumulative live birth rate (CLBR).

PMID- 15193512
TI  - Does raloxifene inhibit the growth of uterine fibroids?

PMID- 15193514
TI  - Sigmoid colpoplasty for vaginal agenesis.

PMID- 15193516
TI  - Potential cofounders in the laparoscopic detection of endometriosis.

PMID- 15193518
TI  - "Backwalling" is not good for the embryo.

PMID- 15193520
TI  - Efficacy of postcoital contraception.

PMID- 15193522
TI  - Spontaneous and induced aberrant sprouting at the site of injury is irrelevant to
      motor function outcome in rats with spinal cord injury.
AB  - In the absence of effective regeneration following spinal cord (SC) injury,
      sprouting from undamaged axons has been regarded as an underlying factor for
      functional improvement after incomplete SC injury. The influence of spontaneous
      and induced axonal sprouting at the injury site on motor function was tested
      using rats subjected to moderate SC contusion at T9 level, using megadoses of
      methylprednisolone (MP) and intralesion implantation of cells from sciatic nerve
      (PNI). Groups using MP and PNI combined, implant vehicle, and injury with no
      treatment were also included. Amount of sprouting at the injury sites was
      significantly different depending on treatment. It was abundant in PNI-treated
      rats, moderate in rats treated with vehicle or nontreated, and limited in rats
      given MP with or without PNI (chi2, p=0.0084). This sprouting showed an aberrant
      course and was located in proliferating tissue at the site of injury,
      characterized by the presence of ependymal cells, macrophages, and myelinating
      and nonmyelinating Schwann cells. Functional scores and amount of spared white
      matter were not significantly different among groups. Correlation of the amount
      of sprouting vs. functional outcome or vs. amount of spared tissue was not
      significant, while correlation of functional outcome vs. amount of spared tissue
      was significant (p<0.0001). In conclusion, PNI increase aberrant sprouting at the
      injury site, while MP limits such sprouting, in either case without impact on
      motor function outcome. Missing guiding channels for sprouting axons could
      explain the absence of any functional improvement.

PMID- 15193523
TI  - Ciliary neurotrophic factor and its receptors are differentially expressed in the
      optic nerve transected adult rat retina.
AB  - Ciliary neurotrophic factor (CNTF) has been implicated in the survival and
      regeneration of adult rat retinal ganglion cells (RGCs). Expression of CNTF and
      its receptors, ciliary neurotrophic factor receptor alpha (CNTFRalpha) and
      leukemia inhibitory factor receptor (LIFR) was studied in normal, 6-h, 1-, and 3
      day optic nerve transected retinas. Optic nerve transection was performed on the
      right eye in one group. In the other group, it was performed 5 days after
      intratectal Fluorogold injection. Retinas were studied using immunohistochemical
      labeling and Western blot analysis. Astrocytes were labeled with GFAP and Muller
      cells with glutamine synthetase. CNTF was observed in identifiable astrocytes and
      Muller cells, and its intensity increased in the experimental retinas. CNTFRalpha
      was localized on RGCs in experimental retinas. LIFR was localized on RGCs and
      Muller cells in normal and experimental retinas. CNTF and its receptors are
      differentially expressed after optic nerve transection and could help delay RGC
      death in such a stressful environment.

PMID- 15193524
TI  - L-type Ca2+ channel antagonists block voltage-dependent Ca2+ channels in
      identified leech neurons.
AB  - We investigated the effect of L-type Ca2+ channel antagonists on the Ca2+ influx
      through voltage-gated Ca2+ channels in leech Retzius, Leydig, AP, AE, P, and N
      neurons. The efficacy of the antagonists was quantified by monitoring their
      effect on the increase in the intracellular free Ca2+ concentration ([Ca2+]i;
      measured by Fura-2) that was induced by depolarizing the cell membrane by raising
      the extracellular K+ concentration. This K+-induced [Ca2+]i increase was blocked
      by the phenylalkylamines verapamil, gallopamil, and devapamil, the
      benzothiazepine diltiazem, as well as by the 1,4-dihydropyridine nifedipine. The
      blocking effect of the three phenylalkylamines was similar, being most pronounced
      in P and N neurons and smaller in Leydig, Retzius, AP, and AE neurons.
      Contrastingly, diltiazem and nifedipine were similarly effective in the neurons
      investigated, whereby their efficacy was like that of the phenylalkylamines in
      Retzius, Leydig, AP, and AE neurons. Depending on cell type and blocking agent,
      the concentrations necessary to suppress the K+-induced [Ca2+]i increase by 50%
      were estimated to vary between 5 and 190 microM. At high concentrations, the
      phenylalkylamines and diltiazem by themselves caused a marked [Ca2+]i increase in
      Leydig, P, and N neurons, which is probably due to activation of the caffeine
      sensitive ion channels present in the plasma membrane of these cells. Together
      with previous observations, the results indicate a distant relationship of the
      voltage-gated Ca2+ channels present in many if not all leech neurons to
      vertebrate L-type Ca2+ channels.

PMID- 15193525
TI  - Protein kinase C inhibition differentially affects 3,4
      methylenedioxymethamphetamine-induced dopamine release in the striatum and
      prefrontal cortex of the rat.
AB  - The acute administration of 3,4-methylenedioxymethamphetamine (MDMA) elevates
      extracellular concentrations of dopamine (DA) and serotonin (5-HT) in the rat
      striatum and medial prefrontal cortex (mPFC). The release of DA induced by MDMA
      is thought to involve both transporter and impulse-mediated processes.
      Furthermore, the impulse-dependent release of DA in the striatum elicited by MDMA
      appears to involve 5-HT2 receptor activation. Since 5-HT2 receptors are known to
      utilize protein kinase C (PKC) for intracellular signaling, we examined the
      effects of modulators of PKC activity on DA release stimulated by MDMA. Reverse
      dialysis of the PKC inhibitors bisindolylmaleimide I (BIM; 30 microM) or
      chelerythrine chloride (100 microM) through a microdialysis probe significantly
      attenuated the MDMA (10 mg/kg, i.p.)-induced increase in the extracellular
      concentration of DA in the striatum. In contrast, BIM did not significantly alter
      the increase in the extracellular concentration of DA in the striatum elicited by
      amphetamine (5 mg/kg, i.p.). Reverse dialysis of a PKC activator, phorbol 12,13
      dibutyrate (PDBu) (0.5 microM), through the microdialysis probe into the
      striatum, significantly increased MDMA-induced DA release. In contrast to the
      inhibitory effects of the PKC inhibitors on MDMA-induced DA release in the
      striatum, intracortical infusion of BIM enhanced MDMA-induced release of DA in
      the mPFC. These data suggest that PKC-mediated signaling pathways differentially
      modulate MDMA-induced DA release from mesocorticolimbic and nigrostriatal
      neurons.

PMID- 15193526
TI  - Levels of brain-derived neurotrophic factor and neurotrophin-4 in lumbar
      motoneurons after low-thoracic spinal cord hemisection.
AB  - Neuroplasticity represents a common phenomenon after spinal cord (SC) injury or
      deafferentation that compensates for the loss of modulatory inputs to the cord.
      Neurotrophins play a crucial role in cell survival and anatomical reorganization
      of damaged spinal cord, and are known to exert an activity-dependent modulation
      of neuroplasticity. Little is known about their role in the earliest plastic
      events, probably involving synaptic plasticity, which are responsible for the
      rapid recovery of hindlimb motility after hemisection, in the rat. In order to
      gain further insight, we evaluated the changes in BDNF and NT-4 expression by
      lumbar motoneurons after low-thoracic spinal cord hemisection. Early after lesion
      (30 min), the immunostaining density within lumbar motoneurons decreased markedly
      on both ipsilateral and contralateral sides of the spinal cord. This reduction
      was statistically significant and was then followed by a significant recovery
      along the experimental period (14 days), during which a substantial recovery of
      hindlimb motility was observed. Our data indicate that BDNF and NT-4 expression
      could be modulated by activity of spinal circuitry and further support putative
      involvement of the endogenous neurotrophins in mechanisms of spinal
      neuroplasticity.

PMID- 15193527
TI  - Nociceptive excited and inhibited neurons within the pedunculopontine tegmental
      nucleus and cuneiform nucleus.
AB  - The pedunculopontine tegmental nucleus (PPTg) is defined by its collection of
      cholinergic neurons surrounding the lateral portion of the superior cerebellar
      peduncle at the midbrain pontine junction. Antinociceptive functions have been
      attributed to the PPTg since electrical stimulation as well as injection of
      cholinergic agonists in this area produces analgesia. Nociceptive neurons have
      also been reported in the vicinity of the PPTg and cuneiform nucleus (CN).
      However, specific histochemical localization of nociceptive modulatory neurons
      has not been determined. Thus, the goal of this study was to classify neurons
      according to their response to a noxious stimulus and map their location based on
      staining of the cholinergic neurons in the PPTg. Extracellular microelectrode
      recordings were conducted in 19 male Sprague-Dawley rats under light halothane
      anesthesia. For each neuron identified, a series of noxious tail pinches were
      administered. The electrode tracts were marked with ionophoresis of pontamine
      blue. The location of 112 recorded neurons was determined on sections stained
      with NADPH diaphorase to identify the cholinergic boundaries of the PPTg. Neurons
      were classified into one of three cell types based on their consistent response
      to a noxious tail pinch (excited, inhibited, and non-responsive). Tail pinch
      excited neurons (n=16), inhibited neurons (n=10) and non-responsive neurons
      (n=23) were mapped within the cholinergic boundaries of the PPTg. Excited (n=9),
      inhibited (n=10) and non-responsive neurons (n=10) were also found more dorsally
      within the cuneiform nucleus. Thus, this study localizes nociception-responsive
      neurons to the region of the largely cholinergic PPTg, as well as the
      noncholinergic cuneiform nucleus.

PMID- 15193528
TI  - GABAA receptor modulation of trigeminovascular nociceptive neurotransmission by
      midazolam is antagonized by flumazenil.
AB  - Studies of the pharmacology of trigeminocervical neurons with input from
      intracranial pain-producing structures have enhanced the understanding of the
      basic neurobiology of primary headache, such as migraine. Clinical observations
      of the treatment of migraine with medicines acting at the gamma-aminobutyric acid
      (GABA) GABAA receptor have lead to studies of their effects on models of
      trigeminovascular nociception. Extracellular recordings were made from neurons in
      the trigeminocervical complex activated by supramaximal electrical stimulation of
      superior sagittal sinus (SSS) in the cat. Intravenous administration of the
      benzodiazepine receptor agonist midazolam, resulted in a dose-dependent
      inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity.
      The inhibition at 50 microg/kg midazolam was 65+/-11% compared to the baseline
      response (n=11). Intravenous administration of the benzodiazepine receptor
      antagonist flumazenil, resulted in a dose-dependent recovery of superior sagittal
      sinus evoked trigeminocervical nucleus activity. At a dose of 50 microg/kg, there
      was a 64+/-5% recovery (n=6). The data demonstrate a potent, reproducible effect
      of facilitation of GABA transmission at the GABAA receptor that results in
      inhibition of trigeminovascular nociceptive transmission. These data are
      consistent with the useful clinical effects reported with compounds that can
      augment GABAergic transmission in the central nervous system (CNS).

PMID- 15193529
TI  - Multiple vulnerability of photoreceptors to mesopic ambient light in the P23H
      transgenic rat.
AB  - The P23H transgenic rat was engineered to mimic a human form of retinal
      degeneration caused by a mutation in rhodopsin. We have tested whether the P23H
      transgene influences the vulnerability of photoreceptors to modest variations in
      ambient light, well within the physiological range. P23H-3 (P23H line 3) and
      control Sprague-Dawley (SD) rats were raised in cyclic light (12 h light, 12 h
      dark), with the light phase set at either 5 lx ('scotopic-reared') or 40-60 lx
      ('mesopic-reared'). Mesopic rearing reduced the length of outer segments (OSs) in
      both SD and P23H-3 strains, but the shortening was more marked in the P23H-3
      strain. Mesopic rearing was associated with thinning of the ONL, again more
      prominently in the P23H-3. Correspondingly, mesopic rearing increased the rate of
      photoreceptor death (assessed by TUNEL labelling), the increase occurring during
      early postnatal life. Mesopic rearing upregulated FGF-2 (basic fibroblast growth
      factor) levels in photoreceptors and glial fibrillary acidic protein (GFAP) in
      Muller cells in both SD and P23H-3 strains; again the changes were more marked in
      the P23H-3. Finally, mesopic rearing decreased the amplitude of the a-wave of the
      ERG in both strains; again the effect was greater in the P23H-3 strain. The ERG
      decline induced in both strains by mesopic-rearing can be explained by a
      reduction of functional OS membrane, due to a combination of photoreceptor death
      and OS shortening. The P23H-3 transgene makes photoreceptors abnormally
      vulnerable to modest levels of ambient light, their vulnerability being evident
      in multiple ways. In humans suffering photoreceptor degeneration from comparable
      genetic causes, light restriction may preserve the number and the function of
      photoreceptors.

PMID- 15193530
TI  - Signal transmission from the suprachiasmatic nucleus to the pineal gland via the
      paraventricular nucleus: analysed from arg-vasopressin peptide, rPer2 mRNA and
      AVP mRNA changes and pineal AA-NAT mRNA after the melatonin injection during
      light and dark periods.
AB  - Arg-vasopressin (AVP) containing neurons are one of the output paths from the
      suprachiasmatic nucleus (SCN), the center of the biological clock. AVP mRNA
      transcription is controlled by a negative feedback loop of clock genes. Circadian
      rhythm of melatonin release from the pineal gland is regulated by the SCN via the
      paraventricular nucleus (PVN). To clarify the transduction system of circadian
      signals from the SCN to the pineal gland, we determined the effects of melatonin
      injection (1 mg/kg, i.p.) during light and dark periods on Per2 and AVP mRNAs in
      the SCN and PVN, in addition to arylalkylamine N-acetyltransferase (AA-NAT) and
      inducible cAMP early repressor (ICER) mRNAs in the pineal gland of rats using RT
      PCR. AVP peptide contents were also measured in the SCN and PVN. AVP content in
      the SCN decreased during the light period, while no changes were observed in the
      PVN. In the SCN, Per2 mRNA increased during both light and dark periods. In the
      PVN, Per2 decreased during the light period and increased during the dark period
      at 180 min after melatonin injection. In the pineal gland, Per2 mRNA increased
      between 60 and 180 min after the melatonin injection during the light period,
      while it did not significantly change during the dark period. The AA-NAT mRNA
      varied similar to the Per2 mRNA changes. These results might suggest that the
      different responses to melatonin in the pineal gland during the light and dark
      periods was originated in the changes of Per2 in the PVN via SCN.

PMID- 15193531
TI  - A quantitative morphometric study of the human anterior cingulate cortex.
AB  - Morphometric alterations in the anterior cingulate cortex (ACC) have been
      reported in schizophrenia and mood disorders. Parameters affected include glial
      and neuronal density, neuronal size and cortical thickness. Some data, especially
      in mood disorders, suggest that the left subgenual ACC is preferentially
      involved. Qualitative studies show that the ACC cytoarchitecture is
      heterogeneous, but there are few quantitative data. We performed a quantitative
      morphometric study of five anatomical levels within the ACC (caudal and rostral
      subgenual [area 24b sg], rostral and intermediate supragenual [area 24b] and
      caudal supragenual [area 24b']) in both hemispheres of five normal brains. We
      measured cortical depth, layer depths, neuronal density, neuronal size, and glial
      density, using the optical disector and nucleator. Relative to the subgenual ACC,
      the supragenual ACC was thicker, with a deeper layer V. Supragenual neurons were
      substantially larger in all layers, and were less densely packed in layers V and
      VI, than subgenual neurons. Glial density, and the glia to neuron ratio, was
      higher in supragenual than subgenual ACC. Only minor differences were seen
      between left and right ACC, between caudal and rostral subgenual ACC, and between
      the three supragenual levels. These data complement the qualitative descriptions
      of the heterogeneity of human ACC cytoarchitecture, connections, and functions,
      especially between supragenual and subgenual regions. Our findings also indicate
      that care must be taken when selecting ACC tissue to be used for morphometric
      studies of psychiatric disorders, since the normal anatomical variation is of a
      similar magnitude as the reported disease-related alterations.

PMID- 15193532
TI  - Post-ischemic diazepam does not reduce hippocampal CA1 injury and does not
      improve hypothermic neuroprotection after forebrain ischemia in gerbils.
AB  - The hippocampal CA1 sector is especially vulnerable to brief forebrain ischemia.
      Excitotoxicity is widely thought to contribute to this cell death. Accordingly,
      drugs that presumably counteract excitotoxicity, such as GABAergic agonists, have
      been repeatedly tested and found to reduce CA1 cell loss. Post-ischemic diazepam
      reduces CA1 injury. However, diazepam also causes hypothermia, which by itself is
      neuroprotective. Most studies fail to adequately control for this confound. In
      this study, we tested whether diazepam reduces injury in temperature controlled
      gerbils subjected to brief forebrain ischemia. Furthermore, we tested whether
      diazepam augments hypothermic neuroprotection. All gerbils were implanted with a
      core temperature telemetry probe and a cannula for the subsequent insertion of a
      thermocouple probe to measure ischemic brain temperature. Subsequently, they were
      given a 5-min normothermic ischemic insult. In Experiment 1, two groups of
      gerbils were given 10 mg/kg doses of diazepam (i.p.) at both 30 and 90 min post
      ischemia. Temperature was maintained in one group by heating lamps. Another group
      was administered saline. Diazepam reduced cell death at 7 days post-ischemia when
      the drug-induced hypothermia was permitted, but not when it was prevented. In
      Experiment 2, four groups of ischemic gerbils were treated starting at 12 h post
      ischemia with prolonged hypothermia, diazepam and the combination or saline
      treatment. Hypothermia, but not diazepam, provided partial neuroprotection and
      diazepam did not augment hypothermic neuroprotection. Thus, neuroprotection with
      diazepam is solely due to hypothermia. These data do not support the clinical use
      of diazepam as a neuroprotectant after global ischemia.

PMID- 15193533
TI  - Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired
      absence epilepsy model.
AB  - Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been
      shown to be a faithful model of acquired absence epilepsy, a devastating
      condition for which few therapies or models exist. We employed the CSI model to
      study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats.
      Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated
      from the nucleus reticularis of thalamus (nRt) treated and untreated with a
      cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats
      developed EEG spike-waves (SWs). Patchclamp results revealed that although there
      was no remarkable change in GABAA receptor affinity, both a loss of ability of
      benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+
      inhibition of GABAA-receptor responses of nRt neurons occurred in Long-Evans
      Hooded rats previously administered U18666A. This change was specific, since no
      significant changes were found in neurons exposed to the GABA allosteric
      modulator, pentobarbital. Taken collectively, these findings provide evidence for
      abnormalities in benzodiazepine and Zn2+ modulation of GABAA receptors in the CSI
      model, and suggest that decreased gamma2 subunit expression may underlie
      important aspects of generation of thalamocortical SWs in atypical absence
      seizures. The present results are also consistent with recent findings that
      mutation of the gamma2 subunit of the GABAA receptor changes benzodiazepine
      modulation in families with generalized epilepsy syndromes.

PMID- 15193534
TI  - Alterations in neurofilament light in optic nerve in rat kainate and monkey
      ocular hypertension models.
AB  - The purpose of this study is to evaluate the changes in neurofilament light (NF
      L) protein in the optic nerve in rat kainate and monkey ocular hypertension
      models. In the rat model, optic nerve damage was induced by kainate injection
      into the vitreous body. In the monkey model, photocoagulation of the trabecular
      meshwork led to laser-induced ocular hypertension. NF-L in optic nerve extract
      was quantified by quantitative immunoblot using an imaging analyzer. The amount
      of NF-L in optic nerve was compared between normal and kainate-treated groups at
      7 days after kainate injection. Specimens from rat optic nerves and retinas were
      evaluated histologically to examine the correlations between damage and amount of
      NF-L in the optic nerve. In monkeys, the amount of NF-L in the optic nerve was
      compared between control fellow and ocular hypertensive eyes. Injection of
      kainate induced morphological optic nerve and retinal damage in rats. The amount
      of NF-L in the optic nerve was significantly reduced in kainate-treated eyes (vs.
      normal eyes). The amount of NF-L correlated with the cell count in the ganglion
      cell layer and the axon number in the optic nerve at 7 days after kainate
      injection. Further, 6-cyano-7-nitro-quinoxaline-2,3-dione, a non N-methyl-D
      aspartate receptor antagonist, suppressed the kainate-induced reduction in NF-L
      and retinal damage. In the monkey model, ocular hypertension and morphological
      optic nerve damage were shown by laser-treated eyes. The amount of NF-L in the
      optic nerve was reduced in laser-treated eyes. In conclusion, in rat kainate and
      monkey ocular hypertension models, immunoblot evaluation of NF-L shows the
      reduction of the amount of NF-L in the optic nerves of treated-eyes. The amount
      of NF-L correlated with the morphological retinal and optic nerve damage in rats.
      These findings indicate that immunoblot evaluation of NF-L in the optic nerve may
      provide a quantitative index of optic nerve damage.

PMID- 15193535
TI  - Nefopam blocks voltage-sensitive sodium channels and modulates glutamatergic
      transmission in rodents.
AB  - In order to specify the nature of interactions between the analgesic compound
      nefopam and the glutamatergic system, we examined the effects of nefopam on
      binding of specific ligands on the three main subtypes ionotropic glutamate
      receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4
      propionic acid (AMPA), or quisqualic acid (QA) and kainic acid (KA) in rat brain
      membrane preparations. Functionally, we investigated the effects of nefopam
      against the seizures induced by agonists of these excitatory glutamate receptors
      in mice. Since the synaptic release of glutamate mainly depends upon the
      activation of membrane voltage-sensitive sodium channels (VSSCs), the nature of
      interactions between nefopam and these ionic channels was studied by evaluating
      the effects of nefopam on binding of 3H-batrachotoxinin, a specific ligand of the
      VSSCs in rat brain membrane preparations. The functional counterpart of the
      binding of nefopam on VSSCs was evaluated by its effects on the 22Na uptake
      stimulated by veratridine on human neuroblastoma cells and in the maximal
      electroshock test in mice. Nefopam showed no affinity for the subtypes of
      ionotropic glutamate receptors up to 100 microM. On the other hand, nefopam was
      effective against NMDA, QA and KA induced clonic seizures in mice. Nefopam
      displaced 3H-batrachotoxinin and inhibited the uptake of 22Na in the micromolar
      range and it protected mice against electroshock induced seizures. Nefopam may
      block the VSSCs activity: consequently, at the presynaptic level, this effect led
      to a reduction of glutamate release and at the postsynaptic level, it led to a
      decrease of the neuronal excitability following activation of the glutamate
      receptors.

PMID- 15193536
TI  - Vascular endothelial growth factor-A, vascular endothelial growth factor receptor
      2 and angiopoietin-2 expression in the mouse choroid plexuses.
AB  - In this study, for the first time, we investigated about the localization of VEGF
      A, VEGFR-2 and Ang-2 in the choroid plexuses of the adult mouse by Western blot
      and immunohistochemistry. Results showed that VEGF-A stained epithelial cells,
      while anti-VEGFR-2 and -Ang-2 antibodies stained endothelial cells. These data
      suggest that Ang-2, converting blood vessels into a more plastic and immature
      phenotype, would provide more accessibility of VEGF-A to endothelial cells.

PMID- 15193537
TI  - WAY100635 and female rat lordosis behavior.
AB  - Sexually receptive proestrous rats with bilateral cannulae in the ventromedial
      nucleus of the hypothalamus (VMN) were infused with 200 ng of (+/-)-8-hydroxy-2
      (di-n-propylamino) tetralin (8-OH-DPAT) or with 8-OH-DPAT plus varying
      concentrations (200 to 2000 ng) of the 5-HT1A receptor antagonist, N-[2[4-(2
      methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl)cyclohexanecarboxamide
      trihydrochloride (WAY100635). 8-OH-DPAT inhibited lordosis behavior within 15 min
      of the infusion and every dose of WAY100635 prevented the inhibition. When non
      sexually receptive, ovariectomized rats, hormonally primed with 0.5 microg
      estradiol benzoate and 500 microg progesterone, were infused with WAY100635 (400
      to 2000 ng), the 5-HT1A receptor antagonist did not facilitate lordosis
      responding. These findings support earlier findings that activation of 5-HT1A
      receptors in the mediobasal hypothalamus inhibits lordosis behavior. However,
      they further demonstrate that tonic activation of 5-HT1A receptors is not
      responsible for the absence of sexual receptivity in suboptimally hormonally
      primed ovariectomized rats.

PMID- 15193538
TI  - Differential expression patterns of the dentin matrix proteins during mineralized
      tissue formation.
AB  - Sequential and reciprocal interactions between the oral ectoderm and neural crest
      derived mesenchyme are responsible for tooth development. During dentin
      formation, there are three components that are necessary for proper
      mineralization, namely, collagen which forms a scaffold, noncollagenous proteins
      that can specifically bind to the collagen template and function as a mineral
      nucleator and crystalline calcium phosphate deposited in an ordered manner. It is
      well established that noncollagenous proteins play an important role during
      mineralized tissue formation. Here we demonstrate by in situ hybridization
      techniques that the noncollagenous dentin matrix proteins 1, 2 (DMP1, 2) and
      dentin sialoprotein (DSP) have characteristic temporal and spatial expression
      patterns within odontogenic tissues during dentin mineralization. DMP1, DMP2 and
      DSP mRNA are expressed in the odontoblasts at specific and overlapping time
      points and are thus presumably used for different functions during dentin
      formation. In developing rat incisors and molars, high levels of expression of
      DMP2 mRNA were seen in polarized odontoblasts and preameloblasts, while DSP mRNA
      was expressed at significantly lower levels and was expressed by highly
      differentiated odontoblasts. However, their expression was continuously
      maintained during the mineralization of the organic matrix. In the adult rats,
      DMP2 and DSP mRNA was also detected in the osteoblasts. The expression of DMP1
      mRNA was found to coincide with the start of the mineral nucleation process and
      gradually decreased during the maturation of the mineralized matrix during
      odontogenesis. In this study, we have also correlated the expression of these
      proteins relative to the presence of type I collagen and calcium phosphate
      crystals. Thus, the temporal and spatial differences between DMP1, DMP2 and DSP
      might implicate a direct demonstration of the functional difference between these
      three genes during calcified tissue formation.

PMID- 15193539
TI  - Sex hormone-binding globulin, estradiol, and bone turnover markers in male
      osteoporosis.
AB  - The role of estrogen deficiency in male osteoporosis is still under discussion.
      One hundred five subjects, 65 of them suffering from osteoporosis (mean age, 53.9
      years) and 40 age-matched controls were studied. Osteoporosis was defined by a T
      score < -2.5 in the lumbar spine or at the femoral neck. Forty-one (63.1%) of the
      subjects had a history of low-energy fractures, involving vertebrae in 33 cases
      (50.8%). Osteoporosis was considered to be idiopathic in 33 subjects (50.8%) for
      whom no etiology could be found. We measured levels of total estradiol (pg/ml,
      with a detection threshold of 4 pg/ml), total testosterone (ng/ml), and their
      carrier protein, that is, sex hormone-binding globulin (SHBG, pmol/ml). Various
      markers of bone remodeling were also measured. Two of them provide an estimate of
      bone formation-osteocalcin (OC) and bone alkaline phosphatase (BAP). Two others
      evaluate bone resorption-procollagen type I C-terminal telopeptide (ICTP) and
      serum C-telopeptide of type I collagen (sCTX). There was no significant
      difference in estradiol levels between controls and osteroporosis patients. We
      did not find any significant correlation between estradiol levels and spinal bone
      mineral density (BMD) (r = 0.15, P > 0.05), and the relationship between
      estradiol levels and BMD at the femoral neck was weak (r = 0.25, P < 0.05). On
      the other hand, SHBG was significantly higher in the osteoporotic patients than
      in controls (P < 0.01). This difference persisted after adjustment for body mass
      index (BMI) and after exclusion of patients with a condition known to increase
      SHBG levels. Moreover, this carrier protein was negatively correlated with BMD at
      the femoral neck (r = -0.37, P < 0.01) and at the lumbar spine (r = -0.27, P <
      0.05). SHBG also correlates strongly with sCTX (r = 0.37, P < 0.01). Finally,
      logistic regression analysis showed that serum SHBG concentration was
      significantly associated with the presence of fractures; the odds ratio of having
      a fracture was 2.04 [95% confidence interval (CI) 1.2-3.4, P < 0.01] for each
      increase of 1 standard deviation (SD) in the patient's SHBG level. The stronger
      relationship was nearly the same for the whole group and for patients with
      idiopathic osteoporosis. This study therefore suggests that SHBG may play a key
      role in male patients with idiopathic or secondary osteoporosis. It shows that
      serum SHBG concentration is increased in middle-aged men with osteoporosis and is
      correlated with hip, spine BMD, and sCTX levels. Finally, our findings are in
      agreement with previous studies which suggest that serum SHBG is a new biological
      marker of fracture risk in men.

PMID- 15193540
TI  - Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone
      repair of femoral cortex after drill-hole injury associated with local
      upregulation of bone turnover in mature rats.
AB  - Prostaglandin E(2) (PGE(2)) is essential for fracture healing. Systemic
      administration of EP4 ligands such as PGE(2) and other synthetic EP4 agonists
      appears to transduce anabolic signals by binding to receptor EP4. Therefore, the
      present study was designed to test whether administration of EP4 agonist
      accelerates the healing of drill-hole injury in the femoral diaphysis. After
      surgery, a total of 128 Wistar rats, at the age of 12 weeks, were assigned to
      basal control (n = 8), and three groups with respective doses of 0 (vehicle
      control), 10 (low-dose), and 30 (high-dose) microg/kg body weight of the agent
      were subcutaneously injected twice a day. Femoral specimens were obtained at 0,
      5, 7, 14, 21, and 28 days. In EP4 agonist-treated groups, the total bone volume
      of the regenerating bone in the defect did not significantly differ, but the
      regenerated cortical bone volume measured by histomorphometry and cortical bone
      mineral content (Ct. BMC) by pQCT dose-dependently increased at 14 and 21 days
      compared to the control. In the high-dose group, the value of osteoclast surface
      significantly increased compared with that in the control at 14 days. Expression
      levels of osteocalcin and TRAP mRNAs in the injured tissue increased at 14 days.
      Expression levels of EP4, BMP-2, and RANKL mRNAs increased at 7 days in the high
      dose group. The bone mineral values of the lumbar bone at 28 days, measured by
      DXA, did not differ in the three groups. These data indicated that systemic
      administration of EP4 agonist ONO-4819.CD accelerated cortical bone healing after
      drill-hole injury by upregulating the local turnover of the regenerating bone.

PMID- 15193541
TI  - Nucleobindin is produced by bone cells and secreted into the osteoid, with a
      potential role as a modulator of matrix maturation.
AB  - Nucleobindin (Nuc), also known as CALNUC, is a Ca(2+)-binding protein, located in
      the nucleus, the Golgi apparatus and the endoplasmic reticulum (ER). The presence
      of a signal sequence in Nuc suggests secretion from the cell and it has been
      found in bone extracellular matrix. Within the present study, molecular
      biological and morphological methods were combined to evaluate the synthesis and
      distribution of Nuc in and around cells of rat metaphyseal and calvarial bone.
      Northern blot analysis and in situ hybridization of bone tissues confirmed that
      the protein was a product of bone cells. By electron microscopy, immunolabeling
      for Nuc was seen in osteoid of newly formed bone, on all surfaces facing the
      various bone cells and also in compact bone. Intracellularly, the gold particles
      were found in the rough ER of osteoblasts, which suggested synthesis of the
      protein by these cells. Compared to bone sialoprotein and osteopontin, Nuc
      demonstrated different localization pattern in bone trabeculae, with the majority
      of labeling restricted to nonmineralized osteoid. Moreover, the role of Nuc
      during the mineralization process was investigated in rat calvaria-derived
      primary osteoblasts grown under osteogenic conditions. Semiquantitative RT-PCR
      and Northern blot analysis showed Nuc expression to be low during cell
      proliferation, upregulated during differentiation and matrix maturation, but
      subsequently downregulated during mineralization. In summary, our data show that
      Nuc was synthesized by osteoblasts and osteocytes, and secreted into the osteoid,
      suggesting a role as a modulator of matrix maturation in the mineralization
      process in bone.

PMID- 15193542
TI  - Primary culture of rat growth plate chondrocytes: an in vitro model of growth
      plate histotype, matrix vesicle biogenesis and mineralization.
AB  - During endochondral ossification (EO), cartilage is replaced by bone.
      Chondrocytes of growth plate undergo proliferation, maturation, hypertrophy,
      matrix vesicle (MV) biogenesis and programmed cell death (PCD, apoptosis). The in
      vitro system presented here provides a potential experimental model for studying
      in vitro differentiation and MV biogenesis in chondrocyte cultures. Chondrocytes
      were obtained from collagenase-digested tibial and femoral growth plate cartilage
      of 7-week-old rachitic rats. The isolated chondrocytes were plated as monolayers
      at a density of 0.5 x 10(6) cells per 35-mm plate and grown for 17 days in BGJ(b)
      medium supplemented with 10% fetal bovine serum, 50 microg/ml ascorbic acid.
      Light microscopy revealed Sirius red-positive, apparent bone matrix in layers at
      the surfaces of cartilaginous nodules that developed in the cultures. The central
      matrix was largely alcian blue staining thus resembling cartilage matrix.
      Electron microscopy revealed superficial areas of bone like matrix with large
      banded collagen fibrils, consistent with type I collagen. Most of the central
      matrix was cartilaginous, with small fibrils, randomly arranged consistent with
      type II collagen. The presence of peripheral type I and central type II and type
      X collagen was confirmed by immunohistochemical staining. Immunohistochemistry
      with anti-Bone morphogenetic proteins 2, 4 and 6 showed that BMP expression is
      associated with maturing hypertrophic central chondrocytes, many of which were
      TUNEL positive and undergoing cell death with plasma membrane breaks, hydropic
      swelling and cell fragmentation. During early mineralization, small radial
      clusters of hydroxyapatite-like mineral were associated with matrix vesicles.
      Collagenase digestion-released MVs from the cultures showed a high specific
      activity for alkaline phosphatase and demonstrated a pattern of AMP-stimulated
      nonradioactive (40)Calcium deposition comparable to that observed with native
      MVs. These studies confirm that primary cultures of rat growth plate chondrocytes
      are a reasonable in vitro model of growth plate histotype, MV biogenesis and
      programmed cell death.

PMID- 15193543
TI  - Thapsigargin potentiates TRAIL-induced apoptosis in giant cell tumor of bone.
AB  - TNF-related apoptosis-inducing ligand (TRAIL) is capable of causing apoptosis in
      tumor cells but not in normal cells; however, it has been shown that certain
      types of tumor cells are resistant to TRAIL-induced apoptosis. In this study, we
      examined the potentiation of TRAIL-induced apoptosis in the stromal-like tumor
      cells of giant cell tumor of bone (GCT). We show that both mRNA and protein of
      TRAIL receptors-death receptors (DR4, DR5) and decoy receptors (DcR1, DcR2) are
      present in GCT stromal tumor cells. However, the expression profiles in all GCT
      clones tested do not readily correlate with their differential sensitivity to
      TRAIL. To this end, we selected thapsigargin (TG), an agent known to cause
      perturbations in intracellular Ca(2+) homeostasis to enhance the apoptotic action
      of TRAIL. When added alone, neither TRAIL nor TG induces a therapeutically
      important magnitude of cell death in GCT tumor cells. Interdependently, scheduled
      treatment of the cultures with TG followed by subsequent addition of TRAIL
      resulted in a significant synergistic apoptotic activity, while in contrast, no
      obvious augmentation was seen when TRAIL was added before TG. This effect was in
      accord with our observation that TG predominantly up-regulated both mRNA and
      protein expression of DR5, as well as DR4 mRNA while down-regulating DcR1 protein
      in GCT stromal-like tumor cells. Taken together, our findings suggest that TG is
      able to sensitize tumor cells of GCT to TRAIL-induced cell death, perhaps in part
      through up-regulating the death receptor DR5 and down-regulating the decoy
      receptor DcR1. These findings provide an additional insight into the design of
      new treatment modalities for patients suffering from GCT.

PMID- 15193544
TI  - Ex vivo gene therapy-induced endochondral bone formation: comparison of muscle
      derived stem cells and different subpopulations of primary muscle-derived cells.
AB  - Muscle-based gene therapy and tissue engineering hold great promise for improving
      bone healing. However, the relative advantage of muscle-derived stem cells
      (MDSCs) or primary muscle-derived cells (MDCs) remains to be defined. We compared
      the ability of MDSCs and different subpopulations of MDCs (PP1 and PP3) to induce
      bone formation via ex vivo gene therapy. We were able to efficiently transduce
      the MDSCs and all the other evaluated populations of MDCs (efficiency of
      transduction = approximately 80%) by using a retroviral vector expressing human
      bone morphogenetic protein 4 (BMP4). All the transduced cell populations secreted
      high levels of BMP4 (140-300 ng/10(6) cells/24 h), but the MDSCs differentiated
      toward the osteogenic lineage more effectively than did the other muscle cell
      populations, as indicated by the expression of alkaline phosphatase, an early
      osteogenic marker. von Kossa staining indicated that mineralized bone formed as
      early as 7 days after implantation of any of the BMP4-expressing cell populations
      into immunocompetent syngeneic mice; however, MDSCs expressing BMP4 produced
      significantly more bone than did the other MDC populations, as evidenced by both
      histomorphometry and biochemical analysis. Further investigation revealed that
      MDSCs expressing BMP4 persisted for a significantly longer period of time at the
      bone forming sites than did the other BMP4-expressing MDC populations.
      Additionally, MDSCs expressing BMP4 triggered a smaller infiltration of CD4
      lymphocytes within the bone forming areas than did the other MDC populations
      expressing BMP4. Finally, we demonstrated that MDSCs expressing BMP4 can heal a
      critical-sized skull bone defect in immunocompetent mice. In summary, this study
      shows that MDSCs are better than primary MDCs for use as cellular vehicles in
      BMP4-based ex vivo gene therapy to improve bone healing. The advantage of MDSCs
      may be attributable, at least in part, to their lower immunogenicity and higher
      capacity for in vivo survival.

PMID- 15193545
TI  - Isolation and characterization of a mesenchymal cell line that differentiates
      into osteoblasts in response to BMP-2 from calvariae of GFP transgenic mice.
AB  - We established the clonal mesenchymal cell line, GFP-C3 (C3), which
      differentiates into osteoblasts in response to BMP-2 from calvariae of newborn
      green fluorescence protein (GFP) transgenic mice. This cell line cultured with
      control medium expressed low levels of alkaline phosphatase (ALP) activity and
      osterix mRNA and undetectable ALP and osteocalcin mRNA. Incubation of these cells
      with rhBMP-2 increased ALP activity dose-dependently and induced substantial
      levels of ALP, osteocalcin and osterix mRNA expression. C3 cells infected with
      adenovirus vector encoding BMP-2 (AdBMP-2) or Runx2 (AdRunx2) showed greatly
      increased ALP mRNA expression in a time-dependent fashion. Transduction with
      AdRunx2-induced expression of ALP and osteocalcin mRNA, but not osterix mRNA by
      day 3. Transduction with AdBMP-2 induced apparent expression of ALP and osterix
      mRNA by day 1 after transduction, but induced only weak expression of osteocalcin
      mRNA day 3 after transduction. Transplantation of C3 cells transduced with AdBMP
      2 into back subfascia in wild-type mice with a complex of poly-d,l-lactic-co
      glycolic acid/gelatin sponge (PGS) generated ectopic bone formation involving GFP
      positive osteoblasts and osteocytes 2 weeks after transplantation. C3 cells
      transduced with AdRunx2 or AdLacZ failed to induce ectopic bone formation.
      Transplantation of C3 cells transduced with AdBMP-2 into craniotomy defects in
      wild-type mice using PGS as a carrier induced bone formation 2 weeks after
      transplantation, and replaced defects 4 weeks after transplantation. C3 cells
      transduced with AdRunx2 failed to induce bone repair after transplantation into
      craniotomy defects. These results indicate that C3 cells retain differentiation
      potential into osteoblasts in response to BMP-2. They are useful tools for
      analyzing the process of osteoblast differentiation in vivo after
      transplantation.

PMID- 15193546
TI  - Creation and characterization of a mouse model of mandibular distraction
      osteogenesis.
AB  - While the histological and ultrastructural changes associated with distraction
      osteogenesis have been extensively characterized using various animal models, the
      molecular mechanisms governing this technique remain poorly understood. In the
      current study, for the first time, we describe a mouse mandibular distraction
      osteogenesis model. Development of this model will allow assessment of factors
      involved in normal vs. abnormal healing (especially in non-unions) of
      craniofacial skeletal elements. Complete osteotomies were created on the right
      hemimandibles of 51 adult male CD-1 mice and customized distraction devices
      attached. Thirty-three animals underwent gradual distraction (5 days latency,
      distraction at 0.2 mm BID x 8 days, 28 days consolidation), while the remaining
      18 mice underwent acute lengthening (immediate distraction to 3.2 mm) at the time
      of surgery. Mandibles were harvested at time points corresponding to the latent
      (POD 5), distraction (POD 9, 13), and consolidation (POD 28, 41) periods and
      processed for histological or quantitative real-time RT-PCR analysis. Specimens
      from each group were processed for microCT analysis. Histological and
      radiological data demonstrated that all mandibles undergoing gradual distraction
      achieved complete bony union by the end of consolidation, while those undergoing
      acute lengthening formed a fibrous non-union. Quantitative real-time RT-PCR
      demonstrated upregulation of mRNA for VEGF, FGF-2, collagen I, and osteopontin
      during gradual distraction but not during acute lengthening. These data validate
      our novel mouse mandibular distraction model and demonstrate its utility in
      elucidating the molecular mechanisms regulating bone formation during distraction
      osteogenesis as compared to those that are expressed during the formation of
      fibrous non-unions.

PMID- 15193547
TI  - Bone turnover markers in patients with osteogenesis imperfecta.
AB  - Osteogenesis imperfecta (OI) is a heterologous group of rare inherited bone
      disorders resulting from defect in collagen synthesis or function. In previous
      studies, bone turnover has been found either increased or low-normal. These
      contradictory results might result from the study population made of children
      with prior recent fractures. We measured serum total and bone alkaline
      phosphatase (total and bone AP) serum osteocalcin (sOC), serum type I collagen C
      telopeptide breakdown products (sCTX), urinary free-deoxypyridinoline (ufDPD),
      and urinary cross-linked N-telopeptides of type I collagen (uNTX) in 39 male and
      38 premenopausal patients with different types of OI aged between 18 and 51 years
      who had not experienced new clinical fracture during 12 months preceding the
      laboratory assessment. The study also includes a control group of 29 men and 26
      women matched for age and gender. Most bone markers were 50-200% higher in
      patients than in controls. Only sCTX was comparable to that found in controls.
      From a sub-analysis of the data, a trend for higher bone resorption markers was
      observed for any OI type, but patients with OI type III and IV had significantly
      higher values in ufDPD and uNTX than patients with type I OI, and their sOC
      levels were not significantly higher than in controls. These results provide a
      strong rational for the use of anti-resorbing agent in OI.

PMID- 15193548
TI  - Relationships between bone mass and circulating leptin concentrations in
      Hutterites.
AB  - A limited number of previous studies have shown inverse associations between bone
      mass or density and circulating leptin in humans. Relationships between bone mass
      and circulating leptin in Hutterites, who have elevated bone density, are
      unknown. Knowledge gained from studies in mice suggests that Hutterites exhibit
      traits consistent with a deficiency in circulating leptin or in leptin signaling.
      We examined relationships between whole body (WB) and regional (lumbar, total
      hip, femoral neck, trochanter) bone mineral content (BMC) by dual energy X-ray
      absorptiometry and circulating leptin in 249 Hutterites (137 female) ages 20-55
      years and 72 similarly aged non-Hutterites (37 female). We tested the hypothesis
      that (1) Hutterites will have low circulating leptin concentrations for a given
      amount of body fat compared to non-Hutterites, and (2) controlling for body fat,
      there will be an inverse relationship between BMC and circulating leptin among
      Hutterites. Hutterites had higher BMC than non-Hutterites at all skeletal sites
      after adjusting for site-specific bone area, age, and sex (P </= 0.02). Hutterite
      females had higher leptin concentrations than non-Hutterite females [geometric
      mean and 95% confidence interval (CI): 18.38 (17.18, 19.67) vs. 14.30 (12.55,
      16.28), P </= 0.001) after adjusting for WB fat mass. Hutterite males also had
      higher leptin concentrations than non-Hutterite males [geometric mean and 95% CI:
      6.53 (6.11, 6.98) vs. 5.62 (4.98, 6.35), P = 0.03) after adjusting for WB fat
      mass. We used backward stepwise regression to determine significant (P </= 0.10)
      covariates to include in models predicting WB and regional BMC among Hutterites
      (separately by sex). Subsequently, we entered leptin (log-transformed) to models
      to test for significance (P </= 0.05). After adjusting for covariates, leptin
      concentration was not a significant predictor of BMC at any site, in either sex,
      among Hutterites. It is possible that genetic influences that interfere with
      hypothalamic leptin signaling, in a manner unrelated to adipocyte leptin
      production, contribute to elevated Hutterite bone density.

PMID- 15193549
TI  - Ex vivo bone mineral density of the wrist: influence of medullar fat.
AB  - The cone beam technology was recently proposed in a third generation of
      densitometers (dual photon X-ray absorptiometry, DXA such as the Lexxos
      densitometer). Because fat is a well-known problem with DXA, we have designed a
      cadaver study to compare the influence of medullary lipids on the measures
      performed with the Hologic QDR4500 and the Lexxos. Twenty-three human distal
      radii were obtained and analyzed in parallel on both densitometers; bone mineral
      density (BMD) was measured at the distal radius with standard softwares and on a
      standardized square regions of interest (ROI). Bones were then defatted and a new
      series of measurement was performed. Bones were then thoroughly dried and a cube
      was prepared at the distal radius with a banding saw. Trabecular and total bone
      volumes were measured by microcomputerized tomography. Ash eight was obtained
      after calcination of the blocks. BMD could be measured on the Lexxos before and
      after delipidation but this was not possible with the QDR4500. The X-ray image
      quality was better with the Lexxos. Delipidation had a very significant effect on
      measurements: after defatting, BMD values were considerably reduced (-49.8 +/-
      19.4%). BMD before/after defatting were significantly correlated (r = 0.81, P <
      0.0001) but bone mass appeared to reflect 66% of the variance. BMD was
      significantly correlated with BV/TV after defatting (r = 0.44, P < 0.03) but the
      correlation improved when cortices were taken into account (r = 0.70, P <
      0.0001). Ash weight was significantly correlated with BMD and total bone volume
      (respectively, r = 0.84, P < 0.0001; r = 0.53, P < 0.03), but not with BV/TV. BMD
      at the distal radius is influenced by marrow fat and cortical density.

PMID- 15193550
TI  - RUNX2 alleles associated with BMD in Scottish women; interaction of RUNX2 alleles
      with menopausal status and body mass index.
AB  - Bone mineral density (BMD) is influenced by both environmental and genetic
      factors. We previously reported the association of the RUNX2 A allele with
      increased bone mineral density (BMD) and protection against a common form of
      osteoporotic fracture within a Geelong population. We genotyped 991 women from a
      Scottish cohort to decipher the role of RUNX2 alleles in regulating BMD. The
      alleles of RUNX2 within the glutamine-alanine repeat were determined by MspA1I
      restriction digest. Allele frequencies estimated from Scottish cohort were G
      allele, 0.87 +/- 0.01; A allele, 0.08 +/- 0.01; and 11Ala alanine deletion
      allele, 0.05 +/- 0.01. Analysis of covariance (ANCOVA) was used to adjust for the
      covariates weight and age for BMD at the femoral neck (FN). The A allele was
      associated with higher FN BMD (P = 0.035) within a postmenopausal subgroup of the
      population (n = 312). The effect of RUNX2 A alleles increased with increasing
      weight; A alleles were associated with FN BMD in those above the median BMI (BMI
      > 25), while no association was observed in thin/normal (BMI </= 25)
      postmenopausal women. Glutamine variants and an alanine insertion were identified
      within the group. These data suggest that the RUNX2 alleles are associated with
      BMD in a menopause- and weight-dependent manner.

PMID- 15193551
TI  - Bone mineral density and total body bone mineral content in 18- to 22-year-old
      women.
AB  - One hundred sixty-four (164) healthy, young Caucasian women enrolled as
      midshipmen at the United States Naval Academy with no known disease or bone
      injury were followed for 3.6 years. Change in bone mineral density (BMD) of the
      hip, lumbar spine and distal tibia, and total body bone mineral content (TBMC)
      was measured by dual energy X-ray absorptiometry (DXA). Bone mineral density and
      TBMC of these women were measured within 2 months (60 +/- 4 days) of entering the
      Academy and annually. Over the study period, hip BMD increased 2.26% (P < 0.001),
      lumbar spine BMD increased 3.27% (P < 0.001) and distal tibia BMD increased 5.2%
      (P < 0.001). Total body bone mineral content showed a 5.25% (P < 0.001) increase
      during the study period. In this group of young women, gain in BMD and TBMC
      continued until age 22. These results suggest that bone mass may accrue in
      certain groups of women beyond age 22. The significance of this increase in bone
      mass during early adulthood on risk for osteoporotic fractures in later life and
      its impact on exercise-related bone injuries are unknown and warrant further
      examination.

PMID- 15193552
TI  - Interpretation of whole body dual energy X-ray absorptiometry measures in
      children: comparison with peripheral quantitative computed tomography.
AB  - The assessment of bone health in children requires strategies to minimize the
      confounding effects of bone size on dual energy X-ray absorptiometry (DXA) areal
      bone mineral density (BMD) results. Cortical bone composes 80% of the total
      skeletal bone mass. The objective of this study was to develop analytic
      strategies for the assessment of whole body DXA that describe the biomechanical
      characteristics of cortical bone across a wide range of body sizes using
      peripheral quantitative computed tomography (pQCT) measures of cortical geometry,
      density (mg/mm(3)), and strength as the gold standard. Whole body DXA (Hologic
      QDR 4500) and pQCT (Stratec XCT-2000) of the tibia diaphysis were completed in
      150 healthy children 6-21 years of age. To assess DXA and pQCT measures relative
      to age, body size, and bone size, gender-specific regression models were used to
      establish z scores for DXA bone mineral content (BMC) for age, areal BMD for age,
      bone area for height, bone area for lean mass, BMC for height, BMC for lean mass,
      and BMC for bone area; and for pQCT, bone cross-sectional area (CSA) for tibia
      length and bone strength (stress-strain index, SSI) for tibia length. DXA bone
      area for height and BMC for height were both strongly and positively associated
      with pQCT CSA for length and with SSI for length (all P < 0.0001), suggesting
      that decreases in DXA bone area for height or DXA BMC for height represent
      narrower bones with less resistance to bending. DXA BMC for age (P < 0.01) and
      areal BMD (P < 0.05) for age were moderately correlated with strength. Neither
      DXA bone area for lean mass nor BMC for lean mass correlated with pQCT CSA for
      length or SSI for length. DXA BMC for bone area was weakly associated with pQCT
      SSI for length, in females only. Therefore, normalizing whole body DXA bone area
      for height and BMC for height provided the best measures of bone dimensions and
      strength. DXA BMC normalized for bone area and lean mass were poor indicators of
      bone strength.

PMID- 15193553
TI  - The relations among upper-extremity loading characteristics and bone mineral
      density changes in young women.
AB  - The relations among the reaction forces engendered during an upper-extremity
      dynamic impact-loading exercise (DILE) program and bone mineral density
      adaptations (DeltaBMD) in the radius were investigated in 24 healthy
      premenopausal women (mean age = 29 +/- 6 years). Subjects performed DILE 36
      cycles/day, 3 days/week for 24 weeks. The exercised arm was allocated randomly to
      either the dominant or the nondominant limb. In addition, subjects were assigned
      randomly into either damped or nondamped treatment arms to examine the effects of
      both higher- and lower-magnitude loading prescriptions. Measurements including
      anthropometrics, self-reported physical activity levels, hand-grip strength,
      radial BMD (DEXA, Hologic QDR1500, MA) at the ultradistal radius (UD), distal 1/3
      radius (DR), and total distal radius (TOTAL), and exercise-related loading
      characteristics (impact load, loading rate, and impulse) were recorded at
      baseline and at 6 months. Simple linear regression models were used to fit the
      regional BMD changes to the reaction force, changes in hand-grip strength
      (DeltaGRIP), and changes in body weight (DeltaBW). Findings demonstrated that the
      damping condition utilized during DILE influenced the relations between loading
      events and BMD changes. Specifically, none of the reaction-force characteristics
      significantly predicted changes in BMD in participants performing DILE using the
      damped condition, whereas, in the nondamped condition, impact load accounted for
      58% of the variance in BMD change at DR and 66% of the variance in BMD change at
      TOTAL. Thresholds of 345 and 285 N of impact force to promote BMD increases at DR
      and TOTAL, respectively, were obtained from the regression models in the
      nondamped group. Impulse was also an independent predictor of BMD changes at
      TOTAL, accounting for 56% of the variance. Neither DeltaGRIP nor DeltaBW
      significantly predicted DeltaBMD at any radial site. These findings, in young
      adult women, parallel previous reports identifying significant, regionally
      specific relations among external loading events and BMD changes in both animal
      and human models.

PMID- 15193554
TI  - Cost effectiveness of alendronate for the treatment of male osteoporosis in
      Sweden.
AB  - BACKGROUND: One third of all the hip fractures occur in men. The risk for
      mortality following hip fracture is higher for men compared to women. The
      Fracture Intervention Trial (FIT) showed that the bisphosphonate alendronate
      reduces the risk of fractures and increases bone mineral density (BMD) in
      osteoporotic women. Similar effects of alendronate were observed in men in some
      other trials. There are also results demonstrating alendronate to be cost
      effective in the treatment of osteoporosis in women. OBJECTIVE: To investigate
      the cost effectiveness of alendronate for male osteoporosis in Sweden by assuming
      the same relative risk reduction of fractures in men as for women, based on the
      FIT trial. DESIGN: A Markov model earlier used to analyze cost effectiveness of
      alendronate in treatment of postmenopausal osteoporosis in Sweden was adapted to
      fit a cohort of Swedish men. Cost effectiveness of alendronate vs. no treatment
      was assessed by transitioning men in the model over time between different health
      states. TIME HORIZON: The patients were followed from start of intervention until
      100 years of age or death. In the base-case alendronate was assumed to have a
      fracture-risk-reducing effect for 10 years; a treatment duration period of 5
      years followed by a 5-year period where the effect declined linearly to zero.
      RESULTS: Taking a societal perspective treating a 71-year-old man (mean age in
      the FIT) with low BMD and prior vertebral fracture (VFA) with alendronate was
      found to be associated with a cost of 14,843 per quality adjusted life year
      (QALY) gained. CONCLUSIONS: The results in this study indicate that treating
      osteoporotic men with alendronate was projected to be cost-effective, under the
      assumption of the same fracture-risk-reducing effect of alendronate for men as
      for women.

PMID- 15193555
TI  - Increased fragility in patients with fracture of the proximal humerus: a case
      control study.
AB  - The aim of this study was to evaluate whether a fracture of the proximal humerus
      is associated with an increased prevalence of preceding fractures or a risk of
      subsequent fractures. All patients who were treated at the Malmo General Hospital
      in 1987 for a fresh fracture of the proximal humerus were identified,
      representing practically all fractures of the proximal humerus in Malmo city
      (250,000) that year. Two hundred fifty-three adult patients, 54 men with an
      average age of 66 (24-90) and 199 women with a mean age of 74 (22-98) years, were
      included in the study together with 475 age- and gender-matched control persons.
      In 1999, fracture prevalence of patients and controls were rated by a survey at
      the Dept. of Radiology. There was a significantly increased prevalence of
      previous fractures before 1987 in the humerus fracture group with an odds ratio
      (OR) of 3.5 [95% confidence interval (95% CI), 2.2-5.5] for a spinal fracture, OR
      1.8 (95% CI, 1.3-2.6) for a previous fracture to the upper extremity, and OR 1.8
      (95% CI, 1.2-2.6) for a preceding fracture of the lower limb. The proximal
      humerus fracture also predicted a significantly increased risk of a subsequent
      fracture. The hazard ratio (HR) was 2.5 (95% CI, 1.7-3.7) for a forthcoming
      spinal fracture, HR 2.8 (95% CI, 2.0-3.7) for a future fracture of the upper
      extremity, and HR 2.0 (95% CI, 1.2-3.5) for a lower limb fracture. In a subgroup
      of male patients, an almost five times increased risk of sustaining subsequent
      extremity fractures was observed. In summary, a fracture of the proximal humerus
      is associated both with increased prevalence of previous fractures of the spine
      and extremities and also predicting an increased risk of future fractures.

PMID- 15193556
TI  - Virulence and disease in leishmaniasis: what is relevant for the patient?

PMID- 15193558
TI  - Schistosome transcriptome: insights and perspectives for functional genomics.

PMID- 15193557
TI  - Schistosome transcriptome analysis at the cutting edge.
AB  - We live in the era of post-genomics, a term that was, until recently,
      inappropriate when considering the blood flukes of humans because of the relative
      lack of knowledge of the schistosome genome. The position has, however, changed
      dramatically following the recent publication of two landmark papers on
      transcriptome analysis of Schistosoma japonicum and Schistosoma mansoni. In a
      quantum leap, both studies report on the identification of many novel genes and
      genes not previously known from schistosomes. The datasets provide new insights
      into the biology of the schistosomes and offer an opportunity for identification
      of potential antischistosome vaccine candidates and drug targets. Remarkable
      recent progress has also been achieved in genomic sequencing, and completed
      genomes for both species can be expected shortly.

PMID- 15193559
TI  - Continuing tsetse and Trypanosoma genome sequencing projects.

PMID- 15193561
TI  - Are fitness costs associated with resistance to human serum in Trypanosoma brucei
      rhodesiense?

PMID- 15193562
TI  - Infection and autoimmunity: are we winning the war, only to lose the peace?

PMID- 15193563
TI  - Natural plant cysteine proteinases as anthelmintics?

PMID- 15193564
TI  - Leishmaniasis in Israel and the Palestinian Authority.

PMID- 15193565
TI  - The co-existence of Plasmodium: sidelights from falciparum and vivax malaria in
      Thailand.

PMID- 15193566
TI  - Linked thioredoxin-glutathione systems in platyhelminths.
AB  - The thioredoxin and glutathione systems play a central role in thiol-disulfide
      redox homeostasis in many organisms by providing electrons to essential enzymes,
      and defence against oxidative stress. These systems have recently been
      characterized in platyhelminth parasites, and the emerging biochemical scenario
      is the existence of linked processes with the enzyme thioredoxin glutathione
      reductase supplying reducing equivalents to both pathways. In contrast to their
      hosts, conventional thioredoxin reductase and glutathione reductase enzymes
      appear to be absent. Analysis of published data and expressed-sequence tag
      databases indicates the presence of linked thioredoxin-glutathione systems in the
      cytosolic and mitochondrial compartments of these parasites.

PMID- 15193569
TI  - A cross-national comparison of risk and protective factors for adolescent
      substance use: the United States and Australia.
AB  - PURPOSE: To compare risk and protective factors that influence youth substance
      use in Australia and the United States. The two countries have different policy
      orientations toward substance use: Australia has adopted harm-reduction policies,
      and the United States has adopted abstinence-focused policies. METHODS: Cross
      sectional survey data were collected from independent samples of adolescents in
      the states of Maine (N = 16,861; 53% female, 7% Non-white) and Oregon (N =
      15,542; 51% female, 24% Non-white) in the United States and Victoria in Australia
      (N = 8442; 54% Female, 11% Non-white) in 1998 (Maine and Oregon) and 1999
      (Victoria). Chi-square tests, t-tests, effect size comparisons, and logistic
      regression analyses that accounted for age and gender were used to investigate
      cross-national similarities and differences in: (a) rates of cigarette, alcohol,
      and marijuana use; (b) levels of risk and protective factors; and (c) magnitudes
      of associations between risk and protective factors and substance use. RESULTS:
      More adolescents in Victoria reported using cigarettes and alcohol, whereas more
      of the U.S. adolescents reported using marijuana. Exposure to risk and protective
      factors was generally similar in the cross-national samples. However, adolescents
      in Maine and Oregon perceived handguns to be more readily available, reported
      more participation in religious activities, and were higher in sensation-seeking
      and social skills; and adolescents in Victoria had more favorable attitudes
      toward drug use and reported community norms and parental attitudes more
      favorable to drug use. Most of the risk and protective factors were strongly
      associated with substance use to a similar degree in Victoria, Maine, and Oregon.
      However, among adolescents in Maine and Oregon peer/individual risk and
      protective factors associated with social detachment were more strongly related
      to substance use, and among adolescents in Victoria, family protective factors
      were less strongly related to alcohol use. CONCLUSIONS: Inter-country influences
      on youth substance use are generally similar despite different policy directions.
      Existing differences suggest that the abstinence policy context is associated
      with higher levels of illicit drug use and stronger relations between individual
      indicators of social detachment and substance use, whereas the harm reduction
      policy context is related to more cigarette and alcohol use, possibly from
      exposure to normative influences that are more tolerant of youth drug use.

PMID- 15193570
TI  - Trauma and coping in Somali and Oromo refugee youth.
AB  - PURPOSE: To describe war-related trauma history, immigration factors, problems,
      and coping of Somali and Oromo refugee youth. METHODS: Analysis of a subset of
      participants (N = 338) aged 18-25 years from a population-based survey of Somali
      and Oromo refugees conducted in 2000-2002. Data included trauma history, life
      situation, and scales for physical (Cronbach alpha =.69), psychological (alpha
      =.56), and social problems (alpha =.69). Data were analyzed using Chi-square and
      Mann-Whitney U tests. RESULTS: Average emigration age was 14.8 years, with 4.2
      years in transit and 2.0 years in the United States; 60% reported plans to return
      home to live. Two-thirds (66%) had less than a high school education, 49% had
      English language problems, 49% were employed (38% female vs. 57% male); 70% were
      single, with Somali females more likely than Oromo to be partnered and mothers
      (39% vs. 19%). There were significant ethnicity/gender differences for all
      problem scales. More females reported feeling alone (24% vs. 61%, p <.001). Youth
      with symptoms of posttraumatic stress syndrome reported more traumatic events
      (mean number of events: 28 vs.16). Trauma history was strongly associated with
      physical, psychological, and social problems. Most frequent strategies to combat
      sadness were praying (55.3%), sleeping (39.9%), reading (32.3%), and talking to
      friends (27.8%). CONCLUSIONS: Many young Somali and Oromo immigrants to the
      United States experience life problems associated with war trauma and torture,
      but many others are coping well. The findings suggest a need to develop age
      appropriate strategies to promote the health of refugee youth to facilitate their
      successful adaptation to adult life in the United States.

PMID- 15193572
TI  - Chronic fatigue syndrome and other fatiguing illnesses in adolescents: a
      population-based study.
AB  - PURPOSE: To estimate the prevalence of chronic fatigue syndrome (CFS) and
      describe characteristics of other fatiguing illnesses in adolescents (aged 12
      through 17 years). METHODS: We conducted a random digit dialing survey of the
      residents of Wichita, Kansas. Adults identified fatigued adolescents in the
      household and answered questions relating to the child's health. Selected
      adolescents were invited to attend a clinic with a parent/guardian. After
      clinical evaluation they were classified as CFS or another fatigue state as
      defined in the 1994 CFS definition. Annual telephone interviews and clinical
      evaluations monitored subjects' fatigue status. Data were analyzed using the
      Kruskal-Wallis test, the Mantel-Haenszel test, and the exact McNemar test.
      RESULTS: The survey contacted 34,018 households with 90,316 residents. Of 8586
      adolescents, 138 had fatigue for > or =1 month and most (107 or 78%) had chronic
      fatigue (> or =6 months) at some point during the 3-year follow-up. Twenty-eight
      had exclusionary diagnoses. Thirty-one were considered to have a CFS-like illness
      and were invited for clinical evaluation. Eleven agreed to participate and none
      met the CFS case definition. The baseline weighted prevalence of CFS-like illness
      was 338 per 100,000. Significant differences existed between parental and
      adolescents' descriptions of illness. CONCLUSIONS: The prevalence of CFS among
      adolescents was considerably lower than among adults. Evaluation of CFS in
      adolescents must consider both parent and patient perception of fatigue and other
      illnesses that might explain the symptom complex.

PMID- 15193573
TI  - The influence of wanting to look like media figures on adolescent physical
      activity.
AB  - PURPOSE: To examine the association of adolescents' wanting to look like figures
      in the media with physical activity levels. METHODS: Cross-sectional mailed
      survey of 11,606 boys and girls, between the ages of 9 and 16 years,
      participating in the Growing Up Today Study in 1997. Participants reported
      detailed information on physical activities over the previous year, and the
      degree to which they were trying to look like same-sex images in television,
      movies, and magazines. We performed linear regression modeling to assess the
      independent effects of wanting to look like figures in the media on physical
      activity levels. RESULTS: Mean total weekly physical activity levels were 12.4
      hours in girls and 15.2 hours in boys. 3019 (46%) girls and 1360 (27%) boys
      reported making at least some effort to look like figures in the media. Adjusted
      for age, body mass index, sexual maturity rating, and race/ethnicity, total
      physical activity levels were higher by 0.7 (95% CI 0.5-0.9) and 1.2 (95% CI 0.9
      1.6) hours per week in girls and boys, respectively, for every 1 (out of 5)
      category increase in wanting to look like figures in the media. Adjustment for
      intrapersonal and social confounders modestly attenuated the associations.
      CONCLUSIONS: Wanting to look like figures in the media was associated with higher
      physical activity levels among older children and adolescents, independent of
      other personal and social influences. These data suggest that television, movie,
      and magazine industries should be encouraged to cultivate and reinforce realistic
      and healthy norms of physical activity and body image.

PMID- 15193571
TI  - Defining and understanding healthy lifestyles choices for adolescents.
AB  - PURPOSE: To: (a) establish criteria for defining positive health behaviors and
      lifestyle; and (b) identify characteristics of adolescents who practice a healthy
      lifestyle. METHODS: Responses from a 1998 survey via questionnaire, of 1487
      students, from a public high school, Cambridge, Massachusetts, were used to
      assess correlates of healthy lifestyle choices. Strict and broad assessments of
      healthy behaviors were defined for students: use of alcohol, tobacco, and illegal
      drugs; sexual behavior; attempted suicide. Whereas the "strict" criteria included
      only those adolescents who did not practice any of the behaviors in question, the
      broad criteria reflected experimentation and moderate risk-taking. The prevalence
      of positive behaviors was assessed by demographic and student characteristics. In
      addition, logistic regression models were created to predict determinants of
      teenagers' healthy lifestyles using both strict and broad definitions. RESULTS:
      Using strict criteria of healthy lifestyle, significant predictors were being
      female, born outside the United States, higher academic performance, and fewer
      stressful life events. Using a broad definition of a healthy lifestyle,
      significant predictors were being non-Caucasian, in the lower grade levels at the
      school, higher academic performance, and fewer stressful life events. In both
      models, peers' approval of risky behaviors negatively influenced teens'
      lifestyles, whereas parents' disapproval of risky behaviors was a positive
      influence. CONCLUSIONS: These results reinforce the importance of school, peer,
      and parent support of positive behaviors. It is important for public health
      workers and families to understand and define healthy lifestyles choices for
      adolescents.

PMID- 15193574
TI  - The development and pilot-testing of a training curriculum in adolescent medicine
      and health.
AB  - PURPOSE: To select and propose a set of knowledge, attitudes, and skills
      essential for the care of adolescents; to encourage the development of adolescent
      health multidisciplinary networks; and to set up training programs in as many
      European countries as possible. METHODS: The curriculum was developed by 16
      physicians from 11 European countries with various professional specializations.
      In line with modern guidelines in medical education, it is a modular, flexible
      instrument which covers the main teaching areas in the field, such as basic
      skills (i.e. setting, rights and confidentiality, gender and cultural issues) as
      well as specific themes (i.e. sexual and reproductive health, eating disorders,
      chronic conditions). It consists of 17 thematic modules, each containing detailed
      objectives, learning approaches, examples, and evaluation methods. RESULT: Two
      international one-week summer schools were used to assess the feasibility and
      appropriateness of the curriculum. The overall evaluation was good, with most of
      the items surpassing three on a four-point Likert scale. However, it pointed to
      several aspects (process and content) which will need to be refined in the
      future, such as an increase in interactive sessions (role playing), and a better
      mix of clinical and public health issues.

PMID- 15193575
TI  - Contemporary college students and body piercing.
AB  - Student (N = 450) demographic characteristics (parental composition and
      relationships, and religious participation) were documented in those with body
      piercings (32%) and those without body piercings (55%), yet many risky behaviors
      were present, including tattooing (22%). Major piercing purposes were self
      expression and identity, rather than deviancy or rebellion.

PMID- 15193576
TI  - Evaluation of a brief computer-mediated intervention to reduce HIV risk among
      early adolescent females.
AB  - PURPOSE: To evaluate the efficacy of a brief computer-mediated intervention,
      relative to no intervention, in altering HIV/AIDS-related knowledge, protective
      attitudes, and self-efficacy for risk reduction among early adolescent females
      aged 11 through 14 years. METHOD: Recruited through the auspices of a large
      social services agency with multiple sites across New York City, a volunteer
      sample of 205 Black, White, and Hispanic young women participated in this
      research. The efficacy of the software intervention was examined in a randomized
      blocks design with site as the unit of randomization. Young women at experimental
      arm sites interacted with the software in a single 30-minute session. Youths at
      control arm sites participated in regular programs offered at these sites, but
      did not receive the intervention until all planned assessments were concluded.
      Before and after intervention, participants completed measures of HIV/AIDS
      related knowledge, protective attitudes, and self-efficacy for HIV risk
      reduction. Analyses of covariance were used to test for significant between-arm
      effects. RESULTS: Between-arm effects were observed for HIV/AIDS-related
      knowledge and risk reduction self-efficacy. Experimental arm youths evidenced
      greater improvements from pretest to posttest than control-arm youths on these
      outcomes. CONCLUSION: Computer-mediated interventions may improve HIV/AIDS
      related knowledge and risk reduction self-efficacy among early adolescent
      females. However, additional research is needed to find effective computer
      mediated approaches for enhancing protective attitudes among this population.

PMID- 15193577
TI  - Singularities in diffusion tensor fields and their relevance in white matter
      fiber tractography.
AB  - The technique of diffusion tensor tractography utilizes directions of maximum
      diffusion to reconstruct pathways of white matter structures in the brain.
      Critically, successful tracking of these white matter pathways depends on well
      defined maximal diffusion directional information. By examination of diffusion
      tensor field properties in the human brain, we demonstrate that the geometry of
      tracked pathways is influenced by points in the field where the maximum diffusion
      direction is poorly defined. In common with tensor fields describing other
      mathematical and physical phenomena, such as 3D surface differential geometry and
      gravitational fields, we refer to these points as singularities. Here we describe
      an automated procedure for detecting singularities and demonstrate that these
      occur where there is (i) fiber crossing, (ii) pathways passing close to one
      another within a voxel (partial volume effect), and (iii) noise propagation into
      low anisotropy regions. In order to highlight the relevance of singularities in
      tracking white matter structures, we determined their effect on computation of
      the cortico-spinal pathway.

PMID- 15193578
TI  - Statistical parametric mapping for event-related potentials: I. Generic
      considerations.
AB  - In this paper, we frame the strategy and motivations behind developments in
      statistical parametric mapping (SPM) for the analysis of electroencephalogram
      (EEG) data. This work deals specifically with SPM procedures for the analysis of
      event-related potentials (ERP). We place these developments in the larger context
      of integrating electrophysiological and hemodynamic measurements of evoked brain
      responses through the fusion of EEG and fMRI data. In this paper, we consider
      some fundamental issues when selecting an appropriate statistical model that
      enables diverse questions to be asked of the data and at the same time retains
      maximum sensitivity. The three key issues addressed in this paper are as follows:
      (i) should multivariate or mass univariate analyses be adopted, (ii) should time
      be treated as an experimental factor or as a dimension of the measured response
      variable, and (iii) how to form appropriate explanatory variables in a
      hierarchical observation model. We review the relative merits of the different
      options and explain the rationale for our choices. In brief, we motivate a mass
      univariate approach in terms of sensitivity to region-specific responses. This
      involves modeling responses at each voxel or space bin separately. In
      contradistinction, we treat time as an experimental factor to enable inferences
      about temporally distributed responses that encompass multiple time bins. In a
      companion paper, we develop statistical models of ERPs in the time domain that
      follow from the heuristics established here and illustrate the approach using
      simulated and real data.

PMID- 15193579
TI  - Statistical parametric mapping for event-related potentials (II): a hierarchical
      temporal model.
AB  - In this paper, we describe a temporal model for event-related potentials (ERP) in
      the context of statistical parametric mapping (SPM). In brief, we project channel
      data onto a two-dimensional scalp surface or into three-dimensional brain space
      using some appropriate inverse solution. We then treat the spatiotemporal data in
      a mass-univariate fashion. This implicitly factorises the model into spatial and
      temporal components. The key contribution of this paper is the use of observation
      models that afford an explicit distinction between observation error and
      variation in the expression of ERPs. This distinction is created by employing a
      two-level hierarchical model, in which the first level models the ERP effects
      within-subject and trial type, while the second models differences in ERP
      expression among trial types and subjects. By bringing the analysis of ERP data
      into a classical hierarchical (i.e., mixed effects) framework, many apparently
      disparate approaches (e.g., conventional P300 analyses and time-frequency
      analyses of stimulus-locked oscillations) can be reconciled within the same
      estimation and inference procedure. Inference proceeds in the normal way using t
      or F statistics to test for effects that are localised in peristimulus time or in
      some time-frequency window. The use of F statistics is an important
      generalisation of classical approaches, because it allows one to test for effects
      that lie in a multidimensional subspace (i.e., of unknown but constrained form).
      We describe the analysis procedures, the underlying theory and compare its
      performance to established techniques.

PMID- 15193580
TI  - Reciprocal modulation of neuromagnetic induced gamma activity by attention in the
      human visual and auditory cortex.
AB  - For attentional control of behavior, the brain permanently resolves a competition
      between the impressions supplied by different senses. Here, using a dual-modality
      temporal order detection task, we studied attentional modulation of oscillatory
      neuromagnetic activity in the human cerebral cortex. On each trial, after
      simultaneous exposure to visual and auditory noise, subjects were presented with
      an asynchronous pair of a visual and an auditory stimulus. Either of the two
      stimuli could occur first equally often, their order was not cued. Subjects had
      to determine the leading stimulus in a pair and attentively monitor it to respond
      upon its offset. With the attended visual or auditory stimuli, spectral power
      analysis revealed marked enhancements of induced gamma activity within 250 ms
      post-stimulus onset over the modality-specific cortices (occipital at 64 Hz,
      right temporal at 53 Hz). When unattended, however, the stimuli led to a
      significantly decreased (beneath baseline) gamma response in these cortical
      regions. The gamma decreases occurred at lower frequencies ( approximately 30 Hz)
      than did the gamma increases. An increase in the gamma power and frequency for
      the attended modality and their decrease for the unattended modality suggest that
      attentional regulation of multisensory processing involves reciprocal changes in
      synchronization of respective cortical networks. We assume that the gamma
      decrease reflects an active suppression of the task-irrelevant sensory input.
      This suppression occurs at lower frequencies, suggesting an involvement of larger
      scale cell assemblies.

PMID- 15193581
TI  - Attentional systems in target and distractor processing: a combined ERP and fMRI
      study.
AB  - The interplay of "top-down" and "bottom-up" regulated mechanisms is of particular
      relevance for the rapid (re-)focusing of attention to environmental changes. The
      purpose of the study was to explore the differential contributions of
      frontoparietal attentional networks involved in top-down and stimulus-driven
      processing to the detection of "target" and "distractor" events in a visual three
      stimulus oddball paradigm. Thirteen healthy subjects underwent separate event
      related potential (ERP) and whole-brain functional magnetic resonance imaging
      (fMRI) measurements during the oddball task. The targets, which were difficult to
      detect, elicited a classical posterior P3b whereas the distractor stimuli were
      followed by a centro-frontal P3a ERP. The fMRI data showed activation of the
      temporoparietal junction (TPJ) bilaterally and right prefrontal cortex associated
      with both the target and distractor conditions. This network has previously been
      described as an attentional system that is predominantly stimulus driven and that
      responds to rare events. Furthermore, target processing produced bilateral
      perisylvian activity, which has been related to the "retrieval mode". Processing
      of the distractors activated the frontal eye fields (FEFs) and bilateral superior
      parietal cortex, areas engaged in attention switching and voluntary allocation of
      attention. Additional left prefrontal activation suggested an involvement of the
      cortical system for working memory encoding. Our results thus demonstrate that
      distractor and target processing engage a common neuronal system for the
      detection of rare events, but also task-specific subsystems related to attention
      and memory processes.

PMID- 15193583
TI  - Cognitive- and motor-related regions in Parkinson's disease: FDOPA and FDG PET
      studies.
AB  - OBJECTIVE: Using 6-[(18)F]fluoro-L-dopa (FDOPA) and [(18)F]fluorodeoxyglucoce
      (FDG) positron emission tomography (PET), multiple regression analyses were
      performed to determine the specific brain regions that are related to cognitive
      and motor symptoms in nondemented patients with Parkinson's disease. METHODS:
      Spatially normalized images of FDOPA influx rate constant (Ki) values and
      relative regional cerebral metabolic rates for glucose (rrCMRglc) were created.
      Raven's Coloured Progressive Matrices (RCPM) scores and the Unified Parkinson's
      Disease Rating Scale (UPDRS) motor scores were used to determine the patients'
      cognitive and motor functions, respectively. Multiple correlation analyses
      between the FDOPA and FDG images and the cognitive and motor scores were
      performed for each voxel. RESULTS: RCPM score was significantly positively
      correlated with the FDOPA Ki in the left hippocampus and with the rrCMRglc in the
      left middle frontal gyrus and right retrosplenial cortex. Motor function was
      significantly positively correlated with the FDOPA Ki in the bilateral striatum
      and with the rrCMRglc in association areas and primary visual cortex. The level
      of motor function was significantly inversely correlated with the FDOPA Ki in the
      anterior cingulate gyrus and with the rrCMRglc in bilateral primary motor cortex
      and right putamen. CONCLUSIONS: Changes of striatal FDOPA uptake and rrCMRglc in
      the primary motor cortex likely represent dysfunction in the motor system
      involving the corticobasal ganglia-thalamocortical loop. Change of FDOPA uptake
      in the anterior cingulate gyrus may be related to up-regulation of dopamine
      synthesis in surviving dopamine neurons. The regions where correlation with
      cognitive function was observed belong to a cognitive frontoparietal-hippocampal
      network.

PMID- 15193582
TI  - Neural mechanism underlying impaired visual judgement in the dysmetabolic brain:
      an fMRI study.
AB  - An altered brain metabolism in the parietal and prefrontal regions of the
      cerebral cortex as well as cognitive alterations have been found in patients
      suffering from hepatic encephalopathy. The neural mechanisms underlying these
      metabolically induced cognitive alterations, however, are not known. Since
      patients with liver cirrhosis without clinically overt encephalopathy already
      show an impaired performance in a flicker light test, the aim of this study was
      to analyze the normal and pathologically impaired neural mechanisms of these
      patients using functional magnetic resonance imaging (fMRI). Nine subjects at the
      early stage of encephalopathy [nonmanifest hepatic encephalopathy (nmHE)] and ten
      controls underwent scanning, while they indicated the apparent transition from a
      steady light to the onset of a flicker light, that is, the critical flicker
      frequency (CFF). Judgement-related blood oxygenation level-dependent (BOLD)
      activation was decreased in nmHE compared to controls in the right inferior
      parietal cortex (IPL). Furthermore, the analysis of psychophysiologic interaction
      suggests impaired neural interaction in patients with nmHE, especially between
      the IPL and the parietooccipital cortex (Poc), the intraparietal sulcus, the
      anterior cingulate cortex (ACC), the right prefrontal cortex (PFC), the medial
      temporal lobe, and the extrastriate cortex V5. In contrast, nonmanifest patients
      revealed an enhanced coupling between IPL and the postcentral cortex. Our
      findings provide evidence of an early-impaired and compensatory neural mechanism
      during visual judgement already in the earliest stages of hepatic encephalopathy
      and suggest an aberrant coupling between cerebral regions in the dysmetabolic
      brain.

PMID- 15193584
TI  - Functional dissociations within the inferior parietal cortex in verbal working
      memory.
AB  - Neuroimaging studies of working memory have revealed two sites in the left
      supramarginal gyrus that may support the short-term storage of phonological
      information. Activation in the left dorsal aspect of the inferior parietal cortex
      (DIPC) has been observed in contrasts of working memory load, whereas activation
      in the ventral aspect of the inferior parietal cortex (VIPC) has been found
      primarily in contrast of information type (verbal vs. nonverbal). Our goal was to
      determine whether these two areas are functionally distinct or if instead they
      are part of a homogeneous region with large variations in the focus of peak
      activity. Toward this end, we used fMRI to assess the neural response in two
      working memory tasks (N-back and item recognition) in which we also manipulated
      memory load and the type of information to be recalled (verbal vs. nonverbal). We
      found both DIPC and VIPC activation in the same group of subjects and further
      demonstrated that they have differential sensitivity to our experimental factors.
      Only the DIPC showed robust load effects, whereas only the VIPC showed reliable
      effects of information type. These results help to account for the differences
      observed in between-subject comparisons, and they indicate that the two regions
      are functionally dissociable. In contrast to the DIPC, activity of the VIPC was
      also recruited in the fixation and low-load conditions, a surprising result that
      has not been fully explored in prior studies. Despite their distinctive patterns
      of performance, neither of these regions displayed a pattern of activity that
      entirely corresponds to common assumptions of a dedicated phonological short-term
      store (STS). Instead, we hypothesize that the DIPC may support domain-general
      executive processes, while the VIPC may support phonological encoding-recoding
      processes central to a variety of language tasks.

PMID- 15193585
TI  - Popout modulates focal attention in the primary visual cortex.
AB  - The influence of context-dependent interactions on attention-related neural
      activity was studied in the human primary visual cortex (V1) with event-related
      fMRI. Retinotopic field-sign mapping was used to determine the localization of V1
      with respect to adjacent retinotopic areas. Observers reported the orientation of
      a Gabor patch at pre-cued extrafoveal locations when it was salient among
      distractor Gabors and when it was not. Saliency was caused by local orientation
      contrast between Gabors-a mechanism that is thought to arise from context
      dependent interactions in the V1 proper. A comparison of the attention-related
      BOLD response for salient and non-salient stimuli in V1 revealed that salient
      Gabors caused a significantly smaller BOLD response than non-salient Gabors. This
      differential effect was not observed in higher-order visual areas (V3/V3A,
      MT+/LO, IPS). When attention was not focused onto the target, the size of the
      BOLD response was generally reduced in all visual areas, and no difference was
      seen in V1 for salient and non-salient Gabors. These findings suggest that
      contextual interactions underlying saliency influence attentional modulations in
      V1 and support the view that perceptual and attentional mechanisms share neural
      circuits at this early stage of visual processing.

PMID- 15193586
TI  - Separability and cross talk: optimizing dual wavelength combinations for near
      infrared spectroscopy of the adult head.
AB  - By means of noninvasive near-infrared spectroscopy (NIRS), cerebral concentration
      changes in oxygenated and deoxygenated hemoglobin ([oxy-Hb] and [deoxy-Hb]) can
      be determined. The quality of the concentration changes' assessment critically
      depends on the wavelength combination used. Trying to optimize this combination,
      two spectroscopic effects must be taken into account: cross talk and
      separability. Cross talk between [oxy-Hb] and [deoxy-Hb] occurs because the
      assumption made in the analysis-that there is a homogeneous concentration change
      does not hold true for the adult human head. Separability-to be introduced in
      this paper-is a measure for the degree of physical noise of the measurement that
      will influence the noise of the concentration changes' assessment. In other
      words, high separability corresponds to a low noise with respect to the
      concentration changes assessed. Here, we present analytical expressions for both
      measures and provide model-based estimates of cross talk and separability for any
      combination of two wavelengths between 610 and 920 nm. These theoretical
      considerations allow for two predictions: (a) if both wavelengths used are
      greater than approximately 780 nm, cross talk is high and separability is low
      resulting in erroneous and noisy concentration data. (b) If one wavelength is
      chosen below 720 nm while the other is greater than 730 nm, cross talk is low and
      separability is high resulting in accurate concentration changes. We show the
      relevance of these theoretical results for noninvasive NIRS by testing the
      predictions on experimental data obtained in adults undergoing visual
      stimulation.

PMID- 15193587
TI  - Parallel systems of error processing in the brain.
AB  - Major neurophysiological principles of performance monitoring are not precisely
      known. It is a current debate in cognitive neuroscience if an error-detection
      neural system is involved in behavioral control and adaptation. Such a system
      should generate error-specific signals, but their existence is questioned by
      observations that correct and incorrect reactions may elicit similar
      neuroelectric potentials. A new approach based on a time-frequency decomposition
      of event-related brain potentials was applied to extract covert sub-components
      from the classical error-related negativity (Ne) and correct-response-related
      negativity (Nc) in humans. A unique error-specific sub-component from the delta
      (1.5-3.5 Hz) frequency band was revealed only for Ne, which was associated with
      error detection at the level of overall performance monitoring. A sub-component
      from the theta frequency band (4-8 Hz) was associated with motor response
      execution, but this sub-component also differentiated error from correct
      reactions indicating error detection at the level of movement monitoring. It is
      demonstrated that error-specific signals do exist in the brain. More importantly,
      error detection may occur in multiple functional systems operating in parallel at
      different levels of behavioral control.

PMID- 15193588
TI  - Improvement of fMRI data processing of olfactory responses with a perception
      based template.
AB  - Neuroimaging and in particular functional magnetic resonance imaging (fMRI) of
      olfactory function relies on the ability to model the time course of brain
      responses elicited by odor stimuli. In this study we compared two templates of
      olfactory brain activation by comparing levels of correlation in regions critical
      to olfactory processing with either a stimulation-based template or a perception
      based template, derived from perception profiles acquired off-line during a
      simulated fMRI session. fMRI signal was more correlated with the perception-based
      template than with the stimulation-based template in all regions. This effect was
      not observed when comparing correlations obtained with the exact same templates
      shifted in time by 12 s. Therefore, the improvement due to the use of the
      perception-based template was not only caused by a difference of shape between
      the stimulation-based and the perception-based template but was specifically
      related to the olfactory stimulation performed. These results suggest that the
      perception-based template better represents brain activity in response to
      olfactory stimulation and might help improve data processing of fMRI studies
      investigating olfactory function.

PMID- 15193589
TI  - Proton MRI of metabolically produced H2 17O using an efficient 17O2 delivery
      system.
AB  - In vivo detection of H(2)(17)O produced via metabolic reduction of inhaled (17)O
      enriched gas is demonstrated using proton magnetic resonance imaging (MRI).
      Specifically, (1)H T(1rho)-weighted MRI, which may be readily implemented on any
      MRI scanner, is applied as an indirect (17)O imaging method to quantitatively
      monitor the distribution of metabolically produced (17)O water (mpH(2)(17)O) in
      the rat brain. The delivery of (17)O(2) to rats is conducted via a specially
      designed closed respiration circuit that conserves the expensive gas.
      Quantitative mapping of H(2)(17)O performed via (1)H T(1rho)-weighted MRI is
      validated by direct (17)O-magnetic resonance spectroscopy. The MRI data show that
      a steady-state H(2)(17)O concentration of 25.7 +/- 1.66 mM (n = 4) is achieved in
      the rat brain within approximately 30 min under the (17)O inhalation paradigm
      used. From the first minute of the mpH(2)(17)O time courses, cerebral metabolic
      rate of oxygen (CMRO(2)) is estimated to be 2.10 +/- 0.44 micromol g(-1) min(-1)
      (n = 4), a value that is consistent with the literature.

PMID- 15193590
TI  - A voxel-based investigation of brain structure in male adolescents with autistic
      spectrum disorder.
AB  - Autistic spectrum disorder (ASD) has been associated with abnormal neuroanatomy
      in many imaging and neuropathological studies. Both global brain volume
      differences and differences in the size of specific neural structures have been
      reported. Here, we report a voxel-based morphometric whole brain analysis, using
      a group specific template, on 16 individuals of normal intelligence with autistic
      spectrum disorder (ASD), and a group of 16 age-, sex- and IQ-matched controls.
      Total grey matter volume was increased in the ASD group relative to the control
      group, with local volume increases in the right fusiform gyrus, the right temporo
      occipital region and the left frontal pole extending to the medial frontal
      cortex. A local decrease in grey matter volume was found in the right thalamus. A
      decrease in global white matter volume in the ASD group did not reach
      significance. We found the increase in grey matter volume in ASD subjects was
      greatest in those areas recognised for their role in social cognition,
      particularly face recognition (right fusiform gyrus), mental state attribution:
      'theory of mind' (anterior cingulate and superior temporal sulcus) and perception
      of eye gaze (superior temporal gyrus). The picture as a whole may reflect an
      abnormally functioning social cognitive neural network. We suggest that increased
      grey matter volume may play a pivotal role in the aetiology of the autistic
      syndrome.

PMID- 15193591
TI  - Gender differences in the left inferior frontal gyrus in normal children.
AB  - This study examined frontal lobe subregions in 46 normal children and adolescents
      (25 females, mean age: 11.08, SD: 3.07; and 21 males, mean age: 10.76, SD: 2.61)
      to assess the effects of age and gender on volumetric measures as well as
      hemispheric asymmetries. Superior, middle, inferior, and orbito-frontal gray,
      white, and cerebrospinal (CSF) volumes were manually delineated in high
      resolution magnetic resonance imaging (MRI) data to assess possible morphological
      changes. We report a significant age-related increase in the white matter of the
      left inferior frontal gyrus (IFG) in boys (P = 0.007). Additionally, the left IFG
      was significantly larger in boys compared to girls (P = 0.004). Boys showed
      increased gray matter volume relative to girls even after correcting for total
      cerebral volume. Also, boys were found to have significant Right > Left asymmetry
      patterns with greater right hemispheric volumes for total cerebral volume, total
      cerebral white matter, MFG white matter, and SFG white matter (P < 0.001). Girls
      showed significant Right > Left asymmetry patterns in total cerebral and SFG
      white matter (P < 0.001). These findings suggest continued modification of the
      IFG during normal development in boys, and significant gender differences in IFG
      gray matter between boys and girls that may be possibly linked to gender
      differences in speech development and lateralization of language.

PMID- 15193592
TI  - The thalamus as the generator and modulator of EEG alpha rhythm: a combined
      PET/EEG study with lorazepam challenge in humans.
AB  - BACKGROUND: Purpose of this study was to investigate the functional relationship
      between electroencephalographic (EEG) alpha power and cerebral glucose metabolism
      before and after pharmacological alpha suppression by lorazepam. METHODS: Ten
      healthy male volunteers were examined undergoing two F18-fluorodeoxyglucose (18
      FDG) positron emission tomography (PET) scans with simultaneous EEG recording: 1x
      placebo, 1x lorazepam. EEG power spectra were computed by means of Fourier
      analysis. The PET data were analyzed using SPM99, and the correlations between
      metabolism and alpha power were calculated for both conditions. RESULTS: The
      comparison lorazepam versus placebo revealed reduced glucose metabolism of the
      bilateral thalamus and adjacent subthalamic areas, the occipital cortex and
      temporo-insular areas (P < 0.001). EEG alpha power was reduced in all derivations
      (P < 0.001). Under placebo, there was a positive correlation between alpha power
      and metabolism of the bilateral thalamus and the occipital and adjacent parietal
      cortex (P < 0.001). Under lorazepam, the thalamic and parietal correlations were
      maintained, whereas the occipital correlation was no longer detectable (P <
      0.001). The correlation analysis of the difference lorazepam-placebo showed the
      alpha power exclusively correlated with the thalamic activity (P < 0.0001).
      CONCLUSIONS: These results support the hypothesis of a close functional
      relationship between thalamic activity and alpha rhythm in humans mediated by
      corticothalamic loops which are independent of sensory afferences. The study
      paradigm could be a promising approach for the investigation of cortico-thalamo
      cortical feedback loops in neuropsychiatric diseases.

PMID- 15193593
TI  - Detection and detrending in fMRI data analysis.
AB  - This article addresses the impact that colored noise, temporal filtering, and
      temporal detrending have on the fMRI analysis situation. Specifically, it is
      shown why the detection of event-related designs benefit more from pre-whitening
      than blocked designs in a colored noise structure. Both theoretical and empirical
      results are provided. Furthermore, a novel exploratory method for producing drift
      models that efficiently capture trends and drifts in the fMRI data is introduced.
      A comparison to currently employed detrending approaches is presented. It is
      shown that the novel exploratory model is able to remove a major part of the
      slowly varying drifts that are abundant in fMRI data. The value of such a model
      lies in its ability to remove drift components that otherwise would have
      contributed to a colored noise structure in the voxel time series.

PMID- 15193594
TI  - A voxel-based approach to gray matter asymmetries.
AB  - Voxel-based morphometry (VBM) was used to analyze gray matter (GM) asymmetries in
      a large sample (n = 60) of male and female professional musicians with and
      without absolute pitch (AP). We chose to examine these particular groups because
      previous studies using traditional region-of-interest (ROI) analyses have shown
      differences in hemispheric asymmetry related to AP and gender. Voxel-based
      methods may have advantages over traditional ROI-based methods since the analysis
      can be performed across the whole brain with minimal user bias. After determining
      that the VBM method was sufficiently sensitive for the detection of differences
      in GM asymmetries between groups, we found that male AP musicians were more
      leftward lateralized in the anterior region of the planum temporale (PT) than
      male non-AP musicians. This confirmed the results of previous studies using ROI
      based methods that showed an association between PT asymmetry and the AP
      phenotype. We further observed that male non-AP musicians revealed an increased
      leftward GM asymmetry in the postcentral gyrus compared to female non-AP
      musicians, again corroborating results of a previously published study using ROI
      based methods. By analyzing hemispheric GM differences across our entire sample,
      we were able to partially confirm findings of previous studies using traditional
      morphometric techniques, as well as more recent, voxel-based analyses. In
      addition, we found some unusually pronounced GM asymmetries in our musician
      sample not previously detected in subjects unselected for musical training. Since
      we were able to validate gender- and AP-related brain asymmetries previously
      described using traditional ROI-based morphometric techniques, the results of our
      analyses support the use of VBM for examinations of GM asymmetries.

PMID- 15193595
TI  - Cortical lateralization during verb generation: a combined ERP and fMRI study.
AB  - Lateralization of scalp-recorded event-related potentials (ERPs) and functional
      MRI (fMRI) activation was investigated using a verb generation task in 10 healthy
      right-handed adults. ERPs showed an early transient positivity in the left
      inferior temporal region (500-1250 ms) following auditory presentation of the
      stimulus noun. A sustained slow cortical negativity of later onset (1250-3000 ms)
      was then recorded, most pronounced over left inferior frontal regions. fMRI data
      were in agreement with both ERP effects, showing left lateralized activation in
      inferior and superior temporal as well as inferior frontal cortices. Lateralized
      ERP effects occurred during the verb generation task but not during passive word
      listening or during word- and nonword repetition. Thus, ERPs and fMRI provided
      convergent evidence regarding language lateralization, with ERPs revealing the
      temporal sequence of posterior to anterior cortical activation during semantic
      retrieval.

PMID- 15193596
TI  - Nonstationary cluster-size inference with random field and permutation methods.
AB  - Because of their increased sensitivity to spatially extended signals, cluster
      size tests are widely used to detect changes and activations in brain images.
      However, when images are nonstationary, the cluster-size distribution varies
      depending on local smoothness. Clusters tend to be large in smooth regions,
      resulting in increased false positives, while in rough regions, clusters tend to
      be small, resulting in decreased sensitivity. Worsley et al. proposed a random
      field theory (RFT) method that adjusts cluster sizes according to local roughness
      of images [Worsley, K.J., 2002. Nonstationary FWHM and its effect on statistical
      inference of fMRI data. Presented at the 8th International Conference on
      Functional Mapping of the Human Brain, June 2-6, 2002, Sendai, Japan. Available
      on CD-ROM in NeuroImage 16 (2) 779-780; Hum. Brain Mapp. 8 (1999) 98]. In this
      paper, we implement this method in a permutation test framework, which requires
      very few assumptions, is known to be exact [J. Cereb. Blood Flow Metab. 16 (1996)
      7] and is robust [NeuroImage 20 (2003) 2343]. We compared our method to
      stationary permutation, stationary RFT, and nonstationary RFT methods. Using
      simulated data, we found that our permutation test performs well under any
      setting examined, whereas the nonstationary RFT test performs well only for
      smooth images under high df. We also found that the stationary RFT test becomes
      anticonservative under nonstationarity, while both nonstationary RFT and
      permutation tests remain valid under nonstationarity. On a real PET data set we
      found that, though the nonstationary tests have reduced sensitivity due to
      smoothness estimation variability, these tests have better sensitivity for
      clusters in rough regions compared to stationary cluster-size tests. We include a
      detailed and consolidated description of Worsley nonstationary RFT cluster-size
      test.

PMID- 15193597
TI  - Where arousal meets attention: a simultaneous fMRI and EEG recording study.
AB  - In this fMRI study, we looked for the regions supporting interaction between
      cortical arousal and attention during three conditions: detection, observation,
      and rest. Arousal measurements were obtained from the EEG low-frequency (LF)
      power (5-9.5 Hz) recorded continuously together with fMRI. Whatever the
      condition, arousal was positively correlated with the fMRI signal of the right
      dorsal-lateral prefrontal and superior parietal cortices, closely overlapping
      regions involved in the maintenance of attention. Although the inferior temporal
      areas also presented a correlation with arousal during detection, path analysis
      suggests that this influence may be indirect, through the top-down influence of
      the previously mentioned network. However, those visual-processing areas could
      account for the correlation between arousal and performances. Lastly, the medial
      frontal cortex, frontal opercula, and thalamus were inversely correlated with
      arousal but only during detection and observation so that they could account for
      the control of arousal.

PMID- 15193598
TI  - ADC mapping of neurodegeneration in the brainstem and cerebellum of patients with
      progressive ataxias.
AB  - Analysis of the apparent diffusion coefficient (ADC) maps derived from diffusion
      weighted MR imaging is emerging as a reproducible, sensitive, and quantitative
      tool to evaluate brain damage in diseases of the white and gray matter. To
      explore the potentials of ADC maps analysis in degenerative ataxias, we examined
      28 patients and 26 age-matched controls with T1, T2, and diffusion (b values 0
      1000 along the three main body axes)-weighted MR images. Twenty-four patients had
      inherited genetically proven diseases including spinocerebellar ataxia type 1
      (SCA1) (n = 9), spinocerebellar ataxia type 2 (SCA2) (n = 8), and Friedreich's
      ataxia (FA) (n = 7), whereas four patients had sporadic adult onset pure
      cerebellar ataxia (three idiopathic, one gluten intolerance). Area and linear
      measurements of the CNS structures contained in the posterior cranial fossa (PCF)
      preliminary enabled classification of the patients in the three morphological
      categories reflecting the gross pathology findings, namely olivopontocerebellar
      atrophy (OPCA) (n = 10: six SCA2 and four SCA1), spinal atrophy (SA) (n = 7: all
      FA), and cortical cerebellar atrophy (CCA) (n = 4: three idiopathic and one
      gluten intolerance). Seven patients with SCA1 (n = 5) or SCA2 (n = 2) had
      morphologic changes reminiscent of OPCA, but their values were still in the lower
      normal range and were classified as undefined. Mean diffusivity (D) maps of the
      entire brain were generated and D was measured with regions of interest (ROI) in
      the medulla, pons, middle cerebellar peduncles, and the peridentate white matter.
      Moreover, after exclusion of the skull with manual segmentation and of the CSF
      with application of a threshold value, histograms were obtained for D of the
      brainstem and cerebellum and for D of the cerebral hemispheres. As compared to
      controls, a (P < 0.001) increase of D was observed in the medulla, middle
      cerebellar peduncles, and peridentate white matter in OPCA and undefined patients
      groups who had also significantly increased values of the 25th and 50th
      percentiles in the brainstem and cerebellum D histogram. In CCA (P = 0.01), an
      increase of the 25th and 50th percentile of the D value was observed in the
      brainstem and cerebellum histograms. The SA group showed (P < 0.001) an increased
      D in the medulla only. A correlation between clinical severity as assessed with
      the Inherited Ataxias Clinical Rating Scale (IACRS) and the 50th percentile of
      the D value in the brainstem and cerebellum histogram (r = 0.69) was observed in
      patients with SCA1 or SCA2. Diffusion MR imaging reveals variable patterns of
      increase of D in the brainstem, cerebellum, and cerebral hemispheres in
      degenerative ataxias that match the known distribution of the neuropathological
      changes.

PMID- 15193600
TI  - Abnormal association between reduced magnetic mismatch field to speech sounds and
      smaller left planum temporale volume in schizophrenia.
AB  - Schizophrenia is associated with language-related dysfunction. A previous study
      [Schizophr. Res. 59 (2003c) 159] has shown that this abnormality is present at
      the level of automatic discrimination of change in speech sounds, as revealed by
      magnetoencephalographic recording of auditory mismatch field in response to
      across-category change in vowels. Here, we investigated the neuroanatomical
      substrate for this physiological abnormality. Thirteen patients with
      schizophrenia and 19 matched control subjects were examined using
      magnetoencephalography (MEG) and high-resolution magnetic resonance imaging (MRI)
      to evaluate both mismatch field strengths in response to change between vowel /a/
      and /o/, and gray matter volumes of Heschl's gyrus (HG) and planum temporale
      (PT). The magnetic global field power of mismatch response to change in phonemes
      showed a bilateral reduction in patients with schizophrenia. The gray matter
      volume of left planum temporale, but not right planum temporale or bilateral
      Heschl's gyrus, was significantly smaller in patients with schizophrenia compared
      with that in control subjects. Furthermore, the phonetic mismatch strength in the
      left hemisphere was significantly correlated with left planum temporale gray
      matter volume in patients with schizophrenia only. These results suggest that
      structural abnormalities of the planum temporale may underlie the functional
      abnormalities of fundamental language-related processing in schizophrenia.

PMID- 15193601
TI  - Structure-seeking multilinear methods for the analysis of fMRI data.
AB  - In comprehensive fMRI studies of brain function, the data structures often
      contain higher-order ways such as trial, task condition, subject, and group in
      addition to the intrinsic dimensions of time and space. While multivariate
      bilinear methods such as principal component analysis (PCA) have been used
      successfully for extracting information about spatial and temporal features in
      data from a single fMRI run, the need to unfold higher-order data sets into
      bilinear arrays has led to decompositions that are nonunique and to the loss of
      multiway linkages and interactions present in the data. These additional
      dimensions or ways can be retained in multilinear models to produce structures
      that are unique and which admit interpretations that are neurophysiologically
      meaningful. Multiway analysis of fMRI data from multiple runs of a bilateral
      finger-tapping paradigm was performed using the parallel factor (PARAFAC) model.
      A trilinear model was fitted to a data cube of dimensions voxels by time by run.
      Similarly, a quadrilinear model was fitted to a higher-way structure of
      dimensions voxels by time by trial by run. The spatial and temporal response
      components were extracted and validated by comparison to results from traditional
      SVD/PCA analyses based on scenarios of unfolding into lower-order bilinear
      structures.

PMID- 15193599
TI  - Sulcal pattern and morphology of the superior temporal sulcus.
AB  - The superior temporal sulcus (STs) is the main sulcal landmark of the external
      temporal cortex and is very important for functional (posterior language areas on
      the left) mapping and surgery. The methodology we use is based on the extraction
      of the 3D shape of sulci and their separation into subunits called sulcal roots.
      Seventeen normal brains (male: 11, female: 6, age: 22-60) were systematically
      analyzed. Additionally, parameters generated by visual observation were recorded.
      Non-parametric statistics were performed to evaluate the variation of the STs and
      influence of side, handedness and sex. We found that the 3D architecture of the
      STs was consistent with our generic model in four sulcal roots and four "plis de
      passage" (PP) and significant differences between right and left hemispheres.
      These morphological differences may be related to the language-relevant cortical
      areas difference and are pertinent for defining the limits of morphometric
      variability of the STs in "normal humans".

PMID- 15193602
TI  - Noninvasive in vivo demonstration of the connections of the human parahippocampal
      gyrus.
AB  - MR tractography techniques provide a method for noninvasively studying white
      matter pathways in vivo. In this study we have used diffusion tensor imaging
      (DTI) and the fast marching tractography (FMT) algorithm to plot the structural
      connectivity of the human parahippocampal gyrus (PHG) in 10 healthy subjects,
      using seed points selected in the anterior parahippocampal gyrus. Our results
      demonstrate connectivity between the parahippocampal gyrus and the anterior
      temporal lobe, orbitofrontal areas, posterior temporal lobe and extrastriate
      occipital lobe via the lingual and fusiform gyri. We also demonstrate for the
      first time noninvasively direct connectivity between the parahippocampal gyrus
      and the hippocampus itself. These results agree with previous histological tract
      tracing studies in animals. The connections demonstrated between neocortical
      areas and the hippocampus via the parahippocampal gyrus may provide the
      structural basis for theoretical models of memory and higher visual processing.

PMID- 15193603
TI  - Resolving dual-task interference: an fMRI study.
AB  - The human cognitive system is severely limited in the amount of information it
      can process simultaneously. When two tasks are presented within a short stimulus
      onset-asynchrony (SOA), reaction time of each task, especially task 2, is
      dramatically delayed. Previous studies have shown that such delay is accompanied
      by increased activation in the right inferior frontal gyrus (GFi). In this study,
      we address the role of right GFi in resolving dual-task interference at two
      different stages: allocation of perceptual attention and response selection. We
      scan 12 subjects using functional MRI while they conduct two tasks-shape
      discrimination in task 1 and color discrimination in task 2-and vary the SOA
      between tasks as 100 or 1500 ms. The targets are located at the center or at the
      periphery. When both are at the center, they compete primarily for response
      selection. When both are at the periphery, they additionally compete for the
      allocation of perceptual attention. Results show that the right GFi and frontal
      operculum regions are significantly more active in the short SOA than the long
      SOA condition, but only when subjects attend to the periphery in both tasks. We
      conclude that the right lateral frontal regions are important for resolving dual
      task interference at the perceptual attention stage.

PMID- 15193604
TI  - Temporal dynamics of pitch in human auditory cortex.
AB  - Recent functional imaging studies have shown that sounds with temporal pitch
      produce selective activation in anterolateral Heschl's gyrus. This paper reports
      a magnetoencephalographic (MEG) study of the temporal dynamics of this
      activation. The cortical response specific to pitch was isolated from the
      intensity-related response in Planum temporale using a 'continuous stimulation'
      paradigm in which regular and irregular click trains alternate without
      interruption. The mean interclick interval (ICI) was 6, 12, 24, or 48 ms; the
      train length was 720 ms. The auditory sustained field serves as a level-dependent
      baseline that enhances the signal-to-noise ratio over previous techniques. The
      onset of pitch was accompanied by a prominent transient field, followed by a
      strong sustained field, both of which were associated with sources in lateral
      Heschl's gyrus. The sustained field rose from baseline about 70 ms after the
      onset of temporal regularity, asymptoted at about 450 ms, and commenced its
      return to baseline about 70 ms after pitch offset. The peak of the transient
      field occurred between 130 and 190 ms after regularity onset depending on the
      ICI. The latencies of the cortical pitch response are substantially longer than
      might be anticipated from temporal models of pitch perception. This finding
      suggests that the temporal integration associated with periodicity processing
      occurs in a subcortical structure, and that the cortical responses reflect
      subsequent processes involving the measurement of pitch values and changes in
      pitch.

PMID- 15193605
TI  - Infrared oculography-validation of a new method to monitor startle eyeblink
      amplitudes during fMRI.
AB  - Amplitude modulation of the eyeblink component of the startle response is a
      commonly used index for the emotional state of an organism. The use of
      electromyography (EMG) to determine startle eyeblink amplitudes during functional
      magnetic resonance imaging (fMRI) is limited as interactions between strong
      switching magnetic fields, radio pulses and electrodes introduce large artefacts
      in EMG recordings. We demonstrate a robust linear correlation between time
      courses and amplitudes of startle eyeblinks recorded by EMG and infrared
      oculography (IOG), an fMRI compatible technique based on infrared light
      reflection from the subject's eye. Moreover, our data indicate that IOG, like
      EMG, recordings of startle eyeblink amplitudes are predicted by verbal ratings of
      the emotional valence of pictorial foreground stimuli. Thus, IOG provides a valid
      method to record startle eyeblinks and might be used to monitor affective state
      during fMRI.

PMID- 15193606
TI  - Hemodynamic and metabolic responses to neuronal inhibition.
AB  - Functional magnetic resonance imaging (fMRI) was used to investigate the changes
      in blood oxygenation level dependent (BOLD) signal, cerebral blood flow (CBF) and
      cerebral metabolic rate of oxygen consumption (CMR(O(2))) accompanying neuronal
      inhibition. Eight healthy volunteers performed a periodic right-hand pinch grip
      every second using 5% of their maximum voluntary contraction (MVC), a paradigm
      previously shown to produce robust ipsilateral neuronal inhibition. To
      simultaneously quantify CBF and BOLD signals, an interleaved multislice pulsed
      arterial spin labeling (PASL) and T(2)*-weighted gradient echo sequence was
      employed. The CMR(O(2)) was calculated using the deoxyhemoglobin dilution model,
      calibrated by data measured during graded hypercapnia. In all subjects, BOLD, CBF
      and CMR(O(2)) signals increased in the contralateral and decreased in the
      ipsilateral primary motor (M1) cortex. The relative changes in CMR(O(2)) and CBF
      were linearly related, with a slope of approximately 0.4. The coupling ratio thus
      established for both positive and negative CMR(O(2)) and CBF changes is in close
      agreement with the ones observed by earlier studies investigating M1 perfusion
      and oxygen consumption increases. These findings characterize the hemodynamic and
      metabolic downregulation accompanying neuronal inhibition and thereby establish
      the sustained negative BOLD response as a marker of neuronal deactivation.

PMID- 15193608
TI  - Differentiation of extrastriatal dopamine D2 receptor density and affinity in the
      human brain using PET.
AB  - Dopaminergic neurotransmission in extrastriatal regions may play a crucial role
      in the pathophysiology and treatment of neuropsychiatric disorders. The high
      affinity radioligands [(11)C]FLB 457, [(123)I]epidepride, and [(18)F]fallypride
      are now used in clinical studies to measure these low-density receptor
      populations in vivo. However, a single determination of the regional binding
      potential (BP) does not differentiate receptor density (B(max)) from the apparent
      affinity (K(D)). In this positron emission tomography (PET) study, we measured
      extrastriatal dopamine D2 receptor density (B(max)) and apparent affinity (K(D))
      in 10 healthy subjects using an in vivo saturation approach. Each subject
      participated in two to three PET measurements with different specific
      radioactivity of [(11)C]FLB 457. The commonly used simplified reference tissue
      model (SRTM) was used in a comparison of BP values with the B(max) values
      obtained from the saturation analysis. The calculated regional receptor density
      values were of the same magnitude (0.33-1.68 nM) and showed the same rank order
      as reported from postmortem studies, that is, in descending order thalamus,
      lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity
      ranged from 0.27 to 0.43 nM, that is, approximately 10-20 times the value found
      in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was
      slightly lower (11 +/- 8%, mean +/- SD, P = 0.004, n = 10) after injection of low
      as compared with high specific radioactivity, indicating sensitivity to the
      minute density of dopamine D2 receptors in the this region. The results of the
      present study support that dopamine D2 receptor density and affinity can be
      differentiated in low-density regions using a saturation approach. There was a
      significant (P < 0.001) correlation between the binding potential calculated with
      SRTM and the receptor density (B(max)), which supports the use of BP in clinical
      studies where differentiation of B(max) and K(D) is not required. In such
      studies, the mass of FLB 457 has to be less than 0.5 microg injected to avoid a
      mass effect of the radioligand itself.

PMID- 15193609
TI  - Estimation and classification of fMRI hemodynamic response patterns.
AB  - In this paper, we propose an approach to modeling functional magnetic resonance
      imaging (fMRI) data that combines hierarchical polynomial models, Bayes
      estimation, and clustering. A cubic polynomial is used to fit the voxel time
      courses of event-related design experiments. The coefficients of the polynomials
      are estimated by Bayes estimation, in a two-level hierarchical model, which
      allows us to borrow strength from all voxels. The voxel-specific Bayes polynomial
      coefficients are then transformed to the times and magnitudes of the minimum and
      maximum points on the hemodynamic response curve, which are in turn used to
      classify the voxels as being activated or not. The procedure is demonstrated on
      real data from an event-related design experiment of visually guided saccades and
      shown to be an effective alternative to existing methods.

PMID- 15193607
TI  - Localization of realistic cortical activity in MEG using current multipoles.
AB  - We present a novel approach to MEG source estimation based on a regularized first
      order multipole solution. The Gaussian regularizing prior is obtained by
      calculation of the sample mean and covariance matrix for the equivalent moments
      of realistic simulated cortical activity. We compare the regularized multipole
      localization framework to the classical dipole and general multipole source
      estimation methods by evaluating the ability of all three solutions to localize
      the centroids of physiologically plausible patches of activity simulated on the
      surface of a human cerebral cortex. The results, obtained with a realistic sensor
      configuration, a spherical head model, and given in terms of field and
      localization error, depict the performance of the dipolar and multipolar models
      as a function of variable source surface area (50-500 mm(2)), noise conditions
      (20, 10, and 5 dB SNR), source orientation (0-90 degrees ), and source depth (3
      11 cm). We show that as the sources increase in size, they become less accurately
      modeled as current dipoles. The regularized multipole systematically outperforms
      the single dipole model, increasingly so as the spatial extent of the sources
      increases. In addition, our simulations demonstrate that as the orientation of
      the sources becomes more radial, dipole localization accuracy decreases
      substantially, while the performance of the regularized multipole model is far
      less sensitive to orientation and even succeeds in localizing quasi-radial source
      configurations. Furthermore, our results show that the multipole model is able to
      localize superficial sources with higher accuracy than the current dipole. These
      results indicate that the regularized multipole solution may be an attractive
      alternative to current-dipole-based source estimation methods in MEG.

PMID- 15193610
TI  - Cortical activation during a spatiotemporal tactile comparison task.
AB  - Tactile sensory memory is needed to infer shape or motion from the spatiotemporal
      pattern of sensory input during manual exploration. Here we applied triplets of
      pressure pulses to the fingertips of subjects who were asked to respond when
      successive triplets were the same (COMPARE task) or when a particular stimulus
      was included in a triplet (CONTROL task). Stimulus sequences (30 s) alternated
      with rest blocks (30 s) and functional magnetic resonance images (fMRIs) were
      acquired in a 1.5-T scanner. During the COMPARE task, we found enhanced
      activation in inferior parietal cortex, supplementary motor area (SMA), and right
      dorsolateral prefrontal cortex (DLPFC). Activation of DLPFC is likely to be
      related to the attempt to memorize the stimulus sequences and activations of SMA
      and inferior parietal cortex to the analysis of temporospatial tactile patterns
      and, more generally, to guidance of haptic exploration. In addition, task
      specific activation was seen in anterior cingulate gyrus, possibly related to the
      high mental effort required by the comparison task. Our rhythmic tactile stimulus
      as such, without any task-specific enhancement, activated also left cerebellum
      and (mainly left) putamen, supporting the idea that these structures are related
      to perception of temporal order of tactile stimuli.

PMID- 15193611
TI  - Endogenous and exogenous attention shifts are mediated by the same large-scale
      neural network.
AB  - Event-related fMRI was used to examine the neural basis of endogenous (top-down)
      and exogenous (bottom-up) spatial orienting. Shifts of attention were induced by
      central (endogenous) or peripheral (exogenous) cues. Reaction times on
      subsequently presented targets showed the expected pattern of facilitation and
      inhibition in both conditions. No difference in brain activity was observed when
      the two orienting conditions were contrasted with a liberal threshold, showing
      that both forms of orienting were mediated by the same neural network. Compared
      to within-block control trials, both endogenous and exogenous orienting activated
      a fronto-parietal network consisting of premotor cortex, posterior parietal
      cortex, medial frontal cortex and right inferior frontal cortex. Within these
      regions, equally strong activation was observed for both orienting conditions. It
      is concluded that endogenous and exogenous orienting are mediated by the same
      large-scale network of frontal and parietal brain areas.

PMID- 15193612
TI  - Deformable model with surface registration for hippocampal shape deformity
      analysis in schizophrenia.
AB  - Changes to the hippocampal structure have been reported as consistent structural
      abnormalities in schizophrenic patients and have been related to the learning and
      memory deficits in such patients. Although many magnetic resonance (MR) imaging
      studies have focused on the hippocampal volume, local structural changes were
      difficult to discriminate from normal neuroanatomical variations. 3D shape
      deformation analysis of the brain structure may reflect localized schizophrenic
      abnormalities. A deformable model, evolved from the ellipsoid to hippocampal
      surface, with 2562 vertexes, was developed to analyze the left and right
      hippocampus shapes in 22 schizophrenic patients and 22 healthy age and gender
      matched controls. One of the most critical issues in the shape analysis is the
      determination of homologous points between two objects. To determine more
      accurate corresponding points, an alignment procedure, consisting of coarse and
      fine steps, following a deformation process, was applied. The performance of the
      alignment process was tested using artificial data, to get the alignment error to
      within 3 degrees for each angle. A volume analysis indicated the hippocampal
      volume to be bilaterally reduced in schizophrenic patients compared to the normal
      controls, with a shape analysis showing a deformity pattern of the hippocampal
      surface. Bilateral inward deformities in the anterior and posterior hippocampus
      and a unilateral outward deformity in the right anterior hippocampus were
      observed, respectively.

PMID- 15193613
TI  - Implementation of T2*-weighted MR for multimodal image guidance in cerebral
      cavernomas.
AB  - The aim of this study was to evaluate the feasibility, the safety, and the
      usefulness of T2*-weighted magnetic resonance (MR) for neuronavigational guidance
      in patients with cerebral cavernomas. Eight patients with intracerebral
      cavernomas were operated assisted by T2*-weighted MR image-guidance. The
      cavernomas were either deep-seated or in eloquent regions. Image fusion of a
      contrast-enhanced T1-weighted gradient-echo (GRE) sequence with a T2*-weighted
      GRE sequence was performed via an automated fusion software (StealthMerge). The
      T2*-weighted images were used to secure complete resection of the cavernoma in
      all patients and to verify resection of surrounding hemosiderin-stained tissue in
      epilepsy cases. Furthermore, the multimodal neuronavigational concept included
      ultrasonography, corticography, and evoked potentials. Postoperative MR excluded
      any residual malformation in all cases. There was no postoperative morbidity; all
      epilepsy patients are seizure-free up to now. In our preliminary series, T2*-GRE
      guided neuronavigation proved useful for resection control in cavernoma surgery,
      and we suppose that it will be helpful to clarify the discussion on the value of
      resection of the surrounding hemosiderin-stained tissue.

PMID- 15193614
TI  - Imaging localised dynamic changes in the nucleus accumbens following nicotine
      withdrawal in rats.
AB  - This study utilises pharmacological functional magnetic resonance imaging (fMRI)
      to examine the neurobiological mechanisms through which nicotine produces
      dependence. Using an established regime to induce physical dependence to nicotine
      in rats (osmotic minipumps delivering 3.16 mg/kg/day nicotine for 7 days SC),
      animals were subsequently anaesthetised under urethane and positioned in a
      stereotaxic frame to allow collection of gradient echo whole brain images with a
      4.7-T MRI spectrometer. Rats were initially scanned for 34 min (40 baseline image
      volumes, 1 volume per 51 s) then challenged with mecamylamine (1.0 mg/kg SC) or
      saline (1 ml/kg) and scanned for a further 68 min (80 image volumes).
      Mecamylamine precipitated highly significant positive changes in fMRI blood
      oxygen level dependent (BOLD) contrast that were predominantly localised to the
      NAc of nicotine-dependent rats. Saline-treated rats challenged with the same dose
      of mecamylamine exhibited similar but smaller increases in BOLD contrast although
      such changes were less defined around the NAc. Precipitated withdrawal also
      elicited statistically significant negative BOLD contrast changes in widespread
      cortical regions. These findings are consistent with previous neurochemical
      reports on decreases in dopamine in the NAc during nicotine withdrawal. This fMRI
      study further highlights the potential and power to image the neurobiological
      events during nicotine dependence.

PMID- 15193615
TI  - Hemispheric asymmetry in supplementary motor area connectivity during unilateral
      finger movements.
AB  - Studies of unilateral finger movement in right-handed subjects have shown
      asymmetrical patterns of activation in primary motor cortex. Some studies have
      measured a similar asymmetry in the supplementary motor area (SMA), but others
      have not. To shed more light on the symmetry of function in the SMA, we used path
      analysis of functional MRI data to investigate effective connectivity during a
      unilateral finger movement task. We observed a slight asymmetry in task
      activation: left SMA was equally active during movement of either hand, while
      right SMA was more active for left-hand movement, suggesting a dominant role of
      left SMA. In addition, we tested for a corresponding asymmetry in the influence
      of SMA on sensorimotor cortex (SMC) using a path model based on the well
      established principle that SMA is involved in motor control and SMC in execution.
      We observed that the influence of left SMA on left SMC increased during right
      hand movement, and the influence of left SMA on right SMC increased during left
      hand movement. However, there was no significant hand-dependent change in the
      influences of the right SMA. This asymmetry in connectivity implies that left SMA
      does play a dominant role in unilateral movements of either hand in right
      handers. The experiment also provides a basis for further studies of motor system
      connectivity in healthy or patient populations.

PMID- 15193616
TI  - In vivo 3D MRI staining of the mouse hippocampal system using intracerebral
      injection of MnCl2.
AB  - The morphology and function of the hippocampal system of C57BL/6J mice (n = 8)
      was studied in vivo using T1-weighted 3D magnetic resonance imaging (MRI) (117
      microm isotropic resolution) after bilateral injection of MnCl(2) (0.25 microl, 5
      or 200 mM) into the posterior hippocampal formation. The neuronal uptake of the
      T1-shortening Mn(2+) ions resulted in a pronounced MRI signal enhancement within
      the CA3 subfield and dentate gyrus with milder increases in CA1 and subiculum.
      This finding is in line with differences in the excitability of hippocampal
      neurons previously reported using electrophysiologic recordings. The subsequent
      axonal transport of Mn(2+) highlighted the principal extrinsic projections from
      the posterior hippocampal formation via the fimbria and the precommissural fornix
      to the dorsal part of the lateral septal nucleus. A strong MRI signal enhancement
      was also observed in the ventral hippocampal commissure. A time-course analysis
      revealed unsaturated conditions of Mn(2+) accumulation at about 2 h after
      injection and optimal contrast-to-noise ratios at about 6 h after injection. The
      present results using Mn(2+)-enhanced 3D MRI open new ways for studying the role
      of the hippocampal system in specific aspects of learning and memory in normal
      and mutant mice.

PMID- 15193617
TI  - fMRI correlates of the episodic retrieval of emotional contexts.
AB  - Functional neuroimaging studies reveal differences in neural correlates of the
      retrieval of emotional and nonemotional memories. In the present experiment,
      encoding of emotionally neutral pictures in association with positively,
      neutrally or negatively valenced background contexts led to differential
      modulation of neural activity elicited in a subsequent recognition memory test
      for these pictures. Recognition of stimuli previously studied in emotional
      compared to neutral contexts elicited enhanced activity in structures previously
      implicated in episodic memory, including the parahippocampal cortex, hippocampus
      and prefrontal cortex. In addition, there was engagement of structures linked
      more specifically to emotional processing, including the amygdala, orbitofrontal
      cortex and anterior cingulate cortex. These emotion-related effects displayed
      both valence-independent and valence-specific components. We discuss the findings
      in terms of current models of emotional memory retrieval.

PMID- 15193618
TI  - An empirical investigation into the number of subjects required for an event
      related fMRI study.
AB  - Optimising the number of subjects required for an event-related functional
      imaging study is critical for ensuring sufficient statistical power. We report an
      empirical investigation of this issue by employing a resampling approach to the
      data of 58 subjects drawn from four previous GO/NOGO studies. Using voxelwise
      measures and setting the activation map from the complete sample to be a "gold
      standard", analyses revealed the statistical power to be surprisingly low at
      typical sample sizes (n = 20). However, voxels that were significantly active
      from smaller samples tended to be true positives, that is, they were typically
      active in the gold standard map and correlated well with the gold standard
      activation measure. The numerous false negatives that resulted from the lower SNR
      of the smaller samples drove the poor statistical power of those samples.
      Splitting the sample into two groups provided a test of the reproducibility of
      activation maps that was assessed using an alternative measure that quantified
      the distances between centres-of-mass of activated areas. These analyses revealed
      that although the voxelwise overlap may be poor, the locations of activated areas
      provide some optimism for studies with typical sample sizes. With n = 20 in each
      of two groups, it was found that the centres-of-mass for 80% of activated areas
      fell within 25 mm of each other. The reported analyses, by quantifying the
      spatial reproducibility for various sample sizes performing a typical event
      related cognitive task, thus provide an empirical measure of the disparity to be
      expected in comparing activation maps.

PMID- 15193619
TI  - Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe
      epilepsy with hippocampal ictal onset on intracranial EEG.
AB  - Experimental data in animals show that 5-HT(1A) receptors are predominantly
      located in limbic areas and suggest that serotonin, via these receptors, mediates
      an antiepileptic and anticonvulsant effect. In this PET study, we used an
      antagonist of the 5-HT(1A) receptor, [(18)F]MPPF, to assess the extent of 5
      HT(1A) receptor binding changes in a group of seven temporal lobe epilepsy (TLE)
      patients with hippocampal ictal onset demonstrated by intracerebral EEG
      recording. On the basis of MRI-measured hippocampal volumes (HV), patients were
      classified into "normal HV" or "hippocampal atrophy" (HA). Voxel-based analyses
      (SPM99) were performed to objectively assess the differences in [(18)F]MPPF
      binding potential (BP) between patients (taken as a group or as individuals) and
      a database of 48 controls subjects. In the full group of patients, a significant
      decreased BP was detected ipsilateral to the epileptogenic zone in the
      hippocampus, temporal pole, insula, and temporal neocortex. This result was
      confirmed in the subgroup of patients with HA. In patients with normal HV, the BP
      decrease was restricted to the temporal pole. TLE patients also demonstrated an
      increased BP in various regions contralateral to the epileptogenic zone. These
      data suggest that in TLE patients with hippocampal seizure onset, the decrease in
      5-HT(1A) receptor binding partly reflects hippocampal neuronal loss, but is also
      observed in various regions involved in temporo-limbic epileptogenic networks
      that appeared normal on MRI. Further studies are warranted to evaluate the
      clinical usefulness of [(18)F]MPPF-PET as compared to other established PET
      tracers in drug resistant TLE.

PMID- 15193620
TI  - Delayed myelination in children with developmental delay detected by volumetric
      MRI.
AB  - Delayed acquisition of developmental motor and cognitive milestones is a common
      clinical expression of many etiological processes. Imaging exams of
      developmentally delayed children often show no structural brain alterations
      despite suspicion of brain maturation delay. MRI studies increasingly suggest
      that white matter myelination finely reflects the progression in functional brain
      maturation. In this volumetric MRI study, we sought to evaluate whether
      developmental delay in children with normal conventional MRI exams is associated
      with reduced myelinated white matter. A total of 100 children (mean age, 4.4
      years) with developmental delay and 50 normally developing age-matched control
      children underwent 3-D MRI to measure the volume of myelinated white matter.
      Patients showed a significant reduction in the relative content of myelinated
      white matter (accounting for 19.8% of brain volume in patients and 21.4% in
      control subjects, P = 0.005). The observed difference was equivalent to a 3.2
      year myelination delay. Although the whole hemispheres were invariably
      symmetrical, the volume of myelinated white matter was asymmetrical in 30% of
      patients and 10% of control subjects (P = 0.006). We conclude that volumetric
      assessment of white matter may reveal a reduction in brain myelination beyond
      early childhood in developmentally delayed children showing normal brain
      appearance. This finding further emphasizes the view of white matter myelination
      as an indicator of functional brain maturation.

PMID- 15193621
TI  - A shared neural network for simple reaction time.
AB  - Simple reaction time, a simple model of sensory-to-motor behavior, has been
      extensively investigated and its role in inferring elementary mental organization
      has been postulated. However, little is known about the neuronal mechanisms
      underlying it. To elucidate the neuronal substrates, functional magnetic
      resonance imaging (fMRI) signals were collected during a simple reaction task
      paradigm using simple cues consisting of different modalities and simple
      triggered movements executed by different effectors. We hypothesized that a
      specific neural network that characterizes simple reaction time would be
      activated irrespective of the input modalities and output effectors. Such a
      neural network was found in the right posterior superior temporal cortex, right
      premotor cortex, left ventral premotor cortex, cerebellar vermis, and medial
      frontal gyrus. The right posterior superior temporal cortex and right premotor
      cortex were also activated by different modality sensory cues in the absence of
      movements. The shared neural network may play a role in sensory triggered
      movements.

PMID- 15193622
TI  - Brain localization of attentional control in different age groups by combining
      functional and structural MRI.
AB  - The present study used functional and structural MRI to investigate differences
      in neuronal substrates underlying shifts of attention in young and old subjects,
      studied with dichotic listening. Two different consonant-vowel syllables were
      presented and the subjects were instructed to attend to and report from either
      the left or right ear stimulus. Typically, a right-ear advantage is observed when
      attending to the right-ear stimulus, and a left-ear advantage when attending to
      the left-ear stimulus. The behavioral results showed that the old group had
      difficulties with attentional modulation of the right-ear advantage in the attend
      left condition. This is interpreted as a failure of an important aspect of
      attentional control; the top-down biasing of attention for selection of task
      relevant stimulus. The fMRI results showed that an area in the left middle
      frontal gyrus was more activated in the young group compared to the old group in
      the attend left condition. The structural MRI data showed reduced gray matter
      density of the same area in the old group. Based on these converging findings, we
      suggest that the left middle frontal gyrus plays an important role in top-down
      biasing of selecting task-relevant stimuli, and to inhibit processing of task
      irrelevant stimuli. To our knowledge, this is one of the first studies addressing
      the question on how age-related changes in attentional processing is reflected in
      both functional and structural differences in the brain.

PMID- 15193623
TI  - Assessing the sensitivity of fMRI group maps.
AB  - Group maps created from individual functional maps provide useful summaries of
      patterns of brain activation. Different methods for combining information have
      been proposed in the statistical literature and have been recently applied to
      fMRI data. Since these group maps are statistics, it is natural to ask how robust
      they are, that is, are they sensitive to the effects of unusual subjects?
      "Unusual" might be in terms of extent, location, or strength of activation. Our
      approach in this paper is to jackknife group maps formed by different combining
      procedures; the jackknife method, which involves deleting each observation
      (subject) in turn and recalculating the statistic (the group map), is commonly
      used for the purpose of assessing sensitivity. We examine the theoretical
      properties of four combining methods. In addition, via a collection of measures
      defined on the difference between group maps based on the entire sample and based
      on the jackknifed samples, we evaluate the robustness of these same methods on
      data from an fMRI experiment. Results indicate that there is a type of tradeoff
      in the combining techniques we consider, between robustness and conservativeness:
      methods that are liberal, in that they allow for the discovery of many active
      voxels, tend also to be more sensitive to the influences of individual subjects.

PMID- 15193624
TI  - Modulation of cerebellar activities by acupuncture stimulation: evidence from
      fMRI study.
AB  - Recent neuroimaging studies have revealed that acupuncture stimulation modulates
      human central nervous system including cerebral limbic/paralimbic and subcortical
      structures. Due to the wide and intricate connections with cerebrum, we
      hypothesized that anatomically specific areas in human cerebellum are also
      modulated by acupuncture stimulation beyond classical involvement of cerebellum
      in motor coordination. Functional MRI (fMRI) was used to investigate neural
      substrates responding to the acupuncture stimulation of Pericardium 6 (PC6,
      Neiguan), an acupoint relevant for the management of nausea including vestibular
      related motion sickness. Sham stimulation near the acupoint and tactile
      stimulation on the skin of the acupoint were given as separate conditions.
      Psychophysical scores as well as the heart and respiratory rates were measured
      during each condition. Acupuncture manipulation on PC6, in comparison to the sham
      acupuncture and tactile stimulation conditions, selectively activated left
      superior frontal gyrus, anterior cingulate gyrus, and dorsomedial nucleus of
      thalamus. Acupuncture-specific neural substrates in cerebellum were also evident
      in declive, nodulus, and uvula of vermis, quadrangular lobule, cerebellar tonsil,
      and superior semilunar lobule. Negative MR signal changes, often seen during the
      acupuncture of analgesic points, were not observed in the present study. Our data
      suggest that cerebellum serves as important activation loci during the
      acupuncture stimulation of PC6, and clinical efficacy of PC6 may be mediated by
      the cerebellar vestibular neuromatrix.

PMID- 15193625
TI  - Metacognitive evaluation, self-relevance, and the right prefrontal cortex.
AB  - The capability to foster metacognitive evaluations (MEs) of oneself and others
      represents a major component of conscious awareness. Separate emerging lines of
      brain activation research examining ME have converged on the medial prefrontal
      cortex as a common finding. The current functional magnetic resonance imaging
      (fMRI) study utilized a task that directly compared ME associated with two
      referentially discrete targets: oneself and a significant other (e.g., close
      friend or relative). Nineteen healthy young adult participants (mean age 24; 9
      female, 10 male) were required to make yes/no decisions based on individually
      presented trait adjectives across two separate referential conditions and a
      nonreferential control condition: self-evaluation (SE), significant other
      evaluation (OE), and semantic positivity-evaluation (SPE), respectively. Results
      of random-effects group analyses indicated a common area of medial prefrontal
      activation during the ME conditions of self- and other-evaluation versus the
      baseline semantic positivity-evaluation condition. A direct comparison of brain
      activation between the self and other evaluative conditions revealed a right
      dorsolateral prefrontal response that was significantly more active when making
      evaluations about the self. The present study extends upon the prior findings of
      separate research domains by directly comparing the cerebral response to ME about
      the self and others, and finding right PFC activation increases as a function of
      self-relevance.

PMID- 15193626
TI  - Distinct functional substrates along the right superior temporal sulcus for the
      processing of voices.
AB  - The right superior temporal sulcus (STS) is involved in processing the human
      voice. In this paper, we report fMRI findings showing that segregated cortical
      regions along the STS are involved in distinct aspects of voice processing and
      that they functionally cooperate during speaker recognition. Subjects listened to
      identical sets of auditory sentences while recognizing either a target sentence
      irrespective of the speaking voice or a target voice irrespective of the sentence
      meaning. As the same stimulus material was used in both conditions, task-related
      activations were not confounded by differences in speech acoustic features. Half
      of the stimuli were voices of familiar persons and half of persons that were
      never encountered before. Recognizing voices activated the right anterior and
      posterior STS more than recognizing verbal content. While the right anterior STS
      responded equally to both voice categories, the right posterior STS displayed
      stronger responses to non-familiar than to familiar speakers' voices. It also
      responded to our baseline condition of amplitude modulated noises that required a
      detailed analysis of complex temporal patterns. Analyses of connectivity
      (psychophysiological interactions) revealed that during speaker recognition both
      anterior and posterior right STS interacted with a region in the mid/anterior
      part of the right STS, a region that has been implicated in processing the
      acoustic properties of voices. Moreover, the anterior and posterior STS displayed
      distinct connectivity patterns depending on familiarity. Our results thus
      distinguish three STS regions that process different properties of voices and
      interact in a specific manner depending on familiarity with the speaker.

PMID- 15193627
TI  - Nonlinear coupling of neural activity and CBF in rodent barrel cortex.
AB  - The relationship between neural activity and accompanying changes in cerebral
      blood flow (CBF) and oxygenation must be fully understood before data from brain
      imaging techniques can be correctly interpreted. Whether signals in fMRI reflect
      the neural input or output of an activated region is still unclear. Similarly,
      quantitative relationships between neural activity and changes in CBF are not
      well understood. The present study addresses these issues by using simultaneous
      laser Doppler flowmetry (LDF) to measure CBF and multichannel electrophysiology
      to record neural activity in the form of field potentials and multiunit spiking.
      We demonstrate that CBF-activation coupling is a nonlinear inverse sigmoid
      function. Comparing the data with previous work suggests that within a cortical
      model, CBF shows greatest spatial correlation with a current sink 500 microm
      below the surface corresponding to sensory input. These results show that care
      must be exercised when interpreting imaging data elicited by particularly strong
      or weak stimuli and that hemodynamic changes may better reflect the input to a
      region rather than its spiking output.

PMID- 15193628
TI  - Focal changes of oxygen consumption in cerebral cortex of patients with
      Parkinson's disease during subthalamic stimulation.
AB  - Motor symptoms of Parkinson's disease (PD) are substantially improved by
      bilateral high-frequency electrical stimulation of the subthalamic nucleus (STN).
      Altered cerebral blood flow (CBF) in a network of frontal cortical and
      subcortical structures has been reported in numerous studies of patients
      undergoing subthalamic stimulation. However, CBF is a controversial indicator of
      brain activation because measures of blood flow bear a variable relation to
      measures of brain work and energy metabolism. We hypothesized that STN
      stimulation would alter the rate of oxygen consumption (CMRO(2)) in cerebral
      cortical areas in proportion to previously reported changes in CBF in patients
      undergoing stimulation at rest. We used quantitative PET to map CMRO(2) in brain
      of seven patients with Parkinson's disease, first in a baseline condition with
      pause of stimulation and medication for a period of 12 h, and again after 4 h of
      stimulation. Comparison of these two conditions revealed activation of CMRO(2) in
      the cerebellum, and in specific posterior neocortical regions, most notably in
      the left lingual gyrus and in the right lateral occipitotemporal gyrus, both of
      which latter regions are linked to higher-order visual processing. CMRO(2) was
      unaffected in the frontal cortex. Thus, the present findings do not support the
      original hypothesis, but suggest that STN stimulation increases energy metabolism
      in the posterior cerebral cortex, especially in regions involved in perception of
      movement and the direction of movement to visual cues.

PMID- 15193629
TI  - Comparison of sustained and transient activity in children and adults using a
      mixed blocked/event-related fMRI design.
AB  - The ability to make direct comparisons between adult and child neuroimaging data
      is important to the study of the neural basis of cognitive development. Recent
      fMRI studies in adults have used mixed blocked/event-related designs to extract
      activity consistent with separable sustained, task-related processes and
      transient, trial-related processes. Because brain regions with different time
      courses of activity may have different roles in cognitive processing, the ability
      to distinguish between sustained and transient signals would contribute to
      understanding the functional roles of regions involved in cognitive processing.
      The developmental profile of such activity would give insight into how cognitive
      processing develops over time. The purpose of this study was to assess the
      utility of the mixed design to detect and dissociate sustained and transient
      activity in children, and to determine if the time courses or magnitudes of the
      extracted signals differ from those extracted from adults. An fMRI experiment was
      performed on 10 adults and 10 children (ages 7-8) using counterphase flickering
      checkerboard stimuli that produced sustained, transient, and a combination of
      sustained and transient responses in visual cortex. Analyses were performed using
      the general linear model (GLM) assuming a shape for sustained effects, but not
      for transient effects. In visual cortex, neither transient nor sustained effects
      showed significant between-group differences. For both groups, flickering
      checkerboard stimuli produced robust responses in visual cortex contralateral but
      not ipsilateral to the stimulus. Results extend the feasibility of direct
      statistical comparison of adults and children; mixed designs provide a means to
      examine neural activity in both adults and children related to sustained, task
      level processes, likely related to task-level control.

PMID- 15193631
TI  - Brainstem involvement in the initial response to pain.
AB  - The autonomic responses to acute pain exposure usually habituate rapidly while
      the subjective ratings of pain remain high for more extended periods of time.
      Thus, systems involved in the autonomic response to painful stimulation, for
      example the hypothalamus and the brainstem, would be expected to attenuate the
      response to pain during prolonged stimulation. This suggestion is in line with
      the hypothesis that the brainstem is specifically involved in the initial
      response to pain. To probe this hypothesis, we performed a positron emission
      tomography (PET) study where we scanned subjects during the first and second
      minute of a prolonged tonic painful cold stimulation (cold pressor test) and
      nonpainful cold stimulation. Galvanic skin response (GSR) was recorded during the
      PET scanning as an index of autonomic sympathetic response. In the main effect of
      pain, we observed increased activity in the thalamus bilaterally, in the
      contralateral insula and in the contralateral anterior cingulate cortex but no
      significant increases in activity in the primary or secondary somatosensory
      cortex. The autonomic response (GSR) decreased with stimulus duration.
      Concomitant with the autonomic response, increased activity was observed in
      brainstem and hypothalamus areas during the initial vs. the late stimulation.
      This effect was significantly stronger for the painful than for the cold
      stimulation. Activity in the brainstem showed pain-specific covariation with
      areas involved in pain processing, indicating an interaction between the
      brainstem and cortical pain networks. The findings indicate that areas in the
      brainstem are involved in the initial response to noxious stimulation, which is
      also characterized by an increased sympathetic response.

PMID- 15193630
TI  - Neuroanatomy of adult strabismus: a voxel-based morphometric analysis of magnetic
      resonance structural scans.
AB  - Cerebral deficit has been implicated in the genesis of strabismus and in the
      mechanisms adopted to compensate for the visual disorder. Voxel-based morphometry
      (VBM) was applied to magnetic resonance images of strabismic adults to detect any
      abnormal brain anatomy, which could not be easily identified by simple
      inspection. The gray matter volume in strabismic adults was smaller than that in
      normal subjects at the areas consistent with the occipital eye field (OEF) and
      parietal eye field (PEF). However, greater gray matter volume was found in
      strabismic adults relative to normal controls at the areas consistent with the
      frontal eye field (FEF), the supplementary eye field (SEF), the prefrontal cortex
      (PFC), and subcortical regions such as the thalamus and the basal ganglia. These
      opposite gray matter changes in the visual and the oculomotor processing areas
      are compatible with a hypothesis of plasticity in the oculomotor regions to
      compensate for the cortical deficits in the visual processing areas.

PMID- 15193632
TI  - The amygdala processes the emotional significance of facial expressions: an fMRI
      investigation using the interaction between expression and face direction.
AB  - Neuroimaging studies have shown activity in the amygdala in response to facial
      expressions of emotion, but the specific role of the amygdala remains unknown. We
      hypothesized that the amygdala is involved in emotional but not basic sensory
      processing for facial expressions. To test this hypothesis, we manipulated the
      face directions of emotional expressions in the unilateral visual fields; this
      manipulation made it possible to alter the emotional significance of the facial
      expression for the observer without affecting the physical features of the
      expression. We presented angry/neutral expressions looking toward/away from the
      subject and depicted brain activity using fMRI. After the image acquisitions, the
      subject's experience of negative emotion when perceiving each stimulus was also
      investigated. The left amygdala showed the interaction between emotional
      expression and face direction, indicating higher activity for angry expressions
      looking toward the subjects than angry expressions looking away from them. The
      experienced emotion showed the corresponding interaction. Regression analysis
      showed a positive relation between the left amygdala activity and experienced
      emotion. These results suggest that the amygdala is involved in emotional but not
      visuoperceptual processing for emotional facial expressions, which specifically
      includes the decoding of emotional significance and elicitation of one's own
      emotions corresponding to that significance.

PMID- 15193633
TI  - Two-photon imaging of spontaneous vesicular release in acute brain slices and its
      modulation by presynaptic GABAA receptors.
AB  - Action potential-independent spontaneous vesicular release of gamma-aminobutyric
      acid (GABA) in the CNS mediates miniature inhibitory postsynaptic currents
      (mIPSCs) and exerts an important control on central excitability. Using dual
      photon laser scan microscopy and hyperosmotic loading of the readily releasable
      vesicle pool with the fluorescent styryl dye FM1-43 in hippocampal slice, we
      demonstrate action potential-independent release of vesicles (fluorescence
      destaining) from proximal perisomatic, presumed GABAergic terminals and
      significant inhibition of this release by the specific GABA(A) receptor agonist
      muscimol in the presence of tetrodotoxin and glutamate receptor antagonists CNQX
      and AP5. These data agree with reduction of mIPSCs by muscimol in whole-cell
      recordings from CA3 pyramidal neurons. In contrast, rate of vesicle release from
      distal, presumably glutamatergic terminals, was significantly lower and not
      changed by muscimol. The effect of muscimol on mIPSCs was not blocked but rather
      enhanced in the absence of external calcium. Our data directly demonstrate a
      potent disinhibitory reduction of GABA release by GABA(A) receptor activation.
      Those novel methods should be well suited to study pathophysiological changes in
      inhibition in resections obtained from neurosurgical treatment of epilepsy
      patients.

PMID- 15193634
TI  - Women's cognitive health: postmenopausal dementia and the women's health
      initiative memory study.

PMID- 15193635
TI  - Associations between forced sex, sexual and protective practices, and sexually
      transmitted diseases among a national sample of adolescent girls.
AB  - OBJECTIVE: The main objective of this study is to better understand the
      associations between forced sex history and history of sexually transmitted
      disease (STD) infection. Three research questions are investigated. Is history of
      forced sex associated with risk-taking behaviors? Are these risk-taking behaviors
      associated with history of STD? Is history of forced sex independently associated
      with history of STD? METHODS: Information on the sexual and STD histories is
      obtained from 3,579 sexually active adolescent girls using data from the National
      Longitudinal Study of Adolescent Health. Weighted logistic and OLS regressions
      are employed, using techniques that account for the complex sampling design.
      RESULTS: Girls with a history of forced sex are significantly more likely to have
      a greater number of sexual partners, be younger at first sex, and be more likely
      to use alcohol or drugs at last sex; there is no difference in condom use at last
      sex. These factors, in turn, are significantly associated with a positive STD
      history. Condom use at last sex is negatively associated with ever having had an
      STD. When all five sexual and protective practices are investigated
      simultaneously, history of forced sex remains significantly associated with STD
      history (odds ratio [OR] = 1.39, p =.014); number of sexual partners and early
      onset of sex remain significant. Condom use and substance use at last sex reduce
      to marginal significance. CONCLUSIONS: These results suggest that a history of
      forced sex is independently associated with a history of STD among sexually
      active adolescent girls. Programmatic strategies aimed at reducing STDs through
      encouraging responsible sexual behavior would potentially benefit from also
      including a component that addresses sexual victimization.

PMID- 15193636
TI  - Acceptability of an existing, female-controlled contraceptive method that could
      potentially protect against HIV: a comparison of diaphragm users and other method
      users.
AB  - OBJECTIVE: The diaphragm, an internal barrier contraceptive device, is a
      candidate for a female-controlled method for preventing human immunodeficiency
      virus (HIV) and other sexually transmitted infections (STIs). This study's
      objective was to examine how women who use the diaphragm differ from women using
      the pill and/or condoms with respect to factors hypothesized to influence the
      acceptability of contraceptive methods. Our goal was to increase understanding of
      who finds the diaphragm acceptable and why. METHODS: We conducted a cross
      sectional telephone survey with selected female members of a managed care
      organization. For this analysis, we limited the sample to 585 women currently
      using the diaphragm (n = 196), pill (n = 200), condoms (n = 132), or pill and
      condoms (n = 57). We conducted bivariate analyses and multinomial logistic
      regression analyses to assess the associations between selected characteristics
      and diaphragm use. RESULTS: Diaphragm use was significantly associated with
      several variables. Of particular interest, placing less importance on hormonal
      method characteristics was significantly associated with diaphragm use (versus
      use of the pill, condoms, or both). Placing more importance on barrier method
      attributes was significantly associated with diaphragm use (versus pill use,
      alone or with condoms). In addition, lower condom use self-efficacy was
      significantly associated with diaphragm use (versus condom use, alone or with
      pill). Lack of motivation to avoid HIV/STIs was significantly associated with
      using the diaphragm versus condoms (only). CONCLUSION: These results have
      important implications for future research, interventions, counseling strategies
      for providers, and product development. Our findings suggest that if the
      diaphragm protects against HIV, it could be a desirable option for some women.

PMID- 15193637
TI  - The relationship of health care delivery system characteristics and legal factors
      to mode of delivery in women with prior cesarean section: a systematic review.
AB  - OBJECTIVE: To evaluate the relationship of health care delivery system
      characteristics and legal factors to mode of delivery in women with prior
      cesarean section. METHODS: We identified relevant studies by searching MEDLINE
      and HealthSTAR (1980 to May 2002), reference lists of pertinent articles, and
      recommendations of local and national experts. We also searched the online
      Cochrane systematic reviews and controlled trials registries, Database of
      Abstracts and Reviews on Effectiveness, and EMBASE databases. RESULTS: Studies of
      guidelines suggested that opinion leaders influence provider behavior regarding
      repeat cesarean delivery versus trial of labor decisions. Studies of hospital and
      insurance characteristics provided inconsistent results. There was insufficient
      evidence to evaluate the relationship between provider characteristics and
      delivery outcomes. Legislation and liability-related factors effected limited
      change. CONCLUSION: Studies of health care system characteristics and other
      factors focused primarily on rates of delivery modes (vaginal birth after
      cesarean or repeat cesarean delivery) rather than patient safety or health
      outcomes. Future studies must account for case mix, time trends, and other
      potential confounders, especially concerning associations of provider
      characteristics.

PMID- 15193638
TI  - An improved strategy for automated electron microscopic tomography.
AB  - A prediction-based scheme is proposed and implemented for automated electron
      microscopic tomography. By assuming that the sample follows a simple geometric
      rotation and that the optical system can be characterized in terms of an offset
      between the optical and mechanical axes, it is found that the image movement in
      the x, y, and z directions due to stage tilt can be dynamically predicted with
      desired accuracy (15 nm in x-y position and 100 nm in focus). Thus, the
      microscope optical system (beam/image shift and focus) can be automatically
      adjusted to compensate for the predicted image movement prior to taking the
      projected image at each tilt angle. As a consequence, it is not necessary to
      either record additional images for tracking and focusing during the course of
      data collections or to spend valuable setup time in a lengthy pre-calibration of
      stage motions. Furthermore, this scheme is also found to tolerate a significant
      degree of non-eucentricity and to be quite robust in the collection of regular
      and cryo low-dose images on thin or thick samples even at magnifications greater
      than 62000x and angular step as large as 10 degrees. For interested users the
      software can be freely downloaded for non-profit use at
      http://www.msg.ucsf.edu/tomography.

PMID- 15193639
TI  - Visualization of the funis of Giardia lamblia by high-resolution field emission
      scanning electron microscopy--new insights.
AB  - Giardia lamblia is a multiflagellar parasite and one of the earliest diverging
      eukaryotic cells. It possesses a cytoskeleton made of several microtubular
      structures-an adhesive disc, four pairs of flagella, median body, and funis. This
      protozoan displays different types of movements, including a lateral and dorso
      ventral dislocation of its posterior region, which has not been completely
      elucidated. In the present study, high-resolution field emission scanning
      electron microscopy was used to analyze the funis structure of G. lamblia
      trophozoites. It was shown that the funis is made of short arrays of microtubules
      emanating from the axonemes of the caudal flagella, which are anchored to dense
      rods that run parallel to the posterior-lateral flagella. After emergence of the
      posterior-lateral flagella, funis microtubules are anchored to the epiplasm, a
      fibrous layer that underlies the portion of membrane that presents tail
      contractility. Based on these observations a model for the tail flexion of G.
      lamblia is proposed.

PMID- 15193641
TI  - Mapping of cellular compartments based on ultrastructural immunogold labeling.
AB  - Ultrastructural identification of subcellular morphologically inconspicuous
      compartments is based on detection of specific molecules or by a presence of
      specific functions. Such compartments are detected using antibodies with attached
      label, usually gold particles. However, the gold particles have a point pattern,
      while a compartment is a coherent area. In addition, some background labeling is
      always present that complicates identification of the labeled compartments. The
      aim of this study was therefore to develop a stereological method that would
      enable us to define cellular compartments based on delineating the borders of
      gold particle clusters, and to test the practical use of the method using
      biological experimental data. New computer program plug-ins were developed to
      facilitate the practical use of the stereological method. The kernel estimation
      method was successfully tested by detection of ribosomal rRNA over
      morphologically recognizable nucleoli. In a next step, we successfully detected
      individual chromosomal domains-nuclear compartments that cannot be distinguished
      in cell nuclei morphologically. The results show that the new stereological/image
      analysis method is well able to discriminate cellular compartments based on
      density of immunogold particles. The plug-ins were made available to scientific
      community at http://nucleus.biomed.cas.cz/gold.

PMID- 15193640
TI  - A 9 angstroms single particle reconstruction from CCD captured images on a 200 kV
      electron cryomicroscope.
AB  - Sub-nanometer resolution structure determination is becoming a common practice in
      electron cryomicroscopy of macromolecular assemblies. The data for these studies
      have until now been collected on photographic film. Using cytoplasmic
      polyhedrosis virus (CPV), a previously determined structure, as a test specimen,
      we show the feasibility of obtaining a 9 angstroms structure from images acquired
      from a 4 k x 4 k Gatan CCD on a 200 kV electron cryomicroscope. The match of the
      alpha-helices in the protein components of the CPV with the previous structure of
      the same virus validates the suitability of this type of camera as the recording
      media targeted for single particle reconstructions at sub-nanometer resolution.

PMID- 15193642
TI  - Visualization of alpha-helical features in a density map constructed using 9
      molecular images of the 1.8 MDa icosahedral core of pyruvate dehydrogenase.
AB  - Strategies to achieve the highest resolutions in structures of protein complexes
      determined by cryo-electron microscopy generally involve averaging information
      from large numbers of individual molecular images. However, significant
      limitations are posed by heterogeneity in image quality and in protein
      conformation that are inherent to large data sets of images. Here, we demonstrate
      that the combination of iterative refinement and stringent molecular sorting is
      an effective method to obtain substantial improvements in map quality of the 1.8
      MDa icosahedral catalytic core of the pyruvate dehydrogenase complex from
      Bacillus stearothermophilus. From a starting set of 42,945 images of the core
      complex, we show that using only the best 139 particles in the data set produces
      a map that is superior to those constructed with greater numbers of images, and
      that the location of many of the alpha-helices in the structure can be
      unambiguously visualized in a map constructed from as few as 9 particles.

PMID- 15193644
TI  - Collagen fibrils of an invertebrate (Sepia officinalis) are heterotypic:
      immunocytochemical demonstration.
AB  - Collagen fibrils from the dermis of Sepia officinalis were processed for
      immunoelectron microscopy to reveal reactions to antibodies against mammalian
      types I, III, and V, teleost type I and cephalopod type I-like collagens, by
      single and double immunogold localization. The fibrils were observed: (a) in
      suspensions of prepared fibrils, (b) in ultrathin sections of embedded fibril
      preparations, and (c) in ultrathin sections of dermal tissue. Some samples were
      subjected to acetic acid or urea dissociation. It was found that collagen fibrils
      from Sepia dermis are heterotypic in that they are composed of type I-like and
      type V collagens. Type I-like collagen epitopes were present mainly at the
      periphery of the fibrils; type V collagen epitopes were present throughout the
      fibrils. This is the first demonstration that collagen fibrils from an
      invertebrate are heterotypic, suggesting that heterotypy may be an intrinsic
      characteristic of the fibrils of fibrillar collagens, independent of evolutionary
      or taxonomic status.

PMID- 15193643
TI  - Studies on the compaction of isolated nucleoids from Escherichia coli.
AB  - The genomic DNA of Escherichia coli is contained in one or two compact bodies
      known as nucleoids. Isolation of typically shaped nucleoids requires control of
      DNA expansion, accomplished here by a modification of the polylysine-spermidine
      procedure. The ability to control expansion of in vitro nucleoids has application
      in nucleoid purification and in preparation of samples for high-resolution
      imaging, and may allow an increased resolution in gene localization studies.
      Polylysine of relatively low average molecular weight (approximately 3 kDa) is
      used to produce lysates containing nucleoids that are several-fold expanded
      relative to the sizes of in vivo nucleoids. These expanded forms can be converted
      to compact forms similar in dimensions to the cellular nucleoids by either a
      further addition of polylysine or by incubation of diluted lysates at 37 degrees
      C. The incubation at 37 degrees C is accompanied by autolytic degradation of most
      ribosomal RNA. Hyperchromism and circular dichroism spectra indicate that
      polylysine-DNA complexes are modified during the incubation. Compact forms of the
      nucleoid can be progressively reexpanded by exposure to salt solutions. Nucleoid
      compaction was similar in lysates made from rapidly or slowly growing cells or
      from cells that had been briefly treated with chloramphenicol to reduce linkages
      between DNA and cell envelope.

PMID- 15193645
TI  - Electron nanodiffraction and high-resolution electron microscopy studies of the
      structure and composition of physiological and pathological ferritin.
AB  - Structures of core nanocrystals of physiological (horse spleen, human liver, and
      brain) and pathological human brain of patients with progressive supranuclear
      palsy (PSP) and Alzheimer's disease (AD) ferritin molecules were determined using
      electron nanodiffraction and high-resolution transmission electron microscopy.
      The poly-phasic structure of the ferritin cores is confirmed. There are
      significant differences in the mineral composition between the physiological and
      pathological ferritins. The physiological ferritin cores mainly consist of single
      nanocrystals containing hexagonal ferrihydrite (Fh) and hematite (Hm) and some
      cubic magnetite/maghemite phase. In the pathological cores, Fh is present but
      only as a minor phase and Hm is absent. The major phases are a face-centered
      cubic (fcc) structure with a = 0.43 nm and a high degree of disorder, related to
      wustite, and a cubic magnetite-like structure. These two cubic phases are also
      present in human aged normal brain. Evidence for the presence of hemosiderin
      together with ferritin in the pathological brains is deduced from the
      similarities of the diffraction patterns with those from patients with primary
      hemochromatosis, and differences in the shapes and protein composition of the
      protein shell. These findings suggest a disfunction of the ferritin associated
      with PSP and AD, associated with an increase in the concentration of brain
      ferrous toxic iron.

PMID- 15193646
TI  - Molecular characterization of the plant biopolyester cutin by AFM and
      spectroscopic techniques.
AB  - Atomic force microscopy, FT-IR spectroscopy, and solid-state nuclear magnetic
      resonance have been used to improve our current knowledge on the molecular
      characteristics of the biopolyester cutin, the main component of the plant
      cuticle. After comparison of samples of cutin isolated from young and mature
      tomato fruit cuticles has been possible to establish different degrees of cross
      linking in the biopolymer and that the polymer is mainly formed after
      esterification of secondary hydroxyl groups of the monomers that form this type
      of cutin. Atomic force microscopy gave useful structural information on the
      molecular topography of the outer surface of the isolated samples. The texture of
      these samples is a consequence of the cross-linking degree or chemical status of
      the polymer. Thus, the more dense and cross-linked cutin from ripe or mature
      tomato fruit is characterized by a flatter and more globular texture in addition
      to the development of elongated and orientated superstructures.

PMID- 15193648
TI  - The emerging structural understanding of transglutaminase 3.
AB  - Transglutaminases (TGase; protein-glutamine: amine gamma-glutamyl-transferase)
      are a family of calcium-dependent acyl-transfer enzymes ubiquitously expressed in
      mammalian cells and responsible for catalyzing covalent cross-links between
      proteins or peptides. A series of recent crystal structures have revealed the
      overall architecture of TGase enzymes, and provided a deep look at their active
      site, calcium and magnesium ions, and the manner by which guanine nucleotides
      interact with this enzyme. These structures, backed with extensive biochemical
      studies, are providing new insights as to how access to the enzyme's active site
      may be gated through the coordinated changes in cellular calcium and magnesium
      concentrations and GTP/GDP. Calcium-activated TGase 3 can bind, hydrolyze, and is
      inhibited by GTP, despite lacking structural homology with other GTP binding
      proteins. A structure based sequence homology among the TGase enzyme family shows
      that these essential structural features are shared among other members of the
      TGase family.

PMID- 15193647
TI  - MicroCT quantification of in vitro bone resorption of neonatal murine calvaria
      exposed to IL-1 or PTH.
AB  - This study investigated how effectively a laboratory microCT (X-ray micro
      computed tomography) system can quantify bone resorption in an in vitro calvarial
      model and how well this measure correlates with a conventional assay for calcium
      release (fluorometric titration). In vitro bone resorption in neonatal murine
      calvaria was quantified for 0.3 or 1.0 nM interleukin-1 (IL-1) or for 1.0 or 10.0
      nM parathyroid hormone (PTH) treatment. Compared to control calvaria, a
      significantly greater fraction F of the calvarial "shell" (computed from the
      volumetric microCT data) was resorbed in treated calvaria of 5- to 7-day-old pups
      from the same litter. Excellent correlation (R2 = 0.8234) was observed between F
      and calcium release, and, unlike the calcium assay, the 3-D maps revealed where
      bone was resorbed. Mineral was preferentially lost near the sutures, and areas
      away from the suture were left relatively intact. MicroCT of calvaria before and
      after 96 h culture demonstrated that this X-irradiation neither increased control
      resorption nor prevented responses in the treated calvaria. Observations on
      calvaria from intact mice aged 1, 3, 5, 8, and 11 days showed uniformly
      distributed mineral (not a pronounced patchwork of "high" and "low" mineral
      regions) and increasing levels of mineral with age; this suggested that the
      spatial patterns of resorption were not related to inhomogeneities in the
      starting mineral distribution.

PMID- 15193649
TI  - Effect of artificially lengthened vocal tract on vocal fold oscillation's
      fundamental frequency.
AB  - The fundamental frequency of vocal fold oscillation (F(0)) is controlled by
      laryngeal mechanics and aerodynamic properties. F(0) change per unit change of
      transglottal pressure (dF/dP) using a shutter valve has been studied and found to
      have nonlinear, V-shaped relationship with F(0). On the other hand, the vocal
      tract is also known to affect vocal fold oscillation. This study examined the
      effect of artificially lengthened vocal tract length on dF/dP. dF/dP was measured
      in six men using two mouthpieces of different lengths. RESULTS: The dF/dP graph
      for the longer vocal tract was shifted leftward relative to the shorter one.
      CONCLUSION: Using the one-mass model, the nadir of the "V" on the dF/dP graph was
      strongly influenced by the resonance around the first formant frequency. However,
      a more precise model is needed to account for the effects of viscosity and
      turbulence.

PMID- 15193650
TI  - The effect of task on determination of habitual loudness.
AB  - The purpose of this study was to investigate if there is an effect of task on
      determination of habitual loudness. Four tasks commonly used to elicit habitual
      loudness were compared (automatic speech, elicited speech, spontaneous speech,
      and reading aloud). Participants were adult female speakers (N=30) with normal
      voice. A one-way analysis of variance (ANOVA) revealed a statistically
      significant (p < 0.05) effect of task, with post-hoc analyses indicating that
      there was a statistically significant difference in habitual loudness elicited
      via automatic versus spontaneous speech (p < 0.05), and automatic speech versus
      reading aloud (p < 0.001). The issue of how habitual loudness is defined is
      considered. Implications of the use of one task for determination of habitual
      loudness are discussed, as is the possibility of a task effect on determination
      of other clinically useful vocal parameters.

PMID- 15193651
TI  - The relationship between ratings of voice quality and quality of life measures.
AB  - In the past several years, a number of scales have been developed that elicit a
      patient's self-assessment of the severity of his or her voice problem. The Voice
      Related Quality of Life Measure (V-RQOL) assesses a patient's perception of the
      impact of the voice problem on quality of life. Although this tool assesses the
      patient's perception of the voice disorder, it may not reflect the severity of
      dysphonia as perceived by a clinician. The GRBAS is an auditory-perceptual scale
      developed in Japan and used by clinicians to categorize the voice using five
      descriptive perceptual parameters: overall grade or severity (G), roughness of
      the voice (R), breathiness (B), asthenia (A), and strain (S). The purpose of this
      research is to determine the relationship between the patient's perception of
      voice related quality of life using the V-RQOL and the clinician's perception of
      voice severity using the GRBAS scale. Fifty patients with a complaint of a voice
      disorder completed the V-RQOL prior to their examination. In addition, 45
      patients without voice complaints (controls) also completed the V-RQOL. All
      patients and control subjects were assessed by one of the voice clinicians using
      the GRBAS. For 25 of the subjects, both clinicians provided GRBAS perceptual
      ratings. Each of the two groups, were subsequently divided into subgroups
      consisting of those age 66 years and under and those over 66 years of age. The
      results indicate that the two clinicians were highly reliable in rating severity
      in the normal and voice disordered groups using the GRBAS scale. The results also
      indicate that perceived voice severity and voice-related quality of life are
      related; however, the relationship is a moderate one, which suggests that factors
      other than those directly related to voice quality may contribute to responses on
      voice assessment scales completed by patients. The relationship was stronger for
      the subgroup under 66 years old compared with the subgroup 66 years and older.

PMID- 15193652
TI  - Vocal aging and the impact on daily life: a longitudinal study.
AB  - Longitudinal studies on vocal aging are scarce, and information on the impact of
      age-related voice changes on daily life is lacking. This longitudinal study
      reports on age-related voice changes and the impact on daily life over a time
      period of 5 years on 11 healthy male speakers, age ranging from 50 to 81 years.
      All males completed a questionnaire on vocal performance in daily life, and
      perceptual and acoustical analyses of vocal quality and analyses of maximum
      performance tasks of vocal function (voice range profile) were performed. Results
      showed a significant deterioration of the acoustic voice signal as well as
      increased ratings on vocal roughness judged by experts after the time period of 5
      years. An increase of self-reported voice instability and the tendency to avoid
      social parties supported these findings. Smoking males had a lower speaking
      fundamental frequency compared with nonsmoking males, and this seemed reversible
      for males who stop smoking. This study suggests a normal gradual vocal aging
      process with clear consequences in daily life, which should be taken into
      consideration in clinical practice as well as in studies concerning communication
      in social life.

PMID- 15193653
TI  - Reliability of calculating the cepstral peak without linear regression analysis.
AB  - Measures of cepstral peak prominence, using the smoothing algorithm and linear
      regression analysis software developed by Hillenbrand, have been shown to be
      reliable predictors of dysphonia in voice samples.(1-4) Recently, the
      Computerized Speech Laboratory [(CSL) Kay Elemetrics, Pinebrook, New Jersey] has
      introduced cepstral analysis as a component of that software package. The
      cepstral peak, in this instance, is calculated by the voice clinician analyzing
      the phonatory sample by subtracting the value of the peak from the apparent
      baseline signal. This study compares the ability of cepstral peak values
      calculated from the CSL software to predict dysphonia reliably with that of the
      values produced by the smoothing algorithm and linear regression analysis of
      Hillenbrand. The results of this study show that linear regression analysis is an
      important step in calculating the cepstral peak prominence, thus limiting the
      usefulness of software programs that do not employ this step.

PMID- 15193654
TI  - Voice field measurements--a new method of examination: the influence of hearing
      on the human voice.
AB  - There are various methods to evaluate voice parameters. Original software was
      used to assess the voice quality by the staff of AUDIO-Fon centr Brno, Czech
      Republic. A group of hereditary deaf persons was examined. Deaf persons have all
      of the biological conditions to make voice except for the possibility of acoustic
      feedback. We examined the voices of 35 persons (20 men and 15 women) with
      hereditary profound hearing impairments, and we compared voice parameters with
      the voice of intact persons. To measure we used special software called voice
      field measurements (VFMs). The program graphically records voice frequency and
      intensity. VFM is an objective method that enables the assessment of basic
      physical voice characteristics. It is suitable for the examination of both intact
      and disturbed voice. The voice of the deaf has a higher basic voice frequency in
      men as well as in women. This type of voice production, ie, childlike voice,
      which is fixed only by a motor stereotype, is much more demanding for a mature
      larynx. Hearing influences both the voice development and speech production. The
      voice of persons with hearing impairments has a higher basic voice frequency
      regardless of their sex. This type of voice production, which is fixed only by a
      motor stereotype, ie, child voice, is much more demanding for a larynx of an
      adult. Thus, phonation of deaf people is more demanding and their voice
      production needs greater effort. Deaf people, despite an intact phonic apparatus,
      cannot produce more than one type of voice. They cannot modulate their voices
      concerning the frequency and dynamics. They cannot change their voices
      continually. The voice is limited in both of these parameters (frequency and
      dynamics). If a deaf person wants to change a voice characteristic, it is
      possible only by discontinuous changes-"skipping."

PMID- 15193655
TI  - The relationship between measured vibrato characteristics and perception in
      Western operatic singing.
AB  - This study examined the association between acoustic and perceptual data related
      to vibrato in Western operatic singing using recordings of performances by
      internationally famous opera singers. Three related studies were conducted. Study
      1 used commercial recordings of the same five singers and the same cadenza
      examined by Siegwart and Scherer(1), measured vibrato rate and extent in each
      singer's performance of the cadenza and tested possible associations between
      these vibrato attributes and judges' preference for singers. Studies 2 and 3,
      using recordings of different internationally famous singers and a different
      cadenza, measured vibrato onset, rate, and extent in each singer's performance of
      the cadenza, required judges to rank the singers in order of personal preference,
      to identify the emotion expressed, and to assess the degree of success in
      communicating emotion achieved by the singer. The findings showed that the
      perception of the singers' vibrato did not always agree with acoustic
      measurements. However, a comparison of the acoustic measurements with the
      preference and emotion judgments suggest that some elements of vibrato may affect
      listeners' perception of the voice, their preference for a particular singer, and
      assist the communication of emotion between singer and audience.

PMID- 15193656
TI  - The potential role of ultrasound in differentiating solid and cystic swellings of
      the true vocal fold.
AB  - This study was designed to investigate the potential role of ultrasound in the
      diagnosis of cysts of the true vocal fold. MATERIALS AND METHODS: Grayscale
      ultrasound of the larynx was carried out in 29 patients with a swelling of the
      true vocal fold and dysphonia. The findings were then compared with those at
      subsequent microlaryngoscopy, in the majority of cases. RESULTS AND CONCLUSIONS:
      Whereas preoperative laryngeal ultrasound correctly predicted the surgical
      findings of a cystic lesion in only 5 of 11 cases, it correctly identified that
      no cyst was present in 15 of 16 instances when this had been queried. This study
      suggests that ultrasound may have some role in investigation of unilateral vocal
      fold pathology, but that further fine-tuning of the technique may be necessary.

PMID- 15193657
TI  - Effects of a professional solo singer education on auditory and kinesthetic
      feedback--a longitudinal study of singers' pitch control.
AB  - The significance of auditory and kinesthetic feedback to pitch control in singing
      was described in a previous report of this project for students at the beginning
      of their professional solo singer education.(1) As it seems reasonable to assume
      that pitch control can be improved by training, the same students were
      reinvestigated after 3 years of professional singing education. As in the
      previous study, the singers sang an ascending and descending triad pattern with
      and without masking noise in legato and staccato and in a slow and a fast tempo.
      Fundamental frequency and interval sizes between adjacent tones were determined
      and compared with their equivalents in the equally tempered tuning. The average
      deviations from these values were used as estimates of intonation accuracy.
      Intonation accuracy was reduced by masking noise, by staccato as opposed to
      legato singing, and by fast as opposed to slow performance. The contribution of
      the auditory feedback to pitch control was not significantly improved after
      education, whereas the kinesthetic feedback circuit was improved in slow legato
      and slow staccato tasks. The results support the assumption that the kinesthetic
      feedback contributes substantially to intonation accuracy.

PMID- 15193660
TI  - Bilateral vocal fold paralysis: an unusual treatment with botulinum toxin.
AB  - We presented a patient with bilateral vocal fold paralysis treated with
      intralaryngeal Botox injection to improve the glottal airway. The use of Botox in
      this manner has not been previously reported and highlights the value and role of
      intralaryngeal Botox in changing the configuration of the glottis. The concept
      and various approaches for using Botox to alter pathologic vocal fold position is
      reviewed and discussed.

PMID- 15193659
TI  - Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results.
AB  - We report the results of a clinical study using Indole-3-Carbinol (I3C) for the
      treatment of recurrent respiratory papillomatosis (RRP). I3C is abundant in
      cruciferous vegetables and has been shown to decrease papillomatous growth in
      cell cultures and be effective in an animal model of RRP. This is a prospective,
      open-label study design. Patients with RRP were enrolled from September 1996 to
      August 2001 and treated with I3C (adult dose of 200 mg PO BID). All patients
      underwent complete surgical removal and then started I3C. Further surgery was
      performed on an as-needed basis. Patients were categorized as having a complete,
      partial, or no response to I3C. Thirty-three patients treated with I3C were
      available for long-term follow-up (mean=4.8 years), whereas 12 patients were lost
      to follow-up. Eleven (33%) patients experienced remission of papillomatous growth
      and did not require surgery while on I3C. Ten (30%) patients had a reduction in
      papillomatous growth that resulted in less frequent surgery. Twelve patients
      (36%) had no clinical response. No patients experienced a worsening of their RRP.
      Of the 9 pediatric patients available, 1 experienced a complete response, 3 a
      partial response, and 5 had no response to I3C. Twelve patients with a positive
      response (partial or complete) to I3C are still taking I3C. Seven positive
      responders discontinued I3C, 3 of which have remained disease-free, whereas 4
      continue to have RRP. No immediate or long-term side effects related to I3C were
      found. I3C has been found to be a successful treatment option for RRP. I3C's
      efficacy in pediatric patients merits further study.

PMID- 15193658
TI  - The effect of head position on glottic closure in patients with unilateral vocal
      fold paralysis.
AB  - The present study was designed to assess the effect of head position on glottic
      closure as reflected in airflow rates (open quotient and maximum flow declination
      rate), in patients with unilateral vocal fold paralysis. Ten patients, 2 males
      and 8 females ranging in age from 40 to 75, with a mean age of 57.3, served as
      subjects. Airflow measures were taken during sustained phonation of two vowels
      (/i/ and /a/) in 3 head positions (center, right, left). Vowels /i/ and /a/ were
      produced at subject's comfortable pitch and loudness, with random ordering of
      both vowel order and head orientation. Subjects were trained to focus eye gaze on
      right and left markers (70-degree angle) and a central marker at eye level
      directly in front of the subject. Theoretically, if turning the head during
      phonation alters the laryngeal anatomic relationship by bringing the vocal folds
      in closer proximity to one another, then airflow rate should lessen. Our results
      indicate that head position does not improve glottic closure in these patients,
      which is in contrast to previously published research.(1) Our results question
      the utility and underlying theoretical construct for the use of head turning as a
      therapeutic technique for improvement of voice in patients with unilateral vocal
      fold paralysis.

PMID- 15193661
TI  - Electrophysiologic monitoring of the recurrent laryngeal nerves may not predict
      bilateral vocal fold immobility after thyroid surgery.
AB  - Two cases of bilateral vocal fold immobility (VFI) after identification and
      preservation of the recurrent laryngeal nerves (RLNs) required tracheotomy until
      vocal fold recovery. The first patient underwent thyroid surgery without
      preoperative or postoperative evaluation of the vocal folds, administration of
      postoperative intravenous steroids, or electrophysiologic monitoring of the RLNs,
      whereas the second patient underwent a thyroid procedure in which all of the
      aforementioned were executed. Preoperative and postoperative clinical evaluation
      of the RLNs is strongly suggested in patients undergoing thyroid surgery,
      especially revision surgery. Patients potentially undergoing total thyroidectomy
      should be counseled about the remote chance of airway obstruction and should be
      properly selected for this operation. Subclinical stretching of the RLNs or
      ischemia from the endotracheal tube cuff can result in unilateral VFI, and rarely
      bilateral VFI, requiring reintubation, tracheotomy, or vocal fold lateralization.
      Electrophysiologic monitoring may not always predict bilateral VFI.

PMID- 15193662
TI  - Practice parameter: laryngeal electromyography (an evidence-based review).
AB  - This paper reports on an evidence-based review of laryngeal electromyography
      (EMG) as a technique for use in the diagnosis, prognosis, and treatment of
      laryngeal movement disorders, including the laryngeal dystonias, vocal fold
      paralysis, and other neurolaryngological disorders. The authors performed a
      systematic review of the medical literature from 1944 through 2001 on the
      clinical application of EMG to laryngeal disorders. Thirty-three of the 584
      articles met the predefined inclusion criteria. The evidence demonstrated that in
      a double-blind treatment trial of botulinum toxin versus saline, laryngeal EMG
      used to guide injections into the thyroarytenoid muscle in persons with adductor
      spasmodic dysphonia was beneficial. A cross-over comparison between laryngeal EMG
      guided injection and endoscopic injection of botulinum toxin into the posterior
      cricoarytenoid muscle in abductor spasmodic dysphonia found no significant
      difference between the two techniques and no significant treatment benefit. Based
      on the evidence, laryngeal EMG is possibly useful for the injection of botulinum
      toxin into the thyroarytenoid muscle in the treatment of adductor spasmodic
      dysphonia. There were no evidence-based data sufficient to support or refute the
      value of laryngeal EMG for the other uses investigated, although there is
      extensive anecdotal literature suggesting that it is useful for each of them.
      There is an urgent need for evidence-based research addressing other applications
      in the use of laryngeal EMG for other applications.

PMID- 15193663
TI  - Extrinsic muscular tension in patients with voice disorders.

PMID- 15193665
TI  - Is there madness in the method of evidence based reviews?

PMID- 15193667
TI  - Life events as correlates of problem behavior and mental health in a residential
      population of adults with developmental disabilities.
AB  - Very few existing empirical studies have explored the putative association
      between exposure to negative life events and psychological well-being in adults
      with developmental disabilities. In the present study, data on exposure to life
      events in the previous 12 months, adaptive behavior, problem behavior, and
      psychiatric problems were provided by care staff for 93 adults with developmental
      disabilities living in a residential hospital setting. Residents had typically
      been exposed to between three and four negative life events mainly relating to
      staffing and residence changes, conflict, family bereavements and relationships,
      and illness or injury. Those exposed to more recent life events were also rated
      as displaying more frequent aggressive/destructive behavior, and were at
      increased risk for affective/neurotic disorder. The need for replication of these
      data, especially using designs allowing causality to be inferred, is emphasized.

PMID- 15193668
TI  - Combined descriptive and explanatory information improves peers' perceptions of
      autism.
AB  - Authors examined the combined effects of descriptive and explanatory information
      on peers' perceptions and behavioral intentions toward an unfamiliar child with
      autism. Children (N = 576; M age = 10.06) were randomly assigned to view two
      videotapes of a boy engaging in typical and autistic behaviors receiving either
      descriptive (AUT-D) or descriptive and explanatory information (AUT-D + E).
      Children responded to measures of attitudes (Adjective Checklist) and behavioral
      intentions (Shared Activities Questionnaire). Children rated the typical boy more
      favorably than the boy showing autistic symptoms. When compared to descriptive
      information alone, the combination of descriptive and explanatory information
      resulted in improved third- and fourth-graders' but not fifth-graders' attitudes
      toward the child with autism. Combined information improved behavioral intentions
      across grades; however, girls (vs. boys) were more responsive to information as
      evidenced by differences in academic intentions. The combination of descriptive
      and explanatory information about autism appears to have a positive effect on
      children's attitudes and behavioral intentions. Implications of the findings are
      briefly discussed as well as study limitations and recommendations for future
      research.

PMID- 15193669
TI  - CBCL in the assessment of psychopathology in Finnish children with intellectual
      disability.
AB  - Structured checklists have been used to supplement psychiatric assessment of
      children with normal intelligence, but for children with intellectual disability,
      only a few checklists exist. We evaluated the Child Behavior Checklist (CBCL) in
      the assessment of psychopathology in Finnish children with intellectual
      disability. The CBCL was completed by parents or other carers of 90 children aged
      6-13 years. Of the 118 CBCL problem items, the lowest scores were for 'Suicidal
      talks' and 'Alcohol, drugs', and the highest score for 'Acts too young'. Total
      Problem, Internalizing, and Externalizing scores were highest among children with
      moderate intellectual disability and lowest among those with profound
      intellectual disability. Externalizing scores were significantly higher among
      children with mild or moderate intellectual disability than among those with
      severe or profound intellectual disability. Compared with the original normative
      samples, Total Problem scores were higher in the present study. With a T-score
      cut-off point of 60, the rated frequency of psychiatric disorders was 43%. We
      conclude that, despite certain limitations, the CBCL can be used in the
      assessment of psychopathology among children with mild intellectual disability
      but is less reliable for those with moderate, severe, or profound intellectual
      disability.

PMID- 15193670
TI  - Effects of ambient stimuli on measures of behavioral state and microswitch use in
      adults with profound multiple impairments.
AB  - The effects of different types and amounts of environmental stimuli (visual and
      auditory) on microswitch use and behavioral states of three individuals with
      profound multiple impairments were examined. The individual's switch use and
      behavioral states were measured under three setting conditions: natural stimuli
      (typical visual and auditory stimuli in a recreational situation), reduced visual
      stimuli, and reduced visual and auditory stimuli. Results demonstrated
      differential switch use in all participants with the varying environmental
      setting conditions. No consistent effects were observed in behavioral state
      related to environmental condition. Predominant behavioral state scores and
      switch use did not systematically covary with any participant. Results suggest
      the importance of considering environmental stimuli in relationship to switch use
      when working with individuals with profound multiple impairments.

PMID- 15193671
TI  - Teaching students with developmental disabilities to locate their AAC device.
AB  - Students with autism and related developmental disabilities who do not speak are
      often taught to use some type of augmentative and alternative communication (AAC)
      system, such as a voice output communication aid (VOCA). One problem with such
      devices is that the person may be unable to communicate when the device is not
      readily accessible. We first taught three nonverbal students with autism to use a
      VOCA to request access to preferred items. Following this initial acquisition
      phase, however, none of the students would locate their VOCA when it was not
      within reach. A least-to-most prompting procedure was implemented to teach the
      students to locate their AAC device. The effectiveness of this procedure for
      teaching VOCA location skills was evaluated in a delayed multiple-baseline across
      subjects design. The results showed that the intervention was effective in
      teaching the students to locate their AAC device when they needed it to request
      access to preferred objects. Teaching VOCA location skills may be a useful and
      necessary component in AAC interventions for some people with developmental
      disabilities.

PMID- 15193672
TI  - The Adaptive Behaviour Dementia Questionnaire (ABDQ): screening questionnaire for
      dementia in Alzheimer's disease in adults with Down syndrome.
AB  - The diagnosis of dementia in Alzheimer's disease remains at times problematic in
      adults with intellectual disability. The analysis of 5-year consecutive data
      developed a researched-based clinical screening tool for dementia in Alzheimer's
      disease in adults with Down syndrome. The Adaptive Behaviour Dementia
      Questionnaire (ABDQ) is a 15-item questionnaire, which is used to detect change
      in adaptive behaviour. The scale has good reliability and validity, with an
      overall accuracy of 92%. It is the first clinical tool designed specifically to
      screen for dementia in Alzheimer's disease in adults with Down syndrome.

PMID- 15193673
TI  - Rationale and strategies for implementing community-based transfer protocols for
      primary percutaneous coronary intervention for acute ST-segment elevation
      myocardial infarction.
AB  - The focus for the initial approach to the treatment of acute ST-segment elevation
      myocardial infarction (STEMI) has shifted toward extending the benefits of
      mechanical reperfusion with primary percutaneous coronary intervention (PCI) to
      patients who present to community hospitals that have no interventional
      capabilities. Several randomized clinical trials have shown that transferring
      STEMI patients to tertiary centers for primary PCI leads to better outcomes than
      when fibrinolytic therapy is administered at community hospitals. Furthermore,
      potent pharmacologic reperfusion regimens that enhance early reperfusion of the
      infarct vessel before primary PCI may enhance the positive result of the transfer
      approach. Despite these promising findings, several obstacles have hindered the
      adoption of patient-transfer strategies in the U.S., including greater distances
      between community and tertiary hospitals, a lack of integrated emergency medical
      services, and the medical community's limited experience with centralized acute
      myocardial infarction (AMI) care networks. Nonetheless, the implementation of
      system-wide changes in the care of STEMI patients analogous to the creation of
      trauma networks could facilitate the creation and ongoing evaluation of dedicated
      patient transfer strategies and better early invasive care in the U.S. Within
      this context, a systematic, stepwise approach to the creation of AMI care
      networks and to the development of standard nomenclature and performance
      indicators is necessary to guide quality assurance monitoring and future research
      efforts as the care of STEMI patients is redefined. Consequently, this current
      evolution of reperfusion strategies has the potential to further reduce morbidity
      and mortality for patients presenting with STEMI.

PMID- 15193676
TI  - The cardiologist's toolbox: improving care.

PMID- 15193674
TI  - Evaluation of the effect of oral verapamil on clinical outcome and angiographic
      restenosis after percutaneous coronary intervention: the randomized, double
      blind, placebo-controlled, multicenter Verapamil Slow-Release for Prevention of
      Cardiovascular Events After Angioplasty (VESPA) Trial.
AB  - OBJECTIVES: We investigated the effect of oral verapamil on clinical outcome and
      angiographic restenosis after percutaneous coronary intervention (PCI).
      BACKGROUND: Thus far, there is no established systemic pharmacologic approach for
      the prevention of restenosis after PCIs. Five small studies reported encouraging
      results for calcium channel blockers. METHODS: Our randomized double-blind trial
      included 700 consecutive patients with successful PCI of a native coronary
      artery. Patients received the calcium channel blocker verapamil, 240 mg twice
      daily for six months, or placebo. Primary clinical end point was the composite
      rate of death, myocardial infarction, and target vessel revascularization (TVR)
      during one-year follow-up; the angiographic end point was late lumen loss at the
      six-month follow-up angiography. RESULTS: We obtained complete clinical follow-up
      in 95% of the patients, and scheduled angiography was performed in 94%. The
      proportion of patients treated with stents was 83%. The primary clinical end
      point was reached in 67 (19.3%) patients on verapamil and in 103 (29.3%) patients
      on placebo (relative risk [RR] 0.66 [95% confidence interval (CI) 0.48 to 0.89];
      p = 0.002). This difference between the groups was driven by TVR (17.5% with
      verapamil vs. 26.2% with placebo; RR 0.67 [95% CI 0.49 to 0.93]; p = 0.006). Late
      lumen loss was 0.74 +/- 0.70 mm with verapamil and 0.81 +/- 0.75 mm with placebo
      (p = 0.11). Compared with placebo, verapamil reduced the rate of restenosis > or
      =75% (7.8% vs. 13.7%; RR 0.57 [95% CI 0.35 to 0.92]; p = 0.014). CONCLUSIONS:
      Verapamil compared with placebo improves long-term clinical outcome after PCI of
      native coronary arteries by reducing the need for TVR. This was caused by a
      reduction in the rate of high-grade restenosis.

PMID- 15193675
TI  - Enhancing quality of care for acute myocardial infarction: shifting the focus of
      improvement from key indicators to process of care and tool use: the American
      College of Cardiology Acute Myocardial Infarction Guidelines Applied in Practice
      Project in Michigan: Flint and Saginaw Expansion.
AB  - OBJECTIVES: This project evaluated if by focusing on process changes and tool use
      rather than key indicator rates, the use of evidence-based therapies in patients
      with acute myocardial infarction (AMI) would increase. BACKGROUND: The use of
      tools designed to improve quality of care in the American College of Cardiology
      AMI Guidelines Applied in Practice Pilot Project resulted in improved adherence
      to evidence-based therapies for patients, but overall, tool use was modest.
      METHODS: The current project, implemented in five hospitals, was modeled after
      the previous project, but with greater emphasis on tool use. This allowed early
      identification of barriers to tool use and strategies to overcome barriers. Main
      outcome measures were AMI quality indicators in pre-measurement (January 1, 2001
      to June 30, 2001) and post-measurement (December 15, 2001 to March 31, 2002)
      samples. RESULTS: One or more tools were used in 93% of patients (standard orders
      = 82%, and discharge document = 47%). Tool use was associated with significantly
      higher adherence to most discharge quality indicator rates with increases in
      aspirin, angiotensin-converting enzyme inhibitors, and smoking cessation and
      dietary counseling. Patients undergoing coronary artery bypass grafting (CABG)
      had low rates of discharge indicators. Patients undergoing percutaneous coronary
      revascularization were more likely to receive evidence-based therapies.
      CONCLUSIONS: These data validate the results of the pilot project that quality of
      AMI care can be improved through the use of guideline-based tools. Identifying
      and overcoming barriers to tool use led to substantially higher rates of tool
      use. The low rates of adherence to quality indicators in patients undergoing CABG
      suggest that these patients should be particularly targeted for quality
      improvement efforts.

PMID- 15193677
TI  - The calcium sensitizer levosimendan improves the function of stunned myocardium
      after percutaneous transluminal coronary angioplasty in acute myocardial
      ischemia.
AB  - OBJECTIVES: We assessed the effects of levosimendan on left ventricular (LV)
      function in patients with acute myocardial ischemia and after coronary
      angioplasty. BACKGROUND: The calcium sensitizer levosimendan improves the
      function of myocardium in experimental stunning. METHODS: Twenty-four patients
      with an acute coronary syndrome underwent angioplasty followed by double-blinded,
      randomized treatment with 24 microg/kg of levosimendan (n = 16) or placebo (n =
      8). Left ventricular pressures and volumes were recorded by cineventriculography
      and micromanometer-tipped catheters 10 min after angioplasty before drug
      administration (baseline) and 20 min after drug administration. Left ventricular
      function was assessed by the pressure-volume loop, and regional function analysis
      by the Slager method. RESULTS: The number of hypokinetic segments decreased with
      levosimendan, from 8.9 +/- 0.9 to 6.5 +/- 1.1 (mean +/- SEM), as compared with an
      increase from 7.8 +/- 1.0 to 8.5 +/- 1.1 with placebo (p = 0.016). A leftward
      and/or upward shift of the systolic part of the pressure-volume loop, indicating
      improved systolic function, was observed in eight of 16 of the levosimendan
      treated and one of eight of the placebo patients (p = 0.178). In addition, the
      single-beat elastance was increased by levosimendan (p = 0.045). The pressure
      volume area (p = 0.001), end-systolic pressure (p = 0.002), and volume index (p <
      0.001) were decreased by levosimendan, but there was no change in the end
      systolic pressure-volume ratio. End-diastolic pressure remained unchanged,
      whereas the end-diastolic volume index was decreased by levosimendan (p = 0.002).
      The time constant of isovolumic LV pressure fall decreased with levosimendan (p =
      0.001). CONCLUSIONS: Levosimendan improved the function of stunned myocardium
      without obvious impairment of diastolic function.

PMID- 15193679
TI  - Human hibernating myocardium is jeopardized by apoptotic and autophagic cell
      death.
AB  - OBJECTIVES: The aim of the present study was to objectify the loss of myocytes
      and the mechanism by which myocytes die in human hibernating myocardium (HHM).
      BACKGROUND: Intracellular degeneration, reduced cellular protein synthesis, and
      the replacement fibrosis contribute to structural disintegration of HHM. METHODS:
      In 14 patients, HHM was diagnosed by dobutamine echocardiography, radionuclide
      ventriculography, and thallium-201 scintigraphy. Functional recovery was
      documented by repeating the preoperative clinical investigations three months
      after successful coronary artery bypass graft surgery (CABG). During CABG,
      transmural biopsies were taken from the center of HHM regions and studied by
      electron microscopy, immunohistochemistry, the terminal deoxynucleotidyl
      transferase-mediated nick end-labeling (TUNEL) method, reverse transcription
      polymerase chain reaction, and Western blotting. Control samples were taken from
      nondiseased human myocardium. RESULTS: All patients showed significant
      improvement or normalization of the regional function of HHM. Ubiquitin-related
      autophagic cell death was evident ultrastructurally by the occurrence of
      autophagic vacuoles, cellular degeneration, and nuclear disassembly. Ubiquitin
      protein complexes were found in 0.03 +/- 0.008% (control: 0%, p < 0.005) of all
      myocytes. The proteasome 20S subunit/total myocytes were reduced from 63.3 +/-
      9.6% in control myocardium to 36.9 +/- 8.4% in HHM. Complement-9, indicating
      oncosis, was found in only one of 14 biopsies. TUNEL-positive myocytes were 0.002
      +/- 0.0003%. Electron microscopy showed apoptotic cells in 3 of 14 samples.
      However, the bcl-2/bax ratio was significantly reduced. Moreover, caspase-3
      messenger ribonucleic acid was 8.5 times upregulated, and caspase-3 was
      activated. Cell death was absent in controls. CONCLUSIONS: In HHM, ubiquitin
      related autophagic cell death and apoptosis cause a loss of myocytes. This plays
      an important role in progressive tissue damage and causes a reduction of the
      extent of functional recovery of HHM.

PMID- 15193678
TI  - A dose-finding study of fondaparinux in patients with non-ST-segment elevation
      acute coronary syndromes: the Pentasaccharide in Unstable Angina (PENTUA) Study.
AB  - OBJECTIVES: In this dose-finding study, we sought to compare fondaparinux with
      enoxaparin in patients with acute coronary syndromes (ACS). BACKGROUND:
      Fondaparinux is a synthetic pentasaccharide that selectively inhibits activated
      clotting factor X. It has been demonstrated as effective in preventing
      thromboembolic complications in orthopedic surgery. METHODS: Four doses
      fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice
      daily) were compared, both given for three to seven days, in patients with ACS
      without persistent ST-segment elevation. RESULTS: The rates of the combined
      primary end point of death, myocardial infarction, or recurrent ischemia after
      nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to
      fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS).
      In the per-protocol analysis (929 patients who received adequate study drug and
      had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%,
      34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates
      were observed in the 2.5-mg fondaparinux group, which had significantly lower
      rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per
      protocol analysis (p < 0.05). Bleeding rates were low and not different among the
      patient groups. No differences were observed in fondaparinux concentrations in
      patients with or without death, myocardial infarction, recurrent ischemia, or
      bleeding events. CONCLUSIONS: This dose-finding study revealed no dose response
      for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and
      suggests that the efficacy and safety of fondaparinux may be similar to that of
      enoxaparin. Further studies with fondaparinux in ACS might include the lowest
      dose (2.5 mg) investigated in this study.

PMID- 15193680
TI  - Effects of ramipril on left ventricular mass and function in cardiovascular
      patients with controlled blood pressure and with preserved left ventricular
      ejection fraction: a substudy of the Heart Outcomes Prevention Evaluation (HOPE)
      Trial.
AB  - OBJECTIVES: The purpose of this study was to assess the effects of ramipril on
      left ventricular mass (LVM) and function in vascular disease patients with
      controlled blood pressure (BP) and with preserved left ventricular ejection
      fraction (LVEF). BACKGROUND: Increased LVM and left ventricular (LV) volume and
      decreased LVEF predict clinical events. Angiotensin-converting enzyme inhibitors
      reduce LVM and LV volume and preserve LVEF in patients with hypertension and/or
      LV dysfunction, but have not been studied in patients with controlled BP and
      preserved LVEF. METHODS: We compared the effects of two doses of ramipril (10
      mg/day and 2.5 mg/day) versus placebo in 506 patients with vascular disease on
      echocardiographic measures of LVM and LV function. RESULTS: Baseline BP and LVEF
      were similar, 131/76 mm Hg and 58%, in all treatment groups. After four years,
      LVM index increased by 3.98 +/- 2.08 g/m2 in the placebo and by 4.16 +/- 1.86
      g/m2 in the ramipril 2.5 mg/day groups and decreased by 2.02 +/- 2.25 g/m2 in the
      ramipril 10 mg/day group (p = 0.02). The changes in LV end-diastolic and end
      systolic volumes were 4.16 +/- 2.55 ml and 5.31 +/- 1.67 ml in the placebo, -0.43
      +/- 2.75 ml and 2.90 +/- 1.45 ml in the ramipril 2.5 mg/day, and -5.90 +/- 2.93
      ml and -1.90 +/- 1.55 ml in the ramipril 10 mg/day groups (p = 0.02 and p =
      0.001). The changes in LVEF were -2.02 +/- 0.72%, -1.54 +/- 0.74%, and -0.17 +/-
      0.72%, respectively (p = 0.01). CONCLUSIONS: Ramipril has beneficial effects on
      LV structure and function in vascular patients with controlled BP and with
      preserved LVEF.

PMID- 15193681
TI  - Increased left ventricular mass is a risk factor for the development of a
      depressed left ventricular ejection fraction within five years: the
      Cardiovascular Health Study.
AB  - OBJECTIVES: Our aim in this study was to determine whether increased left
      ventricular mass (LVM) is a risk factor for the development of a reduced left
      ventricular ejection fraction (LVEF). BACKGROUND: Prior studies have shown that
      increased LVM is a risk factor for heart failure but not whether it is a risk
      factor for a low LVEF. METHODS: As part of the Cardiovascular Health Study, a
      prospective population-based longitudinal study, we performed echocardiograms
      upon participant enrollment and again at follow-up of 4.9 +/- 0.14 years. In the
      present analysis, we identified 3,042 participants who had at baseline a normal
      LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram),
      and at follow-up a measurable LVEF. The frequency of the development of a
      qualitatively depressed LVEF on two-dimensional echocardiography, corresponding
      approximately to an LVEF <55%, was analyzed by quartiles of baseline LVM.
      Multivariable regression determined whether LVM was independently associated with
      the development of depressed LVEF. RESULTS: Baseline quartile of
      echocardiographic LVM indexed to body surface area was associated with
      development of a depressed LVEF (4.8% in quartile 1, 4.4% in quartile 2, 7.5% in
      quartile 3, and 14.1% in quartile 4 [p < 0.001]). A similar relationship was seen
      in the subgroup of participants without myocardial infarction (p < 0.001). In
      multivariable regression that adjusted for confounders, both baseline
      echocardiographic (p < 0.001) and electrocardiographic (p < 0.001) LVM remained
      associated with development of depressed LVEF. CONCLUSIONS: Increased LVM as
      assessed by electrocardiography or echocardiography is an independent risk factor
      for the development of depressed LVEF.

PMID- 15193682
TI  - Left ventricular hypertrophy: a "factor of risk": mass is reversible, but is the
      risk?

PMID- 15193683
TI  - Prognostic value of remnant-like lipoprotein particle levels in patients with
      coronary artery disease and type II diabetes mellitus.
AB  - OBJECTIVES: This study prospectively examined whether the levels of high remnant
      like lipoprotein particles (RLP) cholesterol have a significant risk and
      influence prognosis in patients with coronary artery disease (CAD) and type II
      diabetes mellitus (DM). BACKGROUND: Several studies have shown that triglyceride
      rich lipoproteins contribute to atherosclerotic complications in type II DM.
      However, it remains to be established which triglyceride-rich lipoproteins
      contribute to this risk. METHODS: Levels of RLP cholesterol in fasting serum were
      measured by an immunoseparation method in 240 type II DM patients with (n = 120)
      or without (n = 120) CAD. The patients with CAD were followed up for a period of
      < or =24 months until the occurrence of one of the following clinical coronary
      events: re-admission or coronary revascularization due to recurrent or refractory
      angina pectoris, nonfatal myocardial infarction, or cardiac death. RESULTS:
      Patients with CAD had higher RLP levels than patients without CAD. Multivariate
      logistic regression analysis showed that high RLP cholesterol levels (>4.7 mg
      cholesterol/dl, representing the 75th percentile of the distribution of RLP
      cholesterol levels in control subjects) were a significant risk factor for the
      presence of CAD, independent of traditional risk factors. Kaplan-Meier analysis
      demonstrated that higher RLP cholesterol levels in patients with CAD resulted in
      a significantly higher probability for the development of coronary events.
      Multivariate Cox hazards analysis showed that high RLP cholesterol levels in
      patients with CAD were a significant predictor of future coronary events,
      independent of other risk factors. CONCLUSIONS: Increased levels of RLP
      cholesterol are a significant and independent risk factor of CAD and predict
      future coronary events in patients with CAD and type II DM.

PMID- 15193684
TI  - Impaired intravascular triglyceride lipolysis constitutes a marker of clinical
      outcome in patients with stable angina undergoing secondary prevention treatment:
      a long-term follow-up study.
AB  - OBJECTIVES: We sought to verify whether the intravascular metabolism of
      chylomicron-like emulsion may predict the clinical evolution of patients with
      coronary artery disease (CAD) undergoing secondary prevention therapy of CAD.
      BACKGROUND: Case-control studies have suggested an association between impaired
      intravascular catabolism of triglyceride (TG)-rich lipoproteins and CAD. However,
      evidence is lacking with respect to the potential clinical relevance of this
      metabolic disorder in CAD patients. METHODS: During a period of 4.5 +/- 0.9
      years, we followed up 63 stable CAD patients (mean age 60 +/- 10 years)
      undergoing secondary prevention therapy (low-density lipoprotein cholesterol <100
      mg/dl) in whom kinetic studies of the in vivo catabolism of chylomicron-like
      emulsions were performed. At enrollment into the study, fasting patients were
      injected intravenously with a chylomicron-like emulsion labeled with radioactive
      triglyceride (3H-TG) and cholesteryl esters (14C-CE) to evaluate the efficacy of
      intravascular TG lipolysis. RESULTS: At baseline, CAD patients displayed a
      diminished fractional clearance rate (FCR) for 3H-TG (-26%; p = 0.027), for 14C
      CE (-37%; p = 0.015), and for delipidation index (DI) (-26%; p = 0.02) as
      compared with 35 control subjects. During follow-up of secondary prevention
      therapy, 33% of CAD patients (n = 21) presented with clinically refractory angina
      and aggravated coronary angiographic severity. The FCR for 3H-TG (-44%; p =
      0.005) and DI (-41%; p = 0.006) in those patients with refractory angina was
      significantly lower than that observed in those with stable evolution. Moreover,
      in a Cox multivariate regression analysis, the presence of a DI less than the
      median value was an independent predictor of an unfavorable clinical evolution
      (adjusted hazard ratio 3.32; 95% confidence interval 1.21 to 9.14; p = 0.020).
      CONCLUSIONS: The current study establishes that delayed intravascular TG
      lipolysis is a strong and independent predictor of evolution to severe angina
      among patients undergoing secondary prevention therapy of CAD.

PMID- 15193685
TI  - Triglyceride-rich lipoprotein remnant levels and metabolism: time to adopt these
      orphan risk factors?

PMID- 15193686
TI  - The association of fasting glucose levels with congestive heart failure in
      diabetic adults > or =65 years: the Cardiovascular Health Study.
AB  - OBJECTIVES: The purpose of this study was to determine if fasting glucose levels
      are an independent risk factor for congestive heart failure (CHF) in elderly
      individuals with diabetes mellitus (DM) with or without coronary heart disease
      (CHD). BACKGROUND: Diabetes mellitus and CHF frequently coexist in the elderly.
      It is not clear whether fasting glucose levels in the setting of DM are a risk
      factor for incident CHF in the elderly. METHODS: A cohort of 829 diabetic
      participants, age > or =65 years, without prevalent CHF, was followed for five to
      eight years. The Cox proportional hazards modeling was used to determine the risk
      of CHF by fasting glucose levels. The cohort was categorized by the presence or
      absence of prevalent CHD. RESULTS: For a 1 standard deviation (60.6 mg/dl)
      increase in fasting glucose, the adjusted hazard ratios for incident CHF among
      participants without CHD at baseline, with or without an incident myocardial
      infarction (MI) or CHD event on follow-up, was 1.41 (95% confidence interval 1.24
      to 1.61; p < 0.0001). Among those with prevalent CHD at baseline, with or without
      another incident MI or CHD event on follow-up, the corresponding adjusted hazard
      ratio was 1.27 (95% confidence interval 1.02 to 1.58; p < 0.05). CONCLUSIONS:
      Among older adults with DM, elevated fasting glucose levels are a risk factor for
      incident CHF. The relationship of fasting glucose to CHF differs somewhat by the
      presence or absence of prevalent CHD.

PMID- 15193687
TI  - Exercise echocardiographic findings and outcome of patients referred for
      evaluation of dyspnea.
AB  - OBJECTIVES: The purpose of this study was to characterize the outcome of patients
      referred for exercise echocardiographic evaluation of dyspnea. BACKGROUND: Little
      information exists regarding outcome of patients with dyspnea. METHODS: We
      identified 443 patients with unexplained dyspnea, 2,033 with chest pain, and 587
      with both symptoms referred for exercise echocardiography. RESULTS: Compared to
      those with chest pain alone, patients referred for dyspnea alone were older,
      predominantly men, and had lower workload, lower ejection fraction (EF), more
      prior myocardial infarction (MI), and abnormal rest electrocardiograms. Patients
      with both symptoms were similar to those with dyspnea, but more had prior
      revascularization. Exercise echocardiography showed ischemia in 42% of patients
      with dyspnea, 19% with chest pain, and 58% with both symptoms. During 3.1 +/- 1.8
      years follow-up, cardiac death (5.2% vs. 0.9%, p < 0.0001) and nonfatal MI (4.7%
      vs. 2.0%, p < 0.0001) occurred more often in patients with dyspnea. Events in
      patients with both symptoms were similar to those with dyspnea, except for
      revascularization (20% vs. 13%, p = 0.0004). For patients with dyspnea,
      independent predictors of events were previous MI (hazard ratio [HR] 3.35, p <
      0.0001), male gender (HR 1.94, p = 0.0252), EF (HR 0.95/10% increment, p <
      0.0001), and increase in wall motion score index with exercise (HR 4.19/0.25 U, p
      < 0.0001), but not chest pain. CONCLUSIONS: Patients with unexplained dyspnea
      have a high likelihood of ischemia and an increased incidence of cardiac events.
      Exercise echocardiography provides independent information for identifying
      patients at risk. In patients with known or suspected coronary artery disease,
      dyspnea is a symptom requiring investigation.

PMID- 15193688
TI  - Accuracy of dipyridamole myocardial contrast echocardiography for the detection
      of residual stenosis of the infarct-related artery and multivessel disease early
      after acute myocardial infarction.
AB  - OBJECTIVES: We aimed to evaluate the ability of vasodilator myocardial contrast
      echocardiography (MCE) to detect significant infarct-related artery (IRA)
      stenosis and multivessel disease (MVD) after thrombolysis. BACKGROUND: The
      detection of residual IRA stenosis subtending significant viable myocardium and
      the identification of MVD may help to triage patients who may benefit from
      mechanical revascularization after acute myocardial infarction (AMI) and
      thrombolysis. METHODS: Patients with AMI underwent low-power MCE at rest and
      after dipyridamole stress during SonoVue infusion seven to 10 days after
      thrombolysis. RESULTS: Of the 73 patients, 61 demonstrated significant myocardial
      viability, of whom 57 (93%) showed significant IRA stenosis. Sensitivities to
      detect >50% IRA stenosis and MVD were 88% and 72%, respectively. The accuracy of
      detecting significant coronary stenosis in the anterior (left anterior descending
      coronary artery) versus inferoposterior (right coronary artery/left circumflex
      artery) circulation was similar for both IRA (85% vs. 91%) and remote territories
      (91% vs. 81%). Quantitative peak contrast intensity (p = 0.02), microbubble
      velocity (p = 0.0001), and myocardial blood flow (p < 0.0001) were significantly
      lower in patients with significant coronary stenosis during dipyridamole compared
      with rest. Only beta reserve discriminated various grades of coronary stenosis.
      CONCLUSIONS: Use of MCE accurately predicted significant IRA stenosis and MVD
      after thrombolysis. This information is valuable for identifying patients who may
      benefit from mechanical revascularization.

PMID- 15193689
TI  - Gadolinium delayed enhancement cardiovascular magnetic resonance correlates with
      clinical measures of myocardial infarction.
AB  - OBJECTIVES: The current study tested the hypothesis that gadolinium delayed
      enhancement assessment of infarct size correlates with clinical indices of
      myocardial infarction (MI) in humans. Acute infarct mass by cardiac magnetic
      resonance (CMR) was compared with peak troponin I, acute and chronic left
      ventricular (LV) systolic function, and chronic infarct mass in patients imaged
      after recent acute MI. BACKGROUND: Cardiac magnetic resonance accurately
      determines myocardial viability in patients with chronic ischemic heart disease
      but is not well validated for recent MI. METHODS: Patients with first acute MI (n
      = 33) or chronic MI (n = 10) underwent cine CMR followed by gadolinium delayed
      enhancement imaging. A follow-up CMR scan was performed on 20 of the 33 acute MI
      patients and all of the chronic MI patients. RESULTS: In patients with acute
      percutaneous coronary intervention, acute MI mass correlated with peak troponin I
      (r = 0.83, p < 0.001, n = 23). In the 20 acute infarct patients with follow-up
      CMR scans, the acute infarct size correlated well with the follow-up LV ejection
      fraction (r = 0.86, p < 0.001). The transmural extent of delayed enhancement
      imaged acutely correlated inversely with wall thickening measured acutely (p <
      0.001) and at follow-up (p < 0.001). Although chronic infarct size was
      reproducible (11 +/- 4% vs. 12 +/- 7%, p = NS), acute infarct size decreased from
      16 +/- 12% to 11 +/- 9% (p < 0.003). CONCLUSION: In humans imaged shortly after
      acute MI, gadolinium delayed enhancement acute CMR infarct size correlates with
      acute and chronic indices of infarct size but will appear to diminish in size on
      follow-up.

PMID- 15193690
TI  - The histologic basis of late gadolinium enhancement cardiovascular magnetic
      resonance in hypertrophic cardiomyopathy.
AB  - OBJECTIVES: We sought to identify the histologic basis of myocardial late
      gadolinium enhancement cardiovascular magnetic resonance (CMR) in hypertrophic
      cardiomyopathy (HCM). BACKGROUND: The histologic basis of late gadolinium CMR in
      patients with HCM is unknown. METHODS: A 28-year-old male patient with HCM and
      heart failure underwent late gadolinium enhancement CMR and, 49 days later, heart
      transplantation. The explanted heart was examined histologically for the extent
      of collagen and disarray, and the results were compared with a previous in vivo
      CMR scan. RESULTS: Overall, 19% of the myocardium was collagen, but the amount
      per segment varied widely (SD +/- 19, range 0% to 71%). Both disarray and
      collagen were more likely to be found in the mesocardium than in the endo- or
      epicardium. There was a significant relationship between the extent of late
      gadolinium enhancement and collagen (r = 0.7, p < 0.0001) but not myocardial
      disarray (p = 0.58). Segments containing >15% collagen were more likely to have
      late gadolinium enhancement. Regional wall motion was inversely related to the
      extent of myocardial collagen and late gadolinium enhancement but not disarray (p
      = 0.0003, 0.04, and NS, respectively). CONCLUSIONS: In this patient with HCM and
      heart failure, regions of myocardial late gadolinium enhancement by CMR
      represented regions of increased myocardial collagen but not disarray.

PMID- 15193691
TI  - Multislice spiral computed tomography coronary angiography in patients with
      stable angina pectoris.
AB  - OBJECTIVES: This study was designed to prospectively evaluate the diagnostic
      performance of multislice spiral computed tomography (MSCT) coronary angiography
      for the detection of significant lesions in all segments of the coronary tree
      potentially suitable for revascularization. BACKGROUND: Noninvasive MSCT coronary
      angiography is a promising coronary imaging technique. METHODS: Sixteen-row MSCT
      coronary angiography was performed in 128 patients (89% men, mean age 58.9 +/-
      11.7 years) in sinus rhythm with stable angina pectoris scheduled for
      conventional coronary angiography. Sixty percent (77 of 128) of patients received
      pre-scan oral beta-blockers, resulting in a mean heart rate of 57.7 +/- 7.7
      beats/min. The diagnostic performance of MSCT for detection of significant
      lesions (> or =50% diameter reduction) was compared with that of quantitative
      coronary angiography (QCA). RESULTS: The sensitivity of MSCT for detection of
      significant lesions was 92% (216 of 234, 95% confidence interval [CI]: 88 to 95).
      Specificity was 95% (1,092 of 1,150, 95% CI: 93 to 96), positive predictive value
      79% (216 of 274, 95% CI: 73 to 88), and negative predictive value 98% (1,092 of
      1,110, 95% CI: 97 to 99). Two > or =50% lesions were missed because of motion
      artifacts and two because of severe coronary calcifications. The rest (78%, 14 of
      18) were detected but incorrectly classified as <50% obstructions. All patients
      with and 86% (18 of 21) of patients without significant lesions on QCA were
      correctly classified by MSCT. All patients with significant left main disease or
      total occlusions were correctly identified on MSCT. CONCLUSIONS: Sixteen-row MSCT
      coronary angiography permits reliable detection of significant obstructive
      coronary artery disease in patients with stable angina in sinus rhythm.

PMID- 15193692
TI  - Dissection of long-range heart rate variability: controlled induction of
      prognostic measures by activity in the laboratory.
AB  - OBJECTIVES: We sought to determine whether the long-range measures of heart rate
      variability (HRV)--the standard deviation of sequential 5-min heart period mean
      values (SDANN) and the heart period spectral amplitude in the ultra-low frequency
      band <0.0033 Hz (ULF)--had their origins partly in physical activity. BACKGROUND:
      The SDANN and ULF are prognostic HRV factors whose physiologic origins are
      obscure. Their discontinuous presence throughout the day suggested that they
      arise from changes in heart period due to activity. METHODS: Heart period
      sequences were recorded from 14 patients with left ventricular dysfunction and 14
      control subjects during an unrestricted 24-h day, 4-h supine rest, and 4-h epoch
      with scripted activities. RESULTS: The SDANN was higher during activity than
      during rest (74 +/- 23 ms vs. 43 +/- 17 ms, p < 0.0001), as were ULF magnitudes
      (p < 0.0001). The increase in SDANN was due to specific activities that
      contributed heavily (p < 0.0001 by analysis of variance); for example, a 10-min
      walk and 90-min rest each contributed 22% of total SDANN. Patients with heart
      disease had a lower SDANN and ULF and a higher mean heart rate than control
      subjects during all recordings. The proportional ranges in heart period were the
      same in the two groups during controlled, scripted activities but were wider in
      control subjects than in patients during ambulatory recordings, suggesting
      decreased activity by patients. CONCLUSIONS: Activity increases SDANN by
      increasing the range of heart periods. Patients with diminished ventricular
      function have a reduced SDANN on ambulatory electrocardiograms, possibly and
      partly because of a higher mean heart rate and reduced variations in physical
      activity.

PMID- 15193693
TI  - Origin and significance of heart rate variability.

PMID- 15193694
TI  - Electrophysiologic properties of pulmonary veins assessed using a multielectrode
      basket catheter.
AB  - OBJECTIVES: The purpose of the present study was to evaluate the
      electrophysiologic properties within the pulmonary vein (PV) and at the PV-left
      atrial (LA) junction. BACKGROUND: It has been recognized that atrial fibrillation
      (AF) can originate from PVs. However, the electrophysiologic properties of the PV
      have not been well characterized. METHODS: Thirty-two bipolar electrograms were
      recorded simultaneously from a basket catheter placed in 81 PVs of 48 patients
      with paroxysmal AF. The programmed stimulation was performed in the distal PV and
      PV-LA junction. Activation maps of PVs were analyzed from episodes of spontaneous
      onset of AF and initiation of induced AF by a single extrastimulus. RESULTS: The
      effective refractory period (ERP) of the distal PV was significantly shorter than
      that of the PV-LA junction (177 +/- 43 vs. 222 +/- 30 ms, p < 0.0001). The
      conduction delay from the distal PV to the PV-LA junction was significantly
      longer than that from the PV-LA junction to distal PV (73 +/- 40 vs. 32 +/- 17
      ms, p < 0.0001). During initiation of AF, a short coupled extrastimulus or rapid,
      repetitive focal activities originating from the PV formed a PV-LA reciprocating
      re-entrant circuit involving exit and entrance breakthrough points at the PV-LA
      junction. Also, an unstable re-entrant circuit within the PV was observed.
      CONCLUSIONS: The presence of ERP heterogeneity and anisotropic conduction
      properties within the PV and at the PV-LA junction may be crucial to promote re
      entry formation and thus might play an important role as a substrate for the
      maintenance of AF.

PMID- 15193695
TI  - Pulmonary veins in the substrate for atrial fibrillation: the "venous wave"
      hypothesis.

PMID- 15193696
TI  - Gender differences in ventricular arrhythmia recurrence in patients with coronary
      artery disease and implantable cardioverter-defibrillators.
AB  - OBJECTIVES: We sought to determine whether men and women with coronary artery
      disease (CAD) and implantable cardioverter-defibrillators (ICDs) differ in
      frequency of arrhythmia recurrence and whether gender differences are independent
      of clinical, electrocardiographic, and electrophysiologic characteristics.
      BACKGROUND: Epidemiologic studies show that women have a lower rate of sudden
      cardiac death (SCD) than men, even among patients with CAD. Whether this is due
      to differing susceptibilities to ischemia or to arrhythmia is unknown. METHODS:
      The clinical records and ICD data disks of 340 men and 59 women with CAD who
      received an ICD between June 1990 and June 2000 were reviewed. Ventricular
      tachycardia (VT) or ventricular fibrillation (VF) recurrences were compared
      between genders and relationship with other factors was analyzed. RESULTS:
      Sustained VT/VF occurred in 52% of men and 34% of women (p < 0.01). Men
      experienced more total VT/VF events (p < 0.01), more shock-treated VT/VF events
      (p < 0.03), more electrical storms (p < 0.001), and had VT/VF on more days in
      follow-up (p < 0.01). Gender differences were independent of measured clinical,
      electrocardiographic, and electrophysiologic factors. In stratified analyses, the
      gender differences in VT/VF recurrence were greatest in patients presenting with
      sustained monomorphic VT and those with inducible VT at electrophysiology study.
      CONCLUSIONS: Women were less likely to experience VT/VF, and had fewer VT/VF
      episodes, than men. These findings were strongest in patients with evidence of a
      stable anatomic VT circuit: those with clinical or electrophysiologically induced
      VT. This study suggests that differing susceptibility to arrhythmia triggering
      may underlie the known differences in SCD rates between men and women.

PMID- 15193697
TI  - Characteristics of virtual unipolar electrograms for detecting isthmus block
      during radiofrequency ablation of typical atrial flutter.
AB  - OBJECTIVES: The purpose of this study was to investigate the characteristics of
      the second component of local virtual unipolar electrograms recorded at the
      ablation line during coronary sinus (CS) pacing after radiofrequency ablation
      (RFA) of the cavotricuspid isthmus (CTI) for typical atrial flutter (AFL).
      BACKGROUND: Radiofrequency ablation of the CTI can produce local double
      potentials at the ablation line. The second component of unipolar electrograms
      represents the approaching wavefront in the right atrium opposite the pacing
      site. We hypothesized that the morphologic characteristics of the second
      component of double potentials would be useful in detecting complete CTI block.
      METHODS: Radiofrequency ablation of the CTI was performed in 52 patients (males =
      37, females = 15, 62 +/- 12 years) with typical AFL. The noncontact mapping
      system (Ensite 3000, Endocardial Solutions, St. Paul, Minnesota) was used to
      guide RFA. Virtual unipolar electrograms along the ablation line during CS pacing
      after RFA were analyzed. Complete or incomplete CTI block was confirmed by the
      activation sequence on the halo catheter and noncontact mapping. RESULTS: Three
      groups were classified after ablation. Group I (n = 37) had complete
      bidirectional CTI block. During CS pacing, the second component of unipolar
      electrograms showed an R or Rs pattern. Group II (n = 12) had incomplete CTI
      block. The second component of unipolar electrograms showed an rS pattern. Group
      III (n = 3) had complete CTI block with transcristal conduction. The second
      component of unipolar electrograms showed an rSR pattern. CONCLUSIONS: A
      predominant R-wave pattern in the second component of unipolar double potentials
      at the ablation line indicates complete CTI block, even in the presence of
      transcristal conduction.

PMID- 15193698
TI  - Histologic findings in patients with clinical and instrumental diagnosis of
      sporadic arrhythmogenic right ventricular dysplasia.
AB  - OBJECTIVES: We sought to analyze the histologic findings of 30 patients with a
      diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) based on
      established clinical and instrumental criteria, who did not have a family history
      of ARVD. BACKGROUND: The diagnostic role of endomyocardial biopsy (EMB) in
      patients with a clinical profile of ARVD is still debated. METHODS: Thirty
      patients (19 male, 11 female, mean age 27 +/- 10 years) with left bundle branch
      block morphology ventricular tachyarrhythmias and echocardiographic,
      angiographic, and magnetic resonance imaging (MRI) findings diagnostic of ARVD
      were studied. All patients, besides diagnostic, noninvasive, and invasive cardiac
      studies, underwent EMB in the apex, anterior free wall, inferior wall of the
      right ventricle (RV) and in the septal-apical region of the left ventricle.
      RESULTS: Diagnostic histologic features of ARVD were found only in 9 (30%)
      patients and a myocarditis, according to the Dallas criteria, in the remaining 21
      (70%) patients. Morphometric evaluation of RV samples showed significant
      differences in fatty tissue and myocyte percent area between ARVD and myocarditis
      (p < 0.001). Conversely, no difference was found between the two groups in
      arrhythmic patterns and structural and functional echocardiographic,
      angiographic, and MRI RV alterations. Magnetic resonance imaging showed
      hyperintense signals in 67% of ARVD and in 62% of myocarditis group (p = NS).
      During follow-up (mean, 23 +/- 14 months), all patients with myocarditis remained
      stable on antiarrhythmic therapy while five patients with ARVD required
      implantation of an implantable cardioverter defibrillator. CONCLUSIONS: A
      myocarditis involving the RV can mimic ARVD. An EMB appears the most reliable
      diagnostic technique, with significant prognostic and therapeutic implications.

PMID- 15193699
TI  - Exercise acutely increases circulating endothelial progenitor cells and monocyte
      /macrophage-derived angiogenic cells.
AB  - OBJECTIVES: We investigated whether a single episode of exercise could acutely
      increase the numbers of endothelial progenitor cells (EPCs) and
      cultured/circulating angiogenic cells (CACs) in human subjects. BACKGROUND:
      Endothelial progenitor cells and CACs can be isolated from peripheral blood and
      have been shown to participate in vascular repair and angiogenesis. We
      hypothesized that exercise may acutely increase either circulating EPCs or CACs.
      METHODS: Volunteer subjects (n = 22) underwent exhaustive dynamic exercise. Blood
      was drawn before and after exercise, and circulating EPC numbers as well as
      plasma levels of angiogenic growth factors were assessed. The CACs were obtained
      by culturing mononuclear cells and the secretion of multiple angiogenic growth
      factors by CACs was determined. RESULTS: Circulating EPCs (AC133+/VE-Cadherin+
      cells) increased nearly four-fold in peripheral blood from 66 +/- 27 cells/ml to
      236 +/- 34 cells/ml (p < 0.05). The number of isolated CACs increased 2.5-fold
      from 8,754 +/- 2,048 cells/ml of peripheral blood to 20,759 +/- 4,676 cells/ml (p
      < 0.005). Cultured angiogenic cells isolated before and after exercise showed
      similar secretion patterns of angiogenic growth factors. CONCLUSIONS: Our study
      demonstrates that exercise can acutely increase EPCs and CACs. Given the ability
      of these cell populations to promote angiogenesis and vascular regeneration, the
      exercise-induced cell mobilization may serve as a physiologic repair or
      compensation mechanism.

PMID- 15193700
TI  - Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and
      actin polymerization.
AB  - OBJECTIVES: The purpose of this study was to examine the effects of glycoprotein
      (GP) IIb/IIIa antagonists (abciximab, eptifibatide, and tirofiban) and other
      inhibitors on translocation of CD40L from intraplatelet stores to the platelet
      surface and on the release of soluble CD40L (sCD40L) from platelets. BACKGROUND:
      CD40L is a proinflammatory and prothrombotic ligand in the tumor necrosis factor
      family. METHODS: Platelet surface CD40L was measured by flow cytometry, and
      sCD40L was measured by enzyme-linked immunosorbent assay. RESULTS: Translocation
      of CD40L from intraplatelet stores to the platelet surface was not inhibited by
      GP IIb/IIIa antagonists. However, release of sCD40L from the surface of activated
      platelets was inhibited by GP IIb/IIIa antagonists in a dose-dependent manner, in
      concert with inhibition of PAC1 binding to platelets (a surrogate marker for
      fibrinogen binding). Release of sCD40L from activated platelets was also markedly
      reduced in Glanzmann platelets (deficient in GP IIb/IIIa).
      Ethylenediaminetetraacetic acid was an effective inhibitor of sCD40L release, but
      only when added before platelet activation. Both cytochalasin D (an inhibitor of
      actin polymerization) and GM6001 (an inhibitor of matrix metalloproteinases
      [MMPs]) inhibited the release of sCD40L from platelets when added before, as well
      as 3 min after, platelet activation. However, neither cytochalasin D nor GM6001
      affected translocation of CD40L to the platelet surface. CONCLUSIONS: The GP
      IIb/IIIa antagonists inhibit release of sCD40L from activated platelets. Release
      of sCD40L from platelets is regulated, at least in part, by GP IIb/IIIa, actin
      polymerization, and an MMP inhibitor-sensitive pathway. In addition to their well
      characterized inhibition of platelet aggregation, GP IIb/IIIa antagonists may
      obviate the proinflammatory and prothrombotic effects of sCD40L.

PMID- 15193701
TI  - Soluble CD40 ligand and platelets: self-perpetuating pathogenic loop in
      thrombosis and inflammation?

PMID- 15193702
TI  - Ultrastructural evidence of increased tolerance of hibernating myocardium to
      cardioplegic ischemia-reperfusion injury.
AB  - OBJECTIVES: The goal of this study was to investigate the effects of ischemia
      reperfusion on myocardial ultrastructure in patients with and without hibernating
      myocardium. BACKGROUND: It is generally accepted that chronically dysfunctional,
      hibernating myocardium may remain nonetheless viable for a long time. It has been
      postulated that hibernating myocytes may survive, despite being subtended by a
      severe coronary artery stenosis, as they might be less susceptible to ischemic
      insults. However, whether hibernating myocardium is indeed more resistant to
      ischemia has never been investigated. METHODS: Myocardial biopsies were taken
      before cardiac arrest and after reperfusion from the anterior wall of the left
      ventricle in patients undergoing coronary artery bypass surgery, divided
      according to presence (n = 7) or absence (n = 7) of hibernating myocardium.
      Ultrastructural changes were studied by electron microscopy. Because ischemia
      reperfusion injury is related to oxidative stress, we also evaluated coronary
      sinus concentration of the antioxidants alpha-tocopherol, beta-carotene, and
      ubiquinol, and of lipid peroxidation products pre-ischemia and after reperfusion.
      RESULTS: Both groups were similar with respect to length of ischemia and changes
      in the various indexes of oxidative stress. In normally contracting myocardium,
      ischemia/reperfusion induced moderate overall ultrastructural changes, and marked
      alterations at the mitochondrial level. In contrast, post-reperfusion biopsies of
      hibernating myocardium displayed only minor overall ultrastructural changes, and
      scored significantly better on mitochondrial damage. CONCLUSIONS: Despite similar
      severity of ischemia/reperfusion, hibernating myocardium showed significantly
      less ultrastructural evidence of cell injury compared with normally contracting
      myocardium. These data indicate that human hibernating myocardium is
      intrinsically more resistant to ischemia/reperfusion injury.

PMID- 15193705
TI  - Prepublication embargo of news release.

PMID- 15193703
TI  - Transplantation of cardiotrophin-1-expressing myoblasts to the left ventricular
      wall alleviates the transition from compensatory hypertrophy to congestive heart
      failure in Dahl salt-sensitive hypertensive rats.
AB  - OBJECTIVES: We investigated whether autologous transplantation of skeletal
      myoblasts (MB) transferred with cardiotrophin-1 (CT-1) gene could retard the
      transition to heart failure (HF) in Dahl salt-sensitive (DS) hypertensive rats.
      BACKGROUND: Although MB is a therapeutic candidate for chronic HF, little is
      known about the efficiency of this strategy when applied in nonischemic HF.
      Cardiotrophin-1 has potent hypertrophic and survival effects on cardiac myocytes.
      We hypothesized that transplantation of CT-1-expressing myoblasts could provide
      cardioprotective effects against ventricular remodeling in DS hypertensive rats.
      METHODS: The DS rats were fed a high salt diet for 6 weeks and developed left
      ventricular (LV) hypertrophy at 11 weeks. At this stage, animals underwent MB to
      the myocardium with skeletal myoblasts transferred with CT-1 gene using
      retrovirus (transplantation of CT-1-expressing myoblasts [MB + CT], n = 31) or
      myoblasts alone (MB, n = 31). The sham group rats were injected with phosphate
      buffered saline (n = 24). RESULTS: At 17 weeks, MB and MB + CT groups showed a
      significant alleviation of LV dilation and contractile dysfunction compared with
      the sham group. The degree of alleviation was significantly greater in the MB +
      CT group than the MB group (LV end-diastolic dimension: sham 7.06 +/- 0.14 mm, MB
      6.51 +/- 0.16 mm, MB + CT 6.24 +/- 0.07 mm; fractional shortening: sham 32.1 +/-
      1.4%, MB 38.5 +/- 1.5%, MB + CT 43.2 +/- 0.8%). Histological examination revealed
      that the myocyte size was 20% larger in the MB + CT group at 17 weeks than in the
      age-matched sham group. Upregulation of renin-angiotensin and endothelin systems
      during the transition to HF was attenuated by myoblast transplantation, and this
      effect was enhanced in the MB + CT group. CONCLUSIONS: Transplantation of
      skeletal myoblasts combined with CT-1-gene transfer could be a useful therapeutic
      strategy for HF.

PMID- 15193706
TI  - President's page: Strategic framework: How does the ACC meet its members' needs?
      Demonstrating how college processes generate organizational plans and decisions.

PMID- 15193704
TI  - Peroxynitrite decomposition catalysts prevent myocardial dysfunction and
      inflammation in endotoxemic rats.
AB  - OBJECTIVES: The aim of this study was to test whether peroxynitrite neutralizers
      would reduce peroxynitrite accumulation and improve myocardial contractile
      dysfunction and inflammation in endotoxin-treated rats. BACKGROUND: Release of
      endogenous proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha in
      response to endotoxin is responsible for the production of large amounts of
      nitric oxide (NO), which may exert detrimental effects on the myocardium in
      animal models, isolated hearts, and isolated cardiac myocytes. Recent studies
      have indicated that many of the deleterious effects of NO are mediated by
      peroxynitrite, a powerful oxidant generated from a fast diffusion-limited
      reaction of NO and superoxide anion. METHODS: We studied the effects of
      peroxynitrite neutralizers, such as mercaptoethylguanidine (MEG) sodium succinate
      (10 mg/kg) and 5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrinato iron (III)
      (FeTPPS) (30 mg/kg) on peroxynitrite accumulation, in vivo endothelial cell
      leukocyte activation on the mesenteric venule, and myocardial contractile
      dysfunction and inflammation in a model of sepsis induced by injection of
      endotoxin (10 mg/kg) in rats. RESULTS: Mercaptoethylguanidine sodium succinate
      and FeTPPS largely prevented the accumulation of peroxynitrite as measured by
      plasma rhodamine fluorescence and heart nitrotyrosine staining. Interestingly,
      MEG sodium succinate and FeTPPS improved endotoxin-induced myocardial contractile
      dysfunction, which was associated with reduced degradation of nuclear factor
      kappa B inhibitory protein I-kappa-B, plasma TNF-alpha levels, and microvascular
      endothelial cell-leukocyte activation. CONCLUSIONS: These observations suggest
      that the beneficial effects of MEG and FeTPPS on endotoxin-induced myocardial
      contractile dysfunction could be related to the unique effects of these compounds
      on cardiovascular inflammation processes.

PMID- 15193707
TI  - Expression of angiotensin II receptors in human left and right atrial tissue in
      atrial fibrillation with and without underlying mitral valve disease.

PMID- 15193711
TI  - Medical malpractice insurance: a multifaceted problem.

PMID- 15193709
TI  - From controlled trials to clinical practice: monitoring transmyocardial
      revascularization use and outcomes.

PMID- 15193712
TI  - QSAR analysis of cyclooxygenase inhibitor using particle swarm optimization and
      multiple linear regression.
AB  - Quantitative structure-activity relationship (QSAR) models of inhibiting action
      of some diarylimidazole derivatives on cylcooxygenase (COX) enzyme were
      constructed using modified particle swarm optimization (PSO) method. As a
      comparison to this method, the genetic algorithm (GA) was also tested. It has
      been demonstrated that the modified PSO is a useful tool for variable selection
      comparable to GA and even superior to GA. QSAR models are constructed separately
      for COX-2 inhibitory activity and selectivity of COX-2 inhibition over COX-1. The
      spatial descriptors play a key role in the compounds' activity and selectivity to
      COX-2, especially Jurs descriptors. Polar interactions are the principal binding
      strength between compounds and COX-2 enzyme. In addition, the aqueous desolvation
      free energy (FH2O) value of substituent will affect the COX-2 inhibitory
      activity, while the charge distribution can affect the selectivity to COX-2.

PMID- 15193713
TI  - A single spectroscopic flow-through sensing device for determination of
      ciprofloxacin.
AB  - A simple flow injection UV spectrophotometric sensing device was developed for
      the determination of ciprofloxacin. The method is based on its transient
      retention and concentration on Sephadex SP C-25 cation-exchange gel beads packed
      in the flow cell and the continuous monitoring of its native absorbance on the
      solid phase at 277 nm. The procedure is carried out without any derivatisation.
      Formic acid/NaOH 1.75 M at pH 2.2 is used as carrier solution in a simple
      monochannel FIA manifold. When the analytical signal reached the maximum value,
      ciprofloxacin was eluted from the solid support by the carrier solution itself.
      The response of the sensor was linear in the concentration range 0.5-10 microg
      ml(-1) with an RSD (%) of 0.79, a detection limit (3sigma criterion) of
      0.035microg ml(-1) and a sampling rate of 16 h(-1). Application to the analysis
      of pharmaceutical samples testifies the utility of this sensor.

PMID- 15193714
TI  - Development and validation of an HPLC method for AG331 bulk drug substance and
      lyophilized powder for injection.
AB  - AG331 is a water soluble glucuronate salt of a novel antitumor compound
      synthesized by protein structure based drug design. A lyophilized powder for
      injection was developed for clinical studies. During HPLC assay development,
      AG331 showed an inherent tailing problem due to an amino group in the structure.
      An optimized reverse-phase gradient HPLC method was developed to minimize the
      tailing and separate AG331 from its synthetic intermediates (I-1, I-2, I-3, I-4,
      I-5, I-6, I-8), other impurities and degradation compounds. The method was shown
      to be linear, precise, accurate, rugged and stability-indicating.

PMID- 15193715
TI  - HPLC and chemometric methods for the simultaneous determination of cyproheptadine
      hydrochloride, multivitamins, and sorbic acid.
AB  - Three methods are presented for the simultaneous determination of cyproheptadine
      hydrochloride (CP), thiamine hydrochloride (B1), riboflavin-5-phosphate sodium
      dihydrate (B2), nicotinamide (B3), pyridoxine hydrochloride (B6), and sorbic acid
      (SO). The chromatographic method depends on a high performance liquid
      chromatographic (HPLC) separation on a reversed-phase, RP 18 column. Elution was
      carried out with 0.1% methanolic hexane sulphonic acid sodium salt (solvent A)
      and 0.01 M phosphate buffer containing 0.1% hexane sulphonic acid sodium salt,
      adjusted to an apparent pH of 2.7 (solvent B). Gradient HPLC was used with the
      solvent ratio changed from 20:80 to 70:30 (over 9 min), then to 80:20 (over 11
      min) for solvent A:B, respectively. Quantitation was achieved with UV detection
      at 220 and 288 nm based on peak area. The other two chemometric methods applied
      were principal component regression (PCR) and partial least squares (PLS). These
      approaches were successfully applied to quantify each drug in the mixture using
      the information included in the UV absorption spectra of appropriate solutions in
      the range 250-290 nm with the intervals Deltalambda = 0.4 nm at 100 wavelengths.
      The chemometric methods do not require any separation step. The three methods
      were successfully applied to a pharmaceutical formulation and the results were
      compared with each other.

PMID- 15193716
TI  - Influence of solvent composition on the solid phase at equilibrium with saturated
      solutions of quinolones in different solvent mixtures.
AB  - The dissolution profiles and solubilities of three quinolonic drugs (oxolinic,
      pipemidic, and nalidixic acids) in different solvent mixtures were studied. The
      behavior of the solid phase, during solubility experiments was in-depth
      investigated with the aim of detecting possible crystalline modifications, such
      as polymorphic transitions or solvate formations, that might modify drug
      stability and/or solubility properties. In order to test the influence of both
      the nature and polarity of the co-solvents, aqueous and non-aqueous binary
      mixtures have been prepared by using Lewis base (dioxane and ethyl acetate) and
      amphiprotic co-solvents (ethanol and water). Differential scanning calorimetry
      (DSC), hot stage microscopy, IR spectroscopy and X-ray powder diffraction were
      used in combination with solubility and dissolution studies to characterize and
      investigate the solid state properties of the original powders and the
      corresponding ones at equilibrium with the different pure solvents and solvent
      mixtures examined. The solid phases of nalidixic and oxolinic acids did not show
      any change after equilibration with the various pure solvents or binary solvent
      mixtures, regardless the chemical nature of the examined solvents. On the
      contrary, in the case of pipemidic acid, the different analytical techniques used
      to characterize the drug solid state enabled identification of a solvated form at
      equilibrium with pure dioxane and a trihydrated form in aqueous mixtures of water
      with both ethanol (amphiprotic) or dioxane (Lewis base) in a concentration range
      from 10 to 100% water.

PMID- 15193717
TI  - Improving the detection of degradants and impurities in pharmaceutical drug
      products by applying mass spectral and chromatographic searching.
AB  - Liquid chromatography/mass spectrometry (LC/MS) and NMR are commonly used to
      identify metabolites, impurities and degradation products in the pharmaceutical
      industry. To more efficiently deal with the large volumes of data these
      techniques generate, software programs have been developed by various vendors to
      assist in the identification of these compounds through the use of spectral and
      chromatographic search algorithms. The feasibility of using such programs for
      detecting drug degradants and impurities is assessed. A number of compounds
      encompassing a wide range of both chemical and pharmaceutical properties were
      tested using LC/UV/MS and the spectral/chromatographic search algorithm
      MetaboLynx (Micromass UK Ltd.) to determine the feasibility of detecting analytes
      at low concentrations. In addition, drug product and stressed drug substance
      samples containing quinapril hydrochloride, the active ingredient in Accupril
      tablets, were determined by liquid chromatography with atmospheric pressure
      ionization-time-of-flight (API LC-TOF) and an API LC-quadrupole (Q) mass
      spectrometer, and the resulting data was processed using MetaboLynx. The ability
      of this program to detect and list a variety of analytes known to be present in
      the samples was evaluated. The combination of LC/UV, LC/MS and
      spectral/chromatographic searching is a valuable tool for the detection of
      impurities at low levels.

PMID- 15193718
TI  - A rapid ICP-MS screen for heavy metals in pharmaceutical compounds.
AB  - A robust general inductively coupled plasma-mass spectrometry (ICP-MS) based
      method was developed as an alternative to the wet chemical heavy metals test
      prescribed in the United States Pharmacopoeia (USP), British Pharmacopoeia (BP),
      Japanese Pharmacopoeia (JP) and European Pharmacopoeia (EP). The described method
      provides specific detection and quantitation for each of the elements expected to
      give rise to a positive response in the compendial methods: arsenic (As),
      selenium (Se), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), lead (Pb),
      bismuth (Bi), silver (Ag), palladium (Pd), platinum (Pt), mercury (Hg),
      molybdenum (Mo) and ruthenium (Ru). The subjectiveness of the visual based semi
      quantitative comparison that is performed in the compendial methods is eliminated
      through the utilization of the ICP-MS. The described method has been in use for
      several years and its versatility has been demonstrated by successfully applying
      it to a wide variety of sample matrices. Analysis of the specific elemental data
      from the numerous sample matrices investigated indicates that there is no
      dependence of the various chemical functionalities contained in the sample
      matrices on the individual element recoveries. The average recovery for each
      element from the various sample matrices investigated ranged from 89 to 102%.

PMID- 15193719
TI  - Determination of the binding parameter constants of Renagel capsules and tablets
      at pH 7 by high performance capillary electrophoresis.
AB  - Sevelamer hydrochloride is a cross-linked polymeric amine; it is the active
      ingredient in Renagel capsules and tablets. Sevelamer hydrochloride is indicated
      for the control of hyperphosphatemia in patients with end-stage renal disease
      (ESRD). The binding parameter constants of sevelamer hydrochloride were
      determined using high performance capillary electrophoresis (HPCE) and the
      Langmuir approximation for three different dosage forms at pH 7.0. The three
      dosage forms were Renagel 403 mg capsules, Renagel 400 mg tablets and Renagel 800
      mg tablets. The results demonstrate the in vitro bioequivalence of all three
      dosage forms at pH 7.0. These results are in very good agreement with previously
      published results obtained by ion chromatography.

PMID- 15193720
TI  - Aminoglutethimide included in nanocapsules suspension: comparison of GC-MS and
      HPLC methods for control.
AB  - Gas chromatography-mass spectrometry (GC-MS) and high performance liquid
      chromatography (HPLC) offer highly efficient and potentially sensitive separation
      and detection techniques. This work describes the quantification of
      aminoglutethimide (AG) in nanocapsules suspension with both techniques. The
      analysis of different lots containing known concentrations of drug (1, 2, 3 and 4
      mg ml(-1)) were used to investigate the quantitative capabilities of both
      chromatographic techniques. Both chromatographic methods were successful and on
      an analytical point of view the validations of aminoglutethimide dosing were
      suitable in both cases. In routine, the determination of the quality of
      nanocapsules suspension could be preferentially evaluated by difference between
      total AG concentration in suspension (evaluated by direct HPLC measure of the
      suspension diluted in acetonitrile) and free AG concentration (evaluated by
      direct HPLC measure of simple dilution of the supernatant).

PMID- 15193721
TI  - CE versus HPLC for the dissolution test in a pharmaceutical formulation
      containing acetaminophen, phenylephrine and chlorpheniramine.
AB  - A new polar reverse phase stationary phase has permitted our group to develop and
      validate an isocratic HPLC method for the simultaneous determination of
      acetaminophen, phenylephrine and chlorpheniramine in capsules as pharmaceutical
      formulation after their dissolution test. Final optimised chromatographic
      conditions employed a Supelco Discovery HS PEG column (polyethylene glycol), 5
      microm, 15 cm x 0.46 cm. The mobile phase was 20 mM phosphate buffer at pH
      7.0/acetonitrile 80:20 (v/v) at a flow rate of 1 ml/min. UV detection was
      performed at 210 nm for phenylephrine and chlorpheniramine and at 305 nm for
      acetaminophen. On the other hand, to evaluate the capability of CE to work in a
      routine analytical method fulfilling the pharmaceutical requirements and to study
      the behaviour of the technique with these compounds, we developed a CE method
      with the same objective. Normal and reverted polarity, the pH and concentration
      of the buffer, and the presence and concentration of surfactants were assayed.
      Forty millimolar phosphate buffer at pH 6.20 with 0.5 mM SDS at 30k V in an
      uncoated silica capillary provided a runtime of 4.5 min to separate the three
      analytes and the excipients. Moreover, parameters affecting precision in CE, such
      as the injection of buffer after the sample to refill the capillary were also
      tested. After development, the validation was performed in parallel for HPLC and
      CE with the same standards and samples to avoid differences due to the
      manipulation. The validation parameters of both techniques were adequate for the
      intended purpose.

PMID- 15193722
TI  - Identification and quantitation of extractables from cellulose acetate butyrate
      (CAB) and estimation of their in vivo exposure levels.
AB  - The purpose of this study was to qualitatively and quantitatively determine
      potential cellulose acetate butyrate (CAB) extractables in a way to meaningfully
      predict the in vivo exposure resulting from clinical administration. Extractions
      of CAB-381-20 were performed in several solvent systems, consistently resulting
      in the detection of three extractables. The extractables have been identified as
      acetic acid, butyric acid, and E-2-ethyl-2-hexenoic acid (E-EHA) by LC/UV, LC/MS
      and NMR. Extraction studies of CAB powders in acetonitrile/phosphate buffer
      demonstrated quantitative extraction in 1 h for acetic acid (approximately 150
      microg/g), butyric acid (approximately 200 microg/g), and EHA (approximately 20
      microg/g). Subsequently, extraction studies for CAB powders and coated tablets in
      USP simulated gastric and intestinal fluids were performed to evaluate potential
      in vivo exposure. Similarly, acetic and butyric acids were quantitatively
      extracted from CAB-381-20 powder after 24 h exposure in both USP simulated
      fluids. The amounts of EHA extracted from CAB powder after 24 h were determined
      to be 2 and 16 microg/g in USP simulated gastric and intestinal fluids,
      respectively. After 24 h exposure in USP simulated fluids, the maximum amount of
      EHA extracted corresponds to < 0.3 microg of EHA per tablet. Pepsin and
      pancreatin in USP simulated fluids had no effect on EHA extraction and
      quantitation.

PMID- 15193724
TI  - Determination of guaifenesin in human serum by capillary gas chromatography and
      electron capture detection.
AB  - A method for the quantitation of guaifenesin in human serum has been developed
      and validated. The procedure involves liquid-liquid extraction of the serum
      sample in the presence of mephenesin as an internal standard, followed by
      derivatization and analysis using capillary gas chromatography (GC) and electron
      capture detection (ECD). Different solvents were tested for extraction of
      guaifenesin from serum. n-Hexane/dichloromethane (1:1, v/v) gave the highest
      recovery and the lowest background and was chosen as the extraction solvent.
      After extraction, the residue of guaifenesin was derivatized at 60 degrees C for
      30 min, with trifluoroacetic acid anhydride (TFAA) in toluene in the presence of
      pyridine. Excess trifluoroacetic acid anhydride was removed using dilute solution
      of ammonium hydroxide. The method proved to be linear over the range of 25.0-1000
      ng/ml. Recovery of guaifenesin from spiked samples was consistent, averaging
      75.5% at 50.0 ng/ml with a range of 72.0-80.0% (N = 8 determinations) and
      averaging 78% at 800 ng/ml with a range of 76.0-81.0% (N = 8 determinations). The
      internal standard recovery was also consistent averaging 72.8% with a range of
      67.0-76.0% (N = 16 determinations).

PMID- 15193723
TI  - Comparison of the miniaturised techniques capillary electrochromatography and
      capillary liquid chromatography for the chiral separation of chlorthalidone.
AB  - The aim of this study was to compare the miniaturised techniques, capillary
      electrochromatography (CEC) and capillary liquid chromatography (CLC), for the
      chiral separation of chlorthalidone. In both cases, hydroxypropyl-beta
      cyclodextrin was used as a chiral selector in the mobile phase, while an achiral
      stationary phase was used. Earlier, this separation was already optimised in CEC.
      Now, the separation was optimised in CLC. The influence of the organic modifier
      content and the cyclodextrin concentration on the separation was studied by means
      of a central composite design. Optimal separation conditions were determined,
      after response modelling, from the response surface contour plots. When these
      conditions were compared with those of the CEC optimisation, we can see the
      potential of using CLC as a chiral separation technique since less chiral
      selector was used, faster separations were obtained and better repeatability was
      observed in comparison with its electrical-driven counterpart.

PMID- 15193726
TI  - Development of an LC-MS based enzyme activity assay for MurC: application to
      evaluation of inhibitors and kinetic analysis.
AB  - An enzyme activity assay, based on mass spectrometric (MS) detection of specific
      reaction product following HPLC separation, has been developed to evaluate
      pharmaceutical hits identified from primary high throughput screening (HTS)
      against target enzyme Escherichia coli UDP-N-acetyl-muramyl-L-alanine ligase
      (MurC), an essential enzyme in the bacterial peptidoglycan biosynthetic pathway,
      and to study the kinetics of the enzyme. A comparative analysis of this new
      liquid chromatographic-MS (LC-MS) based assay with a conventional
      spectrophotometric Malachite Green (MG) assay, which detects phosphate produced
      in the reaction, was performed. The results demonstrated that the LC-MS assay,
      which determines specific ligase activity of MurC, offers several advantages
      including a lower background (0.2% versus 26%), higher sensitivity (> or = 10
      fold), lower limit of quantitation (LOQ) (0.02 microM versus 1 microM) and wider
      linear dynamic range (> or = 4 fold) than the MG assay. Good precision for the LC
      MS assay was demonstrated by the low intraday and interday coefficient of
      variation (CV) values (3 and 6%, respectively). The LC-MS assay, free of the
      artifacts often seen in the Malachite Green assay, offers a valuable secondary
      assay for hit evaluation in which the false positives from the primary high
      throughput screening can be eliminated. In addition, the applicability of this
      assay to the study of enzyme kinetics has also been demonstrated.

PMID- 15193725
TI  - High performance capillary electrophoresis for determination of the enantiomers
      of 2-arylpropionic acid derivatives in human serum. Pharmacokinetic studies of
      ketoprofen enantiomers following administration of standard and sustained release
      tablets.
AB  - A stereospecific capillary zone electrophoresis (CZE) method for determination of
      the enantiomers of some 2-arylpropionic acid derivatives (2-APA, profens) in
      human serum has been developed. Racemic-ibuprofen (rac-IBP), racemic-flurbiprofen
      (rac-FBP), racemic-ketoprofen (rac-KTP) and (+)-S-naproxen ((+)-S-NPX--an
      internal standard) were chosen for these studies. The 2-APA enantiomers were
      extracted from acidified serum samples using methylene chloride separated in a
      fused silica capillary. The capillary was filled with a background electrolyte,
      which consisted of 0.05 M heptakis 2,3,6-tri-O-methyl-beta-cyclodextrin
      (TMbetaCD) (chiral selector) in 0.02 M triethanolamine-phosphate buffer of pH
      5.0. Separation and resolution of the enantiomer mixture were obtained in one
      analytical run. The calculated electrophoretic parameters of the analytes were as
      follows: electrophoretic mobility, micorep(-)-R = -0.75 x 10(-4) to -0.30 x 10(
      4) cm2/Vs; micorep(+)-S = -0.83 -(-0.38) cm2/Vs and electroosmotic mobility,
      microEOF = 2.35 x 10(-4) cm2/Vs, migration times, tmigr R = 12.55 - 16.07 min;
      tmigr s = 13.08 - 16.9 min, resolution factors, RS = 1.88 - 3.70 and chiral
      selectivity, alpha = 1.16 - 1.34. The method developed for the enantiomers was
      validated. The calibration curves were linear in the range of 0.5-50.0 microg/ml
      for FBP or KTP and of 1.0-50.0 microg/ml for IBP enantiomer concentrations.
      Recovery of the enantiomers from serum was about 90%. At the limit of
      quantification (LOQ) precision and accuracy were within 15%. The validated method
      was successfully applied to pharmacokinetic and bioavailability studies on KTP
      enantiomers in humans after administration of standard and sustained release
      tablets of rac-KTP. Significant differences in the pharmacokinetic parameters of
      both formulations were observed and the studied formulations were not
      bioequivalent.

PMID- 15193727
TI  - Simultaneous determination of albendazole and its major active metabolite in
      human plasma using a sensitive and specific liquid chromatographic-tandem mass
      spectrometric method.
AB  - A method for the simultaneous determination of albendazole (ABZ) and its major
      active metabolite albendazole sulfoxide (ABZ-SO) was developed and validated. The
      analytes were extracted from plasma samples by liquid-liquid extraction and
      analyzed using liquid chromatography-tandem mass spectrometry with an
      electrospray ionization interface. Estazolam was used as the internal standard.
      The assay was linear in the concentration range 0.4-200 ng/ml for ABZ and 4.0
      2000 ng/ml for ABZ-SO. The intra- and inter-run precision (R.S.D.), calculated
      from quality control (QC) samples was less than 7.1 and 9.4% for ABZ and ABZ-SO,
      respectively. The accuracy as determined from QC samples was within +/- 3% for
      the analytes. Recoveries of ABZ and ABZ-SO were greater than 77 and 53%,
      respectively, over the calibration curve range. The method developed was
      successfully applied to pharmacokinetic studies of ABZ and ABZ-SO after an oral
      dose of 400 mg albendazole to healthy volunteers.

PMID- 15193728
TI  - Determination of fexofenadine in human plasma using 96-well solid phase
      extraction and HPLC with tandem mass spectrometric detection.
AB  - A fast and sensitive HPLC-MS/MS method, utilizing atmospheric pressure chemical
      ionization, for the determination of fexofenadine in human plasma is described. A
      deuterated analog, d6-fexofenadine is used as the internal standard (IS). Plasma
      samples are prepared using 96-well solid phase extraction with plates containing
      Waters Oasis HLB sorbent. The analytes are chromatographed on a Restek Ultra IBD
      column (3.2 mm x 50 mm, 3 microm) using a mobile phase consisting of a mixture of
      90% acetonitrile and 10% 10 mM ammonium acetate buffer and 0.1% formic acid.
      Quantitation of the analyte is based on the response from the multiple reaction
      monitoring of the precursor to product ion pairs for fexofenadine (m/z 502 -->
      466) and d6-fexofenadine (m/z 508 --> 472). The assay has been validated over the
      concentration range of 1-200 ng/ml based on the analysis of 0.5 ml aliquots of
      plasma. Within-day assay accuracy was between 97 and 102% of nominal, while
      within-day precision was better than 3.5% CV at all points on the standard curve.
      Analyte extraction recovery was better than 70% over the range of the standard
      curve. The method was found to be suitable for the analysis of human plasma
      samples obtained 24 h following the administration of a single 60 mg dose of
      fexofenadine.

PMID- 15193729
TI  - Simple method for the assay of eperezolid in brain heart infusion broth by high
      performance liquid chromatography.
AB  - A sensitive high-performance liquid chromatography (HPLC) method was developed
      and validated for quantification of eperezolid in Brain Heart Infusion (BHI)
      broth. Linezolid was employed as internal standard and sample deproteinization
      with methanol was used. Calibration standards ranged from 0.10 to 20 mg/l.
      Recovery was approximately 100% at the concentrations examined. Eperezolid was
      stable in the autosampler vial for at least 72 h at ambient temperature and in
      BHI broth for 72 h at 37 degrees C. The intra- and inter-day accuracy and
      reproducibility (relative standard deviation, R.S.D.) were less than 12.3%. This
      assay is rapid and ideal for analysis of a large number of samples.

PMID- 15193730
TI  - Determination of LAG078, a lipid-lowering compound, in dog plasma using liquid
      chromatography-tandem mass spectrometry: application in a toxicokinetic study.
AB  - A high throughput method was developed and validated for the quantitative
      determination of LAG078, a lipid-lowering compound, in dog plasma obtained during
      toxicokinetic studies. The method was based on reverse phase liquid
      chromatographic separation of the analyte from plasma extract followed by turbo
      ionspray (TIS) in the negative ion mode and tandem mass spectrometry in the
      multiple reaction monitoring (MRM) mode. Extraction was performed using a
      combination of protein precipitation and liquid-liquid extraction in the 96-well
      plate format to increase the throughput of the method. Optimized chromatographic
      separation under basic condition (pH approximately 10) in a short polymer based
      column (50 mm x 2.0 mm i.d.) coupled with MRM mode of detection yielded clean
      chromatograms with minimal signal suppression. The standard curve was linear (r =
      0.997) within the concentration range of 0.05 (lower limit of quantification;
      LLOQ) to 50 ng/ml using only 0.1 ml of dog plasma. The accuracy of the method
      varied from 95 to 100% with a precision (CV) of 3.04-10.8% over the concentration
      range. The method was simple, rapid, and robust.

PMID- 15193731
TI  - High-throughput pharmacokinetics screen of VLA-4 antagonists by LC/MS/MS coupled
      with automated solid-phase extraction sample preparation.
AB  - Automation of plasma sample preparation for pharmacokinetic studies on VLA-4
      antagonists has been achieved by using 96-well format solid-phase extraction
      operated by Beckman Coulter Biomek 2000 liquid handling system. A Biomek 2000
      robot is used to perform fully automated plasma sample preparation tasks that
      include serial dilution of standard solutions, pipetting plasma samples, addition
      of standard and internal standard solutions, performing solid-phase extraction
      (SPE) on Waters OASIS 96-well plates. This automated sample preparation process
      takes less than 2 h for a typical pharmacokinetic study, including 51 samples, 24
      standards, 9 quality controls, and 3-6 dose checks with minimal manual
      intervention. Extensive validation has been made to ensure the accuracy and
      reliability of this method. A two-stage vacuum pressure controller has been
      incorporated in the program to improve SPE efficiency. This automated SPE sample
      preparation approach combined with liquid chromatography coupled with the high
      sensitivity and selectivity of tandem mass spectrometry (LC/MS)/MS has been
      successfully applied on both individual and cassette dosing for pharmacokinetic
      screening of a large number of VLA-4 antagonists with a limit of quantitation in
      the range of 1-5 ng/ml. Consequently, a significant throughput increase has been
      achieved along with an elimination of tedious labor and its consequential
      tendency to produce errors.

PMID- 15193732
TI  - Protein binding study of clozapine by capillary electrophoresis in the frontal
      analysis mode.
AB  - We have used capillary electrophoresis in the frontal analysis mode (CE-FA) to
      determine the unbound concentration of clozapine in human serum albumin (HSA),
      human plasma, rabbit serum and plasma sample. The unbound clozapine concentration
      was directly measured from the height of the frontal peak. Samples were injected
      directly into an uncoated fused silica capillary (0.65 m (LC) x 75 microm i.d.;
      LE = 0.35 m) and separation was accomplished within 11 min without extensive
      sample pretreatment. The most suitable running buffer to separate unbound
      clozapine peak from the other peaks due to endogenous substances was found to
      contain 1 mmol1(-1) EDTA, 0.5 mol1(-1) glycine, and 67 mmol1(-1) phosphate with
      pH 7.4. The concentrations of unbound clozapine agreed well with those determined
      by the conventional ultrafiltration method. The methodology is validated and good
      correlation and precision are obtained. It was found that clozapine is strongly
      bound to protein in human plasma, rabbit plasma, and serum, while hardly bound to
      HSA. The present method enables the determination of the unbound drug
      concentration in multiple equilibrium system with less than ultra-micro injection
      volume, and would be hence especially useful for the protein binding study in
      biological samples that are only available in minute quantities.

PMID- 15193733
TI  - Bioanalytical method validation: a risk-based approach?
AB  - Bioanalysis frequently involves the measurement of very low analyte
      concentrations in complex and potentially variable matrices. It is not possible
      to test in validation every possible circumstance that may be encountered when
      analyzing study samples; logically, therefore, some risk of obtaining erroneous
      results exists when validated methods are applied to study samples. An initial
      attempt has been made to apply a risk management tool to the bioanalytical
      situation, with the hope that this will stimulate further discussion on the idea
      of more formally addressing "risk" with regards to bioanalytical method
      validation.

PMID- 15193734
TI  - Fractionation of peptides and identification of proteins from Saccharomyces
      cerevisiae in proteomics with the use of reversed-phase capillary liquid
      chromatography and pI-based approach.
AB  - The aim of the work was to explore the identification of proteins from
      Saccharomyces cerevisiae using combined capillary reversed-phase liquid
      chromatography (RPLC) and in-solution isoelectric focusing (sIEF) for
      fractionation of peptides prior to mass spectrometry analysis. That method was
      proved to be the alternative separation method for complex mixtures of protein
      tryptic digests in proteomics. Analysis of the identification of peptides was
      performed with the use of electrospray ionization-ion trap tandem mass
      spectrometry (ESI-IT-MS/MS). First, the sIEF fractionation was carried out prior
      to separation and mass spectrometry identification by nano-LC/ESI-MS/MS
      instrument. The proposed approach based on sIEF and nano-LC/ESI-MS/MS analysis
      was proved to be an efficient and accurate alternative fractionation method of
      complex protein digests and can be considered as the useful tool for
      identification of proteins. Moreover, analytical information from that approach
      can be considered as the additional source of database matching constraint and
      can be valuable tool for analytical and bioinformatics studies of peptides
      fractionation in proteomics. Based on the MS/MS results obtained with ESI-IT
      MS/MS instrument, 851 proteins from S. cerevisiae were identified. However, after
      careful analysis of the data reduction in number of proteins to 126 was obtained.
      Those results are discussed and interpreted in the view of the evaluation method
      used.

PMID- 15193735
TI  - Electrochemical genosensor for mitomycin C-DNA interaction based on guanine
      signal.
AB  - The interaction of mitomycin C (MC) with fish sperm or calf thymus DNA
      immobilized onto carbon screen-printed electrodes (CSPE) and carbon paste
      electrode (CPE) have been studied by using electrochemical techniques as square
      wave voltammetry (SWV) and differential pulse voltammetry (DPV). After the
      interaction was occurred between DNA and MC on electrode surface, it was observed
      that the guanine signal was higher with bare electrode than DNA-modified one. The
      changes in the experimental parameters such as the concentration of MC, and the
      accumulation time of MC were studied by using SWV and DPV. In addition,
      reproducibility, and detection limit parameters were determined using both
      electrodes. The partition coefficient of MC was also calculated before and after
      interaction of MC with dsDNA at CPE surface. These results showed that these two
      different DNA biosensors could be used for the sensitive, rapid and cost
      effective detection of MC-DNA interaction.

PMID- 15193736
TI  - Protein precipitation for the analysis of a drug cocktail in plasma by LC-ESI-MS.
AB  - Three protein precipitation (PP) procedures with acetonitrile (ACN), perchloric
      acid (PA) and trichloroacetic acid (TCA) were investigated for the analysis of a
      drug cocktail from human plasma samples containing three pharmaceutical compounds
      and their primary metabolites. For this purpose, a capillary liquid
      chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) method was
      developed for the simultaneous analysis of the six tested compounds in less than
      6 min. Matrix effect was tested for each PP procedure by means of a post-column
      infusion system. The three PP techniques were found effective in removing
      proteins from human plasma and were fully compatible with capillary LC-ESI-MS
      analysis. However, with acid precipitations, low analyte recovery and a high
      variability, probably due to analyte coprecipitation, were obtained. Finally, ACN
      was found to be the most effective PP technique with a recovery higher than 80%
      and CV inferior to 6%.

PMID- 15193737
TI  - LC-MS determination of desmopressin acetate in human skin samples.
AB  - A sensitive, selective and accurate high-performance liquid chromatography-mass
      spectroscopy (LC-MS) assay for the determination of desmopressin acetate (1
      deamino-8-D-arginine vasopressin, DDAVP) from human skin samples was developed
      and validated. Pieces of human breast skin were impregnated with DDAVP solutions
      and DDAVP was extracted with an optimum extraction procedure. The extracted
      solutions were then analyzed by a LC system, comprising of a Nucleosil C18 column
      (CC 125/2, 120-3) and a mobile phase of 0.01% formic acid in a mixture of 1.6 mM
      ammonium acetate and acetonitrile (33:67, v/v), coupled with electrospray
      ionization mass spectrometry (ESI-MS). Satisfactory results were obtained with
      limits of detection and quantification as low as 10 and 40 ng/ml, respectively,
      and with very good intra- and inter-day repeatability.

PMID- 15193738
TI  - Development of HPLC method for the determination of levosulpiride in human
      plasma.
AB  - A rapid and simple high performance liquid chromatography (HPLC) method was
      developed and validated for determination of levosulpiride in human plasma. After
      extraction with ethylacetate/methylene chloride (5:1, v/v), analysis of
      levosulpiride in plasma samples was carried out using a reverse phase C18 column
      with fluorescence detector (maximum excitation at 300 nm and maximum emission at
      365 nm) for separation and quantification. A mixture of methanol-20 mM phosphate
      buffer (pH 3.5, 16:84, v/v) was used as a mobile phase. The method was specific
      and sensitive with a limit of quantification of 5 ng/ml. This HPLC method was
      validated by examining the precision and accuracy for inter- and intra-day
      analysis in the concentration range of 5-150 ng/ml. The relative standard
      deviation (R.S.D.) in inter- and intra-day validation were 8.16-19.75 and 3.90
      11.69%, respectively. In stability tests, levosulpiride in human plasma was
      stable during the storage and assay procedure. The method was applied to the
      bioequivalence study of two levosulpiride tablet formulations (25 mg) after a
      single oral administration.

PMID- 15193739
TI  - Liquid chromatographic determination of fexofenadine in human plasma with
      fluorescence detection.
AB  - A simple and sensitive method was developed for determination of fexofenadine by
      liquid chromatography with fluorescence detection. Fexofenadine in human plasma
      was extracted on a C18 bonded-phase extraction cartridge. The mobile phases were:
      (A) 0.05 M KH2PO4 buffer/acetonitrile/methanol (60:35:10, v/v/v) and (B) 0.05 M
      KH2PO4 buffer/acetonitrile (40:60, v/v). Chromatographic separation was achieved
      on an ODS-80A column (150 mm x 4.6 mm i.d., particle size 5 microm) using a
      linear gradient from A to B in 10 min. The peak was detected using a fluorescence
      detector set at Ex 220 nm and Em 290 nm, and the total time for a chromatographic
      separation was approximately 17 min. The validated quantitation ranges of this
      method were 1.0-500 ng/ml with coefficients of variation of 0.6-9.1%. Mean
      recoveries were 72.8-76.7% with coefficients of variation of 2.7-5.8%. This
      method is successfully applicable for therapeutic drug monitoring in patients
      treated with clinical doses of fexofenadine and for analyses within
      pharmacokinetic studies.

PMID- 15193740
TI  - Quantification of gliclazide by semi-micro high-performance liquid
      chromatography: application to a bioequivalence study of two formulations in
      healthy subjects.
AB  - The objective of the present study was to evaluate the bioequivalence of two
      formulations of gliclazide in healthy human volunteers. Bioequivalence of the two
      formulations was determined in 20 healthy subjects with a single-dose, two
      period, crossover study. A new high-performance liquid chromatographic method for
      the pharmacokinetic analysis of gliclazide was developed, using a semi-micro
      column to quantify gliclazide in plasma samples. Chromatographic separation was
      achieved with a semi-micro C18 column and 40 mM KH2PO4 (pH 4.6)-acetonitrile
      isopropyl alcohol (5:4:1, v/v/v) as the mobile phase, and with UV detection at
      229 nm. The method displayed good precision (coefficients of variation (CV <
      8.0%)), was fast (total analysis time 8 min), and required only a small amount of
      mobile phase (0.22 ml/min), with a reasonable limit of quantification (0.1
      microg/ml). The calibration curve was linear in the concentration range 0.1-10
      microg/ml. When the pharmacokinetic parameters of gliclazide in the two
      formulations were calculated and compared statistically using crossover analysis
      of variance, they were similar, with no statistically significant difference.
      Ninety percent confidence intervals for AUC0-last, AUC0-infinity, and Cmax, used
      to evaluate bioequivalence, were in the stipulated range of 0.80-1.25. This
      result suggests that two formulations are bioequivalent when administered orally
      at a dose of 80 mg gliclazide.

PMID- 15193741
TI  - Isolation, synthesis and characterization of impurities in celecoxib, a COX-2
      inhibitor.
AB  - During the impurity profile of Celecoxib, four polar impurities (impurity I, II,
      III and IV) and one non-polar impurity (impurity V) with respect to Celecoxib
      were detected by HPLC. LC-MS has been employed in this impurity profile study.
      The three polar impurities (I, II and III) were found to be process related while
      impurities (IV and V) turned out to be isomers. The impurities III, IV and V were
      isolated with the help of preparative HPLC. The structure of impurities III, IV
      (ortho-isomer) and V (regio-isomer) were confirmed as [5-(4-methylphenyl)-3
      trifluoromethyl-1H-pyrazole], 4-[5-(2'-methyl phenyl)-3-(trifluoromethyl)-1H
      pyrazol-1-yl] benzenesulfonamide, and 4-[4-(4'-methylphenyl)-3-(trifluoromethyl)
      1H-pyrazol-1-yl]-benzenesulfonamide, respectively. The structures of impurities
      I, II, III and IV were confirmed by synthesis and structural characterization
      using spectral data. However, the impurity V was not synthesized.

PMID- 15193742
TI  - Determination of active ingredients in Huangdan Yinchen Keli by CZE with
      amperometric detection.
AB  - A simple, reliable and reproducible method, based on capillary zone
      electrophoresis with amperometric detection (CZE-AD), has been developed for
      simultaneous determination of five active ingredients in complicated traditional
      Chinese medicines including chlorogenic acid, caffeic acid, aloe-emodin, emodin
      and rhein. A carbon-disk electrode was used as working electrode. The optimal
      conditions of CZE detection were 30 mM borate solution (pH 9.5) as running
      buffer, 18 kV as separation voltage and 1.00 V (versus Ag/AgCl) as detection
      potential. There was excellent linearity between current response and analyte
      concentration over two orders of magnitude, while the limits of detection were
      1.1 x 10(-7), 3.0 x 10(-7), 1.5 x 10(-7), 2.9 x 10(-7), 1.4 x 10(-6) mol/l for
      aloe-emodin, emodin, rhein, chlorogenic acid and caffeic acid, respectively (S/N
      = 3). The utility of this method was demonstrated by monitoring a kind of
      complicated Chinese medicine named Huangdan Yinchen Keli. Two samples
      manufactured by different companies were monitored with satisfactory results.

PMID- 15193743
TI  - Mechanistic explanation to the variable degradation behaviour of stavudine and
      zidovudine under hydrolytic, oxidative and photolytic conditions.
AB  - The kinetics of decomposition of zidovudine and stavudine was studied under ICH
      recommended stress conditions of hydrolysis, oxidation and photolysis. The two
      drugs, which are closely related in structure, showed the same order of
      sensitivity under hydrolytic conditions, viz. acid > water > alkali. But
      stavudine was found to hydrolyse overall much faster than zidovudine. Both drugs
      were almost stable under basic conditions. Stavudine showed decomposition on
      exposure to peroxide while zidovudine was stable. On the contrary, zidovudine
      showed more sensitivity to light than stavudine, which was almost photostable.
      Thymine was formed as a major decomposition product of both the drugs under all
      the three stress conditions. The observed behaviour is explained mechanistically.

PMID- 15193744
TI  - Oleamide and anandamide effects on food intake and sexual behavior of rats.
AB  - Oleamide is a lipid with diverse properties, including cannabinoid-like activity.
      For example, it induces the classic triad of effects attributable to these
      molecules: decrease in core temperature, hypolocomotion, and reduction in pain
      perception. However, as it binds to the cannabinoid receptors (CB1) only at high
      concentrations, it is not considered an actual endocannabinoid. In this study, we
      tested the effect of oleamide on food intake and sexual behavior and compared it
      to the effect induced by anandamide. Results indicate that oleamide and
      anandamide increased food intake during the 3h post-injection. In addition,
      anandamide but not oleamide induced changes in sexual performance. This study
      further supports the role of endocannabinoids in food ingestion and male sexual
      behavior and gives additional support to the notion that, although oleamide might
      not be an endocannabinoid, it shares some effects with them.

PMID- 15193746
TI  - Axonal regrowth downregulates the synthesis of glial cell line-derived
      neurotrophic factor in the lesioned rat sciatic nerve.
AB  - The effect of axonal regeneration on de novo synthesis of glial cell line-derived
      neurotrophic factor (GDNF) in rat sciatic nerves was examined. Transection of the
      sciatic nerve caused a prominent increase in the GDNF content in the distal
      segments within 1 week. The high level was sustained until 4 weeks in the animal
      model in which the nerve ends were ligated with thread (non-regeneration group);
      however, it was reduced to the original level within 2 or 4 weeks after the
      transection only in the segments invaded by regenerating axons in the models in
      which the nerve ends were coaptated (regeneration group). Expression of both GDNF
      protein and mRNA was decreased with a reciprocal increase in the density of
      neurofilaments, used as a marker of axonal ingrowth in distal segments of the
      regeneration group, suggesting that axonal contact turned off the GDNF-mediated
      nerve regeneration activity.

PMID- 15193745
TI  - Glutathione content is altered in Muller cells of monkey eyes with experimental
      glaucoma.
AB  - Extracellular levels of glutamate are thought to be increased in glaucoma and
      thus contribute to retinal damage. An increase in glutamate concentration or
      duration in the extracellular retinal space is expected to impact glutathione
      content in Muller cells since glutamate is the rate-limiting constituent in
      glutathione synthesis. We have investigated whether glutathione content is
      changed in retinal Muller cells of monkeys with experimental glaucoma using
      immunocytochemistry and image analysis. Muller cells in glaucomatous retinas
      showed significantly greater immunoreactivity (27-57%) for glutathione than those
      in fellow control retinas, increasing with the duration of elevated intraocular
      pressure (IOP). This pattern of labeling was prominent in all four monkeys
      studied. The presence of more glutathione in Muller cells of glaucomatous retinas
      is consistent with an increase in extracellular glutamate and an increase in
      transport and metabolism of glutamate.

PMID- 15193747
TI  - Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced
      increases in dopamine levels via multireceptor actions in the rat medial
      prefrontal cortex.
AB  - Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT1A
      receptor agonism as well as 5-HT2A and D2 receptor antagonism. We investigated
      the effect of perospirone in combination with fluoxetine on dopamine release in
      the rat medial prefrontal cortex using microdialysis. Perospirone and fluoxetine
      increased dopamine release to 270 and 210% of the baseline value, respectively. A
      combination of perospirone and fluoxetine markedly increased dopamine release to
      800% of the baseline value. Pretreatment with a selective 5-HT1A receptor
      antagonist, WAY 100635, suppressed the increase in dopamine levels induced by the
      administration of perospirone and fluoxetine to 330% of the baseline value. These
      findings suggest that perospirone potentiates fluoxetine-induced dopamine
      increases in part via the action of the 5-HT1A receptor and may augment the
      effect of fluoxetine in treatment-resistant depression.

PMID- 15193748
TI  - Nitrous oxide impairs selective stages of working memory in rats.
AB  - Working memory impairment under narcosis has never been investigated.
      Furthermore, mechanisms by which narcosis disturbs working memory processes
      remain relatively unknown. The present work was aimed at answering to these two
      questions using a well-known normobaric narcotic gas, nitrous oxide (N2O), and a
      classical working memory task (a two-trial recognition memory task). Ten Long
      Evans rats were tested in this behavioral task under nitrous oxide exposure. The
      results showed (i) a dose-related impairment of working memory, (ii) a selective
      effect of N2O on two out of three mnemonic processes: acquisition, and retention,
      and (iii) a compensatory effect of increasing the acquisition phase duration on
      these impairments. These results, as previously suggested for long-term memory,
      agree with the fact that nitrous oxide disrupts in a dose-related manner working
      memory by notably slowing down acquisition processes.

PMID- 15193750
TI  - Direct visualization of peptide uptake activity in the central nervous system of
      the rat.
AB  - Carrier-mediated transport of small peptides and peptidomimetics offers the
      opportunity for a targeted drug delivery across cell membranes in the central
      nervous system (CNS). This process is mediated by the proton-coupled transporter
      PEPT2 which is expressed in glial and choroid plexus cells. In the present
      studies, an uptake assay was established to visualize directly peptide uptake in
      intact rat brain slices. Accumulation of a reporter molecule, the fluorophore
      labeled dipeptide derivative D-Ala-L-Lys-AMCA, was found in plexus choroideus and
      glial cells and uptake was inhibited by prototypical PEPT2 substrates, such as
      glycyl-L-glutamine and cefadroxil. The presence of PEPT2 was confirmed by RT-PCR
      and Northern blot analysis. This first CNS peptide and drug transport-visualizing
      assay may be used to examine new compounds which are carried by the proton-driven
      CNS peptide transporter.

PMID- 15193749
TI  - Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia
      and hyperalgesia in a rat model for mononeuropathy.
AB  - Recent imaging reports demonstrate the activation of the orbitofrontal cortical
      (OFC) area during acute and chronic pain. The aim of this study was to compare
      the effects of chronic perfusion of this area with morphine on nociception in
      control rats and in rats subjected to mononeuropathy. Chronic perfusion of
      morphine, using miniosmotic pumps, produced significant and naloxone-reversible
      depression of tactile and cold allodynias and thermal hyperalgesia, observed in
      neuropathic rats, while it produced significant elevation and naloxone
      insensitive increase of acute nociceptive thresholds in control rats. The
      observed results support the idea that this area is a component of a flexible
      cerebral network involved in pain processing and perception.

PMID- 15193751
TI  - The effect of anxiety on postural control in humans depends on visual information
      processing.
AB  - To examine the possibility that anxiety affects the control of postural balance,
      state anxiety, and body sway during orthostatic standing were measured twice in
      college students with an interval of 1 month. Correlations between the changes in
      state anxiety and the parameters of body sway were examined by Pearson's
      correlation analysis. The changes in the enveloped area of body sway and in the
      maximum length of the antero-posterior body sway showed a positive correlation
      with the changes in state anxiety (r = 0.543 and 0.659, respectively). The data
      showed that an increase in anxiety caused instability in the control of postural
      balance. These correlations were abolished when the eyes were closed. In
      conclusion, anxiety affects the processing of visual input and influences the net
      performance of postural control.

PMID- 15193752
TI  - Cannabinoid CB1 receptor protein expression in the rat choroid plexus: a possible
      involvement of cannabinoids in the regulation of cerebrospinal fluid.
AB  - Cannabinoid CB1 receptors in the brain are expressed on axon terminals
      presynaptic to neurons that express fatty acid amide hydrolase (FAAH).
      Postsynaptic FAAH catabolizes endocannabinoids which act as short-range
      transmitters. It has been previously shown that FAAH is also expressed in the
      epithelial cells of the choroid plexus. Using immunohistochemisty, we found that
      CB1 receptor protein is also expressed in choroid plexus epithelia. This is
      consistent with the hypothesis that FAAH in choroid plexus epithelial cells
      catabolizes endocannabinoids close to their site of action. Cannabinoids may then
      act directly on choroid plexus cells, and thereby contribute to the regulation of
      the composition of the CSF.

PMID- 15193753
TI  - The N-methyl-D-aspartate (NMDA)-type glutamate receptor GluRepsilon2 is important
      for delay and trace eyeblink conditioning in mice.
AB  - It has been proposed that the N-methyl-d-aspartate (NMDA)-type glutamate receptor
      (GluR) plays an important role in synaptic plasticity, learning, and memory. The
      four GluRepsilon (NR2) subunits, which constitute NMDA receptors with a GluRzeta
      (NR1) subunit, differ both in their expression patterns in the brain and in their
      functional properties. In order to specify the distinct participation of each of
      these subunits, we focused on the GluRepsilon2 subunits, which are expressed
      mainly in the forebrain. We investigated delay and trace eyeblink conditioning in
      GluRepsilon2 heterozygous mutant mice whose content of GluRepsilon2 protein was
      decreased to about half of that in wild-type mice. GluRepsilon2 mutant mice
      exhibited severe impairment of the attained level of conditioned response (CR) in
      the delay paradigm, for which the cerebellum is essential and modulation by the
      forebrain has been suggested. Moreover, GluRepsilon2 mutant mice showed no trend
      toward CR acquisition in the trace paradigm with a trace interval of 500 ms, in
      which the forebrain is critically involved in successful learning. On the other
      hand, the reduction of GluRepsilon2 proteins did not disturb any basic sensory
      and motor functions which might have explained the observed impairment. These
      results are different from those obtained with GluRepsilon1 null mutant mice,
      which attain a normal level of the CR but at a slower rate in the delay paradigm,
      and showed a severe impairment in the trace paradigm. Therefore, the NMDA
      receptor GluRepsilon2 plays a more critical role than the GluRepsilon1 subunit in
      classical eyeblink conditioning.

PMID- 15193754
TI  - Estimated magnitude and interactions of cortico-motoneuronal and Ia afferent
      input to spinal motoneurones of the human hand.
AB  - Magnitude and interactions of cortico-motoneuronal (CM) and Ia afferent input to
      spinal alpha-motoneurones (MNs) of the human hand are largely unknown. This is,
      however, an important question, which bears on the cortical versus peripheral
      segmental 'interest' in controlling alpha-MN excitation. Alpha-MN excitation can
      be quantified by estimating the amplitude of alpha-MN compound excitatory post
      synaptic potentials (cEPSPs) from single motor unit (SMU) recordings, if certain
      assumptions about the membrane trajectory are made [Exp. Brain Res. 47 (1982)
      33]. Here we recorded 29 SMUs from three different hand muscles (FDI, first
      dorsal interosseous; ADM, abductor digiti minimi; APB, abductor pollicis brevis)
      of healthy subjects. Each SMU was tested for CM input by transcranial magnetic
      stimulation of the contralateral motor cortex, for Ia afferent input by
      electrical peripheral nerve stimulation, and for the interaction between inputs
      by paired stimulation timed to arrive coincidently at the alpha-MN. Mean cEPSP
      amplitude elicited by CM input was larger in the alpha-MNs of the FDI than in
      those of the ADM or APB, whereas mean cEPSP amplitude elicited by Ia input was
      larger in the alpha-MNs of the APB than in those of the FDI. Generally, cEPSP
      amplitude evoked by paired input closely matched the arithmetic sum of the cEPSP
      amplitudes evoked by the single inputs. In conclusion, alpha-MNs of the human
      hand can be viewed as linear integrators of CM and Ia excitatory inputs. The
      weights of these inputs may relate to the specific functions of the different
      intrinsic hand muscles in skilled finger movements.

PMID- 15193755
TI  - Evaluation of GABA uptake in subcellular fractions of bovine frontal cortex and
      brainstem.
AB  - GABA uptake as well as the distribution of GAT-1, GAT-2 and GAT-3 were
      investigated in bovine brain membrane fractions. GABA uptake was characterised by
      kinetic constants and IC50-values for a series of known inhibitors in subcellular
      fractions of frontal cortex and brainstem obtained by subsequent centrifugations
      on sucrose gradients. Additionally, the immunoreactivity for rGAT-1, rGAT-2 and
      rGAT-3 antibodies was studied in these fractions. The pharmacological profile for
      GABA uptake inhibition as well as results from immunoblotting indicated that GABA
      uptake in a selected subcellular fraction of frontal cortex (P2B) is almost
      exclusively due to GAT-1 whereas GABA uptake performed with a selected
      subcellular fraction of brainstem (P2A) in the presence of NNC 711 is mainly
      attributable to GAT-3.

PMID- 15193756
TI  - L-histidine stimulates sympathetic nerve activity to brown adipose tissue in
      rats.
AB  - Hypothalamic neuronal histamine is involved in the central regulation of energy
      expenditure through the activation of sympathetic nerves innervating brown
      adipose tissue (BAT). The present study examined the effect of L-histidine, a
      precursor of neuronal histamine, on BAT sympathetic nerve activity in rats.
      Infusion of histamine at a dose of 1 nmol/rat into the third cerebroventricle
      significantly increased BAT sympathetic nerve activity as compared with the
      effect of phosphate buffered saline (P < 0.05). Intraperitoneal (i.p.) injection
      of L-histidine (0.3 mmol/rat) also significantly increased BAT sympathetic nerve
      activity as compared with the effect of PBS (P < 0.05). Pretreatment with an i.p.
      bolus injection of 224 micromol/kg alpha-fluoromethylhistidine, a suicide
      inhibitor of the histamine synthesizing enzyme histidine decarboxylase, blocked
      the stimulatory effect of l-histidine on BAT sympathetic nerve activity. These
      results indicate that L-histidine regulates BAT sympathetic nerve activity
      through its conversion into neuronal histamine in the hypothalamus.

PMID- 15193757
TI  - Lesions of the medial pallium, but not of the lateral pallium, disrupt spaced
      trial avoidance learning in goldfish (Carassius auratus).
AB  - The effects of telencephalic lesions of the medial pallium (MP) and lateral
      pallium (LP) of goldfish on avoidance learning were studied in a two-way, shuttle
      response, spaced-trial avoidance conditioning situation. Animals received one
      trial per day, a training regime that permits the assessment of avoidance
      learning in the absence of stimulus carry-over effects from prior trials. Control
      and LP-lesioned goldfish exhibited significantly faster avoidance learning than
      MP-lesioned animals. These results suggest that the MP, but not the LP, is
      responsible for the widely described deficits in avoidance learning after lesions
      of the entire telencephalon. The proposal of a functional similarity between the
      fish MP and the mammalian amygdala, known to be involved in fear conditioning,
      suggests a conservative phylogenetic role of this area in avoidance learning.

PMID- 15193758
TI  - Striatal tyrosine hydroxylase immunoreactive neurons are induced by L
      dihydroxyphenylalanine and nerve growth factor treatment in 6-hydroxydopamine
      lesioned rats.
AB  - Only a few studies mention the existence of tyrosine hydroxylase immunoreactive
      neurons in the striatum. These neurons are known to be increased following lesion
      of the dopaminergic nigrostriatal pathway. Recently it has been shown that glial
      cell line-derived neurotrophic factor treatment was able to increase the number
      of these neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated
      primate. Here we report that, in the rat, these neurons are responsive to
      intrastriatal injection of 6-hydroxydopamine and that following the lesion their
      number tends to increase with time. Moreover, we have shown that L-DOPA treatment
      for 2 weeks or nerve growth factor treatment for 8 weeks are able to dramatically
      augment their number.

PMID- 15193759
TI  - Neuron-specific expression of neuroglobin in mammals.
AB  - Neuroglobin, a vertebrate oxygen-binding protein, is expressed in many regions of
      the adult brain. We examined the cell type-specific expression of neuroglobin in
      neurons and astroglial cells in primary cultures of fetal hippocampal cells and
      sections of the adult mouse brain using neuroglobin-specific polyclonal
      antibodies and cell type-specific markers NeuN and GFAP to differentiate between
      neurons and glial cells. Neuroglobin is exclusively expressed in neurons, but not
      in astroglial cells. Accordingly, neuroglobin was detected in two neuroblastoma
      cell lines (N2a, SH-SY5Y) and the pheochromocytoma cell line PC-12, but not in
      glioblastoma cell lines (DKMG, GAMG) or other, non-neural cells (HeLa, Vero).
      Analysis of the neuroglobin genomic sequence from man and mouse identifies
      sequence motifs with similarity to the neuron-restrictive silencer element,
      possibly explaining a neuron-specific expression of neuroglobin.

PMID- 15193760
TI  - The role of Period1 in non-photic resetting of the hamster circadian pacemaker in
      the suprachiasmatic nucleus.
AB  - Non-photic stimuli, such as diurnal wheel running in rodents, phase shift the
      circadian clock and suppress the expression of Per1 in the suprachiasmatic
      nucleus (SCN). The goal of the present study was to directly decrease Per1
      expression using antisense (AS) oligodeoxynucleotides to determine if such
      suppression produced non-photic phase shifts. Injections of Per1-AS suppressed
      expression of Per1 within the SCN and produced phase shifts similar to those
      resulting from other non-photic manipulation, with large phase advances to
      injections during the subjective day. These results indicate that the decrease in
      expression of Per1 is a cause rather than a consequence of non-photic phase
      shifts.

PMID- 15193761
TI  - The A9 allele of the dopamine transporter gene increases the risk of visual
      hallucinations during alcohol withdrawal in alcohol-dependent women.
AB  - Previous studies have found an association between the A9 allele (nine-copy
      repeat) of the dopamine transporter (DAT) gene and two complications of alcohol
      withdrawal, namely delirium tremens (DT) and alcohol withdrawal seizures (AWS).
      Most of these studies only included male alcohol-dependent patients. Even those
      that included a small proportion of women did not look at the effect of gender.
      We compared the frequency of the A9 allele in 64 French Caucasian alcohol
      dependent women with a history of alcohol withdrawal complications. Women
      carrying the A9 allele had more visual hallucinations during withdrawal than
      those without this allele (P = 0.03). However, women with the A9 allele were not
      more susceptible to DT or AWS than those without (P = 0.48 and P = 1.00,
      respectively). Our results suggest that the A9 allele of the DAT gene is involved
      in vulnerability to alcohol withdrawal complications in women, but that these
      complications differ from those associated with this polymorphism in alcohol
      dependent men.

PMID- 15193762
TI  - Motor cortex excitability in Alzheimer's disease and in subcortical ischemic
      vascular dementia.
AB  - Twenty Alzheimer's disease (AD) patients, 20 subcortical ischemic vascular
      dementia (SIVD) patients and 20 neurologically and cognitively normal subjects
      underwent transcranial magnetic stimulation to study motor cortex excitability
      changes. Motor threshold (MT), amplitude of motor evoked potentials, silent
      period and the H/M ratio (amplitude of maximal Hoffman reflex vs. that of maximal
      motor response) were considered. MT was lower in SIVD patients when compared with
      AD patients (P = 0.003) and the control group (P < 0.001) and lower in AD
      patients when compared with the control group (P < 0.001). The increment of motor
      cortex excitability in AD and SIVD did not lead us to distinguish clearly the two
      types of dementia. It is likely that the electrophysiological similarity between
      AD and SIVD could represent another common mechanism shared from these forms of
      dementia.

PMID- 15193763
TI  - Interleukin-6 promoter polymorphism: risk and pathology of Alzheimer's disease.
AB  - Inflammatory and immune responses are involved in the pathogenesis of Alzheimer's
      disease (AD). Interleukin-6 (IL-6), an inflammatory cytokine, is thought to play
      a role in neurodegeneration of the central nervous system and has been associated
      with increased amyloid precursor protein expression in vitro and greater
      cognitive decline. Previously a C-174G polymorphism in the promoter of IL-6,
      which influences expression in vitro, has been found associated in some studies
      but not all. We investigated this polymorphism in a large independent UK sample
      of AD cases (n = 356) and controls (n 434) but found no association. We extended
      the study to genotype/phenotype correlations but found no correlation with age of
      onset (n = 338), brain amyloid load (n = 126) or Tau load (n = 101), brain
      microglial cell load (n = 65) or brain reactive astrocytes (n = 127). Our data do
      not support a pathogenic role in AD for the C-174G polymorphism in isolation.

PMID- 15193764
TI  - Ghrelin effects on gonadotropin secretion in male and female rats.
AB  - Ghrelin is a 28-amino acid peptide primarily involved in the control of food
      intake and growth hormone secretion. The present experiments were carried out to
      analyze the potential involvement of ghrelin in the control of gonadotropin
      secretion. Prepubertal intact and gonadectomized female and male rats, cyclic
      rats in diestrus, lactating rats and aged female rats were i.c.v. injected with
      ghrelin (3 nmol/rat) and blood samples were obtained by decapitation 15 min
      later. In addition, we analyzed the effects of ghrelin on in vitro basal and
      luteinizing hormone-releasing hormone (LHRH)-stimulated gonadotropin secretion.
      Our present results indicate that ghrelin inhibited luteinizing hormone (LH)
      secretion in vivo in prepubertal males as well as gonadectomized males and
      females, whereas follicle-stimulating hormone (FSH) remained unaffected. In
      vitro, ghrelin stimulated the secretion of both gonadotropins, and differentially
      modulated the response to LHRH; the LH response was inhibited, while the FSH
      response was enhanced. Overall, our current data open up the possibility that
      ghrelin may be involved in the control of LH secretion, and in the dissociation
      of both gonadotropins that takes place in many physiological, pathological and
      experimental situations.

PMID- 15193765
TI  - Nitric oxide-mediated alterations of protein tyrosine phosphatase activity and
      expression during hypoxia in the cerebral cortex of newborn piglets.
AB  - The present study tested the hypothesis that the hypoxia-induced decrease in
      protein tyrosine phosphatase (PTP) activity in the membranes and increased
      activity and expression of PTPs (PTP-1B, PTP-SH1 and 2) in the cytosol of the
      cerebral cortex of newborn piglets are mediated by nitric oxide (NO). To test
      this hypothesis, PTP activity in cell membranes and activity and expression were
      measured in the cytosol of normoxic (Nx, n = 5), hypoxic (Hx, n = 5), and 7-nitro
      indazole sodium salt (7-NINA), a selective inhibitor of neuronal nitric oxide
      synthase (nNOS), pretreated hypoxic (7-NINA+Hx, n = 6) newborn piglets. PTP
      activity in cortical cell membranes was lower in the Hx group as compared to the
      Nx group and this decrease was prevented in the 7-NINA+Hx group. The density of
      cytosolic PTP-1B, cytosolic PTP-SH1 and PTP-SH2 was increased in the Hx group and
      this increase was prevented in the 7-NINA+Hx group. Immunohistochemistry results
      show an increased immunoreactivity to PTP-1B in the Hx as compared to Nx animals.
      The data show that pretreatment with 7-NINA, a selective inhibitor of nNOS,
      prevents the hypoxia-induced decrease in PTP activity in membranes. nNOS
      inhibition also prevented the hypoxia-induced increase in PTP activity and
      expression in cytosol, and therefore we conclude that modification of PTP during
      hypoxia is NO-mediated.

PMID- 15193766
TI  - Proton magnetic resonance spectroscopy in ecstasy (MDMA) users.
AB  - The popular recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)
      has well-recognized neurotoxic effects upon central serotonergic systems in
      animal studies. In humans, the use of MDMA has been linked to cognitive problems,
      particularly to deficits in long-term memory and learning. Recent studies with
      proton magnetic resonance spectroscopy (1H MRS) have reported relatively low
      levels of the neuronal marker N-acetylaspartate (NAA) in MDMA users, however,
      these results have been ambiguous. Moreover, the only available 1H MRS study of
      the hippocampus reported normal findings in a small sample of five MDMA users. In
      the present study, we compared 13 polyvalent ecstasy users with 13 matched
      controls. We found no differences between the NAA/creatine/phosphocreatine (Cr)
      ratios of users and controls in neocortical regions, and only a tendency towards
      lower NAA/Cr ratios in the left hippocampus of MDMA users. Thus, compared with
      cognitive deficits, 1H MRS appears to be a less sensitive marker of potential
      neurotoxic damage in ecstasy users.

PMID- 15193767
TI  - Forskolin cooperating with growth factor on generation of dopaminergic neurons
      from human fetal mesencephalic neural progenitor cells.
AB  - Forskolin was tested for its co-activating ability to enhance the function of
      fibroblast growth factor (FGF) 8 on dopaminergic (DAergic) differentiation from
      human fetal mesencephalic neural progenitor cells (NPCs). When NPCs were treated
      with FGF8 alone, the DAergic phenotype was expressed lightly. The addition of 10
      microM forskolin increased the number of DAergic neurons, cooperating with 50
      ng/ml FGF8. These cells produced neurotransmitter DA, which was measured by high
      performance liquid chromatography. Reverse transcriptase-polymerase chain
      reaction analysis demonstrated that differentiated cells expressed DAergic
      development-relative genes tyrosine hydroxylase (TH), nuclear receptor-related
      factor 1 (Nurr1) and D2 receptor (D2R), indicating that matured DAergic neurons
      could be obtained under these present conditions. The results suggest that
      forskolin plus FGF8 may contribute to more efficient production of DAergic
      neurons from human-derived NPCs for therapy of neurodegenerative diseases.

PMID- 15193768
TI  - Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, reduces
      delayed neuronal death following transient forebrain ischemia in the adult rat
      hippocampus.
AB  - Recent evidence indicates that statins have beneficial effects on the brain in
      the ischemic condition. However, there is a lack of studies related to the effect
      of statins on delayed neuronal death. We investigated the effect of prophylactic
      therapy with pravastatin on delayed neuronal death in the rat hippocampus. The
      rats were given a daily dose of 20 mg/kg of pravastatin orally for 14 days.
      Transient forebrain ischemia was induced by the four-vessel occlusion method.
      Three days after ischemia, surviving neurons of the hippocampal CA1 subfield were
      counted. Our results demonstrated that prophylactic statin treatment
      significantly reduced delayed neuronal death after transient forebrain ischemia.
      Our findings suggest that prophylactic statin treatment may be useful in
      preventing functional neurological disorders after transient cerebral ischemic
      insult.

PMID- 15193769
TI  - Prostaglandin E2 regulates amyloid precursor protein expression via the EP2
      receptor in cultured rat microglia.
AB  - We investigated the effects of prostaglandin E2 (PGE2) on amyloid precursor
      protein (APP) expression in cultured rat microglia. PGE2 treatment significantly
      increased the expression of APP holoprotein and was associated with an elevation
      in cyclic AMP (cAMP). Direct activation of adenylate cyclase with forskolin also
      increased APP expression. Co-treatment of microglia with PGE2 and the PKA
      inhibitor H-89 suppressed the overexpression of APP caused by PGE2 alone. The
      prostaglandin EP2 receptor is known to be positively coupled to cAMP production.
      Stimulation of the EP2 receptor with butaprost increased APP holoprotein, whereas
      co-incubation of the cells with PGE(2) and the EP2 receptor antagonist AH-6809
      blocked the effect of PGE2 on APP expression. These data suggest that PGE2 is
      able to regulate the expression of APP, and that this effect may be mediated by
      the EP2 receptor and the cAMP signaling cascade.

PMID- 15193770
TI  - Morphological and conduction changes in the sciatic nerve of spontaneously
      hypertensive rats.
AB  - The morphology and function of sciatic nerve were investigated in spontaneously
      hypertensive rats (SHR), either control or hydralazine-treated, and in
      normotensive Wistar Kyoto rats of 6 months of age. In control SHR decreased
      percentages of class I fibers (20-15 microm in diameter), of axonal NFP-H 200 kDa
      neurofilament protein immunoreactivity and of nerve conduction velocity were
      found. The percentages of class III (10-5 microm in diameter) and IV (<5 microm
      in diameter) and of S100beta-immunoreactive Schwann cell profiles were increased.
      Treatment with the hypotensive drug hydralazine countered sciatic nerve changes.
      The shift of nerve composition vs. smaller fibers is probably the cause of
      reduced nerve conduction velocity found in SHR and is consistent with the
      occurrence of a sympathetic hyper innervation in this animal model of
      hypertension. Our findings support the hypothesis that arterial hypertension may
      represent a risk factor of neuropathy.

PMID- 15193771
TI  - Ursolic acid protects hippocampal neurons against kainate-induced excitotoxicity
      in rats.
AB  - Ursolic acid is the major component of extracts of the Chinese herb, Souyang.
      This study determines whether and how ursolic acid protects against kainate
      induced excitotoxicity in rat hippocampus. Primary neuronal cultures of cells
      isolated from the hippocampi of 7-day-old rats were treated with 150 microM
      kainate. After 2 h of treatment, free radicals were elevated and mitochondrial
      membrane potential was reduced significantly, and after 12 h, cell viability was
      decreased. Pretreatment with 5-15 microM ursolic acid dose-dependently and
      significantly attenuated the kainate-induced damage as well as alleviating the
      decrease in mitochondrial membrane potential and suppressing the increase in free
      radical generation. The results suggest that multiple mechanisms including
      modulation of AMPA receptor, protection of mitochondria, decrease in free radical
      generation, and scavenging of free radicals might be involved in ursolic acid
      protection against kainate-induced cell toxicity.

PMID- 15193772
TI  - Acupuncture suppresses intrastriatal hemorrhage-induced apoptotic neuronal cell
      death in rats.
AB  - Intracerebral hemorrhage is one of the most devastating types of stroke. In the
      present study, the effect of acupuncture on intrastriatal hemorrhage-induced
      neuronal cell death in rats was investigated via Nissl staining, terminal
      deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and
      immunohistochemistry for caspase-3. The present results showed that lesion size
      and apoptotic neuronal cell death in the striatum were significantly increased
      following intrastriatal hemorrhage in rats and that acupunctural treatment at the
      Zusanli acupoint suppressed the hemorrhage-induced increase in lesion size and
      apoptotic neuronal cell death in the striatum. In the present study, it can be
      suggested that acupunctural treatment, especially at the Zusanli acupoint, may
      aid in the recovery following central nervous system sequellae following
      intracerebral hemorrhage.

PMID- 15193774
TI  - Lack of role for the vanilloid receptor in response to several inspired irritant
      air pollutants in the C57Bl/6J mouse.
AB  - Sensory irritants initiate respiratory reflexes by stimulating trigeminal sensory
      nerves. The vanilloid receptor (TRPV1) is expressed on sensory C fibers. The
      current experiments were aimed at examining the role of this receptor in
      mediating responses to several airborne irritants including an acidic (acetic
      acid), electrophilic (acrolein), and lipophilic solvent (styrene) vapor. Wild
      type (C57Bl/6J) and VR1 knockout [B6.129S4-VR1(tm1jul)] mice were exposed to
      these irritants and breathing pattern responses were assessed by plethysmographic
      techniques; both wild-type and knockout animals responded similarly to the
      irritants. The TRPV1 antagonist iodoresiniferatoxin was also without effect on
      the responses to the irritants. Thus, in the C57Bl/6J mouse the TRPV1 receptor
      does not appear to play a major role in the stimulation of nasal trigeminal
      central reflex responses by these irritant air pollutants.

PMID- 15193773
TI  - Expression of calcitonin gene-related peptide type 1 receptor mRNA and their
      activity-modifying proteins in the rat nucleus accumbens.
AB  - The calcitonin receptor-like receptor (CRLR) and the orphan receptor RDC-1 have
      been proposed to be calcitonin gene-related peptide type 1 (CGRP1) receptors, and
      receptor activity-modifying proteins (RAMPs) determine the ligand specificity of
      CRLR. Coexpression of RAMP1 and CRLR resulted in functional CGRP1 receptors; the
      complex of RAMP2 or RAMP3 and CRLR created functional adrenomedullin receptor.
      Although high levels of CGRP binding sites in the nucleus accumbens have been
      reported, little is known about the expression of these novel CGRP receptors. In
      the present study, we used real-time quantitative RT-PCR to detect and quantitate
      the relative expression of CGRP, CRLR, RAMP1-3 and RDC-1 in the nucleus accumbens
      of intact rats and rats with inflammation. Our results demonstrate that CGRP,
      CRLR, RAMP1 and RAMP2 exist in the nucleus accumbens of intact rats, and that
      they were significantly upregulated in rats with inflammation. In contrast, no
      expression was detected for RDC-1 and RAMP3. These findings indicated a
      functional role for CGRP and its receptors in inflammation and pain modulation.

PMID- 15193776
TI  - Localization of the Cl(-)-ATPase activity on NAP-22 enriched membrane microdomain
      (raft) of rat brain.
AB  - Much attention has been paid to the membrane microdomain enriched in cholesterol
      and sphingolipids called raft. In the central nervous system, however, the
      physiological role of this domain is not so evident at present, partly because of
      the complexity of the protein components in the raft fraction. In this study we
      surveyed ATPase activities in the raft fraction obtained from the synaptic plasma
      membrane of rat brain and found the enrichment of an ethacrynic acid-sensitive
      ATPase (Cl(-)-pump) activity. Immunoprecipitation experiments using antibodies to
      raft-localized proteins showed the co-precipitation of the ATPase activity with
      NAP-22, a major raft-localized protein. This result suggests the participation of
      the raft in the regulation of ion transport in addition to the presence of
      heterogeneity of raft domains in neurons.

PMID- 15193775
TI  - Intracellular coexpression of endothelin-1 and inducible nitric oxide synthase
      underlies hypoperfusion after traumatic brain injury in the rat.
AB  - We used Marmarou's rat model of traumatic brain injury to demonstrate
      colocalization of mRNAs for endothelin-1 (ET-1, a powerful vasoconstrictor) and
      inducible nitric oxide synthase (iNOS, generator of NO, a vasodilator) in
      individual cells that form the brain's microvascular wall. The results were
      confirmed with double immunocytochemistry. After trauma endothelial, smooth
      muscle cells and macrophages contributed to the abnormal synthesis of ET-1 and
      iNOS which may underlie a dysfunctional brain microcirculation. This is the first
      in vivo single cell demonstration of ET-1 and iNOS colocalization, suggesting
      reciprocal regulation of each other's expression both at the transcriptional and
      translational levels. The results further indicate that interaction between ET-1
      and iNOS occurs at the cytosol and possibly the nuclear membranes, implicating
      mediation via endothelin receptors.

PMID- 15193777
TI  - Interactions between tactile and noxious visceral inputs in rat nucleus gracilus.
AB  - Recent studies have revealed that noxious visceral inputs travel in the dorsal
      column pathway, and interactions between colorectal noxious and tactile inputs
      occur in the ventrobasal thalamus. This investigation was to test whether the
      somatovisceral interactions also take place at a lower level in the dorsal column
      nuclei. Extracellular single neuron recordings were carried out in nucleus
      gracilus of anesthetized rats. Forty-three neurons responsive to colorectal
      distension (CRD) all had excitatory responses to tactile stimuli, and their
      tactile responses were predominantly (31/43 units) enhanced by preceding CRD. In
      contrast, the neuronal responses to CRD were reduced in 22/43 units when preceded
      by tactile stimulation but in two units there was an enhancement. The similarity
      and differences in the gracile response features in comparison with the thalamic
      recordings suggest that somatovisceral interactions take place at multiple levels
      in the dorsal column-medial lemniscus system.

PMID- 15193778
TI  - Kindling and status epilepticus models of epilepsy: rewiring the brain.
AB  - This review focuses on the remodeling of brain circuitry associated with
      epilepsy, particularly in excitatory glutamate and inhibitory GABA systems,
      including alterations in synaptic efficacy, growth of new connections, and loss
      of existing connections. From recent studies on the kindling and status
      epilepticus models, which have been used most extensively to investigate temporal
      lobe epilepsy, it is now clear that the brain reorganizes itself in response to
      excess neural activation, such as seizure activity. The contributing factors to
      this reorganization include activation of glutamate receptors, second messengers,
      immediate early genes, transcription factors, neurotrophic factors, axon guidance
      molecules, protein synthesis, neurogenesis, and synaptogenesis. Some of the
      resulting changes may, in turn, contribute to the permanent alterations in
      seizure susceptibility. There is increasing evidence that neurogenesis and
      synaptogenesis can appear not only in the mossy fiber pathway in the hippocampus
      but also in other limbic structures. Neuronal loss, induced by prolonged seizure
      activity, may also contribute to circuit restructuring, particularly in the
      status epilepticus model. However, it is unlikely that any one structure, plastic
      system, neurotrophin, or downstream effector pathway is uniquely critical for
      epileptogenesis. The sensitivity of neural systems to the modulation of
      inhibition makes a disinhibition hypothesis compelling for both the triggering
      stage of the epileptic response and the long-term changes that promote the
      epileptic state. Loss of selective types of interneurons, alteration of GABA
      receptor configuration, and/or decrease in dendritic inhibition could contribute
      to the development of spontaneous seizures.

PMID- 15193779
TI  - Motor rehabilitation and brain plasticity after hemiparetic stroke.
AB  - This review intends to begin to build a bridge between our understanding of the
      effect of motor rehabilitation and brain plasticity on recovery after hemiparetic
      stroke. It discusses the impact of intensive post-stroke motor rehabilitation on
      motor recovery. This is followed by an overview of our current understanding,
      based on human brain mapping technologies, of brain plasticity underlying
      spontaneous recovery after hemiparetic stroke. These discussions lead to a
      descriptive review of human brain mapping studies that have begun to provide an
      understanding of the neural basis of rehabilitation-induced gains in motor
      function after stroke. Finally, it speculates on how a solid understanding of the
      neural underpinnings of spontaneous and rehabilitation-induced motor recovery
      will permit brain mapping technologies to be applied toward optimizing post
      stroke motor rehabilitation.

PMID- 15193782
TI  - An overview of the current status of national reporting systems for adverse
      reactions to dental materials.
AB  - OBJECTIVES: Since all dental materials pose a potential risk to patients and
      members of the dental team, the post-market monitoring of adverse reactions
      caused by dental materials should be considered essential. This article reviews
      the current status of post-market monitoring of adverse reactions to dental
      materials and highlights some of the issues that arise in trying to establish an
      evidence base on the characteristics of adverse reactions to dental materials.
      METHODS: Norway, Sweden and more recently the UK have sought to monitor adverse
      reactions to dental materials systematically and proactively in an effort to add
      to the evidence base on the safety of dental materials. Their experiences in
      undertaking post-market surveillance have been combined in preparing this
      article. RESULTS: To date the Norwegian, Swedish and the UK projects has received
      1268 reports over 11 years, 848 reports over 5.5 years and 1117 reports over 3
      years, respectively, relating to adverse reactions seen or experienced by dental
      personnel and patients. Presently, there are no harmonized criteria for what can
      be classified as an adverse reaction related to dental materials. Under reporting
      is a recognised problem and lack of awareness and lack of clarity as to what
      constitutes an adverse reaction may be contributory factors. A pro-active
      reporting system takes a considerable time to become established, but can
      generate a lot of potentially useful information. CONCLUSIONS: There is a need to
      raise the awareness among dental professionals of the potential for adverse
      reactions due to dental materials and to develop an internationally accepted
      system of data gathering that can produce the evidence that reflect the extent,
      severity and incidence of adverse reactions to dental materials.

PMID- 15193781
TI  - Amalgam to tooth-coloured materials--implications for clinical practice and
      dental education: governmental restrictions and amalgam-usage survey results.
AB  - OBJECTIVES: To review governmental guidelines on amalgam use worldwide and to
      assess trends in the usage of amalgam and composite materials in restoration of
      posterior teeth. METHODS: A letter was sent to 24 government health agencies or
      representative organisations requesting details of regulations pertaining to
      amalgam use. A literature search was carried out in order to identify papers in
      which the incidence of amalgam and composite restorations was stated. RESULTS:
      Ten replies were received, indicating few restrictions on the use of amalgam.
      Results obtained from published work appear to indicate that amalgam use is
      declining, but at rates which are unclear in many countries because of the
      paucity of published data. Amalgam use has been found to be decreasing in the
      USA, Australia and Scandinavia, with lesser decreases being apparent in the UK.
      CONCLUSIONS: There are few restrictions to the use of amalgam worldwide. In
      countries where data are available, such as USA, Australia and Scandinavia,
      amalgam use has been found to be decreasing, with smaller decreases being
      apparent in the UK.

PMID- 15193783
TI  - Amalgam toxicity--environmental and occupational hazards.
AB  - OBJECTIVES: To discuss briefly the recent developments in mercury production,
      consumption and waste handling especially in relation to the use of mercury in
      dentistry. Furthermore, to discuss the toxicological and reproductive aspects of
      the mercury body burden of dental personnel. DATA, SOURCES AND STUDY SELECTION:
      The data discussed are primarily based on published scientific studies and on
      publications and reviews from governmental and other official authorities which
      have been published within the last 10 years, References have been traced
      manually or by MEDLINE. CONCLUSIONS: Global production and consumption of mercury
      is decreasing, as is the production of amalgam fillings in some countries. By
      proper measures it is possible to further reduce the environmental burden of
      mercury from dental clinics. In general, the mercury body burden of the dental
      personnel can be kept below the normally accepted toxicological limits and
      reproductive effects have not been proven provided a proper mercury hygiene
      regimen is adopted.

PMID- 15193784
TI  - Curricular issues changing from amalgam to tooth-coloured materials.
AB  - OBJECTIVE: To provide an overview of curriculum issues in changing from amalgam
      to tooth-coloured materials. KEY POINTS: Changing from amalgam to tooth-coloured
      materials in teaching the restoration of posterior teeth may be found to have a
      considerable enriching effect on the dental curriculum. Subject to meeting a
      number of prerequisites, the change from amalgam to tooth-coloured materials may
      cause relatively little curriculum disruption, with the added bonus of a
      consequential shift from reparative to preservative, minimal invasive dentistry.
      CONCLUSION: Changing from amalgam to tooth-coloured materials may enrich the
      typical dental curriculum.

PMID- 15193785
TI  - The amalgam-free dental school.
AB  - OBJECTIVES: To review the change in teaching of Restorative Dentistry at Nijmegen
      dental school over the period 1986 to the present. KEY POINTS: In 1986, class I
      and II resin composite restorations were included in the pre-clinical program.
      However, these courses still started with class I and II amalgam restorations.
      From 1990 on, the number of amalgam restorations placed in the clinic gradually
      decreased while the number of resin composite restorations increased. Meanwhile,
      resin composite had become the first choice for treatment of primary caries
      (class I and class II) lesions. Finally in 1994, the pre-clinical training
      started with resin composite restorations before dental amalgam was taught and
      the advantage of a minimal preparation was further emphasized. Since 2001 the
      teaching of dental amalgam ceased at the dental school. This was not an abrupt
      change but the result of a long transitional stage during which it was gradually
      substituted by resin composite. This step-by-step introduction allowed the
      acceptance of composite resin by the staff as an alternative for dental amalgam
      in posterior restorations. As in 2001 students placed only 2.5 amalgam
      restorations before graduation, it was decided to stop with the pre-clinical
      training program. CONCLUSIONS: The introduction of resin composites meant an
      important change in teaching restorative dentistry at Nijmegen dental school. It
      was not just a change in materials and techniques but also a change in treatment
      philosophy. The reduced need for preparation and the strengthening effect on the
      remaining tooth were the principal reasons for the shift from dental amalgam to
      adhesive dentistry with resin composite at Nijmegen dental school.

PMID- 15193786
TI  - Five-year clinical performance of posterior resin composite restorations placed
      by dental students.
AB  - OBJECTIVES: To investigate the survival over a five-year period of posterior
      resin composite restorations placed by students. METHODS: Class I and II resin
      composite restorations placed by second-fourth year dental students were
      evaluated. Patients attended the dental school every 6 months for a regular check
      up during which all restorations were checked on their clinical acceptability. In
      case of replacement or repair of a restoration, this was registered in the
      patient's record. From each record the survival time and reasons for failure of
      resin composite restorations were gathered. RESULTS: Seven-hundred three
      posterior resin composite restorations in 382 patients (49% female and 51% male,
      age 22-78) were evaluated. At 5 years 560 of the 703 restorations were still
      considered to be "clinically acceptable". Forty-nine restorations were considered
      as "functionally present", of which 44 were restored with a crown and four had
      received a new restoration adjacent to the existing restoration without its
      removal. Ninety-four restorations had failed. The main reasons for failure were
      restoration fracture, caries, endodontic treatment, defective margin and lack of
      proximal contact. The survival rate of the restorations was 87% at 5 years,
      resulting in an annual failure rate of 2.8%. CONCLUSIONS: Dental students are
      able to place resin composite restorations in posterior teeth with an acceptable
      mean annual failure rate.

PMID- 15193787
TI  - Efficacy of three surface disinfectants for dental radiographic films and gloves.
AB  - Contaminated radiographic films and gloves may transmit infectious diseases.
      Objective. To determine whether Pre Sept (NaDC), a sodium dichloroisocyanurate
      based disinfectant; Bronocide SP (AIP) an alcohol-phenol-iodine disinfectant and
      polyvinyl pyrrolidine iodine (PVPI) can be used to disinfect radiographic films
      and gloves. Study design. Radiographic films were contaminated with Candida
      albicans, Streptococcus mutans, Lactobacilli or saliva and placed in either 0.1,
      0.25 or 0.5 NaDC for 1, 2 or 5 min; PVPI for 5 min or sprayed with AIP. Gloves
      contaminated with C. albicans, S. mutans or Lactobacilli were sprayed with AIP.
      After treatment the films and gloves were tested for viable microorganisms.
      Results. A 0.5% solution of NaDC killed all microorganisms after one-minute
      exposure. PVPI killed 99.8% and AIP spray between 95.8 and 99% of microorganisms.
      Conclusions. NaDC was the most successful disinfectant in the laboratory and
      clinical setting followed by PVPI and AIP.

PMID- 15193788
TI  - Evaluation of silver methenamine method for nanoleakage.
AB  - OBJECTIVES: The aim of this study was to evaluate nanoleakage patterns following
      silver methenamine staining of restorations bonded with a total-etch single
      bottle system, a self-etching primer system and a total-etch single bottle system
      after collagen depletion. METHODS: The dentin bonding systems used in this study
      were Prime and bond 2.1 (PB) and Clearfil SE Bond (CSEB). Cavities were made in
      grounded labial surfaces of 15 extracted bovine lower incisors, randomly divided
      into 3 Groups. Group 1 (PB), Group 2 (CSEB) and Group 3 (PB/SH) PB after collagen
      depletion with sodium hypochlorite (SH). The specimens were restored, sectioned
      and submitted to silver methenamine staining, polished and observed with low
      vacuum back-scattered SEM. One way ANOVA and multiple-comparison Tukey's test
      were used for statistical analysis of the leakage scores. RESULTS: PB presented
      significantly greater silver deposition and a distinct pattern when compared to
      CSEB. No silver deposition was detected for PB after collagen depletion.
      SIGNIFICANCE: The dentine bonding systems tested were unable to prevent
      nanoleakage when used according to the manufacturers' instructions; however, CSEB
      presented a lower level of silver deposition. Collagen depletion prior to PB
      application may prevent nanoleakage occurrence in dentine walls. Silver
      methenamine staining may be a useful method for detection of nanoleakage in
      dentine when the collagen fibrils remain exposed within the hybrid layers.

PMID- 15193789
TI  - Er:YAG laser treatments on dentine surface: micro-Raman spectroscopy and SEM
      analysis.
AB  - OBJECTIVE: This study aims to give an insight into the chemical and structural
      modifications occurring in laser treated dentine surface, as a tool to plan a new
      class of dental materials specific for the dental restoration when laser
      technologies are used. For this purpose the effect of Er:YAG (Erbium-Yttrium
      Aluminium Garnet) laser treatments on human dentine surface has been
      investigated. METHODS: The dentine surface of periodontally compromised teeth cut
      along the main axis was treated in vitro with laser pulses having the same energy
      but time duration varying in the range of 100-1000 micros. The chemical
      characteristics and the morphology of the laser treated surface have been studied
      with micro-Raman spectroscopy (micro-RS) and scansion electron microscopy (SEM).
      RESULTS: The micro-RS and SEM analysis of laser treated teeth have been compared
      with those of surfaces treated with conventional mechanical methodologies. The
      laser pulse time duration affects the surface morphology and the chemistry of
      dentine, mainly of organic components. The effects have been monitored by
      analysing the C-H group stretch vibration mode of the micro-RS spectrum.
      CONCLUSION: The laser treatment can determine different chemical
      microenvironments on the treated dentine surface, depending on the time duration
      of laser pulse used. Treatments with very long pulse results in a the dentine
      surface very similar to that obtained with a conventional mechanical drill, while
      with very short laser pulses a strong modification of the dentine organic
      components has been observed.

PMID- 15193790
TI  - Polymerization contraction stress of low-shrinkage composites and its correlation
      with microleakage in class V restorations.
AB  - OBJECTIVE: The aim of this study was to compare the behavior of two new, low
      shrinkage hybrid composites (Aelite LS and Inten-S) with a microfilled
      (Heliomolar) and a hybrid composite (Filtek Z250), in terms of polymerization
      contraction stress and microleakage. METHODS: Maximum contraction stress after 10
      min was recorded in a "tensilometer", using a C-factor (C) of 2.5 and energy
      density of 26 J/cm(2). For the microleakage test, cylindrical cavities with
      enamel margins prepared in bovine incisors (4 mm diameter, 1.5 mm depth, C = 2.5)
      were restored in bulk, applying the same energy density used in the contraction
      stress test. After immersion in 0.5% methylene blue for 4 h, specimens were
      sectioned twice, perpendicularly, and the highest dye penetration score was
      recorded. Contraction stress results were analyzed by one-way ANOVA/Tukey's test
      and microleakage was analyzed by Kruskal-Wallis test. Regression analysis between
      the two variables was also performed. RESULTS: Aelite LS showed significantly
      higher stress than the other composites tested. Inten-S and Filtek Z250 had
      similar stress levels, statistically higher than Heliomolar. In the microleakage
      test, a significant difference was observed between Aelite LS and Heliomolar
      only. Regression analysis showed a good linear correlation between the two
      variables (R2(adjusted) = 0.811). CONCLUSIONS: The low-shrinkage materials
      exhibited contraction stress values similar or higher than the hybrid composite.
      A direct relationship between contraction stress values and microleakage for the
      composites evaluated was verified. SIGNIFICANCE: The low-shrinkage composites
      tested did not seem to represent an improvement in terms of reducing contraction
      stress or microleakage.

PMID- 15193792
TI  - Chronic exposure to gamma radiation of wild populations of meadow voles (Microtus
      pennsylvanicus).
AB  - Free-ranging, wild meadow voles (Microtus pennsylvanicus) were exposed to gamma
      radiation from a (137)Cs irradiator in a series of experiments conducted on six 1
      ha meadows within a mixed deciduous forest in Manitoba, Canada. Over a period of
      1-1.5 years in each of three experiments, vole populations were monitored with
      capture-mark-release techniques at nominal exposure rates of 200x, 9000x and
      40,000x background. No effects on population or individual characteristics were
      detected up to the highest exposure rate (81 mGy/d). At this level, third
      generation voles were monitored up to a lifetime dose of about 5.7 Gy, at a
      measured dose rate of 44 mGy/d. Smaller numbers of overwintered animals survived
      and reproduced normally at doses up to 10 Gy. These results are discussed in
      terms of low-LET, external chronic radiation effects on rodents in the laboratory
      and the field, relative to current views on appropriate benchmarks for the
      protection of biota.

PMID- 15193791
TI  - In vitro dentine permeability: the relative effect of a dentine bonding agent on
      crown preparations.
AB  - OBJECTIVE: The aim of this study was to determine whether a dentine bonding agent
      (DBA) had an effect in reducing fluid filtration under cemented provisional
      crowns. METHODS: Crown preparations on 34 premolars, randomly allocated to two
      equal-sized test and control groups, were assessed for dentine permeability by a
      fluid filtration technique. In the test group, prepared crowns were acid-etched
      and then treated with a DBA (Prime & Bond NT). In the control group, no such DBA
      was applied. Provisional crowns were cemented on both groups of teeth using non
      eugenol zinc oxide cement. Fluid filtration rates were measured repeatedly after
      crown preparation, at cementation, 1 h, 1 day, 1 week and 3 weeks following crown
      cementation for both groups. Filtration rates were also measured after acid
      etching and dentine bonding for the test group. RESULTS: There was insufficient
      evidence to suggest any statistically significant differences either between the
      two groups or, on average, across the five time points in each group in terms of
      the relative percentage of fluid filtration. CONCLUSION: The DBA used did not
      seal dentinal tubules any more than did the smear layer and provisional crowns
      luted with a non-eugenol ZnO cement.

PMID- 15193794
TI  - Distribution and flux of 238Pu, 239,240Pu, 241Am, 137Cs and 210Pb to high arctic
      lakes in the Thule district (Greenland).
AB  - Environmental samples (soil, sediment and lake water) in the Thule area (NW
      Greenland) have been studied to assess the contamination of radionuclides
      originating from a nuclear weapons accident (the Thule accident in 1968). Four
      lakes were chosen at different distances from the point of impact with the Thule
      air base community situated in between. The sedimentation rates in the lakes
      varied from 0.4 mm a(-1) (5 mg cm(-2) a(-1)) to 1.6 mm a(-1) (82 mg cm(-2) a(
      1)). With these sedimentation rates, it is not possible to resolve the
      (239,240)Pu global fallout peak from a possible (239,240)Pu "accident" peak in
      the sediment depth profiles. However, the (239,240)Pu/(137)Cs and the
      (238)Pu/(239,240)Pu ratios agreed well with global fallout ratios, indicating
      that plutonium originating from the accident had not reached these lakes. This
      also indicates that the Thule air base community has probably only been exposed
      to radionuclides from the accident to a very limited extent. A limited study
      showed that (210)Pb could not be used as a normalizing nuclide to explain the
      transport of transuranic elements from the catchment area to the lake, i.e.
      (210)Pb has a different transport mechanism from that of the transuranic elements
      studied in this investigation.

PMID- 15193793
TI  - Field observations of the effects of protracted low levels of ionizing radiation
      on natural aquatic population by using a cytogenetic tool.
AB  - In the present study, an effort is attempted to record the impact of chronic
      radiation on natural aquatic populations exposed to protracted doses (lower if
      compared to intervention levels but higher if compared to typical background) and
      to chemical pollution. The methodology is based on the analyses of chromosome
      aberrations observed in cells. Therefore, some preliminary research results on
      the cytogenetic effects on aquatic organisms of various taxa, in coastal
      ecosystems are presented, considering some selective regions of elevated natural
      gamma radiation and conventional pollution. These areas are the geothermal spring
      areas in the island of Ikaria-Eastern Aegean Sea and the port of Pireus, in
      Greece. The data are compared to the findings recorded in some organisms
      collected from the North Aegean Sea the early period after the Chernobyl
      accident. With regard to the different species examined, a first evaluation of
      the results is made using the reported field findings for the wide area of
      Chernobyl. The environmental assessment of the studied areas in terms of
      radiation impact is based on the cytogenetic injuries observed, and evidence of
      ecosystem disturbance is also pointed out. The final environmental assessment
      based on the quantified effects observed in the organisms from the studied areas
      takes into account a published conceptual model of zones of radiation dose rates
      and the resulting organism responses in a step function scale.

PMID- 15193795
TI  - Equilibrium of radiocesium with stable cesium within the biological cycle of
      contaminated forest ecosystems.
AB  - Concentrations of (137)Cs and stable Cs were determined in plant, mushroom,
      lichen and soil samples collected at two forest sites with different
      contamination levels in Belarus in 1998. The concentration of (137)Cs in soil was
      the highest in near-surface organic layers (Of and Oh horizons) and decreased
      with depth in the mineral layers, whereas the concentrations of stable Cs were
      almost constant in the soil profile. The levels of (137)Cs and stable Cs in
      biological samples varied depending both on the species and the plant part
      sampled. Even though different species and parts of the same species were
      included, the concentration ratios of (137)Cs to stable Cs were fairly constant
      for samples collected at the same forest site, and were in the same order of
      magnitude as the (137)Cs to stable Cs ratios for the organic soil layers. This
      finding suggests that (137)Cs, mainly deposited on the forest ecosystems from the
      Chernobyl accident in 1986, was well mixed with stable Cs within the biological
      cycle in the forest ecosystems by 1998. The transfer factor for each biological
      sample of (137)Cs was almost the same as that of stable Cs, if they were
      calculated based on the concentrations in the Of + Oh layer. This suggests that
      the stable-Cs-based transfer factor could be used as equilibrium transfer factor
      of (137)Cs for different types of biological samples in the forest.

PMID- 15193796
TI  - Specific activity and hazards of granite samples collected from the Eastern
      Desert of Egypt.
AB  - Fifty granitic rock samples were collected from different plutons in the central
      part of the Eastern Desert of Egypt and were analyzed for specific concentrations
      of (238)U, (232)Th and (40)K radionuclei. The measurements were carried out using
      a high performance and stability Nomad Plus spectroscopy system attached to a 1.7
      keV (FWHM) HPGe detector. The spectra were analyzed using the direct gamma
      counting comparison method as well as the traditional absolute efficiency curve
      method. The highest average value of (238)U concentration (1184 Bq kg(-1)) was
      observed at EI Misikat region whereas the highest average values of (40)K and
      (232)Th concentration (2301.8 and 162.5 Bq kg(-1) respectively), were detected at
      Gabal Homret Waggat area. The radium equivalent activity (Ra(eq)), the absorbed
      dose rate (D), the external hazard index (H(ex)) and the annual gonadal dose
      equivalent were also calculated and compared to the international recommended
      values. Radon exhalation rate from the rock samples were measured using the
      activated charcoal canister method. The average value of radon exhalation varies
      from 0.052 to 0.69 Bq m(-2) h(-1) and depends on the specific concentration of
      uranium.

PMID- 15193797
TI  - 239+240Pu, 90Sr and 137Cs inventories in surface soils of Vietnam.
AB  - Fallout 239+240Pu, 238Pu, 90Sr and 137Cs inventories in surface soils were
      measured for 20 locations in northern Vietnam yielding the mean values (+/-
      standard error) of 26.5+/-3.8 Bq m(-2) for 239+240Pu, 1048+/-143 Bq m(-2) for
      137Cs and 212+/-28 Bq m(-2) for 90Sr. The concentrations of 137Cs and plutonium
      isotopes strongly correlate with each other resulting in a stable 239+240Pu/137Cs
      inventory ratio of 0.025+/-0.002. Among soil parameters, organic matter and
      fulvic acids strongly correlate with caesium and plutonium isotopes, especially
      in the 0-10 cm layer. 137Cs and 239+240Pu are distributed rather similarly over
      the 0-10 cm and 10-20 cm layers. At locations with high contents of sand (82-93%)
      along the South China Sea coast, the downward percolation by rainwater results in
      a higher accumulation of 239+240Pu and 137Cs in the 10-20 cm layer. The mean
      137Cs/ 90Sr inventory ratio is 9.3+/-2.2, and the correlation is weak between
      these isotopes.

PMID- 15193798
TI  - Comparison between the predictions of a Gaussian plume model and a Lagrangian
      particle dispersion model for annual average calculations of long-range
      dispersion of radionuclides.
AB  - This study attempts to validate the applicability of a simple Gaussian dispersion
      model for predicting long-range dispersion of continuous releases from an
      industrial site, by comparison with a Lagrangian particle dispersion model. The
      United Kingdom Meteorological Office model NAME has been used to predict annual
      average concentrations of radionuclides over Western Europe, resulting from
      discharges from the British Nuclear Fuels (BNFL) site at Sellafield, UK. The
      results are compared here to calculations performed using a conventional Gaussian
      type of dispersion model, PLUME. The results of the Gaussian model were compared
      at 14 locations within Western Europe at long range (up to 1700 km). The
      differences in predictions between the models were explained readily by
      differences in the way dispersion and deposition processes are represented in the
      two models. However, differences are generally small compared to the expected
      precision of the models. The implementation of environmental processes in NAME is
      more complete and realistic than in PLUME, and as such the results from this
      model may be considered more realistic. However, given that PLUME is much simpler
      to use, and appears to over-estimate, rather than under-estimate, environmental
      concentrations, its use for radiological assessments appears appropriate.

PMID- 15193799
TI  - The usefulness of molecular techniques to assess the presence of Aeromonas spp.
      harboring virulence markers in foods.
AB  - A total of 78 raw and 123 processed and ready-to-eat retail food samples were
      used to assess the presence of motile Aeromonas spp. harboring virulence genes
      (cytotoxic enterotoxin and hemolysin genes) using a recently described PCR method
      in comparison with the conventional cultivation method based on the use of
      Ampicillin-Dextrin Agar (ADA) medium. With the ADA-based method, 65/201 (32.3%)
      samples showed presumptive Aeromonas spp. colonies whereas the PCR method
      revealed the presence of Aeromonas spp. harboring the targeted virulence genes in
      51/201 (25.4%) of the tested samples. The rate of contaminated samples and the
      presence of pathogenic Aeromonas were significantly lower with both methods for
      processed than in case of raw samples. A polyphasic identification approach
      including biochemical and molecular techniques was applied to a selection of 34
      PCR-positive presumptive Aeromonas isolates. Following fatty acid methyl ester
      (FAME) analysis and amplified fragment length polymorphism (AFLP) fingerprinting,
      a total of 33 isolates (97%) could be identified to the DNA hybridization group
      (HG) level. The majority of these isolates belonged to the species Aeromonas
      hydrophila HG3 (50%) and Aeromonas veronii biovar sobria (HG8/10) (38%).
      Molecular characterization of PCR amplicons obtained from these strains by PCR
      Restriction Fragment Length Polymorphism (PCR-RFLP) fingerprinting and PCR
      Amplicon Sequence Analysis (PCR-ASA) allowed classification of all strains in a
      known PCR-RFLP and PCR-ASA type. In conclusion, the current findings demonstrate
      that the combined use of PCR-based virulence marker detection, PCR-RFLP and PCR
      ASA offers a rapid, sensitive, and specific system to assess the presence and
      prevalence of Aeromonas spp. harboring virulence markers in food samples.

PMID- 15193800
TI  - Interactions between high pressure homogenization and antimicrobial activity of
      lysozyme and lactoperoxidase.
AB  - It was the objective of this work to evaluate the effect of high pressure
      homogenization on the activity of antimicrobial enzymes such as lysozyme and
      lactoperoxidase against a selected group of Gram positive and Gram negative
      species inoculated in skim milk. Lactobacillus helveticus, Lactobacillus
      plantarum and Listeria monocytogenes were the most pressure resistant species
      while Bacillus subtilis, Pseudomonas putida, Salmonella typhimurium,
      Staphylococcus aureus, Proteus vulgaris and Salmonella enteritidis were found to
      be very sensitive to the hyperbaric treatment. The enzyme addition enhanced the
      instantaneous pressure efficacy on almost all the considered species as indicated
      by their instantaneous viability loss following the treatment. Moreover, the
      combination of the enzyme and high pressure homogenization significantly affected
      the recovery and growth dynamics of several of the considered species. Although
      L. monocytogenes was slightly sensitive to pressure, the combination of the two
      stress factors induced a significant viability loss within 3 h and an extension
      of lag phases in skim milk during incubation at 37 degrees C. The hypothesis
      formulated in this work is that the interaction of high pressure homogenization
      and lysozyme or lactoperoxidase is associated to conformational modifications of
      the two proteins with a consequent enhancement of their activity. This hypothesis
      is supported by the experimental results also regarding the increased
      antimicrobial activity against L. plantarum of the previously pressurised
      lysozyme with respect to that of the native enzyme.

PMID- 15193801
TI  - Predictive modelling of the microbial lag phase: a review.
AB  - This paper summarises recent trends in predictive modelling of microbial lag
      phenomena. The lag phase is approached from both a qualitative and a quantitative
      point of view. First, a definition of lag and an analysis of the prevailing
      measuring techniques for the determination of lag time is presented. Furthermore,
      based on experimental results presented in literature, factors influencing the
      lag phase are discussed. Major modelling approaches concerning lag phase
      estimation are critically assessed. In predictive microbiology, a two-step
      modelling approach is used. Primary models describe the evolution of microbial
      numbers with time and can be subdivided into deterministic and stochastic models.
      Primary deterministic models, e.g., Baranyi and Roberts [Int. J. Food Microbiol.
      23 (1994) 277], Hills and Wright [J. Theor. Biol. 168 (1994) 31] and McKellar
      [Int. J. Food Microbiol. 36 (1997) 179], describe the evolution of
      microorganisms, using one single (deterministic) set of model parameters. In
      stochastic models, e.g., Buchanan et al. [Food Microbiol. 14 (1997) 313], Baranyi
      [J. Theor. Biol. 192 (1998) 403] and McKellar [J. Appl. Microbiol. 90 (2001)
      407], the model parameters are distributed or random variables. Secondary models
      describe the relation between primary model parameters and influencing factors
      (e.g., environmental conditions). This survey mainly focuses on the influence of
      temperature and culture history on the lag phase during growth of bacteria.

PMID- 15193802
TI  - Solid substrate production of Epicoccum nigrum conidia for biological control of
      brown rot on stone fruits.
AB  - Production of conidia of Epicoccum nigrum, a biocontrol agent of the fungal
      pathogen Monilinia laxa, was tested in liquid- and solid-state fermentation.
      Liquid fermentation was conducted in 250 ml Erlenmeyer flasks containing 50 ml of
      a mineral medium (containing per litre: 20 g lactose, 10 g NO3K, 1 g K2HPO4, 0.5
      g MgSO4.7H2O, and 1 ml of a minor-element solution), inoculated with 2 x 10(5) E.
      nigrum conidia ml(-1), and incubated at 20-25 degrees C and 150 rpm for 7 days.
      Solid-state fermentation was carried out in specially designed plastic bags (600
      cm3) (VALMIC) containing either 50 g of peat/vermiculite (1:1, w/w), or 50 g of
      peat/vermiculite/lentil meal (1:1:1, w/w/w) with 40% (v/w) initial moisture
      content. Substrate was inoculated with a conidial suspension of E. nigrum to give
      10(5) conidia g(-1) substrate, and bags were incubated at 20-25 degrees C for 7
      days in darkness. The amount of conidia of E. nigrum obtained in solid-state
      fermentation with substrate based on peat/vermiculite/lentil meal was 10-fold
      higher than with substrate based on peat/vermiculite or in liquid fermentation.
      Conidial production under these conditions was maintained in the range of 10(8)
      conidia g(-1) substrate from 10 to 150 days after inoculation. Germinability of
      these conidia was >90%. Addition of other nutrients than lentil meal to
      peat/vermiculite did not enhance production of conidia. Presence of peat in the
      substrate was necessary for good conidia production, but change in the kind of
      peat or vermiculite did not improve conidial production. Conidial production was
      similar when the substrate was inoculated with 10(5), 10(6) or 10(7) conidia g(
      1) dry substrate. Incubation of bags in light conditions did not enhance conidial
      production. Fresh conidia produced in this solid-state fermentation system
      reduced the incidence and lesion diameter induced by M. laxa on peaches.

PMID- 15193803
TI  - In vitro inhibitory activity of Chinese leek extract against Campylobacter
      species.
AB  - Three aqueous extracts of dietary materials of Chinese leek (leek flower stem,
      soft leek and green leek) and two other reference extracts of Allium plants were
      used to investigate the antibacterial effects against Campylobacter jejuni and
      Campylobacter coli. All the tested strains of Campylobacter species were isolated
      from chickens. The minimum concentration of aqueous leek extracts (ALEs) required
      to inhibit the bacterial growth was 2.0 mg/ml. Among the plant extracts tested,
      ALEs shared the lowest value of minimum inhibitory concentration (MIC), and soft
      leek significantly demonstrated the strongest inhibitory activities (P < 0.05).
      All the Allium plants tested shared similar characteristics of heat and pH
      susceptibility. Heat treatment (>75 degrees C) of the extracts reduced the
      inhibitory activity. The boiled ALEs revealed significant loss of inhibition (P <
      0.05), but they retained some inhibitory effect. The antibacterial activities of
      the ALEs were stable between pH 2.0 and 8.0, while the effects were significantly
      decreased (P < 0.05) when pH of the ALEs were adjusted to 1.0 or 9.0 above. The
      results indicated that the antibacterial activities of the ALEs against
      Campylobacter species were more effective than that of aqueous garlic extract.

PMID- 15193804
TI  - Sperm bioassay for rapid detection of cereulide-producing Bacillus cereus in food
      and related environments.
AB  - A novel in vitro method, sperm micro assay for rapidly distinguishing cereulide,
      the emetic toxin producing Bacillus cereus from non-producers is described and
      its use for quantitating cereulide and screening large numbers of B. cereus
      strains/colonies evaluated. The assay is non-laborious and can be executed with
      equipment present in most laboratories. Boar spermatozoa, purchased as standard
      semen from artificial insemination suppliers, are used to detect toxicity. Boar
      sperms respond within 5 min by cessation of motility when exposed at 37 degrees C
      to heat-treated (100 degrees C) extract prepared from a cereulide containing B.
      cereus. The assay can be done on individual colonies on the primary plate, with
      no need for pure culture and the qualitative result is obtained within 30 min.
      The assay is robust, not sensitive to age or storage of the culture plates. The
      use of the sperm micro assay for semiquantitative estimation of cereulide in B.
      cereus was validated with 14 different B. cereus strains using as reference the
      specific chemical assay for cereulide, based on liquid chromatography-ion trap
      mass spectrometry (LC-ion trap MS). The cereulide contents calculated from
      endpoint dilutions of the sperm micro assay matched the result of the chemical
      analysis closely. The detection threshold of the sperm micro assay was measured
      as 0.3 +/- 0.1 ng of cereulide per 5.4 x 10(6) sperm cells in 0.2 ml or 0.9 ng of
      cereulide per mg of B. cereus biomass (wet wt.). Food-related B. cereus strains
      contained 4-400 ng of cereulide per mg (wet wt.). When a large number of B.
      cereus of food, non-food, clinical and environmental origins were screened and
      107 independent strains/isolates were identified as cereulide producers, it was
      observed that all of these had low or no haemolytic activity when cultivated on
      bovine blood agar. None of the strains/isolates with wide, clear zones of
      haemolysis, considered typical of B. cereus, produced cereulide.

PMID- 15193805
TI  - Survey of bacterial proteins released in cheese: a proteomic approach.
AB  - During the ripening of Emmental cheese, the bacterial ecosystem confers its
      organoleptic characteristics to the evolving curd both by the action of the
      living cells, and through the release of numerous proteins, including various
      types of enzymes into the cheese when the cells lyse. In Emmental cheese these
      proteins can be released from thermophilic lactic acid bacteria used as starters
      like Lactobacillus helveticus, Lb delbruecki subsp. lactis and Streptococcus
      salivarius subsp. thermophilus and ripening bacteria such as Propionibacterium
      freudenreichii. The aim of this study was to obtain a proteomic view of the
      different groups of proteins within the cheese using proteomic tools to create a
      reference map. A methodology was therefore developed to reduce the complexity of
      cheese matrix prior to 2D-PAGE analysis. The aqueous phase of cheese was
      prefractionated by size exclusion chromatography, bacterial and milk proteins
      were separated and subsequently characterised by mass spectrometry, prior to
      peptide mass fingerprint and sequence homology database search. Five functional
      groups of proteins were identified involved in: (i) proteolysis, (ii) glycolysis,
      (iii) stress response, (iv) DNA and RNA repair and (v) oxidoreduction. The
      results revealed stress responses triggered by thermophilic lactic acid bacteria
      and Propionibacterium strains at the end of ripening. Information was also
      obtained regarding the origin and nature of the peptidases released into the
      cheese, thus providing a greater understanding of casein degradation mechanisms
      during ripening. Different peptidases arose from St thermophilus and Lb
      helveticus, suggesting that streptococci are involved in peptide degradation in
      addition to the proteolytic activity of lactobacilli.

PMID- 15193806
TI  - Genotyping of broiler-originated Campylobacter jejuni and Campylobacter coli
      isolates using fla typing and random amplified polymorphic DNA methods.
AB  - Liver and intestine samples taken from 200 broilers at 20 flocks were inoculated
      onto Preston Enrichment broth and agar for selective isolation of Campylobacter
      jejuni and Campylobacter coli. The isolates were identified by both conventional
      and polymerase chain reaction (PCR) methods. Campylobacter spp. were identified
      in 102 of 400 samples (200 liver and 200 intestine), 57 (14.25%) of which were
      identified as C. jejuni and 45 (11.25%) as C. coli. PCR-restriction fragment
      length polymorphism (RFLP) of the flagellin gene (flaA) and random amplified
      polymorphic DNA (RAPD) typing were used to describe the heterogeneity among
      amplified DNA products of C. jejuni and C. coli isolates. Flagellin gene analysis
      by RFLP of the isolates produced seven different band profiles. On the other
      hand, five distinct band profiles were obtained in the examination of the
      isolates with RAPD assay using a random primer (OPA-11). The results of this
      study demonstrated that a relatively low heterogeneity existed among C. jejuni
      and C. coli strains isolated from the commercial broiler flocks in eastern
      Turkey. In the comparison of both typing methods, fla typing provided more
      discrimination than the RAPD assay used.

PMID- 15193807
TI  - Aflatoxins in pozol, a nixtamalized, maize-based food.
AB  - To determine whether pozol, a nixtamalized maize-based food was contaminated with
      aflatoxins, samples of non-fermented pozol were collected during the period
      November 2002 to April 2003 from local markets at Comitan in Chiapas, Mexico. The
      samples were analyzed for the presence of aflatoxins. Nineteen out of one hundred
      and eleven samples were contaminated with aflatoxin B2 (AFB2) and traces of
      aflatoxin B1 (AFB1). The percentage of samples contaminated with AFB2 in pozol
      prepared with white maize was 5.4%. Pozol mixed with toasted cacao paste had a
      contamination rate of 41.5%. No aflatoxins were detected in pozol prepared with
      yellow maize. It was found that only 1 of 19 contaminated samples had aflatoxin
      concentrations above 20 ppb.

PMID- 15193808
TI  - The impact of Sirolimus Eluting stents in interventional cardiology.

PMID- 15193809
TI  - The renin-angiotensin hypothesis for the pathogenesis of cardiac allograft
      vasculopathy.
AB  - The precise molecular mechanism for the development of cardiac allograft
      vasculopathy (CAV) after heart transplantation is not known. We, thus,
      hypothesize that increased activity of renin-angiotensin system (RAS) is
      important for the progression of CAV. There is evidence to support this concept.
      RAS via its principal effector molecule, angiotensin II exerts multitude of
      actions on vascular structure and function including regulation of vasomotor
      tone, cell growth/apoptosis, fibrosis and inflammation, which are particularly
      relevant to the genesis of atherosclerotic lesions. Risk factors, which increase
      predisposition to CAD, are known to activate tissue RAS and thus influence its
      progression. Importantly, CAD risk factors are also associated with accelerated
      CAV progression after transplantation. Whereas angiotensin converting enzyme
      (ACE) gene polymorphism increases the predisposition, pharmacological inhibition
      of RAS seems to reduce the incidence of CAV. These observations may support our
      hypothesis, provide a plausible explanation for the molecular mechanisms
      underlying the development of accelerated CAV and has predictions that can be
      tested.

PMID- 15193810
TI  - Specific cardiac disorders in 402 consecutive patients with ischaemic
      cardioembolic stroke.
AB  - BACKGROUND: To determine the cardiological substrate in acute stroke patients
      presenting with a cardioembolic stroke subtype. METHODS: Data of 402 consecutive
      patients with cardioembolic stroke (cerebral infarction, n=347; transient
      ischaemic attack, n=55) were collected from a prospective hospital-based stroke
      registry in which data on 2000 stroke patients over a 10-year period were
      included. In all patients, specific cardiac disorders were identified by physical
      examination and results of electrocardiography and transthoracic
      echocardiography. Holter monitoring and more sensitive techniques of cardiac
      imaging were used in selected cases. RESULTS: Cardioembolic cerebral ischaemia
      accounted for 20% of all acute strokes (25% of ischaemic cerebrovascular events).
      Cardiac sources of embolism included the following: (a) structural cardiac
      disorders associated with arrhythmia (n=232), the most frequent being left
      ventricular hypertrophic hypertensive disease (n=120) and rheumatic mitral valve
      disease (n=49); (b) structural cardiac disease with sustained sinus rhythm
      (n=81), the most frequent being systolic left ventricular dysfunction of both
      ischaemic (n=35) or non-ischaemic (n=24) aetiology; and (c) isolated atrial
      dysrhythmia (atrial fibrillation, n=88 and atrial flutter, n=1). CONCLUSIONS:
      Hypertrophic hypertensive cardiac disease complicated with atrial fibrillation
      was the most frequent cardiac source of emboli in cardioembolic stroke. Other
      important cardiac sources were isolated atrial fibrillation, rheumatic mitral
      valve disease, and systolic left ventricular dysfunction of ischaemic and non
      ischaemic cause. The incidence of traditional emboligenous-prone cardiac
      disorders, such as mitral valve prolapse and mitral annular calcification was
      low.

PMID- 15193811
TI  - Effects of thyroxin therapy on cardiac function in patients with subclinical
      hypothyroidism: index of myocardial performance in the evaluation of left
      ventricular function.
AB  - OBJECTIVE: We investigated the effects of thyroxine (T4) therapy on the cardiac
      function in subclinical hypothyroidism (SHT) by using the index of myocardial
      performance (IMP) and the conventional echocardiographic parameters. METHODS:
      Forty-five SHT patients (F/M:38/7, age 39.9+/-7.9) and 29 healthy subjects
      (F/M:25/4, age 38.3+/-8.6) were studied. Patients were randomly assigned, in a
      double-blind manner to receive T4 therapy (group I) or a placebo (group II) and
      for a period of up to 12 months, were followed up using thyroid function tests
      and both conventional and Doppler echocardiographic measurements. RESULTS: At the
      baseline, the SHT patients has a significantly higher isovolumic relaxation time
      (IRT) (98.3+/-23.7 vs. 81.7+/-14.7<0.01), IMP (0.52+/-0.06 vs. 0.42+/-0.05;
      P<0.001), A max (late mitral peak velocity) (83.4+/-12.6 vs. 74.3+/-13.5; P<0.01)
      and significantly lower (early mitral peak velocity) Emax/Amax ratio (1.19+/-0.18
      vs. 1.34+/-0.17; P<0.01) than the individuals in the control group. In group I,
      the thyroid hormone profile became normalized after 1 year of L-T4 therapy, but
      there was no significant change in the left ventricular (LV) morphology or
      systolic function. After 1 year of follow-up, group I showed a significant
      reduction of MPI (0.53+/-0.05 vs. 0.42+/-0.07; P<0.001), Amax (84.2+/-13.7 vs.
      74.5+/-11; P<0.001) and IRT (98.6+/-23.7 vs. 82.9+/- 23.3; P<0.001) along with a
      normalization of the E/A ratio (1.17+/-0.16 vs. 1.33+/-0.19; P<0.001).
      Conversely, no change was observed in group II. CONCLUSIONS: An impairment of
      left ventricular diastolic function, which may be reversible with T4 therapy, was
      observed in the SHT patients, and IMP may be useful in the evaluation of LV
      myocardial dysfunction in these patients.

PMID- 15193812
TI  - Angiotensin-converting enzyme and p22(phox) polymorphisms and the risk of
      coronary heart disease in a low-risk Spanish population.
AB  - OBJECTIVE: To evaluate the genetic contribution to myocardial infarction in a
      homogeneous Caucasian population (a Mediterranean Spanish population) with very
      low frequency of coronary heart disease (CHD). DESIGN: We analyzed a total of 210
      subjects, younger than 55 years, considered to be a low-risk population (104
      cases of myocardial infarction and 106 control), and genotyped them (using
      polymerase chain reaction and sequencing) for the angiotensin-converting enzyme
      (ACE) insertion/deletion (ACE I/D) and for the C242T polymorphism of NADPH
      oxidase p22(phox). Also, we sequenced 23 alleles of the ACE gene (9 D and 14 I)
      for the region that includes the end of the intron 16 and the exon 17. RESULTS:
      The ACE genotype-prevalence values for II, ID and DD were 4.81%, 28.85% and
      66.34%, respectively, among the myocardial infarction patients, and 2.83%, 71.70%
      and 25.47% among controls. The statistical analysis comparing patients and
      controls revealed significant differences (chi(2)=25.09, P=0.00000055) between
      the two subpopulations. Also, we found a strong association between the genotype
      DD and the risk of suffering CHD (odds ratio (OR): 3.64; 95% CI: 2.37-8.07). The
      prevalence of the CC, TC and TT genotypes of p22(phox) gene among healthy
      controls proved to be 53.77%, 44.34% and 1.89%, while those of myocardial
      infarction were 58.65%, 39.42% and 1.93%, respectively. The association of C242T
      polymorphism of the p22(phox) gene with CHD was not statistically significant,
      (chi(2)=0.49, P=0.48). Logistic-regression analysis demonstrated that the
      independent risk factor for developing myocardial infarction was the DD genotype
      of ACE gene. Finally, our results indicate that alleles I and D of ACE gene are
      differentiated at three positions (nucleotide sites 14,480, 14,488 and 14,521) of
      which, the positions 14,480 and 14,488 were in absolute linkage disequilibrium.
      CONCLUSIONS: Among subjects of a Mediterranean population with low risk for CHD,
      the presence of DD ACE genotype could be a risk factor for myocardial infarction,
      and we confirm the linkage disequilibrium between two nucleotide positions of the
      ACE gene and the polymorphism for an Alu insertion.

PMID- 15193813
TI  - Gender significance of ST-segment deviation detected by ambulatory (Holter)
      monitoring.
AB  - OBJECTIVE: To evaluate the gender influence in diagnostic and prognostic value of
      Holter-detected ST-segment deviation. METHODS: Two-hundred seventy-seven
      consecutive patients (196 men) who underwent coronary angiography for evaluation
      of chest pain were studied with 24-h Holter monitoring within 72 h of coronary
      angiography, and were followed up for 65+/-21 months. RESULTS: Men had a higher
      prevalence of coronary artery disease (169 of 196, 86%) compared to that of women
      (54 of 81, 67%), p<0.00025. Thirty-three (17%) men and 15 (19%) women had ST
      segment deviation during 24-h recording. The sensitivity, specificity and
      positive predictive values of ST-segment deviation (elevation, depression, or
      both) for the detection of significant coronary artery disease were similar in
      men and women. The negative predictive values were significantly higher in women
      than men for ST-segment deviation (36% vs. 15%, p<0.001), ST-segment elevation
      (35% vs. 14%, p<0.001), and ST-segment depression (34% vs. 15%, p<0.001).
      Similarly, the diagnostic accuracies were significantly higher in women than men
      for ST-segment deviation (44% vs. 29%, p<0.025), ST-segment elevation (38% vs.
      19%, p<0.001), and ST-segment depression (40% vs. 24%, p<0.025). There was no
      significant difference in composite end-point of events (mortality, nonfatal
      myocardial infarction, unstable angina, and coronary revascularization) in men
      versus women with ST-segment deviation (elevation, depression, or both).
      CONCLUSION: Holter-detected ST-segment deviation has a higher negative predictive
      value and diagnostic accuracy for detection of significant coronary artery
      disease in women than in men, although the prognostic values are not
      significantly different between men and women.

PMID- 15193815
TI  - Increased P wave dispersion after the radiofrequency catheter ablation in overt
      pre-excitation patients: the role of atrial vulnerability.
AB  - The pathogenesis of paroxysmal atrial fibrillation (PAF) in patients with overt
      pre-excitation and effect of elimination of accessory pathways on the appearance
      of AF are still controversial. We demonstrated the increased P max and P wave
      dispersion (PWD) reflecting more inhomogeneous and prolonged atrial conduction in
      patients with Wolff-Parkinson-White (WPW) syndrome and PAF attacks. One-hundred
      and fifty-one patients who underwent radiofrequency (RF) catheter ablation due to
      paroxysmal tachycardia medicated by accessory pathway were enrolled in this
      study. The patients were classified into two groups according to the presence of
      previous PAF attacks. We compared the clinical characteristics, echocardiograhic
      findings, P max and PWD values measured after normalization of PR intervals and
      disappearance of pre-excitation after ablation in overt pre-excitation patients.
      Although the differences in age, left atrial diameter and left ventricular
      ejection fraction (LVEF) were not significant in both groups, P maximum (130.0+/
      8.4 vs. 122.3+/-8.7 ms, p=0.002) and P wave dispersion values measured after
      ablation (50.3+/-7.2 vs. 35.7+/-6.1 ms, p=0.001) were significantly higher in
      patients with previous PAF attacks. Accessory pathway (AP) antegrade and
      retrograde effective refractory period (ERP) values were shorter (276+/-27.3 vs.
      321.0+/-48.7, p=0.001; 263.4+/-41.3 vs. 299.7+/-38.2, p=0.002, respectively) in
      patients with PAF attack when compared to those without PAF attacks. Higher P
      wave dispersion values in patients with previous PAF attacks suggest the
      important role of inhomogenous and discontinuous propagation of sinus impulses.
      Therefore, we concluded that not only the accessory pathway but also inhomogenous
      propagation of sinus impulses may play an important role in occurrence of AF in
      patients with pre-excitation.

PMID- 15193814
TI  - Effect of ramipril on postrevascularization prevalence of angina and quality of
      life.
AB  - BACKGROUND: The prevalence of angina after invasive revascularization is not
      negligible and impacts on quality of life. It has not been clarified whether
      potential anti-ischemic actions of angiotensin-converting enzyme inhibitors (1)
      may apply to non high-risk patients and (2) may reduce the prevalence of angina.
      We sought to test the hypothesis that ramipril, an angiotensin-converting enzyme
      inhibitor, may reduce the postrevascularization prevalence of angina pectoris and
      improve quality of life. METHODS: In the Angiotensin-converting enzyme Post
      Revascularization Study (APRES), 159 patients who underwent invasive
      revascularization for chronic angina and who had not had heart failure, acute
      myocardial infarction (AMI), or severe left ventricular dysfunction were
      randomized to receive 10 mg of ramipril or placebo. During the 12- to 46-month
      follow-up, the Specific Activity Scale class, exercise tests, and SF-36 quality
      of life scores were serially assessed. RESULTS: The average prevalence of angina
      of Specific Activity Scale class II or worse was 26.6% in the ramipril group and
      19.9% in the placebo group (p=0.16). The average prevalence of exercise-inducible
      ischemia was 30.8% in the ramipril group and 25.2% in the placebo group (p=0.39).
      There were no significant differences between the two treatment groups in the SF
      36 quality of life scores or in the Duke treadmill score. Post-hoc power
      calculations revealed that the power to rule out a clinical significant benefit
      of ramipril on the prevalence of angina, quality of life, and Duke treadmill
      score was >90%. CONCLUSIONS: These data do not suggest that ramipril reduces the
      prevalence of angina pectoris or improves quality of life after invasive
      revascularization in such patients

PMID- 15193816
TI  - Sudden unexpected death in children with a previously diagnosed cardiovascular
      disorder.
AB  - BACKGROUND: It is known that children with previously diagnosed heart defects die
      suddenly. The causes of death are often unknown. OBJECTIVE: The aim of the study
      was to identify all infants and children within the Netherlands with previously
      diagnosed heart disease who had a sudden unexpected death (SUD), and to identify
      the possible cause of death. DESIGN: Retrospective, cross-sectional study.
      PATIENTS AND SETTING: All children (<19 years) with a previously diagnosed heart
      defect and SUD between January 1990 and June 2001 in seven out of eight tertiary
      centres in the Netherlands were identified using the hospital databases. We
      excluded patients receiving compassionate care. Diagnoses, clinical status and
      circumstances of death were sought from case notes and post mortem reports.
      Deaths were classified as of cardiac or non-cardiac origin. RESULTS: We
      identified 150 cases of SUD (89 male) at a median age of 2.3 years (range 18 days
      18.9 years); 49/150 patients (33%) were </=1 year. Diagnostic categories included
      left to right shunts (N=34, 14 </=1 year), cyanotic lesions (N=38, 13 <==1 yar),
      cardiomyopathy (N=11, 2 </=1 year), univentricular heart (N=24, 10 </=1 year),
      obstructive lesions (N=11, 3 </=1 year), arrhythmia (N=8, 0 </=1 year), and
      miscellaneous defects (N=18, 5 </=1 year). 108/150 patients (72%) had been
      operated of whom 61 (57%) had corrective surgery. Of the infants with SUD, 32/49
      (65%) had undergone surgery (11 corrective); 76/101 older children had undergone
      previous surgery (50 corrective). 114/150 children (76%) died of a cardiac cause.
      Causes of death were arryhythmia (59), heart failure (25), shunt occlusion (10),
      pulmonary hypertensive crisis (8) and acute myocardial infarction (4). 30/49
      infants (61%) died of a cardiac cause; causes of death included arrythmia (10),
      heart failure (8), shunt occlusion (7), acute myocardial infarction (2).
      CONCLUSIONS: SUD in children with heart defects were predominantly of cardiac
      origin. Pumpfailure and arrhythmias were the terminal events in a significant
      number of patients in the entire population.

PMID- 15193817
TI  - A survey of outpatient management of elderly heart failure patients in Poland
      treatment patterns.
AB  - BACKGROUND: Despite the fact that heart failure constitutes a major health
      problem there are only limited data regarding pharmacotherapy along with
      characterization and prognosis of heart failure in the community. AIM: The aim of
      this study was to investigate treatment pattern in ambulatory patients with heart
      failure. METHODS: The study is a cross-country epidemiological survey, based on
      registration, by 417 participating physicians, 50 consecutive ambulatory patients
      aged >/=65 years seeking medical care for any cause. RESULTS: From a total of
      19,877 individuals, 10,579 patients (3901 men and 6678 women, 53% of total) were
      diagnosed with HF. Therapy with angiotensin converting enzyme inhibitors was
      recommended in 68%, long acting nitrates in 62%, diuretics in 55%, cardiac
      glycosides in 31%, Ca blockers in 29% and beta blockers in 22% of all individuals
      with HF. The prevalence of particular groups of drugs administered in both
      genders was similar with the exception for calcium blockers, which were more
      frequently used in women (p<0.001), whereas long acting nitrates in men
      (p<0.001). In general, angiotensin converting enzyme inhibitors, long acting
      nitrates and cardiac glycosides use increased with age. On the contrary, beta
      blockers and calcium blockers were given mostly to younger patients. The most
      sick patients were more likely to receive angiotensin converting enzyme
      inhibitors, cardiac glycosides, long acting nitrates and diuretics, whereas less
      frequently beta blockers and calcium blockers. Combination therapy was used
      relatively rarely, with lowest percentage in NYHA IV. CONCLUSION: Compared to the
      other population studies, both angiotensin converting enzyme inhibitors and beta
      blockers were used relatively more frequently, although in the absolute terms the
      latter was clearly underused. The high rate of Ca blockers prescription is a
      matter of concern. More attention should be paid to optimising combination usage
      and introducing beta blockers early in all stable patients.

PMID- 15193818
TI  - Vascular effects of diet and statin in hypercholesterolemic patients.
AB  - OBJECTIVE: We investigated whether statin improves nitric oxide (NO) bioactivity
      and reduces serological markers of oxidant stress and inflammation and whether
      statin-induced reduction in markers of oxidant stress and inflammation is
      mediated by improvement in NO bioactivity or lipoprotein changes, compared with
      American Heart Association Step I Diet (Diet). METHODS: We administered
      diet+placebo and diet+simvastatin 20 mg daily during 14 weeks with randomized
      order to 31 and 32 patients with coronary artery disease, respectively, with a
      randomized design. RESULTS: Compared with diet alone, simvastatin significantly
      improved the percent flow-mediated dilator response to hyperemia and lowered
      plasma levels of tumor necrosis factor (TNF)-alpha, intercellular adhesion
      molecule type-1 (ICAM-1), serum levels of CRP, and fibrinogen (P<0.001, P<0.001,
      P=0.035, P<0.001 and P=0.014, respectively). Compared with diet alone,
      simvastatin lowered but statistically insignificant plasma levels of nitrate and
      malondialdehyde (MDA) (P=0.164 and P=0.150, respectively). Further, we observed
      that patients with the highest pretreatment TNF-alpha, ICAM-1, and CRP levels
      showed the greatest extent of reductions on simvastatin. There were significant
      inverse correlation between low-density lipoprotein (LDL) cholesterol or the
      ratio of LDL to HDL cholesterol levels and flow-mediated dilation percent (r=
      0.342, P=0.009 and r=-0.356, P=0.006, respectively). Of interest, there were
      significant inverse correlations between flow-mediated dilation percent and TNF
      alpha levels (r=-0.329, P=0.010). However, no significant correlations between
      lipoprotein levels and levels of inflammation markers were determined. Despite
      the significant changes of lipoproteins, diet alone did not decrease the markers
      of inflammation. CONCLUSIONS: Compared with diet alone, simvastatin significantly
      reduced markers of inflammation more. These effects were independent of
      lipoprotein changes.

PMID- 15193819
TI  - Value of technetium-99m diethyltriamine pentaaceticacid radioaerosol inhalation
      lung scintigraphy for the stage of amiodarone-induced pulmonary toxicity.
AB  - BACKGROUND: Amiodarone is a potent antiarrhythmic agent that is limited in
      clinical use by its adverse effects, including potentially life threatening
      amiodarone-induced pulmonary toxicity (AIPT). The alteration of technetium-99m
      diethyltriaminepentaaceticacid (Tc-99m DTPA) radioaerosol lung clearance in AIPT
      was experimentally investigated. METHODS: Eighteen white New Zealand rabbits
      (initial weight 4.1+/-0.2 kg) were divided into two groups. AIPT group (n=13) was
      administered amiodarone (20 mg/kg BW) ip as a 5% aqueous solution for 6 week. The
      controls (n=5) were administered the same amount of 0.9% saline ip. Four rabbits
      of AIPT group died due to AIPT. The reminders of AIPT group (n=9) and controls
      underwent Tc-99m DTPA radioaerosol lung scintigraphy at the end of the treatment
      period. AIPT group was divided into two subgroups according to histopathologic
      evaluation. AIPT-I had interstitial pneumonitis (n=4) and AIPT-II had
      interstitial pneumonitis with fibrosis (n=5). RESULTS: The mean T(1/2) values of
      in control, AIPT-I, and AIPT-II groups were found 54+/-4.4, 39.2+/-11.7 and
      114.6+/-16.7 min, respectively. The mean T(1/2) values of Tc-99m DTPA
      significantly differ than other groups (X(2)=11.78, P=0.02). The significantly
      increased T(1/2) values was noted in AIPT-II group when compared with control
      (P=0.001). In contrast, AIPT-I group has significantly lower T(1/2) values than
      control group (P=0.03). CONCLUSION: We suggested that Tc-99m DTPA radioaerosol
      inhalation lung scintigraphy provides an accurate evaluation about stage of lung
      toxicity and therefore may be a useful tool for the monitoring of AIPT.

PMID- 15193820
TI  - The appropriateness of percutaneous transluminal coronary angioplasty in Korea.
AB  - BACKGROUND: The rapid adoption of percutaneous transluminal coronary angioplasty
      (PTCA) in Korea is provoking a widespread concern about possible overuse of this
      procedure with inappropriate indications. This study aimed to assess the rate of
      appropriate application of PTCA in Korea and investigate factors affecting this
      rate. METHODS: An assessment tool was developed according to the Delphi-RAND
      technique, in which an expert panel of seven members (two cardiac surgeons, three
      interventional cardiologists, and two internists) was formed and its members
      rated mutually exclusive indications. Medical records of 1228 patients who
      underwent PTCA at 25 centers across Korea were analyzed based on the developed
      appropriateness criteria. RESULTS: Overall, 13.2% of PTCA procedures were
      appropriate and 3.7% were inappropriate. By diagnoses, the rate of
      appropriateness was highest in acute myocardial infarction, and the rate of
      inappropriateness was highest in chronic stable angina. The appropriateness rate
      was correlated with the number of procedures performed at a hospital. In a
      multivariate analysis, diagnoses, risk, annual PTCA volume, number of PTCA
      interventionists, and interventionists' training experience in foreign countries
      were significantly correlated with the appropriateness. CONCLUSIONS: The
      appropriateness and inappropriateness rates in Korea are comparable to those in
      countries in which PTCA has been introduced earlier and performed more
      frequently. However, the appropriateness in hospitals performing a small number
      of PTCA cases should be monitored and improved.

PMID- 15193822
TI  - Importance of left ventricular activation in determining myocardial performance
      (Tei) index: comparison with total isovolumic time.
AB  - BACKGROUND: The Tei index is commonly used as a measure of "combined systolic and
      diastolic function". A sensitive and specific index of intrinsic myocardial
      contraction and relaxation would be independent of abnormal activation. We aimed
      to determine whether the Tei index fulfils this criterion in patients with normal
      activation or left bundle branch block (LBBB), normal or dilated left ventricular
      (LV) cavities, with or without coronary artery disease (CAD). METHODS: We studied
      32 controls and 124 patients; 49 had CAD and normal LV size (11 LBBB), 27 had non
      ischaemic dilated cardiomyopathy (DCM, 11 LBBB), and 48 had ischaemic DCM (17
      LBBB). Tei index (isovolumic contraction time+isovolumic relaxation time/ejection
      time) and total isovolumic time (t-IVT: [60-(total ejection time+total filling
      time]) were measured using Doppler echocardiography. RESULTS: Tei index and t-IVT
      were prolonged in LBBB (by 0.6 and 9.1 s/min, P<0.001). T-IVT identified LBBB
      with greater predictive accuracy than Tei index (sensitivity 97% vs. 90%,
      specificity 93% vs. 91%, P<0.05). Tei index and t-IVT were also prolonged in DCM
      (by 0.2 and 3.1 s/min, both P<0.001). Although Tei index identified DCM with
      sensitivity 71%, this fell to 53% when LBBB was excluded (P<0.05). CAD had no
      effect on Tei index or t-IVT. CONCLUSIONS: The Tei index is not a measure of
      intrinsic myocardial systolic and diastolic function, since its main determinant
      is ventricular activation rather than cavity size. T-IVT, however, is more
      sensitive to activation, is unrelated to cavity size or CAD, and may thus be a
      more accurate measure of the mechanical consequences of ventricular activation in
      a variety of cardiac conditions.

PMID- 15193821
TI  - Results of ajmaline testing in patients with arrhythmogenic right ventricular
      dysplasia-cardiomyopathy.
AB  - An association between arrhythmogenic right ventricular dysplasia-cardiomyopathy
      (ARVD/C) and Brugada syndrome can be supposed according to several case reports.
      In order to examine a possible link between ARVD/C and Brugada syndrome,
      systematic ajmaline testing with 1 mg/kg body weight intravenously, was done in
      55 patients (32 males, mean age 46.7+/-12.3 years) with ISFC/ESC criteria of
      ARVD/C. In nine patients ajmaline testing could demonstrate coved ST segment
      elevation of at least 2 mm in at least two right precordial leads. Three of these
      patients had recurrent syncopes. Electrophysiological study revealed non
      sustained ventricular tachycardia with left bundle branch block configuration and
      inferior axis in only one case. Systematic ajmaline testing could demonstrate a
      definite link between ARVD/C and Brugada syndrome.

PMID- 15193823
TI  - Female preponderance in ibutilide-induced torsade de pointes.
AB  - OBJECTIVE: Ibutilide, a class III antiarrhythmic agent used for pharmacological
      cardioversion of atrial arrhythmias, has a potential to cause QT-interval
      prolongation and torsade de pointes. Purpose of this study was to determine
      whether women are more prone to develop ibutilide-induced torsade de pointes.
      METHODS: All clinical trials, cases, case series, and related articles in English
      language in addition to 51 patients from our institution on the subject were
      examined. RESULTS: In a database derived from 23 reports in literature and from
      our institution, 1720 patients received ibutilide for cardioversion of atrial
      arrhythmias. Only in 87% (n=1492) patients, data were reported whether or not
      ibutilide caused torsade de pointes. The overall incidence of torsade de pointes
      was 3.9% (n=58) patients. Data on sex distribution of ibutilide-induced torsade
      de pointes was available in 73% (n=1096) patients. Torsade de pointes developed
      in 17 (5.6%) of 304 women and 24 (3%) of 792 men (P=0.05). It occurred during or
      within 45 min after completion of the infusion of ibutilide. Treatment instituted
      was with intravenous magnesium sulfate alone in 14% (n=8) patients, magnesium
      sulfate plus lidocaine in 5% (n=3) patients, magnesium sulfate with electrical
      cardioversion in 17% (n=10) patients, electrical cardioversion alone in 19%
      (n=11) patients, and precordial thump in 3% (n=2) patients. In 41% (n=24) of
      patients who developed torsade de pointes, it resolved without treatment. There
      were no reported deaths secondary to torsade de pointes associated with ibutilide
      infusion. CONCLUSION: Incidence of ibutilide-induced torsade de pointes is higher
      in women than in men. Greater caution must be observed while using ibutilide in
      women.

PMID- 15193825
TI  - Right and left ventricular diastolic function of male endurance athletes.
AB  - BACKGROUND: Echocardiography of endurance athletes has demonstrated a substantial
      increase in left ventricular mass with no disturbance of diastolic function as
      assessed by the e:a ratio. Few studies have examined the right ventricle of
      athletes. The present study evaluated diastolic function of both right and left
      ventricles of endurance athletes through use of measurements of the motion of the
      atrioventricular (AV) plane. METHODS: Endurance athletes (runners) and sedentary
      subjects were studied. All subjects were male, aged 30-45 years and were free of
      cardiovascular disease. There were 21 runners and 40 sedentary subjects. The
      diastolic motion of the AV plane was assessed by measurement of total
      displacement and peak early velocity. RESULTS: The runners had a greater peak
      oxygen consumption (ml kg(-1) min(-1)) (59.5 vs. 33.5, P<10(-3)) and left
      ventricular mass (g) (281 vs. 202, P<10(-3)). The e:a ratio for both groups was
      similar (1.41 vs. 1.45, P=0.8). Both total displacement and peak early velocity
      for both ventricles were similar between groups, P>0.3. No correlation with age
      was found for total displacement or peak early velocity for either group in
      either ventricle, with the exception of peak early velocity for the right
      ventricle in the runners, where a highly significant correlation was found: peak
      early velocity=24.0-0.4 age, r(2)=0.75, P=10(-5). CONCLUSION: Chronic endurance
      training is associated with a greater LV mass than in comparable sedentary
      subjects. Despite this, no effect on AV plane motion was found. A decline in
      right ventricular peak early velocity of the AV plane with increasing age was
      identified in the runners. This was an unexpected finding and requires further
      study.

PMID- 15193824
TI  - Correlation of angiographic morphology immediately after coronary balloon
      angioplasty with coronary vasomotion late after angioplasty.
AB  - BACKGROUND: Various vasomotor responses to acetylcholine have been observed after
      coronary angioplasty. However, the relationship between the grade of vascular
      injury due to balloon angioplasty and vasomotor response to acetylcholine in the
      chronic stage is unknown. In this study we examined the correlation between the
      morphology immediately after coronary angioplasty and the vasomotor response to
      acetylcholine 1 year after angioplasty. METHODS: Thirty nine patients with a
      total of 45 coronary lesions without restenosis 1 year after angioplasty were
      studied. The 45 lesions were divided into two groups according to the morphology
      immediately after angioplasty. Group A comprised smooth-walled dilation and
      smooth-walled dilation with intraluminal haziness which were considered to be
      related to injury limited to the intima or the surface of the media. Group B
      comprised intraluminal and extraluminal haziness and extraluminal type dissection
      which were considered to be related to extensive medial injury. In the 39
      patients, acetylcholine provocation test was performed. RESULTS: Transient total
      occlusion of angioplasty site was induced by acetylcholine in four lesions only
      in Group A. Percent change in coronary diameter after acetylcholine injection
      relative to that after injection of isosorbide dinitrate at the angioplasty site
      was larger in Group A than that of Group B. CONCLUSION: In the chronic stage,
      vessels with minor vascular injury exhibited a large vasomotor response to
      acetylcholine; conversely, the response was low in vessels with severe vascular
      injury by angioplasty. These observations suggest that severe vascular injury by
      balloon angioplasty may control coronary vasomotion in the chronic stage.

PMID- 15193826
TI  - Diabetes and haemodynamic reactions to acute coronary occlusion.
AB  - BACKGROUND: The risk of early sudden death before hospital admission is higher in
      diabetic than non-diabetic men with acute myocardial infarction and autonomic
      nervous activity may modify the clinical outcome of abrupt coronary occlusion.
      Since diabetes mellitus may interfere with autonomic and myocardial function, we
      decided to study whether diabetes alters autonomic and haemodynamic responses to
      acute coronary occlusion. METHODS: We analyzed the changes in heart rate, heart
      rate variability and blood pressure, and the occurrence of ventricular ectopy
      during a 2-min coronary occlusion in 238 non-diabetic and 32 diabetic patients
      referred for single vessel coronary angioplasty. The ranges of non-specific
      responses were determined by analyzing a control group of 19 patients with no
      ischaemia during a 2-min balloon inflation in a totally occluded coronary artery.
      RESULTS: Diabetic patients were more often (p<0.05) female, but there were no
      significant differences in the occluded vessel or incidence of ST changes or
      chest pain during coronary occlusion between the groups. Incidence of significant
      heart rate reactions and ventricular arrhythmias was comparable in both groups.
      Systolic blood pressure decreased (p=0.01) in the diabetic patients during
      coronary occlusion, but did not change significantly in the non-diabetic group.
      Coronary occlusion caused more often (34% vs. 14%, p<0.01) a significant decrease
      in blood pressure in diabetic patients. Logistic regression models developed to
      analyze the significance of diabetes while controlling for baseline variables and
      signs of ischaemia identified diabetes to be an independent predictor of
      hypotensive reactions (odds ratio [OR] 2.9, 95% confidence intervals 1.1-7.8,
      p<0.05), while female gender and high short-term heart rate variability were
      other independent predictors of hypotensive reactions. CONCLUSIONS: Diabetic
      patients often develop significant hypotension during the early phase of acute
      coronary occlusion. This abnormality may be related to diabetic cardiomyopathy
      and impairment of baroreflex-mediated regulation of circulation. Predisposition
      to hypotension may contribute to the observed differences in the clinical
      presentation and outcome of acute coronary events.

PMID- 15193827
TI  - Increase in QT/QTc dispersion after low energy cardioversion of chronic
      persistent atrial fibrillation.
AB  - BACKGROUND: The effects of atrial internal cardioversion on QT interval and QT
      dispersion (parameters associated with increased risk of ventricular
      tachyarrhythmias) are unknown. We investigated changes in QT interval, QTc and QT
      dispersion immediately after shock delivery for internal cardioversion in
      patients with chronic persistent atrial fibrillation. METHOD: Twenty-two patients
      with chronic persistent atrial fibrillation (mean duration, 17+/-23 months)
      underwent transvenous low-energy internal atrial cardioversion with a step-up
      protocol of shocks delivered between catheters in the right atrium and coronary
      sinus. (successful shock, 7.2+/-4.2 J). RR interval, QT interval, QTc interval,
      QT dispersion, and QTc dispersion were all measured on three consecutive beats
      (at 75 mm/s on at least 9 of 12 leads) and then averaged both before and after
      (1) the last unsuccessful shock, and (2) sinus rhythm restoration. RESULTS: All
      parameters remained similar in the minute before and after the last unsuccessful
      shock. At 1 min after the successful shock, abrupt increases in QT dispersion
      (+43.8% vs. pre-shock; P<0.001 at least significant difference analysis) and QTc
      dispersion (+30.0%; P<0.05) were observed, followed by a gradual return to pre
      shock values at 15 min. CONCLUSIONS: These findings strongly suggest the likely
      existence of a brief period of increased electrical vulnerability immediately
      after restoration of sinus rhythm by internal cardioversion. Particular caution
      should therefore be applied whenever class III antiarrhythmic drugs are
      administered immediately after successful internal atrial cardioversion.

PMID- 15193828
TI  - Correlation between non-reversible thallium-201 myocardial perfusion defect and
      ECG criteria in the diagnosis of apical myocardial infarction.
AB  - BACKGROUND: ECG identification of apical myocardial infarction (MI) is
      controversial and lacks of accuracy. Our aim was to investigate the sensitivity
      of different proposed ECG criteria in the presence of apical perfusion defects
      assessed with SPECT analysis. METHODS: One hundred twenty-four (98 M, 26 F) out
      of 1500 patients with suspected coronary artery disease, showed apical perfusion
      defect not reversible at rest and after reinjection at tomographic SPECT analysis
      during thallium-201 scintigraphy. RESULTS: In the group of 29 patients presenting
      wide isolated apical perfusion defect (wAPD) Q waves in anterior segments with
      definition of antero-septal MI was prevalent (51.7%), while few patients (41.3%)
      presented the ECG criteria of apical MI as proposed in the literature. In 19 of
      the 25 patients with partial isolated apical perfusion defect (pAPD), the absence
      of Q wave was clearly prevalent. Fifty patients had a wAPD partially extended in
      surrounding regions, as anterior or septal, inferior or lateral myocardial
      segments, in these patients, the site of Q wave location was more variable, with
      prevalent Q wave in anterior leads, but with more incidence of Q waves in leads
      II III aVF, especially in patients with associated perfusion defect in inferior
      segments. Substantially, the same finding resulted in the 20 patients showing a
      pAPD extended in surrounding myocardial segments. CONCLUSION: In conclusion, the
      low diagnostic sensitivity of the ECG criteria of identification of apical MI is
      clearly demonstrated by our analysis carried out using SPECT perfusion
      scintigraphy, with ECG findings of anterior/anterior-septal myocardial necrosis
      in the patients with wAPD.

PMID- 15193829
TI  - N-acetyl-cysteine in the prevention of vascular restenosis after percutaneous
      balloon angioplasty.
AB  - BACKGROUND: Vascular inflammation generating oxidized metabolites at the site of
      balloon angioplasty is believed to play a major role in the process of vessel
      restenosis. Glutathione, the most potent endogenous antioxidant, may have
      protective effects after angioplasty by suppressing local inflammatory response.
      The aim of the study was to test the hypothesis that oral administration of N
      acetyl-cysteine (NAC, a precursor of glutathione) reduces restenosis in an animal
      model of vascular injury. METHODS: In New Zealand white rabbits, an
      atherosclerotic lesion was introduced to both iliac arteries by air denudation of
      the endothelium while feeding the animals a high-cholesterol diet. After 4 weeks,
      all animals underwent balloon angioplasty of the endothelial injury site and half
      of the group was started on 150 mg/kg NAC per day. Quantitative angiography was
      performed prior to the angioplasty and at the final procedure 3 weeks later.
      Glutathione levels were determined in all animals at the beginning and the end of
      the study. RESULTS: Although not statistically significant, plasma glutathione
      level increased in the NAC group from 32.4+/-4.4 to 39.7+/-11.6 micromol/l, while
      it decreased from 30.6+/-13.4 to 28.3+/-11.5 micromol/l in the control group.
      During the study period, 6 vessels occluded leaving 14 vessels for analysis.
      Quantitative angiographic analyses prior to angioplasty and at follow-up showed
      no significant difference with respect to stenosis progression between the
      groups. Measurement of neointima formation by histology showed also no
      significant difference between the groups (0.175+/-0.040 mm(2) vs. 0.123+/-0.075
      mm(2)), neither did intimal macrophage count as a marker for local inflammatory
      response. CONCLUSIONS: Despite an increase in plasma glutathione level in the NAC
      treated group, there was no reduction in lesion progression after balloon
      angioplasty. Therefore, NAC does not seem to prevent restenosis after vascular
      intervention in this animal model.

PMID- 15193831
TI  - Effect of atorvastatin on different fibrinolyis mechanisms in
      hypercholesterolemic subjects.
AB  - BACKGROUND: Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce
      cardiovascular events by cholesterol lowering as well as non-lipid related
      actions. Among them, the modulation of fibrinolysis could play a relevant role in
      vascular protection. Atorvastatin is able of reducing platelet activity and
      thrombin generation before low-density lipoprotein cholesterol (LDL-C) decrease
      in hypercholesterolemic subjects in which coagulation and fibrinolysis are linked
      by the activation of thrombin activable fibrinolysis inhibitor (TAFI). The aim of
      our study was to evaluate whether atorvastatin could modulate fibrinolysis by
      interactions with endothelial mechanisms and thrombin generation. METHODS: Forty
      four pure hypercholesterolemic subjects (26 M, 18 F, mean age 52.7+/-13.7, LDL-C
      194.8+/-9.3t mg/dl) were evaluated for plasmin-antiplasmin complexes (PAP),
      tissue-plasminogen acivator (t-PA) and its inhibitor (PAI-1) (ELISA), TAFI
      activity (HPLC), platelet P-selectin (P-sel) (cytofluorymetric detection),
      platelet-dependent thrombin generation (PDTG, coagulative-chromogenic method) and
      lipid profile at baseline and after 7, 14, 28 and 90 days of atorvastatin (10
      mg/die) treatment. RESULTS: PAP were significantly reduced at baseline in
      hypercholesterolemic versus control subjects (P<0.05) and were related to P-sel
      (P<0.01), PDTG (P<0.01) and its inhibitor (PAI-1) after venous occlusion (VO)
      (P<0.05). Atorvastatin induced a significant increase of PAP at T(2) related to
      modifications of P-sel (P<0.01) and PDTG (P<0.01) before significant LDL-C
      reduction (P=0.132). PAI-1 was significantly changed at T(3) with relation to LDL
      C (P<0.01), Von Willebrand factor (VWF) (P<0.01) and sE-sel (P<0.05).
      CONCLUSIONS: The profibrinolytic activity of atorvastatin in hypercholesterolemic
      subjects is related, initially, to the positive effects exerted on platelet
      function and thrombin generation which can modulate fibrinolysis by TAFI
      activity.

PMID- 15193830
TI  - Changes in body surface potential distributions induced by isoproterenol and Na
      channel blockers in patients with the Brugada syndrome.
AB  - BACKGROUND: The characteristics of unique ECG findings in the Brugada syndrome
      have not been well explained. METHODS: To clarify their characteristics and
      mechanisms, body surface maps (BSM) were recorded from patients with the Brugada
      syndrome (13 cases; a mean age of 48 years) before and after administration of
      isoproterenol (ISP) or Na channel blockers (12 cases). RESULTS: ST elevation in
      V1-V3 was decreased by 0.1 mV or more after ISP infusion in 8 of 11 cases and
      elevated after Na channel blockers in 8 of 12. In ventricular activation time
      (VAT) isochronal map, delayed conduction was noted on upper anterior chest in 11
      and on anterior left chest in two. Delayed conduction areas were decreased by ISP
      and expanded by Na channel blockers. QRST isointegral map showed normal findings
      in baseline with minimal changes after ISP or Na channel blockers. Activation
      recovery interval (ARI) isochronal map showed prolonged area on upper anterior
      chest in baseline, being reduced by ISP and expanded by Na channel blockers. ARI
      dispersion (ARI-d), defined as difference between the maximum and minimum value
      of ARI, was larger in Brugada patients than that of normal subjects in baseline,
      and decreased after ISP and increased after Na channel blockers. CONCLUSION: ST
      elevation in the Brugada syndrome is primarily caused by abnormality in
      depolarization rather than in repolarization. BSM can provide better information
      to clarify a mechanism of ECG changes adding its diagnostic value for this unique
      syndrome.

PMID- 15193832
TI  - Impaired left ventricular diastolic function during isometric exercise in
      asymptomatic patients with hyperlipidaemia.
AB  - BACKGROUND: Left ventricular (LV) diastolic dysfunction is an early sign, and may
      be more sensitive indicator, of ischaemic heart disease (IHD) than systolic
      dysfunction. METHODS: LV diastolic function was assessed during isometric
      exercise (IME) in 37 consecutive normotensive hyperlipidaemics (LIP), without
      cardiac history or symptoms. Each patient underwent a stress ECG test and 2-D
      echo and Doppler cardiography. During the latter, transmitral flow at rest and at
      peak standardised IME using handgrip was studied. From the tracings, the E/A
      (peak velocity of the early/atrial components), the contribution of atrial
      systole to LV filling (ACF), the deceleration time (DT) of the E wave and the
      isovolumic relaxation time (IVRT) were calculated. Results were compared to 37
      age-matched normal healthy volunteers (NOR). RESULTS: Resting E/A was not
      different between NOR and the LIP. A significant reduction in E/A with IME was
      observed in LIP but not in NOR. Impaired LV filling (shown by E/A<1) was
      demonstrated in five patients (13%) at rest and in 20 patients (54%) at peak IME.
      All NOR had E/A>1 suggesting normal LV filling. Fifteen of the 30 patients with
      negative stress ECG test demonstrated LV diastolic dysfunction. ACF was higher in
      LIP than NOR and increased significantly (P<0.005) by 23% during IME. DT and IVRT
      in LIP were not different from NOR. In neither NOR nor LIP, were the LV diastolic
      functional parameters related to gender, smoking habit or levels of total
      cholesterol, LDL- or HDL-cholesterol or triglycerides. CONCLUSION: The prevalence
      of LV diastolic dysfunction in asymptomatic patients with hyperlipidaemia despite
      a negative stress ECG test may be evidence of early underlying pre-clinical
      myocardial ischaemia.

PMID- 15193833
TI  - Reinforcement as a means for quality improvement in management of coronary
      syndromes: adherence to evidence-based medicine.
AB  - OBJECTIVE: To study the effect of reinforcement as a quality improvement
      intervention in the evidence-based management of the coronary syndromes. METHODS:
      In the pre-intervention phase, the charts of 140 consecutive patients with ICD-9
      codes 410-414 for coronary syndromes were reviewed for measurement of total
      cholesterol on admission and fasting low density lipoprotein (LDL) cholesterol,
      implementation of aspirin therapy on admission, beta-blockers' use during
      hospitalization, and treatment with angiotensin converting enzyme (ACE)
      inhibitors in patients with left ventricular systolic dysfunction. Reinforcement
      was used as an intervention for quality improvement. All personnel of Division of
      Cardiology including nursing staff, medical residents, cardiology fellows, and
      attending physicians were reinforced to adhere to the evidence-based management.
      In the post-intervention phase, charts of 140 consecutive patients with ICD-9
      codes 410-414 for coronary syndromes were reviewed to assess the improvement in
      the same quality of care parameters. RESULTS: By reinforcement, a significant
      improvement was noted in all quality of care parameters studied. Proportion of
      patients who had total cholesterol measured on admission increased from 78% to
      92% (P<0.005), and those who had fasting LDL cholesterol measured increased from
      22% to 70% (P<0.0001). Use of aspirin at admission (in 74% of patients pre- vs.
      80% of patients post-intervention, P<0.05), beta-blockers during hospitalization
      (in 62% of patients pre- vs. 78% of patients post-intervention, P<0.001), and ACE
      inhibitors in patients with left ventricular systolic dysfunction (in 58% of
      patients pre- vs. 89% of patients post-intervention, P<0.001) improved
      significantly after reinforcement to the medical personal. CONCLUSION:
      Reinforcement to adhere to the evidence-based management results in a significant
      improvement in the quality of care provided to the patients with coronary
      syndromes.

PMID- 15193834
TI  - Cardiac rupture complicating myocardial infarction.
AB  - Rupture of the ventricular free wall is a leading cause of death in patients with
      acute myocardial infarction (MI). There are a number of risk indicators that are
      associated with cardiac rupture, such as female gender, old age, hypertension,
      and first MI. Typical symptoms of cardiac rupture are recurrent or persistent
      chest pain, syncope, and distension of jugular veins. Electrocardiographic signs
      may include sinus tachycardia, new Q-waves in 2 or more leads, persistent or
      recurrent ST segment elevation, deviation of expected evolutionary T-wave
      pattern, and electromechanical dissociation in end-stage cases. Once patients at
      risk have been identified using clinical symptoms and electrocardiographic signs,
      a fast and sensitive diagnostic test to confirm cardiac rupture is transthoracic
      echocardiography (TTE). New insights in the etiology of subacute myocardial
      rupture suggests that defective cardiac remodeling may predispose the heart for
      rupture. The matrix metalloproteinase (MMP) system has been shown to play an
      important role in cardiac extracellular matrix (ECM) remodeling and cardiac
      rupture. Current therapy of cardiac rupture consists mainly of surgery, and
      conservative management with hemodynamic monitoring, prolonged bed rest, beta
      blockers, and angiotensin-converting enzyme (ACE) inhibitors in selected cases.

PMID- 15193835
TI  - Changes in antibody titers against Chlamydia pneumoniae after coronary
      angioplasty.
AB  - OBJECTIVES: The potential role of common infectious agents in the pathogenesis
      and progression of atherosclerosis has been studied increasingly over the last
      decade. The evidence for Chlamydia pneumoniae as a potential causative agent is
      strong and is based on the findings of numerous sero-epidemiological studies,
      examination of atheromatous plaque specimens, in vitro animal models. We
      performed a prospective study in percutaneous transluminal coronary angioplasty
      (PTCA) patients to investigate whether the angioplasty procedure influenced the
      specific humoral immune response reaction against C. pneumoniae antigens.
      METHODS: We studied 76 patients who successfully underwent PTCA for de novo
      lesions. Blood samples were drawn immediately before PTCA and 1 month after PTCA.
      IgG and IgA antibodies against C. pneumoniae (strain CDC/CWL-029) were determined
      by an in-house developed enzyme immunoassay. RESULTS: At the time of angioplasty
      75% and 34% of the patients had seropositive antibodies to elementary bodies
      (EBs) of classes IgG and IgA, respectively. Mean titers of IgG antibodies before
      and 1 month after PTCA were 46+/-31 and 50+/-28 relative units (RU/ml) (P>0.05).
      One month after PTCA, 97% and 34% of the patients had seropositive antibodies to
      EBs of classes IgG and IgA, respectively. We divided our patients into two groups
      on the basis of IgG seropositivity (group I: Chlamydia antibody IgG seronegative
      patients, group II: Chlamydia antibody IgG seropositive) before PTCA. Significant
      increase in the antibody titers of IgG (12+/-5 vs. 40+/-18, P<0.001) and IgA
      (0.6+/-0.33 vs. 1.15+/-0.83, P=0.007) was observed in group I patients 1 month
      after PTCA and 88% of them gained IgG seropositivity. There were no significant
      changes in IgG and IgA antibody levels in group II after PTCA. CONCLUSION: We
      have demonstrated a statistically significant rise in C. pneumoniae antibodies
      (especially IgG) induced by PTCA in patients previously seronegative.

PMID- 15193836
TI  - Association between COL3A1 collagen gene exon 31 polymorphism and risk of floppy
      mitral valve/mitral valve prolapse.
AB  - BACKGROUND: Collagen structure is a key element in mitral valves. Collagen
      defects were proposed as the primary events causing floppy mitral valves (FMV).
      The role of collagen genetic variant in floppy mitral valve/mitral valve prolapse
      (FMV/MVP) has not been well studied. The purpose of this study is to investigate
      the possible relationship between the collagen gene polymorphisms and risk of
      FMV/MVP among the Chinese population in Taiwan. METHODS: We studied 100 patients
      with FMV/MVP diagnosed by echocardiography and 243 age- and sex-matched normal
      control subjects. The polymorphisms of exon 31 and exon 52 of the collagen type
      III-alpha1 gene (COL3A1) were identified by polymerase chain reaction (PCR)-based
      restriction analysis. RESULTS: There was a significant difference in either the
      genotype distribution (P<0.0001) or allelic frequencies (P<0.0001) between
      FMV/MVP cases and controls for COL3A1 exon 31 polymorphism. An odds ratio for
      risk of FMV/MVP associated with COL3A1 exon 31 GG genotype was 7.42 (95%
      confidence interval 4.40-12.52). An odds ratio for risk of FMV/MVP associated
      with COL3A1 exon 31 G allele was 2.28 (95% confidence interval 1.57-3.29). There
      was no significant difference in the distribution of COL3A1 exon 52 genotypes
      (P=0.31) and allelic frequencies (P=0.32) between FMV/MVP cases and controls.
      Further categorization of the FMV/MVP patients into mild and severe subgroups
      revealed no statistical difference from the controls for exon 31 or exon 52
      polymorphism. CONCLUSIONS: This study shows that patients with FMV/MVP have
      higher frequency of COL3A1 exon 31 GG genotype that supports a role of the COL3A1
      exon 31 polymorphism in determining the risk of FMV/MVP among the Chinese
      population in Taiwan.

PMID- 15193837
TI  - Automated quantitation of peripheral blood neutrophil activation in patients with
      myocardial ischaemia.
AB  - BACKGROUND: Coronary ischaemic syndromes are associated with neutrophil
      activation. The Bayer automated haematology analysers can detect increased light
      scatter of neutrophil populations, which correlates with neutrophil activation.
      We aimed to assess the role of an automated analyser in detecting systemic
      neutrophil activation in peripheral blood samples of patients with coronary
      ischaemia. METHODS: A prospective cross-sectional study was undertaken in 18
      patients with chronic stable angina, 9 with unstable angina and 26 normal control
      subjects. Whole blood samples were taken to assess neutrophil count and light
      scatter, and serum samples were taken from some patients for assessment of
      Troponin T, C-reactive protein (CRP) and myeloperoxidase (MPO). In addition,
      whole blood was stimulated in vitro with interleukin (IL)-8 and N-formyl
      methionyl-leucyl-phenylalanine (fMLP) to assess changes in neutrophil light
      scatter detected by the analyser. RESULTS: Neutrophil light scatter was increased
      in patients with chronic stable and unstable angina compared to normal control
      subjects (normal subjects 74.1 (73.3, 75.0) (mean arbitrary units (95% confidence
      intervals, (CI)) vs. 78.6 (76.9, 80.3) in the chronic stable angina group P<0.001
      and 77.1 (75.3, 79.0) in the unstable angina group P<0.007). In vitro stimulation
      of whole blood produced comparable increases in neutrophil light scatter when
      morphological changes in neutrophils were demonstrable under electron microscopy.
      CONCLUSIONS: Automated measurement of neutrophil activation by light scatter is
      possible using the Advia 120 analyser and is superior to a neutrophil count in
      discriminating groups with angina. This technique may be useful in monitoring
      disease activity and progression in coronary artery disease and in guiding the
      use of anti-inflammatory therapies.

PMID- 15193838
TI  - Thioredoxin, a redox-regulating protein, is expressed in spontaneous myocarditis
      in inbred strains of mice.
AB  - Redox-regulating mechanisms may be involved in the pathogenesis of aging.
      Thioredoxin (TRX) is a small multifunctional protein which contains a redox
      active sequence. Spontaneous myocarditis is often observed in aged mice. In this
      study, we examined the histopathology and characteristics of TRX expression in
      spontaneous myocarditis in inbred strains of mice. No spontaneous myocarditis was
      found in adult 4-week-old inbred strains of mice. High incidence of spontaneous
      myocarditis was found in aged 8-week-old DBA/2 mice, and low incidence was in 8
      week-old BALB/c or C57BL/6 mice. The lesions, limited to the right ventricle,
      were most severe in DBA/2 mice. TRX was upregulated, and the expression was
      correlated with the severity of the disease in these strains. Also, 8-hydroxy-2'
      deoxyguanosine (8-OHdG), which was an established marker for oxidative stress,
      was concomitantly positive in necrotic lesions among them. In addition, the long
      term anti-oxidant treatment with N-acetylcysteine (NAC) suppressed the
      development of spontaneous myocarditis. Thus, TRX may be induced by the
      spontaneously developed myocarditis, and the redox-regulating system may play an
      important role in the development of aging-related myocarditis.

PMID- 15193839
TI  - Clinical impact of functional testing strategy among stented and non-stented
      patients: insights from the ROSETTA Registry.
AB  - The clinical utility of routine functional testing following percutaneous
      coronary intervention (PCI) among patients with and without coronary stenting is
      unclear. We established an international registry to evaluate the functional
      testing strategies following successful PCI. Among patients treated with stents,
      adverse cardiovascular outcomes were similar between those who underwent routine
      or clinically-driven functional testing. Conversely, among those who were not
      treated with stents, the rate of death, myocardial infarction or unstable angina
      was lower than those who underwent routine functional testing (14.8% vs. 6.6%;
      P=0.033). Our study suggests that routine functional testing may be beneficial to
      patients not treated with stents. BACKGROUND: The role of routine functional
      testing following successful PCI is unclear. By improving patient outcomes with
      coronary stenting, the value of such a strategy may diminish. HYPOTHESIS: To
      determine the clinical utility of routine functional testing following PCI
      between patients with and without stenting. METHODS: The routine versus selective
      exercise testing after angioplasty (ROSETTA) Registry was established to evaluate
      the utilization of functional testing following PCI. Use of functional testing,
      either routine or selective (clinically-driven), was left to the discretion of
      the attending physician. RESULTS: Of 791 patients enrolled, 462 (58%) underwent
      coronary stenting. Stented patients were less likely to suffer from concomitant
      diseases but had more complex angiographic morphological characteristics. Between
      the groups of patients with and without stents, there was no difference in the
      proportion of patients undergoing routine functional testing (24% vs. 36%) or
      subsequent cardiac procedures (18.4% vs. 16.0%). Among patients with stents,
      outcomes at 6 months were similar between the groups undergoing routine and
      selective functional testing, including death (0% vs. 1.7%), myocardial
      infarction (0.9% vs. 2.0%), unstable angina (9.9% vs. 13.7%), repeat angiography
      (16.2% vs. 16.9%) and revascularization procedures (11.7% vs. 10.8%). However,
      among non-stented patients, selective functional testing was associated with a
      higher occurrence of death, myocardial infarction or unstable angina (14.8% vs.
      6.6%; P=0.033). There was also no difference in the rates of repeat coronary
      angiography or revascularization procedures between these two strategies.
      CONCLUSION: Although routine functional testing has little impact on outcomes
      among patients treated with coronary stents, non-stented patients may derive
      particular benefit.

PMID- 15193840
TI  - MOONLIGHT: a controlled registry of an iridium oxide-coated stent with
      angiographic follow-up.

PMID- 15193841
TI  - Hypersensitivity skin rash: an adverse drug reaction to clopidogrel loading dose.

PMID- 15193842
TI  - Myocardial bridging on left anterior descending coronary artery evaluated by
      multidetector computed tomography.

PMID- 15193843
TI  - Myocardial infarction in a patient with thrombotic thrombocytopenic purpura.
AB  - A 63-year-old male with a prior history of thrombotic thrombocytopenic purpura
      was admitted with sudden onset of syncope. He denied chest pain. His initial
      blood chemistries were consistent with acute relapse of thrombotic
      thrombocytopenic purpura as indicated by microangiopathic hemolytic anemia and
      thrombocytopenia. The patient had evidence of myocardial injury as indicated by
      elevation of cardiac enzymes. A 12-lead electrocardiogram demonstrated ST
      elevation (up to 5 mm) in leads V(2) to V(6). The patient was treated with plasma
      exchange with fresh frozen plasma in addition to nitroglycerin, metoprolol and
      prednisone in a tapering dose. After reviewing the literature, we believe that
      the etiology of myocardial damage remains elusive, but may be secondary to an
      autoimmune phenomenon resulting in microthrombosis and myocarditis. We were
      unable to find any documentation about any specific treatment in such patients.
      Further studies are awaited regarding appropriate treatment of patients with
      thrombotic thrombocytopenic purpura and acute electrocardiographic changes.

PMID- 15193844
TI  - Accelerated idioventricular rhythm associated to ophthalmic timolol/dorzolamide
      solution.

PMID- 15193845
TI  - Early twentieth century descriptions of the Chagas heart disease.
AB  - Chagas heart disease is endemic in 21 countries with approximately 100 million
      people at risk. It is the most common cause of myocarditis in the Americas and is
      recognized to have existed for more than 4000 years (isolated from mummies).
      Chagas disease was discovered during the search to find a cause for the
      overwhelming deaths occurring in Brazil in the late 18th century. Physician
      Carlos Chagas discovered Trypanosome minasense in 1908 while researching on
      malaria. Subsequently, the existence of the barbeiro triatomine (insects bites on
      the face), the isolation of the Trypanosome cruzi in the triatomine and the first
      human description of a disease in a 9-month-old child depicted the existence of a
      new human trypanosomiasis. Chagas named the trypanosome species after his
      colleague and mentor Oswaldo Cruz. In subsequent papers, Chagas described the
      morphology and evolutionary cycle of the trypanosome and the clinical features of
      the disease, including involvement of the heart. Never before or since one
      physician has fully characterized a disease from its grass roots to the clinical
      forms more or less all by himself.

PMID- 15193846
TI  - Takayasu arteritis of subclavian artery in a Caucasian.
AB  - Takayasu arteritis, an inflammatory and obliterative disease of medium and large
      arteries, is classified as a giant cell arteritis. It has a predilection for the
      aortic arch, its main branches, and coronary and pulmonary arteries. The early
      symptoms of Takayasu arteritis may be mainly systemic and may resemble
      polymyalgia rheumatica. The etiology is unknown but autoimmunity has been
      suggested to play a role. Diagnosis is based on symptoms, physical findings, and
      imaging, because tissue diagnosis is rarely feasible. Unlike atherosclerotic
      vascular disease, Takayasu arteritis affects primarily, but not exclusively,
      young women. Contrary to earlier reports, it is not limited to the women of
      Japanese origin but is present worldwide. The current report is of a Caucasian
      woman who presented with nonspecific complaints of upper back pain, weakness,
      malaise, and fatigue. Her physical examination revealed absent left radial pulse
      and a blood pressure differential, later confirmed by radiological imaging
      studies to be due to left subclavian artery stenosis consistent with Takayasu
      arteritis. The presentation and management of the patient is described, and
      Takayasu arteritis is succinctly reviewed.

PMID- 15193847
TI  - Radiofrequency catheter ablation for atrioventricular nodal reentrant tachycardia
      in a patient with persistent left superior vena cava.

PMID- 15193848
TI  - Acute triple-barreled aortic dissection in an uncontrolled hypertensive patient.

PMID- 15193849
TI  - Subarachnoid hemorrhage mimicking acute myocardial infarction.

PMID- 15193850
TI  - Is it time to rethink Healthy Start/Healthy Families?

PMID- 15193851
TI  - Randomized trial of a statewide home visiting program: impact in preventing child
      abuse and neglect.
AB  - OBJECTIVES: To assess the impact of home visiting in preventing child abuse and
      neglect in the first 3 years of life in families identified as at-risk of child
      abuse through population-based screening at the child's birth. METHODS: This
      experimental study focused on Hawaii Healthy Start Program (HSP) sites operated
      by three community-based agencies. From 11/94 to 12/95, 643 families were
      enrolled and randomly assigned to intervention and control groups. Child abuse
      and neglect were measured by observed and self-reported parenting behaviors, all
      hospitalizations for trauma and for conditions where hospitalization might have
      been avoided with adequate preventive care, maternal relinquishment of her role
      as primary caregiver, and substantiated CPS reports. Data were collected through
      annual maternal interviews (88% follow-up each year of all families with baseline
      interviews); observation of the home environment; and review of CPS, HSP, and
      pediatric medical records. RESULTS: HSP records rarely noted home visitor concern
      about possible abuse. The HSP and control groups were similar on most measures of
      maltreatment. HSP group mothers were less likely to use common corporal/verbal
      punishment (AOR=.59, p=.01) but this was attributable to one agency's reduction
      in threatening to spank the child. HSP group mothers reported less neglectful
      behavior (AOR=.72, .02), related to a trend toward decreased maternal
      preoccupation with problems and to improved access to medical care for
      intervention families at one agency. CONCLUSIONS: The program did not prevent
      child abuse or promote use of nonviolent discipline; it had a modest impact in
      preventing neglect. Possible targets for improved effectiveness include the
      program's implementation system and model.

PMID- 15193852
TI  - Randomized trial of a statewide home visiting program to prevent child abuse:
      impact in reducing parental risk factors.
AB  - OBJECTIVES: To assess the impact of a home visiting program in reducing malleable
      parental risk factors for child abuse in families of newborns identified, through
      population-based screening, as at-risk of child abuse. METHODS: This randomized
      trial focused on Healthy Start Program (HSP) sites operated by three community
      based organizations on Oahu, HI, USA. From 11/94 to 12/95, 643 families were
      enrolled and randomly assigned to intervention and control groups. Mothers in
      both groups were interviewed annually for 3 years (88% follow-up each year) to
      measure mental health, substance use, and partner violence. HSP records were
      reviewed to measure home visiting services provided. Home visitors were surveyed
      annually to measure their perceived competence. RESULTS: Malleable parental risks
      for child abuse were common at baseline. There was no significant overall program
      effect on any risk or on at-risk mothers' desire for and use of community
      services to address risks. There was a significant reduction in one measure of
      poor mental health at one agency and a significant reduction in maternal problem
      alcohol use and repeated incidents of physical partner violence for families
      receiving > or =75% of visits called for in the model. Home visitors often failed
      to recognize parental risks and seldom linked families with community resources.
      HSP training programs were under-developed in preparing staff to address risks
      and to link families with community resources. CONCLUSIONS: Overall, the home
      visiting program did not reduce major risk factors for child abuse that made
      families eligible for service. Research is needed to develop and test strategies
      to improve home visiting effectiveness in reducing parental risks for child
      abuse.

PMID- 15193853
TI  - Risk of mother-reported child abuse in the first 3 years of life.
AB  - OBJECTIVE: The purpose of this research was to investigate, within an at-risk
      population, parent and child characteristics associated with a mother's self
      reports of severe physical assault and assault on the self-esteem of the child in
      the first 3 years of life. DESIGN: The study population consisted of a community
      based sample of mothers of newborns identified as at-risk for child maltreatment
      (n=595). Families were assessed annually from the child's birth through age 3
      using instruments with established psychometric properties. Independent variables
      investigated included: family socio-demographics, parity, mother's social
      support, maternal depression, maternal problem drug or alcohol use, partner
      violence, child's age, child's sex, low birth weight/small for gestational age
      (SGA), and mother's perception of child's demand level. Associations with
      maltreatment were examined using multivariable methods for longitudinal data.
      RESULTS: Child severe physical assault was significantly associated with parent
      characteristics (maternal depression and partner violence); and child
      characteristics (SGA). Assault to the child's self-esteem was significantly
      associated with maternal depression, maternal illicit drug use, partner violence
      and mother's perception of child's demand level. Controlling for family
      sociodemographic characteristics did not change the associations. Likewise, while
      mother's perception of child demand level had an independent association with
      self-esteem assault, the associations described above persisted while demand
      level was held constant. In this high-risk sample, abuse was not associated with
      mother's age, education, race, parity, or household income level. CONCLUSIONS:
      While characteristics such as SGA can serve as markers for increased abuse risk,
      they are not amenable to intervention after the child is born. However, certain
      other risk factors, such as maternal depression and domestic violence are
      malleable and should be targeted for intervention with the goal of preventing
      child maltreatment.

PMID- 15193854
TI  - History of childhood abuse in Portuguese parents.
AB  - OBJECTIVE: The study examines the self-reported prevalence of childhood physical
      and sexual abuse in a large sample of Portuguese parents. METHOD: Nearly 1,000
      parents (506 mothers and 426 fathers) were selected through public primary
      schools from the Northern area of Portugal. All completed the Portuguese version
      of the Childhood History Questionnaire (CHQ) [Journal of Family Violence 5 (1990)
      15]. RESULTS: Results show that the prevalence of abuse was 73%, but more severe
      physical abuse involving sequelae/injury was reported by 9.5%. Most physical
      abuses began prior to age 13, with half continuing after age 13. No gender
      differences were found for rates of physical abuse. However, among the milder
      physical abuse without sequelae/injury, those women who experienced "whipping" or
      "slapping/kicking" were more likely to do so from their mothers than fathers.
      Among men who were "slapped/kicked" this was more likely to be from their
      fathers. Low rates of sexual abuse were found at 2.6% with no gender or age
      differences. Lack of a supportive adult in childhood related to the more severe
      abuses, but only in adolescence. Portuguese rates of abuse were consistently
      lower than those reported in USA and Spanish studies using the CHQ. CONCLUSIONS:
      This is the first retrospective, self-report study of childhood abuse in a large
      sample of Portuguese parents and, even with a participation rate of 69%, shows
      lower rates than in US and Spanish samples.

PMID- 15193856
TI  - Outpatient mental health services for children in foster care: a national
      perspective.
AB  - OBJECTIVE: To determine factors influencing the use of outpatient mental health
      services provided by mental health professionals (OMHS) for children in foster
      care using a national probability sample in the United States. METHOD: As part of
      the National Survey of Child and Adolescent Well-being, detailed survey data were
      collected on 462 children, ages 2-15, who had been in out-of-home care for
      approximately 12 months at the time of sampling. A multivariate logistic
      regression model was used to determine how clinical need, as measured by a Total
      Problem, Externalizing, or Internalizing Scale T-score of 64 or greater on the
      Achenbach Child Behavior Checklist (CBCL), and non-clinical factors affected
      OSMHS use. RESULTS: Over half of the children in the sample received at least one
      OMHS. Need, older age, and history of sexual abuse history all positively
      predicted OMHS. A history of physical neglect negatively predicted OSMHS. African
      Americans used fewer services than children of Caucasian ancestry at all values
      on the CBCL. This finding was particularly salient at lower levels of CBCL
      scores; at higher levels, the discrepancy in the use of services diminished but
      the proportion of children receiving services remained lower for African-American
      children. CONCLUSIONS: This national study confirms previous findings regarding
      the use of mental health services based on regional data. Limitations in the use
      of services imposed by non-clinical factors, specifically, age, race/ethnicity
      and type of abuse, need to be examined in order to address implicit and explicit
      policies and practices that may result in inequitable distribution of services.

PMID- 15193857
TI  - Recovery of Ins(1,4,5)-trisphosphate-dependent calcium signaling in neonatal
      gonadotrophs.
AB  - Pituitary gonadotrophs express non-desensitizing gonadotropin-releasing hormone
      (GnRH) receptors and their activations leads to inositol 1,4,5-trisphosphate
      (InsP3)-dependent Ca2+ mobilization. When added in physiological concentration
      range GnRH induces baseline Ca2+ oscillations, whereas in higher concentrations
      it induces a prolonged spike response accompanied with non-oscillatory or
      oscillatory plateau response. Here, we studied the recovery of calcium signaling
      during repetitive stimulation with short (10-30 s) GnRH pulses and variable
      interpulse intervals in neonatal gonadotrophs perfused with Ca2+/Na+ -containing,
      Ca2+ -deficient/Na+ -containing, and Ca2+ -containing/Na+ -deficient media. In
      Ca2+/Na+ -containing medium, baseline Ca2+ oscillations recovered without
      refractory period and with a time constant of approximately 20 s, whereas the
      recovery of spike response occurred after 25-35 s refractory period and with a
      time constant of approximately 30 s. During repetitive GnRH stimulation, removal
      of Ca2+ had only a minor effect on baseline oscillations but abolished spike
      response, whereas removal of Na+ slightly extended duration of baseline
      oscillations and considerably prolonged spike response. These results indicate
      that two calcium handling mechanisms are operative in gonadotrophs:
      redistribution of calcium within InsP3-sensitive and -insensitive pools and a
      sodium-dependent calcium efflux followed by calcium influx. Redistribution of
      Ca2+ within the cell leads to rapid recovery of InsP3-dependent pool, whereas the
      Na+ -dependent Ca2+ efflux pathway is activated by spike response and limits the
      time of exposure to elevated cytosolic Ca2+ concentrations.

PMID- 15193858
TI  - Apparent cytosolic calcium gradients in T-lymphocytes due to fura-2 accumulation
      in mitochondria.
AB  - Fura-2 is the most common dye to measure cytosolic Ca2+ concentrations ([Ca2+]i).
      To facilitate simultaneous imaging of many cells while preserving their cytosolic
      environment, fura-2 is often loaded into the cytosol in its membrane-permeant
      ester form. It has been reported that small amounts of fura-2 accumulate in
      intracellular compartments, an effect that is usually neglected. We show that
      either focal or non-focal stimulation methods induce large [Ca2+]i gradients in T
      lymphocytes during both, Ca2+ release and Ca2+ influx across the plasma membrane.
      Interfering with mitochondrial Ca2+ homeostasis and by labeling mitochondria with
      MitoTracker, we demonstrate that [Ca2+]i gradients co-localize with mitochondria
      and are attributable to mitochondrial fura-2 sequestration. Gradients could not
      be avoided by different loading protocols, compromising measurements of "real"
      [Ca2+]i gradients following T-cell stimulation. They were observed in human blood
      and lamina propria lymphocytes, Jurkat T-cells, mast cells, but not to the same
      extent in HEK-293 cells. Finally, we show that T-lymphocytes can be efficiently
      loaded with the membrane-impermeant fura-2 salt by electroporation and by osmotic
      lysis of pinocytic vesicles, which result in the loss of [Ca2+]i gradients. These
      methods are therefore suitable to study localized Ca2+ signals in large
      populations of T-cells while preserving their cytosolic integrity.

PMID- 15193855
TI  - Substance abuse and behavioral correlates of sexual assault among South African
      adolescents.
AB  - OBJECTIVE: The aim of this article is twofold: first, to examine the prevalence
      of being the victim of actual and attempted rape among a large representative
      sample of Cape Town high school students; and second, to identify the correlates
      of sexual assault for both boys and girls, including alcohol, tobacco and other
      drug use, behavioral problems, and suicidality. METHOD: Data for this study were
      derived from the 1997 South African Community Epidemiology Network on Drug Use
      (SACENDU) school survey. A stratified sampling procedure was used to select
      students in Grades 8 and 11 at non-private high schools in Cape Town. A total of
      2,946 students completed a survey consisting of socio-demographic questions and
      items about substance abuse, sexual activity, and other adolescent health risk
      behaviors. A subsample of 939 was randomly selected to complete items about
      sexual violence. RESULTS: The results revealed that 8.4% of respondents were
      victims of attempted rape, while 5.8% were victims of actual rape. Ordinal
      logistic regression showed that girls were 3.9 times more likely than boys to
      have been victims of sexual abuse. Family structure was also significantly
      related to rape as persons who lived with a single parent (OR = 1.74, CI = 1.00
      3.04) and those who resided with one biological parent and one step parent (OR =
      2.59, CI = 1.34-5.01) were more likely to have been have been victims of sexual
      abuse than those living with both biological parents. Alcohol use (OR = 2.0, CI =
      1.10-3.62), anti-social behavior (stolen property, caused physical damage to
      property, bullied others, or been in physical fights) (OR = 1.44, CI = 1.12
      1.86), suicidal dialogue (OR = 2.48, CI = 1.19-5.19), and suicidal attempts (OR =
      3.2, CI = 1.65-6.30) were also significant predictors of sexual abuse
      victimization. Racially classified social groups (RCSG), age, drug use, and
      cigarette smoking were not significant predictors of sexual abuse victimization,
      while socioeconomic status was found to be marginally significant. CONCLUSION:
      This study reinforces the importance of multiple factors including alcohol use,
      anti-social behavior, suicidal thoughts and actions, and family structure with
      respect to sexual assault of adolescents in South Africa. Establishing and
      strengthening intervention programs, school based child protective protocols,
      professional education of teachers and school personnel, community prevention
      programs, and initiatives could help prevent adolescent sexual violence and
      reduce the sequelae associated with this problem.

PMID- 15193859
TI  - The effects of overexpression of the Na+/Ca2+ exchanger on calcium regulation in
      hypertrophied mouse cardiac myocytes.
AB  - In cardiac hypertrophy and failure it has been shown that the amount of Na/Ca
      exchanger protein can increase. Several studies have investigated this
      modification in overt heart failure. However, the role of Na/Ca exchanger
      overexpression during the development of hypertrophy is unknown. To address this
      question we investigated Ca2+ regulation in an early stage of cardiac hypertrophy
      before signs of heart failure occurred and evaluated the role of Na/Ca exchanger
      overexpression. Cardiac hypertrophy was induced by a constant infusion of
      angiotensin II (Ang, 1 microg/min/kg) via an osmotic pump for 14 days.
      Thereafter, ventricular myocytes from either wild type (NON) or transgenic mice
      overexpressing the Na/Ca exchanger (TR) were isolated. Myocytes were loaded with
      indo-1 AM or fluo-4 AM to monitor cytoplasmic [Ca2+] with all experiments
      performed at 37 degrees C. In myocytes exposed to Ang there was an increase in
      cell capacitance of more than 20% indicating cellular hypertrophy. Ca2+
      transients were prolonged in hypertrophied NON myocytes but not in TR myocytes.
      Action potentials had a less negative plateau in TR myocytes. Sarcoplasmic
      reticulum (SR) Ca2+ content, measured using rapid caffeine application, was
      greater in TR myocytes but unaffected by hypertrophy. Ca2+ spark frequency was
      significantly greater in TR. Na/Ca exchanger overexpression prevented the
      prolongation of the Ca2+ transient observed in hypertrophy and maintained a
      similar SR Ca2+ leak suggesting a compensatory role in Ca2+ regulation in
      hypertrophied cardiac myocytes from transgenic mice. We suggest this compensatory
      effect is mediated by increased SR Ca2+ content and faster Ca2+ removal via the
      Na/Ca exchanger.

PMID- 15193860
TI  - Differential Ca2+ and Sr2+ regulation of intracellular divalent cations release
      in ventricular myocytes.
AB  - The regulation of the Ca2+ -induced Ca2+ release (CICR) from intracellular stores
      is a critical step in the cardiac cycle. The inherent positive feedback of CICR
      should make it a self-regenerating process. It is accepted that CICR must be
      governed by some negative control, but its nature is still debated. We explore
      here the importance of the Ca2+ released from sarcoplasmic reticulum (SR) on the
      mechanisms that may control CICR. Specifically, we compared the effect of
      replacing Ca2+ with Sr2+ on intracellular Ca2+ signaling in intact cardiac
      myocytes as well as on the function of single ryanodine receptor (RyR) Ca2+
      release channels in panar bilayers. In cells, both CICR and Sr2+ -induced Sr2+
      release (SISR) were observed. Action potential induced Ca2+ -transients and
      spontaneous Ca2+ waves were considerably faster than their Sr2+ -mediated
      counterparts. However, the kinetics of Ca2+ and Sr2+ sparks was similar. At the
      single RyR channel level, the affinities of Ca2+ and Sr2+ activation were
      different but the affinities of Ca2+ and Sr2+ inactivation were similar. Fast
      Ca2+ and Sr2+ stimuli activated RyR channels equally fast but adaptation (a
      spontaneous slow transition back to steady-state activity levels) was not
      observed in the Sr2+ case. Together, these results suggest that regulation of the
      RyR channel by cytosolic Ca2+ is not involved in turning off the Ca2+ spark. In
      contrast, cytosolic Ca2+ is important in the propagation global Ca2+ release
      events and in this regard single RyR channel sensitivity to cytosolic Ca2+
      activation, not low-affinity cytosolic Ca2+ inactivation, is a key factor. This
      suggests that the kinetics of local and global RyR-mediated Ca2+ release signals
      are affected in a distinct way by different divalent cations in cardiac muscle
      cells.

PMID- 15193861
TI  - Functional expression of Ca2+ signaling pathways in mouse embryonic stem cells.
AB  - Mouse embryonic stem (mES) cells have the potential to differentiate into all
      types of cells, but the physiological properties of undifferentiated mES cells,
      including Ca2+ signaling systems, are not fully understood. In this study, we
      investigated Ca2+ signaling pathways in mES cells by using confocal Ca2+ imaging
      systems, patch clamp techniques and RT-PCR. The stimulations with ATP and
      histamine (His) induced a transient increase of intracellular Ca2+ concentration
      ([Ca2+]i), which were prevented by the pretreatment of 2-amino-ethoxydiphenyl
      borate (2-APB), a blocker for inositol-1,4,5-triphosphate receptors (InsP3Rs).
      The application of caffeine (Caff) or ryanodine (Ry) did not change [Ca2+]i. When
      stores were depleted with Ca2+ -ATPase blocker, thapsigargin (TG), or histamine,
      the capacitative Ca2+ entry (CCE) was observed. In whole cell patch clamp mode,
      store-operated Ca2+ currents could be recorded in cells treated with histamine
      and thapsigargin. On the other hand, voltage-operated Ca2+ channels (VOCCs) could
      not be elicited. The application of blockers for plasma membrane Ca2+ pump
      (PMCAs) (carboxeosin or caloxin2A1) induced a large increase of [Ca2+]i. When the
      Na+/Ca2+ exchangers (NCXs) were blocked by Na+ free solution or KBR7943, [Ca2+]i
      was also elevated. Using RT-PCR, mRNAs for InsP3Rs type-1, -2, and -3, PMCA-1 and
      -4, NCX-1, -2, and -3 could be detected. From these results, we conclude that
      Ca2+ release from ER is mediated by InsP3Rs in mES cells before differentiation
      and Ca2+ entry through plasma membrane is mainly mediated by the store-operated
      Ca2+ channels (SOCs). For the Ca2+ extrusion systems, both NCXs and PMCAs play
      important roles for maintaining the low level of [Ca2+]i.

PMID- 15193862
TI  - Molecular characterization, functional expression and tissue distribution of a
      second NCKX Na+/Ca2+ -K+ exchanger from Drosophila.
AB  - The Na+/Ca2+ -K+ exchanger (NCKX) utilizes the inward Na+ gradient and the
      outward K+ gradient to promote Ca2+ extrusion from cells. Here, we have
      characterized a second NCKX from Drosophila. Based on its chromosomal location (X
      chromosome) we have named it Ncxk-x. Three splice variants were isolated with
      three distinct N-terminal sequences. NCKX-X differs from NCKX proteins described
      so far in other species by lacking an N-terminal signal peptide. Heterologous
      expression of the respective cDNA's resulted in NCKX-X protein expression and K+ 
      dependent Na+/Ca2+ exchange activity for two of the three splice variants.
      Transcript localization of Nckx-x was investigated and compared with that
      previously described by us for Nckx30C.

PMID- 15193863
TI  - Stimulation of intracellular Ca2+ oscillations by diacylglycerol in human
      myometrial cells.
AB  - Stimulation of G-protein coupled membrane receptors linked to phospholipase C
      results in production of the second messengers diacylglycerol and inositol-1,4,5
      trisphosphate (IP3). IP3 releases Ca2+ from the endoplasmic reticulum, which
      triggers increased Ca2+ influx across the plasma membrane, so-called capacitative
      calcium entry. DAG can also activate plasma membrane calcium-permeable channels
      but the mechanism is still not fully understood. In the pregnant human myometrial
      cell line PHM1 and in primary myometrial cells, 1-oleoyl-2-acetyl-sn-glycerol
      (OAG), a membrane-permeant analogue of diacylglycerol, induced variable
      oscillatory patterns of intracellular free Ca2+. Similar behavior was seen with
      Sr2+ entry. The Ca2+ oscillations were not blocked by a broad spectrum of protein
      kinase C inhibitors, including chelerytrine, bisindolylmaleimide I and calphostin
      C, and were enhanced and prolonged by RHC-80267, an inhibitor of diacylglycerol
      lipase. The OAG-induced oscillatory response was not dependent on Ca2+ release
      from the endoplasmic reticulum but required extracellular Ca2+. Our results
      indicate that diacylglycerol directly activates cation channels in PHM1 and
      primary myometrial cells and promotes intracellular Ca2+ oscillations by actions
      independent of intracellular Ca2+ -ATPase activity and protein kinase C
      involvement.

PMID- 15193864
TI  - Nitric oxide relaxes rat tail artery smooth muscle by cyclic GMP-independent
      decrease in calcium sensitivity of myofilaments.
AB  - The effects of authentic nitric oxide (NO, 10(-6) M) and NO-donors such as sodium
      nitroprusside (SNP, 10(-5) M) and glyceryl trinitrate (GTN, 10(-4) M) on
      contractile force and free intracellular calcium level ([Ca2+]i) were studied on
      precontracted with high potassium chloride (KCl, 70 mM) isolated rings of rat
      tail artery. The sensitivity of contractile myofilaments to Ca2+ was measured
      using chemically permeabilized (alpha-toxin, beta-escin, Triton X-100) vascular
      rings. [Ca2+]i and contractile activity were measured simultaneously. The
      relationship of [Ca2+]i and tension developed was studied in endothelium-denuded
      rings and controlled calcium response was evaluated in both endothelium-denuded
      and permeabilized vascular rings. Both authentic NO and NO-donors decreased
      [Ca2+]i and high potassium-induced tension with a different time course.
      Inhibitor of soluble guanylyl cyclase (sGC) LY83583 (10(-5) M) did not affect SNP
      induced relaxation whereas the other sGC inhibitor ODQ (10(-6) M) attenuated SNP
      induced relaxation. Both inhibitors had no effect on NO- and SNP-induced
      reduction in [Ca2+]i. On the contrary, GTN induced neither relaxation nor
      decrease in [Ca2+]i on application of both LY83583 and ODQ. Tail artery rings
      permeabilized with alpha-toxin, beta-escin, but not with Triton X-100 were
      relaxed by authentic NO and NO-donors, but to a less extent than non
      permeabilized rings. Dithioerythritol (DTE, 5 x 10(-3) M) that maintains
      sulfhydryl (SH) groups in reduced state preventing their nitrosylation attenuated
      NO-induced relaxation in both non-permeabilized and permeabilized tail artery
      rings. The cyclic heptapeptide mycrocystin-LR (MC-LR) (10(-5) M), an inhibitor of
      type 1 and 2A phosphatases, induced sustained increase in tension of beta-escin
      permeabilized rings in low Ca2+ (10(-8) M) solution. The tension was not affected
      by authentic NO and SNP. We conclude that authentic NO and SNP relax rat tail
      artery smooth muscle (SM) in the presence of inhibitors of sGC via cyclic
      guanosine monophosphate (cGMP)-independent pathway, whereas relaxation induced by
      GTN is inhibited. The data demonstrate that cGMP-dependent pathway in vascular
      smooth muscle is ubiquitous, but not the only way of relaxation induced by NO. NO
      can modulate vascular tone directly by reducing sensitivity of contractile
      myofilaments to [Ca2+]i and may involve activation of protein phosphatase(s).

PMID- 15193865
TI  - Progesterone inhibits capacitative Ca2+ entry in Jurkat T lymphocytes by a
      membrane delimited mechanism, independently of plasma membrane depolarization.
AB  - The non-genomic inhibitory effect of progesterone on capacitative calcium entry
      was studied in Jurkat T lymphocytes. Capacitative calcium entry was induced by
      depleting intracellular calcium stores with thapsigargin and evaluated by a
      calcium free/calcium readmission protocol, in Fura-2 loaded cells. Progesterone
      (10-40 microg/ml) inhibited calcium entry and concomitantly depolarized cells, as
      revealed by measuring the plasma membrane potential with the fluorescent probe
      bis-oxonol. However, experiments run under depolarizing conditions (i.e. by
      substituting for Na+ with K+ ions in the medium) revealed that progesterone (10
      40 microg/ml) could inhibit capacitative calcium entry independently of plasma
      membrane depolarization. The direct inhibition of calcium entry by progesterone
      was: (i) reverted by a treatment suitable to remove progesterone bound to cell
      surface, (ii) apparently related to the extent of membrane bound progesterone
      (measured radioisotopically), and (iii) specific, in that other related steroid
      compounds did not inhibit calcium entry.

PMID- 15193866
TI  - Gap junctions are required for trophoblast proliferation in early human placental
      development.
AB  - Little is known about the role of gap junctional intercellular communication
      (GJIC) in human trophoblast differentiation, particularly during the formation of
      extravillous trophoblast (EVT) cell columns and their subsequent differentiation
      into invasive cells. We have identified transcripts for five connexin gap
      junction proteins in the early human placenta (Cx32, Cx37, Cx40, Cx43 and Cx45).
      Of these, Cx40 and Cx45 proteins immunolocalize to EVT in anchoring cell columns.
      Cx40 expression is prominent in the anchoring column throughout the first
      trimester of pregnancy (6-14 weeks gestation). We used first trimester placental
      villous explant cultures to determine the functional significance of the
      inhibition of GJIC in EVT cell proliferation and differentiation using two known
      GJIC inhibitors, carbenoxolone (CBX) and heptanol. The morphology of EVT
      outgrowths changed dramatically upon GJIC-blockade, from compact and organized
      outgrowths into a scattered group of rounded individual trophoblast cells,
      reminiscent of an early invasive phenotype. Furthermore, the inhibition of GJIC
      in placental explants by CBX or heptanol induced a switch away from the
      proliferative and towards an invasive EVT phenotype, as evident from (a) the loss
      of the proliferation marker Ki67 and (b) an increase in the invasive marker
      alpha1 integrin. We also utilized antisense oligonucleotides to inhibit Cx40
      protein expression in placental explants. Cx40 antisense treatment also resulted
      in the abolishment of outgrowth EVT cell proliferation (as determined by Ki67
      immunostaining). Together, these results suggest that gap junctions composed
      particularly of Cx40 channels are required for the proliferation of EVT cells in
      anchoring cell columns, and that a loss of GJIC contributes to differentiation to
      the invasive EVT phenotype.

PMID- 15193868
TI  - Eph and ephrin expression in normal placental development and preeclampsia.
AB  - Eph receptors and their ephrin ligands play a fundamental role in embryogenesis.
      Their functions include cell targeting and angiogenesis. In placental
      development, trophoblasts migrate and invade maternal tissue and spiral arteries,
      where they play a role in both anchoring the placenta to the uterus and
      increasing blood flow to the developing fetus (interstitial and endovascular
      invasions). We investigated the cellular distribution and expression patterns of
      representative Eph and ephrin RNA and protein in an effort to identify the
      molecules involved in trophoblast migration during normal placental development
      and placental pathologies. We found ephrin-A1 expressed exclusively in the
      invasive extravillous trophoblast (EVT) cell lineage. We therefore proceeded to
      investigate ephrin-A1 in placental pathologies with defects in EVT invasion. In
      preeclampsia, where trophoblast invasion is shallow, we observed ephrin-A1
      expression similar to normal placenta. Furthermore, in initial experiments on the
      deeply invading trophoblasts of placenta accreta, which lacks decidua, ephrin-A1
      is found to be expressed highly in extravillous trophoblasts that have invaded
      the myometrium. In addition, we found the prototype ephrin-A1 receptor, EphA2,
      localized in several placental cell types. EphB4 and ephrin-B2 molecules, which
      have specific expression patterns during artery and vein development,
      respectively, were also expressed in the placenta. The cell specific distribution
      of ephrin-A1 suggests that it may play a role in targeting and migration of
      trophoblasts, and in the vascular remodeling induced by the invading extravillous
      trophoblasts. Failure of ephrin-A1 expression is unlikely to be the primary cause
      in defective migration of trophoblasts observed in preeclampsia. Specific roles
      for other Eph and ephrin proteins remain to be investigated.

PMID- 15193867
TI  - Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection
      in human body fluids in normal and pathological pregnancies.
AB  - Placental tissue protein 13 (PP-13), one of the 56 known placental proteins
      identified till today, was purified from placentas obtained from women at
      delivery, and used to evoke antibodies against it. The purified PP-13 was lysed
      to peptides, which were sequenced, leading to the full-length cDNA sequencing and
      its expression in Escherichia coli. Sequence analysis in databases showed
      homology to the galectin family. Of the various antibody preparations developed,
      a pair of monoclonal antibodies (MAbs) coupled to the recombinant PP-13 (PP-13-R)
      was used for the immunodetection of PP-13 in pregnant women's serum with the
      solid-phase ELISA format. With a dynamic range of 25-500 pg/mL with no background
      in non-pregnant women's serum and men's serum, the ELISA test was suitable for
      the detection of PP-13 in the 1st, 2nd, and 3rd trimesters. PP-13 levels slowly
      increase during pregnancy. In the 1st trimester, lower than normal PP-13 levels
      were found in fetal growth restriction (IUGR), preeclampsia (PE), and
      particularly in early PE (<34 weeks of gestation). In the 2nd and 3rd trimesters,
      higher than normal concentrations were found in PE, IUGR and in preterm delivery
      (PTD). Application of PP-13 to cultured trophoblasts elicited depolarization
      carried by calcium ions, followed by liberation of linoleic and arachidonic acids
      from the trophoblast membrane, and a subsequent elevation of prostacyclin and
      thromboxane. These effects were negligible when PP-13 derived from the placentas
      of patients with IUGR, PE or PTD was used. The results are discussed in view of
      the potential utilization of PP-13 for early serum screening to assess the risk
      to develop placental insufficiency, coupled to a differential analysis of the
      various pathologies by analyzing cultured trophoblasts.

PMID- 15193869
TI  - Raised prorenin and renin concentrations in pre-eclamptic placentae when measured
      after acid activation.
AB  - AIM: The aim of the study was to ascertain if there was any difference in the
      levels of prorenin and active renin between pre-eclamptic and normotensive feto
      placental tissues. METHODS: Supernatants of homogenates from fresh, vaginally
      delivered placentae from 15 normotensive and 15 pre-eclamptic women were measured
      for renin concentration (RC), prorenin concentration and renin activity (RA). RA
      and RC were measured in the absence and presence of nephrectomised sheep plasma,
      respectively. Prorenin was estimated as the difference between renin
      concentration in the sample before and after acid activation. All concentrations
      are expressed as rate of angiotensin generation (ng/ml/h). Angiotensin I was
      measured by radioimmunoassay. Statistical analysis was performed using Student's
      't' test for unpaired samples. All results are presented as mean+/-SEM. RESULTS:
      The concentrations of renin and prorenin were highest in the chorion laeve when
      compared to amnion and placenta (p < 0.01) in both the groups. Furthermore, the
      concentrations of renin and prorenin were significantly higher in all the tissues
      from women with pre-eclampsia (p < 0.01). CONCLUSION: Renin and prorenin levels
      are raised in the placental tissues from women with pre-eclampsia. With recent
      evidence suggesting that both prorenin and renin may have cellular effects
      independent of angiotensin II generation, there is a need for further study into
      its role in placentation.

PMID- 15193870
TI  - Study on the expression of angiotensin II (ANG II) receptor subtype 1 (AT1R) in
      the placenta of pregnancy-induced hypertension.
AB  - OBJECTIVE: To study the expression of angiotensin II (ANG II) receptor subtype 1
      (AT(1)R) in the human placenta with pregnancy-induced hypertension (PIH).
      METHODS: Immunohistochemistry was used to detect the expression of AT(1)R in
      placental tissues of 30 patients with PIH and 10 patients with normal pregnancies
      (control group). The PIH tissues were further divided into 3 groups: mild PIH
      group, moderate PIH group and severe PIH group. Each group consisted of 10
      patients. A high-resolution pathological image analysis system (HPIAS-1000) was
      used to determine the quantity of AT(1)R expression. RESULTS: The integral
      optical density and area of staining in the syncytiotrophoblast (STB) layer and
      villous endothelium of the placenta were significantly increased in PIH patients,
      in the moderate and severe PIH groups, as compared with the control group (P <
      0.05), indicating that the expression of AT(1)R was highly increased in PIH.
      However, there was no significant difference between normal pregnancy and the
      mild PIH group (P > 0.05). Furthermore, statistically significant differences in
      AT(1)R expression were observed between mild, moderate and severe PIH groups (P <
      0.05). CONCLUSION: The expression of AT(1)R is statistically significantly
      increased in the STB layer and villous endothelium of human placenta with PIH.
      Expression increases with the severity of the disease. Increased expression may
      be involved in the pathogenesis of PIH.

PMID- 15193871
TI  - Histologic features of placentas and abortion specimens from women with
      antiphospholipid and antiphospholipid-like syndromes.
AB  - OBJECTIVE: Antiphospholipid syndrome is characterized by recurrent pregnancy
      loss, thrombosis, and antiphospholipid antibodies. However, some women with
      clinical features of antiphospholipid syndrome test negative for antiphospholipid
      antibodies ("antiphospholipid-like syndrome"). Women with antiphospholipid and
      antiphospholipid-like syndromes have serum immunoglobulin G that harms murine
      pregnancy, suggesting that the mechanisms of fetal death may be similar in both
      groups. The objective of our study was to determine whether patients with
      antiphospholipid and antiphospholipid-like syndromes share pathophysiology by
      comparing the histology of gestational tissues from these groups. METHODS:
      Placenta and abortion specimens were obtained from 44 pregnancies in 26 women
      with antiphospholipid syndrome and 37 pregnancies in 21 women with
      antiphospholipid-like syndrome. Of these, 16 pregnancies with antiphospholipid
      syndrome and 8 with antiphospholipid-like syndrome were treated with a variety of
      medications intended to improve pregnancy outcome. Placentas from 31 elective
      pregnancy terminations and 40 pregnancies complicated by idiopathic preterm
      delivery served as an additional control group. Twenty histologic parameters were
      systematically assessed by a single investigator who was blinded to the clinical
      status of the specimens. Histopathologic findings were compared among groups
      using multivariate logistic regression analysis. RESULTS: Antiphospholipid
      syndrome pregnancies included 15 spontaneous abortions, 13 fetal deaths, and 16
      live births. Pregnancies in the antiphospholipid-like syndrome group resulted in
      5 spontaneous abortions, 30 fetal deaths, and one live birth. Gestational tissues
      from antiphospholipid and antiphospholipid-like syndrome pregnancies were similar
      for every histologic feature tested. Decidua from women with both
      antiphospholipid and antiphospholipid-like syndromes had more necrosis, acute and
      chronic inflammation, and vascular thrombus compared to controls. Placental
      tissue from antiphospholipid and antiphospholipid-like syndrome pregnancies
      showed more infarction, intravascular fibrin deposition, syncytial knot
      formation, and fibrosis than controls. Histologic features were variable within
      groups. There were no histologic differences in tissues from live births and
      pregnancy losses, or in treated and untreated pregnancies. CONCLUSIONS: Placental
      histopathology is similar in antiphospholipid and antiphospholipid-like syndrome
      pregnancies, suggesting that these disorders may share pathophysiology.
      Histologic findings in women with APS are non-specific and may not differentiate
      between women with APS and APS-like syndromes.

PMID- 15193872
TI  - Placental glycosylation in peccary species and its relation to that of swine and
      dromedary.
AB  - Comparison has been made between glycans at the fetomaternal interface of two
      Tayassu species (New World peccaries or wild pigs) and those of swine (true pigs)
      and dromedary, which have similar epitheliochorial placentae. Plastic sections of
      near-term fetomaternal interface from Tayassu tajacu (120 days gestation) and
      Tayassu pecari (140 days gestation) were stained with 20 lectins and compared
      with those of swine (109 days) and dromedary (375 days). Both Tayassu species
      showed similar staining characteristics, which differed only slightly from those
      of the swine. Most differences were quantitative rather than qualitative, except
      for binding of Arachis hypogaea lectin to terminal beta-galactose which was
      absent in swine uterine epithelium though present in both Tayassu species, and
      binding of Sambucus nigra lectin to sialic acid which was absent in swine
      epithelium and trophoblast though present in Tayassu. Glycosylation of the
      dromedary fetomaternal interface showed, in contrast, significant differences
      compared to Tayassu and swine, particularly regarding fucosyl, sialyl and
      terminal galactosyl residues. Despite a divergence of between 33 million and 37
      million years between true pigs and peccaries, glycosylation of the fetomaternal
      interface has remained similar, with most of the observed changes affecting
      terminal structures. The dromedary has an epitheliochorial placenta with a
      similar architecture, but different glycan expression, suggesting modification of
      glycosyl transferases with evolution. These data contain clues to changes of
      glycosyl transferase activity that accompany speciation.

PMID- 15193873
TI  - Ontogeny of StAR and ACTH-R genes in ovine placenta.
AB  - It has been demonstrated that the ovine placenta secretes estrogen, progesterone
      and cortisol, and that plasma concentrations of estrogen and cortisol increase
      before birth. Among the elements important for steroid production is
      steroidogenic acute regulatory protein (StAR) which acutely delivers cholesterol
      from the outer to the inner mitochondrial membrane for rapid steroidogenesis.
      This study was designed to determine if StAR is present in ovine placenta, and if
      its expression changes during fetal development. In addition, because cortisol is
      secreted by the placenta, we also examined the expression of adrenocorticotropic
      hormone receptor (ACTH-R) to determine if it was present and if the pattern of
      expression changed as gestation proceeded. The mRNA levels for StAR and ACTH-R
      were assessed by RNase protection assay (RPA) and protein levels were measured by
      Western blot in placentas from pregnant ewes (100-105 days of gestation, n = 8;
      120 days of gestation, n = 5; 135-142 days of gestation, n = 8). The data show
      that the ovine placenta expresses StAR and ACTH-R. There was a significant
      increase in the StAR mRNA and protein between 100 and 142 days of gestation, but
      there were no significant age-related changes in ACTH-R mRNA and protein levels.
      The data suggest that the increased steroid production by the placenta in late
      gestation may be related to the increased expression of StAR.

PMID- 15193874
TI  - Derivation of rate of arterio-arterial anastomotic transfusion between
      monochorionic twin fetuses by Doppler waveform analysis.
AB  - We aimed to determine rates of interfetal transfusion along arterio-arterial (AA)
      anastomoses in monochorionic twins in vivo from analysis of Doppler waveform
      patterns. Twenty-one monochorionic twin pregnancies in which an AA anastomosis
      was identified antenatally underwent serial Doppler velocimetry. Unidirectional
      AA anastomotic flow rates increased with increasing gestational age (log y = 8 x
      10(-9)x - 5 x 10(-8); p = 0.0002). The mean net rate of flow through an AA
      anastomosis at 28 weeks gestation was 7.6 x 10(-8) l/s (SD = 4.9 x 10(-8) l/s).
      This flow was significantly related to the distribution of arterio-venous (AV)
      anastomoses (p = 0.009) and birthweight discordancy (p = 0.006). We derived
      estimates of flow along individual AV anastomoses by assuming that net AA
      countertransfusion is shared equally among uncompensated AV anastomoses, and
      speculate that the median AV flow rate at 28 weeks is in the order of 6 x 10(-8)
      l/s. In conclusion, this study demonstrates that flow rates along AA anastomoses
      can be quantified antenatally. These are the first estimates of flow rates in
      vivo along placental anastomoses. Although AA net flows are modest, chronic
      unbalanced counterflow of this magnitude in the absence of compensatory
      superficial anastomoses could lead to significant haemodynamic compromise.

PMID- 15193875
TI  - Mesenchymal dysplasia of the placenta.
AB  - Placental mesenchymal dysplasia is a rare human placental disorder in which the
      placenta is enlarged and contains cystic villi and dilated vasculature. It is
      important to recognize this disorder because it may mimic a partial hydatidiform
      mole. In contrast to a partial mole, mesenchymal dysplasia may coexist with a
      normal fetus. This case occurred at the Madigan Army Medical Center in Tacoma,
      Washington, in June 2002.

PMID- 15193876
TI  - Low temperature formation of hydroxyapatite-poly(alkyl oxybenzoate)phosphazene
      composites for biomedical applications.
AB  - The formation of biodegradable composites which may be suitable as bone analogs
      is described. Polyphosphazene-hydroxyapatite (HAp) composites were produced via
      an acid-base reaction of tetracalcium phosphate and anhydrous dicalcium phosphate
      in the presence of polyphosphazenes bearing alkyl ester containing side-groups.
      The polyphosphazenes used were poly(ethyl oxybenzoate)phosphazene (PN-EOB) and
      poly(propyl oxybenzoate) phosphazene (PN-POB). The effects of temperature and the
      proportions of polymers, PN-EOB and PN-POB on the kinetics, reaction chemistry
      and phase evolution during the formation of stoichiometric HAp were studied.
      Kinetics, phase evolution and microstructural development were evaluated using
      isothermal calorimetry, X-ray diffraction and scanning electron microscopy,
      respectively. Analysis of solution chemistry revealed that the increases in the
      pH during the formation of SHAp, resulted in partial hydrolysis of the polymer
      surfaces, which led in turn to the formation of a calcium cross-linked polymer
      surface. The calcium cross-linked polymer surface appeared to facilitate the
      nucleation and growth of apatite deposits on the polymer. The current study
      illustrates the in situ formation of HAp in the presence of polyphosphazenes,
      where HAp is chemically bonded to the polymer.

PMID- 15193877
TI  - Comparison of metal release from various metallic biomaterials in vitro.
AB  - To investigate the metal release of each base and alloying elements in vitro,
      SUS316L stainless steel, Co-Cr-Mo casting alloy, commercially pure Ti grade 2,
      and Ti-6Al-4V, V-free Ti-6Al-7Nb and Ti-15Zr-4Nb-4Ta alloys were immersed in
      various solutions, namely, alpha-medium, PBS(-), calf serum, 0.9% NaCl,
      artificial saliva, 1.2 mass% L-cysteine, 1 mass% lactic acid and 0.01 mass% HCl
      for 7d. The difference in the quantity of Co released from the Co-Cr-Mo casting
      alloy was relatively small in all the solutions. The quantities of Ti released
      into alpha-medium, PBS(-), calf serum, 0.9% NaCl and artificial saliva were much
      lower than those released into 1.2% L-cysteine, 1% lactic acid and 0.01% HCl. The
      quantity of Fe released from SUS316L stainless steel decreased linearly with
      increasing pH. On the other hand, the quantity of Ti released from Ti materials
      increased with decreasing pH, and it markedly attenuated at pHs of approximately
      4 and higher. The quantity of Ni released from stainless steel gradually
      decreased with increasing pH. The quantities of Al released from the Ti-6Al-4V
      and Ti-6Al-7Nb alloys gradually decreased with increasing pH. A small V release
      was observed in calf serum, PBS(-), artificial saliva, 1% lactic acid, 1.2% l
      cysteine and 0.01% HCl. The quantity of Ti released from the Ti-15Zr-4Nb-4Ta
      alloy was smaller than those released from the Ti-6Al-4V and Ti-6Al-7Nb alloys in
      all the solutions. In particular, it was approximately 30% or smaller in 1%
      lactic acid, 1.2% L-cysteine and 0.01% HCl. The quantity of (Zr + Nb + Ta)
      released was also considerably lower than that of (Al + Nb) or (Al + V) released.
      Therefore, the Ti-15Zr-4Nb-4Ta alloy with its low metal release in vitro is
      considered advantageous for long-term implants.

PMID- 15193878
TI  - Biological performance of uncoated and octacalcium phosphate-coated Ti6Al4V.
AB  - The in vivo behavior of a porous Ti6Al4V material that was produced by a positive
      replica technique, with and without an octacalcium phosphate (OCP) coating, has
      been studied both in the back muscle and femur of goats. Macro- and microporous
      biphasic calcium phosphate (BCP) ceramic, known to be both osteoconductive and
      able to induce ectopic bone formation, was used for comparison purpose. The three
      groups of materials (Ti6Al4V, OCP Ti6Al4V and BCP) were implanted transcortically
      and intramuscularly for 6 and 12 weeks in 10 adult Dutch milk goats in order to
      study their osteointegration and osteoinductive potential. In femoral defects,
      both OCP Ti6Al4V and BCP were performing better than the uncoated Ti6Al4V, at
      both time points. BCP showed a higher bone amount than OCP Ti6Al4V after 6 weeks
      of implantation, while after 12 weeks, this difference was no longer significant.
      Ectopic bone formation was found in both OCP Ti6Al4V and BCP implants after 6 and
      12 weeks. The quantity of ectopically formed bone was limited as was the amount
      of animals in which the bone was observed. Ectopic bone formation was not found
      in uncoated titanium alloy implants, suggesting that the presence of calcium
      phosphate (CaP) is important for bone induction. This study showed that CaPs in
      the form of coating on metal implants or in the form of bulk ceramic have a
      significantly positive effect on the bone healing process.

PMID- 15193879
TI  - Mesoscopic spatial designs of nano- and microfiber meshes for tissue-engineering
      matrix and scaffold based on newly devised multilayering and mixing
      electrospinning techniques.
AB  - To design a mesoscopically ordered structure of the matrices and scaffolds
      composed of nano- and microscale fiber meshes for artificial and tissue
      engineering devices, two new electrospinning techniques are proposed:
      multilayering electrospinning and mixing electrospinning. First, the following
      four kinds of component polymers were individually electrospun to determine the
      conditions for producing stable nano- and microfibers by optimizing the
      formulation parameters (solvent and polymer concentration) and operation
      parameters (voltage, air gap, and flow rate) for each polymer: (a) type I
      collagen, (b) styrenated gelatin (ST-gelatin), (c) segmented polyurethane (SPU),
      and (d) poly(ethylene oxide). A trilayered electrospun mesh, in which individual
      fiber meshes (type I collagen, ST-gelatin, and SPU) were deposited layer by
      layer, was formed by sequential electrospinning; this was clearly visualized by
      confocal laser scanning microscopy. The mixed electrospun-fiber mesh composed of
      SPU and PEO was prepared by simultaneous electrospinning on a stainless-steel
      mandrel with high-speed rotation and traverse movement. A bilayered tubular
      construct composed of a thick SPU microfiber mesh as an outer layer and a thin
      type I collagen nanofiber mesh as an inner layer was fabricated as a prototype
      scaffold of artificial grafts, and visualized by scanning electron microscopy.

PMID- 15193880
TI  - Neurite outgrowth on well-characterized surfaces: preparation and
      characterization of chemically and spatially controlled fibronectin and RGD
      substrates with good bioactivity.
AB  - Study of axonal growth and ligand-receptor interactions requires specificity and
      careful characterization of the biomaterial substrates to which the neurons bind.
      It would be impossible to predict the effects of important variables such as
      composition, surface density, spatial distribution, and conformation of the
      ligands on axonal growth of a neuron without highly specific surface
      characterization. Here, we compare two methods of surface modification (hereafter
      referred to as "Heterobifunctional Crosslinker" and "Pluronics" methods) used for
      immobilization of fibronectin (FN) and FN-derived, RGD-containing peptides to the
      substrates. We also characterized their performance in neurite outgrowth
      experiments. Various surface analytical techniques such as contact angle
      measurement, XPS, and time-of-flight secondary ion mass spectrometry (TOF-SIMS)
      were used for the analysis of the substrates at each step of the two different
      chemistries involved. FN-patterned surfaces were created by micro-contact
      printing methods and confirmed by imaging TOF-SIMS, and AFM techniques. After
      immobilization of FN and/or FN-derived RGD-containing peptide, including the
      formation of micron-scale patterns of FN, the modified surfaces were plated with
      neurons from postnatal rat dorsal root ganglia (DRG) and incubated in serum-free
      medium. Both the peptide- and/or protein-modified substrates supported
      significantly greater neurite outgrowth than controls, and outgrowth on both
      substrate chemistries was inhibited by the addition of soluble RGD peptide.
      Patterned FN surfaces were successful in spatially controlling the neuron
      attachment and outgrowth.

PMID- 15193881
TI  - The effect of PEGT/PBT scaffold architecture on the composition of tissue
      engineered cartilage.
AB  - A highly interconnecting and accessible pore network has been suggested as one of
      a number of prerequisites in the design of scaffolds for tissue engineering. In
      the present study, two processing techniques, compression-molding/particulate
      leaching (CM), and 3D fiber deposition (3DF), were used to develop porous
      scaffolds from biodegradable poly(ethylene glycol)-terephthalate/poly(butylene
      terephthalate) (PEGT/PBT) co-polymers with varying pore architectures. Three
      dimensional micro-computed tomography (microCT) was used to characterize scaffold
      architectures and scaffolds were seeded with articular chondrocytes to evaluate
      tissue formation. Scaffold porosity ranged between 75% and 80%. Average pore size
      of tortuous CM scaffolds (182 microm) was lower than those of organized 3DF
      scaffolds (525 microm). The weight ratio of glycosaminoglycans (GAG)/DNA, as a
      measure of cartilage-like tissue formation, did not change after 14 days of
      culture whereas, following subcutaneous implantation, GAG/DNA increased
      significantly and was significantly higher in 3DF constructs than in CM
      constructs, whilst collagen type II was present within both constructs. In
      conclusion, 3DF PEGT/PBT scaffolds create an environment in vivo that enhances
      cartilaginous matrix deposition and hold particular promise for treatment of
      articular cartilage defects.

PMID- 15193882
TI  - Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration
      by a PLA-PEG/hydroxyapatite composite.
AB  - Bone morphogenetic proteins (BMPs) are biologically active molecules capable of
      inducing new bone formation, and show potential for clinical use in bone defect
      repair. However, an ideal system for delivering BMPs that can potentiate their
      bone-inducing ability and provide initial mechanical strength and scaffold for
      bone ingrowth has not yet been developed. In this study, to construct a
      carrier/scaffold system for BMPs, we combined two biomaterials: interconnected
      porous calcium hydroxyapatite ceramics (IP-CHA), and the synthetic biodegradable
      polymer poly D,L,-lactic acid-polyethyleneglycol block co-polymer (PLA-PEG). We
      used a rabbit radii model to evaluate the bone-regenerating efficacy of rhBMP
      2/PLA-PEG/IP-CHA composite. At 8 weeks after implantation, all bone defects in
      groups treated with 5 or 20 microg of BMP were completely repaired with
      sufficient strength. Furthermore, using this carrier scaffold system, we reduced
      the amount of BMP necessary for such results to about a tenth of the amount
      needed in previous studies, probably due to the superior osteoconduction ability
      of IP-CHA and the optimal drug delivery system provided by PLA-PEG, inducing new
      bone formation in the interconnected pores. The present findings indicate that
      the synthetic biodegradable polymer/IP-CHA composite is an excellent combination
      carrier/scaffold delivery system for rhBMP-2, and that it strongly promotes the
      clinical effects of rhBMP-2 in bone tissue regeneration.

PMID- 15193883
TI  - Tissue response of defined collagen-elastin scaffolds in young and adult rats
      with special attention to calcification.
AB  - Collagen-elastin scaffolds may be valuable biomaterials for tissue engineering
      because they combine tensile strength with elasticity. In this study, the tissue
      response to and the calcification of these scaffolds were evaluated. In
      particular, the hypothesis was tested that calcification, a common phenomenon in
      biomaterials, may be due to microfibrils within the elastic fibre, and that these
      microfibrils might generate a tissue response. Four scaffolds were subcutaneously
      implanted, viz. collagen, collagen + pure elastin, collagen+microfibril
      containing, and collagen + pulverised elastic ligament (the source for elastin).
      Explants were evaluated at day 3, 7 and 21. In young Sprague Dawley rats,
      collagen + ligament calcified substantially, whereas collagen + elastin (with and
      without microfibrils) calcified less, and collagen did not. Calcification started
      at elastic fibres. In both Sprague Dawley and Wistar adult rats, however, none of
      the scaffolds calcified. Mononuclear cell infiltration was prominent in young and
      adult Sprague Dawley rats. In adult Wistar rats, this infiltration was associated
      with the presence of microfibrils. Degradation of scaffolds and new matrix
      formation were related with cellular influx and degree of vascularisation. In
      conclusion, absence of microfibrils from the elastic fibre does not prevent
      calcification in young Sprague Dawley rats, but does reduce the tissue response
      in adult Wistar rats. Cellular response and calcification differs with age and
      strain and therefore the choice of animal model is of key importance in
      biomaterial evaluation.

PMID- 15193884
TI  - Inkjet printing of viable mammalian cells.
AB  - The purpose of this study was to explore the use of a commercial thermal printer
      to deposit Chinese Hamster Ovary (CHO) and embryonic motoneuron cells into pre
      defined patterns. These experiments were undertaken to verify the
      biocompatibility of thermal inkjet printing of mammalian cells and the ability to
      assemble them into viable constructs. Using a modified Hewlett Packard (HP) 550C
      computer printer and an HP 51626a ink cartridge, CHO cells and rat embryonic
      motoneurons were suspended separately in a concentrated phosphate buffered saline
      solution (3 x). The cells were subsequently printed as a kind of "ink" onto
      several "bio-papers" made from soy agar and collagen gel. The appearance of the
      CHO cells and motoneurons on the bio-papers indicated an healthy cell morphology.
      Furthermore, the analyses of the CHO cell viability showed that less than 8% of
      the cells were lysed during printing. These data indicate that mammalian cells
      can be effectively delivered by a modified thermal inkjet printer onto biological
      substrates and that they retain their ability to function. The computer-aided
      inkjet printing of viable mammalian cells holds potential for creating living
      tissue analogs, and may eventually lead to the construction of engineered human
      organs.

PMID- 15193885
TI  - Hydrogen embrittlement of work-hardened Ni-Ti alloy in fluoride solutions.
AB  - Hydrogen embrittlement of work-hardened Ni-Ti alloy has been examined in
      acidulated phosphate fluoride (APF) solutions. Upon immersion in a 2.0% APF
      solution with a pH of 5.0, tensile strength decreased markedly with immersion
      time. Moreover, the fracture mode changed from ductile to brittle due to brittle
      layer formation at the peripheral part of the cross section of the specimen. The
      amount of absorbed hydrogen increased linearly with immersion time, and it
      reached above 5000 mass ppm after 24 h. The hydrogen desorption temperature of
      the immersed specimens shifted from 450 degrees C to a lower temperature with
      immersion time. As the amount of absorbed hydrogen was larger than 500 mass ppm,
      the degradation of mechanical properties was recognized. Although the tensile
      properties and fracture mode scarcely change in a 0.2% APF solution, the slight
      reduction in hardness and hydrogen absorption of several hundreds mass ppm were
      observed. The results of the present study imply that work-hardened Ni-Ti alloy
      is less sensitive to hydrogen embrittlement compared with Ni-Ti superelastic
      alloy.

PMID- 15193886
TI  - Microspheres of corn protein, zein, for an ivermectin drug delivery system.
AB  - A novel microsphere drug delivery system of ivermectin (IVM) using hydrophobic
      protein zein was prepared by the phase separation method and characterized by a
      scanning electron microscope and laser light scattering particle size analyzer.
      Releases of model drug IVM from zein microspheres, tabletted microspheres and
      pepsin degradation of tabletted microspheres were also performed in vitro to
      investigate the mechanism of model drug release. The results show that the zein
      microspheres and tabletted microspheres are suitable for use as a sustained
      release form of IVM. The microspheres may also be useful in drug targeting system
      since the diameter of the microspheres is appropriate for phagocytosis by
      macrophages. Moreover, the release of IVM from enzymatic degraded tabletted
      microspheres shows a zero-order release, implying a potential application in
      tissue engineering for preparing scaffold, which is composed of microspheres
      encapsulating bioactive components for stimulating cell differentiation and
      proliferation.

PMID- 15193887
TI  - A survey of women regarding factors affecting colorectal cancer screening
      compliance.
AB  - BACKGROUND: Women participate in colorectal cancer (CRC) screening less often
      than men. Our study objective was to understand factors related to women's use of
      CRC screening. We examined the personal health, medical care, and psychosocial
      responses to CRC and screening use of a community-based sample of women. METHODS:
      Women aged 50-80 years at average CRC risk completed a telephone questionnaire.
      We asked about demographics, past use of CRC and other cancer screening tests,
      preventive health measures, source of primary care, and comorbidities. We also
      inquired about attitudes and risk perceptions regarding CRC, knowledge about CRC
      screening, and other frequent health concerns. Logistic regression identified
      predictors of screening compliance. RESULTS: Four hundred six women (52% of women
      contacted, average age 63 years) provided responses. Sixty-five percent had
      completed some form of CRC screening in the past 5 years. Four factors were
      positively related to CRC screening: increasing age [adjusted odds ratio (AOR) =
      1.05, (95% CI 1.03, 1.08)], perceived CRC risk [AOR = 1.92, (95% CI 1.19, 3.16)],
      belief that screening reduces CRC risk (AOR = 2.49, 95% CI 1.45, 4.27), and
      belief in following screening guidelines [AOR = 4.95, (95% CI 2.07, 11.90)].
      Belief that screening would be painful [AOR = 0.52, (95% CI 0.32, 0.84)] was
      inversely related. CONCLUSIONS: Fear about CRC screening-related pain was the
      strongest impediment to screening, whereas positive attitudes about the value of
      CRC screening were strongly related to compliance. Addressing fears and
      emphasizing positive messages by providers should be included in programs
      promoting CRC screening in women.

PMID- 15193888
TI  - Community-based cancer screening programs in older populations: making progress
      but can we do better?
AB  - BACKGROUND: Older individuals have higher rates of most types of cancer.
      Community-based cancer screening programs offer one avenue for addressing the
      need to prevent or detect cancers in early stages in this population. Identifying
      characteristics of successful interventions can assist researchers in the
      development of future studies. METHODS: A comprehensive literature review of
      community-based cancer screening interventions was undertaken and 114 behavioral
      interventions for breast, cervical and colorectal cancer screening published
      prior to 2000 and 42 studies published during 2000-2003 were identified. From
      these, 17 studies were identified as model interventions that were effective in
      significantly increasing screening rates among older populations. RESULTS:
      Effective interventions employed a variety of strategies including the use of
      social networks and lay health care workers, mass media, community-based
      education, reminder notices/behavioral cues, and health care provider assistance.
      CONCLUSION: Although subgroups of individuals still have lower rates of
      screening, the results indicate that older populations can be encouraged to
      engage in appropriate cancer screening behaviors through community-based
      interventions. The next round of interventions could be strengthened by
      evaluating intervention components, integrating theory and community
      participation into designs, focusing on those most at need, and considering
      program sustainability and costs.

PMID- 15193889
TI  - Short- and long-term effects of tailored information versus general information
      on determinants and intentions related to early detection of cancer.
AB  - BACKGROUND: Since it is widely accepted that the earlier cancer is detected, the
      better the chances of treatment and survival, people should be encouraged to
      create positive intentions toward early detection of several types of cancer, for
      instance, skin cancer, breast cancer, and colon cancer. This can be done by being
      alert to the warning signs of cancer and seeking help once a cancer symptom is
      detected. METHODS: A randomized controlled study (n = 1,500) assessed the effects
      of computer-tailored information and general information on determinants and
      intentions to engage in early detection behaviors (i.e., passive detection and
      help seeking) compared with those in a control group. Possible negative side
      effects, like increased chronic fear of cancer and more fatalistic attitudes
      toward cancer, were studied as well. RESULTS: Shortly after the intervention,
      differences between the study groups were found in intention, several social
      psychological determinants, and knowledge. Six months after the intervention,
      there were still differences between the tailored information group and the
      control group in intentions toward help seeking. Neither of the interventions
      resulted in increased chronic fear nor more fatalistic attitudes toward cancer.
      CONCLUSIONS: It is concluded that there were positive effects of the tailored
      intervention on determinants, passive detection, and help-seeking intentions in
      the short-term, but additional research is needed to assess ways of maintaining
      these effects in the long-term.

PMID- 15193890
TI  - Participation in annual skin cancer screening among women seeking routine
      mammography.
AB  - BACKGROUND: Early detection of skin cancer is associated with improved prognosis.
      The American Cancer Society's current skin cancer screening (SCS) recommendation
      states that adults over the age of 40 should receive an annual skin examination
      conducted by a health professional. However, little is known about the
      psychosocial factors related to participation in annual SCS, which remains
      relatively low among the general public. METHODS: Data were collected from women,
      aged 50 and older, seeking routine mammography at a large, urban, breast
      diagnostic facility. RESULTS: A total of 253 eligible women completed the survey.
      Overall, 20.2% of women reported receiving annual clinical SCS. Physician
      recommendation, self-efficacy, perceived susceptibility, and age were
      significantly associated with participation in annual skin screening.
      CONCLUSIONS: Similar to previously reported findings in the literature, our rates
      of participation in annual clinical skin screening were lower than reported rates
      for other types of cancer screening. Among older women, multiple covariates for
      participation in annual skin cancer screening were determined and may serve to
      guide future health education interventions to promote screening. Our findings
      suggest that participation could improve through increasing physician
      recommendation, screening self-efficacy, and individuals' sense of perceived
      susceptibility to skin cancer.

PMID- 15193891
TI  - Use of Pap test among Hispanics and non-Hispanic whites in a rural setting.
AB  - BACKGROUND: Hispanic women in the United States have a higher incidence of
      invasive cervical cancer than non-Hispanic whites. A key factor related to the
      relatively high incidence is the underutilization of cancer-screening services.
      Several previous investigations have reported that Hispanic women are less likely
      to comply with screening recommendations for Pap testing; some have identified
      factors that are associated with non-compliance with screening recommendations.
      METHODS: Using baseline personal interview data from a randomized community trial
      on cancer prevention in a rural area, we assessed the association between health
      barriers and non-compliance with cervical screening recommendations. RESULTS:
      Among Hispanic women (n = 382), those with a lower level of acculturation were
      more likely than highly acculturated Hispanic and non-Hispanic white women (n =
      385) to report personal barriers as reasons for not getting an initial or
      subsequent screening exam. Such barriers include fear of finding cancer, fear of
      finding diseases other than cancer, and embarrassment about receiving a physical
      exam. Certain structural barriers, such as cost of care, no time off work, and
      lack of transportation, were reported to be associated with non-compliance with
      routine cervical cancer screening, especially among non-Hispanic white women.
      CONCLUSIONS: Future research should examine barriers related to initial and
      subsequent screening among Hispanics with varying levels of acculturation.

PMID- 15193892
TI  - Impact of benign breast biopsy upon breast self-examination.
AB  - Current American Cancer Society guidelines recommend monthly performance of
      breast self-examination (BSE) for women over 20 years of age. While the
      experience of a benign breast biopsy can result in elevated levels of distress,
      the impact of benign biopsy upon breast cancer (BC) screening behavior is not
      well known. The present study examined frequency of BSE practice in 102 women
      after benign breast biopsy (biopsy group). Telephone interviews were completed a
      mean of 21 days (initial interview) and 8 months after biopsy (follow-up
      interview). A healthy comparison (HC) group of women (n = 76) without a history
      of breast biopsy completed an initial interview only. Information regarding
      distress, dispositional characteristics, BC screening-related attitudes and
      behaviors, and subjective and objective risk for BC was collected. Results
      indicated that the biopsy and HC groups did not differ in typical (i.e.,
      prebiopsy) practice of BSE. However, practice of BSE changed after biopsy with a
      general trend toward a decrease in BSE frequency. Only 8% of women in the biopsy
      group reported appropriate (once per month) practice of BSE at the 8-month Follow
      up while 28% reported appropriate practice at the initial interview. Decreases in
      BSE performance after biopsy were characteristic of younger women, women who
      lacked confidence in the ability to perform BSE correctly, and women whose biopsy
      was preceded by discovery of a breast lump or abnormality during BSE. Results
      suggest the potential value of a psychoeducational intervention after biopsy to
      enhance appropriate performance of BSE.

PMID- 15193893
TI  - Prostate-specific antigen test use reported in the 2000 National Health Interview
      Survey.
AB  - BACKGROUND: In 2000, the National Health Interview Survey (NHIS) collected
      information about prostate-specific antigen (PSA) test use in a representative
      sample of U.S. men. METHODS: This study examined PSA test use in subgroups
      defined by personal and social characteristics. RESULTS: Among men aged 50 and
      older with no history of prostate cancer, 56.8% reported ever having had a PSA
      test, 34.1% reported having had a screening PSA test during the previous year,
      and 30.0% reported having had three or more tests during the previous 5 years.
      Screening was greater among men aged 60-79 years, those with greater access to
      care, and those practicing other preventive behaviors. Among men in their 40s,
      use tended to be higher among African-American men. CONCLUSIONS: The prevalence
      and patterns of PSA screening suggest that PSA is used like other cancer
      screening tests among about a third of U.S. men. Because of the lack of
      scientific consensus on whether prostate cancer screening is beneficial, more
      information is needed on how knowledgeable both patients and practitioners are
      about the potential benefits and harms of screening and how prostate cancer
      screening decisions are made.

PMID- 15193894
TI  - Beliefs about the risk factors for cervical cancer in a British population
      sample.
AB  - BACKGROUND: The introduction of human papillomavirus (HPV) testing into cervical
      screening has the potential to alter public perceptions of cervical cancer by
      making explicit the role of a sexually transmitted virus in its etiology. HPV
      knowledge has been found to be poor, although there is evidence of public
      awareness of a link between sexual activity and cervical cancer risk. We explored
      beliefs about the risk factors for cervical cancer in a large population sample.
      METHODS: Face-to-face interviews were carried out with a representative sample of
      the British population. All participants were asked what they thought increased a
      women's chances of developing cervical cancer. RESULTS: The response rate was 71%
      (n = 1940). The most common single response was 'don't know' (38%). Forty-one
      percent of respondents mentioned factors relating to sex, but only 14% were aware
      of a link with sexual transmission and fewer than 1% named HPV. Women and more
      educated people had better knowledge of the established risk factors. The
      patterning of risk factor awareness by age varied across risk factors.
      CONCLUSIONS: Awareness of the role of a sexually transmitted virus in the
      etiology of cervical cancer is very low in Britain. Provision of information
      associated with the introduction of HPV testing could change public perceptions
      of cervical cancer.

PMID- 15193895
TI  - Measuring adherence to mammography screening recommendations among low-income
      women.
AB  - OBJECTIVES: (1) To describe the accuracy of self-report and administrative claims
      for measuring mammography adherence among low-income women; (2) to determine
      whether the accuracy of self-report differed between telephone interview and
      mailed questionnaire; and (3) to explore whether the method of measuring
      adherence affected associations between mammography adherence and participant
      sociodemographic characteristics. DESIGN: Retrospective cohort study of women
      receiving care from a Philadelphia Medicaid Managed Care Organization (MCO).
      PARTICIPANTS: Three hundred and ninety-nine low-income women eligible for
      screening mammography of whom 64% were African American, 14% Caucasian, 13%
      Hispanic, and 8% Asian American. MEASURES: Self-reported use of mammography
      screening, administrative mammography claims data, and dates of mammograms from
      radiology facility records. The "gold standard" categorized women as having
      undergone screening if they had either a billing claim or facility record for a
      mammogram in the past 12 months. MAIN RESULTS: Two hundred and eighty-three of
      the 399 women reported having had a mammogram in the past 12 months. The
      sensitivity of self-report was 0.93, specificity was 0.54, positive predictive
      value was 0.70, and negative predictive value was 0.86. One hundred and seventy
      nine of the 399 women had a claim for a mammogram in the past 12 months. The
      sensitivity of claims data was 0.83 with a negative predictive value of 0.84. The
      sensitivity of self-report was higher with telephone data collection (0.98) than
      with mailed data collection (0.82), while the specificity was higher with mail
      (0.64) than telephone (0.50). African American race was associated with adherence
      to screening recommendations when mammography use was measured by self-report (RR
      1.31, P = 0.002) but not when it was measured by claims or facility validation
      (RR 1.03, P = 0.56, and RR 1.12, P = 0.15, respectively). CONCLUSIONS: Accurate
      measurement of adherence to mammography screening among low-income women is
      difficult. Self-report substantially overestimates adherence (particularly when
      collected through telephone interviews), while also misclassifying some women who
      underwent screening as not having been screened (particularly when collected
      through mailed questionnaires). In contrast, administrative claims data
      substantially underestimates adherence. Inaccurate measurement of mammography
      adherence can lead to a biased understanding of the factors associated with
      adherence.

PMID- 15193896
TI  - Reliability of assessment and circumstances of performance of thorough skin self
      examination for the early detection of melanoma in the Check-It-Out Project.
AB  - BACKGROUND: Thorough skin self-examination (TSSE) has substantial potential to
      reduce melanoma mortality by early detection. METHODS: We interviewed 2,126
      patients before a scheduled routine visit with a primary care physician, at which
      participation in a randomized trial was offered as part of the Check-It-Out
      Project. We asked about skin examination behavior and related issues. RESULTS: By
      our a priori definition of TSSE, 18% of participants performed this activity, but
      other definitions led to widely varying estimates of 12% to 38%. Using a partner
      to assist in the examination was strongly associated with TSSE. That partner was
      generally the spouse, and wives were more likely to assist their husbands in
      these examinations than the reverse. The availability of a wall mirror was a
      particularly important predictor of TSSE performance. Visual impairment also
      affected performance. CONCLUSIONS: Estimates of TSSE performance vary
      substantially with the questions used to elicit this information. Partners,
      particularly spouses, appear to play a critical role in the conduct of TSSE, and
      wives appear more often and more effectively engaged in this process. Appropriate
      circumstances, such as availability of a wall mirror, are also important factors.
      These findings can be used to design interventions to increase TSSE performance
      with the ultimate aim of reducing melanoma mortality.

PMID- 15193897
TI  - Implementation of a cancer prevention program for working class, multiethnic
      populations.
AB  - BACKGROUND: This paper describes the implementation of the Healthy Directions
      Health Centers intervention and examines the characteristics of participants
      associated with completion of intervention activities. Healthy Directions-Health
      Centers was designed to address social contextual factors relevant to cancer
      prevention interventions for working class, multi-ethnic populations. METHODS:
      Ten community health centers were paired and randomly assigned to intervention or
      control. Patients who resided in low income, multi-ethnic neighborhoods were
      approached for participation. This study targeted fruit and vegetable
      consumption, red meat consumption, multi-vitamin intake, and physical activity.
      The intervention components consisted of: (1) a brief study endorsement from a
      clinician; (2) an in-person counseling session with a health advisor; (3) four
      follow-up telephone counseling sessions; and (4) multiple distributions of
      tailored materials. RESULTS: Among the 1,088 intervention group participants, 978
      participants (90%) completed at least five out of six intervention activities.
      Participants who missed clinical appointments were less likely to complete all
      components of the intervention. Participant characteristics that predicted
      receipt of clinician endorsement differed from characteristics that predicted
      completion of health advisor activities. Low acculturation did not present a
      barrier to delivery of the intervention once the participant was enrolled.
      CONCLUSIONS: Collection and reporting on process evaluation results can help
      explain variations in program implementation.

PMID- 15193898
TI  - The role of trust in use of preventive services among low-income African-American
      women.
AB  - BACKGROUND: This study explored factors that predict higher trust in primary care
      providers, and examined the role of patient trust on the use of preventive
      services for low-income African-American women. METHODS: We conducted a cross
      sectional, population-based telephone survey of 961 African-American women over
      age 40 in Washington, DC. Two dimensions of trust were examined: overall trust in
      one's regular primary care provider, and trust that the regular provider had no
      financial conflict of interest. Self-reported use of mammography, Pap tests,
      clinical breast exams, colorectal cancer screening, blood pressure, height and
      weight measurement, diet counseling, and depression screening, as delivered by
      one's primary care provider, were assessed. An index summarizing overall use of
      these interventions was the main outcome variable. RESULTS: More than two-thirds
      of respondents reported high trust in their physician. Older respondents (>65)
      were more trusting of their physicians overall than were younger respondents (P <
      0.01). Primary care characteristics (continuity of care, accessibility of the
      practice, coordination of specialty care by one's regular provider) were more
      strongly associated with having high trust than were sociodemographic, health
      status, and insurance characteristics. Higher trust was significantly associated
      with greater use of recommended preventive services (OR: 2.3, 95% CI: 1.3, 4.0),
      controlling for the effects of insurance status, primary care, and patient
      characteristics. CONCLUSIONS: Trust is associated with use of recommended
      preventive services in low-income African-American women. Stronger patient
      provider relationships, with high levels of trust, may indirectly lead to better
      health through adherence to recommended preventive services for low income
      African-American women.

PMID- 15193899
TI  - Impact of health education and screening over all-cause mortality in Japan:
      evidence from a cohort study during 1984-2002.
AB  - BACKGROUND: Health education and screening are two components of preventive
      health services in Japan since 1983. This study investigated their relationships
      with all-cause mortality as they are studied insufficiently in Hokkaido, Japan.
      METHODS: This study enrolled 1,532 men and 1,653 women aged 40-97 years from
      1,702 randomly selected households of 60 areas during 1984-1985 and followed them
      until 2002. At baseline survey, staffs of 45 health centers collected
      sociodemographic, medical, behavioral, and dietary information including health
      education and screening from study subjects with informed consent. RESULTS: For
      men, age-adjusted Cox proportional hazard model indicated lower mortality for
      those who received health education (RR = 0.76, P < 0.01) and screening (RR =
      0.83, P < 0.05) than those who did not. Health education showed lower mortality
      even after adjusting for many variables. Similarly for women, health education
      (RR = 0.66, P < 0.01) and screening (RR = 0.64, P < 0.001) revealed lower age
      adjusted mortality. Almost similar results were found for both services when
      models were adjusted for many variables and when the deaths including lost to
      follow-up cases of the first 4 years of baseline survey are excluded.
      CONCLUSIONS: This study shows protective effects of health education and
      screening over all-cause mortality for both sexes. However, further studies are
      needed to confirm the results.

PMID- 15193900
TI  - Role of mentholated cigarettes in increased nicotine dependence and greater risk
      of tobacco-attributable disease.
AB  - BACKGROUND: Cold air stimulates upper airway cold receptors causing a reflex
      depressive effect on respiratory activity. Menthol, in low concentrations can
      also stimulate these same cold receptors causing a depressive effect on
      respiratory activity. Menthol cigarettes when smoked, deliver enough menthol to
      stimulate cold receptors resulting in the smoker experiencing a "cool sensation."
      The "cool sensation" experienced by the menthol smoker can result in a reflex
      depressive effect on respiratory activity. METHOD: Literature searches were done
      for the NLM databases (e.g., MEDLINE from 1966, TOXLINE, OLDMEDLINE (1985-1965),
      CANCERLIT, plus tobacco industry documents and hardcopy indices. The evidence was
      evaluated with application to mentholated cigarette smoking. RESULTS AND
      DISCUSSION: A logical progression is presented that develops the framework to
      prove that menthol found in mentholated cigarettes may cause respiratory
      depression resulting in greater exposure to the toxic substances found in tobacco
      smoke. CONCLUSION: As a result of breath holding that results from the
      stimulation of cold receptors there is a greater opportunity for exposure and
      transfer of the contents of the lungs to the pulmonary circulation. For the
      menthol smoker this results in a greater exposure to nicotine and the particulate
      matter (tar) of the smoked cigarette. This exposure can result in increased
      nicotine dependence and greater chance of tobacco-attributable disease.

PMID- 15193901
TI  - The safety of pumpkin carving tools.
AB  - BACKGROUND: Even with optimal treatment, injuries from pumpkin carving accidents
      may leave people with compromised hand function. Pumpkin carving tools may reduce
      the incidence and/or magnitude of these injuries. However, evidence that they are
      safer is required before these knives can be recommended. METHODS: Two pumpkin
      carving knives were compared to a serrated and a plain kitchen knife. The forces
      required to cut and pierce a pumpkin were determined and then applied by a servo
      hydraulic machine to each knife placed against cadaver hands in a manner designed
      to either lacerate Zone 2 of the finger (six tests for each knife) or to puncture
      the hand. Inspection and dissection determined the extent of injury. RESULTS: The
      pumpkin knives produced some injuries, however, they were fewer and less severe
      than those caused by the kitchen knives. CONCLUSIONS: Tools designed specifically
      for pumpkin carving may indeed be safer. Use of these products, and increased
      overall awareness of the risks of pumpkin carving in general, which clinicians
      could help promote, might reduce the frequency and severity of pumpkin carving
      injuries.

PMID- 15193902
TI  - Socio-environmental exercise preferences among older adults.
AB  - BACKGROUND: To examine preferences concerning social and environmental aspects of
      exercise in the elderly population. METHODS: Participants were 324 community
      dwelling persons aged 74-85 years who completed a health questionnaire that
      included items on exercise preferences as well as questions on demographic
      variables, health, and exercise habits. Selected participants then completed a
      physical performance battery to measure lower body functioning. RESULTS: A
      physician's advice to exercise, monitoring by a health professional, an
      evaluation of the exercise program by a professional, and the quality of the
      instructor were all rated as important or very important by at least 70% of the
      participants. Several other factors such as easy access to exercise facilities,
      type of exercise performed, free or low cost of a program, and other participants
      being of the same age were rated as slightly important or important. Preferences
      were related to participants' health and demographic characteristics. For
      example, participants who were not married were more interested in the social
      aspects of exercise programs, and those with higher levels of education and more
      resources were less concerned with program costs. CONCLUSIONS: The findings
      suggest that exercise programs should be tailored to meet the needs and wishes of
      subgroups of this population. In order to motivate at-risk elderly persons to
      exercise, programs must take these varying preferences into account and explore
      their meaning for program design.

PMID- 15193903
TI  - Hypertension-related dietary patterns of rural older adults.
AB  - BACKGROUND: Prevalence of hypertension is greater in older adults, and increased
      intake of fruits, vegetables, and dairy-good sources of potassium, calcium, and
      magnesium-can reduce blood pressure. This study examined the hypertension-related
      dietary patterns of older adults. METHODS: A cohort of 180 Pennsylvania adults
      (aged >/=65), 90 with hypertension, were randomly selected from the Geisinger
      Rural Aging Study (GRAS). Data were collected by trained interviewers at a home
      visit. Dietary assessment used five 24-h recalls. We compared the characteristics
      and dietary intake of people with hypertension to those without hypertension and
      compared their intakes to current recommendations. RESULTS: Mean intakes of all
      participants were less than two thirds of the DRI for calcium and magnesium and
      fell far short of the 3,500 mg of potassium recommended for prevention and
      treatment of hypertension. Participants with hypertension consumed less sodium
      than controls. Both groups ate fewer fruits and vegetables than recommended but
      reached the dairy recommendation. Calcium intake was mainly from high-fat dairy
      products, beans were the top source of potassium and magnesium. CONCLUSIONS:
      Older adults with hypertension should be guided to choose more low-fat dairy
      products and other low-fat calcium sources and to increase intakes of beans, dark
      green leafy vegetables, and other potassium and magnesium sources.

PMID- 15193904
TI  - Speaking of weight: how patients and primary care clinicians initiate weight loss
      counseling.
AB  - BACKGROUND: Obesity is epidemic in the US and other industrialized countries and
      contributes significantly to population morbidity and mortality. Primary care
      physicians see a substantial portion of the obese population, yet rarely counsel
      patients to lose weight. METHODS: Descriptive field notes of outpatient visits
      collected as part of a multimethod comparative case study were used to study
      patterns of physician-patient communication around weight control in 633
      encounters in family practices in a Midwestern state. RESULTS: Sixty-eight
      percent of adults and 35% of children were overweight. Excess weight was
      mentioned in 17% of encounters with overweight patients, while weight loss
      counseling occurred with 11% of overweight adults and 8% of overweight children.
      In weight loss counseling encounters, patients formulated weight as a problem by
      making it a reason for visit or explicitly or implicitly asking for help with
      weight loss. Clinicians did so by framing weight as a medical problem in itself
      or as an exacerbating factor for another medical problem. CONCLUSIONS: Strategies
      that increase the likelihood of patients identifying weight as a problem, or that
      provide clinicians with a way to "medicalize" the patient's obesity, are likely
      to increase the frequency of weight loss counseling in primary care visits.

PMID- 15193905
TI  - Prisoners' attitudes toward Hepatitis B vaccination.
AB  - BACKGROUND: Hepatitis B continues to be a substantial problem in the United
      States despite the existence of a safe and effective vaccine. Vaccination
      programs for inmates could reach many high-risk individuals but little is known
      about U.S. inmates' willingness to accept hepatitis B virus (HBV) vaccination
      while incarcerated. The goal of this study was to assess inmates' knowledge about
      hepatitis B and their willingness to accept hepatitis B vaccination while
      incarcerated. METHODS: We interviewed 153 male and female inmates at the Rhode
      Island Department of Corrections (RIDOC) using a voluntary, anonymous survey.
      RESULTS: Ninety-three percent of inmates said they would agree to receive the
      hepatitis B vaccine while incarcerated. More than half of the 30% who reported
      having risk factors for hepatitis B did not consider themselves to be at risk for
      hepatitis B and almost half (44%) of all inmates were not aware that hepatitis B
      can be transmitted through unprotected sex. CONCLUSION: Hepatitis B vaccination
      programs in correctional settings are a public health priority and would be well
      received by the target population. Such programs would help protect the health of
      incarcerated persons and the communities to which they return.

PMID- 15193906
TI  - Smoking, body weight, and CHD mortality in diverse populations.
AB  - BACKGROUND: It is well documented that smokers tend to be leaner than nonsmokers.
      It is also clearly established that smoking is detrimental to health. The
      question that immediately comes to mind, therefore, is whether the possible
      weight-controlling aspects of the smoking habit offset the harm induced by
      smoking. METHODS: In this report, we present an analysis of 21 observational
      studies that examine the relationship between smoking status and BMI. With few
      exceptions, smokers are leaner than nonsmokers. RESULTS: The average differences
      between smokers and nonsmokers are 0.97 kg/m(2) for men (95% CI = 0.82-1.13) and
      1.38 kg/m(2) for women (95% CI = 1.19-1.58). However, considering the
      relationship of both BMI and smoking to coronary heart disease (CHD) mortality,
      adjusting for age, we find that 15.9 kg/m(2) BMI units is required for men and
      15.8 kg/m(2) is required for women to offset the detrimental effect of smoking.
      This weight differential is 42 kg (93 lb) for a woman 163 cm (64 in.) tall.
      CONCLUSION: Our results demonstrate that the risk of CHD death among smokers is
      not reduced sufficiently by the lower BMIs to justify the habit. It is
      unquestionably better to quit smoking and gain weight than to continue to smoke.

PMID- 15193907
TI  - Preventive effects of diets supplemented with sweetie fruits in
      hypercholesterolemic patients suffering from coronary artery disease.
AB  - BACKGROUND: Diets rich in vegetables and fruits prevent development of
      atherosclerosis. OBJECTIVE: To investigate the preventive effects of diets
      supplemented with a new kind of citrus fruit-pummelo-grapefruit hybrid in
      hypercholesterolemic patients suffering from coronary artery disease (CAD).
      SUBJECTS AND METHODS: Sixty-six hypercholesterolemic volunteers after coronary
      bypass surgery ages 47-68 years were randomly divided into two experimental (EG1
      and EG2) groups and one control (CG) group, 22 each. The diets of the patients of
      the experimental groups (EG1 and EG2) were supplemented with one or two peeled
      sweeties, respectively. A comprehensive clinical investigation of all 66 patients
      was done. Blood samples were collected before and after the investigation for a
      wide range of laboratory tests. RESULTS: A high content of dietary fibers and
      antioxidant compounds in peeled sweeties was found. After 30 days of the
      investigation, peeled sweeties-supplemented diets have decreased plasma lipids
      levels in EG1 and EG2 vs. CG group: (a) total cholesterol (TC)-7.38 vs. 8.08
      mmol/L, - 8.7%, and 6.78 vs. 8.08. mmol/L, -16.1%, respectively; (b) low-density
      lipoprotein cholesterol (LDL-C)-5.65 vs. 6.39 mmol/L, - 1.6%, and 5.04 vs. 6.39
      mmol/L, -21.2%, respectively; (c) triglycerides (TG)-2.01 vs. 2.27 mmol/L, 
      11.5%, and 1.71 vs. 2.27 mmol/L, -24.7%, respectively. In addition, a significant
      increase in the plasma antioxidant capacity in EG2, and to a lesser degree in EG1
      groups, was observed. No changes in the studied indices in the patients of the CG
      were detected. CONCLUSION: Peeled sweeties have high contents of dietary fibers
      and antioxidant compounds. Diets supplemented with peeled sweeties positively
      influence plasma lipid metabolism and plasma antioxidant capacity in patients
      suffering from hypercholesterolemia. Therefore, the addition of peeled sweeties
      to a generally accepted antiatherosclerotic diet may be beneficial in prevention
      of atherosclerosis, mainly in hypercholesterolemic patients.

PMID- 15193908
TI  - The Los Angeles Lift Off: a sociocultural environmental change intervention to
      integrate physical activity into the workplace.
AB  - PURPOSE: To present the development and feasibility testing of a sociocultural
      environmental change intervention strategy aimed at integrating physical activity
      into workplace routine. DESIGN: Randomized, controlled, post-test only,
      intervention trial. Setting. Los Angeles County Department of Health Services'
      worksites. PARTICIPANTS: Four hundred forty-nine employees, predominantly
      sedentary, overweight, middle-aged women of color, distributed across 26
      meetings. INTERVENTION: A single 10-min exercise break during work time involving
      moderate intensity, low-impact aerobic dance and calisthenic movements to music.
      MEASURES: Primary-level of participation, particularly among sedentary staff;
      secondary-self-perceived health status, satisfaction with current fitness level,
      and mood/affective state. RESULTS: More than 90% of meeting attendees
      participated in the exercises. Among completely sedentary individuals,
      intervention participants' self-perceived health status ratings were
      significantly lower than controls' (OR = 0.17; 95% CI = 0.05, 0.60; P = 0.0003).
      Among all respondents not regularly physically active, intervention participants'
      levels of satisfaction with fitness were more highly correlated with self-ranked
      physical activity stage of change (r = 0.588) than the control participants' (r =
      0.376, z = -2.32, p = 0.02). Among the completely sedentary, control participants
      reported significantly higher levels of energy than did intervention participants
      (P < 0.01). CONCLUSIONS: Captive audiences may be engaged in brief bouts of
      exercise as a part of the workday, regardless of physical activity level or stage
      of change. This experience may also appropriately erode sedentary individuals'
      self-perception of good health and fitness, providing motivation for adoption of
      more active lifestyles.

PMID- 15193909
TI  - BMI-referenced standards for recommended pedometer-determined steps/day in
      children.
AB  - BACKGROUND: Recommended levels of youth physical activity (PA) should emerge from
      data related to important health outcomes. The purpose of the present study was
      to establish criterion-referenced standards for PA (using pedometer-assessed
      steps/day) related to healthy body composition. METHODS: This is a secondary
      analysis of an existing data set (including pedometer-assessed PA and objectively
      measured BMI) of 1,954 children (995 girls, 959 boys; ages 6-12 years) from the
      USA, Australia, and Sweden. The contrasting groups method [M.J. Sarif,
      Introduction to Measurement in Physical Education and Exercise Science, St.
      Louis, MO: Mosby College Publishing; 1986] for establishing criterion-referenced
      cut points was used to identify optimal age- and sex-specific standards for
      steps/day related to international BMI cut points for normal weight and
      overweight/obesity. RESULTS: The selected cut points for steps/day for 6-12 year
      olds were 12,000 steps/day for girls and 15,000 steps/day for boys. CONCLUSIONS:
      The analytical process undertaken in this study illuminated the difference in
      previously used norm-referenced standards vs. criterion-referenced standards
      based on BMI categories. The steps/day cut points established herein, using an
      international sample, are higher than previously suggested normative standards
      but are not inconsistent with recent advances in our understanding of PA needs in
      youth. This analysis provides the foundation for cross-validation and evaluation
      of these BMI-referenced steps/day cut points in independent samples and with
      longitudinal study designs.

PMID- 15193910
TI  - Depressive symptoms and adolescent eating and health behaviors: a multifaceted
      view in a population-based sample.
AB  - BACKGROUND: Previous research has shown significant associations between
      depression and substance use and eating disordered behaviors. However, no
      research to date has described associations between depressive symptoms and
      nutritional intake or physical activity among adolescents in a nonclinical,
      population-based sample. METHODS: Classroom surveys were completed by 4,734
      ethnically diverse, middle- and high school students. Based on their depressive
      symptom scores, males and females were categorized with low-, moderate-, or high
      depressive symptom status. Linear models were used to examine eating and health
      behavior variables by depressive symptom groups. RESULTS: Depressive symptoms
      were positively associated with health-compromising attitudes such as perceived
      barriers to healthy eating and weight concerns, and health-compromising behaviors
      such as unhealthy weight-control behaviors and substance use, including caffeine.
      Depressive symptoms were negatively associated with health-promoting behaviors
      such as eating breakfast, lunch, and dinner. However, most associations between
      depressive symptoms and dietary micronutrients were not statistically
      significant. Health-promoting moderate-to-vigorous physical activity was
      negatively associated with depressive symptoms among males. CONCLUSIONS:
      Adolescents who report depressive symptoms are at risk for other health
      compromising attitudes and behaviors and are also less likely to engage in health
      promoting behaviors. Depressive symptoms may be an underlying trait in the
      expression of health behaviors among adolescents.

PMID- 15193911
TI  - Retailer participation in cigarette company incentive programs is related to
      increased levels of cigarette advertising and cheaper cigarette prices in stores.
AB  - PURPOSE: The retail outlet is the cigarette companies' major marketing channel to
      reach present and future customers. Of the $11.2 billion spent by them to market
      their products in 2001, approximately 85% was spent on retailer and consumer
      incentives to stimulate sales. This study examines the extent of retailer
      participation in these incentive programs, and the relationship between
      participation and the amount and placement of cigarette marketing materials and
      products, and prices in stores. METHODS: Observational assessments of cigarette
      marketing materials, products, and prices were conducted in 468 stores in 15 U.S.
      states. Telephone interviews were conducted with store owners or managers of
      these stores to determine the details of their participation in incentive
      programs. RESULTS: Cigarette companies engaged 65% of retailers in an incentive
      program. Nearly 80% of participating retailers reported cigarette company control
      over placement of marketing materials in their stores. Stores that reported
      receiving over $3,000 from incentive programs in the past 3 months averaged 19.5
      cigarette marketing materials, and stores receiving no money averaged only 8.2
      marketing materials. In multivariate analyses, participation in incentive
      programs offered by Philip Morris and R.J. Reynolds was positively related to the
      number of cigarette marketing materials for each of these companies' brands in
      stores and the placement of their cigarettes on the top shelf. The price of
      Newports was significantly lower in stores that received incentives; no price
      difference was found for Marlboro. CONCLUSIONS: Stores that participate in
      cigarette company incentive programs feature more prominent placement of
      cigarettes and advertising, and may have cheaper cigarette prices.

PMID- 15193912
TI  - Improvements in glucose tolerance in obese males with abnormal glucose tolerance
      following 10 days of aerobic exercise.
AB  - BACKGROUND: Aerobic exercise training has been shown to produce beneficial
      changes in glucose tolerance and insulin sensitivity in obese individuals if
      performed at high enough intensities and/or durations. We examined the effects of
      a moderate intensity, short-term exercise training protocol on glucose tolerance
      in obese males with glucose intolerance. METHODS: Fourteen abdominally obese,
      sedentary males with normal glucose tolerance (NGT; n = 7) and abnormal glucose
      tolerance (AGT; n = 7) completed 40 min of exercise bouts for 10 consecutive days
      at approximately 75% of age-predicted maximum heart rate. Fasting glucose and
      insulin levels, and glucose tolerance and insulin response to glucose were
      measured before and after the training period. RESULTS: Participants did not
      experience significant mass loss during the 10-day investigation. Individuals in
      the AGT group experienced significant (P < 0.05) improvement in glucose tolerance
      [glucose area: 1,763.67 (255.98) mmol L(-1) x 120 min(-1) vs. 1,682.98 (266.91)
      mmol L(-1) x 120 min(-1)] and fasting insulin levels [44.57 (7.58) microU mL(-1)
      vs. 36.14 (3.97) microU mL(-1)] as a result of training. Significant (P < 0.05)
      reductions in fasting glucose concentrations [5.82 (0.19) mmol L(-1) vs. 5.42
      (0.18) mmol L(-1)] and a decrease in fasting insulin concentrations [44.71 (9.39)
      microU mL(-1) vs. 35.0 (7.15) microU mL(-1); P = 0.064] were observed in the NGT
      group following the training period. CONCLUSIONS: The data suggest that moderate,
      short-term exercise without concomitant mass loss is effective in improving
      glucose tolerance and insulin response to a glucose load in obese males with
      abnormal glucose tolerance.

PMID- 15193913
TI  - RNA interference as a new strategy against viral hepatitis.
AB  - Hepatitis viruses are the leading cause of liver cirrhosis and hepatocellular
      carcinoma worldwide. Since currently available treatment options against these
      viruses are limited, there is a need for development of alternative therapies. In
      this minireview, we concentrate on three hepatitis viruses--hepatitis C virus,
      hepatitis B virus, and hepatitis delta virus and discuss how RNA interference
      (RNAi) has been utilized against them. RNAi is a process by which small double
      stranded RNA can effectively target a homologous RNA sequence for degradation by
      cellular ribonucleases. Though RNAi was exploited in the beginning for down
      regulating cellular genes, it has recently been demonstrated that this process is
      equally effective against many types of human and animal viruses including the
      hepatitis viruses. Both synthetic small-interfering RNAs (siRNAs) and plasmid
      based siRNA expression systems have been useful in suppressing the hepatitis
      viruses. Though this new approach looks promising, problems of nonspecific
      effects and delivery may need to be addressed before the full therapeutic
      potential of RNAi against viral infections in patients is realized.

PMID- 15193914
TI  - BKV and SV40 infection of human kidney tubular epithelial cells in vitro.
AB  - The interaction of BKV with its natural target cells, human kidney epithelial
      cells, has not been studied. In vitro infections of human primary kidney
      epithelial cells were performed to investigate a BKV infection in its natural
      host cell. BKV undergoes a lytic replication cycle in this system: high levels of
      T antigen expression were first detected at 36 h postinfection, while viral DNA
      replication, capsid protein expression, and progeny virus were observed at 48 h
      postinfection. It was observed that the related polyomavirus SV40 is incapable of
      infecting human kidney epithelium except in the presence of the GM1 ganglioside,
      recently reported to be an SV40 receptor.

PMID- 15193915
TI  - Atomic force microscopy investigation of wild-type Moloney murine leukemia virus
      particles and virus particles lacking the envelope protein.
AB  - Moloney murine leukemia virus (M-MuLV) lacking the gene for the envelope
      glycoprotein (env(-)) was produced in NIH 3T3 cells and investigated using atomic
      force microscopy (AFM). The particles were compared with similarly produced wild
      type virions, some of which had been exposed to a monoclonal antibody against the
      surface component of the envelope protein (SU protein). The env(-) particles
      generally exhibit a distinctly different external appearance suggesting only a
      low density of associated proteins that have an almost fluid, mechanically
      unstable character. The weakly associated proteins may be host cell membrane
      proteins that are incorporated into the viral membrane in place of or in addition
      to virus envelope protein. The amount of this non-viral protein on virion
      surfaces appears to vary from negligible in most cases to a substantial
      complement in others. It seems clear that the presence of the envelope protein,
      in a mechanical sense, significantly strengthens and stabilizes the virion
      envelope. Binding of monoclonal antibody to wild-type virions indicates that some
      particles expose a significant amount of antigen while adjacent virions may not.
      This suggests that the conformation of the envelope glycoprotein or the
      disposition of oligosaccharides may be different among particles, on some virions
      exposing the specific epitope, and others little or none.

PMID- 15193916
TI  - Identification of residues in an orthopoxvirus interleukin-18 binding protein
      involved in ligand binding and species specificity.
AB  - Interleukin-18 (IL-18) is a critical cytokine in inflammation and adaptive immune
      responses. The IL-18 binding proteins (IL-18BP) are a family of proteins that
      bind to, and inhibit the activity of, IL-18. Using point mutagenesis, we analyzed
      the ectromelia virus IL-18BP to identify residues involved in binding. Because
      p13 can bind both human and murine IL-18, and because it is highly homologous to
      the variola virus IL-18BP, we set out to identify residues that may be involved
      in species specificity. Several of the mutations resulted in complete abrogation
      of binding affinity. Three (F49A, E77A, and E69A) significantly affected binding
      with both species of IL-18, but not to the same extent. Mutant H70A showed
      reduced affinity for human IL-18 while binding to murine IL-18 was not affected.
      This study demonstrated that interaction of IL-18 with p13 was similar to other
      IL-18BPs, however, novel species-specific interactions were identified.

PMID- 15193918
TI  - Inverted terminal repeat sequences of adeno-associated virus enhance the antibody
      and CD8(+) responses to a HIV-1 p55Gag/LAMP DNA vaccine chimera.
AB  - The immune responses to an HIV-1 p55Gag vaccine encoded as a DNA chimera with the
      lysosomal associated membrane protein-1 (LAMP) have been examined for the effect
      of the addition of the inverted terminal repeat (ITR) sequences of the adeno
      associated virus (AAV) to the DNA plasmid construct, and of packaging the
      LAMP/gag gene as a recombinant AAV vector (rAAV). DNA plasmids encoding Gag and
      the LAMP/Gag protein chimera were constructed in two vectors, the pcDNA3.1 and a
      corresponding plasmid containing the ITR sequences (pITR) flanking the expression
      elements of the plasmid, and the pITR LAMP/gag DNA plasmid was encapsidated in
      the rAAV vector. Human 293 cells transfected in vitro with LAMP/gag plasmids
      either in pcDNA3.1 or pITR produced much Gag protein in cell extracts (1.6 and
      2.2 ng of Gag/mg of protein, respectively). The immune responses of mice to
      immunization with these constructs were examined under three protocols: DNA
      prime/DNA boost, DNA prime/rAAV boost, and a single rAAV immunization. The
      results demonstrated that under DNA prime/DNA boost protocol, the "naked" DNA
      vaccines encoding the LAMP/gag chimera, either as pcDNA3.1 or pITR DNA plasmid
      constructs, elicited strong CD4(+) T cell responses. In contrast, significantly
      higher levels of CD8(+) and antibody responses were observed with the pITR-DNA
      constructs. Immunization with the rAAV vector under the DNA prime/rAAV boost
      protocol resulted in sustained T cell responses and a markedly increased antibody
      response, predominantly of the IgG(1) isotype resulting from the activation of
      the Th2 subset of CD4(+) T cells, that was sustained for at least 5 months after
      immunization.

PMID- 15193919
TI  - Morphology and genome organization of the virus PSV of the hyperthermophilic
      archaeal genera Pyrobaculum and Thermoproteus: a novel virus family, the
      Globuloviridae.
AB  - A novel virus, termed Pyrobaculum spherical virus (PSV), is described that
      infects anaerobic hyperthermophilic archaea of the genera Pyrobaculum and
      Thermoproteus. Spherical enveloped virions, about 100 nm in diameter, contain a
      major multimeric 33-kDa protein and host-derived lipids. A viral envelope encases
      a superhelical nucleoprotein core containing linear double-stranded DNA. The PSV
      infection cycle does not cause lysis of host cells. The viral genome was
      sequenced and contains 28337 bp. The genome is unique for known archaeal viruses
      in that none of the genes, including that encoding the major structural protein,
      show any significant sequence matches to genes in public sequence databases.
      Exceptionally for an archaeal double-stranded DNA virus, almost all the
      recognizable genes are located on one DNA strand. The ends of the genome consist
      of 190-bp inverted repeats that contain multiple copies of short direct repeats.
      The two DNA strands are probably covalently linked at their termini. On the basis
      of the unusual morphological and genomic properties of this DNA virus, we propose
      to assign PSV to a new viral family, the Globuloviridae.

PMID- 15193917
TI  - Persistence of low levels of simian immunodeficiency virus in macaques that were
      transiently viremic by conventional testing.
AB  - Transient SIV viremia after experimental SIV challenge has been documented.
      Whether SIV persists in these transiently viremic macaques remains unclear. In
      the present study, we applied a sensitive PCR and found persistent low levels of
      SIVmne infection (LLSI) (range: 0.1-5.3 SIV DNA copies/10(6) PBMC) in seven
      macaques that were transiently positive by conventional assays, which was 10(2)-
      to 10(6)-fold less than those of SIVmne infected monkeys with typical disease
      progression. SIV envelope V1 sequences remained homogeneous in these macaques for
      the 6-year study period, with a mean evolution rate of 0.005% per site per year,
      which was not different from zero (P = 0.612) and significantly lower than that
      (0.56-1.18%) in macaques with progressive infection of SIVmne. LLSI macaques have
      remained free from SIV-associated illness, and are still alive 10 years after
      virus inoculation. Understanding the mechanisms underlying this outcome may
      provide valuable insight into therapy and vaccine development.

PMID- 15193920
TI  - A conserved leucine that constricts the pore through the capsid fivefold cylinder
      plays a central role in parvoviral infection.
AB  - The atomic structure of the DNA-containing T = 1 particle of the parvovirus
      minute virus of mice (MVM) reveals cylindrical projections at each fivefold
      symmetry axis, each containing an 8 Angstrom pore through which runs 10 amino
      acids of a single VP2 N-terminus. The tightest constriction of this pore is
      formed at its inner end by the juxtaposition of leucine side chains from position
      172 of five independent VP2 molecules. To test whether L172 modulates the
      extrusion of VP N-termini, we constructed and analyzed a complete set of amino
      acid substitution mutants at this highly conserved residue. All but one mutant
      produced DNA-containing virions, but only two, L172V and L172I, were infectious,
      the others being blocked for viral entry. Several mutants were significantly
      defective for assembly at 39 degrees C, but not at 32 degrees C. L172W
      significantly impaired genome encapsidation, indicating that the fivefold
      cylinder may also be the DNA packaging portal. Although tryptic cleavage of the
      VP2 N-terminus was not affected for the mutants, VP1 was degraded during
      proteolysis of mutant, but not wild-type, virions.

PMID- 15193921
TI  - Functional replacement of Wheat streak mosaic virus HC-Pro with the corresponding
      cistron from a diverse array of viruses in the family Potyviridae.
AB  - Helper component-proteinase (HC-Pro) of Wheat streak mosaic virus strain Sidney
      81 (WSMV-Sidney 81) was systematically replaced with the corresponding cistron
      derived from four strains of WSMV (Type, TK1, CZ, and El Batan 3), the
      tritimovirus Oat necrotic mottle virus (ONMV), the rymoviruses Agropyron mosaic
      virus (AgMV) and Hordeum mosaic virus (HoMV), or the potyviruses Tobacco etch
      virus (TEV) and Turnip mosaic virus (TuMV). These HC-Pro proteins varied in amino
      acid sequence identity shared with HC-Pro of WSMV-Sidney 81 from high (strains of
      WSMV at approximately 86-99%) to moderate (ONMV at 70%) to low (rymoviruses and
      potyviruses at approximately 15-17%). Surprisingly, all chimeric viral genomes
      examined were capable of systemic infection of wheat upon inoculation with RNA
      transcripts produced in vitro. HC-Pro replacements derived from tritimoviruses
      did not alter host range relative to WSMV-Sidney 81, as each of these chimeric
      viruses was able to systemically infect wheat, oat, and corn line SDp2. These
      results indicate that differences in host range among tritimoviruses, including
      the inability of ONMV to infect wheat or the inability of WSMV strains Type and
      El Batan 3 to infect SDp2 corn, are not determined by HC-Pro. In contrast, all
      chimeric viruses bearing HC-Pro replacements derived from rymoviruses or
      potyviruses were unable to infect SDp2 corn and oat. Collectively, these results
      indicate that HC-Pro from distantly related virus species of the family
      Potyviridae are competent to provide WSMV-Sidney 81 with all functions necessary
      for infection of a permissive host (wheat) and that virus-host interactions
      required for systemic infection of oat and SDp2 corn are more stringent. Changes
      in symptom severity or mechanical transmission efficiency observed for some
      chimeric viruses further suggest that HC-Pro affects virulence in WSMV.

PMID- 15193923
TI  - TYLCSV DNA, but not infectivity, can be transovarially inherited by the progeny
      of the whitefly vector Bemisia tabaci (Gennadius).
AB  - The transovarial transmission of two species of begomovirus, Tomato yellow leaf
      curl virus (TYLCV) and Tomato yellow leaf curl Sardinia virus (TYLCSV), through
      generations of Bemisia tabaci of the B and Q biotypes has been investigated.
      Different life stages of the progeny of viruliferous female whiteflies have been
      analysed by PCR detection of viral DNA and infectivity tests. Our results
      indicate that TYLCSV DNA can be detected in eggs and nymphs, and to a lesser
      extent adults, of the first-generation progeny. Infectivity tests using a large
      number of adult progeny of the first, second, and third generation indicate that
      even when viral DNA is inherited, infectivity is not. For TYLCV, neither viral
      DNA nor infectivity were associated with the progeny of viruliferous female
      whiteflies. Because the inherited viral DNA is unable to give rise to infections,
      the transovarial transmission of TYLCSV DNA appears to have no epidemiological
      relevance.

PMID- 15193922
TI  - Inactivation of viruses infecting ectothermic animals by amphibian and piscine
      antimicrobial peptides.
AB  - The ability of five purified amphibian antimicrobial peptides (dermaseptin-1,
      temporin A, magainin I, and II, PGLa), crude peptide fractions isolated from the
      skin of Rana pipiens and R. catesbeiana, and four antimicrobial peptides (AMPs)
      from hybrid striped bass (piscidin-1N, -1H, -2, and -3) were examined for their
      ability to reduce the infectivity of channel catfish virus (CCV) and frog virus 3
      (FV3). All compounds, with the exception of magainin I, markedly reduced the
      infectivity of CCV. In contrast to CCV, FV3 was 2- to 4-fold less sensitive to
      these agents. Similar to an earlier study employing two other amphibian peptides,
      the agents used here acted rapidly and over a wide, physiologically relevant,
      temperature range to reduce virus infectivity. These results extend our previous
      findings and strongly suggest that various amphibian and piscine AMPs may play
      important roles in protecting fish and amphibians from pathogenic viruses.

PMID- 15193924
TI  - Systemic and oral immunogenicity of hemagglutinin protein of rinderpest virus
      expressed by transgenic peanut plants in a mouse model.
AB  - Rinderpest causes a devastating disease, often fatal, in wild and domestic
      ruminants. It has been eradicated successfully using a live, attenuated vaccine
      from most part of the world leaving a few foci of disease in parts of Africa, the
      Middle East, and South Asia. We have developed transgenic peanut (Arachis
      hypogaea L.) plants expressing hemagglutinin (H) protein of rinderpest virus
      (RPV), which is antigenically authentic. In this work, we have evaluated the
      immunogenicity of peanut-expressed H protein using mouse model, administered
      parenterally as well as orally. Intraperitoneal immunization of mice with the
      transgenic peanut extract elicited antibody response specific to H. These
      antibodies neutralized virus infectivity in vitro. Oral immunization of mice with
      transgenic peanut induced H-specific serum IgG and IgA antibodies. The systemic
      and oral immunogenicity of plant-derived H in absence of any adjuvant indicates
      the potential of edible vaccine for rinderpest.

PMID- 15193926
TI  - How to approach cardiac diagnosis from the chest radiograph.
AB  - Direct visualization of pathologic changes in the heart has significantly
      influenced the diagnostic accuracy and management of patients with cardiovascular
      disease. This article presents an approach to plain film examination of the heart
      based on basic principles of radiologic evaluation. It emphasizes the
      relationship between the radiologic appearance of a structure and the technique
      used to obtain that image, and the relationship between the observation of a
      structural abnormality and the anatomic relationships that allow that observation
      to be made. This approach is simple, organized in a logical manner, and when
      applied rigorously results in not only accurate and insightful differential
      diagnosis, but also a deep understanding of cardiovascular disease processes.

PMID- 15193925
TI  - Measles virus interacts with human SLAM receptor on dendritic cells to cause
      immunosuppression.
AB  - Measles virus (MV) infects dendritic cells (DCs) resulting in immunosuppression.
      Human DCs express two MV receptors: CD46 and human signaling lymphocyte
      activation molecule (hSLAM); thus, the role played by either alone is unclear.
      Because wild-type (wt) MV uses hSLAM receptor preferentially, we dissected the
      molecular basis of MV-DC interaction and resultant immunosuppression through the
      hSLAM receptor by creating transgenic (tg) mice expressing hSLAM on DCs. After
      infection with wt MV, murine splenic DCs expressing hSLAM receptor had less B7-1,
      B7-2, CD40, MHC class I, and MHC class II molecules on their surfaces and
      displayed an increased rate of apoptosis when compared to uninfected DCs.
      Further, MV-infected DCs failed to stimulate allogeneic T cells and inhibited
      mitogen-dependent T-cell proliferation. Individual expression of human SLAM,
      interferon alpha/beta receptor, tumor necrosis factor-alpha, and lymphotoxin
      alpha or beta from T cells was not required for MV-infected DCs to inhibit the
      proliferation of T cells.

PMID- 15193928
TI  - Plain film / MR imaging correlation in heart disease.
AB  - This article reviews common cardiovascular pathologies that can be noted first on
      plain film when previously unsuspected, and then illustrates how cross-sectional
      imaging can provide the follow-up information needed to make a diagnosis. First
      reviewed are the normal cardiac structures and contours as seen on the plain film
      of the chest, followed by specific types of pathologies as seen in older adults;
      patients with lung cancer invading the heart, pericardium, or large vessels; and
      postsurgical and posttraumatic findings. Also provided is a review of non-cardiac
      related areas of plain film and cross-sectional imaging correlation. It is hoped
      that the reader gains a better understanding and appreciation for the great value
      of cross-sectional imaging, and the power of the plain film in helping detect and
      recognize thoracic pathology.

PMID- 15193927
TI  - How to plan and perform a cardiac MR imaging examination.
AB  - Because of the enormous economic and social impact of cardiovascular disease in
      the United States there is a need for improved noninvasive diagnosis. Cardiac MR
      imaging isa versatile, comprehensive technique for assessing cardiac morphology
      and function. With an understanding of cardiac anatomy and physiology and MR
      imaging physical principles,cardiac MR imaging can be performed and can play an
      important role in patient management. This article provides the reader with a
      basic understanding of cardiac MR imaging and the practical applications required
      to perform cardiac MR imaging.

PMID- 15193929
TI  - Postoperative cardiopulmonary thoracic imaging.
AB  - An appreciation of the normal postoperative changes and complications following
      cardiac surgical procedures is essential when interpreting postoperative imaging
      studies. This article focuses on both the normal postoperative appearances and
      the imaging of complications following common cardiac surgical procedures.
      Irrespective of the specific nature of the surgery, certain common complications
      may occur, either from the surgery itself,the use of cardiac bypass, or the
      patient's underlying cardiac disorder. Postoperative imaging after specific
      thoracic cardiovascular surgeries is also discussed.

PMID- 15193930
TI  - CT and MR imaging of the thoracic aorta: current techniques and clinical
      applications.
AB  - Disease of the thoracic aorta can present with a broad clinical spectrum of
      symptoms and signs. The accepted diagnostic gold standard, selective digital
      subtraction angiography, is now being challenged by state-of-the-art CT
      angiography (CTA) and MR angiography(MRA). Currently, in many centers, cross
      sectional imaging modalities are being used as the first line of diagnosis to
      evaluate the cardiovascular system, and conventional angiography is reserved for
      therapeutic intervention. Understanding the principles of CTA and MRA techniques
      is essential to acquire diagnostic images consistently. This article reviews
      current CTA and MRA methods used in the evaluation of thoracic aortic disease.

PMID- 15193931
TI  - CT and MR imaging of pericardial disease.
AB  - The diagnosis and therapy of pericardial diseases are still a physician's
      challenge. Advanced CT and MR imaging technologies can display the complete
      morphology of the heart and the pericardium and of the adjacent thoracic
      structures with a spatial and contrast resolution below 1 mm. All the
      macromorphologic determinants of pericardial constriction and their functional
      sequels may be identified by these remarkable technologies. A careful systematic
      image analysis defines not only a precise diagnosis but also determines the
      optimal surgical or conservative therapy for the individual patient and minimizes
      the risk of perisurgical mortality.

PMID- 15193932
TI  - Calcifications of the heart.
AB  - Cardiac calcification usually represents the result of a pathologic process. Some
      forms of calcification represent chronic change in an ageing population, and must
      be differentiated from pathologic calcification. Still other forms of
      calcification are associated with ageing and chronic degeneration, but also
      reflect ongoing pathologic processes. Recognition of cardiac calcification may be
      an early sign or only sign of a pathologic process. Characterization of the
      calcification in terms of its distribution and appearance is a helpful means for
      determining which structures are calcified, differentiating pathologic from
      nonpathologic processes. This article provides an overview of the types of
      calcifications of the heart, pathogenesis, and utility of the various imaging
      modalities for their detection.

PMID- 15193935
TI  - MR imaging in ischemic heart disease.
AB  - This article reviews the current MR imaging literature with respect to ischemic
      heart disease and focuses on the clinical practicalities of cardiac MR imaging
      today.

PMID- 15193933
TI  - Cardiac imaging using nuclear medicine and positron emission tomography.
AB  - This article concentrates on specific issues that are of current interest in
      mainstream nuclear cardiology. These include developments in myocardial perfusion
      technique, the potential diagnostic benefits of ECG-gating and attenuation
      correction, nuclear imaging in the diagnosis of hibernating myocardium, and the
      cost-effectiveness of perfusion imaging in patients with suspected angina.

PMID- 15193936
TI  - Congenital heart disease in the adult: 2004.
AB  - The number of newborn infants with congenital heart disease is relatively
      stable.However, because of marked advances in correction and palliation of these
      conditions,the great majority will survive into adult life, significantly
      increasing the number of such patients in our population. Most patients with
      congenital heart disease, treated or not,will require routine, continued medical
      observation and, therefore, many radiologists will become involved in their care.
      Not uncommonly, pertinent clinical information is not provided to the
      radiologist, particularly when the patient presents to an Emergency Room because
      of intercurrent disease. In order to interpret the chest film or CT examination
      and provide a pertinent report, the radiologist must be conversant with the
      patterns of the more common congenital cardiac anomalies as well as their post
      operative appearances and potential complications.

PMID- 15193938
TI  - Visual paired comparison performance is impaired in a patient with selective
      hippocampal lesions and relatively intact item recognition.
AB  - In this study, we have examined visual recognition memory in a patient, YR, with
      discrete hippocampal damage who has shown normal or nearly normal item
      recognition over a large number of tests. We directly compared her performance as
      measured using a visual paired comparison task (VPC) with her performance on
      delayed matching to sample (DMS) tasks. We also investigated the effect of
      retention interval between familiarisation and test. YR shows good visual
      recognition with the DMS task up to 10 s after the familiarisation period, but
      only shows recognition with the VPC task for the shortest retention interval (0
      s). Our results are consistent with the view that hippocampal damage disrupts
      recollection and recall, but not item familiarity memory.

PMID- 15193939
TI  - Brain activity correlates differentially with increasing temporal complexity of
      rhythms during initialisation, synchronisation, and continuation phases of paced
      finger tapping.
AB  - Activity in parts of the human motor system has been shown to correlate with the
      complexity of performed motor sequences in terms of the number of limbs moved,
      number of movements, and number of trajectories. Here, we searched for activity
      correlating with temporal complexity, in terms of the number of different
      intervals produced in the sequence, using an overlearned tapping task. Our task
      was divided into three phases: movement selection and initiation (initiate),
      synchronisation of finger tapping with an external auditory cue (synchronise),
      and continued tapping in absence of the auditory pacer (continue). Comparisons
      between synchronisation and continuation showed a pattern in keeping with prior
      neuroimaging studies of paced finger tapping. Thus, activation of bilateral SMA
      and basal ganglia was greater in continuation tapping than in synchronisation
      tapping. Parametric analysis revealed activity correlating with temporal
      complexity during initiate in bilateral supplementary and pre-supplementary motor
      cortex (SMA and preSMA), rostral dorsal premotor cortex (PMC), basal ganglia, and
      dorsolateral prefrontal cortex (DLPFC), among other areas. During synchronise,
      correlated activity was observed in bilateral SMA, more caudal dorsal and ventral
      PMC, right DLPFC and right primary motor cortex. No correlated activity was
      observed during continue at P<0.01 (corrected, cluster level), though left
      angular gyrus was active at P<0.05. We suggest that the preSMA and rostral dorsal
      PMC activities during initiate may be associated with selection of timing
      parameters, while activation in centromedial prefrontal cortex during both
      initiate and synchronise may be associated with temporal error monitoring or
      correction. The absence of activity significantly correlated with temporal
      complexity during continue suggests that, once an overlearned timed movement
      sequence has been selected and initiated, there is no further adjustment of the
      timing control processes related to its continued production in absence of
      external cues.

PMID- 15193940
TI  - Memory and executive function in older adults: relationships with temporal and
      prefrontal gray matter volumes and white matter hyperintensities.
AB  - Forty-eight healthy adults aged 65-85 were recruited for structural magnetic
      resonance scans after an extensive neuropsychological battery that ensured a high
      degree of variability across the sample in performance on long-term memory tests,
      and on tests traditionally thought to rely on prefrontal cortex. Gray matter
      volumes were measured for three gyri in the frontal lobe (superior, middle,
      inferior), six gyri in the temporal lobe (superior, middle, inferior, fusiform,
      parahippocampal, and hippocampus), and the occipital lobe. Gray matter volumes
      declined across the age range evaluated, but with substantial regional variation-
      greatest in the inferior frontal, superior temporal, and middle temporal gyri but
      negligible in the occipital lobe. Both memory performance and executive function
      declined as the number of hyperintense regions in the subcortical white matter
      increased. Memory performance was also significantly correlated with gray matter
      volumes of the middle frontal gyrus (MFG), and several regions of temporal
      neocortex. However, the correlations were all in the negative direction; better
      memory performance was associated with smaller volumes. Several previous reports
      of significant negative correlations between gray matter volumes and memory
      performance are described, so that the possible reasons for this surprising
      finding are discussed.

PMID- 15193941
TI  - Autobiographical and episodic memory--one and the same? Evidence from prefrontal
      activation in neuroimaging studies.
AB  - Laboratory investigations of episodic memory often require participants to encode
      and later retrieve lists of items (words, pictures, or faces). The underlying
      assumption is that recollection of items from the list is analogous to
      recollection of events from one's past, i.e. autobiographical re-experiencing.
      Functional neuroimaging studies of episodic memory have provided extensive
      evidence suggesting that regions of the prefrontal cortex (PFC) play a role in
      episodic memory retrieval. A review of PFC activations reported in imaging
      studies of autobiographical memory and matched sub-sets of list-learning episodic
      memory studies reveals patterns of similarity but also substantial differences.
      Episodic memory studies often report activations in the right mid-dorsolateral
      PFC, but such activations are absent in autobiographical memory studies.
      Additionally, activations in the ventromedial PFC, primarily on the left, are
      almost invariably found in autobiographical memory studies, but rarely occur in
      studies of episodic memory. It is suggested that these two regions mediate
      different modes of post-retrieval monitoring and verification. Autobiographical
      memory relies on quick intuitive 'feeling of rightness' to monitor the veracity
      and cohesiveness of retrieved memories in relation to an activated self-schema.
      Episodic memory for lists requires more conscious elaborate monitoring to avoid
      omissions, commissions and repetitions. The present analysis suggests that care
      and caution should be exercised in extrapolating from the way we recollect
      'events' from a list learned in the laboratory to the way we recollect events
      from our lives.

PMID- 15193942
TI  - Learning of ambiguous versus hybrid sequences by patients with Parkinson's
      disease.
AB  - Implicit motor learning as indexed by the serial reaction time (SRT) task has
      been shown to be impaired in patients with Parkinson's disease (PD). This has
      only been conclusively demonstrated for sequences that require learning of second
      order sequential information (ambiguous sequences). This study examines implicit
      learning of ambiguous sequences as well as sequences which contain first-order
      information (hybrid sequences) in a sample of 12 early to middle stage
      Parkinson's disease patients and matched controls. The study used dual-task
      methodology in order to prevent strategic/attentional learning of second-order
      information. The results showed that while ambiguous sequences were not learned
      by either group, both patient and control groups demonstrated learning of the
      hybrid sequence under dual-task conditions. This suggests that first-order
      associations may be learned by people with Parkinson's disease, even under
      attentionally demanding conditions. This may be interpreted as providing evidence
      for a non-attentional learning mechanism which is relatively intact in
      Parkinson's disease.

PMID- 15193943
TI  - Preserved visuo-spatial transformations in representational neglect.
AB  - Patients with representational unilateral neglect were impaired in immediate
      recall of novel material on the neglected side as presented (viewed and removed
      or verbally described) or following mental rotation. Transforming material from
      the neglected (left) side to the non-neglected (right) side resulted in no
      additional loss; patients were unimpaired in directing attention to the neglected
      side of their representation in order to perform the mental rotation. These
      findings cannot be explained by the widely adopted attention deficit hypothesis
      for representational neglect. It is suggested that the disorder arises from
      damage to temporary storage functions of visuo-spatial working memory.

PMID- 15193944
TI  - Cross-modal recognition of shape from hand to eyes and handedness in human
      newborns.
AB  - The present research addresses the question of the generality of the ability to
      transfer shape information from one hand to the eyes recently evidenced in human
      newborns. Using an intersensory paired-preference procedure, we confirmed that
      newborns can visually recognize the shape of an object that they have previously
      manipulated with their right hand, out of sight. However, the results revealed
      that this ability is absent when the left hand is involved. Handedness in cross
      modal transfer task is discussed in relation to other behavioral asymmetries in
      newborns. Taken together, the present research confirms the existence in some
      conditions of an early fragile ability to extract shape information in a tactual
      format and transfer it to a visual format, independent of common experience.

PMID- 15193945
TI  - Electrophysiological correlates of stimulus-driven multiplication facts
      retrieval.
AB  - We investigated ERPs elicited by stimulus-driven retrieval of arithmetic facts
      related to multiplication. To this purpose, we recorded the electrophysiological
      activity from the scalp of participants while they were performing a number
      matching task. Crucially, arithmetic was task-irrelevant within this paradigm,
      because participants were simply to physically compare a cue composed of two one-
      or two-digit numbers and a single probe number. In line with past literature,
      behavioral data showed that, in non-matching trials, participants were
      significantly slower and/or less accurate to respond when the probe number was
      the product of the two numbers in the cue compared to when the probe number was
      arithmetically unrelated (i.e., neutral) to those numbers (interference effect).
      Consistent with recent findings on ERPs and task-relevant arithmetic facts
      retrieval, we showed that the interference effect resulted in a modulation of the
      amplitude of an N400-like ERP component, with neutral probes generating
      relatively more negativity than product probes. The observed dissociation between
      behavioral data and ERP measures is interpreted as evidence of activation
      spreading in the lexicon of arithmetic facts, because alternative accounts that
      rely on strategic factors such as expectancy or semantic matching would have
      predicted the two measures to show a converging trend.

PMID- 15193946
TI  - Different neurons in different regions of human temporal lobe distinguish correct
      from incorrect identification or memory.
AB  - Changes in the frequency of neural activity differentiating correct from
      incorrect responses were identified in extracellular recordings from 113 neurons
      at 62 sites in temporal lobe of 26 patients undergoing awake neurosurgery, during
      identification and recent explicit memory for object names, text or auditory
      words. Activity significantly differentiating correct from incorrect performance
      was identified in 22 neurons at 16 sites in 12 patients. Different neurons in
      different regions differentiated identification or memory performance. The 13
      neurons differentiating identification performance were overrepresented in medial
      basal recordings, the 9 neurons differentiating memory performance in superior
      temporal gyrus. All memory changes occurred during encoding. For both
      identification and memory there was separation of neurons showing differentiation
      early during perception and processing from those showing differentiation late,
      when output should occur, perhaps reflecting response monitoring. Early
      differentiating neurons were located more superior-laterally within the different
      regions related to accuracy of identification or memory.

PMID- 15193947
TI  - Relationship between hippocampal volume and memory ability in healthy individuals
      across the lifespan: review and meta-analysis.
AB  - Poor memory ability and small hippocampal volume measurements in magnetic
      resonance images co-occur in neurological patients. Numerous studies have
      examined the relationship between memory performance and hippocampal volumes in
      participants without neurological or psychiatric disorders, with widely varying
      results. Three hypotheses about volume-memory relationships in the normal human
      brain are discussed: "bigger is always better", a neuropsychological view that
      volume decreases due to normal aging are accompanied by memory decline, and a
      developmental perspective that regressive events in development may result in
      negative correlations between hippocampal volume and memory ability. Meta
      analysis of results from 33 studies led to little support for the bigger-is
      better hypothesis. A negative relationship between hippocampal volume and memory
      (smaller is better) was significant for studies with children, adolescents, and
      young adults. For studies with older adults, the most striking observation was
      extreme variability: the evidence for a positive relationship between hippocampal
      size and episodic memory ability in older adults was surprisingly weak. Some of
      the variability in results from older adults was associated with statistical
      methods of normalizing for age and head size, which are discussed.

PMID- 15193948
TI  - The neuropsychology of narrative: story comprehension, story production and their
      interrelation.
AB  - Stories are used extensively for human communication; both the comprehension and
      production of oral and written narratives constitute a fundamental part of our
      experience. While study of this topic has largely been the domain of cognitive
      psychology, neuroscience has also made progress in uncovering the processes
      underlying these abilities. In an attempt to synthesize work from both
      literatures, this review: (1) summarizes the current neuroimaging and patient
      research pertaining to narrative comprehension and production, (2) attempts to
      integrate this information with the processes described by the discourse models
      of cognitive psychology, and (3) uses this information to examine the possible
      interrelation between comprehension and production. Story comprehension appears
      to entail a network of frontal, temporal and cingulate areas that support working
      memory and theory-of-mind processes. The specific functions associated with these
      areas are congruent with the processes proposed by cognitive models of
      comprehension. Moreover, these same areas appear necessary for story production,
      and the causal-temporal ordering of selected information may partially account
      for this common ground. A basic description of comprehension and production based
      solely on neuropsychological evidence is presented to complement current
      cognitive models, and a number of avenues for future research are suggested.

PMID- 15193949
TI  - Novel roles for arrestins in the post-endocytic trafficking of G protein-coupled
      receptors.
AB  - G protein-coupled receptors (GPCRs) represent the largest family of transmembrane
      signaling molecules in the human genome. As such, they interact with numerous
      intracellular molecules, which can act either to propagate or curtail signaling
      from the receptor. Their primary mode of cellular activation occurs through
      heterotrimeric G proteins, which in turn can activate a wide spectrum of effector
      molecules, including phosphodiesterases, phospholipases, adenylyl cyclases and
      ion channels. Active GPCRs are also the target of G protein-coupled receptor
      kinases, which phosphorylate the receptors culminating in the binding of the
      protein arrestin. This results in rapid desensitization through inhibition of G
      protein binding, as well as novel mechanisms of cellular activation that involve
      the scaffolding of cellular kinases to GPCR-arrestin complexes. Arrestins can
      also serve to mediate the internalization of certain GPCRs, a process which plays
      an important role in regulating cellular activity both by mediating long-term
      desensitization through down regulation (degradation) of receptors and by
      recycling desensitized receptors back to the cell surface to initiate additional
      rounds of signaling. The mechanisms that regulate the subsequent intracellular
      trafficking of GPCRs following internalization are largely unknown. Recently
      however, it has become clear that the pattern of receptor phosphorylation and
      subsequent binding of arrestin play a critical role in the intracellular
      trafficking of internalized receptors, thereby dictating the ultimate fate of the
      receptor. In addition, arrestins have now been shown to be required for the
      recycling of GPCRs that are capable of internalizing through arrestin-independent
      mechanisms. This review will summarize recent advances in our understanding of
      the roles of arrestins in post-endocytic GPCR trafficking.

PMID- 15193950
TI  - The role of C-reactive protein in ischemia/reperfusion injury and preconditioning
      in a rat model of myocardial infarction.
AB  - For the first time the involvement of C-Reactive protein (CRP) in early (acute)
      and delayed ischemic (IPC) and pharmacological (chemical) preconditioning (CPC)
      in an in vivo model of rat myocardial infarction was presented. Acute IPC was
      produced by three 5 minute occlusion (ischemia) periods interspersed with 5
      minute reperfusion, followed by 30 minute occlusion of the left coronary artery
      and 2 hour reperfusion injury. Acute CPC was produced by a k-opioid receptor
      agonist U50488H (5 mg/kg) applied i.v. 15 minutes before 30 minute ischemia/ 2
      hour reperfusion. Delayed preconditioning was produced by 30 minute ischemia/ 2
      hour reperfusion, induced 24 hour after either ischemic or pharmacological
      preconditioning. The myocardial ischemia/reperfusion injury was evaluated on the
      basis of total and cardiac creatine kinase isoenzyme activity, functional
      recovery of the heart (ECG), infarct size (% IS/RA) and mortality at the end of
      the experiments. The results obtained showed that: k-opioid receptor agonist
      U50488H mimics both the acute and delayed IPC in the above experimental protocol;
      Both acute IPC and most probably CPC act by opening of K(ATP) channels (the
      effects were blocked by nonspecific ATP-sensitive K channel blocker
      glybenclamide), and via activation of protein kinase C (a selective protein
      kinase C inhibitor chelerythrine blocked the efects); C-reactive protein (CRP)
      was significantly elevated by 54% in non-preconditioned acute
      ischemia/reperfusion injury. The elevation was more pronounced (82% increase) 24
      hour after non-preconditioned ischemia/reperfusion injury. It reflected very well
      the increase in cardiac isoenzymes, infarct size and mortality of the rats, and
      can be used as a marker of the severity of myocardial injury in this model; The
      increase of CRP was prevented by both IPC and CPC in early, and especially in
      late preconditioning. This confirms the involvement of CRP as a marker in cardiac
      ischemic/reperfusion injury. It was concluded that in addition to the established
      involvement of adenosine, bradykinin, opioid and other receptors, a suppression
      of myocardial CRP/complement production might be involved in the biological
      mechanism of preconditioning. This could be a promising perspective in clinical
      interventions against ischemia/reperfusion injuries of the heart.

PMID- 15193951
TI  - A secondary surge of prolactin on the estrus afternoon.
AB  - It has been described that throughout the estrous cycle of the rat, plasma
      prolactin (PRL) is basal except on proestrus afternoon when a preovulatory surge
      occurs. However, there have been controversies about PRL levels on the estrus
      day. Thus, the aim of this study was to evaluate the existence of a secondary
      surge of PRL on estrus afternoon and correlate it with plasma estradiol levels.
      The jugular vein of cycling rats was cannulated at 14:00 h on proestrus and a
      blood sample was withdrawn at 17:00 h for plasma LH measurement and determination
      of the preovulatory LH surge occurrence. In order to exclude the regular cycling
      rats that do not present the gonadotropins preovulatory surge and do not ovulate,
      only rats showing the LH surge on proestrus were considered in this study. Blood
      samples were collected hourly during estrus from midnight to 9:00 h (group 1) and
      from 10:00 to 18:00 h (group 2). In group 1, PRL showed a descending profile from
      midnight to 9:00 h, whereas the estradiol concentrations were constant. In group
      2, a secondary surge of PRL was observed in 20 of 25 (80%) rats and plasma
      estradiol remained constant, but was higher in animals with the PRL surge. Thus
      the present data suggest the occurrence of a secondary surge of PRL in the
      afternoon of estrus that seems to be related to plasma estradiol levels of estrus
      day, which might exert only a permissive role in this surge generation.

PMID- 15193952
TI  - Effect of thyroid hormones on the gene expression of calcium transport systems in
      rat muscles.
AB  - It has been previously shown that modification of thyroid hormone levels have a
      profound impact on cardiac function, predominantly through a direct regulation of
      the sarcoplasmic reticulum protein levels. Nevertheless, little is known about
      the regulation of calcium transport systems in skeletal muscle due to the altered
      concentration of thyroid hormones. Thus, the goal of our study was to find out
      whether altered thyroid status could change the gene expression of the
      Na(+)/Ca(2+) exchanger (NCX), the inositol 1,4,5-trisphosphate (IP(3)) receptors
      and ryanodine receptors (RyRs) in slow and fast skeletal muscles of rats. A
      hyperthyroid state was maintained in rats by triiodothyronine (T(3))
      administration, while methimazole was employed for inducing hypothyroidism. After
      a period of 2-10 months of T(3) treatment we observed a significant increase in
      mRNA levels of the NCX, RyRs and IP(3) receptors. This increase was more
      pronounced in the slow soleus than in the fast extensor digitorum longus (EDL)
      muscle. It is tempting to speculate that thyroid hormones also alter calcium
      concentration and thus influence the process of excitation-contraction coupling
      in the skeletal muscle.

PMID- 15193953
TI  - Oxidative stress in neonates: evaluation using specific biomarkers.
AB  - Increased oxidative stress has been implicated in pathogenesis of serious
      diseases in neonates. We measured urinary levels of 8-hydroxy-2'-deoxyguanosine
      (a marker of oxidative DNA damage), acrolein-lysine adduct (a marker of lipid
      peroxidation and oxidative protein damage), and nitrite/nitrate (a marker of
      endogenous nitric oxide formation) in one-month-old neonates to examine the
      status of oxidative stress and its relationship to the degree of prematurity and
      clinical condition in neonates. Study subjects comprised three groups: healthy
      term neonates, clinically stable preterm neonates requiring no supplemental
      oxygen, and clinically sick preterm neonates requiring supplemental oxygen and
      ventilator support. Urinary levels of 8-hydroxy-2'-deoxyguanosine and acrolein
      lysine adduct were significantly higher in sick preterm neonates than those of
      stable preterm and healthy term neonates. In the sick preterm group, neonates
      developing active retinopathy showed significantly higher levels of acrolein
      lysine adduct than the other neonates without retinopathy. There were no
      significant differences in both urinary markers of oxidative stress between
      stable preterm and healthy term neonates. The urinary nitrite/nitrate levels were
      not significantly different among the three groups, suggesting no difference in
      endogenous nitric oxide formation. Collectively, these results provide evidence
      of augmentation of oxidative damage to DNA, lipids and proteins, especially in
      clinically sick preterm neonates.

PMID- 15193954
TI  - Effect of treatment at weaning with the serotonin antagonist mianserin on the
      brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a
      case of late imprinting.
AB  - Four weeks old (weanling) female rats were treated with the tricyclic
      antidepressant and histamine/serotonin receptor blocker mianserin for studying
      its faulty hormonal imprinting effect. Measurements were done four months later.
      Brain serotonin levels significantly decreased in four regions (hippocampus,
      hypothalamus, striatum and brainstem), without any change in the cortex. Sexual
      activity of the treated and control rats was similar. Cerebrospinal fluid
      nocistatin level was one magnitude higher in the treated rats, than in the
      controls. The density of uterine estrogen receptors was significantly reduced,
      while binding capacity of glucocorticoid receptors of liver and thymus remained
      at control level. The results call attention to the possibility of 1. a broad
      spectrum imprinting at the time of weaning by a receptor level acting non-hormone
      molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a
      very durable (lifelong?) effect of the late imprinting with an antidepressant.

PMID- 15193955
TI  - Inhibition of human hepatic CYP isoforms by mGluR5 antagonists.
AB  - Characterization of new chemical entities for their potential to produce drug
      drug interactions is an important aspect of early drug discovery screening. In
      the present study, the potential for three metabotropic glutamate receptor
      antagonists to interact with recombinant human CYPs was investigated. 2-Methyl-6
      (phenylethenyl) pyridine (SIB-1893), 2-methyl-6-(phenylethynyl) pyridine (MPEP)
      and 3-[2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) were moderate
      competitive inhibitors of recombinant human CYP1A2 (Ki, 0.5-1 microM). SIB-1893,
      but not MPEP or MTEP, was also a moderate competitive inhibitor of CYP1B1. MPEP
      and MTEP were weak inhibitors of CYP2C19. None of the three compounds tested were
      significant inhibitors (IC(50) values >50 microM) of CYP3A4, 2C9, 2D6, 2A6, 2B6
      or 2E1. The results suggest that MTEP is a selective inhibitor of CYP1A2 and may
      prove to be a useful tool in studying drug-drug interactions involving this
      enzyme.

PMID- 15193956
TI  - Inhibition of the development of metastases by dietary vitamin C:K3 combination.
AB  - The tumor growth-inhibiting and chemo-potentiating effects of vitamin C and
      K(3)combinations have been demonstrated both in vitro and in vivo. The purpose of
      this study was to investigate the influence of orally administered vitamin C and
      K(3) on the metastasis of mouse liver tumor (T.L.T.) cells implanted in C3H mice.
      Adult male C3H mice were given water containing vitamin C and K3 (15 g/0.15 g
      dissolved in 1000 ml) beginning 2 weeks before tumor transplantation until the
      end of the experiment. T.L.T. cells (106) were implanted intramuscularly in the
      right thigh of mice. All mice were sacrificed 42 days after tumor
      transplantation. Primary tumor, lungs, lymph nodes and other organs or tissues
      suspected of harboring metastases were macroscopically examined. Samples of
      primary tumors, their local lymph nodes, lungs and main organs such as liver,
      kidneys, spleen were taken for histological examination. Forty-two percent of
      control mice exhibited lung metastases and 27% possessed metastases in local
      lymph nodes whereas 24% of vitamin-treated mice exhibited lung metastases and 10%
      possessed local lymph nodes metastases. The total number of lung metastases was
      19 in control group and 10 in vitamin C and K(3)-treated mice. Histopathological
      examination of the metastatic tumors from the vitamin-treated mice revealed the
      presence of many tumor cells undergoing autoschizic cell death. These results
      demonstrate that oral vitamin C and K(3) significantly inhibited the metastases
      of T.L.T. tumors in C3H mice. At least a portion of this inhibition was due to
      tumor cell death by autoschizis.

PMID- 15193957
TI  - Cannabinoid receptor-independent suppression of the superoxide generation of
      human neutrophils (PMN) by CP55 940, but not by anandamide.
AB  - Cannabinoids have been shown to affect various immune functions. To date, almost
      no data exist on PMN, which provide the first line antimicrobial defense. The
      objective of the present study was to investigate the effects of the synthetic
      dibenzopyrane ligand CP55 940, the endogenous cannabinoid anandamide and
      methanandamide on the "respiratory burst" of isolated human PMN in vitro. After
      preincubation with high micromolar concentrations of CP55 940, fMLP-stimulated
      PMN showed a reduction in superoxide production, whereas the spontaneous burst
      activity of resting PMN remained unaffected. This inhibitory effect of CP55 940
      was not CB-receptor-mediated. In contrast, anandamide and methanandamide did not
      alter the oxidative microbicidal PMN function.

PMID- 15193958
TI  - Time course of production of hydroxyl free radical after subarachnoid hemorrhage
      in dogs.
AB  - Vasospasm after subarachnoid hemorrhage (SAH) is associated with lipid
      peroxidation. However, lipid peroxides increase in a delayed fashion after SAH
      and may be a byproduct of but not a cause of vasospasm. This study correlated
      vasospasm with hydroxyl free radical and lipid peroxide levels. 24 dogs had
      baseline cerebral angiography and induction of SAH by 2 injections of blood into
      the cisterna magna at baseline and 2 days later. Angiography was repeated 4, 7,
      10, 14 or 21 days after the first injection (n = 4 per group) and a microdialysis
      catheter was inserted into the premedullary cistern. Control dogs (n = 4)
      underwent angiography and microdialysis but not SAH. Salicylic acid, 100 mg/kg,
      was administered intravenously, and microdialysis fluid was collected and
      analyzed by high pressure liquid chromatography for 2,3- and 2,5-dihydroxybenzoic
      acids (DHBA). Malondialdehyde was measured in subarachnoid clot removed from the
      prepontine cistern and in the basilar artery itself at the time of euthanasia.
      Significant vasospasm developed 4 to 14 days after SAH. Malondialdehyde levels
      were significantly elevated in the basilar artery and subarachnoid clot 4 days
      after SAH (p < 0.0001, ANOVA) but not at other times. 2,5-DHBA levels were
      significantly greater than control at 4 to 14 days and they peaked at 4 days (p <
      0.05, ANOVA). 2,3-DHBA was significantly increased at 4 days after SAH (p < 0.05,
      ANOVA). There were significant correlations between basilar artery
      malondialdehyde levels and vasospasm and cerebrospinal fluid 2,5-DHBA levels and
      vasospasm. These results suggest the presence of hydroxyl free radical after SAH
      and demonstrate a correlation between such production, as measured by trapping
      with salicylate, and the early phase of vasospasm. The correlation with vasospasm
      implicates free radicals and lipid peroxidation in this phase of vasospasm.

PMID- 15193959
TI  - Protease-activated receptor 2 in regulation of bronchomotor tone: effect of
      tobacco smoking.
AB  - Protease-activated receptors are G protein-coupled receptors activated by serine
      proteases. Protease-activated receptor 2 is involved in the regulation of airway
      smooth muscle tone but its effects vary according to species and experimental
      conditions. We determined the effects of protease-activated receptor 2 activation
      on smooth muscle tone and airway reactivity to histamine in guinea pigs and
      smoking or non-smoking humans. The effects of trypsin and protease-activated
      receptor activating peptide on the isometric tension and response to histamine of
      guinea pig tracheal and human bronchial rings were studied. Human tissues were
      obtained from 6 smokers and 4 non-smokers. We assessed the effects of epithelial
      removal, inhibitors of cyclooxygenases, nitric oxide synthases, neutral
      endopeptidase and antagonists of acetylcholine, histamine, bradykinin and
      tachykinin receptors. Bronchomotor responses to protease-activated receptor 2
      activation were variable in guinea pig, in half of animals PAR2 activation
      induced smooth muscle relaxation through the epithelial release of prostanoids
      but not of nitric oxide. In human airways, protease-activated receptor 2
      activation reduced responsiveness to histamine in bronchial rings from smokers
      but increased responsiveness in bronchi from non-smokers. This study demonstrates
      an influence of tobacco smoking on the effect of protease-activated receptor 2
      activation on airway responsiveness in humans, with an increased protection
      against histamine-induced contractions, probably through an increased epithelial
      release of prostanoids. The role of airway protease-activated receptor 2 may be
      to maintain smooth muscle tone homeostasis.

PMID- 15193960
TI  - Ethnic differences of coronary artery disease-associated SNPs in two Israeli
      healthy populations using MALDI-TOF mass spectrometry.
AB  - Differences in prevalence and mortality from coronary artery disease (CAD) were
      observed among the different Israeli ethnic groups. The incidence of CAD in
      Israel is highest among Ashkenazi Jews and is much lower among Yemenite Jews. In
      this present study, we selected 15 single nucleotide polymorphisms (SNPs) from 14
      candidate genes involved in (1) the renin-angiotensin system, (2) lipid
      metabolism, (3) cytokines and adhesion molecules, and (4) growth factors, and (5)
      the coagulation-fibrinolysis system. We analyzed the 15 SNPs in 94 Israeli
      healthy populations (47 Ashkenazi Jews and 47 Yemenite Jews) obtained from the
      National Laboratory for the Genetics of Israeli Populations. We applied chip
      based MALDI-TOF mass spectrometry as a method for screening multiplexed
      genotyping of SNPs for ethnic difference in these healthy populations. Among the
      15 candidate SNPs, significant differences in allelic frequency were observed in
      the 1166A>C of the AGTR1 gene, R158C of the Apo E gene, W64R of the ADRB3 gene,
      S101S of the TIMP 2 gene, and A222V of the MTHFR gene with respect to allele
      frequency. The incidence of A/C allele of the AGTR1 gene were 0.638/0.362 vs
      0.765/0.235, C/T allele in the apo E gene was 0.915/0.085 vs 0.989/0.011, T/C
      allele of the ADRB3 gene was 0.989/0.0011 vs 0.926/0.074, G/A allele of the TIMP2
      gene was 0.974/0.054 vs 0.830/0.170, and C/T allele in the MTHFR gene was
      0.521/0.479 vs 0.819/0.181 for Ashkenazi Jews and Yemenite Jews, respectively. We
      demonstrated an ethnic difference of CAD-associated SNPs in two Israeli healthy
      populations using MALDI-TOF mass spectrometry. Further study is necessary to
      prove causal relation with CAD-associated SNPs and the prevalence of CAD.

PMID- 15193961
TI  - Porcine FAD-containing monooxygenase metabolizes lidocaine, bupivacaine and
      propranolol in vitro.
AB  - Lidocaine, bupivacaine and propranolol are amines that can be expected to act as
      substrates for FAD-containing monooxygensae (FMO) (EC 1. 14. 13. 8). We found
      that FMO metabolizes lidocaine, bupivacaine and propranolol. The Km and Vmax
      values of lidocaine, bupivacaine and propranolol for FMO are 143, 408 and 210
      microM, and 145, 119 and 135 nmol/min/mg FMO protein, respectively. The
      lipophilicity of the drugs decreased in the following order:
      lidocaine>propranolol>bupivacaine, under our experimental conditions.
      Furthermore, the metabolic products of FMO were separated by high-performance
      liquid chromatography and analyzed by gas chromatography-mass spectrometry, and
      were found to be the N-oxides and N-hydroxylamines of the respective drugs. These
      findings suggest that lidocaine, bupivacaine and propranolol are substrates for
      FMO, and the enzymatic toward lidocaine or bupivacaine may be inhibited
      exclusively and competitively by propranolol.

PMID- 15193962
TI  - The journal, the EACLPP and the ICPM.

PMID- 15193963
TI  - Psychosomatic research in Europe: quo vadis-where we are going?

PMID- 15193964
TI  - Body image dissatisfaction among males across the lifespan: a review of past
      literature.
AB  - OBJECTIVE: Most past research has focused on body dissatisfaction among females.
      This paper provides a review and evaluation of studies that have examined body
      dissatisfaction among males. Body dissatisfaction in males has been associated
      with poor psychological adjustment, eating disorders, steroid use, exercise
      dependence, as well as other health behaviors. It is therefore important to
      understand the level of body dissatisfaction, as well as the factors that are
      related to this construct. METHOD: The review is divided into three sections:
      body dissatisfaction among children, adolescents and adults. Within each section,
      levels of body dissatisfaction are examined, as well as the research that relates
      to sociocultural influences on body dissatisfaction. Difficulties in drawing
      valid conclusions from the data due to methodological problems are highlighted.
      RESULTS: From the current data, it would appear that there are strong
      similarities in the levels of body dissatisfaction of male and female children,
      with most children demonstrating high levels of body satisfaction. During
      adolescence, boys are about equally divided between wanting to lose weight and
      increasing weight, but there are few studies that have examined a desire for
      increased muscle size. In adulthood, men evidence a stronger desire to lose
      weight as they get older. CONCLUSION: Overall, past studies have primarily
      focused on questions that are relevant to females, and there is a need to conduct
      studies that evaluate areas of body dissatisfaction that have greater relevance
      for males. This will then allow a better understanding of the relationship
      between body dissatisfaction and psychological and behavioral problems
      experienced by males at all stages of the lifespan.

PMID- 15193965
TI  - Effect of psychotherapy and relaxation on the psychosocial and somatic course of
      Crohn's disease: main results of the German Prospective Multicenter Psychotherapy
      Treatment study on Crohn's Disease.
AB  - OBJECTIVE: Few studies have been published on the influence of psychotherapy on
      the physical and psychosocial course of Crohn's disease (CD). METHODS: The
      present study, a prospective, randomized multicenter investigation conducted with
      108 of 488 consecutive CD patients, was designed to investigate the influence of
      short-term psychodynamic therapy and relaxation in addition to a standardized
      glucocorticoid therapy on the somatic course of the disease as well as on patient
      psychosocial status. Based on the same standardized somatic treatment, the
      psychotherapy and control groups were compared after a 1-year treatment period
      and a follow-up of another year with regard to somatic course and psychosocial
      situation. RESULTS: A total of 81 (75%) of 108 randomized patients completed the
      psychosocial follow-up. The comparison between the therapy groups after 1 year
      showed no significant differences in the four main target criteria of
      psychosocial status (depression, anxiety, psychosocial-communicative status and
      health-related quality of life). The mean Beck's Depression Inventory (BDI) score
      at admission was 12.3 in the psychotherapy group and 8.7 in the control group. At
      the 1-year follow-up, the scores for depression have been 7.8 (psychotherapy
      group) and 7.8 (control group). In the 2-year follow-up, 84 patients were
      classified into four groups on the basis of somatic course; 23% of the control
      group and 30% of the psychotherapy group showed episode-free courses, 29% and 17%
      respectively underwent surgery due to failure of immunosuppressive or medical
      therapy, and a further subranking showed no significant differences between the
      two groups (P=.125). At the 1-year follow-up, the scores for depression of
      patients with an active episode respective remission were 14.6 vs. 5.8. From the
      patient's point of view, at the end of the 2-year follow-up, the overall
      subjective evaluation of the effectiveness of psychotherapy was positive.
      CONCLUSION: The patients included showed no psychosocial disturbances of clinical
      relevance. Although a tendency toward fewer surgical interventions, fewer
      relapses and reduction of depression was noted, the analysis was unable to
      demonstrate any benefit from psychosocial intervention on hypothesized parameters
      of psychosocial status and somatic course. Further studies should be performed to
      identify patient subgroups that may benefit from psychosocial intervention.

PMID- 15193966
TI  - Psychological treatment in Crohn's disease.

PMID- 15193967
TI  - Alexithymia is no risk factor for exacerbation in spasmodic torticollis patients.
AB  - OBJECTIVE: To assess whether alexithymia is a risk factor for exacerbation in
      spasmodic torticollis (ST). METHODS: ST patients (2 x 10) with high vs. low
      alexithymia scores (mean score on the 20-item Toronto Alexithymia Scale [TAS
      20]=69.2 vs. 28.7) were compared on physiological, motor and subjective responses
      to a cognitive and an emotional laboratory stressor. Changes in sustained
      abnormal head/shoulder positions and maximum range of motion (ROM) of the
      cervical spine were kinematically quantified. Skin conductance level (SCL),
      nonspecific skin conductance fluctuations (NS.SCF), heart rate (HR) and skin
      temperature (T) were measured. RESULTS: High alexithymia had no effect on the
      abnormal head posture or movements, but high-alexithymic ST patients showed
      generally increased levels of autonomic arousal (more NS.SCF, higher SCL;
      analysis of variance [ANOVA]: P=.016 and P=.051, respectively) under all
      experimental conditions. When ST symptom severity (TSUI-score) was partialled
      out, these group differences were somewhat reduced (analysis of covariance
      [ANCOVA]: P=.052 and P=.143). CONCLUSIONS: High alexithymia did not lead to
      increased abnormal head movements to stressors, but may result in a subtle
      increase in tonic level of sympathetic activity.

PMID- 15193968
TI  - Study on alexithymia in adult non-patients.
AB  - OBJECTIVE: We tested the purported complex relationships between alexithymia and
      somatization, depression, borderline pathology and general health. METHODS: A
      total of 139 medical students and 84 members of nursing personnel completed
      questionnaires. RESULTS: Thirteen (6%) alexithymic participants indicated more
      depression and borderline pathology and worse mental health. Path analysis
      confirmed a significant positive effect of borderline pathology and a significant
      negative effect of mental health on alexithymia but did not reveal any effects of
      somatization and depression. CONCLUSION: Presence of borderline pathology may
      indicate higher probability of alexithymia.

PMID- 15193969
TI  - Behavioral interventions in asthma: biofeedback techniques.
AB  - OBJECTIVES: Biofeedback techniques have long been recommended as an adjunctive
      treatment for bronchial asthma. Techniques that target lung function directly, or
      indirectly by altering facial muscle tension, heart rate, heart rate variability
      (HRV) or inspiratory volume together with accessory muscle tension, have been
      proposed. We review evidence for the effectiveness of these biofeedback
      interventions and discuss the psychophysiological rationale behind individual
      techniques. METHOD: Controlled studies of biofeedback in asthma were retrieved
      using relevant search engines and reference lists of published articles. Effect
      sizes comparing intervention with control groups were calculated where
      appropriate. RESULTS: Most of the studies suffer from methodological inadequacies
      or poor reporting of methods and results. Interventions targeting respiratory
      resistance directly have yielded only small and inconsistent changes in lung
      function and are difficult to implement without producing dynamic hyperinflation.
      Biofeedback-assisted facial muscle relaxation as an indirect intervention has
      yielded mixed results across studies, with only half of the studies showing
      significant albeit very small and clinically irrelevant improvements in lung
      function. The underlying physiological assumptions of the technique are
      questionable in the light of current knowledge of respiratory physiology. For
      other indirect techniques, only preliminary evidence of small effects is
      available. CONCLUSION: Currently, there is little good evidence that biofeedback
      techniques can contribute substantially to the treatment of asthma.

PMID- 15193970
TI  - The contribution of expectations to motion sickness symptoms and gastric
      activity.
AB  - OBJECTIVE: The goal of this investigation was to determine in healthy adults the
      effect of expectation manipulations on the development of motion sickness, as
      indicated by abnormal gastric myoelectric activity and subjective reports of
      symptoms of motion sickness. METHOD: Eighty participants, moderately susceptible
      to motion sickness, experienced one of four conditions created from a two
      variable (Expectation, Drum), two-factor model (High/Low expectation for
      sickness; Rotating/Stable Drum). The electrogastrogram (EGG) was recorded 6 min
      prior to the expectation manipulation; 6 min following the expectation
      manipulation; 6 min before drum activation; and 16 min during drum activation.
      Self-report questionnaires indicating expectation for sickness (MSEx) and motion
      sickness symptoms (Nausea Profile [NP]) were obtained following the expectation
      manipulation and exposure to the drum, respectively. RESULTS: No significant
      differences were observed among expectation groups for retrospective reports of
      motion sickness (NP); however, significant differences in EGG responses to drum
      rotation were obtained. The unexpected results of a univariate analysis of
      variance (ANOVA) revealed significantly greater gastric tachyarrhythmia and less
      normal activity, an indication of motion sickness, in the low expectation for
      sickness conditions. CONCLUSION: These results suggest that inducing a high
      expectation for sickness in healthy individuals about to be exposed to
      provocative motion results in a protective effect from motion sickness following
      exposure to the stimulus, while low expectations may induce abnormal gastric
      activity.

PMID- 15193971
TI  - Semantic integration and syntactic planning in language production.
AB  - Five experiments, using a subject-verb agreement error elicitation procedure,
      investigated syntactic planning processes in production. The experiments examined
      the influence of semantic integration--the degree to which phrases are tightly
      linked at the conceptual level--and contrasted two accounts of planning: serial
      stack-based systems and parallel activation-based systems. Serial stack-based
      systems rely on memory-shifting processes to coordinate ongoing planning. Memory
      shifting should be easier for more integrated phrases, resulting in fewer errors.
      Parallel, activation-based systems, on the other hand, maintain multiple
      representations simultaneously in memory. More integrated phrases will be more
      likely to be processed together, resulting in increased interference and more
      errors. Participants completed stimuli like The drawing of/with the flower(s),
      which varied local noun number (flower(s)) and the relationship between the head
      (drawing) and local noun. In some constructions, the nouns were tightly
      integrated (e.g., of), whereas in others the relationship was looser (e.g., with,
      specifying accompaniment). In addition to the well-established local noun
      mismatch effect (more errors for plural than for singular local nouns), all
      experiments revealed larger mismatch error effects following tightly integrated
      stimuli. These results are compatible with parallel activation-based accounts and
      cannot be explained by serial, memory-shift-based accounts. The experiments and
      three meta-analyses also ruled out alternative accounts based on plausibility,
      argumenthood, conceptual number, clause packaging, or hierarchical feature
      passing, reinforcing the general finding that error rates increase with degree of
      semantic integration.

PMID- 15193972
TI  - Assessing the distinguishability of models and the informativeness of data.
AB  - A difficulty in the development and testing of psychological models is that they
      are typically evaluated solely on their ability to fit experimental data, with
      little consideration given to their ability to fit other possible data patterns.
      By examining how well model A fits data generated by model B, and vice versa (a
      technique that we call landscaping), much safer inferences can be made about the
      meaning of a model's fit to data. We demonstrate the landscaping technique using
      four models of retention and 77 historical data sets, and show how the method can
      be used to: (1) evaluate the distinguishability of models, (2) evaluate the
      informativeness of data in distinguishing between models, and (3) suggest new
      ways to distinguish between models. The generality of the method is demonstrated
      in two other research areas (information integration and categorization), and its
      relationship to the important notion of model complexity is discussed.

PMID- 15193973
TI  - Laboratory variables and stratification of metastatic colorectal cancer patients:
      recommendations for therapeutic trials and for clinical practice guidelines.
AB  - OBJECTIVE: To identify, through a systematic review of the literature, the
      laboratory variables that, in addition to performance status and to the degree of
      tumor invasion, would allow a more accurate stratification of metastatic
      colorectal cancer patients who participate in chemotherapy trials, with or
      without radiotherapy. SECONDARY AIM: To compare the results of our systematic
      review with the recommendations made in current clinical practice guidelines, and
      with the results of related systematic reviews. METHODS: Update of two recently
      published systematic reviews, without metaanalysis, following the recommendations
      of the International Federation of Clinical Chemistry and Laboratory Medicine,
      and taking into account the Consolidated Standards of Reporting Trials statement.
      RESULTS: Of 877 publications retrieved, reasonable exclusion and inclusion
      criteria allow us to include 15 studies in our systematic review, thus confirming
      the low quality of clinical research in laboratory medicine. Four variables were
      most often found "significant" in multivariate statistical analysis:
      pretherapeutic levels of laboratory tests (13/15, 87%), degree of tumor invasion
      (9/13, 69%), treatment, or response to treatment (6/9, 67%), and performance
      status (8/13, 62%). The laboratory variable whose measurements are quite often
      recommended in the 10 clinical practice guidelines or in the four related
      systematic reviews that we retrieved are carcinoembryonic antigen (CEA), and
      liver function tests to a lesser extent. CONCLUSIONS: Available evidence supports
      the recommendation that in all metastatic colorectal cancer patients who
      participate in therapeutic trials, the following pretreatment laboratory
      variables should be systematically measured: blood cell counts, and haemoglobin,
      plasma prothrombin time, serum alkaline phosphatase (ALP), lactate dehydrogenase,
      transaminases, albumin, bilirubin, and CEA. If other tests were to be added,
      gamma glutamyl transferase, and erythrocyte sedimentation rate might perhaps be
      proposed. Further studies would be necessary to support the addition to this
      list, of other tests [e.g., cancer antigen (CA) 19-9]. Rather than using
      laboratory variables according to arbitrary thresholds, it seems recommendable to
      use them as continuous variables, and if possible, in terms of kinetics. Many
      clinical practice guidelines do not use levels of evidence in order to grade the
      strength of their recommendations, but rather seem to be based on experts
      opinions which are not always in agreement with the results of systematic
      reviews.

PMID- 15193974
TI  - Idiopathic calcium oxalate urolithiasis: risk factors and conservative treatment.
AB  - Idiopathic calcium oxalate urolithiasis is a frequent and recurrent
      multifactorial disease. This review focuses on urinary and dietary risk factors
      for this disease and conservative strategies for rectifying them. Dietary oxalate
      and calcium and their respective urinary excretions have been extensively
      investigated during the last 10 years. Urinary oxalate has emerged as the most
      important determinant of calcium oxalate crystallization while the role of
      urinary calcium has shifted to bone balance and osteoporosis. Dietary calcium
      restriction increases urinary oxalate and contributes to a negative bone balance.
      It has therefore been abandoned as a means to reduce the risk of calcium oxalate
      kidney stone formation. Calcium oxalate kidney stone patients are advised to
      increase their fluid intake to achieve a urine volume of 2 l or more; the
      recommended calcium intake is 800-1200 mg/day; high oxalate foods should be
      restricted; daily protein intake should be between 0.8 and 1 g/kg body
      weight/day; essential fats should be included; vegetable and fruit (except
      oxalate-rich vegetables) intake should be increased. The use of calcium
      supplements has potential benefits but needs to be examined further.

PMID- 15193975
TI  - Haptoglobin polymorphisms and iron homeostasis in health and in disease.
AB  - Haptoglobin (Hpt) is a plasma protein with hemoglobin-binding capacity. It is a
      well-known marker of hemolysis. Hpt is also an acute-phase protein that functions
      as a bacteriostatic agent, an inhibitor of prostaglandin synthesis and
      angiogenesis. However, the best-known biological function of Hpt is capture of
      hemoglobin (Hb). The identification of functional differences in haptoglobin
      molecules resulting from relatively common polymorphisms has further elucidated
      the importance of haptoglobin in iron homeostasis and in disease processes
      influenced by iron metabolism. In this review the effect of Hpt polymorphism on
      these different disease entities will be discussed.

PMID- 15193976
TI  - Plasma neuropeptide Y immunoreactivity influences left ventricular mass in
      pheochromocytoma.
AB  - Left ventricular hypertrophy (LVH) in patients with arterial hypertension is
      closely related to the levels of blood pressure (BP), catecholamines, angiotensin
      II and other mitogenic peptides. Pheochromocytoma (pheo) is a type of
      hypertension caused by excessive production of catecholamines. The aim of this
      study was to determinate if left ventricular hypertrophy in patients with
      pheochromocytoma is related to catecholamines and neuropeptide Y (NPY). METHODS:
      29 patients with pheochromocytoma (22 F, age 40 +/- 13 years), plasma
      concentration of neuropeptide Y immunoreactivity, noradrenaline (NA), and
      adrenaline (A) were determined. Twenty-four hour urine collection for
      determination of noradrenaline and adrenaline were performed. Every patient had
      echocardiographic examination and 24 h ambulatory blood pressure monitoring.
      RESULTS: Left ventricular hypertrophy was diagnosed in 14 patients. No
      differences in systolic and diastolic blood pressure in patients with and without
      left ventricular hypertrophy were found. Plasma noradrenaline and adrenaline
      levels did not differ between both groups, while plasma neuropeptide Y
      immunoreactivity was higher in patients with left ventricular hypertrophy than in
      patients without left ventricular hypertrophy (18.46 +/- 13.26 vs. 9.3 +/- 5.9
      fmol/ml (p = 0.02)). Left ventricular mass index (LVMI) correlated with plasma
      neuropeptide Y-immunoreactivity (r = 0.42 p = 0.023), however, no relationship
      between left ventricular mass index and plasma or urine noradrenaline and
      adrenaline levels were found. CONCLUSION: Our results indicate that mitogenic
      effect of neuropeptide Y may play a role in pathogenesis of left ventricular
      hypertrophy in patients with pheochromocytoma.

PMID- 15193978
TI  - Study of proteomic changes associated with healthy and tumoral murine samples in
      neuroblastoma by principal component analysis and classification methods.
AB  - BACKGROUND: The adrenal gland is the election organ forming primary neuroblastoma
      (NB) tumours, the most common extracranial solid tumours of infancy and
      childhood. METHODS: Samples of adrenal gland belonging to healthy and diseased
      nude mouse were analysed by 2D gel-electrophoresis. The resulting 2D-PAGE maps
      were digitized by PDQuest and investigated by principal component analysis (PCA).
      RESULTS: The analysis of the loadings of the first principal component (PC)
      permitted the evaluation of the spots characterising each class of samples.
      Moreover, the soft-independent model of class analogy (SIMCA) method confirmed
      the separation of the samples in the two classes and allowed the identification
      of the modelling and discriminating spots. Very good correlation was found
      between the data obtained by analysis of 2D maps via the commercial software
      PDQuest and the present PCA analysis. In both cases, the comparison between such
      maps showed up- and down-regulation of 84 polypeptide chains, out of a total of
      700 spots detected by a fluorescent stain, Sypro Ruby. Spots that were
      differentially expressed between the two groups were analysed by matrix-assisted
      laser desorption time-of-flight (MALDI-TOF) mass spectrometry and 14 of these
      spots were identified so far.

PMID- 15193977
TI  - Does KCNE5 play a role in long QT syndrome?
AB  - BACKGROUND: Long QT syndrome [LQTS] is a congenital cardiac disease characterised
      by prolonged QTC-time, syncopes and sudden cardiac death. LQTS is caused by
      mutations in genes coding for ion channels involved in the action potential.
      KCNE5 codes for a novel beta-subunit of the ion channel conducting the delayed
      rectifier repolarizing current IKs. As KCNE5 is expressed in the human heart and
      suppresses the IKs current in heterologous systems, it is a candidate gene that
      may be mutated in LQTS families where no causative mutations in known LQTS
      associated genes have been found. We examined whether this was the case. METHODS:
      Genomic DNA from LQTS patients [n=88] and normal controls [n=90] was screened for
      mutations in KCNE5 by endonuclease-enhanced single strand conformation
      polymorphism analysis [EE-SSCP], and DNA sequencing of aberrant conformers.
      Mutations in other LQTS associated ion channels were excluded by SSCP. RESULTS:
      No mutations were found in the coding region of the KCNE5 gene in LQTS patients.
      One polymorphism, a T-to-C transition at nucleotide 97, causing an amino acid
      polymorphism P33S, was present in 16 persons, nine heterozygotes and seven
      homozygotes. The T-allele frequency was 0.13 in LQTS patients and 0.10 in
      controls.

PMID- 15193979
TI  - Evidence for injurious effect of cocaethylene in human microvascular endothelial
      cells.
AB  - BACKGROUND: Cocaethylene (CE) is a conjugate of cocaine and ethanol that may
      contribute to the pathogenesis of systemic vascular diseases. This study was
      conducted to investigate the effect of CE on human microvascular endothelial
      cells (HMEC-1) in culture. METHODS: Proliferating and confluent monolayers of
      HMEC-1 were used for assessing growth kinetics, viability, cytotoxicity, and
      morphologic/barrier alterations after CE treatment (0-1 mmol/l) for up to 7 days.
      The Trypan blue exclusion, lactate dehydrogenase (LDH) release assay, manual cell
      counts, and silver nitrate staining technique were used. RESULTS: The doubling
      times of 30.0 and 31.4 h for the 0.5 and 1.0 mmol/l CE-treated HMEC-1,
      respectively, were significantly longer than the 28.6 h for the control group (p
      < 0.05). The viabilities of 90.4 +/- 3.8% (control) and 93.1 +/- 1.9% (CE
      treated) from the Trypan blue exclusion-staining experiments indicated non
      lethality of CE. LDH activities of 173 +/- 33 U/l (control) and 157 +/- 43 U/l
      (CE-treated) confirmed the absence of CE cytotoxicity. Silver staining results
      indicated increased monolayer permeability as demonstrated by the formation of
      intercellular gaps after 1 h of exposure. CONCLUSIONS: HMEC-1 exposure to CE
      induced cellular injury that could affect the permeability of small blood
      vessels. These cellular changes could in part be the pivotal point for studies to
      explain the edema and inflammation in surrounding tissues of individuals exposed
      to CE.

PMID- 15193980
TI  - The predictive characteristics of D-dimer testing in outpatients with suspected
      venous thromboembolism: a Bayesian approach.
AB  - BACKGROUND: Despite the widespread use of quantitative methods to measure D
      dimer, clinical decisions commonly are based only on binary test information
      (positive/negative). This study aimed to determine the significance of
      quantitative D-dimer results in the evaluation of venous thromboembolism (VTE) by
      means of a differentiated Bayesian approach. METHODS: Prospective study in 118
      outpatients referred for workup of suspected pulmonary embolism (n = 75) or deep
      vein thrombosis (n = 43). The sensitivity and specificity of D-dimer results
      obtained by DD VIDAS (Biomerieux, France), STA Liatest (Diagnostica Stago,
      France), and D-dimer plus (Dade, US) were assessed for five different cut-offs.
      Further, predictive values and multilevel likelihood ratios were calculated in
      order to assess the operative test characteristics in excluding or confirming
      VTE. RESULTS: At a cut-off of 500 ng/ml and pretest probabilities < 47%, the
      VIDAS provides a negative predictive value (NPV) > 95%, whereas a positive
      predictive value (PPV) > 95% is obtained in patients with a D-dimer > 10,000
      ng/ml and pretest probabilities > 50%. At a cut-off of 500 ng/ml and pretest
      probabilities < 33%, the Liatest exhibits a NPV > 95%, whereas a PPV > 95% is
      obtained in patients with a D-dimer >10,000 ng/ml and pretest probabilities >
      37%. Finally, with the D-dimer plus, a NPV > 95% is seen at a cut-off of 150
      ng/ml and pretest probabilities < 30%, whereas a PPV > 95% is obtained at a cut
      off > 1000 ng/ml and pretest probabilities > 67%. CONCLUSIONS: D-dimer
      measurements in outpatients cannot only allow for exclusion but, in some
      situations, also for confirmation of venous thromboembolism. It is therefore
      advisable to conduct a quantitative interpretation of D-dimer results.

PMID- 15193981
TI  - Analysis of cysteinyl leukotrienes and their metabolites in bile of patients with
      peroxisomal or mitochondrial beta-oxidation defects.
AB  - Cysteinyl leukotrienes (LTs) are potent lipid mediators which are predominantly
      eliminated via bile. Their metabolic inactivation and degradation proceeds by
      beta-oxidation. However, although bile is the optimal material for analysis of
      LTs in man, only very sparse data on bile LT concentration under normal or
      pathophysiological conditions exist. The aim of the present study was to present
      for the first time a complete profile of endogenous LTs in human bile and to
      investigate the importance of bile LT analysis in peroxisomal and mitochondrial
      beta-oxidation deficiency. Cysteinyl LTs and their oxidation metabolites were
      analysed after HPLC separation by specific immunoassays or gas chromatography
      mass spectrometry. Under physiological conditions, LTs are found in human bile (n
      = 8) in the nanomolar range with LTD4 predominating, whereas the other LTs were
      present in similar amounts. In bile of a patient with a peroxisome biogenesis
      disorder (Zellweger syndrome, ZS) LTE(4) was found to be slightly increased,
      whereas both omega-oxidation metabolites of LTE4, omega-hydroxy-LTE4 and omega
      carboxy-LTE4, were highly increased (about 12-18 times). The beta-oxidation
      metabolite omega-carboxy-tetranor-LTE3 was below the detection limit (< 0.1
      nmol/l; controls 1.4 +/- 1.2 nmol/l). This abnormal profile demonstrates an
      impaired degradation of LTs in ZS. In contrast, patients with X-linked
      adrenoleukodystrophy (X-ALD), medium-chain acyl CoA dehydrogenase deficiency
      (MCAD) as well as very long-chain acyl CoA dehydrogenase deficiency (VLCAD) did
      not show any differences in their biliary profile of LTs compared to controls.
      Increased levels of the biologically active cysteinyl LTs in the bile of patients
      with ZS might be of pathophysiological significance in the course of the disease,
      e.g. contributing to liver injury. In addition, our data confirm that the beta
      oxidation of cysteinyl LTs in vivo occurs in peroxisomes and not in mitochondria.

PMID- 15193982
TI  - Effect of sodium molybdate on the status of lipids, lipid peroxidation and
      antioxidant systems in alloxan-induced diabetic rats.
AB  - BACKGROUND: Diabetes mellitus manifests itself in a wide variety of complications
      and the symptoms of the disease are multi-factorial. METHODS: The lipid
      peroxidation (LPO) and antioxidant status were investigated in hemolysate, liver
      and kidney in alloxan-induced diabetic rats and the effect of molybdate
      supplementation on antioxidant defense systems. RESULTS: Diabetic rats exhibited
      an increase in the levels of lipids, lipid peroxidation and decrease in
      antioxidant status when compared to control rats. Oral administration of
      molybdate to diabetic rats for 30 days significantly reduced the levels of lipids
      like cholesterol, triglycerides, phospholipids and lipid peroxidation whereas
      increased the activities of antioxidants like superoxide dismutase (SOD),
      catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH).
      CONCLUSION: Molybdate prevents oxidation of lipids and protects antioxidant
      systems in experimental diabetic rats, and thus, may be useful for the prevention
      or early treatment of diabetic mellitus.

PMID- 15193984
TI  - In vitro glycation of human immunoglobulin G.
AB  - BACKGROUND: Glucose can covalently bind to the proteins by nonenzymatic process
      often termed glycation. Glycation of IgG is of special interest due to its
      possible influence on the functionality of immunoglobulins and overall
      immunocompetence. METHODS: The glycation of IgG was studied using radioactive D
      [U-14C]-glucose. RESULTS: The kinetics, concentration/temperature dependence and
      distribution of glycation binding sites of human IgG were studied under various
      conditions. (a) In average, 0.7 glucose molecules were found to be bound per IgG
      after 90 days of incubation at 37 degrees C with normal serum IgG and glucose
      concentrations, and 3.1 molecules after incubation with glucose in the
      concentration characteristic for diabetics. (b) Incubation of the same solutions
      for 270 days at 4-8 degrees C resulted in binding of 0.3 and 0.8 glucose
      molecules per IgG, respectively. (c) After 90 days at 37 degrees C in the
      presence of 0.56 mol/l of glucose, IgG was glycated with averagely 47 glucose
      molecules per IgG and with 9 after 270 days at 4-8 degrees C. (d) At very high
      glucose concentration (1.67 mol/l) in concentrated IgG solution (87 g/l), the
      molar ratio glucose/IgG reached 41 after incubation at 60 degrees C for 10 h.
      CONCLUSIONS: Glycation of IgG with glucose nearly resembled the first order
      reaction kinetics. No preferential glycation sites were found as bound glucose
      was equally distributed throughout F(ab)2 and Fc fragments as well as on the
      light and heavy immunoglobulin chains.

PMID- 15193983
TI  - Increase in the ratio of matrix metalloproteinase-9 to tissue inhibitor of
      metalloproteinase-1 in saliva from patients with primary Sjogren's syndrome.
AB  - BACKGROUND: To investigate the ratio of matrix metalloproteinase (MMP) to tissue
      inhibitor of metalloproteinase (TIMP) in primary Sjogren's syndrome (PSS),
      patients and healthy subjects MMP-2, 9 and TIMP-1, 2 levels were measured in
      saliva. METHODS: Stimulated whole-mixed saliva was collected from 32 patients and
      26 healthy subjects. MMP-2, 9 and TIMP-1, 2 levels were measured using enzyme
      linked immunosorbent assay (ELISA) and the sandwich enzyme immunoassay (sandwich
      EIA). Zymography and reverse zymography were used to identify MMPs and TIMPs.
      RESULTS: MMP-9 (gelatinase-B) level in saliva was significantly increased in the
      patients. MMP-9 (ng/ml): patients 231.02 +/- 151.77 (mean +/- S.D.), healthy
      subjects 145.87 +/- 111.65 (p < 0.05). MMP-2 levels were not detected with this
      system kit in either healthy subjects or patients. The differences in TIMPs were
      only trends and not statistically significant (p > 0.05). Accordingly, MMP-9/TIMP
      1 was greatly increased in the patients (2.60 +/- 1.18) than in the healthy
      subjects (1.28 +/- 1.11) (p < 0.01). CONCLUSION: This study found that MMP-9/TIMP
      1 and MMP-9 levels in the saliva were significantly higher in pSS patients than
      those in healthy subjects. Our results indicate that the increase in MMP-9/TIMP
      1, rather than the increase in MMP-9, in pSS patients' saliva is strongly
      involved in destruction of glandular and salivary duct tissues.

PMID- 15193985
TI  - Comparison of ultrafiltration and solid phase extraction for the separation of
      free and protein-bound serum copper for the Wilson's disease diagnosis.
AB  - BACKGROUND: The determination of the ratio free/protein-bound serum copper along
      with urinary copper can be used as a preliminary test for the Wilson's Disease
      diagnosis. In this work, the determination of these copper fractions in serum
      samples was carried out in two different ways; after separation of the copper
      bound to proteins from the free fraction by a column for protein adsorption and
      by ultrafiltration. As proteins can be adsorbed onto plastic polymeric surfaces,
      polyethylene (PE) with different molecular weights in powder form was
      investigated for protein adsorption. A small column was adapted in a flow system
      to carry out a solid-phase extraction (SPE) on-line. Preliminary experiments
      defined conditions for protein retention and elution and column saturation. Good
      performance was achieved using Mg(NO3)2 solution as carrier and methanol as
      eluent. The presence of proteins in both fraction (column effluent and eluate)
      was checked by the Coomassie Brilliant Blue test. Copper was measured by graphite
      furnace atomic absorption spectrometry. The measurement in the column effluent
      furnished the free-fraction of copper while the copper measured in the eluate the
      bound-fraction. The method was compared with ultrafiltration (20 kDa), measuring
      the free-copper in the ultrafiltrate. For the determination of protein-bound
      copper, the copper found in the ultrafitrate was discounted from the total copper
      measured in the sample. RESULTS: Serum samples of 10 individuals were analyzed by
      both methods with good agreement of the results. The regression plots, obtained
      by analysing the samples by both methods, presented r2 and slope of 0.97 and 0.96
      for free copper and 1.00 and 1.00 for bound copper, respectively. Protein-bound
      copper (PB) concentrations ranged from 74 to 2074 microg/l and free-copper (F)
      from 22 to 54 microg/l. The ratio F/PB, calculated from SPE data, was 29.7% for
      one individual, with Wilson Disease well-characterized, and ranged from 1.2% to
      5.2% for the others. CONCLUSION: The SPE method performed well in terms of
      accuracy and precision, and showed good agreement with the UF. Advantages of SPE
      are small sample volume (50 microl), separation carried out in 10 min, and the
      use of the same column for several analyses.

PMID- 15193986
TI  - Analytical performance of the i-STAT cardiac troponin I assay.
AB  - BACKGROUND: This study determines the analytical characteristics of the i-STAT
      cardiac troponin I assay (cTnI; i-STAT, Princeton, NJ), a 10-min POC assay,
      designed to be performed at the bedside. METHODS: Three different hospitals
      participated in a patient specimen and analytical validation study (n=186) for
      the i-STAT cTnI assay carried out in real time. A total of 186 whole blood
      specimens (lithium heparin) were collected from patients presenting with symptoms
      suggestive of acute coronary syndromes (ACS) for correlation studies as well as
      from 162 healthy subjects for reference interval determination. Factors studied
      included antibody specificity, detection limit, imprecision, linearity, assay
      specificity, sample type stability, interferences, reference limit determination
      and comparison vs. the Dade Stratus CS cTnI assay. RESULTS: Total imprecision
      (CV) of 10% and 20% were seen at 0.09 and 0.07 microg/l, respectively. The
      detection limit was 0.02 microg/l. The 99th percentile reference limit was 0.08
      microg/l. The assay was not affected by common interferents. An equimolar
      response within 5% was found for reduced and phosphorylated forms of TIC and IC
      complexes. Regression analysis for the i-STAT cTnI between whole blood and plasma
      specimens and for whole blood between the i-STAT and Stratus CS cTnI assays
      demonstrated slopes of 1.06 and 0.89, respectively. CONCLUSIONS: The i-STAT cTnI
      assay is a sensitive and precise monitor of cTnI, poised for point-of-care/near
      bedside clinical utilization for triage, diagnostics and risk management of acute
      coronary syndrome patients.

PMID- 15193987
TI  - Increased breath nitrous oxide after ingesting nitrate in patients with atrophic
      gastritis and partial gastrectomy.
AB  - BACKGROUND: Toxic nitrite and N-nitroso compounds due to gastric bacterial growth
      are often detected in the stomach of patients with atrophic gastritis and partial
      gastrectomy. The aim of this study is to investigate whether breath N2O, a major
      metabolite of denitrification, detected after ingestion of nitrate is associated
      with atrophic gastritis and partial gastrectomy. METHODS: Nine young, 16 normal
      older, nine atrophic gastritis and six partial gastrectomy subjects ingested 100
      g lettuce, equal to 130 mg nitrate, and breath N2O was measured at 15-min
      intervals for 5 h. N2O was analyzed using an infrared-photoacoustic analyzer, and
      atrophic gastritis was diagnosed by pepsinogen test. RESULTS: The mean breath N2O
      concentrations were higher in the following order at all times: partial
      gastrectomy>atrophic gastritis>normal>young. The maximum N2O concentrations in
      the patients with partial gastrectomy and atrophic gastritis were 1655 +/- 296
      and 1350 +/- 200 (mean +/- S.E.) ppb, respectively, which were higher than that
      of the normal subjects, 827 +/- 91 ppb (P < 0.05). The maximum N2O concentration
      in young people was 527 +/- 86 ppb, which was lower than that of the normal older
      people (P < 0.051). CONCLUSION: These higher N2O concentrations in gastric
      patients reflect bacterial growth in the stomach due to the reduction of gastric
      acid.

PMID- 15193988
TI  - Evaluation of reliability for urine mucopolysaccharidosis screening by
      dimethylmethylene blue and Berry spot tests.
AB  - BACKGROUND: The mucopolysaccharidosis (MPS) are a group of inherited metabolic
      disorders resulting from the deficiency of the enzyme responsible for
      intralysosomal catabolism of glycosaminoglycans (GAGs). GAGs are progressively
      accumulated in multiple tissues and released into the corporal fluids. The first
      laboratory approximation to MPS diagnosis is the identification of an increased
      urinary GAG excretion. For this, several semiquantitative and quantitative
      methods have been developed. The aim of this retrospective statistical study was
      to evaluate the reliability of MPS urine screening for the semiquantitative Berry
      spot test (BST) and the quantitative dimethylmethylene blue test (DMB). METHODS:
      The 24-h-urine samples (n = 246) were tested through BST, DMB, and for GAG
      excretion pattern by one-dimensional electrophoresis or thin layer
      chromatography. RESULTS: the 204 samples that demonstrated a normal GAG excretion
      pattern were considered as non-MPS samples. Forty-two samples presented an
      abnormal GAG excretion pattern. Enzyme analysis was available for 31 out of 42
      patients (31/42), confirming that all were affected by MPS. Urinary GAG
      concentrations of MPS patients by DMB were increased 1.04- to 7.1-folds, compared
      to age-related normal levels. The sensitivity was 100% for DMB and 93.6% for BST.
      DMB demonstrated a specificity of 74.5%, while BST a specificity of 53.9%. The
      specificity of MPS screening increased to 84.3%, considering conjunctly DMB and
      BST. CONCLUSION: The DMB is a sensitive method, however, inclusion of BST could
      increase the specificity of MPS urine screening.

PMID- 15193989
TI  - Effect of macrocyclic binuclear oxovanadium complex on tissue defense system in
      streptozotocin-induced diabetic rats.
AB  - BACKGROUND: Oxidative stress plays an important role in chronic complications of
      diabetes mellitus and hence the regulation of free radicals is essential in the
      treatment of diabetes. The protective effect of a new macrocyclic binuclear
      oxovanadium complex on antioxidant defense systems of liver and kidney was
      examined in streptozotocin-induced experimental diabetes in rats. METHODS: The
      levels of lipid peroxides, glutathione and the activities of superoxide
      dismutase, catalase, glutathione peroxidase and glutathione-S-transferase were
      assayed according to standard procedures in the liver and kidney of control and
      experimental groups of rats. RESULTS: A significant decrease (p < 0.05) was
      observed in both the glutathione content and in the activities of antioxidant
      enzymes such as superoxide dismutase, catalase, glutathione peroxidase and a
      concomitant increase in the level of lipid peroxides in diabetic rats. The
      observed alterations in the antioxidant status of tissues reverted back to near
      normal levels after the oral administration of macrocyclic vanadium complex at a
      dose of 5 mg/kg body weight/rat/day for a period of 30 days. CONCLUSION: The
      normoglycemic efficacy of the vanadium complex alleviates oxidative stress in
      streptozotocin-induced diabetes in rats.

PMID- 15193990
TI  - PCR/RFLP-based cost-effective identification of SOD2 signal (leader) sequence
      polymorphism (Ala-9Val) using NgoM IV: a detailed methodological approach.
AB  - BACKGROUND: Superoxide dismutases (SOD) play an important role in the protection
      of cells and extracellular space from the products of oxidative stress. Two
      allelic variants have been described for the SOD2 gene (Ile58Thr involves a C to
      T substitution at nucleotide residue 339 and Ala-9Val involves a T to C
      substitution at nucleotide residue 1183). The enzyme proteins encoded by the
      different alleles have been suggested to have different activity patterns.
      METHODS: The SOD2 polymorphism was determined using a polymerase chain reaction
      (PCR) and RFLP techniques with restriction endonuclease NgoM IV. RESULTS: The
      most available results were obtained from with 20 pmol primer final concentration
      in PCR reaction. A total of 20 pmol seems the cost-effective primer concentration
      with maximum quality. There were no difference between the band quality of 1-5
      units of restriction endonucleases. On the other hand, short and long incubation
      times seem to be similar in order to obtain sharp bands on agarose gel.
      CONCLUSIONS: We have extended a method of SOD2 polymorphism (Ala-9Val) in
      mitochondrial sequence. This method provides the ability to genotype of SOD2, and
      it represents a fast, reliable, cost-effective and semi-automated methodology to
      determine SOD2 polymorphism in order to perform large-scale population studies.

PMID- 15193991
TI  - Increased serum iron may contribute to enhanced oxidation of low-density
      lipoprotein in smokers in part through changes in lipoxygenase and catalase.
AB  - BACKGROUND: Increased oxidative stress is considered to be causative for
      cardiovascular disease (CVD) in smokers, but its mechanisms are still unclear. We
      compared oxidative stress markers between male smokers and male nonsmokers.
      METHODS: Twenty-three healthy men (11 nonsmokers and 12 smokers) were enrolled,
      and blood samples after 12 h of fasting were collected to assess plasma lipids
      and oxidative stress markers. The effects of iron loading on 12-lipoxygenase (12
      LO) expression and activity in human umbilical vein endothelial cells (HUVECs)
      were tested in vitro to investigate the relevance of iron to oxidation potential
      in vivo. RESULTS: Higher levels of plasma-oxidized low-density lipoprotein (LDL)
      and lipid peroxide (LPO), and higher oxidizability of LDL were observed in
      smokers than in nonsmokers. Higher levels of serum iron and lower levels of
      plasma vitamin E were observed in smokers than in nonsmokers. Stepwise multiple
      regression analysis showed that serum iron was an independent determinant for
      both plasma-oxidized LDL and lag time of LDL oxidation. Iron loading enhanced 12
      LO expression threefold and its activity 1.5-fold. Moreover, iron loading
      decreased catalase expression by 50% and significantly reduced its activity by
      75%. CONCLUSIONS: Enhanced oxidative stress in smokers may be due to increased
      iron levels. Iron-induced modulation of expression and activity of 12-LO and
      catalase may be relevant to increased iron-related oxidative stress as observed
      in smokers.

PMID- 15193992
TI  - Peptidase activities in rats treated chronically with N(omega)-nitro-L-arginine
      methyl ester (L-NAME).
AB  - The chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L
      NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension.
      This inhibition of NO production results in activation of the renin-angiotensin
      system, with increased activity of the carboxypeptidase angiotensin I-converting
      enzyme (ACE). Since chronic NO inhibition increases ACE activity, we hypothesized
      that this inhibition could also affect the activities of other peptidases
      involved in cardiovascular functions. To test this possibility, we examined the
      activities of aminopeptidase M (APM), dipeptidyl peptidase IV (DPP IV),
      metalloendopeptidase 24.15 (MEP 24.15) and neutral endopeptidase 24.11 (NEP
      24.11) in rat brain, heart, kidney, liver, lung and thoracic aorta. Male Wistar
      rats were treated chronically with L-NAME (80mgkg(-1) per day) administered in
      the drinking water for 4 weeks and their organs then removed and processed for
      the determination of peptidase activities. Treatment with L-NAME did not
      significantly alter the activities of the four peptidases in brain, heart,
      kidney, liver and lung. In contrast, in aorta, the activity of APM was slightly
      but significantly reduced whereas those of DPP IV and MEP 24.15 were markedly
      enhanced; NEP 24.11 was not detected in this tissue. Immunoblotting for DPP IV
      and MEP 24.15 showed increased expression in aortic tissue. Neither L-NAME (1
      100microM) nor the NO donors sodium nitroprusside and 3-morpholinosydnonimine
      (SIN-1; 1-100microM) had any consistent effect on the activity of recombinant MEP
      24.15 or renal DPP IV. The importance of MEP 24.15 in peptide metabolism was
      confirmed in pentobartibal-anesthetized rats pretreated with the MEP 24.15
      inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2),
      which significantly potentiated the hypotensive response to bradykinin. The
      altered peptidase activities seen in aorta may contribute to modulating vascular
      responses in this model of hypertension.

PMID- 15193993
TI  - Effects of phosphoinositide 3-kinase on endothelin-1-induced activation of
      voltage-independent Ca2+ channels and vasoconstriction.
AB  - We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)
      permeable nonselective cation channel (designated NSCC-1 and NSCC-2) and a store
      operated Ca(2+) channel (SOCC) in rabbit basilar artery (BA) vascular smooth
      muscle cells (VSMCs). In this study, we investigated the effects of
      phosphoinositide 3-kinase (PI3K) on ET-1-induced activation of these channels and
      BA contraction by using PI3K inhibitors, wortmannin and LY 249002. To determine
      which Ca(2+) channels are activated via PI3K, monitoring of intracellular Ca(2+)
      concentration was performed. Role of PI3K in ET-1-induced vasoconstriction was
      examined by tension study using rabbit BA rings. Only NSCC-1 was activated by ET
      1 in wortmannin- or LY 294002-pretreated VSMCs. In contrast, addition of these
      drugs after ET-1 stimulation did not suppress Ca(2+) influx. Wortmannin inhibited
      the ET-1-induced contraction of rabbit BA rings that depends on the Ca(2+) influx
      through NSCC-2 and SOCC. The IC(50) values of wortmannin for the ET-1-induced
      Ca(2+) influx and vasoconstriction were similar to those for the ET-1-induced
      PI3K activation. These results indicate that (1) NSCC-2 and SOCC are stimulated
      by ET-1 via PI3K-dependent cascade, whereas NSCC-1 is stimulated via PI3K
      independent cascade; (2) PI3K is required for the activation of the Ca(2+) entry,
      but not for its maintenance; and (3) PI3K is involved in the ET-1-induced
      contraction of rabbit BA rings that depends on the extracellular Ca(2+) influx
      through SOCC and NSCC-2.

PMID- 15193994
TI  - N-(methylamino)isobutyric acid inhibits proliferation of CFSC-2C hepatic stellate
      cells.
AB  - Activation of hepatic stellate cells (HSCs) involves the induction of ECM protein
      synthesis and rapid cell proliferation. Thus, agents that interfere with either
      process could potentially mitigate the development of liver disease by reducing
      the synthesis of proteins associated with fibrosis or by reducing the number of
      activated HSC. Previously, we described that the non-metabolizable amino acid
      analog N-(methylamino)isobutyric acid (MeAIB) reduced hepatic collagen content of
      rats in a model of CCl(4)-induced liver injury, and in vitro studies using CFSC
      2G cells indicated that MeAIB directly reduced collagen synthesis. However, the
      MeAIB-mediated reduction of hepatic collagen, in vivo, following liver injury was
      associated with a decrease in hepatic alpha-smooth muscle actin (alpha-SMA) which
      suggested that MeAIB also inhibited the activation of HSCs. Because HSC
      activation is inseparable from proliferation, the purpose of this study was to
      examine the effect of MeAIB treatment on the proliferation of HSCs in an in vitro
      model utilizing CFSC-2G cell cultures. In these studies, MeAIB effectively
      inhibited the proliferation of CFSC-2G cells by interfering with the progression
      of the cells through the G(1)-phase of the cell cycle which delayed entry into S
      phase. MeAIB prevented the phosphorylation of p70S6 kinase (p70S6K) at Thr389 and
      reduced the phosphorylation at Thr421/Ser424. Because p70S6K is required for G(1)
      cell cycle progression and is known to be regulated by nutrient availability,
      this correlates well with MeAIB interfering with the proliferation of CFSC-2G
      HSCs. In addition, the rate of protein synthesis was reduced by MeAIB treatment
      following mitogenic stimulation, which agrees with a p70S6K-mediated reduction in
      translation. These data are consistent with MeAIB inhibiting the proliferation of
      CFSC-2G cells by altering the mitogen activated pathway(s) leading to
      phosphorylation of p70S6K by a yet to be described mechanism.

PMID- 15193996
TI  - Biochemical and morphological effects of K-111, a peroxisome proliferator
      activated receptor (PPAR)alpha activator, in non-human primates.
AB  - K-111 has been characterized as a potent peroxisome proliferator-activated
      receptor (PPAR)alpha activator. Antidiabetic potency and amelioration of
      disturbed lipid metabolism were demonstrated in rodents, which were accompanied
      by elevations of peroxisomal enzymes and liver weight. To examine the possible
      therapeutic application of K-111 we have now assessed its efficacy in non-human
      primates with high transferability to humans. For this purpose obese,
      hypertriglyceridaemic, hyperinsulinaemic prediabetic rhesus monkeys were dosed
      sequentially with 0, 1, 3 and 10mg/kg per day orally over a period of 4 weeks
      each. In addition, the effect of K-111 on the peroxisome compartment was analyzed
      in cynomolgus monkeys using liver samples obtained following a 13-week oral
      toxicity study. In prediabetic monkeys, the reduction of hyperinsulinaemia and
      improvement of insulin-stimulated glucose uptake rate indicated amelioration of
      insulin resistance. These effects were nearly maximal at a dose of 3mg/kg per
      day, while triglycerides and body weight were lowered significantly in a dose
      dependent manner. This reduction of body weight contrasts sharply with the
      adipogenic response observed with thiazolidinediones, another family of insulin
      sensitizing agents. In young cynomolgus monkeys at a dosage of 5mg/kg per day and
      more, K-111 induced an up to three-fold increase in lipid beta-oxidation enzymes
      with an 1.5- to 2-fold increase in peroxisome volume density. This moderate
      increase in peroxisomal activity by K-111 in monkeys is consistent with its role
      as an PPARalpha activator and corresponds to the observations with fibrates in
      other low responder mammalian species. The increase in beta-oxidation may
      explain, at least in part, the lipid modulating effect as well as the
      antidiabetic potency of K-111. This pharmacological profile makes K-111 a highly
      promising drug candidate for clinical applications in the treatment of type 2
      diabetes, dyslipidaemia, obesity and the metabolic syndrome.

PMID- 15193997
TI  - Increased chloride efflux in colchicine-resistant airway epithelial cell lines.
AB  - Colchicine has been proposed as a treatment to alleviate chronic lung
      inflammation in cystic fibrosis patients and clinical trials are ongoing. Our aim
      was to investigate whether chronic exposure of cystic fibrosis cells to
      colchicine can affect their ability to transport chloride in response to cAMP.
      Colchicine-resistant cells were selected by growing in medium containing
      nanomolar concentrations of the drug. While microtubuli were affected by acute
      exposure to colchicine, they appeared normal in colchicine-resistant cells.
      Colchicine-resistant clones had higher expression of multidrug resistance
      proteins compared to untreated cells. Cystic fibrosis transmembrane conductance
      regulator (CFTR) labelling by immunocytochemistry showed no significant changes.
      The intracellular chloride concentration and basal chloride efflux of the cystic
      fibrosis treated cells increased significantly compared with untreated cells,
      while for the cAMP-stimulated Cl-efflux there was no significant change. The
      results suggest that colchicine promotes chloride efflux via alternative chloride
      channels. Since this is an accepted strategy for pharmacological treatment of
      cystic fibrosis, the results strengthen the notion that colchicine would be
      beneficial to these patients.

PMID- 15193995
TI  - 2,2'-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without
      affecting nucleotide binding.
AB  - The effect of 2,2'-pyridylisatogen tosylate (PIT) on the human P2Y(1) receptor
      and on other recombinant P2Y receptors has been studied. We first examined the
      modulation by PIT of the agonist-induced accumulation of inositol phosphates. PIT
      blocked 2-methylthio-ADP (2-MeSADP)-induced accumulation of inositol phosphates
      in 1321N1 astrocytoma cells stably expressing human P2Y(1) receptors in a non
      competitive and concentration-dependent manner. The IC(50) for reduction of the
      maximal agonist effect was 0.14microM. In contrast, MRS2179, a competitive P2Y(1)
      receptor antagonist, parallel-shifted the agonist concentration-response curve to
      the right. PIT also concentration-dependently blocked the P2Y(1) receptor
      signaling induced by the endogenous agonists, ADP and ATP. A simple structural
      analogue of PIT was synthesized and found to be inactive as a P2Y(1) receptor
      antagonist, suggesting that the nitroxyl group of PIT is a necessary structural
      component for P2Y(1) receptor antagonism. We next examined the possible
      modulation of the binding of the newly available antagonist radioligand for the
      P2Y(1) receptor, [3H] MRS2279. It was found that PIT (0.01-10microM) did not
      inhibit [3H] MRS2279 binding to the human P2Y(1) receptor. PIT (10microM) had no
      effect on the competition for [3H] MRS2279 binding by agonists, ADP and ATP,
      suggesting that its antagonism of the P2Y(1) receptor may be allosteric. PIT had
      no significant effect on agonist activation of other P2Y receptors, including
      P2Y(2), P2Y(4), P2Y(6), P2Y(11) and P2Y(12) receptors. Thus, PIT selectively and
      non-competitively blocked P2Y(1) receptor signaling without affecting nucleotide
      binding.

PMID- 15193998
TI  - Leptomycin B-induced apoptosis is mediated through caspase activation and down
      regulation of Mcl-1 and XIAP expression, but not through the generation of ROS in
      U937 leukemia cells.
AB  - Leptomycin B (LMB), which is originally isolated from Streptomyces, possesses
      anti-tumor properties in vivo and in vitro. Though it was previously reported
      that LMB induces cell cycle arrest and p53-mediated apoptosis in certain cancer
      cells, however, the mechanism by which LMB induces apoptosis remains poorly
      understood. Here, we investigated the mechanisms of apoptosis induced by LMB in
      U937 cells. Treatment with LMB concentration-dependently induced cytotoxicity and
      apoptosis in U937 cells that correlated temporally with activation of caspases
      and down-regulation of Mcl-1 and XIAP. LMB did not change the expressions of Bcl
      2 or Bax. A broad spectrum caspase inhibitor, z-VAD-fmk, blocked caspase-3
      activation and elevated the survival in LMB-treated U937 cells, suggesting that
      caspase-3 activation is critical for LMB-induced apoptosis. Interestingly, Bcl-2
      overexpression that blocked cytochrome c release by LMB effectively attenuated
      the apoptotic response to LMB, suggesting that LMB-induced apoptosis is mediated
      through the mitochondrial pathway. Antioxidants or antioxidant enzymes had no
      effects on LMB-induced apoptosis. Data of flow cytometry analysis using 2',7'
      dichlorofluorescein-diacetate further revealed no reactive oxygen species (ROS)
      generation by LMB, indicating that apoptosis induced by LMB is ROS-independent.
      However, the apoptotic response to LMB was not shown in U937 cells pretreated
      with the sulfhydryl group-containing antioxidant N-acetylcysteine (NAC). Further
      analysis suggested that NAC directly binds LMB and abolishes the apoptotic
      effects of LMB. Collectively, these findings suggest that LMB potently induces
      apoptosis in U937 cells, and LMB-induced apoptosis in U937 cells is related with
      cytochrome c release, activation of caspases, and selective down-regulation of
      Mcl-1 and XIAP.

PMID- 15193999
TI  - Increase by FK960, a novel cognitive enhancer, in glial cell line-derived
      neurotrophic factor production in cultured rat astrocytes.
AB  - We examined the effect of N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide
      monohydrate (FK960), a novel anti-dementia drug, on neurotrophic factor
      production in cultured rat astrocytes. FK960 (100nM) increased mRNA and protein
      levels of glial cell line-derived neurotrophic factor (GDNF). FK960 did not
      affect mRNA levels of neurotrophic factors other than GDNF. The effect of FK960
      was not affected by antagonists of dopamine and alpha7-nicotinic acetylcholine
      receptors. FK960 stimulated phosphorylation of mitogen-activated
      protein/extracellular signal-regulated kinase (ERK) without any effect on
      phosphoryolation of p38 and c-Jun N-terminal kinase. FK960 increased the levels
      of c-Fos and phosphorylation of cAMP responsive element binding protein (CREB).
      The effect of FK960 on c-Fos was inhibited by PD98059 (10microM), an ERK kinase
      inhibitor, and cycloheximide (1microg/ml), a transcription inhibitor, and the
      effect of FK960 on CREB phosphorylation was blocked by PD98059. The effect of
      FK960 on GDNF mRNA expression was attenuated by PD98059, curcumin (10microM), an
      activator protein-1 inhibitor, cycloheximide and actinomycin D (10microg/ml).
      These results suggest that FK960 stimulates GDNF production in c-Fos- and CREB
      dependent mechanisms in cultured astrocytes and that ERK signal is responsible
      for both c-Fos expression and CREB phosphorylation in the cascades.

PMID- 15194000
TI  - Cellular pharmacology of cisplatin in relation to the expression of human copper
      transporter CTR1 in different pairs of cisplatin-sensitive and -resistant cells.
AB  - The molecular mechanism of cisplatin uptake remains poorly defined and impaired
      drug accumulation may be implicated in the acquisition of resistance to
      cisplatin. Thus, we used cell lines of different tumor types (ovarian carcinoma
      A2780 and IGROV-1, osteosarcoma U2-OS, cervix squamous cell carcinoma A431) and
      stable cisplatin-resistant sublines, exhibiting variable levels of resistance
      (between 2.5 and 18.4), to investigate the mechanisms of cellular accumulation of
      cisplatin. Among the resistant lines we found that reduced cisplatin uptake was a
      common feature and ranged between 23 and 76%. In an attempt to examine the role
      of human copper transporter 1 (CTR1) in cisplatin accumulation by human cells, we
      selected the well characterized A431 cell line and the resistant variant A431/Pt.
      As compared with A431/Pt cells, A431/Pt transfectants overexpressing CTR1 (3.4
      fold) exhibited increased uptake of copper, thereby supporting the expression of
      a functional transporter. However, no changes in cisplatin uptake and cellular
      sensitivity to drug were observed. Also overexpression of CTR1 in A431 cells did
      not produce modulation of cisplatin accumulation. An analysis of the expression
      of other factors that could affect drug accumulation indicated that A431/Pt cells
      displayed increased expression of ATPase, Cu(2+) transporting, alfa polypeptide.
      In conclusion, our results indicate that the overexpression of a functional CTR1
      in a human cell line characterized by impaired cisplatin uptake fails (a) to
      restore cellular drug accumulation to the level of the parental cell line and (b)
      to modulate cisplatin sensitivity. Our data are consistent with the
      interpretation that the defects in cellular accumulation by resistant cells are
      not mediated by expression of CTR1, that plays a marginal role, if any, in
      cisplatin transport.

PMID- 15194002
TI  - [3H]OSIP339391, a selective, novel, and high affinity antagonist radioligand for
      adenosine A2B receptors.
AB  - Until recently, the characterization of adenosine A(2B) receptors has been
      hampered by the lack of high affinity radioligands. This study describes the
      synthesis and in vitro characterization of the radiolabeled derivative of
      OSIP339391, a novel, potent, and selective pyrrolopyrimidine A(2B) antagonist.
      OSIP339391 had a selectivity of greater than 70-fold for A(2B) receptors over
      other human adenosine receptor subtypes. The radiolabel was introduced by
      hydrogenation of the acetylenic precursor with tritium gas resulting in the
      incorporation (on average) of three tritium atoms in the molecule, yielding a
      ligand with specific activity of 87Ci/mmol (3.2TBq/mmol). Using membranes from
      HEK-293 cells expressing the human recombinant A(2B) receptor, [3H]OSIP339391 was
      characterized in kinetic, saturation, and competition binding experiments. From
      the association and dissociation rate studies, the affinity was 0.41nM and in
      close agreement with that found in saturation binding experiments (0.17nM). In
      competition, binding studies using 0.5nM [3H]OSIP339391, the affinity of a range
      of agonists and antagonists was consistent with previously reported data. Thus,
      [3H]OSIP339391 is a novel, selective, and high affinity radioligand that can be a
      useful tool in the further exploration and characterization of recombinant and
      endogenous adenosine A(2B) receptors.

PMID- 15194001
TI  - A novel bis-benzylidenecyclopentanone derivative, BPR0Y007, inducing a rapid
      caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53
      in human oral epidermoid carcinoma cells.
AB  - BPR0Y007, a bis-benzylidenecyclopentanone derivative (2,5-bis- (4-hydroxy-3
      methoxybenzylidene) cyclopentanone), was identified in our laboratory as a novel
      antineoplastic agent with a broad spectrum of antitumor activity against many
      human cancer cells. A previous study showed that BPR0Y007 inhibited DNA
      topoisomerase I (Top 1) activity and prevented tubulin polymerization. Notably,
      no cross-resistance with BPR0Y007 was observed in camptothecin-, VP-16- or
      vincristine-resistant cell lines. In this study, we further investigated the
      cellular and molecular events underlying the antitumoral function of this
      compound in human oral epidermoid carcinoma KB cells, focusing on the early
      cytotoxic effect. Treatment of KB cells with BPR0Y007-induced G(2)/M phase arrest
      followed by sub-G(1) phase accumulation. Annexin-V-propidium iodide (PI) binding
      assay and DNA fragmentation assay further indicated that BPR0Y007-induced cell
      death proceeded through an apoptotic pathway as opposed to via necrosis. This
      compound produced a time-dependent activation of caspases-3 and -8, however,
      another caspase-3 initiator, caspase-9, was only marginally activated at later
      time point. We further demonstrated that the activation of the caspases cascade
      and nuclear fragmentation was not associated with inactivated Bcl-2 and perturbed
      mitochondrial membrane potential by BPR0Y007. The finding that BPR0Y007-induced
      apoptosis through a membrane-mediated mechanism was supported by up-regulated
      expression of Fas (CD95/APO-1), but not Fas-L. Furthermore, up-regulation of p53
      and its affected gene, MDM2, in KB cells was found after BPR0Y007 exposure.
      Overall, our results demonstrated that the BPR0Y007 could induce an early
      cytotoxic apoptosis through a caspase-8-dependent but mitochondrial-caspase-9
      independent pathway, and involving upregulation of p53.

PMID- 15194003
TI  - PPARalpha agonists clofibrate and gemfibrozil inhibit cell growth, down-regulate
      hCG and up-regulate progesterone secretions in immortalized human trophoblast
      cells.
AB  - We studied effects of PPARalpha agonists clofibric acid and gemfibrozil on cell
      growth and functions of immortalized human extravillous trophoblast cells. Levels
      of DNA and protein gradually increased during incubation for 4 days. Gemfibrozil
      (>0.25mM) and clofibric acid (2.5mM) suppressed the rate of increase in DNA and
      protein. Specific activities of fatty acyl-CoA oxidase and catalase were
      increased to about 1.2-2.0 times the control value by 0.05mM gemfibrozil and 1.0
      and 2.5mM clofibric acid after incubation for 3 days. Acid phosphatase activity
      showed a small increase in response to both agents, but esterase activity changed
      little. The secretion of progesterone from the cells into the medium was
      increased by 0.25mM gemfibrozil and 1.0 and 2.5mM clofibric acid after incubation
      for 3 days, but that of human chorionic gonadotropin (hCG) was decreased by
      0.35mM gemfibrozil and 2.5mM clofibric acid. The specific activity of lactate
      dehydrogenase in the cells was hardly changed at all after incubation for 3 days.
      These results suggest that gemfibrozil and clofibric acid inhibit the
      proliferation of trophoblast cells. Cell metabolism is probably affected by both
      agents. The two agents may down-regulate hCG and up-regulate progesterone
      secretions.

PMID- 15194004
TI  - Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in
      human HepG2 hepatoma cells.
AB  - We examined the effects of diallyl disulfide (DADS), an oil-soluble organosulfur
      compound found in garlic, on human HepG2 hepatoma cells to better understand its
      effect on apoptosis and apoptosis-related genes. Our study has demonstrated that
      DADS affects cell proliferation activity and viability and elicits typical
      apoptotic morphologic changes (chromatic condensation and nuclear fragmentation)
      in human HepG2 hepatoma cells. Also, treatment with DADS induces a temporary
      increase in phosphorylated p38 MAPK (phospho-p38) and phosphorylated p42/44 MAPK
      (phospho-p42/p44) in a time- and concentration-dependent manner. Inhibition of
      activated/phosphorylated mitogen-activated protein kinase (MAPK) with phospho-p38
      or phospho-p42/44 specific inhibitors, SB203580 or U0126, induces apoptosis
      without DADS treatment, indicating that at least the endogenous activated forms
      of p38 MAPK and p42/p44 MAPK markedly exert cytoprotective roles from cell
      apoptosis in the HepG2 hepatoma cells. Combined treatment with these inhibitors
      followed by DADS further enhances the DADS-induced apoptosis. Taken together,
      these results show that both DADS and the specific inhibitors of MAPKs could
      induce apoptosis in HepG2 hepatoma cells and that the MAPKs inhibitors further
      enhance the apoptotic effect in DADS-treated HepG2 hepatoma cells.

PMID- 15194005
TI  - Stimulation of early gene induction and cell proliferation by lysophosphatidic
      acid in human amnion-derived WISH cells: role of phospholipase D-mediated
      pathway.
AB  - Human-amniotic WISH cells express the lysophosphatidic acid (LPA) receptor,
      LPA(1), LPA(2) but not LPA(3). When WISH cells were stimulated with LPA,
      phospholipase D (PLD) activation was dramatically induced via a cytosolic calcium
      increase and protein kinase C activation. We also found that LPA stimulated two
      kinds of mitogen-activated protein kinase (MAPK), extracellular signal-regulated
      kinase (ERK) and p38 kinase via PLD-dependent signaling pathways in WISH cells.
      In terms of the LPA-mediated functional modulation of WISH cells, we observed
      that LPA stimulates the induction of two early genes (c-Jun and c-Fos) and
      cellular proliferation in WISH cells. We examined the signaling pathways involved
      in LPA-mediated cellular responses. LPA-induced early gene induction was
      completely blocked by normal butanol (n-butanol) but not by t-butanol, suggesting
      that PLD activity is essentially required for the process. PD98059 (2'-amino-3'
      methoxyflavone) but not SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5
      (4-pyridyl)1H-imidazole) also significantly blocked LPA-induced early gene
      induction, suggesting a crucial role for ERK. Pertussis toxin (PTX) did not
      affect on the LPA-induced early gene induction and ERK activation, ruling out the
      role of Gi/o protein(s) in the process. The cellular proliferation of WISH cells
      was also dramatically inhibited by n-butanol or PD98059. This study demonstrates
      the physiological role of LPA on the modulation of early gene induction and on
      WISH cell proliferation, and the crucial role played by PLD in the process.

PMID- 15194007
TI  - Aggravation of necrotic death of glucose-deprived cells by the MEK1 inhibitors
      U0126 and PD184161 through depletion of ATP.
AB  - The extracellular-regulated kinases (ERK) modulate cell proliferation and
      survival in response to several different stimuli and are therefore important
      drug targets. ERKs are activated by the dual phosphorylation kinase MEK1 and MEK1
      inhibitors PD98059, U0126 and CI-1040 are now widely used to inhibit ERKs in cell
      and animal studies. In an analysis of ERK functions in astrocytes we found that
      PD98059 (100microM) failed to inhibit ERK phosphorylation but U0126 (50microM)
      inhibited ERK phosphorylation to approximately 80%. Surprisingly, U0126 also
      caused profound depletion of ATP in glucose-deprived cells, leading to death by
      necrosis. Since glucose-deprived cells depend mainly on mitochondrial ATP
      synthase for ATP production, we tested whether U0126 or PD184161, a derivative of
      CI-1040, might inhibit ATP synthase activity, using 143B(Rho0) cells (which lack
      a functional F0 subunit) to further parse this effect. We found that the
      F1F0ATPase activity extracted from U0126- or PD184161-treated parental 143B cells
      or astrocytes was indeed inhibited by >or=80% suggesting a covalent change in the
      enzyme. However, F1F0ATPase activity extracted from similarly treated 143B(Rho0)
      cells was spared. Because F1F0ATPase activity in isolated mitochondria was not
      inhibited directly, we propose that U0126 and PD184161 inhibit ATP-synthase via
      an indirect action on F0. The MEK1 inhibitors also induced necrosis of other
      glucose-deprived cell types including primary neurons at the same concentrations
      required for inhibition of ERK phosphorylation. Thus, the MEK1/ERK signalling
      pathway may modulate ATP synthase function, and its inhibition may cause cells
      unable to perform glycolysis to die by necrosis.

PMID- 15194006
TI  - Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human
      vascular cells.
AB  - Rheumatoid arthritis (RA) is associated with a reduced life expectancy considered
      to be partly caused by cardiovascular events. A growing concern is that
      accelerated atherosclerosis is driven by inflammatory mechanisms similar to those
      responsible for RA. Therefore, selective COX-2 inhibitors, which are widely used
      for the symptomatic treatment of pain and inflammation in RA, may have an impact
      on atherosclerotic processes. Their anti-inflammatory properties might provoke
      anti-atherogenic effects but on the other hand, selective inhibition of anti
      thrombotic prostacyclin and COX-2 independent effects might promote the risk of
      increased prothrombotic activity. In the current study, the effects of the
      presently marketed selective COX-2 inhibitors celecoxib and rofecoxib on vascular
      cells have been investigated. Celecoxib inhibited the proliferation of human
      umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. At
      high concentrations, it induced apoptosis and the modulation of inhibitory cell
      cycle proteins. In contrast rofecoxib-even at high concentrations-had no effect
      on cell proliferation, apoptosis or cell cycle distribution indicating that
      celecoxib and rofecoxib do not affect the same signal transduction pathways in
      endothelial cells. Both drugs did not affect apoptosis induction or cell cycle
      proliferation in human vascular smooth muscle cells. The observed effects on
      endothelial cells appear to be COX-independent since both drugs selectively
      inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for
      inhibition of prostacyclin production. Regarding endothelial apoptosis as a
      relevant event in the initiation and progression of atherosclerosis the present
      data put forward the hypothesis that the presently marketed COX-2 inhibitors have
      a different impact on atherosclerotic processes.

PMID- 15194008
TI  - Inhibitory effect of emodin on tumor invasion through suppression of activator
      protein-1 and nuclear factor-kappaB.
AB  - 3-Methyl-1,6,8-trihydroxyanthraquinone (emodin) is an active component from the
      rhizome of Rheum palmatum, a widely used traditional Chinese herb. In this study,
      we found that emodin significantly inhibited 12-O-tetradecanoylphorbol-13-acetate
      (TPA)-induced in vitro invasion of human cancer cells including HSC5 and MDA-MB
      231 cells. Matrix metalloproteinases (MMPs) are known to be associated with
      cancer invasion. Zymographic analysis showed that emodin suppressed TPA-induced
      MMP-9 activity in a concentration-dependent manner. We further demonstrated that
      emodin reduced the transcriptional activity of activator protein-1 (AP-1) and
      nuclear factor kappaB (NF-kappaB), two important nuclear transcription factors
      involved in MMP-9 expression. Emodin suppressed the phosphorylation of two
      mitogen-activated protein kinases, extracellular signal-regulated protein kinase
      and c-Jun N-terminal kinase, but not p38 kinase, leading to reduced c-Jun
      phosphorylation and AP-1 DNA-binding. Moreover, emodin inhibited TPA-induced
      degradation of inhibitor of kappaBalpha, nuclear translocation of p65, and NF
      kappaB DNA-binding activity. Taken together, these results suggest that emodin
      inhibits the invasiveness of human cancer cells by suppressing MMP-9 expression
      through inhibiting AP-1 and NF-kappaB signaling pathways.

PMID- 15194009
TI  - Redox-interaction of alpha-tocopheryl quinone with isolated mitochondrial
      cytochrome bc1 complex.
AB  - The homogenous distribution of vitamin E in lipid membranes is a prerequisite for
      its universal function as lipophilic antioxidant. Its antioxidant activity leads
      to the irreversible formation of alpha-tocopheryl quinone (TQ) in those
      membranes. Very little is known about the interference of TQ with redox-cycling
      enzymes normally interacting with ubiquinone (UQ), which exerts important
      bioenergetic functions in the mitochondrial respiratory chain. One of the most
      complex redox reactions of the respiratory chain is the interaction of reduced UQ
      (UQH(2)) with the cytochrome bc(1) complex (ubiquinol:cytochrome c reductase, EC
      1.10.2.2). The aim of this study was to elucidate the influence of TQ on the
      electron transfer from UQH(2) to cytochrome c via the isolated mitochondrial
      cytochrome bc(1) complex. Although TQ is present in substoichiometric amounts
      with respect to UQ in mitochondria and in our experiments with isolated bc(1)
      complex, we observed a decrease of the total electron transfer rate via the bc(1)
      complex with increasing amounts of TQ. Both reduced TQ (TQH(2)) and UQH(2) are
      able to reduce b-cytochromes in the bc(1) complex, however, they act in a
      completely different way. While reduction of b-cytochromes by UQH(2) can occur
      both via the Q(o) and the Q(i) pocket of the cytochrome bc(1) complex, TQH(2) can
      preferably reduce b-cytochromes via the Q(i) pocket. These differences are also
      reflected by the extremely low turnover numbers of the bc(1) activity for
      TQ/TQH(2) compared to UQ/UQH(2) suggesting that TQ/TQH(2) acts as a weak
      competitive inhibitor for binding sites of UQ/UQH(2). In contrast, the oxidation
      properties of TQ and UQ are similar. Furthermore, oxidized TQ was observed to
      decrease the O(2)(*)(-) release rate of UQH(2)-consuming cytochrome bc(1)
      complex. These findings suggest that the irreversible oxidation of vitamin E to
      TQ in mitochondrial membranes causes a downregulation of respiratory activities
      as well as a lower O(2)(*)(-) formation rate by the cytochrome bc(1) complex.

PMID- 15194010
TI  - Isolation and characterization at cholinergic nicotinic receptors of a neurotoxin
      from the venom of the Acanthophis sp. Seram death adder.
AB  - The present study describes the isolation of the first neurotoxin (acantoxin IVa)
      from Acanthophis sp. Seram death adder venom and an examination of its activity
      at nicotinic acetylcholine receptor (nAChR) subtypes. Acantoxin IVa (MW 6815; 0.1
      1.0 microM) caused concentration-dependent inhibition of indirect twitches (0.1
      Hz, 0.2 ms, supramaximal V) and inhibited contractile responses to exogenous
      nicotinic agonists in the chick biventer cervicis nerve-muscle, confirming that
      this toxin is a postsynaptic neurotoxin. Acantoxin IVa (1-10 nM) caused pseudo
      irreversible antagonism at skeletal muscle nAChR with an estimated pA2 of 8.36+/
      0.17. Acantoxin IVa was approximately two-fold less potent than the long-chain
      (Type II) neurotoxin, alpha-bungarotoxin. With a pKi value of 4.48, acantoxin IVa
      was approximately 25,000 times less potent than alpha-bungarotoxin at alpha7-type
      neuronal nAChR. However, in contrast to alpha-bungarotoxin, acantoxin IVa
      completely inhibited specific [3H]-methyllycaconitine (MLA) binding in rat
      hippocampus homogenate. Acantoxin IVa had no activity at ganglionic nAChR,
      alpha4beta2 subtype neuronal nAChR or cytisine-resistant [3H]-epibatidine binding
      sites. While long-chain neurotoxin resistant [3H]-MLA binding in hippocampus
      homogenate requires further investigation, we have shown that a short-chain (Type
      I) neurotoxin is capable of fully inhibiting specific [3H]-MLA binding.

PMID- 15194011
TI  - Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction.
AB  - In this study the drug interaction between ciprofloxacin (CIPRO) and
      pentoxifylline (PTX) was investigated and the role of CYP1A2 in the drug
      interaction was determined with the aid of a selective CYP1A2 inhibitor,
      furafylline (FURA), and the Cyp1A2 knockout mouse. Serum concentrations of PTX
      (83.4+/-1 micromol/l) and metabolite-1 (M-1) (13.7+/-2.8 micromol/l) following a
      single injection of PTX (100 mg/kg i.p.) were significantly higher (P<0.05) in
      mice treated with CIPRO (25 mg/kg i.p. 9 days) compared to serum concentrations
      of PTX (46.3+/-0.5 micromol/l) and M-1 (6.4+/-1.1 micromol/l) in mice
      administered saline. Murine hepatic microsomes were incubated with PTX alone or
      the combination of PTX and CIPRO. The metabolism of PTX in the murine hepatic
      microsomes containing both CIPRO and PTX was significantly decreased compared to
      microsomes incubated with PTX alone, suggesting that CIPRO may inhibit the
      metabolism of PTX. To further clarify the role of CYP1A2 in the metabolism of PTX
      in mice, the effect of a selective CYP1A2 mechanism based inhibitor, FURA, on the
      metabolism of PTX was investigated and our results indicate that FURA inhibited
      metabolism of PTX. We then investigated PTX elimination in the Cyp1A2 knockout
      mouse. Blood levels of PTX were assessed at 2 and 20 min following a single
      injection of PTX (32 mg/kg i.v). Serum concentration of PTX was determined in
      Cyp1A2 knockout mice compared to Cyp1A2 wild type control mice. The serum
      concentration of PTX in Cyp1A2 wild type mice (n=9) was 22.2+/-3.2 micromol/l at
      20 min following injection of PTX. The serum concentration of PTX in Cyp1A2
      knockout mice (n=11) was significantly elevated at 20 min following injection of
      PTX compared to Cyp1A2 wild type mice. These results clearly indicate that
      inhibition of CYP1A2 catalytic activity that occurs in the Cyp1A2 knockout mice
      is sufficient to alter metabolism of PTX and result in markedly elevated levels
      in serum of Cyp1A2 knockout mice. The results of Western analysis in murine
      microsomes suggest that CYP1A2 protein levels were not altered by CIPRO
      indicating that CIPRO did not downregulate Cyp1A2. The results of Western
      analysis also indicated that CIPRO treatment increased CYP2E1 in mouse microsomes
      and the implications of these will be discussed.

PMID- 15194012
TI  - Incidence of out-of-hospital cardiac arrest.
AB  - Estimates of the incidence of out-of-hospital primary cardiac arrest (CA) have
      typically relied solely upon emergency medical service or death certificate
      records and have not investigated incidence in clinical subgroups. Overall and
      temporal patterns of CA incidence were investigated in clinically defined groups
      using systematic methods to ascertain CA. Estimates of incidence were derived
      from a population-based case-control study in a large health plan from 1986 to
      1994. Subjects were enrollees aged 50 to 79 years who had had CA (n = 1,275). A
      stratified random sample of enrollees who had not had CA was used to estimate the
      population at risk with various clinical characteristics (n = 2,323). Poisson's
      regression was used to estimate incidence overall and for 3-year time periods
      (1986 to 1988, 1989 to 1991, and 1992 to 1994). The overall CA incidence was
      1.89/1,000 subject-years and varied up to 30-fold across clinical subgroups. For
      example, incidence was 5.98/1,000 subject-years in subjects with any clinically
      recognized heart disease compared with 0.82/1,000 subject-years in subjects
      without heart disease. In subgroups with heart disease, incidence was 13.69/1,000
      subject-years in subjects with prior myocardial infarction and 21.87/1,000
      subject-years in subjects with heart failure. Risk decreased by 20% from the
      initial to the final time period, with a greater decrease observed in those with
      (25%) compared with those without (12%) clinical heart disease. Thus, CA
      incidence varied considerably across clinical groups. The results provide
      insights regarding absolute and population-attributable risk in clinically
      defined subgroups, information that may aid strategies aimed at reducing
      mortality from CA.

PMID- 15194013
TI  - Head-to-head comparison between contrast-enhanced magnetic resonance imaging and
      dobutamine magnetic resonance imaging in men with ischemic cardiomyopathy.
AB  - Contrast-enhanced magnetic resonance imaging (MRI) can predict functional
      recovery after revascularization. Segments with small, subendocardial scars have
      a large likelihood of recovery, and segments with transmural infarction have a
      small likelihood of recovery. Segments with an intermediate extent of infarction
      have an intermediate likelihood of recovery, and therefore, additional
      information is needed. Accordingly, the transmurality of infarction on contrast
      enhanced MRI was compared with low-dose dobutamine MRI to further define
      viability in 48 patients. Regional contractile dysfunction was determined by cine
      MRI at rest (17-segment model), and contractile reserve was determined using low
      dose dobutamine infusion. Contrast-enhanced MRI was performed to assess the
      extent of scar tissue. A total of 338 segments (41%) were dysfunctional, with 61%
      having contractile reserve. Most segments (approximately 75%) with small,
      subendocardial scars (hyperenhancement scores 1 or 2) had contractile reserve,
      whereas contractile reserve was not frequently (17%) observed in segments with
      transmural infarction (hyperenhancement score 4) (p <0.05). Of segments with an
      intermediate infarct transmurality (hyperenhancement score 3), contractile
      reserve was observed in 42%, whereas 58% did not have contractile reserve. In
      conclusion, the agreement between contrast-enhanced MRI and low-dose dobutamine
      MRI is large in the extremes (subendocardial scars and transmural scars), and
      contrast-enhanced MRI may be sufficient to assess the likelihood of the recovery
      of function after revascularization. However, 61% of segments with an
      intermediate extent of scar tissue on MRI have contractile reserve and 39% lack
      contractile reserve. In these segments, low-dose dobutamine MRI may be needed to
      optimally differentiate myocardium with large and small likelihoods of functional
      recovery after revascularization.

PMID- 15194014
TI  - Comparison of rapidity of coronary recanalization in men with tenecteplase versus
      alteplase in acute myocardial infarction.
AB  - To determine whether tenecteplase (TNK-t-PA), a bioengineered variant of tissue
      type plasminogen activator (t-PA) designed to accelerate thrombolysis, exhibits
      favorable properties compared with those of alteplase, 266 men were studied </=6
      hours after the onset of symptoms and signs of acute myocardial infarction. The
      primary end point was the rapidity of recanalization as judged from analysis of
      serial changes in the concentrations in blood of isoforms of creatine kinase-MM
      in serially obtained blood samples. Additional end points included enzymatically
      estimated infarct size and mortality. Patients were treated quite promptly after
      the onset of symptoms. The interval from the onset of chest pain to
      recanalization seen with TNK-t-PA was 208 +/- 10 (SE) minutes compared with 237
      +/- 9 minutes seen with alteplase (p = 0.04). Thirty-day mortality was low with
      the use of the 2 agents (2%). TNK-t-PA appears to induce recanalization more
      rapidly than alteplase, and thrombolysis initiated early after the onset of
      symptoms is associated with remarkably low mortality.

PMID- 15194015
TI  - Effect of glycoprotein IIIa PlA2 polymorphism on outcome of patients with stable
      coronary artery disease and effect of smoking.
AB  - A polymorphism of glycoprotein IIb/IIIa has been associated with myocardial
      infarction and restenosis after percutaneous coronary intervention. The influence
      on outcome and the interaction of the Pl(A1) genotype with classic risk factors
      for coronary artery disease (CAD) were characterized in patients with chronic CAD
      followed prospectively for 3 years. Pl(A1) genotypes were assessed in 592
      patients enrolled in the Medical, Angioplasty, or Surgery Study II, a randomized
      trial comparing treatments for patients with CAD and preserved left ventricular
      function. The incidence of the composite end point of cardiac death, myocardial
      infarction, and refractory angina requiring revascularization were determined in
      each genotype group. Risk was assessed with the Cox proportional-hazards model.
      The clinical characteristics and treatment of each genotype were similar.
      Although the composite end point tended to be more common in patients with the
      Pl(A2) allele, only smokers with the Pl(A2) allele had a significantly increased
      incidence of the composite end point (p = 0.01). Moreover, a 2.2-fold increased
      risk was apparent in smokers with the Pl(A2) allele (p = 0.03). Thus, taken
      together, these data provide support for the interaction effect between smoking
      and the Pl(A1) gene variant. Smokers with the Pl(A2) polymorphism of platelet
      glycoprotein IIIa are at greater risk for subsequent cardiac events in stable
      coronary disease.

PMID- 15194016
TI  - The Dallas Heart Study: a population-based probability sample for the
      multidisciplinary study of ethnic differences in cardiovascular health.
AB  - The decrease in cardiovascular death rates in the United States has been slower
      in blacks than whites, especially in patients <65 years of age. The Dallas Heart
      Study was designed as a single-site, multiethnic, population-based probability
      sample to (1) produce unbiased population estimates of biologic and social
      variables that pinpoint ethnic differences in cardiovascular health at the
      community level and (2) support hypothesis-driven research on the mechanisms
      causing these differences using genetics, advanced imaging modalities, social
      sciences, and clinical research center methods. A probability-based sample of
      Dallas County residents aged 18 to 65 years was surveyed with an extensive
      household health interview. The subset of participants 30 to 65 years of age
      provided in-home fasting blood and urine samples and underwent multiple imaging
      studies, including cardiac magnetic resonance imaging and electron beam computed
      tomography. Completed interviews were obtained for 6,101 subjects (54% black),
      phlebotomy visits for 3,398 (52% black), and clinic visits for 2,971 (50% black).
      Participation rates were 80.4% for interviews, 75.1% for phlebotomy visits, and
      87.4% for clinic visits. Weighted population estimates of many measured variables
      agreed closely with those of the United States census and were relatively stable
      from the interview sample to the phlebotomy and clinic subsamples. Thus, the
      Dallas Heart Study provides a phenotypically well-characterized probability
      sample for multidisciplinary research that will be used to improve the
      mechanistic understanding and prevention of cardiovascular disease, especially in
      black Americans.

PMID- 15194017
TI  - Treatment of high-risk patients with ezetimibe plus simvastatin co-administration
      versus simvastatin alone to attain National Cholesterol Education Program Adult
      Treatment Panel III low-density lipoprotein cholesterol goals.
AB  - This study assessed whether the co-administration of ezetimibe and simvastatin
      would be more effective than simvastatin monotherapy in allowing high-risk
      patients to achieve a low-density lipoprotein (LDL) cholesterol goal of <100
      mg/dl. Men and women with LDL cholesterol >/=130 mg/dl and meeting National
      Cholesterol Education Program Adult Treatment Panel III criteria for coronary
      heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily
      treatments for 23 weeks: simvastatin 20 mg (n = 253), ezetimibe 10 mg plus
      simvastatin 10 mg (n = 251), ezetimibe 10 mg plus simvastatin 20 mg (n = 109),
      and ezetimibe 10 mg plus simvastatin 40 mg (n = 97). In all groups, patients not
      at goal had their simvastatin doses doubled at weeks 6, 12, and/or 18, up to a
      maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal
      attainment (<100 mg/dl) after 5 weeks of treatment. Ezetimibe plus any dose of
      simvastatin produced greater reductions in LDL cholesterol and allowed more
      patients to achieve goal after 5 weeks (p <0.001) and at the end of the study (p
      <0.001) than simvastatin 20 mg alone. At 5 weeks, 75%, 83%, and 87% of patients
      receiving ezetimibe plus simvastatin 10, 20, and 40 mg had LDL cholesterol <100
      mg/dl compared with 46% of patients receiving simvastatin 20 mg. In patients who
      started on ezetimibe plus simvastatin 10, 20 and 40 mg, 33%, 22%, and 12%,
      respectively, required simvastatin titration during the study compared with 68%
      of patients who started on simvastatin 20 mg. The corresponding median
      simvastatin doses used were 10, 20, 40, and 40 mg, respectively. Ezetimibe plus
      simvastatin was well tolerated, with an overall safety profile similar to that of
      simvastatin monotherapy. Thus, through the dual inhibition of cholesterol
      absorption and synthesis, ezetimibe plus simvastatin allowed more patients to
      reach LDL cholesterol <100 mg/dl at a lower simvastatin dose and with fewer dose
      titrations than simvastatin monotherapy.

PMID- 15194018
TI  - Efficacy and safety of ezetimibe co-administered with simvastatin compared with
      atorvastatin in adults with hypercholesterolemia.
AB  - This study compared the efficacy and safety of co-administered ezetimibe +
      simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia.
      Seven hundred eighty-eight patients were randomized 1:1:1 to 3 treatment groups;
      each group was force-titrated over four 6-week treatment periods: (1) 10 mg of
      atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co
      administration of 10 mg of ezetimibe and 10 mg of simvastatin (10/10 mg) was
      titrated to 10/20, 10/40, and 10/80 mg of ezetimibe + simvastatin; and (3) co
      administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg
      (for 2 treatment periods) and 10/80 mg of ezetimibe + simvastatin. Key efficacy
      measures included percent changes in low-density lipoprotein cholesterol (LDL)
      and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1)
      treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of
      10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and
      (2) treatment period 4 (for LDL cholesterol and HDL cholesterol) comparing co
      administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin.
      Baseline LDL and HDL cholesterol levels were comparable between treatment groups.
      At the end of treatment period 1, the mean decrease of LDL cholesterol was
      significantly (p </=0.001) greater for co-administration of 10/10 mg and 10/20 mg
      of ezetimibe + simvastatin than for 10 mg of atorvastatin. At the end of
      treatment period 4 and after comparing maximum doses, co-administration of 10/80
      mg of ezetimibe + simvastatin was superior to 80 mg of atorvastatin in the
      percent LDL cholesterol decrease (-59.4% vs -52.5%, p <0.001) and HDL cholesterol
      increase (12.3% vs 6.5%; p <0.001). All treatments were well tolerated. Thus, a
      greater LDL cholesterol decrease and HDL cholesterol increase were attained by
      treating patients with co-administration of ezetimibe and simvastatin than with
      atorvastatin.

PMID- 15194019
TI  - Comparison of the rectilinear biphasic waveform with the monophasic damped sine
      waveform for external cardioversion of atrial fibrillation and flutter.
AB  - External cardioversion using the monophasic damped sine (MDS) waveform is
      successful 70% to 94% of the time when using up to 360 J. The rectilinear
      biphasic (RLB) defibrillator has been shown to be superior in efficacy to the MDS
      waveform in atrial cardioversion in a small randomized study. This larger,
      retrospective study compares the results of the RLB waveform with those of the
      MDS waveform for cardioversion of atrial fibrillation (AF) and atrial flutter in
      a large cohort of patients. We performed 1,877 external cardioversion procedures
      in 1,361 patients for AF and atrial flutter by using the RLB defibrillator. We
      compared these results with those of the MDS defibrillator in 2,025 patients who
      underwent 2,818 cardioversion procedures. The overall success rates for the RLB
      defibrillator were 99.1% for AF and 99.2% for atrial flutter, and the
      corresponding success rates for the MDS defibrillator were 92.4% and 99.8% (p
      <0.001; RLB superior for AF). The median overall successful energy level for the
      MDS waveform was 200 J, whereas the corresponding RLB energy level was 100 J.
      Multivariate analyses demonstrated that underlying clinical conditions or use of
      antiarrhythmic drugs does not significantly affect overall success rates. Our
      results from >4,000 procedures confirmed and extended those of the previous
      report by showing a very high success rate for cardioversion of AF and atrial
      flutter using the RLB waveform. The MDS waveform was equally effective for atrial
      flutter but significantly less effective in terminating AF.

PMID- 15194020
TI  - Effect of optimizing the VV interval on left ventricular contractility in cardiac
      resynchronization therapy.
AB  - Simultaneous biventricular pacing improves left ventricular (LV) function in
      patients with heart failure and LV asynchrony. Proper timing of the
      interventricular pacing interval (VV interval) may further optimize LV function.
      We investigated the acute hemodynamic response of changing the VV interval using
      maximum LV dP/dt (LV dP/dt(max)) as a parameter for LV function. A biventricular
      pacemaker was implanted in 53 patients with severely impaired LV function, New
      York Heart Association class III and IV heart failure, left bundle branch block,
      LV asynchrony, and a QRS interval >150 ms. Optimization of the atrioventricular
      and VV intervals was based on measurement of LV dP/dt(max) by a 0.014-in sensor
      tipped pressure guidewire. Measurement of LV dP/dt(max) was obtained without
      complications in all patients. In patients in sinus rhythm with ischemic
      cardiomyopathy or idiopathic dilated cardiomyopathy, mean improvements by
      simultaneous biventricular pacing were 17% and 18%, respectively. Patients in
      atrial fibrillation showed an improvement of 21%. Optimizing the VV interval
      resulted in further absolute increases of 8%, 7%, and 3%, respectively, in
      dP/dt(max) in the 3 groups. Maximum dP/dt was achieved with LV pacing first in 44
      patients, simultaneous right and left ventricular pacing in 6 patients, and right
      ventricular pacing first in 3 patients. The mean optimal VV intervals were 37 +/-
      32 ms in the atrial fibrillation group, 28 +/- 30 ms in the idiopathic dilated
      cardiomyopathy group, and 52 +/- 31 ms in the ischemic cardiomyopathy group.
      Optimization of the VV interval significantly increased LV dP/dt(max) compared
      with simultaneous biventricular pacing, and such optimization could be easily,
      accurately, and reliably evaluated by a 0.014-in sensor-tipped pressure
      guidewire.

PMID- 15194021
TI  - Segmental wall motion abnormalities in idiopathic dilated cardiomyopathy and
      their effect on prognosis.
AB  - There is considerable variability in segmental wall motion abnormalities and in
      the prognosis of idiopathic dilated cardiomyopathy (IDC). Radionuclide
      ventriculography with Fourier analysis was performed in 107 patients with
      angiographically proved IDC. Amplitude analysis located the wall motion
      abnormalities. Using phase analysis in the left and right ventricles, the
      interventricular delay between the mean phase of the right and left ventricles
      was used to assess interventricular dyssynchrony and SDs of the mean phase in
      each ventricle was used to assess intraventricular dyssynchrony. Hypokinesis was
      global in 56 patients (52%) and localized in the anteroseptal wall in 34 (32%),
      the inferior wall in 12 (11%), the anteroseptal and inferior walls in 2 (2%), and
      the lateral wall in 3 (3%). Patients with localized wall motion abnormalities had
      larger left ventricular (LV) end-diastolic diameters (70 +/- 9 vs 66 +/- 8 mm, p
      = 0.009) and lower LV ejection fractions (25 +/- 9% vs 31 +/- 12%, p = 0.005).
      Intraventricular dyssynchrony was lower in patients with global hypokinesis (SD
      of LV mean phase 67 +/- 35 vs 48 +/- 22 ms, p = 0.002). With a follow-up of 27 +/
      23 months, increased SD of the LV phase (p = 0.005), decreased right ventricular
      ejection fraction (p = 0.006), decreased LV ejection fraction (p = 0.04), and
      localized wall motion abnormality (p = 0.009) were independent predictors of
      cardiac death or worsening heart failure leading to heart transplantation. Thus,
      segmental wall motion abnormalities are frequent in IDC and are associated with
      severe systolic dysfunction and a worse prognosis.

PMID- 15194022
TI  - Prevalence of hypertrophic cardiomyopathy in a population-based sample of
      American Indians aged 51 to 77 years (the Strong Heart Study).
AB  - Recognition of the frequency with which hypertrophic cardiomyopathy (HC) occurs
      in the general population is critical to understanding its demographics and
      public health implications. However, few data are available for estimating HC
      prevalence in large populations of different age strata and ethnic or racial
      groups. The Strong Heart Study is a prospective, population-based epidemiologic
      survey of cardiovascular disease in residents of 13 geographically diverse
      American Indian communities. The study population was comprised of 3,501 subjects
      with echocardiograms performed in 1993 and 1995 to determine the prevalence of HC
      in middle-aged and older adult populations. Evidence of the HC phenotype was
      present in 8 previously undiagnosed patients (0.23%; 2 of 1,000) based on a left
      ventricular (LV) wall thickness >/=15 mm and a nondilated cavity that was not
      associated with another cardiac disease and was sufficient to produce the
      magnitude of hypertrophy evident. Ages were 51 to 77 years (mean 64 +/- 9). Four
      subjects were men and 4 were women, with prevalences by gender of 0.3% (3 of
      1,000) and 0.18% (1.8 of 1,000), respectively. Maximum LV thicknesses were 19 to
      29 mm (mean 21 +/- 3). Two subjects had mitral valve systolic anterior motion,
      which was sufficient to produce LV outflow obstruction at rest in 1 patient.
      Different electrocardiographic abnormalities were present in 5 subjects. In
      conclusion, clinically unrecognized HC was present in 1:500 of an aging American
      Indian cohort. This prevalence was similar to that reported in other general
      populations comprised of younger subjects of other races, offering evidence that
      HC is a relatively common genetic disease with widespread occurrence within the
      United States.

PMID- 15194023
TI  - Impact of nephropathy after percutaneous coronary intervention and a method for
      risk stratification.
AB  - Radiocontrast-induced nephropathy (RCIN) after percutaneous coronary intervention
      (PCI) is associated with grave consequences, but risk stratification of patients
      has not been well elucidated. This analysis derived a time-insensitive score to
      predict the risk of RCIN after PCI. A derivation cohort (1993 to 1998) and a
      validation cohort (1999 to 2002) comprised 20,479 patients who underwent PCI.
      RCIN after PCI was defined as a >/=1.0 mg/dl increase in serum creatinine.
      Variables having an independent correlation for RCIN after PCI were used to
      derive the RCIN risk score from the derivation cohort and were tested in the
      validation cohort. RCIN occurred in 2% of patients after PCI. Independent
      variables (with weighted scores) include estimated creatinine clearance <60
      ml/min (2), urgent PCI (2), intra-aortic balloon pump use (2), diabetes mellitus
      (1), congestive heart failure (1), hypertension (1), peripheral vascular disease
      (1), and contrast volume >260 ml (1). The incidence of RCIN after PCI increased
      with each unit increase in score (p <0.0001, concordance statistic 0.89). No
      patient with a score </=1 developed nephropathy, whereas 26% of patients with a
      score >/=9 developed RCIN after PCI (p <0.0001). Propensity score analysis showed
      that patients who developed RCIN after PCI, irrespective of the need for
      hemodialysis, had higher in-hospital rates of major adverse cardiac events (odds
      ratio 15, 95% confidence interval 11 to 20, p <0.0001). RCIN occurred in 2.0% of
      PCI patients and was associated with a 15-fold increase in adverse cardiac
      events. The RCIN risk score was a clinical assessment tool with excellent
      predictive ability in identifying the larger population at risk for nephropathy
      in whom preventative strategies are indicated.

PMID- 15194024
TI  - Avoiding authorship and editorship pitfalls in multi-authored and multi-edition
      textbooks.

PMID- 15194025
TI  - Angiographic and volumetric intravascular ultrasound comparison between direct
      sirolimus-eluting stent implantation versus predilation.
AB  - Conventional sirolimus-eluting stent (SES) implantation typically follows balloon
      predilation. The impact of direct SES implantation on in-stent neointimal
      hyperplasia and the adjacent reference segments has not been evaluated. The aim
      of this study was to analyze direct and conventional SES implantation techniques
      by angiography and serial intravascular ultrasound. Fifty-three patients with
      single de novo coronary lesions underwent successful conventional (n = 26) and
      direct (n = 27) SES implantation. At 6-month follow-up, similar in-stent late
      luminal loss and decreased neointimal hyperplasia volume were seen in the 2
      groups, preserving the luminal dimensions at the edges of the stents.

PMID- 15194026
TI  - Prognostic significance of serum creatinine concentration for in-hospital
      mortality in patients with acute myocardial infarction who underwent successful
      primary percutaneous coronary intervention (from the Heart Institute of Japan
      Acute Myocardial Infarction [HIJAMI] Registry).
AB  - This study evaluated the impact of serum creatinine levels on in-hospital
      mortality in 1,359 consecutive patients with acute myocardial infarction (from a
      Japanese prospective multicenter registry) who underwent successful primary
      percutaneous coronary intervention (PCI). Even in the patients who underwent
      successful primary PCI, the in-hospital mortality of patients with mild (1.2 </=
      creatinine < 2.0 mg/dl) and severe (creatinine >/=2.0 mg/dl) renal dysfunction
      was greater (17.1% and 34.5%, respectively) than that of patients without renal
      dysfunction (3.9%) (relative risk [RR] 1.72, 95% confidence interval [CI] 0.94 to
      3.14, p = 0.080; and RR 4.26, 95% CI 1.48 to 12.27, p <0.0001, respectively).

PMID- 15194027
TI  - Comparison of frequency of left ventricular thrombi in patients with anterior
      wall versus non-anterior wall acute myocardial infarction treated with
      antithrombotic and antiplatelet therapy with or without coronary
      revascularization.
AB  - Of 200 patients with ST-segment elevation acute myocardial infarction (AMI), all
      received antiplatelet and antithrombotic therapy, and 186 patients (93%)
      underwent coronary revascularization. Left ventricular thrombi were diagnosed by
      2-dimensional echocardiography </=1 week after AMI in 19 of 114 patients (17%)
      with anterior wall AMI and in 3 of 86 patients (3%) with non-anterior wall AMI (p
      <0.001).

PMID- 15194028
TI  - Results of angioplasty (with or without stent) at the site of a narrowed coronary
      anastomosis of the left internal mammary artery graft or via the internal mammary
      artery.
AB  - During the past 6 years, 50 patients underwent percutaneous transluminal coronary
      angioplasty (PTCA) of a narrowed coronary anastomosis of a left internal mammary
      artery (LIMA) graft or PTCA of a left anterior descending coronary artery
      stenosis via LIMA grafts at the investigators' institution. The success rate was
      high at 88%. Thirty-four of the 44 successfully treated patients (77%) underwent
      repeat angiography, which showed restenosis in 14 patients (41%). In cases of
      stent implantation at the coronary LIMA graft anastomosis angioplasty site, the
      restenosis rate was 80%, but it was only 14% in cases of pure balloon dilation (p
      = 0.001). Therefore, in cases of coronary LIMA graft anastomosis, stent
      implantation should be avoided, because it implicates an excessively high
      restenosis rate.

PMID- 15194029
TI  - Usefulness of hyperbaric oxygen therapy to inhibit restenosis after percutaneous
      coronary intervention for acute myocardial infarction or unstable angina
      pectoris.
AB  - The purpose of this trial was to assess whether the addition of hyperbaric oxygen
      to percutaneous coronary intervention can reduce clinical restenosis. Major
      adverse cardiac events at 8 months were found in only 1 of 24 patients (4%) who
      received hyperbaric oxygen compared with 13 of 37 patients (35%) who did not.

PMID- 15194031
TI  - Occlusion of pseudoaneurysms using human or bovine thrombin using contrast
      enhanced ultrasound guidance.
AB  - Percutaneous thrombin occlusion of pseudoaneurysms complicating invasive coronary
      interventions has emerged as a useful therapeutic tool. To facilitate thrombin
      occlusion and make the procedure even more secure, preinjection of echo contrast
      medium during duplex ultrasound was tested in 132 patients. Complete and
      immediate occlusion of the pseudoaneurysm was achieved in 99.2% (131 of 132
      patients). No complications related to the injection of thrombin were documented.
      Contrast-enhanced ultrasound-guided thrombin occlusion was a safe and effective
      therapeutic option. In aneurysms with complex morphology or multiple cavities,
      preinjection of contrast medium was helpful for documenting the flow pattern.

PMID- 15194030
TI  - Prognostic significance of cerebrovascular and peripheral arterial disease in
      patients having percutaneous coronary interventions.
AB  - This study shows that cerebrovascular and peripheral arterial diseases frequently
      co-exist in patients with coronary artery disease who undergo percutaneous
      coronary interventions. These 2 conditions are associated with adverse in
      hospital and 1-year outcomes and independently predict early and 1-year
      mortality.

PMID- 15194032
TI  - Different treatments and outcomes of consecutive patients with non-ST-elevation
      myocardial infarction depending on initial electrocardiographic changes (results
      of the Acute Coronary Syndromes [ACOS] Registry).
AB  - Of 6,302 consecutive patients with acute non-ST-elevation myocardial infarction,
      42.8% presented with ST depression, 31.9% showed no significant
      electrocardiographic changes, and 25.3% presented with T inversion. In comparison
      with patients with T inversion or no significant electrocardiographic changes,
      patients with ST depression more often had 3-vessel coronary disease, received
      less acute therapy despite a strong benefit in a subgroup analysis, and had a
      worse clinical outcome even after adjustment in a multivariate analysis. Patients
      with T inversion received a high rate of acute therapy and had a better outcome
      than did patients without significant electrocardiographic changes and patients
      with ST depression.

PMID- 15194033
TI  - Comparison of frequency of interferon-gamma-positive CD4+ T cells before and
      after percutaneous coronary intervention and the effect of statin therapy in
      patients with stable angina pectoris.
AB  - We investigated the effect of statin therapy on T-cell activation in patients who
      underwent percutaneous coronary intervention by using flow cytometric analysis.
      The increased frequency of interferon-gamma-positive CD4(+) T cells after
      percutaneous coronary intervention was significant in the group treated without
      statins but not in the group treated with statins.

PMID- 15194034
TI  - Risk factors and outcomes in patients with coronary artery aneurysms.
AB  - Previous small series have provided conflicting data on the association between
      coronary artery aneurysms and traditional cardiac risk factors, as well as
      limited information on patient outcomes. This investigation sought to determine
      whether the presence of coronary artery aneurysms has an adverse affect on
      patient outcomes. The results show that coronary aneurysms were an independent
      predictor of mortality, and overall 5-year survival in patients with aneurysms
      was only 71%. We believe that clinicians should aggressively monitor and modify
      coronary risk factors in patients with coronary aneurysms.

PMID- 15194036
TI  - Effect of sinus rhythm restoration on plasma brain natriuretic peptide in
      patients with atrial fibrillation.
AB  - Plasma brain natriuretic peptide (BNP) was evaluated before and after sinus
      rhythm restoration in patients with paroxysmal and persistent atrial fibrillation
      (AF) who had underlying hypertension or coronary heart disease and normal left
      ventricle function. Twenty-four hours after successful cardioversion, plasma BNP
      decreased significantly to levels that had been measured in controlled subjects:
      from 95 to 28 pg/ml in 24 patients in the paroxysmal AF group and from 75 to 41
      pg/ml in 36 patients in the persistent AF group. This indicates that AF affects
      BNP secretion in patients with AF and that some BNP may be atrially delivered.

PMID- 15194035
TI  - Impact of carotid arterial narrowing on outcomes of patients with acute coronary
      syndromes.
AB  - The present prospective observational study was conducted in 323 consecutive
      patients with acute coronary syndrome, 101 (31%) of whom were diagnosed with
      carotid arterial narrowing by ultrasonography. At follow-up, patients with
      carotid disease had a greater incidence of cardiovascular events than did those
      with normal carotid arteries. Outcomes of patients with concomitant carotid
      disease who underwent cardiac revascularization were similar to those who
      received conservative treatment.

PMID- 15194037
TI  - Efficacy of substituting innovator propafenone for its generic formulation in
      patients with atrial fibrillation.
AB  - The clinical outcomes of 114 patients with atrial fibrillation who had been
      treated with the innovator propafenone, and in whom the drug was then replaced
      with generic propafenone because of cost containment, were compared. The generic
      formulation was found to be at least as safe and effective as the innovator drug,
      with regard to atrial fibrillation recurrence, emergency room and hospital
      admissions, and necessity for concomitant therapy.

PMID- 15194038
TI  - Comparison of plasma N-brain natriuretic peptide, peak oxygen consumption, and
      left ventricular ejection fraction for severity of chronic heart failure.
AB  - We investigated whether a simple blood test of plasma N-brain natriuretic peptide
      (N-BNP), compared with echocardiographic left ventricular ejection fraction
      (LVEF), both measured at rest, correlated well with aerobic exercise capacity
      (peak oxygen consumption [VO(2)]) in patients with chronic heart failure. Plasma
      N-BNP was found to significantly correlate with peak VO(2) (p <0.001) and
      exercise duration (p = 0.001), whereas LVEF showed very poor correlations with
      peak VO(2) and exercise duration (both p >0.3). The results suggest that N-BNP
      actually reflects functional cardiac impairment better than LVEF.

PMID- 15194039
TI  - Optimum blood collection intervals for B-type natriuretic peptide testing in
      patients with heart failure.
AB  - Patients with congestive heart failure have increased concentrations of B-type
      natriuretic peptide (BNP) in blood. We determined the frequency of serial BNP
      measurements that exceeded the biologic variation of BNP of 100% as a function of
      days between blood collections. Samples collected 7 days apart were associated
      with the highest frequency (50%) of statistically different results (increased or
      decreased) compared with daily collections, where increased or decreased results
      occurred less often (22%).

PMID- 15194040
TI  - Effect of spironolactone on endothelial function in patients with congestive
      heart failure on conventional medical therapy.
AB  - We prospectively studied the effect of spironolactone, an aldosterone antagonist,
      on endothelial function in patients with advanced congestive heart failure (CHF)
      using the brachial artery reactivity method. Twenty patients optimized on
      conventional CHF therapy were treated with spironolactone, and brachial artery
      flow- mediated dilation was measured at baseline and at 4 and 8 weeks.
      Spironolactone improved endothelial function at 4 weeks, and sustained the
      improvement at 8 weeks, in patients with CHF on conventional medical therapy,
      presumably due to reversal of aldosterone impairment of endothelial nitric oxide
      activity.

PMID- 15194041
TI  - Comparison of myocardial function in children with body mass indexes >/=25 versus
      those <25 kg/m2.
AB  - Diastolic functions of the heart, measured by pulsed tissue Doppler
      echocardiography from 25 overweight and obese children, were compared with 91
      children of normal weight who were 10 to 18 years old and had normal 2
      dimensional echocardiographic examinations. Overweight and obese subjects, as
      compared with the control group, had a significant decrease in the peak early
      diastolic E wave at the ventricular septum (12.8 +/- 2.1 vs 13.8 +/- 1.8, p =
      0.025) and a significant increase in the late diastolic A wave at the ventricular
      septum (7.3 +/- 1.8 vs 6.4 +/- 1.4, p = 0.016), lateral wall (7.8 +/- 4.3 vs 6.4
      +/- 2.7, p = 0.000), and posterior wall (4.2 +/- 1.7 vs 3.6 +/- 0.9, p = 0.041).
      In addition, the overweight children had a significantly lower E/A ratio at the
      septum that was inversely related to body mass index.

PMID- 15194042
TI  - Comparison of right and left ventricular function in obese and nonobese men.
AB  - We studied systolic and diastolic function of the left and right ventricles in
      obese male subjects. Obese subjects had increased left ventricular mass and
      normal left ventricular systolic and diastolic function. They also had impaired
      right ventricular relaxation and right ventricular filling.

PMID- 15194044
TI  - Visa crisis hurts U.S. science.

PMID- 15194043
TI  - Diffuse T-wave inversions associated with electroconvulsive therapy.
AB  - Electroconvulsive therapy (ECT) can lead to ST depression and arrhythmias in
      patients with coronary artery disease, most likely secondary to increased
      myocardial oxygen demand. This report describes a case of ECT-associated, global
      T-wave inversions in a patient with chronic atrial fibrillation treated with
      digoxin. Laboratory evaluation and echocardiography were normal. These T-wave
      changes may result from increased sympathetic activity associated with ECT.
      Prospective studies suggest that this finding may be seen in up to 4% of patients
      undergoing ECT.

PMID- 15194045
TI  - Novel mouse model for carcinoembryonic antigen-based therapy.
AB  - Many novel cancer therapies, including immunotherapy and gene therapy, are
      specifically targeted to tumor-associated molecules, among which carcinoembryonic
      antigen (CEA) represents a popular example. Discrepancies between preclinical
      experimental data in animal models and clinical outcome in terms of therapeutic
      response and toxicity, however, often arise. Preclinical testing can be
      compromised by the lack of CEA and other closely related human CEA family members
      in rodents, which lack analogous genes for most human CEA family members. Here,
      we report the construction of a transgenic mouse with a 187-kb human bacterial
      artificial chromosome (CEABAC) that contains part of the human CEA family gene
      cluster including complete human CEA (CEACAM5), CEACAM3, CEACAM6, and CEACAM7
      genes. The spatiotemporal expression pattern of these genes in the CEABAC mice
      was found to be remarkably similar to that of humans. This novel mouse will
      ensure better assessment than previously utilized models for the preclinical
      testing of CEA-targeted therapies and perhaps allow the testing of CEACAM6, which
      is overexpressed in many solid tumors and leukemias, as a therapeutic target.
      Moreover, expression of CEA family genes in gastrointestinal, breast,
      hematopoietic, urogenital, and respiratory systems could facilitate other
      clinical applications, such as the development of therapeutic agents against
      Neisseria gonorrhoeae infections, which use CEA family members as major
      receptors.

PMID- 15194046
TI  - An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor
      enhanced cancer selectivity and enhanced oncolytic potency.
AB  - Oncolytic adenoviruses hold promise as a new treatment platform for cancer, but
      limitations have been identified, including limited spread and potency. The
      adenoviral protein E1B-19 kDa is a Bcl-2 homologue that blocks apoptosis
      induction via the intrinsic and extrinsic pathways, specifically including tumor
      necrosis factor-mediated cell death. We demonstrate that an E1B-19 kDa gene
      deletion mutant had tumor necrosis factor-enhanced cancer selectivity, in vitro
      and in vivo, due to genetic blocks in apoptosis pathways in cancer cells. In
      addition, this mutant demonstrated significantly enhanced viral spread and
      antitumoral potency relative to dl1520 (aka Onyx-015) and wild-type adenovirus in
      vitro. Significant antitumoral efficacy was demonstrated in vivo by intratumoral
      and intravenous routes of administration. E1B-19 kDa deletion should be
      considered as a feature of oncolytic adenoviruses to enhance their safety,
      spread, and efficacy.

PMID- 15194047
TI  - A conditionally replicating adenovirus for nasopharyngeal carcinoma gene therapy.
AB  - Successful attainment of tumor-specific gene expression was achieved in
      nasopharyngeal carcinoma (NPC) by exploiting the exclusive presence of the
      Epstein-Barr virus (EBV) genome in the cancer cells. In the current study, we
      have utilized an EBV-dependent transcriptional targeting strategy to construct a
      novel conditionally replicating adenovirus, adv.oriP.E1A. After treatment with
      adv.oriP.E1A, we observed extensive cell death in the EBV-positive NPC cell line
      C666-1. In contrast, no cytotoxicity was observed in a panel of other human EBV
      negative cell lines, including fibroblasts from the nasopharynx. In vitro
      adenoviral replication was confirmed by the time-dependent increase in the
      expression of adenoviral capsid fiber protein and adenoviral DNA after C666-1
      cells were infected with adv.oriP.E1A. Tumor formation was inhibited for more
      than 100 days after ex vivo infection of C666-1 cells with adv.oriP.E1A.
      Combination of local tumor radiation and adv.oriP.E1A caused complete
      disappearance of established tumors for at least 2 weeks in two distinct EBV
      positive NPC xenograft models. Safety of this treatment was determined through
      the systemic delivery of adv.oriP.E1A in vivo, whereby minimal temporary
      perturbation of liver function was observed. We have successfully established a
      conditionally replicating adenovirus for EBV-positive NPC, which is both safe and
      efficacious, indicating a strategy that may be therapeutically applicable.

PMID- 15194048
TI  - Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and
      sensitizes NSCLC xenograft tumors to radiation.
AB  - Melanoma differentiation-associated gene-7 (mda-7), recently classified as
      interleukin-24 (approved gene symbol IL24), is thought to be a tumor suppressor
      gene based on the loss of its expression in many different types of cancer. Gene
      therapy by adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to
      inhibit the growth of several different tumor cell lines, in vitro and in vivo.
      We previously demonstrated that Ad-mda7 radiosensitized non-small-cell lung
      cancer (NSCLC) cell lines by enhancing an apoptosis pathway through the
      activation of JNK and c-Jun. In the present study, we investigated the efficacy
      of intratumoral administration of Ad-mda7 combined with ionizing radiation for
      treating A549 xenograft tumors in nude mice. Substantial and long-lasting
      inhibition of tumor growth was evident following the combined treatment.
      Histological examination revealed marked reduction of angiogenic factors (bFGF,
      VEGF) and microvessel density and enhanced apoptosis in the tumors treated with
      the combination therapy compared to those treated with Ad-mda7 alone or radiation
      alone. To confirm the radiosensitizing effect of secreted MDA-7 protein, we
      performed clonogenic survival assays using human umbilical vein endothelial cells
      (HUVECs), A549 cells, and normal human lung fibroblasts, CCD16 cells, pretreated
      with the conditioned medium from 293 cells that had been stably transfected with
      mda-7 or a control vector. The results showed that MDA-7 protein sensitized
      HUVECs to ionizing radiation but not A549 cells or CCD16 cells. Our results
      suggest that Ad-mda7 in combination with radiation enhances apoptosis in the
      tumors and that secreted MDA-7 protein inhibits angiogenesis by sensitizing
      endothelial cells to ionizing radiation without affecting other normal cells. We
      conclude that the combination of mda-7 gene therapy and radiotherapy may be a
      feasible and effective strategy for treatment of NSCLC.

PMID- 15194049
TI  - Combination of local, nonviral IL12 gene therapy and systemic paclitaxel
      treatment in a metastatic breast cancer model.
AB  - Repeated, local, nonviral IL12 (interleukin-12) gene delivery decreased tumor
      progression and increased immunogenicity. We combined our IL12 gene delivery with
      systemic paclitaxel chemotherapy as a treatment for paclitaxel (PCT)-resistant
      4T1 subcutaneous mouse mammary carcinomas and PCT-sensitive,
      immunogenic/nonimmunogenic tumors. We mixed PCT with either a biodegradable
      polymeric solubilizer, HySolv, or Cremophor EL for bimonthly systemic treatments
      and injected water-soluble lipopolymer (WSLP)/p2CMVmIL-12 (plasmid encoding IL12
      gene) complexes locally every week. We compared treated subcutaneous tumor volume
      and lung metastasis with controls. HySolv alone performed better compared to
      Cremophor EL in combination with WSLP/p2CMVmIL-12. We showed inhibition of 4T1
      tumor growth and lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group
      compared to the controls and the paclitaxel-only treated groups. In parallel
      experiments we also demonstrated additive responses for tumor growth and number
      of lung metastases within other PCT-sensitive mammary tumor models using this
      combination strategy. Our combination therapy provides evidence for the efficacy
      and feasibility of improved drug delivery systems. Local cytokine gene delivery
      can augment local and systemic chemotherapy without placing the host at risk for
      further systemic toxicity.

PMID- 15194050
TI  - Tumor efficacy and biodistribution of linear polyethylenimine-cholesterol/DNA
      complexes.
AB  - Non-viral polymer/pDNA complexes were formed using linear polyethylenimine (LPEI)
      Mw 25 k conjugated to cholesterol in a T-shaped geometry (LPC-T) and pDNA
      encoding murine interleukin-12 (pmIL-12e). These complexes were subsequently
      injected weekly into BALB/c mice intravenously and locally for the treatment of
      murine renal cell adenocarcinoma (Renca) induced pulmonary metastases and
      subcutaneous (SC) Renca tumors, respectively. At the cessation of the pulmonary
      metastases study, the number of pulmonary metastases was significantly less (p <
      0.001) with systemic injections of LPC-T/pmIL-12e formulations than with pmIL-12e
      alone or pmIL-12e complexed with LPEI, branched polyethylenimine (BPEI) Mw 25 k,
      or an LPEI/pEGFP control. In addition, biodistribution studies showed increased
      pulmonary levels of both the LPC-T carrier and pmIL-12e vector up to 3 hr after
      systemic injection of the LPC-T/pmIL-12e complexes into mice carrying pulmonary
      metastases. Furthermore, mice systemically treated with LPC-T/pmIL-12e showed a
      near linear profile in weight gain in the course of the pulmonary metastases
      study that suggests increased biocompatibility. Finally, due to favorable
      characteristics in vitro, LPC-T was also used for local (peritumoral) injection
      of SC Renca tumors. Tumor stasis and slight tumor regression were seen only with
      the LPC-T/pmIL-12e treated mice compared to BPEI/pmIL-12e, LPEI/pmIL-12e, and
      naked pmIL-12e controls. Thus, it was concluded that LPC-T is an effective
      carrier for passive targeting of the pulmonary tissue, treatment of Renca-induced
      pulmonary metastases, and local administration of Renca cell SC tumors.

PMID- 15194051
TI  - The angiostatic activity of interferon-inducible protein-10/CXCL10 in human
      melanoma depends on binding to CXCR3 but not to glycosaminoglycan.
AB  - Human interferon-inducible protein 10 (IP-10; HGMW-approved gene symbol CXCL10)
      is an ELR(-) CXC chemokine that contains binding domains for both the chemokine
      receptor CXCR3 and glycosaminoglycans. IP-10 has been recently demonstrated to be
      a potent angiostatic protein in vivo. Whether IP-10 exerts its angiostatic
      function through binding to CXCR3, glycosaminoglycans, or both, is not clear. To
      clarify this issue, we created expression constructs for mutants of IP-10 that
      exhibit partial (IP-10C) or total (IP-10C22) loss of binding to CXCR3 or loss of
      binding to glycosaminoglycans (IP-10H and IP-10C22H). The A375 human melanoma
      cell line was transfected with these expression vectors, and stable clones were
      selected and inoculated subcutaneously into nude mice. As expected, tumor cells
      secreting wild-type IP-10 showed remarkable reduction in tumor growth compared to
      control vector-transfected tumor cells. Surprisingly, mutation of IP-10 resulting
      in partial loss of receptor binding (IP-10C), or loss of GAG binding (IP-10H),
      did not significantly alter the ability to inhibit tumor growth. This tumor
      growth inhibition was associated with a reduction in microvessel density, leading
      to the observed increase in both tumor cell apoptosis and necrosis. In contrast,
      expression of the IP-10C22 mutant failed to inhibit melanoma tumor growth. These
      data suggest that CXCR3 receptor binding, but not glycosaminoglycan binding, is
      essential for the tumor angiostatic activity of IP-10. We conclude that the
      arginine 22 amino acid residue of IP-10 is essential for both CXCR3 binding and
      angiostasis.

PMID- 15194052
TI  - Human CD34+ hematopoietic progenitor cell-directed lentiviral-mediated gene
      therapy in a xenotransplantation model of lysosomal storage disease.
AB  - As a group, lysosomal storage diseases (LSDs) affect roughly 1 in 6700 live
      births. Treatment of patients with enzyme replacement therapy or allogeneic bone
      marrow transplantation is severely limited by cost and clinical complications,
      respectively. In this study, the efficacy of gene therapy targeted to human
      hematopoietic progenitor cells was investigated for mucopolysaccharidosis type
      VII (MPSVII), a LSD caused by beta-glucuronidase (GUSB) deficiency. Clinical
      experience has emphasized the need to evaluate transduction protocols directly
      with human cells through in vivo assays. Therefore, GUSB-deficient mobilized
      peripheral blood CD34(+) cells from a patient with MPSVII were transduced with a
      third-generation lentiviral vector encoding human GUSB and then assessed in a
      xenotransplantation system. In this novel strategy, the xenotransplanted murine
      recipients were also GUSB-deficient, allowing a detailed evaluation of
      therapeutic efficacy in a host with MPSVII. Twelve weeks posttransplantation,
      lymphomyeloid expression of GUSB was detected in 10.8 +/- 1.6% of the human cells
      in the bone marrow with an average of 1 to 2 vector genomes measured per positive
      cell. The corrected cells distributed widely throughout recipient tissues,
      resulting in significant therapeutic effects including improvements in
      biochemical parameters and reduction of the lysosomal distension of several host
      tissues.

PMID- 15194053
TI  - Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice
      treated at birth with adeno-associated virus vector transducing the human alpha-L
      iduronidase gene.
AB  - Murine models of lysosomal storage diseases provide an opportunity to evaluate
      the potential for gene therapy to prevent systemic manifestations of the disease.
      To determine the potential for treatment of mucopolysaccharidosis type I using a
      gene delivery approach, a recombinant adeno-associated virus (AAV) vector,
      vTRCA1, transducing the human iduronidase (IDUA) gene was constructed and 1 x
      10(10) particles were injected intravenously into 1-day-old Idua(-/-) mice. High
      levels of IDUA activity were present in the plasma of vTRCA1-treated animals that
      persisted for the 5-month duration of the study, with heart and lung of this
      group demonstrating the highest tissue levels of gene transfer and enzyme
      activity overall. vTRCA1-treated Idua(-/-) animals with measurable plasma IDUA
      activity exhibited histopathological evidence of reduced lysosomal storage in a
      number of tissues and were normalized with respect to urinary GAG excretion,
      craniofacial bony parameters, and body weight. In an open field test, vTRCA1
      treated Idua(-/-) animals exhibited a significant reduction in total squares
      covered and a trend toward normalization in rearing events and grooming time
      compared to control-treated Idua(-/-) animals. We conclude that AAV-mediated
      transduction of the IDUA gene in newborn Idua(-/-) mice was sufficient to have a
      major curative impact on several of the most important parameters of the disease.

PMID- 15194054
TI  - Potent inhibition of arterial intimal hyperplasia by TIMP1 gene transfer using
      AAV vectors.
AB  - Seminal to the process of arterial restenosis after balloon angioplasty is
      extracellular matrix degradation by metalloproteinases (MMPs); activity of these
      proteins is strongly inhibited by the tissue inhibitors of MMPs (TIMPs). Here we
      exploit gene transfer using an adeno-associated virus (AAV) for TIMP1 gene
      delivery in a rat model of intimal hyperplasia. High-titer AAV-Timp1 efficiently
      transduced human coronary artery smooth muscle cells (SMCs) in vitro and
      inhibited the capacity of these cells to migrate through a Matrigel barrier. In
      injured rat carotid arteries, AAV vectors were found to transduce SMCs
      efficiently and to maintain transgene expression for several weeks in vivo. In
      AAV-Timp1-transduced animals, the intima:media ratio of injured carotids was
      significantly reduced by 70.5% after 2 weeks, by 58.5% after 1 month, and by
      52.4% after 2 months from treatment. The decrease in intimal hyperplasia was
      paralleled by a significant inhibition of collagen accumulation and by increased
      elastin deposition in the neointima, two findings that relate to the inhibition
      of MMP activity. These results indicate that AAV vectors are efficient tools for
      delivering genes to the arterial wall and emphasize the importance of MMPs for
      the generation of intimal hyperplasia. Local TIMP1 gene transfer might thus
      represent an efficient strategy to prevent restenosis.

PMID- 15194055
TI  - Development of a self-inactivating tet-on retroviral vector expressing bone
      morphogenetic protein 4 to achieve regulated bone formation.
AB  - The aims of this study were to explore the possibility of improving the design of
      self-inactivating (SI) retroviral vectors and to develop an SI vector that would
      allow optimal tet-on-regulated therapeutic gene expression. To minimize any
      interference between the viral promoter and the inducible promoter, we deleted
      different regulatory elements in the 3'LTR and examined their effects on
      transgene expression in transfected or transduced cells. In transfected cells,
      such deletions reduced the transgene expression. The insertion of a
      polyadenylation sequence could not completely compensate for this effect. We
      observed three patterns of transgene expression in cells transduced with these
      tet-on retroviral vectors: (1) high levels of both basal and inducible
      expression, (2) low levels of both basal and inducible expression, and (3) low
      levels of basal and high levels of inducible expression. After using the optimal
      vector to transduce muscle-derived stem cells, we were able to regulate the
      strong in vitro expression of transgenes-including enhanced green fluorescent
      protein and bone morphogenetic protein 4-via the addition or withdrawal of
      doxycycline (Dox). Implantation of the transduced cells and subsequent Dox
      dependent induction of gene expression resulted in bone formation in vivo. Thus,
      we have developed an optimal SI retroviral vector that maintains a high titer,
      efficiently transduces muscle-derived stem cells, and enables both high levels of
      inducible gene expression in vitro and robust regulated bone formation in vivo.

PMID- 15194056
TI  - Retroviral-mediated gene transfer restores IL-12 and IL-23 signaling pathways in
      T cells from IL-12 receptor beta1-deficient patients.
AB  - Genetic deficiency of human IL-12 receptor beta1 chain (IL-12Rbeta1) results in
      increased vulnerability to weakly pathogenic strains of Mycobacteria and
      Salmonella. This phenotype results from the combined lack of IL-12 and IL-23
      signaling as both cytokine receptors share IL-12Rbeta1. Such infections can be
      treated by administration of antibiotics and IFN-gamma; however, patients can
      succumb to infections despite these treatments. Reversion of patients'
      susceptibility by corrective gene transfer could prevent the infectious episodes,
      thus providing a beneficial alternative. We therefore evaluated the feasibility
      of retroviral-mediated gene correction of T cells obtained from patients carrying
      "null" mutations of IL-12Rbeta1. Transduction of the IL-12Rbeta1 cDNA restored
      the expression of IL-12Rbeta1 and resulted in the reconstitution of a functional
      IL-12 signaling pathway, as demonstrated by STAT4 phosphorylation and IFN-gamma
      production. IFN-gamma production in response to IL-23 was also corrected after
      gene transfer. These results indicate that the biological defects of T cells from
      patients carrying IL-12Rbeta1 deficiency can be corrected by gene transfer and
      form the basis for further development of gene therapy for this disease.

PMID- 15194057
TI  - Efficient lentiviral vector-mediated control of HIV-1 replication in CD4
      lymphocytes from diverse HIV+ infected patients grouped according to CD4 count
      and viral load.
AB  - We present preclinical studies that demonstrate in vitro the feasibility and
      efficacy of lentivirus-based vector antisense gene therapy for control of HIV
      replication in primary T lymphocytes isolated from HIV-infected patients
      discordant for clinical status. VRX496 is a VSV-G-pseudotyped HIV-based vector
      that encodes an antisense payload against the HIV envelope gene. The antisense
      payload is under the control of the native LTR promoter, which is highly
      transactivated by tat upon HIV infection in the cell. Transfer of autologous
      CD4(+) T lymphocytes genetically modified with VRX496 (VRX496T) into HIV-infected
      patients is intended to provide a reservoir of cells capable of controlling HIV,
      potentially delaying AIDS onset. To determine the patient population likely to
      respond to VRX496 for optimal efficacy, we examined the ability of our research
      vector, VRX494, to modify and suppress HIV in vitro in lymphocytes isolated from
      20 study subjects discordant for CD4 count and viral load. VRX494 is analogous to
      the clinical vector VRX496, except that it contains GFP as a marker gene instead
      of the 186-tag marker in the clinical vector. To transfer VRX494 to target cells
      we developed a novel scalable two-step transduction procedure that has been
      translated to the clinic in an ongoing clinical trial. This procedure achieved
      unprecedented transduction efficiencies of 94 +/- 5% in HIV(+) study subject
      cells. In addition the vector inhibited HIV replication >/=93% in culture
      regardless of the viral load or CD4 count of the subject or tropism of the virus
      strain with which they were infected. These findings demonstrate that VRX496T
      therapy is expected to be beneficial to patients that differ in their status in
      term of CD4 count and viral load. The methods described represent significant
      technical advances facilitating execution of lentivirus vector-mediated gene
      therapy for treatment of HIV and are currently being employed in the first trial
      evaluating lentivirus vector safety in humans.

PMID- 15194058
TI  - Efficient marking of murine long-term repopulating stem cells targeting
      unseparated marrow cells at low lentiviral vector particle concentration.
AB  - HIV-1-derived lentivirus vectors offer unique biological properties for gene
      delivery to hematopoietic stem cells and, when used at high multiplicities of
      infection (m.o.i.), permit efficient gene transfer after minimal target cell
      stimulation. However, such a strategy has been shown to promote multicopy
      proviral integration, potentially increasing the risk of insertional mutagenesis.
      To minimize cell manipulation, we targeted unseparated marrow and demonstrated
      that transduction at an m.o.i. of 1 resulted in up to 12% vector-modified
      peripheral blood leukocytes and successful repopulation of secondary recipients
      with vector-marked cells. Real-time PCR showed on average 1.8 proviral integrants
      per GFP-marked cell. By comparison, a cohort of animals transplanted with cells
      transduced at m.o.i. of 10 under otherwise unchanged conditions showed up to 45%
      marking with an average of 7 copies per GFP-expressing cell. Both m.o.i. groups
      demonstrated sustained proviral expression with stable GFP fluorescence
      intensity. In summary, we have identified conditions for lentiviral gene transfer
      involving minimal ex vivo target cell manipulation and have shown that the m.o.i.
      is a critical determinant of proviral copy number in lentivirus-transduced murine
      long-term repopulating cells. Thus, gene transfer efficiencies may be limited
      when single-copy integration is desired and additional strategies such as in vivo
      selection may be required to improve the frequency of gene-modified cells.

PMID- 15194059
TI  - Limited lentiviral transgene expression with increasing copy number in an MGMT
      selection model: lack of copy number selection by drug treatment.
AB  - Retroviral vector integration into the human genome carries increased risk of
      oncogenesis with increasing integrations. To boost transgene expression for gene
      therapy, multiple integrations are often sought. We studied the relationship
      between the number of vector integrations and transgene expression and the effect
      that drug selection in an MGMT-selection model would have on vector copy number.
      K562 cells were transduced using a lentiviral vector and a library of clones was
      generated. Median proviral copy number was 4 and a positive correlation with
      transgene expression was observed. Transgene expression increased at a linear
      rate between 1 and 4 vector copies/cell, but was unpredictable at >4
      integrations/cell. When lentivirus MGMT(P140K)-transduced K562 cells were treated
      with O(6)-benzylguanine (BG)/BCNU, there was no selection for increased median
      copy number in colony-forming units, despite strong selection pressure and an
      increase in transgene expression and activity. These data show a direct and
      linear correlation between MGMT(P140K) transgene expression and vector copy
      number. Strong BG/BCNU selective pressure does not result in preferential
      survival of high-copy-number clones but does select for strong transgene
      expression. Thus drug selection would not be expected to increase the risk of
      oncogenesis due to exaggerated selection in favor of high-copy-number vector
      integration.

PMID- 15194060
TI  - Severe pulmonary pathology after intravenous administration of vectors in
      cirrhotic rats.
AB  - After an intravascular injection, adenoviral vectors are normally taken up by the
      reticuloendothelial system in the liver, where they rapidly trigger an innate
      response. However, we have previously found that the biodistribution of
      adenoviral vectors is altered in cirrhotic rats due to the presence of pulmonary
      intravascular macrophages, which cause a shift in vector uptake from the liver to
      the lungs. We now report that this is correlated with fatal pulmonary hemorrhagic
      edema in cirrhotic rats. In addition, cirrhotic rats reacted to vector with
      enormous increases in TNF-alpha and IL-6 and markedly prolonged coagulation
      times. Although we also saw fatal reactions to high doses of adenoviral vectors
      in normal rats, the time course and symptoms were very different, and pulmonary
      hemorrhagic edema was seen only in cirrhotic rats. Because abnormal pulmonary
      reticuloendothelial uptake is known to occur in humans during cirrhosis and other
      diseases, there is the potential that intravascular administration of adenoviral
      vectors might cause lung pathology in such patients.

PMID- 15194061
TI  - Avidin-based targeting and purification of a protein IX-modified, metabolically
      biotinylated adenoviral vector.
AB  - While genetic modification of adenoviral vectors can produce vectors with
      modified tropism, incorporation of targeting peptides/proteins into the
      structural context of the virion can also result in destruction of ligand
      targeting or virion integrity. To combat this problem, we have developed a
      versatile targeting system using metabolically biotinylated adenoviral vectors
      bearing biotinylated fiber proteins. These vectors have been demonstrated to be
      useful as a platform for avidin-based ligand screening and vector targeting by
      conjugating biotinylated ligands to the virus using high-affinity tetrameric
      avidin (K(d) = 10(-15) M). The biotinylated vector could also be purified by
      biotin-reversible binding on monomeric avidin (K(d) = 10(-7) M). In this report,
      a second metabolically biotinylated adenovirus vector, Ad-IX-BAP, has been
      engineered by fusing a biotin acceptor peptide (BAP) to the C-terminus of the
      adenovirus pIX protein. This biotinylated vector displays twice as many biotins
      and was markedly superior for single-step affinity purification on monomeric
      avidin resin. However, unlike the fiber-biotinylated vector, Ad-IX-BAP failed to
      retarget to cells with biotinylated antibodies including anti-CD71 against the
      transferrin receptor. In contrast, Ad-IX-BAP was retargeted if transferrin, the
      cognate ligand for CD71, was used as a ligand rather than the anti-CD71. This
      work demonstrates the utility of metabolic biotinylation as a molecular screening
      tool to assess the utility of different viral capsid proteins for ligand display
      and the biology and compatibility of different ligands and receptors for vector
      targeting applications. These results also demonstrate the utility of the pIX
      biotinylated vector as a platform for gentle single-step affinity purification of
      adenoviral vectors.

PMID- 15194062
TI  - The fate of mesenchymal stem cells transplanted into immunocompetent neonatal
      mice: implications for skeletal gene therapy via stem cells.
AB  - To explore the feasibility of skeletal gene and cell therapies, we transduced
      murine bone marrow-derived mesenchymal stem cells (MSCs) with a retrovirus
      carrying the enhanced green fluorescent protein and zeocin-resistance genes prior
      to transplantation into 2-day-old immunocompetent neonatal mice. Whole-body
      imaging of the recipient mice at 7 days post-systemic cell injection demonstrated
      a wide distribution of the cells in vivo. Twenty-five days posttransplantation,
      most of the infused cells were present in the lung as assessed by examination of
      the cells cultured from the lungs of the recipient mice. The cells persisted in
      lung and maintained a high level of gene expression and could be recovered from
      the recipient mice at 150 days after cell transplantation. A significant number
      of GFP-positive cells were also present in the bones of the recipient mice at 35
      days post-cell transplantation. Recycling of the cells recovered from femurs of
      the recipient mice at 25 days posttransplantation by repeated injections into
      different neonatal mice resulted in the isolation of a clone of cells that was
      detected in bone and cartilage, but not in lung and liver after systemic
      injection. These data demonstrate that MSCs persist in immunocompetent neonatal
      mice, maintain a high level of gene expression, and may participate in skeletal
      growth and development of the recipient animals.

PMID- 15194063
TI  - Intracytoplasmic delivery of anionic proteins.
AB  - Protein delivery is emerging as an interesting alternative to gene delivery. We
      have used our experience with transfection to develop a technique for efficient
      delivery of anionic proteins such as antibodies into the cytoplasm of cells. As
      for DNA, when complexed with cationic lipids, large amounts of proteins are shown
      to enter adherent cells via ubiquitously expressed syndecans. However, protein
      surface area rather than electric charge ratio governs the delivery
      characteristics. Delivery of anti-beta-actin and anti-alpha-tubulin IgG's leads
      to fiber depolymerization. Intracellular delivery of an antibody could thus be
      regarded as another method for interfering with gene activity.

PMID- 15194064
TI  - Total fundoplication is superior to partial fundoplication even when esophageal
      peristalsis is weak.
AB  - BACKGROUND: About a decade ago, partial (240 degrees) fundoplication became
      popular for treating gastroesophageal reflux disease in cases where the patient's
      primary esophageal peristalsis was weak. A total (360 degrees) fundoplication was
      reserved for patients with normal peristalsis (tailored approach). The theory was
      that partial fundoplication was an adequate antireflux measure, and by posing
      less resistance for the weak esophageal peristalsis to overcome, it would give
      rise to less dysphagia. Short-term results seemed to confirm these ideas. STUDY
      DESIGN: This study reports the longterm followup of patients in whom a tailored
      approach (type of wrap chosen to match esophageal peristalsis) was used, and the
      results of a nonselective approach, using a total fundoplication regardless of
      the amplitude of esophageal peristalsis. We analyzed clinical and laboratory
      findings in 357 patients who had an operation for gastroesophageal reflux disease
      between October 1992 and November 2002. Group 1 was composed of 235 patients in
      whom a tailored approach was used between October 1992 and December 1999 (141
      patients, partial fundoplication and 94 patients, total fundoplication). Group 2
      contained 122 patients in whom a nonselective approach was used (total
      fundoplication regardless of quality of peristalsis). RESULTS: In group 1,
      heartburn from reflux (ie, pH monitoring test was abnormal) recurred in 19% of
      patients after partial fundoplication and in 4% after total fundoplication. In
      group 2, heartburn recurred in 4% of patients after total fundoplication. The
      incidence of postoperative dysphagia was similar in the two groups. CONCLUSIONS:
      These data show that laparoscopic partial fundoplication was less effective than
      total fundoplication in curing gastroesophageal reflux disease, and compared with
      a partial (240 degrees) fundoplication, a total (360 degrees) fundoplication was
      not followed by more dysphagia, even when esophageal peristalsis was weak.

PMID- 15194068
TI  - Outcomes and prediction of hospital readmission after intestinal surgery.
AB  - BACKGROUND: Clinical care pathways reduce postoperative stay after major bowel
      operations. Concerns about unexpected early readmissions and delays in diagnosis
      of complications remain unanswered. The objectives of this study were
      determination of readmission rate and outcomes for patients undergoing intestinal
      operations. STUDY DESIGN: Patients readmitted (PR) within 30 days of discharge
      after intestinal operations were compared with patients who were not readmitted
      (NR). Variables that might predict readmission were evaluated. RESULTS: Of 553
      patients, 56 (10.1%) were readmitted after 10 days (interquartile range [IQR] 4.5
      to 15.5 days). PR and NR groups had similar age, gender, diagnosis, preoperative
      comorbidities, and index operations. Discharge hemoglobin level, white cell
      count, antibiotic use, or presence of stoma did not affect readmission. PR had a
      greater frequency of steroid use (p = 0.03) during index admission. Median length
      of stay for the index hospitalization was 5 days (IQR 4 to 8 days) for the NR and
      6 days (IQR 4.8 to 9 days) for the PR group (p = 0.049). Duration of readmission
      was 4 days (IQR 2 to 9 days) in the PR group, with equal total median length of
      stay identical for PR and NR patients with complications (median 12 days).
      Clinical outcomes for PR patients and NR patients with complications were
      similar. CONCLUSIONS: Early readmission is an unpredictable sequel of major bowel
      operations; it does not correlate with shorter hospital stay. Identification of
      unpredictable complications after discharge that require later invasive
      intervention does not adversely affect clinical outcomes. Readmission within 30
      days of a patient who has attained standardized discharge criteria may not be a
      valid indicator of poor quality of care.

PMID- 15194067
TI  - Pancreaticogastrostomy: a novel application after central pancreatectomy.
AB  - BACKGROUND: Limited middle segment pancreatectomy, or central pancreatectomy, has
      been described for sparing normal pancreatic tissue during resection of benign
      neoplasms of the pancreatic neck. Anatomic reconstruction after central
      pancreatectomy has been reported in other series with creation of a Roux-en-Y
      loop of jejunum for a mucosa-to-mucosa pancreaticojejunostomy. STUDY DESIGN:
      Hospital charts and outpatient records were reviewed for 12 consecutive patients
      undergoing central pancreatectomy from August 1999 to November 2002. RESULTS: We
      performed central pancreatectomy with pancreaticogastrostomy in 12 patients: 5
      with serous cystadenomas, 6 with mucinous cystadenomas, and 1 with neuroendocrine
      tumor. All tumors were located in the body or neck of the pancreas, measuring a
      mean +/- standard deviation (SD) of 2.5 +/- 1.2 cm. Median postoperative hospital
      stay was 6.5 days (range 5 to 15 days). There were no intraoperative
      complications. Perioperative complications included two urinary tract infections
      and one readmission for acute pancreatitis. There were no pancreatic leaks or
      fistulas in this series. Two of the 12 patients experienced endocrine
      insufficiency with elevated glycosylated hemoglobin levels during outpatient
      followup. None of the 12 patients experienced exocrine insufficiency.
      CONCLUSIONS: Central pancreatectomy with pancreaticogastrostomy reconstruction is
      safe and technically advantageous over Roux-en-Y pancreaticojejunostomy, and
      should be considered a safe reconstruction technique after central pancreatectomy
      for benign disease.

PMID- 15194069
TI  - Impact of microscopic hepatic lymph node involvement on survival after resection
      of colorectal liver metastasis.
AB  - BACKGROUND: Macroscopic hepatic lymph node involvement is usually a
      contraindication to hepatic resection. Only a few studies have investigated the
      impact of hepatic lymph node involvement on survival. The aim of this
      retrospective study was to assess microscopic hepatic lymph node involvement in
      resectable colorectal liver metastasis and outcomes in patients with such
      involvement. STUDY DESIGN: From January 1985 to December 2000, 156 patients
      underwent curative liver resection in association with systematic hepatic lymph
      node dissection for colorectal liver metastasis. A first analysis was performed
      to assess the association between hepatic lymph node metastasis and patients'
      characteristics. A second analysis assessed survival after resection of liver
      colorectal metastasis by using the Kaplan-Meier method. RESULTS: Twenty-three of
      the 156 patients (15%) had microscopically involved hepatic lymph nodes. No
      predictive factor of lymph node metastasis was identified. Multivariate analysis
      showed that lymph node metastasis, preoperative carcinoembryonic antigen level,
      number of metastases, and morbidity were factors influencing survival. The 3- and
      5-year survival rates of patients with lymph node metastasis were 27% and 5%,
      respectively, compared with 56% and 43% without lymph node metastasis (p =
      0.0001). CONCLUSIONS: During resection of liver colorectal metastasis,
      microscopic lymph node involvement occurred in 15% of the patients and was
      associated with a poor 5-year survival. Hepatic lymph node dissection should be
      performed systematically to select high-risk patients.

PMID- 15194070
TI  - Laparoscopic kidney donation from patients older than 60 years.
AB  - BACKGROUND: The current study seeks to determine if the efficacy and safety of
      laparoscopic donor nephrectomy holds true when performed in patients older than
      60 years of age. STUDY DESIGN: Medical records of 42 renal donors older than 60
      years were reviewed compared with younger controls carefully matched for gender,
      race, nephrectomy side, auxiliary recipient procedures, and date of surgery.
      RESULTS: Preoperative baseline serum creatinine was identical in both groups (0.9
      +/- 0.2 mg/dL) although controls had a slightly higher (NS) creatinine clearance
      (106.9 +/- 19.1 versus 100.0 +/- 35.5 mL/m). Operatively, there was no
      substantial difference between groups in operative time, warm ischemia time,
      estimated blood loss, number or size of ports used, and length of incision needed
      for removal of kidney. Intraoperative and postoperative complication rates were
      also equivalent between old and young donors. Postnephrectomy serum creatinine
      was identical. There was no increased length of hospitalization for older donors
      and they tended to require less morphine sulfate patient-controlled anesthesia.
      Recipient renal function was slightly better in the younger kidneys early and the
      difference became statistically significant at 6 to 12 months, but the magnitude
      of the improvement is not clinically important. CONCLUSIONS: Laparoscopic donor
      nephrectomy may be performed safely in patients older than 60 years of age. There
      was no increase in complication rates or length of hospital stay. Older donors
      did not have a greater increase in serum creatinine after donation compared with
      donors younger than 40 years of age, nor did recipients of these older kidneys
      have clinically significantly higher serum creatinine than recipients of kidneys
      from donors less than 40 years old.

PMID- 15194071
TI  - Less extensive techniques for repair of pectus carinatum: the undertreated chest
      deformity.
AB  - BACKGROUND: Although patients with pectus carinatum (PC) often experience
      moderate to severe symptoms, there are sparse published data about the
      indications for correction, the newer techniques of surgical repair, and the
      results. This study reviews clinical experience with new, less extensive, open
      operative techniques for repair of PC. STUDY DESIGN: Since 1970, 154 patients
      (119 men and 35 women) with symptomatic PC (mean severity index 1.76) underwent
      correction at the UCLA Medical Center using modifications of the Ravitch repair.
      The last 60 consecutive patients had a less extensive open repair with resection
      of only small chips of cartilage medially and laterally, and suture reattachment
      of the remaining costal cartilages to the corrected sternum and ribs. For
      patients with chondromanubrial protrusion, two or three sternal osteotomies were
      used, and for those with concomitant lower sternal depression, a lower sternal
      wedge osteotomy was used. For most patients, a temporary support bar anterior to
      the sternum and cartilages was used for 6 months. RESULTS: Each of the 154
      patients with reduced endurance or dyspnea with mild exercise experienced marked
      improvement within 6 months. There were no major recurrent deformities; six
      patients underwent minor surgical revision of localized persistent costal
      cartilage protrusion or depression. Postoperative complications in the last 60
      patients were minor and less frequent, pain was less severe, hospitalization was
      shorter (mean 2.5 days), and postoperative results were better than when more
      extensive repairs were used in previous years. With a mean overall followup of
      7.9 years, more than 97% of all patients experienced a very good or excellent
      result. CONCLUSIONS: New, less extensive, open techniques for repair of PC have
      low morbidity, short hospital stay, and very good physiologic and cosmetic
      results.

PMID- 15194072
TI  - Injury prevention priority score: a new method for trauma centers to prioritize
      injury prevention initiatives.
AB  - BACKGROUND: Trauma centers are expected to develop injury prevention programs
      that address needs of the local population. A relatively simple, objective, and
      quantitative method is needed for prioritizing local injury prevention
      initiatives based on both injury frequency and severity. STUDY DESIGN: Pediatric
      trauma patients (16 years or younger; n= 7,958) admitted to two Level I regional
      trauma centers (Johns Hopkins Children Center and Westchester Medical Center)
      from 1993 to 1999 were grouped by injury causal mechanism according to ICD-9
      external cause codes. An Injury Prevention Priority Score (IPPS), balancing the
      influences of severity (based on the Injury Severity Score) and frequency, was
      calculated for each mechanism and mechanisms were ranked accordingly. RESULTS:
      IPPS-based rank lists differed across centers. The highest ranked mechanism of
      injury among children presenting to Johns Hopkins Children Center was "pedestrian
      struck by motor vehicle," and at Westchester Medical Center it was "motor vehicle
      crash." Different age groups also had specific injury prevention priorities, eg,
      "child abuse" was ranked second highest among infants at both centers. IPPS was
      found to be stable (r = 0.82 to 0.93, p < 0.05) across alternate measures of
      injury severity. CONCLUSIONS: IPPS is a relatively simple and objective tool that
      uses data available in trauma center registries to rank injury causes according
      to both frequency and severity. Differences between two centers and across age
      groups suggest IPPS may be useful in tailoring injury prevention programs to
      local population needs.

PMID- 15194073
TI  - Office-based cryoablation of breast fibroadenomas: 12-month followup.
AB  - BACKGROUND: Fibroadenomas comprise between 30% and 50% of all breast biopsies.
      Despite their benign nature, many women have their fibroadenomas surgically
      removed. We previously reported on a minimally invasive therapy using
      cryoablation to treat fibroadenomas. We now report on 12-month followup using
      this technique. STUDY DESIGN: A prospective, nonrandomized trial was initiated in
      June 2000 with IRB approval. The Visica Treatment System was used to cryoablate
      70 biopsy-proved fibroadenomas in 57 patients using a freeze-thaw-freeze cycle
      lasting 6 to 30 minutes. Each patient was serially evaluated for safety,
      efficacy, and satisfaction. RESULTS: Fifty-seven fibroadenomas (mean 2.1 cm,
      range 0.8 to 4.2 cm) in 47 patients were followed for 12 months. At 1 year, with
      89% median tumor volume reduction measured by ultrasonography, 75% of
      fibroadenomas were nonpalpable. There were no adverse events and only minor
      complications. Two patients (4%) had their lesions excised after 12 months;
      pathology revealed no viable fibroadenoma. Serial mammograms showed resorption of
      the fibroadenoma leaving minimal residual density without calcifications.
      Cosmesis was excellent with no volume deficit, as no tissue is removed. Ninety
      one percent of patients were satisfied at 12 months. CONCLUSIONS: Cryoablation is
      safe and effective in treating breast fibroadenomas. It offers a nonsurgical,
      office-based treatment that is well tolerated by patients and accurately
      monitored with ultrasonographic guidance. At 12 months we found progressive tumor
      volume reduction and reduced palpability, with no volume deficit, excellent
      cosmesis, and satisfied patients. Ultrasonography-guided cryoablation is a
      preferred option for treatment of breast fibroadenomas without open surgery.

PMID- 15194074
TI  - Reliability of identification of 655 sentinel lymph nodes in 263 consecutive
      patients with malignant melanoma.
AB  - BACKGROUND: The purpose of this study of sentinel lymph node biopsies (SLN) was
      threefold: to compare the reliability of lymphazurin blue dye to radioactive
      technetium 99m sulfur colloid (TC); to evaluate the reliability of frozen section
      examinations of sentinel lymph nodes; and to determine how much SLN dissections
      prolonged operative time. STUDY DESIGN: We evaluated the records of 263
      consecutive patients with intermediate and high-risk melanomas (1.0 mm or
      thicker, or Clark Level IV or greater), who were treated by a single surgeon at
      the Yale Melanoma Unit between October 1, 1997, and September 30, 2001, and
      followed for more than 18 months. RESULTS: A total of 655 SLN were identified and
      removed from these 263 consecutive patients. Radioactive colloid was found to be
      more reliable (100%) in identifying the SLN than lymphazurin blue dye (51%) in
      the nodes of the patients. Twenty-eight patients (11%) had positive sentinel
      lymph nodes, and 2 patients (7%) had false-negative frozen sections. Three
      patients (11%) had false-negative frozen sections; tumor was found subsequently
      on permanent sections only after special immunohistochemical stains were used.
      The location or removal of SLN did not prolong the operative procedure
      unreasonably, requiring an average of 7 to 20 minutes for removal of SLN, and 33
      minutes for frozen section reports, during which time the primary tumor resection
      and wound coverage were performed. CONCLUSIONS: SLN were found in all 263
      patients. All SLN were identified reliably with radioactive colloid. Because blue
      dye was found in only half of the radioactive nodes, it is not appropriate to use
      this as the only marker for locating the SLN. This large series of patients
      attests to the reliability of frozen sections in identifying SLN harboring
      metastases, with 82% of the patients with nodal metastases identified in this
      fashion.

PMID- 15194075
TI  - Laparoscopy-assisted distal gastrectomy with systemic lymph node dissection: a
      critical reappraisal from the viewpoint of lymph node retrieval.
AB  - BACKGROUND: Laparoscopy-assisted surgery has proved useful in the treatment of
      early gastric cancer, but its use in advanced cancer may be hindered by
      limitations in lymphadenectomy. STUDY DESIGN: Data on lymph node retrieval after
      distal gastrectomy with D1 or D2 lymphadenectomy (n = 89) performed by the
      laparoscopy-assisted approach were collected between 1998 and 2002 and compared
      with data obtained from conventional open surgery performed for T1 cancer at a
      high-volume hospital (n = 342) during the same period. Comparisons of total
      number of lymph nodes, retrieval at each lymph node station, and the rate of
      noncompliance (no nodal tissue documented at a node station that should have been
      resected) were conducted using Student's t-test and the chi-square test. RESULTS:
      D2 resection by the laparoscopy-assisted approach harvested a sufficient number
      of nodes for adequate TNM classification (>15 nodes) in 86% of patients.
      Nevertheless, a significantly greater number of lymph nodes were harvested by
      open surgery. The difference was significant for the perigastric lymph nodes
      along the major curvature (Nos. 4 and 6) and second tier nodes along the celiac
      and splenic arteries (Nos. 9 and 11). CONCLUSIONS: The extent of lymphadenectomy
      achieved by current laparoscopic procedure approaches the global standard for
      accurate staging, although performing extended resection as recommended in Japan
      remains a challenge.

PMID- 15194076
TI  - Arterial misplacement of large-caliber cannulas during jugular vein
      catheterization: case for surgical management.
AB  - BACKGROUND: Accidental placement of a large sheath or catheter in an artery
      during central venous cannulation, though rare, is a potentially devastating
      complication. The present study reviews our 14-year experience with this
      complication to determine appropriate role of surgical management. STUDY DESIGN:
      Review was conducted of all cases involving patients treated by the vascular
      surgery service from July 1989 to June 2003 for accidental placement of a large
      caliber cannula (>or= 7 F) in an artery during catheterization of the jugular
      vein. Two management techniques were used during this period: removal of cannula
      followed by application of local pressure; and surgical exploration, removal of
      cannula under direct vision, and repair of artery. RESULTS: Eleven patients (5
      men, 6 women) aged 35 to 73 years (mean age 56 years) were treated for cannulas
      placed accidentally in an artery. In nine patients, the cannula entered the
      carotid artery, and in two patients it entered the subclavian artery. Three
      patients had undergone placement of 8.5-F sheaths for monitoring cardiac
      hemodynamics, and 8 patients had triple-lumen catheters for fluid infusion or
      parenteral nutrition. Eight patients (three sheath, five catheter) were
      asymptomatic at the time of cannula removal. In three patients, the correct
      diagnosis was missed initially and infusion was started. All three developed
      neurologic symptoms. In two patients, the cannula (sheath) was pulled and
      pressure applied. One of them developed a stroke and the other developed a
      pseudoaneurysm that was treated surgically. Nine patients in whom the sheath or
      catheter was removed by surgical exploration had no new complications related to
      surgery. CONCLUSIONS: Surgical management seems to be the most effective and safe
      treatment of arterial misplacement of cannulas during jugular vein
      catheterization. Further study is needed to determine the optimum management of
      this potentially devastating complication.

PMID- 15194077
TI  - Heme-oxygenase-1 expression correlates with severity of acute cellular rejection
      in lung transplantation.
AB  - BACKGROUND: Heme-oxygenase-1 (HO-1) has been shown to play an important role in
      oxidative stress, and recent studies indicate that it is a graft survival protein
      in cardiac and liver transplant models. Our laboratory previously found HO-1 to
      be increased in human lung allografts with acute cellular rejection (ACR) and in
      active obliterative bronchiolitis. To better understand the role of HO-1 in ACR
      we studied the relationship between HO-1 expression and ACR in a rodent model of
      lung transplantation. STUDY DESIGN: Orthotopic left lung transplantation was
      performed from Lewis (donor) to Sprague-Dawley (recipient) rats, and ACR (Grade
      A0 to A4) was evaluated at days 3, 5, and 7. HO-1 expression was assessed by
      immunohistochemistry and Western analysis, and compared with the degree of ACR.
      Myeloperoxidase staining was evaluated as an indirect measure of oxidant stress.
      Donors and recipients were also treated with either an inhibitor of HO activity,
      tin protoporphyrin or an inducer, cobalt protoporphyrin, and the severity of ACR
      was compared with that in untreated allografts. RESULTS: HO-1 expression was
      elevated in transplanted versus native lungs or isografts, and the degree of
      elevation was closely correlated with ACR grade (p < 0.001). Similarly,
      myeloperoxidase expression increased with time and severity of ACR.
      Administration of the metalloporphyrins, tin protoporphyrin and cobalt
      protoporphyrin, produced no significant difference in the degree of ACR, but did
      alter the severity of ischemia-reperfusion injury. CONCLUSIONS: Similar to what
      occurs in human lung transplantation, HO-1 expression is increased in a rodent
      lung transplant model of ACR and correlates with the severity of rejection.
      Altering its expression does not appear to affect the degree of ACR.

PMID- 15194078
TI  - siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine
      chemosensitivity.
AB  - BACKGROUND: The c-Src tyrosine kinase is a determinant of malignant cellular
      behavior in a variety of human cancers. We sought to determine the effect of
      suppressing c-Src expression on pancreatic adenocarcinoma chemosensitivity to
      gemcitabine. STUDY DESIGN: PANC1, MIAPaCa2, BxPC3, and Capan2 pancreatic
      adenocarcinoma cell lines were studied. Expression of c-Src was determined by
      Western blot analysis. c-Src kinase activity was determined by in vitro kinase
      assay. RNA interference was used to suppress c-Src expression. Gemcitabine
      induced cytotoxicity was determined by tetrazolium reduction assay and caspase
      profiling was performed. The effect of Src-specific siRNA on Akt activity was
      quantified. RESULTS: Src expression and kinase activity in cell lines were
      directly correlated with gemcitabine chemoresistance. c-Src-specific siRNA
      suppressed c-Src expression and kinase activity. c-Src-specific siRNA increased
      gemcitabine-induced, caspase-mediated apoptosis. Akt activity was decreased by
      suppression of c-Src expression. CONCLUSIONS: c-Src is a determinant of
      pancreatic adenocarcinoma chemoresistance and represents a potential target for
      therapeutic intervention.

PMID- 15194079
TI  - Plasmolemmal potassium gradient does not affect lung protection by an ATP
      regulated potassium channel opener.
AB  - BACKGROUND: We have previously shown that metabolic arrest induced with ATP
      regulated potassium channel openers (PCOs) can improve lung preservation by
      adding Aprikalim (a PCO, Rhone-Poulene Roher) to modified Euro-Collins solution
      for pulmonary artery flush. Because the membrane hyperpolarizing effects of a PCO
      potentially competes with the depolarizing effects of a hyperkalemic solution,
      this study evaluated the effects of the potassium gradient on PCO-mediated lung
      protection. STUDY DESIGN: Twenty rabbits underwent lung protection in four
      groups. Group 1 underwent harvest and reperfusion as a "no ischemia" control.
      Groups 2, 3, and 4 underwent harvest followed by 18 hours of cold ischemic
      storage before reperfusion. Groups 1 and 4 received Euro Collins as the pulmonary
      flush at induction of ischemia. Group 2 received Euro Collins plus Aprikalim (100
      microM); and group 3 received lactated Ringer's plus Aprikalim. After ischemic
      storage, the lungs were reperfused with autologous blood for 2 hours. Every 30
      minutes, the lungs were given a 10-minute 100% fractional inspired oxygen
      (F(i)O(2)) challenge to measure maximal gas exchange as an indication of graft
      function. RESULTS: Repeated measures ANOVA showed Aprikalim improved graft
      function after 18 hours of cold ischemia (p < 0.0001). No significant differences
      were found when Aprikalim was used in either Euro-Collins (group 2) or lactated
      Ringer's (group 3) solution. CONCLUSIONS: The ability of the PCO Aprikalim to
      preserve gas exchange in a model of hypothermic pulmonary ischemia-reperfusion
      injury was not affected by the plasmolemmal potassium gradient. This is
      consistent with recent findings in myocardial protection studies that the
      protective effects of PCOs may be intracellular.

PMID- 15194080
TI  - What's new in general surgery: surgical oncology.

PMID- 15194081
TI  - Viewpoints from generation X: a survey of candidate and associate viewpoints on
      resident duty-hour regulations.
AB  - BACKGROUND: The American Medical Student Association, the Committee of Interns
      and Residents, and Public Citizen petitioned the Occupational Safety and Health
      Administration for national resident duty-hour limitations. Subsequently, federal
      legislation was introduced to limit resident duty hours. To preempt the federal
      government, the Accreditation of Graduate Medical Education implemented resident
      duty-hour guidelines. STUDY DESIGN: To evaluate the viewpoints and attitudes of
      surgical resident and staff physicians as they pertain to the national resident
      duty-hour guidelines, we asked attendees of the American College of Surgeons'
      Candidate Associate Society Forum during the American College of Surgeons
      Clinical Congress meeting in 2001 to complete a self-administered questionnaire.
      Analyses were performed to determine the frequency of response for each survey
      item. RESULTS: Eighty-six of the 102 (84%) surgeons who attended the American
      College of Surgeons Forum completed the survey. Most disagreed with the federal
      government involvement in regulating duty hours. Although most agreed that
      residents should not be on call more than every third night, viewpoints varied on
      the other duty-hour guidelines. Most (63.4%) reported that residents should work
      81 to 100 hours per week, but 11% reported that residents should work > 101 hours
      per week and 25.6% reported that <or= 80 hours per week was optimal. CONCLUSIONS:
      As future guidelines are considered, further studies must be done to determine
      the viewpoints and attitudes of surgical resident and staff physicians with
      regard to resident duty-hour reform. These "front line" individuals may have
      unique insights into the benefits and barriers of duty-hour regulations.

PMID- 15194082
TI  - Malignant ascites: past, present, and future.

PMID- 15194084
TI  - Defining palliative surgery in patients receiving noncurative resections for
      gastric cancer.
AB  - BACKGROUND: Effective palliation rather than cure is often the most appropriate
      goal in the management of patients with advanced gastric cancer. The literature
      to date is limited by the imprecise use of the term palliative and subsequent
      variable designation of patients into evaluable groups. STUDY DESIGN: Between
      July 1985 and July 2001, 1,595 patients were entered into a prospective database
      after undergoing a resection for gastric adenocarcinoma. Patients who received a
      noncurative (R1/R2) resection were identified. A procedure was defined as
      palliative if it was performed explicitly to palliate symptoms or improve quality
      of life. RESULTS: Three hundred seven patients received a noncurative gastric
      resection. The operation was palliative in 48% (147/307) and nonpalliative in 52%
      (160/307). Palliative operations included an esophageal anastomosis less
      frequently (46% versus 69%, p < 0.001) and had a less extensive lymphadenectomy
      performed compared with nonpalliative operations. Surgical intent did not alter
      operative morbidity (54%) or mortality (6%) significantly. The overall median
      survival after a noncurative gastric resection was 10.6 months and was
      independently associated with operations performed with explicit palliative
      indications (8.3 months [palliative] versus 13.5 months [nonpalliative], p <
      0.001) and patient age > 65 years. CONCLUSIONS: There are important differences
      among patients undergoing noncurative operations for gastric cancer. Studies
      designed to measure palliative interventions would benefit from precise
      designations of palliative intent in patients receiving noncurative operations.

PMID- 15194085
TI  - Complications of chronic pelvic radiation injury.

PMID- 15194086
TI  - Renal artery aneurysm.

PMID- 15194087
TI  - New method of laparoscopy-assisted function-preserving surgery for early gastric
      cancer: vagus-sparing segmental gastrectomy under sentinel node navigation.

PMID- 15194089
TI  - Surface engineering of prosthetic knee components.
AB  - Conventional total and uni-compartmental knee replacement designs usually
      incorporate metal femoral and tibial components with an ultra high molecular
      weight polyethylene (UHMWPE) bearing surface. The tibial components can be
      modular or monobloc and are of the fixed bearing type in the majority of cases.
      Mobile bearings are also in common use with a modular meniscal insert with either
      rotation only or a combination of rotation and translation. Wear of the UHMWPE
      components remains of primary concern in these prosthetic devices. Catastrophic
      wear and delamination has been largely addressed by improvements in UHMWPE
      quality and manufacturing methods, however, abrasive and adhesive wear of the
      UHMWPE components remains a concern for long-term survivorship of total knee
      replacement. This review very briefly covers published long-term survivorship of
      primary knee arthroplasties, primary wear mechanisms present in knee replacements
      and the potential for wear reduction by surface engineering of the metal wear
      counterfaces. There are several methods and materials available, which offer the
      potential for significantly reduced wear.

PMID- 15194090
TI  - Alternative femoral bearing surface options for knee replacement in young
      patients.

PMID- 15194091
TI  - Influences of sterilising techniques on polyethylene wear.
AB  - Over the last 10 years there has been increasing concern over wear of
      polyethylene and osteolytic potential in the knee. During this period there have
      been considerable developments in both the design, materials and sterilisation
      techniques used for polyethylene in the knee. This paper reviews wear performance
      of polyethylene sterilised by different techniques, under a range of kinematics
      conditions in a single knee joint simulator system. Reducations in polyethylene
      wear were found with both stabilised polyethylene and cross-linked polyethylene,
      and with rotating platform mobile bearing designs.

PMID- 15194092
TI  - Polyethylene wear in a non-congruous unicompartmental knee replacement: a
      retrieval analysis.
AB  - Polyethylene wear is considered a threat to the long-term survival of
      unicompartmental knee replacement (UKR). This study aims to determine the linear
      penetration and volumetric wear associated with a non-congruent commonly used
      UKR, the St Georg Sled. This prosthesis has a biconvex femoral component which
      articulates with a flat polyethylene tibial component resulting in point contact.
      Components were retrieved from the knees of 19 patients undergoing revision for a
      failed UKR after primary replacement. Linear penetration and volumetric wear was
      measured using a coordinate measuring machine. Using an un-used implant, a three
      dimensional computer model of the surface was generated and compared to the
      explanted specimen. Most patients had revisions because of disease progression to
      other compartments rather than specific wear related pathology. The mean linear
      wear for the sample was 0.89 mm (S.D. 0.59 mm) over an average period of 5.6
      years giving the mean linear penetration rate of 0.15 mm/year. The mean
      volumetric wear was 99.7 mm3 (S.D. 79.3 mm3) over the same period giving a mean
      annual volumetric wear rate of 17.3 mm3/year. The results in this study indicate
      that clinically significant wear is not necessarily a feature of this fixed
      bearing unicompartmental knee replacement. The pattern of wear is consistent with
      clinical findings and indicates excavation of the polyethylene after implantation
      but at a slower rate than would be anticipated.

PMID- 15194093
TI  - In vivo measurement of total knee replacement wear.
AB  - Polyethylene wear is one of the most important causes of failure of total knee
      replacements (TKRs). Currently, wear can only be accurately measured by retrieval
      studies. There is a need for a method to measure wear accurately in vivo. We have
      developed a Roentgen stereophotogrammetric analysis (RSA) system that can measure
      penetration of the metallic femoral component into the polyethylene of the tibia.
      We have used this system to study six AGC TKRs at 6 years postoperatively and six
      control AGC TKRs at 2 weeks postoperatively. The mean difference between the RSA
      measured bearing thickness and the manufacturer's quoted values for the control
      group was -0.03 mm (S.D. 0.17). The average linear penetration in the study group
      was 0.8 mm (S.D. 0.46). This was significantly (P<0.0001) different from the
      control group. The average linear penetration rate was 0.13 mm per year (S.D.
      0.08). We would expect the penetration to deepen with time. In young active
      patients, this could be a cause for concern, particularly with a thin bearing.
      The current system is accurate enough to measure wear at 5 years post TKR. It has
      the potential for predicting long-term wear problems with new designs of TKR and
      new materials within 2 years.

PMID- 15194094
TI  - All-poly tibial component better than metal-backed: a randomized RSA study.
AB  - The quality of the fixation of the tibial component in 21 patients (23 knees)
      undergoing a cemented total-knee arthroplasty of the Profix design was
      investigated using radiostereometric analysis during 24 months. The patients were
      randomized to either an all-polyethylene (AP) or a metal-backed (MB) tibial
      component. The articulating geometry and the stem design of the implants were
      identical, as were the operative technique and the postoperative regimen. The
      results showed no negative consequences as regards fixation using AP tibial
      components. In all aspects, the AP components displayed magnitudes of migration
      on par with, or sometimes even lower than their MB counterparts. Five of 11 MB
      components displayed continuous migration between 1 and 2 years, compared to none
      of the AP implants, a finding known to be of positive prognostic significance
      when predicting future aseptic loosening.

PMID- 15194095
TI  - Varus/valgus alignment of the femur in total knee arthroplasty. Can accuracy be
      improved by pre-operative CT scanning?
AB  - In a series of 80 consecutive knee replacements, pre-operative scout scans of the
      femur were taken and the angle between the slope of the worn femur and the
      mechanical axis was measured. At surgery the angle of the distal femoral cut was
      adjusted to make it perpendicular to the mechanical axis. Post-operative scans
      revealed that 97.5% of femoral components were implanted within 2 degrees of the
      target. The angle between a perfectly positioned virtual intra-medullary rod on
      the pre-operative films and the mechanical axis showed marked variations between
      individuals indicating that the use of a fixed angular correction from an intra
      medullary rod is unreliable even under perfect circumstances. In practice it is
      subject to further inaccuracy due to variability in the anatomy of the femur and
      rod placement. With the advent of robotically assisted surgery, the technical
      limits of conventional instruments need to be explored in terms of improving
      accuracy for each individual patient. In terms of the coronal alignment of the
      femur, this involves some degree of preplanning rather than relying on arbitrary
      targets based on incorrect assumptions.

PMID- 15194096
TI  - Modification of the posterior cruciate ligament tension following total knee
      arthroplasty: comparison of the Genesis CR and LCS meniscal bearing prostheses.
AB  - AIM: A biomechanical study was conducted to determine the in-vitro modification
      of the posterior cruciate ligament tension following different types of total
      knee arthroplasty (TKA). MATERIALS AND METHODS: The Genesis CR (non-mobile tibial
      inlay, n=9) and LCS meniscal bearing prostheses (mobile meniscal bearings, n=8)
      were compared with the human cadaveric knee joint. Posterior cruciate ligament
      (PCL) tension was assessed with implantable force transducers. A six-degree-of
      freedom manipulator was used to measure knee kinematics at 10 degrees intervals
      from 0 degrees to 120 degrees of flexion with [300 Newton (N)] and without load
      application (0 N). Statistical analysis was performed with the Wilcoxon rank sum
      test. RESULTS: Analysis of the PCL tension following TKA using the Genesis CR
      prosthesis revealed a non-significant (P=0.20) decrease of transducer output with
      load (300 N) and a non-significant (P=0.73) increase without load (0 N).
      Concerning the LCS meniscal bearing prosthesis a significant (P=0.01) decrease of
      transducer output was assessed with load (300 N) whereas a non-significant
      (P=1.0) modification was seen without load (0 N). CONCLUSION: The Genesis CR
      prosthesis allows PCL tension to be close to normal as the knee flexes, which is
      contradictory to the assumed evidence for a missing restorability of a regular
      PCL tension after TKA. Our results hence indicate, that the effected tension of
      the PCL strongly depends on the balance and interaction between design of the
      implant and the functional role of the retained PCL.

PMID- 15194097
TI  - A clinical method for locating the femoral head centre during total knee
      arthroplasty.
AB  - Localisation of the femoral head centre (FHC) during total knee arthroplasty
      (TKA) is necessary when assessing the overall alignment of the leg using an
      extramedullary guide for the femur. On-table radiographs for this purpose are
      time consuming and inconvenient. We describe a clinical method for estimating the
      FHC: it is marked 1.5 cm lateral to the point where the femoral artery crosses
      the line joining the pubic tubercle and the anterior superior iliac spine. Using
      this method the estimated FHC was within 15 mm of the anatomic centre in 84% of
      cases, and within 24 mm in 99%. This translates into possible knee alignment
      errors of 2 degrees and 3 degrees, respectively. As alignment error of up to +/-3
      degrees is compatible with satisfactory clinical results of TKA, our method
      provides useful approximation of the FHC. For greater accuracy however, an on
      table radiograph is recommended.

PMID- 15194098
TI  - Transepicondylar line and condylar line as parameters for axial alignment in knee
      arthroplasty.
AB  - In order to investigate the reliability of the transepicondylar line and the
      condylar line as indicators for lower limb alignment in knee arthroplasty, the
      femorotibial angle (FTA), and the angle between the transepicondylar line and the
      tangential line of tibial plateau (angle epsilon) and condylar-plateau angle
      (CPA) were measured in 107 (78 patients) full-length standing X-ray films of
      lower limbs. The mean FTA was measured to be 178.0+/-9.3 degrees, the CPA 1.5+/
      8.5 degrees and angle epsilon -0.8+/-8.5 degrees. The correlation between FTA and
      the CPA was analyzed to be significant with a correlation coefficient of 0.63,
      while another correlation between FTA and angle epsilon was calculated to be
      significant with a correlation coefficient of 0.81 at the same time. As a result,
      the correlation of the latter one was highly significant, having a R2 value of
      0.648 (P<0.001), while the R2 of the former was only 0.397 (P<0.001). In
      conclusion, the transepicondylar line could be considered as a more reliable
      indicator for lower limb alignment, which may play an important role in ligament
      balancing and improvement of the guiding system in knee arthroplasty.

PMID- 15194099
TI  - Transient osteoporosis of the knee.
AB  - We report 12 cases of transient osteoporosis in 10 patients. The presenting
      symptoms, diagnostic investigations and management are considered here as well as
      a discussion on the aetiology and the pathology. Arthroscopic surgery was carried
      out in some of the patients to exclude intraarticular pathology. Resolution of
      symptoms occurred in all patients within 6 months and the MRI findings returned
      to normal.

PMID- 15194100
TI  - A new biomechanical model for the functional assessment of knee osteoarthritis.
AB  - The severity of symptoms in osteoarthritis (OA) of the knee can be difficult to
      assess. A new method for assessing medial compartment OA of the knee is proposed.
      The purpose of this study was to determine if a relationship exists between the
      severity of OA and single limb stance knee adduction moment (SSKAM). Fourteen
      patients with medial compartment OA of the knee were tested and compared with 14
      age-matched volunteers. WOMAC OA index scores were documented. Biomechanical data
      were collected from a single Kistler force platform and a six-camera ProReflex
      motion analysis system, and the knee adduction moments were calculated. A
      significant difference in the maximum, minimum and mean adduction moments was
      found between the two groups, and a correlation of r=0.66 for WOMAC physical
      function subscale, r=0.63 for the WOMAC pain subscale and r=0.63 for the sum of
      the subscales and mean SSKAM was found. Single limb stance adduction moments
      provide additional, objective information in the assessment of medial compartment
      OA of the knee. It may be useful in the selection of patients for surgery and for
      evaluating various treatment modalities for medial compartment OA of the knee.

PMID- 15194101
TI  - Arthroscopic washout of the knee--a 5-year survival analysis.
AB  - Arthroscopy and washout of the knee is commonly performed for early
      osteoarthritis. Very little information exists regarding long-term prognosis,
      especially in terms of avoidance of further surgery. Using a prospectively
      gathered database, 100 consecutive patients having knee arthroscopy with a
      finding of OA between 1991 and 1993 were identified and their outcome at 5 years
      ascertained. Ninety-nine patients with 100 arthroscoped knees were identified.
      Fifty-eight had isolated medial compartment disease and six had isolated lateral
      compartment disease. In 36, both compartments were affected. Eighteen knees had
      further major surgery during follow up; 11 had total knee replacement, four had
      high tibial osteotomy and three had unicondylar knee arthroplasty. Those
      requiring surgery were significantly older (62 cf. 53 years, P=0.008).
      Meniscectomy was not an important risk factor (chi2, P=0.67). The rate of knee
      survival without operation at 5 years was much lower in those aged over 60 years
      than in those younger (68% cf. 89%). (chi2, P=0.02). Only 18% of patients
      progress to major knee surgery within 5 years of arthroscopic washout for
      osteoarthritis. Age greater than 60 years worsens the prognosis considerably.

PMID- 15194102
TI  - Informed consent and knee arthroscopies: an evaluation of patient understanding
      and satisfaction.
AB  - Fifty patients who had been admitted to a public hospital in Australia for an
      elective knee arthroscopy were asked to complete a detailed questionnaire prior
      to theatre, designed to evaluate patient understanding and satisfaction of the
      informed consent process. While patients generally felt that they received an
      appropriate amount of information on the nature of their injury and the actual
      operative procedure, little information was given on possible complications and
      post-operative care. This study clearly indicates that patients are dissatisfied
      when they perceive a lack of basic information being given. The findings are of
      some concern as they suggest that the majority of consents gained in this study
      were not truly 'informed'. However, recognition by medical staff of the areas
      that appear to be poorly explained to patients enables these issues to be
      addressed. This in turn is likely to improve patient understanding of and
      satisfaction with the consent process.

PMID- 15194103
TI  - The fabella: a forgotten source of knee pain?
AB  - We present a case of chondromalacia of the fabella, describe a provocative
      diagnostic test and review the literature on this unusual cause of knee pain.

PMID- 15194104
TI  - Knee synovial cyst presenting as iliotibial band friction syndrome.
AB  - We present the case of a 28-year-old competitive runner with iliotibial band
      (ITB) friction syndrome associated with a synovial cyst. Magnetic resonance
      imaging (MRI) did not demonstrate a fluid collection. However, open exploration
      revealed a large cyst beneath the ITB arising from the capsule of the knee
      proximal to the lateral meniscus. The cyst disappeared on extension. The pre
      operative MRI scan may have revealed the cyst, if it had been taken with the knee
      flexed.

PMID- 15194106
TI  - Transcriptional control of synaptic differentiation by retrograde signals.
AB  - Synaptic differentiation during development is a multi-step process, which
      requires reciprocal communication between pre- and postsynaptic cells. Cell
      surface interactions can induce the assembly of synaptic specializations but
      maintenance and growth of synapses depend on transcriptional regulation.
      Transcriptional responses associated with synaptic differentiation are observed
      in central and peripheral neurons and depend on retrograde signals coming from
      the target region. Although the identity of most of the retrograde signaling
      pathways remains to be identified, the TGFbeta family of growth factors have
      emerged as one crucial signal at the neuromuscular junction. Here, we discuss
      evidence for transcriptional control during synaptic differentiation and the
      signaling pathways mediating retrograde TGFbeta signaling.

PMID- 15194107
TI  - Presynaptic terminal differentiation: transport and assembly.
AB  - The formation of chemical synapses involves reciprocal induction and independent
      assembly of pre- and postsynaptic structures. The major events in presynaptic
      terminal differentiation are the formation of the active zone and the clustering
      of synaptic vesicles. A number of proteins that are present in the presynaptic
      active zone have been identified. Recent studies of various mutants have
      clarified the in vivo functions of some of the main players. Time-lapse imaging
      studies have captured dynamic and transient events in the transport of synaptic
      components, and therefore provided insight into the early stages of
      synaptogenesis.

PMID- 15194108
TI  - Eph receptors in the adult brain.
AB  - The Eph receptors are a large family of receptor tyrosine kinases with important
      roles in the establishment of neuronal and vascular networks during embryonic
      development. The functions of Eph receptors in the adult brain have only recently
      been investigated, and the results are forcing us to amend the conventional view
      that these molecules function predominantly in a developmental context. This
      review summarizes this rapidly expanding new area of research, which has shown
      that the Eph receptors regulate the structure and physiological function of
      excitatory synapses through multiple mechanisms, and might thus play a
      significant role in higher brain functions.

PMID- 15194109
TI  - Rho GTPases and activity-dependent dendrite development.
AB  - Dendritic morphology has an important influence on neuronal information
      processing. Multiple environmental cues, including neuronal activity, the
      neurotrophin family of growth factors, and extracellular guidance molecules have
      been shown to influence dendritic size, shape, and development. The Rho GTPases
      have emerged as key integrators of these environmental cues to regulate the
      underlying dendritic cytoskeleton.

PMID- 15194110
TI  - Local protein synthesis during axon guidance and synaptic plasticity.
AB  - mRNA localization and regulated translation take central roles in axon guidance
      and synaptic plasticity. By spatially restricting gene expression within neurons,
      local protein synthesis provides growth cones and synapses with the capacity to
      autonomously regulate their structure and function. Studies in a variety of
      systems have provided insight into the specific roles of local protein synthesis
      during axonal navigation and during synaptic plasticity, and have begun to
      delineate the mechanisms underlying mRNA localization and regulated translation.
      Several powerful new tools have recently been developed to visualize each of
      these processes.

PMID- 15194111
TI  - Mitogen-activated protein kinases in synaptic plasticity and memory.
AB  - This review highlights five areas of recent discovery concerning the role of
      extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs
      have recently been directly implicated in human learning through studies of a
      human mental retardation syndrome. Second, new models are being formulated for
      how ERKs contribute to molecular information processing in dendrites. Third, a
      role of ERKs in stabilizing structural changes in dendritic spines has been
      defined. Fourth, a crucial role for ERKs in regulating local dendritic protein
      synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding
      and structural proteins at the synapse is increasingly apparent. These topics are
      discussed within the context of an emerging role for ERKs in a wide variety of
      forms of synaptic plasticity and memory formation in the behaving animal.

PMID- 15194112
TI  - Calcium/calmodulin-dependent protein kinase II and synaptic plasticity.
AB  - A prominent role for calcium/calmodulin-dependent protein kinase II (CaMKII) in
      regulation of excitatory synaptic transmission was proposed two decades ago when
      it was identified as a major postsynaptic density protein. Since then,
      fascinating mechanisms optimized to fine-tune the magnitude and locations of
      CaMKII activity have been revealed. The importance of CaMKII activity and
      autophosphorylation to synaptic plasticity in vitro, and to a variety of learning
      and memory paradigms in vivo has been demonstrated. Recent progress brings us
      closer to understanding the regulation of dendritic CaMKII activity,
      localization, and expression, and its role in modulating synaptic transmission
      and cell morphology.

PMID- 15194113
TI  - Divergent and convergent signaling by the diacylglycerol second messenger pathway
      in mammals.
AB  - Diacylglycerol is an essential second messenger in mammalian cells. The most
      prominent intracellular targets of diacylglycerol and the functionally analogous
      phorbol esters belong to the protein kinase C family, but at least five
      alternative types of high affinity diacylglycerol/phorbol ester receptors are
      known: protein kinase D, diacylglycerol kinases alpha, beta, and gamma, RasGRPs,
      chimaerins, and Munc13s. These function independently of protein kinase C
      isozymes, and form a network of signaling pathways in the diacylglycerol second
      messenger system that regulates processes as diverse as gene transcription, lipid
      signaling, cytoskeletal dynamics, intracellular membrane trafficking, or
      neurotransmitter release.

PMID- 15194114
TI  - Presynaptic function.
AB  - Changing the strength of synapses is key to the adaptive modifications of what
      neuronal circuits compute. Unsurprisingly, many different mechanisms have evolved
      to alter synaptic strength. Some of these mechanisms depend on the history of
      synaptic use, others reflect the activity of modulatory neurons that are
      controlled through neural computations, and still others involve more global
      measures of neural activity. The molecular machinery synapses use to convey
      information from one neuron to the next not only plays an essential part in brain
      function but also is at the basis of processes that are vital to all cells.
      Because membrane fusion events at synapses are so precisely controlled, synapses
      offer an especially favorable system in which to study these basic processes.
      Here, I review some of the recent progress that has been made in understanding
      both how synaptic strength is regulated and how fundamental cell biological
      mechanisms are used to accomplish neuronal intercommunication.

PMID- 15194115
TI  - Glutamate transporters bring competition to the synapse.
AB  - Glutamate transporters (GluTs) prevent the accumulation of glutamate and
      influence the occupancy of receptors at synapses. The ability of extrasynaptic
      NMDA receptors and metabotropic glutamate receptors to participate in signaling
      is tightly regulated by GluT activity. Astrocytes express the highest density of
      GluTs and dominate clearance away from these receptors; synapses that are not
      associated with astrocyte processes experience greater mGluR activation and can
      be exposed to glutamate released at adjacent synapses. Although less abundant,
      neuronal transporters residing in the postsynaptic membrane can also shield
      receptors from the glutamate that is released. The diversity in synaptic
      morphology suggests a correspondingly rich diversity of GluT function in
      excitatory transmission.

PMID- 15194116
TI  - NMDA receptors are movin' in.
AB  - Dynamic modulation of the number of postsynaptic glutamate receptors is
      considered one of the main mechanisms for altering the strength of excitatory
      synapses in the central nervous system (CNS). However, until recently N-methyl-d
      aspartate (NMDA) receptors were considered relatively stable once in the plasma
      membrane, especially in comparison with alpha-amino-3-hydroxy-5-methyl-4
      isoxazole propionic acid (AMPA) receptors that are internalized at a high rate. A
      series of recent studies has changed this viewpoint by revealing that NMDA
      receptors are subject to constitutive as well as agonist-induced internalization
      through clathrin-mediated endocytosis. Surprisingly, agonist-induced
      internalization is not dependent on current flow through the NMDA channel, and
      the receptors are primed for this type of internalization by selective
      stimulation of the glycine site but not of the glutamate site. Endocytosis of
      NMDA receptors provides a fundamental mechanism for dynamic regulation of the
      number of NMDA receptors at synapses, which might be important for physiological
      and pathological functioning of the CNS.

PMID- 15194117
TI  - TRP ion channels in the nervous system.
AB  - The transient receptor potential (TRP) superfamily comprises a group of non
      selective cation channels that sense and respond to changes in their local
      environments. TRP channels are found in many eukaryotes, from yeast to mammals.
      They are a diverse group of proteins organized into six families: classical
      (TRPC), vanilloid (TRPV), melastatin (TRPM), muclopins (TRPML), polycystin
      (TRPP), and ANKTM1 (TRPA). In the peripheral nervous system, stimuli including
      temperature, pressure, inflammatory agents, and receptor activation effect TRP
      mediated responses. In the central nervous system, TRPs participate in neurite
      outgrowth, receptor signalling and excitotoxic cell death resulting from anoxia.
      TRP channels are emerging as essential cellular switches that allow animals to
      respond to their environments.

PMID- 15194118
TI  - Mu opioid receptor: a gateway to drug addiction.
AB  - Mu opioid receptors mediate positive reinforcement following direct (morphine) or
      indirect (alcohol, cannabinoids, nicotine) activation, and our understanding of
      mu receptor function is central to the development of addiction therapies. Recent
      data obtained in native neurons confirm that mu receptor signaling and regulation
      are strongly agonist-dependent. Current functional mapping reveals morphine
      activated neurons in the extended amygdala and early genomic approaches have
      identified novel mu receptor-associated proteins. A classification of about 30
      genes either promoting or counteracting the addictive properties of morphine is
      proposed from the analysis of knockout mice data. The targeting of effectors or
      regulatory proteins, beyond the mu receptor itself, might provide valuable
      strategies to treat addictive disorders.

PMID- 15194119
TI  - The gamma-secretase complex: machinery for intramembrane proteolysis.
AB  - Gamma-secretase is a membrane protease complex that possesses presenilin as a
      catalytic subunit. Presenilin generates amyloid beta peptides in the brains of
      Alzheimer's patients and is indispensable to Notch signaling in tissue
      development and renewal. Recent studies have revealed how presenilin is assembled
      with its cofactor proteins and acquires the gamma-secretase activity: Aph-1 and
      nicastrin initially form a subcomplex to bind and stabilize presenilin, and then
      Pen-2 confers the gamma-secretase activity and facilitates endoproteolysis of
      presenilin. Understanding the mechanism of gamma-secretase cleavage will help to
      clarify how intercellular cell signaling through transmembrane proteins is
      regulated by intramembrane proteolysis, and will hopefully eventually lead to a
      cure for Alzheimer's disease.

PMID- 15194120
TI  - How do Parkin mutations result in neurodegeneration?
AB  - The gene product responsible for autosomal recessive juvenile Parkinsonism,
      Parkin, has been observed to have ubiquitin ligase activity. This finding has
      changed the direction of studies on Parkinson's disease by suggesting that
      abnormal protein turnover might be involved in its pathogenesis. A number of
      potentially neurotoxic Parkin-specific substrates have been identified. Further
      investigation of Parkin knockout mice will hopefully provide new evidence in the
      search for Parkin's substrates and further clarify their role in Parkinson's
      disease.

PMID- 15194121
TI  - A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease.
AB  - Cyclin-dependent kinase 5 (Cdk5) is a multi-faced kinase implicated in both
      development and disease of the mammalian central nervous system. These different
      faces of Cdk5 are preferentially regulated by the activation of Cdk5 by its
      different binding partners. The precise molecular and cellular mechanisms
      governing the role of Cdk5 in brain development and disease are unclear. Emerging
      evidence is now unraveling how Cdk5 normally orchestrates new signaling pathways
      that dictate the proper maturation and maintenance of the central nervous system.
      Under pathological conditions, however, Cdk5 activity goes awry and the
      malevolent face of Cdk5 surfaces. Recently developed animal models that display
      this deregulated Cdk5 activity reveal the intimate involvement of Cdk5 in tau
      pathology and neuronal cell death, and underscore the importance of
      phosphorylation in the progression of neurodegenerative diseases.

PMID- 15194122
TI  - Genetic methods for illuminating the function of neural circuits.
AB  - Guided by the notion that biology itself offers some of the most incisive tools
      for studying biological systems, neurophysiologists rely increasingly on cell
      biological mechanisms and materials encoded in DNA to visualize and control the
      activity of neurons in functional circuits. Optical reporter proteins can
      broadcast the operational states of genetically designated cells and synapses;
      remote-controlled effectors can suppress or induce electrical activity. Many
      challenges, however, remain. These include the development of novel gene
      expression systems that target reporters and effectors to functionally relevant
      neuronal ensembles, the capacity to monitor and manipulate multiple populations
      of neurons in parallel, the ability to observe and elicit precisely timed action
      potentials, and the power to communicate with genetically designated target
      neurons through electromagnetic signals other than light.

PMID- 15194123
TI  - Antimicrobial selection for community-acquired lower respiratory tract infections
      in the 21st century: a review of gemifloxacin.
AB  - Community-acquired lower respiratory tract infections (LRTIs) are more prevalent
      in the elderly than in children and younger adults and form a significant
      proportion of all consultations and hospital admissions in this older age group.
      Furthermore, in a world of increasing life expectancy the trend seems unlikely to
      be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must
      cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis,
      and in many circumstances should also cover the intracellular (atypical)
      pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are
      mainly associated with H. influenzae and S. pneumoniae and not with atypical
      bacteria: in severe cases, other Gram-negative bacteria may be involved.
      Frequently in LRTIs, the aetiology of the infection cannot be identified from the
      laboratory specimens and treatment has to be empirical. In such situations it is
      important to not only to use an antibiotic that covers all likely organisms, but
      also one that has good activity against these organisms given the local
      resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets
      pneumococcal DNA gyrase and topoisomerase IV and is highly active against S.
      pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant
      strains, as well as H. influenzae and the atypical pathogens. In clinical trials
      in CAP and AECB, gemifloxacin has been shown to be as effective a range of
      comparators and demonstrated an adverse event profile that was in line with the
      comparator agents. In one long-term study in AECB significantly more patients
      receiving gemifloxacin than clarithromycin remained free of recurrence after 26
      weeks. The improved potency, broad spectrum of activity and proven clinical and
      bacteriological efficacy and safety profile should make it a useful agent in the
      21st century battle against community-acquired LRTIs.

PMID- 15194124
TI  - Expanded-spectrum cephalosporin resistance in non-typhoid Salmonella.
AB  - Expanded-spectrum cephalosporins (ESCs) such as ceftriaxone, together with
      fluorinated quinolones, are the choice antibiotics in the treatment of invasive
      salmonella infections. Resistance to ESCs among non-typhoid salmonella has been
      recognised since the late 1980s. Currently, ESC-resistant salmonella strains are
      reported world-wide and in some areas their incidence is significant. Resistance
      is mainly due to acquisition of multi-resistant plasmids encoding a variety of
      extended-spectrum and AmpC-type beta-lactamases. The origins of ESC-resistant
      salmonellae are diverse. Exchange of resistance determinants between salmonellae
      and nosocomial enterobacteria seems to be frequent, at least in developing
      countries. Also, the use of newer beta-lactams in animal husbandry and veterinary
      medicine may have facilitated the spread of ESC-resistant salmonella strains in
      livestock.

PMID- 15194125
TI  - Integrons and beta-lactamases--a novel perspective on resistance.
AB  - The understanding of microbial resistance to the beta-lactam class of antibiotics
      in the form of beta-lactamases has come a long way since the early discoveries of
      narrow-spectrum penicillinases. Integron-borne beta-lactamases co-occurring with
      a wide array of non-beta-lactam resistance genes, particularly pose an increasing
      threat to the nosocomial environment, giving rise to multi-drug resistant
      microbes with complex resistance patterns. Selection of potent beta-lactamases
      through the use of non-beta-lactam agents may be possible through integron
      mediated resistance. It has become imperative that we should continuously strive
      to understand these complex mechanisms of antimicrobial resistance, not only to
      overcome them, but to avoid them from evolving further.

PMID- 15194126
TI  - New real-time PCR-based method for in vitro susceptibility testing of Anaplasma
      phagocytophilum against antimicrobial agents.
AB  - Up to now, only a few isolates of Anaplasma phagocytophilum have been tested for
      their susceptibility against a small number of antimicrobial agents. In addition,
      as with other fastidious or intracellular bacteria, the test methods are
      laborious and neither minimal inhibitory concentration (MIC) definitions, nor the
      test conditions and the inocula are standardised to date. A new 16S-rDNA-based
      real-time PCR assay has been developed and used under standardised conditions to
      analyse the activity of seven antimicrobial agents against two A. phagocytophilum
      isolates. After 72 h incubation, MICs were determined by software-assisted
      calculation of bacterial growth in samples and controls from semi-quantitative
      PCR results. In our study, the rank order of potency on a mg/l basis for the
      antimicrobial agents with enhanced in vitro activity against A. phagocytophilum
      was moxifloxacin (MIC: < or = 0.03 mg/l) > doxycycline (MIC: < or = 0.125 mg/l) >
      ciprofloxacin (MIC: 0.125 mg/l). Gentamicin, ampicillin, azithromycin and
      cethromycin showed no activity against the isolates tested in this investigation.
      Our new 16S-rDNA-PCR-based microdilution test system was shown to be sensitive,
      reproducible and reliable. The assay is capable of testing larger numbers of
      isolates and antimicrobial agents under standardised and very precise test
      conditions and may therefore offer a competent technical solution of the
      difficulties known to be associated with in vitro testing of other bacterial
      pathogens that grow intracellularly, such as chlamydia or rickettsia.

PMID- 15194127
TI  - Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis
      clinical strains isolated in the Philippines.
AB  - The prevalence of mutations in the katG, inhA and oxyR-ahpC genes of isoniazid
      (INH)-resistant Mycobacterium tuberculosis isolates in the Philippines were
      determined. Of 306 M. tuberculosis isolates studied, 81 (26.5%) exhibited INH
      resistance. Forty-four strains (54.3%) had mutations in the katG gene, eighteen
      strains (22.2%) had mutations in the putative inhA locus region, seven had
      mutations in both regions and five strains had mutations in the oxyR-ahpC operon.
      Only seven strains had no mutations. A total of 71 of the 81 (87.6%) resistant
      strains and 65 of the 72 (90.3%) INH sensitive randomly selected strains showed
      amino acid substitution in codon 463 (Arg to Leu) (88.9%). This fact supports the
      hypothesis that mutations at codon 463 are independent of INH-resistance and are
      linked to the geographical origins of the strains.

PMID- 15194128
TI  - Prevalence of mupirocin resistance in clinical isolates of Staphylococcus aureus
      and Staphylococcus epidermidis: results of the Antimicrobial Resistance
      Surveillance Study of the Paul-Ehrlich-Society for Chemotherapy, 2001.
AB  - A multicentre surveillance study comprising 26 laboratories located in Austria,
      Germany, and Switzerland was carried out in November 2001. A total of 787
      isolates of Staphylococcus aureus and 456 isolates of Staphylococcus epidermidis
      mainly recovered from hospitalised patients, were tested. MICs for mupirocin were
      determined using the broth microdilution procedure. Breakpoints were < or = 4
      mg/l (susceptible), 8-256 mg/l (low-level resistance) and > or = 512 mg/l (high
      level resistance). Rates of low- and high-level resistances were 2.9 and 0.9% in
      S. aureus, and 9.4 and 3.3% in S. epidermidis, respectively. Mupirocin resistance
      was almost exclusively observed in oxacillin-resistant isolates of S. aureus
      (MRSA) and S. epidermidis (MRSE). High-level mupirocin resistance was detected in
      3.1 and 4.5% of MRSA and MRSE, respectively.

PMID- 15194129
TI  - Macrolide resistance phenotypes of commensal viridans group streptococci and
      Gemella spp. and PCR detection of resistance genes.
AB  - One hundred and sixty viridans group streptococci (VGS) and 26 Gemella spp.
      resistant to erythromycin were studied to detect macrolide lincosamide and
      streptogramin B (MLS(B)) phenotypes and to investigate resistance rates to other
      antibiotics. The M phenotype was most prevalent in both bacterial groups (59.6%
      in VGS, 69.2% in gemellae) and the iMLS(B) phenotype was found least often (9.3
      and 13.9%, respectively). All isolates with M phenotype had the mef(A/E) gene,
      being prevalent the mef(E) subclass. cMLS(B) and iMLS(B) strains contained the
      erm(B) gene, alone or in combination with the mef(A/E) gene. Thirteen isolates
      were intermediately resistant to quinupristin/dalfopristin and 11 strains showed
      low susceptibility to telithromycin. Linezolid was active against all the
      isolates tested and tetracycline resistance was the major one in VGS (41.6%) and
      Gemella spp. (46.2%).

PMID- 15194130
TI  - In vitro activities of beta-lactam antibiotics alone and in combination with
      sulbactam against Gram-negative bacteria.
AB  - The resistance rates of ampicillin/sulbactam 2:1 against imipenem-susceptible and
      -resistant Acinetobacter baumannii were 23.5 and 30%, respectively.
      Ceftazidime/sulbactam combination showed significant reduction of resistant rates
      against Enterobacter cloacae, A. baumannii, ESBL Klebsiella pneumoniae. MIC90 of
      cefoperazone against E. cloacae, Serratia marcescens, A. baumannii and ESBL K.
      pneumoniae were > 128 mg/l. Addition of sulbactam enhanced the antimicrobial
      activities significantly. When imipenem was combined with sulbactam, the
      resistant rates against imipenem-resistant A. baumanni were significantly
      reduced. Cefepime/sulbactam combination was active against imipenem-resistant A.
      baumanni. The resistance rates of aztreonam/sulbactam combination against E.
      cloacae, imipenem-sensitive and resistant A. baumannii, ESBL K. pneumoniae were
      lowered significantly. The cefotaxime/sulbactam combination showed a significant
      improvement of activities against E. cloacae, S. marcescens, A. baumannii and
      ESBL K. pneumoniae.

PMID- 15194131
TI  - Gatifloxacin 400 mg as a single shot or 200 mg once daily for 3 days is as
      effective as ciprofloxacin 250 mg twice daily for the treatment of patients with
      uncomplicated urinary tract infections.
AB  - The efficacy and safety of two oral dosing regimens of gatifloxacin compared with
      ciprofloxacin for the treatment of acute uncomplicated lower urinary tract
      infection was investigated in a double-blind, randomised study, in adult female
      patients who received either gatifloxacin (400 mg as a single shot or 3 days of
      200 mg once daily) or ciprofloxacin (250 mg given twice daily for 3 days).
      Bacteriological and clinical responses were assessed 7-9 days after the end of
      treatment (EOT), and 4-6 weeks post-treatment (end of study, EOS). One thousand
      one hundred and two women were treated, 741 (248 in the gatifloxacin 400 mg
      group, 252 in the gatifloxacin 200 mg group, and 241 in the ciprofloxacin group)
      presented with bacteriological proof of infection and entered the efficacy
      analysis. The bacteriological response per patient at EOT in the three groups
      were 80% (177/220) [95% CI to ciprofloxacin -8.4%; 6.4%], 83% (184/222) [95% CI
      to ciprofloxacin -5.9%; 8.7%] and 81% (176/216), respectively. At the follow-up
      assessment they were slightly lower, 75% (167/224), 79% (169/213) and 79%
      (171/217), respectively. The clinical responses at EOT were 81% (197/243) [95% CI
      to ciprofloxacin -10.2%; 3.4%], 85% (213/250) [95% CI to ciprofloxacin -5.7%;
      7.2%] and 85% (201/238), respectively. At EOS they were 82% (195/239), 88%
      (212/241) and 86% (200/233), respectively. The eradication rates for all initial
      pathogens at the EOT were 90.3% in the gatifloxacin 400 mg S.D. group, 90.6% in
      the gatifloxacin 200 mg group, and 88.3% in the ciprofloxacin group. All
      treatment groups showed a similar safety profile. The incidence of treatment
      related adverse events was comparable, the majority of adverse events were of
      mild or moderate intensity and the medications were well tolerated. Both the
      administration of gatifloxacin 200 mg once daily for 3 days, and gatifloxacin 400
      mg as a single shot were shown to be equivalent to ciprofloxacin 250 mg twice
      daily for 3 days for the treatment of acute uncomplicated lower urinary tract
      infections.

PMID- 15194132
TI  - Reduction in the bactericidal activity of selected cathelicidin peptides by
      bovine calf serum or exogenous endotoxin.
AB  - Synthetic cathelicidin peptides exhibit enhanced antimicrobial action and avid
      binding to LPS, thereby detoxifying the action of endotoxin released from
      degrading bacteria. A series of cathelicidin antimicrobial peptide (CAP) and
      sheep myeloid antimicrobial peptide (SMAP) congeners were examined to determine
      whether LPS-binding could predict other beneficial characteristics of the
      peptides. The peptides were challenged in complex media with bovine calf serum or
      LPS, and their ability to kill the Gram negative pathogens Klebsiella pneumoniae
      (ATCC 43816) or Pseudomonas aeruginosa (PA103) was then assessed. LPS-binding
      efficiency was not correlated with antimicrobial activity in complex media.
      Additionally, LPS- and serum-binding may interfere with the antimicrobial
      activity of peptides in complex media.

PMID- 15194133
TI  - In vitro activity of extracts and constituents of Pelagonium against rapidly
      growing mycobacteria.
AB  - Extracts of the roots of plants of the Geraniaceae family have been used for many
      years in South Africa as native herbal remedies and there is circumstantial
      evidence for efficacy in the treatment of pulmonary tuberculosis. We have
      examined dried roots of Pelargonium reniforme and P. sidoides for antibacterial
      activity against rapidly growing mycobacteria. Fractions with activity against
      Mycobacterium aurum and M. smegmatis were obtained from both plant species by
      bioassay-guided fractionation of n-hexane extracts and were found to contain
      mixtures of straight-chain fatty acids. Analysis by gas chromatography-mass
      spectrometry (GC-MS) of the corresponding fatty acid methyl esters revealed
      structures with chain lengths ranging from C12 to C26. Unsaturated compounds were
      analysed as the corresponding dimethyl disulfide adducts to determine double-bond
      positions. Active mixtures differed in the relative abundance of their
      components, but all contained 16:0 (palmitic), Delta9-18:1 (oleic) and Delta9,12
      18:2 (linoleic acid) as the major components. When tested against M. aurum, M.
      smegmatis and other rapidly growing mycobacteria (M. fortuitum, M. abscessus and
      M. phlei), all saturated compounds except 12:0 were devoid of antimycobacterial
      activity, whereas unsaturated compounds showed antimycobacterial activity related
      to their degree of unsaturation, their chain length and the bacterial species
      tested. The most potent compound was linoleic acid, with MIC of 2 mg/l against M.
      aurum.

PMID- 15194134
TI  - Selective anti-Toxoplasma gondii activities of azasterols.
AB  - We report potent and selective inhibitory effects of 22,26-azasterol and 24,25
      (R,S)-epiminolanosterol, known inhibitors of Delta24(25)-sterol methyltranferase
      (SMT) in fungi and protozoa, on the proliferation of Toxoplasma gondii in LLCMK2
      cells. These compounds produced a dose-dependent reduction in parasite
      proliferation. 22,26-azasterol had an IC50 of 5.3 microM after 24 h and 4.5
      microM after 48 h, while for 24,25-(R,S)-epiminolanosterol the IC50 values were 1
      microM after 24 h and 0.12 microM after 48 h. The rapid reduction of parasite
      load suggested these compounds have selective cytotoxic effects against T.
      gondii. However, we were unable to detect 24-alkyl sterols in purified T. gondii
      tachyzoites using highly sensitive gas-liquid chromatography/mass spectrometry
      methods, a fact which indicated that the anti-proliferative effects of these
      azasterols were not mediated by inhibition of SMT. Transmission electron
      microscopy showed that the mitochondrion was the major target of drugs.
      Ultrastructural effects on plasma membrane, apicoplast and the formation of
      autophagosomal structures were also observed.

PMID- 15194135
TI  - Influence of the cell wall on ciprofloxacin susceptibility in selected wild-type
      Gram-negative and Gram-positive bacteria.
AB  - The susceptibility of several wild-type bacteria to ciprofloxacin and
      accumulation of the drug in these bacteria were evaluated. Species studied
      included Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa,
      Staphylococcus aureus, Bacillus subtilis and Bacillus cereus. Ciprofloxacin
      susceptibility was measured for each strain using two different methods: the
      minimal inhibitory concentration and the bactericidal index. Significant
      differences were observed between the results derived from these two methods.
      Whereas the minimal inhibitory concentration was low in all strains tested,
      ciprofloxacin's bactericidal activity, as indicated by the bactericidal index,
      varied with the species studied. To determine whether this finding was due to
      variations in cell envelope permeability to ciprofloxacin (i.e. to combined cell
      uptake and efflux), we studied ciprofloxacin accumulation using
      spectrofluorometry. In Gram-negative bacteria, differences in permeability can
      lead to altered susceptibility to antibiotics. In fact, the combination of slow
      uptake and efficient efflux seems to be crucial to the characteristic poor
      susceptibility of P. aeruginosa to ciprofloxacin. However, the low level of
      activity of ciprofloxacin against S. aureus and two Bacillus species may have
      resulted from the drug's interaction with its target enzymes (i.e. topoisomerase
      IV in S. aureus and DNA gyrase in Bacillus spp.) rather than diminished
      permeability.

PMID- 15194136
TI  - Inhibitory action of a new proton pump inhibitor, trifluoromethyl ketone
      derivative, against the motility of clarithromycin-susceptible and-resistant
      Helicobacter pylori.
AB  - We previously reported that a trifluoromethyl ketone derivative, 1-(2
      benzoxazolyl)-3,3,3-trifluoro-2-propanone (TF18), exhibited the potent
      antibacterial activity against Helicobacter pylori, but had no urease activity.
      In order to clarify the mechanism of anti-H. pylori action of TF18, we evaluated
      the growth and motility of TF18 on clarithromycin-susceptible H. pylori (CSHP)
      and -resistant H. pylori (CRHP). An effective proton pump inhibitor (TF18) had
      remarkable dose-dependent antibacterial activity and was able to inhibit the
      flagellar motor of both CSHP and CRHP isolates. The antimotility effect of TF18
      was more pronounced at subinhibitory concentration in CRHP than in CSHP. The
      swimming (the forward motion) was more sensitive to the inhibition than the
      tumbling. Based on the results, it is supposed that TF18 works as an uncoupler
      similar to the 'clutch' in a biological motor, in which counterclockwise rotation
      is more sensitive to the effect of TF18 than the clockwise rotation.

PMID- 15194137
TI  - Thioridazine treatment prevents cardiopathy in Trypanosoma cruzi infected mice.
AB  - Trypanosoma cruzi trypanothione reductase is an enzyme that has been identified
      as a potential target for chemotherapy. Thioridazine inhibits it and prevented
      cardiopathy in mice infected with T. cruzi Tulahuen strain. As not all T. cruzi
      strains respond to treatment in the same way, an isolate from a chronic patient
      (SGO Z12) was used; parasitaemias were studied along with, survival, serology,
      electrocardiography, histology and cardiac beta receptor function. Parasitaemia
      in thioridazine (80 mg/(kg day) for 3 days) treated mice was less and lasted for
      a shorter period (P < 0.01), there were reduced electrocardiographic and
      histological alterations and significantly improved survival (80% of non-treated
      died). Treated mice had lower receptor affinity and higher density as a
      compensatory mechanism, modifying the course of T. cruzi infection (SGO Z12
      isolate) and preventing the consequent cardiopathy.

PMID- 15194138
TI  - Antibiotic susceptibility of coagulase-negative staphylococci isolated from
      goats' milk.
AB  - The antibiotic susceptibility of 70 strains of coagulase-negative staphylococci
      (CNS) isolated during the 2001 lactating period from the milk of dairy goats, was
      evaluated. The antibiotics tested were benzylpenicillin, cloxacillin,
      amoxicillin, amoxicillin plus clavulanic acid, cephalonium and cefoperazone,
      erythromycin and tylmicosin, kanamycin and tetracycline. Minimum inhibitory
      concentration (MIC) measurements showed that all beta-lactams (except
      cefoperazone) were effective against Staphylococcus epidermidis and
      Staphylococcus caprae, whereas the other antibiotics were either less effective
      or showed no activity. Other CNS species showed very variable sensitivity to the
      antibiotics; testing would be required before therapy for the clinical control of
      goat mammary infections.

PMID- 15194139
TI  - Epidemiology of antibiotic-resistant Streptococcus pneumoniae strains in Far East
      Russia.

PMID- 15194140
TI  - In vitro activity of daptomycin against isolates of Staphylococcus aureus and
      enterococci: first results from Turkey.

PMID- 15194141
TI  - New insights into the biology and pathology of the cutaneous lymphatic system.
AB  - The cutaneous lymphatic system plays an important role in the maintenance of
      tissue fluid homeostasis, in the afferent phase of the immune response, and in
      the metastatic spread of skin cancers. The recent identification of genes that
      specifically control lymphatic development and the growth of lymphatic vessels
      (lymphangiogenesis), together with the discovery of new lymphatic endothelium
      specific markers have now provided new insights into the molecular mechanisms
      that control lymphatic development and function. These scientific advances have
      also led to a new understanding of the genetic basis of several hereditary
      diseases that are associated with lymphedema, and they have provided surprising
      evidence that malignant tumors can directly promote lymphangiogenesis and
      lymphatic metastasis.

PMID- 15194142
TI  - Role of TGF-beta2 in the human hair cycle.
AB  - Male pattern baldness is the result of premature entry into catagen due to
      androgens. In order to prevent hair loss, it is important to understand two
      critical steps, i.e., the induction mechanism of premature entry and the
      regression process of catagen. At the initiation, dihydrotestosterone (DHT)
      stimulates synthesis of transforming growth factor-beta2 (TGF-beta2) in dermal
      papilla cells. TGF-beta2 suppresses proliferation of epithelial cells and
      stimulates synthesis of certain caspases. Then TGF-beta2 triggers the intrinsic
      caspase network and subsequently epithelial cells are eliminated through
      apoptotic cell death. TGF-beta antagonists are effective in preventing catagen
      like morphological changes and in promoting elongation of hair follicles in vivo
      and in vitro. These lines of evidence strongly suggest the presence of a "catagen
      cascade" in male pattern baldness, involving: (1) the conversion of testosterone
      to DHT by type II 5-alpha-reductase; (2) the synthesis of TGF-beta2 in dermal
      papilla cells; and (3) the activation of the intrinsic caspase network. These
      sequential events contribute to the shortening of the human hair cycle.

PMID- 15194143
TI  - An in vitro outgrowth culture system for normal human keratinocytes.
AB  - BACKGROUND: Normal human epidermal keratinocytes usually proliferate in low
      calcium and differentiate in high-calcium without a feeder layer, but they stop
      proliferating and differentiate at confluency even in low-calcium, serum-free
      medium. OBJECTIVE: We speculated that this contact inhibition would be mediated
      in part by mechanical tension. To prove this, we created a new assay system.
      METHODS: A 10 mm diameter cloning ring was put on the center of a 60 mm dish
      coated with type I collagen. Keratinocytes were plated in the ring and incubated
      for 4h, then we had a circular epidermal monolayer sheet. We changed the
      mechanical tension by removing the ring and measured the diameter of the sheet
      under various conditions. RESULTS: When we used keratinocyte-serum free medium
      (SFM) whose calcium concentration is below 0.1 mM as a medium, the keratinocytes
      in the perimeter migrated individually, and the keratinocytes in the center
      portion started differentiation. However, when we added calcium chloride to SFM
      (final concentration more than 0.5 mM), keratinocytes at the periphery showed
      marked lamellipodia without losing contact with the surrounding cells. These
      keratinocytes showed coordinate sheet-like outgrowth as a whole even in high
      concentrations of calcium. CONCLUSION: These results suggest that other than
      calcium concentration, change of the mechanical tension would be one of the
      factors that mediate proliferation or differentiation of keratinocytes and that
      this new assay can be useful in analyzing proliferation, differentiation, and
      migration of keratinocytes.

PMID- 15194144
TI  - New KIT mutations in patients with piebaldism.
AB  - BACKGROUND: Piebaldism is an autosomal dominantly inherited disorder
      characterized by congenital leukoderma, typically on the forehead, abdomen, and
      knees. The leukoderma is usually stable throughout life. KIT mutations have been
      demonstrated in about 75% of patients with piebaldism. OBJECTIVES: To identify
      KIT mutations of the family with piebaldism and examine genotype-phenotype
      correlations in this disorder. METHODS: PCR-direct-sequencing technique using
      genomic DNA from peripheral leukocytes. RESULTS: We have studied 10 individuals
      within six piebaldism families and able to identify six novel mutations in the
      KIT gene in patients with piebaldism. These include four frameshift mutations:
      142delG, 1768-1769delAG, 2139delC, 2246-2249delAAAG, and two missense mutations:
      M541L, Y870C. CONCLUSIONS: These six new mutations are associated with phenotypes
      that are well in accordance with our knowledge of genotype-phenotype correlations
      in KIT.

PMID- 15194145
TI  - Enhanced TARC production by dust-mite allergens and its modulation by
      immunosuppressive drugs in PBMCs from patients with atopic dermatitis.
AB  - BACKGROUND: Thymus and activation regulated chemokine (TARC) is a CC chemokine
      that attracts CCR4+ T cells. We reported previously that TARC is an important
      chemokine that defines Th2 imbalance in the pathogenesis of atopic dermatitis
      (AD). OBJECTIVES: This study was undertaken to clarify TARC producing cells in
      peripheral blood mononuclear cells (PBMCs), the regulation of dust mite-allergen
      clude extract (DME) and different immunosuppressive drugs (Tacrolimus (FK506),
      cyclosporine (CsA), dexamethasone (Dex)) on TARC production by peripheral PBMCs
      from AD patients in vitro. METHODS: Monocyte derived dendritic cells (MoDCs) were
      generated from and TARC mRNA levels were examined and comapared with those from T
      cells in PBMCs from AD patients. PBMCs were cultured with or without DME and/or
      immunosuppressive drugs (Tacrolimus, CsA, Dex) for 7 days and TARC levels were
      measured. RESULTS: PBMCs from AD patients which were cultured with DME
      stimulation for 7 days showed significantly higher levels of TARC production than
      those from healthy controls. RT-PCR demonstrated that TARC mRNA was expressed in
      CD4+ T cells, CD8+ T cells and MoDCs. Tacrolimus, CsA and Dex individually
      suppressed TARC production by PBMCs from AD patients which were co-cultured with
      DME for 7 days. Gel shift analysis revealed differential inhibitory effects of
      these immunosuppressive drugs on NFkappaB activity in PBMCs from AD patients.
      CONCLUSION: Our data demonstrate that TARC producing cells are MoDCs, T cells as
      well as epidermal keratinocytes in AD. We suggest that MoDCs might regulate the
      immune responses by attracting T cells and CD25+ T cells in the pathogenesis of
      AD. We also showed the important role of DME on TARC production and the
      inhibitory effect of the immunosuppressive drugs on TARC production by PBMCs from
      AD patients, that can regulate ongoing immune responses in the pathogenesis of
      AD.

PMID- 15194146
TI  - Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and
      MDC, are elevated in patients with systemic sclerosis.
AB  - BACKGROUND: Although abnormalities of various chemokines are detected in systemic
      sclerosis (SSc), there are few findings concerning Th1 or Th2 chemoattractants.
      OBJECTIVE: To determine whether serum levels of chemokines preferentially
      chemotactic for Th1 cells (IP-10 and MIG) and predominantly chemotactic for Th2
      cells (TARC and MDC) are elevated and whether they correlate with clinical
      features in patients with SSc. METHODS: Serum samples from patients with diffuse
      cutaneous SSc (dSSc; n = 34), limited cutaneous SSc (lSSc; n = 30),
      dermatomyositis (DM; n = 15), systemic lupus erythematosus (SLE; n = 22), and
      normal controls (n = 30) were examined by sandwich ELISA. RESULTS: Serum TARC
      levels were significantly elevated in dSSc patients (P < 0.0002) and lSSc
      patients (P < 0.0001) compared with normal controls. Similarly, serum MDC levels
      were significantly increased in patients with dSSc (P < 0.02) or lSSc (P < 0.05)
      relative to normal controls. In addition, serum IP-10 was detected significantly
      more frequently in patients with dSSc (44%), lSSc (30%), or DM (53%) than normal
      controls (0%) and patients with SLE (0%). Furthermore, elevated TARC levels
      correlated with the presence of pitting scars and anti-topoisomerase I antibody,
      increased titers of anti-topoisomerase I and antinuclear antibody, and decreased
      glomerular filtration rate. Increased MDC levels were associated with pitting
      scars and younger ages at onset. CONCLUSION: These results suggest that both Th2
      chemoattractants, TARC and MDC, and a Th1 chemoattractant IP-10 play a role in
      the development of SSc.

PMID- 15194147
TI  - Elevated expression of CD23 on peripheral blood B lymphocytes from patients with
      bullous pemphigoid: correlation with increased serum IgE.
AB  - BACKGROUND: Increased serum IgE levels are occasionally found in patients with
      severe bullous pemphigoid (BP). CD23, a low affinity Fc receptor for IgE, is
      mainly expressed on mature B lymphocytes. Studies have suggested that serum
      levels of soluble CD23 (sCD23) correlate with serum IgE levels and disease
      severity in BP. OBJECTIVE: The purpose of our study is to examine whether the
      expression of CD23 is elevated in BP and whether this expression correlates with
      serum IgE levels and disease severity. METHODS: We measured CD23 expression on B
      cells from patients with active BP, pemphigus vulgaris, pemphigus foliaceus, and
      atopic dermatitis (AD), as well as healthy control subjects, using a flow
      cytometer. Serum levels of IgE and sCD23 were also measured. RESULTS: The
      expression of CD23 was significantly higher in BP patients compared with healthy
      control subjects (P < 0.05), whereas the levels were normal in the other bullous
      diseases. CD23 expression tended to be higher in severe BP compared with moderate
      BP, and the levels in severe BP were comparable to the levels in AD. Furthermore,
      CD23 expression correlated positively with serum IgE levels (P < 0.002), and the
      IgE levels were significantly higher in severe BP than in moderate BP (P < 0.01
      ). CD23 expression in BP did not correlate with sCD23 levels. CONCLUSIONS: These
      results suggest that the up-regulated surface CD23 on B cells may be involved in
      IgE synthesis and inflammatory events in BP.

PMID- 15194148
TI  - FHL2 expression in keratinocytes and transcriptional effect on
      PPARalpha/RXRalpha.

PMID- 15194149
TI  - In vitro antifungal activity of membrane-active peptides against dermatophytes
      and yeasts using broth microdilution method.

PMID- 15194150
TI  - Vitamin D receptor gene polymorphism is not associated with psoriasis in the
      Italian Caucasian population.

PMID- 15194151
TI  - Possible antipruritic effects of K+ channel openers in mice.

PMID- 15194152
TI  - Effects of hair follicle dermal sheath cells in the reconstruction of skin
      equivalents.

PMID- 15194153
TI  - Proximal promoter polymorphisms of the interleukin-4 receptor alpha are
      associated with psoriasis in Japan: inverse association pattern compared with
      atopic dermatitis.

PMID- 15194154
TI  - Effect of W07-toxin on gut physiological response in mice.
AB  - A number of unknown secretogenic factor(s) from Vibrio cholerae have been
      implicated to play a role in inducing cholera-like symptoms observed in patients.
      The present study has been carried out on the novel W07-toxin (pI 5.2) from V.
      cholerae W07, an epidemic cholera strain devoid of the ctx gene. The toxin showed
      maximum binding to GM(1) and interacted with a 20 kDa glycoprotein present on the
      cell membrane of mice enterocytes in a GM(1) specific manner. The analysis of
      biochemical parameters in enterocytes triggered with this toxin revealed a
      significant increase in intracellular calcium concentration and a massive
      secretion of Cl(-). However, no absorption of Na(+) was observed under the same
      condition. This toxin also elevated the level of cyclic adenosine 3',5'
      monophosphate (cAMP) as well as protein kinase A (PKA). Thus, the novel toxin,
      although distinct from cholera-toxin, showed some functional homology to it and
      may be one of the key players inducing electrolyte imbalance within intestinal
      cells in the cholera-like symptoms associated with V. cholerae W07.

PMID- 15194155
TI  - Lipid raft microdomains mediate class A scavenger receptor-dependent infection of
      Brucella abortus.
AB  - Brucella abortus is a facultative intracellular bacterium that can survive inside
      macrophages. Intracellular replication of B. abortus requires the VirB complex,
      which is highly similar to the conjugative DNA transfer system. In this study, we
      showed that a class A scavenger receptor (SR-A) of macrophages is required to
      internalize B. abortus and contributes to the establishment of bacterial
      infection in mice. Macrophages from SR-A-deficient mice inhibited internalization
      and intracellular replication of both wild type strain and the virB4 mutant, and
      that bacterial proliferation was inhibited in SR-A-deficient mice. Adding
      lipopolysaccharide from B. abortus and Salmonella enterica serovar Typhimurium,
      but not from Escherichia coli, to macrophages inhibited bacterial
      internalization. VirB-dependent bacterial internalization induced localization of
      SR-A into detergent-resistant membrane lipid rafts. These results indicate that
      B. abortus internalizes into macrophages by using SR-A as a receptor and that the
      VirB type IV secretion system of B. abortus regulates signal transduction
      dependent on SR-A to form replicative phagosomes, and which is mediated by lipid
      rafts.

PMID- 15194156
TI  - Differential expression of sheep beta-defensin-1 and -2 and interleukin 8 during
      acute Mannheimia haemolytica pneumonia.
AB  - Beta-defensins are antimicrobial peptides produced by several cell types,
      including respiratory epithelia and leukocytes. Expression of some beta-defensins
      is increased by bacterial-induced inflammatory responses whereas expression of
      other beta-defensins is constitutive. Two beta-defensins are expressed in lungs
      of sheep (sheep beta-defensin-1 and -2; SBD-1/-2) and expression of SBD-1 is
      increased during parainfluenza virus type 3 (PI-3) infection. The effect of
      Mannheimia haemolytica, a Gram-negative bacteria known to induce expression of
      bovine beta-defensins and NF-kappa B in lung, has not been determined for SBD-1/
      2. In this study, different concentrations of M. haemolytica were inoculated into
      pulmonary bronchi of lambs. SBD-1 and SBD-2 mRNA levels detected by real time
      reverse transcriptase polymerase chain reaction in lung homogenates did not
      increase. In fact, SBD-1 mRNA levels were significantly decreased with the
      highest administered inoculum concentration (10(9)). In contrast, mRNA levels of
      interleukin-8 (IL-8) were significantly increased over controls and progressively
      increased with M. haemolytica concentrations. Co-inoculation of M. haemolytica
      with xylitol, an osmotic agent, did not alter mRNA levels of SBD-1, SBD-2 or IL
      8. SBD-1 mRNA expression was detected in lung epithelia, but not in leukocytes.
      This study suggests that SDB-1 expression occurs in epithelia and decreases
      during severe bacterial pneumonia, which is in contrast to the increase that
      occurs with PI-3 infection.

PMID- 15194157
TI  - Anaerobiosis, growth phase and Actinobacillus pleuropneumoniae RTX toxin
      production.
AB  - Actinobacillus pleuropneumoniae is the causative agent of an economically
      significant form of porcine pleuropneumonia. This bacterium produces four
      distinct RTX toxins (ApxI-ApxIV) that play a key role in its pathogenesis, but
      further characterization of these hemolytic toxins is needed to identify the
      environmental signals and genes that affect their production during infection. In
      this report, we examined the effect of oxygen limitation on the production of
      ApxI and ApxII, the two RTX toxins that are produced by all highly virulent
      strains in North America. Batch cultures of ApxI- and ApxII-producing strains
      were grown in heart infusion broth supplemented with NAD, and samples were
      prepared throughout the growth curve. We compared batch cultures with normal
      oxygen levels to those that were maintained in an oxygen-depleted state. ApxI and
      ApxII hemolytic activity were nearly identical under both growth conditions. The
      level of toxin activity was confirmed by examination of extracellular ApxI
      concentrations and apxII mRNA levels. In addition, toxin activity examined on
      blood agar plates grown aerobically or anaerobically showed no significant
      difference. These results have important implications for the disease state where
      high-density growth is likely to result in local anaerobic or microaerophilic
      environments.

PMID- 15194158
TI  - Borrelia burgdorferi outer surface protein (osp) B expression independent of
      ospA.
AB  - The outer surface proteins (Osp) A and B are two important lipoproteins of
      Borrelia burgdorferi, the Lyme disease spirochete. Extensive in vitro studies
      indicate that ospB shares a common promoter with ospA and thus these two
      lipoprotein genes are coordinately transcribed. We show here that B. burgdorferi
      expresses ospB at much higher levels than ospA during experimental murine
      infection. The ratio of ospA and ospB mRNA transcripts was 3.5:1 in tick-adapted
      spirochetes while B. burgdorferi matched every ospA mRNA with up to 70 ospB
      transcripts during murine infection. This was consistent with the analysis of
      antibody responses to the two lipoproteins, which showed a more frequent OspB
      response than OspA during chronic murine infection.

PMID- 15194159
TI  - Visualisation of zebrafish infection by GFP-labelled Vibrio anguillarum.
AB  - Vibrio anguillarum is an invasive pathogen of fish causing a septicaemia called
      vibriosis. In this work, transparent zebrafish were immersed in water containing
      green fluorescent protein labelled V. anguillarum. The infection was visualised
      at the whole fish and single bacterium levels using microscopy. The
      gastrointestinal tract was the first site where the pathogen was detected. This
      enteric localisation occurred independently of the flagellum or motility. On the
      other hand, chemotactic motility was essential for association of the pathogen
      with the fish surface. In conclusion, the zebrafish infection model provides
      evidence that the intestine and skin represent sites of infection by V.
      anguillarum and suggests a host site where chemotaxis may function in virulence.

PMID- 15194161
TI  - Dossier: auto-immunity and biotherapy.

PMID- 15194160
TI  - Intracellular signalling and cytoskeletal rearrangement involved in Yersinia
      pestis plasminogen activator (Pla) mediated HeLa cell invasion.
AB  - Yersinia pestis, the etiologic agent of plague is a highly invasive organism
      being able to invade non-phagocytic epithelial cells. Its plasminogen activator
      (Pla), encoded by the pPCP1 plasmid plays a pivotal role in internalisation of
      bacteria by HeLa cells. The aim of this study was to analyse the intracellular
      signalling processes and cytoskeletal rearrangement events associated with
      invasion. Wortmannin caused a 50% decrease of invasiveness at 50nM concentration
      pointing to the involvement of phosphatidyl-inosinol-4 kinase (PtINs4). Pre
      treatment with staurosporin, a potent inhibitor of protein kinases (PKs) and with
      genistein, a specific tyrosine kinase inhibitor decreased the number of
      internalised bacteria about seven-fold and two-fold, respectively, indicating the
      involvement of PKs including tyrosine kinases in Pla-mediated internalisation.
      Cytochalasin D, an actin polymerisation inhibitor, C3 exoenzyme of Clostridium
      botulinum, a specific inhibitor of small GTPase Rho, and NDGA, a 5-lipoxygenase
      inhibitor also involved in Rho activation strongly reduced the number of
      internalised bacteria revealing the role of cytoskeletal events in the invasion
      process. All the tested inhibitors changed the invasion but not the adhesion
      pattern of the Pla producing recombinant strain. Actin rearrangement could also
      be visualised also with rhodamin-phalloidin staining.

PMID- 15194163
TI  - Auto-antibodies in multiple sclerosis: an hypothesis.

PMID- 15194162
TI  - The natural autoantibody repertoire and autoimmune disease.
AB  - The incidence of autoimmune diseases has shown a significant increase in
      developed countries during the last 40 years. The cause of this increase is still
      unknown, and reliable methods for the detection of individuals at risk of
      developing autoimmune disease are not available yet. To explore new methods for
      the diagnosis and monitoring of autoimmune disease, we have studied the
      repertoire of natural autoantibodies (NA) and its relationship with autoimmune
      disease using large arrays of defined antigens. NA are found in healthy humans
      and mice, apparently in the absence of immunization with their target antigens.
      We used knock-out mice to demonstrate that the repertoire of NA is influenced by
      factors not directly related to antigenic stimulation such as endogenous levels
      of histamine. By studying strains of mice known to differ in their susceptibility
      to autoimmune disease, we could conclude that the repertoire of NA reflects the
      susceptibility to develop autoimmune disease. The study of the human repertoire
      of NA required the development of bio-informatic tools to overcome the variation
      introduced by individual differences in the genetic background and immune
      history. We found that human NA are organized in clusters that can differentiate
      healthy subjects from patients with type 1 diabetes mellitus, type 2 diabetes
      mellitus or Behcet's disease patients. The development of new tools to undertake
      large-scale NA analysis could also enhance our understanding of the immune
      system, and leave us in a better position to face the up-coming epidemics of
      autoimmune disorders.

PMID- 15194164
TI  - The role of FcgammaRIIA and IIIA polymorphisms in autoimmune diseases.
AB  - Our knowledge about the role of human Fc receptors for IgG (FcgammaR) has
      increased considerably within the last several years. These receptors vary in
      their affinity for IgG, their preferences for IgG subclasses, the cell type
      specific expression patterns, and the intracellular signals that they elicit.
      Additional FcgammaR heterogeneity is introduced by the presence of well
      characterized genetic polymorphisms. Allelic variants of FcgammaR genes may
      influence phagocyte biologic activity, providing a basis for inherited
      predisposition to disease. Recent evidence suggests that certain FcgammaR alleles
      are genetic risk factors for systemic autoimmune diseases and the development of
      major manifestations of these diseases. The FcgammaRIIA-R/H131 polymorphism is an
      important determinant of predisposition to systemic lupus erythematosus (SLE) and
      antiphospholipid syndrome (APS). FcgammaRIIA-R131, the low-binding IgG2 allele,
      seems to confer risk for APS under a recessive model, whereas its effect on SLE
      susceptibility probably has a dose-response character. The population
      attributable fraction of lupus cases due to the R131 allele is 13% and for APS
      cases is at least 10%, in subjects of European descent. The FcgammaRIIIA-V/F158
      polymorphism has a significant impact on renal involvement in lupus patients. The
      proportion of nephritis cases that could be attributed to the low-binding IgG1
      and IgG3 F158 allele is approximately 10-14%. These genetic associations have
      been well documented in meta-analyses including a large number of studies.
      Besides the epidemiologic and pathophysiologic interest, this knowledge may be of
      use in the future in designing novel therapeutic interventions.

PMID- 15194165
TI  - A role of FcgammaRIIB in the development of collagen-induced arthritis.
AB  - Immune inhibitory receptors play an important role in the maintenance of adequate
      activation threshold of various cells in our immune system. The inhibitory Fc
      receptor, type IIB Fc receptor for IgG (FcgammaRIIB), is one of the critical
      molecules for the regulation of immune responses through antibodies. Analysis of
      murine models indicates that FcgammaRIIB plays an essential role in the
      suppression of various autoimmune disorders. Recent studies reveal the novel
      regulatory role of FcgammaR in the development of collagen-induced arthritis
      (CIA), an animal model relevant to human rheumatoid arthritis (RA). This review
      provides an overview of FcgammaRIIB-mediated immune regulation, highlighting the
      implication of FcgammaRIIB in the selection of peripheral B cell development
      during the CIA course.

PMID- 15194166
TI  - Rituximab in autoimmune diseases.
AB  - Modern treatments of autoimmune diseases are based on immunological therapies.
      Rituximab induces a targeted B-cell depletion in the aim of eradicating
      autoreactive clones in various autoimmune disorders. Several studies are being
      undertaken and preliminary reports are very encouraging. The mechanism of action
      is not evident, but appears to be connected with the lowering of autoantibody
      levels, in the diseases where relevant antibody titres are relievable. Most of
      the patients treated were affected by idiopathic thrombocytopenic purpura (ITP)
      and autoimmune haemolytic anaemia, but also very rare diseases like acquired
      haemophilia are reported. Best results are described in autoimmune haemolytic
      anaemia, in many others there is clear evidence for efficacy; in all the diseases
      the number of complete or partial remission, though temporary, is much greater
      than 50%. Side effects are rarely reported, and immunosuppression is not a great
      problem. The persistence of clinical improvement for more than 1 year after B
      lymphocyte repopulation supports the hypothesis of a stochastic generation of
      pathogenic B-cell subsets. Other studies and controlled trials are required to
      establish when and which patients are to be treated, and find the opportunity of
      the association of others drugs.

PMID- 15194167
TI  - Prolactin as a modulator of B cell function: implications for SLE.
AB  - Prolactin is not only a lactigenic hormone but also an immunomodulator involved
      in lymphocyte survival, activation and proliferation. There is increasing data
      implicating prolactin in autoimmunity, and specifically in SLE. Increased serum
      prolactin levels have been reported in lupus patients of both genders, and have
      been associated with accelerated disease expression and early mortality in lupus
      prone mice. Furthermore, suppression of prolactin secretion with bromocriptine
      provides beneficial effects in murine lupus, and perhaps in some SLE patients as
      well. Treatment with prolactin that causes mild to moderate hyperprolactinemia,
      similar to that present in SLE patients, breaks tolerance and induces a lupus
      like illness in non-spontaneously autoimmune mice with a susceptible genetic
      background. These immuno stimulatory effects of prolactin are mediated by a
      decrease in negative selection and the maturation of autoreactive B cells to the
      follicular subset. Consistent with the fact that follicular B cells are T cell
      dependent, CD4+ T cells are necessary for the prolactin-mediated break down of B
      cell tolerance. In mice, the effects of prolactin on the immune system are
      genetically determined, suggesting that only a subset of SLE patients are likely
      to have a prolactin-responsive disease. The manipulation of serum prolactin or,
      even more specifically, follicular B cells that are susceptible to the immuno
      stimulatory effects of prolactin, may provide novel therapeutic options for those
      SLE patients with a prolactin-modulated disease.

PMID- 15194168
TI  - Multidrug resistance-1 (MDR-1) in autoimmune disorders IV. P-glycoprotein
      overfunction in lymphocytes from myasthenia gravis patients.
AB  - Multidrug resistance (MDR) mechanisms have been widely studied in cancer. Among
      them, P-glycoprotein (P-gp) overfunction has been associated with resistance to
      several antineoplastic agents. The physiological role of P-gp involves hormone
      and metabolite secretion, bacterial product detoxification, and transport of
      several drugs to the extracellular space, thus inhibiting their toxic or
      therapeutic effects. The study of MDR-1 in diseases of autoimmune origin has just
      recently emerged. Corticosteroids remain the mainstay therapy for autoimmune
      diseases. As prednisone (PDN) is transported by P-gp, the aim of this study was
      to evaluate the P-gp function in lymphocytes from myasthenia gravis (MG)
      patients. Thirty MG patients and 25 healthy controls were studied. Peripheral
      blood mononuclear cells were isolated by gradient centrifugation and incubated
      with daunorubicin (DNR) (a fluorescent drug extruded by P-gp). Functional
      activity of P-gp was analyzed by flow cytometry. Results were expressed as
      percentage of gated lymphocytes able to efflux DNR. Overall, MG patients showed
      increased numbers of lymphocytes with functional P-gp activity when compared with
      controls (x = 4.92 +/- 5.26% vs. x = 0.7 +/- 0.48%, respectively) (P < 0.0001).
      When patients were classified as responders (n = 21) or refractory (n = 9) to
      treatment, the latter group exhibited higher values of functional P-gp (x = 10.18
      +/- 6.39%) when compared to the responder group (x = 2.66 +/- 2.45%) (P =
      0.0076). These data suggest, on the one hand, that drug resistance may be induced
      by long-term treatment or by high PDN doses and, on the other, emphasize the need
      for the study of P-gp antagonists in order to improve the current therapeutical
      schemes for the treatment of MG.

PMID- 15194169
TI  - Autoimmunity induced by adjuvant hydrocarbon oil components of vaccine.
AB  - Adjuvant oils such as Bayol F (Incomplete Freund's adjuvant: IFA) and squalene
      (MF59) have been used in human and veterinary vaccines despite poor understanding
      of their mechanisms of action. Several reports suggest an association of
      vaccination and various autoimmune diseases, however, few were confirmed
      epidemiologically and the risk of vaccination for autoimmune diseases has been
      considered minimal. Microbial components, not the adjuvant components, are
      considered to be of primary importance for adverse effects of vaccines. We have
      reported that a single intraperitoneal injection of the adjuvant oils pristane,
      IFA or squalene induces lupus-related autoantibodies to nRNP/Sm and -Su in non
      autoimmune BALB/c mice. Induction of these autoantibodies appeared to be
      associated with the hydrocarbon's ability to induce IL-12, IL-6, and TNF-alpha,
      suggesting a relationship with hydrocarbon's adjuvanticity. Whether this is
      relevant in human vaccination is a difficult issue due to the complex effects of
      vaccines and the fact that immunotoxicological effects vary depending on species,
      route, dose, and duration of administration. Nevertheless, the potential of
      adjuvant hydrocarbon oils to induce autoimmunity has implications in the use of
      oil adjuvants in human and veterinary vaccines as well as basic research.

PMID- 15194170
TI  - Increased peripheral blood B-cells expressing the CD5 molecules in association to
      autoantibodies in patients with lupus erythematosus and evidence to selectively
      down-modulate them.
AB  - The present investigation has been undertaken to analyze absolute and relative
      CD5+ B-cell numbers in patients with lupus erythematosus (LE), and concomitant B
      CLL, and to monitor them under therapy. Peripheral blood lymphocytes of LE
      patients, and healthy controls were analyzed by flow cytometry and direct
      immunofluorescence technique. Patients were treated with low-dose methotrexate
      (MTX). Before and during MTX treatment laboratory monitoring has been done. LE
      patients had increased percentages of CD5+CD19+ as compared to controls (p <
      0.0002), the absolute number of CD5+ B-cells was equal in controls and patients.
      Autoantibodies were positively correlated to the number of CD5+ B-cells in LE
      patients. In a total of 140 LE-patients one male patient suffered from both LE
      and B-CLL (0.7%). He had increased absolute and relative CD5+ B-cells. MTX
      induced significant decrease of both total B-cell numbers, and CD5+ B-cells. The
      decrease of CD5+CD19+ cells was more pronounced than the decrease of total B
      cells. Apoptosis rate increased in parallel to the drop-down of elevated
      CD5+CD19+ cells. Peripheral T-cell subsets remained stable under low-dose MTX.
      Both absolute and relative numbers of CD5+CD19+ cells should be taken into
      account in patients with LE. MTX seems to decrease B-cells, and preferentially to
      down-regulate B-cells expressing the CD5 molecule, which opens new therapeutic
      options and cell biological activities. The mechanism is unclear but apoptosis
      induction seems to be likely.

PMID- 15194171
TI  - Proceedings of the 3rd World Symposium on Pulmonary Arterial Hypertension.
      Venice, Italy, June 23-25, 2003.

PMID- 15194172
TI  - Primary pulmonary arterial hypertension: a look back.
AB  - For the first half of the twentieth century, the published reports on primary
      pulmonary hypertension (PPH) were confined to clinical pathological correlations.
      In the 1950s the physiological aspects began to be reported followed by
      epidemiologic studies triggered by an epidemic of PPH due to the ingestion of an
      appetite suppressant, aminorex fumarate. The epidemic prompted a series of
      meetings of the World Health Organization, which led, in turn, to the creation of
      the U.S. Registry of Primary Pulmonary Hypertension, standardization of
      nomenclature, and an etiologic classification of all types of pulmonary
      hypertension.

PMID- 15194173
TI  - Clinical classification of pulmonary hypertension.
AB  - In 1998, during the Second World Symposium on Pulmonary Hypertension (PH) held in
      Evian, France, a clinical classification of PH was proposed. The aim of the Evian
      classification was to individualize different categories sharing similarities in
      pathophysiological mechanisms, clinical presentation, and therapeutic options.
      The Evian classification is now well accepted and widely used in clinical
      practice, especially in specialized centers. In addition, this classification has
      been used by the U.S. Food and Drug Administration and the European Agency for
      Drug Evaluation for the labeling of newly approved medications in PH. In 2003,
      during the Third World Symposium on Pulmonary Arterial Hypertension held in
      Venice, Italy, it was decided to maintain the general architecture and philosophy
      of the Evian classification. However, some modifications have been proposed,
      mainly to abandon the term "primary pulmonary hypertension" and to replace it
      with "idiopathic pulmonary hypertension"; to reclassify pulmonary veno-occlusive
      disease and pulmonary capillary hemangiomatosis; to update risk factors and
      associated conditions for pulmonary arterial hypertension and to propose
      guidelines in order to improve the classification of congenital systemic-to
      pulmonary shunts.

PMID- 15194174
TI  - Cellular and molecular pathobiology of pulmonary arterial hypertension.
AB  - Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology.
      Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis
      contribute to increased pulmonary vascular resistance in PAH. The process of
      pulmonary vascular remodeling involves all layers of the vessel wall and is
      complicated by cellular heterogeneity within each compartment of the pulmonary
      arterial wall. Indeed, each cell type (endothelial, smooth muscle, and
      fibroblast), as well as inflammatory cells and platelets, may play a significant
      role in PAH. Pulmonary vasoconstriction is believed to be an early component of
      the pulmonary hypertensive process. Excessive vasoconstriction has been related
      to abnormal function or expression of potassium channels and to endothelial
      dysfunction. Endothelial dysfunction leads to chronically impaired production of
      vasodilators such as nitric oxide and prostacyclin along with overexpression of
      vasoconstrictors such as endothelin (ET)-1. Many of these abnormalities not only
      elevate vascular tone and promote vascular remodeling but also represent logical
      pharmacological targets. Recent genetic and pathophysiologic studies have
      emphasized the relevance of several mediators in this condition, including
      prostacyclin, nitric oxide, ET-1, angiopoietin-1, serotonin, cytokines,
      chemokines, and members of the transforming-growth-factor-beta superfamily.
      Disordered proteolysis of the extracellular matrix is also evident in PAH. Future
      studies are required to find which if any of these abnormalities initiates PAH
      and which ones are best targeted to cure the disease.

PMID- 15194175
TI  - Pathologic assessment of vasculopathies in pulmonary hypertension.
AB  - Pulmonary arterial hypertension (PAH) includes various forms of pulmonary
      hypertension of different etiology but similar clinical presentation and
      functional derangement. Histopathological vascular changes in all forms of PAH
      are qualitatively similar but with quantitative differences in the distribution
      and prevalence of pathological changes in various portions of the pulmonary
      vascular bed. The documentation of these topographic variations in the response
      of the pulmonary vasculature to injury may be important to understand the
      pathogenesis of the various subsets of PAH. To standardize the precise
      histopathological documentation of the pulmonary vasculopathy in PAH we propose a
      histopathological classification that includes both the predominant segment of
      the pulmonary vasculature affected and the possible coexistence of pathological
      changes in other vascular segments.

PMID- 15194176
TI  - Genetic basis of pulmonary arterial hypertension: current understanding and
      future directions.
AB  - Mutations in two receptors of the transforming growth factor-beta family have
      recently been shown to be present in the majority of cases of inherited
      (familial) pulmonary arterial hypertension (PAH). Study of the biology of these
      receptors, bone morphogenetic protein receptor type-2 (BMPR2), and activin-like
      kinase type-1 (ALK-1) will certainly reveal pathogenic mechanisms of disease.
      Exonic mutations in BMPR2 are found in about 50% of patients with familial PAH,
      and ALK1 mutations are found in a minority of patients with hereditary
      hemorrhagic telangiectasia and co-existent PAH. Because familial PAH is highly
      linked to chromosome 2q33, it is likely that the remaining 50% of family cases
      without exonic mutations have either intronic BMPR2 abnormalities or alterations
      in the promoter or regulatory genes. Also, only about 10% of patients with
      "sporadic" idiopathic PAH have identifiable BMPR2 mutations. Mutations in BMPR2
      confer a 15% to 20% chance of developing PAH in a carrier's lifetime. Thus, there
      must be gene-gene or gene-environment interactions that either enhance or prevent
      the development of the vascular disease in persons carrying a mutation, and there
      must be other patterns of susceptibility based on genetic makeup. To elucidate
      the genetic basis of PAH further, investigations are needed, including genome
      scanning for major and minor genes, analysis of genetic profiles of patients for
      candidate genes likely to modify risk for disease (e.g., serotonin transporter
      alleles, nitric oxide-synthases), proteomics, transgenic mice, and altered signal
      transduction. Advances in genetic testing, presymptomatic screening, and
      biomarkers should permit early detection of disease in those at risk of PAH and
      allow trials of preventive therapy in carriers.

PMID- 15194177
TI  - Diagnosis and differential assessment of pulmonary arterial hypertension.
AB  - Pulmonary arterial hypertension (PAH) is diagnosed by various investigations that
      are essential for making the diagnosis, and by additional tests to clarify the
      category of pulmonary hypertension (PH). A diagnostic algorithm can guide the
      evaluation of PH, but like all guidelines the algorithm can be modified according
      to specific clinical circumstances. Most patients are diagnosed as the result of
      an evaluation of symptoms, whereas others are diagnosed during screening of
      asymptomatic populations at risk. Right heart catheterization (RHC) must be
      performed in patients with suspected PH to establish the diagnosis and document
      pulmonary hemodynamics. Before initiation of medical therapy, assessment of acute
      vasoreactivity (during catheterization) is necessary to determine the appropriate
      therapy for an individual patient. An acute response is generally defined as a
      decrease in mean pulmonary arterial pressure of at least 10 mm Hg with the mean
      pulmonary arterial pressure decreasing to 40 mm Hg or below, accompanied by a
      normal or high cardiac output. After PAH is diagnosed, disease severity should be
      assessed in order to accurately determine risk:benefit profiles for various
      therapeutic options. Useful tools to predict outcome include functional class,
      exercise capacity, pulmonary hemodynamics, acute vasoreactivity, right
      ventricular function, as well as brain natriuretic peptide, endothelin-1, uric
      acid, and troponin levels. Repeating these tests serially on treatment is useful
      for monitoring the response to a given therapy. Close follow-up at a center
      specializing in management of PH is recommended, with careful periodic
      reassessment and adjustment of therapy.

PMID- 15194178
TI  - End points and clinical trial designs in pulmonary arterial hypertension:
      clinical and regulatory perspectives.
AB  - To date, randomized controlled clinical trials performed in pulmonary arterial
      hypertension (PAH) have been relatively short-term studies involving mainly
      patients with advanced disease. The primary end points in these trials have
      addressed exercise capacity, usually by using the 6-min walk test. Although this
      approach is still warranted in future trials assessing new treatments, it is
      likely that the focus will shift toward trials of longer duration, involving
      patients with less advanced disease, and that different drugs and drug
      combination regimens will be compared. In such trials, it is possible that a
      composite of markers indicating clinical deterioration (e.g., hospitalization for
      right heart failure, the requirement for the introduction of an alternative
      treatment, and predefined indicators of worsening exercise tolerance) may be more
      useful as primary end points. Quality of life will become a very important issue;
      however, appropriate quality-of-life questionnaires for PAH have yet to be
      developed. In addition, hemodynamics will likely remain valuable as secondary end
      points, but future clinical trials should include hemodynamics obtained both
      during exercise and at rest. Finally, cardiopulmonary exercise testing,
      echocardiographic studies, and biochemical parameters, such as brain natriuretic
      peptide or troponin T, may also prove useful as secondary end points in the
      future.

PMID- 15194179
TI  - Prostanoid therapy for pulmonary arterial hypertension.
AB  - Prostanoids have played a prominent role in the treatment of pulmonary arterial
      hypertension (PAH). Several compounds and methods of administration have been
      studied: chronic intravenously infused epoprostenol, chronic subcutaneously
      infused treprostinil, inhaled iloprost, and oral beraprost. Chronic intravenous
      epoprostenol therapy has had a substantial impact on the clinical management of
      patients with severe PAH. It improves exercise capacity, hemodynamics, and
      survival in patients with idiopathic pulmonary arterial hypertension (IPAH). It
      also improves exercise capacity and hemodynamics in patients with PAH occurring
      in association with scleroderma. The complexity of epoprostenol therapy (chronic
      indwelling catheters, reconstitution of the drug, operation of the infusion pump,
      and others) has led to attempts to develop other prostanoids with simpler modes
      of delivery. Treprostinil, a stable prostacyclin analogue with a half-life of 3
      h, has been developed for subcutaneous delivery. It has beneficial effects on
      exercise and hemodynamics, which depend somewhat on the dose achieved. This, in
      turn, is determined by the patient's ability to tolerate the drug's side effects,
      including pain and erythema at the infusion site. Inhaled iloprost therapy may
      provide selectivity of the hemodynamic effects to the lung vasculature, thus
      avoiding systemic side effects. In a randomized and controlled trial, iloprost
      resulted in improvement in a combined end point incorporating the New York Heart
      Association functional class, 6-min walk test, and deterioration or death.
      Beraprost is the first orally active prostacyclin analogue. In the first of two
      randomized controlled trials, beraprost increased exercise capacity in patients
      with IPAH, with no significant changes in subjects with associated conditions.
      Hemodynamics did not change significantly, and no difference in survival was
      detected between the two treatment groups. The second study showed that beraprost
      treated patients had less disease progression at six months and confirmed the
      results of the previous trial. However, this improvement was no longer present at
      9 or 12 months. In conclusion, though treatment with prostanoids is complicated
      by their generally short half-lives and complicated drug delivery systems, they
      continue to play an important role in the treatment of PAH.

PMID- 15194180
TI  - Endothelin receptor antagonists in pulmonary arterial hypertension.
AB  - Endothelin receptor antagonism has emerged as an important therapeutic strategy
      in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations
      have clearly shown that endothelin (ET)-1 is overexpressed in several forms of
      pulmonary vascular disease and likely plays a significant pathogenetic role in
      the development and progression of pulmonary vasculopathy. Oral endothelin
      receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics,
      exercise capacity, functional status, and clinical outcome in several randomized
      placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by
      the U.S. Food and Drug Administration for class III and IV patients with PAH,
      based on two phase III trials. In addition to its efficacy as sole therapy,
      bosentan may have a role as part of a combination of drugs such as a prostanoid
      or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and
      ambrisentan are currently undergoing investigation.

PMID- 15194181
TI  - Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial
      hypertension.
AB  - Pulmonary hypertension (PH) is a disease of various origins. Nitric oxide-a
      potent vasodilator-is a key player of pulmonary vasoregulation. Nitric oxide
      signaling is mainly mediated by the guanylate cyclase/cyclic guanylate
      monophosphate pathway. The effects of this second messenger system are limited by
      enzymatic degradation through phosphodiesterases (PDEs). Recently, beneficial
      effects of the oral PDE-5 inhibitor sildenafil (originally approved for the
      treatment of erectile dysfunction) were reported for the treatment of PH. We
      provide a brief overview of the experimental and clinical application of PDE
      inhibitors in the field of PH. In particular, studies reporting the clinical
      effectiveness of sildenafil are highlighted. This agent, despite oral
      application, displays characteristics of a pulmonary selective vasodilator. In
      addition, evidence shows that sildenafil is operative mainly in the vasculature
      of well-ventilated areas of the lung. However, to date, controlled randomized
      trials proving the efficacy of this approach for the treatment of pulmonary
      arterial hypertension are lacking. The results of such studies have to confirm
      the current encouraging findings before recommendations regarding the use of PDE
      5 inhibitors as a new treatment for PH can be made.

PMID- 15194182
TI  - Interventional and surgical modalities of treatment for pulmonary arterial
      hypertension.
AB  - Beyond medical therapy, different interventional and surgical approaches exist
      for treatment of pulmonary arterial hypertension (PAH). Atrial septostomy has
      been applied in patients with lack of response to medical therapy in the absence
      of other surgical treatment options. With growing experience, procedure-related
      death rates have been reduced to 5.4%, and the most suitable patient group has
      been identified among patients with a mean right atrial pressure between 10 and
      20 mm Hg. Pulmonary endarterectomy is the accepted form of treatment for patients
      with chronic thromboembolic pulmonary hypertension. Establishing the diagnosis
      and the classification of the type of lesions by pulmonary angiography is crucial
      for optimal patient selection. Perioperative mortality rates have been reduced to
      <10% in experienced centers, and the hemodynamic improvement is dramatic and
      sustained. Lung and heart-lung transplantation remains the procedure of choice
      for patients unsuitable for other treatment modalities. Timing of the procedure
      is difficult because waiting times vary between centers and usually are in a high
      range. Early referral of patients unresponsive to other treatment forms is
      therefore of importance to avoid transplantation of patients with established
      significant comorbidity. The survival rate during the first five years after
      transplantation for PAH is intermediate among the lung diseases, lower than
      chronic obstructive pulmonary disease but higher than idiopathic pulmonary
      fibrosis.

PMID- 15194183
TI  - Comparative analysis of clinical trials and evidence-based treatment algorithm in
      pulmonary arterial hypertension.
AB  - The numerous controlled clinical trials performed recently in pulmonary arterial
      hypertension (PAH) can allow us to abandon a clinical-based treatment strategy
      and adopt an evidence-based therapy. Both uncontrolled and controlled clinical
      trials with different compounds and procedures are reviewed and compared in order
      to define the efficacy-to-side-effect ratio of each treatment. A grading system
      for the level of evidence of treatments based on the number of favorable
      controlled clinical trials performed with a given compound is adopted; a
      treatment algorithm based on the evidence derived by clinical trials is proposed.
      It includes drugs approved by regulatory agencies for the treatment of patients
      with PAH and/or drugs available on the market for other indications. The
      algorithm is restricted to patients in New York Heart Association (NYHA)
      functional class III or IV because they represent the largest population included
      in controlled clinical trials. In addition, the different treatments have been
      evaluated mainly in sporadic, idiopathic PAH and in PAH associated with
      scleroderma or to anorexigen use. Extrapolation of these recommendations to the
      other PAH subgroups should be done with caution. Oral anticoagulation is proposed
      for all patients, whereas diuretic treatment and supplemental oxygen are
      indicated in cases of fluid retention and hypoxemia, respectively. High doses of
      calcium channel blockers are indicated only in the minority of patients who are
      responders to acute vasoreactivity testing. Nonresponders to acute vasoreactivity
      testing, or responders who remain in NYHA functional class III, should be
      considered candidates for treatment with either an endothelin receptor antagonist
      or a prostanoid. Continuous intravenous administration of epoprostenol is
      proposed as rescue treatment in NYHA functional class IV patients.
      Phosphodiesterase-V inhibitors should be considered in patients who have failed
      or are not candidates to other therapies. Combination therapy can be attempted in
      selected cases. Both balloon atrial septostomy and lung transplantation are
      indicated for refractory patients or where medical treatment is unavailable.

PMID- 15194184
TI  - Pulmonary arterial hypertension: a look to the future.
AB  - The Third World Symposium on Pulmonary Arterial Hypertension served not only as a
      forum for the presentation of state-of-the art overviews of the pathobiologic and
      clinical aspects of pulmonary arterial hypertension (PAH), but also afforded an
      opportunity to the international scientific community to explore future
      directions of research and collaboration. This summary provides a brief overview
      of future directions in the field.

PMID- 15194185
TI  - Gene relics in the genome of the yeast Saccharomyces cerevisiae.
AB  - There is increasing evidence that DNA duplication is a common and ongoing process
      that plays a major role in molecular evolution of genomes and that a large
      fraction of the duplicated gene copies becomes non-functional by accumulation of
      deleterious mutations. In order to describe this phenomenon, we systematically
      searched the 6404 intergenic regions (IRs) of the genome of Saccharomyces
      cerevisiae for traces of coding sequences presenting degenerated but still
      recognizable sequence similarity with active open reading frames (5823 annotated
      ORFs). We detected a total of 124 anciently coding regions, or "gene relics",
      showing similarity to a total of 149 distinct active ORFs. This set of relics
      shows a continuum of sequence degeneration from those whose sequence is slightly
      altered compared to the functional ORF (classically defined as pseudogenes), to
      those that contains so many deleterious mutations, as to reach the limit of
      recognition. Gene relics are more concentrated in the subtelomeric regions of the
      chromosomes, reflecting the high plasticity of these regions. The presence of
      relics also revealed ancestral duplication events of chromosomal segments that
      were previously undetected. Some of these segments are intermingled with the more
      easily recognizable ancestral blocks of duplication, indicating successive
      duplication events. We present a compilation of all the data available, leading
      to a total of 278 pseudogenes in the genome of S. cerevisiae.

PMID- 15194186
TI  - The 'weighted sum of relative entropy': a new index for synonymous codon usage
      bias.
AB  - Shannon entropy from information theory has been applied to estimate the degree
      of deviation from equal usage of synonymous codons; however, previous attempts
      have failed to take into account all three aspects of amino acid usage, i.e. (i)
      the number of distinct amino acids, (ii) their relative frequencies, and (iii)
      their degree of codon degeneracy. A new index taking into account all of these
      aspects is proposed. The index, designated as the 'weighted sum of relative
      entropy' (E(w)), is defined as the sum of the relative entropy of each amino acid
      weighted by its relative frequency in the sequence. In this paper, we demonstrate
      that E(w) allows us to avoid some amino acid usage biases and can yield results
      contradictory to those obtained by previous methods.

PMID- 15194187
TI  - Two novel asparaginyl endopeptidase-like cysteine proteinases from the protist
      Trichomonas vaginalis: their evolutionary relationship within the clan CD
      cysteine proteinases.
AB  - Cysteine proteinases (CPs) are important virulence factors of the protozoan
      parasite Trichomonas vaginalis. A total of six genes coding for cathepsin L-like
      CPs belonging to clan CA have been identified in T. vaginalis. At least 23
      distinct spots with proteolytic activity have been detected by two-dimensional (2
      D) substrate gel electrophoresis from in vitro grown parasites; however, only few
      of them have been characterized. In this work, we detected six spots with
      proteolytic activity and molecular weights between 25 and 35 kDa. The six
      proteinases correspond to two distinct CP families: the papain-like family,
      represented by four spots with pIs between 4.5 and 5.5; and the legumain-like
      family represented by two spots with pI 6.3 and 6.5. Next, we obtained two cDNAs
      encoding for legumain-like CPs from T. vaginalis, which were named Tvlegu-1 and
      Tvlegu-2. The size of these cDNA clones were 1225 and 1364 bp, which encoded for
      388 and 415 amino acids, respectively. Their putative translation products have
      molecular masses of 42.8 and 47.2 kDa, corresponding to inactive legumain-like CP
      precursors. The two sequences share approximately 40% identity at the amino acid
      level. These protein products can be classified within a branch of the legumain
      like family in clan CD cysteine proteinases due to their sensitivity to specific
      proteinases inhibitors, their DNA sequences, and phylogenetic reconstruction.
      However, they do not correspond either to the typical asparaginyl endopeptidase
      or the glycosylphosphatidylinositol (GPI): protein transamidase subfamilies.
      These results suggest that the TVLEGU-1 and TVLEGU-2 peptidases are likely to be
      part of a new subfamily within the legumain-like family of clan CD cysteine
      proteinases. Furthermore, they could be one of the missing links between
      prokaryotic and eukaryotic CPs in clan CD enzymes.

PMID- 15194188
TI  - Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C
      G-protein-coupled receptor.
AB  - By similarity searching of the human genome sequence using known family C G
      protein-coupled receptors (GPCRs) as query sequences, we have identified a
      putative novel human gene product of unknown function (located on chromosome band
      6q22.31). The transcript, entitled GPRC6A (isoform 1), was cloned from a human
      kidney cDNA (DNA complementary to RNA) library and shown to encode a protein of
      926 amino acids (aa). Protein sequence analysis revealed the presence of a seven
      transmembrane (7TM) domain and an unusually long amino-terminal domain (ATD) of
      590 amino acids. These traits, along with a significant homology to the human
      calcium-sensing receptor (CaR, 34% aa sequence identity), the taste receptor 1
      (T1R1, 28%), and the metabotropic glutamate receptor 1 (mGluR1, 24%), places
      GPRC6A in family C of the GPCRs. Interestingly, GPRC6A bears the highest
      resemblance with an odorant goldfish 5.24 receptor (45%) which suggests that
      GPRC6A is the human orthologue of this receptor. GPRC6A is widely expressed in
      brain and peripheral tissues with highest levels in kidney, skeletal muscle,
      testis, and leucocytes. All three isoforms are expressed in mammalian cells, but
      are poorly expressed on the cell surface. In this work, we report the existence
      of two additional GPRC6A isoforms (2 and 3) carrying in-frame deletions in the
      ATD. Except for the kidney, where isoforms 1 and 2 appear equally expressed,
      isoforms 2 and 3 are generally less abundant than isoform 1. Analysis of the
      intron-exon composition of the GPRC6A gene confirms that isoforms 2 and 3 are
      naturally occurring splice variants.

PMID- 15194189
TI  - Isolation of eight novel Caenorhabditis elegans small RNAs.
AB  - Eight novel small RNAs that were encoded in the regions corresponding to the
      introns of protein-coding genes were isolated from Caenorhabditis elegans. Seven
      of them showed a typical snoRNA secondary structure: one C/D snoRNA and six H/ACA
      snoRNAs. The remaining one RNA did not show any homology to other RNAs in a
      database. Four of the seven isolated snoRNAs could form base pairings with parts
      of rRNAs, suggesting that they are potential pseudouridilation sites and
      methylation sites. The results of our study suggest that there are more as-yet
      unidentified small ncRNAs of which genes are located in the intron regions of
      protein-coding genes in C. elegans.

PMID- 15194190
TI  - Evolution of tRNA-like sequences and genome variability.
AB  - Transfer RNA (tRNA)-like sequences were searched for in the nine basic taxonomic
      divisions of GenBank-121 (viruses, phages, bacteria, plants, invertebrates,
      vertebrates, rodents, mammals, and primates) by an original program package
      implementing a dynamic profile alignment approach for the genetic texts'
      analysis, in using 22 profiles of tRNAs of different isotypes. In total, 175,901
      previously unknown tRNA-like sequences were revealed. The locations of the tRNA
      likes were considered over the regions whose functional meaning is described by
      standard Feature Keys in GenBank. Many regions containing the tRNA-like sequences
      were recognized as known repeats. A mode of distribution of the tRNA-like
      sequences in a genome was proposed as expansion in a content of the various
      transposable elements. An analysis of the integrity of RNA polymerase III inner
      promoters in the tRNA-like sequences over the GenBank divisions has shown a high
      possibility of generating new copies of short interspersed nuclear element (SINE)
      repeats in all divisions, excepting primates. The numerous tRNA-likes found in
      the regions of RNA polymerase II promoters have suggested an adaptation of RNA
      polymerase III promoter to a binding of RNA polymerase II.

PMID- 15194191
TI  - Evolution of bacterial RNA polymerase: implications for large-scale bacterial
      phylogeny, domain accretion, and horizontal gene transfer.
AB  - Comparative analysis of the domain architectures of the beta, beta', and
      sigma(70) subunits of bacterial DNA-dependent RNA polymerases (DdRp), combined
      with sequence-based phylogenetic analysis, revealed a fundamental split among
      bacteria. DNA-dependent RNA polymerase subunits of Group I, which includes
      Proteobacteria, Aquifex, Chlamydia, Spirochaetes, Cytophaga-Chlorobium, and
      Planctomycetes, are characterized by three distinct inserts, namely a Sandwich
      Barrel Hybrid Motif domain in the beta subunit, a beta-beta' module (BBM) 1
      domain in the beta' subunit, and a distinct helical module in the sigma subunit.
      The DdRp subunits of remaining bacteria, which comprise Group II, lack these
      inserts, although some additional inserted domains are present in individual
      lineages. The separation of bacteria into Group I and Group II is generally
      compatible with the topologies of phylogenetic trees of the conserved regions of
      DdRp subunits and concatenated ribosomal proteins and might represent the primary
      bifurcation in bacterial evolution. A striking deviation from this evolutionary
      pattern is Aquifex whose DdRp subunits cluster within Group I, whereas
      phylogenetic analysis of ribosomal proteins identifies Aquifex as grouping with
      Thermotoga another bacterial hyperthemophile belonging to Group II. The inferred
      evolutionary scenario for the DdRp subunits includes domain accretion and
      rearrangement, with some likely horizontal transfer events. Although evolution of
      bacterial DdRp appeared to be generally dominated by vertical inheritance,
      horizontal transfer of complete genes for all or some of the subunits, resulting
      in displacement of the ancestral genes, might have played a role in several
      lineages, such as Aquifex, Thermotoga, and Fusobacterium.

PMID- 15194192
TI  - Genomic organization and developmental expression of globin genes in the teleost
      Oryzias latipes.
AB  - We isolated globin genes from a genomic DNA library of the drR strain of medaka
      Oryzias latipes, and walked on chromosome. The present study is the first
      demonstration of the full-length structure of globin gene locus in the teleosts.
      Two gene clusters were found. One cluster of 36 kbp consisted of nine globin
      genes and two pseudogenes. Based on structural and phylogenetic similarity of
      amino acid sequences, the cluster was named embryonic globin gene cluster (E1).
      The orientation of the genes was in (5')alpha0(3')-(3')beta1(5')-(5')alpha1(3')
      (5')beta2(3')-(5')alpha2(3')-(3')alpha3(5')-(5')beta3(3')-(3')beta4(5')
      (5')alpha4(3')-(3')psialpha(5')-(5')psibeta(3'). The other cluster of 20 kbp
      contained three globin genes ((3')ad.alpha1(5')-(5')ad.beta1(3')
      (3')ad.alpha2(5')), and was named adult globin gene cluster (A1). Genetic linkage
      analysis clarified that E1 and A1 were mapped on linkage groups 8 and 19,
      respectively. The E1 cluster included other genes homologous to human EST clone
      KIAA0172, Sushi-1 retrotransposon, and protein 14 gene-like gene, while the A1
      cluster linked to aquaporin-8 gene-like gene. The expression patterns of the
      genes were classified into four types: embryo-specific expression (alpha3, beta3,
      alpha4 and beta4), expression in embryo to young fish (alpha0, beta1, alpha1 and
      ad.alpha2), expression in young to adult fish (alpha2 and ad.alpha1) and
      successive expression in embryo to adult (ad.beta1).

PMID- 15194193
TI  - TAIL1: an isthmin-like gene, containing type 1 thrombospondin-repeat and AMOP
      domain, mapped to ARVD1 critical region.
AB  - Isthmins represent a novel family of vertebrate secreted proteins containing one
      copy of the thrombospondin type 1 repeat (TSR), which in mammals is shared by
      several proteins with diverse biological functions, including cell adhesion,
      angiogenesis, and patterning of developing nervous system. We have determined the
      genomic organization of human TAIL1 (thrombospondin and AMOP containing isthmin
      like 1), a novel isthmin-like gene encoding a protein that contains a TSR and a C
      terminal AMOP domain (adhesion-associated domain in MUC4 and other proteins),
      characteristic of extracellular proteins involved in adhesion processes. TAIL1
      gene encompasses more than 24.4 kb. Analysis of the DNA sequence surrounding the
      putative transcriptional start region revealed a TATA-less promoter located in a
      CpG island. Several consensus binding sites for the transcription factors Sp1 and
      MZF-1 were identified in this promoter region. In humans, TAIL1 gene is located
      on chromosome 14q24.3 within ARVD1 (arrhythmogenic right ventricular
      dysplasia/cardiomyopathy, type 1) critical region; preliminary evidence suggests
      that it is expressed in several tissues, showing multiple alternative splicing.

PMID- 15194194
TI  - Cloning, genomic organization, alternative splicing and expression analysis of
      the human gene WNK3 (PRKWNK3).
AB  - We report the isolation of a full length coding WNK3 cDNA from human fetal brain.
      The WNK3 transcript has an open reading frame of 5403 nucleotides and encodes a
      putative protein of 1800 amino acids. The human WNK3 gene comprises 24 exons and
      lies within a 559 kb genomic segment on chromosome Xp11.22 which has conserved
      synteny with a 705 kb genomic segment of human chromosome 9q22.31 which contains
      WNK2. The WNK3 transcript is expressed in several human fetal and adult tissues
      and has at least two splice isoforms generated by the alternative splicing of
      exon 18 and exon 22 which maintain the open reading frame. Usage of exon 18b is
      restricted to brain and introduces an additional 47 amino acids into the
      predicted protein. The predicted WNK3 protein has a similar structural
      organization to the other human WNK kinases. Significant homology between these
      proteins is confined to three conserved regions of their amino acid sequences
      which we have designated CR1, CR2 and CR3. CR1 and CR3 contain highly conserved
      residues which have been shown to be important for the normal function of WNK1
      and WNK4, and CR2 contains a highly conserved 22 amino acid motif specific to
      chordate species. WNK3 lies within the critical linkage interval for several
      human monogenic disorders, including X-linked mental retardation. The function of
      mammalian WNK3 kinase remains to be investigated.

PMID- 15194195
TI  - Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and
      B.
AB  - Members of the killer immunoglobulin (Ig)-like receptor (KIR) gene family are
      tightly clustered on human chromosome 19q13.4. Despite considerable variation in
      KIR gene content and allelic polymorphism, most KIR haplotypes belong to one of
      two broad groups termed A and B. The availability of contiguous genomic sequences
      for these haplotypes has allowed us to compare their genomic organization,
      nucleotide (nt) diversity and reconstruct their evolutionary history. The
      haplotypes have a framework of three conserved blocks containing (i) KIR3DL3,
      (ii) KIR3DP1, 2DL4, and (iii) KIR3DL2 that are interrupted by two variable
      segments that differ in the number and type of KIR genes. Low (0.05%) nucleotide
      diversity was detected across the centromeric and telomeric boundaries of the KIR
      gene cluster while higher SNP density (0.2%) occurred within the central region
      containing the KIR2DL4 gene. Phylogenetic and genomic analyses have permitted the
      reconstruction of a hypothetical ancestral haplotype that has revealed common
      groupings and differences between the KIR genes of the two haplotypes. The
      present phylogenetic and genomic comparison of the two sequenced KIR haplotypes
      provides a framework for a more thorough examination of KIR haplotype variations,
      diversity and evolution in human populations and between humans and non-human
      primates.

PMID- 15194196
TI  - NOX-2S is a new member of the NOX family of NADPH oxidases.
AB  - A novel isoform of the NOX-2 subunit of nicotinamide adenine dinucleotide
      phosphate (NADPH) oxidase has been identified using expressed sequence tag (EST)
      database mining. The novel isoform, NOX-2S, is a splice variant of NOX-2 and
      includes a previously unidentified exon, mapped 6.4 kb downstream of exon III,
      and encodes an in-frame stop codon generating a predicted truncated protein of
      approximately 12.7 kDa, the smallest reported member of the NOX family. Thus, NOX
      2S is predicted to have only two transmembrane domains, however, the new C
      terminal sequence includes two new potential protein kinase C (PKC)
      phosphorylation sites. Expression of NOX-2S mRNA was detected in many mouse
      tissues, and several human cell lines including the myeloid cell line HL-60, and
      the B cell line Ramos, indicating that the splice variant is conserved in mouse
      and man. NOX-2S is found co-expressed together with NOX-2 in all of the tissues
      and cells under investigation, both nonphagocytic and phagocytic. Induction of
      the myeloid cell line HL-60 into the neutrophil phagocytic lineage by dimethyl
      sulphoxide (DMSO), led to a marked increase in NOX-2S and NOX-2 expression in the
      myelocyte rather than promyelocyte stages of differentiation. Furthermore, in the
      B-cell line Ramos, differentiated with the cytokine interferon-gamma (IFN-gamma),
      splicing was altered to increase NOX-2S mRNA generation over NOX-2. Here we have
      identified NOX-2S, the first reported normally occurring splice variant of NOX-2.
      The sequence identity between mouse and human NOX-2S strongly implies
      conservation in function and possibly a role for NOX-2S in the regulation of
      NADPH oxidase activity.

PMID- 15194197
TI  - Genomic structure and differential expression of two tandem-arranged GSTZ genes
      in rice.
AB  - Glutathione S-transferases (GSTs) are scavenging enzymes that detoxify cellular
      xenobiotics and toxins by catalyzing the conjugation of these substrates with a
      tripeptide glutathione. GSTs are classified depending on gene organization and
      sequence similarity. The sequence analysis of genomic DNA for zeta class GST
      (GSTZ) locus in rice indicated that two homologous GSTZ genes lay in a tandem
      orientation with a short (0.4 kb) intergenic spacer. The upstream OsGSTZ1 and
      downstream OsGSTZ2 spanned 3.5 and 3.2 kb with nine coding exons, respectively.
      The transcript of OsGSTZ1 had a long 3' untranslated region (3' UTR) that was
      mostly encoded by a 10th noncoding exon, whereas OsGSTZ2 mRNA contained a long 5'
      UTR. Northern blot analysis showed that OsGSTZ1/2 messages were strongly
      expressed in leaf blades, while transcripts from roots were low level. Because
      OsGSTZ1/2 messages in leaf tissues were strongly induced only by water treatment,
      it was difficult to assay for the induction of OsGSTZ1/2 transcripts by various
      stress treatments. Thus, using rice culture cells, we analyzed the respective
      responses of OsGSTZ1 and OsGSTZ2 genes against various treatments by real-time
      reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that
      OsGSTZ1 was expressed at a level ca. 1000-fold higher than OsGSTZ2 in suspension
      cells without stress treatment. OsGSTZ1 was expressed constitutively under
      various stress conditions. In contrast, the expression of OsGSTZ2 gene was
      strongly enhanced to 30-fold by treatment with jasmonic acid. These observations
      suggested that the expression of OsGSTZ1 and OsGSTZ2 genes are differentially
      regulated in the culture cell of rice.

PMID- 15194198
TI  - Comparative analysis of the PDCD2-TBP-PSMB1 region in vertebrates.
AB  - Three orthologous genes encoding programmed cell death 2 (PDCD2), TATA-binding
      protein (TBP), and proteasomal subunit C5 (PSMB1) proteins have been shown
      previously to be nonrandomly distributed in both mammalian and invertebrate
      genomes. Here we analyze a conserved synteny of the PDCD2, TBP, and PSMB1
      orthologs in four nonmammalian vertebrates. Homologous genes of the chicken,
      zebrafish, fugu, and Tetraodon nigroviridis were identified. A chicken cosmid
      harboring the orthologs of these three genes was completely sequenced. The fish
      genes were analyzed in silico. In all seven vertebrates thus far investigated,
      the PDCD2 and TBP genes are located tail-to-tail. In six tested species but the
      zebrafish, the PSMB1 gene mapped head-to-head or in the close vicinity to the
      TBP, but even in the zebrafish, all three genes were syntenic. In contrast, a
      three times reused synteny breakpoint in the 5'-region from PDCD2 was detected. A
      comparative analysis revealed the distribution of putative matrix-attached
      regions (MARs), which may affect the synteny conservation.

PMID- 15194199
TI  - Genomic organization and expression analysis of the murine Fam3c gene.
AB  - Previously, we identified FAM3C as a candidate gene for autosomal recessive
      nonsyndromic hearing loss locus 17 (DFNB17). This gene has since been found to be
      a member of a cytokine-like gene family, but its function has not been
      determined. The purpose of this study was thus to elucidate the gene structure
      and pattern of expression, providing information that might allow a hypothesis to
      be developed about FAM3C function of in the inner ear. To do this we analyzed its
      mouse ortholog, Fam3c. Fam3c was found to be ubiquitously expressed in all
      analyzed tissues, and had two major transcript variants presumed to result from
      an alternative use of two distinct polyadenylation signals. In situ hybridization
      experiments revealed a predominant Fam3c pattern of expression in the nonsensory
      epithelium of the growing semicircular canals at embryonic day (E) 15.5. This
      expression pattern resembles the known pattern of the Nkx5 homeobox genes.
      Analysis of the Fam3c promoter region demonstrated a putative Nkx5.1 binding
      site. Based on our findings, we hypothesize that Fam3c may be a downstream target
      gene for the Nkx5.1 transcription factor, and may thus be involved in cell
      differentiation and proliferation during inner ear embryogenesis. Additionally,
      analyses of putative amino acid sequences of FAM3C orthologous proteins showed
      that their primary and secondary structures and overall topology were highly
      conserved. Further study is underway to determine the role of FAM3C in inner ear
      development.

PMID- 15194200
TI  - The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United
      States, 1991-1992 and 2001-2002.
AB  - BACKGROUND: Alcohol abuse and dependence can be disabling disorders, but accurate
      information is lacking on the prevalence of current DSM-IV alcohol abuse and
      dependence and how this has changed over the past decade. The purpose of this
      study was to present nationally representative data on the prevalence of 12-month
      DSM-IV alcohol abuse and dependence in 2001-2002 and, for the first time, to
      examine trends in alcohol abuse and dependence between 1991-1992 and 2001-2002.
      METHODS: Prevalences and trends of alcohol abuse and dependence in the United
      States were derived from face-to-face interviews in the National Institute on
      Alcohol Abuse and Alcoholism's (NIAAA) 2001-2002 National Epidemiologic Survey on
      Alcohol and Related Conditions (NESARC: n = 43, 093 ) and NIAAA's 1991-1992
      National Longitudinal Alcohol Epidemiologic Survey (NLAES: n= 42, 862 ). RESULTS:
      Prevalences of DSM-IV alcohol abuse and dependence in 2001-2002 were 4.65 and
      3.81%. Abuse and dependence were more common among males and among younger
      respondents. The prevalence of abuse was greater among Whites than among Blacks,
      Asians, and Hispanics. The prevalence of dependence was higher in Whites, Native
      Americans, and Hispanics than Asians. Between 1991-1992 and 2001-2002, abuse
      increased while dependence declined. Increases in alcohol abuse were observed
      among males, females, and young Black and Hispanic minorities, while the rates of
      dependence rose among males, young Black females and Asian males. CONCLUSIONS:
      This study underscores the need to continue monitoring prevalence and trends and
      to design culturally sensitive prevention and intervention programs.

PMID- 15194201
TI  - Dependent and problem drinking over 5 years: a latent class growth analysis.
AB  - Understanding the long-term course of problematic drinking is a fundamental
      concern for health services research in the alcohol field. The stability of, or
      change in, the course of drinking--especially heavy drinking--has both
      theoretical and applied relevance to alcohol research. We explore the application
      of latent class growth modeling to 5 years of survey data collected from
      dependent and problem drinkers--some not in treatment at baseline--in an attempt
      to uncover prototypical longitudinal drinking patterns. Results indicated that
      five profiles of drinkers can be used to represent their longitudinal course of
      alcohol consumption: early quitters (N = 88), light/non-drinkers (N = 76),
      gradual improvers (N = 129), moderate drinkers (N = 229), and heavy drinkers (N =
      572). Significant baseline factors included ASI drug severity, dependence
      symptoms, and marital status. Attendance at AA meetings, the size of one's heavy
      drinking and drug using social network, past treatment, receiving suggestions
      about one's drinking, and contacts with the medical system were significant
      influences. The size of heavy drinking and drug using social networks was
      noticeably larger for the heavy drinkers. Findings also support the usefulness of
      a semi-parametric latent group-based approach as a tool for analyzing alcohol
      related behaviors.

PMID- 15194202
TI  - Psychosocial profiles of older adolescent MDMA users.
AB  - PURPOSE: Using a case-control design, patterns of drug use, psychological
      symptoms, and behavioral characteristics associated with 3,4
      methylenedioxymethamphetamine (MDMA ) use were surveyed in a sample of older
      adolescents (median age 20). METHODS: One hundred (42 MDMA users; 58 non-MDMA
      users) older adolescents were recruited using the "snowball" technique and
      interviewed regarding their use of MDMA and other drugs. The Brief Symptom
      Inventory (BSI), the Problem Oriented Screening Instrument for Teenagers (POSIT),
      the HIV/sexually transmitted diseases (STD) risk scale, and the Childhood Trauma
      Questionnaire (CTQ) were also administered. RESULTS: MDMA users were more likely
      to use other substances, endorse more symptoms of psychological distress, and had
      more problems in functional lifestyle areas. They also reported more childhood
      experiences of physical abuse, emotional neglect, and physical neglect than non
      MDMA users. MDMA users also reported more sexually risky behaviors. CONCLUSIONS:
      Occasional MDMA use among older adolescents was associated with polydrug use,
      multiple social difficulties, psychological symptoms, and health risk behaviors.
      Further research is warranted to understand the long term psychosocial
      consequences of chronic MDMA and polydrug usage.

PMID- 15194203
TI  - Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum,
      denicotinized cigarettes, and nicotine-containing cigarettes.
AB  - Both pharmacological and nonpharmacological stimuli may be responsible for the
      reinforcement and maintenance of tobacco smoking. The present study examined the
      self-administration of nicotine gum, denicotinized cigarettes, and nicotine
      containing cigarettes utilizing a behavioral economic design in order to
      investigate the pharmacological and nonpharmacological aspects of cigarette
      smoking. Cigarette-deprived, dependent smokers worked for cigarette puffs and
      nicotine gum in daily operant sessions. In one phase, nicotine-containing
      cigarettes were available at increasing unit prices across sessions. Three phases
      replicated these sessions with nicotine gum, denicotinized cigarettes, or both,
      concurrently available at a constant unit price. As nicotine-containing cigarette
      unit price increased, consumption decreased. However, as nicotine-containing
      cigarette unit price increased, nicotine gum and denicotinized cigarette
      consumption increased. Consumption of nicotine gum, but not denicotinized
      cigarettes, diminished when all three reinforcers were concurrently available.
      Concurrently available denicotinized cigarettes, but not nicotine gum, caused a
      statistically significant reduction in nicotine-containing cigarette consumption.
      In another phase, denicotinized cigarettes were available at increasing unit
      prices across sessions while nicotine gum was concurrently available at a
      constant unit price. This phase demonstrated that nicotine content had no
      reliable effect on cigarette or nicotine gum consumption. These results suggest
      that denicotinized cigarettes are a more effective alternative reinforcer than
      nicotine gum, indicating that nonpharmacological stimuli of smoking merit
      attention in smoking cessation treatment. Furthermore, these findings indicate
      that alternative reinforcement would be most effective in smoking cessation
      treatment when combined with high prices for cigarettes.

PMID- 15194204
TI  - Opioid-, cannabis- and alcohol-dependent women show more rapid progression to
      substance abuse treatment.
AB  - Alcohol-dependent women progress faster from onset of alcohol drinking to entry
      into treatment, experiencing an earlier onset (i.e., "telescoping") of alcohol
      related complications. This phenomenon also appears to be evident in drug
      dependent women, though the data available to support telescoping in drug
      dependence is less abundant. OBJECTIVE: To evaluate gender effects on progression
      to treatment entry and on the frequency, severity and related complications of
      DSM-III-R drug and alcohol dependence among 271 substance-dependent patients
      (mean age: 32.6 years; 156 women). METHOD: Multivariate and univariate ANCOVA was
      used to compare age at onset of regular use of cocaine, opioids, cannabis and
      alcohol and time elapsed between initiation of regular use of each substance and
      entry into an index or current substance abuse treatment. Scores on the Addiction
      Severity Index (ASI) were also examined. RESULTS: There was no gender difference
      among patients in the age at onset of regular use of any substance. Women
      experienced fewer years of regular use of opioids and cannabis, and fewer years
      of regular alcohol drinking before entering treatment. Although the severity of
      drug and alcohol dependence did not differ by gender, women reported more severe
      psychiatric, medical and employment complications. CONCLUSIONS: These findings
      support the notion of an accelerated progression to treatment entry among opioid
      , cannabis- and alcohol-dependent women, and suggest that there exists a gender
      based vulnerability to the adverse consequences of these disorders.

PMID- 15194205
TI  - The use of biological laboratory markers in the diagnosis of alcohol misuse: an
      evidence-based approach.
AB  - BACKGROUND: A large number of patients seen in clinical practice have an
      underlying alcohol problem. There is a pressing need for accurate methods to
      diagnose alcohol over-consumption objectively. Our aim was to determine how best
      to use biological markers to objectify alcohol problems in patients with clinical
      suspicion of alcohol misuse. METHODS: A 6-month longitudinal multicenter trial
      was conducted, using four study groups (alcohol abusers, alcohol-dependents,
      healthy controls and consulting controls). CDT, GGT and MCV were measured.
      Statistical analyses used a computer learning system that created classification
      systems displayed in decision trees. RESULTS: In 379 subjects the marker that
      best discriminated those with alcohol problems from controls was CDT. GGT then
      helped to differentiate between alcohol abuse and alcohol dependence in cases of
      high CDT. MCV, age and gender provided no extra information. DISCUSSION: We
      recommend CDT as a first-line biological marker to confirm or disprove suspected
      alcohol misuse. High CDT plus GGT above normal points to alcohol dependence,
      while high CDT plus GGT below normal is evidence of alcohol abuse.

PMID- 15194206
TI  - Comparison of the discriminative stimulus effects of 3,4
      methylenedioxymethamphetamine (MDMA) and cocaine: asymmetric generalization.
AB  - Evidence suggests that +/- 3,4-methylenedioxymethamphetamine (MDMA) and
      psychostimulants produce similar but non-identical stimulus effects in animals.
      To examine this hypothesis, groups of rats were trained to discriminate either
      MDMA (1.5 mg/kg) or cocaine (8 mg/kg) from saline vehicle using a two-lever
      operant procedure under a variable interval (VI) 15 s schedule of reinforcement.
      Once the animals were trained, tests of stimulus generalization were conducted
      with +/- MDMA, cocaine, S+ MDMA, and R- MDMA. As previously demonstrated, both S+
      MDMA and R- MDMA (ED50 = 0.8 and 1.2 mg/kg, respectively) substituted for +/-
      MDMA. Stimulus generalization also occurred upon administration of cocaine (ED50
      = 4.6 mg/kg) to the +/- MDMA-trained animals. In the cocaine-trained animals,
      however, stimulus generalization did not occur to +/- MDMA, S+ MDMA nor R- MDMA.
      Receptor binding profiles for MDMA and cocaine were compared in an effort to
      identify any novel and common receptor-based mechanism(s) to explain stimulus
      generalization of MDMA-trained animals to the effects of cocaine, but only their
      actions on neurotransmitter transporters seem applicable. Taken together, the
      results indicate that stimulus substitution between MDMA and cocaine is
      asymmetric and suggest that although similarities exist between the stimulus
      actions of MDMA and cocaine, differences might be explained by their differential
      effects on increasing synaptic concentrations of serotonin (5-HT), dopamine (DA),
      and/or norepinephrine (NE).

PMID- 15194207
TI  - Effectiveness of a brief-intervention and continuity of care in enhancing
      attendance for treatment by adolescent substance users.
AB  - AIMS: To evaluate the effectiveness of a brief intervention enhanced by a
      consistent support person in facilitating attendance for substance use treatment
      following a hospital alcohol or other drug (AOD) presentation. PARTICIPANTS: We
      recruited 127 adolescents (aged 12-19 years) from hospital emergency departments,
      57 were female. Sixty were randomly assigned to receive the intervention and 67
      to receive standard hospital care. For the purpose of comparison, normative data
      were also collected (at baseline) from 122 non-AOD presenting adolescents.
      INTERVENTION: The brief intervention involved identifying impediments to
      treatment service attendance and facilitating attendance via a consistent support
      person. RESULTS: At 4 months, a significantly greater proportion of the
      intervention group, both daily and "occasional" drug users, had attended
      treatment than the usual care group. Regardless of attendance at the treatment
      service the intervention group showed a greater improvement in GHQ-12 scores than
      the usual care group. Across groups, a greater proportion of those who attended
      treatment moved to "safer" drug use behaviour (non-hazardous alcohol consumption
      and/or non-injecting drug use (IDU)), and showed a greater decline on a composite
      total drug use score. CONCLUSIONS: Adolescent attendance for treatment can be
      improved by brief intervention with harmful substance use behaviours reduced for
      both "occasional" and daily users. Improvements in psychosocial well-being is
      observed regardless of attendance at a treatment service.

PMID- 15194208
TI  - Effects of chronic methadone treatment on cocaine- and food-maintained responding
      under second-order, progressive-ratio and concurrent-choice schedules in rhesus
      monkeys.
AB  - The effects of chronic infusion with saline or methadone (0.032-1.0 mg/kg/h) were
      examined on cocaine- and food-maintained responding in rhesus monkeys using three
      procedures. In one procedure, cocaine injections (0.0032-0.032 mg/kg per
      injection) and food pellets were available under a second-order schedule during
      alternating daily sessions. During saline treatment, cocaine maintained a dose
      dependent increase in the number of cocaine injections per day, and monkeys
      usually responded for the maximum number of pellets. Methadone dose-dependently
      decreased cocaine self-administration, and methadone doses that decreased cocaine
      self-administration had variable effects on food-maintained responding. In the
      second procedure, 0.032 mg/kg per injection cocaine or food pellets were
      available under a progressive-ratio schedule. During saline treatment, cocaine
      and food maintained similar break points. Methadone produced a dose-dependent and
      non-selective decrease in break points maintained by both cocaine and food. In
      the third procedure, cocaine injections (0-0.1 mg/kg per injection) and food
      pellets were available under a concurrent-choice schedule. During saline
      treatment, increasing unit doses of cocaine produced a dose-dependent increase in
      cocaine choice. Methadone had little effect on the cocaine choice dose-effect
      curve up to doses that eliminated responding. These results provide little
      evidence to suggest that chronic methadone altered the reinforcing effects of
      cocaine; rather methadone appeared to non-selectively decrease rates of operant
      responding.

PMID- 15194209
TI  - Impairment due to intake of carisoprodol.
AB  - BACKGROUND: Carisoprodol is a centrally acting muscle relaxant commonly used for
      lower back pain. It is a drug of abuse and has been detected among impaired
      drivers. Carisoprodol's active metabolite meprobamate is thought to act through
      the GABA(A) receptor complex and produces a well-known impairing effect. It is
      unclear whether therapeutic intake of carisoprodol leads to impairment, and the
      effect of supratherapeutic doses has not been investigated. Possible impairment
      could further be a product of the parent drug and/or the metabolite meprobamate.
      The present study aimed to investigate if carisoprodol had an impairing effect by
      it self. METHODS: From the database at the Norwegian Institute of Public Health,
      Division for Forensic Toxicology and Drug Abuse 62 cases containing carisoprodol
      and meprobamate as only drugs were identified. These cases constituted our
      material. RESULTS: Impaired drivers (73%) had higher blood carisoprodol
      concentration than not impaired drivers (27%), but no difference in blood
      meprobamate concentration was found for all the drivers viewed together. Amongst
      occasional users of carisoprodol, however, there was difference in blood
      meprobamate concentration between not impaired and impaired drivers. The risk of
      being judged impaired rose with increasing blood carisoprodol concentration, but
      not with increasing blood meprobamate concentration. The clinical effects of
      carisoprodol as measured by the clinical test for impairment (CTI) resembled
      those of benzodiazepines with some important differences such as tachycardia,
      involuntary movements, hand tremor and horizontal gaze nystagmus, which may be
      specific carisoprodol effects. CONCLUSION: Carisoprodol probably has an impairing
      effect by itself, at least at blood concentration levels above which can be seen
      after therapeutic intake of the drug.

PMID- 15194210
TI  - Evaluation of a modified contingency management intervention for consistent
      attendance in therapeutic workplace participants.
AB  - In a therapeutic workplace business, drug abuse patients are hired as data entry
      operators and paid to perform data entry work contingent upon documented drug
      abstinence. Reliable attendance has been difficult to maintain despite the
      opportunity for operators to earn a living wage, 6 h per day, 5 days per week. A
      within-subject reversal design experiment evaluated a contingency management
      intervention that allowed for flexibility regarding when operators could arrive
      to work, yet maintained a contingency for reliable workplace attendance. Results
      from a within-subject reversal design experiment demonstrated the contingency
      management intervention to be effective in increasing the frequency of completed
      work shifts in four of five operators. Repeated measures ANOVA and Tukey's post
      hoc tests of grouped data showed that the contingency management intervention
      significantly (P < 0.05) increased the mean percent of days that operators
      completed work shifts (5% baseline; 63% contingency management; 7% baseline).
      This study demonstrates an effective procedure for maintaining attendance in
      therapeutic workplace participants.

PMID- 15194211
TI  - Effects of estrogens and metabolites on endometrial carcinogenesis in young adult
      mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine.
AB  - The present study assessed effects of estrogens and their steroid metabolites on
      the endometrial carcinogenesis in young adult mice initiated with N-ethyl-N'
      nitro-N-nitrosoguanidine (ENNG). A total of 272 female CD-1 (ICR) mice were used
      and equally divided into 17 groups. Mice were implanted cholesterol pellets to
      the back subcutis at 9 weeks of age. Pellets contained nothing (control) or one
      of the experimental agents, three different estrogens and their 13 different
      steroid metabolites, at a concentration of 0.5% (w/w). At 10 weeks of age, mice
      were given a single intra-uterine administration of ENNG at a dose of 25 mg/kg
      body weight. When reaching the 30 weeks of age (20 weeks after the ENNG
      treatment), mice were sacrificed to assess the development of endometrial
      proliferative lesions. While endometrial proliferative lesions, including
      hyperplasias and adenocarcinomas, were observed in all groups, the incidences of
      hyperplasias in the groups treated with 2-hydroxyestriol, 2-methoxyestradiol, 2
      methoxyestriol and 16-epiestriol were significantly higher than that in the
      control group. On the other hand, adenocarcinomas were significantly developed in
      the groups treated with estrone, estradiol, estriol, 16beta-hydroxyestrone,
      16alpha-hydroxyestrone and 17-epiestriol. These results indicate that, on the
      endometrial carcinogenesis in mice initiated with ENNG, estrogens and their
      metabolites belonging to the 16alpha-hydroxylation pathway and the upstream of
      the 16beta-hydroxylation pathway exert both promoting and progressing effects,
      whereas, the estrogen metabolites belonging to the 2- and 4-hydroxylation
      pathways (catechol estrogens) and the downstream of the 16beta-hydroxylation
      pathway exert only promoting or no effects. It is thus suggested that a metabolic
      profile of estrogens may be crucial for the endometrial carcinogenesis and that
      the rate of the 16alpha-hydroxylation may be associated with the increased
      carcinogenic risks of estrogens on the endometrium.

PMID- 15194212
TI  - V-val subtype of Epstein-Barr virus nuclear antigen 1 preferentially exists in
      biopsies of nasopharyngeal carcinoma.
AB  - Epstein-Barr virus (EBV) has been suggested to be involved in pathogenesis of
      nasopharyngeal carcinoma (NPC). However, EBV infection is ubiquitous, whereas NPC
      occurs with strong geographic and racial distribution. Whether a substrain of EBV
      contributes to this phenomenon remains uncertain. Epstein-Barr virus nuclear
      antigen 1 (EBNA-1) is one of the most frequently detected EBV proteins in NPC
      tissues. Based on the polymorphism of amino acids at position 487, EBNA-1 is
      classified into five subtypes: P-ala, P-thr, V-val, V-leu and V-pro. To examine
      the relationship between subtypes of EBNA-1 and NPC, we determined the subtypes
      of EBNA-1 in biopsies of NPC, peripheral blood lymphocytes (PBL), and throat
      washings (TWs) obtained in endemic and non-endemic areas of NPC within China. The
      results revealed that V-val was the only subtype detected in NPC tissue, whereas
      three subtypes of EBNA-1, V-val, P-ala, and P-thr, were detected in PBL and TWs
      irrespective of origin, and mixed infection of V-val and P-ala was also observed.
      In addition, the variations of V-val derived from biopsies of NPC were identical
      to those derived from PBL and TWs in the context of N-terminus and C-terminus of
      EBNA-1. These facts indicate that a substrain of EBV with V-val subtype of EBNA-1
      infects NPC preferentially and a susceptibility to a particular EBV isolate in
      the nasopharynx may exist during development of NPC.

PMID- 15194213
TI  - Association of matrix metalloproteinase (MMP)-1 promoter polymorphism with head
      and neck squamous cell carcinoma.
AB  - To explore the relation of the MMP-1 1G/2G and MMP-3 5A/6A promoter polymorphisms
      with head and neck squamous cell carcinoma (HNSCC), DNA specimens extracted from
      peripheral blood cells of HNSCC patients and healthy controls were genotyped. The
      frequency of the MMP-1 2G/2G genotype was significantly higher in HNSCC patients
      (n = 140) than in age- and sex-matched controls (n = 223) (P = 0.042; OR, 1.56).
      In the MMP-3 polymorphism, there was no significant difference in the genotype
      distribution between patients and controls. These data suggest that the MMP-1
      promoter polymorphism may be associated with HNSCC.

PMID- 15194214
TI  - Upregulation of connexin 43 protein expression and increased gap junctional
      communication by water soluble disodium disuccinate astaxanthin derivatives.
AB  - Carotenoids are plant pigments whose consumption is associated with lower cancer
      rates in humans. Studies in experimental animal and cell systems have confirmed
      the cancer chemopreventive activity of these compounds. However, their extremely
      hydrophobic nature makes these compounds biologically unavailable unless
      delivered in organic solution to model systems. We have synthesized novel
      disodium salt disuccinate astaxanthin derivatives that possess high aqueous
      dispersibility. When delivered to mouse embryonic fibroblast C3H/10T1/2 cell
      cultures, either in aqueous or aqueous/ethanol solutions, these derivatives are
      biologically active. Biological activity was demonstrated by (1) upregulated
      expression of connexin 43 (Cx43) protein; (2) increased formation of Cx43
      immunoreactive plaques in regions of the plasma membrane consistent with
      localization of gap junctions; (3) significantly upregulated gap junctional
      intercellular communication (GJIC) as demonstrated by Lucifer Yellow dye transfer
      after microinjection (P < 0.03; Fisher's Exact test). Enhanced expression of Cx43
      and increased GJIC have been previously demonstrated to result in inhibition of
      in vitro neoplastic transformation of 10T1/2 cells as well as growth reduction of
      human tumors in xenografts. These novel derivatives possess increased utility as
      water soluble and water dispersible agents, allowing for aqueous delivery both in
      vitro and in vivo, properties that could enhance their potential clinical utility
      as potent cancer chemopreventive agents.

PMID- 15194215
TI  - Inhibition of cyclooxygenase-2 activity in head and neck cancer cells by
      genistein.
AB  - Genistein, rich in soybean, has been reported to have anti-cancer activity on
      several cancers. However, the molecular mechanism of its anti-cancer activity
      still remains unclear. We investigated the effect of genistein on a human oral
      squamous carcinoma line (SCC-25), and demonstrated that genistein inhibited SCC
      25 cell growth via G2/M phase arrest. We observed a significant decrease of
      proliferating cell nuclear antigen expression in these cells after treatment, but
      no significant change in the number of apoptotic cells, indicating that the major
      action of genistein is inhibition of cancer cell proliferation. We also observed
      a high level of prostaglandin E2 (PGE2) in these cells and PGE2 synthesis in SCC
      25 cells was significantly suppressed by genistein. We demonstrated that
      genistein directly inhibited cycloxygenase-2 (COX-2) activity, an inducible
      enzyme that converts arachidonic acid to prostaglandins, similar to the action of
      celecoxib, a selective COX-2 inhibitor. However, the anticancer activity of
      genistein was much weaker than that of indomethacin (non-selective COX
      inhibitor), celecoxib and baicalein (flavonoid isolated from Scutellaria
      baicalensis). These results suggested that genistein might be useful as a
      chemopreventive agent rather than a chemotherapeutic agent.

PMID- 15194216
TI  - Cytotoxicity and oncostatic activity of the thiazolidinedione derivative CGP
      52608 on central nervous system cancer cells.
AB  - Oncostatic activity of CGP 52608 at concentrations 1 microM or lower, and
      cytotoxicity at 5 and 10 microM, are showed in central nervous system cancer cell
      lines. Inhibition of cell growth is accompanied by arrest of the cell cycle in
      G0/G1 or G2/M, depending on the cells, and suggests different intracellular
      pathways used on each cell type. Cytotoxicity is not mediated by oxidative
      stress, since no intra or extracellular peroxides were found after treatment and
      antioxidants failed to rescue cells from apoptosis induced by CGP 52608. Its use
      as anticancer drug susceptible of being concomitantly administered with
      antioxidants must be considered provided its antitumoral effects do not rely on
      free radical production.

PMID- 15194217
TI  - Medication use, tamoxifen (TAM), and TAM metabolite concentrations in women with
      breast cancer.
AB  - Tamoxifen (TAM) is commonly used as an adjuvant treatment for breast cancer.
      Although patients taking TAM are often taking medications for comorbidities, data
      regarding the interaction of TAM with other medications are limited. Thus, this
      study was carried out to determine whether medications co-prescribed with TAM
      significantly influence the plasma concentrations of TAM and its metabolites (N
      desmethyltamoxifen; N-DMT and 4-hydroxytamoxifen; 4-OHT) in 98 women diagnosed
      with breast cancer. Participants taking diuretics had significantly higher plasma
      concentrations of TAM and N-DMT than participants not taking a diuretic.
      Arthritis/pain medication intake was negatively associated with plasma TAM
      concentrations. Chemotherapeutic agents, allergy drugs, anti-depressants, and
      diabetes medications did not significantly alter plasma TAM or metabolite
      concentrations. This suggests that diuretic or an arthritis/pain medication may
      affect TAM metabolism.

PMID- 15194218
TI  - Molecular signature linked to acquired resistance to cisplatin in esophageal
      cancer cells.
AB  - To clarify the molecular basis of acquired cisplatin (CDDP) resistance in
      esophageal squamous cell carcinoma (ESCC), we used cDNA microarray technology. A
      CDDP-resistant cell line (YES-2/CDDP), which shows a 7.5-fold increase in
      resistance to CDDP and a 3-fold decrease in CDDP accumulation compared with the
      parental YES-2 ESCC cell line, was generated from YES-2 by exposure to increased
      concentrations of CDDP. By cDNA microarray analysis, we identified 44 genes with
      significantly different expression levels between YES-2/CDDP and YES-2 cells.
      Interestingly, 15 of these 44 genes encoded ribosome-related proteins, almost all
      of which were underexpressed in YES-2/CDDP cells. Our present data suggest that
      many ribosome-related genes may be involved in the acquired resistance to CDDP in
      ESCC and that such information may allow us to better understand the mechanism of
      CDDP resistance.

PMID- 15194219
TI  - Anoxia/reoxygenation down-regulates the expression of E-cadherin in human colon
      cancer cell lines.
AB  - The E-cadherin-mediated cell-cell adhesiveness is a critical factor for carcinoma
      cell invasion and metastasis. Anoxia/reoxygenation is known to occur in cancer
      tissues. In this study, we investigated whether anoxia/reoxygenation induces the
      down-regulation of E-cadherin expression in the human colon cancer cell lines HT
      29, and SW1116. Colon cancer cells were exposed to anoxia (2 h) followed by
      reoxygenation (4-46 h). The subsequent expression of E-cadherin on the cell
      surface was examined by immunocytochemistry and enzyme-linked immunosorbent
      assays, the total amount of E-cadherin protein was examined by Western blotting,
      and the E-cadherin mRNA level was examined by a real-time polymerase chain
      reaction assay. The expression of E-cadherin on the cell surface and the total
      amount of E-cadherin protein were transiently reduced after anoxia/reoxygenation.
      On the other hand, the E-cadherin mRNA level was not decreased during
      reoxygenation. Pretreatment with actinomycin D or reagents that interfere with
      the activation of NF-kappaB significantly attenuated the down-regulation of E
      cadherin, which implicated a role for the de novo protein synthesis. These
      results indicate that anoxia/reoxygenation induces a transient reduction of E
      cadherin expression in human colon cancer cells through NF-kappaB dependent
      transcriptional pathway.

PMID- 15194220
TI  - Expression analysis of endogenous retroviral elements belonging to the HERV-F
      family from human tissues and cancer cells.
AB  - Based on the primer binding site for Phe-tRNA, human endogenous retroviruses
      (HERVs) have been classified as HERV-F family members, HERV-F, HERV-FXA, HERV-Fb,
      and HERV-Fc. The HERV-F family was expressed in human placenta preferentially. We
      investigated pol fragments of HERV-F family in various human tissues and cancer
      cells. The pol gene was expressed in human placenta only among tissues (brain,
      prostate, testis, heart, kidney, liver, lung, placenta, skeletal muscle, spleen,
      thymus, uterus), but detected in various cancer cell lines (RT4, BT-474, HCT-116,
      TE-1, UO-31, Jurkat, A549, MCF7, OVCAR-3, MIA-PaCa-2, PC3, LOX-IMVI, AZ521, 2F7,
      U-937, and C-33A) except for PFSK-1 and HepG2 by RT-PCR analysis. Expression and
      sequencing data of the 37 clones imply that the pol gene of HERV-F family is
      active in cancer cells, which may have potential role related to cancer
      development.

PMID- 15194221
TI  - Targeting of epidermal growth factor receptor by cyclopentenone prostaglandin 15
      Deoxy-Delta12,14-prostaglandin J2 in human oral squamous carcinoma cells.
AB  - Antineoplastic properties of cyclopentenone 15-deoxy-Delta12,14-prostaglandin J2
      (15d-PGJ2) involve peroxisome proliferator-activated receptor gamma (PPARgamma)
      dependent and independent mechanisms. We recently reported that 15d-PGJ2 inhibits
      cell growth and induces apoptosis in human oral squamous cell carcinoma (SCC)
      partly independent of PPARgamma activation. Given the importance of epidermal
      growth factor receptor (EGFR) as a therapeutic target in head and neck SCC, we
      addressed the effects of 15d-PGJ2 on EGFR expression. 15d-PGJ2, but not other
      PPARgamma ligands, abrogated EGFR protein expression in oral SCC cells. 15d-PGJ2
      also decreased EGFR mRNA, indicating downmodulation at the transcriptional level.
      Moreover, treatment with 9,10-dihydro-15d-PGJ2, a 15d-PGJ2 analog lacking the
      reactive carbonyl group, failed to effect EGFR expression. These findings provide
      evidence for EGFR downregulation in oral SCC cells through a novel anticancer
      effect of 15d-PGJ2 that is attributed to the reactive cyclopentenone ring system.

PMID- 15194222
TI  - Both BRAF and KRAS mutations are rare in colorectal carcinomas from patients with
      hereditary nonpolyposis colorectal cancer.
AB  - The BRAF mutations have been suggested to be linked with defective mismatch
      repair in colorectal carcinomas. To clarify the extent of BRAF mutations in HNPCC
      colorectal carcinomas, which are typical mismatch repair deficient carcinomas, we
      compared the frequency of BRAF mutations between HNPCC, familial adenomatous
      polyposis (FAP) and sporadic cases. The frequency of KRAS mutations was also
      compared between these three syndromes. No BRAF mutations were detected in 33
      HNPCC colorectal carcinomas, while they were detected in 3 of 26 (12%) FAP
      carcinomas and 2 of 53 (4%) microsatellite stable sporadic carcinomas. KRAS
      mutations were detected in 2 of 33 (6%) HNPCC, 9 of 26 (35%) FAP and 18 of 53
      (34%) sporadic carcinomas. Such extremely low frequencies of BRAF and KRAS
      mutations in HNPCC colorectal carcinomas suggest that the participation of RAS
      RAF signaling is minor in HNPCC, and that the previously suggested high frequency
      of BRAF mutations in mismatch repair deficient colorectal carcinomas is not due
      to mutations of mismatch repair genes.

PMID- 15194223
TI  - Quantitative analysis of free ubiquitin and multi-ubiquitin chain in colorectal
      cancer.
AB  - Accumulation of ubiquitin (Ub) has been documented in various cancers. The levels
      of the two forms of Ub, i.e. free ubiquitin (FUb) and multi-ubiquitin chain (MUC)
      were measured in colorectal cancers and in matched normal colonic tissues in 43
      patients. When compared to normal colonic tissues, the levels of both FUb and MUC
      were significantly higher in the cancerous tissues (P < 0.01, respectively). The
      level of FUb was related to the depth of invasion (P < 0.05). The level of MUC
      was related to blood vessel invasion and lymphatic vessel invasion (P < 0.05).
      The levels of FUb and MUC had no correlation with histological grade, lymph node
      metastasis, liver metastasis or relapse-free survival. We conclude that the
      levels of FUb and MUC were up-regulated in colorectal cancer and were correlated
      with the pathological findings.

PMID- 15194224
TI  - Walker 256 tumor MHC class I expression during the shift from A variant to the
      immunogenic AR variant.
AB  - Novel tumor cell variants can be obtained by serially passaging tumor cells in
      different media and/or environments. Serial intraperitoneal (ip) passages of the
      Walker 256 tumor A variant was followed for studying the generation of its
      regressive AR variant. MHC class I molecule expression was assessed since
      variations in this molecule would explain changes in tumor cell immunogenicity
      and therefore, the shift from progressive A variant to the regressive AR variant.
      Within 25 ip passages all serial repetitions shifted from A to AR variant, which
      was characterized by a significant increase in red blood cell (RBC) osmotic
      fragility with marked spleen hypertrophy in the host. In one serial repetition AR
      tumor cells were rejected (ip passage number 36) and immunity against the AR and
      A variants was conferred. Flow cytometry analysis showed a significant increase
      in the number MHC class I positive cells in AR variant (n = 15, 14.21 +/- 1.32)
      compared with A variant (n = 10, 9.10 +/- 1.22). These data provide evidence that
      the generation of the AR variant could result from factors present in the ip
      environment leading to an increase in the number of Walker 256 MHC class I
      positive tumor cells, probably due to immune selection of MHC class I negative
      tumor cells.

PMID- 15194225
TI  - A proposed role for ZO-1 in targeting connexin 43 gap junctions to the endocytic
      pathway.
AB  - Gap junctions are intercellular channels organized in plaque that directly link
      adjacent cells. Connexins (Cx), the constitutive proteins of gap junctions are
      associated with several partner proteins (cytoskeletal, anchoring) which could
      participate in plaque formation and degradation. Coimmunoprecipitation and
      indirect immunofluorescence analyses showed that ZO-1, a tight junction
      associated protein, was linked to Cx43 in the testis. By using gamma
      hexachlorocyclohexane (HCH), known to induce gap junction endocytosis, we
      demonstrated that endocytosis increased Cx43/ZO-1 association within the
      cytoplasm of treated Sertoli cells. In control cells, the two proteins were
      present, as expected, at the plasma membrane level, but poorly colocalized. The
      increased intracytoplasmic Cx43/ZO-1 complex was associated with a shift towards
      increased levels of Cx43 P1 and P2 isoforms. The HCH induced Cx43
      hyperphosphorylation was abolished by the ERK inhibitor PD98059 suggesting that
      this effect could be mediated through activation of the ERK pathway. These data
      strongly support a novel role for ZO-1 in the turnover of Cx43 during gap
      junction plaque endocytosis.

PMID- 15194226
TI  - Porphyromonas gingivalis fimbriae binds to neoglycoproteins: evidence for a
      lectin-like interaction.
AB  - Porphyromonas gingivalis is a likely major pathogen in adult periodontitis.
      Fimbriae in particular have been suggested as playing an important role in
      facilitating the initial interaction between the bacteria and the host and
      triggers host responses. Murakami et al. [Biochem. Biophys. Res. Commun. 192
      (1993) 826] have shown that fimbriae of P. gingivalis strongly induced TNF-alpha
      gene expression in macrophages and expression of TNF-alpha was inhibited by N
      acetyl-D-galactosamine, but not inhibited by other sugars. Studies by Sojar et
      al. [FEBS Lett. 422 (1998) 205] suggested that the oligosaccharide moiety of
      lactoferrin is involved in the interaction of P. gingivalis fimbriae and human
      lactoferrin. In the present study, purified fimbriae from P. gingivalis and
      neoglycoproteins were used to assess lectin-like interaction of fimbriae. In dot
      blot and overlay assays, iodinated purified P. gingivalis fimbriae as well as
      biotinylated purified P. gingivalis fimbriae bound strongly to albumin
      fucosylamide (albumin-1-amido-1-deoxy-L-fucose) and by lesser extent to albumin-N
      acetyl-D-galactosamine (albumin-p-aminophenyl-N-acetyl-beta-D-galactosaminide).
      However, fimbriae failed to bind carbohydrate free bovine serum albumin, which
      was used in preparation of the neoglycoproteins. These results suggests that P.
      gingivalis fimbriae bind to glycoconjugates through lectin-like interaction with
      carbohydrate. This protein-carbohydrate interactions may be important for
      triggering events in these cells, which mediate the host response of this
      pathogen.

PMID- 15194227
TI  - IGF-I affects glycosaminoglycan/proteoglycan synthesis in breast cancer cells
      through tyrosine kinase-dependent and -independent pathways.
AB  - The insulin-like growth factor I (IGF-I) has been implicated in breast cancer
      development acting through insulin-like growth factor I receptor (IGF-IR), but
      also through estrogen receptor (ER). The effect of IGF on proteoglycan (PG)
      synthesis by two human breast cancer epithelial cell lines, the ER-positive MCF-7
      and the ER-negative BT-20, was studied alone and in combination with genistein.
      Both cell lines synthesise hyaluronan (HA), matrix secreted and cell membrane
      associated galactosaminoglycan containing proteoglycans (GalAGPGs) and heparan
      sulphate proteoglycans (HSPGs) in variable amounts. IGF-I affects the synthesis
      of PGs by BT-20 cells by decreasing the amounts of HA and secreted GalAGPGs and
      HSPGs and upregulates the expression of cell membrane-associated GalAGPGs and
      HSPGs. IGF-I exerts this effect on BT-20 cells acting mainly through receptors
      with protein tyrosine kinase activity (PTK). In contrast, IGF-I stimulates the
      synthesis of secreted GalAGPGs and HSPGs by MCF-7 cells, exhibiting only a slight
      suppression on synthesis of cell-associated GalAGPGs and HSPGs. The regulatory
      effect of IGF-I on PGs distribution in MCF-7 cells is mediated through a mix of
      pathways, which involves both receptors with PTK activity and PTK-independent
      signalling. It is suggested that the effects of IGF-I on the synthesis and
      distribution of PGs by epithelial breast cancer cells also depend on the presence
      or the absence of ER. The result of the IGF-I action is the balanced biosynthesis
      between the matrix and cell-associated PGs in both cell lines, approaching a
      common biosynthetic phenotype.

PMID- 15194228
TI  - Reactive amino acid residues involved in glutamate-binding of human glutamate
      dehydrogenase isozymes.
AB  - In the present study, the cassette mutagenesis at several putative positions
      (K94, G96, K118, K130, or D172) was performed to examine the residues involved in
      the glutamate-binding of the human glutamate dehydrogenase isozymes (hGDH1 and
      hGDH2). None of the mutations tested affected the expression or stability of the
      proteins. There was dramatic reduction in the catalytic efficiency in mutant
      proteins at K94, G96, K118, or K130 site, but not at D172 site. The K(M) values
      for glutamate were 4-10-fold greater for the mutants at K94, G96, or K118 site
      than for the wild-type hGDH1 and hGDH2, whereas no differences in the K(M) values
      for NAD(+) were detected between the mutant and wild-type enzymes. For K130Y
      mutant, the K(M) value for glutamate increased 1.6-fold, whereas the catalytic
      efficiency (k(cat)/K(M)) showed only 2-3% of the wild-type. Therefore, the
      decreased catalytic efficiency of the K130 mutant mainly results from the reduced
      k(cat) value, suggesting a possibility that the K130Y residue may be involved in
      the catalysis rather than in the glutamate-binding. The D172Y mutant did not show
      any changes in k(cat) value and K(M) values for glutamate and NAD(+), indicating
      that D172Y is not directly involved in catalysis and substrates binding of the
      hGDH isozymes. For sensitivity to ADP activation, only the D172Y mutant showed a
      reduced sensitivity to ADP activation. The reduction of ADP activation in D172Y
      mutant was more profoundly observed in hGDH2 than in hGDH1. There were no
      differences in their sensitivities to GTP inhibition between the wild-type and
      mutant GDHs at all positions tested. Our results suggest that K94, G96, and K118
      residues play an important role, although at different degrees, in the binding of
      glutamate to hGDH isozymes.

PMID- 15194229
TI  - Hydrolysis of nuclear phospholipids in relation with proliferative state in
      uterine stromal cells.
AB  - The current study examined the metabolism of phospholipid (PL) in the whole cell
      homogenate and in the nuclear fraction in proliferative and non-proliferative
      uterine stromal cells (U(III) cells). Growth arrested cells were obtained either
      from contact-inhibited confluent cells or from proliferative cells treated with
      aristolochic acid (AR) for 2 days. Fatty acid composition and fatty acid amount
      of both total and nuclear PL were not significantly different between
      proliferative, confluent and AR-treated cells. In contrast, marked differences
      were observed in the incorporation of [(3)H]AA, with greater incorporation in
      proliferative cells than in confluent or AR-treated cells, particularly in
      nuclear PL. Considering endogenous level of arachidonic acid (AA) in total and
      nuclear PL, we found that AA turnover in nuclear PL was especially high compared
      to that in total PL and that this difference was accentuated in proliferative
      cells compared to non-proliferative cells. Interestingly, [(3)H]AA incorporation
      and AA turnover in proliferative, confluent and AR-treated cells vary accordingly
      to the expression, activity and/or content of pancreatic phospholipase A(2)
      (PLA(2)-I) in the nuclear compartment of these cells that we reported in previous
      studies. The changes in metabolism of nuclear PL during cell proliferation are
      consistent with an enhanced PL hydrolysis that could involve PLA(2)-I.

PMID- 15194230
TI  - Genetic regulation of mouse glycosylphosphatidylinositol-phospholipase D.
AB  - Glycosylphosphatidylinositol phospholipase D (GPI-PLD) has been proposed to be
      responsible for cleaving membrane-associated glycosylphosphatidyl inositol (GPI)
      molecules to generate inositol phosphoglycan (IPGs), which have growth factor
      mimetic properties. We have cloned the mouse liver GPI-PLD cDNA, which has a
      sequence that differs from that previously isolated from a mouse glucagonoma cell
      library. Using a highly specific and very sensitive RNase protection assay, we
      found that the GPI-PLD expressed in adult/post-natal brain, antrum and insulin
      producing cells is identical to that isolated from liver. The expression of mouse
      GPI-PLD in liver shows a complex genetic regulation with a mouse strain-specific
      variation. In addition, GPI-PLD mRNA levels were higher in 4-week old animals
      compared to older animals, and the GPI-PLD mRNA levels increased in mice that
      developed insulin dependent type 1 diabetes spontaneously. This suggests that the
      expression of liver GPI-PLD in mice is highly regulated.

PMID- 15194231
TI  - Putative membrane assembly of EtpM-colicin V chimeras.
AB  - EtpM of the enterohemorrhagic E. coli O157:H7 is a bitopic membrane protein of
      the type II protein secretion apparatus. There is a twin-arginine (RR) motif in
      front of its signal anchor, suggesting a Tat-dependent membrane targeting of
      EtpM. By exploiting the periplasmic bactericidal activity of colicin V (ColV), we
      constructed EtpM-ColV fusions and studied the EtpM-mediated translocation of
      ColV. The wild type strain and the DeltatatC mutant were killed by the expressed
      fusions and were fully protected from the killing effect by the ColV-specific
      immunity protein. In contrast, cold-inactivation of YidC, which is generally
      required for integral membrane protein assembly, significantly attenuated the
      killing effect in the cold-sensitive yidC mutant. These results confirmed the
      predicted N(in)-C(out) EtpM topology, and suggests an EtpM-mediated, Tat
      independent and YidC-dependent translocation of ColV.

PMID- 15194232
TI  - Regulation of A1/Bfl-1 expression in peripheral splenic B cells.
AB  - We analyzed here the expression of the prosurvival Bcl-2 homologue A1 in
      peripheral B cell compartment. We observed that A1 mRNA are highly expressed in
      peripheral B cells as compared with other anti-apoptotic genes of the Bcl-2
      family such as bcl-xl and bcl-2 itself. The expression of A1 is up-regulated in
      immature B cells at the transition between transitional type 1 (T1) and type 2
      (T2) cells, and remained highly expressed in mature (M) B cells. We, therefore,
      analyzed the effect of B cell antigen receptor (BCR) and BAFF receptor (BAFF-R)
      engagement on the regulation of A1 in total B220(+) cells but also FACS-sorted
      immature T1, T2 and M B cells. We demonstrated that only BCR engagement up
      regulated the expression of A1 mRNA and protein. These results suggest that A1
      may play a key role in antigen-dependent signals that are required for survival
      and/or proliferation of peripheral B cells.

PMID- 15194233
TI  - Molecular adaptation: the malate dehydrogenase from the extreme halophilic
      bacterium Salinibacter ruber behaves like a non-halophilic protein.
AB  - Malate dehydrogenase from the extreme halophilic bacterium, Salinibacter ruber
      (Sr MalDH) was purified and characterised as a tetramer by sedimentation velocity
      measurements, showing the enzyme belongs to the LDH-like group of MalDHs. In
      contrast to most other halophilic enzymes, which unfold when incubated at low
      salt concentration, Sr MalDH is completely stable in absence of salt. Its amino
      acid composition does not display the strong acidic character specific of
      halophilic proteins. The enzyme displays a strong KCl-concentration dependent
      variation in K(m) for oxaloacetate, but not for the NADH co-factor. Its activity
      is reduced by high salt concentration, but remains sufficient for the enzyme to
      sustain catalysis at approximately 30% of its maximal rates in 3 M KCl. The
      properties of the protein were compared with those from other LDH-like MalDHs of
      bacterial and archaeal origins, showing that Sr MalDH in fact behaves like a non
      halophilic enzyme.

PMID- 15194234
TI  - Shiga toxin 1 acting on DNA in vitro is a heat-stable enzyme not requiring
      proteolytic activation.
AB  - Shiga toxin 1 (Stx1) catalyses the removal of a specific adenine from 28S rRNA
      within ribosomes (RNA-N-glycosylase activity) and the removal of multiple
      adenines from DNA (DNA-glycosylase activity). For the in vitro activity the toxin
      requires activation by trypsin, urea and DTT which releases the enzymatically
      active A1 fragment. We show that activated Stx1 acts on DNA as a heat-stable
      enzyme. Moreover, heat-treatment of the pro-enzyme at acidic pH turns it into an
      enzymatically active species which efficiently depurinates DNA. Although the
      effect of this treatment is centred on the enzyme and not on DNA, we found no
      evidence for covalent modification of the holotoxin. We suggest that high
      temperatures and acidic buffer induce unfolding of the holotoxin allowing the
      substrate to gain access to the active site. Possible practical applications
      (rapid assay for Stx1 detection, use of the toxin for DNA sequencing) are
      discussed.

PMID- 15194235
TI  - Dihydrodipicolinate synthase (DHDPS) from Escherichia coli displays partial mixed
      inhibition with respect to its first substrate, pyruvate.
AB  - Dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52) mediates the first unique
      reaction of (S)-lysine biosynthesis in plants and microbes-the condensation of
      (S)-aspartate-beta-semialdehyde ((S)-ASA) and pyruvate. It has been shown that
      DHDPS is partially feedback inhibited by (S)-lysine; it is suggested that this
      mechanism regulates flux through the DAP biosynthetic pathway. Others have
      characterised DHDPS from Escherichia coli with respect to (S)-lysine inhibition.
      They have concluded that, with respect to pyruvate, the first substrate of the
      reaction, DHDPS shows uncompetitive inhibition: as such, they further suggest
      that (S)-lysine inhibits DHDPS via interaction with the binding site for the
      second substrate, (S)-ASA. Yet, this finding is based on the assumption that (S)
      lysine is a fully uncompetitive inhibitor. In light of crystallographic studies,
      which lead to the proposal that (S)-lysine affects the putative proton-relay of
      DHDPS, we re-evaluated the inhibition mechanism of DHDPS with respect to (S)
      lysine by incorporating the observed hyperbolic inhibition. Our data showed that
      lysine is not an uncompetitive inhibitor, but a mixed inhibitor when pyruvate and
      (S)-lysine concentrations were varied. Thus, consistent with the crystallographic
      data, (S)-lysine must have an effect on the initial steps of the DHDPS reaction,
      including the binding of pyruvate and Schiff base formation.

PMID- 15194236
TI  - Effects of polyvalency of glycotopes and natural modifications of human blood
      group ABH/Lewis sugars at the Galbeta1-terminated core saccharides on the binding
      of domain-I of recombinant tandem-repeat-type galectin-4 from rat
      gastrointestinal tract (G4-N).
AB  - In our recent publication, we defined core aspects of the carbohydrate
      specificity of domain-I of recombinant tandem-repeat-type galectin-4 from rat
      gastrointestinal tract (G4-N), especially its potent interaction with the linear
      tetrasaccharide Galbeta1-3GlcNAcbeta1-3Galbeta1-4Glc (Ibeta1-3L). The assumed
      role of galectin-4 as a microvillar raft stabilizer/organizer and as a malignancy
      associated factor in hepatocellular and gastrointestinal carcinomas called for
      further refinement of its binding specificity. Thus, the effects of polyvalency
      of glycotopes and natural modifications of human blood group ABH/Lewis sugars at
      the terminal Galbeta1-core saccharides were thoroughly examined by the enzyme
      linked lectinosorbent and lectin-glycan inhibition assays. The results indicate
      that (a) a high-density of polyvalent Galbeta1-3/4GlcNAc (I/II), Galbeta1-3GalNAc
      (T) and/or GalNAcalpha1-Ser/Thr (Tn) strongly favors G4-N/glycoform binding.
      These glycans were up to 2.3 x 10(6), 1.4 x 10(6), 8.8 x 10(5), and 1.4 x 10(5)
      more active than Gal, GalNAc, monomeric I/II and T, respectively; (b) while lFuc
      is a poor inhibitor, its presence as alpha1-2 linked to terminal Galbeta1
      containing oligosaccharides, such as H active Ibeta1-3L, markedly enhances the
      reactivities of these ligands; (c) when blood group A (GalNAcalpha1-) or B
      (Galalpha1-) determinants are attached to terminal Galbeta1-3/4GlcNAc (or Glc)
      oligosaccharides, the reactivities are also increased; (d) with lFucalpha1-3/4
      linked to sub-terminal GlcNAc, the reactivities of these haptens are reduced; and
      (e) short chain Le(a)/Le(x)/Le(y) and the short chains of sialyl Le(a)/Le(x) are
      poor inhibitors. These distinct binding features of G4-N establish the important
      concept of affinity enhancement by high density polyvalencies of glycotopes (vs.
      multi-antennary I/II) and by introduction of an ABH key sugar to Galbeta1
      terminated core glycotopes. The polyvalent ligand binding properties of G4-N may
      help our understanding of its crucial role for cell membrane raft stability and
      provide salient information for the optimal design of blocking substances such as
      anti-tumoral glycodendrimers.

PMID- 15194237
TI  - Abrin-a A chain expressed as soluble form in Escherichia coli from a PCR
      synthesized gene is catalytically and functionally active.
AB  - Abrin-a A chain (ABRaA) is a potent plant toxin, which possesses N-glycosylase
      activity toward eukaryotic 28S rRNA, and may have potential use in cancer
      therapy. To improve levels of expression in Escherichia coli, the gene encoding
      ABRaA was optimized by replacing rare codons with high-frequency ones, and
      synthesized using two-step PCR. The optimized ABRaA was cloned into the pET-His
      vector, and highly expressed in cytoplasm of E. coli. The yield of the purified
      recombinant (r) ABRaA proteins was up to 80 mg/l of induced culture. The rABRaA
      was one-step purified to homogeneity and its RNA-N-glycosylase ability to inhibit
      protein biosynthesis in a cell-free system and to depurinate 28S rRNA in rat
      liver ribosomes was demonstrated in vitro. The MTT assay showed that it also had
      a killing effect on human hepatoma cell line SMMC-7721 and myeloma cell line
      Sp2/0. For the first time, ABRaA expressed as soluble form in E. coli from a PCR
      synthesized gene is catalytically and functionally active.

PMID- 15194238
TI  - Purification and characterization of complex carbohydrate specific isolectins
      from wild legume seeds: Acacia constricta is (vinorama) highly homologous to
      Phaseolus vulgaris lectins.
AB  - Vinorama isolectins (VL2-VL4) were purified from seeds of Acacia constricta
      (vinorama) using affinity chromatography on a fetuin-fractogel column followed by
      cationic-exchange chromatography. Each isolectin fraction presented a
      characteristic isoelectric point range from 5.5 to 8.4. Under native conditions,
      VL containing fractions migrated as tetramers of 133 kDa, while in SDS-PAGE, in
      presence of 2-mercaptoethanol, a single subunit band with M(r) of 34 kDa was
      observed. VL was found to be a glycoprotein with a 7.5% neutral sugar content.
      Antibodies to Phaseolus vulgaris lectins PHA and other wild legume lectins as
      Olneya tesota (palo fierro) PF2 and PF3, and Parkinsonia aculeate (palo verde) PV
      reacted with VL, but not with anti Glycine max agglutinin SBA or anti Lotus
      tetragonolobus agglutinin LTA. Furthermore, direct analysis of VL peptides showed
      sequences homologous to those reported in different lectins of the Phaseolus
      genus. VL2-VL4 did not have ABO serological or simple sugar specificity, but were
      inhibited by complex carbohydrates from fetuin and thyroglobulin. Asialofetuin
      carbohydrates strongly interacted with VL4 and VL3. Vinorama isolectins could be
      classified as "complex lectins".

PMID- 15194239
TI  - Phospholipase C-dependent phosphoinositide breakdown induced by ELF-EMF in
      Peganum harmala calli.
AB  - With the aim of examining the response of plant cells to extremely low frequency
      (ELF) electromagnetic fields (EMF), we investigated the behaviour of the
      phosphatidylinositol 4,5 bisphosphate (PtdIns 4,5-P(2)) molecule (the precursor
      of the phosphoinositide signal transduction cascade) by exposing callus cells
      from Peganum harmala to 50 Hz, 1 gauss EMF for 10 min and by examining the level
      and the fatty acid composition of PtdIns 4,5-P(2) after the exposure. Our results
      evidenced a statistically significant decrease in PtdIns 4,5-P(2) concentrations
      and a different involvement of the constituting fatty acids in the induced
      breakdown. The manipulation of the lipid-based signalling pathway by
      phosphoinositide-phospholipase C (PI-PLC) inhibitors (i.e., neomycin, U-73122 and
      ET-18-OCH(3)) seems to support the hypothesis that, as in animals, also in
      plants, the cell membrane is the primary impact site of ELF electromagnetic
      stimulus and that this interaction could probably involve the activation of PI
      signal transduction pathway including a heterotrimeric G protein.

PMID- 15194240
TI  - Hospital management of adults with severe acute respiratory syndrome (SARS) if
      SARS re-emerges--updated 10 February 2004.
AB  - Severe Acute Respiratory Syndrome (SARS) is a potentially severe and highly
      infectious disease to which healthcare workers involved in the management of
      cases are particularly vulnerable. These guidelines briefly summarise optimal and
      safe practice for clinicians involved in the emergency care of patients with
      probable or confirmed SARS.

PMID- 15194241
TI  - Helicobacter pylori active infection in patients with acute coronary heart
      disease.
AB  - OBJECTIVES: To evaluate the possible role of the active Helicobacter pylori
      infection as a trigger factor in acute coronary heart disease (CHD). METHODS:
      Forty patients with acute coronary syndromes, 40 patients with infections other
      than H. pylori (control group A) and 40 healthy subjects (control group B), pair
      matched for age, sex and CHD risk factors were studied. In each patient and
      control subject the presence of H. pylori stool antigen (HpsA) and serum anti
      CagA were tested. RESULTS: Twenty-eight of patients with CHD resulted positive
      for HpSA compared to 14 patients of control group A and 16 subjects of group B
      (p=0.00095). No significant difference was found in the anti-CagA positivity
      among patients with CHD and control groups. Concomitant positivity for anti-CagA
      and HpSA was found in 13 patients with CHD, four controls of group A and five
      controls of group B (p=0.017) CONCLUSIONS: Our findings revealed a higher rate of
      HpSA positivity and a significantly higher association between HpSA and anti-CagA
      positivity in patients with acute CHD compared to control groups. These data
      suggest that active H. pylori infection may play a role as a trigger factor in
      acute cardiovascular events.

PMID- 15194242
TI  - Estimating hospital admissions due to rotavirus gastroenteritis from hospital
      episode statistics.
AB  - OBJECTIVES: To determine the proportion of hospital admissions, in children < 5
      years old, coded for intestinal infectious disease or non-infectious
      gastroenteritis, using ICD-10 codes, that were due to rotavirus infection. To
      assess how many children admitted with rotavirus gastroenteritis were given the
      specific ICD-10 code (A080) for this disease. METHODS: Sixteen-month prospective,
      observational study of children < 5 years old, admitted to district general
      hospital with: acute gastroenteritis (> or =3 loose stools/day), proven rotavirus
      infection and those coded as intestinal infectious disease or non-infectious
      gastroenteritis. RESULTS: Four hundred and twenty children < 5 years old were
      admitted with acute gastroenteritis. Rotavirus was detected in 170 children's
      stools. Acute rotavirus gastroenteritis accounted for 81/397 (20%) children coded
      as having non-infectious gastroenteritis and 32/81 (40%) coded for intestinal
      infectious disease. Only 18 children were coded for rotavirus gastroenteritis.
      Potentially preventable rotavirus gastroenteritis occurred in 122 children; 78
      coded as non-infectious gastroenteritis (20%) and 26 coded for intestinal
      infectious disease (34%). CONCLUSIONS: The proportion of children coded with
      diarrhoeal diseases and found to have rotavirus is less than previously
      estimated. Using the specific code for rotavirus infection to estimate hospital
      admissions would be a gross underestimate. Hospital episode statistics cannot
      reliably estimate the burden of disease due to rotavirus.

PMID- 15194243
TI  - Cavitary pneumonia secondary to Tsukamurella in an AIDS patient. First case and a
      review of the literature.
AB  - Tsukamurella is a Gram-positive, variable rod-shaped, weakly acid-alcohol-fast,
      non motile, aerobic bacterium that belongs to the genus Rhodococcus. Tsukamurella
      has been reported as a cause of infections in humans with immunosuppression and
      indwelling foreign bodies. It has also been isolated in one patient with AIDS
      (Acquired Immunodeficiency Syndrome) as a saprophytic organism. Optimal
      management of infections secondary to this micro-organism is still uncertain due
      to the paucity of cases. The combination of a beta-lactam and an aminoglycoside,
      along with removal of medical devices, appear to be the treatment of choice. We
      report the case of an AIDS patient who presented with multiple lung cavitary
      lesions secondary to Tsukamurella. This is the first case reported of
      Tsukamurella as a pathogenic agent in an AIDS patient. We also propose a
      successful oral antibiotic regimen with fluoroquinolone and rifampin to treat
      infections secondary to this uncommon micro-organism.

PMID- 15194244
TI  - Use of ethanol locks to prevent recurrent central line sepsis.
AB  - Catheter-related sepsis (CRS) is a common complication of long-term parenteral
      nutrition. Conventional antibiotic therapy is often effective in the short-term
      but, because of poor activity against intraluminal microbial biofilms, may not
      prevent relapse. Ethanol is an effective antiseptic. We describe a case of a
      patient with recurrent CRS successfully treated with 70% ethanol locks.

PMID- 15194245
TI  - Predictive period of incubation for Whipple's disease.

PMID- 15194246
TI  - Is GSK guilty of fraud?

PMID- 15194247
TI  - How to study stroke incidence.

PMID- 15194248
TI  - Preventing unnecessary caesarean sections: marginal benefit of a second opinion.

PMID- 15194249
TI  - Clinical care for seriously ill children in district hospitals: a global public
      health issue.

PMID- 15194250
TI  - Does Laribacter hongkongensis cause diarrhoea, or does diarrhoea "cause" L
      hongkongensis?

PMID- 15194251
TI  - Change in stroke incidence, mortality, case-fatality, severity, and risk factors
      in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).
AB  - BACKGROUND: The incidence of stroke is predicted to rise because of the rapidly
      ageing population. However, over the past two decades, findings of randomised
      trials have identified several interventions that are effective in prevention of
      stroke. Reliable data on time-trends in stroke incidence, major risk factors, and
      use of preventive treatments in an ageing population are required to ascertain
      whether implementation of preventive strategies can offset the predicted rise in
      stroke incidence. We aimed to obtain these data. METHODS: We ascertained changes
      in incidence of transient ischaemic attack and stroke, risk factors, and
      premorbid use of preventive treatments from 1981-84 (Oxford Community Stroke
      Project; OCSP) to 2002-04 (Oxford Vascular Study; OXVASC). FINDINGS: Of 476
      patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and
      93 transient ischaemic attacks were incident events. Despite more complete case
      ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever
      stroke fell by 29% (relative incidence 0.71, 95% CI 0.61-0.83, p=0.0002).
      Incidence declined by more than 50% for primary intracerebral haemorrhage (0.47,
      0.27-0.83, p=0.01) but was unchanged for subarachnoid haemorrhage (0.83, 0.44
      1.57, p=0.57). Thus, although 28% more incident strokes (366 vs 286) were
      expected in OXVASC due to demographic change alone (33% increase in those aged 75
      or older), the observed number fell (262 vs 286). Major reductions were recorded
      in mortality rates for incident stroke (0.63, 0.44-0.90, p=0.02) and in incidence
      of disabling or fatal stroke (0.60, 0.50-0.73, p<0.0001), but no change was seen
      in case-fatality due to incident stroke (17.2% vs 17.8%; age and sex adjusted
      relative risk 0.85, 95% CI 0.57-1.28, p=0.45). Comparison of premorbid risk
      factors revealed substantial reductions in the proportion of smokers, mean total
      cholesterol, and mean systolic and diastolic blood pressures and major increases
      in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure
      lowering drugs (all p<0.0001). INTERPRETATION: The age-specific incidence of
      major stroke in Oxfordshire has fallen by 40% over the past 20 years in
      association with increased use of preventive treatments and major reductions in
      premorbid risk factors.

PMID- 15194252
TI  - Mandatory second opinion to reduce rates of unnecessary caesarean sections in
      Latin America: a cluster randomised controlled trial.
AB  - BACKGROUND: Latin America has a high rate of caesarean sections. We tested the
      hypothesis that a hospital policy of mandatory second opinion, based on the best
      existing scientific evidence, reduces the hospital caesarean section rate by 25%,
      without increasing maternal and perinatal morbidity and mortality. METHODS: 36
      hospitals in Argentina (18), Brazil (eight), Cuba (four), Guatemala (two), and
      Mexico (four), were randomly assigned to intervention or control in a matched
      pair design. All physicians in the intervention hospitals deciding a non
      emergency caesarean section had to follow a policy of mandatory second opinion.
      The primary outcome was the overall caesarean section rate in the hospitals after
      a 6-month implementation period. We also assessed women's satisfaction with
      labour and delivery care and physicians'acceptance of the second opinion policy.
      FINDINGS: A total of 34 hospitals attending 149?276 deliveries were randomised
      and completed the protocol. The mandatory second opinion policy was associated
      with a small but significant reduction in rates of caesarean section (relative
      rate reduction 7.3%; 95% CI 0.2-14.5), mostly in intrapartum sections (12.6%; 0.6
      24.7). Other maternal and neonatal outcomes and women's perceptions and
      satisfaction with the process of care were similarly distributed between the
      groups. INTERPRETATION: In hospitals applying this policy of second opinion, 22
      intrapartum caesarean sections could be prevented per 1000 deliveries, without
      affecting maternal or perinatal morbidity, and without affecting mothers'
      satisfaction with the care process.

PMID- 15194253
TI  - Association of Laribacter hongkongensis in community-acquired gastroenteritis
      with travel and eating fish: a multicentre case-control study.
AB  - BACKGROUND: Laribacter hongkongensis has been recovered from several patients
      with gastroenteritis. However, the causative role of this organism in human
      gastroenteritis is still unproven, and sources of the bacterium are unknown. We
      undertook a multicentre case-control study to investigate the association of L
      hongkongensis with gastroenteritis. METHODS: Faecal samples from patients with
      community-acquired gastroenteritis and controls were cultured for L
      hongkongensis. Targeted food surveillance was done to identify potential sources
      of this bacterium. All isolates of this organism from patients and food items
      were characterised by pulsed-field gel electrophoresis and ribotyping. FINDINGS:
      During a 4-month period, L hongkongensis was recovered from 17 of 3788 patients
      with community-acquired gastroenteritis, but was absent in 1894 controls
      (p=0.001). Those who were culture-positive for this bacterium had a recent
      history of travel (ten [59%] patients vs two [6%] of 34 matched controls,
      p<0.0001), of fish consumption (16 [94%] vs 19 [56%], p=0.009), and of eating
      minced freshwater fish meat (five [29%] vs one [3%], p=0.012). We recovered 25 L
      hongkongensis isolates from intestinal samples of freshwater fish and two from
      minced freshwater fish meat. Bacteria with the same pulsed-field gel
      electrophoretic pattern and ribotype were recovered from one patient and a sample
      of minced freshwater fish meat, which was from the same retail market recently
      visited by the patient. We did not see this particular combination of
      electrophoretic pattern and ribotype in any other isolates. INTERPRETATION: L
      hongkongensis is associated with community-acquired gastroenteritis and
      traveller's diarrhoea. However, its causative role has not been shown. Freshwater
      fish is one source of this bacterium.

PMID- 15194254
TI  - Assessment of inpatient paediatric care in first referral level hospitals in 13
      districts in Kenya.
AB  - BACKGROUND: The district hospital is considered essential for delivering basic,
      cost-effective health care to children in resource poor countries. We aimed to
      investigate the performance of these facilities in Kenya. METHODS: Government
      hospitals providing first referral level care were prospectively sampled from 13
      Kenyan districts. Workload statistics and data documenting the management and
      care of admitted children were obtained by specially trained health workers.
      FINDINGS: Data from 14 hospitals were surveyed with routine statistics showing
      considerable variation in inpatient paediatric mortality (range 4-15%) and
      specific case fatality rates (eg, anaemia 3-46%). The value of these routine data
      is seriously undermined by missing data, apparent avoidance of a diagnosis of
      HIV/AIDS, and absence of standard definitions. Case management practices are
      often not in line with national or international guidelines. For malaria, signs
      defining severity such as the level of consciousness and degree of respiratory
      distress are often not documented (range per hospital 0-100% and 9-77%,
      respectively), loading doses of quinine are rarely given (3% of cases) and dose
      errors are not uncommon. Resource constraints such as a lack of nutritional
      supplements for malnourished children also restrict the provision of basic,
      effective care. INTERPRETATION: Even crude performance measures suggest there is
      a great need to improve care and data quality, and to identify and tackle key
      health system constraints at the first referral level in Kenya. Appropriate
      intervention might lead to more effective use of health workers' efforts in such
      hospitals.

PMID- 15194256
TI  - Confusion and paraparesis.

PMID- 15194257
TI  - Coping with paediatric referral--Ugandan parents' experience.
AB  - Referral of severely ill children to hospital is key in the Integrated Management
      of Childhood Illness (IMCI). In rural Uganda, we documented the caretakers'
      ability to complete referral to hospital from 12 health facilities. Of 227
      children, only 63 (28%) had completed referral after 2 weeks, at a median cost of
      8.85 US dollars (range 0.40-89.00). Failure to attend hospital resulted from lack
      of money (139 children, 90%), transport problems (39, 26%), and responsibilities
      at home (26, 17%). Children with incomplete referral continued treatment at
      referring health centres (87, 54%) or in the private sector (45, 28%). Our
      results show that cost of referral must decrease to make paediatric referral
      realistic. When referral is difficult, more specific IMCI referral criteria
      should be used and first-level health workers should be empowered to manage
      severely ill children.

PMID- 15194258
TI  - Toxoplasmosis.
AB  - Toxoplasma gondii is a protozoan parasite that infects up to a third of the
      world's population. Infection is mainly acquired by ingestion of food or water
      that is contaminated with oocysts shed by cats or by eating undercooked or raw
      meat containing tissue cysts. Primary infection is usually subclinical but in
      some patients cervical lymphadenopathy or ocular disease can be present.
      Infection acquired during pregnancy may cause severe damage to the fetus. In
      immunocompromised patients, reactivation of latent disease can cause life
      threatening encephalitis. Diagnosis of toxoplasmosis can be established by direct
      detection of the parasite or by serological techniques. The most commonly used
      therapeutic regimen, and probably the most effective, is the combination of
      pyrimethamine with sulfadiazine and folinic acid. This Seminar provides an
      overview and update on management of patients with acute infection, pregnant
      women who acquire infection during gestation, fetuses or infants who are
      congenitally infected, those with ocular disease, and immunocompromised
      individuals. Controversy about the effectiveness of primary and secondary
      prevention in pregnant women is discussed. Important topics of current and future
      research are presented.

PMID- 15194259
TI  - Growth hormone deficiency and related disorders: insights into causation,
      diagnosis, and treatment.
AB  - Advances in molecular biology have led to the identification of mutations within
      several novel genes associated with the phenotype of isolated growth hormone
      deficiency, combined pituitary hormone deficiency, and syndromes such as septo
      optic dysplasia. Progress has also been made in terms of the optimum diagnosis of
      disorders of stature and their treatment. The use of growth hormone for the
      treatment of adults with growth hormone deficiency and conditions such as
      Turner's syndrome, Prader-Willi syndrome, intrauterine growth restriction, and
      chronic renal failure has changed the practice of endocrinology, although cost
      benefit implications remain to be established.

PMID- 15194260
TI  - The next generation in shock resuscitation.
AB  - Resuscitation of the severely injured patient who presents in shock has improved
      greatly, following focused wartime experience and insight from laboratory and
      clinical studies. Further benefit is probable from technologies that are being
      brought into clinical use, especially hypertonic saline dextran, haemoglobin
      based oxygen carriers, less invasive early monitors, and medical informatics.
      These technologies could improve the potential of prehospital and early hospital
      care to pre-empt or more rapidly reverse hypoxaemia, hypovolaemia, and onset of
      shock. Damage control surgery and definitive interventional radiology will
      probably combine with more real-time detection and intervention for hypothermia,
      coagulopathy, and acidosis, to avoid extreme pathophysiology and the "bloody
      vicious cycle". Although now widely practised as standard of care in the USA and
      Europe, shock resuscitation strategies involving haemoglobin replacement and
      fluid volume loading to regain tissue perfusion and oxygenation vary between
      trauma centres. One of the difficulties is the scarcity of published evidence for
      or against seemingly basic intervention strategies, such as early or large-volume
      fluid loading. Standardised protocols for resuscitation, representing the best
      and most current knowledge of the clinical process, could be devised and widely
      implemented as interactive computerised applications among trauma centres in the
      USA and Europe. Prevention of injury is preferable and feasible, but early care
      of the severely injured patient and modulation of exaggerated systemic
      inflammatory response due to transfusion and other complications of traditional
      strategies will probably provide the next generation of improvements in shock
      resuscitation.

PMID- 15194261
TI  - Male circumcision and risk of HIV-1 infection.

PMID- 15194262
TI  - Male circumcision and risk of HIV-1 infection.

PMID- 15194263
TI  - Male circumcision and risk of HIV-1 infection.

PMID- 15194265
TI  - Species identification after treatment for taeniasis.

PMID- 15194267
TI  - The politics of terror.

PMID- 15194268
TI  - Autoimmune disease and other potential side-effects of statins.

PMID- 15194269
TI  - Malaria intermittent preventive treatment and EPI coverage.

PMID- 15194270
TI  - Spontaneous subdural haemorrhage in newborn babies.

PMID- 15194271
TI  - Novel means of spread of bloodborne infections in Pakistan.

PMID- 15194272
TI  - Need for national level outbreak control in Austria.

PMID- 15194273
TI  - Non-compliance.

PMID- 15194274
TI  - Public health goes private.

PMID- 15194276
TI  - Organ transplantation in Brazil in the year 2002.

PMID- 15194277
TI  - Do we need living unrelated organ donation in Brazil?
AB  - The remarkable success achieved by organ transplantation has also engendered the
      major problem of organ shortage. As a consequence, the use of living unrelated
      donors (LURD) has been proposed as an ethically justifiable alternative for
      developed nations to minimize their waiting lists for organ transplantation
      (OTx). This change in attitude has caused an ethical dilemma for developing
      countries like Brazil, which is struggling to increase the cadaver donor pool.
      Due to a huge socioeconomic gap of values and needs among nations, the incentive
      to use LURD in developed countries may not only produce a disincentive to cadaver
      organ donation but also stimulate organ trade in developing countries. In this
      paper we aimed to show that in Brazil, we do not need to use LURD because we have
      not optimized our cadaver donor pool. The exploitation of LURD might be a good
      option for developed countries, but it is not useful for developing countries.
      The Transplantation Society urgently needs to solve and clarify this problem by
      establishing basic ethical and justice principles that can serve as a guide for
      every country, throughout the entire process required, to achieve an adequate
      pool of cadaver donors.

PMID- 15194279
TI  - Organ donation and transplantation in Brazil: university students' awareness and
      opinions.
AB  - This study was aimed at assessing university students' awareness and opinions
      about aspects of the law no. 10.221/01. This exploratory study was performed
      among students at the Sao Paulo Federal University-UNIFESP, from 2001 to July
      2002, including 1284 undergraduates in the following courses: nursing, medicine,
      speech and language therapy, biomedicine, and ophthalmic technology. That data
      show that 47.7% (333) of undergraduates are aware of the kind of donation
      established by the new law. Among the adolescents of first and second grades, and
      courses, there was a difference on the awareness about the kind of donation (P
      =.000). Most undergraduates (57.6%, 402) agree with consented donation. However,
      the high percentage--35.1% (245)--that chose the alternative "I don't know" is
      remarkable. Results show that many undergraduates are unaware of the
      specifications of the technical files for transplants; only 48.3% (337) of them
      chose the correct answer, and 79.4% (554) do not believe that the order in the
      waiting list for transplants is respected. The conclusion is that it is worth
      emphasizing is that there are different opinions and levels of awareness among
      students, considering age, religion and religious practice, and course and level
      at school. In spite of unawareness and lack of belief in the principles of
      distribution of organs and tissue, most students are willing to be donors
      (68.2%).

PMID- 15194278
TI  - Expanding criteria for the use of living donors: what are the limits?
AB  - The cadaver organ shortage has pushed the transplant community to extend the
      boundaries beyond the traditional criteria used for living donor transplantation.
      This new liberal policy involves: (1) the type of donor, such as emotionally
      related individuals, the direct or indirect interchange of donors, anonymous as
      well as rewarded donation; (2) challenging immunological criteria, using
      incompatible ABO blood types and or transplantation across a positive cross
      match; (3) relaxing clinical criteria related to elderly, hypertensive, or obese
      donors, or patients with nephrolithiasis, fibromuscular renal artery disease,
      hematuria, or renal cell carcinomas. However, these practices may be dangerous.
      They must be clearly validated to promote a liberal policy of donor acceptance
      since it may carry a risk for both the donor and the recipient as well as for
      society. It is crucial to ensure the physical integrity of the donor as well as
      to provide guarantees, for instance a 1-year policy of life insurance, an
      indefinite long-term medical follow-up and the assurance of going to the top of
      the waiting list if the donor becomes uremic in the future.

PMID- 15194280
TI  - Almost 50,000 volunteers participate at Redome, the Brazilian Bone Marrow Donor
      Registry.
AB  - Striking progress has been observed in the number of volunteer donors for
      hematopoietic stem cell transplantation in the last years in Brazil. By the end
      of 1998, the number of donors barely reached 4200 but it has grown progressively.
      It was close to 48,000 by the end of May 1993. It is possible to notice a steady
      increase from the first (1993 to 2000) to the last years (2001 to 2003). The
      regulation of each procedure by the Brazilian Health System, with the
      collaboration of the Hematology Societies, was essential for the success of
      Redome and for the stem cell transplantation program in Brazil. However, when
      analyzing these results some problems were detected: 95% of Redome donors come
      from the south and southeastern regions of the country, while few donors are from
      the north, northeast, and central parts of Brazil. The different miscegenation of
      races in different regions and states of Brazil makes this an important issue: to
      represent the whole Brazilian population, Redome must improve the donor search in
      such places. It also became clear that several other centers involved in
      unrelated hematopoietic transplantation must be accredited to avoid a long line
      of patients with compatible donors a waiting transplantation.

PMID- 15194281
TI  - Future doctors and brain death: what is the prognosis?
AB  - OBJECTIVE: To evaluate the knowledge and the opinion of medical students at the
      Pontifical Catholic University of Sao Paulo related to the general aspects of
      donation, organ and tissue procurement, and basic concepts of brain death (BD).
      MATERIALS AND METHODS: Questionnaires of 24 items were distributed among all
      students related to the concept and diagnosis of BD, personal aspects of tissue
      and organ donation, and general question concerning organ donation. The answers
      classified students as good versus bad experts of the concept and the diagnosis
      of BD. RESULTS: Of a total of 580 students, 361 (62.24%) answered the
      questionnaire. Although the concept of BD was known to 70%, only 35% had a good
      knowledge of the diagnosis. One percent of the students were opposed to the organ
      donation and 76% of them were donors. Approximately 90% would authorize organ
      retrieval from their family members but 27% had never discussed organ donation
      with their families. Most students were interested in the general aspects of
      donation and organ procurement (88.36%). CONCLUSION: The majority of the students
      know the concept of BD. General aspects regarding tissue and organ donation and
      diagnosis of BD might be improved with the continued education on the subject.

PMID- 15194282
TI  - Knowledge about transplantation and attitudes toward organ donation: a survey
      among medical students in northeast Brazil.
AB  - During the registration for the second semester of 2002, 779 of the 1001 students
      from the Medical School, Federal University of Bahia, Brazil, answered an
      anonymous multiple-choice questionnaire including demographic variables,
      knowledge about transplantation issues, and willingness to donate organs. Mean
      age was 21.9 +/- 2.9 years (range: 17 to 51 years); 59.5% were men. Regarding the
      knowledge of which organs and tissues could be transplanted, 99.1% answered
      kidneys, 96.1% heart, 88.2% liver, 41.1% lung, 24.0% pancreas, 9% bowel, 98.3%
      corneas, 89.5% bone marrow, 38.1% heart valves, 47.7% skin, and 18.5% bone and
      tendons. Regarding the criteria of death, 82.4% answered that it is the lack of
      all brain activity, 8.2% cardiac arrest, 5.2% irreversible coma, and 4.2% did not
      know. As to the Brazilian transplantation law, 47.3% did not know, 51% had heard
      about it, and 1.7% answered that they knew the law in detail. As to the
      willingness to donate organs, 538 (69.2%) were donors. Of 239 nondonors, 51.1%
      answered the reason for not donating was the lack of confidence in the heath
      system, 14.3% had no knowledge of the matter, 17.7% were concerned about organ
      removal before brain death, and 1.7% for religious reasons. The percentage of
      those willing to donate organs was greater among spiritualists than among
      Catholics and Protestants. The results of this study support a greater emphasis
      on providing information regarding transplantation in medical schools to improve
      the knowledge of future heath care professionals about transplantation and organ
      donation issues.

PMID- 15194283
TI  - Strong linkage disequilibrium between HLA-B*3913 and DRB1*0807 in Brazilians.
AB  - The purpose of this research was to study the HLA-B39 distribution in 2560
      healthy, unrelated, randomly selected individuals living in the southeastern
      region of Brazil (the states of Rio de Janeiro and Sao Paulo). Molecular methods
      were used to type HLA class I and II polymorphism: PCR-SSP, PCR-SSO, and PCR-SBT.
      HLA-B*39 was found in 7% (n = 182) of these individuals. HLA-B*3901, B*3906, and
      B*3913 were the most common alleles in this group (n = 57, 36, and 24,
      respectively). B*3913 was found associated with DRB1*0807 and DQB1*0402 in 16 of
      the 24 individuals and 13 of these were also associated with A*31012. This
      haplotype segregation was confirmed by family studies. Furthermore, in 5 of the
      13 individuals carrying the A*31012, B*3913, DRB1*0807, and DQB1*0402 haplotype,
      HLA-DPB1*2701 was also present, suggesting that these alleles were found
      preferentially in cis association. DRB1-DPB1 linkage disequilibrium analysis was
      performed in 420 of the 2560 individuals and the association of DRB1*0807 with
      the uncommon DPB1*2701 was found to be highly significant (P <.0001). Because HLA
      B*3913 and HLA-DRB1*0807 have been observed only in South American populations,
      it is possible that interlocus association has been selected to act on the same
      haplotype to collaborate in the class I and II restricted immune response to
      local pathogens and functional adaptation. Although numbers are small to predict
      which ethnic groups of the Brazilian population display this haplotype
      prevalently, it is possible to speculate that these data may have clinical
      application, such as in the selection of unrelated donors for bone marrow
      transplantation.

PMID- 15194284
TI  - Tumor necrosis factor and interleukin-10 gene promoter polymorphisms in Brazilian
      population and in Terena Indians.
AB  - The Terena Amerindians are located in the midwestern region of Brazil. We have
      previously reported a restricted polymorphism for HLA class I and class II in 99
      unrelated Terena using PCR-SSO and more recently for MICA. There are single
      nucleotide polymorphisms (SNPs) that determine high or low production of certain
      cytokines. We have now studied the frequencies of mutant allele (A) at position 
      308 in the promoter of the gene tumor necrosis factor (TNF)-alpha (pro
      inflammatory cytokine) and the alleles A and T, at position -1082 and -819,
      respectively, in the promoter of the interleukin (IL)-10 gene, in 51 of these
      subjects from the Terena tribe using PCR SSP and in 195 normal unrelated healthy
      Brazilians using PCR-RLFP. All 51 Terena Indians tested (100%) had the G/G
      genotype at position TNF-alpha -308, with no mutation found thus far. In
      contrast, among the Brazilian general population, the allelic frequency of A was
      18.9%. When anti-inflammatory cytokine IL-10 was studied at two different
      positions, -1082 and -819, a high mutation rate was found when Terena were
      compared with the general Brazilian population (P <.05). The genetic cytokine
      profile may be required to balance the restricted HLA repertoire for peptide
      presentation in this native population.

PMID- 15194285
TI  - Impact of donor and recipient cytokine genotypes on renal allograft outcome.
AB  - Allelic differences in gene promoter or codifying regions have been described to
      affect regulation of gene expression, consequently increasing or decreasing
      cytokine production and signal transduction responses to a given stimulus. This
      observation has been reported for interleukin (IL)-10 (-1082 A/G; -819/-592
      CT/CA), transforming growth factor (TGF)-beta (codon 10 C/T, codon 25 G/C), tumor
      necrosis factor (TNF)-alpha (-308 G/A), TNF-beta (+252 A/G), interferon (IFN)
      gamma (+874 T/A), IL-6 (-174 G/C), and IL-4R alpha (+1902 G/A). To evaluate the
      influence of these cytokine genotypes on the development of acute or chronic
      rejection, we correlated the genotypes of both kidney graft recipients and
      cadaver donors with the clinical outcome. Kidney recipients had 5 years follow
      up, at least 2 HLA-DRB compatibilities, and a maximum of 25% anti-HLA
      pretransplantation sensitization. The clinical outcomes were grouped as follows:
      stable functioning graft (NR, n = 35); acute rejection episodes (AR, n = 31); and
      chronic rejection (CR, n = 31). The cytokine genotype polymorphisms were defined
      using PCR-SSP typing. A statistical analysis showed a significant prevalence of
      recipient IL-10 -819/-592 genotype among CR individuals; whereas among donors,
      the TGF-beta codon 10 CT genotype was significantly associated with the AR cohort
      and the IL-6 -174 CC genotype with CR. Other albeit not significant observations
      included a strong predisposition of recipient TGF-beta codon 10 CT genotype with
      CR, and TNF-beta 252 AA with AR. A low frequency of TNF-alpha -308 AA genotype
      also was observed among recipients and donors who showed poor allograft outcomes.

PMID- 15194286
TI  - T-cell response to self HSP60 peptides in renal transplant recipients: a
      regulatory role?
AB  - T-cell responses to heat shock proteins (Hsp) have been suggested to play a role
      not only in inflammatory conditions, but also in various human autoimmune
      diseases and in the allograft response. Previous data from our group suggested
      that during the early posttransplantation (post-Tx) period (<6 months post-Tx),
      the anti-Hsp60 T-cell repertoires in renal transplant recipients were
      predominantly proinflammatory. In the later period, they were predominantly
      regulatory. In agreement with our results, diversification of the T-cell
      responses toward the carboxy-terminal determinants of Hsp60, related to the
      resolution of the inflammatory process, was shown in an experimental model of
      adjuvant arthritis. It has not been clarified whether this diversification is
      also present in transplantation. In this context, our objective was to analyze
      cytokine production against autologous Hsp60 peptides from different regions of
      the protein, using peripheral blood mononuclear cells of 9 renal transplant
      recipients at 2 timepoints after transplantation: early (<6 months) and late (>1
      year). IFN gamma production induced by Hsp60 peptides was observed in 71% and 75%
      of the patients in the early and late post-Tx periods, respectively. Interleukin
      (IL)-10 production induced by Hsp60 peptides was observed in 28% of the patients
      in the early period and in 62% in the late period. Interestingly, the production
      of IL-10 was induced mainly by peptides of the intermediate and the C-terminal
      regions. This suggests a predominance of autoreactive regulatory anti-Hsp T-cell
      repertoire in the late post-Tx period, which predominantly recognize peptides
      from the intermediate and C-terminal regions of the protein.

PMID- 15194287
TI  - Monitoring anti-HLA Class I IgG antibodies in renal transplant recipients.
AB  - Anti-HLA class I IgG antibodies play an important role in hyperacute rejection
      but the significance of its de novo appearance or increase in levels during the
      posttransplant period remains controversial. The purpose of this study was to
      determine the correlation between the anti-HLA class I IgG antibodies and
      posttransplant events during the first 4 months after renal transplantation. From
      200 renal allograft recipients, 549 serum samples were retrospectively evaluated.
      Patients who experienced graft dysfunction confirmed by biopsy had three serum
      samples tested: before, during (within 24 hours), and after the event. The
      presence of anti-HLA antibodies was observed in recipients with chronic allograft
      nephropathy (60%); acute rejection (clinical criteria without biopsy 57.1%);
      rejection types IIA (7.1%), IIB (40%), and III (50%); borderline changes (42.8%);
      acute tubular necrosis (34.4%); infarction (25%); and no rejection (12.5%). We
      observed a high incidence of anti-HLA class I IgG antibodies during acute tubular
      necrosis, borderline changes, acute rejection types IIB and III, and chronic
      allograft nephropathy.

PMID- 15194288
TI  - Expression of cyclooxygenases during renal allograft rejection.
AB  - The aim of this work was to determine the expression of cyclooxygenases (COX-1
      and COX-2) during acute human renal allograft rejection. RT-PCR and
      immunohistochemistry were performed. The COX-2 mRNA was more abundant than COX-1
      mRNA in the group with acute rejection (P <.001). The locations of COX-1 and COX
      2 protein were consistent with the literature. Expression of COX-2 immunoreactive
      protein was higher in interstitial cells in the group with acute rejection than
      in the control group (P =.04). COX-2 protein was more abundant than COX-1 protein
      in the group with acute rejection, including podocytes (P <.001), proximal
      tubular cells (P <.001), collecting duct cells (P =.003), and interstitial cells
      (P <.001). In conclusion, COX-2 which is up-regulated during acute human renal
      allograft rejection, may play a role in renal inflammation.

PMID- 15194289
TI  - Oxidative stress, hepatocellular integrity, and hepatic function after initial
      reperfusion in human hepatic transplantation.
AB  - BACKGROUND: The mechanisms underlying liver graft dysfunction are not completely
      defined, although much of the injury derives from oxidative stress in organ
      reperfusion. The antioxidant glutathione in its reduced form (GSH) is an
      important agent to detoxify oxygen species after reperfusion. However, this
      effect might be limited by low concentrations at the end of cold storage. The
      objective of this study was to evaluate GSH and glutathione oxidized (GSSG)
      hepatic levels pre- and postreperfusion and correlate with hepatocellular injury
      and liver function in the 5 subsequent days after transplantation. METHODS: Liver
      biopsies were taken immediately before implant and 2 hours after venous
      reperfusion in 34 grafts, determining GSH, GSSG levels, and GSSG/GSH ratio.
      Aminotransferases (ALT, AST) and PT were measured for 5 days. RESULTS: There was
      a strong decrease in GSH concentration (P <.0001), increase of GSSG levels (P
      <.01), and increase of the GSSG/GSH ratio (P <.0001). No correlations were found
      between GSH, GSSG, or GSH/GSSH levels and AST, ALT, and PT. CONCLUSION:
      Glutathione levels showed significant changes after 2 hours of reperfusion, due
      to intense oxidative stress. Therapies to replenish GSH should be considered as a
      protective measure to avoid liver graft dysfunction after transplantation.

PMID- 15194290
TI  - Effects of N-acetylcysteine in hepatic ischemia-reperfusion injury during
      hemorrhagic shock.
AB  - This article seeks to standardize an experimental model of liver ischemia
      reperfusion in rats following hemorrhagic shock modulated by N-acetylcysteine
      (NAC). Twenty-seven adult Wistar rats were randomized into three groups: the HS
      IR-Garm underwent hemorrhagic shock with selective hepatic ischemia followed by
      reperfusion; the HSIR + NAC-G, the same procedure plus NAC; and the control
      group, only venous catheterization. Blood was withdrawn for 10 minutes until MABP
      reached 35 mm Hg, which was maintained for 1 hour. The blood was then reinjected
      as required to maintain MABP at that level. Ringer's lactate solution was infused
      in a volume equivalent to three times the shed blood, over a period of 15
      minutes. Half of the shed blood was reinfused over 5 minutes. HSIR + NAC-G
      received 150 mg/kg of NAC, during treatment of the shock, and again 10 minutes
      before reperfusion and continued for 30 minutes. Finally, both groups were
      subjected to 40 minutes of warm selective hepatic ischemia and reperfusion for 1
      hour. Data were analyzed by nonparametric tests (P < or =.05). Liver enzyme
      levels were higher in HS-IR-G (DHL = 6094 +/- 1688, AST = 746 +/- 175, and ALT =
      457 +/- 90) than in HSIR + NAC-G group (DHL = 2920 +/- 284, AST = 419 +/- 113,
      and ALT = 253 +/- 26). The values in the control group were lower than both
      experimental groups (DHL = 965 +/- 173, AST = 163 +/- 42, and ALT = 82 +/- 28).
      Our data showed that liver ischemia-reperfusion injury following hemorrhagic
      shock produces important hepatic damage and that NAC reduces injury in this rat
      model.

PMID- 15194291
TI  - Tempol, an intracelullar free radical scavenger, reduces liver injury in hepatic
      ischemia-reperfusion in the rat.
AB  - Liver ischemia is of clinical interest because of its role in liver failure and
      also hepatic graft rejection. The generation of reactive oxygen species
      contributes to the injury that follows ischemia-reperfusion. One therapy utilizes
      the administration of antioxidants; however, only limited experience suggests a
      potential benefit of systemic administration of these compounds. To overcome the
      limitations of these compounds, small molecules with improved cell membrane
      permeability characteristics and higher potency, such as tempol, are being tested
      in vivo. Tempol, a membrane-permeable radical scavenger, interferes with the
      formation or the effects of many radicals, including superoxide anions, hydroxyl
      radicals, and peroxynitrite. The aim of this study was to investigate the effects
      of tempol in an in vivo rat model of liver ischemia-reperfusion injury. Male
      Wistar rats were pretreated with tempol (30 mg/kg, i.v.) 5 minutes prior to liver
      ischemia (for 30 minutes) and reperfusion (for 2 hours). The liver injury was
      assessed by measuring serum levels of transaminases, lactate dehydrogenase, and
      gamma-glutamyl transferase. Tempol significantly mitigated the increase in
      transaminases, lactate dehydrogenase, and gamma-glutamyl transferase following
      liver ischemia-reperfusion, suggesting an improvement in liver function and
      resistance to injury.

PMID- 15194292
TI  - FTY720 impairs necrosis development after ischemia-reperfusion injury.
AB  - Ischemia-reperfusion (IR) injury is a common early feature that contributes to
      graft damage by impairing resident cell function. Our previous results showed
      that IR injury impaired renal function, by causing extensive tubular necrosis and
      increasing MHC class II and ICAM-1 molecule expression by mesangial cells (MC).
      MCs are likely candidates to come into close contact with immune cells such as
      monocytes or lymphocytes. It has been suggested that under inflammatory
      circumstances, there is increased MC expression of MHC class II, of adhesion
      molecules (such as ICAM-1), of cytokines receptors, and of molecules associated
      with cellular death (apoptosis). The immunosuppressive properties of FTY720 have
      been shown in clinical and experimental situations. It has also been shown to be
      protective against IR injury in rats. We sought to evaluate the role of FTY720 in
      a murine IR model by measuring renal function, tubular necrosis, and surface
      molecule expression by cultured mesangial cells. Intravenous administration of
      FTY720 (1 mg/kg) immediately before IR induction did not improve the short-term
      (24 hours) outcome of renal function or reduced MHC class II and ICAM-1 surface
      molecule expression. However, there was a decreased percentage of tubular
      necrosis in mice treated with FTY720 (51.3% +/- 1.6%) compared with vehicle
      treated mice (66% +/- 5.5%). These results suggest a protective role of FTY720 in
      an IR injury model. More studies are required to identify the mechanisms involved
      in the protective activity of FTY720 in the IR injury model.

PMID- 15194293
TI  - Gangliosides on intestinal microcirculation and animal survival during
      reperfusion.
AB  - This study investigated the effect of gangliosides (Gang) on small bowel
      microcirculation and animal survival after normothermic intestinal ischemia
      reperfusion injury. Five adult male EPM-1 Wistar rats in each of three groups
      received FK506 (0.2 mg/kg), Gang (3 mg/kg), or vehicle (at same volume) either 24
      or 12 hours prior to the experiment. The animals were anesthetized
      intramuscularly with ketamine (60 mg/kg) and xylazine (10 mg/kg) and hydrated
      with 80 mL/kg of prewarmed saline solution delivered subcutaneously before the
      ischemic insult and 40 mL/kg at 1 hour after reperfusion. Under anesthesia, they
      underwent a laparotomy with clamping of the superior mesenteric artery (SMA) at
      its origin for 75 minutes. Microcirculation was evaluated with a laser Doppler
      flowmeter, 5 minutes before ischemia (baseline) and reperfusion (ischemia), and
      20, 40, and 60 minutes after reperfusion. Animal survival was observed up to 24
      hours. Small bowel flow measured before ischemia was considered to be the
      baseline level (100%). After SMA occlusion a significant reduction in
      microcirculatory tissue perfusion to about 8% was observed in all groups. At 20,
      40, and 60 minutes of reperfusion treatment with Gang (77%, 81%, and 100%) or
      FK506 (70%, 85%, and 98%) promoted better recovery of the intestinal
      microcirculation when compared to the control group (45%, 72%, and 75%).
      Concerning animal survival there was no difference between groups (just one
      animal from each group, Gang and FK506, survived up to 24 hours). Based on our
      data we conclude that Gang and FK506 improve intestinal microcirculation in
      ischemia-reperfusion injury but do not change animal survival after severe
      ischemia.

PMID- 15194294
TI  - Biochemical and morphological evaluation of ischemia-reperfusion injury in rat
      small bowel modulated by ischemic preconditioning.
AB  - The objective of this study was to evaluate the effect of ischemic
      preconditioning upon lesions produced by ischemia-reperfusion of the small
      intestine. Thirty EPM-1 Wistar rats were randomly distributed into three groups:
      ischemic preconditioning (IPC; n = 12), ischemia-reperfusion (I/R; n = 12), and
      control (C; n = 6). Laparotomy permitted isolation of the mesenteric artery for
      clamping. The animals were heparinized and hydrated. IPC was induced by: 10
      minutes of ischemia followed by 10 minutes of reperfusion and then 50 minutes
      ischemia followed by another 30 minutes reperfusion. Group I/R was submitted to
      the same protocol except for the 20 minutes of preconditioning. Group C animals
      underwent only laparotomy for 100 minutes. After reperfusion small intestine
      fragments were examined histologically. Blood samples were obtained to measure
      LDH and lactate prior to euthanasia. Lactate values were significantly lower in
      the IPC as compared to I/R group, 39 versus 67 mg/dL, respectively (P < or =.05).
      However, neither IPC (grade 3) lesions of the mucosa versus I/R (grade 4) nor LDH
      values (PCI = 680, I/R = 873 U/L) were statistically different. Thus No
      morphological evidence of protection was observed following ischemic
      preconditioning.

PMID- 15194295
TI  - Long-term outcome of renal transplantation at a university center in Rio de
      Janeiro between 1975 and 2000.
AB  - This study reports the 25-year experience of a single university center with
      respect to the impact of selected variables on long-term survival and half-life
      of 742 transplants. We calculated 1-, 5-, and 10-year Kaplan-Meier survival rates
      for grafts and patients, with separate analyses for HLA match and for each
      quinquennium. We also investigated the impact of cyclosporine administration and
      OKT3 induction. Global graft and patient survival rates were 85.2%, 61.0%, and
      43.5% and 93.0%, 78.9%, and 66.6% for 1, 5, and 10 years, respectively. The half
      life of 23.3 years for the 105 HLA-identical transplants was significantly better
      (P <.0001) than that for all other matches. Half-lives for 319 1-haplotype
      matched, 116 living-unrelated, and 153 cadaver grafts were 8.2, 5.7, and 5.6
      years, respectively. No survival advantage was noted among these other matches.
      Introduction of cyclosporine in all non HLA-identical transplants and OKT3
      induction for cadaver grafts conferred significant survival advantages compared
      with no use (P =.0002 and P =.009). There has been a continuous improvement in
      the long-term results in each quinquennium studied.

PMID- 15194296
TI  - Chagas seropositive donors in kidney transplantation.
AB  - Among 239 kidney transplantations between September 1992 and September 1997, nine
      recipients' kidneys were obtained from Chagas seropositive donors. All of these
      patients were treated with benznidazole (5 mg/kg/d) for 14 days starting on day
      0. None of them experienced acute Chagas disease or seroconversion even after 10
      years follow-up. We concluded that, due to cadaver shortage, donors with positive
      serology for Chagas disease should not be excluded.

PMID- 15194297
TI  - Pregnancy outcome after renal transplantation.
AB  - AIMS: The aim of our study was to evaluate the frequency and the outcome of
      pregnancies in renal transplant recipients at our center. METHODS: This study
      involved the retrospective analysis of 405 childbearing female renal recipients
      for presence of risk factors, the outcome of pregnancy, and maternal and fetal
      complications. RESULTS: Fourty-four pregnancies occurred in 41 patients (10.8%).
      Mean age at transplantation was 23.6 +/- 6.3 years (range, 12-38 years). Only in
      5 pregnancies were there no risk factors. In 13 (29.5%) pregnancies, the previous
      creatinine level was >1.5 mg/dL, in 16 (36.45%), proteinuria was >500 mg/24
      hours; 29 (65.9%) were hypertensive; 14 (31.8%) had a time between
      transplantation and pregnancy less than 2 years (mean time, 35.5 +/- 30.9 months;
      range, 3-120 months). The outcomes were 27 (61.4%; 11 term and 16 premature
      delivery) successful pregnancies, 6 (13.6%) spontaneous abortions, 10 (22.7%)
      therapeutic abortions, and 1 (3.2%) fetal death. Pre-eclampsia occurred in 9
      (20.4%) pregnancies and eclampsia in 1 (2.2%). The mean weight of the offspring
      was 2195 +/- 490 g (range, 1300- 2980 g). There were 2 cases of acute fetal
      distress and 1 oligodramnios. Median creatinine level was 1.0 (range, 0.4-3.0)
      mg/dL before conception and 1.2 (range, 0.7-9.0) mg/dL 6 month after pregnancy (P
      <.001). The long-term patient and graft survival rates were similar for pregnant
      versus nonpregnant recipients in the childbearing age. CONCLUSION: Most
      pregnancies were successful, although the premature delivery rate was high
      (36.4%). Only 5 conceptions occurred in the absence of risk factors. Pregnancy
      did not impair the patient and graft survival during long-term follow-up.

PMID- 15194298
TI  - Kidney transplantation improves the multidimensional quality of life.
AB  - INTRODUCTION: Quality of life is affected during any illness, especially chronic
      diseases, such as renal failure. OBJECTIVE: To evaluate the quality of life after
      kidney transplantation. METHODS: One hundred patients were interviewed (60 men,
      40 women, mean age 36 +/- 10.4 years, median 35 years) from July to October 2000
      using the multidimensional questionnaire WHOQL-Bref. RESULTS: Eighty-eight
      percent of patients were satisfied/very satisfied with their general health
      condition. Seventy-seven percent manifested a good capacity to carry out daily
      activities, and 75% considered themselves satisfied with their work capacity.
      Quality of life was considered "very good" or "good" among 80%, and "neither good
      nor bad" in 20%. None considered quality of life in general as "bad" or "very
      bad." Most (87%) were satisfied with their current condition and with themselves
      after the kidney transplant. CONCLUSION: Patients perceive kidney transplant as
      capable of improving their quality of life. The most important finding in this
      study is that the results of the physical and psychological domains did not show
      any significant difference. It was possible to conclude that the quality of life
      for most subjects is related to reduction or disappearance of the symptoms caused
      by the previous disease.

PMID- 15194299
TI  - Induction versus noninduction therapy in kidney transplantation: considering
      different PRA levels and different induction therapies.
AB  - To evaluate the rate of acute cellular rejection (ACR) and long-term results in
      different levels of anti-HLA sensitization, using noninduction or different
      induction therapies, 763 patients who underwent transplantation from January 1995
      to December 2001 were evaluated: 213 patients received induction therapy, 71
      received Thymoglobulin (Thymo), 66 Simulect, and 44 OKT3. Follow-up time was at
      least 1 year for all groups. The Simulect group included older recipients and the
      OKT3 group had more female patients. Simulect and OKT3 groups had more black
      patients; Thymo and OKT3 groups had more retransplantations. PRA was low in the
      noninduction group (mean, 7%) and about the same in the Simulect and Thymo groups
      (mean, 30%). OKT3 was the most sensitized group (mean = 59%). Dialysis during the
      first posttransplantation week was more frequent among the induction groups (43%
      vs 65%; P <.005). Fewer patients experienced rejection episodes in the Thymo
      group (20% vs 50%; P =.02). Patients were classified according to their level of
      sensitization, and the Thymo group showed the lower rejection rates in all levels
      (mean, 20%; P =.001). When analyzing PRA >50%, the Thymo group showed lower
      rejection rates (12% vs 50%; P =.02). At this level of sensitization, there was
      no significant difference on graft loss and death with a functioning graft. There
      was a trend to more cytomegalovirus (CMV) disease in the Thymo group (33% vs 23%;
      P =.08). Two PTLD were diagnosed, both in the noninduction group. Renal function
      was better in the Thymo group (1.3 mg/dL). In conclusion, Thymo showed lower ACR
      rates in all PRA groups. No significant differences in CMV infection, tumors, and
      patient survival were observed.

PMID- 15194300
TI  - Cyclosporine versus tacrolimus in kidney transplantation: are there differences
      in nephrotoxicity?
AB  - Cyclosporine and tacrolimus, two calcineurin inhibitors, show different side
      effects and toxicities. The data concerning their nephrotoxicity are few and
      conflicting. A retrospective study was performed in 2 groups of renal transplant
      recipients treated with cyclosporine or tacrolimus to evaluate graft function and
      side effects. All patients had completed at least 6 months of follow-up before
      inclusion in the study. Group I included 10 patients who were converted from
      cyclosporine to tacrolimus, due to cosmetic problems or due to chronic graft
      dysfunction with creatinine values <3 mg/dL. After conversion, there was a
      significant reduction in creatinine values (from 2.43 +/- 1.21 to 1.86 +/- 0.72
      mg/dL; P =.023) and an improvement in creatinine clearance (from 47.5 +/- 19.2 to
      56.1 +/- 18.9 mL/min; P =.047). The lipid profile did not change, but there was a
      trend to better blood pressure control with less antihypertensive drugs. Group II
      compared 2 subgroups of patients receiving kidneys from the same donor, one
      treated with cyclosporine and the other with tacrolimus. Tacrolimus patients
      showed better renal function; namely, creatinine was 1.15 +/- 0.27 versus 1.44 +/
      0.33 mg/dL (P =.029) and creatinine clearance was 87.7 +/- 27.1 versus 60.3 +/-
      25.9 mL/min (P =.043). Lipid and blood pressure values were not different between
      the 2 subgroups, but tacrolimus patients tended to need a lower number of
      antihypertensive medications. The incidence of de novo diabetes mellitus was
      approximately 20% among patients using tacrolimus. We concluded that tacrolimus
      may be less nephrotoxic than cyclosporine. Tacrolimus patients showed better
      graft function and easier blood pressure control, but a high incidence of
      posttransplantation diabetes mellitus.

PMID- 15194302
TI  - Posttransplant diabetes mellitus in cyclosporine-treated renal allograft
      patients: a case-control study.
AB  - The incidence and risk factors for the development of posttransplant diabetes
      mellitus (PTDM) was retrospectively evaluated in cyclosporine-treated renal
      transplant patients. An incidence of 9.4% was observed over a 10-year period.
      Weight and body mass index were risk factors identified in a case-controlled
      study. Age, race, family history of DM, and cyclosporine and prednisone doses
      were not associated with the development of PTDM. We concluded that the
      development of PTDM is mainly related to weight. All efforts must be taken to
      avoid this complication.

PMID- 15194301
TI  - Cyclosporine increases endothelin-1 plasma levels in renal transplant recipients.
AB  - Endothelin-1 (ET-1) has been associated with the development of hypertension in
      cyclosporine-treated renal transplant recipients. To clarify this association,
      this observational study compared ET-1 levels in 33 patients taking cyclosporine
      therapy versus 10 controls. Three hours after cyclosporine administration, ET-1
      levels were higher than in the controls, namely 1.81 + 0.99 versus 1.17 + 0.46
      pg/mL (P <.04). These results suggest a role of ET-1 in the pathogenesis of post
      renal transplantation hypertension in cyclosporine-treated recipients.

PMID- 15194303
TI  - Is hepatitis C a risk factor to posttransplant diabetes mellitus after renal
      transplantation in patients using tacrolimus?
AB  - The objective of this study was to evaluate the association between previous
      hepatitis C virus (HCV) infection and the occurrence of posttransplant diabetes
      mellitus (PTDM) among patients undergoing kidney transplants using tacrolimus
      (FK). From August 1999 to January 2003, 66 patients (36.4 +/- 15.5 years)
      underwent kidney transplantation using an immunosuppressive regimen of
      tacrolimus, mycophenolate mofetil, or azathioprine and steroids. Thirty-four
      patients (52%) received kidneys from living donors and 32 (48%) from cadaveric
      donors. The diagnosis of diabetes mellitus was established after two consecutive
      ambulatory measurements of fasting glycemia > or = 126 mg/dL. Thirty-five percent
      of the patients (23/66) were HCV+ and 65% (43/66) HCV-. Of the 66 patients, 33%
      (22) developed PTDM, 19 (82%) from the HCV+ group and only 3 (7%) from the HCV-
      group. Among those who developed PDTM, the diagnosis was established in the first
      2 posttransplant months in most cases (68.2%). The results showed a significant
      association between HCV and PTDM (P < or = .0001). In this group of patients HCV
      infection was strongly associated with the development of PTDM. Therefore,
      additional care is required regarding the immunosuppressive regimen among
      patients with chronic HCV infection.

PMID- 15194304
TI  - Posttransplant diabetes mellitus in renal transplant patients with hepatitis C
      virus.
AB  - The aim of this study was to assess the possible association between
      posttransplant diabetes mellitus (DM) and hepatitis C virus (HCV) infection in
      renal transplant recipients. This study included 124 patients who underwent renal
      transplantation between 1997 and 2002. Inclusion criteria were patients who were
      not diabetic prior to transplantation and posttransplant follow-up longer than 6
      months. DM was defined as fasting blood glucose levels higher than 126 mg/dL on
      at least two occasions. HCV infection was detected using second- or third
      generation ELISA methods and/or polymerase chain reactions for HCV-RNA. Twenty
      five HCV positive (HCV+) patients were compared with 25 consecutive HCV negative
      (HCV-) transplant patients. Demographic and clinical data of the groups were
      compared. Posttransplantation DM was observed in 24% of the HCV+ patients. There
      were no statistical differences in age, gender, race, family history of DM,
      follow-up, or body mass index between the two groups. There was a higher
      prevalence of posttransplantation DM in HCV+ patients, but the difference did not
      reach statistical significance (24% vs 12%, P = NS). Alternatively, comparing
      patients of the two groups (n = 50) who did versus not develop DM, the incidence
      of posttransplantation DM was higher among HCV+ patients, but the difference did
      not reach statistical significance (66.6% vs 46.3%, P = NS). In conclusion, there
      was no association between HCV infection and the development of
      posttransplantation DM in this cohort of renal transplant recipients. However,
      there was a trend that suggested an association.

PMID- 15194305
TI  - Effectiveness of diet in hyperlipidemia in renal transplant patients.
AB  - In renal transplant patients dietary therapy alone does not always provide
      satisfactory results to control hyperlipidemia. To assess the effectiveness of
      diet, 151 renal transplant patients were selected for a prospective clinical
      study using pre- and posttest groups. During 8 weeks these patients received a
      diet with 25% energy intake from lipids, less than 10% from saturated fats, and
      less than 500 mg of cholesterol per day. Total cholesterol, LDL cholesterol, HDL
      cholesterol, and triglycerides were measured (pre- versus postdiet). The degree
      of compliance with the diet was measured by a 24-hour food recall record.
      Patients who had 90% compatibility between the questionnaire and the prescribed
      diet were considered compliant. The diet was considered effective in the patients
      who achieved a reduction of cholesterolemia to less than 200 mg/dL after 8 weeks
      of treatment. Ultimately 108 patients completed the study, with a significant
      reduction in total serum cholesterol from 262.37 mg/dL pretest to 252.85 mg/dL
      posttest (P =.010); LDL cholesterol from 174.29 mg/dL pretest to 166.60 mg/dL
      posttest (P =.036), of body weight from 68.98 kg pretest to 67.78 kg posttest (P
      =.01) and of body mass index from 25.86 kg/m(2) pretest to 25.41 kg/m(2) posttest
      (P =.01). Cholesterol variation was 3.63% as compared to prediet levels. Only 22
      patients (20.4%) achieved cholesterol levels below 200 mg/dL. In conclusion,
      although diets decrease cholesterolemia, they alone are not effective to control
      hyperlipidemia in most renal transplant patients.

PMID- 15194306
TI  - Comparison between RFLP-PCR and antigenemia for pp65 antigen for diagnosis of
      cytomegalovirus disease after kidney transplantation.
AB  - Cytomegalovirus (CMV) infection is the single most frequent infectious
      complication in renal transplant recipients. The purpose of this study was to
      analyze the diagnostic efficacy of PCR-RFLP compared to antigenemia for CMV
      disease (CMVD) in kidney transplant recipients. From November 2001 to February
      2002, 19 renal adult transplant recipients were followed with weekly measurements
      of CMV pp65 antigen to monitor the activity of CMV from the week 4 to 12
      posttransplantation. Only 4 (21.1%) patients did not develop viremia during the
      first 12 posttransplantation weeks. Active infection was observed in 15 patients
      (78.9%): asymptomatic viremia in 6 (31.6%) and CMVD in 9 (47%). All patients who
      developed CMVD showed positivity in both methods during the observation period.
      The number of positive cells ranged from 11 to 292 cells in patients with CMVD
      and one to eight cells among those with asymptomatic viremia. Both methods
      revealed 100% sensitivity for CMVD diagnosis. The specificity was 60% for
      antigenemia and 70% for PCR, with positive predictive values of 60% and 75%,
      respectively.

PMID- 15194307
TI  - Serial beta-2 microglobulin measurement as an auxilliary method in the early
      diagnosis of cytomegalovirus infection in renal transplant patients.
AB  - Infection by cytomegalovirus is one of the most important causes of morbidity and
      mortality after renal transplant. During episodes of acute rejection serum levels
      of beta-2 microglobulin (B2M) are elevated due to decreased excretion and/or
      increased production from T-cell proliferation. Sequential measurement of B2M in
      the first months after transplantation may detect patients at increased risk of
      rejection. This study assesses the usefulness of serum B2M for early detection of
      patients with increased risk of cytomegalovirus disease. Among 16 of 18 cases of
      CMV infection, there was an increase in serum B2M levels before CMV diagnosis. In
      all cases, B2M serum levels increased at an average of 10.8 days before the
      symptoms or the positive antigenemia. From a mean baseline B2M value of 5.0 mg/L,
      the mean value at the time of diagnosis was 7.7 mg/L before any clinical or
      laboratory evidence of CMV infection. These findings suggest that B2M serum
      levels can be used as a marker for early diagnosis of cytomegalovirus infection.

PMID- 15194308
TI  - Cytomegalovirus disease latent and active infection rates during the first
      trimester after kidney transplantation.
AB  - Cytomegalovirus (CMV) infection is the single most frequent infectious
      complication in renal transplant recipients. The aim of this study was to
      determine the incidence of latent and active infections with CMV during the first
      3 months after kidney transplantation. From January 2000 to December 2001, 203
      consecutive adult renal transplant recipients underwent weekly measurements of
      pp65 CMV antigen from the 4th to the 12th posttransplantation week. Latent
      infection (seropositivity) was found in 92% of the population. Primary infection
      occurred in 4.9% (10 of 203), among whom 66% were previously seronegative
      patients. Among the primary infection patients, 70% (7 of 10) developed severe
      disease. The overall incidence of viremia was 69.5%, being more frequent among
      cadaver recipients (79% vs 59%; P =.02). The overall incidence of CMV disease was
      38.4% (78 of 203) with 24.6% classified as severe disease requiring antiviral
      therapy. In conclusion, our population showed a high prevalence of latent
      infection with viremia. Not all patients developed clinical disease. Most
      subjects experienced a mild spectrum of symptoms, probably due to the prospective
      search for active infection during the major risk period after kidney
      transplantation.

PMID- 15194309
TI  - Urine cytology as a screening method for polyoma virus active infection.
AB  - Polyoma virus nephropathy (PVN) occurs in 3% to 4% of renal transplants, causing
      graft loss in about 50% of cases. The presence of viral cytopathic changes in
      graft epithelial cells is the only diagnostic tool for PVN. However,
      identification of cells with viral inclusions (decoy cells) in urine can be used
      as a screening tool for viral replication of or for active infection with PV. The
      aim of the present study was to identify the occurrence of PV active infection in
      renal transplant recipients. Two hundred forty urine cytology samples, collected
      from 80 transplant patients with stable renal function, were collected on a
      monthly basis and stained with the Pap smear for decoy cells. Active infection
      with polyoma virus was confirmed by urine immunostaining. All samples were
      analyzed blindly and classified as negative or positive (>1 decoy cell/sample).
      Among 240 urine cytologies collected from 48 men and 32 women, decoy cells were
      identified in 37.5%. No differences were observed in serum creatinine or
      immunosuppressive regimen between patients with positive versus negative
      cytology. No graft losses occurred secondary to PVN in the present study setting.
      The incidence of decoy cells in this series (37.5%) was consistent with previous
      reports (20% to 40%), suggesting that active infection may be confirmed by PV
      immunohistochemistry. The absence of PVN in this group may be attributed to the
      low doses of immunosuppressive drugs in the late posttransplant transplant
      period, but also to the unknown incidence of polyoma virus infection in Brazil.

PMID- 15194310
TI  - Human herpes virus-8 serology and DNA analysis in recipients of renal allografts
      showing Kaposi's sarcoma and their respective donors.
AB  - Kaposi's sarcoma (KS) developed among 11 of 416 renal allograft recipients
      transplanted between 1985 and 2000. Only 3 among 364 Caucasian recipients
      developed KS, while it affected 8 of 52 Black patients, all of whom had been born
      in African countries (P <.001). All patients had their immunosuppression reduced;
      two also received daunorubicin and one received electrotherapy. Three patients
      developed accelerated renal allograft dysfunction, probably due to the reduced
      immunosuppression. Remission of KS was observed in seven patients, while lesions
      stabilized or improved partially in the other four. After resuming dialysis 2 of
      11 patients died; both were in KS remission. Human herpes virus-8 (HHV-8)
      serology and DNA analysis was evaluated in sera obtained from seven donors: all
      were negative. Conversely, among eight sera collected pretransplant from the nine
      living recipients, HHV-8 IgG was detected in six and DNA was present in one. HHV
      8 IgG was expressed in all patients (9/9) at some point posttransplant; DNA was
      detected in three patients. Therefore, the robust ethnic predisposition to KS was
      associated with a high pretransplant prevalence of HHV-8 among African
      recipients. Although some seroconversions were detected posttransplant, there was
      no evidence for donor-to-recipient transmission.

PMID- 15194311
TI  - Tuberculosis in renal transplants in Rio de Janeiro.
AB  - Retrospective analysis of 982 renal transplants over 21 years (1981 to 2002)
      sought to evaluate the prevalence of tuberculosis (TB). This analysis included 74
      patients: 30 with a past TB history, who had INH prophylaxis since the beginning
      of immunosuppression, and 44 who only became TB infected after receiving
      transplants. The diagnosis of TB was made by a compatible medical situation with
      bacteriological/histological confirmation, which when not possible, underwent a
      therapeutic test occur. The average time for the illness to surge was 3 years.
      The mortality rate was 34.9% (15/44). Patients with hepatitis C were more
      affected. Among those who used INH prophylaxis only one contracted TB, showing
      that the drug displayed a protection rate of 96.6% (29/30).

PMID- 15194312
TI  - Impact of steatotic grafts on initial function and prognosis after liver
      transplantation.
AB  - Steatotic grafts are considered a risk factor for dysfunction or even primary
      nonfunction of liver transplants; grafts with more than 50% fatty infiltration
      are routinely discarded. This retrospective study evaluated the impact of
      macrovesicular and microvesicular steatosis on postoperative initial liver
      function and prognosis by comparing outcomes to nonsteatotic grafts in 48 liver
      transplantation patients. Fifteen grafts had macrovesicular steatosis, 13
      (27.09%) up to 50% fatty infiltration (MG2), and 2 (4.16%) more than 50% (MG3).
      Thirty-three (69.75%) grafts had no macrovesicular steatosis (MG1). Initial liver
      function was adequate in 26 (78.78%), 10 (76.93), and 2 (100%) patients,
      respectively, in subgroups MG1, MG2, and MG3 (P =.892). Thirty-day survival rates
      were 90.90%, 100%, and 100%, respectively, in subgroups MG1, MG2, and MG3 (P
      =.606). Twenty-six grafts showed microvesicular steatosis: 18 (37.50%) showed
      less than 50% fatty infiltration (mG2), and 8 (16.67%) more than 50% (mG3).
      Twenty-two (45.83%) grafts had no microvesicular steatosis (mG1). Initial liver
      function was adequate in 16 (72.72%), 16 (88.88%), and 6 (75%) patients,
      respectively, in subgroups mG1, mG2, and mG3 (P =.547). Thirty-day survival rates
      were 90.90%, 100%, and 87.5% respectively, in subgroups mG1, mG2, and mG3 (P
      =.380). In conclusion, macrovesicular and microvesicular steatotic liver grafts
      displayed adequate initial function, did not compromise survival, and thus should
      not be routinely discarded.

PMID- 15194313
TI  - Donor quality of life after living donor liver transplantation.
AB  - Living donor liver transplantation (LDLT) for children and adults has gained
      widespread acceptance due to the severe organ shortage. LDLT provides potential
      recipients with timely transplantation, but this procedure engenders a
      potentially significant risk to the donor. This study analyzed medical,
      functional, and psychological donor outcomes after LDLT. Nineteen donors (mean
      age 33.9 +/- 12 years), who underwent hepatectomy for LDLT (13 right lobectomy
      for adult LDLT) from March 1998 to November 2002, were interviewed at a median of
      13 months after donation (range, 2 to 58 months). According to the Clavien System
      classification, major complications occurred in three donors (16%), and minor in
      four (21%). The mean length of hospital stay was 5.7 +/- 1.6 days. Five patients
      (27%) needed rehospitalization. Complete recovery was achieved at a mean time of
      8.5 +/- 3.5 weeks. All 19 donors were able to return to predonation activities.
      The donor's relationship to the recipient and to their families was improved
      after donation in all cases; 12 (63%) cited a positive psychological impact on
      their lives. About 90% would donate again and 84% would recommend donation to
      someone contemplating it. In conclusion, all donors are alive and well after
      donation and were able to return to their predonation occupation. Most of them
      felt that this experience changed their lives for the better and would donate
      again. Donor safety and quality of life should remain the priority in all
      donation processes.

PMID- 15194314
TI  - Can the use of marginal liver donors change recipient survival rate?
AB  - Liver transplantation as a therapeutic method for the treatment of end-stage
      liver disease is beclouded by a scarcity of organs. The aim of this study was to
      retrospectively analyze the relation between the classification of donors as
      marginal versus ideal and recipients survival after 148 of 197 orthotopic liver
      transplantations (OLT) performed from 1991 to 2001. Donors were classified as
      marginal if they showed the major criteria of: age over 55 years, aspartate
      aminotransferase greater than 150 UI/L; serum bilirubin greater than 2 mg/dL,
      serum sodium greater 150 mEq/L, high-dose dopamine or any other vasoactive amine,
      cardiac arrest, intensive care unit (ICU) stay over 5 days, and moderate severe
      macrosteatosis. The minor criteria for a marginal donor were: use of dopamine
      below 10 microg/kg/min, history of alcoholism, drug abuse, ICU stays less than 4
      days, microsteatosis of any degree, and mild macrosteatosis. Statistical analysis
      was performed using Cox regression analyzing and the Kaplan-Meier survival
      method. The rate of marginal donors was 61.5%. The 180 postoperative day survival
      was 77.0%. Survival rates were 81.1% for recipients of marginal donor organs, and
      70.7% for ideal donor recipients (P >.05). In conclusion, the use of marginal
      liver donors is viable and safely expands the numbers of liver transplants,
      thereby diminishing the number of waiting list deaths.

PMID- 15194315
TI  - Domino liver transplant: influence on the number of donors and transplant
      coordination.
AB  - The shortage of organs forces coordinators to seek new forms of generating organs
      for transplantation of the increasing numbers of patients on waiting lists. A
      recent technique called sequential transplant or domino liver transplant (DLT)
      allows the transplantation of a patient with chronic liver disease by
      implantation of a full-size liver derived from a patient with familial
      amyloidosis polyneuropathy (FAP) who receives a cadaveric graft. Therefore, it is
      possible to transplant two patients with only one cadaveric liver. The present
      report illustrates the use of this technique for the first time in our country,
      thereby increasing the number of hepatic transplants by 25%.

PMID- 15194316
TI  - Results of 60 consecutive hepatectomies for pediatric living donor liver
      transplantation.
AB  - Several technical improvements have been made to increase donor pool for
      pediatric liver transplantation, including reduced-size grafts, split-liver, and
      recently living donors. The objective of the present study is to report our
      single-center experience with 60 hepatectomies for living donor liver
      transplantation in pediatric recipients between June 2000 and December 2002.
      Donor workup consisted of a complete history and physical examination followed by
      laboratory test and liver function tests. Graft size was estimated using computed
      tomography scan or abdominal ultrasound. Liver biopsy was performed in all
      donors. Arteriogram was performed to evaluate hepatic arterial anatomy. All
      donors survived the procedure. Only seven patients experienced complications
      (10.2%), most of which were short term. We conclude that liver living donation
      for pediatric population is a safe procedure.

PMID- 15194317
TI  - Liver transplant recipients mortality on the waiting list: long-term comparison
      to Child-Pugh classification and MELD.
AB  - We sought to evaluate our experience concerning the high waiting list mortality
      rate for orthotopic liver transplantation (OLT) using the MELD (Model for End
      Stage Liver Disease), which has been shown to predict short-term survival better
      than Child-Turcotte-Pugh (CTP) classification. The predominant end-stage disease
      was cirrhosis due to hepatitis C virus (67%), patient mean age was 36.8 years,
      and 72.1% were men. When the patients were included on a waiting list, the MELD
      score was stratified into W: 0 to 10; X: 11 to 20, and Y: 21 to 40 and the CPT as
      A: 5 to 6, B: 7 to 9, and C: 10 to 15. It was also observed that 77.8% of
      patients were on the waiting list, 16.4% underwent OLT and 5.8% had been removed.
      The estimated survival rate after 1 year was W = 85.4%; X = 83.3%, Y = 46.8%; A =
      81.3%, B = 84.2%, C = 45.9%. Child median score was 8 +/- 1.5 (5 to 15) and the
      MELD was 14.7 +/- 5.1 (8 to 43). The mortality rate was 20.2%. Severe patients
      classified as Y or C showed greater mortality than the other groups (P <.001),
      but no significant difference between Y and C strata. The mortality rate was the
      same as in previous years.

PMID- 15194318
TI  - Prevalence of malnutrition in liver transplant candidates.
AB  - OBJECTIVE: To determine the prevalence of malnutrition among liver transplant
      (LT) candidates. MATERIALS AND METHODS: A prospective study evaluated 219 adult
      LT candidates including 141 men and 78 women. Cholestatic disease was present in
      21 (Child: A = 1, B = 11, and C = 9) and noncholestatic disease in 198 (Child: A
      = 12, B = 93, and C = 93. The mean age was respectively 45.6 and 46.5 years.
      Anthropometric and biochemical assessments were performed for statistical
      analysis using Student t test (P <.05). RESULTS: In the noncholestatic group,
      41.5% were obese according to keep a body mass index (BMI); 61.6% were depleted
      according to adequacy of tricipital skin fold (%TSF); and 71.1% were above normal
      levels for generalized adipose reserve (%F). In terms of adequacy of mid-upper
      arm muscle circumference (%MMC), 58% were depleted and 50.5% were depleted for
      the current body weight/usual body weight (%CBW/UBW). Otherwise 52.2% of current
      body weight/ideal body weight (%CBW/IBW) values were above normal. Serum albumin
      was below normal in 64.9% of cases. In the cholestatic group 62% were normal for
      BMI; 66.7% were depleted for %TSF; 77.8% were above normal for %F. As to %MMC,
      47.6% were depleted and 47.6% were depleted for %CBW/UBW. Otherwise 47.6% were
      above normal weight for %CBW/IBW. Serum albumin was below normal in 53.9% and
      %MMC values showed statistically significant differences (P =.02) when compared
      with Child B and C in the noncholestatic group, as well as %F (P =.01) and serum
      albumin (P =.0002) in the cholestatic and noncholestatic groups. Serum albumin
      values also showed statistically significant differences (P =.0004) when
      noncholestatic Child B and C patients were compared. CONCLUSION: Patients with
      cholestatic disease were more affected by calorie depletion compared to
      noncholestatic patients who were more affected by protein depletion.

PMID- 15194319
TI  - Complications following transjugular intrahepatic portosystemic shunt: a
      retrospective analysis.
AB  - Transjugular intrahepatic portosystemic shunt (TIPS) has been the therapeutic
      option for severe decompensation of chronic liver disease and as a bridge to
      liver transplantation. The aim of this study was to analyze the complications of
      this procedure. The records of 47 patients (39 men) of mean age 48 years
      underwent TIPS procedures from 1998 to 2003 were reviewed. Forty-one patients
      received 45 successful TIPS; it failed in six patients. Improvement was observed
      in 20 of 28 patients with upper gastrointestinal bleeding (71%); 9 of 11 with
      ascites (82%); and 5 of 8 with impaired renal function (62%). The Child-Pugh
      scores improved in 6 of the 47 patients (13%). Transplantation was performed in
      11 patients (23%). The complications were: encephalopathy (49%); infection (19%);
      renal failure (17%); TIPS migration to the portal vein (4%) and to the right
      atrium (4%). Mortality was 32% (15/47) over 3 months. Eight patients developed
      active bleeding during TIPS installation requiring mechanical ventilation and
      intensive care, and died within the first week. Other causes of death were sepsis
      (n = 2), liver failure (n = 1), accidental puncture of the Glisson's capsule
      leading to intra-abdominal bleeding (n = 1) and refractory upper gastrointestinal
      bleeding (n = 3). The latter four patients had TIPS placement failure. In
      conclusion, TIPS produced clinical improvement among 51% of patients with
      complications in 49%. The main complications were encephalopathy (49%), infection
      (19%), and renal failure (17%). The 3-month mortality rate after TIPS placement
      was 32%.

PMID- 15194320
TI  - The first clinical liver transplantation of Brazil revisited.
AB  - The first clinical orthotopic liver transplantation in Brazil was performed on
      August 5, 1968. The patient was awake after surgery and died on the seventh
      postoperative day due to subdural hematoma, bronchopneumonia, renal failure, and
      graft rejection. The report of this case is important to understand the evolution
      of clinical liver transplantation in Brazil, where this procedure is now
      routinely carried out in many medical centers.

PMID- 15194322
TI  - Anesthetic management of liver transplantation in patients with fulminant hepatic
      failure: case reports.
AB  - Fulminant hepatic failure (FHF), although not frequent, produces a high mortality
      rate of 70% to 90%. This study describes the management of FHF patients without
      the use of any intracranial pressure monitoring device.

PMID- 15194321
TI  - Early mortality in liver transplantation: bilirubin as predictor of outcome.
AB  - The shortage of donor organs and the long waiting lists have increased the need
      to better select liver transplant candidates using predictors of success. We
      reviewed the results of 29 liver transplantations performed from January 2002 to
      February 2003 analyzing the correlations with early mortality (30 days) of
      patient data, pretransplant laboratory data, warm ischemia time, intraoperations
      blood unit transfusions, and postoperative complications of prolonged mechanical
      ventilation, dialysis, and infection. Overall early mortality was 27.6% and 44%
      in fulminant hepatic failure (n = 9), there were four retransplants with one
      death, and two intraoperative deaths. Only pretransplant bilirubin (P =.045) and
      postoperative lactate levels (P =.002) were significantly different between alive
      versus dead patients. In this small population bilirubin was more related to
      death than the MELD score. Lactate levels, nonspecific predictor of death in
      shock syndromes were probably related to septic complications.

PMID- 15194323
TI  - Rapamycin even when combined with cyclosporine attenuates tumor growth but does
      not induce regression of established walker sarcomas.
AB  - PURPOSE: To investigate the effect of rapamycin (Rapa) on growth or regression of
      Walker tumor used alone or in combination with CsA and MMF. METHODS AND RESULTS:
      Wistar rats received water (control) or Rapa or CsA 1 day before and daily after
      tumor inoculation. On day 10, tumor volume (TV) was smaller among Rapa (6.8 +/-
      2.7 cm(3)) versus control (14.9 +/- 4.2 cm(3), P <.001) or CsA (13.9 +/- 3.0
      cm(3), P <.0001) treatment groups. Tumor growth was greatly inhibited (TI) by
      Rapa (-49.3%). Tumor weight (TW) was significantly (P < or =.001) lower in Rapa
      (3.7 +/- 1.2 g) versus CsA (8.8 +/- 2.1 g) or control (7.3 +/- 2.0 g) animals. An
      additional set of rats received water or Rapa or CsA + Rapa, or MMF + Rapa 1 day
      before tumor inoculation. On day 10, TV and TW were lower among Rapa (3.8 +/- 1.5
      cm(3)) and Rapa + CsA (3.1 +/- 1.2 cm(3)) and Rapa + MMF (4.6 +/- 2.7 cm(3))
      groups compared with controls (10.9 +/- 3.8 cm(3), P <.0001). TI was -52.1% in
      Rapa, -68.5% in Rapa + CsA, and -63% in Rapa + MMF. A further set of rats
      received either water or Rapa on the day 4 after tumor inoculation. On day 10,
      tumor growth and TW among the Rapa and control groups were similar. CONCLUSION:
      Rapamycin greatly inhibited tumor growth when used alone or with CsA or MMF, but
      did not produce an effect on a well-established Walker sarcoma.

PMID- 15194324
TI  - Retrospective analysis of patients who developed pulmonary hypertension during
      the early postoperative period after liver transplantation.
AB  - INTRODUCTION: Pulmonary hypertension (PH) (mean pulmonary arterial pressure
      [mPAP] > 25 mm Hg) is frequently observed during the postoperative period after
      liver transplantation (LT). OBJECTIVE: The objective was to compare respiratory
      function, intensive care unit (ICU) length of stay (LOS), and 30-day survival
      rates among patients evolving with PH with those who do versus do not develop it
      during the postoperative period after LT. METHODS: Fifty-seven patients
      undergoing LT from January 1999 to December 2000 were divided into 2 groups:
      Group 1 (G1; n = 26), without PH; and Group 2 (G2; n = 31), with moderate PH.
      Preoperative parameters were Child-Pugh's classification, pulmonary function
      tests, mPAP, and P(A-a)O(2). During the intraoperative period, warm and cold
      ischemic times and the amount of blood transfusion were evaluated, whereas mPAP,
      PaO(2)/FiO(2) ratio, weaning time, ICU LOS, and 30-day survival rates were
      evaluated postoperatively. RESULTS: mPAP in early postoperative period was 21 +/-
      13 mm Hg and 32 +/- 4 mm Hg in G1 and G2, respectively (P <.0001). PaO(2)/FiO(2)
      was 310 +/- 82 mm Hg in G1 and 272 +/- 84 mm Hg in G2 (P =.48). In G1 and G2, 77%
      and 74% of patients, respectively, were successfully weaned in the first 24 hours
      postoperative (P =.10). ICU LOS was 111 hours (range, 45-1098 hours) in G1 and
      102 hours (range, 59-284 hours) in G2 (P =.36). The 30-day survival rate was 20
      of 26 (77%) in G1 and 26 of 31 (84%) in G2 (P =.44). CONCLUSION: Our data suggest
      that moderate PH during the early postoperative phases of LT cannot be considered
      an additional risk factor for pulmonary dysfunction, and for an increased ICU LOS
      or 30-day mortality rate.

PMID- 15194325
TI  - Pediatric liver transplantation: fourteen years of experience at the children
      institute in Sao Paulo, Brazil.
AB  - This study reports the 14-year experience of a single center on 206 liver
      transplantations from living and cadaveric donors performed in 179 pediatric
      patients. Biliary atresia (57.2%) and fulminant hepatitis (9.8%) were the most
      frequent indications. The mean age of the recipients was 3 years, 7 months (9
      months to 18 years) and mean weight was 14 kg (7 to 57 kg). The allografts were
      distributed as 82 (39.8%) whole cadaveric, 76 (36.9%) reduced-size cadaveric, 46
      (22.3%) living donor liver transplants, and 2 (0.9%) ex situ split livers. The
      waiting periods were 25 days for living donors and 2.5 years for cadaveric donors
      (P <.001). Twenty-seven children were retransplanted with hepatic artery
      thrombosis the most frequent indication. The postoperative complications were:
      primary nonfunction (12.2%), biliary stenosis (28.8%), hepatic artery thrombosis
      (12.2%), portal vein stenosis (4.9%), hepatic vein stenosis (6.9%), and
      lymphoproliferative disorder (5.9%). The diagnosis of biliary stenosis was
      obtained by liver biopsy and transhepatic cholangiography and treated by balloon
      dilatation, although four children (3.9%) required a redo hepaticojejunostomy.
      The venous stenoses were percutaneously dilated with five-children (4.9%)
      requiring venous stents. The incidence of hepatic vein stenosis was 15.6% among
      living donor and 2.5% in cadaveric liver transplantation (P <.05). The overall 5
      year patient and graft survivals were 70.2% and 65.1%. Liver transplantation
      provides excellent long-term survival. The use of grafts from living donors
      decreases the waiting periods but increases the incidence of hepatic vein
      stenosis.

PMID- 15194326
TI  - Impact of successful liver transplantation on reproductive function and sexuality
      in women with advanced liver disease.
AB  - Abnormalities in the reproductive function and sexuality, which are common among
      women with advanced liver disease, may reverse after successful liver
      transplantation (LT). To analyze reproductive function and sexuality in women who
      underwent successful LT, we interviewed 28 recipients (mean age 44.17 +/- 13.6
      years old) at a median posttransplant survival of 36.5 months (range, 6 to 110
      months), with good graft function and obeying regular follow-up at our
      institution. In addition to medical records, all subjects answered a
      questionnaire on their menstrual pattern, sexual activity, contraceptive
      practice, pregnancy, and sexuality domain. Nineteen of 22 patients in the child
      bearing age (86.4%) recovered menstrual function at a median of 1 month after LT
      (range, 1 to 7 months). Twenty of 28 recipients (71.4%) were sexually active. The
      most frequent contraceptive practices were barrier methods and tubal ligation.
      There were four successful pregnancies (one twin) in three patients; five healthy
      babies were delivered. Overall, 70% of sexually active patients indicated
      satisfaction with their relationship, 75% had weekly intercourse, and 70%
      experienced orgasm with intercourse. Eighty percent expressed a desire to receive
      information concerning sexuality. In conclusion, LT has a positive impact on
      sexuality and reproductive function in female recipients. It would desirable that
      LT programs included information regarding these issues for this population.

PMID- 15194327
TI  - Management of vascular complications after pediatric liver transplantation.
AB  - Sixty-five children underwent liver transplantation (LTx) from March 1995 to
      December 2002. Cirrhosis due to biliary atresia was the main indication, and
      hepatic artery thrombosis (HAT) the most common vascular complication (n = 5).
      Other vascular problems were portal vein thrombosis and stenosis. Another patient
      developed hepatomegaly and ascites due to a late stenosis of the left hepatic
      vein anastomosis. The two cases of venous stenosis were successfully treated by
      percutaneous angioplasty. One graft with HAT was saved, but four children died
      awaiting retransplant.

PMID- 15194329
TI  - A comparison of nutritional status in three time points of liver transplant.
AB  - Patients undergoing liver transplantation (LT) often experience dietary
      restrictions that may influence their nutritional status. With the objective of
      comparing the status of liver transplant patients pre- versus in the early and
      late postoperative periods, a retrospective study evaluated 33 adults (63.6% men
      and 36.4% women) mean age 47 years for body mass index (BMI), current body
      weight/ideal body weight (%CBW/IBW), current body weight/usual body weight
      (%CBW/UBW), adequacy of tricipital skin fold (%TSF), generalized adipose reserve
      (%F), adequacy of mid-upper arm muscle circumference (%MMC), and serum albumin.
      The elapsed time between nutritional evaluation and LT was 446 days for the pre
      LT group, 31 for the early post-LT group, and 244 for the late post-LT group;
      30.3% were Child C and 63.6% B in the pre-LT phase. The median value to %TST in
      pre-LT, early LT, and late LT were 91.7%, 70.8%, and 78.0%, respectively. The
      analysis of mean value of %F was 25.9% in the pretransplant, 23.3% in early
      postoperative, and 25.3% in late postoperative stages %MMC was 85.5% for
      pretransplant patients, it was 86.6% in the early versus 89.9% in the late
      stages. While BMI was 24.9 kg/m(2) in the preoperative 22.9 kg/m(2) in early, and
      24.2 kg/m(2) in late phases. Similarly, concerning %CBW/UBW the mean values were
      96.2% in the preoperative group, 64.1% in early, and 101.9% in late groups. The
      %CBW/IBW mean values were 113.9% in the pre- versus 104.6% in the early and
      111.2% in the late periods. The values of serum albumin and %CBW/UBW were
      statistically different for Child B,C as well as when the patients were not
      classified by the Child criteria. There was a deterioration in status from
      pretransplant period to early postoperative with improvement in the late period.

PMID- 15194328
TI  - Magnetic resonance cholangiography in the diagnosis of biliary complications
      after orthotopic liver transplantation.
AB  - OBJECTIVE: The aim of our study was to evaluate the role of magnetic resonance
      cholangiography (MRC) in the diagnosis of biliary tract complications (BC) after
      orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Among 21 OLT
      patients who underwent routine follow-up MRC using a breath-hold T2-weighted
      turbo spin-echo sequence with half-Fourier acquisition (HASTE), 5 had an elevated
      serum alkaline phosphatase level. Diagnostic confirmation was obtained with
      endoscopic retrograde cholangiography (ERC) (n = 11), surgery (n = 3), or
      clinical and laboratory follow-up of at least 1 year (n = 8). RESULTS: In 13
      patients, no abnormality of the biliary tract was detected using MRC. In 8
      patients, anastomotic strictures were diagnosed, 7 of which were confirmed at
      surgery or using ERC. One patient with normal findings at MRC and abnormal liver
      function test results was found to have a stricture at ERC. All patients with
      normal MRC and liver function tests had 1 year of uneventful follow-up and were
      considered true-negative cases. We found that MRC had 87.5% sensitivity, 92.3%
      specificity, 87.5% positive predictive value, 92.3% negative predictive value,
      and 90.4% accuracy for the diagnosis of BC. CONCLUSION: MRC is a valuable
      examination to detect BC after OLT. It provides useful information for planning
      interventional procedures.

PMID- 15194330
TI  - Biliary reconstruction without T-tube in liver transplantation.
AB  - Biliary complications have been reported in 9% to 34% of liver transplant
      patients. Although most centers seem to prefer a duct-to-duct anastomosis without
      a T-tube when feasible, the best method of biliary reconstruction remains
      controversial. The aim of this study was to review our experience on
      reconstruction of the biliary tract without drainage. Forty-one patients
      underwent 45 liver transplants over two periods. Forty patients underwent 15
      liver transplants from October 1992 to March 1995; and 27 underwent 30 liver
      transplants from January 2002 to February 2003. Our standard biliary
      reconstruction was an end-to-end anastomosis without drain. The overall actuarial
      survival was 72.7% at 1 year, 64.7% at 3 years, and 56.6% at 5 years. The mean
      follow-up was 23 months. Eight patients (22.2%) developed biliary tract
      complications: five patients papillary dysfunction (13.9%); two, biliary
      stricture (5.5%); and one, biliary sludge without evidence of stricture (2.8%).
      Papillary dysfunction represented 62.5% of all complications. Biliary
      reconstruction without drainage may be routinely performed since the
      complications are only those not related to the T-tube.

PMID- 15194333
TI  - Outcome of infections caused by multiple drug-resistant bacteria in liver
      transplant recipients.
AB  - OBJECTIVE: To evaluate the impact of infections caused by multiple-drug-resistant
      (MDR) bacteria on the clinical outcome of liver transplant recipients. METHODS:
      Retrospective study including all episodes of bacterial infection diagnosed in
      patients undergoing liver transplantation from January 19, 1999, to June 30,
      2002. The diagnosis of bacterial infection required microbiological
      documentation. Mortality associated with episodes of infection by MDR bacteria
      was compared to that observed after antibiotic-susceptible bacterial infections.
      RESULTS: Among 99 patients undergoing liver transplantation during the study
      period, there were 57 episodes of bacterial infections. Gram-negative bacilli
      were the predominant etiologic agents (76%) and Pseudomonas aeruginosa was the
      most frequent bacterial species found in these cases (23 isolates, 28%). Thirty
      six episodes of infection (63%) were caused by MDR bacteria. Mean time after
      transplantation to the diagnosis of infection was 17 days. Mortality associated
      with episodes of MDR bacterial infections (nine deaths, 25%) was not
      significantly different from that observed during episodes of antibiotic
      susceptible bacteria (five deaths, 24%; P =.92). CONCLUSION: These data suggest
      that resistance to multiple antimicrobial agents does not have an impact on the
      mortality associated to bacterial infections in liver transplant recipients.

PMID- 15194332
TI  - Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver
      transplantation: comparative study.
AB  - Basiliximab is a monoclonal antibody that binds to the alpha subunit (CD(25)) of
      the interleukin-2 receptor of activated T lymphocytes. The advantage of
      basiliximab in organ transplantation is the reduce possibility to calcineurin
      inhibitor dosages to avoid nephrotoxicity. Basiliximab has significantly reduced
      the incidence of acute rejection (AR) in renal transplant recipients; however,
      the results are uncertain in liver transplantation (LT). The objective of this
      investigation was to assess the effect of basiliximab to prevent AR in the first
      6 months after pediatric LT. From March 2000 to October 2001, 32 recipients of a
      primary orthotopic cadaveric or living donor LT were given basiliximab by
      intravenous bolus injection on the day of transplantation (day 0) and on day 4.
      Four children who received one dose were excluded from the study. The rate and
      the intensity of AR episodes, the incidence of chronic rejection, serum
      creatinine level, incidence of infections, adverse side effects, and daily oral
      dosage of cyclosporine (Neoral) to maintain the target blood level of 850 to 1000
      mg/dL at C2, 2 hours after the administration, were analyzed in the remaining 28
      recipients. Results were compared to those obtained from a matched historical
      group (n = 28) of similar age, weight, and hepatic diseases distribution. None of
      the analyzed parameters was statistically significant (P >.05) except for the
      daily oral dose of cyclosporine (7 to 13 mg/kg/dose, P <.05). In our series, the
      addition of basiliximab to the immunosuppressive therapy did not reduce the
      incidence of AR in pediatric LT.

PMID- 15194331
TI  - Development of donor-specific microchimerism in liver transplant recipient with
      HLA-DRB1 and -DQB1 mismatch related to rejection episodes.
AB  - Migration of donor-derived cells to recipient tissues after liver transplantation
      has been suggested as a mechanism to induce and maintain allograft tolerance,
      although important issues remain including acute rejection posttransplantation
      mortality, and complications related to immunosuppressive therapy. We therefore
      examined the relation of rejection to chimerism based upon recipient and donor
      mismatch of HLA-DRB1 and -DQB1 alleles. Laboratory analysis of peripheral blood
      was performed before and 10 days to 16 months after liver transplantation in 32
      recipients, using ganglion or spleen cell samples of respective donors. DNA was
      extracted for HLA-DRB1 and DQB1 allele typing using polymerase chain reactions
      with sequence-specific primers (PCR-SSP). Microchimerism was analyzed through
      nested PCR. Our results confirmed that patients with one or two mismatched HLA
      DRB1 and-DQB1 alleles showed microchimerism and no rejection (P <.05).
      Microchimerism was present in 71.88% of the patients, and a significant
      association of rejection P <.05 was found when microchimerism was correlated to
      graft rejection. These results suggest that the presence of microchimerism may be
      associated with acceptance, tolerance and survival of the allograft.

PMID- 15194335
TI  - Subcapsular hematoma of the graft after liver transplantation.
AB  - Subcapsular hematoma of the graft is an underreported complication of liver
      transplantation (LT). Among 408 LT performed from September 1, 1985, to September
      1, 2000, eight patients developed a subcapsular hematoma within 30 days after LT
      (8/408 = 2.0%). Among the six early cases observed, five required further
      surgical approaches due to hematoma progression, rupture, and hemorrhage. One
      patient underwent liver retransplantation due to uncontrollable hepatic
      hemorrhage. The two more recent cases were successfully treated by early opening
      of the Glisson's capsule with hemostasis of the hepatic raw bleeding surface. The
      five patients who developed acute renal failure required dialysis. Three patients
      died during hospitalization. Among the survivors, two were discharged on the
      postoperative (PO) day 15; the others on PO day 37, 38, and 56. In conclusion,
      subcapsular hematoma of the graft is a potentially serious complication of LT
      that may produce severe hemorrhage, shock, and in extreme cases, graft loss or
      even death. The severity of the complication is related to the extension of the
      decapsulated area of the graft. An early surgical approach with intentional
      opening of the hematoma before progression of the lesion seems to facilitate
      hemostasis and improve results.

PMID- 15194334
TI  - Risk factors associated with cytomegalovirus-positive antigenemia in orthotopic
      liver transplant patients.
AB  - The aim of the study was to investigate risk factors associated with
      cytomegalovirus (CMV)-positive antigenemia in orthotopic liver transplant (OLT)
      patients. Sixty-nine patients undergoing OLT during 2001 were retrospectively
      evaluated for CMV antigenemia during a follow-up of 6 months after
      transplantation for demographic variables, pretransplant donor and recipient CMV
      serologic status, etiology of liver disease, number of blood transfusions, and
      type of immunosuppression. Among the 69 patients who underwent 71 OLT in this
      period, 43 met study criteria. Mean age was 49.7 +/- 10.8 years and 60.5% were
      men. End-stage liver disease was the indication for liver transplant, except in
      one case. The most prevalent etiology of liver disease was hepatitis C and/or
      alcohol in 66% of the cases. CMV-positive status was recorded in 74% of donors
      and 95% of recipients. None of the CMV-negative recipients received a positive
      donor allograft. CMV-positive antigenemia was 84% with 12% having two episodes of
      infection. There was no correlation between CMV infection and age, gender,
      etiology of liver disease, or number of blood transfusions. However, all patients
      using cyclosporine had CMV-positive antigenemia compared with 61% using
      tacrolimus (P <.032). In this study, the incidence of CMV infection after OLT in
      adult patients was slightly higher than reported in literature. No risk factor
      was associated with CMV antigenemia; however, this study suggests a higher
      probability of CMV infection among patients treated with cyclosporine.

PMID- 15194336
TI  - Late hepatic artery thrombosis after liver transplantation: clinical setting and
      risk factors.
AB  - The aim of this study was to assess the prevalence clinical presentation, and
      impact on outcome of late hepatic artery thrombosis (HAT) after OLT. We also
      sought risk factors other than technical problems that predispose to the
      pathogenesis of late HAT among 178 OLT performed from 1999 to 2002. Late HAT was
      diagnosed using Doppler ultrasonography and arteriography. Late HAT was observed
      in nine patients (3.8%), all of whom had experienced chronic HCV infection.
      Median time to HAT diagnosis was 4.88 months after OLT. Mean follow-up time was
      40.25 months. Recipient age ranged from 30 to 61 years and median donor age, 28
      years. Mean warm ischemia time was 63 minutes and mean cold ischemia time, 660
      minutes. All of our study group were cigarette smokers. Postoperative CMV
      infection, presenting with hepatitis, had been treated in 55.6%. Before the
      diagnosis of HAT more than one episode of acute cellular rejection had been
      observed in six patients (55.6%) and 44.5% had chronic rejection. The diagnosis
      of CR was established after the diagnosis of HAT in all cases. Recurrence of HCV
      infection was histologically documented in 44.5%. Only one patient experienced
      graft loss (77 months after OLT). Six of nine patients had biliary complications,
      treated either by endoscopic stenting or by surgical drainage. Two patients were
      asymptomatic. In conclusion, late HAT shows a benign presentation that has no
      impact on graft survival. Possible risk factors have yet to be defined by
      multicenter trials.

PMID- 15194337
TI  - Portal vein aneurysm as late complication of liver transplantation: a case
      report.
AB  - OBJECTIVE: A case of intrahepatic portal vein aneurysm in the late postoperative
      period after liver transplantation, as well its complications, is reported. CASE
      REPORT: A 59-year-old man underwent orthotopic liver transplantation in 1996 for
      treatment of hepatitis C virus cirrhosis. The patient received a graft from a 10
      year-old child. During the follow-up from 1996 to 1998, the patient did not show
      any alterations. In 1999, during an annual routine exam, a portal vein aneurysm
      was identified; however, it had no impact on graft function. In November 2002,
      the patient developed jaundice and serious graft dysfunction requiring hospital
      admission. Helicoidal CT scan showed an intrahepatic image compatible with a
      portal vein aneurysm without biliary tract dilatation. During the same
      hospitalization, he developed upper gastrointestinal bleeding due to variceal
      rupture as well as kidney and liver failure, and expired on December 31, 2002.
      The necropsy demonstrated an intrahepatic portal vein aneurysm with portal vein
      thrombosis and chronic liver disease. The evolution in this case suggests that if
      there is an intrahepatic portal vein aneurysm after liver transplantation, the
      patient is likely to experience an eventual recurrence of portal hypertension;
      retransplant may be an alternative.

PMID- 15194338
TI  - Immunosuppression in pancreas transplantation: mycophenolate mofetil versus
      sirolimus.
AB  - The use of mycophenolate mofetil (MMF) in pancreas transplantation has increased
      graft survival and decreased the incidence of acute rejections episodes (ARE),
      regardless of the choice of calcineurin inhibitor. The combination of MMF with
      tacrolimus (TAC) is the most common protocol, it is considered the gold standard
      for new protocols. In the last few years, there have been reports of a small
      number of patients treated with sirolimus (RAPA), usually combined with TAC.
      Patient and pancreas survival rates as well as the incidence of ARE were similar
      to protocols with TAC and MMF. Twenty simultaneous pancreas and kidney (SPK)
      transplantations were performed using an immunosuppressive protocol of TAC, RAPA,
      and steroids (STE) after 2000. The incidence of ARE was 25%; all episodes
      responded to STE. Only 2 patients (10%) displayed hypercholesterolemia requiring
      treatment with statins. The use of RAPA as an alternative to MMF is promising,
      although presently one with limited experience. The combination of MMF and RAPA
      with or without a calcineurin inhibitor is an option to be evaluated in the
      future.

PMID- 15194339
TI  - Enteric conversion after bladder drained pancreas transplantation experience of
      14 cases.
AB  - The method of exocrine diversion in pancreas allograft continues to be
      controversial due to the advantages versus disadvantages of bladder versus
      enteric techniques. Bladder drainage (BD) exposes the patient to urological and
      metabolic problems that may require conversion to enteric drainage (ED). The
      purpose of this study was to review our initial experience of conversion from BD
      to ED for patients who underwent pancreas transplantation originally with bladder
      diversion. Among 114 pancreas transplantation performed with BD, from January
      1996 to April 2003, 60 were simultaneous pancreas-kidney transplantation (SPKT),
      35 were pancreas transplantation alone (PA), and 19 were pancreas after kidney
      transplantations (PAK). Twenty-three (20.2%) cases were excluded due to early
      death of the patient or the graft, yielding an analyses of 91 patients. Enteric
      conversion (EC) was performed in 14 (15.4%) patients with a mean follow-up of
      15.7 months (range, 3-51 months) after transplantation including 8 (8.8%) SPKT, 4
      (4.4%) PAK, and 2 (2.2%) PA. No surgical morbidity or mortality was observed
      related to EC. All patients had complete resolution of the initial problem with
      preservation of pancreatic function. EC represents an easy, safe procedure with
      low morbidity and mortality rates, representing the option of choice for patients
      with persistent urological or metabolic disturbances.

PMID- 15194340
TI  - Simultaneous pancreas-kidney transplantation: infectious complications and
      microbiological aspects.
AB  - OBJECTIVE: The purpose of this study was to describe the clinical and
      microbiological characteristics of the infectious complications among
      simultaneous pancreas-kidney transplantations (SPKT). MATERIALS AND METHODS:
      Among the first 45 SPKT the mean age was 34 years (range, 21 to 49) and the mean
      duration of follow-up 13 months (range, 2 to 27 months). RESULTS: Twenty-three
      patients (51%) presented at least one to three episodes (1.7 mean) of infectious
      complications that needed hospitalization. The etiology of the infections
      included 71% bacterial (44% gram-negative rods and 27% gram-positive cocci), 16%
      viral (12% from CMV and 4% from Herpes sp) and 13% fungal (8% by Candida sp and
      4% by others fungus). Wound and urinary infections were most frequent, occurring
      in 22% and 28% of the patients, respectively. All patients who were submitted to
      vesical drainage developed infections in contrast a rate of only 44% among
      patients undergoing enteric drainage. CONCLUSION: Infectious complications are
      the main cause of morbidity and mortality following simultaneous pancreas-kidney
      transplantation, especially with vesical drainage. The use of enteric drainage
      combined with administration of broad spectrum prophylactic antibiotics is
      recommended.

PMID- 15194342
TI  - Glycemic control during pancreas transplantation: continous infusion versus
      bolus.
AB  - Pancreas transplantation is a method to restore endogenous insulin secretion in
      insulin-dependent diabetic patients. Because glycemia >150 mg/dL may harm
      pancreatic graft beta cells, early glucose control using insulin administration
      is recommended during transplantation. The aim of this study was to evaluate the
      benefits of strict glycemic control during pancreas transplantation by comparing
      two types of insulin and glucose administration: continuous infusion and bolus.
      Capillary glucose was measured every 30 minutes after anesthetic induction for
      pancreas transplantation alone or simultaneously with kidney transplantation.
      Intravenous regular insulin was administered for values >150 mg/dL or glucose for
      values <100 mg/dL. The following timepoints were evaluated: anesthetic induction,
      before pancreatic graft reperfusion, and the first 4 minutes after reperfusion.
      Pancreatic graft ischemia time was significantly lower in the bolus group (P
      <.02). Immediately after reperfusion, there was a small increase in glycemia with
      a decrease in subsequent measurements in both groups. No significant difference
      in glycemia was observed between the groups at any time. Induction values were
      greater than all other timepoints in both groups. Glycemic control is important;
      it was successfully obtained with both methods. The trend to decrease glucose
      after reperfusion suggest early graft function.

PMID- 15194341
TI  - Risk factors for the development of posttransplantation diabetes mellitus in
      simultaneous pancreas and kidney recipients.
AB  - We sought to determine the risk factors involved in the development of
      posttransplantation diabetes mellitus (PTDM) following simultaneous pancreas and
      kidney transplantation. Correlations were sought between tacrolimus (FK-506)
      levels/dose 2-hour capillary glucose (CG) and glycosylated hemoglobin (HbA(1c)),
      cyclosporine (CSA) levels/dose with HbA1c, 2-hour CG with prednisone dose and
      body mass index (BMI) and PTDM. Four patients (9.3%) developed PTDM. Three
      treated with FK-506 had altered 2-hour CG at 3 months after transplantation; 1
      prescribed CSA displayed diabetes diagnosed after 1 year. There was no
      statistically significant difference among HbA(1c) values and FK-506 (P =.18) or
      CSA (P =.81) doses or FK-506 (P =.53) and CSA (P =.54) levels. In contrast, there
      was a statistically significant relationship between elevated 2-hour CG (> or
      =200 mg/dL) and daily prednisone dose (9.7 mg vs. 16.2 mg; P =.003). There was no
      correlation between 2-hour CG and FK-506 dose (P =.084) or FK-506 levels (P
      =.075). The greater BMI correlated with an increased risk of PTDM (21.25 +/- 3.13
      kg/m(2) vs 24.67 +/- 2.38 kg/m(2); P =.034). Two-hour CG may be a useful tool to
      screen the diabetogenic effects of corticosteroids. A BMI increase should be
      discouraged due to the risk of PTDM.

PMID- 15194343
TI  - Renal failure as a determinant of mortality after cardiac transplantation.
AB  - INTRODUCTION: Patients with heart failure frequently develop renal failure, which
      increases the mortality rate among patients undergoing cardiac transplantation.
      PURPOSE: To determine whether preoperative renal function influenced
      postoperative mortality in cardiac transplantation recipients. MATERIALS AND
      METHODS: The measurements of plasma urea, plasma creatinine, and 24-hour
      creatinine clearance in patients who underwent cardiac transplantation were
      correlated with mortality at 30, 90, and 365 days after the procedure, using
      Student t test for continuous variables and the chi-square test for categorical
      variables. RESULTS: All variables correlated with mortality, particularly plasma
      creatinine at 30, 90, and 365 days (P =.029,.003, and.0029, respectively).
      CONCLUSION: Preoperative renal failure is a mortality indicator in cardiac
      transplantation recipients.

PMID- 15194344
TI  - Could the coculture of skeletal myoblasts and mesenchymal stem cells be a
      solution for postinfarction myocardial scar?
AB  - Currently two lines of research have been proposed for treatment of heart failure
      in an attempt to address its main cause: skeletal myoblast (SM) transplants,
      which increase the contractile muscular mass, and mesenchymal stem cell (MSC)
      transplants, which increase neoangiogenesis. The objective of this study was to
      establish methods whereby cocultures of SM and MSC proliferate and expand, making
      possible the interaction of these cell types prior to their transplantation to
      the myocardium. Seeking to support the survival of these cells after myocardial
      transplantation and achieve subsequent functional improvement, SM and MSC from 10
      rats were isolated and cultivated in DMEM medium supplemented with 15% fetal calf
      serum, 1% ATB, and growth factors. Following plating in variable proportions of
      satellite cells/mononuclear cells namely 2:1, 1:1, 1:2, morphological
      observations were made regarding cell survival, adhesion to substrate, and
      confluence. After 48 hours nonadherent cells were aspirated from the flasks,
      leaving the adherent cells, SM, and MSC. The better level of cell proliferation
      was observed with the proportion 2:1 cocultivated at a concentration of 5 x
      10(5)/mL for 14 days. The results were satisfactory; the cell production was up
      to 10(8), increasing the chances of transplant success after myocardial
      infarction. Transplants with this model are ongoing.

PMID- 15194345
TI  - Banked cadaveric fascia lata: 3-year follow-up.
AB  - Autologous fascial and synthetic materials have been widely used to repair the
      stress form of urinary incontinence (SUI) as well as pelvic floor prolapse. The
      safety and long-term durability of cadaveric fascia lata in orthopedic and
      ophthalmologic surgery have encouraged urogynecologists to use this material for
      a sling material. The rationale of placement of a sling from cadaveric fascia
      lata is based upon decreasing the complication rates caused by autologous and
      synthetic materials. However, the high costs of the commercially available
      tissues in Brazil have limited its use in public health. In our institution we
      developed a cadaveric fascia lata bank, harvesting the material according to the
      Brazilian Transplantation Legislation and storing it at -70 degrees C. The safety
      of the tissue is achieved by 25-kGy irradiation. Since 1999, 30 patients have
      undergone surgery using material from five donors in repairs for stress urinary
      incontinence and pelvic floor prolapse at a mean of 34 months' follow-up (ranging
      from 30 to 40 months), there was no evidence of rejection. Therefore, we have
      shown the safety of cadaveric fascia lata harvested and treated as described
      above in our group of patients.

PMID- 15194346
TI  - Pubovaginal sling using cadaveric allograft fascia for the treatment of female
      urinary incontinence.
AB  - OBJECTIVES: The technique and outcomes of patients treated with allografts or
      autografts as pubovaginal sling are compared. METHODS: Fascia lata was included
      among the tissues harvested from brain-dead patients considered for multiple
      organ donation. After informed consent, segments of allograft (group A) cadaveric
      fascia lata autografts (group B) were compared with used for sling operations in
      60 women from 37 to 73 years of age (mean 53.4 years), who presented with stress
      incontinence requiring a pubovaginal sling. RESULTS: At a mean follow-up of 36
      months (range = 22 to 44 months), 40% of group A patients were cured and 28% were
      improved. At a mean follow-up of 33 months (range = 24 to 41) 70% of group B
      patients were cured and 20% improved (P <.05). There were no adverse outcomes of
      sling erosion or infection in either group. Placement of allograft sling took an
      average of 62 minutes while the mean duration of sling placement requiring
      fascial harvest was 81 minutes (P <.05). The mean duration of hospital stay was
      shorter in the allograft (1.25 days) than the autograft (2.48 days) group (P
      <.05). CONCLUSION: Use of allografts was associated with a shorter operative time
      and duration of hospital stay compared to an autograft, but the 3-year continence
      rate was lower in the autograft group.

PMID- 15194347
TI  - Rejection of grafts without histocompatibility antigen disparity by TAP1-/- mice:
      a role for CD4+ T cells.
AB  - We have previously shown that TAP1-/- mice reject heart and skin grafts lacking
      an H-2 disparity. TAP1-/- mice, which are deficient for MHC-I molecules, probably
      have a T-cell repertoire with distinct reactivity to these molecules. We
      speculated that this rejection could be mediated by CD4+ T cells reactive to H
      2(b) class I molecules, or to class I-derived peptides presented by self-APC.
      This hypothesis was tested in the present work. Presensitization of TAP1-/- mice
      with H-2K(b) peptides accelerated the rejection of C57BL/6 (H-2(b)) skin grafts
      (MST 13 days, P <.0057), indicating that these peptides were able to mobilize
      effector T cells that participate in rejection. In addition, CD4 T-cell depletion
      before transplantation induced a significant delay in rejection (P <.0011),
      showing that CD4 T cells have a major role in the rejection process, though other
      cells may also contribute. In conclusion, these results support our hypothesis
      that H-2(b) molecules may be targeted in graft rejection without an H-2
      disparity. The low expression of MHC-I molecules on TAP1-/- mice may determine
      the selection of a T-cell repertoire that is reactive to self-MHC-I molecules, a
      phenomenon that is probably beyond the control of peripheral regulatory
      mechanisms.

PMID- 15194348
TI  - N-Domain angiotensin I-converting enzyme expression in renal artery of Wistar,
      Wistar Kyoto, and spontaneously hypertensive rats.
AB  - One of the most intriguing features in kidney transplantation is the finding that
      kidneys from hypertensive rats can transfer arterial hypertension on
      transplantation into normotensive rats. Some evidence also suggest that, in
      humans undergoing renal transplantation, the genotype of the donor kidney
      determines the blood pressure in the recipient. The renin-angiotensin-aldosterone
      system is the major etiological candidate in hypertension because it plays an
      important role in the control of cardiovascular homeostasis. Angiotensin
      converting enzyme (ACE) cleaves the C-terminal from angiotensin I as well as from
      bradykinin. Thus, by generating the potent vasoconstrictor angiotensin II and by
      degrading the vasodepressor bradykinin, ACE is considered to play a role in blood
      pressure regulation. We have previously described the presence of N-domain ACE in
      urine of Wistar (W), Wistar Kyoto (WKY), and spontaneously hypertensive rats
      (SHR), all of which can hydrolyze the vasodilator peptide Angiotensin 1-7 and
      also the N-Acetyl-Ser-Asp-Lys-Pro, two peptides described as specific for N
      domain ACE. These findings suggest that the 90 kd ACE isoform found in urine and
      in tissues of SHR is a possible genetic marker of hypertension. Based on the fact
      that the renal artery has an important role in the control of renal blood flow,
      we evaluated the presence of N-domain ACE in the renal artery of hypertensive and
      normotensive rats. Using Western blotting techniques on the renal arteries of W
      and WKY rats, we detected the 190-kd ACE (similar to somatic ACE) and also the 65
      kd ACE previously described in urine and renal tissue as N-domain ACE. The 65-kd
      and 90-kd isoforms of ACE were also detected in renal arteries in SHR rats.
      Further studies are required to understand the role of 90-kd enzyme described as
      a possible local marker of hypertension, its contribution in angiotensin
      catabolism, and whether this abnormal form of the enzyme has any link with the
      development and transfer of hypertension after transplantation.

PMID- 15194350
TI  - Liver transplantation in pigs with small-for-size grafts: effect of portocaval
      shunt.
AB  - Small-for-size livers are associated with graft dysfunction, probably due to
      portal hyperperfusion. Modulation of the recipient portal inflow is a new option
      in these cases. This article sought to analyze the effect of portocaval shunt in
      small-for-size liver grafts in pigs. Twelve liver transplants were performed in
      white pigs. The donors' mean weight was 10 kg and the recipient's mean weight was
      34 kg. In all cases a standard technique was utilized. A portocaval shunt was
      added on the back-table in six cases. One hour after the procedure, the livers
      were sent for histologic examination. In all six cases without a portocaval
      shunt, the livers showed hemorrhagic necrosis, which was not observed in any of
      the six livers with a portocaval shunt. In small-for-size liver grafts in pigs, a
      portocaval shunt prevents hemorrhagic necrosis.

PMID- 15194349
TI  - Mycophenolate mofetil attenuates Walker's tumor growth when used alone, but the
      effect is lost when associated with cyclosporine.
AB  - PURPOSE: To investigate the effect of mycophenolate mofetil on Walker's
      carcinosarcoma, without versus with the growth and regression of cyclosporine.
      METHODS AND RESULTS: Wistar rats received water (control), MMF, and/or CsA-N 1
      day before tumor inoculation. On day 10, tumor volume (TV) was lower among MMF
      (10.3 +/- 2.8 cm(3)) than control rats (14.9 +/- 4.2 cm(3), P <.05), and similar
      to that in CsA-N (13.9 +/- 3.0 cm(3)). However, tumor weight (TW) was
      significantly lower in MMF (5.2 +/- 2.0 g) than CsA-N (8.8 +/- 2.1g) or control
      hosts (7.3 +/- 2.0 g, P < or =.01). Growth was inhibited by MMF (-28.2%). In
      experiment II, CsA-N, MMF + CsA-N, or water were introduced 1 day before tumor
      inoculation. On day 10, TV and TW were similar for MMF + CsA-N as compared to CsA
      N and control animals. In experiment III, water or MMF was introduced on the day
      4 after tumor inoculation. On day 10, tumor growth are TW in the MMF group was
      similar to, that in the controls. CONCLUSIONS: MMF produces an anti-tumoral
      effect against Walker's carcinosarcoma. However, this inhibitory effect was lost
      when MMF was used in combination with CsA-N or administered in the presence of a
      well- established tumor.

PMID- 15194351
TI  - Repercussions of extensive small bowel resections in growing rats.
AB  - OBJECTIVE: To study the effects of extensive intestinal resection on growing
      rats, with regard to animal weight and histomorphometry of the remaining small
      intestine. METHODS: Forty growing rats were allocated according to the extent of
      small intestine resection: 60%, 70%, 80%, or 90%. The animals were weighed every
      week and observed for 30 days. Following sacrifice the remaining small intestine
      was resected, fixed in 10% formol for 24 hours, embedded in paraffin, and stained
      using hematoxylin and eosin. The histological changes in the remaining small
      intestine were assessed for the length and thickness of villi, the thickness of
      the muscle layer, and the number of intestinal glands. RESULTS: All growing rats
      showed a fall in body weight, although it was more significant with the largest
      intestinal resection (80% and 90%). Villus length and muscle thickness increased
      after 30 postoperative days in all rats, but the number of intestinal glands
      remained unaltered. CONCLUSION: Growing rats with greatest resection of small
      intestine (80% and 90%) had better intestinal adaptation and slower recovery of
      body weight.

PMID- 15194352
TI  - Helicoidal enteromyotomy in rats: an experimental model of intestinal
      lengthening.
AB  - Short bowel syndrome (SBS) is a congenital or acquired condition of poor
      absorption resulting from a reduced surface of the enteric mucosa. In most cases,
      it spontaneously resolves via an adaptive process in the remaining intestine.
      Intestinal lengthening is one therapeutic method used for refractory SBS. The
      present study evaluates the intestinal changes and weight gains following a new
      lengthening technique (helicoidal enteromyotomy) performed in growing rats.
      Thirty Wistar rats underwent enteromyotomy (group I) in a 5-cm jejunal segment or
      laparotomy only (group II). No animal underwent intestinal resection.
      Postoperatively monitored weight was animals were sacrificed on the day 28.
      Measurements were made of the anterior and middle half-perimeters and the length
      of the marked-out intestinal segment. Two animals in group I were excluded due to
      infraction of the technique (perforation of the mucosa). Group I had an initial
      weight loss, although variance analysis (ANOVA) showed that the speed of the
      weight gain was similar in the two groups after the postoperative day 4 (P
      =.245). When the half-perimeter dimensions and length of the manipulated
      intestinal segment were compared, group I showed an increased caliber and length
      (P <.001, for both comparisons). There was no baseline difference in caliber
      between the two groups (P =.127). Our results led us to conclude that helicoidal
      enteromyotomy increases intestinal length and caliber without causing upstream
      dilatation or interfering in weight gain.

PMID- 15194353
TI  - FTY720 treatment prolongs skin graft survival in a completely incompatible strain
      combination.
AB  - FTY720 has shown potent immunomodulatory activity in a variety of animal organ
      transplant models. However, the in vivo immunosuppressive mechanism of FTY720 is
      still not fully understood. It has been suggested that the marked decrease in the
      number of peripheral blood lymphocytes during FTY720 administration could be
      responsible for its immunosuppressive effects. Our aims were: (1) to study the
      effects of FTY720 treatment on skin graft survival using a fully mismatched
      strain combination and (2) to evaluate lymphocyte numbers in different sites at 5
      days after skin transplant. C57BL/6 mice and BALB/c mice were the donors and
      recipients respectively. BALB/c mice received FTY720 (1 mg/kg/d) orally for 4
      consecutive days. Drug administration started 1 day before skin transplants. A
      small segment of tail skin was affixed on the right dorsal side of the mouse via
      sutures. The administration of FTY720 (4 mg/kg) prolonged skin graft survival
      from 12.6 +/- 2.2 days (no treatment) to 16.6 +/- 4.2 days. The histologic
      findings of rejection were similar for all groups. Five days after transplant,
      lymphocyte numbers were significantly increased in lymph nodes compared with
      nontransplanted or isogenic graft mice. FTY720 decreased lymphocyte numbers only
      in the spleen. In conclusion, FTY720 prolonged skin graft survival in a fully
      mismatched strain combination when administered for 4 days (day -1 to day +2) at
      a dose of 1 mg/kg/d. The decreased number of lymphocytes in the spleen suggests
      that the spleen may be a target of FTY720 activity, during the early
      posttransplant period.

PMID- 15194354
TI  - Effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival
      in rabbits.
AB  - The present study evaluated the effects of thalidomide, cyclosporine, and
      diclofenac on skin allograft survival in 42 rabbits divided into the following
      groups (n = 6): group 1, autograft control; group 2, allograft control; group 3,
      allografts under thalidomide (100 mg/kg/d); group 4, allografts under sodium
      diclofenac (2 mg/kg/d); group 5, allografts under cyclosporine (10 mg/kg/d);
      group 6, allografts under cyclosporine (5 mg/kg/d); group 7, allografts under
      cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). The drugs were given via
      the orogastric tube the day before transplantation and daily during the
      postoperative period. Total circular skin grafts from the ear were exchanged
      between California and White New Zealand rabbits. Cyclosporine (10 mg/kg/d)
      increased allograft survival, an effect that was comparable to cyclosporine (5
      mg/kg/d) plus thalidomide (100 mg/kg/d). Thalidomide and diclofenac given alone
      had minimally significant effects on the mean survival of skin allografts. The
      number of eosinophils around the necrotic skin was higher in the diclofenac
      group. The group receiving cyclosporine combined with thalidomide displayed the
      lowest number of eosinophils surrounding the allograft. In conclusion, the
      combination of thalidomide and cyclosporine in subtherapeutic doses may be useful
      for the treatment of skin allografts.

PMID- 15194355
TI  - Microchimerism does not correlate with survival of murine cardiac allografts.
AB  - The development of microchimerism was evaluated at different time points after
      infusion of a mixed population of bone marrow and spleen cells from (BALB/c x
      C57Bl/6)F1 mice in the presence or absence of a cardiac transplant.
      Microchimerism was observed in the spleen, bone marrow and thymus of transplanted
      BALB/c mice even after graft rejection. In the absence of transplantation, donor
      cells persisted especially in the thymus. The results show that despite
      augmentation of graft survival after donor cell infusion compared to nontreated
      controls, the development of microchimerism did not sustain cardiac
      semihistocompatible grafts. Moreover, the persistence of donor cells in the
      thymus in both situations suggests a role for this organ in the increased graft
      survival in our model.

PMID- 15194356
TI  - Aneural culture of rat myoblasts for myocardial transplant.
AB  - Due to the peculiar characteristics of skeletal muscle, myoblast transplants have
      emerged as a therapy for cardiomyopathy, particularly after myocardial
      infarction. The objectives of this study were to define the mean time of
      cultivation necessary to obtain a cellular concentration of 10(6) to expand the
      mass for transplant, and to identify the proliferation phase of myoblasts. Ten
      myoblast cultures were performed using newborn Wistar rats. The isolation method
      used enzymatic dissociation in culture medium (HAM-F12 and 199) supplement with
      basic-fibroblast growth factor (b-FGF) and insulin growth factor (IGF-I). The
      mean cultivation time to obtain the desired concentration of 10(6) was 7 days,
      with expansion of up to 10(8)/g. When b-FGF was used, the cellular yield was
      approximately 10(7), with IGF-I the cellular yield was approximately 10(8),
      independent of the medium. We concluded that IGF-I is the better option for mass
      cellular expansion of myoblasts for application in myocardial transplants.

PMID- 15194358
TI  - Islet isolation under cGMP conditions: replacing the coil.
AB  - INTRODUCTION: Clinical islet transplantation is increasingly regulated, with
      isolation standards defined under current good manufacturing practices (cGMPs).
      cGMP requires validation of equipment cleaning and sterilization. The automated
      process for islet isolation requires rapid thermal exchange during processing,
      manipulating a metal coil containing cellular product into and out of
      chilled/heated waterbaths. We recognize challenges of validating cleaning and
      sterilization of this coil and propose replacement with a disposable blood
      warming system. Our specific aims were to assess the system's ability to
      accommodate flow rates utilized during various phases of pancreatic digestion and
      to assess its efficiency of heat exchange and temperature control. METHODS: In a
      pancreas digestion circuit, heat exchange occurred via the coil in a digital
      water bath, or Warmflo blood warming bag in a digital warming unit. Temperature
      within the digestion chamber was assessed using an inserted thermocouple. Time to
      achieve 37 degrees C was measured for set heating element temperatures 38.5
      degrees C to 41 degrees C. Circuit temperature maintenance characteristics were
      also recorded. RESULTS: The Warmflo bloodbag easily accommodated flows of 150 and
      300 mL/min. At all set temperatures, the bag resulted in shorter or equivalent
      time to 37 degrees C than the coil. Maintenance of 37 degrees C was also
      equivalent. We have utilized this system for four human islet isolations with
      mean time to 37 degrees C of 5.5 minutes, without difference in digestion
      quality. CONCLUSIONS: Use of a disposable blood warming system in place of the
      coil during islet isolation provides adequate flow characteristics, heat
      exchange, and temperature control and may facilitate evolution of islet isolation
      toward cGMP compliance.

PMID- 15194359
TI  - Analysis of donor factors affecting human islet isolation with current isolation
      protocol.
AB  - BACKGROUND: Appropriate donor selection is one of the keys for successful human
      islet isolation. Previous studies identified several critical donor factors;
      however, significant improvements in current human islet isolation protocols make
      reevaluation of donor factors necessary. STUDY DESIGN: Review was performed on 31
      human islet isolations. Islet isolations were conducted using the standard
      automated islet isolation method with three protocol revisions that included the
      two-layer method (TLM) of pancreas preservation prior to islet isolation, usage
      of purified collagenase mixture Liberase, and continuous density gradient for
      islet purification. Factors leading to successful isolations (islet yield >
      100,000 IE and static incubation stimulation index greater than 2.0) were
      analyzed. The impacts of various risk factors were also examined. RESULTS: Donors
      in the successful islet isolation group had a significantly lower incidence of
      elevated peak transaminases and creatinine levels, lower usage of norepinephrine
      or cardiac arrest, less prolonged hospitalization (> 96 hours), and less
      prolonged preservation time of donor pancreata (>25 hours). The TLM extended
      acceptable preservation time of donor pancreata from 8 to 25 hours. When donors
      had no risk factor, the success rate was 14/16 (87.5%). In sharp contrast, when
      donors had two or more risk factors, the success rate was 0/7 (0%; P <.001).
      CONCLUSION: Risk factors for human islet isolation with the current islet
      isolation protocol were identified. The decision to process pancreata based on
      review of donor factors should improve the consistency of human islet isolations
      and transplantation for curing type 1 diabetes.

PMID- 15194360
TI  - The effect of two-layer (University of Wisconsin solution/perfluorochemical)
      preservation method on clinical grade pancreata prior to islet isolation and
      transplantation.
AB  - BACKGROUND: Research-grade pancreata preserved by the two-layer method (TLM)
      compared to organs stored with University of Wisconsin (UW) solution prior to
      islet isolation result in significantly better islet yields. However, it is
      unknown whether the TLM improves islet yields from pancreata that meet the
      criteria for the selection of clinical-grade organs. METHODS: Six clinical-grade
      pancreata were preserved for 4.8 +/- 0.5 hour in UW and three clinical-grade
      pancreata were preserved by the TLM for 11.7 +/- 2.0 hour. The local team
      procured all pancreata. All donors were hemodynamically stable without
      norepinephrine usage and length of hospitalization was less than 96 hour. Causes
      of death were either head trauma or cerebrovascular accident. Islets were
      isolated and evaluated according to the Edmonton protocol. RESULTS: The TLM as
      compared to UW resulted in a significant increase in islet yields (3415 +/- 227
      vs 2006 +/- 337 IE/g pancreas, P <.03). The quality of islets as assessed by
      visual score was significantly better in the TLM group (8.7 +/- 0.2 vs 7.3 +/-
      0.3, P <.02) but other parameters (viability, survival rate after culture,
      insulin content, stimulation index) were similar between the two groups. We
      transplanted all three islet preparations in the TLM group but only two of six
      preparations from the UW group. CONCLUSION: Compared to UW, exposure of pancreata
      to the TLM resulted in greater islet yields and extended preservation times with
      clinical grade pancreas. Pancreata should be preserved by the TLM prior to islet
      isolation even for donors that meet clinical grade organ selection criteria. The
      Human Islet Transplantation in Seattle (HITS) Consortium is supported in part by
      a grant from the Juvenile Diabetes Research Foundation International. The HITS
      consortium is an islet transplant program involving the University of Washington,
      Pacific Northwest Research Institute, the Puget Sound Blood Center, Fred
      Hutchinson Cancer Research Center, Swedish Hospital, and the Virginia Mason
      Research Center.

PMID- 15194361
TI  - AIRarg and AIRgluc as predictors of insulin secretory reserve.
AB  - Various brief metabolic tests have been proposed as surrogate measures of insulin
      secretory reserve, which is normally determined by the more complicated and labor
      intensive method of glucose potentiation of arginine-induced insulin secretion
      (GPAIS). This article provides correlations between insulin responses to
      intravenous arginine (AIRarg) and intravenous glucose (AIRgluc) in 39 normal
      control subjects in whom insulin secretory reserve was measured by GPAIS. The
      correlation coefficients were.78 and.77, respectively, both of which were highly
      statistically significant (P <.001). These results indicate that either AIRarg or
      AIRgluc, tests that can be performed in less than 15 minutes, can be used as
      reliable predictors of insulin secretory reserve in normal controls and,
      presumably, in recipients of islet and pancreas transplantation.

PMID- 15194362
TI  - The influence of desmopressin and vasopressors in the donor management on graft
      function following pancreas transplantation.
AB  - INTRODUCTION: The use of desmopressin and vasopressors in cadaveric organ donors
      is considered a risk factor for graft dysfunction following pancreas
      transplantation by influencing the microcirculation. The aim of this study was to
      investigate the influence of these substances on early graft function. PATIENTS
      AND METHODS: This single-center retrospective trial included 59 patients who
      underwent simultaneous or solitary pancreas transplantation. The corresponding
      donor charts were reviewed for the use of vasopressors and desmopressin. Impaired
      graft function was determined as graft thrombosis or as insulin-dependence for
      more then 3 days posttransplant. Daily amylase and lipase concentrations from
      abdominal drains were measured to quantify reperfusion pancreatitis and fistula
      formation. RESULTS: Overall, pancreas thrombosis was observed in 4 of 59 (6.8%)
      recipients. There were no significant differences in thrombosis rate whether the
      donors received desmopressin (3/38 vs 1/21, P >.1) or the needed vasopressors
      (3/53 vs 1/9, P >.1). The number of patients who required insulin for more than 3
      days posttransplant was comparable whether the donors received desmopressin (9/38
      vs 4/21, P >.1), or vasopressors (9/46 vs 3/8, P >.1). At present all recipients
      with functioning pancreatic grafts (ie, 92.7%) are free of exogenous insulin
      therapy at 2 to 80 months posttransplant. The amylase/lipase concentrations of
      peritoneal fluid were independent of the administration of desmopressin or
      vasopressors in the donors. CONCLUSION: In this study donor desmopressin and
      vasopressor administration did not influence graft function after pancreas
      transplantation.

PMID- 15194363
TI  - The "fatty pancreas allograft": anatomopathologic findings and clinical
      experience.
AB  - Thirty-three hematoxylin and eosin-stained sections from 7 turned down pancreata
      from donors with body mass index (BMI) of 33.3 (range, 28-42) were examined.
      There was more fat infiltration between the superficial pancreatic lobules,
      interspersed with superficial islands of pancreatic tissue with its vessels and
      ductules. Thicker fatty interlobular septa were observed with numerous
      intralobular fat vacuoles. One organ had widespread autolysis. No microthrombi
      were noted. One pancreas from a 24-year-old donor with BMI of 30 was transplanted
      successfully. The "fatty pancreas" can be defatted and used for transplantation.

PMID- 15194364
TI  - Does treatment of cadaveric organ donors with desmopressin increase the
      likelihood of pancreas graft thrombosis? Results of a preliminary study.
AB  - Desmopressin (DDAVP) is commonly used in cadaveric organ donors to treat diabetes
      insipidus. The thrombogenic potential of DDAVP is well known. Recent animal data
      have demonstrated that DDAVP impairs pancreas graft (PG) microcirculation and
      perfusion. The aim of this study was too evaluate the effect of DDAVP on the
      incidence of PG thrombosis in clinical pancreas transplantation. A retrospective
      review of simultaneous kidney-pancreas transplant (SKPT) entered in the
      Scientific Registry of Transplant Recipients (SRTR) between 10/5/87 and 9/27/02
      was performed. Patients were included for analysis if there was definitive
      documentation as to whether DDAVP was (DDAVP-Y) or was not (DDAVP-N) administered
      to the donor. Both dose and duration of DDAVP treatment were not recorded by
      SRTR. A total of 2804 SKPTs were available for analysis. Mean follow-up was 1.75
      years (range, 1 month to 8.4 years). A total of 1287 SKPT patients (46%) received
      a PG from a DDAVP-Y donor. Graft ischemia times, donor and recipient ages,
      recipient gender distribution, surgical techniques, and immunosuppressive
      regimens were similar in both groups. The overall incidence of PG thrombosis was
      4.3%. The incidence of PG thrombosis in recipients of grafts from DDAVP-Y donors
      was 5.1% compared to 3.5% in recipients of grafts from DDAVP-N donors (P =.04).
      Fifty-eight percent of thrombosed PG came from DDAVP-Y donors compared to 42%
      from DDAVP-N donors (P =.04). We conclude that there appears to be a relationship
      between donor treatment with DDAVP and PG thrombosis. A prospective study is
      needed to verify these findings and to determine their clinical significance.

PMID- 15194365
TI  - Pulsatile pump perfusion of pancreata before human islet cell isolation.
AB  - Machine pulsatile perfusion for whole pancreas preservation might improve yield,
      viability, and function of human islets recovered after prolonged cold ischemia
      times. Four human pancreata were procured from cadaver donors (1 non-heart
      beating donor) and stored in cold University of Wisconsin (UW) solution for a
      mean 13 hours prior to placement on a machine pulsatile perfusion device. The
      four pancreata were perfused for 4 hours with UW solution before undergoing islet
      isolation. Islets were quantified, viability was assessed, and insulin secretion
      was measured. Results were compared with nonpumped islet isolations stratified
      for cold ischemia time (CIT) <8 hours or cold ischemia time >8 hours. The islet
      yield for the four pumped pancreata was 3435 (+/-1951) islet equivalents/gram
      pancreas tissue (IEQ/g), compared with a mean yield of 5134 (+/-2700) IEQ/g and
      2640 (+/-1000) IEQ/g from pancreas with <8 hours and >8 hours CIT, respectively.
      The mean viability after machine pulsatile perfusion was 86% (vs 74% and 74% for
      the <8 hour and >8 hour CIT groups). The mean viable yield (total yield x
      viability) was 2937 IEQ/g for machine perfusion, compared with 3799 IEQ/g and
      1937 IEQ/g from pancreata with <8 hours and >8 hours CIT, respectively. The
      insulin secretion index of islets after machine perfusion was 6.4, compared with
      indices of 1.9 and 1.8 for the <8 hour and >8 hour CIT groups. This preliminary
      data indicates that low-flow machine pulsatile perfusion of pancreata with
      prolonged cold ischemia time can result in excellent yield, viability, and
      function.

PMID- 15194366
TI  - African-American ethnicity is no longer a risk factor for early adverse outcomes
      in simultaneous kidney-pancreas transplantation with contemporary
      immunosuppression.
AB  - The influence of ethnicity on the outcome of simultaneous kidney-pancreas
      transplantation (SKPT) is controversial. The aim of this study was to determine
      the impact of ethnicity on the major endpoints of a prospective, multicenter,
      randomized trial of two dosing regimens of daclizumab compared to no-antibody
      induction in SKPT. A total of 297 patients were randomized into three groups:
      daclizumab 1 mg/kg/dose every 14 days for five doses (group I, n = 107);
      daclizumab 2 mg/kg/dose every 14 days for two doses (group II, n = 112), and no
      antibody induction (group III, n = 78). All patients received tacrolimus,
      mycophenolate mofetil, and steroids for maintenance immunosuppression. Thirty
      seven patients (12.5%) were African-American (AA) and 260 were non-African
      American (NAA). Demographics and transplant characteristics were comparable
      between AA and NAA patients. At 1 year, no differences were seen in patient
      survival (97% AA, 96% NAA), kidney graft survival (94% AA, 93% NAA), and pancreas
      graft survival (84% AA, 85% NAA). Rejection rate and incidence of adverse events
      were similar between AA and NAA subjects. Kidney graft function was comparable
      between AA and NAA patients at 1 year; however, mean HgbA1C was higher, C-peptide
      was lower, and oral hypoglycemic use was more common in AA subjects. Thus, in
      this prospective multicenter study, AA ethnicity was not associated with an
      increased risk of early adverse outcomes in SKPT. Follow-up will be required to
      determine whether long-term outcomes remain equivalent, particularly with regard
      to pancreas graft function.

PMID- 15194367
TI  - Long-term outcome of sirolimus rescue in kidney-pancreas transplantation.
AB  - The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue
      in kidney-pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our
      institution from 12/3/95 to 6/27/02. All patients received antibody (Ab)
      induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty
      five patients (31%) had SRL substituted for MMF for the following indications:
      (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2)
      intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced
      hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively.
      Mean follow-up was 3 +/- 2 years overall and 1.2 +/- 0.5 years after SRL rescue.
      No patients died. One- and 3-year actuarial kidney and pancreas graft survival
      was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR,
      1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the
      other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL
      levels; of these, 6 (86%) had mean TAC levels of <4.5 in the month preceding AR.
      Mean creatinine overall and for the rising creatinine group remained stable. All
      patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance
      demonstrated biochemical or clinical improvement. Sirolimus-related infection or
      other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients
      can be safely switched to SRL with long-term stabilization of renal function,
      excellent graft and patient survival, and no increase in SAE. A minimum TAC level
      of 4.5 ng/mL may be necessary to prevent late AR.

PMID- 15194368
TI  - Simultaneous pancreas-kidney transplantation is improved by living kidney
      donation program.
AB  - BACKGROUND: Shortage of suitable donors and current graft allocation priorities
      reduce the number of cadaveric kidneys available to diabetic recipients. The
      concurrent excess of solitary cadaveric pancreata and the excellent results of
      living kidney transplantation make simultaneous cadaveric pancreas-living kidney
      transplantation (SPLKTx) an attractive alternative to simultaneous pancreas
      kidney transplantation (SPKTx). METHODS: Between June 2001 and June 2003, 80
      recipients were enrolled in the SPKTx waiting list. Each recipient's family was
      counseled about living kidney donation (LKD). Twenty-nine (36.2%) candidates were
      evaluated for LKD and 8 (27.6%) were disqualified. The remaining 21 candidates
      were scheduled for LKD and 18 actually donated. RESULTS: Thanks to LKD 18
      additional recipients were transplanted, thus expanding the donor pool from 33 to
      51 (P =.004). The median waiting time for SPLKTx was 14 days as compared with 95
      days for SPKTx (P =.006). Without LKD the median waiting time for SPKTx would
      have been 198 days (P =.02). Similarly, 1 year after the enrollment on the
      waiting list 60% of recipients had been transplanted, while without LKD only 42%
      would had been grafted (P =.01). Two-year recipient survival rate was 100% for
      SPLKTx compared with 96.9% for SPKTx. Equivalent figures for kidney and pancreas
      were 80.0% and 84.0% for SPLKTx compared with 96.9% and 96.9% for SPKTx.
      CONCLUSIONS: LKD expanded the kidney donor pool, reduced the waiting time of
      recipients listed for a totally cadaveric procedure, and increased their chance
      to get a timely graft. One-year outcome of SPLKTx equaled that of SPKTx.

PMID- 15194369
TI  - Single-center, open, prospective, randomized pilot study comparing cyclosporine
      versus tacrolimus in simultaneous pancreas-kidney transplantation.
AB  - BACKGROUND: Although tacrolimus (Prograf) is the calcineurin inhibitor usually
      employed in simultaneous pancreas-kidney transplantation (SPKTx), no prospective
      randomized studies have compared its efficacy to cyclosporine (Neoral), when
      either drug is used in combination with mycophenolate mofetil (MMF) and the
      pancreas is drained into the portal vein. METHODS: Between May 2001 and June
      2003, 16 SPKTx recipients were randomized to be prescribed Neoral and 17 Prograf
      in addition to basiliximab, steroids, and MMF. All pancreata were drained into
      the portal vein. RESULTS: After a median follow-up of 15.6 months, six kidney
      acute rejection episodes were observed with Prograf (36.5%; one steroid
      resistant) and one Neoral (n = 1, 6.2%; P =.04). No pancreas rejection episode
      was recorded. Two infections occurred in two recipients from each group. No major
      adverse events were noted other than a severe hematological toxicity (Prograf).
      Metabolic parameters were equivalent in the two groups, save for higher total
      cholesterol (212 +/- 39 mg/dL vs 173 +/- 23 mg/dL; P =.008), LDL (129 +/- 33
      mg/dL vs 101 +/- 21 mg/dL; P =.029), and triglyceride (191 +/- 86 mg/dL vs 126 +/
      40 mg/dL; P =.028), values with Neoral, although the same differences were
      already present at baseline. One recipient (Neoral) died with functioning grafts.
      Patient, pancreas, and kidney survival rates were all 94% for Neoral versus 100%
      for Prograf. CONCLUSIONS: Although a larger series and a longer follow-up are
      needed, Neoral and Prograf used in combination with MMF seem to achieve
      equivalent success rates among primary SPKTx when the pancreas is drained into
      the portal vein.

PMID- 15194370
TI  - Experience with steroid-free maintenance immunosuppression in simultaneous
      pancreas-kidney transplantation.
AB  - INTRODUCTION: Steroid avoidance is possible in simultaneous pancreas-kidney
      transplantation with the use of newer immunosuppressive agents and induction
      therapy. We undertook a retrospective consecutive case review of patients treated
      at a university tertiary referral center. METHODS: Medical records of 44
      consecutive patients receiving a pancreas-kidney transplant from November 2000 to
      September 2002 were reviewed. The immunosuppression protocol used in this series
      of patients consisted of thymoglobulin induction, combined with mycophenolate
      mofetil, tacrolimus, and sirolimus for maintenance immunosuppression. Steroids
      were used only while thymoglobulin was given and were typically discontinued by
      postoperative week 1. Main outcome measures included graft and patient survival
      rates, rejection rates of the kidney or pancreas, infection rates, and surgical
      complication rates. RESULTS: All 44 patients received a kidney-pancreas
      transplant with systemic venous anastomosis and enteric drainage of the pancreas.
      Patient kidney, and pancreas survival rates were 95.6%, 93.2%, and 88.7%,
      respectively. Biopsy-proven pancreas rejection rates at 1 and 6 months
      posttransplant were 2.3% and 2.3%. Kidney rejection rates at 1 and 6 months were
      2.3% and 4.6%. Reasons for patient loss included one death from sepsis and one
      cardiovascular death. Reasons for kidney loss besides death included a thrombotic
      microangiopathy. Reasons for pancreas loss included three thromboses, one mild
      rejection/infection, and one duodenal segment leak with infection. All patients
      who have been free of rejection have been off steroids for the duration of follow
      up. CONCLUSIONS: Newer immunosuppression protocols without maintenance steroids
      are possible with minimal rejection in the first 3 months and equivalent patient
      and graft survival rates compared with earlier protocols utilizing steroids. The
      potential beneficial long-term impact of steroid avoidance will require further
      study.

PMID- 15194371
TI  - The effect of pancreas transplantation on peripheral vascular disease
      complications.
AB  - BACKGROUND: We sought to determine whether pancreas transplantation reduced the
      incidence of peripheral vascular complications in diabetics with renal
      insufficiency. METHODS: A retrospective single-center review was done of 36
      kidney-pancreas (KP) and 88 kidney-alone (KA) recipients with a diagnosis of
      diabetes and end-stage renal disease (ESRD) transplanted between May 1997 and
      July 2002. Risk factors studied included type of transplant, age, gender, history
      of smoking, coronary artery disease, hypertension, and peripheral vascular
      disease (PVD). The endpoint was first peripheral vascular event occurring after
      transplantation, defined as either an amputation or revascularization procedure.
      RESULTS: The mean age of the cohort was 51 +/- 9 years, 64% of patients were of
      male gender, 20% with a history of smoking, 98% with hypertension, 15% with
      coronary artery disease (CAD), and 12% with a history of PVD. With a median
      follow-up of 45 months (12 to 79 months), 3/36 (8%) of KP recipients suffered a
      PVD complication, compared to 10/88 (11%) of KA recipients (P = NS). Similarly,
      age, gender, a past history of smoking, CAD, and hypertension were not predictive
      of PVD complications. Five of 15 patients (33%) with a pretransplant history of
      PVD suffered a postoperative PVD event compared to only 8 of 109 patients (7%)
      with no prior history of PVD (P =.008). CONCLUSIONS: Restoration of normoglycemia
      by pancreas transplantation did not reduce the risk of PVD complications in
      diabetics with renal failure. A pretransplant history of PVD was the only risk
      factor associated with posttransplant PVD events.

PMID- 15194372
TI  - Long-term survival after kidney and kidney-pancreas transplantation in diabetic
      patients.
AB  - PURPOSE: To investigate the influence of diabetes mellitus on patient and graft
      survival among renal versus renal-pancreatic recipients. METHODS: Among 270 renal
      transplants performed from 1985 to 2002, a total of 204 (75%) were in diabetic
      patients and 66 (25%) in nondiabetic patients. Among the 204 diabetic patients
      161 (60%) kidneys were transplanted simultaneously with a pancreatic graft (SKPT
      group). The overall group of patient included 164 (61%) men and 106 (39%) women
      with mean time on dialysis of 31 +/- 21 months (range 0 to 126 months). The mean
      duration of diabetes was 24 +/- 7 years (range 5 to 51 years). Ninety-nine
      percent of the patients were on renal replacement therapy (79% hemodialysis and
      20% peritoneal dialysis). RESULTS: The overall rejection rate was similar (NS).
      Both patient and kidney graft survival rates were worse in diabetics. Patient
      survival was 82% at 5 years among patients undergoing SKPT, 60% in diabetics
      receiving only a kidney, and 88% in nondiabetic transplanted patients. Kidney
      graft survival at 5 years was 77% in diabetics receiving SKPT, 68% in diabetics
      receiving a kidney alone, and 82% in nondiabetic patients. Overall patient
      survival was significantly greater among nondiabetics (P =.002) or in diabetics
      who received SKPT compared with diabetics who only had a kidney transplant (P
      =.001). CONCLUSIONS: This retrospective clinical evaluation confirms that
      combined pancreas and kidney transplantation should be the first choice to
      insulin-dependent diabetes mellitus (IDDM) patients with end-stage diabetic
      nephropathy.

PMID- 15194374
TI  - The impact of delayed graft function of the kidney on the pancreas allograft in
      simultaneous kidney-pancreas transplantation.
AB  - It is unclear whether delayed graft function (DGF) of the kidney has any
      influence on pancreas graft function following simultaneous kidney-pancreas
      transplantation (SKPT). A subgroup analysis was conducted using data from a
      multicenter study to determine the impact of DGF of the kidney on pancreas graft
      function following SKPT. METHODS: Of the 297 SKPT patients, 24 (8%) had DGF of
      the kidney, defined as the need for dialysis during the first week
      posttransplant. Clinical parameters including patient and graft survival,
      incidence of acute rejection, and pancreas and renal function were compared
      between patients with and without DGF at 1 week, and at 1, 3, 6, and 12 months
      posttransplant. RESULTS: Demographic and transplant characteristics were similar
      between the two groups except for longer kidney and pancreas cold ischemia times,
      more males, and more primary cytomegalovirus (CMV) exposure in the DGF group (P
      <.05). No differences were seen in patient and graft survival rates, but the
      incidence of acute renal rejection was higher in patients with DGF (42%) than in
      those without DGF (15%, P =.001). More patients with DGF (25%) received oral
      hypoglycemic agents at 1-year posttransplant than in those without DGF (5%, P
      <.01). At 1 year, the mean serum creatinine was 1.8 mg/dL and 1.4 mg/dL in
      patients with and without DGF, respectively (P <.01). CONCLUSIONS: Patients with
      DGF of the kidney had a higher incidence of acute renal rejection and received
      oral hypoglycemic agents more often during the first year posttransplant compared
      to those who did not have DGF following SKPT.

PMID- 15194373
TI  - Does surgical technique influence outcomes after simultaneous kidney-pancreas
      transplantation?
AB  - Since 1995, many centers have switched from bladder to enteric drainage of the
      exocrine secretions in simultaneous kidney-pancreas transplantation (SKPT).
      Enteric exocrine drainage may be performed with either systemic (systemic-enteric
      [S-E]) or portal (portal-enteric [P-E]) venous delivery of insulin. Controversy
      exists regarding the optimal surgical technique. From March 1999 to May 2001, a
      total of 297 SKPT patients were enrolled into a prospective, multicenter,
      randomized, open-label, comparative trial of two daclizumab dosing strategies
      versus no-antibody induction in combination with tacrolimus, mycophenolate
      mofetil, and steroids in SKPT recipients. Surgical techniques were center
      specific. A total of 171 patients (58%) underwent SKPT with S-E drainage, 96
      (32%) with P-E drainage, and 30 (10%) with systemic-bladder (S-B) drainage. The
      two groups randomized to daclizumab induction were similar with regard to
      surgical technique (64% S-E, 25% P-E, 11% S-B drainage). Demographic and
      transplant characteristics and immunosuppression were similar among the three
      groups, except that more patients with P-E drainage did not receive antibody
      induction. At 6 months, no differences were seen in patient and graft survival
      rates, surgical complications including pancreas thrombosis, rates of rejection
      or infection, readmissions, and kidney and pancreas allograft function among the
      three different surgical techniques. The 6-month results of this multicenter
      study suggest no significant differences in outcomes in SKPT recipients according
      to surgical technique.

PMID- 15194375
TI  - One-year outcomes in simultaneous kidney-pancreas transplant recipients receiving
      an alternative dosing regimen of daclizumab.
AB  - The purpose of this study was to compare the safety and efficacy of two dosing
      regimen of daclizumab with no-antibody induction in simultaneous kidney-pancreas
      transplant (SKPT) recipients receiving tacrolimus, mycophenolate mofetil, and
      steroids. METHODS: A total of 297 SKPT patients were enrolled into this
      prospective, multicenter, randomized, open-label study. The patients were
      randomized into three groups: daclizumab 1 mg/kg/dose every 14 days for five
      doses (group I, n = 107), daclizumab 2 mg/kg/dose every 14 days for two doses
      (group II, n = 112), and no-antibody induction (group III, n = 78). RESULTS:
      There were no differences in baseline characteristics among the three groups,
      except for a higher proportion of African-Americans in group II. The incidence of
      composite events (acute rejection, graft loss, or death) at 1 year was 36.4%,
      32.7%, and 48.7% for groups I, II, and III, respectively (P <.05, group II vs
      group III). The incidence of acute rejection was highest in group III (34.6%)
      compared to groups I and II (22.4% and 22.1%, respectively, P <.05). The mean
      time to acute rejection was delayed in group II (96 days) compared to 23 days in
      group I and 20 days in group III (P <.05). The adverse-event profiles were
      comparable among the three groups, except for a higher incidence of infection and
      readmissions in group III. CONCLUSIONS: Daclizumab was safe and effective in
      reducing the incidence of acute rejection when compared to no induction. The
      alternative two-dose regimen of daclizumab was as effective as the conventional
      five-dose regimen and is logistically more desirable.

PMID- 15194376
TI  - Effect of donor-recipient cytomegalovirus serologic status on outcomes in
      simultaneous kidney-pancreas transplant recipients.
AB  - Diabetic patients undergoing simultaneous kidney-pancreas transplantation (SKPT)
      may be at high risk for developing cytomegalovirus (CMV) infection. To study this
      issue, we analyzed 297 SKPT patients enrolled into a multicenter trial of two
      daclizumab dosing strategies versus no antibody induction in combination with
      tacrolimus, mycophenolate mofetil, and steroids. Complete donor (D) and recipient
      (R) CMV serology values were available in 294 cases and were distributed as
      follows: 86 (29%) D+/R-. Eighty-six (29%) D+R+; 45 (16%) D-/R+; 77 (26%) D-/R-;
      CMV antiviral prophylaxis was center specific, but 98% of patients received
      either ganciclovir or acyclovir. No differences existed in demographic or
      transplant characteristics or immunosuppressive regimens among the four groups
      except that more African-American SKPT recipients were CMV positive at transplant
      (P <.001). At 6 months, no differences were seen in patient and graft survival
      rates (GSR) and the incidence of acute rejection (AR) among the groups. However,
      the CMV D+/R- group had a significantly higher incidence of CMV infection/disease
      (14%) than the other groups collectively (4%, P <.05). Most cases of CMV
      infection/disease occurred greater than 3 months posttransplant when prophylaxis
      was discontinued. In the D-/R- group, the pancreas GSR was higher (94% vs 86% in
      the remaining three groups) and the incidence of AR was lower (16% vs 25% in the
      remaining three groups, both P =.09). Primary CMV exposure remains a major risk
      factor for CMV infection/disease, but does not have an adverse impact on short
      term outcomes. Conversely, protective CMV seronegative matching may have a
      beneficial effect on outcomes.

PMID- 15194377
TI  - There are no differences in pretransplant characteristics of individuals
      receiving simultaneous pancreas-kidney transplant and individuals with type 1
      diabetes mellitus receiving living-related kidney transplant.
AB  - Simultaneous pancreas-kidney transplantation (SPK) recipients have longer
      survival compared to type 1 diabetes mellitus (DM1) cadaveric kidney recipients.
      However, DM1 living-related kidney transplant (KTX-LR) recipients have the same
      mortality as SPK recipients. It is unknown whether cardiovascular (CVD) risk
      factors pretransplant are similar between the two groups, SPK and DM1 KTX-LR. We
      analyzed pretransplant characteristics of SPK recipients (n = 39) and DM1 KTX
      LR/living unrelated (LUR) recipients (KTX-LR/LUR, n = 20). In individuals who had
      multiple transplants, only pretransplant data from the first transplant was used.
      As all characteristics of KTX-LR/LUR recipients were the same, they were grouped
      for comparison with SPK. Pretransplant blood pressure (BP), body mass index,
      (BMI), hemoglobin A1c (A1c), total cholesterol (TC), high-density lipoproteins
      (HDL), low-density lipoproteins (LDL), triglycerides (TG), serum creatinine, type
      and duration of dialysis, and duration of diabetes were compared between the two
      groups. Mean age at time of transplantation was 41 +/- 1 years (mean +/- SEM) for
      SPK versus 39 +/- 2 years for KTX-LR/LUR (P = NS). Pretransplant BP, BMI,
      duration of diabetes, TC, HDL, LDL, TG, and lipid agent use were not different
      between the groups. Pretransplant A1c was 7.8 +/- 0.3% for SPK recipients and 8.3
      +/- 0.5% for KTX-LR/LUR recipients (P = NS). Pretransplant serum creatinine was
      higher in KTX-LR/LUR compared to SPK (7.9 +/- 0.6 mg/dL versus 5.4 +/- 0.5 mg/dL;
      P =.01). Except for serum creatinine, there were no significant differences in
      traditional CVD risk factors pretransplant. However, factors posttransplant in
      addition to better glucose control with SPK may still be different between SPK
      and KTX-LR/LUR groups.

PMID- 15194378
TI  - Characteristics of pancreas transplantation currently performed in japan.
AB  - The Pancreas Transplantation (tx) Program under the Japanese Organ Transplant Act
      was started in 2000. PTx is indicated for type 1 diabetic patients on
      hemodialysis therapy. As of April 2003 93 patients are listed as candidates. Ten
      cases of PTx with enteric or bladder-drained technique were performed during the
      last 3 years as well as nine SPK and one PAK. Of 10 cases, nine recipients are
      insulin-free with HbA1c values ranging from 4.4% to 5.7%, although exogenous
      insulin was required in six cases temporarily, namely for a median 63 days (12 to
      225 days). One case was lost due to pancreatic graft thrombosis. All 10 kidney
      grafts are functioning. Based on the experiences with 14 cases of pancreas tx
      using non-heart-beating (NHB) donors, we defined the criteria of NHB donor as:
      age younger than 40 years and cessation of respiratory support. One case of SPK
      with graft of NHB donor was done, and the recipient is off insulin. Pancreas and
      kidney are allocated for SPK if the recipient shares at least one HLA-DR antigen.
      Marginal donors were defined as higher mean donor age, median 37 (range 18 to 58
      years); mean 38 +/- 12 years), and no death cause of by trauma. The
      revascularization of gastroduodenal artery to the pancreatic graft was performed
      in eight cases to minimize the risk of ischemic injury to the pancreatic graft
      and technical failure in cases of marginal donor.

PMID- 15194379
TI  - Portal enteric-drained solitary pancreas transplantation without surveillance
      biopsy: is it safe?
AB  - BACKGROUND: Most solitary pancreas transplants (SPTx) fail due to unrecognized
      rejection episodes. Consequently, SPTx are monitored by drainage into the bladder
      or by surveillance biopsies. METHODS: Between April 2001 and June 2003, a
      consecutive series of 48 SPTx were performed using portal enteric drainage (PED).
      Rejection episodes were diagnosed empirically, based on the elevated pancreatic
      enzymes without a surveillance biopsy. Immunosuppression consisted of basiliximab
      (n = 42) or ATG (n = 6), low-dose steroids, MMF, and tacrolimus. Donors (mean age
      28.9 year; range 9 to 54 year) were selected according to standard criteria
      irrespective of HLA match, although the best HLA matching was considered at the
      time of graft allocation. RESULTS: After a mean cold ischemia time of 676 minutes
      (range 475 to 900 minutes), all but two pancreata (95.8%) functioned immediately.
      Relaparotomy was required in seven cases (14.6%). Three grafts were lost in the
      early posttransplant period due to hyperacute rejection. Two additional grafts
      were lost later due to arterial thrombosis or to chronic rejection. After a
      median follow-up period of 12.2 months (range 0.2 to 27 months) three further
      recipients were diagnosed with rejection episodes that were reversed with steroid
      boluses. Actuarial 1-year patient and graft survival rates were 100% and 93.1%
      and 2-year figures 100% and 88.7%, respectively. At the longest follow-up no
      recipient was diagnosed with a malignancy. CONCLUSIONS: With current
      immunosuppression protocols SPTx achieves high rates of insulin independence even
      without surveillance biopsy or routine use of T-cell-depleting therapies.

PMID- 15194380
TI  - A prospective comparison of bladder versus enteric drainage in vascularized
      pancreas transplantation.
AB  - Although the number of pancreas transplants has increased significantly in
      previous years, debate continues concerning the optimum technique for exocrine
      pancreas drainage. Enteric drainage (ED) has recently been increasingly popular
      due to the long-term complications with bladder drainage (BD). We prospectively
      assigned 40 consecutive pancreas transplant recipients to either bladder (n = 20)
      or enteric (n = 20) drainage. Patient, kidney, and pancreas graft survival rates
      at 1 year after simultaneous kidney-pancreas transplantation were 95%, 95%, 85%,
      for BD group and 90%, 85%, 85% for ED group, respectively. Surgical complications
      were not significantly different between the two groups. The incidence of acute
      rejection, major infections, and CMV disease were similar between groups. The
      length of the initial hospital stay was likewise comparable. However, the BD
      group showed a slight increase in the number of urologic complications, metabolic
      acidosis, and dehydration. Based on the results of our study, patient and graft
      survivals were excellent irrespective of technique.

PMID- 15194381
TI  - Renal pathology and clinical presentations of polyomavirus nephropathy in
      simultaneous kidney pancreas transplant recipients compared with kidney
      transplant recipients.
AB  - INTRODUCTION: The purpose of this study was to describe and compare the renal
      histopathology and clinical course of simultaneous kidney-pancreas transplant
      (SKP) recipients with kidney transplant (KT) recipients with polyomavirus
      nephropathy (PVN). METHODS: Between 1997 and 2002, 20 patients (7 SKP, 13 KT)
      were diagnosed with PVN. Clinical characteristics and outcomes of PV-N were
      correlated with histopathologic examinations of renal allograft biopsy and
      compared between SKP and KT recipients. RESULTS: There were no differences in
      demographics between SKP and KT recipients with PV-N. The mean time to PVN was
      611 (172 to 1174) days posttransplant in SKP and 343 (83 to 720) days
      posttransplant in KT (P =.05). The serum creatinine at the time of diagnosis was
      similar between SKP and KT recipients. All patients were treated with reduction
      in immunosuppression. After a median follow-up of 2 years, the patient survival
      was 71% in SKP and 100% in KT. Four grafts (57%) were lost owing to PVN in SKP
      group and three grafts (23%) were lost owing to PVN in the KT group. More
      patients (43%) in SKP had a history of acute rejection prior to diagnosis of PVN
      compared to KT (8%) and biopsy-proven tacrolimus nephrotoxicity prior to PVN was
      more common in SKPT (86%) than in KT (8%) patients (P <.05). SKP patients with
      evidence of diffuse fibrosis and high total sum scores at time of presentation
      all subsequently lost their grafts. CONCLUSIONS: SKP recipients with PVN had a
      worse clinical course than KT recipients.

PMID- 15194382
TI  - Polyomavirus-associated nephropathy in simultaneous kidney-pancreas transplant
      recipients: a single-center experience.
AB  - BACKGROUND: With the introduction of more potent immunosuppressive agents,
      rejection rates have decreased markedly in simultaneous pancreas-kidney
      transplant (SPK) recipients. However, with more intense immunosuppression,
      opportunistic infections such as polyoma virus have been more frequent. The
      purpose of this article is to outline the clinical course of SPK patients who
      developed documented polyoma infection in the transplanted kidney. METHODS: A
      retrospective review of 146 consecutive SPK recipients from 1996 to 2002 was
      performed. Induction and maintenance immunosuppression, surgical complications,
      rejection episodes, and opportunistic infections were reviewed. Patients who
      developed biopsy-proven polyoma virus infection in the renal allograft were
      identified. RESULTS: Nine patients (6%) were identified who developed polyoma.
      All had received induction therapy with either OKT3 (5 mg/d for 10.5 days) or
      thymoglobulin (5.7 mg/kg). Patients without polyoma had received similar
      induction. Maintenance immunosuppression included Prograf/MMF in six patients,
      CsA/MMF in two, and CsA/azathioprine in one. Time to diagnosis was an average of
      359.3 days (range 136 to 836) after transplantation. Two patients had undergone
      treatment for kidney rejection prior to the diagnosis of polyoma.
      Immunosuppression was decreased in all patients when polyoma was identified, and
      more recently Cidofovir has been administered. Despite these interventions, five
      of the nine lost kidney function (creatinine > 5.0 or resumption of dialysis).
      However, none of the nine developed pancreatic abnormalities as demonstrated by
      normal blood glucose and amylase and no requirement for exogenous insulin. Two
      patients underwent LRRT more than 1 year after polyoma diagnosis; both have
      normal kidney function (Cr < 1.5 mg/dL) at 4 years of follow-up. Polyoma virus
      was the leading cause of renal loss in this cohort of patients. CONCLUSIONS:
      Polyoma is a serious concern for SPK transplant recipients. The pancreas,
      however, is spared from clinical evidence of infection, and no rejection was
      noted when immunosuppression was decreased. These graft losses appear to be a
      penalty of more potent immunosuppression, and a better treatment strategy is
      needed to prevent renal graft loss when polyoma is diagnosed. Retransplantation
      can be considered based on our limited experience.

PMID- 15194383
TI  - Modulating amylase and lipase secretion in the pancreatic graft by somatostatin
      administration: preliminary results of a prospective, randomized trial.
AB  - Pancreas transplantation is a routine method for the treatment of diabetes
      mellitus. One of the main challenges of a transplant with extraperitoneal
      placement of the pancreatic graft is impaired wound healing due to massive
      amylase and lipase secretion by the pancreatic graft, evoking edemtous fluid.
      From February 2002 through January 2003, we performed pancreatic transplant
      procedures in 21 patients who were prospectively and randomly assigned to two
      groups: 8 organ donors and the recipients were administered somatostatin by
      continuous infusion. Thirteen grafts were harvested and transplanted without
      somatostatin infusion. The two groups did not show significantly differences in
      mean donor or recipient ages, weights, of serum amylase and lipase content values
      or drain output until day 6. There was a significantly lower lipase in the drain
      output of transplant recipients given somatostatin (12.5 and 54.2 micromol/L,
      respectively; P <.05). Neither the post-pancreatic transplant wound healing nor
      the number of rejection episodes were affected by somatostatin administration.

PMID- 15194384
TI  - Eligibility of diabetic patients receiving dialysis for islet after kidney
      transplantation.
AB  - INTRODUCTION: The aim of this study was to assess the selection of candidates
      among 38 dialyzed diabetic patients referred between January 1, 1998 and December
      31 2002 for kidney followed by islet transplantation (IAK). The main criteria of
      eligibility for possible IAK were as follows: (1) plasma C-peptide negative; (2)
      need for a kidney graft; (3) kidney plus whole pancreas transplantation not
      desired by the patient; and (4) acceptable results of postkidney graft preislet
      transplantation evaluation. RESULTS: Seventeen of 38 patients with positive C-p
      diabetes received a kidney graft alone. Among the 21 C-p-negative diabetic
      patients, 3 were not eligible for kidney transplantation mainly for psychological
      reasons and 4 were eligible for kidney plus pancreas transplantation. The
      remaining 14 C-p-negative patients underwent kidney transplantation or had
      previously undergone kidney transplantation. Among them, 1 had moved away, 1
      refused IAK, one had slightly positive stimulation tests, 1 was overweight, 1 had
      breast cancer, and 1 had postkidney graft complications. Among the remaining 8 of
      14 C-p-negative, kidney-engrafted patients listed for IAK, 5 have undergone
      transplantation, 3 with a pre-Edmonton and 2 with the Edmonton protocol.
      CONCLUSION: In conclusion among this series of 38 diabetic patients undergoing
      dialysis, more than 90% were kidney-grafted. Approximately 50% were ineligible
      for pancreas transplantation or IAK because of a positive C-p, and 20% were
      enlisted for IAK. These results highlight the importance of C-p determinations in
      diabetic dialysis patients to identify eligible patients for pancreas
      transplantation or IAK.

PMID- 15194385
TI  - Eligibility of diabetic patients for islet transplantation alone.
AB  - Since the Edmonton protocol, islet transplantation alone (ITA) offers the
      prospect of adequate glycemic control in type 1 diabetes without kidney failure.
      Patient motivation, evolution of diabetic complications, and hypoglycemia
      unawareness have to be balanced against the risks of portal puncture and long
      term immunosuppressive therapy. The aim of this work was to assess the profile of
      41 type 1 diabetic patients (21 men and 20 women of age 18 to 63 years) for whom
      islet transplantation was considered, between January 2000 and December 2002.
      Thirty-one of these patients lived in the area. The patients were divided into 3
      groups according to their recruitment: 20, personal initiative (G1); 8, recruited
      from hospitalization (G2) for marked glycemic imbalance; and 13, (G3) referred by
      their diabetologist. Among this series of 41 patients, 14 (8 in G1, 4 in G2, and
      2 in G3) did not fit the eligibility criteria, mainly because of a positive C
      peptide, kidney failure, desire for pregnancy (G1, G3), liver disorders related
      to alcohol or iron overload related to HFE heterozygosity (G2), or good glycemic
      balance (G3). Sixteen did not wish to proceed after the first information step, 6
      of these being more interested in a pump. Eleven, mainly recruited in G1 or G3,
      went through the clinical pretransplantation assessment. Among these, 2 have
      undergone transplantation, another 1 is enlisted. Therefore, it appears that
      patient motivation and information to the diabetologists are two important issues
      in the recruitment of patients eligible for islet transplantation. Equally
      important is the measurement of C-peptide, plasma creatinine, and
      microalbuminuria.

PMID- 15194386
TI  - Human islet graft function in NOD-SCID mice predicts clinical response in islet
      transplant recipients.
AB  - The purpose of this study was to evaluate the utility of nondiabetic immune
      deficient NOD-SCID mouse model in assessing the functional capacity of isolated
      human islets. We transplanted 2000 islet equivalents obtained from six
      preparations used for human islet transplantation in three patients under the
      kidney capsule of groups of 10 mice. Human (Hu) C-peptide and insulin levels were
      determined following intraperitoneal (i.p.) glucose challenge at days 0, 7, 14,
      21, 30, 60, 90, and 120. The Hu C-peptide level >1.5 ng/mL was the threshold for
      islet function in this model. The first patient did not achieve insulin
      independence and had minimal (0.5 ng/mL) fasting C-peptide levels that mirrored
      the low C-peptide levels observed in the mice. After the first infusion, the
      insulin requirements were reduced by 50% in the second patient. She became
      insulin free 10 days after her second infusion with a C-peptide level of 3.0
      ng/mL, which corresponded to the peak C-peptide level (3.9 ng/mL) observed in the
      mice. By 150 days' posttransplant, the decline in C-peptide level paralleled the
      decline observed in mice. Within 2 weeks after the first transplant, insulin dose
      was reduced by 75% in the third patient, which corresponded to the robust C
      peptide production in mice (7.3 ng/mL). Both patient and mice had a delay in
      islet function following the second infusion. She remained with a C-peptide level
      of 1.8 ng/mL and insulin free until suffering a rejection episode 3 months later.
      We observed that human islet graft function in NOD-SCID mice correlated with
      clinical response in islet transplant recipients.

PMID- 15194387
TI  - Disseminated periportal fatty degeneration after allogeneic intraportal islet
      transplantation in a patient with type 1 diabetes mellitus: a case report.
AB  - Insulin independence after islet transplantation has been significantly improved
      by using new steroid-free immunosuppressive protocols and increased islet mass.
      Only little is known about the influence on the morphology of the liver of
      intraportally transplanted islets. We describe a case of disseminated periportal
      fatty degeneration after allogeneic intraportal islet transplantation (ITx). A 35
      year-old patient with type-1 diabetes mellitus who was suffering from repeated
      severe hypoglycemic episodes received two sequential intraportal islet grafts.
      Liver structure was normal before the first ITx, based upon ultrasound and
      magnetic resonance imaging (MRI). One week after the first ITx, ultrasound
      demonstrated normal liver morphology. Four months later, at the second ITx, we
      detected small, disseminated, and hypodense hepatic lesions (1 to 3 mm) by
      ultrasound, which were confirmed by MRI and interpreted to be fatty
      degenerations. Histologically we found focal drop-shaped fatty degenerations with
      signs of mild periportal chronic inflammation. These liver alterations without
      clinical symptoms or pathological liver function tests matched the predicted
      distribution of infused islets. Glucose metabolism markedly improved after the
      first ITx, namely 58.6% reduction of daily insulin requirements, 1.4% decrease in
      HbA1c, basal C-peptide of 0.8 to 1.3 ng/dl with no severe hypoglycemia. We
      interpreted these benign changes in liver morphology as reactions to a local
      hyperinsulinemia in the neighborhood of the transplanted islets. We hypothesized
      that a steroid-free immunosuppression with rapamycin and tacrolimus may have
      contributed to changes in the portal microenvironment.

PMID- 15194388
TI  - First Brazilian pancreatic islet transplantation in a patient with type 1
      diabetes mellitus.

PMID- 15194389
TI  - Morbidity associated with intraportal islet transplantation.
AB  - INTRODUCTION: Complications associated with intraportal islet infusion have been
      reported. In this study, we analyzed the relationship between occurrence of
      complications and islet preparation characteristics/infusion technique. METHODS:
      We reviewed all intraportal islet infusions from 1992 to 2003. RESULTS: Sixteen
      islet autotransplantations were performed without infusion-related complications.
      The tissue volume injected was 13 +/- 11 mL with basal and peak portal pressures
      of 13 +/- 6 and 21 +/- 6 mm Hg. Seventy-seven intraportal islet
      allotransplantations were performed in 51 patients. Fifteen islet infusions were
      done by laparotomy during simultaneous islet/kidney transplantation without
      complication. Among 62 percutaneous transhepatic injections, nine complications
      (two portal branch thrombosis and seven intra-abdominal hemorrhages) were
      recorded. Rise in portal pressure was related to tissue volume injected (P <.05).
      Basal and peak portal pressures were 14 +/- 5 and 18 +/- 6 mm Hg in uncomplicated
      infusions, 14 +/- 9 and 18 +/- 9 mm Hg in the thrombosis group, and 13 +/- 7 and
      18 +/- 5 mm Hg in the hemorrhage group (P >.05). Complications occurred only
      after percutaneous islet infusion (P <.03). CONCLUSIONS: Procedure-related
      morbidity of intraportal islet infusion is low. Changes in portal pressure are
      related to volume of tissue injected but do not seem to be associated with the
      occurrence of complications. Percutaneous infusion is a minimally invasive
      procedure, but this advantage must be balanced by the higher rate of
      complications.

PMID- 15194390
TI  - Islet of Langerhans allogeneic transplantation at the University of Geneva in the
      steroid free era in islet after kidney and simultaneous islet-kidney
      transplantations.
AB  - AIMS: We report a single-center experience of islet allogeneic transplantation in
      islet after kidney (IAK) and simultaneous islet-kidney (SIK) type 1 diabetic
      recipients using a steroid-free immunosuppressive regimen. METHODS: Eight
      patients received 12 islet infusions in 5 IAK and 3 SIK procedures. Median age
      was 51 years (range, 30-58 years) with a male:female ratio of 2:6. IAK was
      considered only for patients with a stable kidney function and a creatinine
      clearance level >60 mL/min. SIK was considered for patients with a
      counterindication for simultaneous kidney-pancreas transplantation.
      Immunosuppression was based on sirolimus/tacrolimus combined with daclizumab
      induction. Two consecutive infusions of >5000 islet equivalents (IEQ)/kg were
      planned. RESULTS: Five patients completed the transplantation course, whereas 3
      patients received only 1 islet infusion. All patients have functional grafts (C
      peptide >166 pmol/L) at 6-month median follow-up. Of 5 patients who completed
      their transplantation course 4 became insulin independent. HbA1c and fructosamine
      decreased over time, showing improved metabolic control. Severe adverse events
      were observed in 4 patients. One SIK patient died after OKT-3 treatment of severe
      kidney rejection. CONCLUSIONS: The Edmonton immunosuppressive protocol can be
      applied for patients undergoing either IAK or SIK procedures, with a high rate of
      graft function and insulin independence. Morbidity is higher than among patients
      undergoing solitary islet transplantation for type 1 brittle diabetes.

PMID- 15194391
TI  - Islet autotransplantation for the prevention of surgical diabetes after extended
      pancreatectomy for the resection of benign tumors of the pancreas.
AB  - OBJECTIVE: The objective of this article is to report a single-center experience
      with islet autotransplantation after extensive pancreatic resection for benign
      tumors of the pancreas. MATERIALS AND METHODS: Seven patients underwent extensive
      left pancreatectomy for benign lesions located at the neck of the pancreas. Once
      an unequivocal diagnosis of a benign nature was ascertained, the rest of the
      specimen was processed and the unpurified pancreatic digest was infused into the
      portal vein. The results were compared with those of 8 autotransplantations
      performed for chronic pancreatitis over the same period. RESULTS: Tumors were 4
      cystadenomas, 2 insulinomas and 1 neuroendocrine tumor. Mean islet yields were
      275,000 islet equivalents (IEQ) versus 129,000 in chronic pancreatitis (P =.04)
      or 6700 IEQ/g of tissue versus 1900 (P =.002), resulting in transplantation of
      4200 IEQ/kg body weight vs 2150 in chronic pancreatitis (P =.03), respectively at
      4-month to 7.5-year follow-up, all patients are alive and 6 of 7 are off insulin.
      All patients off insulin after at least 1 year currently have a normal IVGTT,
      with K values ranging between -1.19 and -2.36 (normal < -1.00). All patients,
      including 1 on insulin, display positive basal and glucagon-stimulated C-peptide
      levels. CONCLUSIONS: Compared with chronic pancreatitis tissue resected for
      benign tumors is more likely to achieve good islet yields, and thus insulin
      independence after autotransplantation. Islet autotransplantation should be
      considered when extensive pancreatectomy is required for resection of a benign
      tumor, and only if the benign nature of the lesion is demonstrated unequivocally.

PMID- 15194392
TI  - Islet autotransplantation combined with pancreatectomy for treatment of
      pancreatic adenocarcinoma: a case report.
AB  - Extensive pancreatectomy (EP) may increase the resection rate of pancreatic
      adenocarcinoma (PA). Unfortunately, EP often results in unstable diabetes.
      Recently, islet autotransplantation (auto-Tx) has offered the potential to
      prevent this metabolic disorder. Because of the fear of contamination of prepared
      islets by malignant cells, this procedure has so far not been used as a treatment
      for PA. We herein report a case of a 63-year-old nondiabetic patient who
      underwent EP combined with islet auto-Tx in an emergency operation following
      histologically proved R(0)-resection for PA (pT(3)pN(1)G(2)). Islets were
      isolated from the excised pancreas using a continuous digestion filtration
      device. The resultant preparation was injected into the portal vein. Owing to the
      moderate fasting hyperglycemia, postoperative exogenous insulin therapy was
      necessary (26 U/d). After discharge, the patient's daily insulin dose was
      gradually reduced. At 1-year follow-up the fasting C-peptide level was 0.66
      ng/mL, and an oral glucose tolerance test (oGTT) and an intravenous (IV) glucagon
      stimulation (GS) showed functioning engrafted islets. The K-ras mutations were
      detected in the paraffin-embedded PA, but not in the prepared islets or in the
      peripheral blood. Computed tomographic (CT) imaging revealed neither local tumor
      recurrence nor liver metastases. At 2-year follow-up, the patient was on a
      balanced food regimen and gaining weight. Although he remains insulin-dependent
      (16 U/d), he is metabolically stable (HbA(1)(c) 5.9%). The fasting C-peptide
      level is 0.68 ng/mL. The peak value of C-peptide in response to oGTT was 0.92
      ng/mL and to GS 0.89 ng/mL. At this time Ca19-9 and CEA are increased to 35.3
      U/mL and 19.2 ng/mL, respectively. The patient died 2.5 years after operation
      owing to tumor recurrence. There was no evidence for liver metastases. We
      postulate that histologic evaluation (R(0)-resection) and detection of K-ras
      mutations may be useful techniques. However, islet auto-Tx after EP for
      adenocarcinoma should only be regarded for rescue therapy. Studies on strategies
      to exclude possible contamination of islet tissue with carcinoma cells are
      critically important.

PMID- 15194393
TI  - Achievement of insulin independence via pancreatic islet transplantation using a
      remote isolation center: a first-year review.
AB  - BACKGROUND: Owing to advances in both immunosuppressive protocols and pancreatic
      islet isolation techniques, insulin independence has recently been achieved in
      type 1 insulin-dependent diabetics (IDDM) via pancreatic islet transplantation
      (PIT). Although the dissemination of immunosuppressive protocols is relatively
      easy, transferring the knowledge and expertise required to isolate a large number
      of quality human islets for transplantation is a far greater challenge.
      Therefore, in an attempt to centralize the critical islet processing needed for
      islet transplantation and to avoid the development of another islet processing
      center, we have established a collaborative islet transplant program between two
      geographically distant transplant centers. PATIENTS AND METHODS: Eleven
      consecutive type 1 IDDM patients with a history of severe hypoglycemia and
      metabolic instability underwent PIT at the Methodist Hospital (TMH) in Houston,
      Texas, utilizing pancreatic islets isolated at the Diabetes Research Institute
      (DRI) at the University of Miami in Miami, Florida between January 1, 2002 and
      June 31, 2003. Forty-one pancreata have been procured in the Houston area and
      have subsequently been transported for isolation at the DRI following enzymatic
      ductal perfusion by the automated method (Ricordi chamber). Following
      purification the islets were immediately transported back to TMH in Houston and
      transplanted via percutaneous transhepatic portal infusion. Immunosuppression
      regimen consisted of sirolimus, tacrolimus, and daclizumab. RESULTS: Following
      harvesting, donor pancreata arrived at the DRI for initiation of the isolation
      process within 6.5 hours of cross-clamping (median time 5.4 hours; range 4.8 to
      6.5 hours). The islets were immediately transported back to TMH for final
      sterility and viability tests and transplanted via percutaneous transhepatic
      portal vein infusion. The harvesting of 41 pancreata has yielded a number of
      pancreatic islets sufficient for transplantation (>5000 IEQ/kg recipient body
      weight) 26 times (63% of harvested pancreata). Thus far, three patients have
      received three PITs and eight patients have received two PITs. Six remain insulin
      independent. All have experienced a decrease in serum hemoglobin A(1c) levels,
      and both basal and stimulated C-peptide levels have increased. There have been no
      major complications related to the procedure or the immunosuppressive regimen
      used. CONCLUSIONS: Our series demonstrates that pancreatic islets isolated at a
      remote isolation center can successfully and safely be used for PIT and the
      achievement of insulin independence.

PMID- 15194394
TI  - Are organ preservation solutions useful for the storage of isolated human islets?
AB  - Clinical islet transplantation invariably requires more than one donor per
      recipient. Delay between transplants could be reduced if islets were stored and
      transported between centers. This study assessed viability and response to
      glucose of isolated human islets after storage in tissue culture medium (TCM) 199
      at 30 degrees C (control), TCM 199 at 22 degrees C (RT), University of Wisconsin
      solution @ 4 degrees C (UW), or Eurocollins Solution at 4 degrees C (EC) and
      compared 18 hours storage (group 1) or overnight culture followed by 4 hours
      storage (group 2). Insulin stimulation index (SI) (mean +/- SD, n = 5), after 1
      hour glucose static challenge was not significantly different (P >.05) from
      islets in group 1 stored in RT 1.76 +/- 1.08 or EC 1.14 +/- 0.29 versus control
      2.41 +/- 1.13 or group 2, RT 1.73 +/- 0.51, EC 2.07 +/- 0.63 versus control 2.12
      +/- 0.58. However, SI UW was significantly lower (P <.05) than the control in
      group 1 (1.19 +/- 0.30) and group 2 (1.36 +/- 0.34). Islet viability represented
      by the ATP/ADP ratio (mean +/- SD, n = 5) was not significantly different after
      storage in RT 0.201 +/- 0.159; EC 0.205 +/- 0.123; or UW 0.611 +/- 0.992 versus
      the control 0.223 +/- 0.158 in group 1, and RT 0.178 +/- 0.055; EC 0.137 +/-
      0.018; or UW 0.173 +/- 0.085, compared with the control 0.199 +/- 0.069 in group
      2. We conclude, organ preservation solutions EC and UW do not have an advantage
      over TCM 199 for the storage of isolated human islets.

PMID- 15194395
TI  - Simplified method for cryopreservation of islets using hydroxyethyl starch and
      dimethyl sulfoxide as cryoprotectants.
AB  - Cryopreservation is an ideal method for long-term storage of human islets.
      Dimethyl sulfoxide (DMSO) has been used as an intracellular cryoprotectant.
      However, because of its toxicity, DMSO has to be added stepwise and diluted
      stepwise with sucrose. We combined hydroxyethyl starch (HES) as an extracellular
      cryoprotectant with DMSO to simplify the freeze-thawing procedure. Islets were
      isolated from the pancreas of beagle dogs by an automated digestion method and
      Ficoll purification. After overnight culture, the islets were cryogeneically
      stored using cooling by a programmed freezing system. After 4-week storage in
      liquid nitrogen, the container was rapidly thawed in a 37 degrees C water bath.
      The function of the islets was assessed upon static incubation immediately after
      thawing, showing a recovery rate of 71.16% +/- 20.14% and a stimulation index of
      1.80 +/- 0.78. In conclusion use of HES allowed a decrease in DMSO concentration
      and simplified the freeze-thawing procedure for islets.

PMID- 15194396
TI  - Development of a novel digestion chamber for human and porcine islet isolation.
AB  - BACKGROUND: The current technique of human pancreas digestion for islet isolation
      relies on selective distribution of collagenase delivered via the pancreatic duct
      to produce digestion and removal of peri-acinar fibrous tissue. However, the
      collagenase has relatively little effect on the interlobular fibrous tissue,
      which must therefore be broken down by mechanical means within the digestion
      chamber so as to release the contained acini and islets. The current way of
      achieving this in the Ricordi chamber is to place five or six stainless steel
      balls within the chamber and shake vigorously. The shaking presumably breaks down
      the interlobular fibrous tissue by a combination of shear force induced by the
      movement of tissue through the shaking process, assisted by numerous blows from
      the steel balls. Intuitively, one would expect some islets would be destroyed
      rather than released by such a battering. METHODS: In an attempt to improve the
      efficiency of islet isolation we have designed a new digestion/filtration chamber
      that consists of a glass cylinder, sealed with Teflon plates holding in mesh
      filters at each end, secured in place by a central threaded tie-rod and external
      knurled nuts. A ring-shaped piston within the cylinder can be pushed up and down
      the travel by two rods passing out through sealed ports in the Teflon disk at one
      end and connected to an external handle. The handle is used to gently push the
      piston up and down the travel of the cylinder, which pushes the fluid and tissue
      through the central lumen of the ring-piston. A series of hooks attached to the
      central tie-rod catch the fibrous strands of the passing tissue; the shearing
      forces produced cause disruption by a process thought to be similar to teasing
      the tissue apart with fine forceps. RESULTS: A series of initial experiments with
      human pancreas showed the prototype to be too large, causing temperature control
      problems, and a redesigned smaller chamber was produced, maintaining the crucial
      design features. Experience processing five human pancreata has now demonstrated
      that in three of five pancreata the new chamber produced a good yield (>200,000
      I.E.) of remarkably well separated and intact islets, the entire dispersion
      process being under 1 hour. However, in two isolations the collagenase digestion
      was poor, with few free islets. A copy of the new chamber (reserved for porcine
      work only) has been produced, as well as a copy of the Ricordi chamber. We have
      confirmed that the new chamber can isolate porcine islets in large numbers (>5000
      islets/g pancreas [n = 2], but note that pig islets are small). CONCLUSION: These
      preliminary studies are sufficiently encouraging to justify further direct
      comparison with the Ricordi chamber for the purpose of animal and human islet
      isolation.

PMID- 15194397
TI  - Enhanced recovery of cryopreserved islets using SIS.
AB  - Although cryopreservation of pancreatic islets would add flexibility to
      transplantation, the recoveries are only 60% to 90% and function is decreased.
      Islets are multicellular structures approximately 50 to 250 microm in diameter
      organized into a network of cells and vascular channels. Due to this complexity,
      islets are more susceptible to damage during cryopreservation than an individual
      cell. This study investigated porcine small intestinal submucosa (SIS) as a
      matrix to support islets recovery and function post-thaw. Groups of frozen/thawed
      human islets (150 IE/condition; n = 4 preparations) were cultured for 5 weeks in
      plates containing noncoated Biopore membrane inserts alone or inserts covered
      with SIS. Islets were placed directly on the insert post-thaw (SIS(1)), or
      cultured overnight in standard plates, washed, and then transferred to the SIS
      (SIS(2)). Function was assessed by determining glucose-stimulated release of
      insulin, which was measured by radioimmunoassay. Analysis of basal insulin
      secretion showed time and treatment to be significantly different (P =.0043 and P
      =.0123, respectively) but without an interaction (P >.05). The two SIS treatments
      were not significantly different (P >.05); however, both SIS(1) and SIS(2) were
      significantly different from controls (P =.0108 and P =.0420, respectively).
      Similar results were obtained for stimulation indices; time and treatment were
      significantly different (P =.0161 and P =.0264, respectively) but not an
      interaction (P >.05). The two SIS treatments were not significantly different (P
      =.05); however, both SIS(1) and SIS(2) differed from controls (P =.0248 and P
      =.0407, respectively). The results indicate that SIS enables frozen-thawed islets
      to exhibit superior post-thaw function compared with a non-SIS-supported
      condition.

PMID- 15194398
TI  - Serva collagenase NB1: a new enzyme preparation for human islet isolation.
AB  - INTRODUCTION: Advances in the rate of success of human islet isolation are due in
      part to the availability of new purified enzyme blends. In this study we
      evaluated a new enzyme preparation composed of a highly purified collagenase that
      can be reproducibly blended with predetermined amounts of separately packaged
      neutral protease. METHODS: Nine human islet isolations were performed with
      collagenase NB1 supplemented with neutral protease (Serva Electrophoresis GMbH,
      group I). Yields, purity, morphology, in vitro function and islet cell apoptosis
      were assessed. The results were compared to those of nine human islet isolations
      performed with Liberase (Roche, group II) and matched for donor age, BMI, and
      circumstances of death. RESULTS: Islet yields were similar in both groups.
      However, islet equivalents (IE) per gram of pancreas and IE number to islet
      number were higher in group I (P <.05). Stimulation indices after insulin
      response to glucose (static incubation) were similar in both groups. Islet cell
      apoptosis rate was statistically significantly lower in group I. Islet morphology
      was significantly improved in group I with a higher proportion of intact islets.
      CONCLUSION: This new enzyme preparation (collagenase NB1 with neutral protease
      adjunct) was as effective as Liberase in terms of islet yields and function.
      Islet morphology was improved and rate of islet cell apoptosis was lower with
      this new collagenase. The absence of lot-to-lot variability in terms of neutral
      protease to collagenase ratio makes collagenase NB1 a promising enzyme for human
      islet isolation.

PMID- 15194399
TI  - Optimization of neutral protease to collagenase activity ratio for islet of
      Langerhans isolation.
AB  - AIM: The optimal neutral protease to collagenase activity ratio has not been
      determined for islet isolation. We evaluated a new highly purified collagenase
      that can be blended with predetermined amounts of neutral protease (NP). METHODS:
      Islets were isolated from 7 groups of Sprague-Dawley rats. In group I,
      collagenase type XI (Sigma) at 2 mg/mL, and, in group II, Liberase at 0.6 mg/mL
      (2.4 PZ- U/mL; Roche) were used as controls. In groups III to VII, collagenase
      NB1 0.6 mg/mL (2.4 PZ-U/mL; Serva Electrophoresis) was used with increasing
      amounts of added NP. The NP to collagenase activity ratio (DMC-U/PZ-U) increased
      from 0.5% in group III to 2.0% in group VII. RESULTS: Mean islet equivalent (IE)
      yields per rat were 1367, 1755, 597, 895, 1712, 1043, and 905 in groups I to VII.
      IE yields were maximal at DMC-U/PZ-U = 1.2%. Islet morphology was influenced by
      NP concentration with decreasing numbers of trapped islets and increasing numbers
      of fragmented islets as NP contents increased. Cytokine release, islet cell
      apoptosis, and in vitro function were significantly better in groups III to VII
      as compared with groups I and II. CONCLUSION: NP is a crucial additive to
      collagenase for islet isolation. Optimization of the NP to collagenase activity
      ratio (1.2% in this model) improves yields and morphology after islet isolation.

PMID- 15194400
TI  - Microbial surveillance during human pancreatic islet isolation.
AB  - OBJECTIVES: The study aim was to investigate the microbiological safety of islet
      isolation and transplantation. MATERIALS AND METHODS: Between 1996 and 2002,
      prospective microbiological screening was performed on all pancreata procured for
      islet transplantation. Pancreas transport media and postpurification preparations
      were screened for microbiological contamination. Prior to isolation, pancreata
      were washed with either Hanks solution (group I, n = 170) or decontaminated with
      antiseptic and antimicrobial drugs (group II, n = 45). RESULTS: Microbiological
      contamination of the pancreas preservation media was shown in 62%. Analysis of
      the contaminants showed 74% gram-positive, 21% gram-negative organisms, and 5%
      fungi. The donor condition or procurement center did not influence the
      contamination rate. Longer pancreas transport duration was significantly
      associated with bacterial contamination (P <.05). In group I, 16 (9.4%) of 170
      islet preparations presented microbial contamination at the end of the isolation
      procedures. Gram-positive organisms were present in 10 (6%), gram-negative
      organisms in 4 (2.4%), and fungi in 2 (1.2%) preparations. Four islet
      preparations (2.4%) from pancreata with noninfected transport medium were
      positive on postpurification cultures, all with gram-positive organisms. In group
      II, only 2 of 45 islet preparations (4.4%) presented microbial contamination at
      the end of the isolation process. CONCLUSIONS: The rate of microbial
      contamination during pancreas procurement and transport is high. Significant
      contaminants present when beginning islet isolation become undetectable by the
      conclusion of isolation. Diminishing the bio-burden by pancreas decontamination
      reduces the risk of contamination of the final islet preparation.

PMID- 15194401
TI  - Expression in murine teratocarcinoma F9 cells of transcription factors involved
      in pancreas development.
AB  - BACKGROUND: Although it has been established that formation and functional
      differentiation of the pancreas from embryonic endoderm is associated with
      activation/inactivation of many genes controlled by specific sets of
      transcription factors, the role and activation sequence of individual
      transcription factors has not yet been fully elucidated. This study sought to
      differentiate a murine teratocarcinoma cell line, F9, to endodermal-like cells
      and, subsequently; to investigate the effects of regulated expression of
      transcription factors in pancreas development. METHODS: Following differentiation
      using retinoic acid and db cAMP (RAC), resulting F9 cells (F9-RAC) were
      transfected with cDNAs for PDX-1, ngn3, beta 2/NeuroD (beta 2), and Nkx2.2,
      singly or in combination. Expression of these transcription factors was
      investigated using RT-PCR and immunofluorescence techniques. RT-PCR analysis was
      used to assess the subsequent effects of expression of these factors on
      endogenous genes related to pancreas development. RESULTS: Regulated
      differentiation of F9 cells generated endodermal-like cell types. Following
      transfection, PDX-1, ngn3, beta 2, and Nkx2.2 were expressed in F9-RAC cells,
      with their proteins localized mainly in cellular nuclei. Expression of these
      factors apparently did not affect the endogenous expression of preproinsulin, PDX
      1, beta 2, Isl1, Pax4, Pax6, Sonic hedgehog, and Indian hedgehog. CONCLUSION:
      This study describes the successful transient expression of transcription factors
      related to pancreas development, following directed differentiation of F9 cells
      to endoderm-like cells, and shows that treatment of F9 cells with a combination
      of RAC causes up-regulation of genes relevant to pancreatic development. The lack
      of further effect of regulated transcription factor expression on these genes may
      suggest that parietal endoderm- like cells derived from F9 cells is not the
      optimal lineage from which to develop beta cells. It may be useful to include F9
      derived visceral endoderm in future studies.

PMID- 15194402
TI  - Mechanisms associated with loss of glucose responsiveness in beta cells.
AB  - BACKGROUND: Cell replacement therapies have been proposed as possible
      alternatives to the current treatments for controlling blood glucose in insulin
      dependent diabetes. Beta cells, however, often lose their glucose-stimulated
      insulin secretion (GSIS) when maintained for prolonged periods in culture. For
      beta cell lines to be considered as a suitable source of transplantable tissue,
      it is essential that their GSIS is maintained. This study aimed to investigate
      cellular events involved in this loss of GSIS, to enable future optimization and
      enhancement of this response. METHODS: GSIS was investigated in low and high
      passage murine insulinoma MIN-6 cells (using in vitro static procedures) and
      assessing levels of secreted (pro)insulin by enzyme-linked immunosorbent assays.
      Expression of relevant islet gene transcripts, including insulin, glucagon,
      somatostatin, and pancreatic polypeptide, was investigated by RT-PCR analysis.
      RESULTS: At low-passage, MIN-6 cells produced an approximately four- to fivefold
      increase in (pro)insulin secretion in response to 26.7 mmol/L glucose compared to
      3.3 mmol/L glucose; at high passage, this response was lost. Expression of
      glucagon and somatostatin mRNAs were down-regulated with increased passage, while
      levels of insulin and pancreatic polypeptide mRNAs were apparently unchanged.
      CONCLUSION: The maintenance of insulin mRNA levels in high-passage MIN-6 cells
      with down-regulation of glucagon (stimulates insulin secretion) and somatostatin
      (inhibits insulin secretion) gene transcript levels suggests that these cells
      have not lost their ability to maintain insulin production, but that the loss of
      glucose responsiveness may be due to a general effect on regulated secretion.
      Further studies investigating the regulated secretory pathway in these cells may
      further explain the mechanistic changes occurring with passaging of beta cells.

PMID- 15194403
TI  - Epidermal growth factor and insulin inhibit cell death in pancreatic beta cells
      by activation of PI3-kinase/AKT signaling pathway under oxidative stress.
AB  - Production of reactive oxygen species (ROS) during islet purification by
      enzymatic digestion as well as during warm and cold ischemia causes islet cell
      damage. Recent reports have shown that activated Akt, the downstream protein
      after phosphatidylinositol (PI) 3-kinase, is involved in cell survival by
      phosphorylating several proteins that mediate apoptosis. We analyzed the role of
      PI3-kinase/Akt pathway activation using insulin or epidermal growth factor (EGF)
      on islet beta cell survival during oxidative stress. Canine islets and murine
      beta cell line (BTC) were cultured in the presence of hydrogen peroxide
      (H(2)O(2)) for 12 to 20 hours. Viability and cell death were measured by MTT
      assay. Maximum cell damage was observed with as little as 100 micromol/L of
      H(2)O(2). Pretreatment with 100 ng/mL of insulin significantly decreased cell
      damage. Meanwhile, the protective effect of insulin was partially blocked with an
      inhibitor of PI3-kinase, LY294002, suggesting the utilization of PI3-kinase/Akt
      signaling pathway for the observed cytoprotective effect. Similar to insulin, EGF
      also protected beta cells from oxidative stress. Our results suggest that PI3
      kinase/Akt activation by insulin or EGF is beneficial for islet beta cell
      protection.

PMID- 15194404
TI  - Presence of nonhematopoietic side population cells in the adult human and
      nonhuman primate pancreas.
AB  - Side population (SP) cells defined by their ability to efflux Hoechst dye 33342
      (Hst), demonstrate functional stem cell capabilities in adult murine tissues and
      may represent organ-specific stem cells. We examined adult human (Hu) and rhesus
      macaque (Rh) pancreatic tissue for the presence of SP cells. METHODS: Hu cadaver
      (n = 4) and Rh donor (n = 5) pancreata were dispersed with collagenase and
      separated by density gradient centrifugation to relatively enrich fractions for
      islet, ductal, and acinar tissue in human and islet and nonislet tissue in Rh.
      Single cell suspensions were incubated with varying Hst concentrations to
      determine optimal conditions for SP cell analysis. Cellular heterogeneity was
      assessed using a panel of monoclonal antibodies positive for hematopoietic and/or
      endothelial cells. RESULTS: Hu SP cells comprised approximately 0.12%, 0.08%, and
      0.45% of the gated populations for Hu islet, ductal, and acinar fractions
      respectively. In Rh, 5.5% and 3.7% of the islet and nonislet fractions were
      identified as SP cells. FACS analysis of Hu pancreas-derived SP cells indicated
      that greater than 95% were CD45(-), and only 6% were CD34(+)CD45(-). A similar
      phenotype was detected in Rh pancreas-derived SP cell populations: greater than
      70% were CD45(-) and less than 2% were endothelial lineage positive. CONCLUSIONS:
      SP cells are found in both islet- and nonislet-enriched fractions of the adult Hu
      and Rh pancreas. The majority of pancreatic SPs are CD45(-) and CD34(-),
      suggesting nonhematopoietic lineage. Further preclinical study is needed to
      establish the phenotype and functional role of adult tissue-specific versus
      tissue-resident stem cells.

PMID- 15194405
TI  - Distinct requirements for host CD80/CD86 costimulatory molecules in cardiac
      versus islet rejection.
AB  - The role of B7 family members CD80 and CD86 in providing costimulatory signals to
      T cells is well established. Interestingly, previous studies show that host
      CD80/CD86 expression is required for cardiac allograft rejection. However, the
      role for host costimulation by CD80/CD86 molecules for the rejection of
      neovascularized islet allografts and xenografts is unknown. The purpose of this
      study was to determine whether islet allografts and/or rat islet xenografts
      required host CD80/CD86 molecules for acute rejection. Streptozotocin-induced
      diabetic C57Bl/6 (B6, H-2(b)) or B6 CD80/CD86 double-deficient mice were grafted
      with allogeneic BALB/c (H-2(d)) islet allografts or with WF (RT1(u)) islet
      xenografts. Nondiabetic B6 mice were grafted with BALB/c heterotopic cardiac
      allografts. Consistent with previous reports, BALB/c islet allografts were
      acutely rejected in wild-type B6 mice could survive long-term (>100 days) in B6
      CD80/CD86-deficient animals. In stark contrast, both islet allografts and WF rat
      islet xenografts demonstrated acute rejection in both control B6 and in B6
      CD80/CD86 deficient hosts. In conclusion, varied studies imply that the inherent
      pathways for rejecting primarily vascularized versus cellular allografts or
      xenografts may be distinct. The present study illustrates this concept by showing
      a marked difference in the role of host-derived CD80/CD86 costimulatory molecules
      for cardiac allograft versus islet allograft/xenograft rejection in vivo.
      Although such costimulation is rate limiting for cardiac allograft rejection,
      these same molecules are not necessary for acute rejection of either islet
      allografts or xenografts.

PMID- 15194406
TI  - A major role for host MHC class I antigen presentation for promoting islet
      allograft survival.
AB  - The purpose of this study was to determine the role for CD8 T cells versus
      generalized MHC class I-restricted antigen presentation in islet allograft
      rejection and tolerance. Diabetic C57BI/6 (B6, H-2(b)) controls, C57BI/6 CD8
      deficient (CD8 KO), or MHC class I-deficient C57BI/6 (beta 2m KO) recipients were
      grafted with allogeneic BALB/c (H-2(d)) islets. Islet allografts were acutely
      rejected in untreated B6, CD8 KO, and in beta 2m KO mice, indicating that neither
      CD8 T cells nor host MHC class I is required for allograft rejection. We then
      determined the efficacy of costimulation blockade in these same strains.
      Costimulation blockade with anti-CD154 therapy facilitated long-term islet
      allograft survival in both B6 and in CD8 KO recipients. However, anti-CD154
      treated beta 2m KO recipients were completely refractory to anti-CD154 therapy;
      all treated animals acutely rejected islet allografts with or without therapy.
      Also, anti-NK1.1 treatment of wild-type B6 mice abrogated graft prolongation
      following anti-CD154 therapy. Taken together, results show a dramatic distinction
      between two forms of MHC class I-restricted pathways in allograft prolongation.
      Although anti-CD154-induced allograft survival was CD8 T-cell independent, an
      intact host MHC class I-restricted (beta 2m-dependent) pathway is nevertheless
      necessary for allograft survival. This pathway required NK1.1+ cells, implicating
      NK and/or NKT cells in promoting allograft prolongation in vivo.

PMID- 15194407
TI  - Improved in vitro function of islets using small intestinal submucosa.
AB  - Transplantation of human pancreatic islets has been demonstrated to be a viable
      alternative to exogenous insulin therapy for diabetes mellitus. However, optimum
      results require transplantation of islets from two to three pancreas donors after
      a minimum number of days in culture. This implies that a substantial part of the
      transplanted islet mass may be nonfunctional. This study investigates the ability
      of an optimized technique to retain islet function using porcine-derived small
      intestinal submucosa (SIS) during in vitro culture. Groups of purified human
      islets were cultured for 3 weeks in modified standard islet culture conditions of
      CMRL = 1066 tissue culture medium supplemented with 25 mmol/L HEPES,
      penicillin/streptomycin, and a commercial insulin-transferin-selenium (ITS)
      supplement. Islets (50 to 200 IE/condition; n = 5 preparations) were cultured in
      plates containing noncoated Biopore membrane inserts alone, or on inserts that
      had been covered with SIS. Function was assessed by static incubation with low (4
      mmol/L), or high (20 mmol/L) glucose at the end of each week. Glucose-stimulated
      release of human insulin was measured by radioimmunoassay (Linco, St. Charles,
      Missouri). Remaining islets were stained and evaluated visually. Neither culture
      condition resulted in significantly different basal secretion until week 3 (P
      =.05). However, by the end of week 2 and for the duration of the experiment
      thereafter, SIS-treated islets exhibited a higher SI (P <.05). At the end of the
      experiment, islets cultured on the SIS exhibited excellent morphology, with
      greater than 90% staining positive with Dithizone. Islets cultured on the inserts
      alone lost their initial morphology, becoming "loose" in appearance. The results
      of this study indicate that SIS enables enhanced function of islets in vitro as
      compared to non-SIS supported culture conditions.

PMID- 15194408
TI  - Beta-cell sparing in transplanted islets by vascular endothelial growth factor.
AB  - We have reported that vascular endothelial growth factor (VEGF) promotes the
      revascularization of transplanted islets, thereby reducing the initial number
      required to prevent diabetes. The present study was undertaken to assess other
      mechanisms of beta-cell sparing by VEGF. For in vitro studies, islets were
      cultured for 14 days with versus without 20 ng/mL VEGF. Viability, necrosis, and
      apoptosis were examined by specific staining (Alcein AM, propidium iodide, and
      annexin/phosphatidylserine). The effects of VEGF on islets were also examined in
      a proteomic study. In vivo streptozotocin-treated diabetic Lewis rats received
      1000 Lewis or Sprague-Dawley islets beneath the renal capsule. Oxygen levels at
      the transplant site were monitored by a Clark-type oxygen electrode. Fasting
      blood glucose served as an indicator of islet survival and function. VEGF
      enhanced oxygen levels at the transplant site. Syngeneic recipients were
      euglycemic for over 6 months, whereas control islets failed within 30 to 60 days.
      VEGF prevented allograft rejection for over 14 days, whereas controls were
      rejected within 6 to 7 days. Immunostaining suggested that VEGF inhibited the
      presentation of MHC II antigen and promoted islet survival by the inhibition of
      necrosis and apoptosis. Our proteomic study suggested VEGF preserved systems
      required for cellular preservation (heat shock proteins) and insulin secretion.
      VEGF promotes the preservation of isolated and transplanted islets by a variety
      of mechanisms, including enhanced oxygenation and inhibition of immune rejection,
      necrosis, and apoptosis. The provision of exogenous VEGF may be a useful adjunct
      to islet transplantation.

PMID- 15194409
TI  - Cobalt-Protoporphyrin treatment renders islets tolerant to interleukin-1 beta
      suppression.
AB  - This study examined whether treating donor mice with a single dose of cobalt
      protoporphyrin (CoPP) induced heme oxygenase-1 (HO-1) and protected islet cells
      from interleukin-1 beta (IL-1 beta) suppression. Islets were isolated from mice
      receiving a single dose of either CoPP (20 mg/kg of body weight, CoPP islets) or
      isotonic NaCl solution vehicle (control islets), 24 hours before isolation.
      Glucose-stimulated insulin secretion (GSIS) and insulin content (IC) of the
      islets were determined following incubation in the presence versus absence of
      murine IL-1 beta for 21 or 65 hours. The HO-1 protein level of CoPP-induced
      islets, as determined by an enzyme immunoassay, was significantly higher than
      that of control islets at 12 hours (P <.01) and 30 hours (P <.05), and returned
      to basal levels at 56 hours (P = NS). Following a 21-hour incubation with IL-1
      beta, CoPP islets secreted significantly more insulin upon glucose stimulation
      and preserved significantly more IC than control islets. After 65-hour incubation
      with IL-1 beta, CoPP islets secreted significantly less insulin upon glucose
      stimulation than control islets and preserved significantly less IC compared to
      islets incubated without IL-1 beta. In conclusion, treatment with cobalt
      protoporphyrin to induce heme oxygenase-1 protects islets against the suppressive
      effects of IL-1 beta.

PMID- 15194410
TI  - Transforming growth factor-beta signaling is enhanced following mitomycin-C
      treatment of islet xenograft.
AB  - Mitomycin-C (MMC) is categorized as an agent that causes genotoxic stress by
      triggering various intracellular signaling pathways. We have previously shown
      that MMC pretreatment of highly immunogenic crude islets leads to significant
      prolongation of graft survival in a rat-to-mouse model. In the present study, we
      examined whether TH1/TH2 cytokine, including the inflammatory cytokines
      interferon-gamma and interleukin (IL)-2, or the Th2 group, IL-4, IL-10, TNF
      alpha, IL-1 beta, IL-6, GM-CSF, and transforming growth factor (TGF)-beta were up
      regulated or down-regulated following MMC treatment of islets. We found changes
      in TGF-beta messenger RNA (mRNA) transcription as the only events among the
      measured cytokines. TGF-beta concentration was elevated in blebs formed under the
      kidney capsule, but not in the serum or ascites among animals given MMC-treated
      islets than in animals given untreated islets, suggesting local processes induced
      by MMC might inhibit xenograft rejection.

PMID- 15194411
TI  - Low-molecular weight dextran sulfate abrogates the instant blood-mediated
      inflammatory reaction induced by adult porcine islets both in vitro and in vivo.
AB  - BACKGROUND: One of the main obstacles to clinical application of islet
      xenotransplantation is the injurious inflammatory reaction elicited by porcine
      islets when they are exposed to fresh human blood in vitro and in vivo. This
      instant blood-mediated inflammatory reaction (IBMIR) causes rapid binding of
      platelets to the islet surface, activation of the coagulation and complement
      systems, and leukocyte infiltration of the islets. As a consequence of IBMIR,
      morphological destruction of porcine islets occurs within the first few hours
      after transplantation. MATERIALS AND METHODS: In the present study, by analyzing
      the plasma samples and performing immunohistochemical investigation, we assessed
      the effect of adding low-molecular weight dextran sulfate (LMW-DS) at 0.01-1
      mg/mL to an in vitro tubing loop assay in which porcine islets were exposed to
      fresh human blood. The effect of LMW-DS also was investigated in an in vivo model
      using diabetic athymic mice, which provides an innate inflammatory milieu without
      influence of T cells. The possible toxicity of LMW-DS was assessed by culturing
      pig islets in the presence or absence of LMW-DS for 3 days. RESULTS: In the in
      vitro study, in the presence of LMW-DS at 0.01 mg/mL, platelet consumption,
      coagulation, and complement activation were reduced, and, at 0.1 mg/mL, LMW-DS
      totally prevented IBMIR. Immunohistochemical investigation showed that leukocyte
      infiltration was totally abrogated at the highest dose. A similar finding was
      observed in the in vivo study. No adverse effect of LMW-DS was observed on the
      quality of the islets. CONCLUSIONS: LMW-DS appears to be an effective drug
      candidate that is able to control the strong innate immune response induced by
      pig islets in contact with human blood.

PMID- 15194412
TI  - A model utilizing adult murine stem cells for creation of personalized islets for
      transplantation.
AB  - Clinical islet cell transplantation has demonstrated great promise for diabetes
      treatment. Two major obstacles are the organ donor shortage and the
      immunoresponse. The purpose of this study was to create a model using the
      patient's own adult stem cell sources, possibly in combination with non-self
      cells, such as pancreatic, hepatic, or embryonic stem cells, to create
      "personalized" islets. We hypothesize that the reconstructed islets have the
      normal capability to produce insulin and glucagon with reduced immunoresponses
      after transplantation. Stem cells are a proliferating population of master cells
      that have the ability for self-renewal and multilineage differentiation. The
      recently developed photolithograph-based, biologic, microelectromechanic system
      (BioMEMS) technique supplies a useful tool for biomedical applications. Our lab
      has developed a novel method that integrates the adult stem cell and BioMEMS to
      reconstruct personalized islets. We selected islet-derived progenitor cells (IPC)
      for repairing and reconstructing STZ-diabetic islets. A6(+)/PYY(+) or
      A6(+)/ngn3(+) cells were selected to manipulate the neoislets. After 3 to 4 weeks
      in culture, the reconstructed cells formed islet-like clusters containing insulin
      or glucagon producing cells. The pilot results showed the ability of these
      reconstructed islets to correct hyperglycemia when transplanted into a STZ
      diabetic isograft mouse model. Although several technical problems remain with
      the mouse model, namely, the difficulty to collect enough islets from a single
      mouse because of animal size, the mouse isograft model is suitable for
      personalized islet development.

PMID- 15194413
TI  - A novel method for determination of ATP, ADP, and AMP contents of a single
      pancreatic islet before transplantation.
AB  - Assessment of islet viability before transplantation is mandatory for successful
      clinical transplantation. ATP content or energy charge (EC) of islets may
      represent a good parameter to assess viability. We have introduced a novel
      bioluminescent enzymatic cycling assay using synthetic firefly luciferase,
      pyruvate kinase) (PK), and pyruvate orthophosphate dikinase (PPDK) to determine
      adenine nucleotides (AN) in isolated islets. A complete assay requires several
      minutes. The ATP contents of 1, 3, 10, 30 or 100 islets each with a diameter of
      150 microm were 9.95 +/- 0.03, 28.3 +/- 1.18, 89.5 +/- 1.48, 282 +/- 10.2, and
      673 +/- 27.1 pmol, respectively, showing a relatively constant ATP content per 30
      islets (9.95, 9.42, 8.95, and 9.41 pmol/IEQ). ECs of each group were 0.74 +/-
      0.02, 0.74 +/- 0.02, 0.75 +/- 0.02, 0.74 +/- 0.02, and 0.65 +/- 0.01,
      respectively, a value that was quite constant up to 30 islets. The quantity of
      ATP and EC in a single islet can be measured quickly and reproducibly, offering a
      new method to determine viability of isolated islets prior to transplantation.

PMID- 15194414
TI  - Neovascularization of the amniotic membrane as a biological immune barrier.
AB  - The clinical application of islet transplantation is limited due to the limited
      source and the morbidity of systemic immunosuppression to prevent rejection. The
      two problems can be solved by using encapsulated islets. We have used amniotic
      membranes as biocompatible natural immune barriers. The objective of this study
      was to assess the revascularization of the membrane, which is necessary to ensure
      islet viability when the membrane is used for islet encapsulation. The amniotic
      membranes, obtained from full-term pregnant female dogs, were molded to form
      macrocapsules, which were implanted in the peritoneal cavity. The capsules were
      removed after 3, 10, 15, and 30 days and examined histopathologically using
      hematoxylin and eosin and by immunohistochemistry for neovascularization using
      factor VIII to detect angiogenesis. Upon histopathological examination, all
      specimens showed localized, moderate inflammation and congested blood vessels
      with no thrombosis or rejection. There was a mild degree of fibroblast
      proliferation starting from day 10 to day 30. Immunohistochemical staining
      revealed that the number of blood vessels was 7, 11, 13, 10 per high-power
      microscopic field on days 3, 10, 15, and 30, respectively. We concluded from this
      study that implanted amniotic sac capsules were vascularized within the omental
      tissue from day 10 on with significant blood vessel formation starting on day 3
      by immunohistochemical study.

PMID- 15194415
TI  - Short-term immunosuppression reduces fibrotic cellular infiltration around barium
      M-alginate microbeads injected intraportally.
AB  - INTRODUCTION: One of the major barriers affecting the viability of encapsulated
      islets is pericapsular fibrotic infiltration (PFI). This study aimed to design
      strategies to reduce PFI around intraportally injected alginate microbeads.
      METHODS: Empty, highly purified, barium-M-alginate microbeads (400 microm) were
      injected intraportally into Lewis rats (3000 beads/rat). Rats (n = 9/group) were
      treated daily with either rapamycine (RAPA; 1 mg/kg/d p.o.), tacrolimus (TAC; 2
      mg/kg/d p.o.), a combination of both, or gadolinium-chloride (GdC13, 20 mg/kg/d
      i.v., at day -1 and day +4). Treatment was discontinued at 10 days. Three
      rats/group were sacrificed at 3, 7, and 42 days after transplantation. Cellular
      composition of PFI was evaluated by immunohistochemistry. Severity of the
      reaction to the beads was determined by measuring the thickness of PFI on
      histology. RESULTS: The main cellular components of PFI in the liver were
      macrophages and myofibroblasts. There was a significant (P <.05) reduction in the
      thickness of PFI in all treated groups, even 6 weeks after transplantation.
      Encapsulated rat islets showed excellent insulin response to glucose in vitro,
      with a stimulation index of 3.6 +/- 2.0. CONCLUSION: Combination of highly
      purified alginate with short-term immunosuppression reduces fibrotic overgrowth
      around microbeads injected intraportally.

PMID- 15194416
TI  - Retransplantation of discordant xenogeneic islets with costimulatory blockade.
AB  - BACKGROUND: The aim of the study was to analyze the possibility of xenogeneic
      islet retransplantation using costimulatory blockade. METHODS: Streptozotocin
      induced diabetic mice were transplanted under the kidney capsule with human
      islets. Mice were nephrectomized and retransplanted with 1000 human islets under
      the contralateral kidney capsule 14 days later. Four groups were performed group
      I, first and second Tx without MR1; group II, first Tx without MR1, second Tx
      with MR1; group III, first Tx with MR1, second Tx without MR1; group IV, first
      and second Tx with MR1. A control group was transplanted only once without MR1
      with human islets. After second Tx, cross-matches between recipient, serum and
      human lymphocyte were done for detection of antidonor antibodies. RESULTS: In the
      control group, mean graft survival was 13 (+/-7) days. In group I, mean graft
      survival was 5 +/- 3 days. In group II, mean graft survival was 16 +/- 13 days.
      In group III, mean graft survival was 81 +/- 22 days. In group IV, no rejection
      were recorded and all graft survived more than 120 days. Pretransplant cross
      matches were negative. In groups I and II all cross-matches were positive, while
      none were positive in group IV. CONCLUSION: Retransplantation of xenogeneic
      islets was associated with accelerated rejection. After presensitization, MR1 was
      unable to induce tolerance to a second Tx. MR1 given at the first Tx only allowed
      prolonged survival of the second Tx, but rejection still occurred. MR1 given at
      first and second Tx allowed long-term survival of retransplanted xenoislets and
      prevented occurrence of antidonor antibodies.

PMID- 15194417
TI  - Characteristics and transplantation of the porcine neonatal pancreatic cell
      clusters isolated from 1- to 3-day-old versus 1-month-old pigs.
AB  - Porcine neonatal pancreatic cell clusters (NPCCs) isolated from 1- to 3-day-old
      pigs (I-A) cured diabetic nude mice within 8 weeks after transplantation. To
      shorten the latent period between transplantation and reversal of hyperglycemia,
      we studied NPCCs isolated from 1-month-old pigs (I-B). One- to 3-day-old or 1
      month-old pig pancreata were cut into fragments, digested by collagenase, and
      then studied for islet characteristics. In addition, 300 cultured NPCCs were
      transplanted under kidney capsule of nondiabetic nude mice. At 1 and 3 months
      after transplantation, the grafts were removed to measure the insulin content and
      beta-cell mass. Immediately after isolation, I-B was larger than I-A (0.211 +/-
      0.006 vs 0.189 +/- 0.003 mm(2), P =.0003) and after a 6-day culture period, I-B
      contained more insulin than I-A (6.8 +/- 1.4 vs 2.3 +/- 0.2 microg/150 NPCCs, P
      =.02). However, the stimulation indices of I-A and I-B during static incubation
      with 500 mg/dL glucose (26.5 +/- 3.2 vs 23.9 +/- 1.7) or 500 mg/dL glucose plus
      50 mol/L IBMX (41.9 +/- 4.4 vs 62.2 +/- 14.0) were not significantly different.
      Furthermore, neither I-A nor I-B showed first or second phase insulin secretion
      during sequential perifusion with 100 or 300 mg/dL glucose. In nondiabetic
      recipients, the insulin content of the graft at 1 month after transplantation was
      0.3 +/- 0.0 and 0.3 +/- 0.1 microg, and the beta-cell mass of the graft at 3
      months was 0.069 +/- 0.022 and 0.067 +/- 0.023 mg in mice receiving I-A or I-B,
      respectively (P >.05). Our data indicate NPCCs isolated from 1- to 3-day-old and
      1-month-old pigs have different characteristics but similar transplantation
      effects.

PMID- 15194418
TI  - A membrane-mimetic barrier for islet encapsulation.
AB  - BACKGROUND: Enhanced control of both transport properties and surface
      physiochemical characteristics will be important steps in the development of an
      effective immunoisolation barrier critical to the success of pancreatic islet
      cell transplantation. We hypothesize that the cell membrane establishes an
      important paradigm for the design of a biomimetic immunoisolation barrier with
      improved performance characteristics because of its capacity to control
      interfacial mass transport, as well as its ability to act as a template for more
      complex structures with other immunoregulatory macromolecules. METHODS: Islets
      were isolated from Wistar rats using collagenase digestion and a discontinuous
      Ficoll-Histopaque gradient and subsequently encapsulated in 2% alginate. After
      coating with a polyelectrolyte multilayer of polylysine and alginate, a polymeric
      membrane-mimetic coating was applied to the capsule surface. Individual islet
      viability was evaluated at each stage of the encapsulation procedure by use of a
      two-color live/dead cell assay. Preservation of islet function was determined by
      transplanting 1000 encapsulated islets into the peritoneal cavity of
      streptozotocin-induced diabetic nonobese diabetic NOD/Scid mice. RESULTS: At the
      end of the coating procedure, the proportion of viable cells within each islet
      was >50% in 88% of encapsulated rat islets and >75% in over half of the
      encapsulated cohort. Nonfasting blood glucose levels normalized within 24 hours
      after transplantation (n = 8). Normoglycemia has been maintained in all mice with
      the longest time course being 73 days thus far. CONCLUSIONS: We have demonstrated
      that microencapsulated islets coated with a membrane-mimetic thin film can be
      generated with high viability in vitro and persistent function in vivo.

PMID- 15194419
TI  - Apoptosis is caused by prolonged organ preservation and blocked by apoptosis
      inhibitor in experimental rat pancreatic grafts.
AB  - Apoptosis is a major mode of cell death after ischemia/reperfusion injury in
      several organs. The aims of this study were to evaluate apoptosis induction after
      different conditions of pancreas preservation and to investigate the impact of a
      caspase inhibitor on apoptosis induction in pancreatic grafts. METHODS: Inbred
      male Lewis rats served as donors and recipients. Apoptosis was detected using an
      in situ cell death detection kit and an apoptotic DNA ladder kit (Roche,
      Germany). An apoptotic index (AI) was defined as the number of apoptotic cells
      per field (400x) under a light microscope. The five groups included: group 1 (n =
      5), normal pancreata; group 2 (n = 7), pancreata stored in University of
      Wisconsin (UW) solution (4 degrees C) for 6 hours (hr); group 3 (n = 7),
      pancreata preserved in UW solution (4 degrees C) for 18 hr; group 4 (n = 7),
      pancreata preserved in 0.9% saline (4 degrees C) for 6 hours; and group 5 (n =
      5), pancreata preserved in 0.9% saline (4 degrees C) for 6 hours with Z-Asp-2,6
      dichlorobenzoyloxymethylketone (caspase inhibitor) treatment. The pancreatic
      grafts in all experimental groups underwent a 2-hr period of reperfusion after
      transplantation. RESULTS: The results in this study showed that the AI was not
      significantly increased among pancreatic grafts in group 2 compared to group 1 (P
      >.05). However, AI in group 3 was significantly higher than that in group 2 (P
      <.05). The highest AI was observed in group 4. Interestingly, AI in group 5 was
      significantly lower than that in group 4 (P <.01), and not significantly
      different from group 1 (P >.05). Apoptotic DNA ladders were detected in the
      pancreatic grafts in group 2, 3, and 4, but not in group 1 and 5. CONCLUSIONS:
      Prolonged preservation of pancreata in cold UW solution induces a dramatic
      increase in apoptotic cell death among the pancreatic grafts following Tx. This
      observation may well be an important mechanism of graft damage. A caspase
      inhibitor might be useful to inhibit apoptosis induction in pancreatic grafts.

PMID- 15194420
TI  - The role of the Nir/rdgB protein family in membrane trafficking and cytoskeleton
      remodeling.
AB  - The Nir/rdgB family of proteins has been identified in a variety of eukaryotic
      organisms, ranging from worms to mammals. The Drosophila retinal degeneration B
      (rdgB), a protein that is required for photoreceptor cell viability and light
      response, was the first to be identified. It consists an amino-terminal
      phosphatidylinositol (PI)-transfer domain and was proposed to play an essential
      role in photoreceptor membrane renewal and biogenesis. The other Nir/rdgB family
      members are functionally and structurally related to the Drosophila homolog and
      are implicated in regulation of lipid trafficking, metabolism, and signaling.
      Recent advances have revealed that Nir/rdgB proteins are also involved in
      regulation of cytoskeletal elements. Thus, these family members exert a broad
      spectrum of cellular functions and are involved in multiple cellular processes.
      The physiological functions of these closely related proteins are described in
      this review.

PMID- 15194421
TI  - Keratin 8/18 breakdown and reorganization during apoptosis.
AB  - Monoclonal antibodies that specifically recognize caspase cleaved K18 fragments
      or specific (phospho)epitopes on intact K8 and K18 were used for a detailed
      investigation of the temporal and causal relationship of proteolysis and
      phosphorylation in the collapse of the keratin cytoskeleton during apoptosis.
      Caspases involved in the specific proteolysis of keratins were analyzed
      biochemically using recombinant caspases and specific caspase inhibitors.
      Finally, the fate of the keratin aggregates was analyzed using the M30
      ApoptoSense trade mark Elisa kit to measure shedding of caspase cleaved fragments
      into the supernatant of apoptotic cell cultures. From our studies, we conclude
      that C-terminal K18 cleavage at the (393)DALD/S site is an early event during
      apoptosis for which caspase 9 is responsible, both directly and indirectly by
      activating downstream caspases 3 and 7. Cleavage of the L1-2 linker region of the
      central alpha-helical rod domain is responsible for the final collapse of the
      keratin scaffold into large aggregates. Phosphorylation facilitates formation of
      these aggregates, but is not crucial. K8 and K18 remain associated in
      heteropolymeric aggregates during apoptosis. At later stages of the apoptotic
      process, that is, when the integrity of the cytoplasmic membrane becomes
      compromised, keratin aggregates are shed from the cells.

PMID- 15194422
TI  - IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of
      mice lacking FGF6.
AB  - Important functions in myogenesis have been proposed for FGF6, a member of the
      fibroblast growth factor family accumulating almost exclusively in the myogenic
      lineage. However, the use of FGF6(-/-) mutant mice gave contradictory results and
      the role of FGF6 during myogenesis remains largely unclear. Using FGF6(-/-) mice,
      we first analysed the morphology of the regenerated soleus following cardiotoxin
      injection and showed hypertrophied myofibres in soleus of the mutant mice as
      compared to wild-type mice. Secondly, to examine the function of the IGF family
      in the hypertrophy process, we used semiquantitative and real-time RT-PCR assays
      and Western blots to monitor the expression of the insulin-like growth factors
      (IGF-I and IGF-II), their receptors [type I IGF receptor (IGF1R) and IGF-II
      receptor (IGF2R)], and of a binding protein IGFBP-5 in regenerating soleus
      muscles of FGF6(-/-) knockout mice vs. wild-type mice. In the mutant, both IGF-II
      and IGF2R, but not IGF-I and IGF1R, were strongly up-regulated, whereas IGFBP5
      was down-regulated, strongly suggesting that, in the absence of FGF6, the
      mechanisms leading to myofibre hypertrophy were mediated specifically by an IGF
      II/IGF2R signalling pathway distinct from the classic mechanism involving IGF-I
      and IGF1R previously described for skeletal muscle hypertrophy. The potential
      regulating role of IGFBP5 on IGF-II expression is also discussed. This report
      shows for the first time a specific role for FGF6 in the regulation of myofibre
      size during a process of in vivo myogenesis.

PMID- 15194423
TI  - Overexpression of myocilin in cultured human trabecular meshwork cells.
AB  - The trabecular meshwork, a specialized eye tissue, is a major site for regulation
      of the aqueous humor outflow. Malfunctioning of the trabecular meshwork is
      believed to be responsible for development of glaucoma, a blinding disease.
      Myocilin is a gene linked to the most common form of glaucoma. Its expression is
      known to be upregulated by glucocorticoids in trabecular meshwork cells and the
      altered myocilin level may be the culprit for glaucomatous conditions such as
      corticosteroid-induced glaucoma. In this study, we examined the influence of
      myocilin overexpression on the adhesion, spreading, migration, phagocytosis, and
      apoptosis of human trabecular meshwork cells in culture. When the myocilin
      expression was increased by 3- to 4-fold, the transfectants showed a dramatic
      loss of actin stress fibers and focal adhesions. Cell adhesion to fibronectin and
      spreading were also compromised. Myocilin thus appeared to have a de-adhesive
      activity, similar to that reported extensively with matricellular proteins. The
      transfected cells in addition displayed an increased sensitivity to apoptosis.
      These results demonstrate that overexpression of myocilin renders trabecular
      meshwork cells in a de-adhesive and vulnerable state. This vulnerability may be
      the basis for pathologic consequences in subtypes of glaucoma.

PMID- 15194424
TI  - Deficiency of tenascin-X causes a decrease in the level of expression of type VI
      collagen.
AB  - Tenascin-X (TNX) is an extracellular matrix glycoprotein. We previously
      demonstrated that TNX-null fibroblasts exhibit decreased cell-matrix and cell
      cell adhesion. In this study, we used a differential display technique to
      determine the genes involved in this process. Differential display analysis of
      wild-type and TNX-null fibroblasts revealed that mRNA expression level of type VI
      collagen alpha3 is predominantly decreased in TNX-null fibroblasts. Expression
      levels of mRNAs of other subunits of type VI collagen, alpha2 and alpha3 chains,
      were also remarkably decreased in TNX-null fibroblasts. The protein level of
      alpha3 chain of type VI collagen was also reduced in TNX-null fibroblasts.
      However, the organization of type VI collagen in the extracellular matrix of TNX
      null fibroblasts was similar to that of wild-type fibroblasts. Transient
      expression of TNX in Balb3T3 cells caused an increase in the level of mRNA of
      type VI collagen compared with that in vector control and increased the promoter
      activity of type VI collagen alpha1 subunit gene. In addition, the expression
      levels of type I collagen and other collagen fibril-associated molecules such as
      type XII and type XIV collagens, decorin, lumican and fibromodulin in wild-type
      and TNX-null fibroblasts were compared. It was found that the mRNA expression
      levels of type I collagen and collagen fibril-associated molecules other than
      decorin were decreased and that the expression level of decorin was increased in
      TNX-null fibroblasts. The results suggest the possibility that TNX mediates not
      only cell-cell and cell-matrix interactions but also fibrillogenesis via collagen
      fibril-associated molecules.

PMID- 15194425
TI  - Transcriptional regulation of 15-lipoxygenase expression by promoter methylation.
AB  - 15-Lipoxygenase type 1 (15-LO), a lipid-peroxidating enzyme implicated in
      physiological membrane remodeling and the pathogenesis of atherosclerosis,
      inflammation, and carcinogenesis, is highly regulated and expressed in a tissue-
      and cell-type-specific fashion. It is known that interleukins (IL) 4 and 13 play
      important roles in transactivating the 15-LO gene. However, the fact that they
      only exert such effects on a few types of cells suggests additional mechanism(s)
      for the profile control of 15-LO expression. In the present study, we demonstrate
      that hyper- and hypomethylation of CpG islands in the 15-LO promoter region is
      intimately associated with the transcriptional repression and activation of the
      15-LO gene, respectively. The 15-LO promoter was exclusively methylated in all
      examined cells incapable of expressing 15-LO (certain solid tumor and human
      lymphoma cell lines and human T lymphocytes) while unmethylated in 15-LO
      competent cells (the human airway epithelial cell line A549 and human monocytes)
      where 15-LO expression is IL4-inducible. Inhibition of DNA methylation in L428
      lymphoma cells restores IL4 inducibility to 15-LO expression. Consistent with
      this, the unmethylated 15-LO promoter reporter construct exhibited threefold
      higher activity in A549 cells compared to its methylated counterpart. Taken
      together, demethylation of the 15-LO promoter is a prerequisite for the gene
      transactivation, which contributes to tissue- and cell-type-specific regulation
      of 15-LO expression.

PMID- 15194427
TI  - A novel role for non-muscle gamma-actin in skeletal muscle sarcomere assembly.
AB  - Existing models describing sarcomere assembly have arisen primarily from studies
      using cardiac muscle. In contrast to cardiac muscle, skeletal muscle
      differentiation is characterised by dramatic changes in protein expression, from
      non-muscle to muscle-specific isoforms before organisation of the sarcomeres.
      Consequently, little is understood of the potential influence of non-muscle
      cytoskeletal proteins on skeletal sarcomere assembly. To address this issue,
      transfectant (gamma33-B1) and control mouse C2 myoblasts were differentiated to
      form myotubes, and various stages of skeletal sarcomere assembly were studied.
      Organisation of non-muscle gamma-actin and co-localisation with sarcomeric alpha
      actinin, an early marker of sarcomere assembly and a major component of Z lines,
      was noted. gamma-Actin was also identified in young myotubes with developing
      sarcomeric myofibrils in regenerating adult mouse muscle. Localisation of gamma
      actin in a different area of the myotube to the muscle-specific sarcomeric alpha
      actin also indicated a distinct role for gamma-actin. The effects of aberrant
      gamma-actin expression in other myoblast lines, further suggested a sequestering
      role for gamma-actin. These observations make the novel suggestion that non
      muscle gamma-actin plays a role in skeletal sarcomere assembly both in vitro and
      in vivo. Consequently, a modified model is proposed which describes the role of
      gamma-actin in skeletal sarcomere assembly.

PMID- 15194428
TI  - Adenylate kinase I does not affect cellular growth characteristics under normal
      and metabolic stress conditions.
AB  - Adenylate kinase (AK)-catalyzed phosphotransfer is essential in the maintenance
      of cellular energetic economy in cells of fully differentiated tissues with
      highly variable energy demand, such as muscle and brain. To investigate if AK
      isoenzymes have a comparable function in the energy-demand management of
      proliferating cells, AK1 and AK1beta were expressed in mouse neuroblastoma N2a
      cells and in human colon carcinoma SW480 cells. Glucose deprivation, galactose
      feeding, and metabolic inhibitor tests revealed a differential energy dependency
      for these two cell lines. N2a cells showed a faster proliferation rate and
      strongest coupling to mitochondrial activity, SW480 proliferation was more
      dependent on glycolysis. Despite these differences, ectopic expression of AK1 or
      AK1beta did not affect their growth characteristics under normal conditions.
      Also, no differential effects were seen under metabolic stress upon treatment
      with mitochondrial and glycolytic inhibitors in in vitro culture or in solid
      tumors grown in vivo. Although many intimate connections have been revealed
      between cell death and metabolism, our results suggest that AK1- or AK1beta
      mediated high-energy phosphoryl transfer is not a modulating factor in the
      survival of tumor cells during episodes of metabolic crisis.

PMID- 15194426
TI  - Retinoic acid regulates cell cycle progression and cell differentiation in human
      monocytic THP-1 cells.
AB  - All-trans-retinoic acid (RA), a natural metabolite of retinol, carries out most
      of the biological activities of vitamin A and is required for normal growth, cell
      differentiation, and immune functions. In the present studies, THP-1 human
      monocytes were used to investigate the mechanisms by which RA may regulate
      progression through the G1/S phase of the cell cycle. Physiological
      concentrations of all-trans-RA reduced the levels of cyclin E mRNA by 6 h and
      reduced cyclin E protein in a dose- and time-dependent manner. Similar reductions
      were observed for the retinoic acid receptor RARalpha and RXRalpha proteins.
      Concomitantly, RA increased the level of the cyclin-dependent kinase inhibitor
      p27 (Kip-1). The levels of retinoblastoma mRNA and protein (pRb) were also
      increased, while the proportion of hyperphosphorylated (phosphoserine 807/811)
      pRb was markedly reduced. Overall, RA increased the functionality of pRb as an
      inhibitor of cell cycle progression. Furthermore, RA reduced the binding activity
      of the transcription factor E2F to its core DNA element. Retinoic acid-induced
      changes in cell cycle-related proteins occurred in 4-6 h, including reduced
      cyclin E expression in bromodeoxyuridine (BrdU)-labeled cells, before the onset
      of cell differentiation as indicated by an increase in the percentage of G1 phase
      cells and a reduction in S phase cells at 24 h. The expression of CD11b, a cell
      surface marker of macrophage-like differentiation was increased by RA, as was
      phagocytic activity. The multiple effects of RA on cell cycle progression may
      help to explain its well-documented ability to induce the differentiation of THP
      1 cells, and thereby to enhance macrophage-like immune functions.

PMID- 15194429
TI  - Proteomics shows Hsp70 does not bind peptide sequences indiscriminately in vivo.
AB  - Heat shock protein 70 (Hsp70) binds peptide and has several functions that
      include protein folding, protein trafficking, and involvement with immune
      function. However, endogenous Hsp70-binding peptides had not previously been
      identified. Therefore, we eluted and identified several hundred endogenously
      bound peptides from Hsp70 using liquid chromatography ion trap mass
      spectrophotometry (LC-ITMS). Our work shows that the peptides are capable of
      binding Hsp70 as previously described. They are generally 8-26 amino acids in
      length and correspond to specific regions of many proteins. Through
      computationally assisted analysis of peptides eluted from Hsp70 we determined
      variable amino acid sequences, including a 5 amino acid core sequence that Hsp70
      favorably binds. We also developed a computer algorithm that predicts Hsp70
      binding within proteins. This work helps to define what peptides are bound by
      Hsp70 in vivo and suggests that Hsp70 facilitates peptide selection by aiding a
      funneling mechanism that is flexible but allows only a limited number of peptides
      to be processed.

PMID- 15194430
TI  - c-Myb associates with PML in nuclear bodies in hematopoietic cells.
AB  - The c-Myb transcription factor plays a central role in the regulation of cell
      growth and differentiation of hematopoietic cells. Being the product of a proto
      oncogene, one would expect c-Myb function to be modulated by signal transduction
      pathways, but our knowledge on such regulation of c-Myb is rather limited.
      Recently, we and others showed that c-Myb is subjected to sumoylation and that
      this posttranslational modification has considerable effect on c-Myb's activity.
      Interestingly, many proteins subjected to SUMO-1 conjugation associate with the
      promyelocytic leukemia (PML) protein and localize to PML nuclear bodies (PML
      NBs). Although the precise molecular function of PML NBs still remains to be
      defined, they seem to play a role in regulation of gene expression and are linked
      to specific cellular signaling. We show here that c-Myb localizes to PML NBs and
      that c-Myb interacts with PML as judged by immunofluorescence microcopy and co
      immunoprecipitation experiments. Enforced expression of PML IV was shown to
      enhance c-Myb-dependent reporter activation. Our results imply a role for PML and
      possibly other components of PML NBs in regulating c-Myb's activity. This novel
      link between c-Myb and PML, two gene products being implicated in leukemic
      disorders, suggests that previously unknown mechanisms for regulating c-Myb's
      activity involving PML may exist.

PMID- 15194431
TI  - Overexpression of human acyl-CoA thioesterase upregulates peroxisome biogenesis.
AB  - The biological functions of human acyl-CoA thioesterase III (ACTEIII/PTE-1),
      initially identified as an HIV-1 Nef binding protein, have remained unclear. We
      report herein that the stable overexpression of ACTEIII/PTE-1 in human and murine
      T-cell lines resulted in an increase in both peroxisome number and lipid droplet
      formation in a manner dependent on the amount of the protein. Peroxisome
      proliferation was evidenced by immunofluorescence staining for catalase, a
      peroxisome marker protein, as well as by direct peroxisome enumeration on
      electron micrographs. Consistently, the amount of catalase was elevated as the
      amount of ACTEIII/PTE-1 was increased. ACTEIII/PTE-1 mutants with reduced
      enzymatic activity or with the defect in peroxisome localization did not induce
      peroxisome proliferation, indicating that peroxisome proliferation was mediated
      by metabolites generated by ACTEIII/PTE-1 within peroxisomes. Finally, thymocytes
      isolated from a T-cell-specific ACTEIII/PTE-1 transgenic mouse as well as human
      and murine cell lines of lymphoid and non-lymphoid origins exhibited a similar
      proliferation of peroxisomes. Thus, ACTEIII/PTE-1 may be involved in the
      metabolic regulation of peroxisome proliferation.

PMID- 15194432
TI  - Reversal of melanocytic malignancy by keratinocytes is an E-cadherin-mediated
      process overriding beta-catenin signaling.
AB  - Loss of E-cadherin in melanoma cells frees them from keratinocytes-mediated
      proliferation and phenotypic control, which can be restored by forced E-cadherin
      expression. In this study, E-cadherin and its derivatives were introduced into
      metastatic melanoma line 1205Lu. E-cadherin and E-cadherin-alpha-catenin fusion
      protein were functional in mediating cell adhesion, downregulating MCAM(4) in
      coculture, and inhibiting proliferation regardless of beta-catenin expression
      levels and activation status. In contrast, cytoplasmic domain-deleted (E
      cadDeltaCYT) derivative was not able to reverse malignancy. The results indicate
      that E-cadherin-mediated cell adhesion is required for keratinocyte-mediated
      control of melanocytic cells, which can override proliferative activity of beta
      catenin.

PMID- 15194433
TI  - FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells.
AB  - Several forms of human dwarfism are due to activating mutations in FGFR3
      highlighting the role of FGF signaling in the growth attenuation of cartilage.
      Here, we studied the effects of FGF2 on RCS chondrocytes. Treatment with FGF2
      induced growth arrest in the G1 phase of the cell cycle and partial de
      differentiation of cells manifested by changes in cell morphology, loss of the
      cartilage-like extracellular matrix, and down-regulation of aggrecan expression.
      FGF2 activated phospholipase Cgamma, protein kinase B, and Erk and p38 MAP
      kinases. Chemical inhibition of FGFR3 and MEK1/2 antagonized FGF2-mediated growth
      arrest. Expression of a dominant-negative Ras mutant resulted in a partial
      reversal of growth inhibition while expression of constitutively activated Ras
      led to Erk-dependent growth arrest, further demonstrating the role of the Ras/Erk
      pathway in this phenotype. At the molecular level, FGF2-induced growth arrest was
      initiated by disintegration of cyclin D3-cdk6 complex followed by increased
      association of p21(WAF1) and p27(Kip1) with the cyclin-cdk2 and cyclin-cdk4
      complexes leading to inhibition of their kinase activities and ultimately to
      underphosphorylation of the p107 and p130 pocket proteins. Both p21(WAF1) and
      p27(Kip1) accumulated upon FGF2 treatment, but this accumulation occurred at the
      protein level at least partially due to interaction with transcriptionally
      induced cyclin D1.

PMID- 15194434
TI  - Cytokine-induced upregulation of NF-kappaB, IL-8, and ICAM-1 is dependent on
      colonic cell polarity: implication for PKCdelta.
AB  - As described for a long time, carcinoma-derived Caco-2 cells form a polarized
      epithelium in culture, whereas HT29-D4 cells are nonpolarized and
      undifferentiated but can form a polarized monolayer when cultured in a galactose
      supplemented medium. Using NF-kappaB translocation and IL-8 and ICAM-1 gene
      activation as an index, we have studied the relationship between the
      differentiation state and the cell response to cytokines. We found that
      differentiated Caco-2 and HT29-D4 cells were responsive to both cytokines
      TNFalpha- and IL-1beta-mediated activation of NF-kappaB but that undifferentiated
      HT29-D4 cells were unresponsive to IL-1beta. However, the expression of
      endogenous ICAM-1 and IL-8 genes was upregulated by these cytokines in either
      cell lines differentiated or not. Upregulation of ICAM-1 gene occurred when IL
      1beta or TNFalpha was added to the basal, but not apical surface of the
      differentiated epithelia. Finally, it appeared that in polarized HT29-D4 cells,
      the IL-1beta-induced translocation of NF-kappaB was connected to PKCdelta
      translocation.

PMID- 15194435
TI  - Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons.
AB  - The aim of this study was to evaluate whether the direct activation of the Wnt
      signaling pathway by its endogenous Wnt-3a ligand prevents the toxic effects
      induced by amyloid-beta-peptide (Abeta) in rat hippocampal neurons. We report
      herein that the Wnt-3a ligand was indeed able to overcome toxic effects induced
      by Abeta in hippocampal neurons, including a neuronal impairment on cell
      survival, an increase in glycogen synthase kinase-3beta (GSK-3beta) and tau
      phosphorylation, a decrease in cytoplasmic beta-catenin and a decrease in the
      expression of the Wnt target gene engrailed-1. We further demonstrate that Wnt-3a
      protects hippocampal neurons from apoptosis induced by Abeta. Our results support
      the hypothesis that a loss of function of Wnt signaling may play a role in the
      progression of neurodegenerative diseases such as Alzheimer's disease.

PMID- 15194436
TI  - Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are
      involved in both excitotoxin-induced neurodegeneration and regeneration.
AB  - Intrahippocamal injections of kainic acid (KA) significantly increase the
      expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage
      inflammatory protein-2 (MIP-2) in the ipsilateral hippocampus at 2-4 h and 21-45
      days post-administration, suggesting the possible involvement of these chemokines
      in both neurodegenerative and regenerative processes. To examine the possible
      role of these chemokines on neuronal cell death, hippocampal neurons were
      incubated with either MCP-1 or MIP-2 in vitro and examined to assess the effects
      on neuronal cell viability. These treatments resulted in significant neuronal
      apoptosis that could be abrogated by prior treatment with the caspase-1
      inhibitor, Z-VAD-FMK, the caspase-3 inhibitor, Z-DEVD-FMK, the Galphai inhibitor,
      pertussis toxin, or the MAO-B inhibitor, (-)deprenyl. Furthermore, this chemokine
      apoptotic effect could also be observed in vivo as intrahippocampal injections of
      MCP-1 or MIP-2 resulted in the apoptosis of hippocampal neurons, thus supporting
      a direct role of these chemokines in neuronal death. In contrast,
      immunohistological analysis of kainic acid lesions on days 21-45 revealed
      significant expression of MCP-1 and MIP-2 associated with reactive astrocytes and
      macrophages, respectively, with no apoptotic populations being observed. These
      results suggested that these chemokines might also mediate distinct biological
      effects on local microenvironmental cell populations at various stages post
      truama and during cellular repair. To address this possibility, astrocyte were
      cultured in the presence or absence of these chemokines and examined by
      microarray analysis for effects on astrocytes gene expression. A number of genes
      encoding proteins associated with inflammation, cellular signaling,
      differentiation, and repair were directly modulated by chemokine treatment. More
      specifically, the RNA and protein expression of the neurotrophic factor, basic
      fibroblast growth factor (bFGF), was found to be significantly increased upon
      culture with MCP-1 and MIP-2. Conditioned media derived from chemokine-stimulated
      astrocytes also facilitated bFGF-dependent neuronal cell differentiation and
      promoted survival of H19-7 neurons in vitro, suggesting a possible role for
      chemokine-activated astrocytes as a source of trophic support. Taken together,
      these data support possible autocrine and paracrine roles for MCP-1 and MIP-2 in
      both the "death and life" of hippocampal neurons following CNS injury.

PMID- 15194437
TI  - Activation of intrinsic and extrinsic pathways in apoptotic signaling during UV-C
      induced death of Jurkat cells: the role of caspase inhibition.
AB  - We have examined UV irradiation-induced cell death in Jurkat cells and evaluated
      the relationships that exist between inhibition of caspase activity and the
      signaling mechanisms and pathways of apoptosis. Jurkat cells were irradiated with
      UV-C light, either with or without pretreatment with the pan-caspase inhibitor, z
      VAD-fmk (ZVAD), or the more selective caspase inhibitors z-IETD-fmk (IETD), z
      LEHD-fmk (LEHD), and z-DEVD-fmk (DEVD). Flow cytometry was used to examine
      alterations in viability, cell size, plasma membrane potential (PMP),
      mitochondrial membrane potential (DeltaPsi(mito)), intracellular Na(+) and K(+)
      concentrations, and DNA degradation. Processing of pro-caspases 3, 8, and 9 and
      the pro-apoptotic protein Bid was determined by Western blotting. UV-C
      irradiation of Jurkat cells resulted in characteristic apoptosis within 6 h after
      treatment and pretreatment of cells with ZVAD blocked these features. In
      contrast, pretreatment of the cells with the more selective caspase inhibitors
      under conditions that effectively blocked DNA degradation and inhibited caspase 3
      and 8 processing as well as Bid cleavage had little protective effect on the
      other apoptotic characteristics examined. Thus, both intrinsic and extrinsic
      pathways are activated during UV-induced apoptosis in Jurkat cells and this
      redundancy appears to assure cell death during selective caspase inhibition.

PMID- 15194438
TI  - Differential regulation of the phosphoinositide 3-kinase and MAP kinase pathways
      by hepatocyte growth factor vs. insulin-like growth factor-I in myogenic cells.
AB  - Hepatocyte growth factor (HGF) promotes the proliferation of adult myoblasts and
      inhibits their differentiation, whereas insulin-like growth factor I (IGF-I)
      enhances both processes. Recent studies indicate that activation of the
      phosphoinositide 3'-kinase (PI3K) pathway promotes myoblast differentiation,
      whereas activation of the mitogen-activated protein kinase/extracellular signal
      regulated protein kinase (MAPK/ERK) promotes proliferation and inhibits their
      differentiation. This simple model is confounded by the fact that both HGF and
      IGF-I have been shown to activate both pathways. In this study, we have compared
      the ability of HGF and IGF-I to activate PI3K and MAPK/ERK in i28 myogenic cells.
      We find that, although the two stimuli result in comparable recruitment of the
      p85alpha subunit of PI3K into complexes with tyrosine-phosphorylated proteins,
      the p85beta regulatory subunit and p110alpha catalytic subunit of PI3K are
      preferentially recruited into these complexes in response to IGF-I. In agreement
      with this observation, IGF-I is much more potent than HGF in stimulating
      phosphorylation of Akt/PKB, a protein kinase downstream of PI3K. In contrast,
      MAPK/ERK phosphorylation was higher in response to HGF and lasted longer,
      relative to IGF-I. Moreover, the specific PI3K inhibitor, Wortmannin, abolished
      MAPK/ERK and Elk-1 phosphorylation in HGF-treated cells, suggesting the
      requirement of PI3K in mediating the HGF-induced MAPK pathway. UO126, a specific
      MAPK pathway inhibitor, had no effect on PI3K activity or Akt phosphorylation,
      implying that at least in muscle cells, the MAPK/ERK pathway is not required for
      HGF-induced PI3K activation. These results provide a biochemical rationale for
      the previous observations that HGF and IGF-I have opposite effects on myogenic
      cells, consistent with studies linking PI3K activation to differentiation and
      MAPK/ERK activation to proliferation in these cells. Moreover, the finding that
      PI3K activity is required for HGF-induced MAPK activation suggests its additional
      role in proliferation, rather than exclusively in the differentiation of adult
      myoblasts.

PMID- 15194439
TI  - Fibroblast growth factor-2 induces osteoblast survival through a
      phosphatidylinositol 3-kinase-dependent, -beta-catenin-independent signaling
      pathway.
AB  - Fibroblast growth factor-2 (FGF-2) is an important molecule that controls bone
      formation through activation of osteoblastic cell replication and
      differentiation. The role of FGF-2 on human osteoblast survival and the signaling
      pathway that mediates its effect are not known. We studied the effect of FGF-2 on
      apoptosis induced by low serum concentration and the signal transduction pathway
      involved in this effect in human primary calvaria osteoblasts and immortalized
      osteoblastic cells. Treatment with FGF-2 for 24-48 h protected against osteoblast
      apoptosis induced by low serum concentration, through specific inhibition of
      caspase-2 and caspase-3 activity. Pharmacological inhibition of MEK-1 and p38
      MAPK had no effect on the inhibition of caspases-2 and -3 induced by FGF-2. In
      contrast, inhibition of PI3K with LY294002 abolished the FGF-2-induced inhibition
      of caspases-2 and -3. FGF-2 increased PI3K activity but did not induce
      phosphorylation of Akt or the downstream effector p70 S6 kinase. FGF-2 also
      induced GSK-3alpha and beta phosphorylation in osteoblastic cells, which however
      did not result in beta-catenin accumulation or Lef/Tcf transcriptional activity.
      In contrast, lithium induced beta-catenin accumulation, Lef/Tcf transcriptional
      activation and increased caspase-2 and -3 activity. The results indicate that the
      immediate protective effect of FGF-2 on human osteoblastic cell apoptosis
      involves PI3K and inhibition of downstream caspases, independently of GSK-3 and
      beta-catenin-Lef/Tcf-mediated transcription.

PMID- 15194440
TI  - Characterization of the tight junction protein ZO-2 localized at the nucleus of
      epithelial cells.
AB  - ZO-2 is a MAGUK protein that in confluent epithelial sheets localizes at tight
      junctions (TJ) whereas in sparse cultures accumulates in clusters at the nucleus.
      Here, we have characterized several nuclear properties of ZO-2. We observe that
      ZO-2 is present in the nuclear matrix and co-immunoprecipitates with lamin B(1)
      and actin from the nuclei of sparse cultures. We show that ZO-2 presents several
      NLS at its amino region, that when deleted, diminish the nuclear import of the ZO
      2 amino segment and impair the ability of the region to regulate the
      transcriptional activity of promoters controlled by AP-1. Several RS repeats are
      detected in the ZO-2 amino segment, however, their deletion does not preclude the
      display of a speckled nuclear pattern. ZO-2 displays two putative NES. However,
      only the second one appears to be functional, as when conjugated to ovalbumin
      (OV), it is able to translocate this protein from the nucleus to the cytoplasm in
      a leptomycin B-sensitive way.

PMID- 15194441
TI  - Kinetic analysis of plasminogen activator inhibitor type-2: urokinase complex
      formation and subsequent internalisation by carcinoma cell lines.
AB  - The overexpression of urokinase (uPA), which plays a key role in tumour invasion
      and metastasis, is an established prognostic marker and potential therapeutic
      target. Plasminogen activator inhibitor type 2 (PAI-2), an efficient and specific
      inhibitor of uPA, has been shown to selectively deliver potent cytotoxins to
      tumour cells. However, a direct quantitative analysis of both the inhibition
      kinetics and subsequent fate of PAI-2 upon interaction with cell-surface uPA has
      not been previously undertaken. In this study, we analysed specific PAI-2 binding
      to receptor-bound uPA on human breast and prostate cancer cell lines to directly
      measure inhibition kinetics. Cell-surface uPA:PAI-2 complex formation, which is
      reflective of complete uPA inhibition, was found to be very efficient
      (inactivation constant [K(I)] = 60-80 pM, depending on cell line used) and rapid
      (inactivation rate constant [k(inact)] = 0.32-0.47 min(-1) at 37 degrees C,
      depending on cell line used). To directly quantify and visualise cellular
      internalisation and localisation, we developed a novel assay based on the use of
      PAI-2 labelled with Alexa(488) fluorochrome and a polyclonal antibody to quench
      Alexa(488) fluorescence. The efficient and rapid formation of uPA:PAI-2 complexes
      was thus shown to be associated with specific and rapid internalisation of PAI-2,
      which could be localised within endosomes and lysosomes. PAI-2 was subsequently
      degraded, presumably within lysosomes. This study is the first to provide
      definitive evidence for uPA/uPAR-mediated PAI-2 endocytosis.

PMID- 15194442
TI  - EGF-dependent cell cycle progression is controlled by density-dependent
      regulation of Akt activation.
AB  - The normal human breast epithelial cell line, MCF10A, was used to investigate the
      mechanism by which high-density inhibits EGF-dependent cell cycle progression.
      EGF-dependent Akt activation was found to be transient in high-density cells and
      sustained in low-density cells. High-density cells also showed decreased EGF
      receptor (EGFR) autophosphorylation, decreased retinoblastoma protein
      phosphorylation, and increased p27 protein expression. Although EGFR activation
      was decreased in the high-density cells, the activation was sufficient to
      stimulate EGFR substrates comparable to low-density cells. EGF-dependent
      activation of the Erk1/2 pathway and the upstream activators of Akt (Gab1, erbB3,
      PI3 kinase, and PDK1) showed no density dependency. Antagonists of Akt activity
      provided further evidence that regulation of Akt activation is the critical
      signal transduction step controlling EGF-dependent cell cycle progression. Both
      adenovirus-mediated expression of dominant-negative Akt and inhibition of PI3
      kinase-mediated Akt activation with LY294002 blocked cell cycle progression of
      low-density cells. In summary, we report the novel finding that high-density
      blocks EGF-dependent cell cycle progression by inhibiting EGF signaling at the
      level of EGF-dependent Akt activation rather than at the level of EGFR
      activation.

PMID- 15194443
TI  - Importin alpha/beta-mediated nuclear protein import is regulated in a cell cycle
      dependent manner.
AB  - Functional nuclear proteins are selectively imported into the nucleus by
      transport factors such as importins alpha and beta. The relationship between the
      efficiency of nuclear protein import and the cell cycle was measured using
      specific import substrates for the importin alpha/beta-mediated pathway. After
      the microinjection of SV40 T antigen nuclear localization signal (NLS)-containing
      substrates into the cytoplasm of synchronized culture cells at a certain phase of
      the cell cycle, the nuclear import of the substrates was measured kinetically.
      Cell cycle-dependent change in import efficiency, but not capacity, was found.
      That is, import efficiency was found low in the early S, G2/M, and M/G1 phases
      compared with other phases. In addition, we found that the extent of co
      imunoprecipitation of importin alpha with importin beta from cell extracts was
      strongly associated with import efficiency. These results indicate that the
      importin alpha/beta-mediated nuclear import machinery is regulated in a cell
      cycle-dependent manner through the modulation of interaction modes between
      importins alpha and beta.

PMID- 15194444
TI  - The infrared spectrum of human glioma cells is related to their in vitro and in
      vivo behavior.
AB  - The present research investigates whether infrared spectra can be related to the
      biological characteristics of glioma cell lines. We used nine human glioma cell
      lines for which a series of in vitro and in vivo biological features had already
      been established [Glia 36 (2001) 375] and were able to show that their
      characteristic infrared spectra reflect their in vitro migration (i.e., motility
      and invasiveness) properties and their in vivo aggressiveness. More particularly,
      the infrared data evidenced correlations at the level of the lipid/protein ratio.
      These relationships were found to be tissue-dependent when controlled on seven
      pancreatic carcinoma cell lines. We also showed that oligodendroglial and
      astrocytic tumor cells, whose identification remains difficult, can easily be
      identified by their infrared spectra in the lipid acyl chain region as well as in
      the nucleic acid region. We concluded that infrared spectroscopy could usefully
      complement information provided by more conventional diagnostic and prognostic
      (e.g., morphological and molecular) approaches.

PMID- 15194445
TI  - Triptolide inhibits murine-inducible nitric oxide synthase expression by down
      regulating lipopolysaccharide-induced activity of nuclear factor-kappa B and c
      Jun NH2-terminal kinase.
AB  - Triptolide (PG490) is a natural, biologically active compound extracted from the
      Chinese herb Tripterygium wilfordii. It has been shown to possess potent anti
      inflammatory and immunosuppressive properties. In Raw 264.7 cells stimulated with
      lipopolysaccharide (LPS) to mimic inflammation, triptolide inhibits nitric oxide
      (NO) production in a dose-dependent manner and abrogates inducible nitric oxide
      synthase (iNOS) gene expression. To investigate the mechanism by which triptolide
      inhibits murine iNOS gene expression, we examined activation of mitogen-activated
      protein kinases (MAP kinases) and nuclear factor-kappa B (NF-kappa B) in these
      cells. Addition of triptolide inhibited phosphorylation of c-Jun NH(2)-terminal
      kinase (JNK) but not that of extracellular signal-regulated kinase (ERK) or p38
      mitogen-activated protein kinase. In addition, triptolide significantly inhibited
      the DNA binding activity of NF-kappa B. Taken together, these results suggest
      that triptolide acts to inhibit inflammation through inhibition of NO production
      and iNOS expression through blockade of NF-kappa B and JNK activation.

PMID- 15194446
TI  - Role of extracellular cysteine residues in dimerization/oligomerization of the
      human prostacyclin receptor.
AB  - Prostacyclin activation of prostanoid IP receptors may result in pain sensation,
      inflammatory responses, inhibition of platelet aggregation, and vasodilation in
      vascular tissue. The prostanoid IP receptor is a G-protein-coupled receptor. In
      the present study, we investigated the determinants responsible, at least in
      part, for the prostacyclin receptor (IP) dimerization/oligomerization. Using co
      immunoprecipitation of differentially tagged IP expressed in COS-7 cells, we
      demonstrate that IP can form dimers and oligomers. Treatment of IP-expressing
      cells with the stable agonist carbaprostacyclin failed to alter the ratios of
      oligomeric/dimeric/monomeric forms of the receptor, suggesting that IP
      dimerization/oligomerization is an agonist-independent process. The reducing
      agents dithiothreitol and 2-mercaptoethanol were highly efficient in converting
      the receptor from its oligomeric form to the monomeric state, indicating the
      involvement of disulfide bonds in IP oligomerization. Immunoblotting of the
      osteoblastic MG-63 cell line lysates with an anti-IP specific antibody revealed
      the presence of endogenous IP oligomers which were converted to dimers and
      monomers upon treatment with dithiothreitol. Individual substitutions of the four
      extracellular IP Cys residues (Cys(5), Cys(92), Cys(165) and Cys(170)) for Ser
      resulted in greatly decreased receptor protein expression in COS-7 cells. The C92
      170S double mutant showed receptor protein expression level similar to the
      individual mutants. However, expression of the C92-165S and C165-170S mutants was
      drastically reduced, suggesting that there was formation of disulfide bonds
      between Cys(5) and Cys(165), and between Cys(92) and Cys(170). The Cys receptor
      mutants showed altered oligomer/dimer/monomer ratios.
      Dimerization/oligomerization likely occurs intracellularly since these Cys
      receptor mutants could still form dimers/oligomers despite their lack of
      expression at the cell surface.

PMID- 15194447
TI  - Effect of the 5HT1A receptor partial agonist buspirone on colorectal distension
      induced pseudoaffective and behavioral responses in the female Wistar rat.
AB  - In the present study, we have evaluated the visceral analgesic property of
      buspirone, a 5HT(1A) receptor partial agonist, on colorectal distension-induced
      mean arterial pressure and behavioral changes in anesthetized and awake Wistar
      rats, respectively. The selection of the rat strain was based on the observation
      that anesthetized Wistar rats exhibited a more prominent mean arterial pressure
      change in response to colorectal distention when compared to other strains
      (Sprague-Dawley, Wistar-Kyoto and Spontaneously Hypertensive). Buspirone dose
      dependently (0.1-1 mg/kg, i.v.) antagonized mean arterial pressure change over a
      range of distensions (10-90 mmHg). In parallel studies conducted in awake
      animals, buspirone (1-5 mg/kg, s.c.) attenuated the abdominal withdrawal
      response, a nociceptive behavior, in response to colorectal distension. This
      effect was antagonized by co-administration of the 5-HT(1A) receptor antagonist N
      [2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide
      (WAY-100635) (5 mg/kg, s.c.). We conclude that buspirone exhibits significant
      visceral analgesic property in two models of abdominal nociception.

PMID- 15194448
TI  - Effects of nicotine preexposure on sulpiride-induced dopamine release in the
      nucleus accumbens.
AB  - We examined the effects of nicotine preexposure or saline on dopamine release to
      sulpiride in the rat nucleus accumbens. Microdialysis was used to locally perfuse
      the sulpiride into the ventral tegmental area while sampling dopamine levels in
      the nucleus accumbens. The increase (130% and 165% of basal) in extracellular
      accumbens dopamine levels observed during ventral tegmental area perfusion for 80
      min with 10-100 microM sulpiride in saline-treated animals was reduced (128% and
      105% of basal) in nicotine-preexposed animals. The reduction of sulpiride-induced
      nucleus accumbens dopamine release after nicotine treatment is likely the result
      of down-regulation of somatodendritic dopamine autoreceptors.

PMID- 15194449
TI  - Effects of repeated testing in two inbred strains on flesinoxan dose-response
      curves in three mouse models for anxiety.
AB  - Over the last decade, many genetically modified mice have been developed as
      models for psychiatric diseases such as anxiety. Limited availability of such
      mutant mice highlights the importance of studying the possibility of repeatedly
      testing the same individuals. We tested mice four times with 1-week intervals
      with the same dose of the 5-HT(1A) receptor agonist flesinoxan (0-0.3-1.0-3.0
      mg/kg s.c.) in three anxiety-related paradigms: light-dark exploration, open
      field activity and stress-induced hyperthermia. The two inbred strains studied
      were the highly anxious 129S6/SvEvTac (S6) and low-anxiety C57BL/6J (B6) mice.
      The results indicate that the effects of repeated testing were relatively mild.
      B6 mice showed some mild habituation in the open-field test when treated with
      vehicle, whereas S6 mice developed reduced initial activity in the light-dark box
      after drug treatment. In contrast, responses to flesinoxan treatment were strong
      and highly consistent for most parameters. In the open-field and light-dark
      tests, B6 mice showed reduced activity and anxiogenic-like behavioral responses,
      whereas S6 mice were minimally affected. Anxiolytic-like responses were found in
      both strains in the stress-induced hyperthermia paradigm. We conclude that B6 and
      S6 mice can be tested repeatedly with agents such as 5-HT(1A) receptor agonists
      with 1-week intervals in the three paradigms tested.

PMID- 15194450
TI  - Behavioral and physiological mouse models for anxiety: effects of flesinoxan in
      129S6/SvEvTac and C57BL/6J mice.
AB  - Serotonin(1A) (5-HT(1A)) receptors are involved in anxiety. This study focuses on
      the role of genetic factors on the anxiety-related effects of 5-HT(1A) receptor
      stimulation using both a within subject design. The effects of 5-HT(1A) receptor
      activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and
      C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related
      assays. These two strains were also selected because they are frequently used in
      gene-targeting studies. Mice were treated with the selective 5-HT(1A) receptor
      agonist flesinoxan (0-0.3-1.0-3.0 mg/kg s.c.) and tested in either the open-field
      activity test, the light-dark exploration test, or the stress-induced
      hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also
      decreased activity on several behavioral measures in B6 mice. Flesinoxan produced
      only minimal effects in the behavioral tests in the high-anxiety S6 strain. In
      contrast, the physiological hyperthermia response showed anxiolytic-like effects
      of flesinoxan in both strains. Our data indicate that the role of 5-HT(1A)
      receptor activation on anxiety-related responses is dependent on genetic
      background and selected paradigm used to assess anxiety. These findings indicate
      that it is critical to use a multi-level approach to develop mouse models for
      human diseases. In addition, the implication of such findings for studies on
      genetically modified mice is discussed.

PMID- 15194451
TI  - Cannabinoid agonists induce contractile responses through Gi/o-dependent
      activation of phospholipase C in the bovine ciliary muscle.
AB  - This study was undertaken to investigate the effect of some cannabinoid agonists
      on the bovine ciliary muscle. Both anandamide and CP 55,940 (cis-3-(2-hydroxy-4
      (1,1-dimethyl heptyl) phenyl)-trans-4-(3-hydroxypropyl) cyclohexanol) produced a
      concentration-dependent contractile response in ciliary muscle. These responses
      were inhibited by SR 141716A (N-[piperidin-1-yl]-5-(4-cholophenyl)-1-(2,4
      dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (0.1 and 1 microM) but not by
      SR 144528 (N-[1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl] 5-(4-chloro-3
      methylphenyl)-1-(4 methoxy benzyl)-pyrazole-3-carboxamide) (1 and 10 microM). A
      preincubation with G(i/o) protein inhibitor pertussis toxin (500 ng/ml) for 20
      min inhibited the contractile action of anandamide and CP 55,940. In addition,
      the phospholipase C inhibitor U73122 (1[6-[[(17 beta)-3-methoxyestra-1,3,5(10)
      trien-17-yl] amino] hexyl]-1H-pyrrole-2,5-dione) blocked the anandamide- and CP
      55,940-induced contractions, whereas the protein kinase C activator, phorbol
      12,13 dibutyrate (PDBu) significantly potentiated the contractions evoked by
      cannabinoid receptor agonists. We evaluated the binding of [(3)H]CP 55,940, which
      specifically labelled a single class of cannabinoid sites with affinity in low
      subnanomolar range (K(d)=0.6 nM) and the maximal number of binding sites of 1243
      fmol/mg protein. Binding of [(3)H]CP 55,940 was inhibited by ligands having a
      major selectivity for cannabinoid (CB(1)) receptors. These findings provide
      strong evidence of the involvement of cannabinoid CB(1) receptors promoting
      contraction in the bovine ciliary muscle. Furthermore, the action of cannabinoid
      receptor agonists appears to be mediated via phospholipase C. These data also
      contribute to elucidate the cannabinoid CB(1) receptor pivotal role in the
      modulation of intraocular pressure and to show that cannabinoid receptor agonists
      may be regarded as potential antiglaucoma agents.

PMID- 15194452
TI  - Role of endothelin ETB receptor in partial ablation-induced chronic renal failure
      in rats.
AB  - We investigated the role of endothelin ET(B) receptor in the remnant kidney model
      of chronic renal failure, by using the spotting-lethal (sl) rat, which carries a
      naturally occurring deletion in the endothelin ET(B) receptor gene. After 5/6
      nephrectomy, systolic blood pressure and renal functional parameters were
      measured for 12 weeks. At the end of the experimental period, arterial blood
      sample, remnant kidney, heart and aorta were collected and used for biochemical
      measurements and histopathological studies. The ET(B)-deficient sl/sl rats
      exhibited earlier and higher increases in systolic blood pressure, urinary
      protein excretion, blood urea nitrogen and plasma creatinine concentration,
      compared with cases in wild-type rats. Histopathologic examination of the kidney
      revealed glomerular and tubular lesions, alterations of which were more severe in
      sl/sl than in wild-type rats. While aortic endothelin-1 contents were increased
      similarly in both groups, the level of renal endothelin-1 content was
      significantly elevated in sl/sl rats, but not in the wild-type rats. These
      results suggest that enhanced endothelin-1 production is at least partly
      responsible for the increased susceptibility to partial ablation-induced chronic
      renal failure in ET(B) receptor-deficient rats and that ET(B) receptor-mediated
      actions are protective against vascular and renal injuries in this disease.

PMID- 15194453
TI  - Growth factor-induced contraction of human bronchial smooth muscle is Rho-kinase
      dependent.
AB  - Growth factors have been implicated in the pathophysiology of asthma. However,
      the putative effects of these growth factors on human airway smooth muscle tone
      are still largely unknown. We performed contraction experiments using human
      bronchial smooth muscle ring preparations. The growth factor insulin-like growth
      factor-1 (IGF-1) induced a slowly developing sustained contraction, which was
      dependent on Rho-kinase, since contraction was almost completely inhibited by (+)
      (R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide (Y-27632; 1
      microM). Angiotensin II, a G(q)-coupled receptor agonist which can act as a
      growth factor as well, induced a biphasic contraction, the sustained phase of
      which was also almost completely inhibited by Y-27632. We conclude that
      angiotensin II and IGF-1 induce a Rho-kinase-dependent sustained contraction of
      human bronchial smooth muscle. Since growth factors are associated with
      pathophysiological conditions such as asthma, inhibition of Rho-kinase could be
      effective under these conditions.

PMID- 15194454
TI  - The multi-faceted behavior of nitric oxide in vascular "inflammation": catchy
      terminology or true phenomenon?

PMID- 15194455
TI  - Increased endothelin levels in congestive heart failure: does it come from the
      lungs? Does it matter?

PMID- 15194456
TI  - Inhibition of the activation of nuclear factor kappa B to reduce myocardial
      reperfusion injury and infarct size.

PMID- 15194457
TI  - Control of vascular cell proliferation and migration by cyclin-dependent kinase
      signalling: new perspectives and therapeutic potential.
AB  - Neointimal lesion development is a chronic inflammatory process that involves
      excessive cell proliferation and migration within the artery wall. Progression
      through the mammalian cell cycle requires the sequential activation of
      holoenzymes composed of a catalytic cyclin-dependent protein kinase (CDK) and a
      regulatory subunit named cyclin. Members of the family of CDK inhibitory proteins
      (CKIs) interact with and inhibit the activity of CDK/cyclins. Cell migration
      occurs predominantly at the G1/S phase of the cell cycle, and both CDKs and CKIs
      are among the molecular machines that coordinately regulate the cycling events
      that control cell proliferation and locomotion. The purpose of this review is to
      discuss the role of CDK/cyclins and CKIs in the regulation of vascular cell
      proliferation and migration and in the control of neointimal thickening.
      Pharmacological and gene therapy strategies targeting these cell cycle regulators
      for the treatment of cardiovascular disease will also be discussed.

PMID- 15194458
TI  - Biological aspects of radiation and drug-eluting stents for the prevention of
      restenosis.
AB  - Based on recent advances, this article aims to review the biological basis for
      the use of either radiation or drug-eluting stents for the prevention of
      restenosis, and to elucidate the complementary role that they may play in the
      future. Vascular restenosis is a multifactorial process primarily driven by the
      remodeling of the arterial wall, as well as by the hyperproliferation of smooth
      muscle cells (SMC). These pathophysiological features are the target of
      therapeutic strategies aimed at inhibiting constrictive remodeling as well as
      inhibiting SMC proliferation. The success of radiation as well as anti
      proliferative drugs such as paclitaxel and sirolimus lies in the primary and/or
      multifactorial inhibition of cell proliferation. Radiation has the additional
      feature of preventing constrictive remodeling while sirolimus has the potential
      property of being anti-inflammatory, which may be a desirable feature. The
      effects of radiation are not reliant on any uptake and "metabolism" by the target
      cells, as in the case with drugs, and thus radiation potentially may be more
      effective as a result of its more-direct action. However, radiation does have
      some significant drawbacks compared to drug-eluting stents, including a much
      delayed re-endothelialization resulting in the need for prolonged anti-platelet
      therapy. Based on recent clinical data, drug-eluting stents have been shown to
      markedly reduce the likelihood of restenosis, which actually favors this approach
      for the prevention of restenosis. From a biological perspective, drug-eluting
      stents and radiation have certain differences, which are reviewed in this
      article.

PMID- 15194459
TI  - NO suppresses while peroxynitrite sustains NF-kappaB: a paradigm to rationalize
      cytoprotective and cytotoxic actions attributed to NO.
AB  - OBJECTIVE: NO has both cytoprotective and cytotoxic effects. A key cytoprotective
      action of NO is attributed to inhibition of nuclear factor-kappaB (NF-kappaB)
      mediated gene expression; this potentially endows NO with ubiquitous anti
      inflammatory activity. Since immunostimulant-induced iNOS gene expression is
      itself dependent on NF-kappaB, NO is expected to limit its own synthesis. On the
      other hand, many cytotoxic actions of NO have been attributed to the chemical
      reactivity of peroxynitrite (ONOO-) formed from NO by near diffusion-limited
      reaction with O2-. To assess whether ONOO- shares the ability of NO to inhibit NF
      kappaB activation and consequent iNOS gene expression, we compared effects of NO
      donors (NOR3 and SNAP), an ONOO- donor (SIN-1), and pure ONOO- on LPS-induced
      responses in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: NO donors,
      but not ONOO-, suppressed LPS-induced NF-kappaB activation and expression of a
      murine iNOS promoter/reporter construct. An NO donor also suppressed NF-kappaB
      activation when induced by IL-1beta or TNFalpha. Northern blot and RT-PCR
      analyses showed that NO, but not ONOO- or 8-bromo-cGMP, decreases LPS-induced
      expression of iNOS mRNA. Electrophoretic mobility shift assays (EMSA) and
      immunocytochemical analyses confirmed that NO but not ONOO- inhibits nuclear
      translocation of NF-kappaB. Although ONOO- generation from SIN-1 did not inhibit
      NF-kappaB activation, conversion of SIN-1 to a pure NO donor (by addition of
      excess superoxide dismutase) resulted in potent inhibition of NF-kappaB
      activation. Dose-response analyses suggest that the inhibitory effect of NO on
      iNOS gene transcription results specifically from inhibition of NF-kappaB
      activation, and is mediated by a G-cyclase-independent mechanism that is
      unavailable to ONOO-. LPS stimulates IkappaB-alpha phosphorylation by inducing
      IkappaB kinase (IKK) activity, and NO, but not ONOO-, inhibits LPS-induced
      IkappaB-alpha phosphorylation and IKK activity. CONCLUSION: We demonstrate that
      only NO inhibits the activation of NF-kappaB and suppresses iNOS gene expression.
      This distinction provides a novel paradigm to rationalize cytoprotective and
      cytotoxic actions attributed to NO.

PMID- 15194460
TI  - Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary
      synthesis and secretion of endothelin-1.
AB  - OBJECTIVE: The pulmonary circulation may contribute to elevated plasma levels of
      endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present
      study were to determine the mechanisms of increased secretion of ET-1 from the
      pulmonary circulation in CHF. METHODS: Juvenile pigs were subjected to sham
      operation (n=9) or rapid cardiac pacing-induced CHF (215-240 bpm, n=15). RESULTS:
      Three weeks of rapid pacing led to significant left ventricular dilatation,
      increased cardiac filling pressures, and reduced contractility (CHF pigs).
      Arterial plasma ET-1 levels in the CHF pigs were increased 4-fold compared to
      sham pigs (P<0.001). Single-bolus multiple indicator-dilution experiments
      revealed that pulmonary synthesis and release of ET-1 was increased in CHF, while
      pulmonary clearance of plasma ET-1 remained unaltered despite significant
      reduction of pulmonary fractional extraction of plasma ET-1. Pulmonary ECE-1
      isozyme activity (pmol.min-1.mg protein-1) was selectively increased in lower
      lobe segments of CHF pigs (2.0+/-0.3) compared to lower lobe segments of controls
      (1.1+/-0.1, P<0.02), and to upper lobe segments of CHF pigs (1.1+/-0.1, P<0.005),
      and correlated significantly with the wet/dry weight ratios of the pulmonary
      tissue samples (R=0.75, P<0.001), i.e. a marker of pulmonary congestion.
      Furthermore, alveolar macrophages in congested lobe segments were identified as
      likely sites of increased synthesis and release of ET-1. CONCLUSIONS: In rapid
      pacing-induced CHF, a complex cardiopulmonary interaction revealed by pulmonary
      congestion causes increased pulmonary production and secretion of ET-1 due to
      enhanced pulmonary ECE-1 activities. Pulmonary secretion of ET-1 during evolving
      CHF is an important contributor to elevated plasma ET-1 levels in the systemic
      circulation.

PMID- 15194461
TI  - Inhibition of IkappaB phosphorylation in cardiomyocytes attenuates myocardial
      ischemia/reperfusion injury.
AB  - OBJECTIVE: Reperfusion injury is related closely to inflammatory reactions such
      as activation of inflammatory cells and expression of cytotoxic cytokines. We
      investigated the efficacy of IkappaB phosphorylation blockade in a rat myocardial
      ischemia/reperfusion injury model. METHODS AND RESULTS: IMD-0354 inhibited
      phosphorylation of IkappaBalpha and nuclear translocation of nuclear factor-kappa
      B (NF-kappaB) induced by tumor necrosis factor-alpha (TNF-alpha) in cultured
      cardiomyocytes. TNF-alpha-induced production of interleukin-1beta and monocyte
      chemoattractant protein-1 from cultured cardiomyocytes was reduced significantly
      by IMD-0354. Transient left coronary artery occlusion (30 min) and reperfusion
      (24 h) were carried out in Sprague-Dawley rats. IMD-0354 (1, 5, 10 mg/kg) was
      injected intraperitoneally 5 min before the start of reperfusion. Treatment with
      IMD-0354 resulted in a significant dose-dependent reduction of the infarction
      area/area at risk ratio (vehicle, 47.0+/-3.4%; 10 mg/kg of IMD-0354, 19.4+/-4.0%;
      P<0.01) and the preservation of fractional shortening ratio (vehicle, 25.0+/
      1.5%; 10 mg/kg of IMD-0354, 42.3+/-1.7%; P<0.01). Histological analysis showed
      that accumulation of polymorphonuclear neutrophils in the area at risk was
      decreased significantly. CONCLUSIONS: Inhibition of nuclear translocation of NF
      kappaB by IkappaBalpha phosphorylation blockade could provide an effective
      approach to attenuation of ischemia/reperfusion injury. The cardioprotective
      effects of IMD-0354 include not only reduction of harmful neutrophil accumulation
      in myocardium but also inhibition of harmful cytokine and chemokine production by
      cardiomyocytes.

PMID- 15194462
TI  - New KCNQ1 mutations leading to haploinsufficiency in a general population;
      Defective trafficking of a KvLQT1 mutant.
AB  - OBJECTIVE: KCNQ1 mutations lead to the long QT syndrome (LQTS), characterized by
      a prolonged QT interval, syncopes and sudden death. However, some mutations are
      associated with non-penetrant phenotype (no symptoms, QTc normal or borderline).
      The objective of this study was to determine whether KCNQ1 variants are
      associated with borderline QTc prolongation in a general population and to
      evaluate the frequency of carriers. METHODS: We selected 2008 unrelated and
      untreated healthy individuals from a non-patient population. The KCNQ1 gene was
      screened by denaturing high-performance liquid chromatography (dHPLC) in 50 men
      and 50 women presenting the longest QTc intervals (403 to 443 ms). RESULTS: We
      identified a nonsense mutation, Y148X, and an in-frame deletion of the serine
      residue 276 (DeltaS276), in S2 and S5 transmembrane domains, respectively.
      DeltaS276 KvLQT1 channels expressed in COS-7 cells failed to conduct any K+
      current in the homozygous state. Besides, a slight reduction in channel activity
      was observed when coexpressed with WT KvLQT1 and IsK. Confocal microscopy
      performed on transfected COS-7 cells revealed that DeltaS276 KvLQT1 was retained
      in the endoplasmic reticulum, whereas WT KvLQT1 was localized in the cell
      membrane. The two mutation carriers presented borderline QTc interval
      prolongation at slow heart rate but a 24-h ECG recording revealed a marked QTc
      prolongation at higher heart rate for the Y148X carrier. CONCLUSIONS: In this
      population, two subjects with borderline QTc prolongations (438 and 443 ms) were
      carriers of KCNQ1 mutations leading to haploinsufficiency and are potentially at
      risk of developing drug-induced arrhythmia. The study provides the first
      demonstration of a defective cell surface localization of a KvLQT1 mutant missing
      one amino acid in a transmembrane domain.

PMID- 15194463
TI  - Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge
      model of long QT 3.
AB  - OBJECTIVE: Ventricular tachyarrhythmias (VTs) occur frequently in patients having
      long QT syndrome (LQTS) or after acute myocardial ischemia. However, the
      synergistic effects of ischemia and LQTS on arrhythmia development are unclear.
      We evaluated the contribution of a prior episode of ischemia on the
      arrhythmogenicity of the LQTS. METHODS: Using a 256-channel optical mapping
      system, we mapped action potentials on the cut-exposed transmural surfaces of
      perfused and preconditioned muscle wedges isolated from canine left ventricular
      walls and recorded their transmural electrocardiogram (ECG). RESULTS: We observed
      that 40 min of global ischemia followed by 60 min of reperfusion, at which time
      action potential duration (APD) and conduction velocity had recovered,
      significantly enhanced the APD prolongation produced by 20 nmol/l anemone toxin
      II (ATX-II). Wedges after the above ischemia, reperfusion, and ATX-II procedures
      had 100% (8/8) occurrences of early afterdepolarizations (EADs) and 87.5% (7/8)
      occurrences of spontaneous VTs and reentry. We observed epicardial,
      midmyocardial, and endocardial occurrences of EADs in one, seven, and four
      wedges, respectively. Focal EADs and reentry were responsible for 73% and 18% of
      the repetitive activations in the VTs. In contrast, neither EADs nor VTs occurred
      in eight control wedges following identical procedures except without ischemia,
      and VT occurred in 20% wedges (2/10) after ischemia and reperfusion but before
      ATX-II. CONCLUSION: A prior episode of acute ischemia, even after apparent
      electrophysiologic recovery, enhances the arrhythmogenicity of LQTS induced by
      ATX-II through the development of EADs and reentry.

PMID- 15194464
TI  - Architectural and functional asymmetry of the His-Purkinje system of the murine
      heart.
AB  - OBJECTIVE: The aim of this work was to target a vital reporter gene in the mouse
      cardiac conduction system (CS) to distinguish this tissue from the surrounding
      myocardium in the adult heart. METHODS: A transgenic mouse line has been created
      in which EGFP is expressed under the control of the Cx40 gene. Correlative
      investigations associating EGFP imaging and electrophysiological techniques were
      carried out on the adult heart and isolated cardiomyocytes. RESULTS: In the heart
      of the Cx40(EGFP/+) mice, EGFP signal was seen in the coronary arteries, the
      atria, the atrioventricular (AV) node and the His-Purkinje system. The latter was
      found to be structurally and functionally asymmetrical. The anatomical asymmetry
      was apparent in both the number of strands or fasciculi making up the His bundle
      branches (BBs) (1 strand on the right, 20 or so on the left), and the density
      (low on the right, high on the left) of the network of Purkinje fibers (PFs) that
      extends over the ventricular wall surfaces. The profiles of the electrical
      activation patterns recorded on the right and left flanks of the septum were also
      asymmetrical, mirroring the architecture of the branches. EGFP made it easy to
      identify the Purkinje cells in populations of dissociated cardiomyocytes and they
      were investigated using the patch-clamp technique. The hyperpolarization
      activated current (If) was recorded in all spontaneously active Purkinje cells.
      CONCLUSIONS: This investigation provides positive evidence of the asymmetry of
      the His-Purkinje system of the adult mouse, and the first patch-clamp recording
      data on murine cardiac Purkinje cells. This mouse model opens up new perspectives
      for investigating the contribution of specific genes to the morphology and
      function of the His-Purkinje system.

PMID- 15194465
TI  - Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by
      TGF-beta1 involves furin-convertase.
AB  - OBJECTIVE: Heart failure is characterized by an imbalance of matrix
      synthesis/turnover, finally resulting in fibrosis. Cardiac myocytes and
      fibroblasts play a pivotal role in the remodeling process. Cardiac remodeling
      involves the expression of TGF-beta1 and matrix metalloproteinases (MMPs) in
      cardiac fibroblasts (CFBs). Furin, a subtilisin/kexin-like proprotein convertase
      (PC), activates TGF-beta1 and membrane-bound MT1-MMP, which facilitates pro
      gelatinase A (MMP-2) activation. Even though several reports identified TGF-beta1
      as a pro-fibrotic cytokine in the heart, it increases MMP-activity and cell
      migration/invasion in several cell types. The present study was done to
      investigate the contribution of TGF-beta1 and furin to CFBs MMP-activity and
      motility. METHODS AND RESULTS: Stimulation of CFBs from adult Sprague-Dawley rats
      with TGF-beta1 (20 ng/ml) induced furin, but had no effect on the closely related
      PC5. Inhibition of furin inhibited angiotensin II-induced TGF-beta1 activation,
      indicating that TGF-beta1 amplifies its activating convertase in CFBs.
      Pretreatment of CFBs with TGF-beta1 (20 ng/ml, 24 h) increased their migration by
      about two-fold (p<0.05), which was accompanied by an enhanced expression and
      activity of MT1-MMP and MMP-2. Brefeldin A (BFA), a Golgi-disturbing agent,
      inhibited MT1-MMP activation, indicating that it occurs in the trans-Golgi
      network (TGN), where furin is concentrated and colocalized with MT1-MMP.
      Inhibition of furin significantly inhibited TGF-beta1-induced MT1-MMP/MMP-2
      activation. Furthermore, inhibition of furin attenuated TGF-beta1-enhanced
      migration on gelatin-coated membranes (p<0.05). This was comparable to the
      effects of the MMP-inhibitor GM6001, pointing out that MMPs are major mediators
      of TGF-beta1-enhanced CFB motility. CONCLUSION: We demonstrate that TGF-beta1
      induces MMP-activity in CFBs, thereby facilitating CFBs motility. Furthermore,
      TGF-beta1 amplifies its activating convertase furin, which is also required for
      MT1-MMP/MMP-2 activation in CFBs. Thus, furin is central for TGF-beta1 and MT1
      MMP activation and might be a novel target in cardiac remodeling.

PMID- 15194466
TI  - Amphetamine activates connexin43 gene expression in cultured neonatal rat
      cardiomyocytes through JNK and AP-1 pathway.
AB  - OBJECTIVE: Amphetamine has been known to induce cardiac dysrhythmia and sudden
      death. However, the molecular mechanism for the induction of dysrhythmia is not
      known. Connexin43 (Cx43) plays an important role for arrhythmogenesis. This study
      was undertaken to test the hypothesis that amphetamine could induce Cx43
      expression in cardiac myocytes. METHODS: Neonatal Wistar rat cardiac myocytes
      were cultured under the stimulation of amphetamine. Cx43 mRNA and protein
      expression were examined by Northern and Western blots, respectively. We used c
      Jun N-terminal kinase (JNK) inhibitor, SP600125, and JNK1 dsRNAi to investigate
      the signal pathway of amphetamine-induced expression of Cx43. RESULTS: The level
      of Cx43 protein significantly increased from 4 to 24 h after addition of
      amphetamine (10 microM). The Cx43 mRNA increased maximally to 4.2-fold at 6 h
      after addition of amphetamine and returned to the baseline level at 48 h. These
      increases of Cx43 protein at 24 h were completely attenuated (P<0.001) by
      SP600125 (20 microM) and JNK1 dsRNAi. Amphetamine increased and SP600125
      decreased the immunohistochemical labeling of Cx43. Amphetamine increased and
      SP600125 decreased the phosphorylated JNK and c-Jun proteins. Gel-shifting assay
      showed that DNA-binding activity of AP-1 increased after addition of amphetamine
      and SP600125 and JNK1 dsRNAi abolished the binding activity induced by
      amphetamine. CONCLUSIONS: These findings indicate that amphetamine activates Cx43
      gene expression in cultured rat neonatal cardiac myocytes. Amphetamine mediates
      the Cx43 gene expression, at least in part, through the JNK pathway. These
      findings from our study suggest that Cx43 plays a role for the molecular
      mechanism of amphetamine-induced cardiac dysrhythmias.

PMID- 15194467
TI  - Adjunctive 17beta-estradiol administration reduces infarct size by altered
      expression of canine myocardial connexin43 protein.
AB  - BACKGROUND: Traffic of potentially harmful cytosolic messengers through gap
      junctions might cause increased injury during ischemia. The present study was to
      determine whether the infarct size-reducing effect of adjunctive estradiol
      administration prior to reperfusion is associated with an attenuated expression
      of connexin43 at the border of infarction in a canine model. METHODS: Experiments
      were performed in 48 dogs (n=16 each group), assigned to receive either vehicle
      (control group), 17beta-estradiol administered before coronary occlusion (early
      group), or 3 min before coronary reperfusion following 60-min ischemia (late
      group). Changes in the amount of phosphorylated connexin43 were measured by
      Western blot. RESULTS: Infarct size was significantly larger in the control (38+/
      7% of area at risk) than in the supplemented groups (16+/-6% in the early group;
      16+/-8% in the late group, P<0.0001, both). Reperfusion caused a significant
      elevation in free radicals as measured by lucigenin-derived chemiluminescence.
      The rise of free radicals was significantly inhibited in animals treated with
      estrogen, either early or late. The amount of phosphorylated connexin43 was
      reduced, as assessed by Western blot in control hearts at the border zone. These
      changes were significantly enhanced by estrogen administration. The magnitude of
      infarct size positively correlated with the magnitude of phosphorylated
      connexin43 expression assessed by Western blot (r=0.83, P<0.0001). Confocal
      microscopy confirmed the changes of junctional complexes. CONCLUSIONS: This
      result demonstrated that the cardioprotective effect of estrogen as an
      antioxidant may be associated with the reduced amount of phosphorylated
      myocardial connexin43 protein.

PMID- 15194468
TI  - Effect of classic preconditioning and diazoxide on endothelial function and O2-
      and NO generation in the post-ischemic guinea-pig heart.
AB  - OBJECTIVES: A hypothesis was tested that a reaction product between superoxide
      (O2-) and nitric oxide (NO) mediates post-ischemic coronary endothelial
      dysfunction that ischemic preconditioning (IPC) protects the endothelium by
      preventing post-ischemic cardiac O2- and/or NO formation, and that the opening of
      the mitochondrial ATP-dependent potassium channel (mKATP) plays a role in the
      mechanism of IPC. METHODS: Langendorff-perfused guinea-pig hearts were subjected
      either to 30 min global ischemia/30 min reperfusion (IR) or were preconditioned
      prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min
      infusion/5 min wash-out of mKATP opener, diazoxide (0.5 microM). Coronary flow
      responses to acetylcholine (ACh) and nitroprusside were used as measures of
      endothelium-dependent and -independent vascular function, respectively.
      Myocardial outflow of O2- and NO, and functional recoveries were followed during
      reperfusion. RESULTS: IR impaired the ACh response by approximately 60% and
      augmented cardiac O2- and NO outflow. Superoxide dismutase (150 U/ml) and NO
      synthase inhibitor, l-NMMA (100 microM) inhibited the burst of O2- and NO,
      respectively, and afforded partial preservation of the ACh response in IR hearts.
      NO scavenger, oxyhemoglobin (25 microM), afforded similar endothelial protection.
      IPC and diazoxide preconditioning attenuated post-ischemic burst of O2-, but not
      of NO, and afforded a complete endothelial protection. Diazoxide given after 30
      min ischemia increased the O2- burst and was not protective. The effects of IPC
      and diazoxide preconditioning were not affected by HMR-1098 (25 microM), a
      selective blocker of plasmalemmal KATP, and were abolished by glibenclamide (0.6
      microM) and 5-hydroxydecanoate (100 microM), a nonselective and selective mK(ATP)
      blocker, respectively. 5-Hydroxydecanoate produced similar effects, whether it
      was given as a continuous treatment or was washed out prior to IR. CONCLUSION:
      The results suggest that in guinea-pig heart: (i) a reaction product between O2-
      and NO mediates the post-ischemic endothelial dysfunction; (ii) the mK(ATP)
      opening serves as a trigger of the IPC and diazoxide protection; and (iii) the
      mK(ATP) opening protects the endothelium in the mechanism that involves the
      attenuation of the O2- burst at reperfusion.

PMID- 15194469
TI  - Effect of lipoprotein (a) on platelet activation induced by platelet-activating
      factor: role of apolipoprotein (a) and endogenous PAF-acetylhydrolase.
AB  - OBJECTIVE: Lipoprotein (a) [Lp(a)] is considered an atherogenic lipoprotein,
      which is also implicated in thrombosis. Lp(a) binds to platelets and modulates
      the effects of various platelet agonists. Platelet activating factor (PAF) is a
      potent platelet agonist degraded and inactivated by PAF-acetylhydrolase (PAF-AH),
      which in plasma is associated with lipoproteins. Lp(a) is enriched in PAF-AH,
      thus a functional characteristic of this lipoprotein is its capability to
      hydrolyze and inactivate PAF. In the present study, we investigated the effect of
      Lp(a) on PAF-induced platelet activation. The potential roles of the apo(a)
      moiety and especially of the PAF-AH content of Lp(a) on the above effect were
      also addressed. METHODS: Lp(a) was isolated by affinity chromatography from
      plasma of apparently healthy fasting donors with serum Lp(a) concentrations >/=20
      mg/dl. Reduced Lp(a) [Lp(a-)] was prepared by incubation of Lp(a) with
      dithiothreitol (DTT), whereas inactivation of Lp(a)-associated PAF-AH was
      performed by incubation of Lp(a) with pefabloc [pefa-Lp(a)]. Platelet-rich plasma
      (PRP) or washed platelets were prepared from peripheral venous blood samples of
      normolipidemic, apparently healthy fasting donors with their serum Lp(a) levels
      lower than 0.8 mg/dl. The surface expression of the platelet integrin-receptor
      alpha(IIb)beta3 and the fibrinogen binding to the activated alpha(IIb)beta3 was
      studied by flow cytometry. RESULTS: Lp(a), at doses higher than 20 microg/ml,
      inhibits PAF-induced platelet activation in a dose-dependent manner. Pefa-Lp(a),
      lacking PAF-AH activity, exhibited a similar to Lp(a) inhibitory effect.
      Importantly, the Lp(a) inhibitory effect was not influenced by the apo(a) isoform
      size, whereas Lp(a-) was a more potent inhibitor compared to Lp(a). Similarly to
      PAF, Lp(a) inhibits platelet aggregation induced by ADP or Calcium ionophore
      A23187. Lp(a), pefa-Lp(a) or Lp(a-) effectively inhibited PAF- or ADP-induced
      surface expression of alphaIIbbeta3, the Lp(a-) being more potent compared to
      Lp(a) or to pefa-Lp(a). Finally, Lp(a) significantly inhibited fibrinogen binding
      to platelets activated with PAF. CONCLUSIONS: Lp(a) inhibits PAF-induced platelet
      activation in a non-specific manner. The Lp(a)-associated PAF-AH does not play
      any important role in this effect, whereas the apo(a) moiety of Lp(a)
      significantly reduces its inhibitory effect. The inhibition of alpha(IIb)beta3
      activation and fibrinogen binding to the activated platelets may represent the
      major mechanism by which Lp(a) inhibits PAF-induced platelet aggregation.

PMID- 15194470
TI  - Estrogen-mediated protection against HIV Tat protein-induced inflammatory
      pathways in human vascular endothelial cells.
AB  - OBJECTIVE: It has been proposed that human immunodeficiency virus (HIV) infection
      induced inflammatory environment may contribute to the pathogenesis of
      cardiovascular diseases. Recent studies have also demonstrated the potential role
      of estrogen as therapeutic agents in the prevention or treatment of
      cardiovascular diseases. In the present study, we assessed the hypothesis that
      estrogen may attenuate the HIV Tat protein-induced inflammatory pathways in human
      vascular endothelium. METHODS: Expression of inflammatory mediators in human
      endothelial cells was analyzed by reverse transcriptase-polymerase chain reaction
      (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Electrophoretic mobility
      shift assay (EMSA) also was performed to investigate the DNA-binding activities
      of several transcription factors, which are known to regulate expression of these
      inflammatory genes. RESULTS: Acute exposure of human endothelial cells to Tat
      markedly induced the mRNA and protein expression of IL-1beta, MCP-1, VCAM-1, and
      E-selectin. Tat also stimulated the adherence of inflammatory cells to
      endothelial cell monolayers. Significant and dose-dependent increases in NF
      kappaB DNA-binding activity were observed in human endothelial cells treated with
      Tat. However, Tat did not affect DNA-binding activities of AP-1, CREB, and STAT1.
      Pretreatment with 17beta-estradiol dramatically blocked the activation of NF
      kappaB in human endothelial cells exposed to Tat. In addition, 17beta-estradiol
      selectively inhibited the Tat-induced expression of IL-1beta. CONCLUSION: Our
      results suggest that estrogen may protect against Tat-induced inflammatory
      reactions in human vascular endothelium via blocking the NF-kappaB-mediated
      molecular signaling pathways. These data may contribute to understanding the
      pathogenesis of cardiovascular complications and development of therapeutic
      strategies for HIV-infected patients.

PMID- 15194471
TI  - Transendothelial lipoprotein exchange and microalbuminuria.
AB  - OBJECTIVE: Microalbuminuria associates with increased risk of atherosclerosis in
      individuals without diabetes. We hypothesized that transendothelial lipoprotein
      exchange is elevated among such individuals, possibly explaining increased
      intimal lipoprotein accumulation and thus atherosclerosis. METHODS: Using an in
      vivo isotope technique, transendothelial exchange of low density lipoprotein
      (LDL) was measured in 77 non-diabetic individuals. Autologous 131-iodinated LDL
      was reinjected intravenously, and the 1-h fractional escape rate was calculated
      as index of transendothelial exchange. RESULTS: There was no difference in
      transendothelial LDL exchange between subjects with microalbuminuria versus
      normoalbuminuria (mean (95% confidence interval) 3.8%/h (3.3-4.3%/h) versus
      4.2%/h (3.7-4.7%/h); P=0.33). In contrast, there was a positive correlation
      between transendothelial LDL exchange and (logarithmically transformed) plasma
      insulin: beta=0.6 (95% CI: 0.1-1.1); R=0.22; P<0.05. This correlation was
      independent of age, sex, blood pressure, plasma concentration of lipoproteins,
      LDL size, body mass index, plasma volume, and use of medicine, and it was
      unlikely caused by altered hepatic LDL receptor expression, or glycosylation of
      LDL. CONCLUSION: In non-diabetic individuals, transendothelial LDL exchange is
      not associated with microalbuminuria, but possibly with hyperinsulinemia.

PMID- 15194472
TI  - 2-Arachidonoyl glycerol induces contraction of isolated rat aorta: role of
      cyclooxygenase-derived products.
AB  - OBJECTIVES: Endocannabinoids have been shown to play a role in the regulation of
      vascular tone. The effects of 2-arachidonoyl glycerol (2-AG) on induced-tone were
      examined in rat aortic rings in vitro. METHODS: Aortic rings from Wistar Kyoto
      (WKY) rats were suspended in organ chambers for recording isometric tension
      development in response to 2-AG. The production of TXA2 in response to 2-AG was
      also assessed by enzyme immunoassay. RESULTS: In endothelium-intact rings pre
      contracted to PGF(2alpha), 2-AG (10 nM-30 microM) induced a biphasic effect: a
      weak relaxation from 10 nM to 0.1 microM, which turned into a concentration
      dependent contraction from 3 to 30 microM. Endothelium-denudation did not change
      2-AG-mediated vascular effects. 2-AG-induced contraction was unaffected by both
      the cannabinoid CB1 receptor antagonist SR141716A (3 microM) and the CB2 receptor
      antagonist SR144528 (1 microM). In contrast, the anandamine transport inhibitor
      (AM404, 100 microM) and the amino hydrolase inhibitor (PMSF, 30 microM)
      attenuated (P<0.05) the contractile response evoked by 2-AG in endothelium-intact
      and rubbed aortic rings. In addition, the cyclooxygenase inhibitor (indomethacin,
      10 microM) and the thromboxane A2 (TXA2) receptor (TP receptor) antagonist
      GR32191 (0.3 microM) totally abolished the contraction elicited by 2-AG in
      endothelium-intact and rubbed aortic rings. Challenge of isolated aortic rings
      with 2-AG (10 microM) evoked a significant increase in TXA2 level (measured as
      TXB2 level) in endothelium-intact and rubbed aortic rings. CONCLUSION: These data
      suggested that the contraction elicited by 2-AG resulted from the vascular smooth
      muscle cell uptake and conversion of 2-AG to constrictor prostanoid TXA2, which
      in turn caused vasoconstriction through the stimulation of TP receptor.

PMID- 15194473
TI  - Vascular endothelial dysfunction and superoxide anion production in heart failure
      are p38 MAP kinase-dependent.
AB  - OBJECTIVE: The mitogen-activated protein (MAP) kinase system, especially the p38
      MAP kinase, is activated in chronic heart failure (CHF). However, the role of
      vascular p38 MAP kinase in CHF has not been analyzed yet. METHODS AND RESULTS: In
      aortic rings from rats with CHF 10 weeks after myocardial infarction,
      acetylcholine-induced relaxation was attenuated (maximum relaxation, Rmax: 54+/
      5%) compared to sham-operated animals (Rmax: 77+/-5%, p<0.01), while endothelium
      independent relaxation elicited by sodium nitroprusside was not significantly
      changed. Aortic levels of phosphorylated p38 MAP kinase protein were
      significantly elevated in rats with CHF. In addition, phosphorylation of MAP
      kinase-activated protein kinase-2 (MAPKAPK-2), an index of p38 MAP kinase
      activity, was increased. Aortic superoxide anion generation was significantly
      enhanced in rats with CHF accompanied by elevation of the NAD(P)H oxidase subunit
      p47phox protein expression. Inhibition of p38 MAP kinase by treatment with the
      p38 MAP kinase inhibitor SB239063 (800 ppm in standard rat chow) reduced MAPKAPK
      2 phosphorylation, preserved acetylcholine-induced relaxation (Rmax: 80+/-4%,
      p<0.01), and reduced vascular superoxide formation. SB239063 treatment did not
      affect blood pressure and left ventricular enddiastolic pressure. In aortic
      tissue from CHF animals treated with the angiotensin-converting enzyme (ACE)
      inhibitor trandolapril, p38 MAP kinase phosphorylation was significantly reduced.
      CONCLUSIONS: Vascular p38 MAP kinase is markedly activated in rats with CHF.
      Chronic p38 MAP kinase inhibition with SB239063 prevented endothelial vasomotor
      dysfunction through reduction of superoxide anion production.

PMID- 15194475
TI  - Influence of the 4G/5G PAI-1 genotype on angiotensin II-stimulated human
      endothelial cells and in patients with hypertension.
AB  - BACKGROUND: We examined the influence of the 4G/5G PAI-1 (plasminogen activator
      inhibitor) genotype on Angiotensin II (Ang II)-induced PAI-1 expression by human
      endothelial cells (HUVEC) in the presence and absence of AT1-receptor blocker
      losartan, and screened for this polymorphism in relation to plasma PAI-1 and
      arterial pressure in apparently healthy subjects. METHODS AND RESULTS: Genotyped
      cultured HUVEC were incubated with Ang II (10(-8) M) with or without losartan up
      to 24 h. PAI-1 mRNA was determined in cell extracts and protein and activity
      assessed in supernatants and extracellular matrix (ECM). Ang II increased PAI-1
      mRNA and activity in a genotype-dependent manner, higher values observed for
      4G/4G HUVEC compared with 4G/5G and 5G/5G genotypes (p<0.05). Laser confocal
      microscopy and Western blot analysis showed increased PAI-1 protein within ECM in
      Ang II-stimulated cultures. PAI-1 expression and protein secretion induced by Ang
      II in 4G/4G HUVEC was completely inhibited by preincubation with 0.05 microM
      losartan (p<0.01), indicating an AT1-mediated effect. In a group of hypertensives
      homozygous for the 4G allele, PAI-1 antigen was significantly increased (51.0+/
      10.1 ng/ml) compared with normotensives (28.3+/-4.0 ng/ml) and hypertensives
      carrying the 5G allele (p<0.05). CONCLUSIONS: The 4G/5G PAI-1 polymorphism
      determines the endothelial PAI-1 upregulation by Ang II and the inhibitory
      response to losartan. Analysis of PAI-1 genotypes may help identifying subgroups
      of hypertensives at higher cardiovascular risk.

PMID- 15194474
TI  - HIV protease inhibitor ritonavir decreases endothelium-dependent vasorelaxation
      and increases superoxide in porcine arteries.
AB  - OBJECTIVE: Although HIV Protease inhibitors significantly reduce the viral load,
      they are associated with increased risk of cardiovascular disease. The aim of
      this study was to investigate the effects of HIV protease inhibitor ritonavir on
      vascular endothelial cell function. METHODS: Porcine carotid arteries were
      perfusion-cultured for 24 h as controls or with 15 microM of ritonavir. Vessels
      were precontracted with norepinephrine followed by endothelium-dependent
      vasorelaxation with acetylcholine. Rings of vessels were cultured as controls or
      with ritonavir for 24 h and basal and NADPH-stimulated superoxide levels were
      determined using lucigenin-enhanced chemiluminescence. Superoxide levels in situ
      were also examined using dihydroethidium (DHE) staining, and nitrotyrosine levels
      were examined using a nitrotyrosine antibody. RESULTS: Endothelium-dependent
      vasorelaxation was significantly reduced in ritonavir-treated vessels compared to
      controls. There were significant increases in basal and NADPH-stimulated
      superoxide production in vessel rings treated with ritonavir compared to control
      vessels. Dihydroethidium staining and nitrotyrosine staining were also elevated
      in endothelial cells of ritonavir-treated vessels, indicating increased
      superoxide production and increased oxidative stress, respectively, in ritonavir
      treated vessels compared to controls. CONCLUSIONS: These data demonstrate that
      HIV protease inhibitor ritonavir causes a significant reduction in endothelium
      dependent vasorelaxation in cultured porcine carotid arteries. Increased
      oxidative stress may be a possible mechanism of HIV protease inhibitor ritonavir
      induced endothelial dysfunction.

PMID- 15194476
TI  - Heme deficiency causes apoptosis but does not increase ROS generation in HeLa
      cells.
AB  - Mitochondria provide cellular energy supply via respiration and are the major
      sites for the generation of reactive oxygen species (ROS). Mitochondria also play
      a fundamental role in apoptosis. Heme is a key factor in mitochondrial function.
      Defective heme synthesis or altered heme metabolism is associated with numerous
      diseases. Here we investigated the molecular mechanism by which heme promotes
      HeLa cell growth and survival. We found that heme deficiency-induced apoptosis
      involves the release of cytochrome c and the activation of caspase 3. However,
      heme deficiency-induced apoptosis appears to occur by a unique mechanism distinct
      from those known to mediate mitochondrial-dependent apoptosis. Specifically, our
      data show that heme deficiency causes apoptosis in a pathway that is independent
      of ROS generation and the collapse of mitochondrial membrane potential. These
      results provide insights into how defective heme synthesis or altered heme
      metabolism causes diseases and how heme may control cell growth and cell death.

PMID- 15194477
TI  - Intramolecular disulfide bonds are required for folding hydrolase B into a
      catalytically active conformation but not for maintaining it during catalysis.
AB  - Carboxylesterases represent a large class of hydrolytic enzymes that are involved
      in lipid metabolism, pharmacological determination, and detoxication of
      organophosphorus pesticides. These enzymes have several notable structural
      features including two intramolecular disulfide bonds. This study was undertaken
      to test the hypothesis that the disulfide bonds are required during catalysis by
      stabilizing the catalytically active conformation. Hydrolase B, a rat liver
      microsomal carboxylesterase, was reduced by dithiothreitol, electrophoretically
      separated and assayed for hydrolysis. Contrary to the hypothesis, reduced
      hydrolase B was as active as the native enzyme on the hydrolysis of 1
      naphthylacetate, and sulfhydryl alkylation following reduction caused no changes
      in the hydrolytic activity. Interestingly, substitution of a disulfide bond
      forming cysteine with an alanine caused marked reduction or complete loss of the
      catalytic activity, suggesting that disulfide bond formation plays a role in the
      biosynthetic process of hydrolase B. In support of this notion, refolding
      experiments restored a significant amount of hydrolytic activity when hydrolase B
      was unfolded with urea alone. In contrast, little activity was restored when
      unfolding was performed in the presence of reducing agent dithiothreitol. These
      results suggest that formation of the disulfide bonds plays a critical role in
      folding hydrolase B into the catalytically active conformation, and that the
      disulfide bonds play little role or function redundantly in maintaining this
      conformation during catalysis.

PMID- 15194478
TI  - Isolation and characterization of three novel Gla-containing Conus marmoreus
      venom peptides, one with a novel cysteine pattern.
AB  - One defining characteristic of Conus venom peptides is the high frequency of
      posttranslational modifications found. We report the discovery and initial
      characterization of three novel gamma-carboxyglutamic acid (Gla)-containing
      conotoxins, Gla-MrII, Gla-MrIII, and Gla-MrIV, isolated from the venom of the
      mollusc-hunting cone snail Conus marmoreus. Peptide Gla-MrII, a 50 amino acid
      residue peptide, carries eight cysteine residues arranged in a novel cysteine
      pattern, and five gamma-carboxyglutamic acid residues. The monoisotopic molecular
      mass was determined by electrospray ionization mass spectrometry to 5860.23 Da,
      consistent with the peptide having the cysteine residues disulphide-bonded and
      having a free acid C-terminus. Peptides Gla-MrIII and Gla-MrIV each contain two
      gamma-carboxyglutamic acid residues and share little sequence similarity to
      previously identified conotoxins. Both peptides contain four cysteine residues
      that are positioned in the linear sequence in a manner reminiscent of conotoxins
      belonging to cysteine scaffold superfamily T (scaffold T-1). Determination of the
      monoisotopic molecular masses revealed that Gla-MrIII is amidated at its C
      terminus while Gla-MrIV has a free C-terminal acid.

PMID- 15194479
TI  - Bacterial heat shock protein 60 may increase epithelial cell migration through
      activation of MAP kinases and inhibition of alpha6beta4 integrin expression.
AB  - Exogenous heat shock proteins may modify cell behavior of infected epithelium.
      The effect of heat shock protein 60 (hsp60) of Actinobacillus
      actinomycetemcomitans and Escherichia coli, and human recombinant hsp60 on
      migration of HaCaT skin keratinocytes was studied using the Boyden chamber assay.
      Hsp60 from different species increased cell migration by two- to fivefold and
      this effect was inhibited by ERK inhibitor PD 98059, p38 inhibitor SB 203580, and
      a function-blocking epidermal growth factor receptor (EGFR) antibody. Hsp60
      reduced the expression of alpha6-integrin mRNA and its protein levels on the cell
      surface but had no effect on the expression of beta4, beta1, alpha1, alpha5 or
      alphav integrin subunits. Hsp60 also significantly inhibited cell adhesion to
      laminin-5, a ligand of alpha6beta4 integrin. These results suggest that exogenous
      hsp60 released from bacteria or inflammatory cells may promote epithelial cell
      migration through activation of EGFR and MAP kinases, and inhibition of
      alpha6beta4 integrin expression.

PMID- 15194480
TI  - Delivery of ferric ion to mouse spermatozoa is mediated by lipocalin
      internalization.
AB  - The aim of this study was to illustrate the further process of 24p3 protein after
      association with epididymal spermatozoa. We have previously identified a caput
      initiated 24p3 protein, which interacts with the spermatozoa surface in vitro. In
      the present study, we investigate another role of the 24p3 protein with
      spermatozoa. Mouse epididymal spermatozoa exhibit the ability to bind
      spontaneously with exogenous 24p3 protein, a part of which is further
      internalized into the spermatozoa in epididymal caput. We have now focused on
      this issue using freshly prepared spermatozoa from caudal region of epididymis.
      First, the cytosolic fractionation of spermatozoa has revealed that biotinylated
      24p3 protein signal could be detected by supplying biotinylated protein under 37
      degrees C incubation after 30 min at this experiment. Further, flow cytometric
      analysis of FITC-protein containing spermatozoa has revealed two distinct types
      of fluorescent spermatozoa, and microscopical experimentation with fluorescent
      FITC-24p3 protein has shown that the 24p3 protein did accumulate in the cytosolic
      portion of spermatozoa. All of these events, which showed protein uptake into the
      cell, demonstrated time- and temperature-dependence of endocytotic
      characteristics, these constituting the critical points in the process of
      endocytosis for spermatozoa as for other cells. Using a fluorometric method, the
      binding affinities of ferrous ion and ferric ion to 24p3 protein were shown to be
      (1.5+/-0.2)x10(6) and (3.0+/-0.4)x10(7)M(-1), respectively. We have also
      determined the internalization of this protein in the transition of iron into
      spermatozoa. We report here that spermatozoa, from the caudal epididymis,
      demonstrate the ability to bind with 24p3 protein and further internalize it and
      deliver the ferric ion to the spermatozoa via protein internalization. We suggest
      that the 24p3 protein plays a physiological role in spermatozoa in the context of
      protein-ligand complex internalization.

PMID- 15194482
TI  - Cloning and heterologous expression of a novel insecticidal gene (tccC1) from
      Xenorhabdus nematophilus strain.
AB  - We have identified and cloned a novel toxin gene (tccC1/xptB1) from Xenorhabdus
      nematophilus strain isolated from Korea-specific entomophagous nematode
      Steinernema glaseri MK. The DNA sequence of cloned toxin gene (3048 bp) has an
      open reading frame encoding 1016 amino acids with a predicted molecular mass of
      111058 Da. The toxin sequence shares 50-96% identical amino acid residues with
      the previously reported tccC1 cloned from X. nematophilus, Photorhabdus
      luminescens W14 P. luminescens TTO1, and Yersinia pestis CO92. The toxin gene was
      successfully expressed in Escherichia coli, and the recombinant toxin protein
      caused a rapid cessation in mortality of Galleria mellonella larvae (80% death of
      larvae within 2 days). Conclusively, the heterologous expression of the novel
      gene tccC1 cloned into E. coli plasmid vector produced recombinant toxin with
      high insecticidal activity.

PMID- 15194481
TI  - The human Ski-interacting protein functionally substitutes for the yeast PRP45
      gene.
AB  - The PRP45 gene has been identified as encoding a protein involved in mRNA
      splicing that is essential in Saccharomyces cerevisiae. PRP45's human homolog
      SKIP has been identified as a mediator of transcriptional programming in a
      variety of signal transduction pathways including TGFbeta, nuclear hormones,
      Notch, and retinoblastoma signaling. However, Skip has been also identified in
      purified spliceosomal complexes but an explicit role in splicing has not been
      identified in mammalian cells. To determine if the Skip protein could function as
      a splicing factor we investigated if the SKIP gene could functionally complement
      the yeast PRP45 gene. We show that SKIP complements the PRP45 deletion and
      rescues the lethal phenotype. These results show that the human SKIP gene can
      functionally substitute for the mRNA splicing gene PRP45 of S. cerevisiae.

PMID- 15194483
TI  - Somatic DNA recombination yielding circular DNA and deletion of a genomic region
      in embryonic brain.
AB  - In this study, a mouse genomic region is identified that undergoes DNA
      rearrangement and yields circular DNA in brain during embryogenesis. External
      region-directed inverse polymerase chain reaction on circular DNA extracted from
      late embryonic brain tissue repeatedly detected DNA of this region containing
      recombination joints. Wide-range genomic PCR and digestion-circularization PCR
      analysis showed this region underwent recombination accompanied with deletion of
      intervening sequences, including the circularized regions. This region was mapped
      by fluorescence in situ hybridization to C1 on mouse chromosome 16, where no gene
      and no physiological DNA rearrangement had been identified. DNA sequence in the
      region has segmental homology to an orthologous region on human chromosome 3q.13.
      These observations demonstrated somatic DNA recombination yielding genomic
      deletions in brain during embryogenesis.

PMID- 15194484
TI  - Pyronaridine, a novel modulator of P-glycoprotein-mediated multidrug resistance
      in tumor cells in vitro and in vivo.
AB  - One of the major mechanisms of multidrug resistance (MDR) in cancer therapy is
      the overexpression of P-glycoprotein (Pgp). We previously reported that
      pyronaridine (PND), a synthetic quinoline derivative in the clinic for the
      treatment of malaria infections, was capable of reversing MDR phenotype in Pgp
      overexpressing tumor cells. Here we further evaluated the reversal activity of
      PND using two Pgp-overexpressing human tumor cell lines: K562/A02 and MCF-7/ADR.
      PND significantly enhanced the sensitivity of K562/A02 and MCF-7/ADR cells to
      doxorubicin (DOX), but had no such effect on the parent K562 and MCF-7 cells. The
      MDR-modulating effect of PND persisted for longer than 24h after removal of the
      agent from the culture. In nude mice bearing K562/A02 xenografts PND
      significantly enhanced the antitumor activity of DOX when given intraperitoneally
      or orally without increasing the toxicity of DOX. Our observations suggest that
      PND represents a promising agent for overcoming MDR in cancer therapy.

PMID- 15194485
TI  - Regulation of apical surface fluid and protein secretion in human airway
      epithelial cell line Calu-3.
AB  - We evaluated the relationship between apical surface fluid (ASF) and protein
      secretion in Calu-3 cells grown at an air-liquid interface. Calu-3 monolayers
      responded to forskolin, a cystic fibrosis transmembrane regulator (CFTR) channel
      agonist, by secreting a significant amount of ASF. Such a response from Calu-3
      monolayers was not observed with CFTR channel blockers glybenclamide and DPC.
      Other ion channel mediators, PGF-2alpha, PMA, DNDS, and DIDS, had no effect on
      Calu-3 ASF secretion. Forskolin decreased Calu-3 protein secretion and
      glybenclamide increased protein secretion. Similarly, forskolin decreased Calu-3
      lysozyme secretion, whereas glybenclamide and DPC increased lysozyme secretion.
      We observed significant changes in Calu-3 fluid and protein secretions with ion
      channel mediators known to alter CFTR activity. Our results demonstrate a
      functional link between fluid and protein secretions in Calu-3 apical surface and
      suggested a possible involvement of CFTR in these processes.

PMID- 15194486
TI  - Role of Phe308 in the seventh transmembrane domain of the AT2 receptor in ligand
      binding and signaling.
AB  - Studies on Angiotensin II (Ang II) receptor type AT1 have suggested that
      interaction between the two highly conserved residues, Tyr292 in the 7th
      transmembrane domain (TMD) and the Asp74 in the 2nd TMD, is critical for linking
      the Ang II binding and AT1 receptor-Gq protein coupling. In the Ang II receptor
      type AT2, the Asp is conserved (Asp90 in 2nd TMD), however, there is no Tyr
      residue in the 7th TMD and Phe308 occupies the analogous position to Tyr292 of
      the AT1. Replacing this Phe308 with Ala reduced receptor affinity to peptidic
      ligands (125)I-Ang II (K(d) = 0.37 nM) and (125)I-CGP42112A (K(d) = 0.56 nM), but
      retained the ability of the AT2 to reduce cGMP levels in Xenopus oocytes. Thus,
      the Phe308 of the AT2 does not mimic the role of Tyr292 of the AT1 in the
      receptor activation upon Ang II binding. We have also shown that the M8 mutant of
      the AT2 with the 7th TMD similar to that of wild type AT2 can couple to PLC like
      the AT1 and bind the AT2-specific ligands with high affinity. Since the Ang II is
      shown to bind to both the AT1 and the AT2 in an identical manner, we propose that
      the absence of Tyr in the 7th TMD of the AT2 does not prevent the receptor from
      coupling to Gq-protein, rather may contribute to the freedom of the AT2 to couple
      to trimeric G-proteins in both G- betagamma dependent and independent manners
      upon Ang II binding.

PMID- 15194487
TI  - Adenoviral delivery of human connexin37 induces endothelial cell death through
      apoptosis.
AB  - Gap junction channels formed of connexins directly link the cytoplasm of adjacent
      cells and have been implicated in intercellular signaling that may regulate the
      functions of vascular cells. To facilitate connexin manipulation and analysis of
      their roles in adult endothelial cells, we developed adenoviruses containing the
      vascular connexins (Cx37, Cx40, and Cx43). We infected cultured human umbilical
      vein endothelial cells with control or connexin adenoviruses. Connexin expression
      was verified by immunoblotting and immunofluorescence. Infection with the Cx37
      adenovirus (but not control or other connexin adenoviruses) led to a dose
      dependent death of the endothelial cells that was partially antagonized by the
      gap junction blocker alpha-glycyrrhetinic acid and altered the intercellular
      transfer of Lucifer yellow and neurobiotin. Cell morphology, Annexin V and TUNEL
      staining, and caspase 3 assays all implicated apoptosis in the cell death. These
      data suggest that connexin-specific alterations of intercellular communication
      may modulate endothelial cell growth and death.

PMID- 15194489
TI  - Insulin secretory defects and impaired islet architecture in pancreatic beta-cell
      specific STAT3 knockout mice.
AB  - Normal islet formation and function depends on the action of various growth
      factors operating in pre- and postnatal development; however, the specific
      physiological function of each factor is largely unknown. Loss-of-function
      analyses in mice have provided little information so far, perhaps due to
      functional redundancies of the growth factors acting on the pancreas. The present
      study focuses on the role of the transcription factor STAT3 in insulin-producing
      cells. STAT3 is one of the potential downstream mediators for multiple growth
      factors acting on the pancreatic beta-cells, including betacellulin, hepatocyte
      growth factor, growth hormone, and heparin-binding EGF-like growth factor. To
      elucidate its role in the beta-cells, the STAT3 gene was disrupted in insulin
      producing cells in mice (STAT3-insKO), using a cre-mediated gene recombination
      approach. Unexpectedly, STAT3-insKO mice exhibited an increase in appetite and
      obesity at 8 weeks of age or older. The mice showed partial leptin resistance,
      suggesting that expression of the RIP (rat insulin promoter)-cre transgene in
      hypothalamus partially inhibited the appetite-regulating system. Intraperitoneal
      glucose tolerance tests, performed in non-obese 5-week-old mice, showed that the
      STAT3-insKO mice were glucose intolerant. Islet perifusion experiments further
      revealed a deficiency in early-phase insulin secretion. Whereas islet insulin
      content or islet mass was not affected, expression levels of GLUT2, SUR1, and
      VEGF-A were significantly reduced in STAT3-insKO islets. Interestingly, STAT3
      insKO mice displayed impaired islet morphology: alpha-cells were frequently seen
      in central regions of islets. Our present observations demonstrate a unique role
      of STAT3 in maintaining glucose-mediated early-phase insulin secretion and normal
      islet morphology.

PMID- 15194488
TI  - Hepatocyte growth factor attenuates cerebral ischemia-induced learning
      dysfunction.
AB  - Hepatocyte growth factor (HGF) acts as an organotropic factor for regeneration
      and protection in various organs and has the ability to attenuate cerebral
      ischemia-induced cell death. However, the effect of HGF on learning and memory
      function after a cerebral ischemic event is unknown. We demonstrate here that
      administration of human recombinant HGF (hrHGF) into the ventricle reduced the
      prolongation of the escape latency in the acquisition and retention tests in the
      water maze task on days 12-28 after microsphere embolism-induced cerebral
      ischemia. In addition, disruption of the blood-brain barrier at the early stage
      after microsphere embolism, which was determined by FITC-albumin leakage, was
      markedly reduced by treatment with hrHGF. We demonstrated that this effect of
      hrHGF on the blood-brain barrier was associated with protection against the
      apoptotic death of the cerebral endothelial cells at the early stage after the
      ischemia. These results suggest that hrHGF can prevent the learning and memory
      dysfunction soon after sustained cerebral ischemia by protecting against injury
      to the endothelial cells. The use of HGF may be a potent strategy for the
      treatment of cerebrovascular diseases, including cerebral infarct and vascular
      dementia.

PMID- 15194490
TI  - Delta12-Prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits
      ubiquitin-protein aggregation without proteasome inhibition.
AB  - To investigate molecular mechanisms linking inflammation with neurodegeneration,
      we treated neuronal cultures with prostaglandins (PGs), which are mediators of
      inflammation. PGA1, D2, J2, and Delta12-PGJ2, but not PGE2, reduced the viability
      and raised the levels of ubiquitinated proteins in the neuronal cells. PGJ2 and
      its metabolite, Delta12-PGJ2, were the most potent of the four neurotoxic PGs
      tested in inducing both effects. To address the mechanism by which these agents
      lead to the accumulation of ubiquitinated proteins, we tested their effects on
      neuronal ubiquitin hydrolases UCH-L1 and UCH-L3 as well as on proteasome
      activity. Notably, Delta12-PGJ2 inhibited the activities of UCH-L1 (K(i)
      approximately 3.5 microM) and UCH-L3 (K(i) approximately 8.1 microM) without
      affecting proteasome activity. Intracellular aggregates containing ubiquitinated
      proteins were detected in Delta12-PGJ2-treated cells, indicating that these
      aggregates can form independently of proteasome inhibition. In conclusion,
      impairment of ubiquitin hydrolase activity, such as triggered by Delta12-PGJ2,
      may be an important contributor to neurodegeneration associated with accumulation
      of ubiquitinated proteins and inflammation.

PMID- 15194491
TI  - Initial characterization of an uromodulin-like 1 gene on human chromosome
      21q22.3.
AB  - We have isolated a novel gene, designated UMODL1, similar to uromodulin
      (UMOD)/Tamm-Horsfall glycoprotein, on human chromosome 21q22.3. Uromodulin like-1
      (UMODL1) consists of 22 exons and spans approximately 80 kb in a direction from
      centromere to telomere. Two major transcripts produced by alternative splicing
      have been identified. These transcripts contain open reading frames of 4125 and
      3741 bp encoding proteins of 1374 and 1246 amino acids, respectively. Expression
      of UMODL1 mRNA was detected only in 14 human tissues, e.g., kidney, testis, and
      fetal thymus at low level. Interestingly, two gene products (UMODL1L and UMODL1S)
      contain multiple domains including whey acidic protein, sea urchin sperm protein,
      enterokinase, and agrin, zona pellucida domain, and so on. Both proteins seemed
      to localize in cytoplasm, but UMODL1 is likely to be ubiquitinated and rapidly
      degraded in HEK293 cells. This gene may be a potent candidate for Down syndrome
      or bipolar affective disorder.

PMID- 15194492
TI  - Direct involvement of hydrogen peroxide in curvature of wheat coleoptile in blue
      light-treated and dark-grown coleoptiles.
AB  - Blue-light-induced photomorphogenesis is the sum total of a sequence of phenomena
      involving absorption of light by specific receptors, generation of a signal,
      processing transmembrane transport of signal, and the activation of a cascade of
      reactions in the cell interior. Though four blue-light receptors cryptochrome1,
      cryptochrome2, phototropin1, and phototropin2 have been identified, the signal
      transduction events associated with blue-light receptor activation are not
      understood. In this report, we demonstrate the generation and spatiotemporal
      distribution of H(2)O(2) in wheat coleoptile in response to blue light.
      Interception of the free-radical generation pathways dithiothreitol and propyl
      gallate rendered wheat coleoptile tips phototropically non-responsive. Unilateral
      application of H(2)O(2) onto the sub-apical region of a growing coleoptile
      brought about curvature in dark. Blue light also caused lipid peroxidation and
      augmented membrane rigidity of coleoptile cell membranes. We conclude that
      H(2)O(2) can act as a translocating second messenger that could bring about
      coleoptile curvature, and the signaling events may trigger Ca(2+) signaling
      cascades, changes in gene expression, and protein modifications.

PMID- 15194493
TI  - Establishment of Cre/LoxP recombination system in transgenic rats.
AB  - The rat has offered an important animal model in biomedical research including
      surgical procedure. However, advanced genetic manipulation has progressed less
      far in the rat than in the mouse. Here we report the Cre/LoxP transgenic rat
      system, demonstrating conditional chromosomal translocation both in the
      fertilization and adult stage, spatio-temporal gene controlling by catheter-based
      adenoviral gene transfer, and muscular fusion events in the limb transplant.
      Taking advantage of the larger body size of the rat than the mouse, this rat
      system provides a potential value to evaluate biomedical and therapeutic
      significance for gene therapy and regenerative medicine.

PMID- 15194494
TI  - Aspartate(69) of the calcitonin-like receptor is required for its functional
      expression together with receptor-activity-modifying proteins 1 and -2.
AB  - The calcitonin-like receptor (CLR) associated with receptor-activity-modifying
      proteins (RAMP) 1 or -2 recognizes calcitonin gene-related peptide (CGRP) and
      adrenomedullin (AM), respectively. The amino acid sequence CNRTWDGWLCW
      corresponding to residues 64-74 in the extracellular N-terminus of the CLR is
      conserved. The Asp(69) (D(69)) is present in all family B1 G-protein-coupled
      receptors. Here the D(69) of a V5-tagged mouse CLR has been mutated to Ala (A),
      Glu (E), and Asn (N). The function of the intact and the mutant CLR was
      investigated in COS-7 cells coexpressing myc-tagged mouse RAMP1 or -2. In
      CLR/RAMP1 and -2 expressing cells CGRP and AM stimulated cAMP formation with an
      EC(50) of 0.17 and 0.50 nM, respectively. The expression of the D69A, D69E, and
      D69N mutants at the cell surface was comparable to that of the intact CLR. cAMP
      stimulation by CGRP and AM was abolished in the D69A mutant. With the D69E mutant
      the EC(50) of CGRP and AM were 1000-fold higher than those with the intact CLR.
      With the D69N mutant the EC(50) of CGRP was 0.48 nM and that of AM 0.44 nM, but
      the maximal cAMP formation was reduced to 24% and to 12% of cells with the intact
      CLR. Co-immunoprecipitation of RAMP1 with the CLR, indicating complex formation,
      was reduced with the D69A, D69N, and D69E mutants. RAMP2 co-precipitated with the
      mutant receptors indistinguishable from the intact CLR. In conclusion, mutation
      of D69 to N, E or A in the CLR did not affect its expression at the cell surface,
      but impaired or abolished the CGRP and AM receptor function in the presence of
      RAMP1 and -2, respectively.

PMID- 15194495
TI  - Cardiac disease due to random mitochondrial DNA mutations is prevented by
      cyclosporin A.
AB  - Mice expressing an error-prone mitochondrial DNA polymerase rapidly accumulate
      random mutations in mitochondrial DNA. Expression of the transgene in the heart
      leads to dilated cardiomyopathy accompanied by a wave of apoptosis in
      cardiomyocytes, and a vigorous and persistent protective response, including
      upregulation of the anti-apoptotic protein, Bcl-2. To investigate the role of the
      mitochondrial permeability transition pore in the development of disease, we
      treated mice with cyclosporin A (CsA), an inhibitor of pore opening. Drug
      treatment prevented cardiac dilatation, transgene-specific apoptosis, and
      upregulation of Bcl-2. It also rescued hearts from the profound decrease in
      connexin 43, which characterizes the dilatated heart. Treatment with FK506, which
      like CsA inhibits cytoplasmic calcineurin but not the mitochondrial pore, did not
      affect disease development, suggesting that the relevant target of CsA was the
      mitochondrial pore. These data implicate breakdowns in the mitochondrial
      permeability barrier in pathogenesis of elevated frequencies of mtDNA mutations.

PMID- 15194496
TI  - Susceptibility to SARS coronavirus S protein-driven infection correlates with
      expression of angiotensin converting enzyme 2 and infection can be blocked by
      soluble receptor.
AB  - The angiotensin converting enzyme 2 (ACE2) has been identified as a receptor for
      the severe acute respiratory syndrome associated coronavirus (SARS-CoV). Here we
      show that ACE2 expression on cell lines correlates with susceptibility to SARS
      CoV S-driven infection, suggesting that ACE2 is a major receptor for SARS-CoV.
      The soluble ectodomain of ACE2 specifically abrogated S-mediated infection and
      might therefore be exploited for the generation of inhibitors. Deletion of a
      major portion of the cytoplasmic domain of ACE2 had no effect on S-driven
      infection, indicating that this domain is not important for receptor function.
      Our results point to a central role of ACE2 in SARS-CoV infection and suggest a
      minor contribution of the cytoplasmic domain to receptor function.

PMID- 15194498
TI  - Phosphorylation of p38 MAPK and its downstream targets in SARS coronavirus
      infected cells.
AB  - Severe acute respiratory syndrome (SARS) has become a global public health
      emergency. Understanding the molecular mechanisms of SARS-induced cytopathic
      effects (CPEs) is a rational approach for the prevention of SARS, and an
      understanding of the cellular stress responses induced by viral infection is
      important for understanding the CPEs. Polyclonal antibodies, which recognized
      nucleocapsid (N) and membrane (M) proteins, detected viral N and M proteins in
      virus-infected Vero E6 cells at least 6 and 12 h post-infection (h.p.i.),
      respectively. Furthermore, detection of DNA ladder and cleaved caspase-3 in the
      virus-infected cells at 24h.p.i. indicated that SARS-CoV infection induced
      apoptotic cell death. Phosphorylation of p38 MAPK was significantly up-regulated
      at 18 h.p.i. in SARS-CoV-infected cells. The downstream targets of p38 MAPK,
      MAPKAPK-2, HSP-27, CREB, and eIF4E were phosphorylated in virus-infected cells.
      The p38 MAPK inhibitor, SB203580, inhibited effectively phosphorylation of HSP
      27, CREB, and eIF4E in SARS-CoV-infected cells. However, viral protein synthesis
      was not affected by treatment of SB203580.

PMID- 15194497
TI  - Somatostatin regulates intracellular signaling in human carotid endothelial
      cells.
AB  - Somatostatin (somatotropin release inhibitory factor; SRIF) is an endogenous
      peptide produced at sites of inflammation, making the SRIF a candidate in
      regulating vascular inflammation. We have used primary human coronary artery
      endothelial cells (hCAEC) as a model to study SRIF's vascular actions. RT-PCR
      analysis of hCAEC total mRNA demonstrated the presence of the sst(4) receptor
      subtype, providing a target for SRIF intracellular signaling. Western blotting
      with phospho-specific ERK1/2 antibodies showed that SRIF-14 acutely inhibited
      basal phosphorylation of the extracellular regulated kinases (ERK1/2) by 80%. In
      addition, SRIF-14 treated hCAEC cell lysates showed a 2.6-fold increase in
      phosphatase activity, which was inhibited by sodium vanadate. Furthermore, SRIF
      14 appeared to be anti-inflammatory in hCAEC as IL-1beta-induced adhesion
      molecule expression was reduced by 50%. Together, these results show that the
      coronary artery endothelium is a direct target of SRIF action.

PMID- 15194499
TI  - The primary defect in glycogen synthase activity is not based on increased
      glycogen synthase kinase-3alpha activity in diabetic myotubes.
AB  - The mechanism responsible for the diminished activation of glycogen synthase (GS)
      in diabetic myotubes remains unclear, but may involve increased activity and/or
      expression of glycogen synthase kinase-3 (GSK-3). In myotubes established from
      type 2 diabetic and healthy control subjects we determined GS activity ratio,
      protein expression, and activity of GSK-3alpha and beta under basal and insulin
      stimulated conditions when precultured in increasing insulin concentrations. In
      myotubes precultured at low insulin concentrations acute insulin stimulation
      increased GS activity more in control than in diabetic subjects, whereas the
      corresponding GSK-3alpha but not GSK-3beta activity was significantly reduced by
      acute insulin treatment in both groups. However, in myotubes precultured at high
      insulin concentrations the effect of insulin on GS and GSK-3alpha activity was
      blunted in both groups. The protein expression of GSK-3alpha or beta was
      unaffected. In conclusion, myotubes with a primary defect in GS activity express
      insulin responsive GSK-3alpha, suggesting that failure of insulin to decrease GS
      phosphorylation involves abnormal activity of another kinase or phosphatase.

PMID- 15194500
TI  - Local database and the search program for proteomic analysis of sperm proteins in
      the ascidian Ciona intestinalis.
AB  - Separation of proteins by two-dimensional electrophoresis and following mass
      spectrometry (MS) is now a conventional technique for proteomic analysis. For
      proteomic analysis of a certain tissue with a limited information of primary
      structures of proteins, we have developed an analytical system for peptide mass
      fingerprinting in gene products in the testis of the ascidian Ciona intestinalis.
      Ciona sperm proteins were separated by two-dimensional gel electrophoresis and
      the tryptic fragments were subjected to MALDI-TOF/MS. The mass pattern was
      searched against on-line databases but resulted in less identification of these
      proteins. We have constructed a MS database from Ciona testis ESTs and the genome
      draft sequence, along with a newly devised, perl-based search program PerMS for
      peptide mass fingerprinting. This system could identify more than 80% of Ciona
      sperm proteins, suggesting that it could be widely applied for proteomic analysis
      for a limited tissue with less genomic information.

PMID- 15194501
TI  - Doppel-induced Purkinje cell death is stoichiometrically abrogated by prion
      protein.
AB  - Mice devoid of prion protein (PrP) exhibiting ataxia and Purkinje cell
      degeneration, such as Ngsk Prnp(-/-) mice, ectopically express PrP-like protein,
      Dpl, in neurons including Purkinje cells. In this study, two types of transgenic
      (tg) mice expressing Dpl in neurons, tg(N-Dpl), or Purkinje cells only, tg(P
      Dpl), were generated on the background of non-ataxic Zrch I Prnp(-/-) mice. In
      contrast to the tg mice with the Prnp(+/+) background, both tg mice with the
      Prnp(-/-) alleles developed Purkinje cell degeneration after incubation periods
      inversely correlated to the levels of Dpl. Some tg mice hemizygous for Prnp
      allele also developed disease but much later than those carrying the Prnp(-/-)
      alleles. This indicates that Dpl expressed by Purkinje cells itself is toxic to
      the cells, and that the neurotoxicity is stoichiometrically antagonized by PrP.

PMID- 15194502
TI  - Ligand stimulation of CD155alpha inhibits cell adhesion and enhances cell
      migration in fibroblasts.
AB  - CD155 (poliovirus receptor) localizes in cell-matrix adhesions and cell-cell
      junctions, but its role in the regulation of cell adhesion and cell motility has
      not been investigated. We identified a conserved immunoreceptor tyrosine-based
      inhibitory motif (ITIM) in the cytoplasmic domain of human CD155alpha. The ITIM
      was tyrosine-phosphorylated upon binding of anti-CD155 monoclonal antibody D171,
      poliovirus, and DNAM-1 (CD226) to human CD155alpha, and recruited SH2-domain
      containing tyrosine phosphatase-2 (SHP-2). After CD155alpha stimulation with its
      ligands, cell adhesion was inhibited and cell motility was enhanced, effects that
      were associated with the phosphorylation of ITIM by Src kinases and accompanied
      by dephosphorylation of focal adhesion kinase and paxillin. These effects were
      abolished by introducing a point-mutation in Y398F into the ITIM of CD155alpha
      and by coexpression of a dominant negative SHP-2 mutant with CD155alpha. These
      results suggest that CD155alpha plays a role in the regulation of cell adhesion
      and cell motility.

PMID- 15194503
TI  - Inhibitory effects of tannin on human salivary alpha-amylase.
AB  - Here, we first report on the effectiveness and specificity of tannin inhibition
      of 2-chloro-4-nitrophenyl-4-O-beta-d-galactopyranosylmaltoside hydrolysis that is
      catalyzed by human salivary alpha-amylase (HSA). Tannin was gallotannin in which
      quinic acid was esterified with 2-7 units of gallic acid. A number of studies
      establish that polyphenols-like tannins-may prevent oral diseases, e.g., dental
      caries. Kinetic analyses confirmed that the inhibition of hydrolysis is a mixed
      non-competitive type and only one molecule of tannin binds to the active site or
      the secondary site of the enzyme. Since Dixon plots were linear, product
      formation could be excluded from the enzyme-substrate-inhibitor complex (ESI).
      Kinetic constants calculated from secondary plots and non-linear regression are
      almost identical, thereby confirming the suggested model. Kinetic constants
      (K(EI) = 9.03 microgmL(-1), K(ESI) = 47.84 microgmL(-1)) show that tannin is as
      an effective inhibitor of HSA as acarbose and indicate a higher stability for the
      enzyme-inhibitor complex than ESI.

PMID- 15194504
TI  - The two major imatinib resistance mutations E255K and T315I enhance the activity
      of BCR/ABL fusion kinase.
AB  - The resistance to the tyrosine kinase inhibitor imatinib in BCR/ABL-positive
      leukemias is mostly associated with mutations in the kinase domain of BCR/ABL,
      which include the most prevalent mutations E255K and T315I. Intriguingly, these
      mutations have also been identified in some patients before imatinib treatment.
      Here we examined the effects of these mutations on the kinase activity of a
      BCR/ABL kinase domain construct that also contained the SH3 and SH2 domains. When
      expressed in COS7 cells, the BCR/ABL construct with either E255K or T315I
      exhibited not only the resistance to imatinib but also the increase in activity
      to induce autophosphorylation as well as tyrosine phosphorylation of various
      cellular proteins, which included STAT5. The mutant kinases also showed increased
      activities in in vitro kinase assays. These results raise a possibility that the
      major imatinib resistance mutations E255K and T315I may confer the growth
      advantage on leukemic cells to expand in the absence of selective pressure from
      imatinib treatment.

PMID- 15194505
TI  - A cleavable signal peptide is required for the full function of the polytopic
      inner membrane protein FliP of Escherichia coli.
AB  - FliP is a rare bacterial polytopic membrane protein synthesized with a cleavable
      highly hydrophobic signal peptide. It is essential for flagellum assembly and for
      bacterial motility. In this study, we assessed specificity of signal peptide for
      the FliP function. Like the wild type FliP, two altered FliPs with more
      hydrophilic Tat- or Sec-dependent signal peptides were both able to restore the
      motility of the DeltafliP mutant. Therefore, the Tat- and the Sec-dependent
      signal peptides seemed to be compatible with the FliP function. Moreover,
      deletion of the FliP signal peptide or replacing it with the transmembrane
      segment of MotA severely impaired the FliP function. Together these results
      showed that a cleavable signal peptide is required for the full function of FliP.

PMID- 15194506
TI  - Association of G72/G30 with schizophrenia in the Chinese population.
AB  - Recently, the G72 gene was reported to be associated with schizophrenia in the
      French Canadian and Russian populations. Here, we report the results obtained
      from the study of six single-nucleotide polymorphisms (SNPs: rs3916965,
      rs3916967, rs2391191, rs1935062, rs778293, and rs3918342), which span an 82-kb
      region covering the complementary DNA sequences of G72 and G30, in 537
      schizophrenia cases and 538 controls of the Han Chinese. In this work, we have
      identified statistically significant differences in allele distributions of two
      markers rs3916965 (P = 0.019) and rs2391191 (P = 0.0010), and a highly
      significant association between haplotype AGAC of the G72/G30 locus (P = 1.7 x
      10(-4)) and schizophrenia. Our data provide further evidence that markers of the
      G72/G30 genes are associated with schizophrenia in a non-Caucasian population.

PMID- 15194507
TI  - Null genotype of glutathione S-transferase M1 is associated with senile cataract
      susceptibility in non-smoker females.
AB  - In the present study, we investigated whether the polymorphisms of glutathione S
      transferase M1 (GSTM1) and T1 (GSTT1) genes are risk factors of cataract among
      Iranian population in a molecular epidemiological way. Blood samples from 150
      subjects with cataract (72 male; 78 female) and 150 age- and sex-matched healthy
      persons were collected. Both patient and control groups were unrelated Iranian
      Muslims. Using PCR-based method, the genotypes were determined. The null GSTM1
      genotype was associated with a 2.38-fold increase in the risk of developing
      cataract (OR=2.38; 95% CI=1.46-3.89; P = 0.0003). After stratification by sex of
      subjects, the association was apparent only among women (OR=3.20; 95% CI=1.58
      6.52; P = 0.0007). The GSTT1 null genotype was associated with a 1.10-fold
      increased risk of developing cataract, but this association was not statistically
      significant. After stratification by sex of subjects, same results were obtained.
      Female patients with null genotype for GSTM1 and no history of smoking had a 3.45
      fold increased cataract risk (P < 0.05), whereas females who were null for GSTM1
      and having history of smoking were not at increased risk of cataract.

PMID- 15194508
TI  - Molecular cloning and characterization of a new peptide deformylase from human
      pathogenic bacterium Helicobacter pylori.
AB  - Helicobacter pylori is a gram-negative pathogenic bacterium, which is associated
      with peptic ulcer disease and gastric cancer. It is urgent to discover novel drug
      targets for appropriate antimicrobial agents against this human pathogen. In
      bacteria, peptide deformylase (PDF) catalyzes the removal of a formyl group from
      the N-termini of nascent polypeptides. Due to its essentiality and absence in
      mammalian cells, PDF has been considered as an attractive target for the
      discovery of novel antibiotics. In this work, a new PDF gene (def) from H. pylori
      strain SS1 was cloned, expressed, and purified in Escherichia coli system.
      Sequence alignment shows that H. pylori PDF (HpPDF) shares about 40% identity to
      E. coli PDF (EcPDF). The enzymatic properties of HpPDF demonstrate its relatively
      high activity toward formyl-Met-Ala-Ser, with K(cat) of 3.4s(-1), K(m) of 1.7 mM,
      and K(cat) / K(m) of 2000M(-1)s(-1). HpPDF enzyme appears to be fully active at
      pH between 8.0 and 9.0, and temperature 50 degrees C. The enzyme activity of
      Co(2+)-containing HpPDF is apparently higher than that of Zn(2+)-containing
      HpPDF. This present work thereby supplies a potential platform that facilitates
      the discovery of novel HpPDF inhibitors and further of possible antimicrobial
      agents against H. pylori.

PMID- 15194509
TI  - A comparative study of the subcellular distribution of native and deglycosylated
      gelonin in rat liver and kidney.
AB  - Intravenous injection of gelonin and deglycosylated gelonin led to rapid
      clearance from the blood. Both molecules distributed similarly in liver and
      kidney suggesting that they followed the same pathway. Deglycosylation reduced
      the uptake by a third in liver, but did not affect uptake by kidney. Studies with
      Triton WR1339 showed a classical lysosomal pathway for both molecules. The
      deglycosylated molecule was degraded to a greater extent than native gelonin as
      seen by the presence of acid soluble radioactivity. Cell separation showed that
      while endothelial cells mainly took up native gelonin, Kupffer cells took up the
      deglycosylated molecule.

PMID- 15194510
TI  - Caenorhabditis elegans development requires mitochondrial function in the nervous
      system.
AB  - The mitochondrial respiratory chain (MRC) supplies the majority of the energy
      requirements of most eucaryotic cells. A null mutation in the Caenorhabditis
      elegans nuo-1 gene encoding a subunit of complex I (NADH-ubiquinone
      oxidoreductase) is lethal, leading to a developmental arrest at the third larval
      stage. To identify the tissues that regulate development in response to
      mitochondrial dysfunction, we restored nuo-1 expression with tissue-specific
      promoters. Only expression of nuo-1 ubiquitously or in the nervous system
      supported development to the adult stage. Pharyngeal expression of nuo-1 allowed
      development to proceed to the fourth larval stage. Expression of nuo-1 in the
      body muscles or in the germline had no effect. Furthermore, only ubiquitous or
      nervous system expression of nuo-1 allowed exit from the dauer state. Our results
      indicate that MRC function in the nervous system is needed to send and receive
      signals that control larval development and exit from dauer.

PMID- 15194511
TI  - Asp49 phospholipase A(2)-elaidoylamide complex: a new mode of inhibition.
AB  - The inhibition of phospholipase A(2)s (PLA(2)s) is of pharmacological and
      therapeutic interest because these enzymes are involved in several inflammatory
      diseases. Elaidoylamide is a powerful inhibitor of a neurotoxic PLA(2) from the
      Vipera ammodytes meridionalis venom. The X-ray structure of the enzyme-inhibitor
      complex reveals a new mode of Asp49 PLA(2) inhibition by a fatty acid hydrocarbon
      chain. The structure contains two identical homodimers in the asymmetric unit. In
      each dimer one subunit is rotated by 180 degrees with respect to the other and
      the two molecules are oriented head-to-tail. One molecule of elaidoylamide is
      bound simultaneously to the substrate binding sites of two associated neurotoxic
      phospholipase A(2) molecules. The inhibitor binds symmetrically to the
      hydrophobic channels of the two monomers. The structure can be used to design
      anti-inflammatory drugs.

PMID- 15194512
TI  - Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz
      concentrations in HIV-1 patients treated with standard efavirenz-containing
      regimens.
AB  - Efavirenz (EFV) is metabolized by cytochrome P450 2B6 (CYP2B6) in the liver. We
      analyzed the genotypes of CYP2B6 and their contribution to plasma EFV
      concentrations in 35 EFV-treated patients in International Medical Center of
      Japan. The mean plasma EFV concentration of patients with CYP2B6 *6/*6 (Q172H and
      K262R) (25.4+/-7.5 microM, +/-SD, n = 2) was significantly higher than that of
      patients with genotypes *6 heterozygote (9.9+/-3.3 microM, n = 10) or without
      alleles *6 (8.0+/-2.6 microM, n = 23) (p < 0.0001). To confirm our result, we
      further analyzed nine patients (three with high EFV concentrations and
      arbitrarily selected six with normal EFV concentrations) treated in Osaka
      National Hospital, and it resulted that the only three patients with the high
      concentrations were the *6/*6 holder. EFV dose could be decreased in those
      patients harboring the genotype to reduce toxicity with compromising potency,
      representing the first step of the Tailor-Made therapy of HIV-1 infection.

PMID- 15194513
TI  - The carboxyl-terminal half region of ADAMTS-1 suppresses both tumorigenicity and
      experimental tumor metastatic potential.
AB  - ADAMTS-1 is an ECM-anchored metalloproteinase with proteoglycan-degrading
      activity as well as an angiogenesis inhibiting activity. Here, we examined the
      effects of ADAMTS-1 overexpression on in vivo tumor growth and tumor metastasis.
      Overexpression of only the C-terminal half region of ADAMTS-1, consisting of TSP
      type I motifs and the spacer region, suppressed Chinese hamster ovary (CHO) tumor
      growth in mice. In addition, a significant reduction in tumor metastatic
      potential was observed in ADAMTS-1-transfected CHO cells in an experimental
      metastasis assay. Furthermore, deletional analyses revealed that the C-terminal
      half region of ADAMTS-1 is responsible for its experimental metastasis-inhibitory
      activity. Our data suggest that the C-terminal half region of ADAMTS-1 has
      therapeutic potential as an inhibitor of tumor growth and metastasis.

PMID- 15194514
TI  - Predicting anxiety in magnetic resonance imaging scans.
AB  - This study evaluated a brief screening instrument for predicting psychological
      distress in patients undertaking magnetic resonance imaging (MRI) scans. The
      scale is adapted from Wolpe and Lang's (1964) Fear Survey Schedule (FSS; see
      Lukins, Davan, & Drummond, 1997). Noise and/or confinement were identified as the
      most unpleasant feature of the MRI by 48.3% of 118 outpatients. The MRI-FSS
      (Lukins et al., 1997; 9 items) significantly predicted the number of panic attack
      symptoms and state anxiety experienced during MRI scan better than a range of
      other measures. There was a significant increase in MRI-FSS scores from prescan
      to postscan among those who experienced high levels of anxiety during the scan.
      The MRI-FSS appears to be a useful indicator of likely adverse psychological
      reactions in the MRI scan that is sensitive to the sequelae of the MRI procedure.

PMID- 15194515
TI  - Exercise motivation and adherence in cancer survivors after participation in a
      randomized controlled trial: an attribution theory perspective.
AB  - The purpose of this study was to examine postprogram exercise motivation and
      adherence in cancer survivors who participated in the Group Psychotherapy and
      Home-Based Physical Exercise (GROUP-HOPE; Courneya, Friedenreich, Sela, Quinney,
      & Rhodes, 2002) trial. At the completion of the GROUP-HOPE trial, 46 of 51 (90%)
      participants in the exercise group completed measures of attribution theory
      constructs. A 5-week follow-up self-report of exercise was then completed by 30
      (65%) participants. Correlational analyses indicated that program exercise,
      perceived success, expected success, and affective reactions were strong
      predictors of postprogram exercise. In multivariate stepwise regression analyses,
      program exercise and perceived success were the strongest predictors of
      postprogram exercise. Additionally, perceived success was more important than
      objective success in understanding the attribution process, and it interacted
      with personal control to influence expected success and negative affect. Finally,
      postprogram quality of life and changes in physical fitness were correlates of
      perceived success. We concluded that attribution theory may have utility for
      understanding postprogram exercise motivation and adherence in cancer survivors.

PMID- 15194516
TI  - Does it make sense in a coherent way? Determinants of sense of coherence in
      Swedish women 40 to 50 years of age.
AB  - The aim of this study was to explore how socioeconomic and psychosocial life
      experiences in childhood and at adult age influence the level of sense of
      coherence (SOC) in women. The idea was to seek empirical support for establishing
      whether SOC is an individual construct being developed in early life and
      basically resistant toward adverse environmental factors or rather an entity
      influenced by adult psychosocial factors and as such, sensitive to health
      promotion activities; that is, if evidence could be found for a causal direction
      from classic factors involved in health promotion, such as social network and
      support, to SOC. A questionnaire (Krantz & Ostergren, 1999) was mailed to a
      random sample of 486 women, equivalent to 50% of the women between the ages of 40
      and 50 in a medium-sized municipality (population 13,200) in Sweden. The response
      rate was 81.7% (397 women). Odds ratios (OR) were used to estimate bivariate
      associations between socioeconomic and psychosocial variables and low SOC.
      Logistic regression analysis was used to test for confounding and as a method of
      analyzing the structure of tentative causal chains. It was found that adult
      factors such as job strain (OR = 3.42, 95% confidence interval [CI] = 2.11-5.54),
      low social support (OR = 4.00, CI = 2.48-6.46), and low social anchorage (OR =
      4.14, CI = 2.57-6.67) were independent predictors for low SOC in adult women.
      Childhood conditions such as family disruption and child abuse proved not to
      influence SOC to a statistically significant degree. Our study suggests that SOC
      is an entity partly associated with an individual's position in the social
      structure and partly by work conditions and social network and support rather
      than by childhood conditions. We could not claim this study to be a critical test
      of Antonovsky's (1979) theories in the full refutationistic sense. To approach
      this goal, it would take a carefully designed prospective study assessing the
      effect of different factors on SOC in a true life course perspective.

PMID- 15194517
TI  - Depression, perceived control, and life satisfaction in university students from
      Central-Eastern and Western Europe.
AB  - The poor health and psychological well-being of people in the former socialist
      states of Centeral-Eastern Europe are of serious concern and may be related to
      low perceived control. We compared depressive symptoms, life satisfaction, and
      self-rated health in 3,571 male and female university students from 5 Western
      European countries and 4,793 students from 5 Central-Eastern European countries.
      Depression scores (short Beck Depression Inventory; Beck & Beck, 1972) were
      higher in Central-Eastern than Western European samples. The prevalence of low
      life satisfaction was also greater in Central-Eastern Europeans, but ratings of
      self-rated health did not differ. Ratings of perceived control were diminished,
      but sense of mastery and internal health locus of control were higher in Central
      Eastern Europe. Depression and low life satisfaction were associated with low
      perceived control and mastery and with strong beliefs in the influence of chance
      over health. However, taking these factors into account did not explain the East
      West difference in depressive symptoms and low life satisfaction.

PMID- 15194518
TI  - Higher risk of colic in infants of nonmanual employee mothers with a demanding
      work situation in pregnancy.
AB  - In this population-based study, we assessed the relation between socioeconomic
      and psychosocial conditions in 1,094 pregnant women and subsequent infantile
      colic by means of self-administered questionnaires measuring exposures in the
      17th pregnancy week and telephone interviews at infant age 5 weeks. There was a
      higher risk of colic in infants born to younger mothers, mothers with low
      instrumental support in pregnancy, and mothers with nonmanual occupations. Having
      an "active" job situation, that is, high demands and high decision latitude at
      work, acted synergistically with a nonmanual occupation, yielding even higher
      odds ratios for colic as did concomitant low instrumental support and nonmanual
      occupation. An expected synergy between low social participation and nonmanual
      occupation could not be demonstrated. Findings from gender-related research may
      partly explain some of these results.

PMID- 15194519
TI  - The role of spirituality in the psychological adjustment to cancer: a test of the
      transactional model of stress and coping.
AB  - Recent studies in the oncology literature have shown that spirituality, defined
      as the combination of existential and religious well-being (RWB), is related to
      both emotional well-being and quality of life. Indeed, spirituality may be
      particularly important in coping with the potential life threat of the disease.
      Based on Frankl's (1963) existential theory, in this study, we examined whether
      the relations between spirituality and emotional well-being are moderated by
      degree of perceived life threat (PLT). In addition, in this study, we examined
      the relative importance of religious versus existential well-being in relation to
      psychological adjustment. Patients diagnosed with various types of cancer (N =
      95) completed questionnaires assessing spirituality, PLT, quality of life, and
      distress. Contrary to theoretical predictions, spirituality was associated with
      less distress and better quality of life regardless of PLT. Interestingly,
      existential but not RWB accounted for a major portion of the variance in these
      outcomes. Taken together, these findings suggest that spirituality, particularly
      the existential component, may be associated with reduced symptoms of distress in
      cancer patients regardless of life threat.

PMID- 15194520
TI  - Predictors of neurocognitive performance in chronic pain patients.
AB  - In a sample of 70 chronic pain patients, hierarchical multiple regression
      analyses were utilized to assess the additive and interactive contributions of
      pain severity and psychological distress variables to neurocognitive performance
      across attention and concentration, memory, and reasoning ability domains.
      Although the full model predicting attention and concentration was found to be
      significant, there was no significant contribution of pain severity,
      psychological distress, or the Pain Severity x Psychological Distress interaction
      to the prediction of attention and concentration scores after controlling for the
      effect of years of formal education. After controlling for the effect of years of
      formal education, pain severity and psychological distress did make separate and
      significant contributions to the prediction of memory scores; however, the Pain
      Severity x Psychological Distress interaction did not significantly affect memory
      scores. After controlling for the effect of years of formal education, there was
      no significant contribution of pain severity, psychological distress, or the Pain
      Severity x Psychological Distress interaction to reasoning ability scores.
      Results suggest the importance of assessing memory function when managing
      psychologically distressed chronic pain patients.

PMID- 15194522
TI  - Reality and conflict in punishment fantasies.

PMID- 15194523
TI  - Reflections on the obsessive-compulsive disorders: a psychodynamic and
      therapeutic perspective.

PMID- 15194524
TI  - A psychoanalytical approach to premenstrual tension syndrome.

PMID- 15194525
TI  - The waves: tensions between creativity and containment in the life and writings
      of Virginia Woolf.

PMID- 15194526
TI  - Perversion in the twenty-first century: from the Holocaust to the Karaoke bar.

PMID- 15194527
TI  - Psychological man in classic European art films.

PMID- 15194530
TI  - Hemophilia research in Haematologica.

PMID- 15194529
TI  - Issues surrounding therapeutic choices for hemophilia patients.

PMID- 15194531
TI  - Increased resistance of PIG-A- bone marrow progenitors to tumor necrosis factor a
      and interferon gamma: possible implications for the in vivo dominance of
      paroxysmal nocturnal hemoglobinuria clones.
AB  - BACKGROUND AND OBJECTIVES: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal
      disorder due to a PIG-A gene mutation, resulting in deficient expression of GPI
      anchored-proteins. Both immune-mediated suppression of hematopoiesis and cytokine
      alterations have been reported in aplastic anemia, a disease closely related to
      PNH whereas no data are available on PNH itself. The aim of this study was to
      investigate the effect of exogenous cytokines on clonogenic activity in PNH.
      DESIGN AND METHODS: We evaluated burst-forming units-erythroid (BFU-E) and colony
      forming units-granulocyte-macrophage (CFU-GM) in bone marrow mononuclear cells
      (BMMC) from 5 PNH patients and 5 controls, alone or in the presence of
      transforming-growth-factor (TGF)-beta, interferon (IFN)-gamma, tumor necrosis
      factor (TNF)-alpha, and specific antibodies. Molecular analysis of the PIG-A gene
      was performed by polymerase chain reaction (PCR) and direct sequencing on every
      single colony. RESULTS: Patients' cells showed less clonogenic activity than did
      control cells. In PNH, addition of TGF-beta inhibited both BFU-E and CFU-GM; IFN
      gamma and TNF-alpha inhibited BFU-E alone. In patients cytokines modulated normal
      and mutated clones differently: TGF-b reduced the number of PIG-A- and PIG-A+
      colony-forming-cells (CFC), whereas TNF-alpha and IFN-gamma reduced PIG-A+ CFC
      only. BMMC from patients showed higher TGF-beta production than did BMMC from
      controls. INTERPRETATION AND CONCLUSIONS: TGF-beta could contribute to the
      genesis of the unfavorable bone marrow microenvironment but does not seem to play
      a role in the in vivo dominance of PIG-A deficient cells. Mutated clones were
      more resistant to the inhibitory effects of IFN-gamma and TNF-alpha, suggesting
      that PNH cells may have a growth advantage in an unfavorable microenvironment.

PMID- 15194532
TI  - Increased levels of plasma interleukin-6 soluble receptor in patients with
      essential thrombocythemia.
AB  - BACKGROUND AND OBJECTIVES: The pathogenesis of essential thrombocythemia (ET), a
      disease characterized by megakaryocyte hyperplasia and persistent thrombocytosis,
      is not completely clarified. Interleukin-6 (IL-6), one of the cytokines related
      to megakaryocytic development, exerts its effect through binding to a cell
      surface receptor, IL-6Ra, and a signal transducing unit, gp130. Interestingly,
      the soluble form of the IL-6Ra, IL-6sR, is an agonist for IL-6 activity. In order
      to evaluate the possible participation of IL-6sR in ET we measured its levels in
      plasma, platelets and in the supernatant of a mononuclear cell culture. We also
      evaluated IL-6R on leukocyte membrane and IL-6R/IL-6sR mRNA expression in
      mononuclear cells. DESIGN AND METHODS: Fifty-five patients with ET were
      evaluated. IL-6sR and IL-6 were measured by an ELISA technique. Mononuclear cells
      were cultured for 48 hr and IL-6sR released into the supernatant was measured. IL
      6R on leukocyte surfaces was evaluated by flow cytometry. IL-6R and IL-6sR mRNA
      levels were assessed by semi-quantitative reverse transcription polymerase chain
      reaction. RESULTS: Plasma IL-6sR levels were increased while intraplatelet levels
      were low in untreated ET patients. Plasma levels decreased during treatment. Non
      stimulated mononuclear cells from ET patients released greater amounts of IL-6sR
      than did cells from normal controls in 48-hour culture. No abnormality was found
      in IL-6R or IL-6sR mRNA expression by mononuclear ET cells. IL-6R on leukocyte
      surfaces was normal. INTERPRETATION AND CONCLUSIONS: Increased plasma IL-6sR
      levels might have a role in the abnormal megakaryocytic proliferation seen in ET
      patients, while platelets and mononuclear cells could be the source of the above
      mentioned high levels of plasma IL-6sR.

PMID- 15194533
TI  - Polymorphisms of CYP1A1 and glutathione S-transferase and susceptibility to adult
      acute myeloid leukemia.
AB  - BACKGROUND AND OBJECTIVES: The origin of acute myeloid leukemia (AML) may be
      explained by a combination of genetic susceptibility factors and environmental
      exposure. We studied the polymorphisms of cytochrome P450 CYP1A1 and glutathione
      S-transferase (GST), enzymes involved in the metabolism of carcinogens and anti
      cancer drugs, as risk factors for adult AML. DESIGN AND METHODS: The prevalence
      of CYP1A1*2A, *2B and *4 alleles and of GSTM1 and GSTT1 homozygous deletions was
      examined in 193 patients with AML and 273 normal individuals using polymerase
      chain reaction (PCR)-based methods. RESULTS: A higher prevalence of the CYP1A1*4
      allele was found in AML patients than in controls (19.1% vs 9.9%, OR =2.2, 95%
      C.I. 1.3-3.7, p=0.006). GSTT1 homozygous deletions were also more frequent in AML
      patients (29% vs 19%, OR = 1.7, 95% CI 1.1-2.7, p=0.02). The combination of GSTT1
      null genotype and CYP1A1 *2B and *4 alleles further increased the risk of AML (OR
      =10.2, 95% CI 1.2-83.9, p=0.01, and OR =7.0, 95% CI 2.0-24.8, p=0.001,
      respectively). INTERPRETATION AND CONCLUSIONS: Polymorphic variants in xenobiotic
      metabolism genes, including CYP1A1 and GSTT1, may increase the risk of adult AML,
      particularly when present together.

PMID- 15194534
TI  - Two dual-color split signal fluorescence in situ hybridization assays to detect
      t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia.
AB  - BACKGROUND AND OBJECTIVES: The t(5;14)(q35;q32) is a novel cryptic translocation
      in pediatric T-cell acute lymphoblastic leukemia (T-ALL), involving HOX11L2 or
      CSX on 5q35. The 14q32 breakpoints are heterogeneous. Because the
      t(5;14)(q35;q32) is hard to detect using conventional karyotyping, it is easily
      missed in routine diagnostics. Here we describe the development and application
      of split signal fluorescence in situ hybridization (FISH) assays for both HOX11L2
      and CSX, for detection of t(5;14) possibly present in T-ALL patients. DESIGN AND
      METHODS: We developed and validated two split signal FISH assays for metaphase
      and interphase detection of t(5;14) in T-ALL patients. We also investigated the
      involvement of IGH on 14q32. In addition, HOX11L2 and SIL-TAL1 expression was
      studied using reverse transcription polymerase chain reaction (RT-PCR). RESULTS:
      The FISH assays were validated on cell lines and T-ALL patients. We did not
      identify cases with a t(5;14)(q35;q32) involving CSX, but we did identify 5 cases
      of t(5;14) involving HOX11L2 out of 32 T-ALL cases studied; in each case the
      14q32 breakpoint was found to be centromeric to the IGH region. All 5 positive
      cases showed HOX11L2 expression, as did 1 case without t(5;14)(q35;q32). Cases
      with t(5;14)(q35;q32) involving HOX11L2 did not show TAL1 abnormalities, whereas
      5 HOX11L2 negative cases did. INTERPRETATION AND CONCLUSIONS: Using the newly
      developed and validated FISH probe sets, we identified 5 new cases of t(5;14)
      involving HOX11L2 both on metaphases and interphases. The incidence of the
      t(5;14)(q35;q32) involving CSX is probably low. RT-PCR results suggest that TAL1
      and HOX11L2 expression, or TAL1 aberrations and the t(5;14)(q35;q32) involving
      HOX11L2 are mutually exclusive.

PMID- 15194535
TI  - Real-time polymerase chain reaction determination of cytokine mRNA expression
      profiles in Hodgkin's lymphoma.
AB  - BACKGROUND AND OBJECTIVES: Classical Hodgkin's lymphoma (HL) is a malignant
      disorder characterized by a small number of tumor cells and inflammatory cells.
      Both the tumor cells and the inflammatory cells produce cytokines which are
      thought to contribute to the clinical parameters of HL. Quantification of these
      cytokines at a protein level is still somewhat imprecise. We, therefore, used a
      method to quantify cytokine mRNA expression in HL cell lines and lymph node
      biopsies. DESIGN AND METHODS: We used real-time quantitative polymerase chain
      reaction (RQ-PCR) to investigate mRNA expression for interleukin (IL)-1alpha, IL
      1beta, IL-2, IL-4, IL-5, IL-8, IL-12p35, IL-12p40, IL-13, IL-15, interferon (IFN)
      gamma and tumor necrosis factor (TNF-alpha) in lymph node tissue from 15 patients
      with classic Hodgkin's lymphoma (c-HL) and one with lymphocyte predominance (LP)
      HL. HL-derived cell lines L1236, L540, and L428 were also investigated. Reactive
      lymphatic tissue (n=6) and peripheral blood mononuclear cells (PBMC) from healthy
      donors (n=4) before and after stimulation were used as controls. In 5 c-HL
      samples the cytokine expression in T lymphocytes was also studied by flow
      cytometry. RESULTS: All c-HL samples (but not LP) expressed IL-13 mRNA. This
      cytokine was not found in non-stimulated PBMC or in reactive lymphatic tissue.
      Expression of IL-10, IL-1beta, IL-15 and IL-12p35 mRNA was higher in HL samples
      than in PBMC and reactive lymphatic tissue. Expression of IL-10, IL-1beta, TNF
      alpha and IFN-gamma mRNA was significantly higher in the EBV+ HL samples (n=6)
      than in the EBV- cases. All HL cell lines showed high expression of IL-13, IL
      12p35, TNF-alpha and IL-15 mRNA. IFNg mRNA levels were high in L428 and L540
      cells, IL-10 in L1236 cells and L540 cells, IL-5 in L428 cells and IL-4 in L1236
      cells. INTERPRETATION AND CONCLUSIONS: Cytokine mRNA levels can be measured by RQ
      PCR using a limited amount of tissue. This method gives valuable information on
      biological variation between different HL samples and may contribute to
      unraveling the complex cytokine network contributing to the clinical and
      biological heterogeneity of this disease.

PMID- 15194536
TI  - Increased expression of Ki-67 in mantle cell lymphoma is associated with de
      regulation of several cell cycle regulatory components, as identified by global
      gene expression analysis.
AB  - BACKGROUND AND OBJECTIVES: Mantle cell lymphoma (MCL) is an aggressive disease.
      Patients with this malignancy have a median survival of 3 years. To better
      understand disease progression, which is characterized by increased
      proliferation, we analyzed the gene expression of MCL with different
      proliferative indices, as determined by immunohistochemical staining for Ki-67.
      Furthermore, primary and relapsed tumors were compared to identify the possible
      growth advantages possessed by cells which persist after therapy and which might
      evolve into a tumor relapse. DESIGN AND METHODS: Twenty-one samples of MCL were
      analyzed, using the Affymetrix U95Av2 chip, containing probes for approximately
      12,000 transcripts. Samples with a high versus low fraction of Ki-67+ cells were
      compared as were relapsed versus primary tumors. Immunohistochemistry was used to
      confirm the expression of some gene products. RESULTS: A distinct genetic
      signature, consisting of 32 genes, was found when comparing Ki-67high with Ki
      67low MCL. The signature consisted of genes involved in cellular processes, such
      as mitotic spindle formation, gene transcription and cell cycle regulation, e.g.
      components of the p53 and retinoblastoma protein (pRb) pathways. Of note, cyclin
      D1, the hallmark of MCL, as well as Ki-67 were up-regulated in the samples with a
      high proliferative index. Comparing primary vs. relapsed tumors, 26 individual
      genes were found, several involved in cell adhesion. Furthermore, increased
      expression of transferrin receptor was found in the relapsed tumors.
      INTERPRETATION AND CONCLUSIONS: A genetic signature distinguishing Ki-67high MCL
      from Ki-67low was established. The generated signature was used to assign new MCL
      samples to the high proliferative group, validating the association between these
      genes and proliferation in MCL.

PMID- 15194537
TI  - Association of anti-idiotypic antibodies with immune tolerance induction for the
      treatment of hemophilia A with inhibitors.
AB  - BACKGROUND AND OBJECTIVES: Hemophilia A patients with inhibitors can be treated
      effectively with immune tolerance induction therapy (ITI). One of the underlying
      mechanisms of ITI is conceived to be a neutralizing activity of anti-idiotypic
      antibodies on inhibitors. The goal of the present study was to develop an
      uncomplicated method for assessing antiidiotypic antibodies and to prove the
      advent of anti-idiotypic antibodies in ITI. DESIGN AND METHODS: We studied a
      total of 26 plasma samples obtained from 9 hemophilic inhibitor patients who were
      treated with ITI. The samples were investigated with a novel method for detecting
      anti-idiotypic antibodies based on a liquid phase blocking immunoprecipitation.
      RESULTS: Plasma anti-factor VIII (FVIII) antibody titer was reduced by adding
      plasma from patients who had received completely successful ITI. This anti-FVIII
      antibody-neutralization activity of the plasma was impaired by treating the
      plasma with protein G beads. In addition, treating inhibitor plasma from patients
      in whom ITI had been unsuccessful with FVIII affinity beads resulted in the
      development of the anti-FVIII antibody-neutralization activity. Furthermore, the
      anti-FVIII antibody-neutralization activity of anti-FVIII antibody-depleted
      plasma obtained in a late period of ITI on inhibitor plasmas obtained during ITI
      increased over time. INTERPRETATION AND CONCLUSIONS: Our results suggest that;
      (i) plasma from patients in whom ITI was completely successful contained an anti
      FVIII antibody-neutralization factor; (ii) the anti-FVIII antibody-neutralization
      factor was in the IgG fraction (i.e., the factor would be anti-idiotypic
      antibodies), and (iii) anti-idiotypic antibodies existed even in plasma from
      patients in whom ITI was unsuccessful. Our observations support the notion that
      the mechanism of ITI is associated with the development of anti-idiotypic
      antibodies.

PMID- 15194538
TI  - Analysis of biological phenotypes from 42 patients with inherited factor VII
      deficiency: can biological tests predict the bleeding risk?
AB  - BACKGROUND AND OBJECTIVES: Inherited factor VII (FVII) deficiency is a rare
      bleeding disorder characterized by a poor relationship between reported FVII
      clotting activity (FVII:C) and bleeding tendency. Our study was aimed at defining
      biological parameters that are possibly predictive for bleeding risk in this
      condition. DESIGN AND METHODS: Forty-two FVII-deficient patients (FVII:C <30%)
      were classified into two opposite clinical groups defined as severe and non-or
      mild bleeders. For each patient, plasma samples were collected and then
      investigated for FVII:C (using a sensitive method and human recombinant
      thromboplastin as the reagent), FVII antigen, activated FVII coagulant activity
      (FVIIa:C) and the free-form of tissue factor pathway inhibitor. RESULTS: None of
      these tests could be used as highly accurate predictors of bleeding.
      Nevertheless, both FVII:C and FVIIa:C differed significantly between the two
      clinical groups. Using ROC-curve analysis, two critical values of 8% and 3mIU/mL
      for FVII:C and FVIIa:C, respectively, could be proposed to discriminate between
      severe bleeders and non-or-mild bleeders. INTERPRETATION AND CONCLUSIONS: A
      highly accurate diagnostic test for predicting bleeding tendency in inherited
      FVII deficiency still eludes definition, highlighting the fact that factors other
      than FVII itself interfere with the expression of bleeding phenotypes in this
      condition. Nevertheless, potential critical values using sensitive FVII:C and
      FVIIa:C methods may be useful in clinical laboratories for FVII-deficient
      patients. Those patients with FVII:C levels higher than 8% FVII:C or FVIIa:C
      higher than 3 mIU/mL, with no other hemostatic defect, seem to have a minimal
      risk of severe bleeding. Extended clinical studies are needed to support these
      findings.

PMID- 15194539
TI  - Cytokine production during myeloablative and reduced intensity therapy before
      allogeneic stem cell transplantation.
AB  - BACKGROUND AND OBJECTIVES: The aim of this study was to elucidate the effect of
      the type of chemo-radio therapy given before allogeneic hematopoietic stem-cell
      transplantation (HSCT) on cytokine release. DESIGN AND METHODS: We analyzed serum
      cytokine levels during pre-transplant therapy in 178 HSCT recipients. Samples
      were drawn daily during the treatment and serum levels of tumor necrosis factor
      alpha (TNF-alpha) were analyzed by automated chemo-luminescence immunoassay.
      Conventional high-dose myeloablative therapy was given to 119 patients, while 59
      patients received reduced intensity therapy (RIC). Most patients had a
      hematologic malignancy: their median age was 37 years (range 1-67). Anti
      thymocyte globulin (ATG) was given to 126 patients as part of the pre-transplant
      treatment. RESULTS: The use of ATG significantly increased the TNF-alpha levels
      in the last four days before transplantation. We found significantly higher TNF
      alpha levels, days -4 to -2 before transplant, in patients given RIC compared to
      myeloablative therapy independently of ATG treatment. No effect of age or disease
      stage was found. In patients not given ATG, we found a correlation between high
      TNF-alpha levels on day -2 and moderate-to-severe acute graft-versus-host disease
      (GVHD). INTERPRETATION AND CONCLUSIONS: To conclude, during the pre-transplant
      treatment for HSCT, patients receiving RIC and those treated with ATG had
      increased levels of TNF-alpha.

PMID- 15194540
TI  - Management of multiple myeloma and related-disorders: guidelines from the Italian
      Society of Hematology (SIE), Italian Society of Experimental Hematology (SIES)
      and Italian Group for Bone Marrow Transplantation (GITMO).
AB  - OBJECTIVES: Perceiving the need for rigorous recommendations to facilitate
      decisions concerning the management of patients with multiple myeloma (MM), the
      Italian Society of Hematology (SIE) and the two affiliate societies (SIES and
      GITMO) commissioned a project to develop guidelines for the therapy of MM using
      evidence-based knowledge and consensus formation techniques. METHODS: After a
      comprehensive systematic review of 1,450 papers, an Expert Panel formulated and
      graded sixty recommendations according to the supporting evidence. Evidence gaps
      were filled with twenty-two consensus-based statements. High grade
      recommendations (grade A) are reported below. RESULTS: Treatment should be
      immediately initiated in MM patients with related organ damage: those patients
      aged below 65 years who do not have severe co-morbidities should receive
      autologous stem cell transplantation, while patients not candidates for
      autologous stem cell transplantation should receive oral melphalan and
      prednisone. Interferon-a should not be associated with conventional chemotherapy,
      but it can be offered with or without steroids as a maintenance therapy to
      patients who have reached a plateau phase. High-dose dexamethasone-containing
      regimens or high-dose dexamethasone alone are recommended as a first-line therapy
      when cytoreduction is urgently required (i.e., MM with spinal cord compression or
      with rapidly progressive renal failure). MM patients with moderate-to-severe
      anemia should receive erythropoietin, while patients with bone disease or
      osteopenia should receive long-term bisphophonates. Recommendations for the
      management of the clinical manifestations caused by the monoclonal protein (i.e.
      hyperviscosity, cast nephropathy, AL amyloidosis) and of solitary bone and
      extramedullary plasmacytoma were also elaborated. CONCLUSIONS: A substantial
      proportion of clinical care for MM can be guided by evidence-based treatment
      recommendations.

PMID- 15194541
TI  - Prevalence of the G320V mutation of the HJV gene, associated with juvenile
      hemochromatosis, in Greece.
AB  - Mutations of the HJV gene, which maps on chromosome 1q21, underlie most cases of
      juvenile hemochromatosis. We evaluated the frequency of the most common mutation
      (G320V) of the HJV gene in the Greek population, since 50% of cases of hereditary
      hemochromatosis in Greece carry mutations of the HJV gene.

PMID- 15194542
TI  - Hb Gun Hill: a further de novo observation.
AB  - Here we report the third observation (the second de novo) of unstable Hb Gun Hill
      or [b91(F7)-95(FG2)Leu-His-Cys-Asp-Lys-->0]. The two-year old male carrier showed
      low mean corpuscular hemoglobin (MCH) and mean hemoglobim concentration (MCHC),
      8.5% fetal hemoglobin and trade mark 30% variant hemoglobin. Mild hemolytic
      symptoms were detected seven years later. DNA sequencing and functional studies
      of mRNA and globin chains were performed.

PMID- 15194543
TI  - Impact of erythropoietic activity on red cell parameters in chronic renal failure
      patients.
AB  - We measured red cell parameters during recombinant human erythropoietin (rHuEPO)
      therapy associated with appropriate iron supplementation in chronic hemodialysis
      patients. Increased erythropoietic activity led to a bias in red cell parameter
      determination. The percentage of hypochromic red blood cells, usually used as the
      most effective predictor of response to iron supplementation, increased following
      the appearance of a younger red cell population since the same Hb content in
      these younger, larger cells gives a lower Hb concentration.

PMID- 15194545
TI  - Efficacy of a modified Stanford V regimen in patients with advanced Hodgkin's
      lymphoma.
AB  - We report treatment results obtained with a modified Stanford V regimen in 32
      patients with advanced Hodgkin's lymphoma (stage II bulky disease, III, IV).
      Treatment results were not superior to those achieved with conventional treatment
      (ABVD) in terms of complete remission and survival rates (progression-free
      survival and overall survival at 3 years: 66% and 91%, respectively).

PMID- 15194544
TI  - Instability of PRV-1 mRNA: a factor to be considered in PRV-1 quantification for
      the diagnosis of polycythemia vera.
AB  - High expression of PRV-1 mRNA in granulocytes has been proposed as a new
      diagnostic marker for polycythemia vera. We used real-time reverse transcription
      polymerase chain reaction (RT-PCR) to measure the levels of PRV-1 mRNA, GAPDH
      mRNA and 18S rRNA in granulocytes obtained from blood samples processed 2, 24 and
      48 hours after collection and observed a significant decrease of PRV-1 levels
      after 24 and 48 hours. The instability of PRV-1 mRNA may affect the diagnostic
      value of the PRV-1 test in blood samples stored for extended periods.

PMID- 15194546
TI  - Intraventricular treatment of relapsed central nervous system lymphoma with the
      anti-CD20 antibody rituximab.
AB  - Most patients with primary central nervous system (CNS) lymphoma or systemic non
      Hodgkin's lymphoma (NHL) involving the CNS relapse after an initial response to
      treatment, often presenting with leptomeningeal disease. Since the majority of
      these lymphomas are B-cell neoplasms expressing the CD20 surface antigen
      treatment with the chimeric monoclonal antibody (Mab) rituximab might be a new
      therapeutic option. Here, we report on 6 patients with relapsed CNS B-cell
      lymphoma who were treated with intraventricular or intrathecal applications of
      rituximab. One of these cases has already been reported.

PMID- 15194547
TI  - CD45RA+ and CD45RO+ lymphocyte subpopulations in patients with monoclonal
      gammopathies: correlations with diagnosis, clinical stage and treatment status.
AB  - Alterations in blood lymphocyte subsets may be involved in the development of
      overt myeloma. Naive (CD4+CD45RA+) and memory (CD4+CD45RO+) helper T-cell subsets
      are important effectors of immune T-cell regulation. We analyzed the distribution
      of these blood lymphocyte subpopulations in patients with monoclonal
      gammopathies, considering the type of disorder, clinical stage, and treatment
      status.

PMID- 15194548
TI  - Role of fibrinolysis in tissue-factor-induced disseminated intravascular
      coagulation in rats - an effect of tranexamic acid.
AB  - We clarified the role of fibrinolysis in tissue-factor (TF)-induced rat
      disseminated intravascular coagulation (DIC) using tranexamic acid (TA). TA
      suppressed the elevation in D-dimer levels normally observed following TF-induced
      DIC, and an increase in organ dysfunction was seen. Enhanced fibrinolysis plays
      an important role in preventing the development of organ failure in TF-induced
      DIC.

PMID- 15194549
TI  - Duplication of exon 13 causes one third of the cases of mild hemophilia A in
      northern Italy.
AB  - A rearrangement of exon 13 in the factor VIII gene has been identified as the
      causative mutation in 32% of Northern Italian patients with mild hemophilia A. We
      have demonstrated that all share a common haplotype, thus suggesting that the
      mutation likely occurred in a single ancestor. To date, no predominant mutation
      has been identified in mild hemophilia A, therefore it would be extremely useful
      to carry out more extensive studies to ascertain whether the mutation is confined
      to northern Italy.

PMID- 15194550
TI  - Treatment of acquired factor VIII inhibitor with recombinant activated factor
      VIIa: data from the Italian registry of acquired hemophilia.
AB  - We report on the data collected in the Italian Registry of acquired haemophilia
      (AH) in 2001. Recombinant activated factor VII (rFVIIa) was selected as first
      line therapy in 19 bleeding episodes because of their severity and as salvage in
      one case. Bleeding was controlled in 90% of the episodes, indicating the efficacy
      of rFVIIa in HA.

PMID- 15194551
TI  - Rescue of activated protein C-resistance phenotype by cis-acting factor V
      Gly2032Asp mutation.
AB  - A 60-year-old Italian woman presenting with factor VLeiden mutation but a normal
      activated protein C (APC) resistance, low functional and antigenic factor (FV)
      plasma levels, was found to have a novel heterozygous Gly2032Asp substitution
      located on the same allele. In transfected cells, the Gly2032Asp mutation caused
      an approximately 2-fold reduction of the intracellular FV protein and a 9-fold
      reduction of the secreted protein, suggesting that the Gly2032Asp substitution
      acts in cis on the allele carrying the FVLeiden mutation and rescues the APC
      resistance phenotype.

PMID- 15194552
TI  - Definition of myeloid engraftment after allogeneic hematopoietic stem cell
      transplantation.
AB  - Neutrophil counts continued to rise after reaching 0.5x10(9)/L in 78 allograft
      recipients receiving granulocyte colony-stimulating factor (G-CSF) post
      transplant. This was confirmed in 44 subsequent patients not receiving G-CSF.
      This suggests that the first day of neutrophils >or=0.5x10(9)/L can be considered
      a valid definition of myeloid recovery after allogeneic transplantation.

PMID- 15194553
TI  - Successful treatment of pure red cell aplasia with cyclosporin A and
      erythropoietin after thymectomy in a 88-year old woman.
AB  - An 88-year old Japanese female with pure red cell aplasia was treated safely and
      effectively by a combination of thymectomy, cyclosporin A, and erythropoietin.
      The thymoma was histologically classified as lymphocytic type or cortical type,
      which are uncommon in cases of a thymoma accompanied by pure red cell aplasia.
      Immunohistochemical analysis of the thymoma and bone marrow revealed a
      predominance of CD8(+) cells. Thymectomy alone was ineffective, but cyclosporin A
      treatment subsequent to thymectomy was safe and effective and resulted in the
      disappearance of a Vbeta12 bearing T-cell clone in the bone marrow. Additional
      treatment with erythropoietin enhanced the effects of cyclosporin A and restored
      the patient's hemoglobin to normal levels. The beneficial effect of cyclosporin A
      may be attributed not to a broad immunomodulatory effect, but to a local effect
      on a limited T-cell subset.

PMID- 15194554
TI  - Gemtuzumab ozogamicin plus cytarabine determines complete remission in acute
      myeloid leukemia refractory to a double conventional treatment: a case report.

PMID- 15194555
TI  - Severe T-mediated bone marrow aplasia in a patient with splenic lymphoma with
      villous lymphocytes (SLVL) previously treated with fludarabine regimen.

PMID- 15194556
TI  - Edema of the eyelids and sclera after rituximab infusion for orbital MALT
      lymphoma.

PMID- 15194557
TI  - Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms
      of alcoholic fatty liver.
AB  - Alcohol has long been thought to cause fatty liver by way of altered NADH/NAD(+)
      redox potential in the liver, which, in turn, inhibits fatty acid oxidation and
      the activity of tricarboxylic acid cycle reactions. More recent studies indicate
      that additional effects of ethanol both impair fat oxidation and stimulate
      lipogenesis. Ethanol interferes with DNA binding and transcription-activating
      properties of peroxisome proliferator-activated receptor-alpha (PPARalpha), as
      demonstrated with cultured cells and in ethanol-fed mice. Treatment of ethanol
      fed mice with a PPARalpha agonist can reverse fatty liver even in the face of
      continued ethanol consumption. Ethanol also activated sterol regulatory element
      binding protein 1, inducing a battery of lipogenic enzymes. These effects may be
      due in part to inhibition of AMP-dependent protein kinase, reduction in plasma
      adiponectin, or increased levels of TNF-alpha in the liver. The understanding of
      these ethanol effects provides new therapeutic targets to reverse alcoholic fatty
      liver.

PMID- 15194558
TI  - Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the
      role of inflammation.
AB  - Patients with ulcerative colitis and Crohn's disease are at increased risk for
      developing colorectal cancer. To date, no known genetic basis has been identified
      to explain colorectal cancer predisposition in these inflammatory bowel diseases.
      Instead, it is assumed that chronic inflammation is what causes cancer. This is
      supported by the fact that colon cancer risk increases with longer duration of
      colitis, greater anatomic extent of colitis, the concomitant presence of other
      inflammatory manifestations such as primary sclerosing cholangitis, and the fact
      that certain drugs used to treat inflammation, such as 5-aminosalicylates and
      steroids, may prevent the development of colorectal cancer. The major
      carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal
      instability, microsatellite instability, and hypermethylation, also occur in
      colitis-associated colorectal cancers. Unlike normal colonic mucosa, however,
      inflamed colonic mucosa demonstrates abnormalities in these molecular pathways
      even before any histological evidence of dysplasia or cancer. Whereas the reasons
      for this are unknown, oxidative stress likely plays a role. Reactive oxygen and
      nitrogen species produced by inflammatory cells can interact with key genes
      involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and
      even DNA base excision-repair genes. Other factors such as NF-kappaB and
      cyclooxygenases may also contribute. Administering agents that cause colitis in
      healthy rodents or genetically engineered cancer-prone mice accelerates the
      development of colorectal cancer. Mice genetically prone to inflammatory bowel
      disease also develop colorectal cancer especially in the presence of bacterial
      colonization. These observations offer compelling support for the role of
      inflammation in colon carcinogenesis.

PMID- 15194559
TI  - Mrp2 is involved in benzylpenicillin-induced choleresis.
AB  - Benzylpenicillin (PCG; 180 micromol/kg), a classic beta-lactam antibiotic, was
      intravenously given to Sprague-Dawley (SD) rats and multidrug resistance
      associated protein 2 (Mrp2)-deficient Eisai hyperbilirubinemic rats (EHBR). A
      percentage of the [(3)H]PCG was excreted into the bile of the rats within 60 min
      (SD rats: 31.7% and EHBR: 4.3%). Remarkably, a transient increase in the bile
      flow ( approximately 2-fold) and a slight increase in the total biliary bilirubin
      excretion were observed in SD rats but not in the EHBR after PCG administration.
      This suggests that the biliary excretion of PCG and its choleretic effect are
      Mrp2-dependent. Positive correlations were observed between the biliary excretion
      rate of PCG and bile flow (r(2) = 0.768) and more remarkably between the biliary
      excretion rate of GSH and bile flow (r(2) = 0.968). No ATP-dependent uptake of
      [(3)H]PCG was observed in Mrp2-expressing Sf9 membrane vesicles, whereas other
      forms of Mrp2-substrate transport were stimulated in the presence of PCG. GSH
      efflux mediated by human MRP2 expressed in Madin-Darby canine kidney II cells was
      enhanced in the presence of PCG in a concentration-dependent manner. In
      conclusion, the choleretic effect of PCG is caused by the stimulation of biliary
      GSH efflux as well as the concentrative biliary excretion of PCG itself, both of
      which were Mrp2 dependent.

PMID- 15194560
TI  - Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate
      secretion in rats.
AB  - We examined, by using a specific PGE receptor subtype EP4 agonist and antagonist,
      the involvement of EP4 receptors in duodenal HCO(3)(-) secretion induced by
      PGE(2) and mucosal acidification in rats. Mucosal acidification was achieved by
      exposing a duodenal loop to 10 mM HCl for 10 min, and various EP agonists were
      given intravenously 10 min before the acidification. Secretion of HCO(3)(-) was
      dose-dependently stimulated by AE1-329 (EP4 agonist), the maximal response being
      equivalent to that induced by sulprostone (EP1/EP3 agonist) or PGE(2). The
      stimulatory action of AE1-329 and PGE(2) but not sulprostone was attenuated by
      AE3-208, a specific EP4 antagonist. This antagonist also significantly mitigated
      the acid-induced HCO(3)(-) secretion. Coadministration of sulprostone and AE1-329
      caused a greater secretory response than either agent alone. IBMX potentiated the
      stimulatory action of both sulprostone and AE1-329, whereas verapamil mitigated
      the effect of sulprostone but not AE1-329. Chemical ablation of capsaicin
      sensitive afferent neurons did not affect the response to any of the EP agonists
      used. We conclude that EP4 receptors are involved in the duodenal HCO(3)(-)
      response induced by PGE(2) or acidification in addition to EP3 receptors. The
      process by which HCO(3)(-) is secreted through these receptors differs regarding
      second-messenger coupling. Stimulation through EP4 receptors is mediated by cAMP,
      whereas that through EP3 receptors is regulated by both cAMP and Ca(2+); yet
      there is cooperation between the actions mediated by these two receptors. The
      neuronal reflex pathway is not involved in stimulatory actions of these
      prostanoids.

PMID- 15194561
TI  - Leukocyte elastase induces epithelial apoptosis: role of mitochondial
      permeability changes and Akt.
AB  - During acute inflammation, neutrophil-mediated injury to epithelium may lead to
      disruption of epithelial function, including the induction of epithelial
      apoptosis. Herein, we report the effects of neutrophil transmigration and of
      purified leukocyte elastase on epithelial cell survival. Neutrophil
      transmigration induced apoptosis of epithelial cells [control monolayers: 5 +/- 1
      cells/25 high-power fields (HPF) vs. neutrophil-treated monolayers: 29 +/- 10
      cells/HPF, P < 0.05, n = 3 as determined by terminal deoxynucleotidyl transferase
      dUTP nick-end labeling assay] as did low concentrations (0.1 U/ml) of purified
      leukocyte elastase (control monolayers: 6.4 +/- 2.5% apoptotic vs. elastase: 26.2
      +/- 2.9% apoptotic, P < 0.05, as determined by cytokeratin 18 cleavage).
      Treatment with elastase resulted in decreased mitochondrial membrane potential,
      release of cytochrome c to the cytosol, and cleavage of caspases-9 and -3 as
      determined by Western blot analysis, implicating altered mitochondrial membrane
      permeability as a primary mechanism for elastase-induced apoptosis. Additionally,
      incubation of epithelial cells with leukocyte elastase resulted in an early
      increase followed by a decrease in the phosphorylation of epithelial Akt, a
      serine/threonine kinase important in cell survival. Inhibition of epithelial Akt
      before elastase treatment potentiated epithelial cell apoptosis, suggesting that
      the initial activation of Akt represents a protective response by the epithelial
      cells to the proapoptotic effects of leukocyte elastase. Taken together, these
      observations suggest that epithelial cells exhibit a dual response to cellular
      stress imposed by leukocyte elastase with a proapoptotic response mediated via
      early alterations in mitochondrial membrane permeability countered by activation
      of the survival pathway involving Akt.

PMID- 15194562
TI  - Pollination and reproductive biology of twelve species of neotropical
      Malpighiaceae: stigma morphology and its implications for the breeding system.
AB  - BACKGROUND AND AIMS: This study on reproductive biology examines the stigmatic
      morphology of 12 Brazilian Malpighiaceae species with regard to their pollination
      and breeding system. METHODS: The species were studied in natural populations of
      a semi-deciduous forest fragment. Style tips were processed for observation by
      SEM and pollen-tube growth was analyzed under fluorescence microscopy. The
      breeding system was investigated by isolating flowers within waterproof bags.
      Floral visitors were recorded through notes and photographs. KEY RESULTS: Flowers
      are yellow, pink or white, protogynous, herkogamous and sometimes lack oil
      glands. While Banisteriopsis pubipetala has functional female flowers (with
      indehiscent anthers), 11 species present hermaphrodite flowers. Stigmas of these
      species may be terminal, with a slightly concave surface, or internal, consisting
      of a circular cavity with a large orifice, and are covered with a thin,
      impermeable cuticle that prevents pollen from adhering, hydrating, or
      germinating. Malpighiaceae have a special type of 'wet' stigma, where a secretion
      accumulates under the cuticle and is released by mechanical means-mainly rupture
      by pollinators. Even though six species show a certain degree of self
      compatibility, four of them present a form of late-acting self-incompatibility,
      and the individual of B. pubipetala is agamospermous. Species of Centris,
      Epicharis and Monoeca bees pollinate these flowers, mainly collecting oil. Some
      Epicharis and Monoeca species collected pollen by vibration. Paratetrapedia and
      Tetrapedia bees are pollen and oil thieves. CONCLUSIONS: The Malpiguiaceae
      species studied are pollinator-dependent, as spontaneous self-pollination is
      limited by herkogamy, protogyny and the stigmatic cuticle. Both the oil- and
      pollen-collecting behaviours of the pollinators favour the rupture of the
      stigmatic cuticle and the deposition of pollen on or inside the stigmas. As fruit
      set rates in natural conditions are low, population fragmentation may have
      limited the sexual reproduction of these species.

PMID- 15194563
TI  - Wnt-responsive element controls Lef-1 promoter expression during submucosal gland
      morphogenesis.
AB  - Regulated expression of lymphoid enhancer factor 1 (Lef-1) plays an obligatory
      role in the transcriptional control of epithelial bud formation during airway
      submucosal gland and mammary gland development. However, regions of the Lef-1
      promoter required for spatial and temporal regulation during glandular
      development have yet to be defined. We hypothesized that a previously reported
      110-bp Wnt-responsive element (WRE) in the Lef-1 promoter, which can be induced
      by Wnt-3a/beta-catenin signals, may also play a role in regulating Lef-1
      expression during airway and mammary gland development. Here we show that the Lef
      1 promoter is also responsive to Wnt-1 signals in both airway and mammary
      epithelial cell lines. To better understand the importance of the WRE in
      dynamically regulating Lef-1 promoter activation in these two types of epithelia
      in vivo, we utilized LacZ reporter transgenic mice to evaluate the significance
      of Wnt-responsive sequences in the Lef-1 promoter during glandular bud formation.
      A 2.5-kb Lef-1 promoter fragment partially reproduced endogenous Lef-1 expression
      patterns in a subset of cell types involved in both mammary gland and submucosal
      glandular bud development. Interestingly, removal of the 110-bp WRE from the Lef
      1 promoter ablated expression in nasal and tracheal submucosal glandular buds
      while having no significant effect on developmental expression in mammary
      glandular buds. These findings suggest that Wnt regulation of the Lef-1 promoter
      at the WRE may play an important role during airway submucosal glandular bud
      formation.

PMID- 15194564
TI  - Colloidal gold particles as a new in vivo marker of early acute lung injury.
AB  - Permeability of the endothelial barrier to large molecules plays a pivotal role
      in the manifestation of early acute lung injury. We present a novel and sensitive
      technique that brings microanatomical visualization and quantification of
      microvascular permeability in line. White New Zealand rabbits were anesthetized
      and ventilated mechanically. Rabbit serum albumin (RSA) was labeled with
      colloidal gold particles. We quantified macromolecular leakage of gold-labeled
      RSA and thickening of the gas exchange distance by electron microscopy, taking
      into account morphology of microvessels. The control group receiving a saline
      solution represented a normal gas exchange barrier without extravasation of gold
      labeled albumin. Infusion of lipopolysaccharide (LPS) resulted in a significant
      displacement of gold-labeled albumin into pulmonary cells, the lung interstitium,
      and even the alveolar space. Correspondingly, intravital fluorescence microscopy
      and digital image analysis indicated thickening of width of alveolar septa. The
      findings were accompanied by a deterioration of alveolo-arterial oxygen
      difference, whereas wet/dry ratio and albumin concentration in the
      bronchoalveolar lavage fluid failed to detect that early stage of pulmonary
      edema. Inhibition of the nuclear enzyme poly(ADP-ribose) synthetase by 3
      aminobenzamide prevented LPS-induced microvascular injury. To summarize:
      colloidal gold particles visualized by standard electron microscopy are a new and
      very sensitive in vivo marker of microvascular permeability in early acute lung
      injury. This technique enabling detailed microanatomical and quantitative
      pathophysiological characterization of edema formation can form the basis for
      evaluating novel treatment strategies against acute lung injury.

PMID- 15194565
TI  - Mucins and their O-Glycans from human bronchial epithelial cell cultures.
AB  - A longstanding question in obstructive airway disease is whether observed changes
      in mucin composition and/or posttranslational glycosylation are due to genetic or
      to environmental factors. We tested whether the mucins secreted by second-passage
      primary human bronchial epithelial cell cultures derived from noncystic fibrosis
      (CF) or CF patients have intrinsically different specific mucin compositions, and
      whether these mucins are glycosylated differently. Both CF and non-CF cultures
      produced MUC5B, predominantly, as judged by quantitative agarose gel Western
      blots with mucin-specific antibodies: MUC5B was present at approximately 10-fold
      higher levels than MUC5AC, consistent with our previous mRNA studies (Bernacki
      SH, Nelson AL, Abdullah L, Sheehan JK, Harris A, William DC, and Randell SH. Am J
      Respir Cell Mol Biol 20: 595-604, 1999). O-linked oligosaccharides released from
      purified non-CF and CF mucins and studied by HPLC mass spectrometry had highly
      variable glycan structures, and there were no observable differences between the
      two groups. Hence, there were no differences in either the specific mucins or
      their O-glycans that correlated with the CF phenotype under the
      noninfected/noninflammatory conditions of cell culture. We conclude that the
      differences observed in the mucins sampled directly from patients are most likely
      due to environmental factors relating to infection and/or inflammation.

PMID- 15194566
TI  - Substance P and neutral endopeptidase in development of acute respiratory
      distress syndrome following fire smoke inhalation.
AB  - To characterize the tachykininergic effects in fire smoke (FS)-induced acute
      respiratory distress syndrome (ARDS), we designed a series of studies in rats.
      Initially, 20 min of FS inhalation induced a significant increase of substance P
      (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after
      insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity
      of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and
      24 h after insult, respectively. Immunolabeling density of NEP in the airway
      epithelium largely disappeared 1 h after insult due to acute cell damage and
      shedding. These changes were also accompanied by extensive influx of albumin and
      granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP
      activity dose dependently increased and decreased, respectively, following 0, low
      (10 min), and high (20 min) levels of FS inhalation. However, neither the time
      course nor the dose-response study observed a significant change in the highest
      affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im)
      with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced
      hypoxemia and pulmonary edema 24 h after insult. Further examination indicated
      that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma
      extravasation following FS. Collectively, these findings suggest that a
      combination of sustained SP and NEP inactivity induces an exaggerated neurogenic
      inflammation mediated by NK-1R, which may lead to an uncontrolled influx of
      protein-rich edema fluid and cells into the alveoli as a consequence of increased
      vascular permeability.

PMID- 15194567
TI  - TNFalpha therapy in psoriatic arthritis and psoriasis.

PMID- 15194569
TI  - Tophaceous gout of the pubic symphysis: an unusual cause of groin pain.

PMID- 15194568
TI  - Time dependent risk of gastrointestinal complications induced by non-steroidal
      anti-inflammatory drug use: a consensus statement using a meta-analytic approach.
AB  - OBJECTIVES: To provide an updated document assessing the global, NSAID-specific,
      and time dependent risk of gastrointestinal (GI) complications through meta
      analyses of high quality studies. METHODS: An exhaustive systematic search was
      performed. Inclusion criteria were: RCT or controlled study, duration of 5 days
      at least, inactive control, assessment of minor or major NSAID adverse effects,
      publication range January 1985 to January 2003. The publications retrieved were
      assessed during a specifically dedicated WHO meeting including leading experts in
      all related fields. Statistics were performed conservatively. Meta-regression was
      performed by regressing NSAID adjusted estimates against study duration
      categories. RESULTS: Among RCT data, indolic derivates provided a significantly
      higher risk of GI complications related to NSAID use than for non-users: RR =
      2.25 (1.00; 5.08) than did other compounds: naproxen: RR = 1.83 (1.25; 2.68);
      diclofenac: RR = 1.73 (1.21; 2.46); piroxicam: RR = 1.66 (1.14; 2.44); tenoxicam:
      RR = 1.43 (0.40; 5.14); meloxicam: RR = 1.24 (0.98; 1.56), and ibuprofen: RR =
      1.19 (0.93; 1.54). Indometacin users had a maximum relative risk for complication
      at 14 days. The other compounds presented a better profile, with a maximum risk
      at 50 days. Significant additional risk factors included age, dose, and
      underlying disease. The controlled cohort studies provided higher estimates: RR =
      2.22 (1.7; 2.9). Publication bias testing was significant, towards a selective
      publication of deleterious effects of NSAIDs from small sized studies.
      CONCLUSION: This meta-analysis characterised the "compound" and "time" aspects of
      the GI toxicity of non-selective NSAIDs. The risk/benefit ratio of such compounds
      should thus be carefully and individually evaluated at the start of long term
      treatment.

PMID- 15194570
TI  - Early effects of tumour necrosis factor alpha blockade on skin and synovial
      tissue in patients with active psoriasis and psoriatic arthritis.
AB  - BACKGROUND: Tumour necrosis factor alpha (TNFalpha) blockade using infliximab, a
      chimeric anti-TNFalpha antibody, is an effective treatment for both psoriasis and
      psoriatic arthritis (PsA). OBJECTIVE: To analyse the early effects of infliximab
      treatment on serial skin and synovial tissue biopsy samples. METHODS: Twelve
      patients with both active psoriasis and PsA received a single infusion of either
      infliximab (3 mg/kg) (n = 6) or placebo (n = 6) intravenously. Synovial tissue
      and lesional skin biopsy specimens were obtained at baseline and 48 hours after
      treatment. Immunohistochemical analysis was performed to analyse the inflammatory
      infiltrate. In situ detection of apoptotic cells was performed by TUNEL assay and
      by immunohistochemical staining with anti-caspase-3 antibodies. Stained tissue
      sections were evaluated by digital image analysis. RESULTS: A significant
      reduction in mean (SEM) T cell numbers was found in both lesional epidermis
      (baseline 37 (11) cells/mm, 48 hours 26 (11), p = 0.028) and synovial tissue (67
      (56) cells/mm(2)v 32 (30), p = 0.043) after infliximab treatment, but not after
      placebo treatment (epidermis 18 (8) v 43 (20), NS; synovium 110 (62) v 46 (21),
      NS). Similarly, the number of macrophages in the synovial sublining was
      significantly reduced after anti-TNFalpha treatment (100 (73) v 10 (8), p =
      0.043). The changes in cell numbers could not be explained by induction of
      apoptosis at the site of inflammation. CONCLUSIONS: The effects of anti-TNFalpha
      therapy in psoriasis and psoriatic arthritis may be explained by decreased cell
      infiltration in lesional skin and inflamed synovial tissue early after initiation
      of treatment.

PMID- 15194571
TI  - Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and
      PGM1) widely used for immunohistochemistry and flow cytometry.
AB  - OBJECTIVES: To investigate the specificity of three anti-CD68 monoclonal
      antibodies (mAbs) for macrophages (Mphi) in immunohistochemistry (IHC) and flow
      cytometry (FACS). METHODS: IHC was performed on cryostat sections of rheumatoid
      arthritis (RA) and osteoarthritis (OA) synovial membranes using the anti-CD68
      mAbs KP1, EBM11, and PGM1, and the fibroblast (FB) markers CD90 and prolyl 4
      hydroxylase. Expression of CD68 was also analysed by FACS on the monocytic cell
      lines THP-1 and U937, as well as on synovial fibroblasts (SFB), skin FB, and
      gingival FB (both surface and intracellular staining). RESULTS: In IHC, there was
      an overlap between CD68 (mAbs KP1 and EBM11) and the FB markers CD90/prolyl 4
      hydroxylase in the lining layer, diffuse infiltrates, and stroma of RA and OA
      synovial membranes. In FACS analysis of THP-1 and U937 cells, the percentage of
      cells positive for the anti-CD68 mAbs KP1 and EBM11 progressively increased from
      surface staining of unfixed cells, to surface staining of pre-fixed cells, to
      intracellular staining of the cells. Upon intracellular FACS of different FB,
      nearly all cells were positive for KP1 and EBM11, but only a small percentage for
      PGM1. In surface staining FACS, a small percentage of FB were positive for all
      three anti-CD68 mAbs. CONCLUSION: An overlap between CD68 (mAbs KP1 or EBM11) and
      the FB markers CD90 or prolyl 4-hydroxylase may prevent unequivocal
      identification of Mphi in synovial tissue by IHC or in monocytic cells and FB
      upon intracellular FACS. This may be due to sharing of common markers by
      completely different cell lineages.

PMID- 15194572
TI  - Immunohistochemistry of normal human knee synovium: a quantitative study.
AB  - OBJECTIVE: To describe the immunohistochemical characteristics of knee synovium
      from normal healthy subjects. METHODS: 12 healthy subjects underwent needle
      biopsy of knee synovium. Using antibodies directed against CD3, CD4, CD8, L26, Kp
      1,and HLA-DR, detailed quantitative immunohistochemical analysis of various cell
      subpopulations was undertaken. RESULTS: The mean (SD) age of the subjects was 37
      (9) years (five male, seven female). All had a negative history for arthritis, no
      knee pain, and a totally normal joint examination except for the presence of
      retropatellar crepitus in five. For technical reasons staining for all
      immunohistochemical markers could not be achieved in all subjects. CD3+ T
      lymphocytes were seen in nine of 10 subjects, either diffusely or, more commonly,
      in perivascular areas. CD4+ cells were seen in synovium in three of seven
      subjects and CD8+ cells in six of eight subjects, in almost equal numbers
      (CD4:CD8, 1.1:1). L26+ B lymphocytes were not seen in any biopsy. Kp1+
      macrophages were found in 10 of 10 subjects, predominantly in surface lining
      cells, and in small numbers in diffuse and perivascular locations. HLA-DR+ cells
      were seen in 10 of 10 subjects, predominantly in surface lining cells and
      diffusely, but a few were seen perivascularly. CONCLUSIONS: Synovium from
      apparently normal subjects contained a wide range of different cell
      subpopulations but no B cells. The significance of these immune cells in normal
      synovium is unclear. A better understanding of their role in normal synovium may
      be important in analysing the transition to synovitis.

PMID- 15194573
TI  - Longitudinal development of skin involvement and reliability of high frequency
      ultrasound in systemic sclerosis.
AB  - BACKGROUND: Measurement of skin involvement is essential for diagnosis and
      prognosis in systemic sclerosis. Assessment by palpation skin score is the
      current method. OBJECTIVE: To explore high frequency ultrasound as an objective
      method to improve skin characterisation by combining measurements of skin
      thickness and echogenicity. METHODS: Skin thickness and echogenicity were
      measured at the proximal phalanx of the second digit, the back of the hand, the
      forearm, and the lower leg and, in order to separate limited (lSSc) from diffuse
      SSc (dSSc), at the chest in 16 patients with early disease and in 16 controls.
      Measurements were repeated in each patient three or four times with an interval
      of 1-2 years. Ultrasound measurements of skin thickness were compared with the
      palpation skin score. RESULTS: Compared with controls, the skin was thickened on
      the phalanx, hand, forearm, and chest of patients with dSSc, but not patients
      with lSSc, at the 1 year examination. In dSSc the degree of thickening tended to
      diminish with time, and at 4 years, thickness was significantly decreased on the
      forearm and chest compared with the 1 year measurements. Low reflectancy was most
      pronounced at the 1 year evaluation on the forearm, hand, and phalanx in dSSc,
      and on the phalanx in lSSc. CONCLUSION: Separate measurements of skin thickness
      and echogenicity by high frequency ultrasound add a new dimension to the
      assessment of skin involvement in SSc, and this seems to be an objective non
      invasive tool for use in the study of disease development and in clinical trials.

PMID- 15194574
TI  - Lack of radiological and clinical benefit over two years of low dose prednisolone
      for rheumatoid arthritis: results of a randomised controlled trial.
AB  - BACKGROUND: Evidence for disease modifying activity of low dose corticosteroid
      treatment in rheumatoid arthritis is contradictory. Studies showing radiological
      benefit suggest that continued treatment is required to sustain the effect.
      OBJECTIVE: To evaluate the effect of low dose oral prednisolone in early
      rheumatoid arthritis on disease activity over two years. DESIGN: Double blind
      placebo controlled trial. METHODS: Patients with rheumatoid arthritis, duration
      <3 years (n = 167), were started on a disease modifying antirheumatic drug
      (DMARD; sulphasalazine) and allocated by stratified randomisation to prednisolone
      7 mg/day or placebo. Primary outcome measure was radiological damage, assessed by
      the modified Sharp method. Clinical benefit was a secondary outcome. A proactive
      approach to identifying and treating corticosteroid adverse events was adopted.
      Patients who discontinued sulphasalazine were offered an alternative DMARD.
      RESULTS: 90 of 257 patients eligible for the study refused to participate (more
      women than men). Of those enrolled, 84% were seropositive for rheumatoid factor,
      median age 56 years, median disease duration 12 months, female to male ratio
      1.8:1. Prednisolone was given to 84 patients; of these 73% continued prednisolone
      and 70% sulphasalazine at 2 years. Of the 83 patients on placebo, 80% continued
      placebo and 64% sulphasalazine at 2 years. There were no significant differences
      in radiological score or clinical and laboratory measures at 0 and 2 years.
      CONCLUSIONS: Low dose prednisolone conferred no radiological or clinical benefit
      on patients maintained on a DMARD over two years. Low dose corticosteroids have
      no role in the routine management of rheumatoid arthritis treated with
      conventional disease modifying drugs.

PMID- 15194575
TI  - High intensity exercise or conventional exercise for patients with rheumatoid
      arthritis? Outcome expectations of patients, rheumatologists, and
      physiotherapists.
AB  - OBJECTIVE: To examine the outcome expectations of RA patients, rheumatologists,
      and physiotherapists regarding high intensity exercise programmes compared with
      conventional exercise programmes. METHODS: An exercise outcome expectations
      questionnaire was administered to 807 RA patients, 153 rheumatologists, and 624
      physiotherapists. The questionnaire consisted of four statements regarding
      positive and negative outcomes of high intensity exercise programmes and four
      similar statements for conventional exercise programmes. A total expectation
      score for both conventional and high intensity exercise was calculated, ranging
      from -2 (very negative expectation) to 2 (very positive expectation). RESULTS:
      The questionnaire was returned by 662 RA patients (82%), 132 rheumatologists
      (86%), and 467 physiotherapists (75%). The mean (95% confidence interval) scores
      for high intensity exercise programmes were 0.30 (0.25 to 0.34), 0.68 (0.62 to
      0.74), and -0.06 (-0.15 to 0.02), and for conventional exercise programmes were
      0.99 (0.96 to 1.02), 1.13 (1.09 to 1.17), and 1.27 (1.21 to 1.34) for RA
      patients, rheumatologists, and physiotherapists, respectively. In all three
      respondent groups, the outcome expectations of high intensity exercise were
      significantly less positive than those of conventional exercise programme.
      CONCLUSIONS: Despite the existing evidence regarding the effectiveness and safety
      of high intensity exercise programmes, RA patients, rheumatologists, and
      physiotherapists have more positive expectations of conventional exercise
      programmes than of high intensity exercise programmes. Physiotherapists were the
      least positive about outcomes of high intensity exercise programmes while
      rheumatologists were the most positive. To help the implementation of new
      insights in the effectiveness of physical therapy modalities in rheumatology, the
      need for continuous education of patients, rheumatologists and physiotherapists
      is emphasised.

PMID- 15194577
TI  - Determinants of direct costs in Dutch rheumatoid arthritis patients.
AB  - OBJECTIVES: To estimate annual direct costs in four distinct disease duration
      groups (0 to < or =2, 2 to < or =6, 6 to < or =10, and >10 years) of patients
      with rheumatoid arthritis (RA), to determine predictors of high costs and to
      describe characteristics of patients with high and with low costs. METHODS: A
      questionnaire assessing RA related care and resource utilisation rates and costs
      was completed by 615 RA patients. Predictive variables for incurred costs, as
      observed during the first year after disease onset, were determined in a subgroup
      of patients (n = 347). RESULTS: Mean (median) annual direct costs for the four
      groups with increasing disease duration were respectively: 5235 (2923) Euros,
      3930 (1968) Euros, 4664 (1952)Euros, and 8243 (3778) Euros, (p < 0.05). During
      the first 2 years of the disease total direct costs comprised mainly of
      consultations with healthcare workers (28%). After 10 years, devices and
      adaptations were the main contributors (40%) to total costs. Positive rheumatoid
      factor results at the time of diagnosis and deterioration of functional
      disability in the first year of disease were predictors of high costs later on in
      the course of the disease. CONCLUSION: Annual direct costs among patients with a
      disease duration of less than 2 years tend to be lower among patients with a
      disease duration of between 2 and 10 years than among patients with a disease
      duration of more than 10 years. In addition, the proportional distribution of
      different cost categories to total costs increases with with increasing disease
      duration.

PMID- 15194576
TI  - Possible role of leptin in hypoandrogenicity in patients with systemic lupus
      erythematosus and rheumatoid arthritis.
AB  - BACKGROUND: Hypoandrogenicity is common in obesity and in chronic inflammatory
      diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis
      (RA). Adrenal androgens such as androstenedione (ASD) and dehydroepiandrosterone
      (DHEA) sulphate are low, which partly depends on the influence of TNF in chronic
      inflammatory diseases. Leptin is stimulated by TNF and is associated with
      hypoandrogenicity in non-inflammatory conditions. OBJECTIVE: To study the
      interrelation between serum levels of leptin and adrenal steroids in SLE and RA.
      METHODS: In a retrospective study, serum levels of leptin, ASD, DHEA, and 17
      hydroxyprogesterone (17OHP) were measured by ELISA, and serum levels of cortisol
      by radioimmunoassay in 30 patients with RA, 32 with SLE, and 54 healthy control
      subjects (HS). RESULTS: In SLE and RA but not HS, serum levels of ASD correlated
      negatively with serum levels of leptin (p<0.01) independently of prior
      prednisolone treatment in patients with SLE (p = 0.013) and tended to be
      independent of prednisolone in patients with RA (p = 0.067). In a partial
      correlation analysis, this interrelation remained significant after controlling
      for daily prednisolone dose in both patient groups. In both patient groups, serum
      leptin levels correlated negatively with the molar ratio of serum ASD/serum
      cortisol and serum ASD/serum 17OHP, and positively with the molar ratio of serum
      DHEA/serum ASD. CONCLUSIONS: The negative correlation of serum leptin and ASD or,
      particularly, ASD/17OHP, together with its known anti-androgenic effects indicate
      that leptin is also involved in hypoandrogenicity in patients with SLE and RA.
      Leptin may be an important link between chronic inflammation and the
      hypoandrogenic state.

PMID- 15194578
TI  - Trends in hip and knee joint replacement: socioeconomic inequalities and
      projections of need.
AB  - OBJECTIVES: To examine trends in primary and revision joint (hip and knee)
      replacement in England between 1991 and 2000. METHODS: Analysis of hospital
      episodes statistics between 1 April 1991 and 30 March 2001 for total hip
      replacement (THR) and total knee replacement (TKR). Descriptive statistics and
      regression modelling were used to summarise patients' demographic and clinical
      characteristics and to explore variations in joint surgery rates by age, sex, and
      deprivation. RESULTS: Between 1991 and 2000, the incidence of primary THR
      increased by 18%, while the incidence of revision THR more than doubled. The
      incidence of primary TKR doubled, with revision TKR increasing by 300%. Over the
      10 year period, the proportion of THR episodes that involved revision operations
      rose from 8% to 20%. Substantial variations in operation rates by socioeconomic
      status were seen, with the most deprived fifth of the population experiencing
      significantly lower rates. Projections estimate that primary THR numbers could
      rise by up to 22% by the year 2010, with primary TKR numbers rising by up to 63%.
      CONCLUSIONS: Provision of joint replacement surgery in English NHS hospitals has
      increased substantially over the past decade. Revision operations in particular
      have increased markedly. The growth in primary operations has mostly occurred
      among those aged 60 years and over; rates among young people have changed very
      little. There is a significant deprivation based gradient in rates. If current
      trends continue there would be almost 47 000 primary hip and 54 000 primary knee
      operations annually by 2010.

PMID- 15194579
TI  - Serum amyloid P component levels are not decreased in patients with systemic
      lupus erythematosus and do not rise during an acute phase reaction.
AB  - BACKGROUND: Serum amyloid P component (SAP) and acute phase proteins like C
      reactive protein contribute to the clearance of apoptotic cells. This response is
      diminished in systemic lupus erythematosus (SLE). OBJECTIVES: To analyse SAP
      concentrations in SLE in relation to disease activity, and investigate whether
      SAP reacts like an acute phase protein. METHODS: SAP was measured in 40 patients
      with SLE during active and inactive disease and compared with healthy controls
      and patients with rheumatoid arthritis and Wegener's granulomatosis. Normal SAP
      values were determined in 120 healthy controls by ELISA. C reactive protein and
      serum amyloid A (SAA) were measured in all subjects and their levels related to
      SAP. SAP was also measured serially in 11 patients with breast cancer treated
      with recombinant human interleukin-6, and in 16 patients with sepsis. RESULTS: In
      SLE, SAP was unaltered compared with healthy controls and was not influenced by
      disease activity, in contrast to C reactive protein and SAA, which increased
      during active disease. SAP increased in Wegener's granulomatosis but not in
      rheumatoid arthritis. The rise in C reactive protein and SAA was most pronounced
      in Wegener's granulomatosis with active disease. SAP did not change significantly
      during an acute phase response. No correlation was found between SAP and C
      reactive protein or SAA, but there was a correlation between SAA and C reactive
      protein (r = 0.4989, p = 0.0492). CONCLUSIONS: Patients with SLE have normal
      circulating SAP levels. In contrast to C reactive protein or SAA, SAP does not
      act as an acute phase protein.

PMID- 15194580
TI  - Burden and cost of illness in patients with juvenile idiopathic arthritis.
AB  - OBJECTIVE: To estimate the cost of illness in an incidence based cohort of
      patients with juvenile idiopathic arthritis. METHODS: Direct costs (healthcare
      and non-healthcare costs) and indirect costs (productivity loss due to sick leave
      and work disability) were measured in 215 JIA patients, assessed on an average of
      17 years after disease onset. Assessment included a clinical evaluation, a
      structured interview, and two self completion questionnaires. Annual direct costs
      were estimated based on the reported use of healthcare services and resources,
      using average unit prices. Indirect costs were estimated from the number of work
      days missed-that is, using the human capital approach. RESULTS: The mean total
      cost of late JIA was estimated to be 3500 per patient and year, of which the
      direct cost contributed more than half. Patients with still active disease (55%)
      incurred the major share (90%) of the cost. They had a mean total cost of 5700
      per patient year, with those under rheumatological care incurring a cost of 9300.
      Having a certain JIA subgroup, functional disability, or receipt of specialised
      care independently contributed to the total cost in active JIA. Highest mean
      total costs were found in active seropositive polyarthritis (17 000) and extended
      oligoarthritis (11 000), while the lowest were found in active enthesitis related
      arthritis (1500) and persistent oligoarthritis (2700). CONCLUSIONS: Estimated 12
      month costs in late JIA are considerable, differing among the various JIA
      subgroups. Treatment strategies in JIA should be analysed for their cost
      effectiveness in the long term.

PMID- 15194581
TI  - Vitamin C and the risk of developing inflammatory polyarthritis: prospective
      nested case-control study.
AB  - OBJECTIVE: To investigate whether, there is an association between consumption of
      fruit and vegetables and dietary antioxidants and the risk of developing
      inflammatory polyarthritis (IP). METHODS: In a prospective, population based,
      nested case-control study of residents of Norfolk, UK, men and women aged 45-74
      years were recruited, between 1993 and 1997 through general practice age-sex
      registers to the Norfolk arm of the European Prospective Investigation of Cancer
      (EPIC-Norfolk). Dietary intake was assessed at baseline using 7 day diet diaries.
      Seventy three participants who went on to develop IP between 1993 and 2001 and
      were registered by the Norfolk Arthritis Register (NOAR) were identified.
      Incident cases of IP, assessed by general practitioners, fulfilled the criteria
      of two or more swollen joints, persisting for a minimum of 4 weeks. Each case of
      IP was matched for age and sex with two controls free of IP. RESULTS: Lower
      intakes of fruit and vegetables, and vitamin C were associated with an increased
      risk of developing IP. Those in the lowest category of vitamin C intake, compared
      with the highest, increased their risk of developing IP more than threefold,
      adjusted odds ratio (OR) with 95% confidence intervals (CI) 3.3 (95% CI 1.4 to
      7.9). Weak inverse associations between vitamin E and beta-carotene intake and IP
      risk were found. CONCLUSION: Patients with IP (cases) consumed less fruit and
      vitamin C than matched controls, which appeared to increase their risk of
      developing IP. The mechanism for this effect is uncertain. Thus similar studies
      are necessary to confirm these results.

PMID- 15194583
TI  - Pharmaceutical treatment of symptomatic vertebral fractures in primary care.
AB  - BACKGROUND: Vertebral fractures are associated with a reduction in quality of
      life and are an important predictor of other non-spine fractures. Previous work
      has shown that up to 60% of patients with a vertebral fracture identified in
      primary care remain untreated. OBJECTIVE: To examine the prevalence of
      pharmaceutical treatment and predictors of treatment in a primary care setting.
      METHODS: Case-control study using the general practice research database (GPRD).
      All women aged 50 years and over with a first diagnosis of a vertebral fracture
      since 1990 were identified and matched with a control by age and practice.
      Appropriate use of a pharmaceutical agent was defined as a prescription occurring
      within 30 days of the diagnosis being recorded. RESULTS: We identified 2719 women
      with the same number of controls. Within 30 days of diagnosis 61% of women were
      prescribed treatment, compared with only 3% of the controls. Bisphosphonate was
      the single most important treatment prescribed. Predictors of any drug treatment
      included: year of fracture (most recent year increased the likelihood of
      treatment); age (younger patients were more likely to receive treatment); history
      of back pain; low body weight; history of steroid use. CONCLUSIONS: Treatment of
      diagnosed vertebral fractures is becoming more common. Treated patients tend to
      be younger but to have a higher prevalence of clinical risk factors than
      untreated patients. There remain significant numbers of patients who are not
      offered treatment.

PMID- 15194582
TI  - Relationship between inflammation and joint destruction in early rheumatoid
      arthritis: a mathematical description.
AB  - BACKGROUND: The relationship between inflammation and joint destruction in
      rheumatoid arthritis (RA) has not been unequivocally characterised. Joint
      destruction may result from the cumulative inflammatory burden over time,
      modified by an individual constant factor. OBJECTIVE: To test the hypothesis that
      the relationship between radiological progression and inflammation can
      mathematically be expressed as: [equation: see text] where Re is a factor that
      varies from person to person. METHODS: Clinical data and radiographs of 76
      patients with early RA receiving different disease modifying antirheumatic drugs
      were analysed. Radiographs were quantified using the modified Larsen score and
      the "X-Ray RheumaCoach" software. The cumulative inflammatory burden was
      estimated by the time integrated 28 joint Disease Activity Score (DAS28),
      calculated as the area under the curve. RESULTS: 76 patients with early RA who
      started treatment with methotrexate (n = 20), sulfasalazine (n = 37), or oral
      gold (n = 19) monotherapy were evaluated. The mean (SEM) DAS28 decreased from 4.6
      (0.1) at baseline to 2.3 (0.1) after 2 years. The mean (SEM) DeltaLarsen score
      from baseline to year 2 was 10.3 (1.5). Correlation between cumulative
      inflammation and radiographic change was poor. In contrast, when calculating a
      person's factor Re in year 1 ( Re 1) and year 2 ( Re 2), a strong and significant
      correlation (r = 0.58, p<0.000001) was seen between Re 1 and Re 2. CONCLUSIONS:
      Joint destruction is the result of the cumulative burden of inflammation over
      time, modified by an individual factor Re that remains relatively constant over
      the first 2 years of observation. The data support a mathematical model that
      expresses the interrelationship between inflammation and joint destruction.

PMID- 15194584
TI  - Effects of ibuprofen on molecular markers of cartilage and synovium turnover in
      patients with knee osteoarthritis.
AB  - OBJECTIVE: The aim of this study was to evaluate the effect of ibuprofen on the
      urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX
      II) and urinary glucosyl galactosyl pyridinoline (Glc-Gal-PYD), two new molecular
      markers of cartilage and synovial tissue metabolism, respectively, in patients
      with knee osteoarthritis (OA). METHODS: We studied 201 patients with knee pain
      and radiographic evidence of knee OA who were on treatment with non-steroidal
      anti-inflammatory drugs (NSAIDs) prior to study initiation. After an initial
      screening visit, patients were withdrawn from their pre-study NSAID and,
      following a flare of their OA symptoms, were randomised to ibuprofen (2400
      mg/day) or placebo. Urinary CTX-II and Glc-Gal-PYD levels were measured at time
      of randomisation (baseline) and after 4-6 weeks of treatment. RESULTS: After 4 to
      6 weeks, urinary CTX-II (+17%, p = 0.023) and Glc-Gal-PYD (+10%, p = 0.020)
      increased significantly from baseline in the placebo group whereas marginal or no
      increase was observed in the ibuprofen group (CTX-II +2%, NS and Glc-Gal-PYD +4%,
      p = 0.045). For urinary CTX-II, the difference in the change from baseline
      between placebo and ibuprofen treated groups was significant (13%, p = 0.017). At
      baseline, urinary levels of CTX-II and Glc-Gal-PYD were higher in patients with
      knee swelling (n = 127) than in those without (n = 74) (p<0.02 for both markers).
      When patients were stratified according to presence or absence of knee swelling
      at baseline, the increases over 4-6 weeks of urinary CTX-II and Glc-Gal-PYD in
      the placebo group were restricted to patients with knee swelling (+22% from
      baseline, p = 0.001 and +12%, p = 0.011, for urinary CTX-II and Glc-Gal-PYD
      respectively). In patients with knee swelling who were treated with ibuprofen
      this increase was not observed and the difference from placebo was significant
      for urinary CTX-II (p = 0.014). CONCLUSION: In patients with a flare of knee OA,
      specifically in patients with evidence of joint inflammation documented by knee
      swelling, there was a significant increase in markers reflecting cartilage and
      synovium metabolism that could partly be prevented by high doses of ibuprofen.
      These data suggest that patients with a flare of knee OA are characterised by
      increased cartilage and synovial tissue degradation, which may be partly
      prevented by high doses of NSAIDs.

PMID- 15194585
TI  - Autoantibodies against granulocyte-macrophage colony stimulating factor and
      interleukin-3 are rare in patients with Felty's syndrome.
AB  - OBJECTIVES: Antibodies against granulocyte colony stimulating factor are
      frequently found in patients with Felty's syndrome (FS). In this study, we
      examined the prevalence of antibodies against two other granulopoietic cytokines:
      granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-3
      (IL3). METHODS: Sera of 32 patients with FS, 20 normocytic patients with
      rheumatoid arthritis (RA), and 72 healthy individuals were screened for the
      presence of antibodies against GM-CSF and IL3 by ELISA and bioassays, using the
      human erythroleukaemia cell line TF-1. RESULTS: In two of the 32 patients with
      FS, antibodies to GM-CSF and IL3 were detectable by ELISA. Binding anti-GM-CSF
      antibodies were also detected in one of the 72 healthy controls, while in another
      healthy subject and in one of the patients with normocytic RA, anti-IL3
      antibodies were present. Serum from one of the two patients with FS who tested
      positive for anti-IL3 and anti-GM-CSF antibodies by ELISA showed strong
      neutralising capacity to the biological effect of IL3, but not to GM-CSF in
      vitro. Patients with FS had significantly higher serum levels of GM-CSF (median;
      2.82 pg/mL; interquartile range 2.64-3.19 pg/mL) compared with patients with RA
      (2.52 pg/mL; 2.28-2.72 pg/mL; p = 0.012) and healthy controls (2.23 pg/mL; 2.04
      2.52; p<0.001). In addition, serum levels of IL3 in patients were significantly
      higher in FS (10.05 pg/mL; 8.94-11.98) compared with controls (4.79 pg/mL; 3.72
      7.22; p<0.001), but not compared with RA patients (9.52 pg/mL; 8.32-10.42; p =
      0.17). CONCLUSIONS: Antibodies to GM-CSF and IL3 are rare in patients with FS and
      RA and in healthy subjects. In individual patients with FS, the presence of
      neutralising anti-IL3 antibodies may contribute to the development of cytopenia.

PMID- 15194587
TI  - Correlation between 18-fluorodeoxyglucose accumulation in large vessels and
      serological markers of inflammation in polymyalgia rheumatica: a quantitative PET
      study.
AB  - OBJECTIVE: To quantify 18-fluorodeoxyglucose (FDG) accumulation in large vessels
      in patients with polymyalgia rheumatica by positron emission tomography (PET),
      and to compare these data with serological markers of inflammation. METHODS: 13
      untreated patients with active polymyalgia rheumatica underwent FDG positron
      emission tomography; eight were analysed in a second PET when in clinical
      remission. Six patients with other highly inflammatory conditions served as
      controls. For quantitative analysis, FDG uptake over nine defined vascular
      regions, divided by an individual background value, was expressed as a region of
      interest (ROI) index. These data were compared with the clinical status of the
      patient and with erythrocyte sedimentation rate (ESR), C reactive protein,
      haemoglobin, and platelet and leucocyte counts. RESULTS: By visual evaluation, 12
      of the 13 patients showed an increased tracer uptake of the aorta or its major
      branches. By quantitative analysis, FDG uptake was significantly increased in
      polymyalgia rheumatica. In patients with active disease, the mean ROI index for
      all vascular regions exceeded that of controls by 70% (mean (SD): 1.58 (0.37) v
      0.93 (0.12); p<0.001). In the eight patients who underwent follow up PET, the
      index declined substantially. In active polymyalgia rheumatica, FDG uptake was
      significantly correlated with C reactive protein (r = 0.8), ESR (r = 0.79), and
      platelet counts (r = 0.68). CONCLUSIONS: The observed FDG accumulation in the
      aorta and its branches and a strong correlation between tracer uptake and markers
      of inflammation is suggestive of large vessel arteritis. Quantitative ROI
      analysis appears to be a sensitive tool for detecting such inflammation.

PMID- 15194588
TI  - Incidence of primary Sjogren's syndrome in Slovenia.
AB  - OBJECTIVE: To determine the annual incidence of primary Sjogren's syndrome (pSS)
      in Slovenia. METHODS: All patients admitted to our department of rheumatology or
      referred to our outpatient clinic between 1 January 2000 and 31 December 2002
      owing to sicca symptoms or because of a suspicion of SS were examined. Our
      rheumatological department is the only tertiary referral centre for the Ljubljana
      region, which has a population of 599 895 Caucasian people. All patients were
      evaluated by the validated European criteria for SS. The exact 95% confidence
      interval (CI) based on binomial distribution was created for the incidence
      estimate. RESULTS: 248 patients were examined; 71 of them (28.6%; 65 women, 6
      men) were diagnosed as having pSS. Their mean (SD) age was 51.3 (14.5) years
      (range 19-78). The average annual incidence for pSS in our study population was
      calculated as 3.9 cases per 100 000 inhabitants (95% CI 1.1 to 10.2). CONCLUSION:
      The estimated annual incidence of pSS in Slovenia is 3.9/100 000.

PMID- 15194586
TI  - Simvastatin reduces MMP-3 level in interleukin 1beta stimulated human chondrocyte
      culture.
AB  - OBJECTIVES: Matrix metalloproteinases (MMPs) produced by chondrocytes play a role
      in the development of cartilage degradation in joint diseases. Moreover,
      inhibition of MMP secretion by macrophages accumulating in arteriosclerotic
      plaques would account for the plaque stabilising activity of statins in
      cardiovascular patients. Recently, simvastatin has been shown to inhibit both
      developing and established collagen induced arthritis in a murine model. We thus
      decided to investigate the effect of simvastatin on the production of MMP-3 from
      cultured interleukin (IL)1 stimulated human chondrocytes. METHODS: Cells from
      human cartilage, obtained from eight subjects with osteoarthritis undergoing
      surgery for total hip prostheses, were cultured in the presence of different
      concentrations of simvastatin (5, 10, and 50 micromol/l) with and without IL1beta
      (5 ng/ml). MMP-3 level was measured in the culture medium after 48 h of
      incubation. RESULTS: IL1beta stimulation of chondrocytes increased MMP-3
      concentration in the cultures (from 0.69 (0.09) to 1.94 (0.12) ng/microg
      protein). Incubation with simvastatin was associated with a dose dependent
      reduction in MMP-3 increase, both in the presence (-15%, -17%, and -26% with 5,
      10, and 50 micromol/l, respectively) and in the absence (-32% with 50 micromol/l)
      of IL1beta. The inhibiting effect of simvastatin was completely reversed by the
      addition of mevalonate (100 micromol/l) or farnesol (10 micromol/l). CONCLUSIONS:
      Our data show that simvastatin, by blocking HMGCoA-reductase and interfering in
      the prenylation processes, is able to inhibit MMP-3 production from cultured
      human chondrocytes that have been either unstimulated or stimulated with IL1beta,
      thus suggesting a possible additional mechanism for statins in counteracting
      chronic joint disease related cartilage damage.

PMID- 15194589
TI  - Fcgamma receptor IIa, IIIa, and IIIb polymorphisms of systemic lupus
      erythematosus in Taiwan.
AB  - OBJECTIVE: To determine whether the distribution of Fcgamma receptor IIa, IIIa,
      and IIIb polymorphisms confers a risk factor for disease susceptibility, and
      correlates with the clinical characteristics and serological parameters of
      patients with SLE in Taiwan. METHODS: Genotyping of Fcgamma receptors IIa H/R131,
      IIIa F/V158, and IIIb NA1/NA2 was performed in 302 patients with SLE and 311
      healthy blood donor controls. The distribution of Fcgamma receptor IIa, IIIa, and
      IIIb genotypes in patients and controls was analysed. Frequencies of three
      Fcgamma receptor polymorphisms were also compared between lupus patients with and
      without different clinical manifestations and autoantibodies. RESULTS: No
      significant skewing in the distribution of Fcgamma RIIa H/R131, Fcgamma RIIIa
      F/V158, and Fcgamma RIIIb NA1/NA2 was found between patients and controls in
      Taiwan. The following clinical associations were found: Fcgamma RIIIb NA1/NA1
      protected against neuropsychiatric lupus (p = 0.028) but conferred susceptibility
      to discoid rash (p<0.005); increased Fcgamma RIIIa V/V158 was associated with
      infections (p = 0.039); increased Fcgamma RIIa H/H131 was associated with earlier
      onset of lupus (p = 0.01). CONCLUSION: Fcgamma receptor IIa, IIIa, and IIIb
      polymorphisms may be responsible for the development of distinct manifestations
      of lupus patients in Taiwan, but there is no significantly skewed distribution in
      the susceptibility to lupus as a whole.

PMID- 15194591
TI  - Methotrexate (MTX) and albumin coupled with MTX (MTX-HSA) suppress synovial
      fibroblast invasion and cartilage degradation in vivo.
AB  - OBJECTIVE: To investigate the effect of methotrexate (MTX) and albumin coupled
      with methotrexate (MTX-HSA) on cartilage invasion and induction of
      perichondrocytic degradation by rheumatoid arthritis synovial fibroblasts (RA SF)
      in vivo. METHODS: Human cartilage and RA SF were co-transplanted in three groups
      of severe combined immunodeficient mice (SCID), which received 1 mg/kg free MTX
      (n = 9), 1 mg/kg MTX-HSA (n = 6), or 0.9% NaCl (n = 5), respectively,
      intraperitoneally twice a week. After 4 weeks' treatment, the mice were killed
      and the implants analysed histologically. RESULTS: The control group had a mean
      (SEM) score for cartilage invasion of RA SF of 2.0 (0.26) and for
      perichondrocytic cartilage degradation of 1.5 (0.34). In contrast, mice which
      received MTX showed a significantly reduced invasion (0.78 (0.14), p<0.01) and a
      reduction in perichondrocytic cartilage degradation scores (0.69 (0.2), p<0.05)
      in comparison with the control group. Mice treated with MTX-HSA also had
      significantly reduced scores for RA SF invasion into the cartilage (0.92 (0.41),
      p<0.05) and for cartilage degradation (0.83 (0.44), p<0.05) compared with
      controls. The effects of MTX and MTX-HSA were not significantly different between
      these two groups. CONCLUSION: Treatment with MTX or MTX-HSA significantly
      ameliorates cartilage destruction in the SCID mouse model for human RA.

PMID- 15194590
TI  - MMP profile in paired serum and synovial fluid samples of patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: To analyse matrix metalloproteinases (MMPs) and tissue inhibitor-1 of
      MMPs (TIMP-1) levels in the systemic circulation and synovial fluid (SF) of
      patients with RA and to compare these levels with inflammatory and collagen
      degradation markers. METHODS: ProMMP-1, -2, -3, -8, -9, TIMP-1, levels of
      MMP/alpha(2)-macroglobulin complexes, and collagen degradation products were
      measured by sandwich ELISA, activity assays, and HPLC in paired SF and serum
      samples from 15 patients with RA and 13 with OA. RESULTS: MMPs were higher in SF
      of patients with RA than in OA or controls. MMP levels in SF of patients with OA
      were higher than in controls. In serum, levels of proMMP-3, -8 and -9 were higher
      in patients with RA than in OA or controls, whereas only proMMP-8 and -9 were
      higher in serum of patients with OA than in controls. A strong correlation was
      seen between serum and SF levels of MMP-8 and -9 in RA. Increased levels of
      MMP/alpha(2)-macroglobulin complexes indicated an MMP/TIMP imbalance in serum and
      SF in RA. SF hydroxyproline correlated significantly with SF levels of proMMP-9
      in RA. CONCLUSIONS: Systemic MMP-8 and -9 levels represent the situation in the
      inflamed joint; MMP-9 is likely to be involved in degradation of joint collagen.
      The hypothesis of MMP/TIMP imbalance in RA is strengthened.

PMID- 15194592
TI  - An unusual presentation of a common disease.

PMID- 15194593
TI  - Combined therapy for pyoderma gangrenosum.

PMID- 15194594
TI  - Benefit of immunosuppression for severe Takayasu's arteritis and coincident
      primary biliary cirrhosis.

PMID- 15194595
TI  - Effect of etanercept on matrix metalloproteinases and angiogenic vascular
      endothelial growth factor: a time kinetic study.

PMID- 15194596
TI  - Cytokine profile of bronchoalveolar lavage in systemic sclerosis with
      interstitial lung disease: comparison with usual interstitial pneumonia.

PMID- 15194597
TI  - Gout in liver transplant patients receiving tacrolimus.

PMID- 15194598
TI  - Etanercept is effective in patients with rheumatoid arthritis with no response to
      infliximab therapy.

PMID- 15194599
TI  - Stigma, shame, and blame experienced by patients with lung cancer: qualitative
      study.
AB  - OBJECTIVES: To draw on narrative interviews with patients with lung cancer and to
      explore their perceptions and experience of stigma. DESIGN: Qualitative study.
      SETTING: United Kingdom. PARTICIPANTS: 45 patients with lung cancer recruited
      through several sources. RESULTS: Participants experienced stigma commonly felt
      by patients with other types of cancer, but, whether they smoked or not, they
      felt particularly stigmatised because the disease is so strongly associated with
      smoking. Interaction with family, friends, and doctors was often affected as a
      result, and many patients, particularly those who had stopped smoking years ago
      or had never smoked, felt unjustly blamed for their illness. Those who resisted
      victim blaming maintained that the real culprits were tobacco companies with
      unscrupulous policies. Some patients concealed their illness, which sometimes had
      adverse financial consequences or made it hard for them to gain support from
      other people. Some indicated that newspaper and television reports may have added
      to the stigma: television advertisements aim to put young people off tobacco, but
      they usually portray a dreadful death, which may exacerbate fear and anxiety. A
      few patients were worried that diagnosis, access to care, and research into lung
      cancer might be adversely affected by the stigma attached to the disease and
      those who smoke. CONCLUSION: Patients with lung cancer report stigmatisation with
      far reaching consequences. Efforts to help people to quit smoking are important,
      but clinical and educational interventions should be presented with care so as
      not to add to the stigma experienced by patients with lung cancer and other
      smoking related diseases.

PMID- 15194602
TI  - NBIC Convergence 2003: Converging Technologies for Improving Human Performance.
      February 5-7, 2003, Los Angeles, California, USA. Proceedings.

PMID- 15194600
TI  - Blood pressure control by home monitoring: meta-analysis of randomised trials.
AB  - OBJECTIVE: To determine the effect of home blood pressure monitoring on blood
      pressure levels and proportion of people with essential hypertension achieving
      targets. DESIGN: Meta-analysis of 18 randomised controlled trials. PARTICIPANTS:
      1359 people with essential hypertension allocated to home blood pressure
      monitoring and 1355 allocated to the "control" group seen in the healthcare
      system for 2-36 months. MAIN OUTCOME MEASURES: Differences in systolic (13
      studies), diastolic (16 studies), or mean (3 studies) blood pressures, and
      proportion of patients achieving targets (6 studies), between intervention and
      control groups. RESULTS: Systolic blood pressure was lower in people with
      hypertension who had home blood pressure monitoring than in those who had
      standard blood pressure monitoring in the healthcare system (standardised mean
      difference 4.2 (95% confidence interval 1.5 to 6.9) mm Hg), diastolic blood
      pressure was lower by 2.4 (1.2 to 3.5) mm Hg, and mean blood pressure was lower
      by 4.4 (2.0 to 6.8) mm Hg. The relative risk of blood pressure above
      predetermined targets was lower in people with home blood pressure monitoring
      (risk ratio 0.90, 0.80 to 1.00). When publication bias was allowed for, the
      differences were attenuated: 2.2 (-0.9 to 5.3) mm Hg for systolic blood pressure
      and 1.9 (0.6 to 3.2) mm Hg for diastolic blood pressure. CONCLUSIONS: Blood
      pressure control in people with hypertension (assessed in the clinic) and the
      proportion achieving targets are increased when home blood pressure monitoring is
      used rather than standard blood pressure monitoring in the healthcare system. The
      reasons for this are not clear. The difference in blood pressure control between
      the two methods is small but likely to contribute to an important reduction in
      vascular complications in the hypertensive population.

PMID- 15194601
TI  - Atypical antipsychotic drugs in the treatment of behavioural and psychological
      symptoms of dementia: systematic review.
AB  - OBJECTIVE: To review the role of oral atypical antipsychotic drugs in the
      management of the behavioural and psychological symptoms of dementia (BPSD). DATA
      SOURCES: Medline, Embase, and the Cochrane Library. Reference lists were reviewed
      and experts were contacted to identify additional trials. STUDY SELECTION: Double
      blind randomised controlled trials that evaluated the four oral atypical
      antipsychotic therapies for BPSD. REVIEW METHODS: Two reviewers assessed trial
      validity independently. DATA EXTRACTION: Demographics of patients, study
      duration, dose of antipsychotic, primary end points, adverse events. RESULTS: 77
      abstracts were reviewed. Five randomised trials (1570 patients) evaluating
      risperidone and olanzapine were identified. The quality of trials was generally
      good. Most participants were in an institution (> 96%), elderly (weighted mean
      82.3 years), and had Alzheimer's disease (76.3%). Trials lasted 6-12 weeks.
      Treatment with atypical antipsychotic drugs was superior to placebo for the
      primary end point in three of the five trials. Two trials comparing risperidone
      with haloperidol did not find any differences in the primary measures of
      efficacy. Adverse events were common and included extrapyramidal symptoms,
      somnolence, and abnormal gait. CONCLUSIONS: Although atypical antipsychotic drugs
      are being used with increasing frequency, few randomised trials have evaluated
      their use for BPSD. Limited evidence supports the perception of improved efficacy
      and adverse event profiles compared with typical antipsychotic drugs.

PMID- 15194603
TI  - Science and technology integration for increased human potential and societal
      outcomes.
AB  - Unifying science based on the material unity of nature at the nanoscale provides
      a new foundation for knowledge, innovation, and integration of technology.
      Revolutionary and synergistic advances at the interfaces between previously
      separated fields of science, engineering and areas of relevance are ready to
      create nano-bio-info-cogno (NBIC) transforming tools. Developments in systems
      approach, mathematics, and computation in conjunction with NBIC allow us to
      understand the natural world and scientific research as closely coupled, complex,
      hierarchical entities. At this unique moment of scientific and technical
      achievement, improvement of human performance at individual and group levels, as
      well as development of suitable revolutionary products, becomes possible and
      these are primary goals for converging new technologies. NBIC addresses long-term
      advances in key areas of human activity, including working, learning, aging,
      group interaction, organizations, and human evolution ((Roco and Bainbridge,
      2003)). Fundamentally new tools, technologies, and products will be integrated
      into individual and social human architecture. This introductory chapter of the
      Annals outlines research and education trends, funding activities, and the
      potential of development of revolutionary products and services.

PMID- 15194604
TI  - Vision for converging technologies and future society.
AB  - This brief presentation places the challenges of nanotechnology in a political,
      social, and economic context.

PMID- 15194605
TI  - Collaborating on convergent technologies: education and practice.
AB  - Converging technologies will require collaboration across disciplines. A good
      metaphor for such collaborations is the kind of trading zone that emerges
      whenever human beings from different cultures interact. NBIC must avoid trading
      zones that are dominated by one discipline or set of interests and instead
      encourage multiple stakeholders to form a shared mental model of what needs to be
      accomplished. An example is drawn from current work on societal dimensions of
      nanotechnology. Students need to gain experience working in such trading zones,
      in addition to acquiring disciplinary depth.

PMID- 15194606
TI  - Integrative technology for the twenty-first century.
AB  - Presented is the concept of Integrative Technology, the intersection of the
      precision assembly of matter (nanotechnology), coupled with the functional
      building blocks of nature (biotechnology), and fused by the network flow of
      spatiotemporal information (informatics). The power of Integrative Technology is
      illuminated through an illustrative example; the engineering of nano-sized
      excitable vesicles with the ability to intrinsically process information. The
      fusion of the tools of nanotechnology and biotechnology to produce excitable
      vesicles is described, as is the mechanics of information flow that ultimately
      lead to the manifestations of emergent higher-order behavior. Finally, the
      potential of using systems engineered and produced from nanoscale components to
      create complex systems and materials that manifest embedded functional behavior
      is discussed.

PMID- 15194607
TI  - Converging technologies for enhancing human performance: science and business
      perspectives.
AB  - Our goal is to provide a rough sketch of some of the possible implications of
      converging technologies for enhancing human performance ((Roco and Bainbridge,
      2002)) from both a science and a business perspective. Converging technologies
      refers to a type of coevolutionary progress that is characterized by rapid
      advances across multiple areas of technology (nano-bio-info-cogno or NBIC),
      accelerated by interdisciplinary cross-fertilization as the advances in one area
      spill over and speed progress in other areas. The rapid, multi-front progress
      characteristic of converging technologies results in better technological
      capabilities which are faster and cheaper, and can be broadly applied for many
      different purposes. In this paper, we specifically explore applications of
      converging technologies for enhancing human performance, that is, enhancing our
      human ability to achieve goals both individually and collectively. These
      applications hold the promise to make people healthier, wealthier, and wiser as
      well as to make businesses more responsive, resilient, and adaptive.

PMID- 15194608
TI  - Tactile sensory substitution studies.
AB  - Forty years ago a project to explore late brain plasticity was initiated that was
      to lead into a broad area of sensory substitution studies. The questions at that
      time were: Can a person who has never seen learn to see as an adult? Is the brain
      sufficiently plastic to develop an entirely new sensory system? The short answer
      to both questions is yes, first clearly demonstrated in 1969 ((Bach-y-Rita et
      al., 1969)). To reach that conclusion, it was first necessary to find a way to
      get visual information to the brain. That took many years and is still the most
      challenging aspect of the research and the development of practical sensory
      substitution and augmentation systems. The sensor array is not a problem: a TV
      camera for blind persons; an accelerometer for persons with vestibular loss; a
      microphone for deaf persons. These are common and fully developed devices. The
      problem is the brain-machine interface (BMI). In this short report, only two
      substitution systems are discussed, vision and vestibular substitution.

PMID- 15194609
TI  - Bio-inspired nano-sensor-enhanced CNN visual computer.
AB  - Nanotechnology opens new ways to utilize recent discoveries in biological image
      processing by translating the underlying functional concepts into the design of
      CNN (cellular neural/nonlinear network)-based systems incorporating
      nanoelectronic devices. There is a natural intersection joining studies of
      retinal processing, spatio-temporal nonlinear dynamics embodied in CNN, and the
      possibility of miniaturizing the technology through nanotechnology. This
      intersection serves as the springboard for our multidisciplinary project.
      Biological feature and motion detectors map directly into the spatio-temporal
      dynamics of CNN for target recognition, image stabilization, and tracking. The
      neural interactions underlying color processing will drive the development of
      nanoscale multispectral sensor arrays for image fusion. Implementing such
      nanoscale sensors on a CNN platform will allow the implementation of device
      feedback control, a hallmark of biological sensory systems. These biologically
      inspired CNN subroutines are incorporated into the new world of analog-and-logic
      algorithms and software, containing also many other active-wave computing
      mechanisms, including nature-inspired (physics and chemistry) as well as PDE
      based sophisticated spatio-temporal algorithms. Our goal is to design and develop
      several miniature prototype devices for target detection, navigation, tracking,
      and robotics. This paper presents an example illustrating the synergies emerging
      from the convergence of nanotechnology, biotechnology, and information and
      cognitive science.

PMID- 15194610
TI  - Object-oriented design tools for supramolecular devices and biomedical
      nanotechnology.
AB  - Nanotechnology provides multifunctional agents for in vivo use that increasingly
      blur the distinction between pharmaceuticals and medical devices. Realization of
      such therapeutic nanodevices requires multidisciplinary effort that is difficult
      for individual device developers to sustain, and identification of appropriate
      collaborations outside ones own field can itself be challenging. Further, as in
      vivo nanodevices become increasingly complex, their design will increasingly
      demand systems level thinking. System engineering tools such as object-oriented
      analysis, object-oriented design (OOA/D) and unified modeling language (UML) are
      applicable to nanodevices built from biological components, help logically manage
      the knowledge needed to design them, and help identify useful collaborative
      relationships for device designers. We demonstrate the utility of these systems
      engineering tools by reverse engineering an existing molecular device (the bacmid
      molecular cloning system) using them, and illustrate how object-oriented
      approaches identify fungible components (objects) in nanodevices in a way that
      facilitates design of families of related devices, rather than single inventions.
      We also explore the utility of object-oriented approaches for design of another
      class of therapeutic nanodevices, vaccines. While they are useful for design of
      current nanodevices, the power of systems design tools for biomedical
      nanotechnology will become increasingly apparent as the complexity and
      sophistication of in vivo nanosystems increases. The nested, hierarchical nature
      of object-oriented approaches allows treatment of devices as objects in higher
      order structures, and so will facilitate concatenation of multiple devices into
      higher-order, higher-function nanosystems.

PMID- 15194611
TI  - Systems theory and the ethics of human enhancement: a framework for NBIC
      convergence.
AB  - Representatives from government and the private sector recommend a major,
      cooperative initiative directed toward using NBIC (nano-, bio-, info-, and cogno
      ) technologies for human enhancement. By appropriately seeding the convergence of
      NBIC domains, they believe that the rate of development can be both accelerated
      and simultaneously channeled to avoid adverse risk and advance human good.
      However, to accomplish these goals, leaders of the convergence efforts identified
      as a major intellectual barrier the "development of a hierarchical architecture
      for integrating science across many scales, disciplines, and data modalities."
      Such a holistic framework requires a radical rethinking of the nature of science
      and engineering, and, beyond this, is also necessary for addressing their
      normative ethical and societal implications. In the first part of this essay, I
      consider the claim that a new view of science and engineering is needed. After
      reviewing the central features of a classical view of science, I consider aspects
      of the nano-revolution, showing why the classical conception is inappropriate and
      how a systems-oriented perspective is responsive to the character of this new
      science. I then consider how both science and engineering are transformed,
      calling into question older dichotomies between pure and applied domains. With
      the reworking of this distinction comes opportunities for rethinking the relation
      between science and the humanities more generally, which is necessary if we are
      to more appropriately address normative ethical aspects of the convergence
      initiative. After providing this groundwork for the needed hierarchical
      architecture, I consider a useful example of how a systems perspective might
      guide NBIC convergence. In the 1960s-1990s George Engel advocated a systems
      theoretic model as an alternative to a more reductionistic "biomedical model" in
      medicine, and he did it for the exact same reasons as those advocated by the
      leaders of the NBIC convergence; namely, it embodies a more appropriate notion of
      science and enables one to address ethical aspects of medicine that were
      insufficiently addressed in the older model. By reviewing Engel's
      "biopsychosocial model" we can learn important lessons for developing the needed
      NBIC framework. I close by extending Engel's model so that it addresses all areas
      of enhancement envisioned as a part of NBIC convergence, and then identify areas
      where future research is still needed.

PMID- 15194613
TI  - How the legal system should change as a result of converging technologies.
AB  - A forecast is given for how the legal system will change to meet some of the
      challenges for improvement that converging technologies raise for society.

PMID- 15194612
TI  - The evolution of semantic systems.
AB  - Semantic or cultural systems are sets of concepts connected by meaningful
      relationships, and they exhibit properties similar to those of populations of
      biological organisms. Drawing upon ideas from evolutionary biology and methods
      from information technology, this article explores the potential for research and
      engineering on the evolution of semantic systems. Such work in cultural genetics
      requires two things: (1) a rigorous but evolving taxonomic system to categorize
      cultural artifacts, elements, and clusters, and (2) a set of hypotheses about the
      processes that cause evolutionary change. This article illustrates systematic
      approaches to cultural taxonomy with data on the popular ideology of the space
      program, science fiction motion pictures, nanotechnology books, and
      nanotechnology research grants. It offers hypotheses derived from evolutionary
      and population biology that might be useful in explaining cultural evolution.

PMID- 15194614
TI  - Designing the future: NBIC technologies and human performance enhancement.
AB  - Never before has any civilization had the unique opportunity to enhance human
      performance on the scale that we will face in the near future. The convergence of
      nanotechnology, biotechnology, information technology, and cognitive science
      (NBIC) is creating a set of powerful tools that have the potential to
      significantly enhance human performance as well as transform society, science,
      economics, and human evolution. As the NBIC convergence becomes more understood,
      the possibility that we may be able to enhance human performance in the three
      domains of therapy, augmentation, and designed evolution will become anticipated
      and even expected. In addition, NBIC convergence represents entirely new
      challenges for scientists, policymakers, and business leaders who will have, for
      the first time, vast new and powerful tools to shape markets, societies, and
      lifestyles. The emergence of NBIC convergence will challenge us in new ways to
      balance risk and return, threat and opportunity, and social responsibility and
      competitive advantage as we step into the 21st century.

PMID- 15194615
TI  - Multidisciplinary opportunities and challenges in NBIC.
AB  - This paper is divided into two primary sections: challenges and opportunities in
      the field of NBIC. Potential interactions between information technology and
      cognitive technology are principally discussed.

PMID- 15194616
TI  - To think bigger thoughts: why the Human Cognome Project requires visual language
      tools to address social messes.
AB  - The need and use of visual languages in complex situations is outlined.

PMID- 15194617
TI  - Neuroethical considerations: cognitive liberty and converging technologies for
      improving human cognition.
AB  - Developers of NBIC (Nano-Bio-Info-Cogno) technologies face a multitude of
      obstacles, not the least of which is navigating the public ethics of their
      applied research. Biotechnologies have received widespread media attention and
      spawned heated interest in their perceived social implications. Now, in view of
      the rapidly expanding purview of neuroscience and the growing array of
      technologic developments capable of affecting or monitoring cognition, the
      emerging field of neuroethics calls for a consideration of the social and ethical
      implications of neuroscientific discoveries and trends. To negotiate the complex
      ethical issues at stake in new and emerging kinds of technologies for improving
      human cognition, we need to overcome political, disciplinary, and religious
      sectarianism. We need analytical models that protect values of personhood at the
      heart of a functional democracy-values that allow, as much as possible, for
      individual decision-making, despite transformations in our understanding and
      ability to manipulate cognitive processes. Addressing cognitive enhancement from
      the legal and ethical notion of "cognitive liberty" provides a powerful tool for
      assessing and encouraging NBIC developments.

PMID- 15194618
TI  - Neurotechnology and society (2010-2060).
AB  - To illuminate the societal implications of NBIC (nano-bio-info-cogno)
      technologies it is critical to place them within a broad historical context. By
      viewing recent human history as a series of techno-economic waves with
      accompanying socio-political responses, a framework emerges that can be used to
      understand how business, politics, and human culture will be affected by NBIC
      technologies. One important development that the NBIC convergence is making
      possible is neurotechnology, the set of tools that can influence the human
      central nervous system, especially the brain. The diffusion of neurotechnology
      will give rise to a new type of human society-a post-industrial, post
      informational neurosociety.

PMID- 15194619
TI  - Early convergence research and education supported by the National Science
      Foundation.
AB  - The following pages describe research grants awarded by the National Science
      Foundation that illustrate how different fields of science and technology can
      converge in order to increase human potential. Technological convergence involves
      the unification of the sciences of Nanotechnology, Biotechnology, Information
      Technology, and new technologies based on Cognitive Science (NBIC). Because it
      supports research across all major branches of science and technology, including
      the social and behavioral sciences, the NSF has been a focus of discussions about
      converging technologies to enhance human capabilities and serve human needs.

PMID- 15194620
TI  - Estimate of uncertainty of measurement from a single-laboratory validation study:
      application to the determination of lead in blood.
AB  - BACKGROUND: Lead is an environmental pollutant, and human exposure is assessed by
      monitoring lead concentrations in blood. Because the main source of environmental
      exposure has been the use of leaded gasoline, its phase-out has led to decreased
      lead concentrations in the general population. Therefore, validated analytical
      methods for the determination of lower lead concentrations in blood (<150
      microg/L) are needed. In addition, new ISO standards require that laboratories
      determine and specify the uncertainty of their results. METHODS: We validated a
      method to determine lead in blood at concentrations up to 150 microg/L by
      electrothermal atomic absorption spectrometry with Zeeman background correction
      according to EURACHEM guidelines. Blood samples were diluted (1:1 by volume) with
      2 mL/L Triton X-100. NH4H2PO4 (5 g/L) and Mg(NO3)2 (0.5 g/L) were used as
      modifiers. Matrix-matched standards were used for calibration. RESULTS: We
      determined the limits of detection (3.1 microg/L) and quantification (9.4
      microg/L). Repeatability and intermediate imprecision within the range 35-150
      microg/L were <5.5% and <6.0%, respectively. We assessed trueness by use of
      certified reference materials, by recovery tests, and by comparison with target
      values of other reference materials (candidate external quality assessment
      samples). The expanded uncertainty ranged from 20% to 16% (with a confidence
      level of 95%) depending on concentration. CONCLUSIONS: This study provides a
      working example of the estimate of uncertainty from method performance data
      according to the EURACHEM/CITAC guidelines. The estimated uncertainty is
      compatible with quality specifications for the analysis of lead in blood adopted
      in the US and the European Union.

PMID- 15194621
TI  - Management of advanced ARDS complicated by bilateral pneumothoraces with high
      frequency oscillatory ventilation in an adult.
AB  - We report the case of a 33-yr-old patient with adult respiratory distress
      syndrome (ARDS) complicated by bilateral pneumothoraces, who was successfully
      treated with high-frequency oscillatory ventilation following failure to respond
      to conventional ventilation. The role of high-frequency ventilation in the
      management of ARDS and air leaks is discussed.

PMID- 15194622
TI  - Mid-arm approach to basilic and cephalic vein cannulation using ultrasound
      guidance.
AB  - Central venous lines are often used when there is difficulty obtaining peripheral
      venous access. The basilic and cephalic veins in the mid-arm region, although
      difficult to see or palpate, can be imaged longitudinally and cannulated using
      real-time ultrasonography, providing an easy alternative. These techniques are
      described, with reports of four typical cases.

PMID- 15194623
TI  - Comparability of Narcotrend index and bispectral index during propofol
      anaesthesia.
AB  - BACKGROUND: The dimensionless Narcotrend (NCT) index (MonitorTechnik, Germany,
      version 4.0), from 100 (awake) to 0, is a new index based on electroencephalogram
      pattern recognition. Transferring guidelines for titrating the Bispectral Index
      (BIS, Aspect Medical Systems, USA, version XP) to the NCT index depends on their
      comparability. We compared the relationship between BIS and NCT values during
      propofol anaesthesia. METHODS: Eighteen adult patients about to have radical
      prostatectomy were investigated. An epidural catheter was placed in the lumbar
      space and electrodes for BIS and NCT were applied as recommended by the
      manufacturers. After i.v. fentanyl 0.1 mg, anaesthesia was induced with a
      propofol infusion. After intubation, patients received bupivacaine 0.5% 15 ml via
      the epidural catheter. Forty-five minutes after induction, the propofol
      concentration was increased to substantial burst suppression pattern and then
      decreased. This was done twice in each patient, and BIS and Narcotrend values
      were recorded at intervals of 5 s. The efficacy of NCT and BIS in predicting
      consciousness vs unconsciousness was evaluated using the prediction probability
      (P(K)). RESULTS: We collected 38 629 artefact-free data pairs of BIS and NCT
      values from the respective 5-s epochs. Because of artefacts, another 5008 epochs
      had been excluded from data analysis (3855 epochs for the NCT index alone, 245
      epochs for the BIS alone and 908 epochs for both indices). Mean (sd) values in
      awake patients were 94 (6) for Narcotrend and 91 (8) for BIS. With loss of the
      eyelash reflex, both values were significantly reduced, to 72 (9) for NCT
      (P<0.001) and to 77 (11) for the BIS index (P<0.001). The PK value for loss of
      eyelash reflex was similar for BIS (0.95) and NCT (0.93). Decreasing BIS values
      coincided with decreasing NCT values. A sigmoid model [NCT
      index=52.8+26.8/(1+exp(-(BIS-78.3)/4.8))(0.4); r=0.52] described the correlation
      between BIS and NCT index in a BIS range between 100 and 50. For BIS values lower
      than 50, a second sigmoid model with a correlation of r=0.83 was applied [NCT
      index=6.6+45.3/(1+exp(-(BIS-29.8)/2.4)) (0.6) r=0.83]. The relationship between
      burst suppression ratio (BSR) and NCT index was best described by the following
      sigmoid model: NCT index=265/(1+exp((-BSR+108)/-49); r=0.73. CONCLUSIONS: We
      found a sufficient correlation between BIS and NCT index, but deviations from the
      line of identity in some ranges require attention. Therefore, a simple 1:1
      transfer from BIS to NCT values is not adequate. Our results might serve as a
      blueprint for the rational translation of BIS into NCT values.

PMID- 15194624
TI  - Thiopental and isoflurane attenuate the decrease in hippocampal phosphorylated
      Focal Adhesion Kinase (pp125FAK) content induced by oxygen-glucose deprivation.
AB  - BACKGROUND: Thiopental and isoflurane exhibit neuroprotective effects against
      cerebral ischaemia. Here, we hypothesized that oxygen-glucose deprivation
      decreases the ATP-dependent phosphorylation process of Focal Adhesion Kinase
      (pp125FAK, a functionally important non-receptor tyrosine kinase), and that this
      phenomenon is attenuated by thiopental and isoflurane. METHODS: Rathippocampal
      slices were subjected to an anoxic-aglycaemic (or physiologic, control) challenge
      followed by 3-h reperfusion, and treated with various concentrations of
      thiopental and isoflurane. PP125FAK phosphorylation was measured by
      immunoblotting. Neuronal death was assessed by immunostaining with bis-benzimide.
      RESULTS: Significant neuronal death was detected after 30 min (but not 10) of
      anoxia-aglycaemia (40 (4) vs 14 (5)% of control, P<0.05). At 30 min,
      phosphorylated pp125FAK content was significantly decreased by anoxic glucose
      free conditions (55 (27)% of control, P<0.05). This effect was markedly
      attenuated by thiopental (10 and 100 microM) and isoflurane (1 and 2%). Under
      control conditions, thiopental (1, 10, and 100 microM) and isoflurane (0.5, 1,
      and 2%) increased pp125FAK phosphorylation in a concentration-related fashion.
      This effect was blocked by chelerythrin and bisindolylmaleimide I and IX (10
      microM, three structurally distinct inhibitors of protein kinase C, PKC) but not
      the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (10 microM).
      CONCLUSION: Phosphorylated pp125FAK content was markedly decreased in hippocampal
      slices subjected to oxygen-glucose deprivation. Thiopental and isoflurane
      significantly attenuated this phenomenon, possibly via PKC activation.

PMID- 15194625
TI  - Differential effects of propofol, ketamine, and thiopental anaesthesia on the
      skeletal muscle microcirculation of normotensive and hypertensive rats in vivo.
AB  - BACKGROUND: This study utilized the dorsal microcirculatory chamber (DMC) model
      to determine differential effects of i.v. propofol, ketamine, and thiopental
      anaesthesia on the skeletal muscle microcirculation (10-180 micro m) of
      normotensive (Male Wistar Kyoto, WKY) and hypertensive (spontaneously
      hypertensive Harlan, SHR) rats, importantly, comparing responses to a conscious
      baseline. METHODS: Three weeks following implantation of the DMC in WKY (n=8) and
      SHR (n=6) (130 g) 0.25 ml 100 g(-1) FITC-BSA (i.v.) was administered and the
      microcirculation viewed using fluorescent in vivo microscopy for a 30 min
      baseline (t=0-30 min). This was followed by either propofol, thiopental,
      ketamine, or saline (i.v. bolus induction over 5 min (t=30-35 min)), then
      maintenance step-up infusion for 60 min (t=45-105 min), so that animals received
      all four agents 1 week apart (56 experiments). RESULTS: Dilation of A3 arterioles
      (15-30 micro m) and V3 venules (20-40 microm) with propofol was greater in SHR
      (t=95 min, A3 36.7 (12)%, V3 15.5 (2.3)%) than WKY (t=95 min, A3 19.4 (7.4)%, V3
      8.0 (2.3)%) (P<0.05). Constriction of A3 with ketamine was greater in SHR (t=95
      min, A3 -29.1 (6.4)%) than WKY (A3 -17.5 (8.8)%) (P<0.05). This was accompanied
      by hypotension with propofol in SHR (-32% decrease in systolic arterial
      pressure), but not WKY (-6%) and hypertension with ketamine in WKY (-15%) and SHR
      (-24%) (P<0.05). During thiopental anaesthesia there was dilation of A1 (80-180
      microm), A3, and V3 in WKY (P<0.05). Conversely, in SHR dilation of venules (29.2
      (8.7)%) was accompanied by constriction of A1 and A3 (t=95 min, A1 -25.1 (5.9)%,
      A3-45.2 (3.1)%) (P<0.05). CONCLUSION: Within the skeletal muscle microcirculation
      of hypertensive rats there is enhanced dilation with propofol and constriction
      with ketamine, associated with exaggerated changes in arterial pressure. Thus,
      dysfunctional control mechanisms at the level of the microcirculation alter
      responses to anaesthesia during hypertension.

PMID- 15194626
TI  - Effects of tirofiban on haemostatic activation in vitro.
AB  - BACKGROUND: Thrombin plays a critical role in normal haemostasis and pathological
      thrombosis. Heparin has long been a mainstay choice of antithrombotic regimen in
      cardiac patients, but persistent thrombin generation seems to occur during
      heparin therapy. Because platelets are integral to primary haemostasis and clot
      formation, we evaluated the use of tirofiban (Aggrastat),a platelet inhibitor, as
      a therapy to improve heparin sensitivity and delay thrombin formation. METHODS:
      Blood samples were obtained from healthy subjects (n=8) and cardiac surgical
      patients (n=34). Thrombin formation was measured in platelet-rich plasma with a
      Thrombogram-Ascent fluorescent plate reader system. Platelet inhibition by
      tirofiban was evaluated with Plateletworks, and the interaction of tirofiban and
      heparin (>1.5 U ml(-1)) on clot formation was evaluated with Sonoclot Analyzer or
      kaolin activated clotting times (ACTs). RESULTS: Addition of tirofiban (70-280 ng
      ml(-1)) progressively delayed onset of thrombin generation triggered by adenosine
      diphosphate (ADP). Plateletworks showed platelet inhibition with tirofiban (>35
      ng ml(-1)), whereas heparin per se failed to produce platelet inhibition at 7 U
      ml(-1). Heparin (1.5 U ml(-1)) slowed the onset and rate of fibrin formation on
      Sonoclot analyses, and this was further slowed after addition of tirofiban (70 ng
      ml(-1)) to heparin-containing blood samples. Significant increases in ACT at all
      heparin concentrations were observed with the addition of tirofiban (70 ng ml(
      1)). The addition of antithrombin (0.2 units/ml) to heparinized blood samples
      further prolonged ACTs, but the difference was not statistically significant when
      compared with heparin alone. CONCLUSION: Tirofiban delays platelet activation
      mediated thrombin generation and prolongs ACT in heparinized blood.

PMID- 15194627
TI  - Recognition and management of maternal cardiac disease in pregnancy.
AB  - Heart disease is a leading cause of maternal death. The aim of this study is to
      review the most common causes of cardiac disease, highlight factors that should
      be recognized by the clinician, and address recent advances in the anaesthetic
      management of these patients. Incipient cardiac disease, including peripartum
      cardiomyopathy, myocardial infarction and aortic dissection, accounts for
      approximately one in six maternal deaths. The keys to successful diagnosis and
      management of incipient disease are: a high index of suspicion, particularly in
      women with known risk factors for cardiovascular disease; a low threshold for
      radiological investigations; early cardiology input; and invasive monitoring
      during labour and delivery. Echocardiography is a safe, non-invasive test, under
      used in pregnancy. Management of pregnant women with pre-existing cardiac
      problems should be undertaken by multidisciplinary teams in tertiary centres. In
      women with pre-existing cardiac disease wishing to proceed to term, cardiac
      status must be optimized preoperatively and planned elective delivery is
      preferable. Vaginal delivery is preferable, and with careful incremental regional
      anaesthesia is safe in most women with cardiac disease. The presence of adequate
      systems for early detection, appropriate referral to specialist centres, and
      timely delivery with multidisciplinary support can minimize the serious
      consequences of poorly controlled heart disease in pregnancy.

PMID- 15194629
TI  - Use of recombinant factor VIIa to treat life-threatening non-surgical bleeding in
      a post-partum patient.
AB  - Ongoing bleeding from patients who have an acquired coagulopathy post-surgery is
      a common problem. Strategies that are available to combat this problem revolve
      around the replacement of coagulation factors, platelets, and red blood cells as
      necessary. These strategies are not always successful and a more direct approach
      to activating the coagulation system can be more effective and in some instances
      life saving. We describe the use of recombinant factor VIIa in a patient with
      ongoing post partum bleeding.

PMID- 15194628
TI  - Effects of Pringle manoeuvre and ischaemic preconditioning on haemodynamic
      stability in patients undergoing elective hepatectomy: a randomized trial.
AB  - BACKGROUND: The Pringle manoeuvre and ischaemic preconditioning are applied to
      prevent blood loss and ischaemia-reperfusion injury, respectively, during liver
      surgery. In this prospective clinical trial we report on the intraoperative
      haemodynamic effects of the Pringle manoeuvre alone or in combination with
      ischaemic preconditioning. METHODS: Patients (n=68) were assigned randomly to
      three groups: (i) resection with the Pringle manoeuvre; (ii) with ischaemic
      preconditioning before the Pringle manoeuvre for resection; (iii) without pedicle
      clamping. RESULTS: Following the Pringle manoeuvre the mean arterial pressure
      increased transiently, but significantly decreased after unclamping as a result
      of peripheral vasodilation. Ischaemic preconditioning improved cardiovascular
      stability by lowering the need for catecholamines after liver reperfusion without
      affecting the blood sparing benefits of the Pringle manoeuvre. In addition,
      ischaemic preconditioning protected against reperfusion-induced tissue injury.
      CONCLUSIONS: Ischaemic preconditioning provides both better intraoperative
      haemodynamic stability and anti-ischaemic effects thereby allowing us to take
      full advantage of blood loss reduction by the Pringle manoeuvre.

PMID- 15194630
TI  - Apparent hyperkalaemia from blood sampled from an arterial cannula.
AB  - Blood samples were obtained from a radial artery cannula in a 60-yr-old man
      during coronary artery surgery. Serum potassium concentrations of 9.3, 8.4, and
      7.4 mmol litre(-1) were obtained. A simultaneous venous blood sample gave a serum
      potassium concentration of 4.4 mmol litre(-1). The ECG was unchanged. After the
      arterial cannula was repositioned, subsequent blood samples gave expected ranges
      of serum potassium concentration. We suggest that the initial arterial cannula
      position caused a high shear rate in the blood when samples were withdrawn,
      causing haemolysis and hyperkalaemia.

PMID- 15194631
TI  - Lysis of adhesions and epidural injection of steroid/local anaesthetic during
      epiduroscopy potentially alleviate low back and leg pain in elderly patients with
      lumbar spinal stenosis.
AB  - BACKGROUND: Lumbar spinal stenosis causes various forms of back or leg pain, and
      is recognized with increasing frequency in elderly patients whose physical status
      is not always suitable for surgery. Epiduroscopy, a new, minimally invasive
      diagnostic and therapeutic technique, may be useful for pain relief in such
      patients. We investigated the epiduroscopic findings and immediate and long-term
      changes in back and leg pain after epiduroscopy in elderly patients with spinal
      stenosis. METHODS: Patients with degenerative lumbar spinal stenosis (n=58,
      median age 71 yr) were divided into two groups based on presenting symptoms: a
      monosegmental group (n=34) and a multisegmental group (n=24). Each patient
      underwent epiduroscopy, and the findings were evaluated using visual analogue
      scales for low back and leg symptoms. Epiduroscopy included breaking down
      adhesions in the epidural space by injections of saline, and injection of
      steroids/local anaesthetic. RESULTS: Epiduroscopy showed that the amount of fatty
      tissue and the degree of vascularity were greater in the monosegmental group than
      in the multisegmental group. Relief of low back pain was observed up to 12 months
      after epiduroscopy in both groups. Relief of leg pain was evident up to 12 months
      after epiduroscopy in the monosegmental group, and up to 3 months after
      epiduroscopy in the multisegmental group. None of the patients showed
      deterioration of motor or sensory deficits during follow-up. One patient was
      excluded from analysis because of accidental dural puncture during the procedure.
      CONCLUSIONS: The findings of epiduroscopy corresponded to the symptoms.
      Epiduroscopy may reduce low back and leg pain in elderly patients with
      degenerative lumbar spinal stenosis, particularly those with radiculopathy.

PMID- 15194632
TI  - Expression profiling: fishing and chips.
AB  - Expression profiling approaches are potentially valuable in helping to define
      novel gene products which may be important in disease pathogenesis or treatment
      response. However, there are many pitfalls which need to be considered in the
      design of experiments of this kind and in considering interpretation of data from
      such studies. Some of these are discussed.

PMID- 15194634
TI  - Leptin in intestinal inflammation: good and bad gut feelings.
AB  - Leptin has a the potent effect on T cell mediated intestinal autoimmunity and may
      have a role in the development of such diseases.

PMID- 15194633
TI  - Corticotropin releasing factor receptor antagonists: potential future therapy in
      gastroenterology?
AB  - New corticotropin releasing factor (CRF) antagonists in irritable bowel disease
      (IBS) warrant testing, and CRF1 receptors may be a promising target for the
      treatment of IBS.

PMID- 15194635
TI  - Fatty liver, hypertension, and the metabolic syndrome.
AB  - The prevalence of fatty liver in non-obese non-diabetic hypertensive patients is
      at least twice that of the general population and may be related to increases in
      insulin resistance and body weight.

PMID- 15194636
TI  - Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and
      meta-analysis.
AB  - BACKGROUND: The benefit of neoadjuvant chemoradiotherapy in oesophageal cancer
      has been extensively studied but data on survival are still equivocal. OBJECTIVE:
      To assess the effectiveness of chemoradiotherapy followed by surgery in the
      reduction of mortality in patients with resectable oesophageal cancer. METHODS:
      Computerised bibliographic searches of MEDLINE and CANCERLIT (1970-2002) were
      supplemented with hand searches of reference lists. STUDY SELECTION: Studies were
      included if they were randomised controlled trials (RCTs) comparing preoperative
      chemoradiotherapy plus surgery with surgery alone, and if they included patients
      with resectable histologically proven oesophageal cancer without metastatic
      disease. Six eligible RCTs were identified and included in the meta-analysis.
      DATA EXTRACTION: Data on study populations, interventions, and outcomes were
      extracted from each RCT according to the intention to treat method by three
      independent observers and combined using the DerSimonian and Laird method.
      RESULTS: Chemoradiotherapy plus surgery compared with surgery alone significantly
      reduced the three year mortality rate (odds ratio (OR) 0.53 (95% confidence
      interval (CI) 0.31-0.93); p = 0.03) (number needed to treat = 10). Pathological
      examination showed that preoperative chemoradiotherapy downstaged the tumour
      (that is, less advanced stage at pathological examination at the time of surgery)
      compared with surgery alone (OR 0.43 (95% CI 0.26-0.72); p = 0.001). The risk for
      postoperative mortality was higher in the chemoradiotherapy plus surgery group
      (OR 2.10 (95% CI 1.18-3.73); p = 0.01). CONCLUSIONS: In patients with resectable
      oesophageal cancer, chemoradiotherapy plus surgery significantly reduces three
      year mortality compared with surgery alone. However, postoperative mortality was
      significantly increased by neoadjuvant chemoradiotherapy. Further large scale
      multicentre RCTs may prove useful to substantiate the benefit on overall
      survival.

PMID- 15194638
TI  - A painful liver.

PMID- 15194637
TI  - Identification of a genetic marker of Helicobacter pylori strains involved in
      gastric extranodal marginal zone B cell lymphoma of the MALT-type.
AB  - BACKGROUND AND AIMS: Gastric extranodal marginal zone B cell lymphoma of the
      mucosa associated lymphoid tissue (MALT)-type (MZBL) is a rare complication of
      Helicobacter pylori infection. Currently, no bacterial factor has been associated
      with the development of this disease. Our aim was to identify genes associated
      with lymphoma development. METHODS: We used subtractive hybridisation as a tool
      for comparative genomics between H pylori strains isolated from a patient with
      gastric MZBL and from a patient with gastritis only. RESULTS: When gastric MZBL
      strains were compared with gastritis strains, two open reading frames (ORFs) were
      significantly associated with gastric MZBL: JHP950 (74.4% v 48.7%, respectively;
      p = 0.023) and JHP1462 (25.6% v 2.6%, respectively; p = 0.004). The prevalence of
      JHP950 was 48.8% (p = 0.024) in duodenal ulcer strains and 39.3% (p = 0.006) in
      gastric adenocarcinoma strains, which makes this ORF a specific marker for
      gastric MZBL strains. In contrast, the prevalence of JHP1462 was 16% (p = 0.545)
      and 35.7% (p = 0.429) in duodenal ulcer and adenocarcinoma strains, respectively.
      These ORFs were present in reference strain J99 but not in reference strain
      26695. JHP950 is located in the plasticity zone whereas the other, JHP1462, is
      located outside. Both encode for H pylori putative proteins with unknown
      functions. CONCLUSION: Despite its low prevalence, the ORF JHP1462 can be
      considered a candidate marker for H pylori strains involved in severe
      gastroduodenal diseases. In contrast, the ORF JHP950 has a high prevalence, and
      is the first candidate marker for strains giving rise to an increased risk of
      gastric MZBL strains. Further confirmation in other studies is needed.

PMID- 15194639
TI  - Differences in the sensorimotor response to distension between the proximal and
      distal stomach in humans.
AB  - BACKGROUND: It is not known which region of the stomach is responsible for
      symptom generation or whether symptoms induced by gastric distension are region
      specific. Also, it is unclear whether low level gastric distension has a
      modulatory role on gastric tone and mechanosensitivity. AIMS: To define
      differences in the sensorimotor response to distension between proximal and
      distal gastric distension, and to determine the effects of low level gastric
      distension on gastric tone and mechanosensitivity. METHODS: In 14 healthy
      volunteers, a double barostat assembly incorporating a distal (antral) and
      proximal (fundic) bag was introduced into the stomach. Pressure sensitivity tests
      with either bag were performed with and without simultaneous background
      distension of the other bag in a randomised manner. Proximal gastric
      accommodation to a meal was measured with and without simultaneous distal gastric
      distension. RESULTS: The distal stomach was less compliant than the proximal
      stomach to low level distension. Thresholds for first perception and discomfort,
      and symptom profiles did not differ between distal and proximal gastric
      distension. Simultaneously applied low level gastric distension of one segment
      did not affect gastric mechanosensitivity of the other segment. Both the proximal
      and distal stomach relax after ingestion of a meal. Simultaneous low level antral
      distension decreases proximal gastric accommodation to a meal. CONCLUSIONS:
      Compared with the proximal stomach, the distal stomach is less compliant but its
      mechanosensitivity is not different. Symptoms induced by gastric distension are
      not region specific and no spatial summation occurred. Meal induced relaxation
      occurs both in the proximal and distal stomach.

PMID- 15194641
TI  - A microarray screen for novel candidate genes in coeliac disease pathogenesis.
AB  - BACKGROUND AND AIMS: The causative molecular pathways underlying the pathogenesis
      of coeliac disease are poorly understood. To unravel novel aspects of disease
      pathogenesis, we used microarrays to determine changes in gene expression of
      duodenal biopsies. METHODS: cDNA microarrays representing 19 200 genes were used
      to compare gene expression profiles of duodenal biopsies from 15 coeliac disease
      patients with villous atrophy (Marsh III) and seven control individuals with
      normal biopsies (Marsh 0). In addition, the specific effect of gluten was studied
      by comparing the expression profiles of Marsh III lesions of seven patients
      exposed to gluten with four patients on a gluten free diet. RESULTS: Comparing
      Marsh III with Marsh 0 lesions identified 109 genes that differed significantly
      (p<0.001) in expression levels between patients and controls. A large number of
      these genes have functions in proliferation and differentiation pathways and
      might be important for correct development of crypt-villous units. Alterations in
      these pathways may lead to the characteristic hyperplasia and villous atrophy
      seen in coeliac disease. The analyses also revealed 120 differentially expressed
      genes (p<0.005) when comparing patients on a gluten free diet with those exposed
      to gluten. These genes further strengthen our observation of increased cell
      proliferation in the presence of gluten. CONCLUSIONS: Our study provides new
      candidate genes in the pathogenesis of coeliac disease. Based on our results, we
      hypothesise that villous atrophy in coeliac disease patients is due to failure in
      cell differentiation. These genes are involved in pathways not previously
      implicated in coeliac disease pathogenesis and they may provide new targets for
      therapy.

PMID- 15194642
TI  - Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus
      diarrhoea.
AB  - BACKGROUND AND AIMS: The mechanisms underlying intestinal secretion in rotavirus
      diarrhoea remain to be established. We previously reported that rotavirus evokes
      intestinal fluid and electrolyte secretion by activation of the enteric nervous
      system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5
      HT(3)) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for
      5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus
      induced diarrhoea. METHODS: Neurotransmitter antagonists were administered to
      wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM)
      or heterologous (RRV) rotavirus. RESULTS: While RRV infected mice had diarrhoea
      for 3.3 (0.2) days (95% confidence interval (CI) 3.04-3.56), the 5-HT(3) receptor
      antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe(6),Leu(17))
      VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3)
      (95% CI 1.31-2.9) (p<0.01). EDIM infected mice treated with granisetron had a
      significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with
      untreated mice (8.0 (0.4) days; p<0.01). Experiments with neurokinin 1 receptor
      antagonists suggest that this receptor may possibly be involved in the secretory
      response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated
      in the neurokinin 1 receptor knockout mice. CONCLUSIONS: Our results suggest that
      the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea;
      observations that could imply new principles for treatment of this disease with
      significant global impact.

PMID- 15194643
TI  - Effect of a corticotropin releasing hormone receptor antagonist on colonic
      sensory and motor function in patients with irritable bowel syndrome.
AB  - BACKGROUND AND AIMS: Corticotropin releasing hormone (CRH) is a major mediator of
      the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is
      presumed to be a disorder of the brain-gut link associated with an exaggerated
      response to stress. We hypothesised that peripheral administration of alpha
      helical CRH (alphahCRH), a non-selective CRH receptor antagonist, would improve
      gastrointestinal motility, visceral perception, and negative mood in response to
      gut stimulation in IBS patients. METHODS: Ten normal healthy subjects and 10 IBS
      patients, diagnosed according to the Rome II criteria, were studied. The tone of
      the descending colon and intraluminal pressure of the sigmoid colon were measured
      at baseline, during rectal electrical stimulation (ES), and at recovery after
      administration of saline. Visceral perception after colonic distension or rectal
      ES was evaluated as threshold values on an ordinate scale. The same measurements
      were repeated after administration of alphahCRH (10 micro g/kg). RESULTS: ES
      induced significantly higher motility indices of the colon in IBS patients
      compared with controls. This response was significantly suppressed in IBS
      patients but not in controls after administration of alphahCRH. Administration of
      alphahCRH induced a significant increase in the barostat bag volume of controls
      but not in that of IBS patients. alphahCRH significantly reduced the ordinate
      scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma
      adrenocorticotropic hormone and serum cortisol levels were generally not
      suppressed by alphahCRH. CONCLUSION: Peripheral administration of alphahCRH
      improves gastrointestinal motility, visceral perception, and negative mood in
      response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal
      axis in IBS patients.

PMID- 15194644
TI  - An unusual case of bowel obstruction.

PMID- 15194645
TI  - Leptin receptor expression on T lymphocytes modulates chronic intestinal
      inflammation in mice.
AB  - BACKGROUND: Leptin regulates appetite through the long isoform of its receptor in
      the hypothalamus. Although leptin regulates immune responses, it is still unknown
      whether a direct effect of leptin on lymphocytes is required. AIMS: To clarify
      whether expression of leptin receptors on T lymphocytes modulates intestinal
      inflammation in mice. METHODS: The model of colitis induced by transfer of
      CD4(+)CD45RB(high) (RB(high)) cells into scid mice was used. Wild-type (WT) or
      leptin receptor deficient (db/db) RB(high) cells were transferred into scid mice
      and development of colitis evaluated. RESULTS: Leptin receptors were expressed on
      both RB(high) and RB(low) cells. Intestinal lymphocytes of mice with colitis
      expressed high leptin levels compared with healthy controls whereas the opposite
      was true for serum leptin levels. Transfer of RB(high) cells from db/db mice
      induced delayed disease compared with transfer of WT cells. A high rate of
      apoptosis in lamina propria lymphocytes and reduced cytokine production were
      observed early on in scid mice receiving db/db RB(high) cells. These effects were
      not due to the high levels of glucocorticoids present in db/db mice as
      administration of corticosterone to WT mice failed to reproduce this phenomenon.
      High expression of peroxisome proliferator activated receptor gamma was observed
      in the colon of recipients of db/db compared with WT cells. Freshly isolated
      db/db RB(high) cells produced low levels of interferon gamma. Despite delayed
      onset of colitis, as disease progressed differences between mice receiving WT or
      db/db cells were no longer apparent. CONCLUSIONS: These results suggest that
      leptin affects the immune response, partly by acting on the long isoform of its
      receptor expressed on T lymphocytes.

PMID- 15194648
TI  - Genome wide scan in a Flemish inflammatory bowel disease population: support for
      the IBD4 locus, population heterogeneity, and epistasis.
AB  - BACKGROUND AND AIMS: Genome wide scans in inflammatory bowel disease (IBD) have
      indicated various susceptibility regions with replication of 16cen (IBD1), 12q
      (IBD2), 6p (IBD3), 14q11 (IBD4), and 3p21. As no linkage was previously found on
      IBD regions 3, 7, 12, and 16 in Flemish IBD families, a genome wide scan was
      performed to detect other susceptibility regions in this population. METHODS: A
      cohort of 149 IBD affected relative pairs, all recruited from the Northern
      Flemish part of Belgium, were genotyped using microsatellite markers at 12 cM
      intervals, and analysed by Genehunter non-parametric linkage software. All
      families were further genotyped for the three main Crohn's disease associated
      variants in the NOD2/CARD15 gene. RESULTS: Nominal evidence for linkage was
      observed on chromosomes 1 (D1S197: multipoint non-parametric linkage (NPL) score
      2.57, p = 0.004; and at D1S305-D1S252: NPL 2.97, p = 0.001), 4q (D4S406: NPL
      1.95, p = 0.03), 6q16 (D6S314: NPL 2.44, p = 0.007), 10p12 (D10S197: NPL 2.05, p
      = 0.02), 11q22 (D11S35-D11S927: NPL 1.95, p = 0.02) 14q11-12 (D14S80: NPL 2.41, p
      = 0.008), 20p12 (D20S192: NPL 2.7, p = 0.003), and Xq (DXS990: NPL 1.70, p =
      0.04). A total of 51.4% of patients carried at least one NOD2/CARD15 variant.
      Furthermore, epistasis was observed between susceptibility regions 6q/10p and
      20p/10p. CONCLUSION: Genome scanning in a Flemish IBD population found nominal
      evidence for linkage on 1p, 4q, 10p12, and 14q11, overlapping with other genome
      scan results, with linkage on 14q11-12 supporting the IBD4 locus. The results
      further show that epistasis is contributing to the complex model of IBD and
      indicate that population heterogeneity is not to be underestimated. Finally,
      NOD2/CARD15 is clearly implicated in the Flemish IBD population.

PMID- 15194646
TI  - Epidemiology of appendicectomy in primary sclerosing cholangitis and ulcerative
      colitis: its influence on the clinical behaviour of these diseases.
AB  - BACKGROUND AND AIMS: Appendicectomy and smoking are environmental factors that
      are known to influence ulcerative colitis (UC). The phenotype of UC is different
      in patients with coexistent primary sclerosing cholangitis (PSC). This study
      investigates the interaction of appendicectomy and PSC on the epidemiology and
      clinical behaviour of colitis. METHODS: Patients were from the Brisbane IBD
      Research Group database. Controls were from the Australian twin registry. Seventy
      eight PSC-inflammatory bowel disease (PSC-IBD) patients, 12 pure PSC, and 294 UC
      patients were matched with 1466 controls by sex and birth cohort that comprised
      randomly selected twins from each twin pair. The effects of appendicectomy,
      smoking, or PSC on the onset of disease, disease extent, disease severity (as
      identified by immunosuppression-colectomy or liver transplant), and disease
      related complications (high grade dysplasia, colorectal cancer, or
      cholangiocarcinoma) were investigated using univariate and multiple logistic
      regression analyses. RESULTS: PSC-IBD patients had a more extensive colitis than
      UC patients (p<0.0001) but required less immunosuppression (p = 0.007), which was
      independent of disease extent. They were more likely to have high grade dysplasia
      or colorectal cancer (p = 0.029) than UC patients. Appendicectomy rates in the
      PSC groups were not different from the control groups (p = 0.72, 0.76), which was
      in sharp contrast with UC where the rate was four times less (p = 0.0001). Prior
      appendicectomy appeared to be associated with an approximate five year delay in
      the onset of intestinal (PSC-IBD or UC) or hepatic (PSC) disease, which was
      independent of smoking. Appendicectomy did not independently alter the extent or
      severity of disease in PSC. In contrast, prior appendicectomy in UC was
      associated with more extensive disease but with a lesser requirement for
      immunosuppression or colectomy for the treatment of colitis (p = 0.004). There
      were trends for high grade dysplasia or colorectal cancer with appendicectomy in
      both PSC-IBD and UC. Although these trends were not statistically significant,
      colorectal cancer appeared more frequent with appendicectomy in a meta-analysis
      of the available UC data from this and another Australian study. CONCLUSIONS: In
      contradistinction to UC, appendicectomy did not significantly influence the
      prevalence of the PSC groups, or the extent of colitis in PSC-IBD, but as with
      UC, did appear to delay their onset. The extensive milder colitis, which is
      characteristic of PSC-IBD, relates to other poorly understood factors. Further
      prospective studies are required to determine any influence of appendicectomy on
      the extent of colitis in IBD and an associated dysplasia or colorectal cancer.

PMID- 15194650
TI  - Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II
      on the membrane of pancreatic cancer cells activates plasminogen and promotes
      invasion in vitro.
AB  - BACKGROUND: Overexpression of tissue plasminogen activator (t-PA) in pancreatic
      cancer cells promotes invasion and proliferation in vitro and tumour growth and
      angiogenesis in vivo. AIMS: To understand the mechanisms by which t-PA favours
      cancer progression, we analysed the surface membrane proteins responsible for
      binding specifically t-PA and studied the contribution of this interaction to the
      t-PA promoted invasion of pancreatic cancer cells. METHODS: The ability of t-PA
      to activate plasmin and a fluorogenic plasmin substrate was used to analyse the
      nature of the binding of active t-PA to cell surfaces. Specific binding was
      determined in two pancreatic cancer cell lines (SK-PC-1 and PANC-1), and complex
      formation analysed by co-immunoprecipitation experiments and co
      immunolocalisation in tumours. The functional role of the interaction was studied
      in Matrigel invasion assays. RESULTS: t-PA bound to PANC-1 and SK-PC-1 cells in a
      specific and saturable manner while maintaining its activity. This binding was
      competitively inhibited by specific peptides interfering with the interaction of
      t-PA with annexin II. The t-PA/annexin II interaction on pancreatic cancer cells
      was also supported by co-immunoprecipitation assays using anti-t-PA antibodies
      and, reciprocally, with antiannexin II antibodies. In addition, confocal
      microscopy showed t-PA and annexin II colocalisation in tumour tissues. Finally,
      disruption of the t-PA/annexin II interaction by a specific hexapeptide
      significantly decreased the invasive capacity of SK-PC-1 cells in vitro.
      CONCLUSION: t-PA specifically binds to annexin II on the extracellular membrane
      of pancreatic cancer cells where it activates local plasmin production and tumour
      cell invasion. These findings may be clinically relevant for future therapeutic
      strategies based on specific drugs that counteract the activity of t-PA or its
      receptor annexin II, or their interaction at the surface level.

PMID- 15194651
TI  - An unusual treatment for a colonic polyp.

PMID- 15194649
TI  - Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like
      receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and
      ulcerative colitis.
AB  - BACKGROUND AND AIMS: Elicitation of an innate immune response to bacterial
      products is mediated through pattern recognition receptors (PRRs) such as the
      toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly
      polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with
      impaired LPS signalling and increased susceptibility to Gram negative infections.
      We sought to determine whether this polymorphism was associated with Crohn's
      disease (CD) and/or ulcerative colitis (UC). METHODS: Allele frequencies of the
      TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp,
      Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD
      patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140
      controls. A transmission disequilibrium test (TDT) was then performed on 318
      inflammatory bowel disease (IBD) trios. RESULTS: The allele frequency of the TLR4
      Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds
      ratio (OR) 2.31 (95% confidence interval (CI) 1.28-4.17), p = 0.004; and cohort
      2: 12% v 5%, OR 2.45 (95% CI 1.24-4.81), p = 0.007) and UC patients (10% v 5%, OR
      2.05 (95% CI 1.07-3.93), p = 0.027) compared with the control population. A TDT
      on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly
      polymorphism from heterozygous parents to affected children (T/U: 68/34, p =
      0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a
      genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and
      NOD2 variants separately. CONCLUSION: We have reported on a novel association of
      the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further
      supports the genetic influence of PRRs in triggering IBD.

PMID- 15194652
TI  - Prevention of critical telomere shortening by oestradiol in human normal hepatic
      cultured cells and carbon tetrachloride induced rat liver fibrosis.
AB  - BACKGROUND AND AIM: Significant telomere shortening of hepatocytes is associated
      with replicative senescence and a non-dividing state in chronic liver disease,
      resulting in end stage liver failure and/or development of hepatocellular
      carcinoma. To prevent critical telomere shortening in hepatocytes, we have
      focused on oestrogen dependent transactivation of the human telomerase reverse
      transcriptase (hTERT) gene as a form of telomerase therapy in chronic liver
      disease. METHODS: We examined expression of hTERT mRNA and its protein, and
      telomerase activity (TA) in three human normal hepatic cell lines (Hc-cells, h
      Nheps, and WRL-68) before and after treatment with 17beta-oestradiol. The effects
      of exogenous oestradiol administration were examined in a carbon tetrachloride
      (CCl(4)) induced model of liver fibrosis in rats. RESULTS: Expression of hTERT
      mRNA and its protein was upregulated by oestradiol treatment. Telomere length
      decreased in Hc-cells and h-Nheps with accumulated passages whereas with long
      term oestradiol exposure it was greater than without oestradiol. The incidence of
      beta-galactosidase positive cells, indicating a state of senescence, decreased
      significantly in oestradiol treated cells in comparison with non-treated cells
      (p<0.05). TA in both male and female rats with CCl(4) induced liver fibrosis was
      significantly higher with oestradiol administration than without (p<0.05). Long
      term oestradiol administration markedly rescued the hepatic telomere from
      extensive shortening in both male and female rats. CONCLUSION: These results
      suggest that oestradiol acts as a positive modulator of the hTERT gene in the
      liver. Oestrogen dependent transactivation of the hTERT gene is a new strategy
      for slowing the progression of chronic liver disease.

PMID- 15194653
TI  - Endothelin receptor antagonist TAK-044 arrests and reverses the development of
      carbon tetrachloride induced cirrhosis in rats.
AB  - BACKGROUND AND AIMS: Hepatic concentrations of the powerful vasoconstrictor and
      fibrogen endothelin 1 (ET-1) and its receptors increase in human and experimental
      cirrhosis, suggesting a major role for ET-1 in the pathology of chronic liver
      disease. We investigated whether ET-1 receptor antagonism, after the development
      of fibrosis and cirrhosis, arrests/reverses the progression of chronic liver
      disease. METHODS: Chronic liver injury was induced in rats by carbon
      tetrachloride (CCl(4)) treatment (0.15 ml/kg intraperitoneally twice a week) in
      conjunction with phenobarbital in drinking water (0.4 g/l) for four (group 1:
      fibrosis) and eight (group 2: cirrhosis) weeks. Rat were then treated
      concurrently with the ET-1 receptor antagonist TAK-044 (10 mg/kg/day) and
      CCl(4)/phenobarbital for a further four weeks. RESULTS: Histopathological
      examination revealed significant arrest of progression to cirrhosis in group 1
      and reversal of cirrhosis in group 2 rats. TAK-044 treatment caused significant
      amelioration of portal hypertension, systemic hypotension, and liver injury
      (reduced activities of serum aspartate aminotransferase, alanine
      aminotransferase, and lactate dehydrogenase), and improved hepatic synthetic
      capacity (increased serum albumin concentration) in both groups of rats relative
      to vehicle treated rats. TAK-044 treatment reduced collagen synthesis, as
      evidenced by decreased hepatic hydroxyproline content, mRNA expression of
      collagen-alpha type I, and tissue inhibitors of matrix metalloproteinases 1 and
      2, and mRNA and protein expression of a potent fibrogenic cytokine, transforming
      growth factor beta1. CONCLUSIONS: The results emphasise the role of ET-1 in the
      development of cirrhosis and strongly suggest that blockade of its actions can be
      a rational therapy for chronic liver disease and its complications.

PMID- 15194655
TI  - Increased prevalence of fatty liver in arterial hypertensive patients with normal
      liver enzymes: role of insulin resistance.
AB  - BACKGROUND: The conditions associated with fatty liver disease presenting with
      normal liver enzymes and the mechanism involved in its development remain to be
      fully elucidated. AIMS: The aim of the present study was to test the hypothesis
      that fatty liver with normal liver enzymes occurs more frequently in arterial
      hypertensive patients and to establish whether this condition is associated with
      insulin resistance. PATIENTS: A total of 55 non-obese, non-diabetic, non-heavy
      alcohol drinking patients with arterial hypertensive and normal liver enzymes and
      55 sex and age matched healthy subjects were enrolled into the study. METHODS:
      Plasma metabolic parameters, body mass index, and the presence of fatty liver
      were investigated. Insulin resistance was estimated from plasma insulin and
      glucose as the homeostasis model assessment index. Stepwise logistic regression
      and multivariate regression analysis were used on the combined sample to identify
      variables independently associated with fatty liver and insulin resistance.
      RESULTS: Hypertensive patients had a significantly higher prevalence of fatty
      liver (30.9% v 12.7%; p<0.041), higher insulin resistance (mean 2.27 (SD 1.81) v
      1.56 (0.70); p = 0.022), and slightly higher body mass index (24.9 (3.0) v 24.0
      (2.2); p = 0.043) than controls. Multivariate logistic regression identified
      insulin resistance (odds ratio 1.66 (95% confidence interval (CI) 1.03-2.52)) and
      body mass index (OR 1.22 (95% CI 1.00-1.49)) as factors independently associated
      with fatty liver. Multivariate regression analysis showed insulin resistance to
      be predicted by alanine transaminase (p = 0.002), presence of arterial
      hypertension (p = 0.029), and body mass index (p = 0.048). CONCLUSION: The higher
      prevalence of non-alcoholic fatty liver in non-obese hypertensive patients with
      normal liver enzymes appears to be related to increases in insulin resistance and
      body weight.

PMID- 15194657
TI  - Nodular regenerative hyperplasia of the liver and coeliac disease: potential role
      of IgA anticardiolipin antibody.
AB  - Nodular regenerative hyperplasia (NRH) of the liver is a rare disorder that is
      often associated with connective tissue disorders, haematological malignancy, or
      drugs, and is a cause of non-cirrhotic portal hypertension. We describe two cases
      of NRH in individuals with adult coeliac disease and IgA anticardiolipin
      antibodies. We discuss the potential impact of this observation on the
      understanding of the pathogenesis of NRH.

PMID- 15194656
TI  - Gastro-oesophageal reflux monitoring: review and consensus report on detection
      and definitions of acid, non-acid, and gas reflux.
AB  - To date, most concepts on the frequency of gastro-oesophageal reflux episodes and
      the efficiency of the antireflux barrier have been based on inferences derived
      from measurement of oesophageal pH. The development of intraluminal impedance
      monitoring has highlighted the fact that pH monitoring does not detect all gastro
      oesophageal reflux events when little or no acid is present in the refluxate,
      even if special pH tracing analysis criteria are used. In November 2002, a
      workshop took place at which 11 specialists in the field of gastro-oesophageal
      reflux disease discussed and criticised all currently available techniques for
      measurement of reflux. Here, a summary of their conclusions and recommendations
      of how to achieve the best results from the various techniques now available for
      reflux measurement is presented.

PMID- 15194658
TI  - The CD40/CD40L costimulatory pathway in inflammatory bowel disease.

PMID- 15194661
TI  - Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC).

PMID- 15194659
TI  - New thoughts on managing obesity.

PMID- 15194662
TI  - Platelet count/spleen diameter ratio as a predictor of oesophageal varices in
      alcoholic cirrhosis.

PMID- 15194663
TI  - Poor bowel preparation: a poor excuse.

PMID- 15194664
TI  - Sporadic duodenal adenoma and colorectal neoplasia.

PMID- 15194665
TI  - Bone density loss in Crohn's disease: role of TNF and potential for prevention by
      bupropion.

PMID- 15194666
TI  - Remarkable difference in the mode of HCV transmission among haemodialysis
      patients and IVDAs.

PMID- 15194667
TI  - COX 2 inhibition and bowel strictures.

PMID- 15194668
TI  - Dysbiosis as a prerequisite for IBD.

PMID- 15194669
TI  - Intravenous pulse cyclophosphamide therapy in Crohn's disease and ulcerative
      colitis.

PMID- 15194671
TI  - Effects of undernutrition on respiratory mechanics and lung parenchyma
      remodeling.
AB  - Undernutrition thwarts lung structure and function, but there are disagreements
      about the behavior of lung mechanics in malnourished animals. To clarify this
      issue, lung and chest wall mechanical properties were subdivided into their
      resistive, elastic, and viscoelastic properties in nutritionally deprived (ND)
      rats and correlated with the data gathered from histology (light and electron
      microscopy and elastic fiber content), and bronchoalveolar lavage fluid analysis
      (lipid and protein content). Twenty-four Wistar rats were assigned into two
      groups. In the control (Ctrl) group the animals received food ad libitum. In the
      ND group, rats received one-third of their usual daily food consumption until
      they lost 40% of their initial body weight. Lung static elastance, viscoelastic
      and resistive pressures (normalized by functional residual capacity), and chest
      wall pressures were higher in the ND group than in the Ctrl group. The ND group
      exhibited patchy atelectasis, areas of emphysema, interstitial edema, and reduced
      elastic fiber content. The amount of lipid and protein in bronchoalveolar lavage
      fluid was significantly reduced in the ND group. Electron microscopy showed 1)
      type II pneumocytes with a reduction in lamellar body content, multilamellated
      structures, membrane vesicles, granular debris, and structurally aberrant
      mitochondria; and 2) diaphragm and intercostals with atrophy, disarrangement of
      the myofibrils, and deposition of collagen type I fibers. In conclusion,
      undernutrition led to lung and chest wall mechanical changes that were the result
      from a balance among the following modifications: 1) distorted structure of
      diaphragm and intercostals, 2) surfactant content reduction, and 3) decrease in
      elastic fiber content.

PMID- 15194670
TI  - Role of the carotid bodies in chemosensory ventilatory responses in the
      anesthetized mouse.
AB  - We examined the effects of carotid body denervation on ventilatory responses to
      normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90
      and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in
      the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements
      were made with a whole body, single-chamber plethysmograph before and after
      cutting both carotid sinus nerves. Baseline measurements in air showed that
      carotid body denervation was accompanied by lower minute ventilation with a
      reduction in respiratory frequency. On the basis of measurements with an open
      circuit system, no significant differences in O2 consumption or CO2 production
      before and after chemodenervation were found. During both levels of hypoxia,
      animals with intact sinus nerves had increased respiratory frequency, tidal
      volume, and minute ventilation; however, after chemodenervation, animals
      experienced a drop in respiratory frequency and ventilatory depression. Tidal
      volume responses during 15% hypoxia were similar before and after carotid body
      denervation; during 10% hypoxia in chemodenervated animals, there was a sudden
      increase in tidal volume with an increase in the rate of inspiration, suggesting
      that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were
      lower with a smaller tidal volume after chemodenervation than before. We conclude
      that the carotid bodies are essential for maintaining ventilation during eupnea,
      hypoxia, and hypercapnia in the anesthetized mouse.

PMID- 15194673
TI  - Fructose feeding and intermittent hypoxia affect ventilatory responsiveness to
      hypoxia and hypercapnia in rats.
AB  - We hypothesized that, in male rats, 10% fructose in drinking water would depress
      ventilatory responsiveness to acute hypoxia (10% O2 in N2) and hypercapnia (5%
      CO2 in O2) that would be depressed further by exposure to intermittent hypoxia.
      Minute ventilation (Ve) in air and in response to acute hypoxia and hypercapnia
      was evaluated in 10 rats before fructose feeding (FF), during 6 wk of FF, and
      after FF was removed for 2 wk. During FF, five rats were exposed to intermittent
      air and five to intermittent hypoxia for 13 days. Six rats given tap water acted
      as control and were exposed to intermittent air and subsequently intermittent
      hypoxia. In FF rats, plasma insulin levels increased threefold in the rats
      exposed to intermittent hypoxia and during washout returned to levels observed in
      rats exposed to intermittent air. During FF, ventilatory responsiveness to acute
      hypoxia was depressed because of decreased tidal volume (Vt) responsiveness.
      During washout, Ve decreased as a result of decreased Vt and frequency of
      breathing, and the ventilatory responsiveness to hypoxia in intermittent hypoxia
      rats did not recover. In all rats, the ventilatory responses to hypercapnia were
      decreased during FF and recovered after washout because of an increased Vt
      responsiveness. In the control group, hypoxic responsiveness was not depressed
      after intermittent hypoxia and was augmented after washout. Thus FF attenuated
      the ventilatory responsiveness of conscious rats to hypoxia and hypercapnia.
      Intermittent hypoxia interacted with FF to increase insulin levels and depress
      ventilatory responses to acute hypoxia that remained depressed during washout.

PMID- 15194672
TI  - Active hexose correlated compound enhances the immune function of mice in the
      hindlimb-unloading model of spaceflight conditions.
AB  - Hindlimb unloading is a ground-based model that simulates some of the aspects of
      spaceflight conditions, including lack of load bearing on hindlimbs and a fluid
      shift to the head. It has been shown that treatment with active hexose correlated
      compound (AHCC) restores resistance to infection in mice maintained under
      hindlimb-unloading conditions. The present study was designed to clarify the
      mechanisms by which AHCC enhances resistance to infection in this model. We
      hypothesized that oral administration of AHCC will enhance the function of the
      immune system, which could lead to the increased resistance to infection observed
      in this model. AHCC or the excipient was orally administered to mice, and the
      function of the immune system was assessed in spleen and peritoneal cells
      isolated from those groups. The results of the present study showed that
      administration of AHCC for 1 wk before and throughout the second day of the
      hindlimb-unloading period enhanced the function of the immune system assessed by
      spleen cell proliferation and cytokine production in spleens and nitric oxide and
      cytokine production in peritoneal cells. These findings suggest that AHCC can be
      used as a potent immunoenhancer, especially in cases in which the immune system
      is suppressed by any condition, including diseases such as human immunodeficiency
      virus infection and cancer.

PMID- 15194674
TI  - Effects of exercise on gene expression in human peripheral blood mononuclear
      cells.
AB  - Exercise leads to increases in circulating levels of peripheral blood mononuclear
      cells (PBMCs) and to a simultaneous, seemingly paradoxical increase in both pro-
      and anti-inflammatory mediators. Whether this is paralleled by changes in gene
      expression within the circulating population of PBMCs is not fully understood.
      Fifteen healthy men (18-30 yr old) performed 30 min of constant work rate cycle
      ergometry (approximately 80% peak O2 uptake). Blood samples were obtained
      preexercise (Pre), end-exercise (End-Ex), and 60 min into recovery (Recovery),
      and gene expression was measured using microarray analysis (Affymetrix
      GeneChips). Significant differential gene expression was defined with a posterior
      probability of differential expression of 0.99 and a Bayesian P value of 0.005.
      Significant changes were observed from Pre to End-Ex in 311 genes, from End-Ex to
      Recovery in 552 genes, and from Pre to Recovery in 293 genes. Pre to End-Ex
      upregulation of PBMC genes related to stress and inflammation [e.g., heat shock
      protein 70 (3.70-fold) and dual-specificity phosphatase-1 (4.45-fold)] was
      followed by a return of these genes to baseline by Recovery. The gene for
      interleukin-1 receptor antagonist (an anti-inflammatory mediator) increased
      between End-Ex and Recovery (1.52-fold). Chemokine genes associated with
      inflammatory diseases [macrophage inflammatory protein-1alpha (1.84-fold) and 
      1beta (2.88-fold), and regulation-on-activation, normal T cell expressed and
      secreted (1.34-fold)] were upregulated but returned to baseline by Recovery.
      Exercise also upregulated growth and repair genes such as epiregulin (3.50-fold),
      platelet-derived growth factor (1.55-fold), and hypoxia-inducible factor-I (2.40
      fold). A single bout of heavy exercise substantially alters PBMC gene expression
      characterized in many cases by a brisk activation and deactivation of genes
      associated with stress, inflammation, and tissue repair.

PMID- 15194675
TI  - N-acetylcysteine enhances muscle cysteine and glutathione availability and
      attenuates fatigue during prolonged exercise in endurance-trained individuals.
AB  - The production of reactive oxygen species in skeletal muscle is linked with
      muscle fatigue. This study investigated the effects of the antioxidant compound N
      acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to
      fatigue during prolonged, submaximal exercise in endurance athletes. Eight men
      completed a double-blind, crossover study, receiving NAC or placebo before and
      during cycling for 45 min at 71% peak oxygen consumption (VO2 peak) and then to
      fatigue at 92% VO2 peak. NAC was intravenously infused at 125 mg.kg(-1).h(-1) for
      15 min and then at 25 mg.kg(-1).h(-1) for 20 min before and throughout exercise.
      Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine
      concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of
      exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH),
      reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% VO2 peak
      was reproducible in preliminary trials (coefficient of variation 5.6 +/- 0.6%)
      and with NAC was enhanced by 26.3 +/- 9.1% (NAC 6.4 +/- 0.6 min vs. Con 5.3 +/-
      0.7 min; P <0.05). NAC increased muscle total and reduced NAC at both 45 min and
      fatigue (P <0.005). Muscle cysteine and cystine were unchanged during Con, but
      were elevated above preinfusion levels with NAC (P <0.001). Muscle TGSH (P <0.05)
      declined and muscle GSH tended to decline (P=0.06) during exercise. Both were
      greater with NAC (P <0.05). Neither exercise nor NAC affected whole blood TGSH.
      Whereas blood GSH was decreased and calculated oxidized glutathione increased
      with exercise (P <0.05), both were unaffected by NAC. In conclusion, NAC improved
      performance in well-trained individuals, with enhanced muscle cysteine and GSH
      availability a likely mechanism.

PMID- 15194676
TI  - Active force inhibition and stretch-induced force enhancement in frog muscle
      treated with BDM.
AB  - There is evidence that the stretch-induced residual force enhancement observed in
      skeletal muscles is associated with 1) cross-bridge dynamics and 2) an increase
      in passive force. The purpose of this study was to characterize the total and
      passive force enhancement and to evaluate whether these phenomena may be
      associated with a slow detachment of cross bridges. Single fibers from frog
      lumbrical muscles were placed at a length 20% longer than the plateau of the
      force-length relationship, and active and passive stretches (amplitudes of 5 and
      10% of fiber length and at a speed of 40% fiber length/s) were performed.
      Experiments were conducted in Ringer solution and with the addition of 2, 5, and
      10 mM of 2,3-butanedione monoxime (BDM), a cross-bridge inhibitor. The steady
      state active and passive isometric forces after stretch of an activated fiber
      were higher than the corresponding forces measured after isometric contractions
      or passive stretches. BDM decreased the absolute isometric force and increased
      the total force enhancement in all conditions investigated. These results suggest
      that total force enhancement is directly associated with cross-bridge kinetics.
      Addition of 2 mM BDM did not change the passive force enhancement after 5 and 10%
      stretches. Addition of 5 and 10 mM did not change (5% stretches) or increased
      (10% stretches) the passive force enhancement. Increasing stretch amplitudes and
      increasing concentrations of BDM caused relaxation after stretch to be slower,
      and because passive force enhancement is increased at the greatest stretch
      amplitudes and the highest BDM concentrations, it appears that passive force
      enhancement may be related to slow-detaching cross bridges.

PMID- 15194678
TI  - Cerebral blood flow response to isocapnic hypoxia during slow-wave sleep and
      wakefulness.
AB  - Nocturnal hypoxia is a major pathological factor associated with
      cardiorespiratory disease. During wakefulness, a decrease in arterial O2 tension
      results in a decrease in cerebral vascular tone and a consequent increase in
      cerebral blood flow; however, the cerebral vascular response to hypoxia during
      sleep is unknown. In the present study, we determined the cerebral vascular
      reactivity to isocapnic hypoxia during wakefulness and during stage 3/4 non-rapid
      eye movement (NREM) sleep. In 13 healthy individuals, left middle cerebral artery
      velocity (MCAV) was measured with the use of transcranial Doppler ultrasound as
      an index of cerebral blood flow. During wakefulness, in response to isocapnic
      hypoxia (arterial O2 saturation -10%), the mean (+/-SE) MCAV increased by 12.9 +/
      2.2% (P < 0.001); during NREM sleep, isocapnic hypoxia was associated with a 
      7.4 +/- 1.6% reduction in MCAV (P <0.001). Mean arterial blood pressure was
      unaffected by isocapnic hypoxia (P >0.05); R-R interval decreased similarly in
      response to isocapnic hypoxia during wakefulness (-21.9 +/- 10.4%; P <0.001) and
      sleep (-20.5 +/- 8.5%; P <0.001). The failure of the cerebral vasculature to
      react to hypoxia during sleep suggests a major state-dependent vulnerability
      associated with the control of the cerebral circulation and may contribute to the
      pathophysiologies of stroke and sleep apnea.

PMID- 15194677
TI  - Leg glucose and protein metabolism during an acute bout of resistance exercise in
      humans.
AB  - The present study investigated the responses of leg glucose and protein
      metabolism during an acute bout of resistance exercise. Seven subjects (5 men, 2
      women) were studied at rest and during a strenuous lower body resistance exercise
      regimen consisting of approximately 8 sets of 10 repetitions of leg press at
      approximately 75% 1 repetition maximum and 8 sets of 8 repetitions of knee
      extensions at approximately 80% 1 repetition maximum. L-[ring-2H5]phenylalanine
      was infused throughout the study for measurement of phenylalanine rates of
      appearance, disappearance, protein synthesis, and protein breakdown across the
      leg. Femoral arterial and venous blood samples were collected at rest and during
      exercise for determination of leg blood flow, concentrations of glucose, lactate,
      alanine, glutamine, glutamate, leucine, and phenylalanine, and phenylalanine
      enrichments. Muscle biopsies were obtained at rest and immediately after
      exercise. Leg blood flow was nearly three times (P <0.009) higher and glucose
      uptake more than five times higher (P=0.009) during exercise than at rest. Leg
      lactate release was 86 times higher than rest during the exercise bout. Although
      whole body phenylalanine rate of appearance, an indicator of whole body protein
      breakdown, was reduced during exercise; leg phenylalanine rate of appearance,
      rate of disappearance, protein synthesis, and protein breakdown did not change.
      Arterial and venous alanine concentrations and glutamate uptake were
      significantly higher during exercise than at rest. We conclude that lower body
      resistance exercise potently stimulates leg glucose uptake and lactate release.
      In addition, muscle protein synthesis is not elevated during a bout of resistance
      exercise.

PMID- 15194679
TI  - Labeled carbon dioxide (C18O2): an indicator gas for phase II in expirograms.
AB  - Carbon dioxide labeled with 18O (C18O2) was used as a tracer gas for single
      breath measurements in six anesthetized, mechanically ventilated beagle dogs.
      C18O2 is taken up quasi-instantaneously in the gas-exchanging region of the lungs
      but much less so in the conducting airways. Its use allows a clear separation of
      phase II in an expirogram even from diseased individuals and excludes the
      influence of alveolar concentration differences. Phase II of a C18O2 expirogram
      mathematically corresponds to the cumulative distribution of bronchial pathways
      to be traversed completely in the course of exhalation. The derivative of this
      cumulative distribution with respect to respired volume was submitted to a power
      moment analysis to characterize volumetric mean (position), standard deviation
      (broadness), and skewness (asymmetry) of phase II. Position is an estimate of
      dead space volume, whereas broadness and skewness are measures of the range and
      asymmetry of functional airway pathway lengths. The effects of changing
      ventilatory patterns and of changes in airway size (via carbachol-induced
      bronchoconstriction) were studied. Increasing inspiratory or expiratory flow
      rates or tidal volume had only minor influence on position and shape of phase II.
      With the introduction of a postinspiratory breath hold, phase II was continually
      shifted toward the airway opening (maximum 45% at 16 s) and became steeper by up
      to 16%, whereas skewness showed a biphasic response with a moderate decrease at
      short breath holding and a significant increase at longer breath holds. Stepwise
      bronchoconstriction decreased position up to 45 +/- 2% and broadness of phase II
      up to 43 +/- 4%, whereas skewness was increased up to twofold at high-carbachol
      concentrations. Under all circumstances, position of phase II by power moment
      analysis and dead space volume by the Fowler technique agreed closely in our
      healthy dogs. Overall, power moment analysis provides a more comprehensive view
      on phase II of single-breath expirograms than conventional dead space volume
      determinations and may be useful for respiratory physiology studies as well as
      for the study of diseased lungs.

PMID- 15194680
TI  - Histone deacetylase activity is required to recruit RNA polymerase II to the
      promoters of selected interferon-stimulated early response genes.
AB  - Posttranslational modification of histones by acetylation, methylation or
      phosphorylation has emerged as a major mechanism to modify chromatin structure
      and gene expression. In most cases, transcriptionally active genes display
      enhanced binding of acetylated histones in their promoters. Activation of histone
      acetyltransferases or inhibition of histone deacetylases (HDACs) allows chromatin
      to assume a more open state permitting transcriptional activators to form a
      preinitiation complex. To our surprise, treatment of cells with the HDAC
      inhibitor, trichostatin A (TSA), inhibits selected interferon beta (IFNbeta)
      stimulated immediate early genes that are activated by the transcription factors
      Stat1 and Stat2. However, IFNbeta activation of IRF-1, which requires tyrosine
      phosphorylated Stat1 homodimers binding to a gamma interferon activation sequence
      in its promoter is not affected by TSA. Exposure of cells to TSA does not alter
      tyrosine phosphorylation of Stat1 or Stat2. TSA treatment of cells also does not
      alter the binding of Stat 1 or Stat2 to the endogenous ISG54 promoter. However,
      IFNbeta-stimulated binding of RNA polymerase II to the ISG54 promoter is
      prevented by TSA. Interestingly, ectopic expression of IRF9 reverses the
      inhibitory actions of TSA, suggesting that IRF9 functions to recruit RNA
      polymerase II to the promoter of interferon-stimulated genes. This particular
      function of IRF9 requires the activity of histone deacetylases.

PMID- 15194682
TI  - Synthetic two-piece and three-piece split inteins for protein trans-splicing.
AB  - Inteins are protein-intervening sequences that can self-excise and concomitantly
      splice together the flanking polypeptides. Two-piece split inteins capable of
      protein trans-splicing have been found in nature and engineered in laboratories,
      but they all have a similar split site corresponding to the endonuclease domain
      of the intein. Can inteins be split at other sites and do trans-splicing? After
      testing 13 split sites engineered into a Ssp DnaB mini-intein, we report the
      finding of three new split sites that each produced a two-piece split intein
      capable of protein trans-splicing. These three functional split sites are located
      in different loop regions between beta-strands of the intein structure, and one
      of them is just 11 amino acids from the beginning of the intein. Because
      different inteins have similar structures and similar beta-strands, these new
      split sites may be generalized to other inteins. We have also demonstrated for
      the first time that a three-piece split intein could function in protein trans
      splicing. These findings have implications for intein structure-function,
      evolution, and uses in biotechnology.

PMID- 15194681
TI  - Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of
      threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic
      nucleotides.
AB  - Regulation of smooth muscle myosin phosphatase (SMPP-1M) is thought to be a
      primary mechanism for explaining Ca(2+) sensitization/desensitization in smooth
      muscle. Ca(2+) sensitization induced by activation of G protein-coupled receptors
      acting through RhoA involves phosphorylation of Thr-696 (of the human isoform) of
      the myosin targeting subunit (MYPT1) of SMPP-1M inhibiting activity. In contrast,
      agonists that elevate intracellular cGMP and cAMP promote Ca(2+) desensitization
      in smooth muscle through apparent activation of SMPP-1M. We show that cGMP
      dependent protein kinase (PKG)/cAMP-dependent protein kinase (PKA) efficiently
      phosphorylates MYPT1 in vitro at Ser-692, Ser-695, and Ser-852 (numbering for
      human isoform). Although phosphorylation of MYPT1 by PKA/PKG has no direct effect
      on SMPP-1M activity, a primary site of phosphorylation is Ser-695, which is
      immediately adjacent to the inactivating Thr-696. In vitro, phosphorylation of
      Ser-695 by PKA/PKG appeared to prevent phosphorylation of Thr-696 by MYPT1K. In
      ileum smooth muscle, Ser-695 showed a 3-fold increase in phosphorylation in
      response to 8-bromo-cGMP. Addition of constitutively active recombinant MYPT1K to
      permeabilized smooth muscles caused phosphorylation of Thr-696 and Ca(2+)
      sensitization; however, this phosphorylation was blocked by preincubation with 8
      bromo-cGMP. These findings suggest a mechanism of Ca(2+) desensitization in
      smooth muscle that involves mutual exclusion of phosphorylation, whereby
      phosphorylation of Ser-695 prevents phosphorylation of Thr-696 and therefore
      inhibition of SMPP-1M.

PMID- 15194683
TI  - Regulated tissue-specific alternative splicing of enhanced green fluorescent
      protein transgenes conferred by alpha-tropomyosin regulatory elements in
      transgenic mice.
AB  - The mutually exclusive exons 2 and 3 of alpha-tropomyosin (alphaTM) have been
      used as a model system for strictly regulated alternative splicing. Exon 2
      inclusion is only observed at high levels in smooth muscle (SM) tissues, whereas
      striated muscle and non-muscle cells use predominantly exon 3. Experiments in
      cell culture have shown that exon 2 selection results from repression of exon 3
      and that this repression is mediated by regulatory elements flanking exon 3. We
      have now tested the cell culture-derived model in transgenic mice. We show that
      by harnessing the intronic splicing regulatory elements, expression of an
      enhanced green fluorescent protein transgene with a constitutively active
      promoter can be restricted to SM cells. Splicing of both endogenous alphaTM and a
      series of transgenes carrying regulatory element mutations was analyzed by
      reverse transcriptasePCR. These studies indicated that although SM-rich tissues
      are equipped to regulate splicing of high levels of endogenous or transgene
      alphaTM RNA, other non-SM tissues such as spleen, which express lower amounts of
      alphaTM, also splice significant proportions of exon 2, and this splicing pattern
      can be recapitulated by transgenes expressed at low levels. We confirm the
      importance in vivo of the negatively acting regulatory elements for regulated
      skipping of exon 3. Moreover, we provide evidence that some of the regulatory
      factors responsible for exon 3 skipping appear to be titratable, with loss of
      regulated splicing sometimes being associated with high transgene expression
      levels.

PMID- 15194684
TI  - Expression of the human myotonic dystrophy kinase-related Cdc42-binding kinase
      gamma is regulated by promoter DNA methylation and Sp1 binding.
AB  - Myotonic dystrophy kinase-related Cdc42 binding kinases (MRCKs) are family
      members most related to the myotonic dystrophy kinase (DMPK), RhoA-binding kinase
      (ROK), and citron kinase. Two highly conserved members, MRCKalpha and -beta, have
      been previously identified and characterized. We now describe a novel isoform,
      MRCKgamma, which is functionally and structurally related to members of this
      kinase family. We show these kinases to have marked similarities in their genomic
      organization, substrate phosphorylation, and catalytic autoinhibition. Unlike
      MRCKalpha and -beta, which are expressed ubiquitously, MRCKgamma mRNA was only
      expressed in heart and skeletal muscle. In cultured cells, MRCKgamma showed
      differential expression with high levels of expression only in certain cell
      lines. DNA analysis showed that lack of expression is correlated with promoter
      DNA methylation. We have mapped the methylation sites in the MRCKgamma promoter.
      Significantly, agents that suppressed DNA methylation caused increases in the
      expression of the kinase in low-expressing cells, further supporting the notion
      that promoter DNA methylation plays an important role in the expression of
      MRCKgamma. Analysis of the MRCKgamma promoter has also revealed two proximal Sp1
      sites that are essential for transcriptional activity. We conclude that both
      promoter DNA methylation and Sp1 binding are important regulators for MRCKgamma
      expression.

PMID- 15194685
TI  - Structural variability of the initiation complex of HIV-1 reverse transcription.
AB  - HIV-1 reverse transcription is initiated from a tRNA(3)(Lys) molecule annealed to
      the viral RNA at the primer binding site (PBS), but the structure of the
      initiation complex of reverse transcription remains controversial. Here, we
      performed in situ structural probing, as well as in vitro structural and
      functional studies, of the initiation complexes formed by highly divergent
      isolates (MAL and NL4.3/HXB2). Our results show that the structure of the
      initiation complex is not conserved. In MAL, and according to sequence analysis
      in 14% of HIV-1 isolates, formation of the initiation complex is accompanied by
      complex rearrangements of the viral RNA, and extensive interactions with
      tRNA(3)(Lys) are required for efficient initiation of reverse transcription. In
      NL4.3, HXB2, and most isolates, tRNA(3)(Lys) annealing minimally affects the
      viral RNA structure and no interaction outside the PBS is required for optimal
      initiation of reverse transcription. We suggest that in MAL, extensive
      interactions with tRNA(3)(Lys) are required to drive the structural
      rearrangements generating the structural elements ultimately recognized by
      reverse transcriptase. In NL4.3 and HXB2, these elements are already present in
      the viral RNA prior to tRNA(3)(Lys) annealing, thus explaining that extensive
      interactions with the primer are not required. Interestingly, such interactions
      are required in HXB2 mutants designed to use a non-cognate tRNA as primer
      (tRNA(His)). In the latter case, the extended interactions are required to
      counteract a negative contribution associate with the alternate primer.

PMID- 15194686
TI  - Insulin-response element-binding protein 1: a novel Akt substrate involved in
      transcriptional action of insulin.
AB  - Although the cis-acting elements that mediate the actions of insulin on gene
      transcription have been defined for a significant number of genes, the
      transcription factors responsible for the transactivation of these target
      sequences remain unknown. In this report, we identified a novel transcription
      factor that binds and transactivates the insulin-response elements of the insulin
      like growth factor-binding protein-3 and other insulin responsive genes. This
      factor is a target of insulin signal transduction downstream of the
      phosphatidylinositol 3'-kinase/protein kinase B (Akt) pathway. Akt phosphorylates
      this factor in vivo and in vitro. Changes in expression level, phosphorylation,
      and nuclear translocation modulate the transactivation effects of the factor, and
      its expression is decreased in conditions of diabetes and insulin deficiency.
      Identification of a novel target of Akt that appears to mediate signals specific
      for insulin action should provide further insight into the mechanism of insulin
      action at the genomic level.

PMID- 15194687
TI  - 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3.
AB  - The transient receptor potential (TRP) superfamily contains a large number of
      proteins encoding cation permeable channels that are further divided into TRPC
      (canonical), TRPM (melastatin), and TRPV (vanilloid) subfamilies. Among the six
      TRPV members, TRPV1, TRPV2, TRPV3, and TRPV4 form heat-activated cation channels,
      which serve diverse functions ranging from nociception to osmolality regulation.
      Although chemical activators for TRPV1 and TRPV4 are well documented, those for
      TRPV2 and TRPV3 are lacking. Here we show that in the absence of other stimuli, 2
      aminoethoxydiphenyl borate (2APB) activates TRPV1, TRPV2, and TRPV3, but not
      TRPV4, TRPV5, and TRPV6 expressed in HEK293 cells. In contrast, 2APB inhibits the
      activity of TRPC6 and TRPM8 evoked by 1-oleolyl-2-acetyl-sn-glycerol and menthol,
      respectively. In addition, low levels of 2APB strongly potentiate the effect of
      capsaicin, protons, and heat on TRPV1 as well as that of heat on TRPV3 expressed
      in Xenopus oocytes. In dorsal root ganglia neurons, supra-additive stimulations
      were evoked by 2APB and capsaicin or 2APB and acid. Our data suggest the
      existence of a common activation mechanism for TRPV1, TRPV2, and TRPV3 that may
      serve as a therapeutic target for pain management and treatment for diseases
      caused by hypersensitivity and temperature misregulation.

PMID- 15194688
TI  - Crystal structure of the hemolytic lectin CEL-III isolated from the marine
      invertebrate Cucumaria echinata: implications of domain structure for its
      membrane pore-formation mechanism.
AB  - CEL-III is a Ca(2+)-dependent and galactose-specific lectin purified from the sea
      cucumber, Cucumaria echinata, which exhibits hemolytic and hemagglutinating
      activities. Six molecules of CEL-III are assumed to oligomerize to form an ion
      permeable pore in the cell membrane. We have determined the crystal structure of
      CELIII by using single isomorphous replacement aided by anomalous scattering in
      lead at 1.7 A resolution. CEL-III consists of three distinct domains as follows:
      the N-terminal two carbohydrate-binding domains (1 and 2), which adopt beta
      trefoil folds such as the B-chain of ricin and are members of the (QXW)(3) motif
      family; and domain 3, which is a novel fold composed of two alpha-helices and one
      beta-sandwich. CEL-III is the first Ca(2+)-dependent lectin structure with two
      beta-trefoil folds. Despite sharing the structure of the B-chain of ricin, CEL
      III binds five Ca(2+) ions at five of the six subdomains in both domains 1 and 2.
      Considering the relatively high similarity among the five subdomains, they are
      putative binding sites for galactose-related carbohydrates, although it remains
      to be elucidated whether bound Ca(2+) is directly involved in interaction with
      carbohydrates. The paucity of hydrophobic interactions in the interfaces between
      the domains and biochemical data suggest that these domains rearrange upon
      carbohydrate binding in the erythrocyte membrane. This conformational change may
      be responsible for oligomerization of CEL-III molecules and hemolysis in the
      erythrocyte membranes.

PMID- 15194689
TI  - UvsX recombinase and Dda helicase rescue stalled bacteriophage T4 DNA replication
      forks in vitro.
AB  - The rescue of stalled replication forks via a series of steps that include fork
      regression, template switching, and fork restoration often has been proposed as a
      major mechanism for accurately bypassing non-coding DNA lesions. Bacteriophage T4
      encodes almost all of the proteins required for its own DNA replication,
      recombination, and repair. Both recombination and recombination repair in T4 rely
      on UvsX, a RecA-like recombinase. We show here that UvsX plus the T4-encoded
      helicase Dda suffice to rescue stalled T4 replication forks in vitro. This rescue
      is based on two sequential template-switching reactions that allow DNA
      replication to bypass a non-coding DNA lesion in a non-mutagenic manner.

PMID- 15194690
TI  - Functional replacement of the FabA and FabB proteins of Escherichia coli fatty
      acid synthesis by Enterococcus faecalis FabZ and FabF homologues.
AB  - The anaerobic unsaturated fatty acid synthetic pathway of Escherichia coli
      requires two specialized proteins, FabA and FabB. However, the fabA and fabB
      genes are found only in the Gram-negative alpha- and gamma-proteobacteria, and
      thus other anaerobic bacteria must synthesize these acids using different
      enzymes. We report that the Gram-positive bacterium Enterococcus faecalis encodes
      a protein, annotated as FabZ1, that functionally replaces the E. coli FabA
      protein, although the sequence of this protein aligns much more closely with E.
      coli FabZ, a protein that plays no specific role in unsaturated fatty acid
      synthesis. Therefore E. faecalis FabZ1 is a bifunctional dehydratase/isomerase,
      an enzyme activity heretofore confined to a group of Gram-negative bacteria. The
      FabZ2 protein is unable to replace the function of E. coli FabZ, although FabZ2,
      a second E. faecalis FabZ homologue, has this ability. Moreover, an E. faecalis
      FabF homologue (FabF1) was found to replace the function of E. coli FabB, whereas
      a second FabF homologue was inactive. From these data it is clear that bacterial
      fatty acid biosynthetic pathways cannot be deduced solely by sequence
      comparisons.

PMID- 15194691
TI  - Subtype-selective noncompetitive or competitive inhibition of human alpha1
      adrenergic receptors by rho-TIA.
AB  - The 19-amino acid conopeptide (rho-TIA) was shown previously to antagonize
      noncompetitively alpha(1B)-adrenergic receptors (ARs). Because this is the first
      peptide ligand for these receptors, we compared its interactions with the three
      recombinant human alpha(1)-AR subtypes (alpha(1A), alpha(1B), and alpha(1D)).
      Radioligand binding assays showed that rho-TIA was 10-fold selective for human
      alpha(1B)-over alpha(1A)- and alpha(1D)-ARs. As observed with hamster alpha(1B)
      ARs, rho-TIA decreased the number of binding sites (B(max)) for human alpha(1B)
      ARs without changing affinity (K(D)), and this inhibition was unaffected by the
      length of incubation but was reversed by washing. However, rho-TIA had opposite
      effects at human alpha(1A)-ARs and alpha(1D)-ARs, decreasing K(D) without
      changing B(max), suggesting it acts competitively at these subtypes. rho-TIA
      reduced maximal NE-stimulated [(3)H]inositol phosphate formation in HEK293 cells
      expressing human alpha(1B)-ARs but competitively inhibited responses in cells
      expressing alpha(1A)- or alpha(1D)-ARs. Truncation mutants showed that the amino
      terminal domains of alpha(1B)- or alpha(1D)-ARs are not involved in interaction
      with rho-TIA. Alanine-scanning mutagenesis of rho-TIA showed F18A had an
      increased selectivity for alpha(1B)-ARs, and F18N also increased subtype
      selectivity. I8A had a slightly reduced potency at alpha(1B)-ARs and was found to
      be a competitive, rather than noncompetitive, inhibitor in both radioligand and
      functional assays. Thus rho-TIA noncompetitively inhibits alpha(1B)-ARs but
      competitively inhibits the other two subtypes, and this selectivity can be
      increased by mutation. These differential interactions do not involve the
      receptor amino termini and are not because of the charged nature of the peptide,
      and isoleucine 8 is critical for its noncompetitive inhibition at alpha(1B)-ARs.

PMID- 15194692
TI  - Cell surface ceramide generation precedes and controls FcgammaRII clustering and
      phosphorylation in rafts.
AB  - Despite the role of sphingolipid/cholesterol rafts as signaling platforms for
      Fcgamma receptor II (FcgammaRII), the mechanism governing translocation of an
      activated receptor toward the rafts is unknown. We show that at the onset of
      FcgammaRII cross-linking acid sphingomyelinase is rapidly activated. This enzyme
      is extruded from intracellular compartments to the cell surface, and
      concomitantly, exofacially oriented ceramide is produced. Both non-raft and, to a
      lesser extent, raft sphingomyelin pools were hydrolyzed at the onset of
      FcgammaRII cross-linking. The time course of ceramide production preceded the
      recruitment of FcgammaRII to rafts and the receptor phosphorylation. Exogenous
      C(16)-ceramide facilitated clustering of FcgammaRII and its association with
      rafts. In contrast, inhibition of acid sphingomyelinase diminished both the
      ceramide generation and clustering of cross-linked FcgammaRII. Under these
      conditions, tyrosine phosphorylation of FcgammaRII and receptor-accompanying
      proteins was also reduced. All the inhibitory effects were bypassed by treatment
      of cells with exogenous ceramide. These data provide evidence that the generation
      of cell surface ceramide is a prerequisite for fusion of cross-linked FcgammaRII
      and rafts, which triggers the receptor tyrosine phosphorylation and signaling.

PMID- 15194694
TI  - Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent
      protein kinase.
AB  - DNA ligase IV (Lig4), x-ray cross-complementation group 4 (XRCC4), and DNA
      dependent protein kinase (DNA-PK) are essential mammalian nonhomologous end
      joining proteins used for V(D)J recombination and DNA repair. Previously a Lig4
      peptide was reported to be an in vitro substrate for DNA-PK, but the
      phosphorylation state of Lig4 protein in vivo is not known. In this study, we
      report that a full-length Lig4 construct was expressed as a phosphoprotein in the
      cell. Also the full-length Lig4 protein, in complex with XRCC4, was an in vitro
      substrate for DNA-PK. Using tandem mass spectrometry, we identified a DNA-PK
      phosphorylation site at Thr-650 in human Lig4 and a potential second
      phosphorylation site at Ser-668 or Ser-672. Phosphorylation of Lig4 per se was
      not required for Lig4 DNA end joining activity. Substitution of these amino acids
      with alanine, individually or in combination, led to changes in Lig4 protein
      stability of mouse Lig4. The phosphomimetic mutation S650D returned Lig4
      stability to that of the wild-type protein. Furthermore DNA-PK was found to
      negatively regulate Lig4 protein stability. Our results suggest that Lig4
      stability is regulated by multiple factors, including interaction with XRCC4,
      phosphorylation status, and possibly Lig4 conformation.

PMID- 15194693
TI  - N-cadherin activation substitutes for the cell contact control in cell cycle
      arrest and myogenic differentiation: involvement of p120 and beta-catenin.
AB  - N-cadherin is expressed throughout skeletal myogenesis and has been proposed to
      be involved in the differentiation program of myogenic precursors. Here, we
      further characterize the N-cadherin involvement and its mechanism of action at
      the onset of differentiation, through controlled N-cadherin activation by plating
      isolated C2 myoblasts on surfaces coated with a chimeric Ncad-Fc homophilic
      ligand (N-cadherin ectodomain fused to the immunoglobulin G Fc fragment). We show
      that N-cadherin activation substitutes for the cell density in myogenic
      differentiation by promoting myogenin and troponin T expression. In addition, N
      cadherin adhesion participates to the associated cell cycle arrest through the
      nuclear accumulation of cyclin-dependent kinase inhibitors p21 and p27. Mouse
      primary myoblast cultures exhibited similar responses to N-cadherin as C2 cells.
      RNA interference knockdowns of the N-cadherin-associated cytoplasmic proteins
      p120 and beta-catenin produced opposite effects on the differentiation pathway.
      p120 silencing resulted in a decreased myogenic differentiation, associated with
      a reduction in cadherin-catenin content, which may explain its action on myogenic
      differentiation. beta-Catenin silencing led to a stimulatory effect on myogenin
      expression, without any effect on cell cycle. Our results demonstrate that N
      cadherin adhesion may account for cell-cell contact-dependent cell cycle arrest
      and differentiation of myogenic cells, involving regulation through p120 and beta
      catenins.

PMID- 15194695
TI  - Atg21 is required for effective recruitment of Atg8 to the preautophagosomal
      structure during the Cvt pathway.
AB  - Atg21 and Atg18 are homologue yeast proteins. Whereas Atg18 is essential for the
      Cvt pathway and autophagy, a lack of Atg21 only blocks the Cvt pathway. Our
      proteinase protection experiments now demonstrate that growing atg21Delta cells
      fail to form proaminopeptidase I-containing Cvt vesicles. Quantitative
      measurement of autophagy in starving atg21Delta cells showed only 35% of the wild
      type rate. This suggests that Atg21 plays a nonessential role in improving the
      fidelity of autophagy. The intracellular localization of Atg21 is unique among
      the Atg proteins. In cells containing multiple vacuoles, Atg21-yellow fluorescent
      protein clearly localizes to the vertices of the vacuole junctions. Cells with a
      single vacuole show most of the protein at few perivacuolar punctae. This
      distribution pattern is reminiscent to the Vps class C(HOPS) (homotypic fusion
      and vacuolar protein sorting) protein complex. In growing cells, Atg21 is
      required for effective recruitment of Atg8 to the preautophagosomal structure.
      Consistently, the covalent linkage of Atg8 to the lipid phosphatidylethanolamine
      is significantly retarded. Lipidated Atg8 is supposed to act during the
      elongation of autophagosome precursors. However, despite the reduced autophagic
      rate and the retardation of Atg8 lipidation, electron microscopy of starved
      atg21Delta ypt7Delta double mutant cells demonstrates the formation of normally
      sized autophagosomes with an average diameter of 450 nm.

PMID- 15194696
TI  - Heart fatty acid uptake is decreased in heart fatty acid-binding protein gene
      ablated mice.
AB  - Cell culture systems have demonstrated a role for cytoplasmic fatty acid-binding
      proteins (FABP) in lipid metabolism, although a similar function in intact
      animals is unknown. We addressed this issue using heart fatty acid-binding
      protein (H-FABP) gene-ablated mice. H-FABP gene ablation reduced total heart
      fatty acid uptake 40 and 52% for [1-(14)C]16:0 and [1-(14)C]20:4n-6 compared with
      controls, respectively. Similarly, the amount of fatty acid found in the aqueous
      fraction was reduced 40 and 52% for [1-(14)C]16:0 and [1-(14)C]20:4n-6,
      respectively. Less [1-(14)C]16:0 entered the triacylglycerol pool, with
      significant redistribution of fatty acid between the triacylglycerol pool and the
      total phospholipid pool. Less [1-(14)C]20:4n-6 entered each lipid pool measured,
      but these changes did not alter the distribution of tracer among these pools. In
      gene-ablated mice, significantly more [1-(14)C]16:0 was targeted to choline and
      ethanolamine glycerophospholipids, whereas more [1-(14)C]20:4n-6 was targeted to
      the phosphatidylinositol (PtdIns) pool. H-FABP gene ablation significantly
      increased PtdIns mass 1.4-fold but reduced PtdIns 20:4n-6 mass 30%. Consistent
      with a reported effect of FABP on plasmalogen mass, ethanolamine plasmalogen mass
      was reduced 30% in gene-ablated mice. Further, 20:4n-6 mass was reduced in each
      of the three other major phospholipid classes, suggesting H-FABP has a role in
      maintaining steady-state 20:4n-6 mass in heart. In summary, H-FABP was important
      for heart fatty acid uptake and targeting of fatty acids to specific heart lipid
      pools as well as for maintenance of phospholipid pool mass and acyl chain
      composition.

PMID- 15194698
TI  - Functional coupling of chromogranin with the inositol 1,4,5-trisphosphate
      receptor shapes calcium signaling.
AB  - Chromogranins A and B are high capacity, low affinity calcium (Ca(2+)) storage
      proteins that bind to the inositol 1,4,5-trisphosphate-gated receptor (InsP(3)
      R). Although most commonly associated with secretory granules of neuroendocrine
      cells, chromogranins have also been found in the lumen of the endoplasmic
      reticulum (ER) of many cell types. To investigate the functional consequences of
      the interaction between the InsP(3) R and the chromogranins, we disrupted the
      interaction between the two proteins by adding a chromogranin fragment, which
      competed with chromogranin for its binding site on the InsP(3)R. Responses were
      monitored at the single channel level and in intact cells. When using InsP(3) R
      type I incorporated into planar lipid bilayers and activated by cytoplasmic
      InsP(3) and luminal chromogranin, the addition of the fragment reversed the
      enhancing effect of chromogranin. Moreover, the expression of the fragment in the
      ER of neuronally differentiated PC12 cells attenuated agonist-induced
      intracellular Ca(2+) signaling. These results show that the InsP(3)R/chromogranin
      interaction amplifies Ca(2+) release from the ER and that chromogranin is an
      essential component of this intracellular channel complex.

PMID- 15194697
TI  - Possible function of the ADAM1a/ADAM2 Fertilin complex in the appearance of ADAM3
      on the sperm surface.
AB  - In mouse, two different isoforms of ADAM1 (fertilin alpha), ADAM1a and ADAM1b,
      are produced in the testis. ADAM1a is localized within the endoplasmic reticulum
      of testicular germ cells, whereas epididymal sperm contain only ADAM1b on the
      plasma membrane. In this study, we show that the loss of ADAM1a results in the
      male infertility because of the severely impaired ability of sperm to migrate
      from the uterus into the oviduct through the uterotubal junction. However,
      epididymal sperm of ADAM1a-deficient mice were capable of fertilizing cumulus
      intact, zona pellucida-intact eggs in vitro despite the delayed dispersal of
      cumulus cells and the reduced adhesion/binding to the zona pellucida. Among
      testis (sperm)-specific proteins examined, only the level of ADAM3 (cyritestin)
      was strongly reduced in ADAM1a-deficient mouse sperm. Moreover, the appearance of
      ADAM3 on the sperm surface was dependent on the formation of a fertilin protein
      complex between ADAM1a and ADAM2 (fertilin beta) in testicular germ cells,
      although no direct interaction between the fertilin complex and ADAM3 was found.
      These results suggest that ADAM1a/ADAM2 fertilin may be implicated in the
      selective transport of specific sperm proteins including ADAM3 from the
      endoplasmic reticulum of testicular germ cells onto the cell surface. These
      proteins then can participate in sperm migration into the oviduct, the dispersal
      of cumulus cells, and sperm binding to the zona pellucida.

PMID- 15194699
TI  - PIGEA-14, a novel coiled-coil protein affecting the intracellular distribution of
      polycystin-2.
AB  - Employing a yeast two-hybrid screen with the COOH terminus of polycystin-2, one
      of the proteins mutated in patients with polycystic kidney disease, we were able
      to isolate a novel protein that we call PIGEA-14 (polycystin-2 interactor, Golgi-
      and endoplasmic reticulum-associated protein with a molecular mass of 14 kDa).
      Molecular modeling only predicts a coiled-coil motif, but no other functional
      domains, in PIGEA-14. In a subsequent two-hybrid screen using PIGEA-14 as a bait,
      we found GM130, a component of the cis-compartment of the Golgi apparatus. Co
      expression of the PIGEA-14 and PKD2 cDNAs in LLC-PK(1) and HeLa cells resulted in
      a redistribution of PIGEA-14 and polycystin-2 to the trans-Golgi network, which
      suggests that PIGEA-14 plays an important role in regulating the intracellular
      location of polycystin-2 and possibly other intracellular proteins. Our results
      also indicate that the intracellular trafficking of polycystin-2 is regulated
      both at the level of the endo-plasmic reticulum and that of the trans-Golgi
      network.

PMID- 15194700
TI  - Characterization of the signaling capacities of the novel gp130-like cytokine
      receptor.
AB  - The gp130-like receptor (GPL) is a recently cloned member of the family of type I
      cytokine receptors. The name reflects its close relationship to gp130, the common
      receptor subunit of the interleukin (IL)-6-type cytokines. Indeed, the recently
      proposed ligand for GPL, IL-31, is closely related to the IL-6-type cytokines
      oncostatin M, leukemia inhibitory factor, and cardiotrophin-1. The second signal
      transducing receptor for IL-31 seems to be the oncostatin M receptor beta
      (OSMRbeta). The present study characterizes in depth the molecular mechanisms
      underlying GPL-mediated signal transduction. GPL is a strong activator of STAT3
      and STAT5, whereas STAT1 is only marginally tyrosine-phosphorylated. We identify
      tyrosine residues 652 and 721 in the cytoplasmic region of the longest isoform of
      GPL (GPL(745)) as the major STAT5- and STAT3-activating sites, respectively.
      Additionally, we demonstrate Jak1 binding to GPL and its activation in
      heteromeric complexes with the OSMRbeta but also in a homomeric receptor complex.
      Most interesting, unlike OSMRbeta and gp130, GPL is insufficient to mediate
      ERK1/2 phosphorylation. We propose that this is due to a lack of recruitment of
      the tyrosine phosphatase SHP-2 or the adaptor protein Shc to the cytoplasmic
      domain of GPL.

PMID- 15194701
TI  - tRNA recognition by glutamyl-tRNA reductase.
AB  - During the first step of porphyrin biosynthesis in Archaea, most bacteria, and in
      chloroplasts glutamyl-tRNA reductase (GluTR) catalyzes the NADPH-dependent
      reduction of glutamyl-tRNA to glutamate-1-semialdehyde. Elements in tRNA(Glu)
      important for utilization by Escherichia coli GluTR were determined by kinetic
      analysis of 51 variant transcripts of E. coli Glu-tRNA(Glu). Base U8, the
      U13*G22**A46 base triple, the tertiary Watson-Crick base pair 19*56, and the lack
      of residue 47 are required for GluTR recognition. All of these bases contribute
      to the formation of the unique tertiary core of E. coli tRNA-(Glu). Two tRNA(Glu)
      molecules lacking the entire anticodon stem/loop but retaining the tertiary core
      structure remained substrates for GluTR, while further decreasing tRNA size
      toward a minihelix abolished GluTR activity. RNA footprinting experiments
      revealed the physical interaction of GluTR with the tertiary core of Glu
      tRNA(Glu). E. coli GluTR showed clear selectivity against mischarged Glu
      tRNA(Gln). We concluded that the unique tertiary core structure of E. coli
      tRNA(Glu) was sufficient for E. coli GluTR to distinguish specifically its
      glutamyl-tRNA substrate.

PMID- 15194702
TI  - WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the
      modulation of hemoglobin vasoactivity.
AB  - This paper has been withdrawn since all of the coauthors had not approved of its
      submission.

PMID- 15194703
TI  - Critical role of transmembrane segment zinc binding in the structure and function
      of rhodopsin.
AB  - Zinc deficiency and retinitis pigmentosa are both important factors resulting in
      retinal dysfunction and night blindness. In this study, we address the critical
      biochemical and structural relevance of zinc ions in rhodopsin and examine
      whether zinc deficiency can lead to rhodopsin dysfunction. We report the
      identification of a high-affinity zinc coordination site within the transmembrane
      domain of rhodopsin, coordinated by the side chains of two highly conserved
      residues, Glu(122) in transmembrane helix III and His(211) in transmembrane helix
      V. We also demonstrate that this zinc coordination is critical for rhodopsin
      folding, 11-cis-retinal binding, and the stability of the chromophore-receptor
      interaction, defects of which are observed in retinitis pigmentosa. Furthermore,
      a cluster of retinitis pigmentosa mutations is localized within and around this
      zinc binding site. Based on these studies, we believe that improvement in zinc
      binding to rhodopsin at this site within the transmembrane domain may be a
      pharmacological approach for the treatment of select retinitis pigmentosa
      mutations. Transmembrane coordination of zinc may also be an important common
      principle across G-protein-coupled receptors.

PMID- 15194704
TI  - Low affinity orthophosphate carriers regulate PHO gene expression independently
      of internal orthophosphate concentration in Saccharomyces cerevisiae.
AB  - Phosphate is an essential nutrient that must be taken up from the growth medium
      through specific transporters. In Saccharomyces cerevisiae, both high and low
      affinity orthophosphate carriers allow this micro-organism to cope with
      environmental variations. Intriguingly, in this study we found a tight
      correlation between selenite resistance and expression of the high affinity
      orthophosphate carrier Pho84p. Our work further revealed that mutations in the
      low affinity orthophosphate carrier genes (PHO87, PHO90, and PHO91) cause
      deregulation of phosphate-repressed genes. Strikingly, the deregulation due to
      pho87Delta, pho90Delta, or pho91Delta mutations was neither correlated to
      impaired orthophosphate uptake capacity nor to a decrease of the intracellular
      orthophosphate or polyphosphate pools, as shown by (31)P NMR spectroscopy. Thus,
      our data clearly establish that the low affinity orthophosphate carriers affect
      phosphate regulation independently of intracellular orthophosphate concentration
      through a new signaling pathway that was found to strictly require the cyclin
      dependent kinase inhibitor Pho81p. We propose that phosphate-regulated gene
      expression is under the control of two different regulatory signals as follows:
      the sensing of internal orthophosphate by a yet unidentified protein and the
      sensing of external orthophosphate by low affinity orthophosphate transporters;
      the former would be required to maintain phosphate homeostasis, and the latter
      would keep the cell informed on the medium phosphate richness.

PMID- 15194705
TI  - Crystal structure of the oxygen-dependant coproporphyrinogen oxidase (Hem13p) of
      Saccharomyces cerevisiae.
AB  - Coproporphyrinogen oxidase (CPO) is an essential enzyme that catalyzes the sixth
      step of the heme biosynthetic pathway. Unusually for heme biosynthetic enzymes,
      CPO exists in two evolutionarily and mechanistically distinct families, with
      eukaryotes and some prokaryotes employing members of the highly conserved oxygen
      dependent CPO family. Here, we report the crystal structure of the oxygen
      dependent CPO from Saccharomyces cerevisiae (Hem13p), which was determined by
      optimized sulfur anomalous scattering and refined to a resolution of 2.0 A. The
      protein adopts a novel structure that is quite different from predicted models
      and features a central flat seven-stranded anti-parallel sheet that is flanked by
      helices. The dimeric assembly, which is seen in different crystal forms, is
      formed by packing of helices and a short isolated strand that forms a beta-ladder
      with its counterpart in the partner subunit. The deep active-site cleft is lined
      by conserved residues and has been captured in open and closed conformations in
      two different crystal forms. A substratesized cavity is completely buried in the
      closed conformation by the approximately 8-A movement of a helix that forms a lid
      over the active site. The structure therefore suggests residues that likely play
      critical roles in catalysis and explains the deleterious effect of many of the
      mutations associated with the disease hereditary coproporphyria.

PMID- 15194706
TI  - The role of the length and sequence of the linker domain of cytochrome b5 in
      stimulating cytochrome P450 2B4 catalysis.
AB  - Cytochrome b(5) (cyt b(5)) is a 15-kDa amphipathic protein with a cytosolic amino
      terminal catalytic heme domain, which is anchored to the microsomal membrane by a
      hydrophobic transmembrane alpha-helix at its carboxyl terminus. These two domains
      are connected by an approximately 15-amino acid linker domain, Ser(90)-Asp(104),
      which has been modified by site-directed mutagenesis to investigate whether the
      length or sequence of the linker influences the ability of cyt b(5) to bind
      ferric cytochrome P450 2B4 and donate an electron to oxyferrous (cyt P450 2B4),
      thereby stimulating catalysis. Because shortening the linker by 8 or more amino
      acids markedly inhibited the ability of cyt b(5) to bind cyt P450 2B4 and
      stimulate catalysis by this isozyme, it is postulated 7 amino acids are
      sufficient to allow a productive interaction. All mutant cyts b(5) except the
      protein lacking the entire 15-amino acid linker inserted normally into the
      microsomal membrane. Alternatively, lengthening the linker by 16 amino acids,
      reversing the sequence of the amino acids in the linker, and mutating conserved
      linker residues did not significantly alter the ability of cyt b(5) to interact
      with cyt P450 2B4. A model for the membrane-bound cyt b(5)-cyt P450 complex is
      presented.

PMID- 15194707
TI  - Gemfibrozil and its glucuronide inhibit the organic anion transporting
      polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated
      metabolism of cerivastatin: analysis of the mechanism of the clinically relevant
      drug-drug interaction between cerivastatin and gemfibrozil.
AB  - A serious pharmacokinetic interaction between cerivastatin (CER) and gemfibrozil
      (GEM) has been reported. In the present study, we examined the inhibitory effects
      of GEM and its metabolites, M3 and gemfibrozil 1-O-beta-glucuronide (GEM-1-O
      glu), on the uptake of CER by human organic anion transporting polypeptide 2
      (OATP2)-expressing cells and its metabolism in cytochrome P450 expression
      systems. Uptake studies showed that GEM and GEM-1-O-glu significantly inhibited
      the OATP2-mediated uptake of CER with IC(50) values of 72 and 24 microM,
      respectively. They also inhibited the CYP2C8-mediated metabolism of CER with
      IC(50) values of 28 and 4 microM, respectively, whereas M3 had no effects. GEM
      and GEM-1-O-glu minimally inhibited the CYP3A4-mediated metabolism of CER. The
      IC(50) values of GEM and GEM-1-O-glu for the uptake and the metabolism of CER
      obtained in the present study were lower than their total, and not unbound,
      plasma concentrations. However, considering the possibly concentrated high
      unbound concentrations of GEM-1-O-glu in the liver and its relatively larger
      plasma unbound fraction compared with GEM itself, the glucuronide inhibition of
      the CYP2C8-mediated metabolism of CER appears to be the main mechanism for the
      clinically relevant drug-drug interaction. Previously reported clinical drug
      interaction studies showing that coadministration of GEM with pravastatin or
      pitavastatin, both of which are known to be cleared from the plasma by the uptake
      transporters in the liver, only minimally (less than 2-fold) increased the area
      under the plasma concentration-time curve of these statins, also supported our
      present conclusion.

PMID- 15194708
TI  - LY-294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] affects calcium
      signaling in airway smooth muscle cells independently of phosphoinositide 3
      kinase inhibition.
AB  - Phosphoinositide 3-kinase (PI3K) may potentially influence intracellular
      [Ca(2+)](i) concentration by several mechanisms. We have investigated the effects
      of phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY-294002 [2-(4
      morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] on Ca(2+) signaling in rat airway
      smooth muscle (ASM) cells using fura-2 and imaging methodology. Wortmannin (1
      microM) and LY-294002 (1 and 10 microM) had opposite effects: wortmannin caused a
      small increase, whereas LY-294002 caused a significant decrease of peak Ca(2+)
      responses to serotonin (5-HT). LY-294002 (10 microM) diminished 5-HT-induced ASM
      cell contraction, measured as a change in cell surface area, and inositol
      phosphate formation, measured by anion exchange chromatography. Thin layer
      chromatography revealed that the levels of phospholipase C (PLC) substrate
      phosphatidylinositol 4,5-bisphosphate were not affected. SDS polyacrylamide gel
      electrophoresis and Western blotting have shown that both wortmannin and LY
      294002 inhibited platelet-derived growth factor-induced PI3K activation. However,
      PI3K activation could not be detected after 5-HT stimulation. The specific casein
      kinase-2 (CK2) inhibitor 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole (10-40
      microM) reduced 5-HT-triggered responses to a similar extent as LY-294002. We
      conclude that LY-294002 modulates Ca(2+) signaling in rat ASM independently of
      its action on PI3K by acting on, or upstream of, PLC, possibly by inhibiting CK2.

PMID- 15194709
TI  - Expression of constitutive androstane receptor splice variants in human tissues
      and their functional consequences.
AB  - The constitutive androstane receptor (CAR) NR1I3 is a transcription factor that
      upon activation by xenobiotics induces transcription of drug-metabolizing and
      drug transporter genes. Our goal was to identify whether alternative splicing of
      CAR makes an important contribution to the generation of novel CAR proteins. The
      wild-type CAR mRNA (CAR.1) and splice variants (SVs) were amplified from human
      liver cDNAs and in a panel of cDNAs from 36 human tissues, using exon 1- and 3'
      untranslated region primers, cloned and sequenced. Twenty-two unique hCAR splice
      variants (CAR-SVs) containing different combinations of splicing (deletion of
      exons 2, 4, 5, 7, partial deletion of exon 9, or insertion of 12 or 15 base pairs
      from introns 6 or 7) were identified. CAR mRNAs were expressed in small
      intestine, kidney, testis, adrenal, and brain caudate nucleus. Intestine
      expressed only CAR.1 mRNA, whereas spleen, heart, and prostate expressed only CAR
      SVs. In vitro transcription and translation of CAR-SVs lacking exon 2 (missing
      ATG start site) generated CAR proteins that differed in M(r) from CAR.1. These
      CAR-SVs used a translation initiation site in exon 1, generating CAR with a
      unique amino-terminal sequence. Transcripts lacking part of exon 9 altered the
      CAR reading frame generating CAR proteins with a unique carboxy-terminal end. CAR
      SVs demonstrated compromised binding to CYP2B6 NR elements and transcriptional
      activation of a CYP2B6 luciferase reporter. The expression of CAR in additional
      human cell types increases the range of tissue specific transcriptional responses
      regulated by this receptor, suggesting additional biological roles for CAR and
      CAR-SV proteins in these tissues.

PMID- 15194711
TI  - Unreported cases of domestic violence against women: towards an epidemiology of
      social silence, tolerance, and inhibition.

PMID- 15194712
TI  - A glossary for evidence based public health.
AB  - This glossary seeks to define and explain some of the main concepts underpinning
      evidence based public health. It draws on the published literature, experience
      gained over several years analysis of the topic, and discussions with public
      health colleagues, including researchers, practitioners, policy makers, and
      students.

PMID- 15194714
TI  - Civil law problems and morbidity.
AB  - STUDY OBJECTIVE: In the United Kingdom, recognition of the links between social
      and health problems has led to government initiatives such as health action
      zones. The principles of civil law apply to many types of social problem, and the
      civil justice system provides one means through which they can be tackled.
      However, little research has been undertaken into the particular links between
      problems to which civil legal principles and processes can be applied and
      morbidity. This study examines these links, and the role of legal advice and
      services in preventing ill health. DESIGN: This study examined survey
      respondents' self reports of longstanding illness/disability and experience of 18
      problems to which legal principles can be applied. SETTING: A random national
      survey conducted across England and Wales. PARTICIPANTS: 5611 adults drawn from
      3348 residential households. MAIN RESULTS: Significant associations were found
      between illness/disability and 13 of the problem types. Moreover, experience of
      greater numbers of problems increased the likelihood of reported
      illness/disability. In attempting to resolve problems respondents' health also
      frequently suffered. CONCLUSIONS: This study highlights the contribution that
      public legal education and legal advice can make to the promotion of public
      health, and the importance of further integration of health and civil justice
      initiatives through health action zones, community legal service partnerships,
      etc, to further this end.

PMID- 15194715
TI  - Screening for depleted uranium in the United Kingdom armed forces: who wants it
      and why?
AB  - BACKGROUND: Depleted uranium (DU) use has been implicated in the poor health of
      many service personnel who have served in the Gulf and the Balkans. Although the
      health related risks are thought to be small the UK government has offered to set
      up a voluntary screening programme for service personnel. This study aimed to
      find out the characteristics and possible exposures to DU for those personnel who
      desire DU screening. METHODS: This study looks at 2369 UK service personnel who
      were asked if they wanted to be screened for DU. Subjects were asked about their
      perceived exposure to deployment associated risks including DU and a number of
      psychological health measures. RESULTS: The study found that 24% of the cohort
      wanted screening, a figure that if extrapolated to all those who have been
      offered screening would represent 36720 requests for screening. Those who wanted
      DU screening were younger, of lower rank, and more likely to be from the Royal
      Navy or Army rather than the Royal Air Force. Those requesting DU screening
      reported poorer health both subjectively and as measured by the GHQ-12 and a
      symptom checklist. They also reported more exposure to DU and to other deployment
      associated risks while in military service. Using combat exposure as a proxy for
      a significant risk of having been exposed to DU, there was a significant
      correlation. CONCLUSIONS: This study found that the desire for DU screening is
      more closely linked to current health status rather than plausible exposure to
      DU.

PMID- 15194713
TI  - Enhancing the evidence base for health impact assessment.
AB  - Health impact assessment differs from other purposes for which evidence is
      collated in a number of ways, including:the focus on complex interventions or
      policy and their diverse effects on determinants of health;the need for evidence
      on the reversibility of adverse factors damaging to health;the diversity of the
      evidence in terms of relevant disciplines, study designs, quality criteria and
      sources of information;the broad range of stakeholders involved;the short
      timescale and limited resources generally available;the pragmatic need to inform
      decision makers regardless of the quality of the evidence. These have
      implications for commissioning and conducting reviews. Methods must be developed
      to: facilitate comprehensive searching across a broad range of disciplines and
      information sources; collate appropriate quality criteria to assess a range of
      study designs; synthesise different kinds of evidence; and facilitate timely
      stakeholder involvement. Good practice standards for reviews are needed to reduce
      the risk of poor quality recommendations. Advice to decision makers must make
      explicit limitations resulting from absent, conflicting, or poor quality
      evidence.

PMID- 15194717
TI  - Trends in the uptake and delivery of smoking cessation services to smokers in
      Great Britain.

PMID- 15194716
TI  - Traffic ticket fixing and driving behaviours in a large French working
      population.
AB  - STUDY OBJECTIVE: The use of connections who have the authority to cancel
      penalties related to traffic violations seems to be very frequent in France. This
      study aimed at describing risk taking driving behaviours associated in France
      with using connections to have traffic tickets cancelled (ticket fixing). DESIGN:
      Retrospective study on driving behaviour and road safety conducted between March
      and December 2001 within a cohort of French employees. SETTING: France.
      PARTICIPANTS: Employees of the French national utility company who have been
      followed up since 1989. The sample comprises 10 594 men aged 53-63 years and 3258
      women aged 48-63 in 2001. MAIN RESULTS: One third of the men and one fifth of the
      women reported that they had had a ticket fixed at some time. Those who reported
      having tickets fixed were more likely than the others to report high driving
      speeds (adjusted odds ratios (aOR) were 1.24, 1.52, and 1.66 in built up areas,
      on rural roads, and on motorways respectively), to report driving while under the
      influence (aOR = 1.39), and to report risky use of cellular phone while driving
      (aOR = 1.83). In addition, participants who reported having tickets fixed were
      more likely to have had at least one serious road traffic accident in the past 11
      years (aOR = 1.21). CONCLUSIONS: Indulgence and the use of connections are common
      practices in France. These results suggest that it is to confer a feeling of
      impunity that jeopardises efforts to combat unsafe driving. Abolition of these
      traditions is essential to ensure the credibility of preventive and repressive
      measures.

PMID- 15194718
TI  - Fetal growth predicts stress susceptibility independent of parental education in
      161991 adolescent Swedish male conscripts.

PMID- 15194719
TI  - Ethnicity, acculturation, and self reported health. A population based study
      among immigrants from Poland, Turkey, and Iran in Sweden.
AB  - STUDY OBJECTIVE: To analyse the association between ethnicity and poor self
      reported health and explore the importance of any mediators such as acculturation
      and discrimination. DESIGN: A simple random sample of immigrants from Poland (n =
      840), Turkey (n = 840), and Iran (n = 480) and of Swedish born persons (n = 2250)
      was used in a cross sectional study in 1996. The risk of poor self reported
      health was estimated by applying logistic models and stepwise inclusion of the
      explanatory variables. The response rate was about 68% for the immigrants and 80%
      for the Swedes. Explanatory variables were: age, ethnicity, educational status,
      marital status, poor economic resources, knowledge of Swedish, and
      discrimination. MAIN RESULTS: Among men from Iran and Turkey there was a
      threefold increased risk of poor self reported health than Swedes (reference)
      while the risk was five times higher for women. When socioeconomic status was
      included in the logistic model the risk decreased slightly. In an explanatory
      model, Iranian and Turkish women and men had a higher risk of poor health than
      Polish women and men (reference). The high risks of Turkish born men and women
      and Iranian born men for poor self reported health decreased to non-significance
      after the inclusion of SES and low knowledge of Swedish. The high risks of
      Iranian born women for poor self reported health decreased to non-significance
      after the inclusion of low SES, low knowledge of Swedish, and discrimination.
      CONCLUSIONS: The strong association between ethnicity and poor self reported
      health seems to be mediated by socioeconomic status, poor acculturation, and
      discrimination.

PMID- 15194720
TI  - Increasing ethnic differences in mortality in Estonia after the collapse of the
      Soviet Union.
AB  - STUDY OBJECTIVE: This study examined the change in ethnic differences in
      mortality in Estonia 1989-2000. DESIGN: Two unlinked cross sectional census based
      analyses were compared. Total and cause specific mortality was analysed for
      ethnic Estonians and Russians. The absolute differences in mortality were
      evaluated through life expectancy at birth and age standardised mortality rates.
      Relative differences were assessed by mortality rate ratios with 95% confidence
      intervals, calculated using Poisson regression. SETTING: Estonia before and after
      the fall of the Soviet Union. PARTICIPANTS: Individual cause specific death data
      for 1987-1990 (69549 deaths) and for 1999-2000 (33809 deaths) came from the
      national mortality database. Population denominators came from the population
      censuses of 1989 and 2000. MAIN RESULTS: In the period 1989-2000, ethnic
      differences in life expectancy increased from 0.4 years to 6.1 years among men
      and from 0.6 years to 3.5 years among women. In 2000, Russians had a higher
      mortality than Estonians in all age groups and for almost all selected causes of
      death. The largest differences were found for some alcohol related causes of
      death especially in 2000. CONCLUSIONS: Political and economic upheaval,
      increasing poverty, and alcohol consumption can be considered the main underlying
      causes of the widening ethnic mortality gap.

PMID- 15194721
TI  - Exploring the relation between class, gender, and self rated general health using
      the new socioeconomic classification. A study using data from the 2001 census.
AB  - OBJECTIVE: To examine the relation between class, gender, and self rated health
      in adults in Great Britain. DESIGN: Cross sectional study using data from the
      2001 national census. SETTING: Great Britain. PARTICIPANTS: Adults aged between
      25 and 64 in Great Britain, enumerated in the 2001 census (n = 30.3 million).
      MAIN OUTCOME MEASURES: Age standardised rates of self rated general health for
      men and women in different socioeconomic groupings as defined by the National
      Statistics classification (NS-SeC), rate ratios and the (modified) relative index
      of inequality. RESULTS: There was a pronounced gradient in rates of "not good"
      health among people in different social positions. The rate for people in class 7
      (routine occupations) was more than double that for people in class 1 (higher
      managerial and professional occupations): 95 per 1000 and 37 per 1000
      respectively. Health inequalities were larger for men than for women-the rate
      ratio of class 7 to class 1 was 2.7 for men and 2.2 for women. The nature and
      size of the gender differences varied by socioeconomic class, with the greatest
      gap among people in class 1 (higher managerial and professional occupations),
      where the rate for women was 25% higher than for men. CONCLUSIONS: The NS-SeC
      shows a pronounced gradient in self rated general health across the population of
      working age in Great Britain in 2001. It was found that the NS-SeC was a useful
      measure for women, although it may be better at classifying men. The size of the
      gender gap in "not good" health varied by NS-SeC class.

PMID- 15194722
TI  - Relative impact of childhood and adulthood socioeconomic conditions on cause
      specific mortality in men.

PMID- 15194723
TI  - Cumulative deprivation and cause specific mortality. A census based study of life
      course influences over three decades.
AB  - OBJECTIVE: To examine whether increasing cumulative deprivation has an
      incremental effect on total as well as cause specific mortality. DESIGN: Census
      data on housing conditions as indicators of deprivation from 1960, 1970, and 1980
      were linked to 1990-98 death registrations. Relative indices of inequalities were
      computed for housing conditions to measure the cumulative impact of differences
      in social conditions. PARTICIPANTS: 97 381 (71.1%) 30-49 year old and 70701
      (80.0%) 50-69 year old inhabitants of Oslo, Norway, in 1990 with census
      information on housing conditions and recorded length of education. MAIN RESULTS:
      Mortality risk was increased when all censuses' housing conditions were summed in
      both age groups and sex. The cause specific analysis indicated such an effect
      particularly for coronary heart disease, chronic obstructive lung disease, and
      smoking related cancers. Violent deaths were essentially associated with housing
      conditions closer to the time of death in men in both age groups and in young
      women. CONCLUSIONS: To fully account for socially mediated risk of death, a full
      life course approach should be adopted. The relative importance of each stage
      seems to vary by cause of death.

PMID- 15194724
TI  - Impact of smoking on the social gradient in health expectancy in Denmark.
AB  - STUDY OBJECTIVE: Health expectancy is arrived at by dividing life expectancy into
      average lifetime in different states of health. The purpose of the study was to
      estimate health expectancy among never smokers and smokers in groups at high,
      medium, and low educational levels in Denmark. DESIGN: Life tables for never
      smokers and smokers with a high, medium, and low educational level were
      constructed on the basis of Statistics Denmark registers and combined with data
      from the Danish Health Interview Survey 2000. Health expectancy was calculated by
      Sullivan's method. MAIN RESULTS: Life expectancy at age 30 differs on average by
      8.5 years between never smokers and heavy smokers. Expected lifetime in self
      rated good health was 39.4 years for a never smoking man corresponding to 82.0%
      of the rest of his life. For male lifelong heavy smokers these figures were
      reduced to 27.3 years and 69.2%. The proportion of expected lifetime in self
      rated good health was 89.5% and 71.3% among male never smokers and lifelong heavy
      smokers with a high educational level, respectively; and the proportion among
      male never smokers and heavy smokers with a low educational level was 73.4% and
      63.6%, respectively. Similar results were seen as regards expected lifetime
      without longstanding illness. For women the social gradient in health expectancy
      was intensified among smokers. CONCLUSIONS: Within each educational group smoking
      reduces expected lifetime in a healthy state. The social gradient in health
      expectancy cannot be explained by a reverse social gradient in smoking
      prevalence.

PMID- 15194725
TI  - Improving estimation of the variance of expectation of life for small
      populations.

PMID- 15194726
TI  - Measuring environmental factors can enhance the search for disease causing genes?
AB  - The value of the concurrent measurement of environmental factors in studies aimed
      at the discovery of disease causing genes has been questioned on the grounds that
      such an approach fails to increase study power. This report discusses the issue
      and shows with examples from the recent literature that the examination of a gene
      disease association within an environmental subgroup can provide enhanced
      opportunities for detecting gene effects. The concurrent collection of
      environmental as well as genetic factors in studies of disease aetiology may
      enhance study informativeness and validity in several ways, including an increase
      in the power of the study to detect gene disease associations.

PMID- 15194727
TI  - Do we need an age specific measure of consensual poverty for older adults?
      Evidence from the poverty and social exclusion survey.

PMID- 15194728
TI  - Self report in clinical and epidemiological studies with non-English speakers:
      the challenge of language and culture.
AB  - Internationally, there is a drive for equality in health care for ethnic groups.
      To achieve equality, produce sound policies, and provide appropriately targeted
      services good quality data are essential. Where data are based upon self report,
      especially from non-English speakers, there are major barriers to the
      accumulation of reliable and valid information. When data collection instruments
      designed for English speakers are simply translated into ethnic minority
      languages, measurement error can result from inadequate translation procedures,
      inappropriate content, insensitivity of items, and the failure of researchers to
      make themselves familiar with cultural norms and beliefs. More attention should
      be paid to conceptual and cultural factors especially in epidemiological and
      clinical studies where self report is used to gather data. More interdisciplinary
      collaboration is necessary as well as a modification of customary methods of data
      collection and the assumptions behind them. The essence of such modifications
      entails participatory research with members of the linguistic communities
      concerned.

PMID- 15194729
TI  - An alternative approach to quantifying and addressing inequity in healthcare
      provision: access to surgery for lung cancer in the east of England.
AB  - STUDY OBJECTIVE: Equitable access to healthcare services should be monitored
      routinely. This study compares provision of surgery for non-small cell lung
      cancer in the east of England with incidence of non-small cell lung cancer. In
      addition to conventional comparisons, process control charts are used to identify
      areas in which access seems to be significantly different from average. DESIGN:
      Ecological comparison of surgery rates for non-small cell lung cancer between
      1998 and 2000 and incidence of non-small cell lung cancer over the same time
      period. SETTING: Population of Norfolk, Suffolk, Cambridgeshire. PARTICIPANTS:
      The denominator was the resident population. Numerators were 4092 deaths from non
      small cell lung cancer and 387 surgical procedures for lung cancer. MAIN RESULTS:
      Incidence of non-small cell lung cancer by primary care trust (PCT) does not
      correlate with surgical procedure rate, in men r = 0.37 (95% confidence intervals
      -0.14 to 0.72), in women r = 0.07 (95% confidence intervals -0.43 to 0.53).
      Control charts indicate that the surgery rate is significantly different from
      average in three PCTs, high in one and low in two others. The optimum surgery
      rate is unclear but raising it from 9% to a theoretical level of 15% would mean
      no PCTs have above average rates while six PCTs have rates that are significantly
      low. CONCLUSIONS: There does not seem to be equity of access to surgery for
      patients with non-small cell lung cancer in the east of England. Control charts
      can help both to identify areas where access is particularly high or low, and
      also to monitor performance against a theoretical optimum surgery rate.

PMID- 15194730
TI  - Erroneous, blurred, and mistaken--comments on the care need index.

PMID- 15194732
TI  - So, why do they dance, after all?

PMID- 15194731
TI  - Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat
      rich diet in pregnancy.
AB  - We recently reported vascular dysfunction in adult offspring of rats fed a fat
      rich (animal lard) diet in pregnancy. This study reports further characterization
      of constrictor and dilator function in mesenteric and caudal femoral arteries
      from 180-day-old offspring of dams fed the high fat diet (OHF). Endothelium
      dependent relaxation in response to acetylcholine (10(-9)-10(-5)m) was impaired
      in mesenteric small arteries from male and female OHF compared with offspring of
      dams fed normal chow (males (maximum percentage relaxation): OHF 67.92 +/- 2.89,
      n= 8 versus control 92.08 +/- 2.19, n= 8, P < 0.01). Substantial relaxation in
      response to acetycholine in control mesenteric arteries remained after inhibition
      of nitric oxide synthase, soluble guanylate cyclase and cyclo-oxygenase but was
      blocked by 25 mm potassium. This component of relaxation, attributed to EDHF, was
      significantly reduced in OHF mesenteric arteries compared with controls. However,
      EDHF played a minor role in acetylcholine-induced relaxation in both control and
      OHF femoral caudal arteries (male and female). In these arteries, in contrast to
      mesenteric vessels, acetylcholine-induced relaxation was significantly enhanced
      in OHF but only in males (ACh (maximum percentage relaxation): OHF 58.40 +/-
      4.39, n= 8 versus male controls 32.18 +/- 6.36, P < 0.05). This was attributable
      to enhanced nitric oxide-mediated relaxation. In conclusion, reduced endothelium
      dependent relaxation in OHF mesenteric arteries is due to impaired EDHF-mediated
      relaxation. This defect was not apparent in femoral arteries in which EDHF has a
      less prominent role.

PMID- 15194733
TI  - Electrophysiological characterization of a recombinant human Na+-coupled
      nucleoside transporter (hCNT1) produced in Xenopus oocytes.
AB  - Human concentrative nucleoside transporter 1 (hCNT1) mediates active transport of
      nucleosides and anticancer and antiviral nucleoside drugs across cell membranes
      by coupling influx to the movement of Na(+) down its electrochemical gradient.
      The two-microelectrode voltage-clamp technique was used to measure steady-state
      and presteady-state currents of recombinant hCNT1 produced in Xenopus oocytes.
      Transport was electrogenic, phloridzin sensitive and specific for pyrimidine
      nucleosides and adenosine. Nucleoside analogues that induced inwardly directed
      Na(+) currents included the anticancer drugs 5-fluorouridine, 5-fluoro-2'
      deoxyuridine, cladribine and cytarabine, the antiviral drugs zidovudine and
      zalcitabine, and the novel thymidine mimics 1-(2-deoxy-beta-d-ribofuranosyl)-2,4
      difluoro-5-methylbenzene and 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5
      iodobenzene. Apparent K(m) values for 5-fluorouridine, 5-fluoro-2'-deoxyuridine
      and zidovudine were 18, 15 and 450 microm, respectively. hCNT1 was Na(+)
      specific, and the kinetics of steady-state uridine-evoked Na(+) currents were
      consistent with an ordered simultaneous transport model in which Na(+) binds
      first followed by uridine. Membrane potential influenced both ion binding and
      carrier translocation. The Na(+)-nucleoside coupling stoichiometry, determined
      directly by comparing the uridine-induced inward charge movement to
      [(14)C]uridine uptake was 1: 1. hCNT1 presteady-state currents were used to
      determine the fraction of the membrane field sensed by Na(+) (61%), the valency
      of the movable charge (-0.81) and the average number of transporters present in
      the oocyte plasma membrane (6.8 x 10(10) per cell). The hCNT1 turnover rate at 
      50 mV was 9.6 molecules of uridine transported per second.

PMID- 15194734
TI  - Long-term potentiation is impaired in rat hippocampal slices that produce
      spontaneous sharp waves.
AB  - Sharp waves (SPWs) occur in the hippocampal EEG during behaviours such as alert
      immobility and slow-wave sleep. Despite their widespread occurrence across brain
      regions and mammalian species, the functional importance of SPWs remains unknown.
      Experiments in the present study indicate that long-term potentiation (LTP) is
      significantly impaired in slices, prepared from the temporal aspect of rat
      hippocampus, that spontaneously generate SPW activity. This was probably not due
      to anatomical and/or biochemical abnormalities in temporal slices because stable
      LTP was uncovered in field CA1 when SPWs were eliminated by severing the
      projection from CA3. The same procedure did not alter LTP in slices lacking SPWs.
      Robust and stable LTP was obtained in the presence of SPWs in slices treated with
      an adenosine A1 receptor antagonist, a finding that links the present results to
      mechanisms related to the LTP reversal effect. In accord with this, single
      stimulation pulses delivered intermittently in a manner similar to the SPW
      pattern interfered with LTP to a similar degree as spontaneous SPWs. Taken
      together, these results suggest the possibility that SPWs in the hippocampus
      constitute a neural mechanism for forgetting.

PMID- 15194735
TI  - Drying and salting send different messages.

PMID- 15194736
TI  - Effect of extracellular acid-base disturbances on the intracellular pH of
      neurones cultured from rat medullary raphe or hippocampus.
AB  - Previous reports suggest that an important characteristic of chemosensitive
      neurones is an unusually large change of steady-state intracellular pH in
      response to a change in extracellular pH (DeltapH(i)/DeltapH(o)). To determine
      whether such a correlation exists between neurones from the medullary raphe (a
      chemosensitive brain region) and hippocampus (a non-chemosensitive region), we
      used BCECF to monitor pH(i) in cultured neurones subjected to extracellular acid
      base disturbances. In medullary raphe neurones, respiratory acidosis (5%--> 9%
      CO(2)) caused a rapid fall in pH(i) (DeltapH(i) approximately 0.2) with no
      recovery and a large DeltapH(i)/DeltapH(o) of 0.71. Hippocampal neurones had a
      similar response, but with a slightly lower DeltapH(i)/DeltapH(o) (0.59). We
      further investigated a possible link between pH(i) regulation and
      chemosensitivity by following the pH(i) measurements on medullary raphe neurones
      with an immunocytochemistry for tryptophan hydroxylase (a marker of serotonergic
      neurones). We found that the DeltapH(i)/DeltapH(o) of 0.69 for serotonergic
      neurones (which are stimulated by acidosis) was not different from either the
      DeltapH(i)/DeltapH(o) of 0.75 for non-serotonergic neurones (most of which are
      not chemosensitive), or from the DeltapH(i)/DeltapH(o) of hippocampal neurones.
      For both respiratory alkalosis (5%--> 3% CO(2)) and metabolic alkalosis (22 mm-->
      35 mm HCO(3)(-)), DeltapH(i)/DeltapH(o) was 0.42-0.53 for all groups of neurones
      studied. The only notable difference between medullary raphe and hippocampal
      neurones was in response to metabolic acidosis (22 mm--> 14 mm HCO(3)(-)), which
      caused a large pH(i) decrease in approximately 80% of medullary raphe neurones
      (DeltapH(i)/DeltapH(o)= 0.71), but relatively little pH(i) decrease in 70% of the
      hippocampal neurones (DeltapH(i)/DeltapH(o)= 0.09). Our comparison of medullary
      raphe and hippocampal neurones indicates that, except in response to metabolic
      acidosis, the neurones from the chemosensitive region do not have a uniquely high
      DeltapH(i)/DeltapH(o). Moreover, regardless of whether neurones were cultured
      from the chemosensitive or the non-chemosensitive region, pH(i) did not recover
      during any of the acid-base stresses.

PMID- 15194737
TI  - Electrotonic coupling between stratum oriens interneurones in the intact in vitro
      mouse juvenile hippocampus.
AB  - Using the isolated juvenile (7-14 days) mouse whole hippocampus preparation,
      which contains intact complex local circuitry, 145 dual whole cell recordings
      were made from stratum oriens (s.o.) interneurones under infrared microscopy. In
      11.7% of paired recordings, evidence for direct electrotonic coupling between the
      s.o. interneurones was obtained from the response of one interneurone to a long
      (400-600 ms) constant current pulse passed into the coupled interneurone. When
      specifically orienting the dual recordings in the transectional plane of the
      hippocampus, 18.5% of paired recordings showed electrotonic coupling. The
      coupling coefficient, estimated from averaged data, was 6.9 +/- 4.7%, ranging
      from 1.3 to 17.6%. The time constant of the electrotonically transmitted
      hyperpolarization was inversely related to the coupling coefficient between the
      two neurones. The electrotonic responses of one neurone to constant current
      pulses injected into the other coupled neurone were intermittent. Spikes in one
      of the coupled neurones were associated with small electrotonic EPSPs (spikelets)
      in the other coupled neurone, in those neuronal pairs with coupling coefficients
      greater than 10%. Failure of spikelet production following a spike in the coupled
      cell occurred 5-10% of the time. Electrotonic coupling and spikelets persisted in
      the presence of chemical synaptic transmission blockade by CNQX, APV and
      bicuculline, or in zero Ca(2+) perfusate, but were abolished by carbenoxolone
      (100 microm), a gap junctional blocker. These data confirm the existence of
      electrotonic coupling between s.o. interneurones, presumably via gap junctions
      located in dendrites.

PMID- 15194738
TI  - An analysis of inhibitory junction potentials in the guinea-pig proximal colon.
AB  - Intracellular recordings were made from either sheets or isolated bundles of the
      circular muscle layer of guinea-pig proximal colon and the responses evoked by
      stimulating inhibitory nerve fibres were analysed. Inhibitory junction potentials
      (IJPs), evoked by single stimuli, had two components which could be separated on
      their pharmacological and temporal characteristics and their voltage
      sensitivities. The initial component, which was abolished by apamin and reduced
      in amplitude by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS),
      had a brief time course: its amplitude was changed when the external
      concentration of potassium ions ([K+](o)) was changed. The second component of
      the IJP had a slower onset than the first component, was abolished by l
      nitroarginine (NOLA) and oxadiazolo quinoxalin-1-one (ODQ), an inhibitor of
      soluble guanylate cyclase: its amplitude was little affected by changing [K+](o)
      and was increased when the membrane potential of the circular layer was
      hyperpolarized. The observations suggest that the initial component of the IJP
      results from the release of ATP which triggers an increase in membrane
      conductance to K+ and that the second component results from the release of
      nitric oxide which suppresses a background inward current.

PMID- 15194739
TI  - Acute shifts in baroreflex control of renal sympathetic nerve activity induced by
      REM sleep and grooming in rats.
AB  - The present study aimed to determine the impact of REM sleep and grooming on the
      baroreflex stimulus-response curve for renal sympathetic nerve activity (RSNA).
      At least 3 days before study, Wistar female rats (n= 12) were chronically
      implanted with catheters to measure systemic arterial pressure (P(a)) and to
      intravenously infuse vasoactive drugs. In addition, electrodes were placed for
      measurements of RSNA, electroencephalogram, trapezius electromyogram and
      electrocardiogram. The baroreflex curve for RSNA was determined by changing P(a)
      using rapid intravenous infusions of phenylephrine and nitroprusside and then
      fitted to an inverse sigmoid function curve. REM sleep induced a vertical
      suppression of the P(a)-RSNA baroreflex curve, which was characterized by
      significant decreases in the maximum response (by 72.0%, P < 0.05) and the
      maximum gain (by 4.02% mmHg(-1), P < 0.05) compared with NREM sleep level.
      Grooming shifted the P(a)-RSNA baroreflex curve upward and to the right, which
      was associated with increases in the maximum response (by 45.2%, P < 0.05), the
      minimum response (by 20.7%, P < 0.05) and the pressure at the centering point (by
      11.1 mmHg, P < 0.05). These data suggest that the P(a)-RSNA baroreflex curve was
      shifted acutely and differently in a state-dependent manner during natural sleep
      and wake cycle in rats.

PMID- 15194740
TI  - Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult
      mouse ventricles.
AB  - Previous studies have documented the expression of four kinetically distinct
      voltage-gated K(+) (Kv) currents, I(to,f), I(to,s), I(K,slow) and I(ss), in mouse
      ventricular myocytes and demonstrated that I(to,f) and I(to,s) are differentially
      expressed in the left ventricular apex and the interventricular septum. The
      experiments here were undertaken to test the hypothesis that there are further
      regional differences in the expression of Kv currents or the Kv subunits (Kv4.2,
      Kv4.3, KChIP2, Kv1.5, Kv2.1) encoding these currents in adult male and female
      (C57BL6) mouse ventricles. Whole-cell voltage-clamp recordings revealed that mean
      (+/-s.e.m.) peak outward K(+) current and I(to,f) densities are significantly (P
      < 0.001) higher in cells isolated from the right (RV) than the left (LV)
      ventricles. Within the LV, peak outward K(+) current and I(to,f) densities are
      significantly (P < 0.05) higher in cells from the apex than the base. In
      addition, I(to,f) and I(K,slow) densities are lower in cells isolated from the
      endocardial (Endo) than the epicardial (Epi) surface of the LV wall. Importantly,
      similar to LV apex cells, I(to,s) is not detected in RV, LV base, LV Epi or LV
      Endo myocytes. No measurable differences in K(+) current densities or properties
      are evident in RV or LV cells from adult male and female mice, although I(to,f),
      I(to,s), I(K,slow) and I(ss) densities are significantly (P < 0.01) higher, and
      action potential durations at 50% (APD(50)) are significantly (P < 0.05) shorter
      in male septum cells. Western blot analysis revealed that the expression levels
      of Kv4.2, Kv4.3, KChIP2, Kv1.5 and Kv2.1 are similar in male and female
      ventricles. In addition, consistent with the similarities in repolarizing Kv
      current densities, no measurable differences in ECG parameters, including
      corrected QT (QT(c)) intervals, are detected in telemetric recordings from adult
      male and female (C57BL6) mice.

PMID- 15194741
TI  - Roles of phosphorylation of myosin binding protein-C and troponin I in mouse
      cardiac muscle twitch dynamics.
AB  - A normal heart increases its contractile force with increasing heart rate.
      Although calcium handling and myofibrillar proteins have been implicated in
      maintaining this positive force-frequency relationship (FFR), the exact
      mechanisms by which it occurs have not been addressed. In this study, we have
      developed an analytical method to define the calcium-force loop data, which
      characterizes the function of the contractile proteins in response to calcium
      that is independent of the calcium handling proteins. Results demonstrate that
      increasing the stimulation frequency causes increased force production per unit
      calcium concentration and decreased frequency-dependent calcium sensitivity
      during the relaxation phase. We hypothesize that phosphorylation of myosin
      binding protein-C (MyBP-C) and troponin I (TnI) acts coordinately to change the
      rates of force generation and relaxation, respectively. To test this hypothesis,
      we performed simultaneous calcium and force measurements on stimulated intact
      mouse papillary bundles before and after inhibition of MyBP-C and TnI
      phosphorylation using the calcium/calmodulin kinase II (CaMK2) inhibitor
      autocamtide-2 related inhibitory peptide, or the protein kinase A (PKA) inhibitor
      14-22 amide. CaMK2 inhibition reduced both MyBP-C and TnI phosphorylation and
      decreased active force without changing the magnitude of the [Ca(2+)](i)
      transient. This reduced the normalized change in force per change in calcium by
      19-39%. Data analyses demonstrated that CaMK2 inhibition changed the myofilament
      characteristics via a crossbridge feedback mechanism. These results strongly
      suggest that the phosphorylation of MyBP-C and TnI contributes significantly to
      the rates of force development and relaxation.

PMID- 15194742
TI  - On the fate of skeletal myoblasts in a cardiac environment: down-regulation of
      voltage-gated ion channels.
AB  - We have analysed the voltage-gated ion channels and fusion competence of skeletal
      muscle myoblasts labelled with green fluorescent protein (GFP) and the membrane
      dye PKH transplanted into the infarcted myocardium of syngenic rats. After cell
      transplantation the animals were killed and GFP(+)-PKH(+) myoblasts enzymatically
      isolated for subsequent studies of ionic currents through voltage-gated sodium,
      calcium and potassium channels. A down-regulation of all three types of ion
      channels after engraftment was observed. The fraction of cells with calcium (68%)
      and sodium channels (65%) declined to zero within 24 h and 1 week, respectively.
      Down-regulation of potassium currents (90% in control) occurred within 2 weeks to
      about 30%. Before injection myoblasts expressed predominantly transient outward
      potassium channels whereas after isolation from the myocardium exclusively rapid
      delayed rectifier channels. The currents recovered completely between 1 and 6
      weeks under cell culture conditions. The down-regulation of ion channels and
      changes in potassium current kinetics suggest that the environment provided by
      infarcted myocardium affects expression of voltage-gated ion channels of skeletal
      myoblasts.

PMID- 15194744
TI  - PAR2 activation alters colonic paracellular permeability in mice via IFN-gamma
      dependent and -independent pathways.
AB  - Activation of colonic proteinase-activated receptor-2 (PAR(2)) caused
      inflammation and increased mucosal permeability in mouse colon. The present study
      was aimed at characterizing the possible links between these two phenomena. We
      evaluated the effects of intracolonic infusion of PAR(2)-activating peptide,
      SLIGRL, on colonic paracellular permeability and inflammation at two different
      doses, 5 and 100 microg per mouse, in an attempt to discriminate between both
      PAR(2)-mediated effects. We further investigated the possible involvement of
      interferon gamma (IFN-gamma) and calmodulin-dependent activation of myosin light
      chain kinase (MLCK), and alterations of zonula occludens-1 (ZO-1) localization in
      PAR(2)-induced responses. Thus, at the lower dose, SLIGRL increased colonic
      permeability without causing inflammation. Western blotting showed
      phosphorylation of mucosal myosin light chain (MLC) expression after both doses
      of SLIGRL. Moreover, while the MLCK inhibitor, ML-7, abolished the permeability
      effects of the low dose of SLIGRL, it only partially inhibited that of the high
      dose. In IFN-gamma-deficient mice (B6 ifng(-/-)), the increases in permeability
      were similar for both doses of SLIGRL and prevented by ML-7. In addition, MLCK
      immunoprecipitation revealed an increase of calmodulin binding to MLCK in the
      mucosa of mice treated with either dose of SLIGRL. Finally, we have shown that
      direct activation of PAR(2) on enterocytes is responsible for increased
      permeability and ZO-1 disruption. Moreover, SLIGRL at a dose that does not
      produce inflammation increases permeability via calmodulin activation, which
      binds and activates MLCK. The resulting tight junction opening does not depend
      upon IFN-gamma secretion, while the increased permeability in response to the
      high dose of PAR(2) agonist involves IFN-gamma secretion.

PMID- 15194743
TI  - Interplay between SERCA and sarcolemmal Ca2+ efflux pathways controls spontaneous
      release of Ca2+ from the sarcoplasmic reticulum in rat ventricular myocytes.
AB  - Waves of calcium-induced calcium release occur in a variety of cell types and
      have been implicated in the origin of cardiac arrhythmias. We have investigated
      the effects of inhibiting the SR Ca(2+)-ATPase (SERCA) with the reversible
      inhibitor 2',5'-di(tert-butyl)-1,4-benzohydroquinone (TBQ) on the properties of
      these waves. Cardiac myocytes were voltage clamped at a constant potential
      between -65 and -40 mV and spontaneous waves evoked by increasing external Ca(2+)
      concentration to 4 mm. Application of 100 microm TBQ decreased the frequency of
      waves. This was associated with increases of resting [Ca(2+)](i), the time
      constant of decay of [Ca(2+)](i) and the integral of the accompanying Na(+)
      Ca(2+) exchange current. There was also a decrease in propagation velocity of the
      waves. There was an increase of the calculated Ca(2+) efflux per wave. The SR
      Ca(2+) content when a wave was about to propagate decreased to 91.7 +/- 3.2%. The
      period between waves increased in direct proportion to the Ca(2+) efflux per wave
      meaning that TBQ had no effect on the Ca(2+) efflux per unit time. We conclude
      that (i) decreased wave frequency is not a direct consequence of decreased Ca(2+)
      pumping by SERCA between waves but, rather, to more Ca(2+) loss on each wave;
      (ii) inhibiting SERCA increases the chance of spontaneous Ca(2+) release
      propagating at a given SR content.

PMID- 15194746
TI  - Metal binding by the D,DX35E motif of human immunodeficiency virus type 1
      integrase: selective rescue of Cys substitutions by Mn2+ in vitro.
AB  - The D,DX(35)E motif characteristic of retroviral integrase enzymes (INs) is
      expected to bind the required metal cofactors (Mg(2+) or Mn(2+)), but direct
      evidence for a catalytic role has been lacking. Here we used a metal rescue
      strategy to investigate metal binding. We established conditions for analysis of
      an activity of IN, disintegration, in both Mg(2+) and Mn(2+), and tested IN
      mutants with cysteine substitutions in each acidic residue of the D,DX(35)E
      motif. Mn(2+) but not Mg(2+) can bind tightly to Cys, so if metal binding at the
      acidic residues is mechanistically important, it is expected that the Cys
      substituted enzymes would be active in the presence of Mn(2+) only. Of the three
      acidic residues, a strong metal rescue effect was obtained for D116C, a weaker
      rescue was seen for D64C, and no rescue was seen with E152C. Modest rescue could
      also be detected for D116C in normal integration in vitro. Comparison to Ser and
      Ala substitutions at D116 established that the rescue was selective for Cys.
      Further studies of the response to pH suggest that the metal cofactor may
      stabilize the deprotonated nucleophile active in catalysis, and studies of the
      response to NaCl titrations disclose an additional role for the metal cofactor in
      stabilizing the IN-DNA complex.

PMID- 15194745
TI  - Pathways of cell infection by parvoviruses and adeno-associated viruses.

PMID- 15194747
TI  - A novel severe acute respiratory syndrome coronavirus protein, U274, is
      transported to the cell surface and undergoes endocytosis.
AB  - The severe acute respiratory syndrome coronavirus (SARS-CoV) genome contains open
      reading frames (ORFs) that encode for several genes that are homologous to
      proteins found in all known coronaviruses. These are the replicase gene 1a/1b and
      the four structural proteins, nucleocapsid (N), spike (S), membrane (M), and
      envelope (E), and these proteins are expected to be essential for the replication
      of the virus. In addition, this genome also contains nine other potential ORFs
      varying in length from 39 to 274 amino acids. The largest among these is the
      first ORF of the second longest subgenomic RNA, and this protein (termed U274 in
      the present study) consists of 274 amino acids and contains three putative
      transmembrane domains. Using antibody specific for the C terminus of U274, we
      show U274 to be expressed in SARS-CoV-infected Vero E6 cells and, in addition to
      the full-length protein, two other processed forms were also detected. By
      indirect immunofluorescence, U274 was localized to the perinuclear region, as
      well as to the plasma membrane, in both transfected and infected cells. Using an
      N terminus myc-tagged U274, the topology of U274 and its expression on the cell
      surface were confirmed. Deletion of a cytoplasmic domain of U274, which contains
      Yxxphi and diacidic motifs, abolished its transport to the cell surface. In
      addition, U274 expressed on the cell surface can internalize antibodies from the
      culture medium into the cells. Coimmunoprecipitation experiments also showed that
      U274 could interact specifically with the M, E, and S structural proteins, as
      well as with U122, another protein that is unique to SARS-CoV.

PMID- 15194748
TI  - Tax relieves transcriptional repression by promoting histone deacetylase 1
      release from the human T-cell leukemia virus type 1 long terminal repeat.
AB  - Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the
      viral transcriptional activator Tax. Tax activates viral transcription through
      interaction with the cellular transcription factor CREB and the coactivators
      CBP/p300. In this study, we have analyzed the role of histone deacetylase 1
      (HDAC1) on HTLV-1 gene expression from an integrated template. First we show that
      trichostatin A, an HDAC inhibitor, enhances Tax expression in HTLV-1-transformed
      cells. Second, using a cell line containing a single-copy HTLV-1 long terminal
      repeat, we demonstrate that overexpression of HDAC1 represses Tax
      transactivation. Furthermore, a chromatin immunoprecipitation assay allowed us to
      analyze the interaction of transcription factors, coactivators, and HDACs with
      the basal and activated HTLV-1 promoter. We demonstrate that HDAC1 is associated
      with the inactive, but not the Tax-transactivated, HTLV-1 promoter. In vitro and
      in vivo glutathione S-transferase-Tax pull-down and coimmunoprecipitation
      experiments demonstrated that there is a direct physical association between Tax
      and HDAC1. Importantly, biotinylated chromatin pull-down assays demonstrated that
      Tax inhibits and/or dissociates the binding of HDAC1 to the HTLV-1 promoter. Our
      results provide evidence that Tax interacts directly with HDAC1 and regulates
      binding of the repressor to the HTLV-1 promoter.

PMID- 15194750
TI  - Geminate structures of African cassava mosaic virus.
AB  - Two types of geminate structures were purified from African cassava mosaic
      geminivirus (ACMV)-infected Nicotiana benthamiana plants and analyzed by electron
      cryomicroscopy and image reconstruction. After cesium sulfate density gradient
      centrifugation, they were separated into lighter top (T) and heavier bottom (B)
      components. T particles comigrated with host proteins, whereas B particles were
      concentrated in a cesium density typical for complete virions. Both particles
      were composed of two incomplete icosahedra of 11 capsomers each, but T particles
      were slightly larger (diameter, 22.5 nm) and less dense in the interior than B
      particles (diameter, 21.5 nm). T particles were frequently associated with small
      globules of approximately 14 nm diameter of unknown origin. The overall structure
      of ACMV, a begomovirus transmitted by whiteflies, was similar to that of Maize
      streak virus (MSV), a mastrevirus transmitted by leafhoppers, although the
      vertices of the icosahedra were less pronounced. Models of ACMV coat proteins
      based on Satellite tobacco necrosis virus support the exposure of parts of the
      molecule essential for transmission specificity by whiteflies and provide
      possible structural explanations for the smaller protrusion of the ACMV capsid
      relative to MSV. The differences of ACMV and MSV virion shapes are discussed with
      reference to their different animal vectors.

PMID- 15194749
TI  - Functional interaction between class II histone deacetylases and ICP0 of herpes
      simplex virus type 1.
AB  - This study describes the physical and functional interactions between ICP0 of
      herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and
      7. Class II HDACs are mainly known for their participation in the control of cell
      differentiation through the regulation of the activity of the transcription
      factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and
      neuronal survival. Immunofluorescence experiments performed on transfected cells
      showed that ICP0 colocalizes with and reorganizes the nuclear distribution of
      ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at
      least one of its binding partners, the corepressor protein SMRT (for silencing
      mediator of retinoid and thyroid receptor), undergo changes in their nuclear
      distribution in ICP0-transfected cells. As a result, during infection endogenous
      HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase
      pull-down assays confirmed that class II but not class I HDACs specifically
      interacted with ICP0 through their amino-terminal regions. This region, which is
      not conserved in class I HDACs but homologous to the MITR (MEF2-interacting
      transcription repressor) protein, is responsible for the repression, in a
      deacetylase-independent manner, of MEF2 by sequestering it under an inactive form
      in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5
      amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This
      is the first report of a viral protein interacting with and controlling the
      repressor activity of class II HDACs. We discuss the putative consequences of
      such an interaction for the biology of the virus both during lytic infection and
      reactivation from latency.

PMID- 15194751
TI  - Identification of the human rhinovirus serotype 1A binding site on the murine low
      density lipoprotein receptor by using human-mouse receptor chimeras.
AB  - Human rhinovirus serotype 1A (HRV1A) binds more strongly to the mouse low-density
      lipoprotein receptor (LDLR) than to the human homologue (M. Reithmayer, A.
      Reischl, L. Snyers, and D. Blaas, J. Virol. 76:6957-6965, 2002). Here, we used
      this fact to determine the binding site of HRV1A by replacing selected ligand
      binding modules of the human receptor with the corresponding ligand binding
      modules of the mouse receptor. The chimeric proteins were expressed in mouse
      fibroblasts deficient in endogenous LDLR and LDLR-related protein, both used by
      minor group HRVs for cell entry. Binding was assessed by virus overlay blots, by
      immunofluorescence microscopy, and by measuring cell attachment of radiolabeled
      virus. Replacement of ligand binding repeat 5 of the human LDLR with the
      corresponding mouse sequence resulted in a substantial increase in HRV1A binding,
      whereas substitution of repeats 3 and 4 was without effect. Replacement of human
      receptor repeats 1 and 2 with the murine homologues also increased virus binding.
      Finally, murine receptor modules 1, 2, and 5 simultaneously introduced into the
      human receptor resulted in HRV1A binding indistinguishable from mouse wild-type
      receptor. Thus, repeats 1 and/or 2 and repeat 5 are involved in HRV1A attachment.
      Changing CDGGPD in the acidic cluster of module 5 in the human receptor to CDGEAD
      present in the mouse receptor led to substantially increased binding of HRV1A,
      indicating an important role of the glutamate residue in HRV1A recognition.

PMID- 15194752
TI  - Modulation of Env content in virions of simian immunodeficiency virus:
      correlation with cell surface expression and virion infectivity.
AB  - Specific mutations were created in the cytoplasmic domain of the gp41
      transmembrane protein of simian immunodeficiency virus strain 239 (SIV239). The
      resultant strains included a mutant in which Env residue 767 was changed to a
      stop codon, a double mutant in which positions 738 and 739 were changed to stop
      codons, another mutant in which a prominent endocytosis motif was changed from
      YRPV to GRPV by the substitution of tyrosine 721, and a final combination mutant
      bearing Q738stop, Q739stop, and Y721G mutations. The effects of these mutations
      on cell surface expression, on Env incorporation into virions, and on viral
      infectivity were examined. The molar ratio of Gag to gp120 of 54:1 that we report
      here for SIV239 virions agrees very well with the ratio of 60:1 reported
      previously by Chertova et al. (E. Chertova, J. W. Bess, Jr., B. J. Crise, R. C.
      Sowder II, T. M. Schaden, J. M. Hilburn, J. A. Hoxie, R. E. Benveniste, J. D.
      Lifson, L. E. Henderson, and L. O. Arthur, J. Virol. 76:5315-5325, 2002),
      although they were determined by very different methodologies. Assuming 1,200 to
      2,500 Gag molecules per virion, this corresponds to 7 to 16 Env trimers per
      SIV239 virion particle. Although all of the mutations increased Env levels in
      virions, E767stop had the most dramatic effect, increasing the Env content per
      virion 25- to 50-fold. Increased levels of Env content in virions correlated
      strictly with higher levels of Env expression on the cell surface. The increased
      Env content with the E767stop mutation also correlated with an increased
      infectivity, but the degree of change was not proportional: the 25- to 50-fold
      increase in Env content only increased infectivity 2- to 3-fold. All of the
      mutants replicated efficiently in the CEMx174 and Rh221-89 cell lines. Although
      some of these findings have been reported previously, our findings show that the
      effects of the cytoplasmic domain of gp41 on the Env content in virions can be
      dramatic, that the Env content in virions correlates strictly with the levels of
      cell surface expression, and that the Env content in virions can determine
      infectivity; furthermore, our results define a particular change with the most
      dramatic effects.

PMID- 15194753
TI  - P74 mediates specific binding of Autographa californica M nucleopolyhedrovirus
      occlusion-derived virus to primary cellular targets in the midgut epithelia of
      Heliothis virescens Larvae.
AB  - P74, an envelope protein of the occlusion-derived virus (ODV) of Autographa
      californica M nucleopolyhedrovirus (AcMNPV), is critical for oral infection of
      Trichoplusia ni larvae. The role of P74 during primary infection, however, is
      unknown. Here we provide evidence that P74 facilitates binding of AcMNPV ODV to a
      specific receptor within the larval midgut epithelia of another host species,
      Heliothis virescens. We adapted a fluorescence dequenching assay to compare
      binding, fusion, and competition of wild-type AcMNPV ODV in vivo with itself and
      with the ODV of a p74-deficient AcMNPV mutant. We found that relative to wild
      type ODV, binding and fusion of ODV deficient in P74 were both qualitatively and
      quantitatively different. Unlike wild-type ODV, an excess of P74-deficient ODV
      failed to compete effectively with wild-type ODV binding, and the overall binding
      level of the mutant ODV was one-third that of the wild type. These results
      implicated P74 as an ODV attachment protein that binds to a specific receptor on
      primary target cells within the midgut.

PMID- 15194754
TI  - Prion infection of skeletal muscle cells and papillae in the tongue.
AB  - The presence of the prion agent in skeletal muscle is thought to be due to the
      infection of nerve fibers located within the muscle. We report here that the
      pathological isoform of the prion protein, PrP(Sc), accumulates within skeletal
      muscle cells, in addition to axons, in the tongue of hamsters following
      intralingual and intracerebral inoculation of the HY strain of the transmissible
      mink encephalopathy agent. Localization of PrP(Sc) to the neuromuscular junction
      suggests that this synapse is a site for prion agent spread between motor axon
      terminals and muscle cells. Following intracerebral inoculation, the majority of
      PrP(Sc) in the tongue was found in the lamina propria, where it was associated
      with sensory nerve fibers in the core of the lingual papillae. PrP(Sc) staining
      was also identified in the stratified squamous epithelium of the lingual mucosa.
      These findings indicate that prion infection of skeletal muscle cells and the
      epithelial layer in the tongue can be established following the spread of the
      prion agent from nerve terminals and/or axons that innervate the tongue. Our data
      suggest that ingestion of meat products containing prion-infected tongue could
      result in human exposure to the prion agent, while sloughing of prion-infected
      epithelial cells at the mucosal surface of the tongue could be a mechanism for
      prion agent shedding and subsequent prion transmission in animals.

PMID- 15194756
TI  - Transduction profiles of recombinant adeno-associated virus vectors derived from
      serotypes 2 and 5 in the nigrostriatal system of rats.
AB  - We compared the transduction efficiencies and tropisms of titer-matched
      recombinant adeno-associated viruses (rAAV) derived from serotypes 2 and 5 (rAAV
      2 and rAAV-5, respectively) within the rat nigrostriatal system. The two
      serotypes (expressing enhanced green fluorescent protein [EGFP]) were delivered
      by stereotaxic surgery into the same animals but different hemispheres of the
      striatum (STR), the substantia nigra (SN), or the medial forebrain bundle (MFB).
      While both serotypes transduced neurons effectively within the STR, rAAV-5
      resulted in a much larger EGFP-expressing area than did rAAV-2. However, neurons
      transduced with rAAV-2 vectors expressed higher levels of EGFP. Consistent with
      this result, EGFP-positive projections emanating from transduced striatal neurons
      covered a larger area of the SN pars reticulata (SNr) after striatal delivery of
      rAAV-5, but EGFP levels in fibers of the SNr were higher after striatal injection
      of rAAV-2. We also compared the potentials of the two vectors for retrograde
      transduction and found that striatal delivery of rAAV-5 resulted in significantly
      more transduced dopaminergic cell bodies within the SN pars compacta and ventral
      tegmental area. Similarly, EGFP-transduced striatal neurons were detected only
      after nigral delivery of rAAV-5. Furthermore, we demonstrate that after striatal
      AAV-5 vector delivery, the transduction profiles were stable for as long as 9
      months. Finally, although we did not target the hippocampus directly, efficient
      and widespread transduction of hippocampal neurons was observed after delivery of
      rAAV-5, but not rAAV-2, into the MFB.

PMID- 15194755
TI  - Complete DNA sequence analyses of the first two varicella-zoster virus
      glycoprotein E (D150N) mutant viruses found in North America: evolution of
      genotypes with an accelerated cell spread phenotype.
AB  - Varicella-zoster virus (VZV) is considered to be one of the most genetically
      stable of all the herpesviruses. Yet two VZV strains with a D150N missense
      mutation within the gE glycoprotein were isolated in North America in 1998 and
      2002. The mutant strains have an accelerated cell spread phenotype, which
      distinguishes them from all wild-type and laboratory viruses. Since the VZV
      genome contains 70 additional open reading frames (ORFs), the possibility existed
      that the phenotypic change was actually due to an as-yet-undiscovered mutation or
      deletion elsewhere in the genome. To exclude this hypothesis, the entire genomes
      of the two mutant viruses were sequenced and found to contain 124,883 (VZV-MSP)
      and 125,459 (VZV-BC) nucleotides. Coding single-nucleotide polymorphisms (SNPs)
      were identified in 14 ORFs. One missense mutation was discovered in gH, but none
      was found in gB, gI, gL, or gK. There were no coding SNPs in the major regulatory
      protein ORF 62. One polymorphism was discovered which could never have been
      anticipated based on current knowledge of herpesvirus genomics, namely, the
      origins of replication differed from those in the prototype strain but not in a
      manner expected to affect cell spread. When the two complete mutant VZV sequences
      were surveyed in their entirety, the most reasonable conclusion was that the
      increased cell spread phenotype was dependent substantially or solely on the
      single D150N polymorphism in glycoprotein gE. The genomic results also expanded
      the evolutionary database by identifying which VZV ORFs were more likely to
      mutate over time.

PMID- 15194757
TI  - RBP-J (CSL) is essential for activation of the K14/vGPCR promoter of Kaposi's
      sarcoma-associated herpesvirus by the lytic switch protein RTA.
AB  - The Kaposi's sarcoma-associated herpesvirus (KSHV) gene product virally encoded G
      protein-coupled receptor (vGPCR) is a homolog of cellular GPCRs and has been
      proposed to play important roles in KSHV-induced angiogenesis. The most abundant
      vGPCR-containing transcripts are K14/vGPCR bicistronic RNAs that are strongly
      induced during lytic reactivation. Here we show that the promoter governing this
      transcript is strongly responsive to activation by the viral lytic switch protein
      RTA. By deletion mapping and scanning mutation analyses, we have identified three
      putative RTA response elements (A, B, and C) in this promoter. However, none of
      these sites appear to directly bind RTA in electrophoretic mobility shift assays
      (EMSA). Site C corresponds to a canonical binding site for RBP-J, a sequence
      specific transcriptional repressor that is normally the target of Notch
      signaling. RBP-J can bind RTA and recruit it to its cognate recognition site;
      when this happens, the activation function of RTA can relieve RBP-J-mediated
      repression and upregulate expression of the targeted gene. EMSA studies reveal
      that both sites A and C can bind to RBP-J; sequence inspection reveals that site
      A is a novel functional variant of known RBP-J recognition sites. (Site B
      corresponds to an as-yet-unknown host DNA-binding protein.) The importance of
      sites A and C in vivo is underscored by the observation that K14/vGPCR promoter
      function is dramatically inhibited in cells genetically deficient in RBP-J. The
      regulation of K14/vGPCR transcripts by RBP-J raises the possibility that other
      modulators of Notch signaling might be able to induce expression of this RNA
      outside the context of lytic KSHV replication.

PMID- 15194758
TI  - An optimized CD4 T-cell response can control productive and latent
      gammaherpesvirus infection.
AB  - CD4 T cells are important for control of infection with murine gammaherpesvirus
      68 (gamma HV68), but it is not known whether CD4 T cells function via provision
      of help to other lymphocyte subsets, such as B cells and CD8 T cells, or have an
      independent antiviral function. Moreover, under conditions of natural infection,
      the CD4 T-cell response is not sufficient to eliminate infection. To determine
      the functional capacities of CD4 T cells under optimal or near-optimal conditions
      and to determine whether CD4 T cells can control gamma HV68 infection in the
      absence of CD8 T cells or B cells, we studied the effect of ovalbumin (OVA)
      specific CD4 T cells on infection with a recombinant gamma HV68 that expresses
      OVA. OVA-specific CD4 T cells limited acute gamma HV68 replication and prolonged
      the life of infected T-cell receptor-transgenic RAG (DO.11.10/RAG) mice,
      demonstrating CD4 T-cell antiviral activity, independent of CD8 T cells and B
      cells. Despite CD4 T-cell-mediated control of acute infection, latent infection
      was established in DO.11.10/RAG mice. However, OVA-specific CD4 T cells reduced
      the frequency of latently infected cells both early (16 days postinfection) and
      late (42 days postinfection) after infection of mice containing CD8 T cells and B
      cells (DO.11.10 mice). These results show that OVA-specific CD4 T cells have B
      cell and CD8 T-cell-independent antiviral functions in the control of acute
      infection and can, in the absence of preexisting CD8 T-cell or B-cell immunity,
      inhibit the establishment of gammaherpesvirus latency.

PMID- 15194759
TI  - Critical role of CD4 T cells in an antibody-independent mechanism of vaccination
      against gammaherpesvirus latency.
AB  - We have previously demonstrated that it is possible to effectively vaccinate
      against long-term murine gammaherpesvirus 68 (gamma HV68) latency by using a
      reactivation-deficient virus as a vaccine (S. A. Tibbetts, J. S. McClellan, S.
      Gangappa, S. H. Speck, and H. W. Virgin IV, J. Virol. 77:2522-2529, 2003). Immune
      antibody was capable of recapitulating aspects of this vaccination. This led us
      to determine whether antibody is required for vaccination against latency. Using
      mice lacking antigen-specific antibody responses, we demonstrate here that
      antibody and B cells are not required for vaccination against latency. We also
      show that surveillance of latent infection in normal animals depends on CD4 and
      CD8 T cells, suggesting that T cells might be capable of preventing the
      establishment of latency. In the absence of an antibody response, CD4 T cells but
      not CD8 T cells are required for effective vaccination against latency in
      peritoneal cells, while either CD4 or CD8 T cells can prevent the establishment
      of splenic latency. Therefore, CD4 T cells play a critical role in immune
      surveillance of gammaherpesvirus latency and can mediate vaccination against
      latency in the absence of antibody responses.

PMID- 15194760
TI  - Human immunodeficiency virus type 1 Tat increases the expression of cleavage and
      polyadenylation specificity factor 73-kilodalton subunit modulating cellular and
      viral expression.
AB  - The human immunodeficiency virus type 1 (HIV-1) Tat protein, which is essential
      for HIV gene expression and viral replication, is known to mediate pleiotropic
      effects on various cell functions. For instance, Tat protein is able to regulate
      the rate of transcription of host cellular genes and to interact with the
      signaling machinery, leading to cellular dysfunction. To study the effect that
      HIV-1 Tat exerts on the host cell, we identified several genes that were up- or
      down-regulated in tat-expressing cell lines by using the differential display
      method. HIV-1 Tat specifically increases the expression of the cleavage and
      polyadenylation specificity factor (CPSF) 73-kDa subunit (CPSF3) without
      affecting the expression of the 160- and 100-kDa subunits of the CPSF complex.
      This complex comprises four subunits and has a key function in the 3'-end
      processing of pre-mRNAs by a coordinated interaction with other factors. CPSF3
      overexpression experiments and knockdown of the endogenous CPSF3 by mRNA
      interference have shown that this subunit of the complex is an important
      regulatory protein for both viral and cellular gene expression. In addition to
      the known CPSF3 function in RNA polyadenylation, we also present evidence that
      this protein exerts transcriptional activities by repressing the mdm2 gene
      promoter. Thus, HIV-1-Tat up-regulation of CPSF3 could represent a novel
      mechanism by which this virus increases mRNA processing, causing an increase in
      both cell and viral gene expression.

PMID- 15194761
TI  - Vaccinia virus G1 protein, a predicted metalloprotease, is essential for
      morphogenesis of infectious virions but not for cleavage of major core proteins.
AB  - Genes encoding orthologs of the vaccinia virus G1 protein are present in all
      poxviruses for which sequence information is available, yet neither the role of
      the protein nor its requirement for virus replication is known. G1 was predicted
      to be involved in the cleavage of core proteins, based on a transfection study
      and the presence of an HXXEH motif found in a subset of metallopeptidases. In the
      present study, we engineered a recombinant vaccinia virus containing a single
      copy of the G1L gene with a C-terminal epitope tag that is stringently regulated
      by the Escherichia coli lac repressor. In the absence of inducer, expression of
      G1 was repressed and virus replication was inhibited. Rescue of infectious virus
      was achieved by expression of wild-type G1 in trans, but not when the putative
      protease active site residues histidine-41, glutamate-44, or histidine-45 were
      mutated. Nevertheless, the synthesis and proteolytic processing of major core and
      membrane proteins appeared unaffected under nonpermissive conditions,
      distinguishing the phenotype of the G1L mutant from one in which the gene
      encoding the I7 protease was repressed. Noninfectious virus particles, assembled
      in the absence of inducer, did not attain the oval shape or characteristic core
      structure of mature virions. The polypeptide composition of these particles,
      however, closely resembled that of wild-type virus. Full-length and shorter forms
      of the G1 protein were found in the core fraction of virus particles assembled in
      the presence of inducer, suggesting that G1 is processed by self-cleavage or by
      another protease.

PMID- 15194764
TI  - The human immunodeficiency virus type 1 promoter contains a CATA box instead of a
      TATA box for optimal transcription and replication.
AB  - The human immunodeficiency virus type 1 (HIV-1) transcriptional promoter contains
      a single polymorphism in the TATA box. Most subtypes contain the sequence
      TATAAGC, but subtype E and some recombinant AG strains have the sequence TAAAAGC.
      Based on mutagenesis studies of cellular RNA polymerase II (pol II) promoters, it
      has been proposed that the subtype E TATA box is nonfunctional due to the T-to-A
      substitution at the critical position 3. By means of transcription and virus
      replication assays, we demonstrate that the true TATA box motif within the viral
      long terminal repeat (LTR) promoter starts two nucleotides further upstream.
      Because of this realignment, subtype E has the sequence CATAAAA and all other
      subtypes have the sequence CATATAA. The polymorphism therefore has shifted from
      position 3 to position 5 and is no longer incompatible with efficient
      transcription according to rules determined for cellular pol II promoters. In
      addition, through sensitive competition experiments, we demonstrate that the CATA
      box of subtypes B and E can be improved for replication by the mutations 1T and
      5T, respectively. The fact that the fitness of both subtype LTRs can be increased
      by specific point mutations in the CATA box suggests that the transcriptional
      promoter of HIV-1 is fine-tuned towards a suboptimal level of replication.
      However, this replication rate may be optimal in the in vivo context of an
      infected individual.

PMID- 15194763
TI  - Characterization of infectious retroviral pseudotype particles bearing hepatitis
      C virus glycoproteins.
AB  - The recent development of infectious retroviral pseudotypes bearing hepatitis C
      virus (HCV) glycoproteins represents an opportunity to study the functionally
      active form of the HCV E1 and E2 glycoproteins. In the culture supernatant of
      cells producing HCV retroviral pseudotypes, the majority of E2 was not associated
      with infectious particles and failed to sediment on sucrose gradients. The E2
      that was incorporated into infectious particles appeared as a triplet of diffuse
      bands at 60, 70, and 90 kDa. Similarly, three major forms of E1 were incorporated
      into the pseudotype particles, migrating at 33, 31, and 25 kDa. Endoglycosidase H
      (endo-H) treatment of particles demonstrated that the incorporated E1 was
      partially or completely sensitive to digestion. In contrast, the majority of the
      incorporated E2 was endo-H resistant. Purified pseudotype particles were found to
      contain both disulfide-linked aggregates and nonaggregated E1 and E2. HCV
      pseudotypes generated from cells expressing E1E2p7 showed similar heterogeneity
      in the incorporated glycoproteins and were of comparable infectivity to those
      generated by expression of E1E2. Our results demonstrate the heterogeneous nature
      of E1 and E2 incorporated into retroviral pseudotypes and highlight the
      difficulty in identifying forms of the HCV glycoproteins that initiate infection.

PMID- 15194765
TI  - Murine cytomegalovirus with a transposon insertional mutation at open reading
      frame m155 is deficient in growth and virulence in mice.
AB  - A pool of murine cytomegalovirus (MCMV) mutants was previously generated by using
      a Tn3-based transposon mutagenesis approach (X. Zhan, M. Lee, J. Xiao, and F.
      Liu, J. Virol. 74:7411-7421, 2000). In this study, one of the MCMV mutants,
      Rvm155, which contained the transposon insertion in open reading frame m155, was
      characterized in vitro for its replication in tissue culture and in vivo for its
      growth and virulence in immunodeficient SCID mice. Compared to the wild-type
      strain and a rescued virus that restored the m155 region, the mutant is
      significantly deficient in growth in many organs of the infected animals. At 21
      days postinfection the titers of Rvm155 in the salivary glands, lungs, spleens,
      livers, and kidneys of the intraperitoneally infected SCID mice were lower than
      the titers of the wild-type virus and the rescued virus by 50-, 1,000-, 500-, 100
      , and 500-fold, respectively. Moreover, the viral mutant was attenuated in
      killing the SCID mice, as none of the SCID mice that were intraperitoneally
      infected with Rvm155 died until 38 days postinfection while all the animals
      infected with the wild-type and rescued viruses died at 27 days postinfection.
      Our results provide the first direct evidence that a disruption of m155
      expression leads to attenuation of viral virulence and growth in animals.
      Moreover, these results suggest that m155 is a viral determinant for optimal MCMV
      growth and virulence in vivo.

PMID- 15194762
TI  - Nef proteins from simian immunodeficiency virus-infected chimpanzees interact
      with p21-activated kinase 2 and modulate cell surface expression of various human
      receptors.
AB  - The accessory Nef protein allows human immunodeficiency virus type 1 (HIV-1) to
      persist at high levels and to cause AIDS in infected humans. The function of HIV
      1 group M subtype B nef alleles has been extensively studied, and a variety of in
      vitro activities believed to be important for viral pathogenesis have been
      established. However, the function of nef alleles derived from naturally simian
      immunodeficiency virus (SIV)-infected chimpanzees, the original host of HIV-1, or
      from the HIV-1 N and O groups resulting from independent zoonotic transmissions
      remains to be investigated. In the present study we demonstrate that SIVcpz and
      HIV-1 group N or O nef alleles down-modulate CD4, CD28, and class I or II MHC
      molecules and up-regulate surface expression of the invariant chain (Ii)
      associated with immature major histocompatibility complex (MHC) class II.
      Furthermore, the ability of Nef to interact with the p21-activated kinase 2 was
      generally conserved. The functional activity of HIV-1 group N and O nef genes did
      not differ significantly from group M nef alleles. However, SIVcpz nef genes as a
      group showed a 1.8- and 2.0-fold-higher activity in modulating CD28 (P = 0.0002)
      and Ii (P = 0.016) surface expression, respectively, but were 1.7-fold less
      active in down-regulating MHC class II molecules (P = 0.006) compared to HIV-1 M
      nef genes. Our finding that primary SIVcpz nef alleles derived from naturally
      infected chimpanzees modulate the surface expression of various human cellular
      receptors involved in T-cell activation and antigen presentation suggests that
      functional nef genes helped the chimpanzee virus to persist efficiently in
      infected humans immediately after zoonotic transmission.

PMID- 15194766
TI  - RNA interference targeting VP1 inhibits foot-and-mouth disease virus replication
      in BHK-21 cells and suckling mice.
AB  - RNA interference (RNAi) is a powerful tool to silence gene expression
      posttranscriptionally. In this study, we evaluated the antiviral potential of
      small interfering RNA (siRNA) targeting VP1 of foot-and-mouth disease virus
      (FMDV), which is essential during the life cycle of the virus and plays a key
      role in virus attachment to susceptible cells. We investigated in vivo the
      inhibitory effect of VP1-specific siRNAs on FMDV replication in BHK-21 cells and
      suckling mice, a commonly used small animal model. The results showed that
      transfection of siRNA-expressing plasmids gave an 80 to 90% reduction in the
      expression of FMDV VP1 in BHK-21 cells. Moreover, BHK-21 cells transiently
      transfected with siRNA-expressing plasmids were specifically resistant to FMDV
      infection when exposed to 100 50% tissue culture infective doses of virus, and
      the antiviral effects extended to almost 48 h postinfection. Furthermore,
      subcutaneous injection of siRNA-expressing plasmids in the neck made suckling
      mice significantly less susceptible to FMDV. In conclusion, our data suggests
      that RNAi may provide a viable therapeutic approach to treat FMDV infection.

PMID- 15194767
TI  - Regulation of hepatitis B virus core promoter by transcription factors HNF1 and
      HNF4 and the viral X protein.
AB  - Hepatitis B virus (HBV) core promoter contains a binding site for nuclear
      receptors. A natural double mutation in this binding site, which changes
      nucleotide (nt) 1765 from A to T and nt 1767 from G to A, selectively abolishes
      the binding of several nuclear receptors without affecting that of HNF4. This
      double mutation also creates a binding site for the transcription factor HNF1 and
      changes two amino acids in the overlapping X protein sequence. In this study, we
      have examined the roles of HNF1, HNF4, and the X protein in the regulation of the
      core promoter activities in Huh7 hepatoma cells. Our results indicate that HNF4
      could stimulate the expression of the precore RNA and the core RNA from the core
      promoter of both the wild-type (WT) HBV and the double mutant, although its
      effect on the former was more prominent. In contrast, HNF1, which did not affect
      the WT core promoter, suppressed the precore RNA expression of the double mutant.
      Further analysis using HBV genomic constructs, with and without the ability to
      express the X protein, indicates that the X protein did not affect the HNF4
      activity on the core promoter and affected the HNF1 activity on the core promoter
      of only the double mutant. Thus, our results indicate that the phenotypic
      differences of HBV WT and double-mutant core promoters are at least partially due
      to the differential activities of HNF1, HNF4, and the X protein on these two
      promoters.

PMID- 15194768
TI  - Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified
      from brain and lymph node tissues of AIDS patients with neuropathology reveals
      two distinct tropism phenotypes and identifies envelopes in the brain that confer
      an enhanced tropism and fusigenicity for macrophages.
AB  - Complete envelope genes were amplified from autopsy brain tissue of five
      individuals who had died of AIDS and had neurological complications. Lymph node
      samples were included for two of the patients. Nineteen different envelope clones
      from the five patients had distinct V1V2 sequences. Thirteen of the envelopes
      were functional and conferred fusigenicity and infectivity for CD4(+) CCR5(+)
      cells. Infectivity and cell-cell fusion assays showed that most envelopes used
      both CCR5 and CCR3. One brain-derived envelope used a broad range of coreceptors,
      while three other brain envelopes from one individual were restricted to CCR5.
      However, there was no correlation between tissue of origin and coreceptor use.
      Envelopes showed two very distinct phenotypes depending on their capacity to
      infect macrophages and to exploit low levels of CD4 and/or CCR5 for infection.
      Envelopes that were highly fusigenic and tropic for macrophages were identified
      in brain tissue from four of the five patients. The enhanced macrophage tropism
      correlated with reduced sensitivity to inhibition by Q4120, a CD4-specific
      antibody, but not with sensitivity to the CCR5 inhibitor, TAK779. The highly
      macrophage-tropic envelopes were able to infect cells expressing low levels of
      CD4 and/or CCR5. Comparison with several well-characterized macrophage-tropic
      envelopes showed that the four identified patient envelopes were at the top limit
      of macrophage tropism. In contrast, all four lymph node-derived envelopes
      exhibited a non-macrophage-tropic phenotype and required high levels of CD4 for
      infection. Our data support the presence of envelopes that are highly fusigenic
      and tropic for macrophages in the brains of patients with neurological
      complications. These envelopes are able to infect cells that express low levels
      of CD4 and/or CCR5 and may have adapted for replication in brain macrophages and
      microglia, which are known to express limited amounts of CD4.

PMID- 15194769
TI  - The two major human metapneumovirus genetic lineages are highly related
      antigenically, and the fusion (F) protein is a major contributor to this
      antigenic relatedness.
AB  - The growth properties and antigenic relatedness of the CAN98-75 (CAN75) and the
      CAN97-83 (CAN83) human metapneumovirus (HMPV) strains, which represent the two
      distinct HMPV genetic lineages and exhibit 5 and 63% amino acid divergence in the
      fusion (F) and attachment (G) proteins, respectively, were investigated in vitro
      and in rodents and nonhuman primates. Both strains replicated to high titers (>
      or =6.0 log(10)) in the upper respiratory tract of hamsters and to moderate
      titers (> or =3.6 log(10)) in the lower respiratory tract. The two lineages
      exhibited 48% antigenic relatedness based on reciprocal cross-neutralization
      assay with postinfection hamster sera, and infection with each strain provided a
      high level of resistance to reinfection with the homologous or heterologous
      strain. Hamsters immunized with a recombinant human parainfluenza virus type 1
      expressing the fusion F protein of the CAN83 strain developed a serum antibody
      response that efficiently neutralized virus from both lineages and were protected
      from challenge with either HMPV strain. This result indicates that the HMPV F
      protein is a major antigenic determinant that mediates extensive cross-lineage
      neutralization and protection. Both HMPV strains replicated to low titers in the
      upper and lower respiratory tracts of rhesus macaques but induced high levels of
      HMPV-neutralizing antibodies in serum effective against both lineages. The level
      of HMPV replication in chimpanzees was moderately higher, and infected animals
      developed mild colds. HMPV replicated the most efficiently in the respiratory
      tracts of African green monkeys, and the infected animals developed a high level
      of HMPV serum-neutralizing antibodies (1:500 to 1:1,000) effective against both
      lineages. Reciprocal cross-neutralization assays in which postinfection sera from
      all three primate species were used indicated that CAN75 and CAN83 are 64 to 99%
      related antigenically. HMPV-infected chimpanzees and African green monkeys were
      highly protected from challenge with the heterologous HMPV strain. Taken
      together, the results from hamsters and nonhuman primates support the conclusion
      that the two HMPV genetic lineages are highly related antigenically and are not
      distinct antigenic subtypes or subgroups as defined by reciprocal cross
      neutralization in vitro.

PMID- 15194770
TI  - Identification of an antigenic determinant on the S2 domain of the severe acute
      respiratory syndrome coronavirus spike glycoprotein capable of inducing
      neutralizing antibodies.
AB  - Severe acute respiratory syndrome (SARS) is a life-threatening disease caused by
      a newly identified coronavirus (CoV), SARS-CoV. The spike (S) glycoprotein of CoV
      is the major structural protein responsible for induction of host immune response
      and virus neutralization by antibodies. Hence, knowledge of neutralization
      determinants on the S protein is helpful for designing protective vaccines. To
      analyze the antigenic structure of the SARS-CoV S2 domain, the carboxyl-terminal
      half of the S protein, we first used sera from convalescent SARS patients to test
      the antigenicity of 12 overlapping fragments spanning the entire S2 and
      identified two antigenic determinants (Leu 803 to Ala 828 and Pro 1061 to Ser
      1093). To determine whether neutralizing antibodies can be elicited by these two
      determinants, we immunized animals and found that both of them could induce the
      S2-specific antisera. In some animals, however, only one determinant (Leu 803 to
      Ala 828) was able to induce the antisera with the binding ability to the native S
      protein and the neutralizing activity to the SARS-CoV pseudovirus. This
      determinant is highly conserved across different SARS-CoV isolates.
      Identification of a conserved antigenic determinant on the S2 domain of the SARS
      CoV S protein, which has the potential for inducing neutralizing antibodies, has
      implications in the development of effective vaccines against SARS-CoV.

PMID- 15194771
TI  - Functional analysis of the putative fusion domain of the baculovirus envelope
      fusion protein F.
AB  - Group II nucleopolyhedroviruses (NPVs), e.g., Spodoptera exigua MNPV, lack a GP64
      like protein that is present in group I NPVs but have an unrelated envelope
      fusion protein named F. In contrast to GP64, the F protein has to be activated by
      a posttranslational cleavage mechanism to become fusogenic. In several vertebrate
      viral fusion proteins, the cleavage activation generates a new N terminus which
      forms the so-called fusion peptide. This fusion peptide inserts in the cellular
      membrane, thereby facilitating apposition of the viral and cellular membrane upon
      sequential conformational changes of the fusion protein. A similar peptide has
      been identified in NPV F proteins at the N terminus of the large membrane
      anchored subunit F(1). The role of individual amino acids in this putative fusion
      peptide on viral infectivity and propagation was studied by mutagenesis. Mutant F
      proteins with single amino acid changes as well as an F protein with a deleted
      putative fusion peptide were introduced in gp64-null Autographa californica MNPV
      budded viruses (BVs). None of the mutations analyzed had an major effect on the
      processing and incorporation of F proteins in the envelope of BVs. Only two
      mutants, one with a substitution for a hydrophobic residue (F152R) and one with a
      deleted putative fusion peptide, were completely unable to rescue the gp64-null
      mutant. Several nonconservative substitutions for other hydrophobic residues and
      the conserved lysine residue had only an effect on viral infectivity. In contrast
      to what was expected from vertebrate virus fusion peptides, alanine substitutions
      for glycines did not show any effect.

PMID- 15194772
TI  - Postinternalization inhibition of adenovirus gene expression and infectious virus
      production in human T-cell lines.
AB  - Detection of adenovirus DNA in human tonsillar T cells in the absence of active
      virus replication suggests that T cells may be a site of latency or of attenuated
      virus replication in persistently infected individuals. The lytic replication
      cycle of Ad5 in permissive epithelial cells (A549) was compared to the behavior
      of Ad5 in four human T-cell lines, Jurkat, HuT78, CEM, and KE37. All four T-cell
      lines expressed the integrin coreceptors for Ad2 and Ad5, but only Jurkat and
      HuT78 express detectable surface levels of the coxsackie adenovirus receptor
      (CAR). Jurkat and HuT78 cells supported full lytic replication of Ad5, albeit at
      a level approximately 10% of that of A549, while CAR-transduced CEM and KE37
      cells (CEM-CARhi and KE37-CARhi, respectively) produced no detectable virus
      following infection. All four T-cell lines bind and internalize fluorescently
      labeled virus. In A549, Jurkat, and HuT78 cells, viral proteins were detected in
      95% of cells. In contrast, only a small subpopulation of CEM-CARhi and KE37-CARhi
      cells contained detectable viral proteins. Interestingly, Jurkat and HuT78 cells
      synthesize four to six times more copies of viral DNA per cell than did A549
      cells, indicating that these cells produce infectious virions with much lower
      efficiency than A549. Similarly, CEM-CARhi and KE37-CARhi cells, which produce no
      detectable infectious virus, synthesize three times more viral genomes per cell
      than A549. The observed blocks to adenovirus gene expression and replication in
      all four human T-cell lines may contribute to the maintenance of naturally
      occurring persistent adenovirus infections in human T cells.

PMID- 15194773
TI  - Integrin alpha v beta 6 is an RGD-dependent receptor for coxsackievirus A9.
AB  - Coxsackievirus A9 (CAV9), a member of the Enterovirus genus of Picornaviridae, is
      a common human pathogen and is one of a significant number of viruses containing
      a functional arginine-glycine-aspartic acid (RGD) motif in one of their capsid
      proteins. Previous studies identified the RGD-recognizing integrin
      alpha(v)beta(3) as its cellular receptor. However, integrin alpha(v)beta(6) has
      been shown to be an efficient receptor for another RGD-containing picornavirus,
      foot-and-mouth disease virus (FMDV). In view of the similarity in sequence
      context of the RGD motifs in CAV9 and FMDV, we investigated whether
      alpha(v)beta(6) can also serve as a receptor for CAV9. We found that CAV9 can
      bind to purified alpha(v)beta(6) and also to SW480 cells transfected with beta(6)
      cDNA, allowing expression of alpha(v)beta(6) on their surface, but it cannot bind
      to mock-transfected cells. In addition, a higher yield of CAV9 was obtained in
      beta(6)-expressing cells than in mock-transfected cells. There was no similar
      enhancement in infection with an RGD-less CAV9 mutant. We also found beta(6) on
      the surface of GMK cells, a cell line which CAV9 infects efficiently by an RGD
      dependent mechanism. Significantly, this infection is blocked by an antibody to
      alpha(v)beta(6), while this antibody did not block the low level of infection by
      the RGD-less mutant. Thus, integrin alpha(v)beta(6) is an RGD-dependent receptor
      for CAV9 and may be important in natural CAV9 infections.

PMID- 15194775
TI  - Complete genome sequence of lymphocystis disease virus isolated from China.
AB  - Lymphocystis diseases in fish throughout the world have been extensively
      described. Here we report the complete genome sequence of lymphocystis disease
      virus isolated in China (LCDV-C), an LCDV isolated from cultured flounder
      (Paralichthys olivaceus) with lymphocystis disease in China. The LCDV-C genome is
      186,250 bp, with a base composition of 27.25% G+C. Computer-assisted analysis
      revealed 240 potential open reading frames (ORFs) and 176 nonoverlapping putative
      viral genes, which encode polypeptides ranging from 40 to 1,193 amino acids. The
      percent coding density is 67%, and the average length of each ORF is 702 bp. A
      search of the GenBank database using the 176 individual putative genes revealed
      103 homologues to the corresponding ORFs of LCDV-1 and 73 potential genes that
      were not found in LCDV-1 and other iridoviruses. Among the 73 genes, there are 8
      genes that contain conserved domains of cellular genes and 65 novel genes that do
      not show any significant homology with the sequences in public databases.
      Although a certain extent of similarity between putative gene products of LCDV-C
      and corresponding proteins of LCDV-1 was revealed, no colinearity was detected
      when their ORF arrangements and coding strategies were compared to each other,
      suggesting that a high degree of genetic rearrangements between them has
      occurred. And a large number of tandem and overlapping repeated sequences were
      observed in the LCDV-C genome. The deduced amino acid sequence of the major
      capsid protein (MCP) presents the highest identity to those of LCDV-1 and other
      iridoviruses among the LCDV-C gene products. Furthermore, a phylogenetic tree was
      constructed based on the multiple alignments of nine MCP amino acid sequences.
      Interestingly, LCDV-C and LCDV-1 were clustered together, but their amino acid
      identity is much less than that in other clusters. The unexpected levels of
      divergence between their genomes in size, gene organization, and gene product
      identity suggest that LCDV-C and LCDV-1 shouldn't belong to a same species and
      that LCDV-C should be considered a species different from LCDV-1.

PMID- 15194774
TI  - The VP7 outer capsid protein of rotavirus induces polyclonal B-cell activation.
AB  - The early response to a homologous rotavirus infection in mice includes a T-cell
      independent increase in the number of activated B lymphocytes in the Peyer's
      patches. The mechanism of this activation has not been previously determined.
      Since rotavirus has a repetitively arranged triple-layered capsid and
      repetitively arranged antigens can induce activation of B cells, one or more of
      the capsid proteins could be responsible for the initial activation of B cells
      during infection. To address this question, we assessed the ability of rotavirus
      and virus-like particles to induce B-cell activation in vivo and in vitro. Using
      infectious rotavirus, inactivated rotavirus, noninfectious but replication
      competent virus, and virus-like particles, we determined that neither infectivity
      nor RNA was necessary for B-cell activation but the presence of the rotavirus
      outer capsid protein, VP7, was sufficient for murine B-cell activation.
      Preincubation of the virus with neutralizing VP7 antibodies inhibited B-cell
      activation. Polymyxin B treatment and boiling of the virus preparation were
      performed, which ruled out possible lipopolysaccharide contamination as the
      source of activation and confirmed that the structural conformation of VP7 is
      important for B-cell activation. These findings indicate that the structure and
      conformation of the outer capsid protein, VP7, initiate intestinal B-cell
      activation during rotavirus infection.

PMID- 15194776
TI  - Immunization with hepatitis C virus-like particles induces humoral and cellular
      immune responses in nonhuman primates.
AB  - We have previously reported the production of hepatitis C virus-like particles
      (HCV-LP) using a recombinant baculovirus containing the cDNA of the HCV
      structural proteins (core, E1, and E2). These particles resemble the putative HCV
      virions and are capable of inducing strong and broad humoral and cellular immune
      responses in mice. Here we present evidence on the immunogenicity of HCV-LP and
      the effects of novel adjuvant systems in a nonhuman primate model, the baboon.
      Three groups of four baboons were immunized with HCV-LP, HCV-LP and adjuvant
      AS01B (monophosphoryl lipid A and QS21), or HCV-LP and the combination of AS01B
      and CpG oligodeoxynucleotides 10105. After four immunizations over an 8-month
      period, all animals developed HCV-specific humoral and cellular immune responses
      including antibodies to HCV structural proteins and gamma interferon(+) (IFN
      gamma(+))CD4(+) and IFN-gamma(+)CD8(+) T-cell responses. The immunogenicity of
      HCV-LP was only marginally enhanced by the use of adjuvants. The overall HCV
      specific immune responses were broad and long lasting. Our results suggest that
      HCV-LP is a potent immunogen to induce HCV-specific humoral and cellular immune
      responses in primates and may be a promising approach to develop novel preventive
      and therapeutic modalities.

PMID- 15194777
TI  - Production of high-titer Epstein-Barr virus recombinants derived from Akata cells
      by using a bacterial artificial chromosome system.
AB  - An Epstein-Barr virus (EBV) genome in Burkitt's lymphoma-derived cell line Akata
      was cloned into a bacterial artificial chromosome (BAC) vector. The BAC clone,
      designated AK-BAC, was rapidly and precisely modified by means of efficient
      homologous recombination in Escherichia coli. This system was used to produce
      recombinant EBVs with transgenes. An expression cassette of green fluorescent
      protein (GFP) was inserted into AK-BAC, and the resultant BAC clone, AK-BAC-GFP,
      was transfected into Akata cells. We found that transfected BAC plasmids
      efficiently formed episomes in EBV-positive Akata cells. Mixtures of wild-type
      and AK-BAC-GFP viruses were then produced and used to infect EBV-negative Akata
      cells. We obtained cell clones that harbored only AK-BAC-GFP but no wild-type
      episome. These cell clones produced infectious viruses after stimulating virus
      production, and the recombinant viruses of AK-BAC-GFP efficiently immortalized
      primary B lymphocytes. We further revised the method so that any kind of cDNA
      could be rapidly inserted into the unique I-PpoI site that had been artificially
      introduced into AK-BAC. The AK-BAC system will have a broad range of
      applications, such as genetic analyses of various viral gene products and
      development of viral vectors for human gene therapy.

PMID- 15194778
TI  - Potent neutralizing serum immunoglobulin A (IgA) in human immunodeficiency virus
      type 2-exposed IgG-seronegative individuals.
AB  - The mechanisms behind the resistance to human immunodeficiency virus type 2 (HIV
      2) infection are still not fully understood. In the present study, we explored
      the HIV-2-specific humoral serum immunoglobulin A (IgA) immune response in HIV-2
      exposed IgG-seronegative (EGSN) individuals. Serum samples from heterosexual EGSN
      individuals and their known HIV-2-infected partners, as well as controls
      originating from Guinea-Bissau in Africa, were studied. Antibody reactivity to
      native and recombinant envelope glycoproteins was investigated, and the capacity
      of purified serum IgA to neutralize HIV-2(SBL6669) was tested. Our results showed
      that 16 of 25 EGSN samples exhibited reactivity against whole HIV-2 antigen, 6 of
      25 samples reacted with recombinant gp36 (rgp36), and 3 of 25 samples were
      positive against HIV-2 rgp105; no reactivity to native HIV-2 gp125 was detected.
      Purified serum IgA antibodies from both EGSN and HIV-2-positive individuals, but
      not that from the negative controls, exhibited neutralization of HIV-2(SBL6669).
      The most potent neutralization activity was exhibited by IgA purified from EGSN
      compared to infected individuals' IgA. The antigenic pattern of the HIV-2
      positive partners showed that all serum IgA samples were reactive to whole HIV-2
      antigen, and 14 of 15 reacted with rgp36. For rgp105 and gp125, 5 of 15 and 4 of
      15 samples exhibited binding, respectively. The serum of the EGSN group had a
      higher mean IgA concentration than that of the negative controls (P < 0.05).
      Thus, we describe HIV-2-specific serum IgA antigen reactivity and show a more
      potent serum IgA-mediated HIV-2-neutralizing activity in EGSN individuals than in
      HIV-2-infected patients.

PMID- 15194779
TI  - Sequence and organization of the Neodiprion lecontei nucleopolyhedrovirus genome.
AB  - All fully sequenced baculovirus genomes, with the exception of the dipteran Culex
      nigripalpus nucleopolyhedrovirus (CuniNPV), have previously been from
      Lepidoptera. This study reports the sequencing and characterization of a
      hymenopteran baculovirus, Neodiprion lecontei nucleopolyhedrovirus (NeleNPV),
      from the redheaded pine sawfly. NeleNPV has the smallest genome so far published
      (81,755 bp) and has a GC content of only 33.3%. It contains 89 potential open
      reading frames, 43 with baculovirus homologues, 6 identified by conserved
      domains, and 1 with homology to a densovirus structural protein. Average amino
      acid identity of homologues ranged from 19.7% with CuniNPV to 24.9% with
      Spodoptera exigua nucleopolyhedrovirus. The conserved set of baculovirus genes
      has dropped to 29, since NeleNPV lacks an F protein homologue (ac23/ld130).
      NeleNPV contains 12 conserved lepidopteran baculovirus genes, including that for
      DNA binding protein, late expression factor 11 (lef-11), polyhedrin, occlusion
      derived virus envelope protein-18 (odv-e18), p40, and p45, but lacks 21 others,
      including lef-3, me53, immediate early gene-1, lef-6, pp31, odv-e66, few
      polyhedra 25k, odv-e25, protein kinase-1, fibroblast growth factor, and
      ubiquitin. The lack of identified baculovirus homologues may be due to
      difficulties in identification, differences in host-virus interactions, or other
      genes performing similar functions. Gene parity plots showed limited colinearity
      of NeleNPV with other baculoviruses, and phylogenetic analysis indicates that
      NeleNPV may have existed before the lepidopteran nucleopolyhedrovirus and
      granulovirus divergence. The creation of two new Baculoviridae genera to fit
      hymenopteran and dipteran baculoviruses may be necessary.

PMID- 15194780
TI  - Sequence analysis of the genome of the Neodiprion sertifer nucleopolyhedrovirus.
AB  - The genome of the Neodiprion sertifer nucleopolyhedrovirus (NeseNPV), which
      infects the European pine sawfly, N. sertifer (Hymenoptera: Diprionidae), was
      sequenced and analyzed. The genome was 86,462 bp in size. The C+G content of 34%
      was lower than that of the majority of baculoviruses. A total of 90 methionine
      initiated open reading frames (ORFs) with more than 50 amino acids and minimal
      overlapping were found. From those, 43 ORFs were homologous to other baculovirus
      ORFs, and 29 of these were from the 30 conserved core genes among all
      baculoviruses. A NeseNPV homolog to the ld130 gene, which is present in all other
      baculovirus genomes sequenced to date, could not be identified. Six NeseNPV ORFs
      were similar to non-baculovirus-related genes, one of which was a trypsin-like
      gene. Only one iap gene, containing a single BIR motif and a RING finger, was
      found in NeseNPV. Two NeseNPV ORFs (nese18 and nese19) were duplicates
      transcribed in opposite orientations from each other. NeseNPV did not have an
      AcMNPV ORF 2 homolog characterized as the baculovirus repeat ORF (bro). Six
      homologous regions (hrs) were located within the NeseNPV genome, each containing
      small palindromes embedded within direct repeats. A phylogenetic analysis was
      done to root the tree based upon the sequences of DNA polymerase genes of
      NeseNPV, 23 other baculoviruses, and other phyla. Baculovirus phylogeny was then
      constructed with 29 conserved genes from 24 baculovirus genomes. Culex
      nigripalpus nucleopolyhedrovirus (CuniNPV) was the most distantly related
      baculovirus, branching to the hymenopteran NeseNPV and the lepidopteran
      nucleopolyhedroviruses and granuloviruses.

PMID- 15194781
TI  - Protection against lethal vaccinia virus challenge in HLA-A2 transgenic mice by
      immunization with a single CD8+ T-cell peptide epitope of vaccinia and variola
      viruses.
AB  - CD8(+) T lymphocytes have been shown to be involved in controlling poxvirus
      infection, but no protective cytotoxic T-lymphocyte (CTL) epitopes are defined
      for variola virus, the causative agent of smallpox, or for vaccinia virus. Of
      several peptides in vaccinia virus predicted to bind HLA-A2.1, three, VETFsm(498
      506), A26L(6-14), and HRP2(74-82), were found to bind HLA-A2.1. Splenocytes from
      HLA-A2.1 transgenic mice immunized with vaccinia virus responded only to HRP2(74
      82) at 1 week and to all three epitopes by ex vivo enzyme-linked immunosorbent
      spot (ELISPOT) assay at 4 weeks postimmunization. To determine if these epitopes
      could elicit a protective CD8(+) T-cell response, we challenged peptide-immunized
      HLA-A2.1 transgenic mice intranasally with a lethal dose of the WR strain of
      vaccinia virus. HRP2(74-82) peptide-immunized mice recovered from infection,
      while naive mice died. Depletion of CD8(+) T cells eliminated protection.
      Protection of HHD-2 mice, lacking mouse class I major histocompatibility complex
      molecules, implicates CTLs restricted by human HLA-A2.1 as mediators of
      protection. These results suggest that HRP2(74-82), which is shared between
      vaccinia and variola viruses, may be a CD8(+) T-cell epitope of vaccinia virus
      that will provide cross-protection against smallpox in HLA-A2.1-positive
      individuals, representing almost half the population.

PMID- 15194782
TI  - Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit
      humoral immune responses in human lymphoid tissue ex vivo.
AB  - Ex vivo human immunodeficiency virus type 1 (HIV-1) infection of human lymphoid
      tissue recapitulates some aspects of in vivo HIV-1 infection, including a severe
      depletion of CD4(+) T cells and suppression of humoral immune responses to recall
      antigens or to polyclonal stimuli. These effects are induced by infection with X4
      HIV-1 variants, whereas infection with R5 variants results in only mild depletion
      of CD4(+) T cells and no suppression of immune responses. To study the mechanisms
      of suppression of immune responses in this ex vivo system, we used aldrithiol-2
      (AT-2)-inactivated virions that have functional envelope glycoproteins but are
      not infectious and do not deplete CD4(+) T cells in human lymphoid tissues ex
      vivo. Nevertheless, AT-2-inactivated X4 (but not R5) HIV-1 virions, even with
      only a brief exposure, inhibit antibody responses in human lymphoid tissue ex
      vivo, similarly to infectious virus. This phenomenon is mediated by soluble
      immunosuppressive factor(s) secreted by tissue exposed to virus.

PMID- 15194784
TI  - Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication
      by use of an HIV type 1-based vector results in severely attenuated mutants
      incapable of developing resistance.
AB  - We have constructed a human immunodeficiency virus type 1 (HIV-1)-based
      lentiviral vector expressing a 937-base antisense sequence against the HIV-1
      envelope gene. Transduction of CD4(+) T lymphocytes with this vector results in
      expression of the therapeutic antisense sequence and subsequent inhibition of
      productive HIV-1 replication. In this report, we examined the effect of antisense
      mediated suppression on the potential development of virus escape mutants using a
      permissive T-cell line cultured under conditions that over serial passages
      specifically allowed for generation and amplification of mutants selected for by
      antisense pressure. In the resulting virus clones, we found a significant
      increase in the number of deletions at the envelope target region (91% compared
      to 27.5% in wild-type HIV). Deletions were most often greater than 1 kb in
      length. These data demonstrate for the first time that during antisense-mediated
      suppression of HIV, mutants develop as a direct result of selective pressure on
      the HIV genomic RNA. Interestingly, in clones where deletions were not observed,
      there was a high rate of A-G transitions in mutants at the antisense target
      region but not outside this region, which is consistent with those mutations that
      are predicted as a result of antisense-mediated modification of double-stranded
      RNA by the enzyme double-stranded RNA-specific adenosine deaminase. These clones
      were not found to be escape mutants, as their replicative ability was severely
      attenuated, and they did not replicate in the presence of vector.

PMID- 15194783
TI  - Selection, transmission, and reversion of an antigen-processing cytotoxic T
      lymphocyte escape mutation in human immunodeficiency virus type 1 infection.
AB  - Numerous studies now support that human immunodeficiency virus type 1 (HIV-1)
      evolution is influenced by immune selection pressure, with population studies
      showing an association between specific HLA alleles and mutations within defined
      cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional
      studies of CD8 T-cell responses to demonstrate that allele-specific immune
      pressures also select for mutations flanking CD8 epitopes that impair antigen
      processing. In persons expressing HLA-A3, we demonstrate consistent selection for
      a mutation in a C-terminal flanking residue of the normally immunodominant Gag
      KK9 epitope that prevents its processing and presentation, resulting in a rapid
      decline in the CD8 T-cell response. This single amino acid substitution also lies
      within a second HLA-A3-restricted epitope, with the mutation directly impairing
      recognition by CD8 T cells. Transmission of the mutation to subjects expressing
      HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase
      responses to both epitopes. However, subsequent in vivo reversion of the mutation
      was coincident with delayed induction of new CD8 T-cell responses to both
      epitopes. These data demonstrate that mutations within the flanking region of an
      HIV-1 epitope can impair recognition by an established CD8 T-cell response and
      that transmission of these mutations alters the acute-phase CD8(+) T-cell
      response. Moreover, reversion of these mutations in the absence of the original
      immune pressure reveals the potential plasticity of immunologically selected
      evolutionary changes.

PMID- 15194785
TI  - Subunit-specific analysis of the human immunodeficiency virus type 1 reverse
      transcriptase in vivo.
AB  - The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a
      heterodimer comprised of two structurally distinct subunits (p51 and p66). Since
      p51 and p66 are derived from the same coding region, subunit-specific structure
      function studies of RT have been conducted exclusively by in vitro biochemical
      approaches. To study RT subunit function in the context of infectious virus, we
      constructed an LTR-vpr-p51-IRES-p66 expression cassette in which the HIV-1 vpr
      gene was fused in frame with p51, followed by an internal ribosome entry site
      (IRES) sequence and the p66 coding region. By coexpression with RT-deficient
      proviral DNA, we demonstrated that the p66 subunit is specifically and
      selectively packaged into virions as a Vpr-p51/p66 complex. Our analysis showed
      that cleavage by the viral protease liberates Vpr and generates functional
      heterodimeric RT (p51/p66) that supports HIV-1 reverse transcription and virus
      infection. By exploiting this novel trans-complementation approach, we
      demonstrated, for the first time with infectious virions, that the YMDD
      aspartates of p66 are both required and sufficient for RT polymerase function.
      Mutational analyses of the p51 YMDD aspartates indicated that they play an
      important structural role in p51 folding and subunit interactions that are
      required for the formation of an active RT heterodimer within infected cells.
      Understanding the role of the individual RT subunits in RNA- and DNA-dependent
      DNA synthesis is integral to our understanding of RT function. Our findings will
      lead to important new insights into the role of the p51 and p66 subunits in HIV-1
      reverse transcription.

PMID- 15194786
TI  - Myxoma virus M11L prevents apoptosis through constitutive interaction with Bak.
AB  - M11L, a 166-amino-acid antiapoptotic protein of myxoma virus, was previously
      shown to bind to the peripheral benzodiazepine receptor by hydrophobic
      interactions at the outer mitochondrial membrane. Here we demonstrate that an
      additional property of M11L is the ability to constitutively form inhibitory
      complexes with the proapoptotic Bcl-2 family member Bak in human cells. This
      binding interaction was identified by both FLAG-tagged pull-down assays and
      tandem affinity purification from transfected and virus-infected human cells.
      M11L binds constitutively to human Bak and, under some inducible conditions, to
      human Bax as well, but not to the other Bcl-2 family members (Bad, Bid, Bcl-2).
      When stably expressed in human embryonic kidney (HEK293) cells, M11L effectively
      protects these cells from Fas ligand-induced apoptosis, thereby blocking release
      of cytochrome c, activation of caspase 9, and cleavage of poly(ADP-ribose)
      polymerase. We also demonstrate in coexpression studies that M11L can interact
      with Bak independently of any involvement with Bax. Furthermore, cells stably
      expressing M11L function to prevent apoptosis that is induced by overexpression
      of Bak. We conclude that M11L inhibits, in a species-independent fashion,
      apoptotic signals mediated by activation of Bak.

PMID- 15194788
TI  - Mutations in the human cytomegalovirus UL27 gene that confer resistance to
      maribavir.
AB  - Previous drug selection experiments resulted in the isolation of a human
      cytomegalovirus (CMV) UL97 phosphotransferase mutant resistant to the
      benzimidazole compound maribavir (1263W94), reflecting the anti-UL97 effect of
      this drug. Three other CMV strains were plaque purified during these experiments.
      These strains showed lower-grade resistance to maribavir than the UL97 mutant.
      Extensive DNA sequence analyses showed no changes from the baseline strain AD169
      in UL97, the genes involved in DNA replication, and most structural proteins.
      However, changes were identified in UL27 where each strain contained a different
      mutation (R233S, W362R, or a combination of A406V and a stop at codon 415). The
      mutation at codon 415 is predicted to truncate the expressed UL27 protein by 193
      codons (32% of UL27) with a loss of nuclear localization. The expression of full
      length UL27 as a green fluorescent fusion protein in uninfected fibroblasts
      resulted in nuclear and nucleolar fluorescence, whereas cytoplasmic localization
      was observed when codons 1 to 415 were similarly expressed. Viable UL27 deletion
      mutants were created by recombination and showed slight growth attenuation and
      maribavir resistance in cell culture. Marker transfer experiments confirmed that
      UL27 mutations conferred maribavir resistance. The UL27 sequence was well
      conserved in a sample of 16 diverse clinical isolates. Mutation in UL27, a
      betaherpesvirus-specific early gene of unknown biological function, may adapt the
      virus for growth in the absence of UL97 activity.

PMID- 15194787
TI  - Sequencing-based detection of low-frequency human immunodeficiency virus type 1
      drug-resistant mutants by an RNA/DNA heteroduplex generator-tracking assay.
AB  - Drug-resistant viruses may be present as minority variants during early treatment
      failures or following discontinuation of failed antiretroviral regimens. A
      limitation of the traditional direct PCR population sequencing method is its
      inability to detect human immunodeficiency virus type 1 (HIV-1) variants present
      at frequencies lower than 20%. A drug resistance genotyping assay based on the
      isolation and DNA sequencing of minority HIV protease variants is presented here.
      A multiple-codon-specific heteroduplex generator probe was constructed to improve
      the separation of HIV protease genes varying in sequence at 12 codons associated
      with resistance to protease inhibitors. Using an RNA molecule as probe allowed
      the simple sequencing of protease variants isolated as RNA/DNA heteroduplexes
      with different electrophoretic mobilities. The protease gene RNA heteroduplex
      generator-tracking assay (RNA-HTA) was tested on plasma quasispecies from 21 HIV
      1-infected persons in whom one or more protease resistance mutations emerged
      during therapy or following initiation of salvage regimens. In 11 of 21 cases,
      RNA-HTA testing of virus from the first episode of virologic failure identified
      protease resistance mutations not seen by population-based PCR sequencing. In 8
      of these 11 cases, all of the low-frequency drug resistance mutations detected
      exclusively by RNA-HTA during the first episode became detectable by population
      based PCR sequencing at the later time point. Distinct sets of protease mutations
      could be linked on different genomes in patients with high-frequency protease
      gene lineages. The enhanced detection of minority drug resistance variants using
      a sequencing-based assay may improve the efficacy of genotype-assisted salvage
      therapies.

PMID- 15194789
TI  - Selection pressure-driven evolution of the Epstein-Barr virus-encoded oncogene
      LMP1 in virus isolates from Southeast Asia.
AB  - The geographically constrained distribution of Epstein-Barr virus (EBV)
      associated nasopharyngeal carcinoma (NPC) in southeast Asian populations suggests
      that both viral and host genetics may influence disease risk. Although
      susceptibility loci have been mapped within the human genome, the role of viral
      genetics in the focal distribution of NPC remains an enigma. Here we report a
      molecular phylogenetic analysis of an NPC-associated viral oncogene, LMP1, in a
      large panel of EBV isolates from southeast Asia and from Papua New Guinea,
      Africa, and Australia, regions of the world where NPC is and is not endemic,
      respectively. This analysis revealed that LMP1 sequences show a distinct
      geographic structure, indicating that the southeast Asian isolates have evolved
      as a lineage distinct from those of Papua New Guinea, African, and Australian
      isolates. Furthermore, a likelihood ratio test revealed that the C termini of the
      LMP1 sequences of the southeast Asian lineage are under significant positive
      selection pressure, particularly at some sites within the C-terminal activator
      regions. We also present evidence that although the N terminus and transmembrane
      region of LMP1 have undergone recombination, the C-terminal region of the gene
      has evolved without any history of recombination. Based on these observations, we
      speculate that selection pressure may be driving the LMP1 sequences in virus
      isolates from southeast Asia towards a more malignant phenotype, thereby
      influencing the endemic distribution of NPC in this region.

PMID- 15194790
TI  - Actin cytoskeletal reorganizations and coreceptor-mediated activation of rac
      during human immunodeficiency virus-induced cell fusion.
AB  - The membrane fusion events which initiate human immunodeficiency virus type 1
      (HIV-1) infection and promote cytopathic syncytium formation in infected cells
      commence with the binding of the HIV envelope glycoprotein (Env) to CD4 and an
      appropriate coreceptor. Here, we show that HIV Env-coreceptor interactions
      activate Rac-1 GTPase and stimulate the actin filament network reorganizations
      that are requisite components of the cell fusion process. Disrupting actin
      filament dynamics with jasplakinolide or latrunculin A arrested fusion at a late
      step in the formation of Env-CD4-coreceptor complexes. Time-lapse confocal
      microscopy of living cells revealed vigorous activity of actin-based, target cell
      membrane extensions at the target cell-Env-expressing cell interface. The
      expression of dominant-negative forms of actin-regulating Rho-family GTPases
      established that HIV Env-mediated syncytium formation relies on Rac-1 but not on
      Cdc42 or Rho activation in target cells. Similar dependencies were found when
      cell fusion was induced by Env expressed on viral or cellular membranes.
      Additionally, Rac activity was specifically upregulated in a coreceptor-dependent
      manner in fusion reaction cell lysates. These results define a role for HIV Env
      coreceptor interactions in activating the cellular factors essential for virus
      cell and cell-cell fusion and provide evidence for the participation of pertussis
      toxin-insensitive signaling pathways in HIV-induced membrane fusion.

PMID- 15194791
TI  - Prion infection of epithelial Rov cells is a polarized event.
AB  - During prion infections, the cellular glycosylphosphatidylinositol-anchored
      glycoprotein PrP is converted into a conformational isoform. This abnormal
      conformer is thought to recruit and convert the normal cellular PrP into a
      likeness of itself and is proposed to be the infectious agent. We investigated
      the distribution of the PrP protein on the surface of Rov cells, an epithelial
      cell line highly permissive to prion multiplication, and we found that PrP is
      primarily expressed on the apical side. We further show that prion transmission
      to Rov cells is much more efficient if infectivity contacts the apical side,
      indicating that the apical and basolateral sides of Rov cells are not equally
      competent for prion infection and adding prions to the list of the conventional
      infectious agents (viruses and bacteria) that infect epithelial cells in a
      polarized manner. These data raise the possibility that apically expressed PrP
      may be involved in this polarized process of infection. This would add further
      support for a crucial role of PrP at the cell surface in prion infection of
      target cells.

PMID- 15194792
TI  - Intracellular trafficking of Gag and Env proteins and their interactions modulate
      pseudotyping of retroviruses.
AB  - Glycoproteins derived from most retroviruses and from several families of
      enveloped viruses can form infectious pseudotypes with murine leukemia virus
      (MLV) and lentiviral core particles, like the MLV envelope glycoproteins (Env)
      that are incorporated on either virus type. However, coexpression of a given
      glycoprotein with heterologous core proteins does not always give rise to highly
      infectious viral particles, and restrictions on pseudotype formation have been
      reported. To understand the mechanisms that control the recruitment of viral
      surface glycoproteins on lentiviral and retroviral cores, we exploited the fact
      that the feline endogenous retrovirus RD114 glycoprotein does not efficiently
      pseudotype lentiviral cores derived from simian immunodeficiency virus, whereas
      it is readily incorporated onto MLV particles. Our results indicate that
      recruitment of glycoproteins by the MLV and lentiviral core proteins occurs in
      intracellular compartments and not at the cell surface. We found that Env and
      core protein colocalization in intracytoplasmic vesicles is required for
      pseudotype formation. By investigating MLV/RD114 Env chimeras, we show that
      signals in the cytoplasmic tail of either glycoprotein differentially influenced
      their intracellular localization; that of MLV allows endosomal localization and
      hence recruitment by both lentiviral and MLV cores. Furthermore, we found that
      upon membrane binding, MLV core proteins could relocalize Env glycoproteins in
      late endosomes and allow their incorporation on viral particles. Thus,
      intracellular colocalization, as well as interactions between Env and core
      proteins, may influence the recruitment of the glycoprotein onto viral particles
      and generate infectious pseudotyped viruses.

PMID- 15194793
TI  - Modulation of p53 cellular function and cell death by African swine fever virus.
AB  - Modulation of the activity of tumor suppressor p53 is a key event in the
      replication of many viruses. We have studied the function of p53 in African swine
      fever virus (ASFV) infection by determining the expression and activity of this
      transcription factor in infected cells. p53 levels are increased at early times
      of infection and are maintained throughout the infectious cycle. The protein is
      transcriptionally active, stabilized by phosphorylation, and localized in the
      nucleus. p53 induces the expression of p21 and Mdm2. Strikingly, these two
      proteins are located at the cytoplasmic virus factories. The retention of Mdm2 at
      the factory may represent a viral mechanism to prevent p53 inactivation by the
      protein. The expression of apoptotic proteins, such as Bax or active caspase-3,
      is also increased following ASFV infection, although the increase in caspase-3
      does not appear to be, at least exclusively, p53 dependent. Bax probably plays a
      role in the induction of apoptosis in the infected cells, as suggested by the
      release of cytochrome c from the mitochondria. The significance of p21 induction
      and localization is discussed in relation to the shutoff of cellular DNA
      synthesis that is observed in ASFV-infected cells.

PMID- 15194795
TI  - Receptor (CD155)-dependent endocytosis of poliovirus and retrograde axonal
      transport of the endosome.
AB  - Poliovirus (PV), when injected intramuscularly into the calf, is incorporated
      into the sciatic nerve and causes an initial paralysis of the inoculated limb in
      transgenic mice carrying the human PV receptor (hPVR/CD155) gene. Here, we
      demonstrated by using an immunoelectron microscope that PV particles exist on
      vesicle structures in nerve terminals of neuromuscular junctions. We also
      demonstrated in glutathione S-transferase pull-down experiments that the dynein
      light chain, Tctex-1, interacts directly with the cytoplasmic domain of hPVR. In
      the axons of differentiated rat PC12 cells transfected with expression vectors
      for hPVRs, vesicles composed of PV and hPVR alpha, as well as a mutant hPVR alpha
      (hPVRM alpha) that had a reduced ability to bind Tctex-1, colocalized with Tctex
      1. However, vesicles containing PV, dextran, and hPVR alpha had only retrograde
      motion, while those containing PV, dextran, and hPVRM alpha had anterograde or
      retrograde motion. Topical application of the antimicrotubule agent vinblastine
      to the sciatic nerve reduced the amount of virus transported from the calf to the
      spinal cord. These results suggest that direct efficient interaction between the
      cytoplasmic domain and Tctex-1 is essential for the efficient retrograde
      transport of PV-containing vesicles along microtubules in vivo.

PMID- 15194794
TI  - Nuclear sequestration of cellular chaperone and proteasomal machinery during
      herpes simplex virus type 1 infection.
AB  - Herpes simplex virus type 1 (HSV-1) encodes a portal protein that forms a large
      oligomeric structure believed to provide the conduit for DNA entry and exit from
      the capsid. Chaperone proteins often facilitate the folding and multimerization
      of such complex structures. In this report, we show that cellular chaperone
      proteins, components of the 26S proteasome, and ubiquitin-conjugated proteins are
      sequestered in discrete foci in the nucleus of the infected cell. The immediate
      early viral protein ICP0 was shown to be necessary to establish these foci at
      early times during infection and sufficient to redistribute chaperone molecules
      in transfected cells. Furthermore, we found that not only is the portal protein,
      UL6, localized to these sites during infection, but it is also a substrate for
      ubiquitin modification. Our results suggest that HSV-1 has evolved an elegant
      mechanism for facilitating protein quality control at specialized foci within the
      nucleus.

PMID- 15194796
TI  - E1 empty set E4 protein of human papillomavirus type 16 associates with
      mitochondria.
AB  - The human papillomavirus (HPV) E1 empty set E4 protein is the most abundantly
      expressed viral protein in HPV-infected epithelia. It possesses diverse
      activities, including the ability to bind to the cytokeratin network and to DEAD
      box proteins, and in some cases induces the collapse of the former. E1 empty set
      E4 is also able to prevent the progression of cells into mitosis by arresting
      them in the G(2) phase of the cell cycle. In spite of these intriguing
      properties, the role of this protein in the life cycle of the virus is not clear.
      Here we report that after binding to and collapsing the cytokeratin network, the
      HPV type 16 E1 empty set E4 protein binds to mitochondria. When cytokeratin is
      not present in the cell, E1 empty set E4 appears associated with mitochondria
      soon after its synthesis. The leucine cluster within the N-terminal portion of
      the E1 empty set E4 protein is pivotal in mediating this association. After the
      initial binding to mitochondria, the E1 empty set E4 protein induces the
      detachment of mitochondria from microtubules, causing the organelles to form a
      single large cluster adjacent to the nucleus. This is followed by a severe
      reduction in the mitochondrial membrane potential and an induction of apoptosis.
      HPV DNA replication and virion production occur in terminally differentiating
      cells which are keratin-rich, rigid squamae that exfoliate after completion of
      the differentiation process. Perturbation of the cytokeratin network and the
      eventual induction of apoptotic properties are processes that could render these
      unyielding cells more fragile and ease the exit of newly synthesized HPVs for
      subsequent rounds of infection.

PMID- 15194797
TI  - Small compounds targeted to subunit interfaces arrest maturation in a
      nonenveloped, icosahedral animal virus.
AB  - Nudaurelia omega capensis virus (N omega V) capsids were previously characterized
      in two morphological forms, a T=4, 485-A-diameter round particle with large pores
      and a tightly sealed 395-A icosahedrally shaped particle with the same quasi
      symmetric surface lattice. The large particle converts to the smaller particle
      when the pH is lowered from 7.6 to 5, and this activates an autocatalytic
      cleavage of the viral subunit at residue 570. Here we report that both 1-anilino
      8 naphthalene sulfonate (ANS) and the covalent attachment of the thiol-reactive
      fluorophore, maleimide-ANS (MIANS), inhibit the structural transition and
      proteolysis at the lower pH. When ANS is exhaustively washed from the particles,
      the maturation proceeds normally; however, MIANS-modified particles are still
      inhibited after the same washing treatment, indicating that covalent attachment
      targets MIANS to a critical location for inhibition. Characterization of the low
      pH MIANS product by electron cryo-microscopy (cryo-EM) and image reconstruction
      demonstrated a morphology intermediate between the two forms previously
      characterized. A pseudoatomic model of the intermediate configuration was
      generated by rigid body refinement of the X-ray structure of the subunits
      (previously determined in the assembled capsid) into the cryo-EM density,
      allowing a quantitative description of the inhibited intermediate and a
      hypothesis for the mechanism of the inhibition.

PMID- 15194798
TI  - An exposed domain in the severe acute respiratory syndrome coronavirus spike
      protein induces neutralizing antibodies.
AB  - Exposed epitopes of the spike protein may be recognized by neutralizing
      antibodies against severe acute respiratory syndrome (SARS) coronavirus (CoV). A
      protein fragment (S-II) containing predicted epitopes of the spike protein was
      expressed in Escherichia coli. The properly refolded protein fragment
      specifically bound to the surface of Vero cells. Monoclonal antibodies raised
      against this fragment recognized the native spike protein of SARS CoV in both
      monomeric and trimeric forms. These monoclonal antibodies were capable of
      blocking S-II attachment to Vero cells and exhibited in vitro antiviral activity.
      These neutralizing antibodies mapped to epitopes in two peptides, each comprising
      20 amino acids. Thus, this region of the spike protein might be a target for
      generation of therapeutic neutralizing antibodies against SARS CoV and for
      vaccine development to elicit protective humoral immunity.

PMID- 15194799
TI  - Gene transduction and cell entry pathway of fiber-modified adenovirus type 5
      vectors carrying novel endocytic peptide ligands selected on human tracheal
      glandular cells.
AB  - Monolayers of cystic fibrosis transmembrane conductance regulator (CFTR)
      deficient human tracheal glandular cells (CF-KM4) were subjected to phage
      biopanning, and cell-internalized phages were isolated and sequenced, in order to
      identify CF-KM4-specific peptide ligands that would confer upon adenovirus type 5
      (Ad5) vector a novel cell target specificity and/or higher efficiency of gene
      delivery into airway cells of patients with cystic fibrosis (CF). Three different
      ligands, corresponding to prototypes of the most represented families of
      phagotopes recovered from intracellular phages, were designed and individually
      inserted into Ad5-green fluorescent protein (GFP) (AdGFP) vectors at the
      extremities of short fiber shafts (seven repeats [R7]) terminated by scissile
      knobs. Only one vector, carrying the decapeptide GHPRQMSHVY (abbreviated as
      QM10), showed an enhanced gene transduction of CF-KM4 cells compared to control
      nonliganded vector with fibers of the same length (AdGFP-R7-knob). The
      enhancement in gene transfer efficiency was not specific to CF-KM4 cells but was
      observed in other mammalian cell lines tested. The QM10-liganded vector was
      referred to as AdGFP-QM10-knob in its knobbed version and as AdGFP-QM10 in its
      proteolytically deknobbed version. AdGFP-QM10 was found to transduce cells with a
      higher efficiency than its knob-bearing version, AdGFP-QM10-knob. Consistent with
      this, competition experiments indicated that the presence of knob domains was not
      an absolute requirement for cell attachment of the QM10-liganded vector and that
      the knobless AdGFP-QM10 used alternative cell-binding domains on its capsid,
      including penton base capsomer, via a site(s) different from its RGD motifs. The
      QM10-mediated effect on gene transduction seemed to take place at the step of
      endocytosis in both quantitative and qualitative manners. Virions of AdGFP-QM10
      were endocytosed in higher numbers than virions of the control vector and were
      directed to a compartment different from the early endosomes targeted by members
      of species C Ad. AdGFP-QM10 was found to accumulate in late endosomal and low-pH
      compartments, suggesting that QM10 acted as an endocytic ligand of the lysosomal
      pathway. These results validated the concept of detargeting and retargeting Ad
      vectors via our deknobbing system and redirecting Ad vectors to an alternative
      endocytic pathway via a peptide ligand inserted in the fiber shaft domain.

PMID- 15194800
TI  - Mitotic chromosome-binding activity of latency-associated nuclear antigen 1 is
      required for DNA replication from terminal repeat sequence of Kaposi's sarcoma
      associated herpesvirus.
AB  - Latency-associated nuclear antigen 1 (LANA1) of Kaposi's sarcoma-associated
      herpesvirus (KSHV) is implicated in the persistence of the viral genome during
      latent infection. It has been suggested that LANA1 tethers the viral genome to
      the host chromosome and also participates actively in DNA replication from the
      terminal repeat of KSHV. Here we show by mutational analysis that the mitotic
      chromosome-binding activity of LANA1 is tightly coupled to its replication
      activity. Thus, KSHV appears to have evolved a unique tactic for its stable
      maintenance.

PMID- 15194801
TI  - Human monoclonal antibody to hepatitis C virus E1 glycoprotein that blocks virus
      attachment and viral infectivity.
AB  - Human antibodies elicited in response to hepatitis C virus (HCV) infection are
      anticipated to react with the native conformation of the viral envelope
      structure. Isolation of these antibodies as human monoclonal antibodies that
      block virus binding and entry will be useful in providing potential therapeutic
      reagents and for vaccine development. H-111, an antibody to HCV envelope 1
      protein (E1) that maps to the YEVRNVSGVYH sequence and is located near the N
      terminus of E1 and is able to immunoprecipitate E1E2 heterodimers, is described.
      Binding of H-111 to HCV E1 genotypes 1a, 1b, 2b, and 3a indicates that the H-111
      epitope is highly conserved. Sequence analysis of antibody V regions showed
      evidence of somatic and affinity maturation of H-111. Finally, H-111 blocks HCV
      like particle binding to and HCV virion infection of target cells, suggesting the
      involvement of this epitope in virus binding and entry.

PMID- 15194802
TI  - Intracellular approach for blocking JC virus gene expression by using RNA
      interference during viral infection.
AB  - The human polyomavirus, JC virus (JCV), encodes two regulatory proteins at the
      early (T antigen) and the late (agnoprotein) phases of viral infection whose
      activities are important for the production of the viral capsid proteins and the
      dysregulation of several host factors and their functions. For this study, we
      designed and utilized an RNA interference strategy via small interfering RNAs
      (siRNAs) that targeted the expression of T antigen and agnoprotein in human
      astrocytic cells. The treatment of cells with specific siRNA oligonucleotides
      targeting a conserved region of T antigen, nucleotides (nt) 4256 to 4276 (Mad-1
      strain), caused a >50% decline in the level of T antigen and in its
      transcriptional activity upon the viral capsid genes as well as a significant
      reduction in viral DNA replication in infected cells. Similarly, a single siRNA
      that aimed at nt 324 to 342 of agnoprotein noticeably reduced early and late
      viral protein production. A combined treatment of the infected cells with both T
      antigen and agnoprotein siRNAs completely abolished viral capsid protein
      production, indicative of the ability of the siRNAs to effectively halt
      multiplication of the virus in infected cells. These observations provide a new
      avenue for possible treatments of patients with the JCV-induced demyelinating
      disease progressive multifocal leukoencephalopathy.

PMID- 15194803
TI  - Inhibition of virus production in JC virus-infected cells by postinfection RNA
      interference.
AB  - RNA interference has been applied for the prevention of virus infections in
      mammalian cells but has not succeeded in eliminating infections from already
      infected cells. We now show that the transfection of JC virus-infected SVG-A
      human glial cells with small interfering RNAs that target late viral proteins,
      including agnoprotein and VP1, results in a marked inhibition both of viral
      protein expression and of virus production. RNA interference directed against JC
      virus genes may thus provide a basis for the development of new strategies to
      control infections with this polyomavirus.

PMID- 15194804
TI  - Influence of N-glycans on processing and biological activity of the nipah virus
      fusion protein.
AB  - Nipah virus (NiV), a new member of the Paramyxoviridae, codes for a fusion (F)
      protein with five potential N-glycosylation sites. Because glycans are known to
      be important structural components affecting the conformation and function of
      viral glycoproteins, we analyzed the effect of the deletion of N-linked
      oligosaccharides on cell surface transport, proteolytic cleavage, and the
      biological activity of the NiV F protein. Each of the five potential
      glycosylation sites was removed either individually or in combination, revealing
      that four sites are actually utilized (g2 and g3 in the F(2) subunit and g4 and
      g5 in the F(1) subunit). While the removal of g2 and/or g3 had no or little
      effect on cleavage, surface transport, and fusion activity, the elimination of g4
      or g5 reduced the surface expression by more than 80%. Similar to a mutant
      lacking all N-glycans, g4 deletion mutants in which the potential glycosylation
      site was destroyed by introducing a glycine residue were neither cleaved nor
      transported to the cell surface and consequently were not able to mediate cell-to
      cell fusion. This finding indicates that in the absence of g4, the amino acid
      sequence around position 414 is important for folding and transport.

PMID- 15194805
TI  - Human immunodeficiency virus type 1 (HIV-1) diversity at time of infection is not
      restricted to certain risk groups or specific HIV-1 subtypes.
AB  - African women frequently acquire several genetically distinct human
      immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner,
      whereas the acquisition of multiple variants appears to be rare in men. To
      determine whether newly infected individuals in other risk groups acquire
      genetically diverse viruses, we examined the viral envelope sequences in plasma
      samples from 13 women and 4 men from the United States infected with subtype B
      viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope
      sequences differed by more than 2% in three U.S. women, one U.S. man, and one
      Kenyan man near the time of seroconversion. These findings suggest that early HIV
      1 genetic diversity is not exclusive to women from Africa or to infection with
      any particular HIV-1 subtype.

PMID- 15194806
TI  - Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells.
AB  - Recent advances in class II tetramer staining technology have allowed reliable
      direct ex vivo visualization of antigen-specific CD4 T cells. In order to define
      the frequency and phenotype of a prototype response to a nonpersistent pathogen,
      we have used such techniques to analyze influenza virus-specific memory CD4 T
      cells directly from blood. These responses are stably detectable ex vivo at low
      frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct
      "central memory" CD62L(+) phenotype.

PMID- 15194807
TI  - The bone morphogenetic protein type Ib receptor is a major mediator of glial
      differentiation and cell survival in adult hippocampal progenitor cell culture.
AB  - Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of
      differentiation. They transduce their signal via three different type I
      receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone
      morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known
      about functional differences between the three type I receptors. Here, we have
      investigated consequences of constitutively active (ca) and dominant negative
      (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells
      (AHPs). The dn receptors have a nonfunctional intracellular but functional
      extracellular domain. They thus trap BMPs that are endogenously produced by AHPs.
      We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were
      similar, suggesting similar ligand binding patterns for these receptors. Thus,
      cell survival was decreased, glial fibrillary acidic protein (GFAP) expression
      was reduced, whereas the number of oligodendrocytes increased. No effect on
      neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA
      remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After
      dnAlk3 overexpression, cell survival and astroglial differentiation increased in
      parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs
      mediate cell survival, astroglial differentiation and the suppression of
      oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture.

PMID- 15194808
TI  - Phg2, a kinase involved in adhesion and focal site modeling in Dictyostelium.
AB  - The amoeba Dictyostelium is a simple genetic system for analyzing substrate
      adhesion, motility and phagocytosis. A new adhesion-defective mutant named phg2
      was isolated in this system, and PHG2 encodes a novel serine/threonine kinase
      with a ras-binding domain. We compared the phenotype of phg2 null cells to other
      previously isolated adhesion mutants to evaluate the specific role of each gene
      product. Phg1, Phg2, myosin VII, and talin all play similar roles in cellular
      adhesion. Like myosin VII and talin, Phg2 also is involved in the organization of
      the actin cytoskeleton. In addition, phg2 mutant cells have defects in the
      organization of the actin cytoskeleton at the cell-substrate interface, and in
      cell motility. Because these last two defects are not seen in phg1, myoVII, or
      talin mutants, this suggests a specific role for Phg2 in the control of local
      actin polymerization/depolymerization. This study establishes a functional
      hierarchy in the roles of Phg1, Phg2, myosinVII, and talin in cellular adhesion,
      actin cytoskeleton organization, and motility.

PMID- 15194809
TI  - Cbl-dependent ubiquitination is required for progression of EGF receptors into
      clathrin-coated pits.
AB  - Ligand binding causes the EGF receptor (EGFR) to become ubiquitinated by Cbl upon
      association with the adaptor protein Grb2. We have investigated the role of
      ubiquitin and Grb2 in ligand-induced endocytosis of the EGFR. Incubation of cells
      with EGF on ice caused translocation of Grb2 and Cbl from the cytosol to the rim
      of coated pits. Grb2 with point mutations in both SH3 domains inhibited
      recruitment of the EGFR to clathrin-coated pits, in a Ras-independent manner. On
      overexpression of the Cbl-binding protein Sprouty, ubiquitination of the EGFR was
      inhibited, the EGFR was recruited only to the rim of coated pits, and endocytosis
      of the EGFR was inhibited. Conjugation-defective ubiquitin similarly inhibited
      recruitment of EGF-EGFR to clathrin-coated pits. Even though this does not prove
      that cargo must be ubiquitinated, this indicates the importance of interaction of
      ubiquitinated protein(s) with proteins harboring ubiquitin-interacting domains.
      We propose that Grb2 mediates transient anchoring of the EGFR to an Eps15
      containing molecular complex at the rim of coated pits and that Cbl-induced
      ubiquitination of the EGFR allows relocation of EGFR from the rim to the center
      of clathrin-coated pits.

PMID- 15194810
TI  - Identification of integrin beta subunit mutations that alter heterodimer function
      in situ.
AB  - We conducted a genetic screen for mutations in myospheroid, the gene encoding the
      Drosophila betaPS integrin subunit, and identified point mutants in all of the
      structural domains of the protein. Surprisingly, we find that mutations in very
      strongly conserved residues will often allow sufficient integrin function to
      support the development of adult animals, including mutations in the ADMIDAS site
      and in a cytoplasmic NPXY motif. Many mutations in the I-like domain reduce
      integrin expression specifically when betaPS is combined with activating alphaPS2
      cytoplasmic mutations, indicating that integrins in the extended conformation are
      unstable relative to the inactive, bent heterodimers. Interestingly, the screen
      has identified alleles that show gain-of-function characteristics in cell
      culture, but have negative effects on animal development or viability. This is
      illustrated by the allele mys(b58); available structural models suggest that the
      molecular lesion of mys(b58), V409>D, should promote the "open" conformation of
      the beta subunit I-like domain. This expectation is supported by the finding that
      alphaPS2betaPS (V409>D) promotes adhesion and spreading of S2 cells more
      effectively than does wild-type alphaPS2betaPS, even when betaPS is paired with
      alphaPS2 containing activating cytoplasmic mutations. Finally, comparisons with
      the sequence of human beta8 suggest that evolution has targeted the "mys(b58)"
      residue as a means of affecting integrin activity.

PMID- 15194811
TI  - Inositol 1,4,5-trisphosphate signaling regulates rhythmic contractile activity of
      myoepithelial sheath cells in Caenorhabditis elegans.
AB  - Intercellular communication between germ cells and neighboring somatic cells is
      essential for reproduction. Caenorhabditis elegans oocytes are surrounded by and
      coupled via gap junctions to smooth muscle-like myoepithelial sheath cells.
      Rhythmic sheath cell contraction drives ovulation and is triggered by a factor
      secreted from oocytes undergoing meiotic maturation. We demonstrate for the first
      time that signaling through the epidermal growth factor-like ligand LIN-3 and the
      LET-23 tyrosine kinase receptor induces ovulatory contractions of sheath cells.
      Reduction-of-function mutations in the inositol 1,4,5-trisphosphate (IP(3))
      receptor gene itr-1 and knockdown of itr-1 expression by RNA interference inhibit
      sheath contractile activity. itr-1 gain-of-function mutations increase the rate
      and force of basal contractions and induce tonic sheath contraction during
      ovulation. Sheath contractile activity is disrupted by RNAi of plc-3, one of six
      phospholipase C-encoding genes in the C. elegans genome. PLC-3 is a PLC-gamma
      homolog and is expressed in contractile sheath cells of the proximal gonad.
      Maintenance of sheath contractile activity requires plasma membrane Ca(2+) entry.
      We conclude that IP(3) generated by LET-23 mediated activation of PLC-gamma
      induces repetitive intracellular Ca(2+) release that drives rhythmic sheath cell
      contraction. Calcium entry may function to trigger Ca(2+) release via IP(3)
      receptors and/or refill intracellular Ca(2+) stores.

PMID- 15194812
TI  - A novel intermediate in initiation complex assembly for fission yeast DNA
      replication.
AB  - Assembly of initiation factors on individual replication origins at onset of S
      phase is crucial for regulation of replication timing and repression of
      initiation by S-phase checkpoint control. We dissected the process of
      preinitiation complex formation using a point mutation in fission yeast nda4
      108/mcm5 that shows tight genetic interactions with sna41(+)/cdc45(+). The
      mutation does not affect loading of MCM complex onto origins, but impairs Cdc45
      loading, presumably because of a defect in interaction of MCM with Cdc45. In the
      mcm5 mutant, however, Sld3, which is required for Cdc45-loading, proficiently
      associates with origins. Origin-association of Sld3 without Cdc45 is also
      observed in the sna41/cdc45 mutant. These results suggest that Sld3-loading is
      independent of Cdc45-loading, which is different from those observed in budding
      yeast. Interestingly, returning the arrested mcm5 cells to the permissive
      temperature results in immediate loading of Cdc45 to the origin and resumption of
      DNA replication. These results suggest that the complex containing MCM and Sld3
      is an intermediate for initiation of DNA replication in fission yeast.

PMID- 15194813
TI  - JAM-C is a component of desmosomes and a ligand for CD11b/CD18-mediated
      neutrophil transepithelial migration.
AB  - Neutrophil (PMN) transepithelial migration is dependent on the leukocyte beta(2)
      integrin CD11b/CD18, yet the identity of epithelial counterreceptors remain
      elusive. Recently, a JAM protein family member termed JAM-C was implicated in
      leukocyte adhesive interactions; however, its expression in epithelia and role in
      PMN-epithelial interactions are unknown. Here, we demonstrate that JAM-C is
      abundantly expressed basolaterally in intestinal epithelia and localizes to
      desmosomes but not tight junctions. Desmosomal localization of JAM-C was further
      confirmed by experiments aimed at selective disruption of tight junctions and
      desmosomes. In assays of PMN transepithelial migration, both JAM-C mAbs and JAM
      C/Fc chimeras significantly inhibited the rate of PMN transmigration. Additional
      experiments revealed specific binding of JAM-C to CD11b/CD18 and provided
      evidence of other epithelial ligands for CD11b/CD18. These findings represent the
      first demonstration of direct adhesive interactions between PMN and epithelial
      intercellular junctions (desmosomes) that regulate PMN transepithelial migration
      and also suggest that JAM-C may play a role in desmosomal structure/function.

PMID- 15194815
TI  - Flagellar radial spokes contain a Ca2+-stimulated nucleoside diphosphate kinase.
AB  - The radial spokes are required for Ca(2+)-initiated intraflagellar signaling,
      resulting in modulation of inner and outer arm dynein activity. However, the
      mechanochemical properties of this signaling pathway remain unknown. Here, we
      describe a novel nucleoside diphosphate kinase (NDK) from the Chlamydomonas
      flagellum. This protein (termed p61 or RSP23) consists of an N-terminal catalytic
      NDK domain followed by a repetitive region that includes three IQ motifs and a
      highly acidic C-terminal segment. We find that p61 is missing in axonemes derived
      from the mutants pf14 (lacks radial spokes) and pf24 (lacks the spoke head and
      several stalk components) but not in those from pf17 (lacking only the spoke
      head). The p61 protein can be extracted from oda1 (lacks outer dynein arms) and
      pf17 axonemes with 0.5 M KI, and copurifies with radial spokes in sucrose density
      gradients. Furthermore, p61 contains two classes of calmodulin binding site: IQ1
      interacts with calmodulin-Sepharose beads in a Ca(2+)-independent manner, whereas
      IQ2 and IQ3 show Ca(2+)-sensitive associations. Wild-type axonemes exhibit two
      distinct NDKase activities, at least one of which is stimulated by Ca(2+). This
      Ca(2+)-responsive enzyme, which accounts for approximately 45% of total axonemal
      NDKase, is missing from pf14 axonemes. We found that purified radial spokes also
      exhibit NDKase activity. Thus, we conclude that p61 is an integral component of
      the radial spoke stalk that binds calmodulin and exhibits Ca(2+)-controlled
      NDKase activity. These observations suggest that nucleotides other than ATP may
      play an important role in the signal transduction pathway that underlies the
      regulatory mechanism defined by the radial spokes.

PMID- 15194814
TI  - Role of the alpha-glucanase Agn1p in fission-yeast cell separation.
AB  - Cell division in the fission yeast Schizosaccharomyces pombe yields two equal
      sized daughter cells. Medial fission is achieved by deposition of a primary
      septum flanked by two secondary septa within the dividing cell. During the final
      step of cell division, cell separation, the primary septum is hydrolyzed by an
      endo-(1,3)-beta-glucanase, Eng1p. We reasoned that the cell wall material
      surrounding the septum, referred to here as the septum edging, also must be
      hydrolyzed before full separation of the daughter cells can occur. Because the
      septum edging contains (1,3)-alpha-glucan, we investigated the cellular functions
      of the putative (1,3)-alpha-glucanases Agn1p and Agn2p. Whereas agn2 deletion
      results in a defect in endolysis of the ascus wall, deletion of agn1 leads to
      clumped cells that remained attached to each other by septum-edging material.
      Purified Agn1p hydrolyzes (1,3)-alpha-glucan predominantly into pentasaccharides,
      indicating an endo-catalytic mode of hydrolysis. Furthermore, we show that the
      transcription factors Sep1p and Ace2p regulate both eng1 and agn1 expression in a
      cell cycle-dependent manner. We propose that Agn1p acts in concert with Eng1p to
      achieve efficient cell separation, thereby exposing the secondary septa as the
      new ends of the daughter cells.

PMID- 15194816
TI  - Cyclic mechanical stretch augments both interleukin-8 and monocyte chemotactic
      protein-3 production in the cultured human uterine cervical fibroblast cells.
AB  - Intensive local leukocyte infiltration in the uterine cervix is a characteristic
      feature in the process of cervical ripening. The infiltrated leukocytes include
      neutrophils, macrophages and monocytes, which are believed to play important
      roles in cervical ripening by secreting elastase, matrix metalloproteinase and
      interleukin-1 (IL-1). Interleukin-8 (IL-8) and monocyte chemotactic protein-3
      (MCP-3) belong to the CXC and CC chemokine families, and mediate the chemotaxis
      of neutrophils and monocytes/macrophages respectively. The aim of the present
      study was to investigate the possible involvement of IL-8 and MCP-3 in leukocyte
      chemotaxis in cervical ripening. Immunohistochemistry and RT-PCR detected both IL
      8 and MCP-3 expression in human pregnant uterine cervices. Labour-like cyclic
      mechanical stretch for 48 h significantly elevated both IL-8 (555%) and MCP-3
      (360%) secretion from cultured human uterine cervical fibroblast (CxF) cells
      (P<0.05 for both). Cyclic mechanical stretch for 24, 36 and 48 h significantly
      increased both IL-8 and MCP-3 mRNA expression in CxF cells (P<0.05 for all). The
      stretch-induced augmentation of both IL-8 and MCP-3 expression was significantly
      suppressed by an activator protein-1 (AP-1) inhibitor, curcumin. These data
      suggest that cyclic mechanical stretch of the uterine cervix by the presenting
      part of the fetus during labour may augment both IL-8 and MCP-3 production in the
      uterine cervix via AP-1 activation.

PMID- 15194817
TI  - MicroRNA-directed cleavage of Nicotiana sylvestris PHAVOLUTA mRNA regulates the
      vascular cambium and structure of apical meristems.
AB  - Leaf initiation in the peripheral zone of the shoot apical meristem involves a
      transition to determinate cell fate, but indeterminacy is maintained in the
      vascular cambium, a tissue critical to the continuous growth of vascular tissue
      in leaves and stems. We show that the orientation of cambial growth is regulated
      by microRNA (miRNA)-directed cleavage of mRNA from the Nicotiana sylvestris
      ortholog of PHAVOLUTA (NsPHAV). Loss of miRNA regulation in semidominant phv1
      mutants misdirects lateral growth of leaf midveins and stem vasculature away from
      the shoot, disrupting vascular connections in stem nodes. The phv1 mutation also
      expands the central zone in vegetative and inflorescence meristems, implicating
      miRNA and NsPHAV in regulation of meristem structure. In flowers, phv1 causes
      reiteration of carpel initiation, a phenocopy for loss of CARPEL FACTORY/DICER
      LIKE1, indicating that miRNA is critical to the termination of indeterminacy in
      floral meristems. Results point to a common role for miRNA in spatial and
      temporal restriction of HD-ZIPIII mediated indeterminacy in apical and vascular
      meristems.

PMID- 15194818
TI  - Direct role of a viroid RNA motif in mediating directional RNA trafficking across
      a specific cellular boundary.
AB  - The plasmodesmata and phloem form a symplasmic network that mediates direct cell
      cell communication and transport throughout a plant. Selected endogenous RNAs,
      viral RNAs, and viroids traffic between specific cells or organs via this
      network. Whether an RNA itself has structural motifs to potentiate trafficking is
      not well understood. We have used mutational analysis to identify a motif that
      the noncoding Potato spindle tuber viroid RNA evolved to potentiate its efficient
      trafficking from the bundle sheath into mesophyll that is vital to establishing
      systemic infection in tobacco (Nicotiana tabacum). Surprisingly, this motif is
      not necessary for trafficking in the reverse direction (i.e., from the mesophyll
      to bundle sheath). It is not required for trafficking between other cell types
      either. We also found that the requirement for this motif to mediate bundle
      sheath-to-mesophyll trafficking is dependent on leaf developmental stages. Our
      results provide genetic evidence that (1) RNA structural motifs can play a direct
      role in mediating trafficking across a cellular boundary in a defined direction,
      (2) the bundle sheath-mesophyll boundary serves as a novel regulatory point for
      RNA trafficking between the phloem and nonvascular tissues, and (3) the
      symplasmic network remodels its capacity to traffic RNAs during plant
      development. These findings may help further studies to elucidate the
      interactions between RNA motifs and cellular factors that potentiate directional
      trafficking across specific cellular boundaries.

PMID- 15194819
TI  - Allelic variation of gene expression in maize hybrids.
AB  - Allelic expression variation of nonimprinted autosomal genes has recently been
      uncovered in mouse hybrids and humans. The allelic expression variation is
      attributed to differences in noncoding DNA sequences and does not involve
      epigenetic regulation or gene imprinting. This expression variation is suggested
      to play important roles in determining phenotypic diversity. Virtually nothing is
      known about such allele-specific expression variation in a hybrid plant where two
      alleles are compared in the same genetic context. We examined parental transcript
      accumulation in maize (Zea mays) hybrids using allele-specific RT-PCR analysis.
      Among 15 genes analyzed, 11 showed differences at the RNA level, ranging from
      unequal expression of the two alleles (biallelic) to expression of a single
      allele (monoallelic). Maternal or paternal transmission had little effect on the
      allele-specific transcript ratio of nearly all genes analyzed, suggesting that
      parent-of-origin effect was minimal. We analyzed the allelic difference in
      genetically contrasting hybrids and hybrids under high planting density and
      drought stress. Whereas a genetically improved modern hybrid expressed both
      alleles, a less improved old hybrid frequently showed mono-allelic expression.
      Furthermore, the two alleles in the hybrid responded differentially to abiotic
      stresses. The results of allele-specific regulation in different tissues in
      responding to environment and stress suggest an unequivalent function of the
      parental alleles in the hybrid, which may have an impact on heterosis.

PMID- 15194820
TI  - Plant body weight-induced secondary growth in Arabidopsis and its transcription
      phenotype revealed by whole-transcriptome profiling.
AB  - Wood is an important raw material and environmentally cost-effective renewable
      source of energy. However, the molecular biology of wood formation (i.e.
      secondary growth) is surprisingly understudied. A novel experimental system was
      employed to study the molecular regulation of secondary xylem formation in
      Arabidopsis. First, we demonstrate that the weight carried by the stem is a
      primary signal for the induction of cambium differentiation and the plant
      hormone, auxin, is a downstream carrier of the signal for this process. We used
      Arabidopsis whole-transcriptome (23 K) GeneChip analysis to examine gene
      expression profile changes in the inflorescent stems treated for wood formation
      by cultural manipulation or artificial weight application. Many of the genes up
      regulated in wood-forming stems had auxin responsive cis-acting elements in their
      promoter region, indicating auxin-mediated regulation of secondary growth. We
      identified 700 genes that were differentially expressed during the transition
      from primary growth to secondary growth. More than 40% of the genes that were up
      regulated (>5x) were associated with signal transduction and transcriptional
      regulation. Biological significance of these regulatory genes is discussed in
      light of the induction and development of secondary xylem.

PMID- 15194821
TI  - Functional analysis of the tandem-duplicated P450 genes SPS/BUS/CYP79F1 and
      CYP79F2 in glucosinolate biosynthesis and plant development by Ds transposition
      generated double mutants.
AB  - A significant fraction (approximately 17%) of Arabidopsis genes are members of
      tandemly repeated families and pose a particular challenge for functional
      studies. We have used the Ac-Ds transposition system to generate single- and
      double-knockout mutants of two tandemly duplicated cytochrome P450 genes,
      SPS/BUS/CYP79F1 and CYP79F2. We have previously described the Arabidopsis
      supershoot mutants in CYP79F1 that exhibit massive overproliferation of shoots.
      Here we use a cytokinin-responsive reporter ARR5::uidA and an auxin-responsive
      reporter DR5::uidA in the sps/cyp79F1 mutant to show that increased levels of
      cytokinin, but not auxin, correlate well with the expression pattern of the
      SPS/CYP79F1 gene, supporting the involvement of this gene in cytokinin
      homeostasis. Further, we isolated Ds gene trap insertions in the CYP79F2 gene,
      and find these mutants to be defective mainly in the root system, consistent with
      a root-specific expression pattern. Finally, we generated double mutants in
      CYP79F1 and CYP79F2 using secondary transpositions, and demonstrate that the
      phenotypes are additive. Previous biochemical studies have suggested partially
      redundant functions for SPS/CYP79F1 and CYP79F2 in aliphatic glucosinolate
      synthesis. Our analysis shows that aliphatic glucosinolate biosynthesis is
      completely abolished in the double-knockout plants, providing genetic proof for
      the proposed biochemical functions of these genes. This study also provides
      further demonstration of how gluconisolate biosynthesis, regarded as secondary
      metabolism, is intricately linked with hormone homeostatis and hence with plant
      growth and development.

PMID- 15194823
TI  - Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+
      channel deficiency.
AB  - Malfunctions of potassium channels are increasingly implicated as causes of
      neurological disorders. However, the functional roles of the large-conductance
      voltage- and Ca(2+)-activated K(+) channel (BK channel), a unique calcium, and
      voltage-activated potassium channel type have remained elusive. Here we report
      that mice lacking BK channels (BK(-/-)) show cerebellar dysfunction in the form
      of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced
      deficiency in motor coordination, which are likely consequences of cerebellar
      learning deficiency. At the cellular level, the BK(-/-) mice showed a dramatic
      reduction in spontaneous activity of the BK(-/-) cerebellar Purkinje neurons,
      which generate the sole output of the cerebellar cortex and, in addition,
      enhanced short-term depression at the only output synapses of the cerebellar
      cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by
      the lack of postsynaptic BK channels were found to be due to depolarization
      induced inactivation of the action potential mechanism. These results identify
      previously unknown roles of potassium channels in mammalian cerebellar function
      and motor control. In addition, they provide a previously undescribed animal
      model of cerebellar ataxia.

PMID- 15194822
TI  - Extracellular ATP induces oscillations of intracellular Ca2+ and membrane
      potential and promotes transcription of IL-6 in macrophages.
AB  - The effects of low concentrations of extracellular ATP on cytosolic Ca(2+),
      membrane potential, and transcription of IL-6 were studied in monocyte-derived
      human macrophages. During inflammation or infection many cells secrete ATP. We
      show here that application of 10 microM ATP or 10 microM UTP induces oscillations
      in cytosolic Ca(2+) with a frequency of approximately 12 min(-1) and oscillations
      in membrane potential. RT-PCR analysis showed expression of P2Y(1), P2Y(2),
      P2Y(11), P2X(1), P2X(4), and P2X(7) receptors, large-conductance (KCNMA1 and
      KCNMB1-4), and intermediate-conductance (KCNN4) Ca(2+)-activated K(+) channels.
      The Ca(2+)oscillations were unchanged after removal of extracellular Ca(2+),
      indicating that they were mainly due to movements of Ca(2+) between intracellular
      compartments. Comparison of the effects of different nucleotides suggests that
      the Ca(2+) oscillations were elicited by activation of P2Y(2) receptors coupled
      to phospholipase C. Patch-clamp experiments showed that ATP induced a transient
      depolarization, probably mediated by activation of P2X(4) receptors, followed by
      membrane potential oscillations due to opening of Ca(2+)-activated K(+) channels.
      We also found that 10 microM ATP gamma S increased transcription of IL-6
      approximately 40-fold within 2 h. This effect was abolished by blockade of P2Y
      receptors with 100 microM suramin. Our results suggest that ATP released from
      inflamed, damaged, or metabolically impaired cells represents a "danger signal"
      that plays a major role in activating the innate immune system.

PMID- 15194824
TI  - HER-2 gene amplification can be acquired as breast cancer progresses.
AB  - Amplification and overexpression of the HER-2 oncogene in breast cancer is felt
      to be stable over the course of disease and concordant between primary tumor and
      metastases. Therefore, patients with HER-2-negative primary tumors rarely will
      receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive
      blood test was used to capture circulating tumor cells (CTCs) and evaluate their
      HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the
      primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no
      false positives. In 10 patients with HER-2-positive tumors, the HER-2/chromosome
      enumerator probe 17 ratio in each tumor was about twice that of the corresponding
      CTCs (mean 6.64 +/- 2.72 vs. 2.8 +/- 0.6). Hence, the ratio of the CTCs is a
      reliable surrogate marker for the expected high ratio in the primary tumor. Her-2
      protein expression of 10 CTCs was sufficient to make a definitive diagnosis of
      the HER-2 gene status of the whole population of CTCs in 19 patients with
      recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor
      was HER-2-negative each acquired HER-2 gene amplification in their CTCs during
      cancer progression, i.e., 37.5% (95% confidence interval of 18.8-59.4%). Four of
      the 9 patients were treated with Herceptin-containing therapy. One had a complete
      response and 2 had a partial response.

PMID- 15194825
TI  - Identification of diamino acids in the Murchison meteorite.
AB  - Amino acids identified in the Murchison chondritic meteorite by molecular and
      isotopic analysis are thought to have been delivered to the early Earth by
      asteroids, comets, and interplanetary dust particles where they may have
      triggered the appearance of life by assisting in the synthesis of proteins via
      prebiotic polycondensation reactions [Oro, J. (1961) Nature 190, 389-390; Chyba,
      C. F. & Sagan, C. (1992) Nature 355, 125-132]. We report the identification of
      diamino acids in the Murchison meteorite by new enantioselective GC-MS analyses.
      dl-2,3-diaminopropanoic acid, dl-2,4-diaminobutanoic acid, 4,4'
      diaminoisopentanoic acid, 3,3'-diaminoisobutanoic acid, and 2,3-diaminobutanoic
      acid were detected in the parts per billion range after chemical transformation
      into N,N-diethoxycarbonyl ethyl ester derivatives. The chiral diamino acids show
      a racemic ratio. Laboratory data indicate that diamino acids support the
      formation of polypeptide structures under primitive Earth conditions [Brack, A. &
      Orgel, L. E. (1975) Nature 256, 383-387] and suggest polycondensation reactions
      of diamino acids into early peptide nucleic acid material as one feasible pathway
      for the prebiotic evolution of DNA and RNA genomes [Joyce, G. F. (2002) Nature
      418, 214-221]. The results obtained in this study favor the assumption that not
      only amino acids (as the required monomers of proteins) form in
      interstellar/circumstellar environments, but also the family of diamino
      monocarboxylic acids, which might have been relevant in prebiotic chemistry.

PMID- 15194828
TI  - Protective activity of group C anticapsular antibodies elicited in two-year-olds
      by an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid
      conjugate vaccine.
AB  - BACKGROUND: Quadrivalent capsular group A, C, Y and W-135 meningococcal conjugate
      (MC-4) vaccines are under development OBJECTIVE: Predict efficacy of an
      investigational MC-4 vaccine in 2-year-old children for prevention of group C
      disease. DESIGN: Measurement of group C antibody concentrations, avidity and
      bactericidal and passive protective activity in sera from 2-year-olds given 1
      dose of MC-4 vaccine (N = 30) and 3-year-olds (N = 30) and adults (N = 26) given
      1 dose of meningococcal polysaccharide (MPS-4) vaccine. RESULTS: One month after
      vaccination, the geometric mean anticapsular antibody concentration of children
      given MC-4 vaccine (3.1 microg/ml) was lower than that of control children (5.1
      microg/ml; P < 0.04) or adults immunized with MPS-4 vaccine (22.9 microg/ml; P <
      0.001). However, the percent of sera with protective bactericidal titers of
      >/=1/4 was higher in children given MC-4 vaccine (50%, versus 17% in children
      given MPS-4 vaccine; P < 0.02) and was not significantly different from that of
      immunized adults (65%). In children, the mean antibody avidity at 1 month was
      higher in the MC-4 group (22 nM versus 16 nM in the MPS-4 group; P = 0.002), and
      at 6 months increased in the MC-4 group (28 nM; P < 0.001), but not in the MPS-4
      vaccine group (17 nM). Higher avidity antibody gave greater passive protection in
      the infant rat bacteremia model than did lower avidity antibody (P < 0.03).
      CONCLUSIONS: Although MPS-4 vaccine elicited higher group C serum antibody
      concentrations in 3-year-olds than did MC-4 vaccine in 2-year-olds, the higher
      antibody avidity after MC-4 vaccine resulted in higher bactericidal and passive
      protective activity.

PMID- 15194827
TI  - Postlicensure surveillance for pneumococcal invasive disease after use of
      heptavalent pneumococcal conjugate vaccine in Northern California Kaiser
      Permanente.
AB  - OBJECTIVE: To assess the direct and indirect effects of the introduction of
      routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for
      invasive disease caused by vaccine serotypes and nonvaccine serotypes in
      vaccinated children and unvaccinated children of the same age. Secondary
      objectives included determination of the risk of pneumococcal infections in
      unvaccinated older children and adults in the same population and the impact of
      vaccine introduction on patterns of antimicrobial resistance. METHODS: Northern
      California Kaiser Permanente provides integrated comprehensive care to 3.1
      million people and has an annual birth cohort of 38,000 infants. Microbiology
      services use a regional laboratory. Automated laboratory results, immunization
      records as well as diagnoses for inpatient and outpatient utilization are
      available from clinical data bases. Beginning in April 2000, the heptavalent
      pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the
      Northern California Kaiser Permanente population. Cases of invasive pneumococcal
      disease were identified from the automated hospital diagnosis as well as
      laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient
      and outpatient. For the purpose of these analyses, pneumococcal invasive disease
      was defined as a positive culture from a normally sterile site. RESULTS: As of
      March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24%
      of those <2 years of age received all 4 doses as a result of shortages of
      vaccine. During the last year of observation, no cases of vaccine serotype
      disease were seen in children <1 year of age compared with an incidence ranging
      between 51.5 and 98.2 cases per 100,000 person-years (16-34 cases per year) in
      the years before vaccine introduction. Similar reductions were seen in children
      <5 years of age. There was no evidence of any concomitant increase in
      pneumococcal disease caused by nonvaccine serotypes. High level resistance of
      pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half
      of 2003. Similar trends were seen for other antibiotics. CONCLUSION: The PNCV7
      vaccine is highly effective in reducing the burden of pneumococcal disease in
      children <5 years of age, and there is evidence of a herd effect as well as a
      decrease in the antibiotic resistant in strains causing disease. For invasive
      disease, there is no current evidence of serotype replacement.

PMID- 15194829
TI  - Varicella-related mortality in California, 1988-2000.
AB  - BACKGROUND: Although surveillance for varicella in the United States has
      documented a reduction in cases since vaccine licensure in 1995, information is
      lacking on varicella-related mortality since vaccine introduction. This study
      identifies varicella-related mortality in California before and after vaccine
      introduction and assesses how high risk conditions and complications contributed
      to varicella deaths during this period. METHODS: California death records
      mentioning varicella as either an underlying or contributing cause of death were
      selected from the 1988-2000 multiple cause-of-death files. Pre- and postvaccine
      periods were compared to assess differences in varicella mortality before and
      after vaccine introduction. Differences in varicella mortality by age,
      race/ethnicity and gender were also examined. ICD codes were used to identify
      high risk conditions and varicella-related complications. RESULTS: A total of 228
      varicella-related deaths were reported between 1988 and 2000 in California. Age
      adjusted varicella mortality rates showed a downward trend during this period,
      dropping from a high of 0.97 per million in 1990 to a low of 0.22 per million in
      1999. The average age-adjusted mortality rate declined from 0.67 per million
      prevaccine to 0.38 per million postvaccine. Compared with the prevaccine period,
      the average rate of decline in varicella mortality was greater after vaccine
      implementation. Infants had the highest mortality rate for the period. At least
      one immunocompromising condition was present in 38% of varicella-related deaths.
      Pneumonia was the most commonly reported complication. CONCLUSIONS: Varicella
      related mortality declined in California after vaccine implementation, but
      potentially preventable varicella-related deaths continue to occur.

PMID- 15194830
TI  - Vaccination of cystic fibrosis patients against Pseudomonas aeruginosa reduces
      the proportion of patients infected and delays time to infection.
AB  - INTRODUCTION: Cystic fibrosis (CF) almost always leads to chronic airway
      infection with Pseudomonas aeruginosa. Despite advances in antibiotic therapy,
      after chronic infection rapid deterioration in lung function occurs, increasing
      morbidity and mortality. Prevention of infection by vaccination is desirable, but
      earlier trials produced disappointing results. The promising short term
      immunogenicity and safety of a new P. aeruginosa vaccine prompted us to evaluate
      its long term efficacy. We conducted a 10-year retrospective analysis of outcomes
      in a group of vaccinated patients. MATERIALS AND METHODS: In 1989-1990, 30 young
      children with CF, mean age 7 years, with no prior history of infection with P.
      aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate
      vaccine. We report the follow-up of 26 of these patients from 1989 to 2001. The
      patients were given yearly vaccine boosters. Comparisons were made with a CF
      patient control group matched for gender, age and, where possible, genetic
      mutation. Vaccinated patients and controls were attending a single CF clinic and
      received the same clinical management throughout the study period. Main outcomes
      were time to infection, proportion of patients infected, development of P.
      aeruginosa mucoid phenotype, lung function and body weight. RESULTS: The time to
      infection with P. aeruginosa was longer in the vaccination group than in the
      control group, and fewer vaccinated patients than controls became chronically
      infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was
      higher in the control group (44%) than in the vaccinated group (25%). Patients
      >/=18 years of age at the end of the study had a lower mean forced expiratory
      volume at 1 s (FEV1) than did those 13-17 years of age, but this difference was
      small in the vaccinated group (73.6% versus 83.7%) compared with the controls
      (48.0% versus 78.7%). In the >/=18 year age category the mean FEV1% at 10 years
      was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group
      only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared
      with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%)
      of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25
      at the beginning of the study. CONCLUSION: Regular vaccination of young CF
      patients for a period of 10 years with a polyvalent conjugate vaccine reduced the
      frequency of chronic infection with P. aeruginosa. This was associated with
      better preservation of lung function. Vaccinated patients gained more weight
      during the study period, a possible indication of an improved overall health
      status.

PMID- 15194831
TI  - Differentiating acute bacterial meningitis from acute viral meningitis among
      children with cerebrospinal fluid pleocytosis: a multivariable regression model.
AB  - BACKGROUND: Although accurate models for predicting acute bacterial meningitis
      exist, most have narrow application because of the specific variables selected
      for them. In this study, we estimate the accuracy of a simple new model with
      potentially broader applicability. METHODS: On the basis of previous reports, we
      created a reduced multivariable logistic regression model for predicting
      bacterial meningitis that relies on age (years) (AGE), cerebrospinal fluid (CSF),
      total protein (TP) and total neutrophil count (TNC) alone. Data were from
      children ages 1 month-18 years diagnosed with acute enteroviral or bacterial
      meningitis whose initial CSF revealed >7 white blood cells/mm. A fractional
      polynomial model was specified and validated internally by the bootstrap
      procedure. The area under the receiver operating characteristic curve
      (discrimination: criterion standard, >0.7), the Hosmer-Lemeshow deciles-of-risk
      statistic (calibration: criterion standard, P > 0.05) and sensitivity-specificity
      pairs at prespecified probability thresholds of the model were computed. RESULTS:
      We identified 60 children with bacterial meningitis and 82 with enteroviral
      meningitis. At an area under the receiver operating characteristic curve of 0.97,
      our model represented by the equation: log odds of bacterial meningitis = 0.343 -
      0.003 TNC - 34.802 TP + 21.991 TP - 0.345 AGE, was highly accurate when
      differentiating between bacterial and enteroviral meningitis. The model fit the
      data well (Hosmer-Lemeshow statistic; P =[r] 0.53). At probability cutoffs
      between 0.1 and 0.4, the model had sensitivity values between 98 and 92% and
      specificity values between 62 and 94%. CONCLUSIONS: Among children with CSF
      pleocytosis, a prediction model based exclusively on age, CSF total protein and
      CSF neutrophils differentiates accurately between acute bacterial and viral
      meningitis.

PMID- 15194832
TI  - Prospective study of respiratory viral infections in pediatric hemopoietic stem
      cell transplantation patients.
AB  - BACKGROUND: Community-acquired respiratory viruses are an important cause of
      respiratory disease in pediatric patients undergoing hemopoietic stem cell
      transplantation. However, there are no studies examining the impact of more rapid
      and sensitive diagnosis by real time polymerase chain reaction (PCR) in this
      population. We performed a prospective study to assess the impact of real time
      PCR diagnosis as well as protective isolation for community-acquired respiratory
      virus infections in pediatric patients undergoing hemopoietic stem cell
      transplantation. METHODS: During a 2-year period, 39 pediatric patients
      undergoing hemopoietic stem cell transplantation were analyzed for presence of
      respiratory viruses. Samples were taken at regular intervals and analyzed by
      culture and newly developed real time PCR methods. All patients were cared for in
      protective isolation. RESULTS: Respiratory symptoms were observed in 10 of the 39
      cases (26%) and a virus was identified in 8 and 6 of these cases by PCR and
      culture, respectively. The PCR detected the respiratory infection a median of 8
      days before culture. However, the morbidity of the respiratory infections was
      generally mild, and no mortality was observed. Additionally all infections were
      observed pretransplant or after discharge; no nosocomial infections were
      observed. CONCLUSIONS: The real time PCR assay is more rapid and sensitive than
      culture and could be used to screen patients before transplant or as respiratory
      symptoms present for timely diagnosis.

PMID- 15194833
TI  - Anticipated costs of hospitalization for respiratory syncytial virus infection in
      young children at risk.
AB  - BACKGROUND: Reliable estimates of hospitalization costs for severe respiratory
      syncytial virus (RSV) infection are necessary to perform economic analyses of
      preventive strategies of severe RSV disease. We aimed to develop a model that
      predicts anticipated mean RSV hospitalization costs of groups of young children
      at risk for hospitalization, but not yet hospitalized, based on readily available
      child characteristics. METHODS: We determined real direct medical costs of RSV
      hospitalization from a societal perspective, using a bottom-up strategy, in 3458
      infants and young children hospitalized for severe RSV disease during the RSV
      seasons 1996-1997 to 1999-2000 in the Southwest of the Netherlands. We used a
      linear regression model to predict anticipated mean RSV hospitalization costs of
      groups of children at risk, based on 4 child characteristics [age, gestational
      age, birth weight and bronchopulmonary dysplasia (BPD)], expressed in EC Euros as
      of the year 2000. FINDINGS: The mean RSV hospitalization costs of all patients
      were 3110 Euros. RSV hospitalization costs were higher for patients with lower
      gestational age (5555 Euros; gestational age, </=28 weeks), lower birth weight
      (3895 Euros; birth weight </=2500 g), BPD (5785 Euros; with BPD) and young age
      (4730 Euros; first month of life). The linear regression model had an adjusted R
      of 0.08. This indicates a low explanatory ability for hospitalization costs of
      individual children. However, the model could accurately estimate the anticipated
      mean hospitalization costs of groups of children with the same characteristics.
      INTERPRETATION: RSV hospitalization costs were substantial, especially of
      specific high risk groups. Anticipated mean hospitalization costs of groups of
      children at risk for RSV hospitalization, but not yet hospitalized, could well be
      estimated with 4 child characteristics (age, gestational age, birth weight and
      BPD). These estimated costs can be used for economic analyses of preventive
      strategies for severe RSV disease.

PMID- 15194834
TI  - Association between low birth weight and infant mortality in children born to
      human immunodeficiency virus 1-infected mothers in Tanzania.
AB  - BACKGROUND: The relationship between low birth weight and infant mortality among
      children born to human immunodeficiency virus (HIV)-infected mothers has not been
      thoroughly investigated. METHODS: A total of 1078 HIV-infected pregnant women in
      Tanzania were followed up until delivery and with their infants thereafter. The
      babies' HIV status was assessed at birth, 6 weeks and every 3 months thereafter.
      Using Cox proportional hazards models, we estimated the associations of low birth
      weight with neonatal, post-neonatal and infant mortality and further examined
      whether the association between low birth weight and mortality was modified by
      pediatric HIV infection. RESULTS: Among 823 singletons, low birth weight was
      strongly related to neonatal mortality (relative risk, 5.14; 95% confidence
      interval, 2.32-11.39). The association with postneonatal mortality was modified
      by child's HIV status. Among infants who were either negative or indeterminate at
      6 weeks of age, low birth weight was associated with a 3-fold increased risk of
      mortality (relative risk, 3.16; 95% confidence interval, 1.36-7.37). In the
      positive infants, however, the association was no longer significant.
      CONCLUSIONS: Although the importance of preventing HIV transmission cannot be
      overemphasized, efforts to reduce the incidence of low birth weight would enhance
      the benefit of preventing HIV transmission. Even in populations with no access to
      antiretroviral treatments, interventions to reduce the incidence of low birth
      weight would result in a significant reduction in infant mortality.

PMID- 15194836
TI  - Low birth weight infants and Calmette-Guerin bacillus vaccination at birth:
      community study from Guinea-Bissau.
AB  - BACKGROUND: In developing countries, low birth weight (LBW) children are often
      not vaccinated with Calmette-Guerin bacillus (BCG) at birth. Recent studies have
      suggested that BCG may have a nonspecific beneficial effect on infant mortality.
      We evaluated the consequences of not vaccinating LBW children at birth in Guinea
      Bissau. METHODS: Between 1989 and 1999, 7138 children born at the central
      hospital had a birth weight registered. We assessed BCG coverage until 3 years of
      age. Data on tuberculin skin test (TST) for 297 children and BCG scar for 1319
      children in the study population were reanalyzed for differences between normal
      birth weight (NBW) children and LBW children. We assessed the effect of early BCG
      vaccination on mortality to 12 months of age. RESULTS: Among LBW children there
      were 1.5- to 3-fold more unvaccinated individuals than among NBW children up to 4
      months of age. There was no overall difference between LBW and NBW children in
      TST or BCG scarring; LBW children vaccinated early may have had slightly reduced
      reactions to tuberculin. Among 845 LBW children, 182 had received BCG within the
      first week of life. Controlling for background factors and censoring at first
      diphtheria-tetanuspertussis vaccination, measles vaccination or at 6 months of
      age (whichever came first), the mortality rate ratio for BCG-vaccinated versus 
      unvaccinated LBW children was 0.17 (95% confidence interval, 0.06-0.49), with an
      even stronger effect for LBW children vaccinated in the first week of life
      (mortality rate ratio, 0.07; 95% confidence interval, 0.01-0.62). CONCLUSIONS:
      The policy of not vaccinating with BCG at birth had a negative impact on
      vaccination coverage for LBW children. Early BCG vaccination had no large
      negative impact on TST and BCG scarring. Mortality was lower for BCG-vaccinated
      than for unvaccinated LBW children controlling for available background factors.
      BCG vaccination of LBW children may have a beneficial effect on survival that
      cannot be explained by protection against tuberculosis. Future studies should
      examine possible adverse effects from equalizing BCG policy for LBW and NBW
      children.

PMID- 15194835
TI  - Predictors of early mortality in a cohort of human immunodeficiency virus type 1
      infected african children.
AB  - BACKGROUND: Pediatric human immunodeficiency virus type 1 (HIV-1) infection
      follows a bimodal clinical course with rapid progression in 10-45% of children
      before the age of 2 years and slower progression in the remainder. A prospective
      observational study was undertaken to determine predictors of mortality in HIV-1
      infected African infants during the first 2 years of life. METHODS: Infants in a
      perinatal cohort identified to be HIV-1-infected by DNA PCR were followed monthly
      to 1 year, then quarterly to 2 years or death. RESULTS: Among 62 HIV-1-infected
      infants, infection occurred by the age of 1 month in 56 (90%) infants, and 32
      (52%) died at median age of 6.2 months. All infant deaths were caused by
      infectious diseases, most frequently pneumonia (75%) and diarrhea (41%).
      Univariate predictors of infant mortality included maternal CD4 count <200
      cells/microl [hazard ratio (HR), 3.4; P = 0.008], maternal anemia (HR = 3.7; P =
      0.005), delivery complications (HR = 2.7; P = 0.01), low birth weight (HR = 4.1;
      P = 0.001), weight, length and head circumference </=5th percentile at age 1
      month (HR = 3.7, P = 0.003; HR = 5.8, P < 0.001; and HR = 10.4, P < 0.001,
      respectively), formula-feeding (HR = 4.0; P = 0.01), infant CD4% </=15% (HR =
      5.5; P = 0.01), infant CD4 count <750 (HR = 9.7; P = 0.006) and maternal death
      (HR = 2.9, P = 0.05). In multivariate analysis, maternal CD4 count <200 (HR =
      2.7; P = 0.03) and delivery complications (HR = 3.4; P = 0.005) were
      independently associated with infant mortality. CONCLUSIONS: Advanced maternal
      HIV disease, maternal anemia, delivery complications, early growth faltering,
      formula-feeding and low infant CD4 were predictors of early mortality in African
      HIV-1-infected infants. In resource-poor settings, these predictors may be useful
      for early identification and treatment of high risk infants.

PMID- 15194837
TI  - Hepatitis A in the United States.

PMID- 15194839
TI  - Heterologous immunity and the nonspecific effects of vaccines: a major medical
      advance?

PMID- 15194838
TI  - Disruptions in the supply of routinely recommended childhood vaccines in the
      United States.

PMID- 15194840
TI  - Effect of highly active antiretroviral therapy on cardiovascular involvement in
      children with human immunodeficiency virus infection.
AB  - The impact of highly active antiretroviral therapy (HAART) on cardiovascular
      involvement was evaluated in 38 vertically human immunodeficiency virus-infected
      children followed up for 5 years. This study demonstrates for the first time in a
      cohort of children the resolution of previous dilated cardiomyopathy after the
      start of HAART and the absence of cardiovascular events related to metabolic
      abnormalities during the period of its administration.

PMID- 15194842
TI  - Lack of evidence of encephalopathy related to pertussis vaccine: active
      surveillance by IMPACT, Canada, 1993-2002.
AB  - To assess whether pertussis-containing vaccines cause encephalitis or
      encephalopathy, the IMPACT network of Canadian pediatric centers screened more
      than 12,000 admissions for neurologic disorders between 1993 and 2002. Seven
      cases of encephalopathy began within 7 days after pertussis vaccination, but a
      more likely cause was found in each instance. No attributable case followed
      administration of >6.5 million doses of vaccine.

PMID- 15194841
TI  - Necrotizing pneumonitis caused by Mycoplasma pneumoniae in pediatric patients:
      report of five cases and review of literature.
AB  - Mycoplasma pneumoniae infection is usually self-limited without severe sequelae.
      We report 5 pediatric patients with necrotizing pneumonitis caused by Mycoplasma
      pneumoniae and reviewed the reported cases in the English language. Protracted
      course of fever and respiratory distress were noted in all 5 patients. Macrolides
      and adequate chest tube drainage for pleural effusion were the mainstay of
      treatment.

PMID- 15194844
TI  - Aortitis in a child with Abiotrophia defectiva endocarditis.
AB  - Abiotrophia defectiva, one of several nutritionally variant Streptococcus
      species, is an uncommon but important cause of endocarditis in children. We
      describe an unusual case complicated by extensive aortitis with pits in the
      ascending aorta and the proximal aortic arch.

PMID- 15194843
TI  - Immunogenicity of inactivated hepatitis A vaccine in children with chronic liver
      disease.
AB  - One and 6 months after vaccination with hepatitis A virus vaccine (HAVRIX 720
      Junior), immunologic responses (anti-hepatitis A virus >/=20 mIU/ml) in children
      with chronic hepatitis C infection seroprotection were 92% (23/25) and 75% (9/12)
      in children with chronic hepatitis B infection 87% (21/24) and 88% (15/17) and in
      healthy children 91% (20/22) at both times. A booster dose induced seroprotection
      in all children.

PMID- 15194845
TI  - Relapsing cellulitis associated with Campylobacter coli bacteremia in an
      agammaglobulinemic patient.
AB  - Campylobacter coli rarely causes bacteremia or extraintestinal infection. We
      report herein a case of agammaglobulinemia in which cellulitis associated with C.
      coli bacteremia relapsed after a disease-free interval of >5 years. Pulsed field
      gel electrophoresis revealed that the organisms in this patient were genetically
      identical, suggesting a latent C. coli infection.

PMID- 15194846
TI  - Severe cytomegalovirus enterocolitis in an immunocompetent infant.
AB  - Gastrointestinal cytomegalovirus infection is a common opportunistic infection in
      immunocompromised patients. It is a rare cause of enterocolitis in
      immunocompetent hosts. We present a case of severe cytomegalovirus enterocolitis
      causing intractable diarrhea in a previously healthy infant. The child was
      successfully treated with intravenous ganciclovir.

PMID- 15194847
TI  - Allergic bronchopulmonary aspergillosis masquerading as pulmonary tuberculosis.
AB  - We present an unusual pediatric patient with severe allergic bronchopulmonary
      aspergillosis that masqueraded as pulmonary tuberculosis. After antituberculous
      therapy, the patient's pulmonary disease flared, prompting an aggressive
      diagnostic evaluation. Radiographic findings included nodular pulmonary densities
      with superimposed infiltrates. Lung biopsy showed evidence of acute and chronic
      inflammation with necrotizing granulomas, giant cells, tissue eosinophilia and
      rare hyphal elements.

PMID- 15194849
TI  - Possible association of Guillain-Barre syndrome and hepatitis A vaccination.
AB  - We report a case of Guillain-Barre syndrome in a previously healthy child who
      received a hepatitis A vaccination (HAVRIX) 5 days before onset of symptoms. No
      other precipitating factor could be identified. The relevant literature is
      reviewed and discussed.

PMID- 15194848
TI  - Successful elimination of an invasive Aspergillus nidulans lung infection by
      voriconazole after failure of a combination of caspofungin and liposomal
      amphotericin B in a boy with chronic granulomatous disease.
AB  - Chronic granulomatous disease is an inherited defect in host defense mechanisms
      mainly affecting neutrophil function. Pulmonary infection with Aspergillus
      nidulans in a child with chronic granulomatous disease could not be eliminated by
      a combination of caspofungin and liposomal amphotericin B. Voriconazole was
      successful in clearing the infection.

PMID- 15194850
TI  - Enlarging parietal mass with lytic skull lesion.

PMID- 15194851
TI  - Mycobacterium bovis versus Mycobacterium tuberculosis as a cause of acute
      cervical lymphadenitis without pulmonary disease.
AB  - Bovine tuberculosis remains a common disease of cattle in countries such as
      Mexico. Children eating unpasteurized dairy products from Mexican cattle can
      develop Mycobacterium bovis cervical lymphadenitis. However, the bovine
      mycobacterium can be misdiagnosed as Mycobacterium tuberculosis based on standard
      laboratory testing. Accurate speciation is important for selection of the
      preferred antibiotic regimen for treatment of Mycobacterium bovis infection.

PMID- 15194852
TI  - Benzathine penicillin formulations.

PMID- 15194854
TI  - Safety of cold-adapted live influenza vaccine.

PMID- 15194856
TI  - Medial olivocochlear efferent activity in awake guinea pigs.
AB  - Cochlear outer hair cells receive numerous connections from the medial
      olivocochlear efferent neurons. Medial olivocochlear efferent activity is highly
      dependent on the level of anesthesia. The present study was thus designed to
      investigate the efficiency of contralateral white noise stimulation on the
      distortion product otoacoustic emissions (DPOAEs) in a large number of awake
      guinea pigs, and to compare in the same animals the effect of urethane- and
      pentobarbitone-anesthesia. The monitoring of DPOAEs during contralateral white
      noise stimulation in awake animals requires the development of a soft restraining
      box, together with a conditioning technique for the animals to accept the
      contralateral sound and DPOAEs monitoring device. This technique allows us to
      demonstrate that contralateral sound suppression is much stronger in awake than
      in anesthetized animals. In all the cases, the contralateral sound suppression
      was abolished 3 h after i.m. injection of gentamicin, an aminoglycoside
      antibiotic which blocks the medial olivocochlear efferents. These results suggest
      that future studies have to explore the function of medial olivocochlear
      efferents in awake animals.

PMID- 15194857
TI  - N100m in adults possessing absolute pitch.
AB  - We recorded the auditory evoked magnetic fields from adults with and without
      absolute pitch under the following conditions: hearing 1000 Hz pure tones
      inattentively (single tone session) and listening to eight random tones and
      identifying each tone (labeling session). In the adults with absolute pitch, the
      bilateral N100m dipole moments increased significantly in the labeling session.
      While, in the adults without absolute pitch, the left N100m dipole moment alone
      increased in the labeling session. These results suggest that the adults with
      absolute pitch execute the labeling task in the bilateral auditory cortices with
      interhemispheric cooperation, which does not operate in the adults without
      absolute pitch.

PMID- 15194858
TI  - Changes in functional coupling patterns during bimanual task performance.
AB  - Functional interaction between cortical areas may involve synchronization of
      activities, manifest as coherence between EEG signals. However, although EEG-EEG
      coherence changes when motor tasks are compared to each other or rest, there is
      little evidence that coherence is modulated within an action. To address this
      issue we used a bimanual drawer-opening task necessitating asymmetrical hand
      actions and comprising distinct movement phases. Pronounced modulations in EEG
      EEG coherence in the beta band (>12-24 Hz) occurred with movement phase.
      Differences in coherence due to a switch in role of the hands were mainly
      observed in the alpha band (8-12 Hz). These findings suggest that inter-regional
      synchronization changes dynamically across task execution in line with behavioral
      performance.

PMID- 15194859
TI  - High-frequency stimulation of the entopeduncular nucleus improves dystonia in
      dtsz hamsters.
AB  - High-frequency stimulation (HFS) of the internal pallidum (GPi) has been reported
      to improve generalized dystonia in patients. Currently, dystonia is thought to be
      associated with disturbed neuronal activity of GPi neurons. Similar findings have
      been observed in the dtsz hamster, a model of idiopathic paroxysmal non
      kinesiogenic dystonia. For this reason, we investigated the effect of bilateral
      HFS of the entopeduncular nucleus (EPN, rodent homologue of GPi) on the severity
      of dystonia. Bilateral EPN-HFS resulted in a reversible decrease of dystonia
      severity up to 50% when compared to both pre- and post-HFS scores, and controls.
      Our results underline the pathophysiological role of the EPN in the dtsz hamster
      and suggest the suitability of this model to further investigate mechanisms of
      HFS in dystonia.

PMID- 15194860
TI  - Membrane-associated prostaglandin E synthase-1 is required for neuropathic pain.
AB  - It is widely accepted that prostaglandin (PG) E2 is the principal pro
      inflammatory prostanoid and plays an important role in inflammatory pain. However
      whether PGE2 is involved in neuropathic pain remains unknown. PGE2 is produced
      from arachidonic acid via PGH2 by at least three PGE synthases (PGES), cytosolic
      PGES (cPGES), and membrane-associated PGES (mPGES)-1 and -2. In the present
      study, to clarify the involvement of PGE2 and identify PGES mediating neuropathic
      pain, we applied a neuropathic pain model prepared by L5 spinal nerve transection
      to mPGES-1 knockout (mPGES-1-/-) mice. Whereas they retained normal nociceptive
      responses, mPGES-1-/- mice did not exhibit mechanical allodynia and thermal
      hyperalgesia over a week. These results demonstrate that PGE2 produced by mPGES-1
      is involved in neuropathic pain.

PMID- 15194861
TI  - Cold-sensitive, menthol-insensitive neurons in the murine sympathetic nervous
      system.
AB  - Several mechanisms have been implicated in underlying the perception of cold,
      most notably the activation of TRPM8 and TRPA1. We have used ratiometric calcium
      imaging to reveal a population of neurons in the superior cervical ganglion (SCG)
      of the mouse that respond to cooling but are insensitive to menthol. Furthermore
      we show that the expression of the mRNA transcripts encoding the recently
      identified noxious cold-sensitive channel TRPA1 but not TRPM8 are expressed in
      the SCG. These data provide evidence for a population of cold-responsive neurons
      in the SCG whose cold-responsiveness could be mediated by the activation of TRPA1
      and suggest that the sympathetic nervous system may play a direct role in
      mediating sympathetic responses to cold temperatures.

PMID- 15194862
TI  - Corticothalamic modulation on formalin-induced change of VPM thalamic activities.
AB  - Spontaneous activities of single cells were extracellularly recorded in ventral
      posterior medial (VPM) thalamus of anesthetized rats to characterize the
      corticothalamic modulation on formalin-induced changes of spontaneous thalamic
      firing. Formalin injected into the peripheral receptive field, dose-dependently
      induced the reversible facilitation of spontaneous activities of VPM. However,
      when the primary somatosensory (SI) cortex was inactivated by muscimol, the
      pattern of formalin-induced changes of VPM firing was altered. This altered
      responsiveness included both first and second phase of facilitated spontaneous
      activities. Bicuculline infused into SI cortex did not alter the pattern of
      formalin-induced thalamic changes. These results suggest that the pain reactivity
      of VPM thalamus may be modulated by cortex via corticothalamic pathway during the
      generation of inflammatory pain.

PMID- 15194863
TI  - The anti-migraine agent sumatriptan induces a calcium-dependent discharge in
      meningeal sensory neurons.
AB  - The anti-migraine agent sumatriptan constricts cerebral blood vessels, and also
      blocks neuropeptide release from meningeal sensory neurons. We investigated
      whether sumatriptan can also affect neuronal discharge, by recording the activity
      of dural primary afferent neurons during dural application of sumatriptan in
      anesthetized rats. Sumatriptan (0.24-24 microM) induced a concentration-dependent
      increase in ongoing discharge. The discharge occurred only in the presence of
      calcium. The suppressive effect of calcium removal was not a result of a general
      decrease in excitability, because calcium removal produced a pronounced increase
      in mechanically evoked discharge. The excitatory effect on dural afferent
      discharge might underlie the initial worsening of the headache that can occur
      following sumatriptan administration, prior to the subsequent onset of headache
      relief.

PMID- 15194864
TI  - Thalamic reductions in children with chromosome 22q11.2 deletion syndrome.
AB  - Children with chromosome 22q11.2 deletion syndrome (22q) suffer from physical and
      behavioral dysfunctions, including neuroanatomical anomalies, visuo-spatial
      processing deficits, and increased risk for psychopathology. Reduced total brain
      volume, parietal lobe volume, and cerebellar volumes, enlarged ventricles, and
      increased basal ganglia volumes have been reported. Since previous literature has
      related the pulvinar nucleus of the thalamus to visuo-spatial processing, we
      compared the thalamic volume in children with 22q to typically developing
      controls. Children with 22q showed a significant reduction of the thalamus
      compared with normally developing children, specifically in the posterior portion
      of the thalamus, including the pulvinar nucleus. These results provide the first
      evidence for a potential relationship between posterior thalamic reductions and
      the characteristic visuo-spatial deficits demonstrated in this group.

PMID- 15194865
TI  - Undernutrition and food rehabilitation effects on the locus coeruleus in the rat.
AB  - Perinatal nutrition plays a fundamental role on the morphological organization
      and function of a number of brain stem structures. Because little is known of the
      effects of perinatal undernutrition upon sexually dimorphic structures underlying
      reproductive behavior, the locus coeruleus morphology of 60-day-old male and
      female Wistar rats was analyzed. Perinatal food deprivation until weaning
      significantly decreased the volume and neuronal number of locus coerulus in male
      and female rats, while nutritional rehabilitation ameliorated these alterations
      in males but not in females. Data suggest that perinatal undernutrition
      interferes with the neuroendocrine mechanisms underlying the establishment of sex
      differences of the locus coeruleus.

PMID- 15194866
TI  - Distinct domains of Brn-3a regulate apoptosis and neurite outgrowth in vivo.
AB  - The Brn-3a transcription factor is critical for the normal development of the
      nervous system, promoting both neuronal survival and neurite outgrowth. By
      manipulating the Brn-3a gene in intact mice, we show that these two functions are
      separately controlled with an N-terminal domain being essential for neuronal
      survival, whereas the POU domain is essential for neurite outgrowth. Hence the
      two naturally occurring forms of Brn-3a, which either contain or lack the N
      terminal domain, are likely to play distinct roles in the nervous system.

PMID- 15194867
TI  - Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process.
AB  - Activated microglia are closely associated with neuronal damage in Alzheimer's
      disease. In the present study, neurons exposed to low concentrations of amyloid
      beta1-42, a toxic fragment of the amyloid-beta protein, were killed by microglia
      in a process that required cell-cell contact. Pre-treating microglia with
      polyclonal antibodies to the CD14 protein, or treating neurons exposed to amyloid
      beta1-42 with a CD14-IgG chimera, prevented the killing of amyloid-beta1-42
      damaged neurons by microglia. Moreover, microglia from CD14 null mice failed to
      kill amyloid-beta1-42 damaged neurons. Increased neuronal survival was
      accompanied by a significant reduction in the production of interleukin-6
      indicative of reduced microglial activation. These results indicate an important
      role for CD14 in the recognition and subsequent killing of amyloid-beta damaged
      neurons by microglia.

PMID- 15194869
TI  - Down-regulation of Bcl-2 in rat substantia nigra after focal cerebral ischemia.
AB  - After occlusion of the middle cerebral artery in rats, a robust neuronal loss
      occurs in the ipsilateral substantia nigra reticulata. In this study we have
      assessed whether degeneration of the substantia nigra is accompanied by changes
      in the expression of the anti-apoptotic protein Bcl-2. Neuronal loss was assessed
      by neuronal nuclei (NeuN) immunoreactivity. A significant decrease of Bcl-2
      expression was observed in the substantia nigra 12, 24 and 72 h after middle
      cerebral artery occlusion. These results suggest that the secondary neuronal loss
      in the substantia nigra could be related with the modification of proteins
      regulating programmed cell death. Exo-focal cell death may explain the appearance
      of neuropsychiatric symptoms that are not correlated with the primary site of
      lesion.

PMID- 15194868
TI  - Regulation of STAT3 by mu-opioid receptors in human neuroblastoma SH-SY5Y cells.
AB  - Heptahelical opioid receptors are implicated in the transcriptional regulation of
      neuronal development. Here we demonstrated that activation of mu-opioid receptors
      in human neuroblastoma SH-SY5Y cells led to the activation of signal transducer
      and activator of transcription 3 (STAT3), a transcription factor central to the
      regulation of numerous biological processes. The mu-opioid-induced activation of
      STAT3 is sensitive to receptor was further shown to pertussis toxin treatment and
      required JAK and Src tyrosine kinases, but not phosphatidylinositol 3-kinase.
      This mu-opioid-induced response was mediated via the extracellular signal
      regulated protein kinase in a Raf-1-independent manner. The present study
      provides a foundation to explore the importance of STAT3 signaling in the
      regulation of neuronal growth and differentiation by the mu-opioid receptor.

PMID- 15194870
TI  - Elevated adrenomedullin mRNA in lymphoblastoid cells from schizophrenic patients.
AB  - Adrenomedullin (ADM) is a 52 amino acid peptide with multiple physiological
      functions and wide tissue distributions including brain. Recently, elevated
      plasma levels of ADM were found in patients with schizophrenia, bipolar affective
      disorder and autism, suggesting the involvement of ADM in the pathophysiology of
      mental diseases. Using real-time quantitative PCR, we compared the ADM mRNA
      levels in lymphoblastoid cell lines between schizophrenic patients and controls.
      Male but not female schizophrenia patients had 2- to 3-fold higher ADM mRNA
      levels than controls (p<0.01). Our data support that ADM may be associated with
      the pathophysiology of schizophrenia, although the cause of the association needs
      further study.

PMID- 15194871
TI  - Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A.
AB  - The catalytic subunit of the serine-threonine protein phosphatase 2A (PP2A) was
      previously found to bind to the carboxyl domain of NMDA receptor (NMDAR) subunit
      NR3A. We now report that NR3A constitutively associates with the PP2A holoenzyme,
      but not the core enzyme in rat brain synaptic plasma membranes. We also
      identified critical amino acids in NR3A required for binding to PP2A. We
      performed alanine-scanning mutagenesis in the PP2A-binding domain of the NR3A C
      terminal (NR3Ac), then co-expressed the mutants together with the PP2A catalytic
      subunit in a yeast two-hybrid system and human embryonic kidney (HEK) 293 cells.
      We found that mutation of leucine 958, leucine 973 or histidine 974 or deletion
      of a spacer sequence of more than six amino acids between leucine 958 and
      histidine 974 disrupted the NR3A/PP2A interaction.

PMID- 15194872
TI  - Activation kinetics of T-type calcium channel by a path probability
      approximation.
AB  - We previously formulated dynamics of ion channel gates by the path probability
      method. In this study, we apply that theoretical approach to derive the
      activation rate kinetics of T-type calcium channel in thalamic relay neurons. We
      derive explicit expressions of the forward and backward rate constants and show
      that the proposed rate constants accurately capture form of the empirical time
      constant, and that they also provide its saturation to a constant value at
      depolarized membrane potentials. We also compare our derivations with linear and
      nonlinear thermodynamic models of rate kinetics obtained from the same calcium
      channel, and show that it is possible to capture saturation of the time constant
      for the depolarized membrane potentials by the only proposed rate constants.

PMID- 15194873
TI  - Corticosterone strongly increases the affinity of dorsal raphe 5-HT1A receptors.
AB  - The effects of corticosterone (10 mg/kg, s.c., 6 h) on dorsal raphe 5-HT1A
      autoreceptors have been studied in adrenalectomized rats with or without porcine
      galanin modulation. Adrenalectomy diminishes 5-HT1A autoreceptors affinity.
      Corticosterone increases 5-HT1A autoreceptor agonist affinity (+90%, p<0.001) in
      adrenalectomized rats. Galanin (10 nM) increases dorsal raphe 5-HT1A autoreceptor
      density (+65%, p<0.05) and its Kd value (+248%, p<0.05) only in adrenalectomized
      rats treated with corticosterone. Dorsal raphe glucocorticoid receptors
      activation by corticosterone may therefore lead to an increased signalling of 5
      HT1A autoreceptors that may become counteracted by galanin receptor activation.
      Glucocorticoids, by enhancing dorsal raphe 5-HT1A autoreceptor function, may
      therefore cause reduced 5-HT neuronal activity and thus lead to a depressive
      state.

PMID- 15194875
TI  - The level of nitric oxide in the cortex correlates well with brain
      lateralization.
AB  - The correlation between nitric oxide (NO) levels in the cortices and brain
      lateralization was investigated via the paw preference test in which three groups
      of mice (left-pawed, ambidextrous and right pawed) were selected. Results showed
      that the right cortices had higher NO levels than the left cortices for both
      normal and lipopolysaccharide-treated mice. There were significant differences in
      NO levels in the right/left cortices depending on the behavioral lateralization
      as expressed by paw preference. Finally, individual levels of NO in the
      right/left cortices correlated well with individual paw preference scores. The
      relationship was parabolic. The results suggest a strong relationship between NO
      asymmetries as well as the direction and the intensity of behavioral
      lateralization.

PMID- 15194874
TI  - Analysis of the expression, localization and activity of rat casein kinase
      1epsilon-3.
AB  - Casein kinase 1epsilon (CK1epsilon) is a serine/threonine protein kinase that has
      been suggested to participate in the regulation of various signaling pathways. In
      this report, we examined the tissue distributions of three putative alternatively
      spliced forms of rCk1epsilon by RT-PCR. This analysis confirmed that all three
      isoforms are expressed in rat tissues with different tissue-specific expression
      patterns. Immunohistochemical analysis showed that the intracellular distribution
      of rCK1epsilon-3 in neurons was broader than that of rCK1epsilon-1. Moreover, the
      kinase activity of the rCK1epsilon-3 protein differed from that of rCK1epsilon-1.
      These data suggest that rCK1epsilon-1 and rCK1epsilon-3 may play different
      functional roles.

PMID- 15194877
TI  - Antibody response can be conditioned using electroacupuncture as conditioned
      stimulus.
AB  - To establish a new model of conditioned enhancement of antibody production,
      electroacupuncture was served as the conditioned stimulus (CS) and an injection
      of a protein antigen ovalbumin as the unconditioned stimulus (UCS). After a
      CS/UCS pairing was made, re-exposure of animals to the CS alone resulted in
      significant conditioned enhancement of anti-ovalbumin antibody production. Even
      in deep sleep induced by anesthesia, the animals can associate a single CS with
      UCS and an antibody response can be elicited upon subsequent re-exposure to CS in
      the absence of exogenous antigen. No effect of electroacupuncture on anti
      ovalbumin antibody production was found.

PMID- 15194876
TI  - Selective modulation of microglial signal transduction by PACAP.
AB  - We have investigated the possible effect of pituitary adenylate cyclase
      activating polypeptide (PACAP) on signal transduction pathways associated with
      inflammatory activation of BV-2 mouse microglia cells. Pretreatment of the cells
      with PACAP resulted in a significant decrease in LPS- or IFNgamma-induced NO
      production as well as iNOS and IL-1beta mRNA levels. The inhibitory effect of
      PACAP appeared to be mediated through an increase in intracellular cAMP. PACAP
      inhibition of LPS-induced NO production was accompanied by inhibition of p38 MAPK
      activation, but not ERK, JNK, or NF-kappaB. IFNgamma-induced STAT-1 activation or
      IRF-1 induction was not significantly influenced by PACAP. Therefore, PACAP
      appears to suppress inflammatory activation of BV-2 microglia via specific
      inhibition of LPS-induced p38 MAPK pathway.

PMID- 15194878
TI  - Decrease of ventral tegmental area dopamine neuronal activity in nicotine
      withdrawal rats.
AB  - The present study was designed to examine the ventral tegmental area (VTA)
      dopamine neuronal activity in nicotine withdrawal rats by means of in vivo single
      unit extracellular recordings. Animals were treated with nicotine base (6
      mg/kg/day, s.c.) four times daily for 12 days. One day after the last nicotine
      administration, the firing rates of the VTA dopamine neurons were found to be
      significantly decreased. Following 2, 3, 5 and 10 days of nicotine withdrawal,
      however, the firing rates returned to the control levels. The number of
      spontaneously active dopamine cells was not altered at any time points. The
      results indicate that the VTA dopamine neuronal activity is reduced during the
      first day of nicotine withdrawal.

PMID- 15194879
TI  - The neural network for the mirror system and mentalizing in normally developed
      children: an fMRI study.
AB  - We performed fMRI measurements in normal children to clarify which cortical areas
      are commonly involved in the mirror system (MS) and mentalizing, which areas are
      specific for mentalizing, and whether children have the same neural networks for
      MS and mentalizing as adults. Normal children had the same neural networks for
      the MS and mentalizing as adults. Common activations were found in the superior
      temporal sulcus and the fusiform gyri, whereas mentalizing specific activation
      was found in the medial prefrontal, temporal pole and the inferior parietal
      cortices. We suggest that mentalizing might evolve from a capacity to detect the
      motion of agents and to infer intentions. Further, mentalizing might require self
      perspectives.

PMID- 15194880
TI  - A dissociation between real and simulated movements in Parkinson's disease.
AB  - Subcortical lesions have been simultaneously implicated in both real and
      simulated movement deficits. However, the analysis of the simulated opposition
      axis in precision grasping reveals that, in individuals with idiopathic bilateral
      Parkinson' disease motor imagery is impaired and that execution of overt
      movements is spared. This constitutes the first lesion observation congruent with
      the anatomical and functional dichotomy between real and simulated movements seen
      in experimental studies. These results underline the modality-specific nature of
      motor imagery and show that subcortical damage differentially impacts on motor
      activity.

PMID- 15194881
TI  - Neurons in the orbitofrontal cortex code both visual shapes and reward types.
AB  - It has been reported that neurons in the orbitofrontal cortex respond to visual
      cues that predict reward; however, few studies have focused on the neuronal
      correlates with the predicted reward type and the cue stimulus. In this study, we
      used a paired association task and introduced a reversal condition, in which cue
      stimuli that usually predict water were switched to predict juice, and vice
      versa. Of 111 cue-responsive neurons, 60 neurons (54.1%) depended on both the cue
      stimulus and the predicted reward type. The results suggest that neurons in the
      orbitofrontal cortex can code both visual and reward information, and contribute
      to the association between these two pieces of information according to the
      current combination of a cue stimulus and a reward type.

PMID- 15194882
TI  - Diurnal rhythms of tryptophan hydroxylase 1 and 2 mRNA expression in the rat
      retina.
AB  - Tryptophan hydroxylase is the first of four enzymes in the melatonin biosynthetic
      pathway. Recent studies have shown that there are two genes, Tph1 and Tph2, that
      encode tryptophan hydroxylase in mammals. In this study, we investigated which of
      the two genes is expressed in the rat retina. To that end, we measured Tph1
      (classical Tph) and Tph2 mRNA levels using real-time quantitative RT-PCR in the
      retina. Our data demonstrate that Tph1 mRNA is the prevalent form expressed in
      the retina; Tph2 mRNA is also present but the level is very low. We also measured
      Tph1 expression levels in the outer nuclear layer, inner nuclear layer, and
      ganglion cell layer by combining laser capture microdissection and real-time RT
      PCR. Tph1 mRNA is more abundant in the photoreceptors of the outer nuclear layer
      than in the inner nuclear layer or ganglion cell layer. Tph1 and Tph2 transcripts
      showed robust diurnal rhythms of abundance, with highest levels at night. Our
      results support the hypothesis that Tph1 is involved in melatonin synthesis in
      retinal photoreceptor cells.

PMID- 15194883
TI  - N250r: a face-selective brain response to stimulus repetitions.
AB  - We investigated event-related brain potentials elicited by repetitions of cars,
      ape faces, and upright and inverted human faces. A face-selective N250r response
      to repetitions emerged over right temporal regions, consistent with a source in
      the fusiform gyrus. N250r was largest for human faces, clear for ape faces, non
      significant for inverted faces, and completely absent for cars. Our results
      suggest that face-selective neural activity starting at 200 ms and peaking at 250
      300 ms is sensitive to repetition and relates to individual recognition.

PMID- 15194884
TI  - Angiogenic signaling in Alzheimer's disease.
AB  - Genome-wide expression profiling has identified significant alterations in the
      abundance of specific mRNA populations in Alzheimer's disease brain when compared
      to age-matched controls. Increases in the expression of certain brain genes are
      in contrast to the majority of expressed RNAs (55-67%), which are down-regulated.
      The data presented here shows, that at the level of mRNA abundance, there is
      marked up-regulation in a family of stress-related genes that have significant
      potential to promote angiogenesis. This supports the hypothesis of an advancement
      in angiogenic signaling in Alzheimer's disease brain. Angiogenesis, perhaps as
      the result of dysfunctional cerebral vasculature, may be both a consequence and a
      contributory factor to the etiopathology of the Alzheimer's disease process.

PMID- 15194885
TI  - Auditory stream segregation relying on timbre involves left auditory cortex.
AB  - An important aspect of auditory scene analysis is sequential grouping of sounds
      that are similar to one another in preference to sounds that follow one another.
      This grouping problem is captured by stream segregation tasks with alternating
      distinct sounds. We examined human auditory cortex activity with low noise fMRI
      in a stream segregation experiment relying on timbre differences of alternating
      harmonic tones (organ-like and trumpet-like). We found that stream segregation
      performance in comparison to monitoring a non-separable control stream increased
      activation exclusively in left auditory cortex and particularly in posterior
      areas. Our results suggest that left auditory cortex is selectively involved in
      this complex sequential task although the available cue for sequential grouping
      was timbre, usually attributed to right hemisphere analysis.

PMID- 15194886
TI  - nNOS is involved in estrogen mediated neuroprotection in neuroblastoma cells.
AB  - Estrogens exert neuroprotective activity in both in vivo and in vitro model
      systems. Herein, we report that both 17beta-estradiol and low concentrations of
      nitric oxide (NO) attenuate hydrogen peroxide (H2O2) induced toxicity in SK-N-SH
      cells, which express the neuronal nitric oxide synthase (nNOS). 17beta-estradiol
      rapidly induced an increase in NO levels. A nNOS inhibitor was able to block the
      neuroprotection of 17beta-estradiol. Cyclic guanylyl mono-phosphate (cGMP) also
      protected against H2O2 induced toxicity, while NO's protection was attenuated by
      ODQ, a soluble guanylyl cyclase (sGC) inhibitor. In SK-N-SH cells, the major
      estrogen receptor isoforms is estrogen receptor beta. Our current study suggests
      that increased activity of nNOS may be involved in the neuroprotection conferred
      by 17beta-estradiol.

PMID- 15194887
TI  - Reward sensitivity in impulsivity.
AB  - Impulsive individuals choose immediate small over delayed larger rewards,
      suggesting reward hypersensitivity. Single-unit studies have shown increased
      ventral tegmental activity to rewards and reward predictors and decreased
      activity when predicted rewards are withheld. The orbitofrontal ventral tegmental
      cortical target also responds to reward and expectation in single-unit and
      neuroimaging studies. The anterior P2a event-related potential component is a
      proposed index of reward-related orbitofrontal activity. In this reward
      prediction study in high and low impulsive subjects, the P2a localized to
      orbitofrontal cortex and was largest to non-predicted rewards and smallest in the
      absence of predicted rewards in subjects higher on self-reported impulsiveness,
      consistent with a P2a index of orbitofrontal reward processing and with reward
      hypersensitivity in impulsivity.

PMID- 15194888
TI  - Human cortical auditory motion areas are not motion selective.
AB  - The existence of a specialized mechanism supporting auditory motion processing in
      humans is a matter of debate in the psychophysical literature. Recent functional
      neuroimaging data appear to have resolved the debate in favor of a specialized
      motion system in that several studies have found cortical regions that seem to be
      motion selective. While all these studies contrast some form of moving auditory
      stimulation with a stationary stimulus, none have adequately controlled for the
      possibility that these areas are simply computing sound-source location and not
      motion per se: a moving stimulus varies in spatial location as well as motion,
      and so a system computing spatial location (and not motion) would be activated in
      response to both a moving and stationary sound source. To control for this
      possibility, ten subjects were scanned while listening to moving stimuli and
      while listening to stationary stimuli that varied randomly in spatial location.
      Consistent with previous imaging studies, we found that a motion stimulus when
      contrasted with rest (scanner noise) activated STG/planum temporale (bilaterally)
      and right parietal lobe. However, stationary stimuli presented at varying
      locations activated these regions equally well, arguing against the existence of
      specialized motion-processing areas in human cortex.

PMID- 15194889
TI  - Intraoperative optical imaging of human face cortical topography: a case study.
AB  - We used intrinsic signal optical imaging to obtain maps of human somatosensory
      cortex during electrocutaneous stimulation of the face during a neurosurgical
      procedure for epilepsy. We found that human face somatotopy is organized like the
      macaque or cebus monkey, with peri-orbital skin located medial to peri-buccal
      skin, and that cortical magnification in the human is comparable to that in non
      human primates. This study demonstrates that intrinsic signal imaging can be
      performed on humans during operative procedures with sufficient spatial
      resolution to reveal high-resolution topographic maps.

PMID- 15194890
TI  - Measuring and evaluating the effects of disease on workplace productivity.

PMID- 15194891
TI  - Health and work productivity assessment: state of the art or state of flux?
AB  - This article describes current models and methods for productivity measurement in
      health care research, examines different methods of data collection, and assesses
      the ease in which they may be used in research. Specific issues regarding the
      validity of current measurement tools and self-reported data are examined.
      Concerns about the interpretation of study results, international adaptation of
      work productivity questionnaires, and regulatory issues also are reviewed.

PMID- 15194892
TI  - Health-related lost productive time (LPT): recall interval and bias in LPT
      estimates.
AB  - We examined the effect of interview characteristics (ie, recall interval,
      interview version) on estimates of health-related lost productive work time
      (LPT). Three versions of a telephone interview were administered using 7-day and
      4-week recall periods. In a population-based survey, 7674 workers randomly were
      assigned to one of six interviews at contact; 615 participants received a follow
      up interview. We found strong evidence of under-reporting using a 4-week recall
      period and a not significant trend in over-reporting LPT using a 7-day recall
      period. Of the three interviews, version 3 could be administered most quickly, on
      average, and yielded the most discriminating estimates of LPT by health condition
      (ie, headache, allergic rhinitis, and cold/flu). Our data suggest that variation
      in relatively short recall periods influences estimates of health-related LPT. A
      2-week recall period may be optimal for minimizing overall reporting error but
      requires additional research to verify.

PMID- 15194893
TI  - Using the World Health Organization Health and Work Performance Questionnaire
      (HPQ) to evaluate the indirect workplace costs of illness.
AB  - This report presents an overview of methodological issues in estimating the
      indirect workplace costs of illness from data obtained in employee surveys using
      the World Health Organization Health and Work Performance Questionnaire (HPQ).
      The HPQ is a brief self-report questionnaire that obtains three types of
      information: screening information about the prevalence and treatment of commonly
      occurring health problems; information about three types of workplace
      consequences (sickness absence, presenteeism, and critical incidents); and basic
      demographic information. The report considers two sets of methodological issues.
      The first set deals with measurement. The rationale for the HPQ approach to
      measurement is described in this section. In addition, data are presented
      regarding the accuracy of HPQ measures, documenting that the HPQ has excellent
      reliability, validity, and sensitivity to change. The second set of
      methodological issues deals with data analysis. A number of analysis problems are
      reviewed that arise in using self-report nonexperimental survey data to estimate
      the workplace costs of illness and the cost-effectiveness of treatment.
      Innovative data analysis strategies are described to address these problems.

PMID- 15194894
TI  - The association of medical conditions and presenteeism.
AB  - A self-reported measure of four domains of work impairment based on the Work
      Limitations Questionnaire was completed by 16,651 employees of a large financial
      services corporation. Using a multivariate model to control for coexisting
      conditions, age, and gender, significant relationships were observed between
      medical conditions and patterns of impaired work performance. Depression was
      highly associated with work limitations in time management (odds ratio [OR] =
      2.05), interpersonal/mental functioning (OR = 2.50), and overall output (OR =
      2.24). Arthritis (OR = 1.56) and low back pain (OR = 1.32) were associated with
      physical function limitations. These same two conditions were associated with
      limitations in mental/interpersonal functioning but with low back pain having the
      higher odds ratio (OR = 1.54 vs. 1.22). These results suggest that worksite
      interventions (eg, disease management programs) should be tailored to the unique
      effects observed with specific medical conditions. More targeted programs could
      have important benefits for productivity in the workplace.

PMID- 15194896
TI  - Making the business case for health and productivity management.
AB  - Health and productivity management (HPM) is an important innovation for
      businesses concerned with rising health care costs. Like any innovation, however,
      it will not be adopted rapidly unless it is tailored to the needs of employers.
      For the last 6 years the Institute for Health and Productivity Management has
      studied the needs of American employers and sponsored employer driven case
      studies of health care and productivity. From these studies and the work of
      academic experts we have fashioned a set of programs to effectively communicate
      the advantages of health and productivity measurement and management. To make the
      business case for health and productivity management, researchers need to (1)
      demonstrate the relative advantage of HPM, (2) keep the evidence simple, (3) show
      that HPM is compatible with employer practices, and (4) communicate the results
      within and across corporate departments.

PMID- 15194895
TI  - The clinical and occupational correlates of work productivity loss among employed
      patients with depression.
AB  - Employers who are developing strategies to reduce health-related productivity
      loss may benefit from aiming their interventions at the employees who need them
      most. We determined whether depression's negative productivity impact varied with
      the type of work employees performed. Subjects (246 with depression and 143
      controls) answered the Work Limitations Questionnaire and additional work
      questions. Occupational requirements were measured objectively. In multiple
      regression analyses, productivity was most influenced by depression severity (P <
      0.01 in 5/5 models). However, certain occupations also significantly increased
      employee vulnerability to productivity loss. Losses increased when employees had
      occupations requiring proficiency in decision-making and communication and/or
      frequent customer contact (P < 0.05 in 3/5 models). The Work Limitations
      Questionnaire can help employers to reduce productivity loss by identifying
      health and productivity improvement priorities.

PMID- 15194897
TI  - Frequency of bed sharing and its relationship to breastfeeding.
AB  - Bed sharing has been promoted as facilitating breastfeeding but also may increase
      risks for sudden, unexpected infant deaths. This prospective cohort study was
      performed to determine the prevalence of adult and infant bed sharing and its
      association with maternal and infant characteristics. Demographic data were
      collected from 10,355 infant-mother pairs at birth hospitals in Eastern
      Massachusetts and Northwest Ohio, and follow-up data were collected at 1, 3, and
      6 months by questionnaire. Associations with bed sharing were estimated using
      odds ratios and 95% confidence intervals from multiple logistic regression models
      while adjusting for confounding variables. At 1, 3, and 6 months, 22%, 14%, and
      13% of infant-mother pairs shared a bed, respectively. On multivariate analysis,
      race/ethnicity and breastfeeding seemed to have the strongest association with
      bed sharing. These factors need to be considered in any comprehensive risk to
      benefit analysis of bed sharing.

PMID- 15194898
TI  - Patterns of agreement between parent and child ratings of emotional and
      behavioral problems in an outpatient clinical setting: when children endorse more
      problems.
AB  - This study examined clinically relevant patterns of agreement between parent and
      child ratings of child behavior problems and factors associated with these
      patterns. Subjects were 274 children, ages 11 to 18 years, and their parents.
      Overall agreement between parent-child ratings was modest. Twenty-five percent of
      parent-child pairs agreed children's behavior problems were clinically elevated
      ("both" group), 29% agreed problems were nonclinical ("neither" group), in 39% of
      pairs only parents reported clinically elevated problems ("parent only" group)
      and in 8% of pairs only children rated clinically elevated problems ("child only"
      group). Maternal stress and child age, but not child gender, were associated with
      parent-child agreement patterns. Children with depressive/mood disorders were
      more likely to be in the "child only" group than in any other group. This study
      discusses the importance of paying attention to child reports of elevated
      behavior problems, particularly when parents report that child behavior problems
      are not clinically elevated.

PMID- 15194899
TI  - Cultural influences on health care use: differences in perceived unmet needs and
      expectations of providers by Latino and Euro-American parents of children with
      special health care needs.
AB  - This study compares service use, perceived unmet needs, and expectations of
      providers of Latino and Euro-American families of children with disabilities
      enrolled in a Title V Program. Eighty-four families and 20 providers participated
      in open-ended, semistructured, and structured interviews. Latino families
      underused Title V services (p <.001). The Latino families were more likely to
      cite unmet needs in the following areas: an unresolved health problem (p <.05),
      rehabilitation therapy programs (p <.001), or need for more information or a
      support group (p <.001). The Euro-American families cited unmet needs in the
      following areas: lack of day care (p <.001), respite services (p <.001),
      recreational programs (p <.001), and home health aides (p <.007). Textual
      analysis of open interviews revealed that the two groups of families had
      different expectations of providers. Latino cultural values play a role in these
      differences, creating barriers for effectively communicating with providers and
      for meeting children's needs.

PMID- 15194900
TI  - Francis Bacon on adolescent burnout.

PMID- 15194901
TI  - The link between health-related quality of life and clinical symptoms among
      children with attention-deficit hyperactivity disorder.
AB  - Clinical research on attention-deficit hyperactivity disorder (ADHD) has begun to
      integrate measures of health-related quality of life (HRQL) as part of the
      overall assessment of treatment outcomes. This study examines the association
      between HRQL and measures of clinical symptoms of ADHD. Data were gathered from
      297 children and adolescents in an 8-week, randomized, double-blind, placebo
      controlled, clinical trial of atomoxetine treatment for ADHD. HRQL was assessed
      with the Child Health Questionnaire 50-item Parent Form. ADHD symptoms were
      assessed with the ADHD Rating Scale-IV; Parent Version and Clinical Global
      Impressions-ADHD-Severity. Associations between HRQL and clinical symptoms were
      assessed with correlations, analyses of variance with post hoc comparisons, and t
      tests. The Child Health Questionnaire 50-item Parent Form scales assessing
      psychosocial domains of HRQL were significantly negatively correlated with
      clinical measures. Improvement in clinical symptoms was associated with
      corresponding improvement in psychosocial aspects of HRQL. The findings suggest
      that HRQL instruments can add important information to efficacy measures in
      clinical trials of ADHD treatment.

PMID- 15194902
TI  - Adoption of romanian children in The Netherlands: behavior problems and parenting
      burden of upbringing for adoptive parents.
AB  - Seventy-two Dutch adoptive parents of 80 Romanian children completed the Child
      Behavior Checklist (CBCL), the Nijmegen Questionnaire for the Upbringing
      Situation (NQUS), and participated in a semistructured interview (response 83%).
      Thirty-four percent of the adopted children scored in the clinical range on
      Externalizing and 36 % on Total Problems scales. Significantly more children who
      were at least two years at placement and had stayed less than five years in the
      adoptive family received scores in the clinical range on almost all CBCL clinical
      clusters. Nevertheless, the adoptive parents judge their upbringing situation
      positive (NQUS).

PMID- 15194903
TI  - Disclosure model for pediatric patients living with HIV in Puerto Rico: design,
      implementation, and evaluation.
AB  - The American Academy of Pediatrics strongly encourages the disclosure of HIV
      status to school-age children and further recommends that adolescents know their
      HIV status. Limited information exists on the impact of disclosure. We designed
      and implemented a disclosure model hypothesized to be associated with healthy
      psychological adjustment and improved medication adherence. We report the model's
      design and implementation and results of a quasi-experimental study of the
      disclosure's effects on health care professionals (n = 16), caregivers (n = 39),
      and HIV-infected youth (n = 40) in Puerto Rico. Information was collected from
      youth, caregivers, and professionals by semistructured interviews and
      questionnaires. Most youth (70%) had feelings of normalcy 6 months post
      disclosure, and most also improved their adherence to therapy after disclosure as
      reported by both patients (58%) and caregivers (59%). Eighty-five percent of
      youth and 97% of caregivers considered disclosure a positive event for themselves
      and their families. Fewer health care professionals reported feelings of fear,
      discomfort, and insecurity after protocol participation.

PMID- 15194904
TI  - When Asperger's syndrome and a nonverbal learning disability look alike.

PMID- 15194905
TI  - The role of media in children's development: an ecological perspective.
AB  - This article reviews the literature on the role of media in children's physical,
      behavioral, and cognitive development. Using Bronfenbrenner's ecological
      perspective, the review focuses on the contexts of childhood that shape the
      availability and use of the media. The relationship between children's media
      uses/exposures and their ecological contexts are traced through three areas of
      the research literature: disordered eating, anti- and prosocial behaviors; and
      school achievement. While traditional and newer forms of electronic and print
      media are considered, the review gives particular attention to the ways in which
      ecological contexts shape the impact of television on children's development. The
      article offers evidence-based suggestions for parents concerning best practices
      for children's media use, and concludes with an agenda for future research in the
      field of children and media.

PMID- 15194906
TI  - The efficacy of hypnosis in the reduction of procedural pain and distress in
      pediatric oncology: a systematic review.
AB  - Children who suffer from cancer have to endure regular, painful medical
      procedures that are associated with a considerable degree of psychosocial
      distress. Hypnosis has been successfully employed in the management of pain and
      distress in the adult population, but is not well studied in pediatric
      populations. This review systematically evaluates the systematic research
      conducted in the field of procedure-related pain management in pediatric oncology
      within the context of a nationally agreed framework for the assessment of
      research evidence. It is concluded that there is not currently enough robust
      research evidence to recommend that hypnosis should form part of best practice
      guidelines for the management of procedure-related pain in pediatric oncology.
      However, there is sufficient evidence to justify larger-scale, appropriately
      controlled studies. A number of recommendations are made regarding future
      research.

PMID- 15194907
TI  - Francis Bacon on youthful thinking.

PMID- 15194909
TI  - In vivo measurement of gadolinium concentration in a rat glioma model by
      monochromatic quantitative computed tomography: comparison between gadopentetate
      dimeglumine and gadobutrol.
AB  - RATIONALE AND OBJECTIVES: Monochromatic quantitative computed tomography allows a
      nondestructive and quantitative measurement of gadolinium (Gd) concentration.
      This technique was used in the C6 rat glioma model to compare gadopentetate
      dimeglumine and gadobutrol. METHODS: Rats bearing late-stage gliomas received 2.5
      mmol/kg (392.5 mg Gd/kg) of gadopentetate dimeglumine (n = 5) and gadobutrol (n =
      6) intravenously before the imaging session performed at the European Synchrotron
      Radiation Facility. RESULTS: Monochromatic quantitative computed tomography
      enabled in vivo follow-up of Gd concentration as a function of time in specified
      regions of interest. Surprisingly, after gadobutrol injection, Gd concentrations
      in the center and periphery of the tumor were higher than those after
      gadopentetate injection, although identical in normal and contralateral area of
      the brain. CONCLUSION: The in vivo assessment of absolute Gd concentrations
      revealed differences in gadobutrol and gadopentetate dimeglumine behaviors in
      tumoral tissues despite injections in the same conditions. These differences
      might be attributed to different characteristics of the contrast agents.

PMID- 15194910
TI  - Phase I clinical evaluation of citrate-coated monocrystalline very small
      superparamagnetic iron oxide particles as a new contrast medium for magnetic
      resonance imaging.
AB  - RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of a newly
      developed MR contrast medium consisting of very small superparamagnetic iron
      oxide particles (VSOP) coated with citrate (VSOP-C184) in a clinical phase I
      trial. METHODS: A total of 18 healthy subjects received either VSOP-C184 (core
      diameter: 4 nm; total diameter: 7 +/- 0.15 nm; relaxivities in water at 0.47 T
      (T1) 18.7 and (T2) 30 L/(mmol*seconds)) at doses of 0.015, 0.045, or 0.075 mmol
      Fe/kg (n = 5 per dose) or placebo (n = 1 per dose) as intravenous injections.
      Physical status and vital parameters were recorded, blood samples were collected
      for clinical chemistry and relaxometry (0.94 T), and urinalyses were performed
      before and for up to 2 weeks after administration. RESULTS: No serious adverse
      events occurred. The most pronounced adverse events occurred in 2 subjects of the
      highest dose group 45-50 minutes after injection. These were a drop in blood
      pressure and a drop in oxygen saturation, which were considered to be possibly
      drug-related and rapidly resolved without medication. Otherwise, no relevant
      changes in vital and laboratory parameters were observed. The parameters of iron
      metabolism exhibited short-term, dose-related changes. The injection of VSOP-C184
      decreased T1 relaxation time of blood below 100 milliseconds for 18 minutes after
      a dose of 0.045 mmol [corrected] Fe/kg and for 60 minutes after 0.075 mmol
      [corrected] Fe/kg. CONCLUSIONS: The favorable data on the safety, tolerability,
      and efficacy of VSOP-C184 justify further clinical phase II and III trials as a
      contrast medium for MRI.

PMID- 15194912
TI  - 3.0 Tesla magnetic resonance angiography of endovascular aortic stent grafts:
      phantom measurements in comparison with 1.5 Tesla.
AB  - RATIONALE AND OBJECTIVES: This study evaluated different stent grafts by 3 T
      magnetic resonance angiography (MRA) with respect to lumen visibility,
      susceptibility-induced signal loss, and type of stent artifacts compared with 1.5
      T MRA in a phantom model. METHODS: Six different stent-grafts (tube: n = 3,
      bifurcated: n = 3) were evaluated by 3 T and 1.5 T MRA using a tube phantom. MRA
      was performed using T1-weighted sequences at both systems with comparable
      parameters (3T: TR 5.4/TE 2.0/FA 30 degrees, 1.5 T: TR 6.2/TE 2.2/FA 30 degrees).
      A blind study of the image quality, including artifacts, was performed by 3
      radiologists. Furthermore, signal-to-noise ratio (SNR) and contrast-to-noise
      ratio (CNR) values were calculated. Statistical analysis was performed with
      Student's t test (P < 0.05). RESULTS: One Elgiloy stent graft showed almost a
      complete intraluminal signal loss at 1.5 and 3 T. All other models could be
      evaluated by both systems by MRA, resulting in a favorable lumen visibility
      (score: 1) for prostheses made of nitinol. Scores for overall image quality and
      artifacts were the same for both MR systems. SNR and CNR values of the stented
      part of the vessel phantom increased from 320 +/- 33 to 618 +/- 40 and from 306
      +/- 34 to 596 +/- 40 at 3 T when compared with 1.5 T, resulting in a significant
      signal gain of 93% at the higher field strength. CONCLUSIONS: 3 Tesla MRA of
      aortic stent grafts in a phantom model demonstrates an increase in SNR and CNR
      when compared with 1.5 T. However, the magnitude of imaging artifacts as well as
      coherent intraluminal signal loss within the stent does not increase equally in
      both MR systems.

PMID- 15194911
TI  - Effects of dimeric radiographic contrast medium iotrolan on Swine renal arteries:
      comparison with monomeric contrast media iohexol and iomeprol.
AB  - RATIONALE AND OBJECTIVES: To investigate whether the lower incidence of
      vasodilatation upon vascular injection of iotrolan, as compared with monomeric
      contrast media, is solely the result of its isotonicity. MATERIALS AND METHODS:
      In an organ bath, isolated segments of swine renal arteries, uncontracted or
      precontracted by 10 microm phenylephrine, were incubated with increasing
      concentrations of iotrolan-300, iohexol-300, iomeprol-300, iomeprol-150, and
      mannitol solutions with the same molarity as the contrast media. RESULTS: At
      equal iodine and equimolar concentrations, iotrolan-300 relaxed precontracted
      arteries less than iohexol-300, iomeprol-300, and iomeprol-150, which was, like
      iotrolan-300, iso-osmolar to blood (P < 0.05). There was no significant
      difference between iohexol-300 and iomeprol-300 (P > 0.05). Iotrolan had no
      significant effect on the basal tonus of the vessels whereas iohexol and iomeprol
      induced a slight relaxation. CONCLUSIONS: Iotrolan, even at equimolar
      concentrations, resulted in less vasorelaxation than iohexol and iomeprol. Both
      osmolarity and chemotoxicity contribute to the greater vasorelaxant effect on
      swine renal artery of monomeric contrast media when compared to that of the
      nonionic dimeric contrast medium, iotrolan.

PMID- 15194913
TI  - Evaluation of semiautomated internal carotid artery stenosis quantification from
      3-dimensional contrast-enhanced magnetic resonance angiograms.
AB  - RATIONALE AND OBJECTIVES: The performance of a semiautomatic technique for
      internal carotid artery (ICA) stenosis quantification of the internal carotid
      artery in contrast-enhanced magnetic resonance angiography was evaluated.
      MATERIALS AND METHODS: The degree of stenosis of 52 ICAs was quantified by
      measuring the cross-sectional area along the center lumen line. This was
      performed both by 3 independent observers and the semiautomated method. The
      degree of stenosis was defined as the amount of cross-sectional lumen reduction.
      RESULTS: Agreement between the method and observers was good (weighted-kappa,
      kappaW = 0.89). Reproducibility of measurements of the semiautomated technique
      was better (kappaW = 0.97) than that of the observers (kappaW = 0.76), and the
      evaluated technique was considerably less time-consuming. CONCLUSIONS: Because
      the user interaction is limited, this technique can be used to replace an expert
      observer in 3-dimensional stenosis quantification of the ICA at CE-MRA in
      clinical practice.

PMID- 15194914
TI  - Functional evaluation of emphysema using diffusion-weighted 3Helium-magnetic
      resonance imaging, high-resolution computed tomography, and lung function tests.
AB  - PURPOSE: To assess the emphysematous enlargement of distal airspaces and
      concomitant large and small airway disease using diffusion-weighted Helium
      magnetic resonance imaging (MRI), high-resolution computed tomography (HRCT), and
      lung function tests (LFT). METHODS: Seven patients were examined after single
      lung transplantation (LTx) and 1 before double LTx for various forms of
      emphysema. Five patients after double LTx served as controls. Patients were
      assessed by Helium-MRI (apparent diffusion coefficient [ADC]), HRCT (mean lung
      density [MLD], emphysema index [EI]), and LFT. RESULTS: Transplanted lungs: mean
      ADC = 0.17 cm/s, MLD = -848 H, EI = 22%. Emphysematous lungs: mean ADC = 0.33
      cm/s, MLD = -922 H; EI = 54%. Good correlations were found between ADC and MLD (r
      = 0.6), EI (r = 0.8), intrathoracic gas volume (r = 0.7), forced expiratory
      volume in 1 second (r = 0.7), and forced expiratory flows (r = 0.7). In contrast,
      HRCT only provided moderate correlations with LFT (EI: r = 0.5; MLD: r [le] 0.4).
      CONCLUSION: In this initial study, He-MRI yield good correlations with HRCT and
      agrees better than HRCT with the functional characterization of emphysema
      regarding hyperinflation, large and small airway disease as provided by LFT.

PMID- 15194915
TI  - Comparison of contrast-enhanced magnetic resonance angiography and digital
      subtraction angiography in patients with chronic critical ischemia and tissue
      loss.
AB  - RATIONALE AND OBJECTIVES: To compare the ability of intra-arterial digital
      subtraction angiography (IA-DSA) and total runoff contrast-enhanced magnetic
      resonance angiography (CE-MRA) to demonstrate peripheral arterial anatomy,
      specifically in patients with chronic critical ischemia and tissue loss.
      MATERIALS AND METHODS: Twenty-three consecutive patients with chronic critical
      ischemia and tissue loss underwent CE-MRA and IA-DSA within 2 days. Two teams,
      consisting of an interventional radiologist and vascular surgeon who were blinded
      to each other's results, determined the number of named arteries (21 segments)
      and the presence of >/=50% stenosis or occlusion. RESULTS: Compared with IA-DSA,
      both teams detected significantly more arterial segments with CE-MRA, both above
      and below the knee (team 1: above knee 7.0 versus 5.2, P = 0.002, and below knee
      8.5 versus 5.4, P < 0.001; team 2: above knee 7.1 versus 5.4, P = 0.004, and
      below knee 8.3 versus 5.9, P < 0.001). Interobserver agreement between the 2
      teams with regard to presence of arteries and the presence of stenoses and/or
      occlusions yielded kappa values of 0.76 (95% confidence interval 0.71-0.81) for
      IA-DSA and 0.73 (95% confidence interval 0.66-0.80) for CE-MRA. Treatment was
      changed based on the CE-MRA findings in 8/23 (35%) patients. CONCLUSIONS: In the
      present study CE-MRA detected more patent arteries than IA-DSA in patients with
      chronic critical ischemia and tissue loss. CE-MRA can modify the choice of
      therapeutic strategy in these patients.

PMID- 15194916
TI  - Effect of triolein emulsion on the blood-testis barrier in cats.
AB  - PURPOSE: Although the blood-testis barrier (BTB) is beneficial physiologically,
      it acts as an obstacle to chemotherapy. We wished to determine whether a triolein
      emulsion could alter the permeability of the BTB in cats. MATERIALS AND METHODS:
      An emulsion of 0.05-mL triolein in 20 mL of saline was infused into the abdominal
      aorta just proximal to the branching of the renal arteries of each of 15 cats
      (embolic group). As controls, 12 cats were each similarly infused with 20 mL of
      normal saline (control group). Pre and postcontrast MR images were obtained 30
      minutes and 2 hours after embolization. The images were analyzed for the presence
      and degree of contrast enhancement (qualitative analysis), and the contrast
      enhancement ratios (CER) derived from one testis of each animal were compared and
      statistically analyzed by the mixed linear model (quantitative analysis).
      RESULTS: Contrast enhancement of the testis was observed in both groups at both
      time points, but it was more prominent in the embolic group. The CERs in the
      embolic group (0.63 at 30 minutes, 0.42 at 2 hours) were significantly higher
      than in the control group (0.36 at 30 minutes, 0.28 at 2 hours; P = 0.0001). In
      each group, the CERs at 2 hours were significantly lower than those at 30 minutes
      (P = 0.006). CONCLUSION: Intra-arterial infusion of triolein emulsion increased
      the permeability of the BTB. This result may be useful in future studies of BTB
      disruptions caused by fat emulsions.

PMID- 15194917
TI  - Time, distance, shielding, and radioprotectants.

PMID- 15194918
TI  - Radiation biology: concepts for radiation protection.
AB  - The opportunity to write a historical review of the field of radiation biology
      allows for the viewing of the development and maturity of a field of study,
      thereby being able to provide the appropriate context for the earlier years of
      research and its findings. The pioneering work of Muller, Sax, and McClintock,
      and many others, has stood the test of time. The idea that x-rays could damage
      the genetic material and result in interactions that could lead to gene mutations
      and a range of chromosomal alterations is now interpretable in terms of induced
      DNA damage and errors of DNA repair. The expanded idea that such genetic
      alterations can be induced by DNA damage that is produced by one or two tracks of
      ionizing radiation remains the mainstay of radiation biology. The impact of the
      more recent molecular approaches to unraveling the mechanism behind this simple
      concept has confirmed this fundamental observation. The remarkable advances have
      allowed for a fairly complete understanding of the specific types of DNA damage
      induced by ionizing radiations and the pivotal role played by the errors of
      repair of double-strand breaks. Given our considerably enhanced knowledge of the
      details of the DNA repair processes involved, misrepair is a very unlikely event.
      The role of potential confounders of the concept of dose-response (e.g.,
      bystander effects, genomic instability, and adaptive responses) is taking on a
      growing importance to the field. The evolving need is to begin to consider
      mechanistically-based dose-response models for cancer risk such that any
      potential impact of confounders on the response at low, environmental doses can
      be assessed. Thus, radiation biology research has always had a focus on how best
      to protect human health from radiation exposures and will continue to do so.

PMID- 15194919
TI  - Estimation of thyroid radiation doses for the hanford thyroid disease study:
      results and implications for statistical power of the epidemiological analyses.
AB  - Residents of eastern Washington, northeastern Oregon, and western Idaho were
      exposed to I released into the atmosphere from operations at the Hanford Nuclear
      Site from 1944 through 1972, especially in the late 1940's and early 1950's. This
      paper describes the estimated doses to the thyroid glands of the 3,440 evaluable
      participants in the Hanford Thyroid Disease Study, which investigated whether
      thyroid morbidity was increased in people exposed to radioactive iodine from
      Hanford during 1944-1957. The participants were born during 1940-1946 to mothers
      living in Benton, Franklin, Walla Walla, Adams, Okanogan, Ferry, or Stevens
      Counties in Washington State. Whenever possible someone with direct knowledge of
      the participant's early life (preferably the participant's mother) was
      interviewed about the participant's individual dose-determining characteristics
      (residence history, sources and quantities of food, milk, and milk products
      consumed, production and processing techniques for home-grown food and milk
      products). Default information was used if no interview respondent was available.
      Thyroid doses were estimated using the computer program Calculation of Individual
      Doses from Environmental Radionuclides (CIDER) developed by the Hanford
      Environmental Dose Reconstruction Project. CIDER provided 100 sets of doses to
      represent uncertainty of the estimates. These sets were not generated
      independently for each participant, but reflected the effects of uncertainties in
      characteristics shared by participants. Estimated doses (medians of each
      participant's 100 realizations) ranged from 0.0029 mGy to 2823 mGy, with mean and
      median of 174 and 97 mGy, respectively. The distribution of estimated doses
      provided the Hanford Thyroid Disease Study with sufficient statistical power to
      test for dose-response relationships between thyroid outcomes and exposure to
      Hanford's I.

PMID- 15194920
TI  - The combined impact on doses to man of multiple, authorized, radionuclide
      discharges for the year 1999 reaching the upper river thames, uk.
AB  - Before issuing a new or revised authorization to discharge liquid radioactive
      waste to a river, past and current practice has been to assess the impact of each
      discharge on a site-by-site basis. This paper reports an assessment of the
      combined impact of all the (year 1999) authorized discharges in the upper River
      Thames (UK) catchment. A modification of the PC-CREAM model, using parameters
      specific to the upper River Thames, was used to estimate "potential doses" to the
      population, using the authorized discharge activity for each of the discharges as
      the main driving variable. The main purpose of this study was to investigate the
      difference in doses between single and multiple discharges in the Thames. A
      partial validation of the model against measurements was also carried out as a
      secondary investigation. The source term of the upper Thames consisted of 90
      authorized discharges for 86 sites, made up of three nuclear licensed sites, 36
      industrial discharges, 25 research organizations, 20 hospitals and two
      miscellaneous organizations. Of the authorized discharges, nuclear sites
      constituted 67% of the total activity in authorizations to discharge; hospitals
      16%, research organizations 13%, and industry only 3%. Three radionuclides made
      up 96% of the total authorized discharge activity: tritium-74%; Tc-15%, and C-7%.
      No other single radionuclide constituted more than 1.5% of the total activity.
      All of the discharges from non-nuclear sites were via a sewage works so that, in
      total, only 39 discrete discharges to the river were included in the model. For
      the purposes of the assessments, it was assumed that all discharges were at the
      authorized limits (rather than using actual discharge). Even with this maximizing
      assumption, all the calculated potential doses from the combined source terms
      were significantly less than the radiation dose limit of 1 mSv y for a member of
      the public. The highest estimated potential doses were investigated further to
      identify the major pathways. Ingestion of fish was the main pathway in several
      river stretches and in the highest case constituted 97% of the dose. In a few
      stretches, external irradiation from the riverbank or ingestion of drinking water
      were the main pathways, but the potential contribution was a very small
      percentage (<1%) of the dose limit for members of the public. An investigation of
      the reasons for the relatively high potential doses resulting from fish showed
      that the radionuclide with the largest contribution was P. Three factors had a
      major effect on potential dose estimations in these circumstances: the fish
      consumption rate, the P concentration factor and the use of P in some cases to
      represent radionuclides authorized for discharge as "any other radionuclide,
      except alpha emitters." Using the precautionary principle, all authorized
      activity in the latter designation was modeled as the radionuclide which would
      produce the highest dose to humans.

PMID- 15194922
TI  - Biologic monitoring for urinary uranium in gulf war I veterans.
AB  - Biologic monitoring for total uranium in urine of Gulf War I veterans concerned
      about past exposure to depleted uranium (DU) has been offered by the Departments
      of Veterans Affairs and Defense since the late 1990's. DU, a component of U.S.
      munitions and tank armor, was first used during that conflict. Two hundred and
      twenty-seven veterans submitted samples for analysis from January 2000 through
      December 2002, which included a 24-h urine sample for determination of total
      urinary uranium concentration and completed questionnaires describing their
      wartime exposure experiences. Thirty questionnaire items characterizing DU
      exposure opportunities were collapsed into 19 exposure categories. Urine uranium
      (U) results were stratified into low and high uranium groups with 0.05 microg U g
      creatinine as the cut point. Exposure scenarios in the high and low uranium
      groups were similar in frequency and type with only the presence of retained
      shrapnel being predictive of a high urine uranium value, as found in the first
      phase of this surveillance of 169 veterans performed prior to 2000. Twenty-two
      veterans exhibited U levels in the high range. Isotopic analysis, available for
      21 of these 22, revealed that all but three of these samples contained natural
      and not depleted uranium. These three participants had retained DU shrapnel as a
      result of their past injuries. Thus, even with an enlarged cohort, elevated urine
      uranium values in the absence of retained DU fragments are unlikely. The utility
      of isotopic analysis to more fully characterize uranium biomonitoring results is
      also demonstrated.

PMID- 15194921
TI  - Difficulty in dislodging in vivo fixed radiostrontium.
AB  - Many trials based on the basic phenomena of isotopic dilution, adsorption, ion
      exchange, chelation, etc., have been attempted for the decorporation of
      radiostrontium, particularly Sr, after its entry in the in vivo system. We have
      recently demonstrated a non-isotopic carrier effect of some common calcium salts
      (calcium = 9 mg mL) to reduce the whole body retention of radiostrontium, if
      administered within 2 h after radiostrontium exposure and furthermore once daily,
      in rats, supplemented with calcium fortified diet. However, 25-30% of
      radiostrontium (compared to 50-60% in untreated animals) was still found to be
      retained in the animal even after 2 wk of treatment. Trial of some simple
      interventional measures, which would not adversely affect the animal metabolism,
      like pyrophosphate and magnesium sulfate, sodium citrate, chitin (a bio
      absorbent), crown ether (a metal-chelator), and ammonium chloride, was therefore
      attempted to dislodge this remaining radiostrontium by switching over these
      animals to normal diet and subjecting them to different lines of treatment with
      these simple interventions through diet and drinking water separately for a
      further 4 wk. However, this remaining portion of radiostrontium is fixed in the
      bone and is difficult to dislodge.

PMID- 15194924
TI  - The U.S. Environmental Protection Agency's assessment of risks from indoor radon.
AB  - The U.S. Environmental Protection Agency has updated its assessment of health
      risks from indoor radon, which has been determined to be the second leading cause
      of lung cancer after cigarette smoking. This risk assessment is based primarily
      on results from a recent study of radon health effects (BEIR VI) by the National
      Academy of Sciences. In BEIR VI, the National Academy of Sciences fit empirical
      risk models to data from 11 cohorts of miners, and estimated that each year about
      20,000 lung cancer deaths in the U.S. are radon related. A summary, abstracted
      from the technical report, is given of the EPA's risk assessment results and
      methods, including some modifications and extensions to the approach used in BEIR
      VI. Results include numerical estimates of lung cancer deaths per unit exposure,
      which had not been provided in BEIR VI.

PMID- 15194923
TI  - Depleted uranium dust from fired munitions: physical, chemical and biological
      properties.
AB  - This paper reports physical, chemical and biological analyses of samples of dust
      resulting from munitions containing depleted uranium (DU) that had been live
      fired and had impacted an armored target. Mass spectroscopic analysis indicated
      that the average atom% of U was 0.198 +/- 0.10, consistent with depleted uranium.
      Other major elements present were iron, aluminum, and silicon. About 47% of the
      total mass was particles with diameters <300 microm, of which about 14% was <10
      microm. X-ray diffraction analysis indicated that the uranium was present in the
      sample as uranium oxides-mainly U3O7 (47%), U3O8 (44%) and UO2 (9%). Depleted
      uranium dust, instilled into the lungs or implanted into the muscle of rats,
      contained a rapidly soluble uranium component and a more slowly soluble uranium
      component. The fraction that underwent dissolution in 7 d declined exponentially
      with increasing initial burden. At the lower lung burdens tested (<15 microg DU
      dust/lung) about 14% of the uranium appeared in urine within 7 d. At the higher
      lung burdens tested (~80-200 microg DU dust/lung) about 5% of the DU appeared in
      urine within 7 d. In both cases about 50% of that total appeared in urine within
      the first day. DU implanted in muscle similarly showed that about half of the
      total excreted within 7 d appeared in the first day. At the lower muscle burdens
      tested (<15 microg DU dust/injection site) about 9% was solubilized within 7 d.
      At muscle burdens >35 microg DU dust/injection site about 2% appeared in urine
      within 7 d. Natural uranium (NU) ore dust was instilled into rat lungs for
      comparison. The fraction dissolving in lung showed a pattern of exponential
      decline with increasing initial burden similar to DU. However, the decline was
      less steep, with about 14% appearing in urine for lung burdens up to about 200
      microg NU dust/lung and 5% at lung burdens >1,100 microg NU dust/lung. NU also
      showed both a fast and a more slowly dissolving component. At the higher lung
      burdens of both DU and NU that showed lowered urine excretion rates, histological
      evidence of kidney damage was seen. Kidney damage was not seen with the muscle
      burdens tested. DU dust produced kidney damage at lower lung burdens and lower
      urine uranium levels than NU dust, suggesting that other toxic metals in DU dust
      may contribute to the damage.

PMID- 15194925
TI  - Measuring method of undamaged samples for the radiation levels of decorative
      building materials.
AB  - When natural radionuclides are well distributed in materials, there is a fixed
      interrelationship between activities in any part of the material and the surface
      flux of alpha and beta rays. Placing an alpha detector on the surface can
      estimate radionuclide activities in the materials without damaging samples. This
      paper studied the relationship between gamma ray specific activities of natural
      radionuclides and alpha ray surface flux of decorative building materials. The
      results show that when the surface alpha ray activities of granite are less than
      0.0052 Bq cm, or the surface alpha ray activities of polished tiles are less than
      0.0082 Bq cm, their internal and external exposure indexes are in the range of
      "A" limits of national criteria of China, Limit of radionuclides in building
      materials. Because there is a great difference between the radioactive levels of
      the surface glaze and the matrix of color-glazed tiles, the natural radionuclides
      are not well distributed in color-glazed tiles, and the ratio between the alpha
      surface activity and the gamma ray activity in unit mass is not fixed. The
      surface alpha ray flux of materials cannot be used to estimate the internal and
      external exposure indexes of color-glazed tiles.

PMID- 15194926
TI  - Effect of a grounded object on radon measurement using AlphaGUARD.
AB  - ABSTRACT-: The effects on radon concentration measurement of a grounded object
      near the opening of a cylindrical ionization chamber were studied using
      AlphaGUARD. AlphaGUARD comes with a flow measurement adapter that fits on the
      front of the AlphaGUARD ionization chamber. If the adapter nozzle is grounded,
      the radon concentration is falsely measured at 0 Bq m. A metal connector for use
      between the AlphaGUARD and the air duct wall was manufactured in our laboratory.
      When the connector is grounded, the radon concentration is again falsely measured
      as 0 Bq m. If the nozzle or connector is ungrounded, the AlphaGUARD measures
      radon concentration accurately. Health Phys.

PMID- 15194927
TI  - Mobile phones in the hospital: improved mobile communication and mitigation of
      EMI concerns can lead to an overall benefit to healthcare.
AB  - There is a growing trend in hospitals throughout the world to incorporate mobile
      phones and other wireless technology to offer more efficient, cost effective, and
      higher quality healthcare. Misunderstanding of mobile phone systems,
      electromagnetic interference with medical devices, and available management
      solutions, however, has led to a wide range of inconsistent hospital policies.
      Recent reviews and commentaries on the subject have provided inconsistent and in
      some cases factually incorrect information that confuses the issue. At one
      extreme, unmanaged use of mobile phones in areas where life-critical medical
      devices are in operation can result in atypical situations that may place
      patients at risk. At the other extreme, overly-restrictive policies based upon
      speculation may deny benefits by acting as an obstacle to technology. Overly
      restrictive policies may also not address growing and legitimate communication
      needs of patients and visitors in times of crisis. While it may not be feasible
      for hospitals to manage every mobile phone handset that is randomly brought into
      their facility without certain limits on use in areas where life-critical devices
      are commonly in operation, restrictions are not usually necessary throughout the
      entire facility. Restrictive policies are also better facilitated when easily
      accessible areas are designated where mobile phone use is encouraged. Controlled
      mobile phone systems for use by doctors and staff for hospital-specific
      communication, by contrast, can operate compatibly throughout the entire hospital
      facility with appropriate system design and management, even in sensitive areas,
      and such systems have already been deployed in a number of hospitals throughout
      the U.S.

PMID- 15194928
TI  - Solubility characterization of airborne uranium from a uranium recycling plant.
AB  - Solubility profiles of uranium dusts in a uranium recycling plant were determined
      by performing in vitro solubility tests on breathing zone air samples conducted
      in all process areas of the processing plant. The recycling plant produces high
      density shields, closed end tubes that are punched and formed from uranium sheet
      metal, and high-fired uranium oxide, which is used as a catalyst. The recycled
      uranium is cut and melted in a vacuum furnace, and part of the molten uranium is
      poured into molds for further processing. Air samples were taken in process areas
      under normal working conditions. The dissolution rate of the uranium in a
      simulant solution of extracellular airway lining fluid (Gamble's solution) was
      then determined over the next 28 d. Airborne uranium in the oxide section of the
      plant was found to be highly insoluble with 99% of the uranium having a
      dissolution half time in excess of 100 d. The solubility of the airborne uranium
      in other areas of the facility was only slightly more soluble with over 90% of
      the airborne uranium having dissolution half times in excess of 90 d.

PMID- 15194931
TI  - The genetic family history assessment in gastroenterology nursing practice.
AB  - Genetic factors influence the risk for disease and the overall health of persons
      throughout their lifespan. The systematic collection of family history
      information in a three-generation format is the most important approach for the
      identification of individuals with a genetic susceptibility to most common
      diseases, and applying genetic concepts in healthcare. The detailed family
      history can play a critical role in diagnosis, lay the foundation for accurate
      risk assessment, and be used to develop subsequent education, individualized
      monitoring and management of the disease, and prevention measures. The purpose of
      this article is to familiarize nurses with why, what, how, when, where and for
      whom a genetic family history assessment should be used in gastroenterology
      nursing practice. Risk assessment specific to the development and prevention of
      colorectal cancer will be described.

PMID- 15194932
TI  - Clinical risk: discharging patients with no-one at home.
AB  - This article reports a study designed to assure if guidelines for discharge
      planning actually promoted optimal patient safety following endoscopic
      procedures. A flow chart was drafted to include discharge planning at the time of
      referral, immediately preprocedure, and postprocedure. A telephone survey was
      carried out postprocedure to see if patients were deemed to be safe at home,
      document pain and discomfort levels, and note if they thought they could have
      managed without their caregiver. Further education of endoscopists and nurses in
      the outpatient department was necessary to emphasize to patients preprocedure the
      need for a responsible adult to stay overnight following the procedure and to
      identify patients who may not be able to meet this requirement. The telephone
      survey showed a significant number of patients experienced a postprocedure issue.
      Planning and reviewing guidelines for patient discharge postendoscopically has
      significantly reduced potential problems and promoted safe practice for patients
      postprocedure.

PMID- 15194933
TI  - Reasons for poor colonic preparation with inpatients.
AB  - In patients often require repeated colonoscopy as a result of poor colonic
      preparation. A study of 101 inpatients was conducted to determine the most
      effective bowel preparation strategies. Results suggest patients on certain
      medications and with certain medical histories react differently to bowel
      preparation. Patients with diabetes, renal disease, chronic obstructive pulmonary
      disease, or chronic constipation should receive a more aggressive preparation to
      obtain optimal results. Likewise, patients who are taking narcotics and laxatives
      need to be identified and can be expected to require additional preparation to be
      properly cleansed. Clear liquid diet prior to the administration of the bowel
      preparation was the only diet modification that affected quality of preparation.
      The optimal bowel preparation was a 6-liter Golytely preparation along with a
      secondary preparation (e.g., tap water enema, Fleets enema, Dulcolax tablets).
      Results showed a 50% satisfactory rating of bowel preparation was achieved in
      patients who took 3/4 to all of their preparation. The best results were obtained
      when the colonoscopy procedure was conducted within 6-11 hours of bowel
      preparation completion.

PMID- 15194934
TI  - Detecting a small bowel tumor via wireless capsule endoscopy: a clinical case
      study.
AB  - Tumors of the small intestine account for fewer than 5% of gastrointestinal
      neoplasms. Approximately 20% of small bowel neoplasms are gastrointestinal
      stromal cell tumors, a spectrum of mesenchymal tumors of the gastrointestinal
      tract that range from benign to highly malignant. Diagnosis of gastrointestinal
      stromal cell tumors is usually incidental, given their rarity and the limitations
      of traditional endoscopy and radiology studies in visualizing the small
      intestine. The advent of wireless capsule endoscopy has improved the definitive
      diagnosis of small bowel disorders. This article outlines the course of diagnosis
      and treatment for a patient who presented to our hospital with severe anemia and
      demonstrates the role of capsule endoscopy in identifying the causes of obscure
      gastrointestinal bleeding.

PMID- 15194935
TI  - Sleep apnea and moderate sedation.
AB  - Anesthesiologists have recognized the increased risk inherent in obstructive
      sleep apnea patients, yet studies on sleep apnea and endoscope procedures are
      limited. As more procedures are being done in clinics, ambulatory care centers,
      and procedures labs, nurses are now performing moderate sedation on this high
      risk patient population with little information to guide them. Of concern, 80-90%
      of the people who have obstructive sleep apnea are unaware they have it. This
      article will explore the definition of sleep apnea, identify risk factors, and
      review literature that relates to obstructive sleep apnea and moderate sedation
      procedures. A resource list of agencies, internet sites, and references are
      included. This review of obstructive sleep apnea can assist gastroenterology
      nurses administering sedation to better recognize and monitor this high risk
      group.

PMID- 15194938
TI  - Ayurved for digestion.

PMID- 15194939
TI  - Making pharmacokinetics clinically useful. Part II: Distribution.

PMID- 15194940
TI  - Slicing through self-doubt.

PMID- 15194941
TI  - Cholera outbreak in 1854. An early use of statistical methods.

PMID- 15194945
TI  - SGNA position statement. Statement on the use of sedation and analgesia in the
      gastrointestinal endoscopy setting.

PMID- 15194946
TI  - Molecular pathology of filamin A: diverse phenotypes, many functions.
AB  - Defective cell signalling during embryonic development is a well-recognized modus
      operandi of mutations in genes that lead to congenital malformations. This
      signalling occurs within and around a dynamic cellular cytoskeleton that is
      continuously under modulating influences during morphogenesis. Evidence is
      accumulating to suggest that filamin A, an actin-binding protein and the product
      of one of three paralogous filamin genes in humans, represents a key molecule
      that connects such signalling events to modulation of the cellular cytoskeletal
      architecture. This review summarizes the clinical consequences of mutations in
      the gene encoding filamin A, FLNA. The molecular pathology of this gene suggests
      remarkable functional pleiotropy, indicative of diverse roles in embryonic, fetal
      and postnatal development.

PMID- 15194947
TI  - Spondyloepimetaphyseal dysplasia (Hall type) with laryngeal stenosis: a new
      diagnostic feature?
AB  - The spondyloepimetaphyseal dysplasias (SEMD) are a large, genetically
      heterogeneous group of disorders of variable severity, which are classified
      according to their clinical and radiological features. SEMD with multiple
      dislocations (Hall type) has been recently delineated (MIM 603546). This
      condition is characterized by striking epiphyseal and metaphyseal changes in the
      long bones, joint laxity, multiple dislocations of the large joints including the
      knees, and dysmorphic features including a short and upturned nose with a
      depressed nasal bridge and midface hypoplasia. An autosomal dominant mode of
      inheritance has been suggested. We report a further patient with a mild form of
      this condition and persistent inspiratory stridor secondary to laryngeal
      stenosis. This complication has been reported in previous reports and is
      certainly an important diagnostic feature.

PMID- 15194948
TI  - Expanding the phenotypic spectrum of Lenz-Majewski syndrome: facial palsy, cleft
      palate and hydrocephalus.
AB  - We report a sporadic case of Lenz-Majewski syndrome (LMS) with newly recognized
      manifestations including facial palsy, cleft palate and hydrocephalus developing
      later in infancy. The clinical course of the patient and neuroimaging studies are
      described. Increased intracranial pressure was recognized and treated early with
      the aim of preventing neurological morbidity.

PMID- 15194949
TI  - Cenani-Lenz syndactyly in a patient with features of Kabuki syndrome.
AB  - We report a 5 9/12-year-old male with Cenani-Lenz syndactyly (CLS). He presented
      with three malformed digits on each hand and bilateral 2,3 partial cutaneous toe
      syndactyly. The expression of this presumed autosomal recessive disorder is
      variable and has been confused with split hand foot malformation (SHFM). Not all
      CLS patients show the typical 'spoon hand' configuration originally described.
      Affected CLS patients show a disorganized appearance of the phalanges with some
      degree of syndactyly/oligodactyly, in addition to metacarpal and carpal fusions.
      Radioulnar synostosis may be present. Cases lacking radioulnar synostosis may
      show proximal dislocation of the radial heads. The distal limb anomalies seen in
      our patient resemble other reported CLS patients. Radiographic evaluation showed
      a disorganized appearance of the phalanges, a 'kissing delta phalanx' of one
      proximal phalanx, metacarpal fusions, carpal coalitions and posterior subluxation
      of the radial heads. Clinical examination revealed features suggestive of Kabuki
      syndrome including large, prominent ears, sparse, medially flared and arched
      eyebrows, wide palpebral fissures, long eyelashes, and oligodontia with flat head
      'screwdriver-shaped' incisors, in addition to persistent finger and thumb-tip
      pads. The faces of CLS patients are rarely shown or described. However, some
      patients in published reports have large, prominent ears. A recent report
      suggested midfacial dysmorphism in two patients with CLS (). Although the
      findings of CLS with features of Kabuki syndrome in our patient may be
      coincidental, the faces of CLS patients need to be carefully evaluated and
      described to determine if there is a distinctive accompanying facial phenotype.

PMID- 15194950
TI  - Oculoauriculovertebral spectrum phenotype caused by an unbalanced
      t(5;8)(p15.31;p23.1) rearrangement.
AB  - We present two siblings with oculoauriculovertebral spectrum phenotype (Goldenhar
      syndrome) and an unbalanced translocation t(5;8)(p15.31;p23.1) resulting in
      monosomy for the region 5p15.31 to 5pter and trisomy for 8p23.2 to 8pter region.
      The father was a carrier of the balanced rearrangement
      46,XY,t(5;8)(p15.31;8p23.1). To our knowledge this is the first report of
      Goldenhar phenotype in association with an unbalanced (5p;8p) translocation.

PMID- 15194951
TI  - Mosaic monosomy 14: clinical features and recognizable facies.
AB  - A 1-year-old child with clinical features of monosomy 14 is reported. She has
      dysmorphic facial features including ocular colobomata, dolichocephaly and
      microcephaly, retinal pigmentation, severe seizures, fair curly hair and tapering
      fingers. There was severe mental retardation. This is the first reported case of
      severe mosaic monosomy 14, with up to 30% mosaicism. A recognizable facial
      gestalt is present in children with 14q deletions or partial monosomy 14, as well
      as susceptibility to infection, feeding difficulties, seizures and retinal
      pigmentation.

PMID- 15194952
TI  - Noonan syndrome and systemic lupus erythematosus: presentation in childhood.
AB  - Noonan syndrome is a relatively common disorder which is usually diagnosed in
      childhood because of the presence of distinctive facial features, short stature
      and cardiac anomalies. Previous clinical studies of Noonan syndrome have
      suggested that autoimmune disorders may be another possible manifestation and
      there have been two recent reports of Noonan syndrome patients with systemic
      lupus erythematosus. In this report we present an 11-year-old boy with Noonan
      syndrome and systemic lupus erythematosus, supporting the previous observations
      of an association between these two conditions.

PMID- 15194954
TI  - Widespread capillary malformation associated with global developmental delay and
      megalencephaly.
AB  - Although port wine stains are seen in 0.3% births, widespread cutaneous capillary
      malformations are unusual and an association with static gliosis has not been
      previously reported. This is a report of a 3-year-old boy with a fixed widespread
      capillary naevus (port wine stain), megalencephaly and global developmental, and
      features of gliosis on brain magnetic resonance imaging (MRI).

PMID- 15194953
TI  - Scalp lesions in Turner syndrome: a result of lymphoedema?
AB  - Lymphoedema and skin naevi are common in children with Turner syndrome (TS).
      Lymphoedema in the early stages of fetal life is thought to cause several of the
      phenotypic characteristics in patients with TS such as nuchal folds and pterygium
      colli. We present two patients with TS who have unusual lesions on the scalp. The
      first patient had an oval circumscribed lesion. Two biopsies were obtained from
      the lesion. Increased numbers of collagen fibres were seen in the reticular
      dermis suggesting the diagnosis of connective tissue naevus. The second patient
      presented with an area with skin folds on the scalp, similar to cutis verticis
      gyrata. Although unusual in TS, both lesions could be considered as resolving
      stages of lymphoedema. We suggest that karyotyping should be performed in cases
      of female infants presenting with similar lesions.

PMID- 15194955
TI  - Short stature, sensorineural deafness, ocular abnormalities and severe mental
      retardation in two siblings. A new syndrome?
AB  - We describe a brother and sister with craniofacial dysmorphism, short stature,
      relative obesity, sensorineural deafness, multiple pigmented naevi and severe
      mental retardation. One sibling had keratoconus and the other had an iris
      coloboma. Dysmorphic features included brachycephaly, hypotelorism, small mouth,
      thin lips, pterygium colli, broad chest, widely spaced nipples and cutaneous
      second and third toe syndactyly. The children demonstrate some features of Noonan
      syndrome, but we believe that they have a different and distinctive phenotype. We
      have reviewed similar cases in the literature and discuss these in the context of
      our cases, who may have a previously undescribed syndrome.

PMID- 15194956
TI  - A case of Fryns syndrome without diaphragmatic hernia and review of the
      literature.
AB  - We report on a child with Fryns syndrome who showed a characteristic coarse
      hirsute facial appearance, bilateral cleft lip and palate, cardiac and renal
      anomalies, dilated bowel and distal limb abnormalities. However, diaphragmatic
      hernia, which is considered a cardinal feature in this condition, was absent in
      our patient. The parents were consanguineous supporting autosomal recessive
      inheritance.

PMID- 15194957
TI  - Mosaic trisomy 15 in a short girl with hemihypotrophy and mental retardation.
AB  - We describe a girl with short stature, mild mental retardation, hemihypotrophy,
      atrial septal defect I, bilateral branchial cleft fistulas and abnormal skin
      pigmentation. Growth hormone deficiency and other frequent causes of short
      stature were excluded. Blood karyotype was investigated twice. In one sample an
      additional marker chromosome was found in one of 53 analysed metaphases, which
      could not be further characterized, whereas a second investigation showed a
      normal female karyotype. Cytogenetic studies in skin fibroblasts revealed a
      mosaic trisomy 15. Although mosaic trisomy 15 is a rare finding the diagnosis
      must be considered in the presence of pigmentary changes, body asymmetry, short
      stature and other minor dysmorphic signs even if blood karyotype is normal.

PMID- 15194958
TI  - Trisomy 16 in a mid-trimester IVF foetus with multiple abnormalities.
AB  - An 18 week foetus with multiple system abnormalities was found to have full
      trisomy 16. This appears to be only the third reported case surviving into mid
      gestation; typically, this common aneuploidy dies post-implantation. Similarities
      exist in the abnormalities found in the three cases suggesting that there is a
      'surviving' trisomy 16 phenotype. It is characterised by: absent hemidiaphragm,
      pulmonary hypoplasia/aplasia, major cardiac defect, small chest, vertebral and
      rib defects, cystic kidneys, absent gall bladder, multiple spleens and
      imperforate anus, together with cleft palate, nuchal webbing/cystic hygroma,
      microcephaly, marked dysmorphic facial features and dorsiflexed great toe.

PMID- 15194959
TI  - 22q13 deletion syndrome with central diabetes insipidus: a previously unreported
      association.
AB  - We describe a two-year-old girl with 22q13 deletion syndrome (MIM # 606232), 46,
      XX, de l (22) (q13.31). ish del (22) (q13.31) (TUPLE 1+,ARSA-). The patient has
      hypotonia, normal growth, severe expressive language delay, mild mental
      retardation, and minor dysmorphic facial features. In addition, she had central
      diabetes insipidus that was diagnosed at age two days and resolved at age 27
      months. To our knowledge, this association has not been reported previously.
      Infants with hypotonia, or those suspected to have this syndrome should have high
      resolution chromosome analysis and fluorescent in situ hybridization (FISH)
      studies or molecular analysis, since the chromosomal deletion may be subtle and
      may go undetected on routine cytogenetic studies. The association of 22q13
      deletion syndrome with central diabetes insipidus is reported for the first time.

PMID- 15194960
TI  - Bilateral cleft lip and palate, hypertelorism and hypoplastic toes.
AB  - We report on a 23-month-old boy with bilateral cleft lip and palate, marked
      hypertelorism, frontal bossing and severe bilateral, asymmetric hypoplasia of
      toes. The mother used bisoprolol, naproxen and sumatriptan for migraine until the
      fifth postmenstrual week of pregnancy. We suggest that this patient's features
      represent a previously undescribed entity of as yet unknown aetiology.

PMID- 15194961
TI  - Neuroblastoma, maternal valproic acid use, in-vitro fertilization and family
      history of mosaic chromosome 22: coincidence or causal relationship?
AB  - We report a family with co-occurring disorders including neuroblastoma in the
      first child conceived by in-vitro fertilization with history of sodium valproate
      use by the mother during pregnancy and mosaic trisomy 22 in the third child. We
      discuss the possibility of an association between the disorders but conclude that
      no firm aetiological connection can be established between the different
      disorders in this family.

PMID- 15194962
TI  - Physical modalities and wound care.

PMID- 15194971
TI  - Adding vitamin C to the wound management mix.

PMID- 15194972
TI  - 2004 Medicare legislation and regulations impact wound management.

PMID- 15194973
TI  - Cutaneous manifestations of HIV: a primer.
AB  - PURPOSE: To provide physicians and nurses with an overview of the characteristics
      and treatments for skin lesions associated with HIV/AIDS. TARGET AUDIENCE: This
      continuing education activity is intended for physicians and nurses with an
      interest in identifying and managing skin lesions in patients with HIV/AIDS.
      OBJECTIVES: After reading the article and taking the test, the participant will
      be able to: 1. Identify the characteristics of skin lesions associated with
      HIV/AIDS. 2. Identify treatment options for skin lesions associated with
      HIV/AIDS.

PMID- 15194975
TI  - Quantifying fibrosis in venous disease: mechanical properties of
      lipodermatosclerotic and healthy tissue.
AB  - OBJECTIVES: To quantify the mechanical properties of medioposterior bulk calf
      tissue in patients with lipodermatosclerotic venous-insufficient tissue and
      individuals with apparently healthy tissue using a novel ultrasound indentometry
      method, and to identify parameters with the potential for quantifying fibrosis in
      subsequent studies. DESIGN: 2-group, quasi-experimental design SETTING: Soft
      Tissue Mechanics Laboratory, University of Pittsburgh, Pittsburgh, PA
      PARTICIPANTS: 9 healthy and 9 venous-insufficient individuals aged 35 to 85 years
      INTERVENTIONS: Ultrasound indentometry and computed tomography (CT) of calf
      tissue MAIN OUTCOME MEASURES: Between group differences and associations among
      quasi-linear viscoelastic (QLV) tissue parameters and CT descriptors MAIN
      RESULTS: Established the accuracy, validity, and reliability of the QLV model and
      ultrasound indentometry method. Demonstrated a range of significant differences
      between the groups (P <.020 to P <.004) for selected QLV parameters. Also found
      significant correlations between CT measures of fibrosis and dermal thickness and
      QLV elastic measures (P <.034 to P <.005). CONCLUSION: Attempts to quantify
      fibrosis in lipodermatosclerosis have included histologic exams,
      palpation/pitting, durometer readings, and imaging techniques, but these efforts
      have failed to produce a clinically practical, noninvasive method. A novel
      ultrasound indentometry method was used to acquire in vivo data from which tissue
      parameters were derived. These data support the further development of ultrasound
      indentometry as a method to quantify fibrosis in venous disease.

PMID- 15194977
TI  - By the numbers: Braden score interventions.

PMID- 15194976
TI  - Direct health care costs of 4 common skin ulcers in New Mexico Medicaid fee-for
      service patients.
AB  - OBJECTIVE: To determine health care costs associated with pressure ulcers, ulcers
      of the lower limbs, other chronic ulcers, and venous leg ulcers from the New
      Mexico Medicaid fee-for-service program perspective. DESIGN: Retrospective
      analysis of claims database MAIN OUTCOME MEASURES: Physician visit, hospital, and
      prescription costs were determined for New Mexico Medicaid patients with a
      primary and/or secondary diagnosis of 1 of 4 identified categories of skin ulcers
      from January 1, 1994, through December 31, 1998. Costs were determined in terms
      of mean and median annual cost per patient and total costs per year. Zero dollar
      claims were included within the cost calculations. All costs are expressed in
      2000-dollar values. MAIN RESULTS: Mean annual physician visit costs per patient
      ranged from $71 (standard deviation [SD] = $60) for venous leg ulcers in 1998 to
      $520 (SD = $1228) for pressure ulcers in 1996. Mean annual hospital costs per
      patient ranged from $266 (SD = $348) for other chronic ulcers in 1998 to $15,760
      (SD = $30,706) for pressure ulcers in 1998. Mean annual prescription costs per
      patient ranged from $145 (SD = $282) for other chronic ulcers in 1998 to $654 (SD
      = $1488) for pressure ulcers in 1994. CONCLUSION: The New Mexico Medicaid fee-for
      service system incurred a total cost of approximately $11.6 million (in 2000
      dollars) from 1994 through 1998 for the treatment of the 4 categories of skin
      ulcers studied. The data showed that the majority of wounds were coded as
      pressure ulcers, which had the highest associated costs.

PMID- 15194978
TI  - Mapping and ablation of ventricular fibrillation.
AB  - Sudden cardiac death frequently results from ventricular fibrillation (VF). While
      VF is frequently the eventual mode of death in patients with abnormal ventricular
      substrates, it has also been described in patients with structurally normally
      hearts. Until recently, the management of patients who have survived sudden
      cardiac death has focused on treating the consequences by implantation of a
      defibrillator. However, such therapy remains restricted in many countries, is
      associated with a prohibitive cost to the community, and may be a cause of
      significant morbidity in patients with frequent episodes or storms of arrhythmia.
      Evidence emerging from the study of fibrillation both in the atria and the
      ventricle suggests an important role for triggers arising from the Purkinje
      network or the right ventricular outflow tract in the initiation of VF. Initial
      experience in patients with idiopathic VF and even those with VF associated with
      abnormal repolarization syndromes (LQT or Brugada syndrome) or myocardial
      infarction suggests that long term suppression of recurrent VF may be feasible by
      the elimination of these triggers. With the development of new mapping and
      ablation technologies, and greater physician experience, catheter ablation of VF,
      with the ultimate aim of curing such patients at risks of sudden cardiac death,
      may not be an unrealistic goal in the future.

PMID- 15194979
TI  - Diagnostic coronary arteriography in the interventional era: a combination of
      technical advancements, new mental attitude, and improved skill.
AB  - Over the past 20 years, coronary angiography has taken many important steps
      forward in enhancing its ability to detect coronary artery disease. The major
      improvements in techniques and materials for percutaneous transluminal coronary
      angioplasty and stenting have led to the progressively widespread use of
      percutaneous revascularization in an increasing number of patients, including
      complex and multi-vessel disease. It is commonly believed that this improved
      interventional prospect has changed the way diagnostic coronary artery
      angiography is performed among the invasive and interventional cardiology
      community. The complete development of the coronary tree with more angulated
      views, the use of intracoronary nitrates in cases of moderate stenosis or spastic
      coronary trees and adequate balloon and stent sizing, improved magnification of
      acquisition, when a precise assessment of bifurcation or ostial stenosis is
      required or when a stented coronary segment is evaluated, and finally an
      interventional mental attitude, are an integral part of the invasive
      cardiologist's tools and skills matching the major technical improvements in
      equipment and materials.

PMID- 15194980
TI  - Procedural and long-term results of sirolimus-eluting stent in patients at high
      risk for restenosis.
AB  - AIM: In-stent restenosis still affects 10-50% of long-term outcome after
      percutaneous coronary intervention (PCI). Large clinical trials have shown that
      sirolimus-eluting stents (SES) have reduced restenosis rate to 0-9% in lesions at
      low-moderate risk. The aim of this study was to evaluate long-term clinical and
      angiographic outcome of SES in a real world population, at very high risk of
      restenosis. METHODS: Ninety lesions at high risk of restenosis (lesion length >20
      mm, target vessel diameter <2.5 mm, in-stent diffuse restenosis, total occlusions
      and complex lesions on bypass grafts and bifurcations) were treated in 75
      patients. A follow-up was scheduled at 6 months. RESULTS: Restenosis rate was
      16.6% with a focal pattern of presentation in most cases. Subacute in-stent
      thrombosis occurred in 2.2%. Resteno-sis occurred mainly in small vessels,
      diabetic patients and in vessels previously treated with brachytherapy.
      CONCLUSION: The treatment of lesions at high risk of restenosis with SES is safe
      with a low restenosis rate at follow-up. An aggressive and prolonged antiplatelet
      regimen is mandatory because of high subacute in-stent thrombosis rates.

PMID- 15194981
TI  - Increased mortality after coronary stenting in patients treated with clopidogrel
      without loading dose. Evidence from a meta-analysis.
AB  - AIM: Clopidogrel is an established alternative to ticlopidine in addition to
      aspirin after coronary stenting because of its hematologic safety, but its
      efficacy in comparison to ticlopidine is debated. We thus systematically reviewed
      randomized trials comparing clopidogrel vs ticlopidine after coronary stenting.
      METHODS: Medline (1/1986-10/2003), BioMed Central, Central, Current Contents,
      LILACS and mRCT were searched. Fixed-effect relative risks (RR [95% CI]) were
      computed, and the primary end-point was death. Heterogeneity tests and subgroup
      analyses were performed according to loading vs non-loading clopidogrel scheme.
      RESULTS: Five trials were retrieved (2 962 patients, average follow-up 7.4
      months). In 3 studies both clopidogrel and ticlopidine were started with a
      loading dose, in 1 trial clopidogrel was administered without loading, and in 1
      trial clopidogrel could be administered with or without loading. Overall analysis
      (p for heterogeneity=0.12) showed a non-significant trend toward increased
      mortality in patients treated with clopidogrel (38/1 649 [2.3%]) vs ticlopidine
      (22/1 313 [1.7%], RR=1.64 [0.94-2.86], p=0.080). After stratification,
      clopidogrel with loading was associated with non-significantly lower mortality
      rates than ticlopidine (9/959 [0.9%] vs 13/798 [1.6%], RR=0.68 [0.29-1.63],
      p=0.39). Instead, clopidogrel without any loading yielded a highly significantly
      3-fold increased risk of death than ticlopidine (29/690 [4.2%] vs 9/515 [1.7%],
      RR=2.9 [1.45-6.1], p=0.0029). Similar results were obtained for the rate of death
      or non-fatal myocardial infarction. CONCLUSION: This meta-analysis suggests that
      clopidogrel treatment including a loading regimen is equivalent or may even be
      superior to ticlopidine after coronary stenting. However, current evidence shows
      conversely that clopidogrel therapy in the absence of a loading dose is
      associated with a significantly higher risk of death or myocardial infarction.

PMID- 15194982
TI  - Effects of rotational atherectomy with a reduced burr-to-artery ratio on coronary
      no-reflow.
AB  - AIM: The use of rotational atherectomy in addition to standard percutaneous
      coronary interventional procedures, although it improves coronary blood flow
      dynamics by improving vessel geometry, is often associated with distal
      embolization and the no-reflow phenomenon. We sought to evaluate the safety and
      effectiveness of a burr size/reference artery diameter (RAD) ratio <0.7 in
      rotational atherectomy in order to reduce the distal embolization and then to
      analyze the procedural and peri-procedural no-reflow phenomenon. METHODS: Between
      March 1999 and May 2003, 50 consecutive patients with a chronic stable angina
      lasting more than 3 months underwent rotablator atherectomy, adjunctive stent im
      plantation (primary coronary stenting, PCS) or plain old balloon angioplasty
      (POBA) in case of de novo lesions or in stent restenosis, respectively. We
      analyzed the target vessel myocardial blush grade and the troponin I, creatine
      kinase and CK-MB values at 1.6 and every 8 h during the first day and then daily
      until discharge. RESULTS: Procedural success was achieved in all 50 patients
      (mean age 55+/-11 years; 45 males, 5 females). Quantitative angiography revealed,
      in the group treated with PCS, an increase in minimal lumen diameter (MLD) from
      0.88+/-0.39 mm at baseline to 1.4+/-0.63 mm after rotablator (p<0.01) to 2.85+/
      0.9 mm after stent implantation (p<0.01). On the other hand, for the group
      treated with POBA, the MLD changed from 1.8+/-0.32 mm at baseline to 2.2+/-0.54
      mm after rotablator (p=0.6) to 3.28+/-0.91 mm after adjunctive balloon
      angioplasty (p<0.01). No statistically significant changes have been observed
      between myocardial blush grade and enzymes between baseline and after the
      procedure. CONCLUSION: Rotablator atherectomy with a reduced burr size/RAD ratio
      is a safe and effective interventional procedure without any peri-procedural no
      reflow phenomenon.

PMID- 15194983
TI  - Amplatzer Muscular VSD Occluder for catheter closure of a 20 mm hypertensive
      patent ductus arteriosus. A case report and literature review.
AB  - The treatment of very large patent ductus arteriosus (PDA) was thought to be
      solely surgical. There is not enough experience in transcatheter closure of large
      hypertensive PDA. In this report, successful catheter closure of a large and
      hypertensive ductus using the Amplatzer Muscular VSD Occluder and a literature
      review are presented.

PMID- 15194984
TI  - [Usefulness of magnetic resonance imaging for the diagnosis of acute myocarditis.
      A case of acute myocarditis as myocardial infarction-like].
AB  - According to the Dallas criteria, myocarditis is defined histologically as an
      inflammatory process involving the myocardium with an inflammatory infiltrate and
      myocyte necrosis or damage. Clinically, myocarditis is an insidious disease that
      is usually asymptomatic and commonly underdiagnosed. Infact, the symptoms are
      often non-specific and the majority of cases recover fully with no sequelae. At
      present, endomyocardial biopsy remains the gold standard for the diagnosis of
      myocarditis, despite its limited sensitivity and specificity. However, the lack
      of an association between biopsy evidence of myocarditis and the presence of
      autoantibodies in patients with clinical signs of myocarditis, the paucity of the
      positive biopsy findings in large cohorts of patients with suspected myocarditis,
      the potential discordance between clinical and histologic features and the
      inherent limitation of histologic diagnosis, suggest that the diagnosis shouldn't
      be based on histologic examination alone. The magnetic resonance imaging (MRI)
      with gadolinium can be useful to visualize the localization, activity and extent
      of inflammation and may be a powerful noninvasive diagnostic tool in acute
      myocarditis. Infact, MRI achieves a 100% sensitivity and a 90% specificity. We
      report the case of a 31-year-old male patient with an acute myocarditis with
      electrocardiographic manifestations like to acute myocardial infarction, whose
      diagnosis was based on the clinical signs and on the characteristic pattern of
      the MRI with paramagnetic contrast. The MRI with gadolinium is suggested as
      noninvasive study to support the diagnosis of acute myocarditis in the correct
      clinical setting.

PMID- 15194985
TI  - An intercoronarty communication between the circumflex and the left anterior
      descending coronary artery with coronary artery disease. A difference from
      collateral coronary vessels.

PMID- 15194986
TI  - Coronary artery anomalies and superimposed coronary artery disease: intimate or
      simply coexisting?

PMID- 15194987
TI  - Life-threating thrombus across patent foramen ovale free-floating in the left
      ventricular outflow tract.

PMID- 15194988
TI  - Discrete aneurysm of the circumflex coronary artery in a patient with aneurysm of
      the atrial septum and patent foramen ovale.

PMID- 15194989
TI  - Molecular biology of atrial fibrillation.
AB  - Atrial fibrillation (AF) is the most common arrhythmia seen in medical practice.
      Despite the overall advance in the treatment of the cardiac dysrhythmias with the
      introduction of radiofrequency ablation, therapeutic options in AF have remained
      largely unchanged and aimed at controlling the heart rate and anticoagulation.
      New surgical and ablation techniques are being developed. While promising, they
      are still extremely laborious and available only to a handful of patients. The
      limited success in the therapy of AF is in part due to our poor understanding of
      its molecular pathophysiology. Molecular research of AF has focused on 2 main
      fields, identification of the genes that play a role in the initiation of the
      disease and altered gene expression during the disease state. These studies are
      aimed at identifying not only the triggering factors in the acute form but also
      those that perpetuate the arrhythmia and convert it into a chronic form. Advances
      in genetics and molecular biology will likely give new insights into the
      development of the disease and improve our understanding and therapeutic options.

PMID- 15194990
TI  - Oesophageal electrical cardioversion of atrial fibrillation.
AB  - Atrial fibrillation is the most common cardiac arrhythmia and the most frequent
      cause of hospitalization and utilization expense among all heart diseases. Taking
      into account persistent atrial fibrillation we know that, in order to cardiovert
      persistent atrial fibrillation, external direct current cardioversion is the
      method most frequently used to restore sinus rhythm. But external cardioversion
      has also some limitations: it requires high energy direct current shocks so that
      patients have to be anaesthetised, which means a dedicated apparatus and place to
      adequately assist the patients. The oesophageal cardioversion is an alternative
      method to restore sinus rhythm, which could obviate some of these limitations of
      external cardioversion. Compared to external cardioversion oesophageal one has
      lower defibrillation impedance and requires lower energies to restore sinus
      rhythm, increasing for the same energy level, success rate. Using low energy
      shocks, a mild sedation is sufficient to make the procedure well tolerated by
      most of patients. Other 2 important advantages coming from low energy shocks are
      the safety in patients with pacemaker or implantable cardioverter-defibrillator
      and the availability of a back up atrial pacing. Oesophageal cardioversion is not
      indeed a new technique. Looking at literature, studies in animals and in humans
      have been performed since the 60s, assessing feasibility, effectiveness and
      safety of such a procedure. The oesophageal-precordial cardioversion is usually
      performed on an outpatient regimen, resulting in a very cost-effective method to
      cardiovert patients with persistent atrial fibrillation, which may definitely
      represent a real alternative technique to external cardioversion.

PMID- 15194991
TI  - Contemporary approach to ablation of paroxysmal atrial fibrillation.
AB  - Pulmonary veins have been shown to play an important role in the initiation and
      maintenance of paroxysmal atrial fibrillation. Seg-mental ostial isolation of the
      pulmonary veins results in cure in about 2/3 of the patients. This approach does
      not address non-pulmonary venous triggers of atrial fibrillation or the
      importance of the left atrium itself. Left atrial circumferential ablation has
      also been shown to be efficacious in patients with paroxysmal atrial
      fibrillation. This approach seems to address not only the various triggers of
      atrial fibrillation but also the left atrial substrate. Recently, a randomized
      study compared the 2 strategies and showed that left atrial ablation is superior
      to segmental ostial isolation. This review will highlight the anatomy and
      electrophysiology of the pulmonary veins, and the possible mechanisms by which
      they initiate and maintain paroxysms of atrial fibrillation. Segmental ostial
      isolation of the pulmonary veins and left atrial ablation will be compared as
      well.

PMID- 15194992
TI  - Ablation of atrial fibrillation: localizing triggers, mapping systems and
      ablation techniques.
AB  - Ablation to eliminate atrial fibrillation (AF) is a therapy in evolution.
      Approaches to the ablation appear to be currently divided into 2 major strategies
      anatomic versus electrically guided. In addition in using an electrically guided
      techniques debate remains whether a targeted approach should be used, whether
      exit block should be documented, and whether all non pulmonary vein triggers
      should be targeted. This review highlights the different ablation strategies and
      identifies a systematic approach to ablation of pulmonary and non pulmonary vein
      triggers that we have adapted at our institution. The role of intracardiac echo,
      trigger provocation and localization and the use of 3-D mapping systems in AF
      ablation are defined.

PMID- 15194993
TI  - Atrial fibrillation and cardioembolic stroke.
AB  - The most disabling consequence of atrial fibrillation (AF) is stroke. In the
      elderly, AF is the single most important cause of stroke. The risk of stroke is
      increased at least 6-fold in subjects with AF. Strokes in patients with AF are in
      general severe, associated with higher risk of fatality and prone to early and
      long-term recurrence. The cardiac origin of stroke can be strongly suspected by
      anamnesis, clinical examination and findings on neuroimaging. Paroxysmal AF is an
      important cause of brain embolism, that is often difficult to document. Risk
      factors for stroke in AF include: previous embolism (including previous transient
      ischaemic attack (TIA), or ischaemic stroke), age >65 years, structural cardiac
      disease, rheumatic or other significant valvular heart disease, valvular
      artificial prosthesis, hypertension, heart failure and significant left
      ventricular systolic dysfunction, diabetes and coronary disease. All AF patients
      with TIA or stroke have a formal indication for long-term anticoagulation. Only
      patients without risk factors or with contraindications to warfarin should be put
      on aspirin. Treating 1 000 patients with AF for 1 year with oral anticoagulants
      rather than aspirin would prevent 23 ischaemic strokes while causing 9 major
      bleedings. Despite its enormous preventive potential, oral anticoagulants are
      underused in AF, because treating physicians often have lack of knowledge about
      trials and guidelines, underestimate the benefits and overestimate the risks
      associated with continuous oral anticoagulation. The introduction of
      anticoagulants that do not need frequent control tests, such as ximelagatran,
      will increase the proportion of AF patients with risk factors for stroke who are
      anticoagulated. There is no evidence to support routine immediate anticoagulation
      in acute ischeamic stroke associated with AF.

PMID- 15194994
TI  - Antithrombotic therapies for stroke prevention in atrial fibrillation.
AB  - Atrial fibrillation (AF) is now regarded as the arrhythmia for which patients are
      hospitalized the most frequently, an arrhythmia that is responsible for
      significant morbidity and mortality. Of particular importance is that the
      arrhythmia is associated with a significant incidence of thromboembolism which
      may induce disabling and incapacitating strokes, sometimes fatal. In the past, it
      was thought that in patients with AF restoration and maintenance of sinus rhythm
      prevent the development of strokes, a presumption that has not been vindicated by
      controlled clinical trials. On the other hand, over many decades, it has been
      established that appropriate anticoagulation especially with warfarin can reduce
      stroke rate in nonvalvular AF by about 70%, and mortality by 26%. Aspirin reduces
      stroke rate by 26%, mortality by about 10%. Thus, in AF oral anticoagulants have
      become the focal point of therapy for the prevention of strokes and the safety
      and efficacy of such a therapy has been established by controlled clinical
      trials; moreover, the subsets of patients with AF in whom anticoagulation is
      mandatory have been defined on the basis of defined risk factors. Warfarin is now
      the anticoagulant of choice although its limitations are considerable in terms of
      drug-drug interactions, narrow range of therapeutic index requiring strict
      monitoring of intensity of anticoagulation, among other limitations which
      influence compliance of therapy with the agent. In this review, the continuing
      role of warfarin in the prevention of stroke in patients with AF is discussed as
      a background for the development of newer anticoagulants. The issue is of
      particular importance in the older patients, in whom the development of safer
      antithrombotic therapies remain a major challenge. In this context, the potential
      role of the direct thrombin inhibitors hold promise for the future and the
      evolving data on leading compounds of this class which may be competitive with
      warfarin are discussed.

PMID- 15194995
TI  - The role of pacemaker and defibrillator therapy for the treatment of atrial
      fibrillation.
AB  - The development of pacemaker and defibrillator technology has provided a new
      direction for the treatment of recurrent symptomatic atrial fibrillation (AF).
      Sophisticated atrial preventative pacing algorithms are now available and newer
      implantable devices have additional atrial termination pacing therapies. Results
      from studies examining the effectiveness of atrial anti-tachycardia pacing
      algorithms have suggested that 50% of atrial arrhythmias (including AF) can be
      pace terminated using these devices. The atrial defibrillator has recently been
      shown to be a safe and effective method of restoring and maintaining sinus rhythm
      in selected patients. Symptoms and quality of life can be improved and some
      patients demonstrate increased sinus rhythm duration (sinus rhythm begets sinus
      rhythm) with repeated use of the device. This review article discusses the
      current application of device therapy for the management of AF and explores some
      of the merits and limitations of these devices.

PMID- 15194996
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 health care 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 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- 15194997
TI  - Molecular imaging: seeing the invisible beyond the "hot spot".

PMID- 15194998
TI  - Classification of ischemic dysfunctional myocardium combining perfusion
      quantification and contractile reserve evaluation using nitrate-enhanced gated
      single photon emission computed tomography with dobutamine test.
AB  - AIM: In patients with ischemic cardiomyopathy, the differentiation of
      dysfunctional myocardium in scarred versus hibernating is oversimplified. We
      evaluated a more complex classification using an imaging technique currently
      employed for viability detection, having as reference the postrevascularization
      outcome of dysfunctional segments. METHODS: In 35 patients, we performed gated
      single-photon emission computed tomography (SPECT) (resting and nitrate-enhanced
      study, the latter with baseline and dobutamine acquisition) before
      revascularization. The outcome after revascularization was assessed by repeating
      resting gated SPECT. Dysfunctional segments without functional recovery in
      postrevascularization gated SPECT were defined scar (either nontransmural or
      transmural according to tracer activity); those with recovery were divided in
      stunned (unchanged uptake) or hibernating (improved postrevascularization
      activity). This reference classification was compared with the categorization
      based on prerevascularization gated SPECT. RESULTS: Contractile reserve in
      dobutamine gated SPECT differentiated scarred from viable segments with 78%
      accuracy. Tracer activity in nitrate imaging distinguished the degree of
      transmurality. Nitrate-induced activity increase was significantly higher
      (p<0.0001) in the hibernating segments (14.9+/-20.4%) than in transmural (4.8+/
      13.4%) nontransmural scars (3.3+/-13%), or stunned segments (2.2+/-8%). The
      presence or absence of nitrate-induced activity increase predicted the
      postrevascularization perfusion changes in viable myocardium and differentiated
      hibernating from stunned segments. The prerevascularization classification showed
      a good agreement with the reference categorization (kappa=0.50). Conclusion.
      Combining contractile reserve evaluation and perfusion quantification within a
      single study with baseline-nitrate gated SPECT and dobutamine test it is possible
      to achieve a comprehensive classification of dysfunctional segments.

PMID- 15194999
TI  - Lung metastases from differentiated thyroid carcinoma. A 40 years' experience.
AB  - AIM: Retrospective studies have been carried out to estimate the survival of 96
      patients with lung metastases from differentiated thyroid carcinoma, observed
      from 1958 to 2000. METHODS: All patients had undergone total thyroidectomy. Case
      histories were analysed with respect to age at diagnosis, sex, histology, local
      lymph node involvement, size of lung metastases and 131I uptake by metastases.
      Survival functions were calculated. Cox regression was performed. RESULTS: There
      was no statistically significant difference in histological type and lymph node
      involvement, whereas a significantly longer survival time was observed in
      patients under 45 years of age at diagnosis (p= or <0.0001), in those with
      metastases concentrating 131I (p= or <0.0001) and in those with fine miliaric
      metastases (p=0.0037). Multi-variate analysis revealed that the risk of death
      increases about 5.4-fold in patients over 45 years old, whereas 131I treatment is
      likely to reduce this risk to nearly 1/6. Conclusion. In conclusion, in patients
      with lung metastases from differentiated thyroid carcinoma, young age at
      diagnosis and 131I uptake by metastases are the most important factors positively
      affecting survival time. Radioiodine therapy, also with high cumulative 131I
      activity, can lead to longer survival time or complete recovery.

PMID- 15195000
TI  - Sympathetic nervous function in patients with hypertrophic cardiomyopathy
      assessed by [123I]-MIBG: relationship with left ventricular perfusion and
      function.
AB  - AIM: The aim of the present study was to evaluate [123I] MIBG uptake and
      clearance in patients with hypertrophic cardiomyopathy (HCM) and to assess their
      relationships with left ventricular function (systolic and diastolic) and
      perfusion. METHODS: Eleven consecutive patients with HCM (8 men and 3 women; mean
      age 38+/-12 years, none in the dilated phase) underwent (in separate days, in
      random order) [123I]-MIBG scintigraphy, [(99m)Tc]-MIBI SPET at rest, and
      echocardiography. All patients were studied in fasting condition, and all
      medications were discontinued. [(99m)Tc]-MIBI SPET study was performed 1 hour
      after tracer injection. [123I]-MIBG study was acquired 5 minutes (planar) and 4
      hours (planar and SPET) after the i.v. injection of [123I]-MIBG. Heart to
      mediastinum ratio (H/M) was computed at 4 hours. Wash out rate (WOR) was computed
      as: (H early - H delayed)/(H early), after decay correction. Both [123I]-MIBG and
      [(99m)Tc]-MIBI SPET were analyzed on 3 short axis views (apical, middle, and
      basal). Left ventricular outflow tract gradient (LVOTG), ejection fraction,
      volumes, septum thickness, and left atrial fractional shortening (LAFS) were
      evaluated on echocardiography. RESULTS: [123I]-MIBG WOR showed a positive
      relationship with LVOTG (r=0.84, p<0.001) and septum thickness (r=0.76, p<0.01),
      while a negative one was found with LAFS (r= -0.66, p<0.05). The study group was
      divided into: Group A (n=5) with higher, and Group B (n=6) with lower WOR than
      the median value (i.e. 11%). Group A patients had significantly lower LAFS
      (17.6+/-4.8 vs 26.8+/-7.2%, p<0.05), higher LVOTG (49+/-35 vs 3+/-3 mmHg), and
      thicker septum (21+/-2 vs 17+/-2 mm) than Group B patients. Inferior and septal
      wall [123I]-MIBG uptake on 4 hour SPET was significantly lower in Group A than in
      Group B. On the other hand, no differences were found in (99m)T-MIBI SPET rest
      regional uptake between the 2 subgroups of patients. CONCLUSION: These results
      suggest that cardiac sympathetic activity correlates to cardiac anatomy (i.e.
      degree of hypertrophy) and diastolic function in patients with HCM.

PMID- 15195001
TI  - 111Indium-octreotide brain scintigraphy: a prognostic factor in skull base
      meningiomas treated with gamma knife radiosurgery.
AB  - AIM: The purpose of this study is to prospectively investigate the prognostic
      role of somatostatin receptor scintigraphy (SRS) using an 111Indium-labelled
      somatostatin analogue, Octreotide, in skull base meningiomas (SBMs) treated with
      gamma knife (GK) radiosurgery. METHODS: From December 1997 to March 2000, SRS was
      performed both before and within 1 year of radiosurgery on 12 patients. Semi
      quantitative data were calculated as SRS index; the index decrease was
      arbitrarily considered significant above 10%. A potential correlation between the
      decrease in post/pre-GK SRS index and radiosurgical outcome was evaluated.
      RESULTS: The follow-up period was at least 30 months in the whole series (median,
      43 months). In all 12 patients, the pre-GK SRS index was always >1, averaging
      3.73+/-2.9. A decrease in the post-GK average SRS index (2.35+/-1.5) was
      observed. The difference between the pre- and post-GK average values was
      statistically significant (p<0.03). At the 1st high-resolution magnetic resonance
      imaging (MRI) follow-up within 1 year of GK, there was no tumor shrinkage in any
      of the 12 patients of our series. A post/pre-GK SRS index decrease >10% was
      observed in 9 patients and <10% in 3. Delayed MRI follow-up documented tumor
      reduction in all 9 cases having an 111In uptake decrease >10%, with stable
      imaging in the others (p=0.00024). CONCLUSION: Our preliminary findings suggest a
      prognostic correlation between a decrease in concentration of somatostatin
      receptors on meningioma cells within 1 year of radiosurgery and delayed
      meningioma shrinkage.

PMID- 15195003
TI  - Bone mass loss and vitamin D metabolism impairment in HIV patients receiving
      highly active antiretroviral therapy.
AB  - AIM: Given the few controversial data about the effect of highly active
      antiretroviral therapy (HAART) on bone mass in HIV patients, we investigated
      whether a relationship between osteopenia/osteoporosis risk and HAART exists.
      METHODS: In 172 HIV patients, 152 on HAART, 92 including and 60 not including
      protease inhibitors (PI), 20 naive and 64 controls, we measured spine/femur bone
      mineral density (BMD) by DEXA, and assayed serum osteocalcin (O), bone alkaline
      phosphatase (BAP), 1,25(OH)2 D, parathormone (PTH), calcium (Ca) and urinary
      pyridinium cross-links (PYD & DPD). RESULTS: Following WHO BMD t-score criteria,
      osteopenia was ascertained in >35% of all HAART groups and in 30% of naive. Only
      HAART patients had osteoporosis, PI patients more frequently, significantly
      (p<0.03) in spine (21.7% vs 8.3%). Males, intravenous drug users and B-C stage
      patients have a higher risk for low bone mass. Mean t-score was significantly
      lower in both spine and femur and O and PYD & DPD higher in PI than non PI
      patients and controls; 1,25(OH)2 D was significantly lower in all HIV groups than
      controls, PI patients having the lowest values positively correlating with BMD
      and negatively with OC and PYD & DPD, and it decreased further in 27 non selected
      monitored patients continuing on HAART. PTH was higher and Ca lower in HAART
      patients than controls but not significantly, PTH negatively correlating with
      BMD. CONCLUSION: HAART could be associated with osteopenia, even osteoporosis,
      and it could aggravate the loss in bone mass due to HIV infection itself. We
      hypothesize that HAART may directly affect bone remodelling and/or may indirectly
      affect vitamin D metabolism.

PMID- 15195002
TI  - Atypical thoracic and supraclavicular FDG-uptake in patients with Hodgkin's and
      non-Hodgkin's lymphoma.
AB  - AIM: In FDG-PET imaging abnormal supraclavicular and paravertebral FDG uptake is
      a frequent finding which recently could be demonstrated to partly represent brown
      fat tissue. This study was carried out to further investigate causes for this
      phenomenon. Patients variables such as age, gender, body mass index (BMI) and the
      value of sedation and delayed imaging were compared with the presence of atypical
      uptake in 2 distinct groups of diseases, Hodgkin's disease (HD) and non-Hodgkin's
      lymphoma (NHL). METHODS: PET images of 81 patients (53 HD and 28 NHL) were
      evaluated for atypical uptake. In 5 patients additional delayed images were
      acquired. Sedatives were used in anxious patients (n=45). RESULTS: Twelve out of
      53 patients with HD and 2 out of 28 patients with NHL showed an atypical uptake.
      The BMI of patients with atypical uptake (median, 21 kg/m2 versus 24 kg/m2;
      p<0.05) and the age (median, 25 y versus 44 y; p<0.05) were significantly lower
      compared with patients without atypical uptake. In nearly 50% of all women with
      HD= or <30 y and 20% of all male patients with HD= or <30 y an atypical uptake
      was observed. Delayed images showed a SUVmax decrease in 4 patients and an
      increase in 1 patient. All patients with atypical uptake received sedatives which
      had an anxiolytic effect in all patients, but did not prevent atypical uptake.
      CONCLUSION: Abnormal supraclavicular and paravertebral FDG accumulation occurs
      particularly in younger patients and those with lower BMI values. The use of
      sedatives or delayed acquisition does not increase the diagnostic information in
      these cases.

PMID- 15195004
TI  - Economic analyses on the use of positron emission tomography for the work-up of
      solitary pulmonary nodules and for staging patients with non-small-cell-lung
      cancer in Italy.
AB  - AIM: Increasing ageing of the population and tumor incidence, along with
      worldwide rationing of the resources for public health systems, spur the use of
      economic analyses for the choice of strategies and technologies in the assessment
      and management of cancer patients. Incidence and clinical managing of tumors vary
      in different countries even if positron emission tomography (PET) with 2-deoxy-2
      [18F]-fluoro-D-glucose (FDG) is becoming a routine clinical method for diagnosis,
      staging, treatment monitoring and follow-up in a variety of tumors. Available
      data indicate that PET can be considered a superior alternative or complementary
      tool to other well-established methods. However, in spite of the above and of the
      rapidly increasing number of PET centers in Europe, USA and Japan, only a few
      studies have dealt with some of the economic aspects raised by the clinical use
      of PET because of differences in values of reimbursements and health costs. The
      main aim of this study is to propose and discuss an economic model of analysis
      for PET applications in the field of detection and management of pulmonary
      tumors. METHODS: In this study 2 assessments were performed by decision tree
      analysis on the economic impact of the availability of PET on decision-making
      processes for 2 conditions: solitary pulmonary nodules assessment and non-small
      cell lung cancer (NSCLC) staging. In order to define a methodology consistent
      with the system of reimbursement and the prevalent clinical views of the Italian
      National Health Service, data on costs, death probability, and life expectancy
      were gathered from the literature and from the Italian system of reimbursement
      (ROD-DRGs). RESULTS: The results of the cost minimization analysis demonstrate
      that the use of PET in the diagnostic path for the workup of patients with SPN
      reduces the overall diagnostic costs, by approximately 50 Euro per patient, by
      reducing inappropriate invasive diagnostic investigation and their complications.
      The results of the cost effectiveness analysis demonstrate that the use of PET in
      the diagnostic path for the staging of patients with NSCLC reduces the overall
      diagnostic costs by approximately 108 Euro for added year, by reducing
      inappropriate surgical interventions and their complications. CONCLUSION: Both
      analyses are based on standard methods used in the literature, so our conclusions
      can be compared with results and assessments of similar studies in different
      countries and health care systems. Also in the Italian case, the use of an
      economic assessment provides relevant information on the efficacy and
      effectiveness of PET.

PMID- 15195005
TI  - Rotary WHIS-Rad: an humanitarian international project for basic radiology
      development.
AB  - Some Rotary Clubs support the World Health Organisation's WHIS-Rad program, a
      program aimed at spreading the diffusion of dedicated radiological equipment in
      developing countries. These X-ray units, an evolution from the BRS (Basic
      Radiological System) standard are easy to install and use, safe, affordable,
      especially assembled for use in extreme environmental and logistic conditions,
      and guarantee high quality output. We describe the pilot action undertaken by
      Rotary Club Bergamo Citta Alta, the first European club to undertake such action.

PMID- 15195006
TI  - What evidence in radiology? Radiological disease registries.

PMID- 15195007
TI  - Evaluation of the response to therapy of neoplastic lesions.
AB  - The introduction of an evaluation standard for the response to therapy of
      neoplastic lesions is necessary not only for the standardisation of clinical
      research protocols, but also to allow the objective and transferable management
      of the oncology patient in routine clinical practice. The international criteria
      that define how to evaluate a neoplastic disease and to determine its response to
      treatment were first introduced in the 80s by the WHO and have been recently
      updated with the new RECIST criteria defined by broad consensus of European and
      U.S. oncology organisations and published in 2000. The new criteria, especially
      those related to lesion measurement are substantially different from the previous
      criteria, they are simpler and easier to use, but present some problems that
      should be brought to the attention of radiologists who must adjust them with the
      common sense and balance of judgement resulting from our practice. These problems
      refer above all to certain types of lesions (such as cystic, bone and nodal
      metastases), to the method for measuring the maximum diameter, to the use of
      contrast agents and to the frequency of follow-up examinations, with consequent
      effects on radioprotection and workloads. In any case, the radiologist who
      examines a patient with neoplastic lesions and compares the examination results
      with previous images, should make sure the report does not contain vague
      language, that the maximum diameters of the lesions are always indicated and that
      any morphological and/or contrast enhancement changes are described: the report
      should enable clinicians to make a complete evaluation of the condition and of
      disease progression, for a global management of the oncology patient.

PMID- 15195008
TI  - Digital mammography: quality and dose control.
AB  - PURPOSE: For almost 3 years, Radiologists and Physicists from Padova and Ferrara
      Universities have collaborated together, with the aim of collecting and comparing
      experimental data useful to define the most significant parameters for quality
      controls in digital mammography. Successively, radiologists and physicists
      working in other sites where a digital mammography unit was installed joined the
      work-group. MATERIALS AND METHODS: In this study we report the results obtained
      from measurements of linearity, uniformity, short- and long-term reproducibility,
      AEC stability performed on 5 digital equipment by using a simple test object. X
      ray beam quality and tube yield were preliminarily checked in such a way that
      possible uncertainties of digital system responses could be separated from those
      due to differences among X-ray tubes. RESULTS: Results showed that the equipment
      considered, comparable in terms of both beam quality (HVL) and tube yield, always
      displayed linear response and reproducibility errors lower than 5%. Uniformity
      was very good and the grey level compensation as a function of exposure
      parameters remained within 5%. Differences in choice of parameters by exposure
      control system (AOP) were emphasised, especially for crossing between
      track/filter combinations (from Mo/Mo to Mo/Rh and from Mo/Rh to Rh/Rh); those
      differences were attributed to the +/-2 mm tolerance of breast thickness
      measurement (mechanically obtained) greater than the AOP tolerance (+/-1 mm).
      DISCUSSION AND CONCLUSIONS: Obtained results can be useful, as comparison and
      reference values, for users employing a digital mammography unit of the same kind
      reported in this paper. Moreover, the same results could be used as "orientation"
      also by other users having different digital mammography technologies, whose
      operation should be nevertheless specifically studied and understood in order to
      find the most useful parameters for quality controls. The acquired experience
      clearly showed us that years of investigations will be necessary in order to be
      able to write reliable protocols. This should induce people to contemplate the
      necessity of not improvising "theoretical" protocols, that are unreliable and
      dangerous for their negative clinical implications.

PMID- 15195009
TI  - Advances in digital mammography.

PMID- 15195010
TI  - Comparison of two commercial systems for computer-assisted detection (CAD) as an
      aid to interpreting screening mammograms.
AB  - PURPOSE: To compare the diagnostic accuracy of two commercial CAD systems (CADx
      and R2) and their impact as an aid to conventional reading of screening
      mammograms. MATERIALS AND METHODS: The image set considered consisted of 120
      mammograms, 89 confirmed negative and 31 with subsequent interval cancers (11
      classified as false negatives (FN), 20 as "minimal signs" (MS)). The set was
      digitised and processed with CAD, and printouts obtained of the mammograms with
      indications of the areas warranting review. Six expert radiologists read the
      mammograms three times, once using conventional reading and twice using CAD
      reading with CADx and R2, respectively. The two CAD systems were compared in
      terms of diagnostic accuracy of the marks and the impact of CAD reading compared
      to conventional reading and to the use of independent second reading simulated by
      combining pairs of single conventional readings. RESULTS: R2 highlighted more
      calcifications (218 vs 132, +65%) and CADx highlighted more masses (208 vs 105,
      +98%). CADx and R2 marked 15 and 17 out of 31 cancers, respectively (sensitivity
      48.3% vs 54.8%, chi squared=6.4, p=0.79), 10 and 6 out of 11 FN (90.9% vs 54.5%,
      chi squared=2.0, p=0.15), respectively, and 5 and 11 out of 20 MS (25.0% vs
      55.0%, chi squared=2.6, p=0.10), respectively. As for specificity, the false
      positive markings for masses were on average (per case) 1.60 for CADx and 0.75
      for R2, those for calcifications were 1.08 for CADx and 1.77 for R2 and the total
      false positive markings were 2.68 for CADx and 2.52 for R2. CADx and R2 marked 73
      and 63 of 89 negative controls (specificity = 0.18 vs 0.29, chi squared=2.52,
      p=0.11), respectively. All the radiologists showed greater sensitivity with CAD
      reading compared to conventional reading. On average, sensitivity with
      conventional reading was 58.6% (109/186), as against 70.9% (132/186) for CADx or
      R2 (chi squared=5.71, p=0.016). Sensitivity for FN cases was 71.2% (47/66) with
      conventional reading, 84.8% (56/66) with CADx (chi squared=2.82, p=0.09) and
      80.3% (53/66) for R2 (chi squared=1.03, p=0.30) (CADx vs R2, chi squared=0.21,
      p=0.64). Sensitivity for MS cases was 51.6% (62/120) for conventional reading,
      63.3% (76/120) for CADx (chi squared=2.88, p=0.08) and 65.8% (79/120) for R2 (chi
      squared=4.40, p=0.03) (CADx vs R2, chi squared=0.07, p=0.78). The recall rates
      were 18.1% (97/534) for conventional reading, 29.7% (159/534) for CADx (chi
      squared=5.72, p=0.01) and 24.3% (130/534) for R2 (chi squared=10.11, p=10-5)
      (CADx vs R2, chi squared=3.71, p=0.05). Double reading was significantly more
      sensitive than conventional reading (chi squared=29.6, p=10-6), CADx (chi
      squared=5.33, p=0.02) and R2 (chi squared=5.33, p=0.02). The recall rate for
      double reading was significantly higher than for conventional reading (chi
      squared=21.5, p=10-6) whereas no significant difference was detected when
      compared to CADx (chi squared=0.16, p=0.68) or R2 (chi squared=3.4, p=0.06).
      CONCLUSIONS: Despite using different algorithms, the two CAD systems exhibit
      comparable levels of diagnostic accuracy and a similar positive impact on
      sensitivity when used as an aid to conventional reading. Single reading with
      either CAD system is as specific but not as sensitive to double independent
      reading: its use as an alternative to double reading cannot be recommended and
      should be investigated further by means of controlled prospective studies.

PMID- 15195011
TI  - Comparison of monophasic vs biphasic administration of contrast material in non
      invasive coronary angiography using a 16-row multislice Computed Tomography.
AB  - PURPOSE: To compare two different techniques for the administration of the bolus
      of contrast material (cm) in coronary angiography with multislice CT (MSCT)
      scanner. MATERIALS AND METHODS: Thirty consecutive patients were divided into two
      groups. In group 1 contrast material was administered with the monophasic
      protocol (140 ml of cm at 4 ml/s). In group 2 contrast material was administered
      with the biphasic protocol (70 ml of cm at 4 ml/s and 70 ml at 3 ml/s). The
      angiographic scan was performed in both groups with a 16-row MSCT scanner. Three
      regions of interest were drawn in each scan throughout the data-set in order to
      measure attenuation: 1) ascending aorta (ROI1); 2) descending aorta (ROI2); 3)
      pulmonary artery (ROI3). Attenuation was also assessed at the origin of the main
      coronary arteries. RESULTS: No significant differences of the attenuation values
      were observed at the origin of the coronary arteries (p>0.05). The attenuation
      profile of the monophasic protocol showed higher and longer attenuation values
      than the biphasic protocol. CONCLUSIONS. The biphasic administration of contrast
      material does not supply significant advantages on the enhancement of the great
      vessels and the coronary arteries in 16-row MSCT coronary angiography.

PMID- 15195012
TI  - Use of saline chaser in the intravenous administration of contrast material in
      non-invasive coronary angiography with 16-row multislice Computed Tomography.
AB  - PURPOSE: To investigate the impact of saline bolus chaser in coronary angiography
      with a 16-row multislice CT (16-MSCT) scanner. MATERIALS AND METHODS: 32 patients
      were divided in two groups for contrast material (cm) administration: group 1
      (140 ml at 4 ml/s), and group 2 (100 ml at 4 ml/s followed by 40 ml of saline
      chaser at 4 ml/s). All patients underwent ECG-gated coronary angiography with a
      16-MSCT scanner. The attenuation at the origin coronary vessels was assessed.
      Three regions of interest were drawn throughout the data-set: ascending aorta
      (ROI1); descending aorta (ROI2); pulmonary artery (ROI3). The attenuation in the
      superior vena cava was recorded (ROI4). The average attenuation and the slope
      were calculated in each ROI. RESULTS: The average attenuation in the coronary
      vessels was not significantly different in the two groups. The attenuation value
      in the superior vena cava was significantly inferior in group 2. CONCLUSIONS: 16
      row MSCT coronary angiography with bolus chaser allows optimal vessel enhancement
      with a lower dose of cm and a lower enhancement of the superior vena cava and the
      right heart.

PMID- 15195013
TI  - Contrast-enhanced US in the assessment of the ilio-caval axis in deep venous
      thrombosis.
AB  - PURPOSE: To assess the feasibility and the accuracy of a new technique in the
      evaluation of deep venous thrombosis (DVT) in the ilio-caval axis. MATERIALS AND
      METHODS: Thirty-eight patients with suspected DVT were prospectively examined
      with unenhanced and enhanced colour-Doppler ultrasonography, and ascending
      contrast venography. Thirty-five out of 38 patients underwent US phlebography,
      consisting in manual injection of Levovist (Schering Ag, Berlin, Germany) through
      a 21-G cannula in a suitable dorsal vein of the foot ipsilateral to the suspected
      DVT. Three patients in whom it was not possible to cannulate a dorsal vein of
      foot underwent contrast-enhanced US after injection of Levovist through an
      antecubital vein, but where excluded from the present study. A contrast venogram
      was nonetheless carried out in all out three patients for comparison with the US
      phlebography findings. RESULTS: US-phlebography allowed better definition of the
      presence and extension of deep vein thrombosis in all patients, when compared to
      conventional color-Doppler US. In the evaluation of suspected acute thrombosis,
      the comparative efficacy of Doppler-US and US phlebography compared with
      ascending phlebography as the gold standard, was as follows: sensitivity of 85.7%
      and 90%, specificity of 71.4 and 100%, accuracy of 80.9 and 95.2%, PPV of 85.7,
      and 100%, and NPV of 71.4, and 75%, respectively. In the assessment of chronic
      thrombosis, US and US phlebography achieved a sensitivity of 90% and 100%, a
      specificity of 75% and 100%, an accuracy of 85.7% and 100%, a PPV of 100, 100%, a
      NPV of 87.5, 100%, respectively. No complications related to US phlebography were
      observed. CONCLUSIONS: US-phlebography is a promising tool in the assessment of
      deep vein thrombosis, being highly accurate and feasible. However, further
      studies based on larger series are mandatory to confirm our promising results and
      establish a standardised role for this new technique.

PMID- 15195014
TI  - Radiological contrast studies after vertical banded gastroplasty (VBG) and Roux
      en-Y gastric bypass (RYGBP) in patients with morbid obesity. Study of the
      complications.
AB  - PURPOSE: The aim of the study was to evaluate the role of radiological upper
      gastroenteric studies to detect early and postoperative complications after
      gastric restrictive surgery for obesity. MATERIALS AND METHODS: From October 1992
      to October 2002, 650 patients submitted to vertical banded gastroplasty (VBG) and
      Roux-en-Y gastric bypass (RYGBP) underwent radiological follow-up to assess the
      presence of both early and late postoperative complications. The patients were
      546 (84%) women and 104 (16%) men whose average weight was 125 kg (range: 78 to
      218 kg). The average female age was 37 years (range: 17 to 69 years) and the
      average male age 36 (range: 19 to 64 years). Preoperative mean body mass index
      was 46 kg/m2 (range 31-78 kg/m2). The patients underwent radiological upper
      gastroenteric investigation employing water soluble contrast material between the
      4th and 7th postoperative day. All patients underwent another late examination
      every year after surgery. RESULTS: At 10 years follow-up in 620 patients
      submitted to modified Mason VBG we observed the following early postoperative
      complications: 16 cases (2.6%) of oedema of the stoma, six cases (0.9%) of gastro
      oesophageal reflux, one case (0.2%) of staple-line disruption, and one case
      (0.2%) of intragastric haemorrhage. Late complications in VBG included 26 cases
      (4.2%) of staple-line disruption, four cases (0.6%) of kinked stomas, six cases
      (0.9%) of pouch dilatations, two cases (0.4%) of stomal stenosis and one case
      (0.2%) of gastro-oesophageal reflux. In 30 RYGBP patients we observed the
      following early postoperative complications: one case (0.8%) of dilated pouch,
      one case (0.8%) of oedema of the anastomosis and one case (0.8%) of anastomotic
      leak. Late postoperative complications in the 30 RYGBP patients included three
      cases (2.5%) of stomal ulcers and one case (0.8%) of gastro-oesophageal reflux.
      We also examined the annual incidence of complications in late follow-up.
      DISCUSSION AND CONCLUSIONS: Both early and late radiological studies after
      gastric bariatric surgery enable the detection of postoperative complications and
      provided morphological and volumetric data after VBG and RYGBP. Post-operative
      complications (gastric perforation, stomal stenosis, etc.) need to be emphasised
      and the clinical approach modified to enable suitable weight loss.

PMID- 15195015
TI  - Pictorial essay: common and uncommon CT features of acute pelvic pain in the
      woman.
AB  - Acute pelvic pain in women is a frequent cause of emergency hospital admission.
      Because the source may be either gynaecological or non-gynaecologic and because
      of the complex anatomy of the pelvic area, the differential diagnosis of the
      underlying disease is extensive. In such cases ultrasonography is the procedure
      of choice, as it leads to a diagnosis in most cases. Sometimes, however, when the
      sonographic findings are non-diagnostic or disagree with the clinical picture,
      especially in acutely ill patients, a Computed Tomography (CT) scan of the
      abdomen and pelvis can assist in the diagnosis. We present the CT features of
      different gynaecological and non-gynaecological conditions in women presenting to
      the Emergency Room with acute pelvic pain.

PMID- 15195016
TI  - The role of diagnostic imaging in synovial sarcoma. Our experience.
AB  - PURPOSE: Synovial sarcoma is a rare malignant mesenchymal tumour of soft tissues.
      It accounts for 8-10% of all soft-tissue sarcomas. The clinical symptoms at onset
      are often subtle and the course of the disease is slow. Therefore, diagnostic
      imaging is essential for the early diagnosis of a malignant tumoral lesion. The
      aim of this study was to assess the role and usefulness of the different imaging
      procedures in the diagnosis of synovial sarcoma and to present their findings.
      MATERIALS AND METHODS: Between 1985 and 2002, we retrospectively reviewed 35
      patients (21 men and 14 women, aged 14-66 years) with synovial sarcoma treated in
      the Orthopaedic Oncological Surgery Division of our hospital. All patients had
      previously undergone conventional radiography, B-mode ultrasound, computed
      tomography and magnetic resonance imaging. RESULTS: Conventional radiography
      showed indirect signs of the neoplasm including soft-tissue swelling,
      calcifications and bone erosions. Ultrasound allowed the detection of focal
      nodular lesions but was non-specific in distinguishing malignant features. CT
      after intravenous injection of contrast medium demonstrated inhomogeneous
      enhancement in 90% of cases, suggesting an alteration in tumour microcirculation.
      In all cases examined, MRI enabled detection of the intrinsic structural
      alterations of the mass indicative of an aggressive lesion. CONCLUSIONS: Contrast
      enhanced CT and MRI provide useful information on the intrinsic structure of the
      neoplasm, suggesting a presumptive diagnosis. Furthermore, they are necessary for
      tumour staging, surgical planning and follow-up. The definitive diagnosis is
      provided by biopsy and histology.

PMID- 15195017
TI  - Cochlear and vestibular acqueducts.

PMID- 15195018
TI  - Value of echo-planar diffusion-weighted MRI in the detection of secondary and
      postoperative relapsing/residual cholesteatoma.
AB  - PURPOSE: To assess the utility of echo-planar diffusion-weighted magnetic
      resonance imaging (EPI-DWI) in the diagnosis of secondary cholesteatoma of the
      middle ear and in the differential diagnosis between residual/relapsing
      cholesteatoma and non-cholesteatomatous tissues (scar, granulation and
      inflammatory tissue) after conservative mastoidectomy. MATERIALS AND METHODS:
      Twenty-four patients, who had previously undergone clinical and CT investigation,
      were prospectively examined by standard and EPI-DWI magnetic resonance imaging
      (MRI) after conservative mastoidectomy. Secondary cholesteatoma was suspected in
      5 patients and residual/relapsing cholesteatoma in 19 patients. Two radiologists,
      blinded to patient's identity, clinical data and CT findings, reached consensus
      on the presence of tissue consistent with cholesteatoma in conventional CT and
      areas of altered signal in EPI-DWI in the petrous bone. All patients underwent
      mastoidectomy, second time of tympanoplasty or review surgery within 15 days from
      MR investigation. Sensitivity, specificity and negative and positive predictive
      values were evaluated separately for standard and EPI-DWI MRI. RESULTS: In EPI
      DWI sequences, 11/12 patients with cholesteatoma showed an area of hyperintense
      signal, whereas patients with non-cholesteatomatous tissue showed no pathologic
      signal in the petrous bone. In the single case of cholesteatoma undetected on EPI
      DWI a cholesteatomatous pearl approx. 2 mm in diameter was visible in the
      surgical cavity. Sensitivity, specificity, positive and negative predictive
      values were 92%, 100%, 100%, 92% for EPI-DWI MRI and 92%, 25%, 55%,75% for
      standard MRI, respectively. CONCLUSIONS: EPI-DWI sequences are useful in the
      diagnosis of secondary cholesteatoma and in the differential diagnosis between
      residual/relapsing cholesteatoma and non-cholesteatomatous tissues after
      conservative mastoidectomy. However, the usefulness of EPI-DWI sequences as a
      screening test after conservative mastoidectomy requires further assessment.

PMID- 15195019
TI  - In vitro analysis of ultrasound second generation contrast agent diluted in
      saline solution.
AB  - PURPOSE: To evaluate the changes in response of a second-generation sonographic
      contrast agent diluted in saline solution at different concentrations when
      different scanning techniques, and saline solution temperatures and pH were used.
      MATERIALS AND METHODS: A series of tests was devised to analyse the behaviour of
      the sonographic contrast agent at different concentrations, temperatures, pH and
      scanning techniques. Latex balloons were used as phantoms. These were filled with
      0.9% Sodium Chloride solution mixed with a suspension of sulphur hexafluoride
      microbubbles stabilised with phospholipids (SonoVue ) and scanned with the
      harmonic imaging technique at low acoustic pressure. For each image obtained, we
      calculated the mean grey-scale level values and the standard deviations of grey
      scale level were calculated within a ROI on the US images obtained; the resulting
      data were used to create echogenicity curves of UCA the echo-enhancer over time
      at the different conditions tested. RESULTS: We noted that SonoVue maintains
      adequate backscatter properties even at low concentration (0.15%) in N/S
      solution. The amount of echogenicity can be considered adequate for the average
      duration of an ultrasound examination. These properties are not affected by the
      scanning technique used on the phantom containing the UCA contrast agent/NaCl
      solution. The pH of the saline solution does not affect the survival of the
      microbubbles. Temperature becomes a significant value beyondover 33-37 degrees C;
      this condition favours rupture of the microbubbles with subsequent reduction of
      the echogenicity after 10-15 min, and complete disappearance after 30 min. US
      beam attenuation related to the concentration of the microbubbles in the saline
      solution volume has a non-linear behaviour; at low amplification levels,
      attenuation becomes more significant when using SonoVue concentrations higher
      than 0.4%. Unexpected greater improvement in US beam transmission was experienced
      for each of the three SonoVue concentrations tested, and especially for 0.2% and
      0.4%, compared to saline solution alone. CONCLUSIONS: Our results show that a
      second-generation contrast agent may be used even diluted at low concentration in
      saline solution. This characteristic opens up new diagnostic perspectives
      possibilities for the use of contrast-enhanced harmonic imaging; in particular,
      its can be suggested used in hollow organs and functional studies. These in vitro
      results require by confirmation by clinical applications which are under
      evaluation and experimentation.

PMID- 15195020
TI  - Classification, epidemiology and implications of chronic prostatitis in North
      America, Europe and Asia.
AB  - The last decade has seen a resurgence of interest and exciting new research on
      chronic prostatitis and related syndromes. One important reason for this
      enthusiasm is the recognition that chronic prostatitis syndromes represent an
      important worldwide health care problem. New data suggesting that chronic
      prostatitis syndromes may have important long-term consequences are a second
      reason for the resurgence of research interest. This article reviews the new
      classification of chronic prostatitis syndromes. Emphasis is then given to
      summarizing new data on the epidemiology of chronic prostatitis. We concentrated
      on population-based studies employing reasonable case-definitions to survey
      various populations from North America, Europe and Asia. These studies suggest
      that prostatitis syndromes are common, with 2-10% of adult men suffering from
      symptoms compatible with chronic prostatitis at any time. Approximately 15% of
      men suffer from symptoms of prostatitis at some point in their lives. Preliminary
      epidemiological and biological studies also suggest that chronic prostatitis may
      be associated with an increased risk for development of benign prostatic
      hyperplasia and prostate cancer. These findings support the conclusions that
      chronic prostatitis is an important international health care problem that merits
      increased priority from clinicians as well as increased clinical and basic
      science research.

PMID- 15195021
TI  - Lower urinary tract symptoms and benign prostatic hyperplasia.
AB  - Benign prostatic hyperplasia (BPH) is an important cause of lower urinary tract
      symptoms (LUTS). However, many other causes, including smooth muscle dysfunction
      and neurological factors may contribute to these symptoms, and accurate diagnosis
      is imperative before invasive treatments are chosen. Careful recording of
      symptoms, giving emphasis on how they interfere with the patient's quality of
      life, as well as the use of properly selected tests, constitutes the mainstay of
      making a correct diagnosis. Men with mild or moderate symptoms not experiencing
      complications are ideal candidates for medical treatment. For the rest with
      persistent symptoms or complications such as infection, bleeding, chronic
      retention or renal impairment further investigation and more invasive forms of
      treatment need to be considered. We review the patho-physiology of the disease,
      and current approaches and management of this common problem.

PMID- 15195023
TI  - Medical therapy of prostate carcinoma.
AB  - Medical treatment of prostatic cancer is one of the most complex and challenging
      issues in oncologic urology, and probably of oncology itself. In fact, in spite
      of the well known sensitivity of the disease to hormonal manipulations, it is
      still substantially unclear whether hormonal therapy achieves survival
      improvement. Furthermore, many prostate cancers become hormone refractory within
      18 to 36 months from the onset of therapy, and until now, no further treatment
      has been able to improve their prognosis, in spite of the often promising early
      results. Medical treatment is now being used as an adjunct to radical surgery and
      to radiotherapy, in both the adjuvant and the neoadjuvant setting, and this
      raises further controversies. This paper is an attempt to give to the readers the
      state of art of medical therapy, even within the limits of a concise review. The
      authors are aware of these limits but hope that this paper can be useful to the
      reader.

PMID- 15195022
TI  - Diagnosis of prostate cancer. State of the art.
AB  - The widespread acceptance of prostate-specific antigen (PSA) measurement as an
      early detection method for prostate cancer (Pca), coupled with the recent
      heightened public awareness of Pca as a common disease, has led to an increase in
      the detection of Pca. It has been established that digital rectal examination
      (DRE) and PSA are the most useful front-line methods for assessing an
      individual's risk of Pca. In addition to an elevated PSA above 4 ng/mL and an
      abnormal DRE, the decision to proceed with TRUS-guided biopsy may also be
      supported by other factors. Determining the presence of a significant rise in PSA
      between tests, whether the degree of PSA is concordant with the size of the
      prostate, and age appropriate PSA may aid in the interpretation of this risk.
      Grayscale transrectal ultrasound (TRUS) has been established as the first choice
      imaging technique making it possible to take biopsies, measure the volume and
      obtain a general overview of the prostate. To improve, however, the TRUS
      detection rate of Pca, many ultrasonographic technique improvements have been
      introduced and continuously evaluated. As for prostate biopsy, in the prostate
      with visible lesions, lesion-guided biopsies only play a role in combination with
      systematic biopsies, while the systematic prostate biopsy scheme should at the
      present time include 10 or 12 cores according to prostatic weight. The other
      imaging techniques actually play a marginal role in Pca detection, but may be
      useful for staging newly diagnosed Pca or in patient re-staging in case of
      biochemical failure after radical treatment.

PMID- 15195024
TI  - Neoadjuvant androgen deprivation before radical prostatectomy. A review.
AB  - Neoadjuvant androgen deprivation (NAD) using LH-RH analogues and antiandrogens
      before radical prostatectomy has been the object of several randomized trials
      over the last decade. From the pathological point of view they show that this
      treatment causes a significant reduction in the incidence of positive surgical
      margins compared to patients undergoing only surgery, and the optimal duration of
      preoperative treatment has not been determined yet. However the incidence of
      seminal vesicle invasion and metastases to the pelvic lymph nodes does not differ
      compared to controls. From the point of view of surgical technique no differences
      in operative time and blood loss have been recorded, while patients receiving NAD
      tend to present more difficult surgical dissections. The studies with longer
      follow-up uniformly fail to reveal an advantage in terms of PSA progression for
      treated patients, while data on cancer-specific survival have not been reported
      yet. Therefore the available information indicates that NAD before radical
      prostatectomy should not be considered outside clinical trials.

PMID- 15195025
TI  - The treatment of non-metastatic prostate cancer with external beam radiation
      therapy.
AB  - Multiple treatment options exist for men with non-metastatic prostate cancer. For
      nearly 50 years, external beam radiation therapy (EBRT) has been an important
      means of treating men with this disease. Improvements in technology and better
      use of pre-treatment variables including prostate specific antigen (PSA), Gleason
      score and prediction nomograms have steadily improved biochemical and clinical
      outcomes. This article reviews the current status of EBRT in the treatment of
      prostate cancer. Differences in technique as well as clinical results using
      conventional, 3D conformal and intensity modulated radiation therapy are compared
      and contrasted. The appropriate use of adjuvant hormones as well as the
      complications of these treatments will also be discussed.

PMID- 15195026
TI  - When and how to use buccal mucosa grafts in penile and bulbar urethroplasty.
AB  - The surgical treatment of adult anterior urethral strictures has been a
      constantly evolving process, and renewed controversy exists over the best means
      of reconstructing the anterior urethra. Recently, considerable changes have been
      introduced: the wider use of buccal mucosa graft versus the use of genital or
      extragenital skin, and the use of dorsal onlay urethroplasties, also named
      Barbagli procedures. Moreover, in the penile urethra the dorsal placement of the
      graft is now combined with the incision and the augmentation of the urethral
      plate, as suggested for childhood hypospadias surgery. In adult male patients,
      the urethral strictures involving the penile and bulbar urethra are due to failed
      hypospadias repair, ischemia, lichen sclerosus, congenital anomalies of the
      mucosal membrane, traumatic scar after blunt perineal trauma. Buccal mucosa is
      receiving increased attention in the urological literature for penile and bulbar
      urethroplasty. We present here, step by step, 4 different surgical techniques for
      penile and bulbar urethroplasty, using buccal mucosa grafts. The surgical
      procedures are selected according to the current and updated literature and to
      the new classification of anterior urethral diseases. The ideal surgical
      technique should be simple, safe, reliable and reproducible in the hands of any
      surgeon, as well as being based on sound anatomical principles. We believe the
      technique we present here fulfil all these criteria.

PMID- 15195027
TI  - Gender and the progression of chronic renal diseases: does apoptosis make the
      difference?
AB  - Several studies in patients with chronic kidney diseases have shown that men have
      a more rapid disease progression than women. Also, with ageing, men exhibit
      greater decrements in renal function and increased glomerular sclerosis than
      women. Data from meta-analysis studies indicate that women with several non
      diabetic renal diseases such as membranous nephropathy, IgA nephropathy and
      polycystic kidney disease present a slower progression, but in diabetic renal
      disease this is not yet established. Thus, men appear to be at greater risk for
      renal injury than are women, but the underlying mechanisms are unknown. Sex
      hormones may mediate the effects of gender on chronic renal disease, through the
      interaction with the renin-angiotensin system, the modulation of nitric oxide
      synthesis and the downregulation of collagen degradation. New observations
      indicate that androgens may contribute to continuous loss of kidney cells though
      the stimulation of apoptotic pathways. Apoptosis is an unique type of programmed
      cell death which is activated in several chronic kidney diseases. Studies in
      vitro indicate that androgens prime a Fas/FasL dependent apoptotic pathway in
      kidney tubule cells. This apoptotic cell death pathway is receptor-linked and
      interacts with the mitochondrial pathway, which may be activated by other
      mechanisms, such as toxins and ischemia. Therefore, the mechanisms to cell death
      which are primed by androgens may interact with others occurring in several
      conditions leading to the loss of renal cells. These findings are consistent with
      a role for androgens to promote chronic renal injury in men.

PMID- 15195028
TI  - Current concepts in urinary tract infections.
AB  - Urinary tract infections (UTIs) are common infectious diseases that can be
      associated with substantial morbidity and significant expenditures. This review
      highlights the current concepts and recent advances in our understanding and
      management of this condition. Specific topics include pathogenesis, host factors,
      antimicrobial resistance, recurrent UTIs in women, diagnosis, treatment of
      uncomplicated and complicated UTIs, prophylaxis, catheter associated bacteriuria,
      pregnancy, diabetes, UTIs in men, prostatitis, and the chronic pelvic pain
      syndrome. UTIs can be viewed as an interaction between specific bacterial
      virulence factors and the patient. A new model explaining the pathogenesis of
      recurrent UTIs has been presented. There is a need to reconsider traditional
      treatment recommendations in the face of local resistance patterns, as well as
      the need to make better use of drugs that are currently available. Prospects for
      prevention of recurrent UTI include natural compounds, bacterial interference and
      immunization. With regard to UTI risk in women, patients can be classified based
      on age, and functional and hormonal status. Appropriate treatment approaches must
      be based on this classification. In contrast to uncomplicated UTIs, management of
      most complicated infections depends on clinical experience and resources at
      individual institutions rather than on evidence based guidelines. Asymptomatic
      bacteriuria generally should not be treated except in high-risk catheterized
      patients and in pregnancy. UTIs in men generally require formal urologic
      evaluation. Our understanding of the etiologies, diagnostic strategies, and
      treatment options for prostatitis and the chronic pelvic pain syndrome in men
      continues to evolve.

PMID- 15195029
TI  - Advances in the surgical management of nephrolithiasis.
AB  - The surgical management of urinary calculus disease has undergone a dramatic
      evolution over the past 2 decades. Twenty years ago, open surgical procedures for
      urinary calculi were some of the most frequently performed urologic procedures.
      Since then, however, stone management has been at the forefront of "minimally
      invasive" intervention. Specifically, the initiation and refinement of
      percutaneous and ureteroscopic access to the upper tracts, along with the rapid
      and nearly simultaneous development of both extracorporeal and intracorporeal
      lithotripsy techniques, has limited the role of open surgery to less than 1% of
      patients undergoing intervention for their stone disease. This manuscript will
      review the current indications for the surgical management of urinary calculi,
      the basic physics of the most frequently utilized vehicles for both
      extracorporeal and intracorporeal lithotripsy, and the respective roles of
      extracorporeal and intracorporeal lithotripsy with percutaneous or ureteroscopic
      access and open surgery. In addition, the results and complications associated
      with each of these forms of intervention will be reviewed. Finally, a discussion
      of specific clinical challenges to the urologist will be presented.

PMID- 15195030
TI  - Calculus fragmentation in laser lithotripsy.
AB  - The intracorporeal treatment of urinary calculi with lasers is presented, which
      describes laser-calculus interactions associated with lithotripsy. Reliable
      fragmentation of calculi with diverse compositions and minimal collateral tissue
      damage are primarily contingent upon laser parameters (wavelength, pulse
      duration, and pulse energy) and physical properties of calculi (optical,
      mechanical, and chemical). The pulse duration governs the dominant mechanism in
      calculi fragmentation, which is either photothermal or
      photoacoustical/photomechanical. Lasers with long pulse durations (i.e. > tens of
      micros) induce a temperature rise in the laser-affected zone with minimal
      acoustic waves; material is removed by means of vaporization, melting, mechanical
      stress, and/or chemical decomposition. Short-pulsed laser ablation (i.e. < 10
      micros), on the other hand, produces shock waves, and the resultant mechanical
      energy fragments calculi. Work continues throughout the world to evaluate the
      feasibility of advanced lasers in lithotripsy and to optimize laser parameters
      and light delivery systems pertinent to efficient fragmentation of calculi.

PMID- 15195031
TI  - Guidelines on diagnosis and treatment of superficial bladder cancer.
AB  - This manuscript reviews the guidelines of the European Association of Urology
      (EAU) on superficial bladder tumors and adds new data which has come available
      since 2001. It emphasises the data which are evidenced based and clearly
      explained where still insufficient research is available to make clear
      recommendations. Intravenous urethrography (IVU) is only necessary in grade 3
      tumors. A good transurethral resection (TUR), with muscle in the specimen is
      essential. Random biopsies are only necessary when there is positive urinary
      cytology or when tumor in situ (TIS) is suspected. The variability in pathology
      interpretation remains a problem which seems not to have been solved by the new
      WHO 1998 classification. A review of pathology seems indicated when aggressive
      therapy is planned or there is a discrepancy between the visual findings and
      pathology. The visual judgement of urologists in superficial bladder tumors is
      very good. Second resection is indicated whenever insufficient material is
      delivered and in any T1 G3 tumor. In the last infiltrative tumors are regularly
      found. The treatment largely depends on prognostic parameters. For recurrence
      rate multiplicity of the tumor is most important, followed by recurrence rate,
      volume of the tumor, grade and T category. For progression the most important
      tumor is the anaplasia grade and the T category. Up to 50% of T1 G3 tumors and
      TIS evaluate to invasive tumors. Even low risk tumors still have an important
      recurrence rate of at least 20%/year in the first years after diagnosis. One
      chemo instillation immediately after TUR is indicated in low and intermediate
      risk superficial bladder tumors. Intravesical chemotherapy prevents recurrence
      but not progression. Ideal dosage and schedule of instillation is not clearly
      defined. Longterm therapy is not worthwhile. Bacille Calmette-Guerin (BCG)
      therapy is indicated in all tumors at high risk for progression. In tumors at
      high risk for recurrence it is also superior to intravesical chemotherapy, but
      its side-effects are more pronounced. Local or systemic side-effects are not
      related to efficacy and side-effects do not increase over time. The ideal
      schedule for BCG has not yet been found. It is however clear that some kind of
      maintenance therapy is necessary to obtain good results. BCG failure is probably
      any tumor which recurs at 3 and 6 months under BCG therapy. One third dose seems
      as sufficient as a full dose BCG. That BCG can spare the bladder in T1g3 tumors
      is largely documented but the chance to save the bladder when the tumor is still
      present after 2 cycles of BCG is very low. Cystectomy is indicated in these BCG
      failures. Vitamin E, A, and Lactobacillus Casei are probably effective in the
      prevention of the disease. Stopping smoking is advocated. Cystoscopy is still the
      gold standard in follow-up. It is advocated at 3 months and thereafter according
      to the prognostic parameters. High grade tumors are at risk life long. Follow-up
      of 5 years for low risk tumors seems reasonable.

PMID- 15195032
TI  - [Efficacy of pretreatment with Serenoa repens on bleeding associated with
      transurethral resection of prostate].
AB  - AIM: Aim of the study is to evaluate the efficacy of a pretreatment with lipidic
      sterolic extract of Serenoa repens (Permixon) to reduce bleeding during
      transurethral resection of prostate (TURP) in patients with benign prostatic
      hyperplasia. METHODS: This is a monocentric, randomised versus control group
      study. We enrolled 108 patients, randomised either in the experimental group or
      in the control one. Patients in the experimental group received a pretreatment
      with Serenoa repens (320 mg/die of Permixon) for at least 8 weeks before the TURP
      procedure. In the control group patients did not receive any medical treatment
      before the intervention. RESULTS: Out of 108 enrolled patients, 88 were evaluated
      per protocol. In the pretreated group the perioperative bleeding was
      significantly lower than in the control one (respectively 124 vs 287 ml) and the
      need of transfusion decreased remarkably. Moreover, in the pretreated group, the
      duration of postoperative catheterization (respectively 3 vs 5 days) and the
      evaluated hematological parameters (red cells 4.5 vs 4 million, hemoglobin 13.4
      vs 11.9 g, hematocrit 40% vs 35%) were significantly lower than in the control
      group. CONCLUSION: The pretreatment with Serenoa repens, before TURP procedure,
      improves the efficacy of the procedure itself and reduces the risk of
      complications, in particular perioperative bleeding and duration of postoperative
      catheterization.

PMID- 15195033
TI  - New therapeutic options for refractory neurogenic detrusor overactivity.
AB  - AIM: Current pharmacologic treatment of detrusor overactivity relies on
      anticholinergic drugs. However, they often have untolerable side effects so that
      they are administered in doses insufficient to restore urinary continence.
      Recently, intravesical instillations and injections into the detrusor muscle of
      new pharmacological agents have been developed. The present study report our own
      experience in the treatment of detrusor overactivity with intravesical
      administrations of vanilloid agents and with botulinum-A toxin injections into
      the detrusor muscle in a group of spinal cord injured patients. In particular, we
      compared the clinical and urodynamic effects of the 2 drugs in an attempt to find
      a new and valid therapeutic option in those cases unresponsive to conventional
      treatment. METHODS: Seventy-five patients with spinal cord injury and refractory
      detrusor overactivity were included in the study: 35 patients received repeated
      intravesical instillations of resiniferatoxin (RTX) dissolved in normal saline;
      40 patients received repeated injections of 300 units botulinum A-toxin diluted
      in 30 ml normal saline. Clinical assessment and urodynamics were performed at
      baseline and 6, 12 and 24 months after treatment. RESULTS: With both treatments
      there was a significant reduction in mean catheterization and episodes of
      incontinence and a significant increase in mean first involuntary detrusor
      contraction and in mean maximum bladder capacity at 6, 12 and 24 months after
      therapy. We did not detect any local side effects with either treatment.
      Botulinum-A toxin significantly reduced also the maximum pressure of uninhibited
      detrusor contractions more than RTX at all follow-up time points. CONCLUSION: In
      patients with spinal cord injury and refractory detrusor overactivity
      intravesical RTX and botulinum-A toxin injections into the detrusor muscle
      provided beneficial clinical and urodynamic results with reduction of detrusor
      overactivity and restoration of urinary continence in most patients. Botulinum-A
      toxin injection provided better clinical and urodynamic benefits than
      intravesical RTX.

PMID- 15195034
TI  - Tension-free transobturator approach for female stress urinary incontinence.
AB  - AIM: UraTape is a new sling for female stress urinary incontinence (SUI) inserted
      via a transobturator percutaneous approach. We report the safety, feasibility and
      short-term results of this new surgical procedure. METHODS: UraTape (Porges
      Mentor) is a non-elastic polypropylene tape, with a silicone coated central part.
      The sling is placed tension-free under the mid-urethra and extended through the
      obturator foramen bypassing the posterior face of the ischiopubic ramus. From
      September 2002 to May 2003, 80 females affected by SUI associated with urethral
      hypermobility and without severe uro-genital prolapse (with cystocele 1st grade)
      received UraTape. Mean age was 56 (39-79) years. Sixty-two out of 80 had a
      positive Q tip test; 16/80 had recurrent incontinence after Burch or colpoplasty
      according to Kelly; 22/60 had mixed incontinence. Preoperative evaluations
      included: complete history and physical examination, urinalysis, urodynamic
      investigations, abdominal and pelvic ultrasound. Quality of life assessment was
      carried out pre- and postoperatively. RESULTS: Mean operative time was 16 (11-36)
      minutes. No major intraoperative complications were observed. One bladder neck
      laceration occurred and was treated intraoperatively. No cystoscopy was
      performed. Mean hospital postoperative stay time was 1.1 (1-6) days. All patients
      were examined periodically at 7, 30 and 90 days from intervention (mean follow-up
      4 months, 1-8). There was no urethral erosion. One vaginal erosion with inguinal
      abscess was diagnosed and treated without removing the sling. Two de novo urge
      incontinence was observed. The objective and subjective cure rates were 92% and
      97%; 96% expressed good quality of life (satisfied/very satisfied). CONCLUSION:
      This procedure is a safe, effective new technique for the treatment of female
      SUI. The easy technique, the short learning curve and the very high grade of
      satisfaction of the patients show that this approach is based upon effective
      anatomical and physiological criteria. Further follow-up is necessary in order to
      evaluate urodynamic changes and overall satisfaction.

PMID- 15195036
TI  - A survey of US chiropractors on clinical preventive services.
AB  - OBJECTIVE: To assess attitudes of current chiropractic students, public health
      faculty, and practitioners toward the topics of clinical preventive and health
      promotion services. DESIGN AND POPULATION: Survey of samples of students and
      faculty at 10 US chiropractic colleges and random sample of US chiropractors
      stratified by zip code region using proportional allocation. DATA ANALYSIS:
      Descriptive statistics were computed for all 3 samples and statistical modeling
      was used to explore relationships between practitioner characteristics and their
      responses concerning counseling on health indicators. RESULTS: A total of 582
      students, 45 faculty, and 496 practitioners were surveyed; the response rate for
      practitioners was 27%. Over 80% of practitioners reported providing information
      to patients on musculoskeletal risk reduction, exercise, diet, stress reduction,
      and injury prevention. Over 80% also reported obtaining information from patients
      on physical activity, stress, dietary habits, obesity, medication use, and
      occupational hazards. Concerning immunization information, a much higher
      proportion of faculty (91%) and students (80%) than practitioners (62%) felt
      chiropractors should provide both pro and con information to patients. In
      general, female, younger, and more recently graduated practitioners appeared to
      be somewhat more likely to agree that chiropractors should provide counseling and
      to report providing it. An association was seen between attitudes toward health
      indicator counseling and respondent education. Practitioners with at least a
      bachelor's degree were statistically significantly more likely to report
      providing counseling for physical activity and to agree that chiropractors should
      provide counseling and to report actually providing counseling within the last
      month for substance abuse, responsible sexual behavior, mental health, and injury
      and violence prevention (P <.05). CONCLUSIONS: Our results indicate that a
      substantial proportion of the US chiropractors and students who completed our
      survey, as well as a number of key faculty, have a positive attitude toward
      providing clinical preventive services, particularly those related to physical
      activity and diet. However, the results also suggest that there may be areas
      where chiropractic training is not consistently meeting the newly established
      national guidelines for clinical preventive services.

PMID- 15195037
TI  - Recruitment and accrual of women in a placebo-controlled clinical pilot study on
      manual therapy.
AB  - OBJECTIVE: To investigate the accrual rates and recruitment processes among 3
      Midwestern sites during a pilot study on manual therapy for chronic pelvic pain.
      DESIGN: Multisite pilot study for a randomized, placebo-controlled clinical
      trial. SETTING: Three chiropractic institutions in or near major metropolitan
      cities in the Midwestern United States. SUBJECTS: Thirty-nine women aged 18 to 45
      with chronic pelvic pain of at least 6 months duration, diagnosed by a board
      certified gynecologist. MAIN OUTCOME MEASURES: The method of recruitment was
      collected for each individual who responded to an advertisement and completed an
      interviewer-administered telephone screen. Participants who were willing and
      eligible after 3 baseline visits were entered into a randomized clinical trial.
      The number of responses and accrual rates were determined for the overall study,
      each of the 3 treatment sites, and each of the 5 recruitment efforts. RESULTS: In
      this study, 355 women were screened over the telephone and 39 were randomized,
      making the rate of randomization approximately 10%. The most effective
      recruitment methods leading to randomization were direct mail (38%) and radio
      advertisements (34%). However, success of the recruitment process differed by
      site. CONCLUSIONS: Based on the accrual of this multisite pilot study, a full
      scale trial would not be feasible using this study's parameters. However, useful
      information was gained on recruitment effectiveness, eligibility criteria, and
      screening protocols among the 3 metropolitan sites.

PMID- 15195038
TI  - Immediate improvements in side-to-side weight bearing and iliac crest symmetry
      after manipulation in patients with low back pain.
AB  - BACKGROUND: Although there is good evidence that spinal manipulation is an
      effective treatment to improve pain and function for patients with low back pain
      (LBP), there is little evidence to support the mechanism by which manipulation
      works. OBJECTIVES: To determine if iliac crest (IC) and weight-bearing (WB)
      symmetry improve after spinal manipulation and to determine if improvements in IC
      and WB symmetry are associated with improvements in pain and function in patients
      with low back pain. DESIGN: Single group, within-subjects, repeated measures
      design. METHOD: Thirty consecutive patients (mean age = 40+/-13) who came to a
      spine specialty center for treatment of acute or chronic LBP and who would be
      receiving spinal manipulation participated in the study (14 male patients).
      Patients completed a series of self-report measures of pain and function and
      received a standardized physical examination, including the assessment of IC and
      WB symmetry. Patients received a standardized manipulative intervention, and
      immediate and 3- to 4-day follow-up examinations were performed by a blinded
      examiner. Paired t tests were performed to determine within-group changes, and
      Pearson product moment correlation coefficients were calculated to determine the
      relationship between improvements in IC and WB symmetry and improvements in pain
      and function. To control for the potential that an association between changes in
      IC and/or WB symmetry and changes in pain and function could be confounded by the
      baseline outcome measure, simultaneous linear regression was performed on any
      significant correlation. Partial F tests were used to determine if the additional
      explained variability was significant. RESULTS: Patients with LBP demonstrated
      significant improvements in IC and WB symmetry after manipulation (P<.001).
      Improvements in WB symmetry were associated with improvements in the patients'
      self-reported levels of pain 3 to 4 days after manipulation (r=.5, P=.007). Based
      on the significant association between improvements in WB symmetry and
      improvements in pain, the final pain score was regressed on the change in WB
      symmetry, after controlling for the baseline level of pain. The addition of the
      change in WB symmetry explained a 10% additional increase in variability in the
      patient's level of pain at the 3- to 4-day follow-up (P =.01). No relationship
      was found between improvements in IC and WB symmetry and improvements in function
      as determined by the Oswestry Disability Questionnaire 3 to 4 days after
      manipulation. CONCLUSION: IC and WB symmetry improved immediately after spinal
      manipulation. Improvements in WB symmetry were related to improvements in the
      patients' self-reported levels of pain, even after controlling for the baseline
      level of pain. Improvements in IC and WB symmetry were not related to changes in
      function. The results of this study provide initial data to elucidate how
      manipulation may work to improve pain and function in patients with LBP.

PMID- 15195039
TI  - Central neuronal plasticity, low back pain and spinal manipulative therapy.
AB  - OBJECTIVE: Recent experimental evidence demonstrating neuronal/synaptic
      plasticity and, in particular, long-term potentiation (LTP) and long-term
      depression (LTD) in spinal neurons is reviewed. The implications of these studies
      for possible mechanistic explanations of low back pain and its remediation by
      spinal manipulative therapy (SMT) are explored. Brief descriptions of LTP and LTD
      and elaboration of the key roles of calcium, glutamate, and glutamate receptors
      in LTP/LTD are provided as separate appendices. DATA SOURCES: The referenced
      articles regarding LTP/LTD in spinal cord neurons and neuronal plasticity, in
      general, were identified from accumulated review of the neuroscience literature.
      Publications cited from chiropractic sources relevant to central neuronal
      plasticity and LTP/LTD were identified using the Index to Chiropractic Literature
      and informal review. STUDY SELECTION: Experimental studies examining LTP/LTD
      mechanisms in spinal neurons and more general references useful as an
      introduction to central neuronal plasticity and LTP/LTD are included.Data
      Extraction Experimental evidence presented in this review has been previously
      published and illustrates neuronal plasticity from an animal model for low back
      pain. DATA SYNTHESIS: Both in vitro and in vivo evidence identifying LTP and LTD
      in dorsal horn nociceptive neurons is reviewed. Of special interest are studies
      showing LTP in response to intense noxious stimulation and reports that Adelta
      mechanosensitive afferent activation can reverse an existing LTP condition in
      dorsal horn neurons. CONCLUSIONS: The potential involvement of LTP in low back
      pain is discussed and a role for LTD in spinal manipulative therapy is proposed.
      The need for future studies is identified in the areas of spatial and temporal
      changes in symptomatology post-SMT of the low back; combining, sequencing, and
      comparing several therapeutic approaches; and demonstrating LTD in spinal cord
      neurons post-SMT-like stimulation.

PMID- 15195040
TI  - Low back pain in Australian adults. health provider utilization and care seeking.
AB  - OBJECTIVE: To determine the characteristics of Australian adults who seek care
      for low back pain (LBP), including the type of care they choose and any factors
      associated with making those choices. DESIGN: A population-based mailed survey.
      SUBJECTS: An age, gender, and state stratified random sample of 2768 Australian
      adults selected from the Electoral Roll. METHODS: A self-administered, fully
      structured questionnaire included a series of questions relating to care seeking
      for LBP, choice of provider, and types of treatment received. In addition, a
      series of questions were asked relating to demographic characteristics,
      socioeconomic variables, severity of LBP, cigarette smoking, anthropometric
      variables, perceived cause of LBP, lifetime emotional distress, job satisfaction,
      lifetime physical fitness, past 5-year health status, and fear of LBP causing
      future impairment. RESULTS: The response rate was 69.1%. The sample proved to be
      similar to the Australian adult population. The majority of respondents with LBP
      in the past 6 months did not seek care for it (55.5%). Factors that increased
      care seeking were higher grades of pain and disability severity, fear of the
      impact of pain on future work and life, and female sex. Factors decreasing the
      likelihood for seeking care were identified as the cause of pain being an
      accident at home and also never being married. General medical practitioners and
      chiropractors are the most popular providers of care. CONCLUSION: This study
      shows that a majority of people did not seek care for their LBP. The reasons for
      care seeking proved to be independent of social or economic status.

PMID- 15195041
TI  - Clinical and cost outcomes of an integrative medicine IPA.
AB  - OBJECTIVE: We hypothesized that primary care physicians (PCPs) specializing in a
      nonpharmaceutical/nonsurgical approach as their primary modality and utilizing a
      variety of complementary/alternative medicine (CAM) techniques integrated with
      allopathic medicine would have superior clinical and cost outcomes compared with
      PCPs utilizing conventional medicine alone. DESIGN: Incurred claims and
      stratified randomized patient surveys were analyzed for clinical outcomes, cost
      offsets, and member satisfaction compared with normative values. Comparative
      blinded data, using nonrandomized matched comparison groups, was analyzed for
      age/sex demographics and disease profiles to examine sample bias. SETTING: An
      integrative medicine independent provider association (IPA) contracted with a
      National Committee for Quality Assurance (NCQA)-accredited health maintenance
      organization (HMO) in metropolitan Chicago. SUBJECTS: All members enrolled with
      the integrative medicine IPA from January 1, 1999 through December 31, 2002.
      RESULTS: Analysis of clinical and cost outcomes on 21,743 member months over a 4
      year period demonstrated decreases of 43.0% in hospital admissions per 1000,
      58.4% hospital days per 1000, 43.2% outpatient surgeries and procedures per 1000,
      and 51.8% pharmaceutical cost reductions when compared with normative
      conventional medicine IPA performance for the same HMO product in the same
      geography over the same time frame. CONCLUSION: In the limited population
      studied, PCPs utilizing an integrative medical approach emphasizing a variety of
      CAM therapies had substantially improved clinical outcomes and cost offsets
      compared with PCPs utilizing conventional medicine alone. While certainly
      promising, these initial results may not be consistent on a larger and more
      diverse population.

PMID- 15195042
TI  - Paraspinal muscles and intervertebral dysfunction: part two.
AB  - BACKGROUND: One of the diagnostic characteristics of the manipulable spinal
      lesion--a musculoskeletal disturbance that is claimed to be detected with manual
      palpation and corrected with manipulation--is said to be altered segmental tissue
      texture. Little evidence for the nature of abnormal paraspinal tissue texture
      exists, but indirect evidence from experimental studies supports the plausibility
      of the concept of protective muscle spasm, although investigations of increased
      paraspinal electromyography (EMG) associated with low back pain suggests complex
      changes in motor control rather than simple protective reflexes. OBJECTIVES: To
      review the literature for evidence that may support or refute proposed
      explanations for clinically observed altered paraspinal tissue texture associated
      with the manipulable spinal lesion. This review aims to highlight areas that
      require further research and make recommendations for future studies. Data Source
      MEDLINE and CINAHL databases were searched using various combinations of the
      keywords paraspinal, muscle, palpation, EMG, spine, low back pain, pain,
      myofascial, hardness, manipulation, reliability, and somatic dysfunction, along
      with searching the bibliographies of selected articles and textbooks. Data
      Extraction All relevant data were used. RESULTS: Decreased paraspinal muscle
      activity and strength associated with low back pain is well established, and
      there is evidence of changes in muscle fiber composition and localized selective
      multifidus atrophy. Disturbances in microcirculation have been implicated in
      nonparaspinal muscle pain. The effect of spinal manipulation on paraspinal EMG
      activity is inconclusive but promising. CONCLUSION: Little direct evidence exists
      to support the existence or nature of paraspinal tissue texture change that is
      claimed to be detected with palpation. The proposal of segmental reflex
      paraspinal muscle contraction was not supported, at least in association with low
      back pain. There appears to be a complex relationship between deep paraspinal
      muscle inhibition during dynamic activity and nonvoluntary guarding behavior
      during static activity. The relationship between these findings and palpable
      tissue change is speculative, but increased activity, decreased activity, or both
      may be responsible for paraspinal tissues detected as abnormal with palpation.
      Recommendations are outlined for future research.

PMID- 15195043
TI  - Chiropractic care of a patient with low back pain associated with subluxations
      and a Malgaigne-type pelvic fracture.
AB  - OBJECTIVE: To describe the chiropractic care of a patient with a pelvic ring
      fracture and concomitant subluxations of multiple segments of the spinal column.
      CLINICAL FEATURES: A 23-year-old male, after falling down a flight of stairs, was
      initially hospitalized for fractures of the pelvis. Five weeks
      posthospitalization, the patient initiated chiropractic care with complaints of
      severe low back pain with lower extremity involvement. He also complained of neck
      pain and occipital headache. The patient had several positive low back orthopedic
      tests with bilaterally absent Achilles deep tendon reflexes. The anteroposterior
      radiographic view revealed ununited fractures at the left superior and inferior
      pubic ramus, noted as a type I Malgaigne fracture. Subluxations were detected at
      the left innominate (ie, fracture-subluxation) and at the patient's lumbar,
      thoracic, and cervical spine. INTERVENTION AND OUTCOME: The patient was cared for
      with contact-specific, high-velocity, low-amplitude adjustments to sites of
      vertebral and sacroiliac subluxations. The patient's response to care was
      positive, receiving great pain relief. Less than 3 months after initiating care,
      the patient returned to work on regular duty. CONCLUSION: There are indications
      that patients suffering from the injuries described above may derive benefits
      from chiropractic care. The practitioner must pay careful attention to issues of
      biomechanical and vascular stability and adjustment modifications in these types
      of patients.

PMID- 15195044
TI  - The stroke issue: paucity of valid data, plethora of unsubstantiated conjecture.

PMID- 15195045
TI  - The amelioration of symptoms in cervical spinal stenosis with spinal cord
      deformation through specific chiropractic manipulation: a case report with long
      term follow-up.
AB  - OBJECTIVE: To describe the chiropractic management of a patient with paresthesia
      on the entire left side of her body and magnetic resonance imaging (MRI)
      documented cervical spinal cord deformation secondary to cervical spinal
      stenosis. CLINICAL FEATURES: A 70-year-old special education teacher had neck
      pain, headaches, and burning paresthesia on the entire left side of her body.
      These symptoms developed within hours of being injured in a side-impact motor
      vehicle accident. Prior to her visit, she had been misdiagnosed with a
      cerebrovascular accident. INTERVENTION AND OUTCOMES: Additional diagnostic
      studies revealed that the patient was suffering from cervical spinal stenosis
      with spinal cord deformation. Two manipulative technique systems (Advanced
      Biostructural Therapy and Atlas Coccygeal Technique) unique to the chiropractic
      profession and based on the theory of relief of adverse mechanical neural tension
      were administered to the patient. This intervention provided complete relief of
      the patient's complaints. The patient remained symptom-free at long-term follow
      up, 1 year postaccident. CONCLUSION: There is a paucity of published reports
      describing the treatment of cervical spinal stenosis through manipulative
      methods. Existing reports of the manipulative management of cervical spondylosis
      suggest that traditional manual therapy is ineffective or even contraindicated.
      This case reports the excellent short-term and long-term response of a 70-year
      old patient with MRI-documented cervical spinal stenosis and spinal cord
      deformation to less traditional, uniquely chiropractic manipulative techniques.
      This appears to be the first case (reported in the indexed literature) that
      describes the successful amelioration of the symptoms of cervical spinal stenosis
      through chiropractic manipulation. More research into the less traditional
      chiropractic systems of spinal manipulation should be undertaken.

PMID- 15195046
TI  - Neck-tongue syndrome.
AB  - OBJECTIVE: To discuss a case of neck-tongue syndrome (NTS) affecting a
      dancer/figure skater, review literature summarizing the pathogenesis and
      treatment, and offer new categorization of neck-tongue syndrome. CLINICAL
      FEATURES: A 24-year-old female dancer/skater sought treatment for recurrent
      episodes of right-sided upper neck pain with associated ipsilateral numbness of
      her tongue following brisk active rotation. Radiographs revealed a narrowing of
      the left para-odontoid space. Physical examination revealed a mildly painful
      restriction in rotation at C1-2 with no apparent muscular hypertonicity.
      INTERVENTION AND OUTCOME: The patient had sought chiropractic treatment for this
      condition several times since she was 8 years old. Diversified chiropractic
      adjustments were applied to restrictions throughout the cervical spine as
      determined by the clinician. No other interventions were employed. The patient
      experienced significant improvement in frequency and intensity of the neck and
      tongue symptoms following spinal manipulative therapy applied to her cervical
      spine. CONCLUSIONS: There are 2 categories of NTS: complicated NTS due to the
      presence of an underlying disease process (inflammatory or degenerative) and
      uncomplicated NTS (idiopathic or trauma-related). This case report is of
      uncomplicated NTS that responded favorably to spinal manipulative therapy
      directed at the cervical spine. In the absence of upper cervical instability,
      spinal manipulative therapy appears to be beneficial and should be considered in
      all cases of uncomplicated NTS.

PMID- 15195047
TI  - Association of autonomic dysfunction and mild obstructive sleep apnea.
AB  - BACKGROUND: Autonomic dysfunction (AD) has been independently associated with
      obstructive sleep apnea (OSA). Autonomic abnormalities are generally considered
      to be secondary to OSA. Autonomic dysfunction may also contribute to OSA. If AD
      contributes to OSA, we postulated that abnormalities may be present in mild OSA
      where the confounding causal effects of hypoxemia and sleep disruption are
      reduced. OBJECTIVE: We evaluated autonomic function tests and sleep studies in a
      cohort of subjects with no known diagnosis of OSA. METHODS: We prospectively
      enrolled a cohort without diagnosed OSA who were part of an ongoing study of
      vasomotor rhinitis (VMR) for testing. A battery of autonomic nervous system tests
      (sudomotor and cardiovagal), nonattended polysomnography, and three-site
      esophageal/pharyngeal pH monitoring were performed. RESULTS: Twenty of 22
      patients completed the test battery and 12 (60%) met criteria for OSA
      (Apnea/Hypopnea Index "AHI" >5 events/hour). AHI correlated to mean tilt table
      blood pressure decrease (R = 0.58, P = 0.007) and the Valsalva-mediated phase 2
      mean blood pressure decrease (R = 0.52, P = 0.017). OSA severity was related to
      sympathetic but not parasympathetic abnormalities. No differences in blood
      pressure responses were related to age, oxygen desaturation nadir,
      gastroesophageal reflux, VMR, or sleepiness. CONCLUSION: Autonomic abnormalities
      suggestive of decreased adrenergic tone are associated with mild OSA. These
      abnormalities may potentially be secondary but may also precede development of
      OSA.

PMID- 15195048
TI  - Popular snore aids: do they work?
AB  - OBJECTIVE: The study goal was to critically evaluate 3 popular noninvasive
      treatments for snoring: an oral spray lubricant applied before bedtime, a nasal
      strip designed to maintain nasal valve patency, and a head-positioning pillow.
      STUDY DESIGN: Prospective, randomized blinded clinical trial of 3 popular
      noninvasive snore aids using objective acoustic snoring analysis and subjective
      patient and bed-partner questionnaires in 40 snoring patients. A digital recorder
      allowed snoring analysis with data collected in the home environment over 1 week.
      RESULTS: There is neither objective nor subjective benefit to the use of tested
      popular noninvasive snore aids. Palatal snoring, palatal loudness, average
      loudness of snoring, averaged palatal flutter frequency, and respiratory
      disturbance index did not significantly change when comparing the 3 snoring aids
      with no treatment. Subjective comments and complications are reviewed as well.
      CONCLUSION: This is the first prospective comparison trial of popular noninvasive
      snoring aids. There is no significant objective or subjective snoring improvement
      in the anti-snoring aids studied compared with the use of no aid. SIGNIFICANCE:
      Outcome studies aid in verifying or refuting claims made by popular noninvasive
      snore aids.

PMID- 15195049
TI  - Survival of veterans with sleep apnea: continuous positive airway pressure versus
      surgery.
AB  - OBJECTIVES: Continuous positive airway pressure (CPAP) improves sleep apnea
      survival. We tested whether CPAP is associated with better survival than
      uvulopalatopharyngoplasty (UPPP). STUDY DESIGN AND METHODS: This retrospective
      cohort database study included all sleep apnea patients treated with CPAP or UPPP
      in Veteran Affairs facilities from October 1997 through September 2001. Treatment
      groups were compared with Cox regression, adjusting for age, gender, race, year
      treatment was initiated, and comorbidity. Sleep apnea severity and CPAP use data
      were not available. RESULTS: By September 2002, 1339 (7.1%) of 18,754 CPAP
      patients and 71 (3.4%) of 2,072 UPPP patients were dead (P < 0.001). After
      adjustment, CPAP patients had 31% (95% confidence interval, 3% to 67%, P = 0.03)
      higher probability of being dead at any time, relative to UPPP patients
      [corrected]. CONCLUSIONS: UPPP confers a survival advantage over CPAP, after
      adjustment for age, gender, race, year of treatment, and comorbidity. However, we
      were unable to adjust for sleep apnea severity or CPAP use. Surgical treatment
      should be considered in sleep apnea patients who use CPAP inadequately.

PMID- 15195050
TI  - Pediatric total tonsillectomy using coblation compared to conventional
      electrosurgery: a prospective, controlled single-blind study.
AB  - OBJECTIVE: Postoperative recovery after tonsillectomy using Coblation excision
      (CES) was compared with conventional electrosurgery (ES). STUDY DESIGN AND
      SETTING: Patients aged 3 to 12 years from 3 clinical sites were randomly assigned
      and blinded to receive tonsillectomy using CES (n = 44) or ES (n = 45). RESULTS:
      Operative parameters did not differ between groups. Return to normal diet,
      activity, and pain-free status were similar, although fewer CES patients
      contacted the physician regarding postoperative complications (33% vs 54%; p =
      0.081), experienced nausea (35% vs 62%, p = 0.013), or had localized site
      specific swelling (p < 0.05) during the 2 weeks after surgery. In addition, CES
      children tended to discontinue prescription narcotics 1 day earlier than ES
      patients (7 vs 8 days, p = 0.071) and took one half as many daily doses. More CES
      than ES parents rated the postoperative experience as 'better than expected' (79%
      vs 60%, p = 0.055). CONCLUSION AND SIGNIFICANCE: Children who received CES
      tonsillectomy appeared to experience a better quality postoperative course, with
      no detriment to operative benefits of conventional electrosurgery.

PMID- 15195051
TI  - Intraoral drainage: recommended as the initial approach for the treatment of
      parapharyngeal abscesses.
AB  - OBJECTIVE: We sought to compare the efficacy, safety, and cost of intraoral
      drainage (IOD) of parapharyngeal abscesses (PPAs) in the pediatric population
      with those of the more commonly used external neck drainage (END). PATIENTS AND
      STUDY DESIGN AND SETTING: An 11-year retrospective review was conducted of all
      patients admitted to a tertiary-care, university-affiliated, pediatric hospital
      with a diagnosis of PPA. Patients were divided into 2 groups according to the
      treatment received (IOD or END) and were followed to 1 month postoperatively. All
      children referred to our institution with a final diagnosis of PPA were included
      in the study. OUTCOME: Outcome measures were duration of anesthesia, duration of
      postoperative intravenous antibiotics (DPOIA), length of postoperative hospital
      stay (LPOHS), and occurrence of complications. RESULTS: Fifteen patients
      underwent IOD, and 10 patients, END. IOD shortened anesthesia time by 31.7
      minutes compared with END (P = 0.0003). IOD was associated with a decrease in
      DPOIA and LPOHS by 1.1 days (P = 0.1931) and 1.6 days (P = 0.0649), respectively.
      The cost of treatment was thereby reduced. No complications were encountered in
      either group. CONCLUSIONS: IOD is a safe and effective treatment for PPA in the
      pediatric population. It leads to decreased morbidity, shortened anesthesia time,
      and reduced economic burden.

PMID- 15195052
TI  - The effectiveness of immersion disinfection for flexible fiberoptic
      laryngoscopes.
AB  - OBJECTIVE: We sought to determine whether high-level disinfection renders
      fiberoptic laryngoscopes free of nonviral infectious microorganisms. METHODS: Six
      flexible fiberoptic laryngoscopes in heavy use were subjected to surveillance
      cultures at the beginning, middle, and end of the clinical workday after high
      level disinfection to determine if microorganisms could be recovered. Control
      cultures were obtained by direct contamination of the endoscope with saliva. The
      rate of microorganism recovery from the endoscopes after high-level disinfection
      was determined and compared with control specimens. RESULTS: Among a total of 48
      cultures submitted from in use but disinfected fiberoptic laryngoscopes, 1
      positive culture (positive rate, 2.1%) for mold species was recovered. No
      positive bacterial cultures occurred. Eleven of 11 (100%) control cultures were
      positive for bacterial species (P < 0.001). The confidence interval for the risk
      of microorganism contamination of a disinfected laryngoscope ranged from 0.11% to
      11.6%. CONCLUSION: High-level disinfection provides a reasonably effective method
      of reducing bacterial and fungal contamination of flexible fiberoptic
      laryngoscopes. Appropriate surveillance technique should be used in each clinical
      setting with flexible fiberoptic scopes to ensure adequate disinfection
      effectiveness.

PMID- 15195053
TI  - Concurrent laryngeal abnormalities in patients with paradoxical vocal fold
      dysfunction.
AB  - OBJECTIVE: Our goal was to investigate the presence of laryngeal abnormalities is
      patients with paradoxical vocal fold dysfunction (PVFD). STUDY DESIGN AND
      SETTING: A retrospective chart review was performed of patients referred for
      evaluation of paradoxical vocal fold dysfunction between July 2002 and December
      2002. The patients completed questionnaires at the time of the office visit. Data
      collected from the medical record included age, gender, duration of symptoms
      before evaluation, asthma, gastroesophageal reflux symptoms, and laryngoscopic
      findings. Exercise stress test was performed when suitable. The diagnosis of PVFD
      was made based on patient history and laryngoscopy. RESULTS: Thirty patients were
      identified. There was a 27:3 (90%) female predominance, and mean age of
      presentation at was 28 years (range, 12 to 67 years). The median time from the
      onset of respiratory symptoms to diagnosis was 4.5 years (range, 0.5 to 30
      years). Of the 30 patients, 17 (56%) had asthma, 16 had laryngeal findings
      suggestive of gastroesophageal reflex disease, 4 (12%) had laryngoscopic findings
      of chronic laryngitis, and 10 (33%) had additional findings, including
      laryngomalacia, vocal fold motion impairment, sulcus vocalis, nodules, and
      subglottic stenosis, mostly in the exercise-induced group. CONCLUSIONS:
      Concomitant laryngeal abnormalities are present in a many patients with PVFD,
      particularly in those with exercise-induced symptoms. Laryngoscopy is important
      in the management of these patients.

PMID- 15195054
TI  - Image-guided radiosurgery of head and neck cancers.
AB  - OBJECTIVES: Radiosurgery precisely delivers a single high dose or a few
      fractionated doses of radiation to a localized tumor via the stereotactic
      approach. Some head and neck sites are suitable for radiosurgery since there is
      minimal or no organ motion. The clinical studies were carried out to determine
      the accuracy of stereotactic radiosurgery and to demonstrate the effectiveness of
      radiosurgery in head and neck cancers. MATERIALS AND METHODS: Thirteen patients
      were treated with either single-dose or fractionated radiosurgery to the tumor.
      All patients except one with cancer of the lip had received prior treatments
      including surgery, radiotherapy, and chemotherapy for the primary cancers. The
      dose ranged 12 to 18 Gy for single-dose radiosurgery and 30 Gy in 5 or 6
      fractions twice a week for fractionated radiosurgery. Tumor localization was
      achieved via the stereotactic approach. RESULTS: Accuracy of radiosurgery was
      within 1.5 mm. Despite the recurrent disease from previous heavy treatments, 9
      patients (70%) showed a significant response (complete or >50% tumor reduction)
      to radiosurgery, and 3 patients had stable disease. Complete tumor response was
      achieved in 6 patients. All patients had excellent pain relief with functional
      and cosmetic preservation. There was no acute and subacute radiation toxicity
      detected clinically during the minimal follow-up of 6 months. CONCLUSION: Image
      guided radiosurgery is effective in achieving the local tumor control and pain
      relief. Radiosurgery provided excellent functional and cosmetic preservation with
      minimal complication. The results indicate the potential of radiosurgery in the
      treatment of recurrent and selected primary head and neck cancers.

PMID- 15195055
TI  - c-met overexpression in supraglottic laryngeal squamous cell carcinoma and its
      relation to lymph node metastases.
AB  - BACKGROUND: The c-met oncogene encodes the receptor for the hepatocyte growth
      factor/scatter factor (HGF/SF), which is known to have the effects of stimulation
      of cell motility, dissociation of epithelial sheets, invasion of cellular matrix,
      and induction of angiogenesis. Many studies in solid tumors have indicated a role
      for c-met and HGF/SF in the progression of the disease. METHODS: The expression
      of c-met in tissue specimens was studied by immunohistochemical examination in 60
      patients with supraglottic laryngeal squamous cell carcinoma. Patients were
      chosen such that there were 30 with lymph node metastases in the neck and 30
      without metastases. TNM staging, differentiation, lymphovascular and perineural
      invasion, and growth pattern for tumors were also recorded, and their relation to
      lymph node metastases was analyzed. RESULTS: Overexpression of c-met was observed
      in 90% of the cases at the primary site and in 83% of the cases with lymph node
      metastases in the neck. Lymphovascular invasion (P = 0.005) and the N stage (P =
      0.001) were found to be related to lymph node metastases, but other variables-c
      met overexpression, the T stage, perineural invasion, and growth pattern-were
      found to have no relation to lymph node metastases in multivariate analysis of
      the data with linear regression. CONCLUSIONS: c-met overexpression is observed in
      both the primary site and the neck in supraglottic laryngeal squamous cell
      carcinoma. We believe that it may have a role in the progression of malignancy,
      but we were unable to find a definite relation between c-met expression and lymph
      node metastases.

PMID- 15195056
TI  - The versatile extended pericranial flap for closure of skull base defects.
AB  - OBJECTIVE: We sought to demonstrate the technical aspects of the extended
      pericranial flap and its versatility in reconstruction of a variety of skull base
      defects. STUDY DESIGN: We conducted a retrospective chart review of 32 patients
      who underwent reconstruction of skull-base defects with an extended pericranial
      flap by the senior author (Y.D.) from September 1997 to July 2003. METHODS:
      Patients with skull base defects after trauma or extirpative surgery were
      reconstructed with either a lateral- or an anterior-based vascularized extended
      pericranial flap. Variables and outcomes measured included: the size and
      anatomical location of the defect, need for other flaps, preoperative and/or
      postoperative radiation therapy and/or chemotherapy, bone flap necrosis, hardware
      exposure, wound dehiscence, postoperative cerebrospinal fluid (CSF) leak, and
      meningitis. RESULTS: There was no evidence of flap failure, 2 cases of transient
      (3 to 4 days) CSF leak without resultant meningitis, 3 patients with hardware
      exposure, and 2 patients with hydroxyapatite infection. The 2 transient cases of
      CSF leak both resolved without further surgical intervention or the placement of
      a lumbar drain. CONCLUSION: Both the lateral and anteriorly based extended
      pericranial flaps are reliable and versatile flaps associated with minimal
      morbidity and a low rate of complications when used to reconstruct defects of the
      anterolateral skull base.

PMID- 15195057
TI  - Management of Ludwig's angina with small neck incisions: 18 years experience.
AB  - OBJECTIVE: To review Ludwig's angina medical and surgical approach with small
      incisions. STUDY DESIGN: Retrospective, open, noncomparative, longitudinal.
      METHODS: All patients with Ludwig's angina who received medical, metabolic,
      airway management, and surgical treatment from January 1, 1983 to December 31,
      2000. STUDIED PARAMETERS: Antibiotic treatment, surgical treatment,
      hospitalization time, associated diseases, etiologic factors, recuperation time.
      RESULTS: Age range was 18 to 87 years, with a female-to-male ratio of 1.1:1 (68
      females, 53 males). Thirty patients belonged to middle or high socioeconomic
      status. The primary site of infection was odontogenic in 107 of the patients. All
      the patients were managed with surgical drainage made within the first 12 hours
      after hospital admission. The most common antibiotic treatments were the
      combination of clindamycin with crystalline penicillin G. The hospital stay for
      more than half of patients was 6 days or less. In 62 patients we found extension
      into the parapharyngeal space and in 32 cases we found retropharyngeal extension
      of the Ludwig's angina. Forty-six patients had or were diagnosed as having
      diabetes mellitus. Tracheotomy was required in 34 patients. The airway of the
      rest of patients was controlled with nasotracheal intubation. Only 33 patients
      had major complications, such as mediastinitis, sepsis, or death. CONCLUSIONS:
      Drainage using small incisions is a safe and effective method as part of
      treatment of Ludwig's angina.

PMID- 15195058
TI  - Genotype and phenotype of glutathione-S-transferase in patients with head and
      neck carcinoma.
AB  - OBJECTIVE: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and
      cancer has been demonstrated. Possible underlying mechanisms and genotype
      phenotype correlations are not adequately investigated. The aim of this study was
      to investigate the influence of the GSTM1-null-genotype on the level of GSTM
      enzyme concentration and on the enzyme activity of GST in patients with head and
      neck cancer (HNC). METHODS: We investigated in 83 patients and 91 healthy
      controls the GSTM1 polymorphisms, GSTM1 protein concentration, GSTM1 protein in
      tumor tissues, and total GST enzyme activity. RESULTS: Total GST enzyme activity
      was significantly lower in patients with HNC (208 +/- 9 micromol/min*l) than in
      controls (264 +/- 11 micromol/min*l, P< 0.0001) but did not depend on GSTM1
      genotype (P = 0.1). GSTM protein concentration in null-genotype patients (3.6 +/-
      2.5 microg/mL, mean +/- SE) was significantly lower than in GSTM1 allele carriers
      (26.7 +/- 9.6 microg/ml, P< 0.0001); GSTM protein expression did not depend on
      GSTM1-genotype (P> 0.5). CONCLUSION: GST enzyme activity in patients with HNC is
      suppressed, indicating impaired detoxification capacity of tobacco-smoke-related
      carcinogens. This suppression is not correlated with the GSTM1-genotype.

PMID- 15195059
TI  - Acoustic neuroma surgical cost and outcome by hospital volume in California.
AB  - CONTEXT: Successful outcome of complex surgical techniques depend on the surgical
      team's level of experience. However, unless benefit is demonstrated in the
      presence of cost savings, insurance companies are reluctant to approve care from
      highly experienced hospitals and surgical teams. OBJECTIVE: To determine the
      relationship between the number of acoustic neuroma surgeries performed at
      California hospitals with surgical outcome and hospital stay cost. DESIGN:
      Acoustic neuroma surgery information was extracted from the California hospital
      discharge database and was grouped according to the number of surgeries performed
      at each hospital. SETTING: A database review of California hospitals. PATIENTS:
      Persons (n=1,213) undergoing acoustic neuroma surgery at a California hospital
      between 1996 and 1998. Main outcome measures Outcome measures included discharge
      status (routine vs. not routine), medical procedures indicating surgical
      complications, total cost of hospitalization, and average cost per
      hospitalization day. Odds ratios were used to compare the hospital volume groups
      on likelihood of a routine surgical outcome. RESULTS: The frequency of routine
      surgical outcome increased as hospital acoustic neuroma surgical volume
      increased, ranging from 68% among patients in the lowest volume group to 97% in
      the highest hospital volume group. Patients in the highest hospital volume group
      were 15 times more likely to have a routine surgical outcome than patients in the
      lowest hospital volume group. Patients in the second highest volume group were 5
      times more likely to have a routine surgical outcome than in the lowest volume
      group. The two highest volume hospital groups had lower total charges and average
      charges per day than the two lower volume hospital groups. CONCLUSIONS: Acoustic
      neuroma surgeries at higher volume hospitals had higher frequency of routine
      discharge, lower frequency of apparent complications, and lower average cost of
      hospitalization.

PMID- 15195060
TI  - Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic
      solution in the treatment of granulation tissue in children with acute otitis
      media with otorrhea through tympanostomy tubes.
AB  - OBJECTIVE: Comparison of topical ciprofloxacin/dexamethasone otic suspension
      (CIP/DEX) to ofloxacin otic solution (OFL) for treatment of granulation tissue in
      children with AOMT. STUDY DESIGN: 599 children aged >/=6 months to 12 years with
      AOMT of up to 3 weeks' duration were enrolled. Patients received either CIP/DEX 4
      drops twice daily for 7 days or OFL 5 drops twice daily for 10 days. Granulation
      tissue severity was graded at clinic visits on days 1, 3, 11, and 18. RESULTS:
      Granulation tissue was present in 90 of 599 AOMT patients (15.0%) at baseline.
      CIP/DEX treatment was superior to OFL for reduction of granulation tissue at the
      day 11 visit (81.3% compared with 56.1%, P = 0.0067) and the day 18 visit (91.7%
      compared with 73.2%, P = 0.0223). Both topical otic preparations are safe and
      well tolerated in pediatric patients. CONCLUSION: CIP/DEX was superior to OFL in
      the treatment of granulation tissue in children with AOMT.

PMID- 15195061
TI  - Contact diode laser myringotomy and mitomycin C in children.
AB  - OBJECTIVE: To investigate the use of contact diode laser myringotomy (C-LAM),
      combined with topical mitomycin C, as an alternative method for prolonged middle
      ear ventilation in children with otitis media with effusion. STUDY DESIGN AND
      SETTING: Prospective study at a tertiary care pediatric institution. METHODS:
      Fifteen children enrolled in the study. Mitomycin C was applied to the intact
      tympanic membrane in the right ears, whereas saline on the left side was used for
      controls. C-LAM was then performed in all ears. Outcome measures included healing
      rate and scarring, ear infection, and long-term audiometric follow-up. RESULTS:
      There was no significant difference in median healing rate. In each group, the
      median was between the third and fourth month. Normal hearing thresholds were
      obtained in all children at 2-year follow-up. CONCLUSION: C-LAM proved to be an
      effective method for medium-term ventilation, but topical mitomycin C before C
      LAM did not prolong patency rate in our patients. No significant complication was
      encountered at 2-year follow-up.

PMID- 15195062
TI  - The role of food allergy in otitis media with effusion.
AB  - OBJECTIVE: To detect the relationship between food allergy and otitis media with
      effusion (OME). MATERIALS AND METHODS: This study was performed on three
      different groups. The patient group was made up of 56 patients with OME (group
      I). There were 28 patients with food allergy in group II and these patients were
      investigated for OME. The control group consisted of 28 patients without any
      complaints concerning food allergy or OME (group III). RESULTS: Food allergy was
      detected in 25 patients with OME (44.6%) (group I). In patients with food allergy
      (group II), OME was detected in 7 patients (25%). In the control group (group
      III) food allergy was diagnosed in 5 patients (18%) and OME in 1 patient (3%).
      The incidence of food allergy in OME group was statistically significant when
      compared to the normal group (P > 0.05). CONCLUSIONS: This study demonstrates
      that food allergy may play a role in the etiopathogenesis of OME.

PMID- 15195063
TI  - Tone perception of Cantonese-speaking prelingually hearing-impaired children with
      cochlear implants.
AB  - OBJECTIVE: To evaluate tone perception performance in Cantonese-speaking
      prelingually hearing-impaired children with cochlear implants. STUDY DESIGN AND
      SETTING: The ability to discriminate and identify Cantonese tones was evaluated
      on 17 native Cantonese-speaking prelingually hearing-impaired children.
      Performance was correlated to factors like age of implantation and general
      communication ability. RESULTS: Subjects' performance in discrimination and
      identification tasks was slightly above chance level. Although variations in the
      contour fundamental frequency of the tones provided some cues for tone
      discrimination, these distinctions proved insufficient for subjects to perform
      well. Tone 6 (low level tone) was the most difficult to identify. Subjects'
      performance did not correlate with gender, age of implantation, duration of
      implant use, frequency of auditory training session, or general communication
      ability. CONCLUSION: Although some children were able to discriminate and/or
      identify Cantonese tones, their performance was poor. Further studies are needed
      to understand how tone perception relate to daily speech understanding.
      SIGNIFICANCE: Cochlear implant speech coding strategies may need modification to
      optimize tone perception.

PMID- 15195064
TI  - Tuberculous otitis media: a significant diagnostic challenge.
AB  - OBJECTIVE: This study was undertaken to revise the diagnostic characteristics of
      tuberculous otitis media (TOM), a disorder that is often diagnosed late, leading
      to delay in specific treatment. STUDY DESIGN AND SETTING: Retrospective study of
      a longitudinal series of 10 TOM patients over a 7-year period at an institutional
      referral center. RESULTS: Most patients showed intractable otorrhea, moderately
      severe hearing loss, and necrotic eardrums with granulation tissue and single
      perforations. Multiple perforations, facial palsy, and cervical adenopathies were
      rare (<10% of patients). CT generally showed soft tissue involvement of the
      middle ear without bone erosion. The most effective laboratory test
      microbiological culture of exudate (diagnostic efficacy 71%). Specific antibiotic
      treatment was effective in all cases. CONCLUSION: The diagnosis of TOM remains a
      significant challenge for otorhinolaryngologists. SIGNIFICANCE: If there are
      strong clinical grounds for suspicion, standard laboratory tests for tuberculosis
      should be repeated even if initially negative.

PMID- 15195065
TI  - Nasal mucociliary clearance in coal mine workers.
AB  - OBJECTIVE: The purpose of this study was to analyze the effect of coal dust
      particles on nasal mucociliary function in coal mine workers. METHOD: Using the
      saccharin method, nasal mucociliary clearance was determined for 77 subjects, of
      which 39 who worked in a coal mine were actively exposed to coal dust whereas 38
      were unexposed control subjects. The measurements were performed in the coal
      mine, at the level of 170 m below sea level. RESULTS: The average saccharin nasal
      transit time in coal mine workers, 12.61 (SD: 4.30) minutes, is longer than that
      of the control subjects, 10.97 (SD: 3.22). CONCLUSION: Although the findings of
      this study demonstrate that the coal particles affect the nasal mucociliary
      clearance, the difference in saccharin nasal transit time between the two groups
      (exposed vs unexposed) is not statistically significant (P = 0.063).

PMID- 15195066
TI  - Practice parameter: laryngeal electromyography (an evidence-based review).
AB  - This paper reports on an evidence-based review of laryngeal electromyography
      (EMG) as a technique for use in the diagnosis, prognosis, and treatment of
      laryngeal movement disorders including the laryngeal dystonias, vocal fold
      paralysis, and other neurolaryngological disorders. The authors performed a
      systematic review of the medical literature from 1944 through 2001 on the
      clinical application of EMG to laryngeal disorders. The review yielded 584
      articles of which 33 met the predefined inclusion criteria. The evidence
      demonstrated that in a double-blind treatment trial of botulinum toxin versus
      saline, laryngeal EMG used to guide injections into the thyroarytenoid muscle in
      persons with adductor spasmodic dysphonia was beneficial. A cross-over comparison
      between laryngeal EMG-guided injection and endoscopic injection of botulinum
      toxin into the posterior cricoarytenoid muscle in abductor spasmodic dysphonia
      found no significant difference between the 2 techniques and no significant
      treatment benefit. Based on the evidence, laryngeal EMG is possibly useful for
      the injection of botulinum toxin into the thyroarytenoid muscle in the treatment
      of adductor spasmodic dysphonia. There were no evidence-based data sufficient to
      support or refute the value of laryngeal EMG for the other uses investigated,
      although there is extensive anecdotal literature suggesting that it is useful for
      each of them. There is an urgent need for evidence-based research addressing
      other applications in the use of laryngeal EMG for other applications.

PMID- 15195067
TI  - Anterior craniofacial resection without facial skin incisions--a review.

PMID- 15195068
TI  - Bilateral vocal cord paresis as a presenting sign of paraneoplastic syndrome:
      case report.

PMID- 15195069
TI  - Isolated traumatic thyroid hemorrhage secondary to air bag deployment.

PMID- 15195071
TI  - Alterations of intracellular pH homeostasis in apoptosis: origins and roles.
AB  - Intracellular pH (pHi) has an important role in the maintenance of normal cell
      function, and hence this parameter has to be tightly controlled within a narrow
      range, largely through the activity of transporters located at the plasma
      membrane. These transporters can be modulated by endogenous or exogenous
      molecules as well as, in some pathological situations, leading to pHi changes
      that have been implicated in both cell proliferation and cell death. Whereas
      intracellular alkalinization seems to be a common feature of proliferative
      processes, the precise role of pHi in apoptosis is still unclear. The present
      review gathers the most recent advances along with previous data on both the
      origin and the role of pHi alterations in apoptosis and highlights the major
      concerns that merit further research in the future. Special attention is given to
      the possible role played by pHi-regulating transporters.

PMID- 15195070
TI  - Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix.
AB  - Programmed cell death (pcd) may take the form of apoptotic or nonapoptotic pcd.
      Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the
      mediators of nonapoptotic cell death programs are much less well characterized.
      Here, we report that paraptosis, an alternative, nonapoptotic cell death program
      that may be induced by the insulin-like growth factor I receptor (among other
      inducers), is mediated by mitogen-activated protein kinases (MAPKs) and inhibited
      by AIP-1/Alix. The inhibition by AIP-1/Alix is specific for paraptosis since
      apoptosis was not inhibited. Caspases were not activated in this paradigm, nor
      were caspase inhibitors effective in blocking cell death. However, insulin-like
      growth factor I receptor (IGFIR)-induced paraptosis was inhibited by MEK-2
      specific inhibitors and by antisense oligonucleotides directed against c-jun N
      terminal kinase-1 (JNK-1). These results suggest that IGFIR-induced paraptosis is
      mediated by MAPKs, and inhibited by AIP-1/Alix.

PMID- 15195072
TI  - Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant
      recipient.

PMID- 15195073
TI  - Acquired hemophilia-A in a patient with multiple sclerosis treated with
      autologous hematopoietic stem cell transplantation and interferon beta-1a.

PMID- 15195074
TI  - Busulphan given as four single daily doses of 150 mg/m2 is safe and effective in
      children of all ages.
AB  - We examined the effects of busulphan (BU) dose and patient age on toxicity and
      outcome in 63 children with acute leukaemia given BUCY prior to allogeneic or
      autologous BMT. BU was administered as four single daily oral doses, based either
      on weight (4 x 4 mg/kg) or surface area (4 x 150 mg/m2). BU pharmacokinetic
      analysis was not used to dose adjust. The average daily (mg/kg) BU dose was 43%
      higher for the group given 150 mg/m2 compared to the 4 mg/kg dose group. This
      produced a median BU AUC 61% higher than with the 4 mg/kg dose. Only one child
      did not achieve full allogeneic donor engraftment. Regimen-related toxicity was
      low. Although younger children had faster BU clearance, the 4 x 150 mg/m2 dose
      ensured equivalent systemic exposure to BU, and resulted in a high frequency of
      engraftment without a significant increase in serious toxicity. BU, given as four
      single daily doses of 150 mg/m2, is appropriate and safe in all age groups of
      children. Given the reliable pharmacokinetics, low toxicity and high rate of
      allogeneic engraftment, there is no need for routine pharmacokinetic monitoring
      or dose modifications. This dosage regimen may be applicable for use with i.v.
      BU.

PMID- 15195075
TI  - Fatal late-onset EBV-associated post transplant lymphoproliferative disease after
      umbilical cord blood transplantation due to persistent mixed chimerism and severe
      delay in T-cell recovery in a patient with Omenn's syndrome.

PMID- 15195076
TI  - Antirecipient helper and cytotoxic T-cell frequencies in bone marrow
      transplantation.
AB  - We assayed helper T-lymphocyte precursor frequencies (HTLPf), interferon (IFN)
      gamma-producing cell frequencies (IFN-gammaPf) and CTL precursor frequencies
      (CTLPf) to see if they could predict the severity of acute graft-versus-host
      disease (aGVHD) and disease relapse after transplantation. In all, 48 bone marrow
      transplantation (BMT) patients and their HLA-identical sibling (n=29) or matched
      unrelated donors (MUD) (n=19) were recruited. HTLPf, IFN-gammaPf and CTLPf were
      measured using a limiting dilution assay (LDA). Patients were followed
      prospectively to assess the severity of aGVHD and the status of the primary
      disease after BMT. High (>5 x 10(-6)) HTLPf, CTLPf and IFN-gammaPf were
      significantly associated with the occurrence and severity of aGVHD in patients
      who received transplants from HLA-identical sibling. Among patients receiving BMT
      from MUD, HTLPf and CTLPf, but not IFN-gammaPf, were associated with aGVHD. Five
      patients had disease relapse post-BMT and the risk was not significantly
      associated with HTLPf, CTLPf or IFN-gammaPf. Patients with high (>5 x 10(-6))
      HTLPf, IFN-gammaPf or CTLPf before BMT are at higher risk of developing aGVHD
      after transplantation from both matched sibling donors and MUD. Whether these
      parameters can predict disease relapse would have to be investigated with a
      larger cohort of patients.

PMID- 15195077
TI  - Isolated HLA-C mismatches in unrelated donor transplantation for CML.
AB  - HLA-incompatibility is a major factor associated with outcome of allogeneic stem
      cell transplantation, but little is known on the impact of isolated HLA-C
      mismatches. We analyzed the outcome of 114 CML patients transplanted with marrow
      from unrelated donors of whom 24 were mismatched for HLA-C only (9/10 match).
      Univariate estimates of 5-year survival (SRV) (median follow-up: 47 months) in
      the HLA-matched group were 68+/-12 vs 42+/-20% (P=0.03) for the patients
      mismatched for HLA-C only and 33+/-33% in the mismatched group (non-HLA-C single
      mismatches and multiple mismatches) (P=0.0004). Disease stage, GVHD-prophylaxis
      (T-cell depletion), CMV-status and HLA-incompatibility were the risk factors
      associated (all P< or =0.005) with poor outcome. In the multivariate analysis,
      patients mismatched for loci other than HLA-C were at high risk of an adverse
      outcome (death: RR, 2.9; CI, 1.6-5.4, P=0.008, transplant-related mortality
      (TRM): RR, 3; CI, 1.5-5.9, P=0.0015). For patients mismatched for HLA-C only, the
      increased risk was of borderline significance (death: RR, 1.9; CI, 1-3.9, P=0.06,
      TRM: RR, 2.1; CI, 1-4.5, P=0.07). In spite of their lower expression, HLA-C
      antigens still represent relevant transplantation barriers that should be
      considered when searching for an unrelated donor.

PMID- 15195078
TI  - High-dose cytosine arabinoside and etoposide with total body irradiation as a
      preparatory regimen for allogeneic hematopoietic stem-cell transplantation in
      patients with acute lymphoblastic leukemia.
AB  - One approach to improving the outcome of allogeneic hematopoietic stem-cell
      transplantation for acute lymphoblastic leukemia (ALL) is to intensify the
      pretransplant conditioning regimen without increasing toxicity. We used an
      intensified conditioning regimen consisting of high-dose cytosine arabinoside (3
      g/m(2) twice daily i.v. for 3 consecutive days, total six doses), high-dose
      etoposide (1 g/m(2) once daily i.v. during the first 2 days) and total body
      irradiation (TBI) (HDACE-TBI) in ALL patients. We retrospectively analyzed 21
      patients treated with HDACE-TBI, of whom 18 were in complete remission (CR) and
      three were in non-CR at transplantation. Although gastrointestinal toxicities
      were common, critical regimen-related toxicities were not seen in any patients.
      One patient demonstrated veno-occlusive disease, which could be controlled
      conservatively. The disease-free survival rate of 18 patients in CR at
      transplantation was 61%. These results demonstrate that the HDACE-TBI combination
      regimen is a feasible alternative to other preparatory regimens and does not
      increase the regimen-related toxicity.

PMID- 15195079
TI  - Treatment of menorrhagia in women undergoing hematopoietic stem cell
      transplantation.
AB  - The management of uterine bleeding in female transplant patients over a 3-year
      period at our institution was reviewed. A total of 33 females who had undergone
      allogeneic hematopoietic stem cell transplant were identified as having received
      gynecologic consultation for the diagnosis of menorrhagia. Hormone therapy
      achieved a resolution of symptoms in 32 (97%) of the patients, and 26 (79%)
      required only one hormone regimen. Following resolution of symptoms, transition
      to standard-dose oral contraceptive pills as maintenance therapy prevented
      recurrent menorrhagia due to high circulating estrogen levels. Alternatives for
      patients who are unable to tolerate oral administration and those with
      hepatotoxicity are also discussed.

PMID- 15195080
TI  - Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for
      Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible
      related donors.
AB  - Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors
      remains the only modality for the correction of hematological abnormalities in
      Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT
      using a novel irradiation and cyclophosphamide-free conditioning regimen. The
      protocol included fludarabine 150 mg/m(2), busulfan 4 mg/kg, and antithymocyte
      globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin
      A, MTX, and daclizumab. The engraftment and occurrence of full stable donor
      hemopoiesis was rapid in all cases with minimal short-term toxic complications.
      There were no infections or febrile episodes during the inpatient phase. Three
      patients developed acute GVHD grade I-II involving gut and skin and one patient
      progressed to extensive chronic GVHD. The preparative conditioning regimen is
      safe and associated with low organ toxicity and effective immunosupression for
      the stable engraftment in FA patients undergoing SCT with matched related donors.

PMID- 15195082
TI  - Scoring for HLA matching? A clinical test of HistoCheck.

PMID- 15195083
TI  - Direct laser writing of three-dimensional photonic-crystal templates for
      telecommunications.
AB  - The past decade has witnessed intensive research efforts related to the design
      and fabrication of photonic crystals. These periodically structured dielectric
      materials can represent the optical analogue of semiconductor crystals, and
      provide a novel platform for the realization of integrated photonics. Despite
      intensive efforts, inexpensive fabrication techniques for large-scale three
      dimensional photonic crystals of high enough quality, with photonic bandgaps at
      near-infrared frequencies, and built-in functional elements for telecommunication
      applications, have been elusive. Direct laser writing by multiphoton
      polymerization of a photoresist has emerged as a technique for the rapid, cheap
      and flexible fabrication of nanostructures for photonics. In 1999, so-called
      layer-by-layer or woodpile photonic crystals were fabricated with a fundamental
      stop band at 3.9 microm wavelength. In 2002, a corresponding 1.9 microm was
      achieved, but the important face-centred-cubic (f.c.c.) symmetry was abandoned.
      Importantly, fundamental stop bands or photonic bandgaps at telecommunication
      wavelengths have not been demonstrated. In this letter, we report the fabrication
      -through direct laser writing--and detailed characterization of high-quality
      large-scale f.c.c. layer-by-layer structures, with fundamental stop bands ranging
      from 1.3 to 1.7 microm.

PMID- 15195084
TI  - The plastic-crystalline phase of succinonitrile as a universal matrix for solid
      state ionic conductors.
AB  - Solid ionic conductors are actively sought for their potential application in
      electrochemical devices, particularly lithium batteries. We have found high ionic
      conductivity for a large variety of salts dissolved in the highly polar medium
      based on the plastic-crystal form of succinonitrile (N[triple
      bond]C[bond]CH(2)[bond]CH(2)[bond]C[triple bond]N). Its high diffusivity,
      plasticity and solvating power allowed the preparation of a large number of
      materials with high ionic conductivity, reaching values of 3 mS cm(-1) at 25
      degrees C (two orders of magnitude above polymers). Their ease of preparation and
      processing allowed us to study the influence of the solute on ionic conduction
      within this medium. Comparisons revealed a dichotomy between plastic crystals and
      conventional polymer media. The usefulness of these new, easily processed
      electrolytes was asserted in electrochemical tests with lithium intercalation
      electrodes.

PMID- 15195085
TI  - Apolipoprotein E promotes astrocyte colocalization and degradation of deposited
      amyloid-beta peptides.
AB  - We have previously shown that apolipoprotein E (Apoe) promotes the formation of
      amyloid in brain and that astrocyte-specific expression of APOE markedly affects
      the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer
      disease. Given the capacity of astrocytes to degrade Abeta, we investigated the
      potential role of Apoe in this astrocyte-mediated degradation. In contrast to
      cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not
      degrade Abeta present in Abeta plaque-bearing brain sections in vitro.
      Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist
      of the low-density lipoprotein receptor family, effectively blocks Abeta
      degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(
      /-) astrocytes do not respond to or internalize Abeta deposits to the same extent
      as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation
      and clearance of deposited Abeta species by astrocytes, a process that may be
      impaired in Alzheimer disease.

PMID- 15195086
TI  - Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling.
AB  - Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous
      system mediated by G-protein-coupled receptors. Here, we examined the role of LPA
      signaling in the development of neuropathic pain by pharmacological and genetic
      approaches, including the use of mice lacking the LPA(1) receptor. Wild-type
      animals with nerve injury develop behavioral allodynia and hyperalgesia
      paralleled by demyelination in the dorsal root and increased expression of both
      the protein kinase C gamma-isoform within the spinal cord dorsal horn and the
      alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal
      injection of LPA induced behavioral, morphological and biochemical changes
      similar to those observed after nerve ligation. In contrast, mice lacking a
      single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho
      kinase pathway do not develop signs of neuropathic pain after peripheral nerve
      injury. Inhibitors of Rho and Rho kinase also prevented these signs of
      neuropathic pain. These results imply that receptor-mediated LPA signaling is
      crucial in the initiation of neuropathic pain.

PMID- 15195087
TI  - Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic
      AMP-activated protein kinase.
AB  - AMP-activated protein kinase (AMPK) functions as a fuel sensor in the cell and is
      activated when cellular energy is depleted. Here we report that alpha-lipoic acid
      (alpha-LA), a cofactor of mitochondrial enzymes, decreases hypothalamic AMPK
      activity and causes profound weight loss in rodents by reducing food intake and
      enhancing energy expenditure. Activation of hypothalamic AMPK reverses the
      effects of alpha-LA on food intake and energy expenditure.
      Intracerebroventricular (i.c.v.) administration of glucose decreases hypothalamic
      AMPK activity, whereas inhibition of intracellular glucose utilization through
      the administration of 2-deoxyglucose increases hypothalamic AMPK activity and
      food intake. The 2-deoxyglucose-induced hyperphagia is reversed by inhibiting
      hypothalamic AMPK. Our findings indicate that hypothalamic AMPK is important in
      the central regulation of food intake and energy expenditure and that alpha-LA
      exerts anti-obesity effects by suppressing hypothalamic AMPK activity.

PMID- 15195088
TI  - Myelomonocytic cells are sufficient for therapeutic cell fusion in liver.
AB  - Liver repopulation with bone marrow-derived hepatocytes (BMHs) can cure the
      genetic liver disease fumarylacetoacetate hydrolase (Fah) deficiency. BMHs emerge
      from fusion between donor bone marrow-derived cells and host hepatocytes. To use
      such in vivo cell fusion efficiently for therapy requires knowing the nature of
      the hematopoietic cells that fuse with hepatocytes. Here we show that the
      transplantation into Fah(-/-) mice of hematopoietic stem cells (HSCs) from
      lymphocyte-deficient Rag1(-/-) mice, lineage-committed granulocyte-macrophage
      progenitors (GMPs) or bone marrow-derived macrophages (BMMs) results in the
      robust production of BMHs. These results provide direct evidence that committed
      myelomonocytic cells such as macrophages can produce functional epithelial cells
      by in vivo fusion. Because stable bone marrow engraftment or HSCs are not
      required for this process, macrophages or their highly proliferative progenitors
      provide potential for targeted and well-tolerated cell therapy aimed at organ
      regeneration.

PMID- 15195089
TI  - Injection of recombinant human type VII collagen restores collagen function in
      dystrophic epidermolysis bullosa.
AB  - Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechano-bullous
      disorders that are caused by mutations in the type VII collagen gene and for
      which ex vivo gene therapy has been considered. To develop a simpler approach for
      treating DEB, we evaluated the feasibility of protein-based therapy by
      intradermally injecting human recombinant type VII collagen into mouse skin and a
      DEB human skin equivalent transplanted onto mice. The injected collagen localized
      to the basement membrane zone of both types of tissues, was organized into human
      anchoring fibril structures and reversed the features of DEB disease in the DEB
      skin equivalent.

PMID- 15195090
TI  - Critical functions for c-Myb at three checkpoints during thymocyte development.
AB  - The transcription factor c-Myb is expressed throughout T cell development in the
      thymus. However, little is understood about c-Myb function because of the
      embryonic lethality of traditional Myb-null mutations. Using tissue-specific
      deletion to abrogate c-Myb expression at distinct stages of T cell development,
      we identify three points at which c-Myb activity is required for normal T cell
      differentiation: transition through the double-negative 3 stage, survival of
      preselection CD4(+)CD8(+) thymocytes, and differentiation of CD4 thymocytes.
      Thus, c-Myb is essential at several stages during T cell development in the
      thymus.

PMID- 15195091
TI  - Separate domains of AID are required for somatic hypermutation and class-switch
      recombination.
AB  - Activation-induced cytidine deaminase (AID) is essential for class-switch
      recombination (CSR) and somatic hypermutation (SHM). Mutants with changes in the
      C-terminal region of AID retain SHM but lose CSR activity. Here we describe five
      mutants with alterations in the N-terminal region of AID that caused selective
      deficiency in SHM but retained CSR, suggesting that the CSR and SHM activities of
      AID may dissociate via interaction of CSR- or SHM-specific cofactors with
      different domains of AID. Unlike cells expressing C-terminal AID mutants, B cells
      expressing N-terminal AID mutants had mutations in the switch micro region,
      indicating that such mutations are generated by reactions involved in CSR but not
      SHM. Thus, we propose that separate domains of AID interact with specific
      cofactors to regulate these two distinct genetic events in a target-specific way.

PMID- 15195092
TI  - Periodic gene expression program of the fission yeast cell cycle.
AB  - Cell-cycle control of transcription seems to be universal, but little is known
      about its global conservation and biological significance. We report on the
      genome-wide transcriptional program of the Schizosaccharomyces pombe cell cycle,
      identifying 407 periodically expressed genes of which 136 show high-amplitude
      changes. These genes cluster in four major waves of expression. The forkhead
      protein Sep1p regulates mitotic genes in the first cluster, including Ace2p,
      which activates transcription in the second cluster during the M-G1 transition
      and cytokinesis. Other genes in the second cluster, which are required for G1-S
      progression, are regulated by the MBF complex independently of Sep1p and Ace2p.
      The third cluster coincides with S phase and a fourth cluster contains genes
      weakly regulated during G2 phase. Despite conserved cell-cycle transcription
      factors, differences in regulatory circuits between fission and budding yeasts
      are evident, revealing evolutionary plasticity of transcriptional control.
      Periodic transcription of most genes is not conserved between the two yeasts,
      except for a core set of approximately 40 genes that seem to be universally
      regulated during the eukaryotic cell cycle and may have key roles in cell-cycle
      progression.

PMID- 15195094
TI  - Neural correlates of second-language word learning: minimal instruction produces
      rapid change.
AB  - Adult second-language (L2) learning is often claimed to be slow and laborious
      compared to native language (L1) acquisition, but little is known about the rate
      of L2 word learning. Here we report that adult second-language learners' brain
      activity, as measured by event-related potentials (ERPs), discriminated between
      L2 words and L2 'pseudowords' (word-like letter strings) after just 14 h of
      classroom instruction. This occurred even while the learners performed at chance
      levels when making overt L2 word-nonword judgments, indicating that the early
      acquisition of some aspects of a new language may be overlooked by current
      behavioral assessments.

PMID- 15195093
TI  - Regulation of ion channel localization and phosphorylation by neuronal activity.
AB  - Voltage-dependent Kv2.1 K(+) channels, which mediate delayed rectifier Kv
      currents (I(K)), are expressed in large clusters on the somata and dendrites of
      principal pyramidal neurons, where they regulate neuronal excitability. Here we
      report activity-dependent changes in the localization and biophysical properties
      of Kv2.1. In the kainate model of continuous seizures in rat, we find a loss of
      Kv2.1 clustering in pyramidal neurons in vivo. Biochemical analysis of Kv2.1 in
      the brains of these rats shows a marked dephosphorylation of Kv2.1. In cultured
      rat hippocampal pyramidal neurons, glutamate stimulation rapidly causes
      dephosphorylation of Kv2.1, translocation of Kv2.1 from clusters to a more
      uniform localization, and a shift in the voltage-dependent activation of I(K). An
      influx of Ca(2+) leading to calcineurin activation is both necessary and
      sufficient for these effects. Our finding that neuronal activity modifies the
      phosphorylation state, localization and function of Kv2.1 suggests an important
      link between excitatory neurotransmission and the intrinsic excitability of
      pyramidal neurons.

PMID- 15195095
TI  - Dopamine depletion impairs precursor cell proliferation in Parkinson disease.
AB  - Cerebral dopamine depletion is the hallmark of Parkinson disease. Because
      dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect
      neural precursors in the subependymal zone and subgranular zone of the adult
      brain. Here we provide ultrastructural evidence showing that highly proliferative
      precursors in the adult subependymal zone express dopamine receptors and receive
      dopaminergic afferents. Experimental depletion of dopamine in rodents decreases
      precursor cell proliferation in both the subependymal zone and the subgranular
      zone. Proliferation is restored completely by a selective agonist of D2-like
      (D2L) receptors. Experiments with neural precursors from the adult subependymal
      zone grown as neurosphere cultures confirm that activation of D2L receptors
      directly increases the proliferation of these precursors. Consistently, the
      numbers of proliferating cells in the subependymal zone and neural precursor
      cells in the subgranular zone and olfactory bulb are reduced in postmortem brains
      of individuals with Parkinson disease. These observations suggest that the
      generation of neural precursor cells is impaired in Parkinson disease as a
      consequence of dopaminergic denervation.

PMID- 15195096
TI  - Calmodulin permanently associates with rat olfactory CNG channels under native
      conditions.
AB  - An important mechanism by which vertebrate olfactory sensory neurons rapidly
      adapt to odorants is feedback modulation of the Ca(2+)-permeable cyclic
      nucleotide-gated (CNG) transduction channels. Extensive heterologous studies of
      homomeric CNGA2 channels have led to a molecular model of channel modulation
      based on the binding of calcium-calmodulin to a site on the cytoplasmic amino
      terminus of CNGA2. Native rat olfactory CNG channels, however, are heteromeric
      complexes of three homologous but distinct subunits. Notably, in heteromeric
      channels, we found no role for CNGA2 in feedback modulation. Instead, an IQ-type
      calmodulin-binding site on CNGB1b and a similar but previously unidentified site
      on CNGA4 are necessary and sufficient. These sites seem to confer binding of
      Ca(2+)-free calmodulin (apocalmodulin), which is then poised to trigger
      inhibition of native channels in the presence of Ca(2+).

PMID- 15195097
TI  - Adaptation changes the direction tuning of macaque MT neurons.
AB  - Prolonged exposure to a stimulus, called 'adaptation', reduces cortical
      responsiveness. Adaptation has been studied extensively in primary visual cortex
      (V1), where responsivity is usually reduced most when the adapting and test
      stimuli are well matched. Theories about the functional benefits of adaptation
      have relied on this specificity, but the resultant changes in neuronal tuning are
      of the wrong type to account for well-documented perceptual aftereffects. Here we
      have used moving sinusoidal gratings to study the effect of adaptation on the
      direction tuning of neurons in area MT in macaques. Responsivity in MT is
      maintained best in the adapted direction and is strongly reduced for nearby
      directions. Consequently, adaptation in the preferred direction reduces the
      direction-tuning bandwidth, whereas adaptation at near-preferred directions
      causes tuning to shift toward the adapted direction. This previously unknown
      effect of adaptation is consistent with perceptual aftereffects and indicates
      that different cortical regions may adjust to constant sensory input in distinct
      ways.

PMID- 15195098
TI  - Recalibration of audiovisual simultaneity.
AB  - To perceive the auditory and visual aspects of a physical event as occurring
      simultaneously, the brain must adjust for differences between the two modalities
      in both physical transmission time and sensory processing time. One possible
      strategy to overcome this difficulty is to adaptively recalibrate the
      simultaneity point from daily experience of audiovisual events. Here we report
      that after exposure to a fixed audiovisual time lag for several minutes, human
      participants showed shifts in their subjective simultaneity responses toward that
      particular lag. This 'lag adaptation' also altered the temporal tuning of an
      auditory-induced visual illusion, suggesting that adaptation occurred via changes
      in sensory processing, rather than as a result of a cognitive shift while making
      task responses. Our findings suggest that the brain attempts to adjust subjective
      simultaneity across different modalities by detecting and reducing time lags
      between inputs that likely arise from the same physical events.

PMID- 15195099
TI  - Deficits in saccade target selection after inactivation of superior colliculus.
AB  - Saccades are rapid eye movements that orient gaze toward areas of interest in the
      visual scene. Neural activity correlated with saccade target selection has been
      identified in several brain regions, including the superior colliculus (SC), but
      it is not known whether the SC is directly involved in target selection, or
      whether the SC merely receives selection-related signals from cortex in
      preparation for the execution of eye movements. In monkeys, we used focal
      reversible inactivation to test the functional contributions of the SC to target
      selection during visual search, and found that inactivation resulted in clear
      deficits. When a target appeared in the inactivated field, saccades were often
      misdirected to distractor stimuli. Control tasks showed that this deficit was not
      caused by low-level visual or motor impairments. Our results indicate that, in
      addition to its well-established involvement in movement execution, the SC has an
      important functional role in target selection.

PMID- 15195100
TI  - PML regulates p53 stability by sequestering Mdm2 to the nucleolus.
AB  - The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53
      function by regulating post-translational modifications, such as CBP-dependent
      acetylation and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB). PML
      was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6);
      however, the mechanism by which PML regulates Mdm2 remains unclear. Here, we show
      that PML enhances p53 stability by sequestering Mdm2 to the nucleolus. We found
      that after DNA damage, PML and Mdm2 accumulate in the nucleolus in an Arf
      independent manner. In addition, we found that the nucleolar localization of PML
      is dependent on ATR activation and phosphorylation of PML by ATR. Notably, in
      Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as
      p53 stabilization and the induction of apoptosis. Furthermore, we demonstrate
      that PML physically associates with the nucleolar protein L11, and that L11
      knockdown impairs the ability of PML to localize to nucleoli after DNA damage.
      These findings demonstrate an unexpected role of PML in the nucleolar network for
      tumour suppression.

PMID- 15195101
TI  - Nanoliter-scale synthesis of arrayed biomaterials and application to human
      embryonic stem cells.
AB  - Identification of biomaterials that support appropriate cellular attachment,
      proliferation and gene expression patterns is critical for tissue engineering and
      cell therapy. Here we describe an approach for rapid, nanoliter-scale synthesis
      of biomaterials and characterization of their interactions with cells. We
      simultaneously characterize over 1,700 human embryonic stem cell-material
      interactions and identify a host of unexpected materials effects that offer new
      levels of control over human embryonic stem cell behavior.

PMID- 15195102
TI  - Ex planta phytoremediation of trichlorophenol and phenolic allelochemicals via an
      engineered secretory laccase.
AB  - Plant roots release a range of enzymes capable of degrading chemical compounds in
      their immediate vicinity. We present a system of phytoremediation ex planta based
      on the overexpression of one such enzyme, a secretory laccase. Laccases catalyze
      the oxidation of a broad range of phenolic compounds, including polychlorinated
      phenols such as 2,4,6-trichlorophenol (TCP), that are among the most hazardous
      and recalcitrant pollutants in the environment. We isolated a secretory laccase
      cDNA of LAC1, which is specifically expressed in the roots of Gossypium arboreum
      (cotton). Transgenic Arabidopsis thaliana plants overexpressing LAC1 exhibited
      enhanced resistance to several phenolic allelochemicals and TCP. The secretory
      laccase activity in these plants was responsible for the conversion of sinapic
      acid into a mono-lactone type dimer and for the transformation of TCP.

PMID- 15195103
TI  - Single-chain antibodies against a plant viral RNA-dependent RNA polymerase confer
      virus resistance.
AB  - Crop loss due to viral diseases is still a major problem for agriculture today.
      We present a strategy to achieve virus resistance based on the expression of
      single-chain Fv fragments (scFvs) against a conserved domain in a plant viral RNA
      dependent RNA polymerase (RdRp), a key enzyme in virus replication. The selected
      scFvs inhibited complementary RNA synthesis of different plant virus RdRps in
      vitro and virus replication in planta. Moreover, the scFvs also bound to the RdRp
      of the distantly related hepatitis C virus. T(1) and T(2) progeny of transgenic
      lines of Nicotiana benthamiana expressing different scFvs either in the cytosol
      or in the endoplasmic reticulum showed varying degrees of resistance against four
      plant viruses from different genera, three of which belong to the Tombusviridae
      family. Virus resistance based on antibodies to RdRps adds another tool to the
      repertoire for combating plant viruses.

PMID- 15195104
TI  - Cold-shock induced high-yield protein production in Escherichia coli.
AB  - Overexpression of proteins in Escherichia coli at low temperature improves their
      solubility and stability. Here, we apply the unique features of the cspA gene to
      develop a series of expression vectors, termed pCold vectors, that drive the high
      expression of cloned genes upon induction by cold-shock. Several proteins were
      produced with very high yields, including E. coli EnvZ ATP-binding domain (EnvZ
      B) and Xenopus laevis calmodulin (CaM). The pCold vector system can also be used
      to selectively enrich target proteins with isotopes to study their properties in
      cell lysates using NMR spectroscopy. We have cloned 38 genes from a range of
      prokaryotic and eukaryotic organisms into both pCold and pET14 (ref. 3) systems,
      and found that pCold vectors are highly complementary to the widely used pET
      vectors.

PMID- 15195105
TI  - Structural basis for vinculin activation at sites of cell adhesion.
AB  - Vinculin is a highly conserved intracellular protein with a crucial role in the
      maintenance and regulation of cell adhesion and migration. In the cytosol,
      vinculin adopts a default autoinhibited conformation. On recruitment to cell-cell
      and cell-matrix adherens-type junctions, vinculin becomes activated and mediates
      various protein-protein interactions that regulate the links between F-actin and
      the cadherin and integrin families of cell-adhesion molecules. Here we describe
      the crystal structure of the full-length vinculin molecule (1,066 amino acids),
      which shows a five-domain autoinhibited conformation in which the carboxy
      terminal tail domain is held pincer-like by the vinculin head, and ligand binding
      is regulated both sterically and allosterically. We show that conformational
      changes in the head, tail and proline-rich domains are linked structurally and
      thermodynamically, and propose a combinatorial pathway to activation that ensures
      that vinculin is activated only at sites of cell adhesion when two or more of its
      binding partners are brought into apposition.

PMID- 15195106
TI  - Fine-needle aspiration in PreservCyt: a novel and reproducible method for
      possible ancillary proteomic pattern expression of breast neoplasms by SELDI-TOF.
AB  - Proteomic profiles of tumor protein expression by the surface enhanced laser
      desorption-ionization time of flight (SELDI-TOF) methodology have been shown to
      have a potential usefulness for protein discovery as well as screening,
      diagnosis, prognosis and therapeutic considerations of cancer from several organ
      systems. Fine-needle aspiration (FNA) specimens from tumor samples is an accepted
      method to diagnose the cells of interest but often can be a limited assessment
      due to quantity of the sample. The current use of fresh or rapidly frozen
      specimens for proteomic profiling can be burdensome for clinicians to collect and
      submit specimens. The current study tests the hypothesis that placement of FNA
      and other cytological material in PreservCyt may be an acceptable method of
      sample handling for protein profiling evaluation by this method though it may not
      be suitable for true protein discovery or characterization. Excised fresh breast
      tissue for evaluation and/or treatment of a variety of breast lesions were
      sampled by FNA technique and placed into PreservCyt. These samples were then
      homogenized under denaturing conditions and evaluated by the SELDI-TOF
      methodology. Most samples collected showed a satisfactory quantity of protein for
      analysis by the SELDI-TOF methodology. Protein patterns from a variety of benign
      and malignant lesions revealed reproducible patterns on triplicate testing.
      Benign lesions had similar protein patterns across age groups in this limited
      series that may have potential diagnostic significance. In conclusion, FNA of
      breast tissue placed in PreservCyt is a potentially acceptable method of sample
      handling for evaluation by the SELDI-TOF methodology for establishment of
      reproducible protein patterns. Preliminary results from a spectrum of breast
      lesions suggest these patterns may have potential for ancillary testing for
      diagnostic consideration of breast lesions. This collection methodology could
      simplify sample gathering for further testing of all types of cytological
      specimens by the SELDI-TOF methodology. Larger studies will be needed to assess
      this methodology as a diagnostic aid.

PMID- 15195107
TI  - Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and
      genotypic study of 42 cases in Singapore.
AB  - We studied the clinicopathologic features of 42 cases of nasal-type extranodal
      natural killer (NK)/T-cell lymphoma in Singapore and compared our findings with
      other series reported in the Asian and Western populations. A panel of
      immunohistochemical stains, which included CD2, CD3, CD4, CD8, CD56, T-cell
      intracellular Antigen-1 and granzyme B, and in situ hybridization for Epstein
      Barr virus encoded RNA (EBER) were performed. Polymerase chain reaction for T
      cell receptor-gamma gene rearrangement using both gel and capillary
      electrophoresis were evaluated to determine the proportion of tumors which are of
      true T-cell lineage. We also studied the functional status of the overexpressed
      p53 protein in these lymphomas by correlating p53 expression with its downstream
      target protein, p21. In all, 31 out of 42 cases presented in the upper
      aerodigestive tract. The other sites of involvement included gastrointestinal
      tract, skin, soft tissue, testis, liver, spleen, bone marrow and brain. The
      tumors displayed characteristic morphologic features. In situ hybridization for
      EBER was detected in 41 out of 42 cases (97.6%). The only significant adverse
      prognostic factor identified was an International Prognostic Index of two or
      more. A significantly higher proportion of the tumors (27%), compared to previous
      studies, demonstrated monoclonal T-cell receptor-gamma gene rearrangement. There
      was, however, no difference in survival or clinicopathologic features between the
      true NK-cell tumors and their T-cell counterparts. Overexpression of p53 was
      present in 40% of the cases, but no significant difference in survival rate was
      detected in patients with p53 overexpression and there was no association between
      p53 overexpression with large cell morphology, and advanced stage of disease.
      These findings suggest that molecular aberrations other than those of the p53
      pathway may be operative in the pathogenesis of this malignancy.

PMID- 15195108
TI  - Expression of PAX5 in CD20-positive multiple myeloma assessed by
      immunohistochemistry and oligonucleotide microarray.
AB  - Silencing of PAX5 gene by upregulation of B-lymphocyte-induced maturation protein
      1 (PRDM1) is essential for terminal differentiation of B cells to plasma cells.
      To investigate PAX5 gene expression and its protein product, B-cell-specific
      activator protein (BSAP), in a subgroup of multiple myeloma characterized by CD20
      expression, we studied PAX5/BSAP by immunohistochemistry in 25 cases of myeloma,
      all expressing moderate to strong CD20 by flow cytometric analysis, and
      correlated the results with PAX5 and PRDM1 mRNA levels analyzed by the Affymetrix
      HuGeneFL GeneChip microarray in 17 cases. Using paraffin-embedded bone marrow
      biopsy sections, we found PAX5/BSAP was expressed in 72% (18/25) of cases overall
      with an intensity ranging from weak (10, 56%) to strong (8, 44%). PAX5/BSAP was
      negative in 10 randomly selected CD20-negative myelomas included as negative
      controls. PAX5 mRNA levels correlated inversely with that of PRDM1 in both CD20
      positive and CD20-negative myelomas and failed to predict the expression levels
      of PAX5/BSAP, suggesting that detected PAX5/BSAP likely represents remnant of
      earlier stage of development. We conclude that CD20-positive myelomas expressing
      PAX5/BSAP can present as a diagnostic pitfall mimicking B-cell neoplasms with
      plasmacytoid differentiation.

PMID- 15195109
TI  - Frequent beta-catenin overexpression without exon 3 mutation in cutaneous
      lymphomas.
AB  - Beta-catenin is a ubiquitously cytoplasmic protein that has a critical role in
      embryonic development and mature tissue homeostasis through its effects on E
      cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Mutations
      that alter specific beta-catenin residues important for GSK-3beta
      phosphorylation, or increase the half-life of the protein, were identified in
      human cancer. However, the role of the Wnt pathway in B- and T-cell oncogenesis
      has not been extensively investigated. To assess the role of beta-catenin defects
      in primary cutaneous lymphomas, we examined the expression pattern and the
      genetic alteration of beta-catenin on 79 samples from 74 patients with primary
      cutaneous lymphomas from B- and T-cell origin. Immunohistochemical analysis
      revealed beta-catenin deregulation in five primary cutaneous B-cell lymphomas
      (21%) and in 21 primary cutaneous T-cell lymphomas (42%) without nuclear
      accumulation suggesting that activation and accumulation of beta-catenin may play
      an important role in the development of skin lymphomas. Mutation analysis of beta
      catenin exon 3, which included the responsible element for Wnt signaling, was
      therefore done in 19 samples. However, genetic alterations of beta-catenin exon 3
      were not detected in any of these cases suggesting that other regulatory
      mechanisms may be relevant in activating beta-catenin signaling in cutaneous
      lymphomas.

PMID- 15195110
TI  - Utilization of polymerase chain reaction on archival cytologic material: a
      comparison with fresh material with special emphasis on cerebrospinal fluids.
AB  - Use of the polymerase chain reaction (PCR) for the detection of B- and T-cell
      clonality, Epstein-Barr virus (EBV) and Human Herpes Virus 8 (HHV 8) infection is
      gaining increasing importance as a diagnostic modality. These tests are usually
      performed on fresh specimens. There are instances when fresh material is not
      available and there is a clinical utility for the performance of PCR on archival
      material via slide scrape lysates (SSL). However, the suitability of archival
      material may be questioned. Records were searched for all archival cytology cases
      submitted for SSL molecular diagnostics tests since 1998. Results for each case
      were analyzed for PCR amplification status and individual test results. A
      randomly chosen control group of equivalent cytologic samples submitted fresh was
      evaluated for comparison of amplification status. In all, 241 PCR runs were
      performed on SSL of archival material from 112 cytologic samples (89
      cerebrospinal fluids (CSFs), 13 fine-needle aspirates (FNAs), 10 effusions). Out
      of these samples, 95 (85%) had amplifiable DNA, as assessed by a positive
      reaction for glyceraldehyde phosphate dehydrogenase (GAPDH). For the control
      group, 320 PCR runs were performed on 112 fresh cytologic samples (89 CSFs, 13
      FNAs, 10 effusions). In total, 102 samples (91%) had amplifiable DNA. There was
      no statistical difference in the amplification yield between the two groups (P =
      0.2177). A morphologic review of 16 of the 17 SSL archival cytologic cases that
      did not show amplification revealed 11/16 to be of sparse cellularity. Molecular
      diagnostic tests are performed routinely on fresh cytologic samples with
      excellent results. At times critical decisions on patient care may need to be
      made when fresh tissue is not available for molecular diagnostic tests. SSL of
      archival cytologic material can be used with excellent results for molecular
      diagnostic tests when fresh material is not available or when the cytologic
      diagnosis needs further clarification.

PMID- 15195111
TI  - BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin,
      diagnosis and treatment.
AB  - Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients
      typically present with advanced disease where there is little hope for cure using
      conventional therapeutic modalities. Understanding the genetic alterations
      underlying the development of anaplastic thyroid carcinoma, such as mutational
      activation of BRAF, could help clarify its relationship with well-differentiated
      forms of thyroid carcinoma (ie follicular and papillary carcinoma) and could help
      select patients most likely to benefit from novel therapeutic strategies
      targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T) -
      > adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly
      developed assay that employs a novel primer extension method (Mutector assay).
      Seven of these anaplastic thyroid carcinomas arose in association with a well
      differentiated thyroid carcinoma, and these were also evaluated. The 1796T --> A
      mutation was detected in eight (50%) of the anaplastic thyroid carcinomas, in
      four of five (80%) associated papillary thyroid carcinomas, and in zero of two
      (0%) associated follicular carcinomas. In all seven cases where anaplastic
      thyroid carcinoma arose in association with a well-differentiated thyroid
      carcinoma, BRAF status in the two components was concordant. Like papillary
      thyroid carcinoma, a significant percentage of anaplastic thyroid carcinomas also
      harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic
      thyroid carcinoma occur together, they consistently share the same BRAF profile,
      supporting the notion that many anaplastic thyroid carcinomas actually represent
      progressive malignant degeneration of a pre-existing well-differentiated thyroid
      carcinoma. The high frequency of BRAF mutations in a tumor that is generally
      regarded as uniformly fatal justifies evaluation of the potential benefits of
      anti-BRAF therapy for patients with anaplastic thyroid carcinoma.

PMID- 15195112
TI  - Survivin expression in hepatocellular carcinoma: correlation with proliferation,
      prognostic parameters, and outcome.
AB  - Survivin is a novel inhibitor of apoptosis. It is detected in fetal and
      neoplastic adult tissue, but not in normal tissues. Several recent studies have
      shown that survivin not only inhibits apoptosis, but also accelerates cancer cell
      proliferative activity. Expression of the protein may be of prognostic
      significance and therapeutic relevance in many cancers. We investigated survivin
      expression in hepatocellular carcinoma, correlating results with proliferation
      (MIB-1), prognostic factors, and outcome. Paraffin-embedded sections of 72
      hepatocellular carcinoma were immunostained for survivin and MIB-1 using tissue
      microarray technology. Expression was evaluated in nuclei and cytoplasm as
      intensity (0-3+), and percentage of positive cells scored on a four-tiered system
      with less than 10%=negative; 10-25%=1; 26-50%=2; 51-75%=3; and 76-100%=4.
      Frequency of nuclear survivin expression was 43%. There was a significant
      correlation between nuclear survivin expression and nuclear grade (P=0.0271),
      microvascular invasion (P=0.0064), mitotic rate (P=0.0017), and MIB-1 (P=0.0001),
      as well as local recurrence (P=0.0487), and disease-free survival (P=0.0098).
      Histologic grade (P=0.0544) and stage (P=0.0548) tended to correlate with
      survivin expression, which did not correlate with cirrhosis, tumor necrosis,
      multiple tumors, metastatic disease, or overall survival. Survivin expression
      correlates with poor prognostic parameters (high nuclear and histologic grade,
      microvascular invasion, increased proliferation (mitotic count, MIB-1)), local
      recurrence, and shorter disease-free survival, but does not correlate with
      overall survival. An important role is suggested for survivin in progression,
      recurrence, and treatment of hepatocellular carcinoma.

PMID- 15195113
TI  - Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma.
AB  - The Wnt signaling pathway is essential for normal development and organogenesis.
      However, inappropriate activation of Wnt signaling, which results in the nuclear
      translocation of beta-catenin, is associated with the development of various
      types of neoplasm. In this study, we investigated possible mutations in the genes
      for components of this pathway, namely, CTNNB1 (the gene for beta-catenin),
      AXIN1, and APC, in adenoid cystic carcinoma, by PCR, analysis of single-strand
      conformational polymorphism, and sequencing. Among a total of 20 cases of adenoid
      cystic carcinoma, seven cases (35%) were associated with mutations in one or more
      of these three components. A mutation in CTNNB1 was detected in one case. Five
      cases, including the case with a mutation in CTNNB1, were associated with
      missense mutations in AXIN1. An aberration in the mutation cluster region of APC
      was detected in two cases. Mutations trended to be detected more frequently in
      adenoid cystic carcinoma with solid growth pattern than that with tubular and
      cribriform growth pattern. In the cases in which we detected mutations, it is
      possible that the presence of the abnormal products of the mutated genes resulted
      in the inappropriate activation of the Wnt signaling pathway to tumorigenesis and
      the growth of adenoid cystic carcinoma.

PMID- 15195114
TI  - Altered expression of adhesion molecules and epithelial-mesenchymal transition in
      silica-induced rat lung carcinogenesis.
AB  - Loss of the epithelial phenotype and disruption of adhesion molecules is a
      hallmark in the epithelial-mesenchymal transition (EMT) reported in several types
      of cancer. Most of the studies about the relevance of adhesion and junction
      molecules in lung cancer have been performed using established tumors or in vitro
      models. The sequential molecular events leading to EMT during lung cancer
      progression are still not well understood. We have used a rat model for multistep
      lung carcinogenesis to study the status of adherens and tight junction proteins
      and mesenchymal markers during EMT. After silica-induced chronic inflammation,
      rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and
      tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with
      normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar
      type II cells, the expression levels of E-cadherin, alpha-catenin and beta
      catenin were significantly reduced in adenomatoid preneoplastic lesions and in
      late tumors. The loss of E-cadherin in tumors was associated with its promoter
      hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic
      accumulation in some carcinomas. No nuclear beta-catenin localization was found
      at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein
      1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell
      carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were
      analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of
      adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor
      cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas.
      Mesenchymal markers were absent in precursor lesions, both hyperplastic and
      adenomatoid. The present results show that silica-induced rat lung carcinogenesis
      is a good model to study EMT in vivo, and also provide in vivo evidence
      suggesting that the changes in cell-cell adhesion molecules are an early event in
      lung carcinogenesis, while EMT occurs at a later stage.

PMID- 15195115
TI  - Expression of a colorectal antigen defined by a new monoclonal antibody, CO-TL1.
AB  - A murine monoclonal antibody (MoAb CO-TL1, IgG1) has been raised by differential
      screening of hybridoma supernatants on sections of human large and small
      intestines, followed by screening on colon adenomas as well as on colorectal
      carcinomas. In both paraffin sections and cryostat sections, the antibody stained
      strongly all cell types in adult, neonatal and fetal human colorectal epithelium,
      that is, the goblet cells, the columnar cells and the endocrine cells. No
      staining was observed in the remaining parts of the normal gastrointestinal tract
      and other tissues. As revealed by immuno electron microscopy the epitope was
      present in the apical and basolateral cell membranes, the Golgi complex,
      secretory vesicles of goblet and columnar cells, and also in granules of the
      endocrine cells. The epitope in colorectal tissue sections was resistant to the
      deglycosylation enzymes neuramidase, diastase and hyaluronidase indicating its
      proteinaceous nature. This colorectal antigen remained expressed in 100% of
      colorectal adenomas (n = 39) and 86% (n = 29) of colorectal carcinomas. The
      expression was reduced in undifferentiated carcinomas. The CO-TL1 antibody
      detected also most other gastrointestinal adenocarcinomas and a few carcinomas of
      the ovary, uterus, breast, gallbladder and pancreas. However, it never detected
      carcinomas derived from the thyroid, lung, liver, bladder, kidney, prostate,
      testis, serous membranes of body cavities and skin. A wild-type variant protein
      of > 300 kDa of the colorectal antigen was identified in normal colorectal
      epithelium. In colorectal tumours, however, two tumour variant forms were found
      of 160-200 and 115-140 kDa, respectively. Our data indicate that this new MoAb CO
      TL1 can be considered as a useful marker, which identifies normal colorectal
      epithelium and gastrointestinal tumours and especially colorectal tumours with
      high accuracy and excludes tumours originated from thyroid, lung, liver, bladder,
      kidney, prostate, testis, mesothelium and skin.

PMID- 15195116
TI  - Long-term preservation of antigenicity on tissue microarrays.
AB  - Tissue microarrays have facilitated the evaluation of large cohort studies;
      however, there is little data on the best method for preserving sections once
      they are cut. We assessed three methods of storing precut breast cancer
      microarray slides: paraffin coating and storage in a nitrogen desiccator, either
      alone or in combination. We tested the durability of three antigens, cytokeratin,
      estrogen receptor, and Ki-67 on microarrays stored under these conditions for 3
      months at room temperature. Staining was assessed with both manual scoring using
      traditional brown stain (0-3+) as well as automated scoring using fluorescently
      stained sections. Staining intensity was compared to that obtained from freshly
      cut slides. Slides stored under ambient conditions (room temperature and air) for
      3 months exhibited marked degradation of all target antigens, in some cases
      resulting in slides that were virtually unreadable. We found that combined
      paraffin coating and nitrogen storage resulted in the best preservation of
      antigenicity, with retention of 72-99% of the antigenicity of a freshly cut
      slide, depending upon the marker and detection system used. The use of either
      paraffin coating or nitrogen storage alone protected slides to a lesser degree.

PMID- 15195117
TI  - Possible involvement of MIP-1alpha in the recruitment of osteoclast progenitors
      to the distal tibia in rats with adjuvant-induced arthritis.
AB  - In the rat model of rheumatoid arthritis, a marked formation of osteoclasts is
      found in the distal tibia and the metatarsal bone. It was therefore postulated
      that osteoclast progenitors would be increased in the bone marrow cavities of
      rats with adjuvant-induced arthritis (AA rats). Bone marrow cells obtained from
      tibia of AA rats were cultured to form cells in the osteoclast lineage to access
      the number of osteoclast progenitors. Unexpectedly, only a suppressed level of
      osteoclast progenitors was detected in the diaphyseal bone marrow of tibia in AA
      rats. Distribution of osteoclast progenitors in the bone marrow cavity was
      examined, and it was shown that osteoclast progenitors accumulated in the distal
      tibia. Macrophage inflammatory protein (MIP)-1alpha, an osteoclastogenic CC
      chemokine, was expressed in ED-1-positive macrophages localizing in the distal
      tibia with marked bone destruction. Chemotaxis studies showed that MIP-1alpha
      expressed significant activity towards bone marrow cells. The suppressed level of
      osteoclastogenesis in bone marrow cells of AA rats was restored to a normal level
      by the addition of MIP-1alpha. It was suggested that MIP-1alpha is involved in
      the migration of osteoclast progenitors to the distal tibia as well as in
      osteoclastogenesis in AA rats. In these rats, in situ hybridization of the distal
      tibia with a high level of bone destruction showed significant expression of
      Receptor activator nuclear factor kappaB ligand (RANKL) messenger RNA in
      aggregates of multinucleated osteoclast-like cells present in the bone marrow
      cavity, a unique pathological feature for these rats. Migrated osteoclast
      progenitors are thought to be efficiently differentiated into osteoclasts in
      response to RANKL expressed by the aggregates of osteoclast-like cells under the
      influence of the MIP-1alpha. Such positive-feedback regulation of
      osteoclastogenesis could result in the highest recruitment of active osteoclasts
      in the area of marked bone destruction.

PMID- 15195118
TI  - Differential role of neutrophils and monocytes during subcutaneous plasma
      extravasation.
AB  - We examined the behavior of polymorphonuclear leukocytes (PMNs) and monocytes
      during subcutaneous plasma extravasation in guinea-pigs. Plasma extravasation was
      induced by intradermal injection of zymosan-activated plasma (ZAP). The degree of
      extravasation correlated logarithmically with the concentration of injected ZAP,
      and was composed of PMN-dependent and -independent components. The latter was
      mediated primarily by histamine. The former accounted for 40-50% of the total
      plasma extravasation, peaked within 15 min, and then rectilinearly decreased with
      a half-life between 30 and 40 min. Histological examination of skin at 15 min
      after ZAP injection demonstrated PMN attachment to the luminal surface of venule
      endothelial cells, without evidence of PMN extravasation. We next examined
      whether monocyte infiltration of subcutaneous tissue played a causal role in
      plasma extravasation. Monocyte-predominant infiltration was initially caused by
      an intradermal injection of a monocyte-specific chemotactic factor, the S19
      ribosomal protein (RP S19) dimer. Monocyte infiltration did not induce plasma
      extravasation even in guinea-pigs with elevated peripheral blood monocyte levels
      following administration of a macrophage-colony stimulating factor. A
      simultaneous injection of prostaglandin E2, a vasodilating agent, with RP S19
      dimer also did not induce plasma extravasation. In contrast, a simultaneous
      injection of RP S19 dimer with ZAP changed the leukocyte infiltration pattern
      from PMN-predominant to monocyte-predominant, and almost completely suppressed
      the PMN-dependent component of the ZAP-induced plasma extravasation. The lack of
      plasma extravasation in the monocyte-predominant pattern was reproduced when a
      strong monocyte infiltration was induced by an intradermal injection of apoptotic
      cells. We conclude that leukocyte-induced plasma extravasation is specific for
      PMN, and is not due to a physical leakage of plasma during leukocyte emigration.
      Rather, plasma extravasation is probably caused by a cognate interaction between
      PMNs and postcapillary venule endothelial cells.

PMID- 15195119
TI  - Protective effect of vascular endothelial growth factor/vascular permeability
      factor 165 and 121 on glomerular endothelial cell injury in the rat.
AB  - Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF)
      promotes the repair of injured vessels by stimulating angiogenesis. VEGF/VPF
      reportedly has cytoprotective activity but no study has shown the protective
      effect of VEGF/VPF on glomerular endothelial cells. We examined whether
      recombinant VEGF/VPF121 and VEGF/VPF165 isoforms could prevent injury of
      glomerular endothelial cells. Mild glomerular injury was induced in rats by an
      intravenous-injection of a limited dose of anti-Thy-1.1 antibody to obtain
      lesions similar to those found in the human disease. Recombinant VEGF/VPF165,
      VEGF/VPF121 or BSA was administered 4 h before the injection of the antibody, and
      once daily for 3 days. In the BSA-injected rats, mesangial cell lysis and
      endothelial cell injury in dilated capillary tufts were evident without
      endothelial cell apoptosis on days 1-4. Thereafter, cell proliferation and repair
      began and remodeling of the glomeruli was completed by day 28. Macrophages but
      not polymorphonuclear leukocytes accumulated significantly in the glomeruli on
      days 1-4. Treatment with VEGF/VPF isoform protected endothelial cells but not
      mesangial cells from destruction on day 1, and accelerated the repair of both
      types of cells, which was completed by day 18, 10 days earlier than that of the
      control animals. The results indicate that VEGF/VPF121 or VEGF/VPF165 can protect
      glomerular endothelial cells against injury, independent of apoptosis-inhibition
      activity, thereby promoting reconstruction of glomeruli. The protective effect of
      VEGF/VPF on endothelial cells suggests that it could provide therapeutic benefit
      for certain kidney diseases.

PMID- 15195120
TI  - Coupling multiplex RT-PCR to a gene chip assay for sensitive and semiquantitative
      detection of severe acute respiratory syndrome-coronavirus.
AB  - An early and accurate diagnostic assay for severe acute respiratory syndrome
      (SARS) is crucial for infection control. However, most of the diagnostic methods
      available today, such as real-time reverse transcriptase-polymerase chain
      reaction (RT-PCR), require a second detection method for confirmation because
      they detect a single sequence region of the SARS-coronavirus (SARS-CoV). For
      sensitive and accurate early diagnosis, we report a novel assay system combining
      multiplex RT-PCR and a diagnostic gene chip to detect multiple virus-specific
      genomic sequences of SARS-CoV. With 53 clinical specimens, we successfully
      demonstrate that this technique offers not only a high-accuracy diagnosis for
      early SARS infection but also a semiquantitative assay.

PMID- 15195122
TI  - What's hot in the prostate?

PMID- 15195123
TI  - Lycopene and prostate cancer.
AB  - The role of diet and dietary supplements in the development and progression of
      prostate cancer represents an increasingly frequent topic of discussion in the
      urologist's office. As access to information becomes forever easier, patients are
      more aware and educated about this subject than ever before. The role of
      antioxidants including carotenoids in all this has been the subject of great
      interest for some time. Lycopene, the carotenoid that gives tomatoes and other
      fruits and vegetables their red colour, has been of particular interest recently
      as regards its role in prostate cancer. The aim of this review is to briefly
      outline the biology and chemistry of lycopene, the scientific basis for its
      proposed anticancer properties and evaluate what conclusions the practicing
      urologist may draw from the data thus far. The media and industry have raced to
      encourage not only diets high in lycopene but also dietary lycopene supplements
      but there is probably only sufficient evidence to recommend to patients a diet
      rich in all vegetables and fruits of which tomatoes and tomato based products
      should certainly be a part.

PMID- 15195124
TI  - PC-SPES: a herbal therapy for the treatment of hormone refractory prostate
      cancer.
AB  - In this review the authors consider the commercially available herbal product PC
      SPES. This is a combination of eight different herbs marketed for its effects of
      reducing prostate specific antigen (PSA) levels, improving pain, and enhancing
      the quality of life of those with hormone refractory prostate cancer. The
      evidence for these claims does not appear to be as conclusive as reported by the
      manufactures of this product. There also appears to be a significant risk of deep
      vein thrombosis (DVT) in those treated with PC-SPES. There have been 116 clinical
      and laboratory based studies of PC-SPES published to date, but there have been no
      randomised controlled trials conducted. Many of these studies contain very few
      patients, thus making the drawing of conclusions difficult. Despite this lack of
      information, there still remains a large patient group taking this supplement,
      therefore caution should be advised in the usage of PC-SPES in the treatment of
      hormone refractory prostate cancer.

PMID- 15195125
TI  - In the prostatic epithelium, dietary isoflavones from red clover significantly
      increase estrogen receptor beta and E-cadherin expression but decrease
      transforming growth factor beta1.
AB  - In mice fed a diet supplemented with red clover isoflavones the prostatic
      epithelium displays a significant increase in the production of estrogen receptor
      beta and the adhesion protein E-cadherin but a decrease in transforming growth
      factor beta1. These proteins are estrogenically-induced markers of proliferation,
      maintenance of histological architecture, preservation of cell phenotype and
      reduction of the potential for neoplastic and metastatic transformation. This
      study suggests that red clover isoflavones represent a non-toxic dietary
      treatment for prostatic hyperplasia and a reduction in the potential for
      neoplastic transformation.

PMID- 15195126
TI  - Polymorphisms of GSTP1 and related genes and prostate cancer risk.
AB  - Glutathione S-transferase P1 (GSTP1) is markedly downregulated in prostate cancer
      and prostatic intraepithelial neoplasia compared to normal prostate tissue.
      Downregulation of GSTP1 may, therefore, be an early event in prostate
      carcinogenesis. An A-->G polymorphism at nucleotide 313 results in an amino acid
      substitution (Ile105Val) in the substrate binding site of GSTP1 and reduces
      catalytic activity of GSTP1. In a study of 36 prostate cancer patients, Harries
      et al. reported that the Ile/Ile genotype is associated with a decreased risk of
      prostate cancer (odds ratio 0.4 (0.17-0.82)). We sought to confirm this finding
      and to examine the impact of this polymorphism together with several related
      polymorphisms implicated as risk factors for carcinogen-associated malignancies.
      One hundred and seventeen patients with prostate adenocarcinoma and 183
      population-based controls were recruited to this case-control study. Genotyping
      of the GSTP1 (Ile105Val), GSTM1 (null), GSTT1 (null) and CYP1A1 (Ile462Val) genes
      was performed using polymerase chain reaction (PCR) based techniques on DNA
      prepared from peripheral blood. A questionnaire was used to collect demographic
      information from each subject. Cases were significantly older (P<0.0001) and had
      significantly greater family history of prostate cancer (P<0.0001), confirming
      known risk factors for this disease. By chi(2) analysis, none of the genotype
      distributions varied among cases and controls. Using a logistic regression model
      to control for known risk factors we were also unable to demonstrate a
      significant association with prostate cancer for any of the polymorphisms tested.
      This population fails to identify a relationship between the above polymorphisms
      and prostate adenocarcinoma.

PMID- 15195127
TI  - No association of the 5' promoter region polymorphism of CYP17 gene with prostate
      cancer risk.
AB  - CYP17 gene encodes the enzyme cytochrome p450c17alpha, which mediates two steps
      in the steroid biosynthesis pathway. Steroid hormones are believed to play a key
      role in the etiology of prostate cancer. A polymorphic T-->C transition in the
      5(') promoter region of CYP17 creates an additional Sp1-type (CCACC box) promoter
      site (allele A2). We have evaluated the genotypic and allelic distribution of
      this polymorphism among 92 prostate cancer patients in order to assess risk by
      comparison with a population-based series of 200 healthy individuals from Brazil.
      Our results provide no evidence for an association between prostate cancer risk
      and CYP17 T/C polymorphism.

PMID- 15195128
TI  - Prostate cancer screening at an equal access tertiary care center: its impact 10
      years after the introduction of PSA.
AB  - INTRODUCTION AND OBJECTIVES: Dwight D. Eisenhower Army Medical Center has been
      involved in Prostate Cancer Awareness Week (PCAW) screening during the period
      1995-2000. The purpose of this study is to review the results of screening in a
      self-selected population of military beneficiaries at our institution. MATERIALS
      AND METHODS: Screening involving a brief urologic history, digital rectal
      examination (DRE) and serum prostatic specific antigen (PSA) measurement was
      offered to our screening population. Patients with an elevated PSA (>4.0 ng/ml)
      and/or a suspicious DRE were considered for transrectal ultrasonography with
      prostate needle biopsy (TRUS/PNB). Patient health records were reviewed
      retrospectively and analyzed to determine patient demographic characteristics,
      PSA distribution, DRE results and cancer detection rates. RESULTS: A total of 455
      screening visits were performed from 1995 to 2000, of which 426 visits were
      included for analysis. Mean age of the study population was 57.4 y (40-83).
      Seventy-one percent of the patients reported prior PSA screening visits. Forty
      four patients met indications for biopsy. A total of 30 TRUS/PNB were performed
      demonstrating presence of cancer in three patients for an overall cancer
      detection rate of 0.7%. CONCLUSIONS: Our study shows that the overall prostate
      cancer detection rate at our institution is lower than detection rates previously
      reported in the literature. Potential reasons for this finding may include that
      the subjects participating in PCAW screening tended to be younger than in other
      series and that a majority of them had already undergone prior screening. These
      findings suggest the need to modify prostate cancer screening recommendations and
      to improve prostate cancer screening efficacy.

PMID- 15195129
TI  - In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi
      213 labeled J591 antibody against the prostate specific membrane antigen.
AB  - Limited options for the treatment of prostate cancer have spurred the search for
      new therapies. One innovative approach is the use of targeted alpha therapy (TAT)
      to inhibit cancer growth, using an alpha particle emitting radioisotope such as
      (213)Bi. Because of its short range and high linear energy transfer (LET), alpha
      particles may be particularly effective in the treatment of cancer, especially in
      inhibiting the development of metastatic tumors from micro-metastases. Prostate
      specific membrane antigen (PSMA) is expressed in prostate cancer cells and the
      neovasculature of a wide variety of malignant neoplasms including lung, colon,
      breast and others, but not in normal vascular endothelium. The expression is
      further increased in higher-grade cancers, metastatic disease and hormone
      refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies
      (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi
      forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical
      study was to design an injectable AIC to treat human prostate tumors growing
      subcutaneously in mice. The anti-proliferative effects of AIC against prostate
      cancer were tested in vitro using the MTS assay and in vivo with the nude mice
      model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]
      mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while
      proliferative index was assessed using the Ki-67 marker. We show that a very high
      density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP
      LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC
      extensively inhibits the growth of LN3 cells in vitro in a concentration
      dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies
      showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation
      gave complete inhibition of tumor growth, whereas results for a non-specific AIC
      were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor
      appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can
      inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice.
      Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the
      first week or 71+/-15 mm(3) in the third week to non-palpable, while in control
      mice treated with a non-specific AIC using the same dose, tumor volume increased
      from 42 to 590 mm(3). There were no observed side effects of the treatment.
      Because of its in vitro cytotoxicity and these anti-proliferative properties in
      vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic
      agent for the treatment of prostate cancer.

PMID- 15195130
TI  - The role of external radiotherapy in patients treated with permanent prostate
      brachytherapy.
AB  - To examine the difference in Prostate Specific Antigen (PSA)-Relapse Free
      Survival (RFS) in patients (pts) with prostate cancer treated with permanent
      prostate brachytherapy (PPB) alone (monotherapy) or combined modality PPB and
      external radiotherapy (CMT) by a matched pair analysis. There were 1476 pts who
      were treated loosely based on the American Brachytherapy Society criteria for
      monotherapy or CMT. PSA-RFS was based upon the Kattan modification of the ASTRO
      consensus panel definition. A computer generated matching process was undertaken
      to produce two equally weighted pairs of patients divided by treatment
      methodology and Kaplan-Meier PSA-RFS curves were generated and compared by chi(2)
      testing. All pts were treated between 1992 and 2000 with a 6-y PSA-RFS of 81.9%.
      The median follow-up was 34.7 months. Patients treated with CMT presented with
      higher pre-treatment PSA values, Gleason sum score, clinical stage, risk
      classification, and were more likely to be treated with neoadjuvant hormones. A
      matched-pair analysis with 314 pts in each group was created stratified by the
      addition of neoadjuvant hormones, Gleason score sum and the pretreatment PSA
      value. Actuarial 5-y PSA-RFS was 77.0% for the monotherapy group and 81.1% for
      the combined therapy group (P=0.54).chi(2) testing by pretreatment PSA value,
      Gleason score sum, risk stratification, isotope and the addition of neoadjuvant
      hormones failed to identify any group with a significant difference in 5-y PSA
      RFS. In conclusion, this retrospective study presents a large cohort of patients
      treated with PPB that failed to identify a significant advantage for the addition
      of combined therapy. A matched pair analysis performed also failed to identify
      any significant difference based on treatment modality.

PMID- 15195131
TI  - Variable definitions influence the reporting of biochemical failure rates.
AB  - The purpose of this study was to assess how the reporting of biochemical failure
      (BF) rates would be affected by the application of three different definitions.
      Three hundred and fifteen men with localized prostate cancer underwent I-125
      brachytherapy (n=109), conformal three-dimensional radiation therapy (n=99), or
      radical prostatectomy (n=107). No patient received adjuvant or neoadjuvant
      hormone therapy in this study. BF rates at 12, 24 and 36 months were assessed
      using three definitions: (1) prostate-specific antigen (PSA) nadir >0.5 ng/ml;
      (2) PSA rise by 0.5 ng/ml; and (3) three consecutive PSA rises. Median follow-up
      for the brachytherapy group, external beam radiotherapy group, and the radical
      prostatectomy group was 27, 30 and 36 months respectively. The applied definition
      influenced reporting of failure rates in two of the three groups. I-125
      brachytherapy group: BF rates at 24 months: 46%-definition 1, 35%-definition 2,
      and 4%-definition 3 (P<0.05). Radiation therapy group: BF rates at 24 months: 39%
      definition 1, 17%-definition 2 and 3%-definition 3 (P<0.05). No patient in the
      radical prostatectomy group had a BF by any applied definition. A more universal
      definition of BF is needed to compare the efficacy of treatments for localized
      prostate cancer.

PMID- 15195132
TI  - Parathyroid hormone-related peptide: expression in prostate cancer bone
      metastases.
AB  - Parathyroid hormone-related peptide (PTHrP) is a regulatory protein associated
      with cell growth in non-osseous tissues and with osteoclast stimulation in bone.
      It has been implicated in the pathogenesis of bone metastases, particularly in
      breast carcinoma. PTHrP is widely expressed in primary prostate cancers, but
      there are few reports of its expression in prostatic metastases. The aim of this
      study was to examine the expression of PTHrP in bone metastases from patients
      with untreated adenocarcinoma of the prostate. Ten bone biopsies containing
      metastatic deposits of untreated prostatic cancer were identified. These were
      immunohistochemically stained for PTHrP using a murine monoclonal antibody
      (PTHLP[Ab1]) and the streptavidin-biotin complex technique. Intensity of staining
      for PTHrP was graded by two observers. In total, PTHrP expression was positive in
      5/10 specimens. This was graded as moderate in four and weak in one. In those
      specimens with positive staining, the expression varied between cells. There was
      no obvious association between expression of PTHrP and tumour differentiation.
      PTHrP is expressed in prostatic bone metastases and may have a role in their
      pathogenesis and pathophysiology. However, expression is not universal.

PMID- 15195133
TI  - Acute periprostatic haematoma following a transrectal ultrasound-guided needle
      biopsy of the prostate.
AB  - Transrectal ultrasound (TRUS)-guided needle biopsy is routinely performed to
      diagnose and stage prostate carcinoma in an outpatient setting. Although serious
      adverse effects are rare, minor complications are common. We report the
      occurrence of an acute periprostatic haematoma as an unusual complication of TRUS
      guided needle-biopsy of the prostate, resulting in the patient requiring prompt
      resuscitation and hospital admission.

PMID- 15195135
TI  - The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell
      proliferation.
AB  - Epithelial cell adhesion molecule (EpCAM) is a membrane glycoprotein expressed on
      adenomatous and simple epithelia, where it is involved in homophilic adhesion at
      the basolateral membrane. Carcinomas strongly overexpress EpCAM through an, as
      yet, unknown mechanism. Interestingly, otherwise EpCAM-negative squamous
      epithelia are seen to express EpCAM concomitant with their transformation and de
      differentiation. The amount of EpCAM and the number of expressing cells both
      increase with the grade of dysplasia. Despite an important amount of data
      correlating the expression of EpCAM with cellular proliferation and de
      differentiation, such as the coexpression with Ki-67, a marker for proliferation,
      it is unknown whether EpCAM may directly contribute to carcinogenesis. Here, we
      show that EpCAM has a direct impact on cell cycle and proliferation, and the
      ability to rapidly upregulate the proto-oncogene c-myc and cyclin A/E. Human
      epithelial 293 cells as well as murine NIH3T3 fibroblasts expressing EpCAM had a
      decreased requirement for growth factors, enhanced metabolic activity and colony
      formation capacity. Importantly, the inhibition of EpCAM expression with
      antisense mRNA led to a strong decrease in proliferation and metabolism in human
      carcinoma cells. Moreover, domain swapping experiments demonstrated that the
      intracellular part of EpCAM is necessary and sufficient to transduce the effects
      described. Thus, the data presented here highlight the role of EpCAM,
      demonstrating for the first time a direct link to cell cycle and proliferation.

PMID- 15195136
TI  - Identification of a Myb-responsive enhancer of the chicken C/EBPbeta gene.
AB  - The retroviral oncogene v-myb encodes a transcription factor (v-Myb) that
      disrupts myelomonocytic differentiation and transforms myelomonocytic cells. It
      is thought that the biological effects of v-Myb are caused by deregulation of
      specific target genes. The CCAAT box/enhancer binding protein beta (C/EBPbeta), a
      member of the basic region-leucine zipper (bzip) class of transcription factors,
      which itself plays an important role during myelomonocytic differentiation, has
      previously been shown to be regulated by Myb. Here we have addressed the
      mechanism by which v-Myb affects C/EBPbeta expression. We have employed the
      mapping of DNase I hypersensitive sites (DHSs) in chromatin as a tool to detect
      in vivo target sites of v-Myb. Our data identify a DHS downstream of the
      C/EBPbeta gene that appears to be specific for v-myb-transformed myeloblasts. We
      have confirmed by chromatin immunoprecipitation that v-Myb is bound to this
      region in vivo. Furthermore, we have found that ectopic expression of v-Myb in a
      myelomonocytic cell line is able to induce a DHS downstream of the C/EBPbeta
      gene, showing for the first time that v-Myb can affect chromatin structure.
      Reporter gene experiments demonstrate that the downstream DHS acts as a Myb
      dependent enhancing element in transiently as well as in stably transfected
      myelomonocytic cells. Previous work has shown that v-Myb acts on the C/EBPbeta
      promoter; it now appears that Myb stimulates C/EBPbeta expression by acting on
      the promoter as well as on an enhancer of the C/EBPbeta gene. Interestingly, the
      mechanisms by which Myb acts on both elements differ; while Myb activation of the
      promoter requires the cooperation with C/EBPbeta, activation of the enhancer by
      Myb is independent of C/EBPbeta. Apart from the identification of a novel Myb
      dependent enhancer, our work demonstrates the potential of chromatin structure
      analysis for the identification of Myb target sites.

PMID- 15195137
TI  - BRAF alterations are associated with complex mutational profiles in malignant
      melanoma.
AB  - To evaluate the mutational profiles associated with BRAF mutations in human
      melanoma, we have studied BRAF, RAS, PTEN, TP53, CDKN2A and CDK4 genes and their
      expression in melanoma lesions. Owing to the lack of sufficient material from
      fresh specimens, we employed short-term cell lines obtained from melanoma
      biopsies. In all, 41 melanoma obtained from eight primary lesions, 20 nodal, 11
      cutaneous and two visceral metastases from patients with sporadic (n=31),
      familial (n=4) and multiple melanoma (n=2) were analysed. The results revealed
      novel missense mutations in the BRAF, PTEN, CDKN2A and CDK4 genes. Overall,
      activating mutations of BRAF and loss of functional p16 and ARF were detected in
      the majority of melanomas (29/41, 36/41 and 29/41, respectively), while PTEN
      alterations/loss, NRAS and TP53 mutations occurred less frequently (6/41, 6/41
      and 10/41, respectively). In the resulting 12 mutational profiles, p16/ARF loss
      associated with mutated BRAFV599E was the most represented (n=15). In addition,
      TP53 and PTEN mutations were always accompanied with BRAF alterations, while PTEN
      loss was found in association with CDKN2A or TP53 mutations in the absence of
      BRAF activation. The p16/ARFDelta+BRAF/RAS profile was significantly associated
      with a longer survival, while complex mutational profiles were detected in highly
      aggressive disease and poor survival. These data support the existence of several
      molecularly defined melanoma groups which likely reflect different
      clinical/biological behaviour, thus suggesting that a more extensive molecular
      classification of melanoma would significantly impact its clinical management.

PMID- 15195138
TI  - Gene expression profiling of 1p35-36 genes in neuroblastoma.
AB  - Deletion of the chromosome 1p36 region is a frequent abnormality in
      neuroblastoma. To gain further insights into the role of this alteration in
      oncogenesis, we have constructed a specific cDNA microarray representing most
      known genes and ESTs from the 1p35-36 region and analysed the expression profiles
      of 15 neuroblastoma cell lines and 28 neuroblastoma tumours. Hierarchical
      clustering using expression levels of 320 cDNAs from 1p35-36 separated localized
      or 4S cases without 1p deletion from advanced stages and cell lines. Supervised
      learning classification enabled to predict reliably the status of chromosome 1p
      according to its expression profile. Around 15% of the genes or ESTs presented a
      significantly decreased expression in samples with 1p deletion as compared to 1p
      normal samples suggesting that 1p deletion results in a gene dosage effect on a
      subset of genes critical for the development of 1p-deleted neuroblastoma. Several
      genes presumed to have functions in neural differentiation (CDC42, VAMP3,
      CLSTN1), signal transduction in neural cells (GNB1) and cell cycle regulation
      (STMN1, RPA2, RBAF600, FBXO6, MAD2L2) exhibited a decreased expression in samples
      presenting 1p deletion. The identification of such genes provides baseline
      information for further studies to elucidate how these genes could individually
      or collectively play a critical role in neuroblastoma tumorigenesis.

PMID- 15195140
TI  - MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold
      protein for frizzled and Ltap.
AB  - A seven-transmembrane protein, frizzled, has been implicated in a planar cell
      polarity (PCP) pathway as well as the canonical Wnt signaling pathway. Although
      both pathways require a cytoplasmic protein, dishevelled, the molecular mechanism
      by which frizzled regulates intracellular signaling remains to be elucidated. In
      the mouse, nine frizzled family members have been identified and six of them
      contain a PDZ-binding motif at their carboxyl-termini. In this study, we show
      that a multi-PDZ containing protein, MAGI-3, specifically binds to frizzled-4 and
      -7. Furthermore, we also demonstrate that MAGI-3 interacts with Ltap, a mouse
      homolog of the Drosophila PCP protein, stbm, and that these three molecules can
      form a ternary complex. In epithelial cells, MAGI-3, frizzled-4, and Ltap
      colocalized at cell contact sites, indicating that these molecules form a
      physiologically significant complex. Finally, we found that MAGI-3 strongly
      activated JNK in conjunction with frizzled-4 and Ltap, and that this activation
      required the small GTPase, Rac. These results indicate that MAGI-3 functions as a
      scaffold protein for frizzled-4 and Ltap and regulates the JNK signaling cascade.

PMID- 15195139
TI  - Characterization of loss-of-inactive X in Klinefelter syndrome and female-derived
      cancer cells.
AB  - The increased risk of several types of cancer in Klinefelter syndrome (47XXY)
      suggests that the extra X chromosome may be involved in the tumorigenesis
      associated with this syndrome. Here, we show that cancer cells (PSK-1) derived
      from a patient with Klinefelter syndrome (47XXY) showing loss of an inactive X
      chromosome subsequently gained active X chromosomes. We found that this abnormal
      X chromosome composition in PSK-1 is caused by a loss of an inactive X chromosome
      followed by multiplication of identical active X chromosomes, not by reactivation
      of an inactive X chromosome. Furthermore, we extended the characterization of
      loss-of-inactive X in a series of 22 female-derived cancer cell lines (eight
      breast cancer cell lines, seven ovarian cancer cell lines, and seven cervical
      cancer cell lines). The data demonstrate that loss-of-inactive X in the female
      derived cancer cells is mainly achieved by loss of an inactive X chromosomes
      followed by multiplication of an identical active X chromosomes. However,
      distinctive pathways, including reactivation of an inactive X chromosome, are
      also involved in the mechanisms for loss-of-inactive X and gain-of-active X in
      female-derived cancer cells. The biological significance of the loss-of-inactive
      X and gain-of-active X in the oncogenesis of Klinefelter syndrome and female
      derived cancer cells are discussed.

PMID- 15195141
TI  - Sonic hedgehog and insulin-like growth factor signaling synergize to induce
      medulloblastoma formation from nestin-expressing neural progenitors in mice.
AB  - Medulloblastoma (MB) is a malignant brain tumor that arises in the cerebellum of
      children. Activation of the Sonic hedgehog/Patched (Shh/Ptc) signaling pathway in
      neural progenitor cells of the cerebellum induces MBs in mice. The incomplete
      penetrance of tumor formation in mice, coupled with the low frequency of
      mutations in Shh/Ptc pathway genes in human tumors, suggests that other signaling
      molecules cooperate with Shh to enhance MB formation. We modeled the ability of
      insulin-like growth factor (IGF) signaling to induce MB using the RCAS/tv-a
      system, which allows postnatal gene transfer and expression in a cell-type
      specific manner. We used RCAS retroviral vectors to target expression of Shh,
      IGF2, and activated Akt to nestin-expressing neural progenitors in the cerebella
      of newborn mice. The incidence of Shh-induced tumor formation (15%) was enhanced
      by coexpression with IGF2 (39%) and Akt (48%). Neither IGF2 nor Akt caused tumors
      when expressed independently. The induced tumors showed upregulated expression of
      insulin receptor substrate 1 and phosphorylated forms of IGF1 receptor and Akt,
      mimicking activated IGF signaling found in human MBs. These results indicate that
      combined activation of the Shh/Ptc and IGF signaling pathways is an important
      mechanism in MB pathogenesis.

PMID- 15195142
TI  - p14ARF is a component of the p53 response following ionizing irradiation of
      normal human fibroblasts.
AB  - Ionizing radiation leads to rapid stabilization and activation of the p53 tumor
      suppressor. Previous reports demonstrate that murine p19ARF cooperates with p53
      in the cellular response to gamma irradiation. Here, we show that endogenous ARF
      sequentially interacts with p53 and MDM2 following irradiation of primary human
      and mouse embryonic fibroblasts. Shortly after irradiation, p14ARF binds p53
      independently of MDM2. As nuclear pools of p53 decline, endogenous p14ARF co
      immunoprecipitates with MDM2 and is localized within the nucleolus.
      Interestingly, p14ARF nucleolar localization during this response is abrogated in
      cells lacking functional p53. Taken together, our data suggest that human and
      murine ARF contribute to the mammalian DNA damage response.

PMID- 15195143
TI  - Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV
      irradiation via the E2F transcription factor.
AB  - MCM10 and TopBP1 function in the initiation of DNA replication, by regulating the
      chromatin binding of the DNA polymerase alpha loading factor, CDC45. TopBP1 is
      also known as a DNA damage response protein. In this study, we showed that the
      transcription of human MCM10 and TopBP1 is activated by transcription factors
      E2F1-3, but not by factors E2F4-7. Analysis of various MCM10 and TopBP1 promoter
      constructs showed that an E2F-responsive sequence in the vicinity of the
      transcription initiation site is necessary for the E2F1-induced activation of
      MCM10 and TopBP1 gene transcription, which is further suppressed by pRb. The
      promoter activities of human MCM10 and TopBP1 were demonstrated to be growth
      dependent via the E2F-responsive sequence. Although E2F1 was stabilized by
      ultraviolet (UV) irradiation, the mRNA expression level of TopBP1 was suppressed
      in HCT116 human diploid colon cancer cells. We showed, by performing chromatin
      immunoprecipitation that, in response to UV irradiation but not doxorubicin
      treatment, E2F4 accumulated on the MCM10 and TopBP1 promoters. Our data suggest a
      model in which UV irradiation-induced DNA damage depends, at least in part, on
      the accumulation of the E2F4 transcription factor on the MCM10 and TopBP1
      promoters, which results in suppression of DNA replication.

PMID- 15195144
TI  - Disparate effects of telomere attrition on gene expression during replicative
      senescence of human mammary epithelial cells cultured under different conditions.
AB  - Telomere shortening in populations of human mammary epithelial cells (HMECs) that
      survive early replicative arrest (M0) by the inactivation of p16(INK4A) during
      cell culture on plastic dishes leads to a state of permanent replicative arrest
      termed senescence. While culture of HMECs on feeder layers abrogates M0 and
      p16(INK4A) inactivation, progressive telomere attrition in these cells also
      eventually results in permanent replicative arrest. Expression of telomerase
      prevents both senescence on plastic (S-P) and senescence on feeder layers (S-FL)
      in HMECs, as it does also in cultured primary human fibroblasts. We report here
      that the gene expression profiles of senescence in HMECs of the same lineage
      maintained under different culture conditions showed surprisingly little
      commonality. Moreover, neither of these senescence-associated profiles in HMECs
      resembles the profile for senescence in human fibroblasts. These results indicate
      that senescence-associated alterations in gene expression resulting from telomere
      attrition are affected by culture conditions as well as by cell origins, and
      argue that replicative senescence at the molecular level is a diverse rather than
      unique cellular process.

PMID- 15195145
TI  - Absence of p21WAF1 cooperates with c-myc in bypassing Ras-induced senescence and
      enhances oncogenic cooperation.
AB  - The absence of p21waf1 combined with an ectopic expression of c-myc prevents ras
      induced senescence in mouse embryo fibroblasts. Extension of lifespan after c-myc
      transduction into p21-null cells was followed at later passages by apoptosis of a
      large fraction of c-myc-overexpressing p21-null cells. This apoptotic effect
      could be overridden by inactivation of the p53 tumor suppressor or oncogenic ras
      expression. Ras-induced inhibition of apoptosis is mediated by PI3K activation.
      These results suggest a functional relationship between ras and myc that may
      explain their oncogenic cooperation. The number of foci formed by myc+ras
      increased cooperatively in the absence of p21waf1. Thus, the reciprocal
      cooperation between myc and ras in a p21-null background during cellular
      immortalization lead to increased oncogenic cooperation between ras and myc.

PMID- 15195146
TI  - TFIIH contains a PH domain involved in DNA nucleotide excision repair.
AB  - The human general transcription factor TFIIH is involved in both transcription
      and DNA repair. We have identified a structural domain in the core subunit of
      TFIIH, p62, which is absolutely required for DNA repair activity through the
      nucleotide excision repair pathway. Using coimmunoprecipitation experiments, we
      showed that this activity involves the interaction between the N-terminal domain
      of p62 and the 3' endonuclease XPG, a major component of the nucleotide excision
      repair machinery. Furthermore, we reconstituted a functional TFIIH particle with
      a mutant of p62 lacking the N-terminal domain, showing that this domain is not
      required for assembly of the TFIIH complex and basal transcription. We solved its
      three-dimensional structure and found an unpredicted pleckstrin homology and
      phosphotyrosine binding (PH/PTB) domain, uncovering a new class of activity for
      this fold.

PMID- 15195147
TI  - Structural basis for distinct ligand-binding and targeting properties of the
      receptors DC-SIGN and DC-SIGNR.
AB  - Both the dendritic cell receptor DC-SIGN and the closely related endothelial cell
      receptor DC-SIGNR bind human immunodeficiency virus and enhance infection.
      However, biochemical and structural comparison of these receptors now reveals
      that they have very different physiological functions. By screening an extensive
      glycan array, we demonstrated that DC-SIGN and DC-SIGNR have distinct ligand
      binding properties. Our structural and mutagenesis data explain how both
      receptors bind high-mannose oligosaccharides on enveloped viruses and why only DC
      SIGN binds blood group antigens, including those present on microorganisms. DC
      SIGN mediates endocytosis, trafficking as a recycling receptor and releasing
      ligand at endosomal pH, whereas DC-SIGNR does not release ligand at low pH or
      mediate endocytosis. Thus, whereas DC-SIGN has dual ligand-binding properties and
      functions both in adhesion and in endocytosis of pathogens, DC-SIGNR binds a
      restricted set of ligands and has only the properties of an adhesion receptor.

PMID- 15195148
TI  - RNA interference demonstrates a novel role for H2A.Z in chromosome segregation.
AB  - The histone variant H2A.Z plays an essential role in metazoans but its function
      remains to be determined. Here, we developed a new inducible RNAi strategy to
      elucidate the role of H2A.Z in mammalian cell lines. We show that in the absence
      of H2A.Z, the genome becomes highly unstable and that this instability is caused
      by defects in the chromosome segregation process. Analysis of H2A.Z localization
      reveals that in these cells it is enriched at heterochromatic foci with HP1alpha
      on the arms of chromosomes but not at centromeric regions. When H2A.Z is
      depleted, normal HP1alpha-chromatin interactions are disrupted on the chromosomal
      arms and, notably, also at pericentric regions. Therefore, H2A.Z controls the
      localization of HP1alpha. We conclude that H2A.Z is essential for the accurate
      transmission of chromosomes.

PMID- 15195149
TI  - Distinct conformational states of nuclear receptor-bound CRSP-Med complexes.
AB  - The human CRSP-Med coactivator complex is targeted by a diverse array of sequence
      specific regulatory proteins. Using EM and single-particle reconstruction
      techniques, we recently completed a structural analysis of CRSP-Med bound to VP16
      and SREBP-1a. Notably, these activators induced distinct conformational states
      upon binding the coactivator. Ostensibly, these different conformational states
      result from VP16 and SREBP-1a targeting distinct subunits in the CRSP-Med
      complex. To test this, we conducted a structural analysis of CRSP-Med bound to
      either thyroid hormone receptor (TR) or vitamin D receptor (VDR), both of which
      interact with the same subunit (Med220) of CRSP-Med. Structural comparison of TR-
      and VDR-bound complexes (at a resolution of 29 A) indeed reveals a shared
      conformational feature that is distinct from other known CRSP- Med structures.
      Importantly, this nuclear receptor-induced structural shift seems largely
      dependent on the movement of Med220 within the complex.

PMID- 15195150
TI  - [Free expressions and editorial liasons].

PMID- 15195151
TI  - [Common reference values].

PMID- 15195152
TI  - [Recommendations not followed].

PMID- 15195153
TI  - [Risk intervention in persons with diabetes mellitus in general practice].
AB  - BACKGROUND: Intervention against cardiovascular risk factors such as
      hypertension, dyslipidaemia and smoking is necessary to reduce the increased
      mortality associated with diabetes mellitus. METHODS: The case notes of 2003
      patients with diabetes in general practice in Rogaland, Salten and Aker were
      reviewed in order to assess the quality of diabetes care including the treatment
      of risk factors for cardiovascular disease. RESULTS: 287 out of 1417 patients
      below the age of 76 had known cardiovascular disease. Of these, 57.5% were
      treated with a statin and 61 % were taking aspirin. 118 patients had had a
      myocardial infarction, 69.5% were on a statin and 60.2% were taking aspirin. 776
      (38.7%) of the patients in the study had been diagnosed as suffering from
      hypertension, 40.3% were on therapy with one anti-hypertensive agent, 28.6%
      received two agents and 12.1% were on three or more anti-hypertensive agents.
      Only 57.5% of patients, who according to current national guidelines ought to be
      on a statin as secondary prevention, received such a treatment. Smoking habits
      were recorded in 35.1% and weight in 45 % of the patients. INTERPRETATION: There
      is considerable room for improvement with regard to intervention against known
      risk factors for cardiovascular disease in patients with diabetes treated in
      primary care.

PMID- 15195154
TI  - [Prevalence of diabetes mellitus in Norway].
AB  - BACKGROUND: Our aim was to combine several regional studies in order to estimate
      the prevalence of diabetes in Norway. MATERIAL AND METHODS: We used data from a
      nation-wide registration of type 1 diabetes in the age group < 30 years. Data for
      other age groups were taken from nine regional surveys, of which six were
      repeated. The average prevalence of known diabetes based on self-administered
      questionnaires was estimated. Data on previously undiagnosed diabetes were
      available from two Norwegian studies and from other countries. RESULTS: The sex
      and age standardised prevalence of "known" diabetes (all age groups) was
      estimated at 2.3%, increasing with age to approximately 8% among the 70 to 79
      year-olds. The prevalence was 3.4% among those aged > or =30 years. The estimated
      increase in prevalence of known diabetes over time was 1.4% per calendar year,
      with variation between sub-groups. The number of unknown cases may be nearly
      equal to the number of known cases in the age-groups > or =30 years, but this is
      uncertain. INTERPRETATION: There are probably about 90,000 to 120,000 people with
      diagnosed diabetes in Norway. Nearly as many may have undiagnosed diabetes, but
      this is uncertain. Studies representative of the Norwegian population using the
      oral glucose tolerance test are needed.

PMID- 15195155
TI  - [Updated reference intervals for clinical chemical components].
AB  - BACKGROUND: More or less outdated reference intervals are still in common use
      with many clinical biochemical components. In order to update them, a Nordic
      cooperative project (the Nordic reference interval project, NORIP) was organised.
      MATERIAL AND METHODS: 102 Nordic laboratories participated; 3036 persons aged 18
      years or above were included. 25 components were measured in serum and/or plasma.
      RESULTS: Common reference intervals for all Nordic countries were calculated for
      each of the 25 components, with age and sex-specific intervals when statistical
      criteria suggested this to be appropriate. INTERPRETATION: The national clinical
      biochemical societies of Norway, Sweden, Finland and Denmark have all recommended
      that the suggested reference intervals should be brought into common use. In
      Norway, new reference intervals for seven enzymes were implemented in May 2003,
      the remaining are recommended implemented in spring 2004. Except for four of the
      enzymes, there will be no simultaneous change in the measuring methods used,
      hence medical decision limits are essentially not affected.

PMID- 15195156
TI  - [Acute bacterial conjunctivitis].
AB  - Acute infectious conjunctivitis is the eye disease most commonly seen by general
      practitioners, and is estimated to represent 2-3% of their total number of
      consultations. The present paper gives a review of the epidemiology, etiology,
      clinical picture, complications, differential diagnoses and therapy of acute
      bacterial conjunctivitis. The condition has an excellent prognosis with a high
      frequency of spontaneous remission. However, topical antibacterial therapy should
      always be instituted, because this will shorten the course of the disease and
      reduce the risk of epidemic outbreaks, particularly in institutions for children.

PMID- 15195157
TI  - [Third-generation oral contraceptives--how big is the risk of venous
      thrombosis?].

PMID- 15195158
TI  - [Social inequality and diet].
AB  - Despite a general improvement of the living standard in Norway, disparities in
      living conditions and health between socio-economic groups have increased over
      the last decades. This article discusses present knowledge on socio-economic
      differences in diet in Europe and particularly in Norway. Several international
      and Norwegian studies indicate that the diet of lower socio-economic groups tends
      to compare poorly to that of higher groups on a number of health-related aspects.
      More documentation is needed on how diet and food selection differs across
      population groups; moreover, better knowledge about why these differences exist
      and persist is needed. This is important for making interventions and other
      preventive efforts effective in eliminating unfavourable dietary differences.

PMID- 15195159
TI  - [Better health with ecologic food?].
AB  - The goals of Norwegian food and nutrition policy are that food should not only be
      nutritionally adequate and safe, it should also be produced in a sustainable way.
      This implies a change towards food produced according to principles of organic
      agriculture. The issue discussed here is whether organic food is also better in
      terms of nutritional adequacy. A review of existing literature reveals that
      organic foods compared to conventionally produced foods seem to have a higher
      content of antioxidants in plant products and a higher content of fat-soluble
      vitamins and omega-3 fatty acids in animal products. Animal studies (among them,
      on rabbits and chickens) show higher fertility and less morbidity in animals fed
      organically. Furthermore, when given a choice, animals prefer organic to
      conventionally produced fodder. It is not possible to draw conclusions from these
      studies on health effects on humans. So far there have been no controlled studies
      in humans that have assessed such effects, though a higher content of
      antioxidants have been found in the urine of subjects put on an organic diet. In
      summary, a change to an organic diet may have a direct positive health effect on
      humans, as well as an indirect effect through a healthier environment.

PMID- 15195160
TI  - [Diet changes and the rise and fall of cardiovascular disease mortality in
      Norway].
AB  - BACKGROUND: Cardiovascular disease mortality in Norway during the last 50 years
      has been analysed and related to changes in dietary habits and serum cholesterol
      in the population. MATERIAL AND METHODS: Mortality and dietary data have been
      collected from official statistics. Changes in serum cholesterol have been
      estimated from changes in intake of fatty acids based on published regression
      equations. Data on changes in serum cholesterol and blood pressure are from the
      former National Health Screening Service. RESULTS: Mortality from ischemic heart
      disease (IHD) peaked in 1966-70 when it was 100% higher than in 1951-55 for men
      and 50% higher for women. For age group 40-69 years mortality has been reduced by
      more than one half during the last 30 years. For the period 1996-2000 and for all
      age groups, 30,903 fewer deaths occurred than expected, had the mortality
      remained the same as during 1971-75, that is 6180 per year. Mortality from sudden
      death has followed the same pattern as for IHD. Cerebrovascular disease mortality
      has shown a declining tendency during the entire period. Since 1960 the
      proportion of total fat in the diet has been reduced from 41 to 34% of energy and
      the proportion of unsaturated to saturated plus trans fatty acids has increased.
      Cholesterol in the diet has been reduced by almost one half. Based on changes in
      consumption in milk fat, fat from meat and margarine, and taken into
      consideration the change from boiled to filtered coffee the estimated reduction
      in serum cholesterol in the population is in the order of 0.8 mmol/l. This
      corresponds closely to the observed 0.5 to 1 mmol/l. Most of the reduction is due
      to changes in milk fat and margarine consumption and composition. INTERPRETATION:
      Based on the established relation between serum cholesterol and risk of IHD we
      conclude that reduction in serum cholesterol may explain most of the decline in
      mortality since 1970. Other factors that may have contributed are reduced smoking
      (in men), a small reduction in blood pressure, increased consumption of fruit,
      vegetables, cod liver - and fish oil and better means of treatment.

PMID- 15195161
TI  - [What do general practitioners expect from the department of neurology?].
AB  - BACKGROUND: In the only department of neurology for the two northernmost counties
      of Norway, activities are organised to minimize waiting time for examination. In
      order to improve provision of services, we asked general practitioners (GPs) for
      advice in a questionnaire survey. MATERIAL AND METHODS: A postal questionnaire
      was sent to all general practitioners in the two northernmost counties of Norway.
      They were asked to suggest order of priority that might improve care for patients
      referred for headache and point out patient groups who need better services.
      RESULTS: A total of 177 out of 269 GPs returned the questionnaire (66%). The
      highest rated suggested activities were telephone meetings with a specialist and
      written information with criteria for the selection of patients who need a
      specialist consultation for headache. Responders were of the opinion that higher
      priority should be given to primary degenerative disorders of the brain such as
      Parkinson's disease and dementia disorders. INTERPRETATION: The study showed that
      better communication between specialists and GPs may improve services for those
      with headache. Increased knowledge about groups of patients who need improved
      care could be achieved by asking GPs working in the community for advice.

PMID- 15195162
TI  - [Impaired work protection should be a concern for the medical profession].

PMID- 15195164
TI  - [The forgotten patients].

PMID- 15195165
TI  - [Increasing needs for neurologic services].

PMID- 15195168
TI  - [Bone density measurement].

PMID- 15195169
TI  - [Doing less to achieve more].

PMID- 15195170
TI  - [We--the incorruptible?].

PMID- 15195171
TI  - [Can we understand psychoses?].

PMID- 15195172
TI  - [Diesel exhaust--also a heart matter].

PMID- 15195173
TI  - [Survival after high-dose therapy with autologous stem cell support].
AB  - BACKGROUND: High-dose therapy with autologous stem cell support has been carried
      out in our hospital since 1996. We have recently collected survival data on
      patients who have undergone this procedure. MATERIAL AND METHODS: The study
      population comprised 111 patients, 58 of whom had been diagnosed with multiple
      myeloma, 38 with various forms of malignant lymphoma, 11 with sarcoma and 4 with
      testicular cancer. RESULTS: Median survival from reinfusion of stem cells was
      74.8 months for patients with myeloma, 47.8 months for patients with malignant
      lymphoma and 11.7 months for patients with sarcoma. Three-year survival was 72.2
      % for myeloma patients and 54.8 % for lymphoma patients. While the survival slope
      decreased steadily throughout the study period for patients with multiple
      myeloma, it seemed to level out after approximately 18 months for patients with
      malignant lymphomas. INTERPRETATION: Our data on myeloma patients show survival
      comparable to previously published data. For malignant lymphoma patients, our
      data support the assumption that high-dose therapy has the potential for cure.

PMID- 15195174
TI  - [Spontaneous intracranial hypotension].
AB  - BACKGROUND: Spontaneous intracranial hypotension is probably an under-reported
      cause of headache and other neurological symptoms. MATERIAL AND METHODS: We
      report six patients with this diagnosis and review the most recent literature on
      the topic. RESULTS AND INTERPRETATION: Spontaneous intracranial hypotension is
      typically manifested by orthostatic headache and low opening pressure on lumbar
      puncture, but atypical presentations are frequently reported. Various imaging
      techniques may be helpful in establishing the diagnosis, and sometimes the
      precise point of leakage can be demonstrated. All our six patients had
      orthostatic headache; five had additional complaints. In four patients the
      diagnosis was verified by typical meningeal enhancement on brain magnetic
      resonance imaging, and in one patient computed tomographic myelography precisely
      revealed the leakage point. All six patients experienced relief of symptoms after
      conservative treatment. Spontaneous intracranial hypotension is a relatively
      benign syndrome, but it may be complicated by subdural haematomas. Connective
      tissue disorders may predispose for the condition.

PMID- 15195175
TI  - [Air pollution and cardiovascular disease in Trondheim].
AB  - BACKGROUND: There is some evidence linking air pollution to cardiovascular
      morbidity. Our aim was to examine whether there is a correlation between air
      pollution and cardiovascular morbidity in the city of Trondheim, Norway. MATERIAL
      AND METHODS: We compared the mean daily number of admissions for cardiovascular
      disease to the St. Olav University hospital on days with relatively low and high
      levels of PM10 (1993-2001), PM2,5, NO, NO2, SO2, O3, toluene and paraxylene (1998
      2001). A time series analysis was carried out to see how day-to-day variations in
      concentrations of air pollutants correlated with the number of hospitalizations
      for cardiovascular disease. RESULTS: In the bivariate analysis, the mean daily
      number of hospitalizations was found to be significantly higher (p < 0.05) on
      days with NO and NO2 levels above the 80 th percentile (57.6 microg/m3 and 43.1
      microg/m3, respectively) than on days with pollutant levels below the 20th
      percentile (11.3 microg/m3 and 16.9 microg/m3, respectively). Time series
      analysis did not show any statistically significant correlation between day-to
      day variations in air pollution and hospital admissions for cardiovascular
      disease. INTERPRETATION: The findings regarding NO2 and NO indicate that exposure
      to gases and/or ultra-small particles from diesel exhaust may influence
      cardiovascular morbidity.

PMID- 15195176
TI  - [Treatment of pseudoaneurysms after vascular interventions].
AB  - BACKGROUND: Increasing numbers of patients undergoing angiographic procedures
      result in an increase in the total number of complications. False aneurysm may
      develop in 1-5% after femoral artery puncture. Until recently, ultrasound-guided
      compression was the preferred method of treatment, in a few cases surgery. A
      newer method with ultrasound-guided injection of thrombin has been shown to be
      effective. MATERIAL AND METHODS: Between 2000 and 2003, twenty-seven patients
      were diagnosed with iatrogenic false aneurysms in our hospital. The diagnosis was
      obtained by ultrasound when clinically suspected. Twelve patients were treated
      with compression technique, one with surgery, twelve with ultrasound-guided
      injection of thrombin, and two received no active treatment. RESULTS AND
      CONCLUSION: Ultrasound-guided needle injection of thrombin was a good method of
      treatment with a success rate of 100%, as compared to 83% with compression
      technique. Days in hospital stay were few and no complications were observed.
      Based on the good results reported in the literature and our own experience, we
      suggest that ultrasound-guided injection of thrombin should be the treatment of
      choice for femoral pseudoaneurysms.

PMID- 15195178
TI  - [Use of antihistaminics during pregnancy and breast feeding].

PMID- 15195177
TI  - [Reduction of myocardial infarction size after primary percutaneous coronary
      intervention].
AB  - BACKGROUND: Achieving reperfusion as soon as possible is essential in order to
      reduce myocardial infarction size and thus improve prognosis. An increasing
      number of patients with myocardial infarction are treated with primary
      percutaneous coronary intervention (PCI). Technetium 99m-tetrofosmin myocardial
      perfusion tomography (SPECT) is a valid test for assessing myocardium at risk and
      final infarct size expressed by a hypoperfusion index (HPI) of the left
      ventricular mass. MATERIAL AND METHODS: 20 patients with acute ST-elevation
      myocardial infarction were treated with primary percutaneous coronary
      intervention within six hours of onset of symptoms. Myocardium at risk and final
      infarct size were assessed by Technetium 99m-tetrofosmin immediately before and a
      few hours, one week and six weeks after. RESULTS: The hypoperfusion index
      immediately before percutaneous coronary intervention was 31%, four to six hours
      after PCI 25%, one week later 16% and six weeks later 12%, i.e. a relative
      reduction of 60% (p < 0.01). Anterior wall infarctions had a higher level of
      myocardium at risk before primary PCI compared to inferior wall infarctions (36%
      vs. 24%), but anterior wall infarctions had a higher salvage index compared to
      inferior wall infarctions. INTERPRETATION: This non-controlled study shows a
      marked reduction in final infarction size in patients with acute ST-elevation
      myocardial infarction treated with primary PCI.

PMID- 15195179
TI  - [Nutrition for preterm infants].
AB  - BACKGROUND: Each year about 630 infants are born with very low birth weight
      (below 1500 g) in Norway. In spite of an increased survival rate over the past 30
      years, many challenges remain in the treatment of premature infants; their
      nutritional need is an important aspect. MATERIAL AND METHODS: This review is
      based on searches in the Medline database. RESULTS AND INTERPRETATION: Human milk
      is the first choice for premature babies in Norway. The beneficial effects of
      human milk for premature babies are well documented, but unfortified human milk
      does not meet the nutritional needs of very low birth weight infants. Infants fed
      human milk grow slower than babies fed preterm formula. Fortification is
      necessary. There are many unsolved problems concerning nutrition for premature
      babies. What is the best rate of advancement in parenteral and enteral nutrition?
      How to improve the energy and protein fortification of human milk? Does human
      milk meet the need for long-chain polyunsaturated fatty acids or is a supplement
      indicated? What are the optimal doses of vitamin and mineral supplements? What is
      the recommended nutrition after discharge? More clinical trials are needed to
      establish evidence-based practice.

PMID- 15195180
TI  - [Intake of fruit and vegetables among Norwegian children and adolescents].
AB  - BACKGROUND: We present a survey of the intake of fruit and vegetables among
      Norwegian children and adolescents and examine the association between fruit and
      vegetable intake and intake of macronutrients and micronutrients. MATERIAL AND
      METHODS: In 2000 and 2001, a nationwide dietary survey using four-days records
      was conducted among four-year-olds and students in the fourth and eighth grades
      (UNGKOST-2000). RESULTS: The average intake of fruit and vegetables was nearly
      250 gram per day, increasing with age. The percentages of children eating more
      than 500 gram fruit and vegetables per day were 5% among the four-year-olds, 7%
      among fourth-graders, and 11% among eighth-graders. A positive association was
      observed between intake of fruit and vegetables and intake of fibre and all
      micronutrients, while a negative association was found between fruit and
      vegetable intake and percentage of energy coming from added sugar and saturated
      fatty acids. INTERPRETATION: The study shows that children and adolescents have
      less than half the recommended intake of fruit and vegetables. Furthermore,
      higher intake of fruit and vegetables is associated with higher dietary quality.

PMID- 15195181
TI  - [Consumption of whole grain foods and chronic disease].
AB  - BACKGROUND: We summarise evidence concerning the health effects of whole grain
      intake, as well as implications for Norway. All forms of whole grain products
      contain both the bran and the germ, which are rich in nutrients, in addition to
      the starch-rich endosperm. However, refined grain consists only of the endosperm,
      which contains far fewer nutrients. MATERIAL AND METHODS: Review of published
      epidemiologic and food consumption data concerning grain intake. RESULTS: Recent
      epidemiologic investigations have found that whole grain intake is associated
      with reduced risk of several chronic diseases, especially cardiovascular diseases
      and diabetes. For example, the follow-up data of the cardiovascular disease study
      in Norwegian counties carried out during 1977-83 showed an inverse relationship
      between total mortality rates and eating whole grain bread. The United States
      Department of Agriculture and the Food and Drug Administration have endorsed
      statements that whole grain products can have positive health effects. About four
      times as much whole grain food is eaten in Norway as in the United States.
      However, many refined grain breads have recently been introduced in Norway.
      INTERPRETATION: Norwegians should be encouraged to maintain or even increase
      their consumption of whole grain foods.

PMID- 15195182
TI  - [Systematic quality control programme for colonoscopy in an endoscopy centre in
      Norway].
AB  - BACKGROUND: Colonoscopy is regarded as the gold standard for diagnosis of
      colorectal disease, and increasingly considered a primary screening approach for
      colorectal cancer. The quality of the procedure varies between centres and
      endoscopists. The aim of the present study was to describe a quality control
      programme for colonoscopy performance in a secondary care centre. MATERIAL AND
      METHODS: Starting in 2001, we established a systematic quality control programme.
      All patients received a questionnaire on their satisfaction with and pain during
      and after examination. The questionnaire was to be filled in the next day and
      mailed back to the centre. Pain and discomfort during and after colonoscopy and
      caecum intubation rate were registered as indicators of quality. RESULTS: During
      the study period of 15 month, 1354 colonoscopies were performed by 16
      endoscopists. 94% of examinations were performed without any sedation. 1054 (78%)
      of patients responded to the questionnaire, 99% of whom were generally satisfied.
      The caecum intubation rate was 82%. While 23% of patients scored for moderate
      pain during the examination and 16% complained of severe pain, 61% had no or only
      light pain. Significant differences between endoscopists regarding pain and
      caecum intubation rate were found in a multiple logistic regression model.
      INTERPRETATION: A satisfactory feedback from patients was observed, with a high
      response rate to the questionnaire survey and high overall satisfaction, in spite
      of the fact that about one third of patients experienced moderate or severe pain.
      There were significant variations in performance between endoscopists.

PMID- 15195183
TI  - [The psychotic crisis--development in a family therapy frame].

PMID- 15195185
TI  - [Risk factors of cervical cancer among women in Mozambique].

PMID- 15195186
TI  - [Use of physicians as expert witnesses by the courts].

PMID- 15195187
TI  - [Why not always diuretics?].
AB  - BACKGROUND: New guidelines adopted in Norway for antihypertensive medication
      implies prescription of a thiazide diuretic as the drug of first choice. The
      background for the change in the rules for prescription drugs paid for by the
      National Insurance system with a capped co-payment is a resolution of the
      Norwegian parliament as part of a budget compromise for 2004. The resolution was
      supported by results from the ALLHAT study (antihypertensive and lipid-lowering
      treatment to prevent heart attack trial). METHODS: ALLHAT was carried out in a
      group of elderly, high-risk patients with a large proportion of Afro-Americans.
      RESULTS AND INTERPRETATION: ALLHAT has important shortcomings with regard to
      design, results, analysis and interpretation. The trial is considered unfit as a
      basis for general guidelines on antihypertensive treatment in Norway.

PMID- 15195188
TI  - [Breast implants and radiology].

PMID- 15195189
TI  - [Activated protein C and treatment of sepsis].

PMID- 15195191
TI  - [Clinical experience and scientific evidence].

PMID- 15195193
TI  - [To be used in accordance with the physician's prescription].

PMID- 15195194
TI  - [Lethal half-fermented fish in Drevsjo in 1831?].

PMID- 15195195
TI  - Persistent pulmonary hypertension of the newborn.
AB  - This article attempts to define a complicated, yet not rare disease of the
      neonate, which presents with extreme hypoxemia due to increased pulmonary
      vascular resistance, resulting in diversion of the pulmonary venous blood through
      persistent fetal channels, namely ductus arteriosus and foramen ovale.
      Pathophysiology, diagnostic approach and the various modalities of management are
      analyzed. Persistent pulmonary hypertension of the newborn is multi-factorial,
      which is reflected in the management as well. These babies are extremely labile
      to hypoxia and should be stabilized with minimum handling. One hundred percent
      oxygen and ventilation are the mainstay of treatment. The role of
      hyperventilation, alkalinization, various non-specific vasodilators such as
      tolazoline, magnesium sulphate, selective vasodilators such as inhaled nitric
      oxide, adenosine and the role of high frequency oscillatory ventilation and extra
      corporeal membrane oxygenation are discussed. With the newer modalities of
      management, the outlook has improved with mortality of less than 20% and fewer
      long-term deficits.

PMID- 15195196
TI  - Drug-induced pulmonary fibrosis.
AB  - Pulmonary fibrosis is characterized by the accumulation of excessive connective
      tissue in the lungs. Its causes include chronic administration of some drugs for
      example bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine,
      gold and nitrofurantoin; exposure to certain environmental factors such as gases,
      asbestos and silica and bacterial or fungal infections. Some systemic diseases
      also predispose to the disease for example rheumatoid arthritis and systemic
      lupus erythematosus. The disease is associated with release of oxygen radicals
      and some mediators such as tumor necrosis factor-alpha TNF-alpha, transforming
      growth factor-beta TGF-beta, PDGF, IGF-I, ET-I and interleukins 1, 4, 8 and 13.
      The symptoms of the disease include dyspnea, non-productive cough, fever and
      damage to the lung cells. It is diagnosed with the aid of chest radiography, high
      resolution computed tomographic scanning and the result of pulmonary function
      tests. Drug-induced pulmonary fibrosis may involve release of free oxygen
      radicals and various cytokines for example IL-Ibeta and TNF-alpha via activation
      of nuclear transcription factor NF-beta as in the case of bleomycin and mitomycin
      or via release of TGF-beta as in case of tamoxifen or via inhibition of
      macrophages' and lymphocytes' phospholipases as in the case of amiodarone with
      the resultant accumulation of phospholipids and reduction of the immune system.

PMID- 15195197
TI  - Views of women towards cesarean section.
AB  - Women who deliver by cesarean section CS differ significantly from those who
      deliver vaginally regarding their childbirth experience. Those who deliver by CS
      are often less satisfied with their experience, and with themselves. They
      experience a feeling of resentment towards the physician, profound disappointment
      at the treatment expectation and loss of the happy moment of natural birth
      leading to postpartum depression. Cesarean delivery carries considerable
      disadvantages in terms of pain and trauma of an abdominal operation and
      complications associated with it. However, the CS rate is constantly on the rise.
      Hence, there is a need to evaluate the views of women undergoing cesarean
      deliveries and to ascertain the role of women in decision making regarding mode
      of delivery. This is a review of studies investigating the views of women from
      different countries towards CS and presents the view points of Saudi women
      regarding this.

PMID- 15195198
TI  - Sex hormones, personality characters and professional status among Saudi females.
AB  - OBJECTIVE: The relationship between male and female sex hormones (testosterone,
      estradiol and progesterone), personality characters and professional status was
      studied. METHODS: The study was conducted in Riyadh City, Kingdom of Saudi Arabia
      between September 2003 and May 2003. The participants completed a questionnaire
      consisting of personal information regarding age, profession, educational level
      and medical history. Then the participant went through an adjective checklist.
      Hormones were determined from blood samples provided by the participant. RESULTS:
      The result indicated that the higher the professional levels, the higher was the
      testosterone concentrations, but not estradiol or estrogen concentration.
      Furthermore, females with higher testosterone concentration (university
      lecturers, bank managers, bank employee, medical doctors and technical workers)
      identify themselves as independent, strong, assertive, impulsive, resourceful,
      spontaneous, uninhibited, rational, patient and arguing. Whereas, females with
      lower testosterone concentrations (housewives and clerical workers) view
      themselves as civilized, socialized, calm, quite, sentimental, shy, nice,
      sensitive, warmhearted, sympathetic, thoughtful, warm, practical and kind.
      CONCLUSION: The current study emphasizes the positive relationship between strong
      personality characters, high professional status and male sex hormone level
      (testosterone) in females.

PMID- 15195199
TI  - Making gynecological and psychiatric sense out of premenstrual pains, tension and
      dysphoria.
AB  - OBJECTIVE: Millions of women worldwide suffer from a variety of gynecological and
      psychiatric syndromes that are specifically linked to the late luteal phase of
      menstrual cycle and hence, need proper treatment for good quality of life. The
      objective of this qualitative review is to examine the latest developments in the
      etiology, diagnosis and treatment of premenstrual syndrome and its connections to
      premenstrual dysphoric disorder. METHODS: A selective search of MEDLINE/PubMed
      retrieved numerous peer-reviewed papers published in international journals for
      the past 10 years (the search was ended in 2003), which were screened
      extensively, but only the latest and most relevant articles were included in this
      review. RESULTS: The 2 main premenstrual disorders manifesting tension, dysphoria
      and pain were etiologically attributed best to the dysregulation of central
      serotonergic and GABAergic systems and noxious sex steroid hormonal milieu during
      normal cyclical ovulation. The women with these syndromes needing proper
      assessment, investigations and correct diagnosis respond effectively to selective
      serotonin-reuptake inhibitors, gonadotrophin-releasing hormone agonists,
      contraceptive pill-Yasmin, cognitive-behavior therapy, life-style changes, and
      also placebo. CONCLUSION: Premenstrual psychiatric syndromes coupled with
      multiple adverse consequences are important clinical entities in a woman's
      reproductive life, which need timely intervention and future research especially
      in Arabian Gulf countries.

PMID- 15195200
TI  - Placenta previa in a referral hospital in Oman.
AB  - OBJECTIVE: To determine the incidence of placenta previa associated pregnancies,
      to find out the strength of association of identified risk factors with the major
      placenta previa associated pregnancies and to identify predictors for preterm
      outcome. METHODS: Records of women with placenta previa, who delivered at Nizwa
      Hospital, Al-Dakhliya region, Sultanate of Oman between October 1998 and
      September 2002, were analyzed retrospectively utilizing a case control approach.
      RESULTS: An incidence of 0.6% for placenta previa was noted in our study. Nearly
      two thirds (64.8%) of the pregnancies resulted in antepartum bleeding.
      Pregnancies with major placenta previa constituted 72% of all the subjects.
      Higher parity (>/=5), maternal age (>/=30) and history of previous abortion had
      high odds of association with major placenta previa of 2.1, 2.4 and 2.5.
      Antepartum hemorrhage was not significantly associated with pregnancies
      presenting with major placenta previa (odds ratio [OR] 1.3; p>0.05). The
      proportion of preterm deliveries was 55.5% in the study. There was a significant
      association between preterm outcome and presence of antepartum hemorrhage (OR
      10.8; p<0.001). CONCLUSION: In spite of higher maternal age, parity and previous
      abortions having high odds of presenting in pregnancies with major placenta
      previa, no significant statistical association could be proven. Also, no
      significant difference among pregnancies presenting with major or minor placenta
      previa as regards the preterm outcome, could be established. Antepartum
      hemorrhage, irrespective of severity, was a strong predictor of preterm outcome.

PMID- 15195201
TI  - Association of mobile phone radiation with fatigue, headache, dizziness, tension
      and sleep disturbance in Saudi population.
AB  - OBJECTIVE: The widespread use of mobile phones has been increased over the past
      decade; they are now an essential part of business, commerce and society. The use
      of mobile phones can cause health problems. Therefore, the aim of the present
      study is to investigate the association of using mobile phones with fatigue,
      headache, dizziness, tension and sleep disturbance in the Saudi population and
      provide health and social awareness in using these devices. METHODS: This study
      was conducted in the Department of Physiology, College of Medicine, King Saud
      University, Riyadh, Kingdom of Saudi Arabia during the year 2002 to 2003. In the
      present study, a total of 437 subjects (55.1% male and 39.9% female) were
      invited, they have and had been using mobile phones. A questionnaire was
      distributed regarding detailed history and association of mobile phones with
      health hazards. RESULTS: The results of the present study showed an association
      between the use of mobile phones and health hazards. The overall mean percentage
      for these clinical findings in all groups were headache (21.6%), sleep
      disturbance (4.%), tension (3.9%), fatigue (3%) and dizziness (2.4%). CONCLUSION:
      Based on the results of the present study, we conclude that the use of mobile
      phones is a risk factor for health hazards and suggest that long term or
      excessive use of mobile phones should be avoided by health promotion activities
      such as group discussions, public presentations and through electronic and print
      media sources.

PMID- 15195202
TI  - Internet use among high school students in Ankara, Turkey.
AB  - OBJECTIVE: Internet use has grown considerably in recent years throughout the
      world, particularly among young people. This study aimed at assessing Internet
      use among high school students. METHODS: This is a cross-sectional
      epidemiological study involving 246 students in 7 classes representing first,
      second, and third year students (754 persons) at a high school in Ankara, Turkey
      during March 2001. An Internet use questionnaire comprising 34 questions was
      used. RESULTS: It was found that 86.5% of the students used the Internet at home.
      The mean daily Internet use was 2.5 hours during vacation, and less while school
      was in session. Although 86.5% of students with computers at home had Internet
      connections, approximately half of the students reported that they had frequently
      gone to Internet cafe's. CONCLUSION: Significant differences between boys and
      girls were found in terms of hours spent on the Internet and purpose of use, and
      changes over time in hours spent. "Daily" and "weekly" Internet use is more
      frequent among boys than girls. Boys visit cyber-sex sites more than girls. Those
      whose weekly Internet use was 4 hours or more were found to have been using the
      Internet for 36 months or more; they had irregular eating habits, and their
      relatives complained more frequently on the amount of time they spent on the
      Internet.

PMID- 15195203
TI  - DNA amplification fingerprinting using 10 x polymerase chain reaction buffer with
      ammonium sulfate for human identification.
AB  - OBJECTIVE: The polymerase chain reaction (PCR) - based DNA amplification
      fingerprinting (DAF) or randomly amplified polymorphic DNA (RAPD) is based on a
      strategy using a single arbitrary oligonucleotide primer to generate anonymous
      amplification of genomic DNA. On this basic strategy, in this study, we aimed to
      test individual differences and usefulness of 2 basic primers (5'-CGCGCCGG-3' and
      5'-TGCCGAGCTG-3') and examined whether there is a positive effect on results of
      10 x PCR buffer with ammonium sulfate. METHODS: A new approach in DNA
      fingerprinting, 10 x PCR buffer with ammonium sulfate, is presented in the study.
      Primers with single 8 and 10 nucleotides in length and 2 different PCR buffers
      with or without ammonium sulfate were used to identify 135 volunteers with no
      blood relationship. This study was carried out at the Pharmacology Laboratory,
      University of Gaziantep, School of Medicine, Turkey between 1999 and 2000.
      RESULTS: An average of 10 major bands representing 500-1500 base pair (bp) in
      length was determined as amplified DNA products on standard agarose gels for
      these volunteers. The use of ammonium sulfate in 10 x PCR buffers has increased
      to 92% success ratio of individual difference obtained from the 8 nucleotides
      primer. CONCLUSION: With this study, more reliable results can be obtained by
      using ammonium sulfate in 10 x PCR buffers.

PMID- 15195204
TI  - Outcome in definite and advanced neonatal necrotizing enterocolitis.
AB  - OBJECTIVE: To evaluate and compare the outcome of newborns with definite (Bells
      stage II) and advanced (Bells stage III) necrotizing enterocolitis (NEC) and to
      assess the role of primary peritoneal drainage. METHODS: This study was conducted
      in the Department of Pediatric Surgery, Maternity and Children's Hospital,
      Dammam, Kingdom of Saudi Arabia. Medical records of all cases diagnosed with NEC
      or suspected NEC between May 1993 and June 2003 were reviewed retrospectively. A
      total of 67 cases meeting the criteria for Modified Bells stage II and III
      disease were selected for the study. Twenty-five (37%) cases were treated
      medically and 42 (63%) needed surgical intervention, namely primary peritoneal
      drainage (PPD) with or without salvage laparotomy (SL) (n=25), or primary
      laparotomy (PL) (n=17). Data regarding patient demographics, neonatal history,
      clinical presentation, laboratory and radiological features, operative findings,
      complications and mortality were collected and compared between the medical and
      surgical group and between the 2 surgical groups. RESULTS: The overall mortality
      was 37%, 8% in the medical group versus 55% in the surgically treated group. The
      PPD group had the highest mortality (72%) versus 29% in the PL group. In the PPD
      group, 14 (56%) needed SL and only 3 (12%) survived without laparotomy. The mean
      gestational age and birthweight were 32.1 weeks and 1713 gms in the PPD group as
      compared to 35.7 weeks and 2484 gms in the PL group. The PPD group were more
      critically sick than the PL group. The average length of time from onset to
      laparotomy was longer, 6.6 days in the PPD group versus 2.2 days in the PL group.
      In the 31 cases undergoing laparotomy, the terminal ileum was involved most
      frequently followed by the cecum and right colon. The PPD + SL group had a higher
      mortality in isolated, multifocal, and pan involvement of bowel when compared to
      the PL group. All babies with only isolated involvement in the PL group survived.
      CONCLUSION: The surgical mortality of NEC in our hospital is very high due to
      advanced disease. The PPD group in our study fared badly, as it comprised a poor
      risk group with ongoing sepsis, with the bias being in favor of PPD as these
      babies were unfit to undergo major surgery. Early SL after PPD in those showing
      signs of persistent disease may improve the outcome in this group.

PMID- 15195205
TI  - Treatment strategy of inguinal hernia in infants and children in Eastern Libya.
AB  - OBJECTIVE: The aim of the study is to evaluate and improve the treatment strategy
      of inguinal hernia in children. METHODS: A retrospective analysis was performed
      on the hospital notes and operation records of 827 (681 boys and 146 girls)
      children who underwent inguinal herniotomy at Al-Fatah Children Hospital,
      Benghazi, Libya, between 1998 and 2002. RESULTS: Eight hundred and sixty-five
      inguinal herniotomies were performed on 827 children. In 497 patients, operations
      were performed on the right side, in 292 on the left side, and in 38 bilateral.
      Thirty-nine (4.7%) children presented as emergencies with irreducible hernia, of
      which 29 (74.4%) patients underwent emergency herniotomies while the remaining 10
      (25.6%) patients could be treated with conservative measures at the time of
      admission. Postoperative complication rate for elective was 6.3% and for
      emergency groups was 24%. The overall postoperative complication rate was 6.6%.
      There were 5 recurrences giving a recurrence rate of 0.5%. CONCLUSION: Early
      detection and repair of inguinal hernia in infancy and childhood is essential to
      decrease the potential operative morbidity rate. This needs an increase in
      parental awareness. Quick and prompt referral of irreducible hernias for surgery
      is strongly recommended.

PMID- 15195207
TI  - Comparison between arthroscopy and 3 dimensional double echo steady state 3D-DESS
      sequences in magnetic resonance imaging of internal derangements of the knee.
AB  - OBJECTIVE: This study was performed with the aim of evaluating the usefulness of
      3 dimensional double-echo steady state sequences in examining the internal
      derangements of the knee. Arthroscopy was used as a referral standard. METHODS:
      The study was performed in the Radiology and Arthroscopy Departments of King's
      College Hospital, London, United Kingdom, during a 6-month period from January
      1997 to June 1997. All patients who had knee magnetic resonance imaging within 3
      months of arthroscopy were retrospectively studied. Thirty-three patients
      fulfilled these criteria and were selected. RESULTS: Three dimensional double
      echo steady state sequences produced sensitivity for detecting meniscal tears of
      87.5% for medial menisci (MM) and 75% for lateral menisci (LM). Specificity was
      76% for MM and 96% for LM; positive predictive value (PPV) was 46.1% for MM and
      85.7% for LM and negative predictive value (NPV) of 95% for MM and 96% for LM.
      The sensitivity for the anterior cruciate ligament was 83.3%, specificity was
      77.7%, PPV was 45.4% and NPV was 95.4%. CONCLUSION: Three dimensional double-echo
      steady state sequences are useful in evaluating internal derangement of the knee,
      especially in advanced cartilage lesions.

PMID- 15195206
TI  - Change of quadriceps angle values with age and activity.
AB  - OBJECTIVE: The lines connecting the anterior superior iliac spine to the center
      of the patella and the center of the patella to the tibial tuberosity make the
      quadriceps angle (Q angle), and this can be used as data for patellar alignment.
      We undertook this study to provide detailed information about the change of Q
      angle values with age and activity. METHODS: The study was conducted on 474
      active (AG) (soccer players) and 765 sedentary (SG) boys (N=1239) from the age of
      9-19, and the sedentary group also served as control to their age matched active
      counterparts. The statistical methods used were the student's t-test and the 3
      way analysis of variance (ANOVA). The study was carried out in the laboratories
      of the Anatomy Departments and School of Physical Education and Sports, Istanbul
      and Hacettepe Universities between 2001 and 2003. RESULTS: The right and left Q
      angle values within both groups were statistically insignificant. The comparison
      of the groups showed a very high level of significant difference between the
      groups for both knees (AG right Q angle = 14.54 +/- 4.76, SG right Q angle =
      17.98 +/- 3.24; AG left Q angle = 14.41 +/- 4.61, SG left Q angle = 18.12 +/-
      3.55). The 3 way ANOVA showed that the age and physical activity had equally
      highly significant effects on Q angle values with a greater change in the active
      group's values. CONCLUSION: We conclude that 1) children and adolescents have
      greater Q angle values than adults, 2) a change in quadriceps strength and tone,
      caused by both growth and activity, results in a decrease of the Q angle and 3)
      activity, particularly playing soccer in our study, has a remarkable effect on
      the Q angle.

PMID- 15195208
TI  - Bone density in rheumatoid arthritis.
AB  - OBJECTIVE: The aim of this study is to examine the bone mineral density (BMD) in
      rheumatoid arthritis (RA) patients and to study the effect of disease activity
      and steroid therapy on BMD. METHODS: Thirty Saudi female patients with RA and 10
      Saudi healthy females matched for age as controls were the material of this work.
      Patients were attending the out-patient clinic of Makkah Rheumatology and
      Rehabilitation Center, Al-Noor Specialist Hospital, Makkah, Kingdom of Saudi
      Arabia between November 2002 and July 2003. All patients were subjected to
      clinical assessment and laboratory investigations. Bone mineral density was
      measured by dual-energy x-ray (DXA) in the lumbar spine at L2-4 and in the
      femoral bone (femoral neck, ward's triangle and trochanteric). RESULTS: The
      results of our study showed a significant decrease in BMD in RA patients compared
      with healthy controls (spine = 0.863 +/-2.29 versus 1.289 +/- 0.54 g/cm2, p<0.05;
      total femoral = 0.755 +/-0.27 versus 1.06 +/-0.49 g/cm2, p<0.05; femoral neck =
      0.725 +/-0.25 versus 1.008 +/-0.482 g/cm2, p<0.05; ward s triangle = 0.586 +/
      0.21 versus 0.909 +/-0.43 g/cm2, p<0.05 and trochanteric = 0.607 +/-0.225 versus
      0.898 +/-0.419 g/cm2, p<0.05). The decreased BMD correlated significantly with
      the impairment of functional activity, increased disease activity and with the
      use of steroids. There was no correlation between the decreased BMD and the body
      weight, height, age and the duration of the disease. CONCLUSION: We conclude that
      the impairment functional activity, increased disease activity and the use of
      steroids for long periods are the major determinants of BMD of both spinal and
      femoral bone in rheumatoid patients.

PMID- 15195209
TI  - Epstein-Barr virus expression in Hodgkin's disease in Jordan.
AB  - OBJECTIVE: Epstein-Barr virus (EBV) has been associated with many hematopoietic
      malignancies including Hodgkin's disease (HD). The association of HD correlates
      with the histologic subtype, age of presentation and geographic location. Our
      aims were to find out if EBV is associated with Jordanian HD; and if EBV
      association exists, to determine its relationship to certain age groups or
      specific histologic subtypes of HD; and finally to establish whether such
      association follows patterns seen in developing or developed countries. METHODS:
      We have examined 64 cases of HD diagnosed in 2 major medical centers in Jordan
      for evidence of EBV association. We used immunohistochemistry and in-situ
      hybridization techniques to detect latent membrane protein (LMP-1) and Epstein
      Barr virus encoded RNA (EBER) in the Reed-Sternberg cells. The study was
      conducted at the Department of Pathology, Jordan University of Science and
      Technology, Irbid, Jordan in the years 2000 and 2001. RESULTS: Epstein Barr virus
      was seen in 47% of our cases: 22 (65%) of the 34 mixed cellularity and 8 (29%) of
      28 nodular sclerosis HD. None of our 2 lymphocyte predominant HD cases showed
      evidence of EBV. Epstein-Barr virus was seen in 73% of HD cases in children below
      15 years of age as opposed to 34% of the young adult group. CONCLUSION: Our
      results confirm the presence of EBV in Jordanian HD in approximately half of the
      cases, a figure close to those reported in the West. Epstein-Barr virus
      association with HD in Jordan is seen mostly in the mixed cellularity subtype and
      childhood HD.

PMID- 15195210
TI  - Pattern of skin cancer in Southwestern Saudi Arabia.
AB  - OBJECTIVE: Skin cancer is a common malignant neoplasm in the Kingdom of Saudi
      Arabia (KSA) and it is the most common malignant neoplasm in Al-Baha area. This
      study was performed to determine the pattern of skin cancers seen at King Fahad
      Hospital, Al-Baha, KSA. METHODS: Histologically diagnosed skin cancers, seen
      between 1990 and 2003, were reviewed and analyzed according to age, gender, race
      and site of distribution. RESULTS: Of a total of 193 patients, there were 79
      (41%) cases of basal cell carcinoma (BCC), 56 (29%) cases of squamous cell
      carcinoma (SCC) and 34 (18%) cases of Kaposi's sarcoma. Malignant melanomas
      represent 4.1% of the cases. The male to female ratio for all cancer was 1.6:1.
      The peak age distribution was in the 70-80-year group. The most common site
      involved in BCC was the head and neck (90%) and in Kaposi's sarcoma were the
      lower limbs (59%). Acral distribution of malignant melanoma was seen in 62%
      cases. CONCLUSION: The most common skin cancers seen are BCC and SCC followed by
      Kaposi's sarcoma. The site of distribution of BCC and SCC in our study is similar
      to studies in Caucasians. The site of distribution of BCC in sun exposed area
      supports the role of the ultraviolet light in the pathogenesis of such tumor. In
      contrast to the western countries, melanoma is a rare skin neoplasm in KSA.

PMID- 15195211
TI  - Antimicrobial susceptibility pattern of clinical isolates of Pseudomonas
      aeruginosa.
AB  - OBJECTIVE: To determine the level of resistance to the widely used
      antipseudomonal antibiotics in clinical isolates of Pseudomonas aeruginosa (P.
      aeruginosa). METHODS: The microbiology database of all clinical isolates of P.
      aeruginosa at the Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia, from
      January 1999 to December 1999 was reviewed. The antimicrobial susceptibilities
      were determined by a standardized method. RESULTS: Seven hundred and four P.
      aeruginosa isolates were tested. These strains were commonly isolated from
      surgical patients followed by intensive care units. Respiratory tract was the
      most common source of isolation. The antibiotic susceptibility rates were as
      follows: ciprofloxacin 92.2%, meropenem 91.6%, imipenem 90.2%, amikacin 85.8%,
      ceftazidime 81.8% piperacillin/tazobactam 81.3% and gentamicin 77.7%. Among 704
      strains 6.4% were designated as being multidrug resistant. These were commonly
      isolated from respiratory tract specimens of patients in intensive care units.
      CONCLUSION: The clinical significance of these findings is important in the
      selection of appropriate empiric treatment of serious P. aeruginosa infections.
      It emphasizes the importance of a conservative approach to antibiotic therapy and
      continued antimicrobial susceptibility testing surveillance programs to curtail
      the problem of antibiotic resistance.

PMID- 15195213
TI  - Herpes gestationis.
AB  - Herpes gestationis, also known as Pemphigoid gestationis, is a rare autoimmune
      disease of pregnancy. It is characterized by itching and skin lesions. The
      disease causes prominently maternal discomfort but fetal and neonatal
      complications have been reported. There are only scattered reports of cutaneous
      neonatal herpes gestationis in the literature; however, the frequency and
      severity of fetal illness are still debated. We describe 2 cases of herpes
      gestationis diagnosed and managed at the King Khalid University Hospital, Riyadh,
      Kingdom of Saudi Arabia.

PMID- 15195212
TI  - Efficacy and safety of sevelamer. Comparison with calcium carbonate in the
      treatment of hyperphosphatemia in hemodialysis patients.
AB  - OBJECTIVE: Current phosphate binders used in hemodialysis patients include
      calcium-based binders that result in frequent hypercalcemia. The use of a calcium
      and aluminum-free phosphate-binding polymer in hemodialysis (sevelamer)
      disclosed efficacy in the short and long-term studies. However, due to race
      differences we performed a short-term study on the Saudi hemodialysis patients
      and compared sevelamer with a standard calcium-based phosphate binder. METHODS:
      An open-label, randomized, cross-over study was performed to evaluate the safety
      and effectiveness of sevelamer hydrochloride in controlling hyperphosphatemia in
      hemodialysis patients. After a 2-week phosphate binder washout period, stable
      hemodialysis patients were given either sevelamer or calcium carbonate, and the
      dosages were titrated to achieve phosphate control over an 8-week period. After a
      2-week washout period, patients crossed over to the alternate agent for 8 weeks.
      Twenty patients from the Dialysis Unit of King Fahd Hospital, Jeddah, Kingdom of
      Saudi Arabia, were recruited for the study between March 2003 and June 2003.
      RESULTS: There was a similar decrease in serum phosphate values over the course
      of the study with both sevelamer (-3.3 +/-2.2 mg/dL) and calcium carbonate (-3.9
      +/-2.8 mg/dL). Fifty-two percent of patients developed serum calcium greater than
      2.75 mmol/L (11.0 mg/dL) while receiving calcium carbonate versus 26% of patients
      receiving sevelamer (p<0.05). The incidence of hypercalcemia for sevelamer was
      not different from the incidence of hypercalcemia during the washout period.
      Patients treated with sevelamer also sustained a 13% mean decrease in serum
      cholesterol levels. CONCLUSION: Sevelamer was effective in controlling
      hyperphosphatemia without resulting in an increase in the incidence of
      hypercalcemia seen with calcium carbonate. This agent appears quite effective in
      the treatment of hyperphosphatemia in hemodialysis patients, and its usage may be
      advantageous in the treatment of dialysis patients.

PMID- 15195214
TI  - Dizziness during pregnancy due to cardiac myxoma.
AB  - A woman in the second trimester of pregnancy with recurrent episodes of dizziness
      is presented. She had a large left atrial myxoma that interfered with left
      ventricular filling, compromising cardiac output accounting for the symptoms.
      Surgical excision of the tumor was performed successfully during pregnancy.

PMID- 15195215
TI  - Tracheobronchomegaly-Mounier-Kuhn syndrome.
AB  - Tracheobronchomegaly is a rare disorder of uncertain etiology, characterized by
      marked dilatation of the trachea and major bronchi, associated with tracheal
      diverticulosis, bronchiectasis and recurrent respiratory tract infection. We are
      reporting a 60-year-old man from the Kingdom of Saudi Arabia with this condition
      and review the literature for such a rare entity.

PMID- 15195216
TI  - Asymptomatic giant pulmonary artery aneurysm in an elderly male patient.
AB  - Pulmonary artery aneurysm is rarely seen in clinical practice. It has been
      reported to develop in patients due to several underlying etiologies. However,
      the natural history is not yet defined, and management remains controversial. We
      report a case of giant main pulmonary artery aneurysm 6.06 cm in diameter in an
      asymptomatic 75-year-old male who has an incidental abnormal chest x-ray for
      preoperative evaluation as management of benign prostatic hypertrophy. The
      patient was managed conservatively. He was discharged home in good general
      condition to be followed up by echocardiography every 6 months. We conclude that
      pulmonary artery aneurysm can reach a massive size with no apparent symptoms. The
      treatment can therefore be conservative as no clear guidelines to support
      interventional management, particularly in the absence of pulmonary hypertension.

PMID- 15195217
TI  - Solitary fibrous tumor of the thyroid gland.
AB  - A solitary fibrous tumor is a mesenchymal neoplasm originally described in the
      pleura. Subsequently, it was found to exist in many extra-pleural sites including
      the thyroid gland. Herein, we report a case of solitary fibrous tumor of the
      thyroid gland associated with symptoms of hoarseness of voice in a 45-year-old
      man. In this report we discuss and illustrate various aspects of this rare tumor
      including, the gross macroscopic appearance, the histological findings, the
      immunohistochemical staining properties, the differential diagnosis, and the
      outcome of our experience regarding fine needle aspiration technique in this
      particular tumor.

PMID- 15195218
TI  - Touraine-Solente-Gole syndrome.

PMID- 15195219
TI  - Determination of fundal height increase in fasting and non-fasting pregnant women
      during Ramadan.

PMID- 15195220
TI  - Achromobacter xylosoxidans isolated from the sputum of a patient with cystic
      fibrosis mutation I1234V with Pseudomonas aeruginosa.

PMID- 15195221
TI  - Columnar lined esophagus. An attempt to find a useful definition and reproducible
      histopathological diagnostic criteria.

PMID- 15195222
TI  - Fever due to malaria in a neutropenic patient. A rare complication of blood
      transfusion.

PMID- 15195223
TI  - The effect of rifampicin on serum cortisol level in patients with active
      tuberculosis.

PMID- 15195224
TI  - H. pylori and myocardial infarction.

PMID- 15195225
TI  - Assessment of a new cell culture perfusion apparatus for in vitro chronic
      toxicity testing. Part 1: technical description.
AB  - In vitro models for chronic toxicity, defined as a recurring exposure to
      compounds over a prolonged period of time, are still underrepresented in drug
      evaluation processes. The classical approach to cell culture is not readily
      suitable to long term repetitive applications. Therefore, we assessed the use of
      a commercially available perfusion cell culture apparatus in its applicability to
      chronic renal toxicity testing and describe the technical aspects of adopting the
      perfusion cell culture system to our purposes. It was apparent that there is a
      subtle dynamic difference between human renal proximal tubular cells cultured
      under perfusion and static conditions as illustrated by the accumulation of
      lactate dehydrogenase (LDH) and the secondary metabolism of resazurin to
      hydroresorufin, which occurred only under static conditions. The major
      achievement was the standardisation of the handling of this system with regard to
      cell cultivation, pH regulation, temperature regulation, and reproducibility of
      common toxicity endpoints.

PMID- 15195227
TI  - Culturing cells without serum: lessons learnt using molecules of plant origin.
AB  - To successfully grow cells in serum-free medium is an interesting challenge to
      cell biology. The use of such media for in vitro cell culture work would be a key
      contribution to the 3Rs concept, enabling the avoidance of the use of animals and
      animal products at all stages of the experiment. In addition, numerous problems
      related to virus infections transmitted by animal serum would be avoided, thus
      increasing reproducibility. Prolifix is a new reagent of plant origin. It
      contains a molecule (GCR 1003) that has an activity similar to that of the
      mitogenic molecules in serum and could be suitable to substitute serum in culture
      medium. Two epithelial cell lines, LLC-PK1 and Caco-2, were progressively adapted
      to a special culture medium containing 10% Prolifix in the absence of serum.
      After adaptation, cell cultures were characterised. We found that these reagents
      of plant origin could be promising alternatives to serum. However, more work and
      effort is needed to improve cell adaptation, cell attachment, growth rates as
      well as freezing/thawing protocols.

PMID- 15195226
TI  - Assessment of a new cell culture perfusion apparatus for in vitro chronic
      toxicity testing. Part 2: toxicological evaluation.
AB  - The goal of replacement, refinement and reduction of animal testing is critically
      dependent on the development and assessment of novel in vitro methodologies and
      the further development of existing methodologies. Here, we evaluated the use of
      a modified perfusion cell culture apparatus for application to chronic in vitro
      nephrotoxicity testing using DMSO, SDS, paracetamol and cyclosporine A as test
      compounds. Renal epithelial monolayers were cultured on microporous growth
      supports and exposed to test compounds under static or perfusion conditions.
      Alamar Blue reduction, gamma-glutamyl transpeptidase activity (GGT), lactate
      dehydrogenase activity (LDH) and remnant protein were used to assay cell
      toxicity. There was no significant difference in IC(50) values between static and
      perfusion cultures up to 72 hours exposure. However, the perfusion system allowed
      continuous real-time monitoring of plasma membrane damage, which gives important
      information of time, duration and scale of toxicity. The complexity of the system
      restrains its use to low-throughput analysis. However, the real and theoretical
      advantages of this and similar systems merit further investigations.

PMID- 15195228
TI  - [Animal experiments in the context of quality control of pharmaceuticals. Review
      of the European Pharmacopoeia, 4th edition, 2002].
AB  - In the 4th edition of the European Pharmacopoeia, animal experiments are
      described, which are required for the quality control of pharmaceuticals. This
      refers to investigations regarding both biological activity and safety aspects of
      the medication. The latter include investigations to find contaminations with
      histamine and pyrogenic substances and tests for abnormal toxicity. Even though
      the safety of medical drugs is of great importance, it should be examined whether
      these tests are still indispensable (in terms of paragraph sign 7 of the German
      Animal Protection Law of 2002). The determination of histamine content may also
      be possible by chemical-analytical methods, which could represent an alternative
      to the animal experiment. The testing of abnormal toxicity should be
      scientifically questioned due to its lack of specificity. Although the in vitro
      test detecting bacterial endotoxins is mentioned in many monographs, the in vivo
      test on rabbits to test for pyrogenicity is still mentioned in some other
      monographs. The in vivo test should be rechallenged as to whether it can be
      replaced. In light of the global trade in pharmaceuticals, which must also
      fulfill national quality standards a reduction in animal experiments can only be
      reached by fruitful cooperation between pharmaceutical companies, health
      authorities and the commissions of the pharmacopoeias, leading to the formation
      of a consensus. The International Conference on Harmonization could prove an
      auspicious panel to take up this subject and to contribute to an internationally
      accepted and scientifically based reduction of animal experiments.

PMID- 15195229
TI  - [Vaccine testing without animal experiments?].
AB  - Vaccines must provide effective protection against disease without any harmful
      side effects. Antigen purity is a crucial factor which until now has had to be
      tested on animals. However, recent scientific developments allow the use of
      alternatives to animal experiments in many cases, e.g. poultry vaccine purity
      testing. The in vitro Polymerase Chain Reaction method (PCR) is one advance which
      could reduce the number of animal experiments.

PMID- 15195231
TI  - Musculoskeletal applications of multichannel computed tomography.

PMID- 15195232
TI  - Fundamentals of multichannel CT.
AB  - Multichannel computed tomography (MCCT) has created a technical revolution in CT
      scanning. Following the introduction of single-channel helical scanning in 1989,
      4-channel systems were introduced in 1998 and 16-channel systems in 2002. The
      core of this new technique is the X-ray detector array design, which allows for
      multiple simultaneous registration of slice information during gantry rotation.
      This design allows for faster scanning and acquisition of thinner slice widths.
      The high-speed scanning also minimizes motion artifacts. The ability to scan with
      very thin slice thickness creates a scanned volume with isotropic voxels. This
      allows for two- and three-dimensional reconstructions with similar resolution as
      the source images. MCCT also allows for higher X-ray tube currents, which create
      better penetration of metallic orthopedic fixation devices. Musculoskeletal
      imaging benefits from MCCT because large anatomic areas may be covered with thin
      slices. When needed, high tube currents can be applied for scanning areas of
      interest in the presence of metal. Thin slice acquisition allows isotropic
      viewing, which we use routinely.

PMID- 15195233
TI  - Application of multidetector CT in skeletal trauma.
AB  - Multidetector computed tomography (MDCT) has improved our ability to image
      patients with skeletal trauma. The chief advantages of this technology include
      the extremely rapid scan times, the ability to produce very-high-quality
      multiplanar reformations, and the ability to reprocess raw data quickly and
      easily. Unlike soft tissue imaging, CT of bony structures requires high spatial
      resolution. Each joint in the body presents a unique challenge, and guidelines
      for imaging of each of the major joints is discussed throughout this article. In
      general, use of the thinnest slice width and a bone-reconstruction algorithm
      maximizes image quality. Imaging of larger joints such as the shoulder and hip
      requires slightly thicker slices to ensure reasonable image quality, particularly
      if surface rendering is to be performed. The demonstration of fracture line
      extension to articular surfaces is a key function of imaging, and image
      postprocessing is an integral component of high-resolution joint imaging. The
      introduction of MDCT has enabled submillimeter slice widths, ensuring
      unparalleled joint visualization in multiple planes from a single scan
      acquisition.

PMID- 15195234
TI  - CT arthrography and postoperative musculoskeletal imaging with multichannel
      computed tomography.
AB  - Multichannel computed tomography (MCCT) allows for rapid, thin slice acquisition
      and the ability to generate high mAs. This combination of features makes the
      modality ideal for MCCT arthrography, which requires thin, overlapping slices for
      robust reformatted images, and for imaging in the presence of orthopedic
      hardware, which necessitate high mAs. This article will explore these uses of
      MCCT.

PMID- 15195235
TI  - Imaging of the wrist with multichannel CT.
AB  - Multichannel computed tomography (MCCT) can produce extremely thin, overlapping
      slices. This capability allows for the acquisition of essentially isotropic data
      sets. These isotropic data sets can be used to produce reformatted images in any
      plane with virtually no loss of spatial resolution. This, imaging can be done
      with a single acquisition. This high-resolution technique is particularly useful
      in the imaging of small body parts, such as the wrist, where fine detail in
      essential. Drawing on clinical examples, this article reviews the use of
      isotropic imaging in the wrist.

PMID- 15195236
TI  - Three-dimensional volume rendering of the tendons of the ankle and foot.
AB  - Three-dimensional (3D) rendering is the process of creating two-dimensional (2D)
      images that convey the 3D relationships of an object or objects. In the past 10
      years, the use of volume-rendering (VR) images has become a commonly used method
      of 3D display. The improved data sets that result from spiral and multidetector
      computed tomography, improved software, and more powerful workstations
      significantly improve radiologists' ability to create these images. The process
      by which these images are obtained is described. It is possible to simultaneously
      demonstrate the tendons and bones of the ankle and hindfoot using VR because of
      significant attenuation differences among the soft tissue, tendons, and bone: fat
      approximately -100, muscle approximately 30, tendon approximately 90, and bone
      approximately 250 to 500 Hounsfield units. These 3D images can be helpful in the
      care of patients with ankle/foot deformities resulting from trauma, idiopathic
      disorders, and arthritis. These images present a global image that provides
      improved understanding of the relationships of the bones and adjacent tendons.

PMID- 15195237
TI  - A cohort study of the effectiveness of influenza vaccine in older people,
      performed using the United Kingdom general practice research database.
AB  - BACKGROUND: The effectiveness of influenza vaccination against hospitalization
      and death can only ethically be assessed in observational studies. A concern is
      that individuals who are vaccinated are healthier than individuals who are not
      vaccinated, potentially biasing estimates of effectiveness upward. METHODS: We
      conducted a historical cohort study of individuals >64 years of age, for whom
      there were data available in the General Practice Research Database for 1989 to
      1999 in England and Wales. Rates of admissions for acute respiratory diseases and
      rates of death due to respiratory disease were compared over 692,819 person-years
      in vaccine recipients and 1,534,280 person-years in vaccine nonrecipients.
      RESULTS: The pooled effectiveness of vaccine against hospitalizations for acute
      respiratory disease was 21% (95% confidence interval [CI], 17%-26%). The rate
      reduction attributable to vaccination was 4.15 hospitalizations/100,000 person
      weeks in the influenza season. Among vaccine recipients, no important reduction
      in the number of admissions to the hospital was seen outside influenza seasons.
      The pooled effectiveness of vaccine against deaths due to respiratory disease was
      12% (95% CI, 8%-16%). A greater proportionate reduction was seen among people
      without medical disorders, but absolute rate reduction was higher in individuals
      with medical disorders, compared with individuals without such disorders (6.14
      deaths due to respiratory disease/100,000 person-weeks vs. 3.12 deaths due to
      respiratory disease/100,000 person-weeks). Clear protection against death due to
      all causes was not seen. CONCLUSIONS: Influenza vaccination reduces the number of
      hospitalizations and deaths due to respiratory disease, after correction for
      confounding in individuals >64 years of age who had a high risk or a low risk for
      influenza. For elderly people, untargeted influenza vaccination is of confirmed
      benefit against serious outcomes.

PMID- 15195238
TI  - Immunity to influenza in older adults with chronic obstructive pulmonary disease.
AB  - BACKGROUND: Chronically ill older adults constitute a population vulnerable for
      complications associated with influenza. Study of their immunity to influenza
      virus may help design better strategies to stimulate protective immune responses.
      METHODS: Immunogenicity of influenza vaccines and immune protection from natural
      influenza were assessed in older adults with chronic obstructive pulmonary
      disease as part of a vaccine efficacy trial. Subjects received either trivalent
      inactivated influenza virus vaccine (TVV) intramuscularly and trivalent live cold
      adapted influenza virus vaccine (CAIV-T; n=1107) intranasally (inl) or TVV and
      placebo inl (P; n=1108). RESULTS: In the subsets of study subjects assessed,
      serum hemagglutination inhibition (HAI) and nasal-wash antihemagglutinin (HA)
      immunoglobulin (Ig) A and IgG antibody levels and anti-influenza virus CD8(+)
      cytotoxic T lymphocyte activity increased after immunization. Mean
      postimmunization nasal-wash IgA antibody levels to influenza A H3/HA and B HA
      were statistically higher in the TVV+CAIV-T group (n=957) than in the TVV+P group
      (n=951). Postimmunization serum HAI and nasal-wash IgA antibodies to influenza
      A/H3N2 and B viruses were associated with a reduced relative risk for natural
      influenza infection. CONCLUSIONS: TVV+CAIV-T appeared more immunogenic than
      TVV+P, but the observed difference may be clinically unimportant. Anti-influenza
      serum and nasal-wash antibodies were associated with immune protection.

PMID- 15195239
TI  - Human metapneumovirus in children tested at a tertiary-care hospital.
AB  - BACKGROUND: Respiratory infections are the leading cause of outpatient visits in
      the United States, but the etiology of many of these infections is unknown. Human
      metapneumovirus (hMPV) is a recently discovered virus that causes respiratory
      infections. METHODS: Respiratory specimens obtained from patients <or=18 years
      old, between 1 October 2000 and 31 August 2002, were tested for hMPV. The results
      of testing for other viruses and epidemiological information were obtained from
      the hospital databases. A logistic regression model, including sex and age of the
      patient and year and season in which the specimen was obtained, was used to
      determine the factors associated with hMPV infection. RESULTS: hMPV was detected
      in 6.2% of patients tested and was significantly more common among children 3-24
      months old than in older or younger children. The seasonal occurrence of hMPV was
      similar to that of respiratory syncytial virus and influenza virus, with most
      cases occurring in the winter and spring. In this tertiary care-center
      population, patients with hMPV infection often had underlying chronic conditions.
      CONCLUSIONS: hMPV is common among young children with apparent respiratory
      infections, suggesting that it is a significant cause of symptomatic respiratory
      infections.

PMID- 15195240
TI  - Outbreaks of acute gastroenteritis on cruise ships and on land: identification of
      a predominant circulating strain of norovirus--United States, 2002.
AB  - In 2002, a sharp increase in outbreaks of norovirus-associated illness, both on
      cruise ships and on land, encouraged us to examine the molecular epidemiology of
      detected noroviruses, to identify a common strain or source. Of 14 laboratory
      confirmed outbreaks on cruise ships, 12 (86%) were attributed to caliciviruses;
      among these 12, outbreak characteristics included continuation on successive
      cruises in 6 (50%), multiple modes of transmission in 7 (58%), and high (>10%)
      attack rates in 7 (58%). Eleven of the 12 calicivirus outbreaks were attributed
      to noroviruses, 7 (64%) of which were attributed to a previously unreported
      lineage, provisionally named "the Farmington Hills strain." From May 2002 to
      December 2002, 10 (45%) of 22 land-based outbreaks also were attributed to this
      strain. Nucleotide-sequence analysis provided insights into norovirus
      transmission, by documenting links among outbreaks, the introduction of strains
      onto ships, and viral persistence on board (despite cleaning). Control measures
      for outbreaks should address all routes of transmission. Better outbreak
      surveillance and collection of data on sequences will help to monitor norovirus
      strains and to identify common sources.

PMID- 15195241
TI  - Persistence of human papillomavirus infection in HIV-infected and -uninfected
      adolescent girls: risk factors and differences, by phylogenetic type.
AB  - BACKGROUND: High rates of persistence of human papillomavirus (HPV) infection
      have been reported for adult women with human immunodeficiency virus (HIV)
      infection. Although most women are first infected with HPV during adolescence,
      persistence of specific HPV types has not been carefully examined among HIV
      infected adolescents. The objective of this study was to examine the rates of and
      risk factors for persistence of HPV types among HIV-infected and -uninfected
      adolescent girls. METHODS: This is a prospective cohort study of female
      adolescents, aged 13-18 years, participating in the Reaching for Excellence in
      Adolescent Care and Health project, a national study of HIV-infected and 
      uninfected adolescents. The main outcome measured was type-specific loss of
      initial HPV DNA detected. Loss of HPV DNA was defined for the following
      categories of HPV DNA types: low risk, which included types 6, 11, 42, 44, 54,
      40, 13, 32, 62, 72, 2, 57, and 55; and high risk, which included types 16-like
      (16, 31, 33, 35, 52, 58, and 67), 18-like (18, 39, 45, 59, 68, 70, 26, 69, and
      51), and 56-like (56, 53, and 66). RESULTS: Prevalent or incident HPV infection
      was detected in 334 girls. When type-specific loss of HPV was examined, HIV
      uninfected girls had a shorter mean time to loss of initial infection than did
      HIV-infected girls (403 days vs. 689 days, respectively; P<.0001). By means of
      multivariate analysis, CD4 immunosuppression and the presence of multiple HPV
      type subgroups were found to be associated with persistence of HPV. CONCLUSION:
      Since persistence of high-risk HPV types has been strongly linked with the
      development of invasive cancer, the prolonged persistence of HPV observed among
      HIV-infected adolescents who are relatively healthy underscores the importance of
      prevention of HPV infection in this group.

PMID- 15195242
TI  - Genomic polymorphism of human papillomavirus type 52 predisposes toward
      persistent infection in sexually active women.
AB  - We investigated the role of human papillomavirus (HPV) type 52 polymorphism in
      the persistence of HPV infection, which is a predictor for cervical lesions.
      Cervical samples obtained at 6-month intervals were tested for HPV-52 in 1055
      women; 41, 12, and 58 women had persistent, transient, and unclassified HPV-52
      infections, respectively. HPV-52 isolates were analyzed by polymerase chain
      reaction sequencing of the long control region (LCR), E6, and E7 genes. Although
      age (odds ratio [OR], 0.90 [95% confidence interval [CI], 0.81-0.99]),
      nonprototypic LCR (OR, 9.26 [95% CI, 2.1-41.7]), and E6 variant (OR, 7.04 [95%
      CI, 1.4-37]) were associated, in univariate analysis, with the persistence of HPV
      52 infection, a nonprototypic LCR variant was the only independent predictor of
      it (OR, 14.1 [95% CI, 1.1-200]). In the latter variants, the loss of a binding
      site for a repressor of HPV expression was associated with the persistence of HPV
      infection (OR, 7.25 [95% CI, 1.67-31.25]).

PMID- 15195243
TI  - Molecular diversity of Epstein-Barr virus IgG and IgA antibody responses in
      nasopharyngeal carcinoma: a comparison of Indonesian, Chinese, and European
      subjects.
AB  - Epstein-Barr virus (EBV)-specific immunoblot analysis was used to reveal the
      molecular diversity of immunoglobulin (Ig) G and IgA antibody responses against
      Epstein-Barr nuclear antigen (EBNA), early antigen (EA), and viral capsid antigen
      (VCA) in serum samples from patients with nasopharyngeal carcinoma (NPC) and
      control subjects, by use of immunofluorescence assay (IFA). Control donors
      (n=150) showed IgG responses to few EBV proteins--VCA-p18, VCA-p40, EBNA1, and
      Zebra--and sporadically weak IgA reactivity to EBNA1 and VCA-p18. Patients with
      NPC stage 1 (n=6) had similar response patterns. Patients with NPC stage 2-4
      (n=132) showed significantly more diverse IgG and IgA responses to EA and VCA
      proteins--VCA-p18/-p40, EBNA1, Z-encoded broadly reactive activator, and EAd
      p47/54, -DNAse, -thymidine kinase, and -p138. No correlation was found between
      IFA titers and the number of EBV proteins recognized by IgG or IgA. Our results
      reveal dissimilarity between EBV polypeptides recognized by IgG and IgA
      antibodies, which suggests independent B cell triggering events.

PMID- 15195244
TI  - Analysis of immune activation and clinical events in acute infectious
      mononucleosis.
AB  - The symptoms of infectious mononucleosis (IM) are thought to be caused by T cell
      activation and cytokine production. Surface lymphocyte activation marker (SLAM)
      associated protein (SAP) regulates lymphocyte activation via signals from cell
      surface CD244 (2B4) and SLAM (CD150). We followed T cell activation via this
      SAP/SLAM/CD244 pathway in IM and analyzed whether the results were associated
      with clinical severity. At diagnosis, SAP, SLAM, and CD244 were significantly up
      regulated on CD4 and CD8 T cells; expression decreased during IM, but CD244 and
      SLAM levels remained higher on CD8 cells 40 days later. There were significantly
      more lymphocytes expressing CD8 and CD244/CD8 in patients with severe sore
      throat. The expression of CD8 alone and CD244 on CD8 cells correlated with
      increased virus load. We suggest that T cells expressing CD244 and SLAM are
      responsible for the clinical features of IM but that the control of activation is
      maintained by parallel increased expression of SAP.

PMID- 15195245
TI  - Development of virus-specific CD4+ T cells on reexposure to Varicella-Zoster
      virus.
AB  - Immunity to childhood diseases is maintained for decades by mechanisms that, at
      present, are still unclear. We longitudinally studied immune responses in 16
      adults exposed to children experiencing varicella (chicken pox). None of the
      individuals showed clinical signs of infection, and varicella-zoster virus (VZV)
      DNA could not be detected in peripheral blood or cultured from nasopharyngeal
      swabs. Exposure to VZV, however, induced expansion of antigen-specific CD4(+) T
      cells in peripheral blood, with concomitant changes in cytotoxic CD8(+) T cells
      and natural killer cells. VZV-specific memory CD4(+) T cells were uniformly
      CD45RA(-) and enriched for CD27(-) cells. The virus-specific cells produced
      interferon- gamma, tumor necrosis factor- alpha, and interleukin-2. These memory
      responses to VZV were compared with the primary immune responses of children
      experiencing varicella. VZV-specific memory CD4(+) T cell responses largely
      resemble the primary immune response to VZV.

PMID- 15195246
TI  - Humoral and cell-mediated immune responses to an early 2-dose measles vaccination
      regimen in the United States.
AB  - BACKGROUND: Shifts in peak measles incidence to children <12 months old and the
      associated high mortality support the study of an early 2-dose measles vaccine
      regimen. METHODS: Fifty-five infants were vaccinated with measles vaccine at age
      6 (n=32) or 9 (n=23) months, followed by measles-mumps-rubella (MMR)-II vaccine
      at age 12 months. A control group received MMR-II only at age 12 months. Measles
      specific humoral and cell-mediated immunity were evaluated before, 12 weeks after
      measles immunization, and 24 weeks after MMR-II. RESULTS: Measles-specific T cell
      proliferation after both doses of vaccine was equivalent, regardless of age or
      the presence of passive antibodies. Seroconversion rates, geometric mean titers,
      and the percentage of infants with antibody titers >120 mIU after the first
      measles vaccine were lower in infants vaccinated at age 6 months, regardless of
      the presence of passive antibodies, but measles humoral responses increased after
      the administration of MMR-II vaccine in children initially vaccinated at age 6 or
      9 months. CONCLUSION: Measles vaccination elicits T cell responses in infants as
      young as 6 months old, which may prime the humoral response to the second dose.
      Initiating measles vaccination as an early 2-dose regimen results in an
      immunologic response that is likely to have clinical benefits in developed and
      developing countries.

PMID- 15195247
TI  - Cleavage and serum reactivity of the severe acute respiratory syndrome
      coronavirus spike protein.
AB  - Severe acute respiratory syndrome (SARS) coronavirus (SCoV) spike (S) protein is
      the major surface antigen of the virus and is responsible for receptor binding
      and the generation of neutralizing antibody. To investigate SCoV S protein, full
      length and individual domains of S protein were expressed on the surface of
      insect cells and were characterized for cleavability and reactivity with serum
      samples obtained from patients during the convalescent phase of SARS. S protein
      could be cleaved by exogenous trypsin but not by coexpressed furin, suggesting
      that the protein is not normally processed during infection. Reactivity was
      evident by both flow cytometry and Western blot assays, but the pattern of
      reactivity varied according to assay and sequence of the antigen. The antibody
      response to SCoV S protein involves antibodies to both linear and conformational
      epitopes, with linear epitopes associated with the carboxyl domain and
      conformational epitopes associated with the amino terminal domain. Recombinant
      SCoV S protein appears to be a suitable antigen for the development of an
      efficient and sensitive diagnostic test for SARS, but our data suggest that assay
      format and choice of S antigen are important considerations.

PMID- 15195248
TI  - Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with
      chronic multidrug-resistant tuberculosis.
AB  - Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem
      because treatment is complicated, cure rates are well below those for drug
      susceptible tuberculosis (TB), and patients may remain infectious for months or
      years, despite receiving the best available therapy. To gain a better
      understanding of MDR-TB, we characterized serial isolates recovered from 13 human
      immunodeficiency virus-negative patients with MDR-TB, by use of IS6110
      restriction fragment-length polymorphism analysis, spacer oligonucleotide
      genotyping (i.e., "spoligotyping"), and sequencing of rpoB, katG, mabA-inhA
      (including promoter), pncA, embB, rpsL, rrs, and gyrA. For all 13 patients,
      chronic MDR-TB was caused by a single strain of Mycobacterium tuberculosis; 8
      (62%) of the 13 strains identified as the cause of MDR-TB belonged to the W
      Beijing family. The sputum-derived isolates of 4 (31%) of the 13 patients had
      acquired additional drug-resistance mutations during the study. In these 4
      patients, heterogeneous populations of bacilli with different resistance
      mutations, as well as mixtures of drug-susceptible and drug-resistant genotypes,
      were observed. This genetic heterogeneity may require treatment targeted at both
      drug-resistant and drug-susceptible phenotypes.

PMID- 15195249
TI  - Potent role of vaccines prepared from macrophages infected with live bacteria in
      protection against Mycobacterium tuberculosis and Salmonella typhimurium
      infections.
AB  - The present study describes a novel and simple vaccination strategy that involves
      the culturing of live Mycobacterium tuberculosis and Salmonella typhimurium in
      syngeneic, allogeneic, and xenogeneic macrophages, followed by drug treatment and
      gamma irradiation, to kill the bacteria. Notable observations were that the
      lymphocytes obtained from the vaccinated mice proliferated and secreted mainly
      interferon- gamma and IgG2a, but not interleukin-4 and IgG1. The enumeration of
      viability of M. tuberculosis indicated a significant level of protection in the
      vaccinated mice after challenge with live M. tuberculosis. This vaccination
      strategy worked successfully for tuberculosis but also showed a significant
      decrease in mortality of mice challenged with live S. typhimurium.

PMID- 15195250
TI  - Enhanced protection against tuberculosis by vaccination with recombinant
      Mycobacterium microti vaccine that induces T cell immunity against region of
      difference 1 antigens.
AB  - Mycobacterium microti, the vole bacillus, which was used as a live vaccine
      against tuberculosis until the 1970s, confers the same protection in humans as
      does Mycobacterium bovis bacille Calmette-Guerin (BCG). However, because the
      efficacy of the BCG vaccine varies considerably, we have tried to develop a
      better vaccine by reintroducing into M. microti the complete region of difference
      1 (RD1), which is required for secretion of the potent T cell antigens early
      secreted antigen target (ESAT)-6 and culture filtrate protein (CFP)-10. The
      resultant recombinant strain, M. microti OV254::RD1-2F9, induced specific ESAT-6
      and CFP-10 immune responses in mice with CD8(+) T lymphocytes that had strong
      expression of the CD44(hi) activation marker. This vaccine also displayed better
      efficacy against disseminated disease in the mouse and the guinea pig models of
      tuberculosis than was seen in animals vaccinated with M. microti alone or with
      BCG. The M. microti OV254::RD1-2F9 vaccine was less virulent and persistent in
      mice and than was BCG::RD1-2F9 may represent a safer alternative to BCG::RD1-2F9.

PMID- 15195251
TI  - Mycobacterium tuberculosis H37Rv: Delta RD1 is more virulent than M. bovis
      bacille Calmette-Guerin in long-term murine infection.
AB  - Region of difference (RD1) genes are present in virulent Mycobacterium
      tuberculosis but not the vaccine strain M. bovis bacille Calmette-Guerin (BCG).
      The deletion of RD1 from M. tuberculosis produces an attenuation strikingly like
      that of BCG, which suggests the use of RD1 mutant strains for improvement of the
      tuberculosis (TB) vaccine. We performed long-term murine infection with M.
      tuberculosis H37Rv: Delta RD1 and BCG. Mice infected with H37Rv: Delta RD1 gained
      less weight than did BCG-infected control mice, and, after >1 year, their lungs
      harbored many more bacteria and displayed significant levels of inflammation.
      This difference in virulence has important implications for the pursuit of
      strains lacking RD1 in the development of the TB vaccine.

PMID- 15195252
TI  - Activation of extracellular signal-regulated kinase mediates apoptosis induced by
      uropathogenic Escherichia coli toxins via nitric oxide synthase: protective role
      of heme oxygenase-1.
AB  - Pyelonephritis is a risk factor for renal tubular epithelial cell damage in
      children. The inter- and intracellular regulator nitric oxide (NO) plays a role
      in the modulation of cellular viability in urinary tract infections, but the role
      of the NO pathway in renal proximal tubular-cell death remains unclear. The
      present study demonstrates that, in renal epithelial cells undergoing death
      mediated by Escherichia coli strain ARD6 serotype O6K13H1 (O6), levels of the
      phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and inducible NO
      synthase (iNOS) proteins are up-regulated, but levels of endothelial NO synthase
      are down-regulated. When NO synthase (NOS) activity is inhibited by the specific
      inhibitor of NOS or mitogen-activated protein kinase kinase, cells are prevented
      from death. Moreover, down-regulating protein 53 (p53) does not prevent the cells
      from dying, although p53 is up-regulated in O6-exposed cells. Up-regulation of
      heme oxygenase (HO)-1 by sodium nitroprusside or by the specific activator hemin
      inhibits cell death. In conclusion, the activation of ERK mediates O6 toxin
      mediated renal cell death via induction of iNOS. Stimulation of HO-1 protects
      cells against death.

PMID- 15195253
TI  - Defenses against oxidative stress in Neisseria gonorrhoeae and Neisseria
      meningitidis: distinctive systems for different lifestyles.
AB  - Defenses against oxidative stress are crucial for the survival of the pathogens
      Neisseria meningitidis and Neisseria gonorrhoeae. An Mn(II) uptake system is
      involved in manganese (Mn)-dependent resistance to superoxide radicals in N.
      gonorrhoeae. Here, we show that accumulation of Mn also confers resistance to
      hydrogen peroxide killing via a catalase-independent mechanism. An mntC mutant of
      N. meningitidis is susceptible to oxidative killing, but supplementation of
      growth media with Mn does not enhance the organism's resistance to oxidative
      killing. N. meningitidis is able to grow in the presence of millimolar levels of
      Mn ion, in contrast to N. gonorrhoeae, whose growth is retarded at Mn
      concentrations >100 micromol/L, indicating that Mn homeostasis in the 2 species
      is probably quite different. N. meningitidis superoxide dismutase B plays a role
      in protection against oxidative killing. However, a sodC mutant of N.
      meningitidis is no more sensitive to oxidative killing than is the wild type. A
      cytochrome c peroxidase (Ccp) is present in N. gonorrhoeae but not in N.
      meningitidis. Investigations of a ccp mutant revealed a role for Ccp in
      protection against hydrogen peroxide killing. These differences in oxidative
      defenses in the pathogenic Neisseria are most likely a result of their
      localization in different ecological niches.

PMID- 15195254
TI  - Predictors of immunological failure after initial response to highly active
      antiretroviral therapy in HIV-1-infected adults: a EuroSIDA study.
AB  - BACKGROUND: Factors that determine the immunological response to highly active
      antiretroviral therapy (HAART) are poorly defined. OBJECTIVE: Our aim was to
      investigate predictors of immunological failure after initial CD4(+) response.
      METHODS: Data were from EuroSIDA, a prospective, international, observational
      human immunodeficiency virus (HIV) type 1 cohort. RESULTS: Of 2347 patients with
      an increase in CD4(+) cell count >or=100 cells/microL within 6-12 months of the
      initiation of HAART, 550 (23%) subsequently experienced immunological failure
      (CD4(+) count less than or equal to the pre-HAART value). The incidence of
      failure was 11.6 incidences/100 person-years of follow-up (95% confidence
      interval [CI], 10.2-13.4) during the first 12 months and decreased significantly
      over time (P<.0001). Independent predictors of immunological failure were pre
      HAART CD4(+) cell count (per 50% higher; relative hazard [RH], 2.05; 95% CI, 1.83
      2.31; P<.0001), time-updated virus load (per 1 log(10) higher; RH, 1.77; 95% CI,
      1.64-1.92; P<.0001), and HIV-1 risk behavior (P=.047 for a global comparison of
      risk groups). CONCLUSION: The risk of immunological failure in patients with an
      immunological response to HAART diminishes with a longer time receiving treatment
      and is associated with pretreatment CD4(+) cell count, ongoing viral replication,
      and intravenous drug use.

PMID- 15195255
TI  - Higher concentration of HIV RNA in rectal mucosa secretions than in blood and
      seminal plasma, among men who have sex with men, independent of antiretroviral
      therapy.
AB  - High levels of human immunodeficiency virus (HIV) in rectal secretions and semen
      likely increase the risk of HIV transmission. HIV-infected men who have sex with
      men made 2-3 study visits, over 4 weeks, to assess rectal, seminal, and plasma
      levels of HIV RNA. Mixed-effects models estimated the effect of factors on HIV
      shedding. Twenty-seven (42%) of 64 men were receiving antiretroviral therapy
      (ART); regardless of ART use, median HIV RNA levels were higher in rectal
      secretions (4.96 log(10) copies/mL) than in blood plasma (4.24 log(10) copies/mL)
      or seminal plasma (3.55 log(10) copies/mL; P<.05, each comparison). ART was
      associated with a 1.3-log(10) reduction in rectal HIV RNA in a model without
      plasma HIV RNA; with and without plasma RNA in models, ART accounted for a >1
      log(10) decrease in seminal HIV RNA levels. Thus, controlling for plasma HIV RNA,
      ART had an independent effect on seminal, but not rectal, HIV levels.

PMID- 15195256
TI  - Modeling the HIV protease inhibitor adherence-resistance curve by use of
      empirically derived estimates.
AB  - The standard view postulates a bell-shaped relationship between adherence to
      therapy and development of drug-resistant human immunodeficiency virus (HIV),
      with a resistance peak at a moderate level of adherence. This relationship has
      not been confirmed empirically. We statistically modeled the relationship between
      adherence and development of drug resistance, using empirically defined
      relationships of the rate of viral suppression and drug-resistance-mutation
      accumulation derived from patients receiving protease-inhibitor-based therapy. We
      found that the maximal rate of drug resistance occurs at 87% adherence and
      declines modestly at 100% adherence. Higher levels of viral suppression at 100%
      adherence (a marker of greater regimen potency) progressively reduce the overall
      population rate of drug resistance and shift the peak resistance rate to lower
      levels of adherence.

PMID- 15195257
TI  - Would universal antenatal screening for HIV infection be cost-effective in a
      setting of very low prevalence? Modelling the data for Australia.
AB  - BACKGROUND: The economics of universal antenatal human immunodeficiency virus
      (HIV) screening should be explored if mother-to-child transmission of HIV occurs,
      the health-service infrastructure for universal screening exists, and optimal
      risk-reducing treatments can be supplied. METHODS: We evaluated a hypothetical
      cohort of the antenatal population of Australia during 2001-2002, to examine
      whether universal antenatal HIV screening is cost-effective in this setting. A
      quasi-societal perspective was adopted, secondary data sources were used, and
      sensitivity analyses were undertaken. Costs and benefits incurred in the future
      were discounted to their present value. RESULTS: The intervention would be cost
      effective if the prevalence of undiagnosed HIV in the currently unscreened
      Australian antenatal population was >or=0.004372%. We predict 6.95 new diagnoses
      of HIV, 1.73 infections avoided, and 46.97 discounted-life-years gained. Applying
      favorable and unfavorable values for key variables suggests that the prevalence
      at which the intervention would be cost-effective is 0.0016%-0.0106%.
      CONCLUSIONS: Universal antenatal HIV screening would be cost-effective at a very
      low prevalence and would generate net benefits under many scenarios; accurate
      statistics on the true prevalence of HIV in the currently unscreened antenatal
      population are required.

PMID- 15195258
TI  - A multihousehold study reveals a positive correlation between age, severity of
      ocular toxoplasmosis, and levels of glycoinositolphospholipid-specific
      immunoglobulin A.
AB  - A cross-sectional household study involving 499 individuals was undertaken in an
      area of Minas Gerais state, Brazil, where infection with Toxoplasma gondii is
      endemic. Nearly 50% (n=247) of the sample had T. gondii-specific antibodies, even
      individuals in the 5-9-year-old age group. Approximately 12.5% (n=28) of a random
      subsample of participants who were positive for T. gondii antibodies had ocular
      lesions associated with T. gondii infection. The frequency of ocular
      toxoplasmosis increased significantly with age, with approximately 50% of
      individuals >60 years of age having lesions. The size of the ocular lesion
      correlated positively (r=0.85; P=.01) with the serum level of immunoglobulin A
      specific for tachyzoite-derived glycoinositolphospholipids. We found that sharing
      the same residence accounted for 30% of the variation in infectivity among
      residents in the sample, whereas age was the main risk factor for development of
      ocular toxoplasmosis in patients who were positive for T. gondii antibodies.

PMID- 15195259
TI  - Inactivation of Plasmodium falciparum by photodynamic excitation of heme-cycle
      intermediates derived from delta-aminolevulinic acid.
AB  - Transfusion-transmitted malaria (TTM), especially that caused by Plasmodium
      falciparum, is of great concern in malaria-endemic areas. As a result of
      increased international travel, migration, and the spread of drug-resistant
      parasites, TTM is also a growing problem in industrialized nations. An effective
      and inexpensive means of inactivating malaria parasites in blood products would
      represent an important advance. In this report, we demonstrate that
      photoactivation of plasmodial heme-cycle intermediates, derived from supplemental
      delta -aminolevulinic acid (ALA), by exposure to simple white light in the
      presence of ALA, reduces P. falciparum in culture to levels that are undetectable
      by light microscopy or lactate dehydrogenase assay. Photodynamic excitation of
      presumed heme-cycle intermediates, which was revealed by fluorescence microscopy,
      did not appear to adversely affect the viability of erythrocytes. These data
      suggest that this pathogen-inactivation strategy, which uses inexpensive reagents
      and white light, may represent an appropriate means of inactivating malaria
      parasites in blood products in resource-poor settings.

PMID- 15195260
TI  - Immunosuppression affects the severity of experimental Fusarium solani keratitis.
AB  - We have established a mouse model of corneal fusariosis that permits the
      evaluation of fungal infection and pathogenesis. Corneas of immunocompetent and
      cyclophosphamide-treated adult BALB/c mice were topically inoculated with
      Fusarium solani after corneal scarification. Eyes were scored for corneal
      involvement daily for 8 days and at 2 weeks after infection. Eyes were enucleated
      at various time points for quantitative fungal recovery and histopathological
      examination. An inoculum-dose response was observed in cyclophosphamide-treated
      mice, and fungi were recovered from the infected eyes by quantitative microbial
      culturing. Treatment with cyclophosphamide increased disease severity and delayed
      fungal clearance. Fungal hyphae, inflammatory cells, and stromal edema were
      histologically evident within corneal tissue and correlated with disease
      severity. Although the mouse cornea resists fungal infections, F. solani
      keratitis could be induced in immunosuppressed mice after surface scarification,
      which resulted in infection and clinical disease that could be evaluated both in
      vivo and in vitro.

PMID- 15195261
TI  - Saliva and the transmission of human herpesvirus 8: potential role of promoter
      arthropod bites.

PMID- 15195263
TI  - Commentary: Bartlett JG, Onderdonk AB, Cisneros RL, Kasper DL. Clindamycin
      associated colitis due to a toxin-producing species of Clostridium in hamsters. J
      Infect Dis 1977; 136:701.

PMID- 15195264
TI  - Cytologic evaluation of bone marrow in rats: indications, methods, and normal
      morphology.
AB  - Bone marrow examination is an important part of the evaluation of the
      hematopoietic system. In pharmaceutical and toxicological research, bone marrow
      evaluation can help determine the potential hematotoxicity or effects of new
      compounds on hematopoietic cells. The rat is a common research animal, and bone
      marrow evaluation often is performed in this species. The goal of this review is
      to provide clinical pathologists and researchers with an updated overview of bone
      marrow evaluation in rats as well as practical guidelines for methods and
      microscopic evaluation. Indications for bone marrow collection in a research
      setting, methods of collection and smear preparation, and unique morphologic
      features of rat bone marrow cells are discussed. A summary of published cell
      differential percentages for bone marrow from healthy rats and possible
      explanations for discrepancies in these values also are provided.

PMID- 15195265
TI  - Hematology and clinical chemistry values in pregnant Wistar Hannover rats
      compared with nonmated controls.
AB  - BACKGROUND: The Wistar Hannover rat has been considered as an alternative animal
      model to the Sprague-Dawley rat in the safety evaluation of candidate
      pharmaceuticals for potential reproductive and developmental toxicity. Hematology
      and clinical chemistry results may provide useful evidence of maternal toxicity
      in the absence of fetal effects. OBJECTIVE: The purpose of this study was to
      evaluate differences in routine laboratory values between nonmated and pregnant
      (near-term)Wistar Hannover rats during a control developmental study. METHODS:
      One hundred fifty pregnant female Wistar Hannover rats (Tac:Glx:WlfBR) were dosed
      orally once per day with distilled water from gestation days (GDs) 6 through 17.
      An additional 150 nonmated (nonpregnant) females used as age-matched controls
      were dosed from study days (SDs) 7 through 18. Blood samples were collected on GD
      18 or 19 (SD 19 or 20) for routine hematology and plasma clinical chemistry
      tests. Reference intervals were established for pregnant and nonmated animals.
      RESULTS: On GD 18/19, pregnant rats had a lower RBC count, hemoglobin
      concentration, and HCT, and higher MCH, MCHC, reticulocyte percentage, and
      platelet, WBC, absolute reticulocyte, segmented neutrophil, lymphocyte, and
      monocyte counts compared with nonmated rats. Pregnant rats had lower albumin,
      glucose, urea, and chloride concentrations, lower creatine kinase and alkaline
      phosphatase activities, higher total bilirubin, cholesterol, triglyceride,
      calcium, phosphorus, and globulin concentrations, and higher ALT activity than
      nonmated rats. Serum triglyceride concentration was approximately fourfold higher
      in pregnant rats compared with nonmated controls. CONCLUSION: Differences in
      hematology and chemistry values in pregnant Wistar Hannover rats are similar to
      those in Sprague-Dawley rats and support use of the Wistar Hannover rat as an
      animal model in the assessment of maternal toxicity. Differences in laboratory
      values of pregnant rats should be considered when interpreting data following
      exposure to candidate pharmaceuticals.

PMID- 15195266
TI  - Hematologic reference intervals for koi (Cyprinus carpio), including blood cell
      morphology, cytochemistry, and ultrastructure.
AB  - BACKGROUND: Hematologic data are used routinely in the health care of humans and
      domestic mammals. Similar data for fish are largely fragmentary or have not been
      collected. OBJECTIVES: The primary purpose of this study was to determine
      hematologic reference intervals for koi, an ornamental strain of the common carp
      (Cyprinus carpio). Secondarily, the morphology, cytochemical reactions, and
      ultrastructure of koi blood cells were characterized. METHODS: A CBC was
      performed manually on heparin-anticoagulated blood specimens using Natt and
      Herrick's diluent and a Neubauer-ruled hemacytometer. Leukocyte differential
      counts were done on Wright-Leishman- and Diff-Quik-stained blood smears.
      Cytochemical reactions of koi leukocytes were determined using commercial kits.
      Transmission electron microscopy was performed to characterize the
      ultrastructural features of koi blood cells. RESULTS: Hematologic reference
      intervals were established for healthy koi for PCV (30-34%), hemoglobin
      concentration (6.3-7.6 g/dL), RBC count (1.7-1.9 X 10(6)/ microL), WBC count
      (19.8-28.1 X 10(3)/ microL), RBC indices, and differential leukocyte counts.
      Lymphocytes were the predominant leukocyte (accounting for up to 80% of all
      leukocytes), whereas eosinophils were rare. Basophils were positive with PAS
      staining. Naphthol AS-D chloroacetate esterase activity was observed only in
      eosinophils. alpha-Naphthyl butyrate esterase and beta-glucuronidase activities
      were positive in monocytes. Some lymphocytes were reactive for alpha-naphthyl
      butyrate esterase and acid phosphatase activity. Ultrastructurally, leukocytes,
      erythrocytes, and thrombocytes were identified on the basis of cytoplasmic
      organelles and granule appearance. CONCLUSION: Hematologic reference intervals
      and knowledge of the cytochemical reactions and ultrastructural characteristics
      of koi leukocytes will help standardize hematologic studies in this species.

PMID- 15195267
TI  - Cytologic diagnosis: expression of probability by clinical pathologists.
AB  - BACKGROUND: Clinical pathologists use descriptive terms or modifiers to express
      the probability or likelihood of a cytologic diagnosis. Words are imprecise in
      meaning, however, and may be used and interpreted differently by pathologists and
      clinicians. OBJECTIVES: The goals of this study were to 1) assess the frequency
      of use of 18 modifiers, 2) determine the probability of a positive diagnosis
      implied by the modifiers, 3) identify preferred modifiers for different levels of
      probability, 4) ascertain the importance of factors that affect expression of
      diagnostic certainty, and 5) evaluate differences based on gender, employment,
      and experience. METHODS: We surveyed 202 clinical pathologists who were board
      certified by the American College of Veterinary Pathologists (Clinical
      Pathology). Surveys were distributed in October 2001 and returned by e-mail, fax,
      or surface mail over a 2-month period. Results were analyzed by parametric and
      nonparametric tests. RESULTS: Survey response rate was 47.5% (n = 96) and
      primarily included clinical pathologists at veterinary schools (n = 58) and
      diagnostic laboratories (n = 31). Eleven of 18 terms were used "often" or
      "sometimes" by >/= 50% of respondents. Broad variability was found in the
      probability assigned to each term, especially those with median values of 75 to
      90%. Preferred modifiers for 7 numerical probabilities ranging from 0 to 100%
      included 68 unique terms; however, a set of 10 terms was used by >/= 50% of
      respondents. Cellularity and quality of the sample, experience of the
      pathologist, and implications of the diagnosis were the most important factors
      affecting the expression of probability. CONCLUSION: Because of wide discrepancy
      in the implied likelihood of a diagnosis using words, defined terminology and
      controlled vocabulary may be useful in improving communication and the quality of
      data in cytology reporting.

PMID- 15195268
TI  - Flow cytometric evaluation of canine bone marrow based on intracytoplasmic
      complexity and CD45 expression.
AB  - BACKGROUND: Because of the complexity, subjectivity, time, and technical skill
      required for determination of manual bone marrow differential cell counts, an
      alternative method is needed. Several flow cytometric methods have been
      described, but all have limitations. OBJECTIVE: The purpose of this study was to
      evaluate a technique for bone marrow differential cell counting based on flow
      cytometric evaluation of CD45 expression and intracellular complexity (CD45
      scatter plots). METHODS: Bone marrow was obtained from 15 dogs that were being
      evaluated for hematologic disorders. In preliminary studies, the location of bone
      marrow subpopulations in the CD45 scatter plots was evaluated by labeling bone
      marrow with lineage-specific markers. A template was developed to identify these
      cell populations. Gates were set to identify granulocytes, myeloblasts,
      monocyte/macrophages, lymphocytes, and nucleated erythroid populations. RESULTS:
      The CD45 labeling technique accurately quantified granulocytes, myeloblasts,
      erythroid precursors, and lymphocytes in canine bone marrow. Correlation
      coefficients with manual counts for granulocytes, myeloblasts, erythroid cells,
      lymphocytes, and monocyte/macrophages were 0.90, 0.89, 0.96, 0.91, and 0.54,
      respectively. CONCLUSIONS: The capacity of the CD45 scatter-plot technique to
      quantify lymphocytes and myeloblasts is an advantage over previously described
      techniques. The simplicity of the CD45 labeling method and the ease with which
      batches of samples can be analyzed makes the technique potentially applicable as
      a routine test in clinical and research laboratories.

PMID- 15195269
TI  - Osteosarcoma with multiple metastases and subcutaneous involvement in a rabbit
      (Oryctolagus cuniculus).
AB  - BACKGROUND: Osteogenic sarcomas are rare in rabbits, but cases involving the
      mandible, ribs, frontal bones, and tibia have been reported. OBJECTIVE: The
      purpose of this study was to describe the clinical and pathologic findings in a
      rabbit with osteosarcoma and multiple metastases with subcutaneous involvement.
      METHODS: A 1-year-old female Polish rabbit was evaluated for dysorexia, lameness,
      gait difficulties with the hind limbs, and the presence of 2 subcutaneous
      nodules, on the left thigh and in the dorsal region. A hard swelling was also
      present at the base of the tail. Radiographic findings revealed multiple
      abnormalities in several bones, which were more severe in the sacrococcygeal
      region and femur. Several areas of calcification involving the thorax and abdomen
      as well as skeletal muscles, also were noted. The thigh nodule was surgically
      removed, and cytologic and histologic evaluations were performed. Following the
      rabbit's death, postmortem radiographs were taken and necropsy was performed.
      Samples of tissues and organs, involved bone segments, and other subcutaneous
      nodules were collected and examined by cytology and histology. RESULTS: Both the
      subcutaneous nodules and the majority of tissues and organs contained neoplastic
      cells whose appearance was consistent with osteogenic sarcoma. CONCLUSION:
      Clinical, radiologic, and pathologic data supported a diagnosis of osteosarcoma
      with multiple metastases and subcutaneous involvement.

PMID- 15195270
TI  - Morphologic, immunohistochemical, and molecular characterization of hepatosplenic
      T-cell lymphoma in a dog.
AB  - A 13-year-old neutered male Jack Russell Terrier (Parson Russell Terrier) was
      presented to the Texas Veterinary Medical Center with a history of lethargy,
      depression, vomiting, and fever. The dog had mildly regenerative anemia, severe
      thrombocytopenia and low antithrombin activity. Marked splenomegaly was found on
      physical examination and imaging studies, and malignant round cell neoplasia and
      marked extramedullary hematopoiesis were diagnosed on aspirates of the spleen.
      The dog underwent exploratory laporatomy and splenectomy. Because of a rapid
      decline in clinical condition postsurgery, the dog was euthanized. Splenic and
      hepatic biopsies were submitted for histopathologic evaluation. A neoplastic
      population of round cells was found throughout the splenic parenchyma and within
      hepatic sinusoids. The neoplastic cells stained strongly positive for CD3 (T-cell
      marker) and were negative for CD79a (B-cell marker) and lysozyme (histiocytic
      marker). A diagnosis of T-cell lymphoma was confirmed by assessment of T-cell
      clonality using canine-specific polymerase chain reaction-based techniques.
      Although expression of the gammadelta T-cell receptor was not evaluated, this
      case shares many similarities with a rare syndrome in humans known as
      hepatosplenic gammadelta T-cell lymphoma.

PMID- 15195271
TI  - Cytology of a mass on the meningeal surface of the left brain in a dog.
AB  - An 11-year-old neutered male Labrador Retriever presented to Tufts University
      School of Veterinary Medicine for a 2-week history of seizures and altered
      behavior. Magnetic resonance imaging (MRI) revealed a homogeneously enhancing
      mass involving the surface of the left temporal, parietal, and occipital lobes of
      the brain, causing secondary hydrocephalus. Cytology samples obtained during
      rostrotentorial craniectomy contained abundant amorphous pink material suggestive
      of neuropil, scattered leukocytes, capillary fragments, large polyhedral nerve
      cell bodies, and other smaller cells with pale blue cytoplasm that occasionally
      were vacuolated and contained fine eosinophilic granules. The cytologic diagnosis
      was neoplasia, possibly meningioma. Ninety days after surgery the patient was
      euthanized after MRI results confirmed regrowth of the tumor. Histologic samples
      of the meningeal lesion collected at necropsy consisted of sheets and nests of
      loosely packed, large polygonal cells that compressed the brain parenchyma. The
      cytoplasm was eosinophilic and slightly granular, whereas nuclei were dense and
      eccentric. Neoplastic cells stained positive for S-100 protein, periodic acid
      Schiff, and were partially diastase resistant. Vimentin staining was negative.
      Ubiquitin staining was light but diffusely positive. Ultrastructural features of
      the neoplastic cells included numerous secondary lysosomes and irregular
      pleomorphic nuclei. The final diagnosis was meningeal granular cell tumor. This
      case documents the cytologic and histologic features of an uncommon type of
      meningeal tumor.

PMID- 15195272
TI  - Pain and comfort issues.

PMID- 15195273
TI  - A survey of current perianesthesia nursing practice for pain and comfort
      management.
AB  - Widespread dissemination of information and high-profile press coverage about
      pain and comfort management has resulted in heightened awareness among health
      care professionals and the public of the need for improvements in the way pain
      and comfort are managed. Despite significant advances in treatment options for
      pain relief and comfort, studies show that both phenomena continue to be poorly
      managed and undertreated. Providing pain relief and comfort to patients are
      important fundamental components of good nursing care; however, no studies have
      been performed to evaluate these responsibilities in perianesthesia nursing
      practice. Therefore, a descriptive survey was undertaken to assess the current
      practices for pain and comfort management among perianesthesia nurses. A
      convenience sample of 220 perianesthesia nurses working in preoperative and
      postoperative settings in rural and urban hospitals, outpatient centers, and
      freestanding facilities completed a questionnaire survey. The survey asked 10
      questions that addressed various aspects of pain and comfort care, including
      assessment in different settings, discharge criteria, and obstacles in the
      management of pain and comfort. Findings showed that perianesthesia nurses
      assessed pain at a frequency of 58% and comfort at a frequency of 56% on
      admission. Preoperative assessment of patients' desired level of pain relief and
      comfort occurred at frequencies of 21% and 20%, respectively. Pain was assessed
      most often with self-report pain ratings and ordinal descriptions such as "no
      pain" to "severe pain." A moderate pain level was used most often as a discharge
      criterion. Inappropriate and inadequate physicians' orders were cited as two of
      the most common obstacles to managing pain and comfort. Findings of this study
      can be used to increase awareness of the need to evaluate and improve pain and
      comfort management education and practices in the perianesthesia settings. ASPAN
      will also use the results as baseline data as it establishes a strategic plan to
      address the educational needs of its members.

PMID- 15195274
TI  - Clinical evaluation of the ASPAN Pain and Comfort Clinical Guideline.
AB  - The ASPAN Pain and Comfort Clinical Guideline was created because of the urgent
      need for a standardized evidence-based approach to the management of patients'
      pain and comfort in all perianesthesia settings. The purpose of the research
      presented here was to test the content of the ASPAN Pain and Comfort Clinical
      Guideline, which included the domains of assessment, intervention, and outcomes.
      Each domain was rated on clarity, usability, and feasibility using a Likert
      scale, which ranged from 1 (strongly disagree) to 4 (strongly agree). A survey
      design was used with a convenience sample of 215 perianesthesia nurses. The
      results of the study demonstrated a mean score of clarity, usability, and
      feasibility in all perianesthesia settings ranging from 3.54 (SD) to 3.80 (SD).
      There were no differences in the clarity, usability, or feasibility of the
      guideline between perianesthesia settings. The results of this study support that
      the ASPAN Pain and Comfort Clinical Guideline has practical utility for
      perianesthesia nurses in all settings. Use of this guideline in perianesthesia
      settings will standardize pain and comfort management and has the potential to
      positively impact pain and comfort in perianesthesia patients.

PMID- 15195275
TI  - Practical application of comfort theory in the perianesthesia setting.
AB  - Comfort management is a priority for patients in all settings. Comfort theory
      provides a foundational and holistic approach to comfort management. This article
      reviews comfort theory and presents the application of comfort theory in the
      perianesthesia setting. OBJECTIVES: -Based on the content of the following
      article, the reader will be able to (1) define comfort; (2) identify comfort
      interventions; and (3) discuss the importance of a goal for enhanced comfort in
      patients.

PMID- 15195276
TI  - Pain management in ambulatory surgery.
AB  - Successful ambulatory surgery is dependent on analgesia that is effective, has
      minimal adverse effects, and can be safely managed by the patient at home after
      discharge. A number of studies have identified that the provision of effective
      postoperative analgesia is inadequate for a significant proportion of patients.
      The following discussion details the current available analgesic options for
      ambulatory surgery patients and the rationale for their use. Preemptive analgesia
      should be given to all patients unless there are specific contraindications.
      Consideration should be given to the use of long-acting oral COX-2 selective
      nonsteroidal anti-inflammatory drugs (NSAIDs) and long-acting oral opioids to
      treat postoperative pain. A standardized multimodal postdischarge analgesic
      regimen tailored to the patient's expected postoperative pain levels should be
      prescribed. Patient follow-up by telephone questionnaire will confirm those
      surgical procedures that result in mild or moderate-to-severe postoperative pain
      and the effectiveness of treatment plans.

PMID- 15195277
TI  - Treating children for acute agitation in the PACU: differentiating pain and
      emergence delirium.
AB  - Differentiating postoperative pain from emergence delirium in children is
      challenging for even the most experienced PACU nurse. This article presents a
      review of the literature and clinical practice experiences that will help guide
      the PACU nurse in recognizing and differentiating these two conditions that are
      common in children recovering from anesthesia. The argument is made that although
      differentiating the cause of postoperative agitation may be difficult, it also
      may be unnecessary. Treatment with opioids is recommended as the primary strategy
      for safely recovering the child experiencing acute postanesthesia agitation,
      whether from pain or emergence delirium. Tools commonly used to assess both pain
      and postanesthesia agitation in children are reviewed, and an algorithm to
      facilitate the decision-making process is provided.

PMID- 15195279
TI  - PACU pain management: how well are we meeting our patients' needs?

PMID- 15195278
TI  - Assessment and treatment of postoperative pain in older adults.
AB  - Hospitals are experiencing an increase in surgical procedures aimed at improving
      function and quality of life for elders. However, recent reports of pain
      management practices of elder patients show that pain is underassessed and
      undertreated. High postoperative pain intensities have been associated with
      delayed ambulation, postoperative pulmonary complications, increased hospital
      length of stay, long-term functional impairment, and chronic pain syndromes in
      this age group. Aggressive pain control is needed, but challenges in assessing
      and treating pain in older adults make this difficult. The purpose of this
      article is to review strategies for assessing and treating postoperative pain in
      older adults. Attention is given to the challenges associated with mental and
      physical impairments experienced by elders and a review of assessment and
      pharmacologic and nonpharmacologic strategies are included.

PMID- 15195281
TI  - The challenges of pain management: adverse effects of analgesics.

PMID- 15195282
TI  - Managing pain: an individual responsibility.

PMID- 15195283
TI  - Why do we doubt the presence of pain?

PMID- 15195285
TI  - EEG-fMRI of focal epileptic spikes: analysis with multiple haemodynamic functions
      and comparison with gadolinium-enhanced MR angiograms.
AB  - Combined EEG-fMRI has recently been used to explore the BOLD responses to
      interictal epileptiform discharges. This study examines whether misspecification
      of the form of the haemodynamic response function (HRF) results in significant
      fMRI responses being missed in the statistical analysis. EEG-fMRI data from 31
      patients with focal epilepsy were analysed with four HRFs peaking from 3 to 9 sec
      after each interictal event, in addition to a standard HRF that peaked after 5.4
      sec. In four patients, fMRI responses were correlated with gadolinium-enhanced MR
      angiograms and with EEG data from intracranial electrodes. In an attempt to
      understand the absence of BOLD responses in a significant group of patients, the
      degree of signal loss occurring as a result of magnetic field inhomogeneities was
      compared with the detected fMRI responses in ten patients with temporal lobe
      spikes. Using multiple HRFs resulted in an increased percentage of data sets with
      significant fMRI activations, from 45% when using the standard HRF alone, to
      62.5%. The standard HRF was good at detecting positive BOLD responses, but less
      appropriate for negative BOLD responses, the majority of which were more
      accurately modelled by an HRF that peaked later than the standard. Co
      registration of statistical maps with gadolinium-enhanced MRIs suggested that the
      detected fMRI responses were not in general related to large veins. Signal loss
      in the temporal lobes seemed to be an important factor in 7 of 12 patients who
      did not show fMRI activations with any of the HRFs.

PMID- 15195284
TI  - Functional connectivity as revealed by spatial independent component analysis of
      fMRI measurements during rest.
AB  - Cortical functional connectivity, as indicated by the concurrent spontaneous
      activity of spatially segregated regions, is being studied increasingly because
      it may determine the reaction of the brain to external stimuli and task
      requirements and it is reportedly altered in many neurological and psychiatric
      disorders. In functional magnetic resonance imaging (fMRI), such functional
      connectivity is investigated commonly by correlating the time course of a chosen
      "seed voxel" with the remaining voxel time courses in a voxel-by-voxel manner.
      This approach is biased by the actual choice of the seed voxel, however, because
      it only shows functional connectivity for the chosen brain region while ignoring
      other potentially interesting patterns of coactivation. We used spatial
      independent component analysis (sICA) to assess cortical functional connectivity
      maps from resting state data. SICA does not depend on any chosen temporal profile
      of local brain activity. We hypothesized that sICA would be able to find
      functionally connected brain regions within sensory and motor regions in the
      absence of task-related brain activity. We also investigated functional
      connectivity patterns of several parietal regions including the superior parietal
      cortex and the posterior cingulate gyrus. The components of interest were
      selected in an automated fashion using predefined anatomical volumes of interest.
      SICA yielded connectivity maps of bilateral auditory, motor and visual cortices.
      Moreover, it showed that prefrontal and parietal areas are also functionally
      connected within and between hemispheres during the resting state. These
      connectivity maps showed an extremely high degree of consistency in spatial,
      temporal, and frequency parameters within and between subjects. These results are
      discussed in the context of the recent debate on the functional relevance of
      fluctuations of neural activity in the resting state.

PMID- 15195286
TI  - Permutation tests for factorially designed neuroimaging experiments.
AB  - Permutation methods for analysis of functional neuroimaging data acquired as
      factorially designed experiments are described and validated. The F ratio was
      estimated for main effects and interactions at each voxel in standard space.
      Critical values corresponding to probability thresholds were derived from a null
      distribution sampled by appropriate permutation of observations. Spatially
      informed, cluster-level test statistics were generated by applying a preliminary
      probability threshold to the voxel F maps and then computing the sum of voxel
      statistics in each of the resulting three-dimensional clusters, i.e., cluster
      "mass." Using simulations comprising two between- or within-subject factors each
      with two or three levels, contaminated by Gaussian and non-normal noise, the
      voxel-wise permutation test was compared to the standard parametric F test and to
      the performance of the spatially informed statistic using receiver operating
      characteristic (ROC) curves. Validity of the permutation-testing algorithm and
      software is endorsed by almost identical performance of parametric and
      permutation tests of the voxel-level F statistic. Permutation testing of
      suprathreshold voxel cluster mass, however, was found to provide consistently
      superior sensitivity to detect simulated signals than either of the voxel-level
      tests. The methods are also illustrated by application to an experimental dataset
      designed to investigate effects of antidepressant drug treatment on brain
      activation by implicit sad facial affect perception in patients with major
      depression. Antidepressant drug effects in left amygdala and ventral striatum
      were detected by this software for an interaction between time (within-subject
      factor) and group (between-subject factor) in a representative two-way factorial
      design.

PMID- 15195287
TI  - Reduced recruitment of motor association areas during bimanual coordination in
      concert pianists.
AB  - Bimanual motor coordination is essential for piano playing. The functional
      neuronal substrate for high-level bimanual performance achieved by professional
      pianists is unclear. We compared professional pianists to musically naive
      controls while carrying out in-phase (mirror) and anti-phase (parallel) bimanual
      sequential finger movements during functional magnetic resonance imaging (fMRI).
      This task corresponds to bimanually playing scales practiced daily by pianists
      from the beginning of piano playing. Musicians and controls showed significantly
      different functional activation patterns. When comparing performance of parallel
      movements to rest, musically naive controls showed stronger activations than did
      pianists within a network including anterior cingulate cortex, right dorsal
      premotor cortex, both cerebellar hemispheres, and right basal ganglia. The direct
      comparison of bimanual parallel to mirror movements between both groups revealed
      stronger signal increases in controls within mesial premotor cortex (SMA),
      bilateral cerebellar hemispheres and vermis, bilateral prefrontal cortex, left
      ventral premotor cortex, right anterior insula, and right basal ganglia. These
      findings suggest increased efficiency of cortical and subcortical systems for
      bimanual movement control in musicians. This may be fundamental to achieve high
      level motor skills allowing the musician to focus on artistic aspects of musical
      performance.

PMID- 15195288
TI  - Nonlinearity of FMRI responses in human auditory cortex.
AB  - An investigation was made into the nature of the nonlinearity observed in
      auditory functional magnetic resonance imaging (fMRI) experiments associated with
      increases in total duration of acoustic imaging noise [e.g., Edmister et al.,
      1999; Shah et al., 1999]. A two-stimulus, four-condition paradigm was used to
      evaluate four acoustic conditions involving: (1) the presence or absence of a
      desired broadband music stimulus; and (2) two possible durations of trains of
      acoustic noise associated with image acquisition. Responses observed while
      increasing the duration of acoustic imaging noise were consistent with previous
      work (Talavage et al. [1999]: Hum Brain Mapp7:79-88) but the response to combined
      stimulation did not exhibit variation as a function of the acoustic imaging noise
      duration. These results suggest that spectral overlap of the stimuli produced
      colocalized responses that did not add linearly. This conclusion has implications
      for conducting both blocked and rapid-presentation event-related auditory fMRI
      experiments. The cortical activity induced by the stimulus may not reflect the
      activation, in spatial extent or magnitude of signal change, occurring in the
      absence of other acoustic noise.

PMID- 15195289
TI  - Specific cerebellar activation during Braille reading in blind subjects.
AB  - The traditional view that the cerebellum is involved only in the control of
      movements has been changed recently. It has been suggested that the human
      cerebellum is involved in cognition and language. Likewise, besides cortical
      activity in sensorimotor and visual areas, an increased global activation of the
      cerebellum has been revealed during Braille reading in blind subjects. Our
      purpose was to investigate whether there is cerebellar activation during Braille
      reading by blind subjects other than sensorimotor activation related to finger
      movements. Early blind and normal sighted subjects were studied with functional
      magnetic resonance imaging (fMRI) during Braille reading, tactile discrimination
      of nonsense dots, dots forming symbols, and finger tapping. The experiments were
      done in block design. Echo planar imaging sequences were carried out on a 1.5-T
      MR scanner. All blind individuals reading Braille showed robust activation of the
      posterior and lateral aspects of cerebellar hemispheral lobules Crus I
      bilaterally but more predominately on the right side. Additionally, activation
      was present in the medial cerebellum within lobules IV, V, and VIIIA,
      predominantly on the right. Discriminating nonsense dots did not reveal any
      activation of Crus I, but did reveal activation within the medial part of lobules
      IV, V, and VIIIA, predominately on the right. Analysis of sighted subjects during
      reading of printed text revealed activation of the posterolateral cerebellar
      hemisphere in Crus I bilaterally, predominantly on the right. Tactile analysis of
      dots representing symbols revealed an activation in lobules IV and VIII and in
      right Crus II but not in Crus I. In conclusion, parts of cerebellar activation
      during Braille reading in blind subjects (i.e., within lobules IV, V, and VIII)
      overlap with the known hand representation within the cerebellum and are likely
      related to the sensorimotor part of the task. Cerebellar activation during
      Braille reading within bilateral Crus I may be due to language processes or inner
      speech similar to those found during text reading in normal sighted subjects.
      Object recognition did not account for Crus I activation.

PMID- 15195290
TI  - Executive processes in Parkinson's disease: FDG-PET and network analysis.
AB  - It is assumed widely that the clinical expression of Parkinson's Disease (PD),
      both motor and cognitive, is subtended by topographically distributed brain
      networks. However, little is known about the functional neuroanatomy of executive
      dysfunction in PD. Our objective was to validate further in a PD group the use of
      network analysis to assess the relationship between executive processes and
      pathological disorganization of frontostriatal networks. We studied 15 patients
      with idiopathic PD, and 7 age-matched normal controls, using resting
      [(18)F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography
      (PET). We carried out network analysis on regional metabolic data to identify
      specific covariation patterns associated with motor and executive dysfunction. We
      detected two independent patterns relating respectively to the two clinical
      abnormalities. The first pattern (principal component 1) was topographically
      similar to that described previously in other PD populations. Subject scores for
      this pattern discriminated patients from controls and correlated significantly
      with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second
      pattern (principal component 2) was characterized by relative ventromedial
      frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal
      thalamic hypermetabolism. In the PD group, scores from this pattern correlated
      with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690)
      and the Brown Peterson paradigm (BPP; P = 0.017, r = -0.651) tests, respectively
      assessing strategy and planning, and working memory. According to these findings,
      the networks subserving bradykinesia and executive dysfunction in PD seems to be
      topographically distinct and to involve different aspects of subcortico-cortical
      processing.

PMID- 15195291
TI  - Autoradiographic distribution of serotonin transporters and receptor subtypes in
      human brain.
AB  - Several neurochemical in vitro and in vivo imaging studies have been aimed at
      characterizing the localization of serotonin receptors and transporters in the
      human brain. In this study, a detailed comparison of the distribution of a number
      of 5-HT receptor subtypes and the 5-HT transporter was carried out in vitro using
      human postmortem brain tissue. Anatomically adjacent whole hemisphere sections
      were incubated with specific radioligands for the 5-HT(1A), 5-HT(1B), 5-HT(2A), 5
      HT(4) receptors and the 5-HT transporter. The autoradiograms revealed different
      laminar and regional distribution patterns in the isocortex, where 5-HT(1A) and 5
      HT(4) receptor binding showed highest densities in superficial layers and 5
      HT(2A) receptor binding was most abundant in middle layers. In cortical regions,
      5-HT transporters were concentrated to several limbic lobe structures (posterior
      uncus, entorhinal, cingulate, insular and temporal polar regions). 5-HT(1A)
      receptor densities were also high in limbic cortical regions (hippocampus,
      posterior entorhinal cortex, and subcallosal area) compared to the isocortex.
      Subregionally different distribution patterns were observed in the basal ganglia
      with a trend toward higher levels in ventral striatal (5-HT(1B) receptors) and
      pallidal (5-HT transporters and 5-HT(1B) receptors) regions. The localization in
      regions belonging to limbic cortico-striato-pallido-thalamic circuits is in line
      with the documented role of 5-HT in modulation of mood and emotion, and the
      suggested involvement of this system in pathophysiology of various psychiatric
      disorders. The qualitative and quantitative information reported in this study
      might provide important complements to in vivo neuroimaging studies of the 5-HT
      system.

PMID- 15195294
TI  - Chemical adaptor systems.
AB  - "Chemical adaptor systems" are molecules used to link different functionalities,
      based on unique reactivity that allows controlled fragmentation. Two different
      mechanistic reactivities were used to prepare chemical adaptor systems. The first
      is based on a spontaneous intra-cyclization reaction to form a stable ring
      molecule. Cleavage of the trigger generates a free nucleophile, for example, an
      amine group, which undergoes intra-cyclization to release the target molecule
      from the handle part (e.g., a targeting antibody or a solid support for
      synthesis). The second applied reactivity is an elimination reaction, which is
      usually based on a quinone-methide-type rearrangement. Similarly, cleavage of the
      trigger generates a free phenol functionality, which can undergo a self
      elimination reaction through a quinone-methide rearrangement to release the
      target molecule. The adaptor molecules have been applied in the field of drug
      delivery to release a drug from a targeting device and in the field of solid
      phase synthesis to release a synthetic molecule from the solid support. A
      chemical adaptor molecule has also been used as a building unit to construct
      dendrimers with a triggered fragmentation.

PMID- 15195295
TI  - Chiral nonracemic late-transition-metal organometallics with a metal-bonded
      stereogenic carbon atom: development of new tools for asymmetric organic
      synthesis.
AB  - Transition-metal-catalyzed cross-coupling reactions and the Heck reaction have
      evolved into powerful tools for the construction of carbon-carbon bonds. In most
      cases, the reactive organometallic intermediates feature a carbon-transition
      metal sigma bond between a sp(2)-hybridized carbon atom and the transition metal
      (Csp(2)--TM). New, and potentially more powerful approach to transition-metal
      catalyzed asymmetric organic synthesis would arise if catalytic chiral nonracemic
      organometallic intermediates with a stereogenic sp(3)-hybridized carbon atoms
      directly bonded to the transition metal (C*sp(3)--TM bond) could be formed from
      racemic or achiral organic substrates, and subsequently participate in the
      formation of a new carbon-carbon bond (C*sp(3)-C) with retention of the
      stereochemical information. To date, only a few catalytic processes that are
      based on this concept, have been developed. In this account, both "classical" and
      recent studies on preparation and reactivity of stable chiral nonracemic
      organometallics with a metal-bonded stereogenic carbon, which provide the
      foundation for the future design of new synthetic transformations exploiting the
      outlined concept, are discussed, along with examples of relevant catalytic
      processes.

PMID- 15195296
TI  - Metal-complex assemblies constructed from the flexible hinge-like ligand H2bhnq:
      structural versatility and dynamic behavior in the solid state.
AB  - Novel metal-complex assemblies constructed from the flexible hinge-like ligand
      H(2)bhnq (H(2)bhnq=2,2'-bi(3-hydroxy-1,4-naphthoquinone)) have been synthesized.
      The X-ray crystal structures of these compounds reveal that four types of
      architectures are accessible by variation of the metal ions. In copper(II)
      compounds 1-3, the chelating bhnq(2-) ions bridge copper(II) centers to form one
      dimensional zigzag chains. The chains of 1-3 are arranged by hydrogen-bonding
      interactions and stacking interactions to produce porous structures. Cobalt(II)
      and zinc(II) compounds 4 and 5 form one-dimensional helical chains. In 4 and 5,
      the crystal packing induces spontaneous resolution of the helical chains with
      chiral cavities formed perpendicular to the helices. Nickel(II) compounds 6 and 7
      form cyclic tetramers. The fourth architecture, a dimer (compound 8), is obtained
      by the reaction of zinc(II) and bhnq(2-) in MeOH. In these compounds, changes of
      the dihedral angles and the metal-coordination mode of the bhnq(2-) ion induce
      the structural versatility. The assemblies of the zigzag chains of the copper(II)
      compounds exhibit reversible vapochromic behavior. UV/Vis, powder X-ray
      diffraction, EPR, and adsorption isotherm measurements indicate that this
      vapochromic behavior is based on the hinge-like flexibility of the bhnq(2-) ion.

PMID- 15195297
TI  - Spontaneous resolution through helical assembly of a conformationally chiral
      molecule with an unusual zwitterionic structure.
AB  - A conformationally chiral zwitterionic molecule forms mutually orthogonal helical
      superstructures in the crystal. This is achieved through a network of hydrogen
      bond pathways, and electrostatic interactions in crystals formed with and without
      water of crystallization. A systematic protocol for the computation of charge
      distribution on the 'molecule-in-the-crystal' is presented; the computed charges
      provide an insight into the origin of the intermolecular electrostatic
      interactions. The coexisting orthogonal helical formations lead to the homochiral
      assembly, and spontaneous resolution observed in the crystals. This material
      facilitates an appraisal of the molecular level interactions, which form the
      basis for the persistent spontaneous resolution of a conformationally chiral
      molecule in the solid state.

PMID- 15195298
TI  - Two-photon absorption in quadrupolar pi-conjugated molecules: influence of the
      nature of the conjugated bridge and the donor-acceptor separation.
AB  - Quadrupolar-type substitution of pi-conjugated chromophores with donor and
      acceptor groups has been shown to increase their two-photon absorption (TPA)
      response by up to two orders of magnitude. Here, we apply highly correlated
      quantum-chemical calculations to evaluate the impact of the nature of conjugated
      bridge and the charge-transfer distance on that enhancement. We compare
      chromophores with phenylenevinylene-, thienylenevinylene-, polyene-, and
      indenofluorene-type backbones substituted by dimethylamino and cyano groups. In
      all compounds, we find a strongly TPA-active A(g) state (either 2A(g) or 3A(g))
      in the low-energy region, as well as a higher lying TPA-active state (mA(g)) at
      close to twice the energy of the lowest lying one-photon allowed state; the
      smaller energy detuning in the mA(g) states results in very large TPA cross
      sections delta. We also investigate the influence of the degree of ground-state
      polarization on TPA. Independent of the nature of the backbone and the donor
      acceptor separation, delta displays the same qualitative evolution with a maximum
      before the cyanine-like limit; the highest TPA cross sections are calculated for
      distirylbenzene- and polyene-based systems.

PMID- 15195299
TI  - Synthesis and characterization of monodisperse oligofluorenes.
AB  - An efficient synthesis of 9,9-bis(2-ethylhexyl)fluorene oligomers up to the
      heptamer is reported, with repetitive Suzuki and Yamamoto coupling reactions
      employed in the synthesis. The key steps for preparation of the essential
      intermediates include Pd-catalyzed transformation of aryl bromides to aryl
      boronic esters (Miyaura reaction) and the application of the much higher
      reactivity of aryl boronic esters over aryl bromides in the Pd-catalyzed cross
      coupling reaction with aryl diazonium salts. Variation of the UV/Vis absorption
      and photoluminescence characteristics with chain length is reported. Moreover,
      glass transition and liquid-crystal characteristics of the oligomers are
      described and compared with those of the polymer.

PMID- 15195300
TI  - Photoinduced electron transfer in multiporphyrinic interlocked structures: the
      effect of copper(I) coordination in the central site.
AB  - Photoinduced processes have been determined in a [2]catenane containing a
      zinc(II) porphyrin, a gold(III) porphyrin, and two free phenanthroline binding
      sites, Zn-Au(+), and in the corresponding copper(I) phenanthroline complex, Zn
      Cu(+)-Au(+). In acetonitrile solution Zn-Au(+) is present in two different
      conformations: an extended one, L, which accounts for 40 % of the total, and a
      compact one, S. In the L conformation, the electron transfer from the excited
      state of the Zn porphyrin to the gold-porphyrin unit (k = 1.3x10(9) s(-1)) is
      followed by a slow recombination (k = 8.3x10(7) s(-1)) to the ground state. The
      processes in the S conformation cannot be clearly resolved but a charge-separated
      (CS) state is rapidly formed and decays with a lifetime on the order of fifty
      picoseconds. In the catenate Zn-Cu(+)-Au(+), the zinc-porphyrin excited state
      initially transfers energy to the Cu(I)-phenantholine unit, producing a metal-to
      ligand charge-transfer (MLCT) excited state localized on the copper complex with
      a rate k = 1.4x10(9) s(-1). From this excited state the transfer of an electron
      to the gold-porphyrin unit takes place, producing the CS state Zn-Cu(2+)-Au(.),
      which decays with a lifetime of 10 ns. The results are discussed in comparison
      with the closely related [2]rotaxane, in which a further charge shift from the
      copper center to the zinc-porphyrin unit leads to the fully CS state. Even in the
      absence of such full charge separation, it is shown that the lifetimes of the CS
      states are increased by a factor of about 2-2.5 over those of the corresponding
      rotaxanes.

PMID- 15195301
TI  - Preparation and reactions of 1,3-diphosphacyclobutane-2,4-diyls that feature an
      amino substituent and/or a carbonyl group.
AB  - The preparation and properties of a 1-amino-1,3-diphosphacyclobutane-2,4-diyl and
      a 1-benzoyl-1,3-diphosphacyclobutane-2,4-diyl, which can be regarded as
      functionalized cyclic biradical derivatives, were investigated. Hydrolysis of 1
      diisopropylamino-3-methyl-2,4-bis(2,4,6-tri-tert-butylphenyl)-1,3
      diphosphacyclobutane-2,4-diyl (7), which is formed by reaction of Mes*C[triple
      chemical bond]P (4; Mes*=2,4,6-tBu(3)C(6)H(2)) with lithium diisopropylamide and
      iodomethane, resulted in ring-opening of the 1,3-diphosphacyclobutane-2,4-diyl
      skeleton, as well as de-aromatization of one of the Mes* rings. 3-Oxo-1,3
      diphosphapropene 8 and 7-phosphabicyclo[4.2.0]octa-1(8),2,4-triene 9 were the
      resultant products, and these were subsequently characterized. Isomerization and
      oxidation of 7 occurred in the presence of TEMPO (2,2,6,6-tetramethyl-1
      piperidinoxy) to give the first example of a cyclic dimethylenephosphorane
      derivative, namely 3-oxo-1,3-diphospha-1,4-diene 10. 1-Benzoyl-3-tert-butyl-2,4
      bis(2,4,6-tri-tert-butylphenyl)-1,3-diphosphacyclobutane-2,4-diyl (12) was
      isolated and characterized from the reaction of 4 with tert-butyllithium and
      benzoyl chloride. Compound 12 was subsequently heated and underwent rearrangement
      of the benzoyl group and ring-expansion to afford 1-oxo-1H-[1,3]diphosphole 13.
      Reaction of 4 with lithium diisopropylamide and benzoyl chloride afforded the 2H
      [1,2,4]oxadiphosphinine 15, which was probably formed through the 1,3
      diphosphacyclobutane-2,4-diyl intermediate 14. Thermolysis of 15 afforded 1-oxo
      1H-[1,3]diphosphole 16 in an Arbuzov-type rearrangement.

PMID- 15195302
TI  - The effect of pressure on hydrogen transfer reactions with quinones.
AB  - The effect of pressure on the oxidation of hydroarenes 3-9 with 2,3-dichloro-5,6
      dicyano-1,4-quinone (DDQ; 1 a) or o-chloranil (10), leading to the corresponding
      arenes, has been investigated. The activation volumes were determined from the
      pressure dependence of the rate constants of these reactions monitored by on-line
      UV/Vis spectroscopic measurements in an optical high-pressure cell (up to 3500
      bar). The finding that they are highly negative and only moderately dependent on
      the solvent polarity (DeltaV( not equal ) = -13 to -25 in MTBE and -15 to -29
      cm(3) mol(-1) in MeCN/AcOEt, 1:1) rules out the formation of ionic species in the
      rate-determining step and is good evidence for a hydrogen atom transfer mechanism
      leading to a pair of radicals in the rate-determining step, as was also suggested
      by kinetic measurements, studies of kinetic isotope effects, and spin-trapping
      experiments. The strong pressure dependence of the kinetic deuterium isotope
      effect for the reaction of 9,10-dihydroanthracene 5/5-9,9,10,10-D(4) with DDQ (1
      a) can be attributed to a tunneling component in the hydrogen transfer. In the
      case of formal 1,3-dienes and enes possessing two vicinal C--H bonds, which have
      to be cleaved during the dehydrogenation, a pericyclic hydrogen transfer has to
      considered as one mechanistic alternative. The comparison of the kinetic
      deuterium isotope effects determined for the oxidation of tetralin 9/9-1,1,4,4
      D(4)/9-2,2,3,3-D(4)/9-D(12) either with DDQ (1 a) or with thymoquinone 1 c
      indicates that the reaction with DDQ (1 a) proceeds in a stepwise manner through
      hydrogen atom transfer, analogously to the oxidations of 1,4-dihydroarenes,
      whereas the reaction with thymoquinone 1 c is concerted, following the course of
      a pericyclic hydrogen transfer. The difference in the mechanistic courses of
      these two reactions may be explained by the effect of the CN and Cl substituents
      in 1 a, which stabilize a radical intermediate better than the alkyl groups in 1
      c. The mechanistic conclusions are substantiated by DFT calculations.

PMID- 15195303
TI  - Enantioselective total syntheses of the Ipecacuanha alkaloid emetine, the
      Alangium alkaloid tubulosine and a novel benzoquinolizidine alkaloid by using a
      domino process.
AB  - The first enantioselective syntheses of the Ipecacuanha alkaloid emetine (1) and
      the Alangium alkaloid tubulosine (2) is described employing a domino
      Knoevenagel/hetero-Diels-Alder reaction and an enantioselective catalytic
      transfer hydrogenation of imines as key steps. Thus, hydrogenation of the imine
      15 with the catalyst (R,R)-16 gives the tetrahydroisoquinoline 14 with 95 % ee
      which was transformed into the aldehyde (1S)-7. The three-component domino
      reaction of (1S)-7 with 6 and 8 led to 19, which in a second domino process was
      treated with K(2)CO(3) in methanol followed by a hydrogenation to give the
      benzoquinolizidine 4 together with the diastereomers 22 and 23 in a overall yield
      of 66 %. Further transformation of 4 with the amines 3 and 5 yielded enantiopure
      emetine (1) and tubulosine (2), respectively. In addition, starting from 19 the
      novel benzoquinolizidine alkaloid 34 was synthesised; this compound resembles the
      vallesiachotamine alkaloid dihydroantirhin 31, which has not been isolated so far
      but probably must also exist in nature.

PMID- 15195304
TI  - Reaction of a terminal phosphinidene complex with azulenes: eta1-complexes, C--H
      bond insertions, and 1,4-adducts.
AB  - Reaction of an in situ generated phosphinidene complex [PhPW(CO)(5)] with the
      aromatic azulene and guaiazulene leads to unexpected 1,4-adducts of the seven
      membered ring and to C--H bond insertion of the five-membered ring. A DFT
      analysis suggests that the reaction is initiated by formation of a eta(1)-complex
      between the phosphinidene and the five-membered ring of the aromatic substrate.
      Four conformations of this complex were identified. Two convert without barrier
      to the slightly more stable syn- and anti-1,2-adducts. These undergo pericyclic
      1,7-sigmatropic rearrangements with remarkably low barriers to give 1,4-adducts,
      with an inverted configuration at the phosphorus center. An X-ray crystal
      structure is presented for one of the 1,4-adducts of guaiazulene. The other two
      eta(1)-complexes insert with modest barriers into a C--H bond of the five
      membered ring.

PMID- 15195305
TI  - Anion complexation by glycocluster thioureamethyl cavitands: novel ESI-MS-based
      methods for the determination of Ka values.
AB  - A series of saccharide-thiourea functionalized cavitands was prepared in good
      yields (72-86 %) by reaction of a tetrakis(aminomethyl) cavitand with the
      thiocyanate derivatives of acetylated glucose, galactose, and cellobiose. The
      anion complexation behavior of the acetylated and deacetylated glycocluster
      thioureamethyl cavitands was studied with electrospray ionization mass
      spectrometry (ESI-MS) in acetonitrile and in a 1:1 acetonitrile/water mixture,
      respectively. All compounds show a preference for Cl(-). A linear relationship
      was found between the square root of the intensity and the concentration of the
      formed host-guest complex. Based on this relationship, novel methods have been
      developed to determine K(a) values, by means of direct titration and competition
      experiments.

PMID- 15195306
TI  - Enantioselective fluorescence sensing of amino acids by modified cyclodextrins:
      role of the cavity and sensing mechanism.
AB  - Two selectors based on modified cyclodextrins containing a metal binding site and
      a dansyl fluorophore-6-deoxy-6-N-(N(alpha)-[(5-dimethylamino-1
      naphthalenesulfonyl)aminoethyl]phenylalanylamino-beta-cyclodextrin-containing D
      Phe (3) and L-Phe (4) moieties were synthesized. The conformations of the two
      selectors were studied by circular dichroism, two-dimensional NMR spectroscopy
      and time-resolved fluorescence spectroscopy. Cyclodextrin 4 was found to have a
      predominant conformation in which the dansyl group is self-included in the
      cyclodextrin cavity, while 3 showed a larger proportion of the conformation with
      the dansyl group outside the cavity. As a consequence, the two cyclodextrins were
      found to bind copper(II) with different affinities, as revealed by fluorescence
      quenching in competitive binding measurements. Addition of D- or L-amino acids
      induced increases in fluorescence intensity, which were dependent on the amino
      acid used and in some cases on its absolute configuration. The cyclodextrin 4 was
      found to be more enantioselective than 3, suggesting that the self-inclusion in
      the cyclodextrin cavity strongly increases the chiral discrimination ability of
      the copper(II) complex. Accordingly, a linear fluorescent ligand N(alpha)-[(5
      dimethylamino-1-naphthalenesulfonyl)aminoethyl]-N(1)-propyl-phenylalaninamide,
      which has the same binding site and absolute configuration as 4, showed very low
      chiral discrimination ability. The enantioselectivity in fluorescence response
      was found to be due to the formation of diastereomeric ternary complexes, which
      were detected by ESI-MS and by circular dichroism. Time-resolved fluorescence
      studies showed that the fluorescence of the dansyl group was completely quenched
      in the ternary complexes formed, and that the residual fluorescence was due to
      uncomplexed ligand.

PMID- 15195307
TI  - Total synthesis and biological evaluation of the protein phosphatase 2A inhibitor
      cytostatin and analogues.
AB  - The total synthesis of the natural product cytostatin is described which inhibits
      protein phosphatase 2A. Cytostatin has anti-metastatic properties and induces
      apoptosis. On the basis of this synthesis the relative and absolute configuration
      of cytostatin could be assigned. Key structural elements of cytostatin are an
      alpha,beta-unsaturated lactone group and a side chain embodying a phosphate and a
      rather unstable (Z,Z,E)-triene subunit. In addition, the natural product carries
      six stereocenters. For the construction of the stereocenters reagent-controlled
      transformations were used in order to ensure maximum stereochemical flexibility.
      The Evans syn-aldol reaction was chosen to establish the stereochemistry at C-4,
      C-5, C-9 and C-10; C-6 was introduced by means of the Evans asymmetric
      alkylation. In all cases the same chiral auxiliary was employed as
      stereodirecting group. The stereocenter at C-11 was established by an asymmetric
      reduction using CBS-oxazaborolidine. Temporary protection of the phosphate group
      was achieved best by using the base-labile 9-fluorenylmethyl group, which could
      be cleanly cleaved by an excess of triethylamine; this reaction yielded
      analytically pure phosphates after a simple aqueous work-up. The (Z,Z,E)-triene
      embodied in cytostatin was synthesized by means of a Stille coupling as key
      transformation. The synthesis sequence established in this way readily gave
      access to a series of analogues with simplified structure. Initial biological
      testing of these analogues proved that the alpha,beta-unsaturated lactone, the C
      11-hydroxy group and a fully deprotected phosphate moiety at C-9 are essential
      for the PP2A-inhibitory activity of cytostatin. The rather unstable triene moiety
      in the side chain can be replaced by other lipophilic residues with only moderate
      decrease of biological activity. Other phosphatases, that is, PP1, VHR, PTP1B,
      CD45, were not inhibited by cytostatin or any of the analogues, demonstrating the
      high selectivity of this compound. These findings will be useful for the design
      and synthesis of cytostatin-derived chemical tools for the study of biological
      processes influenced by PP2A.

PMID- 15195308
TI  - Computational investigation of hydrogen abstraction from 2-aminoethanol by the
      1,5-dideoxyribose-5-yl radical: a model study of a reaction occurring in the
      active site of ethanolamine ammonia lyase.
AB  - Hydrogen abstraction from 2-aminoethanol by the 5'-deoxyadenosyl radical, which
      is formed upon Co--C bond homolysis in coenzyme B(12), was investigated by
      theoretical means with employment of the DFT (B3LYP) and ab initio (MP2)
      approaches. As a model system for the 5'-deoxyadenosyl moiety the computationally
      less demanding 1,5-dideoxyribose was employed; two conformers, which differ in
      ring conformation (C2- and C3-endo), were considered. If hydrogen is abstracted
      from "free" substrate by the C2-endo conformer of the 1,5-dideoxyribose-5-yl
      radical, the activation enthalpy is 16.7 kcal mol(-1); with the C3-endo
      counterpart, the value is 17.3 kcal mol(-1). These energetic requirements are
      slightly above the activation enthalpy limit (15 kcal mol(-1)) determined
      experimentally for the rate-determining step of the sequence, that is, hydrogen
      delivery from 5'-deoxyadenosine to the product radical. The activation enthalpy
      is lower when the substrate interacts with at least one amino acid from the
      active site. According to the computations, when a His model system partially
      protonates the substrate the activation enthalpy is 4.5 kcal mol(-1) for the C3
      endo conformer and 5.8 kcal mol(-1) for the C2-endo counterpart. As hydrogen
      abstraction from the fully as well as the partially protonated substrate is
      preceded by the formation of quite stable encounter complexes, the actual
      activation barriers are around 13-15 kcal mol(-1). A synergistic interaction of 2
      aminoethanol with two amino acids where His partially protonates the NH(2) group
      and Asp partially deprotonates the OH group of the substrate results in an
      activation enthalpy of 12.4 kcal mol(-1) for the C3-endo conformer and 13.2 kcal
      mol(-1) for the C2-endo counterpart. However, if encounter complexes exist in the
      active site, the actual activation barriers are much higher (>25 kcal mol(-1))
      than that reported for the rate-determining step. These findings together with
      previous computations suggest that the energetics of the initial hydrogen
      abstraction decrease with an interaction of the substrate with only a protonating
      auxiliary, but for the rearrangement of the radical the synergistic effects of
      two auxiliaries are essential to pull the barrier below the limit of 15 kcal mol(
      1).

PMID- 15195309
TI  - Fabrication of nanofibers with uniform morphology by self-assembly of designed
      peptides.
AB  - Fabrication of controlled peptide nanofibers with homogeneous morphology has been
      demonstrated. Amphiphilic beta-sheet peptides were designed as sequences of Pro
      Lys-X(1)-Lys-X(2)-X(2)-Glu-X(1)-Glu-Pro. X(1) and X(2) were hydrophobic residues
      selected from Phe, Ile, Val, or Tyr. The peptide FI (X(1)=Phe; X(2)=Ile) self
      assemble into straight fibers with 80-120 nm widths and clear edges, as examined
      by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The
      fiber formation is performed in a hierarchical manner: beta-sheet peptides form a
      protofibril, the protofibrils assemble side-by-side to form a ribbon, and the
      ribbons then coil in a left-handed fashion to make up a straight fiber. These
      type of fibers are formed from peptides possessing hydrophobic aromatic Phe
      residue(s). Furthermore, a peptide with Ala residues at both N and C termini does
      not form fibers (100 nm scale) with clear edges; this causes random aggregation
      of small pieces of fibers instead. Thus, the combination of unique amphiphilic
      sequences and terminal Pro residues determine the fiber morphology.

PMID- 15195310
TI  - The role of hydrogen bonding in the crystal structures of zinc phosphate
      hydrates.
AB  - The compounds alpha- and beta-hopeite have been synthesised by hydrothermal
      crystallisation from aqueous solution at 90 degrees C and 20 degrees C,
      respectively. The crystal structures of these polymorphic forms of zinc phosphate
      tetrahydrate (ZPT), Zn(3)(PO(4))(2).4 H(2)O, have been resolved. Single-crystal
      analysis proves that the main difference between the alpha and beta forms of ZPT
      is caused by the difference in orientation of one of the water molecules in the
      ZnO(6) octahedral network, indicating two different hydrogen-bonding patterns. A
      previously unknown hopeite, Zn(3)(HPO(4))(3).3 H(2)O (ZHPT), has been isolated
      and analysed. This helps to achieve a better understanding of the mechanism of
      formation of zinc phosphate compounds. Unambiguous identification of each phase
      is established by analysis of their unique thermal behaviour and thermodynamic
      interrelationship.

PMID- 15195311
TI  - Topologically chiral covalent assemblies of molecular knots with linear,
      branched, and cyclic architectures.
AB  - Selectively functionalized molecular knots (knotanes) of the amide-type have been
      used as building blocks in syntheses of higher covalent assemblies composed of up
      to four knotane units. Preparation of linear and branched tetraknotanes consisted
      of the consecutive selective removal of allyl groups followed by linking of the
      intermediate hydroxyknotanes with biphenyl-4,4'-disulfonyl chloride. Macrocyclic
      knotane oligomers involving two, three, and four knotane moieties were obtained
      by high-dilution cyclization of dihydroxyknotane and biphenyl-4,4'-disulfonyl
      chloride. Due to their relation with cyclophanes, the latter class of oligomeric
      knotanes was termed "knotanophanes". Chiral resolution analysis of new
      oligoknotanes has been attempted on chemically bonded Chiralpak AD stationary
      phases, however met severe difficulties due to their complex isomeric
      compositions, and in most cases a significant overlap of the isomer fractions was
      observed. In spite of the limits of presently available chiral stationary phases
      that allowed only partial resolution of the synthesized topologies, oligoknotanes
      have been shown to be of high fundamental interest due to their unprecedented
      chirality. The chirality descriptions of topologically chiral unsymmetrical
      dumbbell 4, and the linear tetraknotane 5 are analogous to the Fischer
      projections of erythrose/threose and hexaric acid, respectively, while the
      isomeric composition of the branched tetraknotane 8 is completely unique.
      Moreover, the linear and branched tetraknotanes are constitutional isomers.
      Chirality of knotanophanes represents, in turn, analogies to known cyclic forms
      of peptides or sugars with multiple stereogenic centers.

PMID- 15195312
TI  - Combinatorial synthesis of bimetallic complexes with three halogeno bridges.
AB  - Methods for the synthesis of bimetallic complexes in which two different metal
      fragments are connected by three chloro or bromo bridges are reported. The
      reactions are general, fast, and give rise to structurally defined products in
      quantitative yields. Therefore, they are ideally suited for generating a library
      of homo- and heterobimetallic complexes in a combinatorial fashion. This is of
      special interest for applications in homogeneous catalysis. Selected members of
      this library were synthesized and comprehensively characterized; single-crystal X
      ray analyses were performed for 15 new bimetallic compounds.

PMID- 15195313
TI  - Syntheses and phase-transfer properties of dendritic nanocarriers that contain
      perfluorinated shell structures.
AB  - Perfect dendrimers that contain perfluorinated shells have recently attracted
      attention because they have been shown to encapsulate polar molecules in
      supercritical CO(2) and catalytically active metal nanoparticles in
      perfluorinated solvents. Moreover, they can then be easily separated after
      reaction from the biphasic organic/fluorous system. In this paper several
      dendritic architectures that contain perfluorinated shells were derived by
      covalent modification of glycerol dendrimers ([G0.5]-[G3.5]), hyperbranched
      polyglycerol, and polyethyleneimine. These core-shell architectures show
      interesting physicochemical properties. For example, they are soluble in
      fluorinated solvents, they are able to transport different guest molecules, and
      they display thermomorphic behavior. The transport capacity of these molecular
      nanocarriers increases significantly when amino groups are present in the core.
      Certain functionalized polyethyleneimines that contain perfluorinated shells show
      high transport capacities (up to 3 dye molecules per nanocarrier) in
      perfluorinated solvents. Moreover, these perfluoro-functionalized dendritic
      polyethyleneimines can act as templates that stabilize nanoparticles; for
      example, encapsulation and subsequent chemical reduction of Ag(I) ions. Silver
      nanoparticles with a narrow size distribution (3.9+/-1 nm) have been prepared and
      characterized by transmission electron microscopy. Furthermore, it has been
      demonstrated that the encapsulated guest molecules remain accessible to small
      molecules after transport into the fluorous phase. Therefore, dendritic
      nanocarriers that contain perfluorinated shells are currently being investigated
      as polar environments in nonpolar reaction media such as fluorous phases and
      supercritical CO(2), in particular, for application in homogenous catalysis.

PMID- 15195314
TI  - Self-assembled monolayers of dendritic polyglycerol derivatives on gold that
      resist the adsorption of proteins.
AB  - Highly protein-resistant, self-assembled monolayers (SAMs) of dendritic
      polyglycerols (PGs) on gold can easily be obtained by simple chemical
      modification of these readily available polymers with a surface-active disulfide
      linker group. Several disulfide-functionalized PGs were synthesized by N,N'
      dicyclohexylcarbodiimide-mediated ester coupling of thioctic acid. Monolayers of
      the disulfide-functionalized PG derivatives spontaneously form on a
      semitransparent gold surface and effectively prevent the adsorption of proteins,
      as demonstrated by surface plasmon resonance (SPR) kinetic measurements. A
      structure-activity relationship relating the polymer architecture to its ability
      to effectuate protein resistance has been derived from results of different
      surface characterization techniques (SPR, attenuated total reflectance infrared
      (ATR-IR), and contact-angle measurements). Dendritic PGs combine the
      characteristic structural features of several highly protein-resistant surfaces:
      a highly flexible aliphatic polyether, hydrophilic surface groups, and a highly
      branched architecture. PG monolayers are as protein resistant as poly(ethylene
      glycol) (PEG) SAMs and are significantly better than dextran-coated surfaces,
      which are currently used as the background for SPR spectroscopy. Due to the
      higher thermal and oxidative stability of the bulk PG as compared to the PEG and
      the easy accessibility of these materials, dendritic polyglycerols are novel and
      promising candidates as surface coatings for biomedical applications.

PMID- 15195316
TI  - A comparison of the reactivity of Ni atoms toward CH4, SiH4, and SnH4: a combined
      matrix isolation and quantum-chemical study.
AB  - Nickel atoms are shown to react spontaneously with SiH(4) and SnH(4) to give the
      insertion products HNiSiH(3) and HNiSnH(3). With CH(4), however, no spontaneous
      reaction occurs, in agreement with earlier reports; HNiCH(3) can be formed only
      on photolytic activation of the Ni atom. The reaction products were characterized
      experimentally by IR spectroscopy, including the effect of isotopic substitution
      (H/D), and by quantum-chemical calculations. They all have C(s) symmetry with a
      terminal Ni--H bond and three terminal E--H bonds (E=Si, Sn). Strikingly, the H
      Ni-E bond angles are less than 90 degrees, and there is a weak interaction
      between the H atom bound to Ni and the E atom. The structures are compared with
      those of other molecules of general formula MSiH(4) that have been characterized
      recently in our group (M=Ti, Ni, Ga). While TiSiH(4) has three Ti-H-Si bridges,
      both NiSiH(4) and GaSiH(4) exhibit only terminal Ni--H and E--H bonds, but with
      the difference that there is no interaction between the H atom bound to Ga and
      the Si atom.

PMID- 15195315
TI  - Long-range stereocontrol in the self-assembly of two-nanometer-dimensioned triple
      stranded dinuclear helicates.
AB  - A series of bisimine-bridged dicatechol ligands 2-H(4)-5-H(4) were synthesized
      and were used to prepare triple-stranded dinuclear helicate-type complexes with a
      length of up to more than 2 nm. X-ray structural analyses of Na(4)[(2)(3)V(2)],
      Na(4)[(3)(3)Ti(2)], Na(4)[(4)(3)Ti(2)], and Na(4)[(5)(3)Ti(2)], as well as
      temperature-dependent NMR investigations of Na(4)[(4)(3)Ti(2)] and
      Na(4)[(5)(3)Ti(2)] show that, in the case of the rigid linear ligands 2 and 3,
      and of the ligand 5, which possesses C(2h) symmetry in its idealized structure,
      homochiral helicates are diastereoselectively formed. Ligand 4, on the other
      hand, with idealized C(2v) symmetry, leads with surprisingly high selectivity to
      the formation of the heterochiral meso-helicate. This is attributed to the
      ability of ligand 4 to adopt a less-restricted conformation in the meso compound
      than in the helical complex. NMR investigations indicate that both complex units
      of Na(4)[(4)(3)Ti(2)] invert (LambdaDelta-->DeltaLambda) simultaneously, while in
      the case of Na(4)[(5)(3)Ti(2)] a stepwise racemization proceeds.

PMID- 15195318
TI  - Analysis of pilot and early phase studies with small sample sizes.
AB  - The need for statistical methodologies for analysing a small size study, such as
      a pilot or so-called 'proof of concept' study, has not been paid much attention
      in the past. Recently the Institute of Medicine (IOM) formed a committee and held
      a workshop to discuss methodologies for conducting clinical trials with small
      number participants. In this paper we argue that the hypothesis of treatment
      effect in a small pilot study should be set up to test whether any individual
      subject has an effect rather than whether the group mean or median has shifted as
      often done for large, confirmatory clinical trials. Based on this paradigm we
      propose multiple test procedures as one option when individuals have enough
      observations, and a mixture-distribution approach when individuals have one or
      more observations. The latter approach may be used in either a one- or two-group
      setting, and is our focus in this paper. We present the likelihood ratio tests
      for the mixture models. Examples are given to demonstrate the methods.

PMID- 15195319
TI  - Odds ratios for a continuous outcome variable without dichotomizing.
AB  - The loss of information from dichotomizing a continuous outcome is well
      documented in the literature. One advantage of dichotomizing is that it allows
      estimation of odds ratio parameters through a logistic regression analysis. The
      objective of this paper is to develop a new estimator of the same odds ratio
      parameters through regression analysis on the original continuous outcome without
      the inherent loss of information caused by dichotomizing. Through a mathematical,
      asymptotic development the relative sample sizes required to attain a specified
      power when testing the odds ratio parameter are compared for the dichotomizing
      procedure and the proposed approach. The comparison highlights the substantial
      sample size savings attained by the proposed approach, particularly for large
      values of the odds ratio parameter and for small proportions of dichotomized
      successes or failures. In a Monte Carlo simulation the variances and absolute
      biases of the two odds ratio estimators and the length of their respective
      confidence intervals again demonstrate the improvement attained by the proposed
      approach. In addition, coverage probabilities of the confidence intervals of the
      proposed approach converge quickly to the nominal levels. The cost savings due to
      the reduction in required sample size when using this method make it a very
      attractive study design and analysis tool for medical researchers.

PMID- 15195320
TI  - A non-parametric approach to the design and analysis of two-dimensional dose
      finding trials.
AB  - This paper investigates the design and analysis of dose-finding trials with two
      agents. The set of doses for each agent is fixed in advance. The goal of the
      trial is to find the set of dose combinations with probability of toxicity
      closest to a pre-specified value. For each of the two agents we assume that the
      probability of toxicity of an agent is non-decreasing with dose when the dose of
      the other agent is fixed. Using this assumption we construct a new non-parametric
      design that operates on a two-dimensional grid of all possible dose combinations.
      A bivariate isotonic regression estimator of the maximum tolerated combinations
      is described. We conclude that the new design and the bivariate isotonic
      estimator are superior to the procedure where several independent dose-finding
      trials are run.

PMID- 15195321
TI  - Statistical analysis of MMR vaccine adverse events on aseptic meningitis using
      the case cross-over design.
AB  - Vaccination is quite effective in reducing the incidence of disease. However, it
      may cause some adverse events. For example, one of the adverse events of measles
      mumps-rubella(MMR) vaccination is the occurrence of aseptic meningitis. Since the
      vaccination rate is usually quite high, it is not plausible to use popular study
      designs such as cohort or case-control studies. We considered a case cross-over
      design to investigate the association between MMR vaccination and aseptic
      meningitis in Korean children. We used the Cochran-Mantel-Haenszel(CMH) approach,
      and obtained a Mantel-Haenszel odds ratio estimator as a measure of association.
      However, the validity of case cross-over design or the CMH approach in vaccine
      adverse studies has not been fully investigated. In this paper, through Monte
      Carlo simulation studies, we show the appropriateness of the case cross-over
      design and the CMH approach. We also discuss alternative approaches such as
      Poisson regression using offset and a simple uniformity test. In conclusion, the
      case cross-over design seems useful to investigate the association between
      vaccination and occurrence of acute adverse events.

PMID- 15195322
TI  - Non-parametric estimation of gap time survival functions for ordered multivariate
      failure time data.
AB  - Times between sequentially ordered events (gap times) are often of interest in
      biomedical studies. For example, in a cancer study, the gap times from incidence
      to-remission and remission-to-recurrence may be examined. Such data are usually
      subject to right censoring, and within-subject failure times are generally not
      independent. Statistical challenges in the analysis of the second and subsequent
      gap times include induced dependent censoring and non-identifiability of the
      marginal distributions. We propose a non-parametric method for constructing one
      sample estimators of conditional gap-time specific survival functions. The
      estimators are uniformly consistent and, upon standardization, converge weakly to
      a zero-mean Gaussian process, with a covariance function which can be
      consistently estimated. Simulation studies reveal that the asymptotic
      approximations are appropriate for finite samples. Methods for confidence bands
      are provided. The proposed methods are illustrated on a renal failure data set,
      where the probabilities of transplant wait-listing and kidney transplantation are
      of interest.

PMID- 15195323
TI  - Bayesian analysis of risk factors for anovulation.
AB  - Two algorithms for assessing ovulatory status using daily urinary levels of
      oestrogen and progesterone metabolites have been applied to non-clinic-based,
      free-living populations of women. These relatively new methods for assessing
      ovarian function have been used to assess the potential adverse effects of
      occupational and environmental exposures, such as smoking, on the reproductive
      health of women. One algorithm has been validated against serum hormone
      measurements and gives good sensitivity and specificity for anovulation. However,
      a gold standard is generally not available in epidemiologic field studies in
      which these daily urine samples are collected. In this paper, we used Bayesian
      methods to estimate: (i) the probability of occurrence of anovulation, (ii) the
      sensitivity and specificity of the two algorithms, and (iii) the association
      between anovulation and smoking and other risk factors in the absence of a
      perfect test. We evaluated the two published algorithms for assessing ovulatory
      status, based on their cross-classified results applied to one randomly selected
      cycle from each woman in a sample of 338 employed women. We first assumed that
      the algorithms were independent, conditional on ovulatory status. Then, we used a
      dependence model to allow for correlation between the results of the two
      algorithms. We implemented a Bayesian logistic regression analysis that allowed
      the outcome measurement to be partially imperfect. We incorporated the posterior
      distributions for algorithm accuracy obtained from the dependence model as prior
      distributions for this logistic regression model. Then, we compared the results
      with those obtained from a standard multiple logistic approach using the
      algorithm determination of ovulatory status as if it were perfect. Our results
      indicated that increasing physical activity was associated with a significantly
      increased risk of anovulation; and smokers had a potentially, but not
      statistically significant, increased occurrence of anovulation.

PMID- 15195324
TI  - Sample sizes for clinical trials with normal data.
AB  - This article gives an overview of sample size calculations for parallel group and
      cross-over studies with Normal data. Sample size derivation is given for trials
      where the objective is to demonstrate: superiority, equivalence, non-inferiority,
      bioequivalence and estimation to a given precision, for different types I and II
      errors. It is demonstrated how the different trial objectives influence the null
      and alternative hypotheses of the trials and how these hypotheses influence the
      calculations. Sample size tables for the different types of trials and worked
      examples are given.

PMID- 15195326
TI  - Extinction deficits in male rhesus macaques with a history of self-injurious
      behavior.
AB  - Self-injurious behavior (SIB) occurs in both human and nonhuman primate
      populations. Despite the potential for harm, SIB may persist in part because of
      an inability to inhibit behavior that results in wounding. A lever-pressing task
      was used to test the prediction that monkeys with SIB would show greater
      persistence in lever-pressing on extinction trials than monkeys without the
      disorder. The subjects were 15 individually-housed adult male rhesus macaques, 10
      of which (the SIB group) had a veterinary record of self-inflicted wounding. All
      of the monkeys were trained to lever-press for food rewards to a criterion of 400
      total responses. The test procedures consisted of five daily 30-min sessions
      divided into six 5-min intervals. On day 1, the subjects received continuous
      reinforcement. On days 2-4, testing consisted of alternating
      reinforced/unreinforced 5-min intervals, beginning with reinforcement. Reinforced
      intervals were cued with a buzzer. On day 5, the subjects received no
      reinforcement. The number of lever-presses and behavioral responses were recorded
      during each session. Saliva samples were collected for cortisol measurement
      before and after test sessions on days 1, 2, and 5. As predicted, monkeys with
      SIB lever-pressed more than controls during extinction intervals on days 2-4.
      There was no difference on day 1 or day 5. The frequency of scratching, yawning,
      and abnormal behavior increased when reinforcement was intermittent (days 2-4) or
      absent (day 5). Cortisol levels were highest with continuous reinforcement (day
      1), and may reflect differential levels of food intake rather than stress. The
      presence of extinction deficits suggests that SIB may persist in some monkeys
      because they lack the ability to regulate the intensity of their biting behavior.

PMID- 15195327
TI  - Anogenital gland secretions of Lemur catta and Propithecus verreauxi coquereli: a
      preliminary chemical examination.
AB  - Although prosimians are greatly olfaction-oriented, little is known about the
      specifics of how they use scent to communicate. In this preliminary study we
      attempted to delineate intra- and interspecific differences among the anogenital
      gland secretions of two lemur species (Lemur catta and Propithecus verreauxi
      coquereli) using gas chromatography-mass spectrometry (GC-MS). The results
      indicate that the two species are discernible through scent. Furthermore, we were
      able to identify reproductive status using this technique. The anogenital
      secretions of the different sexes in L. catta, though perhaps not P. v.
      coquereli, are chemically distinguishable. Given this information, it appears
      that at least some lemur species can use scent marks to determine species, sex,
      and reproductive status.

PMID- 15195328
TI  - Changes in social interactions during adolescence in male mandrills (Mandrillus
      sphinx).
AB  - The adolescent period in male mandrills extends from the time the testicles
      descend (at the age of 3-4 years) to the time adult characteristics develop (at
      the age of 10 years), and is thus one of the longest adolescent periods in
      cercopithecines. In this short cross-sectional study of 11 male mandrills (4.7
      9.1 years old), we analyzed social behavioral patterns to investigate partner
      preference and changes in types of interactions throughout puberty. The mandrills
      were separated into two clusters on the basis of all of the social interactions
      scored, as well as the age and sex of the protagonist. During early to mid
      puberty, immature individuals interacted preferentially with other male
      adolescents and juveniles. Playing was an important activity, and some
      affiliative interactions with juveniles were observed. Older adolescents
      interacted more with adult males and females. These older adolescents were
      predominantly aggressive toward other adolescents, females, and juveniles, and
      showed little or no affiliative or playful behaviors. These results indicate a
      shift in social partners: older males interacted more frequently with adult
      males, and their behavior involved more aggression and less submission compared
      to younger adolescents, which showed predominantly submissive and playful
      behavior. These changes are consistent with preparation for dispersal and future
      intermale competition.

PMID- 15195329
TI  - Pre-retirement predator encounters alter the morning behavior of captive
      marmosets (Callithrix geoffroyi).
AB  - Limited data are available on the long-term effect an encounter with a predator
      has on its potential prey. Anecdotal reports from field research indicate that
      even unsuccessful attacks by predators on callitrichids have long-lasting
      effects. The subjects for this study were two groups of Geoffroy's marmosets
      (Callithrix geoffroyi) housed outside, off exhibit, at the Center for
      Reproduction of Endangered Species at the San Diego Wild Animal Park. Before they
      retired in the evening, the marmosets were observed under one of three
      conditions: snake model, cloth control, and no-stimulus control. Data were
      collected the following morning for 1 hr after the animals emerged from the
      sleeping box. Compared to control conditions, exposure to the snake model before
      retirement the previous evening was associated with significantly more vigilance
      checks (i.e., inspecting the area where the stimulus was last seen), and a delay
      in beginning to forage on the ground. These results suggest that callitrichids
      use recent threatening experiences to guide their vigilance behavior 12 hr after
      the threat is detected, and that they adjust their early morning behavior in
      response to potential predatory threats.

PMID- 15195331
TI  - Do males have a better chance of mating when the number of estrous females is
      equal to or greater than the males' ordinal rank? Testing the hypothesis in
      Japanese macaques.
AB  - This study was designed to test the hypothesis that male primates in multi
      male/multi-female social groups with a clear male dominance hierarchy have a
      better chance of mating when the number of estrous females is equal to or greater
      than, as opposed to less than, the males' ordinal rank. I studied a Japanese
      macaque (Macaca fuscata fuscata) troop during mating seasons from 1992 to 1995.
      The mean daily operational sex ratio (OSR; the number of estrous females per
      troop male), which was calculated on observation days, was 0.21, 1.9, 0.48, and
      3.1 in 1992-1995, respectively. Overall, focal animal sampling of males yielded
      118 male-day records. The male-day records for each male were divided into the
      two estrous female number conditions: 1) the male-day records when the number of
      estrous females was equal to or greater than the male's ordinal rank, and 2) the
      male-day records when the number of estrous females was less than the male's
      ordinal rank. In the 1993 and 1995 mating seasons, when the number of estrous
      females was equal to or greater than the ordinal rank of each male, all of the
      males were observed mating. Conversely, when the number of estrous females was
      less than the ordinal rank of some male, they were not observed mating in the
      1992 and 1994 mating seasons. The percentage for each male across each male's
      total mating opportunity was <20% when the number of estrous females was less
      than the male's ordinal rank. By contrast, the percentage for each male across
      each male's total mating opportunity exceeded 45% when the number of estrous
      females was equal to or greater than the male's ordinal rank, except for one
      male. Of all the male-day records for males observed mating with ejaculation, 41
      were obtained when the number of estrous females was equal to or greater than the
      male's rank; conversely, only three records were obtained when the number of
      estrous females was less than the male's ordinal rank. Therefore, it appears that
      males have a better chance of mating when the number of estrous females is equal
      to or greater than the males' ordinal rank, as opposed to when the number is less
      than their ordinal rank.

PMID- 15195330
TI  - Genotyping aids field study of unhabituated wild chimpanzees.
AB  - Prolonged habituation times for wild great apes delay the collection of
      behavioral and environmental data, sometimes for years. However, genotyping of
      noninvasively collected feces can provide useful socioecological information in
      the meantime. We tested this premise on an unhabituated wild population of
      western chimpanzees (Pan troglodytes verus) at Mont Assirik, Senegal. Genotyping
      yielded information on kinship, group size, party size and composition, sex
      ratio, and ranging.

PMID- 15195332
TI  - Transmission of STLV in a closed colony of macaques.
AB  - A 3.3% seroprevalence of simian T-lymphotropic virus (STLV) was found in a closed
      breeding and research colony of rhesus and cynomolgus macaques in Thailand.
      Epidemiology of STLV within the colony was assessed by means of a retrospective
      analysis of banked and freshly collected serum samples, and a review of the
      animals' medical records. Evidence was found that the virus had been imported
      into the colony by some of the original animals, and was subsequently transmitted
      both vertically and horizontally. The cell-associated nature of STLV was
      demonstrated by iatrogenic transmission of the virus following a whole blood
      transfusion, but there was no transmission to animals that received only serum
      from the same infected donor. Transmission by all routes was infrequent, as
      indicated by the overall seroprevalence of 3.3% (14 of 420 samples) after the
      colony had been closed for 11 years. Maternal-infant transmission appeared to be
      < 12%.

PMID- 15195334
TI  - Competencies conference: future directions in education and credentialing in
      professional psychology.
AB  - The Competencies Conference: Future Directions in Education and Credentialing in
      Professional Psychology was organized around eight competency-focused work
      groups, as well as work groups on specialties and the assessment of competence. A
      diverse group of psychologists participated in this multisponsored conference.
      After describing the background and structure of the conference, this article
      reviews the common themes that surfaced across work groups, with attention paid
      to the identification, training, and assessment of competencies and competence.
      Recommendations to advance competency-based education, training, and
      credentialing in professional psychology are discussed. This is one of a series
      of articles published together in this issue of the Journal of Clinical
      Psychology. Several other articles that resulted from the Competencies Conference
      will appear in Professional Psychology: Research and Practice and The Counseling
      Psychologist.

PMID- 15195335
TI  - The scientifically-minded psychologist: science as a core competency.
AB  - At the Competencies Conference: Future Directions in Education and Credentialing
      in Professional Psychology, the Scientific Foundations and Research Competencies
      Work Group focused on identifying how psychologists practice scientifically. This
      article presents the subcomponents associated with the core competency of
      scientific practice. The subcomponents include: 1). access and apply current
      scientific knowledge habitually and appropriately; 2). contribute to knowledge;
      3). critically evaluate interventions and their outcomes; 4). practice vigilance
      about how sociocultural variables influence scientific practice; and 5).
      routinely subject work to the scrutiny of colleagues, stakeholders, and the
      public. In addition, the article briefly discusses how the depth of training for
      and assessment of each subcomponent will vary by training model. Implications and
      future directions for individual psychologists, training programs, and the
      profession are discussed. This is one of a series of articles published in this
      issue of the Journal of Clinical Psychology. Several other articles that resulted
      from the Competencies Conference will appear in Professional Psychology: Research
      and Practice and The Counseling Psychologist.

PMID- 15195336
TI  - Achieving competency in psychological assessment: directions for education and
      training.
AB  - This article provides an overview of issues related to the development and
      evaluation of competency in psychological assessment. Specifically, we delineate
      the goals, ideas, and directions identified by the psychological assessment work
      group in the Competencies Conference: Future Directions in Education and
      Credentialing in Professional Psychology. This is one of a series of articles
      published in this issue of the Journal of Clinical Psychology. Several other
      articles that resulted from the Competencies Conference will appear in
      Professional Psychology: Research and Practice and The Counseling Psychologist.
      The psychological assessment group was charged with the tasks of: (a).
      identifying the core components of psychological assessment competency; (b).
      determining the central educational and training experiences that will aid
      competency development; (c). explicating strategies for evaluating competence;
      and (d). establishing future directions for furthering the identification,
      training, and evaluation of competence in psychological assessment. We present a
      set of eight core competencies that we deemed important for achieving
      psychological assessment competency and discuss four guidelines for training in
      the domain of psychological assessment. A variety of methods for evaluating
      competencies in this domain are suggested, with emphasis on using a collaborative
      model of evaluation. Recommendations for future directions include strengthening
      the academic prerequisites for graduate school training; increasing training in
      culturally sensitive measures; incorporating innovative assessment-related
      technologies into training; and addressing discontinuities between academic
      training, internship, and practice environments.

PMID- 15195337
TI  - Becoming a competent clinician: basic competencies in intervention.
AB  - This article summarizes the results from the Intervention Work Group of the
      Competencies Conference: Future Directions in Education and Credentialing in
      Professional Psychology. The generic charge presented to the Intervention Work
      Group was "to address issues related to interventions." The Intervention Work
      Group identified four competency components of knowledge, skills, and abilities:
      (a). foundational competencies; (b). intervention planning; (c). intervention
      implementation; and (d). intervention evaluation competencies. A fifth component
      that included "practice management" was labeled as "others." Each component is
      discussed, including competencies that were deemed an essential knowledge, skill,
      and/or value. A discussion of training for intervention competence and assessing
      that intervention competence is included. Future directions for the science and
      practice of psychology in the intervention arena are summarized. This is one of a
      series of articles published in this issue of the Journal of Clinical Psychology.
      Several other articles that resulted from the Competencies Conference will appear
      in Professional Psychology: Research and Practice and The Counseling
      Psychologist.

PMID- 15195338
TI  - Individual and cultural-diversity competency: focus on the therapist.
AB  - The Competencies Conference: Future Directions in Education and Credentialing in
      Professional Psychology was held in Arizona in November 2002. One of the
      workshops, Individual and Cultural Differences (ICD), focused on racism,
      homophobia, and ageism. The consensus was that self-awareness and knowledge about
      the three "isms" are critical components in the education and training of
      psychologists. This article, authored by four of the workshop attendees, is a
      review of the current research and theoretical literature. Implications that
      address both content and context in graduate programs and training sites are
      presented. This is one of a series of articles published in this issue of the
      Journal of Clinical Psychology. Several other articles that resulted from the
      Competencies Conference will appear in Professional Psychology: Research and
      Practice and The Counseling Psychologist.

PMID- 15195339
TI  - Defining competencies in psychology supervision: a consensus statement.
AB  - Supervision is a domain of professional practice conducted by many psychologists
      but for which formal training and standards have been largely neglected. In this
      article, supervision is proposed as a core competency area in psychology for
      which a number of elements reflecting specific knowledge, skills, and values must
      be addressed to ensure adequate training and professional development of the
      trainee. Supra-ordinate factors of supervision viewed as permeating all aspects
      of professional development are proposed. These include the perspective that
      professional development is a lifelong, cumulative process requiring attention to
      diversity in all its forms, as well as legal and ethical issues, personal and
      professional factors, and self- and peer-assessment. A competencies framework is
      presented with particular elements representing knowledge (e.g., about
      psychotherapy, research, etc.), skills (including supervising modalities,
      relationship skills, etc.), values (e.g., responsibility for the clients and
      supervisee rests with supervisor, etc.), and meta-knowledge. Social contextual
      factors and issues of education and training, assessment, and future directions
      also are addressed, with specific elements listed. Suggestions for future work in
      this area are addressed, including the need to refine further and operationalize
      competences, develop clear expectations for accreditation and licensure regarding
      supervision competencies, and expand the description of developmental levels of
      supervisors from minimal to optimal competence. This is one of a series of
      articles published together in this issue of the Journal of Clinical Psychology.
      Several other articles that resulted from the Competencies Conference: Future
      Directions in Education and Credentialing in Professional Psychology will appear
      in Professional Psychology: Research and Practice and The Counseling
      Psychologist.

PMID- 15195340
TI  - Consultation and interprofessional collaboration: modeling for the future.
AB  - Consultation and interprofessional collaboration by psychologists occur with
      individuals, groups, programs, and organizations. The practice of consultation
      and interprofessional collaboration involves interdisciplinary relationships,
      preparation, and advanced skill development within specialty areas of psychology
      (e.g., clinical, counseling, industrial-organizational, and school). The
      Workgroup on Consultation and Interdisciplinary Relationships engaged in a
      planning process at the Competencies Conference: Future Directions in Education
      and Credentialing in Professional Psychology to address fundamental issues
      regarding consultation and interprofessional collaboration in professional
      psychology. The Workgroup articulated working definitions, consensus points about
      psychologists as consultants and interprofessional collaborators, a consulting
      and interprofessional competency blueprint for preparation and assessment
      strategies, and future directions. This is one of a series of articles published
      in this issue of the Journal of Clinical Psychology. Several other articles that
      resulted from the Competencies Conference will appear in Professional Psychology:
      Research and Practice and The Counseling Psychologist.

PMID- 15195341
TI  - Sequential therapies for proliferative lupus nephritis.

PMID- 15195343
TI  - Proceedings of Ultrasonics International 2003. Granada, Spain, July 1-3, 2003.

PMID- 15195342
TI  - Sequential therapies for proliferative lupus nephritis.

PMID- 15195344
TI  - Purine-rich foods and the risk of gout in men.

PMID- 15195345
TI  - Pulmonary hypertension as a risk factor for death in patients with sickle cell
      disease.

PMID- 15195346
TI  - Sublingual glyceryl trinitrate as prehospital treatment for hypertension in
      Irukandji syndrome.

PMID- 15195347
TI  - Cellulitis.

PMID- 15195348
TI  - Cellulitis.

PMID- 15195349
TI  - LMO2 and gene therapy for severe combined immunodeficiency.

PMID- 15195350
TI  - Towards a common neural substrate in the immediate and effective inhibition of
      stuttering.
AB  - Stuttering can be effectively inhibited via exogenous sensory signals (e.g.,
      speaking in unison or using altered auditory feedback) or by using endogenous
      motoric strategies (e.g., singing or therapeutically implementing long vowel
      prolongations to reduce speech rates). We propose that these channels, which
      superficially appear to be diametrically opposite, centrally converge in the
      engagement of mirror neurons for fluent gestural productions. Sensory changes
      incurred via exogenous speech signals allow for direct engagement of mirror
      systems, while endogenous motor strategies appear to require significant
      departures from normal speech production (e.g., highly unnatural or droned
      speech) to engage mirror systems. Thus, paradoxically, stuttering is prone to
      resurface during attempts to impose naturalness upon therapeutic speech.

PMID- 15195351
TI  - Lateral pectoral nerve conduction.
AB  - The aim of this study was to measure the motor conduction time (MCT) and velocity
      of the lateral pectoral nerve (LPN) in normal subjects and patients with
      neuropathy. For the LPN, we determined thus the average MCT was 3.9 m/s using Erb
      stimulation with needle recording, and the average motor conduction velocity was
      70.6 m/s using Erb stimulation and axilla stimulation with needle recordings in
      normal subjects. In patients, prolonged MCT in LPN was found in 3 of 6 patients
      with unilateral plexopathy and 3 of 4 patients with polyneuropathy. It was
      determined that MCT and motor conduction velocity in LPN was as sensitive as
      biceps brachii MCT in patients with unilateral plexopathy. Furthermore, the motor
      conduction velocity in the LPN may be beneficial to elucidate the localization of
      involvement in polyneuropathies, such as distal or proximo-distal.

PMID- 15195352
TI  - Greater right frontal EEG asymmetry and nonemphathic behavior are observed in
      children prenatally exposed to cocaine.
AB  - Responses to emotion-inducing stimuli were examined in 27, 3- to 6-year-old
      children, who were prenatally exposed to cocaine, and 27 unexposed controls.
      Children were monitored for EEG activity and their affect during an infant
      crying, simulated maternal distress, and a mildly frustrating task. Multivariate
      analyses indicated that the cocaine-exposed children had greater right frontal
      EEG asymmetry, showed fewer empathic reactions to a crying infant as well as to
      their own mothers, and they were less proficient in completing a cooperative
      task. These findings highlight the need for continued longitudinal research on
      the effects of early drug exposure for later socioemotional development.

PMID- 15195353
TI  - Resistance of delayed-rectifier K+ current to cadmium in Drosophila neurons.
AB  - The delayed-rectifier potassium current (IKDR) is important in repolarizing the
      membrane potential and determining the level of neuronal excitability. We
      investigated the effect of cadmium on this potassium current. The whole-cell
      patch-clamp technique was used to measure IKDR from cultured Drosophila neurons
      derived from embryonic neuroblasts. The current was measured from neurons before
      and after the application of 0.1 mM cadmium to the external saline. IKDR was
      similar in the cadmium-containing saline (383 +/- 47 pA) and the control saline
      (401 +/- 60 pA). These results indicate that cadmium neurotoxicity does not
      specifically affect IKDR in Drosophila neurons.

PMID- 15195354
TI  - Serial position effects in HIV-infected injecting drug users.
AB  - This study examined memory and serial position effects in HIV-positive injecting
      drug users (IDUs), HIV-negative IDUs, and nondrug using control participants.
      Exploratory analyses investigating a possible mediating role of executive
      functions with HIV infection, drug use, and memory were also performed. Control
      participants showed stronger primacy effects than did both HIV-positive and HIV
      negative IDUs and also outperformed the drug using groups on all memory measures.
      Interestingly, analysis of the role of executive functions with HIV infection,
      drug use, and memory suggested that executive functioning may mediate the verbal
      memory deficits associated with HIV infection, but not those associated with IDU.

PMID- 15195355
TI  - Protection of blood-brain barrier breakdown by nifedipine in adrenaline-induced
      acute hypertension.
AB  - The question of whether influxes of ionic Ca+2 into cerebral endothelium plays an
      important role in increased vascular permeability consequent to an acute
      hypertension is not accurately resolved. We tested the effect of nifedipine, a
      calcium entry blocker, on the cerebrovascular permeability for proteins in
      adrenalin-induced acute hypertension. The experiments were carried out on male
      Wistar rats. The experimental groups consisted of normotensive saline controls,
      adrenaline-induced hypertensive rats, and adrenalin-induced hypertensive rats as
      pre-treated or post-treated with a bolus of nifedipine. Brains of hypertensive
      rats showed increased permeability to Evans Blue-Albumin complex, when blood
      pressure elevated rapidly to more than 170 mmHg. The number and size of areas of
      Evans-Blue extravasation were smaller if an increase in blood pressure was
      prevented. The short lasting elevation of blood pressure did not result in
      protein extravasation in brains of hypertensive rats. The results suggest that
      nifedipine can modify the permeability disruptions observed in acutely
      hypertensive rats. The data also support the hypothesis that Ca+2 may be
      responsible for the changes in permeability of BBB in hypertension by mediating
      the contraction of vascular muscles.

PMID- 15195357
TI  - Gender differences in event-related potentials during visual-spatial attention.
AB  - The aim of present work is to test possible gender differences in the ERPs to the
      standards during the performance of a visual-spatial attention task. The sample:
      20 subjects (10 women) aged 18-24. Electrodes: F3, F4, C3, C4, P3, P4, T5, T6,
      O1, O2. ANOVA tests were computed with the following factors: attention, gender,
      visual field, hemisphere, and electrodes. Results showed that men presented
      higher amplitudes in P1 and in P3b than did women, and women presented higher
      amplitudes in the temporal N1 than did men. For the P3, the amplitude in frontal
      central regions for the attended condition was higher in men than in women, and
      men presented a gender-specific right frontal functional asymmetry that was not
      present in women. Since these components are related with the modulation of
      visual processing by the effect of spatial attention, the intra- and inter-gender
      differences obtained suggest possible differences in the processing of visual
      information in both genders. However, the fact that the brain generators could
      have a different orientation is also a possible explanation for the differences
      obtained in the ERPs in both genders.

PMID- 15195356
TI  - Endocrine and immune effects of Qi-training.
AB  - Psychoneuroimmunological approaches have shown that Qi-training influences the
      holistic health state in men. We found that Qi-training increased the plasma
      level of growth hormone (GH) and insulin-like growth factor (IGF)-I. In addition,
      the respiratory function and adhesion capacity of neutrophil was increased after
      Qi-training. In an in vitro analysis, GH primed and increased the respiratory
      function and adhesion of neutrophils through tyrosin kinase passway. Taken
      together, in vivo and in vitro data suggest that the beneficial effects of Qi
      training on immunological functions are mediated via neuroendocrine responses.

PMID- 15195358
TI  - Influence of age on the interrelation between EEG frequency bands during NREM and
      REM sleep.
AB  - The age-dependence of temporal interrelations between distinct frequency bands of
      sleep EEG was investigated in a group of 59 healthy young and middle-aged males
      via cross correlation analysis. Based on global evaluation throughout the entire
      night, a highly significant decline of the delta/theta correlation with
      increasing age was found. A separate analysis for non-rapid eye movement (NREM)
      and rapid eye movement (REM) sleep revealed different changes with aging. During
      NREM sleep, the correlation between the delta and theta frequency bands decreased
      with increasing age. In contrast, during REM sleep, a stronger correlation became
      obvious between the theta, alpha, and beta frequency bands with increasing age,
      whereas the lower frequency components were not affected. These findings indicate
      that aging processes seem to interact with sleep EEG rhythms in a complex manner,
      where most conspicuous is a disintegration of the activities in the lower
      frequency range, both concerning the successive sleep cycles across the night and
      the micro-structure of NREM sleep.

PMID- 15195359
TI  - Morphometry of the eyes in regenerant of genus Dugesia (Platyhelminthes,
      Turbellaria, Dugesiidae).
AB  - The photodocumentation technique was used weekly to observe until the end of the
      regenerative process of eyes in three species of Dugesia. Morphometric data based
      on the measurement of 96 samples of the species: Dugesia tigrina, D. schubarti,
      and D. anderlani were analyzed. A comparative analysis was made through graphic
      representation of statistical parameters of the following morphometric
      characters: the length of the transversal and longitudinal axes of the macula
      alba, pigment spot, and ocular opening. An interesting feature appeared in D.
      schubarti: the average of ocular opening during the regenerative process is
      bigger than in the original samples.

PMID- 15195360
TI  - Longitudinal distribution of Copepoda populations in the transition zone of
      Paranapanema River and Jurumirim Reservoir (Sao Paulo, Brazil) and interchange
      with two lateral lakes.
AB  - Longitudinal changes in composition, abundance, and distribution of copepods were
      studied at the transition zone of Paranapanema River-Jurumirim Reservoir (SP,
      Brazil). The interchange of biotic material between marginal lakes and the river
      system was also examined. Water samples were obtained from 6 stations along a
      stretch of 13 km of the Paranapanema River, from an upstream reach with high
      water velocity up to the river mouth into Jurumirim Reservoir. Two other sites in
      lateral lakes were also sampled. Nine copepod taxa were identified: 3 calanoids
      (Argyrodiaptomus furcatus Sars, Notodiaptomus iheringi Wright, and N. conifer
      Sars) and 6 cyclopoids (Eucyclops Claus, Microcyclops Claus, Mesocyclops
      longisetus Thiebaud, Thermocyclops decipiens Fischer, T. minutus Lowndes, and
      Paracyclops Claus). Harpacticoids were also collected. Calanoid and cyclopoid
      nauplii and copepodids, and harpacticoids were the most abundant organisms. In
      general, there was a longitudinal decrease in copepod abundance, whereas an
      increase was detected near the lakes. The abundance of most copepods was
      inversely correlated with current velocity and suspended solids. Higher abundance
      was observed in the river main course during the rainy season, during which there
      is a higher connectivity between the lakes and the main river. This promotes
      exportation of biologic material from marginal lakes to the river system, a
      biotic exchange reflecting the importance of marginal lakes to the river
      community structure.

PMID- 15195361
TI  - Ultrastructure of the tegument of Metamicrocotyla macracantha (Alexander, 1954)
      Koratha, 1955 (Monogenea, Microcotylidae).
AB  - The ultrastructure of the body tegument of Metamicrocotyla macracantha
      (Alexander, 1954) Koratha, 1955, parasite of Mugil liza from Brazil, was studied
      by transmission electron microscopy. The body tegument is composed of an external
      syncytial layer, musculature, and an inner layer containing tegumental cells. The
      syncytium consists of a matrix containing three types of body inclusions and
      mitochondria. The musculature is constituted of several layers of longitudinal
      and circular muscle fibers. The tegumental cells present a well-developed
      nucleus, cytoplasm filled with ribosomes, rough endoplasmatic reticulum and
      mitochondria, and characteristic organelles of tegumental cells.

PMID- 15195362
TI  - Ground-dwelling ant fauna of sites with high levels of copper.
AB  - Richness and diversity of ant species are related to environmental factors such
      as vegetation, soil, presence of heavy metals, and insecticides, which allow the
      use of the assemblage members as terrestrial indicators of environmental
      conservation status. This study presents the results of ground ants surveyed in
      Minas do Camaqua in the municipality of Cacapava do Sul (Camaqua Basin), State of
      Rio Grande do Sul. Collections were performed in four sites, which high levels of
      copper in the soil, three of which--a mine, a liquid reject, and a solid reject-,
      had sparse or no plant cover, and one site where Pinus has been used for
      rehabilitation. Parque das Guaritas was the control site, since it presented
      normal levels of copper and a dense savanna cover. For each site, three transect
      lines extending 100 m were draw, and at each 10 m sardine baits were distributed;
      after two hours the ants present were collected. Hand collections in all five
      sites were performed during one hour (capture effort). A total of 51 species
      belonging to 17 genera were collected. The control site was the richest in ant
      species (r = 45). Sites with high level of copper and poor plant cover presented
      the lowest richness: mine (r = 14), solid reject (r = 15), and liquid reject (r =
      16). In contrast, the site planted with Pinus presented an increment in richness
      (r = 24) of ground-dwelling ants, suggesting a reahabilitation process.

PMID- 15195363
TI  - Anurans from a local assemblage in central Brazil: linking local processes with
      macroecological patterns.
AB  - Macroecological variables of Anuran species found in a local assemblage from
      Central Brazil (Silvania, Goias State) were linked to population dyamics
      statistics of these species. Geographical range size (GRS), body size, and
      species' midpoints were the macroecological variables investigated for those
      species found in the local assemblage and for all other species (105 in the
      total) found in the Cerrado biome. For each species found in the local
      assemblage, data on abundance was obtained. Using this data, local population
      variability as expressed by the coefficient of variation was estimated.
      Distribution of means, medians, maximum, variances, and skewness (g1), for both
      GRS and body size, estimated in the local assemblage were compared, using null
      models, with the data extracted from the overall Cerrado species pool. The
      results indicated a clear macroecological relationship between GRS and body size
      and a decrease in local abundance when distance between the locality analyzed and
      species midpoint increased. According to null models, both body size and GRS
      values measured in the local assemblage can be considered a random sample from
      the regional species pool (Cerrado region). Finally, a three-dimensional analysis
      using body size, GRS, and local population estimates (abundance and variability),
      indicated that less abundant and more fluctuating species fell near the lower
      boundary of the polygonal relationship between GRS and body size. Thus,
      macroecological results linked with local data on population dynamics supported
      the minimum viable population model.

PMID- 15195364
TI  - Morphological abnormalities in the cladoceran Ilyocryptus spinifer (Apipucos
      Reservoir, Pernambuco State, Brazil).
AB  - In a sample taken from Apipucos Reservoir (Recife, PE, Brazil) for taxonomic
      study, a high percentage (40%) was found of cladoceran Ilyocryptus spinifer
      individuals with morphological abnormalities on their postabdomen. There was not
      a fixed pattern of the malformations, which varied in gravity, and could affect
      the postanal spines or terminal claws. The postabdominal abnormalities are
      described and compared to the ones described in the literature. The hypothesis of
      the morphological abnormalities being induced by an occasional environmental
      toxicant is discussed.

PMID- 15195365
TI  - Oribatid mite (Acari: Oribatida) contribution to decomposition dynamic of leaf
      litter in primary forest, second growth, and polyculture in the Central Amazon.
AB  - We studied the contribution of oribatid mites in the dynamics of litter
      decomposition in an experiment using litterbags of three different mesh sizes (20
      microns, 250 microns, and 1 cm). The experiment was carried out at a primary
      forest (FLO), a secondary forest (SEC), and at two polyculture systems (POA and
      POC). We compared the weight loss of the leaves of Vismia guianensis and the
      changes of the oribatid mite species community. We processed the samples after
      26, 58, 111, 174, 278, and 350 days from the beginning of the experiment by using
      the Berlese-Tullgren to extract the animals. We hypothesized that: 1. the
      abundance and diversity of oribatid mites would exert an influence in the
      decomposition process; 2. there would be a successional changing of the species
      during decomposition; and 3. there would be differences in the colonization of
      species in relation to the mesh size of the litterbags. A total of 95 species of
      oribatid mites was found. The biomass data was the first registered for the
      Amazon region. The great dominance of oribatid mites did not exert an influence
      in the decomposition process. There was not a successional changing of the
      species during the course of the decomposition process, unlike those shown by
      results obtained in the temperate forest, because we found neither early
      colonizers nor species that prefer advanced decomposition stages. The oribatid
      mite community, which developed in the litterbags under tropical conditions, was
      atypical of the normal stages of leaf litter breakdown and decomposition. There
      were differences in the colonization of species in relation to the mesh size of
      the litterbags. These differences were very closely related to the specific
      habits and habitat of the dominant species.

PMID- 15195367
TI  - Phytoplankton nyctemeral variation at a tropical river estuary (Itamaraca
      Pernambuco-Brazil).
AB  - The Botafogo estuary is of socio-economical importance for Pernambuco State. It
      is located at the north of Santa Cruz Channel, Itamaraca, Pernambuco, Brazil (07
      degrees 42' 50 "S and 34 degrees 52' 10" W). There is a critical need to
      understand its functioning because of the rate at which this area is being
      converted to land uses. The phytoplankton dynamics was studied to enhance the
      knowledge of and verify the possible changes which have occurred in this
      ecosystem. Sampling was carried out with a plankton net 65 micrometers mesh size
      for qualitative data, and a Van Dorn bottle for quantitative data. Concurrent
      hydrological and chlorophyll-a data were collected. Samplings were made in one
      fixed station in July 1996 (rainy season) and December 1996 (dry season), at 3
      hour intervals during 24 hours. Eighty-seven specific and infra-specific taxa
      were identified from net plankton samples. Diatoms were most frequent, mainly
      Coscinodiscus centralis and Odontella regia in the rainy and dry seasons,
      respectively. Phytoplankton density varied from 205,000 to 1,210,000 cell.L-1 in
      the dry season, and from 230,000 to 2,510,000 cell.L-1 in the rainy season,
      indicating eutrophic conditions. Most numerically abundant were the diatoms
      Cyclotella meneghiniana and Cylindrotheca closterium and the phytoflagellates.
      The ecosystem is polluted, and deleterious effects are minimized by the marine
      influence which allows periodic water renewal.

PMID- 15195366
TI  - Induction of oocyte maturation in the white croaker Micropogonias furnieri
      (Pisces: Sciaenidae) by human chorionic gonadotropin.
AB  - The present work aimed to identify the best doses of human chorionic gonadotropin
      (hCG) needed to induce oocyte maturation of Micropogonias furnieri and to
      characterize ovarian dynamics during the periovulatory period. Adult M. furnieri
      females with fully developed ovaries were injected intraperitoneally with four
      different doses of hCG. The gonadotropin response was succeeded by analyzing
      morphologically gonadal biopsies and following the postinjection changes in
      follicle diameter. Oocyte maturation was induced by three doses used: 100, 300,
      and 500 IU of hCG kg bw-1, and was reached 48 h after treatment with 300 and 500
      IU of hCG kg bw-1, and 72 h after treatment with 100 IU of hCG kg bw-1.
      Concerning ovarian dynamics, only 100 and 300 IU of hCG kg bw-1 mimicked the
      natural ones which have a synchronic group maturation. In conclusion, the dose
      mimicking natural ovarian dynamics and inducing oocyte maturation more quickly is
      300 IU of hCG kg bw-1.

PMID- 15195368
TI  - Biochemical responses of two erythrinidae fish to environmental ammonia.
AB  - The non-ionized form of ammonia is very toxic to many aquatic species. It is
      especially important in several aspects of fish biology. A large range of
      organismal strategies for coping with environmental stressors is usually observed
      in living organisms. Among those, the responses for managing chemical stressors
      are well studied. The present work compares biochemical responses of two
      evolutionarily close species, Hoplias malabaricus and Hoplerythrinus
      unitaeniatus, exposed to environmental ammonia. Adult fish were submitted to 1.0
      mg/L of ammonium chloride for 24 hours, and plasma ammonia and urea levels were
      determined. The activities of OUC enzymes OCT and ARG, and the accessory enzyme
      GS, were quantified in liver extract and are expressed below in mumol/min/mg of
      wet tissue. Increases in OUC enzymes (GS from 1.14 to 2.43, OCT from 0.81 to
      1.72, and ARG from 3.15 to 4.23), plasma ammonia (from 0.95 to 1.42 mmol/L), and
      plasma urea (from 0.82 to 1.53 mmol/L) were observed (p < 0.05) in H. malabaricus
      exposed to 1 mg/L of ammonia chloride. The GS in H. unitaeniatus increased from
      1.43 to 1.84, however the OCT, ARG, and plasma urea from H. unitaeniatus did not
      change. These data indicate that each species responds differently to the same
      environmental stressor.

PMID- 15195369
TI  - Spatial distribution of chromium and lead in the benthic environment of coastal
      areas of the Rio De La Plata estuary (Montevideo, Uruguay).
AB  - Twenty-four sediment samples were collected seasonally during one year from the
      partially closed Montevideo Bay and the adjacent coastal zone, in Uruguay, in
      order to determine the impact of chromium and lead in the sediments. Analysis of
      related environmental variables included bottom water temperature, salinity, pH,
      dissolved oxygen, and several sedimentological variables such as redox potential
      and total organic matter. Concentrations and range of variation of these two
      metals were similar to those found in urbanized and industrialized estuarine
      environments. Metal enrichment is higher in the bay than in the adjacent coastal
      zone, however an important increase especially in Pb content was detected in an
      area previously considered as a pristine one. Considering both metal content and
      benthic environment characteristics, the study area can be clearly divided in at
      least two well-defined regions. One is the inner region of the bay near the
      streams, and the outermost stations of the bay and the adjacent coastal zone form
      the other. The first one can be considered highly polluted and the other
      moderately polluted. The values of the metals studied indicated that adverse
      biological effects are probably occurring, specially in the innermost region of
      Montevideo Bay.

PMID- 15195370
TI  - Diet shifts related to body size of the pirambeba Serrasalmus brandtii Lutken,
      1875 (Osteichthyes, Serrasalminae) in the Cajuru Reservoir, Sao Francisco River
      Basin, Brazil.
AB  - This study aimed to identify shifts in the Serrasalmus brandtii Lutken, 1875 diet
      related to body size. Specimens were collected from April 1992 to January 1993 at
      the Cajuru Reservoir, in the Para River, Sao Francisco River Basin, by seining
      the shore with nets of nylon, 1 mm opening, and with gill nets. Stomach contents
      of 152 individuals measuring 15-192 mm SL were examined. Food items were
      identified and weighed separately. For qualitative analysis, the frequency of
      occurrence method was used. The relative importance of each food component was
      determined based on the alimentary index (IAi). The frequencies of occurrence
      data were subjected to cluster analysis using the Canberra coefficient of
      dissimilarity and UPGMA as the cluster method. Distinctive gradual changes in
      food habits, associated with body size, were identified in this species. The
      smaller individuals fed predominantly on microcrustaceans and insect larvae. The
      intermediate size classes ingested insects, fish fins, fish scales, and chunks of
      fish flesh, in this order of importance. For the larger pirambebas, fish was the
      most abundant food category identified, followed by insects.

PMID- 15195371
TI  - Age and growth of the duckbill catfish (Sorubim cf. lima) in the Pantanal.
AB  - The Duckbill Catfish, Sorubim lima, is a predator of large South American rivers.
      The age and growth of S. lima were studied based on the pectoral fin-spines of
      samples collected from the Cuiaba River, Pantanal. The samples were taken from
      commercial and experimental hook-and-line fishing. An analysis of the marginal
      increment suggests that the growth rings are formed once a year during the dry
      season, from July to September (ANOVA type I: F = 4.183; g.l. = 3 and 104; p =
      0.008). The estimate of the parameters that describe von Bertalanffy's growth
      curve by nonlinear regression of the observed lengths in the age were: L infinity
      = 56.0 cm (fork length); k = 0.245 year-1; to = -2.605 years. The animals were
      estimated to have a life span of 9.6 years. The findings indicate that the fork
      length is a good predictor of the age of individuals of this fish species.

PMID- 15195372
TI  - Diet of the lizard Mabuya agilis (Sauria; Scincidae) in an insular habitat (Ilha
      Grande, RJ, Brazil).
AB  - We examined the stomach contents of 21 specimens of Mabuya agilis (Sauria;
      Scincidae) collected during February 2001 at the restinga habitat of Praia do
      Sul, in Ilha Grande, RJ, Brazil. Diet was composed of various types of small
      arthropods, with no plant material being eaten. Spiders were the most important
      items in the diet, followed by orthopterans. Apart from the absence of
      isopterans, the diet of Mabuya agilis from this insular area was similar to those
      of other conspecific mainland populations. This suggests that factors such as
      insularity and the absence of other small sympatric lizards may not have a
      significant effect on the feeding habits of the Praia do Sul population.

PMID- 15195373
TI  - Periphytic desmids in Corumba Reservoir, Goias, Brazil: genus Cosmarium Corda.
AB  - With the objective of investigating the taxa of Cosmarium, four collection
      stations along the Corumba Reservoir were set up. This resulted in the first work
      done on the genus in the State of Goias. The collections of the material, of the
      epilithon type, were carried out in July 1996 and in the period between December
      1996 and July 1997. The samples were preserved with 0.5% acetic lugol. The
      qualitative analysis was done by optical microscopic on non-permanent slides.
      Twenty-one taxa of the Cosmarium were described, each one illustrated by means of
      a camera lucida attachment.

PMID- 15195374
TI  - Ecological correlates of polyphenism and gregarious roosting in the grass yellow
      butterfly Eurema elathea (Pieridae).
AB  - Eurema elathea adults were census weekly (1992-1994) in six night-roosts around a
      forest fragment on a farm, and in two roosts in the urban area of Uberlandia,
      Minas Gerais, Brazil. Males were grouped in six phenotypic classes. These were
      based on a range between having a conspicuous wide black bar at the dorsal
      forewing inner margin (wet season dark morphs) and the absence of that bar (dry
      season light morphs). The body mass and wing area of co-occurring morphs were
      compared: differents morphs showed similar means. The abundance of butterflies
      and morph frequencies varied in close relation to humidity (rainfall).
      Individuals were infrequent and monomorphically dark in the wet season while
      light morphs predominated in dry periods when population peaked. A lower fraction
      of recaptured individuals and higher recruitment were recorded compared to other
      night-roosting butterflies. Dispersal potential was similar between the sexes and
      varied seasonally with a more sedentary population in dry periods. The maximum
      residence time recorded was 91 days for a female and 84 days for a male. The
      fraction of individuals that moved from one roosting site to another was similar
      in both sexes and male morphs, but significantly higher on the farm than in the
      urban area. Also, a significantly higher fraction (21.3%) of marked butterflies
      was recaptured in the urban area than on the farm (15.6%), suggesting a
      behavioral modification for sedentariness in the urban individuals. The selective
      forces shaping a gregarious roosting habit in E. elathea and other butterflies
      are discussed and a protocooperational strategy for saving energy is proposed.

PMID- 15195375
TI  - Chirocentrodon bleekerianus (Teleostei: Clupeiformes: Pristigasteridae), a small
      predaceous herring with folded and distinctively oriented prey in stomach.
AB  - Predaceous fish-eating species of the order Clupeiformes have a large mouth with
      well-developed teeth, and reach the greatest sizes within their families (up to
      90 cm). We found that the pristigasterid Chirocentrodon bleekerianus, a small
      clupeiform (about 10 cm) from the tropical SW Atlantic, is able to prey on
      proportionally large clupeoid fishes and caridean shrimps. Fish preys are folded
      in the stomach of this herring, their heads and tails pointing toward the
      predator's head. This distinctive orientation of fish prey is also recorded for
      some small to medium-sized, fish-eating species of the tropical freshwater order
      Characiformes with canine-like teeth similar to those found in C. bleekerianus.

PMID- 15195376
TI  - Community ecology of the metazoan parasites of white sea catfish, Netuma barba
      (Osteichthyes: Ariidae), from the coastal zone of the state of Rio De Janeiro,
      Brazil.
AB  - Between March 2000 and April 2001, 63 specimens of N. barba from Angra dos Reis,
      coastal zone of the State of Rio de Janeiro (23 degrees 0' S, 44 degrees 19' W),
      Brazil, were necropsied to study their infracommunities of metazoan parasites.
      Fifteen species of metazoan parasites were collected: 2 digeneans, 1 monogenean,
      2 cestodes, 1 acantocephalan, 2 nematodes, 6 copepods, and 1 hirudinean. Ninety
      six percent of the catfishes were parasitized by at least one metazoan parasite
      species. A total of 646 individual parasites was collected, with mean of 10.3 +/-
      16.6 parasites/fish. The copepods were 37.5% of the total parasite specimens
      collected. Lepeophtheirus monacanthus was the most dominant species and the only
      species with abundance positively correlated with the host total length. Host sex
      did not influence parasite prevalence or mean abundance of any species. The mean
      diversity in the infracommunities of N. barba was H = 0.130 +/- 0.115 with no
      correlation with host's total length and without differences in relation to sex
      of the host. One pair of endoparasites (Dinosoma clupeola and Pseudoacanthostomum
      floridensis) showed positive association and covariation between their abundances
      and prevalences. The parasite community of N. barba from Rio de Janeiro can be
      defined as a complex of species with low prevalence and abundance and with
      scarcity of interspecific associations. However, because of both the presence of
      assemblages of sympatric ariid species as well as the spawning behavior
      characteristic of these fishes, additional comparative studies of the parasite
      component communities of ariids are necessaries to elucidate this pattern.

PMID- 15195378
TI  - Packing a punch on staff safety.

PMID- 15195377
TI  - The response of Carlos Botelho (Lobo, Broa) Reservoir to the passage of cold
      fronts as reflected by physical, chemical, and biological variables.
AB  - This paper describes and discusses the impacts of the passage of cold fronts on
      the vertical structure of the Carlos Botelho (Lobo-Broa) Reservoir as
      demonstrated by changes in physical, chemical, and biological variables. The data
      were obtained with a continuous system measuring 9 variables in vertical profiles
      in the deepest point of the reservoir (12 m) coupled with climatological
      information and satellite images, during a 32-day period in July and August,
      2003. During periods of incidence of cold fronts the reservoir presented vertical
      mixing. After the dissipation of the cold fronts a period of stability followed
      with thermal, chemical, and biological (chlorophyll-a) stratification.
      Climatological data obtained during the cold front passage showed lower air
      temperature, higher wind speed and lower solar radiation. The response of this
      reservoir can exemplify a generalized process in all shallow reservoirs in the
      Southeast Brazil and could have several implications for management, particularly
      in relation to the phytoplankton population dynamics and development of
      cyanobacterial blooms. Using this as a basis, a predictive model will be
      developed with the aim of advancing management strategies specially for the
      drinking water reservoirs of the Metropolitan Region of Sao Paulo.

PMID- 15195379
TI  - The HSJ interview: Victor Adebowale. Marginal points. Interview by Nick Edwards.

PMID- 15195380
TI  - Data briefing. Mortality rates.

PMID- 15195381
TI  - Clinical management. Where medicine meets management. Acute accent.
AB  - There is urgent need for reform in the care of acutely ill medical patients.
      Problems are being compounded by rising admissions, the reduction in junior
      doctors' hours and changes in training. Care should be delivered in acute medical
      or assessment units by dedicated teams specialising in acute care, according to a
      new report by the Royal College of Physicians.

PMID- 15195382
TI  - Effective boards. Born & bred.
AB  - If a board is to be effective its members must understand their roles and share
      trust with their colleagues. Members must be prepared to challenge colleagues,
      conventions and their own assumptions. Individual responsibility dissolves in
      large groups. Successful boards avoid this phenomenon.

PMID- 15195383
TI  - Mental health. Death defying.

PMID- 15195384
TI  - HSJ people. Young professionals.

PMID- 15195385
TI  - Diving for dead wood.

PMID- 15195387
TI  - Space. Eye on the junk.

PMID- 15195386
TI  - Homo carnivorous.

PMID- 15195388
TI  - Neuroscience. Sitcoms on the brain.

PMID- 15195389
TI  - Energy. Power-thrifty PCs.

PMID- 15195391
TI  - A confederacy of smarts. Can Microsoft's assemblage of all-star researchers
      transform computing?

PMID- 15195390
TI  - Entomology. The 17-year itch.

PMID- 15195393
TI  - Deep silence.

PMID- 15195392
TI  - A transparent enigma.

PMID- 15195394
TI  - Saturn at last!

PMID- 15195395
TI  - Nanotechnology and the double helix.

PMID- 15195397
TI  - Smart sensors to network the world.

PMID- 15195396
TI  - Lessons from the wolf.

PMID- 15195399
TI  - Nuclear explosions in orbit.

PMID- 15195398
TI  - The stem cell challenge.

PMID- 15195400
TI  - Hospitalists and case managers team up for better outcomes.

PMID- 15195401
TI  - Six Sigma improves care, reduces hospitals' costs.

PMID- 15195402
TI  - What to do if physicians dispute your data.

PMID- 15195403
TI  - Physician buy-in helps PI team reduce LOS.

PMID- 15195404
TI  - Pneumonia guidelines will affect 750,000 ED patients.

PMID- 15195405
TI  - A billing analyst can find $300,000 for your ED.

PMID- 15195406
TI  - Advocacy may be a balancing act for CMs.

PMID- 15195407
TI  - Drainage basin security--balancing production, trade and water use. Preface.

PMID- 15195408
TI  - Drainage basin security--a key to reaching the water-related millennium
      development goals.

PMID- 15195409
TI  - Water governance, poverty reduction and sustainable development.

PMID- 15195410
TI  - Fitting the pieces together from the United Nations perspective.

PMID- 15195411
TI  - Applying sustainable water management concepts in rural and urban areas: some
      thoughts about reasons, means and needs.
AB  - Serving the world population with adequate drinking water and sanitation is an
      important prerequisite, not only to hygienic safety, but to prosperity and
      political stability as well, and will foster the adaptive capacity of the
      societies in the developing countries and beyond. To avoid hygienic and political
      disasters impacting the world economy, investment in water supply and sanitation
      must urgently be made. Whether the classical system of urban water supply and
      sanitation is appropriate to satisfy the needs of the developing world, however,
      and whether this system meets the general criteria of sustainability is
      questionable. The costs and the time needed for installation of sewers and
      wastewater treatment plants are tremendous. In water shortage areas, the amount
      of tap water required to transport pollutants to the treatment plant is hardly
      affordable. Recovery and re-introduction of valuable substances, including water,
      into the urban cycle of materials is impossible because of mixing and dilution
      effects inherent in the system. Decentralized water and wastewater management
      should be seriously taken into account as an alternative. Source separation of
      specific fractions of domestic and industrial wastewater, separate treatment of
      these fractions and recovery of water and raw materials including fertilizer and
      energy are the main characteristics of modern high-tech on-site treatment/reuse
      systems. Mass production of the key components of the system could reduce the
      costs of the treatment units to a reasonable level. On-site units could be
      installed independently of the development stage of the urban sewer system. In
      conjunction with building new housing complexes a stepwise improvement of the
      hygienic situation in urban and peri-urban areas could be achieved, therefore.
      Remote control of the satellite systems using modern telecommunication methods
      would allow reliable operation, and comfort for the users. Intensive research is
      required, however, to develop this system and bring it to a standard allowing
      efficient application worldwide.

PMID- 15195412
TI  - Water and climate variability: development impacts and coping strategies.
AB  - This paper provides an overview of the relationship between climate variability,
      integrated water resources management, and the achievement of the Millennium
      Development Goals. It focuses on tropical countries and the impacts of climate
      variability on the ability of such countries to achieve the MDGs; examines the
      coping strategies that must be put in place to address these challenges; and
      makes recommendations on steps forward.

PMID- 15195413
TI  - Virtual water flows and trade liberalization.
AB  - The linkages between agricultural trade and water resources need to be identified
      and analyzed to better understand the potential impacts that a full
      liberalization, or lack thereof, will have on water resources. This paper
      examines trade of virtual water embodied in agricultural products for most
      countries of the world. The main purpose of the paper, however, is to examine the
      impact of trade liberalization on virtual-water trade in the future. Based on a
      simulation of global agricultural trade, a scenario of full liberalization of
      agriculture was used to assess the net effect of virtual water flows from the
      relocation of meat and cereals' trade. The paper also identifies the main reasons
      behind the changes in the magnitude and direction of the net virtual water trade
      over time, and shows that virtual water trade flows are independent of water
      resource endowments, contrary to what the Heckscher-Ohlin Theorem states.
      Finally, based on a formal model, some input demand functions at the country
      level are estimated. The estimates of the income and agricultural support
      elasticities of demand for import of virtual water have the expected sign, and
      are statistically significant. Variables found to have some explanatory power of
      the variance of virtual water imports are average income; population; agriculture
      as value added; irrigated area, and exports of goods and services.

PMID- 15195414
TI  - The use of modelling and reuse techniques in the development of water management
      systems in basins with limited water resources.
AB  - Drawing on experiences in New South Wales from 1950 to 1980 in modeling and re
      use techniques in the development of desalination technology and its application
      in fresh water production for potable use, the paper describes how Australia
      realized its responsibilities in developing participative and sustainable
      approaches to land use and water resources management. An analysis of the lessons
      from the operation of the Bayswater zero-discharge power station significantly
      contributed to the debate on sustainable approaches, highlighting that no
      management policy of a water basin can be implemented without a model based on
      reliable data from all sectors (including the environment), and no management
      model can be implemented without the participation of all stakeholders. These
      ideals were reflected in the conception and establishment of the Murray-Darling
      Basin Commission. The Commission succeeded in bringing together all major
      stakeholders in this huge basin, though it took more than 15 years to do so.
      While widely recognized as one of the most advanced and successful experiences in
      integrated management of a drainage basin, it has still not achieved the reversal
      of many unsustainable agricultural practices, giving a clear indication of the
      difficulties and time required for producing sustainable solutions.

PMID- 15195415
TI  - Forests and water--closing the gap between public and science perceptions.
AB  - The public perception that forests are, in all circumstances, necessarily good
      for the water environment, that they increase rainfall, increase runoff, regulate
      flows, reduce erosion, reduce floods, "sterilize" water supplies and improve
      water quality, has long been questioned by the scientific community. The evolving
      "modern" science perception suggests a more complex and generally less
      advantageous view of forests. It is suggested that the disparity between the two
      perceptions needs to be addressed before we are in a position to devise and
      develop land and water policies which are aimed at either improving the water
      environment, and by doing so improving the livelihoods of poor people by greater
      access to water, or conserving and protecting forests. Examples are given of
      "interactive" research projects in different parts of the world including the UK,
      South Africa, Panama and India where, through the involvement of stakeholder
      groups, often with representatives comprising both the science and public
      perceptions, research programmes have been designed and are being implemented,
      not only to derive new research findings with regard to the biophysical
      processes, but also to achieve better "ownership" and acceptance of these
      research findings by the stakeholder groups.

PMID- 15195416
TI  - Effective subsidies in developing countries.
AB  - During the last decades, significant subsidies have been allocated to government
      owned water and sewerage enterprises in developing countries. However, water and
      sewerage coverage is still far from desirable and the poor are particularly
      affected by the shortage of these services. The truth is that a considerable part
      of these subsidies have been used up to build huge infrastructure works that
      would make some construction firms happy, while often decreasing the service
      costs for the richer. The costs associated of delivering water and sanitation
      services to the poor are significantly higher, as they often live in slums or
      irregular urban developments without urban infrastructure. It is possible, and
      desirable, to improve government's effectiveness through the use of appropriate
      economic incentives. The Brazilian River Basin Pollution Abatement Program, based
      on the "output-based aid" concept, is a good example of how this can be achieved.
      The Program is a success story that shows that the quality of expenditures on
      sanitation can be considerably improved if governments of developing countries
      refrain from contracting sanitation infrastructure works and start paying for
      results, not for promises.

PMID- 15195417
TI  - Growing controversy over "wise international water governance".
AB  - This article takes the perspective that when political relationships are
      strained, there seem to be few examples of wise international water resources
      governance. The Middle East is a striking example. Much effort has been put into
      policy development and the design of international principles, but very little
      into the translation of those into concrete and lasting governance. One of the
      theses of the article is that politics--whether domestic or international--in
      most cases overrides these principles and standards. Moreover readymade regional
      co-operation models of water managements are not directly applicable to every
      geographical, political, economic and social setting. Certain factors are often
      under-estimated in international water negotiations, such as: the complexity of
      any hydro-political negotiations, and need to develop commonly accepted
      standards; the difficulty of translating policy--either politically or legally-
      into an operational and realistic negotiations strategy; the format of the
      procedures and meetings; recognition that third parties should have a long-term
      perspective on any conflict they get involved in. With reservations, the lessons
      learned indicate that the following factors have an impact on grid locked
      situations, such as: new substantive information; new trade-offs between the
      parties; and changed political climate or relationship with external power
      brokers.

PMID- 15195418
TI  - Meeting everyday water needs--a company's contribution.
AB  - As a packaged consumer goods company serving mass markets around the world for
      household and personal hygiene products, laundry detergents and foods, Unilever's
      business is inextricably linked with consumers' interest in meeting their
      everyday water needs. Once the basic need for drinking water is met, almost all
      other "everyday" water needs derive from consumption associated with the type of
      products Unilever sells. Use of some of these products, such as basic toilet
      soap, involve "actual" water consumption; others, such as margarine, concern
      "virtual" water consumption through agricultural production. Global scenarios for
      water and sanitation present a major challenge to long-term business strategies
      that assume sustained economic growth particularly in emerging and developing
      markets. Responsibility for finding and delivering solutions lies with all major
      actors in society. For companies such as Unilever, a priority is to help break
      the link between economic development on the one hand, and increased water use
      and water degradation on the other. Water catchment level perspectives are
      central to realising this vision. Unilever uses such a framework, building an
      experience-based model that demonstrates how a "consumer" company can engage in
      meeting everyday water needs with a sustained positive impact.

PMID- 15195419
TI  - The global change of continental aquatic systems: dominant impacts of human
      activities.
AB  - Continental aquatic systems, particularly rivers, are exposed to major changes
      due to human pressures. Some changes are voluntary such as flow regulation and
      the fragmentation of river courses, both due to damming, or the water consumption
      particularly in dry regions, which results in a partial to complete dry-up of
      some rivers (neo-arheism). Other changes result from indirect impacts of other
      human activities, and include: sediment unbalance of river systems, chemical
      contamination, acidification, eutrophication, thermal unbalance, radioactive
      contamination, microbial contamination, and aquatic species
      introduction/invasion. These changes can be regarded as syndromes which have now
      reached a global amplitude, even in less populated regions, as the result of
      damning, mining and of long-range atmospheric pollution, thus defining a new era,
      the Anthropocene, where continental aquatic systems are no longer controlled by
      earth systems processes but by human activities. Each region of the globe has
      developed specific patterns of syndromes trajectories that can be reconstructed
      from historical analysis and through environmental archives. These trajectories
      reveal multiple types of human responses to aquatic environmental issues (e.g.
      water quality), usually lasting 10 to 50 years for the successful ones. The
      reactions of the earth system to such major changes of fluxes (water, energy,
      nutrients, carbon, pollutants) via the continental waterscape, the land-ocean
      interactions, the water bodies-atmosphere interactions, are likely to take place
      over a longer time scale (100-1,000 years) yet are poorly addressed by scientists
      and not considered in Integrated Water Management, particularly as concerns the
      coastal zone.

PMID- 15195420
TI  - Workshop 1 (synthesis): multipurpose stream management strategies.
AB  - For a meaningful dialogue on balancing water uses between stakeholders in a river
      basin, adequate information and proper understanding, knowledge and access to
      reliable data are essential for all parties. Technological and economic
      components in water resources management have limited significance without the
      social context, and the legal framework plays a key role in the dialogue between
      stakeholders at all levels. Other aspects that fit into strategic planning and
      management of water resources projects are risk assessment, ecosystem
      requirements, credibility and trust building.

PMID- 15195421
TI  - Strategies to manage stream flow to benefit people and nature: a non-government
      conservation organisation's perspective.
AB  - More than for any other biome, freshwater biodiversity is increasingly imperiled,
      particularly due to poor stream flow management and increasing demand for water
      diversions. The adoption by the world's governments of targets to extend water
      services to the poor and at the same time to conserve biodiversity increase the
      need to better direct investments in freshwater management. In this paper WWF
      draws on examples from its work to identify areas where investment can be focused
      to assure efficient water use and improve stream flow management, namely:
      Prioritize and target those river basins and sub-catchments that are most
      critical for conservation of freshwater biodiversity to maintain stream flows;
      Link strategic field, policy and market interventions at different scales in
      river basins to maximize the impact of interventions; Implement the World
      Commission on Dams guidelines to minimize investment in large scale and costly
      infrastructure projects; Apply market mechanisms and incentives for more
      sustainable production of the world's most water consuming crops Enhance
      statutory river basin management organizations to draw on their regulatory and
      financial powers; Implement international agreements, such as the Convention on
      Wetlands; Integrate environment and development policies.

PMID- 15195422
TI  - What role for law in achieving transboundary drainage basin security?--the
      development and testing of the Legal Assessment Model (LAM) for transboundary
      watercourse states.
AB  - The beneficial use of the world's transboundary waters raises difficult issues
      for drainage basin security on most parts of the globe. International law
      provides that each transboundary watercourse State is entitled to, and obliged to
      ensure, an "equitable and reasonable use" of these shared waters. The IWLRI
      developed and tested a Legal Assessment Model (LAM) through the work of
      interdisciplinary teams working in three different transboundary situations-
      China (upstream), Mozambique (downstream) and Palestine (shared groundwater). The
      LAM provides a tool for transboundary watercourse States to use in the
      preparation of their national water strategy for use at the national and
      international levels. The model should now be tested at the basin level, with a
      view to assisting to accomplish the peaceful and rational use of transboundary
      waters in line with the governing rule of international law and thereby to
      facilitate the overall policy objective of drainage basin security.

PMID- 15195423
TI  - Workshop 2a (synthesis): linking drainage basin management to local action plans
      and policy.
AB  - The complexity of linking drainage basin management to local action plans and
      policy has been largely underestimated by the water profession. Water management
      issues may be similar between areas but solutions are not universal--they must be
      specific to each local context. A particular problem is that a drainage basin is
      likely to cover a number of administrative and/or political boundaries.

PMID- 15195424
TI  - Drainage basin management, local action plans and national policy: the
      perspective of the European Framework Directive.
AB  - The EC Water Framework Directive requires that all Member States achieve "good
      water status" by 2015 for both surface water and groundwater. The procedures by
      which Sweden intends to implement the Framework Directive are described and
      involve the establishment of five water districts, each with a water authority;
      local cooperative bodies based on the main river basin areas; cooperative
      associations for water conservation; introduction of a system of charges for
      water conservation; and assigning responsibility for supervision of contingency
      measures to the water authorities.

PMID- 15195425
TI  - Relevance and application of the EU Water Directive in terms of Spain's National
      Hydrological Plan.
AB  - The National Hydrological Plan Act was passed after the publishing of Community
      Directive 2000/60/EC. Officially, the Act has taken the existence of the
      Directive into account, but its handling of the regulation of the Ebro transfer
      ignores fundamental issues of the Directive, in that it does not envisage the
      principle of cost recovery, does not clearly determine the uses to which the
      transferred waters will be put, and it is not orientated towards sustainable
      development. Furthermore, Spanish public contract law is not in line with
      Community Law, and this may have repercussions in the practical aspect of
      possible European subsidies for carrying out the transfer.

PMID- 15195426
TI  - On risky ground: the water professional in politics.
AB  - Best practice in drainage basin management requires consultation and stakeholder
      engagement in the formulation and implementation of plans. The water management
      professional, engaging with the political world, is on risky ground, thanks to
      many stakeholders' accidental or chosen unwillingness to accept science-based
      advice. Technical specialists produce good advice, yet progress is inhibited
      because they do not connect effectively with politicians, administrators and
      managers. A series of short case studies from three countries in different but
      related fields provides evidence of the problems that are encountered.
      Professionals may be cut off from the political world within comfort zones
      defined by the cultural norms and behaviours of bureaucracy, their profession or
      their preferred communications style. The consequence of the professionals' lack
      of engagement in the political world can be that scarce money and effort is
      wasted on low priority issues, and the case for sound, sustainable environmental
      management is discredited. Stakeholder support is worth winning, because it can
      bring positive benefits in the effectiveness of environmental management
      programmes. Where outside help is needed to bring about this result, it should be
      provided by advisers who are sensitive to the culture, at the national,
      professional and organizational level, of the recipients.

PMID- 15195427
TI  - Workshop 2b (synthesis): linking drainage basin management to local action plans
      and national security--theory and practice in eastern European countries.
AB  - Efforts to link and balance national water policies, local water action and
      national security issues are discussed. There needs to be greater clarity of
      water roles, rights and responsibilities among national stakeholders as well as
      between states. In some cases, insufficient attention has been paid to local
      concerns and, in balancing national and local actions, it is necessary to address
      decentralization in the context of a transboundary state. There is a strong need
      for enhanced stakeholder participation in the formulation and implementation of
      national and local water management plans.

PMID- 15195428
TI  - Workshop 3 (synthesis): climate variability, water systems and management
      options.
AB  - Addressing climate variability now will better prepare us for future impacts of
      climate change. Sustained, multi-stakeholder dialogue at local through national
      levels is an approach that will reach the widest audience, helped by tools that
      illustrate vulnerability such as the Climate Vulnerability Index. Integrated
      water resources management deals with managing for variability and change and is
      therefore highly appropriate for dealing with climate impacts.

PMID- 15195429
TI  - Multi-decadal climate variability, New South Wales, Australia.
AB  - Traditional hydrological risk estimation has treated the observations of hydro
      climatological extremes as being independent and identically distributed,
      implying a static climate risk. However, recent research has highlighted the
      persistence of multi-decadal epochs of distinct climate states across New South
      Wales (NSW), Australia. Climatological studies have also revealed multi-decadal
      variability in the magnitude and frequency of El Nino/Southern Oscillation (ENSO)
      impacts. In this paper, examples of multi-decadal variability are presented with
      regard to flood and drought risk. The causal mechanisms for the observed
      variability are then explored. Finally, it is argued that the insights into
      climate variability provide (a) useful lead time for forecasting seasonal
      hydrological risk, (b) a strong rationale for a new framework for hydrological
      design and (c) a strong example of natural climate variability for use in the
      testing of General Circulation Models of climate change.

PMID- 15195430
TI  - Water governance: learning by developing adaptive capacity to incorporate climate
      variability and change.
AB  - There is increasing evidence that global climate variability and change is
      affecting the quality and availability of water supplies. Integrated water
      resources development, use, and management strategies, represent an effective
      approach to achieve sustainable development of water resources in a changing
      environment with competing demands. It is also a key to achieving the Millennium
      Development Goals. It is critical that integrated water management strategies
      must incorporate the impacts of climate variability and change to reduce
      vulnerability of the poor, strengthen sustainable livelihoods and support
      national sustainable development. UNDP's strategy focuses on developing
      adaptation in the water governance sector as an entry point within the framework
      of poverty reduction and national sustainable development. This strategy aims to
      strengthen the capacity of governments and civil society organizations to have
      access to early warning systems, ability to assess the impact of climate
      variability and change on integrated water resources management, and developing
      adaptation intervention through hands-on learning by undertaking pilot
      activities.

PMID- 15195431
TI  - Workshop 4 (synthesis): securing food production under climate variability-
      exploring the options.
AB  - Climate variabilities may result in different types of dry spells, droughts or
      flood situations, having harmful effects on agricultural productivity and food
      security. Long-term trends in climate variabilities and climate extremes may be a
      consequence of an on-going climate change and would thus result in a more
      permanent change in the pre-conditions for food production. The presentations and
      discussion during the workshop concentrated on some different measures to be
      taken in addressing these kind of situations and in particularly on the adverse
      effects of dry spells, droughts and to some extent also floods. The different
      areas presented were examples from Bangladesh, the indus river and delta region,
      examples from India (Tamil Nadu, Karnataka and Andhra Pradesh), Israel, Sri Lanka
      and Uzbekistan.

PMID- 15195432
TI  - Making the best of climatic variability: options for upgrading rainfed farming in
      water scarce regions.
AB  - Coping with climatic variability for livelihood security is part of everyday life
      for rural communities in semi-arid and dry sub-humid savannas. Water scarcity
      caused by rainfall fluctuations is common, causing meteorological droughts and
      dry spells. However, this paper indicates, based on experiences in sub-Saharan
      Africa and India, that the social impact on rural societies of climatically
      induced droughts is exaggerated. Instead, water scarcity causing food deficits is
      more often caused by management induced droughts and dry spells. A conceptual
      framework to distinguish between manageable and unmanageable droughts is
      presented. It is suggested that climatic droughts require focus on social
      resilience building instead of land and water resource management. Focus is then
      set on the manageable part of climatic variability, namely the almost annual
      occurrence of dry spells, short 2-4 week periods of no rainfall, affecting farmer
      yields. On-farm experiences in savannas of sub-Saharan Africa of water harvesting
      systems for dry spell mitigation are presented. It is shown that bridging dry
      spells combined with soil fertility management can double and even triple on-farm
      yield levels. Combined with innovative systems to ensure maximum plant water
      availability and water uptake capacity, through adoption of soil fertility
      improvement and conservation tillage systems, there is a clear opportunity to
      upgrade rainfed farming systems in vulnerable savanna environments, through
      appropriate local management of climatic variability.

PMID- 15195433
TI  - Rainwater harvesting--an alternative for securing food production under climate
      variability.
AB  - Food insecurity is still a challenge in some remote and mountainous areas in
      China. When studying the impact of climate variability on food production, we
      should pay even more attention to the rainfed area. This is because the larger
      part of agriculture is the rainfed one and climate variability has more negative
      impacts on the rainfed agriculture than on the irrigated one. The traditional dry
      farming practices based on the principle of storing as much rain in the soil as
      possible and making best use of soil water could not bridge the gap between the
      time that the corp needs water and the time that rain occurs, so its effects on
      enhancing food production under climate variability is limited. Combining
      artificial water supply from rainwater harvesting systems with the traditional
      dry farming practices is an innovation in water management in rainfed
      agriculture. Experiences in the recent two decades indicate that rainwater
      harvesting irrigation can well mitigate the drought caused by the climate
      variability and bring the rainfed agriculture to a new level.

PMID- 15195434
TI  - Workshop 5 (synthesis): water pollution abatement as related to ecosystem
      protection.
AB  - Water pollution exerts major stress on water systems and the challenge is to
      ensure security in river basins for both water-dependent activities and for the
      aquatic ecosystems. The workshop focused on protection of good ecological status,
      quality criteria, priorities for action, and on achievement of sustainable
      improvements. The three keynote speakers presented the concept applied in the EU
      Water Framework Directive, the need for a multi-stakeholder collaboration in
      order to reach a good ecological status of waters and a concrete example of
      interactive planning of water protection measures in a transboundary lake. The
      additional paper presentations addressed specific pollution problems in
      catchments, the effect of environmental user fees and ecosystem indicators.

PMID- 15195435
TI  - Towards good ecological status of surface waters in Europe--interpretation and
      harmonisation of the concept.
AB  - The Water Framework Directive (WFD) is a new legislative framework to manage,
      use, protect, and restore surface water and groundwater resources and coastal
      waters in the European Union (EU). The aim is to ensure sustainable water
      management and to reach good water quality by 2015. The assessment of the
      ecological status and setting of the practical management goals require several
      steps. The process has started with the characterisation of the river basins
      including identification of surface water bodies and types, and identification of
      significant anthropogenic pressures and impacts. The water bodies will be
      classified in five quality classes (high, good, moderate, poor, bad) based on the
      Ecological Quality Ratio, which is a ratio between reference conditions and
      measured status of the biological quality elements. The normative criteria for
      high, good and moderate ecological status described in the WFD need to be made
      operational because those will be used to set the practical quality targets for
      surface water management. National ecological assessment systems and
      classifications will be harmonised through the WFD intercalibration exercise in
      order to ensure an equal level of ambition in achieving good surface waters
      status all over Europe.

PMID- 15195436
TI  - Interactive management of transboundary waters on the external European Union
      border.
AB  - The paper addresses issues specific to planning of water protection measures in
      transboundary water basins located on the external European Union border. The
      case study of the Lake Peipsi/Chudskoe, a large transboundary lake shared by
      Estonia and Russia, is used to demonstrate issues of management of transboundary
      waters on the Eastern European fringe. The author emphasizes the importance of
      managing transboundary water basins located on the EU external borders
      interactively, i.e., through regular communication and consultation among water
      experts, decision-makers and stakeholders involved in managing waters on
      transboundary, national and subbasin levels, and discusses difficulties in, and
      opportunities for, the interactive management of transboundary waters on the EU
      external borders.

PMID- 15195437
TI  - Workshop 6 (synthesis): monitoring, understanding and managing waste fluxes
      within a drainage basin.
AB  - Waste is produced in a number of activities and transported within the drainage
      basin by natural as well as man-made processes. The pollution of water courses,
      i.e. rivers, lakes, coastal areas and other waterbodies, tends to negatively
      influence both use of the water and aquatic life. Tools are needed in order to
      decide on how to minimise the negative effects of waste fluxes, supported by
      appropriate monitoring procedures.

PMID- 15195438
TI  - Drainage basin security of hazardous chemical fluxe in the Yodo River basin.
AB  - The Yodo River basin consists of three major tributary basins (and other small
      river basins) namely Uji, Katsura and Kizu, which overlap respectively Shiga,
      Kvoto and Nara prefectures' administrative areas. Lake Biwa, the largest lake in
      Japan, drains water through the Uji river. The water quality of the lake, in
      terms of BOD, continuously improved over the last decade. However, the quality in
      terms of COD did not show any improvement in spite of a large amount of
      infrastructure finance being introduced. Eutrophication of the lake still
      continues, showing no improvement in the nitrogen concentration level. Non-point
      as well as point source control is not strong enough. There is a gap between BOD
      and COD evaluations of the lake water quality. Hazardous chemical fluxes are
      estimated based upon PRTR reports of Japan (2001). PCBs are still discharged into
      the lake, although the report of Shiga Prefecture showed zero discharge. Dace
      fish monitoring clearly showed that PCB contamination of the fish had not changed
      since the 1980s in spite of a ban on use and production of PCBs in the 1970s.
      There is still leakage of PCBs into the lake. The major exposure of dioxins to
      Japanese is fish rather than meat and eggs. The risk of water contamination must
      take into consideration not only drinking water safety but also ecological
      magnification of food chains in water. The ecological health aspect of hazardous
      chemicals is also important, such as organotins with imposex of sea snails.
      Finally, public participation in hazardous chemical management is very important
      using the method of risk communication based upon the annual report of PRTR in
      Japan.

PMID- 15195439
TI  - Workshop 7 (synthesis): role and governance implications of virtual water trade.
AB  - Virtual water trade (VWT) is a powerful concept which stimulates fresh thinking
      about water scarcity and management. It is a potential solution for water-short
      countries to achieve food security. VWT may also have the potential to play a key
      role in international negotiations over management of transboundary water
      resources.

PMID- 15195440
TI  - Virtual water trade and world water resources.
AB  - Global virtual water trade was quantitatively estimated and evaluated. The basic
      idea of how to estimate unit requirement of water resources to produce each
      commodity is introduced and values for major agricultural and stock products are
      presented. The concept of virtual water and the quantitative estimates can help
      in assessing a more realistic water scarcity index in each country, projecting
      future water demand for food supply, increasing public awareness on water, and
      identifying the processes wasting water in the production. Really required water
      in exporting countries is generally smaller than virtually required water in
      importing countries, reflecting the comparative advantage of water use
      efficiency, and it is estimated to be 680 km3/y for 2000. On the contrary the
      virtually required water for the same year is estimated to be 1,130 km3/y, and
      the difference of 450 km3/y is virtually saved by global trade. However, solely
      virtual water should not be used for any decision making since the idea of
      virtual water implies only the usage and influence of water and no concerns on
      social, cultural, and environmental implications. Virtual water trade also does
      not consider other limiting factors than water.

PMID- 15195441
TI  - Workshop 8 (synthesis): managing urban development and industrial growth from a
      drainage basin perspective.
AB  - Urban development and industrial growth give rise to the two problems of
      insidious and growing pollution, and an over-exploitation of water resources. To
      solve these problems, various solutions have been promoted, such as multi
      stakeholder dialogues, establishment of river basin committees, strong
      regulation, compensation for water-exporting basins and convincing politicians
      and the public of the need for change.

PMID- 15195442
TI  - Summary and conclusions from the SIWI Seminar for Young Water Professionals
      Drainage basin security--implications of virtual water trade and agricultural
      subsidies at regional, national and local levels.
AB  - This is a summary of the Young Water Professionals Seminar involving more than 50
      young people from all over the world working with water. The presentations and
      following discussion were very lively and were about how subsidies and trade
      barriers imposed by the developed countries are influencing the income-generating
      capacity of millions of people in the developing world. Even though this is a
      very complex issue not easily resolved during the seminar it was also clear that
      there are some fundamental problems that need to be addressed. The importance of
      looking for solutions at different levels (i.e. local, regional, national) was
      highlighted as well as the policy of double standards, preaching free trade but
      only for the benefit of overdeveloped countries themselves. Further it was
      discussed how to achieve basin security through food security, and managing water
      for food security. The conclusion was that win-win solutions would be made if
      agricultural subsidies were to be completely removed.

PMID- 15195444
TI  - To protect and serve. Interview by Jacob Lonsdale.

PMID- 15195445
TI  - The challenges of positive mental health.

PMID- 15195443
TI  - Report on a panel debate on agricultural subsidies from a water perspective.
AB  - The relationships between subsidies, trade and water issues and poverty are
      complex. If trade barriers and subsidies were removed by the developed countries,
      it is likely that opportunities for the developing countries would improve--not
      just for increased trade but also for improved livelihood opportunities.

PMID- 15195446
TI  - Changes in mental health legislation in England and Wales.

PMID- 15195447
TI  - Mental health of older people: new inquiry launched.

PMID- 15195448
TI  - Stress and mental health.

PMID- 15195449
TI  - Changes to hand-arm vibration guidelines--too little too late?

PMID- 15195450
TI  - In-patient mental health services for young people--changing to meet new needs?
AB  - There is currently considerable interest in consulting with young people and
      involving them in the development and delivery of mental health services--both at
      the local and national level. This is a welcome development since, as various
      studies have highlighted, young people can offer both valuable insights into the
      services they receive and suggestions for what they want from services. In 2003,
      YoungMinds, a national charity that works to promote children's mental health,
      completed a two-year, in-depth qualitative study focused on a sample of in
      patient units drawn from across England and Wales. Such units, found at Tier 4
      (the most severe or complex problems) within Child and Adolescent Mental Health
      Services (CAMHS) provide highly specialist care and treatment to some of the most
      seriously ill and vulnerable children and young people. A key aim of the study
      was to give a 'voice' to these young people in order to help in-patient services
      develop their provision in ways that are possibly more 'young-person friendly'.
      Alongside this, information from staff working both within in-patient units and
      the community was gathered, to provide an important contrasting perspective and
      to build up understanding of the current pressures and challenges that face
      service providers in this area. In total, data was gathered from 107 young
      people, 35 parents and 169 staff. Information from a number of other services was
      also compiled to provide case study illustrations of some new models of in
      patient care now emerging. Multi-centre Research Ethics Committee approval was
      gained for the study, with considerable attention being paid to the design of
      clear 'young person' friendly information sheets, consent forms and
      questionnaires. Much attention was also paid to explaining how information would
      be used and confidentiality respected. The study findings reveal a picture of
      considerable change--of improvements but also continuing service gaps. Most
      importantly, there was a high level of consistency amongst young people as to the
      areas of greatest concern and many highly realistic, practical suggestions and
      requests for how in-patient provision for young people should be improved. This
      article outlines some of the issues raised by young people and in particular
      highlights the importance of information sharing and of in-patient units being
      properly staffed. The need for inter-agency links and coordination between in
      patient and community based mental health services is also emphasised.

PMID- 15195451
TI  - Maintaining cognitive health in an ageing society.
AB  - A significant concern associated with growing old is the loss of cognitive
      function, resulting in dementia. Fortunately, the current research on ageing
      indicates that cognitive decline is not an inevitable function of the ageing
      process. Moreover, individuals can take steps to maintain cognitive health
      throughout life. This paper reviews the research findings and recommendations for
      maintaining cognitive health that were presented at a meeting sponsored by the
      Alliance for Health and the Future in November 2003. The meeting, 'Placing
      Cognitive Health on Europe's Social and Economic Agenda', reviewed the current
      state of knowledge about cognitive health and discussed its implications for an
      ageing Europe. Although the brain, for reasons that remain unclear, changes with
      age, a growing body of research suggests that social engagement, intellectual
      stimulation, and physical activity play a key role in maintaining cognitive
      health and preventing cognitive decline. As the number of older people increases
      and people live longer, developing and implementing strategies for maintaining
      cognitive health should be a priority for both individuals and societies.

PMID- 15195452
TI  - Can watching football be a component of developing a state of mental health for
      men?
AB  - Football supporters, by and large, continue to have a negative image and be
      presented in a very destructive way by the media generally. This has been
      reflected academically by the fact that much of the research that has been done
      into football and football fans has focused on negative aspects of small numbers
      of supporters' behaviours such as hooliganism and racism. This paper describes a
      two stage study exploring some of the more positive effects noted during studies
      with football fans from Mansfield Town, a team currently in the third division of
      the English Football League. The study explores the perceived benefits to mental
      health for fans gained from the supporting experience in such areas as stress
      relief, catharsis and the development of good parent-child relationships.
      Discussion takes place around the paradox that some of the behaviours described
      by supporters as beneficial and done in 'the spirit of carnival' may challenge
      liberal beliefs and be viewed as antisocial and offensive. The key feature in
      health promotional terms is the overwhelming view of fans that the
      'carnivalesque' behaviours stay in the football ground where such behaviours are
      viewed as acceptable and socially sanctioned.

PMID- 15195453
TI  - Promoting mental health in students: is there a role for sleep?
AB  - Independently both the role of being a student and reporting insufficient or
      unsatisfactory sleep have been shown to have deleterious consequences on mental
      health. However, few studies have examined the combined relationship between
      students' sleep patterns specifically with mental health in mind, and how
      individual psychological characteristics and situational factors can influence
      this relationship. The purpose of this research was to examine the relationship
      between sleep functioning and students' levels of perceived stress over the
      course of an exam period. Additionally, the influence of perfectionism (as an
      individual characteristic) and daytime sleep-related intrusive thoughts (sleep
      catastrophising) on sleep functioning and stress were also examined. Two
      assumptions were tested. Firstly, that stress would increase between baseline and
      the morning of the exam and secondly, that this relationship would be moderated
      by poor sleep functioning, sleep catastrophising and levels of perfectionism.
      Levels of stress, sleep functioning and sleep catastrophising were examined over
      a seven-day period in 48 Access to Higher Education students about to take an
      exam and 44 non-exam taking controls. For the exam group, levels of stress and
      sleep catastrophising increased between time-points. At baseline higher reported
      perfectionism predicted stress scores. Conversely, low perfectionism predicted
      high stress on the morning of the exam. Additionally, going to bed later and high
      levels of sleep catastrophising were also related to stress levels the morning of
      the exam. The results suggest an association between perfectionism and pre-exam
      stress, and are discussed in terms of mental health promotion for higher
      education students.

PMID- 15195454
TI  - Psychosocial effects of river blindness in a rural community in Nigeria.
AB  - Onchocerciasis (river blindness) is a serious public health problem with
      important socioeconomic consequences. The presence of onchocercal skin lesions is
      unsightly and has a psychosocial effect on the affected. This cross-sectional
      study was undertaken to assess the perception and social implication of
      onchocerciasis in the village of Apana in Nigeria. Apana is a rural community,
      hyper-endemic for onchocerciasis and currently receiving ivermectin treatment.
      The village is one of the ten communities of Uzairue district of Etsako West
      Local Government Area (LGA), Edo State, Nigeria. There are many water streams in
      the community which serve the domestic needs of the inhabitants but also provide
      the breeding sites for the vector flies of onchocerciasis. Multi-stage sampling
      methods were used to select the 385 respondents that participated after informed
      consent was obtained. A structured researcher-administered questionnaire was the
      tool for data collection. Of the 385 respondents that participated in the survey,
      240 (62.3%) were male while 145 (37.7%) were female. The awareness of the disease
      among the respondents was fair. They were aware of the nuisance value of
      blackflies ('Uja-ini') and associated the bite with itching. The signs and
      symptoms of onchocerciasis were recognised as specific diseases with specific
      local names. They called itching and rashes 'Erhue', nodules and leopard skin
      'Evbiomu-Ogui', worm in the eye 'Okogho-Ikpalo' and blindness 'Orunalo'. The
      attitude of the non-affected towards the affected was partially discriminatory
      and suspicious. The affected were socially withdrawn, probably due to the
      frustration of their health condition. There is a need to improve people's
      attitude towards the disease and improve disease awareness through appropriate
      health education, which will encourage the acceptance of ivermectin as adequate
      treatment and compliance to the treatment regimen to reduce morbidity and promote
      self-esteem.

PMID- 15195455
TI  - Gastrointestinal disorders: are health care professionals missing zoonotic
      causes?
AB  - Acute gastrointestinal disorders (AGIDs) of presumed infectious origin are common
      illnesses and among the most frequent infective diseases referred to hospital.
      Much is known about the diagnosis and aetiology of AGIDs, but relatively little
      work appears to have been done regarding the assessment of relevant general
      practitioner (GP) history-taking and the potential for under-recognition of
      sources such as zoonoses. Established sources of zoonosis (for example exotic pet
      keeping, farmyards and zoological parks) seem either rarely considered or
      annotated. Surveillance of food-borne illness and its aetiology attracts rapidly
      increasing attention in the public health community and these infections have
      been targeted for serious reduction. Zoonoses may present as food-borne illness.
      The aim of this study was to assess the potential for under-ascertainment and
      under-reporting of important sources of gastrointestinal infection. The study
      examined history-taking habits among GPs with reference to their general scope
      for either detecting or missing diverse sources of acute gastrointestinal
      infections. From a medical practice perspective, more specific identification of
      pathogenic factors may potentially promote wider preventive measures by alerting
      the public to unconsidered or recurrent problems. The study was conducted at a
      busy British health centre that currently accommodates eight GPs and several
      training personnel. The health centre has approximately 12,000-13,000 patients.
      The patient presentation records and GP notes were accessed via the health
      centre's computer database. Data on acute gastrointestinal disorders were
      obtained using the Read codes for both 'diarrhoea of presumed infectious origin'
      (DPI) and 'gastroenteritis of presumed infectious origin' (GPI). The first 35
      cases were selected from the DPI list (10% of 'names'), and the first 24 cases
      were selected from the GPI list (10% of 'names'). Symptoms were unspecified in 11
      out of the 24 GPI presentations compared to four unspecified out of 35 DPI
      presentations. Potentially significant history was unspecified in 22 out of the
      24 GPI presentations compared to 27 unspecified out of 35 DPI presentations.
      Among potential sources of infection are: pet shops; exotic and domestic pets;
      farm animals/environments; and zoos and other wildlife centres. These established
      sources of potential infection are, however, only infrequently enquired into by
      GPs; thus their pathological significance may be easily overlooked. By using a
      standard setting 'pathogen source questionnaire' GPs might alert themselves to
      domestic or wider media of infection as well as enable more precise cues
      regarding when to sample and when to refer to hospital.

PMID- 15195456
TI  - Challenges of epidemiological studies of mild cognitive impairment.

PMID- 15195457
TI  - Prevalence and cognitive performances of clinical dementia rating 0.5 and mild
      cognitive impairment in Japan. The Tajiri project.
AB  - The borderline zone condition between normal aging and dementia is a major issue
      of concern. Although the term mild cognitive impairment (MCI) is popular, its
      prevalence and neuropsychological features have not been fully investigated. We
      investigated the prevalence and neuropsychological features for Clinical Dementia
      Rating (CDR) 0.5 and MCI. For normal aging, the effects of age and educational
      level on cognitive performance were examined. We examined 1501 older residents
      (46.8%) in Tajiri 65 years of age and older. They performed the Cognitive
      Abilities Screening Instrument (CASI). Depressive scores and subjective memory
      complaints were also evaluated. There was no age effect but an educational effect
      on cognitive performance in healthy adults. We found the overall prevalence of
      CDR 0.5 to be 30.2%, whereas that of MCI was only 4.9%. All CASI domains were
      deteriorated except for long-term memory and visual construction in the CDR 0.5
      participants compared with healthy adults, suggesting that CDR 0.5 is similar to
      very mild Alzheimer disease. Memory complaints' data suggested that it would be
      better to exclude memory complaints from the MCI criteria. We considered that the
      concept of CDR 0.5 would be more applicable to community residents rather than
      that of the MCI.

PMID- 15195458
TI  - Validity of informant reports about AD and MCI patients' memory.
AB  - Efficient, valid, and economical methods are needed to measure memory in elderly
      patients who are participants in clinical trials for the prevention or treatment
      of dementia. Data provided by knowledgeable informants are an ideal means of
      assessment, but factors that may limit the validity of informant-report data are
      not known. This study investigated the living status, relationship type, and
      educational history of informants and determined the impact of these factors on
      the validity of informant-report data about patients (N = 62) diagnosed with
      Alzheimer disease or mild cognitive impairment. Validity of informant-reported
      memory was indicated by the correlation between the reports and patients'
      performance on a neuropsychological memory test. Results indicated that
      informants who lived with patients provided more accurate reports of the
      patients' memory than informants who did not live with the patient. Spouses were
      more accurate than other relationship types, although relationship type was
      confounded with living status. Patient education and neuropsychiatric symptoms
      were not significantly associated with informant accuracy. Results of this study
      will aid in selecting informants who can provide the most accurate data about
      memory disorder patients and will aid in the development of protocols for
      clinical trials for dementia prevention and treatment.

PMID- 15195459
TI  - Mild cognitive impairment is associated with characteristic neuropsychiatric
      symptoms.
AB  - Mild cognitive impairment (MCI) has emerged as an identifiable condition and in
      many cases is a transitional state preceding diagnosable Alzheimer disease (AD).
      Neurobiological and neuroimaging characteristics of amnestic-type MCI have been
      investigated, but few comprehensive neuropsychiatric studies have been reported.
      The aim of this preliminary study was to define the neuropsychiatric features of
      the amnestic-type MCI and compare them with those of mild AD and normal controls.
      The Neuropsychiatric Inventory (NPI) was used to assess the neuropsychiatric
      symptoms in three age and education comparable groups, i.e., 28 MCI, 124 mild AD,
      and 50 normal subjects. Individual subscores of the 10 NPI symptoms and total NPI
      scores were compared between the MCI patients and the other 2 groups. The results
      of this preliminary investigation showed that MCI patients frequently manifested
      neuropsychiatric symptoms. The most common symptoms in the MCI group were
      dysphoria (39%), apathy (39%), irritability (29%), and anxiety (25%). There were
      significant differences in apathy, dysphoria, irritability, anxiety, agitation,
      and aberrant motor behavior between the MCI and control groups; in contrast, only
      delusions were significantly less common in MCI compared with mild AD. There was
      a significant difference between the MCI and control groups on total NPI scores
      (p = 0.001), but not between the MCI and mild AD groups (p = 0.304). Amnestic MCI
      is associated with significant neuropsychiatric symptoms, especially mood
      disturbances and apathy. Psychotic symptoms are significantly more common in the
      early stage of AD than in MCI. These results are derived from a limited clinical
      sample and require confirmation in longitudinal community-based investigations.

PMID- 15195460
TI  - Predicting cognitive decline in Alzheimer disease. Role of platelet amyloid
      precursor protein.
AB  - An altered pattern of platelet amyloid precursor protein (APP) forms, consisting
      of a reduced ratio of the upper (130 kDa) to the lower (110 to 106 kDa)
      immunoreactivity band (APPr), is associated with Alzheimer disease (AD), although
      in the early stages of AD this pattern shows high variability. To explore whether
      APPr values at baseline may predict the rate of cognitive decline, we evaluated
      patients with mild AD before and after 1 year of treatment with
      acetylcholinesterase inhibitors. Lower APPr at baseline was the only predictor of
      progressive cognitive decline, suggesting that this biomarker might be a useful
      indicator of prognosis for patients with AD.

PMID- 15195461
TI  - Normal pressure hydrocephalus and large head size.
AB  - OBJECTIVE: To determine if patients with normal pressure hydrocephalus (NPH) have
      larger head size than normal controls. BACKGROUND: In 1989, Graff-Radford and
      Godersky noted that 3 of 30 patients diagnosed with NPH had large heads. They
      hypothesized that the cause of NPH in their patients was arrested congenital
      hydrocephalus becoming symptomatic later in life. METHODS: Participants included
      31 newly diagnosed NPH patients (21 male, 10 female) seen by the same neurologist
      (N.R.G.-R.) at Mayo Clinic Jacksonville from January 1, 1995 through December 31,
      2000, and 459 normal controls (226 male, 233 female) from the Charlotte County
      Healthy Aging Study. RESULTS: Head size was statistically larger for NPH males
      (median, 59.0 cm, range, 57.0-63.0 cm) compared with normal males (median, 57.8
      cm, range, 53.3-62.8) (p < 0.01). Head size was also larger for NPH females
      (median, 6.3 cm, range, 53.5-58.0 cm) compared with normal females (median, 54.6
      cm, range, 51.4-59.7 cm) (p < 0.02). CONCLUSION: Patients with NPH have larger
      head circumferences as a group than normal controls. This was found in both males
      and females. Results suggest that a significant proportion of patients with NPH
      may have congenital hydrocephalus that becomes symptomatic later in life.

PMID- 15195462
TI  - Current concepts and future prospects for Alzheimer disease vaccines.
AB  - Alzheimer disease (AD) is the most prevalent form of dementia worldwide and is
      characterized by the progressive accumulation of the 42-residue amyloid beta
      protein (A beta) in brain regions serving memory and cognition. Only a few years
      ago, the proposition that AD may be amenable to any kind of therapy would have
      met with considerable skepticism. Yet, recent, exciting developments appear to
      suggest that immunizing against A beta may bear some potential for arresting or
      even curing AD. However, a clinical trial of vaccination with synthetic human A
      beta in AD patients was halted because of the development of meningoencephalitis
      in some patients. Further studies aimed at elucidating the mechanism of A beta
      clearance upon A beta immunization are needed. Such knowledge might facilitate
      the design of specific vaccination regimens, allowing exclusive targeting of A
      beta plaques without inducing detrimental side effects.

PMID- 15195463
TI  - Alzheimer A beta vaccination of rhesus monkeys (Macaca mulatta).
AB  - Recent preliminary data suggest that vaccination with Alzheimer A beta might
      reduce senile plaque load and stabilize cognitive decline in human Alzheimer
      disease. To examine the mechanisms and consequences of anti-A beta-antibody
      formation in a species more closely related to humans, rhesus monkeys (Macaca
      mulatta) were vaccinated with aggregated A beta 1-42. Immunized monkeys developed
      anti-A beta titers exceeding 1:1000, and their plasma A beta levels were 5- to 10
      fold higher than the plasma A beta levels observed in monkeys vaccinated with
      aggregated amylin. These data support the use of nonhuman primates to model
      certain phenomena associated with vaccination of humans with aggregated Alzheimer
      A beta.

PMID- 15195464
TI  - Memantine in moderate-to-severe Alzheimer disease evidence and ethics based?

PMID- 15195465
TI  - Monozygotic twins discordant for primary progressive aphasia.

PMID- 15195466
TI  - Assessment of the influence of energy under-reporting on intake estimates of four
      food additives.
AB  - Under-reporting has been identified as an important source of uncertainty in food
      chemical exposure assessments. The objective of the present study was to assess
      the influence of under-reporting on food additive intake estimates. Dietary
      survey data were derived from the North-South Ireland Food Consumption Survey
      (2001). Data from the Republic of Ireland (n = 958) were used. Energy under
      reporters were identified using a ratio of energy intakes to estimated basal
      metabolic rate. First, food categories (n = 26) included in an assessment of
      exposure of four food additives were created and patterns of food intakes (i.e.
      likelihood of consumption, frequency of consumption and reported portion size)
      between acceptable and under-reporters compared. Second, for each food additive,
      deterministic intake estimates for the total sample (i.e. acceptable and under
      reporters), under-reporters and acceptable reporters were calculated and
      compared. Differential reporting of the majority of food categories between
      acceptable and under-reporters was recorded. Under-reporters were less likely to
      record the consumption of a given food and more likely to under-report the
      frequency of consumption and portion size compared with acceptable reporters.
      Food additive intake estimates amongst acceptable reporters were higher than
      corresponding intake estimates amongst the total sample of reporters and amongst
      under-reporters. With the exception of one food additive (erythrosine), ratios of
      upper percentile additive intakes amongst acceptable reporters to corresponding
      intake estimates amongst the total sample of reporters did not exceed 1.06 when
      results were expressed as total population or consumer-only intakes. Findings
      illustrated that energy under-reporting does not materially influence estimates
      of food additive exposure based on the four food additives studied. However, a
      number of situations were identified where the under-reporting might exert a more
      significant impact on resulting exposure estimates.

PMID- 15195467
TI  - Development of an analytical method for 3-monochloropropane-1,2-diol in soy sauce
      using 4-heptanone as derivatizing agent.
AB  - 3-Monochloro-1,2-propane diol is a suspected carcinogen found in hydrolysed
      vegetable protein products such as soy sauce. A method is described for the
      analysis of 3-monochloro-1,2-propane diol in soy sauce by gas chromatography-mass
      spectrometry at a concentration range of 1-5000 ng g-1 using 4-heptanone as the
      derivatizing ketone and 3-monochloro-1,2-propane diol-d5 as the internal
      standard. The limit of detection for the method in the soy sauce matrix was 0.48
      ng g-1 and the limit of quantification was 1.2 ng g-1.

PMID- 15195468
TI  - Total and acid-soluble fluoride content of infant cereals, beverages and biscuits
      from Brazil.
AB  - Total fluoride (TF) and HCl 0.01 M ('gastric juice')-soluble fluoride (SF) were
      analysed in infant foods, beverages and calcium-rich biscuits. Samples were
      divided into seven categories: children cereals (A), chocolate-flavoured milk
      (B), soy beverages (C), filled biscuits (D), non-filled biscuits (E), wafer
      biscuits (F) and corn starch biscuits (G). Mean TF concentrations +/- SD
      (amplitude, unit microgram F ml-1 or microgram F g-1) were: (A) 4.25 +/- 3.04
      (0.20-7.84, n = 6); (B) 0.34 +/- 0.47 (0.05-1.27, n = 6); (C) 0.15 +/- 0.07 (0.09
      0.29, n = 8); (D) 8.44 +/- 1.76 (7.65-10.47, n = 4); (E) 12.41 +/- 1.15 (10.69
      13.68, n = 4); (F) 0.35 +/- 0 (0.34-0.36, n = 4) and (G) 7.77 +/- 1.12 (6.86
      8.68, n = 2). Five samples of cereals, one sample of chocolate-flavoured milk and
      10 samples of biscuits were analysed for SF. In cereals analysed for SF, all
      fluoride was soluble, while for the chocolate-flavoured milk, approximately 50%
      of TF was soluble. Regarding the biscuits analysed for SF approximately 20% of TF
      was soluble. It was observed that some of the cereals and beverages, and most of
      the biscuits analysed, might be important contributors to total daily fluoride
      intake. When consumed just once per day, cereals and beverages might supply up to
      25% of the maximum recommended daily fluoride intake (0.07 mg F kg-1 body weight)
      for a 2-year-old child (12 kg). For the filled, non-filled and corn starch
      biscuits, when 3, 32 or 20 units of them, respectively, are consumed just once
      per day, they may supply up to 16% of the maximum recommended daily fluoride
      intake. However, only approximately 25% of fluoride absorption occurs from the
      stomach and 75% from the small intestine. Therefore, a higher fluoride
      bioavailability is possible.

PMID- 15195470
TI  - Solid-phase microextraction (SPME) of permethrin residues from cucumber using a
      silica-bonded phase-coated stainless steel fibre.
AB  - Solid-phase microextraction (SPME) is a rapid, economic and solvent-free sample
      preparation method for the isolation of an analyte from its matrix. The technique
      uses a few centimetres of some adsorptive materials such as activated charcoal,
      polydimethylsiloxane or octadecyl silane coated onto fused silica optical fibres
      or, more recently, stainless steel fibres mounted into a microsyringe. The
      proposed method allows the extraction of permethrin from cucumber matrix into the
      coating, avoiding sample handling and saving evaporation of solvents and
      concentration steps. Adsorbed permethrin was desorbed in the split/splitless
      injection port of the gas chromatograph. The time required for each run was about
      1.5 h, which gave a preconcentration of several orders of magnitude. The method
      could separate and quantify cis- and trans-isomers of permethrin. The calibration
      curve showed linearity in the range 1-9 micrograms ml-1, with detection limits of
      0.03 and 0.05 microgram ml-1 for the cis- and trans-isomers of permethrin,
      respectively. The method had a recovery rate of about 70% and a relative standard
      deviation of less than 13%. Results suggest that this procedure provides a rapid
      and sensitive alternative method to those currently available.

PMID- 15195469
TI  - Meeting maximum residue limits: an improved screening technique for the rapid
      detection of antimicrobial residues in animal food products.
AB  - A rapid, high-throughput antimicrobial screening assay was developed using either
      a physical fluid extraction or a solvent extraction technique coupled to the
      commercially available PremiTest. The solvent extraction approach was fully
      validated for a wide range of tissues and the fluid extraction approach partially
      validated for porcine muscle. Both procedures can detect a wide range of
      antimicrobial compounds at or below maximum residue limit concentrations. The use
      of a solvent extraction provides an enhanced test capable of detecting a wider
      range of drugs than the fluid extraction approach at or below half maximum
      residue limit levels in a variety of matrices. Biochemical methods for the class
      specific identification of beta-lactams and sulphonamides following initial
      screening were developed and validated. The approach is a significant improvement
      on existing methodologies as a tool for residues monitoring in surveillance
      programmes.

PMID- 15195471
TI  - Canadian Total Diet Study in 1998: pesticide levels in foods from Whitehorse,
      Yukon, Canada, and corresponding dietary intake estimates.
AB  - The Canadian Total Diet Study is a national survey to determine the level of
      chemical contaminants in the Canadian food supply. Food samples were collected
      from Whitehorse, Yukon, supermarkets as part of the study in 1998. Whitehorse was
      chosen as a sampling centre, despite its small population (n = 19,000), to
      determine if residue levels were different in foods available in northern
      communities relative to levels observed in previous studies in the more populated
      south. Foods were prepared as for consumption before pesticide residue analysis.
      Residue levels observed in most foods were similar to levels observed in samples
      from previous surveys from southern Canadian cities. Malathion and DDE (1,1
      dichloro-2,2-bis(p-chlorophenyl)ethylene), a transformation product of DDT (1,1,1
      trichloro-2,2-bis(p-chlorophenyl(ethane), were the two most frequently detected
      compounds (26.4 and 25.8%, respectively). The majority of pesticides, however,
      had a detection frequency of < 5%. In general, pesticides in food composites were
      well below maximum residue limits established in the Canadian Food and Drug
      Regulations. Chlorpropham and captan had the highest dietary intakes (2.16 and
      1.94 micrograms (kg body weight-day)-1, respectively), based on the results from
      Whitehorse. No dietary intakes above the acceptable daily intakes, however, were
      observed for any of the 39 pesticides investigated in any age-sex category, where
      an acceptable daily intake has been proposed.

PMID- 15195472
TI  - Occurrence of aflatoxins and fumonisins in preharvest maize from south-western
      Nigeria.
AB  - A survey was conducted on the incidence of fungi, and the natural occurrence of
      aflatoxins and fumonisins in preharvest maize from fields in south-western
      Nigeria. Mycological examinations revealed the predominance of F. verticillioides
      (Zea mays) (syn. F. moniliforme), occurring in 89.3% of samples with a mean
      kernel infection of 49.4%, while Aspergillus flavus was isolated from 65% of
      samples having a mean kernel infection of 6.8%. Aflatoxin B1 was detected in
      18.4% of samples with a mean of 22 micrograms kg-1, while aflatoxins B2, G1 and
      G2 were present in 7.8, 2.9 and 1% of the samples with mean levels of 10, 8 and 7
      micrograms kg-1, respectively, in contaminated samples. Total aflatoxins ranged
      from 3 to 138 micrograms kg-1 in positive samples, with a mean of 28 micrograms
      kg-1. Fumonsin B1 was the predominant toxin detected in terms of frequency (78.6%
      of samples) and quantity (concentration range 70-1780 micrograms kg-1, mean = 495
      micrograms kg-1). Fumonisin B2 was detected in 68 samples (66%) with a mean of
      114 micrograms kg-1. Fifteen samples were contaminated with both aflatoxins and
      fumonisins.

PMID- 15195473
TI  - Measurement uncertainty associated with overall migration testing.
AB  - The results from a single laboratory that took part in a series of check-sample
      exercises for overall migration were used to calculate the measurement
      uncertainty for the overall migration methodology. The results span 10 years of
      proficiency testing and cover a range of plastic materials tested using a variety
      of time and temperature test conditions. Twelve sets of results for overall
      migration into olive oil and 10 sets of results for overall migration into
      volatile simulants were used. The measurement uncertainty associated with the
      determination of overall migration from plastics into olive oil was estimated as
      +/- 2.6 mg dm-2 for results between 1.2 and 15.4 mg dm-2. The measurement
      uncertainty associated with the determination of overall migration into volatile
      simulants was estimated as +/- 1.4 mg dm-2 for results between 2.1 and 13 mg dm
      2. These estimates are within the analytical tolerances set in European Union
      regulations, of 3 and 2 mg dm-2, respectively. The performance of all
      laboratories participating in these 22 check sample exercises was also evaluated.
      A very large majority (93%) of the participants used official test methods,
      sometimes with minor modifications as stated. For the simulant olive oil, an
      average of 81% of laboratories (13 rounds with an average of 21 participants in
      each) using official methods was within the tolerance specified in regulations.
      For the volatile food simulants, an average of 87% of laboratories (11 rounds
      with an average of 38 participants in each) using official methods was within the
      tolerance specified. It is concluded from this evaluation of within- and between
      laboratory data that the official European Standard methods for overall migration
      testing are suitable for the analysis of routine samples.

PMID- 15195474
TI  - European survey on post-consumer poly(ethylene terephthalate) (PET) materials to
      determine contamination levels and maximum consumer exposure from food packages
      made from recycled PET.
AB  - Typical contamination and the frequency of misuse of poly(ethylene terephthalate)
      (PET) bottles are crucial parameters in the risk assessment of post-consumer
      recycled (PCR) PET intended for bottle-to-bottle recycling for direct food
      contact applications. Owing to the fact that misuse of PET bottles is a rare
      event, sustainable knowledge about the average concentration of hazardous
      compounds in PCR PET is accessible only by the screening of large numbers of
      samples. In order to establish average levels of contaminants in PET source
      materials for recycling, PET flakes from commercial washing plants (689 samples),
      reprocessed pellets (38) and super-clean pellets (217) were collected from 12
      European countries between 1997 and 2001. Analysis of these materials by
      headspace gas chromatography revealed average and maximum levels in PCR PET of
      18.6 and 86.0 mg kg-1 for acetaldehyde and 2.9 and 20 mg kg-1 for limonene,
      respectively. Acetaldehyde and limonene are typical compounds derived from PET
      itself and from prior PET bottle contents (flavouring components), respectively.
      Maximum levels in PCR PET of real contaminants such as misuse chemicals like
      solvents ranged from 1.4 to 2.7 mg kg-1, and statistically were shown to result
      from 0.03 to 0.04% of recollected PET bottles that had been misused. Based on a
      principal component analysis of the experimental data, the impact of the
      recollecting system and the European Union Member State where the post-consumer
      PET bottles had been collected on the nature and extent of adventitious
      contaminants was not significant. Under consideration of the cleaning efficiency
      of super-clean processes as well as migration from the bottle wall into food, it
      can be concluded that the consumer will be exposed at maximum to levels < 50 ng
      total misuse chemicals day-1. Therefore, PCR PET materials and articles produced
      by modern superclean technologies can be considered to be safe in direct food
      applications in the same way as virgin food-grade PET.

PMID- 15195475
TI  - Migration from can coatings: Part 1. A size-exclusion chromatographic method for
      the simultaneous determination of overall migration and migrating substances
      below 1000 Da.
AB  - The Council of Europe Resolution on coatings suggests a limit of 10 mg dm-2 for
      the sum of substances migrating into food simulants from an internal can coating.
      The Scientific Committee on Food differentiates the migrants into the substances
      with a molecular weight below 1000 Da, potentially being of toxicological
      concern, and the less toxicologically relevant species above 1000 Da. Hitherto,
      the determination of overall migration was based on a gravimetric method. A new
      method is described for the simultaneous determination of both overall migration
      and the migration of substances below 1000 Da based on separation by size
      exclusion chromatography (SEC) followed by ultraviolet detection (UVD) and
      evaporative light scattering detection (ELSD). The method is suitable for all
      volatile extraction media and simulants recommended by the European Union. For
      statistical comparison of both methods, the slightly modified reference method
      was validated in-house and extended to an additional gravimetric measurement of
      the migrants below 1000 Da. For the determination of the overall migration, both
      methods provided similar reproducibility (validated gravimetry: standard
      deviation (SD) = 0.16 mg dm-2; SEC-ELSD/UVD: SD = 0.12 mg dm-2) but significantly
      better results were obtained by the SEC-ELSD/UVD method. For migrating substances
      below 1000 Da, the gravimetric determination provides a poor sensitivity (limit
      of detection = 0.35 mg dm-2) compared with the SEC-ELSD/UVD method (limit of
      detection = 0.04 mg dm-2). The new method offers a lower limit of detection and
      higher precision as well as being less time consuming and easier to use.

PMID- 15195476
TI  - [Knowledge and know-how in medicine].

PMID- 15195477
TI  - [Observational study of patients admitted to an Internal Medicine service].
AB  - OBJECTIVES: To analyse the entered more frequent disease in an Internal Medicine
      Department, the reasons for hospital admission diagnosis at discharge (according
      to entrance symptom's guide), the group of affected population and its
      correlation among them. PATIENTS AND METHODS: Over a total of 758 internal
      medicine admissions of the University Hospital of Valladolid during the year 1999
      based on the information of discharge and clinical histories, a descriptive and
      observational epidemic study was made using the variables of sex, age, reason for
      admission (guide symptom) and diagnosis at discharge. The obtained results were
      represented by mean of diagrams of sectors and bars according to the analyzed
      variables. The data synthesis was made by measures of central tendency and
      dispersion. SPSS 10.0 version for windows program was used for the statistical
      study. The non parametric analysis for independent samples was made by the test
      of median and the U of Mann Whitney, and the parametric by chi-squired test and
      resistance of Kolmogorov-Smirnov. RESULTS: The median of age is 70 years. Rank 84
      years. Interquartile rank 23, fashion in men 75 years and in women 86. The
      distribution in sex men 51%, women 49%. The more frequent reasons for entrance
      are dyspnea (35%) and neurological focus (11%). The more frequent diagnosis at
      discharge are dyspnea and chronic obstructive lung disease worsened by
      respiratory infection (11%), pneumonia (8%) and acute ischemic stroke (7%).
      CONCLUSIONS: In-patients in this service, are advanced in years (mainly women)
      (alpha = 0.05). The age does not get a normal distribution (alpha = 0.05). The
      frequency of the distribution in sex is similar. The most frequent reason for
      admission is dyspnea (35%). The most frequent diagnoses at discharge are chronic
      obstructive lung disease (11%), pneumonia (8%) and acute ischemic stroke (7%).
      The primary and secondary prevention and an improvement of the therapeutic
      measures of chronic cardiopulmonary disease would reduce significantly the
      welfare pressure in Internal Medicine Department and they would improve the
      population's life quality given that we are opposed to the diseases which are
      among the four first mortality causes in the world.

PMID- 15195478
TI  - [Urgent care of the diabetic patient in the province of Valladolid].
AB  - OBJECTIVE: To know the cause of admissions of diabetic patients at an emergency
      room in eastern Valladolid in a year. METHODS: It is a retrospective and
      transversal study that analysed a number of the admission of diabetic patients at
      an emergency room because of a direct complication of diabetes mellitus or
      another different cause. We used t and chi 2 as statistic tests, considering 0.05
      as significance. RESULTS: Up to 2,433 (2.4%) were diabetes mellitus emergencies.
      17.1% because of a direct complication, most of them metabolic complications
      (24.6% hyperglycaemia). CONCLUSION: We emphasize the high prevalence of direct
      complications as emergency admissions in our hospital.

PMID- 15195479
TI  - [Positron emission tomography using 18-FDG-PET in radiologically indeterminate
      pulmonary lesions].
AB  - OBJECTIVE: Fluorine-18 deoxyglucose Positron Emission Tomography (FDG-PET) is a
      non-invasive technique that offers the possibility to define if the
      radiologically indetermined pulmonary lesions are benign or malignant with high
      positive and negative predictive values. Considering the indexed literature we
      can observe that there are few original studies performed with the diagnostic
      possibilities of our means. For this reason, our main objective is to evaluate
      the diagnostic accuracy of positron emission tomography in sixty-seven
      radiologically indetermined pulmonary nodular lesions. MATERIAL AND METHOD:
      Retrospectively, we evaluated the diagnostic ability of FDG-PET globally (by
      means of visual and semiquantitative analysis) and partially (only considering
      the Standardized Uptake Value (SUV)), in sixty-seven patients confirmed by
      pathology or clinical and radiological monitoring, in a time interval superior to
      one year. RESULTS: Globally, FDG-PET had a sensitivity (S) of 92%, specificity
      (SP) of 86.6%, positive predictive value (PPV) of 89.4%, negative predictive
      value (NPV) of 89.6% and diagnostic accuracy (DA) of 89%. The best results were
      obtained for an SUV equal or superior to 2.5. With this value, the clinical
      efficacy parameters were: S 0.92, SP 0.90, PPV 0.92, NPV 0.90 and DA 0.91.
      CONCLUSIONS: We can characterize most of the radiologically indetermined
      pulmonary lesions by FDG-PET. The additional use of SUV facilitates an increase
      in the positive predictive value and specificity of FDG-PET.

PMID- 15195480
TI  - [Indurated erythema as the presenting form of a case of chronic myelomonocytic
      leukemia].
AB  - Chronic myelomonocytic leukemia (CMML) is an oncohematologic disease with a mixed
      nature, myeloproliferative and myelodysplastic, and presenting features are
      usually the consequence of peripheral blood cytopenias (anemic syndrome,
      infections or bleeding). Specific or non-specific cutaneous involvement in
      patients with myelodysplastic syndromes or chronic leukemias is exceptional, and
      it takes place often in advanced stages of the disease, as a preample of a
      transformation from chronic illness to acute leukemia. Recognition and early
      diagnosis of the skin lesion by cutaneous biopsy, in every patient with
      myelodysplastic or myeloproliferative disease, have therapeutic and prognostic
      significance. We describe a patient who presented with a non-especific cutaneous
      lesion, Bazin's erhythema induratum, as initial manifestation of chronic
      myelomonocytic leukemia; we also comment diagnostic, therapeutic and clinical
      evolution aspects.

PMID- 15195481
TI  - [Invasive infection by Aspergillus terreus treated successfully with liposomal
      amphotericin B].
AB  - A woman of 75 years old was admitted at our hospital for evaluation of worsening
      and weakness in inferior limbs. Several vertebral fractures by crushing, one
      doubtful discitis, an infiltrate with cavitation in the right superior lobe and
      one infiltrate in the left superior lobe were detected. In the biopsy of the
      consolidation a filamentous fungus was watched and in the bronchial washing
      specimen culture grew Aspergillus terreus. The infiltrates disappeared with
      liposomal Amphotericin B remaining with oral Itraconazol during three months
      more. The clinical and analytical data demonstrate the existence of a Overlap
      syndrome associate to antiphospholipid-antibody syndrome. We comment the
      peculiarity of the infection by Aspergillus terreus in patients who have not been
      in critical care and the good response at treatment with liposomal Amphotericin
      B. It contrasts with the high mortality referred in a recent review. Other
      aspects to comment are the coexistence with a collagen vascular and an
      antiphospholipid-antibody syndrome with the higher titles of IgM ACA that we have
      found in literature.

PMID- 15195482
TI  - [Infliximab (anti-TNF-alpha) treatment in patients with adult Still's disease.
      Experience in 2 cases].
AB  - Adult Still's disease is a systemic inflammatory disorder of unknown etiology.
      First-line treatment for Still's disease includes nonsteroidal anti-inflammatory
      drugs and corticosteroids. In refractory cases o when the dose of corticosteroid
      is unacceptably high, other disease modifying antirheumatic drugs have been used.
      But recent study showed the efficacy anti-TNF therapy in adult Sill's disease
      refractory to conventional therapy. We report a favourable response to infliximab
      in two patients who has proved resistant to conventional therapy.

PMID- 15195483
TI  - [Metastatic pulmonary angiosarcoma].
AB  - Angiosarcoma involving the lung, usually a result of metastatic disease, is a
      rare disorder. Primary angiosarcoma of the lung is an extremely rare tumor. The
      lung is one of the most common sites of metastatic involvement, along with liver
      and lymph nodes. Hemoptysis is the most frequent presenting symptom even with
      diffuse pulmonary hemorrhage. Chest radiography may reveal a spectrum of findings
      ranging form normal to bilateral nodular lesions. Early diagnosis is not common
      because of the rarity of angiosarcoma in the lung and hence, low index of
      suspicion. The prognosis is generally poor, with a median survival of 9 months
      after diagnosis.

PMID- 15195484
TI  - [Technical project for the management and functioning of an Internal Medicine
      care unit].
AB  - The Internal Medicine Services have a central role in the medical care in our
      hospital system both as to the volume of patients attended and their variety,
      reflecting of the preparation and multi-tasking ability of their professionals.
      The current norms for coverage of heads-of-service demands the presentation of a
      management project that must test our knowledge, skills and aptitudes for the
      clinical and medical management and in order to reflect them in a document of
      commitment with the management and with our fellows who are a part of the care
      unit. The person in charge of the service, as boss, agent or leader, is the one
      who must mark the strategic lines, to indicate the aims, to define the projects,
      to coordinate the tasks and to evaluate the results with other offers to obtain
      agreed-upon aims controlling the different points of view. Our professional and
      social commitment is: sharing clinical management with ethics, quality and
      welfare safety, to offer our patients (consumer or users) the best results
      (effectiveness), with useful measurements (efficacy) and with the minors
      drawbacks and costs (efficiency). The aim of this work is to offer the elements
      that are necessary for the accomplishment and introduction of a project of
      clinical management in a service of internal medicine, highlighting its
      methodology and the most important problems than can arise as well as the
      possible care alternatives.

PMID- 15195486
TI  - [Wunderlich syndrome as the initial manifestation of bilateral renal
      angiolipomatosis].

PMID- 15195485
TI  - [Levothyroxine poisoning: clinical manifestations and therapeutic management].
AB  - Intoxication with L-tyroxine has a low prevalence, high prevalence is observed in
      pediatric age. Toxic dose is unclear, asymptomatic patients have been observed
      with doses under 5 mg. Systems with high prevalence of symptoms are
      cardiovascular system, sympathetic nervous system and gastrointestinal tube.
      Symptoms could appear from hours to days after ingestion. Early hours after L
      tyroxine ingestion, levels of T4 and T3 are not related with severity. However,
      monitoring seric levels is necessary to lead therapeutic approach and to give a
      prognosis. Daily determinations of T3, T4 and TSH are necessaries. Determinations
      of temperature, arterial pressure and blood heart rate are needed to control
      complications. Beta-blockers and intestinal decontamination drugs are used during
      therapeutic approach. Other therapeutic options are iopanoic acid and
      propylthiouracil. In summary, intoxication with L-tyroxine could be a severe
      situation. It is necessary to describe therapeutic protocols in this entity.

PMID- 15195487
TI  - [Vertebral osteomyelitis caused by E. coli].

PMID- 15195488
TI  - [Corynebacterium macginleyi as an unusual cause of infectious endocarditis:
      apropos of a case].

PMID- 15195489
TI  - [Pseudoseptic arthritis].

PMID- 15195490
TI  - [Wernicke's encephalopathy as a complication of hyperemesis gravidarum].

PMID- 15195491
TI  - [Post-traumatic eosinophilic pleural effusion].

PMID- 15195493
TI  - [Malaria, a growing disease. Analysis of the 15-year period 1997-2001 in a Madrid
      hospital].

PMID- 15195492
TI  - [Bone marrow aplasia caused by synthetic antithyroid agents].

PMID- 15195494
TI  - [Primary psoas abscess].

PMID- 15195495
TI  - The osteoporosis dilemma.

PMID- 15195496
TI  - Effect of contaminated preprocessed semen on fertilization rate and embryo
      quality in assisted reproductive techniques.
AB  - We aimed to identify the sources and prevalence of semen contamination from
      mastrubation and determine the effect of bacterospermia on fertilization rate and
      embryo quality in standard in vitro fertilization (IVF) and intracytoplasmic
      sperm injection (ICSI). This was a prospective controlled study, in an IVF unit
      of a university teaching hospital, of 93 consecutive couples undergoing IVF
      embryo transfer cycles. We evaluated handwashing; semen collection and
      processing; and assisted reproductive technology using semen provided by
      masturbation. The main outcome measures were presence and type of micro-organisms
      in the semen samples and embryo culture medium; the effect of hand washing on
      rate of contamination; and the effect of semen contamination on fertilization
      rate and embryo quality. The first consecutive 52 men of the 93 couples were not
      instructed to wash their hands before masturbation, and the remainder were so
      instructed. Forty-nine semen cultures (94.2%) in the first group were
      contaminated compared to only 16 (39%) in the second (p < 0.016); 27 of the 65
      positive cultures (41.5%) were contaminated by more than one organism. The most
      common contaminators were bacteria usually found on the skin. All but four embryo
      medium cultures were negative. There was no significant difference in
      fertilization rate and embryo quality by culture findings in either the IVF or
      the ICSI procedures. We found that a high percentage of manually obtained semen
      for standard IVF or ICSI procedures was contaminated, but this had no effect on
      fertilization rate and embryo quality.

PMID- 15195497
TI  - Relationship between gonadotropin releasing hormone agonist dosage and in vitro
      fertilization outcome.
AB  - A prospective study in 132 women undergoing in vitro fertilization was performed
      in order to assess whether lower doses of gonadotropin releasing hormone agonists
      (GnRH-a) may ensure adequate oocyte retrieval and pregnancy rate, without
      pituitary oversuppression. Forty-five patients received subcutaneous tryptorelin
      depot (Decapeptyl 3.75, IPSEN SpA), 41 received subcutaneous tryptorelin acetate
      daily (Decapeptyl 0.1 mg, IPSEN SpA) and 46 received 0.05 mg tryptorelin acetate
      daily from day 21 of the cycle. From day 3 of the new cycle, if the estradiol
      levels were < 30 pg/ml, patients received two or three ampules of gonadotropin
      daily. In the group receiving subcutaneous tryptorelin acetate depot, the mean
      number of total gonadotropin ampules was significantly higher (p < 0.05),
      otherwise estradiol levels and the number of oocytes retrieved, fertilized and
      cleaved were significantly lower (p < 0.05). Pituitary oversuppression induced by
      GnRH-a causes an increase in the gonadotropin requirement for assisted
      reproductive techniques (ART) and a reduction in the number of oocytes retrieved
      and fertilized. There is a high risk of oversuppression in normal-weight or
      underweight women, because there is greater bioavailability of the peptide, hence
      elevated circulating levels of GnRH-a. Thus, ovarian stimulation in ART cycles
      depends on many factors, not least the identification of the best GnRH-a dose.

PMID- 15195498
TI  - Results of in vitro fertilization cycles in women aged 43-45 years.
AB  - Our objective was to evaluate the results of in vitro fertilization (IVF) cycles
      in the elderly (43-45 years old) female population. All consecutive women aged 43
      45 years admitted to our IVF unit from January 1996 to December 2001 were
      enrolled in the study. Ovarian stimulation characteristics, number of oocytes
      retrieved, number of embryos transferred and pregnancy rate were assessed. Seven
      hundred and eight consecutive IVF cycles in 276 patients were evaluated. Two
      hundred and seven cycles were cancelled (cancellation rate 29.2%). Forty-seven
      patients achieved a clinical pregnancy (pregnancy rate 6.6% per cycle and 9.4%
      embryo transfer) with a 30% live birth rate. In patients who underwent embryo
      transfer, there were no differences between conception and non-conception cycles
      in patient's age, number of gonadotropin ampules used, length of ovarian
      stimulation, number of oocytes retrieved, fertilization rate or cleavage rate.
      However, the conception cycles were associated with a significantly lower peak
      estradiol level (p < 0.04) and higher number of total (p < 0.03) and good-quality
      (p < 0.005) embryos transferred, in addition to a lower ratio of estradiol
      level/number of follicles > 14 mm on day of human chorionic gonadotropin
      administration and of estradiol level/number of oocytes retrieved. We conclude
      that, although older female age is a major contributor to IVF failure, successful
      IVF cycles can be expected in patients aged 43-45 years in the presence of low
      ratios of peak estradiol to either number of follicles > 14 mm on day of human
      chorionic gonadotropin administration or number of oocytes retrieved that reach
      the stage of embryo transfer with at least two good-quality embryos.

PMID- 15195499
TI  - Adrenal response to adrenocorticotropic hormone stimulation in patients with
      premenstrual syndrome.
AB  - Several studies have been performed during recent years to investigate the
      existence of a possible endocrine cause for premenstrual syndrome (PMS); the
      results reported are often discordant. Great interest has been raised around
      allopregnanolone, which could be involved in the determination of mood disorders
      reported by PMS patients. During the luteal phase, lower levels of this hormone
      have been detected in PMS patients. The aim of our study was to evaluate
      estradiol, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS),
      androstenedione, total and free testosterone, cortisol, pregnenolone and
      allopregnanolone levels in 20 patients suffering from PMS and to compare them
      with those found in 20 fertile healthy women in the follicular and the luteal
      phases. Adrenocorticotropic hormone (ACTH) tests after dexamethasone suppression
      were performed in 10 patients of each group during the follicular and the luteal
      phases. In the PMS group, significantly lower allopregnolone levels were found in
      the luteal phase, while progesterone was lower in the PMS group in both phases.
      In the PMS group, higher free testosterone levels were found during the luteal
      phase and higher DHEA levels in both the follicular and the luteal phases. The
      present data confirm reduced allopregnanolone levels in the luteal phase in PMS
      patients, together with higher levels of DHEA and free testosterone. It is
      possible to conclude that, in addition to the previously described reduced luteal
      secretion of allopregnanolone, the adrenal gland production of this steroid in
      PMS sufferers is also impaired in the luteal phase. Considering the specific
      actions of these hormones on the control of mood and behavior, this specific
      hormonal milieu may contribute to the cyclic occurrence of anxiety,
      aggressiveness and irritability reported by PMS patients.

PMID- 15195501
TI  - Thyroid hormone alteration in pre-eclamptic women.
AB  - This study sought a possible relationship between pre-eclampsia and thyroid
      profile. In a case-control setting, total thyroxine (T4), total tri-iodothyronine
      (T3), free T4, free T3, thyroxine binding globulin (TBG) and thyrotropin (TSH)
      levels in 39 pre-eclamptic patients were measured and compared with the levels in
      42 healthy controls. We examined possible variations with regard to the severity
      of pre-eclampsia by dividing cases into mild (n = 17) and severe (n = 22)
      subgroups. Patients with mild pre-eclampsia showed significantly increased free
      T4 and TSH levels compared to healthy controls. In severe cases, TSH level was
      higher, but free T3 and free T4 levels were significantly lower than in controls.
      Other tests returned non-significant differences between the groups. Our findings
      suggest that primary hypofunctioning of the thyroid can accompany mild pre
      eclampsia and possibly contribute to the pathogenesis. Elevated levels of free
      thyroid hormones in severe cases, however, may have reflected a preceding thyroid
      disorder.

PMID- 15195500
TI  - Association of adenylate cyclase with an actin-like protein in the human
      myometrium.
AB  - Regulation of muscle contraction by second messengers such as cAMP and regulation
      of the adenylate cyclase enzyme by the cytoskeleton have been previously
      described. However, the physical association of both effector and structural
      elements is still unknown. In this context, we have co-purified a human
      myometrial adenylate cyclase with an actin-like protein in a two-step
      purification protocol. The adenylate cyclase catalytic unit was solubilized with
      Lubrol-PX, submitted to anionic exchange chromatography and purified about 7
      fold. The eluate was applied to a forskolin-agarose column obtaining an adenylate
      cyclase extract enriched 257-fold (enzymatic activity of 1390 pmol/30 min per mg
      protein) that co-eluted with a 74.6-kDa protein that possessed the 18-27 amino
      acid fragment from the N-terminal region of human actin. Under non-reducing
      conditions, the apparent molecular weight of this protein decreased to 54 kDa,
      which has been previously described for arthrin. These results provide the first
      demonstration of the physical association of human myometrial adenylate cyclase
      with a cytoskeleton-related protein, supporting the hypothesis that adenylate
      cyclase is regulated by mechanical stimuli.

PMID- 15195502
TI  - Proliferation kinetics in adenomyosis during the menstrual cycle and during oral
      contraceptive use.
AB  - Our objective was to investigate the presence of focal p53 expression in relation
      to proliferation rates in adenomyotic lesions during the menstrual cycle and in
      women on oral contraception. Fifty-nine perimenopausal patients with menorrhagia
      and adenomyosis were submitted to endometrial resection. The procedure was
      carried out during menstruation (n = 14), during the proliferative phase (n =
      15), during the luteal phase (n = 20) or following the use of oral contraceptives
      (n = 10). The number of Ki-67-positive cells was low during menstruation, during
      the luteal phase and following the use of progestins. In the proliferative phase,
      on the other hand, there was a significant increase in the percentage of Ki-67
      positive cells. Focal p53 expression was detected mainly during the proliferative
      phase of the menstrual cycle when proliferation rates were high. PTEN expression
      was detected in all cases irrespective of the phase of the menstrual cycle or use
      of oral contraception. We conclude that proliferation rates in adenomyotic
      lesions undergo marked cyclic variations and this affects the percentage of cases
      showing focal p53 expression in the glandular epithelium.

PMID- 15195503
TI  - The prognostic value of serum inhibin, 17 beta-estradiol and progesterone in
      cases of hydatidiform mole.
AB  - The purpose of this study was to provide a diagnostic and a prognostic variable
      that could easily be measured in the laboratory, and that would predict the need
      for future therapy of persistent gestational trophoblastic disease. There would
      no longer be a need to treat all cases of hydatidiform mole prophylactically, to
      improve the outcome in only about 20% predicted to develop malignant gestational
      trophoblastic tumors. Circulating beta-human chorionic gonadotropin (beta-hCG),
      progesterone, 17 beta-estradiol and inhibin levels were measured using standard
      radioimmunoassays in 60 patients with complete hydatidiform mole and in 20 normal
      pregnant women of a corresponding duration of pregnancy and having a maternal
      indication for therapeutic abortion. There were no significant statistical
      differences between the two groups as regards gravidity, parity and gestational
      age. There was a significant statistical difference between patients with a molar
      pregnancy who developed gestational trophoblastic tumors (GTT) and those who did
      not develop GTT as regards pre-evacuation and follow-up mean serum beta-hCG, mean
      serum progesterone and mean serum 17 beta-estradiol levels. These findings
      together with the persistently elevated mean serum progesterone and mean serum 17
      beta-estradiol levels at 6 weeks after evacuation in all cases who developed GTT
      suggested that progesterone as well as 17 beta-estradiol serum levels might be of
      prognostic value in cases of molar pregnancy. However, larger numbers of cases
      are required to correlate findings to beta-hCG serum level. Although mean serum
      inhibin level was significantly higher in women with hydatidiform mole than in
      normal pregnant women, it lacks any prognostic value for detection of subsequent
      gestational trophoblastic tumors.

PMID- 15195504
TI  - Umbilical endometriosis in pregnancy: a case report.
AB  - To our knowledge, this is the first case reported in the literature of umbilical
      endometriosis in a pregnant woman. We report a case of umbilical endometriosis in
      a pregnant woman at 16 weeks of gestation. The patient revealed a reddish-brown
      polypoid nodule within the umbilical depression, with the typical history of
      monthly bleeding from the umbilicus. A nodule biopsy, testing of serum levels of
      CA-125 and a transabdominal ultrasound examination were performed. The diagnosis
      of endometriosis was confirmed by pathological examination. Serum levels of CA
      125 were slightly increased and the pelvic ultrasound examination did not
      identify ovarian cysts of a possible endometriotic nature. The patient was also
      examined at 24 weeks' gestation, after delivery and in the late postpartum
      period. No therapy was given and the lesion resolved spontaneously 2 months after
      the biopsy was taken.

PMID- 15195505
TI  - Introduction: radiosensitization by hyperthermia.

PMID- 15195506
TI  - Role of nuclear protein denaturation and aggregation in thermal
      radiosensitization.
AB  - Hyperthermia at temperatures above 41 degrees C denatures a set of thermolabile
      cellular proteins located in all parts of the cell. Non-histone nuclear proteins,
      including those comprising the nuclear matrix, appear to be particularly
      thermolabile. Heating isolated nuclear matrices of Chinese hamster lung (CHL) V79
      cells to 46 degrees C at 1 degree C/min results in approximately 15%
      denaturation. Protein unfolding during denaturation exposes buried hydrophobic
      residues, which increases protein-protein interactions and results in the co
      aggregation of denatured thermolabile proteins and native, aggregative-sensitive
      nuclear proteins. This aggregated protein, the majority of which is native, is
      insoluble and resistant to extraction during isolation of nuclei and is
      responsible for the increased protein content, usually expressed as an increased
      protein:DNA ratio, of nuclei isolated from heated cells. A large fraction of the
      aggregated protein is found to be associated with the nuclear matrix, distributed
      throughout the fibre network and nucleolus. Three general consequences of nuclear
      protein denaturation and aggregation of relevance to cellular damage are: (1)
      protein (enzyme) inactivation, both direct inactivation of thermolabile proteins
      and indirect inactivation due to co-aggregation; (2) reduced accessibility and
      altered physical properties of DNA due to masking by aggregated protein; and (3)
      protein redistribution into and out of the nucleus. Functional impairment of the
      nucleus appears to be due to one or a combination of these basic mechanisms.

PMID- 15195507
TI  - Mechanism of radiosensitization by hyperthermia (> or = 43 degrees C) as derived
      from studies with DNA repair defective mutant cell lines.
AB  - All biochemical and cytogenetic data on radiosensitization by heat treatment at
      and above 43 degrees C indicate that inhibition of DNA repair plays a central
      role. There are several DNA repair pathways involved in restoration of damage
      after ionising irradiation and the kinetics of all of them are affected by heat
      shock. This, however, does not imply that the inhibition of each of these
      pathways is relevant to the effect of heat on cellular radiosensitivity. The
      current review evaluates the available data on heat radiosensitization in mutant
      or knockout cell lines defective in various DNA repair proteins and/or pathways.
      The data show that thermal inhibition of the non-homologous end-joining pathway
      (NHEJ) plays no role in heat radiosensitization. Furthermore, limited data
      suggest that the homologous recombination pathway may also not be a major heat
      target. By deduction, it is suggested that inhibition of base damage repair (BER)
      could be the crucial step in radiosensitization by heat. While a lack of mutant
      cell lines and redundancy of the BER pathway have hampered efforts toward a
      conclusive study, biochemical and correlative evidence support this hypothesis.

PMID- 15195508
TI  - Is DNA polymerase beta important in thermal radiosensitization?
AB  - Thermal radiosensitization was tested in a pair of mouse cells (MB+ wild-type and
      MB-, DNA polymerase beta knockout cells) and in human breast carcinoma cells
      (MCF7 wild-type and C716 transfected to give elevated DNA polymerase beta
      expression). Results showed that neither reducing DNA polymerase beta (involved
      in base excision repair) nor increasing it had any significant effect on thermal
      radiosensitization. The data indicated that polymerase beta was not involved in
      thermal radiosensitization, and since hyperthermia is known as a radiation damage
      repair inhibitor, other repair pathways might be involved and need to be
      explored.

PMID- 15195509
TI  - Effects of heat shock on the Mre11/Rad50/Nbs1 complex in irradiated or
      unirradiated cells.
AB  - The mechanism by which hyperthermia sensitizes mammalian cells to ionizing
      radiation remains to be elucidated, but an overwhelming amount of circumstantial
      evidence suggests that heat radiosensitization might be mediated by inhibition of
      double-strand break repair, particularly after exposure of irradiated cells to
      heat treatments in excess of about 43 degrees C. In mammalian cells, double
      strand break repair usually occurs via two pathways, non-homologous end-joining
      and homologous recombination. Several reports suggest a role for non-homologous
      end-joining in heat radiosensitization, while others implicate homologous
      recombination as a target. However, cell lines that are compromised in either the
      non-homologous end-joining or homologous recombination pathway are still capable
      of being radiosensitized, suggesting that heat affects both pathways. Indeed,
      several of the proteins involved in one or both of these pathways have been
      observed to undergo alterations or translocation after unirradiated or irradiated
      cells are exposed to heat shock. The work summarized in this review implicates
      proteins of the Mre11/Rad50/Nbs1 complex as targets for heat radiosensitization.

PMID- 15195510
TI  - Transfection of human tumour cells with Mre11 siRNA and the increase in radiation
      sensitivity and the reduction in heat-induced radiosensitization.
AB  - Double-strand DNA breaks (DSBs) are potentially lethal DNA lesions induced by
      ionizing radiation. In eukaryotes, DSBs can be repaired by homologous
      recombination (HR) or non-homologous end-joining (NHEJ). DNA repair protein Mre11
      participates in both the NHEJ and HR DNA repair pathways. Hyperthermia has been
      used clinically as a radiosensitizer. However, the mechanisms by which
      radiosensitization is induced by hyperthermia, especially moderate hyperthermia
      (41 degrees C) are not fully understood. Previous studies suggest that 41 degrees
      C reduces the nuclear Mre11 protein level in a manner that correlates with heat
      induced changes in radiation sensitivity. Therefore, siRNA technology was used in
      the present study to reduce Mre11 gene expression to determine if reduced Mre11
      protein levels induced radiosensitization and if such radiosensitization is
      similar to that induced by moderate hyperthermia. The results show that (1) the
      cellular level of the Mre11 protein was reduced about 60 +/- 18% by a 24-h
      treatment with siRNA. Results from the Mre11 protein turnover assay showed a half
      life of 11.6 +/- 0.5 h for the Mre11 protein, which is consistent with reduction
      in protein level in 24 h after Mre11 siRNA treatment assuming a delay of 4-8 h to
      reduce RNA levels. After 48 h in siRNA, cellular Mre11 protein levels increased
      to approximately pretreatment levels. NSY cells were sensitized to ionizing
      radiation after 24 h of treatment with Mre11 siRNA. Two hours at 41 degrees C did
      not increase the radiation sensitivity of cells with a reduced Mre11 protein
      level following a 24-h siRNA treatment. These data support the conclusion that
      the DSB repair protein, Mre11, appears to be a target for radiosensitization by
      moderate hyperthermia.

PMID- 15195511
TI  - Physiological mechanisms underlying heat-induced radiosensitization.
AB  - The objective of this review is to evaluate hyperthermia related changes in tumor
      physiologic parameters and their relevance for tumor radiosensitization with
      particular emphases on tumor oxygenation. Elevation of temperature above the
      physiological level causes changes in blood flow, vascular permeability,
      metabolism, and tumor oxygenation. These changes in addition to the cellular
      effects such as direct cytotoxicity, inhibition of potentially lethal damage and
      sublethal damage repair, have an important influence on the efficacy of
      radiotherapy. There is now clear evidence that in a variety of rodent and canine,
      as well as human tumors, the changes in tumor oxygenation status caused by
      hyperthermia are temperature dependent and this relationship may greatly
      influence the response of tumors to thermoradiotherapy. The improvement of tumor
      oxygenation after mild hyperthermia, which often lasts for as long as 24-48 h
      after heating, may increase the likelihood of a positive response of tumors to
      radiation therapy. Furthermore, the activity of some chemotherapy drugs is also
      oxygen dependent, therefore, the heat-induced increase in tumor oxygenation may
      significantly increase the effectiveness of thermoradiotherapy in combination
      with certain chemotherapy drugs. Further investigations remain to be conducted to
      obtain clearer insights into the relationship between thermal parameters,
      oxygenation and response of human tumors to hyperthermia in combination with
      radiotherapy and/or chemotherapy.

PMID- 15195512
TI  - Long duration mild temperature hyperthermia and brachytherapy.
AB  - Combining long duration mild temperature hyperthermia (LDMH) and low dose-rate
      (LDR) brachytherapy to enhance therapeutic killing of cancer cells was proposed
      many years ago. The cellular and tumour research that supports this hypothesis is
      presented in this review. Research describing LDMH interaction with pulsed
      brachytherapy and high dose-rate brachytherapy using clinically relevant
      parameters are compared with LDMH/LDR brachytherapy. The mechanism by which LDMH
      sensitizes LDR has been established as the inhibition of sublethal damage repair.
      The molecular mechanisms have been shown to involve DNA repair enzymes, but the
      exact nature of these processes is still under investigation. The relative
      differences between LDMH interactions with human and rodent cells are presented
      to help in the understanding of possible roles of LDMH in clinical application.
      The role of LDMH in modifying tumour blood flow and its possible role in LDR
      sensitization of tumours is also presented. The positive aspects of LDMH
      brachytherapy for clinical application are sixfold; (1) the thermal goals
      (temperature, time and volume) are achievable with currently available
      technology, (2) the hyperthermia by itself has no detectable toxic effects, (3)
      thermotolerance appears to play a minor if any role in radiation sensitization,
      (4) TER of around 2 can be expected, (5) hypoxic fraction may be decreased due to
      blood flow modification and (6) simultaneous chemotherapy may also be sensitized.
      Combined LDMH and brachytherapy is a cancer therapy that has established
      biological rationale and sufficient technical and clinical advancements to be
      appropriately applied. This modality is ripe for clinical testing.

PMID- 15195513
TI  - Optimization of radioimmunotherapy interactions with hyperthermia.
AB  - The efficacy of radioimmunotherapy (RIT) employing radiolabelled monoclonal
      antibodies (MAb) is currently limited in most solid tumours. The combination of
      local hyperthermia (HT) with RIT has the potential to enhance tumour targeting of
      MAb; moreover, this approach may add an antitumour effect to radioresistant
      hypoxic and S-phase cells and may inhibit the cells from repairing sublethal
      damage or potentially lethal damage caused by ionizing radiation. There are
      distinct types of protocols in this combination. Hyperthermic temperature and
      timing relative to RIT administration appear to affect the efficacy of the
      combination therapy. Responses to heating at any particular condition are not
      always the same among different tumour types. There are many papers describing
      influence of HT on the biodistribution of radiolabelled MAb, but only limited
      information is currently available on 'therapeutic' outcomes regarding the
      dependency of combination protocols. A previous study suggested that the best
      therapeutic improvement would be achieved when HT was combined immediately after
      the administration of MAb, which significantly increases the radiation absorbed
      dose to tumours and produces a uniform intratumoural dose distribution. Further
      therapeutic investigation should be required to reach the optimal protocol of
      combining these two modalities.

PMID- 15195514
TI  - Modelling heat-induced radiosensitization: clinical implications.
AB  - Clinically achievable minimum tumour temperatures are in the order of about 41
      degrees C. Therefore, it is important to evaluate mechanisms by which
      temperatures in this range might enhance cytotoxicity. Previous in vitro studies
      have demonstrated that 1-4 h (depending on the sequencing of modalities) of
      heating at 41 degrees C produces substantial heat-induced radiosensitization with
      little or no cell killing by heat alone. The increased radiation sensitivity is
      best modelled as a change in the single hit, alpha, parameter (with no
      significant effect on the two-hit parameter, beta) of the cell survival curve.
      The implications of heat-induced radiosensitization being mediated by a change in
      alpha on the traditional thermal enhancement ratio (for various radiation
      doses/fraction and alpha/beta) are reviewed. Response rates for a cohort of 60
      patients enrolled on a prospective thermal dose escalation study are modelled
      assuming that the thermal dose dependence of heat-induced radiosensitization is
      modulated by a heat-induced delta alpha. The clinical data are fitted with delta
      alpha about 0.05-0.1 Gy-1. Randomized trials reported in the literature and the
      implication for the design of future prospective trials are reviewed in light of
      these observations.

PMID- 15195515
TI  - Thermal stress and the disruption of redox-sensitive signalling and transcription
      factor activation: possible role in radiosensitization.
AB  - In spite of ongoing research efforts, the specific mechanism(s) of heat-induced
      alterations in the cellular response to ionizing radiation (IR) remain ambiguous,
      in part because they likely involve multiple mechanisms and potential targets.
      One such group of potential targets includes a class of cytoplasmic signalling
      and/or nuclear transcription factors known as immediate early response genes,
      which have been suggested to perform cytotoxic as well as cytoprotective roles
      during cancer therapy. One established mechanism regulating the activity of these
      early response elements involves changes in cellular oxidation/reduction (redox)
      status. After establishing common alterations in early response genes by
      oxidative stress and heat exposure, one could infer that heat shock may have
      similarities to other forms of environmental antagonists that induce oxidative
      stress. In this review, recent evidence supporting a mechanistic link between
      heat shock and oxidative stress will be summarized. In addition, the hypothesis
      that one mechanism whereby heat shock alters cellular responses to anticancer
      agents (including hyperthermic radiosensitization) is through heat-induced
      disruption of redox-sensitive signalling factors will be discussed.

PMID- 15195516
TI  - Heat shock and the activation of AP-1 and inhibition of NF-kappa B DNA-binding
      activity: possible role of intracellular redox status.
AB  - The early response genes comprising the AP-1 and NF-kappa B transcription factors
      are induced by environmental stress and thought to modulate responses to injury
      processes through the induction of target genes. Exposure to heat and ionizing
      radiation (IR) has been shown to affect signalling machinery involved in AP-1 and
      NF-kappa B activation. Furthermore, regulation of the signalling pathways leading
      to the activation of these transcription factors has been linked to changes in
      intracellular oxidation/reduction (redox) reactions. The hypothesis is proposed
      that exposure to thermal stress and/or IR might alter metabolic processes
      impacting upon cellular redox state and thereby modify the activity of redox
      sensitive transcription factors such as AP-1 and NF-kappa B. Gel electromobility
      shift assays (EMSA) demonstrated that heat shock-induced AP-1 DNA-binding
      activity but inhibited IR-induced activation of NF-kappa B. A time course showed
      that activation of the AP-1 complex occurs between 4 and 5 h following thermal
      stress, and inhibition of IR-induced NF-kappa B activation also occurs during
      this time interval. Using a redox-sensitive fluorescent probe [5-(and -6)-carboxy
      2',7'-dichlorodihydrofluorescein diacetate], a shift to 40% less intracellular
      dye oxidation was observed in HeLa cells 0-4 h post-heat shock (45 degrees C, 15
      min) relative to cells held at 37 degrees C. This was followed by a shift to
      greater dye oxidation between 4 and 12 h after treatment (about 1.8-fold) that
      returned to control levels by 24 h post-heating. These results show changes in
      DNA-binding activity closely paralleled apparent heat-induced changes in the
      intracellular redox state. Taken together, these results provide correlative
      evidence for disruption of redox-sensitive IR-induced signalling pathways by heat
      shock and support the hypothesis that this mechanism might play a role in heat
      induced alterations in radiation response.

PMID- 15195517
TI  - Heat induced 'masking' of redox sensitive component(s) of the DNA-nuclear matrix
      anchoring complex.
AB  - The 'masking effect' is the observation that heat shock reduces or masks the
      apparent expression of ionizing radiation (IR) damage to DNA. The mechanism of
      this effect is thought to involve the aggregation of proteins to the nuclear
      matrix or chromatin, thereby stabilizing these structures and masking actual DNA
      damage from assays and presumably from DNA repair complexes. Previously, using
      the 'halo assay', it has been shown that nucleoids treated with 1 mM
      dithiothreitol (DTT) and/or inhibited the rewinding of DNA supercoils and that
      this effect was masked in nucloids isolated from heated cells. Here it is
      reported that treatment of living cells with reducing agents diminishes the
      interaction between DNA and Protein Disulphide Isomerase (PDI) and that
      hyperthermia restored the PDI-DNA interaction, indicating that the masking effect
      occurred in vivo. PDI is a nuclear matrix protein which binds MAR DNA sequences
      and may be involved in regulating the degree of DNA supercoiling. It is
      hypothesized that heat-induced stabilization of PDI-DNA interaction will mask
      changes in supercoiling observed with reducing reagents and also IR. This
      stabilization may be affected through either the heat-induced association or
      enhancement of the binding of proteins to MAR DNA at the NM. Several proteins,
      including B23 and Hsp60, have been identified whose interaction with DNA
      increased following heat shock. Further work will be needed to determine if these
      proteins do, in fact, play a role in the masking effect.

PMID- 15195518
TI  - Evidence for an S-phase checkpoint regulating DNA replication after heat shock: a
      review.
AB  - Exposure of cells to heat inhibits a number of nuclear activities associated with
      semi-conservative replication of DNA including the incorporation of radiolabelled
      precursors into acid-insoluble DNA, the initiation of new replicons, the
      elongation of the DNA fibre at the replication fork, the synthesis and deposition
      of new histones into chromatin and the reorganization of nascent DNA into mature
      chromatin. These effects are likely to underlie the heat sensitivity of S-phase
      cells and may contribute to the radiosensitization observed in this phase of the
      cell cycle. While some of these effects may be explained as 'passive'
      consequences of heat-induced damage on chromatin structures experiments reviewed
      here point to the activation of a checkpoint as a contributing factor to the
      observed inhibition of DNA replication. Activation of a heat responsive S-phase
      checkpoint targets the activity of RPA via interaction with nucleolin. Nucleolin,
      a major nucleolar protein, is found normally sequestered in the nucleolus.
      Exposure of cells to heat causes a rapid translocation of nucleolin from the
      nucleolus into the nucleoplasm that enables RPA/nucleolin interaction. This
      interaction inhibits functions of RPA associated with the initiation of DNA
      replication and contributes to the immediate inhibition of DNA synthesis observed
      after heat shock. The results suggest that the nucleolus serves as a
      sequestration centre for the temporary inactivation of regulatory molecules, such
      as nucleolin, capable of regulating essential cellular functions after heat
      shock. It is speculated that this regulatory process is integrated in the network
      of responses that determine cell sensitivity to heat and that it may be involved
      in heat radiosensitization to killing as well.

PMID- 15195519
TI  - [Implementation of habituation theory to pulsatile somato-sounds (tinnitus): the
      heart valve prosthesis sound model].
AB  - OBJECTIVES: To evaluate the habituation process to mechanical heart valve
      prosthesis sound as a model to understand the pulsatile tinnitus or somatosound
      perception changes. STUDY DESIGN: Transversal descriptive. PATIENTS: One hundred
      and fifty patients referred to a University Hospital for one or two mechanical
      heart valve implantation. OUTCOME MEASURES: Questionnaire sent by mail for
      prosthesis sound loudness and interference in quality of life evaluation.
      Detection of factors related to habituation process development. RESULTS: Eighty
      three percent of the patients perceived their prosthesis sound continuously,
      while only a 17% showed high levels of annoyance. No significative differences in
      prosthesis type and localization were described. Anxiety was the most important
      factor for loudness increase. The average of visual analogical scales on sound
      loudness and annoyance showed mild values (3.7 and 1.9 respectively).
      CONCLUSIONS: Extensive medical counselling or tinnitus retraining therapy (TRT)
      program for most severe cases, are proposed for pulsatile tinnitus management
      when etiological treatment cannot be available.

PMID- 15195520
TI  - [Auricular chondritis. Experimental model in rats].
AB  - The general pattern of local inflammation in the rat is developed in the pad of
      the paw. In otorhinolaryngology a model of local inflammation can be reached in
      the rat ear by means of the production of an auricular chondritis. For that, we
      have protocolized the methodology. The induction of inflammation is carried out
      by the substance vegetable carrageenan. It has been verified by histological
      studies the inflammation generated, as well as studying the action of
      antiinflammatory, proinflammatory and inflammatory compounds. The inflammation
      has been measured by nonius and by determination of the activity of the
      myeloperoxidase enzyme. After these studies we can validate the auricular
      chondritis in rat as an experimental model of local inflammation in
      otorhinolaryngology.

PMID- 15195521
TI  - [Sensory interaction in posturography].
AB  - OBJECTIVE: The aim of this work is to show the results obtained with a dynamic
      posturography on a stabilometric platform and to create relative parameters of
      study. MATERIAL AND METHODS: The study was performed on 127 patients with
      dizziness of a peripheral vestibular origin and the results analyzed in a dynamic
      posturography under six conditions of stimulation. RESULTS: The values obtained
      under the studied conditions of dynamic posturography are significantly different
      when the conditions of test increases sensorial conflicts. We could create 15
      news relatives parameters which are in normal distribution. CONCLUSIONS: Dynamic
      posturography over stabilometric platform could be considered as a good test in
      the evaluation of vertiginous patients. Different stimulations introduce more
      sensibility to the test.

PMID- 15195522
TI  - [Hypopharyngeal cancer: analysis of the evolution and surgical results].
AB  - OBJECTIVE: Hypopharyngeal carcinoma is an aggressive malignancy that usually
      presents at a late stage, thereby resulting in an overall poor prognosis for
      these patients. The aim of this study is to determine the evolution and
      postoperative results of patients treated in our department for hypopharyngeal
      cancer. METHODS: We retrospectively reviewed 60 patients who had undergone
      surgery followed by radiation therapy between 1980-1999. Most of them were
      advanced stage (III-IV) and 75% patients showed regional metastases at
      presentation. RESULTS: The 5-year survival rate was 38.4%. The overall incidence
      of distant metastases and second neoplasms was 12.5% and 10.4%. CONCLUSIONS:
      Hypopharyngeal cancer remains one of the most lethal ones in head and neck
      cancer. The poor survival rate is related primary to advanced stage disease and
      particularly to lymph node metastases.

PMID- 15195523
TI  - [Selective neck dissection in patients presenting clinical node metastases].
AB  - OBJECTIVE: To evaluate the results obtained with selective neck dissection in
      patients with clinically positive neck nodes at diagnosis (N+). PATIENTS AND
      METHODS: Retrospective study of N+ patients treated with a lateral or
      supromohyoid selective neck dissection with prophylactic purpose (sides of the
      neck N0) or therapeutic purpose (sides of the neck N+). RESULTS: Forty nine
      selective neck dissections were carried out in 42 N+ patients. In 18 cases the
      neck dissection had a prophylactic purpose (sides of the neck N0), and in 31 of
      them a therapeutic purpose (sides of the neck N+). In 39 patients summary was
      followed by postoperative radiotherapy. There was no regional relapse in either
      side of the neck treated with a selective neck dissection. CONCLUSIONS: Selective
      neck dissections in selected N+ patients are an adequate surgical technique. The
      main advantages of selective neck dissections are to shorten the surgical time,
      and to avoid the morbility associated with the dissection of the neck zones not
      included.

PMID- 15195525
TI  - [CCND1 gene amplification in the adenoid cystic carcinoma of the minor salivary
      glands].
AB  - OBJECTIVE: Adenoid cystic carcinoma (ACC) is a tumour of epithelial origin that
      represents the most common malignant neoplasm of the minor salivary glands.
      However, little is known about the genes involved in the development and
      progression of this tumour. Cyclin D1 gene (CCND1) plays a key role in the
      control of the cell cycle, and its amplification is described in numerous
      cancers. The aim of this study is to determine the amplification of the CCND1
      gene in the ACC of the minor salivary glands. MATERIALS AND METHODS: A
      retrospective study was performed on 12 patients with ACC of the head and neck.
      The amplification of the CCND1 was determined using multiple PCR. RESULTS:
      Amplification of the CCND1 was found in 4 patients (33.3%). No correlation was
      found between CCND1 amplification and clinicopathological parameters, although
      disease-free survival was diminished in patients with amplification.
      DISCUSSION/CONCLUSIONS: Our study demonstrates for the first time the
      amplification of the CCND1 gene in ACC. We have found an amplification rate
      similar to others neoplasms. CCND1 amplification seems to be associated with a
      poorer prognosis in these tumours, although this needs to be confirmed in larger
      studies.

PMID- 15195524
TI  - [Effect of the hyaluronic acid on tracheal healing. A canine experimental mode].
AB  - Several drugs have been used to modulate of the tracheal healing process in order
      to prevent tracheal stenosis. Hyaluronic acid (HA) is a modulator of the
      fibrogenesis. In this work we evaluate the effect in order the application of
      hyaluronic acid has on tracheal healing, after cervical tracheoplasty in dogs. A
      cervical tracheal resection and tracheoplasty was performed in 12 dogs and they
      were treated following surgery as follows: Group I (n = 6) Topical application of
      normal saline solution (0.9%) on the anastomosis site. Group II Topical
      application of hyaluronic acid on the trachea anastomosed. The animals were
      evaluated clinical, radiological and tracheoscopically during 4 weeks and were
      submitted to euthanasia. Macroscopic and microscopic examinations of the tracheal
      anastomotic healing were evaluated. Biochemical collagen quantification by the
      Woessner method was performed to evaluate the collagen development at the
      anastomotic site. All the animals survived the surgical procedure and the study
      time. No animal presented differences in clinical evaluation. Radiological and
      endoscopical findings both two showed more development of the tracheal stenosis
      in-group than in group II. The tracheoscopy and macroscopic studies showed major
      inflammation and development of fibrotic tissue with a firm consistency in the
      healing of the group I than in group II. Microscopic examination in group I
      showed severe fibrosis and inflammatory reaction. The group II presented deposits
      of a thin and organized collagen fibers and minimal inflammatory reaction.
      Biochemical collagen concentration was larger in-group I, however significantly.
      We conclude that the hyaluronic acid applied after cervical tracheoplasty in dogs
      reduces postsurgical tracheal stenosis and inflammation, as well as improve the
      quality of the tracheal healing.

PMID- 15195526
TI  - [Supernumerary nostril].
AB  - Supernumerary nostril is an extremely rare congenital anomaly as a result of
      aberrant embryological development. Frequently it leads to a narrow cavity; in
      the end, opening into the nearest nasal cavity or just stops blindly after a
      short course. It can appear isolated or in association with other anomalies.
      Treatment is always surgical. We present a case of a triple nostril, associated
      to a congenital auricular hypoplasia and we also review the existing literature.

PMID- 15195527
TI  - [Usefulness of the new classification for regional extension on CT of head and
      neck cancer].
AB  - OBJECTIVE: To present the usefulness of the new classification of neck nodes
      based in commuted tomography (CT). MATERIAL AND METHODS: We present several
      illustrative images showing neck nodes in each of the new levels (Ia, Ib, IIa,
      IIb, III, IV, Va, Vb, and VI) as an adjunct to nodal classifications. RESULTS AND
      CONCLUSION: An imaging-based classification for the cervical nodes allows to know
      much better their distribution along the neck, helping to find correlation
      between clinical, radiological and surgical findings.

PMID- 15195528
TI  - [Pharmacological modulation of portal hypertension syndrome: current status and
      future prospects].

PMID- 15195529
TI  - [Influence of circulatory dysfunction on the treatment of ascites and hepatorenal
      syndrome: vasoconstrictor and diuretic drug treatment].

PMID- 15195530
TI  - [Pathogenesis of non-alcoholic fatty liver and potential therapeutic targets].

PMID- 15195531
TI  - [Current and future applications of viral clearance kinetics in the treatment of
      hepatitis C].

PMID- 15195532
TI  - [Physiopathological bases for the treatment of acute alcoholic hepatitis].

PMID- 15195533
TI  - [New concepts in the physiopathology of hepatic encephalopathy and therapeutic
      prospects].

PMID- 15195534
TI  - [Influence of blood coagulation disorders on hepatic vascular diseases and
      therapeutic possibilities].

PMID- 15195535
TI  - [Implications of the immunologic response to the graft in the design of
      immunosuppressive treatment for liver transplantation].

PMID- 15195536
TI  - Taking employers to task on disputes.

PMID- 15195538
TI  - A new approach to cancer nursing.

PMID- 15195537
TI  - Cancer care.

PMID- 15195539
TI  - 'Caring for a patient with cancer was a turning point'.

PMID- 15195540
TI  - The value of cholera vaccination in promoting travel health.
AB  - Cholera is a diarrhoeal disease caused by intestinal infection with Vibrio
      cholerae bacterium (Health Protection Agency, 2004). Travellers are now able to
      obtain a cholera vaccine in the UK. Although cholera is rare in travellers from
      the UK, its potential severity is a cause for concern. Nurses will need to
      consider the availability of this new vaccine when providing health promotion to
      travellers.

PMID- 15195541
TI  - What you need to know about ... sun awareness.

PMID- 15195542
TI  - Ensuring good management of diabetes in intercurrent illness.
AB  - When diabetic patients become unwell with another illness, hyperglycaemia will
      result and patients' usual self-management techniques may be inadequate.
      Education for patients with diabetes should be as much about planning how they
      would manage their diabetes during a period of illness as well as coping at the
      time. This article outlines the aims stated within the National Service Framework
      for Diabetes (Department of Health, 2001) and provides both theoretical
      background and practical application to preventing diabetic ketoacidosis and
      hyperosmolar non-ketotic syndrome.

PMID- 15195543
TI  - Using an assessment tool for mental health team referrals.
AB  - The Threshold Assessment Grid (TAG) (Slade et al, 2000) is a short assessment
      that has been developed to define severe mental illness and identify a client's
      suitability to be treated by secondary mental health services. It was implemented
      into an integrated mental health team.

PMID- 15195544
TI  - Using clinical governance to improve care of older people.

PMID- 15195546
TI  - The assessment of dark skin and dermatological disorders.
AB  - The UK has a multicultural population with a range of skin colours and hair
      types. Dermatological disorders affect up to 33 per cent of the population, and
      cause severe problems for about 10 per cent of cases (All Parliamentary Group on
      Skin, 1997). The detrimental effects of dermatological disorders include social
      isolation and stigma (Lewis-Jones, 2000). In order to minimise these negative
      effects it is important that patients are assessed and diagnosed efficiently and
      with compassion so that they can be treated appropriately.

PMID- 15195545
TI  - Using judgement to improve accuracy in decision-making.
AB  - Nursing judgements are complex, often involving the need to process a large
      number of information cues. Key issues include how accurate they are and how we
      can improve levels of accuracy. Traditional approaches to the study of nursing
      judgement, characterised by qualitative and descriptive research, have provided
      valuable insights into the nature of expert nursing practice and the complexity
      of practice. However, they have largely failed to provide the data needed to
      address judgement accuracy. Social judgement analysis approaches are one way of
      overcoming these limitations. This paper argues that as nurses take on more roles
      requiring accurate judgement, it is time to increase our knowledge of judgement
      and ways to improve it.

PMID- 15195547
TI  - An evaluation of NICE guidelines on foot care for patients with diabetes.
AB  - In the NHS, there is a perceived need for evidence-based guidelines to improve
      outcomes in all fields of health care. Management of the diabetic foot, which is
      a major public health problem, is one clinical field that needs quality
      guidelines. In response to this, the National Institute for Clinical Excellence
      (NICE) has published Clinical Guidelines for Type 2 Diabetes: Prevention and
      Management of Foot Problems (2004).

PMID- 15195548
TI  - Provision of alternating air-pressure mattresses in the community.
AB  - The presence of pressure ulcers is seen as a key indicator of quality (Department
      of Health, 1993) and they are both costly to the patient (Franks, 2001) and the
      NHS. It is important that resources are directed towards prevention rather than
      treatment, which makes the provision of pressure-relieving equipment an integral
      part of any strategy for the prevention and management of pressure ulcers.

PMID- 15195550
TI  - Supporting colleagues when patients die. Interview by Janis Smy.

PMID- 15195549
TI  - Causes and effective management of insect bites in the UK.
AB  - Insects play an important role in maintaining the world's ecosystem (Zhu and
      Stiller, 2002) but many of them feed on other animals. Humans are relatively
      hairless and provide an easy target, especially when partly clothed (Cohn, 2003).
      Biting insects common to the UK include midges, gnats, mosquitoes, flies, fleas,
      lice, mites, ticks, and bedbugs (Fig 1).

PMID- 15195551
TI  - Cytokine stimulation by Pseudomonas aeruginosa--strain variation and modulation
      by pulmonary surfactant.
AB  - Pulmonary surfactant and its components are part of the first-line immune defense
      within the lung. Here the authors show that the surfactant protein (SP) SP-D, but
      not SP-A, agglutinates some clinical isolates of Pseudomonas aeruginosa and
      Stenotrophomonas maltophilia. No agglutination of Staphylococcus aureus or
      Burkholderia cepacia was observed. The SP-D-induced agglutination of P.
      aeruginosa was not dependent on a specific lipopolysaccharide (LPS) serotype. The
      authors also show that SP-D, but not SP-A, increased the tumor necrosis factor
      (TNF alpha) release from human monocytic cells in response to a subset of P.
      aeruginosa and P. aeruginosa LPS. A clinical preparation of surfactant
      (Alveofact) blocked the TNF alpha release from monocytic cells induced by P.
      aeruginosa or its LPS. SP-A reversed the inhibitory effect of Alveofact in 6/8
      strains of P. aeruginosa and 2/9 preparations of P. aeruginosa LPS. SP-D did not
      significantly alter the TNF alpha production induced by vital P. aeruginosa in
      the presence of Alveofact but markedly increased the TNF alpha release induced by
      a preparation of rough and smooth P. aeruginosa LPS. In summary, this study shows
      that the immunomodulatory properties of SP-A and SP-D specifically depend on the
      colonizing strain of P. aeruginosa. In addition, the authors show that the
      function of SP-A and SP-D is modulated in the presence of surfactant lipids.

PMID- 15195552
TI  - Analysis of differentially regulated mRNAs in monocytic cells induced by in vitro
      stimulation with Kveim-Siltzbach test reagent.
AB  - Sarcoidosis is a granulomatous disorder of unknown origin. The sarcoid spleen
      derived Kveim-Siltzbach test reagent (KSTR) elicits a sarcoid-specific,
      granulomatous response and was used to diagnose sarcoidosis. The active component
      and the pathomechanism by which KSTR induces granuloma are still unknown. This
      study investigated the KSTR-associated gene expression pattern in cells of
      patients with sarcoidosis or chronic beryllium disease (CBD). The monocytic-like
      cell line U937, alveolar macrophages of sarcoidosis patients, and peripheral
      blood monocytes of patients with CBD were stimulated with KSTR and other
      granuloma-associated stimuli. The KSTR-associated gene expression pattern was
      analyzed by means of differential display reverse transcription-polymerase chain
      reaction in combination with a multiple comparison of expressed sequence tags
      induced in response to KSTR and other granuloma-associated stimuli. Depending on
      the origin of cells tested, 3.7% to 14.6% of the analyzed sequence tags showed
      differential regulation induced by granuloma-associated stimuli. Alterations
      restricted to KSTR stimulation could be observed in 1.2% for the cell line U937,
      in 2.8% for blood monocytes of patients with CBD, and 1.3% for alveolar
      macrophages of sarcoidosis patients. These data are comparable to those achieved
      for the other granuloma-associated stimuli tested in this study. Therefore, it
      can be assumed that KSTR induces pathomechanisms for granuloma formation in
      sarcoidosis as beryllium in CBD.

PMID- 15195553
TI  - beta-hydroxybutyrate induces acute pulmonary endothelial dysfunction in rabbits.
AB  - The authors examined the effects of high ketone body and glucose concentrations
      on endothelial cell (EC) function in perfused rabbit lungs. beta-Hydroxybutyrate
      (beta OHB), at 5 mM, decreased endothelial angiotensin-converting enzyme (eACE)
      activity, whereas 25 mM glucose (HG), 1 mM beta OHB, or 10 mM acetoacetate (AcAc)
      did not. Dry to wet weight ratios were also reduced in lungs perfused with 5 mM
      beta OHB, but not with AcAc. beta OHB, at 5 mM, caused massive hemorrhage and
      interstitial and alveolar neutrophil infiltration; AcAc only produced engorgement
      of septal capillaries. Thus, pulmonary EC dysfunction occurs in rabbit lungs
      acutely perfused with beta OHB, but not with AcAc or glucose.

PMID- 15195556
TI  - [A genomewide scan for the susceptibility gene loci to ankylosing spondylitis in
      Chinese Han population].
AB  - Ankylosing spondylitis (AS) is a common inflammatory arthritis, with a prevalence
      of 1@1000-3@1000 in Caucasian and 2@1000 in Chinese population. The recognition
      of the association of HLA-B27 with AS confirmed the importance of heritable
      factors in the disease. Whole-genome scans showed that some affected-sibling-pair
      families with AS not only demonstrated strong linkage to the MHC locus, but also
      identified other regions with suggestive or stronger linkage on chromosomes 1p,
      2q, 9q, 10q, 16q and 19q. In order to localize the regions containing genes that
      determine susceptibility to AS in Chinese Han population, a genomewide screen was
      performed in nine Chinese families with AS, including 29 affected individuals.
      LINKAGE and GENEHUNTER packages were used for parametric (LOD) and non-parametric
      (NPL) analysis. The significant two-point LOD score value with D6S276 (at 44.9 cM
      from the 6p terminal) was 3.8821 in parametric analysis. Fine mapping showed LOD
      scores of D6S1691 (at 42.7 cM) and D6S1618 (at 47.6 cM) around D6S276 were 1.5717
      and 2.0056, respectively. Single point NPL score of D6S276, D6S1691 and D6S1618
      were 2.6053, 2.7490, 2.0202, respectively, and minimum P value were 0.0072,
      0.0047, and 0.0265, respectively. Using multipoint NPL, the maximum LOD score
      values, NPL score and minimum P value obtained near D6S276 were 5.0623, 3,7561,
      and 0.000233, respectively. As a result, the strong linkage of the D6S276 with AS
      was found, the region of D6S1691-D6S276-D6S1618 existed a susceptibility gene of
      AS. In addition, the LOD scores of D3S1292, D4S1535 and D18S64 were larger than
      1.0, so they might be some suggestive linkage markers with AS.

PMID- 15195554
TI  - Importance of the angiotensin type 1 receptor in angiotensin II-induced
      bronchoconstriction and bronchial hyperresponsiveness in the guinea pig.
AB  - Although angiotensin II (Ang II) causes bronchoconstriction and bronchial
      hyperresponsiveness to methacholine in mildly asthmatic patients, the responsible
      mechanisms for these reactions are unclear. The authors examined the effect of
      intravenous infusion of Ang II on airway constriction in guinea pigs.
      Furthermore, the effects of subthreshold concentrations of Ang II on bronchial
      responsiveness to methacholine were investigated. Airway opening pressure (Pao),
      an index of bronchoconstriction, increased dose dependently after intravenous
      infusion of 3 and 10 nmol/kg Ang II (72.2 and 236.5 increase above the baseline
      value, respectively). In another set of experiments, animals received a
      methacholine inhalation challenge under a constant intravenous infusion of a
      subthreshold dose of Ang II (2 nmol/kg/min). The Ang II infusion elicited
      bronchial hyperresponsiveness to methacholine. The provocative concentration of
      methacholine, which produced a 200% increase above the baseline Pao (PC200),
      decreased from 306.9 to 156.1 micrograms/mL upon Ang II infusion. Pretreatment
      with TCV-116, a type 1 Ang II (AT1) receptor antagonist, but not PD123319, a type
      2 Ang II (AT2) receptor antagonist, dose dependently prevented both the Ang II
      induced bronchoconstriction and bronchial hyperresponsiveness to methacholine.
      The authors conclude that Ang II caused bronchoconstriction and induced bronchial
      hyperresponsiveness to methacholine via the AT1 receptors and that this effect
      did not involve the release of other bronchoactive mediators.

PMID- 15195555
TI  - Smads as intracellular mediators of airway inflammation.
AB  - Transforming growth factor-beta (TGF-beta) plays an important role in the
      pathogenesis of allergic asthma and other airway diseases. Signals from the
      activated TGF-beta receptor complex are transduced to the nucleus of airway cells
      by Smad proteins, which represent a family of transcription factors that have
      recently been implicated to play a major role as intracellular mediators of
      inflammation. The Smad family consists of the receptor-regulated Smads, a common
      pathway Smad, and inhibitory Smads. Receptor-regulated Smads (R-Smads) are
      phosphorylated by the TGF-beta type Ireceptor. They include Smad2 and Smad3,
      which are recognized by TGF-beta and activin receptors, and Smads 1, 5, 8, and 9,
      which are recognized by bone morphogenetic protein (BMP) receptors. Smad4 is a
      common pathway Smad, which is also defined as cooperating Smad (co-Smad) and is
      not phosphorylated by the TGF-beta type I receptor. Inhibitory Smads(anti-Smads)
      include Smad6 and Smad7, which down-regulate TGF-beta signaling. To date, the
      Smads are the only TGF-beta receptor substrates with a demonstrated ability to
      propagate signals and with regard to the growing number of investigations of Smad
      mediated effects in the airways, Smads may prove to be an important target for
      future development of new therapeutic strategies for asthma and chronic
      obstructive pulmonary disease.

PMID- 15195557
TI  - Cloning and functional analysis of the promoter of ZNF268 gene.
AB  - The human ZNF268 gene is a novel C2H2 zinc finger gene restrictively expressed in
      the liver of human embryo. As an initial study on the regulation of its
      expression, 2.5 kb fragment of the ZNF268 5'-flanking region was cloned from
      human genome by PCR. This fragment was inserted into pEGFP1 vector and then the
      recombinant plasmid was transfected into several cell lines by liposomal
      transfection method. EGFP expression was observed in four cell lines under
      confocal laser scanning microscope. A series of 5'-deletion fragments from -2456(
      )+77 bp to -20(-)+77 bp were inserted into pCAT-Basic vector to construct
      recombinant reporter plasmids, which were then transfected into Hela cells for
      deletion analysis. Results of deletion analysis revealed that an important region
      for transcriptional activity lies between -156 and -20 bp.

PMID- 15195558
TI  - Genotype and allele frequency of the variable number tandem repeat polymorphism
      in the VNTR6-1st of the of human telomerase reverse transcriptase (hTERT) gene in
      Chinese population.
AB  - The variable number of tandem repeat (VNTR) polymorphism in the intron 6 of the
      human telomerase reverse transcriptase(hTERT) was investigated. Seven alleles of
      18, 20, 21, 22, 23, 26 and 35 repeats of the 36 bp VNTR6-1st and 14 genotypes
      were identified among 210 unrelated healthy Chinese individuals (Han people)
      living in Beijing. The 20, 22 and 35 repeats were the most frequent alleles which
      accounted for 94.76% of the total alleles observed. The allele frequency of the
      Chinese population showed no difference with that of the Korea population living
      in Pusan except for allele of 35 repeats. But the 5' flanking region of VNTR6-1st
      polymorphic sequence of the Chinese population included a 53-bp insert compared
      with that of korea population except for some alleles of 22 repeats.

PMID- 15195559
TI  - [Differential expression of apoptosis-related gene induced by clinical and
      laboratory Mycobacterium tuberculosis strain in macrophages U937 revealed by
      oligonucleotide microarray].
AB  - Tuberculosis(TB) remains one of the major problems in global health. Macrophage
      (MPhi) apoptosis, induced by Mycobacterium tuberculosis (Mtb), is a cornerstone
      of effective innate microbial defense mechanism. Elucidation of the complex
      apoptosis-related gene expression may facilitate understanding the mechanism and
      regulation of macrophage apoptosis in response to Mtb, and contribute to
      developing novel measures to counter TB. DNA microarray containing 19,200 gene or
      gene fragments was used to compare the macrophage cell line U937 gene expression
      response to the clinical and laboratory Mtb infection. Northern blotting and RT
      PCR were used to confirm the microarray results. Mtb H37Rv infection were found
      to downregulate the bcl-2, vitamin D receptor, interferon regulatory factor 3,
      cytochrome c oxidase, gene expression by 2-, 3-, 3-, 2.5-fold, respectively,
      while the clinical strain infection leads to upregulate the SOD2, SOD3, serine
      protease, toll-like receptor 2, signal transducer and activator (STAT1), hypoxia
      inducible factor 22, 2.9-, 2.5-, 2.5-, 2.2-, 2.4-, 5.9-fold respectively. The
      findings suggest that the clinical strain infection tends to override the
      macrophage apoptosis by which the host attempt to limit the growth of the
      invader. The research on the complex factors network involved in the interaction
      will benefit the vaccine and novel drug target development.

PMID- 15195561
TI  - [Detection of microsatellite instability in primary gastric cancer using
      fluorescence-labelled primers multiplex PCR].
AB  - To assess the role of microsatellite instability(MSI) on chromosome 19 in the
      carcinogenesis of gastric cancer. 26 microsatellite markers on chromosome 19 were
      amplified by Fluorescence-Labelled Primers Multiplex PCR in 44 paired gastric
      cancer tissues for MSI. The amplified fragments ran in PAGE gel by ABI 377
      sequencer and the gel images were analyzed by GeneScan and Genotyper. Meanwhile,
      MSI of four of all microsatellite sites were also analyzed using PCR-SSLP-silver
      stain method. MSI was observed in 22 of 26(84.62%) microsatellite sites. D19S402
      showed the highest frequency(22.73%). The total frequency of MSI was 8.3%. In 44
      gastric cancer samples, 34(77.27%) cases showed MSI at one or more than one site.
      MSI, as a possible mechanism of carcinogenesis, might play an important role in
      human primary gastric cancer. MSI detections will become an integral part of the
      routine classification of all gastrointestinal tumors in the very near future.

PMID- 15195560
TI  - [The active expression of CenpB, a constitutive protein in the centromeres of
      chromosomes, in breast cancer tissues].
AB  - At present, a point that cell biologists and medicine scientists focus their
      close attention on is the mechanisms of cell proliferation and carceration.
      Breast cancer, one of the frequently occurring cancers, is often been studied
      intensively. Centromere constitutive molecules, related to various regulatory
      factors, play an important role in cell proliferation check point regulation.
      Cell cycle engine molecules, oncogenes, anti-oncogenes and other molecules
      conform a cell proliferation network. The basic courses of all tumors are
      associated to this network. However, there are still many problems to be resolved
      in the analyses of cancer related genes which cause tumors and tumor gene
      markers. In the current study, using Northern blot, 31 samples of breast cancer
      tissues and their normal (not cancerous) tissues a little far away from them in
      the same individuals showed that, in the majority of the tests (87.1%), the mRNA
      of centromere protein CenpB over expressed in breast cancer tissues, and
      moreover, tissue in situ hybridization also revealed that all of the CenpB-over
      expressed cancer tissues, having identified with Northern blot, over expressed
      CenpB mRNA. Analyzing the same samples by means of Western blot, the result was
      highly consistent to the studies in the RNA level. A conclusion was drawn that
      the over expression of CenpB gene probably relates to malignant cell
      proliferation in breast gland. It has been testified by researchers that a few of
      CenpB homogenous proteins are co-operative, the loss of their genes resulting in
      chromosomes' separating abnormally and cell growth's slowing down. Having
      transfected HeLa (Tet-Off) cells with anti-sense Cenp in a previous experiment,
      we ever got a result that cellular duplicating time was prolonged for another
      32.8 h, and together with the inhibition of centromere assembly, the mitotic
      index dropped sharply. In another research, we drew a conclusion that CenpG may
      be related to cancer, and its differential expressing probably relates to
      malignant cell proliferation. Combined with these researches, the results
      obtained from the current study are beneficial to further recognition of the
      mechanism of cancer.

PMID- 15195562
TI  - [Cloning of compaction-related gene Crg1 of mouse preimplantation embryos].
AB  - A total of 181 8-cell embryos and 241 8-cell compacted embryos were collected
      respectively from C57BL/6 mouse and their cDNA was synthesized by SMART-PCR. Then
      PCR productions after SSH were cloned into pUCm-T vector according to the size
      after isolated and purified. Choice the positive clones for sequencing after
      being confirmed with PCR. All fragment cloned were blastered matching in GenBank
      for homology analysis. On the base of this work, we select two ESTs (GenBank
      accession No.: BQ740263 and BQ740251), which were reverse complementary to each
      other, assemble into a cDNA fragment, which include a whole open read frame (ORF)
      and submitted to GenBank with an accession number, AY134859. The target fragment
      were amplified from cDNA of mouse compacted embryos using primers designed
      according to the ORF and cloned into pUCm-T vector and sequenced. It's confirmed
      that the gene, Crg1, was the same as AY134859. Crg1 were also blastered matching
      in GenBank for homology analysis and mapped by database analyses. RT-PCR analysis
      of Crg1 were done in series mouse embryos, mouse embryo stem cell and mouse
      embryo fibroblast. We analyzed the expression of Crg1 in 8-cell embryos and 8
      cell compacted embryos using semi-quantity RT-PCR. Northern-blot analysis of Crg1
      expression in some adult mouse tissues was done too. The results showed that the
      length of Crg1 is 810 bp. It include only one exon and code a 150 amino acid
      protein with a theoretical molecular weight of 17670.34 Dalton. The protein is
      similar to a protein encoded by a known gene, Stella. Crg1 was mapped to
      chromosome 14 by database analyses. RT-PCR analysis shows that Crg1 expressed in
      series mouse embryos (2-cell embryos, 4-cell embryos, 8-cell embryos, compacted
      embryos and blastocyst), and expressed little higher in compacted embryos. Crg1
      also expressed in mouse embryo stem cell but not expressed in mouse embryo
      fibroblast. The gene only expressed weakly in adult mouse ovary, but not
      expressed in other adult mouse tissues (brain, spleen, heart, skeletal muscle,
      kidney, testis, epididymis, liver and lung). So, Crg1 may related to compaction
      in compacted embryos and maintaining cell's pluripotentiality.

PMID- 15195563
TI  - Screening specifically expressed ESTs related to piglet diarrhea resistance.
AB  - RNA was extracted from spleens of diarrhea and non-diarrhea piglets of Jiuyang
      Pig, Jianbai Pig and Landrace. RNA pools were established and DDRT-PCR using
      three anchored and seven arbitrary primers combined with silver staining was
      conducted to identify ESTs differentially expressed in diarrhea resistance to E.
      coli K88. Five cDNA were identified in the non-diarrhea RNA pools. Among them two
      are new sequences and three are highly identical to the ESTs in the GeneBank, of
      which two have known functions. One is the mammalian Nck adaptor protein 1 and
      the other is the human LINE-1 reverse transcriptase.

PMID- 15195564
TI  - [Gene differential expression of liver tissues in crossbred versus purebred
      chicken and their relationship with heterosis of meat trait].
AB  - The concept of heterosis has already been put forward for a century. The
      hypothesis of Dominance, Superdominace and Epistasis has also been brought
      forward to explain the phenomenon of heterosis. As we know, there is spatio
      temporal speciality about the expression of gene and only expressed genes
      contribute to the formation of heterosis. So the study on heterosis in expression
      level becomes more meaningful. A lot of studies on heterosis in this level have
      been done in plants, but there is no such study carried on animals in this area.
      In this study, the technique of mRNA Reverse Transcription Differential Display
      was used to research the heterosis molecular mechanism of animal. In order to
      expound the molecular genetic mechanism of animals heterosis, the 4 x 4
      completely diallele cross experiment of 4 purebreds chicken was conducted among
      White Polymouth Rock (EE), Chinese Silk Chicken (CC), CAU Brown (DD) and White
      Leghorn (AA). The chicken of 16 cross combinations were reared to 8 weeks old,
      then 30 chicken in each combination were selected randomly and slaughtered. The
      traits of body weight of 8 weeks, wing weight, eviscerated weight, eviscerated
      weight with giblet, breast muscle yield, leg muscle yield, body length, abdomen
      fat weight, intramuscular fat width, tibia length were measured, and in which 8
      individuals in each combination were selected randomly to collect the liver
      tissue samples, which were stored in liquid nitrogen or at -80 degrees C to be
      used for total RNA (TRNA) extracting. After the total RNA (TRNA) was extracted,
      16 TRNA pools were formed in the same quantitative according to the concentration
      of 8 individual TRNA. They were reversely transcribed with three anchor primers H
      T11 A, H-T11 G and H-T11 C. Then the reverse transcription PCR for each
      transcript product was done in two repeats at the same time with the same anchor
      primers and 8 random primers. The polyacrylamide gel electrophoresis of each PCR
      product was run in Bio-Rad Power 3,000 temperature control system. After
      electrophoresis, the gel was stained by AgNO3 according to the stain method
      described by Echt et al. The differential display bands in the polyacrylamide gel
      were counted. The band displayed is counted as 1 whereas no band is counted as 0
      and only expression bands reproducible in two repeats were statistically
      analyzed. The correlation analysis between heterosis percentage and gene
      expression patterns was done with statistic analysis software (SAS) package. The
      statistic results indicated that among 690 total numbers of bands, the percentage
      of differential expression bands reproducible (457) is 66.23%. Eight kinds of
      gene differential expression patterns were found and listed as follow: 1): Band
      presents only in one purebred (P1);2): Band in one crossbred and its
      corresponding paternal purebred; or Band in one crossbred and its corresponding
      maternal purebred (P2);3): Band in purebreds and one crossbred (P3); 4): Band
      only in one crossbred (P4);5): Bands in both crossbreds and one purebred (P5);6):
      Bands only in both crossbreds (P6);7): Bands only in purebreds (P7);8): Bands
      both in purebreds and crossbreds P8. The differential expression of gene between
      purebred and crossbred chicken was detected for the first time. The proportion of
      each pattern in each kind of purebred combination is different. The percentage of
      P8 (75.34%) is the highest. The total percentage of differential expression
      patterns (24.66%) showed that the gene differential expression exists as a matter
      of fact. Among all the gene differential expression patterns, the percentage of
      P3 is the highest whereas the percentage of P7, P6 and P4 is very low, it
      indicated that different genes may have different expression patterns in
      purebreds and crossbreds. The results are similar to the study results on plants,
      which indicates that the gene differential expression between purebred and
      crossbred exists universally in biology. The correlation between gene expression
      patterns and heterosis percentage was studied, but correlation between P8 and the
      heterosis percentage is not significant (P > 0.05), it indicates that some
      patterns of gene differential expression may be the molecular genetic basic of
      heterosis. Among all the gene differential expression patterns, each pattern
      affects the expression of meat trait in different manner. There is significantly
      negative correlation between P4 and heterosis percentage of body weight of 8
      weeks, breast muscle yield, leg muscle yield, eviscerated weight with giblet and
      eviscerated weight (P < 0.05); P1 is of significantly negative correlation with
      heterosis percentage of abdomen fat weight (P < 0.05) and of very significantly
      negative correlation with heterosis percentage of body length (P < 0.01); The
      negative correlation between P2 and heterosis percentage of intramuscular fat
      width is significant (P < 0.05); The positive correlation between P7 and
      heterosis percentage of leg muscle yield, wing weight, eviscerated weight with
      giblet and intramuscular fat width is significant (P < 0.05); The positive
      correlation between P5 and heterosis percentage of tibia length (P < 0.05) is
      significant. These results show that these 5 kinds of patterns play important
      role in heterosis forming of meat trait. P1 and P7 show that expressed gene in
      purebreds is depressed; P4 indicates that new gene expression occurs in
      crossbreds; P5 reveals that expressed gene only in one purebred express in all
      crossbreds. All genes of crossbreds come from purebred, which are not only the
      simple adding of these purebred genes, giving birth to unknown interaction
      between these genes coming from different purebreds, then leading to differential
      expression of genes. These gene differential expressions maybe form the heterosis
      of meat trait.

PMID- 15195565
TI  - [Correlation analysis between single nucleotide polymorphism of the leptin
      receptor intron 8 and fatness traits in chickens].
AB  - Leptin receptor plays an important role in leptin functioning signal transduction
      and it may have direct effects on the deposition of adipose tissues and the body
      weight, the leptin receptor (OBR) gene, therefore, can be considered as a
      candidate gene in the study of fat deposition of the chicken. The function of OBR
      gene has been intensively studied in mammals, but study of OBR gene in the
      chicken is still rare. In this paper, the NEAU divergent selection broiler lines
      for abdominal fat were used. Body weight and fatness traits were measured in the
      sixth generation broiler population of the two lines at 7 week of age. Two pairs
      of primers for intron 8 of OBR gene were designed according to the database of
      chicken genomic sequence (Accession No. AF222783). The SNP was detected by DNA
      sequencing, and PCR-SSCP method was then developed to screen the population. The
      correlation analysis between the polymorphisms of the intron 8 of OBR gene and
      growth and fatness traits in the population was carried out using the appropriate
      statistical model. Two SNPs were found in the population. Those were T500C and
      G659A. The least square analysis showed that BB genotype birds had significant
      higher (P < 0.05) abdominal fat weight and percentage of abdominal fat than AA
      and AB genotype birds, and AA genotype birds had significant lower (P < 0.05)
      weights of livers than AB and BB genotype birds at the same time. From these
      results we can putatively drew the conclusion that OBR gene may be a major gene
      to affect the fatness traits or linked to the major gene, and the two
      polymorphisms found in OBR gene intron 8 region could be used to select the
      chicken for low abdominal fat in molecular marker-assisted selection programs.

PMID- 15195566
TI  - [Identification of RAPD markers linked to the resistance gene Yr5 against wheat
      stripe rust with denaturing PAGE-silver staining].
AB  - RAPD analysis was performed between a near-isogenic line (NIL) Yr5/6 x Avocet S
      carrying the resistance gene Yr5 against wheat stripe rust and its susceptible
      parent Avocet S, using the Yr5 gene donor parent Triticum spelta album as
      control. Amplified DNA fragments were separated on 4% denaturing PAGE
      (polyacrylamide gel electrophoresis) and displayed by silver staining. Fifty to
      100 bands were detected, 5 folds more than those revealed on agarose gels. A
      total of 240 random primers were screened, and 23 reproducible polymorphic DNA
      fragments were found, out of which 6 polymorphic bands appeared to be linked to
      Yr5 gene. Genetic linkage was tested on 121 segregating F2 plants derived from a
      cross between Avocet S and Yr5/6 x Avocet S. It was showed that the polymorphic
      DNA fragment S1320(207) was completely linked to Yr5 gene, and S1348(363) closely
      linked to Yr5 gene. The results suggested that using denaturing PAGE-silver
      staining could increase the level of DNA polymorphisms detected in wheat and also
      improve the repeatability of RAPD analysis.

PMID- 15195567
TI  - Genetic dissection for leaf correlative traits of rice (Oryza sativa L.) under
      drought stress.
AB  - Water is becoming a restricted factor of agricultural development owing to the
      global shortage of water resources. Screening and improving drought tolerant rice
      cultivars would be helpful for increasing and stabilizing yield, economizing
      water and reducing environmental pollution. In this study, 127 rice lines of DII
      population derived from an indica variety Zhaiyeqing 8 (ZYQ8) and a japonica
      variety Jingxi 17 (JX17) were used to locate QTLs for leaf rolling, relative
      water content and rate of electric conductivity under drought stress. The results
      showed that significant differences between the parents were detected for all
      measured traits. The tremendous transgressive segregations for these traits were
      observed in the population. The frequency of all traits in the population was
      approximately normally distributed with slight skew. A total of six QTLs for the
      three traits were detected with molecular linkage map of 234 markers, including
      three QTLs (qLR-1, qLR-5 and qLR-11) for leaf rolling, two QTLs (qRWC-1 and qRWC
      6) for relative water content and one QTL (qREC-6) for rate of electric
      conductivity. Visual measurement for leaf rolling can be used to screen a large
      number of rice germplasm resources or varieties, which is of importance to
      screening and utilization of drought tolerant rice varieties.

PMID- 15195568
TI  - Expression pattern of UidA gene under the control of rice glutelin GluA-2 gene
      upstream sequence in transgenic rice endosperm.
AB  - In order to study the expression pattern of rice glutelin endosperm specific
      promoter in Chinese cultivar Zhonghua 8 (Oryza sativa L. subsp japonica), UidA
      gene was fused with rice glutelin GluA-2 gene 5' upstream sequence 2.3 kb and 750
      bp upstream respectively and transferred into rice by Agrobacterium mediated
      transformation. Southern blot indicated that UidA gene was integrated into the
      genome of transgenic plants as single copy. Northern blot demonstrated that the
      expression of UidA gene and endogenous GluA-2 gene reached their highest level at
      13-15 days and 11-13 days after pollination respectively, and then declined.
      Histochemical staining of immature transgenic rice seeds showed UidA gene was
      specifically expressed in endosperm and the highest level GUS expression was
      observed in aleurone layer. Quantitative analysis of GUS activity showed seeds
      GUS activity of that 2.3 kb transgenic plant was about two to three folds of
      those of 750 bp transgenic plant. Sequence analysis suggested that the G-box
      located in the -2,170 bp (from transcription start site) may be a quantitative
      cis-element.

PMID- 15195569
TI  - [QTL analysis for rice stripe disease resistance gene using recombinant inbred
      lines (RILs) derived from crossing of Kinmaze and DV85].
AB  - Rice stripe disease transmitted by small brown planthopper (Laodelphax
      striatellus Fall.) is one of the most serious viral diseases in East Asia. The
      disease is severely epidemic in most rice growing areas where the main cultivars
      are susceptible or moderately susceptible to rice stripe virus. In this research,
      a recombinant inbred lines (RILs) population of 81 lines derived from a cross of
      Kinmaze (japonica)/DV85(indica) by the single seed descent method was used to
      detect quantitative trait loci (QTL) conferring resistance to rice stripe
      virus(RSV). The response of the two parents and 81 RILs to RSV were investigated
      by inoculating seedlings with viruliferous small brown planthopper insects, and
      scored by the disease rate index. The quantitative trait loci for rice stripe
      disease resistance were analyzed by QTL Cartographer software. Three QTL
      controlling RSV resistance were detected on chromosomes 1, 7 and 11,
      respectively. Individual QTL accounted for 19.8%-30.9% of the phenotypic variance
      in the RILs population. The direction of the additive gene effects at two loci
      qStv7 and qStv11 coincided with that predicted by phenotypes of the parents. At
      these two loci, the DV85 alleles increased the resistance to RSV, while at qStv1,
      the Kinmaze alleles increased the resistance to RSV.

PMID- 15195570
TI  - [Preliminary gene-mapping of photoperiod-temperature sensitive genic male
      sterility in wheat (Triticum aestivum L.)].
AB  - The photoperiod-temperature sensitive genic male sterile (PTSGMS) line in wheat
      is important for the utilization of heterosis. The wheat line, BAU3338, is an
      excellent PTSGMS material identified in the recent years. In this study, its
      PTSGMS genes were mapped using molecular markers, SSR and ISSR. The result of
      molecular analysis showed that the two PTSGMS loci were identified and designated
      as ptms1 and ptms2, respectively. In addition, the genetic effect analysis
      indicated that the locus effect of ptms1 was 2-3 times larger than that of ptms2.

PMID- 15195571
TI  - [SSR molecular markers related to wood density and fibre traits in poplar].
AB  - In this study, field experiment was carried out following the randomized complete
      block design with five replications in 1999. F2 population was derived from a
      cross between the female ZH3 and the male ZH1 (ZH3, ZH1 were selected from F1
      individuals derived from the cross of Populus deltoides with P. cathayana,
      produced by HUANG Dong-Sen in 1973). Sixty-eight F2 populations, four F1
      individuals (included ZH3, ZH1) and both parents (Populus deltoides and P.
      cathayana) were measured for wood densities, fibre lengths, fibre widths and
      fibre angles. The results indicated that the trait of fibre length has obviously
      heterosis, there may have positive effects among the genes controlling the trait
      of fibre length, but may have negative effects among the genes controlling the
      trait of wood density. Using the method of single factor variance, the SSR
      markers correlated with wood density, fibre length, fibre width and fibre angle
      were identified to be 5, 7, 4 and 2, respectively. There were some useful markers
      among the above traits in P. cathayana, such as PMGC2873-1 for wood density (its
      contribution was 4.88%), PMGC456-3, PMGC2702-2 for fibre length (their
      contribution were 22.96% and 9.17%, respectively), PMGC2408-1 for fibre width
      (its contribution was 7.18%), and PMGC2525-1 for fibre angle (its contribution
      was 16.59%), these markers might be useful for wood property improvement if using
      them correctly in breeding program.

PMID- 15195572
TI  - [The characteristics of PSCL32.5 protein from Physarum polycephalum and the
      variation of the content through cell cycle].
AB  - Crude fraction of Arg/Ser-rich proteins (SR proteins) were isolated from
      plasmodia of Physarum polycephalum and immunoassayed by western blot with a
      monoclonal antibody against SC35 protein from HeLa cell. Two polypeptides were
      detected by the antibody, suggesting that they were SCL(SC35-like) proteins. The
      SCL proteins have their mass weight of 32.5 kD and 82.5 kD, respectively, and so
      were termed PSCL32.5 and PSCL82.5 in this paper. The PI of PSCI32.5 was
      ascertained as 6.19 by IEF after a further purification of the protein with SDS
      PAGE. The densitometric scanning of the western blot bands of PSCI32.5 isolated
      at different phases of cell cycle of P. polycephalum demonstrated that the
      relative content of the protein varied through the cell cycle: it appeared as the
      lowest at early S phase, showed increases from S phase to G2 phase, and peaked at
      late G2 phase.

PMID- 15195574
TI  - [Human genetics of physical performance].
AB  - Development of human molecular genetics gradually revealed that certain people
      seem to have congenital capacity in physical performance, and this capacity may
      correlate with genes. Recently, more and more evidences have shown that genes
      control some physical characters, such as extreme motion, muscle strength,
      endurance, ductility, fatigue recovery, and VO2max, ect. The development of
      spaceflight in China and nation defence urgently require appearance of this
      study, and its application will help to find physically potential individuals in
      advance and save large amount of money in the later systematic training.

PMID- 15195573
TI  - [The study of optimal conditions of electroporation in Pseudomonas aeruginosa].
AB  - A P. aeruginosa strain PA68 isolated from the sputum of a patient suffering from
      bronchiectasis was used as the recipient strain. Optimum conditions including
      growth stage of the strain, electroshock voltage, concentration and preservation
      of competent cell were defined for the electroporation of PA68 with plasmid
      pSMC28. It was showed that the highest transformation efficiency was up to 1.68 x
      10(3) CFU/microgram DNA under the optimum conditions in which the competent cells
      were collected at logarithmic growth phase (OD(540) = 0.7-0.8) and concentrated
      to about 10(11) cells/ml, the mixture of the competent cells and plasmid pSMC28
      was eletroporated at 2.6 kV. With this optimal condition, Mu transponson
      complexes have been successfully transformed into P. aeruginosa strain PA68 and
      the obtained efficiency was 2.47 x 10(4) CFU/microgram DNA. This is the first
      time to electroporate Mu transposon complexes into Pseudomonas spp. The
      artificial Mu transposons could integrate into bacterial genomes at a single site
      randomly. Then the phenotype change was the result of the gene inactivation
      caused by Mu transposon insertion. That will be very helpful for the study of
      genomic function of Pseudomonas spp.

PMID- 15195575
TI  - [Stones and foreign bodies of the urethra].
AB  - Foreign bodies in the bladder and urethra have been already largely described
      either by their nature itself as well as by the circumstances of their
      introduction. If their presence often reveals dubious psychiatric behaviours, one
      must also evoke possible accidental introductions during transvesical surgery or
      migration from spaces adjacent to the bladder. The treatment of those foreign
      bodies can be sorted out through endoscopy or surgical approach.

PMID- 15195576
TI  - [Vesicovaginal fistula].
AB  - Urinary fistula to the vagina has been described since the beginning of the
      written record. In developed nations, these fistulas are usually unfortunate
      complications of gynecologic or other pelvic surgery and radiotherapy.
      Historically, birth trauma accounted for most vesicovaginal fistulas, and it
      remains the major cause of urinary fistulas in many underdeveloped nations. Once
      a vesicovaginal fistula is suspected, a thorough vaginal examination should be
      performed to identify its size and location, especially in relation to the
      trigone and eliminate a ureterovaginal fistula which can be associated in up to
      10% of cases. Numerous methods for the treatment of vesicovaginal fistulae have
      been described. Abdominal, and vaginal approaches are used for the repair of
      vesicovaginal fistulae. The approach selected is dependent on many factors, but
      is probably best determined by the experience and training of the surgeon. The
      techniques of the vaginal approach involve tension-free closure of the fistula
      with or without excision of the tract, creation of an anterior vaginal wall flap
      and appropriate use of vascularized interposition grafts. The abdominal approach
      may be used to treat all types of vesicovaginal fistulae and is the preferred
      approach when concomittant ureteral reimplantation is required. Postoperative
      care is similar for both vaginal and abdominal vesicovaginal fistula repair.
      Adequate uninterrupted bladder drainage is the most critical aspect of
      postoperative management. A voiding cystourethrogram is performed at 10
      postoperative days to confirm closure of the fistula.

PMID- 15195578
TI  - [Factual surgery or surgery founded on facts].
AB  - In the late 90s, teachers at McMaster's university (Canada) decided to export in
      clinical practice a teaching concept they had developed which included, among
      other concepts, a critical analysis of the medical literature. "Evidence-Based
      Medicine" (EBM) has since been adopted by many medical specialities or physicians
      as a reference in their practice of medicine. However, evidence-based medicine in
      its definition had three legs. Critical analysis of medical literature is the
      most known. The analysis is based on methodological principles that have been
      developed by statisticians and epidemiologists, principles which are not very
      familiar to surgeons. The other two legs are less known, but are important. The
      patient is still in the very middle of the EBM's principles. It is for him, the
      patient with his demands, that the physician must find a solution that may be not
      available in the literature. The surgeon, the third leg of the system, must be
      involved; he must listen to the patient, understand his particular demands, and
      find, for him the best answers to the question asked by the patient. It is the
      surgeon's responsibility to be the interface between science and one individual
      patient. Evidence-based medicine is a new model of the relationship between
      patients and physicians.

PMID- 15195577
TI  - [Ileal bladder replacement. Hautmann ileal neobladder].
AB  - In 1986, Hautmann and al. described the ileal neobladder as one of the first
      orthotopic bladder replacement which approached in configuration and function
      most closely the original organ. The association of the principles of a
      detubularized small bowel reservoir (Kock) and the anastomosis on the urethral
      stump with his sphincter give full functional satisfaction. After many
      modifications and simplifications since the prime description, especially of the
      ureteral implantation, the technique will be described in all details.

PMID- 15195579
TI  - [Trapezo-metacarpal arthroplasty by rotation transfer of the trapezo-metacarpal
      joint. Anatomical study and operative technique].
AB  - INTRODUCTION: To correct trapezium dysplasia we propose a new surgical technique.
      The operation consists of a double osteotomy of the trapezium and of the first
      metacarpal base, thereby harvesting the trapezo-metacarpal joint en-bloc.
      Vascularization is via the radial artery pedicle divided at the first web level.
      The articular block is then rotated 180 degrees on the longitudinal axis of the
      thumb. METHOD: An anatomic study was performed on six fresh cadaveric upper
      limbs. The radial artery was injected with colored latex, 5 cm above the wrist.
      The peri-articular vascular network was studied. The feasibility of harvesting
      and rotating the articular bloc after double osteotomy of the first metacarpal
      basis and the trapezium was also studied. RESULTS: In all the cases, the radial
      artery was present with branches supplying the peri-articular vascular network.
      After double osteotomy of the metacarpal base and of the trapezium, the articular
      bloc was harvested and rotated by 180 degrees. We describe the surgical
      technique. DISCUSSION AND CONCLUSION: The surgical technique has been confirmed
      with the first clinical cases. The double oblique osteotomy with rotation of the
      articular bloc corrects trapezium dysplasia and preserves first metacarpal
      abduction. This procedure appears to be a solution in cases of trapezium
      dysplasia associated with instability and early stage osteoarthritis.

PMID- 15195580
TI  - [Surgical treatment of capitellum fractures in the adult. Eight case reports].
AB  - Fracture of the capitellum is a rare intra-articular fracture and presents a
      frontal fracture line. It occurs in adolescents after the age of 13 years and in
      adults. We report a series of eight patients treated between 1992 and 2002. There
      were five females and three males with a mean age of 25 years (range: 20-34
      years). According to the classification of Bryan and Morrey, three fractures were
      classified as type I, three as type II and two as type III. All patients were
      operated on within the first week after injury. The fixation techniques used were
      screw fixation in five cases and Kirschner wire fixation in three cases. Seven
      patients had excellent results and one patient had some limitation of range of
      movement. There were no instances of infection or avascular necrosis. Diagnosis
      of this fracture is often missed. Poor results of treatment are observed after
      imperfect reduction, delayed treatment or resection of the capitellum. We report
      in this study the results of surgical treatment.

PMID- 15195581
TI  - Intercondylar distal humerus fractures--surgical treatment and results.
AB  - INTRODUCTION: Controversy persists concerning the preferred treatment for
      intercondylar distal humerus fractures. The present study was undertaken to
      evaluate the clinical results after the surgical treatment of 40 intercondylar
      distal humerus fractures with an average follow-up of 3.9 years. METHODS: The
      fractures were classified following the AO/ASIF comprehensive classification.
      Eight patients presented multiplane fractures. Skeletal traction was used
      temporarily in two cases. The stabilization method was selected according to the
      fracture pattern, bone quality and associated lesions. Bone graft was used in
      seven cases. Fibrin-glue was used in two cases. Unilateral hinged external
      fixators were used in addition in four cases. Functional assessment was done
      according to the scoring system of the Orthopedic Trauma Association and
      additional parameters taken from the system of Jupiter. RESULTS: Final global
      results were excellent in 13 patients, good in 21, fair in four and poor in two.
      Complications included three non-unions, two heterotopic ossifications, two
      internal fixation failures and two lateral condyle resorptions (avascular
      necrosis). DISCUSSION: Final results are related to the severity of the initial
      trauma, time elapsed between the accident and definitive surgery, associated
      lesions, bone quality, precise reconstruction of a smooth and congruent joint
      surface, surgical technique, implants used, stability obtained and patient
      cooperation. The type, number and location of the osteosynthesis material must be
      selected according to the fracture pattern, bone quality and associated lesions.

PMID- 15195582
TI  - [Hand trauma from table saw: best prevention].
AB  - OBJECTIVE: Trauma to the hand from a circular saw table is a common occurrence in
      developing countries. It tends to occur in young people, leading to psychologic-
      and socio-economic disability and loss. METHOD AND RESULTS: In this series of 834
      patients. The mean age was 25 years. The left hand was involved in 88%. The
      authors report on the epidemiologic features of these lesions. These accidents
      are correlated with postprandial somnolence. The most frequent causes are absence
      of security systems and heterogeneity of the wood. DISCUSSION: The authors
      emphasize the importance of information for workers, using consciousness raising
      campaigns. They also stress the necessity of improvement of the conditions of
      work. Professional formation must be mandatory for young woodworkers and the laws
      concerning utilization of dangerous machines must be rigorously enforced, in
      order to lower the incidence of these accidents.

PMID- 15195583
TI  - [Treatment of complex hand injuries by stable osteosynthesis using a "multiple
      pinning" technique].
AB  - The multiple pinning technique has been reported by the authors as an effective
      method for the treatment of comminuted osteo-articular fractures of the digits.
      This procedure can be performed rapidly, offers good stability and thereby allows
      early post-operative physiotherapy. The aim of this type of management is to
      offer the patient recovery of thumb to digit pinch by restoring two functional
      joints (MCP, PIP) or at least one functional joint (MCP), particularly as far as
      the radial digits are concerned. TECHNIQUE: After performing reduction, very
      small diameter pins are introduced and the bone fragments are reconstructed like
      a puzzle. The very small calibre of the pins allows multiple pinning and
      simultaneously permits them to be easily orientated. The pins being multiple, and
      parallel or diverging are responsible for the stability of the construct. The
      ends of the pins are either bent over or more frequently, just cut flush with the
      surface of the bone. Comminuted fractures, even the most severe, respond very
      nicely to this management. DISCUSSION: The multiple pinning technique offers
      remarkable stability, allowing early post-operative physiotherapy. This technique
      is particularly effective when faced with the difficulties of treating open
      fractures of the metacarpals and phalanges. Moreover, this technique avoids
      performing an extensive skin incision. The stability of this multiple pinning
      technique could be related to the following factors: the shortness of the pins
      offering more rigidity and less flexibility, the proper fixation of the pins
      within the cortical bone, especially in the diaphysis and the large number of
      pins offering more strength. The disadvantage of this technique is the
      possibility of pin migration.

PMID- 15195584
TI  - [Cubital tunnel syndrome and heterotopic ossification. Eight case reports].
AB  - INTRODUCTION: The occurrence of cubital tunnel syndrome during heterotopic
      ossification is infrequent. Entrapment of the nerve requires early decompression
      whereas definitive elbow release is often delayed to reduce the risk of
      recurrence of periarticular ossification. The pathophysiology and treatment of
      these two conditions are discussed. METHOD: The authors report a retrospective
      study of eight men (average age 37 years), all with previous head injury. The
      nerve entrapment was severe in two cases, moderate in four and mild in two. The
      elbow was ankylosed with a mean flexion deformity of 96 degrees (77 degrees-123
      degrees). Management consisted of early decompression and neurolysis with
      anterior transposition of the ulnar nerve. In four cases elbow release was
      postponed until maturation of the ossification. RESULTS: The neurolysis results
      were assessed according to the score of KLEIMAN modified by TEOH. They were
      excellent in two cases, good in five and bad in one. DISCUSSION: Entrapment of
      the ulnar nerve in the context of heterotopic ossification seems related to
      compression and tension on the ulnar nerve. The compression may be due to
      prolonged pressure of the medial edge of the elbow on the bed of the nerve, or to
      a periarticular bony bridge and the initial inflammatory reaction of the
      heterotopic ossification. Ulnar nerve tension seems to be due to prolonged
      flexion of the elbow joint and to movements of the shoulder and the wrist, on
      either side of the ankyrozed elbow. Treatment should be by early decompression of
      the nerve and we recommend, in addition, anterior transposition to reduce the
      tension on the nerve. The elbow release can be combined with the neurolysis or
      delayed according to the state of activity of the heterotopic ossification.

PMID- 15195585
TI  - [Heterotopic digital transplantation in an 80-year-old man].
AB  - The authors report a case of amputation of the first, second and third fingers of
      the left hand in an 80-year old man. As the thumb was not replantable, a
      pollicization by hetero-replantation of the index was performed as an emergency.
      With a 1-year follow-up, the functional result was satisfactory. Analysis of the
      case report again shows that in the case of thumb amputation, hetero-replantation
      according to the principles of "finger-bank" is the solution of choice and
      demonstrates its feasibility in the elderly. The authors discuss the recovery of
      sensation.

PMID- 15195586
TI  - [Tone recognition and electrode discrimination in prelingually deafened cochlear
      implant listeners].
AB  - OBJECTIVE: To investigate tone recognition and electrode discrimination in
      prelingually deafened children with the Nucleus device, and to develop guidelines
      for customized mapping in the implant users. METHODS: Fourteen prelingually
      deafened children with cochlear implants participated in this study. Tone
      recognition was measured with a four-alternative, forced choice procedure from 25
      consonant-vowel syllables, each of which had four tonal variations. Electrode
      discrimination was measured using a same-difference procedure on 7 pairs of
      electrodes covering the entire electrode array. RESULTS: Tone recognition ranged
      from 35% to 99% correct with a mean of 62.8% and standard deviation of 14.7% in
      these users. Electrode discrimination had the mean threshold of 3.4 +/- 0.9, with
      the best performance from the middle electrodes (E 14 and E 17) at 2.6 and the
      followed performance at the most apical electrode (E 20). CONCLUSION: The results
      showed significant individual differences from both tone recognition and
      electrode discrimination, but there is significant correlation between them.

PMID- 15195587
TI  - [Refractory recovery function of electrical auditory on the survival auditory
      nerve in cochlear implant recipients].
AB  - OBJECTIVE: To evaluate the cochlear implant recipient's electrical auditory
      temporal properties in order to estimate the maximum stimulating rate which can
      be reached when they adopted some speech coding strategies based on time
      mechanism, such as continuous interleaved sampling (CIS). METHODS: Thirty-eight
      Nucleus CI24 cochlear implant recipients were divided into 4 groups by etiology
      and history. Their survival auditory nerve fibers' refractory recovery time
      function was measured via neural response telemetry (NRT). Electrical pulses with
      the amplitude of recipient's loudest acceptable presentation were stimulated in
      mono-polar mode, with the width of 25 microseconds and the frequency of 80 Hz.
      Least-squares regression procedures were used to fit individual recovery
      functions with the equation A = C + K e(-t/tau), in which tau is the time
      constant of recovery from refractory state. Statistic analysis showed the
      relationship between the time constants of individuals and etiology as well as
      electrode position in the cochlea. RESULTS: Congenital deaf patient's recovery
      time constants were shorter than that of postnatal deaf groups of ototoxicity (P
      = 0.0056) and large vestibular aqueduct syndrome (P = 0.0349). There was no
      significant difference between the recovery time constants of congenital deaf
      patients and those of group with long history of deafness. The ANOVA of the
      recovery time constants of 5th, 10th, 15th electrode showed no significant
      statistical difference (P > 0.05). CONCLUSION: The recovery time constants are
      related with etiology. In mono-polar mode, the time constants of congenital
      deafness or subjects with short duration of deafness are shorter than those of
      postnatal deafness or subjects with long duration of deafness. Time constants do
      not vary systematically with electrode location along the implanted array. The
      reciprocal of individual electrode seems to be used in determining the maximum of
      stimulating rate of CIS strategy and as criteria of choosing the usable channels
      from 22 electrode bands.

PMID- 15195588
TI  - [Image examination of postoperative evaluation for the cochlear implanted
      electrode].
AB  - OBJECTIVE: To evaluate the image feature of the X-ray plain film, the spiral
      computed tomography (CT) scans and three dimension reconstruction of inner ear
      with implanted electrode. METHODS: Eighteen patients of cochlear implant (MEDEL
      Combi 40+) recipients were involved in this study. The implanted electrode of all
      patients were examined on the fifth to seventh postoperative day, by the use of X
      ray plain film with either anteroposterior transorbital projection (nine cases)
      or lateral position with coronal 60 degrees away from the examine table (nine
      cases). Three of the cochlear implant recipients were examined by the way of
      spiral CT scans with axial 1 mm image slices. The data of the CT scans was
      transferred to workstation for three-dimensioned reconstruction (direct volume
      rendering) of the inner ear. RESULTS: The X-ray plain film from both of
      anteroposterior projection and lateral with coronal 60 degrees projection provide
      satisfactory image of implanted electrode including the shape and the position in
      the temporal bone. The insertion depth of the electrode can be evaluated
      indirectly. In contrast, the images from CT scans with 3D reconstruction of the
      inner ear demonstrate more accurately the shape, the position, and the insertion
      depth of the electrode. Moreover, each of the electrode pairs can be identified
      clearly. CONCLUSIONS: X-ray plain film can meet the routine needs of
      postoperative evaluation of the implanted electrode with several kinds of head
      position of projection. But CT scans with 3D reconstruction of inner ear provide
      more accurate image of the spacial relationship of the electrode in the cochlear
      canal with direct demonstration of electrode insertion depth in the cochlea.

PMID- 15195589
TI  - [Cochlear implant in patients with congenital malformation of inner ear].
AB  - OBJECTIVE: To study surgical difficulty and key of the cochlear implant in
      patients with congenital malformation of inner ear. METHODS: The cochlear
      implantations were performed in our department from Jan. 2001 to Apr. 2003 for 18
      patients with the malformation of inner ear. RESULTS: In this series, there were
      11 cases of large vestibular aqueduct syndrome (LVAS), 3 cases of Waardenberg
      syndrome, 3 cases of Mondini malformation, and 1 case of Usher syndrome. All 18
      patients accepted the Nucleus 24-channel cochlear implantations, including
      Nucleus straight electrode in 13 cases but Contour implantation in 5 cases of
      LVAS. During operations, leakage of perilymph but not cerebrospinal fluid (CSF)
      from the open of scala tympani occurred in 11 cases of LVAS, however, the
      electrode was inserted successfully. The abnormalities of round window occurred
      in one of 3 cases of Waardenberg syndrome and 3 cases of Mondini malformation,
      respectively. CONCLUSION: The cochlear implant could be conducted successfully
      for the LVAS, and the postoperative effect was same as the ones for the deafness
      persons with normal development of inner ear. However, for the patients with
      Mondini syndrome and common cavity, it is important to accurately assess the
      extent of abnormalities in the inner ear and accompanied malformation before
      operation, and to evaluate the full extent of difficulties of the operation in
      order to minimize the risk of CSF leakage and meningitis.

PMID- 15195591
TI  - [Expression of substance P receptor positive cells in the Corti's organ with
      acute middle ear infection in guinea pigs].
AB  - OBJECTIVE: To investigate the expression of substance P receptor(SPR), SPR
      positive cells in the Corti's organ with acute middle ear infection in guinea
      pigs using the polyclonal antibody of SPR. METHODS: Twelve healthy guinea pigs
      were employed in the experiment. After general anesthesia, by injecting 1 x
      10(8)/L staphylococcosis aureus into the middle cavity of right ear with the left
      ear serving as control, the acute middle ear infection model was established.
      Then three days later, immunohistochemical staining of SPR was performed in the
      Cochlear base membrane preparation. RESULTS: Microscopic examination of whole
      cochlear preparation revealed a number of SPR positive cells expression in the
      cochlear base membrane, these labeled cells usually did not exist in normal
      cochlear tissue. Obvious difference in morphology and distribution could be
      identified with inner hair cells, outer hair cells vascular endothelial cell and
      spiral ganglion neurons. Labeled SP receptor positive cells were similar to
      "neurons", scattering distributed in the free margin of cochlear base membrane,
      with larger size and multiple projections which was 6-12 times than the
      erythrocyte. There were the vesicle and granular substances in the cytoplasm of
      the labeled cells. CONCLUSIONS: Acute middle ear infection could induce the
      expression of SP receptor positive nonspecific cells in the Corti's organ of
      guinea pigs. These cells did not exist in the normal base membrane and might
      participate in initiating or inducing the immune response of inner ear.

PMID- 15195590
TI  - [Multi-channel cochlear implants in patients with Mondini malformation].
AB  - OBJECTIVE: To describe clinical experiences with multi-channel cochlear
      implantation in patients with Mondini malformation. METHODS: Among 300 patients
      who received multi-channel cochlear implants from 1996 to 2002 in Beijing Tongren
      Hospital, 15 patients were diagnosed with Mondini malformation. A retrospective
      analysis was performed dealing with the surgical techniques, mapping and
      rehabilitations characteristics after surgery. 15 patients with normal cochlear
      structure are consider as control group. RESULTS: Gusher is found more common
      than the normal cochlear implantation, most of them are serious. The electrodes
      are inserted in the "cochleostomy" in full length of 13 Patients, 2 pairs of
      electrodes remains outside of "cochleostomy" in 2 patients. No serious
      complications occurred after implantation. All patients have auditory sensations.
      The impedance of the electrodes, the T level, C level and the hearing threshold
      are similar with the normal cochlear implantation group. The results have no
      significant difference in compare with normal cochlear group(P > 0.05).
      CONCLUSION: Multi-channel cochlear implantation could be performed safely in
      patients with Mondini malformation. The primary outcome for patients with Mondini
      malformation are similar to those with normal cochlear structure following the
      multi-channel cochlear implantation.

PMID- 15195592
TI  - [Experimental studies for botulinum toxin type A on allergic rhinitis in the
      rat].
AB  - OBJECTIVE: To study the effect of botulinum toxin-A on inhibiting rhinorrhea, on
      expression of VIP at nasal mucosa, on morphometrical change with an
      immunohistochemical and histological methods in rats allergic rhinitis. METHODS:
      Ovalbumin sensitized the rat as animal model of allergic rhinitis. Animals were
      divided into control group (n = 8), allergic group (n = 12), allergic animal
      treated by BTX-A group (n = 6). VIP immunoreactivity at nasal mucosa in the rat
      allergic rhinitis was studied by immunohistochemical. The morphometrical changes
      at nasal mucosa were observed by histological staining methods. RESULTS: The
      results showed that the symptoms of allergic rhinitis, nasal rhinorrhea and
      sneezing, were remarkably relieved after ovalbumin application in the rat. The
      nasal rhinorrhea symptom diminished after BTX-A treated. The quantity of nasal
      secretion were significantly reduced(P < 0.05) in allergic one treated by BTX-A
      group as compared with allergic group. Hematoxylin and eosin staining
      demonstrated that no edema, small vessels were found in the nasal mucosa and
      after BTX-A treatment, but edema, vasodilational and inflammational cell
      infiltration were observed in the allergic group. Immunohistochemical study
      revealed that VIP immunoreactive fibers in the nasal mucosa showed a marked
      decrease after BTX-A application, but the density and a large number of VIP
      fibers were significantly found in the allergic group. CONCLUSION: The results
      suggested that local BTX-A treatment was a selective and non-traumatic method to
      reduce a long lasting desensitization of the nasal mucosa, to alleviate nasal
      congestion, rhinorrhea and sneezing, and to reduce the sensory neuron sensitivity
      of the mucosa.

PMID- 15195593
TI  - [Investigation of postoperation complications of the congenital aural atresia].
AB  - OBJECTIVE: To investigate the treatments and complications of the congenital
      aural atresia. METHODS: Form 1996 to 2002, 446 ears with congenital aural atresia
      underwent operations in the Otolaryngology Department of the Tongren Hospital.
      During the follow up from 6 months to 5 years, 47 ears occurred postoperative
      complications, which can be divided into five groups: external acoustic pore
      stenosis, external auditory canal stenosis, hearing loss, facial nerve palsysis.
      The hearing results of these 43 ears showed 12 ears had a decrease of 10 dB, 19
      ears of 20 dB, 12 ears of 30-40 dB. RESULTS: The causes of complications mainly
      were insufficient opening of bony external canal, secondary infection and lateral
      healing of the transplanted tympanic membrane, and the surgeon did not master the
      anatomic characters of the abnormal facial nerve. Forty-three ears received
      operation again, including 24 ears with external acoustic pore stenosis, 9 ears
      with external auditory canal stenosis, 8 ears with hearing loss and 1 ear with
      facial nerve palsysis. Hearing improvement was found in 43 ears (100%) in which
      10 ears (23.3%) with improvement of 10-20 dB, 21 ears (48.8%) of 20-30 dB, 12
      ears (27.9%) of 30-40 dB. The one ear with facial nerve palsysis recovered 2
      months after operation. CONCLUSION: External auditory canal stenosis and lateral
      healing of the transplanted tympanic membrane are the primary causes of
      postoperative hearing loss. Do not injure the facial nerve for hearing
      improvement in cases of facial nerve abnormalities.

PMID- 15195594
TI  - [Immunoblot and immunohistochemical analysis of CYP2A expression in human
      olfactory mucosa].
AB  - OBJECTIVE: To investigate the nasal expression of CYP2A proteins in human.
      METHODS: Immunoblot analysis was used to detect fetal tissues at 96-185 days of
      gestational age and in surgical biopsy tissues from different regions of nasal
      cavity of 36 adult patients, and immunohistochemical methods were used to
      localize CYP2A proteins' cellular distribution. RESULTS: In adults, CYP2A protein
      was detected in olfactory microsomes from 8 of 10 individual, but not in the
      respiratory nasal microsomes from 37 individual. Quantitative immunoblot analysis
      confirmed that CYP2A proteins were selectively expressed in the olfactory region
      in both adult and fetal tissues. Interestingly, the levels of CYP2A proteins in
      nasal microsomes were generally higher in fetuses than in adults. The CYP2A
      protein content in olfactory microsomes ranged from 0.1 to 1.1 pmol/mg among
      adult nasal microsomes, while among five fetuses ranged from 0.8 to 5.3 pmol/mg
      microsomal protein, with a trend of developmental increase in expression level.
      Immunohistochemical studies confirmed that the CYP2A proteins were expressed in
      the supporting cells in the olfactory epithelium and in the Bowman's glands in
      the lamina propria. CONCLUSIONS: CYP2A proteins expression in human olfactory
      mucosa indicates that olfactory mucosa is metabolic target site of the
      xenobiotics. Also CYP2A has a relationship with olfaction. The prenatal
      expression of the CYP2A proteins in the OM suggests potential risks of
      developmental toxicity from maternally derived xenobiotics.

PMID- 15195595
TI  - [Transnasal endoscopic frontal surgery for chronic frontal sinusitis].
AB  - OBJECTIVE: The recurrence of chronic frontal sinusitis after endoscopic surgery
      is mainly due to the mismanagement of frontal recess and frontal sinus orifice.
      The aim of this study is to investigate the characteristics of chronic frontal
      sinusitis and to advance the clinical therapeutic efficacy. METHODS: Different
      methods were used to manage different local diseases in frontal sinus orifice or
      frontal recess in 58 cases (96 sides) with chronic frontal sinusitis by nasal
      endoscopic surgery. RESULTS: Different degree of middle meatal obstruction was
      seen in all cases at operation. The situation of frontal sinus ostium and frontal
      recess was as follows: 38 sides obstructed by swollen mucosa, polypoid mucosa or
      polyps, no cell obstruction at frontal sinus orifice; 34 cases constricted by
      over development of agger nasi cells, ethmoid bulla or terminal cell at frontal
      recess; 15 cases obstructed completely by over development cells at frontal
      recess; osteal stenosis at frontal sinus orifice in 9 cases. The situation in
      frontal sinus was as follows: pus accumulation in 18 sides, mucosal swollen in 21
      sides, mucosal congestion in 49 sides, no obvious mucosal diseases in 8 cases.
      Follow-up for 6-20 months showed that 69 sides (71.9%) were cured, 17 sides
      (17.7%) better and 10 cases (10.4%) recurrent. CONCLUSION: Obstruction of
      osteomeatal complex and frontal recess is the main causes of chronic sinusitis.
      There are four pathologic states in obstruction of frontal recess and frontal
      ostium. Different operative methods should be taken according to different
      pathological changes. The operative effects is still needed to improve.

PMID- 15195596
TI  - [Effect of specific immunoglobulin Y in the treatment of acute and chronic
      pharyngitis].
AB  - OBJECTIVE: To evaluate the effect and safety of the specific immunoglobulin Y
      (IgY) for treatment of acute and chronic pharyngitis. METHODS: Double-blind,
      randomized, placebo-controlled trial was conducted on 50 adults with acute
      pharyngitis. Experimental group received a 6 times-daily total 30 doses of IgY
      stomat-spray which contained specific immunoglobulin Y (titer = 512) prepared
      from the egg yolk of hens immunized with a variety of bacteria. Another open
      label trial included 50 patients, whose ages ranged from 21-69 years, including
      25 cases of acute pharyngitis and 25 cases of chronic pharyngitis were also
      treated using IgY stomat-spray. The therapeutic effect were objectively evaluated
      7 days later by the decreased scores based on both the symptoms and physical
      signs. If the symptom did not improve or became severe three days later, these
      patients with acute pharyngitis was inefficiency and antibiotic medicine would be
      added to them. RESULTS: In Double-blind trial, 8 cases (32%) received IgY had
      apparent effect with the decreased scores 5 or more than 5, 13 cases (52%) had
      effective with the decreased scores 3-4, and other 4 cases (16%) had inefficacy
      with the decreased scores only 2 or no more than 2. While in placebo-controlled
      group, only 2 (8%) cases had apparent effect, 5 (20%) cases showed effective and
      18 (72%) cases had non-effect. The difference between the two groups was
      significant (chi 2 = 16.06, P < 0.01). In open label trial, 19 cases (38%) showed
      apparent effect, in which 14 cases were acute pharygitis. 23 cases (46%) had
      effective, in which 10 cases were acute pharyngitis. The left 8 cases (16%) had
      ineffective, in which one case was acute pharyngitis. There was significantly
      difference (chi 2 = 8.90, P < 0.05) between acute pharyngitis and chronic
      pharyngitis. An average of three months followup showed that there were no side
      effect or toxic effect and no allergic reaction. CONCLUSION: The IgY stomat-spray
      is a safe and effective agent in treating acute and chronic pharyngitis,
      especially for acute pharyngitis.

PMID- 15195597
TI  - [Evaluation of the serum endothelin-1 level and sleep architecture change in
      patients with obstructive sleep apnea hypopnea syndrome accompanied
      hypertension].
AB  - OBJECTIVE: To explore the role of endothelin-1 (ET-1) in the pathogenesis of
      hypertension in obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: The
      levels of serum ET-1 in 30 OSAHS patients accompanied by hypertension, 30
      normotensive OSAHS patients and 30 healthy controls were measured by ET-1 enzyme
      immunoassay kit. Meanwhile the correlation about the concentration of ET-1 in
      OSAHS patients with the clinic, polysomnography (PSG) parameters was analyzed.
      RESULTS: OSAHS patients with or without hypertension compared with snoring group
      and normal people, the sleep structure was significantly disturbed. The time
      percentages of awake and stage I sleep were increased, while stage II sleep
      decreased significantly in OSAHS patients than those in snoring group (P < 0.01,
      respectively). There were no significantly difference about the sleep structure
      in the two OSAHS groups. The levels of serum ET-1 (mean +/- s) were significantly
      higher in OSAHS patients accompanied by hypertension and normotensive OSAHS
      patients(42.5 +/- 8.4) ng/L and (38.6 +/- 4.7) ng/L respectively than those in
      the healthy controls(33.1 +/- 5.4) ng/L (P < 0.01, respectively). In the two
      OSAHS groups, the levels of serum ET-1 were significantly higher in OSAHS
      patients accompanied by hypertension than those in the normotensive OSAHS
      patients (P < 0.05). There were positive correlations between the concentration
      of ET-1 and the apnea hypopnea index (AHI) in all the 60 OSAHS patients with and
      without hypertension (r = 0.334, P < 0.01). There were negative correlations
      between the concentration of ET-1 and the lowest oxygen desaturation in all the
      60 OSAHS patients with and without hypertension (r = -0.230, P < 0.05).
      CONCLUSION: These results indicate that the sleep disordered breathing and
      hypoxia may contribute to the elevation of ET-1 in the OSAHS patients and OSAHS
      patients accompanied by hypertension. ET-1 may play an important role in the
      pathogenesis of OSAHS-induced hypertension.

PMID- 15195598
TI  - Adjuvant therapy for breast cancer. An additional hope.

PMID- 15195599
TI  - Health tips. Medical alerts.

PMID- 15195600
TI  - Supplemented orange juice may help lower cholesterol.

PMID- 15195601
TI  - Large doses of zinc may increase risk of prostate cancer.

PMID- 15195602
TI  - Wrinkle solutions. Turning back the age clock.

PMID- 15195603
TI  - Sunscreen. From buying to applying.

PMID- 15195604
TI  - My sister had a heart attack a few months ago, but she didn't realize it at first
      because she didn't have any chest pain. Is this normal?

PMID- 15195605
TI  - I've been told there's a product you can put on your clothes to keep ticks and
      mosquitoes from bothering you. Can you tell me what it's called? I'm worried
      about West Nile virus and want some advice.

PMID- 15195606
TI  - 7 strategies to prevent a heart attack. How to identify your major risk factors
      and diminish their danger.

PMID- 15195607
TI  - It's still "buyer beware" for a popular weight loss herb.

PMID- 15195608
TI  - Where there's no smoke, there's lower heart risk.

PMID- 15195609
TI  - Fighting clots before they form. A new drug may end one of many patients' biggest
      hassles.

PMID- 15195610
TI  - A cardiac "safety net" widens. Here's how to respond, and avoid mistakes, in
      emergencies.

PMID- 15195612
TI  - Ask the doctors. During an ultrasound examination, my internist discovered an
      aneurysm in my belly. What should I do next?

PMID- 15195611
TI  - Simple test reveals future health. Timing heart rate recovery can help head off
      cardiac threats.

PMID- 15195613
TI  - Ask the doctors. I read about a new drug for heart failure called eplerenone. How
      does it work? Is it safe?

PMID- 15195614
TI  - Ask the doctors. I just received a solicitation in the mail for a chelation
      product. It claims that chelation will remove plaque and heavy metal
      concentrations in the arteries, with benefits within three to six months. Is this
      a scam? Is it even possible?

PMID- 15195615
TI  - Lessening the stress of hospitalization. New program offers solace, lifestyle
      training to patients and families.

PMID- 15195616
TI  - "Major surprise" in a new study means likely changes in treatment.

PMID- 15195617
TI  - Another reason to measure blood pressure at home.

PMID- 15195618
TI  - Raise your "good" cholesterol. Seven ways to boost levels of a heart-protective
      scavenger.

PMID- 15195619
TI  - 5 myths about robotic surgery. These real-life systems save hearts, but don't
      replace doctors.

PMID- 15195620
TI  - Should you get a calcium test? It may not add much to what your doctor already
      knows.

PMID- 15195621
TI  - Ask the doctors. I've been having lots of chest pains. Results from a
      catheterization looked normal, and my cardiologist says my heart isn't the
      problem. What's wrong?

PMID- 15195623
TI  - Ask the doctors. I've read newspaper reports about a new disease called
      "prehypertension". What's the term mean, and what should I do to prevent it?

PMID- 15195622
TI  - Ask the doctors. What's the difference between a coated stent and a regular
      stent? I am going in for a stent procedure next week and want to know which one I
      should ask for.

PMID- 15195624
TI  - Flavonoids. Nature's paintbox and medicine cabinet.

PMID- 15195625
TI  - Smoking & diabetes. Helping smokers quit.

PMID- 15195626
TI  - Records & papers. What to keep and what to toss.

PMID- 15195628
TI  - Tracking trans fats. Cutting down on trans fat may help cut down on heart
      disease.

PMID- 15195627
TI  - Are you taking more meds than you need?

PMID- 15195629
TI  - The ins and outs of infusion sets. Changing the infusion set on your pump can be
      intimidating. Here are some tips to make it easier.

PMID- 15195630
TI  - Stocking up for nutrition. Essential ingredients. Load up your pantry shelves
      with these tasty and versatile selections.

PMID- 15195631
TI  - Stocking up for nutrition. Flavor boosters. Add pizzazz to your family's
      mealtimes with these pantry secrets.

PMID- 15195632
TI  - Stocking up for nutrition. Chills & thrills. Put your freezer to work for great
      nutrition and convenience.

PMID- 15195633
TI  - Stocking up for nutrition. Dreamy desserts. With sweet stuff in the pantry,
      they're as easy as pie.

PMID- 15195634
TI  - Research profile. Is there a link? TZDs and congestive heart failure. Andrew
      Karter, PhD.

PMID- 15195635
TI  - [Legal aspects of injuries due to positioning of the patient in urology].
AB  - Each positioning of the patient has method specific risks and risk increasing
      factors which depend on the type of surgery carried out. The causes of damage
      during positioning are pressure and strain when the protective reflexes are out
      of action, as well as a reduction of the shielding muscle tone through
      anaesthesia. The surgeon is responsible for the positioning of the patient, and
      the anaesthetist for the "infusion arm". For this interdisciplinary cooperation,
      the principles of horizontal work division are required: strict role boundaries,
      trust without reciprocal direction, close coordination and reciprocal respect for
      the specialist requirements of the partner, resolution of conflicts taking these
      requirements into consideration and the final decision of the surgeon. Legally,
      the damage caused by the positioning of the patient is considered to be fully
      under control. It can only be reduced by medical care but can not be eliminated.
      For compensation, the medical practitioner must prove that the appropriate amount
      of care was taken in the positioning of the patient as well as in the medical
      cooperation.

PMID- 15195636
TI  - [Effect of the cannabinoid receptor ligand WIN-55,212-2 on the TNF-alpha
      production by human mononuclear cells].
AB  - Synthetic cannabinoid WIN-55,212-2 produces a dose-dependent decrease on the TNF
      alpha production by LPS-stimulated human mononuclear cells in vitro. The most
      pronounced inhibition of the TNF-alpha synthesis was observed for a drug
      concentration of 10 microM.

PMID- 15195637
TI  - John Lundy's influence on Mario Dogliotti's anesthesia career: The Rochester -
      Turin connection.

PMID- 15195639
TI  - [Surgeons in the army of the Grand Duchy of Lithuania in the 18th century].
AB  - The paper presents profiles about 120 surgeons in the army of the Grand Duchy of
      Lithuania in the 18th century. It is based on unpublished archival sources form
      the Central Archives of Historical Records, of Radziwillien Archives, 7th
      section: Military Acts. Both, the acts and the era, that are concerned haven't
      been researched by any historian of medicine so far.

PMID- 15195638
TI  - European guidelines on cardiovascular disease prevention in clinical practice.
      Third Joint Task Force of European and other Societies on Cardiovascular Disease
      Prevention in Clinical Practice (constituted by representatives of eight
      societies and by invited experts).

PMID- 15195640
TI  - [The Krakow Gynaecological Society in the twenty years between the World Wars].
AB  - The Krakow Gynaecological Society (KTG) is the oldest society in Poland. The
      Society was founded in 1890. There are not many studies dealing with its activity
      in the years 1918-1939. The present paper aims at filling in this gap. The source
      materials were mainly provided by the reserved minutes of meetings. The paper
      presents a short outline of activity before 1918 and later discusses the Society
      structure. Its lists names of successive Chairmen anad analyses the makeup of
      Boards. There is presented an outline of basic directions in scientific,
      organizational and social activities of the Society, streeing its significance
      for shaping the professional community. Special attention is given to the causes
      of the crisis in the thirties. Some new, not previously published facts from the
      Society history have been put into light. As an additional information, a list of
      members with membership periods, and a list of people serving on the society
      Boards have also been given.

PMID- 15195642
TI  - Tenet numbers beat forecast.

PMID- 15195641
TI  - Conscience clauses and Catholic health care.

PMID- 15195643
TI  - Bioethics and the war on terrorism: a prospectus.

PMID- 15195644
TI  - Organ donation and financial incentives: a matter of principle.

PMID- 15195645
TI  - [Health service of the Nowogrodzki area section of the Polish Home Army (AK)].
AB  - The article discusses the formation, development and activity of health service
      of the Nowogrodzki area section of the Polish Home Army, methods of acquiring
      staff, medical equipment and supplies, as well as forms and principles of helping
      wounded and suffering. These questions have been discussed against the background
      of military tasks set for the area sections by the Chief Home Army Commanders. In
      July 1944, its soldiers took part in the "Ostra Brama" military operation aimed
      at liberation of the city of Wilno (present Vilnius). During combat, the Home
      Army medical services worked unsparingly. An ordeal for physicians, pharmacists,
      and nurses were the arrests and murders commited.

PMID- 15195646
TI  - The missing link in the public policies on human embryo research.

PMID- 15195647
TI  - Is living organ donation ethically acceptable?

PMID- 15195648
TI  - Is it ethical to legislate an age of consent for health care decision making?

PMID- 15195649
TI  - A Lockean argument against gene patenting.

PMID- 15195650
TI  - Breast implant adverse events during mammography: reports to the Food and Drug
      Administration.
AB  - OBJECTIVE: To characterize reports of adverse events occurring during mammography
      to women with breast implants submitted to the Food and Drug Administration
      (FDA). METHODS: We searched the adverse events database for any report on
      silicone gel breast implants or saline breast implants that included the word
      "mammography" or "mammogram"in the text. We also searched adverse event reports
      for mammographic equipment that included the term "breast implant" in the text.
      RESULTS: We retrieved 714 adverse event reports using this strategy. Sixty-six of
      these reports detailed an adverse event that occurred during mammography or
      described breast implant interference with mammography. The majority of these
      reports, 41 of 66 (62.1%), described breast implant rupture during mammography.
      Other adverse events reported included mammographic compression crushing
      implants, pain during mammography attributed to implants, inability to perform
      mammography because of capsular contracture or fear of implant rupture, and
      delayed detection of cancer attributed to implants. CONCLUSIONS: It is important
      that women considering breast implants be informed of these potential risks and
      that clinicians, radiologists, and mammographic technicians keep them in mind
      when imaging women with implants.

PMID- 15195651
TI  - [The place of ethnomedicine in anthropology and in medicine].

PMID- 15195652
TI  - EACH newspages: 6th & 7th February, 2004. Verona Network on Sequence Analysis.

PMID- 15195654
TI  - Take care: uptick in Lyme disease likely.

PMID- 15195653
TI  - Is the government too lax in advice on tuna consumption?

PMID- 15195655
TI  - "German methods," "unconditional gifts," and the full-time system: The case study
      of the University of Toronto, 1919-23.
AB  - At the end of 1919, The University of Toronto got word that the Rockefeller
      Foundation was looking to give the university a gift of one million dollars (US)
      to "aid medical education.". This was in addition to a gift of $500,000
      (Canadian) from merchant millionaires Sir John Craig and Lady Eaton. The
      implementation of the full-time system of clinical instruction made possible by
      these large gifts touched off a fiery debate among the medical profession and
      prompted a provincial government inquiry that would have thwarted long-awaited
      innovations in medical teaching and threatened the autonomy of the entire
      university. Much has been written about the full-time system of clinical medical
      education, most of it dealing with the United States. Some have documented cases
      where donor dollars were scorned in aiding the shift to full-time clinical
      teaching. Less well known is the tale of the University of Toronto. "The
      Provincial University" is an unique case study of a public university that tried
      to satisfy donor conditions even as it served its constituency- the people of
      Ontario. The challenge of implementing a new medical pedagogy between 1919 and
      1923 was that Toronto lay at the centre of three poles: private versus public
      funding; "research" or laboratory medicine versus "experience" or "practical"
      medicine; and those who wanted to try the full-time system versus the established
      "old guard."

PMID- 15195657
TI  - Bibliography. Current world literature. Surgery.

PMID- 15195658
TI  - Bibliography. Current world literature. Trauma and rehabilitation.

PMID- 15195656
TI  - A comprehensive survey of human Y-chromosomal microsatellites.
AB  - We have screened the nearly complete DNA sequence of the human Y chromosome for
      microsatellites (short tandem repeats) that meet the criteria of having a repeat
      unit size of > or = 3 and a repeat count of > or = 8 and thus are likely to be
      easy to genotype accurately and to be polymorphic. Candidate loci were tested in
      silico for novelty and for probable Y specificity, and then they were tested
      experimentally to identify Y-specific loci and to assess their polymorphism. This
      yielded 166 useful new Y-chromosomal microsatellites, 139 of which were
      polymorphic, in a sample of eight diverse Y chromosomes representing eight Y-SNP
      haplogroups. This large sample of microsatellites, together with 28 previously
      known markers analyzed here--all sharing a common evolutionary history--allowed
      us to investigate the factors influencing their variation. For simple
      microsatellites, the average repeat count accounted for the highest proportion of
      repeat variance (approximately 34%). For complex microsatellites, the largest
      proportion of the variance (again, approximately 34%) was explained by the
      average repeat count of the longest homogeneous array, which normally is
      variable. In these complex microsatellites, the additional repeats outside the
      longest homogeneous array significantly increased the variance, but this was
      lower than the variance of a simple microsatellite with the same total repeat
      count. As a result of this work, a large number of new, highly polymorphic Y
      chromosomal microsatellites are now available for population-genetic,
      evolutionary, genealogical, and forensic investigations.

PMID- 15195659
TI  - Modes of action of HLA-DR susceptibility specificities in multiple sclerosis.

PMID- 15195660
TI  - No accidents.

PMID- 15195661
TI  - Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and
      causes skipping of exon 9: a functional link with disease penetrance.

PMID- 15195662
TI  - [Suicide in Buenos Aires].
AB  - Between 1880 and 1910, a new issue began to concern some in the Argentinean
      medical community: the increase in the suicide rate. The concept of suicide, till
      then considered to be an individual and private behaviour, changes noticeably. A
      group of institutions and discussions would increasingly focus as much on the
      causes of this apparent rise in the suicide rate as on how to reduce their
      number. Despite the variety of specialities and orientations of the Argentinean
      doctors (mental health specialists, psychiatrists, psychologists, criminologists
      and sociologists -before such terms were coined) who try to understand the rise
      in the number of suicides, there is a fundamental issue at the heart of their
      analyses: the deficient framework- perceived by them as non-existent-for the new
      behaviours disturbing the social order, or that the very least, the representaion
      of this order in the doctors' conceptual universe. Is this a social epidemic? An
      obsession? Or is it just a nutural mechanism of social selection? Around the
      complex, process of defining the suicide phenomenon as a social problem, medical
      discourse sheds light on the shaky ground at the limits between the scientific
      claim to objectivity for certain behaviours at the renewal of the concept of
      normalcy in modern societies.

PMID- 15195663
TI  - Ostomies. Alternative methods for waste elimination.

PMID- 15195664
TI  - Hungary makes slow progress in health-system reform    Private funds, which could
      rescue Hungary's ailing health-care system, have been slow to materialise.

PMID- 15195665
TI  - UN appeals for aid for Sudan's humanitarian crisis.

PMID- 15195666
TI  - Scientists lobby UN to allow stem-cell research.

PMID- 15195667
TI  - MSF workers attacked in Afghanistan.

PMID- 15195668
TI  - Kenya proposes tobacco-compensation law.

PMID- 15195669
TI  - Dutch regulations governing euthanasia debated.

PMID- 15195670
TI  - Chinese province leads the way in facing up to HIV/AIDS. Yunnan Province's
      radical approach marks a new openness to HIV/AIDS in China.

PMID- 15195671
TI  - Sanitary medicine and the social body: the case of national civil registration
      and statistics in Canada, 1855-75.
AB  - Civil registration and vital statistics are important elements in the definition
      of a social body, the primary object whose health and well-being is the aim of
      social medicine. The failure of the federal government to organize a national
      system of civil registration in the Confederation era is placed in the context of
      a variety of sources of pressure for it to do so from doctors, social reformers,
      and provincial and municipal officials.

PMID- 15195672
TI  - [Inoculation at 18th century Geneva].
AB  - As it was introduced in 18th century Europe, the smallpox inoculation, presented
      by its supporters as a masterpiece of enlightened rationality , gave rise to
      passionate philosophical, medical, and theological debates. The history of
      inoculation deals with public health as well as individual experience and
      medical, progress. Too young to provide us with first-hand evidence, children are
      central, yet absent figures in this history. Focusing essentially on Geneva, this
      article firstly indicates what, according to doctors, the theoretically ideal age
      to be inoculated is. It then turns to the inoculators, who hesitate to operate on
      children because of their weak constitution, for fear of the negative publicity a
      failure would bring. It finally presents the reception of inoculation by the
      public within two different contexts: the public initiatives taken in Geneva in
      the field of inoculation, and the case of a family drama ensuing from the failure
      of an inoculation. The purpose of this article is to: (1) summarize the
      chronology and social aspects of the history of inoculation in Geneva; (2)
      demonstrate that the reputation of the inoculating physician is a fundamental
      parameter guiding parents in their choice; and (3) raise the question of what
      inoculation can teach us about the perception of childhood during the Ancien
      Regime.

PMID- 15195676
TI  - Professional policy statement. Lifelong learning and the healthcare executive.

PMID- 15195677
TI  - DNA adduct levels in fish from pristine areas are not detectable or low when
      analysed using the nuclease P1 version of the 32P-postlabelling technique.
AB  - In order to understand and apply DNA adduct formation in fish liver as a
      biomarker for aquatic pollution, information concerning the natural background
      levels in noncontaminated organisms, caused by endogenous compounds, is of
      fundamental importance. In this study, DNA adducts were analysed in liver of 11
      fish species from arctic and sub-arctic areas in the northern Atlantic using the
      nuclease P1 version of the 32P-postlabelling technique. The collected fish were
      assumed not to have been influenced by anthropogenic pollution apart from
      possible long-range transported pollutants. As polycyclic aromatic hydrocarbons
      (PAHs) are thought to be fundamental in forming the type of DNA adducts detected
      by the method used, biliary PAH metabolite levels were measured in a selection of
      the investigated species. In all investigated individuals, the levels of PAH
      metabolites were undetectable. Controlled on-site exposure experiments with
      benzo[a]pyrene (polar cod) and laboratory experiments with crude oil (polar cod
      and Atlantic cod) were conducted. DNA adducts were formed in both these species.
      The field-sampled fish showed undetectable levels of DNA adducts or levels just
      above the detection limit. The present study supports the assumption that when
      DNA adducts are detected by the nuclease P1 version of the 32P-postlabelling
      method in fish liver, it can be interpreted as DNA damage caused by pollutants.

PMID- 15195678
TI  - Determinants of serum levels of surfactant proteins A and B and Clara cell
      protein CC16.
AB  - Increased leakage of surfactant proteins A and B (SP-A and SP-B) and Clara cell
      secretory protein (CC16) from the air spaces into the circulation occurs in a
      range of respiratory conditions. However, circulating levels depend not only on
      the rate of entry into the circulation, but also on the rate of clearance. In
      order to clarify the role of the kidney in the clearance of these proteins, serum
      levels were related to markers of glomerular filtration in 54 non-smoking
      patients with varying degrees of renal dysfunction, none of whom had respiratory
      disease or were receiving dialysis at the time of sampling. Serum SP-A was
      related to SP-B (r = 0.53, p < 0.001) and to CC16 (r = 0.33, p < 0.02).
      Similarly, SP-B was related to CC16 (r = 0.39, p < 0.004). Stepwise multiple
      linear regression analysis suggested that serum SP-A and SP-B are influenced by
      age (approximately 20 and approximately 25% of variance, respectively), whereas
      CC16 is determined by renal function and, to a lesser extent, by body weight
      (approximately 63% of variance in total). We conclude that CC16 is cleared from
      blood by the renal route, whereas SP-A and SP-B are not. Serum SP-A and SP-B are
      influenced by age, which we speculate reflects increased damage to the
      alveolocapillary barrier.

PMID- 15195679
TI  - 1H-Nuclear magnetic resonance pattern recognition studies with N
      phenylanthranilic acid in the rat: time- and dose-related metabolic effects.
AB  - N-Phenylanthranilic acid (NPAA) causes renal papillary necrosis (RPN) in the rat
      following repeated oral dosing. Non-invasive early detection of RPN is difficult,
      but a number of potential biomarkers have been investigated, including
      phospholipid and uronic acid excretion. This study used 1H-nuclear magnetic
      resonance (NMR) spectroscopic analysis of urine to investigate urinary metabolic
      perturbations occurring in the rat following exposure to NPAA. Male Alderley Park
      rats received NPAA (300, 500 or 700 mg kg(-1) day(-1) orally) for 7 days, and
      urine was collected on days 7-8, 14-15, 21-22 and 28-29. In a separate study,
      urine was collected on days 1-2, 3-4, 5-6 and 7-8 from rats receiving 500 mg kg(
      1) day(-1). Samples were analysed by 1H NMR spectroscopy combined with
      multivariate data analysis and clinical chemistry. Histopathology and clinical
      chemistry analysis of terminal blood samples was carried out following
      termination on days 4, 6, 8 and 29 (4 week time course) and days 2, 4, 6 and 8 (8
      day study). Urine analysis revealed a marked, though variable, excretion of beta
      hydroxybutyrate, acetoacetate and acetone (ketone bodies) seen on days 3-4, 5-6
      and 7-8 of the study. It is postulated that the ketonuria might be secondary to
      an alteration in fatty acid metabolism due to inhibition of prostaglandin
      synthesis. In addition, an elevation in urinary ascorbate was observed during the
      first 8 days of the study. Ascorbate is considered to be a biomarker of hepatic
      response, probably reflecting an increased hepatic activity due to
      glucuronidation of NPAA.

PMID- 15195680
TI  - Biomarker responses in juvenile rainbow trout (Oncorhynchus mykiss) after single
      and combined exposure to low doses of cadmium, zinc, PCB77 and 17beta-oestradiol.
AB  - The objective of this study was to examine (i) the biochemical responses of
      rainbow trout exposed to sublethal water concentrations of the metals cadmium
      (Cd) (1.5 microg l(-1)) and zinc (Zn) (150 microg l(-1)); and (ii) the potential
      combined effects when applied in mixture (Cd/Zn) with and without co-exposure to
      model organic chemicals 3,3',4,4'-tetrachlorobiphenyl (PCB77) (1 mg kg (-1)) and
      17beta-oestradiol (E2) (0.5 mg kg(-1)). After 21 days of exposure, several
      biomarkers were assessed in the liver (enzymatic and nonenzymatic antioxidants,
      heat shock proteins [HSP70 and HSP60], ethoxyresorufin-O-deethylase [EROD]) and
      in the plasma (vitellogenin [Vtg], aminotransferases). Plasma aminotransferases
      were not affected, whereas the other biomarkers showed different patterns of
      response depending on the treatment. For example, Cd, and Zn to a lesser extent,
      induced an adaptive response in the liver shown by an increase in antioxidant
      defences (total glutathione [GSH], superoxide dismutase, Trolox equivalent
      antioxidant capacity [TEAC]), without any impairment of GSH redox status or
      induction of heat shock proteins. Antagonistic effects were observed in GSH
      related biomarkers after Cd/Zn exposure. PCB77 strongly induced EROD activity,
      HSP70 and TEAC. Co-exposure with metals did not modulate significantly the
      effects of PCB77. E2 induced Vtg and inhibited liver antioxidants and basal EROD
      activity. These inhibitory effects were suppressed in fishes exposed to E2 +
      Cd/Zn, suggesting additive effects of E2 and metals. In addition, E2-induced Vtg
      was not altered by metals. Multivariate analyses confirmed some correlation
      between the biomarkers. The use of complementary biomarkers is necessary to
      discriminate different treatments and to highlight interactive effects.

PMID- 15195681
TI  - DNA damage levels are raised in Barrett's oesophageal mucosa relative to the
      squamous epithelium of the oesophagus.
AB  - Barrett's oesophagus (BE) is a pre-malignant metaplastic tissue predisposing to
      oesophageal adenocarcinoma (EC), and gastro-oesophageal reflux is a risk factor
      for both conditions. Reflux of acid and bile can cause mucosal injury and
      initiate chronic inflammation. These processes can induce DNA damage, possibly
      via an oxidative stress mechanism, thus increasing the likelihood of progression
      from Barrett's metaplasia to dysplasia and finally carcinoma. The comet assay was
      optimized for the detection of DNA damage (strand breaks and alkali-labile sites)
      in oesophageal biopsies, including incorporation of the DNA repair enzyme Fapy
      DNA glycosylase (Fpg). Fpg allows the detection of 8-hydroxy-2-deoxyguanosine (8
      OHdG) sites, a known pro-mutagenic DNA lesion. BE patients were recruited from BE
      surveillance clinics and oesophageal biopsies collected at endoscopy. Comet
      analysis revealed significantly increased (p < 0.001) DNA damage in Barrett's
      epithelium compared with matched squamous epithelium, with median % tail DNA
      values of 25.1% (first to third quartile 21.7-29.6%) and 18.6% (first to third
      quartile 16.9-21.4%), respectively. The median % tail DNA was up to 70% higher in
      the matched BE tissue compared with squamous epithelium from the same patient.
      Fpg sensitive sites were demonstrated in both tissue types at similar levels. The
      raised level of DNA damage in the premalignant BE may contribute to the
      accumulation of genetic alterations occurring during progression to EC.
      Understanding these underlying mechanisms provides a basis for cancer prevention
      strategies in BE patients.

PMID- 15195682
TI  - Metabolic gene polymorphisms and p53 mutations in healthy centenarians and
      younger controls.
AB  - To obtain insights into the genetic mechanisms of ageing, we studied the
      frequency of the simultaneous presence of polymorphisms in phase I and phase II
      genes and of several p53 germline mutations in a group of 66 nonagenarians and
      centenarians in good health, selected from a larger sample of a multicentre
      Italian study in Northern Italy, and in a sample of 150 young healthy volunteers
      of the same ethnic group. We found a statistically significant difference in the
      frequency of 1the GSTT1 deletion and the p53 genotypes: the absence of any p53
      polymorphisms and of GSTT1 deletion, and the simultaneous presence of the three
      p53 polymorphisms and of GSTT1 deletion, were much more frequent in young
      subjects than in centenarians (41.5% versus 26.9% and 8.8% versus 3.8%,
      respectively). One hypothesis to explain this difference is that subjects with
      both GSTT1 deletion and p53 polymorphisms may accumulate carcinogens and may have
      reduced DNA repair ability, and thus are more at risk for cancer. Another
      possible explanation is that both metabolic genes and p53 act on pathways related
      to cell ageing and death, and therefore certain composite genetic patterns could
      represent a generic mechanism of protection against ageing, not just against the
      development of chronic diseases. It is likely that longevity is related to a
      complex genetic trait as well as to certain environmental exposures.

PMID- 15195683
TI  - Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: findings
      in a population-based study in Belgium.
AB  - Dioxins and polychlorinated biphenyls (PCBs) are persistent organic pollutants
      widely distributed in the food chain, which is the main source of human exposure.
      Their effects on human health at background exposure levels are still poorly
      understood. Recent epidemiological evidence suggests a possible association
      between these pollutants and diabetes. We report here the results of a population
      based study in Belgium on 257 (142 women and 115 men) environmentally exposed
      subjects, including 10 cases of endometriosis and nine cases of diabetes.
      Seventeen 2,3,7,8-polychlorinated dibenzodioxins/dibenzofurans (PCDD/Fs or
      dioxins), four coplanar PCBs (International Union of Pure and Applied Chemistry
      [IUPAC] nos 77, 81, 126 and 169) and 12 PCB markers (IUPAC nos 3, 8, 28, 52, 101,
      118, 138, 153, 180, 194, 206 and 209) were quantified in serum fat from fasting
      blood samples in order to estimate the body burden of these pollutants. Whilst no
      difference was found between women with endometriosis and their controls,
      diabetic patients had significantly increased serum levels of dioxins, coplanar
      PCBs and the 12 PCB markers. After adjustment for age and other covariates, serum
      total toxic equivalent activity (sum of PCDD/Fs and coplanar PCBs) and 12 PCB
      marker concentrations in diabetics were 62% (p = 0.0005) and 39% (p = 0.0067)
      higher, respectively, than in controls. The risk of diabetes was significantly
      increased in subjects in the top decile for adjusted concentrations of dioxins
      (odds ratio 5.1, 95% confidence interval [CI] 1.18-21.7), coplanar PCBs (odds
      ratio 13.3, 95% CI 3.31-53.2) or 12 PCB markers (odds ratio 7.6, 95% CI 1.58
      36.3). These findings warrant further studies to assess the significance of the
      associations between diabetes and environmental exposure to polychlorinated
      pollutants.

PMID- 15195684
TI  - Arterial hypertension: a cause of cognitive impairment and of vascular dementia.
AB  - Arterial hypertension is a well-documented modifiable risk factor for
      cerebrovascular disease and for both cerebral infarction and intracerebral
      hemorrhage. Recent studies indicate a relationship between high blood pressure in
      midlife and dementia in late life and suggest that arterial hypertension may
      represent a cause of vascular dementia (VaD). This paper has reviewed the main
      evidence of a link between arterial hypertension and vascular cognitive
      impairment or VaD. Brain lesions induced by hypertension, diagnostic procedures
      for early diagnosis of vascular cognitive impairment in at risk subjects and the
      need to include cognitive assessment in patient's general visits in hypertension
      units are discussed.

PMID- 15195685
TI  - The cerebral cortex of spontaneously hypertensive rats: a quantitative
      microanatomical study.
AB  - The morphology of cerebral cortex was investigated in male spontaneously
      hypertensive rats (SHR) aged 2, 4 and 6 months (pre-hypertensive, developing
      hypertension and established hypertension respectively) and in age-matched
      normotensive Wistar-Kyoto (WKY) rats using quantitative microanatomical
      techniques. Analysis included frontal and occipital cortex as a paradigm of motor
      and sensory cerebrocortical areas respectively. Values of systolic pressure were
      slightly higher in 2-month-old SHR compared to age-matched WKY rats and augmented
      progressively with increasing age in SHR. In frontal cortex of SHR a decrease of
      nerve cell number and of cortical volume was observed in layers V and VI of 4-
      and 6- month-old SHR, and in layers I-IV of 6- month-old SHR. In occipital cortex
      a decrease of the number of nerve cells and of cortical volume was observed in
      layers V and VI of 2-, 4-, 6- month-old SHR, and in layers I-IV of 6-month-old
      SHR. Numerical decrease of neurons in SHR affected to a greater extent occipital
      cortex than frontal cortex. An increase in the number of glial fibrillary acidic
      protein (GFAP)-immunoreactive astrocytes (hyperplasia) as well as in the mean
      immune reaction area (hypertrophy) was found in the two cerebrocortical areas
      investigated of 6-month-old SHR. The occurrence of apoptosis and/or necrosis
      identified using the terminal deoxyribo-nucleotidyl transferase (TdT)-mediated
      biotin-16-dUTP nick-end labeling (TUNEL) technique was also observed in frontal
      and occipital cortex of 6-month-old SHR, but not of younger cohorts. These
      findings indicate the development of microanatomical changes in the cerebral
      cortex of SHR, the extent of which increases parallel with the progression of
      hypertension. The occurrence of cerebrocortical apoptosis and/or necrosis as well
      as the obvious astrogliosis occurring in established hypertension may account for
      the increased risk of vascular dementia that represents a specific trait of
      complicated hypertension.

PMID- 15195686
TI  - Cerebrovascular and brain microanatomy in spontaneously hypertensive rats with
      streptozotocin-induced diabetes.
AB  - The influence of hypertension associated with diabetes on cerebrovascular and
      frontal cortex or hippocampus microanatomy was investigated in 20-week-old
      spontaneously hypertensive rats (SHR) in which diabetes was induced by treatment
      with streptozotocin (STZ) and in control or STZ-diabetic age-matched normotensive
      Wistar Kyoto (WKY) rats. At the beginning of experiment, systolic pressure values
      were similar in WKY rats either control, or exposed to STZ and remarkably higher
      in control or STZ-treated SHR. Systolic pressure values increased in the
      different animal groups examined along the course of experiment. Blood glucose
      levels were increased in either STZ-WKY rats or -SHR compared to WKY rats and SHR
      respectively. The main changes occurring in pial and intracerebral arteries of
      SHR and STZ-SHR were thickening of the arterial wall accompanied by luminal
      narrowing. In medium sized pial arteries of STZ-WKY rats luminal narrowing and a
      decreased thickness of arterial wall were noticeable. Intracerebral arteries of
      STZ-WKY diabetic rats showed a not homogeneous sensitivity of different sized
      branches. The volume of zones III and IV of frontal cortex was decreased in SHR
      and STZ-SHR compared to control WKY rats. The number of nerve cells in these
      cerebrocortical layers was decreased to a similar extent in SHR. STZ-WKY rats or
      STZ-SHR compared to control WKY rats. In dentate gyrus, followed by the CA1
      subfield of hippocampus, decreased volume and number of neurons were found in SHR
      and STZ-SHR compared to control WKY rats. The occurrence of astrogliosis was
      observed in hypertensive, diabetic or hypertensive plus diabetic rats. The above
      findings indicate the occurrence of cerebrovascular and brain microanatomical
      changes in SHR and to a lesser extent in STZ-diabetic rats compared to control
      normotensive and normoglicemic WKY rats. Association of hypertension and diabetes
      caused more pronounced changes than in the single disease models. These results
      support the view that hypertension and diabetes affect the structure of
      cerebrovascular tree and of brain and that association of the two diseases
      results in an increased risk of target-organ damage, involving brain.

PMID- 15195687
TI  - Glial fibrillary acidic protein and vimentin expression is regulated by
      glucocorticoids and neurotrophic factors in primary rat astroglial cultures.
AB  - The neurotrophic factors epidermal growth factor (EGF), basic fibroblast growth
      factor, (bFGF), insulin-like growth factor I (IGF-I) and insulin (INS) regulate
      neural and astroglial cell functions. Glucocorticoids may influence the
      metabolism of astroglial compartment and are key hormones in neurodegenerative
      events. This study was designed to assess the interactions between growth factors
      and dexamethasone (DEX) on cytoskeletal proteins (GFAP and vimentin) expression
      in 25 days in vitro (DIV) astrocyte cultures. An increase in GFAP and vimentin
      expression was observed after 12 h pretreatment with bFGF and subsequent
      treatment for 60 h with DEX. GFAP immunoreactivity was decreased after 24 h
      progression growth factors (EGF, IGF-I and INS) addition, when compared to
      control 36 h DEX and bFGF-pretreated cultures for the last 12 h. Vimentin
      immunoreactivity was decreased after 12 h bFGF pretreatment and subsequent 60 h
      DEX addition in astrocyte cultures compared to 12 h bFGF-pretreated ones.
      Pretreatment for 36 h with DEX plus bFGF in the last 12 h and subsequent
      treatment for 24 h with DMEM (Dulbecco's modified Eagle medium; DMEM) + BSA
      (bovine serum albumine) (harvesting), or with progression growth factors (EGF,
      IGF-I or INS) alone or two of them together, stimulated GFAP expression, compared
      to untreated controls. Immunochemical analysis of the mitogen-activated protein
      kinase ERK2 suggests an involvement of this enzyme in the control of GFAP
      expression. The above findings support the view of an interactive and complex
      dialogue between growth factors and glucocorticoids during astroglial cell
      proliferation and maturation in culture. This may have implications in
      therapeutic approach of neurologic disorders associated with astrogliosis,
      including cerebrovascular disease.

PMID- 15195688
TI  - Increased expression of glial fibrillary acidic protein in the brain of
      spontaneously hypertensive rats.
AB  - Astrogliosis, consisting in astroglial proliferation and increased expression of
      the specific cytoskeletal protein glial fibrillary acid protein (GFAP) is common
      in several situations of brain damage. Arterial hypertension, which induces
      cerebrovascular changes, can cause also brain damage, neurodegeneration and
      dementia (vascular dementia). This study was designed to assess astroglial
      reaction in different brain areas (frontal cortex, occipital cortex, hippocampus
      and striatum) of spontaneously hypertensive rats (SHR) in the pre-hypertensive
      phase (2 months of age), in the developing phase of hypertension (4 months of
      age) and in established hypertension (6 months of age). SHR were compared to age
      matched normotensive Wistar-Kyoto (WKY) rats. Analysis included reverse
      transcription-polymerase chain reaction (RT-PCR) of GFAP mRNA, GFAP
      immunochemistry (Western blot analysis) and immunohistochemistry. A significant
      increase of GFAP mRNA and an increase of GFAP immunoreactivity were noticeable in
      different brain areas of SHR compared to normotensive WKY rats at 6, but not at 2
      or 4 months of age. Immunohistochemistry revealed a numerical augmentation
      (hyperplasia) and an increase in size (hypertrophy) of GFAP-immunoreactive
      astrocytes in frontal cortex, occipital cortex and striatum of SHR. In the
      hippocampus of SHR only a numerical increase of GFAP-immunoreactive astrocytes
      was found. These finding demonstrating the occurrence of astrogliosis in the
      brain of SHR with established hypertension suggest that hypertension induces a
      condition of brain suffering enough to increase biosynthesis and expression of
      GFAP similarly as reported in several neurodegenerative disorders and in brain
      ischemia.

PMID- 15195689
TI  - Treatment with nicardipine protects brain in an animal model of hypertension
      induced damage.
AB  - Control of blood pressure protects from the development of cerebrovascular
      lesions and vascular dementia (VaD). This study has assessed the influence of
      treatment with the dihydropyridine-type Ca2+ antagonist nicardipine on brain
      microanatomical changes in spontaneously hypertensive rats (SHR). SHR were
      treated from 16th to 26th week of age with hypotensive (3 mg/Kg/day) or non
      hypotensive (0.1 mg/Kg/day) doses of nicardipine, with the non-dihydropyridine
      type vasodilator hydralazine (10 mg/kg/day) or with vehicle (control group).
      Untreated age-matched Wistar Kyoto (WKY) rats were used as a normotensive
      reference group. Brain volume, number of neurons, glial fibrillary-acidic protein
      (GFAP)-immunoreactive astrocytes and neurofilament 200 KDa (NFP)-immunoreactivity
      (IR) were assessed in frontal and occipital cortex, hippocampus and striatum. A
      decrease of volume and number of nerve cells and a loss of NFP-IR was found in
      the frontal and occipital cortex and in the CA1 subfield of hippocampus and in
      the striatum of SHR. Treatment with nicardipine countered microanatomical changes
      occurring in SHR, whereas hydralazine displayed a less pronounced effect.
      Comparatively, the non-hypotensive dose of nicardipine was less active than the
      hypotensive one. The observation that equihypotensive doses of nicardipine or
      hydralazine did not protect brain in the same way from hypertensive brain damage
      suggests that lowering blood pressure is per se not enough for affording
      neuroprotection. The demonstration of neuroprotective effect of nicardipine
      suggests an use of the compound in situations in which hypertension is
      accompanied by the risk of brain damage.

PMID- 15195690
TI  - Effect of treatment with the cholinesterase inhibitor rivastigmine on vesicular
      acetylcholine transporter and choline acetyltransferase in rat brain.
AB  - A decline of cholinergic neurotransmission probably contributes to cognitive
      dysfunction occurring in Alzheimer's disease (AD) and vascular dementia (VaD).
      Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors are the only drugs
      authorized for symptomatic treatment of AD and are also under investigation for
      VaD. The present study has investigated the influence of two doses of the AChE
      inhibitor rivastigmine (0.625 mg/Kg/day and 2.5 mg/Kg/day) on vesicular
      acetylcholine transporter (VAChT) and on choline acetyltransferase (ChAT)
      expression in frontal cortex, hippocampus, striatum and cerebellum of
      normotensive and spontaneously hypertensive rats (SHR). Cholinergic markers were
      assessed by immunochemical (Western blotting) and immunohistochemical techniques.
      In frontal cortex and striatum of normotensive rats, treatment with the lower
      dose (0.625 mg/Kg/day) of rivastigmine had no effect on VAChT immunoreactivity
      and increased slightly ChAT protein immunoreactivity. The higher dose (2.5
      mg/Kg/day) of the compound increased significantly VAChT and ChAT protein
      immunoreactivity. In hippocampus rivastigmine induced a concentration-dependent
      increase of VAChT protein expression and no significant changes of ChAT protein
      expression. A similar pattern of VAChT and ChAT protein expression was observed
      in control SHR, whereas treatment of SHR with rivastigmine induced a more
      pronounced increase of VAChT protein immunoreactivity in frontal cortex,
      hippocampus and striatum compared to normotensive rats. Our data showing an
      increase of VAChT after treatment with rivastgmine further support the notion of
      an enhancement of cholinergic neurotransmission by AChE/ChE inhibitors. The
      observation of a greater expression of this cholinergic marker in SHR suggest
      that AChE inhibition may provide beneficial effects on cholinergic
      neurotransmission in an animal model of VaD.

PMID- 15195691
TI  - Bioequivalence study of nicardipine solution versus nicardipine tablets.
AB  - The bioequivalence of a solution (investigational product) and a tablet
      (reference product) formulation of the dihydropyridine-type derivative Ca2+
      antagonist nicardipine were investigated by measuring plasma levels of the
      compound after single randomized administration of 20 mg of the two formulations.
      Drugs were given orally in a single dose to 24 healthy volunteers (12 males and
      12 females) at the beginning of the experiment and after a two weeks wash-out.
      Nicardipine is available in oral and intravenous formulations, the second being
      used for the short-term treatment of hypertensive crises. Oral formulations of
      nicardipine most diffused include immediate release (20 or 30 mg, three times a
      day administration), sustained release (30 mg, 45 mg or 60 mg, twice a day
      administration) and modified release (80 mg, once a day administration) tablets.
      A nicardipine solution is available only in Spain, but no published studies on
      the kinetics of this formulation are available. In the last 15 years, the main
      efforts were aimed to develop sustained or controlled release formulations of
      nicardipine to improve patient compliance by reducing the number of doses
      required each day. However, the use of twice a day or once a day administration
      of Ca2+ antagonists should be not overemphasized in particular situations like
      those of possible risk of cerebrovascular and/or coronary steal effect primarily
      in the elderly. The oral formulation of nicardipine investigated with a
      bioequivalence range > 70% compared to nicardipine immediate release tablets may
      represent an additional resource for treating elderly patients with concomitant
      cerebrovascular or coronary heart disease.

PMID- 15195692
TI  - Adipose tissue as an endocrine organ? A review of recent data related to
      cardiovascular complications of endocrine dysfunctions.
AB  - Clinical and experimental data obtained in the last few years have modified the
      concept of adipose tissue as one solely directed at energy storage and release.
      The adipose tissue is a target organ for glucocorticoids and several studies have
      been carried out on the function of hypothalamic-pituitary-adrenal axis in obese
      subjects without conclusive results. A recent and innovative finding is that
      adipose tissue can produce cortisol from its inactive precursor, cortisone. The
      identification of leptin, a hormone synthesised by fat tissue, has ushered in the
      modern view of this tissue as a true endocrine organ. Leptin is produced
      primarily by subcutaneous and to a lesser extent by visceral adipose tissue, and
      has a central role in controlling body weight and, especially in regulating fat
      stores. Leptin is also involved in several complex functions, including
      physiological processes associated with puberty. Another hormone of fat tissue is
      angiotensinogen, which is produced in larger amounts by visceral than
      subcutaneous fat. Human and animals adipose tissue express a whole renin
      angiotensin system (RAS). Angiotensin II, the final effector of this system is
      probably produced locally by adipose tissue. The function of adipose RAS is not
      well known. RAS can participate together with other hormones and substances, in
      adipocyte differentiation and fat tissue growth, but could be also involved in
      the pathogenesis of complications of obesity including arterial hypertension.

PMID- 15195693
TI  - The interleukin (IL)-2 family cytokines: survival and proliferation signaling
      pathways in T lymphocytes.
AB  - Lymphocyte populations in the immune system are maintained by a well-organized
      balance between cellular proliferation, cellular survival and programmed cell
      death (apoptosis). One of the primary functions of many cytokines is to
      coordinate these processes. In particular, the interleukin (IL)-2 family of
      cytokines, which consists of six cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL
      21) that all share a common receptor subunit (gammac), plays a major role in
      promoting and maintaining T lymphocyte populations. The details of the molecular
      signaling pathways mediated by these cytokines have not been fully elucidated.
      However, the three major pathways clearly involved include the JAK/STAT, MAPK and
      phosphatidylinositol 3-kinase (P13K) pathways. The details of these pathways as
      they apply to the IL-2 family of cytokines is discussed, with a focus on their
      roles in proliferation and survival signaling.

PMID- 15195694
TI  - The effect of B cell receptor signaling on antigen endocytosis and processing.
AB  - B cell receptor (BCR)-mediated antigen processing and presentation involves both
      the BCR-mediated internalization and processing of cognate antigen as well as the
      formation and expression of antigenic peptide-MHC class II complexes. While BCR
      signaling is known to result in changes in the biosynthesis and intracellular
      trafficking of class II molecules, the effect of BCR signaling on the cell
      biology of antigen endocytosis and processing is less clear. Therefore, the
      effect of BCR signaling on the cell biology of fluid phase antigen endocytosis,
      processing and presentation was analyzed in both B cell lines or in normal
      splenic B cells. The results demonstrate that BCR signaling alters neither the
      global level of fluid phase antigen endocytosis nor the duration of intracellular
      persistence of fluid phase internalized antigen. Moreover, while BCR signal does
      result in an increase in the level of total cell surface MHC class II molecules
      as well as specific peptide-class II complexes, stimulation failed to alter the
      fraction of class II molecules loaded with antigen-derived peptide. These results
      indicate that while BCR-mediated signaling elicits an increase in the expression
      of antigenic peptide-class II complexes, signaling does not augment antigen
      presentation by profoundly altering the basic biology of antigen endocytosis and
      processing. These results also demonstrate that the high efficiency of BCR
      mediated antigen processing (when compared to fluid phase antigen processing) is
      likely to occur independent of BCR signaling-induced global alterations in the
      biology of endocytosis, processing and presentation. This finding suggests that
      if BCR signaling augments the efficiency of processing of cognate antigen, it
      must impact unique aspects of BCR-mediated antigen processing, such as the
      intracellular persistence of internalized antigen-BCR complexes.

PMID- 15195695
TI  - Intracellular signaling and cytokine induction upon interactions of Porphyromonas
      gingivalis fimbriae with pattern-recognition receptors.
AB  - Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) of the
      innate immune system form functional receptor complexes that recognize and
      respond to pathogen-associated molecular patterns (PAMPs). Porphyromonas
      gingivalis is an important pathogen in human periodontitis and has also been
      implicated in atherosclerosis. A major virulence factor of this pathogen is the
      fimbriae, which function as a surface adhesin. Here we present evidence that
      fimbriae also constitute a predominant P. gingivalis proinflammatory molecule
      which activates the TLR signaling pathway resulting in induction of
      proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) and chemokines (IL-8)
      in monocytic cells. Although TLR2 and TLR4 mediate cellular activation in
      response to fimbriae, other PRRs, namely CD14 and CD11b/CD18, are involved in the
      recognition of fimbriae. We thus propose that fimbriae function as a PAMP which
      interacts with a PRR multi-receptor complex, where CD14 and CD11b/CD18 function
      as recruiting receptors and TLRs function as signaling receptors. In addition to
      cytokine induction, TLR activation by fimbriae also results in upregulation of
      the CD40, CD80, and CD86 costimulatory molecules in antigen-presenting cells,
      suggesting that fimbriae are sensed as a potential "danger" to the host immune
      system. Moreover, proinflammatory cytokine induction is attenuated upon repeated
      cellular stimulation with P. gingivalis fimbriae. This mechanism of tolerance
      induction which serves to mitigate excessive and potentially harmful inflammatory
      reactions appears to be due partly to fimbria-induced downregulation of the
      expression of interleukin-1 receptor-associated kinase-1 (IRAK-1), an important
      signaling intermediate of the TLR pathway. Understanding the molecular basis of
      how the host recognizes and responds to P. gingivalis fimbriae is essential for
      developing molecular approaches to control P. gingivalis-induced inflammatory
      responses in periodontal disease and perhaps atherosclerosis.

PMID- 15195696
TI  - E2F1 promotes cytokine mediated cell survival via a mechanism that is separable
      from its cell cycle regulatory effects.
AB  - Cytokines are important regulators of lymphocyte proliferation and survival
      during immune responses. The retinoblastoma pathway constitutes an important
      intracellular network that forms the basis of cell cycle regulation and cellular
      proliferation in all mammalian cells. Transcription factors of the E2F family
      form a central component of this pathway, and represent important targets for
      activation by mitogenic cytokines such as interleukin-2 (IL-2). We have
      previously described a model for study of the E2F1 transcription factor by stable
      overexpression in the cytokine-dependent lymphoid progenitor cell line BaF-B03.
      In this model of IL-2 receptor signalling, E2F1 overexpressing BaF-B03 cells
      exhibit cytokine-independent cellular proliferation and survival, thereby
      supporting the concept that E2F activation is a critical step in the genesis of
      clonal expansion of antigen-primed lymphocytes. Here, we provide evidence linking
      E2FI to a serum-dependent cell survival pathway that is separable from its cell
      cycle regulatory effects. Our data show that the serum glycerophospholipid
      lysophosphatidic acid is capable of mediating this survival effect via a
      mechanism that is sensitive to chemical inhibition of phosphatidylinositol 3
      kinase. IL-2 mediated cell survival, but not cell cycle progression, is dependent
      upon this serum-dependent cell survival pathway. The findings presented here
      provide an insight into how mitogenic cytokines such as IL-2 regulate the
      apparently separate processes of lymphocyte proliferation and survival via
      recruitment of the retinoblastoma pathway.

PMID- 15195697
TI  - Normal cell surface expression and selective loss of functions resulting from
      Phe110 to Ser and Cys126 to Trp substitutions in the formyl peptide receptor.
AB  - The N-formyl peptide receptor (FPR) is a G protein-coupled chemoattractant
      receptor that mediates diverse leukocyte functions when stimulated by bacteria
      derived N-formyl peptides such as fMet-Leu-Phe (fMLF). Impaired neutrophil
      responsiveness to fMLF parallels increased susceptibility to periodontal
      microorganisms among patients with localized juvenile periodontitis (LJP). To
      determine whether the recently identified FPR mutations in LJP patients are
      responsible for selective loss of receptor-mediated functions, we prepared and
      analyzed RBL-2H3 cells expressing FPR bearing Phe110 to Ser (FPR-F110S) or Cys
      126 to Trp (FPR-C126W) replacement as well as a FPR double mutant (FPR-FSCW). All
      mutant receptors were expressed normally on the cell surface, but were unable to
      mediate release of beta-hexosaminidase upon fMLF stimulation. FPR-C126W
      effectively mediated fMLF uptake, an indication of receptor-mediated endocytosis,
      whereas FPR-F110S and FSCW exhibited markedly reduced ability to uptake fMLF.
      Both FPR-F110S and FPR-C126W were defective in chemotaxis and displayed reduced
      Ca2+ mobilization, but mutation at both positions partially restored the ability
      to respond to fMLF in chemotaxis assay and was nearly normal in Ca2+ mobilization
      assay. All mutants exhibited diminished accumulation of inositol phosphates. FPR
      F110S displayed a delayed and significantly reduced ERK phosphorylation whereas
      FPR-FSCW nearly lost the ability to phosphorylate ERK. Taken together, these
      results indicate compromised signaling capabilities due to the FPR mutations, but
      the loss of function is selective and could be partially rescued by mutations at
      both positions.

PMID- 15195699
TI  - Secondary lymphoid-tissue chemokine induced modulation of T cells.
AB  - In this study we were interested in investigating the extent to which stimulation
      through a chemokine receptor could modulate TCR function. We report that splenic
      T cells exposed to secondary lymphoid-tissue chemokine (SLC, CCL21) for 72, but
      not 2 or 24 hours, exhibited a decreased ability to produce IFN-gamma following
      CD3 crosslinking. Similar findings were observed with CCL2 and CCL5. The decrease
      in IFN-gamma production was not attributed to a decrease in T cell viability, was
      not accompanied with an increase in IL-4 production, and could be induced using a
      G protein coupled receptor agonist indicating involvement of chemokine receptors.
      One explanation for these findings was that following chemokine exposure the T
      cells were less efficient at TCR capping and exhibited a decrease in ZAP-70
      protein expression. Consequently, these data indicate that CCL21 could modulate
      the function and expression of proteins necessary for T cell activation.

PMID- 15195698
TI  - p38 MAPK regulates IL-1beta induced IL-6 expression through mRNA stability in
      osteoblasts.
AB  - Osteoblast-derived IL-6 functions in coupled bone turnover by supporting
      osteoclastogenesis favoring bone resorption instead of bone deposition. Gene
      regulation of IL-6 is complex occurring both at transcription and post
      transcription levels. The focus of this paper is at the level of mRNA stability,
      which is important in IL-6 gene regulation. Using the MC3T3-E1 as an osteoblastic
      model, IL-6 secretion was dose dependently decreased by SB203580, a p38 MAPK
      inhibitor. Steady state IL-6 mRNA was decreased with SB203580 (2 microM) ca. 85%
      when stimulated by IL-1beta (1-5 ng/ml). These effects require de novo protein
      synthesis as they were inhibited by cycloheximide. p38 MAPK had minor effects on
      proximal IL-6 promoter activity in reporter gene assays. A more significant
      effect on IL-6 mRNA stability was observed in the presence of SB203580. Western
      blot analysis confirmed that SB203580 inhibited p38 MAP kinase, in response to IL
      1beta in a dose dependent manner in MC3T3-E1 cells. Stably transfected MC3T3-E1
      reporter cell lines (MC6) containing green fluorescent protein (GFP) with the
      3'untranslated region of IL-6 were constructed. Results indicated that IL-1beta,
      TNFalpha, LPS but not parathyroid hormone (PTH) could increase GFP expression of
      these reporter cell lines. Endogenous IL-6 and reporter gene eGFP-IL-6 3'UTR mRNA
      was regulated by p38 in MC6 cells. In addition, transient transfection of IL-6
      3'UTR reporter cells with immediate upstream MAP kinase kinase-3 and -6 increased
      GFP expression compared to mock transfected controls. These results indicate that
      p38 MAPK regulates IL-1beta-stimulated IL-6 at a post transcriptional mechanism
      and one of the primary targets of IL-6 gene regulation is the 3'UTR of IL-6.

PMID- 15195700
TI  - Regulation of interleukin-2 induced soluble Fas ligand release from human
      peripheral blood mononuclear cells.
AB  - Adjuvant interleukin (IL)-2 immunotherapy has been used in the treatment of
      different malignant dieseases. However, clinical results have been rather
      disappointing. Therefore, further investigations on IL-2-induced mediators of
      cytotoxicity seem to be necessary in order to possibly create cytokine cocktails
      which could enhance the IL-2-induced cytotoxicity. We therefore investigated the
      regulation of IL-2-induced release of soluble Fas Ligand (sFasL), since this
      factor is known to possess anti-tumor activities. In CD3-stimulated peripheral
      blood mononuclear cells IL-2 induced sFasL in a dose-dependent fashion. Maximum
      sFasL concentrations were obtained after stimulation of MNC for 120 hrs.
      Inhibition of endogenous IL-12 production significantly reduced IL-2-mediated
      sFasL release by about 25%. In contrast, addition of IL-12 enhanced the IL-2
      induced sFasL about 1,5-fold. IL-10 and IL-4 reduced the IL-2-stimulated sFasL by
      about 30%. Interestingly, these suppressive effects could be antagonized by the
      addition of IL-12. Not only exogenous IL-10 but also endogenously produced IL-10
      decreased the sFasL release to that extent which had been stimulated by IL-12.
      Since IL-12 and IL-10 only marginally influenced the IL-2-mediated cell
      proliferation as well as the IL-2-induced cell death, the IL-12- and IL-10
      controlled sFasL release seems to be based on an enhanced production per cell.
      However, the increase in cell numbers as well as the decrease of viability during
      cell culture might additionally contribute to the IL-2-induced increase of sFasL
      release. This secondary effect might explain why IL-2-mediated sFasL production
      is only partially controlled by regulatory cytokines such as IL-4, IL-10 or IL
      12. In conclusion, addition of IL-12 might increase the efficacy of IL-2
      immunotherapy by inhibition of the IL-10-mediated negative feed-back loop on IL-2
      mediated sFasL release.

PMID- 15195701
TI  - Expression of metallothioneins in tumor cells.
AB  - Metallothioneins (MT) are low molecular weight proteins present both in normal
      and in neoplastic cells. They represent the main mechanism of the cell which
      protects it from action of heavy metal ions and the principal zinc-binding
      proteins. MT act as controllers of zinc-dependent enzymes, participating, i.a.,
      in cell proliferation processes. The latter is of basic significance also in
      neoplastic diseases. Despite the relatively short period of studies on the role
      of MT in neoplastic processes, several data confirm their prognostic
      significance. Such data have been obtained in studies on expression of the
      proteins in breast, renal, urinary bladder, ovarian, laryngeal and lung cancers.
      MT are thought to play certain role in carcinogenesis, as indicated by results of
      studies on malignant tumors of large bowel, liver and stomach. The frequently
      noted positive correlation between MT expression and the expression of Ki-67 and
      PCNA antigens points to role of the proteins in the cell proliferation mechanism.
      Results collected and discussed in present paper, obtained by various authors and
      related to the role of MT expression in cells of various malignant tumors suggest
      a potential for using the protein as a prognostic factor in neoplastic diseases.

PMID- 15195702
TI  - Chronic myeloproliferative diseases on a pathologist's desk--a dilemma of
      distinct entities versus a clinico-pathologic continuum. A descriptive study
      based on a material from the Polish population.
AB  - Chronic myeloproliferative disorders (CMPD) are traditionally diagnosed using
      criteria based on clinical parameters. A framework for an alternative, trephine
      bone marrow histology-based approach, was provided by the Hanover group of
      hematopathologist (the "Hanover classification"). The present study describes a
      single institution experience with the Philadelphia-BCR/ABL negative CMPD
      diagnosed on the basis of the histopathology of bone marrow in the three
      consecutive years (2000 - 2002). Among 246 cases of CMPD (M:F=1:1.6), there were
      75 cases of idiopathic myelofibrosis (IMF), 45 of polycythemia vera (PV), 93 of
      essential thrombocythemia (ET), and 33 cases that were unclassifiable on the
      basis of morphology (CMPD-U). The clinical profiles of the IMF, PV and ET group
      emerging from the histological examination correlated with the expected clinical
      features of these diseases. The ET patients were the youngest (median 51 years)
      compared to PV (59.5 years), IMF (63.9), and CMPD-U (54.7). In 158 cases (74.3%),
      the biopsy corroborated the preliminary clinical diagnosis of CMPD, and in the
      half of these cases it refined the clinical diagnosis of suspected unspecified
      CMPD placing the disease in a particular specific category (ET, IMF or PV). In
      the remaining cases the biopsy was done due to an abnormality of unknown origin
      (usually an accidentally discovered thrombocytosis) or the clinical picture
      suggesting a disease other than CMPD (11.7%). Some cases of CMPD presented with
      atypical histological features, such as slight megakaryocytic dysplasia in ET
      (not justifying the diagnosis of IMF), raising the issue of the subjectivity of
      histological diagnosis. The trephine bone marrow biopsy provides a useful tool
      for the diagnosis of CMPD, particularly in the early IMF that may present with a
      clinical picture undistinguishable from ET, but which carries poorer prognosis
      and requires more vigorous treatment. A special attention should be paid to the
      CMPD-U group. Its current nosological status (early phases of IMF/ET/PV or
      distinct entity or entities?) is still unclear and requires further research.

PMID- 15195703
TI  - Influence of vanadyl sulphate [VOSO4] on biochemical activity and morphology of
      control and streptozotocin-diabetic rat liver Golgi complexes.
AB  - The authors describe the influence of vanadyl sulphate on liver Golgi complexes
      in control and streptozotocin (STZ)-diabetic rats. VOSO4, one of inorganic
      vanadium compounds widely used in animal models and human diabetes, acts as an
      insulin-mimetic drug and is relatively well known as a complex activated or
      inhibited on many enzymes involved in carbohydrate or lipid metabolic pathways. A
      relatively small in scope investigation was performed on subcellular levels,
      while changes of Golgi complexes under vanadium influence have not been described
      with the exception of our previous investigations with four organic derivatives.
      This paper presents the action of vanadyl sulphate used in 3mM in 0.5% NaCl as a
      drinking solution for 7 days on control and STZ-diabetic rat liver Golgi
      complexes. Changes induced by this vanadium compound were greater in the controls
      as compared to the diabetic rats, what was true for both biochemical and
      morphological data. Physiological and biochemical analyses showed a partial
      normalization of the investigated parameters in diabetic animals after short time
      treatment with vanadyl ions, although STZ-diabetic, vanadium treated rats were
      affected by two types of adverse effects exterted by these compounds. The
      controls manifested more numerous and advanced subcellular changes. The
      moderately developed Golgi apparatus showed no major changes. In the control
      group, subcellular changes were seen sporadically. More extended Golgi complexes
      showed certain anomalies.

PMID- 15195705
TI  - Cerebellar cortex lesions in cases with subtentorial neoplastic changes.
AB  - The aim of the study was to perform neuropathological examinations of the brains
      of children and adults with various types of neoplasms situated in the
      subtentorial area. In view of the varied opinions on the central nervous system
      (CNS) lesions in the course of neoplastic diseases, it was interesting to analyze
      the cerebellar cortex damage. The study material included fifteen primary tumors
      in children and fourteen tumors in adults. In the former, two primary and three
      metastatic tumors were treated with irradiation and chemotherapy (ChTh). In the
      remaining cases such a treatment was not employed because of the clinical course
      of the disease. Among adult cases, eight primary and six metastatic tumors were
      observed. In all metastatic cases irradiation and ChTh were used, other primary
      tumors were untreated because of the short follow-up period. In all the
      investigated cases, cerebellar cortex damage was observed. Except for lesions
      surrounding the neoplastic proliferation, two types of changes were found: one
      with a prevalence of Purkinje cell loss was similar to the first type of
      paraneoplastic cerebellopathy, while in the other a granular cell layer lesions
      predominated. In the entire material the changes were particularly severe in the
      children, mostly in those with the damage of the granular cell layer, contrary to
      the prevalent opinions that the CNS damage in the course of neoplastic diseases
      is more common in adults. Another interesting observation was that the changes
      did not correlate with the type of tumor and the employed therapy. The results of
      this study may be interesting for clinicians who perform neurological
      examinations in pediatric long-survivors of subtentorial tumors.

PMID- 15195704
TI  - CD44 expression in human meningiomas: an immunohistochemical analysis.
AB  - CD44 molecules play an important role in cell adhesion, interaction between cells
      and extracellular matrix and cellular invasive growth potential. The aim of the
      study was to evaluate CD44 expression in atypical and benign meningiomas. The
      tumor specimens were obtained from 61 patients (27 males and 34 females; aged 19 
      78). The analysed material included 10 atypical meningiomas (G2), and following
      subtypes of benign meningiomas (G1): 21 transitional, 17 meningothelial and 13
      fibroplastic. Paraffin tissue sections were immunostained using CD44 antibody
      (DAKO). The expression of CD44 was multifocal and diffuse. The strong expression
      was observed in atypical meningiomas, no expression in fibroplastic meningiomas
      and moderate expression in the other subtypes of benign meningiomas.
      Statistically significant differences were revealed between the expression of
      CD44 in G2 and G1 tumors. The results of the study support the thesis on the role
      of mutated CD44 molecule in the invasive growth potential of neoplastic cells.

PMID- 15195706
TI  - Three in one kidney. report of a case.
AB  - The case of a 70-year old male in whom imaging studies revealed two separate
      tumors in the left kidney is presented. In the surgical nephrectomy material two
      tumors were seen, 4.5 and 4 cm in diameter; one of them was a clear cell
      carcinoma, and the other--a papillary carcinoma, respectively. In addition, a
      small, subcapsular nodule was detected, which was classified as an adrenal rest.
      According to current opinions, the above lesions have different pathogenesis and
      their coexistence may be regarded as accidental.

PMID- 15195707
TI  - Universal fast walking applied to cDNA.
AB  - The elucidation of cDNA sequence remains problematic in cases such as genes
      possessing long coding regions, low expression levels, or poor library coverage.
      The recently described Universal Fast Walk (UFW) procedure offers a means of
      determining DNA sequence adjacent to characterised regions. To date, however, the
      approach has been applied only to genomic DNA. We demonstrate the first
      successful application of the UFW procedure to the elucidation of cDNA sequence,
      a previously unknown region of the large tammar wallaby ATRX gene in the
      theoretically more challenging 3' direction. To do this, we modified the
      previously published method by including an initial linear amplification and a
      final, fully nested PCR. We also exchanged buffers between preparative enzyme
      reactions to ensure optimal conditions for successive steps. These additional
      steps ensured a product not observed in their absence. UFW, therefore, represents
      a powerful alternative mechanism for the cloning and sequencing of cDNA,
      harnessing the exquisite sensitivity and specificity of fully nested PCR in
      challenging cloning scenarios where conventional 5' or 3' RACE may fail.

PMID- 15195708
TI  - New amperometric biosensors based on diamond paste for the assay of L- and D
      pipecolic acids in serum samples.
AB  - Monocrystalline natural diamond, L-amino acid oxidase (L-AAOD), D-amino acid
      oxidase (D-AAOD), and paraffin oil were used for the design of the modified
      diamond paste. The technique used for the direct voltammetric assay was
      differential pulse voltammetry (DPV) with applied potential pulse amplitude of 25
      mV vs. Ag/AgCl. Using the new amperometric biosensors L-pipecolic acid (L-PA) and
      D-pipecolic acid (D-PA) were determined reliably from serum samples at 700 and
      200 mV vs. Ag/AgCl, respectively, with low limits of detection.

PMID- 15195709
TI  - A single-step chromatographic method for the purification of proteins devoid of
      exposed histidine residues.
AB  - The principle of the immobilized metal affinity chromatography (IMAC) is based on
      the differences in the affinity of proteins for metal ions bound in a 1:1 complex
      of iminodiacetic acid (IDA) immobilized on a chromatographic support. A single
      step purification was carried out for luteinizing hormone (LH) on Cu2+, Zn2+,
      Ni2+, and Co2+ IDA Sepharose affinity columns. Highly purified LH was obtained
      with a Cu2+ IDA Sepharose column. SDS-PAGE and Western blot analysis were done to
      confirm the purity of the hormone. Biological activity has been evaluated by
      radio-immunoassay. This method was found economically viable and suitable for the
      recovery of biologically active hormone.

PMID- 15195710
TI  - Purification and characterization of liver lectins from a lizard, Sceloporus
      spinosus.
AB  - This study discusses the purification of soluble beta-galactose lectins obtained
      from the lizard liver of Sceloporus spinosus. The first lectin named lizard
      hepatic lectin-1 (LHL-1) presented a molecular weight of 31,750, with an
      isoelectric point of 4.25. The highest specific hemagglutinating activity was
      achieved using human blood type A1: N-acetylgalactosamine (GalNAc)-galactose
      (Gal)-fucose (Fuc). Carbohydrate inhibition assays indicated a higher lectin
      specificity for GalNAc. For LHL-2 the molecular weight obtained was 23,850 with
      an isoelectric point of 3.25. The highest carbohydrate specificity was observed
      for Gal. These lizard hepatic lectins are similar to the mammal hepatic lectins
      previously reported. However, it is different from the alligator hepatic lectin
      (AHL). The homology analyses of LHL-1 resulted in 100% identity with the
      Steroidogenic acute regulatory protein (StAR), while LHL-2 was similar to
      adenylate kinase (75% identity). We suggest that these liver lectins are related
      to the inherent functions of liver previously reported.

PMID- 15195711
TI  - Immobilization of lipases on different carriers and their use in synthesis of
      pentyl isovalerates.
AB  - Porcine pancreatic lipase (PPL) and Candida cylindracea lipase (CCL) were
      immobilized on Celite and Amberlite IRA 938 by deposition from the aqueous
      solution by the addition of hexane. The influence of the immobilization on the
      activities of the immobilized lipase derivatives has been studied. The
      immobilized lipases were used in synthesis of pentyl isovalerates. Various
      reaction parameters affecting the synthesis of pentyl isovalerates were
      investigated. The reaction rates were compared with the rates of esterification
      with free lipases. The immobilized lipases were found to be very effective in the
      esterification reaction. The lipases immobilized on Celite 545 exhibited better
      operational stabilities than that of immobilized on Amberlite IRA-938.

PMID- 15195712
TI  - Purification and characterization of two laccase isoenzymes from a ligninolytic
      fungus Trametes gallica.
AB  - Constant laccase activities were detected in culture supernatant of newly
      isolated basidiomycete Trametes gallica. Tryptone and glucose have great effects
      on the production of laccase. Two laccase isoenzymes (Lac I and Lac II) produced
      by T. gallica were purified to homogeneity (51- and 50-fold, respectively) by gel
      filtration chromatography, anion exchange chromatography, and improved native
      PAGE, with an overall yield of 24.8%. Lac I and Lac II from this fungus are
      glycoproteins with 3.6% and 4% carbohydrate content, the same molecular masses
      (by SDS-PAGE) of 60 kDa, and the pI of 3.1 and 3.0, respectively. Native gel
      electrophoresis indicates that the two laccases have different migration ratios.
      Lac I and Lac II have the same optimal pH of 3.0 on 2,6-dimethoxyphenol (DMP), pH
      2.2 on 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and of pH
      4.0 on guaiacol. The highest rate of ABTS oxidation for both laccases was reached
      at 70 degrees C. Both laccases are stable from pH 6 to 9, retaining 88-90%
      activity after 24 hr incubation, and show good stability when incubated at
      temperatures lower than 40 degrees C. The Km values of Lac I for ABTS, DMP, and
      guaiacol are 0.118 x 10(-2), 0.420, and 0.405 mM, respectively; the Km values of
      Lac II for ABTS, DMP, and guaiacol are 0.086 x 10(-2), 0.41, and 0.40 mM,
      respectively. Their N-terminal sequences are determined and show strong
      similarity with those from other basidiomycetes. Graphite-furnace atomic
      absorption analysis revealed that both laccases have four copper atoms per
      protein molecule, but they have no type I copper signal at around 600 nm and a
      type III copper signal near 330 nm. Cyanide, azide, and halides completely
      inhibit the enzyme activity, whereas EDTA has less inhibition.

PMID- 15195713
TI  - [A glance into the mouth--dental aspects for physicians].
AB  - A glance into the mouth at the surgery occasionally confronts the general
      practitioner or specialist with dental aspects or issues. The nursing-bottle
      syndrome and injuries from accidents are frequently observed in children. In
      older patients, mucosal change is not a rare occurrence. A comparatively new
      field is halitosis and its effective and cause-related treatment.

PMID- 15195714
TI  - [Highligts from the interdisciplinary consultation for diseases of the mouth in
      Basel].
AB  - A number of medical specialties traditionally face changes and lesions in the
      mouth, specific for diseases seen routinely in their everyday practice:
      gastroenterologists, paediatricians, orthodontists, to name just a few, will
      easily identify the typical aspect of the tongue, the Koplik spots or a
      dysgnathia respectively, and the treatment of the underlying diseases in question
      will resolve the local problem. However, more unusual lesions with chronic or
      recurrent course may cause a much longer patient career, which may last for
      months or even years and is interspersed with more or less ineffective local
      antiseptic or steroid treatment regimens before underlying diseases like
      pemphigus, lichen, diseases of haematopoetic organs, paraneoplastic lesions or
      even simple mechanical consequences of parafunctions like bruxismus, are
      identified as the underlying cause. The otorhinolaryngologist, the dermatologist
      and the dentist-oral-maxillofacial surgeon offer an interdisciplinary
      consultation at the Center for Dental Medicine at the University of Basel, in
      which the advantages of an advanced diagnostic armamentarium and a combined pool
      of experience proves to be a gain for both the patients and involved medical
      persons. The otolaryngologist offers diagnostic procedures of the entire upper
      airways, the dermatologist bridges the gap to allergology, immunology and
      systemic diseases well known to his specialty. Dental medicine offers diagnostic
      and therapeutic alternatives, of which the first two have but scarce knowledge.
      In this article, the different approaches to the most frequently seen diseases
      and associated problems are described by the dermatologist and dental specialist.
      The dermatologist, in a succinct state of the art review, describes the problem
      of pemphigus and pemphigoid, diseases which may cause diagnostic problems because
      of their tendency to stay limited to the oral mucosa for a longer time. Recurrent
      aphtosis is another problem encountered frequently, in which a vast research
      effort has not yet abutted into pertinent knowledge on ethiology and effective
      therapy for all cases. The dentist-oral-maxillofacial surgeon is especially
      interested in the specific problem in the diagnosis and treatment of lichen
      planus i.e. the differentiation of true idiopathic lichen and the lichenoid
      reaction due to foreign bodies in the mouth. He describes the modern diagnostic
      and treatment procedures. In spite of missing parts in the puzzle of all these
      diseases, special consideration in every individual case contributes to more
      effective management and offers a gain in experience and knowledge to all medical
      persons involved.

PMID- 15195715
TI  - [Etiology, diagnostic and therapeutic management of taste disorders].
AB  - Taste disorders can be subdivided in ageusia, which is the inability to detect
      any qualitative gustatory sensation and hypogeusia, which is a decreased
      sensitivity to all tastants. Dysgeusia or pargeusia is a distortion or perversion
      in the perception of a tastant in contrast to phantosmia, which is a perception
      of taste that occurs in the absence of a tastant. The site of lesion can usually
      be determined by history and clinical examination. History taking should always
      include the assessment of current and former medication. Conditions that
      interfere with access of a tastant to the taste bud are differentiated from
      conditions that either injure the receptor cell or damage the gustatory afferent
      nerves and the central pathways. Psychophysical taste evaluation includes
      identification of quality using sprays or taste strips and testing of intensity
      perception measuring threshold using the 3-drop technique. Moreover, measurement
      of taste in localized areas can be performed either with conventional chemicals
      or using an electrogustometer. Gustatory evoked potentials are not yet routinely
      elicited. Therapy has to be planned according to the cause of the disorder.

PMID- 15195716
TI  - [Burning mouth syndrome--etiology, differentialdiagnostical aspects and therapy].
AB  - Burning Mouth Syndrome (BMS) or glossodynia is a chronic pain syndrome that
      mainly affects middle-aged/elderly women. This condition is probably of
      multifactorial origin, often idiopathic, and its etiopathogenesis remains largely
      enigmatic. Visible pathologic lesions of the oral mucosa or processes are usually
      not evident. Etiologic factors that have been reported include several disorders
      (e. g. hematologic disorders, denture factors, the climacteric, infections,
      endocrinological, neurological or psychiatric disorders). On the other hand
      psychological factors, such as anxiety, depression and phobias have been reported
      to play a significant role at the beginning of this nosological entity. BMS
      related to nutritional deficiency is uncommon. A systemic approach to assessment
      is essential and the opinion of other specialities, particularly internal
      medicine, dentistry or neurology, may be of help. Treatment is of the underlying
      cause but in many cases no specific aetiological factor is identified. Non
      indicated substitution therapy of suspected but unproved deficiency states must
      be avoided. Treatment approaches were divided into topical and systemic
      strategies. However, there is little research evidence that provides clear
      guidance for those treating patients with BMS.

PMID- 15195717
TI  - [De rhoncho dormientium].
AB  - Obstructive sleep apnea (OSA) is a wide spread affliction that affects 4% of men
      and 2% of women in industrialised countries. Patients complain about disruptive
      snoring, daytime sleepiness and loss of intellectual power. OSA is associated
      with increased mortality. OSA has to be distinguished from simple snoring which
      is socially annoying but physically harmless. History taking, clinical
      examination, recording of daytime sleepiness, and cardio-respiratory sleep
      studies are necessary to make a proper diagnosis. In some cases more
      sophisticated studies are requested. Simple snoring does not harm the physical
      health. This indicates that the treatment itself may not harm the patient either.
      Therefore adjuvants or minimally invasive surgical techniques are favoured. The
      patients bedpartners should be involved to find the proper treatment for simple
      snorers. In sleep apneics the treatment focuses on the removal of the sleep
      related breathing disturbances and their health related consequences. Gold
      standard treatment of OSA is nasally applied continuous positive airway pressure
      (nCPAP). Unfortunately the longterm compliance of nCPAP is below 70%. Therefore,
      alternative treatment modalities are used. As conservative approaches oral
      appliances and conditioning (to avoid supine sleeping position) show promising
      results. Nasal appliances and transcutaneously performed electrostimulation have
      shown to be less effective. There are no drugs that have shown to be helpful in
      patients with sleep related breathing disorders. Surgical treatment complies with
      the severity of the disease and with the anatomical findings. A variety of
      surgical approaches to the soft palate, the base of tongue, the tonsils, and the
      upper and lower jaws have been described. Surgical success rates seem to decrease
      with increasing body weight and with increasing severity of OSA. Nasal surgery is
      mainly used to facilitate a necessary nCPAP therapy. Isolated nasal procedures
      show low impact on the severity of OSA. Modern sleep medicine is an
      interdisciplinary field which requires co-operation with different specialists in
      order to cope with our patients complaints.

PMID- 15195718
TI  - [Evidence based indications for tonsillectomy].
AB  - Tonsillectomy (TE) is one of the most frequent as well as one of the most
      controversial surgical interventions. The objective of this paper was to assess
      the evidence of the most common indications for TE. For this purpose the
      literature of the past 25 years was analysed using the criteria of evidence based
      medicine. In children seventy-five percent of TEs are performed because of
      recurrent tonsillitis. Several randomised clinical trials (RCTs) have
      demonstrated the efficacy of TE in this disease. This indication is based on
      evidence grade I-II. No consensus has yet been reached, however, about the number
      of annual episodes that justify TE. The remaining paediatric TEs are performed to
      relieve symptoms of airway obstruction. TE has been shown to improve obstructive
      symptoms in up to 100% of patients. It is the accepted treatment of paediatric
      obstructive sleep apnoea, although the evidence is not based on major RCTs. In
      adults, too, the majority of TEs are performed for recurrent or chronic
      tonsillitis. There are no good RCTs, but the indication can be based on a series
      of well controlled studies (evidence grade III). Obviously, TE is indicated if
      there is suspicion of neoplasm. Peritonsillar abscess per se is no indication for
      TE, unless the abscess cannot be drained otherwise. TE plays no role in the
      standard management of OSAS and mononucleosis.

PMID- 15195719
TI  - [Carcinoma of the mouth and pharynx--better prognosis by an early diagnosis!].
AB  - Carcinomas of the mouth and pharynx rank sixth of all malignant tumours
      worldwide. They are responsible for 10% of the newly diagnosed malignant tumours.
      The median five year survival rate is 50%, depending on tumour localisation and
      size, but mainly determined by lymph node metastases. Carcinomas of the mouth and
      pharynx cause symptoms that resemble those of common harmless diseases of the
      head and neck such as pharyngitis. This can lead to misinterpretation by both,
      the patient and the doctor. Since the initial delay by the patient is difficult
      to influence it is very important that the doctor is aware of a possible
      malignant disease. Persistent common symptoms such as swallowing impairment or
      hoarseness, mucosal lesions, such as leukoplakia, a persistent cervical lymph
      node and unresponsiveness to initial treatment, must prompt the doctor to
      initialise appropriate diagnostic steps (incisional biopsy, e.g.). Only early
      diagnosis can help to improve the prognosis of patients with carcinomas of the
      mouth and pharynx.

PMID- 15195720
TI  - [Oral and pharyngeal dysphagia].
AB  - A severe impairment of nutrition frequently occurs with morphological alterations
      in the oral cavity and the pharynx as well as with neurogenic disorders of the
      swallowing articulation. Complications like frequent aspirations are life
      threatening. If the natural protection reflex for the respiratory tract, the
      cough reflex, does not work because of a reduced tracheal sensitivity, swallowing
      disorders often remain unrecognized. The ability of swallowing must be examined
      particularly with stroke-patients and weakened old patients. With radiological
      and endoscopic evaluations, oropharyngeal dysphagias can be assessed in detail. A
      wide spectrum of surgical measures and exercise treatment can clearly improve the
      life quality of the patients even if the aim, to make a complete and safe oral
      nutrition possible again, is not reached in every case.

PMID- 15195721
TI  - [Angioedema of the oropharynx].
AB  - Sudden onset of edema in the oropharynx is a potentially life threatening event.
      Beside adequate symptomatic therapy and also eventually prophylactic therapy, a
      number of potential triggers and causes have to be taken into account. Among
      these are allergic reactions to food, latex or insect stings, pseudoallergic
      reactions to certain drugs (a.o. ACE-inhibitors, NSAID), C1-esterase deficiency
      and other causes. The typical clinical features, the diagnostic approach and
      therapeutic alternatives are discussed.

PMID- 15195723
TI  - Long-term survival of repaired amalgams, recemented crowns and gold castings.
AB  - This retrospective longitudinal study compared the long-term survival rate of
      repaired versus replaced amalgam restorations and recemented crowns and gold
      castings versus non-recemented similar restorations. Private general dental
      practitioners treated adult subjects at three city practices. No significant
      survival differences were found between the repaired and replaced amalgams at
      five years, although the repaired amalgams showed higher failure rates by 10
      years (p=0.37). However, there were significantly higher failures by five years
      for recemented crowns (p<0.001) and recemented gold castings (p=0.01) when
      compared with the initially cemented restorations. After 10 years, the repaired
      amalgams had survival rates of approximately 37 +/- 15 (SEr) percent, recemented
      crowns 28 +/- 15 (SEr) percent and recemented gold castings 42 +/- 17 (SEr)
      percent.

PMID- 15195722
TI  - A clinical comparison of two cements for levels of post-operative sensitivity in
      a practice-based setting.
AB  - This study compared the post-operative results of cementing full crowns (all
      metal or PFM) with either a conventional (Fuji I, GC; n=102) or a resin modified
      GI luting cement (Rely X, 3M/ESPE; n=107). METHODS: Ten private practitioners
      fabricated 209 crowns using standardized preparation/luting criteria and randomly
      assigned cements. Patients self-reported temperature and biting sensitivity, on a
      0-10 scale at 24 hours, one week, one month and three months post-cementation.
      Data were analyzed using t-tests, confirmatory Mann-Whitney tests and Pearson
      correlations, with a significance level of p < or = 0.05. RESULTS: Of all
      patients, 50.7% reported any sensitivity at any time period. Mean sensitivity for
      all patients on the 10-point scale was 0.52 for temperature and 0.23 for biting.
      Cements did not differ in cold or biting sensitivity at any time. There were many
      significant (though low) correlations between the sensitivity measures and age
      (inverse relationship) and dentin area of preparation (direct). The practice
      based format provided a viable alternative to performing clinical research.

PMID- 15195724
TI  - Clinical evaluation of a polyacid-modified resin composite-based fissure sealant:
      two-year results.
AB  - A 24-month clinical study was carried out to evaluate and compare the retention
      rate, marginal integrity and caries preventing effects of a polyacid-modified
      resin composite based fissure sealant, Dyract Seal, to that of a resin based
      fluoride fissure sealant, Delton FS+. Fifty-three patients (27 female and 26
      male), 7 to 10 years old, were included in the study. At baseline, a total of 192
      permanent first molars were sealed with either fissure sealant (n=96, each),
      using invasive technique. The sealed teeth were evaluated at post-operative 3, 6,
      12 and 24 months with respect to evaluation parameters. The data were analyzed
      with the Chi-Square tests where alpha=0.05. There were no statistically
      significant differences between fissure sealants as regards to retention and
      prevention of caries for all periods of the evaluation (p>0.05). However,
      regarding marginal integrity of the sealants, Delton FS+ gave significantly
      better results than Dyract Seal for the 3-, 6- and 12-month evaluations,
      respectively (p<0.05). In conclusion, the use of Dyract Seal on permanent molars
      with invasive technique was found to be clinically comparable to Delton FS+ for
      the 24-month evaluation period.

PMID- 15195725
TI  - Six-year clinical evaluation of bonded and pin-retained complex amalgam
      restorations.
AB  - This clinical study compared the performance of complex amalgam restorations
      retained with self-threading pins or bonded with a filled, 4-META-based resin.
      Sixty amalgam restorations (28 pin-retained and 32 bonded), each replacing at
      least one cusp, were placed. Self-threading stainless steel pins (Coltene
      Whaledent) were used in the pin-retained group. A filled, 4-META-based bonding
      resin (Amalgambond Plus with HPA powder) was used in the bonded group. For both
      groups, any retention form remaining after removal of an old restoration was left
      in place but not enhanced. At six years, 11 restorations had failed; eight of
      which were pin-retained and three bonded. Using Fisher's exact test to compare
      the groups at six years, there was no significant difference in failure rate,
      marginal adaptation, marginal discoloration, secondary caries, tooth sensitivity
      or tooth vitality. At six years, there was no difference in the performance of
      pin-retained amalgam restorations and bonded amalgam restorations.

PMID- 15195726
TI  - Wear behavior of new composite restoratives.
AB  - This study investigated the wear resistance of recently introduced nanofill
      (Filtek Supreme [FS], 3M-ESPE) and ormocer (Admira [AM], Voco) composites and
      compared their wear characteristics to microfill (Filtek A110 [AO], 3M-ESPE]),
      minifill (Esthet X [EX], Dentsply; Filtek Z250 [ZT], 3M-ESPE) and polyacid
      modified (Dyract AP [DY], Dentsply) composites. Six specimens were made for each
      material. The specimens were conditioned for one week in distilled water at 37
      degrees C and subjected to wear testing at 20 MPa contact stress against SS304
      counter-bodies using reciprocal compression-sliding wear instrumentation.
      Distilled water was used as lubricant. Wear depth (microm) was measured using
      profilometry every 5,000 cycles up to 20,000 cycles. The results were analyzed
      using ANOVA/Scheffe's test (p<0.05). Wear of the materials was cycle and fatigue
      dependent. Although no significance in wear was observed between materials after
      5,000 cycles of wear testing, significant differences were observed at 10,000
      cycles and greater. After 20,000 cycles of wear testing, ranking was as follows:
      ZT > DY >AM > AO > FS > EX. Wear ranged from 39.90 microm for EX to 113.32 microm
      for ZT. The wear resistance of ZT and DY was significantly lower than AO, FS and
      EX In addition, ZT experienced significantly more wear than AM. Under the
      conditions of this in-vitro study, the wear resistance of nanofill and ormocer
      composites was comparable or superior to polyacid-modified, microfill and
      minifill composites.

PMID- 15195727
TI  - Finishing/polishing of composite and compomer restoratives: effectiveness of one
      step systems.
AB  - This study investigated the surface texture of composite (Z100, 3M ESPE) and
      compomer (F2000, 3M ESPE) restoratives after treatment with different one-step
      finishing/polishing systems (One-Gloss [OG], Shofu; PoGo [PG], Dentsply; Sof-Lex
      Brush [SB], 3M ESPE). The surface roughness obtained was compared to that using a
      matrix strip [MS], a two-step rubber abrasive (CompoSite [CS], Shofu) and a
      graded abrasive disk (Super Snap [SS], Shofu) system. Eight specimens (3-mm long
      x 3-mm wide x 2-mm deep) of each material were made according to manufacturer's
      instructions. With exception of the MS group, all groups were roughened with 320
      grit grinding paper using a lapping device prior to finishing/polishing with the
      different systems. The mean surface roughness (microm) was measured with a
      profilometer. Data was subjected to ANOVA/Scheffe's tests and independent samples
      t-test at significance level 0.05. Mean Ra ranged from 0.22 to 0.32 microm for
      Z100 and 0.45 to 0.68 for F2000. For both materials, the smoothest surfaces were
      obtained with MS. The roughest surfaces were observed after treatment with SS and
      OG for Z100 and F2000, respectively. The effectiveness of the finishing/polishing
      systems was material dependent. The surface finish produced by PG and SB was
      superior or comparable to that obtained with CS, SS and OG.

PMID- 15195728
TI  - Staining of non-carious human coronal dentin by caries dyes.
AB  - This study tested the hypothesis that commercially available caries dyes stain
      non-carious human coronal dentin in freshly extracted teeth. Multiple sections
      were cut from 10 non-carious and two control carious teeth using a water-cooled
      saw. Each section was stained with one of five caries dyes. The location of
      staining, if any, was noted and the staining intensity was scored on a four-point
      scale. One of the sections from each tooth was subsequently decalcified and
      processed for observation under a light microscope using four histologic staining
      techniques to evaluate morphology, collagen distribution and bacterial content.
      The association between the stain intensity scores on the undecalcified sections
      and the five dyes was evaluated using the Kruskal-Wallis One-Way ANOVA by Ranks
      test. Outer carious dentin in the control specimens stained intensely with each
      of the five dyes. In the undecalcified, non-carious sections, all had at least
      one area of staining. However, this staining could be differentiated from the
      intensity of dye staining in the carious controls, except in two instances. The
      association between stain intensity scores and the five dyes was not
      statistically significant. In the histologic sections, numerous bacteria were
      seen within the dentinal tubules of carious lesions of the two control specimens;
      however, no bacteria were found in any of the sections from non-carious
      specimens. Histologically, no differences were observed in the morphology or
      staining pattern within mantle or circumpulpal dentin in areas stained with
      caries dye, and in only one unique instance within the main body of the dentin.
      These results suggest that the five dyes evaluated in this study can stain non
      carious dentin, however, this stain can be differentiated from the staining of
      outer carious dentin in vitro.

PMID- 15195729
TI  - Comparison of halogen, plasma and LED curing units.
AB  - This study evaluated the characteristics of two kinds of recently developed light
      curing unit; plasma arc and blue light emitting diodes (LED), in comparison with
      a conventional tungsten-halogen light-curing unit. The light intensity and
      spectral distribution of light from these light-curing units, the temperature
      rise of the bovine enamel surface and the depth of cure of composites exposed to
      each unit were investigated. The light intensity and depth of cure were
      determined according to ISO standards. The spectral distributions of emitted
      light were measured using a spectro-radiometer. The temperature increase induced
      by irradiation was measured by using a thermocouple. Generally, light intensities
      in the range 400-515 nm emitted from the plasma arc were greater than those from
      other types. Light in the UV-A region was emitted from some plasma arc units. The
      required irradiation times were six to nine seconds for the plasma arc units and
      40 to 60 seconds for the LED units to create a depth of cure equal to that
      produced by the tungsten-halogen light with 20 seconds of irradiation. The
      temperature increased by increasing the irradiation time for every light-curing
      unit. The temperature increases were 15 degrees C to 60 degrees C for plasma arc
      units, around 15 degrees C for a conventional halogen unit and under 10 degrees C
      for LED units. Both the plasma arc and LED units required longer irradiation
      times than those recommended by their respective manufacturers. Clinicians should
      be aware of potential thermal rise and UV-A hazard when using plasma arc units.

PMID- 15195730
TI  - Effect of fractured or sectioned fragments on the fracture strength of different
      reattachment techniques.
AB  - This study evaluated the effect of fractured or sectioned fragments on the
      fracture strength recovery of four techniques used for reattachment and resin
      composite buildups. Ninety-one sound, permanent lower central incisors were used.
      Half the teeth were fractured in the incisal-proximal edge; the other half had
      the incisal-proximal edge sectioned by a diamond saw. Teeth from each half were
      randomly divided into five techniques: 1) bonded only; 2) chamfer; 3) over
      contour; 4) internal dentinal groove and 5) resin composite buildup. An adhesive
      system and dual cure resin cement were employed for the reattachment. Restored
      teeth were subjected to load in a specific point on the buccal surface. Based on
      the fracture strength of sound teeth, a fracture strength recovery was calculated
      for each tooth. A one-way ANOVA and Tukey's test (alpha=0.05) were used to
      evaluate differences between the techniques for each method of obtaining
      fragments. The fracture strength recovery of similar techniques was evaluated by
      a Student t-test (alpha=0.05). No differences could be detected among
      reattachment techniques when fragments were obtained by sectioning. In groups
      where the fragments were fractured, Techniques 3 and 4 showed the highest
      fracture strength recovery. The resin composite buildup provided fracture
      strength recovery similar to intact teeth regardless the way fragments were
      obtained.

PMID- 15195731
TI  - Influence of flowable composite lining thickness on Class II composite
      restorations.
AB  - This in vitro study aimed to investigate the influence of flowable composite
      lining with different thicknesses on the marginal quality and internal porosity
      of Class II composite restorations. Thirty-two intact molars, each prepared with
      two box-only Class II cavities, were randomly divided into four groups: Group 1,
      P60 filling alone; Group 2, ultrathin flowable composite lining/co-cured with
      overlaying composite; Group 3, thin lining/pre-cured and Group 4, thick
      lining/pre-cured. The teeth were then thermocycled for 1500 cycles (between 5
      degrees C and 60 degrees C) and dye immersed for 24 hours. Exterior surface
      replicas of these restorations were fabricated before and after thermocycling and
      examined by SEM to evaluate percentages of the five marginal patterns. Data was
      statistically evaluated using one-way ANOVA test. The teeth were subsequently
      sectioned longitudinally. The interface microleakage of cervical margin was
      measured as to the extent of dye penetration. Internal voids were separately
      recorded in the cervical interface and the cervical and occlusal halves of the
      restorations. Mann-Whitney test was applied to analyze the interface microleakage
      and internal voids. Results revealed that replicas of Group 4 presented the
      highest percentage of marginal openings both before and after thermocycling in
      SEM examination. Group 2 exhibited superior marginal quality in interface
      microleakage evaluation compared to the other groups, while Group 4 exhibited the
      worst. The pre-cured groups (Group 3 and 4) showed significant reduction in
      interface and cervical voids. Despite the reduction in interface voids, a thick
      lining may impair the marginal sealing, especially after thermocycling. It was
      concluded that a minimally thin flowable composite lining improved cavity
      adaptation and marginal sealing.

PMID- 15195732
TI  - Aggressiveness of self-etch adhesives on unground enamel.
AB  - Manufacturers of mild self-etch adhesives advocate the adjunctive use of
      phosphoric acid etching when bonding to unground enamel. This study tested the
      null hypothesis that there is no difference between the recently introduced, more
      aggressive self-etch adhesives and a total-etch adhesive in bonding to unground
      enamel. The ultrastructure and microtensile bond strengths (microTBS) of Xeno III
      (Dentsply) and Simplicity (Apex Dental Materials), bonded to unground enamel,
      were examined after thermocycling. Clearfil SE Bond (Kuraray), a mild self-etch
      adhesive, was used as the negative control, and One-Step (BISCO), a total-etch
      adhesive bonded to phosphoric acid-etched unground enamel, was used as the
      positive control. Differences in the thickness of enamel hybrid layers were
      observed and the aggressiveness of apatite dissolution in the four adhesives.

PMID- 15195733
TI  - Post-gel shrinkage with different modes of LED and halogen light curing units.
AB  - This study compared the post-gel shrinkage of two LED (light-emitting diodes)
      lights (Elipar FreeLight [FL], 3M ESPE; GC e-Light [EL], GC), a high intensity
      (Elipar TriLight [TL], 3M ESPE) and a very high intensity (Astralis 10 [AS],
      Ivoclar Vivadent) halogen light to a conventional (Max [MX] (control), Dentsply
      Caulk) halogen light. Ten light curing regimens were investigated. These included
      continuous (FL1, EL2, MX, TL1 and AS1), soft-start (FL2, EL4, TL2), pulse
      activation (EL1) and turbo (EL3) modes. A strain-monitoring device and test
      configuration was used to measure the linear polymerization shrinkage of a
      composite restorative (Z100, [3M ESPE]) during and post-light polymerization up
      to 60 minutes when cured with the different modes. Five specimens were made for
      each cure mode. Results were analyzed using ANOVA/Scheffe's post-hoc test and
      independent sample t-tests at significance level 0.05. Shrinkage associated with
      the various modes of EL was significantly lower than MX immediately after light
      polymerization and at one-minute post-light polymerization. No significant
      difference between MX and the various lights/cure modes was observed at 10, 30
      and 60-minutes post-light polymerization. At all time intervals, post-gel
      shrinkage associated with continuous light curing mode was significantly higher
      than the soft-start light curing mode for FL and TL.

PMID- 15195734
TI  - Temperature rise during adhesive and resin composite polymerization with various
      light curing sources.
AB  - This study evaluated the temperature rise in two different adhesive (Clearfil SE
      Bond [CSEB] and EBS-Multi [EBSM]) and composite systems (Clearfil AP-X [CAPX,]
      Pertac II [PII]) by the same manufacturer when illuminated by four different
      light sources: Light-emitting diode (LED), Plasma arc curing (PAC), high
      intensity quartz tungsten halogen (HQTH) and quartz tungsten halogen (QTH). Forty
      dentin disks were prepared from extracted premolars. These dentin disks were
      placed in apparatus developed to measure temperature rise. Temperature rise
      during photopolymerization of adhesive resin and resin composite was then
      measured. The mean values of temperature increases for adhesive and resin
      composites did not differ significantly (p=0.769). The highest temperature rise
      was observed during photopolymerization of EBSM with PAC (5.16 degrees C) and
      HQTH (4.28 degrees C), respectively. Temperature rise values produced by QTH
      (1.27 degrees C - 2.83 degrees C for adhesive resin; 1.86 degrees C - 2.85
      degrees C for resin composite) for both adhesive and resin composites were
      significantly lower than those induced by PAC and HQTH (p<0.05). However, these
      values were significantly higher than those produced by LED (1.16 degrees C -
      2.08 degrees C for adhesive resin; 1.13 degrees C - 2.59 degrees C for resin
      composite). Light sources with high energy output (PAC and HQTH) caused
      significantly higher temperature rise than sources with low energy output (QTH
      and LED). However, in this study, no temperature rises beneath 1-mm dentin disk
      exceed the critical 5.6 degrees C value for pulpal health.

PMID- 15195735
TI  - The bond of resin to different dentin surface characteristics.
AB  - This study investigated the effects of dentin surface characteristics on bond
      strengths between resin and dentin. The shear bond strengths mediated by two
      dentin adhesive systems (Clearfil SE Bond and OptiBond Solo Plus) were evaluated.
      For each material, flat dentin surfaces prepared from human upper premolars were
      allocated to eight groups according to three characterizations; dentin location
      (occlusal or cervical), dentin depth (superficial or deep) and dentinal tubule
      orientation (perpendicular or parallel). A 0.75-mm diameter area of dentin was
      bonded according to each manufacturer's instructions before placing 0.5-mm high
      resin composite. The bonds were stressed in shear at a crosshead speed of 1
      mm/minute. The mean bond strengths were compared using ANOVA and independent t
      test. No statistically significant differences were found in shear bond strengths
      based on dentin location. Clearfil SE Bond presented higher bond strengths to
      deep dentin specimens bonded perpendicular to the tubules compared to those that
      were bonded parallel to the tubules. Whereas, the opposite results were found for
      deep dentin specimens bonded with OptiBond Solo Plus. In the case of superficial
      dentin, there were no differences between the two materials when bond strengths
      were compared among the different orientations of tubule. The results indicated
      that shear bond strengths may be affected by dentin depth, orientation of the
      tubule and the bonding material used, but not by location of the dentin.

PMID- 15195736
TI  - Combined amalgam and composite restorations.
AB  - All indirect restorative techniques involving cast metals, ceramics or resin
      based materials are expensive compared to directly placed restorations. A
      restorative technique is presented that combines the esthetic properties of
      directly bonded resin-based composite material and the wide range of indications
      for dental amalgam in stress-bearing areas.

PMID- 15195737
TI  - A Tofflemire time saving tip.

PMID- 15195738
TI  - FIT CHECKER for all ceramic restorations.

PMID- 15195739
TI  - Direct composite bonding in conjunction with surgical tissue management.
AB  - This article discussed several issues associated with the intimate relationship
      between attachment apparatus and the restorative interface. First, it is
      essential that the restorative dentist have a clear understanding of crest
      position and its impact on the restorative outcome. Then, the restorative dentist
      must understand the importance of sequencing and timing when orthodontic therapy,
      tissue recontouring and restorative dentistry must be accomplished on the same
      patient.

PMID- 15195740
TI  - Technique on restoring sub-gingival cervical lesion.
AB  - This article outlines an atraumatic isolation approach and a conservative
      instrumentation sequence, followed by use of a highly viscous, rapid-setting,
      capsulated glass ionomer cement to manage a difficult deep proximal-cervical
      Class V lesion.

PMID- 15195741
TI  - Customized and low-cost aspirator device for intra-oral sandblasting.
AB  - This paper presents a simple technique that uses a novel device made of low-cost
      materials and is very helpful in routine clinical activity. This device plays an
      important role in reducing the suspension of particles in the air when a
      sandblaster of aluminum oxide powder is used intraorally to create additional
      micromechanical retention prior to applying a bonded restoration.

PMID- 15195742
TI  - Academy of Operative Dentistry Hollenback Memorial Prize. Dr Ivar A Mjor.

PMID- 15195743
TI  - Academy of Operative Dentistry Award of Excellence. Dr Norm C Ferguson.

PMID- 15195744
TI  - Registration of resected lung cancer in Niigata Prefecture.
AB  - OBJECTIVES: Our registration of surgically treated lung cancer patients in
      Niigata Prefecture began in 2001. The purpose of this study was to identify the
      characteristics of patients and surgical treatment of lung cancer. METHODS: All
      patients who underwent resection for lung cancer in Niigata Prefecture from
      January 2001 to December 2002 were eligible for registration. A total of 31
      medical data for each patient were registered. RESULTS: During the 2-year period,
      1,211 patients were registered. A total of 605 cases (50%) were detected by mass
      screening, and 874 cases (72%) were diagnosed preoperatively. There were 718
      (59%) c-stage IA cases and 317 (26%) c-stage IB cases. The most common operative
      procedure was lobectomy; 850 patients underwent single lobectomy. Limited
      resection was performed in 301 patients (25%), and video-assisted thoracoscopic
      surgery in 193 (16%). The most common histological type was adenocarcinoma in 860
      cases (71%), followed by squamous cell carcinoma in 273 (23%). Pathologic staging
      yielded stage IA in 635 cases (52%) and stage IB in 262 (22%). CONCLUSIONS: The
      results of our registration demonstrate a very high ratio of surgically treated
      stage IA cases in Niigata Prefecture and that limited resection was performed in
      many patients. Accumulation of these data will reveal the characteristics of lung
      cancer surgically treated in Niigata Prefecture and will provide a basis for
      determining the future course of surgical treatment for lung cancer. Registration
      is continuing, and it will provide new and useful information about lung cancer,
      eventually including 5-year survival data.

PMID- 15195745
TI  - Evaluation of an aortic stent graft for use in surgery on esophageal cancer
      involving the thoracic aorta: experimental study.
AB  - OBJECTIVE: The purpose of this experimental study was to investigate whether
      aortic stent grafting can be applied to the treatment of an esophageal cancer
      involving the thoracic aorta. METHODS: The canine thoracic aorta was partially
      resected without aorta being clamped after emplacement of an endovascular stent
      graft. Study I; The aortic whole layer of 1 cm in length and 1/4 of the
      circumference was resected and was covered by a free fascia patch of the
      abdominal rectal muscle immediately after stent graft placement. Study II; The
      aortic adventitia and the outer half of the media of the same size was resected
      on day 3, 7, 14, 21, and on day 28, after the stent graft placement. The resected
      portion was covered by the free fascia patch in half experimental dogs, and was
      uncovered in the others. Study III; The aortic adventitia and the outer half of
      the media of 1 cm in length and 1/2 of the circumference was resected and was
      uncovered on day 7 after stent graft placement. Histological examinations were
      performed on day 28 and at one year after aortic resection. RESULTS: The aortic
      wall could be resected in all cases with no complication, except in resection of
      1/2 the circumference where the aorta had become narrow. There was no difference
      in healing of the resected portion of the aorta between with and without fascia
      covering. CONCLUSION: An aortic endovascular stent graft could be applied to
      surgery for an esophageal cancer involving the aorta.

PMID- 15195746
TI  - Comparison of off-pump and on-pump coronary artery bypass grafting in midterm
      results.
AB  - OBJECTIVE: Off-pump coronary artery bypass grafting (OPCAB) has become a
      procedure of choice for surgical treatment of coronary artery disease. Although
      early advantages of OPCAB were confirmed in comparison with conventional on-pump
      coronary artery bypass grafting (CABG), late cardiac complications are still
      controversial. We examined midterm results of OPCAB compared with standard CABG.
      METHODS: Between July 1997 and April 2002, 736 consecutive patients who underwent
      isolated CABG were retrospectively reviewed. The OPCAB group (Group I) comprised
      357 patients (49%), and the on-pump CABG group (Group II) 379 patients (51%).
      Their preoperative, intraoperative, and follow-up data were analyzed. RESULTS:
      The mean number of distal anastomoses and the early graft patency were not
      greatly different between the two groups. The actuarial survival rate at 3 years
      was not significantly different between Group I (98.3%) and Group II (98.2%) (p =
      0.71). The frequency of cardiac events was 4.2%/patient-year in Group I and
      2.6%/patient-year in Group II (p = 0.12). The actuarial event free rates were not
      different between the two groups (p = 0.61). The cardiac event free rates at 3
      years were significantly (p = 0.011) higher in patients with complete
      revascularization (96.7%) than without complete revascularization in Group I
      (69.2%) and in Group II (92.7% versus 85.9%, p = 0.026). CONCLUSIONS: Midterm
      clinical outcome in OPCAB is as good as conventional on-pump CABG. Incomplete
      revascularization caused cardiac events more frequently than complete
      revascularization both in OPCAB and on-pump CABG in the intermediate follow-up.

PMID- 15195747
TI  - Direct cannulation of the common carotid artery during the ascending aortic or
      aortic arch replacement.
AB  - OBJECTIVE: To evaluate cerebral perfusion using direct cannulation into the
      common carotid artery. A new technique is needed to protect brain ischemic injury
      during ascending aortic or aortic arch replacement. METHODS: This technique was
      evaluated for patients who would have difficulty maintaining adequate cerebral
      perfusion during surgery. The procedure was performed when patients had the
      following diagnoses: pseudoaneurysm formation in contact with the sternum with
      the risk of aneurysmal rupture (n = 5), acute aortic dissection with compression
      of the true lumen of the innominate artery by the pseudolumen (n = 3), or a large
      volume of thrombus in the lumen of the aneurysm with the risk of cerebral
      thromboembolism if standard extracorporeal circulation was used (n = 2). The
      perfusion catheter was cannulated into one side of the common carotid artery
      (right side: n = 6, left side: n = 4) and mean perfusion flow rate was found to
      be 175 mL/min. The operative procedures consisted of ascending aortic and aortic
      arch replacement with coronary artery bypass grafting in six patients, ascending
      aortic replacement in 2 patients, and innominate artery reconstruction/innominate
      artery and right subclavian artery reconstruction in one patient. RESULTS: No
      cerebral accidents or deaths occurred while patients were hospitalized. We have
      followed up patients for a mean of 2.1 years (maximum 3.6 years), with no
      complications noted from the surgical procedure. CONCLUSIONS: Direct cannulation
      of the common carotid artery is a simple, safe, and acceptable cerebral
      protection for patients undergoing aortic or aortic arch replacement procedures
      in the patients with these specific conditions.

PMID- 15195748
TI  - Surgical treatment of congenital right atrial aneurysm in an adult patient.
AB  - A 52-year-old man with atrial flutter was diagnosed as having a large congenital
      aneurysm or diverticulum of the right atrium. Surgical resection of the aneurysm
      under beating heart condition promptly eliminated atrial flutter. The patient has
      maintained sinus rhythm during the past 18 months of follow-up period.

PMID- 15195749
TI  - Successful treatment of chronic thromboembolic pulmonary hypertension with
      inhaled nitric oxide after right ventricular thrombectomy.
AB  - We report a case of a 42-year-old male with chronic thromboembolic pulmonary
      hypertension. His preoperative examination revealed severe hypoxemia (PaO2 48
      mmHg, PaCO2 34 mmHg in room air), a mass in the right ventricle and severe
      pulmonary hypertension (pulmonary arterial pressure 70/33 mmHg). We successfully
      performed right ventricular thrombectomy to prevent further embolization from the
      right ventricular thrombus. Using inhaled low dose nitric oxide (NO) during
      perioperative period, weaning from cardiopulmonary bypass and ventilator were
      easily done. In this case, inhaled NO was successfully administered for the
      perioperative management of chronic pulmonary hypertension.

PMID- 15195750
TI  - Mediastinal cyst with rim calcification.
AB  - A 58-year-old man who had been undergoing treatment for chronic pericarditis for
      15 months was found to have a calcified mediastinal mass shadow on a chest X-ray
      and was referred to us for further study and treatment. Chest computed tomography
      and magnetic resonance imaging showed an anterior mediastinal multilocular tumor
      with rim calcification. Tumor markers were within normal limits. The patient was
      preoperatively diagnosed as having a calcified mediastinal cyst, and median
      sternotomy was performed to remove the cystic tumor and the surrounding thymic
      tissues. Histological examination revealed that the cyst wall consisted of dense
      fibrous tissue and calcification without epithelial cell lining on the inner
      surface. Thymic tissue was present around the cyst wall. Although we suspected a
      thymic cyst from the intraoperative findings, the final diagnosis was made as
      mediastinal cyst with rim calcification. We herein present a rare case of
      mediastinal cyst with rim calcification.

PMID- 15195752
TI  - Sutureless patch repair for small blowout rupture of the left ventricle after
      myocardial infarction.
AB  - Rupture of the left ventricular free wall is one of the most serious
      complications of myocardial infarction. A 73-year-old man with severe chest pain
      visited our hospital. Coronary angiography revealed acute myocardial infarction
      in the territory of the diagonal branch. About six hours after successful
      percutaneous coronary intervention, the patient fell into cardiogenic shock with
      chest pain. Echocardiography showed moderate pericardial effusion with a
      subepicardial hematoma, and percardioentesis led to the diagnosis of free wall
      rupture. Emergency surgery was performed with the use of intra-aortic balloon
      pumping. The rupture was a blowout type in a small tear at the anterolateral wall
      of the left ventricle. We repaired the tear with an off-pump sutureless patch
      using collagen fleece with fibrinogen-based impregnation (TachoComb) and equinous
      pericardium with fibrin spray. The patient was free of both re-rupture and
      pseudoaneurysm postoperatively, and was discharged 20 days after the operation.
      Considering previously reported various procedures for surgical repair, this
      technique may be useful if the tear is small.

PMID- 15195751
TI  - Rupture of infectious aneurysm of the thoracic aorta into the lung after radical
      esophageal cancer surgery.
AB  - A 60-year-old male underwent radical operation for esophageal cancer 45 days
      prior to complaining of several incidents of hemoptysis. The hemoptysis was found
      to be caused by infectious aneurysm of the descending thoracic aorta penetrating
      the lung. The aneurysm was resected and the aortic wall was sutured directly
      under percutaneous circulatory pulmonary support system. The sutured thoracic
      aorta was wrapped with the pedicle of an intercostal muscle flap to prevent
      reinfection. Forty-eight days after the aortic wall suture operation, however,
      the patient experienced massive hemoptysis and went into shock. Angiography was
      reveal no arterial lesions, so emergency left lower lobectomy was performed on
      suspicion of lung vessel rupture. Immediately after the lower lobectomy,
      recurrence of the aortic wall rupture caused uncontrollable bleeding. The patient
      died intraoperatively.

PMID- 15195753
TI  - Midterm result of a case after Starnes operation.
AB  - We describe the midterm result after Starnes operation for a severely symptomatic
      neonate with Ebstein's anomaly by reviewing the reported cases. A 4-day-old baby
      with "wall to wall heart" underwent Starnes operation. The tricuspid valve was
      closed without fenestration and the coronary sinus was drained into the right
      ventricle. Consequently, she underwent bidirectional Glenn shunt and Fontan
      operation at 6 and 23 months, respectively, and is now attending kindergarten
      without limitation. The follow-up study at 5 years revealed normally sized left
      ventricle with good function and the small right ventricle in the absence of
      thrombus formation with systolic forward flow.

PMID- 15195754
TI  - Does neoadjuvant chemotherapy cause increased morbidity after lung surgery?

PMID- 15195755
TI  - Single-photon agents for tumor imaging: 201Tl, 99mTc-MIBI, and 99mTc-tetrofosmin.
AB  - This review aims at fostering comprehension and knowledge not only for expert
      physicians who can skillfully handle various techniques for tumor imaging but
      also for young practitioners in the field of nuclear medicine. As image
      processing software and hardware become smaller, faster and better, SPECT will
      adapt and incorporate these advances. A principal advantage of SPECT over PET is
      the more widespread availability of the equipment and lower cost for the
      introduction of the system in community-based facilities. Moreover, SPECT has
      become less dependent on a limited number of acknowledged experts for its
      interpretation owing to a variety of handy computer tools for imaging analyses.
      The increasing use of PET in tumor imaging is not necessarily proportional to the
      decline of SPECT. General physicians' attention to SPECT technology would also
      increase more by evoking their interest in "tracer imaging."

PMID- 15195756
TI  - The predictive value of 201Tl rest-redistribution and 18F-fluorodeoxyglucose
      SPECT for wall motion recovery after recent reperfused myocardial infarction.
AB  - 201Tl and 18F-FDG are useful for acute myocardial infarction (MI) assessment. The
      goal of this study was to compare their predictive value for wall motion recovery
      in the culprit area after a recent reperfused MI using SPECT technique. METHODS:
      Forty-one patients (mean age: 56 +/- 12 years) were included, 81% of them male;
      all were studied within 1-24 days post MI. They underwent angioplasty in 27 cases
      (12 primary); bypass grafting in 10 cases and successful thrombolysis in 4. SPECT
      201Tl injected at rest and redistribution (R-R) and also 18F-FDG, were performed
      on different days. Processed tomograms were interpreted blinded to clinical or
      angiographic data. Segmental wall motion assessed with echocardiography at
      baseline was compared with the 3 month follow up. RESULTS: Sensitivity
      [Confidence Interval] for 201Tl R-R was 74.6% [60.5-84.5], for FDG it was 82.1%
      [70.8-90.4]; specificities were 73% [64.3-80.5] and 54.8% [45.6-63.7],
      respectively. 18F-FDG tended to be more sensitive than 201Tl R-R, but the latter
      was more specific (p < 0.0004). Both 201Tl RR and 18F-FDG presented high negative
      predictive value (p: ns). CONCLUSION: In recent MI, SPECT 201Tl R-R is a valuable
      and widely available technique for viability detection, with similar sensitivity
      and significant better specificity than SPECT 18F-FDG.

PMID- 15195757
TI  - What is the most appropriate scan timing for intraoperative detection of
      malignancy using 18F-FDG-sensitive gamma probe? Preliminary phantom and
      preoperative patient study.
AB  - PURPOSE: To evaluate the appropriate post-injection timing for hand-held-gamma
      ray-detecting probe (GDP) scanning for the intraoperative detection of malignancy
      after preoperative F-18 FDG (FDG) injection. METHODS: Patient study with
      superficially located cancer was performed on three patients before operation by
      dual-phase whole-body PET at 2 and 6-7 hr post-injection of FDG (370 MBq), and by
      probe scanning from the skin at several points at 1, 3, 5, and 7 hr after FDG
      injection. TNRa (tumor-adjacent-normal ratio) and TNRc (tumor-contralateral
      normal ratio) were calculated. Phantom study was also performed to determine
      basic GDP function. RESULTS: The patient study revealed that tumors showed
      constant TNRa (0.9-1.3) and TNRc (1.1-3.0) by GDP count rate, and that there was
      no tendency of an increase in TNRa with time. The standard deviations of GDP
      count rate were lower at 1-3 hr post-injection compared with those of delayed
      scans. While delayed PET showed an increase or no change in the tumor FDG uptake,
      the decrease of normal tissue FDG uptake was not adequate to create higher TNRs.
      The phantom study revealed that LN model showed TNRa of 1.7 or greater by GDP
      count rate (cps) when background contained no FDG, but that they showed TNRa of
      1.3 or less when the background contained 4% of the LN FDG activity per ml.
      CONCLUSION: The present study suggests that higher FDG count rate of tumors at 1
      3 hr postinjection would be more suitable for the gamma-probe detection compared
      with lower count rate at 6-7 hr delayed scans with wide standard deviations.

PMID- 15195758
TI  - Cerebral hemodynamics and metabolism in adult moyamoya disease: comparison of
      angiographic collateral circulation.
AB  - PURPOSE: The extent of the hemodynamic and metabolic impairments in adult
      patients with moyamoya disease is still controversial. The aim of the present
      study was to evaluate the hemodynamic and metabolic status in relation to the
      development of basal moyamoya vessels (BMVs). METHODS: The cerebral blood flow
      (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction
      (OEF), and cerebral blood volume (CBV) were measured using PET in ten patients
      with ischemic adult moyamoya disease (mean age, 36.6 years) and six age-matched
      normal controls (mean age, 33.3 years). The cerebrovascular reserve (CVR) after
      acetazolamide (ACZ) loading was also estimated using iodine-123 N-isopropyl-p
      iodo amphetamine single photon emission computed tomography (123I-IMP SPECT).
      RESULTS: Based on the angiographic findings, eleven cerebral hemispheres with
      well-developed BMV (extensive BMV hemispheres) and nine cerebral hemispheres with
      diminished BMV (diminished BMV hemispheres) were identified. The main routes of
      collateral circulation in extensive BMV hemispheres were BMVs and leptomeningeal
      anastomoses. On the other hand, in diminished BMV hemispheres, transdural
      anastomosis was predominant, and leptomeningeal anastomoses were less developed.
      In cortices distal to the occluded internal carotid artery, the extensive BMV
      hemispheres exhibited a significantly lower CBF, CMRO2, CBF/CBV, and CVR (p <
      0.05) and a significantly higher CBV and OEF than in diminished BMV hemispheres
      and controls (p < 0.05). Except for the CBF in the white matter, the mean
      hemodynamic and metabolic parameters of the diminished BMV hemispheres were not
      significantly different from those of the controls. CONCLUSION: The extensive
      development of basal moyamoya vessels is a sign of severe hemodynamic impairment
      in adult patients with ischemic moyamoya disease. The results may not apply to
      adults with hemorrhagic onset.

PMID- 15195759
TI  - Single photon emission computed tomography and statistical parametric mapping
      analysis in cirrhotic patients with and without minimal hepatic encephalopathy.
AB  - OBJECTIVE: The early diagnosis and treatment of cognitive impairment in cirrhotic
      patients is needed to improve the patients' daily living. In this study,
      alterations of regional cerebral blood flow (rCBF) were evaluated in cirrhotic
      patients using statistical parametric mapping (SPM). The relationships between
      rCBF and neuropsychological test, severity of disease and biochemical data were
      also assessed. METHODS: 99mTc-ethyl cysteinate dimer single photon emission
      computed tomography was performed in 20 patients with non-alcoholic liver
      cirrhosis without overt hepatic encephalopathy (HE) and in 20 age-matched healthy
      subjects. Neuropsychological tests were performed in 16 patients; of these 7 had
      minimal HE. Regional CBF images were also analyzed in these groups using SPM.
      RESULTS: On SPM analysis, cirrhotic patients showed regions of significant
      hypoperfusion in the superior and middle frontal gyri, and inferior parietal
      lobules compared with the control group. These areas included parts of the
      premotor and parietal associated areas of the cortex. Among the cirrhotic
      patients, those with minimal HE had regions of significant hypoperfusion in the
      cingulate gyri bilaterally as compared with those without minimal HE.
      CONCLUSIONS: Abnormal function in the above regions may account for the
      relatively selective neuropsychological deficits in the cognitive status of
      patients with cirrhosis. These findings may be important in the identification
      and management of cirrhotic patients with minimal HE.

PMID- 15195760
TI  - Lesion detectability of a gamma camera based coincidence system with FDG in
      patients with malignant tumors: a comparison with dedicated positron emission
      tomography.
AB  - OBJECTIVE: The aim of this study was to investigate the lesion detectability of a
      gamma camera based coincidence detector system (c-PET system) in comparison to
      the dedicated PET system (d-PET system), and thereby clarify the feasibility of
      the clinical application of this system and also describe any factors influencing
      the lesion detectability of the c-PET system. METHODS: We examined 74 patients
      including 19 with malignant lymphoma, 16 with lung cancer, 9 with primary
      malignant bone tumor, 7 with esophageal cancer, 6 with malignant melanoma, 3 with
      hepatocellular carcinoma, 3 with primary unknown cancer, 2 with breast cancer, 2
      with colon cancer, and 7 with others. d-PET images were obtained using ECAT EXACT
      HR+ at 60 min, followed by c-PET imaging using ECAM at 120 min after the
      injection of 185 MBq of FDG. Each image was reconstructed without any attenuation
      correction. In the image interpretation, the whole body was classified into 16
      regions (5 superficial regions and 11 deep regions). The FDG accumulation of the
      lesions was evaluated by visual grading based on the consensus of three nuclear
      medicine physicians, and the findings were classified into three grades; (++),
      (+), and (-). The lesions were also classified into 3 groups according to their
      size: large group (> or =2 cm), middle group (1 < or = <2 cm) and small group (<1
      cm). RESULTS: In 627 regions, the abnormal FDG uptake was detected in 109 regions
      by the d-PET system. Out of 109 regions, the c-PET system could detect the
      lesions in 91 regions and was false positive in 1 region. Therefore, the
      sensitivity, specificity, and accuracy of the c-PET system were 83.5%, 99.8% and
      97.0%, respectively. Lesion detectability of the small group (54.5%) was
      significantly lower than that of the large group (97.9%) (p < 0.001) and that of
      the middle group (93.1%) (p < 0.001); however, the difference in lesion
      detectability between the large and middle groups was not significant. Neither
      the degree of FDG accumulation nor the location of the lesion markedly influenced
      the lesion detectability of the c-PET system. However, when we focused on the
      large and middle size lesions, the detectability of deep lesions tended to be
      lower than that of superficial lesions. CONCLUSION: In conclusion, the lesion
      detectability of the c-PET system was inferior to that of the d-PET system,
      especially in the case of small lesions. Further examination is required to
      assess the clinical usefulness of the c-PET system.

PMID- 15195761
TI  - Segmented attenuation correction for myocardial SPECT.
AB  - PURPOSE: One of the main factors contributing to the accuracy of attenuation
      correction for SPECT imaging using transmission computed tomography (TCT) with an
      external gamma-ray source is the radionuclide count. To reduce deterioration of
      TCT images due to inadequate radionuclide counts, a correction method, segmented
      attenuation correction (SAC), in which TCT data are transformed into several
      components (segments) such as water, lungs and spine, providing a satisfactory
      attenuation correction map with less counts, has been developed. The purpose of
      this study was to examine the usefulness of SAC for myocardial SPECT with
      attenuation correction. METHODS: A myocardial phantom filled with Tc-99m was
      scanned with a triple headed SPECT system, equipped with one cardiac fan beam
      collimator for TCT and two parallel hole collimators for ECT. As an external
      gamma-ray source for TCT, 740 MBq of Tc-99m was also used. Since Tc-99m was also
      used for ECT, the TCT and ECT data were acquired separately. To make radionuclide
      counts, the TCT data were acquired in the sequential repetition mode, in which a
      3-min-rotation was repeated 7 times followed by a 10-min-rotation 4 times (a
      total of 61 minutes). The TCT data were reconstructed by adding some of these
      rotations to make TCT maps with various radionuclide counts. Three types of SAC
      were used: (a) 1-segment SAC in which the body structure was regarded as water,
      (b) 2-segment SAC, in which the body structure was regarded as water and lungs,
      and (c) 3-segment SAC, in which the body structure was regarded as water, lungs
      and spine. We compared corrected images obtained with non-segmentation methods,
      and with 1- to 3-segment SACs. We also investigated the influence of radionuclide
      counts of TCT (3, 6, 9, 12, 15, 18, 21, 31, 41, 51, 61 min acquisition) on the
      accuracy of the attenuation correction. RESULTS: Either 1-segment or 2-segment
      SAC was sufficient to correct the attenuation. When non-segmentation TCT
      attenuation methods were used, rotations of at least 31 minutes were required to
      obtain sufficiently large counts for TCT. When the 3-segment SAC was used, the
      minimal acquisition time for a satisfactory TCT map was 7 min. CONCLUSION: The 3
      segment SAC was effective for attenuation correction, requiring fewer counts
      (about 1/5 of the value for non-segmentation TCT), or less radiation for TCT.

PMID- 15195762
TI  - Dynamic 123I-MIBG SPECT reflects sympathetic nervous integrity and predicts
      clinical outcome in patients with chronic heart failure.
AB  - 123I-metaiodobenzylguanidine (123I-MIBG) is useful for assessment of the severity
      and prognosis of patients with chronic heart failure (CHF). To examine 123I-MIBG
      kinetics in the early phase soon after tracer injection, we performed dynamic
      single photon emission computed tomography (SPECT) in 76 patients with CHF and 17
      control subjects. The consecutive 15 images of 2 min-dynamic SPECT were acquired
      for 30 min after injection. From 0 to 4 min, a significant amount of
      radioactivity existed in the blood pool, thus we calculated washout rate of 123I
      MIBG from 4 to 30 min (%WR-E). Patients were followed up with an end-point of
      cardiac death or re-hospitalization for 16 months (6-30 months). As the NYHA
      functional class advanced, %WR-E increased (control, NYHA class I, II, and III: 9
      +/- 4%, 10 +/- 5%, 12 +/- 5%, and 17 +/- 5%*, respectively, *p < 0.01 vs. all
      other groups). Significant correlation was found between %WR-E and conventional
      WR from 30 min to 240 min (r = 0.606, p < 0.0001). %WR-E was positively
      correlated with left ventricular end-diastolic dimension (r = 0.372, p < 0.01)
      and was inversely correlated with left ventricular fractional shortening (r = 
      0.316, p < 0.02). The normal upper limit of %WR-E was defined as mean + 2SD value
      of 17 control subjects (17.1%). Patients with abnormally rapid %WR-E levels had a
      higher cardiac event rate than those with normal %WR-E levels (57% vs. 12%, p <
      0.0001). These data suggest that washout rate of 123I-MIBG in the early phase
      from 4 min to 30 min (%WR-E) reflects cardiac sympathetic nervous integrity and
      is useful to evaluate the severity and prognosis of patients with CHF. The
      present results indicate a potential role of dynamic SPECT in shortening the 123I
      MIBG imaging protocol.

PMID- 15195763
TI  - Single dose planning for radioiodine-131 therapy of Graves' disease.
AB  - OBJECTIVE: Patients with Graves' disease were studied one year after radioiodine
      131 therapy to assess the relationship between the effectiveness of the therapy
      and the radioiodine doses used. METHODS: Patients were classified into three
      groups according to thyroid function as hyperthyroidism, euthyroidism and
      hypothyroidism at one year after I-131 therapy. In these groups we compared the
      mean values of dose, dose per thyroid weight calculated with I-123 uptake before
      the therapy (pre D/W), dose per thyroid weight calculated with therapeutic I-131
      uptake (post D/W), and absorbed dose. RESULTS: No significant differences were
      found between the three groups in terms of dose or pre D/W. The mean values of
      post D/W and absorbed dose in the non-hyperthyroid (euthyroid and hypothyroid)
      group were significantly greater than those in the hyperthyroid group. Post D/W
      of 6.3 MBq/g was a threshold separating the non-hyperthyroid group from the
      hyperthyroid group. There was no correlation between pre D/W and post D/W;
      however, the mean post D/W was significantly greater than the mean pre D/W. All
      patients with pre D/W above 6.3 MBq/g showed non-hyperthyroidism at one year
      after the radioiodine treatment. CONCLUSIONS: No indicators before the
      radioiodine therapy had significant relationships with the effectiveness of the
      therapy at one year after the treatment. However, the single therapy planned for
      setting the pre D/W above 6.3 MBq/g will certainly make the patients non
      hyperthyroid. As this proposal of dose planning is based on a small number of
      patients, further study is needed.

PMID- 15195764
TI  - Extraosseous accumulation of 99mTc-MDP in lymph node metastases of small cell
      carcinoma of the esophagus.
AB  - We report a case of esophageal carcinoma that showed extraosseous accumulation of
      99mTc-MDP in lymph node metastases to the cervical and paracardial lymph nodes.
      There are few cases showing abnormal extraosseous accumulation of 99mTc-MDP in
      esophageal cancer lesion. The patient was a 53-year-old man with advanced
      esophageal cancer. Bone scintigraphy demonstrated extraosseous accumulations in
      left supraclavicular and paracardial lymph node metastases. The histopathological
      diagnosis was small cell carcinoma of the esophagus, which is a rare disease with
      aggressive behavior and poor prognosis. Our patient underwent 2 courses of
      systemic chemotherapy (CDDP + VP16), but died of rapidly growing systemic
      metastases 5 months after the initial treatment.

PMID- 15195765
TI  - A case of renal pelvic tumor visualized by 18F-FDG-PET imaging.
AB  - 18F fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging is a
      useful modality in detecting various tumors, including renal cell carcinoma. We
      evaluated a patient with renal pelvic tumor (transitional cell carcinoma) with
      multiple metastases using 18F-FDG PET imaging and detected abnormal increased
      uptake of a right renal pelvic tumor extending to the renal cortex with liver
      metastasis and paraaortic lymph node metastases. These results suggest that 18F
      FDG PET imaging may be useful in detecting primary and metastatic lesions of
      renal pelvic tumor (transitional cell carcinoma).

PMID- 15195766
TI  - Improved synthesis of [11C]SA4503, [11C]MPDX and [11C]TMSX by use of [11C]methyl
      triflate.
AB  - Recently we have clinically used three new radioligands, [11C]SA4503, [11C]MPDX,
      and [11C]TMSX, for mapping sigma1, adenosine A1, and adenosine A2A receptors,
      respectively, in the human brain by positron emission tomography. These
      radioligands are synthesized by methylation of the respective demethyl precursor
      with [11C]methyl iodide. Here we demonstrate the improved syntheses of these
      compounds by use of [11C]methyl triflate, a highly reactive alternative to
      [11C]methyl iodide.

PMID- 15195767
TI  - Impact of peer group education on HIV prevention among women in Botswana.
AB  - A peer group HIV prevention intervention based on social-cognitive learning
      theory, gender inequality, and the primary health care model for community-based
      health promotion was developed for more than 300 urban employed women in
      Botswana. All women volunteered to participate in the intervention. To control
      for self-selection, matched workplaces were assigned to the intervention group or
      to the delayed control group. Compared with women in the delayed control group,
      women in the intervention group had significantly higher postintervention levels
      of knowledge of HIV transmission, sexually transmitted diseases (STDs), and HIV
      prevention behaviors; positive condom attitudes and confidence in condom use;
      personal safer sex behaviors; and positive attitudes toward persons living with
      HIV/AIDS and community HIV/AIDS-related activities. The peer group leaders have
      sustained the program for more than 5 years after the end of research funding.
      Peer groups are a low-cost and sustainable intervention that can change HIV
      prevention knowledge, attitudes, and behaviors for ordinary urban employed women
      in sub-Saharan Africa.

PMID- 15195768
TI  - Widening the cervical cancer screening net in a South African township: who are
      the underserved?
AB  - Cervical cancer screening services in South Africa have failed to reach the
      majority of the population and to significantly reduce mortality. A household
      survey in a predominantly Black African population living in a low-income
      township on the outskirts of Cape Town was undertaken to ascertain the
      characteristics of women reporting never having been screened. In our group of
      664 representatively sampled women. 45% of women reported having had a cervical
      screening test. However, in what at first glance appears to be a fairly
      homogeneous population, there were significant differences in the types of women
      who access and who do not access cervical smear services. The underserved tend to
      be the older, poorer, less educated, and unemployed (or working in the informal
      sector) women. They tend to live in nonpermanent dwellings without a partner,
      they do not know anyone else who has had a cervical smear, and they have not
      recently sought care for other ailments, or used contraception. Cervical cancer
      is a slow-to-develop, eminently preventable disease, and yet opportunistic
      screening through antenatal and family planning services has failed to reach the
      women most at risk. Efforts in the future must include targeting older women in
      health centres where they present for other curative services (diabetes,
      hypertension). Most importantly, areas of the community with the greatest
      concentration of marginalized women need to be targeted through peer education
      and other innovative programs. As the underserved tend to be the poorer and less
      educated women in the community, we must ensure that messages are culturally
      relevant and appropriate and have a holistic focus on women's physical, mental,
      and emotional health.

PMID- 15195769
TI  - Demands out of context: Tanzanian women combining exclusive breastfeeding with
      employment.
AB  - This research, conducted in Tanzania, involved 6 women and their experiences as
      they combined exclusive breastfeeding with work outside their home. Additional
      data were collected at a conference in Tanzania and from women in North America.
      We found that while public health officials did a spectacular job of convincing
      the women of the advantages of exclusive breastfeeding in terms of their babies'
      health and their own, they then left the women to their own devises when it came
      to solving the practical problems of breastfeeding at the same time as holding
      down a full-time job. We found that the women had to deal with conditions such as
      no on-site child care, lack of expressing or breastfeeding rooms, and short
      maternity leave at most workplaces. In addition, the women suffered the
      embarrassment of dribbling breasts while working. It seems clear that while
      cultural norms persist, these women are victims who are taught the imperative of
      breastfeeding without being given societal and governmental support. Therefore,
      the obvious next step for health professionals is to work for sociopolitical
      action that will provide a context where breastfeeding can take its natural place
      in the growth and development of infants. While structural functionalists might
      insist that structures in place position breastfeeding as having no normal
      function in the workplace, the pressure of the World Health Organization, by the
      shear weight of its international influence, may force a change in structure of
      the workplace.

PMID- 15195770
TI  - Adaptation of health care seeking behavior during childbirth: focus group
      discussions with women living in the suburban areas of Luanda, Angola.
AB  - The aim of this study was to explore how various factors influenced women's
      decisions regarding place of confinement in Luanda, Angola. Ten focus group
      discussions were conducted with pregnant and nonpregnant women residing in
      suburban areas of Luanda and the data were analyzed using the grounded theory
      technique. Four patterns of action of the main theme, "the molding of women's
      care-seeking behavior during childbirth," were identified: (I) the "labor process
      'on-course' avoiding pattern"; (II) the "labor process 'off-course' avoiding
      pattern"; (III) the "labor process 'on-course' approaching pattern"; and (IV) the
      "labor process 'off-course' approaching pattern." Our findings indicate that
      personal "courage" and social support empowered women and impacted on their
      preference for home birth, whereas demand for informal user fees and perceived
      low quality of care influenced women to avoid institutional care during
      childbirth, sometimes even in spite of complications. Ability to meet demands for
      informal user fees and knowledge of childbirth influenced women to seek
      institutional care. The study highlights the need to improve the quality of
      available maternal health care addressing the implicit educational, attitudinal,
      and ethical issues.

PMID- 15195771
TI  - The effect of prenatal knowledge of fetal sex on birth weight: a study from
      Jordan.
AB  - In this article we seek to determine the effect of the knowledge of prenatal
      fetal sex, through the use of ultrasound, on infant mean birth weight and the
      proportion of low birth weight (LBW) babies. A sample population of 1,195 women
      (cases, n = 640; control, n = 555) were studied in relation to their knowledge of
      the sex of the fetus in three hospitals in Amman, Jordan. It was found that
      prenatally known males had the highest mean birth weights (MBWs) as compared with
      females. It is proposed that these differences could be attributed to behavioral
      factors related to son preference. The authors conclude that further research on
      the actual link between prenatal detection of fetal sex and health behavior as
      indicated by birth weight is needed.

PMID- 15195772
TI  - Fantastic voyage: the peeping pill.

PMID- 15195773
TI  - Shared medical appointments: increasing patient access without increasing
      physician hours.
AB  - Shared medical visits are a new concept in patient care. Doctors perform a series
      of one-on-one patient encounters in a group setting during a 90-minute visit and
      manage and advise each patient in front of the others. Patients benefit from
      improved access to their physician and significantly increased education, while
      providers can boost their access and productivity without increasing hours. Such
      group visits are voluntary and for established patients only.

PMID- 15195774
TI  - The case for insulin treatment early in type 2 diabetes.
AB  - Most patients with type 2 diabetes ultimately need insulin therapy. This paper
      presents the case for starting insulin therapy sooner rather than later,
      preferably without oral drugs and in a "basal/bolus" regimen consisting of a
      daily dose of a long-acting insulin for basal coverage plus preprandial doses of
      a short-acting insulin.

PMID- 15195775
TI  - Rheumatoid arthritis: more aggressive approach improves outlook.
AB  - As recently as 10 years ago, many patients with rheumatoid arthritis would
      receive only a nonsteroidal anti-inflammatory drug and low-dose corticosteroids
      until damage to their joints was documented. Now, despite risks of toxicity and
      adverse effects, a disease-modifying antirheumatic drug such as methotrexate is
      given as early as possible to retard disease progression and help prevent new
      erosions. Other agents can be added to or used in place of methotrexate, such as
      a biologic response modifier that regulates the proinflammatory cytokine tumor
      necrosis factor-alpha.

PMID- 15195776
TI  - Video capsule endoscopy: a voyage beyond the end of the scope.
AB  - Video capsule endoscopy (VCE), an important innovation in diagnostic endoscopy,
      was approved in 2001 and is now widely available. In this system, the patient
      swallows a miniature high-resolution camera that is propelled by peristalsis
      through the gastrointestinal tract. It is particularly useful in examining the
      small intestine, which is difficult to visualize by conventional endoscopic
      techniques.

PMID- 15195777
TI  - Strengthening the standards for preventing heart disease and stroke: the recent
      AHA guidelines.
AB  - Recent American Heart Association guidelines to prevent cardiovascular disease
      and stroke call for managing risk factors more aggressively than ever before,
      especially in people identified as being at high risk.

PMID- 15195778
TI  - Six strategies to identify and assist patients burdened by out-of-pocket
      prescription costs.
AB  - Many patients find that their out-of-pocket costs of medications are burdensome.
      Physicians can help, first by remembering to ask about the problem, and then by
      applying simple strategies to limit the patient's costs.

PMID- 15195780
TI  - Quality...I'll know it when I see it.

PMID- 15195781
TI  - The evolving treatment in acute ischemic stroke.

PMID- 15195782
TI  - Teaching learners from varied generations.

PMID- 15195783
TI  - Learning pain assessment and management: a goal of the End-of-Life Nursing
      Education Consortium.
AB  - BACKGROUND: Relief of pain for patients requires that palliative care
      practitioners have knowledge and skill in both pain assessment and the use of
      pharmacologic and complementary therapies. METHOD: Pain assessment and management
      and the teaching strategies suggested within the End-of-Life Nursing Education
      Consortium curriculum are presented. RESULTS: By addressing the pain experienced
      by patients with life-limiting illnesses and those at the end of life, the
      quality of care can be greatly improved. As a multidimensional phenomenon that
      relates to physical, emotional, and spiritual well-being, the relief of pain
      enhances the quality of life of patients and lessens the stress experienced by
      family caregivers. CONCLUSION: The relief of pain and suffering is consistent
      with the philosophy and goals of nursing as a profession and is a nursing
      responsibility.

PMID- 15195784
TI  - Challenges of Web-based education in educating nurses about evidence-based acute
      pain management practices for older adults.
AB  - Internet technology holds potential as a valuable educational tool, but several
      challenges continue to impede its use. This article describes the use of a web
      based course to educate staff nurses regarding evidence-based acute pain
      management practices for older adults. Specific areas highlighted include: the
      steps involved in creating the web-based course; the materials and support
      required to disseminate the course; the challenges encountered in promoting use
      of the course; and responses to and evaluations of the course. The authors'
      experiences provide knowledge to assist other healthcare professionals on the use
      of a web-based course to educate staff nurses.

PMID- 15195785
TI  - Leadership: a key strategy in staff nurse retention.
AB  - Nursing administrators are challenged to recruit and retain staff nurses in the
      midst of increasing job vacancies and staff nurse turnover rates averaging 21%.
      The prevailing issues related to staff nurse recruitment and retention in the
      current healthcare environment are briefly reviewed as introductory content. The
      article outlines the case from nursing administration literature that effective
      leadership styles of nurse managers and nurse administrators enhance staff nurse
      retention. As nurse administrators continue to struggle with staff nurse
      recruitment and retention, evidenced-based strategies are discussed that address
      leader preparation and organizational leadership structure including advanced
      education, leadership training, and shared leadership models.

PMID- 15195786
TI  - The hospital clinical preceptor: essential preparation for success.
AB  - Hospitals have a responsibility to provide preceptors with the knowledge and
      skills required to provide bedside instruction to and evaluation of orientees.
      Formal preceptor preparation programs that provide practical information for
      immediate application are necessary for successful transition of orientees into
      patient care environments. Essential content includes the importance of
      socialization, skill building techniques, critical thinking facilitation, and
      assignment management. Preceptor preparation courses need to be based on adult
      learning principles and incorporate interactive and creative teaching strategies.

PMID- 15195787
TI  - TNM: our language of cancer.

PMID- 15195788
TI  - An evidence-based staging system for cutaneous melanoma.
AB  - A completely revised staging system for cutaneous melanoma was implemented in
      2003. The changes were validated with a prognostic factors analysis involving
      17,600 melanoma patients from prospective databases. This major collaborative
      study of predicting melanoma outcome was conducted specifically for this project,
      and the results were used to finalize the criteria for this evidence-based
      staging system. In fact, this was the largest prognostic factors analysis of
      prospectively followed melanoma patients ever conducted. Important results that
      shaped the staging criteria involved both the tumor-node-metastasis (TNM)
      criteria and stage grouping for all four stages of melanoma. Major changes in the
      staging include: (1) melanoma thickness and ulceration are the dominant
      predictors of survival in patients with localized melanoma (Stages I and II);
      deeper level of invasion (ie, IV and V) was independently associated with reduced
      survival only in patients with thin or T1 melanomas. (2) The number of metastatic
      lymph nodes and the tumor burden were the most dominant predictors of survival in
      patients with Stage III melanoma; patients with metastatic nodes detected by
      palpation had a shorter survival compared with patients whose nodal metastases
      were first detected by sentinel node excision of clinically occult or
      "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus
      lung versus all other visceral metastatic sites) and the presence of elevated
      serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in
      patients with Stage IV or distant metastases. (4) An upstaging was implemented
      for all patients with Stage I, II, and III disease when a primary melanoma is
      ulcerated by histopathological criteria. (5) Satellite metastases around a
      primary melanoma and in-transit metastases were merged into a single staging
      entity that is grouped into Stage III disease. (6) A new convention was
      implemented for defining clinical and pathological staging so as to take into
      account the new staging information gained from lymphatic mapping and sentinel
      node biopsy.

PMID- 15195789
TI  - Chemoprevention of cancer.
AB  - Cancer chemoprevention is defined as the use of natural, synthetic, or biologic
      chemical agents to reverse, suppress, or prevent carcinogenic progression to
      invasive cancer. The success of several recent clinical trials in preventing
      cancer in high-risk populations suggests that chemoprevention is a rational and
      appealing strategy. This review will highlight current clinical research in
      chemoprevention, the biologic effects of chemopreventive agents on epithelial
      carcinogenesis, and the usefulness of intermediate biomarkers as markers of
      premalignancy. Selected chemoprevention trials are discussed with a focus on
      strategies of trial design and clinical outcome. Future directions in the field
      of chemoprevention will be proposed that are based on recently acquired
      mechanistic insight into carcinogenesis.

PMID- 15195790
TI  - Pharmacological management of Dysautonomia following traumatic brain injury.
AB  - PRIMARY OBJECTIVE: To document and critically evaluate the likely effectiveness
      of pharmacological treatments used in a sample of patients with Dysautonomia and
      to link these findings to previously published literature. RESEARCH DESIGN:
      Retrospective case control chart review. METHODS AND PROCEDURES: Data were
      collected on age, sex and GCS matched subjects with and without Dysautonomia (35
      cases and 35 controls). Data included demographic and injury details,
      physiological parameters, medication usage, clinical progress and rehabilitation
      outcome. Descriptive analyses were undertaken to characterize the timing and
      frequency of CNS active medications. MAIN OUTCOMES AND RESULTS: Dysautonomic
      patients were significantly more likely to receive neurologically active
      medications. A wide variety of drugs were utilised with the most frequent being
      morphine/midazolam and chlorpromazine. Cessation of morphine/midazolam produced
      significant increases in heart rate and respiratory rate but not temperature.
      Chlorpromazine may have modified respiratory rate responses, but not temperature
      or heart rate. CONCLUSIONS: The features of Dysautonomia are similar to a number
      of conditions treated as medical emergencies. Despite this, no definitive
      treatment paradigm exists. The best available evidence is for morphine
      (especially intravenously), benzodiazepines, propanolol, bromocriptine and
      possibly intrathecal baclofen. Barriers to improving management include the lack
      of a standardized nomenclature, formal definition or accepted diagnostic test.
      Future research needs to be conducted to improve understanding of Dysautonomia
      with a view to minimizing disability.

PMID- 15195791
TI  - Time-sharing strategies in driving after various cerebral lesions.
AB  - PRIMARY OBJECTIVE: To analyse time-sharing strategies in patients with cerebral
      lesions when they performed everyday in-car tasks in real-life highway driving. A
      case-control study. METHODS AND PROCEDURES: Thirteen male patients with brain
      damage and 11 healthy controls participated. The frequency and duration of
      glances at the in-car tasks, total time of eyes-off the road during tasks, speed
      and lateral displacement of the car were recorded. MAIN OUTCOMES AND RESULTS:
      Long glances away from the road and consequent large lateral displacements were
      characteristic for patients with anterior damage, while the patients with more
      posterior lesions used frequent short glances at the in-car task. CONCLUSION: Two
      different time-sharing strategies that appeared to be related to different
      aetiology were found in the patients, indicating different control of the driving
      task. It is proposed that standardized on-road dual tasks should be used for
      detecting problems in allocation of attention during driving.

PMID- 15195792
TI  - Cumulative effects of concussion in amateur athletes.
AB  - PRIMARY OBJECTIVE: To examine the possibility that athletes with multiple
      concussions show cumulative effects of injury. METHODS AND PROCEDURES: Amateur
      athletes with a history of three or more concussions were carefully matched
      (gender, age, education and sport) with athletes with no prior concussions. All
      completed a computerized neuropsychological test battery at preseason (ImPACT)
      and then within 5 days of sustaining a concussion (mean = 1.7 days). MAIN
      OUTCOMES AND RESULTS: There were differences between groups in symptom reporting
      and memory performance. At baseline (i.e. preseason), athletes with multiple
      concussions reported more symptoms than athletes with no history of concussion.
      At approximately 2 days post-injury, athletes with multiple concussions scored
      significantly lower on memory testing than athletes with a single concussion.
      Athletes with multiple concussions were 7.7 times more likely to demonstrate a
      major drop in memory perfomance than athletes with no previous concussions.
      CONCLUSIONS: This study provides preliminary evidence to suggest that athletes
      with multiple concussions might have cumulative effects.

PMID- 15195793
TI  - Assessing support needs for people with traumatic brain injury: the Care and
      Needs Scale (CANS).
AB  - BACKGROUND: After traumatic brain injury (TBI), many individuals have support
      needs, but the variety, frequency and intensity of such needs vary widely.
      Currently available scales do not assess all facets of required supports and the
      eight-category Care and Needs Scale (CANS) was developed in order to capture the
      range of support needs. The aim of the present study was to examine the
      sensitivity and validity of the CANS. METHOD: Using a sample of 67 people who
      sustained severe TBI 20-26 years previously, the CANS was compared with the
      Supervision Rating Scale (SRS), five scales from the Craig Handicap Assessment
      and Reporting Technique (CHART) and the Sydney Psychosocial Reintegration Scale
      (SPRS). RESULTS: The data showed a spread across all CANS categories: 28.4% of
      participants were fully independent, 46.3% had support needs on less than a daily
      basis (25.4% intermittently, 13.4% at least weekly and 7.5% every few days) and
      the remaining 25.4% had needs on a daily basis (ranging from 11.9% for up to 11
      hours per day to 4.5% for 24 hours per day). By contrast, the 13-category SRS
      classified 61.2% in the best category and five categories did not contain any
      individuals. The CANS showed strong correlation with the SRS (r(s) = 0.75), as
      well as CHART and SPRS scores (range r(s) = -0.46 to -0.85) and statistically
      significant differences were found among participant sub-groups. Logistic
      regression analyses, using variables collected at the time of discharge from
      rehabilitation, were able to predict independence on the CANS with classification
      accuracy of 77% and presence of neuropsychological disability was an individual
      predictor. CONCLUSION: These results suggest that the CANS shows promise as a
      sensitive and valid instrument to measure care and support needs after TBI,
      particularly in the longer term, and further examination of its psychometric
      properties is warranted.

PMID- 15195794
TI  - Evaluating computer-assisted memory retraining programmes for people with post
      head injury amnesia.
AB  - OBJECTIVE: The present study was designed to perform theory-driven empirical work
      that might contribute to a better understanding of computer-assisted training
      effects adopting theoretically different memory retraining strategies for people
      who had amnesia as a result of a brain injury. RESEARCH DESIGN: A pre-test and
      post-test control group quasi-experimental design was adopted to test the
      differences in effectiveness of four different computer-assisted memory training
      strategies, which were hypothesized to improve different memory skills of persons
      with brain injury. METHOD AND PROCEDURES: Twenty-six persons with brain injury
      were randomly assigned to four age- and gender-matched memory training groups
      (self-paced, feedback, personalized, visual presentation) and they were trained
      using the related computer software, evaluated by the Rivermead Behavioural
      Memory Test (RBMT), self-efficacy scale and built-up computer performance
      records. MAIN OUTCOMES AND RESULTS: All the four memory training methods showed
      positive among the persons with brain injury as compared with a control group,
      although there was no statistically significant difference among the four
      training methods. However, clinical improvement was found in all four methods and
      the Feedback group showed significant improvement in self efficacy, in comparison
      with the other groups. CONCLUSION: This attempt to develop and evaluate different
      computer applications for memory retraining was made and the effectiveness of
      applying customized computer technology in memory rehabilitation was critically
      evaluated. Results of the present study showed that the unique customized
      therapeutic characteristics of computer-assisted memory retraining (e.g. self
      paced practice, performance feedback, salient visual presentation and
      personalized training contents) are positive attributes of memory skill
      retraining outcomes.

PMID- 15195795
TI  - Interview study of the effects of paediatric traumatic brain injury on memory.
AB  - PRIMARY OBJECTIVE: To investigate the effects of traumatic brain injury (TBI) on
      children's day-to-day memory functioning. RESEARCH DESIGN: A qualitative,
      interview-based procedure. METHODS AND PROCEDURES: Thirteen parents of children
      and adolescents with TBI were interviewed for 2 hours. Data from 12 of the
      interviews were analysed using content analysis, which involved transcribing
      notes, sorting information into categories, identifying similarities or
      differences among the categories and isolating meaningful trends. MAIN OUTCOMES
      AND RESULTS: Over half of the children experienced explicit (past recall) and
      prospective memory (future intentions) loss, but few experienced implicit memory
      (e.g. procedural) loss. Further, parents utilized their own interventions in
      minimizing their children's memory disabilities. CONCLUSION: Memory loss is
      common and can impact on everyday living, but is selective in the types of memory
      affected. Follow-ups are recommended to assess quantitatively, the so-far, little
      known effects of paediatric TBI on prospective memory and to examine more closely
      parent interventions to assess their wider applicability in TBI rehabilitation.

PMID- 15195796
TI  - Accuracy, efficiency and preferences of survivors of traumatic brain injury when
      using three organization strategies to retrieve words.
AB  - The primary objective was to compare the accuracy and preferences of adult
      survivors of traumatic brain injury (TBI) when using three organization
      strategies--semantic topic, geographic place and a word's first letter (alphabet)
      -to retrieve words using augmentative and alternative communication (AAC)
      technology. A repeated measures research design was employed. Twelve adult
      survivors of TBI ranging in age from 18-50 years participated in the study. These
      participants retrieved words using an AAC system organized using the three
      experimental conditions. In addition, they rank-ordered their preferences for
      each of the three strategies. Results showed that adults with TBI retrieve words
      more accurately and more efficiently when using the alphabet organization
      strategy than when using the topic or place strategies. Despite this,
      participants expressed a preference for using the topic strategy. Explanations
      for the findings and implications for AAC use are provided.

PMID- 15195797
TI  - Therapeutic time window for musicokinetic therapy in a persistent vegetative
      state after severe brain damage.
AB  - OBJECTIVE: To determine the therapeutic time window in which musicokinetic
      therapy (MKT) could be of potential benefit for a persistent vegetative state
      (PVS), this study analysed the relationship between the timing of MKT and changes
      in PVS score following MKT. METHODS: Twenty-six patients who fulfilled the
      definition of PVS were treated consecutively by MKT employing a trampoline with
      live music performance for 3 months. The PVS score ranges from 0-30 and the
      condition which meets the definition of PVS is never scored greater than 20.
      RESULTS: As compared to patients with brain damage caused by trauma (n=12) or
      subarachnoid haemorrhage (SAH; n=9), those caused by other cerebrovascular
      accidents (n=3) or anoxic encephalopathy (n=2) appeared to demonstrate a much
      smaller improvement in their PVS score. When the patients caused by trauma or SAH
      were analysed in isolation, the effects of MKT were clearly better in those
      patients in whom the MKT was initiated within 6 months after brain damage. Among
      nine patients caused by trauma or SAH who had been in a PVS for more than 12
      months, however, six (66.7%) demonstrated improvement of their PVS score by 5 or
      more and four (33.3%) reached a post-MKT score of greater than 20. CONCLUSIONS:
      These findings suggest that, contrary to the commonly held belief, the
      therapeutic time window for MKT is far greater than 6 months, insofar as patients
      with brain damage caused by trauma or SAH are concerned. Although the benefits of
      MKT were not proven directly, this inference is consistent with the hypothesis
      that MKT can induce an improvement in the clinical condition of PVS patients.

PMID- 15195798
TI  - Isotope dilution high-performance liquid chromatography-tandem mass spectrometry
      method for quantifying urinary metabolites of synthetic pyrethroid insecticides.
AB  - This paper describes a method for measuring cis- and trans-3-(2,2-dichlorovinyl)
      2,2-dimethylcyclopropane-1-carboxylic acids (cis-DCCA and trans-DCCA), cis-3-(2,2
      dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), 3-phenoxybenzoic
      acid (3PBA), and 4-fluoro-3-phenoxybenzoic acid (4F3PBA) in human urine. These
      compounds are considered to be reliable biomarkers of exposure for many
      pyrethroid insecticides used in the United States. In this method, stable
      isotopically labeled analogues of trans-DCCA and 3PBA were spiked into urine as
      internal standards. After solid-phase extraction, the extracts were analyzed by
      high-performance liquid chromatography coupled with tandem mass spectrometry
      using turbo ion-spray atmospheric pressure ionization. The limits of detection
      (LODs) ranged from 0.1 to 0.5 microg/L. Within-day relative standard deviations
      ranged from 1.8 to 13% and between-day relative standard deviations ranged from
      0.5 to 18%. Absolute analyte recoveries ranged from 72 to 93%. Chromatographic
      retention times were less than 8 min. This method was used to measure urinary
      concentrations of these metabolites in persons with no known exposure to
      pyrethroids and some with suspected residential exposure. Metabolites of
      synthetic pyrethroids were detected in 74% of the samples analyzed. cis-DCCA,
      trans-DCCA, DBCA, 4F3PBA, and 3PBA were detected in 36, 50, 3, 9, and 64% of the
      samples analyzed, respectively.

PMID- 15195799
TI  - A procedure to purify and culture a clonal strain of the aquatic moss Fontinalis
      antipyretica for use as a bioindicator of heavy metals.
AB  - A procedure to culture the aquatic moss, Fontinalis antipyretica, is described.
      The moss was collected in a stream, carried to the laboratory, and immediately
      treated: apices were isolated and rinsed under a stereomicroscope and submitted
      to ultrasonic cleaning combined with an iodine treatment and then to an
      antibiotic/anti-eukaryotic treatment for 4 days. This procedure permitted us for
      the first time to eliminate the microalgae associated with an aquatic moss in
      culture, solving the problem of proliferation of these microalgae in the culture
      medium. Furthermore, the minimal concentration of eight essential metals required
      by this moss was determined in order to have metal concentrations in the cultured
      moss as low as possible. A perennial culture of a clonal strain of an aquatic
      moss for use as a metal bioaccumulator was obtained and the first step to provide
      a standardized bioindication tool for metal detection in continental waters was
      passed over.

PMID- 15195800
TI  - Atrazine induces homologous recombination but not point mutation in the
      transgenic plant-based biomonitoring assay.
AB  - Herbicides, such as atrazine, are extensively used in agriculture in order to
      suppress growth of weeds. From the soil they inevitably find their way to water
      supplies, leading to human exposure via drinking water. Therefore, it is
      extremely important to know whether those chemicals pose any hazard to public
      health. The genotoxicity of atrazine has been a subject of studies in recent
      years. However, the data that are currently available are inconclusive. There is
      a need to examine the genotoxicity of low, environmentally relevant
      concentrations that are currently assumed to be safe. Up to date, studying the
      genotoxicity of low concentrations of atrazine has constituted a great challenge
      due to the lack of appropriate, sensitive test systems. In the present work, we
      used a new sensitive transgenic plant-based system to study the genotoxicity and
      mutagenicity of atrazine present at minute concentrations in the liquid media.
      This system gave us an opportunity to monitor the two main types of
      rearrangements, the frequency of homologous recombination and point mutations,
      which are indicators of the genotoxicity of atrazine. Atrazine present at low
      concentrations was found to be a strong inducer of homologous recombination. On
      the other hand, it did not have a significant influence on the levels of A --> G
      and T --> G mutations. These results suggest that the transgenic plant-based
      biomonitoring system is a useful tool for analyzing the genotoxicity of water
      contaminated by atrazine. In the future this system can be used to study
      molecular mechanisms of genotoxicity and mutagenicity atrazine and other triazine
      herbicides.

PMID- 15195801
TI  - Atrazine-induced chlorosis in Synechococcus elongatus cells.
AB  - The effects of a widely used herbicide, atrazine, on the freshwater
      cyanobacterium Synechococcus elongatus were studied. The cyanobacteria were
      exposed to varying concentrations of atrazine (0.025, 0.05, 0.1, 0.25, and 0.75
      microM) for 96 h. Different parameters such as growth, autofluorescence of
      chlorophyll a, pigment content, volume, and internal granularity of the cells
      were determined daily. Differences were detected between cultures with and
      cultures without atrazine for the parameters analyzed. Atrazine exposure induced
      the process of chlorosis in cyanobacterial cells, given that this herbicide has
      an effect on photosynthesis, chlorotic subpopulations having low values of
      chlorophyll a autofluorescence. More unpigmented subpopulations (chlorotic)
      appeared as the atrazine concentration increased and better growth rates
      resulted. Atrazine also induced changes in cell volume and internal granularity,
      these being most apparent after 48 h of exposure and in cultures with higher
      atrazine concentrations (0.25 and 0.75 microM).

PMID- 15195802
TI  - Toxicity of atrazine and molinate to the cladoceran Daphnia carinata and the
      effect of river water and bottom sediment on their bioavailability.
AB  - Atrazine and molinate are widely used herbicides and concern has been raised
      about their potential deleterious impacts on aquatic ecosystems. Although there
      have been some studies on the toxicity of herbicides to aquatic organisms using
      laboratory or natural water, information on the effect of sediments, suspended
      particulates, and dissolved organic matter on their bioavailability is quite
      limited. This study aims to provide toxicity data that considers these factors
      and the effect that these factors have on bioavailability. In this study, the
      toxicity of the test chemicals was calculated following the Organisation for
      Economic Co-operation and Development (OECD) methods, whereas change in
      bioavailability was measured using EC50 values based on measured initial
      concentrations of the test chemicals. The acute (48-h) static toxicity of
      atrazine and molinate to the freshwater cladoceran Daphnia carinata was
      determined in cladoceran water and river water in the absence and presence of
      sediment. The 48-h EC50 (immobilization) values of atrazine to D. carinata ranged
      from 22.4 to 26.7 mg/L, while the corresponding values for molinate ranged from
      18.3 to 33.6 mg/L, respectively. Both chemicals were classed as having low acute
      toxicity to D. carinata. The presence of dissolved organic matter and suspended
      particles in river water did not significantly (p > 0.05) reduce the
      bioavailability (measured as toxicity) of atrazine to D. carinata compared to
      that tested in cladoceran water. The presence of sediment, however, significantly
      (p < 0.05) reduced the bioavailability (48-h EC50) of atrazine in cladoceran
      water, from 24.6 to 30.7 mg/L, and in river water, from 22.4 to 31.0 mg/L.
      Similarly, the presence of sediment in cladoceran water, significantly (p < 0.05)
      reduced the bioavailability (48-h EC50) of molinate, from 26.6 to 46.4 mg/L, and
      in river water, from 22.5 to 45.6 mg/L.

PMID- 15195803
TI  - Comparative toxicity of glyphosate-based herbicides: aqueous and sediment
      porewater exposures.
AB  - Glyphosate-based herbicides are widely used for aquatic weed control. However,
      their aquatic toxicity data, especially those on sediment, are relatively scarce.
      In this study, the water-only acute toxicity of three formulations based on
      glyphosate (Rodeo, Roundup Biactive, and Roundup) were compared using a water
      column organism (cladoceran: Ceriodaphnia dubia) and a benthic organism
      (amphipod: Hyalella azteca). In addition, Roundup Biactive and Roundup were
      spiked into a clean sediment which was amended with appropriate amounts of peat
      moss to study the effect of different organic carbon levels (0, 0.4, 1.2, and
      2.1%) on their sediment toxicity, with C. dubia exposed to overlying water or
      porewater prepared from the contaminated sediments. Results showed that the
      toxicity based on 48-h LC50s for the three herbicides in the water-only tests was
      Roundup (1.5-5.7 mg L(-1)) > Roundup Biactive (82-120 mg L(-1)) > Rodeo (225-415
      mg L(-1)), and H. azteca was generally more sensitive than C. dubia to these
      herbicides. Toxicity differences between formulations were due to the different
      surfactant components in these herbicides. From the porewater toxicity tests,
      Roundup Biactive (340 mg kg(-1)) and Roundup (244 mg kg(-1)) were similarly toxic
      in the sediment tests at 0% organic carbon, indicating that the surfactants in
      Roundup were considerably more adsorptive than those in Roundup Biactive to the
      sediment of the same organic carbon. Also, an increase in organic carbon
      significantly decreased the toxicity of Roundup in sediment, but not for Roundup
      Biactive. Sediment-porewater partitioning of glyphosate was found to be
      influenced by sediment organic carbon (i.e., glyphosate adsorption increased with
      sediment organic carbon).

PMID- 15195804
TI  - Comparison of laboratory single species and field population-level effects of the
      pyrethroid insecticide lambda-cyhalothrin on freshwater invertebrates.
AB  - The toxicity of the pyrethroid insecticide lambda-cyhalothrin to freshwater
      invertebrates has been investigated using data from short-term laboratory
      toxicity tests and in situ bioassays and population-level effects in field
      microcosms. In laboratory tests, patterns of toxicity were consistent with
      previous data on pyrethroids. The midge Chaoborus obscuripes was most sensitive
      (48- and 96-h EC50 = 2.8 ng/L). Other insect larvae (Hemiptera, Ephemeroptera)
      and macrocrustacea (Amphipoda, Isopoda) were also relatively sensitive, with 48-
      and 96-h EC50 values between 10 and 100 ng/L. Generally, microcrustacea
      (Cladocera, Copepoda) and larvae of certain insect groups (Odonata and
      Chironomidae) were less sensitive, with 48-h EC50 values higher than 100 ng/L.
      Mollusca and Plathelminthes were insensitive and were unaffected at
      concentrations at and above the water solubility (5 microg/L). Generally, the
      EC50 values based on initial population responses in field enclosures were
      similar to values derived from laboratory tests with the same taxa. Also, the
      corresponding fifth and tenth percentile hazard concentrations (HC5 and HC10)
      were similar (laboratory HC5 = 2.7 ng/L and field HC5 = 4.1 ng/L; laboratory and
      field HC10 = 5.1 ng/L), at least when based on the same sensitive taxonomic
      groups (insects and crustaceans) and when a similar concentration range was taken
      into account. In the three field enclosure experiments and at a treatment level
      of 10 ng/L, consistent effects were observed for only one population (Chaoborus
      obscuripes), with recovery taking place within 3 to 6 weeks. The laboratory HC5
      (2.7 ng/L) and HC10 (5.1 ng/L) based on acute EC50 values of all aquatic
      arthropod taxa were both lower than this 10 ng/L, a concentration that might
      represent the "regulatory acceptable concentration." The HC5 and HC10 values in
      this study in The Netherlands (based on static laboratory tests with freshwater
      arthropods) were very similar to those derived from a previous study in the
      United Kingdom (1.4 and 3.3 ng/L). This suggests that for pesticides like lambda
      cyhalothrin, HC5 values based on static laboratory tests may provide a
      conservative estimate of the potential for community-level effects under field
      conditions. While these HC5 values are conservative for initial effects, they do
      not provide information on recovery potential, which may be important for
      regulatory decision-making.

PMID- 15195805
TI  - Hormetic versus toxic effects of vegetable tannin in a multitest study.
AB  - Tannin from mimosa trees (Acacia sp.) utilized in traditional leather tanning was
      tested for toxicity in sea urchin (Sphaerechinus granularis and Paracentrotus
      lividus) embryos and sperm, marine, and freshwater algae (Selenastrum
      capricornutum and Dunaliella tertiolecta), and Daphnia magna. Based on a two-step
      tanning procedure used in traditional tanneries, two mimosa tannin preparations,
      i.e., fresh tannin (FT) and used tannin (UT), were tested as suspensions. The
      early results in S. granularis embryos showed that UT exerted lower acute
      toxicity than FT, namely, 1 vs 100 mg/L, to obtain 100% mortality, respectively.
      Subsequent bioassays were conducted on fresh tannin water extracts (TWE)
      corresponding to nominal tannin concentrations ranging from 0.1 to 30 mg/L.
      Developmental toxicity, up to embryonic mortality was exerted by TWE at levels >
      1 mg/L, S. granularis being more sensitive than P. lividus embryos/larvae. At the
      concentration of 0.1 mg/L, the frequencies of larval malformations were
      significantly lower than in controls. This positive stimulatory effect (currently
      termed as hormesis) was observed in extended numbers of culture replicates (up to
      14) and was significant in the embryo cultures characterized by a relatively poor
      control quality (with < 70% viable larvae in controls), whereas this effect was
      not observed in good-quality cultures (with > or = 70% viable larvae in
      controls). Cytogenetic analysis of S. granularis embryos reared in FT or UT
      suspensions (1 mg/L to 1 g/L) showed mitotoxic effects (decrease in active
      mitoses per embryo) in FT-exposed, but not in UT-exposed embryos. Mitotic
      aberrations were significantly increased by 10 mg/L UT. Sperm fertilization
      success in both sea urchin species showed an increasing fertilization rate (FR)
      up to 0.3 mg/L TWE and a dose-related decrease in FR up to 30 mg/L. Again, the
      offspring of P. lividus sperm exposed to TWE (0.1 and 0.3 mg/L) showed a decrease
      in larval malformations compared to controls, whereas a dose-related increase in
      developmental defects was observed in the offspring of P. lividus sperm exposed
      to higher TWE levels (1 to 30 mg/L). Algal cell growth bioassays in two species
      (S. capricornutum and D. tertiolecta) also showed a maximum growth at TWE levels
      ranging from 0.3 to 3 mg/L and a subsequent decline up to 30 mg/L TWE. D. magna
      bioassays resulted in daphnid immobilization by TWE concentrations ranging from
      100 to 300 mg/L. The results demonstrate that tannins utilized in traditional
      leather tanning industry may raise concern of environmental damage at relatively
      high concentrations, whereas low-level tannins may result in hormetic effects.
      The present study also points to the need for bioassay design that should rely on
      adequate criteria in control quality, allowing to detect both inhibitory and
      hormetic effects.

PMID- 15195806
TI  - Runoff-related endosulfan contamination and aquatic macroinvertebrate response in
      rural basins near Buenos Aires, Argentina.
AB  - Information in the open literature about the fate and effects of pesticides in
      small streams from agricultural areas of Argentina is very rare. The objective of
      the present work was to study the pesticide contamination and potential
      biological effects in basins that have undergone intense agricultural activity,
      mainly related to the cultivation of soybeans. Three streams (Maguire, Helves,
      and Horqueta) with a low-flow discharge (0.1 and 0.2 m3/s) in March close to the
      city of Arrecifes were studied during the period of maximum insecticide
      application, between February and April 2001. Various sampling devices were
      installed to trap suspended particles, runoff, and floodwater plus sediment
      throughout the study period. The suspended-particle samples were analyzed for the
      insecticides endosulfan (END), chlorpyrifos, and cypermethrin. Water chemistry
      and the macroinvertebrate communities were assessed on four occasions and the
      organismic drift was measured continuously. Following a 184-mm rainfall on March
      1, 2001, beta-endosulfan concentrations up to 318 and 43 microg/kg were measured
      from suspended-particle samples from Horqueta and Helves, respectively. No END
      contamination was detected in Maguire. Chlorpyrifos and cypermethrin were not
      detected in any of the streams. A significant decrease in the average
      macroinvertebrate species density was observed in Horqueta (from 12.8 +/- 0.5 to
      9 +/- 0.7 species; ANOVA, p < 0.05) and Helves (from 10.8 +/- 1.7 to 3.3 +/- 1.3
      species; p < 0.001) following the same rainfall event at the beginning of March,
      while the species density in Maguire remained constant at 7.9 +/- 0.3 species.
      The runoff primarily reduced species abundances of Odonata and Ephemeroptera
      significantly (p < 0.01) in Horqueta and Helves but not in Maguire. A greater
      drift of Smicridae (Trichoptera) and Ephemeroptera occurred in Helves and
      Horqueta during this runoff event, while no changes in the macroinvertebrate
      drift were detectable in Maguire. This study highlights the potential pesticide
      effects on macroinvertebrate communities in Argentinian rural streams. It is
      suggested that a small wetland area formed by Maguire between the agriculturally
      used catchment and the sampling site contributes to the absence of contamination
      and effects at this site.

PMID- 15195807
TI  - Trace metal concentrations and susceptibility to oxidative stress in the
      polychaete Sabella spallanzanii (Gmelin) (Sabellidae): potential role of
      antioxidants in revealing stressful environmental conditions in the
      Mediterranean.
AB  - The polychaete Sabella spallanzanii (Gmelin) (Sabellidae) is a widely distributed
      species throughout the Mediterranean where it is commonly found in sheltered
      shallow areas and up to 30 m depth in more exposed waters. The sedentary habit,
      the filter-feeding behavior and its capability to colonize disturbed environments
      such as harbors, suggest the potential utility of this organism as a bioindicator
      in environmental monitoring programs. The aim of this work was a preliminary
      characterization of S. spallanzanii, integrating chemical data on trace metal
      concentrations with the biochemical analysis of antioxidant defenses which play
      an important role in mediating responses and adaptation to stressful
      environmental conditions. Organisms were collected in four locations of the
      Adriatic and Tyrrhenian Sea, characterized by a moderate impact or influenced by
      organic enrichment or sulphuric emissions. Trace metal concentrations (Cd, Cr,
      Cu, Fe, Mn, Ni, Pb, Zn) were comparable to those of other invertebrate species
      and quite typical for unpolluted environments. Analyses of individual
      antioxidants (superoxide dismutase, catalase, glutathione peroxidases,
      glutathione S-transferases, glutathione reductase) were integrated with
      measurement of the total oxyradical scavenging capacity toward specific forms of
      ROS; the TOSC assay, quantifying the overall capability of a tissue to neutralize
      specific reactive oxygen species provide a more integrated picture of the balance
      between prooxidant factors and antioxidant defenses, with important indications
      about the role of different ROS in appearance of oxidative disease. The
      antioxidant profile was influenced by the different physiological functions of
      the analyzed tissues, namely the branchial crown, involved in filtration of large
      volumes of seawater, and the thorax where digestive processes occur. The analysis
      of antioxidant defenses revealed significant variations in polychaetes from
      various sampling sites suggesting the influence of specific environmental
      conditions like those limiting oxygen availability. Our results confirm the role
      of antioxidants in adaptation to stressful environmental conditions and their
      importance in ecotoxicological studies for the sensitivity in revealing the
      occurrence of biological disturbance.

PMID- 15195808
TI  - Evaluation of lethality and genotoxicity in the freshwater mussel Utterbackia
      imbecillis (Bivalvia: Unionidae) exposed singly and in combination to chemicals
      used in lawn care.
AB  - Many chemicals, including fertilizers, herbicides, and insecticides, are
      routinely applied to turf in the care and maintenance of lawns. These chemicals
      have the potential to leach into nearby surface waters and adversely affect
      aquatic biota. In this study, we evaluated the lethal and genotoxic effects of
      chemicals used in lawn care on an early life stage of freshwater mussels
      (Utterbackia imbecillis). The chemicals tested were copper and commercial
      formulations of atrazine, glyphosate, carbaryl, and diazinon. Mussel glochidia
      were exposed to chemicals singly or in combination (equitoxic and environmentally
      realistic mixtures) for 24 h and toxic interactions were evaluated with Marking's
      additive index. Genotoxicity was quantified with the alkaline single-cell gel
      electrophoresis assay (Comet assay). In acute tests, copper was the most toxic of
      all chemicals evaluated (LC50 = 37.4 microg/L) and carbaryl was the most toxic of
      all pesticides evaluated (LC50 = 7.9 mg/L). In comparison to other aquatic
      organisms commonly used in toxicity tests (e.g., amphipods, cladocerans, and
      chironomids), mussel glochidia were as or more sensitive to the chemicals
      evaluated with the exception of diazinon, where mussels were observed to be less
      sensitive. The combined toxicity of equitoxic and environmentally realistic
      mixtures to mussels was additive. Genotoxic responses were observed in mussels
      exposed to copper, atrazine and diazinon at levels below their respective no
      observed-effect concentrations. Together, these data indicate that freshwater
      mussels are among the most sensitive aquatic organisms tested for some chemicals
      commonly used in lawn care and that DNA damage may be useful as a screening tool
      to evaluate potential sublethal effects of lawn care products on non-target
      aquatic organisms.

PMID- 15195809
TI  - Ovipositional response, developmental effects and toxicity of hexavalent chromium
      to Megaselia scalaris, a terrestrial detritivore.
AB  - The effects of hexavalent chromium (Cr VI) on ovipositional response,
      development, and survival of a common terrestrial detritivore, Megaselia scalaris
      (Diptera: Phoridae), were assessed in the laboratory. Ovipositing females did not
      discriminate between substrates containing 0, 50, 500, or 1000 microg/g,
      indicating a lack of avoidance behavior. Eggs placed on artificial diets
      containing up to 1000 microg/g either did not absorb Cr VI or were unaffected as
      measured by eclosion rates. However, development and survival of larvae were
      significantly reduced at the higher concentrations tested. Concentrations of 500
      microg/g in their food increased larval development times by nearly 65%. At 1000
      microg/g, larval developmental times doubled. The time required from onset to
      completion of pupariation was not significantly different regardless of Cr VI
      concentration. Although males eclosed before females, there was no significant
      difference between the sexes in the time required for adult eclosion. In
      addition, there were no significant differences in the percentage of males and
      females emerging from any of the treatments. At concentrations of 500 or 1000
      microg/g, Cr VI decreased larval survival. Survival was reduced by 44.3% at 500
      microg/g as compared with the controls. There was no additional mortality from
      the onset of the puparial stage to adult eclosion for larvae fed diets containing
      500 microg/g Cr VI. At 1000 microg/g Cr VI, larval survival decreased by 86.6%.
      An additional 7.4% mortality was recorded in the puparial stage, for a decrease
      in total survival (larval plus puparial stages) of 94%. Thus, nearly all of the
      observed mortality occurred during the larval stage rather than the puparial
      stage. The population level implications of lack of avoidance of contaminated
      food and the effects of increased developmental times and reduced survivorship
      are discussed.

PMID- 15195810
TI  - Effect of metal mixtures (Cd and Zn) on body weight in terrestrial isopods.
AB  - The aim of this study was to determine the effect of exposure to cadmium and zinc
      mixtures on the weight of terrestrial isopods. Experiments were conducted using
      uncontaminated specimens of P. laevis. The isopods were exposed to various
      concentrations of cadmium and zinc sulfate in single- and mixed-metal
      experiments. The mean weight of the unexposed isopods in the control group
      increased over the 6 weeks of observation. It was concluded that cadmium and
      zinc, administered separately, had a negative effect on the weight of P. laevis.
      The weight change (gain or loss) of P. laevis in the exposures to mixtures of
      cadmium and zinc sulfate were different from those of woodlice where Cd and Zn
      were administered separately. Combination of the lowest concentrations of Cd and
      Zn (20 and 1000 mg x kg(-1)) produced a stimulating effect compared to the
      control. Weight changes of the other two combinations of Cd and Zn (80/4000 and
      160/8000 mg x kg(-1)) showed no differences from those of the control, and weight
      changes of woodlice exposed to Cd and Zn mixtures were mostly the same as those
      of the control over the 6-week exposure period. It can thus be concluded that
      mixtures of Cd and Zn have an antagonistic effect on each other in terms of
      weight of P. laevis.

PMID- 15195811
TI  - Relations between land use and organochlorine pesticides, PCBs, and semi-volatile
      organic compounds in streambed sediment and fish on the island of Oahu, Hawaii.
AB  - Bed-sediment and/or fish samples were collected from 27 sites around the island
      of Oahu (representing urban, agricultural, mixed, and forested land use) to
      determine the occurrence and distribution of hydrophobic organic compounds
      including organochlorine pesticides, polychlorinated biphenyls (PCBs), and semi
      volatile organic compounds (SVOCs). Of the 28 organochlorine compounds analyzed
      in the fish, 14 were detected during this study. Nineteen of the 31
      organochlorine compounds and 40 of the 65 SVOCs were detected in the sediment.
      Urban sites had the highest number of detections and tended to have the highest
      concentrations of pesticides. Chlordane compounds were the most frequently
      detected constituents at urban sites, followed by dieldrin, polycyclic aromatic
      hydrocarbons (PAHs), and DDT compounds. PAHs were the most frequently detected
      constituents in watersheds with mixed (urban and agricultural) land use. The only
      pesticides detected at agricultural sites were DDT and its degradation products,
      DDD and DDE. No pesticides or PCBs were detected at the forested sites, but a few
      ubiquitous SVOCs were found in sediments at some forested sites. In general,
      concentrations of the most frequently detected pesticides were higher in fish
      than in sediment. Following a trend that has been observed elsewhere in the
      nation, concentrations of most organochlorine pesticides and PCBs are decreasing
      in Hawaii.

PMID- 15195812
TI  - Heavy metal exposure affects the humoral immune response in a free-living small
      songbird, the great tit (Parus major).
AB  - Although many studies have investigated possible effects of heavy metal
      contamination on components of the immune system in captive birds, studies on the
      effects of chronic exposure to heavy metals on the immune system of free-living
      birds are rare. Therefore we studied the effect of heavy metal exposure on the
      humoral immune responsiveness in free-living great tit (Parus major) populations
      from four study sites along a pollution gradient near a metallurgic smelter.
      Although there were no differences in body condition or hematocrit values among
      great tits from the four study sites, the heavy metal exposure appeared to affect
      an individual's humoral immune responsiveness, as measured by antibody titers to
      sheep red blood cells. Great tits from the study site farthest away from the
      smelter complex had a significantly higher immune responsiveness than birds from
      the two areas closest to the metallurgic smelter. Further work is now necessary
      to establish a causal association between heavy metal contamination and
      immunosuppression.

PMID- 15195813
TI  - Occurrence of PCBs, organochlorine insecticides, tris(4-chlorophenyl)methane, and
      tris(4-chlorophenyl)methanol in human breast milk collected from Cambodia.
AB  - The present study determined the concentrations of persistent organochlorines
      (OCs) such as DDT and its metabolites (DDTs), polychlorinated biphenyls (PCBs),
      hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), chlordane
      compounds (CHLs), tris(4-chlorophenyl)methane (TCPMe), and tris(4
      chlorophenyl)methanol (TCPMOH) in human breast milk from Cambodia. DDTs, PCBs,
      HCHs, HCB, CHLs, and TCPMe were detected in almost all the human breast milk
      samples analyzed, and the concentrations ranged from 310 to 11,000, 6.0 to 87,
      <0.12 to 21, <0.12 to 8.1, <0.12 to 5.3, and 2.9 to 70 ng/g lipid wt,
      respectively. TCPMOH was detected in only 10 among 36 samples. Concentrations of
      DDTs in human breast milk from Cambodia were notably higher than those from
      developed countries and comparable to those from other developing countries,
      where usage of DDT for agricultural and public health purposes has been suspected
      to be continuing still, implying the recent usage of DDT in Cambodia. On the
      other hand, concentrations of PCBs, HCHs, HCB, and CHLs in human breast milk from
      Cambodia were 1-2 orders of magnitude less than those from other countries,
      indicating that Cambodia is one of the less contaminated countries by these OCs.
      Significant correlation between concentrations of TCPMe and DDTs in human breast
      milk suggested that exposure to DDT is the source of TCPMe in Cambodian
      residents. Concentrations of OCs in human breast milk tended to decrease with an
      increase in the number of children, implying that the first infant would be
      exposed to higher levels of OCs from breast milk and might be at higher risk by
      these contaminants, especially DDTs in Cambodia. To our knowledge, this is the
      first comprehensive study on the residue levels of OCs in human breast milk from
      Cambodia.

PMID- 15195814
TI  - No effects of hematuria and proteinuria in school days, and probably current
      pregnancy and current lactation also, as risk factors of cadmium-induced renal
      tubular dysfunction among adult women in general populations in Japan.
AB  - This study was initiated to examine if hematuria and proteinuria in school days,
      current pregnancy, or current lactation are risk factors of cadmium-induced
      tubular dysfunction for adult women among general populations in Japan. For this
      purpose, a database of 9,967 never-smoking adult women were reviewed for urinary
      levels of cadmium (Cd) and three other elements, calcium (Ca), magnesium (Mg),
      and zinc (Zn), and two tubular dysfunction markers of alpha1-microglobulin
      (alpha1-MG) and beta2-microglobulin (beta2-MG); the analyte concentrations were
      corrected for creatinine (cr) and expressed as, e.g., Cd-Ucr. From the total, 160
      cases were selected as those who were informed of urinary abnormality (i.e.,
      proteinuria, hematuria, or both) in their school days (the abnormality being
      found to be transient, later), and each case was matched by age and prefecture of
      residence. Separately, seven women with persistent urinary abnormality, seven
      pregnant women, and six lactating women were identified, and the case was matched
      with three cases each of the same age and living in the same prefecture.
      Statistical analyses showed that Cd-Ucr and other markers were not elevated in
      the transient urinary abnormality group as compared with the matched controls.
      This was also observed in the subjects with persistent abnormality. In the
      pregnant women, alpha1-MG-Ucr and possibly beta2-MG-Ucr were elevated, but Cd-Ucr
      did not increase, suggesting that the observed elevation in alpha1-MG and beta2
      MG was not due to the effects of Cd but a part of the physiology of pregnancy
      itself. There was no change in marker levels in lactating women except for an
      increase in alpha1-MG. In overall evaluation, it was considered prudent to
      conclude that urinary abnormality in school days does not increase the risk of Cd
      induced nephrotoxicity in adult women, whereas the negative findings with
      pregnancy and lactation should be taken as preliminary because the numbers of
      cases studied were limited.

PMID- 15195815
TI  - European Lipoprotein Club: report of the 26th ELC Annual Conference, Tutzing, 8
      11 September 2003.

PMID- 15195816
TI  - Air quality status of Visakhapatnam (India)--indices basis.
AB  - Industrial development in Visakhapatnam is conspicuous to urban agglomeration and
      the city is located in a topographical bowl formed by two-hill ranges. A major
      portion of the city is within the bowl area wherein most of the industrial and
      commercial activities are existing and lies within a distance of 10 km from the
      shore of the Bay of Bengal. Due to the peculiar geographic location of city, wind
      movement is either eastern or western and is engulfed within the hill ranges.
      Hence, there is a possibility of buildup of air pollution levels within the city.
      Due to gravity of prevailing situation, air quality status of Visakhapatnam on
      indices basis is analyzed using a non-linear equation for variable parameters
      i.e. Suspended particulate matter (SPM). Sulfur dioxide (SO2) and Oxides of
      nitrogen (NO(x)), which are main criteria pollutants in India. For current
      analysis seasonal air quality data is used, which indicates SPM values in winter
      at most of the sites and in summer at few sites are exceeding the prescribed
      standards. Calculated indices reveal that, in winter as well as in summer, most
      of the locations experienced poor or bad air quality, which is mainly due to
      higher concentration of SPM and certain extent of SO2 values. Application of Oak
      Ridge Air Quality Index (ORAQI) type equations (non-linear) are helpful for air
      quality management plan in the region on long-term basis and it has been also
      observed that there are certain lapses of weightage assignment for individual
      pollutant in application.

PMID- 15195817
TI  - Monitoring for lead pollution using feathers of feral pigeons (Columba livia)
      from Korea.
AB  - We investigated lead exposure conditions using unwashed feathers of feral pigeons
      as a monitor for lead pollution from rural, central urban, and four industrial
      complex areas in Korea with different ambient lead concentrations. Overall, the
      lead levels in the feathers increased when the atmospheric lead levels increased,
      so that the lead levels in the feathers from urban and industrial areas were two
      to four times greater than those in the rural area. However, there are no
      significant differences in the liver lead concentrations between rural and the
      other areas, suggesting that the lead originated from ingestion are not
      differences in locations. A positive correlation was found between the
      concentration of lead in livers and feathers from rural, indicating that the
      feather lead concentrations in this area seem to mainly reflect the internal
      tissue lead through the metabolic process. However, there are no significant
      correlations in the other areas, and we observed a relatively higher lead
      accumulation ratio of feathers to livers. It, therefore, indicates that external
      contamination onto the feather surface may be an important source for lead levels
      in feathers rather than transfer from internal tissue lead.

PMID- 15195818
TI  - Factors causing variations of lead and cadmium accumulation of feral pigeons
      (Columba livia).
AB  - In order to understand the factors causing variation of lead and cadmium
      accumulation in tissues of feral pigeons in Seoul and Ansan, Korea, we
      investigated their age, food items (crop and gizzard contents) as well as
      environmental factors such as soil, atmosphere, and local traffic density. The
      results indicate that concentrations of Pb and Cd were highly increased in the
      order of eggs < chicks < adults. In food analysis, supplementary foods (rice,
      small stones, domestic scraps, cements, hairs, Styrofoam, etc.) could be
      considered as factors considering the Pb concentration differences.
      Concentrations of Cd in foodstuffs, the proportion of crop contents as their
      major foods could have an influence on the difference of Cd levels from a
      nutritional viewpoint. The Pb levels in gizzard contents and soil had an effect
      on the tissue accumulations, these were associated with the volume of vehicular
      traffic. However, we could not find any differences of Cd concentrations in
      gizzard contents and soil, although there were significantly different Cd
      accumulations in target organs of adult pigeons between the study areas. The Pb
      and Cd levels in tissues did not correspond to atmospheric metal levels.

PMID- 15195819
TI  - Evaluation of ecologically relevant bioassays for a lotic system impacted by a
      coal-mine effluent, using Isonychia.
AB  - Many studies investigating the ecotoxicological impacts of industrial effluents
      on fresh-water biota utilize standardized test species such as the daphnids,
      Ceriodaphnia dubia, Daphnia magna, and the fathead minnow, Pimephales promelas.
      Such species may not be the most predictive or ecologically relevant gauges of
      the responses of instream benthic macroinvertebrates to certain stressors, such
      as total dissolved solids. An indigenous species approach should be adopted,
      using a sensitive benthic collector-filterer following development of practical
      laboratory bioassays. In the Leading Creek Watershed (southeast Ohio), an
      aggregated approximately 99% reduction in mean mayfly abundance for all impacted
      sites was observed below a coal-mine effluent with mean specific conductivity
      (SC) of 8,109 (7,750-8,750) microS cm(-1). The mayfly, Isonychia, was exposed for
      7-days to a simulation of this effluent, in lotic microcosms. Based on lowest
      observable adverse effect concentrations, Isonychia survival was a more sensitive
      endpoint to SC (1,562 microS cm(-1)) than were 7-day C. dubia survival and
      fecundity (3,730 microS cm(-1)). Isonychia molting, a potentially more sensitive
      endpoint, was also examined. Using traditional test species to assess discharges
      to surface water alone may not adequately protect benthic macroinvertebrate
      assemblages in systems impaired by discharges high in SC.

PMID- 15195821
TI  - Evaluation of the Operational Street Pollution Model using data from European
      cities.
AB  - This paper presents a sensitivity analysis and an evaluation of the semi
      empirical model known as Operational Street Pollution Model (OSPM). The model is
      capable of calculating airborne concentrations of exhaust gases emitted by
      vehicles, within a street canyon. OSPM has been extensively evaluated using data
      collected over a two year period (1994-1995), during a monitoring campaign
      carried out in Jagtvej, Denmark. Further evaluation of the model was carried out
      using data collected in Gottinger Strasse, Hannover (1994) and Schildhorn
      Strasse, Berlin (1995), both in Germany. In all cases, model runs were carried
      out for carbon monoxide. Two sets of emission factors were used for the two
      street canyons in Germany; namely that available within OSPM and another separate
      set of emission factors derived from data collected in Germany. In the
      calculation of the latter set, the urban driving patterns and variations in the
      vehicle fleet composition according to the engine capacity were assumed
      accordingly. A correlation coefficient of 0.90 between the modelled and measured
      concentrations was obtained for all the cases considered when using the emission
      factors of OSPM. A correlation coefficient of about 0.85 was obtained with the
      newly proposed emission factors when applied to Gottinger and Schildhorn Strasse.

PMID- 15195820
TI  - A preliminary assessment of the Montreal process indicators of air pollution for
      the United States.
AB  - Air pollutants pose a risk to forest health and vitality in the United States.
      Here we present the major findings from a national scale air pollution assessment
      that is part of the United States' 2003 Report on Sustainable Forests. We examine
      trends and the percent forest subjected to specific levels of ozone and wet
      deposition of sulfate, nitrate, and ammonium. Results are reported by Resource
      Planning Act (RPA) reporting region and integrated by forest type using
      multivariate clustering. Estimates of sulfate deposition for forested areas had
      decreasing trends (1994-2000) across RPA regions that were statistically
      significant for North and South RPA regions. Nitrate deposition rates were
      relatively constant for the 1994 to 2000 period, but the South RPA region had a
      statistically decreasing trend. The North and South RPA regions experienced the
      highest ammonium deposition rates and showed slightly decreasing trends. Ozone
      concentrations were highest in portions of the Pacific Coast RPA region and
      relatively high across much of the South RPA region. Both the South and Rocky
      Mountain RPA regions had an increasing trend in ozone exposure. Ozone-induced
      foliar injury to sensitive species was recorded in all regions except for the
      Rocky Mountain region. The multivariate analysis showed that the oak-hickory and
      loblolly-shortleaf pine forest types were generally exposed to more air pollution
      than other forest types, and the redwood, western white pine, and larch forest
      types were generally exposed to less. These findings offer a new approach to
      national air pollution assessments and are intended to help focus research and
      planning initiatives related to air pollution and forest health.

PMID- 15195822
TI  - Estimation of plant diversity at landscape level: a methodological approach
      applied to three Spanish rural areas.
AB  - Approaches linking biodiversity assessment with landscape structure are necessary
      in the framework of sustainable rural development. The present paper describes a
      methodology to estimate plant diversity involving landscape structure as a
      proportional weight associated with different plant communities found in the
      landscape mosaic. The area occupied by a plant community, its patch number or its
      spatial distribution of patches are variables that could be expressed in gamma
      plant diversity of a territory. The methodology applies (1) remote sensing
      information, to identify land cover and land use types; (2) aspect, to
      discriminate composition of plant communities in each land cover type; (3) multi
      scale field techniques, to asses plant diversity; (4) affinity analysis of plant
      community composition, to validate the stratified random sampling design and (5)
      the additive model that partitions gamma diversity into its alpha and beta
      components. The method was applied to three Spanish rural areas and was able to
      record 150-260 species per ha. Species richness, Shannon information index and
      Simpson concentration index were used to measure diversity in each area. The
      estimation using Shannon diversity index and the product of patch number and
      patch interspersion as weighting of plant community diversity was found to be the
      most appropriate method of measuring plant diversity at the landscape level.

PMID- 15195823
TI  - Appropriate preservation of dairy wastewater samples for environmental analysis.
AB  - Thousands of gallons of water are used in dairies to wash cows before milking and
      for cleaning equipment. The wastewater generated contains elevated levels of
      organic matter and pollutants, including nitrogen that once converted, may
      contaminate groundwater with nitrate. This study was conducted to determine the
      amount of sulfuric acid needed to preserve wastewater samples from a New Mexico
      dairy in the southwestern U.S. Titrations of wastewater from a local dairy using
      full strength (18 M) sulfuric acid were performed to determine the amount of acid
      needed to bring the pH of the sample to below two, the recommended pH for sample
      preservation. An average of 0.33 mL of acid was required for every 100 mL of
      wastewater. Due to sample variability, we recommend that 0.4 mL sulfuric acid be
      added for every 100 mL dairy wastewater sample to ensure adequate acidification.
      This quantity is twice the amount currently recommended in U.S. Environmental
      Protection Agency guidelines.

PMID- 15195824
TI  - Analysis of historical salinity and boron surface water monitoring data from the
      San Joaquin River watershed: 1985-2002.
AB  - The objectives of this study were to use both parametric and probabilistic
      approaches to analyze water column concentrations of both salinity (24,845
      measurements) and boron (13,028 measurements) from numerous investigations
      conducted in the San Joaquin River watershed from 1985 to 2002 to assess spatial
      and temporal trends and determine the probability of exceeding regulatory targets
      during both the irrigation and non-irrigation season. Salinity and boron
      concentrations from 26 mainstem and tributary sites were highly correlated based
      on this 17 yr data set. Generally, salinity and boron concentrations were higher
      in winter/spring and lower in summer/fall; higher concentrations of both
      constituents were reported in tributary sites when compared with the mainstem San
      Joaquin River. Approximately half the sites showed showed a negative correlation
      between flow and both constituents. Concentrations of both salinity and boron
      were somewhat variable with flow conditions for the other sites. Both linear and
      curvilinear trends were inconsistent over time. The salinity 90th centiles for
      the 26 sites ranged from 143 to 7,559 micros cm(-1) with the highest 90th
      centiles in tributary sites. Probabilistic analysis of salinity 90th centiles by
      year for five sites with extensive data showed a significant decrease over time
      at two sites and no significant trend for the other three sites. The probability
      of exceeding the salinity targets during either the irrigation (700 microm cm(
      1)) or non-irrigation (1,000 micros cm(-1)) season was greater than 19% for all
      but three sites. The boron 90th centiles for the 26 sites ranged from 0.41 to
      13.6 mg L(-1) with the highest 90th centiles from tributary sites. Probabilistic
      analysis of the boron 90th centile values by year for the five sites with the
      most extensive data showed a significant decrease over time at two sites and no
      significant trend for the other three sites. The probability of exceeding the
      boron target during the irrigation season (0.80 mg L(-1)) and non-irrigation (1.0
      mg L(-1)) season was greater that 18% for all but three sites. Results from this
      analysis have important regulatory implications as targets for both salinity and
      boron are frequently exceeded at various sites in the San Joaquin River
      watershed.

PMID- 15195825
TI  - Biodiversity of Minnesota caddisflies (Insecta: Trichoptera): delineation and
      characterization of regions.
AB  - Despite the value of aquatic insects in aquatic ecosystem biomonitoring, few
      studies within North America have addressed relationships between aquatic insect
      assemblages and landscape-level environmental variables. In this study, over
      300,000 adult caddisfly specimens representing 224 species were collected and
      analyzed from samples of 225 Minnesota aquatic habitats within 58 watersheds.
      Detrended Correspondence Analysis and a UPGMA dendrogram of caddisfly relative
      abundance data determined that five regions of caddisfly biodiversity exist
      within the state. Species richness and diversity were significantly highest in
      the Lake Superior and Northern regions, lowest in the Northwestern and Southern
      regions, and intermediate in the Southeastern region. Canonical Correspondence
      Analysis determined that caddisfly species composition was related to
      temperature, percentage of disturbed habitat, and stream gradient. Although a
      strong correlation between temperature and percentage of disturbed habitat made
      determination of the relative importance of those variables difficult, it is
      likely that anthropogenic disturbance has decreased caddisfly biodiversity in at
      least the Northwestern and Southern regions. Now that regions of biodiversity
      have been established, future changes to the fauna can be evaluated with greater
      precision and confidence. This study represents the most comprehensive faunal
      analysis of an aquatic insect order within the Western Hemisphere.

PMID- 15195826
TI  - Distribution and fractionation of heavy metals in solid waste from selected sites
      in the industrial belt of Delhi, India.
AB  - Solid waste samples were collected from five small-scale industrial sites in the
      National Capital Territory (NCT) of Delhi. These industrial sites represent the
      regional spread of the industrial belt in the NCT of Delhi. Solid waste samples
      were digested using aqua-regia and HF in air tight teflon bombs for the
      quantitative analysis of heavy metals (Hg, Pb, Cd, Mn, Fe, Ni, Cu and Zn) by GBC
      model 902 atomic absorption spectrophotometer. Hg was analysed using hydrid
      generator attachment. Beside this sequential extraction was used to fractionate
      five heavy metals (Pb, Ni, Cd, Cu and Zn) into six operationally defined phases,
      viz. water soluble, exchangeable, carbonate-bound, Fe-Mn oxides, organic-bound
      and residual fractions to ascertain the relative mobility of these metals. The
      result obtained showed metal concentration to be in the range of Hg 0.42-2.3; Pb
      23-530; Cd 014-224; Mn 494-19 964; Fe 35 684-233 119; Ni 192-1534; Cu 3065-10 144
      and Zn 116-23 321 (all units in mg kg(-1)) in all the industrial areas studied.
      The fractionated toxic metals like Pb, Ni and Cd were observed to be in the range
      of 25-35, 15-50 and 40-50%, respectively, in mobile or bio-available fractions of
      solid waste. As this waste is often disposed-off by the roadsides, low lying
      areas, abandoned quarries or in landfill sites which are often not properly
      planned, thus posing potential risk to ground and surface water quality to
      millions of people living downstream.

PMID- 15195827
TI  - Variation of surface ozone in the ambient air of Auckland, New Zealand.
AB  - A study has been performed on the characteristics and behavior of surface ozone
      concentrations at four monitoring sites in Auckland, New Zealand (37 degrees S,
      174.8 degrees E) for a four-year period (October 1997-October 2001). One
      monitoring site (rural) was located upwind of the Auckland urban complex, a
      second downwind (rural-coastal), and a third within the urban area, while the
      fourth was an elevated urban-city site located 250 m up the Sky Tower in the
      central city. In contrast to the high elevation site, the diurnal behaviour of
      ozone at the three low elevation sites followed a typical solar radiation cycle
      with high ozone during the day and low nocturnal values. The effect of NO(x)
      titration was distinct at the urban sites. There was also a seasonal variability
      in the measured ozone levels with high concentrations in spring and a significant
      summer minimum. The observed surface ozone concentrations in Auckland were
      significantly lower than other cities of the world, although a potential for high
      oxidant formation existed. Observed ozone episodes appear to have been either
      generated locally or the precursors transported via the prevailing southwest
      wind. A unique feature of Auckland's air quality is the dilution of polluted city
      air due to the mixing of east-coast air into the clean west-coast circulation
      leading to the overall lower average concentrations in summer. A second feature
      is the potential interaction between sea salt particles and ozone that may
      provide an additional ozone loss mechanism.

PMID- 15195828
TI  - Representativity of a mid-lake surface water chemistry sample.
AB  - A mid-lake sample is the conventional sampling strategy used in lake chemistry
      monitoring programs. Hence, addressing the question of how representative a mid
      lake sample is of in-lake conditions is important for interpreting changes in
      long-term monitoring programs. Our hypotheses were that; (i) the location of a
      sampling site within a lake will affect its representativity and (ii) a mid-lake
      sample could be considered representative of average surface water physico
      chemistry. We focused on the surface water chemistry in 34 Swedish lakes. To
      obtain a wide diversity of lake types, the lakes were classified according to
      mean depth, water residence time, and three main ecoregions. Two sampling seasons
      were selected, representative of high and low biological activity and stratified
      and non-stratified conditions, respectively. Ten samples were collected in each
      lake. The mid-lake samples differed significantly from the nine remaining samples
      in less than 4% of the total number of two-sample t-tests performed. Samples
      collected close to lake inlets differed from the other samples more often than
      samples collected in the central parts of the lakes. We concluded that the
      location of a sampling site within a lake may affect the sample's
      representativity of lake water chemistry, and that a mid-lake surface water
      sample could be considered representative of surface water chemistry.

PMID- 15195829
TI  - The development of biological objectives for streams in a single catchment: a
      case study on the catchment of Western Port Bay, Victoria, Australia.
AB  - Government environment protection policies for waterways have traditionally
      relied on water quality indicators and their objectives. In this paper we
      describe the development of biological objectives based on invertebrate
      indicators for inclusion in a government policy for the catchment of Western Port
      Bay, Victoria. The first step of defining segments (areas with streams in which
      the same objectives are applied) was problematic, requiring two different
      approaches, as follows. Site groups initially based on invertebrate community
      composition derived using multivariate techniques (ordination and classification)
      proved to be unsuitable for policy segments. Segment boundaries were subsequently
      defined using topographical (e.g. boundary of foothills and lowland plains),
      climate (e.g. rainfall) and land-use (e.g. urban) features. We used information
      and data from reference sites inside as well outside the catchment to derive
      specific biological objectives based on aquatic invertebrates for these segments.
      Objectives were specified for the following four indicators--number of
      invertebrate families, the SIGNAL index, the AUSRIVAS predictive model and the
      number of key families.

PMID- 15195830
TI  - Load of heavy metals in the airborne dust particulates of an urban city of
      central India.
AB  - The geographical and temporal distribution patterns of airborne dust particulates
      have been studied in different representative areas of Raipur City. Dust fall
      samples from different sites were collected and some selected toxic metals namely
      Cr, Mn, Fe, Ni, Cu, Zn, Sb and Pb in them were determined by AAS. Total annual
      flux of 11.7, 541.4, 2751.0, 14.2, 9.8, 90.9, 17.6, and 17.7 kg km(-2) y(-1) were
      measured for Cr, Mn, Fe, Ni, Cu, Zn, Sb, and Pb respectively. The occurrence of
      metal concentration were generally in the order industrial > heavy traffic >
      commercial > residential area in Raipur city. The results of analysis show the
      existence of toxic metal concentration in the order Fe > Mn > Zn > Pb
      approximately Sb > Ni > Cr > Cu in Raipur city. These large levels of metal
      pollutants have also been correlated with some meteorological parameters like
      temperature, relative humidity and wind velocity, and strong positive
      correlations have been observed.

PMID- 15195831
TI  - Monitoring ambient sulfur dioxide levels at some residential environments in the
      Greater Cairo urban Region--Egypt.
AB  - The impact of the increased sulfur dioxide emissions within the Greater Cairo
      Urban Region over the part 50 yr has been overwhelming. While previous air
      pollution surveys measuring SO2 levels in the region converged upon the study of
      emissions from specific industrial activities, no correlation between the
      measured concentrations and the induced health-related impacts in living
      environments was provided. As well, no inventory of emissions from other sources
      within some residential areas were accounted for or evaluated. During the study
      period of January to April 2000, the ambient sulfur dioxide levels in four
      residential locations within the capital region were investigated. The results
      indicated that the measured cumulative ambient SO2 concentrations were in excess
      of the national and the international monthly mean exposure limits, irrespective
      of the type of local activity. As well, measurements within three of the selected
      environments surpassed the 0.5 ppm SO2 odor-threshold. The data also showed a
      significant dependency of the measured content upon the physical layout and
      topography of the studied environment as well as with respect to the prevailing
      seasonal weather conditions.

PMID- 15195832
TI  - Comparative toxicological evaluation of untreated and treated tannery effluent
      with Nostoc muscorum L. (algal assay) and microtox bioassay.
AB  - The relative sensitivity of tannery effluent before and after treatment was
      compared by employing Nostoc muscorum and microtox assay in laboratory. The
      effect on chlorophyll, protein and biomass content of Nostoc muscorum was studied
      with the luminescent property inhibition of Photobacterium phosphorium and
      compared with algal bioassay. The results of microtox assay after 5, 15 and 30
      min of exposure were compared with data obtained from algal bioassay. It was
      observed that the luminescent property of Photobacterium phosphorium in microtox
      assay as well as the chlorophyll content of Nostoc muscorum in algal assay were
      the most sensitive parameters in toxicity evaluation of tannery effluent. The
      microtox assay produced notably comparable EC50 values with that of algal
      bioassay. The microtox assay of toxicity showed that EC50 (%) in 30 min was 3.19
      and 63.49 for untreated and treated tannery effluent, respectively while in algal
      bioassay the EC50 for chlorophyll was in between 0-2.5% and 100%, respectively,
      in untreated and treated effluent. More than 60% reduction of toxicity was noted
      in treated tannery effluent in both test system.

PMID- 15195833
TI  - A statistical analysis of particulate data sets for Jawaharlal Nehru Port and
      surrounding harbour region in India.
AB  - The concentrations of total suspended particulate matter (TSP) and particulate
      matter less than 10 microns (PM10) were measured at various locations in a
      Jawaharlal Nehru port and surrounding harbour region. Meteorological data was
      also collected to establish the correlation with air pollutant concentration. The
      results are analysed from the standpoint of monthly and seasonal variations,
      annual trends as well as meteorological effects. The monthly mean concentration
      of TSP was in the range of 88.2 to 199.3 microg m(-3). The maximum and minimum
      recorded value of PM10 was 135.8 and 20.3 microg m(-3), respectively. The annual
      average concentration of PM10 was 66.1 microg m(-3). There are clear associations
      between TSP and PM10 data set at all the measured three sites with a correlation
      coefficient of 0.89, 0.69 and 0.81, respectively. PM10 data appears to be a
      constant fraction of the TSP data throughout the year, indicating common
      influences of meteorology and sources. Particle size analysis showed PM10 to be
      47% of the total TSP concentration, which is lower than reported for industrial
      area and traffic junctions in Mumbai. Anthropogenic sources contribute
      significantly to the PM10 fraction in an industrial region, while contributions
      from natural sources are more in a port and harbour area. Statistical analysis of
      air quality data shows that TSP is strongly correlated with wind speed but weakly
      correlated with temperature. There appears to be a simple inverse relationship
      between TSP and wind speed data, indicating the dilution and transport by winds.

PMID- 15195834
TI  - Size distribution of aerosols (PM10) and lead (Pb) near traffic intersections in
      Mumbai (India).
AB  - The size distribution of aerosols was measured near traffic intersections of
      Marol link road in air quality control region (AQCR1), which is a moderately
      industrial area and Dadar Khodad circle in AQCR2, which is a heavily commercial
      core of the Mumbai City. The reason behind selecting the two unidentical regions
      was to study the contribution from vehicles to the size separated PM10 and that
      of Pb. It is recognised that particulates in urban air are responsible for
      serious health effects. As very small particles are assumed to be important for
      the adverse health effects, the particle size distribution is thus an important
      factor that needs to be addressed whenever the particulates pollution is
      concerned. The size measurements were done with a cascade impactor of eight
      stages with a back-up filter. It effectively separates the particulate matter
      into nine-sizes ranging from 0.0-0.4 to 9.0-10.0 microm. Samples were analysed in
      nine-particle size fractions with special reference to a toxic metal - lead (Pb)
      by atomic absorption spectrophotometry (AAS). It was found that PM10 and Pb at
      both the intersections could easily be classified by the size distribution. The
      fractions of the PM10 and that of Pb showing a tendency of trimodal distributions
      with the first peak at coarse mode approximately 9.0-10.0 microm, second at
      approximately 5.8 microm and the third at coarse mode approximately1.1 microm.
      The significant percentage of Pb was found in the range below 2.5 microm at both
      the intersections. However, Pb in AQCR1 is found in the coarser range as well,
      which could probably be the influence of various industrial activities in the
      area. PM10 concentration values in the coarser range in AQCR2 are associated with
      the resuspension of dust particles and mechanical erosions.

PMID- 15195835
TI  - [Basedow disease].

PMID- 15195836
TI  - [Pharmacological basis of antihypertensive drug therapy].
AB  - In order to lower arterial blood pressure, antihypertensive drugs decrease
      cardiac output, total peripheral resistance or both. Diuretics, beta-blockers,
      and central adrenergic inhibitors decrease cardiac output. ACE inhibitors,
      angiotensin II antagonists, calcium antagonists, alpha-blockers, central
      adrenergic inhibitors, and after a delay also diuretics and beta-blockers
      decrease peripheral resistance. Diuretics are first line therapy for treating low
      renin hypertension. Beta blockers are used for treating high renin hypertension
      and patients suffering additional coronary artery disease. ACE inihibitors can be
      given for treating high renin hypertension particularly in conjunction with
      diabetes, heart failure or left ventricular hypertrophy. Combining ACE inhibitors
      with diuretics potentiates the antihypertensive effect. Angiotensin II
      antagonists exert fewer side effects and better renal protection than ACE
      inhibitors. The main indication for calcium antagonists is low renin
      hypertension, their advantages being strong blood pressure reduction as well as
      in preventing stroke. Central alpha2 receptor agonists and other vasodilators are
      chosen only in selected cases and mostly in combination with other
      antihypertensive drugs.

PMID- 15195837
TI  - [Forgotten metabolic side effects of diuretics: lipids, glucose and vitamin B1
      (thiamin) metabolism].
AB  - Diuretics could lead to an impairment of lipid and glucose metabolism. These
      potentially adverse effects of the diuretics could be compensated by non
      pharmacological strategies such as weight loss or physical activity. Diuretics
      lead to an increased urinary loss of vitamin B1 (thiamine), a diuretic side
      effect which is often forgotten. In the setting of a high vitamin B1 intake the
      increased urinary excretion is of no pathophysiologic relevance. However, in the
      setting of low or suboptimal dietary intakes of thiamine the insufficient
      thiamine nutriture may be of importance. Vitamin B1 plays an important role in
      energy metabolism, especially also at the level of the heart muscle. Wet beri
      beri is the characteristic vitamin B1 deficiency disease, which is besides others
      also characterized by heart failure. Evidence suggests that heart failure can be
      improved by the additional administration of Vitamin B1. Older individuals under
      a chronic diuretic therapy should obtain an oral vitamin B1 supplementation.

PMID- 15195838
TI  - [Combination therapy versus monotherapy: which strategy is better?].
AB  - In patients without target organ damage, a pharmacological antihypertensive
      therapy can be initiated with a monotherapy or a low dose combination therapy. A
      monotherapy often suffices to control blood pressure in patients with mild
      hypertension (140-159 mmHg systolic or 90-99 mmHg diastolic). In order to select
      the blood pressure-lowering drug that is best suited for an individual,
      monotherapies should be sequentially rotated, because it cannot be predicted to
      which drug a patient will best respond. Early initiation of a combination therapy
      is a good alternative. Theoretically, almost any of the six commonly used groups
      of antihypertensive drugs (ACE-Inihibitors, Angiotensin II-Receptor Antagonists,
      Beta-blockers, Calcium antagonists, Diuretics and Alpha blockers) can be combined
      with each other. However, combinations of Thiazid diuretics with inhibitors of
      the Renin-Angiotensin-Aldosteron-System (Beta blockers, ACE-Inhibitors,
      Angiotensin II-Receptor blockers) have proven most useful.

PMID- 15195839
TI  - [Antihypertensives--which adverse drug reactions are clinically relevant?].
AB  - All currently available antihypertensive drugs can cause adverse drug reactions.
      Potential adverse drug reactions should already be taken into account when a new
      antihypertensive regimen is started. It is furthermore important to ask at follow
      up visits specifically about common adverse reactions. The aims of this article
      are therefore to shortly summarise common and typical adverse drug reactions of
      antihypertensives. All antihypertensives may cause dizziness, hypotension,
      allergies, rashes, gastrointestinal complaints and dry mouth. Thiazide diuretics
      furthermore may cause electrolyte disturbances, dehydration and hyperuricemia,
      betablockers may cause bronchospasm, bradycardia, cold extremities and sleep
      disturbances and calcium antagonists may cause flushing, ankle oedema and
      gingival hyperplasia. Concerning potential lethal adverse drug reactions, it is
      important to know that ACE inhibitors and angiotensin receptor antagonists are
      contraindicated in all patients with a history of angioedema. However,
      angiotensin receptor antagonists are well-suited alternatives for patients with
      ACE inhibitor-induced cough or hypogeusia. Rare adverse drug reactions are
      commonly recognised only after drug approval based on spontaneous reporting. This
      demonstrates the importance of considering medications as potential causes of new
      complaints and symptoms and to reports such suspected adverse drug reactions to
      the national pharmacovigilance centres. Only the local or international
      accumulation of comparable spontaneous reports allows the drug regulation
      agencies to recognise new and unexpected adverse drug reactions early and to
      initiate appropriate measures.

PMID- 15195840
TI  - [Healthier thanks to soy products?].

PMID- 15195841
TI  - [Handling exotic animals--an underestimated health risk]].

PMID- 15195842
TI  - [Spectacle of insanity. William Hogarth (1697-1764), The Asylum].

PMID- 15195843
TI  - Computerized control of the procedure for detecting and removing airborne
      particles in operating rooms.
AB  - Surgical-site infections are still a major problem in modern medicine. Normal
      skin fora of patients or healthcare workers causes more than half of all
      infections following clean surgery, but the importance of airborne particles in
      this setting remains controversial. The use of ultraclean air in operating rooms
      has been shown to reduce infection rates significantly. High efficiency
      particlulate air (HEPA) filters are used in some modern operating rooms. Although
      the uses of HEPA filters, the air quality should be controlled by another device
      to make safe the air in operating rooms and intensive care units. In this study,
      a computerized system was established to control the cleanliness of the air by
      measuring the presence of airborne particles of varying sizes and numbers in
      operating rooms. When the maximum values are exceeded, the system warns the
      authorized people by phone, sound, or displays.

PMID- 15195844
TI  - The examination of the effects of obesity on a number of arteries and body mass
      index by using expert systems.
AB  - In this study, the areas affected from obesity were examined by classifying
      divergent arteries and body mass index (BMI) of 30 healthy persons and 52 obese
      persons by using expert systems, and the classifying performances of NEFCLASS and
      CANFIS, which are expert systems were compared. As a result of this comparison,
      it is observed that the classifying performance of NEFCLASS is better than that
      of CANFIS, and the causes of this are examined. Furthermore, it is observed that
      after these classifications, obesity affects the BMI rather than divergent
      arteries.

PMID- 15195845
TI  - Testing the usability of two automated home-based patient-management systems.
AB  - To explore to what extent observation and semistructured in-depth interviews
      provide effective tools for usability testing of two automated home-based systems
      aimed at monitoring patients' health status at home and improving self-care.
      Telephone-Linked Care for Diet Adherence in Dyslipidemia (TLC-DietAid) used
      computer telephony to interact with users and Home Asthma Telemonitoring System
      (HAT System) used a combination of Personal Digital Assistant (palmtops) and the
      Internet for similar purposes. Both systems were evaluated in two separate pilot
      studies. Our pilot studies uncovered "medium-specific" and "content-specific"
      issues that addressed either the process of the interaction or its content. The
      results demonstrated that patient-users tended to evaluate each system on the
      basis of how it fit into everyday life and corresponded to personal preferences.
      The methodology also allowed the system designers to understand users' concerns
      and the context of adoption in order to introduce necessary changes to the design
      to address such concerns.

PMID- 15195846
TI  - Using data envelopment analysis to measure the technical efficiency of public
      health centers in Kenya.
AB  - Data Envelopment Analysis has been widely used to analyze the efficiency of
      health sector in developed countries, since 1978, while in Africa, only a few
      studies have attempted to apply DEA in the health organizations. In this paper we
      measure technical efficiency of public health centers in Kenya. Our finding
      suggests that 44% of public health centers are inefficient. Therefore, the
      objectives of this study are: to determine the degree of technical efficiency of
      individual primary health care facilities in Kenya; to recommend the performance
      targets for inefficient facilities; to estimate the magnitudes of excess inputs;
      and to recommend what should be done with those excess inputs. The authors
      believe that this kind of studies should be undertaken in the other countries in
      the World Health Organization (WHO) African Region with a view to empowering
      Ministries of Health to play their stewardship role more effectively.

PMID- 15195847
TI  - A neurofuzzy classification system for the effects of diabetes mellitus on
      ophtalmic artery.
AB  - Here, we present a classification system for the effects of diabetes mellitus
      (DM) on blood flow hemodynamics of the ophthalmic arteries by using neurofuzzy
      system. Blood flow hemodynamics were obtained from 80 ophthalmic arteries of 20
      healthy persons and 20 patients with DM by using 7.5 MHz transducer and Doppler-M
      unit. Peak systole, peak diastole, resistive index (RI), pulsatile index (PI),
      and systole/diastole rate (SDR) were measured with the use of Doppler sonography.
      These values were applied to neurofuzzy system using NEFCLASS model. The
      performance of this classification system was examined with the application of
      the data obtained from Doppler analyses of the right and left ophthalmic arteries
      to the neurofuzzy system. After learning and testing processes, 85% success rates
      were reached from the data of right ophthalmic arteries, and 87.5% success rates
      were reached from the data of left ophthalmic arteries. Our findings suggest that
      neurofuzzy system may provide a successful classification system for the effects
      of DM on either right or left ophthalmic arteries with the application of Doppler
      signal parameters from carotid arteries to neurofuzzy system may produce a new
      and reliable classification system for diagnosing diameter stenosis.

PMID- 15195848
TI  - Portable stimulator design aimed at differentiating facial nerves from normal
      tissues.
AB  - Facial nerves are very prone to risk of being cut away in the facial surgeries.
      In order to differentiate the normal tissues from the nerves during the
      surgeries, facial stimulator is very essential. These stimulators are
      particularly useful in triggering action potentials in the facial muscle tissue.
      In the case of any damage to these nerves, paralysis is unavoidable. Second use
      of the stimulator would be to diagnose how severe the facial problems are. Third
      use, which is a noninvasive application, is the employment of facial stimulator
      to treat and diagnose facial problems that arose from temperature differences,
      cuts or strain. The stimulation is achieved through DC voltage pulses that
      conform to user-specified amplitude, pulse duration and pulse intervals. These
      variables are set according to the age, sex, and physiological conditions of the
      patient. Peripheral Interface Controller is used to derive different pulse
      patterns. The current specifications of our stimulator are a range of 0.1-20 V
      pulse amplitude, 0.1-2 msec pulse duration, and 0.05-1 sec pulse interval. The
      main benefits of our stimulator are its graphic display that shows the form of
      pulse, its compact size, and operation on a battery power supply and adaptability
      to convert to other stimulation applications.

PMID- 15195849
TI  - America's digital divide: 2000-2003 trends.
AB  - Computer ownership and literacy, along with Internet access and its many
      applications, has become, for many, a trademark for the Americans' lifestyle.
      Research shows that computer ownership and literacy, along with Internet access
      and expertise, is rapidly changing how Americans go about their business. The
      technological industry is providing many opportunities for Americans to operate
      in markets, global and local, not previously available. These changes are
      apparent across all U.S. sociocultural and geographic boundaries. Yet, upon close
      analysis, there are individuals and communities less connected with many
      completely excluded from participation. Those individuals exist below a line
      called the Digital Divide. Growth in computer ownership and Internet use, while
      offering optimism that the Digital Divide is narrowing, also illustrates that,
      without focused intervention will for certain populations, continue. Public and
      private programs, focus groups, and pocks of community activism, each hope to
      correct the disparities among on- and-off line Americans. On many fronts, there
      is evidence that progress is being made by many. Income, race, age, and
      geographic location are often the determining factors.

PMID- 15195851
TI  - The people, the professionals and the government--when can we play our roles
      effectively?

PMID- 15195850
TI  - A systems framework for evaluating nursing care quality in nursing homes.
AB  - Given the ongoing concerns about the quality of care in nursing homes, a
      theoretical framework to guide a systems approach to quality is important.
      Existing frameworks either do not model causality, or do so in a linear fashion
      in which the actual linkages between components of quality may not be well
      specified. Through a review of frameworks for nursing home quality, and empirical
      studies on the subject, the authors construct a framework for nursing home
      quality that links contextual components of quality with structure, structure
      with process, and process with outcomes, focusing on nursing care quality.
      Intrastructural relationships and feedback mechanisms are also modeled. The
      framework is matched with a discussion of multilevel structural equation analysis
      for statistical application. Future research should expand the framework to
      include non-nursing components of quality.

PMID- 15195852
TI  - Upper aero-digestive tract cancer--descriptive analysis of eight years study in
      north east India.
AB  - Medical reports of eight years study of upper aero-digestive tract cancer were
      retrospectively evaluated. The patients were classified according to their age,
      sex, primary tumour localisation and tumoural stage. There were 53.06% males and
      46.94% females, with male to female ratio of 1.13:1. The peak incidence for all
      primary tumour localisations were observed in the sixth decade of life. Most
      common primary tumour localisation site was in the oesophagus (30.41%) followed
      by oropharyngeal cancer (25.91%) and laryngopharyngeal cancer (19.21%). Of all
      the patients, only 13.79% cases presented at the early stage of the disease and
      the rest 86.21% presented in the late stage of the disease. The proportion of
      patients presenting with metastatic nodes was 85.31%.

PMID- 15195853
TI  - Maternal mortality--a ten-year study.
AB  - Maternal deaths in Kasturba Hospital, during the 10-year period from January 1989
      to December 1998 were studied. A total of 419 deaths were recorded among 1,12,133
      deliveries, with an average maternal mortality rate of 360. The year wise
      maternal mortality rate showed an almost consistent decline from 468 to 190 over
      the decade. Almost all the deaths (95%) occurred among unbooked gravidas.
      Indirect causes claimed 62.5% lives while 33.8% were due to direct obstetric
      causes and 15 (3.6%) deaths were due to coincidental causes. Severe anaemia was
      the largest killer, causing 31% of total deaths. Majority (65.6%) of deaths
      occurred in the postnatal period. Most of the deaths could have been prevented by
      better community participation, antenatal care, iron-folate prophylaxis and
      timely medical care.

PMID- 15195854
TI  - A clinical description of rifampicin-induced acute renal failure in 170
      consecutive cases.
AB  - Rifampicin re-administration may cause immunologically mediated acute tubulo
      interstitial injury. Retrospectively, 170 consecutive cases with acute renal
      failure (ARF) following re-treatment with rifampicin (71% males, 29% females, age
      21 to 68 years) were analysed, which accounted for 12% of all ARF patients
      treated by two large dialysis referral centres in Romania, Timisoara and Iasi,
      between 1974-2001 and 1988-2001, respectively. The most frequent clinical
      features of rifampicin-induced ARF were: Anuria, gastro-intestinal (abdominal
      pain, nausea, vomiting and diarrhoea) and "flu-like" symptoms. Urine analysis
      revealed sterile leucocyturia in 54%, proteinuria in 31%, haematuria in 26% and
      haemoglobinuria in 7% of cases. Haemolytic anaemia was frequent, found in 66% of
      the patients; half of these had Hct values of < 30%, thrombocytopenia and also
      more severe renal damage (a longer anuric phase and a slower recovery of the
      renal function), thus suggesting a severe multi-target autoimmune aggression. The
      association of hepatic injury--not explained by prior hepatic disease, B or C
      hepatitis virus infection or history of alcohol abuse--was encountered in 17% of
      the cases, without a significant influence on the renal and the general outcome.
      The outcome of rifampicin-induced ARF is generally favourable, with complete
      recovery of the renal function within 30 days in 52% of the cases and within 90
      days in 92% of the cases. The mortality rate was 3.5%, compared to 21% for the
      overall ARF population treated during the same period (p < 0.05).

PMID- 15195855
TI  - Bioequivalence study of rabeprazole sodium on healthy human volunteers.
AB  - The newly developed proton pump inhibitor rabeprazole sodium is expected to have
      beneficial effects in the treatment of peptic ulcer. The pharmacokinetic
      parameters (C(max), AUC(o-t), t(max)) of this drug have been evaluated to compare
      the single dose (20 mg) bioavailability of rabeprazole sodium with the standard
      reference. High performance liquid chromatography (HPLC) coupled with UV detector
      set at 280 nm has been used to determine plasma concentration of 12 human
      volunteers as per Drugs Controller General of India (DCGI) guidelines. The method
      has been validated over a linear range of 20-480 ng/ml from plasma. The minimum
      quantifiable concentration was set at 10 ng/ml [co-efficient of variance (CV) <
      10%]. By comparing AUC(o-t) the relative bioavailability of test preparation has
      been found to be 100.88% of that of reference preparation.

PMID- 15195856
TI  - Reappraisal of abdominal tuberculosis.
AB  - Tuberculosis, including abdominal tuberculosis, is a common disease responsible
      for considerable mortality and morbidity. The diagnosis of abdominal tuberculosis
      requires a high index of suspicion due to its vague symptomatology. This
      retrospective study (of 3 years duration) was conducted on 84 operated cases in
      whom a diagnosis of abdominal tuberculosis (excluding genito-urinary) was made on
      histopathology. These constituted 5.4% of all the surgical material related to
      gastro-intestinal tract. The mean age of the patient was 23.5 years, with the
      youngest patient being only 7 months old. No sex predilection was noted (41
      males, 43 females). Eighteen patients (21.4%) belonged to the paediatric age
      group (0-15 years). Majority of patients (92.8%) presented with features of
      intestinal obstruction. Sixteen patients were already receiving anti-tuberculous
      treatment. Terminal ileum (49 cases) was the most common site of involvement
      followed by appendix (9), jejunum (5), anal canal (4), caecum (3) and colon (2).
      One case of duodenal tuberculosis was also confirmed. The important features
      noted in this study were high paediatric patient involvement (21.4%),
      significantly higher incidence of intestinal perforation (69%) and rarity of
      gastroduodenal tuberculosis (1.2%). Concomitant infections like typhoid and worm
      infestations were also seen.

PMID- 15195857
TI  - Psychosomatic illnesses in patients attending the medical outpatient department
      in a government hospital.
AB  - The incidence of psychosomatic illness among Indian patients has been found to be
      high. Owing to the stigma attached to psychiatric illnesses, most patients remain
      reluctant to visit a psychiatrist. The result is an overcrowding in the medicine
      and other specialist departments. A psychiatry department with consultation
      liaison psychiatric service in each government hospital is the need of the day.

PMID- 15195858
TI  - Atypical presentation of a primary iris cyst.
AB  - Iris cysts are rare clinical occurrences. They are more commonly seen secondary
      to trauma, medications, or parasitic infestations; or may herald the onset of an
      intra-ocular malignancy. Primary iris cysts without any clinically detectable
      aetiology are rare ophthalmic curiosities. The cyst presented here is atypical in
      its size, shape and location.

PMID- 15195859
TI  - Squamous cell carcinoma in untreated psoriasis: a case report.
AB  - Skin cancer developing after treatment for psoriasis is seen more often than
      expected, however, there has been no report of cutaneous squamous cell carcinoma
      developing in a case of untreated psoriasis. Here, a case has been reported where
      an untreated psoriasis lesion progressed on to develop squamous cell carcinoma,
      with a brief review of literature.

PMID- 15195860
TI  - Hypothyroidism presenting as Hoffman's syndrome.
AB  - Muscle weakness, stiffness and delayed tendon jerk relaxation are usual features
      of hypothyroidism while muscle hypertrophy, myoedema and wasting are occasionally
      seen. A 60-year-old male, who presented with proximal muscle weakness and muscle
      hypertrophy has been reported here. Thyroid function tests, electromyogram and
      muscle biopsy established the diagnosis of thyroid myopathy with Hoffman's
      syndrome.

PMID- 15195861
TI  - Leiomyomatosis peritonealis disseminata--a rare case report.
AB  - An infertile female aged 34 years was admitted with an abdominopelvic lump of 16
      weeks size. On laparotomy innumerable nodular seedlings, in addition to uterine
      fibroid, simulating disseminated intra-abdominal malignancy were found.
      Histopathology of removed specimen of uterus and omentum revealed leiomyomatosis
      peritonealis disseminata.

PMID- 15195862
TI  - A case of chronic chest wall sinus.
AB  - A 17-year-old Muslim female presented with a swelling over the chest wall
      underneath her left breast. The swelling was aspirated and the cytology report of
      the aspirated material showed it to be of pyogenic origin. An incision and
      drainage was done, after which the patient presented with a non-healing
      discharging sinus at the same site. The exact nature of the disease was known
      only after excising the sinus tract with the affected rib.

PMID- 15195863
TI  - Stem cell transplants in ocular surface disorders.

PMID- 15195865
TI  - Children are not beneficiaries of our Revised National Tuberculosis Control
      Programme [corrected].

PMID- 15195864
TI  - Pain--the enigmatic entity.

PMID- 15195866
TI  - December, 2003 issue of JIMA.

PMID- 15195867
TI  - Comparative evaluation of the efficacy, safety, and tolerability of rosuvastatin
      10 mg with atorvastatin 10 mg in adult patients with hypercholesterolaemia: the
      first Indian study.
AB  - To compare the efficacy, safety and tolerability of rosuvastatin 10mg with
      atorvastatin 10 mg in adult Indian patients with hypercholesterolaemia, a
      prospective, open-label, comparative, phase III study was conducted. A total of
      45 patients of either sex, between 18 and 80 years of age with
      hypercholesterolaemia, having LDL cholesterol (LDL-C) of 160 and < 250 mg/dl and
      triglyceride < 400 mg/dl, were included in this trial. After a dietary run-in
      period of 2 weeks, patients received either rosuvastatin 10 mg once daily or
      atorvastatin 10 mg once daily, for 6 weeks. The fall in the mean LDL-C levels
      after 6 weeks of treatment in rosuvastatin group (40.1%) was significantly more
      as compared to the fall in atorvastatin group (29.8%). Other secondary lipid
      parameters like total cholesterol (TC), HDL cholesterol (HDL-C), triglycerides,
      apo-B, apo-AI, and TC/HDL-C ratio also showed more beneficial changes from the
      baseline in rosuvastatin group than in atorvastatin group. Rosuvastatin 10 mg
      shows significantly better efficacy than atorvastatin 10 mg in reducing LDL-C
      levels and produces greater improvements in other elements of the lipid profile.

PMID- 15195868
TI  - 'First reports': the importance of being certain.

PMID- 15195869
TI  - Spontaneous atticotomy.

PMID- 15195870
TI  - A possible case of two Onodi cells in a single patient.

PMID- 15195871
TI  - Rheumatoid nodules and reflux disease.

PMID- 15195872
TI  - Nasopalatine duct cyst.

PMID- 15195873
TI  - History and ENG findings in a patient with fibrous dysplasia of the skull base.

PMID- 15195874
TI  - Embryonal rhabdomyosarcoma of the ear.

PMID- 15195875
TI  - Incompetent lower esophageal sphincter.

PMID- 15195876
TI  - Monthly charge analysis.

PMID- 15195877
TI  - Paramedian forehead flap for the reconstruction of large nasal defects.

PMID- 15195878
TI  - Torus mandibularis: an unusual cause of obstructive sleep apnea.

PMID- 15195879
TI  - Actinomycosis of the temporal bone: a report of a case.
AB  - Actinomycosis is a chronic suppurative infection of the cervicofacial region
      caused by Actinomyces species, which are anaerobic, gram-positive filamentous
      bacteria. Although actinomycosis has a propensity for involving the oral cavity,
      rare cases of actinomycosis involving the temporal bone have been published. We
      report the case of a 14-year-old girl who presented with clinical, audiometric,
      and radiologic findings consistent with right chronic suppurative otitis media
      that persisted despite tympanomastoidectomy. Findings on histologic evaluation of
      a specimen obtained during revision surgery were consistent with a diagnosis of
      actinomycosis. Although actinomycosis of the temporal bone is rare, it should be
      considered in the differential diagnosis of chronic suppurative temporal bone
      infections that are resistant to standard therapy.

PMID- 15195880
TI  - Isolated nasopharyngeal aspergillosis caused by A flavus and associated with
      oxalosis.
AB  - We report a case of isolated nasopharyngeal aspergillosis in a 52-year-old woman
      with Hashimoto's thyroiditis. We found the nasopharyngeal lesion incidentally
      while evaluating bilateral cervical lymphadenopathy, which we had discovered
      during a routine follow-up examination pursuant to the patient's thyroid problem.
      Biopsy analysis of the nasopharyngeal lesion revealed the presence of a mycelium
      made up of septate hyphae and associated oxalosis. Mycologic examination
      confirmed that Aspergillus flavus was the responsible pathogen. No systemic
      involvement or involvement of other head and neck sites was found. The patient
      had been exposed to a considerable amount of dust during the construction of her
      house, and this may have been the precipitating factor in the development of her
      infection. We treated the patient with a 4-week course of itraconazole. At the
      end of therapy, she exhibited no evidence of A flavus on physical and mycologic
      examinations.

PMID- 15195881
TI  - Laryngomalacia: an atypical case and review of the literature.
AB  - Laryngomalacia is the most common cause of stridor in newborns and infants.
      Patients usually present with an inspiratory stridor only, although some exhibit
      other anomalies. To rule out other possible pathologies, bronchoscopy is
      advisable. However, the authors of some recent studies have advocated the use of
      fiberoptic laryngoscopy as a more cost-effective and less-invasive alternative.
      No surgical intervention is required to treat laryngomalacia in most cases. The
      disease usually resolves spontaneously by the time a patient reaches the age of
      24 months. In this article, we describe a case of laryngomalacia that was
      atypical in that the patient was 10 years old. We also review the literature in
      an effort to increase awareness of this condition.

PMID- 15195882
TI  - Langerhans' cell histiocytosis: current trends and the role of the head and neck
      surgeon.
AB  - Langerhans' cell histiocytosis (LCH)--once called histiocytosis X--is a complex
      reticuloendothelial disease that often involves the head and neck. We discuss the
      current nomenclature of this disease and review its pathologic and clinical
      characteristics, with particular emphasis on the role of the head and neck
      surgeon. LCH can be challenging to diagnose, and the otolaryngologist must be
      familiar with its varied presentations. Because LCH usually responds well to
      medical therapy and extensive resection can easily cause more morbidity than the
      disease itself, a minimalist approach to treatment usually provides the best
      outcome. We also discuss the case of a 9-month-old girl with LCH who presented
      with aggressive head and neck disease.

PMID- 15195883
TI  - Simultaneous nonparotid cranial mucosa-associated lymphoid tissue lymphoma and
      common variable immunodeficiency.
AB  - Common variable immunodeficiency (CVID) is a condition characterized by low
      levels of immunoglobulin (Ig) G and either IgA or IgM in the presence of
      recurrent infections. This disorder is associated with an increased risk of
      malignancy. Mucosa-associated lymphoid tissue (MALT) lymphoma is a recently
      recognized form of non-Hodgkin's lymphoma that is not often present in the head.
      MALT lymphoma in patients with CVID is rare, and until now, it has not been
      reported in a cranial location outside of the parotid gland. We report the cases
      of 2 patients who had CVID and cranial MALT lymphoma outside of the parotid
      gland, and we describe their successful treatment with chemotherapy.

PMID- 15195884
TI  - Metastatic seminoma with cervical lymphadenopathy as the initial manifestation.
AB  - Advanced testicular germ cell tumors commonly involve cervical lymph nodes. In
      most circumstances, the diagnosis of germ cell tumor is established before the
      neck disease is noted. In rare cases, these tumors have been found along with
      cervical lymphadenopathy in patients with a previously undiagnosed primary tumor.
      In this article, we report the unusual case of a 71-year-old man whose metastatic
      seminoma initially manifested as an asymptomatic neck mass. This finding
      reinforces the need to include metastatic disease in the differential diagnosis
      of neck masses. Our discussion of this case focuses on the appropriate management
      of cervical metastases of germ cell tumors.

PMID- 15195885
TI  - A case of giant sialolith of the submandibular salivary gland.
AB  - Sialolithiasis is the most common disease of the salivary glands. This report
      describes the case of a patient who had an unusually large submandibular gland
      sialolith that was completely encased in the glandular substance. The author
      describes the management of this patient and reviews the literature.

PMID- 15195886
TI  - Helpful article.

PMID- 15195887
TI  - Systemic treatment of oesophageal cancer.
AB  - Most patients with oesophageal cancer present with locally advanced or metastatic
      disease. In an effort to improve the results of surgery in patients with operable
      disease, strategies to incorporate radiotherapy and chemotherapy, preoperatively
      (neoadjuvant) and postoperatively (adjuvant), have been extensively investigated
      in numerous clinical trials. Meta-analyses of neoadjuvant trials did not
      demonstrate a survival advantage for neoadjuvant chemotherapy or concurrent
      chemoradiotherapy. Although local control seems to be improved with neoadjuvant
      treatment, the currently used chemotherapeutic agents are simply not effective
      enough to eradicate micro-metastatic disease. Patients who undergo neoadjuvant
      treatment and achieve a histologically confirmed complete response have a
      significant better survival than those who do not achieve such a response.
      Although neoadjuvant chemoradiotherapy is able to induce a higher rate of
      complete pathological responses compared to neoadjuvant chemotherapy (25-30% vs 5
      15%), this advantage is counteracted by a higher incidence of operative
      mortality. In patients with metastatic disease there is no evidence that
      chemotherapy (cisplatin, 5-fluorouracil and anthracyclins) improves survival.
      Several new agents such as taxanes, irinotecan and vinorelbine in combination
      with cisplatin and carboplatin have shown promising activity in neoadjuvant
      settings and as palliative treatment of metastatic oesophageal cancer. However,
      the benefit of these new drugs in the treatment of oesophageal cancer has to be
      confirmed in randomized trials.

PMID- 15195888
TI  - Systemic treatment of gastric cancer.
AB  - Gastric cancer is one of the commonest cancers worldwide and is associated with a
      poor prognosis. Surgery remains the only potentially curative treatment, but is
      associated with a high rate of locoregional recurrence. Hence, there is ongoing
      debate regarding both the extent of lymph node dissection and the role of
      perioperative chemotherapy or chemoradiation for localized disease. Untreated
      metastatic gastric cancer is associated with a median survival of only 3-4
      months, but this can be increased to 8-10 months, associated with improved
      quality of life, with combination chemotherapy. Currently, no standard
      combination chemotherapy regimen exists, although regimens utilizing both
      cisplatin and 5-fluorouracil, such as epirubicin/cisplatin/fluorouracil (ECF),
      are amongst the most active. Newer chemotherapeutic agents, including irinotecan,
      oxaliplatin and taxanes, show promising activity, and are currently being tested
      in phase III trials.

PMID- 15195889
TI  - Systemic treatment of pancreatic cancer.
AB  - Patients with pancreatic cancer have a poor prognosis although systemic treatment
      has slightly improved the outcome for those with advanced pancreatic cancer, The
      approach to a patient with pancreatic cancer remains a great challenge. Patients
      often present with advanced disease and many are already in poor general
      condition at the time of diagnosis. Today, surgery remains the only curative
      therapeutic option. A small number of pancreatic adenocarcinomas, however, are
      resectable and relapses after surgery are very frequent. The reference treatment
      in patients with metastatic pancreatic cancer is gemcitabine. The median survival
      of patients with advanced pancreatic cancer who are treated with gemcitabine is
      approximately 6 months and only approximately 20% of patients will be alive at 1
      year. Combinations of gemcitabine with new cytotoxic agents and with novel
      targeted agents hold the promise for improving the outcome. Randomized phase III
      studies are, however, still ongoing. Since most patients will relapse after
      complete surgical resection of pancreatic cancer, a search for a better adjuvant
      or neoadjuvant treatment is important. Although several randomized studies have
      suggested an improved outcome for a postoperative chemoradiotherapy or
      chemotherapy, the role of an adjuvant treatment remains today controversial.
      Randomized phase III studies are ongoing. A neoadjuvant strategy might therefore
      also play a role, but phase III studies are lacking. The systematic evaluation of
      new drugs in well designed clinical trials and the search for new molecular
      targets for treatment are crucial in our aim to improve the outcome for patients
      with pancreatic cancer.

PMID- 15195890
TI  - Systemic treatment of hepatocellular carcinoma.
AB  - The results of systemic treatments for hepatocellular carcinoma are currently
      disappointing. In patients with advanced disease, none of the tested treatments
      (particularly systemic chemotherapy or hormonal treatment, such as tamoxifen)
      demonstrated an unequivocal benefit in terms of survival, and the trials
      including the largest numbers of patients have constantly been negative. After
      successful treatment of a first tumour, the most promising adjuvant strategy
      seems to be the use of interferon to treat patients who have hepatitis C
      infection. Nevertheless, only a few small randomized controlled trials have been
      performed and this result should be confirmed. Methodological improvement of
      clinical trials is needed, as major bias has often hampered the interpretation of
      the results. As recommended at a recent international conference in Barcelona,
      the most reliable methods for assessing the clinical outcome of a treatment in
      hepatocellular carcinoma are large randomized trials that each include a control
      arm of untreated patients, with overall survival as the primary endpoint, and an
      intention-to-treat analysis. New therapeutic strategies should be developed.
      Drugs such as vitamin D or vitamin A derivatives and inhibitors of COX-2 or
      angiogenesis could have a favourable influence on tumour growth. Some of these
      drugs are currently being tested in preliminary studies or even large randomized
      trials.

PMID- 15195891
TI  - Systemic treatment of advanced colorectal carcinoma.
AB  - For advanced colorectal cancer (ACC), 5-fluorouracil (5-FU) based chemotherapy
      has been the standard for some decades. Attempts have been made to improve its
      results by biochemical modulation and schedule modulation of 5-FU which, in
      combination with leucovorin (LV), has been regarded as standard chemotherapy for
      almost two decades. The oral preparations capecitabine and uracil+ftorafur
      combined with LV may be regarded as a useful alternative to 5-FU/LV for the first
      line treatment of ACC. Irinotecan is widely accepted as the standard second line
      treatment Oxaliplatin + 5-FU/LV has been used in the neo-adjuvant setting in
      patients with initially irresectable liver metastasis. Both irinotecan and
      oxaliplatin + 5-FU/LV are also used in first line treatment However, it is still
      an open question whether the concomitant use of irinotecan or oxaliplatin with 5
      FU/LV is really superior to the sequential use of these drugs. In patients with
      ACC anecdotal responses have been documented in small-scale studies with
      different types of cancer vaccines, either alone, or in combination as
      radioimmunotherapy. Favourable results were reported for the monoclonal antibody
      C225 (cetuximab) against the epidermal growth factor receptor in patients with
      ACC refractory to irinotecan. Vascular endothelial growth factor (VEGF) is an
      important angiogenic factor in colorectal cancer and is a marker for poor
      prognosis. Preliminary results of treatment with anti-VEGF antibody in
      combination with 5-FU/LV have shown encouraging results.

PMID- 15195892
TI  - The substitution of endoscopic ultrasonography for endoscopic retrograde
      cholangio-pancreatography: implications for service development and training.
AB  - Diagnostic indications of endoscopic retrograde cholangio-pancreatography (ERCP)
      have not completely disappeared. But the substitution of this examination by
      endoscopic ultrasonography (EUS) in the work-up of biliary and pancreatic
      diseases is supported by EUS's reliability and cost-effectiveness. In the future
      EUS will be challenged by magnetic resonance cholangiopancreatography (MRCP),
      when easily available. Therefore, the choice between EUS, MRCP and ERCP will
      become simplified: MRCP as the first option for diagnosis, EUS in doubtful cases
      needing sampling for pathology and ERCP as a therapeutic alternative to some
      surgical procedures.

PMID- 15195893
TI  - Understanding the mechanisms of paracentesis-induced crculatory dysfunction.
AB  - Large-volume paracentesis induces early beneficial haemodynamic changes that may
      be shortly followed by a disorder known as paracentesis-induced circulatory
      dysfunction, characterized by a marked activation of the renin-angiotensin axis.
      Evidence is accumulating however that this disorder is secondary to an
      accentuation of an already established arteriolar vasodilatation. The causes of
      this syndrome are probably multiple and may include the dynamics of paracentesis
      (the rate of ascitic fluid extraction), release of nitric oxide from the vascular
      endothelium and mechanical modifications due to abdominal decompression. Patients
      developing this syndrome are prone to a faster reaccumulation of ascites, renal
      impairment and shorter survival. Plasma volume expansion after paracentesis
      reduces the incidence of this disorder. Preliminary evidence suggests that other
      approaches, such as the use of splanchnic vasoconstrictors or modulating the rate
      of ascitic fluid extraction, could be also effective, although more studies are
      needed.

PMID- 15195894
TI  - The substitution of endoscopic ultrasound for endoscopic retrograde cholangio
      pancreatography: implications for service development and training.
AB  - OBJECTIVES: Choledocholithiasis and other benign conditions of the biliary tree
      are difficult to define clinically. Endoscopic retrograde cholangio
      pancreatography (ERCP) is increasingly being replaced as the investigation of
      choice by other imaging modalities. The aim of this study was to measure the
      impact of substituting endoscopic ultrasound (EUS) for ERCP in terms of case
      throughput and the proportion of therapeutic ERCPs performed. METHODS: Over a 12
      month period, cases with a low/medium likelihood for biliary pathology were
      triaged to EUS rather than ERCP. Data were collected on the proportion of ERCPs
      performed with diagnostic or therapeutic intent and compared with data from the
      preceding 12-month period. RESULTS: In the 12 months to April 2001, 518 cases
      were referred for ERCP; 140 underwent EUS and 378 underwent ERCP. The proportions
      of diagnostic and therapeutic ERCP were 14% and 86%, respectively. Benign biliary
      disease represented 33% of all referrals for EUS, and calculi were identified in
      6% of these cases. During the preceding year, 637 ERCPs were performed. The
      proportion of diagnostic (33%) and therapeutic (67%) cases differed from the
      index year (P < 0.001). CONCLUSIONS: The substitution of EUS for ERCP results in
      significant quantitative and qualitative change to ERCP practice, which has
      direct consequences for training and service development.

PMID- 15195895
TI  - Ursodeoxycholic acid decreases viscosity and sedimentable fractions of
      gallbladder bile in patients with cholesterol gallstones.
AB  - OBJECTIVES: Ursodeoxycholic acid (UDCA) therapy is associated with reduced risk
      of biliary pain and acute cholecystitis or pancreatitis in patients with
      cholesterol gallstones. The underlying mechanisms are understood incompletely,
      which prompted us to study the influence of UDCA treatment on composition,
      viscosity and sedimentable fractions of gallbladder bile in 25 patients with
      symptomatic cholesterol gallstones. METHODS: In two randomised groups, either
      UDCA (750 mg daily) or placebo was given to each patient 10-12 days before
      cholecystectomy. Gallbladder bile was collected intraoperatively and analysed for
      protein, mucin, lipid composition, cholesterol crystal observation time, amount
      of cholesterol in vesicles, viscosity and sedimentable fractions (cholesterol,
      protein, mucin, bilirubin). RESULTS: UDCA-treated patients showed longer
      cholesterol crystal observation times and lower concentrations of total
      cholesterol and percentages of vesicular cholesterol in gallbladder bile. The
      concentrations of protein and mucin in gallbladder bile tended to be lower in the
      UDCA-treated group, but phospholipids, bile acids and bilirubin did not differ
      between the groups. Viscosity and the total sedimentable fractions of gallbladder
      bile decreased in the UDCA-treated patients. CONCLUSIONS: UDCA treatment reduces
      total and vesicular cholesterol, the formation of cholesterol crystals,
      viscosity, and the total amount of sedimentable fractions in gallbladder bile.
      These observations might explain, at least partially, why UDCA treatment
      attenuates the occurrence of biliary pain and complications in gallstone
      patients.

PMID- 15195896
TI  - Hepatic transit time of an echo enhancer: an indicator of metastatic spread to
      the liver.
AB  - OBJECTIVE: Can sonographic measurements of the transit time of an echo enhancer
      from the hepatic artery to the hepatic vein discriminate between patients with
      and without liver metastases? METHOD: The hepatic transit time (hepatic artery to
      hepatic vein delay) of an echo enhancer (Optison) was measured in pulse inversion
      mode on the basis of time intensity curves (TIC) in patients with
      gastrointestinal tumours with proven liver metastases and in patients without
      liver metastases. RESULTS: Sixty-four patients (46 males, 18 females, mean age 61
      +/- 13 years) were admitted to the study. Fourteen patients had metastatic growth
      in the liver with a primary tumour in situ (group A). Fourteen patients had liver
      metastases following primary tumour resection (group B). Twenty-eight patients
      had a known primary tumour but no liver metastases (group C), and eight patients
      had neither liver symptoms nor a primary tumour (group D). The mean hepatic
      transit time in patients with liver metastases was 6.6 +/- 1.8 s in group A and
      6.7 +/- 1.7 s in group B, whereas in patients without liver metastases it was
      significantly longer; namely, 15.7 +/- 4.4 s in group C and 15.0 +/- 2.0 s in
      group D (P < 0.001). The transit times in all patients with liver metastases were
      < or = 10 s, while in all patients without metastases except for four the times
      were > or = 12 s and one of the four had already developed liver metastases on
      early follow-up. CONCLUSIONS: Measurement of the hepatic transit time permits
      discrimination of patients with and without liver metastases.

PMID- 15195897
TI  - Characteristic clinical features of hepatocellular carcinoma associated with Budd
      Chiari syndrome: evidence of different carcinogenic process from hepatitis B
      virus-associated hepatocellular carcinoma.
AB  - OBJECTIVE: Budd-Chiari syndrome (BCS) is a known risk factor for hepatocellular
      carcinoma (HCC). Considering the pathophysiological mechanism of BCS, BCS
      associated HCC may have a different carcinogenic process to hepatitis B virus
      (HBV)-associated HCC, resulting in different characteristic clinical features.
      METHODS: The clinical, radiological and histopathological characteristics of 15
      HCCs associated with BCS were analysed and compared with 211 HBV-associated HCCs.
      RESULTS: HCC associated with BCS showed a female predominance in contrast to a
      male predominance in HCC associated with HBV infection. Child classes of BCS
      associated HCC patients were not different from the classes of HBV-associated
      HCC. BCS tended to be associated with the single nodular type of HCC. Only one
      BCS-associated HCC patient had portal vein invasion at the time of diagnosis,
      compared with 96 patients with HBV-associated HCC. No HCC patients with BCS
      showed biliary invasion, compared with 47 HBV-associated HCC patients. The median
      survival period of HCC patients associated with BCS was 58 months, which was much
      longer than the median survival period of 10 months in HBV-associated HCC. All of
      the three BCS-associated HCCs available for histological examination were well
      differentiated. CONCLUSIONS: Patients with HCC associated with BCS seemed to
      survive for much longer periods than those with HBV due to the low invasiveness
      of the tumour. Such unique clinical features may be evidence of different
      carcinogenic processes in BCS-associated and HBV-associated HCC.

PMID- 15195898
TI  - Percutaneous injection therapy for hepatocellular carcinoma in patients with
      chronic renal insufficiency.
AB  - OBJECTIVES: Percutaneous injection therapy using acetic acid or pure ethanol is
      effective for hepatocellular carcinoma (HCC). However, its efficacy in HCC
      patients with coexisting chronic renal insufficiency (CRI), defined as a serum
      creatinine level of 1.5 mg/dl or above, is not known. This study compared the
      survival in HCC patients with and without CRI undergoing percutaneous injection
      therapy. METHODS: A total of 172 patients (129 male; age 67 +/- 10 years) during
      a 4-year period were included. Thirty-five of these patients had CRI (creatinine
      level 2.7 +/- 1.8 mg/dl) before treatment Fourteen patient- and tumour-related
      parameters were included for survival analysis. RESULTS: The mean follow-up
      period was 24 +/- 9 (range 4-40) months. Seven (20%) and 39 (28%) patients in the
      groups with and without CRI, respectively, died. There was no significant
      survival difference in patients with and without CRI. The cause of death was
      related to renal failure in two (29%) patients in the former group and one (3%)
      patient in the latter group. For the patients with CRI, the presence of ascites
      and a serum creatinine level of 2.3 mg/dl or above were poor prognostic factors
      in the univariate analysis; the latter was the only independent factor predicting
      a poor survival by the Cox multivariate proportional model. CONCLUSIONS: CRI does
      not affect overall survival in HCC patients undergoing percutaneous injection
      therapy. However, a serum creatinine level of 2.3 mg/dl or above is an
      independent poor prognostic predictor among patients with existing CRI.

PMID- 15195899
TI  - Outcome predictors of cirrhosis patients admitted to the intensive care unit.
AB  - OBJECTIVE: To evaluate outcome predictors of patients with cirrhosis admitted to
      an intensive care unit (ICU). METHODS: One hundred and twenty-nine consecutive
      patients with cirrhosis admitted to the ICU at a tertiary care transplant centre
      in Saudi Arabia between March 1999 and December 2000 were entered prospectively
      in an ICU database. Liver transplantation patients and readmissions to the ICU
      were excluded. The following data were documented: demographic features, severity
      of illness measures, parameters of organ failure, presence of gastrointestinal
      bleeding, and sepsis. The need for mechanical ventilation, renal replacement
      therapy and pulmonary artery catheter placement was recorded. The primary
      endpoint was hospital outcome. RESULTS: Cirrhotic patients admitted to the ICU
      had high hospital mortality (73.6%). However, the actual mortality was not
      significantly different from the predicted mortality using prediction systems.
      There was an association between the number of organs failing and mortality. Coma
      and acute renal failure emerged as independent predictors of mortality. All
      patients who were monitored with pulmonary artery catheterisation in this study
      died. Patients requiring mechanical ventilation and renal replacement therapy had
      very high mortalities (84% and 89%, respectively). All 13 cirrhotic patients
      admitted to ICU immediately post-cardiac arrest in this study died. CONCLUSIONS:
      Cirrhotic patients admitted to ICU have a poor prognosis, especially when
      admitted with coma, acute renal failure or post-cardiac arrest. The consistently
      poor prognosis associated with certain ICU interventions should raise new
      awareness regarding limitations of medical therapy. These mortality statistics
      compel a critical re-examination of uniformly aggressive life support for the
      critically ill cirrhotic patient, a percentage of whom will not benefit from
      invasive measures.

PMID- 15195900
TI  - Expression of Fas antigen in liver tissue of patients with chronic hepatitis B
      and C.
AB  - OBJECTIVES: Cells infected with the hepatitis B or C virus can be eliminated by
      an immune response mediated by cytotoxic T cells. Recently, the Fas Ligand has
      been detected on the surface of cytotoxic T cells, and is thought to induce cells
      to apoptosis by adhering to the Fas antigen. METHODS: To evaluate the role of the
      Fas antigen and apoptosis in chronic hepatitis B or C, we used
      immunohistochemistry to study Fas antigen expression in liver samples obtained
      from 30 patients infected with chronic hepatitis B and 32 patients with chronic
      hepatitis C. RESULTS: In samples from patients with chronic hepatitis C and B,
      Fas antigen was mainly expressed in the cytoplasm (partly at the membrane) of
      hepatocytes, and these positive cells were detected especially at the periportal
      region near 'piecemeal necrosis'. According to Knodell's scoring system for the
      histological activity index, the scores of periportal inflammation and necrosis
      were higher in cases that were positive for Fas antigen than in cases that were
      negative for the antigen (n = 62, P < 0.001) and there was a positive correlation
      between these scores and the degree of Fas antigen expression (r = 0.621). There
      was also a positive correlation between the scores of intralobular inflammation
      and necrosis and the degree of Fas antigen expression (n = 62, r = 0.522, P =
      0.001). Fas antigen was not detected in patients without hepatitis infection.
      CONCLUSIONS: These findings suggest that apoptosis of hepatocytes is induced via
      the Fas antigen and contributes to the elimination of infected cells.

PMID- 15195901
TI  - Mechanisms of early decrease in systemic vascular resistance after total
      paracentesis: influence of flow rate of ascites extraction.
AB  - BACKGROUND: An early decrease in systemic vascular resistance (SVR) after total
      paracentesis has been observed in ascitic patients who developed paracentesis
      induced circulatory dysfunction. AIMS: To investigate the mechanisms of early
      changes in SVR after total paracentesis and the influence of intra-abdominal
      pressure and the flow rate of ascites extraction on the development of an early
      decrease in SVR. METHODS: Twenty-two cirrhotic patients with tense ascites were
      treated by total paracentesis (7 +/- 0.4 l). Measurements of intra-abdominal
      pressure and the volume of ascites removed were recorded every 10 min. Hormonal
      and haemodynamic measurements were performed at baseline and 3 h after total
      paracentesis. RESULTS: SVR decreased 3 h after paracentesis in 17 patients and
      remained stable in five patients. Patients with a decrease in SVR showed a
      significant increase in nitrite/nitrate serum values (4.4 +/- 0.9 to 7.4 +/- 1
      nmol/ml; P < 0.05). A significant correlation was observed between the decrease
      in SVR and nitrite/nitrate serum values (r = 0.566; P < 0.05). The volume of
      ascites removed was similar in patients with and without a decrease in SVR.
      Patients with a decrease in SVR showed higher baseline intra-abdominal pressure,
      shorter duration of paracentesis (60 +/- 4.9 vs 88 +/- 0.4 min; P < 0.01) and
      higher flow rate of ascites extraction (1.18 +/- 0.08 vs 0.81 +/- 0.12 l/min; P <
      0.05). CONCLUSIONS: Our results confirm that an early decrease in SVR after total
      paracentesis is due to an increase in arterial vasodilation that may be related
      to an abrupt decrease in intra-abdominal pressure after fast paracentesis.
      Haemodynamic disturbances after total paracentesis could be prevented by reducing
      the flow rate of ascites extraction.

PMID- 15195902
TI  - Regression of cirrhosis associated with hepatitis B e (HBe) antigen-negative
      chronic hepatitis B infection with prolonged lamivudine therapy.
AB  - In theory, hepatic fibrosis should be a dynamic process with the potential for
      remodelling after the injury-provoking stimulus has been removed. Clinically,
      there has been an accumulation of a small number of cases, including hepatitis B
      e (HBe) antigen-positive chronic hepatitis B infection, in which cirrhosis
      regressed after successful treatment. We report a 42-year-old HBe antigen
      negative Chinese man with detectable serum hepatitis B virus DNA and
      histologically established cirrhosis (Ludwig score 4) who, after 4 years of
      successful lamivudine therapy, was found to have regression of cirrhosis on
      repeat liver biopsy. The repeat biopsy revealed normal liver architecture with
      fibrosis confined to the portal tracts and short fibrosis septae extending into
      the lobule without bridging (Ludwig score 1-2). Although cirrhosis may take many
      years to develop, our experience suggests that successful treatment may reverse
      the process within a relatively short time.

PMID- 15195903
TI  - The importance of ileoscopy in patients with suspected small bowel disease.

PMID- 15195904
TI  - Helicobacter pylori and Roux-en-Y diversion.

PMID- 15195905
TI  - Digestive and metabolic utilization of lauric, myristic and stearic acid in cows,
      and associated effects on milk fat quality.
AB  - In an experiment with 3 x 6 Brown Swiss cows, the effects of dietary
      supplementations (40 g/kg) of non-esterified lauric (12 : 0), myristic (14 : 0)
      and stearic acid (18 : 0) on digestibility, metabolisability, milk fat
      composition and melting properties were investigated. The diet consisted of
      forage and concentrate in a ratio of 3 : 2. Cows were fed the C18 : 0
      supplemented diet for 10 days before treatment feeding started for a 15-day
      experimental period where, at the end, excreta were quantitatively collected and
      gaseous exchange was measured. The DM intake averaged 17.9 kg/d for the C14 : 0
      and C18 : 0 diets and was reduced (P < 0.05) by 18% in the C12 : 0 diet. The
      realised intakes of total C12 : 0, C14 :0 and C18 : 0 amounted to 368, 391 and
      617 g/d in the respective groups. The efficiency of ME utilization for lactation
      was higher (P < 0.001) in the C12 : 0 group than in the two other groups
      indicating differences in metabolism of C12 : 0 in comparison with C14 : 0 and
      C18 : 0. Shifts in dietary fatty acid supplementation were clearly reflected in
      the milk fat composition. Associated changes were elevated CLA and C18 : 1 trans
      when supplementing C12 : 0, and a high C18 : 1 to C16 : 0 ratio (P < 0.05) in the
      C12 : 0and C18 : 0 groups which resulted in an easier melting milk fat than with
      supplementary C14 : 0. Despite certain favourable effects of C12 : 0 in metabolic
      energy utilization and milk fat melting properties (relative to C14 : 0), more
      research is needed on how to improve its palatability for dairy cows.

PMID- 15195907
TI  - The suitability of a faecal suspension of sheep as inocula for the estimation of
      utilizable crude protein of feeds by in vitro incubation.
AB  - The objective of the experiments was to study the suitability of using a faecal
      suspension of sheep for the estimation of the utilizable crude protein (uCP) of
      feeds for sheep by an in vitro incubation. Twenty-four single feeds and eight
      feed mixtures were used as incubation substrates. In Experiment 1, the gas
      production after the in vitro incubation with rumen fluid or with a faecal
      suspension of a sheep were compared using the Hohenheim gas test. It was found
      that there were significant linear regression between the 24, 48 and 72 h gas
      production with rumen fluid and those with faecal suspensions of 35, 50, 100 and
      150 g wet faeces of sheep (which were 18.6, 23.5, 52.0 and 70.5 g faeces DM,
      respectively) per litre McDougall's buffer (P < 0.0001). The highest regression
      coefficient (r2) was calculated between the gas production after inoculation with
      a suspension of 100 g wet faeces per litre McDougall's buffer (x, ml x 200 mg (
      1) feed DM) for 48 h and the gas production after inoculation with rumen fluid
      (y, ml x 200 mg (-1) feed DM) for 24 h: y = 0.82 (+/- 0.07)x + 9.87 (+/-3.83), r2
      = 0.82, n = 32, P < 0.0001. Based on these results, in Experiment 2 the
      estimation of utilizable crude protein (uCP) of feeds was compared by using the
      in vitro incubation technique of Zhao and Lebzien (2000), where feeds were
      inoculated either with rumen fluid or with a faecal suspension (100 g wet faeces
      of sheep, i.e. 52 g faeces DM per litre McDougall's buffer). The results
      indicated that there were no significant differences of the estimated uCP after
      inoculation with rumen fluid or the faecal suspension (P > 0.05). A significant
      regression was found between the uCP after incubation for 48 h with 100 g wet
      faeces (x, g x kg (-1) DM) and the uCP after incubation for 24 h with rumen fluid
      (y, g x kg(-1) DM): y = 0.95 (+/-0.10)x - 4.90 (+/-26.70), r2 = 0.75, n = 32,
      Although this regression was significant, the coefficient r2 was not high.
      Therefore, further research is needed before sheep faeces could replace rumen
      fluid as an inocula for the estimation of uCP by the in vitro incubation
      technique.

PMID- 15195906
TI  - Nutrient supply to dairy cows from processed white lupines.
AB  - The objective of this study was to compare the DVE/OEB system (DVE = truly
      absorbed protein in the small intestine; OEB = degraded protein balance (DPB) in
      Dutch) and the NRC-2001 model in the prediction of supply of protein to dairy
      cows from processed white lupines (Lupinus albus L.). Comparisons were made in
      terms of (1) ruminally synthesized microbial CP, (2) truly absorbed protein in
      the small intestine, and (3) degraded protein balance. In addition, the
      systematic investigation of roasting of the white lupines at various temperatures
      (110, 130, or 150 degrees C) and times (15, 30 or 45 min) on manipulation of
      digestive behaviour and the potential nutrient supply to dairy cows were also
      carried out, to obtain information on best processing conditions as intestinal
      protein sources (to achieve target values for potential high net absorbable
      protein in the small intestine while holding any N loss in the rumen to a low
      level). The results showed that the predicted values from the DVE/OEB system and
      the NRC-2001 model had significant correlations with high R ( > 0.83) values.
      However, using the DVE/OEB system, the overall average microbial protein supply
      based on available energy was 11% higher and the truly absorbed protein in the
      small intestine was 7% higher than that predicted by the NRC-2001 model. The
      difference was also found in the prediction of the degraded protein balances
      (DPB), which was 8% higher based on data from the NRC-2001 model. These
      differences are due to considerably different factors used in calculations in the
      two models, although both are based on similar principles. This indicates that a
      further refinement is needed for a modern protein evaluation and prediction
      system. In addition, this study showed that the roasting at higher temperature
      and time was effective in shifting protein degradation from rumen to intestines
      and it increased the DVE or MP values without reaching the negative degraded
      protein balance. The processing at 15 degrees C for 30 or 45 min might be the
      best treatments for white lupine due to its higher DVE and MP values and the very
      low DPB values.

PMID- 15195908
TI  - The influence of 5% and 10% dietary apple pectin on parameters of fermentation in
      faeces and caecal digesta of weaning pigs.
AB  - In order to determine the effect of pectin on fermentation parameters in the
      faeces and caecal digesta of weaned pigs 18 castrated male crossbred pigs with an
      average body weight of 8 kg were fitted with T-cannulas at the caecum. The
      animals were randomly distributed into three groups and fed with diets
      supplemented with 0, 5 and 10% pectin. Faeces were collected over a period of 3
      days. Thereafter the diets were withdrawn for 24 h followed by ad libitum feeding
      to enhance the feed intake. Caecal chyme was collected 0, 8 and 24 h
      postprandial. In the faeces the addition of 5% pectin to the diet lowered the
      content of dry matter and lactic acid. The pH and the digestibility of pectins,
      the concentration of total SCFA, acetate, propionate, butyrate, bicarbonate and
      chloride increased. Dietary pectin of 10% increased the content of total SCFA and
      acetate further. When the diets were withdrawn and fed ad libitum 24 h later, a
      decline of the pH and an increased concentration of lactate in the caecal chyme
      could be observed in all groups up to 8 h after feeding. With an interval of 8 to
      24 h after feeding, a further decline in pH and a rise of lactate only occurred
      when the diet was not supplemented with pectin. It was concluded that pectin
      might be beneficial for the development of fermentative processes in the large
      intestine.

PMID- 15195909
TI  - Amino acid requirement of growing pigs depending on amino acid efficiency and
      level of protein deposition. 2nd communication: threonine.
AB  - This study was conducted to evaluate the variability of the efficiency of
      threonine in different feed proteins for growing pigs. This information is of
      importance for actual conclusions about threonine requirement within the
      exponential N-utilization model (Liebert and Gebhardt, 1986) used in our
      investigations. Wheat (as basal protein), high-protein soybean meal, low-protein
      soybean meal, rapeseed meal, field bean (Vicia faba), peas (Pisum sativum), corn
      gluten meal and soybean protein concentrate were used as protein sources. Fifty
      six growing barrows (40-65 kg BW) of the genotype Pietrain x (Duroc x Landrace)
      were randomly allotted to eight N-balance experiments (n = 7). Diets were
      formulated with two main ingredients (wheat + one feed protein) with threonine as
      the first limiting amino acid in the mixture which was partly supplemented with
      crystalline amino acids. Based on N-balance data, the efficiency of threonine was
      determined in protein mixtures and individual feed proteins. Threonine
      requirement was calculated depending on efficiency of threonine and level of
      daily protein deposition. The results from the present studies indicate that the
      efficiency of threonine in different feed proteins varied in a wide range.
      Consequently, this factor has to be taken into account for requirement
      calculations. The threonine requirement depending on daily protein deposition
      (130, 145 and 160 g) and the efficiency of threonine according to different
      reference units (g/BW(kg)(-0.67)/d, g/d and % of threonine in the diet) were
      calculated. The threonine requirement of growing barrows (50 kg BW) corresponding
      to an average threonine efficiency was 8.52, 9.92 and 11.61 g/d for a daily
      protein deposition of 130, 145 and 160 g, respectively. The results for a daily
      protein deposition of 145 or 160 g are in agreement with actual studies and
      recommendations for threonine supply.

PMID- 15195910
TI  - On the toxicokinetics and the metabolism of deoxynivalenol (DON) in the pig.
AB  - Eleven castrated male pigs weighing 88.1 +/- 3.9 kg on average were adapted to a
      diet containing DON (4.2 mg DON/kg) over a period of 7 days. Feed was given
      restrictively with 1.1 kg per meal (two meals per day). On the day of
      measurement, all pigs were slaughtered at different time intervals following the
      morning meal containing DON (1, 2, 3, 4, 5, 6, 8, 15, 18 and 24 h after feeding),
      with the exception of one pig which was slaughtered unfed. DON and de-epoxy-DON
      were analysed in serum and digesta from consecutive segments of the digestive
      tract (stomach, small intestine divided into three parts of a similar length,
      caecum, colon, rectum). DON was rapidly and nearly completely absorbed while
      passing through the stomach and the proximal small intestine. Maximum serum
      concentration appeared 4.1 h after the DON-containing meal and half of the
      systemically absorbed DON was eliminated after 5.8 h. De-epoxy-DON appeared in
      increasing proportions from the distal small intestine and reached approximately
      80% of the sum of DON plus de-epoxy-DON in faeces collected from the rectum. It
      was concluded that de-epoxydation of DON, which primarily occurs in the hindgut,
      probably does not contribute much to a detoxification in the pig.

PMID- 15195911
TI  - Utilization of milk energy by suckling mink kits.
AB  - A total of 36 mink dams and their litters of 3, 6 or 9 kits were used for
      determination of milk intake of the suckling young by means of deuterium dilution
      technique, and chemical composition of milk and of kit bodies. Measurements were
      performed during lactation weeks 1-4, each week with 3 dams with each litter
      size. Milk intake was determined over a 48 h measurement period, and by the end
      of this milk samples were collected and 2 kits (litters of 6 and 9) or 1 kit per
      litter (litters of 3) were killed for body chemical composition. Based on the
      results, different models were applied for calculation of the energetic
      efficiency of milk. Dam milk yield increased steadily from week 1 until week 3
      but only slightly from week 3 to 4. The increase declined with increasing litter
      size, and for dams suckling 9 kits the increment from week 3 to week 4 was only 2
      g. The dry matter content of milk increased significantly as lactation
      progressed, being reflected in crude protein increasing from 6.9% in lactation
      week 1 to 8.1% in week 4. Milk fat increased concomitantly from 5.6% to 8.0%. In
      kit bodies, crude protein content increased from 9.4% in week 1 to about 12% in
      weeks 3 and 4. Body fat content increased from week 1 (4.1%) to week 3 (8.4%) and
      then declined in week 4 (7.1%). Animals suckled in litters of 3 kits had the
      highest milk intake and live weight and kits suckled in litters of 9 had the
      lowest milk intake, live weight and daily gain. In terms of milk intake per g
      gain kits in litters of 6 were the most efficient, with 4.1 g milk per g body
      gain. The metabolizable energy requirement for maintenance (MEm) was estimated to
      448 kJ/kg(0.75 and the efficiency of utilization of ME for body gain (kg) to
      0.67, the estimates being higher (MEm) or in good agreement with previous
      findings (kg) in suckling mink kits.

PMID- 15195912
TI  - Breaking up is hard to do.

PMID- 15195913
TI  - The anterior inferior capsular shift.

PMID- 15195914
TI  - Primary coracoid impingement syndrome.
AB  - We measured treatment responses for patients with primary coracoid impingement
      syndrome to determine whether coracoplasty provided pain relief and improved
      function. Eleven patients (12 shoulders) were included in the primary group, and
      secondary cases were excluded. Symptoms included burning pain occurring at the
      site of the coracoid process aggravated by exercise (push-ups). Magnetic
      resonance imaging and computed tomography showed a narrow coracohumeral interval.
      Surgical findings confirmed the diagnosis. Follow-up averaged 2.7 years. After
      follow-up, coracoplasty responses showed significant relief of pain (P < 0.0001)
      and improved function (P = 0.006). Treatment responses were good in primary
      cases, as indicated by pain and function scores.

PMID- 15195915
TI  - Discoid lateral meniscus: evaluation and treatment.
AB  - Although the etiology of the discoid lateral meniscus (DLM) has been the subject
      of debate, the entity is now believed to result from abnormal development
      secondary to a deficiency in normal attachments. In children younger than 10
      years, snapping knee syndrome is pathognomonic for an unstable DLM. In
      adolescents, clinical presentation varies and often includes symptoms typically
      found with meniscal tears. The asymptomatic DLM does not require surgery.
      Treatment for the symptomatic stable DLM is directed toward arthroscopic
      saucerization with preservation of enough meniscus to maintain some biomechanical
      function. Recent reports of meniscal repair for the unstable Wrisberg meniscus
      have been encouraging. Optimal treatment for DLM requires a high index of
      suspicion in the appropriate clinical setting and up-to-date knowledge of
      available therapeutic modalities.

PMID- 15195916
TI  - Progressive bilateral cavovarus deformity: an unusual presentation of
      calcaneonavicular tarsal coalition.

PMID- 15195917
TI  - Rapidly destructive osteoarthropathy of the hip.

PMID- 15195918
TI  - Primary nontraumatic Mycobacterium avium complex osteomyelitis of the distal
      phalanx.

PMID- 15195919
TI  - Less Invasive Stabilization System for treatment of distal femur fractures.
AB  - The low profile of Less Invasive Stabilization System (LISS) plates allows them
      to be inserted between muscle and diaphysis with less bone exposure than that
      obtained with conventional plating techniques. In the unique LISS mechanism,
      unicortical screws thread into both plate and bone and allow the system to act as
      an internal fixator, with compressive pressure no longer bearing down on the
      periosteum. Results are minimal soft-tissue, periosteal, cortical, and vascular
      damage and no compromise in stability. This lesser degree of tissue disruption is
      hypothesized to accelerate bone healing, make bone grafting unnecessary, decrease
      infection rates, and prevent further injury by lessening overall surgical trauma.
      In a prospective, nonrandomized study conducted at a level I trauma center, we
      sought to determine the benefits of LISS plating in the treatment of distal femur
      fractures. Between January 1, 1998, and June 3, 2001, we treated 25 multiply
      injured adult patients admitted through the trauma department with 26 unstable
      distal femur fractures. Treatment involved minimally invasive plate
      osteosynthesis using LISS plating. Main outcome measures were time to union,
      postoperative complications, and functional impairment as measured with the SF
      36v2 Health Survey. Results included no nonunions, no infections, no required
      bone grafting, and excellent range of motion and alignment.

PMID- 15195920
TI  - Using suture anchors for coracoclavicular fixation in treatment of complete
      acromioclavicular separation.
AB  - For the repair of acromioclavicular separations, we describe a new method of
      securing the clavicle to the coracoid process using suture anchors. We have
      repaired 11 consecutive complete acromioclavicular separations in this manner
      with very good results. We find this to be an easy and reproducible method of
      anatomical fixation.

PMID- 15195921
TI  - Oligonucleotide, antibody and peptide therapeutics--from design to the clinic.

PMID- 15195922
TI  - Oligonucleotide therapeutics: 25 years agrowing.
AB  - The year 2003 saw the 25th anniversary of the first publication of research using
      antisense oligonucleotides in cells. Oligonucleotides complementary to RNA use a
      variety of mechanisms to provide a direct link from genomics to gene function,
      drug target validation and new lead therapeutics. Other applications use
      oligonucleotides that bind to DNA or proteins to serve similar purposes. In this
      review, recent advances in mechanisms, chemical modifications and uses of
      oligonucleotides are discussed, and a broad overview of progress, mainly
      concerning RNA inhibition, is provided.

PMID- 15195923
TI  - RNAi in functional genomics.
AB  - There has been a lack of powerful tools for systematic analysis of mammalian gene
      function, but RNA interference (RNAi) may now provide such a strategy. Stable
      transcription of RNAi triggers from suitable expression cassettes integrated into
      the host cell genome by viral gene transfer can induce long-term and heritable
      gene silencing in mammalian cells. However, the use of RNAi as a genetic tool is
      limited by difficulties in identifying efficient RNAi triggers, the problem of
      effective delivery and off-target effects, as well as potential genotoxic side
      effects of viral gene transfer strategies. Recent insights into the molecular
      mechanisms of silencing processes mediated by either siRNA or miRNA will allow
      further optimization of RNAi triggers as genetic tools.

PMID- 15195924
TI  - RNA interference for the identification of disease-associated genes.
AB  - RNA interference (RNAi) has emerged as a novel cellular mechanism regulating gene
      expression at the post-transcriptional level and as a powerful tool to control
      gene function experimentally. Recent advances in the biology and application of
      RNAi include the definition of improved criteria for selecting effective small
      interfering RNA (siRNA) sequences, and the generation of vectors for the delivery
      of siRNAs and stable silencing of genes in mammalian cells, tissues and animals.
      High-throughput screening projects based on RNAi have been initiated to search
      for genes involved in basic biological processes and in complex pathological
      conditions such as cancer, autoimmunity and degenerative disorders. This research
      is helping to identify novel therapeutic targets for a range of diseases and may
      translate into novel clinical applications for RNAi.

PMID- 15195925
TI  - RNA interference as an antiviral approach: targeting HIV-1.
AB  - RNA interference (RNAi) is an evolutionary conserved gene-silencing mechanism in
      which 21- to 23-mer double-stranded short interfering RNA (siRNA) mediates the
      sequence-specific degradation of mRNA. The recent discovery that exogenously
      delivered siRNA can trigger RNAi in mammalian cells raises the possibility of
      using this technology as a therapeutic tool against pathogenic viruses. This
      review describes the antiviral RNAi field, which is barely two years-old, with an
      emphasis on recent studies aimed at suppression of HIV-1.

PMID- 15195926
TI  - DNA vaccination against hepatitis C.
AB  - Hepatitis C virus (HCV) infection is a major health problem worldwide, and often
      causes cirrhosis and liver cancer. Current therapy for hepatitis C is expensive
      and generally effective in less than 50% of cases. This review illustrates
      advances in the field of DNA vaccination against HCV by describing the most
      significant recent studies. Data obtained after immunization of different animal
      models with naked or formulated plasmid DNA encoding HCV structural and non
      structural proteins will be analyzed. Encouraging results based on the co
      expression of DNA vaccines with cytokines and DNA prime/recombinant live vectors
      or protein/boost regimens will also be discussed. Immunogenicity enhancement
      should lead to clinical trials and, hopefully, registration of DNA vaccines for
      the treatment of HCV infection.

PMID- 15195928
TI  - Immunotherapy of cancer by antisense inhibition of Ii protein, an immunoregulator
      of antigen selection by MHC class II molecules.
AB  - Ii protein suppression is a promising antisense drug-based therapy that
      dramatically enhances the immunogenicity of tumor cell major histocompatibility
      complex class II-presented antigenic epitopes. The strength of this approach is
      that the antisense only needs to be transiently effective in a fraction of the
      tumor cells. The systemic antitumor immune response generated subsequently
      eradicates both directly treated cells and distant tumor deposits. The drugs and
      mechanisms of this therapy are considered, in addition to practical developmental
      questions.

PMID- 15195927
TI  - Gene therapy for cardiovascular disease: the potential of VEGF.
AB  - The quest for new therapeutic options and the recent exponential explosion in our
      knowledge of genetics have led to active interest and research into gene therapy.
      One area of gene therapy that has generated much debate and controversy is the
      use of vascular endothelial growth factor (VEGF) for therapeutic angiogenesis for
      palliative intent, and for the prevention of restenosis following percutaneous
      revascularization in coronary and peripheral arterial disease. This review
      highlights the development in VEGF gene therapy in the last 12 to 18 months,
      particularly the results from randomized, double-blind, placebo-controlled phase
      I and II studies that have evolved from encouraging results from animal models
      and early pilot studies in humans.

PMID- 15195929
TI  - Immunotherapeutic utility of stimulatory and suppressive oligodeoxynucleotides.
AB  - Bacterial DNA contains immunostimulatory CpG motifs that interact with toll-like
      receptor 9 on immune cells to stimulate the production of cytokines, chemokines
      and immunoglobulins. Synthetic oligodeoxynucleotides (ODNs) containing CpG motifs
      mimic the activity of bacterial DNA. Recently, several structurally distinct
      types of CpG ODN were identified that differentially activate human immune cells.
      These ODNs may be useful as vaccine adjuvants, anti-allergens and in the
      treatment of infectious diseases and cancer. Yet CpG-driven immune activation can
      have deleterious consequences, such as increasing the host's susceptibility to
      autoimmune disease. The immunomodulatory activity of CpG DNA can be blocked by
      DNA containing G-rich 'suppressive' motifs. The therapeutic potential of these
      immunostimulatory and immunosuppressive ODNs are discussed in this review.

PMID- 15195930
TI  - Antibody therapy for non-Hodgkin's lymphoma.
AB  - Significant advances in the therapy of non-Hodgkin's lymphoma have been made with
      the introduction of monoclonal antibodies. The anti-CD20 antibody rituximab has
      become standard as monotherapy in patients with indolent lymphoma, and in
      combination with chemotherapy in patients with aggressive lymphoma. A number of
      new monoclonal antibodies targeting different molecules on lymphoma cells are now
      in clinical development and show promise both as single agents and in combination
      therapy. Furthermore, anti-CD20 monoclonal antibodies have been radioconjugated
      to increase their efficacy. Future studies will therefore be needed to explore
      the efficacy of combinations of these agents and to develop a rational strategy
      for their use.

PMID- 15195931
TI  - Developing effective delivery systems for Chlamydia vaccines.
AB  - Members of the genus Chlamydia cause a plethora of ocular, genital and
      respiratory diseases, with severe complications, such as blinding trachoma,
      pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility,
      interstitial pneumonia, and chronic diseases that may include atherosclerosis,
      multiple sclerosis, adult-onset asthma and Alzheimer's disease. The current
      medical opinion is that an effective prophylactic vaccine would constitute the
      best approach to protect the human population from the most severe consequences
      of these infections. There are three essential and mutually inclusive areas of
      challenge confronting researchers developing Chlamydia vaccines. These are to
      define the elements of protective immunity and the basis of vaccine evaluation,
      the judicious selection of an immunogenic and safe antigen(s) to form the basis
      of a subunit vaccine, and to develop effective delivery systems that boost the
      immune response to achieve long-lasting protective immunity. The development of
      delivery vehicles and adjuvants to boost protective long-term immunity against
      chlamydiae currently poses the greatest challenge in vaccine research. However,
      enormous progress is being made in the construction of novel delivery systems,
      such as DNA and plasmid expression systems, viral vectors, and living and non
      living bacterial delivery systems, and the use of chemical adjuvants. In
      addition, there is increasing effort being made in designing delivery strategies
      involving specific immunomodulatory procedures that modify the cytokine and
      chemokine environment, upregulate co-stimulatory molecules and target vaccines to
      specific mucosal sites. These efforts will likely culminate in an efficacious
      chlamydial vaccine in the near future.

PMID- 15195932
TI  - Novel approaches to ocular drug delivery.
AB  - Recent advances in surgical techniques, therapeutic approaches and materials
      sciences have produced revolutionary new therapies for ocular diseases. The
      development of prodrug formulations and permeability enhancers, sustained-release
      drug delivery devices, novel injectable medications and new and improved vectors,
      both viral and non-viral, for delivery of genes to all segments of the eye has
      greatly increased the chances of success in treating eye diseases. This review
      will discuss the most recent advances in drug delivery systems for the treatment
      of ocular diseases.

PMID- 15195933
TI  - Technology evaluation: HPV vaccine (quadrivalent), Aventis Pasteur MSD/CSL.
AB  - CSL, licensee of UniQuest's HPV technology, and Aventis Pasteur MSD (a joint
      venture between Merck & Co and Aventis) are jointly developing a vaccine for the
      potential prophylaxis of genital warts and cervical cancer caused by human
      papilloma virus infection. Enrollment for a phase III trial has been completed.

PMID- 15195934
TI  - Technology evaluation: FluINsure, ID Biomedical.
AB  - ID Biomedical (formerly Intellivax International) is developing a trivalent nasal
      influenza vaccine, FluINsure, for the potential treatment of influenza. The
      vaccine is currently in phase II clinical trials.

PMID- 15195935
TI  - Technology evaluation: BAY-50-4798, Bayer.
AB  - Bayer is developing an IL-2-selective recombinant cytokine, BAY-50-4798, as a
      potential adjunct to standard chemotherapy in the treatment of various cancers,
      and for the potential treatment of HIV infection. BAY-50-4798 is currently
      undergoing phase II clinical trials.

PMID- 15195936
TI  - Multimodal acute pain management.
AB  - Unrelieved postoperative pain following arthroplasty has been shown to delay
      patients' recovery and discharge from the hospital. Undertreatment of acute pain
      may also result in greater use of healthcare resources and ultimately lead to
      poor outcomes. This article reviews a multimodal approach to reduce pain at each
      step of the pain nocioception process by combining various analgesics that each
      operate through a different site or mechanism of action, allowing the physician
      to tailor the regimen to the patient. A therapeutic combination of analgesics
      (eg, opioids, nonsteroidal anti-inflammatory drugs, and bupivicaine) can provide
      adequate pain relief; however, regional anesthesia is fraught with side effects.
      The use of multimodal analgesia reduces hospital stay, decreases medical
      complications, and increases patient satisfaction.

PMID- 15195937
TI  - The use of the pain pump and patient-controlled analgesia in joint
      reconstruction.
AB  - Controlling postoperative pain following painful orthopedic procedures such as
      total knee arthroplasty is an ongoing challenge, as current pain management
      techniques often result in undermedication and/or complications. Traditional pain
      management strategies include opioid analgesics administered orally or via
      epidural catheter, patient-controlled analgesia (PCA), or intramuscular (IM)
      injection. This article discusses the use of PCA and the pain pump as effective
      modalities for the management of pain after arthroplasty. While the use of PCA
      has been somewhat controversial, a review of the literature supports its use over
      traditional IM dosing. PCA has been shown to provide more effective analgesia
      than IM dosing, and PCA administration is preferred over IM dosing by both
      patients and nurses. Continuous infusion of bupivacaine via pain pump is also an
      effective modality for reducing postoperative pain and decreasing postoperative
      consumption of opioid analgesics.

PMID- 15195938
TI  - Emerging techniques for postoperative analgesia in orthopedic surgery.
AB  - The current use of multimodal analgesia for the management of postoperative pain
      has resulted in reduced side effects and improved pain relief. Limitations of the
      technology associated with current pump- or catheter-based systems have prompted
      the development of continuous delivery systems and extended-duration techniques
      for pain relief. Among these are morphine sulfate sustained-release liposome
      injection (Morphine SR, DepoMorphine) and the patient-controlled transdermal
      system (PCTS, E-TRANS). Morphine SR utilizes the novel DepoFoam technology, a
      novel delivery system that allows the drug to be gradually released into the
      surrounding epidural space. Morphine SR is compatible with anticoagulation
      therapy and eliminates interference from pump and intravenous (IV) equipment.
      Administration of Morphine SR during hip arthroplasty significantly reduced
      patients' postoperative consumption of fentanyl. E-TRANS fentanyl PCTS is a
      transdermal system attached to the patient's arm or upper chest; a button on the
      device is controlled by the patient to deliver doses of fentanyl. In a study
      comparing fentanyl HCl PCTS with conventional IV-patient-controlled analgesia
      (PCA) morphine, PCTS was found to be as safe and effective as PCA for the
      treatment of postoperative pain. Novel delivery systems that are less invasive,
      that are compatible with anticoagulation regimens, and that provide continuous
      delivery, thus preventing analgesic gaps, will facilitate rehabilitation and
      recovery and ultimately improve patient outcomes.

PMID- 15195939
TI  - Site-directed mutagenesis and generation of chimeric viruses by homologous
      recombination in yeast to facilitate analysis of plant-virus interactions.
AB  - A yeast homologous recombination system was used to generate mutants and chimeras
      in the genome of Potato leafroll virus (PLRV). A yeast-bacteria shuttle vector
      was developed that allows mutants and chimeras generated in yeast to be
      transformed into Escherichia coli for confirmation of the mutations and
      transformed into Agrobacterium tumefaciens to facilitate agroinfection of plants
      by the mutant PLRV genomes. The advantages of the system include the high
      frequency of recovered mutants generated by yeast homologous recombination, the
      ability to generate over 20 mutants and chimeras using only two restriction
      endonuclease sites, the ability to introduce multiple additional sequences using
      three and four DNA fragments, and the mobilization of the same plasmid from yeast
      to E. coli, A. tumefaciens, and plants. The wild-type PLRV genome showed no loss
      of virulence after sequential propagation in yeast, E. coli, and A. tumefaciens.
      Moreover, many PLRV clones with mutations generated in the capsid protein and
      readthrough domain of the capsid protein replicated and moved throughout plants.
      This approach will facilitate the analysis of plant-virus interactions of in vivo
      generated mutants for many plant viruses, especially those not transmissible
      mechanically to plants.

PMID- 15195940
TI  - Identification and characterization of victorin sensitivity in Arabidopsis
      thaliana.
AB  - Cochliobolus victoriae is a necrotrophic fungus that produces a host-selective
      toxin called victorin. Victorin is considered to be host selective because it has
      been known to affect only certain allohexaploid oat cultivars containing the
      dominant Vb gene. Oat cultivars containing Vb are also the only genotypes
      susceptible to C. victoriae. Assays were developed to screen the "nonhost" plant
      of C. victoriae, Arabidopsis thaliana, for victorin sensitivity. Sensitivity to
      victorin was identified in six of 433 bulk populations of Arabidopsis. In crosses
      of Col-4 (victorin-insensitive) x victorin-sensitive Arabidopsis ecotypes,
      victorin sensitivity segregated as a single dominant locus, as it does in oats.
      This Arabidopsis locus was designated LOV, for locus orchestrating victorin
      effects. Allelism tests indicate that LOV loci are allelic or closely linked in
      all six victorin-sensitive ecotypes identified. LOV was localized to the north
      arm of Arabidopsis thaliana chromosome I. The victorin-sensitive Arabidopsis line
      LOV1 but not the victorin-insensitive line Col-4 was susceptible to C. victoriae
      infection. Consequently, the LOV gene appears to be a genetically dominant,
      disease susceptibility gene.

PMID- 15195941
TI  - The Tobacco mosaic virus 126-kDa protein associated with virus replication and
      movement suppresses RNA silencing.
AB  - Systemic symptoms induced on Nicotiana tabacum cv. Xanthi by Tobacco mosaic virus
      (TMV) are modulated by one or both amino-coterminal viral 126- and 183-kDa
      proteins: proteins involved in virus replication and cell-to-cell movement. Here
      we compare the systemic accumulation and gene silencing characteristics of TMV
      strains and mutants that express altered 126- and 183-kDa proteins and induce
      varying intensities of systemic symptoms on N. tabacum. Through grafting
      experiments, it was determined that M(IC)1,3, a mutant of the masked strain of
      TMV that accumulated locally and induced no systemic symptoms, moved through
      vascular tissue but failed to accumulate to high levels in systemic leaves. The
      lack of M(IC)1,3 accumulation in systemic leaves was correlated with RNA
      silencing activity in this tissue through the appearance of virus-specific,
      approximately 25-nucleotide RNAs and the loss of fluorescence from leaves of
      transgenic plants expressing the 126-kDa protein fused with green fluorescent
      protein (GFP). The ability of TMV strains and mutants altered in the 126-kDa
      protein open reading frame to cause systemic symptoms was positively correlated
      with their ability to transiently extend expression of the 126-kDa protein:GFP
      fusion and transiently suppress the silencing of free GFP in transgenic N.
      tabacum and transgenic N. benthamiana, respectively. Suppression of GFP silencing
      in N. benthamiana occurred only where virus accumulated to high levels. Using
      agroinfiltration assays, it was determined that the 126-kDa protein alone could
      delay GFP silencing. Based on these results and the known synergies between TMV
      and other viruses, the mechanism of suppression by the 126-kDa protein is
      compared with those utilized by other originally characterized suppressors of RNA
      silencing.

PMID- 15195942
TI  - Bacterial genes involved in type I secretion and sulfation are required to elicit
      the rice Xa21-mediated innate immune response.
AB  - Innate immunity to microorganisms relies on the specific sensing of pathogen
      associated molecules by host recognition receptors. Whereas studies in animals
      have largely focused on the recognition of extracellular pathogen-associated
      molecules by the TLR (toll-like receptor) superfamily, few studies have been
      carried out in plants, and it is not understood how these molecules are secreted
      or modified. The rice Xa21 gene encodes a receptor-like kinase that provides
      immunity against strains of the bacterial pathogen Xanthomonas oryzae pv. oryzae
      carrying AvrXa21 activity. We identified four X. oryzae pv. oryzae genes that are
      required for AvrXa21 activity. raxA, raxB, and raxC encode proteins with
      similarity to a membrane fusion protein, an ATP-binding cassette transporter, and
      an outer membrane protein, respectively, of bacterial type I secretion systems.
      The fourth gene, raxST, encodes a sulfotransferase-like protein. Sequence
      analysis of three naturally occurring X. oryzae pv. oryzae strains no longer
      recognized by Xa21 revealed alterations in the raxST and raxA genes. The raxC
      gene complemented an Escherichia coli tolC mutant for secretion of a double
      glycine-leader peptide confirming the function of raxC in type I secretion. These
      results indicate that bacterial type I secretion is necessary for Xa21-mediated
      recognition and immunity and further suggest that type I secretion and
      modification of pathogen-associated molecules play an important role in
      triggering the innate immune response in rice.

PMID- 15195943
TI  - RaxH/RaxR: a two-component regulatory system in Xanthomonas oryzae pv. oryzae
      required for AvrXa21 activity.
AB  - Xanthomonas oryzae pv. oryzae is the causal agent of bacterial leaf blight, one
      of the most serious diseases in rice. X. oryzae pv. oryzae Philippine race 6
      (PR6) strains are unable to establish infection in rice lines expressing the
      resistance gene Xa21. Although the pathogen-associated molecule that triggers the
      Xa21-mediated defense response (AvrXa21) is unknown, six rax (required for
      AvrXa21 activity) genes encoding proteins involved in sulfur metabolism and Type
      I secretion were recently identified. Here, we report on the identification of
      two additional rax genes, raxR and raxH, which encode a response regulator and a
      histidine protein kinase of two-component regulatory systems, respectively. Null
      mutants of PR6 strain PXO99 that are impaired in either raxR, raxH, or both cause
      lesions significantly longer and grow to significantly higher levels than does
      the wild-type strain in Xa21-rice leaves. Both raxR and raxH mutants are
      complemented to wild-type levels of AvrXa21 activity by introduction of
      expression vectors carrying raxR and raxH, respectively. These null mutants do
      not affect AvrXa7 and AvrXa10 activities, as observed in inoculation experiments
      with Xa7- and Xa10-rice lines. Western blot and raxR/gfp promoter-reporter
      analyses confirmed RaxR expression in X. oryzae pv. oryzae. The results of
      promoter-reporter studies also suggest that the previously identified raxSTAB
      operon is a target for RaxH/RaxR regulation. Characterization of the RaxH/RaxR
      system provides new opportunities for understanding the specificity of the X.
      oryzae pv. oryzae-Xa21 interaction and may contribute to the identification of
      AvrXa21.

PMID- 15195944
TI  - The expression of MaEXP1, a Melilotus alba expansin gene, is upregulated during
      the sweetclover-Sinorhizobium meliloti interaction.
AB  - Expansins are a highly conserved group of cell wall-localized proteins that
      appear to mediate changes in cell wall plasticity during cell expansion or
      differentiation. The accumulation of expansin protein or the mRNA for specific
      expansin gene family members has been correlated with the growth of various plant
      organs. Because expansin proteins are closely associated with plant cell wall
      expansion, and as part of a larger study to determine the role of different gene
      products in the legume-Rhizobium spp. symbiosis, we investigated whether a
      Melilotus alba (white sweetclover) expansin gene is expressed during nodule
      development. A cDNA fragment encoding an expansin gene (EXP) was isolated from
      Sinorhizobium meliloti-inoculated sweetclover root RNA by reverse-transcriptase
      polymerase chain reaction using degenerate primers, and a full-length sweetclover
      expansin sequence (MaEXP1) was obtained using 5' and 3' rapid amplification of
      cDNA end cloning. The predicted amino acid of the sweetclover expansin is highly
      conserved with the various alpha-expansins in the GenBank database. MaEXP1
      contains a series of eight cysteines and four tryptophans that are conserved in
      the alpha-expansin protein family. Northern analysis and whole-mount in situ
      hybridization analyses indicate that MaEXP1 mRNA expression is enhanced in roots
      within hours after inoculation with S. meliloti and in nodules. Western and
      immunolocalization studies using a cucumber expansin antibody demonstrated that a
      cross-reacting protein accumulated in the expanding cells of the nodule.

PMID- 15195945
TI  - Enhanced resistance to Cucumber mosaic virus in the Arabidopsis thaliana ssi2
      mutant is mediated via an SA-independent mechanism.
AB  - The Arabidopsis thaliana SSI2 gene encodes a plastid-localized stearoyl-ACP
      desaturase. The recessive ssi2 mutant allele confers constitutive accumulation of
      the pathogenesis-related-1 (PR-1) gene transcript and salicylic acid (SA), and
      enhanced resistance to bacterial and oomycete pathogens. In addition, the ssi2
      mutant is a dwarf and spontaneously develops lesions containing dead cells. Here,
      we show that the ssi2 mutant also confers enhanced resistance to Cucumber mosaic
      virus (CMV). Compared with the wild-type plant, viral multiplication and systemic
      spread were diminished in the ssi2 mutant plant. However, unlike the ssi2
      conferred resistance to bacterial and oomycete pathogens, the ssi2-conferred
      enhanced resistance to CMV was retained in the SA-deficient ssi2 nahG plant. In
      addition, SA application was not effective in limiting CMV multiplication and
      systemic spread in the CMV-susceptible wild-type plant. The acd1, acd2, and cpr5
      mutants which, like the ssi2 mutant, accumulate elevated SA levels,
      constitutively express the PR-1 gene, spontaneously develop lesions containing
      dead cells, and are dwarfs, are, however, fully susceptible to CMV. Our results
      suggest that dwarfing, cell death, and constitutive activation of SA signaling
      are not important for the ssi2-conferred enhanced resistance to CMV. However, the
      sfd1 and sfd4 mutations, which affect lipid metabolism, suppress the ssi2
      conferred enhanced resistance to CMV, thus implicating a lipid or lipids in the
      ssi2-conferred resistance to CMV. Interestingly, the ssi2-conferred resistance to
      CMV was compromised in the ssi2 eds5 plant, suggesting the involvement of an SA
      independent, EDS5-dependent mechanism in the ssi2-conferred resistance to CMV.

PMID- 15195946
TI  - Characterization of the Xanthomonas AvrXv4 effector, a SUMO protease translocated
      into plant cells.
AB  - Homologs of the Yersinia virulence factor YopJ are found in both animal and plant
      bacterial pathogens, as well as in plant symbionts. The conservation of this
      effector family indicates that several pathogens may use YopJ-like proteins to
      regulate bacteria-host interactions during infection. YopJ and YopJ-like proteins
      share structural homology with cysteine proteases and are hypothesized to
      functionally mimic small ubiquitin-like modifier (SUMO) proteases in eukaryotic
      cells. Strains of the phytopathogenic bacterium Xanthomonas campestris pv.
      vesicatoria are known to possess four YopJ-like proteins, AvrXv4, AvrBsT, AvrRxv,
      and XopJ. In this work, we have characterized AvrXv4 to determine if AvrXv4
      functions like a SUMO protease in planta during Xanthomonas-plant interactions.
      We provide evidence that X. campestris pv. vesicatoria secretes and translocates
      the AvrXv4 protein into plant cells during infection in a type III-dependent
      manner. Once inside the plant cell, AvrXv4 is localized to the plant cytoplasm.
      By performing AvrXv4 deletion and mutational analysis, we have identified amino
      acids required for type III delivery and for host recognition. We show that
      AvrXv4 recognition by resistant plants requires a functional protease catalytic
      core, the domain that is conserved in all of the putative YopJ-like cysteine
      proteases. We also show that AvrXv4 expression in planta leads to a reduction in
      SUMO-modified proteins, demonstrating that AvrXv4 possesses SUMO isopeptidase
      activity. Overall, our studies reveal that the YopJ-like effector AvrXv4 encodes
      a type III SUMO protease effector that is active in the cytoplasmic compartment
      of plant cells.

PMID- 15195947
TI  - The Erwinia chrysanthemi EC16 hrp/hrc gene cluster encodes an active Hrp type III
      secretion system that is flanked by virulence genes functionally unrelated to the
      Hrp system.
AB  - Erwinia chrysanthemi is a host-promiscuous plant pathogen that possesses a type
      III secretion system (TTSS) similar to that of the host-specific pathogens E.
      amylovora and Pseudomonas syringae. The regions flanking the TTSS-encoding
      hrp/hrc gene clusters in the latter pathogens encode various TTSS-secreted
      proteins. DNA sequencing of the complete E. chrysanthemi hrp/hrc gene cluster and
      approximately 12 kb of the flanking regions (beyond the previously characterized
      hecA adhesin gene in the left flank) revealed that the E. chrysanthemi TTSS genes
      were syntenic and similar (>50% amino-acid identity) with their E. amylovora
      orthologs. However, the hrp/hrc cluster was interrupted by a cluster of four
      genes, only one of which, a homolog of lytic transglycosylases, is implicated in
      TTSS functions. Furthermore, the regions flanking the hrp/hrc cluster lacked
      genes that were likely to encode TTSS substrates. Instead, some of the genes in
      these regions predict ABC transporters and methyl-accepting chemotaxis proteins
      that could have alternative roles in virulence. Mutations affecting all of the
      genes in the regions flanking or interrupting the hrp/hrc cluster were
      constructed in E. chrysanthemi CUCPB5047, a mutant whose reduced pectolytic
      capacity can enhance the phenotype of minor virulence factors. Mutants were
      screened in witloof chicory leaves and then in potato tubers and Nicotiana
      clevelandii seedlings. Mu dII1734 insertion in one gene, designated virA,
      resulted in strongly reduced virulence in all three tests. virA is immediately
      downstream of hecA, has an unusually low G+C content of 38%, and predicts an
      unknown protein of 111 amino acids. The E. chrysanthemi TTSS was shown to be
      active by its ability to translocate AvrPto-Cya (a P. syringae TTSS effector
      fused to an adenylate cyclase reporter that is active in the presence of
      eukaryote calmodulin) into N. benthamiana leaf cells. However, VirA(1-61)-Cya was
      not translocated into plant cells, and virA expression was not affected by
      mutations in E. chrysanthemi Hrp regulator genes hrpL and hrpS. Thus, the 44-kb
      region of the E. chrysanthemi EC16 genome that is centered on the hrplhrc cluster
      encodes a potpourri of virulence factors, but none of these appear to be a TTSS
      effector.

PMID- 15195949
TI  - Molecular characterization of a Melon necrotic spot virus strain that overcomes
      the resistance in melon and nonhost plants.
AB  - Resistance of melon (Cucumis melo L.) to Melon necrotic spot virus (MNSV) is
      inherited as a single recessive gene, denoted nsv. No MNSV isolates described to
      date (e.g., MNSV-Malpha5), except for the MNSV-264 strain described here, are
      able to overcome the resistance conferred by nsv. Analysis of protoplasts of
      susceptible (Nsv/-) and resistant (nsv/nsv) melon cultivars inoculated with MNSV
      264 or MNSV-Malpha5 indicated that the resistance trait conferred by this gene is
      expressed at the single-cell level. The nucleotide sequence of the MNSV-264
      genome has a high nucleotide identity with the sequences of other MNSV isolates,
      with the exception of its genomic 3'-untranslated region (3'-UTR), where less
      than 50% of the nucleotides are shared between MNSV-264 and the other two MNSV
      isolates completely sequenced to date. Uncapped RNAs transcribed from a full
      length MNSV-264 cDNA clone were infectious and caused symptoms indistinguishable
      from those caused by the parental viral RNA. This cDNA clone allowed generation
      of chimeric mutants between MNSV-264 and MNSV-Malpha5 through the exchange of the
      last 74 nucleotides of their coat protein (CP) open reading frames and the
      complete 3'-UTRs. Analysis of protoplasts of susceptible and resistant melon
      cultivars inoculated with chimeric mutants clearly showed that the MNSV
      avirulence determinant resides in the exchanged region. The carboxy-termini of
      the CP of both isolates are identical; therefore, the avirulence determinant
      likely consists of the RNA sequence itself. We also demonstrated that this
      genomic region contains the determinant for the unique ability of the isolate
      MNSV-264 to infect noncucurbit hosts (Nicotiana benthamiana and Gomphrena
      globosa).

PMID- 15195950
TI  - NolR regulates diverse symbiotic signals of Sinorhizobium fredii HH103.
AB  - We have investigated in Sinorhizobium fredii HH103-1 (=HH103 Str(r)) the
      influence of the nolR gene on the production of three different bacterial
      symbiotic signals: Nod factors, signal responsive (SR) proteins, and
      exopolysaccharide (EPS). The presence of multiple copies of nolR (in plasmid
      pMUS675) repressed the transcription of all the flavonoid-inducible genes
      analyzed: nodA, nodD1, nolO, nolX, noeL, rhcJ, hesB, and y4pF. Inactivation of
      nolR (mutant SVQ517) or its overexpression (presence of pMUS675) altered the
      amount of Nod factors detected. Mutant SVQ517 produced Nod factors carrying N
      methyl residues at the nonreducing N-acetyl-glucosamine, which never have been
      detected in S. fredii HH103. Plasmid pMUS675 increased the amounts of EPS
      produced by HH103-1 and SVQ517. The flavonoid genistein repressed EPS production
      of HH103-1 and SVQ517 but the presence of pMUS675 reduced this repression. The
      presence of plasmid pMUS675 clearly decreased the secretion of SR proteins.
      Inactivation, or overexpression, of nolR decreased the capacity of HH103 to
      nodulate Glycine max. However, HH103-1 and SVQ517 carrying plasmid pMUS675 showed
      enhanced nodulation capacity with Vigna unguiculata. The nolR gene was positively
      identified in all S. fredii strains investigated, S. xinjiangense CCBAU110, and
      S. saheli USDA4102. Apparently, S. teranga USDA4101 does not contain this gene.

PMID- 15195951
TI  - Swimming motility, a virulence trait of Ralstonia solanacearum, is regulated by
      FlhDC and the plant host environment.
AB  - Swimming motility allows the bacterial wilt pathogen Ralstonia solanacearum to
      efficiently invade and colonize host plants. However, the bacteria are
      essentially nonmotile once inside plant xylem vessels. To determine how and when
      motility genes are expressed, we cloned and mutated flhDC, which encodes a major
      regulator of flagellar biosynthesis and bacterial motility. An flhDC mutant was
      nonmotile and less virulent than its wild-type parent on both tomato and
      Arabidopsis; on Arabidopsis, the flhDC mutant also was less virulent than a
      nonmotile fliC flagellin mutant. Genes in the R. solanacearum motility regulon
      had strikingly different expression patterns in culture and in the plant. In
      culture, as expected, flhDC expression depended on PehSR, a regulator of early
      virulence factors; and, in turn, FlhDC was required for fliC (flagellin)
      expression. However, when bacteria grew in tomato plants, flhDC was expressed in
      both wild-type and pehR mutant backgrounds, although PehSR is necessary for
      motility both in culture and in planta. Both flhDC and pehSR were significantly
      induced in planta relative to expression levels in culture. Unexpectedly, the
      fliC gene was expressed in planta at cell densities where motile bacteria were
      not observed, as well as in a nonmotile flhDC mutant. Thus, expression of flhDC
      and flagellin itself are uncoupled from bacterial motility in the host
      environment, indicating that additional signals and regulatory circuits repress
      motility during plant pathogenesis.

PMID- 15195952
TI  - Flagellin is not a major defense elicitor in Ralstonia solanacearum cells or
      extracts applied to Arabidopsis thaliana.
AB  - The phytopathogenic bacterium Ralstonia solanacearum requires motility for full
      virulence, and its flagellin is a candidate pathogen-associated molecular pattern
      that may elicit plant defenses. Boiled extracts from R. solanacearum contained a
      strong elicitor of defense-associated responses. However, R. solanacearum
      flagellin is not this elicitor, because extracts from wild-type bacteria and fliC
      or flhDC mutants defective in flagellin production all elicited similar plant
      responses. Equally important, live R. solanacearum caused similar disease on
      Arabidopsis ecotype Col-0, regardless of the presence of flagellin in the
      bacterium or the FLS2-mediated flagellin recognition system in the plant. Unlike
      the previously studied flg22 flagellin peptide, a peptide based on the
      corresponding conserved N-terminal segment of R. solanacearum, flagellin did not
      elicit any response from Arabidopsis seedlings. Thus recognition of flagellin
      plays no readily apparent role in this pathosystem. Flagellin also was not the
      primary elicitor of responses in tobacco. The primary eliciting activity in
      boiled R. solanacearum extracts applied to Arabidopsis was attributable to one or
      more proteins other than flagellin, including species purifying at approximately
      5 to 10 kDa and also at larger molecular masses, possibly due to aggregation.
      Production of this eliciting activity did not require hrpB (positive regulator of
      type III secretion), pehR (positive regulator of polygalacturonase production and
      motility), gspM (general secretion pathway), or phcA (LysR-type global virulence
      regulator). Wild-type R. solanacearum was virulent on Arabidopsis despite the
      presence of this elicitor in pathogen extracts.

PMID- 15195953
TI  - [Possibilities for a legal complaint by an association in animal protection law].
AB  - Access to justice for qualified entities in the area of animal protection should
      not follow the procedures of the access to justice for qualified entities in
      nature protection. This access is limited to certain administrative procedures,
      where damages to nature and landscape are to be expected. This will not carry
      very far with animal protection, because the rights of animals can be injured in
      many ways. Considering this it seems appropriate, to give access to justice to
      any animal, as a creature equal to man. Whenever the rights of an animal are
      neglected by the administration or a citizen, they can be defended in court. As
      the animal cannot represent itself in court, a qualified entity in animal
      protection shall act on its behalf, being its lawyer. In the end this would give
      access to justice to qualified entities in the area of animal protection, but the
      right would not be restricted to certain administrative procedures. It would
      provide the animals with a lawyer to present their interests in court.

PMID- 15195954
TI  - [Veterinarians as experts in court].
AB  - General veterinarians such as veterinary officers act as experts at court. They
      are in so far part of the evidence. Due to his experience the veterinary expert
      shall give systematical uniform principles concerning even domains adjacent to
      the field of animal protection such as protection of animal epidemics and food
      cases, verifiable by science and university research. Examples for expert's
      topics as well as the requirements of expert reports are shown. According to
      paragraph 15 II Tierschutzgesetz (Animal Protection Act), as well as according to
      paragraph paragraph 63, 76 Ordnungswidrigkeitengesetz the experts participation
      in the proceeding is necessary. In consideration of paragraph paragraph 74, 22
      Strafprozessordnung (Code of Criminal Proceedure) conflicts may arise because the
      veterinarian officer is self-contained investigator, witness as well as expert in
      the same proceeding. In general the veterinarian officer, who has been involved
      in the investigations must be excluded from expert activity in the same case. The
      veterinarian officers have to solve this problem by seperating tasks and
      functions within one legal case.

PMID- 15195955
TI  - [Handling of the petition for carrying out ritual slaughter (the area of conflict
      of the official veterinarian between the special requirements and legal
      possibilities). Juristic view].
AB  - With the introduction of Art. 20 a GG in August 2002 the moral thought of animal
      protection has become a constitutional principle. Now an accommodation between
      animal protection on the one hand and with religious freedom (undisturbed
      practice of religion), the right to free development of personality and the right
      to free choice an practice of an occupation on the other hand has become
      necessary. If somebody is able to substantiate a claim because of compelling
      religious reasons, the appropriate authority has still to grant him a certificate
      of exemption for ritual slaughtering pursuant to paragraph 4 a Abs. 2 Nr. 2
      animal-protection-act. The following text tries to explain the conditions
      precedent to get a permission in detail. The author affirms, that the authorities
      are bounded by the law. Veterinarians as appropriate authorities are not allowed
      to turn downed an application on reasons of conscience.

PMID- 15195956
TI  - [Handling of the petition for ritual slaughter (the area of conflict of the
      official veterinarian between the special requirements and legal possibilities).
      Veterinary specialist view].
AB  - During the process for a permission of ritual slaughter, regulated by paragraph
      4a (2) no.2 Animal Protection Law, the licensing authority has to weigh
      carefully, because there are different rights in the constitutional law. Ritual
      slaughter contradicts religious liberty and animal protection so it is necessary
      to find a balance. Demands on requests for ritual slaughter as well as rudiments
      for verification and notification are described and aspects of animal protection
      during ritual slaughter without stunning methods are demonstrated.

PMID- 15195957
TI  - [Electrical stunning of cattle--experiences in New Zealand].
AB  - Ever since the middle of the nineteen-eighties electrical stunning of cattle is
      used in industrial slaughter plants in New Zealand. Today electrical stun boxes
      operate in export slaughter plants throughout New Zealand. The reversible stun is
      utilised on the vast majority of slaughtered cattle. The electrical stunning
      (head only) immediately followed by bleeding is an alternative to ritual
      slaughter without prior stunning. Throughout the world's islamic community this
      alternative is widely accepted as Halal.

PMID- 15195958
TI  - [Avoidance of injuries to migrating fish by hydropower and water intake plants].
AB  - Every year numerous downstream migrating fish are lethally injured by hydro power
      plants and inlet works. Especially the katadromous Eel (Anguilla anguilla) and
      anadromous species like Atlantic Salmon (Salmo salar), which have to migrate
      downstream into the ocean for closing their life cycle, are highly endangered.
      Due to their specific migratory behavioral pattern, size and morphology
      conventional protection techniques, like screens do not properly keep them out
      from getting into the power plant intakes. Despite of the relevance of this
      problem for ecology and fishing, there are no protection and downstream migration
      facilities in Europe available, which can efficiently avoid the damage of all
      species and sizes of downstream migrating fish. Nevertheless according to protect
      the fish populations it's necessary to use consequently fish protection and
      downstream migration facilities, i.e. mechanical barrieres or alternative
      techniques like early warning systems as a prerequisit for a fish-friendly
      operational management of hydro power plants.

PMID- 15195948
TI  - Gene expression profile changes in cotton root and hypocotyl tissues in response
      to infection with Fusarium oxysporum f. sp. vasinfectum.
AB  - Microarray analysis of large-scale temporal and tissue-specific plant gene
      expression changes occurring during a susceptible plant-pathogen interaction
      revealed different gene expression profile changes in cotton root and hypocotyl
      tissues. In hypocotyl tissues infected with Fusarium oxysporum f. sp.
      vasinfectum, increased expression of defense-related genes was observed, whereas
      few changes in the expression levels of defense-related genes were found in
      infected root tissues. In infected roots, more plant genes were repressed than
      were induced, especially at the earlier stages of infection. Although many known
      cotton defense responses were identified, including induction of pathogenesis
      related genes and gossypol biosynthesis genes, potential new defense responses
      also were identified, such as the biosynthesis of lignans. Many of the stress
      related gene responses were common to both tissues. The repression of drought
      responsive proteins such as aquaporins in both roots and hypocotyls represents a
      previously unreported response of a host to pathogen attack that may be specific
      to vascular wilt diseases. Gene expression results implicated the phytohormones
      ethylene and auxin in the disease process. Biochemical analysis of hormone level
      changes supported this observation.

PMID- 15195959
TI  - [Animal welfare relevant issues during the killing of poultry during epidemics].
AB  - In this article firstly the standards of the killing methods of poultry because
      of animal diseases and the parameter for the choice of a method are described.
      The following part deals with the effects of the different killing methods.
      Finally the most important control points during the killing of poultry are
      discussed.

PMID- 15195960
TI  - [Water provision for domestic ducks kept indoors--a review on the basis of the
      literature and our own experiences].
AB  - The wild ancestors of the domestic pekin and muscovy ducks are anatomically,
      physiologically and behaviourally well adapted to living on and at the water. The
      domestic ducks kept for fattening purposes still show clear preferences for open
      water and make use of water for foraging and feeding, drinking, for general
      exploration, locomotion and preening, even without prior experience. For
      hygienic, labour, technical and economical reasons ducks are nowadays mostly kept
      in closed buildings without access to open water. This significantly restricts
      their freedom to show their natural behaviour. An obvious consequence of this
      restriction is a deteriorated plumage condition, especially with regard to
      cleanliness. According to the Council of Europe recommendations, water shall be
      provided in a way that allows the ducks to cover their head with water and shake
      it about their body without difficulty. To date, however, there is a lack of
      solutions satisfying behavioural, hygienic, health, labour and economical
      requirements to about equally tolerable degrees. The presently available types of
      different water provisions are presented and discussed on the basis of existing
      literature as well as experiences and first results from an ongoing research
      project. The provision of shallow bathing water with daily water exchange
      promises to be a practicable solution. However, longer term research on possible
      negative effects of the decreased hygienic quality of the water on duck health is
      necessary before final conclusions can be drawn.

PMID- 15195961
TI  - [Implementation of paragraph 11b of the German Animal Welfare Act on the basis of
      the so-called "Quality Breeding" Report].
AB  - Enforcement of paragraph 11b of the German Animal Welfare Act is a responsibility
      of breeders and their organisations as well as executive local authorities. The
      Report on Defective Breeds of the Federal Ministry of Agriculture describes
      numerous breeding traits which are in conflict with animal welfare and gives
      valuable information for fancy or pet breeding. Yet a selection has to be made
      for taking legal actions, following specific criteria. With four examples
      different cases are presented, each requiring a different approach by the
      veterinarian authorities. Court decisions in Hessen concerning bans on breeding
      white cats and crested ducks show that the paragraph 11b is executable.

PMID- 15195962
TI  - [Critical consideration of the "Guideline for the Evaluation of Raising Horses"
      and keeping horses outside in the winter].
AB  - The guidelines of the Federal Ministry of User Protection, Nutrition and
      Agriculture (BMVEL) regarding "horse keeping with respect to animal welfare" are
      from 1995 (BMELF, 1995). Therefore, they are not suitable for modern horse
      keeping. The Veterinary Association for Animal Welfare (TVT) held it to be
      necessary to rework the guide-lines in light of 1) many subsequent investigations
      concerning horse keeping, and 2) the species-specific needs of horses in
      practice. Each chapter of the BMELF (1995) guide-lines was revised such that the
      literature and practical experiences were updated. Several chapters (recumbency
      resting behaviour, fences, underground outdoor and in stables, litter) were added
      in the position paper of the TVT to reflect the increasing use of boxes with
      paddocks, loose housing systems with open yards, pasture and winter yards as
      housing conditions. Keeping horses outdoors permanently during winter is possible
      because horses have very good thermoregulatory capabilities so that they are able
      to adapt themselves to cold conditions. However, in light of animal welfare, the
      holding system must include adequate shelter (natural or artificial). Shelters
      should protect against wetness, heat, cold and wind, and must be sufficiently
      large and high, with a dry and clean underground. In keeping horses outdoors
      permanently, the paths to the feeding and watering areas and to the shelter must
      be dry. The food must also be protected against mould and soiling. Keeping horses
      permanently without adequate shelter or in deep marsh without any dry places is
      against the Animal Protection Act.

PMID- 15195963
TI  - [Animal welfare aspects in raising sheep].
AB  - Basing on experience in sheep herd health service light is thrown on sheep
      keeping in Germany concerning protection of sheep against cruelty. Despite there
      is at the moment no legislative regulation especially on keeping sheep, there
      exist a number of local and european recommendations. Cruelty and undesirable or
      avoidable disorders and loads occur in small sheep flocks often due to
      unawareness of the owner who keeps his sheep as a hobby. In large herds the
      increasing flock size and the more and more extensive husbandry clash
      increasingly with the requirements of the sheep.

PMID- 15195964
TI  - [Animal welfare aspects of raising South American camelids].
AB  - The number of South American Camelids (SAC) increased over the last years in
      Germany. Therefore it is important to develop guidelines regarding aspects of
      animal welfare. Recommendations for husbandry and feeding are given. In principal
      it is possible to keep llamas and alpacas under middle European conditions with
      respect to animal welfare. However problems do sometimes occur because of a lack
      of knowledge of breeders about the basic requirements of the animals. In contrast
      to other species it is much more difficult to get scientific based informations
      and to guarantee veterinarian service. Therefore more care have to be taken in
      the education of breeders and veterinarians.

PMID- 15195965
TI  - Production of D(-)-lactate from sucrose and molasses.
AB  - Escherichia coli W3110 derivatives, strains SZ63 and SZ85, were previously
      engineered to produce optically pure D(-) and L(+)-lactate from hexose and
      pentose sugars. To expand the substrate range, a cluster of sucrose genes (cscR'
      cscA cscKB) was cloned and characterized from E. coli KO11. The resulting plasmid
      was functionally expressed in SZ63 but was unstable in SZ85. Over 500 mM D(-)
      lactate was produced from sucrose and from molasses by SZ63(pLOI3501).

PMID- 15195966
TI  - New antifungal activity of penicillic acid against Phytophthora species.
AB  - Penicillic acid was isolated from a culture filtrate of Aspergillus sclerotiorum.
      It had a high in vitro antifungal activity against Phytophthora spp., which has
      not been previously reported. MICs of penicillic acid were from 1 to 25 microg
      ml(-1) against Phytophthora spp. Penicillic acid induced abnormal branch
      formation, apical branching, and swelling in P. capsici, in P. cactorum mycelia
      contained irregular branching and small spherical swelling at apices, in P.
      cambivora there was irregular branching and swelling, and in P. drechsleri there
      was irregular multiple spherical swelling at or near hyphal apices.

PMID- 15195967
TI  - Small interfering RNA (siRNA) targetted to Smad3 inhibits transforming growth
      factor-beta signaling.
AB  - RNA interference has become a powerful tool for silencing of gene expression in
      mammals and plants. To determine the effect of Smad3 on transforming growth
      factor-beta signaling, we constructed a small interfering RNA (siRNA) targeted to
      Smad3. This siRNA inhibited expression of the endogenous Smad3 leading to the
      prevention of nuclear localization of Smad3. Further, Smad3 siRNA prevented not
      only anti-proliferative activity of TGF-beta1 but also TGF-beta1-inducible
      promoter activity.

PMID- 15195968
TI  - Quantification of intra- and extra-cellular thermophilic lipase/esterase
      production by Thermus sp.
AB  - Four Thermus strains produced lipolytic activity when grown in liquid medium for
      30 h at 70 degrees C. The highest total lipase/esterase activity (57 U l(-1)) was
      in Thermus aquaticus YT-1, followed by Thermus thermophilus HB27 and HB8 (33 and
      25 U l(-1), respectively), and finally by Thermus sp. (16 U l(-1)). Extra
      cellular activity was detected in T. aquaticus YT-1 and T. thermophilus HB27 (33
      and 17 U l(-1)). All enzymes were stable at 80 degrees C over 30 min, and their
      activity towards fatty acid esters increased as substrate chain-length diminished
      (i.e. hydrolysis rate was up to 6-fold higher on p-nitrophenyl caproate than on
      laurate).

PMID- 15195969
TI  - Tissue engineering of cartilage with chondrocytes cultured in a chemically
      defined, serum-free medium.
AB  - Cell culture with serum-containing medium has potential problems associated with
      contamination of infectious agents. This study demonstrates for the first time
      the feasibility of regenerating cartilage tissues in vivo by implantation of
      chondrocytes cultured in vitro in a chemically-defined, serum-free medium.
      Chondrocytes cultured in the serum-free medium grew similarly to those in a serum
      containing medium. Implantation of chondrocytes cultured in the serum-free medium
      and seeded on to polymer scaffolds resulted in the regeneration of cartilage
      tissues with histological aspects similar to those of cartilage tissues
      regenerated from chondrocytes cultured in serum-containing medium.

PMID- 15195970
TI  - Detoxification of amitriptyline by oligochitosan derivatives.
AB  - Oligo-chitosans were chemically modified with dinitrophenyl groups for selective
      and rapid adsorption of amitriptyline by forming pi-pi complexes. 1H-NMR was
      utilized not only for characterization of modified chitosans but also for
      monitoring the aromatic-aromatic interaction. The variation in the chemical shift
      of aromatic protons was followed to monitor the aromatic-aromatic interaction.
      Upfield shift of aromatic protons of dinitrophenyl groups supports aromatic
      aromatic interactions with amitriptyline. Drug uptake test by HPLC reveals that
      dinitrophenyl chitosan particles (1-2 microm) at 0.4 wt% (w/v) in a saline
      solution (pH 6.9) adsorb 90% amitriptyline within 30 min.

PMID- 15195971
TI  - Enhanced expression of an antibody-targeted plasminogen activator in Escherichia
      coli by fusion to decorsin.
AB  - To improve the thrombolytic specificity of plasminogen activators, an antibody
      targeted plasminogen activator was constructed consisting of a single-chain
      variable fragment of a monoclonal antibody SZ-51 raised specifically against
      human P-selectins on activated platelets and a low molecular weight single-chain
      urokinase. After fusion to the 3' end of the gene coding for decorsin, originally
      isolated from the leech Macrobdella decora, expression of the antibody-targeted
      plasminogen activator gene in E. coli strain Rosetta (DE3) pLysS was greatly
      enhanced.

PMID- 15195972
TI  - Expression in sugar beet of the introduced cercosporin toxin export (CFP) gene
      from Cercospora kikuchii, the causative organism of purple seed stain in soybean.
AB  - The Cercospora kikuchii cercosporin export gene, CFP, introduced into Beta
      vulgaris L. by conjugation with Rhizobium radiobacter, was stably maintained
      during vegetative propagation as verified by PCR using primers specific for the
      CFP gene. Transcriptional expression of the CFP gene in leaves was determined by
      RT-PCR using CFP-specific primers. CFP protein was detected using Western
      analysis with an affinity-purified polypeptide-specifc antibody. Analysis of the
      relative susceptibility of CFP-transgenic and non-transgenic sugar beet plants is
      planned but will probably take several years to complete.

PMID- 15195973
TI  - Lotus hairy roots expressing inducible arginine decarboxylase activity.
AB  - Biotechnological uses of plant cell-tissue culture usually rely on constitutive
      transgene expression. However, such expression of transgenes may not always be
      desirable. In those cases, the use of an inducible promoter could be an
      alternative approach. To test this hypothesis, we developed two binary vectors
      harboring a stress-inducible promoter from Arabidopsis thaliana, driving the beta
      glucuronidase reporter gene and the oat arginine decarboxylase. Transgenic hairy
      roots of Lotus corniculatus were obtained with osmotic- and cold-inducible beta
      glucuronidase and arginine decarboxylase activities. The increase in the activity
      of the latter was accompanied by a significant rise in total free polyamines
      level. Through an organogenesis process, we obtained L. corniculatus transgenic
      plants avoiding deleterious phenotypes frequently associated with the
      constitutive over-expression of arginine decarboxylation and putrescine
      accumulation.

PMID- 15195974
TI  - A short alpha-helical antimicrobial peptide with antibacterial selectivity.
AB  - A 13-residue alpha-helical peptide (K6L5WP), designed from Leu6-->Pro
      substitution of a hemolytic alpha-helical peptide (K6L6W), exhibited strong
      antibacterial activity (MIC: 2 to approximately 4 microM against three gram
      positives and three gram-negatives) comparable to that of melittin but had no
      hemolytic activity. Tryptophan fluorescence studies indicated bacterial
      selectivity of K6L5WP is closely related to the selective interaction with
      negatively charged phospholipids on the surface of bacterial cells. These results
      suggested that the central Pro6 in K6L5WP plays an important role in its
      bacterial cell selectivity. In conclusion, K6L5WP with antibacterial selectivity
      may serve as an attractive candidate for the development of antimicrobial agents.

PMID- 15195975
TI  - Kinetics of improved productivity of beta-galactosidase by a cycloheximide
      resistant mutant of Kluyveromyces marxianus.
AB  - The maximum volumetric productivity of beta-galactosidase by a Kluyveromyces
      marxianus mutant, grown on lactose/corn steep liquor medium for 3 d, was 150 IU
      l(-1) h(-1) which is twice that of the parent organism. During product formation,
      mutated cells provided more resistance against thermal inactivation.

PMID- 15195977
TI  - Chemical modification of L-asparaginase from Escherichia coli with a modified
      polyethyleneglycol under substrate protection conditions.
AB  - L-Asparaginase was chemically modified with 2,4-bis(O-methoxypolyethyleneglycol)
      6-chloro-S-triazine (mPEG2) in the presence of L-asparagine. Optimal modification
      was performed under the condition that the molar ratio of mPEG2/-NH2 is 10. The
      modified enzyme retained 33% of initial enzymatic activity with complete
      abolishment of immunogenicity. In vitro half-life increment from 4.6 h to 33 h
      has been obtained.

PMID- 15195976
TI  - Improved use of organic phosphate by Skeletonema costatum through regulation of
      Zn2+ concentrations.
AB  - The maximum growth rate (1.4-2 x 10(5) cells ml(-1) d(-1)), cell final yields
      (2.6-5.2 x 10(5) cells ml(-1)) and extracellular alkaline phosphatase activity
      (2.4-10.6 microg phosphate released ml(-1) h(-1)) of the red tide alga,
      Skeletonema costatum, increased when Zn2+ was increased from 0 to 24 pM, but
      decreased with 66 pM Zn2+ in growth medium with glycerophosphate as the sole
      phosphorus source. Extracellular carbonic anhydrase activity and the affinity for
      HCO3- and CO2 uptake increased when Zn2+ was increased from 0 to 12 pM, but then
      decreased at higher concentrations. The results suggested that utilization of
      organic phosphate required more Zn2+ than the uptake of inorganic carbon did,
      while utilization of dissolved inorganic carbon by Skeletonema costatum was very
      sensitive to Zn2+ concentration variations.

PMID- 15195978
TI  - Changes in volatile compounds and aromatic series in sherry wine with high
      gluconic acid levels subjected to aging by submerged flor yeast cultures.
AB  - Volatile compounds of sherry wine containing gluconic acid under aging by
      submerged flor yeast cultures were analyzed. The aroma profile was obtained by
      grouping the compounds in nine aromatic series. The balsamic, fatty, herbaceous
      and empyreumatic series increased significantly as consequence of the increase of
      pantolactone, acids (butanoic, 2-methylbutanoic and 3-methylbutanoic), methionol
      and gamma-butyrolactone compounds, respectively. The decrease of higher alcohols
      promoted solvent series diminished. These changes are consistent with those
      observed in the production of commercial sherry wine using traditional biological
      aging.

PMID- 15195979
TI  - On-line oxygen uptake rate and culture viability measurement of animal cell
      culture using microplates with integrated oxygen sensors.
AB  - O2 uptake rates of animal cells (Chinese hamster ovary-CHO) were measured in 96
      well microtiter plates by integrating with fluorescent sensors thereby measuring
      fluorescence intensity ratios of an O2-sensitive and an insensitive fluorophor.
      O2 consumption rate was estimated from measured dissolved O2 and from O2 mass
      transfer coefficient determined in advance. Specific uptake decreased with time
      from 3.2 x 10(-13) mol O2 cell(-1) h(-1) at 15 h cultivation to 1.8 x 10(-13) mol
      O2 cell(-1) h(-1) at 48 h. Specific O2 uptake was also determined by sampling
      from a spinner-flask culture giving identical values. A cell viability assay for
      cultures based on O2 measurements is described in which cells are incubated
      outside the fluorescence reader and then the dissolved O2 is measured only once
      at a fixed time after the start of incubation. This protocol can be directly
      applied for high-throughput measurements.

PMID- 15195980
TI  - Factors associated with family caregivers' burden and depression in Korea.
AB  - This study determines the relative effects of functional impairment, cognitive
      impairment, and duration of care of the elderly on caregivers' depression, and
      identifies the factors that influence this relationship. The variables were
      entered individually, based on a logical order in the path modeling. For
      mediators, the order of three types of social support was assumed to be financial
      support, instrumental support, and emotional support. The order of five
      dimensions of caregiver burden was assumed to be impact on finances, feelings of
      abandonment, impact on schedule, impact on health, and sense of entrapment.
      Findings indicate that functional impairment had both direct and indirect effects
      on caregiver depression, and direct effects on impact on schedule, impact on
      health, and sense of entrapment. The effect of cognitive impairment on caregiver
      depression was primarily indirect but had direct impact on sense of entrapment.
      Duration of care had no direct effect on caregiver depression and burden, but did
      have indirect effects on impact on finances, feelings of abandonment, and impact
      on health through emotional support. Caregivers of elders with functional
      impairment were more likely to give care for longer periods, and those who give
      care for longer periods were likely to receive less emotional support and
      experience more burden in the dimensions of impact on finances, feelings of
      abandonment, and impact on health. Caregivers who experience greater impact on
      finances and impact on health ultimately were at higher risk of depression. The
      results have important implications for intervention models aimed to increase
      emotional support for the caregiver.

PMID- 15195981
TI  - Fostering social ties through a volunteer role: implications for older-adults'
      psychological health.
AB  - This study examined the effects on older adults' psychological health of
      participation in a volunteer role that afforded opportunities to form friendships
      with age peers and to express nurturance toward another person. Access to these
      important social provisions was expected, in turn, to contribute to greater self
      esteem, less loneliness, and less depression. The study hypotheses were tested by
      comparing older adults who served as foster grandparents to a developmentally
      disabled child (N = 52) with older adults in two comparison groups (Ns = 69, 59).
      Three assessments were conducted over a two-year period. The analyses revealed
      that the foster grandparents exhibited a significant increase in the number of
      new ties formed, but participation in the Foster Grandparent Program was not
      associated with the expected gains in emotional health. Explanations for the
      limited findings and implications for future research are discussed.

PMID- 15195982
TI  - Subjective cognitive complaints, memory performance, and depressive affect in old
      age: a change-oriented approach.
AB  - The question of whether and how subjective cognitive complaints are related to
      actual cognitive performance represents a central issue in applied cognitive
      aging research. Until recently, however, many studies have failed to find a
      strong association between subjective cognitive complaints and actual cognitive
      performance. In our study, we examine two alternative explanations: a) for
      methodological reasons, strong associations exist only when latent changes rather
      than differences are examined, and b) strong associations exist only between
      changes in depression and complaints, not between changes in cognitive
      performance and complaints. With 427 participants (M = 63 years) and two
      measurements, we examine both the relation between functioning, complaints, and
      depressive affect at each measurement point, and the relation between changes in
      functioning, changes in complaints, and changes in depressive affect between the
      measurement points with latent difference variables. The results indicate that
      there are substantial relations between changes in functioning, changes in
      depression, and changes in complaints.

PMID- 15195983
TI  - Death and dying from old people's point of view. A literature review.
AB  - Providing high-quality end-of-life care to older people is a requirement
      especially for countries with a high proportion of old and very old people. This
      calls for an understanding of older people's view of death and dying, and one way
      forward is to investigate the current knowledge base. This study aimed at
      reviewing the literature of empirical studies about older people's view of death
      and dying, whether in a terminal phase of life or not. A total of 33 publications
      were included, identified in a stepwise literature search done in Medline, CINAHL
      and PsychInfo, using the terms "death", "attitude to death", "death" and "dying"
      in combination with "aged". Very few studies focused solely on the oldest old.
      The designs were mainly cross-sectional, quantitative or qualitative, using
      personal interviews. Some common themes of importance for further research were
      revealed, such as older people's readiness to talk about death and dying,
      conceptions of death, after-death and dying, and were seemingly related to
      anxiety about death, the impact on and of those close by, having both negative
      and positive connotations, especially related to balancing closeness, being a
      burden and dependency, death anxiety and its possible antecedents, the fine line
      between natural sadness and suffering from depression, and worry about the end-of
      life phase. The lack of studies dealing with older people's view of death and
      dying, and the heterogeneity with regard to research questions and samples
      implies that findings may serve mainly as inspiration for further research.

PMID- 15195984
TI  - The aging factor in health and disease: the promise of basic research on aging.

PMID- 15195985
TI  - Effects of home exercises and group training on functional abilities in home
      dwelling older persons with mobility and balance problems. A randomized study.
AB  - BACKGROUND AND AIMS: Exercise in older people may reduce falls and improve
      functional abilities. Less is known about the optimal amount of training. The aim
      of this study was to determine the effectiveness of home training, and whether
      group training in addition to home training enhances the effect. METHODS: This
      randomized trial included 77 persons aged 75 years and older (mean 81, SD 4.5),
      living at home. Home training (HT) comprised twice-daily functional balance and
      strength exercises and 3 group meetings. Combined training (CT) included group
      training twice weekly and the same home exercises. The trial lasted 12 weeks.
      Physical therapists ran both programs. Exercises and falls were recorded daily.
      We assessed function at baseline, 3 and 9 months, and falls at one year. RESULTS:
      Mean participation for group meetings was 2.5 out of 3 (HT group) and, for group
      training sessions, 21 out of 24 (CT group). The mean numbers of daily home
      sessions were 1.29 and 1.35 in the HT and CT groups. Overall improvement, but no
      group differences, were found at 3 months for walking speed, Figure of Eight,
      Timed Up & Go, Maximum Step Length, Timed Pick-up and Sit-to-stand (p<0.02).
      Posturography (p=0.85) and isometric quadriceps strength (p=0.26) showed no
      improvement. Function at 9 months was equivalent to baseline level. There were no
      group differences in fall rate (p=0.78) or time to first fall (p=0.84).
      CONCLUSIONS: Daily home training supervised by physical therapists improved
      functional abilities. Supplementary individualized group training gave no
      additional effect. The effect on function was not present 6 months after the end
      of the intervention.

PMID- 15195986
TI  - Strength, mobility and falling in women referred to a geriatric outpatient
      clinic.
AB  - BACKGROUND AND AIMS: Mobility impairment and falling have a multifactorial
      etiology in frail older people. Muscle weakness is one of the risk factors and is
      accessible to intervention. The aim of this study was to determine the most
      important contributors of mobility and indicators of fall occurrence in women
      referred to a geriatric outpatient clinic. METHODS: Mobility was assessed using
      the Timed 'Get-Up-and-Go' test (TGUG) and the modified Coopertest (COOP). Falling
      was assessed retrospectively and isometric knee extension force was measured
      using fixed dynamometry. Habitual physical activity was quantified using a
      questionnaire for the elderly. Height, weight, medical conditions and current
      medication were recorded. RESULTS: Isometric knee extension strength and habitual
      physical activity, which consisted predominantly of household work, were
      independent variables of performance on TGUG and COOP and together explained 57%
      of the variance in TGUG (r=0.75, p<0.001), and 64% of that in COOP, (r=0.80,
      p<0.001). Age, total number of medical conditions, and presence of cardiovascular
      disease were not significant in the model. Women in the lowest tertile of knee
      extension strength had a significantly higher probability of falling (0.75, 95%
      CI 0.56-0.91) compared with women in the highest tertile (0.27, 95% CI 0.14
      0.50). CONCLUSIONS: Knee extension strength remains a strong determinant of
      mobility and fall occurrence in women referred to a geriatric outpatient clinic.
      Performing light to moderate household work remains independently associated with
      functional mobility.

PMID- 15195987
TI  - A pilot study of falls, fear of falling, activity levels and fall prevention
      actions in older people with polio.
AB  - BACKGROUND AND AIMS: Polio survivors are ageing, and reporting new complications
      including falls. The aims of this study were: 1) to determine the frequency of
      falls, circumstances surrounding them, and the consequences of falls in older
      people who have polio; and 2) to investigate the range of fall prevention
      interventions undertaken to reduce the individual's risk of falling. METHODS: A
      survey was conducted of members of the Eastern Polio Support Group of Victoria.
      Twenty-eight respondents (70%; 7 male, 21 female) had a mean age of 66 years and
      an average duration of 57 years since the onset of polio. The survey addressed
      demographic data, mobility, frequency and description of falls over the last 12
      months, their consequences, and community services utilized. The Modified Falls
      Efficacy Scale (MFES) and Human Activity Profile (HAP) were also completed.
      Comparative data on the MFES and HAP were obtained from age- and gender-matched
      healthy community-dwelling older people. RESULTS: Fourteen respondents (50%)
      reported one or more falls over the past 12 months, half reporting multiple
      falls. Two-thirds of falls occurred while walking. Of those who fell, 67% did not
      require medical attention. The highest percentage of injuries were bruises or
      grazes (44%), with one fracture reported. Sixty-one percent reported being
      fearful of falling, with an average MFES of 7.4 (+/-2.0), compared with the
      average of 9.7 (+/-0.5) for the age- and gender-matched controls (p<0.05). Only 5
      of the respondents reported changing their level of activity as the result of a
      fall. A significant difference was identified on the Adjusted Activity Score
      (AAS) of the HAP between polio non-fallers (mean 56.3+/-19.1), polio fallers
      (mean 40.1+/-15.6) and age- and gender-matched controls (mean 73.5+/-10.3)
      (F2,46=25.5, p=0.000). The median number of fall prevention activities undertaken
      in the previous 12 months was one, 11 of the 28 respondents undertaking two or
      more. The most common interventions implemented were vision checks (42%) and
      review of medications by a doctor (25%). CONCLUSIONS: A high rate of falling,
      fear of falling and low activity levels exist in older people with polio. There
      is a need for further research and clinical programs to reduce falls and injuries
      in this group.

PMID- 15195988
TI  - Effect of nutritional status on clinical outcome in a population of geriatric
      rehabilitation patients.
AB  - BACKGROUND AND AIMS: In a geriatric patient, nutritional status (NS),
      particularly in the case of malnutrition (M), may influence not only clinical
      results but also achievement of targets expected by geriatric rehabilitation. The
      aim of this study was to evaluate the effect of nutritional status (NS) on the
      occurrence of Adverse Clinical Events (ACE) and on mortality in geriatric
      rehabilitation patients. METHODS: We retrospectively examined the clinical
      records of 278 elderly subjects (154 women, 124 men), admitted to a geriatric
      hospital between September 2000 and December 2001 and evaluated for clinical,
      functional, cognitive and NS within the first 48 hours of admission. Clinical
      outcomes (ACE, mortality) were recorded during follow-up. Logistic regression
      analysis estimated models having mortality or the occurrence of ACE as outcome
      variables. RESULTS: Malnutrition was detected upon admission in 56.1% of the
      sample population. Incidence of ACE in malnourished subjects was higher than that
      in well-nourished patients (28.2 vs 13.1%). Equally, mortality among malnourished
      subjects was higher than among those whose NS was normal (23.1 vs 9.8%). The
      logistic regression models were able to predict: 1) mortality from comorbidity
      (OR 1.43; 95% CI 1.16-1.78; p=0.001) and NS (OR 2.64; 95% CI 1.29-5.4; p=0.008),
      and 2) occurrence of ACE from comorbidity (OR 1.69; 95% CI 1.36-2.1; p=0.000),
      cognitive (OR 1.22; 95% CI 1.11-1.35; p=0.000) and nutritional status (OR 2.38;
      95% CI 1.19-4.8; p=0.015). CONCLUSIONS: NS emerged as the main independent
      predictor of both mortality and occurrence of ACE. Although most patients fell
      into the category of mild/moderate (energy) malnutrition (148/156), a mild
      deterioration of NS, for instance, reduction in triceps skinfold thickness (TSF)
      seemed to be sufficient to cause an increase in the incidence of ACE and in
      mortality.

PMID- 15195989
TI  - Postural balance and health-related factors in middle-aged and older women with
      injurious falls and non-fallers.
AB  - BACKGROUND AND AIMS: Older fallers aged over 70 years have shown impaired balance
      abilities, but it is unclear if impairment in balance control can be detected
      among fallers who are in their 50's and 60's. The aim of this study was to
      analyze possible differences in balance control and other health-related factors
      between female fallers and non-fallers aged 50-68 years. METHODS: Women 50-68
      years of age (N=40) who had fallen outside and needed medical attention were
      recruited through a larger fall accident study. Non-fallers (N=97) were women
      representing the same age group who had not fallen during the preceding 12
      months. A battery of standing force platform balance tests were administered
      together with an interview on health status, use of medication, dizziness,
      vision, hearing, and physical activity. RESULTS: Significant differences were not
      found between women with injurious falls and non-fallers in the various balance
      tests. In the younger age group (50-58 years), chronic illnesses, use of
      medication, dizziness, and self-reported problems with vision and hearing were
      more common in fallers than in non-fallers. CONCLUSIONS: Our results suggest
      that, in active and independent women aged 50-68 years, it is not possible to use
      standing force platform balance tests to detect differences between fallers and
      non-fallers. However, younger women (50-58 years) with injurious falls reported
      more health-related problems than other groups, a fact which should be taken into
      consideration to prevent further development of fall-related problems.

PMID- 15195990
TI  - Left ventricular hypertrophy and blood pressure as predictors of cognitive
      decline in old age.
AB  - BACKGROUND AND AIMS: The relationships between blood pressure (BP) and cognition
      are complex and are still partly unclear. The impact of history of hypertension,
      present BP levels, and left ventricular hypertrophy (LVH) on cognition was
      investigated in a 10-year follow-up study of an aged population. METHODS: The
      population-based sample consisted of 75-, 80- and 85-year-old individuals at
      baseline (N=650). Their history of hypertension was investigated, and present BP
      values were recorded several times. Echocardiographic examinations were performed
      twice at 3-year intervals, and electrocardiography (ECG) at entry. Cognitive
      function was assessed by the Mini-Mental State Examination (MMSE) at baseline and
      at 10 years, and by the Clinical Dementia Rating (CDR) at baseline, at 1, 5 and
      10 years. RESULTS: At baseline, elderly individuals with impaired cognition or
      dementia had lower BP, but thicker left ventricle posterior wall (LVPW), greater
      cardiac mass, and more often signs of LVH in ECG than those without cognitive
      deficits. Echocardiographic LVH, but not BP, predicted cognitive decline in a 5
      year follow-up. Patients who died demented within 5 years were characterized by
      low BP and thin LVPW. Baseline BP and echocardiographic variables were not
      significantly different between those who had and had not cognitive decline at 10
      years, but declining BP tended to precede cognitive deficits. CONCLUSIONS:
      Results indicate that, the closer cognitive decline, the lower the BP, and
      suggest that, although LVH is a risk factor of cognitive decline, it loses its
      predictive value in old age.

PMID- 15195991
TI  - Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone
      sulfate (DHEA-S), and their relationships with serum interleukin-6, in the
      geriatric syndrome of frailty.
AB  - BACKGROUND AND AIMS: The geriatric syndrome of frailty has been conceptualized as
      a loss of physiologic reserve associated with endocrine dysregulation and immune
      dysfunction. Our prior studies suggest that the frailty syndrome is associated
      with elevated serum IL-6 levels. In the present study, our aim is to evaluate the
      possible role of endocrine dysregulation and its relationship with serum IL-6 in
      the pathogenesis of this syndrome. METHODS: Using a recently validated screening
      algorithm for frailty, we identified 18 frail and 33 non-frail community-dwelling
      older adults for inclusion in this study. Serum levels of insulin-like growth
      factor-I (IGF-I), DHEA-S, and IL-6 were measured by immunoassays. The inter
      relationships among serum levels of IL-6, DHEA-S, and IGF-I were determined by
      linear regression analysis. RESULTS: Age-adjusted serum levels of IGF-I (88+/-49
      vs 122+/-47 [ng/mL], p<0.023) and DHEA-S (0.30+/-0.21 vs 0.53+/-0.25 [microg/mL],
      p=0.016) were significantly lower in frail vs non-frail individuals,
      respectively. There was a trend for IL-6 to be inversely correlated with IGF-I in
      the frail (r=-0.42; p=0.082) but not the non-frail group (r=0.12, p=0.521).
      CONCLUSIONS: Frail subjects have lower levels of serum IGF-I and DHEA-S and
      higher levels of IL-6 than do non-frail, age-matched individuals. The trend
      toward an inverse correlation between IGF-I and IL-6 in the frail, but not the
      non-frail group, suggests potential interaction between endocrine and
      immune/cytokine dysregulation that requires further study in larger cohorts.

PMID- 15195992
TI  - A longitudinal study integrating population, care and social services data. The
      Swedish National study on Aging and Care (SNAC).
AB  - BACKGROUND AND AIMS: A large, national, long-term, longitudinal, multi-purpose
      study has been launched in Sweden--the Swedish National study on Aging and Care
      (SNAC). The study involves four research centers collecting data in four
      different areas of Sweden. METHODS: The study consists of two parts: the
      population part and the care and services part. In the population part, a large,
      representative panel of elders in different age cohorts is followed over time to
      record and describe the aging process from different aspects. In the care and
      services part, a systematic, longitudinal, individually-based collection of data
      is performed concerning provision of care and services together with functional
      ability, specific health care problems, and living conditions of the recipients
      living in the area. RESULTS: The data collection in the population part of the
      SNAC is not yet completed. In the present article, some preliminary results are
      reported from the care and services part. These pertain to comparisons between
      the participating areas with respect to the prevalence of disability among those
      receiving care and social services in their ordinary homes and those receiving
      care in special accommodation. A comparison is also presented with regard to the
      amount of home help provided to subjects with a given disability. CONCLUSIONS:
      This project has several advantages. It is expected to generate a rich data base
      relevant for future research on aging and care and to have a direct impact on the
      future Swedish system of care and services for the elderly.

PMID- 15195993
TI  - Lower platelet count in healthy centenarians correlates with dispersion of the QT
      interval.
AB  - BACKGROUND AND AIMS: Centenarians display a lower incidence of vascular ischemic
      events. A high platelet count and increased QT dispersion (QTd) represents a risk
      factor for cardiovascular events. The aim of this study was to evaluate platelet
      count and QTd in healthy centenarians and to establish correlations between these
      two indices. METHODS: 16 healthy centenarians (4 males, 12 females, range 100-105
      years) living in a municipality of Eastern Sicily, and 40 healthy control
      subjects, divided into two groups: group A (N=20), age range 45-65 years, 7
      males, 13 females; and group B (N=20), range 65-85 years, 6 males, 14 females,
      were examined. Platelets were counted using a blood analyzer and QTd was measured
      in standard 12-lead electrocardiograms. Differences in platelet count were
      assessed by one-way analysis of variance (ANOVA) and the Bonferroni test.
      Correlation coefficients between platelet count and QTd were calculated with the
      Spearman rank test. RESULTS: Centenarians showed a lower platelet count compared
      with controls, which was significant with respect to older controls, group B
      (p<0.05). QTd values did not significantly differ between centenarians and
      controls. A significant correlation between QTd and platelet count was evident in
      centenarians but not in controls. This correlation became evident in control
      subjects with a platelet count < or = 240,000/mm3. CONCLUSIONS: We hypothesize
      that a reduced number of platelets and the maintenance of normal QTd may
      contribute to extreme longevity and protect centenarians from cardiovascular
      events.

PMID- 15195994
TI  - Role of reporter gene imaging in molecular and cellular biology.
AB  - Molecular imaging, including reporter gene methods, provides a unique opportunity
      to study biology in a living subject, thereby allowing physiological events to be
      monitored in an intact microenvironment. This review takes a molecular and cell
      biology perspective on recent studies which utilize reporter gene imaging as a
      tool to non-invasively monitor specific molecular biology pathways in vivo.
      Studies in rodent models demonstrate the feasibility of reporter gene imaging to
      visualize and measure key cellular pathways, such as transcription, translation
      and protein-protein interactions. The review indicates that molecular imaging is
      likely to be useful in the translation of molecular biology to medicine and
      biotechnological applications.

PMID- 15195995
TI  - Comprehensive search for cysteine cathepsins in the human genome.
AB  - Our study was aimed at examinating whether or not the human genome encodes for
      previously unreported cysteine cathepsins. To this end, we used analyses of the
      genome sequence and mRNA expression levels. The program TBLASTN was employed to
      scan the draft sequence of the human genome for the 11 known cysteine cathepsins.
      The cathepsin-like segments in the genome were inspected, filtered, and
      annotated. In addition to the known cysteine cathepsins, the scan identified
      three pseudogenes, closely related to cathepsin L, on chromosome 10, as well as
      two remote homologs, tubulointerstitial protein antigen and tubulointerstitial
      protein antigen-related protein. No new members of the family were identified.
      mRNA expression profiles for 10 known human cysteine cathepsins showed varying
      expression levels in 46 different human tissues and cell lines. No expression of
      any of the three cathepsin L-like pseudogenes was found. Based on these results,
      it is likely that to date all human cysteine cathepsins are known.

PMID- 15195997
TI  - Identification of arginine residues important for the activity of Escherichia
      coli signal peptidase I.
AB  - Escherichia coil signal peptidase I (leader peptidase, SPase I) is an integral
      membrane serine protease that catalyzes the cleavage of signal (leader) peptides
      from pre-forms of membrane or secretory proteins. We previously demonstrated that
      E. coil SPase I was significantly inactivated by reaction with phenylglyoxal with
      concomitant modification of three to four of the total 17 arginine residues in
      the enzyme. This result indicated that several arginine residues are important
      for the optimal activity of the enzyme. In the present study, we have constructed
      17 mutants of the enzyme by site-directed mutagenesis to investigate the role of
      individual arginine residues in the enzyme. Mutation of Arg127, Arg146, Arg198,
      Arg199, Arg226, Arg236, Arg275, Arg282, and Arg295 scarcely affected the enzyme
      activity in vivo and in vitro. However, the enzymatic activity toward a synthetic
      substrate was significantly decreased by replacements of Arg77, Arg222, Arg315,
      or Arg318 with alanine/lysine. The kcat values of the R77A, R77K, R222A, R222K,
      R315A, R318A, and R318K mutant enzymes were about 5.5-fold smaller than that of
      the wild-type enzyme, whereas the Km values of these mutant enzymes were almost
      identical with that of the wild-type. Moreover, the complementing abilities in E.
      Arg222, Arg315, coil IT41 were lost completely when Arg77, or Arg318 was replaced
      with alanine/lysine. The circular dichroism spectra and other enzymatic
      properties of these mutants were comparable to those of the wild-type enzyme,
      indicating no global conformational changes. However, the thermostability of
      R222A, R222K, R315A, and R318K was significantly lower compared to the wild type.
      Therefore, Arg77, Arg222, Arg315, and Arg318 are thought to be important for
      maintaining the proper and stable conformation of SPase I.

PMID- 15195996
TI  - Structure of the Q237W mutant of HhaI DNA methyltransferase: an insight into
      protein-protein interactions.
AB  - We have determined the structure of a mutant (Q237W) of HhaI DNA
      methyltransferase, complexed with the methyl-donor product AdoHcy. The Q237W
      mutant proteins were crystallized in the monoclinic space group C2 with two
      molecules in the crystallographic asymmetric unit. Protein-protein interface
      calculations in the crystal lattices suggest that the dimer interface has the
      specific characteristics for homodimer protein-protein interactions, while the
      two active sites are spatially independent on the outer surface of the dimer. The
      solution behavior suggests the formation of HhaI dimers as well. The same HhaI
      dimer interface is also observed in the previously characterized binary (M.HhaI
      AdoMet) and ternary (M.HhaI-DNA-AdoHcy) complex structures, crystallized in
      different space groups. The dimer is characterized either by a non
      crystallographic two-fold symmetry or a crystallographic symmetry. The dimer
      interface involves three segments: the amino-terminal residues 2-8, the carboxy
      terminal residues 313-327, and the linker (amino acids 179-184) between the two
      functional domains--the catalytic methylation domain and the DNA target
      recognition domain. Both the amino- and carboxy-terminal segments are part of the
      methylation domain. We also examined protein-protein interactions of other
      structurally characterized DNA MTases, which are often found as a 2-fold related
      'dimer' with the largest dimer interface area for the group-beta MTases. A
      possible evolutionary link between the Type I and Type II restriction
      modification systems is discussed.

PMID- 15195998
TI  - Characterization of pancreatic ERj3p, a homolog of yeast DnaJ-like protein Scj1p.
AB  - We have previously identified in the human EST sequence data base four
      overlapping clones that could be aligned with both a predicted protein sequence,
      deduced from the C. elegans genomic sequence, and partial amino acid sequences,
      obtained for a protein from canine pancreatic microsomes. We suggested that these
      proteins are homologs of yeast microsomal and DnaJ-like protein Scj1p and termed
      them ERj3p. Here we verified the predicted protein sequence of human ERj3p by
      sequence analysis of the corresponding cDNA. Multiple alignment of related
      sequences identified these proteins as true homologs of yeast Scj1p. Biochemical
      analysis of the canine protein characterized ERj3p as a soluble glycoprotein of
      the pancreatic endoplasmic reticulum. This pancreatic DnaJ-like protein was shown
      to interact with lumenal DnaK-like proteins, such as BiP. Furthermore, we found
      that ERj3p interacts with SDF2L1 protein that may be involved in protein O
      glycosylation. We propose that ERj3p represents a cochaperone of DnaK-like
      chaperones of the mammalian endoplasmic reticulum and is involved in folding and
      maturation of newly synthesized proteins.

PMID- 15195999
TI  - Carbohydrate moieties can induce mediator release: a detailed characterization of
      two major timothy grass pollen allergens.
AB  - Specific IgE binding to carbohydrate moieties of glycosylated allergens has been
      known for years, but the importance of these structures for the elicitation of
      allergic reactions is still a matter of debate. Because of their conserved
      carbohydrate structures, especially N-glycans have always been prime candidates
      for IgE cross-reactivity between allergens from unrelated species. The aim of our
      study was to determine whether carbohydrate structures on glycoproteins can by
      themselves elucidate allergic reactions. We characterized in detail the
      carbohydrate moieties of the major allergens Phl p 1 and Phl p 13 of timothy
      grass pollen (Phleum pratense L.) by performing tryptic digests followed by HPLC,
      N-terminal sequencing, sugar analysis, MALDI-TOF- and ESI-ICRFT-MS. Phl p 1
      contains one N-glycan with one of the two glycoforms MMXF3 and M0XF3 and a single
      furanosidic arabinose, which is bound to a hydroxyproline residue in direct
      vicinity to the N-glycan. This O-glycosylation is probably due to an
      arabinosylation consensus sequence found in the N-terminal part of Phl p 1 and
      other group 1 allergens, but displayed no IgE-reactivity. Thus, Phl p 1 is
      monovalent with respect to its IgE-binding carbohydrate epitopes and showed no
      mediator release. In contrast, the carbohydrate moiety of Phl p 13, which carries
      four of the same N-glycans (like Phl p 1), can cross-link IgE-receptors via
      carbohydrate chains and elicits IL-4 release from basophils.

PMID- 15196001
TI  - Activation of NF-kappaB/Rel transcription factors in human primary peripheral
      blood mononuclear cells by interleukin 7.
AB  - Pathways that regulate the activation of NF-kappaB/Rel transcription factors are
      known to include signaling through a number of cytokine receptors. Interleukin 7
      (IL-7), produced by bone marrow and other stromal cells, is a key factor for
      differentiation and survival in the lymphoid and other compartments. We found
      that human recombinant IL-7 induced NF-kappaB/Rel activation, analyzed by
      electrophoretic mobility shift assay (EMSA), in human peripheral blood T
      lymphocytes from healthy donors. Induced complexes included p65 and p50 NF
      kappaB/Rel subunits. These results demonstrate for the first time that IL-7 can
      participate in signaling leading to NF-kappaB/Rel activation.

PMID- 15196000
TI  - The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity.
AB  - LFM-A13, or alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5
      dibromophenyl)propenamide, was shown to inhibit Bruton's tyrosine kinase (Btk).
      Here we show that LFM-A13 efficiently inhibits erythropoietin (Epo)-induced
      phosphorylation of the erythropoietin receptor, Janus kinase 2 (Jak2) and
      downstream signalling molecules. However, the tyrosine kinase activity of
      immunoprecipitated or in vitro translated Btk and Jak2 was equally inhibited by
      LFM-A13 in in vitro kinase assays. Finally, Epo-induced signal transduction was
      also inhibited in cells lacking Btk. Taken together, we conclude that LFM-A13 is
      a potent inhibitor of Jak2 and cannot be used as a specific tyrosine kinase
      inhibitor to study the role of Btk in Jak2-dependent cytokine signalling.

PMID- 15196002
TI  - Cystatin SA, a cysteine proteinase inhibitor, induces interferon-gamma expression
      in CD4-positive T cells.
AB  - Recently, it has been demonstrated that family 2 cystatins upregulate interleukin
      6 production by human gingival fibroblasts. In the present study, we investigated
      the effects of cystatin SA on cytokine production by helper T cells. Human CD4
      positive T cells were cultured with phytohemagglutinin in the presence or absence
      of 0.1 microM recombinant cystatin SA1 or SA2. When the amounts of interleukin-4
      (IL-4) and interferon-gamma (IFNgamma) were analyzed in an ELISA system after
      stimulation with either cystatin, no significantly increased levels of IL-4 were
      detected. However, the amounts of IFNgamma were significantly increased after
      stimulation with the cystatins. Our results suggest that salivary family 2
      cystatins are involved in immune responses through the cytokine network.

PMID- 15196003
TI  - Inhibition of human pancreatic proteinases by human plasma alpha2-antiplasmin and
      antithrombin.
AB  - Human plasma alpha1-antitrypsin inhibits human pancreatic trypsin, chymotrypsin
      and elastase, which are massively released into the blood stream during acute
      pancreatitis. To examine whether the plasma proteins of individuals with genetic
      deficiency of alpha1-antitrypsin are protected against the deleterious action of
      these enzymes by other inhibitors, we have tested their inhibition by alpha2
      antiplasmin and antithrombin. We have determined the inhibition rate constants
      kass and calculated d(t), the in vivo inhibition time. Surprisingly, trypsin is
      inhibited faster by alpha2-antiplasmin [kass=2.5 x 10(6) M(-1)S(-1), d(t)=2.3 s]
      and antithrombin [kass=1.7 x 10(5) M(-1)s(-1), d(t)=5.8 s] than by alpha1
      antitrypsin [d(t)=17 s or 116 s in alpha1-antitrypsin-sufficient or alpha1
      antitrypsin-deficient individuals, respectively]. Low molecular weight heparin
      accelerates the inhibition of trypsin by antithrombin by a factor of 16
      [d(t)=0.36 s]. Antithrombin and alpha2-antiplasmin are not physiological
      inhibitors of chymotrypsin and elastase. These enzymes are, however,
      physiologically inhibited by alpha1-antitrypsin and alpha1-antichymotrypsin even
      in alpha1-antitrypsin-deficient individuals. We conclude that (i) low molecular
      weight heparin may be helpful in the management of acute pancreatitis, and (ii)
      genetically determined alpha1-antitrypsin deficiency probably does not lead to a
      significantly increased risk of plasma protein degradation during this disease.

PMID- 15196004
TI  - New protease inhibitors from buckwheat seeds: properties, partial amino acid
      sequences and possible biological role.
AB  - Preparations of new low molecular weight protein inhibitors of serine proteinases
      have been obtained from buckwheat Fagopyrum esculentum seeds by chromatography of
      seed extracts on trypsin-Sepharose 4B, Mono-Q and Mono-S ion-exchangers. Their
      molecular masses, determined by mass spectrometry, were equal to 5203 (BWI-1c),
      5347 (BWI-2c), 7760 (BWI-3c) and 6031 daltons (BWI-4c). All inhibitors possessed
      high pH-stability in the pH range 2-12 and thermostability. In addition to
      trypsin, BWI-3c and BWI-4c inhibitors inhibited chymotrypsin and subtilisin-like
      proteases. The inhibition constants (Ki) for trypsin, chymotrypsin and subtilisin
      by the studied inhibitors were determined. The N-terminal sequences of all
      inhibitors were established: BWI-1c (23 residues), BWI-2c (33 residues), BWI-3c
      (18 residues) and BWI-4c (20 residues). According to the physicochemical
      properties and N-terminal amino acid sequences, buckwheat seed protease
      inhibitors BWI-3c and BWI-4c are suggested to belong to the potato proteinase
      inhibitor I family.

PMID- 15196005
TI  - Synthesis and antiplasmodial activity of a cysteine protease-inhibiting
      biotinylated aziridine-2,3-dicarboxylate.
AB  - Cysteine proteases have been implicated in a variety of processes essential for
      the survival and progression of the malarial parasite Plasmodium falciparum.
      Here, we synthesized a cysteine protease inhibitor that contains the
      electrophilic aziridine-2,3-dicarboxylic acid as the reactive agent and biotin as
      a targeting label. Diethyl ester and dibenzyl ester derivatives of the inhibitor
      were active against cathepsin L and the plasmodial protease falcipain 2, but only
      the latter displayed potent antiplasmodial activity against viable parasites. The
      morphological changes observed during the intraerythrocytic life stages of
      Plasmodium suggest that degradation of hemoglobin of the host cell is seriously
      affected, eventually leading to growth arrest and cell death of the parasites.
      After incubation of infected erythrocytes with the compound plasmodial proteins
      were captured, with the biotinyl group of the inhibitor serving as an affinity
      tag. Among these the cysteine proteases falcipain 2 and falcipain 3 were
      identified as potential target proteins of the compound as evidenced by tandem
      mass spectrometry. Apparently, the compound gets access to intracellular
      compartments and therein targets plasmodial cysteine proteases. Accordingly, the
      reagent described here appears to be a valuable template to develop cell
      permeable, non-radioactive reagents that selectively target enzymes involved in
      pathogenicity of the parasite.

PMID- 15196006
TI  - Cathepsins K, L, B, X and W are differentially expressed in normal and
      chronically inflamed gastric mucosa.
AB  - The expression of cathepsins K, L, B, X and W was studied by quantitative RT-PCR
      in normal and inflamed gastric mucosa (antrum, corpus, cardia). Cathepsins B, L,
      K and X were expressed ubiquitously. In contrast, cathepsin W was expressed at
      very low levels. Infection by Helicobacter pylori caused a significant induction
      of cathepsin X (p<0.008), whereas the other cathepsins were not or only locally
      affected by H. pylori infection or reflux disease. Immunohistochemistry revealed
      specific expression of cathepsin X (macrophages), cathepsin K (parietal cells)
      and cathepsin W (lymphocytes), whereas cathepsins B and L were predominantly
      expressed in epithelial cells.

PMID- 15196007
TI  - Exploring molecular and mechanical gradients in structural bioscaffolds.
AB  - Most organisms consist of a functionally adaptive assemblage of hard and soft
      tissues. Despite the obvious advantages of reinforcing soft protoplasm with a
      hard scaffold, such composites can lead to tremendous mechanical stresses where
      the two meet. Although little is known about how nature relieves these stresses,
      it is generally agreed that fundamental insights about molecular adaptation at
      hard/soft interfaces could profoundly influence how we think about biomaterials.
      Based on two noncellular tissues, mussel byssus and polychaete jaws, recent
      studies suggest that one natural strategy to minimize interfacial stresses
      between adjoining stiff and soft tissue appears to be the creation of a "fuzzy"
      boundary, which avoids abrupt changes in mechanical properties. Instead there is
      a gradual mechanical change that accompanies the transcendence from stiff to soft
      and vice versa. In byssal threads, the biochemical medium for achieving such a
      gradual mechanical change involves the elegant use of collagen-based self
      assembling block copolymers. There are three distinct diblock copolymer types in
      which one block is always collagenous, whereas the other can be either elastin
      like (soft), amorphous polyglycine (intermediate), or silk-like (stiff).
      Gradients of these are made by an incrementally titrated expression of the three
      proteins in secretory cells the titration phenotype of which is linked to their
      location. Thus, reflecting exactly the composition of each thread, the distal
      cells secrete primarily the silk- and polyglycine-collagen diblocks, whereas the
      proximal cells secrete the elastin- and polyglycine-collagen diblocks. Those
      cells in between exhibit gradations of collagens with silk or elastin blocks.
      Spontaneous self-assembly appears to be by pH triggered metal binding by
      histidine (HIS)-rich sequences at both the amino and carboxy termini of the
      diblocks. In the polychaete jaws, HIS-rich sequences are expanded into a major
      block domain. Histidine predominates at over 20 mol % near the distal tip and
      diminishes to about 5 mol % near the proximal base. The abundance of histidine is
      directly correlated to transition metal content (Zn or Cu) as well as hardness
      determined by nanoindentation. EXAFS analyses of the jaws indicate that
      transition metals such as Zn are directly bound to histidine ligands and may
      serve as cross-linkers.

PMID- 15196008
TI  - Three-dimensional structure of human adenine phosphoribosyltransferase and its
      relation to DHA-urolithiasis.
AB  - In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in
      all tissues and provides the only known mechanism for the metabolic salvage of
      adenine resulting from the polyamine biosynthesis pathway or from dietary
      sources. In humans, APRT deficiency results in serious kidney illness such as
      nephrolithiasis, interstitial nephritis, and chronic renal failure as a result of
      2,8-dihydroxyadenine (DHA) precipitation in the renal interstitium. To address
      the molecular basis of DHA-urolithiasis, the recombinant human APRT was
      crystallized in complex with adenosine 5'-monophosphate (AMP). Refinement of X
      ray diffraction data extended to 2.1 A resolution led to a final crystallographic
      R(factor) of 13.3% and an R(free) of 17.6%. This structure is composed of nine
      beta-strands and six alpha-helices, and the active site pocket opens slightly to
      accommodate the AMP product. The core of APRT is similar to that of other
      phosphoribosyltransferases (PRTases), although the adenine-binding domain is
      quite different. Structural comparisons between the human APRT and other "type I"
      PRTases of known structure revealed several important features of the
      biochemistry of PRTases. We propose that the residues located at positions
      corresponding to Leu159 and Ala131 in hAPRT are responsible for the base
      specificities of type I PRTases. The comparative analysis shown here also
      provides structural information for the mechanism by which mutations in the human
      APRT lead to DHA-urolithiasis.

PMID- 15196009
TI  - Generation of a thermostable and denaturant-resistant peptide ligase.
AB  - The construction and characterization of a novel, thermostable, peptide ligase
      are described. Three amino acid substitutions were introduced into the secreted
      bacterial protease Streptomyces griseus protease B (SGPB). Mutations were chosen
      on the basis of two separate observations: (i) that a single substitution of the
      nucleophilic serine (S195A) created an enzyme with significant peptide-ligation
      activity, albeit greatly reduced stability [(2000) Chem. Biol. 7, 163], and (ii)
      that a pair of substitutions in the substrate-binding pocket (T213L and F228H)
      greatly increased the thermostability of the wild-type enzyme [(1996) J. Mol.
      Biol. 257, 233]. The triple mutant, named streptoligase, was found to catalyze
      peptide ligation (aminolysis of both a thiobenzyl ester and a p-nitroanilide
      activated peptide) efficiently in nondenaturing and denaturing conditions
      including SDS (0.5% w/v) and guanidine hydrochloride (4.0 M). Moreover,
      streptoligase exhibited a half-live for unfolding of 16.3 min at 55 degrees C in
      the absence of stabilizing substrates. The fraction of the streptoligase
      catalyzed reaction that gave coupled product with the acceptor peptide FAASR
      NH(2) was greater for the p-nitroanilide donor (Sc-AAPF-pNA) than for the benzyl
      thioester substrate (Sc-AAPF-SBn). These observations are consistent with
      ligation proceeding through an acyl-enzyme intermediate involving histidine-57.
      In the case of the thioester donor the triple mutant promotes the direct attack
      of water on the thioester carbonyl carbon, in addition to hydrolysis occurring at
      the stage of the acyl-enzyme intermediate. The strategy of multiple point
      mutations outlined in this study may provide a general means of converting
      enzymes with chymotrypsin-like protein folds into peptide ligases.

PMID- 15196010
TI  - A molecular ruler for chain elongation catalyzed by octaprenyl pyrophosphate
      synthase and its structure-based engineering to produce unprecedented long chain
      trans-prenyl products.
AB  - Octaprenyl pyrophosphate synthase (OPPs) catalyzes consecutive condensation
      reactions of farnesyl pyrophosphate (FPP) with five molecules of isopentenyl
      pyrophosphate (IPP) to generate C(40) octaprenyl pyrophosphate (OPP) which
      constitutes the side chain of menaquinone. We have previously reported the X-ray
      structure of OPPs from Thermotoga maritima, which is composed entirely of alpha
      helices joined by connecting loops and is arranged with nine core helices around
      a large central cavity [Guo, R. T., Kuo, C. J., Ko, T. P., Chou, C. C., Shr, R.
      L., Liang, P. H., and Wang, A. H.-J. (2004) J. Biol. Chem. 279, 4903-4912]. A76
      and S77 are located on top of the active site close to where FPP is bound. A76Y
      and A76Y/S77F OPPs mutants produce C(20), indicating that the substituted larger
      residues interfere with the substrate chain elongation. Surprisingly, the
      A76Y/S77F mutant synthesizes a larger amount of C(20) than the A76Y mutant. In
      the crystal structure of the A76Y/S77F mutant, F77 is pushed away by Y76, thereby
      creating more space between those two large amino acids to accommodate the C(20)
      product. A large F132 residue at the bottom of the tunnel-shaped active site
      serves as the "floor" and determines the final product chain length. The
      substitution of F132 with a small Ala, thereby removing the blockade, led to the
      synthesis of a C(50) product larger than that produced by the wild-type enzyme.
      On the basis of the structure, we have sequentially mutated the large amino
      acids, including F132, L128, I123, and D62, to Ala underneath the tunnel. The
      products of the F132A/L128A/I123A/D62A mutant reach C(95), beyond the largest
      chain length generated by all known trans-prenyltransferases. Further
      modifications of the enzyme reaction conditions, including new IPP derivatives,
      may allow the preparation of high-molecular weight polyprenyl products resembling
      the rubber molecule.

PMID- 15196011
TI  - Structure of the His44 --> Ala single point mutant of the distal finger motif of
      HIV-1 nucleocapsid protein: a combined NMR, molecular dynamics simulation, and
      fluorescence study.
AB  - The nucleocapsid protein (NCp7) of human immunodeficiency virus type 1 (HIV-1)
      contains two highly conserved CCHC zinc fingers that strongly bind Zn(2+) through
      coordination of one His and three Cys residues. It has been suggested that NCp7
      function is conformation specific since substitution of any of the zinc
      coordinating residues in the zinc finger motifs leads to subsequent loss of viral
      infectivity. To further determine the structural requirements necessary for this
      specific conformation, we investigated by (1)H 2D NMR and molecular dynamics
      simulations the structure of the distal finger motif of NCp7 in which the zinc
      coordinating amino acid, His 44, was substituted by a noncoordinating Ala
      residue. While the fold of the N-terminal part of this mutated peptide was
      similar to that of the native peptide, an increased lability and significant
      conformational changes were observed in the vicinity of the His-to-Ala mutation.
      Moreover, molecular dynamics simulations suggested a mechanism by which the
      variant peptide can bind zinc ion even though one zinc-coordinating amino acid
      was lacking. Using the fluorescence of the naturally occurring Trp37 residue, the
      binding affinity of the variant peptide to the (TG)(3) model oligonucleotide was
      found to be decreased by about 2 orders of magnitude with respect with the native
      peptide. Modeling of the DNA:NCp7 complex using structures of the variant peptide
      suggests that the residues forming a hydrophobic cleft in the native protein are
      improperly oriented for efficient DNA binding by the variant peptide.

PMID- 15196012
TI  - Primary amphipathic cell-penetrating peptides: structural requirements and
      interactions with model membranes.
AB  - To identify rules for the design of efficient cell-penetrating peptides that
      deliver therapeutic agents into subcellular compartments, we compared the
      properties of two closely related primary amphipathic peptides that mainly differ
      by their conformational state. On the basis of a peptide Pbeta that is
      nonstructured in water and that promotes efficient cellular uptake of nucleic
      acids through noncovalent association, we have designed a peptide [Palpha] that
      is predicted to adopt a helical conformation. We show that [Pbeta] undergoes a
      lipid-induced conformational transition into a sheet structure, while [Palpha]
      remains helical. Penetration experiments show that both peptides can
      spontaneously insert into phospholipid membranes. Analysis of compression
      isotherms indicates that both peptides interact with phospholipids in the liquid
      expanded and liquid condensed states. AFM observations reveal that the peptides
      strongly disrupt the lipid organization of the monolayers and that the
      conformational state can influence the uptake by model membranes.

PMID- 15196013
TI  - The inhibitor DBMIB provides insight into the functional architecture of the Qo
      site in the cytochrome b6f complex.
AB  - Previously [Roberts, A. G., and Kramer, D. M. (2001) Biochemistry 40, 13407
      13412], we showed that 2 equiv of the quinone analogue 2,5-dibromo-3-methyl-6
      isopropylbenzoquinone (DBMIB) could occupy the Q(o) site of the cytochrome (cyt)
      b(6)f complex simultaneously. In this work, a study of electron paramagnetic
      resonance (EPR) spectra from the oriented cyt b(6)f complex shows that the Rieske
      iron-sulfur protein (ISP) is in distinct orientations, depending on the
      stoichiometry of the inhibitor at the Q(o) site. With a single DBMIB at the Q(o)
      site, the ISP is oriented with the 2Fe-2S cluster toward cyt f, which is similar
      to the orientation of the ISP in the X-ray crystal structure of the cyt b(6)f
      complex from thermophilic cyanobacterium Mastigocladus laminosus in the presence
      of DBMIB, as well as that of the chicken mitochondrial cyt bc(1) complex in the
      presence of the class II inhibitor myxothiazol, which binds in the so-called
      "proximal niche", near the cyt b(L) heme. These data suggest that the high
      affinity DBMIB site is at the proximal niche Q(o) pocket. With >or=2 equiv of
      DBMIB bound, the Rieske ISP is in a position that resembles the ISP(B) position
      of the chicken mitochondrial cyt bc(1) complex in the presence of stigmatellin
      and the Chlamydomonas reinhardtii cyt b(6)f complex in the presence of
      tridecylstigmatellin (TDS), which suggests that the low-affinity DBMIB site is at
      the distal niche. The close interaction of DBMIB bound at the distal niche with
      the ISP induced the well-known effects on the 2Fe-2S EPR spectrum and redox
      potential. To further test the effects of DBMIB on the ISP, the extents of cyt f
      oxidation after flash excitation in the presence of photosystem II inhibitor DCMU
      were measured as a function of DBMIB concentration in thylakoids. Addition of
      DBMIB concentrations at which a single binding was expected did not markedly
      affect the extent of cyt f oxidation, whereas higher concentrations, at which
      double occupancy was expected, increased the extent of cyt f oxidation to levels
      similar to that of cyt f oxidation in the presence of a saturating concentration
      of stigmatellin. Simulations of the EPR g-tensor orientations of the 2Fe-2S
      cluster versus the physical orientations based on single-crystal studies of the
      cyt bc(1) complex suggest that the soluble ISP domain of the spinach cyt b(6)f
      complex can rotate by at least 53 degrees, which is consistent with long-range
      ISP domain movement. Implications of these results are discussed in the context
      of the X-ray crystal structures of the chicken mitochondrial cyt bc(1) complex
      and the M. laminosus and C. reinhardtii cyt b(6)f complexes.

PMID- 15196014
TI  - Protein dynamics in the region of the sixth ligand methionine revealed by studies
      of imidazole binding to Rhodobacter capsulatus cytochrome c2 hinge mutants.
AB  - All class I c-type cytochromes studied to date undergo a dynamic process in the
      oxidized state, which results in the transient breaking of the iron-methionine
      sulfur bond and sufficient movement to allow the binding of exogenous ligands
      (imidazole in this work). In the case of Rhodobacter capsulatus cytochrome c(2),
      the sixth heme ligand Met96 and up to 14 flanking residues (positions 88-100,
      termed the hinge region), located between two relatively rigid helical regions,
      may be involved in structural changes leading to a transient high-spin species
      able to bind ligands. We have examined 14 mutations at 9 positions in the hinge
      region of Rhodobacter capsulatus cytochrome c(2) and have determined the
      structure of the G95E mutant. Mutations near the N- and C-terminus of the hinge
      region do not affect the kinetics of movement but allow us to further define that
      portion of the hinge that moves away from the heme to the 93-100 region in the
      amino acid sequence. Mutations at positions 93 and 95 can alter the rate constant
      for hinge movement (up to 20-fold), presumably as a result of altering the
      structure of the native cytochrome to favor a more open conformation. The
      structure of one of these mutants, G95E, suggests that interactions within the
      hinge region are stabilized while interaction between the hinge and the heme are
      destabilized. In contrast, mutations at positions 98 and 99 alter imidazole
      binding kinetics but not the hinge movement. Thus, it appears that these
      mutations affect the structure of the cytochrome after the hinge region has moved
      away from the heme, resulting in increased solvent access to the bound imidazole
      or alter interactions between the protein and the bound imidazole.

PMID- 15196015
TI  - Mandelamide hydrolase from Pseudomonas putida: characterization of a new member
      of the amidase signature family.
AB  - A recently discovered enzyme in the mandelate pathway of Pseudomonas putida,
      mandelamide hydrolase (MAH), catalyzes the hydrolysis of mandelamide to mandelic
      acid and ammonia. Sequence analysis suggests that MAH is a member of the amidase
      signature family, which is widespread in nature and contains a novel Ser-cis-Ser
      Lys catalytic triad. Here we report the expression in Escherichia coli,
      purification, and characterization of both wild-type and His(6)-tagged MAH. The
      recombinant enzyme was stable, exhibited a pH optimum of 7.8, and was able to
      hydrolyze both enantiomers of mandelamide with little enantiospecificity. The His
      tagged variant showed no significant change in kinetic constants. Phenylacetamide
      was found to be the best substrate, with changes in chain length or replacement
      of the phenyl group producing greatly decreased values of k(cat)/K(m). As with
      another member of this family, fatty acid amide hydrolase, MAH has the uncommon
      ability to hydrolyze esters and amides at similar rates. MAH is even more unusual
      in that it will only hydrolyze esters and amides with little steric bulk. Ethyl
      and larger esters and N-ethyl and larger amides are not substrates, suggesting
      that the MAH active site is very sterically hindered. Mutation of each residue in
      the putative catalytic triad to alanine resulted in total loss of activity for
      S204A and K100A, while S180A exhibited a 1500-fold decrease in k(cat) and
      significant increases in K(m) values. Overall, the MAH data are similar to those
      of fatty acid amide hydrolase and support the suggestion that there are two
      distinct subgroups within the amidase signature family.

PMID- 15196017
TI  - The typically disordered N-terminus of PKA can fold as a helix and project the
      myristoylation site into solution.
AB  - Protein kinases comprise the major enzyme family critically involved in signal
      transduction pathways; posttranslational modifications affect their regulation
      and determine signaling states. The prototype protein kinase A (PKA) possesses an
      N-terminal alpha-helix (Helix A) that is atypical for kinases and is thus a major
      distinguishing feature of PKA. Its physiological function may involve
      myristoylation at the N-terminus and modulation via phosphorylation at serine 10.
      Here we describe an unusual structure of an unmyristoylated PKA, unphosphorylated
      at serine 10, with a completely ordered N-terminus. Using standard conditions
      (e.g., PKI 5-24, ATP site ligand, MEGA-8), a novel 2-fold phosphorylated PKA
      variant showed the ordered N-terminus in a new crystal packing arrangement. Thus,
      the critical factor for structuring the N-terminus is apparently the absence of
      phosphorylation of Ser10. The flexibility of the N-terminus, its myristoylation,
      and the conformational dependence on the phosphorylation state are consistent
      with a functional role for myristoylation.

PMID- 15196016
TI  - Structures of the yeast ribonucleotide reductase Rnr2 and Rnr4 homodimers.
AB  - Class I ribonucleotide reductases (RNRs) catalyze the reduction of
      ribonucleotides to deoxyribonucleotides. Eukaryotic RNRs comprise two subunits,
      the R1 subunit, which contains substrate and allosteric effector binding sites,
      and the R2 subunit, which houses a catalytically essential diiron-tyrosyl radical
      cofactor. In Saccharomyces cerevisiae, there are two variants of the R2 subunit,
      called Rnr2 and Rnr4. Rnr4 is unique in that it lacks three iron-binding residues
      conserved in all other R2s. Nevertheless, Rnr4 is required to activate Rnr2, and
      the functional species in vivo is believed to be a heterodimeric complex between
      the two proteins. The crystal structures of the Rnr2 and Rnr4 homodimers have
      been determined and are compared to that of the heterodimer. The homodimers are
      very similar to the heterodimer and to mouse R2 in overall fold, but there are
      several key differences. In the Rnr2 homodimer, one of the iron-binding helices,
      helix alphaB, is not well-ordered. In the heterodimer, interactions with a loop
      region connecting Rnr4 helices alphaA and alpha3 stabilize this Rnr2 helix, which
      donates iron ligand Asp 145. Sequence differences between Rnr2 and Rnr4 prevent
      the same interactions from occurring in the Rnr2 homodimer. These findings
      provide a structural rationale for why the heterodimer is the preferred complex
      in vivo. The active-site region in the Rnr4 homodimer reveals interactions not
      apparent in the heterodimer, supporting previous conclusions that this subunit
      does not bind iron. When taken together, these results support a model in which
      Rnr4 stabilizes Rnr2 for cofactor assembly and activity.

PMID- 15196018
TI  - Altering DNA polymerase incorporation fidelity by distorting the dNTP binding
      pocket with a bulky carcinogen-damaged template.
AB  - Fidelity of DNA polymerases is predominantly governed by an induced fit mechanism
      in which the incoming dNTP in the ternary complex fits tightly into a binding
      pocket whose geometry is determined by the nature of the templating base.
      However, modification of the template with a bulky carcinogen may alter the dNTP
      binding pocket and thereby the polymerase incorporation fidelity. High fidelity
      DNA polymerases, such as bacteriophage T7 DNA polymerase, are predominantly
      blocked by bulky chemical lesions on the template strand during DNA replication.
      However, some mutagenic bypass can occur, which may lead to carcinogenesis.
      Experimental studies have shown that a DNA covalent adduct derived from (+)-anti
      BPDE [(+)-(7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10
      tetrahydrobenzo[a]pyrene], a carcinogenic metabolite of benzo[a]pyrene (BP),
      primarily blocks Sequenase 2.0, an exo(-) T7 DNA polymerase; however, a
      mismatched dATP can be preferentially inserted opposite the damaged adenine
      templating base within the active site of the polymerase [Chary, P., and Lloyd,
      R. S. (1995) Nucleic Acids Res. 23, 1398-1405]. The goal of this work is to
      elucidate structural features that contribute to DNA polymerase incorporation
      fidelity in the presence of this bulky covalent adduct and to interpret the
      experimental findings on a molecular level. We have carried out molecular
      modeling and molecular dynamics simulations with AMBER 6.0, investigating a T7
      DNA polymerase primer-template closed ternary complex containing this 10S (+)
      trans-anti-[BP]-N(6)-dA adduct in the templating position within the polymerase
      active site. All four incoming dNTPs were studied. The simulations show that the
      BP ring system fits well into an open pocket on the major groove side of the
      modified template adenine with anti glycosidic bond conformation, without
      disturbing critical polymerase-DNA interactions. However, steric hindrance
      between the BP ring system and the primer-template DNA causes displacement of the
      modified template adenine, so that the dNTP base binding pocket is enlarged. This
      alteration can explain the experimentally observed preference for incorporation
      of dATP opposite this lesion. These studies also rationalize the observed lower
      probabilities of incorporation of the other three nucleotides. Our results
      suggest that the differences in incorporation of dGTP, dCTP, and dTTP are due to
      the effects of imperfect geometric complementarity. Thus, the simulations suggest
      that altered DNA polymerase incorporation fidelity can result from adduct-induced
      changes in the dNTP base binding pocket geometry. Furthermore, plausible
      structural explanations for the observed effects of [BP]-N(6)-dA adduct
      stereochemistry on the observed stalling patterns are proposed.

PMID- 15196019
TI  - PL-I of Spisula solidissima, a highly elongated sperm-specific histone H1.
AB  - The major chromosomal protein of the mature sperm of the surf clam, Spisula
      solidissima, is a histone H1-related protamine-like (PL-I) protein of low
      electrophoretic mobility. We report here the complete sequence of two isoforms of
      its encoding genes. These genes encode a protein of 453 and 454 amino acids,
      respectively. The predicted mass of the larger isoforms (51,437 Da) was confirmed
      using electrospray ionization mass spectrometry. The amino-terminal tail of the
      S. solidissima PL-I is greatly elongated because of the presence of 39 tandem
      hexapeptide repeats of the motif (K/R)KRSAS with a few semiconservative amino
      acid substitutions. These repeats are very closely mirrored by their encoding DNA
      sequence, which indicates that an expansion because of sequence duplication most
      likely occurred. The C-terminal domain consists of a histone H1-related core with
      a predicted winged-helix tertiary structure, which is followed by an unstructured
      lysine-rich tail. This information provides additional molecular support for the
      classification and underlying evolution of sperm nuclear basic proteins in
      bivalve molluscs.

PMID- 15196020
TI  - Trifunctional dinuclear platinum complexes as DNA-protein cross-linking agents.
AB  - The trifunctional dinuclear platinum compounds 1,2/c,c [[cis-PtCl(NH(3))(2)]mu
      H(2)N(CH(2))(6)NH(2)[cis-PtCl(2)(NH(3))]](+) and 1,2/t,c [[trans
      PtCl(NH(3))(2)]mu-H(2)N(CH(2))(6)NH(2)[cis-PtCl(2)(NH(3))]](+) contain a
      monofunctional platinum coordination sphere linked to a cis-[PtCl(2)(amine)(2)]
      moiety. The compounds have been examined for their DNA binding and ability to
      induce covalent ternary DNA-protein cross-links. Comparison was made with
      representative bifunctional dinuclear platinum compounds [[PtCl(NH(3))(2)](2)mu
      H(2)N(CH(2))(n)NH(2)](2+). DNA modified by the trifunctional compounds is able to
      bind and cross-link BamHI, a sequence-specific DNA-binding protein that
      recognizes the palindromic sequence GGATCC and also very efficiently binds and
      cross-links SP1, a sequence-specific Zn finger protein that induces a bend in the
      DNA upon binding. Two representative nonsequence-specific DNA-binding proteins,
      the Klenow fragment from DNA polymerase I and Klenow exonuclease minus (which has
      been mutated to remove the 3'-5' proofreading domain), both bind modified DNA and
      effectively cross-link to the DNA. Data from circular dichroism, inhibition of
      ethidium bromide fluorescence, interstrand cross-linking and unwinding assays are
      all consistent with (Pt,Pt) interstrand cross-links as the dominant lesion of
      trifunctional compounds and the most likely structure to form the ternary DNA
      protein cross-links. In vitro transcription of RNA is inhibited by the platinum
      compounds and indicate G residues as primary binding sites. Binding to calf
      thymus DNA as assessed by differential pulse polarography is rapid and
      essentially quantitative. An increase in melting temperature of CT DNA adducted
      by the platinum compounds is observed at low salt concentrations but at high
      salt, modification results in a decrease of t(m). In summary, the trifunctional
      agents may find use as protein-targeting drugs and as probes for conformational
      effects on DNA-protein interactions.

PMID- 15196021
TI  - Thermodynamics of binding to SH3 domains: the energetic impact of polyproline II
      (PII) helix formation.
AB  - Although numerous biophysical studies have focused on elucidating the structural
      and thermodynamic determinants that govern the free energy of binding between
      various SH3 domains and their putative recognition sequences, a quantitative
      accounting of the energetics of this interaction has proven enigmatic.
      Specifically, the binding results in a large and negative change on the standard
      enthalpy and entropy functions, a result which is inconsistent with the positive
      values for these quantities that is expected from the hydrophobic nature of the
      binding pocket. Here, the binding of the C-terminal SH3 domain of Sem-5 to its
      putative recognition peptide on the Sos (Son of Sevenless) protein is
      investigated using isothermal titration calorimetry under a variety of
      temperature and pH conditions. In addition, the energy associated with folding
      the Sos peptide into the binding competent polyproline II conformation is
      quantitatively evaluated. These results provide a rationale for the observed
      discrepancy between the experimental and predicted behavior and indicate that the
      determinants of binding in this system cannot be ascertained from a static
      structural representation of the binding process.

PMID- 15196022
TI  - The C-terminus of prohormone convertase 2 is sufficient and necessary for Raft
      association and sorting to the regulated secretory pathway.
AB  - Prohormone convertase 2 (PC2) is a member of the subtilisin family of proteases
      involved in prohormone maturation in the granules of the regulated secretory
      pathway (RSP). It has been suggested that targeting of this enzyme to the RSP is
      dependent on its association with lipid rafts in membranes at the trans-Golgi
      network. Here, we investigate the orientation of PC2 in granule membranes and the
      role of the C-terminus in sorting of the enzyme to the RSP. Molecular modeling
      and circular dichroism showed that this domain of PC2 forms an alpha-helix and
      inserts into artificial membranes. Furthermore, we show that the C-terminus of
      PC2 can be biotinylated at the C-terminus in intact chromaffin granules,
      indicating that it is a transmembrane protein. To determine if the PC2 C-terminus
      is necessary for raft association and sorting, we transfected a chimera of
      CPEDelta15 (carboxypeptidase E without the last 15 residues) and the last 25
      residues of PC2 (CPEDelta15-PC2), and a truncated PC2 mutant with the last 6
      residues deleted (PC2Delta6) into Neuro2a cells. Whereas CPEDelta15 was not raft
      associated or sorted to the RSP, addition of the 25 residues of PC2 C-terminus to
      CPEDelta15 restored raft association and localization to the RSP granules, as
      determined by immunocytochemistry. Deletion of the last 6 residues of PC2
      eliminated lipid raft association and sorting of PC2Delta6 to the RSP. These
      results showed that the PC2 C-terminus confers raft association and is sufficient
      and necessary for sorting PC2 to the RSP.

PMID- 15196023
TI  - Oligomeric assembly of native-like precursors precedes amyloid formation by beta
      2 microglobulin.
AB  - The deposition of beta-2-microglobulin (beta2m) as amyloid fibers results in
      debilitating complications for renal failure patients who are treated by
      hemodialysis. In vitro, wild-type beta2m can be converted to amyloid under
      physiological conditions by exposure to biomedically relevant concentrations of
      Cu(2+). In this work, we have made comparative measurements of the structural and
      oligomeric changes in beta2m at time points preceding fibrillogenesis. Our
      results show Cu(2+) mediates the formation of a monomeric, activated state
      followed by the formation of a discrete dimeric intermediate. The dimeric
      intermediates then assemble into tetra- and hexameric forms which display little
      additional oligomerization on the time scales of their own formation (<1 h).
      Amyloid fiber formation progresses from these intermediate states but on much
      longer time scales (>1 week). Although Cu(2+) is necessary for the generation and
      stabilization of these intermediates, it is not required for the stability of
      mature amyloid fibers. This suggests that Cu(2+) acts as an initiating factor of
      amyloidosis by inducing oligomer formation. (1)H NMR and near-UV circular
      dichroism are used to establish that oligomeric intermediates are native-like in
      structure. The native-like structure and discrete oligomeric size of beta2m
      amyloid intermediates suggest that this protein forms fibrils by structural
      domain swapping.

PMID- 15196024
TI  - Comparison of the subunit compositions of the PSI-LHCI supercomplex and the LHCI
      in the green alga Chlamydomonas reinhardtii.
AB  - Although the light-harvesting chlorophyll protein complex I (LHCI) of photosystem
      I (PSI) is intimately associated with the PSI core complex and forms the PSI-LHCI
      supercomplex, the LHCI is normally synthesized in PSI-deficient mutants. In this
      paper, we compared the subunit compositions of the PSI-LHCI supercomplex and the
      LHCI by immunoblot analysis and two-dimensional gel electrophoresis combined with
      mass spectrometry. The PSI-LHCI supercomplex and the LHCI were purified by
      sucrose density gradient centrifugation and (diethylamino)ethyl column
      chromatography from n-dodecyl-beta-D-maltoside-solubilized thylakoids of the wild
      type and DeltapsaB mutant of the green alga Chlamydomonas reinhardtii. The PSI
      LHCI supercomplex contained all of the nine Lhca polypeptides (Lhca1-9) that are
      detected in wild-type thylakoids. In contrast, the LHCI retained only six Lhca
      polypeptides, whereas Lhca3 and two minor polypeptides, Lhca2 and Lhca9, were
      lost during the purification procedure. Sucrose density gradient centrifugation
      showed that the purified LHCI retains an oligomeric structure with an apparent
      molecular mass of 300-400 kDa. We therefore concluded that Lhca2, Lhca3, and
      Lhca9 are not required for the stable oligomeric structure of the LHCI and that
      the association of these polypeptides in the LHCI is stabilized by the presence
      of the PSI core complex. Finally, we discuss the possible localization and
      function of Lhca polypeptides in the LHCI.

PMID- 15196025
TI  - Light-modulated exposure of the light-harvesting complex II (LHCII) to protein
      kinase(s) and state transition in Chlamydomonas reinhardtii xanthophyll mutants.
AB  - Reversible phosphorylation of chl a/b protein complex II (LHCII), the mobile
      light-harvesting antenna, regulates its association and energy
      transfer/dissipation to photosystem (PS) II or I (state transition). Excitation
      of LHCII induces conformational changes affecting the exposure of the
      phosphorylation site at the N-terminal domain to protein kinase(s) [Zer, H., et
      al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96, 8277-8282; Zer, H., et al. (2003)
      Biochemistry 42, 728-738]. Thus, it was of interest to examine whether the
      pigment composition of LHCII affects the light-induced modulation of LHCII
      phosphorylation and state transition. To this end, we have used thylakoids of
      wild-type Chlamydomonas reinhardtii and xanthophyll deficient mutants npq1, lor1,
      npq2, npq1 lor1, and npq2 lor1. Phosphorylated protein bands P11, P13, and P17
      are considered components of the mobile C. reinhardtii LHCII complex. The protein
      composition of these bands has been analyzed by mass spectrometry using Qtof-2
      with a nanospray attachment. P11 and P13 contain C. reinhardtii light-harvesting
      chlorophyll a/b binding protein LhcII type I. P17 contains C. reinhardtii LhcII
      types III and IV. Illumination of isolated thylakoids inhibits the redox
      controlled phosphorylation of polypeptide bands P13 and P17 and to a lower extent
      that of P11. The light-induced inhibition of LHCII phosphorylation and the state
      transition process are not influenced by extensive differences in the xanthophyll
      composition of the mutants. Thus, LHCII can be visualized as possessing two
      functionally distinct, independent domains: (i) the pigment binding transmembrane
      domain regulating the extent of energy transfer/dissipation and (ii) the surface
      exposed phosphorylation site regulating the association of LHCII with PSII or
      PSI.

PMID- 15196026
TI  - Differential contribution of active site residues in substrate recognition sites
      1 and 5 to cytochrome P450 2C8 substrate selectivity and regioselectivity.
AB  - Selected active site residues in substrate recognition sites (SRS) 1 and 5 of
      cytochrome P450 2C8 (CYP2C8) were mutated to the corresponding amino acids
      present in CYP2C9 to investigate the contribution of these positions to the
      unique substrate selectivity and regioselectivity of CYP2C8. The effects of
      mutations, singly and in combination, were assessed from changes in the kinetics
      of paclitaxel 6alpha-hydroxylation, a CYP2C8-specific pathway, and the
      tolylmethyl and ring hydroxylations of torsemide, a mixed CYP2C9/CYP2C8
      substrate. Within SRS1, the single mutation S114F abolished paclitaxel 6alpha
      hydroxylation, while the I113V substitution resulted in modest parallel
      reductions in K(m) and V(max). Mutations in SRS5 (viz., V362L, G365S, and V366L)
      reduced paclitaxel intrinsic clearance (V(max)/K(m)) by 88-100%. Torsemide is
      preferentially metabolized by CYP2C9, and it was anticipated that the mutations
      in CYP2C8 might increase activity. However, methyl and ring hydroxylation
      intrinsic clearances were either unchanged or decreased by the mutations,
      although hydroxylation regioselectivity was often altered relative to wild-type
      CYP2C8. The mutations significantly increased (28-968%) K(m) values for both
      torsemide methyl and ring hydroxylation but had variable effects on V(max). The
      effects of the combined mutations in SRS1, SRS5, and SRS1 plus SRS5 were
      generally consistent with the changes produced by the separate mutations.
      Mutation of CYP2C8 at position 359 (S359I), a site of genetic polymorphism in
      CYP2C9, resulted in relatively minor changes in paclitaxel- and torsemide
      hydroxylase activities. The results are consistent with multiple substrate
      binding orientations within the CYP2C8 active site and a differential
      contribution of active site residues to paclitaxel and torsemide binding and
      turnover.

PMID- 15196027
TI  - Ligand binding to symmetrical FeZn hybrids of variants of human HbA with
      modifications in the alpha1-beta2 interface.
AB  - The equilibria of oxygen binding to and kinetics of CO combination with the
      symmetrical iron-zinc hybrids of a series of variants of human adult hemoglobin A
      have been measured at pH 7 in the presence of inositol hexaphosphate (IHP). In
      addition, the kinetics of CO combination have also been measured in the absence
      of IHP. The hybrids have the heme groups of either the alpha or the beta subunits
      replaced by zinc protoporphyrin IX, which is unable to bind a ligand and is a
      good model for permanently deoxygenated heme. The variants examined involve
      residues located in the alpha1beta2 interface of the hemoglobin tetramer.
      Alterations of residues located in the hinge region of the interface are found to
      affect the properties of both the alpha and the beta subunits of the protein. In
      contrast, alterations of residues in the switch region of the interface have
      substantial effects only on the mutant subunit and are poorly communicated to the
      normal partner subunit. When the logarithms of the rate constants for the
      combination of the first CO molecule with a single subunit in the presence of IHP
      are analyzed as functions of the logarithms of the dissociation equilibrium
      constants for the binding of the first oxygen under the same conditions, a linear
      relationship is found. The relationship is somewhat different for the alpha and
      beta subunits, consistent with the well-known differences in the geometries of
      their ligand binding sites.

PMID- 15196028
TI  - Effects of heterotropic allosteric effectors on the equilibrium and kinetics of
      the reaction of a single ligand molecule with an alpha or beta subunit of
      deoxygenated HbA.
AB  - Symmetrical FeZn hybrids of human HbA have been used to measure K(1)(alpha) and
      K(1)(beta), the dissociation constants for the binding of a single molecule of
      oxygen to unliganded HbA at an alpha subunit and at a beta subunit, respectively.
      The kinetic constants, l(1)'(alpha) and l(1)'(beta), for the combination of the
      first CO molecule to unliganded HbA at an alpha or a beta subunit, respectively,
      were also measured. Measurements were carried out between pH 6 and pH 8 in the
      presence and absence of inositol hexaphosphate (IHP). Both equilibrium constants
      exhibit a significant Bohr effect in the absence of IHP. The addition of IHP to a
      concentration of 0.1 mM increases both dissociation constants in a pH-dependent
      manner with the result that both Bohr effects are greatly reduced. These results
      require a negative thermodynamic linkage between the binding of a single oxygen
      at either an alpha or a beta subunit and the binding of IHP to the T quaternary
      structure of HbA. Although the beta hemes are relatively near the IHP binding
      site, a linkage between that site and the alpha hemes, such that the binding of a
      single oxygen molecule to the heme of one alpha subunit reduces the affinity of
      the T state for IHP, requires communication across the molecule. l(1)'(alpha)
      exhibits a very slight pH dependence, with a maximum variation of 20%, while
      l(1)'(beta) varies with pH three times as much. IHP has no effect on the pH
      dependence of either rate constant but reduces l(1)'(alpha) marginally, 20%, and
      l(1)'(beta) by 2-fold at all pH values.

PMID- 15196029
TI  - Studies on three E. coli DEAD-box helicases point to an unwinding mechanism
      different from that of model DNA helicases.
AB  - DEAD-box proteins participate in various aspects of RNA metabolism in all
      organisms. These RNA-dependent ATPases are usually regarded as double-stranded
      RNA unwinding enzymes, though in vitro this activity has only been demonstrated
      for a subset of them. Given their high biological specificity, their equivocal
      unwinding activity may reflect the noncognate character of the substrates used in
      vitro. Here, we pinpoint other reasons for this elusiveness. We have compared the
      ATPase and helicase activities of three E. coli DEAD-box proteins, CsdA, RhlE and
      SrmB. Whereas the ATPase activity of all proteins is stimulated (albeit to
      various degree) by long RNAs, only RhlE is stimulated by short
      oligoribonucleotides. Consistently, all three proteins can unwind RNA duplexes
      with long single-stranded extensions, but only RhlE is effective when extensions
      are short or absent. Another critical constraint concerns the length of the
      duplex region: in the case of RhlE, the ratio (duplex unwound)/(ATP hydrolyzed)
      drops 1000-fold upon going from 11 to 14 base pairs, indicating a low
      processivity. Remarkably, allowing for these constraints, all three proteins can
      unwind substrates with either 5' or 3' extensions (or no extension in the case of
      RhlE). This behavior, which contrasts with that of well studied SF1 DNA
      helicases, is discussed in the light of available structural and biochemical
      data.

PMID- 15196030
TI  - Linker histone interaction shows divalent character with both supercoiled and
      linear DNA.
AB  - The interaction of linker histone H1 with both linear and superhelical double
      stranded DNA has been investigated at low ionic strengths. Gel mobility
      retardation experiments demonstrate strikingly different behavior for the two
      forms of DNA. First, the experiments strongly suggest that linker histone binds
      to superhelical DNA in a negatively cooperative mode. In contrast, binding of
      linker histone to linear DNA under the conditions employed here shows no
      cooperativity. Second, binding of linker histone to linear DNA results in
      aggregation of histone-DNA complexes, even at very low levels of input histone
      H1. Because H1 has been shown to interact as a monomer, this aggregation is
      evidence of the divalent character of the linker histone, for without H1's
      ability to bind to two duplex strands of DNA, aggregation could not occur.
      Although aggregation can be made to occur with superhelical DNA, it can do so
      only at near-saturation levels of input histone H1. Finally, in direct
      competition, linker histone binds to superhelical DNA to the complete exclusion
      of linear DNA, indicating that the linker histone's function is related to the
      crossover structures that differentiate superhelical DNA from linear DNA. We
      develop a model that explains the observed behavior of binding of linker histone
      to superhelical DNA that is consistent with both the divalent character of the
      linker histone and the negative cooperativity by which linker histone and
      superhelical DNA interact.

PMID- 15196031
TI  - T7 RNA polymerase mediates fast promoter-independent extension of unstable
      nucleic acid complexes.
AB  - T7 RNA polymerase is a processive, DNA-dependent RNA polymerase that has a high
      specificity for its 17 base pair (bp) promoter. In addition to normal
      transcription, the enzyme can produce anomalous transcripts in the absence of a
      promoter. We report here the systematic characterization of the transient aspects
      of this promoter-independent process. Oligonucleotides that are able to form
      transient unimolecular loop structures closed by as little as one Watson-Crick
      base pair between the 3' terminal residue and an internal nucleotide proved to be
      viable substrates. A single nucleotide triphosphate assay system found that
      incorporation was encoded by the nucleotide 5' to the predicted transient base
      pair. When this coding nucleotide was identical to the internal nucleotide
      participating in the transient base pair, multiple nucleotide incorporations were
      observed and could only be explained by a continuous shifting and resetting of
      the transient base-pairing required for extension. This intermittent extension
      process can be quite efficient. Short DNA or RNA substrates were good substrates
      for the enzyme (affinities ranged from 2 to 43 microM) and were extended rapidly
      with apparent catalytic rates of up to 240 min(-1) being observed, only 2-fold
      slower than the rate of transcriptional initiation. Our data suggest a possible
      mechanism for this promoter-independent extension activity and may add to the
      understanding of viral RNA replicative strategies.

PMID- 15196032
TI  - Alpha-L-fucosidases: exoglycosidases with unusual transglycosylation properties.
AB  - Apha-LFucosidases (EC 3.2.1.51), the only members of the CAZy family GH-29, are
      widespread glycosidases involved in many biological processes including
      inflammation, metastasis, and the lysosomal storage disease fucosidosis. Despite
      their biological significance, information concerning the mechanism of alpha
      Lfucosidases has only recently become available. In an attempt to obtain further
      data concerning their mechanism, we have investigated the hydrolytic and
      transglycosylation properties of a canine and a mollusk (Pecten maximus) alpha
      Lfucosidase. Our results show that, despite the evolutionary distance between
      these two species, both enzymes have similar hydrolysis and transglycosylation
      properties. Surprisingly, we found that, starting from monosaccharides, these
      exoglycosidases were able to catalyze efficiently the synthesis of highly
      branched fuco-oligosaccharides as large as tetrasaccharides, a unique feature for
      a wild-type exoglycosidase. The structural analysis of the compounds formed
      revealed that the regioselectivity of alpha-Lfucosidases is strongly influenced
      by the structure of the acceptor. This leads us to propose an enzymatic approach
      for the preparative synthesis of fuco-oligosaccharides. This will not only allow
      the synthesis of biological determinants containing fucose but also of new fucose
      containing oligosaccharides as alpha-glycosynthases appear to be difficult to
      obtain.

PMID- 15196033
TI  - Characterization of full length and truncated type I human methionine
      aminopeptidases expressed from Escherichia coli.
AB  - Methionine aminopeptidase (MetAP) carries out an essential posttranslational
      modification of nascent proteins by removing the initiator methionine and is
      recognized as a potential target for developing antibacterial, antifungal, and
      anticancer agents. We have established an Escherichia coli expression system for
      human type I MetAP (HsMetAP1) and characterized the full length HsMetAP1 and its
      N-terminal-truncated mutants HsMetAP1(Delta1-66) and HsMetAP1(Delta1-135) for
      hydrolysis of several thiopeptolide and peptide substrates and inhibition by a
      series of nonpeptidic inhibitors. Although the N-terminal extension with zinc
      finger motifs in HsMetAP1 is not required for enzyme activity, it has a
      significant impact on the interaction of the enzyme with substrates and
      inhibitors. In hydrolysis of the thiopeptolide substrates, a relaxation of
      stringent specificity for the terminal methionine was observed in the truncated
      mutants. However, this relaxation of specificity was not detectable in hydrolysis
      of tripeptide or tetrapeptide substrates. Several nonpeptidic inhibitors showed
      potent inhibition of the mutant HsMetAP1(Delta1-66) but exhibited only weak or no
      inhibition of the full length enzyme. With the recombinant HsMetAP1 available, we
      have identified several MetAP inhibitors with submicromolar inhibitory potencies
      against E. coli MetAP (EcMetAP1) that do not affect HsMetAP1. These results have
      demonstrated the possibility of developing MetAP inhibitors as antibacterial
      agents with minimum human toxicity. In addition, micromolar inhibitors of
      HsMetAP1 identified in this study can serve as tools for investigating the
      functions of HsMetAP1 in physiological and pathological processes.

PMID- 15196034
TI  - Solid-state NMR spin diffusion for measurement of membrane-bound peptide
      structure: gramicidin A.
AB  - A recently developed solid-state NMR method for measurement of depths in membrane
      systems is applied to gramicidin A, a membrane-bound peptide of known structure,
      to investigate the potential of this method. (15)N-detected, (1)H spin diffusion
      experiments demonstrate the resolution of the technique by measuring the 4-5 A
      depth differences between three (15)N-labeled backbone sites (Trp13, Val7, Gly2)
      in gramicidin A. We also show that (13)C-detected, (1)H spin diffusion
      experiments on unlabeled gramicidin A are sufficient to discriminate between the
      end-to-end dimer and double-helix structures of gramicidin A. Thus, spin
      diffusion solid-state NMR experiments can provide a simple approach, which does
      not require labeled samples, for testing structural models of membrane-bound
      peptides.

PMID- 15196035
TI  - Oxidative and nonoxidative decarboxylation of N-Alkyl-N-phenylglycines by
      horseradish peroxidase. Mechanistic switching by varying hydrogen peroxide,
      oxygen, and solvent deuterium.
AB  - Horseradish peroxidase (HRP) typically oxidizes aniline derivatives using
      hydrogen peroxide as the oxidant. The action of HRP on N-alkyl-N-phenylglycine
      derivatives 1b-1e (PhN(R)CH(2)COOH; R = Me, Et, n-Pr, i-Pr, respectively) is
      highly unusual if not unique. Under standard peroxidatic conditions
      (HRP/H(2)O(2)/air), the major product (ca. 70%) is the secondary aniline 2b-2e
      (PhNHR) resulting from the expected oxidative decarboxylation process, but a
      significant amount (ca. 30%) of the related tertiary aniline PhN(CH(3))R (3b-3e)
      arises from an unexpected nonoxidative decarboxylation process. Under anaerobic,
      peroxide-free conditions only the tertiary anilines 3b-3e are formed in a
      reaction that is extremely rapid compared to those in which H(2)O(2), molecular
      oxygen, or both are present. In D(2)O buffers, the product is exclusively the
      monodeutero tertiary aniline PhN(CH(2)D)R and the reaction is much slower
      (k(H(2)O)/k(D(2)O) = 5.7), suggesting that a proton transfer step is
      substantially rate-limiting in turnover. It is proposed that ferric HRP oxidizes
      1 to a cation radical, which then decarboxylates to an alpha-amino radical having
      carbanion character on carbon; protonation of the latter, followed by electron
      capture from ferrous HRP, completes the cycle. Hydrogen peroxide and oxygen slow
      turnover by diverting ferric HRP toward the compound I/compound II forms or
      toward compound III, respectively. Finally, under peroxidatic conditions, 1a (R =
      cyclopropyl) inactivates HRP with concurrent formation of 2a but not N
      phenylglycine, but under anaerobic, peroxide-free conditions, 1a inactivates HRP
      almost instantly with no detectable product formation.

PMID- 15196036
TI  - Reconstitution of the Rhodobacter sphaeroides cbb3-PrrBA signal transduction
      pathway in vitro.
AB  - The PrrBA two-component system in Rhodobacter sphaeroides 2.4.1, which is
      composed of the PrrB histidine kinase and the PrrA response regulator, controls
      the expression of all of the photosynthesis genes, either directly or indirectly,
      in response to changes in oxygen tension. In vivo under aerobic conditions it is
      the cbb(3) cytochrome c oxidase which generates an inhibitory signal preventing
      the accumulation of activated PrrA. Using purified cbb(3) cytochrome c oxidase,
      PrrB, and PrrA, we demonstrate in vitro that the cbb(3) oxidase inhibits PrrB
      activity by apparently increasing the intrinsic PrrB phosphatase activity, which
      dephosphorylates phosphorylated PrrA without alteration of the PrrB kinase
      activity. The transmembrane domain of PrrB is required for the enhancement of
      PrrB phosphatase activity by the cbb(3) oxidase. Full-length PrrB has a
      significantly greater ability to phosphorylate PrrA than does truncated PrrB
      lacking the transmembrane domain. This is at least in part due to the lower
      autophosphorylation rate of the truncated PrrB relative to the full-length PrrB.
      This finding provides evidence that the sensing domain (transmembrane domain) of
      PrrB plays an important role not only in optimally sensing the state of the
      cbb(3) oxidase but also in maintaining the correct conformation of PrrB,
      providing optimal autokinase activity.

PMID- 15196037
TI  - Membrane fusion correlates with surface charge in exocytic vesicles.
AB  - Stimulation of gastric parietal cells results in exocytic recruitment of the
      proton pump (H(+),K(+)-ATPase) from a pool of intracellular membranes
      (tubulovesicles) to the apical plasma membrane. We have previously reconstituted
      a step in this process, the homotypic fusion of tubulovesicles, and shown that
      they also fuse with liposomes in a protein-dependent manner [Duman, J. G., Singh,
      G., Lee, G. Y., Machen, T. E., and Forte, J. G. (2002) Traffic 3, 203-17].
      Further, the lipid composition of the liposomes affects their ability to undergo
      fusion with tubulovesicles. In the present study, we investigated the lipid
      requirements for tubulovesicular membrane fusion using a fluorescent probe
      relaxation assay as well as transfer of protein between tubulovesicles and
      liposomes of defined composition. Initially, we tested the ability of
      tubulovesicles to undergo fusion with a panel of synthetic phosphatidylcholine
      based liposomes containing a variety of common membrane lipids of various shapes
      and charges. We found that anionic lipids such as phosphatidylserine,
      phosphatidic acid, and phosphoinositides were best able to enhance tubulovesicle
      liposome fusion and that they did it in a dose-dependent, apparently saturable
      manner. Next, we altered the lipid compositions of actual tubulovesicles and
      observed that addition of anionic lipids was able to enhance tubulovesicle
      tubulovesicle fusion in vitro; thus, we hypothesized that the charge imparted by
      the lipids, per se, was responsible for the enhancement of membrane fusion.
      Accordingly, addition of negative charges to one of two pools of tubulovesicles
      in a fusion assay using anionic detergents increased membrane fusion; whereas,
      addition of positively charged cationic detergent decreased membrane fusion and
      could be used to back-titrate the anionic effects. Surprisingly, when both pools
      of fusing membranes were loaded with anionic detergents, fusion was markedly
      increased. The ability of anionic charges to enhance fusion was diminished as the
      ionic strength of the fusion medium was increased, suggesting that the mechanism
      of fusion enhancement depends on the surface charge of the membranes. Finally,
      the fusion reaction was highly dependent on temperature, and anionic charge
      appears to lower the activation energy of the fusion reaction. Taken together,
      these data suggest that (1) tubulovesicular fusion is enhanced by an increase in
      membrane surface negative charge associated with a lower activation energy and
      (2) neutralization or reversal of the surface charge prevents tubulovesicular
      fusion.

PMID- 15196038
TI  - Role of cysteine residues in the NCKX2 Na+/Ca(2+)-K+ Exchanger: generation of a
      functional cysteine-free exchanger.
AB  - Cysteine residues play an important role in many proteins, either in enzymatic
      activity or by mediating inter- or intramolecular interactions. The Na(+)/Ca(2+)
      K(+) exchanger plays a critical role in Ca(2+) homeostasis in retinal rod (NCKX1)
      and cone (NCKX2) photoreceptors by extruding Ca(2+) that enters rod and cone
      cells via the cGMP-gated channels. NCKX1 and NCKX2 contain five highly conserved
      cysteine residues. The objectives of this study were threefold: (1) to examine
      the importance of cysteine residues in NCKX2 protein function; (2) to examine
      their role in the interaction between NCKX2 and the CNGA subunit of the cGMP
      gated channel; and (3) to generate a functional cysteine-free NCKX2 protein. The
      latter will facilitate structural studies taking advantage of the unique
      chemistry of the thiol group following insertion of cysteine residues at specific
      positions in the cysteine-free background. We generated a cysteine-free NCKX2
      mutant protein that showed normal protein synthesis and processing and
      approximately 50% wild-type cation transport function. Cysteine residues were
      also not critical for the formation of NCKX2 homo-oligmers or NCKX2 hetero
      oligomers with the CNGA subunit of the cGMP-gated channel. Our results appear to
      rule out a critical importance of an intramolecular disulfide linkage in NCKX2
      protein synthesis and folding as had been reported before.

PMID- 15196039
TI  - Identification of essential residues within Lit, a cell death peptidase of
      Escherichia coli K-12.
AB  - Bacteriophage exclusion is a suicide response to viral infection. In strains of
      Escherichia coli K-12 infected with T4 phage this process is mediated by the host
      encoded Lit peptidase. Lit is activated by a unique sequence in the major head
      protein of the T4 phage (the Gol sequence) which then cleaves site-specifically
      the host translation factor EF-Tu, ultimately leading to cell death. Lit has very
      low sequence identity with other peptidases, with only a putative
      metallopeptidase motif, H(160)EXXH, giving an indication of its catalytic
      activity. The aim of the present study was to ascertain if Lit is a
      metallopeptidase, identify residues essential for Lit activity, and probe the
      involvement of the Gol sequence in the activation of enzymatic activity. Lit
      activity was inhibited by the zinc chelator 1,10-phenanthroline, consistent with
      the suggestion that it is a metallopeptidase. Preliminary covalent modification
      experiments found that Lit was susceptible to inactivation by diethyl
      pyrocarbonate, with about three histidines reversibly modified, one of which was
      found to be essential for proteolytic activity. Subsequently, 13 mutants of the
      Lit enzyme were constructed that included all 10 histidines as well as other
      residues within the metallopeptidase motif. This demonstrated that the residues
      within the HEXXH motif are required for Lit activity and further defined the
      essential catalytic core as H(160)EXXHX(67)H, with additional residues such as
      His169 being important but not essential for activity. Kinetic analysis of Lit
      activation by a synthetic Gol peptide highlighted that elevated concentrations of
      the peptide (>10-fold above activation K(M)) are inhibitory to Lit, with this
      effect also seen in partially active Lit mutants. The susceptibility of Lit to
      inhibition by its own activating peptide suggests that the Gol sequence may be
      able to bind nonproductively to the enzyme at high concentration. We discuss
      these data in the context of the currently understood models for Gol-mediated
      activation of the Lit peptidase and its mechanism of action.

PMID- 15196040
TI  - The binding mechanism of pyoverdin with the outer membrane receptor FpvA in
      Pseudomonas aeruginosa is dependent on its iron-loaded status.
AB  - In iron-deficient conditions, Pseudomonas aeruginosa secretes a major fluorescent
      siderophore named pyoverdin (Pvd), which after chelating iron(III) is transported
      back into the cell via its outer membrane receptor FpvA. FpvA is a TonB-dependent
      transport protein and has the ability to bind Pvd in its apo- or iron-loaded
      form. The fluorescence properties of Pvd were used to determine the binding
      kinetics of metal-free and metal-loaded Pvd to FpvA and showed two major
      features. First, the kinetics of formation of the FpvA-Pvd complex, in vivo and
      in vitro, are markedly slower compared to those observed for FpvA-Pvd-metal.
      Second, apo-Pvd and Pvd-metal absorbed with biphasic kinetics to FpvA: the
      bimolecular step (association of the ligand with the receptor) is followed by a
      slower step (t(1/2) values of 5 and 34 min for Pvd-metal and Pvd, respectively)
      that presumably leads to a more stable complex. The most likely explanation for
      this second step is that the binding of the ligand to the receptor induces a
      conformational change on FpvA, which may be different, depending on the loading
      status of Pvd. Analysis of the dissociation of metal-free Pvd from FpvA revealed
      an energy and a TonB dependency. The dissociation of iron-free Pvd from FpvA in
      the absence of the TonB protein occurs with slow kinetics in the range of hours,
      but it can be highly activated by the protonmotive force and TonB to reach a
      kinetic with a t(1/2) of 1 min. Apparently, under iron-limited conditions, TonB
      activates the FpvA receptor, resulting in a fast release of iron-free Pvd and
      generating an unloaded FpvA receptor, competent for binding extracellular Pvd-Fe.

PMID- 15196041
TI  - Structural and mutational studies of the carboxylate cluster in iron-free
      ribonucleotide reductase R2.
AB  - The R2 protein of ribonucleotide reductase features a di-iron site deeply buried
      in the protein interior. The apo form of the R2 protein has an unusual clustering
      of carboxylate side chains at the empty metal-binding site. In a previous study,
      it was found that the loss of the four positive charge equivalents of the
      diferrous site in the apo protein appeared to be compensated for by the
      protonation of two histidine and two carboxylate side chains. We have studied the
      consequences of removing and introducing charged residues on the local hydrogen
      bonding pattern in the region of the carboxylate cluster of Corynebacterium
      ammoniagenes and Escherichia coli protein R2 using site-directed mutagenesis and
      X-ray crystallography. The structures of the metal-free forms of wild-type C.
      ammoniagenes R2 and the mutant E. coli proteins D84N, S114D, E115A, H118A, and
      E238A have been determined and their hydrogen bonding and protonation states have
      been structurally assigned as far as possible. Significant alterations to the
      hydrogen-bonding patterns, protonation states, and hydration is observed for all
      mutant E. coli apo proteins as compared to wild-type apo R2. Further structural
      variations are revealed by the wild-type apo C. ammoniagenes R2 structure. The
      protonation and hydration effects seen in the carboxylate cluster appear to be
      due to two major factors: conservation of the overall charge of the site and the
      requirement of electrostatic shielding of clustered carboxylate residues. Very
      short hydrogen-bonding distances between some protonated carboxylate pairs are
      indicative of low-barrier hydrogen bonding.

PMID- 15196042
TI  - Secondary binding site of the potato carboxypeptidase inhibitor. Contribution to
      its structure, folding, and biological properties.
AB  - The contribution of each residue of the potato carboxypeptidase inhibitor (PCI)
      secondary binding site to the overall properties of this protein has been
      examined using alanine-scanning mutagenesis. Structural and enzymatic studies,
      performed on a series of PCI mutants, demonstrate that the proper positioning of
      the primary site for efficient binding and inhibition of carboxypeptidase A is
      significantly dependent on such a secondary contact region. The aromatic residues
      in this region play a key role in the stabilization of the PCI-enzyme complex,
      whereas polar residues contribute little to this task. A comparative study of the
      oxidative folding of these PCI mutants has been carried out using the disulfide
      quenching approach. The data, together with the structural characterization of
      some of these mutants, clearly indicate that noncovalent forces drive the
      refolding of this small disulfide-rich protein at the reshuffling stage, the rate
      limiting step of the process. Moreover, it reveals that by introducing new
      noncovalent intramolecular contacts in PCI, we may create more stable variants,
      which also show improved folding efficiency. Taken together, the collected
      results clarify the folding determinants of the primary and secondary binding
      sites of PCI and their contribution to the inhibition of the carboxypeptidase,
      providing clues about PCI evolution and knowledge for its biotechnological
      redesign.

PMID- 15196043
TI  - Nanomaterials based on phosphorus dendrimers.
AB  - Dendrimers constitute an increasingly important field of research in chemistry
      for more than 15 years. After pioneering works concerning synthesis, the interest
      in dendrimers is now mainly driven by their properties and applications. This
      Account will emphasize the properties of a special class of dendrimers, that is,
      phosphorus-containing dendritic macromolecules, as tools for the elaboration of
      nanomaterials. Indeed, these dendrimers can be considered themselves as
      materials, or they can be used as an intrinsic constituent of a material or as a
      modifier of the surface of a material. In this latter case, a fundamental work
      about surfaces covalently modified by dendrimers recently opened the way to the
      elaboration of DNA chips.

PMID- 15196044
TI  - Breaking, making, and twisting of chemical bonds in gas, liquid, and
      nanocavities.
AB  - In this Account, we recount on our studies of 1'-hydroxy-2'-acetonaphthone (HAN,
      a proton transfer prototype molecule) in gas, solutions, and nanocavities. The
      internal H-bond photoreaction in HAN leads to a keto type structure, and
      following its formation, an internal twisting motion gives birth to keto
      rotamers. Theory, temperature, and solvent effects on its photodynamics show the
      involvement of efficient radiationless processes in both keto structures. When
      HAN is caged in a cyclodextrin nanocavity, the spectroscopy, photodynamics, and
      issues of twisting motion are strongly affected and could be tuned: a behavior
      relevant to those of many chemical and biological systems.

PMID- 15196045
TI  - Rapid photochemical cross-linking--a new tool for studies of metastable,
      amyloidogenic protein assemblies.
AB  - Amyloidoses comprise a class of diseases characterized pathologically by the
      presence of deposits of fibrillar, aberrantly folded proteins, known as amyloids.
      Historically, these deposits were considered the key factors causing disease.
      However, recent evidence suggests that soluble protein oligomers, which are
      precursors for amyloid fibrils, are the primary toxic effectors responsible for
      the disease process. Understanding the mechanism by which these oligomers exert
      their toxicity requires knowledge of the structure, kinetics, and thermodynamics
      of their formation and conversion into larger assemblies. Such studies have been
      difficult due to the metastable nature of the oligomers. For the amyloid beta
      protein (Abeta), a consensus about the size and relative abundance of small
      oligomers has not been achieved. We describe here the application of the method
      Photoinduced Cross-Linking of Unmodified Proteins (PICUP) to the study of Abeta
      oligomerization. This approach distinguishes oligomerization patterns of
      amyloidogenic and nonamyloidogenic proteins, allows quantification of each
      component in oligomer mixtures, and provides a means of correlating primary
      structure modifications with assembly characteristics. PICUP thus is a powerful
      tool for the investigation of small, metastable protein oligomers. The method
      provides essential insights into the factors that control the assembly of
      pathogenic protein oligomers, facilitating efforts toward the development of
      therapeutic agents.

PMID- 15196046
TI  - Evolution of dithiane-based strategies for the construction of architecturally
      complex natural products.
AB  - Umpolung-based strategies play a significant role in organic synthesis.
      Particularly important are 1,3-dithiane linchpins, which serve as convenient acyl
      anion equivalents. The general synthetic accessibility and impressive reactivity
      of 1,3-dithianes have thus led to widespread application. Since the late 1970s,
      dithianes have featured prominently in our program directed toward the synthesis
      of complex natural and unnatural products, both for effective union of advanced
      fragments and for multicomponent linchpin couplings. In this Account, we present
      the evolution of dithiane chemistry in our laboratory.

PMID- 15196047
TI  - Transient species in the stepwise interconversion of NADH and NAD+.
AB  - Two mechanisms of the interconversion of NADH and NAD+ in the coenzyme itself and
      in its analogues are discussed: a one-step hydride transfer and a stepwise
      electron-proton-electron transfer. Direct characterization of the transient
      species in the stepwise process and inversion of the stability order of the keto
      and enol tautomers is presented. The nonenzymatic and enzyme-mediated reactions
      of selected pyridinium salts that affect the NADH <==>NAD+ equilibrium are
      discussed in terms of their potential cytotoxicity.

PMID- 15196048
TI  - Boron-mediated aldol reaction of carboxylic esters.
AB  - This Account outlines the unique features of the boron-mediated aldol reaction of
      carboxylic esters, which include (i) facile isomerization of E-enolate to Z
      enolate and (ii) formation of a doubly borylated enolate upon enolization of
      acetate esters. The first carbon-bound boron enolates were spectroscopically
      characterized, and they appeared to be responsible for these unique properties.
      Furthermore, complementary anti- and syn-selective boron-mediated asymmetric
      aldol reactions of chiral propionate esters have been developed. A novel double
      aldol reaction of acetate esters has been discovered, and a plausible mechanism
      of the double aldol reaction is proposed.

PMID- 15196049
TI  - Knowledge of the proposed chemical mechanism of action and cytochrome p450
      metabolism of antimalarial trioxanes like artemisinin allows rational design of
      new antimalarial peroxides.
AB  - Evidence is reviewed elucidating the mechanism of iron-induced triggering of
      antimalarial trioxanes. As prodrugs, trioxanes undergo homolytic, inner-sphere,
      reductive cleavage by ferrous iron to form sequentially oxy radicals, carbon
      radicals, high-valent iron-oxo species, epoxides, aldehydes, and dicarbonyl
      compounds. One or more of these reactive intermediates and neutral alkylating
      agents likely kill the malaria parasites. Several new, orally active antimalarial
      peroxides have been designed rationally based on this fundamental mechanistic
      paradigm. Incorporating metabolism-blocking substituents also provides some new,
      potent, semi-synthetic artemisinin derivatives.

PMID- 15196050
TI  - Ca2+-regulated photoproteins: structural insight into the bioluminescence
      mechanism.
AB  - The bioluminescent jellyfish has contributed two famous proteins to modern
      science: green fluorescent protein or GFP, which finds wide use as a probe in
      cell biology studies, and aequorin, which has been used for intracellular calcium
      measurement for more than 30 years. More recently, obelin, a protein from the
      bioluminescent hydroid and also in the family of what are called "Ca2+-regulated
      photoproteins", has been shown to have very attractive properties both in general
      applications and for basic structural biology investigations. This review will
      survey the new information into their molecular mechanism of bioluminescence
      action.

PMID- 15196051
TI  - Structural requirements of the glucocorticoid-response unit of the carbamoyl
      phosphate synthase gene.
AB  - The GRU (glucocorticoid-response unit) within the distal enhancer of the gene
      encoding carbamoyl-phosphate synthase, which comprises REs (response elements)
      for the GR (glucocorticoid receptor) and the liver-enriched transcription factors
      FoxA (forkhead box A) and C/EBP (CCAAT/enhancer-binding protein), and a binding
      site for an unknown protein denoted P3, is one of the simplest GRUs described. In
      this study, we have established that the activity of this GRU depends strongly on
      the positioning and spacing of its REs. Mutation of the P3 site within the 25 bp
      FoxA-GR spacer eliminated GRU activity, but the requirement for P3 could be
      overcome by decreasing the length of this spacer to < or =12 bp, by optimizing
      the sequence of the REs in the GRU, and by replacing the P3 sequence with a
      C/EBPbeta sequence. With spacers of < or =12 bp, the activity of the GRU depended
      on the helical orientation of the FoxA and GR REs, with highest activities
      observed at 2 and 12 bp respectively. Elimination of the 6 bp C/EBP-FoxA spacer
      also increased GRU activity 2-fold. Together, these results indicate that the
      spatial positioning of the transcription factors that bind to the GRU determines
      its activity and that the P3 complex, which binds to the DNA via a 75 kDa
      protein, functions to facilitate interaction between the FoxA and glucocorticoid
      response elements when the distance between these transcription factors means
      that they have difficulties contacting each other.

PMID- 15196052
TI  - Structure, conformation and biological activity of a novel lipodepsipeptide from
      Pseudomonas corrugata: cormycin A.
AB  - Cationic lipodepsipeptides from Pseudomonas spp. have been characterized for
      their structural and antimicrobial properties. In the present study, the
      structure of a novel lipodepsipeptide, cormycin A, produced in culture by the
      tomato pathogen Pseudomonas corrugata was elucidated by combined protein
      chemistry, mass spectrometry and two-dimensional NMR procedures. Its peptide
      moiety corresponds to L-Ser-D-Orn-L-Asn-D-Hse-L-His-L-aThr-Z-Dhb-L-Asp(3-OH)-L
      Thr(4-Cl) [where Orn represents ornithine, Hse is homoserine, aThr is allo
      threonine, Z-Dhb is 2,3-dehydro-2-aminobutanoic acid, Asp(3-OH) is 3
      hydroxyaspartic acid and Thr(4-Cl) is 4-chlorothreonine], with the terminal
      carboxy group closing a macrocyclic ring with the hydroxy group of the N-terminal
      serine residue. This is, in turn, N-acylated by 3,4-dihydroxy-esadecanoate. In
      aqueous solution, cormycin A showed a rather compact structure, being derived
      from an inward orientation of some amino acid side chains and from the 'hairpin
      bent' conformation of the lipid, due to inter-residue interactions involving its
      terminal part. Cormycin was significantly more active than the other
      lipodepsipeptides from Pseudomonas spp., as demonstrated by phytotoxicity and
      antibiosis assays, as well as by red-blood-cell lysis. Differences in biological
      activity were putatively ascribed to its weak positive net charge at neutral pH.
      Planar lipid membrane experiments showed step-like current transitions,
      suggesting that cormycin is able to form pores. This ability was strongly
      influenced by the phospholipid composition of the membrane and, in particular, by
      the presence of sterols. All of these findings suggest that cormycin derivatives
      could find promising applications, either as antifungal compounds for topical use
      or as post-harvest biocontrol agents.

PMID- 15196053
TI  - Characterization of the ligandin site of maize glutathione S-transferase I.
AB  - Cytosolic GSTs (glutathione S-transferases) are a major reserve of high-capacity
      binding proteins and exhibit ligand-binding properties for a large variety of
      compounds. In the present study, the binding of two non-substrate anthraquinone
      dyes VBAR (Vilmafix Blue A-R) and CB3GA (Cibacron Blue 3GA) to maize (Zea mays)
      GST I was investigated. The results showed that the enzyme was specifically and
      irreversible inactivated by VBAR with a K(d) of 35.5+/-2.2 microM and a k(3) of
      0.47 min(-1). Proteolytic cleavage of the VBAR-modified enzyme and subsequent
      separation of peptides gave only one modified peptide. Sequencing of the modified
      peptide revealed the target site of VBAR reaction to be Lys(41). CB3GA binds
      reversibly to GST I and behaves as a competitive inhibitor towards CDNB (1-chloro
      2,4-dinitrobenzene) and glutathione. CB3GA binding to GST I is accompanied by a
      characteristic spectral change in the absorption at positive maximum (670 nm)
      which exhibited a hyperbolic dependence on dye concentration with a K(d) of
      12.1+/-0.5 microM. Site-directed mutagenesis of selected residues (Trp(12),
      Phe(35), Lys(41), Asn(49), Gln(53), Ser(67) and Ile(118)) was employed, and the
      mutated enzymes were assessed for CB3GA binding. These results, together with
      molecular-modelling studies, established that the ligandin-binding site of GST I
      is located mainly in the hydrophobic binding site. The ability of VBAR to
      specifically inactivate GST I was exploited further to demonstrate the specific
      binding of several plant hormones and flavonoids to GST I. The inactivation of
      other GST isoenzymes by VBAR was also investigated, and it was concluded that
      VBAR may have wide applicability as an affinity label for probing structure
      function relationships of GST isoenzymes.

PMID- 15196054
TI  - Characterization of a calmodulin-regulated Ca2+-dependent-protein-kinase-related
      protein kinase, AtCRK1, from Arabidopsis.
AB  - An AtCRK1 [Arabidopsis thaliana CDPK (Ca2+-dependent protein kinase)-related
      protein kinase 1] has been characterized molecularly and biochemically. AtCRK1
      contains the kinase catalytic domain and a CaM (calmodulin)-binding site. Our
      results demonstrated that AtCRK1 could bind CaM in a Ca2+-dependent manner. This
      kinase phosphorylated itself and substrates such as histone IIIS and syntide-2 in
      a Ca2+-independent manner and the activity was stimulated by several CaM isoforms
      through its CaM-binding domain. This domain was localized within a stretch of 39
      amino acid residues at positions from 403 to 441 with K(d)=67 nM for CaM binding.
      However, the stimulation amplification of the kinase activity of AtCRK1 by
      different CaM isoforms was similar.

PMID- 15196055
TI  - ABO incompatible transplantation: to B or not to B.

PMID- 15196056
TI  - Statins in solid organ transplantation: is there an immunosuppressive effect?
AB  - Cardiac allograft vasculopathy is one of the major causes of mortality late after
      heart transplantation. This disease process occurs to a lesser extent in patients
      with other donor organs; however, a long-term graft dysfunction is similarly
      described in kidney, liver and lung transplant recipients. There are multiple
      immune and nonimmune risk factors associated with this vasculopathic disease
      process, one of which includes hyperlipidemia. Use of lipid lowering agents,
      specifically HMG-CoA reductase inhibitors (statins) was initially reported to
      have possible immunosuppressive effects in a single center study of heart
      transplant recipients. This has not been observed in kidney transplant
      recipients; however, a large randomized trial demonstrated a significant
      cardiovascular risk reduction in fluvastatin-treated kidney transplant patients,
      outcome similar to the numerous nontransplant clinical trials of statins in
      atherosclerosis. In two recent in vitro studies, statins have been reported to
      repress induction of MHC-II by interferon-gamma and selectively block leukocyte
      function antigen-1, both of which decrease T-lymphocyte activation. In
      conclusion, statins appear to have outcome benefits in heart and kidney
      transplant patients; however, firm evidence for a clinical immunosuppressive
      effect is lacking. Further studies in humans will be needed to demonstrate this
      potential effect of statins. Overall, the outcome benefits of statins from the
      heart and kidney clinical studies provide a firm rationale to support the use of
      statins in organ transplantation.

PMID- 15196057
TI  - FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress
      and endothelial barrier function.
AB  - The novel immunomodulator FTY720 is effective in experimental models of
      transplantation and autoimmunity, and is currently undergoing Phase III clinical
      trials for prevention of kidney graft rejection. In contrast to conventional
      immunosuppressants, FTY720 does not impair T- and B-cell activation,
      proliferation and effector function, but interferes with cell traffic between
      lymphoid organs and blood. The molecular basis for the mode of action of the drug
      has only recently been established. FTY720, after phosphorylation, acts as a high
      affinity agonist at the G protein-coupled sphingosine 1-phosphate receptor-1
      (S1P(1)) on thymocytes and lymphocytes, thereby inducing aberrant internalization
      of the receptor. This renders the cells unresponsive to the serum lipid
      sphingosine 1-phosphate (S1P), depriving them from an obligatory signal to egress
      from lymphoid organs. As a consequence, lymphocytes are unable to recirculate to
      peripheral inflammatory tissues and graft sites but remain functional in the
      lymphoid compartment. In addition to the effects on lymphocyte recirculation, the
      drug acts on endothelial cells and preserves vascular integrity by enhancing
      adherens junction assembly and endothelial barrier function. The available data
      establish S1P(1) as a key target for FTY720, and further point to therapeutically
      relevant effects of the drug on lymphocytes and vascular endothelium.

PMID- 15196058
TI  - Role of integrin CD103 in promoting destruction of renal allografts by CD8 T
      cells.
AB  - Infiltration of CD8(+)TCRalphabeta(+) T-effector populations (CD8 effectors) into
      graft epithelial compartments has long been recognized as a key lesion in
      progression of clinical renal allograft rejection. While the afferent phase of
      allograft immunity is increasingly well-defined, the efferent pathways by which
      donor-reactive CD8-effector populations access and ultimately destroy the graft
      renal tubules (rejection per se) have received remarkably little attention. This
      is an important gap in our knowledge of transplantation immunology, because
      epithelial compartments comprise the functional elements of most commonly
      transplanted organs including not only kidney, but also liver, lung, pancreas,
      and intestine. Furthermore, there is increasing evidence that attack of graft
      epithelial elements by CD8-effector populations not only causes short-term graft
      dysfunction but is also a major contributor to development of chronic allograft
      nephropathy and late graft loss, which now represent the salient clinical
      problems. Recent studies of the T-cell integrin, alpha(E)beta(7) (CD103), have
      provided insight into the mechanisms that promote interaction of CD8 effectors
      with graft epithelial compartments. The purpose of this communication is to
      review the known properties of the CD103 molecule and its postulated role in the
      efferent phase of renal allograft rejection.

PMID- 15196059
TI  - National conference to assess antibody-mediated rejection in solid organ
      transplantation.
AB  - The process of humoral rejection is multifaceted and has different manifestations
      in the various types of organ transplants. Because this process is emerging as a
      leading cause of graft loss, a conference was held in April 2003 to
      comprehensively address issues regarding humoral rejection. Though humoral
      rejection may result from different factors, discussion focused on a paradigm
      caused by antibodies, typically against donor HLA antigens, leading to the term
      'antibody-mediated rejection' (AMR). Conference deliberations were separated into
      four workgroups: The Profiling Workgroup evaluated strengths and limitations of
      different methods for detecting HLA reactive antibody, and created risk
      assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical,
      pathologic, and serologic criteria for assessing AMR in renal, heart and lung
      transplant recipients; The Treatment Workgroup discussed advantages, limitations
      and possible mechanisms of action for desensitization protocols that may reverse
      AMR; and The Basic Science Workgroup presented animal and human immunologic
      models for humoral rejection and proposed potential targets for future
      intervention. This work represents a comprehensive review with contributions from
      experts in the fields of Transplantation Surgery, Medicine, Pathology,
      Histocompatibility, Immunology, and clinical trial design. Immunologic barriers
      once considered insurmountable are now consistently overcome to enable more
      patients to undergo organ transplantation.

PMID- 15196060
TI  - Effects of organ preservation, ischemia time and caspase inhibition on apoptosis
      and microcirculation in rat pancreas transplantation.
AB  - This study was undertaken to examine the impact of ischemia-reperfusion (I/R)
      injury on microcirculation and apoptosis in experimental pancreas
      transplantation. Pancreatic grafts were subjected to different preservation
      solutions and cold ischemia times (CITs): University of Wisconsin (UW), 6-h CITs
      (group U6); UW, 18-h CITs (group U18); normal saline, 6-h CITs (group S6); and
      normal saline, 6-h CITs with Z-Asp-2,6-dichlorobenzoyloxymethylketone (pan
      caspase inhibitor; group S6 & CI). Nontransplanted animals served as controls. At
      1- and 2-h reperfusion microcirculation was assessed by means of intravital
      microscopy. Apoptosis was detected by in situ nick end-labeling method (TUNEL) at
      2-h reperfusion. Deterioration of microcirculation was lowest in group U6 and
      highest in groups S6 and S6 & CI compared with controls. The apoptotic index
      (cells per high power fields) of groups U6, U18 and S6 correlated well with
      functional capillary density (r=- 0,70, p < 0.0001) and leucocyte sticking (r=
      0,69, p < 0.0001) at 1-h reperfusion. Caspase inhibition had no impact on
      microcirculation but significantly reduced AI compared with group S6 (p < 0.001).
      These data suggest that pancreatic I/R injury-induced apoptotic cell death well
      predicts the extent of [corrected] microcirculatory impairment. Caspase
      inhibition might be a promising strategy in reducing I/R injury in pancreas
      transplantation.

PMID- 15196062
TI  - Critical role for CD8 T cells in allograft acceptance induced by DST and
      CD40/CD154 costimulatory blockade.
AB  - Donor-specific transfusion (DST) and CD40/CD154 costimulation blockade is a
      powerful immunosuppressive strategy which prolongs survival of many allografts.
      The efficacy of DST and anti-CD154 mAb for prolongation of hepatocellular
      allograft survival was only realized in C57BL/6 mice that have both CD4- and CD8
      dependent pathways available (median survival time, MST, 82 days). Hepatocyte
      rejection in CD8 KO mice which is CD4-dependent was not suppressed by DST and
      anti-CD154 mAb treatment (MST, 7 days); unexpectedly DST abrogated the beneficial
      effects of anti-CD154 mAb for suppression of hepatocyte rejection (MST, 42 days)
      and on donor-reactive alloantibody production. Hepatocyte rejection in CD4 KO
      mice which is CD8-dependent was suppressed by treatment with DST and anti-CD154
      mAb therapy (MST, 35 days) but did not differ significantly from immunotherapy
      with anti-CD154 mAb alone (MST, 32 days). Induction of hepatocellular allograft
      acceptance by DST and anti-CD154 mAb immunotherapy was dependent on host CD8(+) T
      cells, as demonstrated by CD8 depletion studies in C57BL/6 mice (MST, 14 days)
      and CD8 reconstitution of CD8 KO mice (MST, 56 days). These studies demonstrate
      that both CD4(+) and CD8(+) T-cell subsets contribute to induction of
      hepatocellular allograft acceptance by this immunotherapeutic strategy.

PMID- 15196061
TI  - Porcine endogenous retroviral nucleic acid in peripheral tissues is associated
      with migration of porcine cells post islet transplant.
AB  - Porcine islets represent an alternative source of insulin-producing tissue,
      however, porcine endogenous retrovirus (PERV) remains a concern. In this study,
      SCID mice were transplanted with nonencapsulated (non-EC), microencapsulated (EC)
      or macroencapsulated (in a TheraCyte trade mark device) neonatal porcine islets
      (NPIs), and peripheral tissues were screened for presence of viral DNA and mRNA.
      To understand the role of an intact immune system in PERV incidence, mice with
      established NPI grafts were reconstituted with splenocytes. Peripheral tissues
      were screened for PERV and porcine DNA using PCR. Tissues with positive DNA were
      analyzed for PERV mRNA using RT-PCR. No significant difference was observed
      between non-EC and EC transplants regarding presence of PERV or porcine-specific
      DNA or mRNA. In reconstituted animals, little PERV or porcine DNA, and no PERV
      mRNA was detected. No PERV or porcine-specific DNA was observed in animals
      implanted with a TheraCyte trade mark device. In conclusion, an intact immune
      system significantly lowered the presence of PERV. Microencapsulation of islets
      did not alter PERV presence, however, macroencapsulation in the TheraCyte device
      did. Lower PERV incidence coincided with lower porcine DNA in peripheral tissues,
      linking the presence of PERV to migration of porcine cells.

PMID- 15196063
TI  - Mitochondrial permeability transition in cardiomyocyte apoptosis during acute
      graft rejection.
AB  - Evidence indicates that acute cardiac graft rejection is associated with
      cardiomyocyte apoptosis. Mitochondrial permeability transition (MPT) induces
      apoptotic cell death. We sought to determine whether MPT might play a role in
      cardiomyocyte apoptosis in the rat model of heterotopic cardiac transplantation.
      Syngenic and allogenic transplantations were performed, and both native and
      grafted hearts were harvested 3 or 5 d after transplantation for detection of
      acute rejection, assessment of Ca(2+)-induced MPT, and myocardial apoptosis by
      TUNEL staining and caspase 3 activity. Allogenic grafts developed severe acute
      rejection at day 5 with concomitant cardiomyocyte apoptosis (apoptotic index: 7.1
      +/- 1.0% vs. 1.0 +/- 0.2% in syngenic hearts, and caspase 3 activity: 38 +/- 25
      vs. 5 +/- 9 nmol/mg, in allogenic vs. syngenic grafts, respectively). At day 5,
      Ca(2+)-induced MPT was dramatically altered in allogenic when compared with
      syngenic grafts (mean Ca(2+) overload averaged 0 +/- 20 vs. 280 +/- 30 microM in
      allogenic and syngenic grafts, respectively). NIM811, a nonimmunosuppressive
      derivative of cyclosporin A (CsA), that specifically inhibits the MPT pore, did
      not alter acute rejection, but significantly delayed Ca(2+)-induced MPT pore
      opening, attenuated caspase 3 activity and cardiomyocyte apoptosis in allogenic
      grafts. This suggests that mitochondrial permeability transition pore opening may
      play an important role in cardiomyocyte apoptosis associated with acute cardiac
      graft rejection.

PMID- 15196064
TI  - Early adequate mycophenolic acid exposure is associated with less rejection in
      kidney transplantation.
AB  - This study examines the importance of early mycophenolic acid (MPA) exposure in
      the cyclosporine- and mycophenolate mofetil (MMF)-treated kidney transplant
      population. We prospectively evaluated 94 first solitary kidney transplant
      patients treated with cyclosporine (Neoral), MMF, and prednisone. Basiliximab was
      also given to 72 recipients. MPA exposure was measured by HPLC using a limited
      sampling estimate of 12 h area under the curve (AUC [0-12]) within the first
      week. Efficacy was determined by the occurrence of acute rejection and toxicity
      by the need to reduce MMF doses within the first 3 months post-transplantation.
      Acute rejection was observed in 14 (15%) and MMF toxicity in 27 (29%). Receiver
      operator curve analysis shows that MPA AUC [0-12] on day 3 was predictive of
      efficacy (c = 0.72, p = 0.007) but not toxicity (c = 0.57, p = 0.285). A separate
      analysis of only patients on basiliximab shows that the MPA AUC [0-12] on day 3
      was also predictive of efficacy (c = 0.80, p = 0.01). Therefore early adequate
      exposure to MPA by day 3 is associated with low acute rejection but cannot
      predict toxicity. Adequate MPA exposure is also important with basiliximab
      induction therapy.

PMID- 15196065
TI  - Sirolimus impairs gonadal function in heart transplant recipients.
AB  - The impact of sirolimus on hormone levels involved in the hypothalamus-pituitary
      gonad axis in male heart transplant recipients was investigated. A pair-matched
      analysis with 132 male heart transplant recipients on either sirolimus based- or
      calcineurin inhibitor-based immunosuppression was performed. Matching criteria
      were age, years after transplantation and creatinine levels. Measured parameters
      were testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH),
      sexual hormone-binding globulin (SHBG) and free androgen index (FAI). Mean
      testosterone was 3.86 +/- 1.41 ng/mL in the sirolimus group and 4.55 +/- 1.94
      ng/mL in the controls (p = 0.025). Serum LH was 12.82 +/- 11.19 mlU/mL in the
      sirolimus patients and 6.2 +/- 5.25 mlU/mL in the controls (p = 0.015). Follicle
      stimulating hormone levels were 13.31 +/- 18.4 mlU/mL vs. 7.32 +/- 5.53 mlU/mL,
      respectively (p = 0.015). The analysis revealed a significant decrease in
      testosterone and a significant increase in FSH and LH in the sirolimus group. The
      duration of sirolimus treatment correlated positively with SHBG (p < 0.01), LH (p
      < 0.05) and FSH (p < 0.05) and negative with the FAI (p < 0.05). Sirolimus trough
      levels correlated with LH and FSH levels (p < 0.01). Heart transplant recipients
      treated with sirolimus revealed significantly lower testosterone levels and a
      significant increase in gonadotropic hormones. These effects were trough-level
      dependent. All candidates awaiting organ transplantation should be informed about
      these adverse effects.

PMID- 15196066
TI  - Excellent long-term outcome of ABO-incompatible living donor kidney
      transplantation in Japan.
AB  - Owing to the severe shortage of cadaveric grafts in Japan, we have performed ABO
      incompatible living donor kidney transplantation since 1989. This study assessed
      short- and long-term outcomes in 441 patients who received ABO-incompatible
      living donor kidney transplants between January 1989 and December 2001. We
      compared our results with historical data from 1055 recipients of living kidney
      transplantation. Overall patient survival rates 1, 3, 5, 7, and 9 years after ABO
      incompatible transplantation were 93%, 89%, 87%, 85%, and 84%, respectively.
      Corresponding overall graft survival rates were 84%, 80%, 71%, 65%, and 59%.
      After ABO-incompatible transplantation, graft survival rates were significantly
      higher in patients 29 years or younger than in those 30 years or older and in
      patients who received anticoagulation therapy than in those who did not receive
      such therapy. There were no significant differences between A-incompatible and B
      incompatible recipients with respect to clinical outcomes. The graft survival
      rate at 1 year in the historical controls was slightly but not significantly
      higher than that in our recipients of ABO-incompatible transplants. We conclude
      that long-term outcome in recipients of ABO-incompatible living kidneys is
      excellent. Transplantation of ABO-incompatible kidneys from living donors is a
      radical, but effective treatment for end-stage renal disease.

PMID- 15196067
TI  - Systemic up-regulation of angiotensin II type 1 receptor in cardiac donors with
      spontaneous intracerebral hemorrhage.
AB  - Donor spontaneous intracerebral hemorrhage (ICH) is a potential risk factor for
      morbidity and mortality after cardiac transplantation. We hypothesized that donor
      ICH is associated with systemic up-regulation of angiotensin II receptor type 1
      (AT1R). We evaluated mRNA expression of AT1R and AT2R in donor spleen lymphocytes
      and in heart biopsies from 20 recipients of hearts from donors with spontaneous
      ICH which were compared with 20 recipients from trauma donors. Heart biopsies
      showed 4.7-fold increased mRNA expression of AT1R (p < 0.0001) in the ICH group
      compared with the Trauma group. The ICH group also showed 2.6-fold (p < 0.01)
      increased mRNA expression of AT1R in the donor spleen lymphocytes, suggesting the
      presence of systemic activation before transplantation. At 1 year, the ICH group
      had increased coronary vasculopathy by vascular ultrasound. Using multivariate
      regression analysis, mRNA expression of AT1R in the donor spleen lymphocytes was
      found to be a strong independent predictor of transplant vasculopathy (odds ratio
      = 4.397, CI = 1.243-15.553, adjusted p = 0.02). This is the first report to
      describe splenic up-regulation of AT1R in the presence of spontaneous ICH and its
      association with subsequent development of transplant vasculopathy.

PMID- 15196068
TI  - Prospective study on lamivudine-resistant hepatitis B in renal allograft
      recipients.
AB  - The natural history of lamivudine-resistant hepatitis B virus (HBV) infection in
      renal transplant recipients (RTx) is unclear, despite its increasing incidence.
      Twenty-nine HBsAg-positive RTx with rising HBV DNA received lamivudine therapy.
      The course of lamivudine-resistant HBV infection was studied prospectively.
      During 68.7 +/- 12.5 months of follow-up, 14 (48.3%) patients developed
      lamivudine resistance, at 10-35 months (mean 16.9 +/- 7.0). All showed mutant
      sequences at codons 552 and 528 of the YMDD motif, while 13 patients demonstrated
      wild-type sequence at codon 555. Lamivudine resistance was unrelated to patient
      demographics, HBeAg status/sero-conversion, or genotype. Following resistance,
      HBV DNA and alanine aminotransferase showed an initial increase followed by
      spontaneous gradual reduction. The subsequent peak HBV DNA was lower (1.26 +/-
      1.09 x 10(9) vs. 6.26 +/- 12.23 x 10(9) copies/mL, p = 0.011), while that of
      alanine aminotransferase was higher (196 +/- 117 vs. 77 +/- 47 imicro/l, p =
      0.005), compared with pretreatment levels. Post-resistance hepatitic flare
      occurred in 11 (78.6%) patients. This was transient in four (36.4%), but became
      chronic in six (54.5%) patients. Decompensation was noted in one patient during
      this flare, but all survived. We conclude that drug resistance is prevalent in
      lamivudine-treated RTx. Despite a lower ensuing peak viremia compared with
      baseline, hepatitic flare is common. While most patients have spontaneous
      resolution, a minority may develop potentially fatal decompensation during the
      preceding exacerbation.

PMID- 15196069
TI  - Twenty-two nondirected kidney donors: an update on a single center's experience.
AB  - At the University of Minnesota, we have defined 'nondirected donation' as organ
      donation by a volunteer who offered to donate an organ to anyone on the cadaver
      waiting list. From October 1, 1997, through October 31, 2003, we have had 360
      inquiries about nondirected donation, have completed 42 detailed nondirected
      donor (NDD) evaluations for kidney donation, and have performed 22 NDD
      transplants. We herein review our program policies and how they have evolved,
      describe our evaluation and the motivation of our potential donors, summarize the
      outcome of NDD transplants, and raise issues requiring further attention and
      study. Our experience continues to support nondirected donation for kidney
      transplants.

PMID- 15196070
TI  - Successful simultaneous islet-kidney transplantation using a steroid-free
      immunosuppression: two-year follow-up.
AB  - We report on the feasibility of a glucocorticoid-free immunosuppression
      (sirolimus, low-dose tacrolimus, and daclizumab) in simultaneous islet-kidney
      transplantation in nine patients with type 1 diabetes. There was one renal
      primary nonfunction. Renal function (n = 8) as assessed by creatinine and
      creatinine clearance over time was 103 +/- 6 micromol/L and 64 +/- 6 mL/min/1.73
      m(2), respectively. Five out of six patients with >or= 2 islet transplantations
      became insulin independent. The mean HbA(1c) during the follow-up period for all
      patients after transplantation is 6.2 +/- 0.9% as compared with 8.7 +/- 1.9%
      prior to transplant. These results in patients with a median follow-up of 2.3
      years suggest that kidney transplantation under a glucocorticoid-free
      immunosuppression is feasible, and that the rate of insulin independence of 80%
      can be achieved not only in patients with no or minimal diabetes complications,
      but also in patients with more advanced late complications and in conjunction
      with kidney transplantation.

PMID- 15196071
TI  - An analysis of the association between serum citrulline and acute rejection among
      26 recipients of intestinal transplant.
AB  - Small preliminary studies suggest that serum citrulline levels may act as a
      marker for acute cellular rejection in small intestinal transplant recipients.
      The results comparing serum citrulline concentrations with biopsy-based grades of
      rejection are summarized here for an expanded group of 26 isolated intestinal and
      multivisceral transplant recipients. Other factors considered included patient
      and donor age and sex, ischemia time, serum creatinine, and type of transplant.
      Straight-line fits reasonably described how each patient's citrulline levels
      changed over time. Among 21 patients who demonstrated increasing citrulline
      levels over time, the estimated median time-to-achieve normal citrulline (>or=30
      micromol/L) was 79 days post-transplant. Using stepwise linear regression, two
      characteristics were associated with a significantly higher maximum grade of
      rejection after 14 d post-transplant: longer time-to-achieve normal citrulline
      (using ranks, p < 0.00001) and the patient not receiving a multivisceral
      transplant (p = 0.0005). Only the latter characteristic was significantly
      associated with maximum grade of rejection during the first 14 d post-transplant
      (p = 0.01). Clearly, time-to-normalization of citrulline was delayed by the
      incidence of rejection, and in some cases with moderate-to-severe rejection,
      normalization of citrulline levels never occurred. We plan to further examine the
      use of citrulline as a marker for rejection in larger prospective studies.

PMID- 15196072
TI  - Impact of donor age and year of transplant on graft survival in liver transplant
      recipients with chronic hepatitis C.
AB  - Studies suggest donor age and year of transplantation are associated with low
      graft survival in liver transplant recipients with hepatitis C. We sought to
      determine if advanced donor age and recent year of transplantation are associated
      with graft survival in hepatitis C recipients and to determine if the effect of
      donor age on graft survival is specific to hepatitis C. We analyzed the United
      Network for Organ Sharing liver transplant database from 1994 to 2002. Six
      thousand four hundred and four subjects transplanted for end-stage liver disease
      from chronic hepatitis C met our criteria. One-year graft survival in hepatitis C
      recipients with organs from donors <40 years old and >or=60 years old was 84% and
      73%, p = 0.003, respectively. These rates in recipients with cholestatic liver
      disease and alcoholic liver disease were 85% and 82%, respectively, p = 0.11 and
      82% and 78%, respectively, p = 0.14. Three-year graft survival in hepatitis C
      recipients transplanted from 1994 to 1995 and 1996 to 1999 was 67% and 69%,
      respectively, p = 0.10. Graft survival in hepatitis C recipients has not declined
      in recent years. Older donor age is associated with lower short-term graft
      survival in recipients with hepatitis C, but not in recipients with cholestatic
      or alcoholic liver disease.

PMID- 15196073
TI  - Liver transplantation from donors aged 80 years and over: pushing the limit.
AB  - Older donors are a growing part of the total donor pool but no definite consensus
      exists on the limit of age for their acceptance. From November 1998 to January
      2003, in a retrospective case-control multicenter study, we compared the outcome
      of 30 orthotopic liver transplantations (OLTs) with octogenarian donors and of 60
      chronologically correlated OLTs performed with donors <40 years. The percentage
      of refusal was greater among older than younger donors (48.2 vs. 14.3%; p <
      0.001). Cold ischemia was significantly shorter in the older than younger groups.
      Recipients with hepatocarcinoma and older age received octogenarian grafts more
      frequently. No differences were seen in post-operative complications and 6-month
      graft and patient survival. However, long-term survival was lower in patients
      transplanted with octogenarian donors (p = 0.04). Interestingly, the mortality
      related to hepatitis C recurrence was greater in patients with octogenarian
      donors. Accordingly, the long-term survival of HCV-positive patients who received
      older grafts was lower than those receiving younger grafts (p = 0.05).
      Octogenarian livers can be used safely but a careful donor evaluation and a short
      cold ischemia are required to prevent additional risk factors. However, hepatitis
      C recurrence is associated with a greater mortality in patients who received
      octogenarian grafts raising concerns whether to allocate these livers to HCV
      positive recipients.

PMID- 15196074
TI  - C-reactive protein and body mass index independently predict mortality in kidney
      transplant recipients.
AB  - C-reactive protein (CRP) is a risk factor for cardiovascular outcomes and
      mortality in the general population. To date, there are no prospective studies of
      the association between CRP and mortality or allograft loss in kidney transplant
      recipients (KTR). In 1995, 438 consecutive KTR were enrolled in this prospective
      study. Important information on demographic, clinical and immunological
      characteristics was collected at baseline, and CRP was measured using standard
      methods. Patients were then followed-up for a median 7.8 years. Time-to-event
      analyses (univariate and multivariate Cox proportional hazards regression models)
      were used to study the main outcomes: all-cause mortality and kidney allograft
      loss, defined as the earlier of return to dialysis, re-transplantation, or death.
      From univariate analyses, we found that CRP >or=0.5 mg/dL was associated with a
      83% greater mortality risk compared with lower levels of this inflammatory marker
      [hazard ratio (HR) = 1.83; 95% confidence interval (CI): 1.23-2.72; p = 0.003].
      After multivariate adjustment, patients with a CRP >or=0.5 mg/dL had a 53% higher
      mortality risk compared with patients whose CRP was below that threshold (HR =
      1.53; 95% CI: 1.01-2.31; p = 0.04). No associations between CRP and the risk of
      kidney allograft loss were detected. Furthermore, we were not able to detect any
      effect modification between CRP and body mass index on the outcomes under study.
      We conclude that CRP predicts all-cause mortality, but not allograft loss in
      stable KTR.

PMID- 15196075
TI  - Cost-effectiveness of lung transplantation in relation to type of end-stage
      pulmonary disease.
AB  - The purpose of this study was to explore the relationship between diagnosis and
      the cost-effectiveness and cost-utility of lung transplantation. A
      microsimulation model was used, based on empirical data from the Dutch lung
      transplantation program, collected between 1991 and 1999. We assessed life-years,
      quality-adjusted life-years, and costs with and without transplantation for the
      diagnostic categories alfa-1 antitrypsin deficiency, COPD/emphysema,
      bronchiectasis, primary and secondary pulmonary hypertension, cystic fibrosis,
      and pulmonary fibrosis. Alfa-1 antitrypsin deficiency and bronchiectasis had the
      highest survival gain. Secondary pulmonary hypertension and pulmonary fibrosis
      had the lowest survival gain and the lowest gain of quality-adjusted life-years.
      As compared with COPD/emphysema, alfa-1 antitrypsin deficiency, bronchiectasis,
      and CF had 25%, 40% and 19% more favorable cost-effectiveness ratios,
      respectively. Cost-utility ratios varied less, with values of -7%, -14% and -11%
      for alfa-1 antitrypsin deficiency, bronchiectasis, and primary pulmonary
      hypertension, respectively, compared with COPD. In conclusion, our model suggests
      that there is considerable variation in cost-effectiveness and, to a lesser
      degree, in cost-utility between the different diagnostic categories. These
      variations are the result of differences in survival and in quality of life with
      and without lung transplantation.

PMID- 15196078
TI  - Surrogate markers and risk factors for chronic lung allograft dysfunction.
AB  - Obliterative bronchiolitis (OB) is the histologic correlate of chronic allograft
      dysfunction in pulmonary transplantation. The histologic diagnosis of OB is
      challenging, therefore a physiologic definition, bronchiolitis obliterans
      syndrome (BOS) based on pulmonary function tests has been used as a surrogate
      marker for OB for the last decade. BOS has proven to be the best available
      surrogate marker for OB and is predictive of the ultimate endpoints of graft and
      patient survival. Multiple other clinical markers have been reported and proposed
      as alternates for or complements to BOS grade, but all need further evaluation
      and validation in large, prospective clinical trials. Lastly, given the early
      occurrence and high incidence of chronic allograft dysfunction, the easily
      measurable endpoint of BOS grade, and our lack of understanding of ways to
      prevent or alter the course of BOS, lung transplant recipients represent an ideal
      population for clinical trials targeting prevention and treatment of chronic
      allograft dysfunction.

PMID- 15196076
TI  - Creatinine reduction ratio on post-transplant day two as criterion in defining
      delayed graft function.
AB  - Delayed graft function (DGF) is a common complication after renal transplant,
      affecting its outcome. A common definition of DGF is the need for dialysis within
      the first week of transplantation, but this criterion has its drawbacks. We tried
      to validate an earlier and better defined parameter of DGF based on the
      creatinine reduction ratio on post-transplant day 2 (CRR2). We analyzed the
      clinical charts of 291 cadaver kidney recipients to compare the outcome of
      patients with immediate graft function (IGF), dialyzed patients (D-DGF) and
      nondialyzed CRR2-defined DGF patients (ND-DGF) and to identify risk factors for D
      DGF and ND-DGF. Creatinine reduction ratio on post-transplant day 2 correlates
      significantly with renal function during the first year. Patients with IGF have
      significantly better renal function throughout the first year and better graft
      survival than patients with D-DGF and ND-DGF, while we found no differences
      either in renal function from days 30-365 or in graft survival between D-DGF and
      ND-DGF patients. Defining DGF by CRR2 allows an objective and quantitative
      diagnosis after transplantation and can help to improve post-transplant
      management. Creatinine reduction ratio on post-transplant day 2 correlates with
      renal function throughout the first year. The worse survival in the ND-DGF group
      is an important finding and a major advantage of the CRR2 criterion.

PMID- 15196079
TI  - Surrogate markers for long-term renal allograft survival.
AB  - Progressive improvement in kidney transplant survival rates and reduction in
      acute rejection rates have ironically restricted our ability to evaluate newer
      therapy. Current short-term endpoints such as acute rejection rates have reduced
      utility in predicting long-term survival. Long-term graft survival is an ideal
      endpoint, but is limited by longer follow-up requirements and the large cohort of
      patients required for such studies. Newer short-term surrogate markers should be
      identified and these markers should correlate with long-term graft failure.
      Hence, identification of short-term surrogate markers is critical to test newer
      immunosuppressive strategies over current therapies, and should also predict long
      term transplant outcome. Potential surrogate markers are clinical parameters such
      as renal function, renal histological findings of fibrosis and immunological
      markers. Post-transplant renal function estimated by serum creatinine within 1
      year has been shown to correlate with long-term survival. Alternative evaluation
      of renal function such as clearance studies and cystatin C, which are more
      accurate, could potentially be useful in clinical trials. Renal histological
      indices such as fibrosis measured as Chronic Allograft Disease Index score or
      Banff score correlate with long-term graft survival. Immunological markers such
      as antidonor antibodies, levels of blood and urine cytokines, real time PCR,
      ELISPOT and microarrays are attractive surrogates to consider. Measurement of
      morbidity and mortality after transplantation is critical to further enhance long
      term survival. Thus, there are many potential surrogate markers and these
      individually or in combination with conventional endpoints should be implemented
      in clinical trials and validated in long-term studies.

PMID- 15196080
TI  - Surrogate markers for late cardiac allograft survival.
AB  - While no definite well-validated surrogate marker for late cardiac allograft
      outcome is available, the early detection of cardiac allograft vasculopathy
      represents the 'key' candidate as an effective surrogate. Intravascular
      ultrasound detected intimal thickening has been noted to possess prognostic
      capability despite the presence of a normal coronary angiogram. Several
      prospective investigations have pointed to accurate thresholds of intimal
      thickening that are prognostically relevant and predict not only future
      angiographic disease but also hard allograft related endpoints including ischemic
      cardiac events, allograft failure, and death. Because of the resolution of
      intravascular ultrasound, this technique accords reproducibility and the ability
      to standardize the degree of intimal thickening over time. Other candidates that
      may serve as surrogates once appropriately evaluated include measures of
      allograft pump function, intragraft histology, and peripheral markers including
      but not limited to structural proteins (cardiac specific troponins), inflammatory
      markers (CRP), fibrogenic markers (TGF-beta, fibroblast growth factor), and
      immune markers (anti-HLA Ab and indirect alloantibodies).

PMID- 15196081
TI  - Management of an ABO-incompatible lung transplant.
AB  - A 24-year-old woman with cystic fibrosis underwent bilateral sequential lung
      transplantation and unintentionally received an ABO incompatible graft (blood
      type A(1) graft into a type O recipient). The recipient had a high titer of IgG
      anti-A antibody (256 by the indirect antiglobulin test). Emergency treatment
      included antibody removal by plasmapheresis and additional immunosuppression with
      mycophenolate, rabbit antithymocyte globulin and polyspecific intravenous
      immunoglobulin. Subsequently, immunoadsorption and the anti-CD20 antibody
      rituximab were used to remove anti-A antibody and inhibit its resynthesis. Early
      graft function was good; one episode of rejection at Day 46 responded promptly to
      treatment with methylprednisolone. Subsequently, graft function continued to
      improve and anti-A antibody titers remained low. No infectious or other
      complications were encountered. The treatment regimen that we adopted may prove
      useful in other cases of unplanned ABO-incompatible organ transplants. The
      successful outcome suggests that planned ABO-incompatible lung transplants may be
      possible.

PMID- 15196082
TI  - Infection with human herpesvirus 6 after kidney-pancreas transplant.
AB  - We describe the first known case of symptomatic infection resulting from human
      herpesvirus-6 (HHV-6) in simultaneous pancreas-kidney transplant recipients. The
      role of HHV-6 in solid-organ transplant recipients is not well defined. In
      hematopoietic stem cell transplantation (SCT) HHV-6 may cause fever, rash,
      myelosuppression, interstitial pneumonitis, and encephalitis.

PMID- 15196083
TI  - Encephalitis owing to human herpesvirus-6 after cardiac transplant.
AB  - Human herpesvirus-6 (HHV-6), a beta herpesvirus closely related to
      cytomegalovirus (CMV), infects the majority of the population in childhood. Human
      herpesvirus-6 can be reactivated in the immunosuppressed patient. After bone
      marrow and orthotopic liver transplant, it has been linked to various clinical
      syndromes, including undifferentiated febrile illness, encephalitis, pneumonitis
      and bone marrow suppression. To date its infectious role after orthotopic heart
      transplant has not been well documented. We present the case of a 32-year-old
      cardiac transplant recipient who initially presented 8 weeks after his transplant
      with high fever and headache. He developed increasing confusion, pulmonary
      infiltrates and neutropenia. Cytomegalovirus viral loads were negative.
      Polymerase chain reaction (PCR) of blood and cerebrospinal fluid detected HHV-6
      DNA, consistent with HHV-6-related encephalitis, pneumonitis and bone marrow
      suppression. He was treated with foscarnet with gradual improvement in clinical
      status. We review the literature on the significance of this virus post cardiac
      transplant.

PMID- 15196084
TI  - Acute polymyositis following renal transplantation.
AB  - Myositis is a rare complication following renal transplantation and is most
      commonly the result of drug-mediated myotoxicity. Other causative disorders
      include viral infection, electrolyte imbalance and myositis of autoimmune origin.
      We describe a 60-year-old patient who developed acute polymyositis 4 weeks after
      a 000 human leukocyte antigen (HLA) mismatch cadaveric renal transplant.
      Following an uncomplicated transplant course with maintenance triple
      immunosuppression (prednisolone, mycophenolate mofetil and cyclosporine), the
      patient presented with severe symmetrical proximal muscle weakness associated
      with a rise in serum creatine kinase to 46800 U/L. Electromyography confirmed
      myopathic changes and muscle biopsy demonstrated extensive muscle-fiber necrosis
      with an inflammatory infiltrate. There were no obviously culpable drugs and viral
      studies were negative. Prompt initiation of high-dose steroid therapy led to
      clinical and biochemical recovery. Acute polymyositis may occur following renal
      transplantation. Potential mechanisms include viral antigen transmission or a
      localized form of graft vs. host disease.

PMID- 15196085
TI  - Squamous cell carcinoma in a chronically rejected renal allograft.
AB  - The malignant degeneration of a chronically rejected kidney allograft has been
      rarely reported. Almost invariably such malignancies originated in the
      transitional epithelium. We herein present the first occurrence of squamous cell
      carcinoma (SCC), originating from occult donor cells, in a chronically rejected
      renal allograft. Nearly 20 years after chronic rejection and loss of function of
      a cadaver renal graft, our patient developed increasing abdominal discomfort,
      decrease in appetite and weight loss. A CT-scan of the abdomen showed an
      abnormally enlarged and irregularly contoured mass at the level of the rejected
      allograft. Given the clinical and radiologic picture suggestive of either an
      infectious or intraparenchymal hemorrhagic process, a transplant nephrectomy was
      performed. At surgery, it was immediately evident that a malignant degenerative
      process had affected the graft. The histological features of the specimen were
      diagnostic for a well-differentiated SCC. The donor origin of the tumor was
      established through a DNA microchimerism assay performed on the operative
      specimens. The patient did well after resection of the malignancy, although he
      died 5 months later owing to a myocardial infarction. In summary, even several
      years following the transplant, the possibility of a malignancy of donor origin
      developing within a failed allograft should always be considered as part of the
      differential diagnosis in unusual post-transplant settings.

PMID- 15196087
TI  - Mechanism of activation of the tonic component of contraction in myocytes of
      guinea pig heart.
AB  - AIM: Contractions of myocytes of guinea pig heart consist of a phasic component
      relaxing independently on the voltage and a tonic component relaxing upon
      repolarization. We found previously that Ca(2+) activating the tonic component is
      released from the sarcoplasmic reticulum. In this study, we analysed the
      mechanism of activation and maintenance of this release. METHODS: Experiments
      were performed at 37 degrees C in ventricular myocytes of guinea pig heart.
      Voltage-clamped myocytes were stimulated by the pulses of the duration of 300 ms
      to 15-45 s from the holding potential of -40 to +5 mV. [Ca(2+)](i) was monitored
      as fluorescence of Indo-1 and contractions were recorded with the TV edge
      tracking system. RESULTS: Myocytes responded to the short and long pulses with
      phasic contraction or Ca(2+) transient followed by the sustained contraction or
      increase in [Ca(2+)](i). Repolarization brought about relaxation. 10 mmol L(-1)
      Ni(2+) blocking Na(+)/Ca(2+) exchange superfused during the tonic component
      increased its amplitude. Superfusion of Ca(2+)-free solution during sustained
      contraction brought about relaxation both in normal cells and in cells superfused
      with Ni(2+) despite preserved sarcoplasmic reticulum Ca(2+) content assessed with
      caffeine spritz. Relaxing effect of Ca(2+)-free solution was not affected by
      carboxyeosin, a blocker of sarcolemmal Ca(2+)-ATPase. Tonic component of
      contraction and of Ca(2+) transient was inhibited by 200 micromol L(-1)
      ryanodine, a blocker of Ca(2+) release channels of the sarcoplasmic reticulum and
      by 20 micromol L(-1) nifedipine, a blocker of L-type I(Ca). CONCLUSION: Tonic
      component of contraction results from Ca(2+) release via the sarcoplasmic
      reticulum Ca(2+) channels activated by sustained, nifedipine-sensitive and Ni(2+)
      insensitive Ca(2+) influx. Alternatively, the SR Ca(2+) release is activated by
      voltage, the dihydropyridine receptors acting like voltage sensors.

PMID- 15196088
TI  - Comparison of vascular distensibility in the upper and lower extremity.
AB  - AIM: Because of the great differences in hydrostatic pressure acting along the
      blood vessels in the erect posture, leg vessels are exposed to greater transmural
      pressures than arm vessels. The in vivo pressure-distension relationship of
      arteries, arterioles and veins in the arm were compared with those of the leg.
      METHODS: Experiments were performed with the subject (n = 11) positioned in a
      pressure chamber with an arm or lower leg (test limb) extended at heart level
      through a hole in the chamber door. Intravascular pressure in the arm/lower leg
      was increased by stepwise increasing chamber pressure to +180 and +210 mmHg,
      respectively. Diameters of blood vessels and arterial flow were measured using
      ultrasonographic/Doppler techniques. Changes in forearm and lower leg volumes
      were assessed using an impedance technique. The subject rated perceived pain in
      the test limb. RESULTS: The brachial and radial arteries were found to be more
      distensible than the posterior tibial artery (P < 0.001). Likewise, the
      distension was more pronounced in the cephalic than in the great saphenous vein
      (P < 0.001). In the brachial artery, but not in the posterior tibial artery, flow
      increased markedly at the highest levels of distending pressure (P < 0.001). At
      the highest intravascular pressures, the rate of change in tissue impedance was
      greater in the forearm than the lower leg (P < 0.01). At any given level of
      markedly increased pressure, pain was rated higher in the arm than in the leg (P
      < 0.001). CONCLUSION: It seems that the wall stiffness of arteries, pre-capillary
      resistance vessels and veins adapts to meet the long-term demands imposed by the
      hydrostatic pressure acting locally on the vessel walls.

PMID- 15196089
TI  - Arterial blood pressure and carotid baroreflex function during arm and combined
      arm and leg exercise in humans.
AB  - AIM: During arm cranking (A) blood pressure is higher than during combined arm
      and leg exercise (A + L), while the carotid baroreflex (CBR) is suggested to
      reset to control a higher blood pressure in direct relation to work intensity and
      the engaged muscle mass. METHOD: This study evaluated the function of the CBR by
      using neck pressure and neck suction during upright A, L and A + L in 12 subjects
      and, in order to evaluate a potential influence of the central blood volume on
      the CBR, also during supine A in five subjects. Exercise intensities for A and L
      were planned to elicit a heart rate response of c. 100 and 120 beats min(-1),
      respectively, in the upright position and both workloads were maintained during A
      + L and supine A. RESULTS: The CBR operating point, corresponding to the pre
      stimulus blood pressure, was 88 +/- 6 mmHg (mean +/- SE) at rest. During upright
      A, L and A + L and supine A it increased to 109 +/- 9, 95 +/- 7, 103 +/- 7 and
      104 +/- 4 mmHg, respectively, and it was thus higher during upright A than during
      A + L and supine A (P < 0.05). In addition, the CBR threshold and saturation
      pressures, corresponding to the minimum and maximum carotid sinus pressure,
      respectively, were higher during upright A than during supine A, A + L, L and at
      rest (P < 0.05) with no significant change in the maximal reflex gain.
      CONCLUSION: These findings demonstrate that during combined arm and leg and
      exercise in the upright position the CBR resets to a lower blood pressure than
      during arm cranking likely because the central blood volume is enhanced by the
      muscle pump of the legs.

PMID- 15196090
TI  - Stimulation of glucose utilization and inhibition of protein glycation and AGE
      products by taurine.
AB  - AIM: Pathological effects of the process of non-enzymatic glycation of proteins
      are reflected in chronic complications of diabetes mellitus. We investigated the
      antiglycating effect of taurine in high fructose fed rats in vivo and the
      inhibiting potency of taurine in the process of in vitro glycation. Additionally,
      we investigated whether taurine enhances glucose utilization in the rat
      diaphragm. METHODS: Rats fed a high fructose diet (60% total calories) were
      provided 2% taurine solution for 30 days. The effects of taurine on plasma
      glucose, fructosamine, protein glycation and glycosylated haemoglobin in high
      fructose rats were determined. For in vitro glycation a mixture of 25 mm glucose
      and 25 mm fructose was used as glycating agent, bovine serum albumin as the model
      protein and taurine as the inhibitor. Incubations were carried out in a constant
      temperature bath at 37 degrees C for 3-30 days. Amadori products and advanced
      glycation end products (AGEs) formed were measured. In vitro utilization of
      glucose was carried out in the rat diaphragm in the presence and absence of
      insulin in which taurine was used as an additive. RESULTS: The contents of
      glucose, glycated protein, glycosylated haemoglobin and fructosamine were
      significantly lowered by taurine treatment to high fructose rats. Taurine
      prevented in vitro glycation and the accumulation of AGEs. Furthermore, taurine
      enhanced glucose utilization in the rat diaphragm. This effect was additive to
      that of insulin and did not interfere with the action of insulin. CONCLUSIONS:
      These results underline the potential use of taurine as a therapeutic supplement
      for the prevention of diabetic pathology.

PMID- 15196091
TI  - Ischaemia in working muscles potentiates the exercise-induced sweating response
      in man.
AB  - AIM: The purpose was to examine whether graded ischaemia in the working muscles
      affects the rate of sweating and the control of exercise core temperature.
      METHODS: Eight subjects performed cycle ergometry exercise in the supine position
      with (ischaemic exercise) and without (control exercise) restriction of blood
      flow in the contracting muscles, accomplished by exposure of the legs to a supra
      atmospheric pressure of 6.6 kPa. Each subject performed one exhaustive
      incremental work rate trial and one steady-state exercise trial (at 33% of
      control peak work rate), in both the control and ischaemia conditions. RESULTS:
      Ischaemia decreased work performance by 45% so that in this condition the steady
      state work rate level corresponded to 63% of ischaemic peak work rate. Ischaemia
      did not affect the oesophageal temperature equilibrium in the steady-state
      trials, but potentiated the exercise sweating response. Exercise responses of
      mean arterial pressure, heart rate and pulmonary ventilation were potentiated by
      ischaemia. CONCLUSION: During ischaemic exercise sweat secretion was potentiated
      by non-thermal and/or local thermal stimuli.

PMID- 15196092
TI  - Effect of acute exercise and training on metabolism of ceramide in the heart
      muscle of the rat.
AB  - AIM: The sphingomyelin signalling pathway operates in the heart muscle. There are
      no data on the effect of exercise on the functioning of this pathway in the
      myocardium and it was the aim of the present study to examine this question.
      METHODS: The experiments were carried out on male Wistar rats, 300-320 g of body
      weight. They were divided into three groups: (1) control, (2) run 3 h on a
      treadmill moving with a speed of 1200 m h(-1) and set at +10 degrees incline, and
      (3) trained on a treadmill for 6 weeks. The rats were anaesthetized and samples
      of the left ventricle were taken. They were immediately frozen in liquid
      nitrogen. Thereafter, lipids were extracted and ceramide and sphingomyelin were
      isolated by means of thin layer chromatography. Their fatty acids were identified
      and quantified by means of gas-liquid chromatography. In separate heart samples
      the activity of neutral, Mg(2+)-dependent sphingomyelinase and acid
      sphingomyelinase was determined using labelled sphingomyelin as a substrate.
      RESULTS: Thirteen different ceramides and sphingomyelins were identified based on
      their fatty acid residue. Exercise markedly reduced the total content of ceramide
      fatty acids and had no effect on the total content of sphingomyelin-fatty acids.
      Training did not affect the total content either of ceramide-, or sphingomyelin
      fatty acids. The activity of both neutral Mg(2+)-sphingomyelinase and acid
      sphingomyelinase was reduced after exercise. Training did not affect the activity
      of neutral sphingomyelinase and reduced the activity of acid sphingomyelinase.
      CONCLUSION: It is concluded that acute, prolonged exercise, but not training,
      markedly affects the operation of the sphingomyelin-signalling pathway in the
      heart.

PMID- 15196094
TI  - Effect of acute hyperoxia during exercise on quadriceps electrical activity in
      active COPD patients.
AB  - AIMS: This study investigated whether acute hyperoxia improves electrical muscle
      activity in active chronic obstructive pulmonary disease (COPD) patients with
      mild hypoxemia (rest PaO(2) = 9.1 +/- 0.4 kPa). METHODS: Two identical
      incremental exercise tests were performed by nine patients while breathing either
      air or 30% oxygen. Pulmonary gas exchanges, venous concentrations of lactate and
      pyruvate, and the electromyographic signal of the quadriceps muscle (vastus
      lateralis and vastus medialis) were sampled each minute. RESULTS: Peak working
      capacity increased significantly in hyperoxia (94.4 +/- 5.2W) compared with
      normoxia (85.4 +/- 5.8W, P < 0.01). During hyperoxic exercise and for a given
      work load, oxygen uptake was increased (P < 0.001) and ventilation decreased (P <
      0.05). Lactate concentration was significantly decreased (P < 0.01) at isowork
      level and during recovery (respectively - 26% and at least - 15%). In the
      quadriceps muscle, M-wave amplitude (P < 0.05), root mean square (P < 0.01) and
      root mean square/oxygen uptake ratio (P < 0.001) were significantly increased
      during hyperoxic exercise compared with room air. Although median frequency
      values did not differ between conditions, the median frequency was significantly
      decreased for higher exercise intensity in hyperoxic condition. These
      modifications reflected better aerobic metabolism, later emergence of muscle
      fatigue, and greater muscle excitability and activation for the same level of
      exercise under hyperoxic condition. CONCLUSION: These data suggest that the acute
      addition of oxygen in active COPD patients improves their muscle electrical
      activity during dynamic exercise. Hypoxemia-induced skeletal muscle dysfunction
      most probably acts through mechanisms based on oxygen availability.

PMID- 15196093
TI  - Highly selective iNOS inhibition and sphincter of Oddi motility in the Australian
      possum.
AB  - AIM: Inducible nitric oxide synthase (iNOS) plays a major role in acute
      pancreatitis. Selective inhibitors of iNOS are being developed as therapeutic
      agents. Sphincter of Oddi (SO) dysfunction may cause pancreatitis and nitric
      oxide is necessary for SO relaxation. A new highly selective iNOS inhibitor, AR
      C102222AA (AR-C), is evaluated together with the established iNOS inhibitor, L
      N(6)-(1-iminoethyl)lysine (L-NIL), and the selective neuronal nitric oxide
      synthase (nNOS) blocker S-methyl-l-thiocitrulline (SMTC). METHODS: In
      anaesthetized Australian Brush-tailed possums, the effect of topical, i.v. or
      i.a. administration of these drugs was evaluated on spontaneous SO motility,
      blood pressure (BP) and pancreatic vascular perfusion. SO motility was recorded
      by manometry and pancreatic vascular perfusion by laser Doppler fluxmetry. Also,
      the effect of SMTC and AR-C on electrical field stimulation (EFS)-induced non
      cholinergic non-adrenergic (NANC) SO relaxation in vitro was evaluated. RESULTS:
      Infusion of AR-C (0.1-30 micromol kg(-1)) increased SO contraction frequency (P =
      0.026) only at the two highest doses. L-NIL infusion (0.15 to 14.7 micromol kg(
      1)) also increased SO contraction frequency at 8.8 micromol kg(-1) (P < 0.05) and
      reduced SO contraction amplitude at the two highest doses (P < 0.05). SMTC
      injections (0.5 nmol-2.4 micromol) produced a dose-dependent increase in SO
      contraction frequency (P = 0.009), but no effect was seen on the other
      parameters. In vitro SMTC (40-400 microm) inhibited EFS-induced NANC relaxation
      in a dose-dependent manner (P < 0.0005). In contrast AR-C (10-500 microm) had no
      effect on EFS-induced NANC relaxation (P > 0.05). CONCLUSIONS: At low doses, AR-C
      does not effect SO motility or EFS-induced NO mediated relaxation. However, high
      doses of AR-C and L-NIL in vivo influenced SO motility by inhibiting nNOS
      activity and these effects need be considered in relation to therapeutic doses of
      this agent.

PMID- 15196095
TI  - Efficacy of a gravity-independent resistance exercise device as a countermeasure
      to muscle atrophy during 29-day bed rest.
AB  - AIM: This study determined changes in knee extensor and plantar flexor muscle
      volume during 29 days of bed rest with or without resistance exercise using a
      gravity-independent flywheel ergometer. METHODS: Seventeen men (26-41 years) were
      subjected to 29 days of bed rest with (n = 8) or without (n = 9) resistance
      exercise; Supine Squat (SS) and Calf Press (CP) performed every third day.
      Quadriceps and triceps surae muscle volume was determined before and after bed
      rest and force and power were measured during training. Prior to these
      interventions, reproducibility of this device for training and testing was
      assessed in 23 subjects who performed bilateral maximal concentric, eccentric and
      isometric (MVC) knee extensions and plantar flexions over repeated sessions with
      simultaneous measurements of force, power and electromyographic (EMG) activity.
      RESULTS: Quadriceps and triceps surae muscle volume decreased (P < 0.05) 10 and
      16%, respectively, after 29 days bed rest. Exercise maintained quadriceps volume
      and mitigated triceps surae atrophy. Thus, either muscle showed different
      response across subject groups (P < 0.05). Force and power output during training
      were either maintained (P > 0.05) or increased (P < 0.05). EMG amplitude in the
      training mode was similar (SS; P > 0.05) or greater (CP; P < 0.05) compared with
      that elicited during MVC. Peak force and power test-retest coefficient of
      variation (CV) ranged 5-6% and 7-8% for SS and CP, respectively. CONCLUSION: The
      present data suggest that this resistance exercise paradigm counteracts
      quadriceps and abates the more substantial triceps surae muscle atrophy in
      bedridden subjects, and therefore should be an important asset to space
      travellers.

PMID- 15196096
TI  - Smooth muscle role on pulmonary arterial function during acute pulmonary
      hypertension in sheep.
AB  - AIM: We determined the wall mechanical response of the pulmonary artery (PA) to
      acute pulmonary hypertension induced pharmacologically and by an occlusion
      maneuver, to study the vascular response of the local segment and its influence
      in the whole pulmonary circulation. METHODS: Pulmonary pressure and diameter were
      measured in six anaesthetized sheep under steady-state conditions. Transient
      hypertension in the PA was induced by phenylephrine (PHE) and a high pressure
      (HP) mechanical occlusion aimed at producing the same pulse and mean pressure
      responses. A viscoelastic arterial wall model was applied and the elastic (E(pd))
      and viscous (micro) indexes were obtained. The micro/E(pd) ratio was adopted to
      quantify the damping performance of the arterial wall segment. The diastolic time
      constant was used as an indicator of the whole pulmonary buffering function. The
      systemic pressure was always measured. RESULTS: The pulmonary mean, systolic and
      pulse pressure increases (P < 0.05) were similar during PHE and HP, with respect
      to control. PHE also induced a systemic pressure rise (P < 0.05). The E(pd)
      elastic index increased during HP (P < 0.05) and tended to increase during PHE
      with respect to control. The viscous index micro only increased with PHE (P <
      0.05) with respect to control and occlusion. The diastolic time constant
      increased with PHE with respect to control (P < 0.05). CONCLUSIONS: A pressure
      rise in the PA, induced by an occlusion maneuver, increased local stiffness.
      Similar pressure rises with smooth muscle activation (PHE), produced both a
      stiffness and viscous index increase. In PHE resistance increases more than
      compliance decreases so that the global net effect is a longer decay time. Smooth
      muscle activation enhances the local damping effect (micro/E(pd)), concomitant
      with the buffering function improvement.

PMID- 15196097
TI  - Immune effect of hypertonic saline: fact or fiction?
AB  - Hypertonicity affects many parts of the immune system. Animal studies and
      experiments in isolated cell cultures show that hypertonicity reversibly
      suppresses several neutrophil functions and at the same time up-regulates T
      lymphocyte function. Infusion of hypertonic saline with or without colloids may
      thus, besides providing efficient plasma volume expansion, ameliorate the
      detrimental consequences on the immune function of trauma, shock, reperfusion,
      and major surgery. However, the few clinical studies conducted to date,
      specifically addressing the immune effect of hypertonic saline infusion, have
      shown little, if any, effect on markers of immune function, and larger clinical
      trials have not demonstrated benefit in terms of morbidity or mortality. Thus, as
      opposed to animal and cell-culture studies, the immune-modulating properties of
      hypertonic saline infusion would appear to be of limited value in clinical
      practice. This review presents in vitro studies, animal experiments, and clinical
      trials which investigated the consequences of hypertonic saline on markers of
      immune function.

PMID- 15196098
TI  - Abolished circadian rhythm of melatonin secretion in sedated and artificially
      ventilated intensive care patients.
AB  - BACKGROUND: Sleep disturbance is common in intensive care patients. Aside from
      its unpleasantness, there is a correlation with intensive care unit (ICU)
      syndrome/delirium. Reasons for sleep deprivation appear to be multifactorial,
      including the underlying illness, an acute superimposed disturbance, medications,
      and the ICU environment itself. There are reasons to believe that alterations of
      the 'biological clock' might contribute. Melatonin secretion is one reflection of
      this internal sleep/wake mechanism. Melatonin levels are normally high during the
      night and low during daytime, being suppressed by bright light. METHODS:
      Melatonin levels in blood and urine were studied over 3 consecutive days in eight
      critically ill patients during deep sedation and mechanical ventilation. Sedation
      was assessed with the sedation-agitation (SAS) scale and bispectral index (BIS)
      monitor. RESULTS: The circadian rhythm of melatonin release was abolished in all
      but one patient, who recovered much more quickly than the others. There was no
      correlation between melatonin levels and levels of sedation. CONCLUSIONS: This
      study indicates that dyssynchronization of the melatonin secretion rhythm is
      common in critically ill and mechanically ventilated patients. It could be
      hypothesized that an impairment of the melatonin rhythm may play a role in the
      development of sleep disturbances and delirium in intensive care patients, and
      that melatonin supply could reduce the incidence of these phenomena.

PMID- 15196099
TI  - Routine X-ray control of upper central venous lines: Is it necessary?
AB  - BACKGROUND: Insertion of central venous catheters (CVCs) is a procedure
      associated with a varying risk of complications, depending on the setting and the
      skill of the clinician who undertakes the procedure. The aim of this study was to
      monitor the complication rate of CVC insertion and evaluate the value of routine
      chest X-ray control. METHODS: Anesthesiologists at eight hospitals filled in a
      questionnaire immediately after insertion of a CVC. The post-procedural clinical
      evaluation, including expected complications, was compared to actual radiological
      findings. Chest X-ray was ordered by the anesthesiologist, and described by staff
      radiologists. RESULTS: The clinicians had from 2 months to 30 years of experience
      as anesthesiologists, and trainees inserted 34% and specialists 66% of the
      catheters, using landmark techniques. Over a period of 2 months, 473 CVC
      insertion procedures were included in the investigation. Two patients (0.4%) had
      a pneumothorax: one was among the 11 cases in which the clinician suspected
      complications after the procedure, and another was found in a high-risk patient
      13 h after CVC insertion. Both patients were treated successfully with chest
      tubes. The favorite approach was right vena jugularis interna with 324 (69%)
      catheters; of these patients one had a pneumothorax, catheter-tip placement was
      correctly predicted in 317 (97%), and no catheters were repositioned. CONCLUSION:
      In the hands of trained clinicians, insertion of CVCs is a safe procedure. We
      found no value of routine X-ray control and omission of routine chest X-ray must
      be considered.

PMID- 15196100
TI  - Multicentre study of validity and interrater reliability of the modified Nursing
      Care Recording System (NCR11) for assessment of workload in the ICU.
AB  - BACKGROUND: Reliable assessment of nursing workload is necessary for the
      quantitative approach to staffing of intensive care units. The Nursing Care
      Recording System (NCR11) scores both the nursing contribution to patient care and
      those related to medical procedures. The purpose of the present work was to
      compare NCR11 scoring with the Therapeutic Intervention Scoring System (TISS) and
      Nine Equivalents of Nurse Manpower use Score (NEMS) and to examine the interrater
      reliability of NCR11 scoring. METHODS: Bias and precision of workload scores
      (NCR11 vs. TISS or NEMS) were assessed for 6126 consecutive admissions (23910 ICU
      days) at three intensive care units. Inter-rater reliability was analyzed by
      having nurses at nine ICUs score workload using NCR11 for three dummy intensive
      care patient cases presented over a 3-year period. Variability in scoring was
      analyzed using the coefficient of variation. RESULTS: Agreement between NCR11 and
      TISS or NEMS was poor and limits of agreement were wide. Linear relationships
      between NCR11 and TISS or NEMS scores differed between units. Variability in
      NCR11 scoring decreased significantly from 10.4% to 5.9% between dummy cases 1
      and 2 and remained low for patient case 3. CONCLUSION: The NCR11 does not measure
      the same elements of workload in the ICU as do TISS and NEMS. Inter-rater
      reliability with NCR11 is good, showing little variation in scoring between
      nurses.

PMID- 15196102
TI  - Increased glomerular permeability and pulmonary dysfunction following major
      surgery: correlation of microalbuminuria and PaO/FiO ratio.
AB  - BACKGROUND: The aim of our trial was to evaluate the ability of microalbuminuria
      as an indicator of outcome and to investigate its relationship with the
      postoperative respiratory dysfunction in the initial postoperative period in a
      high-risk patient group. METHODS: In our prospective, observational study
      patients were consecutively recruited following elective oesophagectomy, total
      gastrectomy, Whipple-resection of the pancreas and liver resection due to tumour
      removal. Microalbuminuria (expressed as urine albumin:creatinine ratio, M:Cr) was
      measured before (tp), and after surgery (t0, t6, t24, t48, t72). Multiple Organ
      Dysfunction Scores were monitored on ICU admission than daily (t1, t2, t3). For
      statistical analysis, Wilcoxon's rank-sum test, Mann-Whitney's U-test, receiver
      operating characteristic curve analysis and Spearman's rho test were used as
      appropriate. RESULTS: One hundred and forty patients (118 survivors and 22 non
      survivors) were recruited. Significantly higher Multiple Organ Dysfunction Scores
      were observed in non-survivors throughout the study period (P < 0.001).
      Microalbuminuria (Cr) increased significantly (P < 0.01) on admission to the ICU
      (t0) compared with the preoperative levels, but levels returned to normal within
      6 h and remained so for the rest of the study. There was a significant difference
      between survivors and non-survivors at t0 (P < 0.01). However the ROC curve
      indicated that M:Cr is not a reliable descriptor of outcome. Comparison of Cr
      values with the PaO2/FiO2 ratio showed an inverse relationship on admission,
      which remained so for t24 and t48. CONCLUSION: M:Cr measured on admission to the
      ICU was significantly higher in non-survivors than in survivors, and also showed
      an inverse relationship with the PaO2/FiO2 ratio following extended abdominal
      surgery. However, on admission, M:Cr did not discriminate survivors from non
      survivors. Further studies are required to evaluate the prognostic value of this
      test for postoperative patients with risk of respiratory failure.

PMID- 15196101
TI  - Splanchnic oxygen transport, hepatic function and gastrointestinal barrier after
      normothermic cardiopulmonary bypass.
AB  - BACKGROUND: The effect of non-pulsatile, normothermic cardiopulmonary-bypass
      (CPB) on the splanchnic blood-flow and oxygen-transport, the hepatic function and
      the gastrointestinal barrier were observed in a prospective observational study
      in 31 adults undergoing cardiac valve replacement surgery. METHODS: The
      splanchnic (i.e. hepatic) blood-flow (HBF) was measured by the constant infusion
      of indocyanine-green (ICG) using a hepatic-venous catheter. Liver function was
      examined by calculation of lactate uptake, ICG extraction and the
      monoethylglycinexylidide (MEGX) test. A day before and after surgery the
      gastrioduodenal and intestinal permeability was measured by determination of
      sucrose and lactulose/mannitol excretion. RESULTS: Splanchnic blood flow and
      oxygen delivery did not decrease during and after surgery while splanchnic oxygen
      consumption (P < 0.0125) and arterial lactate concentrations increased. The
      splanchnic lactate uptake paralleled the lactate concentration. After but not
      during CPB an increase of systemic oxygen consumption was observed. The MEGX test
      values decreased on the first day after surgery. The ICG extraction was
      attenuated during the operation. The gastroduodenal and the intestinal
      permeability increased significantly postoperatively (P < 0.002, respectively, P
      < 0.001). There was no correlation between these findings and the duration of
      CPB. There was a significant correlation of the intestinal permeability but not
      of the gastroduodenal permeability between the prior and after surgery values (P
      < 0.001). CONCLUSION: Increased oxygen consumption during CPB may indicate an
      inflammatory reaction due to the pump beginning in the splanchnic area or a
      redistribution of the splanchinc blood flow during the CPB. Normothermic CPB does
      not lead to a significant or prolonged reduction of liver function. Normothermic
      CPB causes an increase of gastrointestinal permeability. The intestinal barrier
      function prior to surgery was accountable for the degree of loss of intestinal
      barrier function following surgery.

PMID- 15196103
TI  - Predictive value of preoperative transthoracic echocardiography in patients
      undergoing adrenalectomy for pheochromocytoma.
AB  - BACKGROUND: Adrenalectomy for pheochromocytoma is a life-threatening procedure.
      Few echocardiographic assessments have been reported in patients undergoing
      adrenalectomy for pheochromocytoma. METHODS: Sixty-three consecutive patients
      undergoing adrenalectomy for pheochromocytoma underwent routine preoperative M
      mode and two-dimensional echocardiography, and Doppler examination. Abnormal
      echocardiographic findings were defined as left ventricular dilatation or
      dysfunction (left ventricular percentage fractional shortening < 30%), and/or
      left ventricular wall motion abnormalities, and/or left ventricular hypertrophy
      (left ventricular mass index > 110 g m(-2) in women and >134 g m(-2) in men)
      and/or valvular abnormalities. Physical characteristics, daily urinary
      metanephrine and normetanephrine excretions, preoperative functional limitation,
      pre-existing congestive heart failure, type and duration of surgery, and
      haemodynamic instability in the intra and postoperative periods were compared in
      patients with normal and abnormal echocardiographic findings. RESULTS: Twenty
      four out of 63 patients were found to have abnormal preoperative
      echocardiography. There was no difference between patients with normal and
      abnormal preoperative echocardiography as regards to the investigated criteria,
      except for pre-existing self-reported functional limitation and chest pain
      suggesting coronary artery disease. CONCLUSIONS: The relevance of routine
      preoperative echocardiographic examination in patients scheduled for
      adrenalectomy for pheochromocytoma, who have no cardiac symptoms or clinical
      evidence of cardiac involvement, is questionable.

PMID- 15196104
TI  - Isoflurane applied during ischemia enhances intracellular calcium accumulation in
      ventricular myocytes in part by reactive oxygen species.
AB  - BACKGROUND: Isoflurane applied before myocardial ischemia has a beneficial
      preconditioning effect which involves generation of reactive oxygen species
      (ROS); ROS, however, have been implicated in critical cytosolic calcium ([Ca2+]i)
      overload during ischemia. We therefore investigated isoflurane's effects on
      intracellular Ca2+ handling in ischemic ventricular myocytes and the association
      with ROS. METHODS: Simulated ischemia was induced in electrically stimulated rat
      ventricular myocytes for 30 min (ischemia). Isoflurane-treated cells were
      additionally exposed to 1MAC of isoflurane (ischemia + iso). To determine the
      contribution of ROS to Ca2+ homeostasis during ischemia in both groups, the
      intracellular ROS scavenger, N-mercaptopropionylglycine (MPG), was added to the
      superfusion buffer. The fluorescent ratiometric Ca2+ dye fura-2 was employed to
      determine [Ca2+]i. RESULTS: Resting and peak [Ca2+]i increased in the ischemia
      and the ischemia + iso group. However, Ca2+ accumulation was most prominent in
      isoflurane-treated cardiomyocytes (P < 0.05) and could be mitigated by MPG in
      both groups (P < 0.001). Isoflurane also decreased the rate constant of the Ca2+
      transient decline but did not further diminish the amplitude of the transient
      during ischemia. CONCLUSION: Isoflurane when applied during ischemia appears to
      worsen [Ca2+]i overload, which is caused by impeding Ca2+ clearance. As MPG
      mitigated the increase in [Ca2+]i, isoflurane seems to enhance ROS-mediated
      effects on intracellular Ca2+ handling in cellular ischemia.

PMID- 15196105
TI  - Airway pressure release ventilation as a primary ventilatory mode in acute
      respiratory distress syndrome.
AB  - BACKGROUND: Airway pressure release ventilation (APRV) is a ventilatory mode,
      which allows unsupported spontaneous breathing at any phase of the ventilatory
      cycle. Airway pressure release ventilation as compared with pressure support
      (PS), another partial ventilatory mode, has been shown to improve gas exchange
      and cardiac output. We hypothesized whether the use of APRV with maintained
      unsupported spontaneous breathing as an initial mode of ventilatory support
      promotes faster recovery from respiratory failure in patients with acute
      respiratory distress syndrome (ARDS) than PS combined with synchronized
      intermittent ventilation (SIMV-group). METHODS: In a randomized trial 58 patients
      were randomized to receive either APRV or SIMV after a predefined stabilization
      period. Both groups shared common physiological targets, and uniform principles
      of general care were followed. RESULTS: Inspiratory pressure was significantly
      lower in the APRV-group (25.9 +/- 0.6 vs. 28.6 +/- 0.7 cmH2O) within the first
      week of the study (P = 0.007). PEEP-levels and physiological variables (PaO2/FiO2
      ratio, PaCO2, pH, minute ventilation, mean arterial pressure, cardiac output)
      were comparable between the groups. At day 28, the number of ventilator-free days
      was similar (13.4 +/- 1.7 in the APRV-group and 12.2 +/- 1.5 in the SIMV-group),
      as was the mortality (17% and 18%, respectively). CONCLUSION: We conclude that
      when used as a primary ventilatory mode in patients with ARDS, APRV did not
      differ from SIMV with PS in clinically relevant outcome.

PMID- 15196106
TI  - Patient-controlled epidural technique improves analgesia for labor but increases
      cesarean delivery rate compared with the intermittent bolus technique.
AB  - BACKGROUND: We tested the hypothesis that patient-controlled epidural analgesia
      for labor (PCEA) provides better analgesia and satisfaction than the intermittent
      bolus technique (bolus) without affecting the mode of delivery. METHODS: We
      randomized 187 parturients to receive labor analgesia using either the PCEA or
      bolus technique. The PCEA group received a starting bolus of 14 mg of bupivacaine
      and 60 micro g of fentanyl in a 15-ml volume, followed by a background infusion
      (bupivacaine 0.08% and fentanyl 2 microg ml(-1)) 5 ml h(-1) with a 5-ml bolus and
      15-min lock-out interval. The bolus group received boluses of 20 mg of
      bupivacaine and 75 micro g of fentanyl in a 15-ml volume. RESULTS: Parturients in
      the PCEA group had significantly (P < 0.05-0.01) less pain during the first and
      second stages of labor. There was no difference in the spontaneous delivery rate
      between the groups, but the cesarean delivery rate was significantly (P < 0.05)
      higher (16.3% vs. 6.7%) in the PCEA group than in the bolus group. Bupivacaine
      consumption was significantly (P < 0.01) higher (11.2 mg h(-1) vs. 9.6 mg h(-1))
      and the second stage of labor was significantly (P < 0.01) longer (70 min vs. 54
      min) in the PCEA group than in the bolus group. Patient satisfaction was equally
      good in both groups. CONCLUSION: The PCEA technique provided better pain relief.
      This was associated with higher bupivacaine consumption, prolongation of the
      second stage of labor, and an increased rate of cesarean section.

PMID- 15196107
TI  - Effects of post-operative pain treatment using non-steroidal anti-inflammatory
      analgesics, opioids or epidural blockade on systemic and local immune responses
      in children.
AB  - BACKGROUND: Many studies have been carried out on the effects of anaesthetic
      drugs and methods on the immune response, but pain and its relief also affect the
      immune response. We measured systemic immune responses in the blood circulation
      and local responses in the surgical wound when non-steroidal anti-inflammatory
      analgesics (NSAIDs), opioids or epidural blockade was used in the peri-operative
      treatment of pain. METHODS: Responses were measured in 51 children, aged from 2
      to 12 years and undergoing major surgery under balanced anaesthesia. Bolus doses
      of diclofenac intravenously (i.v.) and rectally (NSAID group), continuous i.v.
      infusion of oxycodone (opioid group) or continuous epidural infusion of
      bupivacaine + fentanyl (epidural group) were used peri-operatively for pain
      relief. RESULTS: The only difference related to the analgesic method was shorter
      duration of post-operative leucocytosis and lower phytohaemagglutinin (PHA)
      induced lymphocyte proliferative responses in peripheral blood in the opioid
      group than in the NSAID or epidural groups. By contrast, time-related alterations
      were seen overall in leucocyte and differential counts, lymphocyte and their
      subset counts, lymphocyte proliferative responses, and in serum cortisol, C
      reactive protein, plasma interleukin-6 and group II phospholipase A2
      concentrations and in the appearance of different cell types in the wound.
      CONCLUSIONS: Post-operative pain treatments using diclofenac (NSAID), oxycodone
      (opioid) and epidural blockade have basically similar effects on systemic and
      local immune responses with only slight, probably clinically unimportant
      differences in children undergoing surgery under general anaesthesia.

PMID- 15196108
TI  - The effects of pre-emptive epidural sufentanil on human immune function.
AB  - BACKGROUND: Surgical stress and general anaesthesia suppress immune functions,
      including natural killer cell (NK) activity. This suppression could be
      attributed, at least in part, to the effect of opiates. METHODS: Twenty patients
      undergoing abdominal hysterectomy received epidural sufentanil (50 microg) either
      before (pre-emptive) or at the end (control group) of surgery. Post-operative
      pain relief was provided using sufentanil from a patient-controlled epidural
      analgesia (PCEA) system. Systemic immunity was assessed by determining leucocyte
      counts, NK cell counts and activity, lymphocyte response to mitogen stimulation,
      and secretion of pro-inflammatory cytokines. RESULTS: In the pre-emptive group
      there was a significant decrease in NK activity on the first and third post
      operative day (P < 0.05) compared with baseline values and on the third
      postoperative day (P < 0.05) compared with the control group. The number of total
      leucocytes and neutrophiles increased in both groups post-operatively, but no
      differences were found in the levels of mononuclear lymphocyte populations or in
      their mitogen responses. Interleukin-6 (IL-6) concentration increased in both
      groups after the operation. In addition, at the end of the surgery the IL-6 level
      was greater in the control group than in the pre-emptive group. Interleukin-1 (IL
      1) levels had decreased significantly at the end of surgery and 4 h later
      compared with baseline levels in the pre-emptive, but not in the control group.
      CONCLUSIONS: Pre-emptive epidural sufentanil during combined propofol and
      isoflurane anaesthesia had minor effects on the immune response after
      hysterectomy. The lower production of pro-inflammatory cytokines (IL-1, IL-6) in
      the pre-emptive group compared with the control group is beneficial, but its
      clinical importance remains to be determined.

PMID- 15196109
TI  - Ketamine does not decrease postoperative pain after remifentanil-based
      anaesthesia for tonsillectomy in adults.
AB  - BACKGROUND: There are conflicting results concerning the pre-emptive effect of
      ketamine on central sensitization following surgery. The aim of this prospective,
      randomized, double-blind, placebo-controlled study was to assess the effect of
      the N-methyl-D-aspartate receptor antagonist ketamine on postoperative morphine
      consumption and pain score after remifentanil-based anaesthesia in adult patients
      scheduled for tonsillectomy. METHODS: We studied 40 adult patients undergoing
      elective tonsillectomy. Total intravenous anaesthesia was induced and maintained
      with remifentanil (0.125-1.0 microg kg(-1) min(-1)) and propofol target
      controlled infusion. Patients in group K received a bolus dose of ketamine 0.5 mg
      kg(-1) immediately after anaesthetic induction, followed by a continuous infusion
      of 2 microg kg(-1) min(-1). Saline was administered in the same sequence in group
      S. Propofol, remifentanil, and the study drug infusions were discontinued at the
      end of surgery. RESULTS: Intraoperative remifentanil consumption (0.57 +/- 0.18
      in group K vs. 0.55 +/- 0.14 microg kg(-1) min(-1) in group S), morphine
      requirement in the PACU (11 +/- 3 in group K vs. 9 +/- 4 mg in group S) and in
      the ward (22 +/- 11 in group K vs. 25 +/- 14 mg in group S), median time to first
      analgesia in the ward (338 +/- 126 in group K vs. 328 +/- 144 min in group S),
      and VAS pain scores were comparable in both groups. CONCLUSION: Small-dose of
      ketamine does not seem to be a useful adjunct to remifentanil-based anaesthesia
      during short, painful surgical procedures.

PMID- 15196110
TI  - Disturbing post-operative symptoms are not reduced by prophylactic antiemetic
      treatment in patients at high risk of post-operative nausea and vomiting.
AB  - BACKGROUND: To give prophylactics or timely treatment for post-operative nausea
      and vomiting (PONV) is the question. We compared the intensity and number of
      disturbing post-operative symptoms (i.e. pain, PONV, headache, fatigue, etc.)
      after prophylactic antiemetic treatment in a group of patients with >30% risk for
      post-operative vomiting. METHODS: Four hundred and ninety-five patients, from
      three hospitals, planned for gynaecological surgery were randomized double blind.
      They were given granisetron 3 mg, droperidol 1.25 mg or no prophylactic
      antiemetic. Post-operative symptoms were followed for 24 h using a questionnaire.
      Symptoms were analyzed both according to their intensity and in a dichotomous
      fashion. RESULTS: The intensity of different symptoms differed depending on
      whether droperidol, granisetron or no antiemetic had been given (P = 0.005) but
      the overall incidence of moderate to very severe symptoms was similar in all
      groups. No group fared better in general. The total number of symptoms was higher
      in the groups given prophylactic treatment (P < 0.05). The relative risk
      reduction for PONV with granisetron or droperidol prophylaxis was 27%[95%
      confidence interval (CI) 8-43] and 22% (2-38), respectively. The NNT (number
      needed to treat) for granisetron (0-24 h) was 7 and for droperidol 8. The NNH
      (number needed to harm) (0-24 h) for headache and visual disturbances was 6 and
      13 (NS) for granisteron and, 50 (NS) and 6 for droperidol. CONCLUSION: The
      intensity of symptoms or the total number of disturbing symptoms did not decrease
      after prophylactic antiemetic treatment in a group of patients, but the profile
      of disturbing symptoms changed. The relevance of post-operative symptoms in terms
      of patients' well-being needs to be addressed.

PMID- 15196111
TI  - The effects of etomidate, thiopental, and propofol in induction on hypoperfusion
      reperfusion phenomenon during laparoscopic cholecystectomy.
AB  - BACKGROUND: A hypoperfusion-reperfusion human model is observed during and soon
      after laparoscopic surgery. The aim of the study was to research the preventive
      effects of etomidate, thiopental, and propofol in induction on hypoperfusion-
      reperfusion phenomenon during laparoscopic cholecystectomy. METHODS: Thirty-six
      consecutive ASA I-II patients were randomized into three groups of 12 patients
      each. Anaesthesia was induced with etomidate in group 1, thiopental in group 2,
      and propofol in group 3. Venous blood samples were obtained at different time
      points for measurement of plasma malondialdehyde (MDA) levels. Arterial blood and
      gastric juice samples were obtained for the calculation of gastric intramucosal
      pH (pHi). Also changes in aminotransferases, alkaline phosphatase and total
      bilirubin levels were assessed. RESULTS: There was a significant decrease in pHi
      at 1 min before desufflation (BD) and 20 min after desufflation (AD) compared
      with before insufflation (BI) in all groups. Plasma level of MDA was
      significantly increased in group 1 at 1 min BD and 20 min AD compared with before
      induction of anaesthesia (baseline). Malondialdehyde levels were decreased
      significantly in group 3 and increased non-significantly in group 2 at the same
      time points. Also AST and ALT levels were significantly increased in both groups
      1 and 2 at 24 h postoperatively. CONCLUSION: Propofol with antioxidant activity
      may offer many advantages by scavenging reactive oxygen species and their
      metabolites in case of anticipated hypoperfusion-reperfusion phenomenon, such as
      would occur in laparoscopic surgery.

PMID- 15196112
TI  - Porcine surfactant (Curosurf) for acute respiratory failure after near-drowning
      in 12 year old.
AB  - This case report describes rapid and persistent improvement after one single dose
      of porcine surfactant (Curosurf) 0.5 ml/kg(-1) (40 mg/kg) intratracheally for
      adult respiratory distress syndrome (ARDS) with severe oxygenation failure 8 h
      after freshwater near-drowning in a 12-year-old girl.

PMID- 15196113
TI  - Anaesthesia for cholecystectomy in two non-parturients with Eisenmenger's
      syndrome.
AB  - Eisenmenger's syndrome consists of high pulmonary vascular resistance with
      reversed or bidirectional shunt at aortopulmonary, ventricular or atrial level.
      We describe the anaesthetic management of two adult females with Eisenmenger's
      syndrome admitted for laparoscopic cholecystectomy. One patient suffered post
      operative complications, but the other case was uncomplicated. We used
      sevoflurane and total intravenous anaesthesia to provide general anaesthesia.
      Both techniques were tolerated.

PMID- 15196114
TI  - Acute airway obstruction in an infant with Pierre Robin syndrome after
      palatoplasty.
AB  - This report describes a complication of post-operative oedema of the palate,
      tongue and pharynx after a Perko-revised cleft palate repair, which resulted in a
      life-threatening airway obstruction in an infant with Pierre Robin syndrome.
      Although infants experiencing airway problems after Wardill-Kilner, von
      Langenbeck and Furlow palatoplasty have been described, airway complications in a
      group of Perko-revised repair children have not been previously reported. We
      speculate that this complication, which occurred in the absence of a history of
      previous airway problems, is due to prolonged operating time and excessive
      pressure exerted on the base of the tongue by the Kilner-Doughty retractor.
      Acknowledgments of this risk permits to identify those patients prior to surgery
      so that they can be managed appropriately.

PMID- 15196116
TI  - Blood pressure and central neuraxial blockades.

PMID- 15196115
TI  - Successful treatment with enoximone for severe poisoning with atenolol and
      verapamil: a case report.
AB  - Combined poisoning with calcium channel blockers (CCBs) and beta-blockers is
      usually associated with severe hypotension and heart failure. Due to the block of
      the beta receptors, treatment with adrenergic agonists, even at high doses, can
      be insufficient, and beta-independent inotropes, such as glucagon, may be
      required. Phosphodiesterase III (PDEIII) inhibitors represent a possible
      alternative to glucagon in these cases as they have an inotropic effect which is
      not mediated by a beta receptor.

PMID- 15196117
TI  - Respiratory arrest after intrathecal injection of sufentanil and bupivacaine.

PMID- 15196118
TI  - Catheter-related epidural abscesses--reevaluating a true sterile technique.

PMID- 15196119
TI  - Ventriculo-arterial coupling and remifentanil: importance of the dosage.

PMID- 15196121
TI  - Radial artery pseudoaneurysm.

PMID- 15196123
TI  - Xenotransplant news.

PMID- 15196124
TI  - Tort liability of xenotransplantation centers.
AB  - BACKGROUND: In the view of future clinical trials, defining possible legal
      theories under which xenotransplantation center could be held responsible for any
      adverse effect on public health is becoming increasingly important. METHODS: In
      order to better define the tort liability of xenotransplantation center, we
      reviewed the existing cases and statutes on tort and public health law. RESULTS:
      Xenotransplantation center could be sued under various tort actions, including
      negligence, public nuisance or strict liability for ultrahazardous activity.
      Prerequisites for each legal action are discussed and possible scope of tort
      liability is addressed. CONCLUSION: The promotion of positive public perception
      and the development of appropriate insurance system could prevent future class
      actions to succeed in abating the xenotransplantation industry.

PMID- 15196125
TI  - Different patterns of TCR beta chain regulation following allo- and xeno
      transplantation.
AB  - BACKGROUND: In the concordant hamster-to-rat cardiac xenograft model, recipients
      treated with cobra venom factor for the first 10 days following transplantation
      and daily with Cyclosporine A (CsA) do not reject their grafts. However, when CsA
      is withdrawn on day 40, an acute cellular rejection occurs within 4 +/- 1 days.
      Allografts performed in the same conditions are rejected within 18 +/- 4 days.
      METHODS: In this model, we have compared graft infiltrating T cells through both
      a quantitative (number of Vbeta transcripts) and qualitative (CDR3 length
      distribution) assessment of the T cell receptor (TCR) beta chain transcriptome in
      allo- and xeno-transplantations. RESULTS: We report striking differences in TCR
      usage at day 15 following allo- and xeno-transplantation as well as during
      rejection following CsA withdrawal. The number of Vbeta transcripts was high in
      both rejected allo- and xenografts. However, whereas in xenografts acute
      rejection occurred without skewing of Vbeta CDR3 length distribution, T cells
      infiltrating allografts during rejection after CsA interruption had a highly
      altered CDR3 length distribution pattern. In addition, using a correspondence
      factor analysis of the beta chain transcriptome, we show that some families can
      clusterize and can discriminate allo- or xeno-patterns at the level of both the
      number of Vbeta transcripts and the CDR3 length distribution. CONCLUSIONS: Our
      data show that, in vivo, even in the hamster-to-rat concordant combination, the
      anti-xenograft T cell response is strong and will likely represent another
      challenge for xenotransplantation.

PMID- 15196126
TI  - Fate of alphaGal +/+ pancreatic islet grafts after transplantation into alphaGal
      knockout mice.
AB  - BACKGROUND: Important phylogenetic differences between pig and human tissues
      prevent xenotransplantation from becoming a clinically feasible option. Humans
      lack the galactose-alpha1,3-galactose (alphaGal) epitope on endothelial cell
      surfaces and therefore have preformed anti-alphaGal antibodies. The role of these
      antibodies in rejection of non-vascular xenografts remains controversial. This
      study investigated the role of anti-alphaGal antibodies in rejection of non
      vascularized alphaGal+/+ grafts in alphaGal -/- mice. METHODS: alphaGal +/+ and
      alphaGal -/- pancreatic islets were transplanted under the renal capsule of
      streptozotocin-induced diabetic (1) alphaGal -/- mice and (2) alphaGal +/+ mice.
      alphaGal -/- recepients were immunized with rabbit red blood cell membranes
      (RRBCs) to produce elevated anti-alphaGal antibody levels. RESULTS: Six of the 18
      alphaGal -/- mice rejected the alphaGal +/+ grafts within 68 days whereas
      indefinite graft survival was achieved in the control groups. Animals with
      surviving islet grafts were challenged with alphaGal +/+ skin grafts. Although
      all alphaGal +/+ skin grafts were rejected within 58 days, the islet grafts
      remained intact. This observation correlated with the level of alphaGal
      expression (which was very low on islets compared to skin) rather than the actual
      titre of anti-alphaGal antibody. DISCUSSION: The results suggest that the level
      of alphaGal expression plays an important role in graft survival. Therefore, its
      removal is important in the development of a pig islet donor for future clinical
      therapy.

PMID- 15196127
TI  - Anti-pig antibody levels in non-human primates of various origin.
AB  - BACKGROUND: Natural anti-porcine antibodies play a major role in hyperacute solid
      organ xenograft rejection in the pig-to-non-human primate model. Work from other
      groups and our experience in transplantation experiments has shown that antibody
      levels are highly variable between non-human primate species, and that extremely
      high levels can mediate hyperacute rejection even if organs from animals
      transgenic for human decay-accelerating factor are used. METHODS: Sera were
      obtained from cynomolgus monkeys wild-caught in Mauritius, captive-bred in the
      Philippines, captive-bred in Indonesia (Indonesia-Ind), and originating from
      Indonesia but colony-bred in USA (Indonesia-USA), from baboons wild-caught in
      Kenya, and from rhesus monkeys originating from India but colony-bred in USA (10
      animals in each group). Antibody levels were determined using assays for
      haemolytic antibody (APA), IgM and IgG class anti-Galalpha1-3Gal antibody, and
      IgM and IgG class anti-endothelial cell antibody. RESULTS: Cynomolgus monkeys
      from the Philippines and Indonesia-USA and rhesus monkeys showed median APA and
      IgM antibody levels in the same range as a pooled human serum standard, and
      median IgG levels well below the level in this standard. Cynomolgus monkeys from
      Mauritius and Indonesia-Ind showed extremely high APA levels (median seven to 10
      times the human serum standard): IgM class antibodies were also higher, while IgG
      class antibodies were in the range of the level in the human serum standard.
      Antibody levels in baboons were in between these two categories. The results of
      the APA assay showed a highly statistically significant correlation with the
      assays of IgM antibody, and this was also the case for the IgM antibody assays,
      indicative of the assessment of the same antibodies in these assays. The same was
      observed for the assays for IgG antibody. Taking body weight as an indicator for
      age, there was no relationship between body weight and levels of antibodies.
      CONCLUSIONS: Natural antibody levels show a significant variation between various
      groups of non-human primates, with levels in some groups well above those in a
      human serum standard.

PMID- 15196128
TI  - No transmission of porcine endogenous retrovirus after transplantation of adult
      porcine islets into diabetic nude mice and immunosuppressed rats.
AB  - BACKGROUND: The aim of this study was to investigate whether transmission of
      porcine endogenous retrovirus (PERV) occurs in a model of diabetes reversal by
      the xenotransplantation of adult porcine islets (APIs) into immunoincompetent
      diabetic rodents. METHODS: Black-6 nu/nu mice and Lewis rats were
      immunosuppressed with cyclosporin A (CsA) and FTY 720, and rendered diabetic with
      streptozotocin. Purified APIs were transplanted into the renal subcapsular space;
      5,000 islet equivalents (IEQs) were used in the nude mice (n = 4) and 40,000 IEQs
      in the rats (n = 4). The nude mice were sacrificed at 75 days after
      transplantation. In order to confirm chronic xenograft function, the graft
      bearing kidney was removed prior to sacrifice. The rats were followed until
      xenograft rejection, at which time they were sacrificed. Immediately after
      sacrifice, tissue samples (liver, spleen, and small intestine) were taken for
      analysis. Quantitative polymerase chain reaction (PCR) was used to assess
      evidence of PERV transmission, and porcine cell chimerism. RESULTS: All animals
      became normoglycemic within 48 h of transplantation. The nude mice remained
      normoglycemic during the 75-day study period, with removal of the graft-bearing
      kidney resulting in prompt hyperglycemia. The rats remained normoglycemic until
      xenograft rejection, which occurred at 66 +/- 28 days. Despite the evidence of
      porcine cell microchimerism in recipients, real-time PCR detected no evidence of
      PERV transmission in any of the tissue specimens tested. CONCLUSIONS: There was
      no evidence of PERV transmission following transplantation of pig islets into
      diabetic nude mice and immunosuppressed rats.

PMID- 15196129
TI  - MyD88-dependent toll-like receptor signalling is not a requirement for fetal
      islet xenograft rejection in mice.
AB  - BACKGROUND: Rejection of pancreatic islet xenografts in mice shares
      immunopathological features with a Th1-associated delayed-type hypersensitivity
      (DTH) reaction. The aim of the present study was to investigate the mechanism of
      acute cellular xenograft rejection in a strain of mice with a targeted gene
      disruption of the toll-like receptor (TLR) signal adaptor protein MyD88. These
      mice have been shown to have markedly impaired Th1 immunity. METHODS: The MyD88-/
      and normal mice were transplanted with 2 microl of fetal porcine islet-like cell
      clusters (ICC) under the left kidney capsule. On days 3, 6 or 12 after
      transplantation the mice were killed and the grafts either prepared for
      immunohistochemistry or real-time quantitative reverse transcriptase polymerase
      chain reaction (RT-PCR). The number of remaining ICC and infiltrating cells with
      different phenotypic characteristics was assessed semi-quantitatively. Grafts
      used for quantitative RT-PCR were analysed for content of murine mRNA of
      interferon (IFN)-gamma, interleukin (IL)-12p40, IL-4 and IL-10. RESULTS: On day
      3, the rejection process was initiated in both MyD88-/- and normal mice as
      characterized by a moderate infiltration of F4/80+ and MAC-1+ macrophages and
      occasional CD3+ and CD4+ cells. Expression of IFN-gamma and IL-12p40 was lower
      but still detectable in the MyD88-/- mice, when compared with control animals. By
      day 6, rejection was almost completed in all animals with only few ICC remaining.
      12 days after transplantation all grafts were completely destroyed and heavily
      infiltrated by macrophages. Moderate numbers of CD3+ and CD4+ and occasional CD8+
      cells were also present. CONCLUSIONS: Islet xenograft rejection was found to
      persist in MyD88-/- mice. Despite a relatively lower expression of the Th1
      associated cytokines IFN-gamma and IL12-p40 within the xenograft area, both the
      time course and morphological pattern of the rejection were essentially similar
      to that found in normal animals. Hence, MyD88-dependent TLR signalling does not
      appear to be a crucial component of acute cellular xenograft rejection.

PMID- 15196130
TI  - Initial experience with the human anti-human CD154 monoclonal antibody, ABI793,
      in pig-to-baboon xenotransplantation.
AB  - BACKGROUND: ABI793 (ABI) is a human monoclonal antibody (mAb) specific for human
      CD154. To assess the suitability of ABI for baboon transplantation studies, we
      carried out in vitro studies to determine ABI's reactivity with baboon cells
      expressing CD154, performed in vivo pharmacokinetic studies in two baboons, and
      tested the effect of ABI administration on elicited antibody production in two
      baboons undergoing either pig hematopoietic progenitor cell (PBPC) or heterotopic
      heart transplantation. METHODS: In vitro: Baboon peripheral blood mononuclear
      cells were activated in vitro to upregulate CD154, and binding of ABI to CD154
      was measured by flow cytometry. In vivo: Serum levels of ABI were measured
      immediately before and 15 min after the intravenous administration of ABI (20
      mg/kg) to two baboons over 28 days. Subsequently, ABI (25 mg/kg on days 0, 1, 4
      and 7, and then 20 mg/kg every 5 days) was included in the immunosuppressive
      regimen in two pig-to-baboon transplants (PBPC or heart transplantation).
      RESULTS: In vitro: ABI was almost non-reactive to baboon T cells before
      stimulation, but bound to activated T cells. In vivo: In the pharmacokinetic
      study, trough levels of ABI (before the next dose) ranged between 190 and 580
      microg/ml, and the estimated half-life was 10-15 days. There was no apparent
      toxicity. Following pig PBPC or heart transplantation, no elicited antibody was
      detected while ABI was being administered or during several weeks of follow-up.
      CONCLUSIONS: ABI functions in baboons, is well-tolerated, and prevents an
      elicited antibody response to pig antigens.

PMID- 15196132
TI  - To the core of porcine matter: evaluating arguments against producing transgenic
      pigs.
AB  - BACKGROUND: The production of transgenic pigs for xenotransplantation is based on
      an urgent human need for transplantable organs. Although the particular genetic
      modifications are small and do not alter the organism phenotypically, several
      authors consider it to be morally problematic. In this paper we attempt to
      establish if there are genuine reasons to refrain from producing 'humanized'
      pigs. METHODS: We distinguish between two types of ethical arguments against
      transgenesis often confused in debating the matter: consequentialist and inherent
      arguments. Whereas the first type of argument pertains to the potentially
      negative effects of the procedure, the second type claims that genetic
      engineering of animals is 'inherently' wrong; that the action itself regardless
      of the effects - is to be considered immoral. If this is the case, then the
      discussion need not be taken further. If not, then these arguments do not stand
      in evaluating the procedure. RESULTS: We demonstrate that none of the claims
      asserting inherent wrongness of transgenesis is valid as such. CONCLUSION: Sound
      resistance to producing transgenic pigs is restricted to concerns regarding the
      concrete effects of the applications.

PMID- 15196131
TI  - Bone marrow transplantation from alpha1,3-galactosyltransferase gene-knockout
      pigs in baboons.
AB  - BACKGROUND: Successful hematopoietic cell allotransplantation results in donor
      specific tolerance, but this approach has been unsuccessful in the wild-type pig
      to-baboon xenotransplantation model, as pig cells were lost from the circulation
      within 5 days. However, after cessation of immunosuppressive therapy on day 28,
      all baboons demonstrated non-specific unresponsiveness on mixed leukocyte
      reaction (MLR) for at least 30 days. We have now investigated the transplantation
      of bone marrow (BM) cells from miniature swine homozygous for alpha1,3
      galactosyltransferase gene-knockout (GalT-KO). METHODS: Baboons (n = 3) were pre
      treated with whole body and thymic irradiation, anti-thymocyte globulin, and
      splenectomy, and received immunosuppressive and supportive therapy for 28 days.
      BM was harvested from GalT-KO swine (n = 3). The baboons were monitored for the
      presence of pig cells by flow cytometry and colony-forming units (CFUs), and for
      cellular reactivity by MLR. RESULTS: A mean of 11 x 10(8) BM cells/kg was infused
      into each baboon. The mean absolute numbers and percentages of pig cells detected
      in the blood at 2 h and on days 1, 2 and 4, respectively, were 641/microl (9.5%),
      132/microl (3.4%), 242/microl (3.9%), and 156/microl (2.9%). One baboon died
      (from accidental hemorrhage) on day 6, at which time chimerism was present in the
      blood (2.0%) and BM (6.4%); pig cell engraftment in the BM was confirmed by
      polymerase chain reaction (PCR) of CFUs. In the two other baboons, blood
      chimerism was lost after day 5 but returned at low levels (<1%) between days 9 to
      16 and 7 to 17, respectively, indicating transient BM engraftment. Both surviving
      baboons showed non-specific unresponsiveness on MLR until they were euthanized on
      days 85 and 110, respectively. CONCLUSIONS: By using BM cells from GalT-KO pigs,
      chimerism was detected at levels comparable with previous studies when 30-fold
      more growth factor-mobilized peripheral blood progenitor cells had been
      transplanted. In addition, cellular hyporesponsiveness was prolonged. However,
      long-term engraftment and chimerism were not achieved.

PMID- 15196133
TI  - Human anti-A and anti-B antibodies interact with alphaGal antibody affecting
      xenograft survival.

PMID- 15196134
TI  - Increased apoptosis in porcine cardiac xenografts perfused with human ABO plasma
      containing the anti-B antibody.

PMID- 15196135
TI  - Potential target molecules on pig kidneys recognized by naive and elicited baboon
      antibodies.

PMID- 15196136
TI  - Letter to the editor.

PMID- 15196137
TI  - Xenotransplantation literature update March-April, 2004.

PMID- 15196139
TI  - Update on diabetes mellitus and related oral diseases.
AB  - Diabetes mellitus (DM) is a group of complex multisystem metabolic disorders
      characterized by a relative or absolute insufficiency of insulin secretion and/or
      concomitant resistance to the metabolic action of insulin on target tissues. The
      chronic hyperglycaemia of diabetes is associated with long-term systemic
      dysfunction. The present article summarizes current knowledge of DM and details
      the oral and dental implications of this common endocrine disorder.

PMID- 15196140
TI  - Alterations in expression of retinoid receptor beta and p53 in oral submucous
      fibrosis.
AB  - OBJECTIVE: Knowledge of the molecular pathogenesis of oral submucous fibrosis
      (OSF), a potentially malignant condition with high risk of transition to oral
      cancer, is meagre. Alterations in the expression of retinoic acid receptor beta
      (RARbeta) and tumor suppressor gene, p53 are early events in oral tumorigenesis.
      The aim of this study was to investigate the alterations in the expression of
      RARbeta and p53 in OSF lesions and determine their association with disease
      pathogenesis. METHODS: The expression of RARbeta and p53 proteins was analyzed by
      immunohistochemistry in 50 cases of OSF and 30 histologically normal oral
      tissues. RESULTS: No detectable RARbeta expression was observed in 35 of 50 (70%)
      OSF cases. p53 protein accumulation was observed in 24 of 50 (48%) OSF cases
      analyzed. Thirty-six percent OSF lesions showed loss of RARbeta and p53
      overexpression. Interestingly, 41 of 50 (82%) of OSF lesions showed altered
      expression of at least one of these two proteins. CONCLUSION: Altered expression
      of either RARbeta or p53 in majority of OSF lesions suggests their association
      with disease pathogenesis and warrants follow-up to determine whether OSF lesions
      harboring concomitant alterations in RARbeta and p53 are at a high risk of
      transition to malignancy.

PMID- 15196141
TI  - Effect of bone marrow transplantation on the immunolocalization of p53, hMSH2,
      and hMLH1 proteins on oral mucosa.
AB  - OBJECTIVE: Considering that hMSH2, hMLH1 and p53 are important in maintaining
      genomic stability of the oral mucosa epithelium, the purpose of the present study
      was to investigate the immunolocalization of these proteins in the epithelium of
      the oral mucosa of patients submitted to bone marrow transplantation (BMT)
      compared with controls. MATERIALS AND METHODS: Twenty-one samples of lip biopsies
      from BMT recipients were retrieved. Twenty samples of normal lower labial mucosa
      associated with mucocele in non-transplanted patients were included as control
      group. The streptavidin-biotin complex stain was used to detect the human DNA
      mismatch repair proteins hMSH2, hMLH1 and p53 protein. RESULTS: The main findings
      demonstrated that the mean number of suprabasal epithelial cells positive for
      MSH2 was statistically higher than the control group. The immunostaining of hMLH1
      and p53 at the basal and suprabasal epithelial layers were statistically higher
      in the oral labial mucosa of the BMT patients compared with controls. CONCLUSION:
      The present study shows that oral epithelial cells of BMT patients show increased
      immunolocalization of the DNA repair related proteins.

PMID- 15196142
TI  - Actinic cheilitis: clinical and pathologic characteristics in 65 cases.
AB  - OBJECTIVE: The purpose of this study was to determine the clinical and
      histopathologic presentation of actinic cheilitis. STUDY DESIGN: A retrospective
      study on 65 patients attending an Oral Medicine clinic in Greece over a 10 year
      period. For each case the demographic, clinical and histopathologic information
      were evaluated. RESULTS: The mean age at the time of diagnosis was 53.1 +/- 11.4
      years. Thirty-nine patients (60%) used tobacco in any form. An outdoor occupation
      was indicated for 43 (66.2%) patients. The location of the lesions of actinic
      cheilitis was in all cases on the lower lip. Actinic cheilitis appeared in three
      forms; white non-ulcerated lesions (29%), erosions or ulcers of the lip (48%),
      mixed white and erosive (23%). The histopathologic characteristics included
      increased thickness of keratin layer, alterations of the thickness of spinous
      cell layer, epithelial dysplasia, connective tissue changes, perivascular
      inflammation and basophilic changes of connective tissue. In 11 cases (16.9%) the
      presence of squamous cell carcinoma was observed. CONCLUSIONS: This case-series
      highlights varied clinical presentation of actinic cheilitis among whom a high
      proportion developed squamous cell carcinoma.

PMID- 15196143
TI  - Effects of near-infrared irradiation to stellate ganglion in glossodynia.
AB  - OBJECTIVE: This study was designed to assess the effect of stellate ganglion near
      infrared irradiation (SGR) on glossodynia and the mechanism of action. STUDY
      DESIGN: Thirty-seven patients with glossodynia received SGR once weekly for 4
      weeks. The response to treatment was evaluated on the basis of the change in pain
      intensity, assessed with a visual analogue scale (VAS) before and after 4 weeks
      of treatment. The temperature and blood flow of the tongue were also measured
      before and after first SGR. As control, eight healthy subjects were studied.
      RESULTS: Tongue pain as assessed by the VAS decreased in 28 of the 37 patients
      (75.7%). Mean pain intensity decreased significantly from 5.1 +/- 2.2 to 1.9 +/-
      2.1 (P < 0.05). Tongue blood flow at rest in the patients with glossodynia [7.2
      +/- 1.6 ml min(-1) (100 g)(-1)] was significantly lower than that in the healthy
      subjects [7.8 +/- 0.23 ml min(-1) (100 g)(-1)]. Five minutes after SGR, the
      temperature of the tongue rose 1.5 +/- 0.21 degrees C, and blood flow increased
      to 8.5 +/- 1.2 ml min(-1) (100 g)(-1). Tongue blood flow (at rest) after 4 weeks
      of SGR had increased to 7.7 +/- 1.1 ml min(-1) (100 g)(-1). CONCLUSION: SGR is an
      effective treatment for glossodynia. The mechanism by which SGR improves symptoms
      associated with glossodynia is thought to be as follows: SGR inhibits abnormally
      increased sympathetic activity associated with glossodynia. This is followed by
      normalization of decreased tongue blood flow, thereby alleviating pain.

PMID- 15196144
TI  - Fungicidal effect of three new synthetic cationic peptides against Candida
      albicans.
AB  - OBJECTIVE: Peptide antibiotics are considered a new class of antifungal agents.
      Of these, an alpha-helical, cationic peptide termed Dhvar 4, a relative of
      salivary histatin has been shown to be an antifungal of relatively high potency.
      Similarly, lactoferricin B (LFB) and a derivative thereof, LFB(17-30), disrupts
      the fungal cell membrane and acts against Candida albicans. As Dhvar 4 and LFB(17
      30), exhibit almost identical amino acid sequences at their C-terminal, we
      hypothesized that laboratory synthesis of peptides with an alpha-helical
      structure and having similar amphipathic properties could lead to products with
      candidacidal activity. Hence, three such peptides - JH8194, JH8195 and JH 8944,
      were synthesized and their antifungal properties compared with recognized
      antifungals LFB, LFB(17-30), human lactoferricin (LFH), Histatin-5 and Dhvar 4,
      against two isolates of C. albicans. MATERIALS AND METHODS: The antifungal agents
      were synthesized and their secondary structures evaluated according to a
      previously described protocol of Situ and Bobek (2000)Antimicrob Agents
      Chemother44: 1485-1493. The C. albicans strains were oral isolates from a human
      immunodeficiency virus-infected (isolate A2) and a healthy (A6) individual. A
      standard concentration of yeasts was exposed to a range of dilutions of the
      agents for a specific duration and the cell death (viability) in terms of the
      resultant colony forming units ml(-1) was quantified. RESULTS: Dhvar 4, showed
      the most alpha-helical propensity, and was the least fungicidal while LFB and
      LFB(17-30) showed the highest antifungal potential, and demonstrated total kill
      of A6, and A2 at 5 and 10 microM concentrations, respectively whilst LFH killed
      both isolates at a l0 microM concentration. Of the three new synthetic peptides,
      JH 8194 was the most potent (total kill of A6/A2 strains at 1.25/2.5 microM),
      followed by JH 8195 (total kill of A6/A2 strains at 5/10 microM while JH 8944 was
      the least potent as a 25 microM concentration was required to kill either strain
      of Candida. On further analyses of the relationship between pI value of the
      peptides and their anticandicidal activity, a significant positive correlation
      was noted. In order to rule out a cytotoxic effect of the new synthetic peptides
      we compared the fungicidal and hemolytic activities under similar incubation
      conditions using freshly isolated erythrocytes and all three peptides exhibited
      no detectable hemolysis upto an concentration of 100 microM in contrast to the
      polyene antifungal amphotericin B that elicited significant initiation of
      hemolysis at a concentration of 5.0 microM. CONCLUSION: Our data suggest that
      laboratory synthesis of agents with an alpha-helical structure and having
      amphipathic properties similar to known, natural antifungal agents may be a
      promising avenue to generate products with improved antifungal activity.

PMID- 15196145
TI  - Ranula: another HIV/AIDS associated oral lesion in Zimbabwe?
AB  - AIM: To show that sublingual ranula is associated with HIV/AIDS and as such
      should be considered an HIV/AIDS associated oral lesion in Zimbabwe. OBJECTIVES:
      To retrospectively study the prevalence, age and gender distribution, the HIV
      serostatus of ranula patients and the trend in prevalence of ranula and Kaposi's
      sarcoma (KS) in patients at the two largest referral Oral and Maxillofacial
      Surgery specialist centres in Harare, Zimbabwe. To use this information to infer
      an association between ranula and HIV/AIDS in Zimbabwe. DESIGN: Descriptive study
      with a retrospective and prospective component. SETTING: Oral and Maxillofacial
      Surgical clinics at specialist referral hospitals, Harare Central Hospital and
      Parirenyatwa Government Hospital, Harare, Zimbabwe. SUBJECTS: Eighty-three cases
      of ranula were studied: 45 cases retrospectively and 38 consecutively. A total of
      231 cases of KS were studied retrospectively. METHODS: Histopathologic records of
      patients who presented with ranula and KS during the period January 1981 to
      September 2003 were studied. Gender and age were recorded for each case. Thirty
      eight ranula patients studied consecutively during the period June 1999 to
      September 2003 were consented for HIV testing. RESULTS: There were 83 cases of
      ranula; 43.4% male and 56.6% female. There were 231 cases of KS, 61.2% male and
      38.8% female. Male to female ratio was 1:1.3 for ranula and for KS was 1:0.6.
      Ranula was predominant in the 0-10 year age group (73.5%) while KS was most
      common in the 21-40 year age group (76.4%). Ranula and KS both had a marked rise
      in prevalence from 1992 to 2003. A total of 88.5% of the ranula cases tested HIV
      positive with 95% in the 0-10 year age group. CONCLUSION: There was a rising
      prevalence of ranula which mirrors that of KS (an HIV/AIDS associated oral
      lesion) and that 88.5% of ranula patients were HIV positive with 95% of them in
      the 0-10 year age group. Sublingual ranula should thus be considered another
      HIV/AIDS associated lesion in Zimbabwe, especially in children.

PMID- 15196146
TI  - Immunohistochemical localization and expression of fibromodulin in adult rat
      periodontium and inflamed human gingiva.
AB  - OBJECTIVE: The aim of this study was to determine the distribution and expression
      of fibromodulin in adult rat periodontal tissues and inflamed human gingiva.
      MATERIALS AND METHODS: The distribution of fibromodulin in rat molar periodontium
      and human gingival tissue was studied by immunohistochemistry. The expression of
      fibromodulin mRNA from human gingival fibroblasts, periodontal ligament
      fibroblasts and osteoblasts was studied by reverse transcription-polymerase chain
      reaction (RT-PCR). For comparative purposes, the distribution and mRNA expression
      of collagen types I and III, as well as the two small leucine-rich proteoglycans
      decorin and biglycan were also studied. RESULTS: In the adult rat periodontium,
      fibromodulin was distributed in the suprabasal gingival epithelium, gingival and
      periodontal fibroblasts as well as their surrounding extracellular matrices.
      Strong expression was noted in the palatal gingival tissues and the interfaces of
      the periodontal ligament with alveolar bone and cementum. In human gingival
      tissues, staining of fibromodulin was detected in the connective tissue of
      inflamed gingiva associated with both gingivitis and periodontitis; whereas, weak
      staining for this molecule was noted in healthy gingival tissues. The expression
      of mRNA for fibromodulin was strongest in the cultured osteoblasts. Periodontal
      ligament fibroblasts showed only a weak level of expression for fibromodulin
      mRNA. CONCLUSIONS: Fibromodulin is differentially expressed throughout the
      periodontium being primarily associated with collagen type I in non-mineralized
      sites. In addition fibromodulin showed an upregulation in inflamed gingival
      tissue.

PMID- 15196147
TI  - Focal epithelial hyperplasia (Heck's disease): report of two cases with PCR
      detection of human papillomavirus DNA.
AB  - Focal epithelial hyperplasia (FEH) (Heck's disease) is essentially a benign oral
      infection produced by the human papillomavirus (HPV). Although this condition is
      known to exist in numerous populations and ethnic groups, it is relatively rare
      in South-East Asia. The following report is based on two cases of adult FEH with
      histopathological features in favour of the disease. In addition, polymerase
      chain reaction was performed to detect the presence of HPV DNA in the lesions in
      order to confirm the histopathological diagnosis.

PMID- 15196148
TI  - Stomatodynia (burning mouth) as a complication of enalapril therapy.

PMID- 15196152
TI  - Clinicopathological spectrum of mycosis fungoides.
AB  - Cutaneous lymphomas represent a heterogeneous group of T-, NK- and B-cell
      neoplasms, with mycosis fungoides (MF) being the most common subtype. MF has a
      plethora of clinicopathological manifestations. Many variants of this lymphoma
      differ substantially from the 'classical' Alibert-Bazin disease and are therefore
      sometimes referred to as 'atypical' forms of the disease. This review addresses
      the whole clinicopathological spectrum of mycosis fungoides with respect to
      epidemiology, clinical, histopathological, immunophenotypic and genotypic
      features and the clinical course and prognosis of its variants: classical,
      erythrodermic, follicular, syringotropic, bullous/vesicular, granulomatous,
      poikilodermic, hypo- and hyperpigmented, unilesional, palmoplantar,
      hyperkeratotic/verrucous, vegetating/papillomatous, ichthyosiform, pigmented
      purpura-like, pustular and mucosal involvement in MF.

PMID- 15196153
TI  - Improved efficacy and tolerability of retinoic acid in acne vulgaris: a new
      topical formulation with cyclodextrin complex psi.
AB  - OBJECTIVES: Retinoic acid (RA) has long been used, both topically and
      systemically, for disorders of keratinization, acne and related disorders. In the
      present study, the efficacy and tolerability of topical RA prepared as a
      cyclodextrin beta complex (beta-CD) is investigated in 66 acne vulgaris patients.
      METHODS: This randomized, double-blind, placebo-controlled study compares nightly
      topical application of RA/beta-CD complex hydrogel formulation (0.025%), RA/beta
      CD complex in moisturizing base (0.025%), hydrogel base, moisturizer base or a
      commercial RA gel (0.05%) in acne vulgaris patients. Improvement of acne was
      assessed using a 5-point improvement scale and by measuring sebum and moisture
      content of the skin using an SM 810 sebumeter/corneometer. RESULTS: After 3
      months of treatment, mean scores of acne improvement on the 5-point scale were 4
      with the RA/beta-CD complex hydrogel formulation, 4.1 with the RA/beta-CD complex
      in moisturizing base, 1.2 with hydrogel placebo base, 1.1 with moisturizer
      placebo base and 3 with the commercial RA product. All patients treated with the
      commercial product experienced local side-effects. One patient discontinued due
      to severe irritation. None of the patients treated with the RA/beta-CD complex in
      the moisturizing base and hydrogel formulation experienced significant local
      irritation, although the sebum content of the skin decreased after application of
      the RA/beta-CD preparations. This change was not significant compared to
      controls. The moisture content of the skin was better preserved in the group
      treated with the RA/beta-CD complex in the moisturizing base. CONCLUSION: The
      topical RA/beta-CD complex, in hydrogel and moisturizing base, was more effective
      than the twice concentrated commercial RA product. There were few topical side
      effects with this new formulation, which increases patient compliance. Topical
      RA/beta-CD (0.025% RA) did not significantly reduce sebum secretion but may help
      to preserve optimum epidermal moisture content with the proper base formulation.
      This is the first study in the literature reporting efficacy and tolerability of
      the topical RA/beta-CD complex in acne vulgaris. We conclude that the topical
      RA/beta-CD complex displays an improved efficacy and tolerability profile and is
      an effective treatment alternative for acne vulgaris.

PMID- 15196154
TI  - Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA -- Q
      Medical, Sweden) in European countries: a retrospective study from 1997 to 2001.
AB  - BACKGROUND: In Europe, several filler devices are currently on the market for use
      in aesthetic dermatology and some of them cause severe, permanent, adverse
      reactions. Since 1996 a non-animal stabilized hyaluronic acid (NASHA) from Q
      Medical, Sweden, has been introduced and is becoming a leading product in
      aesthetic dermatology. Hyaluronic acid has no species specificity and skin
      testing is not recommended before treatment. OBJECTIVE: Our purpose was to
      evaluate the incidence of adverse reactions from 1997 to 2001 and the safety of
      NASHA after injections into the skin for aesthetic reasons. METHOD: Surveys were
      sent to physicians in European countries that agreed to participate. This is a
      retrospective study. A total of 12 344 syringes were sold by the Q-Medical to
      these physicians and we evaluated the total number of patients treated to 35% of
      this number (4320). We separated immediate hypersensitivity reactions from
      delayed reactions and analysed infectious and other types of reactions. RESULTS:
      From 1997 until 2001, 34 cases of hypersensitivity were reported: 16 cases of
      immediate hypersensitivity and 18 cases of delayed. The global risk of
      sensitivity is 0.8%. Since 2000, the amount of protein in the raw product has
      decreased and the incidence of hypersensitivity reactions is around 0.6%. As 50%
      of these reactions are immediate and resolved within less than 3 weeks, the risk
      of strong but transient, delayed reaction is around 0.3%. Four cases of abscess
      were reported. They were all sterile. No bacterial infection was found. Herpetic
      recurrence is possible after lip augmentation according to the technique of
      injection. No systemic reactions were reported. CONCLUSION: NASHA is a very
      useful and safe filler product. Skin testing does not seem to be necessary.

PMID- 15196155
TI  - Intramuscular bipenicillin vs. intravenous penicillin in the treatment of
      erysipelas in adults: randomized controlled study.
AB  - The objective of the study was to evaluate the efficacy of intramuscular
      penicillin: mixture of benzyl penicillin and procain penicillin (2 MU x 2 times
      daily) and intravenous benzyl penicillin (4 MU x 6 times daily) in the treatment
      of hospitalized adult patients with erysipelas. A prospective randomized
      unicentric trial was conducted. In total, 112 patients entered the study; 57 in
      the intramuscular group and 55 patients in the intravenous group completed the
      trial. The failure rate was 14% for intramuscular group and 20% for the
      intravenous group (P = 0.40). Local complications such as of the leg abscesses
      were observed in the two groups (intravenous 9.1%, intramuscular 7%; P = 0477).
      Of the patients treated with intravenous benzyl penicillin, 25.5% presented
      complications related to the route (venitis). Intramuscular penicillin should be
      considered an effective and well-tolerated treatment of erysipelas in adult
      patients.

PMID- 15196156
TI  - Otosyphilis: report on six cases.
AB  - Syphilis is a multisystemic disease that may also affect the inner ear. The
      objective of this study was to investigate the frequency, clinical presentation
      and outcome of otosyphilis. A retrospective analysis of inpatients seen by a team
      of ENT specialists and dermatologists at a teaching hospital in Dresden, Germany,
      during 1986-2000. Six cases of otosyphilis had been diagnosed. None was related
      to risk factors such as HIV infection or drug abuse. We identified four female
      and two male patients, age range 25-58 years. Four patients suffered from
      syphilis stage II, one from syphilis stage and another from congenitial syphilis.
      ENT complaints included loss or impairment of hearing, tinnitus and nystagmus.
      All were treated with penicillin G. Adjuvant therapy included systemic
      corticosteroids oral pentoxifillin in two patients each. Improvement of ENT
      symptoms was achieved in all but one patient, who suffered from congenitial
      syphilis. This study confirms that otosyphilis is still a complication of
      syphilis in developed countries. The first line therapy is systemic penicillin G.
      There is a lack of controlled trials for adjuvant treatments such as
      corticosteroids and pentoxifillin. Clinical cooperation between
      dermatologists/venereologists and ENT specialists supports the best outcome.

PMID- 15196157
TI  - Disease-specific quality of life is associated with anxiety and depression in
      patients with acne.
AB  - OBJECTIVE: We aimed to evaluate the relationships between acne severity, anxiety,
      depression and disease-specific quality of life in patients with acne. METHOD: A
      total of 61 patients with acne vulgaris and 38 healthy volunteers were included
      in the study. Acne severity was assessed by the Global Acne Grading System. All
      patients were asked to complete the Acne Quality of Life Scale (AQOL),
      Dermatology Life Quality Index (DLQI) and Hospital Anxiety and Depression Scale
      (HAD), and healthy controls to fill only the HAD. RESULTS: The mean HAD anxiety
      subscale (HAD-A) and HAD depression subscale (HAD-D) scores of the patients were
      significantly higher than those of the controls. The rates of subjects at risk
      for anxiety (26.2%) and for depression (29.5%) were significantly higher in the
      patient group than in the control group (0% and 7.9%, respectively). We found no
      correlations between acne severity and scores of AQOL, DLQI, HAD-A and HAD-D.
      AQOL and DLQI scores were positively correlated with HAD-A and HAD-D scores in
      the patient group. The patients at risk for anxiety had significantly higher
      scores on AQOL and DLQI compared to those who were not at risk. There were no
      statistically significant differences between the female and male patients with
      respect to AQOL, DLQI, HAD-A and HAD-D scores. CONCLUSION: (1) Irrespective of
      the degree of severity, patients with acne are at increased risk for anxiety and
      depression compared to the normal population. (2) Acne negatively affects quality
      of life, and the greater the impairment of quality of life due to acne, the
      greater the level of anxiety and depression. (3) A greater impairment of
      dermatologic quality of life seems to put the patient at an increased risk for
      anxiety disorder.

PMID- 15196158
TI  - Immune response in demodicosis.
AB  - BACKGROUND: Demodex folliculorum and Demodex brevis are obligatory parasites in
      the hair follicles and in the pilosebaceous glands. Although most people are
      infested with these mites, only a small number develop the clinical symptoms of
      demodicosis. The objective of this study was to determine the distinguishing
      features of the immune response to the infestation of the skin by Demodex mites.
      METHODS: Twenty-nine patients with human demodicosis and 13 age- and sex-matched
      healthy subjects participated in the study. The presence of mites was determined
      by microscopic inspection of secretion from sebum glands. The immune response was
      evaluated in the peripheral blood by identifying membrane markers of different
      immune cells using monoclonal antibodies, while the concentration of
      immunoglobulin (Ig)A, IgM and IgG was calculated by simple radial immunodiffusion
      using anti-IgA, anti-IgM and anti-IgG. The level of circulating immune complexes
      and total haemolytic complement, as well as the preparatory and digestive
      function of neutrophils, and the functional activity of leucocytes were also
      studied. RESULTS: The absolute number of CD95+ was higher in patients with
      demodicosis. The absolute number of CD3+, CD4+, CD8+ and CD16+ cells, the ratio
      CD3+/CD20+ and the functional activity of leucocytes were significantly lower in
      individuals infested with Demodex mites. No significant differences were found in
      the percentage and absolute number of CD20+ cells, the ratio of CD4+/CD8+ T-cell
      subpopulations, circulating immune complexes, level of serum complement activity
      (CH(50)), activity and index of phagocytosis and the levels of IgA, IgM and IgG
      antibodies between individuals infested with Demodex mites and the control group.
      CONCLUSION: The readiness of lymphocytes to undergo apoptosis increases in
      parallel to the increasing density of the mites. This could be the result of
      local immunosuppression caused by the mites, which allows them to survive in the
      host skin.

PMID- 15196159
TI  - Treatment of head and neck dermatitis comparing itraconazole 200 mg and 400 mg
      daily for 1 week with placebo.
AB  - BACKGROUND: Head and neck dermatitis (HND) is a variant of atopic dermatitis
      often seen in young adults. A hypersensitivity to Malassezi antigens is
      considered to be of pathogenic importance. Previous mostly uncontrolled studies
      have shown that oral antimycotics might be of use in this condition. OBJECTIVE:
      To evaluate the efficacy of itraconazole in the treatment of HND in a randomized,
      double-blind, placebo-controlled trial. PATIENTS: Adult patients with HND were
      included. Systemic steroids and oral/topical antimycotics were avoided 1 and 2
      months prior to the trial. Topical steroids were not allowed in the head and neck
      area within 2 weeks. Patients in generally good health were included and female
      patients had to have had a negative urine pregnancy test. The patients signed an
      informed consent. STUDY DESIGN: The study included a 7-day treatment period and a
      follow-up period of 105 days. Control visits were carried out on days 3, 7 and 14
      and after 15 weeks. METHODS: The SCORAD index (one for the head and neck area and
      one for the remaining surface area) and global evaluations by patient and
      investigator were used for clinical evaluation at each visit. Prick tests with
      Malassezia antigens and Candida albicans antigen were carried out at the start of
      the trial and included positive and negative controls. The patients were
      randomized into three groups, which were treated with 400 mg itraconazole daily,
      200 mg itraconazole daily or placebo, respectively, for 7 days. RESULTS: The
      number of patients included was 53: 18 had 200 mg itraconazole daily, 17 had 400
      mg itraconazole daily and 18 placebo. At days 7 and 14, significant improvement
      was seen in the SCORAD of the head and neck area for the groups given 400 mg
      itraconazole daily (P = 0.0385 and P = 0.0134), and 200 mg daily (P = 0.0104 and
      P = 0.0006). Patients in the placebo group improved slightly (P = 0.0785). At day
      14, comparison of improvement of SCORAD of the head and neck area between all
      three groups showed a significant difference in favour of the 200 mg itraconazole
      group compared to the placebo group (P = 0.0318). The prick test was positive for
      Pityrosporum ovale in 37% and negative for C. albicans in all patients.
      CONCLUSIONS: One week of treatment with 200 or 400 mg itraconazole as a single
      treatment has a significant effect on the head and neck area. Compared to placebo
      there was a significant improvement in SCORAD of the head and neck area in favour
      of the 200 mg itraconazole group after 14 days. The important observation seems
      to be that antifungal systemic treatment has a significant SCORAD reduction of
      atopic dermatitis, irrespective of the presence of allergy.

PMID- 15196160
TI  - Evidence for diversity within Propionibacterium acnes: a comparison of the T-cell
      stimulatory activity of isolates from inflammatory acne, endocarditis and the
      laboratory.
AB  - BACKGROUND: Propionibacterium acnes is primarily associated with the pathogenesis
      of acne vulgaris but reports are increasing in number implicating P. acnes in
      other diseases such as abscess formation, meningitis and endocarditis. The
      pathogenicity of P. acnes is thought to be partly due to the interaction of the
      bacterium with the immune system. Historically, investigations have focused on
      humoral and cell-mediated immune responses to P. acnes antigens without attention
      to the possibility that different antigens may be expressed by different
      isolates. OBJECTIVE: Investigations were performed to determine whether there
      were differences between a laboratory strain of P. acnes (P-37) and fresh
      clinical isolates in their ability to stimulate naive and adult lymphocytes.
      MATERIAL AND METHODS: The fresh isolates were collected from a patient with
      inflammatory acne and a patient with P. acnes-induced prosthetic valve
      endocarditis. The lymphocyte transformation assay was used to detect responses to
      whole-cell suspensions of stationary phase P. acnes isolates during 7 days of
      incubation. RESULTS: The acne isolate was significantly more stimulatory for cord
      blood mononuclear cells (CBMNCs) than the laboratory isolate (P. acnes P-37) at
      day 4 of incubation. There were no significant differences between the three
      strains at any other time points. However, the isolate cultivated from
      inflammatory acne was significantly more stimulatory for peripheral blood
      mononuclear cells (PBMNCs) from acne donors than the endocarditis isolate or the
      laboratory strain at most time points. There were no significant differences
      between the endocarditis strain and the laboratory strain. CONCLUSION: It can be
      hypothesized that in case of P. acnes-induced endocarditis lymphocyte stimulation
      is a disadvantage for the microorganism and therefore a lack of lymphocyte
      stimulation may be relevant to the pathogenesis of endocarditis.

PMID- 15196161
TI  - Intralesional 5-fluorouracil, lidocaine and epinephrine mixture for the treatment
      of verrucae: a prospective placebo-controlled, single-blind randomized study.
AB  - BACKGROUND: The treatment of viral warts remains challenging. A variety of
      treatment modalities have been used with a range of success. Fluorouracil has
      been shown to be effective in treating warts but the method of its delivery
      directly onto the affected tissue has been of little efficacy. We evaluated the
      safety and efficacy of intralesional 5-fluorouracil in the treatment of verrucae.
      METHODS: Seventy-six patients with a total 315 verrucae were randomized to
      receive either a 5-fluorouracil, lidocaine and epinephrine (5-FU + LE) mixture or
      serum saline injection into the paired verrucae in the same patient. The mixture
      of 5-FU (4 cm(3), 50 mg/mL), lidocaine (1 cm(3), 20 mg/mL) and epinephrine
      (0.0125 mg/mL) was injected into the base of the wart using a mantoux needle.
      Each lesion was infiltrated with either of the solutions once a week for up to a
      maximum of 4 weeks, and the patients were followed up for 6 months. RESULTS:
      Complete response was noted in an average of 70% of the verrucae treated with the
      5-FU + LE mixture and in 29% of those in the placebo group (P < 0.001). No
      clinically significant systemic and local adverse effects occurred. Pain and
      burning were noted as an immediate injection pain. Recurrence rates were
      evaluated and no statistically significant difference between the two groups was
      found. CONCLUSIONS: The results demonstrate that treatment of verrucae with 5-FU
      + LE mixture is safe and effective.

PMID- 15196162
TI  - Elephantoid oedema of the eyelids.
AB  - We describe a male patient with rosacea who had a 2-year history of persistent
      bilateral oedema of the eyelids, leading to an elephantoid condition with
      blepharoptosis. An upper eyelid blepharoplasty was performed, but swelling
      progressively recurred over a few months. Based on the case history, clinical
      appearance and histological findings, rosaceous lymphoedema was considered to be
      the diagnosis. The latter is a bilateral, solid oedema of the mid-third of the
      face, regarded as a rare complication of rosacea. It is thought to occur as a
      result of chronic inflammation and lymphatic stasis, but its exact
      aethiopathogenesis remains elusive. Predominant eyelid involvement, causing
      severe visual impairment as in our patient, is unique.

PMID- 15196163
TI  - Graham Little-Piccardi-Lassueur syndrome associated with androgen insensitivity
      syndrome (testicular feminization).
AB  - Graham Little-Piccardi-Lassueur syndrome is characterized by the presence of
      cicatricial alopecia on the scalp, keratosis pilaris in the skin of trunk and
      extremities, and non-cicatricial hair loss in pubis and axillae. A frequent form
      of male pseudohermaphroditism is complete androgen insensitivity syndrome (CAIS),
      also known as testicular feminization syndrome. It refers to genetic males with
      XY karyotype who, owing to a lack of sensitivity in the peripheral androgenic
      receptors, develop a female phenotype. Axillary and pubic hair is typically
      scarce or absent. To our knowledge, this is the first case describing the
      association of the two processes. The presence of both processes in the same
      patient furthers our understanding of Graham Little-Piccardi-Lassueur syndrome as
      it rejects the influence of androgens in the alopecias accompanying this
      syndrome. The coincidence of non-cicatricial alopecia in axillary and pubic hair
      in both processes is also remarkable.

PMID- 15196164
TI  - HIV seronegative eosinophilic pustular folliculitis successfully treated with
      doxicycline.
AB  - Eosinophilic pustular folliculitis (EPF) is an unusual disease, first described
      in adult East Asians in 1970 by Ofuji. It is characterized by follicular papules
      and pustules tending to coalesce and form plaques involving the trunk, face and
      extremities. In recent years, it has been often associated with human
      immunodeficiency virus (HIV) infection or with immunosuppressed and/or
      oncohaematological patients. EPF has been described in immunocompetent adult
      caucasian patients only occasionally. The diagnosis requires clinical and
      microbiological features such as sterile folliculitis and histopathological
      findings characterized by folliculitis and perifolliculitis with eosinophilic
      infiltrate. We describe an HIV seronegative caucasian male with EPF, allergic to
      non-steroidal anti-inflammatory drugs and indomethacin, treated with oral
      doxicycline. The treatment led to the complete remission of the lesions within 2
      months.

PMID- 15196165
TI  - Elastophagocytosis: a feature of resolving Sweet's syndrome.
AB  - We report the case of a patient with atypical Sweet's syndrome characterized by
      an annular erythema that showed consumption of elastic fibres by giant cells and
      histiocytes. Although the lesions were found on sun-exposed sites and the first
      biopsy demonstrated extensive elastophagocytosis, our patient did not have
      photodamaged skin clinically. A repeat biopsy 5 weeks later demonstrated an
      abundant collection of neutrophils supporting the diagnosis of Sweet's syndrome.
      To our knowledge, an elastolytic granulomatous reaction pattern has not been
      previously reported in Sweet's syndrome.

PMID- 15196166
TI  - Surrogate nits impregnated with white piedra--a case report.
AB  - White piedral spores packed inside empty pedicular nits were accidentally found
      on microscopic examination in a 42-year-old Indian woman who presented with hair
      loss. The diagnosis of piedra was confirmed on culture. She responded to topical
      2% miconazole nitrate solution and manual removal of the nits. This is the first
      case report of pedicular nits found to be impregnated with spores of white
      piedra.

PMID- 15196167
TI  - Antitumour activity of paclitaxel and interferon-alpha in a case of metastatic
      eccrine porocarcinoma.
AB  - BACKGROUND: Eccrine porocarcinoma (EP) is a rare malignant tumour arising in the
      acrosyringium, with about 50% of the cases developing local recurrence or
      metastatic disease. No standard therapy protocols for metastatic disease exist.
      In the past, only short remissions were achieved by applying combinations of
      cytotoxic agents, which were associated with severe side-effects. AIM OF THE
      STUDY: In the case reported here, the aim was to find a protocol with fewer side
      effects for a patient who was not willing to undergo extensive polychemotherapy.
      SUBJECT: A 67-year-old male patient with local recurrence and regional lymph node
      metastases after resection of EP was treated with a combination of interferon
      alpha (IFN-alpha) 9 million units s.c. three times per week and paclitaxel 100
      mg/m(2) weekly i.v., which shows a side-effect profile similar to taxotere and is
      used in the treatment of a variety of neoplasms such as advanced squamous cell
      carcinoma. MAIN OUTCOME: This less aggressive treatment was tolerated well and
      the patient responded with minor remission and long-term stable disease.

PMID- 15196168
TI  - Treatment of papuloerythroderma of Ofuji with Re-PUVA: a case report and review
      of the therapy.
AB  - Papuloerythroderma of Ofuji (PEO) is a disease of elderly men, characterized by
      intensely pruritic and widespread, red, flat-topped papules with sparing of the
      body folds and creases (the so-called 'deck-chair' sign). The etiopathogenesis of
      the disease remains unknown. Psoralen plus UVA (PUVA), topical and systemic
      corticosteroids, etretinate, cyclosporin and interferon are the main approaches
      in the treatment of this rare disease. A case of PEO in a 60-year-old man who
      responded to retinoid plus PUVA (Re-PUVA) treatment is reported here and a review
      of the therapy with other relevant cases is presented.

PMID- 15196169
TI  - Congenital syphilis presenting with nephrotic syndrome and leucocytoclastic
      vasculitis.
AB  - Nephrotic syndrome is a well-recognized entity in congenital syphilis but
      leucocytoclastic vasculitis has not yet been described. We report a case of
      nephrotic syndrome and leucocytoclastic vasculitis associated with congenital
      syphilis in a 45-day-old male infant who did well after treatment with
      intravenous penicillin.

PMID- 15196170
TI  - Sutures and Burrow's triangles placed in the red vermilion in the surgery of
      upper lip defects.
AB  - BACKGROUND: In upper lip defects both the design of the flap and the position of
      the Burrow's triangles may be reversed so as to conceal the scars among skin
      wrinkles, folds and the mucosal lip to maximize the aesthetic outcome. OBJECTIVE:
      To report two cases of upper lip defects in which both scars and Burrow's
      triangles were concealed in the natural folds and the vermilion. METHODS: Both
      surgeries were performed under local anaesthesia. RESULT: In both patients the
      scars were successfully concealed and the results aesthetically acceptable.
      CONCLUSION: The technique described can be used to conceal scars in cases of
      upper lip defects with aesthetically acceptable results.

PMID- 15196171
TI  - Bullous systemic lupus erythematosus with antiphospholipid syndrome.
AB  - We report the case of a 44-year-old male with a 10-year history of manifestations
      of the rare form of bullous systemic lupus erythematosus (SLE) with coexisting
      antiphospholipid syndrome (APS) that remained undiagnosed until thrombotic
      embolic episodes appeared and high titres of anticardiolipin (ACL) antibodies
      were detected. The patient fulfilled the criteria for SLE and the atypical
      cutaneous manifestations together with histopathological changes and a favourable
      response to sulphones were the grounds for the diagnosis of the bullous variety
      of SLE. Treatment with prednisolone, acenocoumarol and dapsone resulted in marked
      clinical improvement, reduction in antinuclear antibodies (ANAs) and
      normalization of ACL antibody titres.

PMID- 15196172
TI  - Spontaneously remitting dermatomyositis.
AB  - Dermatomyositis (DM) is an inflammatory myopathy of skeletal muscle with
      characteristic cutaneous findings. It is a rare disorder with a bimodal age
      distribution that affects almost twice as many women as men. One category of DM,
      normal-enzyme DM, is characterized by cutaneous changes only at baseline, normal
      serum muscle enzyme levels and myositis demonstrated by electromyography (EMG)
      and/or muscle biopsy specimens. Typically, patients with normal-enzyme DM
      progress to severe muscle involvement and require systemic corticosteroid
      therapy. The patient we report has normal-enzyme DM confirmed by serial serum
      enzymes, EMG, and skin and muscle biopsies but is unique in that she never
      experienced progression of muscle weakness although muscle involvement was
      documented histologically and by EMG. Follow-up examination after 1 year revealed
      near-complete resolution of cutaneous involvement after topical therapy and no
      evidence of muscle weakness.

PMID- 15196173
TI  - Cutis verticis gyrata secondary to acne scleroticans capitis.
AB  - We report the case of a 35-year-old patient with secondary cutis verticis gyrata
      (CVG) that histologically presented as acne scleroticans capitis. Clinically, the
      diagnosis of acne conglobata was made. The CVG developed under systemic
      corticosteroid treatment of an ulcerative colitis. Corticosteroids were
      discontinued and a therapeutic attempt was made with isotretinoin. Although under
      this treatment the conglobate acne healed, the CVG remained unaltered.
      Dermatosurgical intervention by a scalp reduction plasty finally resulted in a
      marked improvement of symptoms and acceptable cosmetic outcome.

PMID- 15196174
TI  - The borderline syndrome in psychosomatic dermatology. Overview and case report.
AB  - The borderline syndrome is one of the most severe disturbances of psychosomatic
      dermatology. Patients with borderline syndrome are situated 'on the border' of
      psychosis, neurosis and personality disorders. The skin as a borderline organ
      carries a symbolic role. The clinical picture includes artefactual skin diseases
      due to self-mutilation by conscious or unconscious cutting, and rubbing,
      scratching or para-artefactual manipulations of pre-existing dermatoses. Leading
      symptoms of the borderline syndrome are poor impulse control, emotional
      instability and poor ego strength with low frustration tolerance and unstable
      personal relationships. We present the case of a 38-year-old female patient with
      borderline syndrome suffering from para-artefactual skin diseases of the face and
      a massive hyperhidrosis of the hands and feet. Within 9 months she was treated in
      four acute psychiatric hospitals and by 12 psychiatrists and psychotherapists.
      Early and accurate diagnosis and high-quality, sophisticated long-term therapy
      are necessary.

PMID- 15196175
TI  - Pemphigus vulgaris induced by radiotherapy.
AB  - Pemphigus can be triggered or induced by many insults, such as drugs, infections,
      viruses and neoplasms. X-ray-induced pemphigus has been recorded only rarely in
      the literature. We describe the case of a woman with pemphigus vulgaris in
      remission, who relapsed 1 week after completion of an irradiation course for
      breast cancer, in the exact location of the radiation. We review the previous 15
      cases from the literature and outline the common features of those cases.

PMID- 15196176
TI  - Diffuse plane xanthoma in photoexposed skin.

PMID- 15196177
TI  - Tumour size reduction of basal cell carcinoma waiting for elective surgery:
      possible role of palliative topical medications.

PMID- 15196178
TI  - Atypical fibroxanthoma of the skin on non-photoexposed areas: a diagnosis not to
      be missed.

PMID- 15196179
TI  - Chronic leg ulcers: a manifestation of basal cell carcinoma. Surgical treatment.

PMID- 15196180
TI  - Risk of subsequent non-melanoma skin cancer in a cohort of patients with primary
      basal cell carcinoma.

PMID- 15196181
TI  - Peristomal bullous pemphigoid.

PMID- 15196182
TI  - Syphilitic gumma--cutaneous tertiary syphilis.

PMID- 15196184
TI  - Unity with diversity: ICN's framework of competencies.

PMID- 15196186
TI  - Nurse competence scale: development and psychometric testing.
AB  - BACKGROUND: Self-assessment assists nurses to maintain and improve their practice
      by identifying their strengths and areas that may need to be further developed.
      Professional competence profiles encourage them to take an active part in the
      learning process of continuing education. Although competence recognition offers
      a way to motivate practising nurses to produce quality care, few measuring tools
      are available for this purpose. AIM: This paper describes the development and
      testing of the Nurse Competence Scale, an instrument with which the level of
      nurse competence can be assessed in different hospital work environments.
      METHODS: The categories of the Nurse Competence Scale were derived from Benner's
      From Novice to Expert competency framework. A seven-step approach, including
      literature review and six expert groups, was used to identify and validate the
      indicators of nurse competence. After a pilot test, psychometric testing of the
      Nurse Competence Scale (content, construct and concurrent validity, and internal
      consistency) was undertaken with 498 nurses. The 73-item scale consists of seven
      categories, with responses on a visual analogy scale format. The frequency of
      using competencies was additionally tested with a four-point scale. RESULTS: Self
      assessed overall scores indicated a high level of competence across categories.
      The Nurse Competence Scale data were normally distributed. The higher the
      frequency of using competencies, the higher was the self-assessed level of
      competence. Age and length of work experience had a positive but not very strong
      correlation with level of competence. According to the item analysis, the
      categories of the Nurse Competence Scale showed good internal consistency.
      CONCLUSION: The results provide strong evidence of the reliability and validity
      of the Nurse Competence Scale.

PMID- 15196187
TI  - Knowledge acquisition, synthesis, and validation: a model for decision support
      systems.
AB  - BACKGROUND: Decision tools such as clinical decision support systems must be
      built on a solid foundation of nursing knowledge. However, current methods to
      determine the best evidence do not include a broad range of knowledge sources. As
      clinical decision support systems will be designed to assist nurses when making
      critical decisions, methods need to be devised to glean the best possible
      knowledge. AIMS: This paper presents a comprehensive knowledge development
      process to develop a nursing clinical decision support system. DISCUSSION: The
      Nurse Computer Decision Support Project (N-CODES) is developing a prototype for a
      prospective decision support system. The prototype is being constructed on rules
      and cases generated by the best available evidence. To accommodate the range of
      decisions made in practice, different types of evidence are necessary. The
      process incorporates procedures to uncover, evaluate, and assimilate information
      to develop the knowledge domain for a clinical decision support systems. Both
      formal and practice-based knowledge are included. The model contains several
      innovative approaches including the use of clinical experts and a network of
      practicing clinicians. CONCLUSION: These strategies will assist scientists and
      practitioners interested in determining the best evidence to support clinical
      decision support systems.

PMID- 15196188
TI  - Nurse practitioner education: a research-based curriculum structure.
AB  - BACKGROUND: The process and content of nurse practitioner educational preparation
      has received scant research attention, despite increasing interest in and
      investigations into nurse practitioner services in Australia and internationally.
      AIMS: The aim of this paper is to report a study investigating the educational
      process and content required for nurse practitioner preparation. METHODS: A trial
      of practice was conducted with four nurse practitioner candidates over a 12-month
      period. The candidates practised in different specialities, giving rise to four
      models of the nurse practitioner role. The trial had multiple aims related to the
      role and scope of practice of the nurse practitioner. An action learning model
      was used, in which participating nurse practitioner candidates 'worked-into-the
      role' of extended practice and learned from experience through clinical
      mentoring, reflection and action. Data collection methods centred on transcripts
      from group work activities related to a collaborative engagement with and
      reflections on clinical practice. This resulted in the collaborative production
      of data to inform a research-based nurse practitioner curriculum structure.
      FINDINGS: The findings relate to the content and learning process required for
      nurse practitioner education and are described in terms of three broad areas of
      study: clinical practice, clinical sciences and nursing studies. CONCLUSIONS: A
      curriculum structure that describes content and process for nurse practitioner
      education was developed from the findings. A further outcome of this trial was
      confirmation of importance of the clinical environment for nurse practitioner
      education. Inherent in this aspect of clinical learning is the role of a
      committed clinical mentor who can facilitate purposeful learning.

PMID- 15196189
TI  - Developing lecturer practitioner roles using action research.
AB  - BACKGROUND: Lecturer Practitioner roles are well established in the United
      Kingdom. The national literature demonstrates that these staff are valuable to
      National Health Service trusts and universities however, their roles are busy and
      demanding, with conflicting expectations from the two employers. In addition,
      their role in addressing the theory-practice gap - a major reason for their
      establishment - is at best unclear. Although a number of qualitative studies have
      explored the topic, there have been no systematic attempts to develop the role or
      to quantify the effects on postholders. AIM: This paper reports a study that
      aimed to develop aspects of Lecturer Practitioners' work roles, examine the
      effects of this on individuals at one English university, and to quantify
      Lecturer Practitioners' occupational stress and burnout. METHODS: A flexible,
      'spiral' action research framework and 'collaborative group approach' were used,
      with mixed methods of data collection. Data were collected through focus groups,
      meetings and participant feedback, and participants' reflective diaries. A
      questionnaire using previously validated psychological attitude rating scales was
      also used to measure occupational stress and burnout, the extent to which the
      project influenced these, and the influence of Lecturer Practitioners' experience
      and qualifications. Six null hypotheses were constructed to measure these ideas.
      Findings from qualitative and quantitative perspectives were triangulated to give
      depth to the analysis. FINDINGS: Five themes emerged from the focus groups:
      personal motivation, workload pressures, role clarity, preparation and support,
      and gains from the role. Specific policies and documentation were developed as a
      result of this initial project planning work. The findings from the questionnaire
      indicated that Lecturer Practitioners were no more stressed or burnt out than
      comparable workers. Synthesis of findings indicated, broadly speaking, that these
      LPs were 'thriving rather than just surviving'. CONCLUSION: Action research was
      an effective methodology for uncovering new knowledge, and bringing about
      organizational change in this project.

PMID- 15196190
TI  - Parents' experiences of having a child with cleft lip and palate.
AB  - BACKGROUND: Giving birth to a child with cleft lip and palate (CLP) can be
      emotionally traumatic for parents. The facial appearance awakens feelings and
      reactions in the family and other people. Feeding these children in the neonatal
      period is known to be difficult. Previous research has mainly dealt with visual
      defects, feeding and speech problems. There is a lack of studies about parents'
      experiences of having a child with CLP. AIMS: This study was performed to
      investigate parents' experiences of having a child born with a cleft lip or CLP,
      and how they perceive encouragement and social and mental support from
      professionals, family and friends. METHOD: A phenomenographic approach was used.
      The study was performed at a university hospital in central Sweden. Twenty
      families (20 mothers and 12 fathers) were interviewed using guided interviews.
      FINDINGS: Two categories, consisting of three and two subcategories, emerged.
      Informants described their experiences of having a child with CLP, how they
      slowly adapted to this situation, the first meeting with their child, support
      from professionals, and reactions from family and other people. Parents commented
      on the craniofacial team with satisfaction. Due to a low level of knowledge,
      other professionals often had difficulty in handling the situation and a poor
      quality of advice on feeding was reported. Family and friends commented on the
      child positively or by being neutral, which was seen as a lack of interest. A
      visible scar on the face was seen as a problem, especially for girls. Most
      informants expressed anxiety about possible problems with speech. CONCLUSIONS:
      Parents did not look upon their child as handicapped but as having a congenital
      defect or 'flaw'. The findings of this study could be used in staff education to
      promote understanding of parents' experiences and how best to help them. They
      could also be used in the general media to improve public understanding. Future
      research could explore staff perceptions of this sensitive clinical area.

PMID- 15196191
TI  - Personal understandings of illness among people with type 2 diabetes.
AB  - BACKGROUND: Professionals and patients understand the experience of illness from
      different worlds. Professionals' explanatory models focus on aetiology,
      diagnosis, pathophysiology and treatment, while patients' explanatory models are
      more focused on consequences and influences on daily life. The differences
      between patients and professionals in their understanding often result in
      conflicting expectations about treatment, priorities and outcomes of care. AIM:
      The aim of this study was to describe personal understandings of illness among
      people with type 2 diabetes in Sweden. METHOD: A sample of 44 patients, 47-80
      years, diagnosed with type 2 diabetes within the last 2 years, was recruited from
      four health care centres. Narrative thematic interviews were used covering the
      areas of developing, coping with and living with diabetes. Qualitative content
      analysis was performed. FINDINGS: The findings were formulated into six
      categories: image of the disease, meaning of the diagnosis, integration of the
      illness, space for the illness, responsibility for care and future prospects.
      CONCLUSIONS: The findings demonstrate that patients' personal understanding of
      illness is an important complement to the traditional professional view of
      diabetes. They could serve as a foundation for development of health history
      interviewing, as well as development of systems of documentation. Patients'
      personal understandings of diabetes in their daily lives are considered to be an
      important shared source of information for planning meaningful care.

PMID- 15196192
TI  - Utilization of research findings by graduate nurses and midwives.
AB  - BACKGROUND: There is mounting pressure on nurses and midwives in the United
      Kingdom to use research findings to inform their practice. However, many still
      find research difficult to understand and are poorly prepared by education to
      make use of it. Hence, there is a pressing need to evaluate the research
      education included in nursing and midwifery curricula. AIM: This paper reports a
      study assessing the impact of research education on the attitudes towards
      research and use of research findings in practice by graduate nurses and
      midwives. METHOD: A cross-sectional survey using a self-completed postal
      questionnaire was conducted with a sample of 340 nurse and midwife graduates in
      the South East of England. FINDINGS: A response rate of 51% was obtained. A large
      number of respondents stated that their critical appraisal (96%) and search
      skills (87%) had improved following graduation and they reported using research
      findings in practice (16.8% all the time, 50.5% frequently and 32.6% sometimes).
      Furthermore, the majority expressed positive attitudes towards research and these
      were related to the research education received. However, a significant number
      reported finding statistics difficult to understand, lack of time to read
      research and limited access to research findings at their place of work. Also, a
      number of respondents would still like more help with searching the literature,
      implementing research findings in practice and developing their critical
      appraisal skills further. CONCLUSION: It is crucial that some of the major
      barriers to research utilization are addressed at both individual and
      organizational levels if evidence-based care is to become a reality. Also, health
      service managers should consider a number of strategies suggested by respondents
      to increase the use of research findings in clinical settings.

PMID- 15196193
TI  - Postdischarge nursing interventions for stroke survivors and their families.
AB  - BACKGROUND: The physical, cognitive, and emotional sequelae of stroke underscore
      the need for nursing interventions across the continuum of care. Although there
      are several published studies evaluating community interventions for stroke
      survivors, the nursing role has not been clearly articulated. AIM: The aim of
      this paper is to report a study to describe, using a standardized classification
      system, the nursing interventions used with stroke survivors during the initial 6
      weeks following discharge home. METHODS: In the context of a randomized
      controlled trial, two nurse case managers provided care to 90 community-dwelling
      stroke survivors who were assigned to the intervention arm of the trial. The
      nursing documentation was analysed, using the Nursing Intervention Classification
      (NIC) system, to identify and quantify the interventions that were provided.
      FINDINGS: Stroke survivors received, on average, six different interventions.
      There was a trend for those who were older, more impaired, and who lived alone to
      receive more interventions. The most commonly reported interventions included
      those directed towards ensuring continuity of care between acute and community
      care, family care, and modifying stroke risk factors. The study was limited to
      the nursing documentation, which may represent an underestimation of the care
      delivered. CONCLUSIONS: The NIC system was useful in capturing the interventions
      delivered by the nurse case managers. Nursing interventions are often not clearly
      articulated and less often use standardized terminology. Describing nursing
      activities in a standard manner will contribute to an increase in nursing
      knowledge and to evidence-based practice.

PMID- 15196194
TI  - Nurses' use of online clinical evidence.
AB  - BACKGROUND: The 'information explosion' presents a significant challenge to the
      nursing profession. One way to assist access to information is to provide
      electronic information resources at the point of care. A large-scale survey of
      nurses working in the public health system in New South Wales, Australia, was
      undertaken as part of a 2-year evaluation of the Clinical Information Access
      Program (CIAP). This is a website which provides 24 hour, online access to a
      range of evidence sources at the point of care. AIM: This paper reports a study
      to investigate factors influencing nurses' use of online evidence available at
      the point of care and to examine differences between nurses in different roles.
      METHOD: Nurses from 65 randomly selected hospitals were surveyed. A convenience
      sample representing 25% of nursing staff at these hospitals was sought. Eighty
      four per cent of the survey quota was met and 3128 questionnaires were completed
      and returned. RESULTS: The results showed that 58% of nurses had heard of the
      CIAP and, of those, 70% had used the website's resources. Senior nurses had
      greater awareness and use than others. The most frequent reasons for use were to
      fill a knowledge gap and for personal education. Lack of training was the most
      frequently cited reason for not using the website. Use of online evidence,
      particularly amongst senior staff, was higher than reported in previous studies.
      CONCLUSION: Use of online evidence was associated with nursing role, and with
      managerial and organizational support. Diffusion of innovation theory can help to
      explain some of the patterns observed. The use and impact of online evidence
      should be interpreted in the context of nursing practice and culture.

PMID- 15196195
TI  - Interdisciplinary preoperative patient education in cardiac surgery.
AB  - BACKGROUND: In 1998, we carried out a study of interdisciplinary preoperative
      education in cardiac surgery given by nurses, physicians and health educators.
      Overlaps were found in gathering and providing information by physicians, nurses
      and health educators, and gaps were found in providing psychosocial information
      and emotional support. Based on these findings, an information protocol was
      developed. AIM: This paper reports a study examining the effects of the
      implementation of the information protocol on the content and process of
      preoperative education. METHODS: Dialogues between health educators and patients
      were videotaped at the preoperative clinic (n = 54) and on the day of admission
      (n = 53), and analysed using a checklist of 123 specific topics. RESULTS: The
      information given by health educators at the outpatient clinic and on the day of
      admission accorded with the information protocol to a large extent. There was
      also an increase in the number of psychosocial issues raised. Nurses raised
      significantly more psychosocial issues in comparison with before implementation
      of the protocol. After implementation, patients spent approximately 3 minutes
      less talking with the health educator and about 7 minutes less talking with a
      nurse. This suggests that on the day of admission a more time-efficient co
      ordination in patient education was achieved. CONCLUSIONS: Implementation of the
      information protocol led to a better interdisciplinary division of labour. The
      education is tailored more to the needs of the patient, and psychosocial items
      are mentioned more frequently. This straightforward intervention gave very
      positive results. Inconsistencies, gaps and overlaps in information provision can
      be avoided by the unambiguous delineation of responsibilities and tasks in
      information provision by different health care providers.

PMID- 15196196
TI  - Characteristics of falls in hospitalized patients.
AB  - BACKGROUND: The high incidence of patient falls in a hospital setting is a major
      concern in any health system. Research findings have reported the risk factors
      for these falls as age, gender, certain medications, mental status, chronic
      diseases and environmental factors. Falls may lead to fear, pain, slight or
      severe injuries, increase the duration of hospital stay, cause patient discomfort
      and affect quality of life. AIM: The aim of this paper is to report a study of
      the characteristics of patient falls during hospitalization in 1998 and compare
      them with those in the period 1978-1981. METHODS: A retrospective study was
      performed in a large, 2000-bed medical center in Israel. Reports of 711 fall
      incidents in 1998 were compared with 328 reports in 1978-1981. Information
      gathered included age, gender, department, shift, reasons, severity of injury,
      tests and treatment after injury. RESULTS: The rates of falls per 1000 admissions
      in psychiatric, elder care and rehabilitation departments in 1998 were
      statistically significantly higher than in the earlier period. Rates of 115, 91,
      85, respectively, per 1000 admissions were reported in 1998 compared with 34, 9,
      19, respectively, in the period 1978-1981. The percentage of reported falls in
      the younger age group (under 50) was higher in the later survey (1998), and a
      higher proportion occurred outside the patient's room. Most of the reported falls
      in 1998 occurred during the morning shift (P < 0.001). CONCLUSIONS: The increased
      number of falls could be an outcome of increased awareness. Nevertheless, the
      causes and place of falls differ for the two periods. Some of the reasons may be
      related to an intervention programme carried out after the first survey. The
      latest survey results will serve as an important basis for a further intervention
      programme in specific departments to ensure patient safety.

PMID- 15196201
TI  - Cross-presentation: dendritic cells and macrophages bite off more than they can
      chew!
AB  - As immunologists, our knowledge of the molecular mechanisms which underlie the
      presentation of antigens derived from extracellular or 'exogenous' sources to CD8
      cytotoxic lymphocytes (CTL) has been limited. This process, termed 'cross
      presentation', has been linked to the elicitation of protective CTL responses
      against tumours and may be extremely important in generating immune responses
      against clinically relevant pathogens that do not infect tissues of haemopoietic
      origin. It is now known that cross-presentation of exogenous antigens on major
      histocompatibility complex (MHC) class I occurs through several distinct cellular
      pathways. In this review we outline and discuss some recent advances in our
      understanding of these pathways.

PMID- 15196202
TI  - The increased prevalence of allergy and the hygiene hypothesis: missing immune
      deviation, reduced immune suppression, or both?
AB  - Allergic atopic disorders, such as rhinitis, asthma, and atopic dermatitis, are
      the result of a systemic inflammatory reaction triggered by type 2 T helper (Th2)
      cell-mediated immune responses against 'innocuous' antigens (allergens) of
      complex genetic and environmental origin. A number of epidemiological studies
      have suggested that the increase in the prevalence of allergic disorders that has
      occurred over the past few decades is attributable to a reduced microbial burden
      during childhood, as a consequence of Westernized lifestyle (the 'hygiene
      hypothesis'). However, the mechanisms by which the reduced exposure of children
      to pathogenic and nonpathogenic microbes results in enhanced responses of Th2
      cells are still controversial. The initial interpretation proposed a missing
      immune deviation of allergen-specific responses from a Th2 to a type 1 Th (Th1)
      profile, as a result of the reduced production of interleukin-12 and interferons
      by natural immunity cells which are stimulated by bacterial products via their
      Toll-like receptors. More recently, the role of reduced activity of T regulatory
      cells has been emphasized. The epidemiological findings and the experimental
      evidence available so far suggest that both mechanisms may be involved. A better
      understanding of this question is important not only from a theoretical point of
      view, but also because of its therapeutic implications.

PMID- 15196203
TI  - Integrated immune responses to infection - cross-talk between human gammadelta T
      cells and dendritic cells.

PMID- 15196204
TI  - Polyinosinic-polycytidylic acid-mediated stimulation of human gammadelta T cells
      via CD11c dendritic cell-derived type I interferons.
AB  - The recognition of pathogen-associated molecular patterns (PAMPs) by the innate
      immune system is a crucial step in inducing effective immune responses. Double
      stranded RNA [mimicked by polyinosinic-polycytidylic acid (poly(I:C)],
      synthesized by various types of viruses, represents one important member of these
      immunostimulatory microbial components. Here we report that poly(I:C) has potent
      gammadelta T-cell costimulatory capacity. Within peripheral blood mononuclear
      cells, poly(I:C)-stimulated gammadelta T cells expressed increased levels of CD69
      and exhibited significantly enhanced antigen-mediated proliferation in response
      to isopentenylpyrophosphate (IPP). Among several recombinant cytokines tested,
      type I interferons (IFN-alpha, IFN-beta) and interleukin-15 (IL-15) showed a
      similar activation pattern of gammadelta T cells. gammadelta T-cell clones and
      purified gammadelta T cells did not respond to poly(I:C), indicating indirect
      effects of this compound. Depletion of CD11c(+) dendritic cells (DC), which
      express Toll-like receptor 3 (TLR3), known to recognize poly(I:C), abrogated
      poly(I:C)-mediated stimulation of gammadelta T cells. In addition, the
      supernatant of poly(I:C)-treated CD11c(+) DC was able to mimic the stimulatory
      effects of poly(I:C) on gammadelta T cells. Experiments with neutralizing
      antibodies indicated that type I IFNs, but not IL-15, contributed to the
      poly(I:C)-mediated activation of gammadelta T cells. In conclusion, gammadelta T
      cell activation by immunostimulatory double-stranded RNA, such as poly(I:C), is
      indirectly mediated via type I IFNs derived from TLR3-expressing CD11c(+) DCs.
      These results suggest that upon confrontation with certain viruses, gammadelta T
      cells can be rapidly activated by type I interferons and may contribute to
      effective antiviral responses.

PMID- 15196205
TI  - Inhibitory p41 isoform of invariant chain and its potential target enzymes
      cathepsins L and H in distinct populations of macrophages in human lymph nodes.
AB  - Activation of the CD4(+) T-cell mediated immune response relies on the
      proteolytic capacity of enzymes involved in modulating major histocompatibility
      complex (MHC) II-associated antigen presentation in antigen-presenting cells
      (APC). The MHC II-associated chaperone molecule p41 isoform of invariant chain
      (inhibitory p41 Ii) has been suggested to regulate stability and activity of
      cathepsin L in these APC. In the present study the human lymph node distribution
      of non-inhibitory p31 Ii and inhibitory p41 Ii have been compared by differential
      labelling, using two specific monoclonal antibodies. The distribution of p41 Ii,
      but not p31 Ii, matched the distribution of cathepsins L and H in subcapsular and
      cortical sinuses and germinal centres. Co-localization of p41 Ii with cathepsin H
      was confirmed in strongly CD68(+) sinus-lining macrophages, acting as APC.
      Furthermore, p41 Ii was determined together with cathepsins L and H in tingible
      body macrophages, highly phagocytic, but not antigen-presenting cells inside
      germinal centres. With respect to the physiological function that these two
      populations of macrophages have in human lymph nodes, our results support a
      regulatory function of p41 Ii towards cathepsins L and H in human macrophages,
      associated with the processes of phagocytosis rather than antigen presentation.

PMID- 15196206
TI  - Presentation of alpha-galactosylceramide by murine CD1d to natural killer T cells
      is facilitated by plasma membrane glycolipid rafts.
AB  - CD1 molecules are non-polymorphic major histocompatibility complex class I
      related proteins that bind and present glycolipid antigens to T-cell antigen
      receptors (TCR) expressed by alphabeta T cells or natural killer-like T cells
      (NKT). Anti-metastatic properties of NKT cells reactive to the CD1d-binding
      antigen alpha-galactosylceramide (alpha-GalCer) are now being explored as a
      contributor to tumour cell killing. In this study, we tested the hypothesis that
      presentation of alpha-GalCer by murine CD1d (mCD1d) to mCD1d-restricted NKT cells
      was facilitated by plasma membrane glycolipid rafts. Confocal microscopy of mCD1d
      transfected A20 B cells (A20mCD1d) demonstrated that mCD1d was raft-localized.
      This observation was confirmed by immunoblotting of raft fractions isolated on
      sucrose density gradients. Raft disruption by the cholesterol-binding agent
      nystatin, or short-chain ceramides, inhibited presentation of low concentrations
      of alpha-GalCer to NKT cells. Inhibition of antigen presentation was reversed by
      treatment of A20mCD1d cells with higher alpha-GalCer concentrations, or removal
      of raft-disrupting agents. These data indicate that partitioning of mCD1d into
      membrane rafts increases the capacity of antigen-presenting cells to present
      limiting quantities of glycolipid antigens, perhaps by stabilizing mCD1d/antigen
      structures on the plasma membrane and optimizing TCR engagement on NKT cells.

PMID- 15196207
TI  - Investigation of alpha nascent polypeptide-associated complex functions in a
      human CD8(+) T cell ex vivo expansion model using antisense oligonucleotides.
AB  - In order to determine molecules involved in the differentiation and proliferation
      of human CD8(+) cells, two ex vivo expansion models were established: coculture
      of freshly purified human CD8(+) cells with irradiated autologous feeders (AF) or
      stimulation with anti-CD3. Two different proliferation kinetics of CD8(+) cells
      and expression patterns of CD57 were observed between these conditions.
      Differential display reverse transcriptase-polymerase chain reaction was applied
      to investigate the differential expression of mRNA species between CD8(+) CD57(+)
      and CD8(+) CD57(-) populations. A differentially expressed RNA species called
      alpha nascent polypeptide associated complex (alpha NAC) was found at a higher
      level in CD8(+) CD57(-) cells than in CD8(+) CD57(+) cells. In the presence of
      AF, the expression of alpha NAC was reduced on culturing whilst proliferation
      increased. Similarly, in cultures stimulated with anti-CD3, alpha NAC reverted to
      its inactive form and differentiation and proliferation increased. Using a
      phosphorothioate-modified oligodeoxynucleotide antisense directed specifically
      against alpha NAC mRNA, protein expression was inhibited and increased CD8(+)
      cell proliferation and CD25 expression were observed irrespective of the culture
      conditions. This suggests that alpha NAC protein is antiproliferative molecule.
      This is the first description of the function of the alpha NAC protein in human
      CD8(+) T cells.

PMID- 15196208
TI  - Compound heterozygosity for Pten and SHIP augments T-dependent humoral immune
      responses and cytokine production by CD(4+) T cells.
AB  - Tight regulation of the phosphatidylinositiol 3-kinase (PI3K) pathway is
      essential not only for normal immune system development and responsiveness, but
      also in the prevention of immunopathology. Indeed, unchecked activation of the
      PI3K pathway in T cells induces lymphoproliferation and systemic autoimmunity.
      Evaluating the importance of threshold levels of two key PI3K pathway
      phosphoinositol phosphatases, we previously reported that mice heterozygous for
      both Pten and SHIP develop a more rapid progression of a lymphoproliferative
      autoimmune syndrome than do Pten(+?-) mice. Investigating the basis for this
      difference, we now describe a quantitative and qualitative difference in the
      antibody responses of C57BL?6 Pten(+?-) SHIP(+?-) mice upon challenge with a T
      dependent antigen. Suspecting that this phenotypic difference might be the
      result, at least in part, of a T-helper cell defect, an in vitro analysis of anti
      CD3/interleukin (IL)-2-expanded CD4(+) T cells was performed. After stimulation
      with anti-CD3, cells from mice heterozygous for both Pten and SHIP exhibited a
      striking increase in IL-4 secretion (> 10-fold), without a corresponding increase
      in T helper 2 (Th2) cell numbers being evident by intracellular staining for this
      cytokine. Modest increases were also seen for both IL-13 and IFN-gamma. Perhaps
      in keeping with this abnormal in vitro cytokine profile, IgG1 serum levels were
      significantly elevated in young C57BL?6 Pten(+?-) SHIP(+?-) mice. Thus, the
      relative levels of Pten and SHIP appear to be key variables in CD4(+) T-cell
      function, primarily via their ability to regulate IL-4 production.

PMID- 15196209
TI  - Understanding thymus-independent antigen-induced reduction of thymus-dependent
      immune responses.
AB  - Deficiencies in immune responses against polysaccharides can have direct
      consequences for patients, and therefore, a better understanding of these immune
      reactions is crucial. We have studied the immune response against the
      polysaccharide dextran B512 (Dx). Administration of immunogenic doses of thymus
      independent (TI) Dx reduces the immunoglobulin G1 response to later challenges
      with a thymus-dependent (TD) form of Dx. We investigated if this suppression is a
      general phenomenon caused not only by Dx but also by other TI antigens, and
      examined possible mechanisms contributing to this unresponsiveness. We show that
      clonal exhaustion is not involved in modulating subsequent responses, nor is
      signalling via FcgammaRIIB or other antibody mediated pathways. The reduced TD
      response is not an exclusive Dx phenomenon; it is also induced by TI antigen
      oxazolone (Ox). However, responses against the hapten dinitrophenyl (DNP) are not
      affected, indicating that the TI priming negative effect is not a general
      process. This may be explained by the restricted immune response to both Dx and
      Ox, in contrast to the unrestricted DNP response. Our conclusion from these
      experiments is that the underlying mechanism for the TI-induced reduction of
      latter TD responses is a property of the TI activation itself.

PMID- 15196210
TI  - Insights into the regulation of immunoglobulin light chain gene rearrangements
      via analysis of the kappa light chain locus in lambda myeloma.
AB  - Accumulating evidence indicates that B cells may undergo sequential
      rearrangements at the light chain loci, despite already expressing light chain
      receptors. This phenomenon may occur in the bone marrow and, perhaps, in germinal
      centers. As immunoglobulin (Ig)kappa light chains usually rearrange before
      Iglambda light chains, we analysed, by polymerase chain reaction, the Igkappa
      locus of bone marrow mononuclear cells from 29 patients with Iglambda myeloma to
      identify earlier recombinations in marrow plasma cells. The results demonstrated
      that Igkappa alleles were inactivated via the kappa-deleting element, presumably
      prior to V(kappa)-J(kappa) rearrangement, in many cases. Eighteen alleles (16
      myeloma clones, 55%) showed V(kappa)-J(kappa) rearrangements, with increased
      utilization of 5' distant V(kappa) and 3' distant Jkappa gene segments (Jkappa4,
      56%), an indication of multiple sequential rearrangements. In-frame, potentially
      functional V(kappa)-J(kappa) rearrangements were found in approximately one-third
      of available rearrangements (as expected by chance), each one in different
      myeloma clones: three were germline encoded, while one had several nucleotide
      substitutions, suggesting inactivation after the onset of somatic hypermutation.
      Three of four potentially functional V(kappa)-J(kappa)rearrangements involved
      V(kappa)4-1, a segment considered to be associated with autoimmunity. These
      findings provide insights into the regulation of light chain rearrangements and
      support the view that B cells may occasionally undergo sequential light chain
      rearrangements after the onset of somatic hypermutation.

PMID- 15196211
TI  - Toll-like receptor (TLR) expression and TLR-mediated cytokine/chemokine
      production by human uterine epithelial cells.
AB  - The objective of this study was to examine the expression of toll-like receptors
      (TLRs) by the uterine epithelial cell line ECC-1 and to determine if stimulation
      of the expressed TLRs induces changes in cytokine and/or chemokine secretion. The
      expression of TLR1 to TLR9 by ECC-1 cells was demonstrated by reverse
      transcription polymerase chain reaction, with only TLR10 not being expressed.
      Stimulation of ECC-1 cells using agonists to TLR2, TLR4 and TLR5 induced the
      expression of the chemokines interleukin-8 (IL-8) and monocyte chemotactic
      protein-1 (MCP-1), as well as the pro-inflammatory cytokine IL-6, and occurred in
      a dose-dependent manner. In response to zymosan and flagellin, pathogen
      associated molecular patterns (PAMP) that are recognized by TLR2 and TLR5
      respectively, ECC-1 cells secreted significantly more IL-8, MCP-1 and IL-6 than
      in response to other TLR agonists. In contrast, agonists to TLR3, TLR7, and TLR9
      had no effect on the secretion of the 13 cytokines or chemokines analysed. These
      results indicate that uterine epithelial cells are important sentinels of the
      innate immune system. Further it indicates that all but one of the known TLRs are
      expressed by ECC-1 cells and that stimulation through specific TLRs mediates
      changes in the expression of key chemokines and pro-inflammatory cytokines that
      aid in the defence of the uterus against potential pathogens.

PMID- 15196212
TI  - Expression of Epstein-Barr virus-induced gene 3 and other interleukin-12-related
      molecules by human intestinal epithelium.
AB  - Antigen-presenting cells, including dendritic cells, monocytes and macrophages,
      produce members of the interleukin-12 (IL-12) family that are important in
      initiating and maintaining cell-mediated immune responses. These include IL-12p35
      and p19 that dimerize with IL-12p40 to form IL-12 (also termed IL-12p75) and IL
      23, respectively, and Epstein-Barr virus-induced gene 3 (EBI3) protein (a protein
      related to IL-12p40), that forms a dimer with p28, termed IL-27. Intestinal
      epithelial cells, which are the initial site of contact between the host and
      enteric pathogens, can act as antigen-presenting cells, and are known to express
      mediators important in inflammatory and immune responses. In the current studies,
      we hypothesized that intestinal epithelial cells express members of the IL-12
      family, which can function as an early signalling system important in mucosal
      immunity. Using in vitro and in vivo model systems of human intestinal
      epithelium, we demonstrate the regulated expression of EBI3, IL-12p35 and p19 by
      human intestinal epithelial cells. However, intestinal epithelial cells do not
      coexpress IL-12p40 or p28 that are required to generate heterodimeric IL-12p75,
      IL-23 and IL-27. To the extent that IL-12p35, p19 and EBI3 cannot form IL-12p75,
      IL-23 or IL-27 heterodimers in intestinal epithelial cells, these data suggest
      that those cells may express other, currently unknown, molecules that can
      associate with EBI3, IL-12p35 and/or p19 or, alternatively, intestinal epithelial
      cells may release IL-12-related molecules that by themselves, or in combination
      with other molecules in the mucosal microenvironment, mediate biological
      activities.

PMID- 15196214
TI  - Ca influx shutdown in neutrophils induced by Fas (CD95) cross-linking.
AB  - In neutrophils, as in most other cell types, Ca(2+) signalling is important for a
      number of cellular activities. Although inositol(1,4,5)trisphosphate-mediated
      release of Ca(2+) from intracellular stores is a necessary prelude, it is the
      Ca(2+) influx that is responsible for many of the neutrophil responses. We report
      here that although elevations of cytosolic Ca(2+) do not accompany Fas-mediated
      apoptosis in neutrophils, the Ca(2+) influx component of the response to N-formyl
      methionyl-leucyl-phenylalanine (FMLP) becomes selectively inactived as the
      neutrophils progress towards accelerated apoptosis induced by Fas (CD95) cross
      linking. After 4 hr incubation at 37 degrees, untreated neutrophils display an
      exaggerated Ca(2+) influx phase in response to FMLP. This was absent in
      neutrophils that had been Fas-activated at the same time. No Ca(2+) influx
      component was demonstrable by the removal of extracellular Ca(2+) or by Ca(2+)
      channel blockade with Ni(2+) and no Mn(2+) influx was detectable. The defect
      could not be attributed to a decrease in receptor sensitivity, receptor coupling
      or receptor number because the release of stored Ca(2+) remained constant during
      incubation and was unaffected by Fas activation. Ca(2+) influx became uncoupled
      from store release before detectable gross morphological changes or phosphatidyl
      serine externalization and was also insensitive to caspase 3 and 8 inhibitors.
      These results suggest a mechanism other than caspase-mediated proteolytic damage
      to components important for Ca(2+) influx.

PMID- 15196213
TI  - Effect of an inhibitor of Jun N-terminal protein kinase, SP600125, in single
      allergen challenge in sensitized rats.
AB  - Jun N-terminal kinase (JNK) has been implicated in the pathogenesis of
      inflammatory diseases including asthma. We examined the effect of SP600125
      (anthra [1,9-cd] pyrazol-6 (2H)-one), a novel inhibitor of JNK in a model of
      asthma. Brown-Norway rats were sensitized to ovalbumin and treated with SP600125
      intraperitoneally (90 mg/kg in total). SP600125 inhibited allergen-induced,
      increased activity of phosphorylated c-jun but not of phosphorylated-MAPKAPK2,
      indicative of activation of p38 MAPK, in the lung. SP600125 inhibited macrophage
      (P < 0.04), lymphocyte (P < 0.05), eosinophil (P < 0.04) and neutrophil (P <
      0.005) numbers in bronchoalveolar lavage. Eosinophil and T-cell accumulation in
      the airways, mRNA expression for interleukin-1beta, tumour necrosis factor-beta,
      interleukin-3, interleukin-4 and interleukin-5, serum levels of allergen-specific
      immunoglobulin E and bronchial hyperresponsiveness were not affected by SP600125.
      Selective inhibition of JNK reduced inflammatory cell egress into the airway
      lumen after single allergen exposure. The role of JNK mitogen-activated protein
      kinase activation may be limited in the pathogenesis of bronchial
      hyperresponsiveness after single allergen exposure.

PMID- 15196215
TI  - Cellular immune responses induced in cattle by heterologous prime-boost
      vaccination using recombinant viruses and bacille Calmette-Guerin.
AB  - The development of novel vaccine strategies to replace or supplement bacille
      Calmette-Guerin (BCG) is urgently required. Here we study, in cattle, the use of
      heterologous prime-boost strategies based on vaccination with BCG and the
      mycobacterial mycolyl transferase Ag85A (Rv3804c) expressed either in recombinant
      modified vaccinia virus Ankara (MVA85A) or attenuated fowlpox strain FP9 (FP85A).
      Five different vaccination schedules were tested in the first experiment: MVA85A
      followed by BCG (group 1); BCG followed by MVA85A (group 2); BCG followed by
      FP85A and then MVA85A (group 3); MVA85A followed by MVA85A and then FP85A (group
      4); and FP85A followed by FP85A and then MVA85A (group 5). Vaccine-induced levels
      of cellular immunity were assessed by determining interferon-gamma (IFN-gamma)
      responses in vitro. Prime-boost protocols, using recombinant MVA and BCG in
      combination (groups 1-3), resulted in significantly higher frequencies of Ag85
      specific IFN-gamma-secreting cells than the two viral vectors used in combination
      (P=0.0055), or BCG used alone (groups 2 and 3, P=0.04). The T-cell repertoires of
      the calves in all five groups were significantly broader following heterologous
      booster immunizations than after the primary immunization. In a second
      experiment, the effects of BCG?MVA85A heterologous prime-boost vaccination were
      compared with BCG?BCG homologous revaccination. The results suggested a higher
      Ag85A-specific response with a wider T-cell repertoire in the MVA85A-boosted
      calves than in the BCG?BCG-vaccinated calves. In conclusion therefore, the
      present report demonstrates the effectiveness of heterologous prime-boost
      strategies based on recombinant MVA and BCG to induce strong cellular immune
      responses in cattle and prioritise such vaccination strategies for rapid
      assessment of protective efficacy in this natural target species of tuberculosis.

PMID- 15196216
TI  - Induction of nitric oxide release from the human alveolar epithelial cell line
      A549: an in vitro correlate of innate immune response to Mycobacterium
      tuberculosis.
AB  - In view of the presence of a large number of epithelial cells in the alveoli of
      the lung and their ability to produce various cytokines and chemokines, the
      possible role of alveolar epithelial cells in the innate immune response to
      tuberculosis was examined. The human alveolar epithelial cell line A549 was used
      as a model. The ability of A549 cells to induce nitric oxide (NO) in response to
      Mycobacterium tuberculosis infection was taken as an in vitro correlate of innate
      immunity. M. tuberculosis infection induced A549 cells to produce significant
      levels of NO and to express inducible nitric oxide synthase mRNA at 48 hr of
      infection. However, the amount of NO released at this point was not
      mycobactericidal. Cytokine stimulation (interferon-gamma, tumour necrosis factor
      alpha, interleukin-1beta, alone or in combination) of the infected A549 cells
      induced a higher concentration of NO. The study of colony-forming units (CFU) as
      a measure of the mycobactericidal capacity of A549 cells revealed a reduction in
      CFU of M. tuberculosis by 39.29% (from 10.62 +/- 0.48 - 6.392 +/- 0.54) following
      cytokine stimulation of the infected cells. Interestingly gamma-irradiated M.
      tuberculosis H37Rv could also induce higher than basal level of NO. Therefore we
      examined mycobacterial antigenic components for their possible role in NO
      production. We observed that A549 cells produced significantly higher amounts of
      NO at 48 hr when treated with mycobacterial whole cell lysates, cell wall or cell
      membrane preparations. The release of NO and the resultant mycobactericidal
      activity could be further enhanced by simultaneously conditioning the M.
      tuberculosis infected A549 cells with cytokine and mycobacterial components.
      These results suggest that alveolar epithelial cells respond to their
      microenvironment, which is constituted of various cytokines and macrophage
      processed antigens and may contribute to the innate immune response to
      tuberculosis.

PMID- 15196217
TI  - Echinococcus multilocularis proliferation in mice and respective parasite 14-3-3
      gene expression is mainly controlled by an alphabeta CD4 T-cell-mediated immune
      response.
AB  - The role of specific B lymphocytes and T-cell populations in the control of
      experimental Echinococus multilocularis infection was studied in micro MT, nude,
      T-cell receptor (TCR)-beta(-/-), major histocompatibility complex (MHC)-I(-/-)
      and MHC-II(-/-) mice. At 2 months postinfection, the parasite mass was more than
      10 times higher in nude, TCR-beta(-/-) and MHC-II(-/-) mice than in infected
      C57BL/6 wild-type (WT) mice, and these T-cell-deficient mice started to die of
      the high parasite load at this time-point. In contrast, MHC-I(-/-) and micro MT
      mice exhibited parasite growth rates similar to those found in WT controls. These
      findings clearly point to the major role that CD4(+) alphabeta(+) T cells play in
      limiting the E. multilocularis proliferation, while CD8(+) T and B cells appeared
      to play a minor role in the control of parasite growth. In the absence of T
      cells, especially CD4(+) or alphabeta(+) T cells, the cellular immune response to
      infection was impaired, as documented by the lack of hepatic granuloma formation
      around the parasite and by a decreased splenocyte responsiveness to concanavalin
      A (Con A) and parasite antigen stimulation. Surprisingly, in T-cell-deficient
      mice, the ex vivo expression of interferon-gamma (IFN-gamma) and other
      inflammatory cytokines (except for interleukin-6) were increased in association
      with a high parasite load. Thus, the relative protection mediated by CD4(+)
      alphabeta(+) T cells against E. multilocularis infection seemed not be IFN-gamma
      dependent, but rather to rely on the effector's function of CD4(+) alphabeta(+) T
      cells. The local restriction of parasite germinal cell proliferation was
      reflected by a regulatory effect on the expression of 14-3-3 protein within the
      parasite tissue in T-cell-deficient mice. These results provide a strong
      indication that the CD4(+) alphabeta(+) T-cell-mediated immune response
      contributes to the control of the parasite growth and to the regulation of
      production of the parasite 14-3-3 protein in metacestode tissues.

PMID- 15196222
TI  - The European Association for Cancer Education 17th annual scientific meeting.

PMID- 15196218
TI  - Prenatal exposure to bisphenol A up-regulates immune responses, including T
      helper 1 and T helper 2 responses, in mice.
AB  - The effect of prenatal exposure to bisphenol A (BPA) on the immune system in mice
      was investigated. Virgin female mice were fed varying doses of BPA, on a daily
      basis, over a period of 18 days commencing on the day of pairing with stud males
      (day 0). On day 77, their male offspring of 8 weeks were immunized with hen egg
      lysozyme (HEL). Three weeks later, anti-HEL immunoglobulin G (IgG) in sera, and
      proliferative responses of spleen cells to the antigen, were measured. Anti-HEL
      IgG2a and interferon-gamma (IFN-gamma), secreted from splenic lymphocytes, were
      measured as indicators of T helper 1 (Th1) immune responses, while anti-HEL IgG1
      and interleukin-4 (IL-4) were measured as indicators of Th2 responses. The
      results showed that fetal exposure to BPA was followed by significant increases
      in anti-HEL IgG as well as antigen-specific cell proliferation. Both Th1
      responses (including anti-HEL IgG2a and IFN-gamma production) and Th2 responses
      (including anti-HEL IgG1 and IL-4 production) were augmented by prenatal exposure
      to BPA, although the augmentation of Th1 responses appeared to be greater than
      that of Th2 responses. Two-colour flow cytometric analysis showed that mice
      exposed prenatally to BPA had 29% and 100% more splenic CD3(+) CD4(+) and CD3(+)
      CD8(+) cells, respectively, than control animals. Similar results were obtained
      from females whose mothers had consumed BPA during pregnancy. These results
      suggest that prenatal exposure to BPA may result in the up-regulation of immune
      responses, especially Th1 responses, in adulthood.

PMID- 15196219
TI  - Increased activation-induced cell death in peripheral lymphocytes of rheumatoid
      arthritis patients: the mechanism of action.
AB  - Recently, we have described a soluble survival signal for activated lymphocytes
      from CD14(+) cells. As a result of the importance of T lymphocytes in the
      pathogenesis of rheumatoid arthritis (RA), we speculate a possible role for
      CD14(+) cells in supporting the outgrowth of autoreactive lymphocytes in RA. To
      address this issue further, supernatants from activated CD14(+) cells (CD14
      cocktails) in both normal controls and RA patients were collected. The relative
      strength of the CD14 cocktails from normal controls and RA patients was compared.
      The data showed that depletion of CD14(+) cells resulted in a much higher
      increase of activation-induced cell death (AICD) and a decrease of lymphocyte
      proliferation in the peripheral blood mononuclear cells of RA patients compared
      to normal controls. Interestingly, CD14 cocktails from RA patients provide much
      stronger protection against AICD compared to those from normal controls. The
      observed soluble survival signal from CD14(+) cells is a general phenomenon
      because CD14 cocktails prevent both phytohaemagglutinin A-p- and anti-CD3-induced
      AICD. Furthermore, supernatants collected from human dendritic cell cultures also
      prevent activated lymphocytes from undergoing AICD. The data implicate an
      important role of the CD14(+) cell and its secreted form of survival signal in
      the pathogenesis of RA.

PMID- 15196224
TI  - Complementary and alternative medicine (CAM), cancer and group-based action: a
      critical review of the literature.
AB  - Interest in complementary and alternative medicine (CAM) continues to grow at an
      exponential rate despite the advances made by conventional medicine.
      Complementary and alternative medicine use is increasingly manifest across a wide
      range of health care settings, and is particularly prevalent in cancer and
      palliative care. In these arenas, patient groups and self-help organizations play
      a significant supportive role. There is evidence that they are a key informative
      and pragmatic resource in the provision of CAM services to patients. However,
      there is a significant paucity of research dealing with the functional aspects of
      these groups and the way in which they advocate, promote and supply CAM. In this
      paper we provide a critical review of the literature pertaining to themes around
      CAM provision and cancer care, and suggest that for a more complete picture of
      the field, the impact of group mediation of CAM needs to be addressed, and
      attention focused on the social and interactional dynamics that underpin these
      groups and organizations.

PMID- 15196225
TI  - How do cancer patients who try to take control of their disease differ from those
      who do not?
AB  - The objective of this study was to compare patients who do and do not describe
      their coping strategies as attempts to control their cancer. This was a cross
      sectional study of adult, oncology outpatients from an urban medical centre
      diagnosed 6-24 months previously. Using open-ended questions, we asked
      participants if they tried to 'control' their cancer or situation. If 'yes', how?
      If 'no', how had they 'dealt with' it? The Hospital Anxiety and Depression Scale
      (HAD) measured anxiety and depression. The Mental Adjustment to Cancer Scale
      (MAC) assessed six coping styles. Of the 44 participants, 57% were female. The
      mean age was 57 years. Eighteen (41%) said they used control strategies (control
      yes), 11 (25%) said they did not (control-no), and 15 (34%) gave unclear
      responses (control-unclear). Participants cited 97 different coping strategies
      that were grouped into proactive (e.g. lifestyle changes) and reactive strategies
      (e.g. stoic behaviour). In comparing these groups, the control-yes group was more
      likely to be younger (P = 0.0001), live with other(s) (P = 0.003), be confident
      of being cured (P = 0.006), have greater 'fighting spirit' on the MAC (P = 0.04)
      and use more proactive strategies (P = 0.0001). The conclusion of this study is
      that cancer patients use many coping strategies, but those who think of them as
      methods of control are younger and more confident of being cured, and use more
      proactive strategies.

PMID- 15196226
TI  - Reflections on serious illness as spiritual journey by survivors of
      haematological malignancies.
AB  - Although still in its infancy, research on spirituality is attracting increasing
      attention in health care. There are ongoing calls within the literature for
      research directed specifically toward clarifying what people mean by the word
      'spiritual' and how they express this dimension in their lives. The findings
      presented in this article respond to that call by presenting findings from a
      recent qualitative study on meaning-making in relation to serious illness
      conducted with survivors of haematological malignancies. The findings indicate
      that the language of a secular spiritual journey, rather than a conventional
      religious or theological conceptual framework, was used for meaning-making by the
      survivors interviewed. Such results affirm the recent definitional move away from
      conflating religion with spirituality, while pointing to the richness,
      complexity, and contradiction that individuals bring to their meaning-making. The
      findings provide important insights on the interpretation of spirituality for a
      group of individuals surviving the confrontation with death caused by a life
      threatening illness.

PMID- 15196227
TI  - Cancer patients' experiences of care related to pain management before and after
      palliative care referral.
AB  - Pain is the main problem for patients with cancer referred to palliative care
      (PC). Pain management in PC requires a multidimensional approach. A questionnaire
      was used to determine cancer patients' experiences of care related to pain
      management, before and after being referred to PC, and to also discover possible
      correlations between pain control and other aspects of care. Seventy-five
      consecutive patients from two PC teams were included in the study. The patients
      had experienced a statistically significant (P < 0.01) improvement in care after
      being referred to PC, despite the fact that pain control had not been optimized.
      Patients' description of 'pain control' after being referred to PC had a
      statistically significant correlation with their 'feeling of security' and
      'continuity of care' throughout the same period. The conclusion is that care
      provided in PC is vital to successful pain management. Pain control depends not
      only on analgesics but also on many other aspects of care provided by the nurse.
      Continuity of care and the opportunity to talk increases the patients' feeling of
      security, which is also of utmost importance to successful pain management.

PMID- 15196228
TI  - The changing face of cancer care in the UK: can nurses help to structure new
      services?
AB  - The concept of the lead cancer nurse is relatively new; no models of practice are
      available. An evaluation of lead cancer nurses was undertaken to identify core
      elements of success associated with this role. A two-stage multiple case study
      was used. In stage one, information was collected about post holders, working
      contexts, strategic aims and evidence of achievements from lead nurses, lead
      clinicians and senior nurses. Stage two explored the processes that enhanced and
      inhibited development of the lead nurse role. Site-visits were made to 12
      Macmillan lead cancer nurses throughout the UK. Detailed information from
      interviews, observations and documentary materials were analysed using a
      framework that emphasized four key areas: assessment of current service,
      promotion of evidence-based practice, contribution to strategic decision making
      and consumer perspectives. RESULTS: Enhancing factors important to the lead
      cancer nurses were the ability to: utilize decision-making power, build alliances
      and accommodate to a changing environment. Factors found to hinder achievement
      were: major changes in service and policy, restricted resources and the cancer
      site-specific structure of health service provisions. Further and greater
      contributions to cancer care from lead nurses require influential partnerships
      within local health care organizations and wider networks.

PMID- 15196229
TI  - Deprivation, comorbidity and survival in a cohort of patients with colorectal
      cancer.
AB  - We studied a regionally based cohort of 483 consecutive patients with colorectal
      cancer referred for chemotherapy and/or radiotherapy. These patients were
      assessed and managed according to consistent policies. We investigated the
      effects of socio-economic deprivation and comorbidity upon survival. Significant
      comorbidity was present in 48% of the patients. Overall survival and cause
      specific survival were summarized using Kaplan-Meier curves. Equality of survivor
      functions was assessed using the logrank procedure and Cox's proportional hazards
      analysis. In univariate analysis, the following variables significantly affected
      survival: comorbidity, performance status, age and clinical stage. We could find
      no correlation between deprivation and comorbidity. The presence of comorbidity
      significantly affected cause-specific survival (3-year cause-specific survival
      without comorbidity 54.2%; with comorbidity 44.6%). In adjusted analysis,
      deprivation had an independently adverse effect on overall survival, hazard ratio
      1.04 (95% confidence interval 1.00-1.08), but this was only of borderline
      statistical significance, P = 0.049. This study demonstrates that the
      interrelationships between comorbidity, deprivation and outcome in this group of
      patients are complex: even when care is readily available, patient assessments
      are uniform, and clinical decision making is consistent.

PMID- 15196230
TI  - Clarifying the term 'palliative' in clinical oncology.
AB  - The objective of this study was to clarify the term 'palliative' in clinical
      oncology. A qualitative study design with in-depth interviews was applied. The
      study sample included 30 cancer patients and 16 physicians. In clinical oncology,
      the use of the term 'palliative' to describe both anticancer treatments and
      palliative care may cause confusion and misunderstanding. Different aspects of
      palliative care, as expressed by the WHO definition, are not so easily
      recognizable with regard to palliative oncological treatments. Furthermore, the
      fact that the same anticancer treatments can be given to patients with palliative
      or curative intention is confusing. The distinction between curative and
      palliative oncological treatments is of crucial importance for the treatment
      decision-making process. Close consideration of the use of the term 'palliative'
      will help to clarify the various goals of treatment and care in oncological
      practice.

PMID- 15196231
TI  - The experience of radiotherapy for localized prostate cancer: the men's
      perspective.
AB  - The aim of this study is to examine the experiences of men treated with
      radiotherapy for localized prostate cancer. The recognition that little research
      has been carried out about the impact of illness in men, or how they recover
      following radical treatment, forms the basis for this study. The objectives of
      this study are to explore men's experiences of radiotherapy for prostate cancer
      and to consider if current services meet the needs of these men. This
      investigation took the form of a descriptive qualitative approach using focus
      groups. The focus group meetings were audiotaped and a qualitative thematic
      analysis of transcripts was carried out. The analysis of the data yielded five
      themes that were common to most of the men. The findings from this study suggest:
      a fragmented approach to the overall care and treatment for men with prostate
      cancer; a need to evaluate the provision of information and identify areas for
      improvement in all areas of practice; and an holistic approach to examine each
      aspect of the patient's journey.

PMID- 15196232
TI  - The clinical and epidemiological burden of chronic lymphocytic leukaemia.
AB  - The purpose of this literature review was to identify and summarize published
      studies describing the epidemiology and management of chronic lymphocytic
      leukaemia (CLL). Chronic lymphocytic leukaemia represents 22-30% of all leukaemia
      cases with a worldwide incidence projected to be between < 1 and 5.5 per 100,000
      people. Australia, the USA, Ireland and Italy have the highest CLL incidence
      rates. Chronic lymphocytic leukaemia presents in adults, at higher rates in males
      than in females and in whites than in blacks. Median age at diagnosis is 64-70
      years. Five-year survival rate in the USA is 83% for those < 65 years old and 68%
      for those 65 + years old. Hereditary and genetic links have been noted. Persons
      with close relatives who have CLL have an increased risk of developing it
      themselves. No single environmental risk factor has been found to be predictive
      for CLL. Patients are usually diagnosed at routine health care visits because of
      elevated lymphocyte counts. The most common presenting symptom of CLL is
      lymphadenopathy, while difficulty exercising and fatigue are common complaints.
      Most patients do not receive treatment after initial diagnosis unless presenting
      with clear pathologic conditions. Pharmacological therapy may consist of
      monotherapy or combination therapy involving glucocorticoids, alkylating agents,
      and purine analogs. Fludarabine may be the most effective single drug treatment
      currently available. Combination therapy protocols have not been shown to be more
      effective than fludarabine alone. As no cure is yet available, a strong unmet
      medical need exists for innovative new therapies. Experimental treatments under
      development include allogeneic stem cell transplant, mini-allogeneic transplants,
      and monoclonal antibodies (e.g. alemtuzumab against CD52; rituximab against
      CD20).

PMID- 15196236
TI  - The candidate gene approach: have murine models informed the study of human SLE?
AB  - Genome wide linkage studies in human SLE have identified seven highly significant
      loci linked to SLE, and more than 20 other loci showing suggestive linkage to
      disease. However, pin-pointing the susceptibility alleles in candidate genes
      within these linkage regions is challenging, due the genetic heterogeneity,
      racial differences and environmental influences on disease aetiology. Utilization
      of murine models of spontaneous lupus nephritis provide a complementary approach,
      which may then identify candidate genes for analysis in human cases. This review
      highlights the utility of cross-species approach to identify and characterize the
      effect of given candidate genes in lupus. The examples described in this review
      demonstrate the importance of bringing together both genetic and functional
      information in human and mouse studies.

PMID- 15196237
TI  - Menage a trois of bacterial and viral pulmonary pathogens delivers coup de grace
      to the lung.

PMID- 15196238
TI  - Influence of the route of sensitization on local and systemic immune responses in
      a murine model of type I allergy.
AB  - The pathophysiological and immunological characteristics of allergic immune
      responses are controlled by a variety of factors. We have studied the extent to
      which the route of sensitization influences allergen-specific IgE synthesis and
      local airway inflammation using a mouse model of allergic sensitization to the
      major birch pollen allergen Bet v 1. Sensitization of BALB/c mice with
      recombinant (r)Bet v 1 was performed using intraperitoneal (i.p.), subcutaneous
      (s.c.) or aerosol (a.s.) sensitization protocols. Mice were analysed for allergen
      specific serum antibodies by ELISA and IgE-dependent basophil degranulation.
      Proliferative responses and cytokine production of splenocytes were measured upon
      Bet v 1 stimulation in vitro. Bronchoalveolar lavages were performed after airway
      challenge with aerosolized birch pollen extract for assessment of eosinophilic
      airway inflammation and local cytokine production in vivo. Highest allergen
      specific IgE levels and IgE-dependent basophil degranulation were achieved using
      the SC route. High IL-5 production by spleen and lung cells was associated with
      pronounced eosinophilia in bronchoalveolar lavages. After i.p. sensitization,
      despite giving the highest IgG levels, only low IgE levels, basophil
      degranulation and IL-5 production were seen. On the other hand, a.s.
      sensitization, resulting in the lowest systemic IgE and IL-5 levels, led to a
      comparably strong airway inflammation as the s.c. route. Our finding that the
      route of sensitization can result in a dissociation of local and systemic immune
      responses may contribute to a better understanding of the pathogenesis of
      allergic diseases and help to develop new treatment strategies.

PMID- 15196239
TI  - Mast cells at the host-pathogen interface: host-protection versus immune evasion
      in leishmaniasis.
AB  - Infection of a susceptible host with Leishmania, a protozoan parasite, causes the
      disease leishmaniasis, which is characterized by neutrophil, eosinophil,
      macrophage, lymphocyte and mast cell infiltration into the infected tissue
      followed by parasite growth. Although the roles played by other cells in
      leishmaniasis are known, the role of mast cells remains to be ascertained. Here,
      we demonstrate that Leishmania regulates mast cell infiltration to the site of
      infection, mast cell production and mast cell function resulting in differential
      growth of the parasite in resistant (C57BL/6 or CBA/T6T6) and susceptible
      (BALB/c) macrophages. An interleukin-3-dependent augmentation in mast cell
      committed progenitors is observed in BALB/c but not in C57BL/6 mice during
      Leishmania infection. The mast cell supernatants inhibit IFN-gamma-dependent
      restriction of Leishmania growth in macrophages in BALB/c mice whereas the
      reverse phenomenon occurs in C57BL/6 mice. Our data reveals a different facet of
      host-pathogen interaction.

PMID- 15196240
TI  - Recombinant Mycobacterium bovis bacillus Calmette-Guerin (BCG) expressing mouse
      IL-18 augments Th1 immunity and macrophage cytotoxicity.
AB  - Interleukin-18 (IL-18) has been demonstrated to synergize with BCG for induction
      of a T-helper-type 1 (Th1) immune response. Since successful treatment of
      superficial bladder cancer with BCG requires proper induction of Th1 immunity, we
      have developed a recombinant (r) BCG strain that functionally secretes mouse (m)
      IL-18. This rBCG-mIL-18 strain significantly increased production of the major
      Th1 cytokine IFN-gamma in splenocyte cultures, at levels comparable to that
      elicited by control BCG plus exogenous rIL-18. IFN-gamma production by
      splenocytes was eliminated by addition of neutralizing anti-IL-18 antibody.
      Endogenous IL-12 played a favourable role whereas IL-10 played an adverse role in
      rBCG-mIL-18-induced IFN-gamma production. Enhanced host antimycobacterial
      immunity was observed in mice infected with rBCG-mIL-18 which showed less splenic
      enlargement and reduced bacterial load compared to control mice infected with
      BCG. Further, splenocytes from rBCG-mIL-18-infected mice, in response to BCG
      antigen, displayed increased production of IFN-gamma and GMCSF, decreased
      production of IL-10, elevated cellular proliferation and higher differentiation
      of IFN-gamma-secreting cells. rBCG-mIL-18 also enhanced BCG-induced macrophage
      cytotoxicity against bladder cancer MBT-2 cells in a dose-dependent manner.
      Neutralizing all endogenous macrophage-derived cytokines tested (IL-12, IL-18 and
      TNF-alpha) as well as IFN-gamma severely diminished the rBCG-mIL-18-induced
      macrophage cytolytic activity, indicating a critical role for these cytokines in
      this process. Cytokine analysis for supernatants of macrophage-BCG mixture
      cultures manifested higher levels of IFN-gamma and TNF-alpha in rBCG-mIL-18
      cultures than in control BCG cultures. Taken together, this rBCG-mIL-18 strain
      augments BCG's immunostimulatory property and may serve as a better agent for
      bladder cancer immunotherapy and antimycobacterial immunization.

PMID- 15196241
TI  - Acute infection with influenza virus enhances susceptibility to fatal pneumonia
      following Streptococcus pneumoniae infection in mice with chronic pulmonary
      colonization with Pseudomonas aeruginosa.
AB  - We established a mouse model in which fatal pneumonia was induced by pneumococcal
      superinfection following influenza virus infection in chronic Pseudomonas
      aeruginosa infected mice. In this mouse model, influenza virus infection caused a
      significant increase in inflammatory cells, cytokines and severe tissue damage in
      the lungs of these P. aeruginosa infected mice, before pneumococcal infection.
      Intrapulmonary virus titres were significantly increased in mice with chronic P.
      aeruginosa infection, compared with control mice. Neutrophil function analysis
      showed significant reduction of myeloperoxidase (MPO) activity and lysozyme
      secretion by influenza virus infection in these mice. Our results suggest that
      influenza virus infection may play an important role in inducing pneumococcal
      pneumonia in chronic P. aeruginosa infected mice. Our results suggested that our
      mouse model is useful for investigating the pathogenesis of influenza virus
      infection in patients with chronic lung infection.

PMID- 15196242
TI  - Murine viral hepatitis involves NK cell depletion associated with virus-induced
      apoptosis.
AB  - Mouse hepatitis virus type 3 (MHV3), a coronavirus, is an excellent animal model
      for the study of immunological disorders related to acute and chronic hepatitis.
      In this study, we have verified if the fulminant hepatitis induced by MHV3 could
      be related to an impairment of innate immunity. Groups of three C57BL/6 mice were
      infected with the pathogenic L2-MHV3 or attenuated YAC-MHV3 viruses, and the
      natural killer (NK) cell populations from liver, spleen and bone marrow were
      analysed. The percentage of intrahepatic NK1.1(+)T cell receptor (TCR)- cells did
      not increase while NK1.1(+)TCR(inter) cells decreased in both L2-MHV3- and YAC
      MHV3-infected mice. Concurrently, splenic and myeloid NK1.1+ cells decreased in
      L2-MHV3-infected mice. However, the cytotoxic activity of NK cells increased in
      liver and decreased in bone marrow from pathogenic L2-MHV3-infected mice while no
      modification was detected in YAC-MHV3-infected mice. Flow cytometric analysis
      revealed that both normal and larger splenic or myeloid NK cells decreased more
      in pathogenic L2-MHV3-infected mice than in attenuated YAC-MHV3-infected mice. In
      vitro viral infections of interleukin (IL)-15-stimulated lymphoid cells from
      liver and bone marrow revealed that L2-MHV3 induced higher decreases in cell
      viability of NK1.1+ cells than the YAC-MHV3 variant. The NK cell decreases were
      due to the viral permissivity leading to cytopathic effects characterized by cell
      rounding, syncytia formation and apoptosis. Larger NK+ syncytia were observed in
      L2-MHV3-infected cells than in YAC-MHV3-infected cells. These results suggest
      that NK cell production is impaired by viral infection favouring fulminant
      hepatitis.

PMID- 15196243
TI  - Dietary fructooligosaccharides up-regulate immunoglobulin A response and
      polymeric immunoglobulin receptor expression in intestines of infant mice.
AB  - We examined whether or not dietary fructooligosaccharides (FOS) in infancy can
      have a beneficial effect on the mucosal immune system. Newborn BALB/c mice,
      accompanied by their dams until 21 days of age, were fed either a control diet
      based on casein [FOS- diet group] or a FOS- diet supplemented with 5% (w/w) FOS
      [FOS+ diet group]. Total IgA levels in tissue extracts from the intestines of
      mice in the FOS+ diet group at 38 days of age were about twofold higher (P <
      0.05) than those in the FOS- diet group in the jejunum, ileum and colon. Ileal
      and colonic polymeric immunoglobulin receptor (pIgR) expression in the FOS+ diet
      group at 36 days of age was 1.5-fold higher than in the FOS- diet group (P <
      0.05). Consistent with these results, the ileal IgA secretion rate of the FOS+
      diet group at 37 days of age was twofold higher than that of the FOS- diet group
      (P < 0.05). Moreover, the percentage of B220(+)IgA+ cells in Peyer's patches (PP)
      was significantly higher in the FOS+ diet group than in the FOS- diet group
      (6.2%versus 4.3%, P < 0.05), suggesting that isotype switching from IgM to IgA in
      PP B cells might be enhanced in vivo. Taken together, our findings suggest that
      dietary FOS increases the intestinal IgA response and pIgR expression in the
      small intestine as well as the colon in infant mice.

PMID- 15196244
TI  - Adjuvant oil induces waves of arthritogenic lymph node cells prior to arthritis
      onset.
AB  - A single intradermal injection of the adjuvant-oil squalene induces T cell
      mediated arthritis in DA rats. The chain of events leading from nonspecific
      provocation of the immune system to arthritis is largely unknown. Previous
      studies have demonstrated that lymph node (LN) cells are of pathogenic
      importance, i.e. cells from LNs draining the injection site can transfer
      arthritis to naive DA rats. Recently we have demonstrated cellular uptake of
      adjuvant oil in draining lymph nodes but also that nondraining LNs become
      hyperplastic and harbour arthritogenic cells. Here, we aimed to determine from
      which time-point prior to arthritis onset arthritogenic cells appear in draining
      inguinal and nondraining axillary/brachial LNs, respectively. We demonstrated
      that the ability to transfer arthritis was strongly dependent on the time-point
      after adjuvant-injection with clear-cut differences between draining and
      nondraining LN cells. Cells harvested at day 5 postinjection (p.i) were not able
      to transfer arthritis, while at day 8 p.i, a first wave of arthritogenic cells
      appeared in draining LNs. The ability to transfer arthritis was associated with a
      pro-inflammatory cytokine profile as indicated by the IL-1beta and IFNgamma
      expression in cells from draining LNs. Subsequently, at day 11 p.i., just before
      arthritis onset, arthritogenic cells appeared also in nondraining LNs. These
      results shed new light on the induction of arthritic diseases, implicating a two
      step mechanism for the development of pathogenic cells. Firstly, a pro
      inflammatory burst in responding lymphoid organs leading to a local pool of
      arthritogenic cells and, secondly, a transmission of arthritogenecity to other
      LNs and precipitation of disease in peripheral joints.

PMID- 15196245
TI  - Joint cytokine quantification in two rodent arthritis models: kinetics of
      expression, correlation of mRNA and protein levels and response to prednisolone
      treatment.
AB  - Biomarker quantification in disease tissues from animal models of rheumatoid
      arthritis (RA) can help to provide insights into the mechanisms of action of
      novel therapeutic agents. In this study we validated the kinetics of IL-1beta,
      TNF-alpha and IL-6 mRNA and protein expression levels in joints from DBA/1OlaHsd
      murine collagen-induced arthritis (CIA) and Lewis rat Streptococcal cell wall
      (SCW)-induced arthritis by real-time polymerase chain reaction (PCR) TaqMan and
      Enzyme-linked immunosorbent assay (ELISA). Prednisolone was used as a reference
      to investigate any correlation between clinical response and cytokine levels at
      selected time-points. To our knowledge this is the first report showing a close
      pattern of expression between mRNA and protein for IL-1beta and IL-6, but not for
      TNF-alpha, in these two models of RA. The kinetics of expression for these
      biomarkers suggested that the optimal sampling time-points to study the effect of
      compounds on both inflammation and cytokine levels were day 4 postonset in CIA
      and day 3 after i.v challenge in SCW-induced arthritis. Prednisolone reduced
      joint swelling through a mechanism associated with a reduction in IL-1beta and IL
      6 protein and mRNA expression levels. At the investigated time points, protein
      levels for TNF-alpha in arthritic joints were lower than the lower limit of
      detection of the ELISA, whereas mRNA levels for this cytokine were reliably
      detected. These observations suggest that RT-PCR TaqMan is a sensitive technique
      that can be successfully applied to the quantification of mRNA levels in rodent
      joints from experimental arthritis models providing insights into mechanisms of
      action of novel anti-inflammatory drugs.

PMID- 15196246
TI  - Dendritic cells overexpressing Fas-ligand induce pulmonary vasculitis in mice.
AB  - Dendritic cells (DC) genetically engineered to express Fas (CD95) ligand (FasL
      DC) have been proposed as immunotherapeutic tools to induce tolerance to
      allografts. However, we and others recently showed that FasL-DC elicit a vigorous
      inflammatory response involving granulocytes and can promote Th1-type CD4+ and
      cytotoxic CD8+ T lymphocytes. This prompted us to evaluate the pathology induced
      by intravenous injection of FasL-DC in mice. We observed that FasL-DC obtained
      after retroviral gene transfer of bone marrow precursors derived from Fas
      deficient C57Bl/6 mice induce massive pulmonary inflammation and pleuritis one
      day after a single intravenous injection in C57Bl/6 mice. Two months later, all
      mice presented granulomatous vasculitis of small to medium sized vessels,
      alveolar haemorrhage and pleuritis. In these lesions, apoptotic bodies were found
      in large number. Anti-neutrophilic cytoplasmic and anti-myeloperoxidase
      autoantibodies were not detected. This study documents that intravenous injection
      of FasL-DC causes severe lung granulomatous vasculitis. This new animal model for
      vasculitis is inducible, highly reproducible and shares many features with human
      Wegener granulomatosis. This model may be an appropriate tool to further
      investigate the pathogenesis of vasculitis and test new therapeutic strategies.
      Moreover, our findings highlight the potential severe complications of FasL-DC
      based immunotherapy.

PMID- 15196247
TI  - Differential regulation of mast cell cytokines by both dexamethasone and the p38
      mitogen-activated protein kinase (MAPK) inhibitor SB203580.
AB  - Activated mast cells generate multiple cytokines but it is not known if these can
      be differentially regulated by pharmacological agents. We report here that the
      glucocorticoid dexamethasone (DEX) preferentially inhibited Ag-induced expression
      of IL-4 and IL-6 mRNA relative to TNF-alpha mRNA in RBL-2H3 cells. Likewise, the
      drug more readily inhibited release of IL-4 than TNF-alpha protein. SB203580, an
      inhibitor of p38 mitogen-activated protein kinase (MAPK), enhanced Ag-induced TNF
      alpha mRNA expression without affecting IL-4 or IL-6 mRNA. At the protein level,
      SB203580 exerted little effect on TNF-alpha release but inhibited IL-4 release;
      notably, the ratio of TNF-alpha : IL-4 increased markedly with the concentration
      of SB203580, confirming the differential regulation of these cytokines. PD98059,
      an inhibitor of MAPK kinase (MEK), a component of the p44/42 MAPK pathway,
      partially inhibited Ag-induced expression of mRNA for all three cytokines while
      cyclosporin A inhibited Ag-induced IL-4 and IL-6 mRNA more readily than TNF-alpha
      mRNA. Ag activation of the cells led to phosphorylation of p38 and p44/42 MAPK
      but this was not influenced by DEX. In conclusion, mast cell cytokines can be
      differentially regulated pre- and post-translationally by DEX and SB203580 but
      there does not appear to be a direct mechanistic link between the actions of
      these two drugs.

PMID- 15196248
TI  - Polyreactive antigen-binding B (PAB-) cells are widely distributed and the PAB
      population consists of both B-1+ and B-1- phenotypes.
AB  - B cells that make polyreactive antibodies (PAB+ cells) express polyreactive Ig
      receptors on their surface and can bind a variety of different antigens. The
      present study shows that PAB+ cells are widely distributed, are present in
      varying numbers in different lymphoid organs and that their phenotype varies
      depending on the organs from which they are isolated. Up to 10 times more cells
      in PAB+ enriched populations bind antigens as compared to PAB- populations.
      Comparison of PAB+ with B-1+ cells showed that a high percentage of PAB+ cells
      are B-1+, but that many PAB+ cells do not express B-1 cell surface markers and,
      in fact, are B-1-. It is concluded that the B cell population consists of PAB+/B
      1+, PAB+/B-1-, PAB-/B-1+, and PAB-/B-1- cells. The presence of PAB+ cells in the
      thymus points to the possibility that PAB+ cells may carry endogenous host
      antigens from peripheral tissues to the thymus where they may contribute to
      immunological tolerance.

PMID- 15196249
TI  - The tetraspanin CD9 is preferentially expressed on the human CD4(+)CD45RA+ naive
      T cell population and is involved in T cell activation.
AB  - Human CD4+ T cells can be divided into reciprocal memory and naive T cell subsets
      based on their expression of CD45 isoforms and CD29/integrin beta1 subunit. To
      identify unique cell surface molecules on human T cells, we developed a new
      monoclonal antibody termed anti5H9. Binding of anti5H9 triggers a co-stimulatory
      response in human peripheral blood T cells. Retrovirus-mediated expression
      cloning has revealed that the antigen recognized by anti5H9 is identical to the
      tetraspanin CD9. We now show that human CD9 is preferentially expressed on the
      CD4(+)CD45RA+ naive T cell subset, and that CD9(+)CD45RA+ T cells respond
      preferentially to the recombinant beta2-glycoprotein I, compared to CD9-CD45RA+ T
      cells. Furthermore, anti5H9 inhibits both the recombinant beta2-glycoprotein I-
      and the recall antigen tetanus toxoid-specific T cell proliferation. These
      results suggest that the tetraspanin CD9 plays an important role in T cell
      activation.

PMID- 15196250
TI  - Iron down-regulates macrophage anti-tumour activity by blocking nitric oxide
      production.
AB  - Although the inhibitory effect of iron on macrophage production of tumoricidal
      free radical nitric oxide (NO) has been reported, its possible influence on
      macrophage anti-tumour activity has not been established. In the present study,
      FeSO4 markedly reduced IFN-gamma + LPS-induced NO synthesis in mouse and rat
      macrophages. The effect of iron coincided with the loss of macrophage cytotoxic
      activity against NO-sensitive C6 rat astrocytoma and L929 mouse fibrosarcoma cell
      lines, as measured by MTT assay for cellular respiration and the crystal violet
      test for cell viability. Tumour cell survival did not improve further in the
      presence of FeSO4 if macrophage NO release and cytotoxicity were already blocked
      by aminoguanidine. In accordance with the results obtained with exogenous iron,
      cell membrane permeable iron chelator o-phenanthroline enhanced both macrophage
      NO release and anti-tumour activity. Iron also down-regulated NO production and
      increased the viability of L929 fibrosarcoma cells stimulated with IFN-gamma +
      LPS in the absence of macrophages. However, neither NO release nor cell viability
      was affected by iron addition to cultures of the C6 astrocytoma cell line. Iron
      was unable to prevent L929 and C6 cell death induced by the NO releasing
      chemicals SNP and SIN-1, indicating that iron-mediated inhibition of NO
      synthesis, rather than interference with its cytotoxic action, was responsible
      for the protection of tumour cells. Collectively, these results indicate that
      iron might protect tumour cells by reducing both macrophage and tumour cell
      derived NO release.

PMID- 15196252
TI  - B and T cell responses elicited by monoclonal anti-idiotypic antibody (Ab2beta)
      mimicking gp43 from Paracoccidioides brasiliensis.
AB  - Paracoccidioidomycosis is a systemic mycosis endemic in Latin America, with a
      high prevalence in Brazil, Argentina, Colombia and Venezuela. The aetiological
      agent of disease is the thermal dimorphic fungus, Paracoccidioides brasiliensis.
      A glycoprotein of 43 kD (gp43) is the major antigen of P. brasiliensis.
      Antibodies directed to this antigen are detected in the sera of all patients with
      paracoccidioidomycosis (PCM). Recently, it has been shown that mice immunized
      with anti-gp43 monoclonal antibodies (MAbs) (Ab1), induce the idiotypic cascade
      in the gp43 system, which produced both, anti-Id antibodies (Ab2) and anti-anti
      Id antibodies (Ab3). To further characterize the idiotypic cascade modulation in
      mice immunized with anti-gp43 MAb 17c, hybridomas were produced. Ab2 MAbs named
      7.B12 inhibited (>95%) the binding of gp43 to MAb 17c (Ab1), suggesting that this
      anti-Id MAb bind to the idiotope, thus fulfilling the internal image criteria. To
      elucidate whether Ab2 MAb could act as antigen in serological assays, instead of
      gp43, sera from PCM patients were tested. Using an ELISA test, it was observed
      that antibodies from patients and not normal serum bound to Ab2. However, the
      ELISA test using Ab2 bound to the solid phase made possible to serologically
      monitor the patients after antifungal therapy, showing an equivalent curve when
      compared with ELISA test employing purified gp43. Our results also showed that,
      when mice were immunized with Ab2beta and their cells were exposed to gp43 in
      vitro, a T cell proliferation response was observed.

PMID- 15196251
TI  - Systemic complement activation following human acute ischaemic stroke.
AB  - The brain tissue damage after stroke is mediated partly by inflammation induced
      by ischaemia-reperfusion injury where the complement system plays a pivotal role.
      In the present study we investigated systemic complement activation and its
      relation to C-reactive protein (CRP), a known complement activator, and other
      inflammatory mediators after acute ischaemic stroke. Sequential plasma samples
      from 11 acute stroke patients were obtained from the time of admittance to
      hospital and for a follow-up period of 12 months. Nine healthy gender- and age
      matched subjects served as controls. The terminal SC5b-9 complement complex
      (TCC), CRP, soluble adhesion molecules (L-, E- and P- selectin, ICAM, VCAM) and
      cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-8] were
      analysed. All parameters were within normal values and similar to the controls
      the first hours after stroke. Terminal complement complex (TCC) increased
      significantly from 0.54 to 0.74 AU/ml at 72 h (P = 0.032), reached maximum at 7
      days (0.90 AU/ml, P < 0.001), was still significantly increased at 12 days (0.70
      AU/ml, P = 0.009) and thereafter normalized. CRP increased significantly from
      1.02 to 2.11 mg/l at 24 h (P = 0.023), remained significantly increased for 1
      week (2.53-2.94 mg/l, P = 0.012-0.017) and thereafter normalized. TCC and C
      reactive protein (CRP) correlated significantly (r = 0.36, P < 0.001). The
      increase in TCC and CRP correlated to the size of infarction (r = 0.80 and P =
      0.017 for TCC; r = 0.72 and P = 0.043 for CRP). No significant changes were seen
      for adhesion molecules and cytokines. In conclusion, transitory systemic
      complement activation takes place after stroke. The early rise in CRP and the
      following TCC increase suggest a possible role for CRP in complement activation,
      which may contribute to inflammation after stroke.

PMID- 15196253
TI  - Phenotypic and functional characteristics of CD28+ and CD28- cells from chagasic
      patients: distinct repertoire and cytokine expression.
AB  - Chronic human Chagas' disease ranges from an asymptomatic to a severe cardiac
      clinical form. The involvement of the host's immune response in the development
      and maintenance of chagasic pathology has been demonstrated by several groups. We
      have shown that activated T-cells lacking CD28 expression are increased in the
      peripheral blood of chagasic patients (CP), suggesting a relationship between
      these cells and disease. In order to better characterize this cell population,
      determining their possible role in immunoregulation of human Chagas' disease, we
      evaluated the expression of TCR-Vbeta regions 2, 3.1, 5, 8 and 17, as well as the
      expression of IFN-gamma, TNF-alpha, IL-4 and IL-10 by CD28+ and CD28- cells from
      polarized indeterminate and cardiac CP. Flow cytometric analysis demonstrated
      equivalent TCR-Vbeta usage between CD4+CD28+ and CD4+CD28- cells from all groups
      (chagasic and healthy controls). However, there was a predominance of Vbeta5
      expression in the CD28+ and CD28- populations in the CP groups (indeterminate and
      cardiac). Interestingly, CD8+CD28- cells from CP, but not from nonchagasic
      individuals, displayed a reduced frequency of most analysed Vbetas when compared
      with the CD8+CD28+ subpopulation. Comparison of V-beta expression in CD28+ or
      CD28- cell populations among individuals from different groups also showed
      several interesting differences. Functionally, cardiac CP displayed a higher
      frequency of IFN-gamma, TNF-alpha and IL-4 producing lymphocytes than
      indeterminate CP. Correlation analysis between the frequency of cytokine
      expressing cells, and the frequency of CD4+ T-cells with differential expression
      of CD28 demonstrated that CD4+CD28- T-cells were positively correlated with TNF
      alpha in cardiac and with IL-10 in indeterminate CP, suggesting that these cells
      might have an important regulatory role in human Chagas' disease.

PMID- 15196254
TI  - Lymphocyte apoptosis in acute respiratory syncytial virus bronchiolitis.
AB  - Respiratory syncytial virus (RSV) infection may have an effect on the development
      of T cell memory responses. RSV bronchiolitis in infants is associated with a
      transient decline in circulating lymphocytes. We hypothesized that the mechanism
      underlying this lymphopenia is apoptosis. Blood was taken from 32 infants during
      primary RSV bronchiolitis and three months later. Using flow cytometry, we found
      that absolute numbers of both CD3+/CD4+ T-helper lymphocytes (P = 0.029) and
      CD3+/CD8+ cytotoxic lymphocytes (CTL) (P = 0.043) were significantly reduced
      during acute infection. Up-regulated expression both of Fas (P < 0.001) and
      tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (P <
      0.001) was found during acute illness on both CD3+/CD4+ and CD3+/CD8+
      lymphocytes, when compared with convalescent samples. Expression of Fas on CD4+
      lymphocytes was inversely related to CD4+ number (P = 0.03). Plasma levels of
      soluble Fas ligand (P = 0.028) and caspase-1 (P = 0.037), determined by enzyme
      linked immunosorbent assay, were increased during bronchiolitis. Plasma
      interleukin-18, a product of caspase-1 activity, was not raised. Taken together,
      these data suggest that in acute RSV infection, CD4+ helper lymphocytes and CD8+
      cytotoxic lymphocytes are primed to undergo apoptosis. This is a mechanism
      through which lymphopenia may occur and T cell memory may be altered.

PMID- 15196255
TI  - Decreased interferon-gamma response in respiratory syncytial virus compared to
      other respiratory viral infections in infants.
AB  - An inappropriate interferon-gamma response has been implicated in the
      pathogenesis of severe respiratory syncytial virus (RSV) lower respiratory tract
      illness (LRTI). To assess whether this is unique for RSV primary LRTI compared to
      a first non-RSV LRTI, intracellular interferon-gamma was determined by flow
      cytometry in peripheral blood mononuclear cells from 32 infants with a primary
      RSV infection, 28 with a first non-RSV LRTI due to adenoviral, parainfluenzaviral
      and rhinoviral infection and 13 healthy infants. Interferon-gamma responses were
      increased significantly during adenoviral, parainfluenzaviral and the majority of
      the rhinoviral infections, but remained low during RSV and severe rhinoviral
      infection. Low interferon-gamma responses were associated with a more severe
      clinical course of LRTI. This indicates that depending on the nature of the viral
      pathogen, respiratory virus infections in infants differ significantly with
      regard to the quantity of the interferon-gamma production and that this may
      contribute to the clinical course of the disease.

PMID- 15196256
TI  - Expression of CTLA-4 (CD152) in peripheral blood T cells of children with
      influenza virus infection including encephalopathy in comparison with respiratory
      syncytial virus infection.
AB  - Influenza virus and respiratory syncytial virus (RSV) are the most common causes
      of acute severe respiratory infection in children during the winter. There have
      been few reports about peripheral blood T cell activation in vivo in influenza
      virus infection and conflicting results concerning peripheral blood T cells
      activation in RSV infection. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4,
      CD152) is a receptor present on T cells that plays a critical role in the down
      regulation of antigen-activated immune responses. To clarify the status of
      peripheral blood T cells, we investigated intracellular CTLA-4 expression in T
      cells in patients with influenza virus and RSV infection. We collected blood
      samples from 15 patients with influenza virus infection, including three with
      complications of influenza virus-associated encephalopathy and 18 patients with
      RSV infection, as well as 44 healthy children. We determined the intracellular
      expression of CTLA-4 in CD4+ and CD8+ T cells by flow cytometry. There were no
      significant differences in the percentages of intracellular CTLA-4-positive CD4+
      T cells and CD8+ T cells by age. The percentages of intracellular CTLA-4-positive
      CD4+ T cells in the patients with influenza virus infection were significantly
      higher than those in healthy children (P < 0.01). In particular, the patients
      with influenza virus-associated encephalopathy had sevenfold higher percentages
      of CTLA-4-positive CD4+ T cells than influenza patients without encephalopathy (P
      < 0.05). The patients with influenza virus-associated encephalopathy had
      increased percentages of CTLA-4-positive CD8+ cells at the acute stage in
      comparison with the convalescent stage and in control subjects (P < 0.01,
      respectively). RSV patients showed no increase in CTLA-4-positive CD4+ T cells or
      CD8+ T cells. The immunological status of peripheral T cell activation is
      substantially different in influenza virus infection and RSV infection. The
      patients with RSV infection did not show any increase in CTLA-4-positive
      peripheral blood T cells. There was a remarkable increase in intracellular CTLA-4
      in CD4+ and CD8+ T cells in influenza virus-associated encephalopathy. Down
      regulation of antigen-activated peripheral blood T cell activation might play an
      important role in the pathogenesis of influenza virus-associated encephalopathy
      and host defence against influenza virus infection.

PMID- 15196257
TI  - Down-regulation of CXCR-4 and CCR-5 expression by interferon-gamma is associated
      with inhibition of chemotaxis and human immunodeficiency virus (HIV) replication
      but not HIV entry into human monocytes.
AB  - Alterations in the expression of CXCR4 and CCR5, the co-receptors for HIV entry,
      may be associated with susceptibility of monocytic cells to HIV infection.
      Interferon (IFN)-gamma has been shown to inhibit HIV replication in monocytic
      cells, but the molecular mechanism involved is not well understood. To determine
      if IFN-gamma regulates HIV replication by altering CXCR-4/CCR-5 expression and
      hence virus entry into monocytic cells, we investigated the effects of IFN-gamma
      on CXCR-4 and CCR-5 expression and its biological implications with respect to
      HIV entry, replication and chemotaxis towards the CXCR-4 and CCR-5 ligands SDF-1
      and MIP-1alpha, respectively. IFN-gamma decreased CXCR-4 and CCR-5 expression on
      monocytes derived from HIV-negative adults, HIV-positive adults and HIV-negative
      cord blood. This down-regulation of chemokine receptor expression did not result
      in a corresponding change in mRNA expression but was associated with elevated
      levels of the endogenously produced chemokines SDF-1 and RANTES. Furthermore, IFN
      gamma inhibited chemotaxis in response to SDF-1 and MIP-1alpha, inhibited HIV
      replication, but failed to inhibit virus entry in monocytic cells. These results
      suggest that although IFN-gamma-induced down-regulation of CXCR-4 and CCR-5
      expression is associated with an inhibition of SDF-1-/MIP-1alpha-mediated
      chemotaxis, IFN-gamma-induced inhibition of HIV replication may be mediated at
      levels subsequent to the virus entry.

PMID- 15196258
TI  - Increased Fas-mediated apoptosis in polymorphonuclear cells from HIV-infected
      patients.
AB  - Neutrophils represent an important line of innate host defence against invading
      microorganisms and their functional detriment during HIV infection, including
      accelerated spontaneous cell death, has been shown to contribute to AIDS
      development. Neutrophils are susceptible to apoptosis via Fas and an interaction
      between Fas and FasL was suggested originally as a mechanism to explain
      constitutive neutrophil apoptosis. We have explored some intracellular pathways
      leading to PMN apoptosis from 28 HIV-infected patients and 24 healthy volunteers.
      As previously reported, accelerated spontaneous apoptosis was observed in HIV+
      patients, but this did not correlate with viral load. Furthermore, an increase in
      the level of spontaneous apoptosis was detected in neutrophils from HIV-infected
      patients following inhibition of ERK, suggesting an impairment of this kinase
      pathway during the early stages of infection which may contribute to PMN
      dysfunction. An elevated susceptibility to undergo apoptosis was observed
      following cross-linking of Fas, which correlated both with viral load and co
      expression of Fas/FasL surface molecules. Different mechanisms for spontaneous
      and Fas-induced apoptosis are proposed which together contribute to the
      neutropenia and secondary infections observed during the progression to AIDS.

PMID- 15196259
TI  - Rotavirus-specific T-cell responses in young prospectively followed-up children.
AB  - Rotavirus is a major cause of gastroenteritis in young children. Antibodies seem
      to protect against rotavirus infection but cell-mediated immune responses are
      probably also important for protection. We evaluated the development of T-cell
      responses to rotavirus in follow-up samples from 20 healthy children with an
      increased genetic risk for type 1 diabetes. Blood samples from 16 healthy adults
      were also available for the study. T-cell proliferation was analysed at 3-6 month
      intervals from the age of 3 months to the age of 4-5 years using the Wa strain of
      human rotavirus and the NCDV strain of bovine rotavirus as antigens. IgG and IgA
      antibodies to rotavirus were studied from simultaneously drawn plasma samples
      with EIA method using NCDV as an antigen. A total of 24 infections were revealed
      by antibody analysis. Sixteen children showed diagnostic increases in both IgG
      and IgA antibodies to rotavirus, while 5 children showed increases in IgA
      antibodies only and 3 in IgG only. Antibody rises were accompanied by T-cell
      responses to rotavirus (SI > 3) in 9 of the 24 cases. T-cell responses to
      purified or lysed human rotavirus were stronger after a rise in rotavirus
      antibodies than the responses before infection (P = 0.017 and 0.027,
      respectively). There was a correlation between T-cell responses to purified and
      lysed human rotavirus and NCDV. Strong T-cell responses to rotavirus were
      transient and the ability to respond usually disappeared in one year, but in all
      adults T-cell responses to rotavirus were strong implicating that several
      infections are needed to develop consistent, strong T-cell responsiveness.

PMID- 15196260
TI  - The impact of an early truncating founder ATM mutation on immunoglobulins,
      specific antibodies and lymphocyte populations in ataxia-telangiectasia patients
      and their parents.
AB  - Eleven Norwegian patients (aged 2-33 years, seven males and four females) with
      Ataxia-telangiectasia (A-T) and their parents were investigated. Five of the
      patients were homozygous for the same ATM mutation, 3245delATCinsTGAT, a
      Norwegian founder mutation. They had the lowest IgG2 levels; mean (95% confidence
      interval) 0.23 (0.05-0.41) g/l versus 0.91 (0.58-1.26) g/l in the other patients
      (P = 0.002). Among the 11 A-T patients, six had IgG2 deficiency, six had IgA
      deficiency (three in combination with IgG2 deficiency) and seven had
      low/undetectable IgE values. All patients had very low levels of antibodies to
      Streptococcus pneumoniae 0.9 (0.4-1.4) U/ml, while normal levels were found in
      their parents 11.1 (8.7-13.4) U/ml (P < 0.001). A positive linear relationship
      between pneumococcal antibodies and IgG2 (r = 0.85, P = 0.001) was found in the
      patients. Six of 11 had diphtheria antibodies and 7 of 11 tetanus antibodies
      after childhood vaccinations, while 4 of 7 Hemophilus influenzae type b (Hib)
      vaccinated patients had protective antibodies. Ten patients had low B cell
      (CD19+) counts, while six had low T cell (CD3+) counts. Of the T cell
      subpopulations, 11 had low CD4+ cell counts, six had reduced CD8+ cell counts,
      and four had an increased portion of double negative (CD3+/CD4-/CD8-) gamma delta
      T cells. Of the 22 parents (aged 23-64 years) 12 were heterozygous for the ATM
      founder mutation. Abnormalities in immunoglobulin levels and/or lymphocyte
      subpopulations were also observed in these carriers, with no correlation to a
      special ATM genotype.

PMID- 15196261
TI  - Oligoclonal expansion of circulating and tissue-infiltrating CD8+ T cells with
      killer/effector phenotypes in juvenile dermatomyositis syndrome.
AB  - Although triggering by infectious agents and abnormal immune responses may play
      some role in the pathogenesis of juvenile dermatomyositis syndrome (JDMS), the
      precise mechanism of muscle destruction and vascular damage is largely unknown.
      In this study, we tried to elucidate the role of cytotoxic T cells in two
      patients with JDMS, who were diagnosed based on the characteristic symptoms,
      laboratory data, MRI findings and electromyographic patterns. Peripheral blood T
      cell phenotypes were determined by flow cytometry, using mAbs against specific T
      cell receptor (TCR) Vbetas. Complementarity-determining region3 (CDR3) size
      analysis was performed by gene scanning of CDR3 polymerase chain reaction (PCR)
      amplification products specific for each Vbeta. Subsequently, CDR3 nucleotide
      sequences were obtained after cloning of the predominant products. The
      distribution of lymphocytes infiltrating the muscle tissue was analysed by
      immunohistochemistry. In both patients examined, a unique combination of TCR
      Vbeta repertoires was increased within the CD8+ T cells. These subpopulations
      expressed a characteristic phenotype, indicating that they are memory/effector T
      cells with killer functions. At the same time, immunohistological and molecular
      biological examinations of the biopsied muscle samples revealed that identical
      CD8+ T cell clones with identical phenotypes/TCR Vbeta infiltrated within the
      inflammatory tissue, in particular around vessels. These findings indicate that
      oligoclonal expansion of CD8+ T cells plays a central role in the pathogenesis of
      muscle injury in the juvenile form of dermatomyositis syndrome and may provide a
      useful clinical parameter of disease activity and responsiveness to anti
      inflammatory therapy.

PMID- 15196262
TI  - Anti-desmoglein 1 antibodies in Tunisian healthy subjects: arguments for the role
      of environmental factors in the occurrence of Tunisian pemphigus foliaceus.
AB  - Pemphigus foliaceus is an autoimmune blistering skin disease mediated by
      autoantibodies directed against desmoglein 1 and occurs as a sporadic form
      throughout the world, or as an endemic form called fogo selvagem in Brazil.
      Healthy subjects living in Brazilian endemic areas produce antidesmoglein 1
      antibodies, suggesting the role of environmental factors in the initiation of the
      autoimmune response. Tunisia was described recently as an endemic area where the
      disease is characterized by its high rate among young people, especially women.
      An enzyme-linked immunosorbent assay using recombinant desmoglein 1 as antigen
      was used to detect antibodies against desmoglein 1 and calibrated with sera from
      67 French healthy blood donors, 20 French pemphigus foliaceus patients and
      patients with other bullous skin diseases. When sera from 179 healthy Tunisian
      blood donors were tested, 31 (17%) were found positive. The desmoglein 1 binding
      activity of these 31 sera was confirmed in 10 cases by indirect
      immunofluorescence analysis and/or immunoblotting using human epidermal extract.
      Subclass analysis of antidesmoglein 1 antibodies showed that they were almost
      exclusively of the IgG2 subclass in positive normal sera and of IgG4 subclass in
      patients with PF. Thus, antibodies against desmoglein 1 are prevalent in normal
      subjects living in Tunisia which, along with their IgG2 isotype, suggests the
      role of the environment in the pathogenesis of this endemic type of pemphigus
      foliaceus and the need for additional factors to switch from a subclinical to a
      clinical form of the disease.

PMID- 15196263
TI  - Oral tolerization with peptide 336-351 linked to cholera toxin B subunit in
      preventing relapses of uveitis in Behcet's disease.
AB  - Behcet's disease (BD) specific peptide (p336-351) was identified within the human
      60 kD heat shock protein (HSP60). Oral p336-351 induced uveitis in rats which was
      prevented by oral tolerization with the peptide linked to recombinant cholera
      toxin B subunit (CTB). This strategy was adopted in a phase I/II clinical trial
      by oral administration of p336-351-CTB, 3 times weekly, followed by gradual
      withdrawal of all immunosuppressive drugs used to control the disease in 8
      patients with BD. The patients were monitored by clinical and ophthalmological
      examination, as well as extensive immunological investigations. Oral
      administration of p336-351-CTB had no adverse effect and withdrawal of the
      immunosuppressive drugs showed no relapse of uveitis in 5 of 8 patients or 5 of 6
      selected patients who were free of disease activity prior to initiating the
      tolerization regimen. After tolerization was discontinued, 3 of 5 patients
      remained free of relapsing uveitis for 10-18 months after cessation of all
      treatment. Control of uveitis and extra-ocular manifestations of BD was
      associated with a lack of peptide-specific CD4+ T cell proliferation, a decrease
      in expression of TH1 type cells (CCR5, CXCR3), IFN-gamma and TNF-alpha
      production, CCR7+ T cells and costimulatory molecules (CD40 and CD28), as
      compared with an increase in these parameters in patients in whom uveitis had
      relapsed. The efficacy of oral peptide-CTB tolerization will need to be confirmed
      in a phase III trial, but this novel strategy in humans might be applicable
      generally to autoimmune diseases in which specific antigens have been identified.

PMID- 15196267
TI  - Human seminal plasma allergy: a review of a rare phenomenon.

PMID- 15196264
TI  - Screening of a HUAEC cDNA library identifies actin as a candidate autoantigen
      associated with carotid atherosclerosis.
AB  - The humoral immune response to endothelium has a pivotal role in the development
      of atherosclerosis. Using a molecular method, we sought to identify endothelial
      autoantigens in carotid atherosclerosis. Immunoscreening of a HUAEC expression
      library with IgG from a pool of two sera from patients with carotid
      atherosclerosis identified a clone specific to actin. We evaluated actin-specific
      IgG reactivity in patients with carotid atherosclerosis and compared responses
      with those in patients with systemic lupus erythematosus and type 1 diabetes
      mellitus and in healthy subjects. Enzyme-linked immunoassay detected actin
      specific IgG in a significantly higher percentage of sera from patients with
      atherosclerosis and systemic lupus erythematosus than from healthy subjects
      (16/61, 26% and 13/33, 39%versus 2/41, 5%, P = 0.012 and P < 10(-4), by chi2
      test). Mean optical density values were significantly higher in patients than in
      healthy subjects (P < 10(-4) by Student's t-test). Patients with atherosclerosis
      and uncomplicated plaques had significantly higher serum anti-actin IgG
      reactivity than those with complicated plaques (P = 0.048 by Student's t-test).
      Our findings suggest that actin is an autoantigenic molecule of potential
      clinical interest in carotid atherosclerosis.

PMID- 15196265
TI  - Effect of maternal anti-HPA-1a antibodies and polyclonal IVIG on the activation
      status of vascular endothelial cells.
AB  - Maternal anti-HPA-1a antibodies can cause severe fetal and neonatal alloimmune
      thrombocytopenia (FNAIT), complicated by intracranial haemorrhage (ICH).
      Antenatal treatment with maternal intravenous immunoglobulin (IVIG) seems to
      protect against ICH even when thrombocytopenia persists. The aim of this study
      was to investigate if anti-HPA-1a antibodies and IVIG potentially affect vascular
      endothelial cells (ECs) in order to identify susceptibility for ICH. Human
      umbilical cord endothelial cells (HUVEC) were incubated with anti-HPA-1a
      antibodies with or without polyclonal IVIG and evaluated for EC activation.
      Maternal sera with anti-HPA-1a antibodies affected neither the EC expression of
      intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1)
      and tissue factor (TF) nor the release of van Willebrand factor (vWF) or
      interleukin (IL)-8 nor the integrity of ECs. Maternal sera obtained after IVIG
      treatment and polyclonal IVIG decrease constitutive and cytokine-induced ICAM-1
      and VCAM-1 expression on ECs. The results show that maternal anti-HPA-1a
      antibodies cause no activation or damage of ECs in this model. The clinical
      relevance of the de-activating properties of IVIG on EC activation with respect
      to ICH deserves further investigation.

PMID- 15196268
TI  - Influence of male sex and parental allergic disease on childhood wheezing: role
      of interactions.
AB  - BACKGROUND: Boys have been reported to be more susceptible to childhood wheezing,
      whereas girls are more susceptible later in life. This difference might be
      related to both genetic and environmental factors. OBJECTIVE: To investigate the
      influence of male sex and parental allergic disease on the development of
      childhood wheezing. METHODS: Infants (n=4089) born in Stockholm were recruited in
      a prospective study, BAMSE. Data on parental allergic diseases were obtained from
      questionnaires answered at the children's birth and on symptoms of wheezing at 1,
      2 and 4 years of age. Sensitization to inhalant allergens and lung function was
      investigated at the age of 4 years. RESULTS: Children were classified as having
      recurrent, transient (n=266), early-onset persistent (n=319) and late-onset
      wheezing (n=195). Boys were over-represented in all groups of wheezing (odds
      ratio, OR=1.4-1.5) and both maternal and paternal allergic disease was of
      importance for the wheezing outcomes. A dominating influence from maternal
      allergic disease was only seen in children with persistent wheezing. An
      interaction exceeding additivity was found between male sex and parental allergic
      disease, particularly in children with persistent wheezing (OR=2.9 and 95%
      confidence interval, CI 95% 2.1-4.0 for boys with any parental history vs.
      OR=1.4, CI 95% 1.0-2.1 for girls). Interaction between male sex and parental
      allergic disease was also observed in children who wheezed at the age of 4 years
      and were sensitized to inhalant allergens. CONCLUSION: Our data suggest an
      interaction between male sex and parental allergic disease in childhood wheezing,
      which may represent a sex-specific genetic influence.

PMID- 15196269
TI  - Risk factors for atopy among school children in a rural area of Latin America.
AB  - BACKGROUND: Infection with common childhood infectious diseases including
      geohelminth infections may provide protection against the development of atopy
      and allergic disease. Few studies have investigated risk factors for atopy among
      children living in rural areas of Latin America. OBJECTIVE: To identify risk
      factors associated with atopy among school-age children in a rural area of Latin
      America. METHODS: Analytic cross-sectional study of school-age children conducted
      in seven rural schools in Pichincha Province in Ecuador. Detailed risk factor
      information was obtained by questionnaire, stool samples were collected for
      identification of geohelminth parasites, and Mantoux testing was performed to
      determine tuberculin sensitization. RESULTS: A total of 1002 children from seven
      rural schools were recruited. The prevalence of geohelminth infections was high
      (70.1% were infected with at least one geohelminth parasite) and the prevalence
      of allergic sensitization was high (20.0% had evidence of aeroallergen
      sensitization). Factors associated with significant protection against atopy in
      multivariate analyses were the presence of overcrowding in the child's home, low
      socio-economic level, and infection with geohelminth parasites, and the
      protective effects of the three factors were statistically independent.
      CONCLUSION: Low socio-economic level, overcrowding and geohelminth infection, are
      independently protective against atopy among school-age children living in a
      rural area of Latin America.

PMID- 15196270
TI  - Does maternal immunoglobulin E decrease with increasing order of live offspring?
      Investigation into maternal immune tolerance.
AB  - BACKGROUND: Identifying the protective effect of a higher number of siblings is a
      significant finding in understanding the aetiology of allergic sensitization,
      asthma, eczema, and hayfever. Knowledge about causes behind the sibling effect
      may allow us to prevent atopic manifestations. OBJECTIVE: We tested the
      hypothesis that rising order of live offspring increases maternal immune
      tolerance (immune non-reactivity) against allergens. To this end, we investigated
      whether maternal IgE levels are associated with the number of live offspring.
      METHODS: In a cohort of 1456 newborns recruited between January 1989 and February
      1990 on the Isle of Wight, UK, we determined maternal and cord serum IgE, and the
      order of live offspring. The data were analysed by means of linear and path
      analysis. RESULTS: Maternal and cord serum IgE were available in 820 mother
      infant pairs with birth order information. We found that the number of live
      offspring significantly reduces maternal IgE. The decline was more prominent in
      mothers with atopy (n=268). The geometric means of IgE after the first, second,
      and third or higher delivery were 74.4, 66.6, and 43.0 kU/L, respectively.
      Findings of path analysis suggest a significant direct effect of birth order on
      maternal IgE, but no direct effect of birth order on cord serum IgE. CONCLUSION:
      The findings support that maternal immune tolerance against allergens may
      increase with increasing order of live offspring and thus pass on a lower risk of
      developing atopy in children of higher birth order.

PMID- 15196271
TI  - ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean
      asthmatics.
AB  - BACKGROUND: A disintegrin and metalloprotease 33 (ADAM33) is expressed in the
      lung by fibroblasts and bronchial smooth muscle cells. Given its structure and
      cellular provenance, ADAM33 may be associated with airway remodelling and
      bronchial hyper-responsiveness. Single nucleotide polymorphisms (SNPs) and
      haplotypes of the ADAM33 gene have previously been associated with asthma
      susceptibility in the Caucasian population. OBJECTIVE AND METHODS: To assess
      whether genetic variants of ADAM33 are related to asthma in a Korean population,
      we conducted an association study of the ADAM33 gene with asthma susceptibility,
      bronchial hyper-reactivity and serum IgE in Korean asthmatics (n=326) and normal
      controls (n=151). Five of the 14 polymorphisms originally reported to be
      associated with asthma development (S1 G>A, T1 T>C, V-1 C>A, V1 T>A, V4 C>G) were
      genotyped using single base extension and electrophoresis. Haplotypes and their
      frequencies were inferred using the algorithm implemented by the software
      Arlequin. Allele frequencies of each SNP and haplotypes were compared between the
      patients and the normal controls using logistic regression analysis. RESULTS:
      There was no significant difference in the distribution of SNPs and the six
      haplotypes between asthmatics and normal controls. All single SNPs and six
      haplotypes in ADAM33 were also analysed for the association with level of PC(20)
      using general linear models. The distribution of the T1 T>C SNP and one haplotype
      (ht4: GCGG) showed significant association with log-transformed PC(20)
      methacholine level in the asthma patients (P=0.03 and 0.0007, respectively, using
      a co-dominant model). CONCLUSION: Polymorphism of ADAM33 may contribute to
      development of BHR in asthma.

PMID- 15196272
TI  - Cow's milk-specific immunoglobulin E levels as predictors of clinical reactivity
      in the follow-up of the cow's milk allergy infants.
AB  - BACKGROUND: IgE-mediated cow's milk proteins (CMPs) allergy shows a tendency to
      disappear with age. The sooner tolerance is detected, the earlier the substitute
      diets can be suspended and the quicker family emotional hardship is alleviated.
      OBJECTIVE: To analyse the specific IgE levels to cow's milk and its proteins,
      which help to separate tolerant from no tolerant children in the follow-up of
      infants with allergy to cow's milk. PATIENTS AND METHODS: Sixty-six infants
      diagnosed with IgE-mediated allergy to CMPs were included in this prospective
      follow-up study. Periodic reassessments were carried out every 6 months until
      they were 2-years old and then, annually, until tolerance arose or until the last
      reassessment in which tolerance had not been achieved. Non-tolerant infants were
      followed, at least, for a period of 3 years. In each visit, the same skin tests
      and determination of specific IgE (CAP System FEIA) for milk and its proteins
      were carried out. The open challenge test was repeated unless a clear
      transgression to milk, which came to be positive, had taken place within the
      previous 3 months in each of the follow-up visits. Specific IgE levels to milk
      and its proteins, in different moments of the follow-up were analysed by means of
      the receiver-operating characteristic curve to predict clinical reactivity.
      RESULTS: Throughout the follow-up 45 (68%) infants became tolerant. The follow-up
      mean for tolerant infants was 21.2 months whereas for non-tolerant infants it was
      58 months. The specific IgE levels which were predictors of the clinical
      reactivity (positive predictive value (PPV)> or =90%), grew as the age of the
      infants increased: 1.5, 6 and 14 kU(A)/L for milk in the age range 13-18 and 19
      24 months and in the third year, respectively. Specific IgE levels to casein:
      0.6, 3 and 5 kU(A)/L, respectively, predicted clinical reactivity (PPV> or =90%)
      in the different analysed moments of the follow-up. The cut-off points: 2.7, 9
      and 24 kU(A)/L for milk and 2, 4.2 and 9 kU(A)/L for casein, respectively,
      predicted clinical reactivity with an accuracy > or =95% corresponding to a
      specificity of 90%. CONCLUSIONS: Monitorization of specific IgE concentration for
      milk and casein by means of the CAP system in allergic children to CMPs allows us
      to predict, to a high degree of probability, clinical reactivity. Age factor must
      be taken into account to evaluate the specific IgE levels which are predictors of
      tolerance or clinical reactivity.

PMID- 15196273
TI  - Non-linear short-term effects of airborne pollen levels with allergenic capacity
      on asthma emergency room admissions in Madrid, Spain.
AB  - BACKGROUND: Several time-series studies have shown positive associations between
      pollen levels and asthma morbidity. However, few studies have included air
      pollution as a potential confounder when examining this relationship, and they
      have only done so on a linear basis. OBJECTIVE: To investigate the potential non
      linear short-term effects of the types of pollen with allergenic capacity across
      the whole range of exposure on the daily number of asthma-related hospital
      emergencies in Madrid for the period 1995-1998. METHODS: Data were collected on
      the daily number of asthma emergency room admissions and daily average levels of
      major types of pollen with allergenic capacity: Olea, Plantago, Poaceae and
      Urticaceae. We used Poisson regression with generalized additive models,
      controlling for trend and seasonality, meteorological variables, acute
      respiratory infections and air pollutants. To study the non-linear effect of
      pollen levels on asthma emergency room admissions, pollens were categorized into
      five groups defined on the basis of their respective distributions. RESULTS: The
      strongest associations were registered in respect of a lag of 1 day for
      Urticaceae, a lag of 2 days for Plantago, and a day lag of 3 days for Poaceae.
      Adjustment for the different types of pollen failed to result in major changes.
      Non-linearities were evident for pollen levels. The greatest increase in risk vs.
      the reference category (minimum value - 50th percentile) was observed for the
      categories between the 95th and 99th percentiles, with increases of 32.0% for
      Plantago, 32.2% for Poaceae and 24.6% for Urticaceae, and between the 99th
      percentile and the maximum value, with increases of 31.3%, 78.7% and 49.8%,
      respectively. Olea was not related with asthma emergency room admissions.
      CONCLUSIONS: Pollens with allergenic capacity in Madrid are positively associated
      with asthma-related hospital emergencies. These associations remain stable when
      simultaneous adjustment is made for the four types of pollen and for air
      pollutants and meteorological variables. In terms of non-linear effects, Poaceae
      register the strongest association with asthma emergency room admissions.

PMID- 15196274
TI  - Allergen-specific T cells from birch-pollen-allergic patients and healthy
      controls differ in T helper 2 cytokine and in interleukin-10 production.
AB  - BACKGROUND: T helper (Th)2 cells play an important role in the development of IgE
      mediated diseases, with local overproduction of Th2 cytokines (IL-4, IL-5 and IL
      13) at the site of allergic inflammation. Furthermore, IL-10 has been suggested
      to play a modulatory role in the induction and maintenance of allergen-specific
      tolerance in human atopic diseases. AIM: We studied whether circulating allergen
      specific Th2 cells persist outside the season of exposure in patients mono
      sensitized to birch pollen and whether healthy control individuals also have
      allergen-specific Th2 cells. We also studied whether IL-10-producing allergen
      specific T cells can be found in circulation either in healthy controls or in
      allergic patients. METHODS: Blood was drawn outside the birch-pollen season from
      15 birch-pollen-allergic patients, with seasonal respiratory symptoms and with
      (n=12) or without (n=3) oral allergy syndrome, and from 10 matched healthy
      controls. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro
      with recombinant Bet v 1 allergen, control antigen tetanus toxoid (TT) and anti
      CD3/CD80. In part of the cultures, rIL-4 was added in order to reinforce the
      allergen-specific Th2 cell responses. RESULTS: In the presence of rBet v 1, T
      cells from allergic patients, but not from healthy controls, produced IL-4, IL-5
      and IL-13. IL-5 production by patients' T cells was further enhanced by adding
      more IL-4. In contrast, rBet v 1 together with IL-4-induced significant IL-10
      production in control subjects but not in patients. Both Th1 and Th2 cytokines
      were equally induced by polyclonal stimulation in allergic patients and controls,
      but in the presence of IL-4, polyclonally induced IL-10 production was lower in
      the patient group. CONCLUSION: rBet v 1-specific Th2 cells circulate outside the
      season of exposure in the blood of birch-pollen-allergic subjects but not in
      healthy controls. Allergen-specific T cells were also demonstrated in controls
      but these cells produce IL-10 when stimulated with rBet v 1 in the presence of IL
      4. Our data reveal a different allergen-induced cytokine profile in birch-pollen
      allergic patients vs. controls, and suggest that a regulatory mechanism involving
      IL-4-induced allergen-specific IL-10 production might be defective in allergic
      subjects.

PMID- 15196275
TI  - Permeability of synthetic and feather pillows to live house dust mites and house
      dust.
AB  - BACKGROUND: Previous studies have demonstrated significantly higher house dust
      mite (HDM) allergen levels from synthetic pillows, compared to feather pillows.
      Reasons for these differences could be lower permeability of feather pillow
      coverings to allergen in dust, greater HDM penetration of synthetic pillow
      covering, or both. OBJECTIVES: To determine the permeability of synthetic and
      feather pillow coverings to live HDMs and house dust. METHODS: Twenty live adult
      HDMs were seeded on top of two types of synthetic pillow covering (one standard
      polyester and one newer polyester/cotton type) and one type of feather pillow
      coverings with adequate food supply below in sealed culture dishes, kept at 23
      degrees C and 70% relative humidity. After 24 and 48 h live HDM numbers remaining
      on top of the coverings were enumerated microscopically. Three aliquots of fine
      house dust (each in triplicate) were placed on top of the synthetic and feather
      pillow coverings, shaken gently for 30 min and penetrated dust was collected and
      weighed. RESULTS: After 24 h, all 20 HDMs had penetrated the standard synthetic
      pillow coverings, and no HDMs had penetrated either the feather pillow or the new
      synthetic pillow coverings after 24 or 48 h. Dust permeability (% of applied
      dust) for the standard synthetic, new type synthetic and feather pillow coverings
      were 0.88%, 0.07%, and 0.07%, respectively. This compared to 0.02% for a
      commercial occlusive pillow cover. CONCLUSIONS: These findings of total
      permeability of standard synthetic pillow coverings to live HDMs, and their
      greater permeability to house dust could explain their reported higher HDM
      allergen levels, compared to feather pillow coverings. Newer types of synthetic
      pillow coverings are similar to feather pillow coverings in their permeability to
      live HDMs and house dust.

PMID- 15196276
TI  - Airway function and nasal inflammation in seasonal allergic rhinitis and asthma.
AB  - BACKGROUND: Allergic rhinitis (AR) and asthma are frequently associated and
      characterized by a Th2-dependent inflammation. Nasal and bronchial obstruction
      may be objectively measured. OBJECTIVE: The aim of this study was to evaluate the
      relationships among upper and lower airway function and nasal inflammation in
      subjects with seasonal allergic rhinitis (SAR) and asthma. METHODS: Twenty out
      patients (12 males and eight females, mean age: 23.4+3.6 years) with SAR and
      asthma were evaluated during the pollen season. All of them showed a moderate
      severe grade of nasal obstruction. Total symptom score, rhinomanometry,
      spirometry, nasal lavage, and nasal scraping were obtained in all subjects.
      Eosinophils were counted by conventional staining; IL-4 and IFN-gamma were
      measured by immunoassay on fluids recovered from nasal lavage. RESULTS:
      Functional parameters, i.e. nasal airflow and forced expiratory volume in 1 s
      (FEV(1)), were correlated with nasal eosinophils (R(2)>0.83, P<0.001).
      Inflammatory parameters, i.e. eosinophils were correlated with immunological
      parameters, i.e. IL-4 and IFN-gamma levels (R(2)=0.93, P<0.001). Nasal symptoms
      were correlated with nasal airflow (rho=-0.71, P< or =0.01) and eosinophils
      (rho=0.72, P<0.01). Nasal airflow was correlated with FEV(1) (r=0.89, P<0.0001).
      CONCLUSIONS: This study demonstrates the close connection between Th2 cytokines
      and eosinophil infiltration in the nose. There is also clear evidence concerning
      the relationships between eosinophils infiltration and cytokines levels. Nasal
      eosinophils can be regarded as the most important predictors of upper and lower
      airway functions. These findings constitute first evidence of a relationship
      among nasal Th2-related inflammation and nasal and bronchial airflow in patients
      with SAR and asthma.

PMID- 15196277
TI  - Characteristics of patients with seasonal allergic rhinitis and concomitant
      asthma.
AB  - BACKGROUND: Allergic rhinitis and asthma often co-exist and appear to produce a
      continuum of airway disease, but whether the clinical characteristics of asthma
      in patients with seasonal rhinitis differ from those of persistent asthma has not
      been examined. OBJECTIVE: The aim of this retrospective study was to characterize
      the clinical features of patients with seasonal allergic rhinitis with
      concomitant asthma and to compare them with those in patients with persistent
      asthma. METHODS: The patient populations for this study were derived from nine
      prospective, placebo-controlled planned clinical trials of similar design. Six
      studies (958 patients) enrolled patients with seasonal allergic rhinitis and
      concomitant asthma; three (607 patients) involved patients with persistent
      asthma. In all studies, patients were excluded from oral corticosteroid therapy
      in the preceding 3 months, and from inhaled corticosteroids in the preceding
      month. RESULTS: Patients with seasonal rhinitis and asthma had a significantly
      (P<0.001) higher total asthma symptom score than those with persistent asthma. In
      particular, cough was three times more severe. The need for beta(2)-agonist as a
      rescue medication and the ratio of forced expiratory volume in 1 s/forced vital
      capacity (FVC) were similar in the two groups whereas forced expiratory fraction
      25-75%/FVC was significantly (P<0.02) reduced in the persistent asthmatics.
      Asthma and nasal symptom severity scores were correlated in patients with
      seasonal rhinitis and asthma (P<0.0001). CONCLUSIONS: Patients with seasonal
      allergic rhinitis and concomitant asthma appear to differ from those with
      persistent asthma. A prospective study should be designed to discover whether
      patients with seasonal rhinitis and asthma may represent a distinct nosological
      entity, 'allergic airway disease'.

PMID- 15196278
TI  - Interleukin-18 levels in induced sputum are reduced in asthmatic and normal
      smokers.
AB  - BACKGROUND: IL-18 is a cytokine which is known to have an important role in the
      development of a Th1 lymphocyte response. As such, it may have a regulatory role
      in asthma by modifying Th2 lymphocyte responses. Cigarette smoking may amplify
      the airway inflammation associated with asthma. OBJECTIVE: This study
      investigated if IL-18 could be detected in induced sputum from asthmatics and
      normal subjects and if smoking altered IL-18 levels. METHODS: Induced sputum was
      obtained from asthmatic (31 smokers, 35 non-smokers) and normal (20 smokers, 20
      non-smokers) subjects. All smokers had a smoking history of > or =15 pack years.
      IL-18 levels in sputum supernatant were measured by ELISA. IL-18 mRNA expression
      and cellular localization were assessed by quantitative PCR and
      immunocytochemistry, respectively. RESULTS: Smoking was associated with a
      significant reduction in IL-18 levels (median (interquartile range) - smokers 20
      (0-102) pg/mL vs. non-smokers 358 (50-876) pg/mL, P<0.001). This was more
      pronounced in asthmatics (smokers, 47 (40-64) pg/mL vs. non-smokers, 530 (30
      1484) pg/mL; P<0.001) than in normal subjects (smokers, 25 (0-78) pg/mL vs. non
      smokers, 247 (50-656) pg/mL; P<0.01). Within each of the smoking and non-smoking
      groups there was no significant difference in IL-18 levels between asthmatic and
      normal subjects. There was no correlation between sputum IL-18 levels and any
      specific cell type in the sputum samples nor serum IgE levels. IL-18 mRNA
      expression was reduced in asthmatic smokers compared with non-smokers. IL-18
      production was localized to sputum macrophages by immunocytochemistry.
      CONCLUSIONS: IL-18 is detectable in induced sputum samples from both asthmatic
      and normal subjects. Cigarette smoking significantly reduces sputum IL-18 levels.
      This effect is more pronounced in asthmatics than in normal subjects.

PMID- 15196279
TI  - The expression of stem cell factor and c-kit receptor in human asthmatic airways.
AB  - BACKGROUND: Asthmatic airways are characterized by infiltration with a variety of
      inflammatory cells such as mast cells and eosinophils. Stem cell factor (SCF) is
      an important activating and chemotactic factor for both mast cells and
      eosinophils. In addition, it is a critical growth and differentiation factor for
      mast cells. OBJECTIVES: To investigate the contribution of SCF to the
      pathogenesis of asthma, we examined the expression of SCF and its receptor c-kit
      in bronchial biopsies and bronchoalveolar lavage (BAL) specimens obtained from
      asthmatic subjects (n=13) and non-asthmatic control subjects (n=10). METHODS: SCF
      and c-kit were detected by in situ hybridization (ISH) and immunocytochemistry
      (ICC). In order to phenotype the cells expressing SCF and c-kit in asthmatic
      tissue and BAL cells, combined ISH and ICC were also performed. RESULTS: There
      was a significant difference (P<0.001) in the SCF mRNA expression in asthmatic
      airway epithelium (70.38+/-12.33% positive cells) compared with controls (12.7+/
      17.21% positive cells). There was also a significant difference in subepithelial
      SCF-mRNA expression, being higher in asthmatics (P<0.001). A significant
      difference was also found in c-kit receptor mRNA expression in asthmatic biopsies
      both in epithelium (P<0.001) and subepithelium (P<0.05) compared with controls.
      ICC results were consistent with the ISH for both SCF and c-kit receptor from
      asthmatics and controls. The SCF and c-kit receptor mRNA and immunoreactivity in
      cells recovered from bronchial washing were also significantly higher in
      asthmatics compared with controls (P<0.05). While SCF expression was localized
      predominantly in the epithelial layer in bronchial biopsy tissues, alveolar
      macrophages were found to be the major source of SCF in bronchial washing from
      asthmatic subjects. CONCLUSION: The results of this study demonstrate the
      increased expression of SCF and its receptor, c-kit within human asthmatic
      airways, which suggests an important role of this cytokine in the pathophysiology
      of asthma.

PMID- 15196280
TI  - Functional expression of high-affinity receptor for immunoglobulin E on mast
      cells precedes that of tryptase during differentiation from human bone marrow
      derived CD34 progenitors cultured in the presence of stem cell factor and
      interleukin-6.
AB  - BACKGROUND: CD34(+) progenitor cells develop into tryptase(+), CD117(+) mast
      cells when cultured in the presence of recombinant human stem cell factor
      (rhSCF). However, spontaneous IgE receptor (FcepsilonRI) expression during human
      mast cell development is not well examined. OBJECTIVE: Here, the expression and
      function of FcepsilonRI in and on human bone marrow-derived mast cells (HBMMCs)
      during development were investigated. METHODS AND RESULTS: At 4 weeks of culture,
      predominant cells expressed high-affinity IgE receptor alpha chain
      (FcepsilonRIalpha) on the cell surface determined by flow cytometry, but CD117
      was less expressed. Immunocytochemistry with antitryptase mAb and anti
      FcepsilonRIalpha mAb revealed intracellular and surface expression of
      FcepsilonRIalpha at 2 weeks of culture, but tryptase was less expressed.
      FcepsilonRIalpha mRNA transcript preceded that of tryptase mRNA at 2 weeks of
      culture determined by real-time RT-PCR, and FcepsilonRIalpha, FcepsilonRIbeta,
      FcepsilonRIgamma, and tryptase mRNA increased along with differentiation.
      FcepsilonRIalpha cross-link on HBMMC and 4-week-old mast cells/mast cell
      precursors induced the release of IL-5 and granulocyte macrophage-colony
      stimulating factor, which was enhanced by rhSCF. CONCLUSION: These data indicated
      that HBMMC constitutively and spontaneously expressed functional FcepsilonRI
      subunits at the early stage of differentiation, probably because of the
      differences in the ability and functional property of progenitors.

PMID- 15196281
TI  - Mechanical strain enhances proteoglycan message in fibroblasts from asthmatic
      subjects.
AB  - BACKGROUND: Remodelling of the asthmatic airway includes increased deposition of
      proteoglycan (PG) molecules. One of the stimuli driving airway remodelling may be
      excessive mechanical stimulation. OBJECTIVE: We hypothesized that fibroblasts
      from asthmatic patients would respond to excessive mechanical strain with up
      regulation of message for PGs. METHODS: We obtained fibroblasts from asthmatic
      patients (AF) and normal volunteers (NF) using endobronchial biopsy. Cells were
      maintained in culture until the fifth passage and then grown on a flexible
      collagen-coated membrane. Using the Flexercell device, cells were then subjected
      to cyclic stretch at 30% amplitude at 1 Hz for 24 h. Control cells were
      unstrained. Total RNA was extracted from the cell layer and quantitative RT-PCR
      performed for decorin, lumican and versican mRNA. RESULTS: In unstrained cells,
      the expression of decorin mRNA was greater in AF than NF. With strain, NF showed
      increased expression of versican mRNA and AF showed increased expression of
      versican and decorin mRNA. The relative increase in versican mRNA expression with
      strain was greater in AF than NF. CONCLUSIONS: These data support the hypothesis
      that proteoglycan message is increased in asthmatic fibroblasts subject to
      mechanical strain. This finding has implications for the mechanisms governing
      airway wall remodelling in asthma.

PMID- 15196282
TI  - Urinary 3-bromotyrosine and 3-chlorotyrosine concentrations in asthmatic
      patients: lack of increase in 3-bromotyrosine concentration in urine and plasma
      proteins in aspirin-induced asthma after intravenous aspirin challenge.
AB  - BACKGROUND: Eosinophil peroxidase and myeloperoxidase halogenate tyrosine
      residues in plasma proteins and generate 3-bromotyrosine (BY) and 3
      chlorotyrosine (CY), respectively. OBJECTIVES: (1) To estimate urinary
      concentrations of BY and CY in asthmatic patients. (2) To investigate BY
      concentration in relation to urinary leukotriene E4 (LTE4) concentration in order
      to evaluate the activation of eosinophils in patients with aspirin-induced asthma
      (AIA). METHODS: BY and CY were quantified with a gas chromatograph-mass
      spectrometer using (13)C-labelled compounds as internal standards. RESULTS: (1)
      Activation of eosinophils and neutrophils by immobilized IgG1 induced
      preferential formation of BY and CY, respectively. (2) A significantly higher
      concentration of BY was observed in the urine from asthmatic patients than in
      that from healthy control subjects (45+/-21.7 vs. 22.6+/-10.8 ng/mg-creatinine,
      P<0.01). CY concentration was also elevated in the urine from asthmatic patients
      (4.4+/-3.2 vs. 1.5+/-1.0 ng/mg-creatinine, P<0.01). (3) After intravenous aspirin
      challenge of aspirin-induced asthmatic patients, the concentration of BY in urine
      did not significantly change. No significant change was also observed in the
      ratio of BY concentration to total tyrosine concentration in plasma proteins. In
      contrast, the concentration of urinary LTE4 significantly increased after the
      intravenous aspirin challenge. CONCLUSION: Determination of BY and CY
      concentrations may be useful for monitoring the activation of eosinophils and
      neutrophils in asthmatic patients, respectively. After aspirin challenge of AIA
      patients, the increased concentration of urinary LTE4 did not accompany changes
      in BY concentration in both urine and plasma proteins. These results may preclude
      the activation of eosinophils after aspirin challenge in patients with AIA.

PMID- 15196283
TI  - Effect of cysteinyl leukotriene receptor antagonist on CD11b and CD23 expression
      in asthmatic children.
AB  - BACKGROUND: Cysteinyl leukotrienes are potent pro-inflammatory mediators that
      contribute to the pathophysiologic features observed in allergic asthma.
      Inhibitors of leukotriene receptors represent novel therapy in asthma treatment.
      In addition to the protection from early asthmatic responses, these drugs have
      recently been shown to protect from late airway responses too. METHODS: We
      studied the effect of treatment with an oral antagonist of cysteinyl leukotriene
      receptors on the increased expression of the low-affinity IgE receptor, CD23, on
      B cells, and of its ligands, CD11b and CD11c, on CD4(+) T cells and monocytes in
      peripheral blood of patients with allergic asthma. In this uncontrolled open
      label study, 14 children with allergic asthma received montelukast, a cysteinyl
      leukotrine receptor antagonist, for a period of 6 weeks after demonstrating
      forced expiratory volume in 1 s (FEV(1)) of less than 80% of the predicted value.
      Samples of peripheral heparinized blood and sera were obtained before and after
      therapy completion. Three-colour immunofluorescence analysis was performed, and
      expression of CD11b and CD11c on CD4(+) T lymphocytes and monocytes as well as
      the expression of CD21 and CD23 on B cells were determined (n=12). Peripheral
      blood eosinophil count, changes in FEV(1) and peak expiratory flow rate (PEFR),
      asthma exacerbations, and as-needed use of beta-agonist were also monitored.
      RESULTS: Montelukast improved FEV(1) and PEFR, and decreased peripheral
      eosinophil counts in all study patients. There was no significant change in the
      expression of CD21 and CD23 on B cells. The expression of CD11c on CD4(+) T cells
      and of both CD11b and CD11c on monocytes remained similar to the pretreatment
      expression. However, the percentage of CD11b(+)CD4(+) T lymphocytes significantly
      decreased after treatment with montelukast. This was accompanied by a significant
      decrease in the levels of total IgE. CONCLUSION: The capacity of 6-week
      montelukast therapy to reduce the percentage of CD11b CD4(+) T cells might be a
      mechanism leading to the immune response modulation on this T cell subset
      interaction with CD23-expressing B cells and subsequent down-regulation of IgE
      synthesis.

PMID- 15196284
TI  - Effect of glucocorticosteroids on tumour necrosis factor-alpha-induced
      intercellular adhesion molecule-1 expression in cultured primary human nasal
      epithelial cells.
AB  - OBJECTIVE: In order to confirm the direct effect of glucocorticosteroids on
      epithelial intercellular adhesion molecule-1 (ICAM-1) expression, we examined
      ICAM-1 expression on primary cultured human nasal epithelial cells (HNECs) at
      both protein and mRNA levels. MATERIAL AND METHODS: HNECs were stimulated with
      recombinant human TNF-alpha (20 pg/mL-20 ng/mL) for specified time periods (0,
      12, 24, and 48 h) and ICAM-1 mRNA and the soluble ICAM-1 (sICAM-1) concentrations
      were measured by quantitative RT-PCR and ELISA, respectively. We also evaluated
      surface expression of ICAM-1 by flow cytometry 48 h after stimulation and
      determined the effect of dexamethasone (DEX) on TNF-alpha-induced ICAM-1
      expression. RESULTS: Significant increases in ICAM-1 gene expression in HNECs
      were initially detected at 24 h, peaking at 48 h after the stimulation. The TNF
      mediated-ICAM-1 mRNA and ICAM-1 surface expression at 48 h was significantly
      inhibited by co-incubation with human recombinant soluble TNF receptor I.
      Similarly, TNF-alpha-induced release sICAM-1 occurred in a time- and
      concentration-dependent manner. DEX 10(-6) M attenuated the TNF-alpha-induced
      ICAM-1 expression at mRNA and protein levels. CONCLUSIONS: Our finding suggests a
      potential role for topical steroids in allergic rhinitis in suppressing
      inflammatory reactions in the nasal mucosa by regulating ICAM-1 expression on
      nasal epithelium.

PMID- 15196285
TI  - Treatment with intranasal fluticasone propionate significantly improves ocular
      symptoms in patients with seasonal allergic rhinitis.
AB  - BACKGROUND: If monotherapy with an intranasal corticosteroid can alleviate both
      nasal and ocular symptoms of allergic rhinitis, treatment may be simplified and
      costs may be reduced. OBJECTIVE: The purpose of this study was to evaluate the
      efficacy of once-daily fluticasone propionate (FP) aqueous nasal spray 200 microg
      compared with vehicle placebo and oral loratadine (LOR) 10 mg in reducing ocular
      symptoms associated with seasonal allergic rhinitis. METHODS: A total of 471
      patients received vehicle placebo, LOR, or FP in this multi-centre, double-blind,
      double-dummy, randomized study. Patients were > or =12 years old with a history
      of seasonal allergic rhinitis and a positive skin test for a relevant allergen.
      During the baseline and treatment periods, patients rated the severity of eye
      itching, tearing, and redness via visual analogue scales that ranged from 0 (no
      symptoms) to 100 (most severe symptoms). The three ocular ratings were added to
      derive the total ocular symptom score (TOSS). Patients with a TOSS > or =120 on
      at least 4 of the 7 days before the randomization visit were enrolled. The
      primary outcome was the difference between FP and vehicle placebo in the mean
      change from baseline in the reflective TOSS overall (averaged over the 28-day
      treatment period). A difference between FP and vehicle placebo of 25.5 was
      considered clinically significant. RESULTS: The overall mean change from baseline
      in the TOSS was significantly greater in the FP group compared with vehicle
      placebo (clinically significant difference of 28.8; P<0.001) and compared with
      LOR (difference of 16.2; P=0.028). Overall mean (SEM) changes were -59.9 (5.4)
      for the placebo group, -72.5 (5.4) for the LOR group, and -88.7 (5.3) for the FP
      group. The FP treatment group also showed significantly greater overall mean
      changes in ocular itching, tearing, and redness compared with vehicle placebo
      (P<0.001) and compared with LOR (P< or =0.045). CONCLUSION: Patients treated with
      intranasal FP had clinically and statistically significant decreases in ocular
      symptom scores compared with vehicle placebo. Data also suggest that FP reduced
      ocular symptoms more than or comparable with oral LOR. Patients experiencing
      ocular symptoms associated with allergic rhinitis may benefit from monotherapy
      with intranasal FP.

PMID- 15196286
TI  - Levocetirizine improves nasal obstruction and modulates cytokine pattern in
      patients with seasonal allergic rhinitis: a pilot study.
AB  - BACKGROUND: Allergic rhinitis is characterized by an IgE-dependent inflammation.
      Nasal obstruction is related to allergic inflammation. Some antihistamines have
      been demonstrated to be capable of improving this nasal symptom. OBJECTIVE: The
      aim of this pilot study was to evaluate nasal symptoms, nasal airflow,
      inflammatory cells, and cytokine pattern in patients with seasonal allergic
      rhinitis (SAR), before and after treatment with levocetirizine, desloratadine, or
      placebo. METHODS: Thirty patients with SAR were evaluated, 27 males and three
      females (mean age 26.9+/-5.4 years). All of them received levocetirizine (5
      mg/day), desloratadine (5 mg/day), or placebo for 2 weeks. The study was double
      blind, parallel-group, placebo-controlled, and randomized. Total symptom score
      (TSS) (including: rhinorrhea, nasal itching, sneezing, and nasal obstruction) was
      assessed before and after treatment. Rhinomanometry, nasal lavage, and nasal
      scraping were performed in all subjects before and after treatment. Inflammatory
      cells were counted by conventional staining; IL-4 and IL-8 were measured by
      immunoassay on fluids recovered from nasal lavage. RESULTS: Levocetirizine
      treatment induced significant symptom relief (P=0.0009) and improved nasal
      airflow (P=0.038). Desloratadine also relieved TSS (P=0.01), but did not affect
      nasal airflow. Levocetirizine significantly reduced eosinophils (P=0.029),
      neutrophils (P=0.005), IL-4 (P=0.041), and IL-8 (P=0.02), whereas desloratadine
      diminished IL-4 only (P=0.044). Placebo treatment did not significantly affect
      any evaluated parameters. CONCLUSIONS: This pilot study demonstrates the
      effectiveness of levocetirizine in: (i) relieving nasal symptoms, (ii) improving
      nasal airflow, (iii) reducing leucocyte infiltration, and (iv) diminishing
      cytokine levels. These findings are the first evidence of the effectiveness of
      levocetirizine in SAR.

PMID- 15196287
TI  - Th1-dominant shift of T cell cytokine production, and subsequent reduction of
      serum immunoglobulin E response by administration in vivo of plasmid expressing
      Txk/Rlk, a member of Tec family tyrosine kinases, in a mouse model.
AB  - BACKGROUND: Th1 and Th2 cells, resulting from antigenic stimulation in the
      presence of IL-12 and IL-4, respectively, are implicated in the pathology of
      various diseases including allergic and autoimmune diseases. Txk/Rlk is a member
      of Tec family tyrosine kinases. We reported that Txk acts as a Th1-specific
      transcription factor in the T lymphocytes. OBJECTIVE: In this study we have asked
      whether administration of txk expression plasmid brings about a Th1/Th2 shift in
      vivo of the mice, and subsequent reduction of circulating IgE. METHODS: Mice were
      administered a txk expression plasmid with hemagglutinating virus of Japan (HVJ)
      envelope vector. Txk expressions in spleen cells were assessed by immunoblotting
      and immunocytochemical staining. Cytokine productions by the spleen cells and
      serum Ig concentrations were studied by ELISA. RESULTS: Administration of a txk
      expression plasmid with HVJ vector induced expression of Txk in the spleen cells.
      The spleen cells showed enhanced Th1-specific cytokine production; spleen cells
      from the txk administered mice produced more IFN-gamma as compared with those
      from control plasmid-administered mice in an antigen-specific manner. IL-2 and IL
      4 secretions of the spleen cells were comparable between the two mouse groups.
      Txk administration did not reduce serum IgG concentration. It markedly reduced
      total IgE level and an IgG1/IgG2a ratio, reflection of Th1/Th2 balance, in sera.
      Furthermore, txk administration reduced ovalbumin (OVA)-specific IgE levels in
      sera of the OVA sensitized mice. CONCLUSION: Thus, Txk enhances IFN-gamma
      secretion and thus modulates Th1/Th2 cytokine balance, leading to reduction of
      serum IgE.

PMID- 15196288
TI  - Rosmarinic acid in perilla extract inhibits allergic inflammation induced by mite
      allergen, in a mouse model.
AB  - BACKGROUND: Perilla and its constituent rosmarinic acid have been suggested to
      have anti-allergic activity. However, few studies have examined the effects on
      allergic asthma. OBJECTIVE: The purpose of this study was to evaluate the effect
      of oral administration of perilla leaf extract, which contains high amount of
      rosmarinic acid, on a murine model of allergic asthma induced by house dust mite
      allergen. METHODS: C3H/He mice were sensitized by intratracheal administration of
      Dermatophagoides farinae (Der f). Mice were orally treated with rosmarinic acid
      in perilla extract (PE) (1.5 mg/mouse/day). RESULTS: Der f challenge of
      sensitized mice elicited pulmonary eosinophilic inflammation, accompanied by an
      increase in lung expression of IL-4 and IL-5, and eotaxin. Daily treatment with
      rosmarinic acid in PE significantly prevented the increases in the numbers of
      eosinophils in bronchoalveolar lavage fluids and also in those around murine
      airways. Rosmarinic acid in PE treatment also inhibited the enhanced protein
      expression of IL-4 and IL-5, and eotaxin in the lungs of sensitized mice. Der f
      challenge also enhanced allergen-specific IgG1, which were also inhibited by
      rosmarinic acid in PE. CONCLUSION: These results suggest that oral administration
      of perilla-derived rosmarinic acid is an effective intervention for allergic
      asthma, possibly through the amelioration of increases in cytokines, chemokines,
      and allergen-specific antibody.

PMID- 15196289
TI  - Inhaled cornstarch glove powder increases latex-induced airway hyper-sensitivity
      in guinea-pigs.
AB  - BACKGROUND: Breathing is one of the most important modes of sensitization to
      natural rubber latex (NRL) for health-care workers, a group most at risk.
      Cornstarch powder (CSp) from medical powdered NRL gloves is known to be an
      allergen carrier, and sensitization to NRL can occur by inhaling airborne
      particles from such gloves. OBJECTIVE: The aim of this study was to demonstrate,
      using an experimental model, which CSp may act as an adjuvant in NRL-induced
      airway hyper-responsiveness. METHODS: Guinea-pigs were exposed to aerosolized NRL
      contaminated CSp or to NRL in saline solution for 1 h every day for 2 weeks. The
      control groups were exposed either to CSp or to saline alone. An additional group
      of guinea-pigs was exposed to aerosolized ovalbumin (OVA) in saline. Three weeks
      after the last exposure, specific bronchial challenges were performed. In
      addition, Specific IgG and IgG1 in sera and thromboxane (Tx) B(2) levels in
      bronchoalveolar lavage fluid (BALF) were measured. RESULTS: The NRL challenge
      caused significant bronchospasm in the animals that had been exposed to NRL
      compared with those in the control groups (P<0.02). Guinea-pigs exposed to OVA
      also demonstrated a significant bronchospasm after OVA challenge (P<0.001). The
      guinea-pigs that had inhaled NRL-contaminated CSp had a significantly higher
      bronchoconstriction level than those that had inhaled NRL alone (P<0.02).
      Specific IgG and IgG1 were undetectable in sera from all groups, whereas
      significant amounts of TxB(2) (P<0.001) were found in the lungs of the guinea
      pigs exposed to NRL or OVA. CONCLUSION: Inhaling CSp increases the airway
      response to NRL. The fact that specific IgG and IgG1 were not detected might be
      the result of an immune response limited to the airways. This finding is
      supported by a significant increase of TxB(2) level in the BALF of sensitized
      guinea-pigs.

PMID- 15196290
TI  - Presence of staphylococcal exfoliative toxin A in sera of patients with atopic
      dermatitis.
AB  - BACKGROUND: It has been reported that the toxins that Staphylococcus aureus
      produces are associated with the exacerbation of atopic dermatitis (AD). It has
      been shown in many studies that staphylococcal enterotoxin (SE) A and SEB
      contribute to AD by humoral immunity through IgE production as a superantigen. On
      the other hand, little attention has been paid to the relationship between AD and
      exfoliative toxin x (ETx). OBJECTIVE: We investigated the toxins that are
      frequently detected from the skin of patients and how these toxins affect AD.
      METHODS: S. aureus, isolated from the skin of 100 patients with mild to severe
      AD, were examined for the producibility of toxins by polymerase chain reaction.
      Serum samples were obtained from 21 patients with mild and moderate AD. The
      levels of SEB, ETA, total IgE, specific IgE, and specific IgG in sera were
      measured by ELISA. RESULTS: SEB was most frequently detected from S. aureus on
      the skin of these patients as previously reported. And ETx, to which little
      attention has been paid so far, was frequently detected next to SEB. Furthermore,
      ETA was detected from the sera of almost all the AD patients. SEB was not
      detected at all. Although the level of ETA in the AD group was significantly
      higher than that of controls, ETA-specific IgE was not detected from their sera.
      High levels of ETA tended to be detected from infantile patients. Although there
      were no significant differences in the levels of ETA-IgG between AD and the
      controls, its prevalence was more than twice as high as the controls in AD.
      CONCLUSION: These results suggest that many AD patients were exposed to ETx. We
      conclude that ETx may contribute to exacerbation of AD, particularly in infants,
      by a mechanism that is not through specific IgE production, unlike SEB.

PMID- 15196291
TI  - Cardiovascular safety of triptans.

PMID- 15196292
TI  - Effect of high-dose intravenous eletriptan on coronary artery diameter.
AB  - The goal of this study was to evaluate the coronary vasoconstrictive effects of
      high doses of eletriptan compared with a standard dose of sumatriptan. Patients
      with no clinically significant coronary artery disease were randomized to receive
      high-dose intravenous eletriptan (n = 24) vs a standard dose of sumatriptan (n =
      18; 6 mg subcutaneously) vs placebo (n = 18). Serial angiograms were obtained.
      The primary non-inferiority analysis found equivalence between the mean maximum
      change in left anterior descending coronary artery diameter for eletriptan, 
      22%[95% confidence interval (CI) -26, -19], and sumatriptan, -19% (95% CI -22, 
      16). The change due to placebo was -16% (95% CI -20, -12). No individual cases of
      clinically significant vasoconstriction were observed. The results confirm that
      eletriptan has a broad cardiovascular safety margin, with plasma concentrations
      comparable to three to five times the Cmax of an oral 80-mg dose associated with
      modest vasoconstriction equivalent to standard therapeutic doses of sumatriptan.

PMID- 15196293
TI  - American academic headache specialists in neurology: practice characteristics and
      culture.
AB  - Headache diagnosis and treatment is the most important focus or concentration
      area for practising neurologists in America. The American Headache Society,
      formerly the American Association for the Study of Headache, is made up
      predominantly of neurologists. Recognition of the importance of the teaching and
      practice of headache medicine, especially migraine, is still incomplete at many
      academic teaching institutions. Suggestions that this results from inadequate
      academic hierarchies and education at graduate and post-graduate levels have been
      made. We therefore undertook a survey of academic practitioners of headache
      medicine in departments of neurology with membership of the American Headache
      Society. Subjects and addresses were identified using the 1999-2000 membership
      directory of the American Headache Society. Practice characteristics and time
      distribution were assessed. Teaching in undergraduate and resident programmes was
      also assessed. Fifty-five surveys from 46 institutions in 25 states were judged
      as adequate for this report. Academic neurologists with interest in headache
      medicine spent most of their time in clinic, with less than 25% spent doing
      either research or teaching. Medical schools had an average of 1 h of preclinical
      and 2 h of clinical teaching in headache. Neurology residents received an average
      of 3 h of didactic instruction in headache. This report is the first of its kind
      to review the practice characteristics and culture of headache medicine in the
      setting of academic departments of neurology. It describes a clinical practice
      similar to those of other non-academic American neurologists.

PMID- 15196294
TI  - Flunarizine effects on oxidative stress in migraine patients.
AB  - Prophylactic activity of flunarizine in migraine is attributed to its antioxidant
      properties and to the relief of cerebral vasospasm in which nitric oxide (NO) is
      involved. We investigated the antimigraine activity of flunarizine and its
      influence on NO and oxidative marker bioavailability in 25 subjects suffering
      from migraine without aura and in 25 healthy controls. Urinary samples collected
      before and after treatment with flunarizine (5 mg orally per day for 6 months)
      were assayed for NO stable metabolites (NOx) and thiobarbituric acid reactive
      substances (TBARS). Urinary levels of NOx and TBARS were higher in migraine
      sufferers before treatment than in healthy controls. No differences were observed
      in NOx levels in migraine sufferers, before and after flunarizine treatment;
      urinary TBARS levels were decreased after flunarizine treatment (P < 0.05) and
      remained persistently higher than in healthy controls (P < 0.05). Our results
      suggest that flunarizine did not prevent NO-mediated vasodilatation, while it
      proved effective in limiting the oxidative reactions occurring in migraine
      sufferers.

PMID- 15196295
TI  - Familial hemiplegic migraine: follow-up findings of diffusion-weighted magnetic
      resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAO-SPECT in a patient with
      prolonged hemiplegic aura.
AB  - Familial hemiplegic migraine (FHM) is a rare inherited autosomal dominant
      disorder. Migraine aura may last up to several weeks and then resolve without
      sequel. We report a 21-year-old male with FHM since the age of 3 years. Diffusion
      weighted magnetic resonance imaging (DWI), perfusion-MR imaging (P-MRI) and
      [99mTc] hexamethyl-propyleneamine-oxime-single photon emission tomography (HMPAO
      SPECT) were performed on day 2, when he was somnolent with right-sided
      hemiplegia, on day 9 when a mild hemiparesis was still present and on day 24
      after recovery. The right central region showed normal findings in DWI, whereas P
      MRI and SPECT revealed hyperperfusion on day 2, less marked on day 9, and normal
      findings on day 24. In conclusion, this case report indicates for the first time,
      by means of SPECT, P-MRI and DWI studies, that even extremely long-lasting
      migraine aura is not associated with cerebral ischaemia. Therefore, it supports
      the revised International Headache Society criteria where the term 'persistent'
      aura is proposed.

PMID- 15196296
TI  - Comparison of rizatriptan 5 mg and 10 mg tablets and sumatriptan 25 mg and 50 mg
      tablets.
AB  - This randomized, double-blind, two-attack, placebo-controlled, crossover study
      explored the efficacy and tolerability of rizatriptan 10 mg compared with
      sumatriptan 50 mg as well as rizatriptan 5 mg compared with sumatriptan 25 mg in
      the acute treatment of migraine. Following randomization to one of six possible
      treatment sequences, patients (n = 1447) treated two sequential attacks, of
      moderate or severe intensity, separated by at least 5 days. Patients assessed
      pain severity, migraine-associated symptoms, and functional disability at 0.5, 1,
      1.5, and 2 h post treatment. Compared with placebo, all treatments were
      effective. On the primary endpoint of time to pain relief, rizatriptan 10 mg was
      not statistically different from sumatriptan 50 mg [odds ratio (OR) 1.10, P =
      0.161], and rizatriptan 5 mg was statistically superior to sumatriptan 25 mg (OR
      1.22, P = 0.007). In general, rizatriptan 10 mg and 5 mg treatment resulted in
      improvement compared with the corresponding doses of sumatriptan on measures of
      pain severity, migraine symptoms, and functional disability and the 5-mg dose
      reached statistical significance on almost all measures. All treatments were
      generally well tolerated.

PMID- 15196298
TI  - Auditory event-related potentials and reaction times in migraine children.
AB  - Cognitive processing was investigated interictally in 18 children with migraine
      without aura and 18 age-matched controls by measuring event-related potentials
      (ERPs) and reaction times (RTs) during an acoustic oddball paradigm. Results
      showed that N100 amplitude evoked by frequent stimuli was significantly smaller
      in patients compared with controls. Habituation of target P300 amplitude was
      observed in patients but not in controls. Mean RTs were equivalent in the two
      groups, but migraine children made more errors than controls.

PMID- 15196297
TI  - Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache.
AB  - Sildenafil, a selective inhibitor of the cyclic guanosine monophosphate (cGMP)
      degrading phosphodiestrase 5 (PDE5), induced migraine without aura in 10 of 12
      migraine patients and in healthy subjects it induced significantly more headache
      than placebo. The aim of the present study was to determine whether the pain
      inducing effects of sildenafil would be reflected in plasma levels of important
      signalling molecules in migraine: cGMP, cyclic adenosine monophosphate (cAMP) and
      calcitonin gene-related peptide (CGRP). Ten healthy subjects (four women, six
      men) and 12 patients (12 women) suffering from migraine without aura were
      included in two separate double-blind, placebo-controlled, cross-over studies in
      which placebo or sildenafil 100 mg was administered orally. Plasma levels of
      CGRP, cAMP and cGMP were determined in blood from the antecubital vein. Despite
      the ability of sildenafil to induce headache and migraine, no significant
      differences in plasma levels of CGRP, cGMP and cAMP were detected after
      sildenafil compared with placebo. In conclusion, plasma levels of CGRP, cGMP and
      cAMP remain normal during sildenafil-induced headache or migraine. However, since
      previous studies indicate an important role of these signalling molecules, the
      present study questions whether cAMP and cGMP in peripheral blood can be used for
      monitoring pathophysiological events in headache and migraine mechanisms.

PMID- 15196299
TI  - Clinical characteristics of 362 patients with familial migraine with aura.
AB  - The objectives of the present study were to describe the clinical characteristics
      of patients with severe familial non-hemiplegic migraine with aura (NHMA) and to
      compare these data to those from cases in previous population-based Danish
      studies using the same methodology. NHMA families were recruited from the Danish
      patient registry and from Danish neurology practices. A total of 362 NHMA
      patients were diagnosed according to the 1988 International Headache Society
      criteria using a validated semistructured physician-conducted interview. Visual
      aura occurred in almost every NHMA attack. In aura without headache visual aura
      occurred primarily in isolation. Aura without headache was most common in older,
      male patients. Several clinical characteristics of familial NHMA differed from
      migraine with aura in the general population: firstly, the age at onset was
      lower, secondly, the age at cessation was higher, thirdly, aura symptoms were
      more severe and finally, the co-occurrence of migraine without aura was higher in
      familial NHMA. There seems to be a correlation between more severe symptoms and
      familial aggregation. These results have both clinical and scientific
      implications.

PMID- 15196300
TI  - The prophylactic effect of valproate on glyceryltrinitrate induced migraine.
AB  - In this study the human glyceryltrinitrate (GTN) model of migraine was for the
      first time used to test the effect of a prophylactic drug. We chose to test
      valproate due to its well documented effect as a migraine prophylactic drug.
      Efficacy of this compound would support the usefulness of the model in
      prophylactic antimigraine drug development. Twelve patients with migraine without
      aura were included in a randomized double blind crossover study. Valproate 1000
      mg or placebo was given daily, each for a minimum of 13 days. On the last
      treatment day of each arm a 20 min intravenous infusion of GTN (0.25
      microg/kg/min) was given. Headache was registered for 12 h after the infusion and
      headache intensity was scored on a scale from 0 to 10. Fulfillment of IHS
      criteria was recorded for 24 h. The middle cerebral arteries were evaluated by
      transcranial Doppler and the diameter of the superficial temporal and radial
      arteries were measured with high frequency ultrasound. GTN evoked migraine
      fulfilling IHS criteria 1.1 in 6 patients after placebo and in 2 patients after
      valproate (P = 0.125). Including additionally 3 patients on placebo and 1 patient
      on valproate who felt they had suffered a migraine attack, but who had as
      associated symptoms only photophobia or phonophobia, a significant reduction in
      the number of patients with induced migraine after valproate was seen (P =
      0.031). Median peak headache intensity was 1 (range 0-9) after valproate compared
      to 4.5 (range 0-8) after placebo (P = 0.120). Pretreatment with valproate as
      compared to placebo reduced the velocity in both middle cerebral arteries after
      GTN (left P = 0.021, right P = 0.031). No effect of valproate was seen in the
      diameter of the superficial temporal artery (P = 0.781) or the radial artery (P =
      0.367) before or after GTN. The study indicates that a prophylactic effect of
      valproate may be demonstrated using the GTN human migraine model. Although, all
      headache parameters were reduced after valproate compared to placebo, only one
      parameter was statistically significantly reduced probably because of the small
      number of patients. The size of the effect was similar to that of valproate in
      clinical trials. The GTN model may therefore be a valid tool for testing new
      prophylactic antimigraine drugs.

PMID- 15196301
TI  - The sumatriptan/naratriptan aggregated patient (SNAP) database: aggregation,
      validation and application.
AB  - Pooled data from multiple clinical trials can provide information for medical
      decision-making that typically cannot be derived from a single clinical trial. By
      increasing the sample size beyond that achievable in a single clinical trial,
      pooling individual-patient data from multiple trials provides additional
      statistical power to detect possible effects of study medication, confers the
      ability to detect rare outcomes, and facilitates evaluation of effects among
      subsets of patients. Data from pharmaceutical company-sponsored clinical trials
      lend themselves to data-pooling, meta-analysis, and data mining initiatives.
      Pharmaceutical company-sponsored clinical trials are arguably among the most
      rigorously designed and conducted of studies involving human subjects as a result
      of multidisciplinary collaboration involving clinical, academic and/or
      governmental investigators as well as the input and review of medical
      institutional bodies and regulatory authorities. This paper describes the
      aggregation, validation and initial analysis of data from the
      sumatriptan/naratriptan aggregate patient (SNAP) database, which to date
      comprises pooled individual-patient data from 128 clinical trials conducted from
      1987 to 1998 with the migraine medications sumatriptan and naratriptan. With an
      extremely large sample size (>28000 migraineurs, >140000 treated migraine
      attacks), the SNAP database allows exploration of questions about migraine and
      the efficacy and safety of migraine medications that cannot be answered in single
      clinical trials enrolling smaller numbers of patients. Besides providing the
      adequate sample size to address specific questions, the SNAP database allows for
      subgroup analyses that are not possible in individual trial analyses due to small
      sample size. The SNAP database exemplifies how the wealth of data from
      pharmaceutical company-sponsored clinical trials can be re-used to continue to
      provide benefit.

PMID- 15196303
TI  - Hemicrania continua postpartum.
AB  - Hemicrania continua is a common, but unrecognized headache disorder. We describe
      two patients with hemicrania continua whose symptoms started in the postpartum
      period, coined as hemicrania continua postpartum.

PMID- 15196302
TI  - LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in
      acute migraine.
AB  - Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558,
      an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA)
      receptor antagonist, is effective in preclinical models of migraine. We therefore
      tested LY293558 in acute migraine. We conducted a randomized, triple-blind,
      parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV)
      LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of
      acute migraine. The primary efficacy variable was the headache response rate,
      i.e. headache score improvement from moderate/severe at baseline to mild/none at
      2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9
      years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs.
      placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo.
      LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons)
      on all other measures of improvement in pain and migraine associated symptoms.
      Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n =
      2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n
      = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs
      (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in
      this small migraine proof of concept trial, together with supportive preclinical
      data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists
      in treating migraine. Larger trials are needed to further test the hypothesis.

PMID- 15196304
TI  - Secondary trigeminal autonomic cephalgia associated with multiple sclerosis.

PMID- 15196305
TI  - Chronic paroxysmal hemicrania in early childhood: case report.

PMID- 15196306
TI  - Physician behaviour for antimicrobial prescribing for paediatric upper
      respiratory tract infections: a survey in general practice in Trinidad, West
      Indies.
AB  - BACKGROUND: Upper respiratory tract infections (URTIs) are among the most
      frequent reasons for physician office visits in paediatrics. Despite their
      predominant viral aetiology, URTIs continue to be treated with antimicrobials. We
      explored general practitioners' (GPs) prescribing behaviour for antimicrobials in
      children (< or = 16 years) with URTIs in Trinidad, using the guidelines from the
      Centers for Disease Control and Prevention (CDC) as a reference. METHODS: A cross
      sectional study was conducted on 92 consenting GPs from the 109 contacted in
      Central and East Trinidad, between January to June 2003. Using a pilot-tested
      questionnaire, GPs identified the 5 most frequent URTIs they see in office and
      reported on their antimicrobial prescribing practices for these URTIs to trained
      research students. RESULTS: The 5 most frequent URTIs presenting in children in
      general practice, are the common cold, pharyngitis, tonsillitis, sinusitis and
      acute otitis media (AOM) in rank order. GPs prescribe at least 25 different
      antibiotics for these URTIs with significant associations for amoxicillin, co
      amoxiclav, cefaclor, cefuroxime, erythromycin, clarithromycin and azithromycin (p
      < 0.001). Amoxicillin alone or with clavulanate was the most frequently
      prescribed antibiotic for all URTIs. Prescribing variations from the CDC
      recommendations were observed for all URTIs except for AOM (50%), the most common
      condition for antibiotics. Doctors practicing for >30 years were more likely to
      prescribe antibiotics for the common cold (p = 0.014). Severity (95.7%) and
      duration of illness (82.5%) influenced doctors' prescribing and over prescribing
      in general practice was attributed to parent demands (75%) and concern for
      secondary bacterial infections (70%). Physicians do not request laboratory
      investigations primarily because they are unnecessary (86%) and the waiting time
      for results is too long (51%). CONCLUSIONS: Antibiotics are over prescribed for
      paediatric URTIs in Trinidad and amoxicillin with co-amoxiclav were
      preferentially prescribed. Except for AOM, GPs' prescribing varied from the CDC
      guidelines for drug and duration. Physicians recognise antibiotics are overused
      and consider parents expecting antibiotics and a concern for secondary bacterial
      infections are prescribing pressures. Guidelines to manage URTIs, ongoing
      surveillance programs for antibiotic resistance, public health education on non
      antibiotic strategies, and postgraduate education for rational pharmacotherapy in
      general practice would decrease inappropriate antibiotic use in URTIs.

PMID- 15196307
TI  - Strategies for the introduction and implementation of a guideline for the
      treatment of type 2 diabetics by general practitioners (GPs) of the Lazio region
      of Italy (IMPLEMEG study): protocol for a cluster randomised controlled trial
      [ISRCTN80116232].
AB  - BACKGROUND: Despite broad agreement on the necessity to improve quality of
      diabetic care through implementation of clinical guidelines, in Italy many people
      with diabetes still lack adequate care in general practice. In addition there is
      little evidence to support the choice of implementation strategies, especially in
      the Lazio region (central Italy), where comparative studies among general
      practitioners (GPs) are uncommon. The primary objective of the study is to assess
      the effectiveness of different strategies for the implementation of an evidence
      based guideline for the management of non-complicated type 2 diabetes mellitus
      (DM) among GPs of the Lazio region. METHODS/DESIGN: Three-arm cluster-randomised
      trial (C-RCT). 252 GPs were randomised either to arm 1 (comprising a training
      module and administration of the guideline), or to arm 2 (administration of
      guideline without training), or to arm 3 (control arm), continuing current
      practice. Arm 1 participants attended a two-day course with CME credits. Data
      collection will be performed using current information systems. Patients' health
      data was also collected to describe diabetic populations cared for by GP
      participants. Process outcomes will be measured at the patient level and at the
      cluster level one year after the intervention. We will assess GPs' adherence to
      guideline recommendations for diabetes management relative to: 1) pharmacological
      management of diabetes; 2) pharmacological management of cardiovascular risk
      factors (hypertension and dislypidaemia); 3) measurement of glycosilated
      haemoglobin as the principal indicator of glycaemic control; 4) micro- and
      macrovascular complications assessment tests. Outcomes will be expressed as
      proportions of patients cared for by GPs who will have prescriptions of drugs,
      requests for tests and for outpatient appointment visits. To estimate the
      efficiency of resource use associated with the intervention a cost-effectiveness
      analysis will be carried out. The design of the study is based on three Cochrane
      and one Health Technology Assessment systematic reviews of guideline
      dissemination and implementation strategies.

PMID- 15196308
TI  - A Wireless Health Outcomes Monitoring System (WHOMS): development and field
      testing with cancer patients using mobile phones.
AB  - BACKGROUND: Health-Related Quality of Life assessment is widely used in clinical
      research, but rarely in clinical practice. Barriers including practical
      difficulties administering printed questionnaires have limited their use.
      Telehealth technology could reduce these barriers and encourage better doctor
      patient interaction regarding patient symptoms and quality-of-life monitoring.
      The aim of this study was to develop a new system for transmitting patients' self
      reported outcomes using mobile phones or the internet, and to test whether
      patients can and will use the system via a mobile phone. METHODS: We have
      developed a prototype of a Wireless Health Outcomes Monitoring System, which
      allows structured questionnaires to be sent to the patient by their medical
      management team. The patients' answers are directly sent to an authorised website
      immediately accessible by the medical team, and are displayed in a graphic format
      that highlights the patient's state of health. In the present study, 97 cancer
      inpatients were asked to complete a ten-item questionnaire. The questionnaire was
      delivered by display on a mobile phone, and was answered by the patients using
      the mobile phone keypad. RESULTS: Of the 97 patients, 56 (58%) attempted the
      questionnaire, and all of these 56 completed it. Only 6% of the total number of
      questions were left unanswered by patients. Forty-one (42%) patients refused to
      participate, mostly due to their lack of familiarity with mobile phone use.
      Compared with those who completed the questionnaire, patients who refused to
      participate were older, had fewer years of education and were less familiar with
      new communications technology (mobile phone calls, mobile phone SMS, internet,
      email). CONCLUSION: More than half of the patients self-completed the
      questionnaire using the mobile phone. This proportion may increase with the use
      of multichannel communications which can be incorporated into the system. The
      proportion may also increase if the patient's partner and/or family were able to
      assist the patient with using the technology. These preliminary results encourage
      further studies to identify specific diseases or circumstances where this system
      could be useful in patients' distance monitoring. Such a system is likely to
      detect patient suffering earlier, and to activate a well-timed intervention.

PMID- 15196309
TI  - Inter-observer reproducibility of measurements of range of motion in patients
      with shoulder pain using a digital inclinometer.
AB  - BACKGROUND: Reproducible measurements of the range of motion are an important
      prerequisite for the interpretation of study results. The digital inclinometer is
      considered to be a useful instrument because it is inexpensive and easy to use.
      No previous study assessed inter-observer reproducibility of range of motion
      measurements with a digital inclinometer by physical therapists in a large sample
      of patients. METHODS: Two physical therapists independently measured the passive
      range of motion of the glenohumeral abduction and the external rotation in 155
      patients with shoulder pain. Agreement was quantified by calculation of the mean
      differences between the observers and the standard deviation (SD) of this
      difference and the limits of agreement, defined as the mean difference +/-
      1.96*SD of this difference. Reliability was quantified by means of the intraclass
      correlation coefficient (ICC). RESULTS: The limits of agreement were 0.8 +/- 19.6
      for glenohumeral abduction and -4.6 +/- 18.8 for external rotation (affected
      side) and quite similar for the contralateral side and the differences between
      sides. The percentage agreement within 10 degrees for these measurements were 72%
      and 70% respectively. The ICC ranged from 0.28 to 0.90 (0.83 and 0.90 for the
      affected side). CONCLUSIONS: The inter-observer agreement was found to be poor.
      If individual patients are assessed by two different observers, differences in
      range of motion of less than 20-25 degrees can not be distinguished from
      measurement error. In contrast, acceptable reliability was found for the
      inclinometric measurements of the affected side and the differences between the
      sides, indicating that the inclimeter can be used in studies in which groups are
      compared.

PMID- 15196310
TI  - Jejunal microvilli atrophy and reduced nutrient transport in rats with advanced
      liver cirrhosis: improvement by Insulin-like Growth Factor I.
AB  - BACKGROUND: Previous results have shown that in rats with non-ascitic cirrhosis
      there is an altered transport of sugars and amino acids associated with elongated
      microvilli. These alterations returned to normal with the administration of
      Insulin-Like Growth Factor-I (IGF-I). The aims of this study were to explore the
      evolution of these alterations and analyse the effect of IGF-I in rats with
      advanced cirrhosis and ascites. Thus, jejunal structure and nutrient transport (D
      galactose, L-leucine, L-proline, L-glutamic acid and L-cystine) were studied in
      rats with ascitic cirrhosis. METHODS: Advanced cirrhosis was induced by CCl4
      inhalation and Phenobarbital administration for 30 weeks. Cirrhotic animals were
      divided into two groups which received IGF-I or saline during two weeks. Control
      group was studied in parallel. Jejunal microvilli were studied by electron
      microscopy. Nutrient transport was assessed in brush border membrane vesicles
      using 14C or 35S-labelled subtracts in the three experimental groups. RESULTS:
      Intestinal active Na+-dependent transport was significantly reduced in untreated
      cirrhotic rats. Kinetic studies showed a decreased Vmax and a reduced affinity
      for sugar and four amino acids transporters (expressed as an increased Kt) in the
      brush border membrane vesicles from untreated cirrhotic rats as compared with
      controls. Both parameters were normalised in the IGF-I-treated cirrhotic group.
      Electron microscopy showed elongation and fusion of microvilli with degenerative
      membrane lesions and/or notable atrophy. CONCLUSIONS: The initial microvilli
      elongation reported in non ascitic cirrhosis develops into atrophy in rats with
      advanced cirrhosis and nutrient transports (monosaccharides and amino acids) are
      progressively reduced. Both morphological and functional alterations improved
      significantly with low doses of IGF-I.

PMID- 15196311
TI  - Cloning and functional characterisation of avian transcription factor E2A.
AB  - BACKGROUND: During B lymphocyte development the E2A gene is a critical regulator
      of cell proliferation and differentiation. With regards to the immunoglobulin
      genes the E2A proteins contribute to the regulation of gene rearrangement,
      expression and class switch recombination. We are now using the chicken cell line
      DT40 as a model system to further analyse the function of E2A. RESULTS: Here we
      report the cloning and functional analysis of the transcription factor E2A from
      chicken. Using RACE PCR on the chicken lymphoma cell line DT40 we have isolated
      full-length clones for the two E2A splice variants E12 and E47. Sequence
      conservation between the human and chicken proteins is extensive: the basic-helix
      loop-helix DNA binding domain of human and chicken E47 and E12 are 93% and 92%
      identical, respectively. In addition high levels of conservation are seen in
      activation domain I, the potential NLS and the ubiquitin ligase interaction
      domain. E2A is expressed in a variety of tissues in chicken, with higher levels
      of expression in organs rich in immune cells. We demonstrate that chicken E12 and
      E47 proteins are strong transcriptional activators whose function depends on the
      presence of activation domain I. As in mammals, the dominant negative proteins
      Id1 and Id3 can inhibit the function of chicken E47. CONCLUSIONS: The potential
      for homologous recombination in DT40 allows the genetic dissection of biochemical
      pathways in somatic cells. With the cloning of avian E2A and the recent
      description of an in vitro somatic hypermutation assay in this cell line, it
      should now be possible to dissect the potential role of E2A in the regulation of
      somatic hypermutation and gene conversion.

PMID- 15196312
TI  - Improving signal intensities for genes with low-expression on oligonucleotide
      microarrays.
AB  - BACKGROUND: DNA microarrays using long oligonucleotide probes are widely used to
      evaluate gene expression in biological samples. These oligonucleotides are pre
      synthesized and sequence-optimized to represent specific genes with minimal cross
      hybridization to homologous genes. Probe length and concentration are critical
      factors for signal sensitivity, particularly when genes with various expression
      levels are being tested. We evaluated the effects of oligonucleotide probe length
      and concentration on signal intensity measurements of the expression levels of
      genes in a target sample. RESULTS: Selected genes of various expression levels in
      a single cell line were hybridized to oligonucleotide arrays of four lengths and
      four concentrations of probes to determine how these critical parameters affected
      the intensity of the signal representing their expression. We found that
      oligonucleotides of longer length significantly increased the signals of genes
      with low-expression in the target. High-expressing gene signals were also boosted
      but to a lesser degree. Increasing the probe concentration, however, did not
      linearly increase the signal intensity for either low- or high-expressing genes.
      CONCLUSIONS: We conclude that the longer the oligonuclotide probe the better the
      signal intensities of low expressing genes on oligonucleotide arrays.

PMID- 15196313
TI  - Scope of the problem: epidemiology of anemia and use of blood transfusions in
      critical care.
AB  - Anemia is a common problem in critically ill patients. It is caused, in part, by
      blood loss related to phlebotomy for diagnostic testing, occult gastrointestinal
      bleeding, renal replacement therapies, surgical intervention, and traumatic
      injuries. Reduced red cell life span and nutritional deficiencies (iron, folate,
      vitamin B12) may be other contributing factors. In addition, critically ill
      patients have impaired erythropoiesis because of blunted endogenous
      erythropoietin production and the direct inhibitory effects of inflammatory
      cytokines on red blood cell production by the bone marrow. Blood transfusions are
      commonly utilized for treatment of anemia in critical care, resulting in high use
      of blood transfusions in the intensive care unit (ICU). The percentage of
      patients transfused in the ICU is inversely related to admission hemoglobin and
      directly related to age and severity of illness. Patients with an increased
      length of stay in the ICU are also at increased risk for receiving blood
      transfusions. Studies are needed to improve our understanding of the
      pathophysiology of ICU-acquired anemia, to determine the efficacy of blood
      transfusions in critical care, and to investigate alternatives to blood
      transfusion for the treatment of anemia in the ICU.

PMID- 15196314
TI  - Pathophysiology of intensive care unit-acquired anemia.
AB  - The formation of red blood cells (RBCs) in the bone marrow is regulated by
      erythropoietin in response to a cascade of events. Anemia in the intensive care
      unit can be caused by a host of factors. Patients in the intensive care unit may
      have decreased RBC production and a blunted response to erythropoietin.
      Administration of recombinant human erythropoietin may stimulate erythropoiesis,
      increase hematocrit levels and hemoglobin concentration, and reduce the need for
      RBC transfusions.

PMID- 15196315
TI  - How low is too low? Cardiac risks with anemia.
AB  - Despite the increasing availability of data supporting more restrictive
      transfusion practices, the risks and benefits of transfusing critically ill
      patients continue to evoke controversy. Past retrospective and observational
      studies suggested that liberal transfusion strategies were more beneficial in
      patients whose hematocrit levels fell below 30%. An expanding body of literature
      suggests that an arbitrary trigger for transfusion (the '10/30 rule') is ill
      advised. A recent randomized controlled trial provided compelling evidence that
      similar, and in some cases better, outcomes result if a restrictive transfusion
      strategy is maintained. The impact of this accumulating evidence on clinical
      practice is evident in large reports, which show that the average transfusion
      trigger in critically ill patients was a hemoglobin level in the range 8-8.5
      g/dl. Based on the available evidence, transfusion in the critically ill patient
      without active ischemic heart disease should generally be withheld until the
      hemoglobin level falls to 7 g/dl. Transfusions should be administered as
      clinically indicated for patients with acute, ongoing blood loss and those who
      have objective signs and symptoms of anemia despite maintenance of euvolemia. The
      hemoglobin level at which serious morbidity or mortality occurs in critically ill
      patients with active ischemic heart disease is a subject of continued debate but
      it is likely that a set transfusion trigger will not provide an optimal risk
      benefit profile in this population.

PMID- 15196316
TI  - Alternatives to blood in the 21st century.
AB  - Persons who suffer traumatic injury are likely to be transfused with considerable
      amounts of blood during initial resuscitation efforts. Oxygen-carrying solutions
      are currently in clinical testing as substitutes for red blood cells. Although
      these agents may eliminate many concerns associated with blood administration
      (short shelf life, infectious and immunologic risks, the need to type and cross
      match), early cell-free hemoglobin solutions demonstrated nephrotoxicity and were
      associated with pulmonary and systemic hypertension, among other adverse events.
      Newer polymerized hemoglobin solutions show acceptable safety profiles in the
      surgical setting and studies are being designed, some with funding from the US
      Department of Defense, to evaluate their efficacy in hemorrhaging trauma victims.

PMID- 15196317
TI  - Infectious and immunologic consequences of blood transfusion.
AB  - Blood transfusions remain common practice in the critical care and surgical
      settings. Transfusions carry significant risks, including risks for transmission
      of infectious agents and immune suppression. Transmission of bacterial
      infections, although rare, is the most common adverse event with transfusion. The
      risk for transmission of viral infections has decreased over time, clearly
      because tests are becoming more sensitive in detecting certain viral infections
      such as hepatitis B, hepatitis C, and HIV. Several immunomodulatory effects are
      thought to be related to transfusions, and these can result in cancer recurrence,
      mortality, and postoperative infections. Numerous studies have been performed to
      examine the role of leukoreduction in decreasing these transfusion-related
      complications but results remain contradictory. We review the infectious risks
      associated with blood transfusion and the most recent data on its immunologic
      effects, specifically on cancer recurrence, mortality, and postoperative
      infections in surgical patients. We also review the use of leukoreduction in
      blood transfusion and its role in preventing transfusion-transmitted infections
      and immunomodulatory complications.

PMID- 15196318
TI  - Age of blood: does it make a difference?
AB  - During the past 20 years, the perceived value of blood transfusions has changed
      as it has become appreciated that transfusions are not without risk. Red blood
      cell transfusion has been associated with disease transmission and
      immunosuppression for some time. More recently, proinflammatory consequences of
      red blood cell transfusion have also been documented. Moreover, it has become
      increasingly evident that stored red blood cells undergo time-dependent
      metabolic, biochemical, and molecular changes. This 'storage lesion' may be
      responsible for many of the adverse effects of red blood cell transfusion.
      Clinically, the age of blood has been associated with multiple organ failure,
      postoperative pneumonia, and wound infection. The relationship between age of
      blood and clinical adverse effects needs further study.

PMID- 15196319
TI  - To filter blood or universal leukoreduction: what is the answer?
AB  - The safety of the blood supply has been a concern over the past 20-30 years
      because of the transmission of infectious diseases. Blood is still routinely
      tested for viruses, and leukoreduction is an effective strategy to reduce the
      transmission of cell-associated viruses. Clinically, the benefits of
      leukoreduction include decreases in transfusion reactions, HLA alloimmunization,
      infections, fever episodes, and antibiotic use. Although leukoreduction will add
      cost to a unit of blood, projections indicate that leukoreduced blood will become
      the standard of care.

PMID- 15196320
TI  - Transfusion trigger: when to transfuse?
AB  - The decision to transfuse a hospitalized patient must balance the known risks of
      transfusion with the need to provide adequate tissue oxygenation and the
      appropriate utilization of blood as a scarce resource. The minimum tolerated
      hemoglobin level is not well established, and considerable variation exists in
      intensivists' transfusion practices. Conventional transfusion triggers of 100 g/l
      have been challenged by reports indicating that aerobic metabolism is supported
      by hemoglobin levels of 50 g/l or less. Evidence from randomized trials also
      indicates that withholding transfusions may result in improved outcomes.
      Arbitrary numeric hemoglobin triggers, however, cannot supercede intervention
      based on individual physiologic need and clinical circumstances.

PMID- 15196321
TI  - Phlebotomy in the intensive care unit: strategies for blood conservation.
AB  - The quality and economy of critical care could both be improved if blood losses
      due to phlebotomy and sampling from indwelling catheters for unnecessary
      diagnostic testing were curtailed. Practice guidelines can help to break bad
      diagnostic 'habits', such as fever work-ups that require substantial blood to be
      drawn yet typically yield little useful information. Invasive hemodynamic
      monitoring is associated with morbidity due to blood loss as well as infection,
      and newer noninvasive technologies should be encouraged. Several devices allow
      blood that would otherwise be wasted during sampling to be returned to the
      patient aseptically. Point-of-care testing uses microliter quantities of blood,
      has acceptable precision, and can provide valuable diagnostic information while
      being minimally invasive.

PMID- 15196322
TI  - Iron supplementation in the intensive care unit: when, how much, and by what
      route?
AB  - Derangements of iron metabolism may be present in critically ill patients who
      develop anemia during a stay in the intensive care unit. Iron supplementation may
      be appropriate, especially if an underlying nutritional disorder is present. It
      may be even more critical to replace iron when erythropoietin therapy is used
      because of the consumption of iron stores that occurs during heme synthesis. Iron
      therapy is not without risks, and controversy persists regarding the potential
      for iron overload and infections. Clinical trials that define the optimal dose,
      route, and timing of iron administration in critically ill patients are lacking.
      However, studies of iron supplementation in chronic kidney disease, pregnancy,
      and anemia of prematurity may provide some guidance about approaches to
      treatment. Clinical evidence and limitations that can assist clinicians in
      managing iron therapy in the intensive care unit are presented.

PMID- 15196323
TI  - Anemia and blood transfusion in the critically ill patient: role of
      erythropoietin.
AB  - Critically ill patients receive an extraordinarily large number of blood
      transfusions. Between 40% and 50% of all patients admitted to intensive care
      units receive at least 1 red blood cell (RBC) unit during their stay, and the
      average is close to 5 RBC units. RBC transfusion is not risk free. There is
      little evidence that 'routine' transfusion of stored allogeneic RBCs is
      beneficial to critically ill patients. The efficacy of perioperative recombinant
      human erythropoietin (rHuEPO) has been demonstrated in a variety of elective
      surgical settings. Similarly, in critically ill patients with multiple organ
      failure, rHuEPO therapy will also stimulate erythropoiesis. In a randomized,
      placebo-controlled trial, therapy with rHuEPO resulted in a significant reduction
      in RBC transfusions. Despite receiving fewer RBC transfusions, patients in the
      rHuEPO group had a significantly greater increase in hematocrit. Strategies to
      increase the production of RBCs are complementary to other approaches to reduce
      blood loss in the intensive care unit, and they decrease the transfusion
      threshold in the management of all critically ill patients.

PMID- 15196325
TI  - Autologous blood donation.
AB  - Although preoperative autologous blood donation is employed in elective surgery,
      this is declining because of the increasingly safe allogeneic blood supply.
      However, it continues to be used because of the public's perception of allogeneic
      blood risks and increasing blood shortages. Patients may donate a unit of blood
      (450 +/- 45 ml) as often as twice weekly, up to 72 hours before surgery.
      Preoperative autologous blood is most beneficial in procedures that cause
      significant blood loss. It has been determined that preoperative autologous blood
      donation is poorly cost-effective; the use of this procedure must be based on
      evidence that it is safe and of value for the patient.

PMID- 15196324
TI  - Preoperative recombinant human erythropoietin in anemic surgical patients.
AB  - Preoperative anemia in a surgical patient predisposes to poor outcomes and
      allogeneic blood transfusions. As an alternative to transfusions, pharmacologic
      management of preoperative anemia with recombinant human erythropoietin (rHuEPO)
      has been well studied in many different types of surgery. rHuEPO, when used alone
      or in combination with preoperative autologous blood donation before elective
      surgery, stimulates erythropoiesis and helps to avoid or reduce the need for
      allogeneic blood transfusions. The clinical evidence on preoperative use of
      rHuEPO in orthopedic, cardiac, and cancer surgery, as well as in bloodless
      surgery, is reviewed.

PMID- 15196326
TI  - Intraoperative blood salvage in vascular surgery - worth the effort?
AB  - Intraoperative autologous transfusions have been used for many years to avoid
      transmission of infections, especially in vascular surgery, where blood usage is
      considerable. Several autotransfusion devices exist, but these devices are often
      associated with negative outcomes such as cost, contamination, and removal of
      essential blood components (e.g. platelets). Preoperative autologous blood
      donation is another blood preservation method to avoid possible transfusion
      related infections. Several vascular surgery groups have compared the use of
      these techniques, and their results are discussed in this review. Cell saver
      techniques often do not prevent the need for transfusions, nor are they very cost
      effective; therefore, their use should be considered on a case-by-case basis.

PMID- 15196327
TI  - Methods for improved hemorrhage control.
AB  - Trauma is the leading cause of death from age 1 to 34 years and is the fifth
      leading cause of death overall in the USA, with uncontrolled hemorrhage being the
      leading cause of potentially preventable death. Improving our ability to control
      hemorrhage may represent the next major hurdle in reducing trauma mortality. New
      techniques, devices, and drugs for hemorrhage control are being developed and
      applied across the continuum of trauma care: prehospital, emergency room, and
      operative and postoperative critical care. This brief review focuses on drugs
      directed at life-threatening hemorrhage. The most important of these new drugs
      are injectable hemostatics, fibrin foams, and dressings. The available animal
      studies are encouraging and human studies are required.

PMID- 15196328
TI  - Hemoglobin-based oxygen carriers.
AB  - Transfusable fluids that may be used as alternatives to red blood cell
      transfusion offer the promise of preserving tissue perfusion and minimizing
      hypoxic cellular damage, and this promise may soon be fulfilled. Clinical testing
      of hemoglobin-based oxygen carriers has faced and met challenges involving
      molecular design, safety, efficacy, and regulatory requirements. Three leading
      candidates have emerged: two human (PolyHeme and HemoLink) and one bovine-based
      hemoglobin solution (Hemopure). Because a survival benefit has been difficult to
      demonstrate, avoidance of allogeneic transfusion has been adopted as the standard
      efficacy end-point for these agents. An update on clinical trial status is
      provided, and the potential utility of hemoglobin-based oxygen carriers in
      surgery combined with intraoperative autologous donation is discussed.

PMID- 15196330
TI  - On the design and analysis of competent selecto-recombinative GAs.
AB  - In this paper, we study two recent theoretical models--a population-sizing model
      and a convergence model--and examine their assumptions to gain insights into the
      conditions under which selecto-recombinative GAs work well. We use these insights
      to formulate several design rules to develop competent GAs for practical
      problems. To test the usefulness of the design rules, we consider as a case study
      the map-labeling problem, an NP-hard problem from cartography. We compare the
      predictions of the theoretical models with the actual performance of the GA for
      the map-labeling problem. Experiments show that the predictions match the
      observed scale-up behavior of the GA, thereby strengthening our claim that the
      design rules can guide the design of competent selecto-recombinative GAs for
      realistic problems.

PMID- 15196329
TI  - Estrogen receptor-dependent activation of AP-1 via non-genomic signalling.
AB  - BACKGROUND: Ligand-bound estrogen receptor alpha (ERalpha) and estrogen receptor
      beta (ERbeta) modulate AP-1-dependent transcription via protein-protein
      interactions on DNA, in a manner that depends on the type of cells and the
      subtype of ER. We present here evidence for an additional mechanism by which ERs
      modulate the transcriptional activity of AP-1. RESULTS: We show that ERs located
      in the cytoplasm efficiently activate transcription at AP-1 sites in response to
      17beta-estradiol, while ERs present in the nucleus repress transcription under
      the same conditions. 17beta-estradiol-induced activation of the coll-73-luc
      reporter correlated with cytoplasmic localization of various ERalpha and ERbeta
      mutant receptors, and was inhibited in the presence of the full estrogen
      antagonist ICI 182,780 and the MAP-kinase inhibitor UO126. We also show that the
      selective estrogen receptor modulator (SERM) tamoxifen is as potent as 17beta
      estradiol in inducing activation of AP-1 when ERalpha is present in the
      cytoplasm. CONCLUSIONS: These results suggest that non-genomic signalling is
      involved in the mechanism by which ERalpha and ERbeta influence AP-1-dependent
      transcription. We have previously shown that Stat3 and Stat5 are targeted by non
      genomic actions of ERs, and the results presented here allow us to conclude that
      ERs bound to 17beta-estradiol mediate the transcriptional activation of promoters
      regulated by AP-1 and by Stat proteins via different combinations of signal
      transduction pathways. Our observations thereby provide new insights into the
      mechanisms by which ERs act at alternate response elements, and suggest a
      mechanism by which tamoxifen exerts its action as a tissue-selective agonist.

PMID- 15196331
TI  - [Reevaluation of the clinical importance of respiratory failure].

PMID- 15196336
TI  - [Effect of lung protective ventilation strategy on pulmonary inflammatory
      response in a rabbit model of acute respiratory distress syndrome].
AB  - OBJECTIVE: To evaluate the effect of lung protective ventilation strategy on
      pulmonary inflammatory response in acute respiratory distress syndrome (ARDS).
      METHODS: The ARDS rabbit model was duplicated by saline alveolar-lavage. The
      rabbits were divided into six groups: (1) normal control group (N group); (2)
      ARDS group (M group); (3) low-volume with best end-expiratory pressure (PEEP, A
      group) group: tidal volume (V(T)) 6 ml/kg, PEEP 2 cm H(2)O greater than the
      pressure of lower inflection point in pressure-volume curve (P(LIP)); (4) normal
      volume with best PEEP group (B group): V(T) 6 ml/kg, and PEEP P(LIP) + 2 cm
      H(2)O; (5) low-volume with high PEEP group (C group): V(T) 6 ml/kg, and PEEP 15
      cm H(2)O; and (6) high-volume with zero PEEP group (D group): V(T) 20 ml/kg. Lung
      wet/dry weight ratios (W/D) were recorded to evaluate lung injury. After 4 h of
      ventilation, lung homogenates were prepared to detect nuclear factor-kappaB (NF
      kappaB) activity by electrophoretic mobility gel shift assay (EMSA), tumor
      necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels by enzyme
      linked immunosorbent assay (ELISA) and their mRNA expression by reverse
      transcriptase-polymerase chain reaction (RT-PCR). Myeloperoxidase (MPO) and
      malondialdehyde (MDA) in lung homogenates were also assessed. RESULTS: After 4 h
      ventilation, W/D in A group (5.6 +/- 1.1) were significantly lower than those in
      B group, C group and D group (6.6 +/- 0.8, 6.6 +/- 1.0, 6.9 +/- 1.0, all P <
      0.05). But there was no difference between A group and M group (5.8 +/- 0.5). NF
      kappaB activity was the highest in D group, and that in A group was 331 +/- 113,
      which was decreased significantly as compared with B, C and D groups (455 +/- 63,
      478 +/- 74, 645 +/- 162, all P < 0.05). The mRNA expression of TNF-alpha and IL
      10 and their concentrations in lung homogenates in A group were lower than those
      in B, C and D groups. In A group, the concentrations of MPO and MDA in lung
      homogenates were significantly lower than those in B, C and D groups. CONCLUSION:
      Lung protective ventilation strategy can inhibit lung inflammation and may
      improve lung injury in ARDS, but low tidal volume with high PEEP may increase
      lung inflammation.

PMID- 15196337
TI  - [CD86 expression on alveolar macrophages and effects of anti-CD86 monoclonal
      antibody on the production of inflammatory cytokines in dust-mite allergic asthma
      patients].
AB  - OBJECTIVE: To investigate the CD(86) molecule expression on alveolar macrophages
      (AMs) before and after AM activation with dust-mite allergen and effects of anti
      CD(86) monoclonal antibody on the production of inflammatory cytokines produced
      by cultured CD(34)(+) T cells, and to explore the pathogenesis of anti-CD(86)
      monoclonal antibody on inhibiting asthmatic inflammation. METHODS: AMs and
      CD(34)(+) T cells were isolated from bronchoalveolar lavage fluid (BALF) and from
      peripheral blood derived from 10 asthma patients allergic to house dust-mite
      dermatophagoides pteronyssinus. AMs were stimulated and activated by house dust
      mite allergen and co-cultured with CD(34)(+) T cells. The co-cultured cells were
      divided into anti-CD(86) monoclonal antibody intervention group and CD(86)
      expression group with which the control groups were set up. The anti-CD(86)
      antibody was added to 0.1 mg/L and 1.0 mg/L in the experiment group and no
      antibody was added in the control group. The supernatants were harvested after 72
      hour co-culture. The concentration of interferon-gamma (INF-gamma), interleukin-4
      (IL-4) and IL-5 were determined by enzyme linked immunosorbent assay (ELISA).
      CD(86) expression group was divided into experiment and control groups, and house
      dust-mite allergen was added to the experiment group but no allergen was added in
      the control group. The cells of the two groups were harvested after 24 hour co
      culture. The CD(86) molecule expression on the AMs was detected by flow
      cytometry. RESULTS: After activated by house dust-mite allergen, the average
      fluorescence density of CD(86) on AM in the experiment group [(50 +/- 9)%] was
      significantly higher than that in the control group [(23 +/- 5)%, P < 0.01]. The
      production of IL-4 and IL-5 was (135 +/- 19) ng/L, and (104 +/- 21) ng/L in the
      low-dose group respectively; (90 +/- 17) ng/L and (68 +/- 14) ng/L in the high
      dose group; (187 +/- 24) ng/L and (161 +/- 23) ng/L in the control group; the
      differences among groups were significant (P < 0.01). The production of IFN-gamma
      was (193 +/- 39) ng/L in the low-dose group and (201 +/- 47) ng/L in the high
      dose group respectively, and there was no significant difference between the two
      groups (P > 0.05). CONCLUSION: AMs may effectively present allergen to T cells in
      allergic asthma patients. Anti-CD(86) monoclonal antibody can inhibit the
      production of IL-4 and IL-5 by blocking the co-stimulatory signal of CD(34)(+) T
      cells. These data suggest that anti-CD(86) monoclonal antibody may hold
      therapeutic potentials in asthma by inhibiting airway inflammation.

PMID- 15196338
TI  - [The role of signal transducer and activator of transcription-1 in the regulation
      of allergic airway inflammation in a guinea pig asthma model].
AB  - OBJECTIVE: To study the expression of signal transducer and activator of
      transcription-1 (STAT-1), and to investigate the effect and mechanism of STAT-1
      on airway inflammation. METHODS: Forty-eight guinea pigs were divided randomly
      into control group (group A, n = 8), asthma group (group B) and prevention group
      (group C, n = 8). The guinea pigs in group B were subdivided randomly into groups
      B(1), B(2), B(3) and B(4) (each n = 8). Asthma guinea pig models in group B and
      group C were set up by intraperitoneal injection and nebulization aspiration of
      ovalbumin (OVA). Expression levels of epithelial STAT-1 and intercellular
      adhesion molecule-1 (ICAM-1) were detected by immunohistochemistry, and lung
      tissue extracts were analyzed for phosphorylation of STAT-1 by western blot.
      Total cell and eosinophil (EOS) counts were examined, and expression levels of
      interferon-gamma (INF-gamma) were measured by enzyme-linked immunosorbent assay
      (ELISA) in bronchoalveolar lavage (BAL). RESULTS: After challenge, the expression
      levels of epithelial STAT-1 [(57 +/- 9), (136 +/- 14), (95 +/- 21), (67 +/- 30),
      respectively] and ICMA-1 [(75 +/- 10), (166 +/- 17), (113 +/- 14), (87 +/- 21),
      respectively] in groups B(1 - 4) were significantly different from those in group
      A [(13 +/- 7), (21 +/- 8), P < 0.01]. The expression levels of epithelial STAT-1
      (25 +/- 7) and ICMA-1 (29 +/- 11) in group C were also significantly different
      from those in group B(4) (P < 0.01). The phosphorylation of STAT-1 was found in
      lung extracts from groups B(1 - 3). The dynamic changes of STAT-1 was correlated
      with that of EOS counts, and a positive correlation being observed (r = 0.652, P
      < 0.01). There was a significant correlation between epithelial STAT-1 and ICAM-1
      (r = 0.556, P < 0.001). A negative correlation was found between epithelial
      levels of the STAT-1 and levels of INF-gamma in BALF (r = -0.499, P < 0.05) from
      group B(1 - 4). CONCLUSION: Epithelial STAT-1 showed constitutive activation and
      excess expression in guinea pig asthma models, which was significantly correlated
      with airway inflammation, suggesting that STAT-1 may play an important role in
      airway inflammation and asthma treatment.

PMID- 15196339
TI  - [Percutaneous lung cancer cryotherapy guided by computer tomography].
AB  - OBJECTIVE: To document the feasibility, safety and efficacy of percutaneous lung
      cancer cryotherapy (PLC) guided by Computer Tomography (CT). METHODS: Two hundred
      and thirty seven patients with lung cancer underwent CT-guided PLC from August,
      2001 to April, 2003. CT-visualized immediate ice formation beyond tumor margins
      was compared to tumor size and location. PLC feasibility and safety were
      evaluated. CT scan, lung tissue biopsy and survival rate were observed at
      different stages postcryoablation. RESULTS: All the patients underwent PLC using
      local anesthesia with minimal or no sedation. Iceball formation was well seen as
      negative Hounsfield units within soft tissue masses. Tumor size and location were
      independent determinants of ice coverage which was 97% (n = 124) for masses < 4
      cm in diameter, and 80% (n = 183) for masses > 4 cm in diameter (P < 0.01). Only
      59 patients had transient mild hypertension, and no death occurred during
      cryotherapy. Most of the slight side-effects were self-limited. No major bleeding
      or bronchial sequelae were identified. CT scan showed that necrotic cavitation
      larger than the original mass developed in 78% of the cases within one week, and
      mostly resolved by 6 months (4%). Partial resolution + complete resolution was
      noted by 1 - 6 months, which demonstrated reduced or stable tumor size. Necrotic
      coagulation could be found within 1 month and fibrin scarring 3 months
      postcryoablation. The survival rate in 18 months was 86% for patients at an early
      stage of lung cancer, and 21% for patients at stage III, while the one year
      survival rate for patients at stage IV was 9%. CONCLUSION: CT-guided PLC, with
      minimal procedure associated morbidity or sequelae, is a promising treatment for
      lung neoplasm of any stage in nearly any location.

PMID- 15196340
TI  - [The anti-tumor effects of dendritic cells co-cultured with cytokine induced
      killer cells after chemotherapy].
AB  - OBJECTIVE: To determine the changes in phenotype, proliferation activity and
      cytotoxicity of cytokine induced killer (CIK) cells after in vitro co-culturing
      with dendritic cells (DC), and then to investigate the auxiliary therapeutical
      effect of CIK cells after chemotherapy. METHODS: DC and CIK cells were generated
      by culturing prepheral blood mononuclear cells (PBMC) of healthy blood donors.
      Then the changes in the proliferation activity and phenotype of the cells were
      determined after DC and CIK cell co-culture. MTT assays were used to determine
      the cytotoxicity in vitro. The antitumor activity of DC and CIK cells were
      evaluated after chemotherapy in BALB/c nude mice bearing A549 lung cancer and BEL
      7404 liver cancer respectively. RESULTS: DC and CIK cells promoted the antitumor
      effect of chemotherapy. Co-culture of DC with CIK cells produced a new cell
      population, whose cytotoxicity and proliferation activity were much higher than
      those of CIK cells. CONCLUSION: CIK cells co-cultured with DC are more potent
      than CIK cells alone in the anti-tumor effect.

PMID- 15196341
TI  - [Detection of thromboxane B2, 6-keto-prostaglandin F1alpha and anticardiolipin
      antibody in patients with obstructive sleep apnea-hypopnea syndrome].
AB  - OBJECTIVE: To observe the changes of thromboxane B(2) (TXB(2)), 6-keto
      prostaglandin F1alpha (6-K-PGF1alpha) and anticardiolipin antibody (ACA) in
      patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) before and after
      institution of nasal continuous positive airway pressure (nCPAP). METHODS: Sixty
      cases of OSAHS confirmed by polysomnography (PSG) were selected as the trial
      group, and 20 normal donors without OSAHS were recruited as the control group.
      Nineteen patients with severe OSAHS were treated by nCPAP. Plasma levels of
      TXB(2), 6-K-PGF1alpha were detected by enzyme-linked immunosorbent assay (ELISA).
      RESULTS: Plasma (serum) level of TXB(2) (ACA) was significantly higher in
      patients with moderate to severe OSAHS than that in control group (P < 0.01), and
      nCPAP therapy decreased its level significantly (P < 0.01). Plasma level of 6-K
      PGF1alpha was significantly lower than that in the control group (P < 0.01), and
      nCPAP therapy increased its level significantly (P < 0.01). TXB(2) and ACA were
      correlated positively with AHI, and negatively with minimal oxygen saturation (P
      < 0.01). 6-K-PGF1alpha was correlated negatively with AHI, and positively with
      minimal oxygen saturation (P < 0.01). CONCLUSIONS: The results indicate that
      patients with OSAHS are susceptible to thromboembolism disease. TXB(2), 6-K
      PGF1alpha, ACA may be associated with the high prevalence of thromboembolism in
      patients with OSAHS. nCPAP therapy is effective in correcting TXB(2), 6-K
      PGF1alpha, ACA.

PMID- 15196342
TI  - [A study on the Th1/Th2 cytokines in the pathogenesis of human tuberculous
      pleuritis].
AB  - OBJECTIVE: To evaluate the distribution characteristics of Th1-type cytokines
      (IFN-gamma and IL-2) and Th2-type cytokines (IL-4 and IL-10) in the serum and the
      pleural effusion in patients with pleural tuberculosis, therefore to gain insight
      into the possible role of the local and the systemic Th1/Th2 cell-mediated immune
      response in the pathogenesis of human pleural tuberculosis. METHODS: The
      concentrations of IFN-gamma, IL-2, IL-4, and IL-10 in the serum and the pleural
      effusion of patients with pleural tuberculosis (Group pleuritis) were measured
      with enzyme linked immuno-sorbent assay (ELISA). The serum levels of the four
      cytokines were compared with those of patients with pulmonary tuberculosis (Group
      tuberculosis) and of healthy controls with positive reaction to PPD skin test
      (Group healthy). RESULTS: (1) The median concentrations of IFN-gamma, IL-2, IL-4,
      and IL-10 in serum were 118.60 ng/L, 0.00 ng/L, 1.49 ng/L, and 0.00 ng/L
      respectively in Group pleuritis, 265.75 ng/L, 18.03 ng/L, 16.00 ng/L, and 0.00
      ng/L respectively in Group tuberculosis; and 221.70 ng/L, 18.52 ng/L, 16.00 ng/L,
      and 0.00 ng/L respectively in Group healthy. (2) For IFN-gamma and IL-2, there
      existed no statistical differences among the three groups (K-W chi(2) value was
      1.15 and 4.68, P > 0.05); For IL-4 and IL-10, there existed no statistical
      differences between Group tuberculosis and Group healthy (Mann-Whitney Z value
      was -0.27 and -1.93, P > 0.05), but the level of IL-4 in Group pleuritis was
      lower than that in Group tuberculosis (Mann-Whitney Z value was -2.84, P < 0.01).
      (3) The ratio of the median of IFN-gamma to IL-4 in serum was 27.93 in Group
      pleuritis, 21.72 in Group tuberculosis, and 10.82 in Group healthy respectively.
      There existed no statistical difference among the three groups (K-W chi(2) value
      was 4.18, P > 0.05). (4) The median concentrations of IFN-gamma, IL-2, IL-4, and
      IL-10 in pleural effusion of Group pleuritis were 823.37 ng/L, 43.76 ng/L, 26
      ng/L and 38.69 ng/L respectively, each being statistically higher than that in
      the serum (Wilcoxon Signed Rank test Z value was -4.34, -2.82, -3.29 and -5.15, P
      < 0.05). CONCLUSIONS: Immunocompetent persons including patients with pleural
      tuberculosis, with pulmonary tuberculosis or the healthy with positive results to
      PPD test, showed similar systemic Th1 response to Mycobacterium bacilli. Due to
      the relatively lower level of systemic Th2 response, patients with pleural
      tuberculosis had higher systemic Th1/Th2 level and the enhancement of local Th1
      and Th2 responses in the pleural cavity was a pathophysiologic characteristic of
      human pleural tuberculosis. Both Th1 and Th2 responses might play an important
      role in the pathogenesis of human pleural tuberculosis.

PMID- 15196343
TI  - [Treatment and a follow-up study on wound infection by Mycobacterium chelonae:
      report of 168 cases].
AB  - OBJECTIVE: To summarize the experience of treatment on wound infection by non
      tuberculous Mycobacterium (NTM) after operations. METHODS: A hundred and sixty
      eight patients with NTM incision infection were retrospectively reviewed in terms
      of diagnosis, treatment and follow-up in a period of 4.5 years. On the basis of
      the results of in vitro drug sensitivity test, the main antibiotics used were
      clarithromycin and amikacin. The course of therapy was 4 - 8 months. An
      extirpative excision was performed in 104 cases following one month treatment by
      antibiotics and then followed by antibiotic therapy for 3 - 5 months after
      excision. RESULTS: Primary closure was achieved in 98 of the 104 cases. Fifty
      patients were cured by the use of antibiotics with dressing change. Eight
      patients were cured by dressing change without antibiotics. Five children with
      wound infection by NTM after circumcision were cured by antibiotics with local
      laser therapy. One patient with infection after hernia operation was cured by
      amikacin blocking of the area surrounding the lesion. There was no relapse after
      follow-up for four and half years. CONCLUSION: The study demonstrates that
      sensitive antibiotics combined with surgery extirpative excision is effective for
      wound infection by NTM.

PMID- 15196345
TI  - [Rapid detection of rpoB mutations in Mycobacterium tuberculosis by gene array].
AB  - OBJECTIVE: To develop a new method, gene array, which can be used for rapid
      detection of rpoB mutations in Mycobacterium tuberculosis. METHODS: Probes were
      designed according to the sequence of Mycobacterium tuberculosis rpoB gene and
      the gene array was developed. The DNA fragment which contained hot mutation sites
      of rpoB gene was amplified with biotin-labelled primers by PCR, and then
      hybridized with gene array. Mycobacterium tuberculosis strain H(37)Rv DNA was
      used as the control. The rpoB genes in Mycobacterium tuberculosis clinical
      isolates were also analyzed by polymerase chain reaction-single stranded
      conformational polymorphism (PCR-SSCP) and PCR-DNA sequencing. RESULTS: We
      analyzed the rpoB genes of 111 Mycobacterium tuberculosis clinical isolates by
      PCR-SSCP. Of 70 rifampicin-resistant Mycobacterium tuberculosis isolates, 63
      isolates had different SSCP profiles from that of the standard strain H(37)Rv. No
      difference from the standard strain was found in 41 rifampicin-susceptible and 7
      rifampicin-resistant isolates. We also analyzed their rpoB genes by gene array.
      Of 111 Mycobacterium tuberculosis clinical isolates, the results of gene array in
      41 drug-sensitive strains were similar to that in Mycobacterium tuberculosis
      H(37)Rv. 90% (63/70) rifampicin-resistant strains had rpoB gene mutation. 53%
      (37/70) rifampicin-resistant strains had serine substitution at codon 531. 21%
      (15/70) strains had histidine substitution at codon 526. 16% (11/70) strains had
      amino acids substitution in other position. The results of gene array
      corresponded with that of PCR-SSCP and DNA sequencing. CONCLUSION: Gene array
      might become a rapid, simple, and accurate method for detecting rpoB mutations in
      most of the rifampicin-resistant Mycobacterium tuberculosis.

PMID- 15196346
TI  - [Sputum induction and its application in assessing airway inflammation].

PMID- 15196347
TI  - [The progress of the research in a drug-resistant cancer].

PMID- 15196360
TI  - [Retrospective analysis on 682 cases of liver cancer after surgical treatment].
AB  - OBJECTIVE: To investigate the factors of long-turn survival of liver cancer after
      surgical treatment. METHODS: Five hundred and twenty-two cases of liver cancer
      that received surgical treatment in 14 years were analyzed retrospectively.
      RESULTS: Comparison between the small liver cancer (< 5 cm) and the greater one
      (> 10 cm) revealed that the small liver cancer had a higher survival rates than
      the greater one [3 year (61.25 +/- 4.41)% versus (45.90 +/- 6.98)%; 5 year (53.84
      +/- 5.68)% versus (30.21 +/- 10.23)%]. There were same results between single
      nodule and two or more than two nodule [3 year (61.86 +/- 3.69)% versus (38.31 +/
      4.97)%; 5 year (55.40 +/- 4.91)% versus (28.01 +/- 6.31)%], between child I and
      child II or more than II [3 year (60.68 +/- 3.68)% versus (49.88 +/- 4.13)%; 5
      year (50.99 +/- 5.10)% versus (36.39 +/- 7.58)%], and between single
      segmentectomy of the liver and two or more than two segmentectomy [3 year (68.65
      +/- 4.95)% versus (49.88 +/- 4.13)%; 5 year (65.38 +/- 5.69)% versus (37.98 +/-
      5.70)%]. CONCLUSIONS: Small liver cancer, single-nodule, good hepatic function
      and minor resection were important factors to prolong survival further.

PMID- 15196361
TI  - [The long-term results of managements in 98 cases of gallbladder carcinomas].
AB  - OBJECTIVE: Carcinoma of the gallbladder is an uncommon, but patients with the
      disease are associated with a dismal prognosis. The purpose of this study was to
      analyze the characters, prognostic factors of gallbladder carcinoma and
      investigate the measures of diagnosis and treatment. METHODS: 98 patients
      admitted into our hospital from January 1992 to July 2000 were followed up, with
      a mean follow-up time of 478 days (1 - 2,280 days). All statistical analyses were
      performed with SPSS10.0 statistical package. Survival curves were estimated by
      the Kaplan-Meier method and differences among groups were tested by the log-rank
      test. The Cox multivariate analysis was performed to determine prognostic factors
      on survival. RESULTS: Among 98 patients, 31 with radical resection, 29 with
      palliative resection, 18 with exploration and 20 with chemo- and/or radiotherapy,
      The overall 5-year survival rate of the gallbladder carcinoma was 6.67%, The 1-,
      3-, and 5-year survival rate following radical resection for gallbladder cancer
      was 77.29%, 34.37%, 21.48% respectively, The survival rate in radical resection
      group was remarkably higher than that of the others (P < 0.01). Multivariate
      analysis revealed that tumor, node, metastases (TNM) stage and therapeutic
      interventions had significantly higher risk ratios for gallbladder cancer.
      CONCLUSIONS: With careful patient selection, aggressive resection may help to
      improve the prognosis, although the disease with ominous reputation. Resection
      alone is inadequate for a significant improvement in survival, so there is a need
      to evaluate more effective adjuvant therapy in the form of radiotherapy or newer
      chemotherapeutic agents. Emphasis to improve the long-term survival should be pay
      on early diagnosis and early management.

PMID- 15196362
TI  - [Primary duct closure versus T-tube drainage following laparoscopic
      choledochotomy].
AB  - OBJECTIVE: To evaluate the effects of primary duct closure and T-tube drainage in
      laparoscopy choledochotomy to treat the common bile duct stones. METHODS: The
      enrollment of the patients was in accordance with 6 criteria. 55 patients with
      cholecystolithiasis and secondary common bile duct stones from January 2000 to
      February 2003 were treated with laparoscopic choledochotomy. The patients were
      randomly divided into two groups: primary duct closure group and T-tube drainage
      group. Their all data were recorded and studied prospectively,and patients were
      followed up after discharge. RESULTS: There were 27 patients and 28 patients in
      primary duct closure group and T-tube drainage group respectively. The operation
      time and the results of following up between the two groups had no significant
      difference. Compared with T-tube drainage group, primary duct closure group had
      less the total quantity of postoperative transfusion and hospital costs, shorter
      postoperative hospital stay. The incidence of postoperative complications in
      primary duct closure group was 11.1% (3/27), and all of them were biliary
      complications. The incidence of postoperative complications in T-tube drainage
      group was 28.6% (8/28), and seven of them were biliary complications. The
      incidence of severe complications that needed reoperations was 10.7% (93/28), and
      all of them were caused by T-tubes. There was no mortality in two groups.
      CONCLUSIONS: The primary duct closure in laparoscopic choledochotomy can avoid
      the deficiency of T-tube drainage, and it is feasible and safe and lower
      complications in treating the common bile duct stones, so we advocate it in
      appropriate cases.

PMID- 15196363
TI  - [Diagnosis and treatment of vasoactive intestinal peptide-secreting-tumors: one
      case report and 15 years review in China].
AB  - OBJECTIVE: To discuss the experiences of diagnosis and treatment for vasoactive
      intestinal peptide-secreting-tumors (VIPoma) by summarizing clinical informations
      of 15 patients with VIPoma. METHODS: To analyze Clinical manifestations,
      laboratory examinations, imaging features, operation, pathological findings and
      follow up survey of 15 patients, among them 1 case from our hospital and the
      other 14 cases were searched in chinese biological and medical literature
      database from Jan 1987 to Dec 2002. RESULTS: The main clinical manifestation
      include periodical secretory watery diarrhea, hypokalemia, achlorhydria, in
      addition, periodical backache, skin rash, and polyps of colon were presented in
      the case in our hospital. The immunohistochemical expression of many kinds of
      digestive hormone including VIP presented positive; All clinical symptoms of
      which except polyps disappeared after operation, elevated VIP data in serum also
      markedly decreased. Part resection of superior mesenteric vein was performed in
      the same patient. CONCLUSIONS: VIPoma is rare. Typical symptoms and the serum
      value of VIP were keys to diagnosis, the operation is the most effective means
      for treatment. Resection of tumor, Radiofrequency tissue ablation, liver
      transplantation can be selected for metastatic VIPoma in the liver.

PMID- 15196364
TI  - [Prognostic analysis of patients suffering from distal bile duct cancer].
AB  - OBJECTIVE: To study prognostic factors after surgical procedure for distal bile
      duct cancer. METHODS: A retrospective clinical analysis was made in 173 cases of
      distal bile duct cancer, admitted to our hospital from February 1996 to December
      2002. Fourteen clinicopathologic factors that could possibly influence survival
      were selected. A multivariate analysis of these individuals was performed using
      the Cox Proportional Hazards Model. RESULTS: There were 99 males and 74 females.
      The age ranged from 27 to 74 years old with a mean of 55.5. Radical resection was
      performed on 152 cases with radical resection rate of 87.9%. 29 cases died of
      liver metastasis with a rate of 46.8% in total death cases. The statistical
      analysis showed that surgical procedure, lymph node metastasis and pathological
      differentiation grade affected postoperative survival significantly, but
      transfusion, invasion of pancreas, postoperative radiotherapy and chemotherapy,
      ERCP, diameter of tumour, serum level of CA-19-9, preoperative total serum
      bilirubin level (TBIL), ratio of albumin to globulin (A/G), sex and age are not
      significant factors influencing postoperative survival. CONCLUSIONS: Radical
      resection is only curative treatment modality. Aggressive treatment and
      prevention on postoperative liver metastasis is a important strategy to improve
      the survival for distal bile duct cancer.

PMID- 15196365
TI  - [Surgical treatment for patients with primary hyperparathyroidism].
AB  - OBJECTIVE: To evaluate the feasibility and efficacy of surgical treatment for
      patients with primary hyperparathyroidism (pHPT). METHODS: The studies were
      analyzed for 55 patients with pHPT who underwent parathyroidectomy in our
      hospital from 1985 to 2002. RESULTS: Eight patients were asymptomatic. The
      skeletal manifestations were found in 24 cases, urinary stones in 10 cases, and
      both skeletal manifestations and urinary stones in 13 cases. Pathological bone
      fractures occurred in 16 cases. Hypercalcemia was discovered in all patients with
      the average value of (3.1 +/- 0.4) mmol/L, ranging from 2.7 to 3.9 mmol/L and.
      Fifty patients showed elevated parathyroid hormone (PTH) with the average value
      of (489.2 +/- 69.2) pg/ml, ranging from 102 to 2,000 pg/ml. Preoperatively all
      patients underwent sonography, CT and/or scintigraphy. The overall preoperative
      image-directed localization rate was 90.9%. Follow-up was done from 6 months to 2
      years after surgery. The symptoms and signs of all patients relieved
      postoperatively with the improving of osteoporosis and healing of bone fracture.
      Of all cases, 39 presented with temporary hypocalcemia, 37 showed circumoral
      paresthesia in whom 10 showed tetany, 15 showed eucalcemia and one had mild
      hypercalcemia after operation. The serum calcium was normal in all cases with
      hypocalcemia by Rocaltrol and calcium supplementation for 1 - 3 weeks. PTH level
      decreased to normal fro 2 weeks to 2 months in 47 cases and was still mildly
      higher than normal in 3 cases. CONCLUSIONS: Parathyroidectomy is an effective
      approach to patients with pHPT. With preoperative image-directed localization
      techniques, minimally invasive parathyroidectomy is a valid surgical strategy.

PMID- 15196366
TI  - [Clinical characteristics and outcome of myasthenia gravis with and without
      thymoma after operation].
AB  - OBJECTIVE: To explore the clinical characteristics and outcome of myasthenia
      gravis with and without thymoma after operation. METHODS: Two hundred and forty
      three patients with myasthenia gravis surgically treated in our department from
      1978 to 2003 were studied retrospectively. The clinical characteristics,
      complication, remission and survival were compared between myasthenia gravis with
      and without thymoma. RESULTS: The patients of myasthenia gravis with thymoma were
      significantly older (t = 6.138, P = 0.000), had shorter duration of symptom (t =
      3.783, P = 0.000), and also had higher myasthenia crisis rates after operation
      (chi(2) = 64.77, P = 0.000) than those of myasthenia gravis without thymoma. No
      differences of Osserman classification was found between the two groups (chi(2) =
      7.678, P = 0.104). The complete remission rates and partial remission rates of
      myasthenia gravis with thymoma were significantly lower than those of myasthenia
      gravis without thymoma at 1 and 3 years (P = 0.049, P = 0.000; P = 0.015, P =
      0.010), but no differences at 5 year (P = 0.457; P = 0.699). The survival rates
      of MG with thymoma were lower than that of MG without thymoma (Log-rank = 18.58,
      P = 0.000). CONCLUSIONS: The clinical characteristics are different between
      myasthenia gravis with and without thymoma. The remission of symptom of
      myasthenia gravis with thymoma is worse than that of myasthenia gravis without
      thymoma in the near future, but is similar in the long future. The death rates of
      MG with thymoma is significantly higher than that of MG without thymoma.

PMID- 15196367
TI  - [Myasthenia gravis occurring after resection of thymoma].
AB  - OBJECTIVE: The aim of this study was to analyses the clinicopathologic features
      of the patient with myasthenia gravis (MG) occurring after resection of thymoma.
      METHODS: Data of 15 patients were collected. The follow-up range from 8 to 178
      (average 76.7) months. A retrospective analysis was performed through comparison
      with data of all 112 cases without MG, which had not occurred MG during our
      average 5.5 years follow-up, operated for thymoma in same period. The statistics
      analysis adopted chi(2) and t test. RESULTS: (1) According to Masaoka's
      classification of thymoma, stage I in 7 cases, stage II in 4, stage III in 4.
      Histologic Bernatz's classification: lymphocyte predominant type in 4, epithelial
      type in 3, mixed type in 7, unknown in 1. According to Osserman's classification
      of MG, grade I in 7, IIa in 4, IIb in 3, III in 1. The MG onset times was the
      postoperative narcotic waking duration-137 (average 33.9) months, and the average
      remission time was 30.9 (0.5 - 120) months. (2) 4 cases who occur MG as soon as
      pull up narcotic tube, all adopted nondepolarizing muscular relaxants. (3) MG was
      discovered in 3 cases (3/67) during postoperative radiotherapy until a average
      dosage of 36 Gy was received in average 24 days. (4) The tendency of occurring MG
      following resection was found in female patients with longer duration of disease,
      mixed type, larger and later stage thymoma as compared with the thymoma group.
      CONCLUSIONS: The factors including the operation, relatively using overdose
      relaxation control, choosing unfavorable muscle relaxant and postoperative
      radiotherapy could induce postoperative MG. An intensive care should be put on
      the cases with the tendency of occurring postoperative MG.

PMID- 15196368
TI  - [The study on correlation of c-myc gene expression with vascular smooth muscle
      cell proliferation in patients with portal hypertension].
AB  - OBJECTIVE: To investigate c-myc proto-oncogene expression and the relationship of
      PCNA protein expression of extrahepatic vascular smooth muscle cell in patients
      with portal hypertension and normal vessels. METHODS: RT-PCR was used to
      demonstrate the expression of c-myc mRNA and immuno-chemistry strain was
      performed to detect the expression of PCNA protein in splenic veins of 28
      patients with portal hypertension and 12 normal vessels. RESULTS: The straining
      of PCNA protein was (29.8 +/- 4.7)% in splenic veins with portal hypertension,
      Normal vessels did not detect PCNA protein expression (P < 0.01); RT-PCR showed
      that the expression of c-myc mRNA in PCNA-positive control and in negative
      control of splenic veins with portal hypertension were (7.61 +/- 1.04)% and (3.82
      +/- 0.92)%, respectively. There ws different between two groups (P < 0.01) and
      significant different (P < 0.01) when compared with (1.01 +/- 0.21)% in normal
      vessels. CONCLUSIONS: The c-myc was immediate-early gene when it modulated
      proliferation of vascular smooth muscle cell. Hemodynamic disturbance of portal
      vein system activate the proto-oncogene of smooth muscle cells in splenic vein of
      patients with portal hypertension, promoting the proliferation, migrating and
      phenotypic change and resulting in vascular remodelling of splenic veins.

PMID- 15196369
TI  - [Study on relationship of fucosyltransferase gene types in breast cancer with
      metastasis and prognosis].
AB  - OBJECTIVE: To assess the association of five types of fucosyltransferase gene
      (Fuc-T), the important biosynthesis gene of sialylated carbohydrate antigens
      (Sialyl Lewis A, Sialyl Lewis X), with metastasis and prognosis of breast cancer.
      METHODS: The real-time quantitative PCR of five-type Fuc-T III, IV, V, VI, VII
      genes was performed in 80 patients with breast cancer. RESULTS: The result showed
      that Fuc-TVII gene had higher gene copy compared to other type of Fuc-T in breast
      cancer. The grading of Fuc-TVII gene was related to lymph node metastasis and
      poor disease-free survival. Statistically difference was significant (P < 0.01).
      Fuc-T III, IV, V, VI gene were not significant relation to the metastasis and
      prognosis in 80 cases. CONCLUSIONS: These findings suggest that Fuc-TVII gene is
      a prognostic indicator of breast cancer, and it may be play an important role in
      the biosynthesis of sialylated carbohydrate antigens in breast cancer.

PMID- 15196370
TI  - [The effect of somatostatin analogue on expression of connective tissue growth
      factor gene of rat hepatic stellate cells].
AB  - OBJECTIVE: To investigate the effect of somatostatin analogue-octreotide (OCT) on
      expression of connective tissue growth factor (CTGF) gene of murine hepatic
      stellate cells (HSCs) in vitro. METHODS: HSCs separated from Sprague Dawley rats
      by in situ perfusion and Nycodenz gradient were divided into 5 groups. HSCs in 4
      out of 5 groups were co-cultured with octreotide at different dosages, and the
      remaining group served as control. The expression of CTGF and TGF-beta mRNA were
      assessed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS:
      OCT down-regulates the expression of CTGF and TGF-beta mRNA in HSCs. The effect
      is increased with a dose dependent manner. CONCLUSIONS: OCT could exert the
      inhibitory effect on HSCs by down-regulating the expression of CTGF and TGF-beta.
      This provides a potential for the prevention and management of hepatic fibrosis.

PMID- 15196371
TI  - [Antitumor immune responses induced by gene transfer of 4-1BBL into
      hepatocellular carcinoma Hepa1-6 in vitro].
AB  - OBJECTIVE: To study the cytotoxic activity against tumor cells and cytokines
      production of spleen cells induced in vitro by murine 4-1BBL gene transfected
      Hepa1-6. METHODS: The eukaryotic expression vector pCDNA3.1(+)-m4-1BBL was
      transfected into murine hepatocellular carcinoma cell line Hepa1-6 by Liposomes.
      Then the transfected cells were selected in medium containing G418 (400 - 800
      micro g/ml) and termed as Hepa1-6-m4-1BBL. The TCV-m4-1BBL was obtained by
      treating them with mitomycin (MMC). Cocultivation TCV with syngeneic murine
      spleen cells, then the lymphocytes were tested for cytotoxic activity against
      Hepa1-6-wt cells and the supernatants were harvested for detecting the cytokines
      (IL-2, TNF-alpha and GM-CSF). RESULTS: Hepa1-6-m4-1BBL cells expressed 4-1BBL
      protein with highest cell surface level. The 4-1BBL mRNA could still be detected
      in the cells when cultured 48 h after treated with MMC (80 mg/L). Comparing with
      TCV-Hepa1-6, the tumor cell vaccine derived from Hepa1-6-m4-1BBL (TCV-m4-1BBL)
      could induce a more efficient cytotoxic activity of syngeneic murine lymphocyte
      against its parental tumor cell Hepa1-6 (P < 0.05), but not against non-parental
      tumor cell H22 and NIH3T3. Higher levels of IL-2, TNF-alpha and GM-CSF were
      released by the splencytes after stimulated by TCV-m4-1BBL. CONCLUSIONS: These
      results suggest the expression of m4-1BBL by tumor cells is effective in inducing
      antitumor immune responses.

PMID- 15196372
TI  - [Experimental study on islet cells in rats under condition of three-dimensional
      microgravity].
AB  - OBJECTIVE: To study the survival rate and secretory function of islet cells in
      rats under condition of three-dimensional microgravity. METHODS: Isolated islet
      cells were assigned to flask-cultured or bioreactor-cultured. Survival rate of
      islets cultured for days 3, 7, 14 in stationary flasks or microgravity
      bioreactors was measured by AO-PI double-staining. Cultured islets were
      identified by dithizone (DTZ) staining, and insulin contents of different culture
      liquids were measured by radioimmunoassay. RESULTS: Pancreatic islets stained
      nacarat with DTZ were easily visualized. When islet cells were cultured for 7
      days and 14 days, survival rate of bioreactor-cultured islets was (0.9000 +/-
      0.0107)% and 0.8038% +/- 0.0092% and higher than flask-cultured islets (P <
      0.01). Insulin level of bioreactor-cultured islets is (70.875 +/- 0.31) m micro
      /L on the cultured 7 days while flask-cultured islets is (41.246 +/- 0.35) m
      micro /L. There was statistically significant difference of insulin production
      between the two groups (P < 0.01). Bioreactor-cultured islet contents were higher
      than flask-cultured on the cultured 14, 21 and 30 days (P < 0.01). CONCLUSIONS:
      Islet cells survival rate and secretory function revealed that bioreactor
      cultured islets functioned better compared with flask-cultured islets.

PMID- 15196373
TI  - [Study of three-dimensional computerized reconstruction and CT scanning with thin
      slice after filling hepatic duct system].
AB  - OBJECTIVE: To establish the modal of perfusing and casting in hepatic duct system
      and explore the methods of three dimensional reconstruction with CT scanning
      image after filling hepatic duct. METHODS: All canal of livers with integral
      porta hepatic were perfused with various filling material after pretreatment,
      then fixed and casted. Hepatic preparations that had been perfused were put into
      the model of modelling abdominal cavity and scanned with thin slice. The three
      dimensional duct structures of hepatic with three methods of MIP, SSD and
      computerized treatment. RESULTS: Fourteen hepatic samples were filled and casted.
      Nine hepatic samples were scanned with slice height 1.0 mm, all 2514 slice images
      and average 279 images. Five hepatic samples were scanned with slice height 3.0
      mm, all 512 slice images and average 102 images. Intrahepatic vein and portal
      vein system of three dimensional reconstruction were seen clearly with MIP
      method. The three dimensional established three dimensional images with SSD
      method was shown much stronger than that of MIP method. The three dimensional
      images of hepatic solid and hepatic vein system were established with method of
      comperized treatment. Vary three dimensional shape of hepatic solid and hepatic
      vein was obtained through different direction rotational. CONCLUSIONS: The modal
      filled and casted hepatic duct system were practise. The images established three
      dimensional with methods of MIP, SSD and comperized treatment were seen clearly.
      The modal and images of thin slice CT scanning are a better method for
      researching hepatic duct system.

PMID- 15196374
TI  - [Treatment of portal vein tumor thrombus of hepatocellular carcinoma with
      percutaneous laser ablation].
AB  - OBJECTIVE: To introduce a newly developed procedure in the control of portal vein
      tumor thrombus (PVTT) of hepatocellular carcinoma (HCC), and evaluate the
      efficacy and indicate of this method. METHODS: The PVTT of HCC patients were
      treated by percutaneous transhepatic laser ablation (LA). The blood flow of PVTT
      embolized portal vein, live function, ascites and clinical presentation was
      observed. RESULTS: Twenty-four HCC patients, with a total of 30 PVTT portal vein
      and its main branch were treated with LA. There were no any blood flow signal in
      Doppler color Ultrasonography in these PVTT embolized portal vein before
      treatment. After treatment, blood flow was reappearance in all cases within one
      week. The continued patency blood flow was observed in 16 portal vein and
      continued but not patency blood flow in other 12 portal vein within 30 days. The
      continued patency blood flow was observed in 18 portal vein within 90 days. The
      improvement of liver function and clinical symptom. The reduction of ascites was
      observed in varying degrees. CONCLUSION: LA treatment might be a effective and
      safe procedure in the control of portal vein tumor thrombus of HCC.

PMID- 15196379
TI  - [Evidence-based clinical research is of utmost importance].

PMID- 15196380
TI  - [The relationship between a nucleotide substitution of S100A8 gene and aggressive
      periodontitis].
AB  - OBJECTIVES: To screen polymorphisms in the upstream region of S100A8 gene and to
      detect whether the polymorphisms were associated with aggressive periodontitis.
      METHODS: Thirty aggressive periodontitis patients and twenty-eight healthy
      controls were recruited for the study with informed consent. All subjects were of
      Chinese descent and systemically healthy. The regions about 800 bp upstream from
      the ATG start codon in exon 2 of the S100A8 gene of 10 patients and 8 controls
      were amplified by polymerase chain reaction (PCR) and analyzed by direct
      sequencing. A single nucleotide polymorphism (SNP) at 94 bp upstream from the ATG
      start codon was selected, and then the shorter regions (about 250 bp upstream
      from the ATG start codon) of the rest subjects were also amplified by PCR and
      analyzed by direct sequencing. The frequency of the SNP and the distribution of
      the genotype were detected and compared between the two groups. RESULTS: A
      nucleotide substitution (A-->G) at 94 bp upstream from the ATG start codon was
      demonstrated in Chinese, which was in a cis-acting element, named gamma
      interferon response element (gamma-IRE) in intron 1 of S100A8 gene. All of the
      subjects that carried the polymorphism were heterozygous. There was no
      statistically significant difference in the frequency of allele 2 (corresponding
      to the nucleotide G) between patients and controls (11.7% vs. 17.9%, chi2 =
      0.887, P > 0.05). The prevalence of the heterozygous genotype was 23.2% and 35.7%
      (chi2 = 1.07, P > 0.05) in patients and controls, respectively. CONCLUSIONS: This
      is the first report that a nucleotide substitution of S100A8 gene was
      demonstrated in Chinese. The frequencies of allele 2 and heterozygous genotype
      were lower in patients, but there is no statistically significant difference
      between the aggressive periodontitis patients and healthy controls in this
      preliminary study.

PMID- 15196381
TI  - [Bioassay of the soluble human tumor necrosis factor receptor I recombinant
      plasmid expression in vitro].
AB  - OBJECTIVE: To detect the expression of recombinant plasmid PcDNA3.1-sTNFRI in
      vitro and evaluate the bioactivity of expressed sTNFRI. METHODS: CHO cells were
      transfected with recombinant plasmid PcDNA3.1-sTNFRI by liposome. sTNFRI in cell
      culture supernatant was detected by ELISA and sTNFRI blockage of TNF-alpha
      cytotoxicity in L929 cells evaluated by MTT assay. RESULTS: The expression of
      sTNFRI in transfected cell culture supernatant was higher than control groups (P
      < 0.001). The expressed sTNFRI could significantly neutralize TNF-alpha
      cytotoxicity in L929 cells. CONCLUSIONS: These results showed that the
      recombinant plasmid PcDNA3.1-sTNFRI can be expressed in mammalian cells and the
      recombinant sTNFRI has biological function.

PMID- 15196382
TI  - [A study on the effects of cells and scaffolds tissue engineering on the
      periodontal regeneration].
AB  - OBJECTIVE: To observe the effects of cells and scaffolds tissue engineering on
      the periodontal regeneration, and to evaluate the feasibility of nano-Hap
      collagen (nHAC) as the scaffold material for periodontal tissue engineering.
      METHODS: Dog autogenous periodontal ligament cells (PDLCs) cultured in vitro were
      collected and seeded on the three-dimensional framework of nHAC. The cell growth
      in the scaffolds was observed by scanning electron microscope. And then the PDLCs
      nHAC composites were transplanted into man-made periodontal defects, and the
      groups filled with nothing or filled only with nHAC were the controls. The dogs
      were sacrificed after 8 weeks and the periodontal regeneration was observed
      histologically. RESULTS: Scanning electron microscope showed the porous structure
      of nHAC and the eugonic growth of cells in the nHAC scaffolds. The histological
      observation showed that the PDLCs-nHAC groups exhibited more new bone, new
      periodontal ligament and new cementum occupying the majority of the defects than
      the control groups, and the epitheliums were not observed. CONCLUSIONS:
      Periodontal regeneration could be enhanced by the cells and scaffolds tissue
      engineering, and the PDLCs and nHAC could be used as the seed cell and the
      scaffold material for periodontal tissue engineering.

PMID- 15196383
TI  - [Two-year disease progression in mild, moderate and advanced chronic
      periodontitis patients].
AB  - OBJECTIVE: To observe two-year natural progression of chronic periodontitis in
      mild, moderate and advanced periodontitis patients. METHODS: The periodontal
      status of 169 untreated chronic periodontitis patients aged from 22 to 64, were
      examined for two years. Periodontal measurements were performed on all teeth
      except the third molars and 6 sites examined for each tooth. Probing depth (PD),
      attachment loss (AL), and bleeding on probing (BOP) were measured at baseline,
      one year, and two year by a same experienced periodontist. Forty-five patients
      were diagnosed as having mild periodontitis, 87 with moderate, and 37 with
      advanced periodontitis. The changes of attachment level in these three group
      patients were analyzed. The site with change of AL greater than 3 mm (DeltaAL >
      or = 3 mm) were defined as periodontal disease activity (PDA) sites. The
      occurrence of PDA in three groups was compared. RESULTS: (1) The average AL
      levels at 1 year and at 2 year were greater than that at baseline in mild,
      moderate and advanced periodontitis. (2) The percentage of sites with AL > or = 1
      mm in three groups all increased from baseline to 1 year and to 2 year. (3) The
      occurrence of periodontal disease activity increased significantly from mild
      (0.14% at site level, 15.56% at subject level), moderate (0.39%, 29.89%) to
      advanced (0.73%, 43.24%) periodontitis patients. (4) The mean baseline AL and PD
      levels in active sites were greater than that in inactive sites (PD: 3.03 +/-
      0.45 vs. 2.87 +/- 0.38, P < 0.05; AL: 2.25 +/- 0.93 vs. 1.77 +/- 0.90, P < 0.01).
      CONCLUSION: Untreated advanced periodontitis patients were the risk population
      for further periodontal breakdown.

PMID- 15196384
TI  - [Effects of baicalin on the expression of pro-MMP-1 and MMP-3 in human gingival
      fibroblasts and periodontal ligament cells].
AB  - OBJECTIVE: To investigate the influence of baicalin on the IL-1beta induced pro
      MMP-1 in HGF and the effects of baicalin on MMP-3 expression in periodontal
      ligament cells (PDLCs). METHODS: The amount of secreted pro-MMP-1 and MMP-3
      expression was detected by ELISA and cell immunochemistry. RESULTS: (1) The
      amount of secreted pro-MMP-1 (3.333 +/- 0.123) microg/L increased significantly
      following 1 microg/L of IL-1beta, compared with control group (1.960 +/- 0.180)
      microg/L. Addition of baicalin to cell culture medium for 1 hour following IL
      1beta decreased pro-MMP-1 secretion in a dose-dependent manner in the range of 10
      approximately 1,000 microg/L. (2) 1 microg/L IL-1beta could significantly
      stimulate the synthesis and secretion of MMP-3 in PDLCs. (3) The baicalin could
      not interfere the synthesis of MMP-3, but could inhibit the release of MMP-3 from
      PDLCs. CONCLUSIONS: Baicalin could inhibit the secretion of pro-MMP-1 and MMP-3
      expression in IL-1beta induced HGF and PDLCs, which suggests that baicalin may
      play an important role in preventing and treating periodontal disease.

PMID- 15196385
TI  - [Effects of insulin-like growth factor II on regulating nitric oxide synthase
      gene expression in mouse osteoblast-like MC3T3-E1 cells].
AB  - OBJECTIVE: To study the effects of insulin-like growth factor II (IGF-II) on
      regulating the levels of nitric oxide (NO) and the mRNA transcriptions of
      inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in mouse
      osteoblast-like cells. METHODS: Mouse osteoblastic cell line MC3T3-E1 was
      selected as the effective cell of IGF-II. After the cells were treated with IGF
      II at different concentrations for different intervals of time, MTT colorimetry
      was used for examining the cell proliferation. Nitrate reductase method was
      applied for detecting the NO concentrations in cell culture supernatants and RT
      PCR employed for determining the levels of cellular iNOS and eNOS mRNAs. RESULTS:
      After the MC3T3-E1 cells were treated with IGF-II at the dosages of 1 microg/L
      for 72 h, 10 and 100 microg/L for 24, 48 and 72 h respectively, all the MTT
      values increased markedly (P < 0.05 or P < 0.01). After the cells were treated
      for 48 and 72 h at the dosage of 100 microg/L IGF-II respectively, the levels of
      NO in the supernatants of cell cultures and cellular iNOS mRNA decreased
      significantly (P < 0.01). However, the levels of eNOS mRNA in the cells treated
      with any of the IGF-II dosages for the different times were stable (P > 0.05).
      CONCLUSIONS: IGF-II at the dosages of 1 approximately 100 microg/L showed the
      effects on promoting proliferation, which as probably due to the maintenance of
      low NO levels. Inducible NOS gene expression at the level of transcription was
      down regulated in the MC3T3-E1 cell treated with higher dosage of IGF-II (100
      microg/L) but eNOS mRNA was not, which might be one of the mechanisms for the
      maintenance of low NO levels.

PMID- 15196386
TI  - [Crown lengthening surgery as an aid for restoration of teeth with subgingival
      fracture or caries].

PMID- 15196387
TI  - [Summary of the 7th National Conference on Periodontology].

PMID- 15196388
TI  - [A study on the classification and treatment of zygomatic complex fractures].
AB  - OBJECTIVE: To investigate a new classification and treatment of zygomatic complex
      fractures (ZCF) by clinical and radiographic studies. METHODS: Standard
      radiographs with Waters, submental vertex views had been obtained before and
      after operation in 206 patients (212 sides) with ZCF. Patients with complicated
      fractures underwent two and three dimensional CT. Computer-assisted measuring
      system was used to measure the degree of displacement. RESULTS: ZCF were
      classified into 3 types and 6 subtypes according to the degree of displacement of
      segments and facial deformities. Treatment principles were proposed. The results
      were satisfied through clinical application and measurement of post-operative
      images. CONCLUSIONS: The treatment for ZCF should be selected according to the
      fracture types. The key of operation is to recover the malar prominence.
      Remodeling the length and radian of zygomatic arch guarantee the recovery of
      malar prominence. Zygomatic-sphenoid and zygomatic-maxillary fissures are very
      important reference marks for reduction and fixation.

PMID- 15196389
TI  - [Construction and confirmation of the fused plasmid with Rb bait gene in yeast
      two-hybrid system].
AB  - OBJECTIVE: To screen and clone the novel genes related to cellular proliferation
      of oral squamous cell carcinoma. METHODS: We selected the Rb gene as the bait
      protein gene to construct the fusion bait plasmid of yeast two-hybrid. The whole
      code sequence of Rb gene was acquired by digestion with restricted enzyme EcoRI
      and BamH1 and reclaimed from its original vector pGBT9-pRb. After being confirmed
      by electrophoresis, the Rb gene was cloned into the MCS of the plasmid pGBKT7 to
      construct a recombined plasmid pGBKT7-pRb and the sequence of the recombined
      plasmid was detected in company. According to the protocol of yeast two hybrid
      system III, the competent Y187 yeast was prepared, and transformed with
      recombined plasmid pGBKT7-pRb. Following that, the toxicity and transcriptional
      activation of this recombined plasmid pGBKT7-pRb in Y187 yeast were tested.
      RESULTS: The sequence of the recombined plasmid was correct compared with the
      sequence provided in Genbank. The protein could be correctly synthesized in
      vitro, and no self-activating transcriptional activation and toxicity was
      observed in Y187 yeast. CONCLUSIONS: The construction of the recombined plasmid
      was capable to be used as the fusion bait plasmid in yeast two-hybrid system III,
      and the recombined Rb-protein could be used as the bait protein successfully.

PMID- 15196390
TI  - [Chemotherapy with higher or lower dose of teniposide combined with cisplatin and
      pingyangmycin for oral squamous cell carcinoma].
AB  - OBJECTIVE: To compare the clinical efficacy and toxicity of teniposide (VM26) of
      higher dose with those of lower dose, both combined with cisplatin (CDDP) and
      pingyangmycin (PYM), in the treatment of patients with squamous cell carcinoma of
      oral and maxillofacial region (SCCOMR). METHODS: Sixty-five patients with SCCOMR
      entered into this study prospectively. Thirty-three patients were treated with
      higher dose of VM26 (total dose was 320 mg) combined with CDDP and PYM (PTP1),
      the other thirty-two patients were treated with lower dose (total dose was 158
      mg) of VM26 combined with CDDP and PYM (PTP2). RESULTS: Thirty-three patients
      received a total of 38 cycles of PTP1. The overall response rate was 81.82%
      (27/33). Thirty-two patients received a total of 36 cycles of PTP2 and showed
      overall response rate by 81.25% (26/32). There was no significant difference
      between PTP1 and PTP2 groups in response rate (P > 0.05). But the blood toxicity
      was more severe in PTP1 group than in PTP2 group (P < 0.01). Bone marrow
      depression rate (1-4 stage) was 48.48% in PTP1 group versus 25.00% in the other
      group. CONCLUSIONS: A high response rate of 81.25% and relatively slighter
      adverse events could be obtained for lower dose of VM26 combined with CDDP and
      PYM (PTP2). So, the chemotherapy schedule, PTP2, a novel teniposide based regimen
      in SCCOMR could be employed and spread in clinical practice.

PMID- 15196391
TI  - [The relationship between lymphangiogenesis and cervical lymph node
      micrometastasis in oral squamous cell carcinoma].
AB  - OBJECTIVE: To probe the relationship between lymphangiogenesis and cervical lymph
      node micrometastasis in oral squamous cell carcinoma. METHODS: The microlymphatic
      vessel density was detected with enzyme histo-chemical method in 47 cases of oral
      squamous cell carcinoma and 10 cases of normal oral mucosa; 355 lymphnodes were
      detected with immunohistochemically using monoantibody AE3. RESULTS: The mean
      MLVD was 14.04 +/- 6.92 in tumor group, or 5.48 +/- 2.62 in normal group. The
      difference was (P < 0.001). The percentage of tumor with expression CK was 48.9%.
      The mean MLVD was 16.94 +/- 5.43 in CK positive group, or 11.26 +/- 5.00 in CK
      negative group, There was difference significant (P < 0.001). CONCLUSIONS:
      Lymphangiogenesis plays a key role in cervical lymph node micrometastasis of oral
      squamous cell carcinoma.

PMID- 15196392
TI  - [Analysis of stress distribution of bone around the implant on vertical loads].
AB  - OBJECTIVE: To analyze the stress distribution of bone around the implant on
      vertical loads. METHODS: Four linear strain gauges were placed in strategic
      locations. The vertical loads were applied at different points. The result of the
      stress was recorded at each gauge. RESULTS: The load, the location of load and
      their interactions indicated statistically significant difference in the
      distribution of stress. For the single-implant-supported fixed prosthesis the
      greater stress values were showed at the strain gauges positioned in the
      implant's cervical and apical area near to loading points. For the two-implant
      supported fixed bridge the greater stress values were showed at the stress gauges
      positioned in the two implants cervical and apical area near to loading points,
      especially at the implant near to loading points. As loads were applied at the
      cantilevered points, the magnitude of stress was directly proportional to the
      magnitude of load and the cantilevered length. CONCLUSIONS: For the design of the
      implant-supported prosthesis the relief of load and the avoidance of cantilevered
      prosthesis should be considered to reduce the stress of the bone around the
      implant.

PMID- 15196393
TI  - [Study on elastic limit and relevant enclasp force of non-precious metal casting
      clasp].
AB  - OBJECTIVE: To investigate the elastic limit and relevant enclasp force of the non
      precious metal casting clasp. METHODS: Casting clasp samples of five cobalt
      chromium alloys and one 18 - 8 nickel-chromium alloy were made from prefabricated
      clasp wax by invesing, casting, sandblasting, and ultrasonic cleaning. The
      process of casting clasp samples deflected by loading and returned by unloading
      was tested and electric signals were collected by an omnipotent material machine.
      The analog electric signal was converted to digital signal by an analog to
      digital converter and stored in a computer. The elastic limit and the relevant
      enclasp force were analyzed using a relative software. RESULTS: The elastic limit
      and the relevant enclasp force of the casting clasp made from the 18 - 8 nickel
      chromium alloy were smallest and those of the clasps made from the cobalt
      chromium alloys in various brands were different. The range of the elastic limit
      of the cobalt-chromium alloy casting clasp with the length of 5.0 mm in undercut
      was 0.28 mm-0.33 mm and the relevant enclasp force was 14.42 g-19.28 g.
      CONCLUSIONS: In clinic, we should select the suitable undercut deepness wherein
      the cobalt-chromium alloy casting clasps, according to different brands of the
      casting alloy, undercut length, undercut slope, and the clasp thickness.

PMID- 15196394
TI  - [Influence of eugenol-containing temporary cement on efficacy of dentin-bonding
      systems].
AB  - OBJECTIVE: This study investigated the influence of eugenol-containing temporary
      cement on the efficacy of two relatively new dentin-bonding systems. METHODS:
      Thirty-two freshly extracted bovine central incisors were randomly divided into
      four groups. Dentin was exposed and polished with 320#, 400#, and 600# sand
      papers. After embedded, Group 3 and 4 specimens were covered with ZOE. Specimens
      in Group 1 and 2 were served as control. All specimens were stored for 1 week in
      distilled water at 37 degrees C. Then, the ZOE was mechanically removed. The
      dentin surfaces of Group 1 and 3 were treated with Prime & Bond NT bonding system
      and the dentin surfaces of Group 2 and 4 were treated with GLUMA adhesive system
      according to manufacturer's instructions. Thereafter composite resin columns (6
      mm diameter, 2 mm high) were applied. After specimens stored in distilled water
      at 37 degrees C for 24 hours, the shear bond testing was carried out using a
      SHIMADZU universal testing machine with a cross-head speed of 0.5 mm/minute. The
      mode of failure was examined using SEM. The data were analyzed using ANOVA test
      at a significance level of 0.05. RESULTS: The medians of shear bond strength for
      each group were as follows: Group 1 (Prime & Bond NT) 9.57 MPa, Group 3 (Prime &
      Bond NT + ZOE) 10.72 MPa, Group 2 (GLUMA) 16.89 MPa, Group 4 (GLUMA + ZOE) 16.78
      MPa. Group 1 and 3 had significantly lower bonding strength than did Groups 2 and
      4. But no significant difference was found between the control groups and the
      groups treated with ZOE temporary cement. CONCLUSION: Pretreatment of the dentin
      with ZOE temporary cement has no adverse influence on the efficacy of two
      relatively new dentin-bonding systems.

PMID- 15196395
TI  - [Biomechanical study of open bite treatment with tip forward bend].
AB  - OBJECTIVE: To verify whether it is effective to treat open bite cases with tip
      forward bend. METHODS: Three-dimensional finite element (TDFE) models of the
      lower left central incisor and first molar were set up by means of CT. Stress
      distribution in root, PDL and alveolar bone, and the tendency of the tooth
      movement were obtained by calculation under different orthodontic forces.
      RESULTS: (1) The molar model revealed that the tensile stress concentration was
      at the distal cervix and the compressive stress concentration at mesial cervix.
      (2) The incisor model showed that the tensile stress was concentrated at apical
      tip and the compressive stress concentration was at the lingual side of the
      cervix. (3) The incisor had the tendency to elongate and move lingually. The
      molar tended to tip mesially and buccally. CONCLUSIONS: Arch wire with tip
      forward bend depends on the elongation and lingual movement of anterior teeth to
      treat open bite, but the anchorage molar will incline mesially further, which is
      not consistent with the mechanism to treat open bite.

PMID- 15196397
TI  - [The three-dimensional nonlinear finite element analysis of force system of the
      "rocking-chair archwire"].
AB  - OBJECTIVE: The purpose of this study was to qualitatively and quantitatively
      analyze the initial force system of "rocking-chair archwire" on every tooth.
      METHODS: Three-dimensional finite element model of "rocking-chair archwire" was
      set up, and nonlinear method was used to analyze the force system. RESULTS: The
      archwire exerted intruding force, labial force, lingual-root torque and mesial
      labial moment on incisors; Extruding force, lingual-root torque and mesial-labial
      moment were applied on canines and premolars; The archwire also created intruding
      force, buccal force, buccal-root torque and mesial-labial moment on molars.
      CONCLUSIONS: "rocking-chair archwire" produced a complicated force system. While
      intruding incisors, molars and extruding premolars. It has a tendency to induce
      tooth rotation and tipping.

PMID- 15196396
TI  - [The effect of pre-surgical orthodontics on secondary alveolar bone grafting in
      the patients with complete cleft lip and palate].
AB  - OBJECTIVE: To examine the effect of pre-surgical orthodontics on the outcome of
      the secondary alveolar bone grafting in the patients with complete cleft lip and
      palate. METHODS: Sixteen complete cleft lip and palate patients (9 males and 7
      females) with collapsed upper arch or severe mal-positioned upper incisors were
      selected. The cleft was not easily grafted because of the poor access. The total
      cleft sites were 22 (10 patients with UCLP and 6 patients with BCLP). The age
      range of the patients was from 8 to 22 years. Pre-surgical orthodontic treatment
      was mainly to expand the collapsed upper arch and correct the mal-positioned
      upper incisors. After the secondary alveolar bone grafting, the patients were
      followed up and anterior occlusal radiograph/intraoral panograph were taken
      regularly. The observation period was from 6 months to 4 years. Bergland criteria
      were used to evaluate the interdental septal height. RESULTS: Upper arch
      expansion and the correction of the mal-positioned upper incisors done by the
      orthodontic treatment made the bone grafting procedure easier. The clinically
      successful rate reached 86%. CONCLUSION: The severe upper arch collapse and mal
      positioned upper incisors in the patients with complete cleft lip and palate
      should be corrected orthodontically before the secondary alveolar bone grafting.

PMID- 15196398
TI  - [A three-dimensional finite element analysis on the effect of seven different
      occlusions on TMJ].
AB  - OBJECTIVE: To investigate the effects of tooth apical stress changes caused by
      different types of occlusion on the TMJ stresses. METHODS: The apical stresses
      measured from photo-elastic experiments (2 Kg centric vertical loading to seven
      types of occlusions separately) were applied to the established 3D finite
      elemental model. The stress distributions on condyle, superfacial cartilage of
      condyle and TMJ disc were compared. RESULTS: (1) The stress on both anterior
      surface of condyle and its superfacial cartilage and on the intermediate band of
      disc were mainly compressive, while the stress on both posterior surface of
      condyle and its superficial cartilage and on the posterior band of disc were
      mainly tensile (P < 0.01). (2) The values of TMJ stresses of models with flat
      surface occlusion, distal occlusion, unilateral partial molar teeth cross bite,
      and occlusion with right second and third molar tooth missing were different to
      some extent from that with normal occlusion, among which the TMJ stress from the
      flat surface occlusion differed most significantly (P < 0.01). The TMJ stresses
      of models with unilateral upper third molar hyper-eruption occlusion and
      unilateral lower third molar hyper-eruption occlusion did not significantly
      differ from that with normal occlusion. CONCLUSIONS: Changes of apical principle
      stress resulted from different types of occlusions during centric biting have
      effects to some extent on TMJ stress quantitatively but not qualitatively.

PMID- 15196399
TI  - [A study of electric information monitoring in the treatment of bruxism with
      occlusal splint].
AB  - OBJECTIVE: An electric monitor of bruxism had been invented in order to evaluate
      the curative effect of cuspid occlusal upheaving splint and stabilization splint.
      METHODS: 20 patients with bruxism were randomly divided into two groups. A cuspid
      occlusal upheaving splint or a stabilization splint was fabricated respectively
      for patients. The vertical dimension for each splint was 0.5 mm lower than
      mandibular postural position. Sleeping time, bruxist time and times of bruxism
      were recorded with bruxism monitor that was invented for studying bruxing.
      RESULTS: The bruxist time and the times of bruxism were decreased obviously in
      patients with cuspid occlusal upheaving splint, while no significant difference
      was shown before and after using the stabilization splint. CONCLUSIONS: The
      bruxism monitor can automatically measure and record the data of bruxism with
      splint, which is valuable for clinic. The curative effect of cuspid occlusal
      upheaving splint is better than that of stabilization splint for treating
      bruxism.

PMID- 15196400
TI  - [Enhancement of immune responses in rabbits with a targeted anti-caries DNA
      vaccine pGJA-P].
AB  - OBJECTIVE: To detect the immunoreactivity of targeted fusion anti-caries DNA
      vaccine pGJA-P in vitro, and the ability to enhance the immune responses compared
      with the non-targeted fusion anti-caries DNA vaccine pGLUA-P. METHODS: The CHO
      cells were transfected with pGJA-P and the expression of recombinant protein in
      cultured supernatants were detected using Western blotting. 5 to 6-month-old
      female Japanese rabbits were immunized with either pGJA-P or pGLUA-P via either
      intramuscular injection (i.m.) or intranasal route (i.n.). The sera and saliva
      were collected and the antibody responses were checked by ELISA. The effect of
      immune sera on the synthesis of water-insoluble glucan by glucosyltransferase of
      S. mutans was examined. RESULTS: The expressed protein could response to specific
      anti-GTF antibody. The antibody responses in serum generated by pGJA-P via i.m.
      were significantly higher than those generated by pGLUA-P (P < 0.01). The
      antibody responses in saliva generated by pGJA-P via i.n. were significantly
      higher than those generated by pGLUA-P (P < 0.01). The higher mucosal antibody
      response induced by pGJA-P via i.m. compared with pGLUA-P (P < 0.01) was
      detected. The immune sera of rabbits immunized by pGJA-P via i.m. most
      significantly inhibited the synthesis of water-insoluble glucan by
      glucosyltransferase. CONCLUSIONS: The recombinant protein expressed by pGJA-P had
      the immunoreactivity to anti-GTF antibody. pGJA-P could induce faster and higher
      specific mucosal SIgA antibody responses via i.n. or serum IgG antibody responses
      via i.m. compared with non-targeted DNA vaccine, pGLUA-P. High titres of specific
      mucosal antibodies were found in rabbits immunized with pGJA-P via i.m. The
      immune sera of rabbits immunized by pGJA-P via i.m. displayed the ability of
      inhibiting the synthesis of water-insoluble glucan by glucosyltransferase.

PMID- 15196401
TI  - [Exercise self-discipline and protect doctors' rights in private clinics].

PMID- 15196402
TI  - [Root canal obturation: techniques, problems and management].

PMID- 15196403
TI  - [Guide for The Examination of National Certified Dentist Preparation. Candidates
      review guide on preventive dentistry].

PMID- 15196404
TI  - [Guide for The Examination of National Certified Dentist Preparation. Candidates
      review guide on oral medicine].

PMID- 15196406
TI  - [Laparoscopic operation in the new century].

PMID- 15196405
TI  - [Cylooxgenase-2: a novel molecular target for the prevention and treatment of
      head and neck cancer on the advance of basic and preclinical research].

PMID- 15196407
TI  - [The Second National Conference on Endoscopic Procedures in Gynecology].

PMID- 15196408
TI  - [Evaluation on clinical application and long term outcomes of transcervical
      resection of endometrium].
AB  - OBJECTIVE: To evaluate the short term and long term outcomes of abnormal uterine
      bleeding (AUB) treated by transcervical resection of endometrium (TCRE) as well
      as the factors which influence the outcomes. METHODS: From May 1990 to September
      2002 there were 1431 cases who suffered from menorrhagia. A total of 1468 times
      of TCRE were performed. Hysteroscopic diagnosis and endometrium biopsy was
      performed to rule out malignant diseases in 1203 cases. One stage TCRE was
      performed in 265 cases. Resistance index (RI) and pulse index (PI) of every level
      uterine artery were measured by ultrasound and serum levels of were 6 steroid sex
      hormones were measured by laboratory in 32 cases. The mean duration of follow-up
      was 68.5 months (3 - 148 months). RESULTS: Three cases of uterine perforation
      were encountered. Smog like echo in the anterior uterine wall was found in 714
      cases (49.9%) by B ultrasonography, among them 21 cases (63.6%) were proved
      adenomyosis by pathological examination. One hundred and fifty nine cases (10.8%)
      had been treated by drugs, such as homeostasis, analgesic agent, antibiotics,
      progesterone and endometrium inhibiting agents, etc. Repeat TCRE was performed in
      37 cases. Owing to recurrent bleeding, dysmenorrhea or uterine myoma 87 cases
      (6.1%) were finally received hysterectomy. CONCLUSIONS: (1) The main cause of
      recurrence was incomplete destruction of or leak from basal layer of endometrium.
      Shift wire loop with the sheath together to resect endometrium from the fundus to
      cervix smoothly can solve the problem of incomplete resection. Upon completion of
      operations, "blind area" and "blind point" should be examined and resected again
      if there is some endometrium left behind which could solve leak from basal layer
      of endometrium. (2) The duration of follow-up and adenomyosis are the main
      factors, which influence the long-term successful rate. (3) TCRE dose not
      influence the ovarian function obviously.

PMID- 15196409
TI  - [Analysis of the efficiency of transcervical resection of endometrium for
      treating dysfunctional uterine bleeding and factors reducing the efficiency of
      the operation].
AB  - OBJECTIVE: To investigate the efficiency and factors related to the recurrence of
      transcervical resection of endometrium (TCRE) in treating women with
      dysfunctional uterine bleeding (DUB). METHODS: Two hundred and twenty women with
      DUB were selected for TCRE. Specimens from removed endometrium were obtained
      during the procedures and their menstruation and menorrhagia after the operations
      were followed up. We also studied the uterine specimens obtained from the
      recurrent cases undergoing hysterectomies. The specimens were stained by
      hematoxylin-eosin and immuno-histochemistry respectively to evaluate the depth of
      removed myometrium and the histopathologic changes in relapsed cases. RESULTS:
      The follow up period after operation was 24 to 114 months. (1) Overall effective
      rate was 94.5%, in which amenorrhea rate was 25.9%, menstruation reduction rate
      was 68.6%. (2) The effective rate of corrective anemia was 97.3% and the
      satisfaction rate for the operation was 92.3%. (3) Thirty-eight cases required
      subsequent treatment as a result of recurrence, of which 10 cases underwent
      hysterectomy and 3 cases underwent repeat TCRE and 25 cases were given medicine
      treatment. (4) The average depth of myometrium in removed endometrium strip was
      2.12 approximately 3.26 mm. (5) Endometrium regrowth was seen in the resected
      uterine specimens from relapsed cases and adenomyosis was also found in the intra
      uterine wall in some cases. CONCLUSIONS: (1) TCRE is a safe and effective
      alternative treatment for DUB. (2) The main factor reducing the efficiency is
      either incomplete removal of endometrium or adenomyosis. (3) Standardizing the
      procedures and strengthening postoperative management are essential requirements
      for improving the efficiency of TCRE.

PMID- 15196410
TI  - [Role of radical vaginal trachelectomy and laparoscopic pelvic lymphadenectomy in
      treating early cervical carcinoma].
AB  - OBJECTIVE: To investigate the possibility and effect of radical vaginal
      trachelectomy and laparoscopic pelvic lymphadenectomy in treating women with
      early cervical cancers who desired to maintain fertility. METHODS: From August
      2001 through May 2003, we performed vaginal radical trachelectomy with
      laparoscopic lymphadenectomy on 12 patients with biopsy-proven early stage
      cervical carcinomas. Subjects were selected for this treatment on the basis of
      favorable cervical tumors and a desire to maintain fertility. Pelvic
      lymphadenectomies were performed in all patients. Vaginal radical trachelectomy
      was performed immediately if lymph nodes were negative. RESULTS: Twelve women
      underwent this procedure. The median age was 27.6 years (range 24 - 31 years); 10
      were nulligravid and 2 were multipara. Mean operative time was 142 min (115 - 178
      min), with a mean blood loss of 180 ml (120 - 230 ml), and an average hospital
      stay of 6.7 days. There was no intra- or post-operative complication. With an
      average follow-up of 21.5 months, there have been no recurrences. One woman has
      become pregnant. CONCLUSIONS: Radical vaginal trachelectomy with laparoscopic
      pelvic lymphadenectomy permits preservation of fertility in selected patients. It
      is mini-invasive, and needs shorter recovery time.

PMID- 15196411
TI  - [Clinical analysis of radical hysterectomy plus pelvic lymphadenectomy for
      patients with malignant uterine tumors: laparoscopy versus laparotomy].
AB  - OBJECTIVE: To compare clinical efficacy of laparoscopy with laparotomy in radical
      hysterectomy plus pelvic lymphadenectomy for patients with malignant uterine
      tumors. METHODS: This retrospective study population included two groups: (1) 26
      patients underwent laparoscopy-assisted radical hysterectomy plus pelvic
      lymphadenectomy (group laparoscopy) and (2) 27 patients were treated with radical
      hysterectomy plus pelvic lymphadenectomy through laparotomy (group laparotomy).
      The tumor stage in these two groups of patients was matched. Multiple clinical
      parameters were observed and analyzed statistically. RESULTS: Compared to the
      patients in group laparotomy, the patients in group laparoscopy had a longer
      operative time (310 vs 238 min), more pelvic lymph nodes removed (22 vs 16),
      lower volume of blood loss (756 vs 1129 ml), and transfusion (321 vs 746 ml), a
      shorter postoperative gastrointestinal function recovery time (37 vs 62 h), a
      quicker return to normal temperature (5 vs 8 d), and a shorter period to use
      antibiotics (6 vs 8 d) (P < 0.01) However, there were no significant differences
      in the volume of pelvic drainage (321 vs 216 ml), urination recovery time (13 vs
      10 d), number of WBC found (11 x 10(9)/L vs 10 x 10(9)/L), hospital stay (26 vs
      28 d) and cost (25 986 vs 22 672 Yuan) between the two groups (P > 0.05).
      CONCLUSION: The clinical efficacy of radical hysterectomy plus pelvic
      lymphadenectomy by laparoscopy for patients with malignant uterine tumor is equal
      to that through laparotomy.

PMID- 15196412
TI  - [Ureteral injury in gynecologic laparoscopies].
AB  - OBJECTIVE: To investigate the ureteral injury in gynecological laparoscopies and
      discuss its diagnosis, treatment and prevention. METHODS: Ureteral injury in
      gynecological laparoscopies during the past 13 years was reviewed
      retrospectively. The clinical features of initial operations including the types
      of disease, uterine size, pelvic adhesion, operative procedures and the methods
      of diagnosis, treatment and prognosis of ureteral injury were studied. RESULTS:
      There were 8 ureteral injuries (0.14%) in 5 541 gynecological laparoscopies with
      seven in laparoscopically assisted vaginal hysterectomy (LAVH)/total laparoscopic
      hysterectomy (TLH) (0.45%) and one in non-LAVH (0.03%). The main gynecological
      disorders included adenomyosis, endometriosis and leiomyoma. All patients had
      pelvic adhesions and 4 had previous pelvic operations. Uterine enlargement was
      found in 7. Patients presented increased vaginal drainage, flank pain, increased
      volumes of vaginal discharge, nausea and vomiting, fever, edema, or peritonitis
      from 0 to 13 days postoperatively. Ureteral injuries were mainly diagnosed via
      excretory urogram (IVP). The sites of injury were near the inferior margin of the
      sacroiliac joint in two women and at the inferior part of ureter (near the
      uterine vessel, uterosacral ligament and ureterovesical junction) in 6. Two
      patients whose injuries were found soon after operation received ureteral repair
      by laparotomy successfully. Two of the six patients whose injuries were found
      several days later were treated with internal ureteral stenting successfully, the
      other four failed with ureteral stenting and received ureteral repair by
      laparotomy. Outcomes were good in all cases. CONCLUSIONS: Ureteral injury is an
      uncommon and severe complication in gynecological laparoscopies. Symptoms like
      abnormally increased drainage, fever, flank pain, abnormal vaginal discharge and
      peritonitis after operation should be paid attention to and ureteral injury be
      considered. Surgical repair is the primary treatment.

PMID- 15196413
TI  - [Effect of different surgical approaches on quality of life and cost
      consequence].
AB  - OBJECTIVE: To evaluate the effects of total abdominal hysterectomy (TAH),
      laparoscopic hysterectomy (LH) and transvaginal hysterectomy (TVH) on quality of
      life, cost and health care utilization. METHODS: A study of women who underwent
      elective hysterectomy was performed to assess the effect of operations on quality
      of life using WHO quality of life-bref before operation, at the 4th, 14th and
      28th day after operation, respectively. The data of total cost and health care
      utilization were also analyzed. RESULTS: The score of quality of life at the 4th
      day after operation in TVH patients was significantly higher than that in TAH
      patients (93 +/- 6 vs 81 +/- 11, P < 0.01). There was no significant difference
      in this score between TVH and LH, and between LH and TAH patients. However, at
      the 14th and 28th after operation, the scores in both TVH and LH patients were
      significantly higher than that in TAH patients (95 +/- 7 and 96 +/- 7 vs 85 +/-
      9, P < 0.001 and 0.001; 96 +/- 10 and 98 +/- 7 vs 87 +/- 10, P < 0.01). There was
      no significant difference in the total costs among three groups. The better
      health care utilization was in LH and TVH patients, and the worse in TAH
      patients. CONCLUSIONS: The effect of LH and TVH on quality of life and health
      economics is similar, and appears to be superior than that of TAH.

PMID- 15196414
TI  - [Study of operative procedures of laparoscopy and laparoscopically assisted
      sigmoid transplantation for vaginal construction].
AB  - OBJECTIVE: To explore the procedures and the clinical significance of laparoscopy
      and laparoscopically assisted sigmoid transplantation for vaginal construction.
      METHODS: Nine cases were assigned randomly to laparoscopically assisted sigmoid
      colpopoiesis and laparoscopic sigmoid colon colpopoiesis. The procedure of
      laparoscopically assisted sigmoid colpopoiesis: with the auxiliary of
      laparoscopy, dissected the distal portion of the sigmoid with endoscopic linear
      cutter, then a 4-cm incision was made in the left lower abdomen to retract and
      dissect the proximal portion of sigmoid. After the proximal portion of transplant
      sigmoid was closed, the proximal cut end of reserved-sigmoid was placed with the
      anvil and made a purse-string suture, then put back sigmoid into the peritoneal
      cavity. A curved intraluminal stapler was inserted from the anus to the most
      distal cut end of reserved-sigmoid to end-end anastomose the reserved-sigmoid.
      Finally, an artificial canal was made between urethravesicae and rectum and the
      transplant-sigmoid with the blood supply was placed into the artificial canal to
      create an artificial vagina. The procedure of laparoscopic sigmoid colpopoiesis
      was performed under laparoscopy thoroughly. RESULTS: We have successfully
      completed the operations for 9 patients, and made 1 - 19 month following-up. The
      results of the artificial vaginae of all cases were satisfactory; the abdominal
      scar was small with remarkable cosmetic effects. Moreover, 5 cases had pleasant
      sexual intercourses. CONCLUSION: The procedures of laparoscopy and
      laparoscopically assisted sigmoid transplantation for vaginal construction can
      replace the traditional laparotomy.

PMID- 15196415
TI  - [Influence of transforming growth factor-beta2 on production of tumor necrosis
      factor-alpha and interferon-gamma from placenta of intrahepatic cholestasis of
      pregnancy].
AB  - OBJECTIVE: To investigate the influence of transforming growth factor-beta2 (TGF
      beta2) on production of tumor necrosis factor-alpha (TNF-alpha) and interferon
      gamma (IFN-gamma) from placenta of patients with intrahepatic cholestasis of
      pregnancy (ICP). METHODS: Villous explants from 10 ICP patients (ICP group) and
      10 normal gravidae (control group) were cultured in vitro. The concentrations of
      TNF-alpha and IFN-gamma in the culture medium were determined by enzyme linked
      immunoadsorbent assay (ELISA) after incubation with different concentrations of
      TGF-beta2 for 1, 24 and 48 hours. RESULTS: (1) After cultured for 1, 24 and 48
      hours, TNF-alpha level in ICP group was (771 +/- 187) pg/g, (2 490 +/- 575) pg/g,
      and (3339 +/- 1106) pg/g, respectively, while IFN-gamma level was (931 +/- 148)
      pg/g, (1888 +/- 545) pg/g, and (3027 +/- 667) pg/g, respectively. All were
      significantly higher than those in the normal group (P < 0.001). (2) TGF-beta2
      could inhibit the release of above cytokines in a time- and dose-dependent
      manner: TNF-alpha level was (2490 +/- 575) pg/g, (1806 +/- 502) pg/g, and (1231
      +/- 238) pg/g after 24 h, (3339 +/- 1106) pg/g, (2168 +/- 794) pg/g, and (1047 +/
      183) pg/g after 48 h, respectively; IFN-gamma level was (1888 +/- 545) pg/g, (1
      347 +/- 405) pg/g, and (913 +/- 303) pg/g after 24 h, and (3027 +/- 667) pg/g,
      (2062 +/- 795) pg/g, and (1001 +/- 301) pg/g after 48 h, respectively.
      CONCLUSION: (1) The excessive production of TH1 type cytokines TNF-alpha and IFN
      gamma may involve in the pathogenesis of ICP; (2) TGF-beta2 may exert
      immunoprotection effect through inhibiting the production of TNF-alpha and IFN
      gamma.

PMID- 15196416
TI  - [Pregnancy and delivery outcomes after loop electrosurgical excision procedure of
      cervical intraepithelial neoplasia].
AB  - OBJECTIVE: To investigate the effects of loop electrosurgical excision procedure
      (LEEP) on pregnancy and delivery outcomes of patients with cervical epithelial
      neoplasia (CIN). METHOD: The delivery data of 27 pregnant women who had LEEP from
      May 1995 to April 2002 were retrospectively collected and analysed. RESULTS: The
      mean age of the 27 women was 30.3 years (range 23 approximately 40 years). Ten
      women underwent artificial abortion. One ectopic pregnancy and two spontaneous
      miscarriages occurred at 6 to 8 weeks of gestation. There were 14 term
      pregnancies, 9 of them via vaginal delivery and 5 via caesarean section. The
      birth weight of newborns ranged from 2905 to 4000 g. All of newborns had a high
      Apgar score. No asphyxia occurred. CONCLUSIONS: LEEP is a safe and effective
      treatment for patients with CIN. It will not increase the risk of pregnancy and
      delivery of the patients.

PMID- 15196417
TI  - [Study of the causes of fetal growth restriction with unclear etiologies].
AB  - OBJECTIVE: To investigate different factors related to fetal growth restriction
      (FGR) and to find out the possible causes of FGR with unclear etiologies.
      METHODS: Sixty-three women who were suspected of FGR during pregnancy between
      March 2002 and March 2003 were included in this study. Their age, body mass index
      (BMI) before pregnancy, and gestational weeks were recorded at the time when they
      were first diagnosed. Haemoglobin levels, haematocrit (HCT), TORCH,
      anticardiolipin antibody (ACA), 50 gram glucose challenge test (50g GCT), 75 gram
      oral glucose tolerance test (75g OGTT), leptin levels, systolic/diastolic (S/D)
      ratio by color doppler monitor and chlamydia trachomatis (CT) were detected and
      urine culture was done in these groups during the same period. The gestational
      week, birth weight, body length and the gender were recorded at the delivery
      period. The FGR group was then divided into two subgroups according to the birth
      weights: study A group whose birth weights were lower than 10th% of the birth
      weights at the given gestational weeks (29 cases) and study B group whose birth
      weights were beyond 10th% (34 cases). The chromosome, leptin, C-peptide, insulin
      and TORCH of umbilical blood were measured at delivery. The other 25 normal
      pregnant women were included as control and the same tests were performed
      accordingly. RESULTS: The fasting glucose and the third hour's glucose of 75 gram
      oral glucose tolerance test of study A were (3.8 +/- 0.6) mmol/L and (4.5 +/-
      1.1) mmol/L. The fetal leptin, C-peptide, and insulin were (7.3 +/- 5.2) ng/ml,
      (0.5 +/- 0.3) nmol/L and (2.3 +/- 1.3) mU/L. The S/D ratio of umbilical artery,
      maternal and fetal infection rate of CMV, positive rate of ACA-IgM and the rate
      of asymptomatic bacteriuria were 3.06, 20.7%, 24.1%, 44.8% and 62.1%
      respectively. The fasting glucose and the third hour's glucose of 75 gram oral
      glucose tolerance test of study B were (4.4 +/- 0.7) mmol/L and (4.6 +/- 1.1)
      mmol/L. The fetal leptin, C-peptide, and insulin were (13.2 +/- 11.3) ng/ml, (0.7
      +/- 0.4) nmol/L and (4.3 +/- 3.3) mU/L. The S/D ratio of umbilical artery,
      maternal and fetal infection rate of CMV, positive rate of ACA-IgM and the rate
      of asymptomatic bacteriuria were 2.63, 2.9%, 0%, 5.9% and 44.1% respectively. The
      fasting glucose and the third hour's glucose of 75 gram oral glucose tolerance
      test in control were (4.3 +/- 0.7) mmol/L and (5.3 +/- 1.2) mmol/L. The fetal
      leptin, C-peptide, and insulin were (20.5 +/- 12.0) ng/ml, (1.0 +/- 0.4) nmol/L
      and (6.3 +/- 4.0) mU/L. The S/D ratio of umbilical artery, maternal and fetal
      infection rate of CMV, positive rate of ACA-IgM and the rate of the asymptomatic
      bacteriuria were 2.80, 0, 0, 0 and 24.0% respectively. All these items were
      significantly higher in study A than those in the control (P < 0.05). There was
      no significant difference between the study B and the control in all the items.
      CONCLUSIONS: Many factors may play a role in the pathogenesis of FGR, including
      the maternal blood glucose level, the ability for fetus to use the glucose, the
      infection of some microorganisms, insufficiency of the blood supply and the
      autoimmunity of the mother. Finding out the possible causes of FGR and managing
      them accordingly may improve the outcomes of the fetus.

PMID- 15196418
TI  - [Clinical analysis of 11 cases of ovarian Setoli-Leydig cell tumor].
AB  - OBJECTIVE: To study the clinical characteristics, treatment and prognostic
      factors of ovarian Setoli-Leydig cell tumor. METHODS: During 1962 - 2002, a total
      of 11 patients with Setoli-Leydig cell tumor were retrospectively analyzed.
      RESULTS: Microscopically, seven of the neoplasms were well differentiated, 3 were
      moderately differentiated and 1 was poorly differentiated. Nine of the tumors
      were stage Ia, 1 was stage IIc and 1 was stage IIIc. The most frequent symptoms
      were abdominal-pelvic masses. Six patients presented with androgenization and
      virilization, 3 of which had their serum testosterone tested, and the levels were
      elevated. Five patients presented with metromenorrhagia and abnormal vaginal
      bleeding. One of them was both androgenized and estrogenized. In addition, five
      patients had diseases associated with excessive estrogenic stimulation, such as
      uterine myoma and endometrial hyperplasia. Two patients suffered from breast
      cancer. All patients were subjected to operation. And 5 patients with poorly
      differentiated or stage II-III tumors were subjected to postoperational
      chemotherapy. After 6 months to 34 years follow-up, no patient died of this
      disease. Three patients who received conservative surgery achieved normal
      menstruation 1 - 3 months after operation, and one of them gave birth to a child.
      CONCLUSIONS: Ovarian Setoli-Leydig cell tumor has good prognosis. Surgery alone
      is a currently acceptable treatment for patients with well-differentiated early
      stage tumors. For patients with poorly differentiated or advanced tumors,
      postoperational chemotherapy seems to be necessary. Conservative surgery should
      be the treatment of choice in young patients who need future fertility.

PMID- 15196419
TI  - [Study of GE7-transferring system mediated beta-galactosidase gene transfer in a
      rat model of ovarian tumor by intraarterial route].
AB  - OBJECTIVE: To investigate the efficiency and targeting of the GE7 system mediated
      gene transfer in the chemically induced ovarian tumor by intraarterial route.
      METHODS: Animal models were chemically induced by 7,12-dimethylbenz[a]anthracene
      (DMBA). GE7-polylysine/beta-galactosidase (beta-gal)/polylysine-HA20 complexes
      were constructed. Fifteen rats with induced ovarian tumor were divided into three
      groups, the complexes were injected through ovarian artery and tail vein,
      respectively. The tumor, heart, liver, spleen, lung and kidney were obtained at
      72 h. X-gal staining was used to check expression of beta-gal. RESULTS: beta-gal
      was expressed strongly and well-distributed in tumor in the first group, and
      stained blue in the liver, spleen, lung and kidney, but much weaker than that of
      tumor. In the second group, beta-gal was expressed in the tumor, and weakly
      expressed in the liver, none was detected in the other organs. In the third group
      beta-gal was detected in the lung slightly, none was detected in the tumor and
      other organs. CONCLUSIONS: When GE7 complexes were administrated through ovarian
      artery, the introduced gene expressed preferentially in ovary. This result was
      the basis of intraarterial administration of therapeutic gene to treat ovarian
      cancer.

PMID- 15196420
TI  - [Mechanistic study of radiosensitization by gemcitabine on human squamous
      carcinoma cell line of the cervix].
AB  - OBJECTIVE: To investigate whether gemcitabine (dFdC) at the non-cytotoxic
      concentration enhances the effect of irradiation on human squamous carcinoma
      cells of the uterine cervix (HeLa) in vitro, and to evaluate the mechanism by
      which dFdC at the non-cytotoxic concentration [24 h 10% inhibiting concentration
      (IC(10))] is able to enhance radiation-induced cytotoxicity to HeLa in vitro.
      METHODS: The non-cytotoxic concentration (24 h IC(10)) of dFdC was determined by
      methyl thiazolyl tetrazolium (MTT). After exposure to the non-cytotoxic
      concentration (0.01 micro mol/L) for 4, 8, 12 and 24 hours followed by immediate
      irradiation (4, 6 and 8 Gy), the surviving fraction was counted and the radiation
      enhancement ratio (RER) was evaluated. Cell cycle distribution and apoptosis were
      analyzed by flow cytometry. The expressions of p53, bcl-2 and bax were studied by
      western blot. RESULTS: After exposure to non-cytotoxic concentration (0.01 micro
      mol/L) for 4, 8, 12 and 24 hours followed by immediate irradiation, the RER was
      1.19, 1.35, 1.72 and 1.93, respectively. After exposed to dFdC, HeLa cells showed
      an S phase block. The proportion of S phase cells was elevated with the increase
      of exposure duration (P < 0.01). The S-phase proportion increased to 51.8% at 24
      hours of exposure. Meanwhile, compared with the single-agent treatments,
      combination of dFdC and radiation did not additionally increase the number of
      apoptotic cells and expression of proteins related to apoptosis such as p53, bcl
      2 and bax (P > 0.05). CONCLUSIONS: HeLa cells were radiosensitive at IC(10)
      concentration of dFdC. The radiosensitization effect depends on the exposure
      duration to dFdC. There appears a strong association between the
      radiosensitization and the progression of cells into S-phase after dFdC
      treatment. Combination of dFdC and radiation did not increase apoptosis of HeLa
      cells.

PMID- 15196430
TI  - [Exploration of multigene, multistep and multipathway model of nasopharyngeal and
      colorectal carcinogenesis].
AB  - OBJECTIVE: To construct tree models for nasopharyngeal carcinoma (NPC)and explore
      the oncogenesis process of NPC. METHODS: Based on the software which Desper et al
      developed, tree models were constructed for colorectal carcinoma (CC) from the
      comparative genomic hybridization (CGH) data of 118 CC patients and for NPC from
      the CGH data of 140 southern Chinese patients, respectively. RESULTS: Tree models
      for CC suggested that changes in -18q and +20q were important early events in
      colorectal carcinogenesis. As changes in -18q occurred prior to those in -17p,
      there might be some cause-effect relationship. Tree models for NPC suggested that
      change in -3p was an important early event in nasopharyngeal carcinogenesis, and
      those in -11q, -14q, -16q, -9p were also non-random genetic events in
      carcinogenesis, suggesting that there might be tumor-associated genes existing on
      these chromosome arms. The tree model also suggested the existence of oncogene on
      the short arm of chromosome 12. CONCLUSION: Constructing tree models based on the
      CGH data to demonstrate the initiation and progression of NPC might help
      elucidate its multigene, multistep and multipathway development. It may provide
      valuable clues to explore the mechanism of tumorigenesis.

PMID- 15196431
TI  - [The mechanism of topotecan resistance in ovarian cancer cell line].
AB  - OBJECTIVE: To study the mechanism of topotecan (TPT) resistance in ovarian cancer
      cell line. METHODS: A TPT-resistant ovarian cancer cell line A2780/TPT
      established in this laboratory was used in this study. Intracellular rhodamine
      fluorescence intensity of the TPT-resistant cells and parental cells were
      measured by flow cytometry. The gene expression of membrane protein transporter
      such as transporter P-glycoprotein (P-gp), multidrug resistance associated
      protein (MRP), breast cancer resistance protein (BCRP) was evaluated by RT-PCR.
      The antisense-phosphorothioate oligonucleotide (ASODN) including a translation
      initiation site of BCRP mRNA was transferred into resistant cells by liposome.
      RESULTS: Intracellular rhodamine fluorescence intensity of the resistant cells
      was 31.19% of that in the parental cells (P < 0.01). No expression of P-gp was
      demonstrated, and that of MRP was very weak in the TPT-resistant cells (relative
      expression value = 0.057). BCRP was overexpressed in the TPT-resistant cells
      (relative expression = 0.66), but not in the parental cells. Transfer of ASODN
      into resistant cells resulted in a 59.42% reduction of BCRP gene expression (P <
      0.05) and an obviously increased intracellular rhodamine fluorescence intensity
      from 5.42 to 16.63 (P < 0.05). CONCLUSION: The overexpression of BCRP which
      mediated drug efflux may play an important role in the induction of TPT
      resistance in ovarian cancer.

PMID- 15196432
TI  - [Construction of pEgr-TNFalpha plasmid and experimental study on the effect of
      gene-radiotherapy on mouse melanoma].
AB  - OBJECTIVE: The pEgr-TNFalpha plasmid was constructed to investigate the effect of
      gene-radiotherapy on melanoma and host immune system. METHODS: pEgr-TNFalpha
      plasmids were constructed and injected into tumor tissue, 36 hours later, the
      tumors were given 20 Gy X-ray irradiation. Tumor growth at different timepoints
      was record and immunologic parameters were detected 15 days later. RESULTS: From
      3 to 15 d after pEgr-TNFalpha gene-radiotherapy the tumor growth was
      significantly slower than irradiation or genetherapy alone. NK activity, IL-2,
      TNFalpha and IL-1beta secretion activities of pEgr-TNFalpha gene-radiotherapy
      group and pEgr-TNFalpha gene group were higher than those of irradiation alone
      group significantly. CONCLUSION: The anti-tumor effect of pEgr-TNFalpha gene
      radiotherapy is better than that of either one applied solely, and it can
      alleviate the lesion caused by radiation therapy.

PMID- 15196433
TI  - [Enhancement of the bystander effect by tanshinone IIA in HSV-tK/GCV system is
      related to expression of connexin 43 mRNA].
AB  - OBJECTIVE: To investigate enhancement of the bystander effect by tanshinone IIA
      (Tan) in HSV-tK/GCV system and the correlation with expression of connexin 43
      mRNA. METHODS: The cytotoxic effect in HSV-tK/GCV in cervical carcinoma cell line
      ME180 (ME) and ME/TK was examined by MTT assays. Cx43 mRNA expression was
      detected by fluor-quantitative RT-PCR. RESULTS: Tan markedly increased
      sensitivity of ME/TK cells for GCV in HSV-tK/GCV system. In the presence of 2
      micro g/ml GCV, compared with the absence of Tan (0 mol/L), an obvious decrease
      in survival rate was seen at any given mixture of ME and ME/TK cells exposed to
      1.3 x 10(-9) mol/L Tan. Statistics showed significant difference (P < 0.05).
      However, enhancement of bystander mediated cell killing occurred only in the
      range of Tan concentrations used (1.3 x 10(-8), 1.3 x 10(-9) mol/L). RT-PCR
      showed that the ratio of relative copy number of Cx43 mRNA increased by 8.83 and
      8.47-fold in ME cells exposed to 1.3 x 10(-8) and 1.3 x 10(-9) mol/L Tan,
      respectively. CONCLUSION: For the first time we report that in cervical carcinoma
      ME180 cell line, Tan possesses a remarkable enhancing role on the bystander
      effect in the HSV-tK/GCV system. It is associated with up-regulation of Cx43 mRNA
      expression.

PMID- 15196434
TI  - [Functional modulating effect of CD40 ligand on CD40-transfected human lung
      carcinomas].
AB  - OBJECTIVE: To determine the modulating effect of CD40 ligand (CD40L, CD154) on
      CD40-transfected human lung carcinomas and to assess the potential of CD40 as a
      therapeutic target. METHODS: Tumor cells of a CD40-negative lung cancer cell
      lines (GLC-82) were transfected with a vector expressing CD40 cDNA. The
      transfected cell line, GLC-82/CD40, was shown to express high levels of CD40. GLC
      82/CD40 cells after being exposed to 0.1 micro g/ml CD40L were examined for their
      surface expression, cell cycle, apoptosis and cell growth by flow cytometry and
      MTT assay. RESULTS: The expression of MHC-I, ICAM-1 and Fas in GLC-82/CD40 cells
      was significantly increased, whereas that of EGFR was decreased. Cell
      proliferation was significantly inhibited by CD40L with an inhibition rate of 30%
      on day 5, but no change in cell cycle. All of the changes disappeared after 48 h
      incubation with CD40L. More significant changes were observed in Calu-3 cell
      lines which expressed high levels of CD40, but the CD40-negative GLC-82 cells
      were unresponsive to CD40L. None of the 3 cell lines showed significant changes
      in apoptosis upon CD40L treatment. CONCLUSION: CD40, if over-expressed in tumor
      cells, could be considered as a potential therapeutic target.

PMID- 15196435
TI  - [Detection of hypermethylation of p16 gene in plasma DNA from lung cancer
      patients].
AB  - OBJECTIVE: To detect hyper methylation of p16 gene in plasma DNA from patients
      with lung cancer, and to assess its potential as a malignant marker. METHODS:
      Using a modified semi-nested methylation-specific PCR (MSP), the status of
      methylation of the p16 was investigated in plasma DNA from 137 lung cancer
      patients and 112 matched tumor tissues. RESULTS: Hypermethylation of the p16 was
      present in 75.2% (103/137) of the plasma samples and 80.4% (90/112) of the tumor
      tissues. Hypermethylation of the p16 in the plasma was detected in 77.9% squamous
      cell carcinoma, 65.1% adenocarcionma, 75.1% adeno-squamous-cell carcinoma, and
      91.7% small-cell lung cancer. Only in those patients whose tumor tissues had
      hypermethylation of p16 gene, similar changes could be detected in their plasma
      samples. Hypermethylation of the p16 in plasma and the corresponding tumor
      tissues was not significantly correlated with the clinical stage and pathological
      type of the tumor. CONCLUSION: The result indicates that hypermethylation of the
      p16 may be a useful marker in the auxiliary diagnosis of lung cancer.

PMID- 15196436
TI  - [Zeta chain level of T and NK cells in patients with renal-cell carcinoma and
      bladder cancer and its clinical significance].
AB  - OBJECTIVE: To study the relationship between zeta chain level of peripheral blood
      T/NK cells and tumor progression in renal-cell carcinoma and bladder cancer and
      its clinical significance. METHODS: The peripheral blood mononuclcear cells in 58
      patients with renal cell carcinoma, 22 patients with bladder cancer and 14
      healthy blood donors were examined by flow cytometry with fluorescent anti-CD3
      (for T cells), or anti-CD56 (for NK cells) and anti-zeta chain monoclonal
      antibodies. RESULTS: The zeta chain expression of T cell and NK cell in stage I,
      II and III renal-cell carcinoma decreased to 59.5%, 37.6%, 21.3% and 62.2%,
      27.1%, 18.8% of the healthy control level, respectively. That in stage I, II and
      III bladder cancer decreased to 37.6%, 29.5%, 18.9% and 35.4%, 20.8%, 5.8% of the
      control level, respectively. T and NK cell zeta chain levels in 17.5% (14/80) of
      the patients were within the normal range. T/NK ratios of peripheral blood in
      stage III patients were remarkably lower than those of the healthy donor.
      CONCLUSION: Reduced T and NK zeta chain levels and T/NK ratio in the renal-cell
      carcinoma and bladder cancer are generally consistent with tumor progression. The
      patients with normal T and NK zeta chain level may be indicated for
      immunotherapy.

PMID- 15196437
TI  - [Dual effect of angiopoietin-2 on angiogenesis in gastric cancer].
AB  - OBJECTIVE: To explore the effect of Ang-2 on angiogenesis in gastric cancer.
      METHODS: The expression of Ang-2 mRNA was analyzed by RT-PCR and the expression
      of VEGF and CD34 was detected by immunohistochemistry in 36 cases of gastric
      cancer tissues and their paired adjacent gastric mucosa. RESULTS: The expression
      of Ang-2 mRNA was found both in gastric cancer and their paired adjacent gastric
      mucosa; the correlationship between the general expression levels of Ang-2 mRNA
      and microvessel density (MVD) in gastric cancer tissues was not found. However,
      in 27 cases whose Ang-2 mRNA expression levels in cancer tissues were lower than
      those in adjacent gastric mucosa. A significant positive correlation between the
      expression level of Ang-2 mRNA and MVD in the tumor tissues was found (r = 0.411,
      P < 0.05). In these 27 cases, the MVD in the gastric cancer tissues with positive
      VEGF expression (45.45 +/- 10.30) was higher than that with negative VEGF
      expression (30.15 +/- 8.69, P < 0.05), whereas in the other 9 cases whose
      expression levels of Ang-2 mRNA in cancer tissues were higher than those in
      adjacent gastric mucosa, a significant negative correlation between expression
      level of Ang-2 mRNA and MVD in the tumor tissues (r = -0.758, P < 0.05), but
      without correlation between the MVD and VEGF. CONCLUSION: Under the conditions
      that the expression of Ang-2 mRNA in cancer tissues was lower than that in
      adjacent gastric mucosa, VEGF could promote the sprouting of new vessels along
      with Ang-2 upregulation. But under the conditions that the expression of Ang-2
      mRNA in cancer tissues was higher than that in adjacent gastric mucosa, Ang-2
      inhibited angiogenesis. Angiopoietin-2 may play a dual effect on angiogenesis in
      gastric cancer.

PMID- 15196438
TI  - [Quantitative study of diffusion weighted imaging on magnetic resonance imaging
      in focal hepatic lesions less than 3 cm].
AB  - OBJECTIVE: To evaluate the characteristics of MR imaging of hepatic lesions using
      measurement of apparent diffusion coefficient (ADC) value of hepatic lesions on
      diffusion weighted imaging. METHODS: MR diffusion weighted images were obtained
      in patients with 97 hepatic lesions (22 hepatocellular carcinomas, 21 metastatic
      tumors, 28 hemangiomas, 26 cysts). ADC values were evaluated with different
      sequences. The ADC ratio of lesion/liver was estimated. RESULTS: Average ADC
      values of hepatic lesions were as follows: carcinomas (0.91 +/- 0.07) x 10(-3)
      mm(2)/s, metastatic tumors (1.13 +/- 0.27) x 10(-3) mm(2)/s, cavernous
      hemangiomas (1.94 +/- 0.37) x 10(-3) mm(2)/s, cysts (3.26 +/- 0.30) x 10(-3)
      mm(2)/s. The ADC ratio of lesion/liver was significantly different between
      primary carcinomas and metastatic tumors (P < 0.05). CONCLUSION: Quantitative
      study in hepatic lesions using ADC values and the ADC ratio of lesion/liver,
      would improve the accuracy in diagnosing hepatic lesions.

PMID- 15196440
TI  - [Mast cells in cellular leiomyoma and endometrial stromal sarcoma of the uterus].
AB  - OBJECTIVE: To study the role of mast cells in the differential diagnosis of
      cellular leiomyoma and endometrial stromal sarcoma of uterus and its mechanism.
      METHODS: Using SP immunohistochemical technique, the expression of proliferating
      cell nuclear antigen (PCNA) and mast cells in 25 cellular leiomyoma (CL) and 26
      endometrial stromal sarcoma (ESS) of uterus were examined. The expression of
      estrogen receptor (ER) and CD44v3 in cellular leiomyoma was also studied.
      RESULTS: The expression of PCNA was not significantly different from CL or ESS (P
      > 0.05), while mast cell count was statistically different between them (P <
      0.01). Using a value of less than 7 mast cells per high power field was useful
      for the diagnosis of ESS, yielding 100% sensitivity and 92.0% specificity. There
      was a positive correlation between the mast cell count and CD44v3 in CL (r(s) =
      0.589, P < 0.01), though no correlation was observed between mast cell count and
      PCNA or ER. CONCLUSION: Number of mast cells is valuable for the discrimination
      of CL from ESS in the uterus. The mechanism and the role of higher quantity of
      mast cells in CL need further study.

PMID- 15196442
TI  - [Significance of extended radical resection for cancer of pancreatic head].
AB  - OBJECTIVE: To evaluate the significance of extended radical resection in the
      treatment of pancreatic head cancer and its indication. METHODS: Between Jan.
      1995 and Dec. 1998, 56 patients with pancreatic head cancer were retrospectively
      reviewed, among whom 35 were treated by the Whipple operation and 21 received the
      extended radical resection during the same interval. RESULTS: There was no
      significant difference between the mortality and morbidity rate of complication,
      though with more patients having higher clinical stages in the extended radical
      resection group. The 1-, 2- and 3-year survival rates were 84.8%, 62.8%, 39.9% in
      the extended radical resection group and 70.8%, 47.6%, 17.2% in the Whipple
      operation group with significant difference between the two groups. The total
      mortality rate was 51.4% in Whipple group and 42.9% in extended radical resection
      group with significant difference between the two. The 3-year cumulative rate of
      death from local recurrence decreased from 37.4% in the Whipple group to 23.8% in
      the extended radical operation group. Patients who survived for more than 3 years
      were only those in clinical stage (SC)1 in the Whipple group whereas they were
      found both in patients who had had CS1, CS2 lesions and also in some who had CS3
      lesions in the extended radical resection group. CONCLUSION: The extended radical
      operation does benefit patients with pancreatic head carcinoma in CS1, CS2 and in
      a part of CS3 without too extensive exrtra-pancreatic invasion.

PMID- 15196443
TI  - [Comparison of endocrine therapy and chemotherapy for bone metastasis of breast
      cancer].
AB  - OBJECTIVE: To compare the efficacy of endocrine therapy with chemotherapy for
      bone metastasis of breast cancer. METHODS: A total of 138 breast cancer patients
      with bone metastasis, but without visceral metastasis as retrospectively
      reviewed. RESULTS: The response rates of endocrine therapy and chemotherapy as
      the first-line therapy were 35.4% and 31.7% (P = 0.687), and the total response
      rates were 27.1% and 25.0% (P = 0.690). The clinical benefit rates of endocrine
      therapy and chemotherapy as first-line were 43.9% and 36.6% (P = 0.437), as
      second-line were 47.8% and 24.2% (P = 0.033), in total treatments were 47.5% and
      27.7% (P = 0.001). The median interval to treatment failure (TTF) was 5 months
      and 2 months (P < 0.001), and that to progression (TTP) was 5 and 2.5 months (P <
      0.001) in endocrine therapy and chemotherapy group, respectively. CONCLUSION:
      Endocrine therapy is superior to chemotherapy for bone metastasis of breast
      cancer.

PMID- 15196444
TI  - [Substitution of esophagus with stomach or colon without thoracotomy in the
      treatment of cervical esophageal carcinoma with laryngeal function preserved].
AB  - OBJECTIVE: To study the feasibility and effect of substituting esophagus with
      stomach or colon without thoracotomy in the treatment of cervical esophageal
      carcinoma with laryngeal function preserved. METHODS: Twenty-four patients with
      cervical esophageal carcinoma were retrospectively reviewed. The esophagus was
      resected and substituted with 19 gastric pull-up and 5 colon interposition.
      Nineteen patients received radiotherapy postoperatively (dose 50 - 70 Gy).
      RESULTS: Twenty two patients were follow up over 3 years. The 3- and 5-year
      survival rates for T2 were 3 and 1, for T3, T4 8 and 3, respectively. The
      laryngeal function preservation rate was 77% (17/24) and the decannulation rate
      was 75% (12/16). The complication rate was 29%. CONCLUSION: Surgical resection of
      cervical esophageal carcinoma with removal of the extraesophageal invaded tissues
      while preserving the laryngeal function is possible. The continuity of the
      esophagus is restored by stomach transposition and colon interposition. Combined
      with radiotherapy, the survival rate and life quality of the patient might be
      improved.

PMID- 15196455
TI  - Links between DNA replication and recombination in prokaryotes.
AB  - Recombination plays a crucial role in underpinning genome duplication, ensuring
      that replication blocks are removed or bypassed, and that the replication
      machinery is subsequently reloaded back onto the DNA. Recent studies have
      identified a surprising variety of ways in which damaged replication forks are
      repaired and have shown that the mechanism used depends on the nature of the
      original blocking lesion. Indeed, an emerging theme is that a single
      recombination enzyme or complex can perform highly varied tasks, depending on the
      context of the recombination reaction.

PMID- 15196456
TI  - Switching from high-fidelity replicases to low-fidelity lesion-bypass
      polymerases.
AB  - Replication of damaged DNA often requires a DNA polymerase in addition to the
      cell's normal replicase. Recent research has begun to shed light on the switch
      from a high-fidelity replicative polymerase to a low-fidelity translesion
      polymerase that occurs at a stalled replication fork. A picture is emerging in
      which eukaryotic replicative clamps are posttranslationally modified by
      ubiquitination, SUMOylation or phosphorylation. It is believed that such
      modifications help to regulate the access of translesion polymerases to the
      nascent primer terminus.

PMID- 15196457
TI  - Chromosome segregation and genomic stability.
AB  - The acquisition of genomic instability is a crucial step in the development of
      human cancer. Genomic instability has multiple causes of which chromosomal
      instability (CIN) and microsatellite instability (MIN) have received the most
      attention. Whereas the connection between a MIN phenotype and cancer is now
      proven, the argument that CIN causes cancer remains circumstantial. Nonetheless,
      the ubiquity of aneuploidy in human cancers, particularly solid tumors, suggests
      a fundamental link between errors in chromosome segregation and tumorigenesis.
      Current research in the field is focused on elucidating the molecular basis of
      CIN, including the possible roles of defects in the spindle checkpoint and other
      regulators of mitosis.

PMID- 15196458
TI  - Structure and segregation of the bacterial nucleoid.
AB  - In bacteria, chromosome segregation and DNA replication occur concurrently and
      there is no clear equivalent of a eukaryote mitotic spindle. Chromosome
      segregation can be viewed as a two-step process. As the first step, the origin of
      replication regions are segregated actively, probably by a mechanism involving an
      as yet unidentified motor protein or proteins, and held in position. The second
      step is the separation and migration of the rest of the chromosome probably
      driven by forces generated from various cellular processes such as DNA
      replication, transcription and transertion.

PMID- 15196459
TI  - Transcriptional regulation in Archaea.
AB  - During the past few decades, it has become clear that microorganisms can thrive
      under the most diverse conditions, including extremes of temperature, pressure,
      salinity and pH. Most of these extremophilic organisms belong to the third domain
      of life, that of the Archaea. The organisms of this domain are of particular
      interest because most informational systems that are associated with archaeal
      genomes and their expression are reminiscent of those seen in Eucarya, whereas,
      most of their metabolic aspects are similar to those of Bacteria. A better
      understanding of the regulatory mechanisms of gene expression in Archaea will,
      therefore, help to integrate the body of knowledge regarding the regulatory
      mechanisms that underlie gene expression in all three domains of life.

PMID- 15196460
TI  - Facts about FACT and transcript elongation through chromatin.
AB  - The regulation of transcription elongation within the context of chromatin is a
      topic of great interest. Even though chromatin presents a barrier to
      transcription by the PolII machinery in vitro, this process is rather efficient
      in vivo. Importantly, the chromatin structure of the actively transcribed genes
      is altered as part of this process. A large number of factors implicated in the
      control of transcript elongation have been identified through genetics,
      biochemistry and targeted proteomics approaches. However the precise roles and
      mechanisms of action of these factors remain obscure. A significant advance came
      about this past year with the elucidation of the roles of FACT and Spt6 in
      transcription elongation. These factors facilitate PolII passage through
      chromatin by destabilizing the nucleosome structure as well as reassemble
      nucleosomes traversed by PolII.

PMID- 15196461
TI  - The highly conserved and multifunctional NuA4 HAT complex.
AB  - Histone acetyltransferase complexes have been shown to be key regulators of gene
      expression. Among these, the NuA4 complex, first characterized in yeast, stands
      out as it controls multiple key nuclear functions in eukaryotic cells. Many
      subunits of this protein assembly have been directly linked to global and
      targeted acetylation of histone H4 tails in vivo, regulation of transcription,
      cell-cycle progression as well as to the process of DNA repair. Recent studies
      presented here have established its remarkable structural conservation from yeast
      to human cells and contributed to the understanding of its diverse functions.

PMID- 15196462
TI  - The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3.
AB  - Polycomb group (PcG) proteins are important for maintaining the silenced state of
      homeotic genes. Biochemical and genetic studies in Drosophila and mammalian cells
      indicate that PcG proteins function in at least two distinct protein complexes:
      the ESC-E(Z) or EED-EZH2 complex, and the PRC1 complex. Recent work has shown
      that at least part of the silencing function of the ESC-E(Z) complex is mediated
      by its intrinsic activity for methylating histone H3 on lysine 27. In addition to
      being involved in Hox gene silencing, the complex and its associated histone
      methyltransferase activity are important in other biological processes including
      X-inactivation, germline development, stem cell pluripotency and cancer
      metastasis.

PMID- 15196463
TI  - Mechanisms for ATP-dependent chromatin remodelling: farewell to the tuna-can
      octamer?
AB  - ATP-dependent chromatin remodelling enzymes act to alter chromatin structure
      during gene regulation. Studies of the ATPase motors that drive these enzymes
      support the notion that they function as ATP-dependent DNA translocases with
      limited processivity. The action of these enzymes on nucleosomes results in the
      alteration of nucleosome positioning and structure. Recent studies have shown
      that ATP-dependent chromatin remodelling can also either remove or exchange
      histone dimers between nucleosomes. This provides a new means by which the
      incorporation of histone variants can be directed. Additional observations
      support roles for ATP-dependent remodelling enzymes throughout the transcription
      cycle.

PMID- 15196464
TI  - Those interfering little RNAs! Silencing and eliminating chromatin.
AB  - RNA interference (RNAi) is widely used for knocking down expression of genes of
      interest and in systematic screens for desired phenotypes. In post
      transcriptional gene silencing, double-stranded RNA triggers are processed to
      small interfering RNAs, which act to seek out and destroy homologous transcripts.
      A variety of organisms utilise the RNAi pathway to silence expression of
      potentially harmful endogenous mobile elements and to eliminate unnecessary
      sequences. In plants and fission yeast, RNAi can also mediate chromatin-based
      silencing resulting in transcriptional shutdown of homologous transcription units
      (transcriptional gene silencing) and the formation of centromeric
      heterochromatin. In metazoans, the expression of non-coding RNAs is often
      associated with the formation of silent chromatin domains but it remains to be
      determined if RNAi is involved.

PMID- 15196465
TI  - Small RNAs in genome rearrangement in Tetrahymena.
AB  - Small RNAs produced by an RNAi-related mechanism are involved in DNA elimination
      during development of the somatic macronucleus from the germline micronucleus in
      Tetrahymena. The properties of these small RNAs can explain how the primary
      sequence of the parental macronucleus epigenetically controls genome
      rearrangement in the new macronucleus and provide the first demonstration of an
      RNAi-mediated process that directly alters DNA sequence organization. Methylation
      of histone H3 on lysine 9 and accumulation of chromodomain proteins, hallmarks of
      heterochromatin, also occur specifically on sequences undergoing elimination and
      are dependent on the small RNAs. These findings contribute to a new paradigm of
      chromatin biology: regulation of heterochromatin formation by RNAi-related
      mechanisms in eukaryotes.

PMID- 15196466
TI  - Epigenetic regulation of mammalian genomic imprinting.
AB  - Imprinted genes play important roles in development, and most are clustered in
      large domains. Their allelic repression is regulated by 'imprinting control
      regions' (ICRs), which are methylated on one of the two parental alleles. Non
      histone proteins and nearby sequence elements influence the establishment of this
      differential methylation during gametogenesis. DNA methylation, histone
      modifications, and also polycomb group proteins are important for the somatic
      maintenance of imprinting. The way ICRs regulate imprinting differs between
      domains. At some, the ICR constitutes an insulator that prevents promoter
      enhancer interactions, when unmethylated. At other domains, non-coding RNAs could
      be involved, possibly by attracting chromatin-modifying complexes. The latter
      silencing mechanism has similarities with X-chromosome inactivation.

PMID- 15196467
TI  - Linking lipids to chromatin.
AB  - Dynamic regulation of chromatin structure is thought to be a prerequisite for
      nuclear functions that require accessibility to DNA such as replication,
      transcription and DNA repair. The phosphoinositide (PI) pathway is a second
      messenger signalling system regulated in response to a variety of extracellular
      (growth factors, differentiation signals) and intracellular (cell cycle
      progression, DNA damage) stimuli. The presence of a PI pathway in the nucleus
      together with the recent findings that specific nuclear proteins can interact
      with and are regulated by phosphoinositides suggest that changes in the nuclear
      phosphoinositide profile may have a direct role in modulating chromatin
      structure.

PMID- 15196468
TI  - The spatial organization of the genome in mammalian cells.
AB  - A number of recent studies have indicated that the location of a given mammalian
      chromosome within the interphase nucleus is related to its size, whereas other
      work has implicated a chromosome's gene density as a factor. Recent
      investigations of the degree to which an ordered arrangement of mitotic
      chromosomes on the metaphase plate is inherited and perpetuated during successive
      cell cycles have also yielded somewhat controversial results. The arrangement of
      chromosomes in the nucleus also has been investigated by the analysis of
      chromosomal translocations, with some surprising recent findings.

PMID- 15196469
TI  - At the crossroads of growth control; making ribosomal RNA.
AB  - Although the mechanisms of cell cycle control are well established, the factors
      controlling cell growth and target size are still poorly understood. Much
      evidence suggests that ribosome biogenesis, and in particular the synthesis of
      the rRNAs, plays a central role not only in permitting growth, but also in
      regulating it. In the past few years we have begun to penetrate the network
      linking rRNA gene transcription to growth.

PMID- 15196470
TI  - RNA polymerase II structure: from core to functional complexes.
AB  - New structural studies of RNA polymerase II (Pol II) complexes mark the beginning
      of a detailed mechanistic analysis of the eukaryotic mRNA transcription cycle.
      Crystallographic models of the complete Pol II, together with new biochemical and
      electron microscopic data, give insights into transcription initiation. The first
      X-ray analysis of a Pol II complex with a transcription factor, the elongation
      factor TFIIS, supports the idea that the polymerase has a 'tunable' active site
      that switches between mRNA synthesis and cleavage. The new studies also show that
      domains of transcription factors can enter polymerase openings, to modulate
      function during transcription.

PMID- 15196471
TI  - Convocation address: put your heart into ACC fellowship: a vision for growth and
      achievement.

PMID- 15196474
TI  - Age- and endothelium-dependent changes in coronary artery reactivity to serotonin
      and calcium.
AB  - The influence of ageing and endothelium removal on the sensitivity and
      contractile response of rat coronary arteries to intracellular Ca2+ ([Ca2+]i)
      during activation with serotonin (5-HT) and membrane depolarisation with 125 mM
      K+ was investigated. The sensitivity and contractile response of coronary
      arteries to 5-HT were significantly higher in 2-year-old than in 3-month-old
      rats. The receptor responsible for the 5-HT-induced contractions in coronary
      arteries belongs to a population of 5-HT2 receptors in both young and old rats
      based on the Schild plot. The resting levels of [Ca2+]i and active tension were
      both increased by age and endothelium removal. During depolarisation with 125 mM
      K+, the sensitivity to [Ca2+]i and maximal tension induced by [Ca2+]i were not
      affected by age or endothelium. During activation with 10 microM 5-HT, the
      maximal tension induced by [Ca2+]i was increased by age but not affected by
      endothelium, whereas the sensitivity to [Ca2+]i was increased by endothelium
      removal. In conclusion, ageing is associated with an increased sensitivity to 5
      HT in rat coronary small arteries. The increased sensitivity to 5-HT seems to
      involve an augmented contractile response to [Ca 2+]i in 5-HT-activated coronary
      arteries and a diminished endothelial basal vasodilator function.

PMID- 15196475
TI  - Up-regulation of lymphocytic cholinergic activity by ONO-4819, a selective
      prostaglandin EP4 receptor agonist, in MOLT-3 human leukemic T cells.
AB  - We used a selective EP4 receptor agonist, ONO-4819, and a human leukemic T cell
      line MOLT-3 cells, which express all four prostaglandin E2 (PGE2) receptors (EP1
      EP4), to investigate whether the EP4 PGE2 receptor subtype is involved in
      regulating lymphocytic cholinergic activity. Phytohemagglutinin (PHA), a T cell
      activator, significantly enhanced the expression of EP4 receptor mRNA during the
      first 3-6 h of exposure, after which, expression gradually declined. Furthermore,
      PHA stimulation slightly but significantly up-regulated the expression of EP2
      mRNA after 12 h and of EP3 mRNA after 6 h. By contrast, expression level of EP1
      receptor mRNA was not affected by PHA. ONO-4819 (1 microM), which was added to
      cultures after 3 h of PHA stimulation, significantly increased cellular ACh
      content and release, and up-regulated ChAT mRNA expression and activity but
      inhibited MOLT-3 cell proliferation. These findings suggest that the activation
      of T lymphocytes up-regulates EP4 receptor mRNA expression and, to a lesser
      extent, EP2 and EP3 receptors and that PGE2 enhances nonneuronal lymphocytic
      cholinergic transmission in activated T cells, at least in part, via EP4 receptor
      mediated pathways.

PMID- 15196476
TI  - Contrasting effects of chronic ethanol feeding on centrally and peripherally
      evoked hypotension in telemetered female rats.
AB  - Our previous studies have shown that ethanol compromises hypotension produced by
      centrally acting antihypertensive agents in normotensive and hypertensive male
      rats. The present study investigated whether female rats are as susceptible as
      male rats to the deleterious effect of ethanol on centrally evoked hypotension.
      The study was extended to investigate ethanol effects on the time-domain indices
      of variability in blood pressure [standard deviation of mean arterial pressure
      (SDMAP)] and heart rate [standard deviation of beat-to-beat intervals (SDRR) and
      root mean square of successive differences in R-R intervals (rMSSD)]. The
      hemodynamic effects of a single intraperitoneal dose of clonidine (30 microg/kg)
      were evaluated in radiotelemetered ethanol-fed (5%, 12 weeks) and pair-fed
      control Sprague-Dawley rats. In control rats, clonidine caused a significant
      reduction in MAP that continued for at least 6 h and was associated with
      reductions in SDMAP and SDRR but not rMSSD, suggesting inhibition of central
      sympathetic tone. A maximum hypotensive response of -16.4+/-1.7 mm Hg was
      demonstrated 40 min after clonidine administration. Ethanol feeding significantly
      attenuated clonidine hypotension whereas it potentiated the associated reduction
      in SDMAP. To verify the selectivity of ethanol-clonidine interaction, the effects
      of ethanol on peripherally mediated hemodynamic responses to hydralazine (0.5
      mg/kg ip) were investigated. In contrast to its antagonistic effect on clonidine
      hypotension, ethanol significantly potentiated the hypotensive effect of
      hydralazine. Together, these findings demonstrate that chronic ethanol feeding
      exerts opposite effects on centrally (attenuation) and peripherally
      (potentiation) evoked hypotension in female rats. The interaction of ethanol with
      antihypertensive agents may not be related to changes in hemodynamic variability.

PMID- 15196477
TI  - Statins prevent oxidized low-density lipoprotein- and lysophosphatidylcholine
      induced proliferation of human endothelial cells.
AB  - The proliferation of endothelial cells is induced by oxidized low-density
      lipoprotein (oxLDL) and its major component, lysophosphatidylcholine (LPC). The
      aim of this study was to investigate the effect of statins on the proliferation
      of endothelial cells derived from human umbilical cord veins (HUVEC).
      Cerivastatin, simvastatin and fluvastatin caused a dose-dependent inhibition of
      endothelial cell growth (n=12; P<.01) when using cell counts and [3H]-thymidine
      incorporation, respectively. The strongest inhibition of HUVEC proliferation was
      achieved at statin concentrations of 0.1 micromol/l (cerivastatin), 2.5
      micromol/l (simvastatin) and 1 micromol/l (fluvastatin). Cell counts were
      significantly reduced from 22937+/-280.6 (control) to 7791+/-133.6
      (cerivastatin), 7292+/-146.6 (simvastatin) and 6792+/-135.5 (fluvastatin) (n=12;
      P<.01). Interestingly, cell proliferation induced by oxLDL (10 microg/ml) and LPC
      (20 micromol/l) could be effectively prevented using statins at concentrations
      between 0.01 and 0.1 micromol/l (cerivastatin), 1 and 2.5 micromol/l
      (simvastatin) and 0.25 and 1 micromol/l (fluvastatin). This effect of the statins
      was abolished by preincubation with mevalonate (500 micromol/l). Our results
      demonstrate an interesting direct effect of statins on the proliferation of human
      endothelial cells induced by oxLDL and LPC, which may be beneficial to prevent
      vascular effects of these atherogenic lipids.

PMID- 15196478
TI  - Role of Na+/K+-ATPase in the high extracellular calcium-induced impairment of
      rabbit aorta contractile activity.
AB  - The present study was designed to prove whether the activation of the sarcolemmal
      Na+/K+-ATPase in the rabbit aorta could explain the decreased contraction caused
      in this tissue by high extracellular calcium. To demonstrate this hypothesis, we
      evaluate the modification in the contractile responses to KCl and alpha1
      adrenoceptor agonists (methoxamine and phenylephrine) produced by a high
      extracellular Ca2+ concentration (10 mM) in isolated rabbit aorta rings when the
      Na+/K+-ATPase is inhibited with ouabain. Ouabain 10(-4) M caused an initial rapid
      increase in tone in the rabbit aorta rings, which could be linked to the release
      of catecholamines provoked when the Na+/K+-ATPase in the nerve terminal was
      blocked. This glycoside also caused a delayed contractile response in the
      preparations that could be linked to the inhibition of the Na+/K+-ATPase in the
      sarcolemma of the smooth muscle. The maximum inhibition of the sarcolemmal pump
      was fixed 2 h and 15 min after ouabain 10(-4) M administration. Both responses
      were smaller with the 10-mM Ca2+ concentration than with the 2.5-mM Ca2+
      concentration. The contractions elicited by KCl and the alpha1-adrenoceptor
      agonists were higher in the aorta ring preparations incubated with the 2.5-mM
      Ca2+ solution than in the aorta ring preparations incubated with the 10-mM Ca2+
      solution. When the Ca2+ concentration in the organ bath was 2.5 mM, 10(-4) M
      ouabain administration caused a decrease in the responses to KCl and alpha1
      adrenoceptor agonists. By contrast, when the Ca2+ concentration in the organ bath
      was 10 mM, 10(-4) M ouabain did not modify these responses. As a consequence, the
      contractions elicited by KCl were very similar in all the ouabain-treated
      preparations and those elicited by the alpha1-adrenoceptor agonists in ouabain
      treated preparations were even higher when the Ca2+ concentration in the organ
      bath was 10 mM than when the Ca2+ concentration in the organ bath was 2.5 mM. The
      results of this study suggest that the increase in extracellular Ca2+
      concentration may facilitate the functioning of the Na+/K+-ATPase in the vascular
      smooth muscle (VSM) and produces opposite effects to ouabain. This effect of high
      extracellular Ca2+ concentration on the sarcolemmal pump may explain the decrease
      in the contractile responses elicited by depolarization and alpha1-adrenoceptor
      stimulation observed in rabbit aorta ring preparations.

PMID- 15196479
TI  - Using genomics to help predict drug interactions.
AB  - This article proposes using genomic information to help tailor the output of a
      drug interaction program for a patient. This paper focuses on a particular CYP450
      enzyme to illustrate adding genomic information to an existing drug interaction
      database. The data are formatted as an Extensible Markup Language (XML) document.
      The additional interaction information based on genomics for a patient is added
      to an XML document using XML tags. The suggestion is to combine specifics about a
      patient's genome with genomic information in the drug interactions database to
      increase the accuracy and details of a drug interaction program.

PMID- 15196480
TI  - GLIF3: a representation format for sharable computer-interpretable clinical
      practice guidelines.
AB  - The Guideline Interchange Format (GLIF) is a model for representation of sharable
      computer-interpretable guidelines. The current version of GLIF (GLIF3) is a
      substantial update and enhancement of the model since the previous version
      (GLIF2). GLIF3 enables encoding of a guideline at three levels: a conceptual
      flowchart, a computable specification that can be verified for logical
      consistency and completeness, and an implementable specification that is intended
      to be incorporated into particular institutional information systems. The
      representation has been tested on a wide variety of guidelines that are typical
      of the range of guidelines in clinical use. It builds upon GLIF2 by adding
      several constructs that enable interpretation of encoded guidelines in computer
      based decision-support systems. GLIF3 leverages standards being developed in
      Health Level 7 in order to allow integration of guidelines with clinical
      information systems. The GLIF3 specification consists of an extensible object
      oriented model and a structured syntax based on the resource description
      framework (RDF). Empirical validation of the ability to generate appropriate
      recommendations using GLIF3 has been tested by executing encoded guidelines
      against actual patient data. GLIF3 is accordingly ready for broader
      experimentation and prototype use by organizations that wish to evaluate its
      ability to capture the logic of clinical guidelines, to implement them in
      clinical systems, and thereby to provide integrated decision support to assist
      clinicians.

PMID- 15196481
TI  - Methods for automated concept mapping between medical databases.
AB  - The retrieval and exchange of information between medical databases is often
      impeded by the semantic heterogeneity of concepts contained within the databases.
      Manual identification of equivalent database elements consumes time and
      resources, and may often be the rate-limiting technological step in integrating
      disparate data sources. By employing semantic networks as an intermediary
      representation of the native databases, automated mapping algorithms can identify
      equivalent concepts in disparate databases. The algorithms take advantage of the
      conceptual "context" embodied within a semantic network to produce candidate
      concept mappings. The performance of automated concept mapping was evaluated by
      creating semantic network representations for two test laboratory databases. The
      mapping algorithms identified all equivalent concepts that were present in the
      databases, and did not leave any equivalent concepts unmapped. The utilization of
      conceptual context to perform automated concept mapping facilitates the
      identification of equivalent database concepts and may help decrease the work and
      costs associated with retrieval and integration of information from disparate
      databases.

PMID- 15196482
TI  - How (not) to protect genomic data privacy in a distributed network: using trail
      re-identification to evaluate and design anonymity protection systems.
AB  - The increasing integration of patient-specific genomic data into clinical
      practice and research raises serious privacy concerns. Various systems have been
      proposed that protect privacy by removing or encrypting explicitly identifying
      information, such as name or social security number, into pseudonyms. Though
      these systems claim to protect identity from being disclosed, they lack formal
      proofs. In this paper, we study the erosion of privacy when genomic data, either
      pseudonymous or data believed to be anonymous, are released into a distributed
      healthcare environment. Several algorithms are introduced, collectively called RE
      Identification of Data In Trails (REIDIT), which link genomic data to named
      individuals in publicly available records by leveraging unique features in
      patient-location visit patterns. Algorithmic proofs of re-identification are
      developed and we demonstrate, with experiments on real-world data, that
      susceptibility to re-identification is neither trivial nor the result of bizarre
      isolated occurrences. We propose that such techniques can be applied as system
      tests of privacy protection capabilities.

PMID- 15196483
TI  - A cognitive taxonomy of medical errors.
AB  - OBJECTIVE: Propose a cognitive taxonomy of medical errors at the level of
      individuals and their interactions with technology. DESIGN: Use cognitive
      theories of human error and human action to develop the theoretical foundations
      of the taxonomy, develop the structure of the taxonomy, populate the taxonomy
      with examples of medical error cases, identify cognitive mechanisms for each
      category of medical error under the taxonomy, and apply the taxonomy to practical
      problems. MEASUREMENTS: Four criteria were used to evaluate the cognitive
      taxonomy. The taxonomy should be able (1) to categorize major types of errors at
      the individual level along cognitive dimensions, (2) to associate each type of
      error with a specific underlying cognitive mechanism, (3) to describe how and
      explain why a specific error occurs, and (4) to generate intervention strategies
      for each type of error. RESULTS: The proposed cognitive taxonomy largely
      satisfies the four criteria at a theoretical and conceptual level. CONCLUSION:
      Theoretically, the proposed cognitive taxonomy provides a method to
      systematically categorize medical errors at the individual level along cognitive
      dimensions, leads to a better understanding of the underlying cognitive
      mechanisms of medical errors, and provides a framework that can guide future
      studies on medical errors. Practically, it provides guidelines for the
      development of cognitive interventions to decrease medical errors and foundation
      for the development of medical error reporting system that not only categorizes
      errors but also identifies problems and helps to generate solutions. To validate
      this model empirically, we will next be performing systematic experimental
      studies.

PMID- 15196484
TI  - Bioinformatics integration and agent technology.
AB  - Vast amounts of life sciences data are scattered around the world in the form of
      a variety of heterogeneous data sources. The need to be able to co-relate
      relevant information is fundamental to increase the overall knowledge and
      understanding of a specific subject. Bioinformaticians aspire to find ways to
      integrate biological data sources for this purpose and system integration is a
      very important research topic. The purpose of this paper is to provide an
      overview of important integration issues that should be considered when designing
      a bioinformatics integration system. The currently prevailing approach for
      integration is presented with examples of bioinformatics information systems
      together with their main characteristics. Here, we introduce agent technology and
      we argue why it provides an appropriate solution for designing bioinformatics
      integration systems.

PMID- 15196486
TI  - Microbial risk assessment: don't forget the children.
AB  - Quantitative microbial risk assessment is a rapidly developing field with a
      purpose to quantify risks of infection, disease and mortality from the
      environmental exposure of pathogens. It is currently being applied to the
      development of standards for drinking water, wastewater re-use and foods. A
      growing body of evidence indicates that the greatest risk of infection for
      enteric pathogens is for persons less than 19 years of age. Children are more
      likely to become ill from consumption of contaminated drinking water and
      recreational activities. These increased risks may be because immunological,
      neurological and digestive systems are still developing. In addition, children
      are more environmentally exposed to pathogens. For some enteric pathogens
      children may be the greatest at risk population.

PMID- 15196487
TI  - Molecular microbial ecology: land of the one-eyed king.
AB  - Studies of microbial biodiversity have made astounding discoveries of late due to
      the use of methodologies based on phylogenetic analyses of small subunit
      ribosomal RNA sequences. Although there are limitations to these methods, they
      can nonetheless be very useful if these limitations are kept in mind. These
      limitations range from technical problems such as obtaining representative
      genomic DNA and suitable primers, to conceptual problems such as defining and
      using meaningful taxonomic units of diversity (species). Here we discuss several
      of the limitations inherent in studies of microbial diversity that must be
      considered when interpreting the results obtained using these approaches.

PMID- 15196488
TI  - Prokaryotic diversity and its limits: microbial community structure in nature and
      implications for microbial ecology.
AB  - Recent advances in the estimation of prokaryotic diversity have brought us
      insight into two questions: what is the extent of prokaryotic diversity, and
      perhaps more importantly, why bother finding out. In this review, we highlight
      the insights about the extent of diversity that may be gained by considering
      patterns that occur, or are likely to occur, in the relative abundance of
      prokaryotic taxa. We posit that global reservoirs of diversity are an important
      driving force behind patterns in localised diversity seen in leaves, intestines
      and wastewater treatment reactors. Thus, where the reservoir community is very
      large and relatively even, chance alone will prevent physically identical
      communities from having the same, or sometimes even stable, communities. By
      contrast, communities that tend to be similar (even when not physically
      identical) and stable are observed where the source diversity is low. Thus the
      relationship between structure and function in a community can only be
      understood, predicted and engineered through an understanding of the source of
      diversity from which the community is drawn.

PMID- 15196489
TI  - Engineered passive bioreactive barriers: risk-managing the legacy of industrial
      soil and groundwater pollution.
AB  - Permeable reactive barriers are a technology that is one decade old, with most
      full-scale applications based on abiotic mechanisms. Though there is extensive
      literature on engineered bioreactors, natural biodegradation potential, and in
      situ remediation, it is only recently that engineered passive bioreactive barrier
      technology is being considered at the commercial scale to manage contaminated
      soil and groundwater risks. Recent full-scale studies are providing the
      scientific confidence in our understanding of coupled microbial (and genetic),
      hydrogeologic, and geochemical processes in this approach and have highlighted
      the need to further integrate engineering and science tools.

PMID- 15196490
TI  - The tritrophic trinity: a source of pollutant-degrading enzymes and its
      implications for phytoremediation.
AB  - Barring bioavailability and nutritional limitations, virtually all organic
      anthropogenic chemicals can be naturally biodegraded. It is to this phenomenon we
      owe thanks to the long established 'tritrophic trinity' of microbe-plant-insect
      interactions. Over hundreds of millennia these organisms have coevolved,
      producing hundreds of thousands of different chemicals that are used to attract,
      defend, antagonize, monitor and misdirect one another. In comparison, the numbers
      of truly novel chemicals of anthropogenic origin are negligible. It is only now
      that we are beginning to appreciate the fortuitous evolution of xenobiotic
      degrading enzymes from these interactions. We argue that success in
      phytoremediation can be hastened through understanding the structure, sources,
      uses and targets of these secondary metabolites. Owing to recent developments in
      molecular biology, particularly stable isotope probing, we eagerly anticipate
      highly significant insights into trophic interactions, particularly in the
      rhizosphere, providing phytoremediation with a solid mechanistic understanding.

PMID- 15196491
TI  - Oligonucleotide microarrays in microbial diagnostics.
AB  - Oligonucleotide microarrays offer a fast, high-throughput alternative for the
      parallel detection of microbes from virtually any sample. The application
      potential spreads across most sectors of life sciences, including environmental
      microbiology and microbial ecology; human, veterinary, food and plant
      diagnostics; water quality control; industrial microbiology, and so on. The past
      two years have witnessed a rapid increase of research in this field. Many
      alternative techniques were developed and validated as seen in 'proof-of-concept'
      articles. Publications reporting on the application of oligonucleotide microarray
      technology for microbial diagnostics in microbiology driven projects have just
      started to appear. Current and future technical and bioinformatics developments
      will inevitably improve the potential of this technology further.

PMID- 15196492
TI  - Harnessing the catabolic diversity of rhodococci for environmental and
      biotechnological applications.
AB  - The field of Rhodococcus cell engineering is rapidly advancing because of the
      availability of improved genetic tools and increased insights in their broad
      catabolic and biochemical diversity. Rhodococci harbor large linear plasmids that
      may contribute to their catabolic diversity. In addition, multiple pathways and
      gene homologs are often present, thus further increasing Rhodococcus catabolic
      versatility and efficiency. The recent development of effective genetic tools for
      Rhodococcus, such as unmarked gene deletion, transposon-based mutagenesis, and
      gene expression systems, now allows the construction of biocatalysts with
      desirable properties for industrial purposes. This is exemplified here by a
      description of cell engineering of biocatalysts for improved desulphurization and
      steroid biotransformation.

PMID- 15196493
TI  - Recent applications of biosurfactants as biological and immunological molecules.
AB  - The interest in microbial biosurfactants has steadily increased during the past
      decade. In addition to the classical application as emulsifiers of hydrocarbons,
      they can be used in environmental protection, crude-oil recovery, food-processing
      industries and in various fields of biomedicine. Biosurfactants have several
      advantages over chemical surfactants including lower toxicity and higher
      biodegradability, and are likely to become molecules of the future in areas such
      as biomedicine and therapeutics. Here, we discuss the role and applications of
      biosurfactants (mainly glycolipids and lipopeptides) focusing on medicinal and
      therapeutic perspectives.

PMID- 15196494
TI  - Emerging foundations: nano-engineering and bio-microelectronics for environmental
      biotechnology.
AB  - The growth of nanotechnology, the emergence of 'nanobiotechnology', and the
      incorporation of living organisms in biomicroelectronic devices are
      revolutionizing the interdisciplinary opportunities for microbiologists to
      participate in understanding, developing and exploiting microbial processes in
      and from the environment.

PMID- 15196496
TI  - Benefits and pitfalls of using microarrays to monitor bacterial gene expression
      during infection.
AB  - The understanding of bacterial pathogenesis is dependent on techniques that
      elucidate the underlying genetic and biochemical mechanisms. To study the
      mechanism of bacterial survival and proliferation within host cells we need
      accurate tools that tell us what is occurring within the infecting organism. It
      has now become possible to determine the transcriptional status of in vivo
      derived bacteria at the level of the whole genome. Such expression profiles serve
      as a monitor of the host cell environment as well as an indicator of the
      bacterial adaptation to its intracellular niche. Here, we review the methods used
      to produce microarray data for defining the bacterial intracellular
      transcriptome, and examine the pitfalls in extracting bacterial RNA from the
      infected host compartment.

PMID- 15196497
TI  - Virulence gene expression in vivo.
AB  - The ability to identify and isolate bacterial RNA from animals or humans with
      infections has markedly advanced the capacity to examine microbial gene
      expression in vivo. This advance has been coupled with the development of
      quantitative real-time reverse transcription polymerase chain reaction and
      expression microarrays to allow investigators to accurately measure how organisms
      are manipulating their genetic expression during actual infections. Though the
      full ramifications of these technologies have yet to be realized, they promise to
      open new avenues of therapeutics for a broad range of infectious diseases by
      allowing researchers to focus on in vivo expressed genes. These developments
      provide a framework for efficient utilization of the vast amount of information
      being generated by the accelerating pace of genomic sequencing of microbes.

PMID- 15196498
TI  - Laser microdissection: exploring host-bacterial encounters at the front lines.
AB  - The mucosal surfaces of tissues such as the stomach and intestines are in
      constant contact with indigenous bacterial populations and are major portals of
      entry for bacterial pathogens. Host responses to bacterial encounters at these
      surfaces frequently involve complex interactions between epithelial cells and
      immune cells, and are thus difficult to model in vitro. Laser microdissection is
      a technique in which pure populations of host cells are acquired from sections of
      complex tissue. When coupled with an expanding repertoire of techniques for
      molecular analysis of microdissected cells, laser microdissection allows host
      cellular responses to bacteria to be studied in their native tissue context. This
      approach has already yielded key insights into the nature of mucosal responses to
      commensal, as well as pathogenic bacteria, and promises to be an important
      addition to the cellular microbiologist's toolkit.

PMID- 15196499
TI  - Metabolomics and systems biology: making sense of the soup.
AB  - Novel techniques for acquiring metabolomics data continue to emerge. Such data
      require proper storage in suitably configured databases, which then permit one to
      establish the size of microbial metabolomes (hundreds of major metabolites) and
      allow the nature, organisation and control of metabolic networks to be
      investigated. A variety of algorithms for metabolic network reconstruction
      coupled to suitable modelling algorithms are the ground substances for the
      development of metabolic network and systems biology. Even qualitative models of
      metabolic networks, when subject to stoichiometric constraints, can prove highly
      informative, and are the first step to the quantitative models, which alone can
      allow the true representation of complex biochemical systems.

PMID- 15196500
TI  - Analyses of clonality and the evolution of bacterial pathogens.
AB  - The existence of bacterial clones was evident in early phenotypic studies that
      recognised high levels of similarity in geographically and temporally separated
      isolates. Multilocus sequence typing (MLST) has become the most common method for
      genetically characterizing clones of several bacterial pathogens, allowing the
      tracking of hypervirulent/antibiotic-resistant lineages. MLST has also been used
      to examine the way that bacterial populations, and in particular, bacterial
      clones evolve. Visualisation of MLST datasets has required the development of
      novel tools, such as 'eBURST', a key program in constructing evolutionary models
      that detail how methicillin resistant Staphylococcus aureus (MRSA) and other
      clones emerge and spread.

PMID- 15196501
TI  - Bacterial genomes pave the way to novel vaccines.
AB  - The availability of complete genome sequences of pathogens has dramatically
      changed the scope for developing improved and novel vaccines by increasing the
      speed of target identification. Genomics-based technologies have many advantages,
      compared to conventional approaches, which are time-consuming and usually
      identify only abundant antigens that are expressible under in vitro culture
      conditions. This review focuses on recent reports of genomics-based strategies
      that can be applied to most pathogens and that exploit genome sequence
      information in alliance with adjunct technologies, including bioinformatics,
      expression analyses, random mutagenesis or protein/peptide-based selection
      methods. Despite the caveats that are associated with the individual approaches,
      these technologies have already made major contributions to the identification
      and selection of novel vaccine candidates to combat bacterial infections.

PMID- 15196502
TI  - Striatal plasticity in health and disease. Proceedings of a SWEMODIS symposium.
      Stockholm, Sweden. November 28-29, 2003.

PMID- 15196503
TI  - Harnessing endogenous stem cells to treat neurodegenerative disorders of the
      basal ganglia.
AB  - New neurons are continuously generated in selective regions of the normal adult
      mammalian brain. Recent evidence suggests that neural stem or progenitor cells
      located in the subventricular zone lining of the lateral ventricles can be
      induced to proliferate and migrate to the adjacent striatum following brain
      insults or growth factor treatment. This ability to incorporate new cells into
      the striatum gives the potential of repairing and restoring basal ganglia
      functions in Parkinson's and Huntington's diseases. The future challenges lay in
      directing these new cells to adopt the appropriate neuronal phenotypes and to re
      establish proper connections and functional circuitry.

PMID- 15196504
TI  - Adenosine A2A-dopamine D2 receptor-receptor heteromers. Targets for neuro
      psychiatric disorders.
AB  - Emerging evidence shows that G protein-coupled receptors can form homo- and
      heteromers. These include adenosine A(2A) receptor-dopamine D(2) receptor
      heteromers, which are most probably localized in the dendritic spines of the
      striatopallidal GABAergic neurons, where they are in a position to modulate
      glutamatergic neurotransmission. The discovery of A(2A) receptor-dopamine D(2)
      receptor heteromers gives a frame for the well-known antagonistic interaction
      between both receptors, which is the bases for a new therapeutic approach for
      neuro-psychiatric disorders, such as Parkinson's disease and schizoprenia. The
      present review deals mainly with the biochemical and molecular aspects of A(2A)
      receptor-dopamine D(2) receptor interactions. Recent results at the molecular
      level show that A(2A) receptor-dopamine D(2) receptor heteromers represent the
      first example of epitope-epitope electrostatic interaction underlying receptor
      heteromerization. Most probably A(2A) receptor-D(2) receptor heteromerization is
      not static, but subject to a dynamic regulation, related to the phosphorylation
      dependence of the A(2A) receptor epitope and to the ability of the D(2) receptor
      epitope to bind different partners. Finding out the mechanisms involved in this
      dynamic regulation can have important implications for the treatment of basal
      ganglia disorders, schizophrenia and drug addiction.

PMID- 15196506
TI  - DARPP-32 and modulation of cAMP signaling: involvement in motor control and
      levodopa-induced dyskinesia.
AB  - The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is
      abundantly expressed in the medium spiny neurons of the striatum. Phosphorylation
      catalysed by cAMP-dependent protein kinase (PKA) converts DARPP-32 into an
      inhibitor of protein phosphatase-1. In contrast, phosphorylation catalysed by
      cyclin dependent kinase-5 on Thr75 converts DARPP-32 into an inhibitor of PKA.
      Changes in the state of phosphorylation of DARPP-32 reinforce the behavioral
      effects produced by stimulation or inhibition of the cAMP pathway. Dopamine, via
      D(1) receptors, and adenosine, via A(2A) receptors, affect motor behavior by
      acting on medium spiny neurons, via G(olf) mediated stimulation of the cAMP
      signaling cascade. The involvement of DARPP-32 in dopamine and adenosine
      transmission and the possible role played by abnormal regulation of DARPP-32
      phosphorylation in levodopa-induced dyskinesia are discussed.

PMID- 15196505
TI  - Striatal plasticity at the network level. Focus on adenosine A2A and D2
      interactions in models of Parkinson's Disease.
AB  - Behavioral and microdialysis studies have been performed on antagonistic
      A(2A)/D(2) interactions in animal models of Parkinson's Disease. The behavioral
      analysis involved studies on locomotor activity in reserpinized mice, haloperidol
      induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA
      lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis
      studies were indirectly performed on the striatopallidal GABA neurons by studying
      extracellular glutamate levels in the striatum and globus pallidus of the awake
      freely moving rat. The striatum was perfused with A(2A) and/or D(2) agonists via
      reverse microdialysis. The results show that the A(2A) antagonists SCH58261 and
      KF17837 can increase locomotor activity in reserpinized mice and produce
      contralateral rotational behavior only after administration of subthreshold doses
      of l-DOPA or the D(2) like agonist quinpirole. Furthermore, antagonizing the
      A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results
      underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D(2)
      heterodimers where A(2A) R inhibits the D(2) R transduction and D(2) inhibits the
      adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that
      the A(2A) agonist CGS21680 striatally coperfused with the D(2) agonist quinpirole
      more potently counteract the D(2) agonist (quinpirole) induced reduction of
      pallidal glutamate levels in the DA denervated vs the control striatum indicating
      an enhancement of the inhibitory A(2A)/D(2) interaction. In the DA denervated but
      not in the control striatum the A(2A) agonist CGS21680 could strongly increase
      striatal glutamate levels, indicating an increased receptor signaling in the
      A(2A) R located on the striatal glutamate terminals, where also D(2) like R
      exist, here probably as D(4). Thus, the signaling of this A(2A) R may be set free
      by the loss of D(4) tone on the AC activated by A(2A) in this postulated
      A(2A)/D(4) heteromer on the glutamate terminals. Taken together, the results
      indicate that the antiparkinsonian actions of A(2A) antagonists probably are
      produced by blockade of A(2A) R in the A(2A)/D(2) heterodimers mainly located in
      the striatopallidal GABA neurons.

PMID- 15196507
TI  - Functional plasticity in the organization of signaling complexes in the striatum.
AB  - Dopamine plays a prominent role in regulating fast synaptic transmission in the
      striatum. Following dopamine receptor stimulation, various signal transduction
      pathways are activated, leading to the altered phosphorylation state and
      functional activity of substrate proteins, including glutamate-gated ion
      channels. Protein phosphatase 1 (PP1) plays a central role in these events.
      Recent studies have revealed a system for targeting PP1 to specific substrates in
      dendritic spines, via association with the cytoskeletal scaffolding proteins,
      spinophilin and neurabin. Interactions between these proteins and the actin
      cytoskeleton are dynamically regulated by the cAMP pathway, and thus play a role
      in dopamine-mediated striatal plasticity.

PMID- 15196508
TI  - Network-level neuroplasticity in cortico-basal ganglia pathways.
AB  - The striatum, the largest input nucleus of the basal ganglia, receives massive
      inputs from the neocortex and thalamus, and gives rise to the direct, indirect
      and striosomal pathways of the basal ganglia. Here, the view is developed that
      the striatum is a major site for adaptive plasticity in cortico-basal ganglia
      circuits, affecting in the normal state a broad range of behaviours. This
      plasticity can become a major source of maladaptive responses in disease states
      affecting the basal ganglia.

PMID- 15196509
TI  - Relevance of the MPTP primate model in the study of dyskinesia priming
      mechanisms.
AB  - For nearly 20 years, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
      primate model has allowed great strides to be made in our understanding of the
      maladaptive changes underlying the levodopa-related motor response complications
      occurring in most parkinsonian patients. Studies indicate that sustained dopamine
      D2 receptor occupancy can prevent and reverse existing dyskinesias. Recent
      experiments in levodopa-treated MPTP animals, co-administered either a threshold
      dose of cabergoline or a glutamate NMDA NR2B-selective antagonist (CI-1041), have
      afforded protection against dyskinesia, perhaps through presynaptic inhibition of
      glutamate release and blockade of supersensitive postsynaptic NMDA receptors in
      the striatum, respectively. Some of the biochemical events that have correlated
      with dyskinesias, namely upregulated GABA(A) receptors in the internal pallidum,
      rise in pre-proenkephalin-A gene expression in the striatum, and upregulated
      striatal glutamate ionotropic receptors and adenosine A(2a) receptors, may be
      counteracted by these preventive strategies.

PMID- 15196510
TI  - Striatal plasticity and extrapyramidal motor dysfunction.
AB  - Knowledge of molecular events contributing to motor dysfunction in Parkinson's
      disease has advanced rapidly during the past decade. Studies in animal models as
      well as in patients afflicted by this disorder suggest that the nonphysiologic
      stimulation of striatal dopamine receptors, first as a result of dopaminergic
      denervation and later as a consequence of the intermittent high-intensity
      stimulation produced by standard therapeutic regimens, leads to plastic changes
      in striatal medium spiny neurons. The clinical appearance of parkinsonism and
      subsequently of motor response complications is associated with the aberrant
      activation of signaling cascades within medium spiny neurons that modify the
      phosphorylation state of their ionotropic glutamatergic receptors. Resultant NMDA
      and AMPA receptor sensitization augments cortical excitatory input to these spiny
      efferent neurons, thus altering striatal output in ways that compromise motor
      function. These findings have already yielded new insight into mechanisms
      subserving motor memory and synaptic integration as well as accelerated
      development of novel approaches to the improved treatment of motor disability.

PMID- 15196511
TI  - Striatal plasticity and motor learning-importance of circadian rhythms, sleep
      stages and dreaming....
AB  - In this brief comment, we emphasize the importance of circadian rhythms, sleep
      stages and especially REM sleep for motor and procedural learning which needs to
      be taken into account when studying striatal plasticity. Mode and timing of
      application could also play a crucial role for long-term dopaminergic therapies
      and behavioural and other changes. We further propose a model where the brain,
      during REM sleep/dreaming, by random recombinations of small pieces of past
      experiences, tries to anticipate situations not yet experienced and to prepare it
      self, in an 'off' situation, for adequate new motor procedural responses.

PMID- 15196512
TI  - The neuromythology of Parkinson's Disease.
AB  - Over the last century three central points have become the orthodox dogma
      accepted and taught by those who study Parkinson's Disease. These are:
      Parkinson's Disease is one disease. Lewy bodies in the substantia nigra are an
      acceptable hallmark of Parkinson's Disease. Lewy bodies are responsible for the
      death of nigral neurons in Parkinson's Disease. Each of these tenets now present
      difficulties, and we are beginning to enter an era in which we must look
      critically at the current evidence to decide whether each dictum can be
      sustained.

PMID- 15196513
TI  - Is rectus femoris really a part of quadriceps? Assessment of rectus femoris
      function during gait in able-bodied adults.
AB  - There is conflicting evidence as to the precise activation pattern of the rectus
      femoris (RF) muscle during gait in able-bodied subjects. The aim of this study
      was to determine precise activation pattern of RF during gait in a healthy adult
      population. Surface and fine wire EMG from RF and vastus lateralis (VL) were
      recorded simultaneously at different walking speeds in five able-bodied subjects.
      The results of fine wire EMG showed that, at normal walking speed, RF was active
      only during the stance-to-swing transition. At faster speeds, increased levels of
      RF activity were seen during the same transition period. At the fastest speed,
      there was some activity during terminal stance, in addition to that at stance-to
      swing transition, that could be attributed to rapid hip extension and thereby a
      rapid stretch of RF. However, the RF surface EMG signal was found to exhibit a bi
      phasic pattern whilst walking at all different self-selected speeds. A burst of
      EMG activity recorded at initial contact on the surface signal but not on fine
      wire EMG, was due to cross-talk from vastus intermedius (VI). A close similarity
      was observed between the surface EMG patterns of VL and RF. VL surface and fine
      wire EMG profiles were identical for all the self-selected speeds with a main
      peak of activity beginning in terminal swing and ceasing in mid-stance. We
      conclude that RF is active only during stance-to-swing transition and the
      activity during swing-to-stance transition, as described in the literature, is
      very probably due to cross-talk.

PMID- 15196514
TI  - Impact of changing foot progression angle on foot pressure measurement in
      children with neuromuscular diseases.
AB  - To analyze the effect of lower-limb rotation on foot pressure distribution, 16
      patients (23 feet) with neuromuscular diseases who received derotation osteotomy
      of lower limbs without concomitant foot-ankle procedures were included in this
      retrospective study. The cross-correlation analysis showed that the interval
      change of the foot progression angle was correlated with the interval change of
      the medial-lateral foot pressure impulse distribution. The externally rotated
      foot progression angle tends to introduce higher loading on the medial foot, and
      the internally rotated foot progression angle shifts the loading to lateral side
      of the foot. This study provides evidence that the rotational profile of the
      lower limb has a substantial impact on foot pressure distribution.

PMID- 15196515
TI  - Reliability of the GAITRite walkway system for the quantification of temporo
      spatial parameters of gait in young and older people.
AB  - The purpose of this study was to evaluate the test-retest reliability of an
      instrumented walkway system (the GAITRite mat) for the measurement of temporal
      and spatial parameters of gait in young and older people. Thirty young subjects
      (12 males, 18 females) aged between 22 and 40 years (mean 28.5, S.D. 4.8) and 31
      older subjects (13 males, 18 females) aged between 76 and 87 years (mean 80.8,
      S.D. 3.1) walked at a self-selected comfortable walking speed across the pressure
      sensor mat three times and repeated the process approximately 2 weeks later.
      Intra-class correlation coefficients (ICC), coefficients of variation (CV) and
      95% limits of agreement were then determined. For both groups of subjects, the
      reliability of walking speed, cadence and step length was excellent (ICCs between
      0.82 and 0.92 and CVs between 1.4 and 3.5%). Base of support and toe in/out
      angles, although exhibiting high ICCs, were associated with higher CVs (8.3-17.7%
      in young subjects and 14.3-33.0% in older subjects). It is concluded that the
      GAITRite mat exhibits excellent reliability for most temporo-spatial gait
      parameters in both young and older subjects, however, base of support and toe
      in/out angles need to viewed with some caution, particularly in older people.

PMID- 15196516
TI  - Variability of step kinematics in young and older adults.
AB  - Fall-related injuries are the most common and serious medical problems facing
      older adults. Recent studies of older adults have focused on the variability of
      step kinematics and the relationship to falling. The accuracy of step variability
      estimates is proportional to the number of steps that are collected. The use of
      an instrumented treadmill allows simultaneous collection of spatial and temporal
      step kinematics for a large number of continuous steps. The current study was
      conducted to determine the influence of age, walking velocity and handrail use on
      the variability of step kinematics using a treadmill protocol. Eighteen young
      adults (average age: 27.7 +/- 3.3 years) and 12 healthy older adults (average
      age: 73.4 +/- 2.3 years) were recruited from the community. Temporal and spatial
      gait parameters were quantified using custom designed software from measurements
      collected during treadmill walking. The primary independent variables were the
      variability of step length, step width, and step time. Step width variability of
      older adults was significantly larger than that of young adults. Walking velocity
      did not influence step kinematic variability. Handrail usage influenced the
      variability of step length and step width, but not of step time. The present
      results, and those of previous studies, point to a consistent relationship
      between age and step width variability. Since step width variability has been
      implicated in falls, further research is warranted.

PMID- 15196517
TI  - Temporal and spatial features of gait in older adults transitioning to frailty.
AB  - Examining gait characteristics in older adults who are transitioning to frailty
      enhances our understanding of movement control in this fall-prone population and
      helps to better target preventive interventions. This work presents data on
      temporal and spatial gait parameters of a group of older adults who have been
      operationally defined as "transitionally frail". Gait speed, cadence, stride
      length, stance, swing, double-support, and horizontal heel velocity at heel
      contact were measured in 50 transitionally frail older adults while walking at a
      self-selected pace. These data suggest that the temporal and spatial gait
      features of these older adults differ substantially from published results from
      other older adults.

PMID- 15196518
TI  - Influence of perceptual learning on standing posture balance: repeated training
      for hardness discrimination of foot sole.
AB  - The current study investigated the influence of perceptual learning training for
      hardness discrimination of sponge rubber by the soles on postural sway. Subjects
      consisted of 30 healthy male volunteers. They were divided into two groups of 15
      each at random: perceptual learning training group and a control group. For
      hardness discrimination training, rubber sponges 5, 10, and 20 mm thick were
      combined to change the thickness of rubber to 5, 10, 15, 20, and 25 mm. The
      hardness discrimination training was administered with eyes closed in the
      standing position for each day for 10 days. The center of pressure measured using
      a stabilometer was used as the indicator for postural sway. Postural sway was
      measured for 30 s with eyes open and closed before and after hardness
      discrimination training. Statistical analysis was performed for length, enveloped
      area, and rectangular area. Postural sway after training showed a significant
      decrease compared to sway before training in the perceptual learning training
      group. However, there was no change on postural sway in the control group. In
      conclusion, data indicate that the ability of the healthy subjects to regulate
      their standing posture improved with improvement of the perceptive ability of the
      soles.

PMID- 15196519
TI  - Light touch and center of mass stability during treadmill locomotion.
AB  - PURPOSE: To study the contributions of light fingertip touch on an earth
      referenced object to body stability during treadmill locomotion. METHOD: Twenty
      young healthy adults were tested in two blocks of five testing conditions while
      walking on the treadmill at 3 km/h. In each condition, subjects were tested with
      eyes open (EO) and with eyes closed (EC). In each block, four separate conditions
      of heavy (H) or light (L) touch to either a left or to a right force sensor
      mounted on the respective side rail, as well as one condition of no touch (N),
      were randomly applied. The 3D positions of the center of mass (COM) and the
      midpoint of the posterior aspect of each leg were monitored via a kinematic
      ultrasonic system, while the anterior-posterior (AP) acceleration of the COM was
      measured with a uniaxial linear accelerometer. RESULTS: Light touch had a similar
      stabilizing effect as vision and as heavy touch on COM sway. Thus, COM sway and
      AP acceleration were comparable in conditions of eyes open and eyes closed as
      long as touch was applied. Conversely, without vision and touch, subjects drifted
      backwards, with complete disruption of the coordinated stepping pattern.
      CONCLUSIONS: Somatosensory fingertip input from an external reference provides
      spatial orientation, which, similar to vision, enables the sustaining of body
      stability during treadmill walking.

PMID- 15196520
TI  - Influence of hamstring lengthening on muscle activation timing.
AB  - The purpose of this study was to describe the changes in muscle activation
      patterns using surface electromyography (sEMG) during walking in patients with
      cerebral palsy (CP), before and after hamstring lengthening. In the current
      clinical use of sEMG during walking in CP for pre-operative planning, various
      authors have observed that timing of muscle activation patterns hardly changes
      after surgical intervention. This observation is based on tendon transfer studies
      and visual interpretation of raw EMG signals. Little is known about the effect of
      muscle lengthening on muscle activation patterns of the lengthened muscles and
      their antagonists. Fifteen children with CP comprising a total of 23 hamstring
      lengthenings were included in this study. Surface EMG of semitendinosus and
      vastus lateralis was measured before and after surgery. Timing parameters of the
      sEMG patterns were quantified, using an objective burst detection algorithm and
      statistically evaluated. Results showed that hamstring lengthening causes
      statistically significant differences in timing of both the semitendinosus and
      vastus lateralis. It is concluded that timing parameters of operated muscles and
      their antagonists after surgery do change. The delayed off-time of the
      semitendinosus and the decreased burst duration of the antagonist (the vastus
      lateralis) after surgery were the most important changes.

PMID- 15196522
TI  - Estimation of hamstring length at initial contact based on kinematic gait data.
AB  - This study proposes a simple estimate of hamstring length at initial contact
      (LEST) for use when musculoskeletal modelling is not available. The estimate is
      calculated by using the kinematic curves to measure the excessive flexion (above
      normal) at the hip and knee at initial contact. The excessive hip flexion is then
      multiplied by a scaling factor (k) and the excessive knee flexion subtracted from
      the result. Validation of this estimate was carried out using kinematic gait data
      from 25 children with cerebral palsy (50 limbs) by comparing the results of the
      estimate with an equivalent measure derived from musculoskeletal modelling
      (LTRUE). Very high agreement was found when LTRUE and LEST were compared for the
      three biarticular hamstring muscles, demonstrated by correlation coefficients of
      over 0.9. Different k values were tested with a value of 3 giving the best
      results overall. The estimate is acceptable as a simple 'rule of thumb' for use
      in clinical practice. It can provide useful additional information to complement
      the clinical examination and gait assessment results.

PMID- 15196521
TI  - Reduced plantar sensation causes a cautious walking pattern.
AB  - The aim of this study was to investigate the influence of reduced plantar
      sensation on gait patterns during walking in 20 healthy subjects (25.9 +/- years,
      61.6 +/- 11.5 kg, 178 +/- 9.5 cm) with no history of sensory disorders. Force
      plate measurements, electromyography (EMG) measurements and a three-dimensional
      movement analysis were performed simultaneously during barefoot walking before
      and after reduction of plantar sensation using an ice immersion technique. The
      results show that reduced plantar sensation leads to significant changes in gait
      patterns that are present at the ankle, knee and hip joint and indicate a more
      cautious ground contact and push-off with modified EMG and motion patterns.

PMID- 15196523
TI  - Validation of the portable VmaxST system for oxygen-uptake measurement.
AB  - The aim of this study was to validate the accuracy of a new type of portable gas
      analysis system (Sensormedics VmaxST) for the measurement of oxygen-uptake at
      expenditure levels that are reached during walking in patients with movement
      disorders. The criterion method was the Douglas Bag (DB) method, which is
      considered to be the gold standard. Accuracy evaluations were made in two trials,
      randomly using the VmaxST (ST) and the Douglas Bag method. Ten healthy adult
      subjects participated in the trials (age: 28.8 (4.3) years; body mass: 75
      (13.3)kg; height: 179.3 (8.9)cm). Each trial consisted of two time periods: 5 min
      of resting in a comfortable chair and 5 min of cycling at an 80 W workload.
      During the fifth minute of each block, mean minute ventilation (VE), oxygen
      uptake (VO2), and carbon dioxide production (VCO2) were measured or calculated
      for both systems. Energy expenditure (EE) values were calculated and net values
      calculated by subtracting resting measurements from gross measurements. The
      results show that no significant differences were found between the VmaxST and
      the Douglas Bag method for the primary parameters: EEnet and VO2net.
      Significantly higher values were found for rest and exercise values. However,
      these differences were very small. Therefore, the validity of the VmaxST is
      sufficient for use in gait studies to determine the energy cost of walking,
      especially when net values are calculated.

PMID- 15196524
TI  - Can use of walkers or canes impede lateral compensatory stepping movements?
AB  - Although assistive devices, such as walkers and canes are often prescribed to aid
      in balance control, recent studies have suggested that such devices may actually
      increase risk of falling. In this study, we investigated one possible mechanism:
      the potential for walkers or canes to interfere with, or constrain, lateral
      movement of the feet and thereby impede execution of compensatory stepping
      reactions during lateral loss of balance. Lateral stepping reactions were evoked,
      in 10 healthy young adults (ages 22-27 years), by means of sudden unpredictable
      medio-lateral support surface translation. Subjects were tested while holding and
      loading a standard pickup walker or single-tip cane or while using no assistive
      device (hands free or holding an object). Results supported the hypothesis that
      using a walker or cane can interfere with compensatory stepping. Collisions
      between the swing-foot and mobility aid were remarkably frequent when using the
      walker (60% of stepping reactions) and also occurred in cane trials (11% of
      stepping reactions). Furthermore, such collisions were associated with a
      significant reduction (26-37%) in lateral step length. It appeared that subjects
      were sometimes able to avoid collision by increasing the forward or backward
      displacement of the swing-foot or by moving the cane; however, attempts to lift
      the walker out of the way occurred rarely and were usually impeded due to
      collision between the contralateral walker post and stance foot. The fact that
      compensatory stepping behavior was altered significantly in such a healthy cohort
      clearly demonstrates some of the safety limitations inherent to these assistive
      devices, as currently designed.

PMID- 15196525
TI  - The effect of tibio-talar arthrodesis on foot kinematics and ground reaction
      force progression during walking.
AB  - Degenerative osteoarthritis in the subtalar and mid-tarsal joints occurring after
      tibio-talar arthrodesis is thought to be a consequence of abnormal foot dynamics.
      We hypothesized that the forward tilt of the tibia during stance induces early
      heel-off and alteration of the progression of ground reaction force (GRF) after
      ankle arthrodesis. Three-dimensional gait analysis was performed on nine patients
      who had an ankle arthrodesis fused in a neutral position and on ten control
      subjects. Patients walking barefoot were compared to controls. The GRF
      progression was shifted forward during mid-stance, heel-off occurred earlier and
      was associated with less anterior tilt of the tibia and a more posterior position
      of the GRF with reference to the metatarsal heads. The GRF progression, heel-off
      and tibial tilt were not significantly different between patients and controls
      when walking in shoes but the GRF was still more posterior at heel-off.
      Increasing the walking speed worsened the anomalies of foot dynamics. These
      alterations of foot dynamics are thought to be associated with pathogenic
      stresses applied to the mid-foot.

PMID- 15196526
TI  - Effect of gait cycle selection on EMG analysis during walking in adults and
      children with gait pathology.
AB  - This paper presents the results of a project to evaluate different methods of
      gait cycle selection on the analysis of electromyography recorded during gait.
      Electromyography (EMG) describes the electrical activity associated with the
      muscle and is often interpreted in gait analysis using a simultaneously obtained
      signal to identify phases of the gait cycle. Phase transitions are often selected
      manually from reference signals derived from additional instrumentation, such as
      pressure platforms, footswitches and video cameras. We propose two methods
      (automatic and semi-automatic) as an alternative to the more traditional manual
      selection, and analyse how the gait cycle selection affects the EMG analysis. To
      quantify the differences between the gait cycles obtained using each method and
      to classify each cycle, three indices have been introduced. The effect of the
      gait cycle selection has been evaluated with respect to the EMG step profiles and
      temporal gait descriptors. An asymptomatic adult, an asymptomatic child and two
      children with cerebral palsy were examined using telemetric EMG devices and
      pressure footswitches. The results obtained showed that the method of gait cycle
      selection did not have a major influence for the adult, but it altered
      considerably the analysis in the case of the children with cerebral palsy.

PMID- 15196527
TI  - Evaluation of an ambulatory system for gait analysis in hip osteoarthritis and
      after total hip replacement.
AB  - Spatial and temporal parameters of gait have clinical relevance in the assessment
      of motor pathologies, particularly in orthopaedics. A new gait analysis system is
      proposed which consists of (a) an ambulatory device (Physilog) including a set of
      miniature gyroscopes and a portable datalogger, and (b) an algorithm for gait
      analysis. The aim of this study was the validation of this system, for accuracy
      and clinical applicability. Eleven patients with coxarthrosis, eight patients
      with total hip arthroplasty and nine control subjects were studied using this
      portable system and also a reference motion analyzer and force plate. The small
      differences in the stance period (19 +/- ms), stride length and velocity (0.4 +/-
      9.6 cm and 2.5 +/- 8.3 cm/s, respectively), as well as thigh and shank rotations
      (2.4 +/- 4.3 degrees and 0.3 +/- 3.3 degrees, respectively), confirmed good
      agreement of the proposed system with the reference system. In addition, nearly
      the same accuracy was obtained for all three groups. Gait analysis based on
      Physilog was also in agreement with their Harris Hip Scores (HHS): the subjects
      with lower scores had a greater limp, a slower walking speed and a shorter
      stride. This ambulatory gait analysis system provides an easy, reproducible and
      objective method of quantifying changes in gait after joint replacement surgery
      for coxarthrosis.

PMID- 15196528
TI  - Langerhans cell histiocytosis: portrait of a disease as a rare tumour.

PMID- 15196529
TI  - Langerhans cell histiocytosis in adults: more questions than answers?
AB  - Langerhans cell histiocytosis (LCH) may affect patients of any age but in adults
      the features of this disease are still poorly defined. Most reports are based on
      single-specialty experience and there are only a few describing relatively large
      series of patients. Although child and adult patients share several features of
      the disease, and may either have localised or disseminated disease, the
      proportion of cases with lung involvement is much higher in adults and is partly
      explained by cigarette smoking. Persisting uncertainty about the pathogenesis of
      LCH has certainly limited current treatment alternatives. In particular, no
      clinical trial has been conducted in adults so far and most information derives
      from description of one or a few cases, often reported retrospectively. On the
      basis of the background provided by the data collected in its International
      Registry, the Histiocyte Society is about to start the first prospective,
      cooperative adult LCH study, aimed at: (a) establishing a common platform for
      clinical evaluation; (b) testing in adult patients the efficacy of the best
      standard chemotherapy regimen for children-a combination of prednisone and
      vinblastine-developed by the Society's trials; (c) describing the natural history
      of the disease, the impact of cigarette smoking withdrawal and the efficacy of
      steroid monotherapy in pulmonary LCH. Research studies, ancillary to this trial,
      offer unique opportunities of addressing some of the open questions in LCH
      including: the genetic component of the disease as supported by evidence of
      familial clustering and chromosomal instability, the issue of 'LCH cells'
      clonality, the relation between pulmonary disease, cigarette smoking, and immune
      system polymorphisms that might increase individual susceptibility to LCH. A
      concerted joint effort between paediatricians and adult specialists could be the
      key to the development of insights into LCH in all age groups affected by this
      distressing and often debilitating condition.

PMID- 15196530
TI  - Systemic therapy for advanced hepatocellular carcinoma: a review.
AB  - Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide.
      Whilst local treatments are useful in selected patients, they are not suitable
      for many with advanced disease. Here, we review phase II and III trials for
      systemic therapy of advanced disease, finding no strong evidence that any
      chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date
      benefits survival in this setting. Many trials were inadequately powered, single
      centre, and enrolled highly selected patients. From this review, we cannot
      recommend any therapeutic approach in these patients outside of a clinical trial
      setting. Including an untreated control arm in clinical trials in HCC is still
      justified. Every effort should be made to enroll these patients into adequately
      powered trials, and promising phase II results must be tested in a multicentre
      phase III setting, preferably against a placebo control arm. Prevention of
      hepatitis B and C remains vital to decrease deaths from HCC.

PMID- 15196531
TI  - Expression of HER2 and its association with AP-2 in breast cancer.
AB  - The aim of the study was to investigate the relationship between the expression
      of human epidermal growth factor receptor 2 (HER2) and activator protein 2 (AP
      2), as well as the prognostic significance of HER2 in breast cancer. HER2 and AP
      2 expressions were immunohistochemically (IHC) analysed in a large prospective,
      consecutive series of 425 breast cancer patients diagnosed and treated between
      1990 and 1995 at the Kuopio University Hospital, Kuopio, Finland. In a subset of
      patients (n = 71), the gene amplification status was examined by using a
      chromogenic in situ hybridisation (CISH) analysis. Expression of HER2 was studied
      in relation to AP-2, clinicopathological parameters and patients' survival.
      Pathological membranous overexpression of the HER2 receptor was seen in 13% of
      the carcinomas, which was related both to gene amplification (78% of the cases)
      and high nuclear expression of AP-2 (67%, P = 0.007). HER2-positivity was most
      often seen in carcinomas having both high nuclear and high cytoplasmic AP-2
      expression (P < 0.001). In the univariate survival analyses HER2-positivity
      predicted a shorter recurrence-free survival (RFS) (P < 0.0001) and a shorter
      breast cancer-related survival (BCRS) (P = 0.0063) in the whole patient group, as
      well as in the subgroup of node-negative patients. In the node-positive patients,
      HER2-positivity predicted only a shorter RFS. Combined expression of HER2 and
      nuclear AP-2 resulted in the separation of four groups with different prognoses,
      the best prognosis being for patients in the HER2-/AP-2+ group and the worse
      prognosis for those in the HER2+/AP-2- group. In the multivariate survival
      analyses, HER2-positivity independently predicted a shorter RFS in the whole
      patient group (P = 0.0067), as well as in the subgroup of node-positive patients
      (P = 0.0209). In conclusion, pathological membranous overexpression of the HER2
      receptor in breast cancer is related both to gene amplification and a high AP-2
      expression. Combining HER2 and AP-2 expressions may provide valuable information
      on the prognosis of breast cancer patients.

PMID- 15196532
TI  - Prognostic impact of the early detection of metachronous contralateral breast
      cancer.
AB  - The study aimed to assess whether the early detection of asymptomatic
      metachronous contralateral breast cancer (MCBC) improves the prognosis of the
      patient compared with a diagnosis at symptomatic onset. We reviewed 339 MCBC
      cases that were consecutively diagnosed from 1970 to 2001, for which reliable
      information on subjective symptoms was available. The association of early
      (asymptomatic vs. symptomatic) detection with mortality from breast cancer was
      studied by univariate and multivariate analyses, adjusting for potential
      confounders. A more favourable stage at diagnosis was evident for asymptomatic
      vs. symptomatic MCBC (pT1=84.2% vs. 58.1%, pN0 65.0% vs. 52.4%). The hazard ratio
      (HR) of breast cancer death was approximately half (0.49%, 95% Confidence
      Interval (CI) 0.29-0.83, P = 0.008) for asymptomatic vs. symptomatic MCBC.
      Although length bias may have occurred (symptomatic MCBC had a shorter free
      interval from the first cancer), the present evidence supports the practice of
      active follow-up aimed at the early detection of asymptomatic MCBC.

PMID- 15196533
TI  - Proliferation markers predictive of the pathological response and disease outcome
      of patients with breast carcinomas treated by anthracycline-based preoperative
      chemotherapy.
AB  - The cell proliferation rate has been correlated to the response of breast
      carcinomas to preoperative chemotherapy (CT) and to disease outcome. However,
      this parameter is not yet used to select which tumours should be treated with
      preoperative CT. Furthermore, there is no consensus in the method used to
      evaluate cell proliferation. In poor prognosis breast carcinomas (PPBCs) treated
      by intensive preoperative CT, we compared the predictive value of S phase
      fraction (SPF), mitotic index (MI) and Ki67. We also evaluated the prognostic
      significance of the variation of the MI after CT. A series of 55 T2-T4N0N1M0
      breast carcinomas were treated with 4 cycles of cyclophosphamide, 5-fluorouracil
      (5-FU) and doxorubicin. SPF was determined by flow cytometry on pre-therapeutic
      needle aspiration products. MI and Ki67 were evaluated on pre-therapeutic biopsy
      samples and on the tumours after CT. Fifteen patients (27%) had a pathological
      complete response (pCR), whereas 40 (73%) had residual disease. All three
      proliferative markers were found to have predictive value, but this value was
      higher for MI than for SPF (P = 0.04) and Ki67 (P = 0.03): the rate of pCR was
      50% in cases with MI > 17/3.3 mm2, but was only 7% in cases with MI under this
      threshold (P = 0.0003). A significant decrease of MI (mean 10.97) was observed
      after CT (P = 0.001). Furthermore, we observed that even for patients with
      residual tumour, the variation of MI after CT was a prognostic parameter and
      overall survival. The sequential analysis of MI in breast cancers treated by
      preoperative CT thus provides a surrogate for predicting long-term outcome.

PMID- 15196534
TI  - Psychological factors and patient delay in patients with head and neck cancer.
AB  - There is a rising incidence of patients presenting with advanced cancer in the
      head and neck region. Late presentation may be due to a delay in seeking medical
      attention, which is sometimes surprisingly long. The aim of the present
      prospective study was to investigate the association between patient delay and
      the psychological factors of optimism, health hardiness, overall defensive
      functioning, coping styles and psychological distress in 277 patients with cancer
      of the head and neck. Significant correlations were found between patient delay
      and the psychological factors. Twenty-six percent of the patients waited more
      than three months before seeking medical attention and they reported less
      optimism (P = 0.0001), less health hardiness (P = 0.008), less active coping (P =
      0.019) and less seeking support as a coping style (P = 0.017) than patients
      presenting within three months. Excessive drinkers (5+ alcoholic drinks/day)
      tended to show more delay than patients who did not drink or were moderate
      drinkers (0-2 drinks/day) or moderate-heavy drinkers (3-4 drinks/day). Together,
      the psychological factors could explain 25% of the variance of patient delay in
      excessive drinkers compared with 21% and 6% in moderate-heavy drinkers and non
      drinkers to moderate drinkers, respectively. These results suggest that
      psychological factors affect health-care seeking behaviour. Health education
      aimed at the risk group of excessive drinkers should take psychological factors
      into account that influence their health behaviour.

PMID- 15196535
TI  - Locoregional effects of pegylated liposomal doxorubicin (Caelyx) in irradiated
      area: a phase I-II study in patients with recurrent squamous cell carcinoma of
      the head and neck.
AB  - Aim of this study was to determine the antitumour activity and toxicity of
      pegylated liposomal doxorubicin (Caelyx) in pretreated patients with locally
      recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).
      Caelyx was administrated as 1 h infusion every 3 weeks at doses of 35 mg/m2
      (group A) and then subsequently given at 45 mg/m2 (group B). 26 patients received
      a total of 87 cycles. The median number of cycles was 3 (range 1-7). Four out of
      24 evaluable patients (17%, 95% confidence interval (CI) 0.5-32%) showed
      significant evidence of antitumour activity, with tumour necrosis being observed
      in 2 patients. Grade 3-4 neutropenia was observed in only 2 patients. There were
      no grade 3-4 mucosal, skin, digestive, cardiac or hepatic toxicities. Caelyx has
      activity against locally recurrent SCCHN and is well tolerated up to 45 mg/m2,
      but a careful utilisation of this drug is required for tumours relapsing in
      irradiated areas.

PMID- 15196536
TI  - Outcome of second malignancies after retinoblastoma: a retrospective analysis of
      25 patients treated at the Institut Curie.
AB  - Retinoblastoma is usually curable in developed countries. The morbidity and
      mortality of patients with hereditary retinoblastoma is still threatened by the
      occurrence of secondary tumours. Between 1971 and 1988, 427 patients with
      retinoblastoma were treated in the ophthalmologic, paediatric and radiotherapy
      departments of the Institut Curie. In this study, we report the clinical and
      therapeutic features and the outcome of 25 patients treated for a second
      malignant neoplasm, diagnosed between 1997 and 1999 at the Institut Curie. The
      median time interval between the diagnosis of retinoblastoma and SMN was 11.2
      years (range 3.8-20.6 years). Histopathological diagnoses included: 12
      osteosarcomas, 12 soft tissue sarcomas and, 1 malignant oligodendroglioma. The
      second malignant neoplasm was located inside the radiation field in 21 cases and
      outside in 4. Twenty three patients received pre-operative chemotherapy. Surgery
      was performed in 16 patients. Post-operative chemotherapy was administered in 12
      patients and external beam radiotherapy was used in 2 patients. Response to
      treatment was evaluable in 24 patients: complete remissions were observed in
      14/24, partial remissions in 2/24 and progressive disease in 8/24. Nineteen
      patients died. Six are still alive, with 4 in complete remission (median follow
      up 8.8 years; range 5.8-13.9 years). Despite aggressive therapy, the prognosis of
      patients with second malignant neoplasm occurring after retinoblastoma is very
      poor. It is important to provide information to retinoblastoma patients regarding
      the risk of a second tumour as this may facilitate an early tumour detection.

PMID- 15196537
TI  - Hepatocellular carcinoma in the Netherlands incidence, treatment and survival
      patterns.
AB  - To examine recent trends of hepatocellular carcinoma (HCC) in an unselected
      patient population in the Western world, cancer registration data of HCC in the
      Netherlands were analysed. Trends in incidence, mortality, treatment and
      survival, according to gender, age, stage of disease and period of diagnosis were
      studied. Age-standardised incidence of HCC in the Netherlands did not rise from
      1989 to 2000. In men older than 75 years, there was a significant increase.
      Mortality due to primary liver cancer increased from 1989 to 2000. There was no
      change in the treatment pattern (1989-1998), whereas 73% of patients with HCC
      received no cancer-related therapy during this period of analysis. Twelve percent
      of the patients underwent either a partial liver resection or orthotopic liver
      transplantation. This low percentage suggests that patients with HCC must be
      analysed and discussed in specialised centres to minimise the number of patients
      not receiving possible curative therapy.

PMID- 15196538
TI  - Monoclonal proteinaemia and solid tumours.
AB  - A higher prevalence of solid tumours in patients with M(onoclonal) proteinaemia
      without a co-existing haematological malignancy has been reported. We
      investigated this association by linking a population-based registry of patients
      with newly diagnosed M-proteinaemia (n = 1464) with the Regional Cancer Registry.
      Patients were followed for a median of 7.4 years for those still alive. In total
      167 (11%) patients with 173 solid tumours were compared with 861 patients with 'M
      proteinaemia only' (without a haematological malignancy). The M-protein isotype
      or level or clinical parameters did not differ between the groups. M-protein
      isotype was not associated with a specific tumour type. Standardised Morbidity
      Ratios (SMR) for nearly all solid tumours were elevated in the year of the M
      protein discovery, but the excess risk disappeared during follow-up suggesting
      selection through diagnostic investigations rather than a causal role. In this
      large series of patients with both newly diagnosed M-proteinaemia and a solid
      tumour no relationship could be established.

PMID- 15196539
TI  - Staging in patients with locoregionally recurrent breast cancer: current practice
      and prospects for positron emission tomography.
AB  - The aim of this study was to describe the extent and yield of daily clinical
      practice when staging patients with a locoregional recurrence (LRR) of breast
      carcinoma and to explore the prospects for positron emission tomography (PET).
      The population-based Eindhoven Cancer Registry was used to select all breast
      cancer patients in the southeast of the Netherlands with a first episode of LRR
      between January 1, 1994 and June 30, 2000 (n = 175). Additional data concerning
      staging procedures and follow-up were collected from the medical records.
      Furthermore, we asked 77 physicians (response: 75%) about their opinions on
      staging procedures and actual treatment policy. At LRR presentation, 16% of
      patients were found to have distant metastases. An additional 24% were diagnosed
      with distant metastases within 18 months. The questionnaire revealed that 33% of
      clinicians thought that the sensitivity of conventional imaging techniques was
      too low. We tend to conclude that in daily clinical practice there is a need for
      more sensitive dissemination tests for patients with a LRR of breast cancer.

PMID- 15196540
TI  - In vivo and in vitro evaluation of erianin, a novel anti-angiogenic agent.
AB  - This study evaluated the anti-angiogenic activities of erianin in vivo and in
      vitro. Erianin, a natural product from Dendrobium chrysotoxum, caused moderate
      growth delay in xenografted human hepatoma Bel7402 and melanoma A375 and induced
      significant vascular shutdown within 4 h of administering 100 mg/kg of the drug.
      Erianin also displayed potent anti-angiogenic activities in vitro: it abrogated
      spontaneous or basic fibroblast growth factor-induced neovascularisation in chick
      embryo; it inhibited proliferation of human umbilical vein endothelial cells
      (EC(50) 34.1+/-12.7 nM), disrupted endothelial tube formation, and abolished
      migration across collagen and adhesion to fibronectin. Erianin also exerted
      selective inhibition toward endothelial cells, and quiescent endothelium showed
      more resistance than in proliferative and tumour conditions. In a cytoskeletal
      study, erianin depolymerised both F-actin and beta-tubulin, more significantly in
      proliferating endothelial cells than in confluent cells. In conclusion, erianin
      caused extensive tumour necrosis, growth delay and rapid vascular shutdown in
      hepatoma and melanoma models; it inhibited angiogenesis in vivo and in vitro and
      induced endothelial cytoskeletal disorganisation. These findings suggest that
      erianin has the therapeutic potential to inhibit angiogenesis in vivo and in
      vitro.

PMID- 15196541
TI  - The ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase in tumour
      tissues of patients with metastatic gastric cancer is predictive of the clinical
      response to 5'-deoxy-5-fluorouridine.
AB  - The aim of this work was to determine whether intratumour contents of thymidine
      phosphorylase (TP), which converts 5'-deoxy-5-fluorouridine (5'-DFUR) to 5
      fluorouracil, and dihydropyrimidine dehydrogenase (DPD), which degrades 5
      fluorouracil to inactive molecules, could be useful in predicting the response of
      patients with metastatic gastric cancer to chemotherapy using 5'-DFUR. Endoscopic
      biopsy specimens for the measurement of TP and DPD were obtained from the primary
      lesions before the start of combination chemotherapy, in which 5'-DFUR, cisplatin
      and mitomycin C were administered. TP and DPD were measured by enzyme-linked
      immunosorbent assays after the objective responses to chemotherapy had been
      confirmed. Twenty five patients were enrolled in this study and data for 22
      patients in whom responses were confirmed were analysed. The median levels
      (ranges) of TP and DPD were 80 (4.9-360) and 44 (15-82) U/mg protein,
      respectively. The median value (range) of TP to DPD ratios was 1.9 (0.25-5.1).
      Eight patients with a complete or partial response to chemotherapy had
      significantly higher TP to DPD ratios than did the remaining patients with stable
      or progressive disease (P = 0.014). When a cut-off level of TP to DPD ratio was
      defined as the median value, the high-ratio group (n = 11) showed a significantly
      higher response rate (64% vs. 9.1%, P = 0.024) than the low-ratio group (n = 11).
      Overall survival of the high-ratio group was significantly longer than that of
      the low-ratio group (the median survival time; 300 days vs. 183 days, P = 0.047).
      The efficacy of 5'-DFUR could be optimised by preselecting patients with high TP/
      DPD ratios in their tumour tissues, and this would be applicable to the treatment
      with capecitabine.

PMID- 15196542
TI  - Positive interactive radiosensitisation in vitro with the combination of two
      nucleoside analogues, (E)-2'-deoxy-2'-(fluoromethylene) cytidine and
      iododeoxyuridine.
AB  - (E)-2'-Deoxy-2'-(fluoromethylene) cytidine (FMdC), an inhibitor of ribonucleotide
      diphosphate reductase (RR), is a potent radiation-sensitiser acting through
      alterations in the deoxyribonucleoside triphosphate (dNTP) pool in the de novo
      pathway to DNA synthesis. The activity of thymidine kinase (TK), a key enzyme in
      the 'salvage pathway', is known to increase in response to a lowering of dATP
      induced by FMdC. Nucleoside analogues such as iododeoxyuridine (IdUrd) are
      incorporated into DNA after phosphorylation by TK. Radiation sensitisation by
      IdUrd depends on IdUrd incorporation. Therefore, we have investigated the
      radiosensitising effect of the combination of FMdC and IdUrd on WiDr (a human
      colon cancer cell-line) and compared it to the effect of either drug alone. We
      analysed the effects of FMdC and IdUrd on the dNTP pools by high-performance
      liquid chromatography, and measured whether the incorporation of IdUrd was
      increased by FMdC using a [(125)I]-IdUrd incorporation assay. The combination in
      vitro yielded radiation-sensitiser enhancement ratios of >2, significantly higher
      than those observed with FMdC or IdUrd alone. Isobologram analysis of the
      combination indicated a supra-additive effect. This significant increase in
      radiation sensitivity with the combination of FMdC and IdUrd could not be
      explained by changes in the dNTP pattern since the addition of IdUrd to FMdC did
      not further reduce the dATP. However, the increase in the radiation sensitivity
      of WiDr cells might be due to increased incorporation of IdUrd after FMdC
      treatment. Indeed, a specific and significant incorporation of IdUrd into DNA
      could be observed with the [(125)I]-IdUrd incorporation assay in the presence of
      1 microM unlabelled IdUrd when combined with FMdC treatment.

PMID- 15196543
TI  - Abnormal Fhit protein expression and high frequency of microsatellite instability
      in sporadic colorectal cancer.
AB  - The role of Fhit protein in the oncogenesis of colorectal cancer is still in
      debate. Recent studies have revealed that reduced Fhit protein expression is
      associated with a deficiency of the mismatch repair protein. One hundred and
      twenty unselected patients who underwent curative resection for sporadic
      colorectal cancer in a three-year period were evaluated for microsatellite
      instability (MSI) using six microsatellite markers, and for the presence of Fhit
      and mismatch repair (MMR) proteins (Mlh1 and Msh2) by means of immunostaining.
      The relations between these markers were analysed. Reduced or absent Fhit
      expression was noted in 18 out of 118 patients. This altered expression was
      significantly higher in right-sided cancer (P = 0.005), mucinous tumours (P =
      0.005) and in poorly differentiated histological types (P = 0.0001). MSI was
      found in 22 out of 109 patients, more so in right-sided cancer (P = 0.0001),
      poorly differentiated histology (P = 0.0001), and mucinous tumours (P = 0.0001).
      No association was found with TNM stage. MSI was present in 66.7% of tumours with
      altered Fhit expression and in only 10% of tumours with preserved or intermediate
      Fhit expression (P = 0.0001). Of the tumours with reduced or absent Fhit
      expression, 72.2% had loss of nuclear Mlh1 or Msh2 expression compared with only
      14% of the preserved or intermediate Fhit expression tumours (P = 0.0001). These
      results support the hypothesis that deficiency in a MMR gene could be a cause of
      the high frequency of alterations in Fhit expression, and they permit the
      suggestion that FHIT gene alteration may be part of the genetic pathway involving
      MSI through which some colorectal cancers arise.

PMID- 15196544
TI  - Predicting non-small cell lung cancer expression of epidermal growth factor
      receptor and matrix metalloproteinase 9 from immunohistochemical staining of
      diagnostic biopsy samples.
AB  - Epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9)
      expression in resected non-small cell lung cancer (NSCLC) has been associated
      with a poor prognosis. Specific inhibitors have been developed to these molecules
      and have entered into clinical practice. We performed immunohistochemical
      staining on a series of 36 resected cases of NSCLC in parallel with the
      associated preoperative diagnostic biopsies in order to determine whether
      expression of these markers in the tumour could reliably be predicted from the
      result obtained with the small diagnostic biopsy. The results demonstrated
      considerable intratumour heterogeneity of expression for both markers in the
      resected tumours, and this was associated with a poor negative predictive value
      for the result obtained with the diagnostic biopsy. We conclude that, staining
      small diagnostic biopsies for EGFR and MMP9 is unlikely to be helpful in defining
      tumour status for these markers and allowing targeted therapy.

PMID- 15196545
TI  - Twelve colorectal cancer cell lines exhibit highly variable growth and metastatic
      capacities in an orthotopic model in nude mice.
AB  - Orthotopic tumour models for colorectal cancer are a complementary tool for the
      study of tumours in vivo. They are more closely related to human cancer than are
      subcutaneous tumour models, since evaluation of spontaneous metastasis formation
      is possible. In the present study, fragments of subcutaneous xenografts
      established from 12 well-described and generally available colorectal cancer cell
      lines were implanted in the caecum of nude mice and tumour growth and metastatic
      events registered. The results showed considerable differences between the cell
      lines with respect to take rate, tumour growth and metastatic ability. This
      resulted in variable disease progression that seemingly reflects clinically
      relevant heterogeneity. The most common metastatic findings were mesenteric lymph
      node metastases, occurring at variable frequency in tumour-bearing mice with 10
      out of 12 cell lines, whereas only one line gave rise to liver metastases, in two
      of 10 animals. The study provides useful background information on the 12
      colorectal cancer cell lines in a clinically relevant orthotopic tumour model.

PMID- 15196546
TI  - Truncated mouse adenomatous polyposis coli reduces connexin32 content and
      increases matrilysin secretion from Paneth cells.
AB  - Heterozygous mutations in adenomatous polyposis coli (APC) is an early event in
      inheritable and sporadic colon cancer development. We recently found reduced
      connexin (Cx43) expression in intestinal cell lines with heterozygous Apc
      mutation. In this study we investigated Cx expression and the role of one mutated
      Apc allele in epithelia of multiple intestinal neoplasia (Min) mouse intestines
      by immunohistochemistry. Cx43 was not expressed in intestinal epithelia of Min
      and wild-type mice. Cx32 was specifically expressed in enterochromaffin cells in
      both mice types, and in Paneth cells of wild-type mice. In contrast, Min mice had
      nearly undetectable level of Cx32 in Paneth cells. Isolated small intestinal
      crypts from Min mice had markedly increased secretion of both lysozyme and
      matrilysin compared with wild-type mice. Absence of matrilysin in Min mice
      reduces adenoma development. Reduced Cx32 and increased matrilysin secretion from
      Paneth cells could be important to neoplastic development in the intestine.

PMID- 15196547
TI  - Regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D expression
      by the organ microenvironment in human colon carcinoma.
AB  - Vascular endothelial growth factor (VEGF)-C and VEGF-D are potent lymphangiogenic
      factors produced by tumour and stromal cells. The purpose of this study was to
      investigate the expression of VEGF-C and VEGF-D in the organ microenvironment. We
      implanted human KM12 colon carcinoma cell lines into the subcutis and caecal wall
      of nude mice. The expression of VEGF-C and VEGF-D mRNAs and proteins were
      examined by reverse transcriptase-polymerase chain reaction and
      immunohistochemistry, respectively. Under culture conditions, VEGF-C mRNA was not
      detected in KM12 cells; however, VEGF-C expression was detected after
      implantation of KM12 cells into nude mice. VEGF-C and VEGF-D protein contents
      were higher in orthotopic (caecal wall) tumours than in ectopic (subcutis)
      tumours. Small vessels expressing VEGF receptor-3 were observed in the peripheral
      portions of caecal tumours. In metastatic liver tumours, VEGF-C and VEGF-D
      proteins were produced in lower amounts than those in caecal tumours. These data
      suggest that the expression of lymphangiogenic factors is influenced by the organ
      microenvironment. Therefore, experimental studies of colon cancer
      lymphangiogenesis should be performed with orthotopic implantation models.

PMID- 15196548
TI  - Expression of Cathepsin B and L antigen and activity is associated with early
      colorectal cancer progression.
AB  - Cathepsin B and Cathepsin L are cysteine proteases important in the process of
      invasion and metastasis. The aim of our study was to assay antigen and activity
      levels of these enzymes and to correlate these with established clinical and
      pathological prognostic parameters including patient survival. 99 patients
      undergoing operations for colorectal cancer were included in this study. We
      quantitated cathepsin B and L levels in matched normal mucosa and cancer samples
      using an enzyme-linked immunosorbent assay (ELISA) and specific activity assays
      and expressed the results as tumour/normal ratios. Significant correlations were
      found between tumour/normal cathepsin B and L antigen and activity ratios.
      Cathepsin B and L tumour/normal activity ratios were greater than 1 in early
      stage disease and there were gradual reductions in cathepsin B (P = 0.02) and L
      (P = 0.03) activity ratios with advancing tumour stage. Survival of patients with
      potentially curative disease was inversely related to both cathepsin B (P =
      0.007) and L (P = 0.001) activity ratio, in addition to cathepsin L antigen ratio
      (P = 0.008). Our findings suggest that cysteine proteases play an important role
      in colorectal cancer progression.

PMID- 15196549
TI  - Expression of a novel matrix metalloproteinase regulator, RECK, and its clinical
      significance in resected non-small cell lung cancer.
AB  - The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) was
      initially isolated as a transformation-suppressor gene by expression cloning and
      found to encode a membrane-anchored regulator of the matrix metalloproteinases
      (MMPs). Experimental studies have shown that RECK can suppress tumour - invasion,
      metastasis and angiogenesis. However, the clinical impact of RECK remains
      unclear. To assess the clinical significance of RECK-expression in non-small cell
      lung cancer (NSCLC), a total of 171 patients with completely resected
      pathological stage (p-stage) I-IIIA NSCLC were retrospectively examined.
      Expression of RECK and vascular endothelial growth factor (VEGF) in tumour
      tissues was assessed by immunohistochemical staining (IHS). Intratumoural
      microvessel density (IMVD), a measurement of angiogenesis, was also determined by
      IHS using an anti-CD34 antibody. A significant inverse correlation between RECK
      expression and tumour angiogenesis was documented; the mean IMVD in tumours with
      strong RECK-expression (157.1) was significantly lower than that observed in
      tumours with weak RECK-expression (194.5; P = 0.008). Interestingly, this inverse
      correlation was seen only when VEGF was strongly expressed, which suggests that
      RECK could suppress the angiogenesis induced by VEGF. The 5-year survival rate
      for patients with tumours with strong RECK-expression (75.8%) was significantly
      higher than that for patients with weakly expressing tumours (54.3%; P = 0.016).
      Subset analyses showed that the prognostic impact of RECK-status was evident in
      patients with either adenocarcinoma, poorly differentiated tumours, or p-stage
      IIIA disease. A multivariate analysis confirmed that reduced RECK-expression was
      an independent and significant factor in predicting a poor prognosis (P = 0.009;
      Hazard ratio (HR), 0.474 with a 95% Confidence interval (CI) of 0.271-0.830). In
      conclusion, RECK-status is a significant prognostic factor correlated with tumour
      angiogenesis in NSCLC patients.

PMID- 15196551
TI  - Kaposi's sarcoma in Vaud and Neuchatel, Switzerland, 1978-2002.
AB  - We have considered trends in the incidence of Kaposi sarcoma (KS) between 1978
      and 2002, using data from the Swiss Cancer Registries of Vaud and Neuchatel
      (786000 inhabitants). Overall, 163 cases were registered, 149 in men and 14 in
      women. After a peak reached in 1988-1992 in both men (2.71/100000, world
      standard) and women (0.26/100000), a considerable decline was observed
      thereafter, to reach 0.80/100000 men and 0.06/100000 women in 1998-2002. In men,
      there was a substantial decline (from 4.91/100000 in 1988-1992 to 0.56 in 1998
      2002) at age 15-44 years, a fall from 2.91 in 1993-1997 to 2.37 in 1998-2002 at
      age 45-64 years, but some increases over the last decade in the elderly, likely
      due to cases of classic KS. The declines in KS confirm that earlier anti
      retroviral therapies (HAART) had already reduced the risk of KS, and the newest
      highly active anti-retroviral therapies have further contributed to the decline
      of KS in recent years.

PMID- 15196550
TI  - Analysis of chromosomes 3, 7, X and the EGFR gene in uterine cervical cancer
      progression.
AB  - The aim of this study was to investigate the possible role of genetic alterations
      in the genesis and progression of cervical carcinomas. We analysed the 3, 7, X
      aneusomy of chromosomes and the status of the epidermal growth factor receptor
      (EGFR) gene by fluorescence in situ hybridisation (FISH) analysis. Polysomy of
      chromosomes 3 and X defined the transition from high-grade squamous
      intraepithelium lesions (HSIL) to cervical carcinoma. Chromosome 7 monosomy and
      polysomy did not show any statistical significant differences between the groups
      examined. When we compared the chromosomal aneusomies in all of the specimens
      using the Kruskal-Wallis test, significant differences (P = 0.0001, P = 0.0001
      for chromosomes 3 and X, respectively) were observed. Using a ratio of the EGFR
      gene signals and chromosome 7 centromeric signals, no samples showed gene
      amplification. Our results demonstrate the importance of chromosomal 3 and X
      aneusomies in the development and progression from HSIL to cervical carcinoma,
      highlighting their usefulness as genetic markers for identifying SILs at high
      risk of progression.

PMID- 15196552
TI  - From protein dynamics to animal behavior: new insights into complex cell
      regulatory mechanisms.

PMID- 15196553
TI  - The novel functions of ubiquitination in signaling.
AB  - Ubiquitin is best known for its function in targeting proteins for degradation by
      the proteasome. Recent studies have revealed several new functions of ubiquitin
      that are independent of proteasomal degradation. These functions include the
      novel signaling roles of ubiquitin in DNA repair and the activation of protein
      kinases such as IkappaB kinase. In both cases, a novel form of polyubiquitin
      chain linked through lysine-63 of ubiquitin plays an important regulatory role.
      Monoubiquitination also has signaling roles that are distinct from those of
      polyubiquitination, as illustrated from the studies of DNA repair. Thus,
      polyubiquitination and monoubiquitination have emerged as important signaling
      mechanisms that control diverse physiological and pathological processes.

PMID- 15196554
TI  - Expanding roles for miRNAs and siRNAs in cell regulation.
AB  - The role of small RNAs as key regulators of mRNA turnover and translation has
      been well established. Recent advances indicate that the small RNAs termed
      microRNAs play important roles in cell proliferation, apoptosis and
      differentiation. Moreover, the microRNA mechanism is an efficient means to
      regulate production of a diverse range of proteins. As new microRNAs and their
      mRNA targets rapidly emerge, it is becoming apparent that RNA-based regulation of
      mRNAs may rival ubiquitination as a mechanism to control protein levels.

PMID- 15196555
TI  - Early events in glutamate receptor trafficking.
AB  - Glutamate receptors are the primary mediators of excitatory synaptic transmission
      in the mammalian central nervous system. Activity-dependent changes in the number
      of postsynaptic glutamate receptors underlie aspects of synaptic plasticity and
      provide a mechanism for information storage in the brain. Recent work shows that
      receptor exit from the endoplasmic reticulum represents a critical regulatory
      step in glutamate receptor trafficking to the neuronal cell surface.

PMID- 15196556
TI  - Setting up a selective barrier at the apical junction complex.
AB  - Across the animal kingdom the apical junction complex of epithelial cells creates
      both a permeability barrier and cell polarity. Although based on overlapping and
      evolutionarily conserved proteins, the cell-cell contacts of nematodes, flies and
      mammals appear to differ in morphology and functional organization. Emerging
      evidence shows that the selective pore-like properties of vertebrate and
      invertebrate barriers are created by the claudin family. Similarly, assembly of
      the barriers requires a conserved set of polarity-generating protein complexes,
      particularly the PAR protein complexes.

PMID- 15196557
TI  - Specialised adaptors in immune cells.
AB  - Adaptors are modular proteins implicated in the orchestration of intracellular
      signalling pathways. Studies of adaptors specifically expressed in immune cells
      have provided clear examples of the importance of adaptor molecules in normal
      mammalian biology. Moreover, they have led to the identification of naturally
      occurring mutations in adaptors that can be linked to human diseases. Lastly,
      they have highlighted the plasticity of protein-protein interaction modules, and
      have shed light onto the mechanisms dictating the specificity of adaptor-mediated
      signals.

PMID- 15196558
TI  - Endocytosis and cancer.
AB  - Eukaryotic cells use endocytosis to internalise plasma membrane, surface
      receptors and their ligands, viruses and various extracellular soluble molecules.
      Endocytosis has been regarded as a long-term mechanism of signal attenuation via
      receptor clearance from the cell surface. However, additional, and quite
      unexpected, functions for endocytosis have emerged, which, together with its
      attenuation function, project a central role for this process in cellular
      homeostasis and control of proliferation. Subversion of endocytic control is thus
      predicted to play a causative role in hyperproliferative conditions, first and
      foremost cancer.

PMID- 15196559
TI  - beta-arrestins: traffic cops of cell signaling.
AB  - Once thought to function only in the desensitization of seven membrane spanning
      receptors (7MSRs), the ubiquitous beta-arrestin molecules are increasingly
      appreciated to play important roles in the endocytosis and signaling of these
      receptors. These functions reflect the ability of the beta-arrestins to bind an
      ever-growing list of signaling and endocytic elements, often in an agonist
      dependent fashion. One heavily studied system is that leading to MAP kinase
      activation via beta-arrestin-mediated scaffolding of these pathways in a receptor
      dependent fashion. The beta-arrestins are also found to be involved in the
      regulation of novel receptor systems, such as Frizzled and TGFbeta receptors.

PMID- 15196560
TI  - Guidance of primordial germ cell migration.
AB  - Primordial germ cells (PGCs), the progenitors of the gametes, migrate from the
      position where they are specified towards the region where the gonad develops. To
      reach their target, the PGCs obtain directional cues from cells positioned along
      their migration path. One such cue, the chemokine SDF-1, has recently been found
      to be critical for proper PGC migration in zebrafish and in mice. In Drosophila,
      too, a molecule that is structurally related to chemokine receptors and is
      important for PGC migration has been identified. The ability to visualize
      chemokine-guided migration at a high resolution in vivo in these model organisms
      provides a unique opportunity to study this process, which is relevant for many
      events in normal development and disease.

PMID- 15196561
TI  - The WASP-Arp2/3 pathway: genetic insights.
AB  - Arp2/3 complex nucleates the formation of dendritic actin filament arrays, which
      are especially prominent at the leading edges of motile cells. Recent genetic and
      other loss-of-function studies have highlighted the importance of the Arp2/3
      complex for normal cell functions, and especially for cell motility. WASP/Scar
      family proteins regulate the activity of the Arp2/3 complex, and also link it to
      several signaling pathways. Recent studies suggest that Scar is a more important
      regulator of Arp2/3 activity in actin-dependent morphological processes than
      WASP, which may have a more restricted role in specialized cellular events. It
      has also become clear that precise regulation of both Scar and WASP activity is
      of the utmost importance for their physiological functions.

PMID- 15196562
TI  - Mechanics and regulation of cytokinesis.
AB  - Recent advances are revealing quantitative aspects of cytokinesis. Further,
      genetic analyses and cell imaging are providing insights into the molecular
      dynamics of cleavage furrow ingression as well as further refining our knowledge
      of the zones of the mitotic spindle that regulate the contractile properties of
      the overlying cortex. Ultimately, however, cortical mechanics are the result of
      signals that emanate from the mitotic spindle. A genuine quantitative
      understanding of cytokinesis must include a thorough analysis of the mechanical
      properties of the cortex and how signals modify these properties to dictate a
      well-controlled, error-free cytokinesis.

PMID- 15196563
TI  - Myosin VI: a structural role in actin organization important for protein and
      organelle localization and trafficking.
AB  - Myosin VI is a member of a superfamily of actin-based motors with at least 18
      different sub-types or classes. Myosins are best known as proteins that use ATP
      hydrolysis-mediated conformational changes to move along actin filaments. Because
      of this property, some myosins, including myosins I, V, and VI, are thought to be
      transporters of vesicle or protein cargoes. Myosin VI has been implicated in many
      seemingly different processes through functional studies in flies, worms and
      mammals. In several cases, its role is not easily explained by transport along
      actin. In addition, some of the biochemical and biophysical properties of myosin
      VI suggest other mechanisms of action. In this review, we summarize recent data
      that suggest diverse functions for myosin VI and offer an explanation for how
      myosin VI may function similarly in all of them. We hypothesize that the main
      function of myosin VI is to bind tightly to actin, stabilizing actin cytoskeletal
      structures and linking actin structures to membranes and protein complexes.

PMID- 15196564
TI  - Asymmetric cell division.
AB  - Asymmetric cell division is a conserved mechanism for partitioning information
      during mitosis. Over the past several years, significant progress has been made
      in our understanding of how cells establish polarity during asymmetric cell
      division and how determinants, in the form of localized proteins and mRNAs, are
      segregated. In particular, genetic studies in Drosophila and Caenorhabditis
      elegans have linked cell polarity, G protein signaling and regulation of the
      cytoskeleton to coordination of mitotic spindle orientation and localization of
      determinants. Also, several new studies have furthered our understanding of how
      asymmetrically localized cell fate determinants, such as the Numb, a negative
      regulator Notch signaling, functions in biasing cell fates in the developing
      nervous system in Drosophila. In vertebrates, analysis of dividing neural
      progenitor cells by in vivo imaging has raised questions about the role of
      asymmetric cell divisions during neurogenesis.

PMID- 15196565
TI  - Translating G protein subunit diversity into functional specificity.
AB  - Historically, it has been assumed that the functional roles of G proteins in
      receptor recognition and effector regulation are specified by their diverse alpha
      subunits. However, the discovery of similarly diverse betagamma subunits that
      participate in both of these functional processes has called this assumption into
      question; recent work suggests that G proteins function as heterotrimers whose
      roles in particular receptor signaling pathways are determined by their specific
      alphabetagamma subunit combinations. Although much remains to be learned, the
      assembly of specific alphabetagamma subunit combinations seems to involve both
      structural and spatial factors.

PMID- 15196566
TI  - Sharing time on the fly.
AB  - The investigation of circadian clock function in Drosophila has progressed from
      the identification of clock genes to the analysis of timing mechanisms in the
      cells and tissues where these genes are expressed. As the biological context for
      investigating circadian clock systems is expanded, new features of molecular
      timing mechanisms are becoming apparent. Examples come first from studies on
      peripheral clocks, which perform local, tissue-specific functions as well as
      global functions that relate to the control of individual behavior, and second
      from the evaluation of social influences on circadian rhythms. The identification
      of inter-organismal components of the circadian system in Drosophila suggests new
      perspectives as the progression continues from the systems level to the social
      level and onwards to the level of ecosystems.

PMID- 15196567
TI  - Antibody response to Candida albicans cell wall antigens.
AB  - The cell wall of Candida albicans is not only the structure where many essential
      biological functions reside but is also a significant source of candidal
      antigens. The major cell wall components that elicit a response from the host
      immune system are proteins and glycoproteins, the latter being predominantly
      mannoproteins. Both carbohydrate and protein moieties are able to trigger immune
      responses. Proteins and glycoproteins exposed at the most external layers of the
      wall structure are involved in several types of interactions of fungal cells with
      the exocellular environment. Thus, coating of fungal cells with host antibodies
      has the potential to profoundly influence the host-parasite interaction by
      affecting antibody-mediated functions such as opsonin-enhanced phagocytosis and
      blocking the binding activity of fungal adhesins to host ligands. In this review
      we examine various members of the protein and glycoprotein fraction of the C.
      albicans cell wall that elicit an antibody response in vivo. Some of the studies
      demonstrate that certain cell wall antigens and anti-cell wall antibodies may be
      the basis for developing specific and sensitive serologic tests for the diagnosis
      of candidiasis, particularly the disseminated form. In addition, recent studies
      have focused on the potential of antibodies against the cell wall protein
      determinants in protecting the host against infection. Hence, a better
      understanding of the humoral response triggered by the cell wall antigens of C.
      albicans may provide the basis for the development of (i) effective procedures
      for the serodiagnosis of disseminated candidiasis, and (ii) novel prophylactic
      (vaccination) and therapeutic strategies to control this type of infections.

PMID- 15196568
TI  - Alveolar epithelial cells type II are major target cells for C. pneumoniae in
      chronic but not in acute respiratory infection.
AB  - Pulmonary presence of Chlamydia pneumoniae is associated with acute and chronic
      infections. We show that unapparent chlamydial infection in four out of 31
      chronic obstructive pulmonary disease (COPD) patients (12.9%) is characterized by
      a significant increase in infected alveolar epithelial cells type II (18.2 +/-
      3.5% vs. 2.3 +/- 0.9; IHC/ISH) compared to a newly established model of acute
      chlamydial infection (ACIM) in vital lung specimens from pulmonary lobectomy.
      Expression of cHSP60 demonstrated pathogen viability and virulence in the ACIM.
      We conclude that target cells differ in acute and chronic chlamydial infection
      and suggest the ACIM as a novel tool to analyze the host-pathogen-interactions in
      acute respiratory infections.

PMID- 15196569
TI  - Adjuvant can improve protection induced by OMV vaccine against Neisseria
      meningitidis serogroups B/C in neonatal mice.
AB  - Meningococcal outer membrane vesicle (OMV) vaccines are weak antigens in infants.
      This study aimed at investigating alternative adjuvants for induction of
      functional antibodies in newborn mice. Serogroup B/C anti-meningococcal vaccines,
      consisting of capsular polysaccharide from serogroup C (PSC) conjugated to OMV
      from one serogroup B serosubtype prevalent in Brazil, combined with OMV from
      another prevalent serosubtype, were tested in newborn and adult mice with the
      following adjuvants: aluminum hydroxide, MPL (monophosphoryl lipid A), Titermax
      and MF59. Total IgG, IgG avidity index determination and bactericidal assay were
      performed with sera from immunized mice. Antibodies induced against PSC in
      newborn mice showed avidity and bactericidal titers, similar to those obtained in
      adult mice, independently of the adjuvant. Evidence is presented that the
      inclusion of MF59 enhanced the immune response against OMV in newborn mice.

PMID- 15196570
TI  - The enhancing action of D-galactosamine on lipopolysaccharide-induced nitric
      oxide production in RAW 264.7 macrophage cells.
AB  - The effect of D-galactosamine (D-GalN) on nitric oxide (NO) production in
      lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells was examined. D
      GalN augmented the production of NO, but not tumor necrosis factor (TNF)-alpha in
      LPS-stimulated RAW 264.7 cells. Pretreatment of D-GalN augmented the NO
      production whereas its post-treatment did not. D-GalN augmented the NO production
      in RAW 264.7 cells stimulated with either TNF-alpha and interferon-gamma. The
      augmentation of LPS-induced NO production by D-GalN was due to enhanced
      expressions of an inducible type of NO synthase mRNA and proteins. Intracellular
      reactive oxygen species (ROS) were exclusively generated in RAW 264.7 cells
      stimulated with D-GalN and LPS. Scavenging of intracellular ROS abrogated the
      augmentation of NO production. It was therefore suggested that D-GalN might
      augment LPS-induced NO production through the generation of intracellular ROS.

PMID- 15196571
TI  - The effect of probiotic treatment with Clostridium butyricum on enterohemorrhagic
      Escherichia coli O157:H7 infection in mice.
AB  - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 has been considered as an agent
      responsible for outbreak of hemorrhagic colitis and the hemolytic uremic
      syndrome. We examined the effect of the probiotic agent Clostridium butyricum
      MIYAIRI strain 588 on EHEC O157:H7 infections in vitro and in vivo using
      gnotobiotic mice. The growth of EHEC O157:H7 and the production of Shiga-like
      toxins in broth cultures were inhibited by co-incubation with C. butyricum. The
      antibacterial effects of butyric and lactic acid were demonstrated in a dose
      dependent manner. In addition, the inhibitory effect of butyric acid on the
      viability of EHEC was demonstrated not only at low pH, but also at neutral pH
      adjusted to 7.0. Flowcytometric analysis showed that pre-incubation of Caco-2
      cells with C. butyricum and E. coli K12 inhibited the adhesion of EHEC O157:H7.
      However, the effect of C. butyricum on adhesion of EHEC to Caco-2 cells was more
      inhibitory than that of E. coli K12. Gnotobiotic mice mono-associated with EHEC
      O157:H7 died within 4-7 days after the infection. On the other hand, all
      gnotobiotic mice prophylactically pre-treated with C. butyricum survived exposure
      to EHEC O157:H7 and of the gnotobiotic mice therapeutically post-treated with C.
      butyricum, 50% survived. Both counts of EHEC O157:H7 and the amounts of shiga
      like toxins (Stx1 and Stx2) in fecal contents of gnotobiotic mice di-associated
      with EHEC O157:H7 and C. butyricum were less than those of gnotobiotic mice mono
      associated with EHEC O157:H7. These results indicated that the probiotic
      bacterium C. butyricum MIYAIRI strain 588 has preventive and therapeutic effects
      on EHEC O157:H7 infection in gnotobiotic mice.

PMID- 15196572
TI  - Candida albicans and Saccharomyces cerevisiae induce interleukin-8 production
      from intestinal epithelial-like Caco-2 cells in the presence of butyric acid.
AB  - Intestinal epithelial cells (IEC) are important in initiation and regulation of
      immune responses against numerous foreign substances including food,
      microorganisms and their metabolites in the intestine. Since the responses of IEC
      against yeasts have not yet been well understood, we investigated the effects of
      Candida albicans, Saccharomyces cerevisiae, and their cell wall components on
      interleukin-8 (IL-8) secretion by the IEC-like Caco-2 cells. Live cells of both
      yeast species stimulated Caco-2 cells to produce IL-8 only in the presence of
      butyric acid, which is a metabolite produced by intestinal bacteria. S.
      cerevisiae zymosan and glucan also enhanced IL-8 secretion. Treatment of Caco-2
      cells with butyric acid increased the expression of mRNAs coding for Toll-like
      receptor 1 (TLR1), TLR6 and dectin-1, which recognize zymosan. C. albicans
      induced more IL-8 secretion and also decreased transepithelial electrical
      resistance more rapidly than S. cerevisiae. These results suggest that both
      yeasts in the intestine stimulate the host's mucosal immune systems by
      interacting with IEC.

PMID- 15196573
TI  - Human antibody response to surface layer proteins in Clostridium difficile
      infection.
AB  - Clostridium difficile is a major cause of infectious diarrhoea in hospitalised
      patients. Surface layer proteins (SLPs) are the most abundant surface localised
      proteins expressed by C. difficile. The aim of this study was to examine the
      humoral immune response to C. difficile SLPs and its potential role in protection
      from C. difficile associated diarrhoea (CDAD). Serum antibodies to SLPs from C.
      difficile were measured by ELISA in a cohort of 146 patients (55 patients with
      CDAD, 34 asymptomatic carriers, and 57 controls). No significant difference was
      detected in serum IgM, IgA or IgG antibody levels between cases, carriers or
      control groups at any of the time points tested. However, patients with recurrent
      episodes of C. difficile diarrhoea had significantly lower IgM-anti-SLP levels
      than patients with a single episode on days 1, 3, 6 and 9 (p = 0.05, p = 0.009, p
      = 0.02, p = 0.049). The adjusted odds ratio for recurrent diarrhoea associated
      with a low day 3 serum IgM anti-SLP antibody level was 24.5 (95% confidence
      interval; 1.6-376.3). Further studies which examine the specific anti-SLP
      antibody responses to the colonising strain are warranted to determine if immune
      responses to C. difficile SLPs play a role in protection from CDAD.

PMID- 15196574
TI  - The interaction of F4 fimbriae with porcine enterocytes as analysed by surface
      plasmon resonance.
AB  - Fimbriae often play a prominent role in anchoring bacterial cells to host tissue
      and mediate the first step in pathogenesis. As a consequence, there is a
      continuous development of new strategies to block the binding of fimbriae to
      their specific receptor on host cells. The present study demonstrates the
      specific interaction of F4 (K88) fimbriae and porcine enterocytes using a real
      time biomolecular interaction analysis system (BIAcore 3000), based on the
      principles of surface plasmon resonance (SPR). This method offers new
      opportunities to screen therapeutics for prevention of adhesion and subsequent
      disease without receptor purification.

PMID- 15196575
TI  - Co-administration of immunomodulator tuftsin and liposomised nystatin can combat
      less susceptible Candida albicans infection in temporarily neutropenic mice.
AB  - In order to develop a prospective chemotherapeutic agent against opportunistic
      infections, it is important to know that host factors such as degree of
      immunological debility as well as recovery of immune functions to normality may
      contribute significantly to a successful elimination of the pathogens. We
      demonstrated previously that concomitant delivery of antimicrobial agents and
      immunomodulators to the pathogen harbouring-host contributes to the complete
      elimination of the deep-seated fungal infections (aspergillosis and candidiasis)
      in animals with normal immune status. Considering that neutropenic hosts are the
      main targets of such infections, it can be argued about the potential of the
      immunomodulator-based therapy in subjects with non-functional immune system. To
      resolve the hypothesis, we studied the role of immunomodulator tuftsin against
      experimental murine candidiasis in temporarily neutropenic Balb/c mice. The
      neutropenic mice were challenged with an isolate of Candida albicans that was
      showing less susceptibility to both free and liposomised-amphotericin B. The co
      administration of tuftsin increased the efficiency of liposomised-polyene
      antibiotics (nystatin and amphotericin B) against experimental murine candidiasis
      in immunocompromised Balb/c mice. Pretreatment with liposomised tuftsin prior to
      C. albicans infection clearly enhanced protection against candidiasis, suggesting
      a prophylactic role of tuftsin in normal and temporarily neutropenic animals.

PMID- 15196577
TI  - TUNEL and limited immunophenotypic analyses of apoptosis in paucibacillary and
      multibacillary leprosy lesions.
AB  - Some mycobacterial infections, such as tuberculosis, are characterized by
      apoptosis of infected or by-stander mononuclear immune cells. For localized
      (paucibacillary, PB) and disseminated (multibacillary, MB) leprosy, characterized
      by polarized Th1-like vs. Th2-like immune responses, respectively, little is
      known about lesional apoptosis. We analyzed sections of paraffin-embedded,
      untreated leprosy lesions from 21 patients by an indirect immunofluorescent
      terminal deoxynucleotide-transferase-mediated dUTP-digoxigenin nick end labeling
      (TUNEL) assay. Some TUNEL (+) PB sections were then reacted with phycoerythrin
      conjugated (red) antibodies against T cells, monocytes, or antigen-presenting
      (Langerhans) cells. TUNEL (+) bodies were detected in 9 of 16 PB lesions (56%)
      and in 1 of 5 MB lesions (20%). Some TUNEL (+) bodies in PB disease were CD3+ (T
      cell), as well as CD4+ (T-helper) or CD8+ (T-cytotoxic). Apoptosis characterizes
      PB and MB leprosy lesions and may be more frequent in PB disease. In PB disease,
      some TUNEL (+) bodies may derive from T cells.

PMID- 15196576
TI  - Colony blot assay: a useful method to detect multiple pneumococcal serotypes
      within clinical specimens.
AB  - The efficacy of pneumococal conjugate vaccines in young children may be
      complicated by serotype replacement. We developed a colony blot assay which
      enables the identification of re-colonization with novel serotypes (replacement),
      overgrowth by minor co-colonizing serotypes or suppression of previously
      predominant vaccine serotype strains as a result of vaccination. This method
      allows the identification of multiple serotypes in a single specimen in a ratio
      of 1:1000. In order to demonstrate the potential of our method, we investigated
      the consecutive nasopharyngeal samples of 26 children who had shown a shift in
      pneumococcal colonization after conjugate vaccination. Mixed colonization was
      found once in 15 pre-vaccination samples and four times in 26 post-vaccination
      samples. In the remaining children 'true replacement' had presumably occurred.
      Hence, we conclude that the colony blot assay is an easy to apply method, which
      allows the identification of different pneumococcal serotypes within single
      clinical specimens.

PMID- 15196578
TI  - Mucoadhesion dependence of pharmaceutical polymers on mucosa characteristics.
AB  - Well known mucoadhesive polymers such as Carbopol 974P and Pharmacoat 606 and
      three different mucosas (sublingual, oesophageal and duodenal bovine) were used
      to verify how the mucoadhesive properties of materials may depend on the mucosa
      characteristics and if a polymer may reveal more mucoadhesive than another and
      vice versa by changing the type of interacting mucosa. So, tablets of Carbopol
      974P and Pharmacoat 606 were prepared and their mucoadhesion on the three mucosas
      was set in terms of maximum load and work of detachment, using a texture
      analyzer. At the same time, mucosas were characterized by immunohistochemical
      techniques and lectin histochemistry. Results obtained from the Tensile test
      analyses show that the adhesive power of the two polymers is different in the
      three mucosas. Particularly, in the sublingual mucosa, Carbopol was more
      mucoadhesive than Pharmacoat. On the contrary, Pharmacoat was more mucoadhesive
      than Carbopol in duodenal mucosa. The significantly different behavior of
      polymers was correlated with the desquamation layer thickness and the
      differential sialic acid and fucose exposition in the targeted mucosas.

PMID- 15196579
TI  - The influence of humidity on the aerosolisation of micronised and SEDS produced
      salbutamol sulphate.
AB  - The influence of storage humidity on the aerosolisation efficiency of micronised
      and supercritical fluid salbutamol sulphate formulations (containing a lactose
      carrier) were investigated using the twin stage impinger (TSI). Storage humidity
      had a significant effect on the aerosolisation efficiency of both micronised and
      solution enhanced dispersion by supercritical fluids (SEDS) salbutamol sulphate
      (ANOVA P <0.05), suggesting capillary interactions to be an important factor when
      considering formulation performance. Furthermore, significant differences between
      the aerosolisation performance of micronised and SEDS salbutamol sulphate were
      observed at elevated humidities (>63% RH) (Fishers pairwise P <0.05). It is
      suggested that such variations may be due to differences in physical stability of
      the micronised and SEDS produced material. Dynamic vapor sorption, and atomic
      force microscopy (AFM) phase imaging suggested the micronised material to contain
      amorphous content that was most likely present on the micronised particulate
      surfaces. Thus, at high humidity, surface amorphous regions may have the ability
      to re-crystallize and effectively 'fuse' to the lactose carrier surface. This
      would potentially reduce the ability for the micronised material to be
      aerosolized and thus result in a greater decrease in FPF when compared to SEDS
      produced material at equivalent RH.

PMID- 15196580
TI  - Complexation of the sunscreen agent, phenylbenzimidazole sulphonic acid with
      cyclodextrins: effect on stability and photo-induced free radical formation.
AB  - The interaction between the sunscreen agent, phenylbenzimidazole sulphonic acid
      (PBSA) and hydrophilic alpha-, beta-, and gamma-cyclodextrin derivatives was
      investigated under acidic conditions (pH 4.0) by phase-solubility analysis. Among
      the available cyclodextrins, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and
      random methyl-beta-cyclodextrin (RM-beta-CD) had the greatest solubilizing
      activity. The complexation of the sunscreen agent with HP-beta-CD and RM-beta-CD
      was confirmed by nuclear magnetic resonance spectroscopy. Solid-phase
      characterization of the PBSA/cyclodextrin systems by X-ray diffractometry defined
      the most appropriate method (co-evaporation) and cyclodextrin concentration (10
      fold molar excess) for the preparation of a stable complexed form of PBSA. Long
      term stability studies demonstrated that the decrease of the sunscreen level in
      emulsion preparations (pH 4.0) was almost completely suppressed by HP-beta-CD, RM
      beta-CD being less effective. Moreover, the irradiation-induced decomposition of
      PBSA in the emulsion vehicle was markedly reduced by complexation with HP-beta-CD
      (the extent of degradation was 3.9% for the complex compared to 9.1% for
      uncomplexed PBSA), whereas RM-beta-CD had no significant influence. In addition,
      electron paramagnetic resonance (EPR) spin-trapping studies showed that the
      inclusion of the sunscreen agent into the HP-beta-CD cavity completely inhibited
      the formation of free-radicals generated by PBSA on exposure to simulated
      sunlight, thereby suppressing its photosensitising potential.

PMID- 15196581
TI  - Theoretical analysis of drug release into a finite medium from sphere ensembles
      with various size and concentration distributions.
AB  - Release kinetics for heterogeneous sphere ensembles with a dissolved drug, i.e.,
      initial drug loading below or equal to the drug solubility in the matrix, in a
      finite external medium was modeled with consideration of heterogeneity among and
      within spheres. Numerical solutions were obtained using the finite element method
      for sphere ensemble with normal or log-normal distribution of particle size or
      initial drug loading among spheres. Exact series solutions were derived for
      ensembles with various initial loading distributions within spheres, namely
      linear, quadratic, sigmoidal and uniform distribution, using their mean or
      average radii. Simplified solutions retaining only one term of the series for non
      uniform distributions and three terms for uniform distribution were suggested
      because of their good approximation to the exact solution. The results of finite
      element analysis showed that the release rate of an ensemble decreased with
      increasing standard deviation of particle size. Using weight-average radii in the
      exact solution gave a prediction of release profile closer to that from the
      actual size distribution than using mean radii. The three non-uniform loading
      patterns within spheres all showed reduced initial burst and release rate,
      leading to more steady release rates than uniform loading, among which the
      sigmoidal distribution offered the best near-zero order release. Non-uniform
      initial loading among spheres seemed to have insignificant influence on the
      release profiles. The volume ratio of liquid to a sphere ensemble played an
      important role in release kinetics. The derived analytical solutions are
      applicable to multiple spheres or a single sphere in a finite medium or in a
      perfect sink.

PMID- 15196582
TI  - Prediction of drug-membrane interactions by IAM-HPLC: effects of different
      phospholipid stationary phases on the partition of bases.
AB  - The chromatographic capacity factors of 39 neutral and basic compounds were
      measured on an immobilized artificial membrane-phosphatidylcholine-drug discovery
      (IAM-PC-DD) HPLC column, and the values compared with both octanol/water
      partition coefficients and capacity factors previously obtained on an IAM-PC-MG
      column. These two columns differ in their lipidic phase, since the IAM-PC-MG
      phase is made of phosphatidylcholine as found in biomembranes, whereas the
      glycerol linker is absent in the IAM-PC-DD phase. We found that the two phases
      interact differently with basic compounds at different degrees of ionization. On
      the IAM-PC-MG column, ionized compounds are as strongly or more strongly retained
      than isolipophilic neutral compounds. In contrast, their retention on the IAM-PC
      DD column is less strong than, or at most as strong as, that of isolipophilic
      neutral compounds. The IAM-PC-MG data appear as better predictors of the
      interactions between drugs and biological membranes. Indeed, they correlate
      better than the IAM-PC-DD data with partitioning in both biological membrane and
      liposomes; moreover, they are better correlated with biological activities from
      the literature. These results suggest that even modest modifications in the
      structure of IAM phospholipids can have a major effect on the retention of basic
      compounds. We conclude that an acceptable IAM-HPLC estimate of the interactions
      between biomembranes and basic compounds should rely on stationary phases that
      reproduce the structure of natural phospholipids.

PMID- 15196583
TI  - Getting new bronchodilator compounds from molecular topology.
AB  - Molecular topology has been used to select new lead bronchodilator compounds. The
      main advantage of this method, as compared to others frequently used, is that it
      does not require a previous explicit knowledge of the mechanism of action (MOA)
      of the compounds analyzed. A large database (12,000 chemicals) has been examined
      in this study to find less than 5% compounds with bronchodilator activity. After
      removing those compounds already described as bronchodilators, we present here
      the results for 20 among these compounds, some of them showing other
      pharmacological activities. Some of the compounds selected in this study showed
      higher relaxation and higher potency than theophylline, which is the reference
      drug used in the bronchodilator assay performed. For instance, tetrahydro
      papaveroline showed significantly higher values than theophylline (93.9% versus
      77.0% and pD2=7.30 versus pD2=4.69, respectively). Other compounds, although
      eliciting small or no relaxation at 0.1mM, produced larger relaxation at higher
      concentrations (1mM). In conclusion, the molecular topology based approach used
      in this work has demonstrated to be effective in the search of new
      bronchodilators.

PMID- 15196584
TI  - Sorption of nicotine to cellulose powders.
AB  - The purpose of this study was to investigate the influence of the crystallinity,
      surface area, and pore volume of cellulose powders on the loading, release, and
      stability of nicotine. Four different types of cellulose powders with varying
      crystallinity index, surface area, and pore volume were produced and
      characterized. The powders were loaded with nicotine by rotary evaporation from
      an ethanol solution and by adsorption from nicotine-saturated air. The release of
      nicotine from loaded cellulose powders into both a passing airstream and water
      was investigated by UV spectroscopy. A 3-month stability study was conducted and
      the total sum of nicotine oxidation products was measured. Nicotine loading and
      release were independent of cellulose powder crystallinity, whereas it was
      possible to load more nicotine on the cellulose powder with a large surface area
      and pore volume. Release into water was very rapid and almost complete for all
      samples. Nicotine was most stable when loaded on the powder with a large surface
      area and pore volume. Highly porous cellulose matrices could be useful for
      stabilization and handling of both nicotine and other liquid active
      pharmaceutical ingredients.

PMID- 15196585
TI  - Population pharmacokinetic modelling of BIBN 4096 BS, the first compound of the
      new class of calcitonin gene-related peptide receptor antagonists.
AB  - Pharmacokinetics (PK) of the calcitonin gene-related (CGRP) peptide receptor
      antagonist BIBN 4096 BS, the first compound of this new class tested in humans,
      has been evaluated combining the data from a phase I study performed in healthy
      volunteers and a phase IIa study conducted in migraine patients. A total of 94
      individuals with a total of 556 plasma samples contributed to the analysis.
      Subjects received a single dose of 0.25, 0.5, 1, 2.5, 5 or 10 mg BIBN 4096 BS
      administered in a 10 min i.v. infusion. Blood samples were obtained at selected
      times up to 12 h. Disposition of BIBN 4096 BS was best described with a three
      compartment body model with first order elimination. BIBN 4096 BS showed a
      moderate degree (between 30 and 50%) of inter-subject variability in the apparent
      volume of distribution of the central compartment (V1), total plasma clearance
      (CL), distribution clearance between the central and deep compartment, and the
      apparent volume of distribution of the shallow compartment. Typical estimates of
      V1 were significantly (P <0.01) lower in healthy volunteers (7.16 versus 9.95 L),
      and typical estimates of CL were significantly lower in subjects receiving oral
      contraceptives (11.4 versus 17.1 L/h), although the absolute reduction in the
      unexplained inter-subject variability was negligible (4%). Computer simulations
      showed that the above mentioned covariates lack clinical significance. In
      conclusion, the pharmacokinetics of BIBN 4096 BS was independent of the dose and
      not altered by the tested covariates to a clinically significant degree.

PMID- 15196586
TI  - Biowaiver extension potential to BCS Class III high solubility-low permeability
      drugs: bridging evidence for metformin immediate-release tablet.
AB  - The biopharmaceutics classification system (BCS) allows biowaiver for rapid
      dissolving immediate-release (IR) products of Class I drugs (high solubility and
      high permeability). The possibility of extending biowaivers to Class III high
      solubility and low permeability drugs is currently under scrutiny. In vivo
      bioequivalence data of different formulations of Class III drugs would support
      such an extension. The objective of this work was to demonstrate the
      bioequivalence of two marketed IR tablet products of a Class III drug, metformin
      hydrochloride, that are rapidly dissolving and have similar in vitro dissolution
      profiles. The effect of race on the systemic exposure of metformin was also
      explored. A randomized, open-label, two-period crossover study was conducted in
      12 healthy Chinese male volunteers. Each subject received a single-dose of 500 mg
      of each product after an overnight fasting. The plasma concentrations of
      metformin were followed for 24 h. No significant formulation effect was found for
      the bioequivalence metrics: areas under concentration-time curve (AUC0-t, AUC0
      infinity) and maximal concentration (Cmax). The 90% confidence intervals for the
      ratio of means were found within the acceptance range of 80-125% for the log
      transformed data. Based on these results, it was concluded that the two IR
      products are bioequivalent. The pharmacokinetic parameters of metformin in
      Chinese for both products were similar and were in good agreement with those
      reported for metformin IR tablets in other ethnic populations. This study serves
      as an example for supporting biowaiver for BCS Class III drugs.

PMID- 15196587
TI  - Compaction of enteric-coated pellets: influence of formulation and process
      parameters on tablet properties and in vivo evaluation.
AB  - The aim of this study was to investigate the influence of formulation and
      compression parameters on the properties of tablets, containing enteric-coated
      pellets, and on the integrity of the enteric polymer of the individual pellets
      after compression. In addition the piroxicam plasma concentrations were
      determined after single and multiple oral administration of powder, pellet and
      tablet formulations at a dose of 0.3 mg piroxicam/kg bodyweight to dogs. Tablets
      consisted of enteric-coated pellets (containing 2.5% (w/w) piroxicam in
      combination with microcrystalline cellulose and sodium carboxymethylcellulose
      (using Avicel PH 101 and Avicel CL 611 in a ratio of 1-3), cushioning waxy
      pellets and 10% Kollidon CL (as an external disintegrator). From the D-optimality
      experimental design it was concluded that the ratio of coated pellets to
      cushioning pellets (CoP/CuP) affected all tablet properties evaluated. Variation
      of the pellet size and the CoP/CuP ratio resulted in different in vitro tablet
      disintegration times. Enteric coating of the pellets or compression of the coated
      pellets did not have a significant influence (P >0.05) on AUC(0-->72 h). Cmax
      values obtained after oral administration of coated pellets and compressed coated
      pellets were significantly lower than for the other formulations. Differences in
      in vitro tablet disintegration times were not reflected in the onset of the
      piroxicam plasma concentrations. A dosing interval of 48 h prevented piroxicam
      accumulation following multiple dose administration.

PMID- 15196588
TI  - Development and in vivo evaluation of an oral insulin-PEG delivery system.
AB  - Insulin-monomethoxypoly(ethylene glycol) derivatives were obtained by preparation
      of mono- and di-terbutyl carbonate insulin derivatives, reaction of available
      protein amino groups with activated 750 Da PEG and, finally, amino group de
      protection. This procedure allowed for obtaining high yield of insulin-1PEG and
      insulin-2PEG. In vivo studies carried out by subcutaneous injection into diabetic
      mice demonstrated that the two bioconjugates maintained the native biological
      activity. In vitro, PEGylation was found to enhance the hormone stability towards
      proteases. After 1 h incubation with elastase, native insulin, insulin-1PEG and
      insulin-2PEG undergo about 70, 30 and 10% degradation, respectively, while in the
      presence of pepsin protein degradation was 100, 70 and 50%, respectively. The
      attachment of low molecular weight PEG did not significantly (P >0.05) alter
      insulin permeation behavior across the intestinal mucosa. Insulin-1PEG was
      formulated into mucoadhesive tablets constituted by the thiolated polymer
      poly(acrylic acid)-cysteine. The therapeutic agent was sustained released from
      these tablets within 5 h. In vivo, by oral administration to diabetic mice, the
      glucose levels were found to decrease of about 40% since the third hour from
      administration and the biological activity was maintained up to 30 h. According
      to these results, the combination of PEGylated insulin with a thiolated polymer
      used as drug carrier matrix might be a promising strategy for oral insulin
      administration.

PMID- 15196589
TI  - How do roll compaction/dry granulation affect the tableting behaviour of
      inorganic materials? Microhardness of ribbons and mercury porosimetry
      measurements of tablets.
AB  - The effect of roll compaction/dry granulation on the ribbon and tablet properties
      produced using different magnesium carbonates was evaluated. The ribbon
      microhardness and the pore size distribution of tablets were used as evaluation
      factors. Increasing the specific compaction force resulted in higher
      microhardness for ribbons prepared with all four magnesium carbonates accompanied
      with decreased part of fine. Consequently, the corresponding produced tablets
      displayed a lower tensile strength. A possible correlation between the particle
      shape, surface area and the resulting pore structure of tablets produced with the
      four different types of magnesium carbonate was observed. The tensile strength of
      tablets prepared using granules was lower than tensile strength of tablets
      produced using starting materials. The partial loss of compactibility resulted in
      a demand of low loads during roll compaction. However, the impact of changes in
      the material properties during the roll compaction depended greatly on the type
      of magnesium carbonate, the specific compaction force and the tableting pressure
      applied.

PMID- 15196590
TI  - Biochemical and spectrophotometric significance of advanced oxidized protein
      products.
AB  - We previously described the presence of advanced oxidation protein products
      (AOPP), a novel marker of oxidative stress in the plasma of hemodialyzed patients
      (HD). The present study was carried out to further investigate how
      myeloperoxidase (MPO)-catalyzed reactions could contribute to AOPP generation in
      the plasma. First, patterns of plasma protein oxidation obtained after in vitro
      incubation of control plasma with hypochlorous acid (HOCl) were compared to those
      from HD patients and control plasma. The use of various analytical techniques
      enabled localising and identifying the main oxidized proteins with albumin (HSA)
      after protein separation by size-exclusion chromatography and SDS-PAGE
      electrophoresis. The characterization of the oxidation level of the individual
      plasma proteins in terms of carbonyl groups and 3-nitrotyrosine formations was
      performed by immunoblotting. Secondly, to highlight the significance of AOPP
      index monitored by spectrophotometry, spectra were established for plasma
      fractions from HD patients and compared to data for control plasma and HOCl
      treated plasma. The corresponding absorbance difference spectra were matched with
      external standards such as dityrosine, nitrotyrosine and pentosidine and
      elaborated chromophoric probe models. Indeed, HSA was chlorinated by HOCl reagent
      or HOCl generated via the MPO/H(2)O(2)/Cl(-) system and was nitrated by
      tetranitromethane. Increased absorbances at the range of 340 nm were observed
      both with chlorinated and nitrated HSA. Finally, our results indicate that HOCl,
      and not NO(2)(*), generated via MPO activity, could represent one of the pathways
      for AOPP production in plasma proteins exposed to activated phagocytes.

PMID- 15196591
TI  - Causative factors behind poloxamer 188 (Pluronic F68, Flocor)-induced complement
      activation in human sera. A protective role against poloxamer-mediated complement
      activation by elevated serum lipoprotein levels.
AB  - Poloxamer 188 is a complex polydisperse mixture of non-ionic macromolecules.
      Adverse non-IgE-mediated hypersensitivity reactions occur in some individuals
      following intravenous injection of poloxamer 188-based pharmaceuticals,
      presumably via complement activation. Here we have delineated potential causal
      chemical and biological interactive factors behind poloxamer 188-induced
      complement activation in human serum specimens. We identified the molecular
      constituents inherent in poloxamer 188 preparations and studied their effect on
      generation of the two complement split products, SC5b-9 and Bb. Poloxamer 188
      activated complement at sub-micellar concentrations and the results indicated the
      potential involvement of all three known complement activation pathways. The
      poloxamer-induced rise of SC5b-9 in human sera was abolished in the presence of a
      recombinant truncated soluble form of complement receptor type 1, thus confirming
      the role of C3/C5 convertases in the activation process. Poloxamer 188-mediated
      complement activation is an intrinsic property of these macromolecules and was
      independent of the degree of sample polydispersity, as opposed to other non
      polymeric constituents. Poloxamer 188 preparations also contained unsaturated
      chains of diblock copolymers capable of generating SC5b-9 in human sera; this
      effect was terminated following the removal of double bonds by catalytic
      hydrogenation. By quasi-elastic light scattering, we established interaction
      between poloxamer and lipoproteins; interestingly, poloxamer-induced rise in SC5b
      9 was significantly suppressed when serum HDL and LDL cholesterol levels were
      increased above normal to mimic two relevant clinical situations. This
      observation was consistent with previously reported data from patients with
      abnormal or elevated lipid profiles where no or poor complement activation by
      poloxamer 188 occurred. Our findings could provide the basis of novel approaches
      to the prevention of poloxamer-mediated complement activation.

PMID- 15196592
TI  - Cysteamine prevents and reverses the inhibition of pyruvate kinase activity
      caused by cystine in rat heart.
AB  - Cystinosis is a disorder associated with excessive lysosomal cystine accumulation
      secondary to defective cystine efflux. Patients affected by this disease develop
      a variable degree of symptoms depending on the involved tissues. Accumulation of
      cystine in myocardium may lead to heart failure. However, the mechanisms by which
      cystine is toxic to the tissues are not fully understood. Considering that
      thiolic enzymes like pyruvate kinase (PK) may be altered by disulfides like
      cystine, the main objective of the present study was to investigate the effect of
      cystine on PK activity in the heart of developing rats. We performed kinetic
      studies and investigated the effects of reduced glutathione (GSH), a biologically
      occurring thiol groups protector, and cysteamine, the drug used for cystinosis
      treatment, on the enzyme activity. We observed that cystine inhibited the enzyme
      activity non-competitively in a dose- and time-dependent way. We also observed
      that GSH and cysteamine fully prevented and reversed the inhibition caused by
      cystine, suggesting that cystine inhibits PK activity by oxidation of the
      sulfhydryl groups of the enzyme. Although there is no definite proof of cystine
      within cytoplasm, there is indirect proof t it is able to escape lysosomes and
      come in contact with PK. Considering that cysteamine is used in patients with
      cystinosis because it causes parenchymal organ cystine depletion, the present
      data provide a possible new effect for this drug.

PMID- 15196593
TI  - Identification of changes in the transcriptome profile of human hepatoma HepG2
      cells stimulated with interleukin-1 beta.
AB  - Interleukin-1 (IL-1) is the principal pro-inflammatory cytokine participating in
      the initiation of acute phase response. Human hepatoma HepG2 cells were exposed
      to 15 ng/ml of IL-1beta for times ranging from 1 to 24 h and the total RNA was
      isolated. Then cDNA was obtained and used for differential display with 10
      arbitrary primers and 9 oligo(dT) primers designed by Clontech. Validation of
      observed changes of differentially expressed known genes was carried out by RT
      PCR or Northern blot analysis. Out of 90 cDNA strands modulated by IL-1, 46 have
      been successfully reamplified and their sequencing indicates that they represent
      36 different cDNA templates. By GenBank search, 26 cDNA clones were identified as
      already known genes while 10 showed no homology to any known gene. The identified
      transcripts modulated by IL-1 in HepG2 cells code for intracellular proteins of
      various function: trafficking/motor proteins (3 genes), proteins participating in
      the translation machinery or posttranscriptional/posttranslational modifications
      (7 genes), proteases (1 gene), proteins involved in metabolism (6 genes),
      activity modulators (3 genes), proteins of the cell cycle machinery (2 genes) and
      those functionally unclassified (4 genes). Majority of genes responded to IL-1
      within 1 to 6 h (early genes), while two were late response genes (12-24 h) and
      four showed prolonged response over the whole 24-h period. Most of the observed
      changes of expression were in the range of two- to threefold increase in
      comparison to control untreated cells. Among identified genes, no typical
      secretory acute phase protein was found. The obtained results suggest that IL-1
      affects the expression of several genes in HepG2 cells, especially those engaged
      in the synthesis and modifications of proteins.

PMID- 15196594
TI  - Differential expression of thyroperoxidase mRNA splice variants in human thyroid
      tumors.
AB  - The levels of human thyroperoxidase (hTPO) mRNA expression and the rates of hTPO
      mRNA with alternatively spliced exons 10, 14, and 16 were analyzed in normal,
      benign, and malignant thyroid tissues (13 normal thyroid tissues, 9 adenomas, 4
      papillary carcinomas, 11 follicular variant of papillary carcinomas, 16 minimally
      invasive follicular carcinomas, 6 widely invasive follicular carcinomas) using a
      semi-quantitative reverse-transcription polymerase chain reaction procedure. The
      level of hTPO mRNA decreased in the follicular variant of papillary carcinomas
      and in minimally invasive follicular carcinomas and was more heterogeneous in the
      other pathological tissues than in normal tissues. Based on the mean values
      recorded, the splicing of exons 10 and 16 increased by at least 50% in all the
      carcinomas, as well as in the benign tissues in the case of exon 10. By contrast,
      no significant increase was observed in the splicing of exon 14 except in the
      case of the follicular variant of papillary carcinomas. In conclusion, the
      results of this study show that the splicing of hTPO increases in benign and
      malignant thyroid tissues. This event might partly explain the decrease in both
      the quantity and the level of activity of hTPO observed in thyroid cancer due to
      the loss of stability of the spliced isoforms. In addition, an increase in the
      alternative splicing of other mRNAs may contribute to the process of malignancy.

PMID- 15196595
TI  - Fluoride-induced changes to proteoglycan structure synthesised within the dentine
      pulp complex in vitro.
AB  - Fluoride is known to influence mineralisation patterns within dentine, where
      alterations in the post-translational modification of proteoglycans (PG) have
      been proposed as an implicating factor. In light of recent studies elucidating
      changing PG profiles in the transition of predentine to mineralised dentine, this
      study investigates the influence of fluoride on the major PG populations
      (decorin, biglycan and versican) within the pulp, predentine and dentine. Tooth
      sections from rat incisors were cultured for 14 days in the presence 0, 1 and 6
      mM sodium fluoride and the PG extracted from the pulp, predentine and dentine
      matrices. PG species and corresponding metabolites were identified by their
      immuno-reactivity to antibodies against decorin, biglycan and versican. Component
      glycosaminoglycan chains were characterised with respect to their nature, chain
      length and disaccharide composition. Levels of PG extracted from pulp and
      predentine were reduced, particularly for biglycan. Fluoride did not influence
      levels of decorin or versican within predentine or dentine, although the
      processing of these macromolecules within pulp and predentine was affected,
      particularly at higher fluoride concentrations. Levels of dermatan sulfate were
      reduced within pulp and predentine, although the effect was less pronounced for
      predentine. Fluoride reduced sulfation of glycosaminoglycan chains within pulp
      and predentine tissues, with a notable reduction in Deltadi6S evident. In all
      three tissues, glycosaminoglycan chain length was reduced. Considering the
      various roles for PG in the dentine-pulp complex, either directly or indirectly
      in the mineralisation process, changes in the synthesis, structure and processing
      of the different PG species within the pulp, predentine and dentine matrices
      provides a further molecular explanation for the altered mineralisation patterns
      witnessed during fluorosis.

PMID- 15196596
TI  - Matrix proteoglycans are markedly affected in advanced laryngeal squamous cell
      carcinoma.
AB  - Proteoglycans (PGs) are implicated in the growth and progression of malignant
      tumors. In this study, we examined the concentration and localization of PGs in
      advanced (stage IV) laryngeal squamous cell carcinoma (LSCC) and compared with
      human normal larynx (HNL). LSCC and HNL sections were examined
      immunohistochemically with a panel of antibodies, and tissues extracts were
      analyzed by biochemical methods including immunoblotting and high performance
      liquid chromatography (HPLC). The results demonstrated significant destruction of
      cartilage in LSCC, which was followed by marked decrease of aggrecan and link
      protein. In contrast to the loss of aggrecan in LSCC, accumulation of versican
      and decorin was observed in the tumor-associated stroma. Biochemical analyses
      indicated that aggrecan, versican, decorin and biglycan comprise the vast
      majority of total PGs in both healthy and cancerous tissue. In LSCC the absolute
      amounts of KS/CS/DS-containing PGs were dramatically decreased about 18-fold in
      comparison to HNL. This decrease is due to the loss of aggrecan. Disaccharide
      analysis of CS/DSPGs from LSCC showed a significant reduction of 6-sulfated Delta
      disaccharides (Deltadi-6S) with a parallel increase of 4-sulfated Delta
      disaccharides (Deltadi-4S) as compared to HNL. The obtained data clearly
      demonstrate that tumor progression is closely related to specific alteration of
      matrix PGs in LSCC. The altered composition of PGs in cartilage, as well as in
      tumor-associated stroma, is crucial for the biological behaviour of cancer cells
      in the diseased tissue.

PMID- 15196597
TI  - Impaired mitochondrial respiratory chain and bioenergetics during chagasic
      cardiomyopathy development.
AB  - In this study, we evaluated the activities of respiratory chain complexes and
      oxidative phosphorylation (OXPHOS) capacity of the heart to gain insights into
      the pathological significance of mitochondrial dysfunction in chagasic
      cardiomyopathy (CCM). In a murine model of Trypanosoma cruzi infection,
      biochemical and histochemical analysis of the cardiac mitochondria revealed
      deficiency of the respiratory chain complexes (CI-CV) in infected mice; the
      inhibition of CI activity was more pronounced in the acute infection phase, CIII
      was constitutively repressed throughout the infection and disease phase, and the
      CV defects appeared in chronic phase only. A substantial decline in cardiac mtDNA
      content (54-60%) and mitochondria-encoded transcripts (50-65%) with disease
      development indicated that the alterations in mtDNA contribute to the
      quantitative deficiencies in respiratory chain activity in chagasic hearts. The
      observations of a selective inhibition of redox-sensitive CI and CIII complexes
      that are also the site of free radical generation in mitochondria, and the
      decline in cardiac mtDNA content in infected mice, all support the free radical
      hypothesis of mitochondria dysfunction in CCM. Consequently, OXPHOS-mediated ATP
      synthesis capacity of the cardiac mitochondria in infected mice was substantially
      reduced (37-50%), suggesting an energy homeostasis in the affected tissue.

PMID- 15196598
TI  - The role of personality disorders on drug dependence treatment outcomes following
      inpatient detoxification.
AB  - AIMS: The present 6 month follow-up study was conducted to investigate the
      possible influence of comorbid personality disorders on drug treatment, as well
      as associated psychopathology and HIV-related risk behaviors outcomes. SUBJECTS
      AND METHODS: Data were collected initially from a consecutive sample of 74
      patients with a diagnosis of opiate abuse or dependence, admitted for inpatient
      detoxification. RESULT: During intake, 80.9% of patients reported at least one
      HIV-related risk behavior in the previous 6 months. Not using condoms during
      sexual intercourse was the most common and the only risk behavior that showed a
      statistically significant reduction over the follow-up period. A total of 58.1%
      of subjects had at least one personality disorder (PD). Borderline PD was the
      most prevalent. However, antisocial PD was the only PD that influenced substance
      use outcomes. The presence of this diagnosis increased the chance of worse opiate
      use outcomes, but decreased likelihood of not using condoms. Patients with low
      obsessive-compulsive PD dimensional scores showed a significant increase in the
      number of risk behaviors. However, these influences were only seen at the 3-month
      follow-up assessment. CONCLUSIONS: These results suggest that personality
      disorders need to be considered when planning effective interventions for opiate
      dependent individuals and when preparing and evaluating HIV risk-reduction
      interventions, particularly for the more severe substance dependent patients.

PMID- 15196599
TI  - Temperament and character inventory (TCI) personality profile in metamphetamine
      abusers: a controlled study.
AB  - We applied the temperament and character inventory (TCI) personality
      questionnaire in 41 inpatients dependent on metamphetamine, and 35 controls.
      Novelty seeking, harm avoidance and self-transcendence were significantly higher,
      and persistence, self-directedness and cooperativeness were significantly lower
      in the patients than in the healthy volunteers. The detected differences may be
      important for prevention and treatment.

PMID- 15196601
TI  - Clinical characteristics and treatment response in poor and good insight
      obsessive-compulsive disorder.
AB  - The DSM-IV criteria recognize the existence of obsessive-compulsive disorder
      (OCD) with poor insight. However, there is paucity of literature on the clinical
      correlates and treatment response in poor and good insight OCD. In this study,
      insight is measured by using the Brown Assessment of Beliefs Scale (BABS)
      developed specifically to assess insight. One hundred subjects with DSM-IV OCD
      were ascertained from the OCD clinic of a large psychiatric hospital in India.
      All subjects were evaluated extensively by using structured instruments and
      established measures of psychopathology. The subjects were treated with adequate
      doses of drugs for adequate period. The results showed that 25% of the subjects
      had poor insight. Poor insight was associated with earlier age-at-onset, longer
      duration of illness, more number of obsessive-compulsive symptoms, more severe
      illness and higher comorbidity rate, particularly major depression. Of the
      subjects who were treated adequately (N = 73), 44 (60%) were treatment
      responders. Poor insight was associated with poor response to drug treatment. In
      the step-wise logistic regression analysis, baseline BABS score was highly
      predictive of poor treatment response. Poor insight appears to be associated with
      specific clinical correlates and poor response to drug treatment. Further studies
      are needed in larger samples to replicate our findings.

PMID- 15196600
TI  - Psychosocial functioning in patients with treatment resistant depression.
AB  - BACKGROUND: Depression is a disorder that causes disability, with a profound
      adverse impact on all areas of psychosocial functioning. This is particularly
      true for those with treatment resistant depression (TRD). However, to date, no
      systematic assessments of psychosocial functioning for patients with TRD have
      been conducted. METHODS: In the present study, we used the Longitudinal Interval
      Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92
      patients with TRD. These patients met formal criteria for TRD and were part of a
      clinical trial examining the efficacy of lithium augmentation of nortriptyline.
      RESULTS: Clinicians rated this sample of patients as experiencing mild to
      moderate impairment in work-related activities, good to fair interpersonal
      relations, poor level of involvement in recreational activities, and mild
      impairment of ability to enjoy sexual activity. Patients and clinicians rated
      global social adjustment as poor. CONCLUSIONS: Patients with formally defined TRD
      experience significant impairment in psychosocial functioning. In this sample a
      tendency existed for both clinicians and patients to assign more severely
      impaired global ratings when compared with ratings for specific functional areas.

PMID- 15196602
TI  - Residual symptoms of depression: clinical and theoretical implications.
AB  - Residual symptoms of variable intensity often persist following pharmaco/or
      psychotherapeutic interventions for treatment of major depression (MD). In
      several studies, such persistent symptoms have been clearly shown to be
      associated with a higher risk of relapse, chronicity and functional impairment,
      but their true nature is still controversial. Several authors consider that these
      symptoms belong to the range of depression proper and thus indicate that the
      current episode has been inadequately treated, a hypothesis reinforced by their
      frequent similarity with the symptoms preceding the full-blown picture of MD.
      However, in the current state of research, their connection with certain
      personality traits or comorbid disorders--notably anxiety disorders--cannot be
      completely ruled out. This article reviews the main data from the literature
      concerning residual symptoms and their treatment, as well as the issues related
      to their psychopathological meaning. In practice, once the state of a patient has
      been stabilized in partial remission of the depressive syndrome, the clinician
      should revise the current therapeutic strategy and seek to find how to return as
      fully as possible to the previous euthymic state.

PMID- 15196603
TI  - Examination of type I/type II alcoholism typology in a Greek hospital treatment
      population.
AB  - OBJECTIVE: The study aims at testing the validity of two types of classification
      of male alcoholism in a Greek hospital treatment sample. METHOD: The study
      population was drawn from male patients with alcohol dependence admitted to the
      Alcohol Treatment Unit of the Psychiatric Hospital of Attica. Seventy-three
      patients comprised the study sample after exclusion of subjects with alcohol
      dependence suffering from a comorbid serious medical condition, schizophrenic
      disorder, bipolar disorder, drug dependence or abuse, organic mental disorder or
      inability to read. The alcoholics were grouped in type I and II adopting the
      criterion of age-of-onset used by von Knorring et al. (1985). Impulsivity,
      suicide risk and violence risk were measured by means of the impulse control
      scale (ICS), the suicide risk scale (SRS) and the past feelings and acts of
      violence scale (PFAVS). RESULTS: Fifty patients with alcohol dependence were
      defined as late-onset and 23 as early-onset. Compared to late-onset patients,
      early-onset individuals with alcohol dependence had more familial alcoholism (P =
      0.032); they were in a higher rate unmarried (P = 0.001), had no stable job
      before entry in the Unit (P = 0.007) and scored higher on ICS (P = 0.046) and SRS
      (P = 0.024). CONCLUSION: The present study confirms type I/type II dichotomy of
      male alcoholism and also shows that the age-of-onset is a valid classification
      criterion.

PMID- 15196604
TI  - Patients with schizophrenia previously stabilized on conventional depot
      antipsychotics experience significant clinical improvements following treatment
      with long-acting risperidone.
AB  - BACKGROUND: Conventional depot antipsychotics can provide constant pharmacologic
      treatment, eliminating partial compliance and reducing relapse risk. Atypical
      antipsychotics, have improved clinical profiles but require daily dosing,
      compromising their overall effectiveness. As oral risperidone provides safety and
      efficacy benefits over oral haloperidol, improvements may be realized by
      replacing conventional with atypical agents in long-acting therapy. This report
      examines 50-weeks of long-acting risperidone therapy in patients previously
      stabilized with conventional depot antipsychotics. METHODS: A multi-center, open
      label study enrolled 725 patients with schizophrenia or schizoaffective disorder,
      judged clinically stable and maintained on stable antipsychotic doses for > or =4
      weeks. Assignment by clinician judgment to receive 25-75 mg of long-acting
      risperidone every 2 weeks for 50 weeks followed, with performance of standard
      safety and efficacy assessments. Data are presented on patients receiving
      conventional depot antipsychotic monotherapy at study entry. RESULTS: In the 188
      (25.9%) patients receiving conventional depot antipsychotic monotherapy at entry,
      mild-to-moderate mean (+/-S.D.) Positive and Negative Syndrome Scale (PANSS)
      total scores improved significantly after receiving long-acting risperidone (64.2
      +/- 18.9 to 58.2 +/- 20.3; P < 0.001). Clinical improvement of > or =20%, 40%, or
      60% reduction in PANSS-total score, occurred in 52%, 34%, and 16% of patients,
      respectively. ESRS subjective ratings and objective physician ratings
      (Parkinsonism) decreased significantly (P < 0.001). CONCLUSION: Stable patients
      with mild, residual symptomatology treated with conventional depot antipsychotics
      experienced significant improvement in psychiatric and movement disorder
      symptomatology following 1-year of treatment with long-acting risperidone.

PMID- 15196605
TI  - Opinions of mothers on the first psychotic episode and the start of treatment of
      their child.
AB  - Parents, especially mothers, have a critical role in initiating psychiatric
      treatment for their child with first-episode schizophrenia. Knowledge of
      attitudes of mothers towards the illness of their child prior to psychiatric
      treatment and towards the start of treatment is essential for the development of
      interventions for reducing duration of untreated psychosis (DUP). In the present
      study, mothers (n = 61) of consecutively admitted patients with recent-onset
      schizophrenic disorders were interviewed about: their views on the nature of the
      symptoms at first occurrence of psychotic symptoms in their child and views on
      the main reason for psychiatric treatment; their perception of problems in
      initiating psychiatric treatment; and suggestions they might have for getting
      treatment started at an earlier point in time. About 57% of the mothers did not
      think that their child had a psychosis at first occurrence of psychotic symptoms.
      Most of the mothers who immediately thought that their child suffered from a
      psychotic disorder supposed that this disorder was caused by use of street drugs.
      About one-third (32.8%) of the mothers thought that the reluctance of patients to
      acknowledge that they needed help was the major obstacle in initiating
      psychiatric treatment. More than half of the mothers perceived factors related to
      the delivery of professional care as problems in initiating psychiatric
      treatment. Given the reluctance of patients to accept treatment, these problems
      further complicate the initiating of treatment. Mothers emphasize that a more
      active approach by professional caregivers could reduce treatment delay.

PMID- 15196606
TI  - Language bias in neuroscience--is the Tower of Babel located in Germany?
AB  - In internal medicine German authors tend to publish randomized controlled trials
      (RCTs) with non-significant findings in German journals, RCTs with significant
      findings in international journals. In the neurosciences a similar trend was seen
      but the findings were not statistically significant. The reason for this
      inconclusive finding might be the low number of RCTs published in German.

PMID- 15196607
TI  - A case of social phobia and avoidant personality disorder with erectile
      dysfunction successfully treated with venlafaxine and add-on reboxetine.
AB  - A 25-year-old man with DSM-IV-TR Axis I social phobia and Axis II avoidant
      personality disorder and erectile dysfunction, presenting with depression,
      anxiety and insomnia, responded partially to extended release oral venlafaxine
      (75 mg/die for 6 weeks), but developed side effects and worsening symptoms when
      dose was increased to 150 mg/die; he responded to a combination of 75 mg/die
      venlafaxine and 4 mg/die reboxetine and improved on most of his symptoms.

PMID- 15196608
TI  - Levomepromazine helps to reduce sleep problems in patients with PTSD.

PMID- 15196609
TI  - Mianserin for the rapid improvement of chronic akathisia in a schizophrenia
      patient.

PMID- 15196610
TI  - Naso-gastric administration of risperidone to treat delusions of poisoning.

PMID- 15196611
TI  - Escitalopram in trichotillomania.

PMID- 15196612
TI  - Can the 'hygiene hypothesis' be explained by confounding by behavior?

PMID- 15196613
TI  - Larger effect sizes were associated with higher quality ratings in complementary
      and alternative medicine randomized controlled trials.
AB  - OBJECTIVE: To determine if the quality of complementary and alternative medicine
      (CAM) placebo controlled randomized controlled trials (RCTs) is related to the
      effect sizes they produce when the type of interventions and outcome variables
      are controlled. STUDY DESIGN AND SETTING: A sample of 25 CAM meta-analyses was
      identified from MEDLINE and hand searches containing published effect sizes for
      at least three efficacy trials employing placebo control groups. From these 25
      reviews, 26 pairs of trials were selected: the one reporting the largest effect
      size and the matching trial reporting the smallest effect size. Quality and
      publication characteristics were then abstracted from each trial. RESULTS: Unlike
      the preponderance of past evidence examining the relationship between quality and
      effect size, the present study found that trials possessing the largest effect
      sizes within a meta-analysis were also associated with higher quality ratings
      than their counterparts possessing the lowest effect sizes (P=.019). CONCLUSIONS:
      Possible theoretical reasons for this unexpected positive relationship include
      (a) sampling error, (b) reduced within group variation, (c) fraudulent reporting,
      and (d) the restriction of the analyses to placebo controlled trial.

PMID- 15196614
TI  - The methods for handling missing data in clinical trials influence sample size
      requirements.
AB  - OBJECTIVE: Results of studies estimating osteoarthritis progression may be
      affected by missing values. In clinical trials assessing disease-modifying
      osteoarthritis drugs, sample sizes should be calculated using close estimates of
      outcome variables. STUDY DESIGN AND SETTING: Supposing a two-parallel group
      design in hip osteoarthritis clinical trials, we estimated sample sizes using the
      joint space width (JSW), number of patients with JSW progression >0.5 mm (JSN),
      time to total hip arthroplasty (THA), and time to JSN or THA using several
      approaches to deal with missing data. RESULTS: Three-year clinical trials testing
      a treatment effect of 50%, with a power of 80%, could require sample sizes of 121
      patients for JSW, 57 for JS progression using multiple imputation for handling
      missing values; 200 for THA; and 47 for JSN or THA. These numbers vary greatly
      depending on the approach chosen for handling missing data. CONCLUSIONS: These
      results can help investigators plan clinical trials to select the primary outcome
      and a priori specify the way missing data will be handled.

PMID- 15196615
TI  - Covariate adjustment in randomized controlled trials with dichotomous outcomes
      increases statistical power and reduces sample size requirements.
AB  - OBJECTIVE: Randomized controlled trials (RCTs) with dichotomous outcomes may be
      analyzed with or without adjustment for baseline characteristics (covariates). We
      studied type I error, power, and potential reduction in sample size with several
      covariate adjustment strategies. STUDY DESIGN AND SETTING: Logistic regression
      analysis was applied to simulated data sets (n=360) with different treatment
      effects, covariate effects, outcome incidences, and covariate prevalences.
      Treatment effects were estimated with or without adjustment for a single
      dichotomous covariate. Strategies included always adjusting for the covariate
      ("prespecified"), or only when the covariate was predictive or imbalanced.
      RESULTS: We found that the type I error was generally at the nominal level. The
      power was highest with prespecified adjustment. The potential reduction in sample
      size was higher with stronger covariate effects (from 3 to 46%, at 50% outcome
      incidence and covariate prevalence) and independent of the treatment effect. At
      lower outcome incidences and/or covariate prevalences, the reduction was lower.
      CONCLUSION: We conclude that adjustment for a predictive baseline characteristic
      may lead to a potentially important increase in power of analyses of treatment
      effect. Adjusted analysis should, hence, be considered more often for RCTs with
      dichotomous outcomes.

PMID- 15196616
TI  - The conditional relative odds ratio provided less biased results for comparing
      diagnostic test accuracy in meta-analyses.
AB  - OBJECTIVE: Meta-analytic techniques are used to combine the results of different
      studies that have evaluated the accuracy of a given diagnostic test. The
      techniques commonly generate values that either describe the performance of a
      particular test or compare the discriminative ability of two tests. The later has
      received very little attention in the literature, and is the focus of this
      article. STUDY DESIGN AND SETTING: We summarize existing methods based on an odds
      ratio (OR) and propose a novel technique for conducting such analysis, the
      conditional relative odds ratio (CROR). We demonstrate how to extract the
      required data and calculate several different comparative indexes using a
      hypothetic example. RESULTS: A paired analysis is preferred to decrease selection
      bias and increase statistical power. There is no standard method of obtaining the
      standard error (SE) of each relative OR; thus, the SE of the summary index might
      be underestimated under the assumption of no within-study variability.
      CONCLUSION: The CROR method estimates less biased indexes with SEs, and
      conditioned on discordant results, it is much less problematic ethically and
      economically. However, small cell counts may lead to larger SEs, and it might be
      impossible to construct McNemar's 2 x 2 tables for some studies.

PMID- 15196617
TI  - A Chinese version of the Sleep Apnea Quality of Life Index was evaluated for
      reliability, validity, and responsiveness.
AB  - OBJECTIVE: Obstructive sleep apnea (OSA) is a common disorder in many ethnic
      populations. Patients with OSA have impaired health-related quality of life
      (HRQOL). No sleep apnea-specific HRQOL measure has been validated in Chinese
      patients. STUDY DESIGN AND SETTING: A cross-sectional sample of 106 Chinese OSA
      patients and a longitudinal sample of 51 patients in Hong Kong completed a
      Chinese (Cantonese) version of SAQLI for assessment of its acceptability, scaling
      assumptions, reliability, validity, and responsiveness. RESULTS: The instrument
      was understood and seen as relevant by 97% of subjects. Internal consistency,
      test-retest reliability, item-scale convergent validity and discriminatory
      validity, and construct validity were good to excellent. Construct validity was
      confirmed by significant correlations with SF-36 subscale scores. However, factor
      analysis showed that only items of daily functioning and symptom domains all
      loaded on the hypothesized scales. Longitudinal data showed that SAQLI was more
      responsive than SF-36 to changes after treatment. CONCLUSION: Hence, this version
      of SAQLI was an acceptable, psychometrically valid, and responsive HRQOL measure
      for evaluating impact of illness and treatment effectiveness in Chinese OSA
      patients.

PMID- 15196618
TI  - A new way to estimate the contribution of a risk factor in populations avoided
      nonadditivity.
AB  - OBJECTIVE: Attributable fraction in the exposed and (population) attributable
      fraction have been extensively used to determine the proportion of cases of a
      particular disease that can be attributable to any risk factor. Epidemiologists
      know that these measurements can add up to more than 100%; nevertheless, in a
      clinical context or in mass media, this characteristic is sometimes
      misinterpreted. This article provides a way to estimate the contribution of a
      risk factor in populations. STUDY DESIGN AND SETTING: McElduff et al. have
      suggested a method for estimating the contribution of a risk factor in a person
      with more than one risk factor. We extend their suggestion to populations where
      risk factors are mixed in different proportions. We illustrate the usage of this
      method by enlarging the example provided by them and compare it with the average
      attributable fraction suggested by Eide and Gefeller. RESULTS: Population
      attributable fraction can be modified to obtain additivity; therefore, the
      contribution of a risk factor in populations can be estimated, which would be of
      interest, for example, in clinical or in court settings. CONCLUSION: The
      suggested method and the average attributable fraction provide different results,
      and would be applicable under different assumptions.

PMID- 15196619
TI  - A new statistical approach demonstrated menstrual patterns during the menopausal
      transition did not vary by age at menopause.
AB  - OBJECTIVE: To describe population mean, variance, and correlation of cycle length
      across the life span and by age at menopause and age at menarche using a new
      statistical approach. STUDY DESIGN AND SETTING: Data from the Tremin Trust
      (n=997), a prospective menstrual diary study, was analyzed. Marginal models with
      generalized estimating equations were used to describe changes in menstrual
      parameters across the reproductive life span. RESULTS: During the menopausal
      transition, the increase in standard deviation preceded that in mean by 2 to 6
      years. Although beginning earlier in women with earlier menopause, increases in
      mean and variance for women with different ages at menopause were parallel. Women
      with later menopause had longer cycles throughout life and longer, more variable
      cycles during the transition. CONCLUSION: The transition from late reproductive
      life to early menopausal transition appears to begin in the late thirties when
      variability of cycle length increases. Patterns of change in menstrual function
      during the menopausal transition do not differ by age at menopause; thus,
      differences in age at menopause are likely to reflect changes in the timing and
      not changes in the process of ovarian senescence, at least for the normative ages
      of menopause.

PMID- 15196620
TI  - Patients' sibling history was sensitive for hypertension and specific for
      diabetes.
AB  - OBJECTIVE: We examined the analytic validity of reported family history of
      hypertension and diabetes among siblings in the Seychelles. STUDY DESIGN AND
      SETTING: Four hundred four siblings from 73 families with at least two
      hypertensive persons were identified through a national hypertension register.
      Two gold standards were used prospectively. Sensitivity was the proportion of
      respondents who indicated the presence of disease in a sibling, given that the
      sibling reported to be affected (personal history gold standard) or was
      clinically affected (clinical status gold standard). Specificity was the
      proportion of respondents who reported an unaffected sibling, given that the
      sibling reported to be unaffected or was clinically unaffected. Respondents gave
      information on the disease status in their siblings in approximately two-thirds
      of instances. RESULTS: When sibling history could be obtained (n=348 for
      hypertension, n=404 for diabetes), the sensitivity and the specificity of the
      sibling history were, respectively, 90 and 55% for hypertension, and 61 and 98%
      for diabetes, using clinical status and, respectively, 89 and 78% for
      hypertension, and 53 and 98% for diabetes, using personal history. CONCLUSION:
      The sibling history, when available, is a useful screening test to detect
      hypertension, but it is less useful to detect diabetes.

PMID- 15196621
TI  - The Sharp/van der Heijde method out-performed the Larsen/Scott method on the
      individual patient level in assessing radiographs in early rheumatoid arthritis.
AB  - OBJECTIVE: To test the reliability of two radiologic scoring methods in
      rheumatoid arthritis (RA)--the Sharp/van der Heijde (SvH) and the Larsen/Scott
      (LS)--with generalizability analyses. STUDY DESIGN AND SETTING: Films of 51
      patients representing the spectrum of early RA were read by two raters for each
      method. The discriminative ability and responsiveness were expressed as:
      intraclass correlation coefficients (ICCs), two types of smallest detectable
      difference (SDD), and two types of smallest detectable change (SDC); reflecting
      measurement error when discriminating between or detecting changes within (1)
      individuals or (2) groups. They were calculated for (average) scores of one to
      three raters. RESULTS: The discriminative capacity (0.85-0.97) and responsiveness
      (0.91-0.97) were good when expressed by ICC. On the group level the SDDs and SDCs
      ranged between 0.6-3.3% of the max. obtainable score. On the individual level,
      the scores showed better reliability measured with the SvH (SDDs 2.0-3.4%) than
      with the LS (SDDs 5.3-9.2%). The SvH also assessed changes in scores in
      individuals with less measurement error (SDCs 1.3-2.2%) than the LS (SDCs 2.3
      3.9%). CONCLUSION: For early RA patients, the SvH seems preferable if analyses on
      individual level are included.

PMID- 15196622
TI  - Disability predicted mortality in men but not women with coronary heart disease.
AB  - OBJECTIVE: Disability increases mortality in patients with myocardial infarction
      in acute clinical settings, but the impact of disability on mortality in persons
      with coronary heart disease (CHD) at the population level is largely unknown.
      STUDY DESIGN AND SETTING: We assessed disability as a predictor of mortality
      among 4,501 men and women aged 45 and over in a national sample of the Finnish
      population, examined in 1978-1980. RESULTS: During follow-up until the end of
      1994, 897 men and 846 women died. Disability was related to increased all-cause
      and CHD mortality after adjustment for cardiovascular risk factors in men
      regardless of baseline CHD status. In women with CHD at baseline, disability was
      not related to excess mortality, although disability predicted mortality in women
      without baseline CHD. CONCLUSION: Disability predicts mortality in men with CHD,
      but not in women. This may reflect a gender difference in the nature of CHD, but
      these findings need to be verified in other large-scale population studies.

PMID- 15196624
TI  - A cross-sectional study of postmenopausal women found an association between
      osteoporosis and past gastric surgery or oral corticosteroids.
AB  - OBJECTIVE: To determine the relationship between osteoporosis and the presence of
      specific and nonspecific medical conditions in postmenopausal women. To what
      extent is this relationship useful in detecting osteoporosis in daily general
      practice. STUDY DESIGN AND SETTING: Subjects were 1,684 postmenopausal women
      registered with 23 general practitioners. Multivariate logistic regression
      analysis was done with 52 disease variables and 24 biometrical and lifestyle
      variables, using BMD as the dependent variable. Bivariate analysis was performed
      to calculate their contribution to the risk of having osteoporosis. RESULTS:
      Having more than one disease was associated with a lower prevalence of
      osteoporosis. A positive association with the presence of osteoporosis was only
      found for the use of corticosteroids, gastric surgery, and cervical complaints.
      The risk for osteoporosis in the high risk category increased from 39 to 71% in
      women using oral corticosteroids, from 39 to 56% in women with a history of
      gastric surgery, and from 39 to 63% in women with cervical complaints.
      CONCLUSION: The clinical relevance of medical conditions for detecting
      osteoporosis is limited. However, all patients using oral corticosteroids and
      patients with a history of gastric surgery should be checked for the presence of
      osteoporosis. Cervical compaints in the high risk category was associated with
      osteoporosis.

PMID- 15196623
TI  - Hospital discharge abstract data on comorbidity improved the prediction of death
      among patients hospitalized with aspiration pneumonia.
AB  - OBJECTIVE: To use diagnoses reported as present at admission in California
      hospital discharge abstract data to identify categories of comorbid disease and
      conditions related to aspiration pneumonia and to assess their association with
      hospital mortality. STUDY DESIGN AND SETTING: The study population included all
      persons hospitalized in California from 1996 through 1999, with a principal
      diagnosis of aspiration pneumonia. Present at admission diagnoses representing
      comorbid diseases were separated from conditions closely related to aspiration
      pneumonia by a physician panel through a computer supported Delphi process.
      Multivariable logistic regression was used to assess the probability of hospital
      death after adjusting for these patient characteristics. The statistical
      performance of this method was compared to the performance of two independent
      methods for measuring comorbid disease. The practical significance of differences
      in statistical performance was assessed by comparing the estimated effects of
      age, race, and ethnicity after adjustments using each method. RESULTS: Mortality
      risk adjustment using present at admission diagnoses resulted in substantially
      better statistical performance and in different measurements of the adjusted
      effects of age, race, and ethnicity. CONCLUSION: Reporting present at admission
      diagnoses in hospital discharge data yields meaningful improvements in hospital
      mortality risk adjustment.

PMID- 15196625
TI  - No racial differences in mortality found among Veterans Health Administration out
      patients.
AB  - OBJECTIVE: Health care delivery systems that offer equal access to ambulatory
      care may hold promise for preventing and correcting racial disparities that exist
      in our health care system as a whole. We examined whether racial differences in
      mortality rates exist among patients receiving outpatient care within the
      Veterans Health Administration. STUDY DESIGN AND SETTING: This study used data
      from the 1998 National Survey of Ambulatory Care Patients, a prospective
      monitoring system of patient outcomes. We used an outpatient care system in the
      Veterans Health Administration. We followed 25,172 Whites and 3,517 African
      Americans for 48 months. The main study outcome measures were unadjusted and
      adjusted mortality rates over a 48-month period. RESULTS: African-Americans had
      significantly lower unadjusted 48-month mortality rates than Whites (33 vs. 40
      deaths per 1,000 person-year, hazard ratio, 0.84; 95% confidence interval [CI],
      0.75-0.95). After risk adjustment, the mortality rates became similar for African
      Americans and Whites (hazard ratio, 0.99; 95% CI, 0.89-1.09). These findings were
      consistent across all time points evaluated during the 48-month follow-up.
      CONCLUSIONS: The lack of racial differences in mortality in patients receiving
      ambulatory care in the Veterans Health Administration is reassuring, given the
      emphasis on equal access within this health care system. This warrants further
      research to determine whether efforts to improve access in other settings have
      the potential to reduce racial disparities in health care.

PMID- 15196626
TI  - Stability of crystallised and spray-dried lysozyme.
AB  - Moisture and temperature promote protein degradation. The stabilities of
      commercial, crystallised and spray-dried lysozyme, a model protein, were assessed
      under these stresses to explore whether a crystalline protein had better storage
      stability than a conventionally produced one. Samples were maintained at
      different relative humidities (RH) and temperatures for 20 weeks and stabilities
      estimated in solid and aqueous states. Differential scanning calorimetry (DSC)
      and thermogravimetry (TGA) characterised solid samples. Fourier transform Raman
      (FT-Raman) spectroscopy analysed solid material and aqueous solutions. High
      sensitivity differential scanning calorimetry (HSDSC) and enzymatic assays were
      used to monitor solutions. DSC and HSDSC data revealed that crystals maintained
      thermal stability at high RH; spray drying appreciably changed melting
      characteristics. These results correlated with enzymatic assays that demonstrated
      good activity retention for crystals but less so for spray-dried material (e.g.
      95 and 87% relative to fresh samples after 20 weeks at 40 degrees C/75% RH). FT
      Raman analysis showed that crystallised lysozyme better-maintained protein
      conformational integrity compared to spray-dried samples in accelerated stability
      studies. Based on TGA data, spray-dried protein absorbed water on storage under
      humid conditions, which induced instability. Thus, crystallisation enhanced
      storage stability of lysozyme with negligible loss of activity.

PMID- 15196627
TI  - Solubility of drugs in aqueous solutions. Part 4. Drug solubility by the dilute
      approximation.
AB  - As in our previous publications in this journal [Int. J. Pharm. 258 (2003a) 193;
      Int. J. Pharm. 260 (2003b) 283; Int. J. Pharm. 267 (2003c) 121], this paper is
      concerned with the solubility of poorly soluble drugs in aqueous mixed solvents.
      In the previous publications, the solubilities of drugs were assumed to be low
      enough for the so-called infinite dilution approximation to be applicable. In
      contrast, in the present paper, the solubilities are considered to be finite and
      the dilute solution approximation is employed. As before, the fluctuation theory
      of solutions is used to express the derivatives of the activity coefficient of a
      solute in a ternary solution (dilute solute concentrations in a binary solvent)
      with respect to the concentrations of the solvent and cosolvent. The expressions
      obtained are combined with a theoretical equation for the activity coefficient of
      the solute. As a result, the activity coefficient of the solute was expressed
      through the activity coefficients of the solute at infinite dilution, solute mole
      fraction, some properties of the binary solvent (composition, molar volume and
      activity coefficients of the components) and parameters reflecting the
      nonidealities of binary species. The expression thus obtained was used to derive
      an equation for the solubility of poorly soluble drugs in aqueous binary solvents
      which was applied in two different ways. First, the nonideality parameters were
      considered as adjustable parameters, determined from experimental solubility
      data. Second, the obtained equation was used to correct the solubilities of drugs
      calculated via the infinite dilution approximation. It was shown that both
      procedures provide accurate correlations for the drug solubility.

PMID- 15196628
TI  - Cross-linked high amylose starch derivatives for drug release. II. Swelling
      properties and mechanistic study.
AB  - Acetate (Ac-), aminoethyl (AE-), and carboxymethyl (CM-) high amylose starch
      cross-linked 6 (HASCL-6) derivatives were previously shown to control the release
      of drugs over 20 h from monolithic tablets highly loaded (up to 60% drug). This
      report describes the swelling characteristics, which allow a better understanding
      of the mechanisms involved in the control of the drug release from the said
      polymeric matrices. The tablet swelling of HASCL-6, Ac-HASCL-6, and AE-HASCL-6
      was found to not be affected by the ionic strength and by the pH between 1.2
      (gastric) and 7 (intestinal), whereas the swelling of CM-HASCL-6 was shown to
      depend on both ionic strength and pH of the release medium. For all the studied
      polymers the drug loading did not change the equilibrium swelling ratio but
      affected the initial swelling velocity, seemingly due to the competition between
      drug and polymer for water uptake, a phenomenon probably influenced by the
      loading and the drug solubility. It was also shown that the increase of ionic
      strength would slightly increase the drug release time probably by decreasing the
      amount of free water still available to solubilize the drug present into the
      matrix.

PMID- 15196629
TI  - Incorporation of hydrophobic porphyrins into liposomes: characterization and
      structural requirements.
AB  - The ability of photosensitisers to give reactive oxygenated products is
      considered decisive for photodynamic applications, but the hydrophobic nature of
      many porphyrins makes necessary to obtain suitable pharmaceutical formulations.
      This paper reports the structural photosensitiser features that allow the
      preparation of stable liposomal formulations. Metallated and non-metallated TPPs
      and TPyPs and different lipid/porphyrin ratios were considered in order to
      procure liposomal preparations containing porphyrin concentrations adequate to
      necessary doses. The results show that the incorporation of porphyrins into
      liposomes can be related with their ability to form aggregates in a watery media.
      Thus, ZnTPP, which structural properties avoid the formation of aggregates, was
      efficiently incorporated into stable liposomes. Moreover, the efficient
      generation of singlet oxygen by ZnTPP liposomal suspensions has been shown.
      Because of this, the synthesis of hydrophobic porphyrin derived structures or
      other sensitisers, which do not aggregate in a watery media and with Q-bands
      shifted to higher lambda values than ZnTPP, will be efficiently incorporated into
      liposomes and useful for clinical applications.

PMID- 15196630
TI  - In vivo gene transfection via intravitreal injection of cationic liposome/plasmid
      DNA complexes in rabbits.
AB  - To optimize the in vivo ocular transfection efficiency of plasmid DNA
      (pDNA)/cationic liposome complexes, N-[1-(2,3-dioleyloxy)propyl]-N,N,N
      trimethylammonium chloride (DOTMA)/dioleoylphosphatidylethanolamine (DOPE) (1:1
      molar ratio) liposomes and DOTMA/cholesterol (Chol) (1:1 molar ratio) liposomes
      were prepared with varying amounts of pDNA. pDNA/cationic liposome complexes were
      intravitreally injected (100 microL) in rabbits, and luciferase activity in the
      cornea, aqueous humor, iris-ciliary body, lens, vitreous body, and retina was
      measured. Transfection efficiency of pDNA alone did not change with pDNA ranging
      from 40 to 85 mg. In contrast, transfection efficiency of pDNA complexed with
      DOTMA/Chol liposomes significantly increased with the amount of pDNA ranging from
      40 to 85 microg (P < 0.05). pDNA complexed with DOTMA/DOPE liposomes could not be
      prepared with pDNA greater than 60 microg. Among these experiments, pDNA (85
      microg) complexed with DOTMA/Chol liposomes (pDNA:cationic liposome charge ratio
      (- : +) = 1.0:2.0) showed the highest transfection efficiency in the ocular
      tissue and its transfection-mediated luciferase activity peaked at 3 days. Among
      the ocular tissues, the highest gene expression was observed in the aqueous
      humor.

PMID- 15196631
TI  - Incorporation of ovalbumin into ISCOMs and related colloidal particles prepared
      by the lipid film hydration method.
AB  - The aim of this study was to investigate the incorporation of a model antigen,
      fluorescently labelled ovalbumin (FITC-OVA), into various colloidal particles
      including immune stimulating complexes (ISCOMs), liposomes, ring and worm-like
      micelles, lamellae and lipidic/layered structures that are formed from various
      combinations of the triterpene saponin Quil A, cholesterol and
      phosphatidylethanolamine (PE) following hydration of PE/cholesterol lipid films
      with aqueous solutions of Quil A. Colloidal dispersions of these three components
      were also prepared by the dialysis method for comparison. FITC-OVA was conjugated
      with palmitic acid (P) and PE to produce P-FITC-OVA and PE-FITC-OVA,
      respectively. Both P-FITC-OVA and PE-FITC-OVA could be incorporated in all
      colloidal structures whereas FITC-OVA was incorporated only into liposomes. The
      incorporation of PE-FITC-OVA into all colloidal structures was significantly
      higher than P-FITC-OVA (P < 0.05). The degree of incorporation of protein was in
      the order: ring and worm-like micelles < liposomes and lipidic/layered structures
      < ISCOMs and lamellae. The incorporation of protein into the various particles
      prepared by the lipid film hydration method was similar to those for colloidal
      particles prepared by the dialysis method (provided both methods lead to the
      formation of the same colloidal structures). In the case of different colloidal
      structures arising due to the preparation method, differences in encapsulation
      efficiency were found (P < 0.05) for formulations with the same polar lipid
      composition. This study demonstrates that the various colloidal particles formed
      as a result of hydrating PE/cholesterol lipid films with different amounts of
      Quil A are capable of incorporating antigen, provided it is amphipathic. Some of
      these colloidal particles may be used as effective vaccine delivery systems.

PMID- 15196632
TI  - Evaluation of sustained release suppositories prepared with fatty base including
      solid fats with high melting points.
AB  - To prepare the sustained release suppositories, solid fats such as polyglycerol
      ester of fatty acids (PGEFs) or beeswax were utilized with a fatty suppository
      base, Witepsol H15. PGEFs such as decaglycerol heptabehenate (HB750) and
      hexaglycerol pentastearate (PS500), and beeswax have relatively high melting
      points. The addition of PGEFs or beeswax to Witepsol H15 increased the apparent
      viscosity of suppository bases at 37 degrees C without any large change in the
      melting point of Witepsol H15. Moreover, the apparent viscosity of a mixed base
      with HB750, PS500 or beeswax at 37 degrees C was significantly correlated with
      the amount of each solid fat in a mixed base. The release of acetaminophen (AAP),
      a model drug, from suppositories was delayed by HB750, PS500 or beeswax, and an
      excellent correlation was observed between the apparent viscosity of these mixed
      bases and Higuchi's rate constants in each mixed base suppository, suggesting
      that these solid fats could regulate the drug release from the mixed base
      suppositories by changing their viscosity. In the in vivo absorption study in
      rats, several suppositories made from Witepsol H15-HB750 or Witepsol H15-beeswax
      mixed bases prolonged the rectal absorption of AAP without reducing AUC. In
      conclusion, by using solid fats such as HB750 and beeswax with relatively high
      melting points, it is possible to control the rate of drug release from fatty
      base suppositories for maintaining the plasma concentration of drugs for longer
      time periods.

PMID- 15196633
TI  - Adsorption of methotrexate and calcium leucovorin onto cholestyramine in vitro.
AB  - Methotrexate (MTX), an antimetabolite of folic acid, is a drug widely used in the
      treatment of different types of cancer. When high doses are administered, it is
      necessary to interrupt its action by administering calcium leucovorin (CaL). The
      main pathway of MTX and CaL elimination in humans occurs through the kidney, but
      about 10% is excreted in the faeces via the bile. Drugs, foods and sorbents in
      intestinal lumen modify MTX and CaL reabsorption. Individual and simultaneous
      studies on the adsorption of MTX and CaL from aqueous phosphate buffer by
      cholestyramine were carried out in order to calculate the adsorption process of
      MTX and CaL to cholestyramine, and to characterize the influence of CaL in the
      adsorption of MTX to cholestyramine and vice versa. The Langmuir binding
      isotherms determined in buffer solutions at pH 6 indicated a greater (12.58%)
      adsorption capacity of cholestyramine (1.43 mmol of drug/g of resin) than at pH 7
      (1.25 mmol of drug/g of cholestyramine). The affinity constant of MTX to
      cholestyramine was a 45.27% higher (6.67 mM(-1)) than the affinity constant of
      CaL to the resin (3.65 mM(-1)). Results from simultaneous assays indicate that a
      displacement of the MTX bound to cholestyramine by CaL is not foreseeable. The
      results suggest that cholestyramine may be a potentially useful adjunctive
      therapy in the treatment of an overdose of MTX. Consequently, cholestyramine may
      be of clinical value in patients who develop early renal function impairment
      whilst undergoing MTX therapy.

PMID- 15196634
TI  - Indocyanine green-loaded biodegradable nanoparticles: preparation,
      physicochemical characterization and in vitro release.
AB  - PURPOSE: The objective of this study is to develop indocyanine green (ICG)-loaded
      biodegradable nanoparticles by using biodegradable polymer, poly(DL-lactic-co
      glycolic acid) (PLGA). METHOD: PLGA nanoparticles entrapping ICG were prepared by
      a modified spontaneous emulsification solvent diffusion method. To optimize the
      nanoparticle formulation, the influence of formulation parameters such as types
      of ICG, amount of ICG and the polymer were investigated. The ICG entrapment in
      nanoparticles, nanoparticle size and zeta potential were determined. The surface
      characterization was performed by atomic force microscopy (AFM) and the release
      of ICG from nanoparticles was determined. RESULTS: All PLGA nanoparticle
      formulations were found to have the mean diameter within the range of 300-410 nm
      with polydispersity index (PI) within the range of 0.01-0.06. Indocyanine green
      showed more efficient entrapment as compared to indocyanine green sodium iodide
      salt. All indocyanine green-loaded nanoparticle formulations were found to have
      almost similar ICG content of nanoparticles and showed increase in ICG entrapment
      with increase in the amount of polymer. The ICG entrapment reached 74% when ICG:
      PLGA weight ratio in the formulation reached 1:800. AFM images indicated that the
      nanoparticles were almost spherical in shape and had numerous pores on their
      surfaces. The release pattern consisted of two phases, with initial exponential
      phase releasing about 78% of ICG (within 8 h) followed by a slow phase releasing
      about 2% of ICG (within next 16 h). CONCLUSIONS: ICG-loaded PLGA nanoparticles
      were prepared and the formulation was optimized. The increase in amount of
      polymer in formulation leads to higher ICG entrapment. Nanoparticles formed were
      spherical and had porous surfaces and exhibited the characteristic release
      pattern of a monolithic matrix based system.

PMID- 15196635
TI  - 2-Hydroxypropyl-beta-cyclodextrin extracts 2-phenylphenol from silicone tubing.
AB  - Cyclodextrins are capable to solubilise lipophilic drugs via (partial) inclusion
      in their lipophilic cavity. This, however, also provides the potential for the
      extraction of small molecules from production materials. In the present study,
      the potency of the commercially available and used cyclodextrin, 2-hydroxypropyl
      beta-cyclodextrin (HPbetaCD) to extract the preservative 2-phenylphenol (2-PP)
      from platinum cured silicone tubing was tested. The presence of 2-PP was
      structurally confirmed with HPLC-UV and LC/MS/MS in HPbetaCD solutions after
      incubation with platinum cured silicone tubing. HPbetaCD concentration and prior
      tubing sterilisation were found not to influence the levels of 2-PP extracted.
      Interestingly, extraction to ethanol was 15-fold higher than observed for
      HPbetaCD solutions. 2-PP was extracted from silicone tubing during routine
      manufacture of a blank dosage form formulated with only HPbetaCD, resulting in
      detectable levels of 2-PP in the final product. In a freeze-dried dosage form
      containing HPbetaCD and an active pharmaceutical ingredient (exhibiting a
      stability constant for HPbetaCD/drug of 1045 L/mol), on the other hand, 2-PP was
      undetectable.

PMID- 15196636
TI  - Intravenous liposomal benznidazole as trypanocidal agent: increasing drug
      delivery to liver is not enough.
AB  - With the aim of investigating if delivery of benznidazole (BNZ) to liver could be
      increased by incorporating the drug in multilamellar liposomes, single bolus of
      free BNZ or liposomal BNZ formulations (MLV-BNZ) composed of HSPC:DSPG:Chol 2:1:2
      (mol/mol/mol) at 0.7% (w/w) drug/total lipid ratio, were injected by
      intramuscular (i.m.), subcutaneous (s.c.) and intravenous (i.v.) routes, at 0.2
      mg BNZ/kg, in rats. The resulting blood concentrations were followed along 9 h
      post-injection (p.i.) and drug accumulation in liver was determined after 4 and 9
      h p.i. Only upon i.v. injection of MLV-BNZ, a threefold higher BNZ accumulation
      in liver was obtained, together with blood BNZ concentrations of 1.1 microg/ml
      (30% lower than the blood BNZ concentration achieved upon i.v. administration of
      free drug) occurred 4 h p.i. However, such increased liver uptake of BNZ, raised
      twice a week had no effect on parasitaemia levels of mice infected with the RA
      strain of Trypanosoma cruzi. Our results indicate that the relationship between
      increased selectivity for an infected tissue and therapeutic effect is not always
      straightforward, at least for the MLV-BNZ regimen used in the present study.

PMID- 15196637
TI  - Crosslinked gelatin matrices: release of a random coil macromolecular solute.
AB  - The purpose of this investigation was to evaluate the effect of matrix
      crosslinking and solute size on release of a random coil macromolecular solute
      from crosslinked gelatin matrices. Gelatin hydrogel matrices crosslinked with
      different molar ratios of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
      (EDC):epsilon-amino groups on gelatin (1:1, 4:1, and 10:1) were prepared
      containing dextran of molecular weights 12, 20, and 77 kDa, and hydrodynamic
      diameters 54, 74, and 133 A, respectively. The extent of matrix crosslinking was
      determined quantitatively and used to calculate the molecular weight between
      crosslinks (Mc). The Mc parameter and equilibrium swelling ratio (Qm) were used
      to calculate an estimated matrix mesh size (xi). The in vitro release of
      incorporated dextran was evaluated at 37 degrees C in PBS at pH 7.4 for
      approximately 80 h. The one-, four- and 10-fold molar ratios of crosslinking
      agent EDC yielded 24, 41, and 78% of gelatin matrix crosslinking, respectively.
      The calculated average matrix mesh size ranged from 338 to 90 A. The effect of
      matrix crosslinking varied with solute size, from retarding diffusional release
      of the dextran to completely entrapping it inside the crosslinked matrices. These
      results support the threshold concept of solute size relative to matrix mesh size
      for release of a flexible, random coil macromolecular solute from a hydrogel.

PMID- 15196638
TI  - Drug carrier systems based on water-soluble cationic beta-cyclodextrin polymers.
AB  - This study was designed to synthesize, characterize and investigate the drug
      inclusion property of a series of novel cationic beta-cyclodextrin polymers
      (CPbetaCDs). Proposed water-soluble polymers were synthesized from beta
      cyclodextrin (beta-CD), epichlorohydrin (EP) and choline chloride (CC) through a
      one-step polymerization procedure by varying molar ratio of EP and CC to beta-CD.
      Physicochemical properties of the polymers were characterized with colloidal
      titration, nuclear magnetic resonance spectroscopy (NMR), gel permeation
      chromatography (GPC) and aqueous solubility determination. The formation of
      naproxen/CPbetaCDs inclusion complexes was confirmed by NMR and fourier transform
      infrared spectroscopy (FT-IR). Cationic beta-CD polymers showed better hemolytic
      activities than parent beta-CD and neutral beta-CD polymer in hemolysis test. The
      morphological study of erythrocytes revealed a cell membrane invagination induced
      by the cationic groups. The effects of molecular weight and charge density of the
      polymers on their inclusion and release performance of naproxen were also
      investigated through phase-solubility and dissolution studies. It was found that
      the cationic beta-CD polymers with high molecular weight or low charge density
      exhibited better drug inclusion and dissolution abilities.

PMID- 15196639
TI  - Preparation of poly(N-isopropylacrylamide/itaconic acid) copolymeric hydrogels
      and their drug release behavior.
AB  - N-isopropylacrylamide/itaconic acid copolymeric hydrogels were prepared by
      irradiation of the ternary mixtures of N-isopropylacrylamide/itaconic acid/water
      by gamma-rays at ambient temperature. The effect of comonomer concentration,
      irradiation dose and pH on the swelling equilibria were studied. Lidocaine was
      used as a model drug for the investigation of drug release behaviour of
      hydrogels. Lidocaine adsorption capacity of the hydrogels were found to increase
      from 3.6 to 862.1 (mg lidocaine/g dry gel) with increasing amount of itaconic
      acid in the gel structure. Adsorption and release processes were followed at 4
      and 37 degrees C, respectively. The release studies showed that the basic
      parameters affecting the drug release behaviour of the hydrogels were pH and
      temperature of the solution and cross-link density of the gels.

PMID- 15196640
TI  - Comparative evaluation of cytotoxicity of a glucosamine-TBA conjugate and a
      chitosan-TBA conjugate.
AB  - D-glucosamine and chitosan were modified by the immobilization of thiol groups
      utilizing 2-iminothiolane. The toxicity profile of the resulting D-glucosamine
      TBA (4-thiobutylamidine) conjugate, of chitosan-TBA conjugate and of the
      corresponding unmodified controls was evaluated in vitro. On the one hand, the
      cell membrane damaging effect of 0.025% solutions of the test compounds was
      investigated via red blood cell lysis test. On the other hand, the cytotoxity of
      0.025, 0.25 and 0.5% solutions of the test compounds was evaluated on L-929 mouse
      fibroblast cells utilizing two different bioassays: the MTT assay (3-[4,5
      dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide), which assess the
      mitochondrial metabolic activity of the cells, and the BrdU-based enzyme-linked
      immunosorbent assay, which measures the incorporation in the DNA of 5-bromo-2'
      deoxyuridine and consequently the cell proliferation. Results of the red blood
      cell lysis test showed that both thiolated compounds displayed a lower membrane
      damaging effect causing a significantly lower haemoglobine release than the
      unmodified compounds. Data obtained by the MTT assay and the BrdU assay revealed
      a concentration dependent relative cytotoxicity for all tested compounds. The
      covalent linkage of the TBA-substructure to D-glucosamine did not cause a
      significant increase in cytotoxicity, whereas at higher concentrations a slightly
      enhanced cytotoxic effect was caused by the derivatisation of chitosan. In
      conclusion, the -TBA derivatives show a comparable toxicity profile to the
      corresponding unmodified compounds, which should not compromise their future use
      as save pharmaceutical excipients.

PMID- 15196641
TI  - Effect of anti-inflammatories on Pluronic F127: micellar assembly, gelation and
      partitioning.
AB  - We present results on the effect of two anti-inflammatory agents, naproxen and
      indomethacin, on the structure, assembly and gelation transitions of Pluronic
      F127 micelles. Small-angle neutron scattering experiments on micellar solutions
      indicate that the micelle aggregation number decreases significantly in the
      presence of drug solutes, causing the number density of micelles to increase.
      However, only slight changes were observed in the critical micelle concentration
      of F127 in the presence of these drugs. Both anti-inflammatory agents were found
      to shift the liquid-to-gel and gel-to-liquid transitions of the copolymer to
      lower temperatures. This may be the result of an increase in the micellar volume
      fraction, caused by the presence of the hydrophobic drugs. Using an ultraviolet
      spectroscopy technique, we have also measured the solubilities and micelle-water
      partition coefficients (Kmw) of naproxen and indomethacin in water and F127
      solutions. The values of Kmw for naproxen and indomethacin are 355 +/- 64 and 474
      +/- 33, respectively. They are larger than previously reported lipid-water
      partition coefficients, indicating that F127 micelles may be a better choice for
      drug loading than lipid vesicles. The slightly greater effects of indomethacin on
      the gelation boundary as compared with naproxen may be attributable to a higher
      value of Kmw.

PMID- 15196642
TI  - Cholera toxin B subunit conjugated bile salt stabilized vesicles (bilosomes) for
      oral immunization.
AB  - Bile salt stabilized vesicles, bilosomes appear to be a promising and potential
      carrier system for oral delivery of peptides and proteins. Bilosomes containing
      bovine serum albumin (BSA), a model antigen, were prepared and conjugated with
      cholera toxin B subunit (CTB) in order to enhance their affinity towards M cells
      of Peyer's patches. Stability studies were undertaken to ascertain the effect of
      simulated gastric fluid (SGF, pH 1.2), simulated intestinal fluid (SIF, pH 7.5)
      and different concentrations of bile salts. Intactness and biological activity of
      CTB were checked by hemagglutination test. A single oral dose of CTB-conjugated
      bilosomes produced almost equivalent response compared to parenteral
      administration of antigen with Freund's complete adjuvant (FCA). However, in
      contrast to FCA, oral administration of bilosomes is convenient and devoid of any
      adverse effects that are observed with parenteral administration of FCA. Serum
      IgG titers after single administration were significantly better (P < 0.05) than
      oral administration of antigen with other systems for 3 consecutive days,
      suggesting an effective stimulation of systemic immune response. Mucosal IgA
      titers obtained advocated a possible application of CTB-conjugated bilosomes as
      oral vaccine delivery system.

PMID- 15196643
TI  - Bioadhesive, rheological, lubricant and other aspects of an oral gel formulation
      intended for the treatment of xerostomia.
AB  - Xerostomia is commonly known as 'dry mouth' and is characterised by a reduction
      or loss in salivary production. A bioadhesive gel for its localised treatment was
      formulated to help enhance the residence time of the product, based on the
      polymer Carbopol 974P. The bioadhesion of various formulations was evaluated on
      different mucosal substrates, as simulations of the oral mucosa of xerostomic
      patients. Depending on the type of model substrate used, the mechanism of
      bioadhesion could alter. When the rheology of various formulations was examined,
      changes in bioadhesion were more easily interpreted, as the presence of other
      excipients caused an alteration in the rheological profile, with a change from a
      fully expanded and partially cross-linked system to an entangled system.
      Improving the lubricity of the product was considered important, with optimum
      incorporation of vegetable oil causing a desirable lowering of the observed
      friction of the product. The final complex formulation developed also contained
      salivary levels of electrolytes to help remineralisation of teeth, fluoride to
      prevent caries, zinc to enhance taste sensation, triclosan as the main anti
      microbial/anti-inflammatory agent and non-cariogenic sweeteners with lemon
      flavour to increase the palatability of the product while stimulating any
      residual salivary function.

PMID- 15196644
TI  - Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment.
AB  - Due to their small size, lipid nanocapsules (LNC) might be promising for an
      injectable as well as for an oral drug delivery system, providing both sufficient
      drug solubility avoiding vessel embolisation for the intravenous injection and a
      positive effect of drug absorption after oral administration. Biocompatible
      ibuprofen LNC were developed in a size range of around 50 nm with a new
      preparation method. Drug incorporation into LNC was successful to a high degree
      in all formulations tested (94-98%) and the in vitro drug release in phosphate
      buffer occurred within 24 h. Pharmacokinetic data were recorded in vivo from rats
      after intravenous or oral administration, while the antinociceptive efficiency of
      the LNC formulation was compared with ibuprofen solution by the tail flick test.
      The AUC and half-life of intravenously injected ibuprofen LNC were found to be 16
      and 19%, respectively, higher than a simple drug solution, while the mean
      residence time was not changed. Oral administration of LNC showed an 18% increase
      of AUC and a 27% higher mean residence time. The antinociceptive effect was
      similar for oral administration, drug solution, and LNC at 30 min after
      administration, and was prolonged up to 4 h in the LNC group. The pain relief
      after intravenous administration was prolonged when administering LNC formulation
      for at least 2 h. A drug delivery system for intravenous administration of
      ibuprofen has been developed which exhibits sustained release properties by
      either oral or intravenous route and may be interesting in the treatment of
      postoperative pain.

PMID- 15196645
TI  - Transport of leuprolide across rat intestine, rabbit intestine and Caco-2 cell
      monolayer.
AB  - The purpose of this study was to investigate the transport mechanisms and causes
      of low bioavailability of leuprolide. The everted gut sac technique and Caco-2
      cell monolayer were used to examine: (1) transport properties, enzyme degradation
      and apparent permeation coefficient (Papp); (2) the influence of trypsin
      inhibitor, EDTA, chitosan and alginate on drug transport; and (3) the effect of
      animal species on the intestinal transport. Results showed flux increased with
      increasing concentration of drug, showing a passive diffusion pathway. The enzyme
      degradation in rabbit gut was the highest. The Papp of (4.19 +/- 1.33) x 10(-5)
      cm/s in rat gut was the largest and the Papp of (5.20 +/- 0.20) x 10(-7) cm/s in
      Caco-2 cell the smallest. At a low concentration of drug, trypsin inhibitor had
      strong enhancement effect on the Papp by protecting enough drug for permeation.
      Chitosan had no effect on the activity of alpha-chymotrypsin. The increase in
      Papp was due to opening of the tight junctions and interaction with cells. In
      conclusion, both inhibition of proteolytic enzymes and opening the tight
      junctions to allow for paracellular transport improved the intestinal absorption.
      At low drug concentration, reduction of enzyme degradation is the most important
      factor.

PMID- 15196646
TI  - The preparation of orally disintegrating tablets using a hydrophilic waxy binder.
AB  - The demand for rapidly disintegrating tablets (RDT) has been growing during the
      last decade especially for elderly and children who have swallowing difficulties.
      The problem of certain RDT is their low physical resistance and high friability.
      This work describes a new approach to prepare RDT with sufficient mechanical
      integrity, involving the use of a hydrophilic waxy binder (Superpolystate, PEG-6
      stearate). Superpolystate is a waxy material with a melting point of 33-37
      degrees C and an HLB value of 9. So it will not only act as a binder and increase
      the physical resistance of tablets but will also help the disintegration of the
      tablets as it melts in the mouth and solublises rapidly leaving no residues. The
      incorporation of Superpolystate in the formulation of RDT was realised by means
      of two different granulation methods: wet granulation by using an emulsion of
      this waxy binder as granulating liquid and melt granulation where the molten form
      of the binder was used. Granule size distributions of both wet and melt granules
      of crystallised Paracetamol and D-mannitol were compared using laser light
      diffractometer. Scanning electron microscopy (SEM) was used to examine their
      morphological characteristics. The potential of the intragranular addition of
      croscarmellose sodium as a disintegrating agent was also evaluated. The
      subsequent step encompassed the preparation and the evaluation of the tablets,
      including the effect of the extragranular introduction of croscarmellose sodium.
      An improvement in tablet hardness and friability was observed with both
      granulation methods where we were able to obtain RDT with a disintegration time
      of 40 +/- 2 s and a hardness of 47.9 +/- 2.5N.

PMID- 15196647
TI  - Antitumor activity of Cratylia mollis lectin encapsulated into liposomes.
AB  - The hemagglutinating (HA) activity of Cratylia mollis lectin (Cra) was evaluated
      and the influence of ultrasound and mechanical agitation on its activity
      examined. The antitumor activity of Cra-loaded liposomes was also investigated.
      Liposomes were obtained by the lipid thin film method. Physicochemical
      characterization was carried out and long-term stability of Cra-loaded liposomes
      assessed. Antitumor activity of Cra-loaded liposomes was investigated against
      Sarcoma 180 in Swiss mice. The treatment was performed intraperitoneally (7 mg/kg
      body weight per day) for 7 days. Histopathological analyses of tumor, liver,
      spleen and kidneys were carried out after treatment of the animals. The results
      showed that Cra-HA activity is affected under ultrasound exposure. However, Cra
      was successfully encapsulated into liposomes and the activity of the lectin was
      preserved despite the use of ultrasound in the liposome preparation. Cra-loaded
      liposomes were produced with an 84% encapsulation ratio (700 microg/ml) and a
      tumor inhibition of 71% was achieved. The encapsulation of Cra produced a
      decrease in its tissue toxicity and improved its antitumor activity. In
      particular, histopathological analysis revealed that treatment with Cra-loaded
      liposomes prevented Cra cytotoxicity in the liver and kidney of animals.

PMID- 15196648
TI  - Characteristics of erythritol and formulation of a novel coating with erythritol
      termed thin-layer sugarless coating.
AB  - The purpose of this study was to clarify the characteristics of erythritol and to
      develop the optimum basic formulation of a novel coating with erythritol termed
      thin-layer sugarless coating. Characteristics of erythritol were investigated
      compared with maltitol, mannitol, sorbitol, xylitol, and sucrose. Furthermore,
      the optimum basic formulation of thin-layer sugarless coating with erythritol was
      determined by coating glass beads. We selected a continuous spray mist method for
      thin-layer sugarless coating due to the formation of a thin sugarless coating
      layer by a simple method. We demonstrated that erythritol is a suitable coating
      material for thin-layer sugarless coating compared with maltitol, mannitol,
      sorbitol, xylitol, and sucrose because of its high water solubility, low
      hygroscopicity, instant crystallization, and low tackiness. We also demonstrated
      that thin-layer sugarless coating with erythritol can reduce coating time
      compared with the coating with maltitol or sucrose due to its characteristics. We
      developed the optimum basic formulation of thin-layer sugarless coating consists
      of erythritol, powdered acacia, and talc. We confirmed that a smooth coating
      layer and high coating efficiency were achieved using the formulation.

PMID- 15196649
TI  - Development and evaluation of the tablets coated with the novel formulation
      termed thin-layer sugarless coated tablets.
AB  - The purpose of this study was to develop and evaluate the thin-layer sugarless
      coated tablets containing Vitamin C, Vitamin E, Vitamin B2, calcium pantothenate,
      and L-cysteine. As a result of the formulation study, three coating layers, 2%
      under coating (UC), 38% build-up coating (BC), and 5% syrup coating (SC) were
      necessary for sufficient impact toughness, elegant appearance, and improvement of
      appearance stability after storage at 25 degrees C/75% RH for 6 months under open
      conditions. We demonstrated that the thin-layer sugarless coated tablets are
      superior to the sugar-coated tablets in terms of small tablet size and stability
      of calcium pantothenate. It was due to the coating method, the continuous spray
      mist method, which can minimize the thicknesses of coating layers and the
      moisture content in the tablets. We also demonstrated that the thin-layer
      sugarless coated tablets are superior to the film-coated tablets in terms of
      masking ability of the unpleasant odor and the appearance, stability of the
      appearance, and low hygroscopicity. It was due to the dense, opaque, and stable
      coating layers mainly consist of erythritol. We revealed that thin-layer
      sugarless coated tablets have both advantages of film-coated tablets and sugar
      coated tablets.

PMID- 15196650
TI  - Novel high pressure extraction technology.
AB  - This note describes a novel application of the food processing technology, known
      as high pressure processing (HPP), to the extraction of essential components of
      herbs. Herbal extracts may be used as drugs, as well as ingredients in food and
      cosmetics. We have run some pilot studies in our laboratories to demonstrate the
      applicability of high pressure extraction.

PMID- 15196651
TI  - The content of dopamine, serotonin, and their metabolites in the neural circuit
      that mediates maternal behavior in juvenile and adult rats.
AB  - Continuous exposure of non-parturient rats to pups can induce maternal behavior
      similar in most aspects to that found in the postpartum rat. Surprisingly, young
      juvenile rats (20-24 days of age) only require 1-3 days of exposure to pups,
      while adults require 4-8 days before maternal behavior emerges. Dopamine (DA) and
      possibly serotonin (5-HT) may mediate the expression of adult maternal behavior.
      We hypothesize that postnatal changes in DA and 5-HT within the neural circuit
      that supports maternal behavior including the medial preoptic area (MPOA), medial
      and cortical amygdala (MCA), and nucleus accumbens (NAC), may underlie these
      differences in responsiveness across juveniles and adults. We measured DA, 5-HT,
      and their metabolites in postmortem samples of these regions in maternal and non
      maternal juvenile and adult females. The only difference found across behavioral
      groups was that the MPOA of adults induced into maternal behavior by pup exposure
      had more DA than did that of isolated adult females or maternal juveniles.
      However, when adults versus juveniles were compared, the content of DA and 3,4
      dihydroxyphenylacetic (DOPAC) was higher in the adult than in the juvenile NAC
      and MCA; the content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in these
      structures did not vary across the age groups. In contrast, higher levels of 5-HT
      and 5-HIAA were found in the MPOA in juveniles compared to adults. We propose
      that these region-specific age differences in DA and 5HT may underlie differences
      in juvenile-adult responses to pups.

PMID- 15196652
TI  - Impaired fear processing in right mesial temporal sclerosis: a fMRI study.
AB  - Lesion and neuroimaging studies have demonstrated that the mesial temporal lobe
      is crucial for recognizing emotions from facial expressions. In humans, bilateral
      amygdala damage is followed by impaired recognition of facial expressions of
      fear. To evaluate the influence of unilateral mesial temporal lobe damage we
      examined recognition of facial expressions and functional magnetic resonance
      (fMRI) brain activation associated with incidental processing of fearful faces in
      thirteen mesial temporal lobe epilepsy (MTLE) patients (eight with right MTLE,
      five with left MTLE). We also examined the effect of early versus later damage,
      comparing subjects with hippocampal-amygdalar sclerosis (MTS) and seizures
      occurring before five years of age to epilepsy patients with late onset seizures.
      Fourteen healthy volunteers participated as controls. Neuropsychological testing
      demonstrated that the ability of right MTLE patients to recognize fearful facial
      expressions is impaired. Patients with early onset of seizures were the most
      severely impaired. This deficit was associated with defective activation of a
      neural network involved in the processing of fearful expressions, which in
      controls and left MTLE included the left inferior frontal cortex and several
      occipito-temporal structures of both hemispheres.

PMID- 15196653
TI  - The effect of posterior hypothalamic injection of cholinergic agents on
      hippocampal formation theta in freely moving cat.
AB  - The effect of intra-hypothalamic micro-injection of muscarinic (atropine
      sulphate, pirenzepine and gallamine) and nicotinic (hexamethonium) antagonists on
      spontaneous, sensory and electrically-induced hippocampal formation (HPC) theta
      EEG activity was investigated in the freely behaving cat. Administration of
      hexamethonium and gallamine failed to elicit a detectable effect on HPC theta
      activity. However, the injection of atropine sulphate and pirenzepine abolished
      the theta rhythm recorded from HPC. This effect was reversible. A substantial
      difference in the recovery time course between frequency versus amplitude
      (microV) and power (microV2) of hippocampal theta was observed. While theta
      frequency exhibited a rapid reappearance with a shallow slope, the power and
      amplitude showed a gradual recovery with a steeper slope. The injection of
      carbachol into posterior hypothalamus (PH) produced almost a continuous HPC theta
      with increased power. These results demonstrate that cholinergic (M1) receptors
      localised in the posterior area of the hypothalamus are engaged in mechanisms
      responsible for generating hippocampal theta oscillations in the freely behaving
      cat. The contribution of posterior hypothalamic region to HPC theta frequency and
      amplitude is discussed.

PMID- 15196654
TI  - The role of D1 and D2 receptors in the cocaine conditioned place preference of
      male and female rats.
AB  - The rewarding effects of cocaine have been shown to be sexually dimorphic; female
      rats develop cocaine conditioned place preference at lower doses and with fewer
      cocaine pairings than male rats. The present study was conducted to determine
      whether D1 and D2 receptors contribute to sex differences in cocaine conditioned
      place preference using a 4-day paradigm. Fifteen minutes prior to receiving
      saline or cocaine (5mg/kg for females and 20mg/kg for males), rats were
      pretreated with either SCH 23390, a D1 receptor antagonist, (0.10, 0.25, or
      0.50mg/kg), eticlopride, a D2 receptor antagonist, (0.05, 0.10, or 0.25mg/kg), or
      vehicle (saline). Antagonism of D1 receptors by SCH 23390 fully blocked cocaine
      conditioned place preference in male rats, while only the two lower doses of SCH
      23390 blocked cocaine conditioned place preference in female rats. Conversely,
      antagonism of D2 receptors using eticlopride had no effect on cocaine conditioned
      place preference in male or female rats. Due to the known role of D1 receptors in
      cocaine conditioned place preference, sex differences in D1 receptor sensitivity
      may explain the differences observed in cocaine reward between male and female
      rats.

PMID- 15196655
TI  - Male chemosignals inhibit the neural responses of male mice to female
      chemosignals.
AB  - Reproductive function in mice is regulated by reproductively-stimulating and
      reproductively-inhibiting primer pheromones released by conspecifics. When
      experienced simultaneously, their responses to reproductively-inhibiting
      chemosignals take precedence over their responses to reproductively-stimulating
      chemosignals. For example, while female urine induces luteinizing hormone (LH)
      release in males, this response is blocked when male urine is presented in
      conjunction with female urine. In the present study, we examined the neural
      correlates of these responses to male and female urine. Sexually experienced,
      male CF1 mice were exposed to water, female urine, or a mixture of male and
      female urine. The resulting patterns of Fos-immunoreactivity (Fos-ir) were then
      compared between groups. Female urine induced significantly more Fos-ir within
      the main and accessory olfactory systems (MOS and AOS, respectively) than did
      water, male urine or mixed urine. Notably, within the main and accessory
      olfactory bulbs, male urine attenuated the responses of mitral cells, but not
      granule cells, to female urine. Overall, the results indicate that exposure to
      male urine inhibited the responses of cells within the MOS and AOS to female
      urine. The specific pattern of Fos-ir in the olfactory bulbs suggests that this
      may be due to an inhibition in the responses of mitral cells to female urine.

PMID- 15196656
TI  - Ginkgolide B preferentially blocks chloride channels formed by heteromeric
      glycine receptors in hippocampal pyramidal neurons of rat.
AB  - It has been found recently that the platelet activating factor antagonist
      ginkgolide B is a selective use-dependent blocker of glycine-gated chloride
      channels. GABAA receptor antagonist picrotoxin is known to block alpha homomeric
      glycine (Gly) receptors, being less effective for heteromeric alpha1/beta glycine
      receptors. Studying pyramidal hippocampal neurons of rat, we have confirmed that
      the effect of picrotoxin depends on the age of the animals. Its blocking ability
      was characterised by IC50=140+/-12 microM and IC50=354+/-43 microM for 7 and 14
      days old rats, respectively, indicating at a possibly increased contribution of
      heteromeric receptors with animals age. We have revealed that the blocking action
      of ginkgolide B is subjected to a more drastic change in the same range of ages:
      the IC50 value is decreased from 1.6+/-0.2 microM for 7 days old rats to 0.27+/
      0.01 microM for 14 days old rats. When measured on the background of ginkgolide B
      (1 microM), IC50 for picrotoxin was 92+/-16 microM. Taken together, these
      findings indicate that ginkgolide B has higher affinity to heteromeric Gly
      receptor-gated channels than to the homomeric ones.

PMID- 15196657
TI  - Prolactin releasing peptides modulate background firing rate and milk-ejection
      related burst of oxytocin cells in the supraoptic nucleus.
AB  - The hypothalamic dorsomedial nucleus is suggested to be a final relay site for
      the afferent pathway of milk-ejection reflex. Existence of prolactin releasing
      peptide-immunoreactive cells in the dorsomedial nucleus and synaptic contact of
      prolactin releasing peptide-immunoreactive terminals with oxytocin cells was
      reported. Experiments were done to test the effect of prolactin releasing peptide
      on the electrical activity of oxytocin cells in the supraoptic nucleus. In rat
      brain slice preparations, oxytocin cells were unresponsive to the peptide. In
      lactating rats, although lateral ventricular injection of prolactin releasing
      peptide (20 nmol) was ineffective, a hundred nanomoles of the peptide increased
      basal activity and amplitude of milk-ejection related burst firing of oxytocin
      cells. Cells responded to lateral ventricular injection of peptides were
      unresponsive to direct application of peptides by pressure ejection from the
      recording electrode. These results suggest that prolactin releasing peptide may
      modulate electrical activity of oxytocin cells not through its direct action on
      oxytocin cells but through its action on area other than supraoptic nucleus.

PMID- 15196658
TI  - Pursuit of roles for metabotropic glutamate receptors in the anteroventral third
      ventricular region in regulating vasopressin secretion and cardiovascular
      function in conscious rats.
AB  - This study aimed to evaluate the roles of metabotropic glutamate receptors
      (mGluRs) in the anteroventral third ventricular region (AV3V; a pivotal area for
      osmotic responses and PGE2 actions) in regulating AVP secretion and
      cardiovascular function. In conscious and unrestrained rats, we examined the
      effects of AV3V infusion of t-ACPD (an agonist for mGluRs) and 8-bromo (Br)-cAMP
      (an agonist for cAMP associated with mGluR action) on plasma and cardiovascular
      variables, and the effects of MCPG (an antagonist for mGluRs) on the responses to
      t-ACPD, PGE2, and hyperosmolality. AV3V infusion of t-ACPD or 8-Br-cAMP produced
      dose-dependent rises in plasma AVP, arterial pressure and heart rate after 5 or
      15 min, without altering plasma osmolality, sodium, potassium or chloride. t-ACPD
      administration into the cerebral ventricle had no effects on the variables. The
      plasma AVP and arterial pressure responses to AV3V t-ACPD infusion were blocked
      by preadministration of MCPG 15 min before the infusion. MCPG treatment was also
      potent at inhibiting the augmentation of plasma AVP elicited by AV3V infusion of
      PGE2, although its pressor and tachycardiac actions were not influenced. MCPG
      application, however, had no effect on either the increases in plasma AVP or
      arterial pressure in response to the enhanced plasma osmolality induced by i.v.
      infusion of hypertonic saline or their stable levels during isotonic saline
      infusion. Histological analysis showed that the AV3V drug infusion sites were
      located in structures such as the median or medial preoptic nucleus and
      periventricular nucleus. These results suggest that AV3V mGluRs may act to
      potentiate AVP release and cardiovascular function when stimulated in the basal
      state, and may participate in the hormone secretion prompted by AV3V PGE2,
      despite probable negligible contributions to the mechanisms responsible for the
      PGE2 cardiovascular effects or the phenomenon provoked by osmotic load.

PMID- 15196659
TI  - Role of the locus coeruleus in the prolactin secretion of female rats.
AB  - Since locus coeruleus (LC) lesion blocks preovulatory prolactin surge, the aim of
      this study was to determine if this lesion would also block prolactin surges
      induced by steroids in ovariectomized rats and would modify basal prolactin
      secretion. To determine the time of the steroid-induced prolactin surges,
      ovariectomized rats treated with estradiol (OVE) or estradiol and progesterone
      (OVEP) were cannulated at 08:00 h and blood samples were collected hourly between
      14:00 and 18:00 h. Ovariectomized rats treated with oil (OV-Oil) were used as
      control. Prolactin peaked at 16:00 h in OVE rats and at 15:00 h in OVEP. In a
      second experiment, male rats, cycling rats, OVE, OVEP, and OV-Oil groups were
      cannulated at 08:00 h, followed by LC lesion or sham-surgery. Blood samples were
      withdrawn at times of basal and peak prolactin levels. LC lesion blocked
      afternoon prolactin surges of OVE, OVEP and proestrus rats. However, the low
      levels observed at 16:00 h in OV-Oil, diestrus and male rats as well as at 11:00
      h in OVE, OVEP, estrus, and proestrus rats were not modified by LC lesion. The
      high prolactin levels observed on estrus afternoon were dramatically reduced by
      LC lesion. Data suggest that LC neurons are important for steroid-induced
      prolactin surge genesis, but not for prolactin basal secretion.

PMID- 15196661
TI  - Differential effects of spontaneous versus forced exercise in rats on the
      staining of parvalbumin-positive neurons in the hippocampal formation.
AB  - To investigate whether the type of physical activity, voluntary or forced, would
      promote different morphological changes in hippocampal formation we performed an
      immunocytochemical study using the parvalbumin (PV) distribution as a marker.
      Animals submitted to the voluntary exercise were placed in a voluntary wheel
      running and those submitted to the forced exercise were placed in a motor driven
      treadmill. Both exercise groups were submitted to 10 consecutive days of physical
      activity. It was observed a higher number of PV-positive cells in the hilus of
      dentate gyrus (DG) in the voluntary and forced exercise groups when compared to
      the control group. The voluntary exercise group also presented a stronger fiber
      staining in the DG hilus than the forced exercise and control groups. In
      contrast, no differences were found in the pattern of PV staining in CA1/CA3
      region between exercise and control groups. These findings demonstrate that
      physical activity leads to prominent plastic changes in the hippocampal formation
      of rats that were more evident following voluntary activity.

PMID- 15196660
TI  - Prenatal heroin exposure alters cholinergic receptor stimulated activation of the
      PKCbetaII and PKCgamma isoforms.
AB  - Prenatal exposure of mice to heroin (SC injection of 10mg/kg to the dams on
      gestational days 9-18) resulted at adulthood in behavioral deficits related to
      septohippocampal cholinergic innervation accompanied with both presynaptic and
      postsynaptic cholinergic hyperactivity; including an increase membrane PKC
      activity, and a desensitization of PKC to cholinergic input which were highly
      correlated with the behavioral performance and were reversed by cholinergic
      grafting. Therefore, we studied the receptor induced activation of the
      behaviorally relevant PKCgamma and PKCbetaII isoforms and the less behaviorally
      relevant PKCalpha isoform. Time course studies revealed peak translocation after
      40 min incubation with carbachol for PKCgamma (110% increase from basal, i.e. no
      carbachol level, P < 0.01), 30 min for phosphorylated PKCbetaII (130%, P < 0.05)
      and 5 min for non-phosphorylated PKCbetaII (64%, P < 0.05) with no peak for
      alpha. Prenatal heroin abolished the translocation of PKCgamma and PKCbetaII
      while PKCalpha remained unaffected. A decrease occurred in basal phosphorylated
      membrane (-45%, P < 0.01) and cytosol-associated (-29%, P < 0.01) PKCbetaII, in
      membrane-associated non-phosphorylated PKCbetaII (-32%, P < 0.01) and PKCgamma (
      25%, P < 0.01) and in cytosolic PKCalpha (-27%, P < 0.01), while membrane
      associated PKCalpha was slightly increased (11%, P < 0.05). The results suggest
      that prenatal heroin disrupts cholinergic receptor induced PKC translocation and
      activation with the underlying mechanism of neuroteratogenicity potentially lying
      in the PKCgamma and PKCbetaII, while PKCalpha remains unaffected.

PMID- 15196662
TI  - A new presenilin Alzheimer's disease case confirms the helical alignment of
      pathogenic mutations in transmembrane domain 5.
AB  - In a case of familial early onset Alzheimer's disease, a mutation was detected in
      exon 7 of the presenilin 1 gene at codon 226 with a resultant amino acid change
      from leucine (CTC) to arginine (CGC) (L226R). This is a novel finding, yet is
      consistent with the previously reported mutations at codons 222, 229, 233 and 237
      in transmembrane domain 5 which show a helical alignment of mutations in this
      domain. We conclude that the cause of Alzheimer's disease in this patient is an
      authentic PS1 gene abnormality responsible for the patient's early onset
      Alzheimer's disease.

PMID- 15196663
TI  - Regional cerebral blood volume (rCBV) and trasversal relaxation time (T2) mapping
      of the rat limbic system during pre-puberal and adult age.
AB  - We analyzed modifications in transversal relaxation time (T2) and regional
      cerebral blood volume (rCBV) in two areas of the limbic system, i.e., olfactory
      bulb (OB) and amygdala (AMY), in pre-puberty and post-puberty female rats. The
      aim of this work was to extend the knowledge about physiological modifications of
      these MRI parameters at different developmental phases. No significant difference
      was observed in T2 values of the OB between the two groups (pre-puberty: T2 =
      86.92 +/- 8.57 ms, post-puberty: T2 = 88.11 +/- 13.06 ms; mean +/- S.D.). On the
      contrary T2 values of the AMY were significantly different (P = 0.0001) between
      the two groups (pre-puberty 76.08 +/- 3.2, post-puberty 81.77 +/- 11.77 ms). rCBV
      values of OB were significantly different (P = 0.0025) between pre-puberty (0.38
      +/- 0.12 a.u.) and post-puberty female rats (0.15 +/- 0.09 a.u.). A significant
      decrease in rCBV (P = 5.1 x 10(-13)) between pre-puberty and post-puberty females
      (pre-puberty: 0.36 +/- 0.12, post-puberty: 0.07 +/- 0.05 a.u.) was also observed
      in the AMY. These findings suggest that in the limbic system, microvascular
      plasticity parallels neuronal maturation and indicate the importance of an
      appropriate baseline study in experiments dealing with the limbic system
      performed at different time-points.

PMID- 15196664
TI  - Intratumoral infusion of interleukin-1beta and interferon-gamma induces tumor
      invasion with macrophages and lymphocytes in a rat glioma model.
AB  - Malignant gliomas are hard to treat successfully. Like other treatments immune
      therapy fails presumably due to low concentration of immune modifiers within the
      tumor. However, convection-enhanced delivery (CED) may overcome this problem. So,
      we analyzed the effect of intratumoral delivery of interleukin (IL)-1beta and
      interferon (IFN)-gamma by CED on tumor immune cell invasion in a rat glioma
      model. Tumors were implanted into the left caudate nucleus and tumor growth was
      demonstrated by MRI. Afterwards intratumoral infusion of IL-1beta or IFN-gamma
      was started for 48 h. Then animals were sacrificed and the number of tumor
      infiltrating CD4+ and CD8+ lymphocytes as well as macrophages was analyzed by
      immunohistochemistry. Our results demonstrate that intratumoral cytokine infusion
      using CED leads to a strong tumor invasion with macrophages and lymphocytes
      suggesting a tumor specific immune response.

PMID- 15196665
TI  - Visual change detection: event-related potentials are dependent on stimulus
      location in humans.
AB  - Infrequent colored patterns within sequences of patterns of frequent color
      elicited a posterior negative event-related potential component only in case of
      lower half-field stimulation. This negativity in the 140-200 ms latency range is
      considered as a correlate of automatic visual change detection (visual mismatch
      negativity, vMMN). Retinotopic prestriate visual areas are suggested to be the
      generating loci of vMMN.

PMID- 15196666
TI  - Infusion of epidermal growth factor and basic fibroblast growth factor into the
      striatum of parkinsonian rats leads to in vitro proliferation and differentiation
      of adult neural progenitor cells.
AB  - This study investigated the proliferation and differentiation of adult neural
      progenitor cells (aNPCs) derived from the striatum and substantia nigra (SN) of
      parkinsonian rats. We found that aNPCs isolated from the two areas of
      parkinsonian rats readily formed nestin-enriched neurospheres in vitro and
      exhibited an ability to differentiate into either neurons or astrocytes.
      Injection of epidermal growth factor (EGF) and basic fibroblast growth factor
      (bFGF) into the striatum of parkinsonian rats prior to the harvesting striatal
      aNPCs significantly increased the neurosphere formation rate and multiple
      differentiation capacity of these aNPCs when cultured in vitro. These data
      suggest that striatal and nigral adult NPCs in parkinsonian rats retain the
      abilities of proliferation and differentiation in vitro. In addition, exogenously
      applied growth factors could up-regulate the developmental potential of aNPCs. We
      conclude that our data supports the notion that endogenous cell replacement
      therapies may be useful for the future treatment of Parkinson's disease (PD).

PMID- 15196667
TI  - Developmental changes in the activities of aromatic amino acid decarboxylase and
      catechol-O-methyl transferase in the porcine brain: a positron emission
      tomography study.
AB  - Newborn (7-10 days old) and young (6-8 weeks old) pigs were used to study the
      metabolism of 6-[18F]fluoro-L-DOPA (FDOPA) in various brain regions with positron
      emission tomography (PET). Compartmental modeling of PET data was used to
      calculate the rate constants for the decarboxylation of FDOPA (k3) and for the
      metabolism of the resulting [18F]fluoro-dopamine (kcl). Whereas general
      physiological parameters such as cerebral blood flow, cerebral oxygen uptake,
      arterial blood gases and glucose concentration remained unchanged in young pigs
      as compared to newborns, a 50-200% increase of k3 in frontal cortex, striatum and
      mesencephalon was found. Also a 60% enhancement of kcl in the frontal cortex was
      measured, which is related to changes of the catechol-O-methyl-transferase (COMT)
      activity and implies a special function of this enzyme in the development of this
      brain region. In addition, measurement of plasma metabolites of FDOPA with HPLC
      was performed. The metabolism of FDOPA in young pigs was significantly faster
      than in newborns. Calculation of the rate constant for O-methylation of FDOPA by
      COMT revealed a significant elevation of this enzyme activity in young pigs
      compared to newborns. The increase of AADC and COMT activity with brain
      development is considered to be associated with special stages of neuronal
      maturation and tissue differentiation.

PMID- 15196668
TI  - Endogenous glutathione and catalase protect cultured rat astrocytes from the iron
      mediated toxicity of hydrogen peroxide.
AB  - Primary astrocyte cultures from rat brain were exposed to hydrogen peroxide
      (H2O2) to investigate peroxide toxicity and clearance by astrocytes. After bolus
      application of H2O2 (100 microM), the peroxide was eliminated from the incubation
      medium following first-order kinetics with a half-time of approximately 4 min.
      The rate of peroxide detoxification was significantly slowed by pre-incubating
      the cells with the glutathione synthesis inhibitor buthionine sulfoximine (BSO),
      or the catalase inhibitor 3-amino-1,2,4-triazole (3AT), and was retarded further
      when both treatments were combined. H2O2 application killed a small proportion of
      cells, as indicated by the levels of the cytosolic enzyme lactate dehydrogenase
      in the media 1 and 24h later. In contrast, cell viability was strongly
      compromised when the cells were pre-incubated with 3AT and/or BSO before peroxide
      application. The iron chelator deferoxamine completely prevented this cell loss.
      These results demonstrate that chelatable iron is involved in the toxicity of
      H2O2 and that both the glutathione system and catalase protect astrocytes from
      this toxicity.

PMID- 15196669
TI  - Involvement of classical anterior and posterior language areas in sign language
      production, as investigated by 4 T functional magnetic resonance imaging.
AB  - To investigate the cerebral organization for language production across the
      particular channels supporting linguistic behavior, a functional magnetic
      resonance (fMRI) study was conducted in deaf native users of American Sign
      Language (ASL) and age-matched hearing controls. Seven native ASL speakers and 15
      vocal English speaking subjects covertly performed an object naming task inside
      the 4 T scanner using their native languages ASL or English, respectively. In
      subjects of both groups, classical language areas were found to be activated,
      including posterior Broca's area, the anterior insula, premotor cortex, and the
      posterior parts of the superior temporal cortex. Activations showed a
      predominance of the left hemisphere for both groups. In the deaf group, however,
      there was markedly larger involvement of the cerebellum, the inferior frontal
      gyrus, and the posterior insula and more robust activation in occipito-temporal
      and superior parietal cortices. In summary, it could be demonstrated by fMRI that
      native language production using ASL is associated with activation of classical
      language areas, although the neural organization for language processing is not
      identical in the two language modalities ASL and English language.

PMID- 15196670
TI  - IL-4 is the key regulator in herpes simplex virus-based gene therapy of BALB/c
      experimental autoimmune encephalomyelitis.
AB  - Local delivery of cytokines or other immunomodulatory components has been applied
      as a potential therapy for experimental autoimmune encephalomyelitis (EAE), which
      is used as a model of human multiple sclerosis. We have used herpes simplex virus
      based vectors expressing Th2 cytokines IL-4 and IL-10 and have previously shown a
      significant abolishment of disease symptoms by the virus expressing IL-4 (R8306),
      but not by the one expressing IL-10 (R8308). In the present study, the aim was to
      investigate the local and systemic cytokine response after HSV-based gene
      therapy. We show that the local expression of IL-4 from an HSV vector delivered
      to the brain converts the cytokine environment from the disease-promoting Th1
      prominent to the disease-limiting IL-4 expressing type. We measured the
      expression of cytokines IL-4, IL-10, IFN-gamma, IL-12p35, IL-12p40 and the novel
      IL-23p19 from the brain by quantitative LightCycler RT-PCR. We also investigated
      the systemic cytokine response from the mouse sera. The results indicate that an
      increase in the Th2 cytokine IL-4 is observed if the diseased mice are treated
      with IL-4-expressing virus R8306. Surprisingly, the IL-23 expression of R8306
      treated mice was at the same level as in the untreated EAE mice. On the contrary,
      in the R8308 (IL-10 expression) treated mice, the expression of IL-23 was
      decreased (P < 0.05). We conclude that the favorable effect of IL-4 on the
      disease development is more important than the downregulation of the Th1 type
      cytokines (like IL-23), and that IL-4 would be the key mediator of disease
      abolishment during gene therapy using these vectors.

PMID- 15196671
TI  - Histamine H3 receptor activation inhibits dopamine D1 receptor-induced cAMP
      accumulation in rat striatal slices.
AB  - In striatal membranes bearing significant levels of histamine H3 receptors (72 +/
      14 fmol/mg protein), the H3 agonist immepip (1 microM) increased [35S]GTPgammaS
      binding to 119 +/- 2% of basal, an effect prevented by the H3 antagonist
      clobenpropit and by pre-treatment with pertussis toxin. In slices labelled with
      [3H]adenine and in the presence of 1 mM isobutylmethylxantine (IBMX), the
      selective dopamine D1-like (D1/D5) receptor agonist SKF-81297 stimulated cyclic
      [3H]AMP ([3H]cAMP) accumulation (maximal stimulation 205 +/- 24% of basal, EC50
      113 +/- 12 nM), an effect fully blocked by the D1/D5 antagonist SCH-23390. The
      accumulation of [3H]cAMP induced by 1 microM SKF-81297 was inhibited in a
      concentration-dependent manner by the selective H3 receptor agonist immepip
      (maximal inhibition 60+/-5%, IC50 13 +/- 5 nM). The inhibitory action of 100 nM
      immepip was reversed in a concentration-dependent manner by the H3 antagonist
      thioperamide (EC50 13 +/- 3 nM, Ki 1.4 +/- 0.3 nM). Forskolin-induced [3H]cAMP
      accumulation (726 +/- 57% of basal) was also reduced by H3 receptor activation,
      although to a lesser extent (19.1 +/- 3.2% inhibition), an action not affected by
      the absence of either IBMX or Ca2+ ions in the incubation medium. Neither the
      density of [3H]SCH-23390 binding sites (D1 receptors) nor the inhibition by SKF
      81297 were affected by 1 microM immepip, ruling out a direct interaction between
      D1 and H3 receptors. These results indicate that through H3 receptors coupled to
      Galphai/o proteins, histamine modulates cAMP formation in striatal neurones that
      possess D1 receptors, most probably GABAergic striato-nigral neurones.

PMID- 15196672
TI  - Reading with the ears.
AB  - We studied the cortical networks of Morse code reading with functional magnetic
      resonance imaging (fMRI). Four expert radio telegraphists performed two closely
      matched reading experiments, one in binaurally presented high speed Morse code
      and one in print. Performance was equal for both conditions. Reading single nouns
      in Morse code resulted in predominantly left-sided activation of the frontal and
      temporal perisylvian language areas, prefrontal cortex, and premotor cortex. In a
      within-subject comparison between reading Morse code and reading print, the
      activation pattern in the left temporoparietal association cortex was similar for
      both forms of reading, suggesting that reading Morse code shares part of its
      cortical networks with reading print.

PMID- 15196673
TI  - Nerve injury alters profile of receptor-mediated Ca2+ channel modulation in vagal
      afferent neurons of rat nodose ganglia.
AB  - Although nerve injury is known to up- and down-regulate some metabotropic
      receptors in vagal afferent neurons of the nodose ganglia (NG), the functional
      significance has not been elucidated. In the present study, thus, we examined
      whether nerve injury affected receptor-mediated Ca2+ channel modulation in the NG
      neurons. In this regard, unilateral vagotomy was performed using male Sprague
      Dawley rats. One week after vagotomy, Ca2+ currents were recorded using the whole
      cell variant of patch-clamp technique in enzymatically dissociated NG neurons. In
      sham controls, norepinephrine (NE)-induced Ca2+ current inhibition was
      negligible. Following vagotomy, however, the NE responses were dramatically
      increased. This phenomenon was in accordance with up-regulation of alpha2A/B
      adrenergic receptor mRNAs as quantified using real-time RT-PCR analysis. In
      addition, neuropeptide Y (NPY) and prostaglandin E2 responses were moderately
      augmented in vagotomized NG neurons. The altered NPY response appears to be
      caused by up-regulation of Y2 receptors negatively coupled to Ca2+ channels. In
      contrast, nerve injury significantly suppressed opioid (tested with DAMGO)
      induced Ca2+ current inhibition with down-regulation of micro-receptors. Taken
      together, these results demonstrated for the first time that the profile of
      neurotransmitter-induced Ca2+ channel modulation is significantly altered in the
      NG neurons under pathophysiological state of nerve injury.

PMID- 15196674
TI  - Stimulation of hippocampal acetylcholine release by hyperforin, a constituent of
      St. John's Wort.
AB  - Extracts of the medicinal plant St. John's Wort (Hypericum perforatum) are widely
      used in the therapy of affective disorders and have been reported to exert
      antidepressant, anxiolytic, and cognitive effects in experimental and clinical
      studies. We here report that hyperforin, the major active constituent of the
      extract, increases the release of acetylcholine from rat hippocampus in vivo as
      determined by microdialysis. Hippocampal acetylcholine levels were increased by
      50-100% following the systemic administration of pure hyperforin at doses of 1
      and 10 mg/kg. The effect was almost completely suppressed by local perfusion with
      calcium-free buffer or with tetrodotoxin (1 microM). We conclude that hyperforin
      releases hippocampal acetylcholine by an indirect mechanism of action which is
      calcium-dependent and requires intact neuronal communication and cell firing. Our
      findings suggest therapeutic efficacy of St. John's Wort extracts in central
      cholinergic dysfunction.

PMID- 15196675
TI  - A novel melatonin derivative modulates sleep-wake cycle in rats.
AB  - The aim of this study was to evaluate, in comparison with melatonin (MLT), the
      effects of a novel 2-melatonin derivative, having a 2-trifluoromethyl group
      (MLTD) on the sleep-wake cycle in freely behaving rats. Doses of MLTD (100, 300
      and 500 nmol/100 microl saline) or MLT (500 nmol/100 microl saline) replaced the
      i.c.v. infusion of saline during the diurnal infusion period (7:00-17:00).
      Diurnal infusion of MLTD significantly (P < 0.05) increased NREM sleep at doses
      of 300 and 500 nmol during the second 4-h time interval of the light period and
      the lowest dose showed delayed effects on NREM sleep in the third 4-h time
      interval. However, REM sleep was only increased significantly at the dose of 500
      nmol. The infusion of MLT did not have effects on REM sleep but significantly
      increased NREM sleep. These findings support the notion that MLTD diurnal
      infusion into the third ventricle produces soporific effects dose-dependently and
      more potently than MLT. Thus, MLTD may play an important role in studies of
      sleep.

PMID- 15196676
TI  - Role of endonuclease G in neuronal excitotoxicity in mice.
AB  - Excitotoxicity is a process by which excitatory amino acids induce neuronal cell
      death. To what extent excitotoxicity is regulated by apoptotic molecules is
      currently unclear. We previously found that endonuclease G (EndoG) plays an
      important role in both normal apoptosis in vivo and in pre-implantation
      embryogenesis. To investigate whether EndoG participates in neuronal cell death,
      we compared EndoG expression and kainic acid (KA)-induced seizure behavior and
      excitotoxicity in EndoG+/- and wild-type mice. We found that EndoG expression in
      the hippocampus of EndoG+/- mice is reduced compared to that in the wild-type
      mice. The reduction of EndoG expression levels in the hippocampus did not result
      in altered KA-induced seizure severity in EndoG+/- mice compared to that in wild
      type mice. However, both CA3 and CA1 pyramidal neurons in EndoG+/- mice are more
      resistant to KA-induced cell death than that in wild-type mice. These results
      indicate that reduced expression of EndoG in the hippocampi of EndoG+/- mice
      leads to resistance to excitotoxicity.

PMID- 15196677
TI  - Sural nerve evoked responses in human hip and ankle muscles while standing.
AB  - The objective of this study was to investigate the influence of background EMG,
      as manipulated by changes in limb loading, and electrical stimulus intensity on
      sural nerve evoked EMG responses in proximal hip (ipsilateral gluteus medius and
      contralateral adductor longus) and distal ankle (ipsilateral soleus) muscles
      during quiet standing. We studied 14 healthy subjects who were instructed to
      stand on a force platform and load the right leg to 20, 30, 60, and 80% body
      weight. Trains of stimuli were delivered to the right sural nerve at three
      different intensities (1.5, 2, and 3 perception threshold). Average evoked
      responses from each of the three muscles were obtained for each combination of
      body weight and stimulus intensity. Reflex responses were consistently seen in
      gluteus medius and soleus but not adductor longus. The responses in gluteus
      medius and soleus consisted of complex inhibitory and excitatory responses with
      the primary effect in gluteus medius being a short latency excitation (mean
      latency of 57 ms) and in soleus, a short latency inhibition-excitation (latencies
      of 47 and 58 ms, respectively). The amplitudes of the responses were influenced
      primarily by background EMG. The results demonstrate consistent sural nerve
      evoked EMG responses in both a hip (gluteus medius) and ankle (soleus) muscle.
      While the findings for soleus generally corroborate and extend previous studies,
      the responses observed for the lateral hip muscle have not been previously
      reported.

PMID- 15196678
TI  - Scopolamine-induced amnesia can be prevented by heat shock pretreatment in rats.
AB  - The current study used the passive avoidance test to examine whether heat shock
      pretreatment has an effect on the memory impairment induced by scopolamine. Heat
      shock protein (HSP) 72 overexpression was detected in different brain structures
      in rats 16 h after heat shock treatment, but not in rats receiving no heat shock
      or 48 h after heat shock treatment. The step-through latency of either pre- or
      post-training administration of scopolamine in rats 16 h after heat shock
      treatment was significantly higher than those of the rats receiving no heat shock
      or 48 h after heat shock treatment. However, rats, 16 h after heat shock
      treatment and having been given scopolamine, performed no better than rats
      treated only with scopolamine. Hence, the present results indicate that heat
      shock has a protective, but not therapeutic, effect on the memory impairment
      induced by scopolamine by overexpression of HSP72 in rat brain.

PMID- 15196679
TI  - GABAA receptor alpha1 and alpha6 subunits mediate cell surface anchoring in
      cultured cells.
AB  - The clustering and immobility of gamma-aminobutyric acid type A receptors
      (GABAARs) at discrete and functionally significant domains on the nerve cell
      surface is an important determinant in the integration of synaptic inputs. To
      investigate the role that different GABAAR alpha subunit isoforms play in
      determining receptor mobility, alphaxbeta3gamma2s subunits (where x = subunit
      isoforms 1-6) were co-transfected into COS 7 and human embryonic kidney (HEK) 293
      cells and the surface mobility of these recombinant complexes was measured by
      fluorescence photobleach recovery (FPR). In addition, the lateral mobility of
      endogenous GABAARs in cerebellar granule (CG) cells was measured. We show that
      the alpha1 and alpha6 subunits immobilize recombinant GABAAR in transfected
      cells. This is consistent with the immobility of native receptors in CG cells,
      which express alpha1 and alpha6.

PMID- 15196680
TI  - The role of the human ventromedial prefrontal cortex in memory for contextual
      information.
AB  - There is a growing body of evidence that the ventromedial prefrontal cortex
      (VMPFC) is implicated in the new learning of visual items. Little is known,
      however, as to the involvement of that portion of the prefrontal cortex in the
      learning of temporal and spatial relationship of those items. The aim of the
      present study, therefore, was to investigate the role of the VMPFC in memory for
      temporal and spatial order. Patients who had undergone surgery of the anterior
      communicating artery aneurysm, and normal control subjects (C), participated in
      the study. The patients were subdivided into three groups: with resection of the
      left (LGR+) or right (RGR+) gyrus rectus, and without such a resection (GR-).
      Subjects were presented with two memory tests: a temporal order (TO) test and a
      spatial order (SO) test. In the TO test, the LGR+ and RGR+ groups performed worse
      than the C group, while the GR- group did not differ significantly from the C
      group. In the SO test, the LGR+ and RGR+ groups did not differ significantly from
      the C and GR- groups. However, the trend appears to be the same for both tests,
      although only the TO test provides statistically significant group differences.
      Our results thus suggest that the VMPFC is involved in memory for contextual
      information. Together with previous findings, the data suggest that the learning
      of the relationship between items as well as the learning of those items are
      mediated by overlapping areas of the VMPFC.

PMID- 15196681
TI  - Effects of long duration exercise on cognitive function, blood glucose, and
      counterregulatory hormones in male cyclists.
AB  - Electrocortical effects of long duration exercise on cognitive function were
      investigated by analyzing P300 amplitude and latency changes during a 3-h cycling
      exercise. P300 components were measured in 12 well-trained cyclists and blood
      glucose, cortisol, insulin, glycerol, and free fatty acids (FFAs) epinephrine and
      norepinephrine were analyzed. Results indicated that P300 components were
      affected by exercise with a temporary increase in amplitude between the 1st and
      the 2nd hour and an increase in latency after 2 h of exercise concomitant with
      some hormonal changes, including an increase in cortisol and epinephrine and a
      decrease in blood glucose. These findings suggest a combined effect of arousal
      and central fatigue on electrocortical indices of cognitive function during acute
      physical exercise.

PMID- 15196682
TI  - Neurofilament formation and synaptic activity are delayed in the myenteric
      neurons of the rat fetus with gastroschisis.
AB  - Gastroschisis is a malformation characterized by prenatal evisceration of the
      midgut into the amniotic cavity. Because of the harmful effects of the amniotic
      fluid, the intestinal loops appear matted, thickened, and covered by a peel. At
      birth, the newborn presents altered intestinal motility. In a previous
      publication, we reported a delay in the myenteric ganglia organization and
      neuronal maturity in a rat model of gastroschisis. In the present study, the
      neurofilament formation and synaptic activity were immunohistochemically
      investigated in the myenteric neurons of this animal model. The expression of
      low, medium and high molecular weight neurofilament proteins and of a protein of
      the synaptic vesicles, the synaptophysin, were similar to those found at earlier
      embryonic ages. These findings demonstrate delayed cytoskeletal organization and
      reduced synaptic activity in the myenteric neurons in the rat model of
      gastroschisis.

PMID- 15196683
TI  - "Low" concentrations of sodium fluoride inhibit neurotransmitter release from the
      guinea-pig superior cervical ganglion.
AB  - The role of G proteins and related second messenger system on the modulation of
      acetylcholine release from [3H]choline-preloaded guinea-pig superior cervical
      ganglion was investigated using the potent general activator NaF. The
      electrically evoked (1 Hz, 5 min) [3H] release was inhibited by "low" F-
      concentrations (1-2.5 mM), by the adenylyl cyclase blocker MDL 12330A (10
      microM), alone and in combination with 1 mM NaF, and increased by 0.5 mM 8Br
      cAMP, 100 microM forskolin and 0.5 mM 3-isobutyl-1-methylxantine. No effect of 1
      mM F- was observed on spontaneous release. Fluoride-induced inhibition was
      counteracted by the G protein blocker sulmazole (1 mM), forskolin and alteration
      of calcium influx by increasing [Ca2+]out from 2.2 to 6 mM, raising the rate of
      stimulation (10 Hz, 30 s), or broadening the presynaptic action potential with 10
      microM 4-aminopyridine and 50 microM tetraethylammonium chloride. Thus a NaF
      sensitive G protein, linked to cAMP synthesis, is determinant for the inhibition
      of neurosecretion in this cholinergic synapse, involving Ca2+-dependent
      mechanisms.

PMID- 15196684
TI  - Fully automated localization of the human primary somatosensory cortex in one
      minute by functional magnetic resonance imaging.
AB  - A clinical functional magnetic resonance imaging (fMRI) protocol based on a fully
      automated tactile stimulation was optimized in 10 right-handed volunteers at 1.5
      T for minimum scan time, high BOLD-signals and robust localization of the primary
      somatosensory cortex (S1) by systematically varying the applied block design. All
      volunteers had six different fMRI measurements of 5 stimulation/baseline cycles
      each with equal block duration that was changed between the measurements from 6
      to 30 s. Data sets of 4, 3 and 2 cycles were generated post hoc resulting in a
      total of 240 data sets that were evaluated individually for BOLD-signal intensity
      (dS%), correlation to the hemodynamic reference function (r) and Euclidean
      coordinates (x, y, z). The protocol with 5 cycles, a block duration of 6 s and a
      total scan time of 66 s provided the best BOLD-signal characteristics (dS% =
      1.15, r = 0.78). Compared to the mean scan time of other clinical fMRI protocols
      (174 s) a reduction of 62% was achieved.

PMID- 15196685
TI  - Distinctive pattern of c-fos expression in the feline cervico-lumbar spinal cord
      after stimulation of vanilloid receptors in dorsal neck muscles.
AB  - In the present study, c-fos expression in the spinal cord has been used as a
      marker of neuronal activation induced by capsaicin-sensitive sensory afferents
      from the dorsal neck muscles in cats (n = 6). The number of Fos-immunoreactive
      neurons, which were revealed using the avidin-biotin-peroxidase method, was
      significantly increased in the cervical and lumbar spinal cord. In contrast to
      the control group (n = 3), 2 h after intramuscular capsaicin injection, c-fos
      expression was more extensive ipsilaterally to the injected side in the C3-C6
      segments, and bilaterally in the L4-L6 segments. Most labeled neurons in the
      cervical spinal cord were small and giant cells, predominantly located in the
      middle and lateral parts of lamina I and, additionally, at the neck of the dorsal
      horn (lamina V), i.e., within the zones of termination of high-threshold muscle
      afferents. The widespread distribution of labeled cells throughout the cervical
      cord within the intermediate zone (lamina VII) coincided with the sites of last
      order premotor interneurons and cells of origin of long crossed and uncrossed
      descending propriospinal pathways to the lumbar spinal cord. These findings
      suggest possible mechanisms for spreading of nociceptive signals between cervical
      and lumbar regions.

PMID- 15196686
TI  - Enhancement of re-closure capacity by the intra-amniotic injection of human
      embryonic stem cells in surgically induced spinal open neural tube defects in
      chick embryos.
AB  - To evaluate the re-closure promoting capacity of human embryonic stem (hES) cells
      injected into the amniotic cavity on spinal open neural tube defects (ONTDs) of
      chick embryos, neural tubes were opened at Hamburger and Hamilton stage 18 or 19
      and the embryos were divided into three groups: a control group (no injection), a
      vehicle group, and a hES cell group (injection of 20,000 hES cells immediately
      after neural tube incision). On postoperative days 3, 5, and 7, ONTDs were
      significantly more re-closed in the hES cell group than in the other two groups.
      hES cells were present at the area in the process of re-closure, and covered
      ONTDs, but were not found in the re-closed area, suggesting indirect effects
      rather than cell replacement on the neural tissue.

PMID- 15196687
TI  - Upregulation of GluR2 decreases intracellular Ca2+ following ischemia in
      developing gerbils.
AB  - Developing animals are known to be resistant to cerebral ischemia. To investigate
      the mechanisms by which developing animals exhibit ischemic resistance, we
      examined the changes in intracellular calcium ([Ca2+]i) after oxygen-glucose
      deprivation (OGD) using hippocampal slices from gerbils. We found that increases
      of [Ca2+]i in hippocampal CA1 neurons is significantly less after OGD in
      developing gerbils than in adults. Western blot analysis of AMPA (alpha-amino-3
      hydroxy-5-methyl-4-isoxazole-propionic acid) receptors (AMPARs) showed that GluR2
      expression, but not that of the other AMPARs is significantly higher in
      developing gerbils than in adults. Expression of the anti-apoptotic proteins such
      as HSP70, Bcl-XL, and plasma membrane Ca2+-ATPase type1 (PMCA1) are not higher in
      the developing gerbils than in adults. These results suggest that the higher
      expression of GluR2 is important for the smaller increases in [Ca2+]i and
      enhanced resistance to ischemia-induced neuronal damage in developing animals.

PMID- 15196688
TI  - Selective reduction of gamma-aminobutyric acid type A receptor delta subunit mRNA
      levels by MK-801 in rat dentate gyrus.
AB  - The influence of excitatory blockade elicited by uncompetitive N-methyl-D
      aspartate (NMDA)/glutamate receptor antagonists on inhibitory GABAergic systems
      is not well understood. Adult male rats were injected i.p. with a single dose of
      the prototypical uncompetitive antagonist MK-801 (0.2-10 mg/kg) and in situ
      hybridization was performed to measure mRNA levels of gamma-aminobutyric acid
      type A (GABAA) receptor subunits (alpha1-6, beta1-3, gamma1-3, delta, and theta).
      A significant decrease in delta subunit mRNA levels, that reached approximately
      70% of saline-treated values, was observed in the hippocampal dentate gyrus
      following MK-801 administration. Other subunits did not display statistically
      significant alterations. These data demonstrate selective actions on GABAA
      receptor subunit levels that result from blockade of excitation by MK-801.

PMID- 15196689
TI  - Effect of chronic vincristine treatment on mechanical withdrawal response and pre
      pulse inhibition in the rat.
AB  - Chemotherapeutic agents are associated with a number of serious side-effects. In
      addition to the development of peripheral neuropathy, patients often complain of
      additional symptoms related to attentional mechanisms. Although a great deal of
      interest is directed towards understanding the mechanisms underlying the
      development of peripheral neuropathy, there is a paucity of research that has
      examined the extent of impairment of attention in animals receiving
      chemotherapeutic agents. Therefore, the purpose of this experiment was to examine
      attentional mechanisms using the method of pre-pulse inhibition in animals that
      were chronically treated with vincristine. Although vincristine treated animals
      developed signs of peripheral neuropathy, there was no associated alteration of
      pre-pulse inhibition relative to vehicle treated animals. These results highlight
      the importance of continuing to develop methodology to model symptom burden in
      patients receiving chemotherapy.

PMID- 15196690
TI  - Dendritic growth in response to environmental estrogens in the developing
      Purkinje cell in rats.
AB  - The cerebellar Purkinje cell is a major site for neurosteroid formation. We have
      demonstrated recently that the Purkinje cell actively produces sex steroids, such
      as estradiol and progesterone, de novo from cholesterol only during rat neonatal
      life, when cerebellar cortical formation occurs. We have further demonstrated
      that both estradiol and progesterone promote the growth of Purkinje cells through
      intranuclear receptor-mediated mechanisms during cerebellar development. On the
      other hand, environmental estrogens, such as octylphenol (OP), bisphenol A (BPA),
      and nonylphenol (NP) are thought to mimic the action of estrogen in the
      developing central nervous system. Therefore, in this study, the effect of these
      environmental estrogens on the growth of Purkinje cells was examined in vivo
      using newborn rats. OP and BPA promoted a dose-dependent dendritic outgrowth of
      the Purkinje cell but did not affect its soma and cell number. The stimulatory
      effect of OP and BPA on Purkinje dendritic growth was induced by an injection of
      500 microg/day into the cerebrospinal fluid for 4 days and blocked by the
      estrogen receptor antagonist tamoxifen. However, there was no significant effect
      of NP on any Purkinje cell morphology. These results suggest that the
      environmental estrogens, OP and BPA, promote Purkinje dendritic growth during
      neonatal life. This effect may be mediated by estrogen receptor in the Purkinje
      cell.

PMID- 15196691
TI  - ATP and cytochrome c-dependent inhibition of caspase-9 activity in the cerebral
      cortex of newborn piglets.
AB  - The present study investigates the mechanism of activation of caspase-9 during
      hypoxia and tests the hypothesis that ATP and cytochrome c regulate the activity
      of caspase-9 in the cerebral cortex of newborn piglets. Cerebral tissue hypoxia
      was documented by decreased levels of high energy phosphates, ATP and
      phosphocreatine (PCr). Cytosolic fractions were prepared from cerebral cortices
      and passed through a G50 column, to remove endogenous ATP and cytochrome c.
      Caspase-9 activity was determined spectrofluorometrically using a specific
      fluorogenic substrate for caspase-9 at increasing concentrations of ATP (0-1.0
      mM) or cytochrome c (0-3.0 microM). Caspase-9 activity (nmol/mg protein/h) was
      1.26 +/- 0.15 in the normoxic and 2.13 +/- 0.14 in the hypoxic group (P < 0.05).
      The enzyme activity was inhibited by ATP or cytochrome c in both normoxic and
      hypoxic groups. The IC50 for ATP and cytochrome c increased 5-fold and 1.5-fold,
      respectively, following hypoxia, suggesting a hypoxia-induced modification of the
      ATP and cytochrome binding sites. The data demonstrate that ATP (1 mM) and
      cytochrome c (3.0 microM) inhibit caspase-9 activity by approximately 70%. On the
      basis of these observations, we propose a new and novel concept that the caspase
      9 activity remains inhibited under the normoxic conditions and during hypoxia the
      decrease in ATP and decreases in the affinity for ATP and cytochrome c release
      the inhibitory block to activate the enzyme. Results of ATP- and cytochrome c
      dependent inhibition of purified caspase-9 human recombinant show that the
      inhibitory effect by ATP and cytochrome c does not require Apaf-1. To our
      knowledge, this is a completely new concept and a new mechanism of regulation of
      caspase-9 activity that may lead to hypoxia-induced programmed cell death.

PMID- 15196692
TI  - Enhanced locomotor activity in rats with excitotoxic lesions of the entorhinal
      cortex, a neurodevelopmental animal model of schizophrenia: behavioral and in
      vivo microdialysis studies.
AB  - In order to examine the construct validity of rats with excitotoxic damage of the
      left entorhinal cortex (EC) as an animal model of schizophrenia, we measured
      dopamine (DA)-related behaviors and methamphetamine (MAP)-induced DA release in
      the accumbens nucleus (NAC) in these animals. Quinolinic acid (lesion group) or
      phosphate buffer (sham group) was infused into the left EC of adolescent
      (postnatal 7 weeks) male Wistar rats. On the 14th and 28th postoperative day,
      spontaneous and MAP (1 mg/kg, i.p.)-induced locomotor activities, as well as MAP
      induced stereotypy, were measured. The lesioned rats exhibited significantly
      greater spontaneous or MAP-induced locomotor activity on both of the
      postoperative days than did sham-operated animals, while EC lesions did not
      affect MAP-induced stereotypy on either occasion. MAP (1 mg/kg, i.p.)-induced DA
      release in NAC was measured by in vivo microdialysis on the 28th postoperative
      day. Lesioned rats did not show a significant change in MAP (1 mg/kg, i.p.)
      induced DA release in NAC compared to sham-operated animals. These results
      suggest that excitotoxic damage of the left EC produces behavioral changes
      consistent with altered mesolimbic dopaminergic transmissions, possibly mediated
      by postsynaptic supersensitivity.

PMID- 15196693
TI  - Recovery of glucocorticoid-related loss of synaptic density in the fetal sheep
      brain at 0.75 of gestation.
AB  - Antenatal glucocorticoids routinely used to accelerate fetal lung maturation in
      human pregnancy at risk of preterm delivery decrease synaptic density and complex
      electrocortical activity in the fetal sheep brain at 0.87 gestation. We examined
      whether the effects of betamethasone on synaptic density depend on maturation of
      hypothalamo-pituitary-adrenal (HPA) axis and whether these effects are
      reversible. Betamethasone infusion to fetal sheep comparable to the dose used
      clinically (3.3 microg kg(-1) h(-1) over 48 h) at 0.75 gestation and, thus,
      before the prepartum increase of cortisol, reduced synaptophysin immunoreactivity
      (SY-IR) in the frontal neocortex, caudate putamen and hippocampus (P < 0.05).
      Loss of SY-IR exceeded that shown previously at 0.87 gestation (P < 0.05). It was
      not accompanied by neuronal damage and was reversible within 24h. In conclusion,
      fetal betamethasone exposure induces a gestational age-dependent decrease of
      synaptic density that is transient and more severe in younger fetuses.

PMID- 15196694
TI  - Human follitropin receptor (FSHR) interacts with the adapter protein 14-3-3tau.
AB  - The human follitropin (follicle stimulating hormone, FSH) receptor (FSHR) is a G
      protein-coupled receptor (GPCR). To identify cytoplasmic proteins that may
      regulate FSHR function, a yeast-based interaction trap was performed. A linked
      construct of the first and second intracellular loops (iL1-iL2 bait) of FSHR was
      used as bait and a human ovarian cDNA library was used as prey. Among the
      proteins identified that interacted with the bait was 14-3-3tau, a member of a
      family of homodimeric cytoplasmic adapter proteins. Human granulosa cells, the
      site of FSHR expression in the ovary, were found to contain 14-3-3tau.
      Importantly, 14-3-3tau co-immunoprecipitated with FSHR stably expressed in HEK
      293 cells. Its association with FSHR was follitropin-dependent. Over-expression
      of 14-3-3tau resulted in a modest decrease of follitropin-induced cAMP
      accumulation. Collectively, these data support a role for 14-3-3tau in
      follitropin action. The finding that 14-3-3tau interacts with FSHR is novel and
      should lead to new insights into the regulation of GPCR in general and FSHR
      specifically.

PMID- 15196696
TI  - Cytokine-induced PGE(2) formation is reduced from iNOS deficient murine islets.
AB  - Cytokines may be involved in islet destruction during Type 1 diabetes. Exposure
      to interleukin-1beta (IL-1beta) or IL-1beta plus interferon-gamma (IFN-gamma) of
      rodent islets induces expression of inducible nitric oxide synthase (iNOS) and
      cyclooxygenase-2 (COX-2). Subsequent formation of nitric oxide (NO) and
      prostaglandin E(2) (PGE(2)) may impair beta-cell function. Using iNOS deficient
      (iNOS -/-) islets, we have further investigated the relation between NO formation
      and PGE(2) induction. We found that iNOS -/- islets responded with a reduced
      PGE(2) formation following IL-1beta or (IL-1beta + IFN-gamma) treatment compared
      to wild-type (wt) islets, while COX-2 mRNA or protein content were unchanged. By
      the addition of an NO donor together with IL-1beta, PGE(2) formation could be
      stimulated from iNOS -/- islets. We conclude that the lowered capacity of PGE(2)
      formation observed from cytokine exposed iNOS -/- islets is due to a decreased
      stimulation of PGE(2) formation by the COX-2 enzyme in the absence of NO, rather
      then differences in expressed COX-2 protein.

PMID- 15196695
TI  - Epidermal growth factor and calcitriol synergistically induce osteoblast
      maturation.
AB  - Calcitriol (1alpha,25(OH)(2)D(3)) plays a key role in the differentiation of
      osteoblasts, the cells responsible for the formation and maintenance of healthy
      bone matrix. Recently it has emerged that calcitriol influences the trafficking
      or stability of epidermal growth factor (EGF) receptors. However, how these
      agents might work together in regulating growth and differentiation has not been
      examined. Using the human osteoblast cell line, MG63, we were able to induce a
      profound differentiation response by treating these cells with a combination of
      calcitriol (100 nM) and EGF (10 ng/ml). Co-stimulation of MG63 osteoblasts with
      calcitriol and EGF led to synergistic increases in osteocalcin and alkaline
      phosphatase (ALP), proteins expressed by differentiating cells. Inhibition of
      differentiation was accomplished by MEK and protein kinase C (PKC) inhibitors.
      Other ligands known to signal via receptor tyrosine kinases could not substitute
      for EGF in the maturation response. These novel findings may help identify new
      processes that drive osteoblast differentiation.

PMID- 15196697
TI  - Intrinsic sex differences determine expression of growth hormone-regulated female
      cytochrome P450s.
AB  - The masculine profile of cytochrome P450s found in male liver is determined by
      the episodic secretion of growth hormone characteristic of males. In turn, the
      female pattern of P450s observed in female rat liver is regulated by the
      continuous secretion of growth hormone characteristic of the female. In order to
      determine if intrinsic and possibly permanent sex differences exist in the
      response of hepatic P450s to growth hormone regulation, we compared the effects
      of the episodic and continuous growth hormone profiles on the expression of
      female-dependent isoforms in cultured hepatocytes isolated from both sexes. We
      observed that female-specific CYP2C12 as well as female-predominant CYP2A1, 3A1,
      and 2C6 could be induced by growth hormone concentrations equal to as little as
      6, 0.6, and 0.06% of the mean circulating hormone profile found in normal
      females. Irrespective of sex, all four female-dependent isoforms were far more
      responsive to the continuous growth hormone profile than the episodic pattern.
      Lastly, female-derived hepatocytes in general responded with strikingly greater
      induction levels of P450s than male hepatocytes exposed to the same growth
      hormone profiles. The present findings demonstrate intrinsic, irreversible sex
      differences in growth hormone-regulated female-dependent P450s.

PMID- 15196698
TI  - Prolactin-modulated gene expression profiles in pancreatic islets from adult
      female rats.
AB  - The effects of prolactin (PRL) on transcript profile expression in 24h cultured
      pancreatic adult rat islets were investigated by cDNA expression array analysis
      to identify possible candidate mRNA species that encode proteins involved in the
      maturation and growth of the endocrine pancreas. The expression of 54 out of 588
      genes was altered by treatment with PRL. The differentially expressed transcripts
      identified were distributed in six main categories involved in cell proliferation
      and differentiation, namely, cell cycle regulation, signal transduction,
      transcription factors and coactivators, translational machinery, Ca(2+)-mediated
      exocytosis, and immuno-response. Treatment with PRL also reduced the expression
      of genes related to apoptosis. Several genes, whose expression was previously not
      known to be modulated by PRL were also identified including macrophage migration
      inhibitory factor and Ca(2+)/calmodulin-dependent protein kinase IV. These genes
      have recently been shown to play a crucial role in insulin secretion and insulin
      gene expression, respectively. Treatment with PRL also modified the expression of
      AKT2 and bone morphogenetic protein receptor 1A that control glucose homeostasis
      and directly affect the behavior of endocrine pancreas and/or the sensitivity of
      target tissues to insulin. In conclusion, PRL induces several patterns of gene
      expression in pancreatic islet cells. The analysis of these different patterns
      will be useful for understanding the complex mechanism of action of PRL in the
      maturation and differentiation of pancreatic islets.

PMID- 15196699
TI  - Genistein enhances expression of genes involved in fatty acid catabolism through
      activation of PPARalpha.
AB  - Although evidences are emerging that dietary isoflavones have beneficial effects
      in treatment of hyperlipidemia and cardiovascular diseases, the underlying
      molecular mechanism has not yet been extensively characterized. In this report,
      we showed that genistein, one of the major isoflavones, increased expression of
      genes involved in lipid catabolism such as carnitine palmitoyltransferase 1,
      liver form (CPT1L) in HepG2 cells, when assayed by real-time reverse
      transcriptase polymerase chain reactions as well as Western blotting analysis.
      The increase in mRNA-level of CPT1L after genistein treatment was not changed in
      the presence of ICI182780, a potent inhibitor of estrogen receptor, suggesting
      that this effect of genistein was estrogen receptor-independent. Since these
      genes involved in fatty acid catabolism are considered putative downstream target
      genes of peroxisome proliferators-activated receptor alpha (PPARalpha), we
      examined whether expression of PPARalpha was modulated by genistein treatment.
      Interestingly, genistein induced expression of PPARalpha at both mRNA- and
      protein-level. Further, genistein activated transcriptional activity of
      PPARalpha, when determined by reporter gene analysis, suggesting genistein as a
      potential ligand for PPARalpha. Taken together, this study provides a picture of
      the regulatory action of genistein, as an activator of PPARalpha in fatty acid
      catabolism and potential use of genistein as lipid-lowering agent.

PMID- 15196700
TI  - Activin isoforms signal through type I receptor serine/threonine kinase ALK7.
AB  - Activins play a fundamental role in cell differentiation and development. Activin
      A signaling is mediated through a combination of activin type II receptors
      (ActRIIs) and the activin type IB receptor, ALK4. Signaling receptors of other
      activin isoforms remain to be elucidated. Here, we found that activin AB and
      activin B are ligands for ALK7. ALK7 is an orphan receptor serine/threonine
      kinase expressed in neuroendocrine tissues including pancreatic islets. The
      combination of ActRIIA and ALK7, preferred by activin AB and activin B but not by
      activin A, is responsible for activin-mediated secretion of insulin from
      pancreatic beta cell line, MIN6. In contrast, all activins activate a combination
      of ActRIIA and ALK4 with various levels of potency. Thus, variation in activin
      signaling through type I receptors is dependent upon homo- and heterodimeric
      assembly of activin isoforms. Thus, the differential combination of receptor
      heterodimers mediates variation in activin isoform signaling.

PMID- 15196701
TI  - Diethylstilbestrol inhibits the expression of the steroidogenic acute regulatory
      protein in mouse fetal testis.
AB  - This study investigated the early deleterious effects of an in-utero exposure to
      diethylstilbestrol (DES) on mouse testicular development. To that purpose,
      pregnant mice were injected daily with up to 100 microg/kg DES from 10.5 to 17.5
      days postcoitum (dpc). At 18.5 dpc, testes were removed from fetuses for RNA (RT
      PCR) and protein (Western blot, immunohistochemistry) analysis. Twenty-two genes
      were selected among which transcription factors, markers of differentiation of
      the different testicular cell lineages, steroidogenic enzymes and hormone
      receptors. The Steroidogenic Acute Regulatory (StAR) protein produced by the
      fetal Leydig cells was dramatically reduced in the DES-exposed testes. The
      P450c17 was the other gene modified following DES exposure. The alteration of
      these two genes is consistent with the decrease observed in the intratesticular
      testosterone levels, in the DES-exposed testes. Collectively, we demonstrated
      that DES did not alter testicular cell lineage specification but that it strongly
      inhibited the major function of the fetal Leydig cells.

PMID- 15196702
TI  - Differential expression of thyroid-stimulating hormone beta subunit in gonads
      during sex reversal of orange-spotted and red-spotted groupers.
AB  - We have cloned and characterized the full-length cDNA encoding thyroid
      stimulating hormone beta-subunit (TSHbeta) from orange-spotted grouper
      Epinephelus coioides. It contains 913 nucleotides with an open reading frame
      encoding 146 amino acids with a 20 amino acid signal peptide. The grouper mature
      TSHbeta has 75, 70, 61, 59, 41, 42 and 40% identities to that of rainbow trout,
      Atlantic salmon, zebrafish, European eel, chicken, mouse and human, respectively.
      RT-PCR analysis indicated that the TSHbeta mRNA was expressed abundantly not only
      in pituitary but also in gonads. A more interesting finding is to reveal the
      differential TSHbeta expressions between the ovaries and the transitional gonads
      or testes in natural individuals of orange-spotted grouper and red-spotted
      grouper Epinephelus akaara, and in artificial sex reversal individuals of red
      spotted grouper induced by MT feeding. In situ hybridization localization
      provided direct evidence that the TSHbeta was transcribed in the germ cells. In
      the growing oocytes, the TSHbeta transcripts were concentrated on the ooplasm
      periphery. In testicular tissues, the intensively expressed TSHbeta cells were
      found to be spermatogonia and spermatocytes in the spermatogenic cysts. This is
      the first report of a TSHbeta expressed in the gonads of any vertebrates in
      addition to the expected expression in the pituitary, and it expresses more
      transcripts in the gonads during sex reversal or testis than in the ovaries both
      in E. coioides and E. akaara. Importantly, the TSHbeta identification in germ
      cells allows us to further investigate the functional roles and the molecular
      mechanisms in gametogenesis of groupers, especially in sex reversal and in
      spermatogenesis.

PMID- 15196703
TI  - Involvement of SAPK/JNK in prostaglandin E(1)-induced VEGF synthesis in
      osteoblast-like cells.
AB  - We previously reported that prostaglandin E(1) (PGE(1)) activates both p44/p42
      mitogen-activated protein (MAP) kinase and p38 MAP kinase via cAMP-dependent
      protein kinase in osteoblast-like MC3T3-E1 cells, and that p38 MAP kinase but not
      p42/p44 MAP kinase is involved in PGE(1)-induced synthesis of vascular
      endothelial growth factor (VEGF). In the present study, we investigated the
      involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)
      in the PGE(1)-induced VEGF synthesis in MC3T3-E1 cells. PGE(1) induced the
      phosphorylation of SAPK/JNK. SP600125, a specific inhibitor of SAPK/JNK, markedly
      reduced the PGE(1)-induced VEGF synthesis. Forskolin, a direct activator of
      adenylyl cyclase, elicited the phosphorylation of SAPK/JNK, and 8bromo-cAMP, a
      plasma membrane-permeable cAMP analogue-stimulated VEGF synthesis was
      significantly reduced by SP600125. SP600125 suppressed the PGE(1)-induced
      phosphorylation of SAPK/JNK without affecting the phosphorylation of p38 MAP
      kinase induced by PGE(1). The phosphorylation of c-Jun induced by PGE(1) was also
      inhibited by SP600125. SB203580, a p38 MAP kinase inhibitor, failed to reduce the
      PGE(1) induced phosphorylation of SAPK/JNK. A combination of SP600125 and
      SB203580 suppressed the PGE(1)-stimulated VEGF synthesis in an additive manner.
      These results strongly suggest that PGE(1) activates SAPK/JNK in osteoblasts, and
      that SAPK/JNK plays a part in PGE(1)-induced VEGF synthesis.

PMID- 15196704
TI  - A new MCF-7 breast cancer cell line resistant to the arzoxifene metabolite
      desmethylarzoxifene.
AB  - The development of resistance in tamoxifen-treated breast cancer patients and the
      estrogenic side effects of tamoxifen have lead to the design of many new drugs.
      The new SERM arzoxifene and its active metabolite desmethylarzoxifene (ARZm)
      inhibits growth of breast cancer cells and has less estrogenic effects than
      tamoxifen on gene expression. A cell line with acquired resistance to ARZm (MCF
      7/ARZm(R)-1) was established from MCF-7 cells. MCF-7/ARZm(R)-1 cells responded to
      treatment with tamoxifen and the pure antiestrogen ICI 182,7870. The estrogen
      receptor alpha (ERalpha) level in MCF-7/ARZm(R)-1 cells was lower than in MCF-7
      cells due to a destabilization of the receptor by ARZm. A significant reduction
      in the mRNA and protein level of some estrogen-regulated genes was observed in
      MCF-7/ARZm(R)-1 compared to MCF-7. However, both the level of the ERalpha and
      several ER-regulated gene products increased towards parental MCF-7 level upon
      withdrawal from ARZm, concomitant with an increase in the sensitivity of MCF
      7/ARZm(R)-1 cells to ARZm treatment. These data show that ARZm resistant cells
      remain sensitive to treatment with both tamoxifen and to ICI 182,780.
      Furthermore, the partial reversion to ARZm sensitivity upon withdrawal of the
      SERM suggests that patients may benefit from a rechallenge with ARZm.

PMID- 15196706
TI  - Genesis and Fate of the Preimplantation Embryo. Proceedings of the Serono
      Symposium. Sorrento, Italy, 29 September-1 October 2002.

PMID- 15196705
TI  - Growth hormone (GH) receptors in prostate cancer: gene expression in human
      tissues and cell lines and characterization, GH signaling and androgen receptor
      regulation in LNCaP cells.
AB  - Various hormones and growth factors have been implicated in progression of
      prostate cancer, but their role and the underlying molecular mechanism(s)
      involved remain poorly understood. In this study, we investigated the role of
      human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We
      first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform
      (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma
      patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell
      lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the
      carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3
      cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was
      further characterized, on the basis of its M(r) of 120kDa, its binding to two
      different GHR monoclonal antibodies, its high affinity and purely somatogenic
      binding to (125)I-hGH and its ability to secrete GH binding protein, all
      characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose
      dependent signaling events in LNCaP cells, including phosphorylation of JAK2
      tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44
      MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen
      induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH
      caused a rapid (2-12h) though transient striking increase in immunoreactive
      androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h)
      reduction (< or = 80%), with only modest parallel changes in serine
      phosphorylated AR. In conclusion, the GH-induced activation of signaling
      pathways, its effects on AR protein in LNCaP cells and the isoform-specific
      regulation of GHR in prostate cancer patient tissues, suggest that GH, most
      likely in concert with other hormones and growth factors, may play an important
      role in progression of human prostate cancer.

PMID- 15196707
TI  - Oocyte cryopreservation: a biological perspective.
AB  - Oocyte cryopreservation would amount to a major breakthrough in reproductive
      medicine. Diverse strategies have been tested to minimise cooling-induced cell
      injury. Nevertheless, oocytes from various species have shown a particular
      sensitivity to freezing, due to their unique biological characteristics. Storage
      of human mature oocytes with slow freezing has resulted in low survival rates,
      although recent studies based on modified methods have reported higher success.
      Survival after thawing is not necessarily a guarantee of unaltered viability.
      Developmental failure at pre- or postimplantation stages may originate from
      critical perturbations of various cell components, such as the chromosome
      segregation apparatus, the intracellular calcium signalling system, and the
      cytoskeleton. Germinal vesicle (GV)-stage oocytes have been suggested to be more
      amenable to freezing. But their use would require efficient in vitro maturation
      systems, which are not presently available. Oocyte cryopreservation remains a
      realistic objective, provided that more systematic approaches are applied, such
      as thorough analysis of the plasmalemma permeability to water and the diverse
      cryoprotectants.

PMID- 15196708
TI  - Survival and developmental potential of stored human early cleavage stage
      embryos.
AB  - Human early cleavage stage embryos which survive cryopreservation and thawing
      fully intact demonstrate similar developmental potential to equivalent non frozen
      embryos when returned to the in vivo environment, whereas blastomere loss is
      directly related to the loss of potential for subsequent implantation in thawed
      embryos. This suggests that blastomere lysis during freezing and thawing does not
      occur preferentially in non viable blastomeres. Prefreeze growth rate rather than
      prefreeze blastomere number per se correlates with the developmental potential of
      stored embryos. When blastomere loss occurs as a consequence of cryopreservation,
      development of thawed early cleavage stage embryos to the blastocyst stage in
      vitro is impaired and the resultant blastocysts have a reduced total cell
      content. Blastomere loss is more prevalent in embryos which have been biopsied
      for preimplantation genetic diagnosis but this increased sensitivity can be
      circumvented by modification of the standard cryopreservation protocol.

PMID- 15196709
TI  - Blastocyst freezing.
AB  - Blastocyst are preimplantation embryos that have successfully passed the critical
      step of genomic activation and have so a high developmental potential, thus
      allowing to reduce the number of embryos transferred. Blastocyst culture and
      freezing have really started in IVF programs in the early nineties, when it was
      possible to obtain good blastocysts (essentially using coculture) on a large
      scale. Blastocysts freezing has been performed since the beginning using glycerol
      as cryoprotectant in slow protocols. The transition from coculture to sequential
      media has been a little bit delicate with a drop in the results. Few
      modifications including a change in the freezing curves and thawing at 37 degrees
      C have allowed to reach the same results with the two culture techniques.
      Vitrification with ethylene glycol (EG) has been proposed recently. However, the
      toxicity of the metabolites of EG for rat embryos has to be considered before
      moving to this technology on a large scale.

PMID- 15196710
TI  - Fate of stored embryos: our 10 years experience.
AB  - Couples accepting embryo cryopreservation signed an informed consent in which
      directives were given in case of death, divorce or absence. In this study, we
      tried to analyse our experience in terms of benefits achieved and to understand
      the feelings of couples about their embryos. (1) The majority of couples decided,
      or simply let, their embryos be discarded. In fact, a considerable proportion of
      them (25.1%) did not want to assume the responsibility of signing the disposal of
      their embryos. (2) Embryo donation is the most uncommon and difficult choice to
      make (6.0%) and this ought to be an important point to think over while dealing
      with law design. (3) An unexpected proportion of couples, who did not conceive,
      still have their embryos stored and this forces us to reflect on the difficulty
      of getting over the treatment failure.

PMID- 15196711
TI  - Granulosa cell-oocyte interactions.
AB  - Throughout oogenesis the oocyte and follicle cells establish an intricate system
      of mutual interactions that ultimately lead to the acquisition of their
      respective competences. Paracrine factors released by both cell types are
      believed to stimulate formation of the primordial follicle and support the
      initial phases of follicle growth. At the same time, these processes are also
      dependent on gap junction communication between the germinal and somatic
      compartment. At later stages of follicle development, activities released by the
      oocyte induce the adjacent granulosa cells to express a specialized phenotype. In
      their turn, these cells crucially regulate the ability of the oocyte to progress
      through the meiotic process and acquire full developmental potential.

PMID- 15196712
TI  - The role of mitochondria in the establishment of oocyte functional competence.
AB  - Mitochondria are maternally inherited, semi-autonomous organelles with their own
      genomes (mtDNA), largely responsible for the generation of energy in the form of
      cellular ATP. However, mitochondrial replication and transcription of mtDNA do
      not commence until well into embryonic differentiation. This means that the
      oocyte needs to contain sufficient stocks of functioning mitochondria to fuel the
      first few days of embryonic development. In this review, I examine how
      qualitative and quantitative aspects of mitochondria help us define the notion of
      functional competence.

PMID- 15196713
TI  - FSH: urinary and recombinant.
AB  - Infertility affects approximately 10-15% of couples. To enhance the chances of
      conception, assisted reproductive techniques (ART) have been improved and, in the
      last 5 years, thousands of babies have been delivered after IVF or ICSI
      procedures. To obtain an appropriate and controlled ovarian hyperstimulation
      (COH), clinicians have introduced many drug protocols based on GnRH agonists or
      antagonists for pituitary down-regulation and FSH or HMG for ovarian stimulation.
      Currently FSH is the most common drug used for ovulation induction. It is a
      glycosylated protein with a molecular weight of 28000-30000Da, normally secreted
      by the anterior pituitary gland. The recombinant preparations of follicle
      stimulation hormone (r-FSH) are characterized by a higher level of purity,
      reduced batch to batch variability and no risk of infection. The purpose of this
      review was to establish the efficacy of different trials based on the use of r
      FSH and urinary FSH (u-FSH) comparing published data from randomised studies on
      the ovulation induction for assisted reproductive techniques. Unfortunately, we
      did not find any paper with sufficient power to detect a clinically significant
      difference in pregnancy rates, however, recent meta-analysis among homogeneous
      trials indicates that the use of r-FSH is to be preferred to u-FSH because more
      oocytes were collected in cycles with better embryo quality and with more
      pregnancies. Recombinant FSH has a higher cost per ampoule than urinary FSH, but
      also a higher effectiveness. A recent cost-effectiveness analysis on follitropin
      alfa compared to urinary FSH-HP, using a Markov model, confirmed other previous
      studies that, considering the ongoing pregnancies beyond 12 weeks gestation, r
      FSH is the most effective therapy for ovulation induction in ART.

PMID- 15196714
TI  - FSH and LH together in ovarian stimulation.
AB  - The authors review the physiology of the ovulatory cycle and the role of the
      gonadotrophins in ovulation induction in patients with anovulatory disorders and
      in multifollicular development for assisted reproductive technologies. The use of
      gonadotrophins with luteinizing hormone (LH) activity and the use of recombinant
      LH associated with follicle stimulating hormone (FSH) are discussed. The authors
      point out that administration of gonadotrophins with LH activity is essential in
      hypogonadotropic hypogonadal anovulation, and data available in the medical
      literature allow the conclusion that recombinant LH may be added to all ovarian
      stimulation protocols because it is difficult to determine which patients will
      benefit from LH administration and there is no evidence that LH affects adversely
      the outcome of ovarian stimulation. The use of recombinant LH in addition to
      recombinant FSH may be particularly useful when a GnRH antagonist is associated
      with the ovarian stimulation regimen, by preventing the fall in estradiol and
      diminishing FSH requirements.

PMID- 15196715
TI  - GnRH analogs: depot versus short formulations.
AB  - Gonadotropin releasing hormone agonists (GnRH-a) are widely used in controlled
      ovarian hyperstimulation (COH) for assisted reproduction (ART). Two different
      formulations are now available: short formulations and depot formulation. Some
      authors have suggested that depot GnRH-a induce a too high pituitary suppression
      and have put forward protocols using reduced GnRH-a doses. A reduced dose of
      daily triptorelin is enough for pituitary suppression during ovarian stimulation
      but provides no significant improvement in IVF cycle outcome when compared with
      depot formulation in normally responding women. However, it seems to improve
      ovarian response and overall results in poor responding patients. Low doses of
      short GnRH-a allow shorter treatment, requiring lower amounts of gonadotropins.
      This possibility should be considered in view of its economic advantage.

PMID- 15196716
TI  - GnRH antagonists.
AB  - Ovarian stimulation is an important step in the success rate of in vitro
      fertilization (IVF) allowing multiple follicular growth, several oocytes and
      consequently more embryos. The combination of GnRH-antagonists (GnRH-ant) and
      gonadotrophins is now available for clinical use and represent a valid
      alternative to classical protocol with GnRH agonist. GnRH-antagonists induce a
      direct block of GnRH receptor with a rapid decrease in LH and FSH, preventing LH
      surge. Two protocols has been designed for assisted reproduction technology (ART)
      treatment: multiple-dose protocol and a single-dose. Both protocols are simply,
      efficacious, started in the late follicular phase and do not have side effects. A
      review of GnRH-antagonist applications in ART cycles are presented. Smaller doses
      of gonadotrophins, shorter stimulation period and lower ovarian hyperstimulation
      syndrome (OHSS) incidence are reported in literature using GnRH-antagonist
      compared to agonist. Triggering of ovulation, the use in polycystic ovarian
      syndrome (PCOS) and poor reponders patients are other interesting indication.
      Regarding to pregnancy rate and potentially adverse effects of drugs on
      endometrium or implantation needed more data.

PMID- 15196717
TI  - Egg-sperm interactions at fertilization in mammals.
AB  - Mammalian eggs are surrounded by a zona pellucida (ZP) that regulates egg-sperm
      teractions during fertilization. The ZP consists of long filaments composed of
      two glycoproteins, ZP2 and ZP3, that are crosslinked by a third glycoprotein,
      ZP1. The presence of both ZP2 and ZP3 is essential for assembling a ZP around
      growing oocytes, as well as for fertility of females. Acrosome-intact sperm
      recognize and bind to O-linked oligosaccharides linked to Ser residues at the
      sperm combining-site of ZP3. Structural differences in oligosaccharides on ZP3
      from different species may account for whether or not sperm are able to bind to
      the ZP. Bound sperm undergo the acrosome reaction, penetrate the ZP, and can then
      fuse with egg plasma membrane. Following fertilization, sperm are unable to bind
      to either ZP3 or the ZP of one-cell embryos.

PMID- 15196718
TI  - Ca2+ signalling and cortical re-organisation during the transition from meiosis
      to mitosis in mammalian oocytes.
AB  - In mammals, the mature ovulated egg is arrested in metaphase II of the first
      meiotic division. The signal that triggers the transition from meiosis to mitosis
      is provided by the fertilising sperm and takes the form of a series of Ca(2+)
      oscillations. The pattern of Ca(2+) oscillations is imposed by maternal control
      mechanisms that ensure Ca(2+) transients occur during M-phase of meiosis II and
      during the first mitotic division. The transition from meiosis to mitosis
      involves a major re-organisation. The unfertilised egg is polarised with the
      meiotic spindle located in the cortex of the animal pole and clusters of
      endoplasmic reticulum in the vegetal hemisphere. By the time of the first mitotic
      division some 20h later the spindle has formed in the centre of the embryo and is
      surrounded by endoplasmic reticulum. These changes in organisation have
      implications for the inheritance of ER in meiotic and mitotic cell divisions and
      may reflect different roles and requirements for Ca(2+) in meiosis and mitosis.

PMID- 15196720
TI  - Effects of culture conditions on IVF outcome.
AB  - Although in vitro fertilization (IVF) success rates have improved over the past
      decade, multiple pregnancies have become a formidable problem. The solution to
      this problem seems simple by mandating the reduction in numbers of embryos
      transferred. However, this is typically not accomplished without a compromise in
      the pregnancy rate. There have been a number of approaches designed to address
      high order multiple pregnancies from multi factorial analysis of early cleavage
      stage embryos to the development of extended culture systems, both of which
      require manipulations in the culture environment. Manipulations in embryo culture
      environment may not be benign. Several studies have demonstrated that adverse
      culture conditions have effects on gene expression and imprinting. Studies have
      also demonstrated that singleton human IVF babies have lower birth weight and
      higher incidence of congenital anomalies than natural conception babies. All of
      these factors need to be considered in relation to long term viability of IVF
      babies and the Barker hypothesis.

PMID- 15196719
TI  - In vivo versus in vitro fertilization.
AB  - The complex sequence of biological steps involved in reproduction in vivo is only
      partially reproduced in current IVF procedures. In fact, events playing a key
      role in vivo such as male gamete selection can only be partially mimicked in
      vitro. To understand the role played by the mammalian oviduct in sperm storage
      and selection several in vitro sperm-oviductal cell co-culture systems have been
      developed. Particular sperm subpopulations have been reported to be selected by
      in vitro cultured oviductal cells through cell-cell adhesion, in different
      species. In the bovine, in vitro selected sperm have been demonstrated to be
      endowed with a superior zona pellucida binding and fertilization competence. In
      conclusion, research on in vitro sperm oviduct interaction may provide new basic
      information about early reproductive events allowing the development of
      alternative methods for a more physiological sperm selection in assisted
      reproductive biotechnologies.

PMID- 15196721
TI  - Clinical application of laser-assisted ICSI: a pilot study.
AB  - Human oocyte survival after intracytoplasmic sperm injection (ICSI) can be
      compromised by abnormal oolemma breakage patterns during the penetration of the
      microinjection needle. We previously reported a case of repeated ICSI failures
      associated with abnormal oolemma breakage in which a substantial improvement and
      successful pregnancy were achieved by performing ICSI through a laser-drilled
      hole in the zona pellucida (laser-assisted ICSI). This study was undertaken to
      compare the efficacy of laser-assisted ICSI with that of conventional ICSI in
      patients whose oocytes present this particular feature. Oocytes treated by laser
      assisted ICSI (n=140) survived better (97.9% versus 85.7%; P<0.05) and tended to
      form more two-pronucleated zygotes (78.6% versus 69.2%; P=0.07) and less zygotes
      with three or more pronuclei (2.8% versus 7.8%; P=0.06) as compared with sibling
      oocytes treated by conventional ICSI (n=140). These data show that laser-assisted
      ICSI is suitable for oocytes with propensity for sudden oolemma breakage during
      conventional ICSI. The reduction of oocyte damage with laser-assisted ICSI as
      compared to conventional ICSI may be useful in other clinical indications where
      only few oocytes are available or when the oocyte survival after ICSI can be
      supposed to be compromised.

PMID- 15196722
TI  - Genetics of gametes and embryos.
AB  - Chromosome analysis of oocytes, sperm and embryos has mainly relied on
      fluorescent in situ hybridisation (FISH) and karyotyping. FISH studies have been
      performed on sperm from fertile and infertile men as well as men carrying known
      chromosomal translocations. Molecular DNA analyses has aided in the
      identification and treatment of men with Y chromosome deletions. In oocytes FISH
      and karyotyping have identified non-disjunction of univalents and predivision of
      chromatids. Analysis of the chromosomes from human embryos has shown that a high
      proportion of embryos are mosaic or chaotic, in addition to embryos beings
      uniformly and abnormal. FISH and PCR have also been used clinically for
      preimplantation genetic diagnosis (PGD). For patients at risk of transmitting a
      specific genetic or chromosomal abnormality, 1-2 blastomeres are biopsied from
      embryos and specific genes or chromosomes analysed. Normal embryos are then
      transferred to the uterus.

PMID- 15196723
TI  - A global view of gene expression in the preimplantation mouse embryo: morula
      versus blastocyst.
AB  - As a first step to understand preimplantation development, we performed global
      gene-expression profiling of morula and blastocyst using the NIA 15k mouse cDNA
      microarray. Gene expression levels were measured four times for blastocyst and
      five times for morula. Student's t-test at the 5% significance level identified
      428 genes upregulated and 748 downregulated in blastocyst compared to morula.
      This trend was consistent with semi-quantative RT-PCR analysis of sample genes.
      The upregulated genes known to be involved in critical regulatory processes,
      included Mist1, Id2, Hd1, and Requiem; the downregulated genes included CREB
      binding protein, Per3, zinc finger protein 217, Krox-25, and miwi1. Such well
      characterized genes and many novel genes provide markers for early stages in
      development and starting materials for further functional studies.

PMID- 15196724
TI  - Metabolism and developmental competence of the preimplantation embryo.
AB  - In vitro fertilisation (IVF) has permitted many thousands of couples to conceive
      world-wide yet is limited by low success rates and a confounding high multiple
      birth rate due to the transfer of more than one embryo. These problems could be
      overcome if single embryos of known developmental competence could be selected
      for replacement. It is clear that current embryo selection methods, which rely on
      morphological appearance alone, are poor predictors of viability. Metabolism is
      intrinsic to embryo health and much research has concentrated on developing a non
      invasive metabolic marker of developmental competence.

PMID- 15196725
TI  - Advances in preimplantation genetic diagnosis.
AB  - Strategies for preimplantation genetic diagnosis (PGD) have become increasingly
      complex. For single gene disorders it is now usual for several DNA fragments to
      be simultaneously amplified using multiplex-PCR. This allows redundant diagnostic
      loci to be analyzed, reducing the chance of misdiagnosis due to allele dropout
      (ADO). Additionally, hypervariable 'fingerprinting' loci can be amplified,
      revealing the presence of DNA contaminants. Chromosomal screening has also
      increased in complexity. Current FISH techniques investigate up to nine
      chromosomes per cell and are offered to an increasingly wide range of patients,
      including women of advanced reproductive age and those with a history of repeated
      spontaneous abortion. Technical limitations, which preclude a full assessment of
      all chromosomes using FISH, have encouraged the development alternative tests.
      These include nuclear conversion, comparative genomic hybridization (CGH) and the
      use of DNA microarray 'chip' technology. This paper discusses technical
      innovations that have improved the scope and accuracy of PGD, as well as the
      emergence of new indications for PGD that are sometimes considered controversial
      (e.g. HLA-typing).

PMID- 15196726
TI  - Perifollicular vascularity monitoring and scoring: a clinical tool for selecting
      the best oocyte.
AB  - The aim of our study was to assess relationship between perifollicular
      vascularity and outcome of in vitro fertilization (IVF) cycles. In our study,
      women who received embryos originating from oocytes developed in well
      vascularized follicles had a statistically higher pregnancy rate than women who
      received embryos chosen without considering follicles of origin.

PMID- 15196727
TI  - Cumulative pregnancy rates after transfer of fresh and thawed embryos.
AB  - Frozen-thawed embryo transfer is an effective procedure that allows further
      possibilities of pregnancy in addition to those obtained after the fresh in vitro
      fertilization (IVF). In our follow-up study we analysed all fresh embryo transfer
      procedures and every frozen-thawed embryo transfer performed from January 2000 to
      December 2001 evaluating the cumulative pregnancy rates. The study population was
      divided into two groups according to the female age: <38 years (group I) and >38
      years (group II). All the best embryos were chosen for transfer and all the
      supernumerary good quality embryos were cryopreserved on the day of transfer. The
      embryos were then thawed and manipulated using a new technique. In group I, 527
      patients (619 cycles) underwent fresh embryo transfer and in 232 of them (238
      cycles) the embryos were frozen (44% per patients and 38.4% per cycle). In group
      II, 156 patients (193 cycles) underwent fresh embryo transfer and in 14 of them
      (15 cycles) the embryos were frozen (9% per patient and 7.8% per cycle). The
      pregnancy rate of group I patients that had their supernumerary embryos frozen
      (232 patients and 238 cycles) was 47.4% per cycle and 48.7% per patient whereas
      in the same population of group II patients (14 patients and 15 cycles) the
      clinical pregnancy rate was 35.7% per cycle and 38.5% per patients. The
      cumulative clinical pregnancy rate after transfer of fresh and thawed embryos
      was: group I, 74% per cycle and 76% per patients; group II, 42.8% per cycle and
      46.1% per patient. Frozen-thawed embryo transfer is a cost-effective practice.

PMID- 15196728
TI  - Does insufficient adjustment for smoking explain the preventive effects of fruit
      and vegetables on lung cancer?
AB  - Recent reports have raised the question, whether the previously observed
      protective effects of high intake of fruit and vegetables on the risk of lung
      cancer were due to insufficient adjustment for smoking leading to residual
      confounding. Association of intake of fruit and vegetables on lung cancer risk
      was examined, using the Danish prospective cohort study, "Diet, Cancer and
      Health". Participants completed a food-frequency and lifestyle questionnaire, and
      age-standardized incidence rates and rate ratios were estimated for quartiles of
      dietary exposure. In 1993-2001, 247 out of the 54158 participants were diagnosed
      with lung cancer. The incidence rate of lung cancer was highest in the lowest
      quartile of intake of plant food (fruit, vegetables, legumes and potatoes) and
      the age-standardized rate ratio of lung cancer decreased significantly with
      increasing intake of plant food to 0.35 (95% CI, 0.27-0.45) but after control for
      smoking it was attenuated to 0.65 (95% CI, 0.45-0.93). The incidence rate
      differences of current smokers with high (> or = 400 g per day) and low (< 400 g
      per day) daily intake of plant food were independent of smoking intensity;
      assuming a true biological protective effect, 80-90 lung cancer cases per 100000
      current smokers could be prevented in our cohort if all smokers had a high intake
      of plant food. The observed inverse association between high intakes of plant
      food seems chiefly to be a real protective effect, and not solely due to residual
      confounding.

PMID- 15196729
TI  - Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or
      theophylline while the development of adenocarcinomas is promoted: implications
      for chemoprevention in smokers.
AB  - Lung cancer continues to be the leading cause of cancer death in developed
      countries. With smoking the major etiological factor for lung cancer, there is a
      great need for the development of chemopreventive treatments that inhibit the
      progression of initiated cells and premalignant lesions into overt lung cancer in
      smokers who quit. Although the major focus of chemoprevention research has been
      on agents that inhibit the metabolic activation of genotoxic chemicals contained
      in tobacco products, some of these agents may additionally modulate growth
      regulating signal transduction. In turn, the function of such signaling pathways
      is highly cell type-specific, with a given pathway inhibiting the growth of one
      cell type while stimulating the growth of others. The current experiment has
      tested the hypothesis that green tea and the methylxanthine theophylline
      contained in tea inhibit the progression of neuroendocrine lung carcinogenesis in
      hamsters with hyperoxic lung injury and initiated with the tobacco carcinogen 4
      (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) while promoting the
      development of Clara cell-derived pulmonary adenocarcinomas initiated by NNK in
      healthy hamsters. This hypothesis is based on published evidence that human small
      cell lung cancer as well as the neuroendocrine hamster tumors are regulated via
      autocrine signaling pathways that activate Raf-1 and the mitogen-activated (MAP)
      kinase pathway whereas human pulmonary adenocarcinomas of Clara cell lineage and
      the hamster model of this cancer type are regulated by a beta-adrenergic pathway
      involving the activation of cyclic adenosine 3',5'-monophosphate (cAMP) and the
      arachidonic acid (AA) cascade. In turn, it was hypothesized that theophylline
      would inhibit Raf-1-dependent tumor progression while promoting cAMP-dependent
      tumor progression due to its documented ability to inhibit the enzyme cAMP
      phophodiesterase. The experimental design simulated chemoprevention in former
      smokers in that treatments with tea or theophylline started after completion of a
      10-week tumor induction period with NNK. Our data show that green tea as well as
      theophylline significantly inhibited lung tumor multiplicity in the
      neuroendocrine cancer model whereas identical chemopreventive treatments
      significantly promoted the lung tumor multiplicity in the adenocarcinoma model.
      These findings indicate that green tea and theophylline as well as other
      chemopreventive agents that modulate signal transduction may have opposite
      effects on cancers of different histolopathology and cell lineage. At the current
      state of knowledge such chemopreventive treatments should only be used as
      adjuvant to cancer therapy of cancers that have been fully characterized at the
      pathology and molecular level.

PMID- 15196730
TI  - Evaluation of F-18 fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules
      less than 3 cm in diameter, with special reference to the CT images.
AB  - BACKGROUND: While pulmonary nodules can be substantially divided into solid and
      ground-glass opacity (GGO) ones on CT image, they have different biological
      natures which could cause false positive or false negative to diagnose malignancy
      on positron emission tomography with fluorodeoxyglucose (FDG-PET). To determine
      the effectiveness of PET for small pulmonary nodules, the nodules were classified
      into solid and GGO ones, of which results were compared with the data of PET
      scans. The lower limit size of nodules for PET imaging was also evaluated.
      METHODS: Prospective FDG-PET scans were undertaken for 136 non-calcified nodules
      less than 3 cm in diameter. CT density histograms were made for each nodule to
      classify into solid and GGO ones. RESULTS: Eighty-one nodules were malignant and
      55 were benign. All of the 20 nodules less than 1 cm in diameter (n = 8 in
      malignant, n = 12 in benign), were negative on PET regardless of the histology.
      In the 116 nodules 1-3 cm in diameter (n = 73 in malignant, n = 43 in benign),
      there were 15 false negative and 15 false positive nodules, with a sensitivity of
      79% and specificity of 65%. CT density histograms showed 101 solid nodules (n =
      63 in malignant, n = 38 in benign) and 15 GGO nodules ( n = 10 in malignant, n =
      5 in benign). All of the 10 malignant nodules with GGO images were histologically
      well-differentiated adenocarcinoma and 9 of them (90%) were false negative on
      PET. Four of the 5 (80%) benign nodules with GGO images were focal pneumonia with
      well-preserved air spaces, causing false positive on PET. Sensitivity and
      specificity for nodules with GGO images were 10 and 20%, respectively, which were
      significantly lower than 90 and 71% for nodules with solid images (P < 0.001).
      CONCLUSION: Pulmonary nodules which are less than 1cm in size or show GGO images
      on CT cannot be evaluated accurately by PET.

PMID- 15196731
TI  - Nodules, CT-scans and PET-scans: a good partnership.

PMID- 15196732
TI  - Skin reactivity to histamine and expression of histamine receptors mRNA in
      lymphocytes of healthy subjects and non-small-cell lung cancer patients before
      and after surgery.
AB  - Histamine modulates an immunological response through stimulation of appropriate
      receptor--H1R proinflammatory or H2R suppressive. The participation of histamine
      in regulation of an immunological response in the course of neoplastic disease is
      determined by the expression of particular receptor. The aim of our work was the
      investigation of the expression of mRNA of two types of histamine receptors in
      peripheral blood lymphocytes and the evaluation of skin-prick test with histamine
      in lung cancer patients before and after surgery. The investigation was performed
      on 15 patients qualified to surgery before and 7-10 days after treatment and on
      12 healthy subjects. Reverse transcriptase polymerase chain reaction (RT-PCR)
      with primers labeled with fluorescent dyes was performed. Intensity of
      fluorescence was expressed as relative fluorescence units (RFU). The data were
      analysed using ABI Prism 310 GeneScan collection software Version 3.1. Skin-prick
      test with histamine was evaluated after 10 min by measuring the diameter of the
      weal. The expression of H1R and H2R mRNA in healthy subjects was not
      significantly different in contrast to the lung cancer patients in which a
      significant prevalence of H2R mRNA expression was observed before surgery and
      only slightly decreased after (P < 0.001). Skin-prick test--negative in one
      patient before surgery, after treatment was positive in all patients and the
      diameter of histamine weal was significantly increased (P < 0.001). One may
      assume that the prevalence of the expression of H2R mRNA in patients reflects the
      status of immunosuppression caused by cancer. Since histamine exerts its
      suppressive activity trough H2R it seems reasonably to include the antagonists of
      this receptor to the cancer therapy which may restore a relative balance between
      accessibility of both types of histamine receptors.

PMID- 15196733
TI  - Impact of severe acute respiratory syndrome on the status of lung cancer
      chemotherapy patients and a correlation of the signs and symptoms.
AB  - Our aim was to describe the impact of severe acute respiratory syndrome (SARS) on
      the status and chemotherapy of non-small-cell lung cancer (NSCLC) patients who
      had entered clinical trials, and to review how to differentiate the signs and
      symptoms of SARS from lung cancer and its treatment-related toxicities. A
      prospective case series involving 79 NSCLC patients who were enrolled in clinical
      trials undergoing chemotherapy at Taipei Veterans General Hospital, between April
      1 and July 15, 2003, was studied. Whether or not there existed a delay, omission,
      or refusal of scheduled chemotherapy, was recorded. Whether or not our patients
      had been suspected of or treated as having SARS, was recorded. The patients
      filled out questionnaires regarding lung cancer treatment and the risk of getting
      SARS from the hospital. Among these patients, five were placed in an isolation
      unit to rule out SARS infection during this period of time, and no patient was
      documented to have suffered from a SARS infection after examinations. Of 373
      scheduled chemotherapy injections in 79 patients, a delay in treatment occurred
      only 10 times. Three patients refused further chemotherapy because of a fear of
      getting SARS if they visited the hospital. Fifty-eight patients responded to our
      questionnaires. Thirty-seven patients (63.8%) were afraid of visiting hospital
      during this SARS infection period. Twenty-one patients (36.2%) felt that a SARS
      infection was more severe and fatal than their lung cancer. In conclusion, SARS
      is a new disease entity that is highly contagious. Its clinical manifestations
      overlap with the signs and symptoms of lung cancer. Thus, a clear differentiation
      between the two conditions is needed, especially for those patients who are under
      active anti-cancer treatment.

PMID- 15196734
TI  - Clinical outcomes of stereotactic radiotherapy for stage I non-small cell lung
      cancer using a novel irradiation technique: patient self-controlled breath-hold
      and beam switching using a combination of linear accelerator and CT scanner.
AB  - We have developed a novel irradiation technique for lung cancer that combines a
      linear accelerator and CT scanner with patient-controlled breath-hold and
      radiation beam switching. We applied this technique to stereotactic three
      dimensional (3D) conformal radiotherapy for stage I non-small cell lung cancer
      (NSCLC) and evaluated the primary therapeutic outcomes. A total of 35 patients
      with stage I (15 IA, 20 IB) primary NSCLC (20 adeno, 13 squamous cell, and 2
      others) were treated with this technique. Patients ranged from 65 to 92 years old
      (median, 78 years). Twenty-three (66%) patients were medically inoperable due to
      mainly chronic pulmonary disease or high age. Three-dimensional treatment plans
      were made using 10 different non-coplanar dynamic arcs. The total dose of 60 Gy
      was delivered in 10 fractions (over 5-8 days) at the minimum dose point in the
      planning target volume (PTV) using a 6 MV X-ray. After adjusting the isocenter of
      the PTV to the planned position by a unit comprising CT and linear accelerator,
      irradiation was performed under patient-controlled breath-hold and radiation beam
      switching. All patients completed the treatment course without complaint.
      Complete response (CR) and partial response (PR) rates were 8/35 (23%) and 25/35
      (71%), respectively. Pulmonary complications of National Cancer Institute-Common
      Toxicity Criteria grade >2 were noted in three (9%) patients. During follow-up
      (range, 6-30 months; median, 13 months), two (6%) patients developed local
      progression and five (14%) developed distant or regional lymph node metastases.
      Two-year overall survival rates for total patients and medically operable
      patients were 58 and 83%, respectively. In conclusion, this new irradiation
      technique, utilizing patient-controlled radiation beam switching under self
      breath-hold after precise alignment of the isocenter, allows safe high-dose
      stereotactic radiotherapy with sufficient margins around the CTV and reduced
      treatment times. Based on the initial results, excellent local control with
      minimal complications is expected for stage I NSCLC.

PMID- 15196735
TI  - A treatment planning study evaluating a 'simultaneous integrated boost' technique
      for accelerated radiotherapy of stage III non-small cell lung cancer.
AB  - PURPOSE: As local tumour control is poor in stage III non-small cell lung cancer
      (NSCLC), a radiotherapy planning study was performed to evaluate the potential
      for treatment acceleration by using a simultaneous integrated boost (SIB)
      technique in patients who had completed induction chemotherapy. METHODS AND
      MATERIALS: Co-registered pre- and post-chemotherapy planning CT scans from 10
      patients who showed tumour regression after induction chemotherapy were used to
      compare different treatment schedules: (a) a sequential boost plan delivering, in
      2 Gy per fraction, 50 Gy to the pre-chemotherapy tumour volume, followed by a
      sequential boost of 20 Gy to the post-chemotherapy tumour volume; (b) a SIB
      technique in which the pre- and post-chemotherapy tumour volumes were treated to
      different dose levels during each treatment fraction using identical total doses
      and number of fractions as above; (c) progressively more hypofractionated
      schedules that delivered the SIB technique in 25 and 20 once-daily fractions; (d)
      the actual clinical treatment plan in which 70 Gy was delivered to the pre
      chemotherapy tumour volume in 35 daily fractions. Differences in the
      fractionation schemes used for these plans were accounted for by using the
      normalised total dose (NTD) for comparison, thereby assuming an alpha/beta ratio
      of 10 Gy for tumour and 3 Gy for normal tissues. The risk of normal tissue
      toxicity was estimated using the average lung NTD, the lung volume receiving NTD
      > 20 Gy, the oesophageal volume receiving NTD > 50 Gy, and the length of full
      circumference irradiated to at least 50 Gy. RESULTS: With respect to the
      sequential boost technique, the SIB technique improved the sparing of the normal
      tissues in all patients. In most patients, the SIB plan could also be delivered
      in 25 fractions without increasing the estimated normal tissue toxicity. With
      SIB25, the mean lung NTD was reduced from 12.1 to 11.7 Gy, and the fraction of
      healthy lung tissue receiving NTD > 20 Gy by 2% on average. Although the length
      and volume of oesophagus irradiated to at least 50 Gy increased for some of the
      patients, the observed values were less than that was the case for the actual
      delivered treatment. However, special care should be taken to avoid exceeding the
      spinal cord tolerance in patients whose tumours are located close to the cord.
      CONCLUSIONS: A SIB technique that delivers at least 50 Gy to the pre-chemotherapy
      tumour volume permits accelerated radiotherapy in patients with stage III NSCLC
      without increasing the expected risks of normal tissue toxicity. By reducing the
      overall treatment time, the SIB technique may improve local tumour control and
      survival.

PMID- 15196736
TI  - Integrating concurrent navelbine and cisplatin to hyperfractionated radiotherapy
      in locally advanced non-small cell lung cancer patients treated with induction
      and consolidation chemotherapy: feasibility and activity results.
AB  - OBJECTIVES: The purpose of this study was to determine the effectiveness and
      toxicity of a new combination schedule based on concurrent navelbine, cisplatin
      and hyperfractionated radiotherapy in patients with locally advanced NSCLC
      treated with platinum and gemcitabine induction and consolidation chemotherapy.
      MATERIALS AND METHODS: The 37 patients with pathological confirmed advanced NSCLC
      (non-surgical stages IIIA and IIIB) were included in the study. All of them were
      assessable for survival and 32 for response. The treatment schedule consisted of
      cisplatin (100 mg/m2) or carboplatin (400 mg/m2) on day 1 with gemcitabine (1000
      mg/m2) on days 1, 8 and 15. Treatment was given every 28 days for two courses,
      followed by concurrent administration of accelerated modified hyperfractionated
      radiotherapy, with concomitant boost, with a total dose of 61.64 Gy administered
      for 5 weeks, with cisplatin and navelbine, for two courses, finally followed by
      two courses of the same initial chemotherapy. RESULTS: Four patients achieved
      complete response (12.5%) and 14 (44%) partial response, for an overall objective
      response rate of 56.5%. After a minimum follow-up duration of 35.5 months, median
      progression free survival was 12.2 months. The median survival was 15.4 months
      with actuarial 1-, 2- and 3-year survival of 67, 21 and 15%, respectively. The
      main toxicity was hematological. There was esophagitis (grades III and IV) in 30%
      of the patients and there were two treatment-related deaths. CONCLUSION: Combined
      treatment with concurrent radiotherapy and chemotherapy in non-surgical NSCLC is
      an acceptable treatment modality. However, the toxicity was not negligible.

PMID- 15196738
TI  - Phase I study of docetaxel and irinotecan in patients with advanced non-small
      cell lung cancer.
AB  - The role of non-platinum combination chemotherapy in the treatment of advanced
      non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I
      study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the
      antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan
      (CPT) in patients with advanced NSCLC were evaluated. Previously untreated
      patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV
      were eligible. Both drugs were administered by 1-h intravenous infusion on day 1,
      and repeated every 3 weeks. DCT was given before CPT administration. Five
      escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165
      mg/m2) were studied. Eighteen patients received 44 courses. The DLT was
      considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or
      more was observed in three patients, which was accompanied with three episodes of
      febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred
      in three patients. Since all the three patients treated at the fifth dose level
      (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in
      two patients and grade 3 hepatic toxicity in one), this dose level was determined
      to be the MTD. The objective response rate was 33.3%, and the median survival
      time was 13.6 months. To confirm the effectiveness of this combination for
      advanced NSCLC which was suggested in the present study, a phase II study with
      the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.

PMID- 15196737
TI  - A phase I study and pharmacokinetics of irinotecan (CPT-11) and paclitaxel in
      patients with advanced non-small cell lung cancer.
AB  - PURPOSE: To determine the maximum-tolerated dose (MTD) of irinotecan and
      paclitaxel in this two-drug combination, and to investigate a sequence-dependent
      effect in the pharmacokinetics of these drugs, we conducted a phase I study in
      chemo-naive patients with advanced non-small cell lung cancer (NSCLC). PATIENTS
      AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled in this study. Both
      irinotecan and paclitaxel were administered on days 1 and 8, and repeated every 3
      weeks. The starting dose of both drugs was 40 mg/m2 which was then alternately
      increased by 10 mg/m2 increments. In the first cycle, irinotecan was initially
      administered and followed by paclitaxel infusion, while the sequence of drug
      administration was reversed in the second cycle. Blood samples for
      pharmacokinetic analysis were obtained on day 1 of the first and second cycles.
      RESULTS: Nine patients received a total of 12 cycles, which were evaluated for
      toxicity and efficacy. The main hematological toxicity was neutropenia. Grades 3
      or more neutropenia was observed in 67% of cycles at dose level 2. The main non
      hematological toxicities were grade 3 febrile neutropenia, supraventricular
      arrhythmia, and grade 2 hepatic dysfunction. The MTD of irinotecan and paclitaxel
      were 40 and 50 mg/m2, respectively. In the pharmacokinetic analysis, the maximum
      concentration of paclitaxel was elevated in a dose-dependent manner. There was a
      trend toward elevation of the area under the plasma concentration-time curve
      (AUC) of irinotecan and a decline of the AUC of paclitaxel in cycle 1 (irinotecan
      followed by paclitaxel), compared with those in cycle 2 (paclitaxel followed by
      irinotecan). Hepatic toxicity was strongly associated with the AUC of irinotecan
      (r = 0.894, P < 0.0001). The objective response was not observed in the nine
      patients. CONCLUSION: The combination of irinotecan and paclitaxel with this
      schedule produced considerable toxicities without any antitumor effect for
      advanced NSCLC. The different schedule of administration or other combinations
      should be investigated.

PMID- 15196739
TI  - Risk factors for interstitial lung disease and predictive factors for tumor
      response in patients with advanced non-small cell lung cancer treated with
      gefitinib.
AB  - A high incidence of interstitial lung disease (ILD) has been reported in patients
      with non-small cell lung cancer (NSCLC) treated with gefitinib in Japan. We
      retrospectively analyzed 112 patients with advanced NSCLC who received gefitinib
      monotherapy. Univariate and multivariate analyses were used to identify risk
      factors for gefitinib-related ILD and predictive factors for tumor response to
      gefitinib. The incidence of ILD was 5.4%, and it was higher in the patients with
      pre-existing pulmonary fibrosis (33% versus 2%; P < 0.001). The results of a
      multivariate analysis showed that pulmonary fibrosis was a significant risk
      factor for ILD (odds ratio: 177, 95% confidence interval: 4.53-6927, P = 0.006).
      The response rate was 33% in the 98 evaluable patients and higher in women (53%
      versus 23%; P = 0.003), patients with adenocarcinoma (38% versus 6%; P = 0.010),
      never-smokers (63% versus 18%; P < 0.001), and the patients with no history of
      thoracic radiotherapy (39% versus 13%; P = 0.015). The results of a multivariate
      analysis showed that the predictors of tumor response were "no history of
      smoking" and "no history of thoracic radiotherapy". Never-smokers had a
      significantly longer survival time than smokers (P = 0.007). Although gefitinib
      therapy confers a clinical benefit on patients with advanced NSCLC, especially on
      women, patients with adenocarcinoma, never-smokers, and patients with no history
      of thoracic radiotherapy, it also poses a high risk of ILD, especially to
      patients with pulmonary fibrosis. The risk-benefit ratio must be carefully
      considered.

PMID- 15196740
TI  - Small cell lung cancer: state of the art and future perspectives.
AB  - Small cell lung cancer accounts for less than 20% of all lung cancer. The
      management of this distinct tumor entity differs from the more common non-small
      cell lung cancer. Primary prevention of smoking exposure remains the most
      important public health measure. Although small cell lung is an exquisitely
      chemosensitive disease it remains ultimately fatal for the great majority of
      patients. Combination chemotherapy regimens have improved response rate and
      survival of the last three decades. The combination of cisplatin and etoposide
      has been considered the standard therapy for over a decade. More intensive
      triplet combination chemotherapy and high-dose chemotherapy have shown improved
      response rates and survival. Early concomitant and accelerated radiotherapy
      improves survival in limited stage disease. This review summarizes the current
      state of the art and future perspectives in detection, staging and standard
      therapy of small cell lung cancer. Particular emphasis is given to the importance
      of concomitant and accelerated radiotherapy and consideration of dose-intensive
      combination chemotherapy regimens.

PMID- 15196741
TI  - An open letter to all members of the IASLC.

PMID- 15196742
TI  - Severe myelotoxicity in a combination of gefitinib and vinorelbine.

PMID- 15196743
TI  - Is "no treatment" better than radiotherapy and chemotherapy?

PMID- 15196745
TI  - Does Mycoplasma sp. play role in small cell lung cancer?

PMID- 15196746
TI  - Irinotecan and docetaxel as first line chemotherapy in patients with stage
      IIIB/IV non-small cell lung cancer--experience from a prematurely closed phase II
      study.

PMID- 15196747
TI  - Effective intracellular delivery of oligonucleotides in order to make sense of
      antisense.
AB  - For more than two decades, antisense oligonucleotides (ODNs) have been used to
      modulate gene expression for the purpose of applications in cell biology and for
      development of novel sophisticated medical therapeutics. Conceptually, the
      antisense approach represents an elegant strategy, involving the targeting to and
      association of an ODN sequence with a specific mRNA via base-pairing, resulting
      in an impairment of functional and/or harmful protein expression in normal and
      diseased cells/tissue, respectively. Apart from ODN stability, its efficiency
      very much depends on intracellular delivery and release/access to the target
      side, issues that are still relatively poorly understood. Since free ODNs enter
      cells relatively poorly, appropriate carriers, often composed of polymers and
      cationic lipids, have been developed. Such carriers allow efficient delivery of
      ODNs into cells in vitro, and the mechanisms of delivery, both in terms of
      biophysical requirements for the carrier and cell biological features of uptake,
      are gradually becoming apparent. To become effective, ODNs require delivery into
      the nucleus, which necessitates release of internalized ODNs from endosomal
      compartments, an event that seems to depend on the nature of the delivery vehicle
      and distinct structural shape changes. Interestingly, evidence is accumulating
      which suggests that by modulating the surface properties of the carrier, the
      kinetics of such changes can be controlled, thus providing possibilities for
      programmable release of the carrier contents. Here, consideration will also be
      given to antisense design and chemistry, and the challenge of extra- and
      intracellular barriers to be overcome in the delivery process.

PMID- 15196748
TI  - Prednisolone retention in integrated liposomes by chemical approach and
      pharmaceutical approach.
AB  - The purpose of this study is to demonstrate a stable retention of prednisolone
      (PLS) in the unique liposomes integrated by lipophilic derivative approach and
      PEGylation approach. Palmitoyl prednisolone (Pal-PLS) was newly synthesized and
      used as a lipophilic derivative. The liposomes were composed of egg
      phosphatidylcholine (EggPC)/cholesterol (Chol) and L-alpha
      distearoylphosphatidylcholine (DSPC)/Chol with or without L-alpha
      distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2000) or 
      PEG 5000 (DSPE-PEG 5000). The retentions of PLS and Pal-PLS in the various
      liposomes were examined by ultrafiltration and gel filtration. Although PLS
      showed high trapping efficiency by all liposomes after ultrafiltration, low
      incorporation efficiency was observed in gel filtration. It indicates that PLS
      was released from the liposomes by a dilution with elution medium in gel
      filtration. Pal-PLS showed high incorporation into all liposomes after both
      ultrafiltration and gel filtration. The high incorporation of Pal-PLS into
      EggPC/Chol liposomes, however, was reduced by incubation with rat plasma in gel
      filtration. The reducing effect of rat plasma on drug incorporation into
      liposomes was inhibited by using DSPC and DSPE-PEGs. Thus, we systemically
      examined the drug retention in various liposomes and demonstrated the high
      retention of PLS in the liposomes integrated by lipophilic derivative approach
      and pharmaceutical approach using special lipids.

PMID- 15196749
TI  - SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid
      tumours.
AB  - Copolymer of styrene-maleic acid (SMA) was used to construct micelles containing
      doxorubicin by means of a hydrophobic interaction between the styrene moiety of
      SMA and doxorubicin (Dox). The micelles obtained (SMA-Dox) showed a high
      solubility in water and a constant doxorubicin release rate of about 3-4%/day in
      vitro. The SMA-Dox micelle preparation was less (36-70%) cytotoxic to the SW480
      human colon cancer cell line in vitro compared with free doxorubicin. In vivo
      assay of SMA-Dox in ddY mice bearing S-180 tumor revealed a potent anticancer
      effect with no remarkable toxicity up to a dose of 100 mg/kg of free doxorubicin
      equivalent. The drug concentration in tumor after administration of SMA-Dox was
      13 times higher than that after the free drug. This result can be attributed to
      the enhanced permeability and retention (EPR) effect of macromolecular drugs
      observed in solid tumors. Complete blood counts and cardiac histology showed no
      serious side effects for intravenous (i.v.) doses of the micellar formulation as
      high as 100 mg/kg doxorubicin equivalent in mice. These data indicate that i.v.
      administration of SMA-Dox micellar formulation can enhance the therapeutic effect
      of doxorubicin while reducing greatly cardiac and bone marrow toxicity, which
      should allow safe use of high doses of this agent.

PMID- 15196750
TI  - Intracellular target for photosensitization in cancer antiangiogenic photodynamic
      therapy mediated by polycation liposome.
AB  - Previous study indicated that antiangiogenic photodynamic therapy (PDT), laser
      irradiation at 15 min post-injection of photosensitizer in vivo, is effective for
      cancer treatment, and a photosensitizer, benzoporphyrin derivative monoacid ring
      A (BPD-MA), encapsulated in polycation liposomes (PCLs), liposomes modified with
      cetylated polyethylenimine (cetyl-PEI), is more effective than BPD-MA
      encapsulated in non-modified liposomes [Cancer 97 (2003) 2027]. In the present
      study, we examined intracellular distribution of BPD-MA. BPD-MA encapsulated in
      liposomes or in PCLs was incubated with human endothelial cell line ECV304 cells
      or human umbilical vein endothelial cells (HUVECs), and monitored the
      intracellular distribution of BPD-MA by confocal laser scan microscopy. BPD-MA
      was taken up time-dependently into the cells and was distributed in not only
      cytoplasmic area but also intranuclear region. The enhanced uptake of BPD-MA was
      observed by the PCL formulation. Intracellular distribution of polycation was
      monitored by using fluorescein isothiocyanate-labeled cetyl-PEI (cetyl-PEI-FITC)
      and was colocalized with BPD-MA. Cytoplasmic BPD-MA distribution was partly
      overlapped with that of rhodamine 123, a mitochondrial fluorostaining probe,
      suggesting that mitochondrial photosensitization as well as nuclear
      photosensitization, is involved in the antiangiogenic PDT treatment.

PMID- 15196751
TI  - Entrapment and release of quinoline derivatives using a hydrogel of a low
      molecular weight gelator.
AB  - Gels of low molecular weight gelators (LMWGs) are self-assembled,
      thermoreversible, viscoelastic materials which can also be rendered sensitive to
      light, pH or chemical substances by simple chemical modifications. In addition,
      the ability of some of these LMWGs to gelate water (hydrogelators) makes these
      gels interesting, new materials for drug delivery applications. In this paper,
      for the first time, a release study from LMWG gels is presented. This study
      concerns the release of small (model) drug molecules: 8-aminoquinoline (AQ) and 2
      hydroxyquinoline (HQ), from gels of N,N'-dibenzoyl-L-cystine (DBC). DBC forms
      stable, clear gels in water, 150 mM NaCl solution and PBS (phosphate-buffered
      saline at pH 7.4) with gel-to-sol transition temperatures (Tgs) of 40-120 degrees
      C, depending on the gelator concentration (from 2.23 to 22.3 mM). The release of
      HQ from DBC gels was found to be approximately seven times faster than that of AQ
      and the initial release of the latter follows the kinetics of gel degradation.
      These observations indicate that AQ is preferentially retained in the gel,
      presumably as a result of stronger interactions with the gelator molecules (i.e.
      DBC-COO-+ H3N-AQ). These results indicate the potential of LMWG gels as delivery
      vehicles for small drug molecules and also show that the release profiles for
      such systems can be fine-tuned by the correct choice of gelator-drug combination.

PMID- 15196752
TI  - Hydrotropic agents for study of in vitro paclitaxel release from polymeric
      micelles.
AB  - A new experimental method for in vitro release studies of poorly soluble drugs
      from polymeric micelle systems was developed using a hydrotropic agent, sodium
      salicylate. It is difficult to maintain a good sink condition for poorly water
      soluble drugs, such as paclitaxel (PTX), because of their low aqueous solubility.
      In this study, a good sink condition for PTX was achieved by using aqueous sodium
      salicylate solution which solubilized more than 10 times the total amount of PTX
      incorporated in polymeric micelles. Sodium salicylate at 1 M concentration
      increased the aqueous PTX solubility by 100 times without destroying the micellar
      structure of poly(ethylene glycol)-block-poly(phenylalanine) (PEG-b-PPhe)
      copolymer. PTX was continuously released from PEG-b-PPhe micelles in the
      hydrotropic release medium. The hydrotropic solution presents a simple method for
      studying in vitro release behavior of poorly soluble drugs from polymeric
      micelles in aqueous media.

PMID- 15196753
TI  - Transport of dendrimer nanocarriers through epithelial cells via the
      transcellular route.
AB  - The mechanism of transport of G3 PAMAM and surface-modified (with lauroyl chains)
      G3 PAMAM dendrimer nanocarriers across Caco-2 cell monolayers has been
      investigated. Flow-cytometry studies following quenching of extracellular
      fluorescence demonstrated the cellular internalisation of dendrimers. Optical
      sectioning of cells incubated with fluorescein isothiocyanate (FITC)-conjugated
      dendrimer and lauroyl-dendrimer using confocal laser scanning microscopy revealed
      colocalisation of a marker for cell nuclei (4',6-diamidino-2-phenylindole, DAPI)
      and FITC fluorescence, also suggesting cellular internalisation of dendrimers.
      Transmission electron microscopic analyses of cells incubated with gold-labelled
      G3 PAMAM dendrimers confirmed endocytosis-mediated cellular internalisation when
      dendrimers were applied to the apical domain of Caco-2 cells. These findings are
      in agreement with our previous studies using Caco-2 cell monolayers that showed a
      significant decrease of dendrimer uptake in the presence of colchicine
      (endocytosis inhibitor) and when temperature was reduced from 37 to 4 degrees C.

PMID- 15196754
TI  - Synchrotron FT-IR microscopic study of chemical enhancers in transdermal drug
      delivery: example of fatty acids.
AB  - This article illustrates the analysis by synchrotron infrared microscopy of skin
      treated with penetration enhancers. Pig skin was treated with two fatty acids
      commonly employed as penetration enhancers, palmitic (C16) and myristic (C14)
      acids, in propylene glycol (PG). The use of perdeuterated fatty acid chains
      enabled the penetrating molecules to be perfectly distinguished from the
      endogenous lipids due to the difference between C-D and C-H stretching modes.
      Palmitic acid was detected in the stratum corneum (SC), a particularly alkyl-rich
      region, whereas myristic acid penetrates deeper into the epidermis. Similar
      experiments with lead and calcium soaps were also performed, but no detectable
      signal was observed, indicating a much weaker penetration. Additionally, the C-D2
      stretching frequency provides information about the conformational order of the
      penetrating molecules inside the skin. The results indicate that fatty chains are
      in an ordered state. The improved spatial resolution allows the determination of
      both chemical composition and distribution in the different layers, from the SC
      to the dermis.

PMID- 15196755
TI  - A duplex "Gemini" prodrug of naltrexone for transdermal delivery.
AB  - Transdermal naltrexone delivery is desirable in the treatment of narcotic
      dependence and alcoholism. The purpose of this study was to increase the delivery
      rate of naltrexone (NTX) across human skin by using a novel prodrug. A duplex
      "gemini" prodrug of naltrexone was synthesized and evaluated. In vitro human skin
      permeation rates of naltrexone and prodrug were measured using a flow-through
      diffusion cell system. Drug concentrations in the skin were quantitated at the
      end of the diffusion experiment. The prodrug was hydrolyzed on passing through
      the skin and appeared mainly as naltrexone in the receiver compartment. The
      prodrug provided a significantly higher naltrexone equivalent flux across human
      skin in vitro than naltrexone base. The naltrexone equivalent solubilities of
      naltrexone and the prodrug in the donor solution were not significantly
      different. No significant increase in drug concentration in the skin after
      prodrug treatment, as compared to naltrexone, was observed. The naltrexone
      equivalent permeability from the prodrug exceeded the permeability of naltrexone
      base by two-fold. Due to the design of this prodrug, toxicities associated with
      this compound should be nonexistent, because only naltrexone and carbon dioxide
      (carbonic acid) are released when the prodrug is cleaved.

PMID- 15196756
TI  - Preparation and characterization of propranolol hydrochloride nanoparticles: a
      comparative study.
AB  - The water-in-oil-in-water (w/o/w) emulsification process is the method of choice
      for the encapsulation inside polymeric particles of hydrophilic drugs such as
      proteins and peptides which are high molecular weight macromolecules. Our
      objective was to apply this technique in order to formulate nanoparticles loaded
      with both a hydrophilic and a low molecular weight drug such as propranolol-HCl.
      Nanoparticles were prepared using a pressure homogenization device with various
      polymers (poly--caprolactone, poly(lactide-co-glycolide), ethylcellulose) and
      different amounts of drug and were compared in terms of particle size,
      encapsulation efficiency and drug release. Higher encapsulation efficiencies were
      obtained with both PCL (77.3%) and PLGA (83.3%) compared to ethylcellulose
      (66.8%). The in vitro drug release was characterized by an initial burst and an
      incomplete dissolution of the drug. When decreasing the polymer/drug ratio, the
      release appeared more controlled and prolonged up to 8 h. It can be concluded
      that nanoparticles prepared by w/o/w emulsification followed by solvent
      evaporation might be potential drug carriers for low molecular weight and
      hydrophilic drugs.

PMID- 15196757
TI  - Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water
      soluble drugs: preparation and characterization.
AB  - The objective of the present study was to synthesize novel pH-sensitive block
      copolymers forming supramolecular assemblies and to explore their potential as
      poorly water-soluble drug carriers for oral delivery. Diblock copolymers of
      polyethylene glycol and t-butyl methacrylate (tBMA), ethyl acrylate (EA) or n
      butyl acrylate (nBA) were synthesized by atom transfer radical polymerization
      (ATRP). The pH-sensitive polymers obtained by hydrolysis of t-butyl groups were
      characterized for aggregation behaviour. Poorly water-soluble model drugs, i.e.,
      indomethacin (IND), fenofibrate (FNB) and progesterone (PRG), were incorporated
      in supramolecular assemblies by dialysis or oil-in-water (O/W) emulsion methods.
      Process parameters for emulsion method were studied to maximize drug loading.
      Progesterone release was evaluated in vitro as a function of pH. Polymers with
      controlled molecular weights and low polydispersities were obtained by ATRP. All
      polymers exhibited pH-dependent aggregation behaviour and their critical
      aggregation concentration (CAC) decreased with increase in the hydrophobic block
      length. Drug loadings of <6% and 6-14% w/w were achieved by the dialysis and
      emulsion methods, respectively. Polymer composition, drug concentration and
      solubilization of polymer in water or dichloromethane (DCM) affected the loading.
      Progesterone release from supramolecular assemblies increased when the pH of the
      release medium was raised from 1.2 to 7.2. The results suggest that these
      supramolecular assemblies with high drug loadings and pH-dependent release
      kinetics can potentially enhance the oral bioavailability of poorly water-soluble
      drugs.

PMID- 15196758
TI  - Controlled release of a model antibacterial drug from a novel self-lubricating
      silicone biomaterial.
AB  - There is considerable interest in developing medical devices that provide
      controlled delivery of biologically active agents, for example, to reduce the
      incidence of device-related infection. Silicone elastomers are one of the
      commonest biomaterials used in medical device production. However, they have a
      relatively high coefficient of friction and the resulting lack of lubricity can
      cause pain and tissue damage on device insertion and removal. Novel silicone
      cross-linking agents have recently been reported that produce inherently 'self
      lubricating' silicone elastomers with very low coefficients of friction. In this
      study, the model antibacterial drug metronidazole has been incorporated into
      these self-lubricating silicone elastomers to produce a novel bioactive
      biomaterial. The in vitro release characteristics of the bioactive component were
      evaluated as a function of cross-linker composition and drug loading. Although
      conventional matrix-type release kinetics were observed for metronidazole from
      the silicone systems, it was also observed that increasing the concentration of
      the cross-linking agent responsible for the lubricious character
      (tetra(oleyloxy)silane) relative to that of the standard non-lubricious cross
      linking agent (tetrapropoxysilane) produced an increase in the metronidazole flux
      rate by up to 65% for a specified drug loading. The results highlight the
      potential for developing lubricious silicone medical devices with enhanced drug
      release characteristics.

PMID- 15196759
TI  - Transfection with different colloidal systems: comparison of solid lipid
      nanoparticles and liposomes.
AB  - Cationic solid lipid nanoparticles (SLN) for gene transfer are formulated using
      the same cationic lipids as for liposomal transfection agents. To investigate the
      differences and similarities in structure and performance between SLN and
      liposomes, a SLN preparation (S1), its counterpart formulation without matrix
      lipid (L1), a commercially available liposomal preparation (DLTR)--all based on
      the cationic lipid DOTAP--and a liposomal formulation that additionally contained
      the helper lipid dioleoylphosphatidylethanolamine (DOPE) (Escort) were compared.
      Photon correlation spectroscopy (PCS) showed that the SLN were smaller in
      diameter than the corresponding liposomes (88 vs. 148 nm) and atomic force
      microscopy (AFM) supported the expected structural differences. Desoxy
      ribonuclein acid (DNA) binding differed only marginally. Surprisingly, reporter
      gene expression was comparable between all DOTAP based formulations (S1, L1,
      DLTR), surpassed only by the DOPE containing liposomes (Escort). In conclusion,
      cationic lipid composition seems to be more dominant for in vitro transfection
      performance than the kind of colloidal structure it is arranged in. Hence,
      cationic SLN extend the range of highly potent non-viral transfection agents by
      one with favourable and distinct technological properties. Further SLN
      optimisation should be facilitated by the accumulated knowledge about cationic
      lipids in liposomal formulations.

PMID- 15196760
TI  - Delivering DNA from photocrosslinked, surface eroding polyanhydrides.
AB  - Sustained delivery of DNA has the potential to enhance long-term gene therapy;
      however, precise control of a wide range of DNA release profiles may be needed.
      In this work, multifunctional anhydride monomers were photocrosslinked to produce
      hydrophobic, highly crosslinked polymer networks that degrade by surface erosion.
      Surface-eroding polymers can deliver molecules of a wide range of sizes at
      sustained, steady rates, which is advantageous for DNA delivery, where the high
      molecular weight may complicate control of the release profiles. When plasmid DNA
      was released from photocrosslinked polyanhydride matrices, DNA recovery was low
      (approximately 25%). Electrophoresis indicated that the plasmid DNA was released
      primarily in the relaxed and supercoiled forms, yet the relative fraction of
      released DNA in the supercoiled form decreased over time. To improve DNA recovery
      and reduce the damaging effects of polymer degradation, DNA was pre-encapsulated
      in alginate microparticles, which served as a temporary coating that quickly
      dissolved upon microparticle release from the polyanhydride matrix. As
      photocrosslinked polyanhydrides have highly predictable drug release profiles
      that depend on the polymer erosion rate and implant geometry and not on the
      entrapped molecule size, they can serve dual purposes in many biomaterial
      applications where structural support and drug release would be beneficial.

PMID- 15196761
TI  - Block copolymer-coated calcium phosphate nanoparticles sensing intracellular
      environment for oligodeoxynucleotide and siRNA delivery.
AB  - The organic-inorganic hybrid nanoparticles entrapping oligodeoxynucleotide (ODN)
      or siRNA were prepared through the self-associating phenomenon of the block
      copolymer, poly(ethylene glycol)-block-poly(aspartic acid) (PEG-PAA), with
      calcium phosphate. The nanoparticles have diameters in the range of several
      hundreds of nanometers depending on the PEG-PAA concentration and revealed
      excellent colloidal stability due to the steric repulsion effect of the PEG layer
      surrounding the calcium phosphate core. The loading capacities of ODN and siRNA
      were fairly high, reaching almost 100% under optimal conditions. The
      flowcytometric analysis and confocal microscopy observation indicated that the
      hybrid nanoparticles loaded with ODN were taken up by the cells through the
      endocytosis mechanism. Furthermore, the calcium phosphate core dissociates in the
      intracellular environment with appreciably lowered calcium ion concentration
      compared to the exterior, allowing the release of the incorporated ODN and siRNA
      in a controlled manner. Eventually, effective intracellular delivery and nuclear
      localization of these nucleic acid-based drugs were evidenced through the
      observation of laser confocal microscopy using FITC-labeled ODN. This smart ion
      sensitive characteristic of hybrid nanoparticles was further demonstrated by the
      appreciable silencing of reporter gene expression by siRNA incorporated in the
      nanoparticles.

PMID- 15196762
TI  - Tumor-targeted gene delivery via anti-HER2 antibody (trastuzumab, Herceptin)
      conjugated polyethylenimine.
AB  - A series of novel nonviral vectors targeting the HER-2/neu gene product human
      epidermal growth factor receptor-2 (HER2) were constructed and evaluated in
      breast cancer cell lines to optimize vector formulation for receptor-specific
      gene transfer. These vectors were DNA/polycation complexes (polyplexes) prepared
      by mixing, at varying ratios, plasmid DNA carrying a luciferase reporter gene to
      HerPEI, which is a conjugate of linear polyethylenimine (PEI), a cationic
      polymer, and trastuzumab (Herceptin), a HER2-specific monoclonal antibody.
      Transfection studies were carried out in both HER2 overexpressing Sk-Br-3 and
      HER2 low-expressing MDA-MB-231 breast cancer cells. The HerPEI polyplexes showed
      significantly greater transfection activity up to 20-folds than nonderivatized
      PEI-based polyplexes in the Sk-Br-3 cells. The transfection efficiency of
      targeted polyplexes was dependent on the trastuzumab:PEI ratio and can be blocked
      by excess free trastuzumab, suggesting HER2-mediated gene delivery. In contrast,
      no significant difference in transfection activities was observed between HER2
      targeted and nontargeted polyplexes in the HER2 low-expressing MDA-MB-231 cells.
      The transfection efficiency of HerPEI polyplexes was retained in serum-containing
      medium. In summary, HerPEI polyplexes have shown promising HER2 receptor-specific
      gene transfer properties and warrant further evaluation as a tumor-targeted
      vector for gene therapy.

PMID- 15196763
TI  - Recombinant Escherichia coli as a gene delivery vector into airway epithelial
      cells.
AB  - To transfer genes into airway epithelial cells, we have generated auxotrophic dap
      Escherichia coli BM2710 mutant that expresses the invasin of Yersinia
      pseudotuberculosis and the listeriolysin of Listeria monocytogenes. E. coli
      BM2710 harboring a plasmid carrying the gfp gene was incubated with immortalized
      normal or cystic fibrosis (CF) airway epithelial cells or with primary bronchial
      epithelial cells grown as an explant-outgrowth cell culture model. Approximately
      2% of immortalized cells expressed GFP. Few primary cells were transfected that
      were always poorly differentiated and located at the edge of the outgrowth. This
      was consistent with the expression of beta1-integrins only on these cells and
      with the required interaction for cell entry of E. coli expressing the invasin
      with beta1-integrins. The subsequent intracellular trafficking of E. coli BM2710
      studied by confocal and electronic microscopy showed that the E. coli-containing
      phagosomes rapidly matured into phagolysosomes. This is the first demonstration
      that recombinant bacteria are able to transfer genes into primary airway
      epithelial cells, provided that they are able to invade the cells.

PMID- 15196764
TI  - Surface plasmon resonance immunosensor using self-assembled protein G for the
      detection of Salmonella paratyphi.
AB  - A surface plasmon resonance (SPR) based immunosensor using self-assembled protein
      G was developed for the detection of Salmonella paratyphi. In order to endow a
      solid substrate binding affinity to protein G, the free amine (-NH2) of protein G
      was substituted into thiol (-SH) using 2-iminothiolane. Thus, self-assembled
      protein G was fabricated on gold (Au) substrate. The formation of protein G layer
      on Au surface, and the binding of antibody and antigen in series were confirmed
      by SPR spectroscopy. The surface morphology analysis of the protein G layer on Au
      surface was performed by atomic force microscope (AFM). Consequently, an
      immunosensor based on SPR for the detection of S. paratyphi using self-assembled
      protein G was developed with a detection range of 10(2)-10(7) CFU/ml. The current
      fabrication technique of a SPR immunosensor for the detection of S. paratyphi
      could be applied to construct other immnosensors or protein chips.

PMID- 15196765
TI  - Genome walking of large fragments: an improved method.
AB  - The PCR-based genome walking method has been commonly used to isolate upstream
      regions from known cDNA sequences. The limitation of this technique is based on
      the location of the restriction site upstream to the gene-specific primer in the
      genome; hence, different restriction enzymes have to be used to isolate larger
      upstream fragments. In this paper, we present the advantageous use of partial and
      size-selected DNA as templates for genome walking, in isolating larger upstream
      fragments. We have successfully tested this approach to isolate larger upstream
      fragments using the FailSafe PCR System. Use of partial digestion and size
      selection can provide better chances in obtaining larger flanking regions of
      known DNA sequence, when compared to use of total digested DNA.

PMID- 15196766
TI  - A host/plasmid system that is not dependent on antibiotics and antibiotic
      resistance genes for stable plasmid maintenance in Escherichia coli.
AB  - Uneven distribution of plasmid-based expression vectors to daughter cells during
      bacterial cell division results in an increasing proportion of plasmid free cells
      during growth. This is a major industrial problem leading to reduction of product
      yields and increased production costs during large-scale cultivation of vector
      carrying bacteria. For this reason, a selection must be provided that kills the
      plasmid free cells. The most conventional method to obtain this desired selection
      is to insert some gene for antibiotic resistance in the plasmid and then grow the
      bacteria in the presence of the corresponding antibiotic. We describe here a
      host/plasmid Escherichia coli system with a totally stable plasmid that can be
      maintained without the use of antibiotic selection. The plasmid is maintained,
      since it carries the small essential gene infA (coding for translation initiation
      factor 1, IF1) in an E. coli strain that has been deleted for its chromosomal
      infA gene. As a result only plasmid carrying cells can grow, making the strain
      totally dependent on the maintenance of the plasmid. A selection based on
      antibiotics is thus not necessary during cultivation, and no antibiotic
      resistance genes are present neither in the final strain nor in the final
      plasmid. Plasmid-free cells do not accumulate even after an extended period of
      continuous growth. Growth rates of the control and the plasmid harboring strains
      are indistinguishable from each other in both LB and defined media. The indicated
      approach can be used to modify existing production strains and plasmids to the
      described concept. The infA based plasmid stability system should eliminate
      industrial cultivation problems caused by the loss of expression vector and use
      of antibiotics in the cultivation medium. Also environmental problems caused by
      release of antibiotics and antibiotic resistance genes, that potentially can give
      horizontal gene transfer between bacterial populations, are eliminated.

PMID- 15196767
TI  - Cleaving of S-mandelonitrile catalyzed by S-hydroxynitrile lyase from Hevea
      brasiliensis--a kinetic investigation based on the rate curve method.
AB  - The progress curves of conversion of racemic-mandelonitrile (R-MN) at different
      concentrations to benzaldehyde (BA) and hydrogen cyanide (HCN), catalyzed by S
      hydroxynitrile lyase from Hevea brasiliensis, together with the enantiomeric
      excess curves of R-MN are converted into individual progress curves of the S- and
      R-enantiomers. They reveal that, under the prevailing experimental conditions,
      the non-enzymatic conversion is sufficiently slow compared to its enzyme
      catalyzed counterpart, so that it can be ignored in a simplified analysis.
      Tikhonov regularization is then used to convert the progress curves of the S
      enantiomer into reaction rate curves. These curves are used to determine the rate
      constants in the rate expression based on a three-step reversible ordered Uni-Bi
      reaction scheme that describes this enzyme-catalyzed reaction. The resulting rate
      constants are compared against published data. Some of the problems encountered
      and their solution are briefly discussed.

PMID- 15196768
TI  - High-level expression of Candida parapsilosis lipase/acyltransferase in Pichia
      pastoris.
AB  - Candida parapsilosis has been previously shown to produce a
      lipase/acyltransferase (EC 3.1.1.3) that preferentially catalyses transfer
      reactions such as alcoholysis over hydrolysis in the presence of suitable
      nucleophiles other than water, even in aqueous media (aw > 0.9 ). This enzyme has
      been shown to belong to a new family of lipases. The present work describes the
      cloning of the gene coding for this lipase/acyltransferase in the yeast Pichia
      pastoris and the heterologous high-level expression of the recombinant enzyme.
      The lipase/acyltransferase gene, in which the sequence encoding the signal
      peptide was replaced by that of the alpha-factor of Saccharomyces cerevisiae, was
      placed under the control of the methanol inducible promoter of the alcohol
      oxidase 1 gene (AOX1). A transformed P. pastoris clone, containing five copies of
      the lipase/acyltransferase gene, was selected for the production of recombinant
      enzyme. The fed-batch culture supernatant contained 5.8 gl(-1) (weighted) of
      almost pure recombinant lipase/acyltransferase displaying the same catalytic
      behavior as the original enzyme.

PMID- 15196769
TI  - A system for purification of recombinant proteins in Escherichia coli via
      artificial oil bodies constituted with their oleosin-fused polypeptides.
AB  - An expression/purification system was developed using artificial oil bodies (AOB)
      as carriers for producing recombinant proteins. A target protein, green
      fluorescent protein (GFP), was firstly expressed in Escherichia coli as an
      insoluble recombinant protein fused to oleosin, a unique structural protein of
      seed oil bodies, by a linker sequence susceptible to factor Xa cleavage.
      Artificial oil bodies were constituted with triacylglycerol, phospholipid, and
      the insoluble recombinant protein, oleosin-Xa-GFP. After centrifugation, the
      oleosin-fused GFP was exclusively found on the surface of artificial oil bodies
      presumably with correct folding to emit fluorescence under excitation.
      Proteolytic cleavage with factor Xa separated soluble GFP from oleosin embedded
      in the artificial oil bodies; thus after re-centrifugation, GFP of high yield and
      purity was harvested simply by concentrating the ultimate supernatant.

PMID- 15196770
TI  - Hydroperoxide-lyase activity in mint leaves. Volatile C6-aldehyde production from
      hydroperoxy-fatty acids.
AB  - The extraction of 13-hydroperoxide-lyase activity from mint leaves as well as its
      use for C6-aldehyde production was studied in this work. The enzyme cleaves 13(S)
      hydroperoxy-C18 fatty acids into C6-aldehyde and C12-oxo-acid. Two mint species
      were tested: Mentha veridis and Mentha pulegium. The headspace injection method
      coupled to gas chromatography was used for volatile compound analysis. The
      optimal conditions for temperature and pH were, respectively, 15 and 7 degrees C.
      We also studied the specific synthesis of hexanal and hexenals respectively from
      13(S)-hydroperoxy-linoleic acid and 13(S)-hydroperoxy-linolenic acid.
      Considerable quantities of aldehyde (up to 2.58 micromol) were produced after 15
      min of cleavage reaction in 2 ml stirred at 100 rpm, especially in presence of
      extract of M. veridis. The conversion yields decreased from 52.5% as maximum to
      3.3% when using initial hydroperoxide concentrations between 0.2 and 15 mM. An
      unsaturated aldehyde, the 3(Z)-hexenal was produced from 13(S)-hydroperoxy
      linolenic acid. The 3(Z)-isomer was unstable and isomerized in part to 2(E)
      hexenal. In this work, we observed a very limited isomerization of 3(Z)-hexenal
      to 2(E)-hexenal, since the reaction and the volatile purge were carried out
      successively in the same flask without delay or any contact with the atmosphere.
      These aldehydes contribute to the fresh green odor in plants and are widely used
      in perfumes and in food technology. Their importance increases especially when
      the starting materials are of natural biological origin as used in this work. GC
      MS analysis allowed the identification of the products.

PMID- 15196771
TI  - Production of highly purified hydroxytyrosol from Olea europaea leaf extract
      biotransformed by hyperthermophilic beta-glycosidase.
AB  - A large amount of highly purified hydroxytyrosol (91-94% in weight) is obtained
      in short time by a simple biotransformation of Olea europaea leaf extract by a
      partially purified hyperthermophilic beta-glycosidase immobilized on chitosan
      support. The biotransformation conditions have been modulated for increasing the
      hydroxytyrosol yield, whilst chitosan and chitin matrices are used as adsorbent
      materials in liquid phase hydroxytyrosol extraction from the biotransformed
      mixtures. Natural and non-toxic hydroxytyrosol has been by this way produced from
      a vegetal source, and this compound appeared for the first time highly purified
      by natural and biocompatible safe biopolymers in comparison to previous results.
      Moreover, the GC analyses have displayed that the eluates from a two-step
      bioreactor have qualitative composition very similar to that of the extra-virgin
      olive oil polar fraction. The proposed bioreactor could also find application in
      the utilization of olive mill waste waters (OMWW), medium rich in large amounts
      of oleuropein, which can be converted in pharmacologically active compounds.

PMID- 15196772
TI  - Thermophilic (55 degrees C) conversion of methanol in methanogenic-UASB reactors:
      influence of sulphate on methanol degradation and competition.
AB  - Two upflow sludge bed reactors (UASB) were operated for 80 days at 55 degrees C
      with methanol as the substrate with an organic loading rate (OLR) of about 20 g
      CODl(-1) per day and a hydraulic retention time (HRT) of 10 h. One UASB was
      operated without sulphate addition (control reactor-R1) whereas the second was
      fed with sulphate at a COD:SO4(2-) ratio of 10 (sulphate-fed reactor-R2),
      providing an influent sulphate concentration of 0.6 g l(-1). For both reactors,
      methanogenesis was the dominant process with no considerable accumulation of
      acetate. The methanol removal averaged 93% and 83% for R1 and R2, respectively,
      and total sulphate removal was achieved in the latter. The pathway of methanol
      conversion for both sludges was investigated by measuring the fate of carbon in
      the presence and absence of bicarbonate or specific inhibitors for a sludge
      sample collected at day 72. In both sludges, about 70% of the methanol was
      syntrophically converted to methane and/or sulphide, via the intermediate H2/CO2.
      A strong competition between methanogens and sulphidogens took place in the R2
      sludge with half of the methanol-COD being used by methane-producing bacteria and
      the other half by sulphate-reducing bacteria. Acetate was not an important
      intermediate for both sludges, and played a slightly more important role for the
      sulphate-adapted sludge (R2), sustained by the higher amount of bicarbonate
      produced during sulphate-reduction. The pathway study indicates that, although
      acetate does not represent an important intermediate, the system is susceptible
      to its accumulation.

PMID- 15196773
TI  - Pyruvate formation and suppression in recombinant Bacillus megaterium
      cultivation.
AB  - A recombinant Bacillus megaterium strain showed the ability to secrete large
      amounts of pyruvate (up to 27.8 gl( -1)) for growth rates larger than 0.15 h(-1).
      Cultivation below this growth rate avoids pyruvate formation while minimizing
      acetate and succinate production. Using exponential feeding, final biomass
      concentrations of up to 80 g l(-1) were achieved. Overall molar yields for the
      experiments with pyruvate formation were as high as 0.79 mol mol(-1). Pyruvate
      formation was caused by the discrepancy between glycolytic and pyruvate
      dehydrogenase reaction/tricarboxylic acid cycle capacities during glucose excess.
      High pyruvate resulted in deceleration and subsequent cessation of growth. In
      addition, this inhibitory effect is likely associated with the
      phoshoenolpyruvate:glucose phosphotransferase system used by B. megaterium as the
      main importer for glucose.

PMID- 15196774
TI  - Development of glutamic acid decarboxylase 65 (GAD65) autoantibody assay using
      biotin-GAD65 fusion protein.
AB  - We evaluated a biotin-glutamic acid decarboxylase 65 (GAD65)-based enzyme-linked
      immunosorbent assay (B-ELISA) to detect GAD65 autoantibodies (GAD65Ab) in 78 sera
      from individuals with newly diagnosed type 1 diabetes. The GAD65Ab index of
      patients with type 1 diabetes (mean value of GAD65Ab index of 1.891) was
      significantly higher than those in 50 sera from healthy control group (mean value
      of 0.068). The intra- and inter-assay coefficients of variation (CV) were
      calculated to be 1.042 and 10.703%, respectively. The specificity of the B-GAD65
      ELISA was comparable to the standard radioimmunoassay (RIA) which is routinely
      used in the laboratory. We describe the optimal conditions of the binding
      kinetics from each assay-step for the detection of GAD65Ab using the WHO standard
      serum 97/550 as a model autoantibody serum. We concluded that incubation times of
      15, 90, and 90 min for step 1 (pre-incubation of Biotin14-GAD65 with serum), step
      2 (binding the Ab/Ag complex to NeutrAvidin plate), and step 3 (incubation with
      HRPO-anti-human IgG), respectively, along with human serum dilutions of 1:50,
      would provide an optimal assay signal within a relatively short timeframe.

PMID- 15196775
TI  - Organizing actions of neurosteroids in the Purkinje neuron.
AB  - It is becoming clear that steroids can be synthesized de novo by the brain of
      vertebrates. Such steroids synthesized de novo in the brain, as well as other
      areas of the nervous system, are called neurosteroids. To understand neurosteroid
      actions in the brain, we need data on the specific biosynthesis in particular
      sites of the brain at particular times. Therefore our studies for this exciting
      area of neuroscience research have focused on the biosynthesis and action of
      neurosteroids in the identified neurosteroidogenic cells underlying important
      brain functions. We have demonstrated that the Purkinje cell, a typical
      cerebellar neuron, is a major site for neurosteroid formation in the brain. This
      neuron actively synthesizes progesterone and estradiol de novo from cholesterol
      only during neonatal life, when cerebellar cortical formation occurs
      dramatically. This is the first observation of neuronal neurosteroidogenesis in
      the brain. Subsequently the actions of progesterone and estradiol during
      cerebellar development have become clear by a series of our studies using an
      excellent Purkinje cellular model. These neurosteroids promote dendritic growth,
      spinogenesis and synaptogenesis via each receptor in the Purkinje cell. Here we
      summarize the advances made in our understanding of organizing actions of
      neurosteroids in the Purkinje cell, an important brain neuron.

PMID- 15196776
TI  - Differential expression of AMPA receptor subunits in substance P receptor
      containing neurons of the caudate-putamen of rats.
AB  - Previous evidence has suggested that glutamate-driving neurotransmission and
      glutamate-excitotoxicity are modulated by substance P in the basal ganglia, but
      the assembly of glutamate receptors mediating this process remains to be
      delineated. By using a double immunofluorescence, cellular expression of alpha
      amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits (GluR1
      4) in substance P receptor (SPR)-containing neurons was examined in the striatum
      of rats. It revealed that distribution of SPR-immunoreactive neurons completely
      overlapped with that of GluR1, 2, 3 or 4-immunoreactive neurons in the caudate
      putamen. Neurons showing both SPR and AMPA receptor subunits (except of GluR3)
      immunoreactivity were observed: all (100%) of SPR-positive neurons displayed
      GluR1-, GluR2- or GluR4-immunoreactivity, and the double-labeled neurons
      constituted about 33, 3 or 29% of total GluR-positive ones. In contrast, the
      neurons exhibiting both SPR- and GluR3-immunoreactivity were not detected, though
      numerous GluR3-positive neurons were still distributed in the caudate-putamen
      regions. Co-localization of SPR and distinct AMPA receptor subunits in the
      striatal neurons has provided a basis for functional modulation of neuronal APMA
      receptors by substance P in the caudate-putamen of rodents. Taken together with
      previous observations, this study has also suggested that, through interaction
      with AMPA receptors composed of subunits 1, 2 and 4, substance P or neurokinin
      peptides may play important roles in regulating neuronal properties and
      protecting neurons from excitotoxicity in the basal ganglia of mammals.

PMID- 15196777
TI  - Ionotropic glutamate receptors regulating labeled acetylcholine release from rat
      striatal tissue in vitro: possible involvement of receptor modulation in
      magnesium sensitivity.
AB  - This study evaluated the role of glutamate ionotropic receptors on the control of
      [3H]acetylcholine ([3H]ACh) release by the intrinsic striatal cholinergic cells.
      [3H]-choline previously taken up by chopped striatal tissue and converted to
      [3H]ACh, was released under stimulation by glutamate, N-methyl-d-aspartate
      (NMDA), kainate and a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA).
      Experiments were conducted in the absence of choline uptake inhibitors or
      acetylcholinesterase inhibitors. A paradigm of two stimulations was employed, the
      first in control conditions and the second after 9 min of perfusion with the test
      agents MK-801, 2-amino-5-phosphonopentanoic acid (AP-5), tetrodotoxin (TTX), 6,7
      dinitroquinoxaline-2,3-dione (DNQX), 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo
      [f]quinoxaline-7-sulfonamide (NBQX), glycine and magnesium. Our results support
      that (1) in the absence of Mg2+, NMDA is the most effective agonist to stimulate
      [3H]ACh release from striatal slices (2) magnesium effectively antagonized
      kainate and AMPA stimulation suggesting that at least part of the kainate and
      AMPA effects might be attributed to glutamate release (3) besides NMDA, kainate
      receptors showed a more direct involvement in [3H]ACh release control based on
      the smaller dependence on Mg2+ and less inhibition by TTX and (4) stimulation of
      ionotropic glutamate receptors may induce long lasting biochemical changes in
      receptor/ion channel function since the effects of TTX and/or Mg2+ ions on
      [3H]ACh release were modified by previous exposure of the tissue to agonists.

PMID- 15196778
TI  - Neurobehavioral evaluation of Reln-rl-orl mutant mice and correlations with
      cytochrome oxidase activity.
AB  - The Reln-rl-orl mutation is characterized by a marked deficit in cerebellar
      granule cell and Purkinje cell number as well as ectopias in cerebellum,
      hippocampus, and neocortex. By comparison to Balb/c controls, Reln-rl-orl mutants
      did not alternate spontaneously in a T-maze and were deficient for visuomotor
      guidance in a water maze. Despite cerebellar ataxia and motor coordination
      impairments on stationary beam, coat-hanger, and rotorod tests, the horizontal
      motor activity of Reln-rl-orl mutants was not reduced in an open-field. The
      elevated cytochrome oxidase (CO) activity in Purkinje cells and the reduced CO
      activity in the roof nuclei (interpositus and dentate) of the mutants were
      associated with poor performance on the small stationary beam. In addition,
      deficient CO activity of the granular layer of the motor cortex was associated
      with shorter latencies before falling from the larger stationary beam and a lower
      number of rears in the open-field. Conversely, elevated CO activity in the
      polymorphic layer of primary somatosensory cortex was congruent with higher
      latencies before falling from the same apparatus, indicating functional
      compensation.

PMID- 15196779
TI  - Differential encoding of information about progress through multi-trial reward
      schedules by three groups of ventral striatal neurons.
AB  - In the course of daily activity we continually judge whether the goal sought is
      worth the work that must be done to obtain it. The ventral striatum is thought to
      play a central role in making such judgments. When reward schedules are used to
      investigate these judgments ventral striatum neurons show responses near the time
      of the cue, the bar-release, and/or the reward delivery. We evaluated the type of
      coding that occurs at these three time points by using codes or factorizations
      with: (1) two states for reward versus non-reward, (2) four states for the
      progress in the reward schedule, and (3) six states for all of the states of the
      schedule, quantified using information theory and ANOVA. For the bar-release- and
      reward-related responses the percent variance explained was as high for the two
      states code as with the six states code. The information for the four state code
      rose slightly but significantly for the bar-release-related neurons. For the cue
      related neurons the code with six states carried more information than the
      simpler codes. Thus, responses at different times appear to play different roles.
      Responses occurring early in trials differentiate all states, i.e., the path to a
      reward, whereas those late in trials code knowledge of impending reward.

PMID- 15196780
TI  - Membrane potential changes in vocal cord tensor motoneurons during breathing,
      vocalization, coughing and swallowing in decerebrate cats.
AB  - We studied the patterns of membrane potential changes in vocal cord tensor
      motoneurons, i.e. cricothyroid muscle motoneurons (CTMs), during fictive
      breathing, vocalization, coughing, and swallowing in decerebrate paralyzed cats
      to determine the nature of central drives to CTMs during these behaviors. CTMs
      were identified by antidromic activation from the superior laryngeal nerve.
      During breathing, CTMs always depolarized during the inspiratory phase, and
      sometimes depolarized during the expiratory phase as well. During vocalization,
      CTMs strongly depolarized. During coughing, CTMs exhibited depolarizations during
      both inspiratory and expiratory phases, but it was interrupted by a transient
      repolarization between the last part of the inspiratory phase and the first part
      of the abdominal burst during which chloride-dependent inhibitory postsynaptic
      potentials were revealed. During swallowing, most CTMs hyperpolarized, and this
      hyperpolarization was sometimes followed by a weak depolarization. We conclude
      that the main role of the cricothyroid muscle is vocalization but the functional
      roles in coughing and swallowing are minor, and that the CTM activity during
      resting breathing and vocalization are primarily controlled by excitatory inputs,
      while during coughing and swallowing, inhibitory inputs play roles in shaping
      membrane potential trajectories.

PMID- 15196781
TI  - Jogging improved performance of a behavioral branching task: implications for
      prefrontal activation.
AB  - We studied the effect of habitual jogging on the performance of a frontal lobe
      functioning test. Fourteen subjects were divided into a jogging trained group
      (TG) or a jogging untrained group (NG). The TG jogged for 12 weeks, for 30 min,
      2.6 times per week, while the NG did not. We administered a prefrontal branching
      task (BR) combining a Spatial Delayed-Response Test (DR) and a Go/No-Go Test
      (GNG). Each test alone and a Simple Reaction Time Test (SR) were given as
      controls. All tests were given three times at 6 week intervals over 12 weeks in
      both groups. In the TG, the tests were given two times after termination of the
      jogging. The maximal oxygen uptake (VO2max) was measured in the TG during the 12
      weeks. After 12 weeks, the correct performance rates in the BR task were more
      improved in the TG than in the NG. The control and reaction time tests were
      unchanged in both groups. The improved performance in the BR task in the TG
      decreased after stopping the jogging. The VO2max increased significantly during
      the 12 weeks of jogging in the TG. Thus, the habitual jogging improved
      performance in a prefrontal BR.

PMID- 15196782
TI  - Astroglial responses against Abeta initially occur in cerebral primary cortical
      cultures: species differences between rat and cynomolgus monkey.
AB  - In the present study, we investigated how amyloid beta (Abeta) peptides initially
      affect neuronal cells in primary cerebral cortical cultures from rat and
      cynomolgus monkey. In these cultures, complicated interactions between glial and
      neuronal cells occur; moreover, synaptic interactions similar to those observed
      in vivo also occur between neuronal cells in these cultures. In this study, we
      applied low concentrations of Abeta to these well-characterized primary cultures
      to investigate how Abeta initially affects neurons or astroglial cells. In both
      rat and monkey cortical cultures, treatment with low concentrations of Abeta
      failed to drastically change or damage of neurons. Abeta treatment, however,
      significantly activated astrocytes, resulting in increased apolipoprotein E
      (ApoE) production. Rat astrocytes were more sensitive to Abeta than monkey
      astrocytes, and responded to Abeta via a different mechanism. In monkey astrocyte
      cultures, only direct treatment with Abeta increased ApoE production. In rat
      astrocyte cultures, however, treatment with conditioned media from cortical
      cultures grown with Abeta increased ApoE production, indicating that some sort of
      neuron-derived soluble factor(s) was also involved in activating rat astrocytes.
      These species differences suggest that monkey cortical cultures would be more
      useful as an in vitro model system to understand the details of how Abeta
      accumulates in the human brain, since monkeys are phylogenetically more similar
      to humans.

PMID- 15196783
TI  - Magnesium sulfate fails to reduce infarct volume following transient focal
      cerebral ischemia in rats.
AB  - Studies on the neuroprotective effect of magnesium treatment in animal models of
      focal and global cerebral ischemia have produced inconsistent results.
      Nevertheless, two magnesium acute stroke phase III trials (IMAGES and FAST-MAG)
      have either been completed or are planned. Therefore, we decided to re-evaluate
      the efficacy of magnesium following focal cerebral ischaemia in rats. Two
      experiments were carried out in two independent laboratories based in Australia.
      Both used the intraluminal thread method to induce focal cerebral ischemia in the
      rat. In the Perth study the middle cerebral artery (MCA) was occluded for 45 min
      and body temperature was controlled during and after ischemia. In the Canberra
      laboratory the MCA was occluded for 2 h and body temperature was only controlled
      during surgery. Three different doses (180, 360, or 720 micromol/kg) of MgSO4 in
      the Perth study and two different MgSO4 doses (370 or 740 micromol/kg) in the
      Canberra study were intravenously or intra-arterially administered immediately
      before ischemia. Control animals were given an equal volume of normal saline just
      before ischemia in both studies. Twenty-four or 72 h post-ischemia, infarct
      volume was determined following 2',3',5'-triphenyl-2H-tetrazolium chloride (TTC)
      staining. No significant differences (P > 0.05) in total, cortical and striatal
      infarct volumes between saline and MgSO4 treated animals were observed in either
      study. We conclude MgSO4 does not reduce infarct volume when administered before
      focal cerebral ischemia in rats.

PMID- 15196784
TI  - Gross mapping of alpha1-adrenoceptors that regulate behavioral activation in the
      mouse brain.
AB  - Brain alpha1-adrenoceptors that participate in behavioral activation were mapped
      in the mouse brain by determining where microinjection of the alpha1-antagonist,
      terazosin, inhibited behavioral activity in a novel cage test. A total of 5 out
      of 23 tested regions were shown to be involved including the dorsal pons/locus
      coeruleus region (DP/LC), the dorsal raphe/periaqueductal gray area (DR/PAG), the
      vermis cerebellum (CER), the nucleus accumbens (ACC) and the medial preoptic area
      (MPOA). Injection in the 4th ventricle was also effective perhaps by acting on
      several of these regions simultaneously. A partial inhibition was obtained from
      the motor cortex. Coinjection of the alpha1/2-agonist, 6-fluoronorepinephrine
      (6FNE) but not the alpha2-agonist, dexmedetomidine (DMT) reversed the behavioral
      inhibition in all regions. It is hypothesized that brain motoric alpha1-receptors
      elicit behavioral activation by coordinately exciting several monoaminergic,
      motor and motivational systems.

PMID- 15196785
TI  - Feeding and behavioural effects of central administration of the melanocortin 3/4
      R antagonist SHU9119 in obese and lean Siberian hamsters.
AB  - Siberian hamsters accumulate fat reserves in long photoperiods, but show a long
      term decrease in food intake and body weight when exposed to a short winter
      photoperiod. The aim of this study was to determine the role of central
      melanocortin 3/4 receptors (MC3/4-R) in generating this chronic catabolic state
      by investigating the effects of SHU9119, a MC3/4-R antagonist, on food intake and
      associated behaviours. In adult male hamsters, intra-cerebroventricular infusions
      of SHU9119 significantly increased food intake in a dose-dependent manner. The
      time course of action was slow, food intake being increased between 4 and 24 h
      after intra-cerebroventricular administration. A similar degree of increase in
      food intake occurred in fat hamsters in long days and in lean hamsters
      chronically exposed to short days. Intra-cerebroventricular treatment with MTII
      (a MC3/4-R agonist) significantly decreased food intake for up to 24 h after
      treatment, and SHU9119 reversed these suppressive effects between 4 and 24 h
      after treatment, a similar time course to that observed when SHU9119 was
      administered alone. We conclude that endogenous melanocortin peptides acting via
      MC3/4-R are involved in the regulation of food intake in hamsters in both
      anabolic and catabolic states, but these acute studies do not provide evidence
      that increased activity of this hypothalamic system underlies the seasonal
      decrease in food intake that contributes to the long-term catabolic state in
      short days.

PMID- 15196786
TI  - Electrical stimulation of the hippocampus disrupts prepulse inhibition in rats:
      frequency- and site-dependent effects.
AB  - Prepulse inhibition (PPI) is a normal reduction in the startle response produced
      when a brief, low intensity stimulus is presented prior to a startle-evoking
      stimulus. PPI is often disrupted in humans diagnosed with schizophrenia. As
      similar stimuli elicit PPI in rodents and humans, interventions in rodents that
      disrupt PPI may reveal aspects of neuronal dysfunction relevant to schizophrenia.
      Stimulation of the ventral hippocampus (vHip) with NMDA significantly increases
      dopamine (DA) efflux in the nucleus accumbens (NAc) and disrupts PPI, whereas
      NMDA infusion into the dorsal hippocampus (dHip) fails to alter PPI. Our previous
      research shows that brief periods of 20 Hz electrical vHip stimulation also
      significantly increase NAc DA efflux. The present experiments assessed the
      effects of stimulating the vHip or dHip on PPI and NAc DA efflux. As predicted,
      20 Hz stimulation (10 s, 300 microA) of the vHip, but not the dHip, reversibly
      disrupted PPI. In contrast, 2 Hz stimulation (100 s, 300 microA) of the vHip
      failed to affect PPI. Microdialysis experiments revealed that 20 Hz stimulation
      of the vHip increased NAc DA efflux only in the hemisphere ipsilateral to the
      stimulating electrode, whereas 20 Hz stimulation of the dHip failed to affect NAc
      DA efflux. These data demonstrate the regional specificity and frequency
      dependent effects of hippocampal activity on PPI. Additionally, it is intriguing
      that both chemical and electrical stimulation of the vHip disrupt PPI and
      increase NAc DA efflux, however, the relevance of these changes in NAc DA efflux
      to the disruption of PPI remains to be determined.

PMID- 15196787
TI  - Responsiveness to brightness change in male and female rats following treatment
      with the partial agonist of the N-methyl-D-aspartate receptor, D-cycloserine.
AB  - Male and female hooded rats were intraperitoneally injected with 0 (vehicle
      only), 5 or 10 mg/kg D-cycloserine (DCS) and then individually allowed free
      access to the arms of a Y maze (acquisition trial), one of which was black and
      the other white. Their ability to later recognize the arm that had changed from
      white to black was assessed from the first arm entered, and the number of times
      the novel changed arm was repeatedly entered as well as the total time they spent
      in this arm. DCS increased the number of times the novel arm was entered first
      and, at the higher dose, repeated entries of and time spent in this arm by female
      rats. Males showed increases after the lower but not higher dose. In a second
      experiment, DCS was administered after rather than before the acquisition trial.
      With the exception of the first arm entered for males only, DCS did not
      significantly affect choices of the novel arm. However, contrary to treatment
      with vehicle, such choices were significantly higher than chance expectancies
      after 5 mg/kg DCS, thereby indicating that the treated rats were able to
      recognize the novel arm. It was concluded that, in the first experiment, DCS had
      mainly improved attention and/or encoding, and had slightly enhanced memory in
      the second. Any effects on memory were most likely due to prevention of
      forgetting. There was also evidence of anxiolytic effects of DCS that may have
      facilitated responses to both arms without affecting specific choices of the
      novel alternative.

PMID- 15196788
TI  - Glutamic acid and histamine-sensitive neurons in the ventral hippocampus and the
      basolateral amygdala of the rat: functional interaction on memory and learning
      processes.
AB  - The possibility of a functional interaction between the amygdala and the ventral
      hippocampus during learning of a conditioned avoidance response when both brain
      structures are chemically stimulated with glutamic acid and/or histamine receptor
      antagonists (pyrilamine, H1-histamine antagonist and ranitidine, H2-histamine
      receptor antagonist) was studied in rats. Adult male rats were stereotaxically
      implanted with guide cannulae into the basolateral amygdala (A) and the ventral
      hippocampus (H). Seventy-two hours after the implant, rats were microinjected
      with 1 microl of saline solution, 10 nmol glutamic acid or 45 nmol of histamine
      receptor antagonists in several brain structures combinations. These combinations
      were: HsalAsal; HmsgAmsg; HmsgAsal; HsalAmsg; HpyrAmsg; HmsgApyr; HranAmsg and
      HmsgAran. Five minutes after the injection, rats were subjected to a learning
      task which consisted to avoid an electric shock applied to the animal's feet when
      an ultrasonic tone of 40 kHz is on for 30 s. Results showed that the simultaneous
      application of glutamic acid into hippocampus and amygdala interfered with the
      latency to escape and memory consolidation process. Stimulation with glutamic
      acid alone into the hippocampus or into the amygdala (HsalAmsg and HmsgAsal
      groups) interfered slightly with latency but impaired the consolidation process.
      Blocking the H1-histamine receptors of the amygdala affected slightly latency and
      efficiency of learning, meanwhile the blocking of H2-histamine receptors
      interfered with both parameters. Blocking H1- and H2-histamine receptors of the
      hippocampus significantly impaired latency and efficiency of learning of rats
      stimulated with glutamic acid into the amygdala. In conclusion, the experimental
      evidence suggests that hippocampal glutamic acid-neurons functionally interact
      with histamine-neurons in the basolateral amygdala to modulate memory and
      learning process.

PMID- 15196789
TI  - Increase in reaction time for solving problems during learning-set formation.
AB  - Six rhesus monkeys were tested for a change in reaction time for problem-solving
      during a learning-set task, in which they showed progressive improvement in the
      rate of learning successive problems of visual discrimination. To evaluate the
      processing time for cognitive processes in problem-solving, the differences in
      release latency and movement time between the visual discrimination task and the
      visuomotor control task were defined. In their first experience, the monkeys
      required several hundreds of trials for solving the problem, and the Deltarelease
      latency was constant throughout the learning. With increasing experience, they
      solved problems within fewer trials than with the first problem. At this stage,
      the Deltarelease latency was high at the beginning and then decreased. The rise
      in the Deltarelease latency within the learning acquisition period increased
      depending on the amount of experience with problems they had solved, whereas the
      Deltamovement time within that period was not significantly affected by the
      experience with problems. The present findings suggest that the number of problem
      solving experiences could promote profound cognitive processing, which may be
      related to a conceptual representation that actualizes the flexibility of
      learning, namely, the learning set.

PMID- 15196790
TI  - Impact of enriched-environment housing on brain-derived neurotrophic factor and
      on cognitive performance after a transient global ischemia.
AB  - Environmental enrichment promotes structural and functional changes in the brain,
      including enhanced learning and memory performance in rodents. Transient global
      cerebral ischemia (15 min) causes specific damage to dorsal hippocampal area CA1
      pyramidal cells of the rat concomitantly with cognitive deficits. Thus, we
      investigated if environmental enrichment can protect rats against the cognitive
      and neurological consequences of transient ischemia. We evaluated the impairment
      of learning and memory with three tasks: odour discrimination, object exploration
      and spatial learning. Contrary to expectation, we found that the enriched
      environment improved performances for both ischemic and sham rats in odour
      discrimination and object exploration tasks compared with standard condition
      housed rats. After exposure to an enriched environment, ischemic rats performed
      better in the water maze than those in the standard housing conditions. However,
      exposure to an enriched environment does not protect against actual loss of CA1
      pyramidal cells. Brain-derived neurotrophic factor (BDNF) levels were increased
      in environmental enrichment animals compared to those housed in standard
      conditions. We conclude that environmental enrichment has positive effects that
      are independent of the effects of ischemic brain lesions.

PMID- 15196791
TI  - A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development
      of morphine dependence and tolerance via c-fos expression linked to the
      extracellular signal-regulated protein kinase.
AB  - In the present study, we investigated how the neurosteroid,
      dehydroepiandrosterone sulfate (DHEAS) affects the development of morphine
      dependence and tolerance in mice. Mice administered morphine (10 mg/kg) twice a
      day for 5 days developed tolerance to the analgesic effect and dependence as
      shown by a severe withdrawal syndrome induced by naloxone. Co-administration of
      DHEAS (10 mg/kg) with morphine significantly inhibited the development, but not
      the expression, of tolerance to morphine-induced analgesia and the naloxone
      precipitated withdrawal. The expression of c-fos mRNA was observed in the frontal
      cortex and thalamus of mice showing signs of naloxone-precipitated withdrawal,
      while the expression of c-fos mRNA was significantly diminished by co
      administration of DHEAS with morphine. On the naloxone-precipitated withdrawal,
      mice showed a significant elevation of cyclic AMP (cAMP) levels in the thalamus,
      whereas chronic administration of DHEAS with morphine did not affect the increase
      in cAMP. Interestingly, repeated co-administration of DHEAS with morphine
      prevented the withdrawal-induced phosphorylation of extracellular signal
      regulated protein kinase (ERK) 2 in the frontal cortex. These results showed that
      DHEAS prevented the development of morphine tolerance and dependence and
      suggested that the attenuating effects of DHEAS might result from the regulation
      of c-fos mRNA expression, which is possibly involved the signaling activation of
      ERK, but not of cAMP pathway.

PMID- 15196792
TI  - Valproate prevents the induction, but not the expression of morphine
      sensitization in mice.
AB  - Repetitive exposure to opioids elicits sensitization to its locomotor stimulating
      effects. Several lines of evidence have shown that the central GABAergic system
      is involved in behavioral sensitization induced by morphine. Valproate, a
      clinically widely used anticonvulsant and mood stabilizer, can mainly inhibit
      gamma-aminobutyric acid (GABA) transaminase and activate glutamic acid
      decarboxylase, which result in decrease in the degradation and increase in the
      synthesis of GABA, and then the elevation of extracellular GABA in the central
      nervous system. However, the effects of valproate on behavioral sensitization to
      morphine have not been documented. Herein, we investigated the effects of
      valproate on the induction and the expression of behavioral sensitization to
      morphine. Mice treated daily for 7 days with 10 mg/kg morphine and challenged
      with the same dose after 7 days of washout showed increased locomotor activity.
      Co-administration of valproate (37.5, 75, 150 mg/kg, intraperitoneal (i.p.)), at
      doses that did not affect the spontaneous activity, 30 min prior to morphine dose
      dependently inhibited the induction of morphine sensitization. However, neither
      single nor multiple administration (37.5, 75, 150 mg/kg x 7 injections) of
      valproate had any effect on the expression of morphine sensitization once it
      developed. Our results indicated that GABA plays an important role in the
      induction, but not in the expression of morphine sensitization in mice.

PMID- 15196793
TI  - Attentional cueing reverses deficits in spatial working memory task performance
      in chronic low dose MPTP-treated monkeys.
AB  - Chronic low dose MPTP-treated monkeys develop difficulty in performing spatial
      working memory tasks. Since these tasks have both attentional and memory
      components, the extent to which task performance deficits are attentional or
      memory in nature was examined. Using a modified variable delayed response (VDR)
      task, employment of an attentional cue prior to stimulus presentation
      significantly improved task performance, suggesting a strong attentional
      component to the deficit in spatial working memory task performance. These
      findings suggest that procedures to enhance attention may be useful in
      ameliorating some of the "memory" deficits associated with early Parkinson's
      disease.

PMID- 15196794
TI  - Molecular mechanisms in dizocilpine-induced attenuation of development of
      morphine dependence: an association with cortical Ca2+/calmodulin-dependent
      signal cascade.
AB  - We investigated how dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA)
      receptor antagonist, affects the development of morphine dependence in mice. Co
      administration of dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days
      attenuated the development of tolerance to the antinociceptive effects of
      morphine. The withdrawal manifestation induced by the naloxone-challenge (5
      mg/kg) was significantly reduced in mice that were treated with a combination of
      dizocilpine and morphine, compared to the mice treated with morphine and saline.
      The present study revealed a significant increase in c-Fos protein expression in
      the cortex and thalamus of mice showing naloxone-precipitated withdrawal
      syndrome. The combination of dizocilpine and morphine prevented the increase of c
      Fos protein expression in the cortex and thalamus. Interestingly, repeated co
      administration of dizocilpine and morphine prevented the withdrawal-induced
      phosphorylation of Ca2+/calmodulin kinase II (p-CaMK II) in the cortex, but not
      in the thalamus. Acute dizocilpine treatment prior to the naloxone-challenge and
      repeated treatment with dizocilpine alone had no effect on analgesia, withdrawal
      manifestations, p-CaMK II levels or c-Fos protein levels. These results showed
      that co-administration of dizocilpine and morphine prevented the development of
      morphine tolerance and dependence and suggested that the preventive effect of
      dizocilpine results from the regulation of c-Fos protein expression, which is
      possibly involved in the activation of the Ca2+/calmodulin-dependent signal
      cascade in the cortex.

PMID- 15196795
TI  - Wakefulness-inducing effects of histamine in the basal forebrain of freely moving
      rats.
AB  - Histamine-containing neurons of the tuberomammillary nucleus (TMN) are implicated
      in facilitating wakefulness. They project to many brain areas, including the
      cholinergic basal forebrain (BF). The cholinergic magnocellular regions of the BF
      are important in the regulation of cortical arousal and wakefulness, and a role
      for histamine in this activity is suggested by in vitro data indicating histamine
      excites BF cholinergic and non-cholinergic neurons. To test the hypothesis that
      histamine induces wakefulness via actions in the BF, we performed microdialysis
      perfusion of different concentrations of histamine (100, 500 and 1000 microM) in
      the BF of Sprague-Dawley rats. A MANOVA analysis showed that histamine produced a
      highly statistically significant and dose-dependent increase in wakefulness and
      decrease in non-rapid eye movement (NREM) sleep compared with artificial
      cerebrospinal fluid perfusion. From a wakefulness baseline percentage time of
      about 12% with artificial cerebrospinal fluid, histamine perfusion increased this
      value to 26% (100 microM), 36% (500 microM), or 47% (1000 microM). There was no
      statistically significant change in rapid eye movement (REM) sleep. Histamine
      perfusion (500 microM) in a control site, the centromedian thalamic nucleus, did
      not produce any change in behavioral state. The results indicate a prominent role
      of histamine in wakefulness regulation via the BF and further support the
      hypothesis that the BF has an important role in EEG activation and wakefulness.

PMID- 15196796
TI  - Effect of social isolation on stress-related behavioural and neuroendocrine state
      in the rat.
AB  - The present study investigated the effects of post-weaning social isolation (SI)
      on behavioural and neuroendocrine reactivity to stress of male and female rats.
      Innate aspects of fear and anxiety were assessed in the open field and elevated
      plus maze tests. Spontaneous startle reflex and conditioned fear response were
      further investigated. The neuroendocrine response of isolates was examined by
      measuring basal and stress release of ACTH and corticosterone and by evaluating
      the mRNA expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors
      using in situ hybridization. Locomotor activity in the open field was not
      modified by chronic SI. In males, but not females, SI produced an anxiogenic
      profile in the elevated plus maze. Male isolates showed a trend towards increased
      startle reflex amplitude relative to socially-reared controls. Moreover, SI in
      males produced alterations of the HPA axis functioning as reflected by higher
      basal levels of ACTH, and enhanced release of ACTH and corticosterone following
      stress. In contrast, startle response or HPA axis functioning were not altered in
      female isolates. Social isolates from both genders showed reduced contextual fear
      conditioning. Finally, the mRNA expression of MR and GR was not modified by SI.
      The results of the present study suggest that chronic SI increases emotional
      reactivity to stress and produces a hyperfunction of the HPA axis in adult rats,
      particularly in males.

PMID- 15196797
TI  - Behavioral sensitization to different dopamine agonists in a parkinsonian rodent
      model of drug-induced dyskinesias.
AB  - Repeated treatment with dopamine (DA) receptor agonists strongly potentiates
      contralateral turning behavior due to selective stimulation of D1 or D2-class
      receptors in 6-hydroxydopamine (6-OHDA)-lesioned rats. This phenomenon, referred
      to as sensitization, is believed to be related to the motor response
      complications (dyskinesias, on-off states) that occur during chronic
      administration of levodopa in Parkinson's disease patients. In recent years a new
      method for the evaluation of abnormal involuntary movements (AIMs) secondary to
      dopaminergic stimulation in 6-OHDA-lesioned rats was described. These AIMs
      resemble dyskinesias as seen in parkinsonian patients under levodopa therapy. Our
      objective was to evaluate the effects of repeated treatment with different
      regimes of DA agonists on turning behavior and on an AIMs scale in 6-OHDA
      lesioned rats, with the aim of discriminating between drugs with different
      dyskinesia-inducing potential. In addition, we explored the effects of a previous
      exposure to a DA agonist (priming) on the behavioral response to the subsequent
      administration of a DA agonist with the same or different pharmacologic profile.
      Our results show that in apomorphine-treated rats, rotational behavior and AIMs
      run a parallel course of enhancement, while in those receiving quinpirole there
      is a dissociation, suggesting that they could be mediated by different
      mechanisms. The finding of a significant priming effect on subsequent testing of
      6-OHDA lesioned rats should be borne in mind as the use of these pharmacological
      tests in the screening of well lesioned animals could lead to an erroneous
      interpretation of further results on dyskinesias and rotational behavior.

PMID- 15196798
TI  - Double dissociation of social and environmental stimulation on spatial learning
      and reversal learning in rats.
AB  - Environmental enrichment induces structural and biochemical changes in the brains
      of mammals that correlate with improved learning and memory. Research in rats
      suggests that social compared to inanimate stimulation might affect behavior
      differently, by acting upon dissociable neural substrates. Here we tested this
      hypothesis at the behavioral level by examining whether social and inanimate
      stimulation affect spatial memory formation and non-spatial discrimination
      reversal learning selectively. Spatial memory formation is known to depend on
      hippocampal-neocortical pathways, whereas reversal learning depends primarily on
      prefrontal cortico-striatal pathways. Male Lister hooded rats were housed singly
      or in groups of three in either small barren or large enriched cages, from
      weaning onwards. After 10 weeks of differential housing, spatial learning and
      memory were examined in the Morris water maze, followed by a series of tactile
      and odour discriminations, including discrimination reversal, in a two-choice
      discrimination task. Regardless of inanimate stimulation, social deprivation
      affected neither the acquisition of simple or complex discriminations, nor
      spatial memory formation, but was associated with impaired reversal learning in
      the two-choice discrimination task. By contrast, inanimate deprivation,
      regardless of social stimulation, affected neither acquisition nor reversal of
      two-choice discriminations, but selectively delayed the acquisition of spatial
      memory in the Morris water maze. This is the first demonstration of a double
      dissociation of early social and inanimate stimulation on two distinct
      behavioural functions that are mediated by dissociable underlying neural
      pathways. These findings strengthen the view that social and inanimate
      stimulation act, at least in part, upon dissociable neural substrates.

PMID- 15196799
TI  - Behavioral recovery and anatomical plasticity in adult rats after cortical lesion
      and treatment with monoclonal antibody IN-1.
AB  - We have previously reported that monoclonal antibody (mAb) IN-1 treatment after
      ischemic infarct in adult rats results in significant recovery of skilled
      forelimb use. Such recovery was correlated with axonal outgrowth from the intact,
      opposite motor cortex into deafferented subcortical motor areas. In the present
      study, we investigated the effects of mAb IN-1 treatment after adult sensorimotor
      cortex (SMC) aspiration lesion on behavioral recovery and neuroanatomical
      plasticity in the corticospinal tract. Adult rats underwent unilateral SMC
      aspiration lesion and treatment with either mAb IN-1 or a control Ab, or no
      treatment. Animals were then tested over a 6-week period in the skilled forelimb
      use task and the skilled ladder rung walking task. We found that animals treated
      with mAb IN-1 after SMC lesion fully recovered the use of forelimb reaching, but
      showed no improvement in digit grasping as tested in the skilled forelimb use
      task. The mAb IN-1 treatment group was also significantly improved as compared to
      control groups in the skilled ladder rung walking test. Furthermore,
      neuroanatomical tracing revealed a significant increase in the corticospinal
      projections into the deafferented motor areas of the spinal cord after mAb IN-1
      treatment. These results indicate that treatment with mAb IN-1 after cortical
      aspiration lesion induces remodeling of motor pathways resulting in recovery in
      only certain behavioral tasks, suggesting that the cause of brain damage
      influences behavioral recovery after mAb IN-1 treatment.

PMID- 15196800
TI  - Neural cell adhesion molecule (NCAM) null mice do not show a deficit in odour
      discrimination learning.
AB  - Polysialylated neural cell adhesion molecule (PSA-NCAM) is predominantly
      expressed during development where it regulates biological functions including
      axon targeting and neuronal precursor cell migration. Although dramatically down
      regulated after birth in most regions of the nervous system, PSA-NCAM remains
      highly expressed into adulthood in areas that have ongoing regeneration and
      plasticity such as in the olfactory bulb and hippocampus. Consequently, lack of
      PSA-NCAM in NCAM null mice results in distinct morphological changes to these
      areas. The functional correlates of these changes are not well defined although
      there have been reports that learning is impaired in NCAM null mice. In the
      present study, we assessed the ability of old and young NCAM null mice to learn
      an odour discrimination task. We tested male and female experimental and control
      animals of two different ages: 30-60 days and 12-15 months. During 4 days of
      training, NCAM null and C57BL/6J received trials where one odour (CS+) was paired
      with sugar while another odour (CS-) was not. In a subsequent preference test,
      conducted in the absence of sugar, all animals, regardless of strain or age,
      spent significantly more time digging in the CS+ odour than in the CS- odour. In
      addition, there was no significant difference in digging behaviour in the CS+
      between the NCAM null and the control animals. These data indicate that deletion
      of the NCAM gene may change the morphology of the olfactory bulb but does not
      interfere with the ability to learn an odour discrimination task.

PMID- 15196801
TI  - A tryptophan-rich protein diet efficiently restores sleep after food deprivation
      in the rat.
AB  - Sleep depends on the quantity and quality of the diet. Several studies have shown
      that food deprivation results in a reduction in sleep duration. It has also been
      demonstrated that in the newborn, the supply of certain essential amino acids
      improves sleep through their action on the synthesis of specific
      neurotransmitters. The aim of the present study was to test if the quantity
      and/or quality of dietary protein could improve the recovery of sleep during re
      feeding after caloric deprivation. Sleep parameters were compared in rats fed ad
      libitum, food restricted during 4 days, or reefed isocalorically after food
      restriction with three dietary regimens varying in terms of the amount (14%
      versus 30%) or quality (milk protein or alpha-lactalbumin) of protein. The
      results showed that sleep recovery, in particular slow-wave sleep, was improved
      in rats re-fed with alpha-lactalbumin. This result confirms the close
      relationship between feeding and sleep and suggest that alpha-lactabumin could be
      used to improve sleep in adult submitted to nutritional disturbances such as food
      restriction, shift work, Ramadan.

PMID- 15196802
TI  - The balance between approach and avoidance behaviors in a novel object
      exploration paradigm in mice.
AB  - Approach and avoidance are critical components of novelty seeking, which plays an
      important role in susceptibility to drug abuse and aspects of cognition. This
      experiment was designed to examine whether brief periods of handling or prior
      exposure to a novel environment affect various measures of novel object
      exploration in mice. Forty male C57BL/6J mice were handled by the experimenter or
      received minimal exposure to human contact. In addition to manipulating the
      degree of familiarity with the experimenter (handling), we also manipulated the
      degree of familiarity with the object. All mice were tested over a 3-day period.
      On day 1, all mice were tested in the open field for 60 min. On day 2, there were
      two, 30-min sessions. In the first 30-min session, there was no object present.
      In the second 30-min session, half of the mice were exposed to a novel object. On
      day 3, all mice were placed in the open field for 30 min followed by a 30-min
      period in which the object was placed in the center of the open field. Handled
      mice showed a trend toward more object exploration on day 2 compared to non
      handled mice. Mice with prior exposure to the novel object showed more object
      exploration compared to object-naive mice on day 3. These results are consistent
      with the hypothesis that a certain degree of familiarity with the object or with
      the experimenter decreases avoidance and increases exploration of novel stimuli.
      In combination, these results show that the approach and avoidance dimensions of
      novelty seeking can be manipulated experimentally and may be used in subsequent
      studies to examine the effects of drugs of abuse.

PMID- 15196803
TI  - Individual coping characteristics, rearing conditions and behavioural flexibility
      in pigs.
AB  - Several studies suggest that classification of piglets early in life based on the
      degree of resistance they display in a so-called Backtest may be indicative of
      their coping style at a later age. In the present study behavioural flexibility
      was investigated in pigs diverging for Backtest response and housing environment
      during rearing. Pigs were housed either without a rooting substrate (barren
      housing, B) or in identical pens enriched with deep straw bedding (enriched
      housing, E) from birth. During the suckling period piglets were subjected to the
      Backtest. Each piglet was restrained on its back for 1 min and the resistance
      (i.e. number of escape attempts) was scored. Pigs classified as 'high-resisting'
      (HR) or as 'low-resisting' (LR) were subjected to a simple (left/right) spatial
      discrimination (T-maze) task at 8 weeks of age. The effect of a single, subtle
      intramaze change was determined after acquisition of the task. In addition, pigs
      were subjected to reversal learning to assess their ability to modulate
      established behaviour patterns. Housing and its interaction with Backtest
      classification influenced the behavioural response to the intramaze change: E
      pigs were considerably more distracted than B pigs. Housing condition affected LR
      pigs more than HR pigs, as indicated by the interaction effects on various
      recorded behaviours. These interactions indicate that behavioural responding of
      pigs with diverging coping characteristics cannot simply be generalised across
      rearing conditions. Furthermore, HR pigs were less successful in reversal
      learning than LR pigs, suggesting that they have a higher propensity to develop
      inflexible behavioural routines.

PMID- 15196804
TI  - Antagonism of nitrous oxide antinociception in mice by antisense
      oligodeoxynucleotide directed against neuronal nitric oxide synthase enzyme.
AB  - Nitric oxide (NO) has been implicated in the antinociceptive effect of nitrous
      oxide (N2O) in mice. This study was conducted to determine the sensitivity of N2O
      induced antinociception to antagonism by an antisense oligodeoxynucleotide (AS
      ODN) against neuronal nitric oxide synthase (nNOS). The AS-ODN significantly
      antagonized the antinociceptive effect of N2O in the abdominal constriction test,
      but a mismatch ODN was without effect. This result implicates the specific
      involvement of nNOS in N2O-induced antinociception.

PMID- 15196805
TI  - Characteristics of behavioral abnormalities in alpha1d-adrenoceptors deficient
      mice.
AB  - To investigate the functional role of alpha1d-adrenergic receptor (alpha1d-AR) in
      the CNS, we have generated mutant mice lacking the alpha1d-AR using a gene
      targeting approach and examined in detail the effects of alpha1d-AR knockout mice
      on motor function, sensory function, and learning and memory. alpha1d-AR knockout
      mice showed better motor coordination at the highest rotating speed of the
      rotarod performance and stronger muscle tone using the traction meter, but their
      locomotor activity and swimming ability in the water maze were not affected. In
      the water maze requiring reference memory, alpha1d-AR knockout mice showed normal
      spatial learning. In the Y-maze task requiring working memory or attention,
      alpha1d-AR knockout mice displayed an impaired spontaneous alternation
      performance. The alpha1d-AR knockout mice tended to display lower levels of
      acoustic startle responses than the wild-type group at lower pulse intensities,
      although the acoustic prepulse inhibition was not impaired in the alpha1d-AR
      knockout mice. Furthermore, the NMDA receptor antagonist, MK-801-induced deficits
      of acoustic prepulse inhibition were not observed in the alpha1d-AR knockout
      mice. These results clearly demonstrate that the alpha1d-AR receptor plays an
      important role in the process of auditory sensory function, attention or working
      memory rather than reference memory, and the sensorimotor gating deficits induced
      by the NMDA receptor antagonist.

PMID- 15196806
TI  - Progressive behavioural changes in the spatial open-field in the quinolinic acid
      rat model of Huntington's disease.
AB  - Huntington's disease (HD) is a progressive neurodegenerative disorder,
      characterized by severe degeneration of basal ganglia, motor abnormalities,
      impaired cognitive functions and emotional disturbances. Intrastriatal injection
      of the excitotoxin quinolinic acid (QA), an N-methyl-D-aspartate receptor
      agonist, appears to reproduce in rats some of the clinical features of human HD,
      included motor and behavioural deficits. Aim of this study was to assess whether
      the behavioural alterations described in the QA rat model of HD progressed over
      time. We analysed the effects of bilateral striatal injection of QA (300 nmol/1
      microl) to adult rats in the spatial open-field test, a nonaversive task in which
      exploratory activity and responses to both spatial rearrangement of familiar
      objects and object novelty are measured. Rats were tested 2 weeks, 2 and 6 months
      after the QA lesion. Lesioned rats showed progressive alterations in performance
      in this task. Whereas sham and QA rats did not markedly differ 2 weeks post
      lesion, lesioned rats were significantly more active than controls 2 and 6 months
      after surgery. Specifically, frequency and duration of rearing and wall rearing
      increased progressively over time, while grooming was enhanced at 2 months post
      lesion only. Spatial and object novelty discrimination was not affected. These
      results show that a single injection of QA excitotoxin can induce behavioural
      changes that progress over time. The main implication of these findings is that,
      besides genetic mice models of HD, QA-lesioned rats may represent a suitable mean
      to test the ability of new drugs to slow down disease progression.

PMID- 15196807
TI  - Visual lateralization in response to familiar and unfamiliar stimuli in fish.
AB  - Left- and right-monocular viewing during inspection of their own mirror-image was
      measured in fish (Xenopoecilus sarasinorum) that had been kept for 20 days in a
      tank with a mirror or in a tank in which conspecifics were visible behind a
      transparent glass partition. Results revealed a preferential use of the monocular
      visual field of the left eye in both conditions. The asymmetry was stronger
      during the first 5 min of observation and tended to fade slightly thereafter. In
      a second experiment left- and right-monocular viewing was measured in presence of
      artificial stimuli. Fish were kept for 20 days in a tank with either horizontal
      or vertical stripes positioned along one wall and then tested for eye use in a
      tank with a familiar (same orientation) or an unfamiliar (different orientation)
      pattern of stripes. Fish showed a preferential use of the monocular field of the
      left eye when presented with the familiar pattern and a slight preferential use
      of the right eye with the unfamiliar pattern. The former bias was stronger in the
      first minutes of test, after which it tended first to reverse and then to fade
      away; the latter bias, in contrast, appeared only after some minutes of
      observation. It is argued that the preferential use of the monocular visual field
      of the left eye (mainly serving structures located to the right side of the
      encephalon) is probably part of a more general specialization to establish
      identity, i.e. that an apparently familiar stimulus is indeed identical with one
      previously experienced. Preferential use of the monocular field of the right eye,
      in contrast, is argued to be associated with visual control of response.

PMID- 15196808
TI  - Dissociation of hypertension and fixed interval responding in two separate
      strains of genetically hypertensive rat.
AB  - The behaviour of spontaneously hypertensive rats (SHR) may model attention
      deficit hyperactivity disorder. For example, SHR are hyperactive in an open field
      and show high terminal rates of responding on certain fixed-interval schedules.
      Open field behaviour has been dissociated from the accompanying spontaneous
      hypertension but fixed interval responding has not. We compared the fixed
      interval responding of two unrelated strains of genetically hypertensive rat, the
      SHR (n = 6) and the New Zealand genetically hypertensive rat (GH, n = 5), with
      their normotensive control strains, the Wistar Kyoto (WKY, n = 6) and Wistar (n =
      5), respectively. Both hypertensive rat strains showed increased terminal lever
      pressing rates on a multiple fixed-interval schedule (FI-EXT) compared to
      controls. In order to investigate the association of hypertension and the
      behavioural characteristics in question, an F-2 hybrid strain was obtained by
      cross-breeding GH and Wistar rats. When these F-2 hybrids (n = 33) were tested on
      the FI-EXT schedule, terminal lever-pressing rate was not correlated with blood
      pressure. The independent segregation of these phenotypical characteristics in
      the hybrids suggests independent genetic control. By contrast, other behavioural
      characteristics, including high lever-pressing rates during the extinction
      component and a tendency to emit responses in bursts, did cosegregate with
      terminal lever-pressing rates. Taken together, these findings suggest that the
      genetic loci for high blood pressure and responding on the FI-EXT schedule in
      these two unrelated rat strains are close but distinct.

PMID- 15196809
TI  - Factors governing prepulse inhibition and prepulse facilitation of the acoustic
      startle response in mice.
AB  - The influence of prepulses on the acoustic startle response (ASR) was measured in
      three inbred mouse strains, C57BL/6J, 129/SvHsd, and AKR/OlaHsd, and one hybrid
      strain produced by crossing wild mice and NMRI mice. Prepulse inhibition (PPI),
      i.e. reduction of ASR by prepulses, was maximal when the interval between
      prepulses and startle stimuli was in the range of 37.5-100 ms. Prepulse
      facilitation (PPF), i.e. increase of ASR by prepulses, was maximal when the
      prepulse preceded the startle stimulus by 12.5 ms. PPI increased with increasing
      prepulse SPL, PPF first increased then decreased when prepulse SPL was increased.
      Percent PPI was independent from startle stimulus SPL. All strains showed a long
      term increase of PPI when tested for several days; one strain (129) also showed
      an increase of PPF over days. The present results clearly show that PPI and PPF
      are independent processes, which add to yield the final response change. PPF and
      the observed long-term changes of PPI and PPF are stronger expressed in mice than
      have been observed in rats under similar conditions. Since there were significant
      differences between the strains of mice with respect to PPI and PPF, genetically
      different strains of mice are a promising tool to study these two processes.

PMID- 15196810
TI  - NMDA lesions in the medial prefrontal cortex impair the ability to inhibit
      responses during reversal of a simple spatial discrimination.
AB  - Although lesion studies suggest that the rat medial prefrontal cortex (mPFc) is
      involved in the process necessary for reversal of a particular set of
      contingencies, the nature of lesion-induced deficits is unclear. The involvement
      of rat mPFc in reversal of a simple spatial discrimination was examined in the
      present study. Our hypothesis was that lesion-induced deficits may reflect a
      failure to inhibit a learned instrumental response. Lister Hooded rats were
      trained on a spatial discrimination task (SD), which required a correct barpress
      matching the cue location, then they were trained on reversal of SD (SDR), which
      required a correct barpress opposite to the cue location. Rats with mPFc lesions
      showed a slower learning rate compared to the controls. However, behavior of the
      lesioned rats during early and later reversal differed. During the initial SDR,
      the lesioned rats showed a greater number of barpresses during the intertrial
      interval and a slightly higher percent correct responses than that of the
      controls. Our data suggest that damage to mPFc may produce a lack of response
      inhibition, leading to an increase in nondiscriminated bapresses, thereby
      yielding a 'facilitation' during early reversal. mPFc lesion did not affect
      either open field activity or prepulse inhibition (PPI), a frequently used
      measure of sensorimotor gating. Disruption of reversal learning following damage
      to mPFc is partly due to a failure to inhibit instrumental responses, rather than
      to disruption of other processes involved in sensorimotor gating or general
      activity.

PMID- 15196811
TI  - Expression of the 5-HT receptors in rat brain during memory consolidation.
AB  - Serotonin (5-hydroxytryptamine, 5-HT) system displays more than 14 receptors
      subtypes on brain areas involved in learning and memory processes, and
      pharmacological manipulation of specific receptors selectively affects memory
      formation. In order to begin the search of 5-HT receptors expression during
      memory formation, in this work, we aimed to determine, by autoradiography (using
      3H 5-HT as ligand, 2 nM, specific activity 123 Ci/mmol), 5-HT receptors (5-HTR)
      expression in passive (untrained) and autoshaping trained (3 sessions) adult (3
      months) and old (9 months) male rats. Thus, trained adult rats had better
      retention than old animals. Raphe nuclei of adult and old trained rats expressed
      less receptors on medial and dorsal, respectively. Hippocampal CA1 area and
      dentate gyrus of adult trained rats expressed less 5-HTR, while dentate gyrus of
      old increased them. Basomedial amygdaloid nucleus in old trained rats expressed
      more 5-HTR; while in the basolateral amygdaloid nucleus they were augmented in
      both groups. Training decreased or did not change 5-HTR in caudate-putamen of
      adult or old animals. The above profile of 5-HTR expression is consistent with
      previous reports, and suggests that memory formation and aging modulates 5-HTR
      expression in brain areas relevant to memory systems.

PMID- 15196812
TI  - Bimanual coordination involving homologous and heterologous joint combinations:
      when lower stability is associated with higher flexibility.
AB  - Variability in behavior is often put in an unfavorable light as a marker of lack
      of skill. Here, we provide evidence that increased variability during preferred
      patterns of coordination is associated with higher flexibility in adopting new
      patterns. Twelve right-handed subjects performed cyclical bimanual flexion and
      extension patterns with four homologous and six heterologous joint combinations
      involving shoulder, elbow, wrist, and finger movements. Preferred (isofrequency)
      as well as less preferred (multifrequency) coordination patterns were studied.
      The findings revealed less accurate and less stable 1:1 coordination patterns
      during heterologous as compared to homologous limb segment combinations.
      Conversely, coordination patterns with a 2:1 frequency ratio were performed more
      accurately and more consistently during heterologous as compared to homologous
      conditions. Accordingly, a lower degree of coupling between effectors during
      performance of preferred coordination patterns was associated with more
      successful performance of less familiar patterns. This suggests that variability
      may promote the creative exploration of new performance modes.

PMID- 15196813
TI  - Effect of D-serine on a delayed match-to-place task for the water maze.
AB  - The effect of the amino acid d-serine, a partial NMDA receptor agonist, on a
      delayed match-to-place task in the water maze was examined. Twenty-four male rats
      were first trained to attain baseline measurements, then administered D-serine or
      saline. Rats administered D-serine (100 mg/kg, i.p.) before swim trials did not
      show a decrease in escape latencies, but did show an increase in swim time spent
      within the previous days' escape platform location.

PMID- 15196814
TI  - HIV hollow fiber SCID model for antiviral therapy comparison with SCID/hu model.
AB  - Severe combined immunodeficient (SCID) mice have been evaluated for applicability
      as hosts for a human immunodeficiency virus (HIV) animal model, compatible with
      the pathogenesis of HIV disease and/or for testing compounds for antiviral
      efficacy. McCune et al. [Science 241 (1988) 1632] described the SCID/hu model and
      Namikawa et al. [J. Exp. Med. 172 (1990) 1055] and Rabin et al. [Antimicrob.
      Agents Chemother. 40 (1996) 755] described the SCID/hu (Thy/Liv) model which was
      developed for the evaluation of HIV pathogenic mechanisms and for the
      prioritization of antiviral compounds that were efficacious in vitro.
      Hollingshead et al. [Antiviral Res. 28 (1995) 265] and Xu et al. [Bioorg. Med
      Chem. Lett. 9 (1999) 133] described the HIV hollow fiber SCID mouse model. This
      model was developed to be a low cost, high throughput, time efficient, simple in
      vivo screening system for preliminary anti-HIV efficacy evaluation for the
      prioritization of antiviral compounds that demonstrated in vitro efficacy. The
      hollow fiber model is used as a pharmacologic tool to help separate active and
      inactive agents and direct the best lead compounds into additional animal model
      testing (e.g. SCID/hu). Compounds that are known to have an antiviral effect in
      man (e.g. 3'-azo-3'-deoxythymidine (AZT), dideoxyinosine (ddI) and
      dideoxycytidine (ddC)) were evaluated in both models. The endpoints (e.g. PCR,
      flow cytometry, MTT, p24, RT) evaluated in both models indicate that HIV-1 virus
      replicates in both models and infection is suppressed in the SCID/hu and hollow
      fiber SCID mouse models when treated with approved clinical antiviral agents.
      While both models are useful for the evaluation of antiviral therapies, there are
      distinct advantages (e.g. cost, time, material, equipment, expediency) with the
      hollow fiber assay over the SCID/hu model (Thy/Liv) for antiviral drug
      evaluations particularly in terms of cost effectiveness.

PMID- 15196815
TI  - Molecular mechanism of dioxolane nucleosides against 3TC resistant M184V mutant
      HIV.
AB  - The mutation and resultant adaptability of HIV-1 reverse transcriptase (RT)
      present a major challenge to the design of the effective antiviral strategies
      because many initially potent drugs lose efficacy over time. Even though there is
      an urgent need for a comprehensive understanding of the molecular mechanism of
      anti-HIV drug resistance by mutant RTs, the unavailability of the structural
      information of the mutant RTs has prevented detailed investigations. In this
      study, the active site of the 3TC-resistant (M184V) RT is constructed by a
      computational method, which clearly shows that the side chain of Val184 occupies
      the binding site for the nucleoside triphosphates. Therefore, the distance
      between the side chain of Val184 and the sugar moiety of the nucleoside
      triphosphate must be closely related to the cross-resistance by M184V RT. The
      natural substrates, 2'-deoxyribo nucleoside triphosphates, escape from the steric
      stress from the bulky side chain of Val184 by virtue of the d-sugar conformation
      as well as the interaction of its 3'-OH group with Tyr115, which locates the
      nucleoside triphosphate out of the clashing distance from Val184. Similarly, the
      energy-minimized structures of various d-dioxolane nucleoside triphosphates
      (TP)/RT complexes indicate that the d-dioxolane sugar moiety acquires enough
      distance from Val184 due to the specific interaction of its 3'-oxygen atom with
      the nearby enzyme residues such as Tyr115 and Arg72.

PMID- 15196816
TI  - The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell
      spread of herpes simplex virus.
AB  - Although a number of sulfated polysaccharides have been shown to inhibit
      infection of cells by herpes simplex virus (HSV), little is known about their
      effects on the cell-to-cell spread of the virus. These compounds act by
      inhibiting the virus binding to cells, and their antiviral potencies usually
      increase with increasing molecular weight and sulfation density. We report that
      the low molecular weight HS-mimetic, PI-88, which is a mixture of highly sulfated
      mannose-containing di- to hexa-saccharides, inhibited HSV infection of cells and
      cell-to-cell spread of HSV-1 and HSV-2. Compared to a relatively large heparin
      polysaccharide, PI-88 demonstrated weaker inhibition of HSV infectivity but more
      efficient reduction of cell-to-cell spread of HSV. A tetrasaccharide fraction of
      PI-88 was the minimum fragment necessary to inhibit HSV-1 infectivity, while a
      trisaccharide was sufficient to reduce cell-to-cell spread. A reduction in HSV
      lateral spread was also observed in cells incubated with another low molecular
      weight compound, pentosan polysulfate but not with much larger polysaccharide
      chondroitin sulfate E. Some differences as regards the effects of PI-88, heparin,
      protamine, poly-L-lysine and sodium chlorate on intercellular spread of HSV-1 and
      HSV-2 were found. We conclude that structurally different sulfated
      oligosaccharides are preferred for inhibition of HSV infectivity and the cell-to
      cell spread. The latter was efficiently inhibited by a relatively small but
      densely sulfated PI-88 oligosaccharide, very likely due to the capability of the
      compound to access the narrow intercellular space.

PMID- 15196817
TI  - A prospective study on treatment of chronic hepatitis C with tailored and
      extended interferon-alpha regimens according to pretreatment virological factors.
AB  - Hepatitis C virus genotype and viral loads are important predictors for sustained
      virologic response (SVR) to interferon-alpha therapy for chronic hepatitis C
      (CHC). We have conducted a prospective study on treatment of 90 patients with a
      tailored-dose and extended interferon-alpha regimen according to pretreatment
      virologic factors (low-risk, genotype non-1b/viral < or =0.65 Meq./ml, 6 million
      units thrice weekly for 12 weeks (6 MU x 12 weeks) followed by 3 MU weeks; high
      risk, genotype 1b/viral >0.65 Meq./ml, 6 MU X 24 weeks followed by 3 MU X 24
      weeks; medium-risk, the others, 6 MU X 12 weeks followed by 3 MU X 36 weeks), and
      compared to 123 patients with fixed-dose regimen (6 MU X 24 weeks). Patients with
      tailored-dose regimen had a significantly higher rate of SVR than those receiving
      fixed-dose interferon-alpha (46.7% versus 29.3%, P <0.01, intention-to-treat
      analysis). Improved efficacy was mainly seen in the medium-risk (48.9% versus
      26.6%, P=0.02) and the high-risk groups (26.1% versus 8.3%, P=0.06), but not in
      the low-risk group. By using multivariate logistic regression, low pretreatment
      viral loads and tailored-dose IFN regimens were significantly associated with
      higher SVR in both the high- and medium-risk groups. There were no differences in
      the tolerability and in the incidence of adverse effects between fixed-dose and
      tailored-dose groups. In conclusion, our results demonstrate the efficacy of
      tailored-dose interferon-alpha therapy for CHC; these could provide decision
      making information for standard/pegylated interferon-alpha combining ribavirin
      therapy according to baseline predictors.

PMID- 15196818
TI  - Cutaneous infections of mice with vaccinia or cowpox viruses and efficacy of
      cidofovir.
AB  - Orthopoxviruses, including smallpox, monkeypox and molluscipox, pose risks to
      human health through bioterrorist acts or natural transmission. There is no
      approved therapy for orthopoxvirus infections; however, cidofovir (CDV) has been
      approved as an investigational new drug for emergency treatment of adverse
      effects following smallpox vaccination. For evaluation of new therapies directed
      against orthopoxvirus infections, we have utilized immunocompetent, hairless mice
      (SKH-1) inoculated by a cutaneous route with cowpox virus (CV) or vaccinia virus
      (VV). Mice subsequently developed skin lesions and virus was recovered from the
      site of inoculation and quantified. Skin biopsies were evaluated microscopically,
      revealing brick-like eosinophilic, intracytoplasmic inclusion bodies
      characteristic of orthopoxvirus infection. SKH-1 mice fully recovered from either
      CV or VV infection. Immunodeficient Athymic or Rhino mice inoculated with CV or
      VV had more lesions and severe disease than SKH-1 mice. CV-infected SKH-1 mice
      were treated either with systemic or topical CDV. Although some protection was
      achieved with systemic treatment, 5% topical CDV was most effective at reducing
      virus titers in skin, lung, kidney, and spleen. These models may provide a means
      for evaluating efficacy of new therapies directed against orthopoxvirus diseases
      and further confirm the topical activity of CDV against cutaneous infections.

PMID- 15196819
TI  - Modeling hamsters for evaluating West Nile virus therapies.
AB  - A hamster model infected with a New York crow brain isolate of West Nile virus
      (WNV) was characterized for evaluating potential antiviral therapies. Older
      hamsters (7-11 weeks old) had a lower mortality of approximately 50% and more
      apparent disease signs as compared to >90% mortality in younger hamsters and
      mice. Disease signs such as limb strength, lacrimation, front limb tremors,
      somnolence, and deficiencies in neurological responses were noted at different
      times after viral injection. Weight loss was a marker for WNV disease signs,
      whereas, the ability to climb up an inclined ramp was associated with whether the
      animals survived the disease or died. Infectious WNV assays performed on tissues
      from hamsters during development of the infection indicated that viral titers
      peaked first in plasma, but that titers were eventually highest in kidney tissue.
      Viral titers achieved maximal levels in brain tissue on 6 dpi, which was 1-2 days
      before strong neurological signs and death started to occur. Maximal spleen and
      plasma titers were achieved sooner in young hamsters as compared with older
      hamsters, which correlated with increased susceptibility. To test the hypothesis
      that older hamsters would be more sensitive for identifying antiviral effects,
      Infergen, a consensus human interferon-alpha highly active against WNV in cell
      culture, was administered subcutaneously to older and younger hamsters beginning
      on 2 dpi. The effects of Infergen on weight change, survival, and climbing
      ability of infected animals were more apparent in older hamsters than in younger
      hamsters. The use of older hamsters is another WNV-infectious model, in addition
      to mice, for evaluating potential antiviral therapies.

PMID- 15196820
TI  - Comparison of the inhibition of human metapneumovirus and respiratory syncytial
      virus by NMSO3 in tissue culture assays.
AB  - Human metapneumovirus (hMPV) is a recently elucidated respiratory virus pathogen
      for which there are no agents currently licensed to prevent or treat infections
      caused by it. However, NMSO3 has been reported to inhibit replication of human
      respiratory syncytial virus (hRSV), a virus that is closely related to hMPV, both
      in vitro in tissue culture cells and in vivo in cotton rats. For this reason,
      experiments were performed to compare the antiviral activity of NMSO3 against
      both hRSV and hMPV in tissue culture-based assays. Heparin and ribavirin, two
      other compounds known to inhibit hRSV, and two other paramyxoviruses, human
      parainfluenza virus type 3 (PIV3) and measles virus (MV), were included in these
      tests for comparison. All three compounds significantly inhibited the replication
      of subtype A and B strains of hRSV and serotypes 1 and 2 hMPV. However, unlike
      ribavirin, NMSO3 and heparin inhibited only hMPV and hRSV and not PIV3 or MV.
      Also unlike ribavirin, the activity of the two sulfated molecules was most
      effective if these materials were present during virus attachment and penetration
      of host cells. Interestingly, NMSO3, but not heparin, was able to limit secondary
      infection and spread of both viruses.

PMID- 15196821
TI  - Efficacy of ganciclovir and cidofovir against human cytomegalovirus replication
      in SCID mice implanted with human retinal tissue.
AB  - For immunocompromised hosts, human cytomegalovirus (CMV) can be a serious
      problem. For evaluation of antivirals used to treat CMV retinitis, we have used
      severe combined immunodeficient mice as hosts for human retinal tissue implanted
      in the eye and subsequently infected with CMV. Treatment with ganciclovir or
      cidofovir resulted in a significant suppression of CMV replication.

PMID- 15196822
TI  - An improved method for analyzing coenzyme Q homologues and multiple detection of
      rare biological samples.
AB  - We have developed a simple method for the estimation of coenzyme Q homologues,
      neurotransmitters, metal ions, lipid peroxidation, gene expression, and DNA
      fragmentation simultaneously from genetically engineered mice brain regions and
      cultured neurons. The primary objective of this study was to improve conventional
      time-consuming, cumbersome, and less efficient procedures, and reduce the cost of
      conducting kinetic studies in rare biological samples. The improved method is
      novel, precise, efficient, accurate, sensitive, economical, versatile, and highly
      reproducible. The recovery and shelf life of coenzyme Q homologues was
      significantly increased and the chromatograms exhibited reduced background and
      retention times. It is envisaged that in addition to coenzyme Q homologues, the
      improved method could be utilized for the multiple analyses of DNA, RNA and
      proteins from clinically significant biopsy and autopsy samples.

PMID- 15196823
TI  - Ultrastructure at carbon fiber microelectrode implantation sites after acute
      voltammetric measurements in the striatum of anesthetized rats.
AB  - This work seeks to establish the feasibility of characterizing the ultrastructure
      of brain tissue disruption associated with the implantation of carbon fiber
      voltammetric microelectrodes. In vivo recording was performed by fast scan cyclic
      voltammetry in conjunction with carbon fiber microelectrodes (3.5 microm radius)
      in the striatum of rats anesthetized with chloral hydrate. After 4 h of in vivo
      recording, the microelectrodes were removed from the brain and the animals
      underwent intracardial perfusion. Brain tissue was collected and sectioned in the
      horizontal plane perpendicular to the axis of the microelectrodes. With
      microelectrodes of a conventional single barreled design, the tissue tracks were
      often too small to be followed by light microscopy to the point of deepest
      penetration, which would correspond to the implantation site of the carbon fiber
      itself. The enlarged tissue tracks formed by the implantation of double barreled
      electrodes, however, could be followed to their termination by light microscopy.
      Anatomical mapping was used to identify the fields laying 100 microm deeper than
      the deepest trace of such tracks. Electron microscopy of these fields revealed a
      spot of tissue damage presumed to be associated with the implantation site of the
      carbon fiber microelectrode. The spot of maximal tissue damage had a radius of
      2.5 microm and was surrounded by an annular region with a width of 4 microm that
      contained a mix of healthy and damaged elements. Beyond this annular region, i.e.
      beyond 6.5 microm from the center of the spot of maximal damage, signs of
      microelectrode-associated damage were rare and consisted primarily of neurons
      with darkened cytoplasm.

PMID- 15196824
TI  - Dissociation of retinal ganglion cells without enzymes.
AB  - We describe here methods for dissociating retinal ganglion cells from adult
      goldfish and rat without proteolytic enzymes, and show responses of ganglion
      cells isolated this way to step-wise voltage changes and fluctuating current
      injections. Taking advantage of the laminar organization of vertebrate retinas,
      photoreceptors and other cells were lifted away from the distal side of freshly
      isolated goldfish retinas, after contact with pieces of membrane filter.
      Likewise, cells were sliced away from the distal side of freshly isolated rat
      retinas, after these adhered to a membrane filter. The remaining portions of
      retina were incubated in an enzyme-free, low Ca2+ solution, and triturated. After
      aliquots of the resulting cell suspension were plated, ganglion cells could be
      identified by dye retrogradely transported via the optic nerve. These cells
      showed no obvious morphological degeneration for several days of culture.
      Perforated-patch whole-cell recordings showed that the goldfish ganglion cells
      spike tonically in response to depolarizing constant current injections, that
      these spikes are temporally precise in response to fluctuating current
      injections, and that the largest voltage-gated Na+ currents of these cells were
      larger than those of ganglion cells isolated with a neutral protease.

PMID- 15196825
TI  - Strategies for cellular identification in nucleus tractus solitarius slices.
AB  - The indistinct regional anatomy and intermixing of second order neurons with
      projection and interneurons make cellular studies more difficult within the
      nucleus tractus solitarius (NTS). Here, we outline experimental strategies to
      join in vitro electrophysiological with neuroanatomical protocols to discriminate
      specific subpopulations of NTS neurons. Horizontally cutting the brain stem
      produces slices in which electrical activation of the solitary tract (ST) is free
      of local interneuron contamination. Such ST excitatory synaptic currents (EPSCs)
      functionally identify second order NTS neurons by their minimal variation of
      latency (jitter). Sapphire blades, cold cutting temperatures and a mechanically
      stable microtome were critical to consistently obtain viable slices that were
      optimized for infrared and fluorescence microscopy. Anterogradely transported
      carbocyanine dye implanted on the aortic depressor nerve anatomically identified
      second order NTS neurons and their ST synaptic performance conformed to the
      minimal jitter signature of second order neurons. Retrograde tracers and green
      fluorescent protein labeled neurons afford two additional promising approaches
      for discriminating NTS neuron phenotypes in broader system contexts. Detailed
      methods and troubleshooting are described. Coupling tracing techniques with
      electrophysiology adds important new dimensions to NTS studies and such
      strategies provide bridging information between cellular mechanisms, neuroanatomy
      and systems integration.

PMID- 15196826
TI  - A novel mouse brain slice preparation of the hippocampo-accumbens pathway.
AB  - The nucleus accumbens (NAc) is an important component of circuitry that underlies
      reward related behaviors and the rewarding properties of drugs of abuse.
      Glutamatergic afferents to the nucleus are critical for its normal function and
      for behaviors related to drug addiction. An angled, sagittal mouse brain slice
      preparation has been designed to facilitate concurrent stimulation of two major
      glutamatergic afferent pathways to the nucleus accumbens. Medium spiny neurons at
      the medial core/shell boundary of the accumbens were depolarized by stimulation
      of either hippocampal or limbic cortical afferents through activation of AMPA
      type glutamate receptors. High frequency but not low frequency stimulation of
      hippocampal afferents depolarized medium spiny neurons to a membrane potential
      that resembled the up state observed upon high frequency stimulation in vivo. The
      magnitude of the membrane depolarization was positively correlated with the
      amplitude of the stimulus-evoked EPSP. Concurrent stimulation of hippocampal and
      limbic cortical afferents at theta frequency selectively induced a long-term
      depression (LTD) in the magnitude of stimulus-evoked EPSPs on the hippocampal
      afferent only. These data suggest that this brain slice preparation can be used
      to study mechanisms underlying synaptic plasticity at two of the critical
      glutamatergic afferent synapses in the nucleus accumbens as well as
      characterizing potential interactions between afferents. Additionally, LTD at
      hippocampo-accumbens synapses can be induced at a stimulus frequency known to
      support reinstatement of drug seeking behavior.

PMID- 15196827
TI  - Identification of neurite extension inducing peptides by means of soluble
      combinatorial peptide libraries.
AB  - To identify hexapeptides capable of inducing neurite outgrowth, we used three
      groups of soluble combinatorial peptide libraries each consisting of 100 mixtures
      of hexapeptides (each mixture consisting of 10,000 individual peptides) with
      partially predetermined sequences (in two out of six amino acid positions). Using
      this approach a number of neuritogenic peptides were identified. Three selected
      peptides, QSGKKF, QSGPLA and QSGKQG, were found to induce neurite outgrowth from
      primary hippocampal neurons with potency comparable to that of growth factors.
      None of the peptides protected cerebellar granule neurons from cell death induced
      by withdrawal of potassium chloride. The approach described here suggests the
      feasibility to use combinatorial peptide libraries in order to identify compounds
      capable of modulating a specific functional response in the nervous system,
      without prior knowledge of a molecular target.

PMID- 15196828
TI  - Vibration enhancement of slide-mounted immunofluorescence staining.
AB  - Immunofluorescence techniques allow the determination of protein and small
      molecule distribution within tissues and individual cells. There have been
      important, innovative modifications of these techniques since their introduction
      to the biosciences including the use of a mounting medium that prevents photo
      bleaching, non-ionic detergents to permeabilize membranes, multiple
      immunofluorescence labeling and antigen recovery techniques for optimizing ligand
      target interactions. While methods have been optimized for ligand-target
      accessibility in free-floating sections, little innovation has occurred to
      improve antibody access and epitope recognition in immunohistochemistry on slide
      mounted sections or cell culture. During our studies of brain signaling pathways,
      we sought to improve the immunofluorescence signal to noise ratio in these
      specimens. We present here a minor modification of immunofluorescence procedures
      that significantly increases antibody access to epitopes within tissue and
      improves staining quality while significantly shortening incubation time.
      Antibody-epitope interactions are dependent on access and affinity. Our technique
      is based upon application of a vibration source during antibody incubation which
      increases epitope access, shortens incubation time and thereby minimizes
      background immunofluorescence. Data are presented on benefits evident with
      several antibodies raised against proteins and peptides localized in various
      subcellular compartments. Analysis of the quality of labeling was performed to
      show that signal intensity is enhanced and background intensity is often
      diminished when incubations are performed under gentle vibration. This, together
      with the significant saving of time, should make this procedure applicable to a
      wide range of neurobiological questions.

PMID- 15196829
TI  - A novel toxicity-based assay for the identification of modulators of voltage
      gated Na+ channels.
AB  - Voltage-gated Na+ channels are promising drug targets. Screening of large numbers
      of putative modulators, however, can be demanding and expensive. In this study, a
      simple, cheap, and robust assay to test the pharmacological modulation of Na+
      channel function is presented. The assay makes use of the fact that the
      intracellular accumulation of Na+ ions can be cytotoxic. The toxicity of the Na+
      channel activator veratridine in the presence of an inhibitor of the Na+/K+
      ATPase (ouabain) in a Nav1.2a (rat brain IIA alpha) expressing cell line is
      assessed. Na+ channel blockers should reduce toxicity in this model. CHO cells
      which recombinantly expressed rat Nav1.2a subunits were seeded in 96-well plates,
      and cell survival was tested after 24 h incubation in medium containing
      veratridine and ouabain in the presence or absence of Na+ channel blockers.
      Propidium iodide fluorescence was used as toxicity readout. Veratridine (100
      microM) or ouabain alone (500 microM) were not toxic to the cells. In the
      presence of 500 microM ouabain, however, veratridine induced halfmaximal cell
      death with an EC50 value of 15.1 +/- 2.3 microM. Ouabain's EC50 was 215.3 +/-
      16.7 microM (with 30 microM veratridine). The effects of a number of Na+ channel
      blockers were tested and compared with their Na+ channel blocking activity
      measured in voltage-clamp experiments. Blockers from various chemical classes
      reduced toxicity half maximally with IC50 values ranging from 11.7 +/- 1.4 nM
      (tetrodotoxin) to 280.5 +/- 48.0 microM (lamotrigine). There was a linear
      relationship between the log IC50 values obtained by the two methods (slope: 1.1
      +/- 0.08; correlation coefficient: 0.93). In summary, these data show that this
      novel toxicity assay is well suited to test Na+ channel blockers.

PMID- 15196830
TI  - Method for in situ detection of the mitochondrial function in neurons.
AB  - Conventional studies of neuronal mitochondria have been limited to the use of
      purified preparations of isolated mitochondria, neural cell homogenates, living
      neurons, or brain slices. However, each technique has several drawbacks. Here, we
      demonstrate that the neuronal cell's membrane can be effectively permeabilized by
      saponin-treatment and that these permeabilized neurons can be used for
      qualitative and quantitative assessments of oxygen consumption in combination
      with registration of mitochondrial membrane potential and free [Ca2+] in the
      matrix. Under these conditions, the mitochondrial function can be studied without
      removing the mitochondria from their natural milieu thus avoiding the damage of
      the associated cytoskeleton and outer membrane. At the same time, the method
      allows the estimation of the mitochondrial function independently of other
      processes in the cell, and the easy manipulation of the milieu surrounding the
      mitochondria. Thus, the presented method offers the opportunity to study the
      neuronal mitochondrial function in situ and can also be applied to examine the
      mitochondrial function by other commonly used methods.

PMID- 15196831
TI  - A technique for long-term implantation of a microcatheter into the third
      ventricle of post-pubertal Chinese Meishan pigs based on ventriculography.
AB  - The objectives of this study were to implant a microcatheter into the third
      ventricle of post-pubertal Chinese Meishan pigs, and to maintain the
      microcatheter for a long time without causing stress. Fourteen pigs (45-60 kg BW)
      were used. Each pig was anesthetized and the head was orientated on the
      stereotaxic apparatus. A radiopaque dye was placed into the ventricle via a guide
      cannula inserted 3.5 mm forward of the bregma. A microcatheter was inserted into
      the third ventricle using ventriculography, and fixed with dental cement to a
      metal-mesh protector and screw anchors embedded into the skull. The opposite end
      of the microcatheter was externalized from the dorsal neck so that corticotropin
      releasing hormone (CRH) could be injected easily. Simultaneously, a catheter was
      fitted in the jugular vein, and the free end of the catheter was externalized
      from the dorsal neck. Microcatheter-implanted pigs showed a normal progesterone
      concentration profile, and a constant cortisol level during at least two estrous
      cycles. Furthermore, intracerebroventricular injections of CRH (25 microg/500
      microl) resulted in an increased plasma cortisol concentration (P < 0.05). Thus,
      the technique developed in this study enables us to approach the third ventricle
      in post-pubertal freely-moving pigs effectively over a long time, without causing
      stress.

PMID- 15196832
TI  - An optical telemetry system for underwater recording of electromyogram and
      neuronal activity from non-tethered crayfish.
AB  - We have developed an optical telemetry system for recording electrical signals
      associated with muscle and neuronal activities from freely walking crayfish under
      water. The device was made from conventional electronic parts which are
      commercially available, utilizing infrared light (880 nm) for signal
      transmission. Two or four channels of biological signals were multiplexed, the
      voltage of each data point modulated to the duration of subcarrier pulses and
      further to the interval of narrower carrier pulses that directly drove the
      infrared light emission diode (IRLED) under water. The light-pulse modulated
      signals were received by photodiodes and demodulated to restore the original two
      or four channel signals. Electrical recordings using wired electrodes and
      conventional amplifiers revealed that the optically transmitted signals were
      consistent with the wire-transmitted ones. In order to test the performance of
      this system, we recorded electromyograms (EMGs) from the second and third walking
      legs on each side of crayfish together with the neuronal activity in the ventral
      nerve cord. The results confirmed our previous observation in tethered crayfish
      that the background tonus of leg muscles showed an increase preceding their
      rhythmic activation.

PMID- 15196833
TI  - Cell specificity and efficiency of the Semliki forest virus vector- and
      adenovirus vector-mediated gene expression in mouse cerebellum.
AB  - Establishing efficient gene transfer and expression in post-mitotic neurons is
      important in understanding the genetic basis of neural circuits with cellular
      complexity. This study evaluates the properties of exogenous green fluorescent
      protein (GFP) expression mediated by the Semliki forest virus (SFV) and
      adenovirus (Ad) vectors in dissociated and slice cultures of the mouse
      cerebellum. Infection with SFV-GFP resulted in early-onset and high-level GFP
      expression in about 90% of Purkinje cells and in about 40% of granule cells in
      dissociated cultures at 1 day after infection. Two days after infection, GFP
      positive cells showed signs of SFV-derived cytotoxicity. Ad-GFP infected almost
      all astrocytes and granule cells in dissociated cultures, and showed a steady
      increase in GFP fluorescence with a plateau at around 2 days post-infection. Ad
      vector-mediated GFP expression lasted for several weeks with no significant cell
      damage. In the slice cultures, both viral vectors mainly infected astroglial
      cells, but also showed a similar cell preference as that in dissociated cultures.
      These data indicate that the use of different viral vectors and infection
      conditions offers a powerful means of expressing exogenous genes in cerebellar
      cultures with different cell-type specificity and timing and duration of
      expression.

PMID- 15196834
TI  - A method for direct thalamic stimulation in fMRI studies using a glass-coated
      carbon fiber electrode.
AB  - Recent fMRI studies are of interest in exploring long-range interactions between
      different brain structures and the functional activation of specific brain
      regions by known neuroanatomical pathways. One of the experimental approaches
      requires the invasive implantation of an intracranial electrode to excite
      specific brain structures. In the present report, we describe a procedure for the
      production of a glass-coated carbon fiber electrode and the use of this electrode
      for direct activation of the brain in fMRI studies. The glass-coated carbon fiber
      microelectrode was implanted in the medial thalamus of anaesthetized rats and T2*
      weighted gradient echo images in the sagittal plane obtained on a 4.7 T system
      (Biospec BMT 47/40) during electrical stimulation of the medial thalamus. The
      image quality obtained using this electrode was acceptable without reduction of
      the signal-to-noise ratio and image distortion. Cross-correlation analysis showed
      that the signal intensities of activated areas in the ipsilateral anterior
      cingulate cortex were significantly increased by about 4-5% during medial
      thalamus stimulation. The present study shows that glass-coated carbon fiber
      electrodes are suitable for fMRI studies and can be used to investigate
      functional thalamocingulate activation.

PMID- 15196835
TI  - Stress-70 proteins in marine mussel Mytilus galloprovincialis as biomarkers of
      environmental pollution: a field study.
AB  - In the present work we have investigated levels of stress-70 proteins in the
      gills of mussel Mytilus galloprovincialis collected seasonally from subtidal
      rocky shores at 6 different sites of the Rovinj coastal area (Northern Adriatic,
      Croatia). 1-D analysis (SDS-PAGE) using monoclonal mouse antibodies anti-HSP70
      detected two bands of stress-70 proteins, 70 and 72 kDa constitutively present
      during the year. 2-D analysis (IEF+SDS-PAGE) proved that the antibodies used
      detected HSP70 (pI 5.7-5.9) and HSP72 (pI 5.5-5.6). The quantification of stress
      70 proteins was possible using 200 ng of external HSP70 protein standard included
      on every blot. Maximal levels of HSP72 and HSP70 were observed in mussels in
      summer (September), and minimal levels in winter (December), and only HSP70
      showed significant correlation with the sea temperature (r=+0.822, p<0.05).
      Acclimatization of mussels to a different lower salinity under experimental
      conditions proved that small changes in sea salinity (Delta=2 psu) could not
      cause significant stress-70 proteins induction. Results indicated that there are
      significant differences in HSP70 and HSP72 content in mussels from the control
      site (S-1) and mussels from other sampling sites with urban and industrial
      pollution. The usefulness of stress-70 proteins as biomarkers of environmental
      pollution is discussed.

PMID- 15196836
TI  - Lead in paddy soils and rice plants and its potential health risk around Lechang
      lead/zinc mine, Guangdong, China.
AB  - As part of a project on phytoextraction of lead (Pb) in paddy soils around a
      lead/zinc (Pb/Zn) Mine in Lechang of Guangdong Province, South China, the
      concentration distribution of Pb in paddy soil-rice system was investigated, and
      its potential health risk to animal/human was evaluated. Total and
      diethylenetetraminepentaacetic acid (DTPA)-extractable Pb in soils averaged 1486
      and 268 microg/g, respectively. According to sequential extraction procedure,
      soil Pb occurred primarily in the residual, carbonate and exchangeable fractions
      (30.2%, 26.7% and 19.1%, respectively). Lead extracted by the gastric juice
      simulation test (GJST) was 1068 microg/g and accounted for 75.4% of the total
      concentration. Mean Pb concentrations of 419 microg/g in rice root, 69.1 microg/g
      in whole straw, 51.0 microg/g in part straw (without two leaves near above the
      root), 44.9 microg/g in stalk, 21.9 microg/g in hull, 13.2 microg/g in grain with
      hull and 4.67microg/g in grain without hull (namely, unpolished rice) were found.
      Lead concentrations in both soil and rice plant were far above the corresponding
      tolerable levels. Lead daily intakes by local residents were 2.6 mg for adults
      and 1.2 mg for children, which were much higher than the allowable level. Thus,
      Pb in this area might pose a potential health risk to the local population.

PMID- 15196837
TI  - Toxicological effects of disinfections using sodium hypochlorite on aquatic
      organisms and its contribution to AOX formation in hospital wastewater.
AB  - Sodium hypochlorite (NaOCl) is often used for disinfecting hospital wastewater in
      order to prevent the spread of pathogenic microorganisms, causal agents of
      nosocomial infectious diseases. Chlorine disinfectants in wastewater react with
      organic matters, giving rise to organic chlorine compounds such as AOX
      (halogenated organic compounds adsorbable on activated carbon), which are toxic
      for aquatic organisms and are persistent environmental contaminants. The aim of
      this study was to evaluate the toxicity on aquatic organisms of hospital
      wastewater from services using NaOCl in pre-chlorination. Wastewater samples from
      the infectious and tropical diseases department of a hospital of a large city in
      southeast of France were collected. Three samples per day were collected in the
      connecting well department at 9 a.m., 1 p.m. and 5 p.m. during 8 days from 13
      March to 22 March 2001, and a mixture was made at 6 p.m. with the three samples
      in order to obtain a representative sample for the day. The toxicity test
      comprised the 24-h EC50 on Daphnia magna and a bioluminescence assay using Vibrio
      fischeri photobacteria. Fecal coliforms and physicochemical analyses such as
      total organic carbon (TOC), chloride, AOX, total suspended solids (TSS) and
      chemical oxygen demand (COD) were carried out. Wastewater samples highlighted
      considerable acute toxicity on D. magna and V. fischeri photobacteria. However,
      low most probable numbers (MPN), ranging from <3 to 2400 for 100 ml, were
      detected for fecal coliforms. Statistical analysis, with a confidence interval of
      95%, gave a strong linear regression assessed with r=0.98 between AOX
      concentrations and EC50 (TU) on daphnia. The identification of an ideal
      concentration of NaOCl in disinfecting hospital wastewater, i.e. its non-observed
      effect concentration (NOEC) on algae and D. magna, seems to be a research issue
      that could facilitate the control of AOX toxicity effects on aquatic organisms.
      Therefore, it would be necessary to monitor the biocide properties of NaOCl on
      fecal coliforms at various doses and its toxicity effects on aquatic organisms.

PMID- 15196838
TI  - Profiles of enzymatic activity in earthworms from zinc, lead and cadmium polluted
      areas near Olkusz (Poland).
AB  - The aim of the study was to determine whether there are signs of adaptation of
      soil fauna to a gradient of heavy metal contamination. Earthworms Aporrectodea
      caliginosa, Lumbricus terrestris and Eisenia fetida were collected during the
      spring and summer of 2000 and 2001 from meadow sites situated between 2 and 32 km
      from the Bukowno-Olkusz complex of zinc-lead ore mines and smelters. The heavy
      metal content in the soil near smelters reaches 10,500 mg/kg (d.w.) for Zn, 2600
      mg/kg for Pb and 81.9 mg/kg for Cd. The sites differ with respect to species
      composition of earthworm community, with A. caliginosa being dominant. Complete
      data was obtained only for A. caliginosa, since other species were not abundant
      at all investigated sites during the whole period of investigation. The body
      burdens of Zn, Pb, Cd and Cu in A. caliginosa reached 1500, 100, 220 and 10
      microg/g, respectively, in the vicinity of the smelter (2-4 km), and decreased to
      400, 2, 36 and 6 microg/g at the most distant site (32 km). Cadmium and lead
      content was significantly elevated in the whole body of L. terrestris collected
      at the site 2.5 km distant from the smelters when compared to more distant sites,
      while in E. fetida only the body burden of cadmium was elevated at the nearest
      site compared to the next site of transect. Activities of glutathione peroxidase
      (GPX; EC 1.11.1.9) against hydrogen peroxide (H2O2) or cumene hydroperoxide
      (cumOOH), glutathione reductase (GR; EC 1.6.4.2), glutathione S-transferase (GST;
      EC 2.5.1.18) and catalase (CAT; EC 1.11.1.6) were assayed in postmitochondrial
      supernatant obtained from whole body homogenates. Seasonal and annual variations
      of enzyme activity were reflected by higher GPX activity in the late summer of
      2001 in comparison with the spring and summer of 2000. This may reflect severe
      drought in the spring and summer of 2000. The activity of both GPX isozymes, GR
      and GST in A. caliginosa and L. terrestris increased with increasing distance
      from the smelters and reached maximum at sites III and IV (4 and 8 km from the
      smelters, respectively) and then it decreased in the animals from site V (32 km).
      These may be the effects of antagonism between the enzyme inducing and enzyme
      inhibiting action of smelter emissions, a phenomenon known as a hormetic effect.
      It is postulated here that this effect is of diagnostic value for metal pollution
      biomonitoring.

PMID- 15196839
TI  - Bioremediation of coastal areas 5 years after the Nakhodka oil spill in the Sea
      of Japan: isolation and characterization of hydrocarbon-degrading bacteria.
AB  - Five years after the 1997 Nakhodka oil spill in the Sea of Japan, seven bacterial
      strains capable of utilizing the heavy oil spilled from the Nakhodka Russian oil
      tanker were isolated from three coastal areas (namely Katano Seashore of Fukui
      Prefecture, Osawa and Atake seashores of Ishikawa Prefecture) and the Nakhodka
      Russian oil tanker after a 5-year bioremediation process. All bacterial strains
      isolated could utilize long-chain-length alkanes efficiently, but not aromatic,
      and all of them were able to grow well on heavy oil. Using 16S rDNA sequencing,
      most of the strains were affiliated to Pseudomonas aeruginosa. Comparing between
      the year 1997 (at the beginning of bioremediation process) and the year 2001
      (after 5 years of bioremediation), there was no significant change in morphology
      and size of hydrocarbon-degrading bacteria during the 5-year bioremediation.
      Scanning and transmission electron microscopic observations revealed that a large
      number of hydrocarbon-degrading bacteria still existed in the sites consisting of
      a variety of morphological forms of bacteria, such as coccus (Streptococcus and
      Staphylococcus) and bacillus (Streptobacillus). On the application of
      bioremediation processes on the laboratory-scale, laboratory microcosm
      experiments (containing seawater, beach sand, and heavy oil) under aerobic
      condition by two different treatments (i.e., placed the inside building and the
      outside building) were established for bioremediation of heavy oil to investigate
      the significance of the role of hydrocarbon-degrading bacteria on them. There was
      no significant bacterial activity differentiation in the two treatments, and
      removal of heavy oil by hydrocarbon-degrading bacteria in the outside building
      was slightly greater than that in the inside building. The values of pH, Eh, EC,
      and dissolved oxygen (DO) in two treatments indicated that the bioremediation
      process took place under aerobic conditions (DO: 1-6 mg/l; Eh: 12-300 mV) and
      neutral-alkaline conditions (pH 6.4-8) with NaCl concentrations of 3-15% (ECs of
      45-200 mS/cm).

PMID- 15196840
TI  - Market basket study on dietary intake of PCDD/Fs, PCBs, and PBDEs in Finland.
AB  - We have measured the concentrations of polychlorinated dibenzo-p-dioxins
      (PCDD/F), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers
      (PBDE) in 10 market baskets consisting of almost 4000 individual food samples
      representing 228 different food items, and also in the total diet basket. Lower
      bound concentrations of PCDD/Fs ranged between 0.0057 and 5.6 pg/g fresh weight
      in the market baskets and the corresponding values for PCBs from 39 to 25,000
      pg/g. The fish basket contributed most to the concentrations of dioxins and PCBs,
      and also to concentrations of PBDEs in which the lower bound range was from 0.82
      to 850 pg/g. We also assessed the average daily intakes of these substances by
      the Finnish adult population. The average daily intake of sum of PCDD/Fs and PCBs
      as WHO toxic equivalents was assessed to be 115 pg, which was 1.5 pg WHO-TEq/kg
      body weight using an average mean weight of 76 kg for the general population in
      Finland. The contribution of fish to the intake of PCDD/Fs was between 94% and
      72%, depending on whether lower or upper bound concentrations were used. With
      respect to PCBs, the contribution of fish was 80%. The calculated intake of PBDEs
      of 44 ng/day was comparable to intake assessments from other countries. Fish also
      contributed most to the PBDE intake, but there was some other source of PBDEs
      that distinguishes the exposure to PBDEs from exposure to PCDD/Fs and PCBs. This
      additional source seemed to be found in the market basket that included
      beverages, spices, and sweets.

PMID- 15196841
TI  - Fly ash leachate induces oxidative stress in freshwater fish Channa punctata
      (Bloch).
AB  - Oxidative stress inducing potential of fly ash leachate (FAL) was studied in a
      freshwater fish, Channa punctata (Bloch). Fish were exposed to fly ash leachate
      for 24 h and lipid peroxidation (LPO) was studied as a marker of oxidative
      stress. Catalase (CAT), glutathione S-transferase (GST) activities and levels of
      reduced glutathione (GSH) were also estimated in the exposed fish. FAL (1 ml/l)
      induced LPO in all the organs and most prominent response was in the gill. It
      also caused induction of enzymes and glutathione. Liver showed highest level of
      induction of enzyme activities. The results of this study demonstrate that fly
      ash constituents have potential to induce oxidative stress in fish and gills are
      the most vulnerable organs. It is also suggested that in case of exposure to FAL,
      along with LPO antioxidant defense is also activated to counteract the reactive
      oxygen species (ROS) at least partly in the initial stages of exposure.

PMID- 15196842
TI  - Soil-plant transfer of plutonium and americium in contaminated regions of Belarus
      after the Chernobyl catastrophe.
AB  - Experimental data are presented for the soil to plant transfer of plutonium and
      americium into the main species of grass vegetation of Belarusian grasslands
      contaminated as a result of the Chernobyl catastrophe of 1986. The content of
      radionuclides in pore soil solutions and the total reserve of biologically
      available forms of plutonium and americium in rooting layers of different soil
      varieties have been established. The distribution coefficients of (239,240)Pu and
      241Am between the solid phase and pore waters of soils have been evaluated. The
      migration ability and biological availability of radionuclides in soils with
      different structures of the absorbing complex have been analyzed for various
      landscape conditions. The dependence of soil to plant transfer of plutonium and
      americium on the content and composition of organic matter, and other
      characteristics of the soil complex has been studied. On the basis of these data,
      predictions of the contamination levels of the main grass species of natural and
      agricultural ecosystems by 241Am are presented.

PMID- 15196843
TI  - Plants against the global epidemic of arsenic poisoning.
AB  - Due to the growing current trend around the world of drinking water from
      underground sources, in an attempt to replace heavily polluted surface water
      supplies, arsenic is causing a global epidemic of poisoning with hundreds of
      millions of people now being thought at serious risk in many countries.
      Phytoremediation (bioremediation mediated by plants) has been proposed as an
      effective tool in arsenic cleanup. Actually, some plants (most notably, the
      Chinese brake fern Pteris vittata) have been reported to be suitable for arsenic
      phytoremediation. In this respect, transgenic plants are being developed to
      improve their capacity to accumulate arsenic. Most interestingly, rhizofiltration
      (use of plants to absorb or adsorb pollutants from water) is being considered for
      the ex situ and in situ remediation of arsenic-contaminated water. Similarly,
      some plants show great potential to remove arsenic from polluted soil.

PMID- 15196844
TI  - Removal of synthetic dyes from wastewaters: a review.
AB  - The more recent methods for the removal of synthetic dyes from waters and
      wastewater are complied. The various methods of removal such as adsorption on
      various sorbents, chemical decomposition by oxidation, photodegradation, and
      microbiological decoloration, employing activated sludge, pure cultures and
      microbe consortiums are described. The advantages and disadvantages of the
      various methods are discussed and their efficacies are compared.

PMID- 15196845
TI  - A review of factors affecting the release and bioavailability of contaminants
      during sediment disturbance events.
AB  - The factors affecting the release and bioavailability of contaminants present in
      sediments during natural and anthropogenic disturbance events are discussed and
      our current state of understanding of these processes reviewed. Published data
      are focused on the distribution of contaminants within undisturbed sediment,
      their affinities to the various solid-phase fractions of sediment and the
      interaction of contaminants between sediment and pore water. Sediment disturbance
      can lead to changes in the chemical properties of sediment that stimulate the
      mobilisation of contaminants. Research shows that changes in both redox potential
      (Eh) and pH can accelerate desorption, partitioning, bacterial degradation and
      the oxidation of organic contaminants. However, these processes are both sediment
      and compound-specific. By affecting the affinity of contaminants to sediments,
      disturbance events in turn can have a significant effect on their
      bioavailability. Few studies have examined this phenomenon, and it is clear from
      the data available that there are gaps in our understanding in a number of key
      areas when assessing the release of contaminants from sediments: the fate of
      contaminants in undisturbed sediments and those that are not subjected to major
      disturbances, the kinetic processes that regulate metal release during changes in
      redox potential, the release of organometallic compounds from sediments during
      resuspension, the bioavailability of organic and organometallic compounds and the
      processes affecting contaminant release.

PMID- 15196846
TI  - Carbon emission from farm operations.
AB  - This manuscript is a synthesis of the available information on energy use in farm
      operations, and its conversion into carbon equivalent (CE). A principal advantage
      of expressing energy use in terms of carbon (C) emission as kg CE lies in its
      direct relation to the rate of enrichment of atmospheric concentration of CO2.
      Synthesis of the data shows that estimates of emissions in kg CE/ha are 2-20 for
      different tillage operations, 1-1.4 for spraying chemicals, 2-4 for drilling or
      seeding and 6-12 for combine harvesting. Similarly, estimates of C emissions in
      kg CE/kg for different fertilizer nutrients are 0.9-1.8 for N, 0.1-0.3 for P2O5,
      0.1-0.2 for K20 and 0.03-0.23 for lime. Estimates of C emission in kg CE/kg of
      active ingredient (a.i.) of different pesticides are 6.3 for herbicides, 5.1 for
      insecticides and 3.9 for fungicides. Irrigation, lifting water from deep wells
      and using sprinkling systems, emits 129+/-98 kg CE for applying 25 cm of water
      and 258+/-195 for 50 cm of water. Emission for different tillage methods are 35.3
      kg CE/ha for conventional till, 7.9 kg CE/ha for chisel till or minimum till, and
      5.8 kg CE/ha for no-till method of seedbed preparation. In view of the high C
      costs of major inputs, sustainable management of agricultural ecosystems implies
      that an output/input ratio, expressed either as gross or net output of C, must be
      >1 and has an increasing trend over time.

PMID- 15196847
TI  - Diagnosis and treatment of gestational trophoblastic disease: ACOG Practice
      Bulletin No. 53.
AB  - Gestational trophoblastic disease comprises a spectrum of interrelated conditions
      originating from the placenta. Other terms often used to refer to these
      conditions include gestational trophoblastic neoplasia and gestational
      trophoblastic tumor. Histologically distinct disease entities encompassed by this
      general terminology include complete and partial hydatidiform moles, invasive
      moles, gestational choriocarcinomas, and placental site trophoblastic tumors.
      Before the advent of sensitive assays for human chorionic gonadotropin (hCG) and
      efficacious chemotherapy, the morbidity and mortality from gestational
      trophoblastic disease were substantial. At present, with sensitive quantitative
      assays for beta-hCG and current approaches to chemotherapy, most women with
      malignant gestational trophoblastic disease can be cured and their reproductive
      function preserved. The purpose of this document is to address current evidence
      regarding the diagnosis, staging, and management of gestational trophoblastic
      disease.

PMID- 15196848
TI  - Laparoscopic management of cervical cancer: because we can, or because we should?

PMID- 15196849
TI  - A comparison of laparascopic-assisted radical vaginal hysterectomy and radical
      abdominal hysterectomy in the treatment of cervical cancer.
AB  - OBJECTIVES: The aim of this study was to compare peri-operative morbidity and
      recurrence-free survival of early-stage cervical cancer patients treated by
      laparoscopic-assisted radical vaginal hysterectomy (LARVH) with time-matched
      radical abdominal hysterectomy (RAH) controls at our center. METHODS: Since July
      1984, all patients with FIGO stage IA/IB cervical cancer undergoing radical
      surgery by members of our division have been entered into a prospective database.
      Since November 1996, one surgeon at our center has performed LARVH on all
      surgically appropriate patients. Non-parametric tests were used. Differences
      between medians were compared using Wilcoxon Rank Sum test. Statistical analysis
      used the Kaplan-Meier method to calculate disease-free survival. Differences
      between survival curves were compared with the log rank test. Statistical
      significance was defined as P < 0.05. RESULTS: Between November 1996 and December
      2003, 71 and 205 patients have undergone LARVH and RAH, respectively, for FIGO
      stage IA/IB carcinoma of the cervix. Both groups were similar with respect to age
      and Quetelet index. There were no differences in tumor size, histology, grade,
      depth of invasion, lymph node metastases, or surgical margins. All laparoscopic
      procedures were completed successfully with no conversions to laparotomy. Intra
      operative morbidity characteristics analyzed (LARVH vs. RAH) were blood loss 300
      ml vs. 500 ml (P < 0.001), operative time 3.5 h vs. 2.5 h (P < 0.001), and intra
      operative complications 13% vs. 4% (P < 0.03). Intra-operative complications in
      the LARVH group included: cystotomy (7), ureteric injury (1), and bowel injury
      (1). There was no difference in transfusion rates. There was no difference
      between post-operative infectious and non-infectious complications (LARVH vs.
      RAH), 9% vs. 5% and 5% vs. 2%, respectively. The median time to normal urine
      residual was 10 days vs. 5 days (P < 0.001), and the median length of hospital
      stay was 1 day vs. 5 days (P < 0.001). Twenty-two percent of patients received
      post-operative radiotherapy for high-risk features in both groups. After a median
      follow-up of 17 and 21 months, there have been 4 recurrences in the LARVH group
      and 13 in the RAH (P = NS). The overall 2-year recurrence-free survival was 94%
      and 94% in the LARVH and RAH groups, respectively (P = NS). CONCLUSION: Our data
      demonstrate that early cervical cancer can be treated successfully with LARVH
      with similar efficacy and recurrence rates to RAH. The major benefits are less
      intra-operative blood loss and shorter hospital stay. It is a safe procedure with
      low overall morbidity and complication rates. However, at present, LARVH is
      associated with an increase in intra-operative complications, and patients may
      have an increased time to return to normal bladder function.

PMID- 15196851
TI  - Levels of the DNA adduct, N7-methyldeoxyguanosine, are associated with increased
      risk of failure of treatment of cervical intraepithelial neoplasia.
AB  - OBJECTIVE: To determine whether exposure to methylating agents was a risk factor
      for treatment failure in women undergoing colposcopic examination. METHODS: Nine
      hundred fifty-eight women attending for colposcopic examination after abnormal
      cervical smear test results were recruited into the study cohort. Information on
      demographic factors, smoking and other risk factors was obtained and a pre
      treatment biopsy was taken and stored at -70 degrees C. After follow-up, cases
      who had treatment failure of cervical intraepithelial neoplasia (CIN) within 2
      years following treatment were identified (n = 77) and matched to women with no
      treatment failure of CIN in this time period (controls, n = 154). DNA was
      extracted from the pre-treatment biopsies and levels of N7-methyl-deoxyguanosine
      (N7-MedG), a marker of exposure to methylating agents, were quantified as the
      ring-opened form of the base damage by a validated immunoslotblot assay. RESULTS:
      Sufficient DNA for N7-MedG analysis was extracted from 61 subjects corresponding
      to 20 matched case control pairs. N7-MedG was detected in cervical DNA with
      levels ranging from non-detected (<0.1 micromol/mol dG) to 4.83 micromol/mol dG.
      N7-MedG levels were significantly higher in cases (geometric mean 0.99
      micromol/mol dG) than controls (0.33 micromol/mol dG; P = 0.01). There were no
      associations between N7-MedG levels and HPV or smoking status. Log N7-MedG
      content, after adjustment for HPV status at time of treatment, was found to be
      significantly associated with increased risk of treatment failure (OR 5.74, 95%
      CI 1.05-31.23). CONCLUSIONS: The association between pre-treatment levels of DNA
      damage induced by methylating agents and subsequent treatment failure implicates
      methylating agent exposure as a causative factor in treatment failure.

PMID- 15196850
TI  - Differential induction of apoptosis by tumor necrosis factor-related apoptosis
      inducing ligand in human ovarian carcinoma cells.
AB  - OBJECTIVES: In this study, we examine the sensitivity of a panel of ovarian
      carcinoma cells, which includes four primary ovarian cancer cell samples, and
      four normal ovarian epithelium samples to tumor necrosis factor-related apoptosis
      inducing ligand (TRAIL). We also examine the intracellular regulation of TRAIL
      mediated apoptosis. METHODS: The sensitivity to TRAIL was determined by short
      term survival assays on seven ovarian carcinoma cell lines, four primary samples
      of ovarian cancer, and four normal ovarian epithelium samples. We assessed the
      activation of the apoptotic pathway in TRAIL-resistant and -sensitive tumor
      cells. The expression of TRAIL receptors was determined by flow cytometry. The
      protein expression of FADD, XIAP, caspase-8, caspase-3, BAX, and c-FLIP were
      determined by immunoblot analyses. RESULTS: We show that ovarian cancer cells
      display variable sensitivity to TRAIL-induced apoptosis although most cell lines
      have similar sensitivity to cisplatin. Normal ovarian epithelium samples were
      mostly sensitive to TRAIL. In sensitive cells, TRAIL induced caspase-8-dependent
      apoptosis, which subsequently led to activation of caspase-3. Both sensitive and
      resistant cells expressed caspase-8, caspase-3, FADD, XIAP, and c-FLIP at similar
      levels. A significant enhancement in cell death was observed in TRAIL-resistant
      cells when c-FLIP(L) levels were downregulated by RNA interference. CONCLUSIONS:
      These data suggest that sensitivity to TRAIL and chemotherapy does not
      necessarily correlate in human ovarian cancer cells. Cancerous cells isolated
      from patients with ovarian cancer show variable sensitivity to TRAIL but most
      normal ovarian epithelial cells are sensitive. In human ovarian cancer cells, c
      FLIP(L) may participate to the regulation of the TRAIL signaling cascade.

PMID- 15196852
TI  - Quality of life after pelvic exenteration.
AB  - OBJECTIVES: Pelvic exenteration, for gynecological and urological cancer, is an
      extensive and mutilating procedure. The 5-year survival rate is fairly good (40
      60%), but little is known about the long-term quality of life. METHODS: In this
      retrospective cohort study, the quality of life was assessed using the EORTC QLQ
      C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires. RESULTS: Healthy females
      and those who underwent pelvic exenteration for a gynecological or urological
      malignancy reported comparable levels of emotional functioning and general
      quality of life. More physical, sexual, and social problems were, however, noted
      after exenteration. Younger patients and patients who underwent total pelvic
      exenteration had the most difficulty in adapting to daily life, disease, and
      treatment. They also had a worse body image, and the influence of the operation
      on their sex life was greater compared to other patient groups of this study.
      CONCLUSION: Despite the immense effect of pelvic exenteration on physical,
      sexual, and social functioning, women who underwent this procedure reported
      similar levels of emotional functioning and general quality of life compared to
      healthy women. Adaptation and the mechanism of response shift presumably play an
      important role.

PMID- 15196853
TI  - Genetic variants in SOD2, MPO, and NQO1, and risk of ovarian cancer.
AB  - OBJECTIVE: One way in which parity and use of oral contraceptives may protect
      against ovarian cancer is by preventing inflammation and oxidative stress
      associated with ovulation. Since the genes superoxide dismutase (SOD2),
      myeloperoxidase (MPO), and NAD(P)H:quinone oxidoreductase 1 (NQO1) are involved
      in inflammation and oxidative stress, we investigated whether variants of these
      genes are associated with risk of ovarian cancer. METHODS: In a hospital-based
      case-control study, we compared 125 cases and 193 controls with respect to
      prevalence of (1) the T-->C (val-->ala) substitution at the -9 position in the
      signal sequence of SOD2; (2) the G-->A substitution at the -463 position in the
      promoter region of MPO; and (3) the C-->T (pro-->ser) change in exon 6 of NQO1.
      Genotyping was done using PCR and gel electrophoresis for MPO and NQO1 and using
      MALDI-TOF mass spectrometry for SOD2. RESULTS: For SOD2, women with the TC
      (val/ala) or CC (ala/ala) genotypes were at increased risk [odds ratio (OR) 2.1,
      95% confidence interval (CI) 1.1-4.0]. Results for MPO and NQO1 were in the
      hypothesized directions but were not statistically significant. For MPO, there
      was a small inverse association among women with GA or AA genotypes (OR = 0.72,
      95% CI 0.43-1.2). For NQO1, the TT (ser/ser) genotype was associated with
      somewhat increased risk (OR = 2.3, 95% CI 0.69-7.6). CONCLUSIONS: While these
      results need to be confirmed in other studies, they point to a possible role for
      genes involved in oxidative stress in the development of ovarian cancer.

PMID- 15196854
TI  - Epigenetic and genetic alternation of PTEN in cervical neoplasm.
AB  - OBJECTIVES: We studied the role of epigenetic and genetic changes of PTEN in the
      development of squamous cell carcinoma (SCC) of the uterine cervix and their
      value as a prognostic factor. METHODS: Ten high-grade cervical intraepithelial
      neoplasia (CIN-H) and 62 SCC tissues were used in this study. Microdissection was
      performed before loss of PTEN function through methylation of promoter CpG
      islands, deletion and mutation were studied. The findings were verified with PTEN
      protein expression and correlated with clinicopathologic information. RESULTS:
      PTEN mutation assessed by single-strand conformation polymorphism (PCR-SSCP) was
      not noted in any of the 62 SCC. Loss of heterozygosity (LOH) was only seen in
      eight SCC. PTEN promoter methylation was detected in 40% (4/10) of CIN-H and 58%
      (36/62) of SCC specimens. Loss of PTEN protein expression was associated with
      methylation of PTEN. PTEN methylation was not related to patient age, tumor grade
      or stage. Patients with persistent disease or who died of disease had a
      significantly higher percentage of PTEN methylation than those without evidence
      of recurrence. Multivariate Cox regression models confirmed PTEN was an important
      significant predictor both for total and disease-free survival after controlling
      age, pathologic grade and clinical stage. CONCLUSIONS: PTEN methylation and loss
      of PTEN expression are early events in the development of cervical cancer and may
      have prognostic significance.

PMID- 15196855
TI  - Stromal invasion of the cervix can be excluded from the criteria for using
      adjuvant radiotherapy following radical surgery for patients with cervical
      cancer.
AB  - BACKGROUND: Regarding complications of radiotherapy, the indications for adjuvant
      radiotherapy should be restricted. We conducted the present study to determine
      whether deep stromal invasion of the cervix could be excluded from the criteria
      used to identify patients for this treatment surgery. METHODS: This study
      included 115 patients with FIGO stage Ib to IIb cervical cancer who underwent
      radical hysterectomy and pelvic lymph node dissection. Patients had the following
      tumors: 61 nonkeratinizing squamous cell carcinoma, 21 keratinizing squamous cell
      carcinoma, 26 adenocarcinoma, and 7 adenosquamous cell carcinoma. Our study
      criteria for using adjuvant radiotherapy included positive lymph node
      involvement, a compromised surgical margin, or parametrial extension. Deep
      stromal invasion of the cervix was excluded from the criteria in this study.
      RESULTS: Seventy-two of the 115 patients (62.6%) underwent radical surgery only
      and all were alive. The remaining 43 patients received a complete course of
      external irradiation following radical surgery. The estimated 5-year survival
      rate is 100% for patients with stage Ib, 93.3% for stage IIa, and 52.7% for stage
      IIb. Fifty-five patients (47.8%) had deep stromal invasion. The prognosis for
      patients with deep stromal invasion was significantly worse than that for
      patients without deep stromal invasion (5-year survival rate, 69.8% vs. 98.0%).
      However, 21 patients (18.3%) with deep stromal invasion, but without positive
      lymph node involvement, compromised surgical margin, or parametrial extension,
      were alive without recurrence. Multivariate analysis showed that lymph node
      involvement and parametrial extension were independent prognostic factors, but
      that deep stromal invasion was not. CONCLUSION: Deep stromal invasion of the
      cervix can be excluded from the list of criteria for selecting patients with
      cervical cancer who would benefit from adjuvant radiotherapy following radical
      surgery.

PMID- 15196856
TI  - Cost-effectiveness analysis of the treatment for intermediate risk endometrial
      cancer: postoperative brachytherapy vs. observation.
AB  - OBJECTIVE: To compare the survival, morbidity, and cost of treating women with
      intermediate risk endometrial cancer with postoperative vaginal cuff
      brachytherapy versus observation followed by treatment for vaginal recurrence.
      METHODS: A cost-effectiveness analysis was performed comparing two treatment
      strategies for intermediate risk endometrial cancer (Stage IC, IG3, II-tumors
      limited to the uterus with greater than 50% myometrial invasion or poor
      differentiation or cervical metastasis). All patients undergo hysterectomy,
      oophorectomy, and lymphadenectomy: strategy 1-postoperative vaginal cuff
      brachytherapy, strategy 2-observation. Strategy 2 patients who develop vaginal
      recurrence undergo diagnostic work-up followed by teletherapy and brachytherapy.
      All six principles of cost-effectiveness analysis were employed. Importantly,
      actual payer costs were evaluated, not charges. RESULTS: Although the treatment
      for vaginal cuff recurrence is expensive, since only 8% of patients develop a
      vaginal recurrence, there was a 31% decreased cost by not treating patients with
      postoperative low-dose rate brachytherapy (strategy 2). Also, although the
      complication rate for teletherapy is greater than brachytherapy, since only 8% of
      patients develop a vaginal recurrence and require teletherapy, projected
      complication rates for the two strategies are similar. Survival would be
      decreased 3% by withholding postoperative brachytherapy (strategy 2). With
      postoperative high-dose rate brachytherapy (strategy 1), the cost per life saved
      would be 38,764 US dollars. CONCLUSION: Using a cost-effectiveness analysis, we
      have shown that withholding postoperative brachytherapy for patients with
      intermediate risk endometrial cancer results in a 31% decrease in cost, has a
      similar radiation complication rate, and results in a 3% decrease in survival.

PMID- 15196857
TI  - Depth of cervical stromal invasion as a prognostic factor after radical surgery
      for early stage cervical cancer.
AB  - INTRODUCTION: In the United Kingdom, the Royal College of Pathologists have
      issued guidelines detailing how the depth of stromal invasion (DOI) in cervical
      cancer should be measured as a percentage of the overall cervical radius in
      millimeters. Several studies have found the assessment of the depth of stromal
      invasion by cancer of the cervix to be of prognostic value. These studies did not
      take into account patients whose diagnostic procedures required removal of much
      tumor (large loop excision of the transformation zone [LLETZ] and knife cone
      biopsies). Furthermore, the Royal College of Pathologists guidelines do not
      address this issue. MATERIALS AND METHODS: Over the period of 6 years, 228 women
      had radical hysterectomy (RH) for stage Ib/IIa cervical cancer. The percentage of
      the depth of stromal invasion was measured according to the Royal College of
      Pathologist's guidelines in the UK. Patients who had large loop excision of the
      transformation zone and knife cone biopsies were excluded (91 patients). RESULTS:
      A Cox regression analysis showed that when nodal involvement, depth of stromal
      invasion, endothelial lined space invasion (ELSI), and tumor type were fitted
      simultaneously, only nodal involvement remained as a marker of adverse outcome.
      CONCLUSIONS: We recommend that when the DOI is measured, account should be taken
      of the LLETZ/knife cone biopsy size. A randomized controlled trial, which
      concludes that DOI is an independent prognostic factor, is needed. Until this is
      properly evaluated, we feel that including DOI as an essential part of the
      standard pathological report is not warranted.

PMID- 15196858
TI  - Effects of raloxifene hydrochloride on endometrial cancer cells in vitro.
AB  - OBJECTIVE: Determine effects of raloxifene hydrochloride, a selective estrogen
      receptor modulator (SERM), on growth and proliferation of an estrogen-responsive
      endometrial cancer cell line in vitro. MATERIALS AND METHODS: Studies were
      performed with Ishikawa endometrial adenocarcinoma cells, a well-differentiated
      cancer that expresses estrogen receptors and progesterone receptors. Raloxifene
      was purified as the hydrochloride salt. The four arms of the study were cells
      grown (1) without any further addition (control), (2) with estradiol only, (3)
      with raloxifene only, or (4) with estradiol and raloxifene. Three concentrations
      of estradiol (10, 100, 1000 pg/ml) and raloxifene (1, 10, 100 ng/ml) were used.
      After 1 week of culturing, the number of living cells for each experimental group
      was determined and expressed as a percentage of the control group. RESULTS: Cells
      treated with raloxifene 10 or 100 ng/ml alone grew significantly faster than
      control cells: 10 ng/ml [115.25%; SD, 11.05; 95% confidence interval (CI), 107.35
      123.16; P = 0.002] and 100 ng/ml (111.14%; SD, 14.19; 95% CI, 100.98-121.29; P =
      0.03). Estradiol 10 or 100 pg/ml did not stimulate cell growth, whereas cells
      treated with 1000 pg/ml grew significantly faster than control cells (114.69%;
      SD, 16.84; 95% CI, 102.65-126.74; P = 0.02). Raloxifene and estradiol together in
      any concentration did not affect cell growth. CONCLUSIONS: Raloxifene did not
      inhibit the growth of endometrial cancer cells in vitro. High concentrations even
      promoted cell growth. Estradiol in physiologic concentrations did not stimulate
      the growth of endometrial cancer cells in vitro.

PMID- 15196859
TI  - Drug sensitivity-related benefit of systematic lymphadenectomy during
      cytoreductive surgery in optimally debulked stages IIIc and IV ovarian cancer.
AB  - OBJECTIVE: The purpose of this study is to assess the survival experience
      following systematic lymphadenectomy (LNX) in conjunction with primary but
      optimal cytoreductive surgery in advanced epithelial ovarian cancer (OC) patients
      when followed by intensive chemotherapy. METHODS: This is a retrospective
      analysis of all women with OC who were treated in our institution between 1992
      and 2000. A total of 98 patients with stages IIIc-IV of OC underwent primary
      cytoreductive surgery which was 'optimal' (<1 cm residual disease). All patients
      subsequently received postoperative platinum-containing chemotherapy. Group I,
      consisting of 51 patients underwent LNX; Group II, consisting of 47 patients did
      not undergo LNX. The percentage of patients failing to respond to chemotherapy in
      each group was similar. Each group had statistically equivalent age, stage,
      regimens of chemotherapy performed, and all other known prognostic factors.
      RESULTS: No survival benefit could be seen in platinum-sensitive patients.
      However, in patients who failed to respond to chemotherapy, the 2-year
      progression-free survival (PFS) (42.8% vs. 14.3%) and overall survival (OS)
      (51.2% vs. 28.8%) was quite different. LNX significantly improved those of drug
      resistant patients when optimal cytoreductive surgery was performed [P = 0.008,
      risk ratio (rr) = 2.675, 95% confidence interval (CI) = 1.251-5.724]. Cox's
      proportional analysis shows that LNX was one of the three most significant
      covariate with the tumor grade and the number of postoperative residual lesions.
      CONCLUSIONS: The results show that LNX might be of benefit in patients who have
      optimal primary cytoreductive surgery and who do not respond to platinum-based
      chemotherapy.

PMID- 15196860
TI  - Optimal surgical cytoreduction in patients with Stage III and Stage IV
      endometrial carcinoma: a study of morbidity and survival.
AB  - OBJECTIVE: To evaluate the survival impact of residual disease at the time of
      primary surgery for patients with Stage III and IV endometrial carcinoma; to
      assess morbidity associated with surgical cytoreduction. METHOD: All patients
      with endometrial carcinoma who underwent primary surgical therapy at the
      University of Miami between January 1, 1990 and June 1, 2002 were identified.
      Patients meeting FIGO criteria for Stage III or IV disease were selected.
      Papillary serous and clear cell histology was excluded. RESULTS: Eighty-five
      patients were identified: 66 Stage III and 19 Stage IV. Only Stage IIIC and Stage
      IV were included in survival analysis: 72% (33 Stage IIIC, 9 Stage IV) had
      optimal cytoreduction and 28% (6 Stage IIIC, 10 Stage IV) had suboptimal
      cytoreduction. The median survival for Stage IIIC and IV disease was 6.7 months
      for patients with suboptimal cytoreduction and 17.8 months for patients with
      optimal cytoreduction (P = 0.001). The proportion of patients with major
      postoperative complications (37.50% vs. 7.25%, P = 0.005), unplanned
      postoperative SICU admissions (31.25% vs. 7.25%, P = 0.018), and length of
      hospital stay exceeding 15 days (31.25% vs. 4.35%, P = 0.005) was greater in
      patients with suboptimal cytoreductive surgery. CONCLUSIONS: Overall survival is
      lower and morbidity is higher in patients with advanced endometrial carcinoma
      having suboptimal cytoreduction at the time of primary surgery. Patients with
      suspected advanced stage endometrial carcinoma should be counseled on the
      potential benefits of optimal cytoreductive surgery. Alternative treatment
      options should be considered in those patients with surgically unresectable
      disease.

PMID- 15196861
TI  - Chemoradiation with 5-fluorouracil and mitomycin C in the treatment of vulvar
      squamous cell carcinoma.
AB  - OBJECTIVE: To investigate the acute and late toxicities associated with the use
      of chemoradiation therapy (CRT) with 5-fluorouracil (5-FU) and mitomycin C or
      mitomycin C alone for primary, adjuvant, and salvage therapy for vulvar cancer.
      METHODS: Medical charts of 17 patients who received CRT with this regimen were
      reviewed. Toxicity was scored by 1998 standardized common toxicity criteria,
      Version 2.0, for acute toxicity and the RTOG/EORT Late Radiation Morbidity
      Scoring Schema for late toxicity. Median follow-up was 20 months (range: 5-74
      months). RESULTS: Six patients had grade 4 neutropenia. In three patients, life
      threatening neutropenic sepsis developed after the second cycle of chemotherapy.
      Severe enterocolitis was a direct cause of death in two patients. In four
      patients, the second cycle of chemotherapy was cancelled because of severe
      toxicity associated with the first cycle. One patient had grade 4 skin toxicity
      in the vulvar-perineal area. Six patients had grade 3 and seven patients had
      grade 2 acute skin toxicity. Skin toxicity necessitated the interruption of CRT
      in nine patients at a median dose of 32.4 Gy (range: 16.2-48 Gy). One patient
      developed bowel perforation and colovaginal fistula 1.5 years after completion of
      CRT. CONCLUSION: Chemoradiation therapy utilizing 5-FU and mitomycin C or
      mitomycin C alone in the treatment of vulvar cancer can be associated with a high
      incidence of morbidity and mortality. Strict attention to indications for
      treatment interruptions or chemotherapy dose adjustments is obligatory for safe
      delivery of CRT to these patients.

PMID- 15196862
TI  - A phase II evaluation of Temozolomide in patients with recurrent epithelial
      ovarian cancer.
AB  - OBJECTIVES: To assess the antitumor activity of Temozolomide, a novel alkylating
      agent, in patients with persistent or recurrent ovarian or primary peritoneal
      carcinoma who have failed other second-line chemotherapy agents. To identify the
      nature and degree of toxicity of Temozolomide in this group of patients. METHODS:
      Temozolomide was administered orally at an initial dose of 150 mg/m(2) daily for
      5 days, every 4 weeks. If the initial course was tolerated without dose-limiting
      toxicity, then the dose was increased to 200 mg/m(2). Patients were evaluated for
      response and toxicity. RESULTS: Fifteen patients were enrolled and evaluated. The
      median number of prior treatment regimens was 3. Hematologic toxicity was
      encountered in 26% of patients and was manageable. There were no complete or
      partial responses. One patient had stable disease with significant improvement in
      her performance status while on treatment. CONCLUSION: This dose and schedule of
      Temozolomide had insignificant activity in this heavily pretreated group of
      patients with persistent or recurrent ovarian or primary peritoneal carcinoma.

PMID- 15196863
TI  - Necrotic cell death of ovarian adenocarcinoma caused by seminal plasma.
AB  - OBJECTIVE: From the knowledge of risk factors of epithelial ovarian cancer, we
      deduced a hypothesis that human seminal plasma (HSP) has a preventive role in the
      development of epithelial ovarian cancer. To examine whether HSP directly
      influences the growth of ovarian cancer, we have investigated the in vitro and in
      vivo effect of HSP on ovarian adenocarcinoma cell lines (SK-OV-3 and OVCAR-3) in
      comparison with its effects on normal ovarian surface epithelial cells (NOSE).
      METHODS: Cell viability was determined by MTT assay. Cytotoxic effect was
      evaluated by flow cytometry analysis, by DNA laddering, and by morphological
      analysis. In vivo therapeutic effect of HSP was evaluated by the subcutaneous
      inoculation of SK-OV-3 cells in nude mice (BALB-c) model. RESULTS: HSP at a final
      concentration of 1:50 induced a time- and dose-dependent inhibition of SK-OV-3
      and OVCAR-3 growth, whereas NOSE was not affected. Flow cytometric analysis, DNA
      laddering, and morphological analysis indicated that HSP induced necrosis, rather
      than apoptosis, of both ovarian carcinoma cell lines. In in vivo experiment that
      used the nude mice (Balb-C) with tumor inoculation of SK-OV-3 cells, HSP induced
      necrosis of tumor with no detectable toxic effects on the major organs.
      CONCLUSION: These results show that HSP inhibits the growth and induces the
      necrosis of epithelial ovarian cancer cells and suggests that one or more
      components of HSP may provide a scientific basis for preventing epithelial
      ovarian cancer.

PMID- 15196864
TI  - Immunohistochemical determination of estrogen and progesterone receptor
      positivity in uterine adenosarcoma.
AB  - BACKGROUND: Given the paucity of data regarding hormone dependency, it was the
      purpose of this study to screen for the presence of estrogen and progesterone
      receptors in uterine adenosarcoma (UAS). METHODS: One hundred and five centers
      were asked to screen their files for uterine adenosarcomas. A immunohistochemical
      estrogen and progesterone receptor determination was performed. RESULTS: Twenty
      eight primary UAS were stained, including one cervical adenosarcoma. Sarcomatous
      overgrowth could be observed in eight. Furthermore, two cases of recurrent UAS,
      one only consisting of endometrial stromal sarcoma, were stained. UAS lacking
      sarcomatous overgrowth showed estrogen receptor positivity in 17/20 (85%) and
      16/20 (80%) in the epithelial and sarcomatous component, respectively.
      Progesterone positivity was observed in 13/20 (65%) and 12/20 (60%) in the
      epithelial and sarcomatous component, respectively. In 18/20 (90%) of the cases,
      either the estrogen or the progesterone receptor stained positive in the
      sarcomatous component. UAS with sarcomatous overgrowth showed estrogen receptor
      positivity in 4/8 (50%) and 0/8 (0%) in the epithelial and sarcomatous component,
      respectively. Progesterone positivity was observed in 2/8 (25%) and 1/8 (12%) in
      the epithelial and sarcomatous component, respectively. The stromal component of
      both recurrent cases stained moderately positive for estrogen receptor whereas
      progesterone receptor was considered negative. CONCLUSION: The observation that
      the sarcomatous component of UAS without sarcomatous overgrowth frequently
      expresses hormone receptors might be of significant clinical importance.

PMID- 15196865
TI  - Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar
      cancer.
AB  - OBJECTIVE: Nitric oxide (NO) is involved in angiogenesis and tumor growth. We
      attempted to establish an association between two polymorphisms of the
      endothelial nitric oxide synthase (NOS3) gene and vulvar cancer. METHODS: We used
      peripheral venous blood sampling, DNA extraction, and polymerase chain reaction
      (PCR) and pyrosequencing to genotype 68 women with vulvar cancer and 227 healthy
      Caucasian women for the presence of the intron 4 27-bp-repeat [NOS3*A] and exon 7
      Glu298Asp polymorphisms. RESULTS: The presence of a polymorphic NOS3*A allele
      (26.2% vs. 24.6%; OR: 1.01; 95% CI: 0.6-2.0; P = 0.9) or a polymorphic NOS3 exon
      7 Glu298Asp allele (41.2% vs. 53.7%; OR: 0.6; 95% CI: 0.3-1.0; P = 0.09) was not
      associated with vulvar cancer. Within the vulvar cancer group, the presence of a
      polymorphic NOS3*A or a polymorphic NOS3 exon 7 Glu298Asp allele was not
      associated with clinico-pathological parameters such as advanced tumor stage,
      groin lymph node involvement, tumor grading, and age at diagnosis. Survival
      analysis demonstrated that the presence of a polymorphic NOS3*A allele was
      associated with a significantly reduced disease-free survival time (P = 0.03),
      whereas the presence of the polymorphic NOS3 exon 7 Glu298Asp allele was not
      associated with disease-free survival (P = 0.5). CONCLUSIONS: We are the first to
      report on NOS3 polymorphisms in vulvar cancer. We found that allelic variation
      within intron 4, but not ithin exon 7 of NOS3, influences the length of disease
      free survival, but not the biological phenotype of vulvar cancer.

PMID- 15196866
TI  - Radioimmunotherapy in advanced ovarian cancer: is there a role for pre-targeting
      with (90)Y-biotin?
AB  - OBJECTIVES: Despite recent advances in the management of ovarian cancer, this
      tumor remains the leading cause of death among gynecologic malignancies.
      Moreover, advanced ovarian carcinoma has a poor prognosis, thus requiring new
      therapeutic modalities. Previous studies have indicated a survival advantage for
      ovarian cancer patients (pts) treated with radioimmunotherapy (RIT). Pre
      targeting RIT, based on the avidin-biotin system, has been the objective of
      previous studies performed by our group. PATIENTS AND METHODS: In the present
      study, the therapeutic efficacy and toxicity of RIT in 38 advanced ovarian cancer
      patients have been retrospectively evaluated. RIT was performed according to the
      following three-step protocol: biotinylated monoclonal antibodies (MoAb) and
      avidin were intraperitoneally (ip) injected (1st and 2nd step), and 12-18 h later
      (90)Y-labeled biotin either iv or ip was injected as 3rd step. Sixteen out of 38
      patients were treated by intraperitoneal injection only, whereas other 22 pts
      received the combined treatment (ip + iv); the dose range was 10-100 mCi of (90)Y
      biotin. RESULTS: Both of the two therapy regimens were well tolerated; no acute
      side effects were observed. Two patients (5%) showed temporary hematological
      grade III-IV toxicity. As regards to the therapeutic efficacy, in the ip group we
      observed 6% of objective tumor reduction, stabilization in 31% of pts, and
      progression in 50%. In the group of combined treatment, 9% of patients achieved
      objective responses, 32% showed stable disease, and 41% had a progression.
      CONCLUSIONS: These data show the excellent tolerability (maximum tolerated dose
      (MTD) has not been determined yet) and the potential therapeutic role of RIT in
      advanced ovarian cancer. Patients with minimal residual disease would probably
      take the best advantages of RIT with (90)Y-biotin (electrons). These data warrant
      further prospective studies.

PMID- 15196867
TI  - Survival following the documentation of platinum and taxane resistance in ovarian
      cancer: a single institution experience involving multiple phase 2 clinical
      trials.
AB  - OBJECTIVES: There are very limited data in the oncology literature regarding the
      survival of women with both platinum and taxane-refractory ovarian cancer.
      METHODS: To examine this issue, we retrospectively reviewed the survival of
      patients treated on one (or more) of four previously reported nonrandomized
      single-agent phase 2 trials (topotecan, liposomal doxorubicin, gemcitabine,
      docetaxel), involving women with well-characterized platinum/taxane-resistant
      ovarian, fallopian tube, and primary peritoneal cancers. Following their most
      recent treatment with both classes of agents, patients must have either not
      responded to therapy or experienced a treatment-free interval of <3 months before
      documented disease progression. RESULTS: The median survival of the 111 patients
      (median age 61) included in this analysis was 6 months (range 1-37 months).
      Whereas 36 patients (32%) survived for <4 months, 30 patients (27%) lived for >
      or =12 months following documentation of resistance to both platinum and taxane
      therapy. CONCLUSION: With currently available antineoplastic drug therapy of
      platinum/taxane-resistant ovarian cancer, overall survival is relatively short,
      but a substantial minority of patients can be anticipated to live for periods in
      excess of 1 year. It remains uncertain whether such unexpectedly prolonged
      survival results from a biological response to chemotherapy or simply reflects
      the natural history of disease in a subset of patients with this malignancy.

PMID- 15196868
TI  - Phase I trial of escalating doses of topotecan in combination with a fixed dose
      of pegylated liposomal doxorubicin in women with mullerian malignancies.
AB  - BACKGROUND: Topotecan and pegylated liposomal doxorubicin (Doxil) interact with
      topoisomerase I and II (topo I and II), respectively, with schedule dependent,
      and potentially synergistic cytotoxicity. OBJECTIVES: Define dose-limiting
      toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan
      delivered by 72-h infusion administered immediately after Doxil delivered at a
      fixed dose (30 mg/m(2)) in a cohort of women with recurrent mullerian
      malignancies. METHODS: Topotecan dose was escalated from 0.5 mg/m(2)/day for 3
      days in 0.2 mg/m(2)/day increments with treatment repeated every 21 days.
      Eligibility criteria required ECOG < or = 2 and no more than four prior lines of
      chemotherapy. No dose reductions were allowed in the first two cycles to allow
      evaluation of cutaneous toxicity. RESULTS: Between November 2000 and August 2002,
      18 patients were enrolled. Median age 59 (40-71) years. Patients received a
      median 1 (1-6) cycles of chemotherapy, with 39 cycles of treatment delivered at
      DL 1. All patients were evaluable for toxicity and 12 for response. At dose level
      2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous
      toxicity, and neutropenia. There was no clinically significant cardiac toxicity.
      There were no radiologically confirmed partial responses. CONCLUSIONS: Doxil 30
      mg/m(2) and topotecan 0.5 mg/m(2)/day by 72-h infusion (total dose 1.5 mg/m(2)),
      although a rational combination of cytotoxic therapies, have limited clinical
      activity.

PMID- 15196869
TI  - Endobronchial clear cell adenocarcinoma occurring in a patient 15 years after
      treatment for DES-associated vaginal clear cell adenocarcinoma.
AB  - BACKGROUND: Clear cell adenocarcinoma (CCA) of the vagina and cervix in young
      women is associated with prenatal exposure to diethylstilbestrol (DES).
      Parenchymal pulmonary metastases are known to occur following treatment of the
      primary tumor. Most recurrences present within 2 to 3 years of the initial
      diagnosis. CASE: This is a case report of a solitary endobronchial clear cell
      adenocarcinoma occurring 15.3 years after the initial diagnosis of DES-induced
      CCA. CONCLUSIONS: This case suggests that management of clear cell cancer
      survivors should involve long-term follow-up because of the potential for the
      appearance of a new focus of clear cell adenocarcinoma.

PMID- 15196870
TI  - Chylous ascites following para-aortic lymphadenectomy: a case report.
AB  - BACKGROUND: Chylous ascites is an uncommon complication following para-aortic
      lymph node dissection in the management of gynecologic malignancies. Treatment
      options are serial paracentesis, medium-chain triglyceride diet, total parenteral
      nutrition and somatostatin as conservative management and peritoneovenous
      shunting, and surgical exploration for refractory cases. CASE: A 31-year-old
      female patient developed chylous ascites following para-aortic lymph node
      dissection for borderline mucinous tumor of the ovary. Conservative management
      options failed with recurrence of chylous ascites. Chylous ascites resolved after
      surgical closure of the lymphatic fistula on the cisterna chyli. There was no
      evidence of ascites at 10 months follow-up. CONCLUSION: If the patient is a good
      surgical candidate, surgical exploration should be considered earlier in the
      treatment of refractory chylous ascites.

PMID- 15196871
TI  - Examples of the marked variability in the relationship between the serum CA-125
      antigen level and cancer-related symptoms in ovarian cancer.
AB  - OBJECTIVE: While the clinical utility of the serum CA-125 antigen level in
      demonstrating objective evidence of regression or progression of disease in women
      with ovarian cancer is well-established, the relationship between both the
      absolute value of this tumor maker, or its rate of change over time, and the
      short-term clinical course (e.g., development of cancer-related symptoms) in
      individual patients remains poorly defined. CASE REPORTS: Five women currently
      under the care of physicians in the Gynecologic Cancer program of the Cleveland
      Clinic demonstrate the marked variability in the correlation between the serum CA
      125 antigen and the natural history of disease for individual patients with
      ovarian or primary peritoneal cancers. In these cases, persistent elevations
      (>100 units/ml for >2 years), rapid changes (<200 units/ml to >2000 units/ml over
      < or = 2 months), or extremely high CA-125 values (>5000 units/ml) failed to
      accurately predict the presence, time to development, or severity of symptoms.
      CONCLUSION: In the second-line and palliative management of ovarian or primary
      peritoneal cancers, it is important to emphasize the critical need for clinical
      judgement in the decision to initiate or alter therapy in individual patients
      based solely on changes in the serum level of the CA-125 antigen.

PMID- 15196872
TI  - The protooncogene c-KIT is expressed in leiomyosarcomas of the uterus.

PMID- 15196875
TI  - Commenting on "HIV-associated primary cervical non-Hodgkin's lymphoma and two
      other cases of primary pelvic non-Hodgkin's lymphoma" by Pham et al. 90:204-6.

PMID- 15196873
TI  - Commenting on "Vulvar langerhans cell histocytosis: a case report and review of
      the literature" by Santillan et al. 91:241-246.

PMID- 15196878
TI  - Activation of the ligand-mineralocorticoid receptor functional unit by ancient,
      classical, and novel ligands. Structure-activity relationship.
AB  - The mineralocorticoid effect on epithelial cells is the resultant of an intricate
      net of biochemical regulations that ultimately leads to the maintenance of
      electrolyte homeostasis. Two key protagonists in this plot are the ligand, which
      broadcasts the information, and the receptor, which functions as a receiver and
      transducer. Therefore, the responsibility for the final biological effect is not
      limited to each individual component but to both of them, so they constitute a
      functional unit. In addition, several prereceptor regulatory mechanisms are also
      determinant factors for the final biological response. Because steroids are
      present in both animals and plants and are derived from common precursors, it is
      intriguing how these simple molecules have acquired specialization to shape
      biological development and differentiation. This is particularly true for the
      function of aldosterone in mammals, which is mimicked by glucocorticoids or
      progesterone in some particular cases. Inasmuch as the most potent
      mineralocorticoid in nature, aldosterone, shows a poorly angled steroid nucleus
      at the A?B-ring junction, and because steroids that possess identical functional
      groups and different steroidal frames elicit different mineralocorticoid effects,
      we postulate that a planar conformation of the ligand is a key requirement to
      acquire potent sodium retention properties. The model takes into consideration
      all the mechanisms involved in the regulation of the final biological effect,
      although it does not provide a definitive answer to the original question. It is
      also discussed how the use of novel mineralocorticoid ligands may shed light on
      the still obscure mechanism of action of the mineralocorticoid receptor.

PMID- 15196877
TI  - Reinterpretation of basal glucocorticoid feedback: implications to behavioral and
      metabolic disease.
AB  - A number of metabolic (e.g., abdominal obesity) and psychological (e.g.,
      depression) pathologies commonly present together and have been associated with
      dysregulation in the hypothalamo-pituitary-adrenal (HPA) axis. Glucocorticoid
      hormones represent the final product of this classic neuroendocrine axis, and
      these steroids modulate neuroendocrine, metabolic, and behavioral function. A
      primary characteristic of the HPA axis is a negative feedback loop, and
      glucocorticoids act through the brain to inhibit drive to this neuroendocrine
      system. Slight and chronic perturbations in glucocorticoid levels, below or above
      normal, throughout the body lead to metabolic (e.g., abdominal obesity) and
      behavioral (e.g., depression) pathology. Appropriate feedback in the HPA axis is,
      therefore, critical, and determining how and where glucocorticoids act to impart
      their feedback effects have been the focus of many laboratories. However, the
      answer to these questions remain, in part, elusive. In this chapter, I review
      findings that have led me to reinterpret glucocorticoid feedback in the HPA axis.
      I propose that, under basal (nonstress) conditions, glucocorticoid feedback is a
      consequence of the metabolic actions of the adrenal steroid, not a direct effect
      on brain. This new perspective may provide insight into the etiology of diseases
      such as major depression and the metabolic syndrome X, and might explain the
      commonly observed coexistence of affective and metabolic disturbances.

PMID- 15196879
TI  - Reciprocal regulation and integration of signaling by intracellular calcium and
      cyclic GMP.
AB  - Calcium and guanosine-3',5'-cyclic monophosphate (cGMP) are second messenger
      molecules that regulate opposing physiological functions, reflected in the
      reciprocal regulation of their intracellular concentrations, in many systems.
      Indeed, cGMP and Ca2+ constitute discrete points of integration between multiple
      cell signaling cascades in both convergent and parallel pathways. This chapter
      describes the molecular mechanisms regulating intracellular Ca2+ and cGMP, and
      their integration in specific cellular responses.

PMID- 15196880
TI  - Unusual Guanylyl Cyclases and cGMP Signaling in Dictyostelium discoideum.
AB  - cGMP is used as a second messenger in many eukaryotes. cGMP signaling requires at
      least three components: Guanylyl cyclases synthesize cGMP from GTP. Specific cGMP
      binding proteins propagate the signal, usually by phosphorylation of their target
      proteins. Finally, phosphodiesterases terminate the cGMP signal by hydrolyzing
      cGMP to 5'cGMP. Recently, all guanylyl cyclases and most of the cGMP target
      proteins and phosphodiesterases of the cellular slime mold Dictyostelium
      discoideum have been identified. Characterization of these enzymes show them to
      be structurally and evolutionarily distinct from their bacterial and metazoan
      counterparts. In this chapter we review the properties of the Dictyostelium
      guanylyl cyclases and discuss their role in the unusual cGMP pathway of
      Dictyostelium.

PMID- 15196881
TI  - CRH, stress, and major depression: a psychobiological interplay.
AB  - Major depressive disorder (MDD) is a complex disease and is one of the leading
      causes of disability in our society. The provoking factors are multiple; acute
      and chronic psychological stress, severe early trauma experiences, somatic
      disease, and genetic factors all play a role. This review focuses on hyperdrive
      of corticotropin-releasing hormone (CRH) as the fundamental neurobiological
      correlate of MDD. CRH plays a key role in the adaptation to acute stress, but
      chronic CRH hyperdrive leads to a number of disadvantageous emotional and somatic
      effects. The evidence that the HPA axis is hyperactive in MDD, probably as a
      result of a primary hyperdrive of CRH, comes from multiple sources: biochemical
      studies, functional HPA axis tests, neuroimaging and postmortem studies, and
      clinical trials with HPA axis-related compounds. The liability to develop CRH
      hyperdrive is probably partly genetic. For a number of relevant genes, transgenic
      animal studies and human association studies indicate a role in HPA axis
      regulation and the liability to develop CRH hyperdrive. These data are reviewed.
      Finally, early adverse experience can produce a lasting effect on HPA axis
      regulation as well, probably leading to a lifelong tendency to develop chronic
      CRH hyperdrive in response to stress. This has been shown in a number of animal
      studies, and recently some data in humans with early trauma have become available
      as well. Taken together, these findings allow formulating an integrative
      hypothesis, with CRH hyperdrive at the core, bridging the old dichotomy between
      biology and psychology in our thinking about MDD.

PMID- 15196882
TI  - Gonadotropin-releasing hormone receptors: structure, expression, and signaling
      transduction.

PMID- 15196883
TI  - Familial Growth Hormone Deficiency and Mutations in the GHRH Receptor Gene.
AB  - Growth hormone (GH)-releasing hormone (GHRH) is necessary for the proliferation
      of the somatotropic cells of the anterior pituitary and the synthesis and
      secretion of GH. GHRH is released by the hypothalamus into the portal hypophysial
      circulation to bind to a membrane surface receptor [GHRH receptor (GHRHR)]
      expressed by the somatotropic cells. Because of the need of GHRH for GH
      secretion, it is to be expected that alterations in synthesis or action of GHRH
      would result in isolated GH deficiency (IGHD). Indeed, although GHRH gene
      mutations have never been reported, mutations in the GHRHR gene (GHRHR) are
      emerging as a relatively common cause of inherited autosomal recessive IGHD. The
      first human GHRHR mutations were discovered in families with a history of
      parental consanguinity. More recently, kindreds in which IGHD subjects are
      compound heterozygotes for two distinct mutations indicate that faulty GHRHR
      alleles may be prevalent and that these mutations may need to be suspected even
      in sporadic IGHD cases. Patients with two faulty GHRHR alleles have normal weight
      at birth. Growth failure becomes apparent during the first year of life.
      Biochemical studies show low serum insulin-like growth factor-1 level, and absent
      or markedly reduced GH response to a variety of stimuli. Magnetic resonance
      imaging shows hypoplasia of the anterior pituitary. In this chapter, we describe
      the GHRHR mutations reported to date and the phenotype of affected individuals.

PMID- 15196884
TI  - The roles of phospholipase C-gamma 1 and actin-binding protein filamin A in
      signal transduction of the insulin receptor.

PMID- 15196885
TI  - Regulation of expression of the Na+/H+ exchanger by thyroid hormone.
AB  - The Na+/H+ exchanger is a pH regulatory protein with a ubiquitous distribution in
      eukaryotic cells. Several isoforms of the Na+/H+ exchanger are known. The first
      isoform to be characterized and cloned, NHE1, is present on the plasma membrane
      of cells and functions to remove one intracellular proton in exchange for one
      extracellular sodium ion. It is involved in pH regulation, cell growth,
      differentiation, and cell migration. NHE1 is also involved in the cycle of damage
      that occurs in the heart with ischemic heart disease. Recent studies have shown
      that the Na+/H+ exchanger is regulated in response to thyroid hormone. Reduction
      in circulating thyroid hormone levels reduces the amount of both protein and mRNA
      of NHE1. Conversely, an elevation of thyroid hormone levels has the opposite
      effects. Transcriptional regulation of NHE1 expression has been demonstrated. The
      NHE1 promoter contains a TR alpha(1) binding site located between -841 to -800
      bp. This element responds positively to TR alpha(1). This regulation of the NHE1
      promoter by thyroid hormone is proposed to be responsible for postnatal changes
      in expression of the Na+/H+ exchanger.

PMID- 15196886
TI  - Plasma retinol-binding protein: structure and interactions with retinol,
      retinoids, and transthyretin.
AB  - Retinol-binding protein (RBP) is the retinol-specific transport protein present
      in plasma. The available crystal structures of different forms of RBP have
      provided details of the interactions of this binding protein with retinol,
      retinoids, and transthyretin (TTR, one of the plasma carriers of thyroid
      hormones). The core of RBP is a beta-barrel, the cavity of which accommodates
      retinol, establishing with its buried portions apolar contacts. Instead, the
      retinol hydroxyl is near the protein surface, in the region of the entrance loops
      surrounding the opening of the binding cavity, and participates in polar
      interactions. The stability of the retinol-RBP complex appears to be further
      enhanced when holo-RBP is bound to TTR. Accordingly, the region of the entrance
      loops represents the contact area of RBP interacting with the TTR counterpart,
      such that the hydroxyl of the RBP-bound vitamin becomes fully buried in the holo
      RBP-TTR complex. Limited protein conformational changes affecting the entrance
      loops, which lead to a decrease or loss of the binding affinity of RBP for TTR,
      have been demonstrated for apo-RBP and RBP in complex with retinoids modified in
      the area of the retinol hydroxyl. A relatively small number of amino acid
      residues of RBP, essentially confined to the region of the entrance loops, and of
      TTR appear to play a critical role in the formation of the RBP-TTR complex, as
      established by crystallographic studies, mutational analysis, and amino acid
      sequence analysis of phylogenetically distant RBPs and TTRs. Overall, the
      available evidence indicates the existence of a high degree of complementarity
      between RBP and TTR, the contact areas of which are highly sensitive to
      conformational changes and amino acid replacements.

PMID- 15196887
TI  - Role of magnesium, coenzyme Q10, riboflavin, and vitamin B12 in migraine
      prophylaxis.
AB  - Migraine is a neurovascular syndrome characterized by recurrent headache
      associated with other symptoms, eventually preceded by aura. This chapter reviews
      the involvement of some mineral, coenzyme, and vitamin defects in the
      pathogenesis of migraine headaches and focuses on their potential therapeutic use
      in the preventive treatment for migraine. The therapeutic potential of magnesium,
      coenzyme Q(10), riboflavin, and vitamin B(12) can be cautiously inferred from
      some published open clinical trials; it should, however, be considered that
      double-blind randomized larger studies are needed to correctly estimate the
      impact of the placebo effect in these promising therapies.

PMID- 15196889
TI  - Nuclear receptor-mediated transactivation through interaction with Sp proteins.

PMID- 15196890
TI  - Site-specific DNA damage recognition by enzyme-induced base flipping.

PMID- 15196891
TI  - Bacteriophage T2Dam and T4Dam DNA-[N6-adenine]-methyltransferases.

PMID- 15196893
TI  - Did an early version of the eukaryal replisome enable the emergence of chromatin?

PMID- 15196892
TI  - Site-specific recombination and partitioning systems in the stable high copy
      propagation of the 2-micron yeast plasmid.

PMID- 15196894
TI  - Initiation and elongation factors in mammalian mitochondrial protein
      biosynthesis.

PMID- 15196895
TI  - Cyclin dependent kinase 11 in RNA transcription and splicing.

PMID- 15196896
TI  - The eukaryotic Ccr4-not complex: a regulatory platform integrating mRNA
      metabolism with cellular signaling pathways?

PMID- 15196897
TI  - Signaling repression of transcription by RNA polymerase III in yeast.

PMID- 15196898
TI  - Q fever (coxiellosis): epidemiology and pathogenesis.
AB  - Q fever is a widespread zoonosis caused by the Gram-negative bacterium Coxiella
      burnetii. Aborting domestic ruminants are the main sources of human infection but
      the reservoir of infection is extremely wide. In humans, Q fever may occur as
      acute pneumonia, hepatitis or flu-like illness or may take a severe chronic form,
      characterized by endocarditis, chronic hepatitis and chronic fatigue syndrome. In
      animals, the main clinical manifestation is late abortion. Infection with C.
      burnetii can be diagnosed using cultural, serological and genetic methods but
      because the organism is potentially dangerous and requires specialized skills
      only specialist laboratories are capable of undertaking diagnostic tests. This
      paper provides a brief overview of the epidemiology and pathogenesis of Q fever
      (coxiellosis).

PMID- 15196899
TI  - Enzyme activities in some types of peripheral leukocytes of thoroughbred race
      horses before and after the races.
AB  - Glucose, free fatty acid (FFA), triglyceride (TG) and immunoreactive insulin
      (IRI) concentrations in plasma and activities of enzymes related to energy
      metabolism in some types of peripheral leukocytes were measured in thoroughbred
      race horses before and after racing. Glucose, FFA, TG and IRI concentrations and
      enzyme activities did not change significantly in plasma. However, the activities
      of cytosolic hexokinase, malate dehydrogenase (MDH), mitochondrial MDH and
      aspartate aminotransferase decreased significantly in leukocytes of the horses
      after the races. The cytosolic ratio of MDH/LDH activity (ML ratio) in leukocytes
      decreased significantly after racing, and the ratio may be a useful indicator to
      evaluate energy metabolism in race horses.

PMID- 15196900
TI  - Detection of circulating autoantibodies using living keratinocyte staining on MCA
      B1 method in dogs with pemphigus foliaceus.
AB  - In this study, we compared the sensitivity and specificity of three
      immunofluorescence techniques used to detect circulating autoantibodies in dogs
      with pemphigus foliaceus (PF); living keratinocyte staining on a canine
      keratinocyte cell line, MCA-B1, indirect immunofluorescence (IIF) on canine lip
      and IIF on bovine esophagus. Sera from canine PF cases were positive in four out
      of 27 dogs (14.8%) using living keratinocyte staining on MCA-B1 cells method, and
      five (18.5%) and eight sera (29.6%) using IIF on canine lip and bovine esophagus
      methods, respectively. By contrast, none of the 31 sera from dogs with non
      pemphigus dermatoses reacted with MCA-B1 cells, whereas two (6.5%) as well as
      five sera (16.1%) obtained from those dogs showed positive reactivity with IIF on
      canine lip and bovine esophagus, respectively. Our results suggest that, although
      it exhibits the least sensitivity, the positive reactivity obtained by living
      keratinocyte staining on MCA-B1 cells can support the diagnosis of canine PF.

PMID- 15196901
TI  - Accumulation of CD25+ CD4+ T-cells in the draining lymph node during the
      elicitation phase of DNCB-induced contact hypersensitivity in lambs.
AB  - The elicitation phase of DNCB induced contact hypersensitivity in lambs was
      studied, and the presence of CD25+ cells in the lymph nodes draining the contact
      site was measured. Confocal laser scanning microscopy was used to capture images
      of two sets of triple immunofluorescence labellings. One set labelled CD25+, CD4+
      and CD3+ cells, while the other labelled CD25+, VPM30+ and CD4+ cells. The CD25+
      subpopulation labellings were assessed by area measurements in a morphometric
      protocol. The CD25+CD4+CD3+ cells were found to be increased in the DNCB treated
      group. This subpopulation of CD25+ cells comprised 75% of all CD25+ cells
      measured. The CD25+VPM30+CD4+ cells were also found to be increased in the DNCB
      group, but comprised only 17% of the total CD25+ cells measured. Since the VPM30
      antibody detects an antigen found on activated T-cells, it was concluded that a
      substantial proportion of the triple CD25+CD4+CD3+ cells could represent a
      regulatory phenotype that may be active in suppressing the formation of effector
      immune cells in CHS of sheep.

PMID- 15196902
TI  - Mechanisms of the hypoglycaemic and immunopotentiating effects of Nigella sativa
      L. oil in streptozotocin-induced diabetic hamsters.
AB  - The aim of this study was to elucidate the mechanisms underlying the
      hypoglycaemic effect of N. sativa oil (Nigella sativa oil) in streptozotocin
      (STZ)-induced diabetic hamsters, in terms of hepatic glucose production, and to
      investigate the possible immunopotentiating effect of N. sativa oil on peritoneal
      macrophages. Diabetes was induced by intraperitoneal injection of 65 mg/kg body
      weight of STZ. Treatment with N. sativa oil commenced 6 weeks after induction of
      diabetes at a dose of 400 mg/kg body weight by gastric gavage. Isolated
      hepatocytes were collected using collagenase to determine liver glucose
      production. Phagocytic activity was evaluated by injection of fluorescent latex
      (2 microm diameter) intraperitoneally, followed 24 h later by collection of
      peritoneal macrophages. N. sativa oil reduced blood glucose from 391+/-3.0 mg/dl
      before treatment to 325+/-4.7, 246+/-5.9, 208+/-2.5 and 179+/-3.1 mg/dl after the
      first, second, third and fourth weeks of treatment, respectively. Hepatic glucose
      production from gluconeogenic precursors (alanine, glycerol and lactate) was
      significantly lower in treated hamsters. Treatment with N. sativa oil
      significantly increased the phagocytic activity and phagocytic index of
      peritoneal macrophages and lymphocyte count in peripheral blood compared with
      untreated diabetic hamsters. Our data indicate that the hypoglycaemic effect of
      N. sativa oil is due to, at least in part, a decrease in hepatic gluconeogenesis,
      and that the immunopotentiating effect of N. sativa oil is mediated through
      stimulation of macrophage phagocytic activity either directly or via activation
      of lymphocytes.

PMID- 15196903
TI  - Characterisation of three novel canine osteosarcoma cell lines producing high
      levels of matrix metalloproteinases.
AB  - Three canine osteosarcoma cell lines were established from spontaneous pelvic and
      radial osteosarcomas. The cell populations cultured exhibited characteristics of
      malignancy and consisted of adherent, pleomorphic, mostly large spindle-shaped or
      polyhedral cells, characterised by the presence of numerous cytoplasmic granules
      and vacuoles. The main ultrastructural features included the presence of abundant
      rough endoplasmic reticulum and numerous cytoplasmic vesicles, deposit vacuoles
      and small cytoplasmic protrusions. Zymography showed that the cell lines produce
      high levels of MMP-2 and MMP-9, enzymes directly involved in crucial aspects of
      the metastatic process. Consistent with their osteoblastic lineage and malignant
      phenotype, all cell lines were immunoreactive to vimentin, osteopontin, PCNA,
      p53, MMP-2 and MMP-9, while they were negative for cytokeratin, desmin, SMA,
      Factor VIII, NSE, GFAP, Rb and p21 protein. No retroviral particles or RNA were
      detected ultrastructurally or with RT-PCR, although the possibility of viral
      involvement in osteosarcoma cannot be excluded. The new cell lines provide
      excellent in vitro models that may allow further studies on the pathobiology of
      canine osteosarcoma to be undertaken.

PMID- 15196904
TI  - Detection of enrofloxacin and its metabolite ciprofloxacin in equine hair.
AB  - Hair analysis to detect drug administration has not been studied extensively in
      horses. This study aimed to (a) develop an analytical method for enrofloxacin and
      its metabolite ciprofloxacin in mane and tail hair, (b) relate measured values to
      doses, routes of administration, hair colour, and (c) demonstrate long-term
      detectability. Samples were extracted in trifluoroacetic acid at 70 degrees C.
      Extracts were cleaned-up by solid-phase extraction and analysed by high
      performance liquid chromatography with UV-diode array detection. Analyte
      recoveries were > 87%. Horses were sampled after therapeutic enrofloxacin
      administration either orally at 7.5 mg/kg daily for 3-13 days or twice daily for
      10-14 days (Group 1, n=7) or intravenously at 5.0 mg/kg daily for 12 and 15 days
      (Group 2, n=2). Enrofloxacin and ciprofloxacin were detected at concentrations up
      to 452 and 19 ng/mg, respectively, up to 10 months post-treatment. In vitro,
      enrofloxacin and ciprofloxacin were extensively bound to melanin (> 96%) and in
      vivo, their uptake was 40-fold greater in black than white hair. Enrofloxacin and
      ciprofloxacin concentrations correlated to enrofloxacin dose (r2=0.777 and
      r2=0.769). Enrofloxacin:ciprofloxacin ratios were 21:1 and 13:1 following
      intravenous and oral administration, respectively. Longitudinal analyte
      distributions correlated to treatment-sampling interval.

PMID- 15196905
TI  - Sequence variability in the structural protein-encoding region of foot-and-mouth
      disease virus serotype Asia1 field isolates.
AB  - A total of 30 field isolates of foot-and-mouth disease virus (FMDV) serotype
      Asia1 belonging to two different lineages and five isolates belonging to a
      divergent group as delineated earlier in 1D (encodingVP1 protein) gene-based
      phylogeny were sequenced in the structural protein (P1) coding region.
      Phylogenetic comparison of these isolates along with some of the published exotic
      sequences revealed the presence of five different lineages around the world.
      Similar grouping pattern was observed for the P1 region and 1D gene-based
      phylogeny, where the Indian isolates were clustered in two genetic lineages. The
      recently identified divergent group of virus falls into a separate sub-cluster.
      Similar grouping was also observed in L gene-based phylogeny. Comparison of amino
      acid sequences identified lineage-specific signature residues in all the
      structural proteins. Comparison of Asia1 field isolates at the identified key
      residues of other FMD viruses involved in the formation of the heparan sulfate
      binding ligand confirmed many of them to be conserved and the presence of VP3(56)
      Arg suggested their cell culture adaptation. Although a considerable genetic
      variation was observed among the isolates of present study, all of them tested in
      micro-neutralization test were serologically related to the vaccine strain.

PMID- 15196906
TI  - Development of an optimized protocol for the detection of classical swine fever
      virus in formalin-fixed, paraffin-embedded tissues by seminested reverse
      transcription-polymerase chain reaction and comparison with in situ
      hybridization.
AB  - An optimized protocol was developed for the detection of classical swine fever
      virus (CSFV) in formalin-fixed, paraffin-embedded tissues obtained from
      experimentally and naturally infected pigs by seminested reverse transcription
      polymerase chain reaction (RT-PCR). The results for seminested RT-PCR were
      compared with those determined by in situ hybridization. The results obtained
      show that the use of deparaffinization with xylene, digestion with proteinase K,
      extraction with Trizol LS, followed by seminested RT-PCR is a reliable detection
      method. An increase in sensitivity was observed as amplicon size decreased. The
      highest sensitivity for RT-PCR on formalin-fixed, paraffin-embedded tissues RNA
      was obtained with amplicon sizes less than approximately 200 base pairs. An
      hybridization signal for CSFV was detected in lymph nodes from 12 experimentally
      and 12 naturally infected pigs. The sensitivity of seminested RT-PCR compared
      with in situ hybridization was 100% for CSFV. When only formalin-fixed tissues
      are available, seminested RT-PCR and in situ hybridization would be useful
      diagnostic methods for the detection of CSFV nucleic acid.

PMID- 15196908
TI  - The presence of co-infections in pigs with clinical signs of PMWS in The
      Netherlands: a case-control study.
AB  - In this study, 60 pigs with clinical signs of post-weaning multisystemic wasting
      syndrome (PMWS) from 20 different pig herds and 180 control pigs (without
      clinical signs of PMWS) were examined to get more insights into the frequencies
      of porcine circovirus 2 infections and the presence of co-infections in pigs with
      and without clinical signs of PMWS in the Netherlands. Porcine circovirus type 2
      was detected in 100% of the pigs with clinical signs of PMWS by virus isolation
      and/or PCR and in 50% of the pigs from PMWS-free herds. There was an association
      between the levels of infectious PCV2 and/or PCV2 DNA load and the severity of
      clinical signs as described for PMWS. A high variation in PCV2 antibody titres
      was found in the clinically affected pigs, and 27% of these pigs did not mount
      PCV2 antibody titres higher than 1:200. A concurrent infection of PCV2 and
      porcine reproductive and respiratory syndrome virus (PRRSV) was found in at least
      83% of the pigs with clinical signs of PMWS and in 35% of the pigs from PMWS-free
      herds. Co-infections of European- and American-type PRRSV were detected only in
      PMWS herds and in one control herd with a history of PMWS clinical signs.

PMID- 15196909
TI  - Jeff's View. Postdocs.

PMID- 15196907
TI  - Detection and genetic characterization of porcine circovirus type 2 (PCV2) in
      pigs from Croatia.
AB  - Porcine circovirus type 2 (PCV2) from the Circoviridae family has recently been
      associated with two serious diseases of swine, post-weaning multisystemic wasting
      syndrome (PMWS) and porcine dermatitis and nephropathy syndrome (PDNS). During
      2002, several outbreaks of clinical disease in pigs with weights ranging from 10
      to 70 kg occurred on four farms in different locations in Croatia. The signs were
      consistent with PMWS and PDNS. Apart from progressive weight loss, pneumonia
      and/or diarrhoea, multifocal erythematous skin lesions and dermal necrosis were
      also observed. The PCR results obtained from PCV2 specific oligonucleotide
      primers confirmed a PCV2 infection. In addition, archive samples that were
      classical swine fever virus positive and derived from domestic pigs during an
      outbreak in 1997 were included in this study and one out of the three isolates
      was found to be positive for PCV2. For a better epizootiological understanding,
      genetic typing of representative isolates was carried out and compared with
      available isolates reported in the GenBank databases.

PMID- 15196910
TI  - Links between fatty acids and expression of UCP2 and UCP3 mRNAs.
AB  - Physiological and pathological states that are associated with elevated plasma
      fatty acids (FAs) increase uncoupling protein 2 (UCP2) mRNA in white adipose
      tissue and UCP3 mRNA in skeletal muscle and heart. A direct effect of unsaturated
      fatty acids from all classes has been shown in various cultured cells. There is
      evidence that FAs could induce expression of UCPs by acting as ligands for
      peroxisome proliferator-activated receptors, influencing the function of sterol
      responsive element binding protein or activating 5'-AMP-activated protein kinase.
      Oleic acid has been shown to stimulate the activity of the promoter regions of
      UCP2 and UCP3 genes and the FA responsive regions are beginning to be
      characterised.

PMID- 15196911
TI  - RNA aptamer to thrombin binds anion-binding exosite-2 and alters protease
      inhibition by heparin-binding serpins.
AB  - We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by
      antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI).
      Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was
      slightly enhanced for PCI. In the presence of glycosaminoglycans, AT and PCI had
      significantly reduced thrombin inhibition with Toggle-25, but it was only reduced
      3-fold for HCII. This suggested that the primary effect of aptamer binding was
      through the heparin-binding site of thrombin, anion-binding exosite-2 (exosite
      2). We localized the Toggle-25 binding site to Arg 98, Glu 169, Lys 174, Asp 175,
      Arg 245, and Lys 248 of exosite-2. We conclude that a RNA aptamer to thrombin
      exosite-2 might provide an effective clinical reagent to control heparin's
      anticoagulant action.

PMID- 15196912
TI  - Simulating the effect of alcohol on the structure of a membrane.
AB  - Adsorption of alcohol molecules or other small amphiphilic molecules in the cell
      membrane can induce significant changes in the structure of the membrane. To
      understand the molecular mechanisms underlying these structural changes, we
      developed a mesoscopic membrane model. Molecular simulations on this model nicely
      reproduce the experimental phase diagrams. We find that alcohol can induce an
      interdigitated structure in which the normal bilayer structure changes into a
      monolayer in which the alcohol molecules screen the hydrophobic tails from the
      water phase. We compute the effect of the chain length of the alcohol on the
      phase behaviour of the membrane. At low concentrations of alcohol, the membrane
      has domains of the interdigitated phase that are in coexistence with the normal
      membrane phase. We use our model to clarify some of the experimental questions
      related to the structure of the interdigitated phase and put forward a simple
      model that explains the alcohol chain length dependence of the stability of this
      interdigitated phase.

PMID- 15196913
TI  - Binding site for the C-domain of insulin-like growth factor (IGF) binding protein
      6 on IGF-II; implications for inhibition of IGF actions.
AB  - Insulin-like growth factors (IGFs) are important mediators of growth and IGF
      binding proteins (IGFBPs) 1-6 regulate IGF actions. As IGFBP C-terminal domains
      contribute to high-affinity IGF binding, we have defined the binding site for the
      C-domain of IGFBP-6 on IGF-II using NMR. This site lies adjacent to and between
      the binding sites for the IGFBP N-domain and IGF-I receptor (IGFIR), which have
      previously been found on opposite sides of the IGF molecule. The C-domain is
      therefore likely to interfere with IGF binding to the IGFIR, providing a
      structural basis for the potent inhibitory effects of intact IGFBPs on IGF
      actions.

PMID- 15196914
TI  - Crystal structure of Rab9 complexed to GDP reveals a dimer with an active
      conformation of switch II.
AB  - The small GTPase Rab9 is an essential regulator of vesicular transport from the
      late endosome to the trans-Golgi network, as monitored by the redirection of the
      mannose-6-phosphate receptors. The crystal structure of Rab9 complexed to GDP,
      Mg(2+), and Sr(2+) reveals a unique dimer formed by an intermolecular beta-sheet
      that buries the switch I regions. Surface area and shape complementarity
      calculations suggest that Rab9 dimers can form an inactive, membrane-bound pool
      of Rab9 . GDP that is independent of GDI. Mg(2+)-bound Rab9 represents an
      inactive state, but Sr(2+)-bound Rab9 . GDP displays activated switch region
      conformations, mimicking those of the GTP state. A hydrophobic tetrad is formed
      resembling an effector-discriminating epitope found only in GTP-bound Rab
      proteins.

PMID- 15196915
TI  - Aminoacylase 1 is a sphingosine kinase 1-interacting protein.
AB  - Sphingosine kinase type 1 (SphK1) and its product sphingosine-1-phosphate have
      been shown to promote cell growth and inhibit apoptosis of tumor cells. In an
      effort to further understand the regulation of SphK1, we used a yeast two-hybrid
      screen to find SphK1-interacting proteins. One of these was identified as
      aminoacylase 1 (Acy1), a metalloenzyme that removes amide-linked acyl groups from
      amino acids and may play a role in regulating responses to oxidative stress. Both
      the C-terminal fragment found in the two-hybrid screen and full-length Acy1 co
      immunoprecipitate with SphK1. Though both C-terminal and full-length proteins
      slightly reduce SphK1 activity measured in vitro, the C-terminal fragment
      inhibits while full-length Acy1 potentiates the effects of SphK1 on proliferation
      and apoptosis. Interestingly, Acy1 induces redistribution of SphK1 as observed by
      immunocytochemistry and subcellular fractionation. Collectively, our data suggest
      that Acy1 physically interacts with SphK1 and may influence its physiological
      functions.

PMID- 15196916
TI  - Some amphiphilic cations block the mitochondrial apoptosis-induced channel, MAC.
AB  - The mitochondrial apoptosis-induced channel (MAC) forms in the outer membrane of
      mitochondria early in apoptosis and this activity is altered by physiological
      levels of cytochrome c. While cyclosporine A and lidocaine have no effect,
      dibucaine induces a fast blockade of MAC with an IC(50) of 39 microM. In
      contrast, the IC(50) for propranolol and trifluoperazine are 52 and 0.9 microM,
      respectively, and these drugs likely destabilize the open state of MAC. These
      agents, and others not yet identified, should be valuable tools in the study of
      apoptosis. Profiling MAC's pharmacology may generate novel therapeutic regimes
      for disease.

PMID- 15196917
TI  - Insertional-fusion of basic fibroblast growth factor endowed ribonuclease 1 with
      enhanced cytotoxicity by steric blockade of inhibitor interaction.
AB  - Basic fibroblast growth factor (bFGF) was inserted in the middle of human
      ribonuclease 1 (RNase1) sequence at an RNase inhibitor (RI)-binding site (Gly89)
      by a new gene fusion technique, insertional-fusion. The resultant insertional
      fusion protein (CL-RFN89) was active both as bFGF and as RNase. Furthermore, it
      acquired an additional ability of evading RI through steric blockade of RI
      binding caused by fused bFGF domain. As a result, CL-RFN89 showed stronger growth
      inhibition on B16/BL6 melanoma cells than an RI-sensitive tandem fusion protein.
      Thus, the insertional-fusion technique increases accessible positions for gene
      fusion on RNase, resulting in construction of a potent cytotoxic RNase.

PMID- 15196918
TI  - Heme environment in aldoxime dehydratase involved in carbon-nitrogen triple bond
      synthesis.
AB  - Resonance Raman spectra have been measured to characterize the heme environment
      in aldoxime dehydratase (OxdA), a novel hemoprotein, which catalyzes the
      dehydration of aldoxime into nitrile. The spectra showed that the ferric heme in
      the enzyme is six-coordinate low spin, whereas the ferrous heme is five
      coordinate high spin. We assign a prominent vibration that occurs at 226 cm(-1)
      in the ferrous enzyme to the Fe-proximal histidine stretching vibration. In the
      CO-bound form of OxdA, the correlation between the Fe-CO stretching (512 cm(-1))
      and C-O stretching (1950 cm(-1)) frequencies also supports our assignment of
      proximal histidine coordination.

PMID- 15196919
TI  - Study of cytokine induced neuropathology by high resolution proton NMR
      spectroscopy of rat urine.
AB  - Multiple sclerosis is a major cause of non-traumatic neurological disability. The
      identification of markers that differentiate disease progression is critical to
      effective therapy. A combination of NMR spectroscopic metabolic profiling of
      urine and statistical pattern recognition was used to detect focal inflammatory
      central nervous system (CNS) lesions induced by microinjection of a replication
      deficient recombinant adenovirus expressing TNF-alpha or IL1-beta cDNA into the
      brains of Wistar rats. These animals were compared with a group of naive rats and
      a group of animals injected with an equivalent null adenovirus. Urine samples
      were collected 7 days after adenovirus injection, when the inflammatory lesion is
      maximally active. Principal components analysis and Partial Least Squares
      Discriminate analysis of the urine (1)H NMR spectra revealed significant
      differences between each of the cytokine adenovirus groups and the control
      groups; for the TNF-alpha group the main differences lay in citrate and
      succinate, while for the IL-1beta group the predominant changes occurred in
      leucine, isoleucine, valine and myo-inositol. Thus, we can identify urinary
      metabolic vectors that not only separate rats with inflammatory lesions in the
      brain from control animals, but also distinguish between different types of CNS
      inflammatory lesions.

PMID- 15196920
TI  - Protein kinase A phosphorylates serine 267 in the homeodomain of engrailed-2
      leading to decreased DNA binding.
AB  - Engrailed-2 (En-2) belongs to an evolutionarily conserved family of DNA binding
      homeodomain-containing proteins that are expressed in mammalian brain during
      development. Here, we demonstrate that serine 267 in the homeodomain of En-2 is
      phosphorylated by protein kinase A (PKA) in forskolin-treated COS-7 cells.
      Furthermore, we analyze the physiological function of En-2 phosphorylation by
      PKA. The nuclear localization of En-2 is not influenced by the phosphorylation of
      serine 267. However, substitution of serine 267 with alanine resulted in
      increased binding of En-2 to DNA, while replacing serine 267 with glutamic acid
      resulted in decreased En-2 DNA binding. These results suggest that the
      transcriptional activity of En-2 is regulated by PKA.

PMID- 15196921
TI  - A mechanism of impaired mobility of oligodendrocyte progenitor cells by tenascin
      C through modification of wnt signaling.
AB  - In demyelinating diseases, the mechanisms of how oligodendrocyte (OLG) progenitor
      cells are affected in the demyelinated area remain to be elucidated. To
      investigate one aspect of the mechanisms, we focused on the role of tenascin C in
      regulating the migratory mobility of the progenitor cells via beta-catenin. By
      cDNA subtraction screening, we found tenascin C expression to be increased in OLG
      progenitors (rat primary O2A cells). Tenascin C inhibited the migration of OLG
      progenitors and CG-4 cells, and beta-catenin accumulated at focal adhesions in
      these cells. These changes were associated with the inactivation of canonical wnt
      signaling. Overexpression of the wnt-signaling antagonist Dapper prevented the
      migration of CG-4 cells. This suggests that inactivation of the wnt signal is
      responsible for impaired migration of OLG caused by tenascin C. Our results
      suggest that tenascin C is involved in the impaired mobility of OLG progenitor
      cells through increased amounts of adhesion complex as well as the prevention of
      wnt signaling.

PMID- 15196922
TI  - Identification of the heat shock protein 60 epitope involved in receptor binding
      on macrophages.
AB  - In the present study, we identified the human heat shock protein 60 (HSP60)
      epitope responsible for binding to macrophages. Studies using overlapping 15- and
      20-mer peptides of the human HSP60 sequence to compete with binding of HSP60 to
      macrophages indicated that surface binding was accounted for by the region aa481
      500. Deletion mutants of HSP60, lacking the N-terminal 137, 243 or 359 amino
      acids, strongly inhibited HSP60 binding to macrophages. Monoclonal antibodies
      addressing regions aa1-200, aa335-366 or aa383-447 did not block HSP60 binding.
      We conclude that a single C-terminal region, aa481-500, accounts for the binding
      of HSP60 to macrophages.

PMID- 15196923
TI  - Proteolytic cleavage of platelet endothelial cell adhesion molecule-1 (PECAM
      1/CD31) is regulated by a calmodulin-binding motif.
AB  - Homophilic engagement of platelet endothelial cell adhesion molecule-1 (PECAM
      1/CD31) induces 'outside-in' signal transduction that results in phosphorylation
      events and recruitment and activation of signalling molecules. The formation of
      signalling scaffolds with PECAM-1 are important signalling events that modulate
      platelet secretion, aggregation and platelet thrombus formation. In this study,
      we describe a novel interaction between PECAM-1 and cytosolic calmodulin (CaM) in
      platelets. Reciprocal co-immunoprecipitation studies revealed that cytosolic CaM
      is constitutively associated with PECAM-1 in resting, thrombin activated and
      aggregated human platelets. Our studies demonstrate that CaM directly interacts
      with a PECAM-1 peptide (594-604) C595A containing the sequences
      (594)KAFYLRKAKAK(604). This CaM:PECAM-1 interaction has a threefold higher
      affinity than CaM:GPVI interaction. It is potentiated by the addition of calcium
      ions, and dissociated by the CaM inhibitor, trifluoperazine. Treatment of
      platelets with CaM inhibitors triggers cleavage of PECAM-1 in a time- and dose
      dependent manner. Furthermore, this membrane proximal portion of PECAM-1 is
      conserved across mammalian species and the helical representation of
      basic/hydrophobic residues reveals a charge distribution analogous to other CaM
      binding motifs in other proteins. Taken together, these results suggest that this
      highly charged cluster of amino acids in the PECAM-1 cytoplasmic domain directly
      interacts with CaM and this novel interaction appears to regulate cleavage of
      PECAM-1.

PMID- 15196924
TI  - Ipaf is upregulated by tumor necrosis factor-alpha in human leukemia cells.
AB  - Ipaf has been associated with apoptosis, cytokine processing, and nuclear factor
      kappaB activation. Here, we describe that Ipaf is highly expressed in
      myelomonocytic cells and that the mRNA levels of Ipaf progressively increase
      during differentiation of CD34(+) progenitors to granulocytes and monocytes.
      Additionally, treatment with tumor necrosis factor-alpha and exposure to UV
      radiation induced the transcriptional activation of Ipaf in human leukemia HL-60
      cells. Thus, Ipaf may contribute to modulate the response of myeloid cells to
      genotoxic and pro-inflammatory stimuli.

PMID- 15196925
TI  - Biochemical and cell biological characterization of a mammalian septin, Sept11.
AB  - Septins are a family of conserved cytoskeletal GTPases implicated in a variety of
      cellular functions such as cytokinesis and vesicle trafficking. Here, we report
      identification of an yet uncharacterized septin, Sept11, in septin complexes
      purified from porcine brain. The transcripts were detected in all tested tissues
      except leukocytes. A Sept11 mutant with apparently reduced GTPase activity did
      not form filaments in the transient expression system using COS7 cells. By
      Western blot analysis using a specific antibody, Sept11 was detected in various
      cell lines as well as brain tissues. Septin complexes immunoisolated from porcine
      brain with anti-Sept9 and anti-Sept11 antibodies were found to contain different
      Sept9 isoforms based on SDS-PAGE analyses followed by silver-staining and Western
      blotting. Immunofluorescent study revealed cell type-dependent intracellular
      localization of the protein; Sept11 was colocalized dominantly with microtubules
      and actin stress fibers in HMEC cells and REF52 cells, respectively, and their
      filamentous distribution was dependent on the cytoskeleton structures with which
      the protein is colocalized. Sept11 partially colocalized with stress fibers and
      microtubules in HeLa cells.

PMID- 15196926
TI  - The G-protein-coupled CCK2 receptor associates with phospholipase Cgamma1.
AB  - In ElasCCK2 transgenic mice expressing cholecystokinin (CCK2) receptor in acinar
      cells, pancreatic phenotypic alterations and preneoplastic lesions are observed.
      We determined whether activation of phospholipase C gamma1 (PLCgamma1), known to
      contribute to the tumorigenesis pathophysiology, could take place as a new
      signaling pathway induced by the CCK2 receptor. Overexpression and activation of
      the PLCgamma1 in response to gastrin was observed in acinar cells. The
      possibility that the C-terminal tyrosine 438 of the CCK2 receptor associates with
      the SH2 domains of PLCgamma1 was examined. A specific interaction was
      demonstrated using surface plasmon resonance, confirmed in a cellular system and
      by molecular modeling.

PMID- 15196927
TI  - Binding of phage-display-selected peptides to the periplasmic chaperone protein
      SurA mimics binding of unfolded outer membrane proteins.
AB  - SurA is a periplasmic chaperone protein that facilitates maturation of integral
      outer membrane proteins (OMPs). Short peptides that bind SurA have previously
      been characterized. In this work, an enzyme-linked immunoabsorbent assay-based
      competition assay is utilized to demonstrate that binding of such peptides,
      presented by peptide-tagged phage, mimics binding of biological substrates. Two
      representative unfolded OMPs, OmpF and OmpG, bind SurA and a core structural
      fragment thereof in competition with peptide-tagged phage, and with the same
      order-of-magnitude affinity as the peptides. Additionally, unfolded OmpF and OmpG
      bind SurA more tightly than an unfolded water-soluble protein, while folded
      proteins have no measurable affinity, demonstrating a specificity of SurA for OMP
      polypeptides.

PMID- 15196928
TI  - Twelve receptor molecules attach per viral particle of human rhinovirus serotype
      2 via multiple modules.
AB  - The crystallographic T = 1 (pseudo T = 3) icosahedral symmetry of the human
      rhinovirus capsid dictates the presence of 60 identical, symmetry related surface
      structures that are available for antibody and receptor binding. X-ray
      crystallography has shown that 60 individual very-low density lipoprotein
      receptor (VLDLR) modules bind to HRV2. Their arrangement around the fivefold axes
      of the virion suggested that tandem oligomers of such modules could attach
      simultaneously to symmetry-related sites. By resolving virus particles carrying
      various numbers of artificial recombinant concatemers of VLDLR repeat 3 (V33333)
      by capillary electrophoresis and extrapolation of the measured mobilities to that
      at saturation of all binding sites, we present evidence for up to 12 molecules of
      the concatemer to bind one single virion.

PMID- 15196929
TI  - Stabilization of flagellar filaments by HAP2 capping.
AB  - In vivo growth of bacterial flagellar filaments by self-assembly of flagellin is
      promoted by a capping structure composed of a pentameric assembly of hook
      associated protein 2 (HAP2). Isolated native filaments with intact HAP2 cap
      exhibited higher melting temperature (deltaTm = 4 degrees C) and significantly
      increased resistance against heat-induced depolymerization than non-capped ones.
      Reconstituted filaments were also stabilized by HAP2 binding, but the obtained
      filament-HAP2 complexes were less stable than native assemblies. Their fast
      depolymerization at elevated temperatures and sensitivity to proteolysis
      indicated that native-like filament-HAP2 complexes are rarely obtained by in
      vitro reconstitution. A procedure was developed to isolate perfectly capped
      native filaments to facilitate high-resolution structural analysis.

PMID- 15196931
TI  - Amino acid type selective isotope labelling of the multidrug ABC transporter LmrA
      for solid-state NMR studies.
AB  - The ABC transporter LmrA in Lactococcus lactis confers resistance to a wide range
      of antibiotics and cytotoxic drugs and is a functional homologue of P
      glycoprotein. Recently, solid-state NMR methods have shown potential for
      structural- and non-perturbing, site directed functional studies. These
      experiments require isotopic labelling of selected sites. We have developed a
      strategy to produce large quantities of selectively labelled LmrA reconstituted
      at a high density in lipid membranes. This makes the 64 kDa integral membrane
      protein LmrA and therefore the ABC transporter superfamily accessible to NMR
      analysis.

PMID- 15196930
TI  - Voltage sensor mutations differentially target misfolded K+ channel subunits to
      proteasomal and non-proteasomal disposal pathways.
AB  - In Shaker K(+) channels, formation of an electrostatic interaction between two
      charged residues, D316 and K374 in transmembrane segments S3 and S4,
      respectively, is a key step in voltage sensor biogenesis. Mutations D316K and
      K374E disrupt formation of the voltage sensor and lead to endoplasmic reticulum
      retention. We have now investigated the fates of these misfolded proteins. Both
      are significantly less stable than the wild-type protein. D316K is degraded by
      cytoplasmic proteasomes, whereas K374E is degraded by a lactacystin-insensitive,
      non-proteasomal pathway. Our results suggest that the D316K and K374E proteins
      are misfolded in recognizably different ways, an observation with implications
      for voltage sensor biogenesis.

PMID- 15196932
TI  - Cell-type-specific interactions at regulatory motifs in the first intron of the
      lamin A gene.
AB  - Lamins A, C and C2 are alternatively spliced products of the LMNA gene; lamins A
      and C are expressed in differentiated somatic cells, whereas lamin C2 is
      expressed in germ cells. We have analyzed a segment of the first intron of the
      LMNA gene for cell-type-specific regulatory elements. We identified a 420-bp
      fragment that increased promoter activity in lamin A-expressing cells but
      repressed activity in undifferentiated cells. DNase I footprinting and
      electrophoretic mobility shift assays revealed two binding motifs, footprinted
      region A (FPRA) and FPRB. The hepatocyte nuclear factor-3beta was bound to FPRA
      only in somatic cell extracts and this motif had an inhibitory effect on promoter
      activity. The retinoic X receptor beta, RXRbeta, bound near FPRB with extracts
      from lamin A- or C2-expressing cells, and this site enhanced promoter activity.
      We have, thus, identified two novel binding sites for transcription factors in a
      region likely to function as an important regulatory element for the cell-type
      specific transcription of A-type lamins.

PMID- 15196933
TI  - Two different dihydroorotate dehydrogenases from yeast Saccharomyces kluyveri.
AB  - Genes for two structurally and functionally different dihydroorotate
      dehydrogenases (DHODHs, EC 1.3.99.11), catalyzing the fourth step of pyrimidine
      biosynthesis, have been previously found in yeast Saccharomyces kluyveri. One is
      closely related to the Schizosaccharomyces pombe mitochondrial family 2 enzymes,
      which use quinones as direct and oxygen as the final electron acceptor. The other
      one resembles the Saccharomyces cerevisiae cytosolic family 1A fumarate-utilizing
      DHODH. The DHODHs from S. kluyveri, Sch. pombe and S. cerevisiae, were expressed
      in Escherichia coli and compared for their biochemical properties and interaction
      with inhibitors. Benzoates as pyrimidine ring analogs were shown to be selective
      inhibitors of cytosolic DHODs. This unique property of Saccharomyces DHODHs could
      appoint DHODH as a species-specific target for novel anti-fungal therapeutics.

PMID- 15196934
TI  - Microautophagy and macropexophagy may occur simultaneously in Hansenula
      polymorpha.
AB  - We subjected methanol-grown cells of wild type Hansenula polymorpha
      simultaneously to nitrogen depletion and excess glucose conditions. Both
      treatments induce the degradation of peroxisomes, either selective (via excess
      glucose) or non-selective (via nitrogen limitation). Our combined data strongly
      suggest that both processes occur simultaneously under these conditions. The
      implications of these findings on studies of autophagy and related transport
      pathways to the vacuole in yeast are discussed.

PMID- 15196935
TI  - Aquaporin-2 trafficking is regulated by PDZ-domain containing protein SPA-1.
AB  - Targeted positioning of water channel aquaporin-2 (AQP2) strictly regulates body
      water homeostasis. Trafficking of AQP2 to the apical membrane is critical to the
      reabsorption of water in renal collecting ducts. Controlled apical positioning of
      AQP2 suggests the existence of proteins that interact with AQP2. A biochemical
      search for AQP2-interacting proteins led to the identification of PDZ-domain
      containing protein, signal-induced proliferation-associated gene-1 (SPA-1) which
      is a GTPase-activating protein (GAP) for Rap1. The distribution of SPA-1
      coincided with that of AQP2 in renal collecting ducts. The site of colocalization
      was concomitantly relocated by hydration status. AQP2 trafficking to the apical
      membrane was inhibited by the SPA-1 mutant lacking Rap1GAP activity and by the
      constitutively active mutant of Rap1. AQP2 trafficking was impaired in SPA-1
      deficient mice. Our results show that SPA-1 directly binds to AQP2 and regulates
      at least in part AQP2 trafficking.

PMID- 15196936
TI  - Dihydrolipoamide dehydrogenase from porcine heart catalyzes NADH-dependent
      scavenging of nitric oxide.
AB  - Dihydrolipoamide dehydrogenase (DLDH; EC 1.8.1.4) from porcine heart is capable
      of using nitric oxide (NO) as an electron acceptor, with NADH as the electron
      donor, forming nitrate in the reaction. NADPH was not effective as an electron
      donor. The reaction had a pH optimum near 6 and was not inhibited by cyanide or
      diphenyleneiodonium ions. The Km for NADH was 10 microM, while that for NO was
      0.5 microM. The rate of NO conversion was comparable to the rate of lipoamide
      conversion (200 micromol min(-1) mg(-1) protein at pH 6). Cytochrome c or
      myoglobin were poor electron acceptors by themselves but, in the presence of
      methylene blue, DLDH had an activity of 5-7 micromol min(-1) mg(-1) protein with
      these substrates, indicating that DLDH can act also as a methemoglobin reductase.
      While the Km of DLDH for NO is relatively low, it is in the physiological range
      of NO levels encountered in the tissue. The enzyme may, therefore, have a
      significant role in modifying NO levels under specific cell conditions.

PMID- 15196937
TI  - Functional chimeras between the catalytic domains of the mycobacterial adenylyl
      cyclase Rv1625c and a Paramecium guanylyl cyclase.
AB  - The class IIIa adenylyl cyclase (AC) Rv1625c from Mycobacterium tuberculosis
      forms homodimers with two catalytic centres, whereas the Paramecium guanylyl and
      mammalian ACs operate as pseudoheterodimers with one catalytic centre. The
      functional and structural relationship of the catalytic domains of these related
      class III cyclases was investigated. Point mutations introduced into Rv1625c to
      engineer a forskolin-binding pocket created a single heterodimeric catalytic
      centre, yet did not result in forskolin activation. Chimerization of these
      Rv1625c point mutants with corresponding mammalian AC domains was impossible.
      However, it was successful using a complemental Paramecium guanylyl cyclase
      domain and resulted in an AC. The data signify a divergence of structural and
      functional evolution in class III Acs.

PMID- 15196938
TI  - The mutual information theory for the certification of rice coding sequences.
AB  - We report here the use of the mutual information theory for the certification of
      annotated rice coding sequences of both GenBank and TIGR databases. Considering
      coding sequences larger than 600 bp, we successfully screened out genes with
      aberrant compositional features. We found that they represent about 10% of both
      datasets after cleaning for gene redundancy. Most of the rejected accessions
      showed a different trend in GC3% vs GC2% plot compared to the set of accessions
      that have been published in international journals. This suggests the existence
      of a bias in the pattern recognition algorithms used by gene prediction programs.

PMID- 15196939
TI  - Detection of UDP-glucose:cyclo-DOPA 5-O-glucosyltransferase activity in four
      o'clocks (Mirabilis jalapa L.).
AB  - Although a pathway for betacyanin biosynthesis has been postulated, most of the
      catalytic steps have not yet been identified or demonstrated with biochemical
      evidence. In the postulated pathway, the glucose moiety of betanin is conjugated
      to the aglycone, betanidin, because the glucosyltransferase (GT) activity that
      produces betanin has been reported and its cDNA isolated. However, another
      pathway for betacyanin biosynthesis is proposed in which betanin is formed by GT
      acting at the 5,6-dihydroxyindoline-2-carboxylic acid (cyclo-DOPA) step, followed
      by condensation of the product with betalamic acid. Here, we show that GT
      activity acts upon cyclo-DOPA in the betacyanin synthetic pathway. A crude
      extract from the petals of four o'clocks (Mirabilis jalapa L.) was mixed with
      cyclo-DOPA and UDP-glucose. After the reaction was stopped with phosphoric acid,
      the product was chemically reacted with betalamic acid. In the final reaction
      mixture, betanin formation was confirmed by HPLC analysis, demonstrating cyclo
      DOPA 5-O-glucosyltransferase activity. This activity was correlated with the
      accumulation of betanin during the development of four o'clock flowers and was
      detected in another five species of Centrospermae. These results indicate that
      the glucose moiety of betanin is introduced at the cyclo-DOPA step, which is
      followed by condensation with betalamic acid, and not at the betanidin aglycone
      step.

PMID- 15196940
TI  - Receptor binding specificities of Herstatin and its intron 8-encoded domain.
AB  - Retention of intron 8 in alternative HER-2 mRNA generates an inhibitory secreted
      ligand, Herstatin, with a novel receptor-binding domain (RBD) encoded by the
      intron. This study examines binding interactions with several receptors and
      investigates sequence variations in intron 8. The RBD, expressed as a peptide,
      binds at nM concentrations to HER-2, the EGFR, DeltaEGFR, HER-4 and to the IGF-1
      receptor, but not to HER-3 nor to the FGF-3 receptor, whereas a rare mutation in
      the RBD (Arg to Ile) eliminates receptor binding. The full-length Herstatin binds
      with 3-4-fold higher affinity than its RBD, but with approximately 10-fold lower
      affinity to the IGF-IR. Sequence conservation in rhesus monkey but not in rat
      suggests that intron 8 recently diverged as a receptor-binding module critical
      for the function of Herstatin.

PMID- 15196941
TI  - Potassium channel openers are uncoupling protonophores: implication in
      cardioprotection.
AB  - Excessive build-up of mitochondrial protonic potential is harmful to cellular
      homeostasis, and modulation of inner membrane permeability a proposed
      countermeasure. Here, we demonstrate that structurally distinct potassium channel
      openers, diazoxide and pinacidil, facilitated transmembrane proton translocation
      generating H(+)-selective current through planar phospholipid membrane. Both
      openers depolarized mitochondria, activated state 4 respiration and reduced
      oxidative phosphorylation, recapitulating the signature of mitochondrial
      uncoupling. This effect was maintained in K(+)-free conditions and shared with
      the prototypic protonophore 2,4-dinitrophenol. Diazoxide, pinacidil and 2,4
      dinitrophenol, but not 2,4-dinitrotoluene lacking protonophoric properties,
      preserved functional recovery of ischemic heart. The identified protonophoric
      property of potassium channel openers, thus, implicates a previously unrecognized
      component in their mechanism of cardioprotection.

PMID- 15196942
TI  - Chemically sulfated Escherichia coli K5 polysaccharide derivatives as
      extracellular HIV-1 Tat protein antagonists.
AB  - The HIV-1 transactivating factor (Tat) acts as an extracellular cytokine on
      target cells, including endothelium. Here, we report about the Tat-antagonist
      capacity of chemically sulfated derivatives of the Escherichia coli K5
      polysaccharide. O-sulfated K5 with high sulfation degree (K5-OS(H)) and N,O
      sulfated K5 with high (K5-N,OS(H)) or low (K5-N,OS(L)) sulfation degree, but not
      unmodified K5, N-sulfated K5, and O-sulfated K5 with low sulfation degree, bind
      to Tat preventing its interaction with cell surface heparan sulfate
      proteoglycans, cell internalization, and consequent HIV-LTR-transactivation.
      Also, K5-OS(H) and K5-N,OS(H) prevent the interaction of Tat to the vascular
      endothelial growth factor receptor-2 on endothelial cell (EC) surface. Finally,
      K5-OS(H) inhibits alphav beta3 integrin/Tat interaction and EC adhesion to
      immobilized Tat. Consequently, K5-OS(H) and K5-N,OS(H) inhibit the angiogenic
      activity of Tat in vivo. In conclusion, K5 derivatives with distinct sulfation
      patterns bind extracellular Tat and modulate its interaction with cell surface
      receptors and affect its biological activities. These findings provide the basis
      for the design of novel extracellular Tat antagonists with possible implications
      in anti-AIDS therapies.

PMID- 15196943
TI  - Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423.
AB  - At present, the conformation-dependent monoclonal antibodies (mAb) provide the
      only information on folding of tau in the core PHF. Monoclonal antibody MN423
      recognizes all and only those Alzheimer's disease (AD) core paired helical
      filaments (PHFs) subunits, which terminate at Glu391. Using recombinant analogs
      of the core PHF subunit corresponding to tau residues tau297-391, we found that
      the C-terminal pentapeptide (387)DHGAE(391) represented only one component of the
      structure recognized by mAb 423. Therefore, deletion mutants of the core subunit
      were generated to identify assembled parts of this conformational structure. We
      localized two spatially close components in the region 306-325 ((306)VQIVYK(311)
      and (321)KCGSL(325)) contributing to formation of the structure identified by mAb
      423. Thus, the spatial proximity of three subunit segments (306)VQIVYK(311),
      (321)KCGSL(325) and (387)DHGAE(391) represents constraints for intramolecular
      folding of the core PHF subunit. Since PHF represents a compelling drug target in
      AD, structural knowledge presented could contribute to structure-based drug
      design.

PMID- 15196944
TI  - Overexpression of GD3 synthase induces apoptosis of vascular endothelial ECV304
      cells through downregulation of Bcl-2.
AB  - The disialoganglioside GD3 plays a major role in proliferation, differentiation,
      and apoptosis. It has been reported that ganglioside GD3 can induce apoptosis
      through bcl-2 mediated mitochondrial pathway. However, the relationship between
      ganglioside GD3 and B-cell/CLL lymphoma 2 (Bcl-2) is not fully understood. In
      this study, we have demonstrated that the downregulation of Bcl-2 by
      overexpression of CMP-NeuAc:GM3 alpha-2,8-sialyltransferase (GD3 synthase)
      results in an accelerated apoptosis in vascular endothelial cells (ECV304), as
      evidenced by DNA fragmentation and caspase-3 activation. In addition,
      phosphorylation of AKT and cyclic-AMP responsive element binding protein (CREB)
      was reduced by GD3 synthase overexpression. Moreover, the activation of CREB as a
      transcriptional factor was also inhibited, as evidenced by electrophoretic
      mobility shift assay. Therefore, we conclude that GD3 synthase has an apoptotic
      effect on ECV304 cells through downregulation of Bcl-2 expression via
      dephosphorylation of AKT and CREB.

PMID- 15196945
TI  - Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia.
AB  - Successful healing of skin wounds requires sensory innervation and the release of
      vasoactive neuropeptides that dilate blood vessels and deliver serum proteins to
      the wound, and that cause pain that protects from further injury. Activin has
      been proposed as a target-derived regulator of sensory neuropeptides during
      development, but its role in the mature nervous system is unknown. While adult
      skin contains a low level of activin, protein levels in skin adjacent to a wound
      increase rapidly after an excision. Neurons containing the neuropeptide
      calcitonin gene-related peptide (CGRP) increased in sensory ganglia that
      projected to the wounded skin, but not in ganglia that projected to unwounded
      skin, suggesting that neurons respond to a local skin signal. Indeed, many adult
      sensory neurons respond with increased CGRP expression to the application of
      activin in vitro and utilize a smad-mediated signal transduction pathway in this
      response. A second skin-derived factor nerve growth factor (NGF) also increased
      in wounded skin and increased CGRP in cultured adult dorsal root ganglia (DRG)
      neurons but with lower efficacy. Together, these data support the hypothesis that
      activin made by skin cells regulates changes in sensory neuropeptides following
      skin injury, thereby promoting vasodilation and wound healing.

PMID- 15196946
TI  - The coordinate regulation of pharyngeal development in C. elegans by lin-35/Rb,
      pha-1, and ubc-18.
AB  - Organ development is a complex process involving the coordination of cell
      proliferation, differentiation, and morphogenetic events. Using a screen to
      identify genes that function coordinately with lin-35/Rb during animal
      development, we have isolated a weak loss-of-function (LOF) mutation in pha-1.
      lin-35; pha-1 double mutants are defective at an early step in pharyngeal
      morphogenesis leading to an abnormal pharyngeal architecture. pha-1 is also
      synthetically lethal with other class B synthetic multivulval (SynMuv) genes
      including the C. elegans E2F homolog, efl-1. Reporter analyses indicate that pha
      1 is broadly expressed during embryonic development and that its functions reside
      in the cytoplasm. We also provide genetic and phenotypic evidence to support the
      model that PHA-1, a novel protein, and UBC-18, a ubiquitin-conjugating enzyme
      that we have previously shown to function with lin-35 during pharyngeal
      development, act in parallel pathways to regulate the activity of a common
      cellular target.

PMID- 15196947
TI  - The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to
      promote terminal differentiation of trophoblast stem cells.
AB  - The trophoblast cell lineage is an interesting model system because it is
      composed of a limited number of cell types that are spatially patterned.
      Trophoblast stem (TS) cells reside within a layer called the chorion and either
      remain as stem cells or differentiate into spongiotrophoblast (SpT), trophoblast
      giant (TG) cells or syncytiotrophoblast cells (SynT) of the labyrinth.
      Maintenance of the TS phenotype is dependent on stimulation by FGF4, whereas
      differentiation and/or maintenance of the differentiated derivatives are
      dependent on key transcription factors: Mash2 for SpT, Hand1 for TG cells and
      Gcm1 for SynT cells. TS cells proliferate and retain their stem cell phenotype in
      culture in response to FGF4 and an additional factor(s) that can be provided by
      conditioned medium from embryonic fibroblast feeder cells (CM). To understand the
      functions of Hand1, Mash2 and Gcm1 at a cellular level, we tested the effects of
      their ectopic and over-expression on the ability of TS cells to either continue
      to proliferate or differentiate into their alternative fates. Expression of Mash2
      alone had no effects on TS cell differentiation. However, Mash2-transfected cells
      continued to divide longer after withdrawal of FGF/CM. Hand1 promoted TGC
      differentiation, even in the continued presence of FGF4/CM. Stra13, another bHLH
      factor gene that is expressed in TG cells, also induced TG differentiation. Gcm1
      induced a rapid arrest of TS proliferation but, in contrast to Hand1 and Stra13,
      blocked TG cell differentiation. Although Gcm1 was not sufficient to promote SynT
      formation, expression of an antisense Gcm1 transcript blocked SynT
      differentiation. These data suggest that Mash2 functions to promote transient
      FGF4-independent amplification of trophoblast cells that are progressing towards
      the SpT and TG cell phenotype. By contrast, Hand1 and Stra13 promote cell cycle
      exit and restrict cells towards the TG fate, whereas Gcm1 promotes cell cycle
      exit and restriction towards the SynT fate.

PMID- 15196948
TI  - Complementary roles for dynein and kinesins in the Xenopus egg cortical rotation.
AB  - Aligned vegetal subcortical microtubules in fertilized Xenopus eggs mediate the
      "cortical rotation", a translocation of the vegetal cortex and of dorsalizing
      factors toward the egg equator. Kinesin-related protein (KRP) function is
      essential for the cortical rotation, and dynein has been implicated indirectly;
      however, the role of neither microtubule motor protein family is understood. We
      examined the consequence of inhibiting dynein--dynactin-based transport by
      microinjection of excess dynamitin beneath the vegetal egg surface. Dynamitin
      introduced before the cortical rotation prevented formation of the subcortical
      array, blocking microtubule incorporation from deeper regions. In contrast,
      dynamitin injected after the microtubule array was fully established did not
      block cortical translocation, unlike inhibitory-KRP antibodies. During an early
      phase of cortical rotation, when microtubules showed a distinctive wavy
      organization, dynamitin disrupted microtubule alignment and perturbed cortical
      movement. These findings indicate that dynein is required for formation and early
      maintenance of the vegetal microtubule array, while KRPs are largely responsible
      for displacing the cortex once the microtubule tracks are established. Consistent
      with this model for the cortical rotation, photobleach analysis revealed both
      microtubules that translocated with the vegetal cytoplasm relative to the cortex,
      and ones that moved with the cortex relative to the cytoplasm.

PMID- 15196949
TI  - A homologue of Cdk8 is required for spore cell differentiation in Dictyostelium.
AB  - The Cdk8 proteins are kinases which phosphorylate the carboxy terminal domain
      (CTD) of RNA polymerase II (Pol II) as well as some transcription factors and,
      therefore, are involved in the regulation of transcription. Here, we report that
      a Cdk8 homologue from Dictyostelium discoideum is localized in the nucleus where
      it forms part of a high molecular weight complex that has CTD kinase activity.
      Insertional mutagenesis was used to abrogate gene function, and analysis of the
      null strain revealed that the DdCdk8 protein plays an important role in spore
      formation during late development. As previously reported [Dev. Growth Differ. 44
      (2002) 213] Ddcdk8- cells also exhibit impaired aggregation, although we report
      that the severity of the defect depends upon experimental conditions. When
      aggregation occurs, Ddcdk8- cells form abnormal terminally differentiated
      structures within which the Ddcdk8- cells differentiate into stalk cells but fail
      to form spores, indicating a role for DdCdk8 in cell differentiation. When Ddcdk8
      is expressed from its own promoter, the protein is able to rescue both the late
      developmental defect and the impaired aggregation. However, when expressed from
      an heterologous promoter, only the impaired aggregation is rescued. This result
      demonstrates that the defect during late development is not a consequence of
      impaired aggregation and indicates a direct role for DdCdk8 in spore formation.

PMID- 15196950
TI  - Confocal and video imaging of cytoskeleton dynamics in the leech zygote.
AB  - Ooplasmic segregation in the late interphase zygote of the leech Theromyzon
      trizonare is accomplished by reorganization of an ectoplasmic cytoskeleton formed
      by polar rings and meridional bands. The dynamic properties of this cytoskeleton
      were explored by time-lapse confocal and video microscopy. Cytoskeleton assembly
      was investigated in zygotes pulse-labeled with microinjected fluorophore-tagged
      or biotin-tagged dimeric tubulin and G-actin. Cytoskeleton disassembly was
      studied by comparing the linear dimensions of the cytoskeleton at different time
      points during late interphase. The relative distributions of F- and-G-actin were
      determined after microinjection of rhodamine-labeled actin and fluorescein
      labeled DNase I. Results showed that labeled precursors were readily incorporated
      into a network of microtubules or actin filaments. Bipolar translocation of the
      rings and meridional bands was accompanied by the rapid assembly and disassembly
      of microtubules and actin filaments. Because labeled microtubules and
      microfilaments gradually decreased, the rate of cytoskeleton disassembly was
      greater than the rate of cytoskeleton assembly. Hence, ooplasmic segregation was
      accompanied by the rapid turnover of cytoskeletal components. Co-distribution of
      F- and-G-actin during mid and late interphase may favor polymer-monomer
      interchange. We conclude that cytoskeleton reorganization during foundation of
      cytoplasmic domains can be conveniently studied in the live leech zygote after
      microinjection of labeled precursors.

PMID- 15196951
TI  - The Meis3 protein and retinoid signaling interact to pattern the Xenopus
      hindbrain.
AB  - In Xenopus embryos, proper hindbrain formation requires activities of both XMeis3
      protein and retinoic acid (RA) signaling. In this study, we show that XMeis3
      protein and RA signaling differentially interact to regulate hindbrain
      patterning. The knockdown of XMeis3 protein prevented RA-caudalizing activity
      from inducing hindbrain marker expression in both explants and embryos. In
      contrast, inhibition of RA signaling differentially modulated XMeis3 activity.
      Target genes that are jointly activated by either RA or XMeis3 activities could
      not be efficiently induced by XMeis3 when RA signaling was inhibited. However,
      transcription of an XMeis3 target gene that is not an RA target gene was hyper
      induced in the absence of retinoid signaling. Target genes jointly induced by RA
      or XMeis3 protein were synergistically activated in the presence of both
      activities, while RA treatment inhibits the ability of XMeis3 to activate
      transcription of neural genes that are not RA targets. HoxD1, an RA direct-target
      gene was also identified as an XMeis3 direct-target gene. HoxD1 protein acts
      downstream of XMeis3 to induce hindbrain marker gene transcription. To pattern
      the hindbrain, RA requires functional XMeis3 protein activity. XMeis3 protein
      appears crucial for initial hindbrain induction, whereas RA signaling defines the
      spatial limits of hindbrain gene expression by modifying XMeis3 protein activity.

PMID- 15196952
TI  - Phosphorylation of ezrin on threonine T567 plays a crucial role during compaction
      in the mouse early embryo.
AB  - The preimplantation development of the mouse embryo leads to the divergence of
      the first two cell lineages, the inner cell mass and the trophectoderm. The
      formation of a microvillus pole during compaction at the eight-cell stage and its
      asymmetric inheritance during mitosis are key events in the emergence of these
      two cell populations. Ezrin, a member of the ERM protein family, seems to be
      involved in the formation and stabilization of this apical microvillus pole. To
      further characterize its function in early development, we mutated the key
      residue T567, which was reported to be essential for regulation of ezrin function
      through phosphorylation. Here, we show that expression of ezrin mutants in which
      the COOH-terminal threonine T567 was replaced by an aspartate (to mimic a
      phosphorylated residue; T567D) or by an alanine (to avoid phosphorylation; T567A)
      interferes with E-cadherin function and disrupts the first morphogenetic events
      of development: compaction and cavitation. The active mutant ezrin-T567D induces
      the formation of numerous and abnormally long microvilli at the surface of
      blastomeres. Moreover, it localizes all around the cell cortex and inhibits cell
      cell adhesion and cell polarization at the eight-cell stage. During the following
      stages, only half of the embryos are able to compact and finally to cavitate. In
      those embryos, the amount of ezrin-T567D decreases in the basolateral areas,
      while the proportion of adherens junctions increases. The reverse inactive mutant
      ezrin-T567A is mainly cytoplasmic and does not perturb compaction at the eight
      cell stage. However, at the 16-cell stage, it relocalizes at the basolateral
      cortex, leading to a strong decrease in the surface of adherens junctions, and
      finally, embryos abort development. Our results show that ezrin is directly
      involved in the formation of microvilli in the early mouse embryo. Moreover, they
      indicate that maintenance of ezrin in basolateral areas prevents microvilli
      breakdown and inhibits the formation of normal cell-cell contacts mediated by E
      cadherin, thereby impairing blastomeres polarization and morphogenesis of the
      blastocyst.

PMID- 15196953
TI  - Real-time analysis of ureteric bud branching morphogenesis in vitro.
AB  - While it is clear that the normal branching morphogenesis of the ureteric bud
      (UB) is critical for development of the metanephric kidney, the specific patterns
      of branching and growth have heretofore only been inferred from static images.
      Here, we present a systematic time-lapse analysis of UB branching morphogenesis
      during the early development of the mouse kidney in organ culture. Metanephric
      primordia from Hoxb7/GFP transgenic embryos were cultured for 3-4 days, and GFP
      images of the UB taken every 30 min were assembled into movies. Analysis of these
      movies (available as )revealed that the UB is a highly plastic structure, which
      can branch in a variety of complex patterns, including terminal bifid, terminal
      trifid, and lateral branching. To examine kinetic parameters of branching and
      elongation, skeletal representations of the UB were used to measure the number of
      segments and branch points and the length of each segment as a function of time
      and of branch generation. These measurements provide a baseline for future
      studies on mutant kidneys with defects in renal development. To illustrate how
      these quantitative methods can be applied to the analysis of abnormal kidney
      development, we examined the effects of the MEK1 inhibitor PD98059 on renal organ
      cultures and confirmed a previous report that the drug has a specific inhibitory
      effect on UB branching as opposed to elongation.

PMID- 15196954
TI  - cis-Regulatory control circuits in development.
AB  - During development, an organism undergoes many rounds of pattern formation,
      generating ever-greater complexity with each ensuing round of cell division and
      specification. The instructions for executing this process are encoded in the cis
      regulatory modules that direct the expression of developmental transcription
      factors and signaling molecules. Each transcription factor binding site within a
      cis-regulatory module contributes information about when, where, or how much a
      gene is turned on, and by dissecting the modules driving a given gene, all the
      inputs governing expression of the gene can be accurately identified.
      Furthermore, by mapping the output of each gene to the inputs of other genes, it
      is possible to reverse engineer developmental circuits and even whole networks.
      At this higher level of organization, common bilaterian strategies for specifying
      progenitor fields, locking down regulatory states, and driving development
      forward emerge.

PMID- 15196955
TI  - Beyond the neckless phenotype: influence of reduced retinoic acid signaling on
      motor neuron development in the zebrafish hindbrain.
AB  - Retinoic acid (RA) has been identified as a key signal involved in the
      posteriorization of vertebrate neural ectoderm. The main biosynthetic enzyme
      responsible for RA signaling in the hindbrain and spinal cord is Raldh2. However,
      neckless/raldh2-mutant (nls) zebrafish exhibit only mild degrees of
      anteriorization in the neural ectoderm, compared to full vitamin A deficiency in
      amniotes and the Raldh2-/- mouse. Here we investigated the role of RA during
      neuronal development in the zebrafish hindbrain and anterior spinal cord using
      DEAB, an inhibitor of retinaldehyde dehydrogenases. We show that the nls
      hindbrain and spinal cord are not fully devoid of RA, since blocking Raldh
      mediated RA signaling leads to a more severe hindbrain phenotype than in nls. The
      anteroposterior distribution of branchiomotor neurons in the facial and more
      posterior nuclei depends on full RA signaling throughout early and late gastrula
      stages. In contrast, inhibition of RA synthesis after gastrulation reduces the
      number of branchiomotor neurons in the vagal nucleus, but has no effect on
      anteroposterior cell fates. In addition, blockage of RA-mediated signaling not
      only interferes with the differentiation of branchiomotor neurons and their axons
      in the hindbrain, but also affects the development of the posterior lateral line
      nerve.

PMID- 15196956
TI  - fgf17b, a novel member of Fgf family, helps patterning zebrafish embryos.
AB  - Fibroblast growth factors (Fgfs) play important roles in the pattern formation of
      early vertebrate embryos. We have identified a zebrafish ortholog of human FGF17,
      named fgf17b. The first phase of fgf17b expression occurs in the blastodermal
      margin of late blastulae and in the embryonic shield of early gastrulae. The
      second phase starts after the onset of segmentation, mainly in the presomitic
      mesoderm and newly formed somites. Injection of fgf17b mRNA into one-cell embryos
      induces expression of the mesodermal marker no tail (ntl) and rescues ntl
      expression suppressed by overexpression of lefty1 (lft1). Overexpression of
      fgf17b dorsalizes zebrafish gastrulae by enhancing expression of chordin (chd),
      which is an antagonist of the ventralizing signals BMPs. In addition,
      overexpression of fgf17b posteriorizes the neuroectoderm. Simultaneous knockdown
      of fgf17b and fgf8 with antisense morpholinos results in reduction of chd and
      ntl. Knockdown of fgf17b can alleviate inhibitory effect of ectopic expression of
      fgf3 on otx1. These data together suggest that Fgf17b plays a role in early
      embryonic patterning. We also demonstrate that fgf17b and fgf8 have stronger
      mesoderm inducting activity than fgf3, whereas fgf17b and fgf3 have stronger
      activity in posteriorizing the neuroectoderm than fgf8. Like fgf8, activation of
      fgf17b expression depends on Nodal signaling.

PMID- 15196957
TI  - Retinoic acid signaling is essential for pancreas development and promotes
      endocrine at the expense of exocrine cell differentiation in Xenopus.
AB  - How and when the vertebrate endoderm is first subdivided into discrete progenitor
      cell populations that will give rise to the different major organs, including
      pancreas and liver, are only poorly understood. We have used Xenopus laevis as a
      model system to characterize these events, since it is particularly suited to
      study the early embryonic patterning in vertebrates. Our experimental results
      support the notion that retinoic acid (RA) functions as an essential endodermal
      patterning signal in Xenopus and that it acts as early as during gastrulation. As
      a result of RA treatment, the expression of Sonic Hedgehog (Shh), a known
      inhibitor of pancreas development in other vertebrate systems, is negatively
      regulated in the dorsal prepancreatic endoderm. Furthermore, RA is found to
      promote endocrine at the expense of exocrine differentiation in the dorsal
      pancreas, correlating with a specific inhibition of Notch signaling activities in
      this territory. Conversely, RA enhances exocrine marker gene expression in the
      ventral pancreas.

PMID- 15196958
TI  - Embryonic expression and multifunctional actions of the natriuretic peptides and
      receptors in the developing nervous system.
AB  - Atrial natriuretic peptide (ANP) binding sites have been detected in the
      embryonic brain, but the specific receptor subtypes and biological functions for
      ANP family ligands therein remain undefined. We now characterize the patterns of
      gene expression for the natriuretic peptides [ANP, brain natriuretic peptide
      (BNP), type-C natriuretic peptide (CNP)] and their receptors (NPR-A, NPR-B, NPR
      C) at several early stages in the embryonic mouse nervous system by in situ
      hybridization, and begin to define the potential developmental actions using cell
      culture models of peripheral (PNS) and central nervous systems (CNS). In the CNS,
      gene transcripts for CNP were present at the onset of neurogenesis, embryonic day
      10.5 (E10.5), primarily in the dorsal part of the ventricular zone (VZ)
      throughout the hindbrain and spinal cord. On E14.5, new CNP signals were observed
      in the ventrolateral spinal cord where motor neurons reside, and in bands of
      cells surrounding the spinal cord and hindbrain, localized to dura and/or
      cartilage primordia. ANP and BNP gene transcripts were not detected in embryonic
      brain, but were highly abundant in the heart. The CNP-specific receptor (NPR-B)
      gene was expressed in cells just outside the VZ, in regions where post-mitotic
      neurons are differentiating. Gene expression for NPR-C, which recognizes all
      natriuretic peptides, was present in the roof plate of the hindbrain and spinal
      cord and in bilateral stripes just dorsolateral to the floor plate at E12.5. In
      the PNS, NPR-B and NPR-C transcripts were highly expressed in dorsal root sensory
      (DRG) and cranial ganglia beginning at E10.5, with NPR-C signal also prominent in
      adjoining nerves, consistent with Schwann cell localization. In contrast, NPR-A
      gene expression was undetectable in neural tissues. To define ontogenetic
      functions, we employed embryonic DRG and hindbrain cell cultures. The natriuretic
      peptides potently stimulated DNA synthesis in neuron-depleted as well as neuron
      containing Schwann cell cultures and differentially inhibited neurite outgrowth
      in DRG sensory neuron cultures. CNP also exhibited modest survival-promoting
      effects for sensory neurons. In marked contrast to PNS effects, the peptides
      inhibited proliferation of neural precursor cells of the E10.5 hindbrain.
      Moreover, CNP, alone and in combination with sonic hedgehog (Shh), induced the
      expression of the Shh target gene gli-1 in hindbrain cultures, suggesting that
      natriuretic peptides may also modify patterning events in the embryonic brain.
      These studies reveal widespread, but discrete patterns of natriuretic peptide and
      receptor gene expression in the early embryonic nervous system, and suggest that
      the peptides play region- and stage-specific roles during the development of the
      peripheral and central nervous systems.

PMID- 15196959
TI  - The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate
      mesoderm cell fate.
AB  - During vertebrate embryogenesis, the newly formed mesoderm is allocated to the
      paraxial, intermediate, and lateral domains, each giving rise to different cell
      and tissue types. Here, we provide evidence that the forkhead genes, Foxc1 and
      Foxc2, play a role in the specification of mesoderm to paraxial versus
      intermediate fates. Mouse embryos lacking both Foxc1 and Foxc2 show expansion of
      intermediate mesoderm markers into the paraxial domain, lateralization of somite
      patterning, and ectopic and disorganized mesonephric tubules. In gain of function
      studies in the chick embryo, Foxc1 and Foxc2 negatively regulate intermediate
      mesoderm formation. By contrast, their misexpression in the prospective
      intermediate mesoderm appears to drive cells to acquire paraxial fate, as
      revealed by expression of the somite markers Pax7 and Paraxis. Taken together,
      the data indicate that Foxc1 and Foxc2 regulate the establishment of paraxial
      versus intermediate mesoderm cell fates in the vertebrate embryo.

PMID- 15196960
TI  - Sexual dimorphic expression pattern of a splice variant of zebrafish vasa during
      gonadal development.
AB  - In Drosophila, the RNA helicase VASA (VAS) is required for both germ line
      formation and oocyte differentiation. While the murine VAS homologue is required
      for spermatogenesis, it is dispensable for germ line formation. The molecular
      basis for this apparently dual role of VAS in germ line ontogeny is, however,
      unclear. Recent evidence indicates that fish, like flies, employs VAS both in
      early and late stages of the germ line development and that there is a sex-linked
      differential expression of splice variants. We show here that the longer of two
      splice variants of zebrafish vas is transiently downregulated in the germ line
      around the time when the germ cells reach the developing gonad. Using transgenic
      vas::EGFP fish lines, which allow us to distinguish between male and female
      individuals, we show that the long splice variant reappears in both sexes at
      around day 25 and is subsequently downregulated during male gonadal development.
      Our data further suggest that there is a switch from maternal to zygotic
      expression of the long splice variant of vas as sexual dimorphic development
      commences.

PMID- 15196961
TI  - Wnt 6 regulates the epithelialisation process of the segmental plate mesoderm
      leading to somite formation.
AB  - In higher vertebrates, the paraxial mesoderm undergoes a mesenchymal to
      epithelial transformation to form segmentally organised structures called
      somites. Experiments have shown that signals originating from the ectoderm
      overlying the somites or from midline structures are required for the formation
      of the somites, but their identity has yet to be determined. Wnt6 is a good
      candidate as a somite epithelialisation factor from the ectoderm since it is
      expressed in this tissue. In this study, we show that injection of Wnt6-producing
      cells beneath the ectoderm at the level of the segmental plate or lateral to the
      segmental plate leads to the formation of numerous small epithelial somites.
      Ectopic expression of Wnt6 leads to sustained expression of markers associated
      with the epithelial somites and reduced or delayed expression of markers
      associated with mesenchymally organised somitic tissue. More importantly, we show
      that Wnt6-producing cells are able to rescue somite formation after ectoderm
      ablation. Furthermore, injection of Wnt6-producing cells following the isolation
      of the neural tube/notochord from the segmental plate was able to rescue somite
      formation at both the structural (epithelialisation) and molecular level, as
      determined by the expression of marker genes like Paraxis or Pax-3. We show that
      Wnts are indeed responsible for the epithelialisation of somites by applying Wnt
      antagonists, which result in the segmental plate being unable to form somites.
      These results show that Wnt6, the only known member of this family to be
      localised to the chick paraxial ectoderm, is able to regulate the development of
      epithelial somites and that cellular organisation is pivotal in the execution of
      the differentiation programmes. We propose a model in which the localisation of
      Wnt6 and its antagonists regulates the process of epithelialisation in the
      paraxial mesoderm.

PMID- 15196962
TI  - Multicellular computer simulation of morphogenesis: blastocoel roof thinning and
      matrix assembly in Xenopus laevis.
AB  - In the blastocoel roof (BCR) of the Xenopus laevis embryo, epibolic movements are
      driven by the radial intercalation of deep cell layers and the coordinate
      spreading of the overlying superficial cell layer. Thinning of the lateral
      margins of the BCR by radial intercalation requires fibronectin (FN), which is
      produced and assembled into fibrils by the inner deep cell layer of the BCR. A
      cellular automata (CA) computer model was developed to analyze the spatial and
      temporal movements of BCR cells during epiboly. Simulation parameters were
      defined based on published data and independent results detailing initial tissue
      geometry, cell numbers, cell intercalation rates, and migration rates. Hypotheses
      regarding differential cell adhesion and FN assembly were also considered in
      setting system parameters. A 2-dimensional model simulation was developed that
      predicts BCR thinning time of 4.8 h, which closely approximates the time required
      for the completion of gastrulation in vivo. Additionally, the model predicts a
      temporal increase in FN matrix assembly that parallels fibrillogenesis in the
      embryo. The model is capable of independent predictions of cell rearrangements
      during epiboly, and here was used to predict successfully the lateral dispersion
      of a patch of cells implanted in the BCR, and increased assembly of FN matrix
      following inhibition of radial intercalation by N-cadherin over-expression.

PMID- 15196963
TI  - Input from the presubiculum to dendrites of layer-V neurons of the medial
      entorhinal cortex of the rat.
AB  - The entorhinal cortex (EC) and the hippocampus are reciprocally connected.
      Neurons in the superficial layers of EC project to the hippocampus, whereas deep
      entorhinal layers receive return connections. In the deep layers of EC, pyramidal
      neurons in layer V possess apical dendrites that ascend towards the cortical
      surface through layers IIII and II. These dendrites ramify in layer I. By way of
      their apical dendrites, such layer-V pyramidal cells may be exposed to input
      destined for the superficial entorhinal neurons. A specific and dense fiber
      projection that typically ends in superficial entorhinal layers of the medial EC
      originates in the presubiculum. To investigate whether apical dendrites of deep
      entorhinal pyramidal neurons indeed receive input from this projection, we
      injected the anterograde tracer PHA-L in the presubiculum or we lesioned the
      presubiculum, and we applied in the same experiments the tracer Neurobiotin trade
      mark pericellularly in layer V of the medial EC of 17 rats. PHA-L labeled
      presubiculum axons in the superficial layers apposing apical segments of
      Neurobiotin labeled layer-V cell dendrites were studied with a confocal
      fluorescence laserscanning microscope. Axons and dendrites were 3D reconstructed
      from series of confocal images. In cases in which the presubiculum had been
      lesioned, material was investigated in the electron microscope. At the confocal
      fluorescence microscope level we found numerous close contacts, i.e. appositions
      of boutons on labeled presubiculum fibers with identified dendrites of layer-V
      neurons. In the electron microscope we observed synapses between degenerating
      axon terminals and spines on dendrites belonging to layer-V neurons. Hence we
      conclude that layer-V neurons receive synaptic contacts from presubiculum
      neurons. These findings indicate that entorhinal layer-V neurons have access to
      information destined for the superficial layers and eventually the hippocampal
      formation. At the same time, they have access to the hippocampally processed
      version of that information.

PMID- 15196965
TI  - Role of kinin B1 and B2 receptors in the development of pilocarpine model of
      epilepsy.
AB  - The tissue sclerosis found in epilepsy of limbic origin is characterized by
      shrunken gliotic hippocampus, granule cell loss in the dentate gyrus and
      extensive pyramidal cell loss in Ammon's horn. Evidence has indicated that
      sprouting of dentate granule cell axons into the inner molecular layer of the
      dentate gyrus is related to hyperexcitability. Trying to understand the role of
      kinin B1 and B2 receptors in the physiopathology of temporal lobe epilepsy (TLE),
      the present work was delineated to study the development of the epilepsy model
      induced by pilocarpine in B1 and B2 knockout mice (B1KO and B2KO, respectively).
      Behavior parameters, cell death and mossy fiber sprouting were analyzed. B1KO
      mice showed increased latency for the first seizure, associated to a decreased
      frequency of spontaneous seizures, when compared with wild-type mice. In
      addition, B1KO mice showed less cell death in all hippocampal formation
      associated to a reduced grade of mossy fiber sprouting. Furthermore, B2KO mice
      presented minor duration of the silent period and an increased frequency of
      spontaneous seizures, when compared with wild-type mice. B2KO and their control
      lineage showed similar pattern of cell death in the hippocampus, which was very
      intense when compared with saline-treated animals. The mossy fiber sprouting was
      also increased in B2KO mice, when compared to wild-type mice and saline-treated
      animals. Taken together, these data suggest a deleterious effect for kinin B1
      receptor and a protective effect for kinin B2 receptor during the development of
      the temporal lobe epilepsy.

PMID- 15196964
TI  - Localization of mRNAs encoding alpha and beta subunits of soluble guanylyl
      cyclase in the brain of rainbow trout: comparison with the distribution of
      neuronal nitric oxide synthase.
AB  - Detailed distribution of mRNAs encoding alpha and beta subunits of soluble
      guanylyl cyclase (sGC) was examined in the brain of rainbow trout by in situ
      hybridization. In addition, distribution of nitric oxide synthase (NOS) was
      mapped in adjacent parallel sections by neuronal NOS (nNOS) immunocytochemistry
      and NADPH-diaphorase (NADPHd) histochemistry. Following application of
      digoxigenin-labeled riboprobes for sGC alpha and beta subunit mRNAs, we found
      comparatively intense hybridization signals in the telencephalon, preoptic area,
      thalamus, hypothalamus, pretectum and tegmentum. Both nNOS immunocytochemistry
      and NADPHd histochemistry showed extensive distribution of nitroxergic neurons in
      various brain areas, although various degrees of dissociation of nNOS
      immunoreactivity (ir) and NADPHd staining were detected. In comparison with sGC
      subunit mRNAs, nNOS signals were more widely distributed in many neurons,
      including parvocellular neurons in the preoptic area, nucleus anterior tuberis in
      the hypothalamus, periventricular neurons in the optic tectum, most of the
      rhombencephalic neurons and pituitary cells. However, wide overlaps of sGC mRNA
      containing neurons and nNOS-positive neurons were observed in the olfactory bulb,
      telencephalon, preoptic area, thalamus, hypothalamus, pretectum, optic tectum,
      tegmentum and cerebellum. The widespread overlapping in sGC subunit mRNAs and
      nNOS distribution suggests a role for sGC in various neuronal functions, such as
      processing of olfactory and visual signals and neuroendocrine function, possibly
      via NO/cGMP signaling in the brain of rainbow trout.

PMID- 15196966
TI  - Involvement of mitochondrial Na+-Ca2+ exchange in intracellular Ca2+ increase
      induced by ATP in PC12 cells.
AB  - The involvement of mitochondrial Na+-Ca2+ exchange in Ca2+ responses to ATP was
      examined in rat pheochromocytoma (PC) 12 cells. Intracellular Ca2+ ([Ca2+]i) and
      Na+ concentrations ([Na+]i) were measured using fura-2 and SBFI, respectively.
      ATP caused concentration-dependent increases in [Ca2+]i and [Na+]i. High
      concentrations of ATP elicited a Ca2+ transient followed by a slow recovery of
      [Ca2+]i (a sustained phase) in 77% of PC12 cells. The sustained phase of Ca2+
      response appeared only when the peak Ca2+ transient exceeded 500 nM. FCCP, a
      protonophore, greatly enhanced Ca2+ responses to ATP only in cells with the
      sustained phase but not without this phase. The sustained phase was decreased by
      clonazepam and CGP37157, mitochondrial Na+-Ca2+ exchange inhibitors, and
      extracellular Na+ removal but not by cyclosporin A, an inhibitor of permeability
      transition pores. The reintroduction of Na+ 3.5 min after ATP stimulation in the
      absence of Na+ caused Na+ concentration-dependent increases in [Ca2+]i and
      [Na+]i. The increase in [Na+]i was correlated with that in [Ca2+]i. FCCP caused a
      great increase in [Ca2+]i 4.5 min after ATP stimulation in the absence of
      extracellular Na+ but not in its presence, indicating that mitochondria retain
      Ca2+ in the absence of Na+. These results suggest that ATP causes a large
      increase in [Ca2+]i which was sequestered in mitochondria and that the sustained
      phase of Ca2+ response to ATP are mainly due to the release of mitochondrial Ca2+
      through Na+-Ca2+ exchangers in PC12 cells.

PMID- 15196968
TI  - Synaptic remodeling in the nucleus ambiguus following vagal-hypoglossal nerve
      anastomosis in the cat.
AB  - We reported recently the occurrence of a massive and selective elimination of
      synaptic boutons on motoneurons in the dorsal motor nucleus of the vagus (DMV) in
      the cat following vagal-hypoglossal nerve anastomosis (VHA) [J. Comp. Neurol. 458
      (2003) 195]. This study was aimed to explore the synaptic reorganization in the
      other major nucleus associated with the vagus, namely, the nucleus ambiguus (NA)
      following the same treatment. In view of the tremendous difference in function,
      the NA and DMV are considered to be two ideal nuclei for explanatory studies
      seeking to elucidate how VHA could induce different plasticity of brainstem
      neurons influenced by the newly reestablished neural pathway. The present results
      showed that the vagal efferent neurons in the NA had responded to VHA in a
      different manner compared with those in the DMV. Firstly, the numbers of axon
      terminals containing round (R), round with dense-cored (R+D), pleomorphic (P) or
      flattened (F) synaptic vesicles contacting the NA motoneurons were markedly
      increased at 500-day postoperation, the longest reinnervation interval. The
      percent increases in the synapse frequency for R, R+D, P and F boutons were 8.6%,
      274.4%, 238.3% and 400.0%, respectively. Secondly, the formation of astroglial
      ensheathment around the motoneurons in the DMV following VHA was not evident in
      the NA. Another striking difference was the extensive dendritic sprouting of the
      NA neurons as opposed to the dendritic retraction of the DMV neurons as shown by
      a significant increase in distal dendrites of NA motoneurons. The different modes
      of neural remodeling between NA and DMV may be attributed to the unique nature of
      the two nuclei to structures they normally supply and their different
      compatibility with the newly innervated target, viz. tongue skeletal musculature.

PMID- 15196967
TI  - Accelerated alpha-synuclein aggregation after differentiation of SH-SY5Y
      neuroblastoma cells.
AB  - Alpha-synuclein (alpha-syn) is a major component of inclusion bodies in
      Parkinson's disease (PD) and other synucleinopathies. To clarify the possible
      roles of alpha-syn in the molecular pathogenesis of neurodegenerative diseases,
      we have established a novel cellular model based on the differentiation of SH
      SY5Y cells that overexpress alpha-syn. In the presence of ferrous iron,
      differentiation of the cells led to the formation of large perinuclear inclusion
      bodies, which developed from scattered small aggregates seen in undifferentiated
      cells. The iron-induced alpha-syn-positive inclusions co-localized largely with
      ubiquitin, and some of them were positive for nitrotyrosine, lipid, gamma-tubulin
      and dynein. Notably, treatment with nocodazole, a microtubule depolymerizing
      agent, interrupted the aggregate formation but led to a concomitant increase of
      apoptotic cells. Therefore, it appears that an intracellular retrograde transport
      system via microtubules plays a crucial role in the aggregate formation and also
      that the aggregates may represent a cytoprotective response against noxious
      stimuli. This cellular model will enable better understanding of the molecular
      pathomechanisms of synucleinopathy.

PMID- 15196969
TI  - The time course of ischemic damage and cerebral perfusion in a rat model of space
      occupying cerebral infarction.
AB  - We aimed to establish a rat model of space-occupying hemispheric infarction to
      evaluate potential treatment strategies. For adequate timing of therapy in future
      experiments, we studied the development of tissue damage, edema formation, and
      perfusion over time with different MRI techniques. Permanent middle cerebral
      artery (MCA) occlusion was performed in 32 Fisher-344 rats. Forty-six MRI
      experiments including diffusion weighted (DW), T2-weighted (T2W), flow-sensitive
      alternating inversion recovery (FAIR) perfusion-weighted, and T1-weighted (T1W)
      imaging before and after gadolinium were performed at 1, 3, 8, 16, 24, and 48 h
      of ischemia. MCA occlusion consistently led to infarction of the complete MCA
      territory. Mortality was 75%. Lesion volumes as derived from apparent diffusion
      coefficient (ADC) and T2 maps increased to maximum values of 400+/-48 mm3 at 24 h
      and 420+/-54 mm3 at 48 h of ischemia, respectively. Midline shift peaked at 24 h.
      The area with diffusion-perfusion deficit decreased to a minimum at 24 h after
      onset of ischemia and perfusion of the contralateral hemisphere dropped at the
      same time point. Leakage of gadolinium through the blood-brain barrier in the
      entire infarct occurred within 3 h of ischemia. Permanent intraluminal MCA
      occlusion in Fisher-344 rats is an adequate model for space-occupying cerebral
      infarction. Rats may benefit from intervention aimed at reducing tissue shift and
      intracranial pressure (ICP), and at improving cerebral blood flow, if initiated
      before 24 h after MCA occlusion. The value of treatment modalities depending on
      an intact blood-brain barrier should be questioned.

PMID- 15196970
TI  - Maternal separation affects cocaine-induced locomotion and response to novelty in
      adolescent, but not in adult rats.
AB  - Maternal separation is known to exert long-term effects on both behavior and the
      neuroendocrine system. We investigated cocaine-induced locomotor activation as
      well as the locomotor and corticosterone response to forced novelty in maternally
      separated adolescent and adult rats. Maternal separation consisted of separating
      litters from their dams daily during 5 h from postnatal days 2 to 6. Control
      animals were subjected only to regular cage changes. Cocaine- (10 mg/kg, i.p.)
      and novelty-induced locomotion were recorded in an activity cage. After the
      animals were tested for behavioral response to novelty, trunk blood samples were
      collected and plasma corticosterone levels were determined by radioimmunoassay.
      Adolescent rats exposed to maternal separation exhibited an increased locomotor
      response to novelty and cocaine; corticosterone levels were lower in these
      adolescent animals, after exposure to the novel environment. These effects of
      maternal separation were not observed in rats that were tested as adults. Thus
      the maternal separation protocol produced enduring but transient changes in the
      behavioral response to cocaine and in the stress response to novelty.

PMID- 15196971
TI  - Influence of estradiol on insulin-like growth factor-1-induced luteinizing
      hormone secretion.
AB  - Several studies suggest an interrelationship between estradiol (E2) and insulin
      like growth factor-1 (IGF-1) at the hypothalamic level. The present study was
      designed to discern if the capability of IGF-1 to release LH and influence the
      timing of female puberty is influenced by E2. Twenty-eight-day-old female rats
      were ovariectomized (OVEX), then implanted with a third ventricular (3V) cannula.
      Two weeks later, these animals received subcutaneous (s.c.) injection of oil, or
      either one or two injections of E2 in the form of estradiol benzoate (1 microg).
      Forty-eight hours later, four basal blood samples were drawn then the animals
      received IGF-1 (200 ng) or saline via the 3V and four more blood samples were
      taken. Results indicated that E2 replacement lowered basal LH levels and IGF-1
      induced a significant LH release in only animals that had E2 levels above 20
      pg/ml. These levels of E2 were also associated with increases (p<0.05) in the
      expression of both IGF-1 receptor (IGF-1R) mRNA and protein. In order to further
      support the hypothesis that the action of IGF-1 at the time of puberty is
      influenced by E2, 24-day-old intact female rats received s.c. injection of sesame
      oil or 0.1 microg of E2. The next day, the E2-treated animals also received twice
      daily s.c. injections of either IGF-1 (500 ng) or saline until vaginal opening
      (VO) occurred. The animals that received E2 plus IGF-1 showed VO at 31.1 days,
      which was 2.5 days earlier (p<0.01) than E2-treated animals and 4 days earlier
      (p<0.001) than IGF-1-treated and saline control animals. Taken together, these
      results indicate that the hypothalamic action of IGF-1 to stimulate LH release
      and advance female pubertal development is dependent upon the influence of E2.

PMID- 15196972
TI  - High-frequency stimulation of the subthalamic nucleus reverses limb-use asymmetry
      in rats with unilateral 6-hydroxydopamine lesions.
AB  - Deep brain stimulation (DBS) is a widely used clinical treatment for Parkinson's
      disease (PD). A rodent model of DBS is a necessary tool for understanding the
      neural mechanisms of this method. Our previous study showed that high-frequency
      stimulation (HFS) of the subthalamic nucleus (STN) improved treadmill locomotion
      in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of
      nigrostriatal dopamine (DA) neurons. The present study tested DBS effects on limb
      use asymmetry (LUA) during vertical/lateral exploration in a cylindrical chamber
      in rats with similar unilateral nigrostriatal DA lesions. Limb-use asymmetry
      assessment has been used to detect functional capacity over a wide range of
      dopamine depletion. Before lesioning, rats exhibited regular rearing activity and
      used both forelimbs equally often to support weight during exploration of the
      walls of the cylinder. After unilateral nigrostriatal DA lesioning, rats
      displayed reduced rearing activity and predominant use of the ipsilateral (good)
      forelimb to touch the wall. HFS of the STN, but not of other nearby regions
      surrounding the STN, in the lesioned rats restored normal rearing activity and
      reversed the limb-use asymmetry caused by the unilateral DA depletion. This study
      is consistent with the possibility that there can be beneficial effects of STN
      DBS on behavioral impairments in unilateral DA-depleted rats and may suggest an
      appropriate rodent model for DBS study.

PMID- 15196973
TI  - Effect of prolonged exposure to low concentrations of formaldehyde on the
      corticotropin releasing hormone neurons in the hypothalamus and
      adrenocorticotropic hormone cells in the pituitary gland in female mice.
AB  - We examine the effect on the hypothalamus-pituitary-adrenal gland (HPA) axis of
      prolonged exposure to low levels of formaldehyde in female C3H/He mice, using
      immunocytochemical and RT-PCR methods. Two groups of female mice were exposed to
      differing concentrations (0, 80, 400, 2000 ppb) of formaldehyde inhalation for 16
      h/day, 5 days/week, for 12 weeks. The corticotropin releasing hormone (CRH)
      immunoreactive (ir) neurons in the hypothalamus were then examined, together with
      the adrenocorticotropin hormone (ACTH)-ir cells and ACTH mRNA in the pituitary.
      One group comprised sham control mice. The other group was made allergic by
      injection of ovalbumin (OVA) and alum prior to exposure to formaldehyde, since
      most sick building syndrome (SBS) sufferers are women with allergic disease.
      These animals were further exposed to aerosolized OVA as a booster four times
      during the exposure period. Our results showed a dose-dependent increase in the
      number of CRH-ir neurons in the non-allergy (NAG) group. A similar pattern was
      found in ACTH-ir cells and ACTH mRNA. The allergy (AG) model group showed an
      increase in basal levels of all markers of HPA activity. Moreover, the AG mice
      appeared to respond to the lowest concentration of formaldehyde, and all indices
      of HPA activity were reduced at the highest concentrations of formaldehyde. These
      results relate to an important clinical issue and also have implications in the
      broader area of HPA regulation. We conclude that our experimental system may be a
      suitable animal model for SBS and/or multiple chemical sensitivity (MCS).

PMID- 15196974
TI  - Adenine nucleotide metabolism and cell fate after oxidant exposure of rat
      cortical neurons: effects of inhibition of poly(ADP-ribose) polymerase.
AB  - We exposed cultured neurons prelabeled with 14C-adenine to H2O2 with or without
      the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-Dihydro-5-[4-(1
      piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ) to quantify its effects on acute
      ATP depletion, later ATP synthesis, cellular and nuclear morphology, extent of
      DNA fragmentation, and PARP cleavage. According to the extent of the acute ATP
      depletion, the exposures were classified as 'mild' (50 microM H2O2), 'moderate'
      (100-250 microM H2O2), or 'severe' (500 microM-1 mM H2O2) insults. Mild exposure
      had no significant effects on the parameters studied. In the 'moderately' exposed
      neurons, ATP depletion to 59+/-6% of control was associated with a decrease in
      the cell counts, apoptotic morphology, and cleavage of PARP. In this group, DPQ
      prevented the acute ATP (to 95+/-15% of control), preserved cell morphology, and
      improved cell survival. In the 'severe' group, ATP depletion to 18+/-4% was
      associated with necrosis and intact PARP. DPQ elevated ATP levels (to 44+/-12% of
      control) and post-insult ATP synthesis, improved cell counts, and altered cell
      morphology towards apoptosis rather than necrosis. Post-insult application of DPQ
      was less effective. Our results show that the extent of oxidant-induced ATP
      depletion and cell fate can be modified by PARP inhibition, to some extent also
      after the insult.

PMID- 15196975
TI  - PKC-independent inhibition of neuronal nicotinic acetylcholine receptors by
      diacylglycerol.
AB  - Diacylglycerol modulates cell functions primarily through activation of protein
      kinase C (PKC). In a previous study, however, we found that a diacylglycerol
      analogue, 1-oleoyl-2-acetylglycerol (OAG), accelerated desensitization of
      neuronal nicotinic acetylcholine receptors (nAchRs) independently of PKC
      activation in PC12 cells. In the present study, we investigated whether other
      analogues and endogenous diacylglycerol exert similar effects on neuronal nAchRs
      and characterized the modulation by diacylglycerol. We measured the nicotine
      induced whole-cell current in the absence and presence of diacylglycerol
      analogues in PC12 cells. We also investigated the effects of a blockade of
      metabolic pathways of diacylglycerol by inhibiting diacylglycerol lipase and
      kinase. We found that all four diacylglycerol analogues studied promoted
      desensitization and depressed the nondesensitized component of the nicotine
      induced current. These effects seemed independent of PKC activation because they
      were not antagonized by the PKC inhibitors staurosporine or bisindolylmaleimide
      I; one analogue that lacks the PKC-stimulating action was also effective. The
      effects of diacylglycerol analogues were not antagonized by high doses of
      nicotine and were independent of the membrane potential. Similar modulatory
      effects were observed by treatment with RHC80267, a blocker of diacylglycerol
      lipase, and R59949, an inhibitor of diacylglycerol kinase, in the presence of
      staurosporine. These results suggest that diacylglycerol, both exogenously
      applied and endogenously produced, modulates neuronal nAchRs independently of PKC
      activation in PC12 cells; further, these effects seemed consistent with a
      noncompetitive and voltage-independent block. They raised the possibility that
      PKC-independent inhibition of neuronal nAchRs by diacylglycerol may be a novel
      modulatory process.

PMID- 15196976
TI  - Effects of steroid hormones on the Zn, Cu and MTI/II levels in the mouse brain.
AB  - The effects of some steroid hormones (corticosterone, hydrocortisone,
      testosterone and estrone) on the Zn, Cu metabolism and metallothioneins levels in
      the mouse brain were studied. To administrate the hormones, aqueous suspensions
      and olive oil solutions injected subcutaneously were used alternatively. The
      quantification of metals and metallothioneins concentrations in brain homogenates
      revealed significant alterations of both metal ions and protein expression
      levels, yet the subcutaneous oil injection increased per se the tissue
      metallothionein expression and metal content. We have also defined by
      immunohistochemistry the area-specific distribution of metallothioneins isoforms
      I/II and of glial fibrillar acid protein. Upon treatment, corpus callosum,
      mesencephalon, pons, hippocampus and cerebellum were found to be the areas that
      increase the protein expression levels, whereas all other brain areas were
      marginally affected or were unaffected in terms of immunopositive metallothionein
      reaction. The metallothionein-I/II expression was compared with the
      immunopositivity of glial fibrillar acid protein and the results are discussed
      within the framework of the physiological role of corticosteroids and the
      potential therapeutical importance of sexual hormones.

PMID- 15196977
TI  - Enamel microstructure and microstrain in the fracture of human and pig molar
      cusps.
AB  - The role of microstructure in enamel strain and breakage was investigated in
      human molar cusps and those of the pig, Sus scrofa. Rosette strain gauges were
      affixed to cusp surfaces (buccal human M3, n=15, and lingual pig M1, n=13), and a
      compressive load was applied to individual cusps using an MTS materials testing
      machine. Load and strain data were recorded simultaneously until cusp fracture,
      and these data were used to estimate enamel stresses, principal strains, and
      stiffness. Fractured and polished enamel fragments were examined in multiple
      planes using scanning electron microscopy (SEM). Human cusp enamel showed greater
      stiffness than pig enamel (P=0.02), and tensile stress at yield was higher (17.9
      N/mm2 in humans versus 8.9 N/mm2 in pigs, P=0.06). SEM revealed enamel rod
      decussation in both human and pig enamel; however, only pig enamel showed a
      decussation plane between rod and inter-rod crystallites. Human inter-rod enamel
      was densely packed between rods, whereas in pig enamel, inter-rod enamel formed
      partitions between rows of enamel rods. Overall, human enamel structure enabled
      molar cusps to withstand horizontal tensile stress during both elastic and
      plastic phases of compressive loading. In contrast, pig cusp enamel was less
      resistant to horizontal tensile stresses, but appeared to fortify the enamel
      against crack propagation in multiple directions. These structural and
      biomechanical differences in cusp enamel are likely to reflect species-level
      differences in occlusal function.

PMID- 15196978
TI  - Effects of pregnancy and lactation on the microhardness of rat incisor dentine
      and enamel.
AB  - Pregnancy and lactation affect the rate of maternal dentine apposition and
      mineralization in the rat. In this study we have measured the effects of
      pregnancy and lactation on the degree of mineralization of dentine and enamel by
      using the microhardness method in rat incisors. At incisal sections, pregnant and
      lactation group enamel values were increased compared to that of a control group;
      the pregnancy and post-lactation period dentine values decreased slightly
      compared to the control group. At neck sections, pregnant and lactation group
      enamel values were decreased compared to that of the control group; the pregnancy
      and post-lactation period dentine values were also decreased slightly compared to
      the control group. At the post-lactation period neck section dentine
      mineralization was decreased compared with the incisal section. As a result,
      enamel and dentine layers of rat incisors are affected to varying degrees by
      these changes in mineralization levels during the maternal period.

PMID- 15196979
TI  - The use of the replica technique to record fluid emerging from exposed dentine.
AB  - The effect of pulpal cavity pressure on structures present on etched and unetched
      dentine was determined in 24 human premolars in vitro. The dentine was exposed in
      vivo. After extraction, the pulp was removed and the crown stored in 2.5 N sodium
      hydroxide for 3 days to remove the odontoblasts. The pulp cavity was filled with
      Ringer's solution at atmospheric pressure, +30 or -5 mmHg. After 30s-5 min a
      silicone-rubber impression was taken of the cavity floor and a resin cast
      prepared and examined in a SEM. The replicas reproduced the dentine surface
      accurately when there was no outward flow through dentine. With a pressure of +
      30 mmHg in the pulp cavity, but not at the lower pressures, droplets were present
      on unetched dentine after 30s. Droplets accumulated less rapidly on etched
      dentine, indicating that it may act as a sponge.

PMID- 15196980
TI  - The effect of hereditary disorders on tooth components: a radiographic
      morphometric study of two syndromes.
AB  - OBJECTIVE: The purpose of this study was to compare tooth components (enamel and
      dentin) in Familial Dysautonomia (FD) and Down syndrome (DS) in order to assess
      the extent to which each was affected. DESIGN: The design was cross-sectional.
      The sample consisted of 20 FD patients and 45 DS patients. The control group
      comprised 250 healthy subjects. Mesio-distal crown width (CW), enamel and dentin
      thickness and pulp chamber dimensions were measured on standardized bitewing
      radiographs of mandibular second primary and first permanent molars. Statistical
      analyses were performed between groups using SAS programs. RESULTS: CW was
      reduced in both hereditary disorders. In the DS group enamel height (EH) and
      dentin thickness were reduced. In FD enamel thickness in the primary and
      permanent molars as well as dentin height (DH) in permanent molars was increased.
      CONCLUSIONS: In both syndromes the reduction in CW suggests reduced proliferation
      during tooth germ formation. However, the differences in enamel and dentin
      thickness suggest that ameloblasts and odontoblasts were affected differently in
      the later phases of cell function. In FD cell function is stimulated resulting in
      thicker enamel and dentin. In DS cell function is reduced resulting in thin
      enamel and dentin.

PMID- 15196981
TI  - Vascular endothelial growth factor, fibroblast growth factor 2, platelet derived
      growth factor and transforming growth factor beta released in human dental pulp
      following orthodontic force.
AB  - OBJECTIVE: The release of four diffusible angiogenic growth factors in human
      dental pulp following orthodontic force was investigated by using neutralising
      growth factor antibodies (NAs), individually and in four different combinations
      to block their effects. This study investigated if increasing the number of NAs
      (anti h vascular endothelial growth factor (VEGF), anti h fibroblast growth
      factor (FGF2), anti h platelet derived growth factor (PDGF) and anti Transforming
      growth factor beta (TGFbeta)) in combination resulted in a progressive reduction
      of the angiogenic response of the pulp. MATERIALS AND METHODS: The dental pulps
      from two groups of 40 premolar teeth, four teeth from each of 20 patients treated
      with fixed appliances for 2 weeks, were divided vertically, and sections from
      each half pulp co-cultured with sections of rat aorta in collagen. In one group,
      one of each of the four NAs, and in the other group, one of the four different NA
      combinations were added to the media of the co-cultures from one half of the pulp
      from each of the four teeth of each patient; the other half pulp co-cultures were
      controls. Cultures were examined daily by light microscopy for growth and number
      of microvessels. RESULTS: NAs significantly reduced microvessel numbers in the co
      cultures when added individually (P<0.004), and in each of the four combinations
      (P<0.002), with a trend to progressively reduced microvessel numbers with
      increasing number of NAs in combination. CONCLUSIONS: Results indicated that all
      four angiogenic growth factors examined were released following orthodontic force
      application and play a role in the angiogenic response of the pulp, and that
      these factors may be more effective in combination.

PMID- 15196982
TI  - High IL-6 synthesis in cultured fibroblasts isolated from radicular cysts.
AB  - OBJECTIVE: Inflammatory cytokines have been reported to be related with
      inflammation and expansion of jaw cysts. In this study, to examine the
      relationship between radicular cysts and inflammatory cytokines, it was found
      that there was notable unique evidence on cytokine synthesis from fibroblasts
      isolated from radicular cysts. METHODS: The expression of such cytokines, namely,
      interleukin-1beta, IL-1beta, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF
      alpha), interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF
      beta1), and granulocyte-macrophage colony-stimulating (GM-CSF) mRNA, in nine
      radicular cysts was examined and compared with that detected in six specimens of
      healthy gingival mucosa. Furthermore, separating all fibroblasts from their
      respective radicular cysts, healthy gingival mucosa, and healthy periodontal
      ligaments, these fibroblast groups were cultured without stimulators and a
      supernatant for each was obtained to analyse IL-1beta, IL-6, IL-8, TNF-alpha, and
      IFN-gamma by ELISA. RESULTS: Differences between radicular cysts and healthy
      gingival mucosa were not clearly shown by the expression of cytokine mRNA.
      Analysing inflammatory cytokine synthesis in fibroblast groups from these three
      kinds of tissues, surprisingly, the levels of IL-6 mRNA and protein were
      recognised to be higher in fibroblasts of radicular cysts than in those of
      control tissues by ELISA and a real-time RT-PCR. Significant differences in the
      cultured supernatants of these fibroblast groups were not recognised in the
      release of IL-1beta, IL-8, TNF-alpha, and IFN-gamma by ELISA. CONCLUSIONS: From
      these results, it was suggested that fibroblasts inducing IL-6 production might
      play important roles in the expansion of radicular cysts. It is considered that
      fibroblasts around radicular cysts may lead to high IL-6 synthesis over time in
      chronic inflammation.

PMID- 15196983
TI  - Comparison of differentiation markers between normal and two squamous cell
      carcinoma cell lines in culture.
AB  - This study examines differences between cultures of normal human oral epithelial
      cells and two squamous cell carcinoma cell lines (SCC15 and SCC25) in the
      expression of structural proteins, adhesion molecules, plasma membrane lipid
      composition, and intercellular junctions. Based on immunocytochemistry, most
      normal cell cultures appeared to express more E-cadherin, integrin beta-1,
      cytokeratin (CK) 14, CK19, and involucrin than SCC cultures. By Western blot
      analysis, normal cultures expressing high levels of E-cadherin also expressed
      high levels of involucrin and low levels of CK19. Both SCC cultures demonstrated
      lower expression of E-cadherin and involucrin, whereas only SCC15 cells showed
      high levels of CK19. Expression of beta-catenin, an E-cadherin associated protein
      with potential oncogene function, did not vary among normal and SCC cells.
      Proportions of saturated fatty acids quantified by thin layer chromatography were
      higher in the normal cell cultures, than in both SCC cell lines. No morphological
      differences were evident by transmission electron microscopy (TEM) between normal
      and SCC cell-cell intercellular junctions. Although no quantitation was
      attempted, observation suggested that normal cells form more intercellular
      junctions (TEM observation) and larger intercellular bridges (SEM observation)
      compared to both SCC cell lines. Of the factors examined, main variations between
      cultures of normal oral epithelium and the two SCC cell lines examined include
      the expression of structural and adhesion proteins, lipid composition, and
      intercellular junctions. The extent of the differences varies according to the
      stage of terminal differentiation demonstrated by the normal cell cultures.

PMID- 15196984
TI  - The effects of prolonged gum chewing on salivary flow rate and composition.
AB  - OBJECTIVE: To determine the effect of gum chewing for 2 h on salivary flow rate
      and composition. DESIGN: Five male and five females each collected whole saliva
      at intervals over a 2 h period on three separate days, prior to which they
      collected unstimulated saliva for 5 min. For one 2 h session they continued to
      collect only unstimulated saliva while for the others one tablet of Wrigley's
      Extra peppermint- or fruit-flavoured (peach) gum was chewed continuously. Flow
      rates were calculated and the saliva was assayed for pH and for Na, K, Ca, Cl,
      inorganic P and protein concentrations. The data were subjected to repeated
      measures ANOVA and Duncan tests. RESULTS: When only unstimulated saliva was
      collected, there was no significant change in salivary flow rate over the 2 h.
      With the chewing gums the flow rate increased initially and then, after 35-40
      min, fell to similar plateau values which remained significantly higher than the
      initial unstimulated flow rate and significantly higher than the flow rate at the
      corresponding time intervals when only unstimulated saliva was collected. With
      both gums the salivary pH from 2 min to 2 h was significantly higher than that of
      unstimulated saliva. The changes in the salivary electrolyte and protein
      concentrations due to the flow rate increase elicited by the chewing gum were
      largely as expected from previous studies on parotid and submandibular saliva.
      CONCLUSION: During prolonged chewing gum use, both salivary flow rates and pH
      remained significantly above the values for unstimulated saliva.

PMID- 15196985
TI  - On the wettability of soft tissues in the human oral cavity.
AB  - In this study, the wettability of gingival surfaces in the human oral cavity was
      assessed by the measurement of intra-oral water contact angles. Intra-oral water
      contacts angles were measured in the morning prior to tooth brushing, immediately
      after tooth brushing and prior to and after lunch in order to reveal the
      influences of toothpaste and dietary components on the wettability of the
      gingiva. Within a group of 10 volunteers, gingival surfaces were hydrophobic,
      with water contact angles ranging from 72 to 79 degrees, which is high as
      compared with other soft tissues in the human body. Gingival contact angles were
      not affected by most commercial toothpastes involved in this study, but decreased
      slightly to 65 degrees after brushing with a hexametaphosphate containing
      toothpaste. During the day, however, the hydrophobicity readily recovered and
      after lunch contact angles on the gingival surfaces were higher than early in the
      morning, now ranging from 76 to 83 degrees. It is generally known that soft
      tissues in the human body involved in adsorptive and exchange functions and
      requiring lubrication are more hydrophilic than tissues with more protective
      functions. This study shows that gingival surfaces classify as the most
      hydrophobic soft tissue in the human body, attesting to their important
      protective role in the oral cavity.

PMID- 15196986
TI  - Design and evaluation of inhibitors for dipeptidyl peptidase I (Cathepsin C).
AB  - Dipeptidyl peptidase I (DPPI, cathepsin C) is a lysosomal cysteine protease that
      can activate zymogens of several different serine proteases by one step or
      sequential removal of dipeptides from the N-termini of the pro-protease protein
      substrates. To find DPPI inhibitors more suitable for cellular applications than
      diazomethyl ketones, we synthesized three types of inhibitors: dipeptide
      acyloxymethyl ketones, fluoromethyl ketones, and vinyl sulfones (VS). The
      acyloxymethyl ketones inhibited DPPI slowly and are moderate inhibitors of
      cellular DPPI. The fluoromethyl ketones were potent, but the inhibited DPPI
      regained activity quickly. The dipeptide vinyl sulfones were effective inhibitors
      for DPPI, but they also inhibited cathepsins B, H, and L weakly. The best
      inhibitor, Ala-Hph-VS-Ph, had a k2/K(I) of 2,000,000M(-1)s(-1). The vinyl
      sulfones also inhibited intracellular DPPI, and for this application the more
      stable inhibitors exhibit better potency. We conclude that vinyl sulfones are
      promising inhibitors to study the intracellular functions of DPPI.

PMID- 15196987
TI  - Stability and folding studies of the N-domain of troponin C. Evidence for the
      formation of an intermediate.
AB  - We report here on the stability and folding of the 91 residue alpha-helical F29W
      N-terminal domain of chicken skeletal muscle troponin C (TnC(1-91)F29W), the thin
      filament calcium-binding component. Unfolding was monitored by differential
      scanning calorimetry, circular dichroism, and intrinsic fluorescence spectroscopy
      using urea, pH, and temperature as denaturants, in the absence and in the
      presence of calcium. The unfolding of TnC(1-91)F29W was reversible and did not
      follow a two-state transition, suggesting that an intermediate may be present
      during this reaction. Our results support the hypothesis that intermediates are
      likely to occur during the folding of small proteins and domains. The
      physiological significance of the presence of an intermediate in the folding
      pathway of troponin C is discussed.

PMID- 15196988
TI  - Identification of Val117 and Arg372 as critical amino acid residues for the
      activity difference between human CYP2A6 and CYP2A13 in coumarin 7-hydroxylation.
AB  - Human cytochrome P450 (CYP) 2A6 and 2A13 play an important role in catalyzing the
      metabolism of many environmental chemicals including coumarin, nicotine, and
      several tobacco-specific carcinogens. Both CYP2A6 and CYP2A13 proteins are
      composed of 494 amino acid residues. Although CYP2A13 shares a 93.5% identity
      with CYP2A6 in the amino acid sequence, it is only about one-tenth as active as
      CYP2A6 in catalyzing coumarin 7-hydroxylation. To identify the key amino acid
      residues that account for such a remarkable difference, we generated a series of
      CYP2A6 and CYP2A13 mutants by site-directed mutagenesis/heterologous expression
      and compared their coumarin 7-hydroxylation activities. In CYP2A6, the amino acid
      residues at position 117 and 372 are valine (Val) and arginine (Arg),
      respectively; whereas in CYP2A13, they are alanine (Ala) and histidine (His).
      Kinetic analysis revealed that the catalytic efficiency (Vmax/Km) of the CYP2A6
      Val(117)--> Ala and Arg(372)--> His mutants was drastically reduced (0.41 and
      0.64 versus 3.23 for the wild-type CYP2A6 protein). In contrast, the catalytic
      efficiency of the CYP2A13 Ala(117) --> Val and His(372) --> Arg mutants was
      greatly increased (2.65 and 2.60 versus 0.31 for wild-type CYP2A13 protein).
      These results clearly demonstrate that the Val at position 117 and Arg at
      position 372 are critical amino acid residues for coumarin 7-hydroxylation. Based
      on the crystal structure of CYP2C5, we have generated the homology models of
      CYP2A6 and CYP2A13 and docked the substrate coumarin to the active site. Together
      with the kinetic characterization, our structural modeling provides explanations
      for the amino acid substitution results and the insights of detailed enzyme
      substrate interactions.

PMID- 15196989
TI  - Formation of linear three-iron clusters in Aquifex aeolicus two-iron ferredoxins:
      effect of protein-unfolding speed.
AB  - The presence of a linear [3Fe-4S] cluster in a protein was first observed in beef
      heart aconitase. Here, we report the formation of linear [3Fe-4S] clusters upon
      guanidine hydrochloride (GuHCl)-induced unfolding of Aquifex aeolicus [2Fe-2S]
      ferredoxins (Fd) (AaeFd1, AaeFd4, and AaeFd5) at alkaline conditions (pH 10, 20
      degrees C). We find the mechanism of linear [3Fe-4S] cluster formation to depend
      critically on the speed of polypeptide unfolding. In similarity to seven-iron
      Fds, polypeptide unfolding determines the rate by which linear [3Fe-4S] clusters
      form in AaeFd4 and AaeFd5. In contrast, in a disulfide-lacking variant of AaeFd1,
      which unfolds faster than AaeFd4 and AaeFd5, the polypeptides unfold first and
      the majority of clusters decompose. Next, unfolded polypeptides retaining intact
      clusters scavenge iron and sulfur to form linear [3Fe-4S] clusters in a
      bimolecular reaction. Wild-type AaeFd1 unfolds slower than the speed of linear
      cluster decomposition, and the linear species is never populated. Linear [3Fe-4S]
      clusters may be intermediates during folding of iron-sulfur proteins.

PMID- 15196990
TI  - Polymorphisms in human soluble epoxide hydrolase: effects on enzyme activity,
      enzyme stability, and quaternary structure.
AB  - Human soluble epoxide hydrolase (hsEH) has been shown to play a role in
      regulating blood pressure and inflammation. HsEH consists of an N-terminal
      phosphatase and a C-terminal epoxide hydrolase domain. In the present study, we
      examined the effects of polymorphisms in the hsEH gene on phosphatase activity,
      enzyme stability, and protein quaternary structure. The results showed that
      mutants Lys55Arg, Arg103Cys, Cys154Tyr, Arg287Gln, and the Arg103Cys/Arg287Gln
      (double mutant) have significantly lower phosphatase activity compared to the
      most frequent allele (MFA) of hsEH. In addition, the Lys55Arg, Arg103Cys,
      Cys154Tyr, Arg287Gln, and the double mutant have significantly lower kcat/Km
      values. The stabilities at 37 degrees C of purified Arg287Gln and
      Arg103Cys/Arg287Gln mutants were also significantly reduced compared to the MFA.
      HPLC size-exclusion studies showed that the MFA exists predominantly as a dimer.
      However, the Arg287Gln and Arg103Cys/Arg287Gln mutants show increased
      concentration of the monomer. We conclude that the Arg287Gln polymorphism
      disrupts putative intra- and inter-monomeric salt-bridges responsible for
      dimerization.

PMID- 15196991
TI  - cDNA sequence, 5'-flanking region, and promoter activity of the Neotomodon
      alstoni alstoni Clara cell secretory protein gene.
AB  - To better understand the phylogenetic divergence and the species-specific
      characteristics of the Clara cell secretory protein (CCSP), we cloned the cDNA
      encoding the neotomodon CCSP (nCCSP) and analyzed its tissue-specific expression.
      The full-length cDNA is 451bp long and predicts an amino acid sequence of 93
      residues. Northern blot analysis from different neotomodon tissues demonstrated
      that the mRNA of CCSP appears to be solely expressed in the lung. To study the
      transcriptional regulation of the CCSP gene, we cloned the 5'-flanking region of
      the nCCSP gene and compared its features with those previously reported for the
      hamster gene. The neotomodon and hamster genes share 89% sequence homology in
      their promoter region as well as a number of conserved cis-acting elements.
      However, in H441 cells the expression of a reporter gene driven by the nCCSP
      promoter was about 4-fold greater than its hamster counterpart. Functional
      analysis of progressive 5'-deletion mutants identified a region involved in the
      higher transcriptional activity of the neotomodon promoter.

PMID- 15196992
TI  - Human neuronal nitric oxide synthase can catalyze one-electron reduction of
      adriamycin: role of flavin domain.
AB  - We have analyzed the mechanism of one-electron reduction of adriamycin (Adr)
      using recombinant full-length human neuronal nitric-oxide synthase and its flavin
      domains. Both enzymes catalyzed aerobic NADPH oxidation in the presence of Adr.
      Calcium/calmodulin (Ca(2+)/CaM) stimulated the NADPH oxidation of Adr. In the
      presence or absence of Ca(2+)/CaM, the flavin semiquinone radical species were
      major intermediates observed during the oxidation of the reduced enzyme by Adr.
      The FAD-NADPH binding domain did not significantly catalyze the reduction of Adr.
      Neither the FAD semiquinone (FADH*) nor the air-stable semiquinone (FAD-FMNH*)
      reacted rapidly with Adr. These data indicate that the fully reduced species of
      FMN (FMNH(2)) donates one electron to Adr, and that the rate of Adr reduction is
      stimulated by a rapid electron exchange between the two flavins in the presence
      of Ca(2+)/CaM. Based on these findings, we propose a role for the FAD-FMN pair in
      the one-electron reduction of Adr.

PMID- 15196993
TI  - Visualization of PLP-bound intermediates in hemeless variants of human
      cystathionine beta-synthase: evidence that lysine 119 is a general base.
AB  - Cystathionine beta-synthase catalyzes the condensation of serine and homocysteine
      to give cystathionine in a pyridoxal phosphate (PLP)-dependent reaction. The
      human enzyme contains a single heme per monomer that is bound in an N-terminal 69
      amino acid extension that is missing from the otherwise highly homologous yeast
      enzyme. The heme dominates the UV-visible spectrum and obscures kinetic
      characterization of the PLP-bound reaction intermediates. In this study, we have
      engineered a hemeless mutant of human cystathionine beta-synthase by deletion of
      the N-terminal 69 amino acids. The resulting variant displays approximately 40%
      of the activity seen with the wild type enzyme, binds stoichiometric amounts of
      PLP, and permits spectral characterization of PLP-based intermediates. The enzyme
      as isolated exhibits an absorption maximum at 412nm corresponding to a protonated
      internal aldimine. Addition of serine shifts the lambdamax to 420nm (assigned as
      the external aldimine) with a broad shoulder between 450 and 500nm (assigned as
      the aminoacrylate intermediate). Addition of the product, cystathionine, also
      leads to formation of an external aldimine (420nm). Homocysteine elicits a red
      shift (and a decrease in absorption) in the spectrum from 412 to 424nm and an
      increase in absorption at 330nm, presumably due to formation of a dead-end
      complex. Mutation of K119, the residue that forms the Schiff base, to alanine
      results in a approximately 10(3)-fold decrease in activity, which increases
      approximately 2-fold in the presence of an exogenous base, ethylamine. Spectral
      shifts (412 --> 420nm) consistent with the formation of external aldimines are
      observed in the presence of serine or cystathionine, but an aminoacrylate
      intermediate is not formed at detectable levels. These results are consistent
      with an additional role for K119 as a general base in the reaction catalyzed by
      human cystathionine beta-synthase.

PMID- 15196994
TI  - Age-dependent protein modifications and declining proteasome activity in the
      human lens.
AB  - The proteasome is known to be the main enzymatic complex responsible for the
      intracellular degradation of altered proteins, and the age-related accumulation
      of modified lens proteins is associated to the formation of cataracts. The aim of
      this study was to determine whether the human lens proteasome becomes
      functionally impaired with age. The soluble and insoluble protein fractions of
      human lenses corresponding to various age-groups were characterized in terms of
      their levels of glyco-oxidative damage and found to show increasing anti
      carboxymethyl-lysine immunoreactivity with age. Concomitantly, decreasing
      proteasome contents and peptidase activities were observed in the water-soluble
      fraction. The fact that peptidylglutamyl-peptide hydrolase activity is most
      severely affected with age suggests that specific changes are undergone by the
      proteasome itself. In particular, increasing levels of carboxymethylation were
      observed with age in the proteasome. It was concluded that the lower levels of
      soluble active enzymatic complex present in elderly lenses and the post
      translational modifications affecting the proteasome may at least partly explain
      the decrease in proteasome activity and the concomitant accumulation of
      carboxymethylated and ubiquitinated proteins which occur with age.

PMID- 15196995
TI  - Gangliosides modulate the activity of the plasma membrane Ca(2+)-ATPase from
      porcine brain synaptosomes.
AB  - We systematically examined the effects of gangliosides on the plasma membrane
      Ca(2+)-ATPase (PMCA) from porcine brain synaptosomes. Our results showed that
      GD1b (two sialic acid residues) stimulated the activity, GM1 (one sialic acid
      residue) slightly reduced the activity, while asialo-GM1 (no sialic acid residue)
      markedly inhibited it, suggesting that sialic acid residues of gangliosides are
      important in the modulation of the PMCA. We also examined the oligosaccharide
      effects by using GM1, GM2, and GM3 whose only difference was in the length of
      their oligosaccharide chain. GM1, GM2, and GM3 reduced the enzyme activities,
      whereas GM2 and GM3 were potent inhibitors. Gangliosides affect both affinity for
      Ca(2+) and the Vmax of enzyme. It was observed that GD1b and GM2 increased the
      affinity of the enzyme for Ca(2+). GD1b, GM2 affected the Vmax with an increase
      of GD1b, but decreases of GM2. The study of the affinity for ATP and the Vmax of
      enzyme in the presence of gangliosides showed that GD1b and GM2 had little effect
      on the ATP binding to the enzyme, but the Vmax was apparently changed. Moreover,
      the effects of gangliosides are additive to that of calmodulin, suggesting that
      the modulation of PMCA by gangliosides should be through a different mechanism.
      The conformational changes induced by gangliosides were probed by fluorescence
      quenching. We found that fluorescent quenchers (I(-) and Cs(+)) with opposite
      charges had different accessibility to the IAEDANS binding to the PMCA in the
      presence of gangliosides. An apparent red shift (25nm) with increased maximum of
      fluorescence spectrum was also observed in the presence of GD1b.

PMID- 15196996
TI  - Allergic contact dermatitis in children: strategies of prevention and risk
      management.
AB  - Over recent years, allergic contact dermatitis in children has repeatedly been
      reported as a significant clinical problem. It is generally accepted that
      allergic contact dermatitis is rare in the first years of life, and with
      increasing age (by the age of 10 years) reaches the incidence seen in adults. As
      in adults, metals are one of the most common sensitizers in children, along with
      rubber chemicals and fragrances. The influence of fashion trends and lifestyle
      such as piercing, decorative skin paintings, the hype of natural remedies and
      cosmetics (e.g. tea tree oil) or the use of cosmetical products with fragrances
      or herbal ingredients play an important role in developing allergic contact
      dermatitis. This review aims to give an overview on allergic contact dermatitis
      in childhood by focussing on strategies for prevention, potential risk factors
      and recommendations for parents as well as for physicians. By reporting typical
      cases of our outpatients clinic we point out several characteristics of allergic
      contact dermatitis. Prevention of allergic contact dermatitis in children is a
      current problem of interdisciplinary concern not only for dermatologists and
      paediatricians, but also for midwives. Frequently, children are already exposed
      at an early age to well-known allergens, and therefore, strategies of avoidance
      have to gain or regain importance and should start as early as possible.

PMID- 15196997
TI  - Autoimmune diseases and vaccinations.
AB  - The potential association between vaccination and autoimmune diseases has been
      largely questioned in the past few years, but this assumption has mostly been
      based on case reports. The available evidence derived from several negative
      epidemiological studies is reassuring and at least indicates that vaccines are
      not a major cause of autoimmune diseases. However, there are still uncertainties
      as to whether a susceptible subpopulation may be at a higher risk of developing
      an autoimmune disease without causing an overall increase in the disease
      incidence. Based on selected examples, this review highlights the difficulties in
      assessing this issue. We suggest that a potential link between vaccines and
      autoimmune diseases cannot be definitely ruled out and should be carefully
      explored during the development of new candidate vaccines.

PMID- 15196998
TI  - Ultrastructural alteration of tape-stripped normal human skin after photodynamic
      therapy.
AB  - The effect of photodynamic therapy on tape-stripped normal human skin was
      explored ultrastructurally. Back skin areas of 3 healthy Caucasian volunteers, 2
      men and 1 woman, were tape-stripped 10 consecutive times followed by topical
      treatment with 5-aminolevulinic acid (20%, w/w) for 4 hours under occlusion
      (Tegaderm). Then the areas were irradiated for 30 minutes with Waldman PDT 1200
      lamp (570-650 nm) with a total dose of 70 J/cm(2). Full-thickness punch biopsies
      were taken immediately after irradiation, and at 3 and 24 hours for electron
      microscopy examination. Photodynamic therapy caused morphological alterations
      mainly in the epidermis. Keratinocytes became oedematous and tonofilament bundles
      were split, but desmosomes remained normal. Many keratinocytes contained large
      intracellular vacuoles and extremely electronlucent cytoplasm implying cell
      damage. Although the majority of Langerhans cells were unaffected isolated
      Langerhans cells became apoptotic at 3 hours. The melanocytes preserved their
      normal morphology. The epidermal alterations recovered 24 hours after the
      irradiation. Inflammatory cell infiltrates were evident at 3 and 24 hours but no
      other dermal changes were observed. In conclusion, photodynamic therapy with 5
      aminolevulinic acid affects mainly keratinocytes and can trigger apoptosis in
      Langerhans cells while melanocytes appear refractory, at least morphologically,
      to photodynamic therapy.

PMID- 15196999
TI  - Induction of the differentiation and apoptosis of tumor cells in vivo with
      efficiency and selectivity.
AB  - Hedgehog/smoothened signaling is active in a variety of tumors and is also
      involved in the maintenance of normal stem cells in vivo. We evaluated the
      possibility of preferential affection of tumor versus normal cells following
      inhibition of this signaling. We applied a cream preparation of cyclopamine (an
      inhibitor of the hedgehog/smoothened signaling) onto skin tumors in patients who
      were scheduled for the excision of these tumors (four basal cell carcinomas and a
      trichoepithelioma in four unrelated patients). All of the cyclopamine-treated
      tumors regressed rapidly. Histological and immunohistochemical analyses showed
      inhibition of the proliferation and highly efficient induction of the
      differentiation and apoptosis of tumor cells by a non-genotoxic mechanism. No
      adverse effects were noted and normal skin tissue and putative stem cells that
      were exposed to cyclopamine together with tumors were well preserved under the
      conditions we describe. Our findings show selective and highly efficient
      induction of the differentiation and apoptosis of tumor cells in vivo by
      transient inhibition of the hedgehog/ smoothened signaling and provide a rational
      cancer therapy.

PMID- 15197000
TI  - Treatment of molluscum contagiosum with 585 nm collagen remodeling pulsed dye
      laser.
AB  - The inevitable regression of molluscum contagiosum (MC) has been the major
      argument in favor of leaving the lesions to spontaneous involution. But the
      infection is often widespread and recurrent. Conventional therapies are
      frequently ineffective and require multiple visits. Flashlamp-pumped pulsed dye
      laser is now recommended in the therapy of MC in case reports. There is no
      evaluation of a pulsed dye laser collagen remodeling (wavelength of 585 nm) as a
      possible therapeutic alternative. We treated 76 patients with cutaneous MC with 1
      to 176 MC (mean 27 MC) in a prospective study from April 2002 to September 2002
      (over a period of six months). The female/male sex ratio was of 1.2:1 (42 girls,
      and 34 boys). Patients were aged from 1 to 15 years, with a mean of 4.9 years. We
      used 585 nm collagen remodeling, double flashlamp excited pumped dye laser ED2000
      (manufactured by Deka(c) MELA Calenzano, Italy), spot size 5 mm, energy density
      (fluence J/cm(2)) from 2 to 4 J/cm(2), emission modality (repetition rate) at 0.5
      Hz, with a short pulse duration of 250 microsec in all cases. The therapy was
      well tolerated. No scars or pigment anomalies were observed. 96.3% of the lesions
      healed after the first treatment, the remaining 3.7% after the second (two weeks
      later). Laser photocoagulation causes selective damage to abnormal vessels and
      surrounding connective tissue. The heating effect in these skin layers triggers
      the release of various growth factors that stimulate collagen remodeling and
      tightening. It appears to be a cell-mediated reaction, which brings about an
      elevation in the T lymphocytes, capable of affecting pox viridae. Dye laser
      photocoagulation however, cannot protect against relapse. Hyperpigmentation may
      occur at nearly all sites, however this fades after 1 to 6 months. The pulsed dye
      laser for collagen remodeling is an effective, bloodless, quick, and easy
      therapeutic alternative for MC. The advantage of using a collagen remodeling
      pumped dye laser is the absence of pain, because of the short pulse duration
      (half that of a normal pulsed dye laser), and the use of low fluence (less than 4
      J/cm(2)). It enables the treatment of young patients with a large number of
      lesions, which is impossible with a normal pulsed dye laser. There are no side
      effects.

PMID- 15197001
TI  - Validation of a comprehensive Freiburg Life Quality Assessment (FLQA) core
      questionnaire and development of a threshold system.
AB  - Health related quality of life (HRQOL) has become an important re- search topic
      in dermatology. We developed a series of modular, dermatology-specific HRQOL
      questionnaires: the Freiburg Life Quality Assessment (FLQA). Each FLQA
      questionnaire consists of a core module (FLQA-c) applicable to all skin diseases
      plus a number of items specific to distinct dermatological diseases. The
      objectives of the present study were: 1) to test the psychometric properties of
      the FLQA-c, and 2) to define a threshold indicating a significantly reduced
      HRQOL. 394 psoriasis patients, 253 atopic dermatitis patients, and 240 control
      subjects completed the FLQA-c. Cronbach's alphas were above 0.75 for all six
      scales except for "treatment". Discriminant validity, sensitivity to change, and
      convergent validity were satisfactory. On the different scales, the threshold
      indicating a marked reduction in HRQOL detected 33% to 68% of the patients. These
      data support the reliability and validity of the FLQA-c.

PMID- 15197002
TI  - Successful treatment of Netherton's syndrome with topical calcipotriol.
AB  - We present a case of a 9-year-old boy with Netherton syndrome (NS) and skin
      manifestation of ichthyosis linearis circumflexa (ILC) who was successfully
      treated with topical 0.05% calcipotriol ointment bid. It was applied every fourth
      day on the same body area, which measured from 18% to 27% of the total body
      surface. Significant improvement of erythema and scaling was noted two weeks
      after the beginning of the treatment, with nearly total remission one week later,
      when the treatment was suspended. Remission lasted three to four weeks, when a
      few lesions of ILC appeared on his trunk and limbs and the treatment began again.
      The patient responded well each time he was treated. No adverse effects,
      suggestive of hypercalcemia or nephrocalcinosis, were noted during the treatment
      period which lasted for nine months. To evaluate calcipotriol's long-term
      efficacy and safety it should be tested on a larger group of patients with NS.

PMID- 15197003
TI  - Plexiform fibrohistiocytic tumor.
AB  - We report the case of a 6-year-old Japanese boy with a plexiform fibrohistiocytic
      tumor on the right perioral region. Clinically, the tumor, 5 mm in diameter, was
      a solitary, hard, erythematous, slowly growing, painless nodule. There was no
      preceding trauma. Histology revealed a well-circumscribed plexiform lesion with a
      biphasic appearance. Immuno-histochemistry demonstrated CD68 positivity in many
      of mononuclear macrophages. The lesion was negative for S-100 protein, lysozyme,
      CD57 and factor XIIIa. Interestingly, the tumor showed an intradermal location
      from superficial to deep dermis, and lacked osteoclast-like giant cells. During
      the follow-up for 9 months after the resection, there was no recurrence or
      metastasis.

PMID- 15197004
TI  - Facial demodicosis.
AB  - A 24-year-old man presented with papulopustular, rosacea-like centro- facial
      lesions. Many Demodex mites were found in the affected area by microscopy of
      smears from pustules. This observation provides further evidence that demodicosis
      is a condition distinct from common rosacea. Considering clinical similarities of
      demodicosis, rosacea and some mycotic infections, direct examination to confirm
      the etiological agent is highly recommended prior to treatment.

PMID- 15197005
TI  - Dermatomyositis with tuberculous fasciitis.
AB  - A case of dermatomyositis with tuberculous fasciitis is described. A 69-year-old
      Japanese man treated with prednisolone for dermatomyositis developed erythema and
      bilateral swelling of arms and forearms. A diagnosis of tuberculous fasciitis was
      confirmed by the presence of acid-fast bacilli in a biopsy specimen and the
      growth of Mycobacterium tuberculosis from tissue cultures. The unusual presenting
      clinical features resulted in delayed diagnosis. We emphasize that tuberculous
      fasciitis should be considered in an immunocompromised patient who is treated
      with steroids, especially if the results of initial treatment are not
      satisfactory.

PMID- 15197006
TI  - Nonselective cation transport in native esophageal epithelia.
AB  - Rabbit esophageal epithelia actively transport Na(+) in a manner similar to that
      observed in classic electrically tight Na(+)-absorbing epithelia, such as frog
      skin. However, the nature of the apical entry step is poorly understood. To
      address this issue, we examined the electrophysiological and biochemical nature
      of this channel. Western blotting experiments with epithelial Na(+) channel
      (ENaC) subunit-specific antibodies revealed the presence of all three ENaC
      subunits in both native and immortalized esophageal epithelial cells. The amino
      acid sequence of the rabbit alpha-ENaC cloned from native rabbit esophageal
      epithelia was not significantly different from that of other published alpha-ENaC
      homologs. To characterize the electrophysiological properties of this native
      apical channel, we utilized nystatin permeabilization to eliminate the electrical
      contribution of the basolateral membrane in isolated native epithelia mounted in
      Ussing-type chambers. We find that the previously described apical Na(+) channel
      is nonselective for monovalent cations (Li(+), Na(+), and K(+)). Moreover, this
      channel was not blocked by millimolar concentrations of amiloride. These findings
      document the presence of a nonselective cation channel in a native Na(+)
      transporting epithelia, a finding that hereto has been thought to be limited to
      artificial culture conditions. Moreover, our data are consistent with a potential
      role of ENaC subunits in the formation of a native nonselective cation channel.

PMID- 15197008
TI  - Combined modality therapy of esophageal cancer: changes in the standard of care?

PMID- 15197007
TI  - 5-lipoxygenase and cyclooxygenase regulate wound closure in NIH/3T3 fibroblast
      monolayers.
AB  - Wound healing involves multiple cell signaling pathways, including those
      regulating cell-extracellular matrix adhesion. Previous work demonstrated that
      arachidonate oxidation to leukotriene B(4) (LTB(4)) by 5-lipoxygenase (5-LOX)
      signals fibroblast spreading on fibronectin, whereas cyclooxygenase-2 (COX-2)
      catalyzed prostaglandin E(2) (PGE(2)) formation facilitates subsequent cell
      migration. We investigated arachidonate metabolite signaling in wound closure of
      perturbed NIH/3T3 fibroblast monolayers. We found that during initial stages of
      wound closure (0-120 min), all wound margin cells spread into the wound gap
      perpendicularly to the wound long axis. At regular intervals, between 120 and 300
      min, some cells elongated to project across the wound and meet cells from the
      opposite margin, forming distinct cell bridges spanning the wound that act as
      foci for later wound-directed cell migration and resulting closure. 5-LOX
      inhibition by AA861 demonstrated a required LTB(4) signal for initial marginal
      cell spreading and bridge formation, both of which must precede wound-directed
      cell migration. 5-LOX inhibition effects were reversible by exogenous LTB(4).
      Conversely, COX inhibition by indomethacin reduced directed migration into the
      wound but enhanced early cell spreading and bridge formation. Exogenous PGE(2)
      reversed this effect and increased cell migration into the wound. The
      differential effects of arachidonic acid metabolites produced by LOX and COX were
      further confirmed with NIH/3T3 fibroblast cell lines constitutively over- and
      underexpressing the 5-LOX and COX-2 enzymes. These data suggest that two
      competing oxidative enzymes in arachidonate metabolism, LOX and COX,
      differentially regulate sequential aspects of fibroblast wound closure in vitro.

PMID- 15197009
TI  - Tumor markers for pancreatic cancer: what happens when preoperative CA 19-9 is
      undetectable?

PMID- 15197010
TI  - Secondary cytoreductive surgery for isolated nodal recurrence of ovarian cancer.

PMID- 15197011
TI  - Sentinel node biopsy in head and neck cancer: preliminary results of a
      multicenter trial.
AB  - BACKGROUND: The aim was to determine the reliability and reproducibility of
      sentinel node biopsy (SNB) as a staging tool in head and neck squamous cell
      carcinoma (HNSCC) for T1/2 clinically N0 patients by means of a standardized
      technique. METHODS: Between June 1998 and June 2002, 227 SNB procedures have been
      performed in HNSCC cases at six centers. One hundred thirty-four T1/2 tumors of
      the oral cavity/oropharynx in clinically N0 patients were investigated with
      preoperative lymphoscintigraphy (LSG), intraoperative use of blue dye/gamma
      probe, and pathological evaluation with step serial sectioning and
      immunohistochemistry, with a follow-up of at least 12 months. In 79 cases SNB
      alone was used to stage the neck carcinoma, and in 55 cases SNB was used in
      combination with an elective neck dissection (END). RESULTS: In 125/134 cases
      (93%) a sentinel node was identified. Of 59 positive nodes, 57 were identified
      with the intraoperative gamma probe and 44 with blue dye. Upstaging of disease
      occurred in 42/125 cases (34%): with hematoxylin-eosin in 32/125 (26%) and with
      additional pathological staging in 10/93 (11%). The sensitivity of the technique
      with a mean follow-up of 24 months was 42/45 (93%). The identification of SNB for
      floor of mouth (FOM) tumors was 37/43 (86%), compared with 88/91 (97%) for other
      tumors. The sensitivity for FOM tumors was 12/15 (80%), compared with 30/30
      (100%) for other tumor groups. CONCLUSION: SNB can be successfully applied to
      early T1/2 tumors of the oral cavity/oropharynx in a standardized fashion by
      centers worldwide. For the majority of these tumors the SNB technique can be used
      alone as a staging tool.

PMID- 15197012
TI  - Controversies in the multimodality management of locally advanced esophageal
      cancer: evidence-based review of surgery alone and combined-modality therapy.
AB  - Most patients with esophageal cancer present with locoregional disease, and the
      optimal initial management is controversial. The current National Comprehensive
      Cancer Network (NCCN) practice guidelines support diverse treatment options for
      locoregional disease, including surgical resection alone, definitive
      chemoradiation therapy, and preoperative combined-modality
      (neoadjuvant/trimodality) therapy. Many cancer centers worldwide favor a
      neoadjuvant approach, although the evidence supporting this practice is
      inconsistent. A concise review of the literature is presented. The topics
      discussed do not necessarily reflect each author's opinions or clinical
      practices.

PMID- 15197013
TI  - Outcomes after combined therapy including surgical resection in patients with
      epithelial ovarian cancer recurrence(s) exclusively in lymph nodes.
AB  - BACKGROUND: The aim was to study the prognosis for and survival of patients
      treated with combined therapy (including surgical resection) for nodal
      recurrences from epithelial ovarian cancer (EOC). METHODS: This was a
      retrospective study of a group of 12 patients with a recurrence from EOC, a
      priori, exclusively located in lymph node(s). All patients underwent surgical
      resection of nodal metastases, followed by adjuvant therapy. RESULTS: The median
      age of patients was 51 (range, 42-71) years. The initial disease stages were as
      follows: stage IA, n = 5; stage IIA, n = 1; and stage IIIC, n = 6. The median
      interval between the end of initial treatment and the nodal relapse was 21
      (range, 6-72) months. The recurrence was located in the abdominal nodes in 10
      patients (pelvic and/or para-aortic area) and was extra-pelvic in one patient,
      and the last patient had concomitant para-aortic and supraclavicular nodal
      involvement. Ten patients received postoperative chemotherapy and two had
      radiation therapy (one patient received both treatments). Eight patients relapsed
      and four did not. To date, three patients have died of the disease, three are
      alive with persistent disease, and six are alive and disease-free (including two
      patients who were treated by surgical resection after relapses twice in abdominal
      nodes). Five-year overall survival from the time of treatment of recurrent
      disease is 71% (confidence interval, 41%-90%). CONCLUSIONS: The prognosis of
      patients with an a priori isolated nodal recurrence from EOC was good in this
      group of treated with surgical resection followed by chemoradiation or radiation
      therapy. This finding argues in favor of proposing surgical resection in such
      patients.

PMID- 15197014
TI  - Undetectable preoperative levels of serum CA 19-9 correlate with improved
      survival for patients with resectable pancreatic adenocarcinoma.
AB  - BACKGROUND: Serum levels of CA19-9 have been shown to correlate with both
      recurrence and survival in patients with pancreatic cancer. However, little is
      known about the prognosis for patients with undetectable levels of serum CA19-9.
      METHODS: One hundred twenty-nine patients with pancreatic cancer who underwent
      preoperative assessment of serum CA19-9 followed by resection with curative
      intent between 1990 and 2002 were retrospectively analyzed. Data collected
      included preoperative serum CA19-9 level (U/mL), age, pathologic staging, and
      survival. Data were analyzed with the SAS system according to four distinct
      preoperative serum CA19-9 levels: undetectable, normal (<37), 38-200, and >200
      U/mL. RESULTS: Serum CA19-9 levels ranged from undetectable to 16,300 U/mL. Stage
      III/IV disease accounted for 86%, 67%, 59%, and 53% of patients in the four CA19
      9 groups. The overall median and 5-year survivals were 19 months and 11%,
      respectively. Survival was similar between nonsecretors and those with normal CA
      19-9 levels. However, both groups had statistically significant prolonged
      survival compared with the two groups with elevated CA 19-9 levels (P =.003). The
      only factors that were significant on univariate and multivariate analysis for
      overall survival were lymph node positivity (P =.015 and.002) and CA 19-9
      grouping (P =.003 and P <.0001). Although this group of patients presented with
      predominately advanced-stage disease, their overall survival was superior.
      CONCLUSIONS: These findings suggest that patients who present with undetectable
      preoperative CA19-9 levels and potentially resectable pancreatic cancer,
      regardless of advanced stage, should be considered candidates for aggressive
      therapy.

PMID- 15197015
TI  - Withholding anticoagulation after a negative result on duplex ultrasonography for
      suspected symptomatic deep venous thrombosis.
AB  - BACKGROUND: Negative results on simplified compression ultrasonography cannot
      rule out symptomatic deep venous thrombosis (DVT) without further testing, such
      as repeated ultrasonography several days later. Repeated testing is costly and
      inconvenient, and patients are sometimes less likely to return for follow-up
      tests. OBJECTIVE: To determine the rate of venous thromboembolism when
      anticoagulation is withheld in patients with symptoms of DVT of the leg after
      negative results on a single examination with comprehensive duplex
      ultrasonography. DESIGN: Prospective clinical cohort study. SETTING: Peripheral
      vascular laboratory of a tertiary care academic hospital. PATIENTS: 445
      consecutive patients in whom a first episode of symptomatic DVT was suspected.
      INTERVENTION: The researchers examined the entire leg with comprehensive duplex
      ultrasonography, using compression and Doppler techniques. Anticoagulation was
      withheld from the group with negative results. Patients were observed for
      thromboembolic events for 3 months. MEASUREMENTS: All patients who had new or
      progressive symptoms or signs of venous thromboembolism during follow-up
      underwent objective testing. RESULTS: Comprehensive duplex ultrasonography
      yielded normal results in 384 patients (86.3%) and showed DVT in 61 patients
      (13.7%). Nineteen cases of DVT (31.1%) were isolated to the deep veins of the
      calf. Nine patients in the negative cohort (2.3%) were excluded from analysis
      because they received anticoagulation for reasons unrelated to venous
      thromboembolism. Three of 375 patients (0.80% [95% CI, 0.16% to 2.33%]) in the
      normal cohort had symptomatic venous thrombosis during the 3-month follow-up. All
      384 patients in the negative cohort completed follow-up. LIMITATIONS: The study
      was conducted at a single tertiary care center by a peripheral vascular staff
      with substantial experience in duplex ultrasonography, which may limit the
      applicability of the results to other institutions. Pregnant patients were
      excluded. CONCLUSIONS: It is safe to withhold anticoagulation after negative
      results on comprehensive duplex ultrasonography in nonpregnant patients with a
      suspected first episode of symptomatic DVT of the leg. New or progressive
      symptoms should prompt further testing.

PMID- 15197016
TI  - Visceral adiposity is an independent predictor of incident hypertension in
      Japanese Americans.
AB  - BACKGROUND: Visceral adiposity is generally considered to play a key role in the
      metabolic syndrome. OBJECTIVE: To examine the relationship between directly
      measured visceral adiposity and the risk for incident hypertension, independent
      of other adipose depots and fasting plasma insulin levels. DESIGN: Community
      based prospective cohort study with 10- to 11-year follow-up. SETTING: King
      County, Washington. PARTICIPANTS: 300 Japanese Americans with a systolic blood
      pressure less than 140 mm Hg and a diastolic blood pressure less than 90 mm Hg
      who were not taking antihypertensive medications, oral hypoglycemic medications,
      or insulin at study entry. MEASUREMENTS: Abdominal, thoracic, and thigh fat areas
      were measured by using computed tomography. Total subcutaneous fat area was
      calculated as the sum of these fat areas excluding the intra-abdominal fat area.
      Hypertension during follow-up was defined as having a systolic blood pressure of
      140 mm Hg or greater, having a diastolic blood pressure of 90 mm Hg or greater,
      or taking antihypertensive medications. RESULTS: There were 92 incident cases of
      hypertension during the follow-up period. The intra-abdominal fat area was
      associated with an increased risk for hypertension. Multiple-adjusted odds ratios
      of hypertension for quartiles of intra-abdominal fat area (1 = lowest; 4 =
      highest) were 5.07 (95% CI, 1.75 to 14.73) for quartile 3 and 3.48 (CI, 1.01 to
      11.99) for quartile 4 compared with quartile 1 after adjustment for age, sex,
      fasting plasma insulin level, 2-hour plasma glucose level, body mass index,
      systolic blood pressure, alcohol consumption, smoking status, and energy
      expenditure through exercise (P = 0.003 for quadratic trend). The intra-abdominal
      fat area remained a significant risk factor for hypertension, even after
      adjustment for total subcutaneous fat area, abdominal subcutaneous fat area, or
      waist circumference; however, no measure of these fat areas was associated with
      risk for hypertension in models that contained the intra-abdominal fat area.
      LIMITATIONS: It is not known whether these results pertain to other ethnic
      groups. CONCLUSIONS: Greater visceral adiposity increases the risk for
      hypertension in Japanese Americans.

PMID- 15197017
TI  - Drug provocation tests in patients with a history suggesting an immediate drug
      hypersensitivity reaction.
AB  - BACKGROUND: Drug hypersensitivity reactions are common and can be life
      threatening. Confirmation of the diagnosis should be rigorous and based on
      clinical history and a physical examination, possibly followed by skin tests and
      drug provocation tests. OBJECTIVE: To describe the outcome of drug provocation
      tests in evaluating patients with histories suggesting drug allergy. DESIGN:
      Retrospective analysis of clinic case series. SETTING: The department for drug
      allergy at a university hospital. PATIENTS: 898 consecutive patients with
      suspected immediate drug allergy referred to the clinic between September 1996
      and August 2001. Patients with severe skin reactions and those with positive
      results on skin tests for beta-lactams were excluded. INTERVENTION: Single
      blinded administration of increasing doses of the suspected drug, up to the usual
      daily dose, under strict hospital surveillance. RESULTS: 1372 drug provocation
      tests were performed using various drugs, including beta-lactams (30.3%), aspirin
      (14.5%), other nonsteroidal anti-inflammatory drugs (11.7%), paracetamol (8.9%),
      macrolides (7.4%), and quinolones (2.4%). There were 241 (17.6%) positive drug
      provocation test results. Drug provocation reproduced the same symptoms, albeit
      milder and of a shorter duration, in the following patients: 13 (5.4%) with a
      history of anaphylactic shock, 17 (7.0%) with a history of anaphylaxis without
      shock, 10 (4.1%) with a history of laryngeal edema, 19 (7.9%) with a history of
      bronchospasm, 160 (66.4%) with a history of urticaria, and 22 (9.1%) with a
      history of maculopapular eruption. All adverse reactions were completely reversed
      by prednisolone, H(1)-antihistamines, and epinephrine as needed. LIMITATIONS:
      Falsely negative results on drug provocation tests may have occurred because of
      loss of sensitization, rare cofactors not included in the diagnostic procedure,
      and tolerance induction during provocation. CONCLUSIONS: Drug provocation tests
      in individuals with suspected drug allergy performed in carefully controlled
      settings can confirm drug hypersensitivity.

PMID- 15197018
TI  - Effects of aerobic physical exercise on inflammation and atherosclerosis in men:
      the DNASCO Study: a six-year randomized, controlled trial.
AB  - BACKGROUND: Although regular physical activity is recommended for prevention of
      cardiovascular diseases, no data are available on its antiatherosclerotic effects
      in the general population. OBJECTIVE: To determine whether progressive aerobic
      exercise compared with usual activity slows progression of atherosclerosis in
      men. DESIGN: A 6-year randomized, controlled trial. SETTING: Eastern Finland.
      PARTICIPANTS: 140 middle-aged men randomly selected from the population registry.
      INTERVENTION: Low- to moderate-intensity aerobic exercise. MEASUREMENTS:
      Atherosclerosis was quantitated ultrasonographically as the mean intima-media
      thickness in the carotid artery at baseline and at years 2 through 6. RESULTS: On
      the basis of intention-to-treat analyses, a 19.5% net increase (P < 0.001) in
      ventilatory aerobic threshold was evident in the exercise group after 6 years.
      High-sensitivity C-reactive protein levels were statistically nonsignificantly
      lower in the exercise group than in the control group (P > 0.2). The progression
      of intima-media thickness in the carotid artery did not differ between the study
      groups (P > 0.2). A subgroup analysis that excluded men taking statins showed
      that the 6-year progression of intima-media thickness, adjusted for smoking and
      annual measures of low-density lipoprotein cholesterol level, systolic blood
      pressure, and waist circumference, was 40% less in the exercise group (0.12 mm
      [95% CI, -0.010 to 0.26 mm]) than in the control group (0.20 mm [CI, 0.05 to 0.35
      mm]). LIMITATIONS: Only middle-aged white men were included. The intervention
      included mainly aerobic exercises. CONCLUSIONS: Aerobic physical exercise did not
      attenuate progression of atherosclerosis, except in a subgroup of men not taking
      statins.

PMID- 15197019
TI  - The effectiveness of depression care management on diabetes-related outcomes in
      older patients.
AB  - BACKGROUND: Depression frequently occurs in combination with diabetes mellitus,
      adversely affecting the course of illness. OBJECTIVE: To determine whether
      enhancing care for depression improves affective and diabetic outcomes in older
      adults with diabetes and depression. DESIGN: Preplanned subgroup analysis of the
      Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) randomized,
      controlled trial. SETTING: 18 primary care clinics from 8 health care
      organizations in 5 states. PATIENTS: 1801 patients 60 years of age or older with
      depression; 417 had coexisting diabetes mellitus. INTERVENTION: A care manager
      offered education, problem-solving treatment, or support for antidepressant
      management by the patient's primary care physician; diabetes care was not
      specifically enhanced. MEASUREMENTS: Assessments at baseline and at 3, 6, and 12
      months for depression, functional impairment, and diabetes self-care behaviors.
      Hemoglobin A(1c) levels were obtained for 293 patients at baseline and at 6 and
      12 months. RESULTS: At 12 months, diabetic patients who were assigned to
      intervention had less severe depression (range, 0 to 4 on a checklist of 20
      depression items; between-group difference, -0.43 [95% CI, -0.57 to -0.29]; P <
      0.001) and greater improvement in overall functioning (range, 0 [none] to 10
      [unable to perform activities]; between-group difference, -0.89 [CI, -1.46 to 
      0.32]) than did participants who received usual care. In the intervention group,
      weekly exercise days increased (between-group difference, 0.50 day [CI, 0.12 to
      0.89 day]; P = 0.001); other self-care behaviors were not affected. At baseline,
      mean (+/-SD) hemoglobin A1c levels were 7.28% +/- 1.43%; follow-up values were
      unaffected by the intervention (P > 0.2). LIMITATIONS: Because patients had good
      glycemic control at baseline, power to detect small but clinically important
      improvements in glycemic control was limited. CONCLUSIONS: Collaborative care
      improves affective and functional status in older patients with depression and
      diabetes; however, among patients with good glycemic control, such care minimally
      affects diabetes-specific outcomes.

PMID- 15197020
TI  - Acute decompensation after removing a central line: practical approaches to
      increasing safety in the intensive care unit.
AB  - Intensive care is one of the largest, most expensive, and complex components of
      U.S. health care. Errors and the resulting adverse events are, however, common in
      intensive care units (ICUs). Theories about errors in high-risk environments,
      developed by aviation and other industries, provide insight into why ICUs are
      prone to errors. Complex systems--of which ICUs are certainly an example--are
      breeding grounds for errors because interdependent components interact in
      unexpected ways. To achieve favorable outcomes, ICUs require that many processes
      occur in sequence. For example, patients are cared for by many providers with
      varying levels of expertise across several disciplines, and these providers use
      highly sensitive and potentially dangerous technologies and medications. Such
      complex systems require careful planning, excellent teamwork and communication,
      and designed redundancies to recheck for proper care processes. This paper
      provides a practical framework for improving patient safety.

PMID- 15197021
TI  - Resident redux.

PMID- 15197022
TI  - Medical management of the acute radiation syndrome: recommendations of the
      Strategic National Stockpile Radiation Working Group.
AB  - Physicians, hospitals, and other health care facilities will assume the
      responsibility for aiding individuals injured by a terrorist act involving
      radioactive material. Scenarios have been developed for such acts that include a
      range of exposures resulting in few to many casualties. This consensus document
      was developed by the Strategic National Stockpile Radiation Working Group to
      provide a framework for physicians in internal medicine and the medical
      subspecialties to evaluate and manage large-scale radiation injuries. Individual
      radiation dose is assessed by determining the time to onset and severity of
      nausea and vomiting, decline in absolute lymphocyte count over several hours or
      days after exposure, and appearance of chromosome aberrations (including
      dicentrics and ring forms) in peripheral blood lymphocytes. Documentation of
      clinical signs and symptoms (affecting the hematopoietic, gastrointestinal,
      cerebrovascular, and cutaneous systems) over time is essential for triage of
      victims, selection of therapy, and assignment of prognosis. Recommendations based
      on radiation dose and physiologic response are made for treatment of the
      hematopoietic syndrome. Therapy includes treatment with hematopoietic cytokines;
      blood transfusion; and, in selected cases, stem-cell transplantation. Additional
      medical management based on the evolution of clinical signs and symptoms includes
      the use of antimicrobial agents (quinolones, antiviral therapy, and antifungal
      agents), antiemetic agents, and analgesic agents. Because of the strong
      psychological impact of a possible radiation exposure, psychosocial support will
      be required for those exposed, regardless of the dose, as well as for family and
      friends. Treatment of pregnant women must account for risk to the fetus. For
      terrorist or accidental events involving exposure to radioiodines, prophylaxis
      against malignant disease of the thyroid is also recommended, particularly for
      children and adolescents.

PMID- 15197023
TI  - One-time comprehensive ultrasonography to diagnose deep venous thrombosis: is
      that the solution?

PMID- 15197024
TI  - Can treating depression improve disease outcomes?

PMID- 15197025
TI  - A foreign concept.

PMID- 15197026
TI  - Tolerability of rofecoxib versus naproxen.

PMID- 15197027
TI  - Tolerability of rofecoxib versus naproxen.

PMID- 15197028
TI  - Tolerability of rofecoxib versus naproxen.

PMID- 15197029
TI  - Coping with SARS.

PMID- 15197030
TI  - Improving geriatrics training.

PMID- 15197031
TI  - Hospital procedure volume and outcomes.

PMID- 15197032
TI  - Isolated gastric varices occurring 5 years after chemotherapy for splenic
      lymphoma.

PMID- 15197033
TI  - Summaries for patients. Reliability and safety of managing patients with
      suspected blood clots in the legs using comprehensive duplex ultrasonography.

PMID- 15197034
TI  - Summaries for patients. Fat content inside the abdomen helps predict whether
      Japanese Americans develop hypertension.

PMID- 15197035
TI  - Summaries for patients. Tests to confirm drug allergy in patients with a history
      of possible immediate allergic reactions to drugs.

PMID- 15197036
TI  - Summaries for patients. Does aerobic exercise slow progression of
      atherosclerosis?

PMID- 15197037
TI  - Summaries for patients. Depression care management for older adults with both
      depression and diabetes.

PMID- 15197038
TI  - Summaries for patients. Medical management of the acute radiation syndrome:
      recommendations of the Strategic National Stockpile Radiation Working Group.

PMID- 15197039
TI  - Gamma-hydroxybutyrate use in older adults.

PMID- 15197040
TI  - Opportunities of life: preventing suicide in elderly patients.

PMID- 15197041
TI  - Defending the practice of medicine.

PMID- 15197042
TI  - Medical illness and the risk of suicide in the elderly.
AB  - BACKGROUND: Suicide is a leading cause of death, and rates are especially high
      among the elderly. Medical illnesses may predispose to suicide, but few
      controlled studies have examined the association between specific diseases and
      suicide. We explored the relationship between treatment for several illnesses and
      the risk of suicide in elderly patients using a population-based approach.
      METHODS: All Ontario residents 66 years or older who committed suicide between
      January 1, 1992, and December 31, 2000, were identified from provincial coroners'
      records. Their prescription records during the preceding 6 months were compared
      with those of living matched controls (1:4) to determine the presence or absence
      of 17 illnesses potentially associated with suicide. RESULTS: During the 9-year
      study period, we identified 1354 elderly patients who died of suicide. The most
      common mechanisms involved firearms (28%), hanging (24%), and self-poisoning
      (21%). Specific illnesses associated with suicide included congestive heart
      failure (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.33-2.24), chronic
      obstructive lung disease (OR, 1.62; 95% CI, 1.37-1.92), seizure disorder (OR,
      2.95; 95% CI, 1.89-4.61), urinary incontinence (OR, 2.02; 95% CI, 1.29-3.17),
      anxiety disorders (OR, 4.65; 95% CI, 4.07-5.32), depression (OR, 6.44; 95% CI,
      5.45-7.61), psychotic disorders (OR, 5.09; 95% CI, 3.94-6.59), bipolar disorder
      (OR, 9.20, 95% CI, 4.38-19.33), moderate pain (OR, 1.91; 95% CI, 1.66-2.20), and
      severe pain (OR, 7.52; 95% CI, 4.93-11.46). Treatment for multiple illnesses was
      strongly related to a higher risk of suicide. Almost half the patients who
      committed suicide had visited a physician in the preceding week. CONCLUSIONS:
      Many common illnesses are independently associated with an increased risk of
      suicide in the elderly. The risk is greatly increased among patients with
      multiple illnesses. These data may help clinicians to identify elderly patients
      at risk of suicide and open avenues for prevention.

PMID- 15197043
TI  - Provider and hospital characteristics associated with geographic variation in the
      evaluation and management of elderly patients with heart failure.
AB  - BACKGROUND: Rates of guideline-based care for elderly patients with heart failure
      vary by state, and overall are not optimal. Identifying factors associated with
      the lack of uniformly high-quality health care might aid efforts to improve care.
      We therefore sought to determine the extent to which provider and hospital
      characteristics contribute to small-area geographic variation in heart failure
      care after controlling for patient factors. METHODS: We studied 30 228 Medicare
      patients who were older than 65 years and hospitalized with heart failure. We
      mapped rates for 2 quality measures-documentation of left ventricular ejection
      fraction and appropriate prescription of angiotensin-converting enzyme inhibitors
      across the United States, using a Bayesian technique that smooths rates and
      enhances assessment for significant patterns of small-area variation. We used
      nonlinear hierarchical models to assess for associations between the the quality
      indicators and provider and hospital characteristics independent of patient
      characteristics. RESULTS: Smoothed, unadjusted rates of left ventricular ejection
      fraction documentation ranged from 30.1% to 67.2% and of angiotensin-converting
      enzyme inhibitor prescription from 55.8% to 87.1% among hospital referral
      regions; regional patterns were apparent. After patient factors were controlled
      for, care at hospitals without a medical school affiliation, without invasive
      cardiac capabilities, or in a rural location, as well as not having a
      cardiologist as an attending physician, was significantly associated with lower
      rates of left ventricular ejection fraction documentation. Hospitalization at a
      nonteaching facility was significantly associated with failure to prescribe
      angiotensin-converting enzyme inhibitors. CONCLUSION: Characteristics of
      providers and hospitals explain in part the geographic variation in guideline
      based care for elderly patients with heart failure.

PMID- 15197044
TI  - Reported adverse event cases of methemoglobinemia associated with benzocaine
      products.
AB  - BACKGROUND: Methemoglobinemia (MHb) is characterized by abnormal levels of
      oxidized hemoglobin that cannot bind and transport oxygen. When induced by
      benzocaine anesthetic spray and other chemicals, it can result in cyanosis and
      life-threatening complications. METHODS: From 818 439 adverse event reports
      received by the US Food and Drug Administration from November 1997 through March
      2002, we extracted every report for use of a benzocaine product. We classified
      each case by product type (eg, spray, gel, or solution), by whether MHb was
      involved, and by the dose given. RESULTS: Among 198 reported adverse events of
      all types associated with benzocaine, 132 cases (66.7%) involved definite or
      probable MHb. The MHb cases included 107 serious adverse events (81.1%) and 2
      deaths (1.5%). In 123 cases (93.2%), the product was a spray; in 2 cases (1.5%),
      a benzocaine-containing lozenge; and 1 case, a gel. In the 69 cases that
      specified a dose, 37 (53.6%) indicated that a single spray was applied
      (approximately the recommended amount). CONCLUSIONS: Health professionals
      involved in endoscopy, intubation, bronchoscopy, or similar invasive procedures
      using benzocaine-containing sprays should know that (1) administration may cause
      MHb with potentially serious consequences, (2) identifying the reaction to
      benzocaine usually requires cooximetry (although it can be implied by symptoms),
      and (3) treatment involves immediate intravenous administration of 1 to 2 mg/kg
      of methylene blue.

PMID- 15197045
TI  - Response, partial response, and nonresponse in primary care treatment of
      depression.
AB  - BACKGROUND: Depressive disorders are one of the most common reasons for visits to
      primary care physicians. This study identifies factors related to poor response
      to depression treatment with selective serotonin reuptake inhibitors (SSRIs) in
      primary care settings by (1) examining clinical response taking into account
      treatment, (2) comparing baseline characteristics and outcomes between patients
      classified by response, and (3) examining characteristics predicting poor
      response. METHODS: A Randomized Trial Investigating SSRI Treatment (ARTIST) was a
      prospective naturalistic trial comparing effectiveness of SSRI therapy. Eligible
      patients were randomized to treatment (N = 601) and followed up for 9 months.
      Treatment patterns were classified as "adequate" (6-month continuous medication),
      "aggressive" (defined by a treatment algorithm), or "inadequate"
      (discontinuations) by patient-reported medication use. Clinical response was
      determined by use of the Symptom Checklist-20 (SCL-20), with patients classified
      as remitters (score < or =6), partial remitters (50% decrease in symptoms), or
      nonresponders. Groups were compared on baseline characteristics, functioning, and
      treatment patterns. Multinomial logistic regression was used to determine
      predictors of response. RESULTS: Of patients completing 6-month evaluations (n =
      482), 46% were classified as nonresponders. Additionally, 53% (n = 256) received
      adequate therapy but did not achieve remission and 13% (n = 61) had aggressive
      therapy associated with treatment resistance. Significant predictors of
      nonresponse included older age, diagnosis, worse physical functioning, and lower
      energy level. CONCLUSIONS: A substantial number of adequately treated patients
      did not respond to antidepressant therapy. Some of these patients may be
      considered undertreated or treatment-resistant according to current treatment
      guidelines recommending dose increases or medication switches for less than
      adequate clinical response.

PMID- 15197046
TI  - Improving the process of antibiotic therapy in daily practice: interventions to
      optimize timing, dosage adjustment to renal function, and switch therapy.
AB  - BACKGROUND: Timely administration of the first dose, dosage adjustment to renal
      function, switch from intravenous to oral administration, and streamlining are
      important aspects of rational antibiotic prescription. The goals of this study
      were to investigate all of these variables, compare them with predefined quality
      standards, and implement improvement with specific interventions. METHODS: At the
      departments of internal medicine, surgery, and neurology and the emergency
      department of a tertiary referral university medical center, all consecutive
      patients receiving therapeutic antibiotics were enrolled. Dosages, timing of
      first doses, dosing intervals, administration routes, and adjustment of the
      chosen drug to clinical data were investigated. After the preintervention period,
      barriers to change were identified, followed by specific interventions and a
      postintervention measurement. RESULTS: In the preintervention and
      postintervention periods, 247 and 250 patients were enrolled, receiving 563 and
      598 antibiotic prescriptions, respectively. The mean time from the order to first
      dose at the wards improved from 2.7 to 1.7 hours in potentially severe cases (P
      =.003). Dosage adjustment to renal function remained unchanged at 45% vs 52% (P
      =.09) of cases where necessary. Switching of therapy from intravenous to oral
      improved from 46% to 62% (P =.03) and was performed a mean of 1.6 days earlier (P
      =.002). Streamlining was performed correctly in most cases, and thus no
      interventions were necessary. CONCLUSIONS: Timing of antibiotic therapy and
      switch therapy may be improved with a combination of interventions. To improve
      poor adjustment of dosing to renal function, other strategies are needed. In our
      setting, streamlining was already correct in most cases.

PMID- 15197047
TI  - Changing patterns in causes of death in a cohort of injecting drug users, 1980
      2001.
AB  - BACKGROUND: High mortality among drug users has been widely recognized. This
      study investigates, in a large family practice of 10 000 patients in Edinburgh,
      Scotland, whether there has been a change in causes of mortality over time.
      Patients known to have ever injected drugs were recruited into a cohort study
      from 1980 until 2001. METHODS: Death certificates and clinical notes were
      scrutinized and data relating to demographic features, drug use, and causes of
      death were recorded. RESULTS: Of 667 patients, there were 153 deaths at follow-up
      (110 men and 43 women). Average annual mortality rate was 2.3%. Death rate peaked
      in the early to mid-1990s, reflecting the development of advanced human
      immunodeficiency virus (HIV) from the early epidemic in 1982-1984 and the onset
      of the effect of antiviral chemotherapy. Drug deaths and suicide were the same in
      both sexes but tended to occur in younger subjects. Principal cause of death was
      overdose in the early years and HIV/AIDS in later years. Toward the close of the
      study period, hepatitis C emerged as a cause of death. CONCLUSIONS: Injecting
      drug users have a very high risk of mortality. Infectious diseases from
      nonsterile injecting are the most obvious preventable cause of death. Use of
      death certificate information alone is inaccurate in analyzing drug-related
      deaths and greatly underestimates the full impact of the HIV epidemic. This study
      provides some of the most convincing evidence so far that harm minimization, in
      its broadest sense, is effective in reducing drug-related mortality.

PMID- 15197048
TI  - Attention-deficit/hyperactivity disorder in adults: a survey of current practice
      in psychiatry and primary care.
AB  - BACKGROUND: Recognition and treatment of attention-deficit/hyperactivity disorder
      (ADHD) in adults in psychiatry and primary care have faced many obstacles.
      METHODS: Review by 50 psychiatrists and 50 primary care practitioners (PCPs) of
      537 and 317 medical records, respectively, of adults diagnosed as having ADHD.
      Information on other psychiatric disorders, time of onset of ADHD, source of
      referral, use of referrals for diagnosis, ADHD treatment, and use of drug
      holidays was recorded. RESULTS: Forty-five percent of the patient records
      reviewed by psychiatrists and 65% reviewed by PCPs indicated previous diagnoses
      of ADHD. Only 25% of the adults with ADHD had been first diagnosed as having the
      disorder in childhood or adolescence. A diagnosis of ADHD was the initial cause
      for referral in 80% of psychiatric patients and 60% of PCP patients. Most
      patients with previously diagnosed and undiagnosed ADHD were self-referred. Among
      patients who had not received a prior diagnosis, 56% complained about ADHD
      symptoms to other health professionals without being diagnosed; PCPs were the
      least aggressive in diagnosing ADHD. In psychiatric and PCP settings, there was a
      statistical difference in the use of pharmacotherapy (91% vs 78%, respectively)
      and the proportion of patients taking drug holidays (24% vs 17%, respectively);
      most drug holidays were initiated by the patient (57%). Stimulants were the
      treatment of choice for adult ADHD (84% treated with stimulants). CONCLUSION:
      Data contained within this medical record review suggest that adult ADHD is a
      substantial source of morbidity in both psychiatric and PCP settings.

PMID- 15197049
TI  - Identification of clinically significant prostate cancer by prostate-specific
      antigen screening.
AB  - BACKGROUND: The importance of screening for early-stage prostate cancer has been
      debated in the literature. However, there are well-established prognostic factors
      (Gleason score [GS], pretreatment prostate-specific antigen [PSA], and percent
      positive biopsy findings [%+Bx]) that predict biologically aggressive disease.
      These factors, together with a patient's age and general state of health, will
      permit physicians to project the effect of a prostate tumor over the patient's
      expected lifetime. This study was performed to determine the proportion of
      clinically significant prostate cancers diagnosed in a screened population.
      METHODS: From 1991 through 2002, 977 patients with nonpalpable (T1c) prostate
      cancer were seen for evaluation and comprise the study group. Patients were
      classified according to pretreatment PSA level, GS, %+Bx, and age. RESULTS: Based
      on tumor characteristics alone, 130 patients were noted to be at high risk (GS =
      8-10 or PSA level >20 ng/mL; or GS = 7 or PSA level >10-< or =20 ng/mL and
      >50%+Bx), with a historical 4-year PSA control of 10% to 30% after definitive
      therapy. An additional 45 patients were at intermediate risk (GS = 7, PSA level
      >10-< or =20 ng/mL, and 34%-50%+Bx), with a historical 4-year PSA control of 50%
      to 60% after definitive therapy. Additional patients were identified who had a
      cumulative anticipated prostate cancer mortality greater than 30% to 50% based on
      age and GS (GS = 7, age < or =70 years [n = 89]; GS = 6, age < or =65 years [n =
      337]). The total at risk for clinically significant tumors was 601 (61.5%) of 977
      patients. CONCLUSIONS: A significant proportion of patients with nonpalpable
      disease diagnosed as having prostate cancer by PSA screening have clinically
      significant cancers. This supports the continued use of PSA screening.

PMID- 15197051
TI  - Echinacea purpurea therapy for the treatment of the common cold: a randomized,
      double-blind, placebo-controlled clinical trial.
AB  - BACKGROUND: Echinacea purpurea stimulates the immune response and is promoted to
      reduce symptom severity and the duration of upper respiratory tract infections.
      We sought to determine the efficacy of a standardized preparation of E purpurea
      in reducing symptom severity and duration of the common cold. METHODS: A
      randomized, double-blind, placebo-controlled design was used. Patients received
      either 100 mg of E purpurea (freeze-dried pressed juice from the aerial portion
      of the plant) or a lactose placebo 3 times daily until cold symptoms were
      relieved or until the end of 14 days, whichever came first. Symptoms (sneezing,
      nasal discharge, nasal congestion, headache, sore or scratchy throat, hoarseness,
      muscle aches, and cough) were scored subjectively by the patient and recorded
      daily in a diary. Kaplan-Meier curves were used to estimate the survival function
      of time to resolution in each group. The Wilcoxon rank sum test was used to
      compare time to resolution between the 2 groups. RESULTS: One hundred twenty
      eight patients were enrolled within 24 hours of cold symptom onset. Group
      demographic distribution was comparable for sex, age, time from symptom onset to
      enrollment in the study, average number of colds per year, and smoking history.
      No statistically significant difference was observed between treatment groups for
      either total symptom scores (P range,.29-.90) or mean individual symptom scores
      (P range,.09-.93). The time to resolution of symptoms was not statistically
      different (P =.73). CONCLUSIONS: Some studies have concluded that Echinacea
      effectively reduces the symptoms and duration of the common cold. We were unable
      to replicate such findings. Further studies using different preparations and
      dosages of E purpurea are necessary to validate previous claims.

PMID- 15197052
TI  - Dangers of microwave-heated compresses.

PMID- 15197053
TI  - Over-the-counter pain reliever and aspirin use within a sample of long-term
      cyclooxygenase 2 users.

PMID- 15197050
TI  - The economic impact of chronic prostatitis.
AB  - BACKGROUND: Little information exists on the economic impact of chronic
      prostatitis. The objective of this study was to determine the direct and indirect
      costs associated with chronic prostatitis. METHODS: Outcomes were assessed using
      a questionnaire designed to capture health care resource utilization. Resource
      estimates were converted into unit costs with direct medical cost estimates based
      on hospital cost-accounting data and indirect costs based on modified labor
      force, employment, and earnings data from the US Census Bureau. RESULTS: The
      total direct costs for the 3 months prior to entry into the cohort, excluding
      hospitalization, were $126 915 for the 167 study participants for an average of
      $954 per person among the 133 consumers. Of the men, 26% reported work loss
      valued at an average of $551. The average total costs (direct and indirect) for
      the 3 months was $1099 per person for those 137 men who had resource consumption
      with an expected annual total cost per person of $4397. For those study
      participants with any incurred costs, tests for association revealed that the
      National Institutes of Health Chronic Prostatitis Symptom Index (P<.001) and each
      of the 3 subcategories of pain (P =.003), urinary function (P =.03), and quality
      of-life (P =.002) were significantly associated with resource use, although the
      quality-of-life subscale score from the National Institutes of Health Chronic
      Prostatitis Symptom Index was the only predictor of resource consumption.
      CONCLUSIONS: Chronic prostatitis is associated with substantial costs and lower
      quality-of-life scores, which predicted resource consumption. The economic impact
      of chronic prostatitis warrants increased medical attention and resources to
      identify and test effective treatment strategies.

PMID- 15197054
TI  - The reorganized risk factor-oriented medical database: a progress report.

PMID- 15197055
TI  - The Ocular Hypertension Treatment Study: topical medication delays or prevents
      primary open-angle glaucoma in African American individuals.
AB  - BACKGROUND: The prevalence of glaucoma is higher in African American individuals
      than in white individuals. OBJECTIVE: To report the safety and efficacy of
      topical ocular hypotensive medication in delaying or preventing the onset of
      primary open-angle glaucoma (POAG) among African American participants in the
      Ocular Hypertension Treatment Study. METHODS: Eligibility criteria included age
      between 40 and 80 years, intraocular pressure between 24 and 32 mm Hg in one eye
      and between 21 and 32 mm Hg in the other eye, and no evidence of glaucomatous
      structural or functional damage by standard clinical measures. Participants were
      randomized to either the observation group or medication group. Of the 1636
      participants randomized, 408 were self-identified as African American. MAIN
      OUTCOME MEASURE: The primary outcome was the development of reproducible visual
      field abnormality and/or reproducible optic disc deterioration attributed to
      POAG. RESULTS: Among African American participants, 17 (8.4%) of 203 in the
      medication group developed POAG during the study (median follow-up, 78 months)
      compared with 33 (16.1%) of 205 participants in the observation group (hazard
      ratio, 0.50; 95% confidence interval, 0.28-0.90; P =.02). CONCLUSION: Topical
      ocular hypotensive therapy is effective in delaying or preventing the onset of
      POAG in African American individuals who have ocular hypertension.

PMID- 15197056
TI  - Statins and other cholesterol-lowering medications and the presence of glaucoma.
AB  - OBJECTIVE: To explore whether oral statin and other antihyperlipidemic
      medications are associated with open-angle glaucoma. METHODS: The administrative
      clinical databases maintained at the Veterans Affairs Medical Center, Birmingham,
      Ala, were used to conduct a matched case-control study. Cases were all male
      patients aged 50 years and older with a new diagnosis of glaucoma on an
      outpatient or inpatient visit during the period January 1, 1997, through December
      31, 2001. Ten control subjects were matched to each case according to age (within
      1 year). Prescription files were assessed for statin use as well as additional
      medications to lower cholesterol levels. Information on comorbid medical
      conditions was also obtained. Conditional logistic regression was used to
      calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Longer
      duration of statin use was associated with a lower risk of open-angle glaucoma (P
      for trend =.04) primarily among subjects with 24 months or more of use (OR, 0.60;
      95% CI, 0.39-0.92). When stratified by comorbid medical condition, among those
      with cardiovascular disease (OR, 0.63; 95% CI, 0.42-0.97), lipid metabolism
      disorders (OR, 0.63; 95% CI, 0.41-0.99), and the absence of cerebrovascular
      disease (OR, 0.76; 95% CI, 0.58-0.99), statins demonstrated a protective effect
      on open-angle glaucoma. Finally, a protective association was also observed among
      those who used nonstatin cholesterol-lowering agents (OR, 0.59; 95% CI, 0.37
      0.97). CONCLUSIONS: Initial examination of an administrative clinical database
      indicates the intriguing possibility that long-term use of oral statins may be
      associated with a reduced risk of open-angle glaucoma, particularly among those
      with cardiovascular and lipid diseases. Nonstatin cholesterol-lowering agents
      were also associated with a reduced risk of having open-angle glaucoma.
      Additional investigation is warranted as to whether these classes of agents may
      provide an additional therapeutic addition for glaucoma.

PMID- 15197057
TI  - Comparison of the GDx VCC scanning laser polarimeter, HRT II confocal scanning
      laser ophthalmoscope, and stratus OCT optical coherence tomograph for the
      detection of glaucoma.
AB  - OBJECTIVE: To compare the abilities of current commercially available versions of
      3 optical imaging techniques: scanning laser polarimetry with variable corneal
      compensation (GDx VCC), confocal scanning laser ophthalmoscopy (HRT II
      [Heidelberg Retina Tomograph]), and optical coherence tomography (Stratus OCT) to
      discriminate between healthy eyes and eyes with glaucomatous visual field loss.
      METHODS: We included 107 patients with glaucomatous visual field loss and 76
      healthy subjects of a similar age. All individuals underwent imaging with a GDx
      VCC, HRT II, and fast retinal nerve fiber layer scan with the Stratus OCT as well
      as visual field testing within a 6-month period. Receiver operating
      characteristic curves and sensitivities at fixed specificities (80% and 95%) were
      calculated for parameters reported as continuous variables. Diagnostic
      categorization (outside normal limits, borderline, or within normal limits)
      provided by each instrument after comparison with its respective normative
      database was also evaluated, and likelihood ratios were reported. Agreement on
      categorization between methods (weighted kappa) was assessed. RESULTS: After the
      exclusion of subjects with unacceptable images, the final study sample included
      141 eyes of 141 subjects (75 with glaucoma and 66 healthy control subjects). Mean
      +/- SD mean deviation of the visual field test result for patients with glaucoma
      was -4.87 +/- 3.9 dB, and 70% of these patients had early glaucomatous visual
      field damage. No statistically significant difference was found between the areas
      under the receiver operating characteristic curves (AUCs) for the best parameters
      from the GDx VCC (nerve fiber indicator, AUC = 0.91), Stratus OCT (retinal nerve
      fiber layer inferior thickness, AUC = 0.92), and HRT II (linear discriminant
      function, AUC = 0.86). Abnormal results for each of the instruments, after
      comparison with their normative databases, were associated with strong positive
      likelihood ratios. Chance-corrected agreement (weighted kappa) among the 3
      instruments ranged from moderate to substantial (0.50-0.72). CONCLUSIONS: The
      AUCs and the sensitivities at high specificities were similar among the best
      parameters from each instrument. Abnormal results (as compared with each
      instrument's normative database) were associated with high likelihood ratios and
      large effects on posttest probabilities of having glaucomatous visual field loss.
      Calculation of likelihood ratios may provide additional information to assist the
      clinician in diagnosing glaucoma with these instruments.

PMID- 15197058
TI  - Goniosurgery for glaucoma complicating chronic childhood uveitis.
AB  - OBJECTIVES: To describe the safety and efficacy of goniotomy in medically
      uncontrolled glaucoma complicating chronic uveitis and the factors affecting its
      outcome. METHODS: All goniotomies performed by a single surgeon for refractory
      childhood uveitic glaucoma were retrospectively reviewed. Success was defined as
      final intraocular pressure (IOP) of no greater than 21 mm Hg without medications
      and qualified success as IOP of no greater than 21 mm Hg with medications. Unless
      otherwise indicated, data are expressed as mean +/- SD. RESULTS: Fifty-four
      goniotomies were performed in 40 eyes of 31 patients. Juvenile rheumatoid
      arthritis-associated uveitis was the diagnosis in 30 eyes (75%). Eleven eyes
      (28%) were aphakic. Mean follow-up was 98.9 months (range, 2-324 months). Mean
      age at surgery was 10.3 +/- 4.7 years (range, 4-22 years). Mean preoperative IOP
      was 36.7 +/- 6.4 mm Hg while receiving a mean of 2.9 +/- 1.1 medications. Overall
      surgical success was achieved in 29 eyes (72%), including success in 22 (55%) and
      qualified success in 7 (18%) while receiving a mean of 1.6 +/- 1.1 medications.
      Mean postoperative IOP in the success and qualified-success groups were 14.3 +/-
      2.8 and 15.7 +/- 3.1 mm Hg, respectively. Kaplan-Meier survival probabilities
      (95% confidence interval) at 1, 5, and 10 years were 0.92 (0.82-1.00), 0.81 (0.65
      0.97), and 0.71 (0.49-0.92), respectively. Phakic eyes, eyes with fewer
      peripheral anterior synechiae, patients younger than 10 years, and eyes with no
      prior surgery had significantly better outcomes. Hyphema, typically mild and
      transient, occurred in 43 procedures (80%). CONCLUSIONS: Goniosurgery is low risk
      and effective for refractory glaucoma complicating chronic childhood uveitis. It
      should be considered the surgical procedure of choice for this condition.
      Surgical outcome is adversely affected by increased age, peripheral anterior
      synechiae, prior surgeries, and aphakia.

PMID- 15197059
TI  - Neutralizing tumor necrosis factor activity leads to remission in patients with
      refractory noninfectious posterior uveitis.
AB  - OBJECTIVE: To evaluate the efficacy and safety of tumor necrosis factor (TNF)
      inhibition with the p55 TNF receptor fusion protein (TNFr-Ig) for severe sight
      threatening noninfectious posterior segment intraocular inflammation. METHODS:
      Seventeen patients with refractory noninfectious posterior segment intraocular
      inflammation received TNFr-Ig by intravenous infusion in this nonrandomized, open
      label, pilot study. The primary outcome measure was logMAR visual acuity.
      Secondary outcome measures were binocular indirect ophthalmoscopy score, cystoid
      macular edema, adverse effects, and vision-related (visual core module 1) and
      health-related (36-Item Short-Form Health Survey) quality of life. RESULTS:
      Within 1 month of TNFr-Ig therapy, 9 patients (53%) achieved at least a 2-line
      improvement in visual acuity, 8 (57%) of 14 patients with vitreous haze before
      treatment achieved an improvement in binocular indirect ophthalmoscopy score to
      0, and macular edema resolved in 5 (56%) of 9 affected patients. Twelve (71%) of
      the patients achieved complete cessation of intraocular inflammation following
      TNFr-Ig therapy. A reduction in concomitant immunosuppression was possible for 11
      patients (65%) following TNFr-Ig therapy. However, all but 1 patient required
      continuing adjuvant therapy during the response to TNFr-Ig, which had a median
      duration of 3 months. Adverse effects included mild infusion reactions in 3
      patients and transient lymphocytopenia in 2 patients. CONCLUSION: Therapy with
      TNFr-Ig was safe and effective for treating patients with sight-threatening
      noninfectious posterior segment intraocular inflammation resistant to
      conventional immunotherapy, but adjuvant immunosuppression and repeat infusions
      would be required to maintain long-term remission.

PMID- 15197060
TI  - Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization
      in age-related macular degeneration: results of an effectiveness study.
AB  - OBJECTIVE: To determine the postapproval effectiveness of photodynamic therapy
      (PDT) with verteporfin for the treatment of predominantly classic subfoveal
      choroidal neovascularization (CNV) secondary to age-related macular degeneration.
      METHODS: Forty-five consecutive patients treated with PDT for subfoveal CNV were
      compared with an untreated historical control group. Control patients had
      subfoveal CNV and were first seen by us within 1 year before Health Canada's
      approval of verteporfin. Both groups were followed up for the development of
      significant visual loss, stability, or improvement. Multivariate models were
      constructed to evaluate the effectiveness of PDT, controlling for multiple
      covariates (age, sex, baseline visual acuity, follow-up time, lesion size, and
      number of treatments). RESULTS: Significant differences were noted in the change
      in visual acuity between those who did and did not receive PDT (chi(2) = 5.9, P
      =.048). Patients who received PDT were 2.9 times (95% confidence interval, 0.9
      9.1) less likely to develop a moderate (>2 lines) visual loss (chi(2) = 3.2, P
      =.07). Controlling for covariates, patients who received PDT were 13.7 times (95%
      confidence interval, 1.4-132.6) more likely to develop a visual improvement of at
      least 1 line. CONCLUSION: Compared with historical controls, PDT was demonstrated
      to be effective for the treatment of predominantly classic subfoveal CNV.

PMID- 15197061
TI  - Clinical trial performance of community- vs university-based practices in the
      submacular surgery trials (SST): SST report no. 2.
AB  - OBJECTIVE: To compare the performance of community- vs university-based clinical
      centers in 3 multicenter randomized clinical trials of intraocular surgery.
      METHODS: Each Submacular Surgery Trials clinical center was classified as a
      university-based center, if the contract to perform as a center was signed by a
      university official, or as a community-based center. The 2 groups of centers were
      compared on performance, assessed cumulatively by the Submacular Surgery Trials
      Quality Assurance and Monitoring Subcommittee. OUTCOME MEASURES: Patient accrual,
      completion of scheduled examinations, completion of masked vision examinations 2
      years after enrollment (the designated primary study end point evaluation time),
      timeliness of submission of retinal photographs required by protocol to the
      Photograph Reading Center, completion of health- and vision-related quality-of
      life interviews, and timeliness of submission of the primary outcome data to the
      Coordinating Center after completion of the examination. RESULTS: Almost all
      centers performed at a very high (good) level, although there was a trend for
      some community-based centers to be at the lower end of most distributions.
      CONCLUSIONS: Most community- and university-based centers performed well in these
      multicenter clinical trials. Monitoring performance and periodically providing
      feedback to clinical center investigators may encourage excellent performance in
      areas critical to the success of clinical trials, regardless of whether the
      center is community or university based.

PMID- 15197062
TI  - New dendritic adhesives for sutureless ophthalmic surgical procedures: in vitro
      studies of corneal laceration repair.
AB  - OBJECTIVE: To compare a biodendrimer adhesive with a conventional suture for
      repairing linear and stellate corneal lacerations. METHODS: A keratome knife was
      used to create 4.1-mm full-thickness linear incisions (n = 36) and 3 x 4-mm full
      thickness stellate incisions (n = 25) in the central cornea of enucleated human
      eyes. The incisions were sealed with either a suture or the biodendrimer
      adhesive. The globes were inflated with balanced salt solution, and the increase
      in intraocular pressure was monitored via a cardiac transducer until fluid leaked
      from each eye. This intraocular pressure reading from the transducer was recorded
      at the sight of any leakage through the wound (leakage pressure). By using the
      Wilcoxon rank sum test, the median leakage pressure was compared for each closure
      method, separately for each wound group. By using the 1-sided 1-sample t test,
      each mean leakage pressure value was compared with 34 mm Hg, which is the
      intraocular pressure under certain stressful physiologic conditions (eg, coughing
      and the Valsalva maneuver). RESULTS: For globes that underwent a linear incision,
      the mean leakage pressure was 78.7 mm Hg for the sutured group and 109.6 mm Hg
      for the adhesive group. Globes that underwent a stellate incision had a mean
      leakage pressure of 57.8 mm Hg for the sutured group and 78.7 mm Hg for the
      adhesive group. All of these pressures showed a statistical significance from 34
      mm Hg via a 1-sided 1-sample t test. CONCLUSIONS: The difference in leakage
      pressures for all 4 groups was statistically significant relative to 34 mm Hg.
      This suggests that either method of closure, adhesive or suture, can withstand
      physiologic increases in intraocular pressure postoperatively and that
      biodendrimer adhesives are able to seal large corneal lacerations.Clinical
      Relevance The use of biodendrimer adhesives to repair a corneal wound constitutes
      a viable alternative clinical procedure to conventional sutures.

PMID- 15197063
TI  - Reduction of indocyanine green-associated photosensitizing toxicity in retinal
      pigment epithelium by sodium elimination.
AB  - OBJECTIVE: To determine if eliminating sodium affects indocyanine green (ICG)
      photosensitizing toxicity and uptake in cultured human retinal pigment epithelial
      (RPE) cells. METHODS: Cultured human RPE cells were exposed to ICG (2.5 mg/mL) in
      balanced salt solution and sodium-free balanced salt solution for 2 minutes.
      Afterwards, ICG was removed, and the cells were irradiated with a light beam (4 x
      10(4) lux) for 40 minutes. Toxicity was monitored using light microscopy, calcein
      AM-ethidium homodimer 1 staining, trypan blue exclusion test, and 3-(4,5
      dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
      viability assay. Indocyanine green uptake was measured by optical absorption at
      790 nm. RESULTS: Photoreactive changes occurred in RPE cells exposed to ICG and
      light. These changes included cell shrinkage, cell death, pyknotic nuclei,
      reduced viability, and reduced mitochondrial dehydrogenase activity. These
      changes were less severe when ICG was dissolved in sodium-free balanced salt
      solution. In addition, ICG uptake was reduced when the solvent was sodium-free
      balanced salt solution. CONCLUSION: Indocyanine green and intense light exposure
      in RPE cells caused photosensitizing toxicity that was reduced when sodium in the
      solvent was eliminated and replaced with other cations. CLINICAL RELEVANCE:
      Eliminating sodium from the solvent reduced ICG uptake into RPE and its
      associated photosensitizing toxicity. This reconstitution method of ICG may be
      helpful for safer intravitreal ICG use in macular hole surgery.

PMID- 15197064
TI  - Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and
      risk of age-related maculopathy.
AB  - OBJECTIVE: To examine the intake of antioxidant vitamins and carotenoids as well
      as fruits and vegetables in relation to the development of age-related
      maculopathy (ARM). METHODS: We conducted a prospective follow-up study of women
      in the Nurses' Health Study and men in the Health Professionals Follow-up Study.
      We followed 77 562 women and 40 866 men who were at least 50 years of age and had
      no diagnosis of ARM or cancer at baseline for up to 18 years for women and up to
      12 years for men. Fruit and vegetable intakes were assessed with a validated
      semiquantitative food-frequency questionnaire up to 5 times for women and up to 3
      times for men during follow-up. RESULTS: A total of 464 (329 women and 135 men)
      incident cases of early ARM and 316 (217 women and 99men) cases of neovascular
      ARM, all with visual loss of 20/30 or worse due primarily to ARM, were diagnosed
      during follow-up. Fruit intake was inversely associated with the risk of
      neovascular ARM. Participants who consumed 3 or more servings per day of fruits
      had a pooled multivariate relative risk of 0.64 (95% confidence interval, 0.44
      0.93; P value for trend =.004) compared with those who consumed less than 1.5
      servings per day. The results were similar in women and men. However, intakes of
      vegetables, antioxidant vitamins, or carotenoids were not strongly related to
      either early or neovascular ARM. CONCLUSION: These data suggest a protective role
      for fruit intake on the risk of neovascular ARM.

PMID- 15197065
TI  - X-linked high myopia associated with cone dysfunction.
AB  - OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high
      cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with
      abnormal photopic responses, and deuteranopia. The disease maps to chromosome
      Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a
      second family from Minnesota with a similar X-linked phenotype, also of Danish
      descent. All affected males had protanopia instead of deuteranopia. METHODS: X
      chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from
      22 Minnesota family individuals (8 affected males and 5 carrier females) and 6
      members of the original family with BED were performed. Haplotype comparisons and
      mutation screening of the red-green cone pigment gene array were performed on DNA
      from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38
      and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers
      DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis
      defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a
      red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28
      polymorphic markers of the family with BED, and narrowed the critical interval to
      6.8 cM. The haplotypes of the affected individuals were different from those of
      the Minnesota pedigree. Bornholm eye disease-affected individuals showed the
      presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS:
      Because of the close geographic origin of the 2 families, we expected affected
      individuals to have the same haplotype in the vicinity of the same mutation.
      Mapping studies, however, suggested independent mutations of the same gene. The
      red-green and green-red hybrid genes are common X-linked color vision defects,
      and thus are unrelated to the high myopia and other eye abnormalities in these 2
      families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction
      has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for
      2 families of Danish origin.

PMID- 15197066
TI  - Race and the risk of glaucoma.

PMID- 15197067
TI  - Global health, global vision.

PMID- 15197068
TI  - Cataract in Kniest dysplasia: clinicopathologic correlation.

PMID- 15197069
TI  - Polymorphous low-grade adenocarcinoma of the lacrimal gland.

PMID- 15197070
TI  - Bilateral lacrimal gland involvement with Kimura disease in an African American
      male.

PMID- 15197071
TI  - Wound dehiscence in a patient with keratoconus after penetrating keratoplasty and
      LASIK.

PMID- 15197072
TI  - Recurrent anterior uveitis in patients with Vogt-Koyanagi-Harada syndrome.

PMID- 15197073
TI  - Late posterior migration of glass intraocular foreign bodies.

PMID- 15197074
TI  - Central serous chorioretinopathy associated with periocular corticosteroid
      injection treatment for HLA-B27-associated iritis.

PMID- 15197075
TI  - Acitretin-associated maculopathy.

PMID- 15197076
TI  - Self-induced, bilateral retinal detachment in Tourette syndrome.

PMID- 15197077
TI  - Retinal angiomatous proliferation: optical coherence tomographic confirmation of
      an intraretinal lesion.

PMID- 15197078
TI  - Ocular surface reconstruction in a patient with complete ankyloblepharon
      resulting from stevens-johnson syndrome.

PMID- 15197079
TI  - Traumatic retinal break from a viscoelastic cannula during cataract surgery.

PMID- 15197080
TI  - The benefit of repeated intraocular pressure measurements in clinical trials.

PMID- 15197081
TI  - Oregon Health & Science University.

PMID- 15197082
TI  - Video-assisted thoracic surgery sympathectomy for hyperhidrosis.
AB  - HYPOTHESIS: Video-assisted thoracic surgery sympathectomy is efficacious for
      patients with hyperhidrosis. DESIGN: An experience with patients undergoing
      bilateral video-assisted thoracic surgery sympathectomy was reviewed to evaluate
      the operative technique and to determine morbidity and outcomes. SETTING:
      Academic health center. PATIENTS: The cohort included 31 patients (22 women and 9
      men). All but 2 patients were of Asian descent, and the average age was 24.9
      years. All patients had palmar hyperhidrosis. Two patients also had craniofacial
      hyperhidrosis, and another 2 had pedal hyperhidrosis. INTERVENTIONS: Bilateral
      video-assisted thoracic surgery sympathectomy with resection of the second and
      third ganglia was performed in all patients. Small chest tubes were removed on
      the first postoperative day. In 30 patients, the procedures were simultaneous;
      and in 1, it was staged to accommodate lumbar sympathectomy for pedal disease.
      RESULTS: Perioperatively, no patients died. The only hospital complication was an
      intraoperative injury to an intercostal artery that required conversion to an
      open thoracotomy. The average hospital length of stay was 1.2 days (range, 1-3
      days). No patient developed Horner syndrome. Long-term follow-up was 2.6 years
      (range, 3 months to 7 years). Both hands in all patients were warm and dry at the
      last follow-up, as were the face and scalp in the 2 with craniofacial
      hyperhidrosis. Ten patients (32%) experienced compensatory sweating, which
      improved within 6 months. CONCLUSIONS: In this experience, palmar hyperhidrosis
      is predominantly a disease of young Asian women. Simultaneous bilateral video
      assisted thoracic surgery sympathectomy is effective and can be accomplished with
      minimal morbidity and a short hospitalization. Compensatory sweating occurs in a
      third of patients, but is generally self-limiting.

PMID- 15197083
TI  - Multiple organ dysfunction during resuscitation is not postinjury multiple organ
      failure.
AB  - HYPOTHESIS: Multiple organ dysfunction (MOD) within 48 hours of injury is a
      reversible physiologic response to tissue injury and resuscitation. DESIGN: A
      prospective 10-year inception cohort study ending September 2003. SETTING:
      Regional academic level I trauma center. PATIENTS: One thousand two hundred
      seventy-seven consecutive trauma patients at risk for postinjury multiple organ
      failure (MOF). Inclusion criteria were being 16 years and older, being admitted
      to the trauma intensive care unit, having an Injury Severity Score higher than
      15, and surviving more than 48 hours after injury. Isolated head injuries were
      excluded. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Development of postinjury
      MOD as defined by a Denver MOF score of 4 or higher within 48 hours of injury and
      MOF as defined by a Denver MOF score of 4 or higher more than 48 hours after
      injury. RESULTS: Postinjury MOD and MOF were diagnosed in 209 (16%) and 300 (23%)
      patients, respectively. Age, Injury Severity Score, and 12-hour blood transfusion
      requirements were significantly higher among patients who developed MOD and MOF.
      Of the 209 patients who developed MOD, 134 (64%) progressively developed MOF
      while 75 (36%) had MOD resolve within 48 hours. CONCLUSION: Multiple organ
      dysfunction during resuscitation is a reversible response to severe injury and
      often resolves during the resuscitation period.

PMID- 15197084
TI  - Quantification of pain and satisfaction following laparoscopic and open hernia
      repair.
AB  - HYPOTHESIS: Subjective experiences can be quantified by visual analog scale (VAS)
      scoring to improve comparison of surgical techniques. DESIGN: Prospective
      collection of outcome data by interview of patients at 1 day and 1 week following
      nonrandomized elective hernia repair by a single surgical group between May 1998
      and April 2003. SETTING: Cedars-Sinai Medical Center, Los Angeles, Calif.
      PATIENTS: A total of 253 patients (239 men; mean age, 59 years) underwent repair
      by laparoscopic (n = 110, 105 bilateral, 92 total extraperitoneal, and 18
      transabdominal preperitoneal) or tension-free open (n = 143, 133 unilateral)
      approach. Laparoscopic patients were significantly younger (52.0 vs 63.8 years,
      P<.001). MAIN OUTCOME MEASURES: Subjective measures included VAS scores (1-10, 1
      indicates best) for pain at 1 day and 1 week postoperatively and overall
      satisfaction at 1 week. Objective measures included quantity and days of
      analgesic use and days before return to regular activities, including work and
      driving. Results were also compared by patient age (Spearman analysis). RESULTS:
      Satisfaction was high for both procedures; the laparoscopic procedure was
      superior only for return to work and driving. Spearman analysis showed a
      significant inverse relation between age and first-day pain (r= -0.15, P=.01),
      independent of operative approach. Because laparoscopic patients were younger,
      patients younger than 65 years were analyzed separately; laparoscopic patients
      had significantly less first-day pain (5.44 vs 6.30, P=.02). CONCLUSIONS: Pain
      following hernia repair was age dependent. Following laparoscopic repair,
      patients had lower first-day pain scores in younger patients and earlier return
      to normal activities in all patients. Satisfaction was similar for both
      approaches. Subjective experiences can be quantified, compared to detect subtle
      differences in outcome for competing surgical techniques, and used to counsel
      patients before operation, with the goal of improving satisfaction.

PMID- 15197085
TI  - Early experience with balloon brachytherapy for breast cancer.
AB  - HYPOTHESIS: Partial-breast irradiation for carcinoma by a single source of
      radiation placed in the center of a balloon inserted in the lumpectomy cavity is
      an effective method of treating breast cancer. Previous interstitial radiation
      therapy using iridium seeds placed within multiple catheters has been shown to be
      effective but impractical and cosmetically unacceptable to women. DESIGN:
      Prospective registry study. SETTING: Three university and community hospitals.
      PATIENTS: Women 40 years and older with histologically diagnosed in situ and
      invasive T1 through T2 and N0 or N1 breast cancer treated with lumpectomy and
      axillary node sampling were invited to enter this institutional review board
      approved study. MAIN OUTCOME MEASURES: Evaluation of immediate and short-term
      complications, patients' acceptance of the treatment, and cosmesis are reported.
      RESULTS: Of the 129 eligible patients enrolled, 112 completed the treatment. Of
      these, transient skin erythema was noted in 28, localized edema in 3, and skin
      blisters adjacent to the balloon in 9. Infection developed in 7, necessitating
      drainage and antibiotic administration. In 10 patients, sonographically
      demonstrated seromas that developed after removal of the device were aspirated
      percutaneously. In 4 patients, punctured or ruptured balloons had to be replaced
      before the treatment could be completed. Patients quickly adjusted to the breast
      distension caused by the balloon, and their acceptance of the procedure was good.
      The cosmetic outcome was rated high. There were no recurrences during this very
      short follow-up. CONCLUSIONS: Our early short-term experience indicates balloon
      brachytherapy to be an acceptable alternative to external beam radiation for
      selected operable breast cancers. The 1-week treatment time allows working women
      and those who live at a distance from radiation centers to choose breast
      conservation rather than mastectomy.

PMID- 15197086
TI  - Blunt carotid artery injury: the futility of aggressive screening and diagnosis.
AB  - BACKGROUND: Blunt carotid artery injury (BCI) remains a rare but potentially
      lethal condition. Recent studies recommend that aggressive screening based on
      broad criteria (hyperextension-hyperflexion mechanism of injury, basilar skull
      fracture, cervical spine injury, midface fracture, mandibular fracture, diffuse
      axonal brain injury, and neck seat-belt sign) increases the rate of diagnosis of
      BCI by 9-fold. If this recommendation becomes a standard of care, it will require
      a major consumption of resources and may give rise to liability claims. The
      benefits of aggressive screening are unclear because the natural history of
      asymptomatic BCI is unknown and the existing treatments are controversial.
      HYPOTHESIS: The lack of an aggressive angiographic screening protocol does not
      result in delayed BCI diagnosis or BCI-related neurologic deficits. METHODS: A 10
      year medical record review of patients with BCI was undertaken in 2 level I
      academic trauma centers. In both centers, urgent screening for BCI was performed
      in patients with focal neurologic signs or neurologic symptoms unexplainable by
      results of computed tomography of the brain as well as in selected patients
      undergoing angiography for another reason. RESULTS: Of 35 212 blunt trauma
      admissions, 17 patients (0.05%) were diagnosed as having BCI. Six showed no
      evidence of BCI-related neurologic symptoms during hospitalization or prior to
      death as a result of associated injuries. Eleven sustained a BCI-related stroke,
      9 of whom had it within 2 hours of injury. The remaining 2 had a delayed
      diagnosis (9 and 12 hours after injury) and received only anticoagulation because
      the lesions were surgically inaccessible. Just 1 of these 2 patients met the
      criteria for BCI screening and could have been offered earlier treatment, of
      uncertain benefit, if we had adopted an aggressive screening policy. CONCLUSIONS:
      Of the few patients with BCI, most remain asymptomatic or develop neurologic
      deficits shortly after injury. Although a widely applied, resource-consuming
      screening program may increase the rate of early diagnosis of BCI, an improvement
      in outcome is uncertain. A cost-effectiveness analysis should be done before
      trauma surgeons accept an aggressive screening protocol as the standard of care.

PMID- 15197087
TI  - Validation of subareolar and periareolar injection techniques for breast sentinel
      lymph node biopsy.
AB  - HYPOTHESIS: Subareolar or periareolar injection of radioactive technetium sulfur
      colloid is equivalent to other injection techniques for breast cancer sentinel
      lymph node (SLN) biopsy. DESIGN AND SETTING: Prospective, multicenter clinical
      trial. PATIENTS: A total of 3961 individuals with clinical stage I and II breast
      cancer. INTERVENTIONS: All patients underwent attempted SLN biopsy followed by
      completion axillary dissection. Injection technique was determined by the
      preference of each participating surgeon. Most surgeons had little or no
      experience with SLN biopsy before participation in this study. MAIN OUTCOME
      MEASURES: The SLN identification and false-negative rates. RESULTS: An SLN biopsy
      was performed in 3961 patients using blue dye alone or radioactive colloid plus
      blue dye. Subareolar and periareolar radioactive colloid injection techniques
      were associated with SLN identification rates of 99.3% and 95.6%, respectively,
      with false-negative rates of 8.3% and 8.9%, respectively. The identification
      rates were significantly higher for these 2 techniques than for peritumoral
      injection of radioactive colloid (91.1%) or the use of blue dye alone (88.5%)
      (P<.001). The false-negative rates were similar for all techniques. CONCLUSIONS:
      Although many medical centers have adopted subareolar and periareolar radioactive
      colloid injections because of their simplicity and convenience, a paucity of data
      from a few single-institutional studies has existed to substantiate the false
      negative rates associated with these techniques. The results of this multicenter
      study establish the validity of subareolar and periareolar radioactive colloid
      injections and support the hypothesis that the lymphatic drainage of the entire
      breast is to the same few SLNs.

PMID- 15197088
TI  - Using quality-of-life measurements to predict patient satisfaction outcomes for
      antireflux surgery.
AB  - HYPOTHESIS: Preoperative quality-of-life measurement can predict which patients
      will be satisfied with surgical fundoplication in the treatment of
      gastroesophageal reflux disease (GERD). DESIGN: Review of a prospectively
      gathered database. SETTING: Tertiary referral center. PATIENTS: All patients
      underwent preoperative physiological testing by upper endoscopy, esophageal
      manometry, and 24-hour esophageal pH monitoring, and some had contrast
      radiography and gastric emptying scintigraphy. Patients were examined for
      symptoms and completed a symptom severity questionnaire (the GERD-Health-Related
      Quality of Life questionnaire) and a generic quality-of-life instrument (the 36
      Item Short-Form Health Survey [SF-36]). Patients then underwent either open or
      laparoscopic fundoplication. MAIN OUTCOME MEASUREMENTS: Patients were contacted
      to assess satisfaction 2 months to 5 years postoperatively. They completed the
      GERD-Health-Related Quality of Life questionnaire and the SF-36. Patients were
      grouped into those satisfied and dissatisfied. RESULTS: Two hundred ninety
      patients were included. Median follow-up was 29 months. Thirty-four patients
      (12%) were dissatisfied with their surgical outcomes for any reason. The
      dissatisfied patients had statistically significantly worse scores preoperatively
      in 6 of the 8 domains of the SF-36 than satisfied patients. Dissatisfied patients
      had less symptomatic improvement. The satisfied patients had statistically
      significant improvement in 6 domains, whereas the dissatisfied patients had
      statistically significant worsening of scores in 2 domains. CONCLUSIONS: Quality
      of-life measurements are frequently used as an outcome end point. This study
      shows that a generic quality-of-life instrument can preoperatively identify
      patients with GERD who are likely to be dissatisfied with antireflux surgery. Use
      of quality-of-life instruments as a predictive tool for surgical outcomes
      deserves further study.

PMID- 15197089
TI  - En bloc vs transhiatal esophagectomy for stage T3 N1 adenocarcinoma of the distal
      esophagus.
AB  - HYPOTHESIS: En bloc esophagectomy (EBE) provides improved survival over
      transhiatal esophagectomy (THE) in patients with similarly sized transmural
      tumors (T3) and lymph node metastases (N1). DESIGN: A retrospective case-control
      study of 2 methods of esophageal resection for cancer. SETTING: University
      hospital (tertiary referral center for esophageal disease). PATIENTS: There were
      49 patients (27 who underwent EBE and 22 who underwent THE) with similar T3 N1
      disease and the following matched criteria: tumors of similar size and location,
      more than 20 lymph nodes in the surgical specimen, R0 resection, no previous
      chemotherapy or radiation therapy, and follow-up until death or for a minimum of
      5 years. Main Outcome Measure Survival adjusted for differences in demographic
      and patient characteristics. RESULTS: The number of nodes harvested was greatest
      after EBE vs THE (median, 52 vs 29 [range, 21-85 vs 20-60]; P<.001). The median
      number of involved nodes was similar after EBE vs THE (median, 5 vs 7 [range, 1
      19 vs 1-16]). The only 2 independent factors that affected survival in a Cox
      analysis were the number of involved lymph nodes (P =.01) and the type of
      resection (P =.03). Patients who underwent EBE had a survival benefit over those
      who underwent THE (P =.01). The survival benefit of EBE was seen only in patients
      with fewer than 9 involved lymph nodes (P<.001). CONCLUSION: En bloc
      esophagectomy confers a better survival than THE in patients with T3 N1 disease
      and fewer than 9 lymph node metastases.

PMID- 15197090
TI  - Manipulation of the primary breast tumor and the incidence of sentinel node
      metastases from invasive breast cancer.
AB  - HYPOTHESIS: The incidence of sentinel node (SN) metastases from invasive breast
      cancer might be affected by the technique used to obtain biopsy specimens from
      the primary tumor before sentinel lymph node dissection. DESIGN: Prospective
      database study. SETTING: The John Wayne Cancer Institute. PATIENTS AND METHODS:
      We identified 663 patients with biopsy-proven invasive breast cancer who
      underwent sentinel lymph node dissection between January 1, 1995, and April 30,
      1999. Patients were divided into 3 groups based on type of biopsy: fine-needle
      aspiration (FNA), large-gauge needle core, and excisional. A logistic regression
      model was used to correlate tumor size, tumor grade, and type of biopsy with the
      incidence of SN metastases. RESULTS: Of the 676 cancers, 126 were biopsied by
      FNA, 227 by large-gauge needle core biopsy, and 323 by excisional biopsy before
      sentinel lymph node dissection. Mean patient age was 58 years (range, 28-96
      years), and mean tumor size was 1.85 cm (range, 0.1-9.0 cm). In multivariate
      analysis based on known prognostic factors, the incidence of SN metastases was
      higher in patients whose cancer was diagnosed by FNA (odds ratio, 1.531; 95%
      confidence interval, 0.973-2.406; P =.07, Wald test) or large-gauge needle core
      biopsy (odds ratio, 1.484; 95% confidence interval, 1.018-2.164; P =.04, Wald
      test) than by excision. Tumor size (P<.001) and grade (P =.06) also were
      significant prognostic factors. CONCLUSIONS: Manipulation of an intact tumor by
      FNA or large-gauge needle core biopsy is associated with an increase in the
      incidence of SN metastases, perhaps due in part to the mechanical disruption of
      the tumor by the needle. The clinical significance of this phenomenon is unclear.

PMID- 15197091
TI  - Extended hypermetabolic response of the liver in severely burned pediatric
      patients.
AB  - HYPOTHESIS: The acute phase response is a cascade of events contributing to
      hypermetabolism and substrate catabolism. It was believed to persist for only a
      short time after injury. There is now evidence that systemic catabolism and
      hypermetabolism associated with thermal injury persevere for a long time. We
      hypothesize that the proinflammatory hepatic acute phase response perseveres for
      an extended time and enhances hypermetabolism longer than previously believed.
      DESIGN: Prospective study. SETTING: Intensive Care Burn Unit, Shriners Hospital
      for Children. PATIENTS: Twenty-three children (aged 1-16 years) sustaining a
      severe thermal injury (>/=40% total-body surface area) who remained in the
      intensive care unit longer than 30 days. MAIN OUTCOME MEASURES: Patient
      demographics, nutritional support, incidence of sepsis, inhalation injury,
      mortality, and levels of serum constitutive proteins, type I and type II acute
      phase proteins, free fatty acids, proinflammatory cytokines, insulin-like growth
      factor (IGF) I, IGF binding protein-1, IGF binding protein-3, and hepatocyte
      growth factor. RESULTS: After thermal injury, constitutive hepatic protein levels
      decreased 2- to 3-fold 80 days after burn, whereas acute phase protein levels
      increased. Free fatty acid levels were increased 5 days after burn.
      Proinflammatory cytokine levels (interleukin [IL] 1, IL-6, IL-8, IL-10, and tumor
      necrosis factor) and IGF binding protein-1 levels were elevated for 40 days after
      burn, whereas serum IGF-I and IGF binding protein-3 levels were decreased.
      Hepatocyte growth factor levels were increased immediately after burn but rapidly
      returned to the normal range. CONCLUSIONS: Despite adequate nutritional support,
      a severe thermal injury induces the proinflammatory acute phase response for a
      prolonged period. Thus, the liver with the hepatic acute phase response plays a
      more important role during catabolism after burn than previously believed.
      Pharmacologic agents that improve hepatic function may be an effective approach
      to attenuate hypermetabolism after trauma.

PMID- 15197092
TI  - Predictors of nonsentinel node metastasis in patients with breast cancer after
      sentinel node metastasis.
AB  - HYPOTHESIS: The presence of nonsentinel lymph node (NSLN) metastasis after having
      a positive sentinel lymph node dissection finding is associated with tumor size
      and stage, the presence of lymphovascular invasion, micrometastasis, and
      extranodal extension. DESIGN: Retrospective case series. SETTING: University
      hospital. PATIENTS: Four hundred seven consecutive patients at a single
      institution who underwent sentinel lymph node dissection as part of breast
      conservation or mastectomy with biopsy-proved cancer. INTERVENTION: Completion
      axillary lymph node dissection and definitive therapy. MAIN OUTCOME MEASURES:
      Sentinel node metastasis, NSLN metastasis, tumor size and stage, lymphovacular
      invasion, micrometastasis, extronodal extension, histological tumor
      characteristics, and number of sentinel nodes removed. RESULTS: In a univariate
      analysis, size of the primary tumor and extranodal extension were associated with
      having positive NSLN findings. The presence of micrometastasis was associated
      with negative NSLN findings. When all factors were included in a logistic
      regression analysis, the significant predictor of NSLN metastasis was extranodal
      extension (P =.002). Lymphovascular invasion was not associated with positive
      NSLN findings (P =.11). The number of sentinel nodes removed also had no bearing
      on the status of the NSLNs (P =.37). CONCLUSIONS: Although primary tumor size and
      micrometastases correlate with the status of the NSLNs, extranodal extension is
      the most important independent predictor of NSLN metastasis. These findings may
      ultimately spare patients a full axillary lymph node dissection. However, pending
      results of larger clinical trials, full axillary lymph node dissection is still
      recommended for patients with sentinel lymph node metastases.

PMID- 15197093
TI  - Endotoxin has an indirect vasodilatory effect on isolated human skeletal muscle
      arterioles.
AB  - BACKGROUND: Septic shock and its effects are a major cause of mortality in the
      intensive care environment. The exact effect and mechanism of endotoxin has yet
      to be fully described. With a better understanding of this process, better
      clinical tools could be developed to treat these patients. HYPOTHESIS: Endotoxin
      has no direct effect on human skeletal muscle microvasculature and requires the
      release of an endothelial-derived factor to produce the vasodilation seen in gram
      negative sepsis. DESIGN: Benchtop research using an isolated arteriole model with
      controlled exposure to endotoxin. SETTING: University medical center. METHODS:
      First-order arterioles (approximately 150- micro m diameter) were isolated from
      human cremasteric muscles and pressurized to physiologic levels before exposure
      to an endotoxin-rich effluent with and without an upstream conduit vessel
      (superficial epigastric vein). The vasodilatory effect was measured with
      videomicroscopy and compared with control samples. MAIN OUTCOME MEASURES: Mean
      vessel diameter and percentage of loss in tone. RESULTS: When compared with
      controls, the isolated arteriole had no significant response when exposed to
      endotoxin alone (3.5% change in basal tone). When the endotoxin was allowed to
      pass over an upstream conduit vessel, the arteriole showed marked dilation (14.2%
      loss of basal tone). CONCLUSIONS: This study demonstrates that endotoxin has no
      direct vasodilatory effect on human skeletal muscle arterioles, but it is the
      release of an endothelial factor from the upstream conduit vessels that produces
      the loss of tone in the microvasculature. Further research is ongoing to
      characterize the factors involved (nuclear factor-kappaB, tumor necrosis factor
      alpha, and interleuklin 6) for possible clinical intervention (antioxidants,
      cyclosporine, and nitric oxdide synthase inhibitors).

PMID- 15197094
TI  - Predictors of airway complications after thyroidectomy for substernal goiter.
AB  - HYPOTHESIS: Airway complications after thyroidectomy for substernal goiter can be
      predicted by preoperative symptom profiles, radiologic findings, or other
      factors. DESIGN: Retrospective review. Settings A university tertiary care center
      and a veterans' hospital. PATIENTS: Sixty patients with substernal goiter who
      underwent thyroidectomy between 1993 and 2002. MAIN OUTCOME MEASURES: Symptoms,
      preoperative radiologic findings, extent of thyroid resection, tumor size, and
      postoperative complications. RESULTS: Dysphagia was the most common preoperative
      symptom (n = 26), followed by dyspnea (n = 21), orthopnea (n = 13), and
      hoarseness (n = 6); 18 patients (30%) had superior vena caval obstruction.
      Thirteen patients (22%) were asymptomatic. Preoperative imaging identified
      tracheal deviation or compression in 45 patients (75%). Substernal goiter was
      resected via a cervical approach in 59 patients (98%). Of 47 patients with
      preoperative symptoms, 41 (87%) reported improvement postoperatively. Seven
      patients (12%) had postoperative airway complications: 1 developed a neck
      hematoma requiring reoperation, and 6 could not be immediately extubated; all 6
      were successfully extubated after 1 to 10 days. Patients with airway
      complications were older (mean +/- SEM, 70.3 +/- 3.6 years vs 61.5 +/- 2.2
      years), had larger goiters (mean +/- SEM, 210.7 +/- 37.0 g vs 112.2 +/- 7.7 g),
      and were more likely to have tracheal compression on preoperative imaging than
      those who did not have complications (P<.05). CONCLUSIONS: Most patients with
      substernal goiters underwent thyroid resection via a cervical approach with an
      improvement in symptoms. The few patients who developed postoperative airway
      complications were older, had larger goiters, and were more likely to have
      tracheal compression on preoperative imaging than those without airway
      complications.

PMID- 15197095
TI  - The incomplete bibliography: notes of a bibliography watcher.

PMID- 15197096
TI  - D2.5 dissection for gastric carcinoma.
AB  - Worldwide, gastric cancer ranks second only to lung cancer in mortality and
      accounts for 500 000 deaths annually. Since 1930, the incidence of gastric
      carcinoma in the United States has been declining steadily and plateaued during
      the 1980-1990 decade. Mortality rates for white males in the United States were
      approximately 40 per 100000 in 1930, compared with 5.4 per 100000 in 1994. For
      nonwhite males the rates were 23.7 per 100 000 in 1955 and 12 per 100 000 in
      1985. In the United States in 2002, an estimated 21 600 new cases and 12 400
      deaths were attributable to gastric carcinoma.

PMID- 15197097
TI  - Artificial liver support: potential to retard regeneration?
AB  - HYPOTHESIS: The concept of an "artificial liver" has been in development for over
      40 years. Such devices aim to temporarily assume metabolic and excretory
      functions of the liver, with removal of potentially hepatotoxic substances,
      thereby clinically stabilizing patients and preventing deterioration while
      awaiting transplantation. If sufficient numbers of viable hepatocytes remain,
      regeneration and subsequent recovery of innate liver function may occur. However,
      these devices have not yet become part of routine clinical use. Much less is
      known regarding the effect such devices have, if any, on circulating cytokines
      and growth factors and the subsequent effects on the regenerating liver. If these
      devices remove or reduce factors known to promote regeneration, is the rate of
      regeneration retarded? Conversely, does the incorporation of hepatocytes into
      bioartificial support systems confer an advantage through the production of
      growth-promoting factors from these cultured hepatocytes?Data Sources,
      Extraction, and STUDY SELECTION: Data were obtained using PubMed search for
      reports involving liver support, extracorporeal circuits, dialysis, growth
      factors, and cytokines. Those reports specifically looking at the effect of
      artificial liver support on cytokines and growth factors are discussed.
      CONCLUSIONS: There is a paucity of information on the key events and substances
      involved in hepatic regeneration. In addition, there is a potential impact of
      liver support devices on the regeneration of substances associated with hepatic
      regeneration. Further study is needed.

PMID- 15197098
TI  - George Crile, Harvey Cushing, and the Ambulance Americaine: military medical
      preparedness in World War I.
AB  - In a little-remembered episode of American surgical history, more than 2 years
      before the nation's formal entry into World War I in April 1917, teams of
      surgeons and their support personnel had already been deployed in France. The
      surgeons' service at the Ambulance Americaine in Paris and at other smaller
      hospital facilities in the French countryside brought about the efficient
      integration of civilian American medicine into World War I's military structure.
      Under the leadership of George Crile and Harvey Cushing, this early American
      surgical presence in France created remarkable organizational and scientific
      advances in military medicine and prepared the United States to go to war.

PMID- 15197100
TI  - Image of the month. Gastric duplication cyst.

PMID- 15197101
TI  - Neuroprotective efficacy and therapeutic time window of peroxynitrite
      decomposition catalysts in focal cerebral ischemia in rats.
AB  - Free radicals have been implicated in cerebral ischemia reperfusion (IR) injury.
      Massive production of nitric oxide and superoxide results in continuous formation
      of peroxynitrite even several hours after IR insult. This can produce DNA strand
      nicks, hydroxylation and/or nitration of cytosolic components of neuron, leading
      to neuronal death. Peroxynitrite decomposition catalysts 5,10,15,20-tetrakis(N
      methyl-4'-pyridyl)porphyrinato iron (III) (FeTMPyP) and 5,10,15,20-tetrakis(4
      sulfonatophenyl)porphyrinato iron (III) (FeTPPS) have been demonstrated to
      protect neurons in in vitro cultures; however, their neuroprotective efficacy in
      cerebral IR injury has not been explored. In the present study, we investigated
      the efficacy and the therapeutic time window of FeTMPyP and FeTPPS in focal
      cerebral ischemia (FCI). FCI was induced according to the middle cerebral artery
      occlusion (MCAO) method. After 2 h of MCAO and 70 h of reperfusion, the extent of
      neurological deficits, infarct and edema volume were measured in Sprague-Dawley
      rats. FeTMPyP and FeTPPS were administered at different time points 2, 6, 9 and
      12 h post MCAO. FeTMPyP and FeTPPS (3 mg kg(-1), i.v.) treatment at 2 and 6 h
      post MCAO produced significant reduction in infarct volume, edema volume and
      neurological deficits. However, treatment at latter time points did not produce
      significant neuroprotection. Significant reduction of peroxynitrite in blood and
      nitrotyrosine in brain sections was observed on FeTMPyP and FeTPPS treatment. As
      delayed treatment of FeTMPyP and FeTPPS produced neuroprotection, we tested
      whether treatment had any influence over the apoptotic neuronal death. DNA
      fragmentation and in situ nick end-labeling assays showed that FeTMPyP and FeTPPS
      treatment reduced IR injury-induced DNA fragmentation. In conclusion,
      peroxynitrite decomposition catalysts (FeTMPyP and FeTPPS) produced prominent
      neuroprotection even if administered 6 h post MCAO and the neuroprotective effect
      is at least in part due to the reduction of peroxynitrite and apoptosis.

PMID- 15197102
TI  - Synergistic interaction between enalapril, L-arginine and tetrahydrobiopterin in
      smooth muscle cell apoptosis and aortic remodeling induction in SHR.
AB  - Smooth muscle cell (SMC) apoptosis occurs at the onset of enalapril-induced
      regression of aortic hypertrophy in SHR. A potential mechanism is the correction
      of endothelial dysfunction (ED) leading to reduced production of reactive oxygen
      species and enhanced bioavailability of nitric oxide (NO), a potent apoptosis
      inducer. Stimulants of NO include the precursor L-arginine and the NO synthase
      cofactor tetrahydrobiopterin (BH(4)), which correct ED in several models. The
      objective was to examine the relationships between ED and the cell growth/death
      balance during vascular remodeling induced by enalapril in SHR. SHR, 10-week-old,
      received enalapril (ENA: 30 mg x kg(-1) x day(-1) p.o.) for 1 or 2 weeks, or a co
      treatment of L-arginine (2.0 g x kg(-1) x day(-1) p.o.) and BH(4) (5.4 mg x kg(
      1) x day(-1) i.p. twice daily) administered alone (group: LB) or in combination
      with enalapril (ENA+LB) for 1 week. Controls received vehicle. After 1 week, ED
      was completely corrected with LB but not affected significantly by ENA, whereas
      both treatments failed to induce SMC apoptosis or aortic remodeling. The
      correction of ED and the induction of SMC apoptosis (3.3-fold increase in TUNEL
      labeling) required 2 weeks of ENA treatment. The combination of LB with ENA for 1
      week, however, was additive for the reduction of SMC proliferation, and
      synergistic for the induction of apoptosis and regression of vascular
      hypertrophy. These interactions were independent of blood pressure regulation.
      Our results suggest that the correction of ED is not sufficient to induce SMC
      apoptosis and vascular remodeling, although it facilitates these responses during
      enalapril treatment.

PMID- 15197103
TI  - AT2 receptor-mediated vasodilatation is unmasked by AT1 receptor blockade in
      conscious SHR.
AB  - In the present study, we investigated the role of the angiotensin II type 2
      receptor (AT(2)) receptor in the regulation of regional haemodynamics in
      spontaneously hypertensive rats (SHR). We tested the hypothesis that AT(2)
      receptor activation directly causes vasodilatation. Mean arterial pressure (MAP),
      renal, mesenteric and hindquarters flows and conductances were measured in
      various groups of conscious rats that received the following drug combinations on
      separate days: the AT(1) receptor antagonist, candesartan (5 or 10 microg kg(-1)
      i.v.) alone, the AT(2) receptor agonist, CGP42112 (1 microg kg(-1) min(-1)) alone
      and candesartan plus CGP42112. Low-dose candesartan (5 microg kg(-1)) caused
      renal vasodilatation, while CGP 42112 alone caused minimal haemodynamic effects.
      In the presence of candesartan, CGP42112 caused a marked depressor effect
      together with generalised vasodilatation that was abolished by the coinfusion of
      the AT(2) receptor antagonist, PD123319 (50 microg kg(-1) min(-1)), with the
      candesartan and CGP42112 combination. PD123319, given alone, increased MAP and
      reduced renal and mesenteric conductances. We also confirmed that the enhanced
      vasodilatation evoked by candesartan plus CGP42112 was not due to additional
      AT(1) receptor blockade, since angiotensin II-mediated vasoconstriction was
      inhibited by a similar magnitude in the combination treatment compared with
      candesartan alone. Analogous experiments in Wistar-Kyoto rats did not demonstrate
      significantly enhanced effects due to candesartan plus CGP42112. Collectively,
      these data suggest that, in SHR, AT(2) receptors tonically modulate vascular tone
      and that direct AT(2) receptor-mediated vasodilatation was unmasked by AT(1)
      receptor blockade.

PMID- 15197105
TI  - A quantitative and comparative study of the effects of a synthetic ciguatoxin
      CTX3C on the kinetic properties of voltage-dependent sodium channels.
AB  - Ciguatoxins (CTXs) are known to bind to receptor site 5 of the voltage-dependent
      Na channel, but the toxin's physiological effects are poorly understood. In this
      study, we investigated the effects of a ciguatoxin congener (CTX3C) on three
      different Na-channel isoforms, rNa(v)1.2, rNa(v)1.4, and rNa(v)1.5, which were
      transiently expressed in HEK293 cells. The toxin (1.0 micromol l(-1)) shifted the
      activation potential (V(1/2) of activation curve) in the negative direction by 4
      9 mV and increased the slope factor (k) from 8 mV to between 9 and 12 mV
      (indicative of decreased steepness of the activation curve), thereby resulting in
      a hyperpolarizing shift of the threshold potential by 30 mV for all Na channel
      isoforms. The toxin (1.0 micromol l(-1)) significantly accelerated the time-to
      peak current from 0.62 to 0.52 ms in isoform rNa(v)1.2. Higher doses of the toxin
      (3-10 micromol l(-1)) additionally decreased time-to-peak current in rNa(v)1.4
      and rNa(v)1.5. A toxin effect on decay of I(Na) at -20 mV was either absent or
      marginal even at relatively high doses of CTX3C. The toxin (1 micromol l(-1))
      shifted the inactivation potential (V(1/2) of inactivation curve) in the negative
      direction by 15-18 mV in all isoforms. I(Na) maxima of the I-V curve (at -20 mV)
      were suppressed by application of 1.0 micromol l(-1) CTX3C to a similar extent
      (80-85% of the control) in all the three isoforms. Higher doses of CTX3C up to 10
      micromol l(-1) further suppressed I(Na) to 61-72% of the control. Recovery from
      slow inactivation induced by a depolarizing prepulse of intermediate duration
      (500 ms) was dramatically delayed in the presence of 1.0 micromol l(-1) CTX3C, as
      time constants describing the monoexponential recovery were increased from 38+/-8
      to 588+/-151 ms (n=5), 53+/-6 to 338+/-85 ms (n=4), and 23+/-3 to 232+/-117 ms
      (n=3) in rNa(v)1.2, rNa(v)1.4, and rNa(v)1.5, respectively. CTX3C exerted
      multimodal effects on sodium channels, with simultaneous stimulatory and
      inhibitory aspects, probably due to the large molecular size (3 nm in length) and
      lipophilicity of this membrane-spanning toxin.

PMID- 15197104
TI  - Topiramate modulates pH of hippocampal CA3 neurons by combined effects on
      carbonic anhydrase and Cl-/HCO3- exchange.
AB  - Topiramate (TPM) is an anticonvulsant whose impact on firing activity and
      intracellular pH (pHi) regulation of CA3 neurons was investigated. Using the 4
      aminopyridine-treated hippocampal slice model bathed in bicarbonate-buffered
      solution, TPM (25-50 microm) reduced the frequency of epileptiform bursts and
      action potentials without affecting membrane potential or input resistance.
      Inhibitory effects of TPM were reversed by trimethylamine-induced alkalinization.
      TPM also lowered the steady-state pHi of BCECF-AM-loaded neuronal somata by
      0.18+/-0.07 pH units in CO(2)/HCO(3)(-)-buffered solution. Subsequent to an
      ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery.
      These complex changes were mimicked by the protein phosphatase inhibitor okadaic
      acid. Alkalosis upon withdrawal of extracellular Cl(-) was augmented by TPM.
      Furthermore, at decreased pHi due to the absence of extracellular Na(+), TPM
      reversibly increased pHi. These findings demonstrate that TPM modulates Na(+)
      independent Cl(-)/HCO(3)(-) exchange. In the nominal absence of extracellular
      CO(2)/HCO(3)(-) buffer, both steady-state pHi and firing of epileptiform bursts
      remained unchanged upon adding TPM. However, pHi recovery subsequent to an
      ammonium prepulse was slightly increased, as was the case in the presence of the
      carbonic anhydrase (CA) inhibitor acetazolamide. Thus, a slight reduction of
      intracellular buffer capacity by TPM may be due to an inhibitory effect on
      intracellular CA. Together, these findings show that TPM lowers neuronal pHi most
      likely due to a combined effect on Na(+)-independent Cl(-)/HCO(3)(-) exchange and
      CA. The apparent decrease of steady-state pHi may contribute to the
      anticonvulsive property of TPM.

PMID- 15197106
TI  - Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the
      acoustic startle in rats: possible involvement of central nicotinic alpha7
      receptors.
AB  - Nicotine has been reported to normalize deficits in auditory sensory gating in
      the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine
      receptors in attentional abnormalities. However, the mechanism remains unclear.
      The present study investigated the effects of nicotine on the disruption of
      prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine
      or phencyclidine in rats. Over the dose range tested, nicotine (0.05-1 mg kg(-1),
      s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5-5 mg kg(-1), s.c.), an
      alpha(7) nicotinic receptor antagonist, nor dihydro-beta-erythroidine (0.5-2 mg
      kg(-1), s.c.), an alpha(4)beta(2) nicotinic receptor antagonist, had any effect
      on PPI. Nicotine (0.01-0.2 mg kg(-1), s.c.) dose-dependently reversed the
      disruption of PPI induced by apomorphine (1 mg kg(-1), s.c.), but had no effect
      on the disruption of PPI induced by phencyclidine (2 mg kg(-1), s.c.). The
      reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg(-1)) was
      eliminated by mecamylamine (1 mg kg(-1), i.p.), but not by hexamethonium (10 mg
      kg(-1), i.p.), indicating the involvement of central nicotinic receptors. The
      antagonistic action of nicotine on apomorphine-induced PPI disruption was dose
      dependently blocked by methyllycaconitine (1 and 2 mg kg(-1), s.c.). However,
      dihydro-beta-erythroidine (1 and 2 mg kg(-1), s.c.) had no effect. These results
      suggest that nicotine reverses the disruption of apomorphine-induced PPI through
      central alpha(7) nicotinic receptors.

PMID- 15197107
TI  - Pharmacological characterization of human S1P4 using a novel radioligand, [4,5
      3H]-dihydrosphingosine-1-phosphate.
AB  - Sphingosine-1-phosphate (S1P) is a bioactive lipid that affects a variety of
      cellular processes through both its actions as a second messenger and via
      activation of a family of G protein-coupled receptors (S1P(1-5)). The study of
      S1P receptor pharmacology, particularly S1P(4), has been hindered by the lack of
      high-affinity radioligands with good specific activity. The studies presented
      herein characterize [(3)H]DH-S1P as a stable, high-affinity radioligand for
      S1P(4) pharmacology. Using a transfected Ba/F3 cell line selected for high
      hS1P(4) surface expression, we compared the consequences of different cellular
      backgrounds and commercial sources of sphingophospholipids on S1P(4)
      characterization. The development and subsequent use of the assay described has
      enabled us to extensively and definitively characterize the pharmacology of the
      human S1P(4) receptor.

PMID- 15197109
TI  - Subtype specific internalization of P2Y1 and P2Y2 receptors induced by novel
      adenosine 5'-O-(1-boranotriphosphate) derivatives.
AB  - P2Y-nucleotide receptors represent important targets for drug development. The
      lack of stable and receptor specific agonists, however, has prevented successful
      therapeutic applications. A novel series of P-boronated ATP derivatives (ATP
      alpha-B) were synthesized by substitution of a nonbridging O at P(alpha) with a
      BH(3) group. This introduces a chiral center, thus resulting in diastereoisomers.
      In addition, at C2 of the adenine ring a further substitution was made (Cl- or
      methylthio-). The pairs of diastereoisomers were denoted here as A and B isomers.
      Here, we tested the receptor subtype specificity of these analogs on HEK 293
      cells stably expressing rat P2Y(1) and rat P2Y(2) receptors, respectively, both
      attached to the fluorescent marker protein GFP (rP2Y(1)-GFP, rP2Y(2)-GFP). We
      investigated agonist-induced receptor endocytosis, [Ca(2+)](i) rise and
      arachidonic acid (AA) release. Agonist-induced endocytosis of rP2Y(1)-GFP was
      more pronounced for the A isomers than the corresponding B counterparts for all
      ATP-alpha-B analogs. Both 2-MeS-substituted diastereoisomers induced a greater
      degree of agonist-induced receptor endocytosis as compared to the 2-Cl
      substituted derivatives. Endocytosis results are in accordance with the potency
      to induce Ca(2+) release by these compounds in HEK 293 cells stably transfected
      with rP2Y(1). In case of rP2Y(2)-GFP, the borano-nucleotides were very weak
      agonists in comparison to UTP and ATP in terms of Ca(2+) release, AA release and
      in inducing receptor endocytosis. The different ATP-alpha-B derivatives and also
      the diastereoisomers were equally ineffective. Thus, the new agonists may be
      considered as potent and highly specific agonist drug candidates for P2Y(1)
      receptors. The difference in activity of the ATP analogs at P2Y receptors could
      be used as a tool to investigate structural differences between P2Y receptor
      subtypes.

PMID- 15197108
TI  - Stimulus-specific defect in the phagocytic pathways of annexin 1 null
      macrophages.
AB  - The role of the glucocorticoid-regulated protein annexin 1 during the process of
      phagocytosis has been studied using annexin 1 null peritoneal macrophages. Wild
      type and annexin 1 null macrophages were incubated with several distinct
      phagocytic targets. No differences were observed in rate or the maximal response
      with respect to IgG complexes or opsonised zymosan phagocytosis, as assessed by
      monitoring the production of reactive oxygen species. When annexin 1 null
      macrophages were incubated with non-opsonised zymosan particles, they exhibited
      impaired generation of reactive oxygen species, which was linked to a defect in
      binding of cells to the particles, as determined with fluorescent zymosan. This
      phenomenon was further confirmed by electron microscopy analysis, where annexin 1
      null macrophages internalised fewer non-opsonised zymosan particles. Specific
      alterations in macrophage plasma membrane markers were observed in the annexin 1
      null cells. Whereas no differences in dectin-1 and FcgammaR II/III expression
      were measured between the two genotypes, decreased membrane CD11b and F4/80
      levels were measured selectively in macrophages lacking annexin 1. These cells
      also responded with an enhanced release of PGE(2) and COX-2 protein expression
      following addition of the soluble stimulants, LPS and heat-activated IgG. In
      conclusion, these results suggest that participation of endogenous annexin 1
      during zymosan phagocytosis is critical and that this protein plays a tonic
      inhibitory role during macrophage activation.

PMID- 15197111
TI  - Brain areas involved in speech production.

PMID- 15197110
TI  - Molecular pharmacological profile of the nonredox-type 5-lipoxygenase inhibitor
      CJ-13,610.
AB  - 5-Lipoxygenase (5-LO) is a crucial enzyme in the synthesis of the bioactive
      leukotrienes (LTs) from arachidonic acid (AA), and inhibitors of 5-LO are thought
      to prevent the untowarded pathophysiological effects of LTs. In this study, we
      present the molecular pharmacological profile of the novel nonredox-type 5-LO
      inhibitor CJ-13,610 that was evaluated in various in vitro assays. In intact
      human polymorphonuclear leukocytes (PMNL), challenged with the Ca(2+)-ionophore
      A23187, CJ-13,610 potently suppressed 5-LO product formation with an IC(50)=0.07
      microm. Supplementation of exogenous AA impaired the efficacy of CJ-13,610,
      implying a competitive mode of action. In analogy to ZM230487 and L-739.010, two
      closely related nonredox-type 5-LO inhibitors, CJ-13,610 up to 30 microm failed
      to inhibit 5-LO in cell-free assay systems under nonreducing conditions, but
      inclusion of peroxidase activity restored the efficacy of CJ-13,610 (IC(50)=0.3
      microm). In contrast to ZM230487 and L-739.010, the potency of CJ-13,610 does not
      depend on the cell stimulus or the activation pathway of 5-LO. Thus, 5-LO product
      formation in PMNL induced by phosphorylation events was equally suppressed by CJ
      13,610 as compared to Ca(2+)-mediated 5-LO activation. In transfected HeLa cells,
      CJ-13,610 only slightly discriminated between phosphorylatable wild-type 5-LO and
      a 5-LO mutant that lacks phosphorylation sites. In summary, CJ-13,610 may possess
      considerable potential as a potent orally active nonredox-type 5-LO inhibitor
      that lacks certain disadvantages of former representatives of this class of 5-LO
      inhibitors.

PMID- 15197112
TI  - What's a nice patient like you doing with a complication like this? Diagnosis,
      prognosis and prevention of spinal hematoma.

PMID- 15197113
TI  - Craniotomy for suprasellar meningioma during pregnancy: role of fetal monitoring.

PMID- 15197115
TI  - Intramuscular tramadol increases gastric pH during anesthesia.
AB  - PURPOSE: Tramadol, [(1RS, 2RS)-2-dimethylamino) methyl-1-(3-methoxyphenyl)
      cyclohexanol hydrochloride], is an analgesic in clinical use. It has been
      reported that tramadol inhibits muscarinic type 3 receptor function, which
      primarily mediates smooth muscle contraction and glandular secretion. We
      investigated the effects of tramadol on the pH of gastric juices during
      anesthesia to determine whether tramadol inhibits secretion from the gastric
      glands. METHODS: ASA physical status I or II adult patients (n = 30) presenting
      for major elective orthopedic surgery of the upper extremities or mastectomy were
      enrolled. Patients were randomly assigned to receive treatment with tramadol (n =
      10), famotidine (n = 10), or saline (n = 10). General anesthesia was then induced
      using propofol, vecuronium bromide, and fentanyl. After inducing anesthesia, the
      gastric pH was measured using pH test paper and, then, 100 mg tramadol, 20 mg
      famotidine, or saline were injected into the deltoid muscle. Three hours after
      starting the operation, gastric juice was again aspirated and its gastric pH
      measured. RESULTS: There were no differences in the pH before anesthesia between
      the three groups. By contrast, gastric pH was increased in the tramadol group by
      the same amount as it was in the famotidine group three hours after administering
      the drugs. Gastric pH of the saline, famotidine, and tramadol groups was 2.6 +/-
      2.5, 6.3 +/- 2.0, and 6.4 +/- 0.8, respectively. CONCLUSION: These results
      suggest that tramadol inhibits the secretion of gastric acid.

PMID- 15197114
TI  - The A-line ARX index may be a more sensitive detector of arousal than the
      bispectral index during propofol-fentanyl-nitrous oxide anesthesia: a preliminary
      investigation.
AB  - PURPOSE: To compare changes in the A-line ARX index (AAI) by the Alaris AEP
      monitor(TM) with those of the bispectral index (BIS) during propofol-fentanyl
      nitrous oxide anesthesia. METHODS: Eighty female patients undergoing partial
      mastectomy were randomly allocated to AAI or BIS (40 per group). Anesthesia was
      induced with propofol 2 mg x kg(-1) and fentanyl 3 micro g x kg(-1) during the
      inhalation of oxygen. A laryngeal mask airway (LMA) #3 was inserted. Anesthesia
      was maintained with propofol 4 mg x kg(-1) x hr(-1), fentanyl 1 micro g x kg(-1)
      given at the start of surgery, and nitrous oxide 4 L x min(-1) in oxygen 2 L x
      min(-1). Blood pressure, heart rate, and AAI or BIS were monitored, including
      recovery time of the index after disturbance by electrocautery. RESULTS: The AAI
      but not the BIS increased significantly with LMA insertion and skin incision,
      while blood pressure and heart rate did not change. The BIS decreased from 87 +/-
      7 to 30-60 while the AAI decreased from 75 +/- 8 to 10-25 during anesthesia. The
      increase of the AAI was larger than that of the BIS at recovery from anesthesia.
      The variation of the index was smaller in the AAI than in the BIS. Recovery time
      of the index after electrocautery was significantly longer in the BIS group (21
      +/- 9 sec) than that in the AAI group (5 +/- 3 sec). CONCLUSIONS: During propofol
      fentanyl-nitrous oxide anesthesia, the AAI responded to LMA insertion or surgical
      incision, but not the BIS, and the AAI had smaller variations. The AAI recovered
      faster from the disturbance by electrocautery than the BIS. Thus, the AAI may be
      a more sensitive and useful detector of arousal than the BIS.

PMID- 15197116
TI  - Study design, originality and overall consistency influence acceptance or
      rejection of manuscripts submitted to the Journal.
AB  - PURPOSE: To identify the characteristics of the manuscripts submitted to the
      Canadian Journal of Anesthesia (CJA) associated with their acceptance or
      rejection and to analyze the reviewers' comments and their impact on the editors'
      decision to publish. METHODS: Peer review material was analyzed from 213
      submissions to the CJA. Characteristics of accepted and rejected manuscripts were
      compared. Reviewers' comments were classified according to editorial criteria
      used by the journal and the distribution of the different types of comments
      amongst accepted and rejected submissions was compared. RESULTS: Characteristics
      of 213 manuscripts and comments from 405 reviewers were analyzed. Overall, 57% of
      manuscripts submitted to the CJA were accepted. The type of research (study vs
      case report, clinical vs laboratory science) had no impact on the fate of the
      manuscripts; however, frequency of acceptance differed between articles
      originating from different geographic regions (P < 0.0001) with Canadian
      submissions posting the highest frequency (86%). Comment analysis suggests that
      the relationship between the experimental design, the results, and the conclusion
      was the main determinant of an article's fate. Lack of originality or
      inappropriate experimental design were likely to be associated with rejection.
      Conversely, aspects involving the presentation of manuscripts (tables, figures,
      references) were rarely cited as reasons to justify acceptance or rejection.
      CONCLUSION: Although articles are judged on many criteria, authors need to be
      aware that some aspects of a manuscript, namely the relationship between
      experimental design, results, and conclusions, the originality, and the use of an
      appropriate study design, are the most important features with regard to its
      acceptance or rejection.

PMID- 15197117
TI  - Spontaneous recovery from a spinal epidural hematoma with atypical presentation
      in a nonagenarian.
AB  - PURPOSE: Spinal epidural hematoma following epidural anesthesia is
      extraordinarily rare in association with low-dose sc heparin, and the prognosis
      for neurologic recovery without rapid surgical decompression poor. We report a
      case of spinal epidural hematoma in a nonagenarian who received low-dose sc
      unfractionated heparin postoperatively in accordance with standard guidelines,
      presented with no back pain, and made full neurologic recovery without surgical
      intervention. CLINICAL FEATURES: A 90-yr-old female with gastric adenocarcinoma
      presented for subtotal gastrectomy. Her past medical history and physical
      examination were largely unremarkable and she had no bleeding diathesis. She took
      no medications other than preoperative ranitidine, and had a normal coagulation
      profile. A thoracic epidural catheter was placed uneventfully before induction of
      general anesthesia. Postoperatively, low-dose sc unfractionated heparin was
      started 12 hr after the epidural catheter insertion. On postoperative day two,
      the patient developed flaccid lower extremity paralysis and paresthesia without
      back pain. Her coagulation profile remained normal. Subsequent magnetic resonance
      imaging showed a large epidural hematoma extending from T3 to T11. With
      conservative treatment and no surgery, the patient slowly made full neurologic
      recovery and was discharged home on postoperative day 56. CONCLUSION: Complete
      neurologic recovery from flaccid paralysis following spinal epidural hematoma
      occurred without surgical decompression in a nonagenarian. Low-dose sc heparin
      may be a greater risk factor for spinal epidural hematoma than previously
      assumed, and the absence of back pain does not rule out this diagnosis.

PMID- 15197118
TI  - Sedation after spinal anesthesia in elderly patients: a preliminary observational
      study with the PSA-4000.
AB  - PURPOSE: Neuraxial blockade is known to have a sedative effect, decreasing the
      need for inhalational and iv anesthetic agents. The purpose of the present study
      was to quantify the sedative effect of spinal anesthesia and to determine the
      time of maximum sedation. METHODS: This is an observational study in which 20
      unsedated patients were scheduled to undergo urologic and orthopedic surgeries
      under spinal anesthesia. Patients with pre-existing neurological conditions or
      receiving psychotropic medications were excluded from the study. All received 1.5
      mL (11.25 mg) of hyperbaric bupivacaine 0.75% intrathecally. No sedative or
      narcotic was administered intravenously or intrathecally. The Patient State
      Analyzer, (PSA-4000) was used to monitor sedation along with Observer's
      Assessment of Alertness and Sedation (OAA/S) scores every five minutes.
      Differences in patient state index (PSI) and OAA/S scores are expressed as median
      and range and were evaluated by Wilcoxon's signed rank test for non-parametric
      data; P < 0.05 was considered significant. PSI, OAA/S and time at lowest score
      are expressed as median(range). RESULTS: PSI scores decreased from baseline 99
      (96-99) to 78 (56-87) at 35(14.5-54) min into the spinal anesthetic (P < 0.05).
      OAA/S scores decreased from baseline 5 to 4 (range 3-5) at the time of the lowest
      PSI scores (P < 0.05). CONCLUSIONS: In this elderly patient population, spinal
      anesthesia induced changes in the processed electroencephalogram with reduction
      in PSI and OAA/S scores. The reduction in afferent input to the reticular
      activating system could possibly explain the sedation that has been observed and
      the reduction in the PSA scores.

PMID- 15197119
TI  - Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve
      blockade in mice.
AB  - PURPOSE: Liposomal formulations of local anesthetics (LA) are able to control
      drug-delivery in biological systems, prolonging their anesthetic effect. This
      study aimed to prepare, characterize and evaluate in vivo drug-delivery systems,
      composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and
      mepivacaine (MVC). METHODS: BVC and MVC hydrochloride were encapsulated into LUV
      (0.4 micro m) composed of egg phosphatidylcholine, cholesterol and alpha
      tocopherol (4:3:0.07 molar ratio) to final concentrations of 0.125, 0.25, 0.5%
      for BVC and 0.5, 1, 2% for MVC. Motor function and antinociceptive effects were
      evaluated by sciatic nerve blockade induced by liposomal and plain formulations
      in mice. RESULTS: Liposomal formulations modified neither the intensity nor the
      duration of motor blockade compared to plain solutions. Concerning sensory
      blockade, liposomal BVC (BVC(LUV)) showed no advantage relatively to the plain
      BVC injection while liposomal MVC (MVC(LUV)) improved both the intensity (1.4-1.6
      times) and the duration of sensory blockade (1.3-1.7 times) in comparison to its
      plain solution (P < 0.001) suggesting an increased lipid solubility, availability
      and controlled-release of the drug at the site of injection. CONCLUSION: MVC(LUV)
      provided a LA effect comparable to that of BVC. We propose MVC(LUV) drug delivery
      as a potentially new therapeutic option for the treatment of acute pain since the
      formulation enhances the duration of sensory blockade at lower concentrations
      than those of plain MVC.

PMID- 15197120
TI  - Craniotomy for suprasellar meningioma in a 28-week pregnant woman without fetal
      heart rate monitoring.
AB  - PURPOSE: To illustrate the anesthetic management of a craniotomy for suprasellar
      meningioma in a 28-week pregnant woman and to review the considerations for fetal
      monitoring during surgery. CLINICAL FEATURES: A 33-yr-old woman presented at 28
      weeks of gestation with rapidly deteriorating vision in her right eye.
      Neuroradiological investigations revealed a large suprasellar meningioma
      extending into the frontal lobe. She underwent a craniotomy for excision of the
      tumour at 28 weeks gestation because of the risk of irreversible blindness.
      Anesthetic management was tailored for pregnancy and an intracranial tumour.
      Intraoperative blood pressure was maintained within 10% of baseline and
      respiratory variables were stable. No fetal heart rate monitoring was used during
      the surgery, as there was no plan to perform an emergency Cesarean delivery even
      in the event of change in fetal monitoring. The aim was to treat the mother
      aggressively for any untoward events. She made a good neurological recovery after
      the procedure and had a spontaneous vaginal delivery at 40 weeks of gestation
      without any neonatal complications. CONCLUSIONS: Anesthetic management of a brain
      tumour during pregnancy should be tailored to the individual patient according to
      the circumstances. It is possible to perform this type of procedure without fetal
      heart rate monitoring. The decision regarding fetal monitoring should be based on
      the consensus of the multidisciplinary care team and the mother.

PMID- 15197121
TI  - The lateral recumbent head-down position decreases the incidence of epidural
      venous puncture during catheter insertion in obese parturients.
AB  - PURPOSE: The unintentional and unrecognized cannulation of an extradural vein is
      a potentially serious complication of an epidural anesthetic. The present study
      was undertaken to assess the incidence of blood vessel puncture related to
      epidural catheterization in three different body positions, in a cohort of
      morbidly obese parturients, following the completion of a similar study published
      in 2001 from which such parturients were excluded. METHODS: The study was
      conducted in 450 (three groups of 150) morbidly obese, obstetric patients
      undergoing continuous epidural analgesia during labour. Epidural catheterization
      was performed on patients randomized to the sitting, lateral recumbent
      horizontal, or lateral recumbent head-down position. RESULTS: There was a lower
      incidence of vessel cannulation when this procedure was performed in the lateral
      recumbent head-down position [1.3%; body mass index (BMI): 37.0] than in the
      lateral recumbent horizontal [12.9%; BMI: 38.0] and in the sitting position
      [12.0%; BMI: 38.0]. The incidence of accidental subarachnoid puncture was 2%,
      1.3% and 2% respectively, in these same positions. CONCLUSION: Adoption of the
      lateral recumbent head-down position for the performance of lumbar epidural
      blockade, in labour at term, reduces the incidence of lumbar epidural venous
      puncture in these obese parturients.

PMID- 15197122
TI  - Automated intermittent epidural boluses improve analgesia induced by intrathecal
      fentanyl during labour.
AB  - PURPOSE: We compared the efficacy of epidural continual intermittent boluses
      (CIB) with a continuous epidural infusion (CEI) in prolonging labour analgesia
      induced by the combined spinal epidural (CSE) technique. METHODS: CSE was
      instituted in 42 nulliparous parturients at the L3 to 4 level with intrathecal
      (IT) fentanyl 25 micro g followed by an epidural test dose of 3 mL of 1.5%
      lidocaine. These parturients were then randomly assigned to receive either
      epidural CIB (n = 21) or CEI (n = 21) with 0.1% ropivacaine and fentanyl 2 micro
      g x mL(-1). For the CIB, 5 mL boluses were given hourly, with the first bolus 30
      min postinduction. CEI at the rate of 5 mL.hr(-1) was initiated in the minute
      after CSE. The duration of analgesia, pain score, degree of sensorimotor block
      were compared. RESULTS: From Kaplan Meier survival analysis, the duration of
      analgesia was significantly longer in CIB (mean survival time 239 +/- SD 24 min
      vs 181 +/- 17, P < 0.05 using log rank test). During the first three hours
      postblock, the median sensory block to cold was higher in CIB (P < 0.05, Mann U
      Whitney test) but no difference in blood pressure was detected [P > 0.05,
      repeated measure analysis of variance (RMANOVA)]. The serial pain scores were
      lower in the CIB (P < 0.05, RMANOVA). CONCLUSION: CIB prolonged the duration and
      improved the quality of analgesia. CIB could have resulted in an improved spread
      of analgesics in the epidural space or encouraged a direct passage of infusate
      into the IT space. This could have also rendered a higher sensory block to cold
      in the CIB group. CIB is a good alternative to CEI for the maintenance of
      epidural analgesia after CSE.

PMID- 15197123
TI  - Effects on the fetus and newborn of maternal analgesia and anesthesia: a review.
AB  - PURPOSE: To review the effects of maternal anesthesia and analgesia on the fetus
      and newborn. METHODS: An on-line computerized search of Medline, Embase, and the
      Cochrane Collaboration via PubMed was conducted. English language articles were
      selected. The bibliographies of relevant articles and additional material from
      other published sources were retrieved and reviewed. PRINCIPAL FINDINGS: No one
      test clearly separates the effects on the fetus/newborn, if any, of maternally
      administered medication during labour and delivery, or during surgery for non
      obstetric indications. Supposition in this regard is limited in part by
      methodology previously used to study the transplacental passage of various drugs.
      This work needs to be repeated using a human model. Routine maternal supplemental
      oxygen administration is being questioned in light of research showing that free
      radical generation and oxidative stress are implicated as the underlying
      mechanisms in several neonatal conditions. Maternal hypotension is associated
      with neonatal acidemia and base excess correlates with neonatal outcome. Common
      postpartum analgesics transfer minimally into breast milk. Maternal or fetal
      surgery conducted during pregnancy necessitates modification of both anesthetic
      and surgical approaches. The key to resuscitation of the fetus is resuscitation
      of the mother: intra-uterine maneuvers, including perimortem Cesarean section,
      aim to reverse treatable causes of fetal asphyxia, restore fetal oxygenation, and
      correct fetal acidosis. CONCLUSIONS: The well-being of the infant is a major
      criterion for evaluating the anesthetic management of pregnant women. Many tools
      exist to assist with this determination for the fetus, whereas few are available
      to evaluate the newborn.

PMID- 15197124
TI  - [Continuous Svo2 measurements and co-oximetry are not interchangeable immediately
      after cardiopulmonary bypass].
AB  - OBJECTIVE: To determine the accuracy of continuous (in vivo) measurement of mixed
      venous oxygen saturation (SvO(2)), using a fibreoptic catheter, in patients
      having had cardiopulmonary bypass (CPB). METHODS: Using a pulmonary arterial
      catheter, we prospectively studied 14 patients (age 64 +/- 8) having had
      cardiopulmonary bypass. Mean hematocrit was 30 +/- 4%. The catheter was
      calibrated in vitro and in vivo, according to the manufacturer's instructions.
      Fifty-six simultaneous measurements of continuous SvO(2) (CSvO(2)) and measured
      SvO(2) (MSvO(2)) were taken with a co-oxymeter and the paired values were
      analyzed by the linear regression method. To make the two sets of measurements
      interchangeable, we established, a priori, a maximum limit of 3% (approximately
      5% of the measurement), as being an acceptable difference between the two types
      of measurements. RESULTS: All the measurements were obtained within four hours of
      the placement of the catheter. CSvO(2) was weakly correlated with MSvO(2), with a
      correlation coefficient of r(2) = 0.49 (P < 0.001). The Bland-Altman analysis
      demonstrates an objective mean bias of 0.8 +/- 3%, with 36% of the values
      measured falling outside clinically acceptable limits. For values of CSvO(2) <or=
      65%, the measurements were not correlated (P = NS). The bias was -2 +/- 7%, and
      56% of the values measured fell outside clinically acceptable limits.
      CONCLUSIONS: Our results demonstrate that, in the immediate aftermath of
      cardiopulmonary bypass, the continuous measurement of SvO(2) and the co-oxymetry
      determination of mixed blood is not inter-changeable. Other studies will be
      necessary to confirm these results and enable us to understand the
      pathophysiological phenomena accounting for the lack of agreement between the two
      methods.

PMID- 15197126
TI  - Best evidence in critical care medicine: the use of recombinant human
      erythropoietin to reduce red cell transfusions in critically ill patients.

PMID- 15197125
TI  - Contemporary anesthesia ventilators incur a significant "oxygen cost".
AB  - PURPOSE: Anesthesia ventilators use oxygen or oxygen/air mixtures to drive the
      bellows during controlled ventilation. As a practitioner may find himself in a
      situation that the only available oxygen source is a compressed oxygen cylinder,
      it is important to know the oxygen consumption of anesthesia ventilators during
      controlled ventilation. METHODS: We tested the Datex-Ohmeda 7900 ventilator
      mounted on an Excel 210 anesthesia machine under a variety of conditions. For
      comparison, we also tested the Ohmeda 7800 and the Drager AV-2 ventilator under
      control conditions. All experiments were performed using a test lung. RESULTS:
      The oxygen consumption of the AV-2 and the Datex-Ohmeda ventilators averaged 302
      +/- 17 L x hr(-1) and 564 +/- 68 to 599 +/- 56 L x hr(-1), respectively (P < 0.01
      AV-2 vs 7800 and 7900). When using an E-type cylinder, this would result in a
      mean time to alarm of 93 min and 54 to 57 min, respectively. Decreased lung
      compliance increased the oxygen consumption to 848 +/- 16 L x hr(-1).
      CONCLUSIONS: Machine-driven mechanical ventilation incurs a significant "oxygen
      cost." We show that the amount of oxygen consumed by mechanical ventilation with
      contemporary anesthesia ventilators is influenced by patient-dependent factors
      and may greatly exceed the amount of oxygen delivered to the patient.

PMID- 15197128
TI  - Simple changes can improve conduct of end-of-life care in the intensive care
      unit.
AB  - PURPOSE: To describe changes to the conduct of withdrawal of life support (WOLS)
      in two teaching hospital tertiary care medical surgical intensive care units
      (ICUs) in a single centre over two distinct time periods. METHODS: We used a
      retrospective chart review with a before and after comparison. We assessed
      aspects of end-of-life care for ICU patients dying after a WOLS before and after
      we introduced instruments to clarify do not resuscitate (DNR) orders and to
      standardize the WOLS process, sought family input into the conduct of end-of-life
      care, and modified physicians' orders regarding use of analgesia and sedation.
      RESULTS: One hundred thirty-eight patients died following life support withdrawal
      in the ICUs between July 1996 and June 1997 (PRE) and 168 patients died after a
      WOLS between May 1998 and April 1999 (POST). Time from ICU admission to WOLS
      (mean +/- SD) was shorter in the POST period (191 +/- 260 hr PRE vs 135 +/- 205
      hr POST, P = 0.05). Fewer patients in the POST group received cardiopulmonary
      resuscitation in the 12-hr interval prior to death (PRE = 7; POST = 0: P < 0.05).
      Fewer comfort medications were used (PRE: 1.7 +/- 1.0 vs POST: 1.4 +/- 1.0; P <
      0.05). Median cumulative dose of diazepam (PRE: 20.0 vs POST: 10.0 mg; P < 0.05)
      decreased. Documented involvement of physicians in WOLS discussions was unchanged
      but increased for pastoral care (PRE: 10/138 vs POST: 120/168 cases; P < 0.05).
      The majority of nurses (80%) felt that the DNR and WOLS checklists led to
      improved process around WOLS. CONCLUSION: Simple changes to the process of WOLS
      can improve conduct of end-of-life care in the ICU.

PMID- 15197127
TI  - Most critically ill patients are perceived to die in comfort during withdrawal of
      life support: a Canadian multicentre study.
AB  - PURPOSE: Most deaths in intensive care units (ICUs) follow a withdrawal of life
      support (LS). Evaluation of this process including the related perspectives of
      grieving family members is integral to improvement of palliation in the ICU.
      METHODS: A prospective, multicentre, cohort study in six Canadian university
      affiliated ICUs included 206 ICU patients (length of stay >or=48 hr) who received
      mechanical ventilation (MV) before LS withdrawal. We recorded modes, sequence and
      time course of LS withdrawal and drug usage (4 hr before; 4-8 hr and 8-12 hr
      before death). We asked a specified family member to assess patient comfort and
      key aspects of end-of life care. RESULTS: MV was withdrawn from 155/206 (75.2%)
      patients; 97/155 (62.6%) died after extubation and 58/155 (37.4%) died with an
      airway in place. The most frequently used drugs and the cumulative doses [median
      (range)] in the four hours before death were: morphine 119/206, 24 mg, (2-450
      mg); midazolam 45/206, 24 mg, (2-380 mg); and lorazepam 35/206, 4 mg, (1-80 mg).
      These doses did not differ among the three time periods before death. Of 196
      responses from family members most indicated that patients were perceived to be
      either totally (73, 37.2%), very (48, 24.5%), or mostly comfortable (58, 29.6%).
      Times to death, morphine use and family members' perceptions of comfort were
      similar for each type of change to MV. CONCLUSIONS: Most patients were perceived
      by family members to die in comfort during a withdrawal of LS. Perceptions of
      patient comfort and drug use in the hours before death were not associated with
      the mode or sequence of withdrawal of LS, or the time to death.

PMID- 15197131
TI  - Spinal anesthesia in a patient with Down's syndrome.

PMID- 15197130
TI  - Is PDPH from a 25-gauge Whitacre needle always short-lasting and self-resolving?

PMID- 15197132
TI  - Use of a K(+)-adsorption filter for the massive transfusion of irradiated red
      blood cells in a child.

PMID- 15197133
TI  - Spinal anesthesia for Cesarean delivery in a parturient with Arnold-Chiari type I
      malformation.

PMID- 15197134
TI  - A first report on the diagnosis and treatment of acute postoperative airway
      obstruction with the CobraPLA.

PMID- 15197135
TI  - Ease of intubation with the GlideScope or Macintosh laryngoscope by inexperienced
      operators in simulated difficult airways.

PMID- 15197136
TI  - Miniaturizing the GlideScope video laryngoscope system: a new design for enhanced
      portability.

PMID- 15197138
TI  - Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low
      density lipoprotein receptor-deficient mice.
AB  - BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory
      cytokine expressed widely by vascular cells. However, scant in vivo evidence
      supports direct participation of MIF in atherogenesis. Therefore, we investigated
      whether deficiency of MIF modulates atherosclerotic lesion formation and
      composition in low-density lipoprotein receptor-deficient (LDLr-/-) mice. METHODS
      AND RESULTS: MIF-/-LDLr-/- and LDLr-/- mice were generated and consumed an
      atherogenic diet for 12 or 26 weeks. MIF-/-LDLr-/- mice had significantly reduced
      abdominal aorta lipid deposition and intimal thickening from aortic arch
      throughout the abdominal aorta compared with LDLr-/- mice. Marked retardation of
      atherosclerosis over time in MIF-deficient mice accompanied decreased lesion cell
      proliferation. At 26 weeks, 20% of MIF-deficient mice developed only early, fatty
      streak-like lesions, whereas >80% of LDLr-/- mice developed advanced lesions
      containing calcification and lipid cores. Analysis of smooth muscle cells from
      mouse aortae demonstrated that MIF deficiency reduced smooth muscle cell
      proliferation, cysteine protease expression, and elastinolytic and collagenolytic
      activities. CONCLUSIONS: Deficiency of MIF reduces atherogenesis in LDLr-/- mice.
      These results provide novel insight into inflammatory pathways operating in
      atheromata and identify a new potential target for modulating atherogenesis.

PMID- 15197139
TI  - Unexpected severe calcification after transplantation of bone marrow cells in
      acute myocardial infarction.
AB  - BACKGROUND: There has been a rapid increase in the number of clinical trials
      using unselected bone marrow (BM) cells or the mononuclear fraction of BM cells
      for treating ischemic heart diseases. Thus far, no significant deleterious
      effects or complications have been reported in any studies using BM-derived cells
      for treatment of various cardiac diseases. METHODS AND RESULTS: Seven-week-old
      female Fisher-344 rats underwent surgery to induce acute myocardial infarction
      and were randomized into 3 groups of 16 rats, each receiving intramyocardial
      injection of either 7x10(5) DiI-labeled total BM cells (TBMCs), the same number
      of DiI-labeled, clonally expanded BM multipotent stem cells, or the same volume
      of phosphate-buffered saline in the peri-infarct area. Echocardiography 2 weeks
      after cell transplantation indicated intramyocardial calcification in 4 of 14
      surviving rats (28.5%) in the TBMC group. Histological examination with
      hematoxylin and eosin staining and von Kossa staining confirmed the presence of
      extensive intramyocardial calcification. Alkaline phosphatase staining revealed
      strong positivity surrounding the calcified area suggestive of ongoing osteogenic
      activity. Fluorescent microscopic examination revealed that acellular calcific
      areas were surrounded by DiI-labeled TBMCs, suggesting the direct involvement of
      transplanted TBMCs in myocardial calcification. In contrast, in hearts receiving
      equal volumes of saline or BM multipotent stem cells delivered in the same
      manner, there was no evidence of calcification. CONCLUSIONS: These results
      demonstrate that direct transplantation of unselected BM cells into the acutely
      infarcted myocardium may induce significant intramyocardial calcification.

PMID- 15197140
TI  - Regression of carotid atherosclerosis by control of postprandial hyperglycemia in
      type 2 diabetes mellitus.
AB  - BACKGROUND: Postprandial hyperglycemia may be a risk factor for cardiovascular
      disease. We compared the effects of two insulin secretagogues, repaglinide and
      glyburide, known to have different efficacy on postprandial hyperglycemia, on
      carotid intima-media thickness (CIMT) and markers of systemic vascular
      inflammation in type 2 diabetic patients. METHODS AND RESULTS: We performed a
      randomized, single-blind trial on 175 drug-naive patients with type 2 diabetes
      mellitus (93 men and 82 women), 35 to 70 years of age, selected from a population
      of 401 patients who participated in an epidemiological analysis assessing the
      relation of postprandial hyperglycemia to surrogate measures of atherosclerosis.
      Eighty-eight patients were randomly assigned to receive repaglinide and 87
      patients to glyburide, with a titration period of 6 to 8 weeks for optimization
      of drug dosage and a subsequent 12-month treatment period. The effects of
      repaglinide (1.5 to 12 mg/d) and glyburide (5 to 20 mg/d) on CIMT were compared
      by using blinded, serial assessments of the far wall. After 12 months,
      postprandial glucose peak was 148+/-28 mg/dL in the repaglinide group and 180+/
      32 mg/dL in the glyburide group (P<0.01). HbA(1c) showed a similar decrease in
      both groups (-0.9%). CIMT regression, defined as a decrease of >0.020 mm, was
      observed in 52% of diabetics receiving repaglinide and in 18% of those receiving
      glyburide (P<0.01). Interleukin-6 (P=0.04) and C-reactive protein (P=0.02)
      decreased more in the repaglinide group than in the glyburide group. The
      reduction in CIMT was associated with changes in postprandial but not fasting
      hyperglycemia. CONCLUSIONS: Reduction of postprandial hyperglycemia in type 2
      diabetic patients is associated with CIMT regression.

PMID- 15197141
TI  - Soluble fibrin is the main mediator of Staphylococcus aureus adhesion to
      platelets.
AB  - BACKGROUND: Infective endocarditis (IE) caused by Staphylococcus aureus is
      associated with significant morbidity and mortality rates. Platelets play a dual
      role as adhesive cells forming associates with bacteria as well as specialized
      inflammatory cells. The specific role of the various factors involved in bacteria
      platelet association has not yet been fully elucidated. METHODS AND RESULTS: We
      observed a dramatic increase in the capability to bind S aureus when platelets
      were activated with thrombin (from 5% to 30%, P<0.001). To pinpoint platelet
      binding sites involved in the interaction, platelets from knockout mice and from
      patients with selective inherited deficiency of membrane proteins or of granules
      were used. CD36, GPIIb/IIIa, and P-selectin were excluded as receptors for S
      aureus. Platelets from patients with alpha-delta-storage pool disease and Gray
      platelet syndrome indicate the requirement of alpha-granule contents. Platelet
      activation by ADP did not promote platelet-S aureus associate formation, although
      these platelets were covered with bound fibrinogen. Only small numbers of
      associates between fibrinogen-covered bacteria and ADP-activated platelets were
      observed. Formation of fibrin alone was also not sufficient to induce
      association. Only when fibrin formation and platelet activation occurred together
      were large numbers of associates formed (P<0.001). A potential receptor for
      fibrin on S aureus is clumping factor A. Addition of thrombospondin-1 to control
      platelets increased the number of associates (P=0.02). CONCLUSIONS: Soluble
      fibrin but not fibrinogen is the main mediator of platelet-S aureus association.
      In addition, platelet activation and the release of alpha-granule contents,
      particularly thrombospondin-1, is a requirement for platelet-S aureus
      association.

PMID- 15197142
TI  - Inhibition of platelet adherence to mononuclear cells by alpha-tocopherol: role
      of P-selectin.
AB  - BACKGROUND: Platelet-leukocyte interaction is an early important event for
      thrombogenesis, and this process is mainly mediated by P-selectin on platelets.
      Although alpha-tocopherol has been shown to inhibit thrombotic disorders, the
      effect of alpha-tocopherol on platelet P-selectin expression and platelet
      leukocyte interaction is little known. METHODS AND RESULTS: We examined whether
      alpha-tocopherol inhibited human platelet P-selectin expression and platelet
      leukocyte interaction. Alpha-tocopherol (50 to 500 microg/mL) inhibited thrombin
      induced or phorbol 12-myristate 13-acetate (PMA)-induced P-selectin expression on
      platelets. alpha-Tocopherol suppressed platelet-mononuclear cell (MNC)
      interaction, platelet aggregation, and platelet protein kinase C (PKC) activity
      stimulated with either PMA (100 nmol/L) or thrombin. Inhibitory actions of alpha
      tocopherol against the platelet functions were mimicked by staurosporine, a
      selective PKC inhibitor. After oral supplementation of alpha-tocopherol (300 mg/d
      for 3 weeks) in healthy subjects, thrombin-mediated or PMA-mediated P-selectin
      expression, platelet-MNC interaction, and platelet aggregation ex vivo were
      suppressed. CONCLUSIONS: alpha-Tocopherol inhibited P-selectin expression on
      human platelets and thereby attenuated platelet-MNC interactions, which were
      mediated at least in part by the inhibition of intraplatelet PKC activity. These
      actions of alpha-tocopherol on platelet functions provide new insights into the
      antithromboatherogenic properties of alpha-tocopherol.

PMID- 15197143
TI  - N-terminal pro-brain natriuretic peptide on admission has prognostic value across
      the whole spectrum of acute coronary syndromes.
AB  - BACKGROUND: The prognostic value of natriuretic peptide elevations in patients
      with acute coronary syndromes (ACS) is still incompletely defined. We measured N
      terminal pro-brain natriuretic peptide (NT-proBNP) on admission in patients with
      ACS and ECG evidence of myocardial ischemia. METHODS AND RESULTS: The NT-proBNP
      was measured at a median time of 3 hours after symptom onset in 1756 patients.
      The outcome measure was death at 30 days, which occurred in 113 patients (6.4%).
      The median NT-proBNP level was 353 ng/L (107 to 1357 ng/L). Compared with the
      lowest quartile, patients in the second, third, and fourth quartiles had a
      relative risk of subsequent death of 2.94 (95% CI, 1.15 to 7.52), 5.32 (95% CI,
      2.19 to 12.91), and 11.5 (95% CI, 4.90 to 26.87), respectively. The NT-proBNP was
      independently associated with death in a logistic regression model, which
      included clinical variables, ECG, and troponin T in patients either with (OR of
      highest versus lowest quartile, 7.0; 95% CI, 1.9 to 25.6) or without (OR of
      highest versus lowest quartile, 4.1; 95% CI, 1.1 to 14.6) persistent ST-segment
      elevation. NT-proBNP was also an independent predictor of severe heart failure.
      CONCLUSIONS: The measurement of NT-proBNP on admission improves the early risk
      stratification of patients with ACS, suggesting the need for the development of
      targeted therapeutic strategies.

PMID- 15197144
TI  - Functional tetrahydrobiopterin synthesis in human platelets.
AB  - BACKGROUND: Previous studies have provided evidence for the importance of
      platelet-derived nitric oxide (NO) for the regulation of hemostasis.
      Tetrahydrobiopterin (BH4) is an essential cofactor and regulator of NO synthase
      activity in the vasculature; however, it is as yet unknown whether platelets
      dispose over a functional BH4 synthesis. METHODS AND RESULTS: We quantified mRNA
      expression of genes involved in BH4 synthesis, measured enzymatic activities, and
      determined intraplatelet levels of pteridines in platelets from healthy
      volunteers and from patients treated for prolonged periods of time with
      glucocorticoids. Freshly isolated platelets from healthy volunteers show
      functional BH4 synthesis, as evidenced by the presence of mRNA species and
      enzymatic activity of GTP cyclohydrolase I (GTPCH), 6-pyruvoyl tetrahydropterin
      synthase, and sepiapterin reductase. Biopterin was the major intraplatelet
      pteridine, whereas no neopterin was found. mRNA expression and enzymatic activity
      of GTPCH were undetectably low in platelets that had been stored for 5 days, and
      no pteridines were found in these platelets. Freshly isolated platelets from
      patients treated with glucocorticoids had decreased mRNA expression and activity
      of GTPCH compared with platelets from healthy volunteers. CONCLUSIONS: Human
      platelets dispose over a functional de novo BH4 synthesis. Furthermore, our
      results indicate the potential of external factors, eg, prolonged storage or
      glucocorticoid therapy, to significantly affect BH4 synthesis within platelets.
      Together, these findings offer new insights into the biology and pathobiology of
      platelet function in humans.

PMID- 15197145
TI  - Electrophysiological findings in adolescents with atrial fibrillation who have
      structurally normal hearts.
AB  - BACKGROUND: Atrial fibrillation (AF) is uncommon in children, and its mechanisms
      are unknown. This study describes the electrophysiological findings in children
      and adolescents with AF and the outcome of catheter ablation. METHODS AND
      RESULTS: Nine adolescents with symptomatic, lone AF who failed antiarrhythmic
      drug therapy were evaluated. All patients had ECG-documented AF and underwent
      invasive electrophysiological testing. Intracardiac mapping was performed to
      determine the site of spontaneous onset of AF and rapidly firing atrial foci.
      Only the triggering focus was targeted for ablation or isolation. The patients'
      mean age was 15.9+/-3.3 (range, 8 to 19 years). The most common finding was
      rapid, irregular atrial tachycardias in the region of the pulmonary veins (n=5),
      left atrium (n=2), or crista terminalis (n=3). One patient had foci in both the
      pulmonary veins and crista terminalis. The cycle lengths ranged from 108 to 280
      ms. Catheter ablation was acutely successful in 8 patients (88.9%), whereas 1
      patient with multiple left atrium foci was treated with the surgical maze
      operation. Over a mean of 35+/-22 months, 7 patients (77.8%) were arrhythmia free
      on no medications, while AF recurred in 2 patients who are controlled on
      antiarrhythmic medications. Two patients with tachycardia-induced cardiomyopathy
      had resolution of their left ventricular dysfunction after ablation. CONCLUSIONS:
      AF in adolescents with structurally normal hearts is usually due to foci in the
      pulmonary veins, crista terminalis, or left atrium. These foci usually induce
      irregular atrial tachycardias. Catheter ablation of the foci is effective in
      eliminating recurrent AF.

PMID- 15197146
TI  - Papillary muscles do not attach directly to the solid heart wall.
AB  - BACKGROUND: The papillary muscles (PMs) play an important role in normal cardiac
      function, helping to prevent leakage through the AV valves during systole. The
      nature of their attachment to the heart wall can affect the understanding of
      their function. This attachment is conventionally portrayed as a direct
      connection of their bases to the solid portion of the heart wall. X-ray
      multidetector CT provides a new, noninvasive way to investigate this connection
      in vivo. METHODS AND RESULTS: With the use of x-ray multidetector CT with
      interactive 3D reconstruction, the bases of the PMs are seen to attach to the
      trabeculae carneae lining the ventricular wall rather than directly to the solid
      portion of the wall, as has been conventionally believed. This is true for both
      the left and right ventricular PMs. CONCLUSIONS: This new picture of the geometry
      of the attachment of the PMs to the heart wall may have important implications
      for the understanding of their function, including the nature of the transmission
      of the forces between the PMs and the heart wall.

PMID- 15197148
TI  - Tissue Doppler imaging is superior to strain rate imaging and postsystolic
      shortening on the prediction of reverse remodeling in both ischemic and
      nonischemic heart failure after cardiac resynchronization therapy.
AB  - BACKGROUND: A number of noninvasive techniques have been used to predict the
      effectiveness of cardiac resynchronization therapy (CRT) in heart failure
      patients, in particular left ventricular (LV) reverse remodeling. This study
      compared the relative predictive values of tissue Doppler imaging (TDI) and
      strain-rate imaging (SRI) parameters for LV reverse remodeling in patients who
      received CRT and examined for potential differences in ischemic (n=22) and
      nonischemic (n=32) heart failure. METHODS AND RESULTS: TDI and SRI were performed
      at baseline and 3-month follow-up. Eighteen parameters of intraventricular and
      interventricular asynchrony based on the time to peak myocardial contraction (Ts)
      and time to peak strain rate (Tsr) were compared, along with postsystolic
      shortening (PSS). Reverse remodeling with reduction of LV end-diastolic and end
      systolic volumes and gain in ejection fraction (all P<0.001) was observed in the
      whole study population. The standard deviation of Ts of 12 LV segments (Ts-SD) is
      the most powerful predictor of reverse remodeling in both the ischemic (r=-0.65,
      P<0.001) and nonischemic (r=-0.79, P<0.001) groups. The PSS of 12 LV segments was
      a good predictor only for the nonischemic (r=-0.64, P<0.001) but not the ischemic
      (r=0.32, P=NS) group. However, parameters of SRI and interventricular asynchrony
      failed to predict reverse remodeling. By multiple regression analysis,
      independent parameters included Ts-SD in both groups (P<0.005) and PSS of 12 LV
      segments in the nonischemic group (P=0.03). The area of the receiver operating
      characteristic curve was largest for Ts-SD (0.94; CI=0.88 to 1.00). CONCLUSIONS:
      Ts-SD is the most powerful predictor of LV reverse remodeling and was
      consistently useful for ischemic and nonischemic heart failure. However, PSS is
      useful only for nonischemic pathogenesis, whereas the role of SRI parameters was
      not supported by the present study.

PMID- 15197147
TI  - Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high
      density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport
      from macrophages in apolipoprotein E-null mice.
AB  - BACKGROUND: These studies were designed to determine the mechanism of action of
      an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was
      shown to dramatically reduce atherosclerosis in mice. METHODS AND RESULTS: Twenty
      minutes after 500 microg of D-4F was given orally to apoE-null mice, small
      cholesterol-containing particles (CCPs) of 7 to 8 nm with pre-beta mobility and
      enriched in apoA-I and paraoxonase activity were found in plasma. Before D-4F,
      both mature HDL and the fast protein liquid chromatography fractions containing
      the CCPs were proinflammatory. Twenty minutes after oral D-4F, HDL and CCPs
      became antiinflammatory, and there was an increase in HDL-mediated cholesterol
      efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol
      transport from intraperitoneally injected cholesterol-loaded macrophages in vivo.
      In addition, oral D-4F significantly reduced lipoprotein lipid hydroperoxides
      (LOOH), except for pre-beta HDL fractions, in which LOOH increased. CONCLUSIONS:
      The mechanism of action of oral D-4F in apoE-null mice involves rapid formation
      of CCPs, with pre-beta mobility enriched in apoA-I and paraoxonase activity. As a
      result, lipoprotein LOOH are reduced, HDL becomes antiinflammatory, and HDL
      mediated cholesterol efflux and reverse cholesterol transport from macrophages
      are stimulated.

PMID- 15197149
TI  - Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the
      general population.
AB  - BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) are reversible
      inhibitors of cyclooxygenase (COX)-1 and COX-2. Whether transient and incomplete
      COX-1 inhibition with NSAIDs other than aspirin will translate into clinical
      cardioprotection is unclear. Some reports suggest that concurrent aspirin and
      ibuprofen might be associated with lower cardioprotection than aspirin alone
      because of a pharmacodynamic interaction. METHODS AND RESULTS: We conducted a
      cohort study with a nested case-control analysis. Overall, 4975 cases of acute
      myocardial infarction (MI) and death from coronary heart disease (CHD) were
      identified (January 1997 to December 2000) in the UK. A total of 20,000 controls
      were randomly sampled, and frequency was matched to cases by age, sex, and
      calendar year. The incidence rate was 5.0 per 1000 person-years. The multivariate
      adjusted OR for current NSAID use compared with nonuse was 1.07 (95% CI, 0.95 to
      1.20). Treatment duration or daily dose did not change the results. The effect
      was similar among patients free of CHD history (1.04; 95% CI, 0.90 to 1.20) and
      patients with previous history (1.12; 95% CI, 0.91 to 1.38). Estimates for
      individual NSAIDs were all comparable, with no major effect on the risk of acute
      MI. Naproxen was associated with an OR of 0.89 (95% CI, 0.64 to 1.24). The OR of
      aspirin and concurrent NSAIDs use was 1.10 (95% CI, 0.89 to 1.37) compared with
      aspirin alone. We observed the same result when analyzing ibuprofen and aspirin
      taken concomitantly. CONCLUSIONS: This study could not demonstrate any detectable
      risk reduction of NSAIDs on the occurrence of MI. Our results do not support the
      existence of a clinically meaningful interaction between aspirin and NSAIDs,
      including ibuprofen.

PMID- 15197150
TI  - Sudden death in familial polymorphic ventricular tachycardia associated with
      calcium release channel (ryanodine receptor) leak.
AB  - BACKGROUND: Familial polymorphic ventricular tachycardia (FPVT) is characterized
      by exercise-induced arrhythmias and sudden cardiac death due to missense
      mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release
      channel required for excitation-contraction coupling in the heart. METHODS AND
      RESULTS: Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur
      in Finnish families, result in similar mortality rates of approximately 33% by
      age 35 years and a threshold heart rate of 130 bpm, above which exercise induces
      ventricular arrhythmias. Exercise activates the sympathetic nervous system,
      increasing cardiac performance as part of the fight-or-flight stress response. We
      simulated the effects of exercise on mutant RyR2 channels using protein kinase A
      (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of
      calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel.
      After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of
      function defect consistent with leaky Ca2+ release channels and a significant
      rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50).
      Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to
      RyR2 and normalized channel function. CONCLUSIONS: Sympathetic activation during
      exercise induces ventricular arrhythmias above a threshold heart rate in RyR2
      mutation carriers. Simulating the downstream effects of the sympathetic
      activation by PKA phosphorylation of RyR2 channels containing these FPVT missense
      mutations produced a consistent gain-of-function defect. RyR2 function and
      calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2
      channel complex may represent a molecular target for the treatment and prevention
      of exercise-induced arrhythmias and sudden death in these patients.

PMID- 15197151
TI  - Gender-related differences in acute aortic dissection.
AB  - BACKGROUND: Few data exist on gender-related differences in clinical
      presentation, diagnostic findings, management, and outcomes in acute aortic
      dissection (AAD). METHODS AND RESULTS: Accordingly, we evaluated 1078 patients
      enrolled in the International Registry of Acute Aortic Dissection (IRAD) to
      assess differences in clinical features, management, and in-hospital outcomes
      between men and women. Of the patients enrolled in IRAD (32.1%) with AAD, 346
      were women. Although less frequently affected by AAD (32.1% of AAD), women were
      significantly older and had more often presented later than men (P=0.008);
      symptoms of coma/altered mental status were more common, whereas pulse deficit
      was less common. Diagnostic imaging suggestive of rupture, ie, periaortic
      hematoma, and pleural or pericardial effusion were more commonly observed in
      women. In-hospital complications of hypotension and tamponade occurred with
      greater frequency in women, resulting in higher in-hospital mortality compared
      with men. After adjustment for age and hypertension, women with aortic dissection
      die more frequently than men (OR, 1.4, P=0.04), predominantly in the 66- to 75
      year age group. Moreover, surgical outcome was worse in women than men (P=0.013);
      type A dissection in women was associated with a higher surgical mortality of 32%
      versus 22% in men despite similar delay, surgical technique, and hemodynamics.
      CONCLUSIONS: Our analysis provides insights into gender-related differences in
      AAD with regard to clinical characteristics, management, and outcomes; important
      diagnostic and therapeutic implications may help shed light on aortic dissection
      in women to improve their outcomes.

PMID- 15197152
TI  - Prognosis in women with myocardial ischemia in the absence of obstructive
      coronary disease: results from the National Institutes of Health-National Heart,
      Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).
AB  - BACKGROUND: We previously reported that 20% of women with chest pain but without
      obstructive coronary artery disease (CAD) had stress-induced reduction in
      myocardial phosphocreatine-adenosine triphosphate ratio by phosphorus-31 nuclear
      magnetic resonance spectroscopy (abnormal MRS), consistent with myocardial
      ischemia. The prognostic implications of these findings are unknown. METHODS AND
      RESULTS: Women referred for coronary angiography for suspected myocardial
      ischemia underwent MRS handgrip stress testing and follow-up evaluation. These
      included (1) n=60 with no CAD/normal MRS, (2) n=14 with no CAD/abnormal MRS, and
      (3) n=352 a reference group with CAD. Cardiovascular events were death,
      myocardial infarction, heart failure, stroke, other vascular events, and
      hospitalization for unstable angina. Cumulative freedom from events at 3 years
      was 87%, 57%, and 52% for women with no CAD/normal MRS, no CAD/abnormal MRS, and
      CAD, respectively (P<0.01). After adjusting for CAD and cardiac risk factors, a
      phosphocreatine-adenosine triphosphate ratio decrease of 1% increased the risk of
      a cardiovascular event by 4% (P=0.02). The higher event rate in women with no
      CAD/abnormal MRS was primarily due to hospitalization for unstable angina, which
      is associated with repeat catheterization and higher healthcare costs.
      CONCLUSIONS: Among women without CAD, abnormal MRS consistent with myocardial
      ischemia predicted cardiovascular outcome, notably higher rates of anginal
      hospitalization, repeat catheterization, and greater treatment costs. Further
      evaluation into the underlying pathophysiology and possible treatment options for
      women with evidence of myocardial ischemia but without CAD is indicated.

PMID- 15197153
TI  - Should C-reactive protein be added to metabolic syndrome and to assessment of
      global cardiovascular risk?
AB  - Of novel risk factors for cardiovascular disease currently under investigation,
      high-sensitivity C-reactive protein (hsCRP) is the most promising. To date, more
      than 20 prospective epidemiologic studies have demonstrated that hsCRP
      independently predicts vascular risk, 6 cohort studies have confirmed that hsCRP
      evaluation adds prognostic information beyond that available from the Framingham
      Risk Score, and 8 cohort studies have demonstrated additive prognostic value at
      all levels of metabolic syndrome or in the prediction of type 2 diabetes. In
      contrast to several other biomarkers that also reflect biological aspects of
      inflammation, hypofibrinolysis, and insulin resistance, hsCRP measurement is
      inexpensive, standardized, widely available, and has a decade-to-decade variation
      similar to that of cholesterol. Given the consistency of prognostic data for
      hsCRP and the practicality of its use in outpatient clinical settings, we believe
      the time has come for a careful consideration of adding hsCRP as a clinical
      criterion for metabolic syndrome and for the creation of an hsCRP-modified
      coronary risk score useful for global risk prediction in both men and women.
      Toward this end, we believe experts in the fields of epidemiology, prevention,
      vascular biology, and clinical cardiology should be convened to begin discussing
      the merits of this proposal.

PMID- 15197154
TI  - Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to
      enhance collateral formation and those designed to inhibit atherogenesis.

PMID- 15197155
TI  - Molecular genetic advances in cardiovascular medicine: focus on the myocyte.

PMID- 15197156
TI  - Atrial fibrillation and ventricular dysfunction: a vicious electromechanical
      cycle.

PMID- 15197157
TI  - Images in cardiovascular medicine. Polymorphic ventricular tachycardia induced by
      left ventricular pacing.

PMID- 15197158
TI  - Images in cardiovascular medicine. Superiority of computed tomography coronary
      angiography over calcium scoring to accurately evaluate atherosclerotic disease
      in a 35-year-old man.

PMID- 15197159
TI  - Renal transplant patient survival similar after CABG, PCI.

PMID- 15197160
TI  - Parallels between tissue repair and embryo morphogenesis.
AB  - Wound healing involves a coordinated series of tissue movements that bears a
      striking resemblance to various embryonic morphogenetic episodes. There are
      several ways in which repair recapitulates morphogenesis. We describe how almost
      identical cytoskeletal machinery is used to repair an embryonic epithelial wound
      as is involved during the morphogenetic episodes of dorsal closure in Drosophila
      and eyelid fusion in the mouse foetus. For both naturally occurring and wound
      activated tissue movements, JNK signalling appears to be crucial, as does the
      tight regulation of associated cell divisions and adhesions. In the embryo, both
      morphogenesis and repair are achieved with a perfect end result, whereas repair
      of adult tissues leads to scarring. We discuss whether this may be due to the
      adult inflammatory response, which is absent in the embryo.

PMID- 15197161
TI  - Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule
      neurones through Smad5 signalling.
AB  - During development of the cerebellum, sonic hedgehog (Shh) is directly
      responsible for the proliferation of granule cell precursors in the external
      germinal layer. We have looked for signals able to regulate a switch from the Shh
      mediated proliferative response to one that directs differentiation of granule
      neurones. Bone morphogenetic proteins (BMPs) are expressed in distinct neuronal
      populations within the developing cerebellar cortex. Bmp2 and Bmp4 are expressed
      in the proliferating precursors and subsequently in differentiated granule
      neurones of the internal granular layer, whereas Bmp7 is expressed by Purkinje
      neurones. In primary cultures, Bmp2 and Bmp4, but not Bmp7, are able to prevent
      Shh-induced proliferation, thereby allowing granule neuron differentiation.
      Furthermore, Bmp2 treatment downregulates components of the Shh pathway in
      proliferating granule cell precursors. Smad proteins, the only known BMP receptor
      substrates capable of transducing the signal, are also differentially expressed
      in the developing cerebellum: Smad1 in the external germinal layer and Smad5 in
      newly differentiated granule neurones. Among them, only Smad5 is phosphorylated
      in vivo and in primary cultures treated with Bmp2, and overexpression of Smad5 is
      sufficient to induce granule cell differentiation in the presence of Shh. We
      propose a model in which Bmp2-mediated Smad5 signalling suppresses the
      proliferative response to Shh by downregulation of the pathway, and allows
      granule cell precursor to enter their differentiation programme.

PMID- 15197162
TI  - Identifying candidate causal variants responsible for altered activity of the
      ABCB1 multidrug resistance gene.
AB  - The difficulty of fine localizing the polymorphisms responsible for genotype
      phenotype correlations is emerging as an important constraint in the
      implementation and interpretation of genetic association studies, and calls for
      the definition of protocols for the follow-up of associated variants. One recent
      example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1,
      associated with protein expression and activity, and with several clinical
      conditions. Available data suggest that 3435C>T may not directly cause altered
      transport activity, but may be associated with one or more causal variants in the
      poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here
      we describe a strategy for the follow-up of reported associations, including a
      Bayesian formalization of the associated interval concept previously described by
      Goldstein. We focus on the region of high LD around 3435C>T to compile an
      exhaustive list of variants by (1) using a relatively coarse set of marker
      typings to assess the pattern of LD, and (2) resequencing derived and ancestral
      chromosomes at 3435C>T through the associated interval. We identified three
      intronic sites that are strongly associated with the 3435C>T polymorphism. One of
      them is associated with multidrug resistance in patients with epilepsy (chi2 =
      3.78, P = 0.052), and sits within a stretch of significant evolutionary
      conservation. We argue that these variants represent additional candidates for
      influencing multidrug resistance due to P-glycoprotein activity, with the IVS
      26+80 T>C being the best candidate among the three intronic sites. Finally, we
      describe a set of six haplotype tagging single-nucleotide polymorphisms that
      represent common ABCB1 variation surrounding 3435C>T in Europeans.

PMID- 15197163
TI  - Local definition of Ty1 target preference by long terminal repeats and clustered
      tRNA genes.
AB  - LTR-containing retrotransposons reverse transcribe their RNA genomes, and the
      resulting cDNAs are integrated into the genome by the element-encoded integrase
      protein. The yeast LTR retrotransposon Ty1 preferentially integrates into a
      target window upstream of tDNAs (tRNA genes) in the yeast genome. We investigated
      the nature of these insertions and the target window on a genomic scale by
      analyzing several hundred de novo insertions upstream of tDNAs in two different
      multicopy gene families. The pattern of insertion upstream of tDNAs was nonrandom
      and periodic, with peaks separated by approximately 80 bp. Insertions were not
      distributed equally throughout the genome, as certain tDNAs within a given family
      received higher frequencies of upstream Ty1 insertions than others. We showed
      that the presence and relative position of additional tDNAs and LTRs surrounding
      the target tDNA dramatically influenced the frequency of insertion events
      upstream of that target.

PMID- 15197165
TI  - Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully
      compartmentalized genome-scale metabolic model.
AB  - A fully compartmentalized genome-scale metabolic model of Saccharomyces
      cerevisiae that accounts for 750 genes and their associated transcripts,
      proteins, and reactions has been reconstructed and validated. All of the 1149
      reactions included in this in silico model are both elementally and charge
      balanced and have been assigned to one of eight cellular locations (extracellular
      space, cytosol, mitochondrion, peroxisome, nucleus, endoplasmic reticulum, Golgi
      apparatus, or vacuole). When in silico predictions of 4154 growth phenotypes were
      compared to two published large-scale gene deletion studies, an 83% agreement was
      found between iND750's predictions and the experimental studies. Analysis of the
      failure modes showed that false predictions were primarily caused by iND750's
      limited inclusion of cellular processes outside of metabolism. This study
      systematically identified inconsistencies in our knowledge of yeast metabolism
      that require specific further experimental investigation.

PMID- 15197166
TI  - An efficient method to generate chromosomal rearrangements by targeted DNA double
      strand breaks in Drosophila melanogaster.
AB  - Homologous recombination (HR) is an indispensable tool to modify the genome of
      yeast and mammals. More recently HR is also being used for gene targeting in
      Drosophila. Here we show that HR can be used efficiently to engineer chromosomal
      rearrangements such as pericentric and paracentric inversions and translocations
      in Drosophila. Two chromosomal double-strand breaks (DSBs), introduced by the
      rare-cutting I-SceI endonuclease on two different mobile elements sharing
      homologous sequences, are sufficient to promote rearrangements at a frequency of
      1% to 4%. Such rearrangements, once generated by HR, can be reverted by Cre
      recombinase. However, Cre-mediated recombination efficiency drops with increasing
      distance between recombination sites, unlike HR. We therefore speculate that
      physical constraints on chromosomal movement are modulated during DSB repair, to
      facilitate the homology search throughout the genome.

PMID- 15197164
TI  - A transcript finishing initiative for closing gaps in the human transcriptome.
AB  - We report the results of a transcript finishing initiative, undertaken for the
      purpose of identifying and characterizing novel human transcripts, in which RT
      PCR was used to bridge gaps between paired EST clusters, mapped against the
      genomic sequence. Each pair of EST clusters selected for experimental validation
      was designated a transcript finishing unit (TFU). A total of 489 TFUs were
      selected for validation, and an overall efficiency of 43.1% was achieved. We
      generated a total of 59,975 bp of transcribed sequences organized into 432 exons,
      contributing to the definition of the structure of 211 human transcripts. The
      structure of several transcripts reported here was confirmed during the course of
      this project, through the generation of their corresponding full-length cDNA
      sequences. Nevertheless, for 21% of the validated TFUs, a full-length cDNA
      sequence is not yet available in public databases, and the structure of 69.2% of
      these TFUs was not correctly predicted by computer programs. The TF strategy
      provides a significant contribution to the definition of the complete catalog of
      human genes and transcripts, because it appears to be particularly useful for
      identification of low abundance transcripts expressed in a restricted set of
      tissues as well as for the delineation of gene boundaries and alternatively
      spliced isoforms.

PMID- 15197167
TI  - The insertional history of an active family of L1 retrotransposons in humans.
AB  - As humans contain a currently active L1 (LINE-1) non-LTR retrotransposon family
      (Ta-1), the human genome database likely provides only a partial picture of Ta-1
      generated diversity. We used a non-biased method to clone Ta-1 retrotransposon
      containing loci from representatives of four ethnic populations. We obtained 277
      distinct Ta-1 loci and identified an additional 67 loci in the human genome
      database. This collection represents approximately 90% of the Ta-1 population in
      the individuals examined and is thus more representative of the insertional
      history of Ta-1 than the human genome database, which lacked approximately 40% of
      our cloned Ta-1 elements. As both polymorphic and fixed Ta-1 elements are as
      abundant in the GC-poor genomic regions as in ancestral L1 elements, the
      enrichment of L1 elements in GC-poor areas is likely due to insertional bias
      rather than selection. Although the chromosomal distribution of Ta-1 inserts is
      generally a function of chromosomal length and gene density, chromosome 4
      significantly deviates from this pattern and has been much more hospitable to Ta
      1 insertions than any other chromosome. Also, the intra-chromosomal distribution
      of Ta-1 elements is not uniform. Ta-1 elements tend to cluster, and the maximal
      gaps between Ta-1 inserts are larger than would be expected from a model of
      uniform random insertion.

PMID- 15197168
TI  - Extensive expansion of the claudin gene family in the teleost fish, Fugu
      rubripes.
AB  - In humans, the claudin superfamily consists of 19 homologous proteins that
      commonly localize to tight junctions of epithelial and endothelial cells. Besides
      being structural tight-junction components, claudins participate in cell-cell
      adhesion and the paracellular transport of solutes. Here, we identify and
      annotate the claudin genes in the whole-genome of the teleost fish, Fugu rubripes
      (Fugu), and determine their phylogenetic relationships to those in mammals. Our
      analysis reveals extensive gene duplications in the teleost lineage, leading to
      56 claudin genes in Fugu. A total of 35 Fugu claudin genes can be assigned
      orthology to 17 mammalian claudin genes, with the remaining 21 genes being
      specific to the fish lineage. Thus, a significant number of the additional Fugu
      genes are not the result of the proposed whole-genome duplication in the fish
      lineage. Expression profiling shows that most of the 56 Fugu claudin genes are
      expressed in a more-or-less tissue-specific fashion, or at particular
      developmental stages. We postulate that the expansion of the claudin gene family
      in teleosts allowed the acquisition of novel functions during evolution, and that
      fish-specific novel members of gene families such as claudins contribute to a
      large extent to the distinct physiology of fishes and mammals.

PMID- 15197170
TI  - Platelet-derived growth factor receptor transactivation mediates the trophic
      effects of angiotensin II in vivo.
AB  - In addition to the modulation of vascular tone, angiotensin II (Ang II) has
      growth factor-like effects in vascular tissue. The mechanisms whereby Ang II
      mediates these trophic actions are incompletely understood but are thought to
      include effects on systemic blood pressure, stimulation of transforming growth
      factor-beta (TGF-beta) expression, and transactivation of growth factor receptor
      kinases. To investigate the role of platelet-derived growth factor receptor
      (PDGFR) transactivation in mediating the growth factor-like effects of Ang II we
      administered Ang II (200 ng/kg per minute) or saline to male Sprague-Dawley rats
      by osmotic minipump for 12 days and treated with imatinib mesylate, an inhibitor
      of the PDGFR tyrosine kinase. In addition to systolic blood pressure elevation,
      Ang II infusion led to increased vascular weight, media:lumen ratio, matrix
      expansion, and overexpression of TGF-beta mRNA in mesenteric arteries. Without
      affecting blood pressure or PDGF ligand expression, imatinib attenuated the
      changes in vessel morphology but further increased TGF-beta mRNA. Western blot
      analysis of mesenteric arterial tissue demonstrated the presence of the beta- but
      not the alpha-isoform of PDGFR. Phosphorylation of PDGFR-beta was increased by
      Ang II in vascular smooth muscle cells, and this was inhibited by imatinib. The
      findings of attenuation of vascular hypertrophy and matrix deposition by imatinib
      indicate that transactivation of the PDGFR in vivo contributes to the growth
      factor-like effects of Ang II, independent of its hemodynamic effects or its
      ability to induce TGF-beta gene expression.

PMID- 15197169
TI  - Comparative sequence and x-inactivation analyses of a domain of escape in human
      xp11.2 and the conserved segment in mouse.
AB  - We have performed X-inactivation and sequence analyses on 350 kb of sequence from
      human Xp11.2, a region shown previously to contain a cluster of genes that escape
      X inactivation, and we compared this region with the region of conserved synteny
      in mouse. We identified several new transcripts from this region in human and in
      mouse, which defined the full extent of the domain escaping X inactivation in
      both species. In human, escape from X inactivation involves an uninterrupted 235
      kb domain of multiple genes. Despite highly conserved gene content and order
      between the two species, Smcx is the only mouse gene from the conserved segment
      that escapes inactivation. As repetitive sequences are believed to facilitate
      spreading of X inactivation along the chromosome, we compared the repetitive
      sequence composition of this region between the two species. We found that long
      terminal repeats (LTRs) were decreased in the human domain of escape, but not in
      the majority of the conserved mouse region adjacent to Smcx in which genes were
      subject to X inactivation, suggesting that these repeats might be excluded from
      escape domains to prevent spreading of silencing. Our findings indicate that
      genomic context, as well as gene-specific regulatory elements, interact to
      determine expression of a gene from the inactive X-chromosome.

PMID- 15197171
TI  - A genetic predisposition to hypertension?

PMID- 15197172
TI  - New insights into the proliferation and differentiation of early mouse
      thymocytes.
AB  - Early thymocyte development was compared in normal, recombinase-activating gene 2
      inactivated (RAG-2 KO) and pre-T cell receptor alpha-inactivated (pre-Talpha KO)
      mice, mutants representing either a complete (RAG-2 KO) or partial (pre-Talpha
      KO) block in progenitor development. Using three colour analysis with antibodies
      to CD117, CD44 and CD25, cell numbers in each progenitor subset were quantified,
      demonstrating an accumulation of cells prior to the block. Progenitor number was
      influenced both by the nature of the genetic block and thymus size, as shown in
      the enlarged thymus of a transgenic mouse line. By four colour staining for CD3,
      CD117, CD44 and CD25 and deliberately not gating out CD3(-) cells, a novel aspect
      of gamma delta T cell development in pre-Talpha KO mice was identified. 5
      bromodeoxyuridine labelling and subsequent four colour staining for BrdU, CD117,
      CD44 and CD25 showed firstly that DN1 cells were cycling, secondly that the
      developmental block in pre-Talpha KO mice corresponded to a decrease in DN4 cell
      proliferation, and thirdly provided a novel 'snapshot' of T cell receptor beta
      selected cells transiting the DN3 to DN4 compartment. Taken together, these
      results emphasise the need for a more detailed qualitative and quantitative
      analysis of the progenitor compartment in the thymus.

PMID- 15197173
TI  - Screening of alternative models for transitional B cell maturation.
AB  - Several functional and phenotypic B cell populations have been described in the
      spleen. These include the 'transitional' subsets, which are thought to be late
      differentiation intermediates of marrow-derived, mature follicular B cells. The
      exact progenitor-successor relationships of these transitional subsets, as well
      as whether a proliferative step is requisite for follicular B cell maturation,
      remain controversial. Moreover, whether late B cell differentiation might involve
      branched or asynchronous maturation pathways, thus allowing some cells to 'skip'
      one or more of these stages, has not been investigated. Herein we have used
      mathematical modeling to interrogate these possibilities. Using mathematical
      models that numerically simulate splenic B cell population dynamics, we have
      determined which alternative models of differentiation best fit existing in vivo
      labeling data. Our results indicate that follicular differentiation does not
      involve a proliferating splenic intermediate. Our results further suggest that
      some developing cells move directly from the immature marrow pool to more
      advanced semi-mature peripheral subsets without passing through the least mature
      subset in the spleen.

PMID- 15197174
TI  - Cell-matrix interaction via CD44 is independently regulated by different
      metalloproteinases activated in response to extracellular Ca(2+) influx and PKC
      activation.
AB  - CD44 is an adhesion molecule that interacts with hyaluronic acid (HA) and
      undergoes sequential proteolytic cleavages in its ectodomain and intramembranous
      domain. The ectodomain cleavage is triggered by extracellular Ca(2+) influx or
      the activation of protein kinase C. Here we show that CD44-mediated cell-matrix
      adhesion is terminated by two independent ADAM family metalloproteinases, ADAM10
      and ADAM17, differentially regulated in response to those stimuli. Ca(2+) influx
      activates ADAM10 by regulating the association between calmodulin and ADAM10,
      leading to CD44 ectodomain cleavage. Depletion of ADAM10 strongly inhibits the
      Ca(2+) influx-induced cell detachment from matrix. On the other hand, phorbol
      ester stimulation activates ADAM17 through the activation of PKC and small GTPase
      Rac, inducing proteolysis of CD44. Furthermore, depletion of ADAM10 or ADAM17
      markedly suppressed CD44-dependent cancer cell migration on HA, but not on
      fibronectin. The spatio-temporal regulation of two independent signaling pathways
      for CD44 cleavage plays a crucial role in cell-matrix interaction and cell
      migration.

PMID- 15197175
TI  - Annexin 11 is required for midbody formation and completion of the terminal phase
      of cytokinesis.
AB  - Annexins are Ca(2+)-binding, membrane-fusogenic proteins with diverse but poorly
      understood functions. Here, we show that during cell cycle progression annexin 11
      translocates from the nucleus to the spindle poles in metaphase and to the
      spindle midzone in anaphase. Annexin 11 is recruited to the midbody in late
      telophase, where it forms part of the detergent-resistant matrix that also
      contains CHO1. To investigate the significance of these observations, we used RNA
      interference to deplete cells of annexin 11. A combination of confocal and video
      time-lapse microscopy revealed that cells lacking annexin 11 fail to establish a
      functional midbody. Instead, daughter cells remain connected by intercellular
      bridges that contain bundled microtubules and cytoplasmic organelles but exclude
      normal midbody components such as MKLP1 and Aurora B. Annexin 11-depleted cells
      failed to complete cytokinesis and died by apoptosis. These findings demonstrate
      an essential role for annexin 11 in the terminal phase of cytokinesis.

PMID- 15197176
TI  - The fission yeast heterochromatin protein Rik1 is required for telomere
      clustering during meiosis.
AB  - Telomeres share the ability to silence nearby transcription with heterochromatin,
      but the requirement of heterochromatin proteins for most telomere functions is
      unknown. The fission yeast Rik1 protein is required for heterochromatin formation
      at centromeres and the mating-type locus, as it recruits the Clr4 histone
      methyltransferase, whose modification of histone H3 triggers binding by Swi6, a
      conserved protein involved in spreading of heterochromatin. Here, we demonstrate
      that Rik1 and Clr4, but not Swi6, are required along with the telomere protein
      Taz1 for crucial chromosome movements during meiosis. However, Rik1 is
      dispensable for the protective roles of telomeres in preventing chromosome end
      fusion. Thus, a Swi6-independent heterochromatin function distinct from that at
      centromeres and the mating-type locus operates at telomeres during sexual
      differentiation.

PMID- 15197177
TI  - Absence of BLM leads to accumulation of chromosomal DNA breaks during both
      unperturbed and disrupted S phases.
AB  - Bloom's syndrome (BS), a disorder associated with genomic instability and cancer
      predisposition, results from defects in the Bloom's helicase (BLM) protein. In BS
      cells, chromosomal abnormalities such as sister chromatid exchanges occur at
      highly elevated rates. Using Xenopus egg extracts, we have studied Xenopus BLM
      (Xblm) during both unperturbed and disrupted DNA replication cycles. Xblm binds
      to replicating chromatin and becomes highly phosphorylated in the presence of DNA
      replication blocks. This phosphorylation depends on Xenopus ATR (Xatr) and
      Xenopus Rad17 (Xrad17), but not Claspin. Xblm and Xenopus topoisomerase IIIalpha
      (Xtop3alpha) interact in a regulated manner and associate with replicating
      chromatin interdependently. Immunodepletion of Xblm from egg extracts results in
      accumulation of chromosomal DNA breaks during both normal and perturbed DNA
      replication cycles. Disruption of the interaction between Xblm and Xtop3alpha has
      similar effects. The occurrence of DNA damage in the absence of Xblm, even
      without any exogenous insult to the DNA, may help to explain the genesis of
      chromosomal defects in BS cells.

PMID- 15197179
TI  - DNA replication defects, spontaneous DNA damage, and ATM-dependent checkpoint
      activation in replication protein A-deficient cells.
AB  - Replication protein A (RPA) is a heterotrimeric, single-stranded DNA-binding
      complex comprised of 70-kDa (RPA1), 32-kDa (RPA2), and 14-kDa (RPA3) subunits
      that is essential for DNA replication, recombination, and repair in eukaryotes.
      In addition, recent studies using vertebrate model systems have suggested an
      important role for RPA in the initiation of cell cycle checkpoints following
      exposure to DNA replication stress. Specifically, RPA has been implicated in the
      recruitment and activation of the ATM-Rad3-related protein kinase, ATR, which in
      conjunction with the related kinase, ATM (ataxia-telangiectasia-mutated),
      transmits checkpoint signals via the phosphorylation of downstream effectors. In
      this report, we have explored the effects of RPA insufficiency on DNA
      replication, cell survival, and ATM/ATR-dependent signal transduction in response
      to genotoxic stress. RNA interference-mediated suppression of RPA1 caused a
      slowing of S phase progression, G2/M cell cycle arrest, and apoptosis in HeLa
      cells. RPA-deficient cells demonstrated high levels of spontaneous DNA damage and
      constitutive activation of ATM, which was responsible for the terminal G2/M
      arrest phenotype. Surprisingly, we found that neither RPA1 nor RPA2 were
      essential for the hydroxyurea- or UV-induced phosphorylation of the ATR
      substrates CHK1 and CREB (cyclic AMP-response element-binding protein). These
      findings reveal that RPA is required for genomic stability and suggest that
      activation of ATR can occur through RPA-independent pathways.

PMID- 15197178
TI  - Deregulation of cyclin E in human cells interferes with prereplication complex
      assembly.
AB  - Deregulation of cyclin E expression has been associated with a broad spectrum of
      human malignancies. Analysis of DNA replication in cells constitutively
      expressing cyclin E at levels similar to those observed in a subset of tumor
      derived cell lines indicates that initiation of replication and possibly fork
      movement are severely impaired. Such cells show a specific defect in loading of
      initiator proteins Mcm4, Mcm7, and to a lesser degree, Mcm2 onto chromatin during
      telophase and early G1 when Mcm2-7 are normally recruited to license origins of
      replication. Because minichromosome maintenance complex proteins are thought to
      function as a heterohexamer, loading of Mcm2-, Mcm4-, and Mcm7-depleted complexes
      is likely to underlie the S phase defects observed in cyclin E-deregulated cells,
      consistent with a role for minichromosome maintenance complex proteins in
      initiation of replication and fork movement. Cyclin E-mediated impairment of DNA
      replication provides a potential mechanism for chromosome instability observed as
      a consequence of cyclin E deregulation.

PMID- 15197180
TI  - Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by
      nona-D-arginine.
AB  - Polyarginine-containing peptides represent potent inhibitors of furin, a
      mammalian endoprotease that plays an important role in metabolism, activation of
      pathogenic toxins, and viral proliferation. The therapeutic use of D
      polyarginines is especially interesting because they are not cleaved by furin and
      possess inhibitory potency almost equal to L-polyarginines. In this study we
      attempted to determine the important elements within polyarginines that
      contribute to effective inhibition. Structure-function analyses of polyarginine
      peptides showed that inhibition by polyarginine-containing peptides appeared to
      depend on the total number of basic charges of the positively charged inhibitors
      bound to the negatively charged substrate binding pocket; peptide positioning did
      not appear to be rigorously determined. Screening of L- and D-decapeptide
      positional scanning combinatorial peptide libraries indicated a preference for
      basic residues in nearly all positions, similar to previous results with
      hexapeptide libraries. Length and terminal modification studies showed that the
      most potent D-polyarginine tested was nona-D-arginine (D9R) amide with a K(i) of
      1.3 nm. D9R amide was shown to protect RAW264.7 cells against anthrax toxemia
      with an IC(50) of 3.7 microm. Because of its high stability, specificity, low
      toxicity, small molecular weight, and extremely low K(i) against furin, D9R amide
      or its derivatives may represent promising compounds for therapeutic use.

PMID- 15197181
TI  - Podocyte migration during nephrotic syndrome requires a coordinated interplay
      between cathepsin L and alpha3 integrin.
AB  - Podocyte foot process effacement and disruption of the slit diaphragm are
      typically associated with glomerular proteinuria and can be induced in rats by
      the injection of puromycin aminonucleoside. Here, we show that the induction of
      puromycin aminonucleoside nephrosis involves podocyte migration conducted by a
      coordinated interplay between the cysteine protease cathepsin L and alpha(3)
      integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression
      in podocytes in vivo as well as expression and enzymatic activity of cathepsin L
      in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are
      protected from cell puromycin aminonucleoside-induced cell detachment. The
      functional significance of cathepsin L expression was underscored by the
      observation that puromycin aminonucleoside-induced cell migration was slowed down
      in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts
      and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and
      activity were induced in podocytes lacking alpha(3) integrin. Similarly, acute
      functional inhibition of alpha(3) integrin in wild type podocytes with a blocking
      antibody increased the expression of cathepsin L activity. Down-regulation of
      alpha(3) integrin protected against puromycin aminonucleoside-induced podocyte
      detachment. In summary, these data establish that podocyte foot process
      effacement is a migratory event involving a novel interplay between cathepsin L
      and alpha(3) integrin.

PMID- 15197182
TI  - Internalization of exogenously added memapsin 2 (beta-secretase) ectodomain by
      cells is mediated by amyloid precursor protein.
AB  - Memapsin 2 (beta-secretase) is the protease that initiates cleavage of amyloid
      precursor protein (APP) leading to the production of amyloid-beta (Abeta) peptide
      and the onset of Alzheimer's disease. Both APP and memapsin 2 are Type I
      transmembrane proteins and are endocytosed into endosomes where APP is cleaved by
      memapsin 2. Separate endocytic signals are located in the cytosolic domains of
      these proteins. We demonstrate here that the addition of the ectodomain of
      memapsin 2 (M2(ED)) to cells transfected with native APP or APP Swedish mutant
      (APPsw) resulted in the internalization of M2(ED) into endosomes with increased
      Abeta production. These effects were reduced by treatment with
      glycosylphosphatidylinositol-specific phospholipase C. The nontransfected
      parental cells had little internalization of M2(ED). The internalization of
      M2(ED) was dependent on the endocytosis signal in APP, because the expression of
      a mutant APP that lacks its endocytosis signal failed to support M2(ED)
      internalization. These results suggest that exogenously added M2(ED) interacts
      with the ectodomain of APP on the cell surface leading to the internalization of
      M2(ED), supported by fluorescence resonance energy transfer experiments. The
      interactions between the two proteins is not due to the binding of substrate
      APPsw to the active site of memapsin 2, because neither a potent active site
      binding inhibitor of memapsin 2 nor an antibody directed to the beta-secretase
      site of APPsw had an effect on the uptake of M2(ED). In addition, full-length
      memapsin 2 and APP, immunoprecipitated together from cell lysates, suggested that
      the interaction of these two proteins is part of the native cellular processes.

PMID- 15197183
TI  - Rapid trafficking of the neuronal glutamate transporter, EAAC1: evidence for
      distinct trafficking pathways differentially regulated by protein kinase C and
      platelet-derived growth factor.
AB  - The neuronal glutamate transporter, EAAC1, appears to both limit spillover
      between excitatory synapses and provide precursor for the synthesis of the
      inhibitory neurotransmitter, gamma-aminobutyric acid. There is evidence for a
      large intracellular pool of EAAC1 from which transporter is redistributed to the
      cell surface following activation of protein kinase C (PKC) or platelet-derived
      growth factor (PDGF) receptor by seemingly independent pathways. A variety of
      biotinylation strategies were employed to measure trafficking of EAAC1 to and
      from the plasma membrane and to examine the effects of phorbol ester and PDGF on
      these events. Biotinylation of cell surface protein under trafficking-permissive
      conditions (37 degrees C) resulted in a 2-fold increase in the amount of
      biotinylated EAAC1 within 15 min in C6 glioma and in primary neuronal cultures,
      suggesting that EAAC1 has a half-life of approximately 5-7 min for residence at
      the plasma membrane. Both phorbol ester and PDGF increased the amount of
      transporter labeled under these conditions. Using a reversible biotinylation
      strategy, a similarly rapid internalization of EAAC1 was observed in C6 glioma.
      Phorbol ester, but not PDGF, blocked this measure of internalization. Incubation
      at 18 degrees C, which blocks some forms of intracellular membrane trafficking,
      inhibited PKC- and PDGF-dependent redistribution of EAAC1 but had no effect on
      basal trafficking of EAAC1. These studies suggest that both PKC and PDGF
      accelerate delivery of EAAC1 to the cell surface and that PKC has an additional
      effect on endocytosis. The data also suggest that basal and regulated pools of
      EAAC1 exist in distinct compartments.

PMID- 15197184
TI  - Identification of hyperreactive cysteines within ryanodine receptor type 1 by
      mass spectrometry.
AB  - The skeletal-type ryanodine receptor (RyR1) undergoes covalent adduction by
      nitric oxide (NO), redox-induced shifts in cation regulation, and non-covalent
      interactions driven by the transmembrane redox potential that enable redox
      sensing. Tight redox regulation of RyR1 is thought to be primarily mediated
      through highly reactive (hyperreactive) cysteines. Of the 100 cysteines per
      subunit of RyR1, approximately 25-50 are reduced, with 6-8 considered
      hyperreactive. Thus far, only Cys-3635, which undergoes selective adduction by
      NO, has been identified. In this report, RyR1-enriched junctional sarcoplasmic
      reticulum is labeled with 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin
      (CPM, 1 pmol/microg of protein) in the presence of 10 mm Mg(2+), conditions
      previously shown to selectively label hyperreactive sulfhydryls and eliminate
      redox sensing. The CPM-adducted RyR1 is separated by gel electrophoresis and
      subjected to in-gel tryptic digestion. Isolation of CPM-adducted peptides is
      achieved by analytical and microbore high-performance liquid chromatography
      utilizing fluorescence and UV detection. Subsequent analysis using two direct and
      one tandem mass spectrometry methods results in peptide masses and sequence data
      that, compared with the known primary sequence of RyR1, enable unequivocal
      identification of CPM-adducted cysteines. This work is the first to directly
      identify seven hyperreactive cysteines: 1040, 1303, 2436, 2565, 2606, 2611, and
      3635 of RyR1. In addition to Cys-3635, the nitrosylation site, six additional
      cysteines may contribute toward redox regulation of the RyR1 complex.

PMID- 15197185
TI  - CYP306A1, a cytochrome P450 enzyme, is essential for ecdysteroid biosynthesis in
      the prothoracic glands of Bombyx and Drosophila.
AB  - Ecdysteroids mediate a wide variety of developmental and physiological events in
      insects. In the postembryonic development of insects, ecdysone is synthesized in
      the prothoracic gland (PG). Although many studies have revealed the biochemical
      and physiological properties of the enzymes for ecdysteroid biosynthesis, most of
      the molecular identities of these enzymes have not been elucidated. Here we
      describe an uncharacterized cytochrome P450 gene, designated Cyp306a1, that is
      essential for ecdysteroid biosynthesis in the PGs of the silkworm Bombyx mori and
      fruit fly Drosophila melanogaster. Using the microarray technique for analyzing
      gene expression profiles in PG cells during Bombyx development, we identified two
      PG-specific P450 genes whose temporal expression patterns are correlated with
      changes in ecdysteroid titer during development. Amino acid sequence analysis
      showed that one of the Bombyx P450 genes belongs to the CYP306A1 subfamily. The
      temporal and spatial expression pattern of the Drosophila Cyp306a1 homolog is
      essentially the same as that of Bombyx Cyp306a1. We also found that Drosophila
      Cyp306a1 is disrupted in the phantom (phm) mutant, known also as the Halloween
      mutant. The morphological defects and decreased expression of ecdysone-inducible
      genes in phm suggest that this mutant cannot produce a high titer of ecdysone.
      Finally we demonstrate that S2 cells transfected with Cyp306a1 convert ketodiol
      to ketotriol via carbon 25 hydroxylation. These results strongly suggest that
      CYP306A1 functions as a carbon 25 hydroxylase and has an essential role in
      ecdysteroid biosynthesis during insect development.

PMID- 15197186
TI  - Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1
      protein.
AB  - NDR (nuclear Dbf2-related) kinase belongs to a family of kinases that is highly
      conserved throughout the eukaryotic world. We showed previously that NDR is
      regulated by phosphorylation and by the Ca(2+)-binding protein, S100B. The
      budding yeast relatives of Homo sapiens NDR, Cbk1, and Dbf2, were shown to
      interact with Mob2 (Mps one binder 2) and Mob1, respectively. This interaction is
      required for the activity and biological function of these kinases. In this
      study, we show that hMOB1, the closest relative of yeast Mob1 and Mob2,
      stimulates NDR kinase activity and interacts with NDR both in vivo and in vitro.
      The point mutations of highly conserved residues within the N-terminal domain of
      NDR reduced NDR kinase activity as well as human MOB1 binding. A novel feature of
      NDR kinases is an insert within the catalytic domain between subdomains VII and
      VIII. The amino acid sequence within this insert shows a high basic amino acid
      content in all of the kinases of the NDR family known to interact with MOB
      proteins. We show that this sequence is autoinhibitory, and our data indicate
      that the binding of human MOB1 to the N-terminal domain of NDR induces the
      release of this autoinhibition.

PMID- 15197187
TI  - Dominant-negative inhibition of pheromone receptor signaling by a single point
      mutation in the G protein alpha subunit.
AB  - In yeast, two different constitutive mutants of the G protein alpha subunit have
      been reported. Gpa1(Q323L) cannot hydrolyze GTP and permanently activates the
      pheromone response pathway. Gpa1(N388D) was also proposed to lack GTPase
      activity, yet it has an inhibitory effect on pheromone responsiveness. We have
      characterized this inhibitory mutant (designated Galpha(ND)) and found that it
      binds GTP, interacts with G protein betagamma subunits, and exhibits full GTPase
      activity in vitro. Although pheromone leads to dissociation of the receptor from
      wild-type G protein, the same treatment promotes stable association of the
      receptor with Galpha(ND). We conclude that agonist binding to the receptor
      promotes the formation of a nondissociable complex with Galpha(ND), and in this
      manner prevents activation of the endogenous wild-type G protein. Dominant
      negative mutants may be useful in matching specific receptors and their cognate G
      proteins and in determining mechanisms of G protein signaling specificity.

PMID- 15197188
TI  - Midkine is regulated by hypoxia and causes pulmonary vascular remodeling.
AB  - Midkine (MK) is expressed in a precise temporal-spatial pattern during lung
      morphogenesis; however, its role in pulmonary homeostasis is unknown. Increased
      MK staining and mRNA expression were observed in the lungs of hypoxia-susceptible
      CAST/eiJ mice during hypoxia. MK expression was induced by hypoxia in cell lines
      in vitro. Because the transcription factor hypoxiainducible factor-1alpha (HIF
      1alpha) modulates cellular responses to hypoxia, we tested whether increased
      expression of MK in the lung was mediated by HIF-1alpha. HIF-1alpha enhanced the
      transcription of MK, acting on HIF-1alpha regulatory elements located in the MK
      gene promoter. Site-directed mutagenesis of the 3' HIF response element in the MK
      promoter blocked the stimulatory effects of HIF-1alpha. To directly assess the
      role of MK on lung morphogenesis, transgenic mice were generated in which MK was
      expressed in the respiratory epithelial cells of the developing lung. MK
      increased muscularization of small pulmonary arteries, increasing alpha-smooth
      muscle actin and caldesmon staining and the expression of myocardin. MK directly
      enhanced the expression of myocardin and the smooth muscle-specific genes alpha
      smooth muscle actin, calponin, and SM-22 in vascular smooth muscle precursor
      cells. Expression of MK in the respiratory epithelium is regulated by hypoxia and
      HIF-1alpha. These data provide a model wherein the respiratory epithelium
      responds to hypoxia via HIF-1alpha-dependent regulation of MK, enhancing
      myocardin expression to influence pulmonary vascular gene expression.

PMID- 15197189
TI  - Metabolic adaptations in the absence of perilipin: increased beta-oxidation and
      decreased hepatic glucose production associated with peripheral insulin
      resistance but normal glucose tolerance in perilipin-null mice.
AB  - Targeted disruption of the lipid droplet protein, perilipin, in mice leads to
      constitutional lipolysis associated with marked reduction in white adipose tissue
      as a result of unbridled lipolysis. To investigate the metabolic adaptations in
      response to the constitutive lipolysis, we studied perilipin-null (plin(-/-))
      mice in terms of their fatty acid oxidation and glycerol and glucose metabolism
      homeostasis by using dynamic biochemical testing and clamp and tracer infusion
      methods. plin(-/-) mice showed increased beta-oxidation in muscle, liver, and
      adipose tissue resulting from a coordinated regulation of the enzymes and
      proteins involved in beta-oxidation. The increased beta-oxidation helped remove
      the extra free fatty acids created by the constitutive lipolysis. An increase in
      the expression of the transcripts for uncoupling proteins-2 and -3 also
      accompanied this increase in fatty acid oxidation. Adult plin(-/-) mice had
      normal plasma glucose but a reduced basal hepatic glucose production (46% that of
      plin(+/+)). Insulin infusion during low dose hyperinsulinemic-euglycemic clamp
      further lowered the glucose production in plin(-/-) mice, but plin(-/-) mice also
      showed a 36% decrease (p < 0.007) in glucose disposal rate during the low dose
      insulin clamp, indicating peripheral insulin resistance. However, compared with
      plin(+/+) mice, 14-week-old plin(-/-) mice showed no significant difference in
      glucose disposal rate during the high dose hyperinsulinemic clamp, whereas 42
      week-old plin(-/-) mice displayed significant insulin resistance on high dose
      hyperinsulinemic clamp. Despite increasing insulin resistance with age, plin(-/-)
      mice at different ages maintained a normal glucose response during an
      intraperitoneal glucose tolerance curve, being compensated by the increased beta
      oxidation and reduced hepatic glucose production. These experiments uncover the
      metabolic adaptations associated with the constitutional lipolysis in plin(-/-)
      mice that allowed the mice to continue to exhibit normal glucose tolerance in the
      presence of peripheral insulin resistance.

PMID- 15197190
TI  - The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of
      pathologic response to a neoadjuvant doxorubicin-based regimen in women with
      operable breast cancer: long-term results from a prospective randomized trial.
AB  - PURPOSE: To evaluate the use of an alternate, non-cross-resistant adjuvant
      chemotherapy regimen in women with a poor pathologic response to a preoperative
      doxorubicin-based regimen. PATIENTS AND METHODS: Patients with locally advanced
      breast cancer received three cycles of vincristine, doxorubicin,
      cyclophosphamide, and prednisone (VACP) every 21 days followed by surgery.
      Patients with less than 1 cm(3) residual tumor at mastectomy received an
      additional five cycles of VACP. Those with more than 1 cm(3) residual tumor were
      randomly assigned to receive an additional five cycles of VACP or five cycles of
      vinblastine, methotrexate with calcium leucovorin rescue, and fluorouracil
      (VbMF). RESULTS: One hundred ninety-three patients were evaluable. Overall
      clinical response was seen in 83.4% after three cycles of VACP, whereas the
      pathologic complete response was 12.2%. One hundred six patients were randomly
      assigned to VACP or VbMF. Those receiving VbMF achieved higher relapse-free
      survival (RFS) and overall survival (OS) than those who received additional VACP,
      although the differences did not reach statistical significance. Initial stage of
      tumor, clinical complete response, and pathologic complete response were all
      associated with statistically superior survival rates. CONCLUSION: Clinical and
      pathologic response to preoperative doxorubicin-based chemotherapy predicted for
      improved survival in women with operable breast cancer. For those with a poor
      response to initial neoadjuvant chemotherapy, treatment with VbMF was associated
      with a trend toward improved RFS and OS compared with those continuing with the
      doxorubicin regimen.

PMID- 15197191
TI  - Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer center
      experience.
AB  - PURPOSE: To determine patterns of local-regional recurrence (LRR) and ipsilateral
      breast tumor recurrence (IBTR) among patients treated with breast conservation
      therapy after neoadjuvant chemotherapy. PATIENTS AND METHODS: Between 1987 and
      2000, 340 cases of breast cancer were treated with neoadjuvant chemotherapy
      followed by conservative surgery and radiation therapy. Clinical stage at
      diagnosis (according to the 2003 American Joint Committee on Cancer system) was I
      in 4%, II in 58%, and III in 38% of patients. Only 4% had positive surgical
      margins. RESULTS: At a median follow-up period of 60 months (range, 10 to 180
      months), 29 patients had developed LRR, 16 of which were IBTRs. Five-year
      actuarial rates of IBTR-free and LRR-free survival were 95% and 91%,
      respectively. Variables that positively correlated with IBTR and LRR were
      clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a
      multifocal pattern of residual disease, and lymphovascular space invasion in the
      specimen. The presence of any one of these factors was associated with 5-year
      actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%,
      respectively. Initial T category (T1-2 v T3-4) correlated with LRR but did not
      correlate with IBTR (5-year IBTR-free rates of 96% v 92%, respectively, P =.19).
      CONCLUSION: Breast conservation therapy after neoadjuvant chemotherapy results in
      acceptably low rates of LRR and IBTR in appropriately selected patients, even
      those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual
      tumor larger than 2 cm, multifocal residual disease, and lymphovascular space
      invasion predict higher rates of LRR and IBTR.

PMID- 15197192
TI  - Phase III study of intravenous vinorelbine in combination with epirubicin versus
      epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast
      Group Trial (SBG9403).
AB  - PURPOSE: To determine whether the addition of intravenous (IV) vinorelbine to
      epirubicin increased the progression-free survival in first-line treatment of
      metastatic breast cancer. PATIENTS AND METHODS: A total of 387 patients were
      randomly assigned to receive IV epirubicin 90 mg/m(2) on day 1 and vinorelbine 25
      mg/m(2) on days 1 and 8, or epirubicin 90 mg/m(2) IV on day 1. Both regimens were
      given every 3 weeks for a maximum of 1 year but discontinued prematurely in the
      event of progressive disease or severe toxicity. In addition, epirubicin was
      discontinued at a cumulative dose of 1000 mg/m(2) (950 mg/m(2) from June 1999).
      Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for
      metastatic breast cancer was not allowed. Reported results were all based on
      intent-to-treat analyses. RESULTS: Overall response rates to vinorelbine and
      epirubicin, and epirubicin alone, were 50% and 42%, respectively (P =.15). The
      complete response rate was significantly superior in the combination arm (17% v
      10%; P =.048) as was median duration of progression-free survival (10.1 months v
      8.2 months; P =.019). Median survival was similar in the two arms (19.1 months v
      18.0 months; P =.50). Leukopenia related complications, stomatitis, and
      peripheral neuropathy were more common in the combination arm. The incidences of
      cardiotoxicity and constipation were similar in both arms. CONCLUSION: Addition
      of vinorelbine to epirubicin conferred a significant advantage in terms of
      complete response rate and progression-free survival, but not in terms of
      survival.

PMID- 15197193
TI  - Capecitabine plus paclitaxel as front-line combination therapy for metastatic
      breast cancer: a multicenter phase II study.
AB  - PURPOSE: The goal of this multicenter, open-label phase II study was the clinical
      evaluation of combination therapy with the oral fluoropyrimidine capecitabine and
      the taxane paclitaxel in patients with metastatic breast cancer (MBC). PATIENTS
      AND METHODS: Forty-seven patients with MBC received oral capecitabine at 1650
      mg/m(2)/d (825 mg/m(2) twice daily) on days 1 through 14, and intravenous
      infusion of paclitaxel at 175 mg/m(2) on day 1 of each 21-day treatment cycle.
      Treatment continued until disease progression, intolerable toxicity, or patient'
      s decision to discontinue. Patients (35 to 76 years old) had a median Karnofsky
      performance status of 90%. Forty-four patients (94%) received study treatment as
      first-line therapy for metastatic disease. RESULTS: Objective responses occurred
      in 24 (51%) patients; seven (15%) complete responses and 17 (36%) partial
      responses. Stable disease lasting 180 days or more was observed in nine (19%);
      the clinical response rate was 70%. Median duration of response was 12.6 months,
      median time to disease progression was 10.6 months, and median overall survival
      time was 29.9 months. The most common treatment-related adverse events,
      regardless of severity, were alopecia, hand-foot syndrome, nausea, and fatigue.
      Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only
      grade 3 or 4 treatment-related adverse events that occurred in more than 10% of
      patients. CONCLUSION: The combination of capecitabine plus paclitaxel is a highly
      active and generally well-tolerated regimen for first-line treatment of MBC.

PMID- 15197194
TI  - Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.
AB  - PURPOSE: To estimate the risk of contralateral breast cancer in BRCA1 and BRCA2
      carriers after diagnosis and to determine which factors are predictive of the
      risk of a second primary breast cancer. PATIENTS AND METHODS: Patients included
      491 women with stage I or stage II breast cancer, for whom a BRCA1 or BRCA2
      mutation had been identified in the family. Patients were followed from the
      initial diagnosis of cancer until contralateral mastectomy, contralateral breast
      cancer, death, or last follow-up. RESULTS: The actuarial risk of contralateral
      breast cancer was 29.5% at 10 years. Factors that were predictive of a reduced
      risk were the presence of a BRCA2 mutation (v BRCA1 mutation; hazard ratio [HR],
      0.73; 95% CI, 0.47 to 1.15); age 50 years or older at first diagnosis (v <or= 49
      years; HR, 0.63; 95% CI, 0.36 to 1.10); use of tamoxifen (HR, 0.59; 95% CI, 0.35
      to 1.01); and history of oophorectomy (HR, 0.44; 95% CI, 0.21 to 0.91). The
      effect of oophorectomy was particularly strong in women first diagnosed prior to
      age 49 years (HR, 0.24; 95% CI, 0.07 to 0.77). For women who did not have an
      oophorectomy or take tamoxifen, the 10-year risk of contralateral cancer was
      43.4% for BRCA1 carriers and 34.6% for BRCA2 carriers. CONCLUSION: The risk of
      contralateral breast cancer in women with a BRCA mutation is approximately 40% at
      10 years, and is reduced in women who take tamoxifen or who undergo an
      oophorectomy.

PMID- 15197196
TI  - Randomized controlled trial of the role of positron emission tomography in the
      management of stage I and II non-small-cell lung cancer.
AB  - PURPOSE: Positron emission tomography (PET) is a costly new technology with
      potential to improve preoperative evaluation for patients with non-small-cell
      lung cancer (NSCLC). There is increasing pressure for PET to be included in
      standard diagnostic work-up before decisions about surgical management of NSCLC.
      The resource implications of its widespread use in staging NSCLC are significant.
      METHODS: A randomized controlled trial was conducted to investigate the impact of
      PET on clinical management and surgical outcomes for patients with stage I-II
      NSCLC. The primary hypothesis was that PET would reduce the proportion of
      patients with stage I-II NSCLC who underwent thoracotomy by at least 10% through
      identification of patients with inoperable disease. RESULTS: One hundred eighty
      four patients with stage I-II NSCLC were recruited and randomly assigned; 92% had
      stage I disease. Following exclusion of one ineligible patient, 92 patients were
      assigned to no PET and 91 to PET. Compared with conventional staging, PET
      upstaged 22 patients, confirmed staging in 61 and staged two patients as benign.
      Stage IV disease was rarely detected (two patients). PET led to further
      investigation or a change in clinical management in 13% of patients and provided
      information that could have affected management in a further 13% of patients.
      There was no significant difference between the trial arms in the number of
      thoracotomies avoided (P =.2). CONCLUSION: For patients who are carefully and
      appropriately staged as having stage I-II disease, PET provides potential for
      more appropriate stage-specific therapy but may not lead to a significant
      reduction in the number of thoracotomies avoided.

PMID- 15197195
TI  - Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine,
      vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung
      cancer: from the German and Swiss Lung Cancer Study Group.
AB  - PURPOSE: To evaluate whether cisplatin-based chemotherapy (gemcitabine,
      vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to
      cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line
      treatment in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS
      AND METHODS: Between September 1999 and June 2001, 300 patients with NSCLC stage
      IIIB with malignant pleural effusion or stage IV disease were randomly assigned
      to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8
      every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days
      1 and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the
      study was overall survival. RESULTS: Two hundred eighty-seven patients (GV, 143
      patients; GVP, 144 patients) were eligible for analysis. At the time of analysis,
      April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287
      patients had died (73%). No statistically significant difference was observed for
      overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year
      survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35;
      median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred
      fourteen patients were assessable for best response. The overall response rates
      were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus
      3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic
      toxicity was significantly lower in the GV treatment arm compared with GVP. No
      statistically significant difference in quality of life was observed. CONCLUSION:
      In this phase III study, the cisplatin-based GVP regimen showed no survival
      benefit as first-line chemotherapy in advanced NSCLC when compared with the
      cisplatin-free GV regimen, which was substantially better tolerated.

PMID- 15197197
TI  - Tumor-specific methylation in bronchial lavage for the early detection of non
      small-cell lung cancer.
AB  - PURPOSE: The aim of this study was to identify tumor-specific methylation in
      bronchial lavage for the early detection of non-small-cell lung cancer (NSCLC) by
      differentiating the age-related methylation from the tumor-specific methylation
      in NSCLC. PATIENTS AND METHODS: Eighty-five NSCLC patients and 127 cancer-free
      subjects participated in this study. Aberrant methylation at the promoters of the
      p16, Ras association domain family 1A (RASSF1A), fragile histidine triad (FHIT),
      H-cadherin, and retinoic acid receptor beta (RARbeta) genes were evaluated in the
      resected tumor tissues and bronchial lavage samples of NSCLC patients and in the
      bronchial lavage samples of cancer-free subjects by methylation-specific
      polymerase chain reaction. RESULTS: Of the 127 cancer-free samples, methylation
      was detected in 6% for p16, 13% for RARbeta, 3% for H-cadherin, 4% for RASSF1A,
      and 28% for FHIT. Hypermethylation of the p16, RARbeta, H-cadherin, and RASSF1A
      genes was not associated with patient age and smoking, whereas hypermethylation
      of the FHIT promoter occurred more frequently in older patients (P =.02) and was
      associated with exposure to tobacco smoke (P =.001). A strong correlation between
      age and smoking was found in patients with hypermethylation of the FHIT gene (r =
      0.36; P =.03). A total of 68% of the bronchial lavage samples from the 85 NSCLC
      patients showed methylation of at least one of p16, RARbeta, H-cadherin, and
      RASSF1A genes. CONCLUSION: Our study suggests that tumor-specific methylation of
      the p16, RASSF1A, H-cadherin, and RARbeta genes may be a valuable biomarker for
      the early detection of NSCLC in bronchial lavage, and that the age-related
      methylation of FHIT gene in the normal bronchial epithelium is related to the
      exposure to tobacco smoke.

PMID- 15197198
TI  - Interleukin-6, interleukin-10, and vascular endothelial growth factor in
      metastatic renal cell carcinoma: prognostic value of interleukin-6--from the
      Groupe Francais d'Immunotherapie.
AB  - PURPOSE: Few clinical prognostic factors have been identified for patients with
      metastatic renal cell carcinoma (MRCC), and no biomarker is known in this
      disease. Several endogenous cytokines have demonstrated interesting and
      significant correlations with survival in these patients. Our objective was to
      analyze the prognostic value of circulating vascular endothelial growth factor
      (VEGF), interleukin-10 (IL-10), and interleukin-6 (IL-6). PATIENTS AND METHODS:
      Serum levels of IL-6, IL-10, and VEGF were measured in patients with MRCC. Their
      prognostic value for response to treatment and progression-free and overall
      survival was evaluated. Pretreatment samples were obtained from 138 patients of a
      large randomized multicentric trial. Endogenous cytokine levels were determined
      using immunoassays. Univariate and multivariate analyses were performed to
      evaluate the prognostic value of each factor further controlled by an internal
      validation test. Threshold values for serum IL-6 and VEGF were determined using
      the quartile method. RESULTS: Serum IL-6 was detectable in 70% of the patients.
      IL-10 and VEGF were elevated in 8% and 71% of the patients, respectively. None of
      these circulating factors was correlated with response to treatment. IL-10 was
      not significantly correlated with progression-free or overall survival. Despite
      significant correlation with survival, VEGF was not an independent prognostic
      factor in the multivariate analysis. Finally, IL-6 was significantly correlated
      with progression-free survival and overall survival, and has prognostic value for
      overall survival. CONCLUSION: Circulating IL-6 level appears to be an important
      independent prognostic factor in patients with MRCC; if confirmed in further
      studies, it could be considered for treatment decisions in these patients.

PMID- 15197199
TI  - Effects of a high-fiber, low-fat diet intervention on serum concentrations of
      reproductive steroid hormones in women with a history of breast cancer.
AB  - PURPOSE: Diet intervention trials are testing whether postdiagnosis dietary
      modification can influence breast cancer recurrence and survival. One possible
      mechanism is an effect on reproductive steroid hormones. PARTICIPANTS AND
      METHODS: Serum reproductive steroid hormones were measured at enrollment and 1
      year in 291 women with a history of breast cancer who were enrolled onto a
      randomized, controlled diet intervention trial. Dietary goals for the
      intervention group were increased fiber, vegetable, and fruit intakes and reduced
      fat intake. Estradiol, bioavailable estradiol, estrone, estrone sulfate,
      androstenedione, testosterone, dehydroepiandrosterone sulfate, follicle
      stimulating hormone, and sex hormone-binding globulin were measured. RESULTS: The
      intervention (but not the comparison) group reported a significantly lower intake
      of energy from fat (21% v 28%), and higher intake of fiber (29 g/d v 22 g/d), at
      1-year follow-up (P <.001). Significant weight loss did not occur in either
      group. A significant difference in the change in bioavailable estradiol
      concentration from baseline to 1 year in the intervention (-13 pmol/L) versus the
      comparison (+3 pmol/L) group was observed (P <.05). Change in fiber (but not fat)
      intake was significantly and independently related to change in serum
      bioavailable estradiol (P <.01) and total estradiol (P <.05) concentrations.
      CONCLUSION: Results from this study indicate that a high-fiber, low-fat diet
      intervention is associated with reduced serum bioavailable estradiol
      concentration in women diagnosed with breast cancer, the majority of whom did not
      exhibit weight loss. Increased fiber intake was independently related to the
      reduction in serum estradiol concentration.

PMID- 15197200
TI  - The risk of cancer in users of statins.
AB  - PURPOSE: Several preclinical studies suggested a role for 3-hydroxy-3
      methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of
      cancer. The objective of this study was to compare the risk of incident cancer
      between users of statins and users of other cardiovascular medication. METHODS:
      Data were used from the PHARMO database, containing drug dispensing records from
      community pharmacies and linked hospital discharge records for residents of eight
      Dutch cities. The study base included all patients with one or more prescriptions
      for cardiovascular drugs in the period between January 1, 1985 and December 31,
      1998. Cases were identified as patients in the study base with a diagnosis of
      incident cancer and matched with four to six controls on sex, year of birth,
      geographic region, duration of follow-up, and index date. The analysis was
      adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of
      diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers,
      nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug
      therapies. RESULTS: In the study base, 3129 patients were identified and matched
      to 16976 controls. Statin use was associated with a risk reduction of cancer of
      20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that
      statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI,
      0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR,
      0.60; 95% CI, 0.40 to 0.91). CONCLUSION: This observational study suggests that
      statins may have a protective effect against cancer.

PMID- 15197201
TI  - Multivariate prognostic factor analysis in locally advanced and metastatic
      esophago-gastric cancer--pooled analysis from three multicenter, randomized,
      controlled trials using individual patient data.
AB  - PURPOSE: To identify baseline prognostic factors and assess whether pretreatment
      quality of life (QoL) predicts survival in patients with locally advanced or
      metastatic esophago-gastric cancer. PATIENTS AND METHODS: Between 1992 and 2001,
      1,080 patients were enrolled into three randomized, controlled trials assessing
      fluorouracil-based combination chemotherapy. All patients were required to
      complete the European Organization for Research and Treatment of Cancer core QoL
      questionnaire before random assignment. RESULTS: Of the 1080 patients randomly
      assigned, 979 (91%) died. Four independent poor prognostic factors were
      identified by multivariate analysis: performance status >or= 2 (hazard ratio
      [HR], 1.58; 99% CI, 1.25 to 1.98), liver metastases (HR, 1.41; 99%CI, 1.14 to
      1.74), peritoneal metastases (HR, 1.33; 99%CI, 1.01 to 1.74) and alkaline
      phosphatase >or= 100 U/L (HR, 1.41; 99% CI, 1.14 to 1.76). A prognostic index was
      constructed dividing patients into good (no risk factor), moderate (one or two
      risk factors) or poor (three or four risk factors) risk groups. One-year survival
      for good, moderate, and poor risk groups were 48.5%, 25.7%, and 11%,
      respectively, and the survival differences among these groups were highly
      significant (P <.00001). Compared with the good risk group, the moderate risk
      group had nearly twice the risk of death, and the poor risk group had 3.5-fold
      increased risk of death. Pretreatment physical (P =.003), role functioning (P
      <.001), and global QoL (P <.001) predicted survival. CONCLUSION: Four poor
      prognostic factors were identified and a simple prognostic index was devised.
      Information from this analysis can be used to aid clinical decision-making, help
      individual patient risk stratification, and serve as benchmark for the planning
      for future phase III trials.

PMID- 15197202
TI  - Improved sphincter preservation in low rectal cancer with high-dose preoperative
      radiotherapy: the lyon R96-02 randomized trial.
AB  - PURPOSE: The potential advantage of high-dose preoperative radiotherapy to
      increase tumor response and improve the chance of sphincter preservation for low
      rectal cancer remains controversial. The aim of this trial was to evaluate the
      role of escalating the dose of preoperative radiation to increase sphincter
      saving procedures. PATIENTS AND METHODS: Patients with rectal carcinoma located
      in the lower rectum, staged T2 or T3, Nx, or M0 with endorectal sonography, and
      not involving more than two-thirds circumference, were randomly assigned to one
      of two groups: preoperative external-beam radiotherapy (EBRT; 39 Gy in 13
      fractions over 17 days) versus the same EBRT with boost (85 Gy in three
      fractions) using endocavitary contact x-ray. RESULTS: Between 1996 and 2001, 88
      patients were enrolled onto the study. A significant improvement was seen in
      favor of the contact x-ray boost for complete clinical response (24% v 2%) and
      for a complete or near-complete sterilization of the operative specimen (57% v
      34%). A significant increase in sphincter preservation was observed in the boost
      group (76% v 44%; P =.004). At a median follow-up of 35 months, there was no
      difference in morbidity, local relapse, and 2-year overall survival. CONCLUSION:
      A dose escalation with endocavitary irradiation provides increased tumor response
      and sphincter preservation with no detrimental effect on treatment toxicity and
      early clinical outcome.

PMID- 15197203
TI  - Abnormal cytogenetics at date of morphologic complete remission predicts short
      overall and disease-free survival, and higher relapse rate in adult acute myeloid
      leukemia: results from cancer and leukemia group B study 8461.
AB  - PURPOSE: As most patients with acute myeloid leukemia (AML) with morphologic
      complete remission (CR) ultimately relapse, better predictors for outcome are
      needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as
      part of the criteria for CR. To our knowledge, ours is the first relatively large
      study evaluating the usefulness of CRc attained immediately following induction
      chemotherapy. PATIENTS AND METHODS: We included AML patients treated on Cancer
      and Leukemia Group B front-line studies with cytogenetic samples obtained at
      diagnosis and at the first day of documented CR following induction. Patients
      with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n =
      103) were compared with those with abnormal cytogenetics both at diagnosis and at
      CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and
      cumulative incidence of relapse (CIR). Cox proportional hazards models determined
      the prognostic significance of cytogenetics at CR, adjusting for other
      covariates. RESULTS: Clinical features were similar for both groups, with the
      exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at
      diagnosis, which was more frequent (P =.03) in the NCR group. Median follow-up
      was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter
      OS (P =.006) and DFS (P =.0001), and higher CIR (P =.0001). In multivariable
      models, the NCR and ACR groups were predictors for OS (P =.03), DFS (P =.02), and
      CIR (P =.05). The relative risk of relapse or death was 2.1 times higher for ACR
      patients than for NCR patients (95% CI, 1.1 to 3.9). CONCLUSION: Our data suggest
      that converting to normal karyotype at the time of first CR is an important
      prognostic indicator and support the use of CRc as a criterion of CR in AML.

PMID- 15197204
TI  - Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage
      therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior
      autologous transplantation.
AB  - PURPOSE: Allogeneic transplantation for patients with lymphoma who experience a
      recurrence after an autologous transplantation has been considered a hazardous
      therapeutic choice. We investigated the safety and efficacy of nonmyeloablative
      stem-cell transplantation in these patients. PATIENTS AND METHODS: Patients were
      required to have chemosensitive or stable disease. Twenty consecutive patients
      were treated in two sequential trials. Fifteen patients underwent a preparative
      regimen of fludarabine (30 mg/m(2) daily for 3 days), intravenous
      cyclophosphamide (750 mg/m(2) daily for 3 days), and rituximab. For the remaining
      five patients, the conditioning regimen consisted of cisplatin (25 mg/m(2)
      continuous infusion daily for 4 days), fludarabine (30 mg/m(2) daily for 2 days),
      and cytarabine (1,000 mg/m(2) daily for 2 days). Tacrolimus and methotrexate were
      used for graft-versus-host disease prophylaxis. RESULTS: All patients experienced
      engraftment of donor cells. One patient (5%) experienced grade 2 acute graft
      versus-host disease, and no patients experienced a higher grade. One patient
      experienced disease progression at 115 days post-transplantation and responded to
      donor lymphocyte infusion. The remaining patients remained disease-free. One
      patient died at 10.5 months from a fungal infection. With a median follow-up time
      of 25 months, the estimated 3-year current progression-free survival rate was
      95%. CONCLUSION: These data suggest that nonmyeloablative allogeneic stem-cell
      transplantation is an effective option in lymphoma patients with chemosensitive
      or stable disease who experience disease recurrence following autologous
      transplantation.

PMID- 15197205
TI  - Cost minimization study of image-guided core biopsy versus surgical excisional
      biopsy for women with abnormal mammograms.
AB  - PURPOSE: To describe the clinical and economic consequences of image-guided core
      biopsy versus surgical excisional biopsy of mammographically identified breast
      lesions. PATIENTS AND METHODS: Clinical and economic data were collected for 1121
      patients undergoing core biopsies and 501 patients undergoing surgical biopsies
      between 1996 and 1998. Lesions were classified according to mammographic degree
      of suspicion and type of radiographic abnormality. Costs were measured from the
      societal perspective. A decision analytic model was constructed, with
      probabilistic sensitivity analysis. RESULTS: Lesions diagnosed via core versus
      surgical biopsy were less likely to be masses (39% v 55%), less likely to be
      classified as high cancer suspicion (17% v 26%), and less likely to be treated
      with a single procedure (74% v 81%; P <.001 for each). Cancers diagnosed by a
      surgical biopsy were less likely to have had a single operative procedure (33% v
      84%) and were associated with higher total costs whether mastectomy (US dollars
      2775 v US dollars 1849) or lumpectomy (US dollars 2112 v US dollars 1365) was
      used. Sensitivity analysis showed core biopsy optimal in 95.4% of trials. Core
      biopsy was favored for low-suspicion lesions, calcifications, and masses, and
      overall for patients who underwent lumpectomy alone. CONCLUSION: Image-guided
      core biopsy can be cost-saving compared with surgical biopsy, particularly when
      the mammographic abnormality is classified as low suspicion or consists of
      calcifications or masses. Moving to a policy in which core biopsy is the
      preferred approach in these settings has the potential to result in significant
      cost savings.

PMID- 15197206
TI  - Screening for metastasis from choroidal melanoma: the Collaborative Ocular
      Melanoma Study Group Report 23.
AB  - PURPOSE: To describe the predictive value of liver function tests (LFTs), chest x
      ray, and diagnostic imaging for detecting melanoma metastasis during routine
      follow-up after treatment for choroidal melanoma. MATERIALS AND METHODS:
      Prospective longitudinal follow-up of patients enrolled onto two randomized
      trials was conducted by the Collaborative Ocular Melanoma Study (COMS) Group.
      Baseline and annual or semiannual systemic and laboratory evaluations were
      performed according to a standard protocol for 2320 patients enrolled on the
      COMS. RESULTS: COMS patients were screened annually for metastasis and new
      cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin). Elevated
      findings (1.5 to 2 times upper limit of normal) on LFT prompted a diagnostic or
      imaging test to confirm or rule out cancer recurrence. Of 714 patients with
      clinical reports of metastasis, 675 patients died. Of these 675 patients, all but
      four had either histopathologically confirmed or clinically suspected metastatic
      melanoma present at the time of death. Among all patients, the 5-year cumulative
      diagnosis rate of metastatic melanoma was 24% (95% CI, 22% to 27%). Based on all
      patients with reported metastasis, the sensitivity, specificity, positive
      predictive value and negative predictive value associated with at least one
      abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%,
      45.7% and 71.0%, respectively. CONCLUSION: Use of LFTs results followed by
      diagnostic tests has high specificity and predictive values but low sensitivity.
      Better tests are needed to identify earlier metastatic disease associated with
      choroidal melanoma.

PMID- 15197207
TI  - Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid
      tumors.
AB  - PURPOSE: To determine the maximum tolerated dose, toxicity, and pharmacokinetics
      of gemcitabine in children with refractory solid tumors. PATIENTS AND METHODS:
      Gemcitabine was given as a 30-minute infusion for 2 or 3 consecutive weeks every
      4 weeks, to 42 patients aged 1 to 21 years. Doses of 1000, 1200 and 1500 mg/m(2)
      were administered for 3 weeks. Subsequently, gemcitabine was given for only 2
      consecutive weeks at 1500, 1800, and 2100 mg/m(2). Plasma concentrations of
      gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine, were measured in 28
      patients. RESULTS: Forty patients who received 132 courses of gemcitabine were
      assessable for toxicity. The maximum tolerated dose of gemcitabine given weekly
      for 3 weeks was 1200 mg/m(2). Dose-limiting toxicity was not seen in one-third of
      children treated at any doses given for 2 weeks. The major toxicity was
      myelosuppression in three of five patients at 1500 mg/m(2) for 3 weeks, and one
      of seven patients at 1800 mg/m(2) for 2 weeks. Other serious adverse events were
      somnolence, fever and hypotension, and rash in three patients. Gemcitabine plasma
      concentration-time data were fit to a one- (n = 5) or two-compartment (n = 23)
      open model. Mean gemcitabine clearance and half-life values were 2140 mL/min/m(2)
      and 13.7 minutes, respectively. One patient with pancreatic cancer had a partial
      response. Seven patients had stable disease for 2 to 17 months. CONCLUSION:
      Gemcitabine given by 30-minute infusion for 2 or 3 consecutive weeks every 4
      weeks was tolerated well by children at doses of 2100 mg/m(2) and 1200 mg/m(2),
      respectively.

PMID- 15197208
TI  - Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for
      advanced neuroblastoma.
AB  - PURPOSE: Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) has been shown to be
      active against refractory neuroblastoma. The primary toxicity of (131)I-MIBG is
      myelosuppression, which might necessitate autologous hematopoietic stem-cell
      transplantation (AHSCT). The goal of this study was to determine risk factors for
      myelosuppression and the need for AHSCT after (131)I-MIBG treatment. PATIENTS AND
      METHODS: Fifty-three patients with refractory or relapsed neuroblastoma were
      treated with 18 mCi/kg (131)I-MIBG on a phase I/II protocol. The median whole
      body radiation dose was 2.92 Gy. RESULTS: Almost all patients required at least
      one platelet (96%) or red cell (91%) transfusion and most patients (79%)
      developed neutropenia (< 0.5 x 10(3)/microL). Patients reached platelet nadir
      earlier than neutrophil nadir (P <.0001). Earlier platelet nadir correlated with
      bone marrow tumor, more extensive bone involvement, higher whole-body radiation
      dose, and longer time from diagnosis to (131)I-MIBG therapy (P <or=.04). In
      patients who did not require AHSCT, bone marrow disease predicted longer periods
      of neutropenia and platelet transfusion dependence (P <or=.03). Nineteen patients
      (36%) received AHSCT for prolonged myelosuppression. Of patients who received
      AHSCT, 100% recovered neutrophils, 73% recovered red cells, and 60% recovered
      platelets. Failure to recover red cells or platelets correlated with higher whole
      body radiation dose (P <or=.04). CONCLUSION: These results demonstrate the
      substantial hematotoxicity associated with high-dose (131)I-MIBG therapy, with
      severe thrombocytopenia an early and nearly universal finding. Bone marrow tumor
      at time of treatment was the most useful predictor of hematotoxicity, whereas
      whole-body radiation dose was the most useful predictor of failure to recover
      platelets after AHSCT.

PMID- 15197209
TI  - Determining the relationship between toxicity and quality of life in an ovarian
      cancer chemotherapy clinical trial.
AB  - PURPOSE: This analysis of data from a randomized trial of chemotherapy in
      epithelial ovarian cancer sought to determine whether a relationship exists
      between the presence and severity of the most commonly observed toxic effects and
      the corresponding quality of life (QOL) items. PATIENTS AND METHODS: One hundred
      fifty-two eligible patients accrued from Canada by the National Cancer Institute
      of Canada Clinical Trials Group on a randomized trial of paclitaxel and cisplatin
      versus cyclophosphamide/cisplatin were included in the analysis. Toxicity to the
      chemotherapeutic treatments was subjectively evaluated using a trial-specific
      checklist for ovarian cancer and the European Organization for Research and
      Treatment of Cancer QLQ C30+3 questionnaire. Assessments were conducted at
      baseline, before each cycle of treatment (3 weeks), and at each 3-month follow-up
      during the next 2 years (or until progression). RESULTS: The most frequently
      observed symptoms experienced during or shortly following chemotherapy were
      neurosensory loss, lethargy, nausea, vomiting, and alopecia. Regression analyses
      revealed that change scores of QOL items related to motor weakness and
      gastrointestinal pain were common predictors for the change global QOL score
      during protocol treatment; and change scores of QOL items related to lethargy or
      fatigue and change toxicity grade of mood predicted the change global QOL score
      after patients were off treatment. CONCLUSION: The use of the European
      Organization for Research and Treatment of Cancer QLQ C30+3 and trial-specific
      checklist was able to assess the effect of expected toxicities on patient' s QOL
      during and following treatment, and so may be useful in addressing the concerns
      regarding methodological issues that have limited the acquisition of prospective,
      longitudinal treatment-related toxicity data.

PMID- 15197210
TI  - An eicosapentaenoic acid supplement versus megestrol acetate versus both for
      patients with cancer-associated wasting: a North Central Cancer Treatment Group
      and National Cancer Institute of Canada collaborative effort.
AB  - PURPOSE: Studies suggest eicosapentaenoic acid (EPA), an omega-3 fatty acid,
      augments weight, appetite, and survival in cancer-associated wasting. This study
      determined whether an EPA supplement-administered alone or with megestrol acetate
      (MA)-was more effective than MA. PATIENTS AND METHODS: Four hundred twenty-one
      assessable patients with cancer-associated wasting were randomly assigned to an
      EPA supplement 1.09 g administered bid plus placebo; MA liquid suspension 600
      mg/d plus an isocaloric, isonitrogenous supplement administered twice a day; or
      both. Eligible patients reported a 5-lb, 2-month weight loss and/or intake of
      less than 20 calories/kg/d. RESULTS: A smaller percentage taking the EPA
      supplement gained >or= 10% of baseline weight compared with those taking MA: 6% v
      18%, respectively (P =.004). Combination therapy resulted in weight gain of >or=
      10% in 11% of patients (P =.17 across all arms). The percentage of patients with
      appetite improvement (North Central Cancer Treatment Group Questionnaire) was not
      statistically different: 63%, 69%, and 66%, in EPA-, MA-, and combination-treated
      arms, respectively (P =.69). In contrast, 4-week Functional Assessment of
      Anorexia/Cachexia Therapy scores suggested MA-containing arms experienced
      superior appetite stimulation compared with the EPA arm, with scores of 40, 55,
      and 55 in EPA-, MA-, and combination-treated arms, respectively (P =.004).
      Survival was not significantly different among arms. Global quality of life was
      not significantly different among groups. With the exception of increased
      impotence in MA-treated patients, toxicity was comparable. CONCLUSION: This EPA
      supplement, either alone or in combination with MA, does not improve weight or
      appetite better than MA alone.

PMID- 15197212
TI  - Herbal remedies in the United States: potential adverse interactions with
      anticancer agents.
AB  - PURPOSE: Interest in the use of herbal products has grown dramatically in the
      Western world. Recent estimates suggest an overall prevalence for herbal
      preparation use of 13% to 63% among cancer patients. With the narrow therapeutic
      range associated with most anticancer drugs, there is an increasing need for
      understanding possible adverse drug interactions in medical oncology. METHODS: In
      this article, a literature overview is provided of known or suspected
      interactions of the 15 best-selling herbs in the United States with conventional
      allopathic therapies for cancer. RESULTS: Herbs with the potential to
      significantly modulate the activity of drug-metabolizing enzymes (notably
      cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include
      garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea),
      ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper
      methysticum). All of these products participate in potential pharmacokinetic
      interactions with anticancer drugs. CONCLUSION: It is suggested that health care
      professionals and consumers should be aware of the potential for adverse
      interactions with these herbs, question their patients on their use of them,
      especially among patients whose disease is not responding to treatments as
      expected, and urge patients to avoid herbs that could confound their cancer care.

PMID- 15197211
TI  - Thalidomid: current role in the treatment of non-plasma cell malignancies.
AB  - Thalidomide, initially introduced as a sedative, was withdrawn from the market in
      the early 1960s after it was found to be a teratogen. However, it later found use
      as an investigational agent in the treatment of erythema nodosum leprosum, oral
      ulcers, graft versus host disease, and wasting associated with the human
      immunodeficiency syndrome. Its antiangiogenic properties were recognized in the
      early 1990s during a period where the importance of angiogenesis became
      increasingly apparent as a critical step in the in the proliferation and spread
      of malignant neoplasms. This led to the evaluation of thalidomide as an
      antiangiogenic agent in the treatment of several cancers. Thalidomide has already
      become part of standard therapy for the treatment of patients with relapsed and
      refractory multiple myeloma. It has also been found to have varying degree of
      benefit in various other malignancies. Although more clinical trials are needed,
      Kaposi' s sarcoma and myelofibrosis represent other malignancies in which
      thalidomide has already demonstrated promising activity. The mechanism of action
      of thalidomide in cancer is still unclear, but do appear to be mediated by
      several other mechanisms in addition to its anti-angiogenic properties. This
      article reviews the current status of thalidomide for the treatment of non-plasma
      cell malignancies.

PMID- 15197213
TI  - Side effects of therapy: case 1. Nephrotic syndrome associated with gefitinib
      therapy.

PMID- 15197214
TI  - Side effects of therapy: case 2. Tamoxifen and uterine abnormalities.

PMID- 15197215
TI  - Side effects of therapy: case 3. Gastric cancer after radiotherapy of pediatric
      Hodgkin's disease.

PMID- 15197216
TI  - Prognosis in therapy-related acute myeloid leukemia and impact of karyotype.

PMID- 15197218
TI  - Surgical expertise and outcome in osteosarcoma trials.

PMID- 15197220
TI  - Pathologic complete response and survival advantage in esophageal cancer: old
      news.

PMID- 15197221
TI  - How to avoid going bump in the night: object and place representations in the
      hippocampus.

PMID- 15197222
TI  - Unique inner pore properties of BK channels revealed by quaternary ammonium
      block.
AB  - Potassium channels have a very wide distribution of single-channel conductance,
      with BK type Ca(2+)-activated K(+) channels having by far the largest. Even
      though crystallographic views of K(+) channel pores have become available, the
      structural basis underlying BK channels' large conductance has not been
      completely understood. In this study we use intracellularly applied quaternary
      ammonium compounds to probe the pore of BK channels. We show that molecules as
      large as decyltriethylammonium (C(10)) and tetrabutylammonium (TBA) have much
      faster block and unblock rates in BK channels when compared with any other tested
      K(+) channel types. Additionally, our results suggest that at repolarization
      large QA molecules may be trapped inside blocked BK channels without slowing the
      overall process of deactivation. Based on these findings we propose that BK
      channels may differ from other K(+) channels in its geometrical design at the
      inner mouth, with an enlarged cavity and inner pore providing less spatially
      restricted access to the cytoplasmic solution. These features could potentially
      contribute to the large conductance of BK channels.

PMID- 15197223
TI  - Representation of objects in space by two classes of hippocampal pyramidal cells.
AB  - Humans can recognize and navigate in a room when its contents have been
      rearranged. Rats also adapt rapidly to movements of objects in a familiar
      environment. We therefore set out to investigate the neural machinery that
      underlies this capacity by further investigating the place cell-based map of the
      surroundings found in the rat hippocampus. We recorded from single CA1 pyramidal
      cells as rats foraged for food in a cylindrical arena (the room) containing a
      tall barrier (the furniture). Our main finding is a new class of cells that
      signal proximity to the barrier. If the barrier is fixed in position, these cells
      appear to be ordinary place cells. When, however, the barrier is moved, their
      activity moves equally and thereby conveys information about the barrier's
      position relative to the arena. When the barrier is removed, such cells stop
      firing, further suggesting they represent the barrier. Finally, if the barrier is
      put into a different arena where place cell activity is changed beyond
      recognition ("remapping"), these cells continue to discharge at the barrier. We
      also saw, in addition to barrier cells and place cells, a small number of cells
      whose activity seemed to require the barrier to be in a specific place in the
      environment. We conclude that barrier cells represent the location of the barrier
      in an environment-specific, place cell framework. The combined place + barrier
      cell activity thus mimics the current arrangement of the environment in an
      unexpectedly realistic fashion.

PMID- 15197224
TI  - The linkage of innate to adaptive immunity via maturing dendritic cells in vivo
      requires CD40 ligation in addition to antigen presentation and CD80/86
      costimulation.
AB  - Dendritic cell (DC) maturation is an innate response that leads to adaptive
      immunity to coadministered proteins. To begin to identify underlying mechanisms
      in intact lymphoid tissues, we studied alpha-galactosylceramide. This glycolipid
      activates innate Valpha14(+) natural killer T cell (NKT) lymphocytes, which drive
      DC maturation and T cell responses to ovalbumin antigen. Hours after giving
      glycolipid i.v., tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma
      were released primarily by DCs. These cytokines induced rapid surface remodeling
      of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs
      from CD40(-/-) and CD40L(-/-) mice did not elicit CD4(+) and CD8(+) T cell
      immunity, even though the DCs exhibited presented ovalbumin on major
      histocompatibility complex class I and II products and expressed high levels of
      CD80/86. Likewise, an injection of TNF-alpha up-regulated CD80/86 on DCs, but
      CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12
      production, but IL-12p40(-/-) mice generated normal ovalbumin-specific responses.
      Therefore, the link between innate and adaptive immunity via splenic DCs and
      innate NKT cells has several components under distinct controls: antigen
      presentation in the steady state, increases in costimulatory molecules dependent
      on inflammatory cytokines, and a distinct CD40/CD40L signal that functions
      together with antigen presentation ("signal one") and costimulation ("signal
      two") to generate functioning CD4(+) T helper cell 1 and CD8(+) cytolytic T
      lymphocytes.

PMID- 15197225
TI  - Phosphorylation of histone H2B at DNA double-strand breaks.
AB  - Posttranslational modifications of histone tails regulate numerous biological
      processes including transcription, DNA repair, and apoptosis. Although recent
      studies suggest that structural alterations in chromatin are critical for
      triggering the DNA damage response, very little is known about the nature of DNA
      damage-induced chromatin perturbations. Here we show that the serine 14 residue
      in the NH(2)-terminal tail of histone H2B is rapidly phosphorylated at sites of
      DNA double-strand breaks. At late time points after irradiation, the
      phosphorylated form of H2B, H2B-(Ser14P), accumulates into irradiation-induced
      foci. H2B-(Ser14P) foci formation is not associated with the apoptotic
      phosphorylation of H2B but is strictly dependent on the phosphorylated isoform of
      H2AX. Our results broaden the spectrum of histone modifications that constitute
      the DNA damage "histone code" and suggest a model for the underlying chromatin
      structure within damage-induced foci.

PMID- 15197226
TI  - Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown
      cow's milk allergy.
AB  - Cow's milk allergy in children is often of short duration, which makes this
      disorder an interesting clinical model for studies of tolerance to dietary
      antigens. Here, we studied T cell responses in 21 initially allergic children
      who, after a milk-free period of >2 mo, had cow's milk reintroduced to their
      diet. Children who outgrew their allergy (tolerant children) had higher
      frequencies of circulating CD4(+)CD25(+) T cells and decreased in vitro
      proliferative responses to bovine beta-lactoglobulin in peripheral blood
      mononuclear cells (PBMCs) compared with children who maintained clinically active
      allergy. No significant difference in proliferative activity stimulated by the
      polyclonal mitogen phytohemagglutinin was observed between the two groups.
      Depletion of CD25(+) cells from PBMCs of tolerant children led to a fivefold
      increase in in vitro proliferation against beta-lactoglobulin. This suggests that
      tolerance is associated with the appearance of circulating CD4(+)CD25(+)
      regulatory T (Treg) cells that are capable of suppressing the effector T cells
      generated 1 wk after reintroduction of cow's milk. The suppressive function of
      the CD4(+)CD25(+) Treg cells was shown to be partly cell contact dependent.
      Collectively, our study provides human data to suggest that mucosal induction of
      tolerance against dietary antigens is associated with the development of
      CD4(+)CD25(+) Treg cells.

PMID- 15197229
TI  - Analysis of the CCR7 expression on murine bone marrow-derived and spleen
      dendritic cells.
AB  - About 40% of bone marrow-derived dendritic cells (BM-DCs) generated from stem
      cells of C57BL/6 (B6.WT) mice differentiate in the presence of granulocyte
      macrophage-colony stimulating factor (GM-CSF) without further stimuli to mature
      DCs. These cells are characterized by high levels of major histocompatibility
      complex class II, CD40, and CD86 on their surface. Recent studies have revealed
      that tumor necrosis factor (TNF) is crucial for maturation of BM-DCs. However,
      once matured, the phenotype of mature TNF-negative C57BL/6 (B6.TNF-/-) and B6.WT
      BM-DCs is comparable. Both expressed high levels of CD40 and CD86 and were
      positive for mRNA of the chemokine receptor (CCR)7. To extend our studies, we
      generated a monoclonal antibody (mAb) specific for mouse CCR7. This mAb allowed
      us to analyze the surface expression of CCR7 during maturation of B6.WT and
      B6.TNF-/- BM-DCs in the presence of GM-CSF and stimulated with TNF or
      lipopolysaccharide (LPS) and to compare it with the CCR7 expression on ex vivo
      isolated splenic DCs with or without additional stimulation. Our results showed
      that CCR7 expression on murine BM-DCs is an indication of cell maturity.
      Incubation with LPS induced the maturation of all BM-DCs in culture but increased
      the number of mature CCR7+ splenic DCs only marginally.

PMID- 15197228
TI  - SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis.
AB  - Hepatocellular carcinomas (HCCs) mainly develop from liver cirrhosis and severe
      liver fibrosis that are established with long-lasting inflammation of the liver.
      Silencing of the suppressor of the cytokine signaling-1 (SOCS1) gene, a negative
      regulator of cytokine signaling, by DNA methylation has been implicated in
      development or progress of HCC. However, how SOCS1 contributes to HCC is unknown.
      We examined SOCS1 gene methylation in >200 patients with chronic liver disease
      and found that the severity of liver fibrosis is strongly correlated with SOCS1
      gene methylation. In murine liver fibrosis models using dimethylnitrosamine, mice
      with haploinsufficiency of the SOCS1 gene (SOCS1(-/+) mice) developed more severe
      liver fibrosis than did wild-type littermates (SOCS1(+/+) mice). Moreover,
      carcinogen-induced HCC development was also enhanced by heterozygous deletion of
      the SOCS1 gene. These findings suggest that SOCS1 contributes to protection
      against hepatic injury and fibrosis, and may also protect against
      hepatocarcinogenesis.

PMID- 15197227
TI  - Toll-like receptor 9-dependent and -independent dendritic cell activation by
      chromatin-immunoglobulin G complexes.
AB  - Dendritic cell (DC) activation by nucleic acid-containing immunoglobulin (Ig)G
      complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis.
      However, the mechanisms responsible for activation and subsequent disease
      induction are not completely understood. Here we show that murine DCs are much
      more effectively activated by immune complexes that contain IgG bound to
      chromatin than by immune complexes that contain foreign protein. Activation by
      these chromatin immune complexes occurs by two distinct pathways. One pathway
      involves dual engagement of the Fc receptor FcgammaRIII and Toll-like receptor
      (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a
      characteristic cytokine profile elicited by the chromatin immune complexes that
      distinguishes this response from that of conventional TLR ligands, notably the
      induction of BAFF and the lack of induction of interleukin 12. The data establish
      a critical role for self-antigen in DC activation and explain how the innate
      immune system might drive the adaptive immune response in SLE.

PMID- 15197230
TI  - Autocrine IL-10 partially prevents differentiation of neonatal dendritic
      epidermal leukocytes into Langerhans cells.
AB  - To test whether reduced immune responsiveness in early life may be related to the
      immaturity of neonatal antigen-presenting cells, we comparatively assessed the
      phenotypic and functional characteristics of dendritic epidermal leukocytes (DEL)
      and epidermal Langerhans cells (LC) in newborn (NB) and adult mice, respectively.
      We report that purified, 3-day-cultured DEL do not acquire the morphology and
      phenotype typical of LC and are significantly weaker stimulators of naive,
      allogeneic CD4+ and CD8+ T cells than LC. Freshly isolated DEL are twice as
      efficient as LC in the uptake of fluorescein isothiocyanate-conjugated tracers
      but are not able to present these to antigen-specific T cell hybridomas. To
      clarify the underlying cause, cytokine expression of NB and adult epidermal cells
      (EC) was examined. We found that DEL express considerable amounts of interleukin
      (IL)-10, that IL-10 in NB EC supernatants partially inhibits LC maturation, and
      that DEL-enriched EC from IL-10-/- mice induce stronger primary T cell responses
      compared with those from IL-10+/+ mice. We conclude that IL-10 is one of the
      factors preventing maturation and differentiation of DEL into immunocompetent LC
      in intrauterine life and is at least partly responsible for the poor immune
      responsiveness of neonates.

PMID- 15197231
TI  - Adenosine A2A receptor occupancy stimulates expression of proteins involved in
      reverse cholesterol transport and inhibits foam cell formation in macrophages.
AB  - Transport of cholesterol out of macrophages is critical for prevention of foam
      cell formation, the first step in the pathogenesis of atherosclerosis. Proteins
      involved in this process include cholesterol 27-hydroxylase and adenosine 5'
      triphosphate-binding cassette transporter A1 (ABCA1). Proinflammatory cytokines
      and immune complexes (IC) down-regulate cholesterol 27-hydroxylase and impede
      cholesterol efflux from macrophages, leading to foam cell formation. Prior
      studies have suggested occupancy of the anti-inflammatory adenosine A2A receptor
      (A2AR) minimizes early atherosclerotic changes in arteries following injury. We
      therefore asked whether A2AR occupancy affects macrophage foam cell formation in
      response to IC and the cytokine interferon-gamma. We found that the selective
      A2AR agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine
      (CGS-21680) inhibited foam cell formation in stimulated THP-1 human macrophages,
      and the effects of CGS-21680 were reversed by the selective A2AR antagonist 4-(2
      [7-amino-2-(2-furyl) [1, 2, 4]triazolo[2,3-a] [1, 3, 5]triazin-5
      ylamino]ethyl)phenol. In confirmation of the role of A2AR in prevention of foam
      cell formation, CGS-21680 also inhibited foam cell formation in cultured murine
      peritoneal macrophages but did not affect foam cell formation in A2AR-deficient
      mice. Agents that increase foam cell formation also down-regulate cholesterol 27
      hydroxylase and ABCA1 expression. Therefore, we determined the effect of A2AR
      occupancy on expression of these reverse cholesterol transport (RCT) proteins and
      found that A2AR occupancy stimulates expression of message for both proteins.
      These results indicate that one mechanism for the antiatherogenic effects of
      adenosine is stimulation of the expression of proteins involved in RCT. These
      findings suggest a novel approach to the development of agents that prevent
      progression of atherosclerosis.

PMID- 15197232
TI  - Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative
      stress, adhesion molecule expression, and leukocyte recruitment into the inflamed
      intestine.
AB  - Oxidant stress has been implicated in the pathogenesis of inflammatory bowel
      disease. Antioxidant enzymes, such as superoxide dismutase (SOD), are candidate
      drugs for modulating this pathogenic factor. This study was designed to determine
      the therapeutic value of SOD in an experimental model of colitis and to study the
      mechanisms underlying its effects on intestinal inflammation. For that purpose,
      colitic (trinitrobenzene sulfonic acid-induced) and control rats were studied.
      Groups of colitic animals were treated with different doses of SOD (1, 4, or 13
      mg/kg/day) or vehicle, starting after induction of colitis and during 7 days.
      Clinical and pathological markers of colitis severity and lipid peroxidation in
      colonic tissue were measured. Leukocyte-endothelial cell interactions in colonic
      venules and expression of vascular cell adhesion molecule 1 (VCAM-1) were
      determined. Development of colitis was associated with a significant loss in body
      weight, an increase in macroscopic and microscopic damage scores, and colonic
      myeloperoxidase activity. Administration of SOD significantly attenuated these
      changes in a dose-dependent manner and reduced lipid peroxidation in colonic
      tissue. The increase in leukocyte rolling and adhesion in colonic venules of
      colitic rats were significantly reduced by administration of SOD, 13 mg/kg/day.
      Development of colitis was associated with a marked increase in endothelial VCAM
      1 expression, which was significantly reduced by treatment with SOD. In
      conclusion, treatment with SOD significantly reduces peroxidation reactions in
      the inflamed colon and affords significant amelioration of colonic inflammatory
      changes in experimental colitis. This effect is related to a reduction in VCAM-1
      expression and leukocyte recruitment into the inflamed intestine.

PMID- 15197234
TI  - Enrichment for a CD26hi SIRP- subset in lymph dendritic cells from the upper aero
      digestive tract.
AB  - Dendritic cells (DC) have been reported to migrate in afferent lymph in the
      steady state. However, it is unknown whether DC traffic is modulated by the
      nature of the drained tissue. To analyze the influence of mucosal versus
      cutaneous microenvironments on the constitutive DC release, we exploited a novel
      technique of lymph cannulation in sheep, which allowed a comparison of afferent
      lymph DC migrating from the head mucosae [cervical DC (CerDC)] with DC migrating
      from skin [prescapular DC (PresDC)]. The migration rate was lower for CerDC than
      for PresDC. Compared with PresDC, CerDC contained a higher proportion of the
      CD26hi signal regulatory protein (SIRP)- DC subset. It is interesting that
      cytoplasmic apoptotic DNA as well as cytokeratin-positive inclusions were
      primarily detected among CD26hi SIRP- DC, an observation similar to that made in
      rats, which leads to the suggestion that this subset was involved in self-antigen
      presentation and tolerance induction. After the inoculation of cholera toxin (CT)
      onto the oro-nasal mucosae, migration of CD26hi SIRP- and CD26lo SIRP+ DC was
      accelerated in lymph, indicating that the effect of CT on DC mobilization is not
      subset-specific. Our results show that a mucosal environment influences DC output
      and the relative DC subset representation in lymph. This modulation of DC traffic
      to lymph nodes by mucosal surfaces is likely to affect the bias of the mucosal
      immune responses.

PMID- 15197235
TI  - APC derived from donor splenocytes support retinal autoimmune disease in
      allogeneic recipients.
AB  - T cell adoptive transfer models of autoimmune disease have been used in
      conjunction with radiation/bone marrow chimeras to define the minimal
      requirements for antigen (Ag) recognition. In models with central nervous system
      Ags, major histocompatibility complex (MHC) class II compatibility achieved by
      grafting F1 bone marrow into parental recipients was reported to be necessary and
      sufficient for transfer of CD4 T cell-mediated experimental autoimmune
      encephalomyelitis. Bone marrow-derived, perivascular microglia are now widely
      regarded to play a critical role in the expression of experimental autoimmune
      diseases of the nervous system. Similar results might be expected in the
      experimental autoimmune uveoretinitis model, as retina is an extension of the
      brain. Using an allogeneic Ag-presenting cell (APC) adoptive transfer strategy,
      it was found that resident APC were not essential and that their replacement with
      MHC-compatible cells by bone marrow-grafting techniques was not necessary.
      Instead, APC were recruited from the circulation.

PMID- 15197233
TI  - The role of gammadelta T cells in the regulation of neutrophil-mediated tissue
      damage after thermal injury.
AB  - Thermal injury induces an inflammatory response that contributes to the
      development of secondary tissue damage. Neutrophil recruitment and activation are
      in part responsible for this tissue damage. Although gammadelta T cells have been
      shown to regulate the inflammatory responses in tissues that are prone to
      neutrophil-mediated injury post-burn, their role in the induction of secondary
      tissue injury post-burn remains unknown. To study this, gammadelta T cell
      deficient (gammadelta TCR-/-) and wild-type (WT) mice were subjected to thermal
      injury or sham procedure, and tissue samples were isolated 1-24 h thereafter.
      Burn injury induced neutrophil accumulation in the lung and small intestines of
      WT mice at 1-3 h post-injury. No such increase in neutrophil tissue content was
      observed in gammadelta TCR-/- mice. An increase in tissue wet/dry weight ratios
      was also observed in these organs at 3 h post-burn in WT but not in gammadelta
      TCR-/- mice. A parallel increase in plasma and small intestine levels of the
      chemokines macrophage-inflammatory protein-1beta (chemokine ligand 4) and
      keratinocyte-derived chemokine (CXC chemokine ligand 1) were observed in injured
      WT mice but not in injured gammadelta TCR-/- mice. Increased activation (CD120b
      expression) of the circulating gammadelta T cell population was also observed at
      3 h post-burn in WT mice. These results indicate the gammadelta T cells, through
      the production of chemokines, play a central role in the initiation of neutrophil
      mediated tissue damage post-burn.

PMID- 15197236
TI  - Human eosinophils produce the T cell-attracting chemokines MIG and IP-10 upon
      stimulation with IFN-gamma.
AB  - Eosinophils participate in allergic inflammation, where expression of T helper
      cell type 2 (Th2) cytokines such as interleukin (IL)-4 and IL-5 are seen.
      However, eosinophils sometimes accumulate during disease with expression of Th1
      cytokines [i.e., interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF
      alpha), and IL-1beta]. In this study, we investigated whether eosinophils can
      respond with expression of the IFN-inducible C-X-C chemokines monokine induced by
      IFN-gamma [MIG; CXC chemokine ligand 9 (CXCL9)], IFN-gamma-inducible protein (IP
      10/CXCL10), and IFN-inducible T cell alpha chemoattractant (I-TAC/CXCL11). These
      chemokines share the ability to recruit and activate T cells and natural killer
      cells to sites of inflammation. We found that IFN-gamma induced rapid and
      sustained gene expression of MIG, IP-10, and I-TAC in eosinophils, as detected by
      quantitative reverse transcriptase-polymerase chain reaction. During incubation,
      IFN-gamma-stimulated eosinophils released MIG and IP-10, as detected by enzyme
      linked immunosorbent assay, while I-TAC could not be detected in the medium. TNF
      alpha but not IL-1beta enhanced the IFN-gamma-induced production of MIG and IP
      10. Conversely, addition of the Th2 cytokine IL-4 down-regulated IFN-gamma
      induced synthesis of MIG and IP-10 in eosinophils. Crohn's disease is
      characterized by a Th1-polarized inflammation and presence of eosinophils. In
      lesions from this disease, MIG was detected in eosinophils by
      immunohistochemistry. Taken together, the results point to immunoregulatory roles
      for eosinophils during some diseases with Th1-polarized inflammation.

PMID- 15197237
TI  - Histone deacetylase inhibition improves dendritic cell differentiation of
      leukemic blasts with AML1-containing fusion proteins.
AB  - Recurrent cytogenetic abnormalities in leukemic blasts make these an attractive
      source for dendritic cells (DC) to induce a leukemia-specific immune response. In
      this study, three leukemic cell lines were investigated: Kasumi-1 and SKNO-1 (two
      acute myeloid leukemia (AML) cell lines carrying the (8;21)-chromosomal
      translocation, resulting in the expression of the leukemia-specific fusion
      protein AML1-eight-twenty-one) and REH, an acute lymphoblastic leukemia cell line
      with the (12;21)-chromosomal translocation and expression of translocation ETS
      like leukemia-AML1. These fusion proteins are implicated in the pathogenesis of
      the leukemic state by recruiting corepressors and histone deacetylases (HDAC),
      which interfere with normal cell differentiation. In vitro generation of DC was
      achieved using a cytokine cocktail containing tumor necrosis factor alpha,
      granulocyte macrophage-colony stimulating factor, c-kit ligand, and soluble CD40
      ligand; yet, addition of the HDAC inhibitor (Hdi) trichostatin A enhanced DC
      differentiation with retention of the fusion transcripts. These leukemic DC
      showed high-level CD83 and human leukocyte antigen (HLA)-DR expression and had a
      high allostimulatory potential. Only DC generated from these cell lines after Hdi
      induced blast-specific cytotoxic T cell responses in HLA-A-matched T cells with a
      cytotoxicity of 42% in parental Kasumi-1 and 83% in parental REH cells,
      respectively. This model system suggests that the Hdi supports the in vitro
      differentiation of DC from leukemic blasts with AML1-containing fusion proteins.

PMID- 15197238
TI  - GPI-defective monocytes from paroxysmal nocturnal hemoglobinuria patients show
      impaired in vitro dendritic cell differentiation.
AB  - Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic
      disorder characterized by a phosphatidylinositol (PI) glycan-A gene mutation,
      which impairs the synthesis of the glycosyl-PI (GPI) anchor, thus causing the
      absence of all GPI-linked proteins on the membrane of the clonal-defective cells.
      The presence of a consistent GPI-defective monocyte compartment is a common
      feature in PNH patients. To investigate the functional behavior of this
      population, we analyzed its in vitro differentiation ability toward functional
      dendritic cells (DCs). Our data indicate that GPI-defective monocytes from PNH
      patients are unable to undergo full DC differentiation in vitro after granulocyte
      macrophage-colony stimulating factor and recombinant interleukin (IL)-4
      treatment. In this context, the GPI-defective DC population shows mannose
      receptor expression, high levels of the CD86 molecule, and impaired CD1a up
      regulation. The analysis of lipopolysaccharide and CD40-dependent, functional
      pathways in these DCs revealed a strong decrease in tumor necrosis factor alpha
      and IL-12 production. Finally, GPI-defective DCs showed a severe impairment in
      delivering accessory signals for T cell receptor-dependent T cell proliferation.

PMID- 15197240
TI  - iNOS (NOS2) at a glance.

PMID- 15197239
TI  - Distinct and overlapping roles of CXCR5 and CCR7 in B-1 cell homing and early
      immunity against bacterial pathogens.
AB  - CXC chemokine receptor (CXCR)5 and CC chemokine receptor (CCR)7 are the major
      chemokine receptors required for B cell homing and microenvironmental
      localization during antigen-independent and -dependent B cell differentiation.
      Here, we show markedly decreased B-1 B cell numbers in the peritoneal cavity of
      CXCR5-/- and CXCR5-/-CCR7-/- double-deficient mice paralleled by reduced antigen
      induced phosphorylcholine-specific immunoglobulin (Ig)M responses after
      intraperitoneal (i.p.) administration of streptococcal antigen. CCR7-/- mice also
      revealed a partial reduction in peritoneal B-1 cell numbers combined with a
      reduced humoral response to i.p. injected bacterial antigen. However, opposite
      roles of CXCR5 and CCR7 were observed when the frequency of peritoneal B-2 cells
      was analyzed. CXCR5-/- mice almost completely lacked B-2 cells, whereas CCR7
      deficiency engendered an increase in peritoneal B-2 cells. In addition, CCR7-/-
      mice had enhanced, splenic IgM+ plasma cell responses, whereas the
      extrafollicular B cell response of the CXCR5-/- mice was not significantly
      altered compared with wild-type controls. Thus, the two chemokine receptors exert
      divergent forces at multiple levels of the innate immune response. CXCR5 plays a
      dominant role in peritoneal B-1 B cell homing and body cavity immunity, but both
      chemokine receptors are needed for a proportional peritoneal B-2 cell homing and
      balanced development of an early splenic B cell response.

PMID- 15197241
TI  - Pritinder Kaur. Interview by Fiona Watt.

PMID- 15197242
TI  - Dynamics and inheritance of the endoplasmic reticulum.
AB  - The endoplasmic reticulum (ER) consists of a polygonal array of interconnected
      tubules and sheets that spreads throughout the eukaryotic cell and is contiguous
      with the nuclear envelope. This elaborate structure is created and maintained by
      a constant remodeling process that involves the formation of new tubules, their
      cytoskeletal transport and homotypic fusion. Since the ER is a large, single-copy
      organelle, it must be actively segregated into daughter cells during cell
      division. Recent analysis in budding yeast indicates that ER inheritance involves
      the polarized transport of cytoplasmic ER tubules into newly formed buds along
      actin cables by a type V myosin. The tubules then become anchored to a site at
      the bud tip and this requires the Sec3p subunit of the exocyst complex. The ER is
      then propagated along the cortex of the bud to yield a cortical ER structure
      similar to that of the mother cell. In animal cells, the ER moves predominantly
      along microtubules, whereas actin fibers serve a complementary role. It is not
      yet clear to what extent the other components controlling ER distribution in
      yeast might be conserved in animal cells.

PMID- 15197243
TI  - Visualizing Ras signalling in real-time.
AB  - Ras GTPases are universal molecular switches that act as kinetic timers of signal
      transduction events. They are post-translationally modified by the addition of
      lipid groups to their hypervariable carboxyl termini, which plug the proteins to
      membranes and influence their dynamic sorting and trafficking. For the past
      twenty years, the plasma membrane has been considered to be the predominant
      platform from which Ras operates. Recent work using live-cell imaging and novel
      probes to visualize where and when Ras is active has supported this long-held
      belief. However, an equally fascinating aspect of these imaging studies has been
      the discovery of dynamic Ras activity, as well as distinct signal output, from
      intracellular organelles. Activation of Ras on the Golgi exhibits kinetics
      different from Ras activation on the plasma membrane, and compartmentalized Ras
      signalling seems particularly prominent in lymphocytes. However, data on the
      spatial and temporal regulation of Ras activity has frequently differed depending
      on the nature of the probe, the cell type and the stimulus. Nevertheless, because
      Ras traffics through endomembranes en route to the plasma membrane, it seems
      likely that Ras can signal from such compartments. The burning question in this
      field concerns the significance of this observation for endogenous Ras signalling
      output.

PMID- 15197244
TI  - Quantification of the cytoplasmic spaces of living cells with EGFP reveals
      arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors.
AB  - The hypothesis is tested that enhanced green fluorescent protein (EGFP) can be
      used to quantify the aqueous spaces of living cells, using as a model transgenic
      Xenopus rods. Consistent with the hypothesis, regions of rods having structures
      that exclude EGFP, such as the mitochondrial-rich ellipsoid and the outer
      segments, have highly reduced EGFP fluorescence. Over a 300-fold range of
      expression the average EGFP concentration in the outer segment was approximately
      half that in the most intensely fluorescent regions of the inner segment, in
      quantitative agreement with prior X-ray diffraction estimates of outer segment
      cytoplasmic volume. In contrast, the fluorescence of soluble arrestin-EGFP fusion
      protein in the dark adapted rod outer segment was approximately threefold lower
      than predicted by the EGFP distribution, establishing that the fusion protein is
      not equilibrated with the cytoplasm. Arrestin-EGFP mass was conserved during a
      large-scale, light-driven redistribution in which approximately 40% of the
      protein in the inner segment moved to the outer segment in less than 30 minutes.

PMID- 15197245
TI  - Beta-adrenergic blockade affects initial drug distribution due to decreased
      cardiac output and altered blood flow distribution.
AB  - Beta-adrenergic receptor blockers decrease intravenous anesthetic dose
      requirements. The present study determined the effect of propranolol on
      indocyanine green and antipyrine disposition from the moment of rapid intravenous
      injection. Anti-pyrine is a physiological marker that distributes to a volume as
      large as total body water in a blood flow-dependent manner and is a
      pharmacokinetic surrogate for many lipophilic drugs, including intravenous
      anesthetics. Antipyrine and indocyanine green disposition were determined twice
      in five healthy adult males in this Institutional Review Board-approved study,
      once during propranolol infusion. After rapid indocyanine green and antipyrine
      injection, arterial blood samples were collected frequently for 2 min and less
      frequently thereafter. Plasma indocyanine green and antipyrine concentrations
      were measured by high-performance liquid chromatography. Indocyanine green and
      antipyrine disposition were characterized, using SAAM II, by a recirculatory
      pharmacokinetic model that describes drug disposition from the moment of
      injection. Parameters were compared using the paired t test. The disposition of
      indocyanine green demonstrated that propranolol decreased cardiac output at the
      expense of the fast peripheral (nonsplanchnic) intravascular circuit. The area
      under the antipyrine concentration versus time relationship was doubled for at
      least the first 3 min after injection due to both decreased cardiac output and
      maintenance of nondistributive blood flow at the expense of a two-thirds
      reduction of blood flow (intercompartmental clearance) to the rapidly
      equilibrating (fast, splanchnic) tissue volume. The increase in antipyrine area
      under the curve due to propranolol-induced alteration of initial antipyrine
      disposition could explain decreased intravenous anesthetic dose requirements in
      the presence of beta-adrenergic receptor blockade.

PMID- 15197246
TI  - Direct interaction of NRSF with TBP: chromatin reorganization and core promoter
      repression for neuron-specific gene transcription.
AB  - Neural restrictive silencer factor, NRSF (also known as REST) binds a neuronal
      cell type selective silencer element to mediate transcriptional repression of
      neuron-specific genes in non-neuronal cells and neuronal progenitors. Two
      repression domains (RD-1 and RD-2) occur in its N-terminal and C-terminal
      regions, respectively. RD-1 recruits mSin3 and HDAC, thereby inhibiting
      transcription by inducing reorganization of the chromatin structure. However,
      little is known about how such global repression becomes promoter-specific
      repression or whether the NRSF-HDAC complex can interact with transcriptional
      core factors at each specific promoter. Here we show evidence that NRSF interacts
      with core promoter factors, including TATA-binding protein (TBP). The NRSF-TBP
      interaction occurred between the linear segments of the N- and C-terminal-most
      portions of NRSF and the C-terminal half of TBP. A RD-2 mutant of NRSF lost the
      TBP-binding activity and was unable to repress transcription at an exogenously
      introduced TGTA promoter. These results indicate that the direct interaction
      between the NRSF C-terminal domain and TBP is essential for the C-terminal
      repression mechanism of NRSF. Thus, the RD-1 and RD-2 repression domains of NRSF
      utilize both chromatin-dependent and chromatin-independent mechanisms, which may
      be segregated at various stages of neural development and modulation.

PMID- 15197249
TI  - Rat adult stem cells (marrow stromal cells) engraft and differentiate in chick
      embryos without evidence of cell fusion.
AB  - Cell fusion was recently reported to account for the plasticity of adult stem
      cells in vivo. Adult stem cells, referred to as mesenchymal stem cells or marrow
      stromal cells, from rat marrow, were infused into 1.5- to 2-day-old chick
      embryos. After 4 days, the rat cells had expanded 1.3- to 33-fold in one-third of
      surviving embryos. The cells engrafted into many tissues, and no multinuclear
      cells were detected. The most common site of engraftment was the heart,
      apparently because the cells were infused just above the dorsal aorta. Some of
      the cells in the heart expressed cardiotin, and alpha-heavy-chain myosin. GFP(+)
      cells reisolated from the embryos had a rat karyotype. Therefore, the cells
      engrafted and partially differentiated without evidence of cell fusion.

PMID- 15197250
TI  - TorI, a response regulator inhibitor of phage origin in Escherichia coli.
AB  - The torI gene has been identified by using a genetic multicopy approach as a
      negative regulator of the torCAD operon that encodes the trimethylamine N-oxide
      reductase respiratory system in Escherichia coli. The negative effect was due to
      a previously unidentified small ORF (66 aa) of phage origin that we called torI
      for Tor inhibition. Overexpression of torI led to an 8-fold decrease of the
      torCAD operon transcription. This operon is positively regulated, in the presence
      of trimethylamine N-oxide, by a four-step phosphorelay involving the TorS sensor
      and the TorR response regulator. Epistatic experiments showed that TorI acts
      downstream of TorS and needs the presence of TorR. In vitro experiments showed
      that it is neither a TorR phosphatase nor a histidine kinase inhibitor and that
      it binds to the effector domain of TorR. Unexpectedly, TorI did not impede TorR
      DNA binding, and we propose that it may prevent RNA polymerase recruitment to the
      torC promoter. This study thus reveals a previously uncharacterized class of
      response regulator inhibitors.

PMID- 15197251
TI  - Synaptotagmin IV regulates glial glutamate release.
AB  - Calcium-binding synaptotagmins (Syts) are membrane proteins that are conserved
      from nematode to human. Fifteen Syts (Syts I-XV) have been identified in
      mammalian species. Syt I has been well studied and is a candidate for the Ca(2+)
      sensor that triggers evoked exocytosis underlying fast synaptic transmission.
      Whereas the functions of the other Syts are unclear, Syt IV is of particular
      interest because it is rapidly up-regulated after chronic depolarization or
      seizures, and because null mutations exhibit deficits in fine motor coordination
      and hippocampus-dependent memory. Screening Syts I-XIII, which are enriched in
      brain, we find that Syt IV is located in processes of astroglia in situ.
      Reduction of Syt IV in astrocytes by RNA interference decreases Ca(2+)-dependent
      glutamate release, a gliotransmission pathway that regulates synaptic
      transmission. Mutants of the C2B domain, the only putative Ca(2+)-binding domain
      in Syt IV, act in a dominant-negative fashion over Ca(2+)-regulated glial
      glutamate release, but not gliotransmission induced by changes in osmolarity.
      Because we find that Syt IV is expressed predominantly by astrocytes and is not
      in the presynaptic terminals of the hippocampus, and because Syt IV knockout mice
      exhibit hippocampal-based memory deficits, our data raise the intriguing
      possibility that Syt IV-mediated gliotransmission contributes to hippocampal
      based memory.

PMID- 15197252
TI  - Dynamical basis of intentions and expectations in a simple neuronal network.
AB  - Selection of behavioral responses to external stimuli is strongly influenced by
      internal states, such as intentions and expectations. These internal states are
      often attributed to higher-order brain functions. Yet here we show that even in
      the simple feeding network of Aplysia, external stimuli do not directly specify
      which motor output is expressed; instead, the motor output is specified by the
      state of the network at the moment of stimulation. The history-dependence of this
      network state manifests itself in the same way as do intentions and expectations
      in the behavior of higher animals. Remarkably, we find that activity-dependent
      plasticity of a synapse within the network itself, rather than some higher-order
      network, mediates one important aspect of the change in the network state.
      Through this mechanism, changes in the network state become an automatic
      consequence of the generation of behavior. Altogether, our findings suggest that
      intentions and expectations may emerge within behavior-generating networks
      themselves from the plasticity of the very processes that generate the behavior.

PMID- 15197254
TI  - Exceptional record of mid-Pleistocene vertebrates helps differentiate climatic
      from anthropogenic ecosystem perturbations.
AB  - Mid-Pleistocene vertebrates in North America are scarce but important for
      recognizing the ecological effects of climatic change in the absence of humans.
      We report on a uniquely rich mid-Pleistocene vertebrate sequence from Porcupine
      Cave, Colorado, which records at least 127 species and the earliest appearances
      of 30 mammals and birds. By analyzing >20,000 mammal fossils in relation to
      modern species and independent climatic proxies, we determined how mammal
      communities reacted to presumed glacial-interglacial transitions between
      1,000,000 and 600,000 years ago. We conclude that climatic warming primarily
      affected mammals of lower trophic and size categories, in contrast to documented
      human impacts on higher trophic and size categories historically. Despite changes
      in species composition and minor changes in small-mammal species richness evident
      at times of climatic change, overall structural stability of mammal communities
      persisted >600,000 years before human impacts.

PMID- 15197253
TI  - Phospholipase D alpha 1-derived phosphatidic acid interacts with ABI1 phosphatase
      2C and regulates abscisic acid signaling.
AB  - Phospholipase D (PLD) and protein phosphatase 2C (PP2C) both play a role in
      mediating plant responses to abscisic acid (ABA). In this article, we show that
      PLD alpha 1 and its product, phosphatidic acid (PA), regulate a PP2C, ABI1, which
      is a negative regulator of ABA responses in Arabidopsis. Leaves from a T-DNA
      insertional mutant of PLD alpha 1 and PLD alpha 1-antisense plants lose more
      water than do wild-type plants. The stomatal closure of PLD alpha 1-null leaves
      is insensitive to ABA but is promoted by PA. ABA treatment promotes an increase
      in PA from phosphatidylcholine in wild type but not in PLD alpha 1-null cells.
      PLD alpha 1-derived PA binds to ABI1; the PA-ABI1 binding is demonstrated by
      coprecipitating PA with ABI1 from plant cells, measuring binding of PA from
      vesicles to ABI1, and assaying ABI1 bound to PA immobilized on a filter. Deletion
      and site-specific mutational analyses show that arginine 73 in ABI1 is essential
      for PA-ABI1 binding. PA binding decreases the phosphatase activity of ABI1. The
      lack of ABA-induced production of PA in PLD alpha 1-null cells results in a
      decrease in the association of ABI1 with the plasma membrane in response to ABA.
      These results indicate that PA produced by PLD alpha 1 inhibits the function of
      the negative regulator ABI1, thus promoting ABA signaling. The identification of
      ABI1 as a direct target of the lipid messenger PA provides a functional link
      between the two families of important signaling enzymes, PLD and PP2C.

PMID- 15197255
TI  - Evidence for large methane releases to the atmosphere from deep-sea gas-hydrate
      dissociation during the last glacial episode.
AB  - Past atmospheric methane-concentration oscillations recorded in polar ice cores
      vary together with rapid global climatic changes during the last glacial episode.
      In the "clathrate gun hypothesis," massive releases of deep-sea methane from
      marine gas-hydrate dissociation led to these well known, global, abrupt warmings
      in the past. If evidence for such releases in the water column exists, however,
      the mechanism and eventual transfer to the atmosphere has not yet been documented
      clearly. Here we describe a high-resolution marine-sediment record of stable
      carbon isotopic changes from the Papua Gulf, off Papua New Guinea, which exhibits
      two extremely depleted excursions (down to -9 per thousand ) at approximately
      39,000 and approximately 55,000 years. Morphological, isotopic, and trace metal
      evidence dismisses authigenic calcite as the main source of depleted carbon.
      Massive methane release associated with deep-sea gas-hydrate dissociation is the
      most likely cause for such large depletions of delta(13)C. The absence of a
      delta(13)C gradient in the water column during these events implies that the
      methane rose through the entire water column, reaching the sea-air interface and
      thus the atmosphere. Foraminiferal delta(18)O composition suggests that the rise
      of the methane in the water column created an upwelling flow. These inferred
      emission events suggest that during the last glacial episode, this process was
      likely widespread, including tropical regions. Thus, the release of methane from
      the ocean floor into the atmosphere cannot be dismissed as a strong positive
      feedback in climate dynamics processes.

PMID- 15197256
TI  - Nature of structural inhomogeneities on folding a helix and their influence on
      spectral measurements.
AB  - Extensive conformational sampling and calculations of vibrational coupling
      provide a quantitative basis for the structurally inhomogeneous spectra of the
      amide unit in aqueous solutions containing folded and unfolded state
      distributions of helices. Replica exchange molecular dynamics simulations of the
      capped helical peptide, AA(AAKAA)(3)AAY, is carried out over a range of
      temperatures, where the system populates the folded and unfolded states. This
      sampling defines a set of ensembles that characterizes the conformational
      variability for configurations identified by their fraction of helical content.
      The effects of hydrogen bonding, both internal and external (with water), and the
      coupling between amide-I modes are computed as a function of temperature and
      helical content. End-to-end distance and coupling distributions are also
      computed. The solvent H-bonding, which is present at all temperatures, shifts the
      amide-I band toward lower frequency compared with the unsolvated band. Upon
      thermal denaturation of the peptide, the amide-I band shifts to higher frequency
      because the increase in solvent H-bonding fails to compensate for the loss in
      internal (helical) H-bonds. The loss of uniformity of the mode coupling along the
      helix at higher temperatures accounts for the well-known thermal broadening of
      the amide IR spectrum. The calculated inhomogeneities of segments of the peptide
      predict experimental properties of isotope-edited helices.

PMID- 15197257
TI  - A detailed physical map of the horse Y chromosome.
AB  - We herein report a detailed physical map of the horse Y chromosome. The
      euchromatic region of the chromosome comprises approximately 15 megabases (Mb) of
      the total 45- to 50-Mb size and lies in the distal one-third of the long arm,
      where the pseudoautosomal region (PAR) is located terminally. The rest of the
      chromosome is predominantly heterochromatic. Because of the unusual organization
      of the chromosome (common to all mammalian Y chromosomes), a number of approaches
      were used to crossvalidate the results. Analysis of the 5,000-rad horse x hamster
      radiation hybrid panel produced a map spanning 88 centirays with 8 genes and 15
      sequence-tagged site (STS) markers. The map was verified by several fluorescence
      in situ hybridization approaches. Isolation of bacterial artificial chromosome
      (BAC) clones for the radiation hybrid-mapped markers, end sequencing of the BACs,
      STS development, and bidirectional chromosome walking yielded 109 markers (100
      STS and 9 genes) contained in 73 BACs. STS content mapping grouped the BACs into
      seven physically ordered contigs (of which one is predominantly ampliconic) that
      were verified by metaphase-, interphase-, and fiber-fluorescence in situ
      hybridization and also BAC fingerprinting. The map spans almost the entire
      euchromatic region of the chromosome, of which 20-25% (approximately 4 Mb) is
      covered by isolated BACs. The map is presently the most informative among Y
      chromosome maps in domesticated species, third only to the human and mouse maps.
      The foundation laid through the map will be critical in obtaining complete
      sequence of the euchromatic region of the horse Y chromosome, with an aim to
      identify Y specific factors governing male infertility and phenotypic sex
      variation.

PMID- 15197258
TI  - Rabies virus nucleoprotein as a carrier for foreign antigens.
AB  - Rabies virus (RV) nucleoprotein (N) tightly encapsidates the genomic and
      antigenomic RNA of RV to form the viral ribonucleoprotein (RNP) complex.
      Antigens, such as N, presented in a highly organized structure are sufficient and
      even desirable to activate B cells to proliferate and produce antibodies. In
      addition to activating B cells to proliferate, it has been shown that RV N in the
      RNP complex induces potent T helper cell responses resulting in long-lasting and
      strong humoral immune responses against RV. The possibility to systematically
      incorporate foreign genes into the genome of RV and produce a recombinant virus
      allows us to examine whether the immunogenicity of foreign antigens can be
      enhanced by incorporation into the RV RNP structure. To test this hypothesis we
      constructed a recombinant RV expressing a RV N-GFP fusion protein. The chimeric N
      GFP fusion protein was efficiently expressed and incorporated into RV RNP and
      virions. Moreover, the recombinant RNP induces a strong humoral immune response
      against GFP in mice. In contrast, mice inoculated with GFP alone or a combination
      of wild-type RV RNPs and GFP did not trigger any GFP-specific humoral responses
      using the same immunization schedule. These data indicate the usefulness of RV
      based vectors as killed vaccines against other infectious diseases.

PMID- 15197259
TI  - Direct imaging shows that insulin granule exocytosis occurs by complete vesicle
      fusion.
AB  - Confocal imaging of GFP-tagged secretory granules combined with the use of
      impermeant extracellular dyes permits direct observation of insulin packaged in
      secretory granules, trafficking of these granules to the plasma membrane,
      exocytotic fusion of granules with the plasma membrane, and eventually the
      retrieval of membranes by endocytosis. Most such studies have been done in tumor
      cell lines, using either confocal methods or total internal reflectance
      microscopy. Here we compared these methods by using GFP-syncollin or PC3-GFP plus
      rhodamine dextrans to study insulin granule dynamics in insulinoma cells, normal
      mouse islets, and primary pancreatic beta cells. We found that most apparently
      docked granules did not fuse with the plasma membrane after stimulation. Granules
      that did fuse typically fused completely, but a few dextran-filled granules
      lingered at the membrane. Direct recycling of granules occurred only rarely.
      Similar results were obtained with both confocal and total internal reflection
      microscopy, although each technique had advantages for particular aspects of the
      granule life cycle. We conclude that insulin exocytosis involves a prolonged
      interaction of secretory granules with the plasma membrane, and that the majority
      of exocytotic events occur by full, not partial, fusion.

PMID- 15197260
TI  - Protein tolerance to random amino acid change.
AB  - Mutagenesis of protein-encoding sequences occurs ubiquitously; it enables
      evolution, accumulates during aging, and is associated with disease. Many
      biotechnological methods exploit random mutations to evolve novel proteins. To
      quantitate protein tolerance to random change, it is vital to understand the
      probability that a random amino acid replacement will lead to a protein's
      functional inactivation. We define this probability as the "x factor." Here, we
      develop a broadly applicable approach to calculate x factors and demonstrate this
      method using the human DNA repair enzyme 3-methyladenine DNA glycosylase (AAG).
      Three gene-wide mutagenesis libraries were created, each with 10(5) diversity and
      averaging 2.2, 4.6, and 6.2 random amino acid changes per mutant. After
      determining the percentage of functional mutants in each library using high
      stringency selection (>19,000-fold), the x factor was found to be 34% +/- 6%.
      Remarkably, reanalysis of data from studies of diverse proteins reveals similar
      inactivation probabilities. To delineate the nature of tolerated amino acid
      substitutions, we sequenced 244 surviving AAG mutants. The 920 tolerated
      substitutions were characterized by substitutability index and mapped onto the
      AAG primary, secondary, and known tertiary structures. Evolutionarily conserved
      residues show low substitutability indices. In AAG, beta strands are on average
      less substitutable than alpha helices; and surface loops that are not involved in
      DNA binding are the most substitutable. Our results are relevant to such diverse
      topics as applied molecular evolution, the rate of introduction of deleterious
      alleles into genomes in evolutionary history, and organisms' tolerance of
      mutational burden.

PMID- 15197261
TI  - Immunodominant CD4+ responses identified in a patient vaccinated with full-length
      NY-ESO-1 formulated with ISCOMATRIX adjuvant.
AB  - There is increasing evidence showing the involvement of CD4(+) T cells in
      initiating and maintaining antitumor immune responses. NY-ESO-1 is expressed by
      various tumors but not normal tissues except testis. We conducted a cancer
      clinical trial by using full-length NY-ESO-1 protein formulated with ISCOMATRIX
      adjuvant and injected into patients intramuscularly. Autologous dendritic cells
      pulsed with NY-ESO-1 ISCOMATRIX in combination with overlapping synthetic
      peptides were used to identify immunodominant T cells from a vaccinated patient.
      We show here the identification and characterization of two novel CD4(+) T cell
      epitopes. T cells specific to these epitopes not only recognized autologous
      dendritic cells loaded with NY-ESO-1 but also NY-ESO-1-expressing tumor cell
      lines treated with IFN-gamma. One of the two responses identified was greater
      than the previously identified immunodominant HLA-DP4-restricted response and
      correlated with NY-ESO-1-specific CD8(+) T cell induction after vaccination. This
      T cell response was vaccinated in most patients who expressed HLA-DR2. This study
      has systematically surveyed patients vaccinated with full-length tumor antigen
      for a vaccinated CD4 helper T cell response.

PMID- 15197262
TI  - Antitumor activity of a homing peptide that targets tumor lymphatics and tumor
      cells.
AB  - LyP-1 is a peptide selected from a phage-displayed peptide library that
      specifically binds to tumor and endothelial cells of tumor lymphatics in certain
      tumors. Fluorescein-conjugated LyP-1 and a related peptide, LyP-1b, strongly
      accumulated in primary MDA-MB-435 breast cancer xenografts and their metastases
      from i.v. peptide injections, allowing visualization of orthotopic tumors in
      intact mice. The LyP peptide accumulation coincided with hypoxic areas in tumors.
      LyP-1 induced cell death in cultured human breast carcinoma cells that bind and
      internalize the peptide. Melanoma cells that do not bind LyP-1 were unaffected.
      Systemic LyP-1 peptide treatment of mice with xenografted tumors induced with the
      breast cancer cells inhibited tumor growth. The treated tumors contained foci of
      apoptotic cells and were essentially devoid of lymphatics. These results reveal
      an unexpected antitumor effect by the LyP-1 peptide that seems to be dependent on
      a proapoptotic/cytotoxic activity of the peptide. As LyP-1 affects the poorly
      vascularized tumor compartment, it may complement treatments directed at tumor
      blood vessels.

PMID- 15197263
TI  - Control of cell size through phosphorylation of upstream binding factor 1 by
      nuclear phosphatidylinositol 3-kinase.
AB  - The insulin-like growth factor I/insulin receptor substrate 1 axis controls, in a
      nonredundant way, approximately 50% of cell and body size in animals from
      Drosophila to mice and in cells in culture. Although other factors may also
      intervene, cell size is strongly dependent on ribosome biogenesis, which is under
      the control of RNA polymerase I activity. We have previously shown that insulin
      receptor substrate 1 (IRS-1) translocates to the nuclei and nucleoli, where it
      binds to the upstream binding factor (UBF) 1, a regulator of RNA polymerase I
      activity. Activation of UBF1 requires its phosphorylation. However, IRS-1 is not
      a kinase, and we searched for an intermediate kinase that can phosphorylate UBF1.
      We demonstrate here that IRS-1 binds also to the phosphatidylinositol 3-kinase
      (PI3-K) subunits in nuclear extracts, and that the p110 subunit of PI3-K directly
      phosphorylates and activates UBF1, an exclusively nucleolar protein. The
      interaction of IRS-1, PI3-K, and UBF1 in the nucleoli provides one of the
      mechanisms for the effects of IRS-1 on cell and body size.

PMID- 15197264
TI  - Activation of a paramyxovirus fusion protein is modulated by inside-out signaling
      from the cytoplasmic tail.
AB  - Many viruses have evolved fusion-mediating glycoproteins that couple the energy
      released from irreversible protein refolding to the work of membrane fusion. The
      viral fusion proteins require a triggering event to undergo a cascade of tightly
      regulated conformational changes. Different isolates of the paramyxovirus SV5
      fusion (F) protein have either a short (20-residue) or long (42-residue)
      cytoplasmic tail (CT), and a long CT suppresses fusion activity in a sequence
      specific manner. Addition of a domain to the F protein CT, which has the
      propensity to form a three-helix bundle, stabilizes the F protein and increases
      the energy required for fusion activation. Quantitative cell-cell fusion assays
      and measurement of ectodomain conformation by monoclonal antibody reactivity
      indicate that this suppression of fusion by the long CT or addition of a three
      helix bundle occurs at a step preceding initial membrane merger. The data suggest
      that F protein activation involves CT signaling to the ectodomain.

PMID- 15197265
TI  - Dissecting the maize genome by using chromosome addition and radiation hybrid
      lines.
AB  - We have developed from crosses of oat (Avena sativa L.) and maize (Zea mays L.)
      50 fertile lines that are disomic additions of individual maize chromosomes 1-9
      and chromosome 10 as a short-arm telosome. The whole chromosome 10 addition is
      available only in haploid oat background. Most of the maize chromosome disomic
      addition lines have regular transmission; however, chromosome 5 showed diminished
      paternal transmission, and chromosome 10 is transmitted to offspring only as a
      short-arm telosome. To further dissect the maize genome, we irradiated monosomic
      additions with gamma rays and recovered radiation hybrid (RH) lines providing low
      to medium-resolution mapping for most of the maize chromosomes. For maize
      chromosome 1, mapping 45 simple-sequence repeat markers delineated 10 groups of
      RH plants reflecting different chromosome breaks. The present chromosome 1 RH
      panel dissects this chromosome into eight physical segments defined by the 10
      groups of RH lines. Genomic in situ hybridization revealed the physical size of a
      distal region, which is represented by six of the eight physical segments, as
      being approximately 20% of the length of the short arm, representing
      approximately one-third of the genetic chromosome 1 map. The distal approximately
      20% of the physical length of the long arm of maize chromosome 1 is represented
      by a single group of RH lines that spans >23% of the total genetic map. These oat
      maize RH lines provide valuable tools for physical mapping of the complex highly
      duplicated maize genome and for unique studies of inter-specific gene
      interactions.

PMID- 15197266
TI  - A plant plasma membrane Ca2+ pump is required for normal pollen tube growth and
      fertilization.
AB  - Ca(2+) signals are thought to play important roles in plant growth and
      development, including key aspects of pollen tube growth and fertilization. The
      dynamics of a Ca(2+) signal are largely controlled by influx (through channels)
      and efflux (through pumps and antiporters). The Arabidopsis genome encodes 14
      Ca(2+) pumps, 10 of which belong to a family of autoinhibited Ca(2+) ATPases
      (ACA) that are predicted to be activated by Ca(2+)/calmodulin. Here, we show that
      isoform ACA9 is expressed primarily in pollen and localized to the plasma
      membrane. Three independent T-DNA [portion of the Ti (tumor-inducing) plasmid
      that is transferred to plant cells] gene disruptions of ACA9 were found to result
      in partial male sterility. Complementation was observed by using a ACA9-yellow
      fluorescence protein (YFP) fusion that displayed plasma membrane localization.
      Mutant aca9 pollen displayed a reduced growth potential and a high frequency of
      aborted fertilization, resulting in a >80% reduction in seed set. These findings
      identify a plasma membrane Ca(2+) transporter as a key regulator of pollen
      development and fertilization in flowering plants.

PMID- 15197267
TI  - Spatial synchrony of local populations has increased in association with the
      recent Northern Hemisphere climate trend.
AB  - According to ecological theory, populations whose dynamics are entrained by
      environmental correlation face increased extinction risk as environmental
      conditions become more synchronized spatially. This prediction is highly relevant
      to the study of ecological consequences of climate change. Recent empirical
      studies have indicated, for example, that large-scale climate synchronizes
      trophic interactions and population dynamics over broad spatial scales in
      freshwater and terrestrial systems. Here, we present an analysis of century
      scale, spatially replicated data on local weather and the population dynamics of
      caribou in Greenland. Our results indicate that spatial autocorrelation in local
      weather has increased with large-scale climatic warming. This increase in spatial
      synchrony of environmental conditions has been matched, in turn, by an increase
      in the spatial synchrony of local caribou populations toward the end of the 20th
      century. Our results indicate that spatial synchrony in environmental conditions
      and the populations influenced by them are highly variable through time and can
      increase with climatic warming. We suggest that if future warming can increase
      population synchrony, it may also increase extinction risk.

PMID- 15197268
TI  - Modulation of the polyamine biosynthetic pathway in transgenic rice confers
      tolerance to drought stress.
AB  - We have generated transgenic rice plants expressing the Datura stramonium adc
      gene and investigated their response to drought stress. We monitored the steady
      state mRNA levels of genes involved in polyamine biosynthesis (Datura adc, rice
      adc, and rice samdc) and polyamine levels. Wild-type plants responded to the
      onset of drought stress by increasing endogenous putrescine levels, but this was
      insufficient to trigger the conversion of putrescine into spermidine and spermine
      (the agents that are believed to protect plants under stress). In contrast,
      transgenic plants expressing Datura adc produced much higher levels of putrescine
      under stress, promoting spermidine and spermine synthesis and ultimately
      protecting the plants from drought. We demonstrate clearly that the manipulation
      of polyamine biosynthesis in plants can produce drought-tolerant germplasm, and
      we propose a model consistent with the role of polyamines in the protection of
      plants against abiotic stress.

PMID- 15197270
TI  - A simulation method for calculating the absolute entropy and free energy of
      fluids: application to liquid argon and water.
AB  - The hypothetical scanning (HS) method is a general approach for calculating the
      absolute entropy and free energy by analyzing Boltzmann samples obtained by Monte
      Carlo (MC) or molecular dynamics techniques. With HS applied to a fluid, each
      configuration i of the sample is reconstructed by adding its atoms gradually to
      the initially empty volume, i.e., by placing them in their positions at i using
      transition probabilities (TPs). At each step of the process, the volume is
      divided into two parts, the already visited part (the "past") and the "future"
      part, where obtaining the TP requires calculating partition functions over the
      future part in the presence of the frozen past. In recent publications, the TPs
      were calculated approximately by taking into account only partial future. Here we
      present a "complete HSMC" procedure, where the TPs are calculated from MC
      simulations carried out over the complete future. The complete HSMC method is
      applied to systems of liquid argon and the TIP3P model of water, and very good
      results for the free energy are obtained, as compared with results obtained by
      thermodynamic integration.

PMID- 15197271
TI  - Simulation method for calculating the entropy and free energy of peptides and
      proteins.
AB  - A method called complete hypothetical scanning Monte Carlo has been introduced
      for calculating the absolute entropy, S, and free energy, F, of fluids. Here, the
      method is extended to peptide chains in vacuum. Thus, S is calculated from a
      given sample by reconstructing each conformation step-by-step by using transition
      probabilities (TPs); at each step, part of the chain coordinates have already
      been determined (the "frozen past"), and the TP is obtained from a Monte Carlo
      simulation of the (future) part of the chain whose TPs as yet have not been
      calculated. Very accurate results for S and F are obtained for the helix,
      extended, and hairpin microstates of a simplified model of decaglycine (Gly)(10)
      and (Gly)(16). These results agree well with results obtained by the
      quasiharmonic approximation and the local states method. The complete HSMC method
      can be applied to a macromolecule with any degree of flexibility, ranging from
      local fluctuations to a random coil. Also, the difference in stability, Delta
      F(mn) = F(m) - F(n) between significantly different microstates m and n can be
      obtained from two simulations only without the need to resort to thermodynamic
      integration. Our long-term goal is to extend this method to any peptide and apply
      it to a peptide immersed in a box with explicit water.

PMID- 15197269
TI  - Multimerization and interaction of Toll and Spatzle in Drosophila.
AB  - The Toll family of receptors is required for innate immune response to pathogen
      associated molecules, but the mechanism of signaling is not entirely clear. In
      Drosophila the prototypic Toll regulates both embryonic development and adult
      immune response. We demonstrate here that the host protein Spatzle can function
      as a ligand for Toll because Spatzle forms a complex with Toll in transgenic fly
      extracts and stimulates the expression of a Toll-dependent immunity gene,
      drosomycin, in adult flies. We also show that constitutively active mutants of
      Toll form multimers that contain intermolecular disulfide linkages. These
      disulfide linkages are critical for the activity of one of these mutant
      receptors, indicating that multimerization is essential for the constitutive
      activity. Furthermore, systematic mutational analysis revealed that a conserved
      cysteine-containing motif, different from the cysteines used for the
      intermolecular disulfide linkages, serves as a self-inhibitory module of Toll.
      Deleting or mutating this cysteine-containing motif leads to constitutive
      activity. This motif is located just outside the transmembrane domain and may
      provide a structural hindrance for multimerization and activation of Toll.
      Together, our results suggest that multimerization may be a regulated, essential
      step for Toll-receptor activation.

PMID- 15197272
TI  - Ezrin regulates NHE3 translocation and activation after Na+-glucose cotransport.
AB  - Initiation of Na(+)-glucose cotransport in intestinal epithelial cells leads to
      activation of the apical Na(+)-H(+) exchanger NHE3 and subsequent increases in
      cytoplasmic pH (pH(i)). This process requires activation of p38 mitogen-activated
      protein (MAP) kinase, but additional signaling intermediates have not been
      identified. One candidate is the cytoskeletal linker protein ezrin, which
      interacts with NHE3 via specific regulatory proteins. The data show that
      initiation of Na(+)-glucose cotransport resulted in rapid increases in both
      apical membrane-associated NHE3 and cytoskeletal-associated ezrin and occurred in
      parallel with ezrin phosphorylation at threonine 567. Phosphorylation at this
      site is known to activate ezrin and increase its association with actin.
      Consistent with a central role for ezrin activation in this NHE3 regulation, an N
      terminal dominant negative ezrin construct inhibited both NHE3 recruitment and
      pH(i) increases after Na(+)-glucose cotransport. Ezrin phosphorylation occurred
      in parallel with p38 MAP kinase activation, and the latter proceeded normally in
      cells expressing dominant negative ezrin. In contrast, inhibition of p38 MAP
      kinase prevented increases in ezrin phosphorylation after initiation of Na(+)
      glucose cotransport. Thus, ezrin phosphorylation after Na(+)-glucose cotransport
      requires p38 MAP kinase activity, but p38 MAP kinase activation does not require
      ezrin function. These data describe a specific role for ezrin in the coordinate
      regulation of Na(+)-glucose cotransport and Na(+)-H(+) exchange. Intact ezrin
      function is necessary for NHE3 recruitment to the apical membrane and NHE3
      dependent pH(i) increases triggered by Na(+)-glucose cotransport. The data also
      define a pathway of p38 MAP kinase-dependent ezrin activation.

PMID- 15197273
TI  - Pattern formation by vascular mesenchymal cells.
AB  - In embryogenesis, immature mesenchymal cells aggregate and organize into
      patterned tissues. Later in life, a pathological recapitulation of this process
      takes place in atherosclerotic lesions, when vascular mesenchymal cells organize
      into trabecular bone tissue within the artery wall. Here we show that
      multipotential adult vascular mesenchymal cells self-organize in vitro into
      patterns that are predicted by a mathematical model based on molecular morphogens
      interacting in a reaction-diffusion process. We identify activator and inhibitor
      morphogens for stripe, spot, and labyrinthine patterns and confirm the model
      predictions in vitro. Thus, reaction-diffusion principles may play a significant
      role in morphogenetic processes in adult mesenchymal cells.

PMID- 15197274
TI  - Essential auditory contrast-sharpening is preneuronal.
AB  - Contrast-sharpening is a fundamental feature of mammalian sensory perception.
      Whereas visual contrast-sharpening has been fully understood in terms of the
      retinal neuronal wiring [DeVries, S. H. & Baylor, D. A. (1993) Cell 72, Suppl.,
      139-149], a corresponding explanation of auditory contrast-sharpening is still
      lacking. Here, we show that the essentials of auditory contrast-sharpening can be
      explained by using cochlear biophysics. This finding indicates that the
      phenomenon is basically of preneuronal origin.

PMID- 15197275
TI  - Anchored periplasmic expression, a versatile technology for the isolation of high
      affinity antibodies from Escherichia coli-expressed libraries.
AB  - Anchored periplasmic expression (APEx) is a technology for the isolation of
      ligand-binding proteins from combinatorial libraries anchored on the periplasmic
      face of the inner membrane of Escherichia coli. After disruption of the outer
      membrane by Tris-EDTA-lysozyme, the inner-membrane-anchored proteins readily bind
      fluorescently labeled ligands as large as 240 kDa. Fluorescently labeled cells
      are isolated by flow cytometry, and the DNA of isolated clones is rescued by PCR.
      By using two rounds of APEx, the affinity of a neutralizing antibody to the
      Bacillus anthracis protective antigen was improved >200-fold, exhibiting a final
      K(D) of 21 pM. This approach has several technical advantages compared with
      previous library screening technologies, including the unique ability to screen
      for ligand-binding proteins that bind endogenously expressed ligands fused to a
      short-lived GFP. Further, APEx is able to display proteins either as an N
      terminal fusion to a six-residue sequence derived from the native E. coli
      lipoprotein NlpA, or as a C-terminal fusion to the phage gene three minor coat
      protein of M13. The latter fusions allow hybrid phage display/APEx strategies
      without the need for further subcloning.

PMID- 15197276
TI  - Therapeutic immunization protects dopaminergic neurons in a mouse model of
      Parkinson's disease.
AB  - Degeneration of the nigrostriatal dopaminergic pathway, the hallmark of
      Parkinson's disease, can be recapitulated in 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP)-intoxicated mice. Herein, we demonstrate that adoptive
      transfer of copolymer-1 immune cells to MPTP recipient mice leads to T cell
      accumulation within the substantia nigra pars compacta, suppression of microglial
      activation, and increased local expression of astrocyte-associated glial cell
      line-derived neurotrophic factor. This immunization strategy resulted in
      significant protection of nigrostriatal neurons against MPTP-induced
      neurodegeneration that was abrogated by depletion of donor T cells. Such vaccine
      treatment strategies may provide benefit for Parkinson's disease.

PMID- 15197277
TI  - IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory.
AB  - Heightened protection from infectious disease as conferred by vaccination or
      pathogen exposure relies on the effective generation and preservation of specific
      immunological memory. T cells are irreducibly required for the control of most
      viral infections, and maintenance of CD8(+)T cell memory is regulated by at least
      two cytokines, IL-7 and IL-15, which support survival (IL-7, IL-15) and basal
      homeostatic proliferation (IL-15) of specific CD8(+) memory T cells (T(M)). In
      contrast, the factors governing the homeostasis of pathogen-specific CD4(+)T(M)
      remain at present unknown. Here, we used a physiologic in vivo model system for
      viral infection to delineate homeostatic features and mechanisms of antiviral
      CD4(+)T(M) preservation in direct juxtaposition to CD8(+)T cell memory. Basal
      homeostatic proliferation is comparable between specific CD4(+) and CD8(+)T(M)
      and independent of immunodominant determinants and functional avidities but
      regulated in a tissue-specific fashion. IL-7, identified as the dominant
      cytokine, and IL-15, an accessory cytokine, regulate basal homeostatic
      proliferation and survival of antiviral CD4(+)T(M). Interestingly, a role for
      these cytokines in regulation of CD4(+)T cell memory is not readily discernible
      in the generic "memory-phenotype" population, apparently a consequence of its
      heterogeneous composition. We also describe a prominent, nonredundant role for IL
      7 in supporting basal homeostatic proliferation of CD8(+)T(M). We propose that
      homeostatic control of antiviral CD4(+) and CD8(+) T cell memory is fundamentally
      similar and characterized by quantitative, rather than qualitative, differences.

PMID- 15197278
TI  - Specific binding to intracellular proteins determines arterial transport
      properties for rapamycin and paclitaxel.
AB  - Endovascular drug-eluting stents have changed the practice of medicine, and yet
      it is unclear how they so dramatically reduce restenosis and how to distinguish
      between the different formulations available. Biological drug potency is not the
      sole determinant of biological effect. Physicochemical drug properties also play
      important roles. Historically, two classes of therapeutic compounds emerged:
      hydrophobic drugs, which are retained within tissue and have dramatic effects,
      and hydrophilic drugs, which are rapidly cleared and ineffective. Researchers are
      now questioning whether individual properties of different drugs beyond lipid
      avidity can further distinguish arterial transport and distribution. In bovine
      internal carotid segments, tissue-loading profiles for hydrophobic paclitaxel and
      rapamycin are indistinguishable, reaching load steady state after 2 days.
      Hydrophilic dextran reaches equilibrium in several hours at levels no higher than
      surrounding solution concentrations. Both paclitaxel and rapamycin bind to the
      artery at 30-40 times bulk concentration. Competitive binding assays confirm
      binding to specific tissue elements. Most importantly, transmural drug
      distribution profiles are markedly different for the two compounds, reflecting,
      perhaps, different modes of binding. Rapamycin, which binds specifically to
      FKBP12 binding protein, distributes evenly through the artery, whereas
      paclitaxel, which binds specifically to microtubules, remains primarily in the
      subintimal space. The data demonstrate that binding of rapamycin and paclitaxel
      to specific intracellular proteins plays an essential role in determining
      arterial transport and distribution and in distinguishing one compound from
      another. These results offer further insight into the mechanism of local drug
      delivery and the specific use of existing drug-eluting stent formulations.

PMID- 15197279
TI  - Identification of the amino acid sequence in Sindbis virus nsP4 that binds to the
      promoter for the synthesis of the subgenomic RNA.
AB  - A gel mobility-shift assay was used to demonstrate the binding of the Sindbis
      virus transcriptase to the promoter for the synthesis of subgenomic (SG) RNA. The
      assay made use of a P15 fraction (the cell fraction that is pelleted at 15,000 x
      g) from cells infected with recombinant vaccinia virions expressing various
      Sindbis virus nonstructural proteins (nsPs) and a (32)P-labeled 24-mer
      oligoribonucleotide representing the minimal sequence with SG promoter activity.
      By itself, nsP4, the viral RNA-dependent RNA polymerase, did not bind to the SG
      promoter; rather, all four nsPs were required for the binding of the
      transcriptase to the promoter. UV crosslinking of the transcriptase to a
      thiouridine-containing SG promoter, followed by V8 protease digestion of the
      complex, generated a peptide fragment that was bound to the SG promoter. This
      peptide fragment contained a sequence that corresponded to residues 329-334 of
      nsP4. This peptide may be in the fingers domain of nsP4. The peptide that was
      identified contained Arg residues at positions 331 and 332. Another Arg is
      present at position 327. By changing each of the Arg residues to Ala, we
      demonstrated that only the Arg residues at positions 331 and 332 were required
      for binding nsP4 to the SG promoter.

PMID- 15197280
TI  - Activation of cAMP-response-element-binding protein (CREB) after focal cerebral
      ischemia stimulates neurogenesis in the adult dentate gyrus.
AB  - New neurons are generated in adult mammalians and may contribute to repairing the
      brain after injury. Here, we show that the number of new neurons in the dentate
      gyrus of adult rats increased in cerebral ischemic stroke and correlated with
      activation of the cAMP-response-element-binding protein (CREB). Inhibition of
      endogenous CREB by expression of a dominant-negative mutant of CREB (CREB-S133A
      or CREB-R287L) blocked ischemia-induced neurogenesis in the dentate gyrus of
      adult rats, whereas expression of constitutively active CREB, VP16-CREB,
      increased the number of new neurons. Thus, our findings provide roles and
      regulatory mechanisms for CREB in adult neurogenesis and possibly suggest a
      practical strategy for replacing dead neurons in brain injury.

PMID- 15197281
TI  - Electrostatically optimized Ras-binding Ral guanine dissociation stimulator
      mutants increase the rate of association by stabilizing the encounter complex.
AB  - Association of two proteins can be described as a two-step process, with the
      formation of an encounter complex followed by desolvation and establishment of a
      tight complex. Here, by using the computer algorithm PARE, we designed a set of
      mutants of the Ras effector protein Ral guanine nucleotide dissociation
      stimulator (RalGDS) with optimized electrostatic steering. The fastest binding
      RalGDS mutant, M26K,D47K,E54K, binds Ras 14-fold faster and 25-fold tighter
      compared with WT. A linear correlation was found between the calculated and
      experimental data, with a correlation coefficient of 0.97 and a slope of 0.65 for
      the 24 mutants produced. The data suggest that increased electrostatic steering
      specifically stabilizes the encounter complex and transition state. This
      conclusion is backed up by Phi analysis of the encounter complex and transition
      state of the RalGDS(M26K,D47K,E54K)/Ras complex, with both values being close to
      1. Upon further formation of the final complex, the increased Coulombic
      interactions are probably counterbalanced by the cost of desolvation of charges,
      keeping the dissociation rate constant almost unchanged. This mechanism is also
      reflected by the mutual compensation of enthalpy and entropy changes quantified
      by isothermal titration calorimetry. The binding constants of the faster binding
      RalGDS mutants toward Ras are similar to those of Raf, the most prominent Ras
      effector, suggesting that the design methodology may be used to switch between
      signal transduction pathways.

PMID- 15197282
TI  - Sex pheromone of the pink hibiscus mealybug, Maconellicoccus hirsutus, contains
      an unusual cyclobutanoid monoterpene.
AB  - Two compounds that together constitute the female sex pheromone of the pink
      hibiscus mealybug (PHM), Maconellicoccus hirsutus, were isolated, identified, and
      synthesized. They are (R)-2-isopropenyl-5-methyl-4-hexenyl (S)-2-methylbutanoate
      [common name is (R)-lavandulyl (S)-2-methylbutanoate] and [(R)-2,2-dimethyl-3-(1
      methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [which we refer to as
      (R)-maconelliyl (S)-2-methylbutanoate]. Maconelliol is an unusual cyclobutanoid
      monoterpene, and its structure has been established by enantioselective synthesis
      from precursors of known structure and configuration. A 1:5 synthetic mixture of
      the two RS esters (1 microg per rubber septum) proved to be a potent attractant
      of males in field bioassays. The pheromone component, maconelliyl 2
      methylbutanoate, represents a heretofore undescribed natural product.

PMID- 15197283
TI  - Catalytic activation of multimeric RNase E and RNase G by 5'-monophosphorylated
      RNA.
AB  - RNase E is an endonuclease that plays a central role in RNA processing and
      degradation in Escherichia coli. Like its E. coli homolog RNase G, RNase E shows
      a marked preference for cleaving RNAs that bear a monophosphate, rather than a
      triphosphate or hydroxyl, at the 5' end. To investigate the mechanism by which 5'
      terminal phosphorylation can influence distant cleavage events, we have developed
      fluorogenic RNA substrates that allow the activity of RNase E and RNase G to be
      quantified much more accurately and easily than before. Kinetic analysis of the
      cleavage of these substrates by RNase E and RNase G has revealed that 5'
      monophosphorylation accelerates the reaction not by improving substrate binding,
      but rather by enhancing the catalytic potency of these ribonucleases.
      Furthermore, the presence of a 5' monophosphate can increase the specificity of
      cleavage site selection within an RNA. Although monomeric forms of RNase E and
      RNase G can cut RNA, the ability of these enzymes to discriminate between RNA
      substrates on the basis of their 5' phosphorylation state requires the formation
      of protein multimers. Among the molecular mechanisms that could account for these
      properties are those in which 5'-end binding by one enzyme subunit induces a
      protein structural change that accelerates RNA cleavage by another subunit.

PMID- 15197284
TI  - Anti-aging medicine: can consumers be better protected?
AB  - The use of interventions claiming to prevent, retard, or reverse aging is
      proliferating. Some of these interventions can seriously harm older persons and
      aging baby boomers who consume them. Others that are merely ineffective may
      divert patients from participating in beneficial regimens and also cause them
      economic harm. "Free market regulation" does not seem to weed out risky,
      ineffective, and fraudulent anti-aging treatments and products. Public health
      messages, apparently, are having little effect. What more can be done to achieve
      better protection for older consumers? An analysis of the potential for federal
      and state action reveals many barriers to effective governmental regulation of
      anti-aging interventions. In view of dim prospects for stronger public
      regulation, physicians and other professionals--especially geriatricians and
      gerontologists--will need to be more aggressive in protecting older consumers. In
      particular, The Gerontological Society of America and the American Geriatrics
      Society should undertake a sustained program of specific educational efforts,
      directed at health professionals and the general public, in which they sort out
      as best they can the helpful, the harmful, the fraudulent, and the harmless anti
      aging practices and products.

PMID- 15197285
TI  - Neuroticism and longitudinal change in caregiver depression: impact of a spouse
      caregiver intervention program.
AB  - PURPOSE: We examined the impact of caregiver neuroticism on longitudinal change
      in depression among spouse-caregivers of individuals with Alzheimer's disease
      receiving either enhanced psychosocial treatment or usual care. We were
      interested in whether high levels of caregiver neuroticism would lead to a
      diminished response to the enhanced treatment and whether neuroticism affected
      the longitudinal course of caregiver depression regardless of intervention.
      DESIGN AND METHODS: We analyzed data from the NYU Spouse-Caregiver Intervention
      Study, which randomly assigned caregivers either to an enhanced treatment group
      that received a comprehensive intervention with counseling, support, and
      consultation, or to a usual-care control group. The present study analyzed data
      from 320 caregivers, 160 in each group, who completed the NEO questionnaire. We
      used random-effects growth curve modeling to examine changes in depression in the
      first year after intake, examining possible effects of neuroticism on the course
      of caregiver depression and on response to intervention. RESULTS: Caregivers high
      in neuroticism showed a worse longitudinal course of depression compared with
      those low in neuroticism in both the enhanced treatment and usual-care groups
      after we adjusted for baseline depression as a covariate. Caregivers showed
      benefits from the enhanced treatment compared with usual care, regardless of
      neuroticism score. However, caregivers low in neuroticism responded to treatment
      with declining levels of depression, whereas caregivers high in neuroticism
      maintained their baseline level of depression. IMPLICATIONS: Caregiver
      neuroticism is a risk factor for increased caregiver depression over time. High
      neuroticism does not preclude successful caregiver intervention with a highly
      individualized intervention like ours, but expectations of outcome should be
      different than for caregivers low in neuroticism. Future studies should
      investigate the relationship between neuroticism and response to less
      individualized interventions and the impact of other personality characteristics
      on response to treatment.

PMID- 15197287
TI  - Age, marital processes, and depressed affect.
AB  - PURPOSE: We examined age-cohort differences in the interrelationships among
      marital processes and depressed affect. DESIGN AND METHODS: We used data from
      individuals in first marriages that participated in the National Survey of
      Families and Households (NSFH). The NSFH interviewed one adult per household of a
      nationally representative sample. Participants were categorized into young (n =
      2,289), middle-aged (n = 1,145), and older adult (n = 691) age cohorts. RESULTS:
      The three age cohorts did not differ on negative marital processes (NMP), but
      older adults scored significantly higher on marital satisfaction than young and
      middle-aged adults. Marital satisfaction mediated the link between NMP and
      depressed affect for young adults and older adults. NMP were more strongly
      related to depressed affect for young adults than middle-aged adults, whereas
      marital satisfaction was more strongly related to depressed affect for older
      adults than young adults. IMPLICATIONS: Our findings on age-cohort differences in
      the salience of marital processes to depressed affect are discussed in light of
      socioemotional selectivity theory.

PMID- 15197286
TI  - The relationship between care-recipient behaviors and spousal caregiving stress.
AB  - PURPOSE: This study examines gender differences in spousal caregiver stress
      associated with care-recipient problem behaviors and helping behaviors. DESIGN
      AND METHODS: Using data from the National Long-Term Care Survey, we examined
      bivariate and multivariate relationships between the behaviors of care recipients
      and the stress experienced by their spouses. RESULTS: Gender differences in
      caregiver stress emerged with respect to problem behaviors and helping behaviors
      of the care recipient. Helping behaviors had a moderating effect on the
      relationship between care-recipient problem behaviors and stress for caregiving
      husbands, but not for caregiving wives. IMPLICATIONS: As practitioners attempt to
      reduce spousal caregiving distress, they should assess the extent to which care
      recipient's problem behaviors and efforts to be helpful contribute to caregiver
      stress.

PMID- 15197288
TI  - Factors predicting lawsuits against nursing homes in Florida 1997-2001.
AB  - PURPOSE: We explore how nursing home characteristics affect the number of
      lawsuits filed against the facilities in Florida during the period from 1997 to
      2001. DESIGN AND METHODS: We examined data from 478 nursing homes in 30 Florida
      counties from 1997 to 2001. We obtained the data from Westlaw's Adverse Filings:
      Lawsuits database, the Online Survey, Certification, and Reporting system
      database from the Centers for Medicare and Medicaid Services, and state complaint
      surveys, and we also used primary data. We used negative binomial regression to
      explain total lawsuit variance by year. We controlled for acuity and year
      effects, and our explanatory variables included (a) facility characteristics-
      including staffing, number of beds, multistate system membership, and for-profit
      ownership--and (b) quality measures--including total number and type of state
      licensing survey deficiencies, pressure-sore development, and medication errors
      per resident. RESULTS: Higher registered nurse and certified nursing assistant
      staffing levels were associated with fewer lawsuits. More deficiencies on the
      licensing survey and larger and for-profit nursing homes were positively related
      with higher numbers of lawsuits. IMPLICATIONS: This study suggests that nursing
      homes that meet long-stay staffing standards, meet minimum quality measures, are
      not for profit, and are smaller will experience fewer lawsuits.

PMID- 15197289
TI  - Older adults' satisfaction with integrated capitated health and long-term care.
AB  - PURPOSE: The objective of this study is to develop an instrument to evaluate
      satisfaction with care for older adults in capitated environments. Although
      satisfaction with care is now widely accepted as an important outcome measure,
      there are relatively few satisfaction measures developed or validated on older
      persons. Because many older persons are unable to respond to surveys, separate
      instruments were developed for individuals and for their families. DESIGN AND
      METHODS: There were 402 face-to-face interviews conducted at 11 PACE sites with
      PACE participants or their family members and a non-PACE group. Scales were
      constructed by use of factor analysis and were evaluated for internal-consistency
      reliability, validity, and ability to discriminate. RESULTS: For the participant
      survey, three factors were identified, but only two exhibited adequate internal
      consistency (Perceived Access and Perceived Interpersonal Quality). For the
      family survey, all four identified factors had adequate internal consistency
      (Perceived Access, Family Pressure, Ease of Access, and Family Involvement). The
      participant survey discriminated between the PACE sites and the non-PACE sites,
      but the family-member survey did not. IMPLICATIONS: The PACE Satisfaction Survey
      appears to have adequate reliability and validity for measuring the satisfaction
      of older persons and their family members with capitated care. The domains of
      satisfaction differ between individuals and family members.

PMID- 15197290
TI  - Response formats and satisfaction surveys for elders.
AB  - PURPOSE: A factor common to the results of many satisfaction surveys of elders is
      a lack of response variability. Increasing response variability may be useful if
      satisfaction surveys of elders are to be productively used in the future. In this
      paper, we first examine elders' preferences between five response formats and
      then examine the response variability of these five commonly used formats. DESIGN
      AND METHODS: Satisfaction, demographic, and Short-Form 36 Health Survey data were
      self-reported by patients in four outpatient surgery centers during 1998 and
      1999. We used six different survey instruments randomly given to 3,122 elders.
      Five instruments varied in response format (5-item Likert format, 5-item
      satisfaction format, 5-item valuation format, 4-item Chernoff faces, and 10-item
      visual analogue format). The sixth survey used all five different response sets,
      and then it asked for the respondents' preferences among the different response
      sets. RESULTS: A total of 2,450 questionnaires were examined (response rate of
      78.5%). The response format using four Chernoff faces was liked the least, with
      only 5% of the respondents preferring this format. The 10-item visual analogue
      format (10VAF) was liked the most, with 39% of the respondents preferring this
      format. In addition, 10% more elders thought this format was easier to use than
      the second-place choice (i.e., 32% vs. 22%). The coefficient of variation for the
      10VAF was also higher than those in identical domains using the other response
      formats. This would seem to indicate that the 10VAF is less prone to a ceiling
      effect than the other response formats. IMPLICATIONS: Our results show that
      elders have a preference for some response formats, and from the choices we gave
      them a 10VAF was preferred. The 10VAF also had more response variability then the
      other formats we tested.

PMID- 15197291
TI  - Quality of care in the nursing home: effects of staff assignment and work shift.
AB  - PURPOSE: The purpose of this study was to compare a variety of resident and staff
      outcomes across two types of staffing patterns, permanent and rotating
      assignment, and work shift. Although studies have examined these staffing
      patterns as part of multicomponent intervention packages, few studies have
      examined the isolated effects of staffing pattern by using an experimental
      design. DESIGN AND METHODS: A between-groups comparison design was used to
      compare residents and certified nursing assistants (CNAs) from four nursing
      homes; two self-identified as using permanent assignment (PA) staffing and two as
      using rotating assignment (RA) staffing. Measures yielded data on verbal
      interaction among residents and staff, resident disruptive behavior, and specific
      aspects of resident-staff behavior during care routines. Other assessments
      included resident personal appearance and hygiene, expressed affect, and CNAs'
      job satisfaction, burnout, absenteeism, and turnover rates. A treatment fidelity
      check was conducted to confirm PA and RA staffing patterns. RESULTS: Staffing
      patterns were significantly different between self-identified PA and RA nursing
      homes. Residents in PA nursing homes and on morning shifts received significantly
      higher ratings of personal appearance and hygiene. Rates of expressed sadness and
      interest among residents differed by staffing patterns and shift. However, these
      differences do not appear to be clinically significant. Although absenteeism was
      higher in PA nursing homes, these CNAs reported greater job satisfaction than
      CNAs from RA nursing homes. As expected, evening shifts across nursing homes had
      significantly higher turnover rates and significantly more resident disruptive
      behavior. IMPLICATIONS: Quality-of-care outcomes were similar among the two types
      of nursing homes, despite significantly different staffing patterns. Though staff
      permanency rates in PA nursing homes (50%) were twice that of RA nursing homes
      (26%), more research is needed to determine feasibility of higher rates of staff
      permanency (i.e., > 50%) and effects on resident and CNA outcomes.

PMID- 15197292
TI  - Complexity science and the dynamics of climate and communication: reducing
      nursing home turnover.
AB  - PURPOSE: Turnover in nursing homes is a widespread problem adversely affecting
      care quality. Using complexity theory, we tested the effect of administrative
      climate, communication patterns, and the interaction between the two on turnover,
      controlling for facility context. DESIGN AND METHODS: Perceptions of
      administrative climate and communication were collected from 3,449 employees in
      164 randomly sampled nursing homes, and they were linked to secondary data on
      facility characteristics, resource allocation, and turnover. We used hierarchical
      regression to test the hypotheses. RESULTS: Climate and communication both
      affected turnover, but lower turnover was dependent on the interaction between
      climate and communication. In nursing homes with reward-based administrative
      climates, higher levels of communication openness and accuracy explained lower
      turnover of licensed vocational nurses and certified nurse assistants, relative
      to nursing homes with an ambiguous climate. Adequate staffing and longer tenure
      of the nursing director were also important predictors of turnover. IMPLICATIONS:
      Although context is important, managers can also influence turnover by addressing
      climate and communication patterns and by encouraging stable nursing leadership.

PMID- 15197293
TI  - Comparative costs of home care and residential care.
AB  - PURPOSE: This paper reports on Canadian research that examined the cost
      effectiveness of home care for seniors as a substitute for long-term
      institutional services. DESIGN AND METHODS: Two Canadian cities were included in
      the research: Victoria, British Columbia, and Winnipeg, Manitoba. The research
      computes the costs of formal care and informal care in both settings and ensures
      comparable groups of clients in both settings by comparing individuals at the
      same level of care. RESULTS: The results reveal that costs were significantly
      lower for community clients than for facility clients, regardless of whether
      costs only to the government were taken into account or whether both formal and
      informal costs were taken into account. When informal caregiver time is valued at
      either minimum wage or replacement wage, there was a substantial jump in the
      average annual costs for both community and facility clients relative to when
      informal caregiver time was valued at zero. IMPLICATIONS: Nevertheless, the
      results reveal that home care is significantly less costly than residential care
      even when informal caregiver time is valued at replacement wage.

PMID- 15197294
TI  - The effect of self-reported and performance-based functional impairment on future
      hospital costs of community-dwelling older persons.
AB  - PURPOSE: We determined the prognostic value of self-reported and performance
      based measurement of function, including functional transitions and combining
      different measurement approaches, on utilization. DESIGN AND METHODS: Our cohort
      study used the 6th, 7th, and 10th waves of three sites of the Established
      Populations for Epidemiologic Studies of the Elderly, linked to 1- and 4-year
      Medicare Part A hospital costs. We examined mean hospital expenditures based on
      (a) 1- and 4-year transitions in self-reported functional status; (b) 4-year
      transitions in performance-based functional status; (c) combined baseline self
      reported and performance-based functional status; and (d) poorest self-reported
      and performance-based functional status during a 4-year period. RESULTS: Even
      modest declines in self-reported or performance-based functional status were
      associated with increased expenditures. When baseline self-reported and
      performance-based assessments were combined, mean 1- and 4-year adjusted costs
      were higher with progressively worse performance-based scores, even among those
      who were independent in self-reported function. When the poorest 4-year self
      reported and performance-based functions were examined, self-reported functioning
      was the most important determinant of hospital costs, but within each self
      reported functional level, poorer performance-based function was associated with
      progressively higher costs. IMPLICATIONS: The costs associated with even modest
      functional decline are high. Combining self-reported and performance-based
      measurements can provide more precise estimates of future hospital costs.

PMID- 15197295
TI  - Examination of the Philadelphia Geriatric Morale Scale as a subjective quality-of
      life measure in elderly Hong Kong Chinese.
AB  - PURPOSE: We examine the psychometric properties of the Philadelphia Geriatric
      Morale Scale (PGMS) in an elderly Chinese population in Hong Kong. DESIGN AND
      METHODS: The study consisted of two cohorts: (a) 759 participants aged 70 years
      and older living in the community who were recruited as part of a territory-wide
      health survey and interviewed in 1993-1994; and (b) 388 participants living in
      long-term-care institutions in 1995-1996. Participants who were cognitively
      impaired (Abbreviated Mental Test score less than 7) or who could not answer
      questions for other reasons were excluded. The 15-item PGMS was administered. The
      Rasch dichotomous model was used to assess the validity of the PGMS, and the 15
      item Geriatric Depression Scale, previously validated in Chinese, was also
      administered to examine the concurrent validity. RESULTS: A confirmatory factor
      analysis identified three underlying factors similar to findings among
      Caucasians; however, not all the goodness-of-fit indices were acceptable. An
      exploratory factor analysis using principal axis factoring and promax rotation
      revealed two underlying factors that explained 35% of the total variance:
      reconciled aging and unstrained affect. Some items were redundant when applied to
      the institutional sample. Concurrent validity was demonstrated by the good
      correlation between the reconciled aging and unstrained affect domains and the
      Geriatric Depression Scale (r = -0.72 and r = -0.56 respectively). Female gender,
      older age, and residence in institutions were associated with lower morale.
      IMPLICATIONS: The PGMS is a valid quality-of-life measure in elderly Hong Kong
      Chinese persons, but its psychometric properties are slightly different from
      those for Caucasians.

PMID- 15197296
TI  - Reliability and validity of the SF-36 among older Mexican Americans.
AB  - PURPOSE: The Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF
      36) has been validated in many diverse samples. This measure of health-related
      quality of life, however, has not yet been examined among older Mexican
      Americans, a rapidly growing subset of the older population. DESIGN AND METHODS:
      We address the validity of the SF-36 in a sample of older Mexican Americans (N =
      621) selected from the Hispanic Established Populations for Epidemiologic Study
      of the Elderly. Using confirmatory factor analysis through structural equation
      modeling, we evaluate the construct validity of this scale. RESULTS: The results
      indicate evidence for a model with eight first-order factors consistent with
      previous research on the SF-36 and two second-order factors representing mental
      and physical health. IMPLICATIONS: This, in addition to other evidence given
      here, leads us to the conclusion that the SF-36 is a valid measure of health
      related quality of life in this sample of older Mexican Americans.

PMID- 15197297
TI  - Resident-Assisted Montessori Programming (RAMP): training persons with dementia
      to serve as group activity leaders.
AB  - PURPOSE: The purpose of this study was to determine the effects of an activity
      implemented by means of Resident-Assisted Montessori Programming (RAMP). DESIGN
      AND METHODS: Four persons with early-stage dementia were trained to serve as
      leaders for a small-group activity played by nine persons with more advanced
      dementia. Assessments of leaders' ability to learn the procedures of leading a
      group, as well as their satisfaction with this role, were taken, as were measures
      of players' engagement and affect during standard activities programming and RAMP
      activities. RESULTS: Leaders demonstrated the potential to fill the role of group
      activity leader effectively, and they expressed a high level of satisfaction with
      this role. Players' levels of positive engagement and pleasure during the RAMP
      activity were higher than during standard group activities. IMPLICATIONS: This
      study suggests that to the extent that procedural learning is available to
      persons with early-stage dementia, especially when they are assisted with
      external cueing, these individuals can successfully fill the role of volunteers
      when working with persons with more advanced dementia. This can provide a
      meaningful social role for leaders and increase access to high quality activities
      programming for large numbers of persons with dementia.

PMID- 15197299
TI  - Streptavidin-biotin crosslinking of therapeutic enzymes with carrier antibodies:
      nanoconjugates for protection against endothelial oxidative stress.
AB  - The streptavidin-biotin system may be used to synthesize immunoconjugates for
      targeted delivery of drugs, including therapeutic enzymes. The size of antibody
      enzyme conjugates, which is controlled by the extent of biotinylation and molar
      ratio between the conjugate components, represents an important parameter that in
      some cases dictates subcellular addressing of drugs. This chapter describes the
      methodology of formation and characterization of polymeric immunoconjugates in
      the nanoscale range. A theoretical model of streptavidin conjugation based on
      general principles of polymer chemistry is considered. Factors that influence
      size and functional characterization of resulting polymer conjugates, as well as
      advantages and limitations of this approach, are described in detail. The
      protocols describe the formation of immunoconjugates possessing an antioxidant
      enzyme, catalase, directed to endothelial cells by anti-platelet endothelial cell
      adhesion molecule antibodies. However because of the modular nature of the
      streptavidin-biotin crosslinker system, the techniques herein can be easily
      adapted for the preparation of nanoscale immunoconjugates delivering other
      protein drugs to diverse cellular antigens.

PMID- 15197300
TI  - Characterization of endothelial internalization and targeting of antibody-enzyme
      conjugates in cell cultures and in laboratory animals.
AB  - Streptavidin-biotin conjugates of enzymes with carrier antibodies provide a
      versatile means for targeting selected cellular populations in cell cultures and
      in vivo. Both specific delivery to cells and proper subcellular addressing of
      enzyme cargoes are important parameters of targeting. This chapter describes
      methodologies for evaluating the binding and internalization of labeled
      conjugates directed to endothelial surface adhesion molecules in cell cultures
      using anti-intercellular adhesion molecule/catalase or antiplatelet endothelial
      cell adhesion molecule/catalase conjugates as examples. It also describes
      protocols for characterization of biodistribution and pulmonary targeting of
      radiolabeled conjugates in rats using anti-intercellular adhesion molecule/tPA
      conjugates as an example. The experimental procedures, results, and notes
      provided may help in investigations of vascular immunotargeting of reporter,
      experimental, diagnostic, or therapeutic enzymes to endothelial and, perhaps,
      other cell types, both in vitro and in vivo.

PMID- 15197301
TI  - Smart polymer-streptavidin conjugates.
AB  - The conjugation of stimuli-responsive, or "smart," polymers to streptavidin is
      described. The polymer is synthesized with a thiol-reactive end-group, which is
      used to end-graft the polymer to cysteine or lysine side-chains that are
      genetically engineered into controlled positions on the streptavidin surface. The
      conjugation positions are chosen on the basis of their location relative to the
      binding site, together with the criteria that they be solvent accessible and thus
      reactive. The polymer composition can be controlled to impart responsiveness to
      temperature, pH, and/or specific wavelengths of light. These signals are sent to
      the polymer, which serves as an antennae and actuator to gate biotin or
      biotinylated protein association with the streptavidin binding sites. The
      molecular switching and gating activity is directed by the reversible polymer
      transition between a hydrophilic, expanded coil and a more hydrophobic, collapsed
      state that is smaller in volume. The differences in the polymer steric properties
      serve to block or allow ligand access to the binding site. The control of polymer
      molecular weight is a particularly important design parameter for these molecular
      gates.

PMID- 15197302
TI  - Conjugates of peptides and proteins to polyethylene glycols.
AB  - This chapter provides a critical overview of the technology presently available
      in the field of protein PEGylation. The chemistry of the polymer and of its
      reactive derivatives is discussed and presented together with several protocols
      used to obtain PEG-protein conjugates. The coupling protocols are critically
      discussed on the basis of the properties of the protein to be modified and those
      desired for the final product. Methods for product purification and
      characterization are also provided. The overall information provided will guide
      the reader toward all of the critical steps involved in the preparation of PEG
      protein adducts.

PMID- 15197303
TI  - Chemical production of bispecific antibodies.
AB  - This chapter discusses two related methods for creating Fab' x Fab' chemically
      linked BsAb. Both methods require the generation of purified F(ab')2 fragments of
      each antibody and use reagents that react with the free thiols generated upon
      reduction of interheavy chain disulfide bonds of the F(ab')2 fragments. Upon
      reduction, the resulting Fabs are then recombined to form a Fab' x Fab' BsAb.
      5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) acts to regenerate disulfide bonds
      between the two Fabs, whereas o-phenylenedimaleimide (o-PDM) acts to form a
      thioether bond between the two Fabs. After coupling, the bispecific antibody is
      purified from the uncoupled Fabs by size-exclusion chromatography. The advantages
      and disadvantages of each conjugation method are discussed.

PMID- 15197304
TI  - Preparation of immunoconjugates using antibody oligosaccharide moieties.
AB  - Heterobifunctional crosslinking reagents are small molecular weight chemicals
      containing two different reactive groups that have become important tools in
      generating conjugates of two different biomolecules, such as two proteins. The
      resulting bioconjugates are hybrid molecules or proteins, a new category of
      biomolecules that exhibit the combined functions of the two parent biomolecules.
      An important category of hybrid proteins are conjugates of antibodies with other
      effector molecules, such as drugs or toxins. These antibody conjugates or
      immunoconjugates have a variety of the applications in medicine, with particular
      emphasis on the treatment of cancer. The most commonly used heterobifunctional
      crosslinking reagents for the synthesis of antibody conjugates contain an N
      hydroxysuccinimide ester moiety, which allows derivatization of amino groups in
      proteins. The chemical modification of a functionally important amino group in
      the antigen-binding region of an antibody causes impairment or loss of the
      antigen binding function, resulting in a defective antibody conjugate that lacks
      one of its component functions. Furthermore, even if the chemical derivatization
      does not affect the antigen binding function, the subsequent coupling of an
      effector protein at or near the antigen-binding region can also cause the loss of
      the antigen binding function for steric reasons. In this chapter,
      heterobifunctional crosslinking reagents are described that allow the generation
      of antibody conjugates where the effector proteins are coupled to the antibody
      carbohydrate moieties. Because antibody carbohydrate moieties are distal from the
      antigen-binding region, the use of carbohydrate-directed heterobifunctional
      crosslinking reagents, such as S-(2-thiopyridyl)-L-cysteine hydrazide (TPCH),
      prevents inactivation of the antigen-binding function. The synthesis of two
      carbohydrate-directed heterobifunctional crosslinking reagents is described.
      Coupling protocols for the preparation of antibody conjugates with effector
      proteins of different sizes using carbohydrate-directed heterobifunctional
      crosslinking reagents are also provided.

PMID- 15197305
TI  - Synthesis of hapten-protein conjugates using microbial transglutaminase.
AB  - Hapten-protein conjugates are essential in many immunochemical assays and in
      particular in assays using titration or competitive assay formats. By
      exploitation of the catalytic properties of the microbial transglutaminase from
      Streptoverticillium mobarense species (MTGase), that is, acyl transfer between
      gamma-carboxamide groups and various primary amines, new techniques for the
      enzymatic modification of proteins were developed. One example of bioconjugation
      is the biotinylation of antibodies for immunochemical applications using two
      species of activated biotin. In this case, the activated biotin acts as the acyl
      acceptor and is coupled to the glutamine residues of a monoclonal antibody.
      Because of the substrate specificity of the MTGase with regard to the limited
      number of glutamine residues and the surrounding microenvironment, only a limited
      number of binding sites on the target protein are available; the proposed method
      is thus particularly suitable when only a few biotin molecules need to be
      attached. Another example for the modification of proteins is the synthesis of
      hapten-protein conjugates used in competitive-type immunoassays. Methods for the
      synthesis of 2,4-D-casein conjugates (2,4-diclorophenoxyacetic acid, a herbicide)
      are presented. Various approaches, including a batch procedure and two in situ
      procedures, are described.

PMID- 15197306
TI  - Fluorescent sample labeling for DNA microarray analyses.
AB  - Three fluorophor-labeling methods for gene expression profiling on
      deoxyribonucleic acid (DNA) microarrays are described. All three techniques start
      from total ribonucleic acid (RNA) samples. Two procedures are based on first
      strand complementary DNA synthesis by reverse transcription. Label is introduced
      either by direct incorporation of fluorescently labeled nucleotides or indirectly
      by incorporation of aminoally-dUTP and subsequent coupling of fluorescent dyes.
      The third method is based on an amplification of antisense RNA by in vitro
      transcription subsequent to first- and second-strand complementary DNA synthesis.
      While the first two methods are applied mainly in analyses on microarrays made
      from spotted polymerase chain reaction products or long oligonucleotides, the
      last procedure is mostly used for experiments on in situ synthesized
      oligonucleotide arrays.

PMID- 15197307
TI  - High-density labeling of DNA for single molecule sequencing.
AB  - Two unusual enzymatic activities are required for the realization of a single
      molecule sequencing: a polymerase for copying a deoxyribonuclease (DNA) target
      into complementary flurophore-labeled DNA, and an exonuclease for the successive
      hydrolysis of the completely dye-labeled DNA. Recently, we found that the wild
      type Klenow fragment of Escherichia coli DNA polymerase I is well-suited for the
      synthesis of DNA in a reaction set-up that contains exclusively specific
      rhodamine-labeled analogs of the natural pyrimidine nucleotides (dCTP and dTTP).
      This protocol describes the procedure used for the preparation of DNA that is
      labeled at all pyrimidine bases of one strand, as well as an example of enzymatic
      downstream processing of the DNA product.

PMID- 15197308
TI  - Sequence-specific DNA labeling using methyltransferases.
AB  - Sequence-specific labeling of native deoxyribonucleic acid (DNA) still represents
      a more-or-less unsolved problem. Difficulties mainly arise from the necessity to
      combine two different functions: sequence-specific recognition of DNA and
      covalent bond formation between the label and DNA. DNA methyltransferases
      (MTases) naturally possess these two functions and transfer a methyl group from
      the cofactor S-adenosyl-L-methionine (AdoMet) to adenine or cytosine residues
      within specific DNA sequences, typically ranging from two to eight base pairs.
      Unfortunately, the methyl group itself is a very limited reporter group and it
      would be desirable to transfer larger chemical entities with DNA MTases.
      Replacement of the methionine side chain of the natural cofactor AdoMet by an
      aziridinyl residue leads to the synthetic cofactor N-adenosylaziridine, which is
      quantitatively, base- and sequence-specifically coupled with DNA in a DNA MTase
      catalyzed reaction. By attaching interesting reporter groups to a suitable
      position of N-adenosylaziridine a large variety of new synthetic cofactors are
      obtained for sequence-specific labeling of DNA. This method is illustrated by
      coupling primary amino groups and biotin to short duplex oligodeoxynucleotides or
      plasmid DNA using the DNA MTase M.TaqI.

PMID- 15197310
TI  - Covalent coupling of DNA oligonucleotides and streptavidin.
AB  - Semisynthetic DNA-protein conjugates are synthesized by covalent coupling of
      thiol-modified DNA oligonucleotides and streptavidin. The resulting conjugates
      have a binding capacity for four equivalents of biotin and one nucleic acid of
      complementary sequence. The conjugates are purified to homogeneity by
      ultrafiltration and chromatography and characterized by photometry and gel
      electrophoresis. Subsequently, the conjugates are applied as molecular linkers in
      the DNA-directed immobilization of a biotinylated enzyme on a microplate,
      containing complementary capture oligonucleotides.

PMID- 15197309
TI  - Hapten labeling of nucleic acids for immuno-polymerase chain reaction
      applications.
AB  - A method for the ultrasensitive protein detection in the range of 0.01 to 10,000
      amol of the model antibody anti-mouse-IgG from rabbit is described, using a
      combination of Immuno-polymerase chain reaction (PCR) and PCR-enzyme-linked
      immunosorbent assay (PCR-ELISA). The antibody was first immobilized on antigen
      coated microplates; in a second step, a commercially available DNA-labeled
      species-specific antibody was added; and finally the deoxyribonucleic marker was
      amplified in a PCR step, including twofold labeling with biotinylated primer and
      a hapten-coupled nucleotide during PCR. Subsequently, the labeled PCR product was
      immobilized on streptavidin-coated microplates and detected with an antibody
      enzyme conjugate. The protocol could easily be adapted to the detection of other
      antibodies or antigens by exchanging the antigen-specific antibody. Several
      modifications of the method as well as optimization steps, potential error
      sources, and countermeasures are discussed.

PMID- 15197311
TI  - Synthesis of oligonucleotide-peptide and oligonucleotide-protein conjugates.
AB  - The conjugation of macromolecules offers a rapid and versatile route to improved
      function. Here, the methods for obtaining disulfide-linked oligonucleotide
      peptide and oligonucleotide-protein conjugates are described. These hybrid
      molecules can be used deliver chemical functionality to specific sequences within
      deoxyribonucleic acid and ribonucleic acid. The peptides and proteins can also be
      used to enhance the hybridization properties of the attached oligonucleotides.

PMID- 15197312
TI  - Synthesis of peptide nucleic acid-peptide conjugates.
AB  - Synthetic oligonucleotides are versatile tools for recognizing ribonucleic acid
      and deoxyribonucleic acid. This chapter describes methods for enhancing
      recognition by derivatizing oligonucleotides with either proteins or peptides.

PMID- 15197313
TI  - Protein lipidation.
AB  - This chapter describes the hydrophobic modification of peripheral membrane
      anchored proteins by isoprenylation and S-acylation. The coupling of bacterially
      expressed protein moieties with chemically synthesized lipopeptides is described
      as an in vitro alternative for the generation of lipoproteins.

PMID- 15197314
TI  - Synthesis of lipidated peptides.
AB  - This chapter describes general methodologies for the synthesis of lipidated, that
      is, prenylated and/or palmitoylated peptides. Standard operating procedures are
      given for peptide synthesis both on the polymeric support and in solution.

PMID- 15197315
TI  - In vitro semisynthesis and applications of C-terminally modified rab proteins.
AB  - Expressed protein ligation is a powerful tool for the generation of natively
      folded proteins composed of recombinantly generated and chemically synthesized
      polypeptides. Using this approach, we developed protocols for the production of
      prenylated and/or otherwise-labeled Rab GTPase. The protocols are generally
      applicable to most small GTPases that can be supplied with a variety of new
      chemical functionalities. We used semisynthetic fluorescently labeled Rab7 GTPase
      as a molecular probe to study protein-protein interactions with components of the
      prenylation machinery

PMID- 15197316
TI  - Generation and characterization of ras lipoproteins based on chemical coupling.
AB  - Chemically synthesized truncated Ras proteins are coupled to C-terminal Ras
      peptides via a maleimidocaproyl linker. The resulting product is isolated by
      extraction with Triton X-114. The biological activity of these oncogenic Ras
      lipoproteins can be determined in a cell-based differentiation assay by
      microinjection into PC12 cells.

PMID- 15197317
TI  - Conjugation of glycopeptide thioesters to expressed protein fragments:
      semisynthesis of glycosylated interleukin-2.
AB  - This method describes the conjugation of a synthetic glycopeptide to the N
      terminus of a recombinant human interleukin-2 (IL-2) protein fragment. The IL-2
      protein fragment is produced as an affinity-tagged fusion protein in Escherichia
      coli and then cleaved with the highly selective TEV protease to remove the
      affinity tag and uncover an N-terminal cysteine. The N-terminal cysteine is then
      used in native chemical ligation reaction to join the IL-2 protein fragment to a
      glycosylated tripeptide thioester that had been previously synthesized to produce
      a glycosylated form of IL-2.

PMID- 15197318
TI  - Subtilisin-catalyzed glycopeptide condensation.
AB  - This method describes the use of subtilisin-catalyzed peptide condensation to
      form a 15-residue glycopeptide from two smaller synthetic peptides. A 12-residue
      peptide ester is synthesized by solid-phase peptide synthesis using a PAM
      modified Rink amide resin that allows the formation of a peptide ester suitable
      for subtilisin ligation. The 12-residue acyl donor peptide ester is then ligated
      to a 3-residue acyl acceptor glycopeptide amide using subtilisin (EC 3.4.21.62)
      in a buffered mixture of water and DMF (1:9).

PMID- 15197319
TI  - Peptide nucleic acid microarrays.
AB  - A fast and economical procedure for the production of peptide nucleic acid (PNA)
      microarrays is presented. PNA oligomers are synthesized in a fully automatic
      manner in 96-well plates using standard Fmoc chemistry. Subsequently, the
      oligomers are released from the support and spotted onto glass or silicone
      slides, which were activated by succinimidyl ester. This process allows for a
      concomitant purification of the oligomers directly on the chip surface. Although
      the terminal primary amino groups of the full-length products bind selectively to
      this surface, none of the byproducts of synthesis, such as truncated sequences or
      cleaved side chain protection groups, will bind and are therefore washed away. In
      this chapter, protocols are presented for the whole production process as well as
      sample hybridization.

PMID- 15197320
TI  - Synthesis and characterization of deoxyribonucleic acid-conjugated gold
      nanoparticles.
AB  - Gold nanoparticles functionalized with thiol-modified single-stranded
      oligonucleotides are highly useful reagents for a variety of applications,
      ranging from materials science to bioanalytics. In this chapter, the preparation
      of citrate stabilized 15-nm Au nanoparticles is described. The nanoparticles are
      conjugated with 3'-thiol-modified deoxyribonucleic acid oligomers and the
      resulting conjugates are characterized by determining their shape, size, and
      surface coverage. The hybridization capabilities are quantified in a microplate
      assay.

PMID- 15197321
TI  - Biofunctionalization of carbon nanotubes for atomic force microscopy imaging.
AB  - The study of biological processes relies increasingly on methods for probing
      structure and function of biochemical machinery (proteins, nucleic acids, and so
      on) with submolecular resolution. Atomic force microscopy (AFM) has recently
      emerged as a promising approach for imaging biological structures with resolution
      approaching the nanometer scale. Two important limitations of AFM in biological
      imaging are (1) resolution is constrained by probe tip dimensions, and (2)
      typical probe tips lack chemical specificity to differentiate between functional
      groups in biological structures. Single-walled carbon nanotubes (SWNTs) offer an
      intriguing possibility for providing both high resolution and chemical
      selectivity in AFM imaging, thus overcoming the enumerated limitations.
      Procedures for generating SWNT tips for AFM will be described. Carboxylic acid
      functional groups at the SWNT ends can be functionalized using covalent coupling
      chemistry to attach biological moieties via primary amine groups. Herein, the
      focus will be on describing methods for attaching biotin to SWNT tips and probing
      streptavidin on surfaces; importantly, this same coupling chemistry can also be
      applied to other biomolecules possessing primary amine groups. Underivatized SWNT
      tips can also provide high-resolution AFM images of DNA. Biofunctionalization of
      SWNT AFM tips offers great potential to enable high-resolution, chemically
      selective imaging of biological structures.

PMID- 15197323
TI  - Is low-dose hyper-radiosensitivity a measure of G2-phase cell radiosensitivity?
AB  - Low-dose hyper-radiosensitivity describes a phenomenon by which cells die from
      excessive sensitivity to small single doses of ionizing radiation below
      approximately 20-30 cGy. This review describes experimental data that strongly
      imply that low-dose hyper-radiosensitivity is exclusively associated with the
      survival response of cells in the G2 phase of the cycle. This G2-centric concept
      arose when the characteristic cell survival pattern that denotes low-dose hyper
      radiosensitivity was not detected in the radiation survival response of cell
      populations enriched in G1 or S phase cells. In contrast, an extended or
      exaggerated low-dose hyper-radiosensitivity response was evident from populations
      selected to contain only G2 phase cells by flow cytometry cell sorting. The
      historical data that has defined the field of low-dose hyper-radiosensitivity
      will be considered with respect to the radiation sensitivity of, and cell cycle
      checkpoints specific to, G2 phase cells. A working model of the putative
      mechanism of low-dose hyper-radiosensitivity will be presented within this
      context. The foundation of the model is a rapidly occurring dose-dependent pre
      mitotic cell-cycle checkpoint that is specific to cells irradiated in the G2
      phase. This early G2 phase checkpoint has been demonstrated to exhibit a dose
      expression profile that is comparable to the cell-survival pattern that defines
      low-dose hyper-radiosensitivity and is therefore a likely key regulator of the
      phenomenon.

PMID- 15197324
TI  - Radiation and the cell cycle, revisited.
AB  - The cell cycle has been inextricably linked to the cellular response to radiation
      for many years. However, it is only in the past decade that the concept of a
      coordinated DNA damage response integrating damage recognition, cell cycle
      checkpoints and DNA repair has begun to be elucidated. The ATM protein is
      emerging as a key orchestrator of the damage response activating a wide variety
      of effectors involved in cell cycle arrest and DNA repair to elicit a concerted
      effort to prevent genome instability caused by unwanted changes in DNA sequence.
      The key proteins involved in cell cycle checkpoints in different phases of the
      cell cycle, and their interaction, is a fertile and rapidly developing area of
      research. This review summarizes the current state of knowledge of cellular
      checkpoints in response to radiation-induced double-strand breaks in mammalian
      cells and how this impacts on radiosensitivity.

PMID- 15197325
TI  - The influence of Ras pathway signaling on tumor radiosensitivity.
AB  - Radiotherapy is used to treat approximately 60% of solid tumors in the US. The
      relative radiosensitivity of these tumors can have a significant impact upon
      local control. One factor that has been shown to contribute to the increased
      survival of tumor cells is the activation of signaling pathways in which oncogene
      products play a central role. The Ras oncoprotein family, comprised of H-, K-,
      and N-Ras are frequently activated by mutation in certain tumors such as
      pancreatic and non-small cell lung cancers and are activated by receptor tyrosine
      kinase activity in an even wider range of tumor types. The role of ras mutation
      and more recently Ras signaling has been an area of intense study in both
      radiobiology and tumor biology in general. In this review, we focus on findings
      from our lab and others that led to the current hypotheses relating to the role
      of Ras signaling in tumor radiation survival and the strategies used to block Ras
      activation. We will also point out new means of studying the contribution of Ras
      and Ras pathway components that could contribute to defining new targets for
      inhibition in the context of radiation therapy.

PMID- 15197326
TI  - The p53 protein family and radiation sensitivity: Yes or no?
AB  - The p53 tumor suppressor protein is a key mediator of an ATM-dependent DNA damage
      response cascade following cellular exposure to ionizing radiation. The p53
      family members, p63 and p73, are highly similar to p53, yet are differentially
      activated by IR, UV and cis-platinum via ATM and c-abl/ATR signaling pathways.
      Loss of function of p53 can occur by mutation or degradation; giving rise to
      alterations in G(1) and G(2) cell cycle checkpoint control, cell death, DNA
      repair and genetic stability. The end result of these alterations can be the
      generation of radioresistant mutant tumor cells. Indeed, in isogenic systems,
      loss of p53 or p73 function has been associated with decreased chemosensitivity
      and radiosensitivity, in vitro. However, clinical data supporting a role for p53
      genotype as an independent predictive factor for radiotherapy outcome continues
      to be controversial due to variable endpoints in clinical trial design and in
      methodology in detecting p53 function. Nonetheless, in carefully controlled
      radiotherapy studies where mutations in p53 have been detected using DNA
      sequencing or functional assays, the presence of mutant p53 can be associated
      with decreased local control following radiotherapy. This suggests that novel
      molecular treatment strategies specifically designed to re-institute normal p53
      function within resistant tumors can be used as combined modality protocols to
      improve local control and maintain a therapeutic ratio. A future challenge lies
      in the pre-therapy determination of a 'molecular therapeutic ratio' for
      individual patients which could allow for specific prognostication based on p53
      functional status and subsequent individualized therapy.

PMID- 15197327
TI  - Gene expression profiling after irradiation: clues to understanding acute and
      persistent responses?
AB  - Ionizing radiation (IR) is an ever-present hazard to humans primarily due to its
      mutagenic, carcinogenic, and cell killing ability. In addition to causing DNA
      damage, irradiation initiates a plethora of signal transduction cascades
      responsible for maintaining cellular homeostasis and promoting interactions with
      neighboring cells. Large-scale changes in gene expression have also been found
      after irradiation, and microarrays have helped discern these subsequent
      transcriptional alterations. While some studies have focused on low dose-rate
      experiments, others have analyzed the gene expression response of IR compared to
      other DNA damaging agents. Very few genes have been found to be consistently up
      regulated by IR, but that set includes GADD45, CDKN1A, and genes associated with
      the nucleotide excision repair pathway. Overall, the immediate transcriptional
      responses to IR have implications for DNA repair, cell cycle arrest, growth
      control, and cell signaling. Additionally, there is a substantial p53-independent
      component to the transcriptional profile that could be exploited to increase the
      effectiveness of radiotherapy. Initial characterizations of the persistent
      responses to IR yielded a completely different profile than observed immediately
      after exposure. This profile is ephemeral, shifting even over the course of one
      set of experiments. Microarray analysis of radiation responses has also been
      applied to clinical response to radiotherapy, identifying genes linked to radio
      sensitivity and resistance in B-cell chronic lymphoid leukemia and cervical
      cancer. Overall, these large-scale gene expression studies have added to the
      understanding of the complicated biological responses to IR, and when combined
      with other data sets will yield a complete picture of the short and long-term
      consequences of radiation.

PMID- 15197328
TI  - Radiation and hypoxia inducible gene therapy systems.
AB  - Radiotherapy remains one of the primary treatment modalities for most
      malignancies. Biologically based improvements in the scheduling of conventional
      radiotherapy and treatment planning, innovations like conformal radiotherapy and
      intensity-modulated radiation therapy have considerably improved the targeting
      and effectiveness of radiation for treatment of solid tumors. These new
      radiotherapy technologies are also promising means of focusing the activation of
      anti-tumor gene therapy systems, as an approach to further improve
      radiotherapeutic treatment, particularly for tumors refractive to current
      therapies. Gene therapy vectors that express therapeutic genes following
      irradiation have been produced. Delivery of such vectors to the tumor allows
      temporal and spatial expression of the transgenes within the radiation field.
      Hypoxia is a physiological characteristic of solid tumors and an independent
      prognostic marker for poor radiation treatment outcome. Nevertheless, hypoxia has
      been exploited to drive therapeutic gene expression from gene therapy vectors
      delivered to solid tumors exhibiting significant areas of low oxygen tension.
      Radiation and hypoxia inducible gene therapy systems rely on the activation of
      gene promoters containing specific responsive elements. Recent studies have shown
      the potential to combine these elements, permitting either or both stimuli to
      drive therapeutic gene expression. Furthermore, transgene expression can be
      amplified and sustained using novel 'signal feedback' or recombination systems.
      Such innovations allow promising new strategies to improve radiation treatment
      outcome, particularly where tumor hypoxia is a predominant issue.

PMID- 15197329
TI  - Enhanced radiation response through directed molecular targeting approaches.
AB  - In both the pre- and post-human genome sequencing eras, there has been an
      increase in the understanding of the molecular mechanisms influencing cellular
      sensitivity to DNA damaging agents such as ionizing radiation. Out of this work
      have arisen many cellular factors that could be specifically targeted, at the
      molecular level, to alter the functionality of a single protein or pathway
      involved in the response to radiation damage as a means to increase cell killing
      following radiation treatment. As such, there are many promising new combination
      radio-gene therapy approaches being developed and assessed in pre-clinical and
      clinical studies for several different malignancies. Combination of such
      modalities aims to increase the therapeutic index, giving rise to increased tumor
      cell killing with a simultaneous reduction in normal cell toxicity. Restricted
      delivery and/or targeting modalities combined with conformal radiotherapy regimes
      could provide significant local control of tumors, impeding their development
      into metastatic disease, which poses a greater challenge for palliative and
      curative treatments. This review will summarize current and novel gene therapy
      strategies that are being developed aimed at enhancing the effects of
      radiotherapy through the use of directed molecular targeting approaches.

PMID- 15197330
TI  - Hypoxic gene expression and metastasis.
AB  - Solid tumors possess malformed vasculature that results in the exposure of tumor
      cells to a low oxygen environment. Tumor hypoxia has been demonstrated in human
      and mouse tumors through the use of oxygen microelectrodes, hypoxic specific
      biomarkers, specific transcriptional changes induced by hypoxia, and secreted
      proteins. While many elegant experiments have demonstrated that hypoxia enhances
      metastatic potential, it is still unknown what mechanisms are involved in this
      enhancement. In this review, we discuss the clinical and basic science studies
      that support an important role for hypoxia in increasing the metastatic potential
      of tumor cells by promoting tissue remodeling, inducing angiogenesis and reducing
      apoptosis. Particular emphasis is given to recent findings that provide insight
      to the role of hypoxia in the metastatic process.

PMID- 15197331
TI  - Metabolic oxidation/reduction reactions and cellular responses to ionizing
      radiation: a unifying concept in stress response biology.
AB  - Exposure of eukaryotic cells to ionizing radiation (IR) results in the immediate
      formation of free radicals that last a matter of milliseconds. It has been
      assumed that the subsequent alterations in multiple intracellular processes
      following irradiation is due to the initial oxidative damage caused by these free
      radicals. However, it is becoming increasingly clear that intracellular metabolic
      oxidation/reduction (redox) reactions can be affected by this initial IR-induced
      free radical insult and may remain perturbed for minutes, hours, or days. It
      would seem logical that these cellular redox reactions might contribute to the
      activation of protective or damaging processes that could impact upon the
      damaging effects of IR. These processes include redox sensitive signaling
      pathways, transcription factor activation, gene expression, and metabolic
      activities that govern the formation of intracellular oxidants and reductants.
      The physiological manifestations of these radiation-induced alterations in redox
      sensitive processes have been suggested to contribute to adaptive responses,
      bystander effects, cell cycle perturbations, cytotoxicity, heat-induced
      radiosensitization, genomic instability, inflammation, and fibrosis. While a
      great deal is known about the molecular changes associated with the initial
      production of free radicals at the time of irradiation, the contribution of
      perturbations in redox sensitive metabolic processes to biological outcomes
      following exposure to IR is only recently becoming established. This review will
      focus on evidence supporting the concept that perturbations in intracellular
      metabolic oxidation/reduction reactions contribute to the biological effects of
      radiation exposure as well as new concepts emerging from the field of free
      radical biology that may be relevant to future studies in radiobiology.

PMID- 15197332
TI  - Microbeam developments and applications: a low linear energy transfer
      perspective.
AB  - In the last few years there has been a significant increase in the number of
      centers having, or developing, both high- and low-linear energy transfer (LET)
      microbeams for radiobiological investigations. In this review, we will discuss
      the various approaches for developing low-LET single cell irradiation devices and
      consider the instrument designs and how the machines capabilities can be
      exploited to investigate targeted and non-targeted effects of low-LET
      irradiation.

PMID- 15197333
TI  - Radiation-induced neoplastic transformation in vitro: evidence for a protective
      effect at low doses of low LET radiation.
AB  - The study of radiation-induced transformation in vitro has long been an
      experimental approach to examine mechanisms underlying radiation carcinogenesis.
      Even though the major concern of exposure to radiation is the risk of cancer
      induction at low radiation doses, most laboratory mechanistic studies have
      focused on high dose effects. This, coupled with the fact that epidemiologic data
      are rarely powerful enough to accurately discriminate this risk at doses <5 cGy,
      has led in recent years to an increased effort to study low dose effects using
      the endpoint of neoplastic transformation in vitro. Since transformation
      frequencies at low doses are typically low (< 10(-4)), such studies are, by
      necessity, large and labor intensive. However, they have yielded quantitative
      dose-response data, as well as insights into underlying cellular and molecular
      mechanisms. An interesting, and potentially important, finding is that low doses
      of low LET radiation can suppress neoplastic transformation in vitro to levels
      below that seen spontaneously. Mechanistic studies have revealed that multiple
      mechanisms are likely to be involved, and these include both the death of a
      subpopulation of cells prone to spontaneous neoplastic transformation and the
      induction of DNA repair. The relative contribution of these mechanisms appears to
      be dose-dependent. The relevance of in vitro studies to carcinogenesis in vivo is
      discussed.

PMID- 15197334
TI  - Radiation cytogenetics: from chromosomes to single nucleotides and from metaphase
      cells to tissues.
AB  - This paper provides a broad overview of radiation cytogenetics that is divided
      into four sections. The first section provides a brief history of metaphase-based
      analyses for detecting and quantifying human exposure to ionizing radiation. The
      second section describes technologies for detecting cellular responses to
      radiation exposure other than DNA damage. The third section discusses molecular
      cytological approaches for analyzing some of the long-term effects of radiation
      exposure in tissues, including tumors. The final section provides a look towards
      the future and makes recommendations including suggestions for technological
      innovations that would enhance the field of radiation cytology.

PMID- 15197335
TI  - Opioid peptides in cancer.
AB  - Opioid and somatostatin systems are two main inhibitory systems in mammals
      implicated in a variety of processes from hormone secretion to the modulation of
      cell proliferation. Opioids and opioid receptors were found in a great diversity
      of primary human tumors and in various cancer cell lines. A new area of interest
      that has developed since the early 1980s has been concerned with the role of
      endogenous opioid systems in the growth of normal and abnormal tissues and cells.
      This review presents recent developments on the identification of opioid ligands
      and receptors in different types of human neoplasia. It also deals with the
      mechanisms of opioid peptide action in carcinoma and the involvement of opioids
      in the regulation of tumor growth.

PMID- 15197336
TI  - Implications of apoptosis regulators in tumorigenesis.
AB  - The process of cell loss and cell gain is homeostatically balanced in order to
      not only generate and maintain the complex dynamic architecture of tissues, but
      also to allow adaptation to changing circumstances. Tumor cells survive only by
      virtue of mutations that allow them to proliferate and to evade death signals. In
      fact, defects in the programd cell death inducing pathways contribute to
      neoplastic transformation, progression and metastasis by creating a permissive
      environment for genetic instability and accumulation of gene mutation. Resistance
      to apoptosis can also enhance the escape to tumor cells from surveillance by the
      immune system. Moreover, because chemotherapy and irradiation act mostly by
      inducing apoptosis, dysregulation in the apoptostic pathway can make cancer cells
      resistant to therapy. This review gives an update on the key players involved in
      apoptosis as well as how pathologic alterations in each step of apoptotic
      pathways are involved in the entire progression of neoplastic transformation, how
      impaired apoptosis affects therapy and how direct targeting vs. the apoptotic
      regulators could lead to more effective treatment of cancer.

PMID- 15197337
TI  - Aggressive basal cell carcinoma: presentation, pathogenesis, and management.
AB  - Basal cell carcinoma (BCC) is the most common cutaneous skin malignancy. BCC
      generally has a clinical course characterized by slow growth, minimal soft tissue
      invasiveness, and a high cure rate. Occasionally, however, BCC behaves
      aggressively with deep invasion, recurrence, and potential regional and distant
      metastasis. Several factors, including tumor size, duration, histology, and
      perineural spread, have been postulated as markers of the aggressive BCC
      phenotype. It is undetermined whether intrinsic biological factors within certain
      subsets of BCC predispose these tumors toward an inherently aggressive behavior,
      or whether any BCC with inadequate early management may assume this phenotype.
      Review of the pertinent literature on this topic suggests that both intrinsic
      biological factors and extrinsic management factors play a role in the
      development and progression of aggressive BCC.

PMID- 15197338
TI  - Temporal coupling of spindle disassembly and cytokinesis is disrupted by deletion
      of LTE1 in budding yeast.
AB  - The mitotic exit network (MEN) is a signal transduction cascade that controls
      exit from mitosis in budding yeast by triggering the nucleolar release and hence
      activation of the Cdc14 phosphatase. Activation of the MEN is tightly coordinated
      with spindle position in such a way that Cdc14 is only fully released upon
      spindle pole body (SPB) migration into the daughter cell. This temporal
      regulation of the MEN has been proposed to rely in part on the spatial separation
      of the G-protein Tem1 at the SPB and its nucleotide exchange factor Lte1 confined
      to the daughter cell cortex. However, the dispensability of LTE1 for survival has
      raised questions regarding this model. Here using real-time microscopy we show
      that lte1Delta mutants not only delay exit from mitosis but also uncouple the
      normal coordination between spindle disassembly and contraction of the actomyosin
      ring at cell division. These mitotic defects can be suppressed by a bub2Delta
      mutation or by Cdc14 over-expression suggesting that they are caused by
      compromised MEN activity. Thus Lte1 function is important to fine-tune the timing
      of mitotic exit and to couple this event with cytokinesis in budding yeast.

PMID- 15197339
TI  - The effect of somatostatin and SSTR3 on proliferation and apoptosis of gastric
      cancer cells.
AB  - In the present study, we detected the expression of SSTR3 protein in 40 patients
      with gastric adenocarcinoma and 40 cases of normal gastric mucosa by
      immunoperoxidased staining. SSTR3 mRNA and protein were also examined in gastric
      cancer cell lines and eternal gastric epithelial cell line by RT-PCR,
      immunofluorescence and Western blot. The effect of octreotide on the growth of
      gastric cancer cells was examined by MTT test, and the apoptosis by flow
      cytometry. Competitive protein binding method was also used to evaluate the role
      of SSTR3. The results were: (1) SSTR3 protein existed in the membrane of gastric
      cancer cells. In normal gastric mucosa, SSTR3 protein distributed to the cellular
      membrane and cytoplasm or interstitial tissue in submucosa. The expression of
      SSTR3 protein was significantly lower in gastric cancer compared with normal
      mucosa. Moreover, the poor-differentiated adenocarcinoma was lower than the well
      differentiated adenocarcinoma, and the similar result in cell lines. (2)
      Octreotide could inhibit the growth and induce the apoptosis of gastric cancer
      and normal epithelial cells that expressed SSTR3, but didn't affect the cells
      with no or weakly expression of SSTR3. (3) When the cells were administrated
      octreotide in combination of SSTR3 antibody, the effect of octreotide decreased
      dramatically. The preliminary study suggested that SSTR3 might play a role in the
      growth and apoptosis of gastric cancer. In those gastric cancers that expressed
      SSTR3, octreotide could be effective in inhibiting cell growth and inducing cell
      apoptosis through mediation of SSTR3.

PMID- 15197340
TI  - Novel function of the retinoblastoma protein in fat: regulation of white versus
      brown adipocyte differentiation.
AB  - The differentiation of white and brown fat cells is controlled by a similar set
      of transcription factors, including PPARgamma and C/EBPalpha. However, despite
      many similarities between the two types of fat cells, they carry out essentially
      opposite functions in vivo, with white adipocytes being the major energy store
      and brown adipocytes being potent energy-dissipaters through thermogenesis. Yet,
      little is known about factors differentially regulating the formation of white
      and brown fat cells. Members of the retinoblastoma protein family (pRB, p107,
      p130) have been implicated in the regulation of adipocyte differentiation, and
      expression and phosphorylation of the three retinoblastoma family proteins
      oscillate in a characteristic manner during differentiation of the white
      preadipocyte cell line 3T3-L1. We have recently demonstrated a surprising
      function of the retinoblastoma protein in the regulation of white versus brown
      adipocyte differentiation in vitro and possibly in vivo. Here we summarize the
      current knowledge on the retinoblastoma protein in fat cells, with particular
      emphasis on its potential role in adipocyte lineage commitment and
      differentiation.

PMID- 15197341
TI  - Notch and epithelial-mesenchyme transition in development and tumor progression:
      another turn of the screw.
AB  - Notch is an ancient cell signaling system that regulates cell fate specification,
      stem cell maintenance and initiation of differentiation in embryonic and
      postnatal tissues.(1) Alteration of these functions in the adult have been
      associated to various types of cancer in which Notch may act as an oncogene or as
      a tumor suppressor. As occurs during development, Notch cooperates with other
      signaling pathways in the transformation process. Notch has recently been shown
      to promote epithelial-to-mesenchymal transition (EMT) during cardiac valve
      formation, via snail induction and subsequent cadherin downregulation. One
      implication of this work is that Notch acting through a similar mechanism, may
      also be involved in the EMT process that occurs during tumor progression and
      converts polarized epithelial cells into motile, invasive cells.

PMID- 15197342
TI  - Exploitation of the HIF axis for cancer therapy.
AB  - Hypoxia, a reduction in the normal level of tissue oxygen tension, occurs in most
      solid tumors in regions where tumor growth outstrips new blood vessel formation.
      Hypoxic cancer cells are resistant to both chemotherapy and radiation and are a
      major reason for the failure of cancer therapy. The cellular response to hypoxia
      is mediated through the hypoxia-inducible transcription factor-1 (HIF-1). HIF-1
      is critically important for tumor progression and angiogenesis. In fact, HIF
      1alpha is overexpressed in 70% of human cancers and their metastases. Thus,
      agents that inhibit angiogenesis and tumor growth via inhibition of HIF-1
      represent an attractive yet unexplored new modality for cancer treatment. We will
      overview inhibitors of HIF-1alpha and will discuss their potential use for cancer
      therapy.

PMID- 15197343
TI  - Aneuploidy approaching a perfect score in predicting and preventing cancer:
      highlights from a conference held in Oakland, CA in January, 2004.

PMID- 15197344
TI  - Integrin signaling and lipid rafts.
AB  - Integrin-mediated adhesion regulates the recruitment of the small GTPase Rac to
      the plasma membrane and subsequent activation of downstream signaling. We
      recently reported that Rac binds preferentially to cholesterol-rich membranes
      ("lipid rafts"), and integrins regulate Rac function by preventing the
      internalization of its binding sites within these domains. Regulation of lipid
      rafts by integrins may be important for the spatial control of cell migration and
      signaling pathways involved in anchorage-dependent cell growth.

PMID- 15197345
TI  - Gefitinib (iressa) in oncogene-addictive cancers and therapy for common cancers.
AB  - Activating mutations in the epidermal growth factor receptor (EGF-R) predict
      response to gefitinib. How does this recent discovery affect our outlook on
      selective (targeted) cancer therapy? It allows us to compare mutant EGF-R with
      Bcr-Abl as anticancer drug targets and to discuss the nature of oncogene
      addiction. It emphasizes molecular diagnostics to identify oncogene-addictive
      cancers. It also re-enforces the notion that most cancers with multiple oncogenic
      alterations (common cancers) will unlikely respond to selective drugs alone. In
      such cancers, one strategy is targeting cancer-non-specific, universal and vital
      structures, essential for life of all cells: microtubules, topoisomerases,
      histone deacetylases, the proteasome. But in order to be cancer-selective, these
      chemotherapeutic agents need to be combined with selective agents. Such
      combinations can be effective and selective in common cancers.

PMID- 15197346
TI  - Differential regulation of the protein tyrosine kinase activity following
      interleukin-2 (IL-2), interferron gamma (IFN-gamma) and SRBC administration in
      brain tumor-induced conditions: SRBC acting as a dual potentiator in regulating
      the cytokine profile.
AB  - Protein tyrosine kinases (PTKs) act as an important class of signal transducer in
      cytokine mediated signaling. Defects in phosphorylation of tyrosine residues of
      intracellular substrates of the immunocytes are a noted phenomenon in glioma
      induced immune suppression. Administration of BRMs like Interleukin2 (IL-2),
      Interferon gamma (IFN-gamma) and SRBC in glioma induced experimental models,
      improved their survival status by immune potentiation. It was shown that SRBC
      exerts the maximum anti-tumor immune boosting by augmenting the functional status
      of the two immunocytes-microglia and lymphocytes when compared with IL-2 and IFN
      gamma. The present study focuses on the differential modulation of the protein
      tyrosine kinase activity in lymphocytes and microglia following the
      administration of the 3 BRMs. Our findings indicate that PTKs actively transduce
      signals on administration of exogenous IL-2. But exogenous IFN-gamma
      administration fails to elicit the enzyme activity. With SRBC administration, a
      differential PTK activity modulation was observed in the two immunocytes. SRBC
      not only shifted the cytokine profile to Th1 subset of lymphocytes but also
      simultaneously upregulated the expression of the activation marker IL
      2Ralpha/CD25 thereby resulting in auto-activation of the hosts immunocytes.

PMID- 15197347
TI  - Fanconi anemia pathway defects in neoplasia: cause or effect?

PMID- 15197349
TI  - Interference of glucocorticoids with apoptosis signaling and host-tumor
      interactions.
AB  - The cure of cancer is compromised by a variety of factors and mechanisms, which
      include tissue origin of the malignant cells, tumor load and hypoxia, impediment
      of drug access, and cellular resistance to treatment. Treatment resistance may be
      intrinsic, acquired, or induced, and it may occur to either radiation or a single
      drug alone, or simultaneously to multiple agents. Although the problem of
      corticosteroid-induced and hence, iatrogenic resistance to the treatment of
      cancer has continuously gained some interest over the past several years, no
      measures have been taken yet to diligently examine this problem in the clinical
      situation. In this review, we address several additional mechanisms through which
      glucocorticoids may influence the result of cytotoxic therapy of cancer, like:
      inducible interference of with apoptosis signaling; interference with immune
      response against malignant cells; issues relating to their impact on glucose
      metabolism in cancer patients.

PMID- 15197348
TI  - MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non
      established) human glioma cells.
AB  - We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and
      ionizing radiation on the proliferation and survival of nonestablished human
      glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN
      and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without
      receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose
      dependent reduction in the proliferation of nonestablished glioma cells; however
      only at higher concentrations did GST-MDA-7 reduce cell viability. The anti
      proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a
      greater than additive fashion that correlated with JNK1/2/3 activation. The
      reduction in cell growth and enhancement in cell killing by the combination of
      GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine
      (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an
      inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low
      concentrations of either GST-MDA-7 or radiation reduced clonogenic survival,
      however colony formation ability was significantly further decreased when the two
      treatments were combined, which was also blocked by inhibition of caspase 9
      function. In general agreement with activation of the intrinsic caspase pathway,
      cell death correlated with reduced BCL-XL expression and with increased levels of
      the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination
      treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD
      and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and
      inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3
      activation and cell killing, but not the increases in BAD and BAX expression.
      These findings argue that after combination treatment JNK1/2/3 activation is a
      primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are
      secondary caspase-dependent processes. This data also argues that GST- MDA-7
      induces two parallel pro-apoptotic pathways via ROS-dependent and -independent
      mechanisms. Infection of primary human astrocytes with a recombinant adenovirus
      to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP-
      lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation
      in soft agar overlay assays, an effect that was enhanced in a greater than
      additive fashion by radiation. Collectively, our findings demonstrate that MDA-7
      reduces proliferation and enhances the radiosensitivity of nonestablished human
      GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs
      independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.

PMID- 15197350
TI  - Multiple effects of N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK) on
      apoptotic pathways in human prostatic carcinoma cell lines.
AB  - TPCK is widely used as an inhibitor of chymotrypsin-like proteases but has
      recently been identified as an inhibitor of the PDK1/Akt pathway. In this study,
      we show that TPCK inhibits TRAIL-induced caspase activity but potentiates
      wortmannin-dependent caspase activity in prostatic carcinoma cell lines. The
      inhibitory activity of TPCK was found to be death ligand-specific since TPCK
      inhibits TRAIL-mediated caspase activity but does not affect Fas-induced caspase
      activity. Our data also show that impaired TRAIL-DISC formation in the presence
      of TPCK is responsible for caspase inhibition. Further, TPCK induces p53
      expression and inhibits the PDK1/Akt pathway resulting in BAD dephosphorylation,
      and the release of cytochrome c and Smac/DIABLO from mitochondria. TPCK also
      selectively decreases the levels of androgen receptor and caspase-2 whereas it
      does not change the levels of other proteins (caspases-3, -7, -8, -9; heat shock
      proteins 27, 70, 90). Finally, TPCK-induced degradation of caspase-2 is protected
      by Bcl-2 overexpression, apparently by an adapter protein since direct
      interaction between caspase-2 and Bcl-2 was not detected. Together, these
      features suggest that TPCK could be used as a therapeutic agent for treatment of
      those tumor cells that are resistant to ligand-induced treatment because of
      aberrant signaling pathways downstream of the DISC.

PMID- 15197351
TI  - Direct effects of recombinant human endostatin on tumor cell IL-8 production are
      associated with increased endothelial cell apoptosis in an orthotopic model of
      human pancreatic cancer.
AB  - PURPOSE: Recombinant human endostatin (rhES) is an antiangiogenic agent derived
      from collagen XVIII which inhibits tumor growth in subcutaneous models of various
      human malignancies. However, its effectiveness in an orthotopic xenograft model
      of an abdominal neoplasm has not been demonstrated. DESIGN: An orthotopic model
      of pancreatic cancer was established in 6-week-old male athymic mice from either
      of 2 human cell lines (L3.6pl or BxPC3). Established tumors were treated with 40
      mg/kg rhES or vehicle controls for up to 3 weeks. Tumors were analyzed by
      immunohistochemistry for TUNEL/CD31, IL-8, VEGF, and bFGF. We also measured
      direct effects of rhES on tumor cell angiogenic factor production by ELISA in
      vitro. RESULTS: Overall tumor burden was not reduced with rhES treatment in mice
      inoculated with either cell line. Peritoneal carcinomatosis in the L3.6pl mice
      was greater in those treated with rhES than in those treated with normal saline
      or citrate buffer (p < 0.05). Treatment with rhES lowered IL-8 levels 32-47% in
      vivo (p < 0.001) and 40-65% in vitro (p < 0.05) in the fast-growing L3.6pl tumors
      but not in the slow-growing BxPC3 tumors (p < 0.05). rhES also increased the
      levels of endothelial cell apoptosis 16- to 24-fold in vivo in the L3.6pl mice,
      but not in the BxPC3 mice (p < 0.05). CONCLUSIONS: rhES downregulated IL-8 levels
      and induced endothelial cell apoptosis in the more aggressive cell line in a
      xenograft model of pancreatic cancer. Nonetheless, these effects were not
      sufficient to produce significant inhibition of tumor growth.

PMID- 15197352
TI  - Microbial-based therapy of cancer: a new twist to age old practice.
AB  - The use of bacteria in the regression of tumors has long been known. Various
      approaches for using bacteria in cancer therapy include the use of bacteria as
      sensitizing agents for chemotherapy, as delivery agents for cancer drugs and as
      agents for gene therapy. The tumor regression stimulated by infecting
      microorganisms has been attributed to activation of the immune system of the
      host. However, recent studies indicate that when tumor-harboring mice with
      defective immune systems are infected with certain microorganisms, the regression
      of the tumor is still observed, suggesting that there are other host factors
      contributing to the microbial associated regression of tumors. Since the use of
      live or attenuated bacteria for tumor regression has associated toxic effects,
      studies are in progress to identify a pure microbial metabolite or any component
      of the microbial cell that might have anti-cancer activity. It has now been
      demonstrated that a redox protein from Pseudomonas aeruginosa, a cupredoxin, can
      enter into human cancer cells and trigger the apoptotic cell death. In vivo, this
      cupredoxin can lead to the regression of tumor growth in immunodeficient mice
      harboring xenografted melanomas and breast cancer tumors without inducing
      significant toxic effects, suggesting that it has potential anti-cancer activity.
      This bacterial protein interacts with p53 and modulates mammalian cellular
      activity. Hence, it could potentially be used as an anti-cancer agent for solid
      tumors and has translational value in tumor-targeted or in combinational
      biochemotherapy strategies for cancer treatments. Here, we focus on diverse
      approaches to cancer biotherapy, including bacteriolytic and bacterially-derived
      anti-cancer agents with an emphasis on their mechanism of action and therapeutic
      potential.

PMID- 15197353
TI  - Overview of history and progress in BRCA1 research: the first BRCA1 decade.
AB  - The BRCA1 protein presents a paradox to the scientists investigating its link to
      cancer. BRCA1 provides a function essential to all cell types, but its mutation
      is only associated with a subset of cancers including breast and ovarian cancers.
      The priorities of BRCA1 research are the identification of the function of BRCA1,
      which is required in all cells, and of the function specific to breast and
      ovarian cells that causes their cancerous transformation. BRCA1 has been shown to
      be required for multiple processes including transcription, chromatin remodeling,
      DNA damage repair, and the regulation of centrosome duplication. How BRCA1
      regulates these processes is unclear: is the BRCA1 protein a direct participant
      in the biochemistry of each process, or is the BRCA1 protein regulating the gene
      expression of proteins that directly regulate all of these processes? The
      ubiquity of BRCA1 in multiple cellular processes is difficult to square with the
      specificity of tumors with which it is associated.

PMID- 15197354
TI  - Suppression of tumorigenesis and activation of Wnt signaling by bone
      morphogenetic protein 4 in human cancer cells.
AB  - Aberrations in BMP signaling have recently been implicated as a cause of human
      cancer. Here we demonstrate and define the tumor suppressive properties of BMP4.
      Consistent with its potential role in a tumor suppressor pathway, BMP4 treatment
      eliminated the tumorigenic potential of an undifferentiated human cancer cell
      line. This loss of tumorigenicity was accompanied by an increase in apoptosis,
      alterations in cell cycle profile, and an increase in cell size. Interestingly,
      human colon cancer cells were resistant to the growth-suppressive properties of
      BMP4. To identify putative downstream mediators of BMP4-mediated tumor
      suppression, Affymetrix Genechips were employed to identify BMP4-regulated genes.
      The human BMP4 transcriptome was characterized by the modulation of many genes
      well known to play important roles in differentiation and development, including
      the induction of numerous genes involved in Wnt signaling. Modulation of Wnt gene
      expression by BMP4 had several functional consequences--BMP4 treatment led to
      activation of TCF reporters; complete activation of at least one BMP4-responsive
      gene required TCF sites; and treatment with a Wnt ligand was sufficient to mimic
      several of the phenotypic effects of BMP4 treatment. These data demonstrate the
      tumor suppressive properties of BMP4 signaling, show that colon cancer cells are
      resistant to BMP4-induced differentiation and growth suppression, further define
      the BMP4 transcriptome, and raise the intriguing possibility that interactions
      between the Wnt and BMP signaling pathways may play an important role in
      differentiation and tumor suppression.

PMID- 15197355
TI  - Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1
      blockade.
AB  - Despite reservations regarding potential toxicities, small molecule-mediated
      blockade of the hypoxia-inducible factor-1 transcription factor has emerged as a
      viable anti-cancer strategy in vivo. Recent experiments by Welsh et al. revealed
      unprecedented anti-tumor responses of various aggressive solid tumors to the HIF
      1-inhibitory small molecule drug PX-478. Compared with other anti-cancer drugs,
      PX-478 had markedly improved regression, growth delay and log10 cell kill
      profiles, particularly against large tumors that are normally refractory to small
      molecule drug therapy. Importantly, pharmacokinetic and toxicity profiles were
      within acceptable limits, providing rationale for the clinical development of HIF
      1 inhibitors in general. Though the mechanism of action for PX-478 is not
      completely understood, inhibition of glycolysis rather than angiogenesis appeared
      to be the primary mode of anti-cancer activity.

PMID- 15197356
TI  - Morbidity in immunosuppressed (SCID/NOD) mice treated with reovirus (dearing 3)
      as an anti-cancer biotherapeutic.
AB  - Specific viral oncolysis of cancer cells has aroused great interest as a
      potential anti-cancer therapy. Reovirus was proposed as an anti-cancer
      biotherapeutic several years ago, as it elicits virus-mediated death of human
      cancer cells both in vitro and in mouse model systems. A common model system for
      reovirus oncolysis is the NOD/ LtSz-scid/scid (SCID/NOD) immunocomprimised mouse.
      While human tumour xenografts are effectively killed by intra-tumour injections
      of reovirus, the mice often exhibit discoloration and necrosis of extremities
      including feet, distal leg, tail and ears several weeks after injection. This
      phenomenon never occurs in sham-injected mice, nor is it observed in wild type or
      nude mice. The pathogenesis of this "Black Foot" lesion has not yet been
      described, but may be of relevance for future human studies of biotherapeutics.
      Examination of SCID/NOD mice was performed at various time points following
      intratumoral injection of reovirus. Immunohistological evaluation of tissues
      reveals infection of cardiac myocytes and venous endothelial cells at
      approximately 2 days post infection. Over time, venules and veins showed a mixed
      inflammatory vasculitis and thrombus formation. Synchronously, the heart showed
      diffuse myocyte death, with dystrophic calcification. The results indicate that
      the "Black Foot" syndrome is likely due to venous vasculitis secondary to
      reovirus infection, on a background of reovirus myocarditis and heart failure.
      The rationale for the selective susceptibility of venous over arterial
      endothelium to reovirus infection is currently unknown. The results of this study
      may be relevant to the use of oncolytic viruses, particularly reovirus, in the
      anti-cancer therapy of immunosuppressed patients.

PMID- 15197357
TI  - Pharmacogenomics on gastric cancer.
AB  - Gastric cancer is one of most common malignancies in the world. 5-fluoroyracil,
      CPT-11, TS-1, Paclitaxel and Docetaxel are used as chemotherapeutic agents for
      advanced gastric cancer, although endoscopic mucosal resection and surgical
      gastrectomy are potentially curative treatments. Most important problems
      associated chemotherapeutic agents are side effects and drug resistances. TSG101,
      implicated in membrane trafficking and transcriptional regulation, is upregulated
      in gastric cancer with multidrug resistant phenotype. Shen et al reported that
      transient transfection of TSG101 siRNA reduced the expression level of TSG101
      protein as well as resistance to vincristine and adriamycin in gastric cancer
      cells. Bioinformatics, microarray analyses, SNP typing, and high-throughput
      functional analyses are applied for pharmacogenomics in the post-genome era.
      Therapeutics based on the genotyping of each patient is the future goal of
      personalized medicine (or tailor-made medicine) for gastric cancer.

PMID- 15197359
TI  - Improving the health of communities: the position of nursing.

PMID- 15197360
TI  - Effects of end-of-life discussions on patients' affective outcomes.

PMID- 15197361
TI  - Sleep and chronobiology: recommendations for nursing education.

PMID- 15197362
TI  - Advancing the Magnet Recognition Program in master's education through service
      learning.

PMID- 15197363
TI  - Use of mapping technology in health intervention research.

PMID- 15197364
TI  - Dispelling desperation in nursing education.

PMID- 15197365
TI  - From Nightingale to the new millennium: charting the research and policy agenda
      for the nursing workforce.

PMID- 15197367
TI  - Nursing leadership: new initiatives in case management.

PMID- 15197369
TI  - Editorial in the October issue.

PMID- 15197370
TI  - "Research guiding practices related to cultural issues at end of life".

PMID- 15197371
TI  - "Meaning of bereavement among older African American widows".

PMID- 15197372
TI  - Caring for patients with dementia in an acute care environment.
AB  - Although hospital nurses are skilled in meeting the acute health needs of the
      elderly, they may not have the expertise required to manage the behavioral
      disturbances typically seen in this population. Using the Progressively Lowered
      Stress Threshold Model (PLST), this article helps identify factors that may
      precipitate undesirable behaviors in the acute care setting and suggests
      strategies to help nurses prevent or control them.

PMID- 15197373
TI  - The perceived health of rural caregivers.
AB  - Caregiving can be stressful in any setting; however, some challenges and
      differences are unique to the rural population of caregivers. Gene and Lena
      Tanner The rural elderly report more chronic illness and physical impairment than
      their urban counterparts. This study examines the differences between self
      reported health status in rural caregivers and the general population. The
      participants were 63 caregivers from rural southwest Alabama and southeast
      Mississippi. A statistically significant greater number of caregivers considered
      themselves to be in poor and fair health than in the general population.

PMID- 15197374
TI  - Assisted living: aging in place and palliative care.
AB  - Principles of upstream palliative care can guide the planning, programs, and
      services associated with aging in place in assisted living residences (ALRs).
      Frail older adults who do not need a nursing home level of care are choosing to
      live-and die-in ALRs. This article describes the context of assisted living,
      resident characteristics, key indicators of palliative care, barriers to end-of
      life care, and the role, responsibilities, and potential for professional nursing
      in assisted living. Stakeholder concerns about staff knowledge and skills in care
      of the elderly, medication management, the risks associated with residential
      care, and nursing delegation are discussed.

PMID- 15197375
TI  - Is somatization a significant depressive symptom in older Taiwanese Americans?
AB  - Adapting to psychosocial and physical changes can trigger nonspecific somatic
      complaints and depression. Somatization has been noted in all societies and
      cultures; however, it is more frequently observed in Asian populations. This
      study used the Geriatric Depression Scale (GDS) to screen 100 Taiwanese American
      older adults for depressive symptoms and found that seven participants (7%)
      experienced depressive symptoms (GDS >/= 14). Although the mean number of
      illnesses reported was significantly higher (t = -16.8, P <.001) in the
      depressive group, the seven individuals did not focus on physical symptoms during
      interview. They reported guilt, sadness, anger, resentment, loneliness,
      helplessness, hopelessness, inability to enjoy activities, and anhedonia. If
      older adults are given the time to express themselves, they are able to reveal
      their emotional pain and distress rather than remain preoccupied with somatic
      complaints. A simple depression screening tool, such as the GDS, can help detect
      depression.

PMID- 15197376
TI  - Nurses' observations and experiences of problems and adverse effects of
      medication management in home care.
AB  - The purpose of this nonexperimental, descriptive study was to explore and
      describe the current state of medication management for patients receiving
      services from certified home health care agencies (CHHAs). Data were collected by
      self-report from a convenience sample of 101 home health care nurses from 12
      agencies in six states. Nurses reported on a total of 1467 patients. Results of
      this study support the findings from previous research on medication management
      of older people living in the community. The majority of older home care patients
      were taking more than five prescription drugs. Many patients were taking
      medications in ways that deviated from the prescribed medication regimen. The
      results also suggest that patients are experiencing many adverse effects from
      medication errors. The reasons for these errors were reported to be a result of
      individual patient characteristics and, most frequently, communication problems
      in the system. Results of this study support recommendations for technology
      application, regulatory and policy changes, further research, and nursing
      practice.

PMID- 15197377
TI  - Nurse educators are key to a best practices implementation program.
AB  - In a statewide Best Practices Project, the involvement of nurse educators in the
      implementation process improved the overall success of participating long-term
      care facilities in improving the quality of resident care. Two nurse educators
      provided consultation and training to nursing facility staff on three best
      practice protocols: prevention of decline in the activities of daily living of
      eating and dressing, pain, and depression. Facility staff were given protocols to
      follow, together with documentation forms to assist in determining resident
      appropriateness for participation in the assigned best practice, assessing
      resident involvement in the protocol over time, and tracking staff progress with
      the implementation. The success of the 2-year first phase of the project in
      significantly improving measurable resident quality of care in best practice
      protocol areas has resulted in a second phase involving additional facilities and
      protocols.

PMID- 15197378
TI  - Motion device: an alternative to physical restraints.

PMID- 15197379
TI  - Pros and cons of using paid feeding assistants in nursing homes.
AB  - Recently the Centers for Medicare and Medicaid Services (CMS), citing increasing
      resident acuity, staffing shortages, and high turnover rates that make it
      difficult for nursing homes to provide adequate feeding assistance to residents
      who need minimal help at mealtimes, began allowing nursing facilities to use
      single-task workers to provide assistance during mealtimes. This article
      describes the use of single-task workers to provide feeding assistance to
      nutritionally at-risk residents during a 6-month clinical study designed to
      evaluate the effectiveness and feasibility of implementing a buffet-dining
      program in an academic long-term care facility.

PMID- 15197381
TI  - Community food assistance improves older adults' nutrition.

PMID- 15197382
TI  - Research review: prevention of hip fractures by external hip protectors: a
      randomized controlled trial.

PMID- 15197383
TI  - Pharmacology tips: medications that complicate asthma control in older people.

PMID- 15197384
TI  - Gerontologic nurse practitioner care guidelines: urinary tract infection.

PMID- 15197385
TI  - Effective diabetes management: the cost and quality equation.

PMID- 15197386
TI  - Guiding older adults through the maze of medicare prescription drug benefits.

PMID- 15197388
TI  - Malignant pleural mesothelioma.

PMID- 15197389
TI  - Origins of variation in the fungal cell surface.

PMID- 15197390
TI  - Cellulosomes: plant-cell-wall-degrading enzyme complexes.

PMID- 15197391
TI  - Developing animal models for polymicrobial diseases.

PMID- 15197392
TI  - Microbial perchlorate reduction: rocket-fueled metabolism.

PMID- 15197393
TI  - Regulatory circuits and communication in Gram-negative bacteria.

PMID- 15197394
TI  - Nitrate, bacteria and human health.

PMID- 15197395
TI  - Rapid response research to emerging infectious diseases: lessons from SARS.

PMID- 15197396
TI  - Molecular genetics of autism spectrum disorder.
AB  - We are on the brink of exciting discoveries into the molecular genetic
      underpinnings of autism spectrum disorder. Overwhelming evidence of genetic
      involvement coupled with increased societal attention to the disorder has drawn
      in more researchers and more research funding. Autism is a strongly genetic yet
      strikingly complex disorder, in which evidence from different cases supports
      chromosomal disorders, rare single gene mutations, and multiplicative effects of
      common gene variants. With more and more interesting yet sometimes divergent
      findings emerging every year, it is tempting to view these initial molecular
      studies as so much noise, but the data have also started to coalesce in certain
      areas. In particular, recent studies in families with autism spectrum disorder
      have identified uncommon occurrences of a novel genetic syndrome caused by
      disruptions of the NLGN4 gene on chromosome Xp22. Previous work had identified
      another uncommon syndrome that is caused by maternal duplications of the
      chromosome 15q11-13 region. We highlight other converging findings, point toward
      those areas most likely to yield results, and emphasize the contributions of
      multiple approaches to identifying the genes of interest.

PMID- 15197397
TI  - No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the
      Irish study of high-density schizophrenia families (ISHDSF).
AB  - The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a
      schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK
      populations. The shared ancestry between these populations led us to investigate
      the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or
      association to schizophrenia in the Irish study of high-density schizophrenia
      families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1
      markers gave evidence for linkage independent of our pre-existing findings
      telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb
      interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype
      revealed two separate regions of modest LD, comprising markers SNP8NRG255133,
      SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9
      1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by
      TRANSMIT and FBAT we found no evidence for association with schizophrenia for any
      marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the
      four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows),
      showed no evidence for overtransmission of specific haplotypes to affected
      individuals. We therefore conclude that if NRG1 does contain susceptibility
      alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.

PMID- 15197398
TI  - Analysis of the novel TPH2 gene in bipolar disorder and suicidality.

PMID- 15197399
TI  - GABRA6 gene polymorphism and an attenuated stress response.
AB  - The glucocorticoid component of the stress response has been the subject of
      intense scientific scrutiny because of the wide ranging pathological consequences
      resulting from excess glucocorticoid exposure, including mood and anxiety
      disorders, and cognitive impairment. Exposure to stress activates the
      hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic adrenomedullary
      system, which are regulated by neuronal pathways, including the inhibitory
      GABAergic (gamma-aminobutyric acid) system. Approximately 60% of the variance in
      glucocorticod levels may be attributable to genetic individual differences. In
      the present study, 56 healthy subjects underwent genotyping to determine the
      influence of the T1521C single nucleotide polymorphism (SNP) in the GABA(A)alpha6
      receptor subunit gene (GABRA6) on the hormonal and autonomic responses to
      psychological stress induced by the Trier Social Stress Test (TSST).
      Adrenocorticotropin (ACTH), cortisol, diastolic blood pressure, and mean blood
      pressure responses to the TSST were significantly greater in subjects homozygous
      for the T allele or heterozygous compared to subjects homozygous for the C
      allele. Behavioral data was collected employing the Revised NEO Personality
      Inventory (NEO PI-R); subjects homozygous for the C allele scored significantly
      lower on the Extraversion factor compared to subjects homozygous for the T allele
      or heterozygous. These results suggest that the T1521C polymorphism in the GABRA6
      gene is associated with specific personality characteristics as well as a marked
      attenuation in hormonal and blood pressure responses to psychological stress.

PMID- 15197400
TI  - Replication of 1q42 linkage in Finnish schizophrenia pedigrees.
AB  - Chromosome 1q has been implicated in the etiology of schizophrenia in several
      independent studies. However, the peak linkage findings have been dispersed over
      a large chromosomal region, with negative findings in this region also being
      reported. Our group has previously observed linkage on chromosome 1q42,
      maximizing within the DISC1 gene, which has also been implied in the etiology of
      schizophrenia based on functional studies. In the study presented here, we
      genotyped 300 polymorphic markers on chromosome 1 using a study sample of 70
      families with multiple individuals affected with schizophrenia or related
      conditions, independent of the study samples in our previous reports. We again
      found evidence for linkage on 1q42 maximizing within the DISC1 gene (rs1000731,
      lod=2.70). Further, a haplotype containing the most strongly linked markers
      showed some evidence of association with the disease. This replicates the
      previous linkage finding in the same region and constitutes supportive evidence
      for a susceptibility gene in this region.

PMID- 15197401
TI  - Case report: mantle cell lymphoma, prolymphocytoid variant, with leukostasis
      syndrome.
AB  - A 76-year-old man presented with leukostasis syndrome, including oculodynia,
      blurred vision, and visual field defects, due to mantle cell lymphoma,
      prolymphocytoid variant, with marked leukocytosis, 1227 x 10(9)/l. He had
      splenomegaly but no lymphadenopathy or hepatomegaly. The tumor cells were CD5+,
      CD19+, CD20+, FMC-7+, and kappa light chain restricted. Immunohistochemistry
      showed expression of p53 and of cyclin D1. Fluorescent in situ hybridization
      demonstrated t(11;14) with translocation between CYCLIN D1 and the immunoglobulin
      heavy-chain genes. The patient received leukapheresis and aggressive
      chemotherapy, but the leukocyte count remained above 100 x 10(9)/l. The patient's
      condition rapidly deteriorated with lymphomatous infiltration of his lungs and
      soft tissues, and he expired 6 months after diagnosis. While it is known that
      mantle cell lymphoma may have a leukemic phase, the degree of leukocytosis in
      this case exceeds that previously reported in the literature and resulted in a
      clinical syndrome of leukostasis.

PMID- 15197407
TI  - Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of
      bleomycin-induced pulmonary fibrosis in mice.
AB  - Lung fibrosis is a common feature of interstitial lung diseases, and apoptosis
      and fibrinogenesis play critical roles in its formation and progression.
      Hepatocyte growth factor (HGF) is one of the ideal therapeutic agents for
      prevention of lung fibrosis because of its antiapoptotic and fibrinolytic
      effects. The aim of this study is to establish nonviral HGF gene therapy of
      bleomycin-induced lung fibrosis avoiding the viral vector-related side effects.
      C57BL/6 mice were injected with 3.0 mg/kg body weight of bleomycin
      intratracheally. Following bleomycin injection, 50 microl of pUC-HGF (1 mg/ml)
      was injected into each of the quadriceps muscle. Immediately after plasmid
      injection, in vivo electroporation was performed with pulse generator. Skeletal
      muscle-targeting electroporation induced transgene expression on day 1 and
      persisted for 4 weeks, and human HGF was also detected in the lung. In mice
      transferred with HGF, pathological score (1.0+/-0.3 vs 3.2+/-0.6), TUNEL-positive
      cell index (4.5+/-1.1 vs 14.2+/-3.1), and hydroxyproline content (9.0+/-1.3 vs
      14.4+/-5.1 micromol/g) were significantly reduced compared with the control.
      Furthermore, survival rate of HGF mice was significantly improved compared with
      the control. Our data indicate that HGF gene therapy with a single skeletal
      muscle-targeting electroporation has a therapeutic potential for bleomycin
      induced lung fibrosis and this strategy can be applied as a practical gene
      therapy protocol for various organs.

PMID- 15197408
TI  - Measures of abdominal obesity assessed for visceral adiposity and relation to
      coronary risk.
AB  - AIMS: We aimed to identify by computed tomography (CT) the best suited of three
      anthropometric indices that reflect the visceral adipose tissue (VAT), and to
      discern the relationship between VAT and certain atherogenic risk factors and
      coronary heart disease (CHD) diagnosis in a population sample which had a high
      (34%) prevalence of the metabolic syndrome (MS). METHODS: A single-scan CT was
      performed between the fourth and fifth lumbar vertebrae in 157 unselected men and
      women aged 34-69 y. Total adipose tissue area, abdominal VAT area and the
      abdominal sagittal diameter were determined. Diagnosis of CHD was based on
      clinical findings and Minnesota coding of resting electrocardiograms. RESULTS:
      Men had significantly higher VAT than women. Linear regression analysis for
      correlates of abdominal VAT area, in a model comprising age, sex, waist
      circumference, waist-to-hip ratio (WHR) and body mass index (BMI) identified
      waist circumference as the only independent variable (P<0.001). Waist
      circumference in men and BMI in women were the independently associated
      parameters of sagittal diameter (P<0.001). By stepwise linear regression, it was
      elicited that VAT area rose significantly by a mean of 6.8 cm2 in men and 3 cm2
      in women for every 1 cm increment in waist circumference, independent of WHR. Age
      in women and (inversely) BMI in men were further independent variables,
      indicating in men that a lower BMI at a given waist girth suggests the existence
      of a higher VAT. Apo B and HDL-cholesterol (HDL-C) in men, and the latter in
      women were independently associated with VAT area in linear regression models
      that also comprised triglycerides, fasting insulin and C-reactive protein
      concentrations. In the study sample comprising 13 individuals with a CHD
      diagnosis, the age-adjusted odds ratio of cutpoints of VAT area > vs <140 cm2 in
      men and > vs <120 cm2 in women was 11.3 (95% CI (1.37, 93)). CONCLUSIONS: The
      best surrogate of visceral adiposity across a wide age range is waist
      circumference, in a population in which MS prevails. Apo B and HDL-C in men, and
      the latter in women were independently associated with VAT area, which proved to
      be closely related to CHD risk. A lower BMI at a given waist girth in men
      suggests the existence of a higher VAT.

PMID- 15197409
TI  - Effects of PYY[3-36] in rodent models of diabetes and obesity.
AB  - BACKGROUND: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L
      cells following meals. The cleaved subpeptide PYY[3-36] is biologically active
      and may constitute the majority of circulating PYY-like immunoreactivity. The
      peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted
      for its orexigenic effect following intracerebroventricular administration.
      OBJECTIVE: To investigate the effects of peripheral (intraperitoneal and chronic
      subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic
      indices. DESIGN/RESULTS: Food intake was measured in normal mice and in several
      rodent models of obesity and type II diabetes. In marked contrast to the reported
      central orexigenic effects, in the present study, PYY[3-36] acutely inhibited
      food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female
      NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice,
      without affecting the cumulative food intake. In diet-induced obese male mice,
      PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat
      weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201
      microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c.
      Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight
      gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to
      effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute
      effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty
      Zucker rats, PYY[3-36] infused for 4 weeks reduced HbA1c and fructosamine
      (ED(50)'s 30 and 44 microg/kg/day). CONCLUSION: Peripheral PYY[3-36]
      administration reduced the food intake, body weight gain and glycemic indices in
      diverse rodent models of metabolic disease of both sexes. These findings justify
      further exploration of the potential physiologic and therapeutic roles of PYY[3
      36].

PMID- 15197410
TI  - Tobacco smoking in relation to body fat mass and distribution in a general
      population sample.
AB  - OBJECTIVE: To investigate the effects of variable amounts of tobacco smoking on
      body mass index and waist-to-hip ratio among current smokers. DESIGN: Population
      based cohort study. SUBJECTS: A total of 22 059 apparently healthy men and women,
      who enrolled in the Greek EPIC cohort, aged 25-84 years, who had never smoked (14
      751) or were current cigarette smokers (7308). MEASUREMENTS: Body mass index and
      waist-to-hip ratio (by anthropomentry), amount of tobacco smoking and energy
      expenditure (by an interviewer-administered, lifestyle questionnaire), energy
      intake and ethanol intake (by an interviewer-administered, validated,
      semiquantitative, food frequency questionnaire), at enrollment. RESULTS: In
      comparison to nonsmokers, smokers of the average number of cigarettes have lower
      body mass index. Among smokers, however, increased amount of smoking tends to be
      positively associated with body mass index, particularly among men. Waist-to-hip
      ratio is positively associated with amount of cigarettes smoked per day, among
      both men and women. CONCLUSION: Among smokers, tobacco smoking is positively
      associated with body mass index and waist-to-hip ratio. Our data suggest that the
      lower body mass index of smokers compared to nonsmokers reflects personality
      characteristics of those who choose to smoke and that the tendency to gain weight
      after smoking cessation may have behavioral rather than tobacco-related
      pharmacological roots.

PMID- 15197411
TI  - Metabolic syndrome and ALT: a community study in adult Koreans.
AB  - OBJECTIVE: To investigate an association between the metabolic syndrome (MS) and
      alanine aminotransferase (ALT) of normal ranges. DESIGN: A population-based cross
      sectional survey in three rural communities, South Korea. SUBJECTS: A total of
      1248 men and 2157 women aged 30 y and older. MEASUREMENTS: Body mass index (BMI),
      waist circumference, fasting blood lipid and glucose, resting blood pressure, and
      ALT. RESULTS: ALT and BMI increased with an addition of the MS components. A
      consistent association between ALT more than 15 IU/l and the MS was found in both
      sexes, independently of age, education, BMI, smoking, alcohol drinking, and
      sedentary life style. The odds ratios for the MS in the highest quintiles of ALT
      were 7.1-fold higher than the reference quintile in men and 2.1-fold higher in
      women. The likelihood ratio tests for trend were also significant with ALT
      increments (P<0.001 for trend). CONCLUSION: The MS is significantly associated
      with the higher quintiles of normal ALT in both genders. ALT could be a sensitive
      marker of hepatic dysfunction associated with the MS, even in the range below the
      current limit.

PMID- 15197412
TI  - Effect of obesity on asthma among adult Indian women.
AB  - OBJECTIVE: Both obesity and asthma are on the rise worldwide. This study examined
      the association between obesity and asthma prevalence in adult women in India.
      METHODS: The analysis used information on 82 464 nonpregnant, ever-married women
      aged 15-49 y, included in India's 1998-99 National Family Health Survey. The
      effects of measured Body Mass Index (BMI) on reported asthma were estimated using
      logistic regression, after adjusting for tobacco smoking (active and passive),
      cooking smoke, age, education, work status, media habits, food habits, house
      type, separate kitchen, indoor crowding, religion, caste/tribe, household living
      standard, urban/rural residence, and geographic region. RESULTS: Obese women
      (BMI>/=30.0 kg/m(2)) were about twice as likely as those with a normal BMI (18.5
      25.0 kg/m(2)) to report suffering from asthma (OR=1.92; 95% CI: 1.40-2.65). The
      association between obesity and asthma remained strong and statistically
      significant even when the effects of other selected risk factors and potential
      confounders were controlled (OR=1.85; 95% CI: 1.30-2.63). Overweight women
      (25.0</=BMI<30.0 kg/m(2)) also reported significantly higher adjusted asthma
      prevalence than those with a normal BMI (OR=1.32; 95% CI: 1.07-1.63). Results
      hold in separate analysis for younger (15-29 y) and older (30-49 y) women.
      CONCLUSION: The study finds a strong positive association between obesity and
      asthma among adult Indian women. To validate this relationship and to establish
      causality, prospective epidemiological studies, with better measures of
      overweight conditions and clinical measures of asthma, are needed in developing
      country settings.

PMID- 15197413
TI  - The case for specialist units.
AB  - There is considerable evidence that management in a specialist unit is beneficial
      both for the individual patient and for the economy. A specialised unit provides
      a focus for a campaign for prevention, for the improvement in care in areas such
      as orthopaedic, bladder, bowel, skin, etc and for the promotion of
      interdisciplinary work, combining the needs of public health, low-cost
      technology, and high quality. Strategy and training is dictated by the specific
      problems that occur in patients with spinal injuries, particularly the
      multisystem impairment, which is a feature of such injuries and can only be
      comprehensively dealt with in a specialised unit. For developing countries,
      training may be either on-site or in centres abroad, or a combination of both,
      and rather than training on an individual basis, it is preferable for a team to
      be trained together. The likely cost depends on local circumstances. However,
      even the cost of a purpose-built centre of 44 beds serving 3000 paralysed people
      in the UK is only the equivalent of the lifetime costs of about 12 people with
      SCI.

PMID- 15197414
TI  - Pain disorder, hysteria or somatization?

PMID- 15197415
TI  - Parental judgements of infant pain: importance of perceived cognitive abilities,
      behavioural cues and contextual cues.
AB  - BACKGROUND: Despite blatant indications, such as behavioural and contextual cues,
      infant pain is often undermanaged by adult caretakers. The belief that infants
      are limited in their abilities to comprehend the meaning of an experience or
      recall that experience has been used to minimize or deny the need for
      intervention in this vulnerable population. OBJECTIVES: This investigation
      explored parental beliefs regarding the impact of infant cognitive capabilities,
      behavioural cues and contextual cues to their pain judgments. Particular interest
      was focused on their beliefs regarding the general cognitive capabilities of
      infants of different ages. METHODS: Forty-nine parents viewed videotapes of
      healthy infants, aged two, four, six, 12 and 18 months, receiving routine
      immunization injections and provided judgements of the severity of pain on a 100
      mm Visual Analogue Scale. Upon completion of their pain judgements for each of
      the five age groups (two infants per age group; 10 infants total), parents
      completed questionnaires regarding their beliefs about the capabilities of
      infants in that age group and then reported the importance of the various cues
      utilized to formulate their pain judgements. RESULTS: Parents attributed
      substantial pain to infants in all age groups, almost twice the amount they
      hypothesized an adult undergoing a similar injection would experience. The cues
      rated as most important for judgements were similar for infants of varying ages.
      Overall, facial expressions, sounds and body movements were consistently reported
      to be most important. Parents acknowledged the development of memory and
      understanding of pain throughout infancy. However, these beliefs were not deemed
      by parents as important to their pain ratings, nor were their importance ratings
      directly related to the pain ratings. CONCLUSION: Parents judged that infants
      undergoing a routine immunization were experiencing clinically significant levels
      of pain. However, despite generally acknowledging a developing trajectory for
      memory and understanding across the five age groups, parents did not indicate
      that a child's ability to remember and understand pain were essential features of
      their pain judgements. The results indicated that memory and understanding did
      not influence parental judgements of infant pain demonstrating the validity of
      the parents' self-assessments.

PMID- 15197416
TI  - Do patients with chronic noncancer pain accept treatment of questionable benefit
      more readily than those who are pain free?
AB  - BACKGROUND: The efficacy of some common, questionable chronic pain interventions
      has been debated and it is unclear why sufferers of chronic noncancer pain agree
      to receive them. This study attempts to determine if chronic pain sufferers
      characteristically more readily accept treatment with questionable benefit.
      OBJECTIVES: This study aims to compare the strength of acceptance or rejection of
      a hypothetical, mock chronic pain treatment of debatable value by two groups of
      patients: those reporting chronic noncancer pain and those who are "pain free".
      METHODS: A questionnaire proposing a hypothetical treatment for chronic pain was
      distributed to two groups: Group 1 (n=160), patients attending a chronic pain
      centre, and Group 2 (n=240), patients attending a family practice centre.
      Patients were asked to score their "treatment acceptance" using a modified Likert
      scale. The treatment was based on the risks and benefits of epidural steroids.
      RESULTS: Ninety-three patients in Group 1 were eligible for inclusion in the
      "chronic pain" group and 92 patients from Group 2, for the "pain free" group. The
      median scores were identical at +3; nonparametric testing revealed no significant
      difference between the groups in their acceptance of the treatment. CONCLUSIONS:
      An analogue study such as this removes the potential bias of clinical interaction
      with a physician, but lacks some reality. Nonetheless, the results from this
      study did not support the hypothesis that patients with chronic noncancer pain
      accept treatment of questionable benefit more readily than those who are "pain
      free".

PMID- 15197417
TI  - Insourcing and outsourcing.

PMID- 15197419
TI  - CD40 and vascular inflammation.
AB  - Atherosclerosis is currently considered a chronic inflammatory disease combined
      with a disorder of lipid metabolism and deposition. Risk factors for coronary
      disease, as well as circulating cytokines, are involved in endothelial
      activation, leading to an adhesive and dysfunctional endothelium. The CD40
      receptor (CD40) and its counterpart, the CD40 ligand (CD40L/CD154), were
      originally found to regulate T cell-dependent B cell differentiation. Meanwhile,
      several studies clearly demonstrate that the CD40/CD40L system plays an important
      role not only in cellular immunity and inflammation, but also in the
      pathophysiology of atherosclerosis. This is evidenced by the finding that
      inhibition of CD40/CD40L interaction prevents atherogenesis in animal models.
      Thus, the regulation of proatherogenic factors including CD40L may provide novel
      therapeutic options to treat inflammatory disorders such as atherosclerosis.

PMID- 15197420
TI  - Prediction of in-hospital mortality by brain natriuretic peptide levels and other
      independent variables in acutely ill patients with suspected heart disease.
AB  - BACKGROUND: Brain natriuretic peptide (BNP) measurement can detect and assess
      heart failure. However, compared with traditional clinical parameters, its value
      for predicting the in-hospital mortality of patients with suspected heart disease
      has not been reported. STUDY DESIGN: Examination of the ability of 11 continuous
      and 22 categorical variables, including BNP levels measured at the time of
      admission, was conducted to predict in-hospital mortality. SETTING: A small,
      rural Irish hospital. SUBJECTS: Six hundred forty-two consecutive patients with
      suspected heart disease admitted as acute medical emergencies. RESULTS: Thirty
      eight (5.9%) patients died while in hospital. They had significantly higher BNP
      levels on admission than did patients subsequently discharged alive (763+/-473
      pg/mL versus 368+/-412 pg/mL, P<0.0001). Patients who died in hospital were
      older; had significantly higher white blood cell counts, blood urea, respiratory
      rates and modified early warning scores; and had significantly lower blood
      pressure and hemoglobin levels. Five variables were found to be independent
      predictors of mortality: a systolic blood pressure of 90 mmHg or less; a
      hemoglobin level of 100 g/L or less; a white blood cell count greater than 13.0 x
      10(9)/L being unwell before the current illness; and a BNP level of 700 pg/mL or
      greater. The presence of three or more of these variables was associated with an
      in-hospital mortality rate of 39%. CONCLUSIONS: Five independent variables
      (hypotension, anemia, leukocytosis, prior illness and elevated BNP levels) are
      comparable predictors of in-hospital mortality in patients with suspected heart
      disease.

PMID- 15197421
TI  - Association between insulin resistance and reduced coronary vasoreactivity in
      healthy subjects.
AB  - BACKGROUND: Insulin resistance appears to be an important risk factor for
      coronary artery disease. OBJECTIVE: To examine the role of insulin resistance on
      coronary vasoreactivity in healthy subjects. PATIENTS AND METHODS: Myocardial
      blood flow was quantitated using positron emission tomography and oxygen-15
      labelled water in 10 healthy, nonobese men. The perfusion measurements were
      performed basally and during adenosine infusion, which has been used as a measure
      of coronary vasoreactivity. After perfusion measurements were taken, whole-body
      glucose uptake was determined using the euglycemic hyperinsulinemic clamp
      technique. RESULTS: Basal myocardial blood flow was 0.89+/-0.21 mL.g(-1).min(-1);
      adenosine significantly increased the flow to 4.00+/-1.13 mL.g(-1).min(-1).
      Adenosine-stimulated myocardial blood flow was inversely associated with fasting
      serum insulin concentration (r=-0.69, P<0.05). Concordantly, hyperemic blood flow
      was associated with whole-body glucose uptake during euglycemic hyperinsulinemic
      conditions (r=0.64, P<0.05). Basal myocardial blood flow was not affected by
      insulin resistance. CONCLUSION: The results of the present study demonstrate the
      novel finding that insulin resistance is associated with reduced coronary
      vasoreactivity, even in healthy subjects.

PMID- 15197422
TI  - Reliability and prognostic value of traditional signs and symptoms in outpatients
      with congestive heart failure.
AB  - BACKGROUND: Previous validation studies of congestive heart failure (CHF) signs
      and symptoms were performed in acute settings. Few data have supported the
      validity of CHF clinical findings during the chronic stages of the disease. This
      study was designed to evaluate the reliability and prognostic value of
      traditional signs and symptoms in stable CHF outpatients. METHODS: Sixty CHF
      outpatients who underwent 102 simultaneous clinical and echocardiographic
      evaluations were prospectively examined. A clinical congestion score was built
      summing all grades of CHF signs and symptoms. Hemodynamic parameters were
      estimated according to previously validated echocardiography-based protocols.
      Major cardiac events were evaluated after 180 days. RESULTS: Most CHF patients
      were male (67%), middle-aged (56+/-15 years) and in Specific Activity Scale
      functional classes I to II (70%). Isolated clinical findings demonstrated limited
      sensitivity and specificity to identify hemodynamic parameters. Absence of all
      signs of congestion, however, had a predictive value of 95% for a left atrial
      pressure less than 20 mmHg. Patients with no CHF signs or symptoms (score of 0)
      had significantly lower right (P<0.001) and left (P=0.03) atrial pressures
      compared with those with higher scores (scores of at least 5). In multivariate
      analysis, a congestion score of at least 3 (RR 4.8, 95% CI 1.3 to 17.4, P=0.02)
      and beta-blockers use (P=0.02) remained associated with future cardiac events.
      CONCLUSIONS: Although CHF signs and symptoms did not accurately identify
      hemodynamic parameters, combined data from history and physical examination
      provided meaningful information to guide clinical decisions and for
      prognostication.

PMID- 15197423
TI  - Diagnostic usefulness of postexercise systolic blood pressure response for
      detection of coronary artery disease in patients with echocardiographic left
      ventricular hypertrophy.
AB  - BACKGROUND: Although exercise-induced electrocardiographic ST segment changes are
      used to detect coronary artery disease (CAD), their diagnostic value is markedly
      decreased in patients with left ventricular (LV) hypertrophy. There have been no
      reports concerning postexercise systolic blood pressure (SBP) response in
      patients with ultrasound echocardiographic (UCG) LV hypertrophy and CAD. METHODS:
      Sixty-six patients with both UCG-LV hypertrophy (LV mass index 134 g/m2 or
      greater for men or 110 g/m2 or greater for women) and positive ST depression of
      at least 0.1 mV during treadmill exercise testing were studied. Coronary
      cineangiograms showed normal coronary arteries in 19 patients (group 1) and
      significant CAD in 47 patients (group 2). The SBP ratio was calculated by
      dividing the SBP 3 min after exercise (3 min SBP) by the SBP at peak exercise
      (peak SBP). RESULTS: There were no significant differences between the two groups
      in LV mass index, SBP at rest, exercise duration, ST depression (at rest and
      exercise-induced) or 3 min SBP. However, the SBP ratio was significantly higher
      in group 2 compared with group 1 (0.87+/-0.11 versus 1.01+/-0.18; P=0.004).
      Analysis of relative cumulative frequency distributions revealed an SBP ratio of
      0.92 as the cutoff point for distinguishing a UCG-LV hypertrophy patient with CAD
      from one without CAD. The sensitivity, specificity and accuracy with an SBP ratio
      of 0.92 and an ST segment depression of at least 0.1 mV on treadmill exercise
      testing for detecting CAD in patients with UCG-LV hypertrophy were 77%, 74% and
      76%, respectively. CONCLUSION: These findings suggest that the ratio of early
      post-exercise SBP to peak exercise SBP may be diagnostically useful in detecting
      CAD in patients with positive ST depression during an exercise test and UCG-LV
      hypertrophy.

PMID- 15197424
TI  - Population rates of invasive cardiac procedures in British Columbia, 1995 to
      2001.
AB  - BACKGROUND: This study examined the rates of coronary angiography (CA),
      percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery
      (CABG) in British Columbia (BC) between 1995 and 2001. METHODS: Data sources were
      as follows: CABG--BC Cardiac Registries; CA and PCI--BC Medical Services Plan;
      acute coronary syndromes (ACS)--Hospital Separation database; population data--BC
      Statistics. All rates were age and sex standardized per 100,000 BC resident
      adults over 20 years of age. RESULTS: The rate of diagnostic CA increased from
      352 per 100,000 in 1995 to 400 per 100,000 in 2001 (P<0.01). The rate of PCI
      increased from 101 per 100,000 in 1995 to 154 per 100,000 in 2001 (P<0.01).
      Single stage 'ad hoc' PCI increased from 38% in 1995 to 68% in 2001. The rate of
      CABG remained stable at between 70 and 79 per 100,000. There was a downward trend
      in the annual hospitalized incidence of ACS (477 to 430 per 100,000, P=0.04). The
      incidence of ACS and the rates of CA, PCI and CABG were higher for men in all age
      groups. PCI was more common than CABG in all groups. CONCLUSIONS: The incidence
      of ACS in BC is falling. The rates of diagnostic CA and PCI are increasing. The
      latter finding may reflect an appropriate evidence-based response to data
      supporting greater application of CA following ACS after publication of several
      studies supporting a routine invasive approach. The PCI rate is rising compared
      with the CABG rate, likely reflecting changes in patient selection and improved
      PCI technology, as well as a limited ability of the system to provide surgical
      procedures.

PMID- 15197425
TI  - Hepatitis C virus-associated pericardial effusion and tamponade in a liver
      transplant recipient.
AB  - A liver transplant recipient with hepatitis C presented with unexplained dyspnea,
      fatigue and edema. Diagnostic evaluation revealed a pericardial effusion with
      echocardiographic features of tamponade. The patient underwent therapeutic
      pericardial drainage, resulting in symptomatic relief. The pericardial fluid
      tested positive for hepatitis C virus (viral quantitation of 200,000 copies/mL,
      genotype 1b) and negative for other plausible etiologies. Pericardial biopsy
      revealed normal tissue. This is the fifth case of hepatitis C virus-associated
      pericardial disease worldwide and the first case in North America. It is the
      first in a liver transplant recipient. In contrast to previous reports, this
      patient demonstrated tamponade in the absence of cryoglobulinemia or systemic
      extrahepatic manifestations of hepatitis C.

PMID- 15197426
TI  - Ventricular assist devices as a 'bridge to recovery': where do we stand?
AB  - The use of ventricular assist devices as a 'bridge to recovery' has a lot to
      promise. However, we are at a stage where there are more questions than answers.
      It is still difficult to predict who will be the right candidate and who will
      have sustained recovery after explantation of the device. In addition, we do not
      have a universally accepted protocol to wean patients from assist devices. A case
      that was successfully bridged to recovery with a left ventricular assist device
      is presented, together with a discussion of the literature. The search for
      precise markers of recovery should continue and a multicentre prospective study
      to validate weaning protocols is needed. At present, one should consider all
      available markers and look at the full clinical picture before allocating a
      patient to a bridge to recovery destination.

PMID- 15197427
TI  - Can academic medicine be revitalized?

PMID- 15197429
TI  - Impact factors and publication times.

PMID- 15197428
TI  - Analgesic effect of intra-articular ketorolac in knee arthroscopy: comparison of
      morphine and bupivacaine.
AB  - This prospective study assessed the postoperative analgesic effect of intra
      articular ketorolac, morphine, and bupivacaine during arthroscopic outpatient
      partial meniscectomy. Group 1 patients (n=20) received postoperative injection of
      60 mg intra-articular ketorolac, group 2 patients (n=20) 10 cc intra-articular
      bupivacaine 0.25%, group 3 patients (n=20) 1 mg intra-articular morphine diluted
      in 10 cc saline, and group 4 patients (n=20, controls) only 10 cc saline. We
      evaluated the postoperative analgesic effect (period measured from the end of the
      surgery until further analgesia was demanded), the level of postoperative pain
      (by visual analog scale 1, 2, 3, 12, and 24 h after surgery), and the need for
      additional pain medication (during the first 24 h after surgery). The best
      analgesic effect was in patients treated with intra-articular ketorolac, and this
      was statistically significant in: postoperative analgesic effect and the need for
      additional pain medication immediately after surgery, and after 24 h. No
      complications were found related to the intra-articular treatment. We conclude
      that 60 mg intra-articular ketorolac provides better analgesic effect than 10 cc
      intra-articular bupivacaine 0.25% or 1 mg intra-articular morphine.

PMID- 15197430
TI  - Effect of polymyxin B-immobilized fiber on bone resorption in patients with
      sepsis.
AB  - OBJECTIVE: To analyze the effects of polymyxin B-immobilized fiber (PMX-F) on
      bone resorption in septic patients. DESIGN AND SETTING: Observational prospective
      study in intensive care units of a general hospital. PATIENTS AND PARTICIPANTS:
      25 patients with severe sepsis and 20 healthy controls. MEASUREMENTS AND RESULTS:
      Septic patients were randomly assigned to two groups: PMX-F treatment group
      (n=15) and conventional treatment group (n=10). Total pyridinium crosslink
      pyridinoline (PYD) and deoxypyridinoline (DPD) in urine were determined by
      modified high-performance liquid chromatography. Nitric oxide production was
      assessed by measuring the ratio of the nitric oxide breakdown products to urinary
      creatinine (NOx/Cr). Plasma endotoxin levels were determined by endospecy test.
      The blood albumin, ionized calcium, and parathyroid hormone were also measured.
      PMX-F treatment was performed twice separated by 24 h. Urinary NOx/Cr, PYD/Cr,
      and DPD/Cr were significantly increased in septic patients compared with those in
      healthy controls. Blood ionized calcium in septic patients was lower than in
      healthy controls, while parathyroid hormone levels in septic patients were higher
      than in healthy controls (P<0.01). PMX-F treatment reduced plasma endotoxin,
      urinary NOx/Cr, PYD/Cr, DPD/Cr, and serum parathyroid hormone levels and
      increased blood ionized calcium significantly; however, conventional treatment
      did not affect these levels. CONCLUSIONS: Septic patients increased nitric oxide
      production and bone resorption, and PMX-F treatment is effective in reducing
      nitric oxide levels and bone resorption markers.

PMID- 15197432
TI  - Reducing defects in the use of interventions.

PMID- 15197431
TI  - Nutritional support in 111 pediatric intensive care units: a European survey.
AB  - OBJECTIVE: To study current strategies in nutritional management of pediatric
      intensive care units (PICUs) in Europe, focusing on energy requirements. DESIGN
      AND SETTING: Survey by a 35-item questionnaire sent to representatives of 242
      PICUs in 28 countries. Addresses were obtained from national PICU associations
      and the members' list of the European Society of Pediatric and Neonatal Intensive
      Care. PARTICIPANTS: Staff members of 111 European PICUs (46%) from 24 countries.
      MEASUREMENTS AND RESULTS: Predominantly physicians were reported to be
      responsible for nutritional support. In 73% of PICUs a multidisciplinary
      nutritional team was available. In most PICUs daily energy requirements were
      estimated using weight, age, predictive equations and correction factors. In 17%
      of PICUs energy expenditure was regularly measured by indirect calorimetry.
      Nutritional status was mostly assessed by weight, physical examination, and a
      wide range of biochemical blood parameters. Approximately 70% of PICUs used
      dedicated software for nutritional support. A similar percentage of PICUs
      regarded "nutrition" as a research topic and part of the residents' training
      program. CONCLUSIONS: Most European PICUs regard nutritional support as an
      important aspect of patient care, as shown by the presence of nutritional teams,
      software, research, and education. However, energy requirements of pediatric
      intensive care patient were based predominantly on estimations rather than on
      measurements.

PMID- 15197433
TI  - Monitoring midline shift by transcranial color-coded sonography in traumatic
      brain injury. A comparison with cranial computerized tomography.
AB  - OBJECTIVE: Transcranial color-coded duplex sonography (TCCDS) is a non invasive
      bedside technique that allows the determination of midline shift (MLS). The
      purpose of our study was to compare MLS measurements using TCCDS with those
      obtained with cranial computerized tomography (CT) in patients with traumatic
      brain injury (TBI). DESIGN: Prospective study. SETTINGS: Intensive care unit in a
      university hospital. PATIENTS: Forty-one traumatic brain-injured patients (35 men
      and 6 women). INTERVENTIONS: A total of 60 studies were conducted with a time
      interval between the cranial CT and the TCCDS studies of 322+/-216 min. RESULTS:
      The coefficient of correlation between MLS measured by CT and TCCDS was 0.88, the
      bias was 0.12 mm, the precision was 1.08 mm and the limits of agreement were
      +2.33 to -2.07 mm. There were no statistically significant differences in MLS
      measured by the two techniques in terms of: sex, age or type of lesion according
      to the Traumatic Coma Data Bank classification. CONCLUSION: The TCCDS is a non
      invasive bedside technique that is valid for determining MLS in patients with
      traumatic brain injury. Due to the risks involved in the transportation of
      traumatic brain-injured patients to the radiology department, this bedside
      technique is specially interesting in these patients.

PMID- 15197434
TI  - Perspectives for core and skin surface temperature guided extubation in patients
      after normothermic cardiopulmonary bypass.
AB  - OBJECTIVE: To investigate the relationship between changes in core and skin
      surface temperature and extubation time in patients following normothermic
      cardiopulmonary bypass (CPB). DESIGN: Prospective observational study. SETTING:
      Intensive care unit (ICU) of a university hospital. PATIENTS: Patients admitted
      to the ICU after cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND RESULTS:
      Thirty-two patients undergoing cardiac surgery with the use of normothermic CPB
      were studied. In the ICU, urinary bladder temperature and skin surface
      temperature gradient (forearm temperature minus fingertip temperature) were
      measured at 30-min intervals for 10 h postoperatively. Every half-hour an
      anaesthesiologist, blinded to temperature measurements, checked the possibility
      of extubation. On arrival in the ICU the mean skin surface temperature gradient
      of the patients was 1.9+/-1.6 degrees C, indicating vasoconstriction of the
      dermal vessels (>0 degrees C = vasoconstriction, <0 degrees C = vasodilation)
      while the mean urinary bladder temperature was 36.8+/-0.4 degrees C. The change
      from thermoregulatory vasoconstriction to vasodilation (skin surface temperature
      gradient of 0 degrees C) was 137+/-49 min after arrival in the ICU. The mean time
      until extubation was 135+/-55 min after arrival in the ICU. There was a linear
      relation between a temperature gradient of 0 degrees C and extubation time,
      r(2)=0.49. Later, 181+/-67 min after arrival in the ICU, the urinary bladder
      temperature reached its maximum of 38.2+/-0.6 degrees C. CONCLUSIONS: This study
      demonstrates that the transition period from peripheral vasoconstriction to
      vasodilation provides an opportunity for postoperative extubation.

PMID- 15197435
TI  - Continuous central venous and pulmonary artery oxygen saturation monitoring in
      the critically ill.
AB  - OBJECTIVE: To compare the course of continuously measured mixed and central
      venous O(2) saturations in high-risk patients and to evaluate the impact of
      various factors that might interfere with reflection spectrophotometry. DESIGN
      AND SETTING: Prospective, descriptive study in the interdisciplinary ICU of a
      university hospital. PATIENTS: 32 critically ill patients with triple-lumen
      central vein catheters, including 29 patients requiring pulmonary artery
      catheterization. INTERVENTIONS: The accuracy of fiberoptic measurements was
      assessed by comparison to reference co-oximeter results at regular intervals. We
      examined the effect on measurement accuracy of physiological variables including
      hematocrit, hemoglobin, pH, temperature, and the administration of various
      solutions via central venous catheter. Continuous parallel measurements of SvO(2)
      and ScvO(2) were performed in patients with each type of catheters over a total
      observation time of 1097 h. RESULTS: ScvO(2) values were more accurate and stable
      than in vitro oximeter measurements ( r=0.96 from 150 samples, mean difference
      0.15%, average drift 0.10%/day) and was not significantly affected by synchronous
      infusion therapy or by changes in hematocrit, hemoglobin, pH, or temperature.
      ScvO(2) values closely paralleled SvO(2), whether measured in vitro ( r=0.88 from
      150 samples) or in vivo ( r=0.81 from 395,128 samples) but averaged about 7+/-4
      saturation percentage higher. ScvO(2) changed in parallel in 90% of the 1,498
      instances in which SvO(2) changed more than 5% (over an average of 43 min).
      CONCLUSIONS: Continuous fiberoptic measurement of central vein O(2) saturation
      has potential to be a reliable and convenient tool which could rapidly warn of
      acute change in the oxygen supply/demand ratio of critically ill patients.

PMID- 15197437
TI  - Predicting fluid responsiveness: should we adapt the scale to measure the central
      venous pressure swing?

PMID- 15197438
TI  - Noninvasive vs invasive ventilation in COPD patients with severe acute
      respiratory failure deemed to require ventilatory assistance.
AB  - OBJECTIVE: To determine whether non-invasive ventilation (NIV) may be an
      effective and safe alternative to invasive mechanical ventilation in chronic
      obstructive pulmonary disease (COPD) patients with acute respiratory failure
      (ARF) meeting criteria for mechanical ventilation. DESIGN AND SETTING: Matched
      case-control study conducted in ICU. PATIENTS AND INTERVENTION: NIV was
      prospectively applied to 64 COPD patients with advanced ARF. Their outcomes were
      compared with those of a control group of 64 COPD patients matched on age,
      FEV(1), Simplified Acute Physiology Score II, and pH at ICU admission, previously
      treated in the same ICU with conventional invasive mechanical ventilation.
      METHODS AND RESULTS: NIV failed in 40 patients who required intubation. Mortality
      rate, duration of mechanical ventilation, and lengths of ICU and post-ICU stay
      were not different between the two groups. The NIV group had fewer complications
      ( P = 0.01) and showed a trend toward a lower proportion of patients remaining on
      mechanical ventilation after 30 days ( P = 0.056). Compared to the control group,
      the outcomes of the patients who failed NIV were no different. Compared to the
      patients who received intubation, those who succeeded NIV had reduced mortality
      rate and lengths of ICU and post-ICU stay. CONCLUSIONS: In COPD patients with
      advanced hypercapnic acute respiratory failure, NIV had a high rate of failure,
      but, nevertheless, provided some advantages, compared to conventional invasive
      ventilation. Subgroup analysis suggested that the delay in intubation was not
      deleterious in the patients who failed NIV, whereas a better outcome was
      confirmed for the patients who avoided intubation.

PMID- 15197439
TI  - Use of oral clonidine for sedation in ventilated paediatric intensive care
      patients.
AB  - OBJECTIVES: We aimed to document our experience with oral clonidine when used as
      a sedative in combination with intravenous morphine and lorazepam in a group of
      mechanically ventilated children with single-organ, respiratory failure. In
      particular, our objectives were to establish the relationship between oral dose,
      plasma concentration, and sedative effect, and second, to document the side
      effect profile. DESIGN: Prospective, cohort study over a 72-h period. SETTING:
      Regional paediatric intensive care unit. PATIENTS AND PARTICIPANTS: Twenty-four
      children were enrolled (median age 3 months) of whom ten were excluded (six due
      to extubation before 72 h, three sedation failures, one protocol violation).
      MEASUREMENTS AND RESULTS: Plasma clonidine was measured using gas chromatography
      mass spectrometry, and sedation assessed using the COMFORT score. Using a dose of
      3-5 microg/kg every 8 h, plasma concentrations appeared to plateau at
      approximately 41 h giving a mean value of 1.38 ng/ml (95% confidence interval 1.0
      1.8). Adequate sedation was achieved during 82% (837/1022 h) of the study period;
      however, this decreased to 70.3% when analysed on an intention-to-treat basis.
      There was a concomitant overall decrease in the average hourly requirements for
      both morphine ( P = 0.02) and lorazepam ( P = 0.003). There were no documented
      episodes of bradycardia, hypotension or hyperglycaemia. CONCLUSIONS: Oral
      clonidine may be a safe and effective sedative in combination with morphine and
      lorazepam for young children with single-organ, respiratory failure. This agent
      may also exhibit opioid and benzodiazepine sparing effects in this patient group.
      A full pharmacokinetic study is warranted.

PMID- 15197440
TI  - Morphologic characteristics of central pulmonary thromboemboli predict
      haemodynamic response in massive pulmonary embolism.
AB  - OBJECTIVE: On hospital admission, the morphology of the central pulmonary artery
      thromboemboli is an independent predictor of 30-day mortality in patients with
      massive pulmonary embolism (MPE). This may be due to the differential
      susceptibility of thromboemboli to thrombolysis. The aim of this study was to
      assess haemodynamic response to treatment in patients with MPE and
      morphologically different thromboemboli. DESIGN: Prospective observational study.
      SETTING: An 11-bed closed medical ICU at a 860-bed community general hospital.
      PATIENTS: Twelve consecutive patients with shock or hypotension due to MPE and
      central pulmonary thromboemboli detected by transesophageal echocardiography who
      were treated with thrombolysis between January 2000 through April 2002.
      PROCEDURES: Patients were divided into two groups according to the
      characteristics of detected central pulmonary thromboemboli: group 1, thrombi
      with one or more long, mobile parts; and group 2, immobile thrombi. Urokinase
      infusion was terminated when mixed venous oxygen saturation was stabilized above
      60% for 15 min. RESULTS: At 2 h, the total pulmonary vascular resistance index
      was reduced more in group 1 than group 2 [from 27+/-12 mmHg/(l.min.m(2)) to 14+/
      6 mmHg/(l.min.m(2)) (-52%) vs 27+/-8 mmHg/(l.min.m(2)) to 23+/-10
      mmHg/(l.min.m(2)) (-15%), respectively, P=0.04]. In group 1 thrombolysis was
      terminated earlier than group 2 (89+/-40 min vs 210+/-62 min, respectively, P=
      0.0024). The cumulative dose of urokinase used in group 1 was lower than group 2
      (1.7+/-0.3 M i.u. vs 2.7+/-0.5 M i.u., respectively, P= 0.023). CONCLUSION:
      Haemodynamic stabilization is achieved faster in patients with mobile central
      thromboemboli detected by transesophageal echocardiography during MPE.

PMID- 15197442
TI  - Intra-hospital transport of critically ill patients: minimising risk.

PMID- 15197441
TI  - Role of PARP on iNOS pathway during endotoxin-induced acute lung injury.
AB  - OBJECTIVE: Excessive nitric oxide (NO) and especially peroxynitrite may cause
      pulmonary tissue damage, e.g., through lipid peroxidation and/or exhaustion of
      cellular energy depletion induced by activation of poly (ADP-ribose) polymerase
      (PARP). Furthermore, PARP seems to aggravate tissue destruction by regulating the
      expression of respective genes. DESIGN: Prospective animal study. SETTING:
      University research laboratory. INTERVENTION: We investigated the effect of
      competitive PARP inhibition by 3-aminobenzamide (3-AB) on the pulmonary iNOS
      pathway after infusion of lipopolysaccharide (LPS). MEASUREMENTS AND RESULTS: The
      pretreatment of rabbits with 3-AB attenuated the LPS-induced iNOS mRNA and
      protein expression analyzed by RT-PCR and Western blot, and plasma nitrite
      concentrations quantified by Griess reaction (71+/-6%, 93+/-6% vs baseline).
      Electromobility shift assay showed an enhanced NF-kappaB and attenuated AP-1
      activation after 3-AB vs LPS alone. Lipid peroxidation determined as levels of
      thiobarbituric acid reactive substances in plasma and lung tissue was reduced by
      50% in the LPS+3-AB in comparison to LPS alone. Simultaneously, 3-AB was able to
      inhibit correspondingly the LPS-induced extravasation of gold-labeled albumin and
      increase of alveolo-arterial oxygen difference. CONCLUSION: PARP regulates the
      pulmonary NO pathway during endotoxemia via AP-1 and not NF-kappaB. Thus,
      pharmacological inhibition of PARP might be an effective intervention to prevent
      endotoxin-induced lung injury, interrupting the vicious circle of NO production
      and PARP activation.

PMID- 15197444
TI  - Genomic constitution and variation in five partial amphiploids of wheat-
      Thinopyrum intermedium as revealed by GISH, multicolor GISH and seed storage
      protein analysis.
AB  - Genomic in situ hybridization (GISH) and multicolor GISH (mcGISH) methodology
      were used to establish the cytogenetic constitution of five partial amphiploid
      lines obtained from wheat x Thinopyrum intermedium hybridizations. Line Zhong 1,
      2 n=52, contained 14 chromosomes from each of the wheat genomes plus ten Th.
      intermedium chromosomes, with one pair of A-genome chromosomes having a Th.
      intermedium chromosomal segment translocated to the short arm. Line Zhong 2, 2
      n=54, had intact ABD wheat genome chromosomes plus 12 Th. intermedium
      chromosomes. The multicolor GISH results, using different fluorochrome labeled
      Th. intermedium and the various diploid wheat genomic DNAs as probes, indicated
      that both Zhong 1 and Zhong 2 contained one pair of Th. intermedium chromosomes
      with a significant homology to the wheat D genome. High-molecular-weight (HMW)
      glutenin and gliadin analysis revealed that Zhong 1 and Zhong 2 had identical
      banding patterns that contained all of the wheat bands and a specific HMW band
      from Th. intermedium. Zhong 1 and Zhong 2 had good HMW subunits for wheat
      breeding. Zhong 3 and Zhong 5, both 2 n=56, possessed no gross chromosomal
      aberrations or translocations that were detectable at the GISH level. Zhong 4
      also had a chromosome number of 2 n=56 and contained the complete wheat ABD
      genome chromosomes plus 14 Th. intermedium chromosomes, with one pair of Th.
      intermedium chromosomes being markedly smaller. Multicolor GISH results indicated
      that Zhong 4 also contained two pairs of reciprocally translocated chromosomes
      involving the A and D genomes. Zhong 3, Zhong 4 and Zhong 5 contained a specific
      gliadin band from Th. intermedium. Based on the above data, it was concluded that
      inter-genomic transfer of chromosomal segments and/or sequence introgression had
      occurred in these newly synthesized partial amphiploids despite their diploid
      like meiotic behavior and disomic inheritance.

PMID- 15197443
TI  - Efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia:
      influence of disease severity.
AB  - OBJECTIVE: To test the hypothesis that the outcome of patients with ventilator
      associated pneumonia (VAP) depends on both their baseline severity at VAP onset
      and the adequacy of empirical antibiotic therapy. DESIGN AND SETTING: Prospective
      clinical study in six intensive care units in Paris, France. PATIENTS: One
      hundred and forty-two patients with VAP after >/= 48 h of mechanical ventilation.
      MEASUREMENTS AND RESULTS: Patients were compared according to whether adequate
      antibiotics were started when VAP was first suspected (D0). At day 0, the rate of
      adequate antibiotic therapy was 44.4% and rose to 92% at day 2. Outcomes were
      recorded at the ICU and hospital discharge. Overall, no significant mortality
      difference was found with and without adequate early antibiotics. When patients
      were also classified based on the initial Logistic Organ Dysfunction score (LOD),
      mortality was significantly higher with inadequate early antibiotic therapy in
      the groups with LOD </= 4 (ICU mortality: 37% vs 7%, P=0.006; hospital mortality:
      44% vs 15%, P=0.01). A multivariate logistic regression confirmed that inadequate
      antibiotic therapy increased mortality in patients with LOD </= 4 after
      adjustment on other prognostic factors. CONCLUSIONS: Inadequate empirical
      treatment seemed to be associated with a poor prognosis only in patients with LOD
      </= 4. These results need to be confirmed by further studies before any
      reappraisal of current guidelines for empirical antibiotic therapy of VAP can be
      envisaged.

PMID- 15197445
TI  - [Clarification of tissue contamination in a suspected adenocarcinoma of the
      spermatic cord by microsatellite analysis].
AB  - Malignant tumors of the spermatic cord are rare with primary neoplasms being
      mostly sarcomas. Adenocarcinomas of the spermatic cord are found extremely seldom
      and are predominantly metastases of extragonadal tumors. We present an
      asymptomatic 47-year-old patient who was referred to our clinic after a vasectomy
      had been performed and the histological examination had surprisingly shown
      adenocarcinoma of the left spermatic cord. Extensive laboratory analysis and
      diagnostic imaging did not demonstrate any testicular, spermatic cord, or
      extragonadal tumor. To exclude a mix-up of specimens, we performed DNA analysis.
      Microsatellite PCR clearly demonstrated the different origins of the tumor and
      the vasectomy specimen. Specimen mix-up or contamination may happen in any phase
      of surgical or pathological processing. In any case of clinical uncertainty
      concerning the identity of a tissue specimen, this possibility has to be taken
      into consideration. Microsatellite PCR can clearly identify the origin of tissue
      samples even on embedded material.

PMID- 15197446
TI  - [Locally recurrent malignant fibrous histiocytoma of the kidney and spermatic
      cord].
AB  - OBJECTIVE: In this study, 26 patients with locally recurrent malignant fibrous
      histiocytoma of the kidney and spermatic cord after initial R0 resection were
      reviewed with regard to therapeutic options and prognosis. PATIENTS AND METHODS:
      Based on a literature query in the PubMed database, we identified 24 cases with
      locally recurrent malignant fibrous histiocytoma of the kidney and spermatic cord
      after initial R0 resection. Two of our own patients were included and afterwards
      the entire patient group was analyzed with regard to the time period of the first
      local recurrence and the overall survival rate. RESULTS: The average patient age
      was 58 years; in 17 cases (65%) the left side was affected. After primary therapy
      the 5-year survival rate was 25%; adjuvant therapy did not achieve any
      significant improvement in survival time ( p=0.259). The local recurrence was on
      average diagnosed after 13 months (with a median of 12 months). The prognosis of
      malignant fibrous histiocytoma after detection of the local recurrence was
      extraordinary poor, only 4 of 26 patients survived for longer than 3 years. The 1
      , 2- and 5-year survival rates then were 34%, 28%, and 14%, respectively. The
      mean survival time was 31 months with a median survival of 9 months. Patients
      with a locally recurrent malignant fibrous histiocytoma of the spermatic cord
      showed a significant better survival prognosis than patients with a local
      recurrence of a renal malignant fibrous histiocytoma ( p=0.04). CONCLUSION:
      Malignant fibrous histiocytoma of the genitourinary tract are rare tumors with a
      high rate of local recurrence. If there are no distant metastases a R0 resection
      can result in a curative objective. Nevertheless, the prognosis of this disease
      is poor. Even early detection of local therapy failure and promptly initiated
      aggressive salvage therapy may offer the chance of long-term survival only in
      selected cases. Lifelong follow-up is necessary for patients with a malignant
      fibrous histiocytoma of the kidney or spermatic cord.

PMID- 15197447
TI  - [Erectile dysfunction. New drugs with special consideration of the PDE 5
      inhibitors].
AB  - Erectile dysfunction (ED) tends to be associated with other diseases, the common
      basis of which is endothelial dysfunction. ED is also frequently combined with
      LUTS and the common basis for both conditions seems to be elevation of Rho-kinase
      activity and decrease of NO concentration. Because all three PDE 5 inhibitors
      sildenafil, tadalafil, and vardenafil have a common mode of action, i.e.,
      inhibition of PDE 5, they are not different in terms of their efficacy and safety
      profile except for color vision disturbances which are more common after
      sildenafil and back pain/myalgia more often observed after tadalafil. The main
      differentiating characteristics among the three PDE 5 inhibitors are their
      pharmacokinetics. These are ultimately responsible for the observation that in
      head-to-head comparative trials depending on the respective study design the
      overwhelming majority of the patients opted either for tadalafil as the longest
      acting PDE 5 inhibitor (36 h) or for vardenafil as a relatively rapidly acting
      drug. All published studies so far have shown that in terms of the cardiovascular
      risk profile (myocardial infarction rate) all three PDE 5 inhibitors performed
      better than placebo although the results were not statistically significant.
      Without any exception it applies to all three PDE 5 inhibitors that they are
      absolutely contraindicated in patients taking nitrate- or molsidomine-containing
      medications and that they may interact in particular with non-uroselective alpha
      adrenoceptor blockers. This is why their simultaneous application with PDE 5
      inhibitors has to be avoided.In the near future chronic (daily) application of a
      PDE 5 inhibitor may show advantages, at least in those 50-60% of all patients in
      whom there is a high likelihood of endothelial dysfunction due to the diagnostic
      (penile duplex Doppler) outcome. Possible new developments in the management of
      ED with a time frame of 5-8 years until their market approval are guanylate
      cyclase activators, Rho-kinase inhibitors, melanocortin receptor agonists, gene
      therapy, and tissue engineering.

PMID- 15197448
TI  - [Overactive bladder syndrome in children].
AB  - According to recent terminology, the symptom complex of frequency and urgency
      with or without urge incontinence in childhood is called overactive bladder. The
      main etiologic factor seems to be a delayed maturation of complex neuroanatomic
      structures responsible for normal bladder control. Afflicted children show a
      typical pattern of reflex voiding with different degrees of severity. In many
      cases nocturnal incontinence is the main complaint and this may lead to the wrong
      diagnosis of nocturnal enuresis with resulting false treatment. The diagnostic
      work-up consists of standardized evaluation of children with enuresis and voiding
      dysfunction and should concentrate on the exclusion of any possible underlying
      neurological disorder. Treatment focuses primarily on behavioral modification and
      cognitive education with regard to bladder sensation and voluntary micturition.
      Muscarinic receptor antagonists are very useful as supportive medical treatment
      with a rather low rate of adverse effects. Children who fail to respond to
      treatment or children suffering from side effects can profit from alternative
      treatment modalities including biofeedback programs, pelvic floor stimulation, or
      acupuncture.

PMID- 15197449
TI  - [Psychological and psychiatric aspects of nocturnal enuresis and functional
      urinary incontinence].
AB  - Psychological factors play an important role in nocturnal enuresis and functional
      urinary incontinence. The comorbidity of enuresis/urinary incontinence and
      clinical mental disorders as well as subclinical psychological symptoms is
      reviewed. In epidemiological as well as clinical studies, 20-40% of all children
      with nocturnal enuresis have a manifest clinical disorder-two to four times
      higher than nonwetting children. Children with secondary nocturnal enuresis and
      voiding postponement carry the highest risk for a mental disorder and those with
      urge incontinence and primary monosymptomatic nocturnal enuresis the
      lowest.Internalizing disorders (such as depressive and anxiety disorders) are
      less common than externalizing ones (such as ADHD). In addition, subclinical
      emotional and behavioral symptoms are common. These will often recede upon
      attaining dryness and self-esteem can increase. General screening for
      psychological symptoms and disturbances is recommended.

PMID- 15197450
TI  - [Zoophilia between pathology and normality. Presentation of 3 case reports and an
      internet survey].
AB  - Zoophilia, a sexual preference for animals, has lost its character as a severe
      mental disorder. In clinical practice it is rarely seen nowadays, particularly
      since it was decriminalized in 1970. This research is based on three case reports
      and an anonymous interview over the Internet. Findings from this study do not
      offer explanations about the causes of zoophilia. It is noteworthy, however, that
      the subjects in question were socially well adapted and displayed good
      interpersonal social skills. The authors stress that zoophilia shows a variety of
      manifestations. The subject's desire to be transformed into the animal he or she
      has contact with can be understood as a narcissistic compound and is not related
      to lycanthropia. The authors are optimistic over the possibilities offered by
      this Internet research methodology.

PMID- 15197452
TI  - [Costs of stroke unit care in Germany. Resource use and reimbursements by German
      diagnosis related groups].
AB  - BACKGROUND: Stroke care has a high impact on health costs. Therefore, the costs
      and reimbursements of integrated stroke care were calculated in a German
      neurological university hospital. PATIENTS AND METHODS: Patient cohorts of 2002
      and 2003 were considered. All patients were included who presented with ischemic
      stroke, intracerebral hemorrhage, or transient ischemic attacks. G-DRG
      reimbursements were calculated by using the 3M grouper versions 2.2.0 for 2003
      and 3.1 for 2004. RESULTS: There were no significant differences between the two
      patient cohorts. Compared to the former reimbursement system based on fixed daily
      charges, a base rate of EUR 3,204 was required for a neutral budget in 2002. The
      actual base rate was EUR 3,169. Assuming this base rate, an average reimbursement
      of EUR 4,201 (grouper 2.2.0) and of EUR 3,657 (grouper 3.1) was achieved per
      patient in 2002. An average reimbursement of EUR 4,107 (grouper 2.2.0) and of EUR
      3,351 (grouper 3.1) was achieved per patient in 2003. CONCLUSION: The development
      of reimbursements by the G-DRGs shows a clear downward trend and shows that the
      high resource use in stroke unit care is inadequately reflected by the G-DRGs.

PMID- 15197451
TI  - [Psychiatric-psychotherapeutic inpatient treatment for depression. Process and
      outcome quality based on a model project in Baden-Wurttemberg].
AB  - During 1998-2000 a quality assurance program for diagnosis and treatment of
      depression was conducted in 24 hospitals for psychiatry and psychotherapy in
      Baden-Wurttemberg (southern Germany). Process and outcome quality of 3,000
      depressive patients was documented at admission and discharge. The article
      focuses on therapeutic measures, duration, outcome, patient satisfaction, and
      their interactions. The results show that the patients' satisfaction with the
      care received is very high and the pre-post effect sizes of inpatient treatment
      for depression are high.

PMID- 15197453
TI  - [Adenocarcinoma-associated nonbacterial thrombotic endocarditis as the cause of
      recurrent strokes].
AB  - We describe a 60-year-old female patient without vascular risk factors diagnosed
      with cardioembolic ischemic stroke due to an atrial septal aneurysm with a right
      to-left shunt. However, further investigation after recurrent strokes revealed a
      nonbacterial thrombotic endocarditis (NBTE) caused by a metastatic
      adenocarcinoma. The presented case illustrates the difficulties in establishing
      the diagnosis of NBTE premortally and points out the importance of repeated
      echocardiographic evaluations of cardiac valves and serological examination of
      tumor markers in patients with recurrent strokes of unknown origin.

PMID- 15197454
TI  - [Change of offset after implantation of hip alloarthroplasties].
AB  - The purpose of the present study was to evaluate the change of the offset after
      implantation of hip alloarthroplasties. In an experimental study the X-ray
      templates of 90 different implants (594 different sizes) were digitized (cup and
      stem) and virtually implanted in the hip joint of 50 consecutive patients who
      were on the waiting list for hip replacement. Implantation was performed on AP X
      rays paying heed to the fit of the shaft and adequate leg length. In total 4500
      implantations were performed. After virtual implantation the change of the offset
      was calculated. There was a wide variance in the ability to fit the implants to
      the individual patient. For some patients it seems to be extremely difficult to
      adapt the implant without changing the offset. Some implant designs were only
      suitable for 2 patients while other designs were suitable for 40 patients (mean:
      17). The average change of the offset was 0.27 cm. Considering only the cases in
      which a change occurs this value increases up to 0.56 cm.For the individual
      patient the average number of implants that were suitable was 30 (range: 1-67) of
      a total of 90 designs. Here the average change of the offset was 0.4 cm (-1.04 --
      +1.54 cm). Considering only the cases in which a change occurs this value
      increases up to 0.64 cm. In the majority of the cases the presently available
      implants do not allow anatomic reconstruction of the individual offset.

PMID- 15197456
TI  - [Surgical technique for talus fractures. Tips and tricks].

PMID- 15197455
TI  - [Simple bone cysts of the calcaneus. Differential diagnosis and therapy].
AB  - Fifty-two calcaneal simple bone cysts from our clinic were evaluated. The lesions
      had a pathognomonic radiologic appearance and diagnosis was histologically
      confirmed in all operatively treated cases. Four cases presented with
      pathological fractures, three of which were treated by open reduction internal
      fixation and bone grafting, while one was treated nonoperatively. In addition,
      six patients with large cysts without apparent fracture but spontaneous pain were
      treated by curettage and subsequent autogenous bone grafting or calcium phosphate
      cement filling, and there were no recurrences. The majority of cysts (42 of 52)
      were however asymptomatic and thus followed up nonoperatively. This review
      reports on one of the largest series of cysts in this location. The results
      indicate that nonoperative management is justified in most asymptomatic cases.
      However, the potential risk of fracture as indicated by four fractured calcaneal
      cysts in this series suggests that large cysts should be clinically monitored and
      that operative intervention is useful in all symptomatic cases to prevent
      pathologic fractures. In the latter cases, curettage and bone grafting as well as
      the use of bone substitute material yielded uniformly good results.

PMID- 15197457
TI  - Stimulation of c-Rel transcriptional activity by PKA catalytic subunit beta.
AB  - Nuclear factor kappaB (NF-kappaB) is a eukaryotic transcription factor which
      responds to different extracellular signals. It is involved in immune response,
      inflammation, and cell proliferation. Increased expression of c-Rel (or its viral
      homolog v-Rel), one component of the NF-kappaB factors, induces tumorigenesis in
      different systems. The activity of NF-kappaB can be regulated by protein kinase A
      (PKA) in a cAMP-independent manner. Our previous results showed that c-MYC
      induces the activity of PKA by inducing the transcription of the gene encoding
      the PKA catalytic subunit beta (PKA-Cbeta). Constitutive expression of PKA-Cbeta
      in Rat1a cells induces their transformation. Here we show that CREB is unlikely
      to be a phosphorylation target of PKA-Cbeta as characterized by different cell
      lines. Electrophoretic mobility shift assays showed that c-Rel is present as a
      significant component of the NF-kappaB factors in c-MYC overexpressing status.
      The transcriptional activity of c-Rel was significantly stimulated by PKA-Cbeta.
      Coactivators p300/CBP are at least partially responsible for the enhanced
      activation mediated by c-Rel and PKA-Cbeta. Interaction between c-Rel and PKA
      Cbeta was demonstrated using coimmunoprecipitation assays. Immunoprecipitation-in
      vitro phosphorylation assays showed the direct phosphorylation of c-Rel by PKA
      Cbeta. These results indicate that c-Rel is a reasonable phosphorylation target
      of PKA-Cbeta, and that the transcriptional activity of c-Rel is stimulated by PKA
      Cbeta possibly through the interaction with p300/CBP.

PMID- 15197458
TI  - After chylomicron remnants, what is left?

PMID- 15197459
TI  - [Verbal learning and memory test in children. Analysis of it environmental
      validity].
AB  - BACKGROUND: The VLMT (auditory verbal learning and memory test) was constructed
      for use in children and adults. This study aimed at investigating the ecological
      validity in children. METHODS: In a retrospective study, data from 384 children
      were investigated. Correlations between the VLMT and a newly developed
      questionnaire (AVWS-Q) probing auditory processing skills were calculated.
      RESULTS: Significant albeit very weak correlations between VLMT items and AVWS-Q
      items were found. DISCUSSION: Results indicate that VLMT performance cannot be
      predicted by the AVWS-Q (neither as a sum score nor as questions regarding memory
      skills alone). Either the ecological validity of the VLMT has to be considered
      poor or the AVWS-Q does not probe memory skills sufficiently.

PMID- 15197460
TI  - [Management after a delayed diagnosis of foreign body aspiration].

PMID- 15197461
TI  - [Active ingredients in dermatocosmetics].
AB  - Modern skin care- and anti-aging preparations feature both advanced formulation
      concepts and active ingredients against skin aging. Most of these ingredients are
      based on the recent findings that in aging the balance between collagen synthesis
      and collagen fragmentation is altered. Environmental factors inducing oxidative
      stress as well as decreased estrogen levels during menopause are important
      factors leading to these changes in connective tissue metabolism. Thus the major
      targets of anti-aging ingredients are oxidative stress and collagen metabolism.
      Evaluation of the effects of most of these ingredients has not been completed so
      far. In general scientifically evaluated anti-aging preparations can viewed as
      supplementing effective sunscreens and maximized skin care.

PMID- 15197463
TI  - [Liposuction].
AB  - Through the appropriate use of tumescent anesthesia and the use of modern
      instruments and techniques, liposuction surgery has become a low-risk procedure
      which produces predictable and aesthetically pleasing results. New indications
      for liposuction surgery include lipedema and cellulite. Vibration-assisted
      liposuction has proven to be especially gentle to the tissues. The induced tissue
      contraction helps to create better results in correction procedures after less
      than-satisfactory liposuction. Autologous fat transfer is also firmly established
      as an augmentation procedure. In liporecycling, the fat obtained during reduction
      liposuction is used elsewhere for augmentation. New approaches in fat transfer
      include the microdroplet technique, flatter injection approaches and three
      dimensional tissue augmentation.

PMID- 15197464
TI  - [Spinal anesthesia with bupivacaine].

PMID- 15197462
TI  - [Diagnosis and treatment of eyelid eczema. An interdisciplinary challenge].
AB  - Eyelid eczemas are clinically and therapeutically clearly delineated, but remain
      a pathogenetically heterogeneous entity. The anatomic and functional conditions
      in the periorbital region make treatment difficult. Thus, in addition to frequent
      resistance to therapy and a tendency to recur, they pose a considerable
      diagnostic and therapeutic challenge to dermatologists and ophthalmologists. Even
      a comparatively small area of eyelid eczema can cause substantial suffering
      because of the burdensome symptoms and high aesthetic significance of this body
      region. This interdisciplinary overview deals in particular with current
      pathogenetic and therapeutic aspects of eyelid eczemas.

PMID- 15197465
TI  - [Preconditioning with sevoflurane reduces biochemical markers for myocardial and
      renal dysfunction after aortocoronary procedures].

PMID- 15197466
TI  - [Assessment of psychiatric emergencies by physicians in the pre-hospital
      emergency medical system. A re-evaluation after 7 years].
AB  - OBJECTIVE: In the German emergency medical system (EMS) psychiatric emergency
      situations (PES) are now responsible for up to 15% of all calls for the emergency
      physician (EP). A survey which was first conducted in 1996 to reveal knowledge
      about PES, reported a significant need for training. Seven years later it is
      interesting to investigate whether different conditions in the EMS may have
      changed assessments and attitudes. METHODS: The questionnaire of 1996 was
      modified to enable a comparison of PES and other frequent emergency situations
      with respect to the estimated number and the subjective stress. Open and multiple
      choice questions or visual analogue scales were used to obtain the following
      data: demographic data, frequency of and stress by PES and other medical
      emergencies, own knowledge, and interest about training programs. RESULTS: Of the
      EPs 274 responded (male/female: 74/26%, mean age: 38 years, mean experience as an
      EP 6 years, anaesthesiologists 69%). The frequency of PES was estimated at 5% and
      44% of EPs thought that there had been an increase in recent years. Personal
      knowledge was judged to be good by only 24%. The interest in training programs
      even increased slightly compared to the first survey; of particular interest was
      training in drug abuse disorders. Subsequent to internal, neurological and
      surgical emergencies, PES are considered to rank fourth in frequency, however the
      strain imposed by PES is significantly higher than for these other emergency
      situations. DISCUSSION: The results indicate an increase of relevance of PES in
      the German EMS, however, assessments made by the EP only changed marginally over
      the time period. The subjective awareness of the frequency of PES underestimates
      the reality in emergency medicine. The importance of training programs remains
      high to improve knowledge and to reduce feelings of incapability.

PMID- 15197467
TI  - Biosynthesis of isoprenoids via the non-mevalonate pathway.
AB  - The mevalonate pathway for the biosynthesis of the universal terpenoid
      precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP),
      is known in considerable detail. Only recently, the existence of a second
      mevalonate-independent pathway for the biosynthesis of IPP and DMAPP was detected
      in plants and certain eubacteria. Experiments with 13C and/or 2H-labelled
      precursors were crucial in the elucidation of this novel route. The pathway is
      essential in plants, many eubacteria and apicomplexan parasites, but not in
      archaea and animals. The genes, enzymes and intermediates of this pathway were
      rapidly unravelled over the past few years. Detailed knowledge about the
      mechanisms of this novel route may benefit the development of novel antibiotics,
      antimalarials and herbicides.

PMID- 15197469
TI  - Autophagy: molecular mechanisms, physiological functions and relevance in human
      pathology.
AB  - Autophagy is a degradative mechanism mainly involved in the recycling and
      turnover of cytoplasmic constituents from eukaryotic cells. Over the last years,
      yeast genetic screens have considerably increased our knowledge about the
      molecular mechanisms of autophagy, and a number of genes involved in fundamental
      steps of the autophagic pathway have been identified. Most of these autophagy
      genes are present in higher eukaryotes indicating that this process has been
      evolutionarily conserved. In yeast, autophagy is mainly involved in adaptation to
      starvation, but in multicellular organisms this route has emerged as a
      multifunctional pathway involved in a variety of additional processes such as
      programmed cell death, removal of damaged organelles and development of different
      tissue-specific functions. Furthermore, autophagy is associated with a growing
      number of pathological conditions, including cancer, myopathies and
      neurodegenerative disorders. The physiological and pathological roles of
      autophagy, as well as the molecular mechanisms underlying this multifunctional
      pathway, are discussed in this review.

PMID- 15197468
TI  - The molecular mechanisms of congenital hypofibrinogenaemia.
AB  - Congenital hypofibrinogenaemia is characterized by abnormally low levels of
      fibrinogen and is usually caused by heterozygous mutations in the fibrinogen
      chain genes (alpha, beta and gamma). However, it does not usually result in a
      clinically significant condition unless inherited in a homozygous or compound
      heterozygous state, where it results in a severe bleeding disorder,
      afibrinogenaemia. Various protein and expression studies have improved our
      understanding of how mutations causing hypo- and afibrinogenaemia affect
      secretion of the mature fibrinogen molecule from the hepatocyte. Some mutations
      can perturb chain assembly as in the gamma153 Cys-->Arg case, while others such
      as the Bbeta Leu-->Arg and the Bbeta414 Gly-->Ser mutations allow intracellular
      hexamer assembly but inhibit protein secretion. An interesting group of
      mutations, such as gamma284 Gly-->Arg and gamma375 Arg-->Trp, not only cause
      hypofibrinogenaemia but are also associated with liver disease. The nonexpression
      of these variant chains in plasma fibrinogen is due to retention in the
      endoplasmic reticulum, which in turn leads to hypofibrinogenaemia.

PMID- 15197470
TI  - Protein N-terminal methionine excision.
AB  - N-terminal methionine excision (NME) is the major proteolytic pathway responsible
      for the diversity of N-terminal amino acids in proteins. Dedicated NME components
      have been identified in all organisms, in all compartments in which protein
      synthesis occurs: cytoplasm, plastids and mitochondria. Recent studies have
      revealed that NME is regulated at various levels and plays an important role in
      controlling protein turnover. NME is essential in Eubacteria and lower eukaryotes
      and is the target of many natural and synthetic inhibitors. Such inhibitors have
      considerable potential for use in the treatment of various human diseases, from
      cancer to bacterial and parasitic infections.

PMID- 15197471
TI  - How retinoids regulate breast cancer cell proliferation and apoptosis.
AB  - Breast cancer still remains a major problem in its incidence, morbidity and
      mortality; therefore, more effective strategies for its prevention are urgently
      needed. Retinoids, natural and synthetic derivatives of vitamin A, possess
      antiproliferative and proapoptotic properties, making them a promising class of
      chemopreventive agents against breast cancer. The efficacy of all-trans retinoic
      acid, 9-cis-retinoic acid, LGD1069 (Targretin, bexarotene), and N-(4
      hydroxyphenyl)retinamide (fenretinide) as breast cancer chemopreventive agents is
      being studied. A better understanding of the molecular mechanisms of action of
      these agents should lead to improvements in their clinical application. In this
      review, we discuss the mechanisms by which retinoids exert their
      antiproliferative and apoptotic effects in breast cancer cells.

PMID- 15197473
TI  - Genetic functional inactivation of neuronal nitric oxide synthase affects stress
      related Fos expression in specific brain regions.
AB  - To identify neuronal substrates involved in NO/stress interactions we used Fos
      expression as a marker and examined the pattern of neuronal activation in
      response to swim stress in nNOS knock-out (nNOS-/-) and wild-type (WT) mice.
      Forced swimming enhanced Fos expression in WT and nNOS-/- mice in several brain
      regions, including cortical, limbic and hypothalamic regions. Differences in the
      Fos response between the two groups were observed in a limited set (6 out of 42)
      of these brain areas only: nNOS-/- mice displayed increased stressor-induced Fos
      expression in the medial amygdala, periventricular hypothalamic nucleus,
      supraoptic nucleus, CA1 field of the hippocampus, dentate gyrus and infralimbic
      cortex. No differences were observed in regions including the septum, central
      amygdala, periaqueductal grey and locus coeruleus. During forced swimming, nNOS-/
      mice displayed reduced immobility duration, while no differences in general
      locomotor activity were observed between the groups in the home cage and during
      the open field test. The findings indicate that deletion of nNOS alters stress
      coping ability during forced swimming and leads to an altered pattern of neuronal
      activation in response to this stressor in specific parts of the limbic system,
      hypothalamus and the medial prefrontal cortex.

PMID- 15197472
TI  - Molecular characterization of Arabidopsis PHO80-like proteins, a novel class of
      CDKA;1-interacting cyclins.
AB  - Cyclins are regulatory proteins that interact with cyclin-dependent kinases
      (CDKs) to control progression through the cell cycle. In Arabidopsis thaliana, 34
      cyclin genes have been described, grouped into five different types (A, B, D, H,
      and T). A novel class of seven cyclins was isolated and characterized in
      Arabidopsis, designated P-type cyclins (CYCPs). They all share a conserved
      central region of 100 amino acids ("cyclin box") displaying homology to the
      corresponding region of the PHO80 cyclin from Saccharomyces cerevisiae and the
      related G1 cyclins from Trypanosoma cruzi and T. brucei. The CYCP4;2 gene was
      able to partially re-establish the phosphate-dependent expression of the PHO5
      gene in a pho80 mutant strain of yeast. The CYCPs interact preferentially with
      CDKA;1 in vivo and in vitro as shown by yeast two-hybrid analysis and co
      immunoprecipitation experiments. P-type cyclins were mostly expressed in
      proliferating cells, albeit also in differentiating and mature tissues. The
      possible role of CYCPs in linking cell division, cell differentiation, and the
      nutritional status of the cell is discussed.

PMID- 15197474
TI  - Antimicrobial peptide induction in the haemolymph of the Mexican scorpion
      Centruroides limpidus limpidus in response to septic injury.
AB  - Antimicrobial peptides (AMPs) are essential components of host defences against
      infectious microrganisms. In chelicerate organisms they have been implicated in
      three alternative defensive systems: one is defined by the immediate up
      regulation of genes encoding AMPs, another is characterized by the inducible
      systemic release of AMPs from cellular reservoirs and the third alternative is
      the systemic constitutive production of AMPs. In this work we used a differential
      high-performance liquid chromatography and mass spectrometry approach to show
      that septic injury elicits an immune response in the haemolymph of the Mexican
      scorpion Centruroides limpidus limpidus. We isolated several haemolymph
      components, one of which was characterized extensively (amino acid sequence,
      disulphide pairing, cDNA and genomic clones) and demonstrated to be a novel
      member of the invertebrate defensin family and consequently named C. limpidus
      limpidus defensin-like peptide (Cll-dlp). This peptide accumulates in the
      haemolymph in response to septic injury, independently of transcriptional
      regulation.

PMID- 15197475
TI  - Inhibition of lung carcinoma cell growth by high density lipoprotein-associated
      alpha-tocopheryl-succinate.
AB  - Alpha-tocopheryl-succinate (alphaTS) is a synthetic, anti-neoplastic derivative
      of alpha-tocopherol. Here we studied the effects of free and high-density
      lipoprotein subclass 3 (HDL3)-associated alphaTS on the growth of human (A549)
      and mouse Lewis (LL2) lung carcinoma cells. Both free and HDL3-associated alphaTS
      inhibited A549 growth in a time- and concentration-dependent manner. Treatment of
      A549 cells with alphaTS-enriched HDL3 led to DNA fragmentation and a time
      dependent decrease in immunoreactivity of poly(ADP-ribose)polymerase. Uptake
      experiments revealed a high capacity for selective alphaTS uptake in excess of
      holoparticle endocytosis. Overexpression of scavenger receptor class B, type I
      (SR-BI), the prime receptor mediating selective lipid uptake, in A549 cells
      resulted in significantly increased selective alphaTS uptake, a finding
      associated with complete cellular growth arrest. The present in vitro findings
      were verified in an in vivo model: tumor inoculation in C57BL6 was performed with
      either wild-type, beta-galactosidase- or SR-BI-overexpressing LL2 cells. After
      tumor inoculation, the animals received six consecutive intravenous injections of
      alphaTS. This experimental setup resulted in significantly reduced tumor burden
      in animals that were inoculated with SR-BI-overexpressing LL2 cells but not in
      animals inoculated with wild-type or beta-galactocidase-transfected cells. Based
      on our in vitro and in vivo findings, we propose that SR-BI could provide a novel
      route for HDL3-mediated drug delivery of anti-neoplastic drugs.

PMID- 15197477
TI  - Assessment and management of newborn hydronephrosis.
AB  - The incidence of asymptomatic hydronephrosis in newborns is high. Despite
      extensive clinical and scientific research much controversy still exists about
      the assessment and management of hydronephrosis during infancy. Postnatal
      management demands a detailed prenatal history. Initial workup in newborns with
      unilateral hydronephrosis starts with a physical examination and sonography of
      the urinary tract on day 3-5. Grades 3 and 4 hydronephrosis are further
      investigated with a voiding cystourethrogram (VCUG) and diuretic renogram between
      weeks 4 and 6. An infant with an asymptomatic unilateral hydronephrosis of any
      grade, without urinary infection and stable washout, and stable normal
      differential function on serial controls can be managed conservatively. The goal
      of all therapeutic strategies in the management of newborn hydronephrosis is to
      select all infants with severe obstructive dilatation during serial follow-ups
      and to perform surgical repair before irreversible deterioration and functional
      renal damage occurs. Interdisciplinary cooperation between experienced pediatric
      urologists, nephrologist and radiologists is the basis for optimal decision
      making.

PMID- 15197476
TI  - Differential distribution of TASK-1, TASK-2 and TASK-3 immunoreactivities in the
      rat and human cerebellum.
AB  - In this work, the distributions of some acid-sensitive two-pore-domain K+
      channels (TASK-1, TASK-2 and TASK-3) were investigated in the rat and human
      cerebellum. Astrocytes situated in rat cerebellar tissue sections were positive
      for TASK-2 channels. Purkinje cells were strongly stained and granule cells and
      astrocytes were moderately positive for TASK-3. Astrocytes isolated from the
      hippocampus, cerebellum and cochlear nucleus expressed TASK channels in a primary
      tissue culture. Our results suggest that TASK channel expression may be
      significant in the endoplasmic reticulum of the astrocytes. The human cerebellum
      showed weak TASK-2 immunolabelling. The pia mater, astrocytes, Purkinje and
      granule cells demonstrated strong TASK-1 and TASK-3 positivities. The TASK-3
      labelling was stronger in general, but it was particularly intense in the
      Purkinje cells and pia mater.

PMID- 15197478
TI  - Pediatric MRU--its potential and its role in the diagnostic work-up of upper
      urinary tract dilatation in infants and children.
AB  - Knowledge of the manifestation, physiology and the natural course of pediatric
      upper urinary tract dilatation has grown with the ongoing discussion on adequate
      imaging. Furthermore, MR-urography techniques (MRU) have matured and have become
      applicable to infants and children. Modern MRU offers not only increased spatial
      and temporal resolution, thus enabling an investigation throughout the entire
      childhood, but also provides (semi-)quantitative functional information on renal
      perfusion, excretion and drainage. Thus MRU is increasingly considered the ideal
      non-ionizing "one stop shop" for the assessment of significant upper urinary
      tract dilatation in children. The goal of this review is to briefly comment on
      MRU techniques as applicable in childhood, discuss MRU indications, and summarize
      their potential in children with upper urinary tract dilatation. Additionally,
      diagnostic imaging algorithms for typical clinical conditions and queries that
      try to define the role MRU in pediatric upper urinary tract dilatation are
      suggested and discussed.

PMID- 15197479
TI  - Intrahepatic arterioportal shunting and anomalous venous drainage: understanding
      the CT features in the liver.
AB  - The increased use of high-contrast volume, arterial-phase studies of the liver
      has demonstrated the frequent occurrence of arterioportal shunts within both the
      cirrhotic and non-cirrhotic liver. This article sets out to explain the
      underlying microcirculatory mechanisms behind these commonly encountered altered
      perfusion states. Similarly, well-recognised portal perfusion defects occur
      around the perifalciform and perihilar liver and are largely caused by anomalous
      venous drainage via the paraumbilical and parabiliary venous systems. The
      underlying anatomy will be discussed and illustrated. These vascular anomalies
      are all caused by or result in diminished portal perfusion and are often manifest
      in the setting of portal venous thrombosis. The evolving concept of zonal re
      perfusion following portal vein thrombosis will be discussed.

PMID- 15197480
TI  - An efficient mannose selection protocol for tomato that has no adverse effect on
      the ploidy level of transgenic plants.
AB  - A protocol for Agrobacterium-mediated transformation with mannose selection was
      developed for cotyledon petiole, hypocotyl and leaf explants of tomato
      (Lycopersicon esculentum L. Mill). More than 400 transgenic plants from three
      tomato varieties were selected with 1% mannose in combination with 0.1-0.5%
      glucose. Average transformation frequencies ranged from 2.0 to 15.5% depending on
      the construct, genotype and type of tissue used for transformation. The highest
      transformation rate was obtained for hypocotyl explants from tomato variety
      SG048. The ploidy levels of 264 independent transgenic events and 233 non
      transgenic plants regenerated from tissue culture were assessed by flow
      cytometry. The incidence of polyploids within the total population of transgenic
      plants varied from 10 to 78% and was not significantly different from the non
      transgenic population. The greatest variation in the proportion of polyploids was
      observed in plants derived from different explant types, both in transgenic and
      non-transgenic regenerants, across three studied genotypes. Transgenic and non
      transgenic plants regenerated from leaves included the highest number of normal
      diploid plants (82-100%), followed by cotyledon petiole-derived plants (63-78%).
      Transgenic plants produced from hypocotyls contained 22-58% diploids depending on
      the genotype used in transformation. Results described in this study demonstrate
      that, although transformation frequencies for leaf tissue are still lower under
      current protocols, the high percentage of diploids obtained make leaf tissue an
      attractive transformation target.

PMID- 15197481
TI  - The use of phenotypic markers to identify Brassica oleracea genotypes for routine
      high-throughput Agrobacterium-mediated transformation.
AB  - Doubled haploid (DH) genotypes from a genetic mapping population of Brassica
      oleracea were screened for ease of transformation. Candidate genotypes were
      selected based on prior knowledge of three phenotypic markers: susceptibility to
      Agrobacterium tumefaciens, shoot regeneration potential and mode of shoot
      regeneration. Mode of regeneration was found to be the most significant of the
      three factors. Transgenic plants were successfully obtained from genotypes that
      regenerated multiple shoots via a distinct swelling or callus phase. The absence
      of tissue culture blackening (associated with genotypes that formed callus) was
      found to be critical for transformation success. Transgenic shoots were obtained
      from genotypes that regenerated via an indirect callus mode, even when
      susceptibility to Agrobacterium was low. The most efficient genotype (DH AG1012)
      produced transgenic shoots at an average rate of 15% (percentage of inoculated
      explants giving rise to transgenic plants). The speed and efficiency of
      regeneration enabled the isolation of transgenic shoots 5-6 weeks after
      inoculation with A. tumefaciens. This line was also self-compatible, enabling the
      production of seed without the need for hand-pollination. A genetically uniform
      DH genotype, with an associated genetic map, make DH AG1012 highly desirable as a
      potential model B. oleracea genotype for studying gene function. The possibility
      of applying the same phenotypic tissue culture markers to other Brassica species
      is discussed.

PMID- 15197482
TI  - Enhanced post-germinative growth of encapsulated somatic embryos of Siberian
      ginseng by carbohydrate addition to the encapsulation matrix.
AB  - This experiment was carried out to enhance conversion and ex vitro survival of
      encapsulated somatic embryos of Siberian ginseng (Eleutherococcus senticosus).
      Cotyledonary somatic embryos were encapsulated with 3.0% sodium alginate; 96% of
      the encapsulated embryos converted to plantlets with well-elongated epicotyls in
      Perlite containing sucrose as a carbon source. However, although they germinated,
      post-germinative growth of encapsulated embryos was suppressed on Perlite that
      did not contain sucrose. Instead of sucrose addition to Perlite, addition of
      carbon sources to the encapsulation matrix enhanced post-germinative growth of
      encapsulated embryos. In the encapsulation matrix with 2% sucrose, post
      germinative growth of encapsulated embryos was more than twice (23.5%) that of
      the control capsules without sucrose (10.0%). Embryos encapsulated with both 2%
      sucrose and 1% starch powder showed the highest post-germinative growth
      percentage (42.1%). Iodine staining and analysis of starch content in the
      encapsulation matrix revealed that starch in the encapsulation matrix decomposed
      during embryo germination. This result indicates that carbohydrate treatment in
      the encapsulation matrix enhanced post-germinative growth of encapsulated embryos
      of Siberian ginseng.

PMID- 15197483
TI  - [Gestational trophoblastic disease, Villous gestational trophoblastic disease].
AB  - Gestational trophoblastic disease (GTD) represents a wide range of clinical and
      pathological distinct entities. The villous forms of GTD includes developmental
      disorders of the placental tree, like blighted ovum, embryonal, partial and
      complete moles. The risk of persistent GTD is estimated of 2-14% in partial and
      up to 50% in complete moles. So, the morphologic differentiation between the
      different entities of villous forms of GTD is clinical very important. Sometimes,
      early forms of complete moles (up to 12th weeks of gestation) may represent
      diagnostic problems, even in the diagnosis of regressive alterations of the
      placental villous tree after intrauterine retention.

PMID- 15197484
TI  - Systemic BCNU enhances the efficacy of local delivery of a topoisomerase I
      inhibitor against malignant glioma.
AB  - PURPOSE: To investigate the ability of systemically delivered BCNU to enhance the
      activity of either systemically delivered irinotecan (CPT-11) or locally
      delivered camptothecin from a biodegradable polymer for treatment of an
      intracranial 9L gliosarcoma. METHODS: We used a single systemic dose of BCNU on
      treatment day 1 in combination with systemic doses of CPT-11 on treatment days 1
      5 and 8-12 against an intracranial rat 9L gliosarcoma model implanted into female
      Fischer 344 rats. We also used the same systemic dose of BCNU given on treatment
      day 1, followed by a local dose of a 20% loaded camptothecin biodegradable
      polymer implanted on the same day. RESULTS: Two doses of CPT-11 (10 and 60 mg/kg)
      were delivered systemically against intracranial 9L. Neither dose showed an
      increase in survival compared to controls ( P>0.2 for 10 mg/kg and P=0.17 for 60
      mg/kg). Systemic delivery of CPT-11 (10 mg/kg per day) in combination with
      systemic BCNU (15 mg/kg) did not show a significant effect on survival compared
      to systemic BCNU alone ( P>0.2), even at the maximally tolerated systemic dose of
      CPT-11 (60 mg/kg per day; P=0.06). The combination of systemic BCNU (15 mg/kg)
      and intracranial delivery of camptothecin (20% loaded polymer), however,
      significantly extended survival compared to systemic BCNU alone ( P<0.001) and
      compared to intracranial delivery of camptothecin alone ( P=0.01). CONCLUSIONS:
      In a 9L gliosarcoma model, systemic delivery of CPT-11 showed no benefit in
      survival when delivered alone or in combination with systemic BCNU, because CPT
      11 is unable to cross the blood-brain barrier in cytotoxic levels. When cytotoxic
      levels of a topoisomerase I inhibitor are delivered directly to the brain tumor
      via a biodegradable polymer, however, the systemic delivery of the alkylating
      agent BCNU significantly enhances the antitumor effects of camptothecin in a 9L
      gliosarcoma model.

PMID- 15197485
TI  - The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I
      levels in non-small-cell lung cancer cells.
AB  - PURPOSE: To determine the in vitro drug sensitivity of two non-small-cell lung
      cancer cell lines after treatment with the novel lipophilic camptothecin
      derivative, 7- tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), to
      determine if topoisomerase I protein levels decrease after treatment with DB-67,
      and to assess the duration and extent of topoisomerase I modulation after DB-67
      exposure, in order to provide information about drug resistance that may be
      useful in determining an appropriate dosing schedule for DB-67. METHODS: The
      growth inhibition of the non-small-cell lung cancer cell lines A549 and H460
      after exposure to DB-67 was evaluated with the MTS assay. A549 and H460 cells
      were treated for various times with DB-67 and topoisomerase I levels were
      determined by western blot analysis. In addition, A549 and H460 cells were
      treated with DB-67 for 24 h and topoisomerase I levels were determined by western
      blot analysis daily for 1 week after drug removal. RESULTS: DB-67 inhibited the
      growth of both A549 and H460 cells grown in culture; the A549 cells were more
      resistant to the cytotoxic effects of DB-67 than H460 cells. Notably, A549 cells
      had approximately one-half the baseline topoisomerase I than H460 cells.
      Topoisomerase I protein levels significantly decreased after 8-18 h of exposure
      to DB-67. Both A549 and H460 cells treated with DB-67 for 24 h had only
      negligible amounts of topoisomerase I at the end of treatment. However, within 24
      h of drug removal topoisomerase I levels returned to near baseline levels in both
      cell lines. CONCLUSIONS: The decrease in topoisomerase I levels caused by DB-67
      may represent a mechanism of resistance to this novel camptothecin derivative.
      Dosing DB-67 once every 48-72 h may maximize the interaction of the drug with
      topoisomerase I and should be considered as a potential dosing schedule in the
      preclinical and clinical development of this compound.

PMID- 15197486
TI  - Effects of the proteasome inhibitor bortezomib alone and in combination with
      chemotherapy in the A549 non-small-cell lung cancer cell line.
AB  - BACKGROUND: Non-small-cell lung cancer (NSCLC) has a poor prognosis. Despite
      advances in therapy, survival has improved only slightly. The 26S proteasome
      regulates multiple cellular processes through degradation of ubiquitin-tagged
      proteins. The proteasome inhibitor, bortezomib (Velcade, formerly PS-341), has
      been shown to be an active anticancer agent both in vitro and in vivo in multiple
      tumor types. PURPOSE: To determine the molecular and cellular effects of the
      proteasome inhibitor in NSCLC as well as to evaluate the effectiveness of
      sequential treatment with bortezomib and gemcitabine/carboplatin (G/C)
      chemotherapy both in vitro and in vivo. METHODS: All experiments were performed
      in the A549 NSCLC cell line. MTT assays were used to evaluate cytotoxicity.
      Western blotting evaluated protein levels. Measures of apoptosis included FACS
      analysis, DAPI staining and caspase-3 cleavage. Long-term cell viability was
      determined using an anchorage-dependent clonogenic assay. Sequential studies were
      performed in vitro and in vivo. RESULTS: Bortezomib increased p21(waf1/cip1),
      induced G(2)/M arrest, and triggered a small amount of apoptosis. The apoptotic
      effect of G/C chemotherapy was eliminated when bortezomib was administered prior
      to the chemotherapy; however, it was accentuated when the bortezomib was given
      simultaneously or after the chemotherapy. CONCLUSIONS: Bortezomib improves
      efficacy in combination with gemcitabine and carboplatin in NSCLC, but sequential
      effects are important and must be considered when developing therapeutic
      regimens.

PMID- 15197487
TI  - Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome
      aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis.
AB  - PURPOSE: To test the anticancer properties of a nonhydrolyzable ether-linked
      acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R, 12
      trimethyltridecyl)chroman-6-yloxyacetic acid (alpha-TEA), and a derivative of
      camptothecin, 9-nitrocamptothecin (9-NC)singly and in combination against mouse
      mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent
      protein; 66cl-4-GFP) cultured in vitro or transplanted subcutaneously into the
      inguinal region of female BALB/c mice to form established tumors. METHODS:
      Following in vitro treatment of 66cl-4-GFP cells with alpha-TEA and suboptimal
      concentrations of 9-NC, singly or in combination, apoptosis was measured by
      morphological evaluation of nuclei stained with 4',6-diamidino-2-phenylindole
      (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For
      in vivo analyses alpha-TEA and 9-NC, both water-insoluble compounds, were
      formulated into liposomes using dil-auroylphosphatidylcholine and administered by
      aerosol to deliver doses calculated to be 36 and 0.4 microg/mouse per day,
      respectively, (singly or each separately for combined treatments) 7 days per
      week. RESULTS: Treatment of 66cl-4-GFP cells in culture for 3 days with a
      combination of alpha-TEA (10 microg/ml; singly produces 38% apoptosis), and
      suboptimal concentrations of 9-NC(15.6, 31.3, 62.5, or 125 ng/ml; singly produce
      2-7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise,
      combinations of alpha-TEA 9-NC inhibited DNA synthesis more than either agent
      administered singly. A significant reduction (P< 0.001)in growth of subcutaneous
      transplanted tumors was observed with liposome-formulated and aerosolized
      delivery of alpha-TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung
      metastasis was 83% in control vs 8 % in alpha-TEA-, 9-NC-, or combination-treated
      mice. Fluorescence microscopic examination of lungs and axillary and brachial
      lymph nodes showed a statistically significant decrease in metastasis observed in
      alpha-TEA-,9-NC-, and combination- vs control-treated animals. Analyses of
      primary tumor tissue for proliferation and apoptosis showed treatment groups to
      have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick
      end labeling, respectively. Treatments showed no measurable effects on two
      angiogenesis parameters,namely intratumoral blood volume as assessed by
      hemoglobin content and intratumoral blood vessel density as assessed with CD31
      staining. CONCLUSIONS: Combination treatments enhanced antiproliferative and
      proapoptotic activities in cell culture, and when formulated in liposomes and
      delivered via aerosolization to treat an aggressive and metastatic syngeneic
      murine mammary tumor, the combination treatment showed a significant reduction in
      tumor volume in comparison to either treatment alone. Mechanistically, it appears
      that neither enhanced apoptosis, reduced cell proliferation,nor reduced blood
      vessel density can fully account for the enhanced effects of the combination
      treatment.

PMID- 15197488
TI  - Ascorbate modulation of H(2)O(2) and camptothecin-induced cell death in Jurkat
      cells.
AB  - The effect of ascorbate on cell death was examined in Jurkat cells (human T-cell
      leukemia) by incubation with dehydroascorbate (DHA), which is rapidly taken up by
      cells and efficiently reduced to ascorbate. Apoptosis was evaluated by caspase-3
      activity in cell extracts and flow cytometry of annexin V-labeled cells. In
      parallel, necrosis was estimated by the release of lactate dehydrogenase. Minor
      effects on cell death were observed when Jurkat cells were incubated with either
      DHA alone (100-1,000 microM) or a single dose of 10 microM H(2)O(2). However, pre
      incubation with DHA followed by exposure to H(2)O(2) clearly stimulated both
      apoptosis and necrosis. In complete contrast, pre-incubation of cells with DHA
      significantly inhibited apoptosis, but did not affect necrosis, induced by the
      topoisomerase I inhibitor camptothecin. Our results indicate that intracellular
      ascorbate can modulate cell death in a manner which depends upon the nature of
      the apoptotic stimulus, which in turn has critical implications regarding the
      mechanism and potential application of ascorbate in cancer therapy.

PMID- 15197489
TI  - Involvement of oxidative stress and caspase activation in paclitaxel-induced
      apoptosis of primary effusion lymphoma cells.
AB  - Paclitaxel has significant antitumor activity in several human tumors, including
      Kaposi's sarcoma (KS). Human herpesvirus 8 (HHV-8) is implicated in all forms of
      Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's
      disease (MCD), indicating that it is a DNA tumor virus. Since it is difficult to
      culture cell lines derived from KS patients, we used a cell line derived from PEL
      (BCBL-1) to investigate whether oxidative stress is involved in the cytotoxicity
      of paclitaxel on the HHV-8-related tumors. We found that the generation of
      reactive oxygen species (ROS) in the BCBL-1 cells was increased by paclitaxel
      treatment, and the increase in ROS production was suppressed by antioxidants,
      including catalase and ascorbic acid. Moreover, ascorbic acid also attenuated the
      cytotoxicity induced by paclitaxel. Upon paclitaxel treatment, caspase-2, caspase
      3, and caspase-8 were activated in BCBL-1 cells. Cotreatment with antioxidants
      did not affect caspase-2, caspase-3 or caspase-8 activation. Paclitaxel-induced
      apoptosis was also accompanied by an increase in the protein levels of Bax, and
      this effect was attenuated by antioxidants. Paclitaxel slightly decreased the
      expression of Bcl-2 protein, but antioxidants induced Bcl-2 protein. These
      results suggest that oxidative stress is only partially involved in the
      cytotoxicity of paclitaxel in BCBL-1 cells, and that paclitaxel-induced apoptosis
      of BCBL-1 cells is primarily mediated by the caspase activation pathway.

PMID- 15197490
TI  - Appearance of the mandibular incisive canal on panoramic radiographs.
AB  - Panoramic radiographs are routinely used in the dental office for various
      diagnostic purposes. This study aimed to evaluate the visibility of neurovascular
      structures in the mandibular interforaminal region on such radiographs. Panoramic
      radiographs were obtained with a Cranex Tome (Soredex) from 545 consecutive
      patients using a standard exposure and positioning protocol. For visibility
      scoring of neurovascular structures, a four-point rating scale was used. The
      mandibular canal and the mental foramen could be observed in the majority of the
      cases with good visibility. The lingual foramen was visualized in 71% of the
      cases, with good visibility in 12%. An incisive canal was identified in 15% of
      the images, with good visibility in only 1%. An anatomical variation to be
      considered is the anterior looping of the mental nerve (in 11% of images).
      Panoramic radiographs can be used for visualization of the mental foramen and a
      potential anterior looping but not for locating the mandibular incisive canal. To
      verify its existence for preoperative planning purposes, cross-sectional imaging
      modalities (HR-CT or spiral tomography) should be preferred.

PMID- 15197491
TI  - Imaging and morphology of the paracondylar process in a dry adult human skull: a
      case report.
AB  - An unusually long paracondylar process (PCP) was found articulating with the
      transverse atlantal process in a dry adult male skull. It was 13 mm long and 19
      mm in circumference at its middle and projected to a lower plane than the styloid
      process of the same side. A radiograph revealed the structure of spongiosa of the
      PCP to be like mastoid cells. PCP can lead to clinical symptoms due to
      alterations in posture and functional limitations in neck movements. Thus
      awareness of this process, its topographical relations and its attendant problems
      is of importance to clinicians, radiologists, surgeons and chiropractors. In
      symptomatic cases surgical resection of this process can be attempted to relieve
      the symptoms. The craniovertebral junction constitutes a unique part of the
      somite-derived axial skeleton; the lowest part of the basioccipital component
      including this process develops from occipital sclerotomes. Developmental
      variations in this region can resemble deformities.

PMID- 15197492
TI  - Cubital tunnel release with two limited incisions: a cadaver study.
AB  - Cubital tunnel syndrome is the second most common compressive neuropathy in the
      upper extremity. Treatment of cubital tunnel syndrome consists of releasing the
      compression on the ulnar nerve with conservative or surgical methods. Nerve
      decompression is an alternative simple and less invasive procedure. We have
      proposed a "two limited incisions" technique in order to release the cubital
      tunnel with two minimal incisions on a cadaveric elbow model. Thirty elbows of 15
      formalin-fixed cadavers were studied. The study was performed in two steps. The
      first step involved a two limited incisions technique. During the second step,
      dissected anatomic structures were assessed. The cubital retinaculum was opened
      totally in 27 elbows (91%) and partially in two elbows (7%). The ulnar nerve was
      injured in one elbow (3%), because of the contracture of the forearm muscles. It
      was shown that with relaxation of the elements involved, a two limited incisions
      technique allowed decompression of the ulnar nerve at the elbow to be performed.

PMID- 15197493
TI  - Early results of endoscopic trochanter bursectomy.
AB  - Between 1995 and 2000, we performed 45 endoscopic bursectomies in 42 patients
      (average age 51, range 17-61 years). All patients had at least 6 months of failed
      conservative treatment, and all responded positively to a sonographic-guided
      injection with Mepivacaine 0.5%. The bursa was removed using a synovial resector.
      An additional tractopexie was performed in four cases. We followed 37 patients
      for 12-48 months. Pre-operatively, the mean modified Japanese Orthopaedic
      Association (JOA) disability hip score was 40.5 points. It improved to 72.6
      points after a mean of 25 months. Severe complications did not occur. The
      minimally invasive technique requires only stab incisions, and immobilisation and
      hospitalisation are minimal.

PMID- 15197494
TI  - Activated vitronectin as a target for anticancer therapy with human antibodies.
AB  - The formation of a provisional extracellular matrix represents an important step
      during tumor growth and angiogenesis. Proteins that participate in this process
      become activated and undergo conformational changes that expose biologically
      active cryptic sites. Activated matrix proteins express epitopes not found on
      their native counterparts. We hypothesized that these epitopes may have a
      restricted tissue distribution, rendering them suitable targets for therapeutic
      human monoclonal antibodies (huMabs). In this study, we exploited phage antibody
      display technology and subtractive phage selection to generate human monoclonal
      antibody fragments that discriminate between the activated and native
      conformation of the extracellular matrix protein vitronectin. One of the selected
      antibody fragments, scFv VN18, was used to construct a fully human IgG/kappa
      monoclonal antibody with an affinity of 9.3 nM. In immunohistochemical analysis,
      scFv and huMab VN18 recognized activated vitronectin in tumor tissues, whereas
      hardly any activated vitronectin was detectable in normal tissues. Iodine 123
      radiolabeled huMabVN18 was shown to target to Rous sarcoma virus-induced tumors
      in chickens, an animal model in which the epitope for huMab VN18 is exposed
      during tumor development. Our results establish activated vitronectin as a
      potential target for tumor therapy in humans.

PMID- 15197495
TI  - Escape from immunotherapy: possible mechanisms that influence tumor
      regression/progression.
AB  - Tumor escape is one major obstacle that has to be addressed prior to designing
      and delivering successful immunotherapy. There is compelling evidence to support
      the notion that immunogenic tumors, in murine models and cancer patients, can be
      rejected by the immune system under optimum conditions for activating adaptive
      and nonadaptive antitumor immune responses. Despite this capability, a large
      number of tumors continue to grow and evade recognition and/or destruction by the
      immune system. The limited success in current immunotherapeutic strategies may be
      due to a variety of reasons: failure of effector cells to compete with the
      growing tumor burden, production of humoral factors by tumors that locally block
      cytotoxicity, antigen/MHC loss, T-cell dysfunction, production of suppressor T
      cells-to name but a few causes for therapeutic ineffectiveness for the particular
      malignancy being treated. To optimize immunotherapy strategies, correction of
      immune-activating signals, eradication of inhibitory factors, and the evasion
      from newly developed immunoresistant tumor phenotypes need to be simultaneously
      considered.

PMID- 15197496
TI  - Dendritic cells in colorectal cancer correlate with other tumor-infiltrating
      immune cells.
AB  - Dendritic cells (DCs) are the most efficient antigen-presenting cells and play a
      key role in a cellular antitumor immune response. In this study we investigated
      the exact localization of DCs within colorectal tumors and their relationship to
      tumor-infiltrating lymphocytes as well as clinical outcome of the patients.
      Primary tumor specimens of 104 patients with a diagnosis of colorectal cancer
      were identified retrospectively and analyzed with the dendritic cell markers S
      100 protein and human leukocyte antigens (HLA) class II. The markers were
      individually combined with laminin as a second marker to facilitate the
      observation of the different tumor localizations. S-100 or HLA class II positive
      cells were found in the three different compartments of colorectal tumors: tumor
      epithelium, tumor stroma, and advancing tumor margin, but mainly present in tumor
      stroma and advancing tumor margin. S-100-positive tumor-infiltrating DCs in
      direct contact with tumor cells, i.e., in tumor epithelium, significantly
      correlated to the intraepithelial infiltration of CD4+ (p=0.02) and CD8+ (p=0.01)
      lymphocytes. High HLA class II+ cell infiltration in the tumor stroma correlated
      to a lower intraepithelial infiltration of CD8+ (p=0.02) lymphocytes. High
      intraepithelial infiltration of S-100-positive DCs suggested increased disease
      free survival, but was not statistically significant, while high amounts of HLA
      class II+ cells in the tumor stroma correlated with an adverse survival outcome.
      Our results show that the infiltration of DCs in colorectal cancer, depending on
      both location and type of marker, is correlated with local immune interactions
      and patient prognosis, suggesting a central role for DCs in controlling local
      tumor immunity.

PMID- 15197498
TI  - Source of impaired image quality in 3D whole-body FDG PET scanning.

PMID- 15197500
TI  - A comparison of (111)In-DOTATOC and (111)In-DOTATATE: biodistribution and
      dosimetry in the same patients with metastatic neuroendocrine tumours.
AB  - [Yttrium-90-DOTA-Tyr(3)]-octreotide (DOTATOC) and [(177)Lu-DOTA-Tyr(3)-Thr(8)]
      octreotide (DOTATATE) are used for peptide receptor-mediated radionuclide therapy
      (PRMRT) in neuroendocrine tumours. No human data comparing these two compounds
      are available so far. We used (111)In as a surrogate for (90)Y and (177)Lu and
      examined whether one of the (111)In-labelled peptides had a more favourable
      biodistribution in patients with neuroendocrine tumours. Special emphasis was
      given to kidney uptake and tumour-to-kidney ratio since kidney toxicity is
      usually the dose-limiting factor. Five patients with metastatic neuroendocrine
      tumours were injected with 222 MBq (111)In-DOTATOC and (111)In-DOTATATE within 2
      weeks. Up to 48 h after injection, whole-body scans were performed and blood and
      urine samples were collected. The mean absorbed dose was calculated for tumours,
      kidney, liver, spleen and bone marrow. In all cases (111)In-DOTATATE showed a
      higher uptake (%IA) in kidney and liver. The amount of (111)In-DOTATOC excreted
      into the urine was significantly higher than for (111)In-DOTATATE. The mean
      absorbed dose to the red marrow was nearly identical. (111)In-DOTATOC showed a
      higher tumour-to-kidney absorbed dose ratio in seven of nine evaluated tumours.
      The variability of the tumour-to-kidney ratio was high and the significance level
      in favour of (111)In-DOTATOC was P=0.065. In five patients the pharmacokinetics
      of (111)In-DOTATOC and (111)In-DOTATATE was found to be comparable. The two
      peptides appear to be nearly equivalent for PRMRT in neuroendocrine tumours, with
      minor advantages for (111)In/(90)Y-DOTATOC; on this basis, we shall continue to
      use (90)Y-DOTATOC for PRMRT in patients with metastatic neuroendocrine tumours.

PMID- 15197502
TI  - Assessment of the metabolic activity of bone grafts with (18)F-fluoride PET.
AB  - PURPOSE: The aims of this prospective study were to evaluate quantitative
      approaches to (18)F-fluoride positron emission tomography (PET) imaging in
      allogenic bone grafts of the limbs, and to assess the time course of graft
      healing after surgery. METHODS: We performed a total of 52 dynamic (18)F-fluoride
      PET studies in 34 patients with cancellous and full bone grafts. Seven patients
      were imaged three times at 6, 12, and 24 months after surgery, and four patients
      were imaged twice. PET data were quantitatively analyzed using non-linear
      regression (NLR) analysis, Patlak analysis, and standardized uptake value (SUV).
      RESULTS: Fluoride bone metabolism in cancellous grafts decreased by 25% from 6 to
      12 months post surgery, and revealed a total decrease of 60-65% after 2 years for
      SUV, K(Pat), and K(NLR). Full bone grafts first showed an increase by 20% from 6
      to 12 months and from then on decreased to 70% of the initial activity at the end
      of 2 years with either quantification method. In two patients with non-union of
      their full bone grafts, increases in SUV, K(Pat), K(NLR), and K(1) far above
      average and outside the normal time pattern were observed. Highly significant
      correlations were found between SUV, K(Pat), K(NLR), and K(1) for both grafts and
      normal limb bones. In patients imaged repeatedly, the percentage changes in
      fluoride graft metabolism were also significantly correlated between SUV, K(Pat),
      and K(NLR). CONCLUSION: Quantitative (18)F-fluoride PET is a promising tool for
      assessment of fluoride metabolism and normal healing in bone grafts of the limbs.

PMID- 15197501
TI  - Clinical utility of co-registered respiratory-gated( 99m)Tc-Technegas/MAA SPECT
      CT images in the assessment of regional lung functional impairment in patients
      with lung cancer.
AB  - PURPOSE: The aim of the study was to provide preliminary validation of the
      utility of co-registered respiratory-gated ventilation/perfusion single-photon
      emission computed tomography-computed tomography (SPECT-CT) images in the
      assessment of regional lung functional impairment in patients with lung cancer.
      METHODS: Twenty untreated and three radiotherapy-treated patients with lung
      cancer underwent gated( 99m)Tc-Technegas/macroaggregated albumin (MAA) SPECT,
      using a triple-headed SPECT unit and a respiratory synchroniser. Gated SPECT
      images were obtained from 1/8 data centered at peak inspiration for each regular
      respiratory cycle and co-registered with tidal inspiration CT images using an
      automated three-dimensional registration tool. RESULTS: Gated SPECT images
      detected 10.2% more ventilation defects (205 vs 186) and 9% more perfusion
      defects (218 vs 200) compared with ungated images, with a significantly higher
      lesion-to-normal lung contrast ( P<0.0001). Co-registered gated SPECT-CT images
      accurately visualised the anatomy of ventilation and/or perfusion defects
      associated with bronchial and/or vascular involvement by tumours, resulting in
      changes in surgical planning in two patients with lung cancer. In the three
      patients who had received radiotherapy, perfusion defects along the radiation
      field were identified even in the lung areas without abnormal opacities on CT
      images. In the operated patients, the co-registered gated SPECT-CT images allowed
      accurate placement of regions of interest over the lung lobes to be resected,
      yielding a significantly better prediction of postoperative forced expired volume
      in 1 s (FEV(1)) compared with that predicted without use of these images (
      R=0.993 vs R=0.890; P<0.05), with an excellent inter-observer reproducibility.
      CONCLUSION: Detailed functional-morphological correlation on co-registered gated
      SPECT-CT images contributes to accurate assessment of regional functional
      impairment, and may be useful for surgical planning, prediction of postoperative
      function and assessment of external beam radiotherapy effects in patients with
      lung cancer.

PMID- 15197504
TI  - Positron emission tomography imaging of adrenal masses: (18)F-fluorodeoxyglucose
      and the 11beta-hydroxylase tracer (11)C-metomidate.
AB  - PURPOSE: (11)C-metomidate (MTO), a marker of 11beta-hydroxylase, has been
      suggested as a novel positron emission tomography (PET) tracer for adrenocortical
      imaging. Up to now, experience with this very new tracer is limited. The aims of
      this study were (1) to evaluate this novel tracer, (2) to point out possible
      advantages in comparison with( 18)F-fluorodeoxyglucose (FDG) and (3) to
      investigate in vivo the expression of 11beta-hydroxylase in patients with primary
      aldosteronism. METHODS: Sixteen patients with adrenal masses were investigated
      using both MTO and FDG PET imaging. All patients except one were operated on.
      Five patients had non-functioning adrenal masses, while 11 had functioning
      tumours(Cushing's syndrome, n=4; Conn's syndrome, n=5; phaeochromocytoma, n=2).
      Thirteen patients had benign disease, whereas in three cases the adrenal mass was
      malignant (adrenocortical cancer, n=1; malignant phaeochromocytoma, n=1; adrenal
      metastasis of renal cancer, n=1). RESULTS: MTO imaging clearly distinguished
      cortical from non-cortical adrenal masses (median standardised uptake values of
      18.6 and 1.9, respectively, p<0.01). MTO uptake was slightly lower in patients
      with Cushing's syndrome than in those with Conn's syndrome, but the difference
      did not reach statistical significance. The expression of 11beta-hydroxylase was
      not suppressed in the contralateral gland of patients with Conn's syndrome,
      whereas in Cushing's syndrome this was clearly the case. The single patient with
      adrenocortical carcinoma had MTO uptake in the lower range. CONCLUSION: MTO could
      not definitely distinguish between benign and malignant disease. FDG PET,
      however, identified clearly all three study patients with malignant adrenal
      lesions. We conclude: (1) MTO is an excellent imaging tool to distinguish
      adrenocortical and non-cortical lesions; (2) the in vivo expression of 11beta
      hydroxylase is lower in Cushing's syndrome than in Conn's syndrome, and there is
      no suppression of the contralateral gland in primary aldosteronism; (3) for the
      purpose of discriminating between benign and malignant lesions, FDG is the tracer
      of choice.

PMID- 15197503
TI  - Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3
      [(18)F]trifluoropropyl)acetamide, [(18)F]EF3.
AB  - The 2-nitroimidazole derivative 2-(2-nitroimidazol-1-yl)- N-(3,3,3
      trifluoropropyl)acetamide (EF3) is a marker which forms adducts into hypoxic
      cells. Radiosynthesis of [(18)F]EF3 was recently performed by our group. Our aim
      was to study the pharmacokinetics, biodistribution, metabolism and specificity
      for hypoxia of [(18)F]EF3. MCa-4, SCC VII, NFSA, FSA, FSA II or Sa-NH tumour
      bearing C3H mice were injected intravenously with [(18)F]EF3 and allowed to
      breathe air, 10% O(2) or carbogen until sacrifice 5-770 min after injection.
      Radioactivity was measured ex vivo in various organs, including urine and faeces.
      Selected organs were additionally processed to measure tracer metabolites with
      high-performance liquid chromatography. The half-life in blood was 73.9 min.
      [(18)F]EF3 was eliminated mainly via the kidneys, with 75% of the injected
      activity found in the urine by 12 h 50 min. The biodistribution was fast and
      homogeneous except in the brain and the bone, where it was significantly lower,
      and in the liver and the kidney, where it was significantly higher. In most
      organs, the exceptions being the gastrointestinal and urinary tract, tissue-to
      blood ratios were below or close to unity. In tumours, a relative accumulation of
      the tracer was observed with time, which, at 220 min after injection, depended on
      tumour strain and oxygenation conditions, i.e. 10% O(2) significantly increased
      the tumour-to-muscle ratio whereas carbogen decreased it. [(18)F]EF3 was rapidly
      metabolised in the kidney and the liver. [(18)F]EF3 is a promising tracer for
      detection of tumour hypoxia. A phase I study in head and neck cancer patients is
      in progress at our institution.

PMID- 15197505
TI  - Pancreatic cancer or chronic pancreatitis? An answer from PET/MRI image fusion.

PMID- 15197506
TI  - Imaging techniques in the assessment of myocardial hibernation.

PMID- 15197508
TI  - Rothmund-Thomson syndrome, Klippel-Feil syndrome, and osteosarcoma.
AB  - We report on a 33 year old woman with Rothmund-Thompson syndrome, Klippel-Feil
      syndrome and osteosarcoma. We briefly discuss the relationship of these diseases
      and suggest that the cause for mental retardation is cerebral atrophy as shown on
      imaging.

PMID- 15197509
TI  - Phylogenetic analysis based on genome-scale metabolic pathway reaction content.
AB  - Phylogenetic classifications based on single genes such as rRNA genes do not
      provide a complete and accurate picture of evolution because they do not account
      for evolutionary leaps caused by gene transfer, duplication, deletion and
      functional replacement. Here, we present a whole-genome-scale phylogeny based on
      metabolic pathway reaction content. From the genome sequences of 42
      microorganisms, we deduced the metabolic pathway reactions and used the
      relatedness of these contents to construct a phylogenetic tree that represents
      the similarity of metabolic profiles (relatedness) as well as the extent of
      metabolic pathway similarity (evolutionary distance). This method accounts for
      horizontal gene transfer and specific gene loss by comparison of whole metabolic
      subpathways, and allows evaluation of evolutionary relatedness and changes in
      metabolic pathways. Thus, a tree based on metabolic pathway content represents
      both the evolutionary time scale (changes in genetic content) and the
      evolutionary process (changes in metabolism).

PMID- 15197510
TI  - The effects of extracellular polymeric substances on the formation and stability
      of biogranules.
AB  - Biogranulation is a promising biotechnology developed for wastewater treatment.
      Biogranules exhibit a matrix microbial structure, and intensive research has
      shown that extracellular polymeric substances (EPS) are a major component of the
      biogranule matrix material in both anaerobic and aerobic granules. This paper
      aims to review the role of EPS in biogranulation, factors influencing EPS
      production, the effect of EPS on cell surface properties of biogranules, and the
      relationship of EPS to the structural stability of biogranules. EPS production is
      substantially enhanced when the microbial community is subject to stressful
      culture conditions, and the stimulated EPS production in the microbial matrix in
      turn favours the formation of anaerobic and aerobic granules. EPS can also play
      an essential role in maintaining the integrity and stability of spatial structure
      in mature biogranules. It is expected that this paper can provide deep insights
      into the functions of EPS in the biogranulation process.

PMID- 15197511
TI  - cDNA cloning and genomic structure of the duck (Anas platyrhynchos) MHC class I
      gene.
AB  - In order to provide data for studies on disease resistance, duck MHC class I cDNA
      (Anpl-MHC I) was cloned from a duck cDNA library and the genome structure was
      investigated. Anpl-MHC I genes encoded 344-355 amino acids. The genomic
      organization is composed of eight exons and seven introns. Based on the genetic
      distance, Anpl-MHC I cDNA from six individuals can be classified into four
      lineages (from Anpl-UAA to Anpl-UDA). A total of 28 amino acid positions in the
      peptide-binding domain (PBD) showed high scores by Wu-kabat index analysis. The
      Anpl-MHC amino acid sequence displayed seven critical HLA-A2amino acids that bind
      with antigen polypeptides, and have an 83.6-88.5% amino acid homology with each
      lineage, a 55.2-64.6% amino-acid homology with chicken MHC class I (B-FIV21, B
      FIV2, Rfp-Y), and a 40.3-42.8% homology with mammalian MHC class I. Nested PCR
      detected that Anpl-MHC I can be expressed in the brain, heart, kidney, intestines
      and bursa. Compared with the human HLA-A2 tertiary structure of the PBD, Anpl-MHC
      I had an insertion or deletion variation in four domains (A-D). The phlyogenetic
      tree appears to branch in an order consistent with accepted evolutionary
      pathways.

PMID- 15197513
TI  - Radiation dose and cancer risk to children undergoing skull radiography.
AB  - BACKGROUND: Limited data exist in the literature concerning the patient-effective
      dose from paediatric skull radiography. No information has been provided
      regarding organ doses, patient dose during PA skull projection, risk of cancer
      induction and dose to comforters, i.e. individuals supporting children during
      exposure. OBJECTIVE: To estimate patient-effective dose, organ doses, lifetime
      cancer mortality risk to children and radiation dose to comforters associated
      with skull radiography. MATERIALS AND METHODS: Data were collected from 136
      paediatric examinations, including AP, PA and lateral skull radiographs. Entrance
      surface dose (ESD) and dose to comforters were measured using thermoluminescent
      dosimeters. Patients were divided into the following age groups: 0.5-2, 3-7, 8-12
      and 13-18 years. The patient-effective dose and corresponding organ doses were
      calculated using data from the NRPB and Monte Carlo techniques. The risk for
      fatal cancer induction was assessed using appropriate risk coefficients. RESULTS:
      For AP, PA and lateral skull radiography, effective dose ranges were 8.8-25.4,
      8.2-27.3 and 8.4-22.7 microSv respectively, depending upon the age of the child.
      For each skull projection, the organs receiving doses above 10 microGy are
      presented. The number of fatal cancers was found to be less than or equal to 2
      per 1 million children undergoing a skull radiograph. The mean radiation dose
      absorbed by the hands of comforters was 13.4 microGy. CONCLUSIONS: The current
      study provides detailed tabular and graphical data on ESD, effective dose, organ
      doses and lifetime cancer mortality risk to children associated with AP, PA and
      lateral skull projections at all patient ages.

PMID- 15197512
TI  - The transmembrane domain of Neu in a lipid bilayer: molecular dynamics
      simulations.
AB  - The results of full-atom molecular dynamics simulations of the transmembrane
      domains (TMDs) of both native, and Glu664-mutant (either protonated or
      unprotonated) Neu in an explicit fully hydrated dimyristoylphosphatidylcholine
      (DMPC) lipid bilayer are presented. For the native TMD peptide, a 10.05 ns
      trajectory was collected, while for the mutant TMD peptides 5.05 ns trajectories
      were collected for each. The peptides in all three simulations display stable
      predominantly alpha-helical hydrogen bonding throughout the trajectories. The
      only significant exception occurs near the C-terminal end of the native and
      unprotonated mutant TMDs just outside the level of the lipid headgroups, where pi
      helical hydrogen bonding develops, introducing a kink in the backbone structure.
      However, there is no indication of the formation of a pi bulge within the
      hydrophobic region of either native or mutant peptides. Over the course of the
      simulation of the mutant peptide, it is found that a significant number of water
      molecules penetrate the hydrophobic region of the surrounding lipid molecules,
      effectively hydrating Glu664. If the energy cost of such water penetration is
      significant enough, this may be a factor in the enhanced dimerization affinity of
      Glu664-mutant Neu.

PMID- 15197514
TI  - Reversible transinsular herniation of the lateral ventricle.
AB  - We present a 7-year-old boy, with a history of neonatal intraventricular
      hemorrhage, leading to hydrocephalus with multiple shunt revisions. The current
      presentation of shunt failure and resultant hydrocephalus was complicated by
      herniation of the trigone of the lateral ventricle into the posterior fossa.
      Despite the dramatic radiological appearance, this herniation of the lateral
      ventricle was not accompanied by any additional clinical signs or symptoms other
      than those usually attributed to hydrocephalus. Following successful shunt
      revision, the patient returned to his baseline clinically with the trigone
      reverting back to its normal position. We also present a second companion case.

PMID- 15197515
TI  - The influence of oxalate on renal epithelial and interstitial cells.
AB  - Most renal stones in humans are composed of calcium oxalate. An increase in
      urinary oxalate levels has been shown to result in renal epithelial cell injury
      and crystal retention. However, the underlying mechanisms are unclear. Although
      the localization of primary stone formation and the associated cells playing the
      pivotal role in stone formation are still unknown, renal epithelial cells and
      interstitial cells seem to be involved in this process. The aim of this study was
      to evaluate the effects of oxalate on distinct renal epithelial and endothelial
      cells as well as fibroblasts. The first part focused on the toxicity of oxalate
      on the cells and a potential time- and dose-dependency. In the second part, renal
      epithelial cells were cultured in a two-compartment model to examine the
      vulnerability of the tubular or basolateral side to oxalate. LLCPK1, MDCK, renal
      fibroblast and endothelial cell lines were cultured under standard conditions. In
      part 1, cells were grown in standard culture flasks until confluent layers were
      achieved. Sodium oxalate was delivered at final concentrations of 1, 2 and 4 mM
      to either the apical or basolateral side (plain medium was delivered to the
      contralateral side). Cell survival was assessed microscopically by trypan blue
      staining after 1, 2 and 4 h. The influence of oxalate on proliferation and
      apoptosis induction was also investigated. In the second part, MDCK and LLCPK1
      cells were grown in 6-well plates until confluent layers were achieved. Sodium
      oxalate at the above concentrations was applied, to either the apical or
      basolateral side and plain medium was delivered to the opposite side. The same
      protocol was then followed as in part 1. Part 1: sodium oxalate led to a time-
      and concentration-dependent decline in cell survival that was comparable in
      LLCPK1 and MDCK. Non-tubular cell lines like fibroblasts and endothelial cells
      were significantly more vulnerable to oxalate. These observations were reflected
      by significant impairment to cell proliferation. We could not demonstrate an
      induction of apoptosis in any cell line. Part 2: both cell lines were more
      vulnerable to oxalate on the basolateral side. This effect was more pronounced in
      MDCK cells at high oxalate concentrations (4 mM). Cells are apparently more
      resistant on the apical (tubular) side. Our results show that sodium oxalate has
      a negative effect on the growth and survival of renal epithelial cells and, to a
      greater extent, also fibroblasts and endothelial cells. We could not demonstrate
      any induction of apoptotic processes which implies a direct induction of cell
      necrosis. The finding of interstitial calcification and the proximity of tubules,
      vessels and interstitial cells make involvement of non-tubular renal cells in
      tissue calcification processes possible. Renal epithelial cells are apparently
      more vulnerable to oxalate on their basolateral side. Therefore, calcification
      processes within the interstitium may exert pronounced toxic effects to these
      cells, leading to inflammation and necrosis. These observations further support
      the idea of the interstitium as a site of primary stone formation.

PMID- 15197516
TI  - Homotoxicology--a review of randomised clinical trials.
AB  - AIM: Homotoxicology is a form of therapy that uses homoeopathically diluted
      remedies with a view of eliminating toxins from the body. It is not a therapeutic
      method based on accepted scientific principles or biological plausibility. Yet
      numerous clinical studies have claimed efficacy. The aim of this systematic
      review is to summarise and critically evaluate the evidence from rigorous
      clinical trials of this form of therapy. METHODS: Seven electronic databases were
      searched for all studies of homotoxicological medicines for any human condition.
      To be included, trials had to be randomised and placebo-controlled. Data from
      such studies were validated and extracted according to pre-defined criteria.
      Their methodological quality was formally assessed using the Jadad score. Key
      data of all included trials were tabulated and summarised in narrative form.
      RESULTS: Seven trials met our inclusion criteria. Their Jadad scores indicated
      mostly a high methodological standard. The trials tested the efficacy of seven
      different medicines for seven different indications. The results were positive in
      all but one study. Important flaws were found in all trials. These render the
      results of the primary studies less reliable than their high Jadad scores might
      suggest. CONCLUSION: Despite mostly positive findings and high ratings on the
      Jadad score, the placebo-controlled, randomised clinical trials of homotoxicology
      fail to demonstrate the efficacy of this therapeutic approach.

PMID- 15197517
TI  - Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in
      healthy subjects.
AB  - PURPOSE: The objective of the study was to determine the effect of a potent and
      selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of
      nateglinide (Starlix), a novel antidiabetic drug which is primarily
      (approximately 70%) metabolized via CYP2C9. METHODS: This was a randomized, open
      label, two-period, crossover study in 18 healthy volunteers. Nateglinide was
      administered as a single 120-mg oral dose alone (reference) on day 1 or in
      combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg
      oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic
      parameters of nateglinide were determined following the administration of
      nateglinide alone, and when administered in combination with sulfinpyrazone.
      Plasma nateglinide concentrations were determined using a validated high
      performance liquid chromatography method. RESULTS: The administration of
      nateglinide in combination with sulfinpyrazone resulted in approximately 28%
      higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20-1.39) with
      no differences in mean peak plasma concentration (Cmax; 90% CI test-reference
      ratio: 0.86-1.12) compared with nateglinide-alone treatment. The time to reach
      Cmax (tmax) and the elimination half-life of nateglinide were similar between the
      two treatments. Both treatments were safe and well tolerated. CONCLUSIONS:
      Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs
      were administered in combination. Nateglinide, given as a single dose or co
      administered with multiple doses of sulfinpyrazone, was safe and well tolerated
      in healthy subjects.

PMID- 15197518
TI  - Glutathione S-transferase M1 and T1 null genotype distribution in South Indians.
AB  - OBJECTIVE: To investigate the distribution of the homozygous null genotypes of
      GSTM1 and GSTT1 in the South Indian population. METHODS: Five hundred and
      seventeen unrelated natives of the South Indian states of Tamilnadu and
      Pondicherry (n=170), Kerala (n=122), Karnataka (n=110) and Andhra Pradesh (n=115)
      were analyzed for homozygous deletions of GSTM1 and GSTT1. A multiplex polymerase
      chain reaction method simultaneously detected both GSTM1 and GSTT1 homozygous
      null genotypes. The observed frequencies from the four groups were compared
      statistically with each other and the combined frequencies were compared with
      frequencies of other major populations previously reported in the literature.
      RESULTS: In South India, 30.4% (95% CI 26.4-34.3) lacked the GSTM1 gene, 16.8%
      (13.6-20.1) lacked the GSTT1 gene and 4.6% (3.0-6.8) lacked both the GSTM1 and
      GSTT1 genes. The highest frequency of GSTM1 null was observed in Karnataka
      (36.4%, 27.4-45.4), while Andhra Pradesh had the lowest frequency of the GSTM1
      and GSTT1 combined double-null genotypes (1.7%, 0.21-6.2). CONCLUSION: The
      prevalence of the GSTM1 null genotype differed within India. The frequency of
      GSTM1 null in South Indians was significantly lower than that in Caucasians. The
      frequencies of both GSTM1 and GSTT1 null genotypes in South Indians were
      significantly lower than in the Japanese.

PMID- 15197519
TI  - The use of over-the-counter drugs among surgical and medical patients.
AB  - INTRODUCTION: An increasing number of drugs are sold directly to the consumers
      without a prescription from pharmacies and from non-pharmacies such as
      supermarkets and gas stations. AIM OF STUDY: To analyse the consumption of over
      the-counter drugs (OTCs) among patients recently discharged from two hospital
      departments. Furthermore, to describe where the drugs had been bought and to
      which extent OTCs used prior to admission were recorded in the hospital files.
      METHOD: Patients were visited within 1 week after discharge and interviewed about
      OTC use. Home inventories were inspected. Hospital files and discharge letters
      were examined. RESULTS: In totally, 83 surgical and 117 medical patients were
      included (n=200). Whereas the home inventories of 187 patients comprised 587
      OTCs, 13 patients (7%) stored no OTCs. Of the patients, 134 (67%) used OTCs daily
      and 132 patients (66%) used OTCs on demand; 79 patients (40%) stored a total of
      157 OTCs not currently used. Analgesics were used by 138 patients (78%).
      Acetaminophen was the OTC used most frequently. Of the 240 OTCs used daily, 238
      (99%) had been purchased from pharmacies and 169 (70%) had been prescribed. Of
      the 430 OTCs used daily or on demand, 348 (81%) had been recommended verbally or
      prescribed by health care professionals. Among the 206 OTCs used daily prior to
      admission, 162 (79%) were recorded in hospital files, whereas only 41 (24%) of
      173 OTCs used on demand were recorded. CONCLUSION: Two of three surgical and
      medical patients use OTCs daily. Most OTCs are used with the consent of health
      care professionals and are purchased from pharmacies. Pre-admission OTC use is
      incompletely recorded in the hospital files. If information was systematically
      collected from pharmacies and general practitioners, the number of recall biases
      concerning OTC use in the medication histories may be reduced.

PMID- 15197520
TI  - Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus
      intravenously at daytime versus night-time in healthy men aged 55-70 years.
AB  - OBJECTIVE: To investigate (1) the pharmacokinetic and pharmacodynamic profiles of
      desmopressin in men from an age group with a high incidence of nocturia; and (2)
      circadian variation in the pharmacokinetic parameters. METHODS: The study had an
      open, randomised, four-way cross-over design. Desmopressin was administered
      orally (0.2 mg) and intravenously (2 microg), daytime and night-time, yielding
      four in-hospital sessions, separated by at least 2 days. Blood samples were taken
      before and at predetermined time points up to 12 h after dosing. Pharmacokinetic
      parameters were derived using a two-compartmental model except for AUC(0-->t),
      which was derived using non-compartmental analysis. Bioavailability was estimated
      using AUC(0-->t) for the oral and the intravenous periods. Urine, for
      measurements of volume and osmolality, was collected in predetermined intervals
      before and until 12 h after dosing. RESULTS: Fifteen healthy men aged 55-70 years
      were included in the analysis. The concentration-time curve after 2 microg
      intravenous desmopressin was best described using a biexponential term. The mean
      (95% CI) AUC at night was 302 (272-335) pg x h/ml and in the day was 281 (253
      312) pg x h/ml. No statistically significant differences were detected between
      night and day except for terminal half-life, which was 3.1 h at night and 2.8 h
      in the daytime (P=0.02). After oral desmopressin, concentrations above the limit
      of quantification (2.5 pg/ml) were only detected in 51% of the samples. Peak
      plasma concentration (Cmax) was 6.2 (5.1-7.5) pg/ml at night and 6.6 (5.5-7.9)
      pg/ml in the daytime. Median time to reach Cmax (tmax) was 1.5 (range 1.0-4.1) h
      at night and 1.5 (range 0.5-3.0) h in the day. The bioavailability was 0.08%. The
      pharmacodynamic effects of oral and intravenous desmopressin given in the daytime
      were similar during the first 6 h after dosing. The night-time dosing and daytime
      intravenous dose resulted in antidiuresis throughout the measuring period, while
      the effect of the daytime peroral dose receded after 6 h. CONCLUSION: The
      pharmacokinetic profile of desmopressin is biexponential. Terminal half-life was
      longer at night than in the daytime, but the difference is considered too small
      to be of clinical importance. The plasma levels given by the intravenous dose
      resulted in a duration of action of 12 h or more. Despite low bioavailability,
      the pharmacodynamic effects of oral desmopressin were similar in magnitude to
      those after intravenous dose at night and during the first 6 h after daytime
      administration.

PMID- 15197521
TI  - Increased liability of tramadol-warfarin interaction in individuals with
      mutations in the cytochrome P450 2D6 gene.
AB  - OBJECTIVE: This study aimed to investigate the importance of cytochrome P(450)
      enzymes for the reported interaction between tramadol and warfarin. MATERIALS AND
      METHODS: Cases of suspected interaction between tramadol and warfarin resulting
      in International Normalised Ratios increases that were reported to the Swedish
      Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten
      cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.
      RESULTS: Seven of ten patients carried defective CYP2D6 alleles (population
      prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received
      concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.
      CONCLUSION: The liability to an interaction between tramadol and warfarin may be
      related to the CYP2D6 activity.

PMID- 15197522
TI  - High prevalence of unknown co-medication in hospitalised patients.
AB  - OBJECTIVE: Co-medication unknown to the treating physician, including self
      medication, may compromise drug safety by increasing the risk of duplicate
      therapy, drug interactions and adverse drug reactions that are not recognised as
      such. The aim of the current study was to estimate exposure to unknown co
      medication during hospitalisation by performing an analytical screening for a
      broad range of drugs and drug classes in urine of patients admitted to a general
      internal medicine ward. METHODS: Urine samples of 44 patients were analysed with
      REMEDiHS (high-performance liquid chromatography) and six different immunoassays.
      Positive results were compared with drug history and documented drug
      prescription. If appropriate, gas chromatographic-mass spectrometric confirmatory
      analyses were performed on drugs classified at least once as possible unknown co
      medication. RESULTS: Nine (20%) of the patients tested positive for a compound
      detected by two independent analytical methods and 18 (41%) for a compound
      detected by at least one analytical method. Unknown co-medication consisted
      mostly of analgesics, benzodiazepines or ranitidine. CONCLUSION: At least one in
      five patients exhibits at least once during hospitalisation exposure to drugs not
      documented in the patient record, which may compromise patient safety.

PMID- 15197523
TI  - CYP2C9 genetic variants and losartan oxidation in a Turkish population.
AB  - OBJECTIVE: Cytochrome P(450) 2C9 (CYP2C9) is a polymorphic enzyme catalysing the
      metabolism of several important drugs. Losartan has recently been suggested as a
      selective probe for CYP2C9 metabolic activity. The aim of the study was to
      determine the activity of CYP2C9, using losartan as a probe drug, in relation to
      CYP2C9 genotype in healthy Turkish subjects. METHODS: A single oral dose of 25 mg
      losartan was given to 85 Turkish unrelated subjects. Concentrations of losartan
      and its carboxylic acid metabolite, E3174, were analysed by means of high
      performance liquid chromatography in urine collected for 8 h. The CYP2C9
      genotypes were determined in 85 subjects using polymerase chain reaction-based
      endonuclease digestion methods specific for CYP2C9*2 and *3. Losartan oxidation
      was also studied in vitro, using human CYP2C8 and CYP2C9 enzymes expressed in
      yeast. RESULTS: The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3
      were 0.100 and 0.088, respectively. The urinary losartan/E3174 ratio was
      significantly higher in subjects with CYP2C9*1/*3 genotype (median 2.35, n=12)
      than in subjects with CYP2C9*1/*1 (0.71, n=58) and *1/*2 (0.85, n=10) genotypes (
      P<0.05). In contrast to CYP2C9, no E3174 was formed by CYP2C8 in vitro.
      CONCLUSION: The urinary losartan to E3174 metabolic ratio after a 25-mg losartan
      dose was found to be a safe and useful phenotyping assay for CYP2C9 activity in
      vivo. CYP2C9*3 variant allele is a major determinant of the enzyme activity, and
      it decreases losartan metabolism significantly, while CYP2C9*2 allele has less
      impact on enzyme function.

PMID- 15197525
TI  - Reduced fields of view are neither necessary nor sufficient for distance
      underestimation but reduce precision and may cause calibration problems.
AB  - Watt et al. (Exp Brain Res, 2000, 135:411-416) suggested that a reduced field of
      view causes objects to appear closer than their physical distance. This
      suggestion is based on the observation that individuals terminated open-loop
      prehension prematurely when pretending to grasp a paper rectangle initially
      viewed through a reduced field of view. We tested Watt et al.'s suggestion in an
      open-loop pointing task. In experiment 1, 21 participants pointed at targets in
      three locations (20, 30 and 40 cm relative to the starting position) in three
      viewing conditions (full, 16 degrees and 4 degrees field of view). No difference
      in accuracy was found between conditions but the reduced field of view led to an
      increase in end-point variability across trials. We interpret these results as
      indicating that a reduced field of view decreases precision but does not
      necessarily affect object localisation. In experiment 2, we asked participants to
      reach-and-grasp a real object under the same three open-loop viewing conditions
      but without vision following movement onset. The experimental design ensured that
      haptic feedback was available, which could be used to calibrate reaching
      movements. We found that the reduced field of view caused no changes in grasp but
      we observed changes in the transport kinematics consistent with increased
      variability in the perceptual estimate of target location. Notably there were no
      changes in the spatial path (expected from movements to a closer location). In
      experiment 3, we repeated the Watt et al. design but removed vision and forced
      participants to rely on memory. In this condition we found the same undershoots
      as described by Watt et al. We conclude that a reduced field of view is neither
      necessary nor sufficient for underestimation and suggest that a reduced field of
      view decreases precision. This can cause participants to undershoot and/or alter
      the movement kinematics but we argue that such findings cannot be ascribed
      unambiguously to perceptual underestimation as they may reflect strategic
      alterations in behaviour.

PMID- 15197524
TI  - Gene expression of cytochromes P450 in liver transplants over time.
AB  - OBJECTIVE: The aim of this study was to (a) quantify the gene expression of some
      cytochromes P(450) (CYP), especially CYP3A4, in serial biopsies from liver grafts
      the first year after orthoptic liver transplantation (OLT) and (b) study the
      relationship between hepatic CYP3A4 gene expression and plasma levels of
      cyclosporine and tacrolimus. METHODS: Liver tissue was obtained from surplus
      material of routine liver biopsies performed in 20 patients during the first year
      after OLT. Real-time reverse-transcription polymerase chain reaction was used for
      quantitative analyses of mRNA specific for CYP3A4, CYP3A5, CYP2E1 and CYP1A2
      cytochromes as well as P-glycoprotein (P-gp). The gene expression of beta-actin
      was used as an internal standard for comparisons between samples. RESULTS: The
      median value of the mRNA for all cytochromes, but not for P-gp, was found to
      increase significantly over time. The gene expression of CYP3A5, CYP2E1 and
      CYP1A2 was higher than that of CYP3A4. The gene expression of CYP3A4 was related
      to the plasma concentration of cyclosporine and tacrolimus, i.e. low mRNA
      concentrations corresponded to high serum concentration levels and vice versa.
      The serum concentration of bilirubin or the prothrombin index did not correlate
      with the gene expression level of the cytochromes. CONCLUSION: The hepatic mRNA
      expression of CYP3A4 and the other investigated cytochromes increased during the
      first year after OLT. This was not the case with P-gp. Low CYP3A4 gene expression
      was related to high plasma levels of cyclosporine and tacrolimus and vice versa.

PMID- 15197526
TI  - Does postural chain mobility influence muscular control in sitting ramp pushes?
AB  - This study was conducted under the hypothesis that voluntary movement involves a
      perturbation of body balance and that a counter-perturbation has to be developed
      to limit the perturbation effects, which is a condition necessary to perform the
      movement efficiently. The stabilising action is produced in body segments that
      constitute the "postural" chain, and the voluntary movement by the segments said
      to constitute the "focal" chain. In order to deepen the understanding of how the
      postural chain contributes to the motor act, isometric transient efforts were
      considered. Seven adults in a sitting posture were instructed to exert bilateral
      horizontal pushes on a dynamometric bar, as rapidly as possible, up to their
      maximal force (Fx). Two sitting conditions were considered: full ischio-femoral
      contact (100 BP) and one-third ischio-femoral contact (30 BP), the latter being
      known to yield greater pelvis and spine mobility, that is greater postural
      mobility. Each session consisted of ten maximal pushes for each sitting
      condition. In order to explore the influence of postural mobility on muscular
      control and push force, surface EMGs of 14 postural and focal muscles were
      recorded. In addition, reaction forces (Rx) and displacement (Xp) of the centre
      of pressure (along the anteroposterior axis) were measured, as well as iliac
      crest acceleration (xh and zh, along the anteroposterior and vertical axes,
      respectively). The results showed that push force varied abruptly during the task
      ramp effort. When the ischio-femoral contact was limited, push force was
      enhanced, as well as the rate of push force rise (Fx/Deltat, Deltat being the
      force rise duration), suggesting a greater perturbation to balance. Also, there
      were significant increases in the Rx reaction forces, indicating body segment
      acceleration: "dynamic" phenomena occurred in the articulated body chain in
      response to increases in Fx. In addition, even though muscular contraction was
      isometric, postural EMGs, as well as focal EMGs, were phasic, a feature which
      characterises transient force exertion. The Rx reaction forces were associated
      with backward displacement of the centre of pressure, Xp. The centre of pressure
      displacement was interpreted as a backward pelvis rotation, an interpretation
      which was confirmed by backward and upward iliac crest accelerations. When ischio
      femoral contact was reduced, the backward pelvis rotation was significantly
      increased, resulting from an increased pelvis and spine mobility. Distinct focal
      and postural EMG sequences were found to be associated with the effort. Two
      different sets of muscles were observed when considering recruitment order, the
      focal and the postural muscles. The ankle muscles were activated before the
      pelvis, the back and the scapular girdle, with the upper limb muscles activated
      only after the onset of the primum movens of push action (serratus anterior): the
      activation process followed a distal to proximal progression order. Moreover, the
      postural EMG sequence was anticipatory, that is there were anticipatory postural
      adjustments (APAs). Modifying the ischio-femoral contact did not induce a change
      in either the postural muscle set or in the recruitment order. There were
      significant increases in the level of activation (integrated EMG) of the postural
      muscles when ischio-femoral contact was reduced. They did not result from an
      increase in EMG duration but only from a modulation of EMG amplitude, suggesting
      that postural control for different ischio-femoral contacts involves adapting the
      motor program according to the postural requirements, rather than changing the
      postural strategy. Moreover, as APA amplitude was increased when ischio-femoral
      contact was reduced, it could be assumed that the postural chain is programmed in
      relation to postural chain mobility. In addition, the increase in postural EMGs
      was interpreted as an increased counter-perturbation opposed to an increased push
      force. It is concluded that greater mobility of the postural chain favours a
      greater dynamic counter-perturbat chain favours a greater dynamic counter
      perturbation, which, in turn, allows the development of a greater push force; the
      ability to develop such a counter-perturbation (termed PKC: posturo-kinetic
      capacity) is enhanced when postural chain mobility is greater. Postural chain
      mobility appears to be a task parameter, and postural control appears to involve
      adapting the motor program according to the postural requirements, rather than
      changing the postural strategy.

PMID- 15197527
TI  - Multisensory integration mechanisms in haptic space perception.
AB  - It has been argued that representations of peripersonal space based on haptic
      input are systematically distorted by egocentric reference frames. Interestingly,
      a recent study has shown that noninformative vision (i.e., freely viewing the
      region above the haptic workspace) improves performance on the so-called haptic
      parallel-setting task, in which participants are instructed to rotate a test bar
      until it is parallel to a reference bar. In the present study, we made a start at
      identifying the different sensory integration mechanisms involved in haptic space
      perception by distinguishing the possible effects of orienting mechanisms from
      those of noninformative vision. We found that both the orienting direction of
      head and eyes and the availability of noninformative vision affect parallel
      setting performance and that they do so independently: orienting towards a
      reference bar facilitated the parallel-setting of a test bar in both no-vision
      and noninformative vision conditions, and noninformative vision improved
      performance irrespective of orienting direction. These results suggest the
      effects of orienting and noninformative vision on haptic space perception to
      depend on distinct neurocognitive mechanisms, likely to be expressed in different
      modulations of neural activation in the multimodal parietofrontal network,
      thought to be concerned with multimodal representations of peripersonal space.

PMID- 15197529
TI  - Evaluation of several pneumatic micronebulizers with different designs for use in
      ICP-AES and ICP-MS. Future directions for further improvement.
AB  - This paper reports characterization of the behavior of five pneumatic
      micronebulizers based on slightly different designs in inductively coupled plasma
      atomic-emission spectrometry and mass spectrometry (ICP-AES and ICP-MS). Two
      nebulizers were used as reference nebulizers, a high-efficiency nebulizer (HEN)
      and a micromist (MM). They were compared with a commercially available PFA
      (tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer) nebulizer and with two
      new prototypes called the polymeric pneumatic concentric nebulizer (PMN) and the
      high-solids micronebulizer (HSM). The dimensions of the nebulizers, the gas back
      pressure, and the free liquid uptake rates were measured. The study also included
      tertiary aerosol drop-size distributions, analyte transport rate, and analytical
      figures of merit, i.e. sensitivities and limits of detection, both in ICP-AES and
      ICP-MS. Recoveries for two food solid reference materials were also determined.
      Overall, the results indicated that the PFA and the HEN nebulizers provided the
      best results. These two nebulizers delivered a higher mass of analyte to the
      plasma and showed better sensitivies giving lower limits of detection than the
      PMN, HSM and MM. The results revealed that the liquid prefilming effect occurring
      before aerosol production in the PFA nebulizer promoted more efficient
      interaction of liquid and gas, thus affording good results even though gas back
      pressure values could be maintained below 3 bar. In contrast, the HEN had to be
      operated at about 7 bar under the same conditions. Nebulizer design did not have
      a relevant effect on the recovery, which confirmed that the spray chamber plays
      an important role in terms of non-spectroscopic interferences.

PMID- 15197530
TI  - Separation of traces of heavy metals from an iron matrix by use of an emulsion
      liquid membrane.
AB  - An emulsion liquid membrane method has been developed for separating traces of
      heavy metals from an iron matrix. A 1.0-mL volume of aqueous iron(III) solution
      (pH 2.0) was emulsified with a mixture of 0.6 mL toluene, 2.4 mL n -heptane, and
      80 mg sorbitan monooleate (Span-80). The resulting water-in-oil type emulsion was
      gradually injected into 25 mL of 1.5 mol L(-1) hydrochloric acid solution
      containing 30 mmol L(-1) 8-quinolinol and 1.0 mol L(-1) of ammonium sulfate and
      was dispersed as numerous tiny globules by stirring for 40 min. More than 90% of
      the iron(III) diffused through the oil layer to the external hydrochloric acid
      solution with the aid of complexation with 8-quinolinol, whereas trace heavy
      metals, e.g. Cr(III), Mn(II), Co(II), Ni(II), Cu(II), and Pb(II), remained
      quantitatively in the internal aqueous phase. After collecting the dispersed
      emulsion globules, they were demulsified and trace metals in the segregated
      aqueous phase were determined by graphite-furnace atomic absorption spectrometry.
      Owing to sufficient removal of the iron matrix trace metal impurities in high
      purity iron were successfully determined without interference, as was confirmed
      by analysis of certified reference materials.

PMID- 15197531
TI  - Separation of plutonium from uranium using reactive chemistry in a bandpass
      reaction cell of an inductively coupled plasma mass spectrometer.
AB  - Oxygen and ammonia were evaluated as reaction gases for the chemical separation
      between uranium and plutonium in the bandpass reaction cell or dynamic reaction
      cell (DRC) of the ELAN DRC II mass spectrometer. Both uranium and plutonium
      demonstrated similar reactivity with oxygen giving rise to corresponding oxides.
      At the same time, remarkable selectivity in the reaction with ammonia was
      observed. While uranium was rapidly converted into UNH 2+ and UN2H 4+, plutonium
      remained unreactive in the DRC pressurized with ammonia. This difference in the
      reactivity allowed the determination of plutonium isotopes in urine and water
      samples containing excess uranium without preceding separation procedure.
      Detection limits of 0.245, 0.092, 0.270 and 0.237 ng L(-1) were obtained for
      238Pu, 239Pu, 240Pu and 242Pu, respectively, in urine spiked with 10 microg L(-1)
      of U.

PMID- 15197532
TI  - Behavioral phenotype of pre-proenkephalin-deficient mice on diverse congenic
      backgrounds.
AB  - RATIONALE: The phenotype of genetically modified animals is thought to result
      from an interaction of gene manipulation with the genetic background and
      environmental factors. OBJECTIVES: To test the behavioral and drug responses of
      Penk1(-/-) mice on different genetic backgrounds. METHODS: Congenic C57BL/6J and
      DBA/2J mouse strains with a targeted deletion of the Penk1 gene were generated.
      Behavior and drug effects were tested in models of pain and anxiety. RESULTS:
      Penk1(-/-) mice showed exaggerated responses to painful or threatening
      environmental stimuli, but the expressivity of the mutant phenotype was strongly
      dependent on the behavioral paradigm and on the genetic background. For example,
      elevated levels of anxiety were readily detectable in C57BL/6J-Penk1(-/-) mice in
      the light-dark and startle response tests, but not in the social interaction
      test. In contrast, we found elevated levels of anxiety in DBA/2J-Penk1(-/-) mice
      only in the zero-maze and social interaction tests. In some cases, the
      idiosyncratic behavior masked the appearance of the knockout gene effect. The
      activity of the anxiogenic drug, m-chlorophenylpiperazine, but not the anxiolytic
      drug diazepam, was strain and genotype dependent. Mice with the Penk1 mutation on
      the DBA/2J, but not on other genetic backgrounds, showed an increased opioid
      dependent stress-induced analgesia. CONCLUSIONS: (1) The behavioral effects of
      the Penk1 gene deletion persists on different genetic backgrounds, but its
      detection sometimes requires the use of different behavioral paradigms. (2) The
      behavior of the background strain should be considered in the analysis of
      knockout mice to avoid floor and ceiling effects, which may mask the phenotype.

PMID- 15197534
TI  - Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP
      101: new evidence from rats and mice.
AB  - Receptor antagonist and knockout studies have demonstrated that blockade of
      signalling via nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) has
      antidepressant-like effects in mice submitted to the forced swimming test (FST).
      The aim of the present study was to explore further the antidepressant-like
      properties of the NOP antagonist UFP-101 in different species (mouse and rat) and
      using different assays [FST and tail suspension test (TST)], and to investigate
      the mechanism(s) involved in its actions.UFP-101 (10 nmol i.c.v.) reduced
      immobility time of Swiss mice in the TST (mean+/-SEM) from 179+/-11 to 111+/-10
      s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the
      effect of UFP-101. The spontaneous immobility time of NOP(-/-) CD1-C57BL/6J-129
      mice in the TST was much lower than that of wild-type (NOP(+/+)) littermates
      (75+/-11 vs. 144+/-17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased
      immobility time (-65%) and increased climbing time (71%) in rats submitted to the
      FST. In rat brain slices, N/OFQ (100 nM) triggered robust K(+)-dependent
      hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3
      microM) fully prevented N/OFQ-induced currents, but was inactive per se.
      Fluoxetine, desipramine (both 30 mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced
      immobility time of mice in the FST. The serotonin synthesis inhibitor p
      chlorophenylalanine methylester (PCPA, 4 x 100 mg/kg per day i.p.) prevented the
      antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine),
      whereas N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for
      noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the
      effect of desipramine. Neither pretreatment affected spontaneous immobility time
      per se.Thus, UFP-101 exhibits pronounced antidepressant-like effects in different
      species and animal models, possibly by preventing the inhibitory effects of
      endogenous N/OFQ on brain monoaminergic (in particular serotonergic)
      neurotransmission. Participation of the N/OFQ-NOP receptor system in mood
      modulation sets new potential targets for antidepressant drug development.

PMID- 15197535
TI  - Direct interference of HIV protease inhibitors with pancreatic beta-cell
      function.
AB  - The aim of the present study was to evaluate whether HIV protease inhibitors
      directly interfere with stimulus-secretion coupling in pancreatic beta-cells.
      Insulin secretion was determined by a radioimmunoassay (RIA), cytosolic free Ca2+
      concentration ([Ca2+]c) with the fluorescence dye fura-2 and whole-cell membrane
      currents with the patch-clamp technique. Glucose-induced insulin secretion was
      inhibited in a concentration-dependent manner by ritonavir and nelfinavir but not
      by indinavir. Ritonavir and nelfinavir lowered [Ca2+]c in the presence of a
      stimulatory glucose concentration whereas indinavir again had no effect.
      Ritonavir and nelfinavir completely inhibited the effect of tolbutamide, which
      normally increases [Ca2+]c by blocking KATP channels. This observation points to
      an action of both drugs on KATP channels or a step distal to these channels in
      stimulus-secretion coupling. Ritonavir was used to further evaluate the direct
      effects of HIV protease inhibitors on beta-cell ion channel currents.
      Unexpectedly, ritonavir inhibited neither the whole-cell KATP current nor the
      whole-cell L-type Ca2+ current. Tolbutamide almost completely suppressed the KATP
      current in the presence of ritonavir excluding that ritonavir alters the
      tolbutamide sensitivity of the KATP channel. Ritonavir increased the length and
      decreased the frequency of glucose-induced action potentials. This effect can be
      attributed to inhibition of voltage-dependent K+ currents. Intracellular stores
      seem not to be involved in the ritonavir-induced lowering of [Ca2+]c. In
      conclusion, different HIV protease inhibitors surprisingly reveal distinct
      effects on insulin secretion. Ritonavir inhibits insulin secretion by lowering
      [Ca2+]c but this effect is evidently independent of the opening of KATP channels
      or the closure of voltage-dependent Ca2+ channels, which are commonly considered
      to play a key role in stimulus-secretion coupling.

PMID- 15197533
TI  - Sigma receptors: biology and therapeutic potential.
AB  - More than 20 years after the identification of the sigma receptors as a unique
      binding site in the brain and in the peripheral organs, several questions
      regarding this receptor are still open. Only one of the subtypes of the receptor
      has been cloned to date, but the endogenous ligand still remains unknown, and the
      possible association of the receptor with a conventional second messenger system
      is controversial. From the very beginning, the sigma receptors were associated
      with various central nervous system disorders such as schizophrenia or movement
      disorders. Today, after hundreds of papers dealing with the importance of sigma
      receptors in brain function, it is widely accepted that sigma receptors represent
      a new and different avenue in the possible pharmacological treatment of several
      brain-related disorders. In this review, what is known about the biology of the
      sigma receptor regarding its putative structure and its distribution in the
      central nervous system is summarized first. The role of sigma receptors
      regulating cellular functions and other neurotransmitter systems is also
      addressed, as well as a short overview of the possible endogenous ligands.
      Finally, although no specific sigma ligand has reached the market, different
      pharmacological approaches to the alleviation and treatment of several central
      nervous system disorders and deficits, including schizophrenia, pain, memory
      deficits, etc., are discussed, with an overview of different compounds and their
      potential therapeutic use.

PMID- 15197537
TI  - Polymorphism in the N-acetyltransferase 1 alleles NAT1*10 and NAT1*14A and
      cytological gradings of exfoliated urothelial cells in benzidine-exposed Chinese
      workers: discussion of ethnic differences.
AB  - N-acetyltransferase 1 (NAT1) modifies bladder cancer risk in European populations
      exposed to aromatic amines in cigarette smoke. The present study was performed to
      investigate a possible association between NAT1*10 and NAT1*14A genotypes and
      bladder cancer risk in benzidine-exposed Chinese workers. Based on the
      cytological gradings of exfoliated urothelial cells according to Papanicolaou, an
      exposed research cohort was stratified into subgroups. An allele-specific PCR
      based procedure was used to detect the polymorphism in the polyadenylation signal
      at the locus NAT1 T(1088)A. A nested PCR-RFLP procedure was conducted to
      differentiate NAT1*14A (T(1088)A, C(1095)A, and G(560)A) from NAT1*10 (T(1088)A,
      C(1095)A). No significantly different frequencies of homozygous and heterozygous
      NAT1*10 alleles were found among the subgroups with (i) gradings according to
      Papanicolaou < or = II (18.3 and 40.2%, respectively), (ii) higher gradings
      according to Papanicolaou (> II; 28.0 and 34.1%, respectively), and (iii) with
      bladder cancer (26.3 and 34.2%, respectively). The present data show that NAT1*10
      neither displayed an association with an elevated grading of urothelial cells nor
      a clear impact on the risk for bladder cancer in benzidine-exposed Chinese
      workers. Discrepancies with the findings in European populations could point to
      ethnic differences in the disposition of aromatic amines.

PMID- 15197536
TI  - Dilatation induced by 5-HT in the middle meningeal artery of the anaesthetised
      cat.
AB  - In chloralose-anaesthetised cats, we studied the effects of intravenous and intra
      carotid injections of 5-HT on the middle meningeal artery and the way these were
      modified by 5-HT antagonists. Cats were prepared for blood pressure recording and
      intravenous injections and a catheter inserted into one carotid artery via a
      lingual artery. The middle meningeal arteries were exposed and blood flow
      recorded with laser Doppler probes. Intravenous injections of 5-HT, 2-50 microg
      kg(-1) (5.2-129 nmole kg(-1)), produced a dose-dependent fall in blood pressure,
      a rise in meningeal blood flow, and an associated fall in middle meningeal
      resistance. Resistance changes were the result of a local dilatation and not due
      to changes downstream of the recording probe. Intracarotid injections of 5-HT
      produced similar systemic and craniovascular responses, which were larger in the
      ipsilateral middle meningeal artery. Dose-response curves of vascular resistance
      changes to intravenous injection of 5-HT were not significantly affected by
      WAY100635 (5-HT1A antagonist), GR127935 (5-HT(1B/1D) antagonist), methiothepin (5
      HT2C and 5-HT7 antagonist), ketanserin (5-HT2A antagonist), SB203186 (5-HT4
      antagonist) or cervical sympathectomy, but were blocked by the 5-HT(3/4)
      antagonist tropisetron, the 5-HT3 antagonist ondansetron, the ganglion-blocking
      drug hexamethonium and by vagotomy. These drugs and procedures did not
      significantly antagonise the response to intra-arterially injected 5-HT. We
      conclude that intravenously-administered 5-HT is a vasodilator in vivo in the cat
      dural circulation, and that the dilation is not mediated by 5-HT1, 5-HT2, 5-HT4
      or 5-HT7 receptors, but is primarily mediated by a vagal reflex, initiated via 5
      HT3 receptor activation and brought about by an increase in parasympathetic tone
      to the middle meningeal artery as part of the von Bezold-Jarisch reflex. There
      also appears to be a direct vasodilator effect mediated by unknown receptor
      types, particularly after intra-arterial administration. Neither of these effects
      is, however, likely to be of importance in the pathophysiology of migraine or
      other vascular headaches.

PMID- 15197539
TI  - Vitamin D deficiency in Tunisia.
AB  - This study seeks to estimate the status of serum 25-hydroxyvitamin D [25(OH)D] in
      a healthy section of the population in Tunisia and to compare the achieved
      results with other published data. A transverse descriptive inquiry was carried
      out between January and March 2002. Three hundred and eighty-nine subjects aged
      20-60 years were included in the study. A questionnaire was used to investigate
      clinical characteristics: sunlight exposure to ultraviolet light and, for women,
      parity, breast feeding, whether or not they wore the veil, and menopause. A
      dietary investigation estimated calcium and vitamin D intake. Morning fasting
      blood was collected from each subject for the measurement of the following
      parameters: serum calcium, phosphorus, albumin, alkaline phosphatase, 25(OH)D,
      parathyroid hormone (PTH). Hypovitaminosis D was defined by a cut-off of 37.5
      nmol/l. The population studied was largely female, for the greater part
      housewives. The accumulated prevalence of hypovitaminosis D was 47.6%, increasing
      with age. Hypovitaminosis is highly prevalent in women (P<0.001). Multiparity,
      menopause, wearing the veil, and calcium and vitamin D dietary intake are factors
      associated with hypovitaminosis D (P<0.05). Analysis of logistic regression shows
      that only multiparity and vitamin D dietary intake are independent predictive
      factors. The status of serum 25(OH)D in Tunisia resembles that in southern
      European countries rather than in Middle Eastern countries. Insufficient vitamin
      D diet intake, higher parity and wearing the veil explain this deficiency in
      Tunisia. Dietary enrichment or supplementation by vitamin D and a more outdoor
      lifestyle, especially for older people, should be seriously considered as a way
      to reduce this deficiency in Tunisia.

PMID- 15197538
TI  - Incidence of vertebral deformities in 255 female rheumatoid arthritis patients
      measured by morphometric X-ray absorptiometry.
AB  - To date, no studies have been published on incident deformities in patients with
      rheumatoid arthritis (RA). Morphometric X-ray absorptiometry (MXA) is an
      alternative to conventional X-rays for identifying vertebral deformities. The aim
      of the present study was to describe the incidence of vertebral deformities in
      255 female RA patients measured by MXA, and the relationship between incident
      deformities and clinical and demographic variables. MXA is still under evaluation
      for its ability to identify deformities, so we explored four different cut-off
      thresholds including fixed percentage reduction and the principle of least
      significant change (LSC). MXA (T4-L4) and BMD (L2-L4 and total hip; Lunar Expert)
      were performed on 255 patients (mean age 54.3, range 29.2-70.8 years) at baseline
      and after a mean period of 2.3 years. MXA scans were analyzed pairwise by the
      same trained technician, and incident deformities calculated applying LSC with a
      99.9% and 99.99% confidence limit, and a fixed reduction of 20% and 25% for
      anterior, middle or posterior heights. Long term precision (%CV) of height
      measurements for all vertebrae combined (T4-L4) were 4.8, 4.8 and 4.4,
      respectively. Frequency and distribution of incident deformities varied from 39
      deformities in 33 patients (fixed 20% reduction) to 17 deformities in 15 patients
      (fixed 25% reduction), and quality control analyses revealed a high number of
      presumed false deformities. Incidence per 100 patient years varied from 2.9 to
      6.7 deformities according to method, and was comparable to those obtained from
      intervention studies in corticosteroid-induced osteoporosis. Patients with
      incident deformities were significantly older, had lower BMD, higher disability
      and more often a previous non-vertebral fractures than those without incident
      deformities Incident deformities by MXA need further evaluation in secondary
      osteoporosis. It seems, however, that older patients with previous limb fractures
      and low BMD are especially prone to this complication.

PMID- 15197540
TI  - Identifying postmenopausal women with osteoporosis by calcaneal ultrasound,
      metacarpal digital X-ray radiogrammetry and phalangeal radiographic
      absorptiometry: a comparative study.
AB  - Identifying women with osteoporosis remains a clinical challenge, as it may not
      be feasible or cost-effective to recommend dual-energy X-ray absorptiometry (DXA)
      for all postmenopausal women. In this regard, quantitative ultrasound (QUS) has
      emerged as an attractive screening tool because of the (relatively) low cost and
      because QUS and DXA-assessed BMD appear to be equally predictive of future (hip)
      fracture risk. The objective of this study was to compare the ability of
      calcaneal QUS to identify osteoporosis with two alternative potential screening
      methods: digital X-ray radiogrammetry (DXR) and radiographic absorptiometry (RA).
      We enrolled a total of 221 postmenopausal community-dwelling Caucasian women aged
      50-75 years. Bone mineral density (BMD) was measured at the lumbar spine and the
      total hip regions using DXA. Calcaneal ultrasound attenuation and velocity were
      assessed using QUS and metacarpal and phalangeal bone density were estimated by
      the use of DXR and RA, respectively. Receiver operating characteristic (ROC)
      curves were constructed by calculating the specificity and sensitivity of QUS,
      DXR, and RA at different cut-point values in discriminating osteoporosis, as
      defined by a T-score below -2.5 at the spine or hip using DXA, and the areas
      under the curves (AUCs) were computed. The sensitivity for identifying women with
      osteoporosis was 67.6% [95% confidence interval (CI), 50.2-82.0%] using QUS and
      was 76.9% (95% CI, 60.7-88.8%) and 82.9% (95% CI, 67.9-92.8%), respectively,
      using DXR and RA. The negative predictive value (NPV, the proportion of patients
      with a negative test who have no osteoporosis) was 90% for QUS, compared with an
      NPV of 94% for both DXR and RA. These data suggest that metacarpal DXR and
      phalangeal RA may be as effective as calcaneal QUS for targeting DXA testing in
      high-risk postmenopausal women.

PMID- 15197541
TI  - Effective doses of ibandronate do not influence the 3-year progression of aortic
      calcification in elderly osteoporotic women.
AB  - Animal experiments revealed conflicting results as to the impact of
      bisphosphonate treatment on atherosclerosis and related vascular calcification.
      The effect of long-term treatment with clinical doses of bisphosphonates on
      aortic calcification (AC) in an "at-risk" population of osteoporotic elderly
      women has not been assessed systematically. In the present analysis including 474
      women (55-80 years) participating in two 3-year randomized, placebo-controlled
      clinical trials, we assessed the simultaneous impact of ibandronate given either
      orally (2.5 mg daily or 20 mg intermittently) or intravenously (0.5 mg or 1.0 mg
      IV every 3 months) on bone mass and AC. All women received calcium and vitamin D
      supplements. Bone mineral density (BMD) was measured at the lumbar spine and the
      total hip using dual-energy X-ray absorptiometry (DXA). Calcified deposits of the
      lumbar aorta (L1-L4) were visualized on lateral radiographs and severity was
      graded by a validated scoring system. Measurements were performed at baseline and
      at years 1, 2, and 3. At baseline, there was a significant inverse correlation
      between the severity of AC and BMD at the hip (r=-0.151, P=0.003), but not at the
      lumbar spine. The two oral doses and the 1.0 mg IV dose evoked statistically
      significant increases in both hip and spine BMD compared with placebo, whereas
      the effect of 0.5 mg was significant only at the hip (P<0.05). No differences in
      the yearly rate of progression or the 3-year change in AC was observed between
      the different intervention groups. Furthermore, there were no statistically
      significant correlations between the 3-year change in BMD and the simultaneous
      change in AC. These findings thus suggest that 3-year treatment with effective
      doses of ibandronate does not pose any cardiovascular risk in terms of altering
      vascular calcification.

PMID- 15197543
TI  - An association between respiratory function and hip bone mineral density in older
      men: a cross-sectional study.
AB  - The association between respiratory function and bone mineral density (BMD) among
      women living in the community has been reported previously. We examined the
      association between forced expiratory volume in 1 s (FEV(1)) and BMD measured at
      hip using dual-energy X-ray absorptiometry in a group of 947 men (aged 65 to 76
      years) recruited from general practice age-sex registers in Cambridge between
      1991 and 1995. A positive and significant correlation was seen between FEV(1) and
      BMD measured at total hip, femoral neck, and trochanter. A unit change (1 l) in
      FEV(1) was associated with a change of BMD by 0.019, 0.017, and 0.026 g/cm(2) in
      the total hip, femoral neck, and tochanteric region, respectively. These
      associations were independent of possible confounding factors such as age,
      height, weight, smoking habit, major disease prevalence, and medications, which
      might affect bone metabolism. In categorical analyses, the highest BMD was seen
      in the highest FEV(1) quartile, while the lowest BMD was seen in the lowest
      FEV(1) quartile. This pattern was seen in all three skeletal sites and was
      independent of covariates listed above. Compared with the bottom FEV(1) quartile,
      mean hip BMDs in the top quartile were 2-3.5% higher. The exact mechanism of this
      association is not clear to us. One plausible explanation is that respiratory
      function and bone health both reflect common but as yet unknown determinants.

PMID- 15197544
TI  - Prediction of incident osteoporotic fractures in elderly women using the free
      estradiol index.
AB  - A decline in postmenopausal estrogen concentration accelerates postmenopausal
      bone loss. We have examined the predictive power of endogenous estrogen
      production, DXA hip bone density (BMD), and heel quantitative ultrasound (QUS) on
      incident clinical fracture in a prospective 3-year population based, randomised
      controlled trial of calcium supplementation. Baseline blood testing on 1499 women
      mean (SD) age 75 (3) years for estradiol and sex hormone binding globulin
      measurements and ankle QUS measurements (Lunar Achilles) was undertaken. Bone
      density was measured using DXA (Hologic 4500A) at 1 year. Incident clinical
      fractures were confirmed by X-ray. At 3 years, 10% had sustained more than one
      incident fracture. The fracture group had significantly lower levels of free
      estradiol index (FEI) (0.40+/-0.44 versus 0.49+/-0.54 pmol/nmol), hip BMD
      (0.776+/-0.129 versus 0.815+/-0.124 g/cm(2)) and measures of QUS (BUA 98+/-8
      versus 101+/-8 db/Hz, SOS 1504+/-22 versus 1514 +/-26 m/s; stiffness 67+/-11
      versus 71+/-11 % mean young adult), respectively, than the non-fracture group.
      After adjustment for age, weight, use of topical estrogen, calcium
      supplementation and prevalent fracture, incident fracture was predicted by free
      estradiol index (HR per SD: 1.43:95%CI: 1.08-1.91, P=0.013). After adjustment for
      BMD, SOS or stiffness, the free estradiol index no longer predicted fracture.
      When examined separately, the presence of a vertebral or an appendicular fracture
      was associated with an 18% lower free estradiol index compared with no fracture.
      The risk of vertebral fracture increased with decreased free estradiol index (HR
      per SD reduction: 1.63:95% CI: 0.91-2.92); the risk of appendicular fracture also
      increased with decreased free estradiol index (HR per SD reduction: 1.45:95% CI:
      1.05-2.01) after adjustment for age, weight, use of topical estrogen, calcium
      supplementation and prevalent fracture. After further adjustment for hip BMD or
      QUS measures, the effect of free estradiol index was no longer significant for
      vertebral or appendicular fractures. Therefore, a low free estradiol index
      increases the probability of having an incident fracture as a result of decreased
      BMD. These data confirm the importance of postmenopausal estrogen concentration
      in the pathogenesis of osteoporosis in elderly women.

PMID- 15197546
TI  - Osteoporosis is markedly underdiagnosed: a nationwide study from Denmark.
AB  - AIM: To compare the number of patients diagnosed with osteoporosis and
      osteoporotic fractures in Denmark, with the number of subjects expected to have
      osteoporosis. SUBJECTS AND METHODS: From the National Hospital Discharge
      Register, records for all patients diagnosed with osteoporosis and/or with
      osteoporotic fractures between 1995 and 1999 were retrieved. Based on normal
      Danish values for BMD, the expected number of subjects aged 50 years or more with
      osteoporosis according to the WHO definition was calculated. RESULTS: The
      estimated prevalence of osteoporosis was 40.8% of women aged >or=50 years and
      17.7% among men. The expected annual incidence was 58,658/million inhabitants in
      women >or=50 years of age and 23,648/million in men >or=50 years. However, the
      observed incidence was only 4,823 and 862/million per year, respectively (8.2%
      and 3.6% of the expected). In 1999, a total of 34,691 hip, spine, and forearm
      fractures were reported in subjects >or=50 years, and of these, 18,566 were
      potentially attributable to osteoporosis (14,240 fractures in women and 4,326 in
      men equaling 14,976 and 5,297/million per year). Only 0.3% of men >or=50 years
      were receiving a bisphosphonate, while 2.2% of women received a bisphosphonate or
      raloxifene. Among women >or=50 years, 27.7% received hormone replacement therapy.
      CONCLUSIONS: Osteoporotic fractures of the hip, spine, and forearm are rather
      frequent in Denmark, but the diagnosis of osteoporosis is rarely used. It seems
      that osteoporosis is markedly underdiagnosed and undertreated in Denmark as
      probably also elsewhere. This may have significant implications for the
      prevention of osteoporotic fractures.

PMID- 15197545
TI  - Awareness of osteoporotic patients.
AB  - Osteoporosis has recently been recognized as a major public health problem by
      some governments and health care providers. Despite significant progress in
      knowledge about osteoporosis, public awareness is required for effective
      management if precautions are to be taken. The aim of this study was to evaluate
      the educational status of osteoporotic individuals, and their awareness about the
      disease and sources of information. We also aimed to compare the variables
      between the geographical regions of the country, since significant differences
      exist in socioeconomic status and lifestyle within the same cultural context.
      This multicenter study was carried out in eight cities located in six different
      geographical regions between September 2001 and January 2002. To our knowledge,
      this is the first multicenter study in Turkey evaluating the relationship between
      awareness of osteoporotic patients and other variables such as educational level
      and economic factors. Ten centers took part in this study and consecutive
      patients with either femoral or lumbar T-scores below -2.5 SD were enrolled into
      the study group. Bone mineral density was measured using dual energy X-ray
      absorptiometry (DXA). Patients were interviewed using a questionnaire on past
      medical history, education, awareness about their disease and risk factors for
      osteoporosis. A total of 540 women (93.8%) and 36 men (6.3%) were included in the
      study. Fifty-four percent of patients declared that they were aware of
      osteoporosis. With regard to sources of information, 56.8% of patients reported
      physicians as the main source of information. Awareness of the patients was
      negatively correlated with age (P=0.025, r=-0,94) but positively correlated with
      education (P=0.0001, r=0.327), level of physical activity (P=0.001, r=143),
      calcium intake (P=0.005, r=119) and modern clothing style (P=0.0001, r=309).
      Educational status of the patients was negatively correlated with BMI (P=0.0001,
      r=-283) and positively correlated with physical activity (P=0.0001, r=268),
      modern clothing style (P=0.0001, r=600) and smoking (P=0.0001, r=273). Regional
      comparison of female patients demonstrated that significant differences exist in
      terms of educational status, clothing style, smoking, level of physical activity,
      calcium intake, and knowledge about osteoporosis. As a result, education has
      profound effects on awareness about osteoporosis and many aspects of human
      behavior, such as calcium intake, physical activity, clothing style and smoking.
      Significant disparities may be observed between the geographical regions of the
      same country.

PMID- 15197547
TI  - Rapid long-term bone loss following stroke in a man with osteoporosis and
      atherosclerosis.
AB  - Bone loss in humans has been reported where there is reduced mechanical loading
      such as in space flight, spinal cord injury, and stroke. Whether osteoporotic
      patients are susceptible to further bone loss in states of underloading such as
      hemiparesis is unknown. Here we report the case of a 64-year-old man with
      established idiopathic osteoporosis and atherosclerosis who presented with a
      right middle cerebral artery territory stroke. Annual bone mineral density
      measurements were made at the left hip and spine before and after left
      hemiparesis. The left total hip T-score was -3.2 before the stroke. Following
      stroke, there was rapid and sustained bone loss with a reduction in bone mineral
      density (BMD) of 21.6% over 3 years despite oral bisphosphonate therapy. There
      was also an unexpected decline in vertebral BMD after the stroke. This is the
      first report of the accelerated effect of hemiplegia on bone loss in an already
      osteoporotic skeleton.

PMID- 15197549
TI  - Impact of FDG-PET for staging of oesophageal cancer.
AB  - BACKGROUND AND AIMS: Treatment of oesophageal cancer depends on staging and the
      general health of the patient. In stages I-II b, as well as in some stage III
      diseases, surgical resection remains the therapy of choice for cure, but a
      curative approach is not possible in stage IV. In our hospital we give
      preoperative radio-chemotherapy to all patients with an oesophageal cancer T>1,
      Nx, M0. Therefore, the main purpose of the clinical staging of oesophageal cancer
      is the exclusion of M1 and T4 disease with infiltration into the tracheobronchial
      system or the aorta. The aim of the investigation was the assessment of positron
      emission tomography for detection of M1 disease. PATIENTS/METHODS: Between 1998
      and 2002, 84 patients with oesophageal cancer (64% squamous cell carcinoma and
      36% adenocarcinoma) were enrolled into the study. Of these, 48.8% were operated
      on; 35.7% of the patients were not operated on, for oncological reasons, 7.1% for
      medical reasons, 3.6% chose not to be operated on, and, for unknown reasons, 4.8%
      were not operated on. RESULTS: Twenty-five patients had stage IV disease or
      additional, synchronous cancer of the head and neck ( n=2). As the only
      investigational procedure, positron emission tomography revealed M1 stage in 11
      of 25 patients (44%). In 13/25 (52%) both computed tomography and positron
      emission tomography revealed stage IV disease. False positive results by positron
      emission tomography were observed in three patients. The sensitivity and
      specificity of positron emission tomography (PET) was 0.96 and 0.95,
      respectively. Most of the metastases detected by PET only, were localised within
      the neck, liver and bone. With regard to the 66 of 84 patients deemed medically
      fit for operation and without local infiltration into the tracheobronchial system
      (T4) PET as the only imaging procedure changed the therapeutic strategy in 11 of
      66 (16.6%) patients with to M1 disease. CONCLUSION: Our results demonstrated
      clearly the impact of the PET scan for decision-making in patients with
      oesophageal carcinoma. PET should be performed prior to therapy with curative
      intention. However, addition of a computed tomography scan of the neck might
      reduce the rate of unexpected metastases detected by PET.

PMID- 15197550
TI  - A method for assessing thermal comfort of shoes using a "sweating" foot.

PMID- 15197551
TI  - Immunological biomarkers in salt miners exposed to salt dust, diesel exhaust and
      nitrogen oxides.
AB  - OBJECTIVES: Air pollutants can affect lung function and also the immune system.
      In a study about lung function of salt miners in relation to the complex exposure
      in a salt mine, we also analysed selected immunological parameters and
      inflammation markers in the blood of miners. Effect of salt dust, diesel exhaust,
      nitrogen oxides (NOx) and smoking on the biomarkers was analysed. METHODS: Blood
      was drawn from 286 salt miners, and the soluble intercellular adhesion molecule-1
      (s-ICAM), monocyte chemotactic protein (MCP-1) and clara cell protein (CC16) were
      analysed by an immunoassay, blood profile was done and lymphocyte subpopulations
      (CD3, CD3/CD4, CD3/CD8, CD19, NK-cells, CD3/HLA-DR) were determined by flow
      cytometry. Salt dust was measured by two-step gravimetry (personal sampling).
      Diesel exhaust was measured as elemental carbon concentration by coulometry. NOx
      were determined by an electrochemical cell method. Differences between non
      smokers, former smokers and active smokers were analysed by analysis of variance.
      Linear regression analysis to describe exposure-response relationships was done
      with regard to confounding factors [smoking, inflammatory diseases, time of blood
      drawing, respiratory infection and body-mass index (BMI)]. RESULTS: Significant
      differences between non-smokers and active smokers were found for most of the
      leukocyte types (e.g. granulocytes P = 0.000, lymphocytes P = 0.002, T-cells P =
      0.033) and for some soluble parameters (ICAM P = 0.000, IgM P = 0.007, IgE P =
      0.035). Increasing numbers of total lymphocytes, T-cells and HLA-DR positive T
      cells in relation to exposure were found by linear regression analysis (e.g. for
      inhalable dust:total lymphocytes P = 0.011, T-cells P = 0.061, HLA-DR positive T
      cells P = 0.007). CONCLUSION. Comparison of immunological markers in non-smokers
      and active smokers confirms leukocytosis and inflammation following tobacco
      consumption. The combined exposure of salt dust, diesel exhaust and NOx seems to
      influence the immune system. Together, the results suggest that the analysis of
      leukocytes and their subsets can complete other investigations (lung function,
      questionnaire) to monitor exposure-response relationships in occupational studies
      investigating the effect of inhaled substances. Longitudinal studies will be
      necessary to determine the predictive value of the immunological changes.

PMID- 15197554
TI  - Expression profiles of fibrinolytic components in nasal mucosa.
AB  - Components of the fibrinolytic pathway contribute to diverse pathways in many
      tissues, in addition to their well-recognized role in degradation of fibrin
      clots. In this study of nasal mucosa, we investigated the presence of mRNA of
      tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u
      PA), plasminogen activator inhibitor-1 (PAI-1), and plasminogen activator
      inhibitor-2 (PAI-2) using reverse transcription polymerase chain reaction (RT
      PCR) and in situ hybridization, and compared these results with their
      localization in immunostained tissues. According to real-time RT-PCR results, t
      PA, u-PA, PAI-1, and PAI-2 mRNA were noted in human nasal mucosa. Particularly,
      expression of u-PA and PAI-1 mRNA was significantly high in allergic nasal mucosa
      in comparison with normal mucosa. t-PA mRNA was detected in endothelial cells and
      epithelium in normal nasal mucosa. t-PA mRNA was detected in mucous cells of
      allergic submucosal glands, but not in normal glands. In allergic rhinitis, u-PA
      and PAI-2 mRNA were detected in mucinous cells and epithelium, and PAI-1 mRNA was
      detected in serous cells and epithelium. Expression of u-PA and PAI-1 mRNA in
      normal nasal tissues was decreased in contrast to that in allergic nasal tissues.
      u-PA staining was observed in mucous cells of allergic submucosal glands and the
      staining pattern of PAI-2 was similar to that of u-PA. PAI-1 was present in
      serous cells of submucosal glands from allergy samples, while epithelial cells
      were almost devoid of stain. In contrast, with allergy, immunohistochemical
      staining of t-PA was negative in submucosal glands, though positive in
      endothelial cells and epithelium. However, the expression of t-PA mRNA in
      allergic nasal mucosa was noted in mucous cells. In fibrin autography of nasal
      discharge, u-PA was markedly activated in the allergic patient. These results
      suggest that t-PA synthesized in mucous cells is promptly secreted and modifies
      watery nasal discharge in allergic rhinitis, and that u-PA activity may help the
      passage of large amounts of rhinorrhea by also reducing its viscosity. A lot of
      cellular infiltration (eosinophils in particular) was recognized in allergic
      nasal mucosa. It is most likely that the modifications in expression of PAs and
      PAIs are due to the local release of cytokines or growth factors from these
      inflammatory and immune cells.

PMID- 15197548
TI  - Sentinel lymph node biopsy progress in surgical treatment of cancer.
AB  - BACKGROUND: Forty-three years after the first description of the sentinel lymph
      node technique in malignant tumours of the parotid by Gould, sentinel lymph node
      biopsy (SNLB) has become a precious tool in the treatment of solid tumours.
      METHODS: In the following review we give a synopsis of the fundamentals of the
      sentinel lymph node concept and then proceed to an overview of recent advances of
      SNLB in gastrointestinal cancers. RESULTS: In some tumour entities, SNLB has been
      shown to reflect reliably the lymph node status of the tumour-draining lymph node
      basin. In melanoma and breast cancer, it became a widely accepted element of the
      routine surgical management of these malignant diseases. In gastrointestinal
      tumours, the technique is currently under intense investigation. First reports on
      its application in other solid tumours, such as non-small cell lung cancer,
      thyroid carcinoma, oropharyngeal carcinoma, vulvar carcinoma, and Merckel cell
      carcinoma of the skin, were published more recently. CONCLUSION: SNLB has become
      an important component of diagnosis and treatment of solid tumours. A growing
      number of publications on SNLB in gastrointestinal cancer documents the interest
      of many investigators in the application of this technique in this tumour entity.
      As long as imaging techniques like 18FDG PET or other molecular imaging
      techniques are limited by their spatial resolution, SNLB remains the technique of
      choice for lympho-nodal staging.

PMID- 15197555
TI  - Subretinal electrical stimulation of the rabbit retina with acutely implanted
      electrode arrays.
AB  - BACKGROUND: Subretinal implants intend to replace photoreceptor function in
      patients suffering from degenerative retinal disease by topically applying
      electrical stimuli from the subretinal space. This study intended to prove the
      feasibility of a newly developed transchoroidal surgery and, furthermore, of a
      subretinal electrode array, which closely resembles envisioned human implants to
      electrically stimulate the visual system in rabbits. METHODS: Five rabbits (ten
      eyes) were implanted with a 4x2-electrode array via a transchoroidal access to
      the subretinal space. The electrodes were connected to an arbitrary stimulus
      generator to apply voltage pulses. Retinae were accessed by light microscopy
      after stimulation with various intensities. RESULTS: The stimulating foil could
      be introduced into the subretinal space in all eyes. In seven of ten eyes
      electrically evoked cortical potentials following subretinal electrical
      stimulation could be elicited. Threshold voltages ranged from less than 0.1 to
      2.38 V with a corresponding threshold charge of approximately 1.0 nC per
      electrode or 10 micro C/cm(2). Histology revealed localized retinal damage over
      some of the electrodes succeeding stimulation strengths of 2 V and consistent
      damage over all electrodes succeeding voltages of 3 V. CONCLUSIONS: The study
      demonstrates the feasibility of the transchoroidal surgical access to place
      subretinal implants in rabbit eyes and provides proof of successful cortical
      activation following subretinal electrical stimulation by an electrode array
      envisioned for human implantations.

PMID- 15197556
TI  - Spontaneous separation of epiretinal membrane in young subjects: personal
      observations and review of the literature.
AB  - BACKGROUND: Idiopathic epiretinal membranes (ERM) grow on the surface of the
      internal limiting membrane (ILM) and are a very uncommon condition in young
      subjects. METHODS: We report six young subjects with ERM and describe the
      spontaneous separation of the membranes. The functional and anatomical recovery
      was assessed by Snellen visual acuity, Amsler grid and funduscopy. Selected cases
      were additionally assessed by optical coherence tomography (OCT). RESULTS: All
      subjects initially claimed a sudden, unilateral, reduction in visual acuity (VA)
      with severe distortion at the age of 15-30 years. No ocular trauma or disease was
      ascertained in any case. Initial fundus examination demonstrated a gray-whitish
      ERM with translucent stress lines over the macula. Visual recovery occurred in
      all cases after resolution of the ERM. Sequential OCT demonstrated the successive
      peeling of an ERM accompanied by normalization of foveal thickness. CONCLUSIONS:
      Young subjects should be counseled about the favorable prognosis for maintaining
      good vision and possible spontaneous membrane separation. Conservative
      observation is advocated if the visual disturbance is located temporally, as
      functional recovery and spontaneous membrane separation may occur. When the
      contracting forces of the immature ERM are stronger than its adhesions to the
      retina, the membrane may separate spontaneously.

PMID- 15197557
TI  - Deficits of spatial localization in children with strabismic amblyopia.
AB  - BACKGROUND: Besides loss of visual acuity and binocularity, spatial localization
      deficits (comprising both increased spatial uncertainty and spatial distortions)
      are an important feature of strabismic amblyopia. Although they have been
      extensively investigated in adult amblyopes, there are still many open questions
      concerning their substrate and relationship to clinical parameters. Our aim was
      to develop a procedure for assessing vertical alignment, which enabled us to find
      out whether children with strabismic amblyopia had similar spatial localization
      deficits, and their relation to the children's clinical condition. METHODS:
      Vertical alignment was assessed in children by comparing the visual direction in
      space of three loci along the vertical meridian, separated by 5 deg of visual
      angle. We tested alignment in the amblyopic and dominant eyes of 32 strabismic
      and in both eyes of 35 control children from 4.5 to 10 years, together with a
      careful orthoptic examination. RESULTS: In the amblyopic eyes, increased
      uncertainty and systematic distortions outside the normal range occurred. Large
      angles of deviation and pathological fixation patterns were necessary, but not
      sufficient conditions for gross spatial deficits to occur. The fellow dominant
      eyes showed spatial localization similar to normal eyes. CONCLUSIONS: Children
      with strabismic amblyopia exhibited localization deficits and relationship to
      clinical data similar to those in adult amblyopes. These data are important for
      further investigations about the substrate, plasticity and the clinical relevance
      of perceptual distortions.

PMID- 15197558
TI  - Segmental vertebral motion in the assessment of neck range of motion in whiplash
      patients.
AB  - The purpose of this study was to obtain comparative data concerning the relative
      contribution of segmental cervical vertebral motion to the cervical range of
      motion (ROM) in whiplash and healthy subjects in an effort to evaluate the
      usefulness of X-ray analysis in future forensic and research efforts. Each
      subject's neck ROM was measured with an optoelectronic system and also by X-ray
      measurements of the angular rotation in flexion and extension. The X-rays were
      examined to calculate the angular movement in the sagittal plane of each of the
      functional units C2-C3 to C6-C7. The chronic whiplash subjects showed reduced
      total neck range in all directions as compared to healthy subjects (p<0.001).
      There was a reduced total angular rotation from flexion to extension between
      these two groups (p<0.01), but no significant difference, however, between
      chronic whiplash subjects and controls in the percentage contribution of each of
      the functional units C2-C3 to C6-C7 to this rotation. This data will now allow a
      design of trials where healthy subjects are asked to simulate restricted neck ROM
      while undergoing optokinetic and X-ray evaluation of segmental vertebral motion.
      We will be able to determine if simulators produce a similar pattern to chronic
      whiplash and healthy, non-simulating subjects, and thus determine if, at least
      for forensic and research purposes, this technique is useful in validating
      reported restricted neck range.

PMID- 15197560
TI  - A new chromosome fluorescence banding technique combining DAPI staining with
      image analysis in plants.
AB  - In this study, a new chromosome fluorescence banding technique was developed in
      plants. The technique combined 4',6-diamidino-2-phenylindole (DAPI) staining with
      software analysis including three-dimensional imaging after deconvolution. Clear
      multiple and adjacent DAPI bands like G-bands were obtained by this technique in
      the tested species including Hordeum vulgare L., Oryza officinalis, Wall & Watt,
      Triticum aestivum L., Lilium brownii, Brown, and Vicia faba L. During mitotic
      metaphase, the numbers of bands for the haploid genomes of these species were
      about 185, 141, 309, 456 and 194, respectively. Reproducibility analysis
      demonstrated that banding patterns within a species were stable at the same
      mitotic stage and they could be used for identifying specific chromosomes and
      chromosome regions. The band number fluctuated: the earlier the mitotic stage,
      the greater the number of bands. The technique enables genes to be mapped onto
      specific band regions of the chromosomes by only one fluorescence in situ
      hybridisation (FISH) step with no chemical banding treatments. In this study, the
      45S and 5S rDNAs of some tested species were located on specific band regions of
      specific chromosomes and they were all positioned at the interbands with the new
      technique. Because no chemical banding treatment was used, the banding patterns
      displayed by the technique should reflect the natural conformational features of
      chromatin. Thus it could be expected that this technique should be suitable for
      all eukaryotes and would have widespread utility in chromosomal structure
      analysis and physical mapping of genes.

PMID- 15197559
TI  - Differences in centromere positioning of cycling and postmitotic human cell
      types.
AB  - Centromere positioning in human cell nuclei was traced in non-cycling peripheral
      blood lymphocytes (G0) and in terminally differentiated monocytes, as well as in
      cycling phytohemagglutinin-stimulated lymphocytes, diploid lymphoblastoid cells,
      normal fibroblasts, and neuroblastoma SH-EP cells using immunostaining of
      kinetochores, confocal microscopy and three-dimensional image analysis. Cell
      cycle stages were identified for each individual cell by a combination of
      replication labeling with 5-bromo-2'-deoxyuridine and immunostaining of pKi67. We
      demonstrate that the behavior of centromeres is similar in all cell types
      studied: a large fraction of centromeres are in the nuclear interior during early
      G1; in late G1 and early S phase, centromeres shift to the nuclear periphery and
      fuse in clusters. Peripheral location and clustering of centromeres are most
      pronounced in non-cycling cells (G0) and terminally differentiated monocytes. In
      late S and G2, centromeres partially decluster and migrate towards the nuclear
      interior. In the rather flat nuclei of adherently growing fibroblasts and
      neuroblastoma cells, kinetochores showed asymmetrical distributions with
      preferential kinetochore location close either to the bottom side of the nucleus
      (adjacent to the growth surface) or to the nuclear upper side. This asymmetrical
      distribution of centromeres is considered to be a consequence of chromosome
      arrangement in anaphase rosettes.

PMID- 15197561
TI  - Intramuscular benign lipoma of the sternocleidomastoid muscle: a rare cause of
      neck mass.
AB  - Intramuscular benign lipoma commonly is found on the extremities, but is
      extremely rare in the head and neck region. Intramuscular type lipomas arise
      between the muscle fibers and pass through the intermuscular septa, infiltrating
      the surrounding tissue. A 29-year-old male patient presented with the complaint
      of a painless and slowly growing lateral neck mass on the left side. Physical
      examination revealed a 4x5-cm mass adjacent to the sternocleidomastoid (SCM)
      muscle. CT examination revealed a lobulated, well-circumscribed 5.5x2.5-cm
      diameter mass with adipose tissue signal density inside the SCM muscle. The
      surgical exploration of the mass was done under general anesthesia, and it was
      excised totally. Recurrence was not seen in the 3-year follow-up. This rare
      entity should be considered in the differential diagnosis of intramuscularly
      located neck masses. Complete removal of the tumor can only succeed if planned
      and performed after a thorough preoperative clinical and radiological assessment
      in order to prevent recurrences.

PMID- 15197562
TI  - Detection of bone marrow micrometastases in the rib marrow of head and neck
      cancer patients: a prospective pilot study.
AB  - Flow cytometry has been validated as an objective method of demonstrating and
      quantifying micrometastases. Micrometastases within bone marrow indicate a poor
      prognosis in patients with upper gastrointestinal, colorectal and breast
      epithelial tumours. We prospectively sought to assess the feasibility of testing
      rib marrow for bone marrow micrometastases in head and neck cancer and to report
      their frequency in a cohort of patients. Nine patients were enrolled in the
      study. Bone marrow was obtained before manipulation of the primary tumour.
      Micrometastatic cells were detected by staining contaminant cytokeratin-18
      positive cells and using the twin techniques of immuncytochemistry and flow
      cytometry. Cellular marrow was retrieved in 100% of cases. Micrometastases were
      detected in one out of nine epithelial tumours on both flow cytometry and
      immunocytochemistry. The detection rate appeared to be independent of TN staging.
      We were unable to culture the cells. Preoperative detection of bone marrow
      micrometastases may reflect transient shedding of cells, metastatic potential or
      residual disease. This prospective study confirms the feasibility of using rib
      marrow in future studies investigating micrometastases in head and neck cancer.

PMID- 15197563
TI  - Complete tracheal rings: lower airway symptoms can delay diagnosis.
AB  - Bronchial asthma is a very common condition seen in children diagnosed by
      clinical examination. While treating these children, all the other possible
      causes of breathlessness including complete tracheal rings should be considered.
      Further investigations in the form of endoscopy may need to be carried out in
      doubtful cases.

PMID- 15197564
TI  - Small-cell carcinoma of the uterus and the vagina: experience with ten patients.
AB  - BACKGROUND: Small cell carcinomas (small-CCs) of the uterine cervix are rare and
      highly malignant neoplasms. Patients tend to develop distant metastasis early and
      thus are potential candidates for systemic therapy. We reviewed the experience
      with small-CCs of the uterus and vagina at two Austrian University hospitals.
      MATERIAL AND METHODS: Ten patients (median age, 50 years; range, 18-92) with
      small-CC of the cervix (n=7), uterine corpus (n=2), and the vagina (n=1) were
      treated at the two centers between 1988 and 1998. Eight patients underwent
      radical surgery, 7 of whom also received chemotherapy. Two additional patients
      underwent primary radiotherapy. RESULTS: All Pap smears were suspicious for
      cervical malignancy. The median survival was 12 months (range, 6-86) and overall
      5-year survival was 10%. Five of 8 surgically treated patients had lymph node
      involvement (62%). Of the 7 patients with small-CC of the cervix only one, who
      had FIGO stage IIB disease and positive pelvic nodes, survived long-term (86
      months) with no evidence of disease. She had received six courses of dose
      intensive platinum chemotherapy after radical surgery. All three patients with
      small-CC of the uterine corpus or vagina developed recurrence within the first
      year after diagnosis. Of the 7 patients who received chemotherapy, 5 developed
      progressive or recurrent disease in the paraaortic region (n=2), peritoneum
      (n=1), liver (n=1), or pelvis (n=1). CONCLUSION: These results confirm the
      particularly unfavorable prognosis of patients with small-CC of the genital
      tract. The optimal treatment for these patients most probably including
      concurrent chemo-radiotherapy remains to be defined.

PMID- 15197565
TI  - Surgery for necrotising enterocolitis: primary anastomosis or enterostomy?
AB  - The ideal surgical management of neonates with necrotising enterocolitis (NEC) is
      still a matter of debate. The purpose of this study was to compare the results of
      bowel resection with primary anastomosis with the results of bowel resection with
      enterostomy. Sixty-three neonates with NEC had a bowel resection in the acute
      phase of the disease in the period between February 1990 and March 2001. Thirty
      four of them (54%) underwent resection of the bowel with primary anastomosis
      (Group A), and 29 (46%) had resection with enterostomy (Group B). Group A had a
      lower gestational age and lower birth weight. Mortality, complication rate, and
      postoperative weight gain were not significantly different between the groups.
      However, Group B had a significantly longer primary hospital stay (80 +/- 49 days
      versus 58 +/- 31 days, P < 0.04) and needed a 2nd hospital stay for restoring
      gastrointestinal continuity. For both reasons, it can be argued that primary
      anastomosis is superior to enterostomy after resection.

PMID- 15197566
TI  - Craniopagus twins: clinical and surgical management.
AB  - CASE REPORT: We present the case of 2-year-old craniopagus twins who are in the
      process of undergoing a staged separation of their craniums. In addition, they
      will undergo a full calvarial vault remodeling to reconstruct the lacking skull
      and scalp tissue in each child. We elected to do a staged separation rather than
      a single marathon operation for various reasons, which we will detail in this
      report. DISCUSSION: The philosophy and surgical management of each step will be
      discussed along with the pros and cons behind the reasoning that was used. At the
      time of this report the children have undergone three of what are projected to be
      four stages of separation. Each of the stages has had unique characteristics and
      surgical judgments involved, and those will be reviewed. CONCLUSION: Successful
      separation of viable conjoined twins has been historically a great rarity.
      Successful separation of twins where both have come out of surgery without any
      neurological deficit remains a rare occurrence and in our mind the ultimate goal.

PMID- 15197569
TI  - Long-term complications and definition of failure of neuroendoscopic procedures.
AB  - OBJECTS: A lot has been published about neuroendoscopic procedures over the last
      decade. Most of these publications are about the effectiveness of endoscopic
      third ventriculostomy, the most frequently performed neuroendoscopic procedure.
      Little is published about the effectiveness of other, less frequently performed
      neuroendoscopic procedures. Over the years more reports about the complications
      of endoscopic procedures are published, but again most of these publications are
      about endoscopic third ventriculostomy and only a little is presented about the
      complications of all other neuroendoscopic procedures. Furthermore, most reports
      are about intraoperative and immediate postoperative complications; only a few
      reports evaluated the long-term complications of neuroendoscopic procedures.
      There are also a few publications that analyse the failures of neuroendoscopic
      procedures but a good definition of failure is not given. The reports mention,
      again, mainly endoscopic third ventriculostomy procedures, and are mostly
      directed at the short-term failure rates, defined as the need for a shunt to be
      placed. Less attention is paid to the effects of the endoscopic procedures in the
      longer term. Looking at longer terms emphasises the need for a better definition
      of failure. METHODS: To get more insight into the long-term complications and
      failures of neuroendoscopic procedures, we reviewed the literature and evaluated
      our own series of 485 different cranial endoscopic procedures. With the
      information gathered we tried to answer the questions mentioned above.
      CONCLUSIONS: Most of the complications of neuroendoscopic procedures are
      transient, either spontaneously or by medical intervention. Only a few permanent
      complications are known, in our series 1.6%, and most of them are not typically
      related to the endoscopic procedure itself but are due to the ventricular
      approach necessary for and the management of the endoscopy. Mortality rates are
      less than 1%. A uniform definition of failure cannot be given for all
      neuroendoscopic procedures, because the procedures are too heterogeneous and the
      indications are widespread. Failures are mainly diagnosed within a few months of
      the procedure but neurosurgeons must be aware of failure in the longer term,
      because if not diagnosed they can give rise to increased morbidity and probably
      mortality.

PMID- 15197568
TI  - Neuroendoscopic surgery of intracranial cysts in adults.
AB  - OBJECTS: The purpose of this study was to describe the indications, surgical
      techniques and postoperative outcome of neuroendoscopic interventions in a
      heterogeneous group of intracranial cystic pathologies. PATIENTS AND METHODS:
      Between 1992 and 2003, 127 patients with symptomatic intracranial cysts and
      cystic tumours underwent neuroendoscopic treatment in our department. In 22
      patients indication for surgery was colloid cysts, in 9 patients pineal cysts and
      in 3 patients cavum vergae cysts. Twelve arachnoid cysts, 10 cystic
      craniopharyngiomas, 2 Rathke's cleft cysts and 69 malignant cystic tumours were
      operated on. The patients' mean age was 45 years and their clinical presentations
      varied from typical signs of increased intracranial pressure to focal
      neurological deficits. RESULTS: One hundred and twenty-seven patients with
      intracerebral cystic space-occupying lesions were operated on using stereotactic
      frameless or frame-based endoscopic techniques. There was no operative mortality.
      The operative morbidity was 3.1% including 1 memory deficit due to fornix injury,
      1 hemiparesis due to postoperative haematoma after lesion biopsy, 1 aseptic
      meningitis and 1 subdural fluid collection. CONCLUSIONS: Endoscopic interventions
      enable neurosurgeons to manage intracranial cystic lesions. Via the same
      approach, the obstructed CSF pathways may be restored and consequently the
      increased intracranial pressure diminishes. With the aid of stereotactic guidance
      or a neuronavigation system, access to the lesion can be gained rapidly and with
      high accuracy.

PMID- 15197571
TI  - [Homogeneity of G-DRGs in ophthalmology].
AB  - BACKGROUND: Since the year 2004 hospitals in Germany are obliged to participate
      in a payment system based on diagnosis-related groups (DRG), which bases hospital
      reimbursement on the diagnosis and treatment of patients. The aim of this study
      was to analyze the data of the first German national hospital cost data
      calculation for their homogeneity. METHODS: The cases at the LMU hospital in
      Munich were calculated analogous to the national hospital cost data calculation
      for a period of 7 months. These exemplary data were then analyzed in detail for
      homogeneity. RESULTS: For many DRGs, the numbers of cases in the analysis were
      within a range similar to those in the official nationwide calculation. The costs
      and lengths of stay were similar to those of the official national calculation.
      CONCLUSIONS: Many ophthalmologic DRGs are quite inhomogeneous necessitating
      regrouping to avoid false incentives. For cases with high complexity the current
      system may lead to cost deficits especially for hospitals providing maximum care.

PMID- 15197570
TI  - How does angiogenesis develop in pediatric moyamoya disease after surgery? A
      prospective study with MR angiography.
AB  - OBJECT: The dynamic process of neovascularization seen in patients with moyamoya
      disease who have received bypass surgery has not been sufficiently elucidated.
      Magnetic resonance angiography (MRA)is expected to disclose this process since it
      can be conducted frequently because of its non-invasive nature. In this study, we
      prospectively investigated postoperative neovascularization using repeated MRA.
      METHODS: We studied 14 pediatric patients (23 sides) who have received both
      direct bypass surgery of the superficial temporal artery (STA) to middle cerebral
      artery and indirect surgery of encephalo-duro-arterio-myo-synangiosis during the
      past 3 years. MRA was performed using a 1.5-T machine, image sequences of 512 x
      256 resolution, and the time-of-flight method. MRA was prospectively performed
      preoperatively and repeated 1, 3, and 6 months after surgery. CONCLUSIONS: A
      tendency toward a decrease in moyamoya vessels and the development of the STA was
      observed 1 month after the surgery. Development of the deep temporal artery and
      the middle meningeal artery was observed 3 months after the surgery. The
      progression of stenotic change was apparently accelerated after the surgery. A
      reciprocal relation between neovascularization artificially induced by bypass
      surgery and moyamoya vessels, which are supposed to compensate for the stenotic
      change of the internal carotid artery, was disclosed.

PMID- 15197572
TI  - [Factors influencing corneal endothelium in organ cultures during transport].
AB  - PURPOSE: Experiments were performed to evaluate to what extent low temperature
      and mechanical shock are tolerated by the endothelium of corneal grafts in organ
      culture. METHODS: A total of 40 paired corneal grafts were kept in organ culture
      for 7-28 days at 34.5 degrees C. After this period, the grafts were divided into
      8 groups: (A(1)) organ culture at 20 degrees C for 12 h, thereafter organ culture
      at 34.5 degrees C for 7 days: (A(2)) control for group A(1) maintained at 34.5
      degrees C over the whole culture period: (B(1)) organ culture at 10 degrees C for
      12 h, thereafter organ culture at 34.5 degrees C for 7 days: (B(2)) control for
      group B(1) maintained at 34.5 degrees C over the whole culture period: (C(1))
      mechanical shock exerted 100 times (>100 g), thereafter organ culture at 34.5
      degrees C for 7 days: (C(2)) control for group C(1) maintained at 34.5 degrees C
      over the whole culture period with no mechanical shock: (D(1)) organ culture at
      10 degrees C for 12 h, mechanical shock exerted 100 times (>100 g) and then organ
      culture at 34.5 degrees C for 7 days: (D(2)) control for group D(1) maintained at
      34.5 degrees C over the whole culture period with no mechanical shock.
      Endothelial evaluation was performed immediately before and at the end of the
      final culture period. RESULTS: The following values for loss of endothelial cells
      were obtained: A(1) 5.7%+/-6.9, A(2) 4.3%+/-15.9, B(1) 10.4%+/-14.4, B(2) 7.2%+/
      14.0, C(1) 7.2%+/-6.3, C(2) 0.7%+/-13.4, D(1) 3.7%+/-7.6, D(2) 1.1%+/-7.4.
      CONCLUSIONS: According to these experiments, lowering the temperature to 10
      degrees C over a period of 12 h and/or mechanical shock above 100 g exerted 100
      times did not seem to affect the endothelium of corneal grafts in organ culture.

PMID- 15197573
TI  - [Photodynamic therapy for choroidal hemangioma. Long-term results].
AB  - AIM: Evaluation of functional and anatomical long-term results of patients with
      symptomatic choroidal hemangioma treated with photodynamic therapy (PDT).
      PATIENTS AND METHODS: All 8 patients suffered from progressive loss of vision
      caused by exudation into the macular area. PDT with a verteporfin dose of 6
      mg/m(2) body surface area and a light dose of 100 J/cm(2) at 692 nm was carried
      out. Two to four treatments were applied at 6 week intervals using a single laser
      spot. Standardized evaluation was used before and at 6-week intervals after each
      treatment and at 3, 6 and 12 months. In the further follow-up control intervals
      were extended up to 1 year in the case of stable anatomical and functional
      results. RESULTS: All patients showed complete regression of the tumor. The tumor
      height was reduced from an average of 3.64 mm to undetectable. One patient showed
      a stable visual acuity, seven patients a significant increase. Central scotometry
      showed withdrawal of scotomas from the macula. No patient showed any sign of
      recurrence during the follow-up of up to 60 months. CONCLUSION: The long-term
      results of patients with active choroidal hemangioma demonstrate that PDT is a
      most effective and safe treatment option. Complete tumor regression is combined
      with good functional recovery.

PMID- 15197574
TI  - [Prognosis and differential diagnosis of Purtscher's retinopathy].
AB  - BACKGROUND: Purtscher's retinopathy is accompanied by a distinct loss of vision
      as a result of severe trauma to the chest or skull. Reports on visual prognosis
      in the literature are not uniform. PATIENTS: The data of 10 patients with
      Purtscher's retinopathy from the department of Ophthalmology in Freiburg,
      published data from 55 patients with Purtscher's retinopathy and 20 patients with
      traumatic retinal hemorrhages taken from the literature were evaluated. RESULTS:
      The average visual acuity of the 10 patients from Freiburg was 0.3 within a short
      period after the accident and the final average visual acuity was 0.46. The
      average visual acuity of the 55 patients with Purtscher's retinopathy was 0.21
      within a short period after the accident with an average final visual acuity of
      0.61. The average visual acuity of the 20 patients with traumatic retinal
      hemorrhages from the literature was 0.45 within a short period after the accident
      with an average final visual acuity of 0.74. Therefore the initial and the final
      visual acuity were better in patients with traumatic retinal hemorrhages compared
      to patients with Purtscher's retinopathy. CONCLUSION: In spite of severe initial
      retinal findings, the visual prognosis is usually not disappointing. Prognosis of
      visual acuity was better in patients with traumatic retinal hemorrhages compared
      to patients with Purtscher's retinopathy.

PMID- 15197575
TI  - [Clinical and genetic results with reference to corneal alterations in Lowe
      syndrome].
AB  - BACKGROUND: The Lowe oculo-cerebro-renal syndrome (OCRL1) is a rare X-linked
      disease which causes impairment of visual acuity. The situation may be further
      complicated by corneal alterations. PATIENTS AND METHODS: In total seven patients
      from different families were clinically examined by slit-lamp examination,
      funduscopy, measurement of the intraocular pressure and ultrasound sonography.
      Molecular genetic analysis was performed in six patients by sequencing large PCR
      amplicons with a DNA sequencer and the ABI PRISM Sequence navigator software.
      RESULT: All affected boys were aphakic. Due to high intraocular pressure,
      iridectomy, goniotomy, cyclo-cryo treatment or trabeculectomy were performed. All
      patients showed opacity or pannus-like alterations of the cornea. Molecular
      genetic analysis revealed four novel and two known mutations. CONCLUSION: Reduced
      visual acuity was partly explained by morphological changes due to the underlying
      genetic defect and the development of cataract and glaucoma. Opacity of the
      cornea as well as alterations of the cornea seem to be a major problem in the
      course of the disease.

PMID- 15197576
TI  - [Measurement method for the determination of rotation and decentration of
      intraocular lenses].
AB  - PURPOSE: In the past 50 years the IOL has been improved. Nowadays it is possible
      to exactly calculate the necessary IOL power and correct toric refractive errors.
      In this study we developed methods for measuring rotation and decentration using
      the example of a hydrophilic acrylic IOL. METHODS: Following cataract surgery,
      the first retroilluminated photograph was taken. The position of the IOL was
      determined with the image analysis program Adobe Photoshop. RESULTS: Measurement
      of a rotational movement or of a decentration of an IOL can be done accurately
      and rapidly. Evaluation of the stability of rotation of the hydrophilic acrylic
      IOL measured here showed an average rotation of the IOL of 5.3+/-1.4 degrees
      after 6 months compared to the position directly after implantation. CONCLUSION:
      The measurement methods presented here are easy to use and provide reliable
      results. Examiners must have basic knowledge of the computer programs used. Also,
      these methods depend on good quality of the retroilluminated photographs.

PMID- 15197577
TI  - [Vermiform conjunctival structures].

PMID- 15197578
TI  - Construction of a BAC library of Korean ginseng and initial analysis of BAC-end
      sequences.
AB  - We estimated the genome size of Korean ginseng (Panax ginseng C.A. Meyer), a
      medicinal herb, constructed a HindIII BAC library, and analyzed BAC-end sequences
      to provide an initial characterization of the library. The 1C nuclear DNA content
      of Korean ginseng was estimated to be 3.33 pg (3.12 x 10(3) Mb). The BAC library
      consists of 106,368 clones with an average size of 98.61 kb, amounting to 3.34
      genome equivalents. Sequencing of 2167 BAC clones generated 2492 BAC-end
      sequences with an average length of 400 bp. Analysis using BLAST and motif
      searches revealed that 10.2%, 20.9% and 3.8% of the BAC-end sequences contained
      protein-coding regions, transposable elements and microsatellites, respectively.
      A comparison of the functional categories represented by the protein-coding
      regions found in BAC-end sequences with those of Arabidopsis revealed that
      proteins pertaining to energy metabolism, subcellular localization, cofactor
      requirement and transport facilitation were more highly represented in the P.
      ginseng sample. In addition, a sequence encoding a glucosyltransferase-like
      protein implicated in the ginsenoside biosynthesis pathway was also found. The
      majority of the transposable element sequences found belonged to the gypsy type
      (67.6%), followed by copia (11.7%) and LINE (8.0%) retrotransposons, whereas DNA
      transposons accounted for only 2.1% of the total in our sequence sample. Higher
      levels of transposable elements than protein-coding regions suggest that mobile
      elements have played an important role in the evolution of the genome of Korean
      ginseng, and contributed significantly to its complexity. We also identified 103
      microsatellites with 3-38 repeats in their motifs. The BAC library and BAC-end
      sequences will serve as a useful resource for physical mapping, positional
      cloning and genome sequencing of P. ginseng.

PMID- 15197579
TI  - EST derived SSR markers for comparative mapping in wheat and rice.
AB  - Structural and functional relationships between the genomes of hexaploid wheat (
      Triticum aestivum L.) (2n=6x=42) and rice (Oryza sativa L.) (2n=2x=24) were
      evaluated using linkage maps supplemented with simple sequence repeat (SSR) loci
      obtained from publicly available expressed sequence tags (ESTs). EST-SSR markers
      were developed using two main strategies to design primers for each gene: (1)
      primer design for multiple species based on supercluster analysis, and (2)
      species-specific primer design. Amplification was more consistent using the
      species-specific primer design for each gene. Forty-four percent of the primers
      designed specifically for wheat sequences were successful in amplifying DNA from
      both species. Existing genetic linkage maps were enhanced for the wheat and rice
      genomes using orthologous loci amplified with 58 EST-SSR markers obtained from
      both wheat and rice ESTs. The PCR-based anchor loci identified by these EST-SSR
      markers support previous patterns of conservation between wheat and rice genomes;
      however, there was a high frequency of interrupted colinearity. In addition,
      multiple loci amplified by these primers made the comparative analysis more
      difficult. Enhanced comparative maps of wheat and rice provide a useful tool for
      interpreting and transferring molecular, genetic, and breeding information
      between these two important species. These EST-SSR markers are particularly
      useful for constructing comparative framework maps for different species, because
      they amplify closely related genes to provide anchor points across species.

PMID- 15197580
TI  - Hepatic marker enzymes, biochemical parameters and pathological effects in lambs
      experimentally infected with Dicrocoelium dendriticum (Digenea).
AB  - Hepatic enzymes and biochemical parameter values were analysed in the sera of 32
      lambs: 12 infected with 1,000 Dicrocoelium dendriticum metacercariae, 12 with
      3,000 and eight controls. Blood samples were collected at intervals of 30 days
      from day 0 post-infection (p.i.). Half the lambs in each group were slaughtered
      on days 60 and 180 p.i, respectively. A histopathological and ultrastructural
      study was carried out on the liver, gall bladder and hepatic lymph nodes of all
      animals. A minute increase was detected in the bilirubin (7%) and albumin (3%)
      values in the infected lambs (with 30-2,063 worms) in comparison with those of
      the controls. The hepatic enzyme values did increase, above all aspartate
      aminotransferase (19%) and alanine aminotransferase (22%), mainly in the lambs
      tested with 3,000 metacercariae (38% and 48%, respectively). The increase was
      significant 60 days p.i. The severity of the lesions was closely associated with
      the parasite burden.

PMID- 15197581
TI  - Expression and cross-species reactivity of fatty acid-binding protein of
      Clonorchis sinensis.
AB  - Clonorchis sinensis is a Chinese liver fluke that chronically resides in the
      biliary tract. The fatty acid-binding protein (FABP) is known to play an
      important role in the intracellular transport of long-chain fatty acids that are
      obtained by the fluke from the host. Although FABP has stimulated considerable
      interest as a vaccine target candidate, the nature of FABP from C. sinensis
      (CsFABP) remains unclear. In this paper, we describe the cloning and expression
      of recombinant FABP and immune cross-reaction by Western blot analysis. Sequence
      analysis revealed that the CsFABP cDNA contained a single open reading frame
      (ORF) coding for 134 amino acids with an estimated molecular mass of a 15.2 kDa.
      The DNA sequence of CsFABP cDNA showed significant homology to schistosome
      cytosolic FABPs, with a 49% amino acid sequence identity and 89% similarity to
      Schistosoma japonicum. This DNA also showed a high sequence similarity at the
      amino acid level to S. mansoni (Sm14; 83%) and Fasciola hepatica (80%). The
      CsFABP cDNA was cloned into expression vector pET28a, expressed in Escherichia
      coli and the recombinant protein purified by affinity chromatography. The
      recombinant CsFABP was cross-reacted with sera obtained from patients with
      fascioliasis and paragonimiasis. These results suggest that CsFABP may be useful
      as a vaccine for clonorchiasis.

PMID- 15197582
TI  - Recombination does not generate pinworm susceptibility during experimental
      crosses between two mouse subspecies.
AB  - The susceptibility to Aspiculuris tetraptera of European Mus musculus hybrids is
      thought to reflect the disruption of genomic co-adaptation through recombination
      of the parental genomes. Here, we compared the susceptibility to this parasite
      between parents and experimental hybrids (intersubspecific until F4,
      intrasubspecific F1, F2) to clarify the contributions of heterosis and subspecies
      incompatibility. F1 showed hybrid vigor. Unlike intrasubspecific F2,
      intersubspecific F2 were less resistant than F1, but revealed no increased
      susceptibility relative to the parents. Intersubspecific F3 and F4 showed the
      same hybrid vigor as F1. Heterosis contributed most to the resistance, but the
      differences between intra- and intersubspecific F2 suggested genomic
      incompatibilities between subspecies. However, the susceptibility did not
      increase through the recombination process, showing that disruption of co
      adaptation does not directly affect resistance. Even if previous studies still
      support the selective role of parasites in the current hybrid zone, an
      alternative hypothesis on the origin of hybrid susceptibility is warranted.

PMID- 15197583
TI  - Celecoxib induces apoptosis in cervical cancer cells independent of
      cyclooxygenase using NF-kappaB as a possible target.
AB  - PURPOSE: Recently, many studies have shown that celecoxib induces apoptosis in
      various cancer cells by different mechanisms depending on the cell type. This
      study examined the apoptotic effect of celecoxib in cervical cancer cells and its
      mechanism. METHODS: Cell viability was measured by MTT assay and apoptosis was
      examined by DNA fragmentation and flow cytometry. Western blotting and
      immunoprecipitation were used to explore various mechanisms of celecoxib-induced
      apoptosis. The activation of NF-kappaB was confirmed by EMSA. RESULTS: Celecoxib
      induced apoptosis independent of COX-2 activity. This event accompanied the
      activation of caspase-8 and -9 with Bid cleavage and the loss of mitochondrial
      membrane potential. The protective effect of caspase-8 and -9 inhibitors on
      celecoxib-induced apoptosis suggests the importance of caspase-8 and -9
      activation in this apoptotic pathway. Fas/FADD-mediated apoptotic pathway was
      detected only in C33A cells, demonstrated by the immunoprecipitation of Fas-FADD
      in celecoxib-treated cells and the protective effect of FADD dominant negative
      mutant. Finally, NF-kappaB appeared to be involved in celecoxib-induced
      apoptosis, as revealed by increased NF-kB DNA binding activity in a time
      dependent manner and attenuation of its proapoptotic effect by N-tosyl-L
      phenylalanyl-chloromethyl ketone, an NF-kB blocker. CONCLUSIONS: These data show
      that caspase-8 and -9 are involved in the apoptotic effect of celecoxib in
      cervical cancer cells. This requires the FADD-dependent pathway in a cell type
      specific manner. In addition, NF-kappaB may play a key role in celecoxib-induced
      apoptosis.

PMID- 15197584
TI  - Prognostic significance of the maspin tumor suppressor gene in pulmonary
      adenocarcinoma.
AB  - PURPOSE: Maspin is a member of the serpin family and has tumor suppressor
      activity. We evaluated maspin expression in pulmonary adenocarcinoma in relation
      to a number of clinicopathological features. METHODS: Maspin expression was
      examined immunohistochemically in a series of 78 pulmonary adenocarcinomas by the
      EnVision ChemMate method. RESULTS: . Thirty-seven of 78 cases (47%) showed
      distinct maspin expression (maspin-positive group) and 41 (53%) did not (maspin
      negative group). Maspin expression was not associated significantly with most
      clinicopathological variables including sex, age, tumor size, primary tumor,
      lymph node metastasis, visceral pleural invasion, pulmonary metastasis, and
      disease stage. However, the maspin-positive group had a better 5-year survival
      rate (62%) than did the maspin-negative group (42%). The difference in the 5-year
      survival rate was greatest in stage II patients (maspin-positive group, 69%;
      maspin-negative group, 17%; P = 0.048). CONCLUSION: Our data indicate that maspin
      has prognostic significance for pulmonary adenocarcinoma. A better understanding
      of the role of maspin in tumor suppression may be helpful for development of
      novel chemotherapies for patients with this deadly tumor.

PMID- 15197586
TI  - What can children gain from pneumococcal conjugate vaccines?
AB  - In excess of 1 million young children die every year as a consequence of disease
      caused by Streptococcus pneumoniae, the vast majority in developing countries.
      Although the first vaccine against the Pneumococcus was produced before the First
      World War, licensure of the first vaccine with documented efficacy against severe
      infections in infants and young children did not occur until February 2000 in the
      United States. This conjugate vaccine consists of purified polysaccharide, from
      each of seven pneumococcal serotypes, chemically linked to a carrier protein. A
      high degree of efficacy of the new vaccine against potentially life-threatening
      infections has been shown in both poor and affluent countries. The vaccine's
      potential to protect from acute otitis media, however, is very limited, although
      encouraging indirect effects, such as reduced antibiotic prescriptions, have been
      reported. An inherent problem with the new pneumococcal conjugate vaccines is
      that, while more than 20 pneumococcal serotypes may cause invasive disease, only
      a more limited number of polysaccharides, 11 or so, can in practice be conjugated
      to carrier protein as part of a single vaccine formulation. Because of variation
      in the ranking of serotypes most commonly responsible for pneumococcal disease,
      by region, age and disease manifestation, compromise was required in selecting
      serotype-specific saccharides for inclusion. CONCLUSION: Complex conjugate
      technology comes at a price, and the present costs keep most of the world's
      children far out of reach of an effective vaccine. However, the pneumococcal
      conjugate vaccine is a highly functional weapon against deadly pneumococcal
      infections, and strenuous efforts are needed to maximise its accessibility to
      children most at risk.

PMID- 15197587
TI  - Wrist anomalies in Turner syndrome compared with Leri-Weill dyschondrosteosis: a
      new feature in Turner syndrome.
AB  - We analysed bone age radiographs in 102 girls with Turner syndrome and compared
      the findings with 93 control girls and nine girls with Leri-Weill syndrome.
      Various signs were analysed: radial bowing or Madelung deformity, maximal/minimal
      height of the radial epiphysis, brachymetacarpia of the 4th digit, carpal and
      epiphyseal angle, as well as a new sign the distal radio-ulnar physeal disparity.
      Two values differed significantly between the Turner group and the control group,
      the first being the epiphyseal angle which has already been reported to be
      greater in Turner syndrome, and the second being the new sign we have been able
      to describe. Turner patients had an increased distance between the ulnar and
      radial metaphysis, or "distal radio-ulnar physeal disparity", the ulnar being
      shorter. Furthermore, in 27% of cases the medial extremity of the ulnar epiphysis
      was flattened and passed below the distal extremity of the radius, whose medial
      part projected over the distal extremity of the ulna, thus reproducing in reverse
      the characteristic feature of Leri-Weill syndrome. In the growth hormone-treated
      Turner patients, we found a significant correlation between distal radio-ulnar
      physeal disparity and growth velocity expressed in cm/year (r = 0.28; P < 0.002)
      or in SDS/bone age (r = 0.21; P < 0.03) during the first year of treatment.
      CONCLUSION: the value of this new sign requires further investigation.

PMID- 15197588
TI  - Elicitation of reactive oxygen species in Chlamydia pneumoniae-stimulated
      macrophages: a Ca2+-dependent process involving simultaneous activation of NADPH
      oxidase and cytochrome oxidase genes.
AB  - Chlamydia pneumoniae, a respiratory pathogen implicated in the development and
      progress of atherosclerosis, is known to infect and survive in macrophages,
      despite macrophage producing reactive oxygen species (ROS). To gain insight into
      ROS generation in macrophages infected with C. pneumoniae and to explore factors
      accounting for their final levels and effect, we investigated the role of NADPH
      oxidase and cytochrome oxidase pathways in the production and modulation of ROS.
      We also determined the operational role of Ca2+ signaling in the process.
      Macrophages stimulated with C. pneumoniae exhibit early release of ROS via up
      regulation of NADPH oxidase and cytochrome c oxidase activities. Increasing the
      dose of C. pneumoniae led to an increase in the expression of these enzymes gene
      production, which was accompanied by a significant up-regulation of their gene
      products, implying a probable activation of transcriptional and translational
      processes, respectively. The change in levels of free Ca2+, influx across plasma
      membrane and efflux from intracellular store into cytosol all exhibited a
      significant regulatory role on the ROS generation pathways in macrophages. The
      observed events were shown to be dependent on binding of C. pneumoniae to CD14
      receptors of macrophages. The data reported here imply that macrophages infected
      with C. pneumoniae produce ROS through membrane-associated NADPH oxidase with
      oxidative phosphorylation levels depending on Ca2+ influx signals.

PMID- 15197589
TI  - Mesothelial lamellar bodies in norm and experimental conditions. Transmission and
      scanning electron microscopic observations on the peritoneum, pleura and
      pericardium.
AB  - The ultrastructural characteristics of the mesothelial intracellular and
      extracellular lamellar bodies (LB) in norm, and especially in pathological
      conditions are still unknown. After routine fixation procedure, material from
      organs in the three serous cavities of Wistar rats, as control group were
      compared with animals following experimental hemothorax (EH) and experimental
      peritonitis (EP), using transmission and scanning electron microscopy (TEM, SEM).
      Different membrane-bound profiles, short strip-like structures and single LB
      characterize the control group. Five days after EH small groups of LB were
      observed. Single balloon-like profiles, numerous particles and larger groups of
      LB with wide varieties in size, form and membrane structure characterize the 8th
      day after EH. Thin and concentric membranes build single LB the 5th day of EP.
      Eight days after the same treatment, groups of LB, complex structures with
      several multilamellar centers, strip-like structures with rough granulo
      filamentous material and uninterrupted covering over wide areas were observed. We
      conclude that constant components in the untreated rats are different membrane
      profiles, as initial lamellar formations and single typical LB with predominant
      intracellular position. The preferable sites for exocytosis of LB are the
      intercellular spaces. The present data demonstrate simultaneous findings of the
      two main groups of formations by using routine fixation in the control group and
      in the treated animals. The first represent LB as well as other round profiles,
      observed by TEM and particles, observed by SEM, which are widespread and probably
      have a basic role. The second ones are strip-like structures and its SEM
      equivalents, i.e. uninterrupted covering. TEM-profiles and their SEM-images show
      significant organ differences and in some cases lack of correspondence between
      both electron microscopic techniques in the same treatment. Significant
      enlargement of the number of LB and the length of the strip-like structures
      characterize the mesothelium after pathologic conditions. LB with considerable
      differences in the structure and larger particles over the microvillous border
      predominate after EH. Strip-like profiles, continuous covering and smaller groups
      of LB with similar morphology and preferable submesothelial position characterize
      the mesothelium after EP.

PMID- 15197590
TI  - The novel gene CpEdi-9 from the resurrection plant C. plantagineum encodes a
      hydrophilic protein and is expressed in mature seeds as well as in response to
      dehydration in leaf phloem tissues.
AB  - The resurrection plant Craterostigma plantagineum Hochst. is used as an
      experimental system to investigate desiccation tolerance in higher plants. A
      search for genes activated during early stages of dehydration identified the gene
      CpEdi-9, which is expressed in mature seeds and in response to dehydration in the
      phloem cells of vascular tissues of leaves. Elements for the tissue-specific
      expression pattern reside in the isolated promoter of the CpEdi-9 gene, as shown
      through the analysis of transgenic plants. The CpEdi-9 promoter could be a
      suitable tool for expressing genes in the vascular system of dehydrated plants.
      CpEdi-9 encodes a small (10 kDa) hydrophilic protein, which does not have
      significant sequence homologies to known genes. The predicted protein CpEDI-9
      shares some physicochemical features with LEA proteins from plants and a
      nematode. Based on the unique expression pattern and on the nucleotide sequence
      we propose that CpEdi-9 defines a new class of hydrophilic proteins that are
      supposed to contribute to cellular protection during dehydration. This group of
      proteins may have evolved because desiccation tolerance requires the abundant
      expression of protective proteins during early stages of dehydration in all
      tissues.

PMID- 15197591
TI  - Wild barley eibi1 mutation identifies a gene essential for leaf water
      conservation.
AB  - Drought is a major abiotic stress that limits plant growth and crop productivity.
      A spontaneous wilty mutant (eibi1) hypersensitive to drought was identified from
      wild barley (Hordeum spontaneum Koch). eibi1 showed the highest relative water
      loss rate among the known wilty mutants, which indicates that eibi1 is one of the
      most drought-sensitive mutants. eibi1 had the same abscisic acid (ABA) level, the
      same ability to accumulate stress-induced ABA, and the same stomatal movement in
      response to light, dark, drought, and exogenous ABA as the wild type, revealing
      that eibi1 was neither an ABA-deficient nor an ABA-insensitive mutant. The eibi1
      leaves had a larger chlorophyll efflux rate in 80% ethanol than the wild-type
      leaves; and the transpiration rate of eibi1 was more closely related to
      chlorophyll efflux rate than to stomatal density, demonstrating that the cuticle
      of eibi1 was defective. eibi1 will be a promising candidate to study the actual
      barrier layer in the cuticle that limits water loss of the plant. Exogenous ABA
      reduced leaf length growth in eibi1 more than in the wild type, implying an
      interaction on plant growth of ABA signal transduction and the eibi1 product. One
      may infer that the eibi1 product may reverse the growth inhibition induced by
      ABA.

PMID- 15197592
TI  - Localization to the rhizoid tip implicates a Fucus distichus Rho family GTPase in
      a conserved cell polarity pathway.
AB  - Generation and expression of cell polarity in brown algal zygotes of the Fucales
      involve regulation of the actin cytoskeleton and localized secretion. We used
      degenerate PCR to isolate cDNAs that encode two small GTPases, FdRac1 and FdRab8,
      from zygotes of Fucus distichus (L.) Powell. Sequence analysis placed FdRac1 in
      the Rho family, which regulates actin, and FdRab8 in the Rab family, which
      regulates vesicle transport. As expected, bacterially expressed forms of both
      proteins bound GTP in vitro. When expressed in budding yeast, FdRac1 showed some
      functional overlap with CDC42, the Saccharomyces cerevisiae Rho family gene
      required for yeast cell polarity. Immunolocalization revealed an asymmetric
      distribution of FdRac1 in polarized zygotes and embryos, with FdRac1 concentrated
      at or near the growing tip of the algal rhizoid. Our data support the hypothesis
      that FdRac1 regulates algal cell polarity, possibly via the actin cytoskeleton.
      Because brown algae belong to the heterokont group, which diverged from other
      groups early in eukaryotic evolution, we argue that the Rho family function of
      regulating cell polarity is ancient and may extend throughout the eukaryotes.

PMID- 15197593
TI  - Expression of a deregulated tobacco nitrate reductase gene in potato increases
      biomass production and decreases nitrate concentration in all organs.
AB  - We investigated the physiological consequences for nitrogen metabolism and growth
      of the deregulated expression of an N-terminal-deleted tobacco nitrate reductase
      in two lines of potato (Solanum tuberosum L. cv Safrane). The transgenic plants
      showed a higher biomass accumulation, especially in tubers, but a constant
      nitrogen content per plant. This implies that the transformed lines had a reduced
      nitrogen concentration per unit of dry weight. A severe reduction in nitrate
      concentrations was also observed in all organs, but was more apparent in tubers
      where nitrate was almost undetectable in the transgenic lines. In leaves and
      roots, but not tubers, this nitrate decrease was accompanied by a statistically
      significant increase in the level of malate, which acts as a counter-anion for
      nitrate reduction. Apart from glutamine in tubers, no major changes in amino acid
      concentration were seen in leaves, roots or tubers. We conclude that enhancement
      of nitrate reduction rate leads to higher biomass production, probably by
      allowing a better allocation of N-resources to photosynthesis and C-metabolism.

PMID- 15197595
TI  - Altered expression of the Arabidopsis ortholog of DCL affects normal plant
      development.
AB  - The DCL ( defective chloroplasts and leaves) gene of tomato ( Lycopersicon
      esculentum Mill.) is required for chloroplast development, palisade cell
      morphogenesis, and embryogenesis. Previous work suggested that DCL protein is
      involved in 4.5S rRNA processing. The Arabidopsis thaliana (L.) Heynh. genome
      contains five sequences encoding for DCL-related proteins. In this paper, we
      investigate the function of AtDCL protein, which shows the highest amino acid
      sequence similarity with tomato DCL. AtDCL mRNA was expressed in all tissues
      examined and a fusion between AtDCL and green fluorescent protein (GFP) was
      sufficient to target GFP to plastids in vivo, consistent with the localization of
      AtDCL to chloroplasts. In an effort to clarify the function of AtDCL, transgenic
      plants with altered expression of this gene were constructed. Deregulation of
      AtDCL gene expression caused multiple phenotypes such as chlorosis, sterile
      flowers and abnormal cotyledon development, suggesting that this gene is required
      in different organs. The processing of the 4.5S rRNA was significantly altered in
      these transgenic plants, indicating that AtDCL is involved in plastid rRNA
      maturation. These results suggest that AtDCL is the Arabidopsis ortholog of
      tomato DCL, and indicate that plastid function is required for normal plant
      development.

PMID- 15197594
TI  - Biochemical and molecular characterization of transgenic Lotus japonicus plants
      constitutively over-expressing a cytosolic glutamine synthetase gene.
AB  - Higher plants assimilate nitrogen in the form of ammonia through the concerted
      activity of glutamine synthetase (GS) and glutamate synthase (GOGAT). The GS
      enzyme is either located in the cytoplasm (GS1) or in the chloroplast (GS2). To
      understand how modulation of GS activity affects plant performance, Lotus
      japonicus L. plants were transformed with an alfalfa GS1 gene driven by the CaMV
      35S promoter. The transformants showed increased GS activity and an increase in
      GS1 polypeptide level in all the organs tested. GS was analyzed by non-denaturing
      gel electrophoresis and ion-exchange chromatography. The results showed the
      presence of multiple GS isoenzymes in the different organs and the presence of a
      novel isoform in the transgenic plants. The distribution of GS in the different
      organs was analyzed by immunohistochemical localization. GS was localized in the
      mesophyll cells of the leaves and in the vasculature of the stem and roots of the
      transformants. Our results consistently showed higher soluble protein
      concentration, higher chlorophyll content and a higher biomass accumulation in
      the transgenic plants. The total amino acid content in the leaves and stems of
      the transgenic plants was 22-24% more than in the tissues of the non-transformed
      plants. The relative abundance of individual amino acid was similar except for
      aspartate/asparagine and proline, which were higher in the transformants.

PMID- 15197596
TI  - Expression of proteinase inhibitor II proteins during floral development in
      Solanum americanum.
AB  - The heterologous expression of serine proteinase inhibitor II (PIN2) proteins
      confers insect resistance in transgenic plants, but little is known of their
      endogenous roles. We have cloned two cDNAs encoding Solanum americanum PIN2
      proteins, SaPIN2a and SaPIN2b. SaPIN2a is highly expressed in stem, particularly
      in the phloem, suggesting it could possibly regulate proteolysis in the sieve
      elements. When SaPIN2a was expressed in transgenic lettuce, we observed an
      inhibition of endogenous trypsin- and chymotrypsin-like activities. Here, we
      demonstrate that both SaPIN2a and SaPIN2b are expressed in floral tissues that
      are destined to undergo developmental programmed cell death (PCD), suggesting
      possible endogenous roles in inhibiting trypsin- and chymotrypsin-like activities
      during flower development. Northern and western blot analyses revealed that
      SaPIN2a and SaPIN2b mRNAs and proteins show highest expression early in floral
      development. In situ hybridization analysis and immunolocalization on floral
      sections, localized SaPIN2a and SaPIN2b mRNAs and their proteins to tissues that
      would apparently undergo PCD: the ovules, the stylar transmitting tissue, the
      stigma and the vascular bundles. Detection of PCD in floral sections was achieved
      using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling
      (TUNEL) analysis. Examination of the mid-style before, and 1 day after,
      pollination revealed that high expression of SaPIN2a and SaPIN2b in the style was
      inversely correlated with PCD.

PMID- 15197597
TI  - Characterization of the human renal Na(+)-sulphate cotransporter gene ( NAS1)
      promoter.
AB  - Sulphate (SO(4)(2-)) plays an essential role during growth, development, and
      cellular metabolism. Recently, we have isolated the human renal Na(+)-SO(4)(2-)
      cotransporter (hNaSi-1) that is implicated in the regulation of serum SO(4)(2-)
      levels. To gain an insight into hNaSi-1 regulation, our aims were to clone and
      characterize functionally the hNaSi-1 gene ( NAS1) promoter. We PCR-amplified
      3742 bp of the NAS1 5'-flanking region, which is 64% AT-rich and contains
      numerous putative cis-acting elements. The NAS1 transcription start site was
      mapped to 25 bp upstream from the translation start site. NAS1 promoter
      truncations fused to luciferase gene constructs transfected into renal LLC-PK1,
      MDCK and OK cells allowed us to establish that the first 169 bp of the NAS1
      promoter are sufficient for basal transcription. Furthermore, the NAS1 promoter
      conferred responsiveness to the polycyclic aromatic hydrocarbon 3
      methylcholanthrene (3-MC), but not to thyroid hormone (T(3)) or vitamin D [1,25
      (OH)(2)D(3)]. Site-directed mutagenesis of the NAS1 promoter identified a
      functional xenobiotic response element at -2,052, which conferred 3-MC
      responsiveness. The human NAS1 gene promoter is not responsive to Vitamin D or
      T(3), unlike the mouse Nas1 promoter with which it shares approximately 40%
      sequence similarity, but is transactivated by 3-MC, suggesting that the control
      of renal SO(4)(2-) reabsorption via the regulation of NAS1 transcription may be
      important for maintaining the sulphation potential for kidney polycyclic aromatic
      hydrocarbon metabolism.

PMID- 15197598
TI  - 2-aminoethoxydiphenyl borate inhibits agonist-induced Ca2+ signals by blocking
      inositol trisphosphate formation in acutely dissociated mouse pancreatic acinar
      cells.
AB  - Evidence suggests that 2-aminoethoxydiphenyl borate (2-APB) modulates
      intracellular Ca(2+) signals in a complex manner. 2-APB inhibits or potentiates
      intracellular Ca(2+) signals in different cell types, perhaps through different
      mechanisms. Here, we report a novel mechanism underlying 2-APB-induced inhibition
      of agonist-activated Ca(2+) oscillations in mouse pancreatic acinar cells, using
      patch-clamp and biochemical techniques. Pre-treatment of the cells with 100
      microM 2-APB completely abolished ACh- but not inositol trisphosphate (InsP(3))
      induced Ca(2+) oscillations, suggesting that the mechanism of inhibition occurs
      between cytoplasmic receptors and InsP(3) receptor activation. In addition, 100
      microM 2-APB significantly inhibited ACh-induced phospholipase C (PLC)
      activation. These findings indicate that, in mouse pancreatic acinar cells, in
      addition to modulating InsP(3) receptors and blocking the store-operated Ca(2+)
      pathway, high concentrations of 2-APB also inhibit agonist-induced Ca(2+) signals
      by reducing InsP(3) formation.

PMID- 15197600
TI  - Antifungal activity of Bacillus subtilis 355 against wood-surface contaminant
      fungi.
AB  - A strain of Bacillus subtilis was examined for antifungal activity against
      phytopathogenic and wood-surface contaminant fungi. The bacterium was grown in
      five culture media with different incubation times in order to study cell
      development, sporulation, and the production of metabolites with antifungal
      activity. The anti-sapstain and anti-mould activity of the bacterium grown in
      yeast extract glucose broth (YGB) medium in wood was also evaluated. In YGB, the
      bacterium inhibited the growth of several fungi and displayed a broader spectrum
      of activity than in the other media tested. A relationship between bacterial
      spore production and the formation of metabolites with antifungal activity was
      detected. YGB medium displayed effective control in wood block tests. YGB medium
      was extracted with solvents of increasing polarity and the dry residues were
      applied to silicagel plates, resolved with the appropriate solvent and sprayed
      with different solutions, detecting the presence, of amines, and higher alcohols.
      The bioautographic method revealed the presence of at least two active compounds
      against the blue-stain fungus Cladosporium cucumerinum.

PMID- 15197599
TI  - Group size in folivorous primates: ecological constraints and the possible
      influence of social factors.
AB  - The ecological-constraints model assumes that food items occur in depletable
      patches and proposes that an increase in group size leads to increased day range
      due to more rapid patch depletion. Smaller groups become advantageous when an
      increase in travel costs is not repaid by an increase in energy gained or some
      other fitness advantage. On the other hand, we also know that group size can be
      influenced by social factors. Here we contrast the diet and group size of red
      colobus (Procolobus badius) and black-and-white colobus (Colobus guereza) in
      Kibale National Park, Uganda to consider how ecological and social factors are
      affecting their group sizes. Subsequently, we examine whether the insights gained
      from this detailed comparison can provide an understanding of why the social
      organization and group size of mantled howlers (Alouatta palliata) and black
      howlers (A. pigra) differ. Two groups of red colobus and two groups of black-and
      white colobus were studied over 10 months. Red colobus groups were larger (48 and
      24) than black-and-white colobus groups (9 and 6). The two groups of red colobus
      overlap home ranges with the two groups of black-and-white colobus; 75% and 95%
      of their home ranges were within red colobus's home range. There was a great deal
      of similarity in the plant parts eaten by the two species and both species fed
      primarily on young leaves (red colobus 70%, black-and-white colobus 76%). In
      terms of the actual species consumed, again there was a great deal of similarity
      between species. The average dietary overlap among months for the two neighboring
      groups of red colobus was 37.3%, while the dietary overlap between the red
      colobus and the black-and-white colobus group that had its home range almost
      entirely within the home range of the red colobus groups averaged 43.2% among
      months. If ecological conditions were responsible for the difference in group
      size between the two colobine species, one would expect the density of food trees
      to be lower in the home ranges of the black-and-white colobus monkeys, since they
      have the smaller group size. We found the opposite to be true. Both black-and
      white colobus groups had more food trees and the cumulative size of those trees
      was greater than those in the red colobus's home ranges. We quantify how these
      differences parallel differences in mantled and black howlers. The average group
      size for mantled howlers was 12.9 individuals, and for black howlers it was 5.3
      individuals. We explore possible social constraints, such as infanticide, that
      prevent black-and-white colobus and black howlers from living in large groups.

PMID- 15197601
TI  - On the significance of fiber branching in the human myocardium.
AB  - Myocardial tissue exhibits a high degree of organization in that the cardiac
      muscle fibers are both systematically aligned and highly branched. In this study,
      the influence and significance of fiber branching is analyzed mathematically. In
      order to allow for analytic solutions, a regular geometry and simplified
      constitutive relations are considered. It is found that branching is necessary to
      stabilize the ventricular wall.

PMID- 15197603
TI  - Basic and clinical research on amyotrophic lateral sclerosis and other motor
      neuron disorders in Italy: recent findings and achievements from a network of
      laboratories.
AB  - An Italian collaborative group on motor neuron disorders, including amyotrophic
      lateral sclerosis (ALS) and its variants, has been recently created, combining
      various academic groups and laboratories involved in basic and clinical research.
      The aim is to exploit all the specific expertise and combine efforts at a
      national level to better understand and fight these fatal diseases. This review
      summarizes the achievements of the different groups and outlines prospects for
      future research. Basic research deals with the etiopathogenesis of motor neuron
      diseases. In vitro and in vivo models of superoxide dismutase 1 (SOD1) mutations
      are used to investigate the mechanisms of motor neuron death associated with this
      gene defect. The role of excitotoxicity, immune response, intracellular
      aggregates and mitochondrial alterations is studied with an integrated approach,
      at the molecular and cellular levels. Transgenic mice carrying the human mutated
      SOD1, and the wobbler mouse, a spontaneous model for motor neuron degeneration,
      offer unique opportunities for testing new therapies in vivo related or not to
      SOD1 mutations. Clinical research has focused mostly on the incidence and
      determinants of ALS in several areas of Italy. The incidence of the disease is
      now among the highest according to the results of population-based regional
      registries. Compared to earlier studies, more recent Italian investigations show
      an increase in the incidence and mortality related to ALS. Findings on the role
      of environmental risk factors are inconsistent. Methodological issues have also
      been raised by Italian groups regarding the diagnosis and treatment. The validity
      of the El Escorial diagnostic classification has been questioned where
      investigators and carers have not received formal training. Pitfalls and
      methodological drawbacks of randomized clinical trials have been highlighted
      based on the results of collaborative trials by Italian investigators.
      Information is now available on non-pharmacological treatments and palliative
      care, and the economic aspects and quality of life of ALS patients are being
      investigated.

PMID- 15197604
TI  - Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth
      disease.
AB  - Periaxin (PRX) plays a significant role in the myelination of the peripheral
      nerve. To date, seven non-sense or frameshift PRX mutations have been reported in
      six pedigrees with Dejerine-Sottas neuropathy or severe Charcot-Marie-Tooth
      neuropathy (CMT). We detected a PRX mutation in three patients in the screening
      of 66 Japanese demyelinating CMT patients who were negative for the gene mutation
      causing dominant or X-linked demyelinating CMT. Three unrelated patients were
      homozygous for a novel R1070X mutation and presented early-onset but slowly
      progressive distal motor and sensory neuropathies. Mutations lacking the carboxyl
      terminal acidic domain may show loss-of-function effects and cause severe
      demyelinating CMT.

PMID- 15197605
TI  - Thermophilic bacterial DNA polymerases with reverse-transcriptase activity.
AB  - Conserved motifs found in known bacterial polI DNA polymerase sequences were
      identified, and degenerate PCR primers were designed for PCR amplification of an
      internal portion of polI genes from all bacterial divisions. We describe here a
      method that has allowed the rapid identification and isolation of 13 polI genes
      from a diverse selection of thermophilic bacteria and report on the biochemical
      characteristics of nine of the purified recombinant enzymes. Several enzymes
      showed significant reverse-transcriptase activity in the presence of Mg2+,
      particularly the polymerases from Bacillus caldolyticus EA1, Caldibacillus
      cellovorans CompA.2, and Clostridium stercorarium.

PMID- 15197606
TI  - Identification of replication origins in the genome of the methanogenic archaeon,
      Methanocaldococcus jannaschii.
AB  - Methanocaldococcus jannaschii has been notorious as an archaeon in which the
      replication origins are difficult to identify. Although extensive efforts have
      been exerted on this issue, the locations of replication origins still remain
      elusive 7 years after the publication of its complete genome sequence in 1996.
      Ambiguous results were obtained in identifying the replication origins of M.
      jannaschii based on all theoretical and experimental approaches. In the genome of
      M. jannaschii, we found that an ORF (MJ0774), annotated as a hypothetical
      protein, is a homologue of the Cdc6 protein. The position of the gene is at a
      global minimum of the x component of the Z curve, i.e., RY disparity curve, which
      has been used to identify replication origins in other Archaea. In addition, an
      intergenic region (694,540-695,226 bp) that is between the cdc6 gene and an
      adjacent ORF shows almost all the characteristics of known replication origins,
      i.e., it is highly rich in AT composition (80%) and contains multiple copies of
      repeat elements and AT stretches. Therefore, these lines of evidence strongly
      suggest that the identified region is a replication origin, which is designated
      as oriC1. The analysis of the y component of the Z curve, i.e., MK disparity
      curve, suggests the presence of another replication origin corresponding to one
      of the peaks in the MK disparity curve at around 1,388 kb of the genome.

PMID- 15197607
TI  - Congested residual nidus after preoperative intranidal embolization in midsize
      cerebral arteriovenous malformations of 3-6 cm in diameter.
AB  - BACKGROUND: Modern delicate microcatheters allow intranidal embolization of
      cerebral arteriovenous malformations (AVM). The aim of the current analysis was
      to assess effects of preoperative intranidal deployment of embolic material on
      surgical time and blood loss in cerebral arteriovenous malformations of 3-6 cm in
      diameter. METHODS: The case records of 38 cerebral AVM between 3 and 6 cm in
      maximum diameter were reviewed, that had been embolized intranidally with N-butyl
      2-cyanoacrylate (Histacryl) and subsequently operated on. Surgical time and blood
      loss as well as particular intraoperative findings such as a congested nidus and
      thrombosis of draining veins were registered and correlated with the extent of
      embolization and the time interval between embolization and surgery. FINDINGS:
      Preoperative embolization occluded an estimated range of 10 to 90% of the nidus.
      Minor embolization related bleeding without clinical relevance occurred in 5
      patients. Significant embolization related bleeding resulting in earlier than
      planned surgery occurred in another 5 patients. All embolization related
      haemorrhages occurred within 24 hours. Average total operating time was 343+/-106
      min and average blood loss was 684+/-858 ml. Unequivocal bleeding difficulty from
      the nidus and a total blood loss of more than 1000 ml were encountered in 7
      instances and dissection was tedious due to a bleeding AVM core in 5 other cases.
      A congested AVM core was the source of bleeding in 11 patients and
      paraventricular neovascularization in one. 6 of the 11 cases with a congested AVM
      core had suffered minor or substantial haemorrhage after a preoperative
      endovascular procedure. Intraoperative nidus congestion was noted in this series
      after an interval as long as 2 weeks after the last embolization. Combined
      management resulted in permanent morbidity in 6 of the 38 cases. In 4 of them the
      neurological deficit was associated with an intraoperative bleeding problem, in
      all due to congested nidus. Morbidity had to be correlated with major haemorrhage
      resulting from preoperative embolization in 2 instances. CONCLUSIONS: Intranidal
      embolization prior to surgical removal of AVM can lead to a congested residual
      nidus and intraoperative bleeding. Minor leakage after preoperative embolization
      is an inconsistent warning sign of nidus congestion. Nidus outflow after
      intranidal embolization appears to require a few weeks for normalization. Delay
      of surgery after embolization should be considered in cases of suspected
      congested residual nidus. The danger of major haemorrhage or arterial
      revascularization during this waiting period appears small.

PMID- 15197608
TI  - Seasonal variations in hospital admissions due to aneurysmal subarachnoid
      haemorrhage in the state of Zurich, Switzerland.
AB  - INTRODUCTION: In clinical practice, the occurrence of aneurysmal subarachnoid
      haemorrhage (SAH) often coincides with a particular season. Our objective was to
      examine seasonal variations in hospital admissions due to aneurysmal SAH.
      METHODS: The study population consisted of 489 patients with aneurysmal SAH who
      were admitted to the Department of Neurosurgery, University Hospital of Zurich,
      Switzerland, between 1st of January 1996 and 31st of December 2002. Statistical
      significance of seasonal variation was determined by applying Roger's r test.
      RESULTS: Statistically significant seasonal variation was only found among
      patients younger than 60 years, showing a first peak in spring and second lower
      peak in autumn (Roger's r=6.89, p<0.05). A borderline significance was found in
      men younger than 60 years (Roger's r=5.96, p=0.051). A trend was observed in
      patients presenting with Fisher grade 1-2 (Roger's r=5.70, p=0.058). CONCLUSIONS:
      Previous studies from different countries have shown significant seasonal
      variations, with the peak period for aneurysmal SAH differing widely. There
      appears to be some link between aneurysmal SAH and the season of the year or
      variations in weather conditions. Further investigations are desirable to
      evaluate which weather or climatic parameters correlate well with SAH.

PMID- 15197609
TI  - CT-guided percutaneous aspiration of Tarlov cyst as a useful diagnostic procedure
      prior to operative intervention.
AB  - Tarlov or perineural cysts are lesions of the nerve root most often found in the
      sacral region. Several authors recommend surgical treatment of symptomatic Tarlov
      cysts. However, successful surgical treatment is dependent on appropriate patient
      selection. In this article, we report three cases of a sacral perineural cyst,
      causing sciatic pain, and emphasize the usefulness of CT-guided percutaneous
      aspiration as an important diagnostic and prognostic procedure prior to
      definitive operative treatment.

PMID- 15197610
TI  - Comparison between degree of carotid stenosis observed at angiography and in
      histological examination.
AB  - BACKGROUND: The generally accepted indications for carotid endarterectomy are the
      clinical picture and degree of per cent stenosis of the carotid artery. Despite
      the fact that stenosis measurement is defined, the methods vary considerably. The
      correlation of particular methods, especially angiography and duplex sonography,
      has been repeatedly demonstrated. However, the correlation between any technique
      and true anatomical stenosis, as evaluated on the surgical specimen, has been
      only anecdotally reported. METHOD: During carotid endarterectomy, the
      atherosclerotic plaque was removed in one piece and subsequently stored and
      histologically processed. The histological slides were evaluated under an optical
      microscope, scanned and the slide with maximum stenosis was determined using a
      planimetric program. Both the minimal lumen area and the area of the whole plaque
      were measured. The stenosis was calculated using the planimetric method. On the
      maximum stenosis slice, the minimal diameter and the diameter of the whole plaque
      were also measured. Angiographic images were scanned and the per cent stenoses
      were remeasured, according to the NASCET and ECST criteria. In total, of 147
      cases, all above-mentioned parameters were obtained. Student's t tests for paired
      samples were used to evaluate the results. FINDINGS: The t-tests indicated
      significant differences between the per cent stenosis as measured on the
      anatomical specimen and on the angiogram (p<0.05). The results indicate that the
      angiographic measurement underestimates the degree of in-situ anatomical
      stenosis. The underestimation was more marked the less the degree of stenosis.
      CONCLUSIONS: Our study finds that per cent stenosis measurement obtained by
      angiography with NASCET or ECST methods does not reliably reflect the anatomical
      degree of per cent stenosis, which makes questionable the rigorous following of
      percentage stenosis using angiography as the sole indicator for carotid
      endarterectomy in all cases.

PMID- 15197611
TI  - Lhermitte-Duclos disease and Cowden disease: clinical and genetic study in five
      patients with Lhermitte-Duclos disease and literature review.
AB  - BACKGROUND: Lhermitte-Duclos Disease (LDD) is an infrequent cerebellar disorder
      characterized by focal or diffuse enlargement of cerebellar folia presenting as a
      slowly growing mass in the posterior fossa. Over the past decade its association
      with Cowden disease (CD) has been recognized with increasing frequency. This
      latter disease is a genetic condition leading to the presence of multiple
      hamartomas and neoplasias which affect mainly the skin, thyroid, breast and
      genito-urinary and gastro-intestinal tracts. It has even been hypothesized that
      LDD and CD constitute a single entity. This work is aimed to analyse to what
      extent this association was present in patients treated for LDD at our
      institution. METHOD: We reviewed the medical records of five patients and
      performed clinical studies for CD manifestations, among them, genetic
      investigation for PTEN mutations. The International Cowden Consortium Criteria
      were applied for the diagnosis of CD. FINDINGS: Four of the five patients treated
      for LDD were also diagnosed of CD. The genetic study found PTEN mutations in two
      of them. Interpretation. LDD has been found to be closely related to CD in this
      series, in accordance with previous literature. However, the absence of CD
      diagnosis in one of the patients led us to suggest that, despite the strong
      association between these two diseases, LDD can also appear as an isolated
      condition.

PMID- 15197612
TI  - Quality of life after decompressive craniectomy in patients suffering from
      supratentorial brain ischemia.
AB  - BACKGROUND: Decompressive craniectomy in patients suffering from severe ischemic
      stroke in the middle cerebral artery territory (MCA) decreases mortality to near
      30%. Additionally functional outcome in patients after early craniectomy seems to
      be better than in patients without surgery. The aim of this study was to
      investigate the quality of life of patients who were treated with a decompressive
      craniectomy for severe ischemic stroke. METHODS: We retrospectively investigated
      the patient records of 48 patients (26 men, mean age 48 years) suffering from
      ischemic strokes who underwent craniectomy since 1993. We registrated the
      preoperative neurological status, the diagnostic data as well as the operative
      procedure. The outcome was assessed using the Barthel Index, the Glasgow outcome
      score and a questionnaire to assess the quality of life according to Blau
      consisting of eleven items at follow-up. FINDINGS: The mortality rate was 26%,
      age correlated to mortality (44.5 versus 60.3 years GOS 1, mean, p<0.0006).
      Craniectomy without dura patch correlated to mortality (58% versus 14% GOS 1 with
      dura patch, p<0.005). The quality of life index was 6 points mean. The quality of
      life index did neither differ significantly between patients with left or right
      sided lesions nor in patients with and without aphasia. 83% of the surviving
      patients and/or dependents would agree to surgery in the future. CONCLUSION:
      Despite the fact that some patients remain in a poor neurological condition,
      quality of life after decompressive surgery for ischemic stroke seems to be
      acceptable to the patients.

PMID- 15197613
TI  - Robot-assisted navigated endoscopic ventriculostomy: implementation of a new
      technology and first clinical results.
AB  - BACKGROUND: Important landmarks in the evolution of advanced neurosurgical
      techniques during the past decades include microneurosurgery, neuro-endoscopy and
      its minimally invasive nature, as well as neuronavigation and advanced intra
      operative imaging. With conventional neuroendoscopic techniques, e.g. free-hand
      endoscopy or the use of mechanical or pneumatic holding devices, a definitive and
      controlled movement of the endoscope within the brain does depend on the
      experience and manual skill of the individual neurosurgeon. Therefore, the
      development of robotic systems to assist surgeons in performing complex
      neurosurgical procedures is a growing field of interest. METHOD: With the
      precision robot "Evolution 1" (U.R.S. Universal Robot Systems, Schwerin, Germany)
      a new neurosurgical tool has just become available for the precise steering of
      instruments within the cranium. After preclinical anatomical as well as precision
      studies the system was used for robot-assisted navigated endoscopic third
      ventriculostomies in six patients with hydrocephalus related to aqueductal
      stenosis. FINDINGS: All robot-assisted navigated endoscopic procedures were
      successfully completed. The time for the registration procedure and setup of the
      robot decreased from 60 min. for the first procedure down to 30 min. The time for
      the surgical part of the neuro-endoscopic procedure itself ranged from 17 to 35
      min. During all procedures no system-related complications occurred.
      INTERPRETATION: The use of robotic technology for neuro-endoscopic third
      ventriculostomies is a major step towards the controlled movement of the neuro
      endoscope within the cranium. The start up procedure and calibration of the robot
      is still time consuming, but the real operation time is comparable to free hand
      neuro-endoscopy. The steering of the endoscope is facilitated and the precision
      of the endoscopic movements is noteworthy.

PMID- 15197614
TI  - A modified technique for using elastase to create saccular aneurysms in animals
      that histologically and hemodynamically resemble aneurysms in human.
AB  - BACKGROUND: Treatment of intracranial aneurysms is evolving with the development
      of novel therapies. It is important to have an animal model which simulates human
      aneurysms. We describe a new modified technique to the elastase aneurysm model
      which creates aneurysms that histologically and hemodynamically resemble human
      aneurysms. METHODS: Twelve New Zealand white rabbits underwent the aneurysm
      creation procedure, and 2 underwent a control procedure. In the aneurysm creation
      procedure, the right common carotid artery (RCCA) origin is surgically exposed
      and temporarily occluded with a temporary aneurysm clip. The RCCA is ligated
      distally, and the trapped segment is infused with elastase for 20 minutes, after
      which the clip is removed. In the control procedure, the RCCA is ligated distally
      with no elastase. Animals were assessed neurologically using a previously
      described rabbit neurologic grading scale and food intake scale. Intravenous
      digital subtraction angiography (IVDSA) was performed 21 days after the
      procedure. Aneurysms were harvested and stained with H&E and Verhoeff's stain.
      FINDINGS: All 14 rabbits had normal neurologic and food intake assessments. All
      12 rabbits that underwent aneurysm creation procedures demonstrated saccular
      aneurysms on IVDSA. Mean aneurysm size was 5.9+/-1.9 mm; range 4.3-10.8 mm. The
      close proximity of the LCCA to the origin of the RCCA on the aortic arch of the
      New Zealand white rabbit closely resembles a bifurcation aneurysm. Both rabbits
      that underwent control procedures showed no aneurysm and retrograde thrombosis of
      the RCCA. Histologic analysis showed the aneurysms had histology characteristic
      of true human aneurysms. CONCLUSION: We have developed a new modified technique
      to the elastase aneurysm model which creates aneurysms that hemodynamically and
      histologically resemble human aneurysms. There have been previous elastase models
      described, however we find our model is easier to perform and highly
      reproducible. The aneurysms can be accessed transfemorally making the model ideal
      for testing endovascular therapies.

PMID- 15197615
TI  - Towards waterjet dissection in neurosurgery: experimental in-vivo results with
      two different nozzle types.
AB  - Waterjet dissection is under close investigation as a new neurosurgical tool.
      Experimentally, a precise tissue dissection with vessel preservation has been
      demonstrated in the porcine cadaver brain. The safety of the device has been
      shown in first clinical applications. However, a detailed in-vivo analysis of the
      waterjet device is still awaited. In the present study, two often applied nozzle
      types (100 microm diameter emitting a coherent straight jet; 120 microm diameter
      emitting a helically rotating jet) were experimentally studied in vivo. Forty-one
      rabbits received a frontal waterjet corticotomy on either side with one nozzle
      type after microsurgical removal of the arachnoid membranes. Animals were
      sacrificed at 1, 3, 7 days and 6 weeks after surgery. Dissection morphology and
      vessel preservation were evaluated. Tissue trauma was analyzed by the extent of
      intra-operative haemorrhage, postsurgical oedema formation and astrocytic as well
      as microglial reactions. In all animals, reliable brain dissection was observed.
      Macroscopically, only minor bleeding occurred. Microscopically, also very precise
      brain dissection with both nozzle types was found. Vessels were preserved with
      both pressures applied (5 and 10 bar). Dissections with the 100 microm straight
      nozzle were more precise with respect to dissection margins. However, no
      significant difference in vessel preservation and extent of haemorrhage, oedema
      formation, astrocytic and microglial reactivity was shown. Malfunction defined as
      clotting of the instrument occurred only with the 100 microm nozzle. In four 100
      microm straight nozzle hemispheres, even no brain dissection was seen. The
      results indicate that the waterjet enables very precise and reliable brain
      parenchyma dissection with minimal trauma and vessel preservation in vivo. If
      this can be proven to be of clinical relevance, the instrument will become a
      valuable neurosurgical tool. Based on these results, the authors selected the 120
      microm Helix nozzle for further research with this device in the CNS.

PMID- 15197616
TI  - Cell death induction by betulinic acid, ceramide and TRAIL in primary
      glioblastoma multiforme cells.
AB  - BACKGROUND: Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant
      brain tumour with a mean survival time of less than one year. Betulinic acid,
      ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel
      therapeutic agents for potential use in GBM. METHOD: Primary GBM cells of 21
      patients with macroscopically complete tumour resection were tested in vitro for
      cell death induction by betulinic acid, ceramide, TRAIL and established
      therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation).
      FINDINGS: At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL
      induced cell death in primary GBM cells at higher rates than established
      cytotoxic drugs. Specific cell death > or =75% was observed in 43% (9/21), 38%
      (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively,
      while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated
      cells, and in none of the GBM cultures, where BCNU or vincristin were applied in
      PPC. CONCLUSION: Due to a markedly improved cell death of GBM cells as compared
      with established therapeutics, Betulinic acid, ceramide and TRAIL might represent
      potent substances for future treatment of GBM.

PMID- 15197617
TI  - A model for intratumoural chemotherapy in the rat brain.
AB  - To achieve the best reproducibility in rat brain tumour models several injection
      techniques have been used. Although stereotactic cell injections have proved to
      be effective and reliable, they are expensive and time consuming. A new
      permanently implanted device is presented here. It allows precise cell delivery
      for best tumour reproducibility, and it can be left in place for future
      injections at the exact same location, such as intratumoural chemotherapy. A
      Teflon tube was mounted on a disc, inserted into the rat brain and sealed to the
      skull. The device was tested in two rat strains (Wistar and New Zealand Nude
      rats) with two different glioma cell lines (9L and C6). Rats were treated with
      placebo to determine if repeated treatments had an effect on the device
      placement, or if device-related morbidity was induced. Analysis of brain sections
      showed that the device path was always within the tumour. The device never moved
      or came off the scalp. Both Wistar rats and NZ nude rats tolerated the device
      well. No morbidity or mortality was observed, regardless of the presence of the
      device; no infections were seen. Biocompatible, non-irritating and well
      tolerated, such a device can be used for reproducible tumour cell injections and
      repeated intralesional delivery of drugs.

PMID- 15197618
TI  - Post traumatic retropharyngeal pseudomeningocele.
AB  - The authors report a case of a 33-year-old man who presented, during recovery
      from coma due to severe head injury, dysphagia and respiratory failure. Magnetic
      resonance, retrograde radionuclide myelography and computerized tomographic
      myelography identified a pseudomeningocele in the retropharyngeal space due to a
      tear of the left C2 radicular sleeve. After failed medical management, the
      patient underwent lumbo peritoneal shunt. Magnetic resonance controls showed
      progressive collapse of the collection. After 3 months the patient was able to
      breathe spontaneously and to swallow. The authors describe pathogenesis,
      diagnostic strategy and principles of treatment of traumatic retropharyngeal
      pseudomeningoceles.

PMID- 15197619
TI  - Delayed bleeding after gamma knife surgery for meningioma.
AB  - We report the occurrence of haemorrhage in a meningioma after gamma knife
      surgery.A 52-year-old woman had undergone gamma knife radiosurgery for a growing
      meningioma in the left tentorial hiatus three years earlier (A radiation dose of
      15 Gy was administered to the margin, with a maximum dose of 30 Gy, Fig. 1a). The
      size of the mass decreased steadily, and central lucency was seen in the follow
      up magnetic resonance images, a usual finding seen after gamma knife surgery
      (MRI, Fig. 1b). However, a MRI taken at the 30-month follow-up showed the tumour
      to be swollen, and peritumoural oedema had increased (Fig. 1c). Three years
      later, apoplectic symptoms occurred, and computed tomography revealed a
      peritumoural haemorrhage, with oedema (Fig. 1d). An emergency craniotomy was
      carried out, and the biopsy showed a transitional type of meningioma, with
      vasculopathy and necrosis. After operation she had a right hemiparesis and a
      visual defect.

PMID- 15197620
TI  - Contralateral frontal and cerebellar haemorrhages after peri-insular
      hemispherotomy.

PMID- 15197625
TI  - The classification of outcome following whiplash injury--a comparison of methods.
AB  - There are many definitions and classifications of chronic neck pain and of neck
      pain following whiplash injury, many of them developed for a single study. This
      study compares three different outcome measures (neck disability index, Gargan
      and Bannister grade, general health questionnaire) in 277 patients who were
      examined for medicolegal reporting following isolated whiplash injury. There is
      significant correlation between the physical outcome scales and also between the
      physical and psychological outcome scales examined (both p <0.01). Definitions of
      chronic neck pain (with or without whiplash injury) and measures to assess and
      classify patients with chronic symptoms are reviewed. We recommend the use of a
      simple self-administered questionnaire that does not require physical measurement
      as the most useful tool in the evaluation of these patients and the most accurate
      method of classifying outcome.

PMID- 15197626
TI  - Percutaneous transpedicular discectomy and drainage in pyogenic spondylodiscitis.
AB  - The natural history of uncomplicated hematogenous pyogenic spondylodiscitis is
      self-limiting healing. However, a variable degree of bone destruction frequently
      occurs, predisposing the spine to painful kyphosis. Delayed treatment may result
      in serious neurologic complications. Early debridement of these infections by
      percutaneous transpedicular discectomy can accelerate the natural process of
      healing and prevent progression to bone destruction and epidural abscess. The
      purpose of this manuscript is to present our technique of percutaneous
      transpedicular discectomy (PTD), to revisit this minimally invasive surgical
      technique with stricter patient selection, and to exclude cases of extensive
      vertebral body destruction with kyphosis and neurocompression by epidural
      abscess, infected disc herniation, and foraminal stenosis. In a previously
      published report of 28 unselected patients with primary hematogenous pyogenic
      spondylodiscitis, the immediate relief of pain after PTD was 75%, and in the long
      term follow-up, the success rate was 68%. Applying stricter patient selection
      criteria in a second series of six patients (five with primary hematogenous
      spondylodiscitis and one with secondary postlaminectomy-discectomy
      spondylodiscitis), all patients with primary hematogenous spondylodiskitis (5/5)
      experienced immediate relief of pain that remained sustained at 12-18 months
      follow-up. This procedure was not very effective, however, in the patient who
      suffered from postlaminectomy infection. This lack of response was attributed to
      postlaminectomy-discitis instability. The immediate success rate after surgery
      for unselected patients in this combined series of 34 patients was 76%. This
      technique can be impressively effective and the results sustained when applied in
      the early stages of uncomplicated spondylodiscitis and contraindicated in the
      presence of instability, kyphosis from bone destruction, and neurological
      deficit. The special point of this procedure is a minimally invasive technique
      with high diagnostic and therapeutic effectiveness.

PMID- 15197627
TI  - Correlation between inter-vertebral disc morphology and the results in patients
      undergoing Graf ligament stabilisation.
AB  - BACKGROUND: Previous studies have shown Graf ligament stabilisation procedure to
      give mixed results in the short to medium term. The aim of this study was to
      correlate the pre-operative state of the disc, multifidus muscles, age of the
      patient, levels operated and the clinical outcome after a mean follow-up of 47
      months. METHODS: Graf ligament stabilisation procedure was carried out in 38
      patients between 1996 and 1999. Their post-operative status was assessed using
      MacNab criteria. The post-operative follow-up was by postal questionnaires and
      review of the clinical notes. Disc morphology and multifidus muscle wasting was
      graded blindly and independently. The intra- and interobserver reliability was
      measured with kappa score and classified using the kappa classification of Landis
      and Koch. Correlation was measured with the help of Spearman correlation
      coefficient. RESULTS: Thirty-eight patients (100%) returned the questionnaires.
      Mean follow-up time was 47.55 months. Fifty-nine levels were operated on. Mean
      age was 39.68 years. The overall re-operation rate was 15.8%. The intra- and
      interobserver reliability was graded as good to substantial. Twenty-two patients
      (57.89%) were satisfied with the procedure. There was no statistically
      significant correlation between disc morphology, multifidus muscle wasting, sex,
      age, number of levels operated, the levels operated, and the satisfaction rate.
      CONCLUSIONS: The indications of Graf ligament stabilisation procedure are not
      clear. Further work is necessary to clearly identify the indication for the
      procedure.

PMID- 15197628
TI  - Predictors of outcomes after posterior decompression and fusion in degenerative
      spondylolisthesis.
AB  - No consensus has been reached regarding surgical management of degenerative
      spondylolisthesis. The optimal type of surgical procedure and surgical
      indications have not been precisely defined. In order to screen for predictors of
      outcome, we retrospectively studied patient outcomes after posterior
      decompression and fusion for isolated lumbar degenerative spondylolisthesis.
      Twenty-four consecutive patients (age range 50-78 years) underwent primary
      surgery for isolated lumbar degenerative spondylolisthesis. The surgical
      procedure consisted of posterior decompression and pedicle screw instrumented
      fusion using autogeneous bone graft, with or without interbody fusion. Clinical
      and radiologic status were assessed using the Beaujon functional score and plain
      AP and lateral radiographs. A multivariate analysis was used to correlate the
      functional score increase with surgical procedure modifications and preoperative
      clinical and radiologic features in order to determine which of them led to
      better results. Eighteen patients completed the evaluation. Six others were lost
      to follow-up after a minimum of 0.87 years. Combining all the results, the mean
      follow-up was 2.87 years. The Beaujon score was improved in the 24 patients
      (P<0.001), and fusion was successful in all cases. Additional interbody fusion
      and preoperative leg pain were significantly correlated with larger score
      increase (P=0.016 and P=0.003). Posterior decompression and fusion is successful
      in treating lumbar degenerative spondylolisthesis. From this study,
      circumferential fusion improves the outcomes and leg pain is a fair indication
      for surgery.

PMID- 15197629
TI  - Biomechanical comparison of anterior cervical spine locked and unlocked plate
      fixation systems.
AB  - Three different anterior plate-fixation systems are available for the
      stabilisation of the cervical spine: (1) the cervical spine locking plate (CSLP),
      (2) dynamic plates allowing vertical migration of the fixation screws, and (3)
      various types of plates that are secured with either monocortical or bicortical
      unlocked screws. Unicortical screw purchase does not involve the risk of
      posterior cortex penetration and possible injuries to the spinal cord. The
      development of locking plates with unicortical screw-fixation and intrinsic
      stability of the screw-plate interface, via an angle-stabilised connection, was
      an attempt to increase the stability of unicortical screw-fixation systems. The
      aim of the study was to compare the biomechanical properties of a non-locking,
      anterior-plate system with 4.5 mm screw fixation and a locking anterior-plate
      system, in a single destabilised cervical spine-motion segment. Using fresh
      cadaveric cervical spine specimen C3-C7, multidirectional flexibility was
      measured at the C4-C5 level in an unconstrained test system, before and after
      destabilisation and fixation with an anterior plate with either locked or
      unlocked screw purchase. Direct comparison of the fixed cervical spine segments
      with unlocked and locked anterior-plate fixation did not demonstrate significant
      differences. This in vitro study documented that neither locked nor unlocked
      anterior-plate fixation can increase stability in all modes of testing. H-plate
      spondylodesis with unlocked screws seems to provide sufficient mechanical
      integrity in most cases of monosegmental lesions.

PMID- 15197630
TI  - Blood loss in adult spinal surgery.
AB  - Spinal surgery in adults can vary from simple to complex and can also have
      variable anticipated surgical blood loss. There are several factors that can put
      patients at increased risk for greater intraoperative blood loss. These factors,
      including a review of the literature, will be discussed.

PMID- 15197631
TI  - Preoperative erythropoietin in spine surgery.
AB  - Spine surgery may be associated with profuse intraoperative bleeding that often
      requires blood transfusions. In recent years several techniques have been
      developed to avoid allogenic transfusions and their potential complications to
      surgical patients. In this study we review and analyse the role of preoperative
      recombinant human erythropoietin (rHuEPO) administration in spine surgery as a
      blood conservation strategy. Between 1998 and 2002, a total of 250 patients
      scheduled for spine surgery were included in our blood-sparing program: 114
      patients (group 1), operated on before rHuEPO approval (2000), underwent
      preoperative autologous blood donation (ABD) alone, and 136 patients operated on
      after rHuEPO approval (groups 2 and 3) received rHuEPO while undergoing ABD.
      Adding rHuEPO to ABD resulted in higher haemoglobin and haematocrit values the
      day of surgery, more ABD units retrieved per patient and, consequently, reduced
      allogenic transfusion requirements. The effectiveness of rHuEPO as the only
      preoperative blood conservation technique was evaluated in ten patients with a
      predicted blood loss of less than 30% of their total volume, scheduled for lumbar
      surgery. Data from these patients were matched with those from a similar group of
      patients who had undergone ABD. Patients receiving rHuEPO alone had higher
      haemoglobin levels the day of surgery than did patients in the ABD program.
      Neither group required allogenic transfusions. CONCLUSIONS: preoperative rHuEPO
      is useful for reducing allogenic blood requirements in elective spine surgery. In
      patients with an expected blood loss of around 50% of blood volume, rHuEPO
      improves ABD, minimising preoperative anaemia and increasing the number of ABD
      units collected. In patients with expected blood loss below 30% of total volume,
      rHuEPO administration may replace ABD.

PMID- 15197632
TI  - Acute normovolemic hemodilution.
AB  - Patients and physicians continue to be motivated to find methods to reduce the
      use of allogeneic blood. Even though donor screening has increased the safety of
      donated blood products, autologous blood is the most desirable source of red
      cells during the perioperative period. The methods commonly used to obtain
      autologous blood during the perioperative period can be initiated prior to the
      operative procedure (autologous preoperative donation, acute normovolemic
      hemodilution) or during surgery (cell scavenging). Acute normovolemic
      hemodilution (ANH) involves a controlled removal of whole blood immediately prior
      to the operation. The patient's intravascular volume is maintained with solutions
      that contain non-red cells. The operative procedure is conducted with a normal
      blood volume, but with a reduced red cell mass. At the conclusion of the
      operation, the stored autologous blood is restored to the patient. If operative
      blood loss is not excessive, the replacement of autologous blood may provide an
      acceptable red cell mass. In addition to surgical blood loss, some of the key
      factors in determining how effective acute normovolemic hemodilution will be in
      limiting allogeneic transfusion are: the patient's initial hematocrit and blood
      volume; the volume of autologous blood removed prior to the operation; the
      effectiveness of the hemodilution; and the timing of autologous blood
      replacement. In contrast to autologous pre-donation, autologous blood removed
      during acute normovolemic hemodilution is usually stored and re-infused in the
      operating room.

PMID- 15197633
TI  - Controlled hypotension for spinal surgery.
AB  - Controlled, deliberate hypotension during anesthesia for major spinal surgery
      reduces intraoperative blood loss and transfusion requirement. Hypotension may be
      achieved with increased doses of volatile anesthetic agents or by continuous
      infusion of vasodilating drugs. Safe application of this technique requires
      knowledge of the physiology of hemorrhagic shock and close intraoperative
      monitoring to avoid vasoconstriction and end-organ ischemia.

PMID- 15197634
TI  - Evaluation of mycelial inocula of edible Lactarius species for the production of
      Pinus pinaster and P. sylvestris mycorrhizal seedlings under greenhouse
      conditions.
AB  - Different methods to inoculate seedlings of Pinus pinaster and P. sylvestris with
      edible Lactarius species under standard greenhouse conditions were evaluated.
      Fungal inoculations were performed both under pure culture synthesis in vitro,
      followed by transplantation of acclimatized seedlings, and directly in the
      greenhouse using different techniques for inocula production (mycelial slurries,
      vegetative inoculum grown in peat-vermiculite and alginate-entrapped mycelium).
      In vitro inoculations with L. deliciosus produced thoroughly colonized seedlings.
      However, a sharp decrease in mycorrhizal colonization was detected on
      transplanted seedlings after 4 month's growth in the greenhouse. On the other
      hand, all the inocula applied directly in the greenhouse, except the alginate
      entrapped mycelium, produced a variable number of mycorrhizal seedlings and
      colonization rates after the first growing season, depending on the plant-fungal
      combination and the inoculation method. Inoculations with vegetative inocula of
      the strain 178 of L. deliciosus were the most effective in producing mycorrhizal
      seedlings. All the seedlings inoculated with this strain were colonized although
      the colonization rates were relatively low. The commercial feasibility of the
      different inoculation methods for the production of seedlings colonized with
      edible Lactarius species is discussed.

PMID- 15197635
TI  - Impact of two fluorescent pseudomonads and an arbuscular mycorrhizal fungus on
      tomato plant growth, root architecture and P acquisition.
AB  - The ability of fluorescent pseudomonads and arbuscular mycorrhizal fungi (AMF) to
      promote plant growth is well documented but knowledge of the impact of
      pseudomonad-mycorrhiza mixed inocula on root architecture is scanty. In the
      present work, growth and root architecture of tomato plants (Lycopersicon
      esculentum Mill. cv. Guadalete), inoculated or not with Pseudomonas fluorescens
      92rk and P190r and/or the AMF Glomus mosseae BEG12, were evaluated by measuring
      shoot and root fresh weight and by analysing morphometric parameters of the root
      system. The influence of the microorganisms on phosphorus (P) acquisition was
      assayed as total P accumulated in leaves of plants inoculated or not with the
      three microorganisms. The two bacterial strains and the AMF, alone or in
      combination, promoted plant growth. P. fluorescens 92rk and G. mosseae BEG12 when
      co-inoculated had a synergistic effect on root fresh weight. Moreover, co
      inoculation of the three microorganisms synergistically increased plant growth
      compared with singly inoculated plants. Both the fluorescent pseudomonads and the
      myco-symbiont, depending on the inoculum combination, strongly affected root
      architecture. P. fluorescens 92rk increased mycorrhizal colonization, suggesting
      that this strain is a mycorrhization helper bacterium. Finally, the bacterial
      strains and the AMF, alone or in combination, improved plant mineral nutrition by
      increasing leaf P content. These results support the potential use of fluorescent
      pseudomonads and AMF as mixed inoculants for tomato and suggest that improved
      tomato growth could be related to the increase in P acquisition.

PMID- 15197636
TI  - Comparison of 233U and 33P uptake and translocation by the arbuscular mycorrhizal
      fungus Glomus intraradices in root organ culture conditions.
AB  - This study aimed to quantify and compare 233U and 33P uptake and translocation by
      hyphae of the arbuscular mycorrhizal (AM) fungus Glomus intraradices in root
      organ culture conditions with transformed carrot (Daucus carota L.) roots as
      host. Mycorrhizal roots were grown in two-compartment Petri dishes to spatially
      separate a root compartment (RC) and a hyphal compartment (HC). The HC was
      labelled with 8.33 Bq 233U ml(-1) and 13.33 Bq 33P ml(-1). After 2 weeks contact
      between hyphae and the labelled solution, 233U and 33P activities were measured
      in the RC and in the HC. 233U and 33P were taken up by the extraradical AM
      mycelium grown in the HC and this uptake represented 4.4% and 16% of the initial
      isotope supply, respectively. The translocation into roots developing in the RC
      via hyphae accounted for 5.9% and 72% of the initial isotope supply,
      respectively. Thus, both uptake and translocation were much higher for 33P than
      for 233U. This suggests (1) the existence in hyphal tissues of efficient
      mechanisms limiting the uptake and translocation of non-essential elements such
      as U, and (2) that the hyphae have a higher sequestration than translocation
      function for U, and the converse for P.

PMID- 15197637
TI  - Febrile neutropenia: a prospective study to validate the Multinational
      Association of Supportive Care of Cancer (MASCC) risk-index score.
AB  - OBJECTIVE: The objective of this study was to prospectively validate the
      Multinational Association of Supportive Care of Cancer (MASCC) risk-index score
      in an attempt to accurately predict on presentation with febrile neutropenia
      those cancer patients who are at low- or high-risk for development of serious
      medical complications during the episode. PATIENTS AND METHODS: Patients who
      presented with febrile neutropenia during November 2000 and July 2002 were
      prospectively enrolled in the protocol. All patients were hospitalized until
      recovery or outcome of the event and were treated with broad-spectrum, empiric,
      intravenous antibiotic therapy. The MASCC risk-index score (based on seven
      independent factors present at onset of febrile neutropenia) was calculated in 64
      patients with 80 febrile neutropenic episodes. Patients with a score of > or =21
      were regarded as low risk; patients with a score of <21 were regarded as high
      risk. RESULTS: Of the 80 febrile neutropenic episodes, 58 were classified as low
      risk and 22 as high-risk patients. Fifty-seven (98.3%) of the 58 low-risk
      patients recovered without complications, and three (13.6%) of the 22 high-risk
      patients did not develop medical complications. One low-risk patient developed a
      fungal infection but recovered completely in comparison to 11 high-risk patients
      (50%) who developed serious medical complications ( p<0.001). None of the low
      risk patients died. However, eight (36.4%) of the 22 high-risk patients died
      during the febrile neutropenic episode ( p<0.001), six as a consequence of sepsis
      and two due to rapidly uncontrolled cancer. CONCLUSION: We correctly predicted
      98.3% of low-risk patients and 86.3% of high-risk patients. This study had a
      positive predictive value of 98.3% and a negative predictive value of 86.4% with
      both a sensitivity and specificity of 95%. The MASCC risk-index score correctly
      identifies low- and high-risk patients at presentation with febrile neutropenia.

PMID- 15197638
TI  - The peak bone mass concept: is it still relevant?
AB  - The peak bone mass concept implies that optimal skeletal development during
      childhood and adolescence will prevent fractures in late adulthood. This concept
      is based on the observation that areal bone density increases with growth during
      childhood, is highest around 20 years of age and declines thereafter. However, it
      is now clear that strong bones in the youngster do not necessarily lead to a
      fracture-free old age. In the recent bone densitometric literature, the terms
      bone mass and bone density are typically used synonymously. In physics, density
      has been defined as the mass of a body divided by its volume. In clinical
      practice and science, "bone density" usually has a different meaning-the degree
      to which a radiation beam is attenuated by a bone, as judged from a two
      dimensional projection image (areal bone density). The attenuation of a radiation
      beam does not only depend on physical density, but also on bone size. A small
      bone therefore has a lower areal bone density than a larger bone, even if the
      physical density is the same. Consequently, a low areal bone density value can
      simply reflect the small size of an otherwise normal bone. At present, bone mass
      analysis is very useful for epidemiological studies on factors that may have an
      impact on bone development. There is an ongoing discussion about whether the
      World Health Organization (WHO) definition of osteoporosis is over-simplistic and
      requires upgrading to include indices representing the distribution of bone and
      mineral (bone strength indices). The following suggestions and recommendations
      outline a new concept: bone mass should not be related to age. There is now more
      and more evidence that bone mass should be related to bone size or muscle
      function. Thus analyzed, there is no such entity as a "peak bone mass". Many
      studies are currently under way to evaluate whether these novel approaches
      increase sensitivity and specificity of fracture prediction in an individual.
      Furthermore, the focus of many bone researchers is shifting away from bone mass
      to bone geometry or bone strength. Bone mass is one surrogate marker of bone
      strength. Widely available techniques for measurement of bone mass, such as dual
      energy X-ray absorptiometry, radiogrammetry, and computed tomography, can also be
      used to measure variables of bone geometry such as cortical thickness, cortical
      area, and moment of inertia.

PMID- 15197640
TI  - Plasmapheresis therapy for rapidly progressive Henoch-Schonlein nephritis.
AB  - Six Japanese children with rapidly progressive Henoch-Schonlein purpura nephritis
      (HSPN) received multiple drug therapy combined with plasmapheresis (PP). After
      five courses of PP, multiple drug therapy, including methylprednisolone and
      urokinase pulse therapy, oral prednisolone, cyclophophamide, dipyridamole, and
      warfarin was given. At presentation, urine protein excretion and histological
      indices of the mean activity and chronicity were 245+/-101 mg/m(2) per hour,
      6.6+/-1.2, and 1.5+/-1.3, respectively. After 6 months of therapy, urinary
      protein excretion had decreased significantly ( P<0.001). The activity index
      decreased significantly at the second renal biopsy performed at a mean interval
      of 4.3 months after the first (2.8+/-1.4, P<0.05), while the chronicity index did
      not change. At the most recent observation, all showed clinical improvement. Two
      patients had normal urine, three had proteinuria of <20 mg/m(2) per hour, one had
      proteinuria of >20 mg/m(2) per hour, and none had renal insufficiency. Although
      this case series is without controls, our treatment protocol may be of benefit to
      children with rapidly progressive HSPN.

PMID- 15197641
TI  - Pollinator service only depends on nectar production rates in sparse populations.
AB  - As predicted, approach rate by bumblebees is strongly related to the nectar
      production rate of Echium vulgare plants in a sparse population, while in a dense
      population such a relationship is completely absent. These findings are confirmed
      by additional experiments with potted plants that were placed inside and outside
      a natural population. The results suggest that the direction of selection on
      nectar production may vary in space or time depending on population density. Such
      variation may help to explain the large genetic variation we found earlier for E.
      vulgare in our study area.

PMID- 15197639
TI  - Glucocorticoid pharmacokinetics and growth retardation in children with renal
      transplants.
AB  - Long-term glucocorticoid treatment contributes to the growth retardation in
      children after renal transplantation. We investigated whether determination of
      prednisone (PN) and prednisolone (PL) in plasma and PN, PL, and 6-beta
      hydroxyprednisolone (betaOH-PL) in urine could help to predict growth. PN and PL
      pharmacokinetics were studied in 36 children, from 5 to 15 years of age,
      receiving daily (D) or alternate-day (AD) oral PN treatment. Statural growth
      velocity was evaluated over a 1-year period. We compared three groups of children
      according to the growth kinetics during the study year (catch-up, stable, or
      decline) for clinical and pharmacokinetic parameters. A multiple linear
      regression analysis was performed in order to determine pharmacokinetic
      parameters able to explain height 1 year after inclusion. Height at the beginning
      of the study, creatinine clearance, and type of D or AD treatment explained 94.2%
      of height variance 1 year after inclusion. Only PL clearance was associated with
      growth evolution, but introduction of PL clearance in the multivariate model did
      not improve the variance of height accounted for by the previous model. We,
      therefore, do not recommend using glucocorticoid pharmacokinetics to predict
      growth retardation in children with renal transplantation.

PMID- 15197642
TI  - Fitness optimization of Daphnia in a trade-off between food and temperature.
AB  - In thermally stratified lakes with a deep chlorophyll maximum (DCM), Daphnia face
      a trade-off between food availability and optimum development temperatures. We
      hypothesize that Daphnia optimize their fitness by allocating the time spent in
      the different vertical habitats depending on the distribution of algal resources
      and the temperature gradient. We used the plankton towers (large indoor
      mesocosms) to study the vertical distribution of a population of Daphnia hyalina
      x galeata in three different temperature gradients with a DCM. Additionally, we
      determined the fitness of Daphnia in the epilimnion and hypolimnion by
      transferring water from these layers into flow-through systems where we raised
      Daphnia and assessed their juvenile growth rate as a measure of fitness. The
      fitness distribution was correlated with the vertical distribution. The vertical
      distribution most likely reflected the proportions of time Daphnia allocated to
      dwelling in the two vertical habitats.

PMID- 15197643
TI  - Bulgy tadpoles: inducible defense morph.
AB  - Predator induced morphological defenses are marked morphological shifts induced
      directly by cues associated with a predator. Generally, remote cues, i.e.,
      chemical substances emitted from predators or injured conspecifics, are
      considered to be ideal signals to induce morphological change in aquatic
      environments rather than close cues, i.e., close chemical or tactile cues, since
      chemical substances that can propagate over relatively long distances and persist
      for a long period may allow organisms to keep safe and to deliberately change
      their morph. In fact, most organisms adopting an inducible morphological defense
      utilize remote chemical cues to detect predation risk and to produce
      morphological defenses. In this paper, we report a unique and functionally well
      designed inducible morphological defense strategy where the induction process
      requires close cues from a predator. The tadpoles of Rana pirica exhibited a
      bulgy bodied morphology when threatened with predation by larval salamanders,
      Hynobius retardatus, in close proximity. Predation trials and a function
      experiment showed that the induced bulgy morph is an adaptive defense phenotype
      against the gape-limited predator larval H. retardatus. Furthermore, R. pirica
      tadpoles use two adaptive strategies in terms of cost saving, i.e., adjustment of
      the extent of bulginess according to predation risk and reversibility by actual
      shrink of bulgy body after removing the predation threat. In general, R. pirica
      hatch earlier than H. retardatus. In natural ponds, during the early
      developmental stage R. pirica tadpoles live in close proximity to young H.
      retardatus larvae. As they grow, the salamanders gradually become serious
      predators and the predator-prey interaction becomes intimate. After a while,
      predation, cannibalism and metamorphosis decrease the number of salamanders in
      the ponds, and the predator-prey interaction weakens. Such a phenology in the
      predator-prey interaction allows the evolution of a close-cue detection system
      and adaptive cost-saving strategies. Our results highlight that the
      characteristics of the inducible defense depend on the intensity and specificity
      of the predator-prey system.

PMID- 15197644
TI  - Differential effects of habitat complexity, predators and competitors on
      abundance of juvenile and adult coral reef fishes.
AB  - Greater structural complexity is often associated with greater abundance and
      diversity, perhaps because high complexity habitats reduce predation and
      competition. Using 16 spatially isolated live-coral reefs in the Bahamas, I
      examined how abundance of juvenile (recruit) and adult (non-recruit) fishes was
      affected by two factors: (1) structural habitat complexity and (2) the presence
      of predators and interference competitors. Manipulating the abundance of low and
      high complexity corals created two levels of habitat complexity, which was cross
      factored with the presence or absence of resident predators (sea basses and moray
      eels) plus interference competitors (territorial damselfishes). Over 60 days,
      predators and competitors greatly reduced recruit abundance regardless of habitat
      complexity, but did not affect adult abundance. In contrast, increased habitat
      complexity had a strong positive effect on adult abundance and a weak positive
      effect on recruit abundance. Differential responses of recruits and adults may be
      related to the differential effects of habitat complexity on their primary
      predators. Sedentary recruits are likely most preyed upon by small resident
      predators that ambush prey, while larger adult fishes that forage widely and use
      reefs primarily for shelter are likely most preyed upon by large transient
      predators that chase prey. Increased habitat complexity may have inhibited
      foraging by transient predators but not resident predators. Results demonstrate
      the importance of habitat complexity to community dynamics, which is of concern
      given the accelerated degradation of habitats worldwide.

PMID- 15197645
TI  - Cell-cell junctions between mammalian (human and rat) hepatic stellate cells.
AB  - To investigate intercellular junctions between mammalian hepatic stellate cells,
      we examined cultured human and rat hepatic stellate cells at the ultrastructural
      and molecular levels. Intercellular junctions between cultured human stellate
      cells, which developed irrespective of the type of culture substratum, were
      detected by transmission electron microscopy. On the basis of their
      characteristic ultrastructure, these junctions were identified in cultured human
      hepatic stellate cells as adherens junctions but not as tight junctions,
      desmosomes, or gap junctions. N-cadherin, alpha-catenin and beta-catenin, and
      p120ctn were detected by Western blotting in rat stellate cells as molecular
      components of the intercellular adhesive structures. Immunofluorescence for pan
      cadherin, alpha-catenin, and beta-catenin were also detected in cultured human
      stellate cells. Moreover, pan-cadherin and beta-catenin were co-localized at the
      contact regions between the cultured human stellate cells. These data suggest
      that the junctional adhesion between the stellate cells can be formed both in
      vivo and in vitro. Thus, hepatic stellate cells may participate in the structural
      organization of the cells in liver lobules through the formation of intercellular
      adherens junctions. This is the first description of the presence of cell-cell
      junctions between hepatic stellate cells in mammals at the fine structural and
      molecular levels.

PMID- 15197646
TI  - The subcommissural organ expresses D2, D3, D4, and D5 dopamine receptors.
AB  - Dopamine receptors have been found in certain populations of non-neuronal cells
      in the brain, viz., discrete areas of ciliated ependyma and the ependymal cells
      of the choroid plexus. We have studied the presence of both tyrosine-hydroxylase
      immunoreactive nerve fibers and dopamine receptors in the subcommissural organ
      (SCO), an ependymal brain gland that is located in the roof of the third
      ventricle and that secretes, into the cerebrospinal fluid, glycoproteins that
      aggregate to form Reissner's fiber (RF). Antibodies against D2, D3, D4, and D5
      dopamine receptors were used in immunoblots of bovine striatum, fresh SCO, and
      organ-cultured SCO, and in immunocytochemistry of the bovine, rat, and mouse SCO.
      Only a few tyrosine-hydroxylase fibers appeared to reach the SCO. However,
      virtually all the secretory ependymal and hypendymal cells of the SCO
      immunoreacted with antibodies against D2, D4, and D5 receptors, with the last
      mentioned rendering the strongest reaction, especially at the ventricular cell
      pole of the secretory ependymocytes, suggesting that dopamine might reach the SCO
      via the cerebrospinal fluid. The antibodies against the four subtypes of
      receptors revealed corresponding bands in immunoblots of striatum and fresh SCO.
      Although the cultured SCO displayed dopamine receptors, dopamine had no apparent
      effect on the expression of the SCO-spondin gene/protein or on the release of RF
      glycoproteins (SCO-spondin included) by SCO explants, suggesting that dopamine
      affects the function(s) of the SCO differently from the secretion of RF
      glycoproteins.

PMID- 15197647
TI  - Regulation of the initial segment of the murine epididymis by dihydrotestosterone
      and testicular exocrine secretions studied by expression of specific proteins and
      gene expression.
AB  - The murine caput epididymidis responded to deprivation of luminal fluid from the
      testis by regression of the initial segment but maintenance of the adjacent
      proximal and distal caput regions, as judged by immunohistochemical staining of
      the glutamate transporter EAAC1 and the lipocalin MEP17 and enzymatic activity of
      beta-galactosidase (beta-Gal). Additional removal of circulating androgens by
      bilateral castration similarly led to loss of the initial segment and of the
      proximal caput but the distal caput was transformed into an epithelium containing
      more apical than principal cells staining for EAAC1; this epithelium resembled
      the precursor epithelium usually only seen in prepubertal juveniles.
      Administration of dihydrotestosterone (DHT) to the castrates maintained the
      proximal and distal caput epithelia and induced a proximal epithelium, which
      resembled the initial segment in its prominent staining for Golgi, EAAC1 and beta
      Gal activity, although it was short and exhibited no MEP17 expression. DHT was
      present in the c-ros knockout caput epididymidis lacking the initial segment and
      in the heterozygous organ but the DHT concentration was lower in the knockout
      corpus. The maintenance of the full complement of epithelia in the murine caput
      epididymidis in the adult thus requires a combination of luminal fluid from the
      testis, tissue DHT and the presence of the c-ros oncogene.

PMID- 15197648
TI  - Digestive disease week 2004.

PMID- 15197649
TI  - Digestive Disease Week 2004. Bowel inflammation.

PMID- 15197650
TI  - Clinical microbiology and infectious disease -- 14th European conference.

PMID- 15197651
TI  - American Psychiatric Association -- 157th Annual Meeting.

PMID- 15197652
TI  - Experimental biology 2004: translating the genome.

PMID- 15197653
TI  - Vaccine adjuvants and glycoconjugates -- second international workshop.

PMID- 15197654
TI  - Medicinal chemistry in Eastern England -- 15th symposium.

PMID- 15197656
TI  - Cambridge Healthtech Institute fourth annual conference in structure-based drug
      design.
AB  - The CHI-sponsored fourth annual meeting, held at the Sheraton hotel in Boston,
      USA, was attended by approximately 120 delegates, mainly from the pharmaceutical
      and biotechnology industries. The theme of the conference focused on new
      developments and validation of current techniques in structure-based drug design,
      as well as the successful application of these methods in drug development.

PMID- 15197655
TI  - Advances in anti-arthritic agents -- SMi conference.

PMID- 15197658
TI  - Angiogenesis -- SMi conference.

PMID- 15197657
TI  - Asthma therapeutics - SMi's fifth annual conference.

PMID- 15197659
TI  - Collaborations and licensing in pharma and biotech industries -- second annual
      SMi conference.

PMID- 15197660
TI  - Impact of gene polymorphisms on depression and its treatment.
AB  - Various genetic alterations have been demonstrated to be associated with mood
      disorders and suicide in a number of studies, although there are many
      contradictory findings. The most studied genotype, with the largest number of
      replicated results, is the serotonin transporter genotype. The efficacy of
      antidepressants appears to be influenced by the presence of a functional
      polymorphism within the serotonin transporter gene. In addition, genetic
      variation has an influence on the occurrence of antidepressant-induced side
      effects. Although further studies using larger sample populations are needed, it
      is becoming clear that genetic tools will be a major factor in improving
      diagnosis and optimizing the treatment of depressive disorders in the near
      future.

PMID- 15197661
TI  - Liver X receptors and atherosclerosis.
AB  - Cardiovascular disease, the primary cause of death and illness in the
      industrialized world, is typically due to complications of atherosclerosis, a
      multifactorial disease of the arterial intima. The liver X receptors (LXRs),
      LXRalpha and LXRbeta, are intracellular receptors that appear to play an
      important role in protection against atherosclerosis; however, LXR activation
      also leads to a dramatic increase in liver and serum triglycerides. This presents
      a challenge to developing drugs via these targets. This article discusses the
      role of LXRs in atherosclerosis and lipid regulation and the possibility of
      designing LXR ligands that may be anti-atherogenic without side effects.

PMID- 15197662
TI  - Specific immunoglobulin against HCV: new perspectives.
AB  - Evidence has suggested that the hepatitis C virus (HCV) does not elicit
      neutralizing antibodies, and hence that the presence of anti-HCV antibodies is
      only a marker of infection. Subsequently, HCV neutralizing antibodies have been
      identified and methods for their detection were devised. HCV neutralizing
      antibodies are present in anti-HCV-positive blood units but there is no
      correlation between the anti-HCV antibody titer and the HCV neutralizing antibody
      titer. There are two patented methods for the production of polyclonal HCV
      immunoglobulin: (i) from anti-HCV-positive blood units containing high titers of
      anti-HCV antibodies (EP-00447984); and (ii) from a large number of anti-HCV
      positive blood units that contain high titers of HCV-neutralizing antibodies
      against the different HCV strains (US-06372216 and EP-00896545). Several
      monoclonal antibodies have been patented for clinical use in HCV-infected
      patients; however, only one has undergone a clinical trial. This review examines
      the use of specific immunoglobulin against HCV, which, similarly to specific
      immunoglobulin against hepatitis B virus, contains high titers of antibodies that
      neutralize the different HCV strains, and could thus be efficacious in the same
      settings (e.g., re-infection of transplanted liver, post-exposure prophylaxis,
      sexual transmission and patients undergoing hemodialysis).

PMID- 15197663
TI  - Drug evaluation: Bay-59-8862.
AB  - Bayer Corp, under license from Indena SpA, is developing BAY-59-8862, a taxane
      synthesized from 14beta-hydroxy-10-deacetylbaccatin III, for the potential
      treatment of cancer.

PMID- 15197665
TI  - [Airway management and the anesthesiologist].

PMID- 15197664
TI  - Drug evaluation: E-5564.
AB  - Eisai Co Ltd is developing the injectable endotoxin antagonist E-5564, for the
      potential prevention of the pathophysiological effects of endotoxin-mediated
      responses caused by bacterial infection, including septic shock.

PMID- 15197666
TI  - [Tracheotomy for the long-term ventilator-dependent patient?].
AB  - OBJECTIVE: Tracheotomy is commonly performed in long-term ventilated patients.
      The aim of this review is to discuss the advantages and disadvantages of
      tracheotomy. METHODS: Review of the literature. RESULTS: Disadvantages of
      tracheotomy include the risk of bleeding, infection, injury of the truncus
      brachiocephalicus, and of long-term tracheal injury. These risks must be compared
      with the risk of vocal cord trauma, laryngeal trauma, and subglottic stenosis
      following translaryngeal intubation. Despite a number of disadvantages and
      potentially even life-threatening complications, however, tracheotomy is a well
      established technique for long-term airway management in critically ill patients.
      Potential advantages of tracheotomy include enhanced patient comfort, reduced
      airway resistance and dead space, a lower incidence of ventilator-associated
      pneumonia and a shorter duration of mechanical ventilation and hospital stay.
      Patient comfort before and after tracheotomy has not yet been seriously
      evaluated, using modern ventilators airway resistance does not longer play a
      major role. No data from randomized controlled trials actually support the thesis
      that tracheotomy reduces the incidence of ventilator-associated pneumonia. There
      is weak evidence for the concept that the duration of mechanical ventilation can
      be reduced in patients while using tracheotomy. Patients undergoing percutaneous
      dilational tracheotomy seem to have a reduced risk of bleeding and site infection
      and a shorter duration of the procedure when compared to those with conventional
      surgical tracheotomy. CONCLUSIONS: Many clinicians perform tracheotomies on the
      basis of expert opinion and clinical experience. So far, the benefits, however,
      have not been proven in large-scale randomized trials. Many of these studies
      suffer from design flaws, insufficient randomization and the absence of blinding.
      On the other hand, the lack of positive results do not rule out that tracheotomy
      may be beneficial for the ventilator-dependent patient. Percutaneous tracheotomy
      procedures may be superior to conventional surgical tracheotomies. Long-term
      results, however, will have to prove this preliminary observation.

PMID- 15197667
TI  - [The positioning of reinforced laryngeal masks (LMA) with the "Zerer
      introducer"].
AB  - OBJECTIVE: Correct and rapid positioning of reinforced laryngeal masks (LMA) is
      often a problem in anaesthetics. Although different techniques have been
      developed, none of them are satisfactory. A newly designed introduction device
      was used to place reinforced laryngeal masks. These are first results of a
      clinical observational study. METHODS: A special fork fixed on a handhold was
      constructed. The introduction of the LMA was possible in an arched movement down
      to the hypopharynx using appropriate sizes for different sizes of LMA's. RESULTS:
      The intubation in 500 surgical cases (30 % adult, 70 % children, mostly in ENT
      surgery) was easy and rapidly performed. A leading finger for placement was not
      necessary. There were neither cases of rotation nor retrograde flexion of the top
      of the mask. Direct vision by the ENT-specialist revealed no evidence of any
      injuries of the palate or throat. CONCLUSION: A newly designed introduction
      device allows a fast and efficient placement of reinforced laryngeal masks and
      contributes to the safety of this mode of application.

PMID- 15197668
TI  - [EasyScope - an alternative to the conventional Macintosh laryngoscope?].
AB  - OBJECTIVE: This study was conducted to compare two different techniques used for
      tracheal intubation (TI). We evaluated airway management conditions for a
      conventional Macintosh laryngoscope and the Brummert EasyScope, a new device.
      METHODS: A prospective trial was conducted with 20 medical students who had no
      prior airway management experience. Intubation was performed on an Ambu manikin.
      Following didactic instruction, each participant took turns performing TI using
      the Macintosh and EasyScope devices under direct supervision. Time required for
      TI, the number of attempts, and the number of times teeth were contacted were
      documented for each device. All participants also completed a questionnaire to
      determine self-assessed comfort and skill level for both the Macintosh and
      EasyScope devices. RESULTS: Time required for TI was comparable for both devices,
      although a trend toward slightly lower times for the EasyScope was observed.
      There was a lower rate of tooth contact during laryngoscopy and a lower rate of
      unsuccessful intubation attempts while using the EasyScope. Furthermore, the
      students felt the EasyScope was subjectively easier to use and required less
      effort during TI when compared with the Macintosh laryngoscope. CONCLUSION:
      Personnel not accustomed to a particular airway management technique achieved
      comparable outcomes when using either the Macintosh laryngoscope or the EasyScope
      device for TI. Possible reduction of effort required for tracheal intubation or
      better dental protection have to be evaluated for the EasyScope in further
      clinical studies.

PMID- 15197669
TI  - [A comparison of the Arndt endobronchial blocker with a double lumen tube in
      robotic cardiac surgery].
AB  - OBJECTIVE: In this prospective, randomised study a double lumen tube (DLT) or an
      Arndt bronchial blocker (BB) was used for one lung ventilation (OLV).
      Intraoperative oxygenation, ventilation, haemodynamics, and ease of placement
      were compared. METHODS: In 32 patients undergoing robotic harvesting of the left
      internal thoracic artery (ITA) a left-sided DLT or a BB controlled by
      bronchoscopy was used for OLV of the right lung. In 2 patients randomised for
      DLT, a single lumen tube and BB was used for difficult visualisation of the
      larynx. These 2 patients were excluded from the study. RESULTS: Correct placement
      of DLT (8.8 +/- 5.4 min, 87.5 % of the patients) as well as BB (6.5 +/- 4.0 min;
      n. s.; 100 % of the patients) was achieved rapidly. The Cormack-Lehane score for
      visualisation of the larynx was 2, 1 - 3 (median, range) in group DLT and 3, 1 -
      4 (median, range) in group BB (p < 0.05). OLV lasted for 93 +/- 29 min in group
      DLT and 88 +/- 34 min in group BB (n. s.). Satisfactory conditions for harvesting
      ITA were achieved in all patients of both groups. There was no difference in any
      haemodynamic parameter at any time between the two groups. Mean pulmonary
      arterial pressure and pulmonary vascular resistance were increased without
      significant differences between the two groups during thoracoscopy for robotic
      preparation of left ITA. During OLV, index of paO (2)/FiO (2) was significantly
      (p < 0.05) lower in DLT patients compared to BB patients. Time to extubation did
      not differ between the two groups (DLT 14.3 +/- 4.6 h; BB 11.8 +/- 3.8 h).
      CONCLUSION: OLV in patients undergoing robotic cardiac surgery was safely
      achieved either by BB or by left-sided DLT. Positioning of the BB was easier than
      that of a DLT when intubation was difficult and tube exchange at the end of
      surgery is avoided. Therefore, we prefer a BB in patients undergoing robotic
      harvesting of left ITA.

PMID- 15197670
TI  - [A comparison of the effects of 50 % oxygen combined with CPAP to the non
      ventilated lung vs. 100 % oxygen on oxygenation during one-lung ventilation].
AB  - OBJECTIVE: In a prospective, randomised, double-blind study the effects of FiO
      (2) of 0,5 with CPAP and a FiO (2) of 1.0 without CPAP on oxygenation and
      pulmonary shunt during one-lung ventilation (OLV) were examined. METHODS: In 20
      patients undergoing thoracotomy (ASA II/III) two sequential ventilation methods
      were used during OLV: a) FiO (2) of 1.0 (OLV-100) and b) a FiO (2) of 0.5 in N
      (2)O combined with CPAP of 5 cm H (2)O to the non-ventilated lung (OLV-CPAP),
      whereby the sequence in 10 patients was OLV-CPAP followed by OLV-100; and the
      opposite in the remaining 10 patients. Operating conditions were graded by the
      surgeon. RESULTS: OLV-CPAP was associated with a better oxygenation and a lower
      shunt compared to OLV-100 (paO (2) : 198 +/- 40 mmHg vs 181 +/- 38 mmHg; p < 0.05
      and Qs/Qt: 30 +/- 6 % vs. 34 +/- 8 %; p < 0.01, respectively). The different
      sequence of the ventilation methods did not cause significant differences in the
      results. The surgical conditions were not impaired by the CPAP of 5 cm H (2)O.
      CONCLUSION: The application of low FiO (2) with CPAP provided a better
      oxygenation and a lower pulmonary shunt during the OLV compared to high FiO (2)
      without CPAP.

PMID- 15197671
TI  - [Pro: cuffed endotracheal tubes in small children].

PMID- 15197672
TI  - [Contra: cuffed endotracheal tubes in small children].

PMID- 15197674
TI  - [Herpes zoster oticus: symptom constellation and serological diagnosis].
AB  - BACKGROUND: Herpes zoster oticus is a rare illness with cutaneous symptoms
      (eruptions) and a colored picture of brain nerve failures. The clinical symptoms,
      the symptom constellation, diagnostics and therapy, however, have been examined
      till now only in few studies. PATIENTS AND METHODS: In this study 91 cases of a
      zoster oticus were looked at in retrospect from the complete archives of the
      university ENT clinic Jena/Germany in the period from 1932 to 2001. Inclusion
      criterion was the occurrence eruptions in the ear region. The demographic data,
      subjective and objective symptoms, the symptom constellations, diagnostic methods
      and the therapy were arranged. RESULTS: Women (68.1 %) were concerned more
      frequently than men (31.9 %). The average illness age was 51.2 days. The
      prodromal stage lasted for 2.2 days in the average. Earache (50.2 %) and headache
      (11.0 %) were the most frequent first symptoms. No prodroma appeared in 27.5 % of
      the cases. The facial nerve (86.8 %) was most frequently affected, the vestibular
      nerve in 76.9 % and the cochlear nerve in 36.3 %. Other brain nerve damages were
      extremly rare. The therapy success was identical with regard to the brain nerve
      regeneration at all times. A positive antibody titer for VZV-IgM and/or IgA or an
      IgG is a sign for an acute infektion. VZV-IgA antibody titers appeared more
      constantly, frequent and early than an IgM. CONCLUSIONS: Women have a greater
      risk of falling ill at a zoster oticus than men. Although more than 72 hours is
      behind the beginning of the symptoms in this study, treatment with virostatic
      drugs should always be carried out in zoster oticus. Different therapy methods do
      not have any influence to the success therapy of the therapy. The facial nerve
      showed the best cure trend. A postzosteric pain develops approximately the half
      of the cases at the zoster oticus. The serological diagnostic is not necessary in
      clinically clear cases.

PMID- 15197675
TI  - [Multi-center study of the Jenaer model of the temporal bone].
AB  - BACKGROUND: Preparing exercises at the temporal bone are a prerequisite for the
      knowledge of the anatomical special features of this region and for learning the
      fundamentals of the tympanic cavity surgery. Since however fewer human temporal
      bones are available, the search for back-up models already took place in the last
      years. METHODS: Based on the experiences of the handling and visualization of CT
      data for the 3D-implant construction in the ent department Jena a temporal bone
      model was developed. The model was sent away to surgeons of different training.
      On the basis of identification of anatomical structures and evaluation of general
      parameters by means of a point system the model was evaluated. RESULTS AND
      CONCLUSIONS: The Jenaer temporal bone model is suitable as entrance into the
      preparing exercises. The anatomical structures are good to identify for the
      beginner. The handling with drill and chisel can be learned.

PMID- 15197676
TI  - [Are there olfactory evoked alterations of breathing patterns?].
AB  - BACKGROUND: It is controversially discussed whether strictly olfactory stimuli
      are able to evoke changes of breathing patterns. A number work groups argue that
      the more or less noticeable irritative component of odors are responsible for a
      respiratory response. Other work groups regard changes of breathing pattern as an
      indicator for an intact smell ability during "pure" olfactory stimulation.
      METHODS: 12 normosmic young volunteers were repeatedly challenged with
      hydrogensulfide (H (2)S) for two seconds on inspiration in concentrations just
      above the threshold using a flow olfactometer. Clean air stimuli were presented
      randomly as control blanks. The breathing patterns were registered with a
      differential pressure transducer occluding one nostril via a tube. The signals
      were digitized and recorded on a PC. Nine parameters were calculated for each
      breath using a custom made LabView (R) software. The breath during stimulation
      was compared to the average of five breathing cycles prior to stimulation. An
      increase or reduction of each parameter was equally regarded by means of their
      absolute value. The sum was termed respiration index (RI). RESULTS: The mean RI
      (all trials of each test person) stimulated with H (2)S varied from 201 to 570;
      stimulated with clean air from 85 to 188. The difference was significant (p <
      0,001). A significant group-difference for each single trial was seen as well.
      There was no significant increase or decrease of RI during 15 successive
      stimulations with H (2)S. CONCLUSIONS: Detectable short H (2)S-stimuli are able
      to evoke alterations of breathing patterns which can be identified by computer.
      Respiration-olfactometry is suitable to objectify odor perception.

PMID- 15197677
TI  - [Investigations to the influence of tumor supressor gene p16 inactivation on the
      prognosis of head and neck squamous cell carcinoma].
AB  - BACKGROUND: The inactivation of the tumor suppressor gene p16 plays an important
      role in the development of malignant tumors. P16 loss can result from point
      mutations, loss of heterozygosity (LOH) or methylation of the promoter region.
      MATERIAL AND METHODS: A total of 67 samples of tumor tissue from squamous cell
      carcinomas of the oral cavity, the pharynx and the larynx were analysed for an
      inactivation of p16. The samples were obtained during surgery. In all cases there
      was a curative intention. Point mutations were detected by DNA sequencing.
      Methylation of the promotor region was explored with a methylation-specific PCR.
      A microsatellite analysis of the tumor tissue was used to search for LOH.
      RESULTS: The results of the molecularbiological investigations were correlated to
      the known clinical prognostic parameters (tumor stadium, grading, patho
      histological differentiation, local and regional recurrence) after a follow-up
      period of approximately 3 years. Methylation of the promotor region and LOH were
      the main mechanisms of p16 inactivation encountered in this study. Point
      mutations presented as rare events. The methylation of the promotor region
      appeared frequently parallel with an LOH. An inactivation of p16 did not have any
      statistical influence on the tumor dependent survival, the lymphatic spread, the
      number and time delay of local and regional recurrences. Patients with an
      inactivated p16 gene by promotor methylation appeared to have a slightly lower
      tendency for local and regional recurrences. CONCLUSIONS: The inactivation of the
      tumor suppressor gene p16 plays a role in the carcinogenesis of squamous cell
      carcinomas of the oral cavity, the pharynx and the larynx. There is no influence
      on the tumor dependent prognosis. Tumors with an inactivated p16 gene tend to
      have a lower recurrence rate.

PMID- 15197678
TI  - [Modern diagnostics of tracheal stenosis].
AB  - BACKGROUND: Numerous new modalities in computertomography (CT), in particular
      Multislice-Spiral-CT and Virtual Endoscopy, and novel developments in endoscopy
      and spirometry gave us reason to review the current state of the art in
      diagnostics of tracheal stenosis (TS). METHODS: This review evaluates the
      literature of the last decade regarding new trends and methods in diagnostics of
      tracheal stenosis. Pros and cons are discussed, and the future trends are
      highlighted. CONCLUSIONS: Spiral-CT scans at collimated slices of < or = 3 mm,
      PITCH < or = 1.5 and a segmentation level of - 350 HE permit a valid measurement
      of tracheal lumina. The flow-volume-plot is still the most important
      investigation to evaluate respiratory function in TS. Peak-Flow-Meters are
      suitable for patient self monitoring. The selective estimation of the TS related
      airway resistance using in situ measurements and numerical flow simulation
      studies are likely to reach importance in future. The ability to obtain exact
      measures from endoscopic recordings using EndoScan serves quality control in
      endoscopy. An objective comparison of different treatments becomes possible.
      Endosonography and methods for in-vitro tissue analysis (Optical Coherence
      Tomography) are more focused on the early diagnosis of malignant lesions. The
      Synopsis of endoscopy, CT-scan and spirometry provides the highest diagnostic
      accuracy today.

PMID- 15197679
TI  - [Examination to possibilities of a physiological fitting of cochlear implants].
AB  - BACKGROUND: Cochlear implants (CI) convert acoustic events into electrical
      pulses. The auditory nerve picks these tiny electrical pulses up and sends them
      to the brain. The dynamics of the audible sound is compressed considerably. The
      limits for stimulation are determined with the patient. A map law determines
      which sound pressure level is assigned to which stimulation level. A sufficient
      speech understanding requests an allocation of high stimulation levels for weak
      sound signals. The higher the sound level, the lower the increase. Unfortunately,
      with such kind of map law unwanted background noise is also presented as well
      audible stimulation. These stimuli are often annoying to CI users in everyday
      situations. PATIENTS AND METHOD: The possibility to give an s-shaped course to
      these map laws was examined in 9 patients. After the fitting procedure their
      speech understanding were tested. The results were compared with the results of
      former tests. RESULTS: 8 patients reported definite improvement of their hearing
      situation. Such map laws seem, therefore, suitable to optimise speech processor
      programming.

PMID- 15197680
TI  - [Significance of PET for ENT-tumors].
AB  - Significance for ENT-tumors. Molecular imaging with PET is based on the use of
      specific radioactive molecules as source of image contrast. In ENT-tumors mostly
      glucose and occasionally amino acid/protein metabolism were assessed with PET for
      tumor diagnosis. Thymidine salvage pathway and proliferation as well as tissue
      hypoxia are tested already in clinical studies and bear considerable potential
      for modulation of radiation ports and therapeutic response of cytoreductive
      regimens. This short review summarises actual clinical indications and potential
      of PET in ENT-tumors. For both nodal staging as well as detection of recurrent
      disease, sensitivity and specifity of FDG-PET were 80 - 100 %. FDG-PET proved to
      be superior to conventional imaging in most published studies. In CUP-syndrome
      the primary could be detected in 25 - 50 % of patients. Acquisition of PET and CT
      images in a combined scanner allow versatile PET based metabolic imaging in
      combination with high resolution and anatomical precise CT-based morphological
      imaging and thus combines advantages of both imaging modalities. Clinical as well
      as scientific potential of this functional metabolic and high resolution
      morphological imaging approach is high.

PMID- 15197683
TI  - High-resolution molecular characterization of 15q11-q13 rearrangements by array
      comparative genomic hybridization (array CGH) with detection of gene dosage.
AB  - Maternally derived duplication of the imprinted region of chromosome 15q11-q14
      leads to a complex neurobehavioral phenotype that often includes autism,
      cognitive deficits, and seizures. Multiple repeat elements within the region
      mediate a variety of rearrangements, including interstitial duplications,
      interstitial triplications, and supernumerary isodicentric marker chromosomes, as
      well as the deletions that cause Prader-Willi and Angelman syndromes. To
      elucidate the molecular structure of these duplication chromosomes, we designed a
      high-resolution array comparative genomic hybridization (array CGH) platform. The
      array contains 79 clones that form a gapped contig across the critical region on
      chromosome 15q11-q14 and 21 control clones from other autosomes and the sex
      chromosomes. We used this array to examine a set of 48 samples from patients with
      segmental aneuploidy of chromosome 15q. Using the array, we were able to
      determine accurately the dosage, which ranged from 1 to 6 copies, and also to
      detect atypical and asymmetric rearrangements. In addition, the increased
      resolution of the array allowed us to position two previously reported
      breakpoints within the contig. These results indicate that array CGH is a
      powerful technique to study rearrangements of proximal chromosome 15q.

PMID- 15197686
TI  - The "innocent bystander" complications following esophagectomy: atrial
      fibrillation, recurrent laryngeal nerve injury, chylothorax, and pulmonary
      complications.

PMID- 15197687
TI  - Leaks, strictures, and necrosis: a review of anastomotic complications following
      esophagectomy.
AB  - Since the first reports of esophageal resection for the treatment of various
      esophageal diseases and disorders, morbidity related to the anastomosis and the
      chosen replacement conduit have remained a frequent nemesis, a constant concern,
      and an ongoing area of research and experimentation. In this review of this key
      component of esophageal resection, an analysis is presented of the most frequent
      complications related to the anastomosis and conduit: anastomotic leak, conduit
      necrosis, and conduit stricture. In each case, a review of the current pertinent
      literature and experience is reported with a view to providing management
      recommendations to minimize or prevent occurrences, to improve timely diagnosis
      and to best treat these complications when they arise.

PMID- 15197684
TI  - Common variants in the 5' region of the leptin gene are associated with body mass
      index in men from the National Heart, Lung, and Blood Institute Family Heart
      Study.
AB  - Linkage of body mass index (BMI) to a broad region of chromosome 7q22-35 has been
      reported in multiple studies. We previously published a multipoint LOD score of
      4.9 at D7S1804 for BMI from the National Heart, Lung, and Blood Institute Family
      Heart Study. Leptin (LEP), the human homolog of the mouse obesity (ob) gene, is
      positioned near the linkage peak and is the most prominent candidate gene in this
      region. Interest in LEP as a susceptibility gene for human obesity has led to
      numerous linkage and association studies, but the results of these studies are
      still controversial. In the present study, we employed family-based tests of
      association with both a quantitative measure of BMI adjusted for age and sex and
      a dichotomously defined obesity trait. We genotyped 29 single-nucleotide
      polymorphisms (SNPs) spanning 240 kb around the LEP gene in the 82 extended
      pedigrees with the strongest evidence for linkage. When the programs TRANSMIT and
      FBAT were used, a number of SNPs showed association in men but not women, for
      both the quantitative and qualitative trait definitions (P<.05). Five SNPs
      (H1328084, H1328083, H1328082, H1328081, and H1328080) positioned 2 kb beyond the
      previously defined promoter region showed strong association in single-marker and
      multiple-marker haplotype analysis. This five-marker haplotype (frequency 49% in
      this sample) is overtransmitted to obese offspring (P=.00005). All five of these
      SNPs are predicted to modify transcription-factor binding sites. This may
      indicate new functional variants in an extended promoter region of LEP.

PMID- 15197688
TI  - Complications of minimally invasive esophagectomy.
AB  - Esophagectomy is a complex procedure that is associated with significant
      morbidity and mortality in even the best of hands. With the introduction and
      widespread application of minimally invasive techniques, the possibility of
      improving outcomes has been entertained. In a series of 222 patients that
      underwent minimally invasive esophagectomy at the University of Pittsburgh, the
      mortality rate was 1.4%, with major morbidity occurring in 32%. The overall
      spectrum of complications encountered was similar to that previously reported in
      the largest open series. The marked reduction in mortality and hospital stay when
      compared with many open series may be an important consequence of the minimally
      invasive approach, though prospective randomized studies will be required to
      further assess this potential benefit.

PMID- 15197689
TI  - Gastrointestinal function and related problems following esophagectomy.

PMID- 15197690
TI  - Quality of life after esophagectomy.
AB  - Esophagectomy is associated with high complication rates and consequent
      mortality. The 5-year survival for esophageal cancer is also discouraging with
      rates of 6 to 33% after surgery. Nonsurgical series of selected patients have
      shown similar survival. Therefore, quality of life may be a better assessment of
      patient outcomes than survival. At present few reports have address quality of
      life in patients after esophagectomy, particularly in those patients who succumb
      quickly to recurrent cancer. This article investigates the determinants of
      quality of life after esophagectomy and reviews the use of quality of life
      measures in comparative trials. Quality of life measures may become valuable
      tools in the selection of patients for esophagectomy.

PMID- 15197692
TI  - Artificial chordae.
AB  - Expanded polytetrafluoroethylene sutures have been used for replacement of
      chordae tendineae since 1985. They have been used for correction of prolapse of
      mitral and tricuspid valve leaflets as well as for resuspension of the papillary
      muscles during mitral valve replacement when the native chordae cannot be
      preserved to maintain continuity between the mitral annulus and papillary
      muscles. The sutures used were 5CV Gore-Tex for replacement of the chordae
      tendineae of the anterior leaflet and 6CV for the posterior leaflet and
      commissural areas of the mitral valve. Initially one suture was used to create
      two artificial chordae, but as experience increased, the technique was modified
      and multiple pairs of artificial chordae were created with a single suture by
      passing successively through the fibrous portions of the a papillary muscle and
      the free margin of the prolapsing segment of leaflet, and tying the tends
      together on the papillary muscle head. This technique creates artificial chordae
      that are interdependent and their lengths are self-adjusting when pressure is
      exerted on the leaflets. From 1985 to 1998, 288 patients had artificial chordae
      used during mitral valve repair for degenerative disease of the mitral valve.
      Prolapse of both leaflets was present in 51% of patients, isolated prolapse of
      the anterior leaflet in 28%, and posterior leaflet in 21%. The mean follow-up was
      4.8 +/- 3.0 years and was complete. At 10 years, the freedom from mitral
      regurgitation >2+ was 88 +/- 6% and the freedom from reoperation was 92 +/- 2%.
      Failures of repair were unrelated to the artificial chordae. Gore-Tex sutures are
      an excellent material to replace chordae tendineae, appear to be free of adverse
      effects, and have become a valuable adjunct to the surgical armamentarium to
      treat mitral and tricuspid valve disease.

PMID- 15197693
TI  - Chordal transfer for repair of anterior leaflet prolapse.
AB  - A variety of techniques have been developed for repair of prolapse of the
      anterior leaflet of the mitral valve. At The Cleveland Clinic Foundation, we
      favor chordal transfer for this entity. In most instances, normal chordae with a
      strip of leaflet tissue are transferred from the posterior leaflet to the free
      edge of the unsupported anterior leaflet; the posterior leaflet is repaired in
      standard fashion employed for quadrangular resection. In selected cases, chordal
      transfer is accomplished by transfer of secondary anterior leaflet chordae to the
      unsupported free edge. Because normal chordae are used in both instances, there
      is no need for measurement of chordae or judgment of their length. With this
      technique for correction of anterior leaflet prolapse, 5-year freedom from
      reoperation after mitral valve repair is 96%.

PMID- 15197694
TI  - Surgical repair of the prolapsing anterior leaflet with chordal shortening.
AB  - The purpose of this study was to review the results of mitral valve repair for
      prolapse of the anterior repaired with chordal shortening or shortening of the
      papillary muscle. Sixty three patients operated from June 1988 through June 2003,
      form the cohort of this study. The etiology was degenerative disease in 30
      patients (47%) and rheumatic disease in 23 (37%). All patients survived the
      operation. Predischarge echocardiography showed no or trivial regurgitation in 61
      patients (97%). Mean follow-up was 6.57 +/- 0.65 years. Twenty patients died
      during the follow-up for an actuarial survival of 62% at 14 years. Five patients
      required reoperation on the mitral valve; 88% of the patients were free from
      reoperation at 14 years. In conclusion, shortening plasty of the subvalvular
      apparatus provides good and stable results after repair of anterior leaflet
      prolapse.

PMID- 15197695
TI  - "Edge-to-edge" repair for anterior mitral leaflet prolapse.
AB  - The aim of this study is to report our results in a series of 150 consecutive
      patients (mean age 53 +/- 15.4 years) in whom mitral regurgitation (MR) due to
      isolated anterior mitral leaflet (AML) prolapse was corrected using the edge-to
      edge (E to E) technique over a period of more than 10 years. At admission, 49
      (32.6%) patients were in NYHA class I, 46 (30.6%) in II, 51 (34%) in III and 4
      (2.6%) in IV. In the great majority of the cases (111 patients, 74%),
      degenerative disease was the cause of MR. Hospital mortality was 0.6% (1/150).
      There were 7 late deaths. The actuarial overall survival and freedom from
      reoperation at 9 years were 91.6% +/- 3.16% and 96.6% +/- 1.74%, respectively. At
      follow-up (4.5 +/- 3.21 years, range 2 months-12 years), the mean mitral valve
      area was 2.7 +/- 0.5 cm(2) and mitral regurgitation was absent or mild in 132
      patients (88%). The results of this study demonstrate the effectiveness and
      durability of the E to E repair in the setting of AML prolapse. In our
      institution, this technique, in conjunction with annuloplasty, remains the method
      of choice to correct segmental prolapse of the AML.

PMID- 15197696
TI  - Anterior leaflet resection of the mitral valve.
AB  - Triangular resection is a reconstructive option for treatment of anterior leaflet
      mitral disease with segmental prolapse. In our experience, it is a safe and
      reproducible technique, associated with low rates of recurrent MR or need for
      reoperation, as well as decreased likelihood for systolic anterior motion after
      mitral repair. We review our experience with this technique over a 25-year
      experience with mitral valve reconstruction.

PMID- 15197697
TI  - New concerns about old drugs: Valvular heart disease on ergot derivative dopamine
      agonists as an exemplary situation of pharmacovigilance.

PMID- 15197698
TI  - Smoking and Parkinson's disease: systematic review of prospective studies.
AB  - We estimated the pooled risk of tobacco smoking for Parkinson's disease (PD).
      Inclusion criteria included systematic searches of MedLine, PsycLIT, Embase,
      Current Contents, previously published reviews, examination of cited reference
      sources, and personal contact and discussion with several investigators expert in
      the field. Published prospective studies on PD and cigarette smoking. When two or
      more studies were based on an identical study, the study that principally
      investigated the relationship or the study that was published last was used.
      Seven prospective studies were carried out between 1959 and 1997, of which six
      reported risk estimates. Four cohorts were based on standardised mortality rates,
      which were exclusively of male. Only one study included risk estimates for both
      males and females separately. The risk of ever smoker was 0.51 (95% confidence
      interval, 0.43 to 0.61). There was an obvious protective effect of current
      smoking in the pooled estimate (relative risk, 0.35; 95% CI, 0.26-0.47). Former
      smokers had lower risk compared with never smokers (relative risk, 0.66; 95% CI,
      0.49-0.88). Although our pooled estimates show that smoking is inversely
      associated with the risk of PD, the four prospective studies that were based on
      follow-up of mortality of smokers had many limitations. Further studies
      evaluating the association between smoking and PD in women are strongly needed.

PMID- 15197700
TI  - Clinicopathological investigation of vascular parkinsonism, including clinical
      criteria for diagnosis.
AB  - Vascular parkinsonism (VP) is difficult to diagnose with any degree of clinical
      certainty. We investigated the importance of macroscopic cerebral infarcts and
      pathological findings associated with microscopic "small vessel disease" (SVD) in
      the aetiology of VP. The severity of microscopic SVD pathology (perivascular
      pallor, gliosis, hyaline thickening, and enlargement of perivascular spaces) and
      the presence of macroscopically visible infarcts were assessed in 17 patients
      with parkinsonism and no pathological evidence of either Parkinson's disease or
      any histopathological condition known to be associated with a parkinsonian
      syndrome, and compared with age-matched controls. Microscopic SVD pathology was
      significantly more severe in the parkinsonian brains. Most patients presented
      with bilateral bradykinesia and rigidity together with a gait disorder
      characterised predominantly by a shuffling gait. Four patients presented acutely
      with hemiparesis and then progressed to develop a parkinsonian syndrome. They
      could be distinguished from the remaining VP patients by the presence at autopsy
      of macroscopically visible lacunar infarcts in regions where contralateral
      thalamocortical drive might be reduced. The clinical features at presentation
      varied according to the speed of onset and the underlying vascular pathological
      state. New clinical criteria for a diagnosis of VP are proposed based on the
      clinicopathological findings of this study.

PMID- 15197699
TI  - Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2
      (SCA2).
AB  - Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon
      cause of parkinsonism, an alternate presentation to the typical cerebellar
      disorder. This research review summarizes the existing literature on parkinsonism
      predominant presentation SCA2 and presents new clinical cases of patients with
      this condition. Various phenotypes are noted in this subtype of SCA2, including
      parkinsonism indistinguishable from idiopathic Parkinson's disease (PD),
      parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several
      kindreds with multiple affected family members, the SCA2 expansion segregated
      with disease; in addition, several single cases of parkinsonism with and without
      a family history are also described. The number of repeats in symptomatic
      patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or
      CCG was found in some individuals, possibly stabilizing the repeat structure and
      accounting for the relative stability of the repeat size across generations in
      some families; allele length is not necessarily indicative of trinucleotide
      repeat architecture. Positron emission tomography scanning in one family showed
      reduced fluorodopa uptake and normal to increased raclopride binding with a
      rostrocaudal gradient similar to that found in idiopathic PD. This review
      emphasizes the importance of testing for SCA2 in patients with parkinsonism and a
      family history of neurodegenerative disorders. Testing for SCA2 is also important
      in studies of inherited parkinsonism.

PMID- 15197701
TI  - Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree
      with a novel spastin mutation.
AB  - The most common form of autosomal dominant hereditary spastic paraparesis (HSP),
      SPG4, is caused by mutations in the spastin gene on chromosome 2p. This disease
      is characterized by intra- and interfamilial phenotypic variation. To determine
      the predictive values of clinical signs and symptoms in SPG4, we examined 43
      members of a large pedigree with autosomal dominant HSP. We then identified the
      genetic etiology of the disorder in this family, a novel nonsense mutation in
      exon 1 of spastin, carried by 24 of the examined family members. The best
      clinical predictors of positive gene status were the presence of hyperreflexia in
      the lower extremities, >2 beats of ankle clonus, pes cavus, bladder symptoms and
      increased tone in the legs. The mean age of onset was 32.2 +/- 7.4 years, but the
      age of onset was earlier in children from 10 of 12 child-parent gene-positive
      pairs, with a mean difference of 10.8 +/- 3.3 years. The finding of leg weakness
      was especially common in older-onset affected family member with leg
      hyperreflexia. These results suggest that specific clinical signs and symptoms
      may be of value in differentiating individuals affected with SPG4 from family
      members with nonspecific neurological findings.

PMID- 15197702
TI  - Evaluation of the role of Nurr1 in a large sample of familial Parkinson's
      disease.
AB  - Parkinson's disease (PD) is a common neurodegenerative disorder in humans with
      wide variability in the age of disease onset. Although the disease has been
      thought previously to occur sporadically in most patients, there is increasing
      evidence of a genetic contribution to the disorder. Recently, a polymorphic
      variant within intron 6 of the Nurr1 gene was reported to be associated with
      sporadic and familial PD. In an effort to identify susceptibility genes for PD,
      we have collected 783 PD patients from 372 families and 397 healthy controls from
      217 families. PD patients and healthy controls were genotyped for the intron 6
      insertion polymorphism by BseRI restriction endonuclease digestion. No
      significant difference in either homozygosity or heterozygosity for the 7048G7049
      (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as
      compared with the panel of healthy controls. Moreover, direct sequencing of exon
      1 of the Nurr1 gene in PD patients failed to detect either of the two recently
      reported Nurr1 mutations identified in a small subset of a PD patient cohort.
      Taken together, these data suggest that genetic alteration at the Nurr1 locus is
      not a significant risk factor for the development of Parkinson's disease in our
      large sample of familial PD patients.

PMID- 15197703
TI  - Severe multivalvular heart disease: a new complication of the ergot derivative
      dopamine agonists.
AB  - We report on 4 new cases of valvular heart disease in Parkinson's disease
      patients treated with the ergot derivative dopamine agonists pergolide and
      cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been
      reported to occur in patients with carcinoid syndrome and to occasionally
      complicate therapies with the anti-migraine ergot alkaloid ergotamine and
      methysergide and with the appetite suppressants fenfluramine and dexfenfluramine.
      In these cases, the pathogenesis is suspected to involve serotonin-mediated
      abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in
      the fibroblasts of heart valves. Based on strikingly similar echocardiographic
      and histopathological features, we strongly suspect that ergot-derived dopamine
      agonists may cause a valvular heart disease nearly identical to that seen in
      those conditions. These cases add to a rapidly growing and worrying list of
      similar published reports, suggesting that we may well be facing a novel, yet
      unrecognized, complication of this class of agents, which are widely used not
      only in Parkinson's disease but also in restless legs syndrome and various common
      endocrine dysfunctions. Therefore, until more is known about the true prevalence
      of this side effect, we propose that an assessment of cardiac function be
      performed before and in the course of a long-term therapy with ergot derivative
      dopamine agonists.

PMID- 15197704
TI  - A novel movement disorder of the lower lip.
AB  - Four patients, aged 25 to 42 years presented with acute onset of a movement
      disorder characterized by a tonic, sustained, lateral and outward protrusion of
      one half of the lower lip. The movement disorder was present at rest, while in
      some patients, it was also present during speech. In all cases, the abnormal lip
      posture could be suppressed voluntarily. Neurological examination was otherwise
      normal. Extensive laboratory investigation failed to reveal any causative factors
      for secondary focal dystonia. Treatment with oral medications and botulinum toxin
      was mostly ineffective. Spontaneous remissions were frequent.

PMID- 15197705
TI  - Quality of life in Polish patients with long-lasting Parkinson's disease.
AB  - The objective of this study was to evaluate possible relationships between
      quality of life (QoL) of Polish patients with long-lasting Parkinson's disease
      and various demographic and clinical factors. The study comprised 141 patients of
      Movement Disorders outpatient clinics in Warsaw and Gdansk with at least 5 years
      of the disease duration. Mean age of patients was 68.09 +/- 8.51 years, mean
      duration of disease was 11.87 +/- 5.14 years. To assess the quality of life, the
      Parkinson's Disease Questionnaire (PDQ-39) was used. Additional questions
      concerned duration of disease, initial and current treatment and expenses
      associated with therapy. Self-perceived symptoms of depression were in our study
      the most important factor determining QoL. Duration of the disease and expenses
      related to the treatment also have a significant impact on the QoL. Patient's age
      and presence of dyskinesia seem to be irrelevant to the quality of life.

PMID- 15197706
TI  - Cerebellar metabolic symmetry in essential tremor studied with 1H magnetic
      resonance spectroscopic imaging: implications for disease pathology.
AB  - The pathological basis for essential tremor (ET) is not known; however, metabolic
      changes in the cerebellum can be observed in positron emission tomography (PET)
      and (1)H magnetic resonance spectroscopic imaging (MRSI) studies. Tremor is
      relatively symmetric in ET, suggesting that underlying metabolic changes could be
      also symmetric. The degree of metabolic asymmetry in the cerebellum, however, has
      not yet been studied in ET, and knowledge about distribution and laterality of
      metabolic changes might shed some light on basic disease mechanisms. We measured
      brain metabolism (N-acetylaspartate[NAA]/creatine [tCR]) to obtain an asymmetry
      index for cerebellar cortical metabolism ET patients compared with that in
      controls. This index, a percentage, was calculated as [absolute value (value
      right - value left)]/(value right + value left) x 100. Multislice (1)H MRSI data
      were acquired for 20 patients and 11 controls. In ET patients, mean right and
      left cerebellar cortical NAA/tCR values were 1.61 +/- 0.42 and 1.55 +/- 0.38,
      respectively, compared with 1.81 +/- 0.62 and 1.87 +/- 0.49 in controls. The
      difference between right and left cerebellar cortical NAA/tCR was also calculated
      for each subject. In ET patients, the mean right-left difference was 0.14 +/-
      0.11, compared with 0.32 +/- 0.27 in controls (P = 0.016). The mean cerebellar
      cortical asymmetry index was low in ET (8.8 +/- 6.1%), one-half of that in
      controls (17.0 +/- 13.7%, P = 0.027). These data suggest that pathological
      lesions in ET patients, which remain elusive, might be distributed similarly in
      each cerebellar cortex. Postmortem studies are needed to confirm these
      preliminary imaging results.

PMID- 15197707
TI  - Parkinson's disease in Ireland: clinical presentation and genetic heterogeneity
      in patients with parkin mutations.
AB  - Early-onset autosomal recessive parkinsonism is associated with parkin gene
      mutations. Different parkin mutations occur in many ethnic backgrounds; however,
      the phenotype may vary. We studied 102 young-onset (age at onset <60 years)
      Parkinson's disease (PD) patients. From 102 patients, 40 with early-onset PD (<45
      years at symptomatic onset) were selected for clinical assessment and parkin gene
      molecular analysis for duplications/deletions and point mutations. We identified
      parkin mutations in 7 of 40 early-onset patients; including novel compound
      heterozygotes and potential splice site changes. The mean age at onset in the 7
      parkin mutation-positive patients was 33 +/- 9 years (age range, 18-42 years),
      marginally lower than that of the 33 parkin-negative early-onset patients, 38 +/-
      7 years (age range, 17-45 years). A family history of PD was present in 4 of 7
      patients with parkin mutations, compared with 6 of 33 early-onset parkin-negative
      patients. Overall, parkin mutations were found in 4 of 10 patients with a
      positive family history and 3 of 30 patients without a family history of PD.
      Patients with parkin mutations had more dystonia, dyskinesia, and sleep benefit
      compared with parkin-negative patients. We subsequently identified a single point
      mutation among the 62 young-onset (age at onset 45 to <60 years). Mutations in
      the parkin gene may account for approximately 17% of early-onset (age at onset
      <45 years) parkinsonism in Ireland, in agreement with previous European studies.

PMID- 15197708
TI  - Muscle relaxation is impaired in dystonia: a reaction time study.
AB  - A simple visual reaction time (RT) paradigm was used to investigate whether the
      velocity of relaxation is impaired in dystonia. In 16 subjects with a clinical
      diagnosis of adult-onset focal, segmental or multifocal dystonia and in 15 age
      matched normal controls, the relaxation reaction time (R-RT) and the contraction
      reaction time (C-RT) were compared across different tasks involving the flexor
      carpi radialis (FCR), biceps brachii (BB) and triceps brachii (TR) arm muscles.
      In normal controls, the latency of EMG termination (R-RT) was significantly
      shorter than the latency of electromyographic (EMG) onset (C-RT) in the BB and TR
      muscles, but not in the FCR muscle. In dystonic patients, the latency of EMG
      termination (R-RT) was significantly longer than the latency of EMG onset (C-RT)
      in the FCR and BB muscles. No significant difference of the C-RT was observed
      between patients and controls whereas the R-RT was prolonged significantly in the
      BB and TR muscles of patients with dystonia and almost significantly in the FCR
      muscle. This study indicates that muscle relaxation is abnormal in patients with
      focal (multifocal or segmental) dystonia. The impaired muscle relaxation may
      contribute to the longer overlap of agonist-antagonist activities (co
      contraction) typically observed in dystonia and to the slowness of voluntary
      movement sequencing.

PMID- 15197709
TI  - A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia
      in Parkinson's disease.
AB  - Hyposmia is one of the most prevalent symptoms of Parkinson's disease. It may
      occur even before the motor symptoms start. To determine whether the olfactory
      dysfunctions, like the motor symptoms, are associated with a loss of dopamine,
      the number of dopaminergic cells in the olfactory bulb of Parkinson's disease
      patients was studied using tyrosine hydroxylase immunohistochemistry. The
      quantitative analysis reveals that the total number of tyrosine hydroxylase
      immunoreactive neurons in the olfactory bulb is twice as high in Parkinson
      patients compared to age and gender-matched controls. Because dopamine is known
      to inhibit olfactory transmission in the olfactory glomeruli, we suggest that the
      increase of dopaminergic neurons in the olfactory bulb is responsible for the
      hyposmia in Parkinson patients. The increase of dopamine in the olfactory bulb
      explains why olfaction does not improve with levodopa therapy.

PMID- 15197710
TI  - Minocycline in Huntington's disease: a pilot study.
AB  - Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase
      (iNOS), and has been shown to delay disease progression in the mouse model R6/2
      of Huntington's disease (HD). This safety and tolerability study included 30
      patients with HD who were given minocycline over a 6-month period and underwent
      assessments every 2 months with laboratory studies, the Abnormal Involuntary
      Movements Scale, the Unified Huntington's Disease Rating Scale, and the Mini
      Mental State Examination. Minocycline was well tolerated during this study period
      and no serious adverse events were noted.

PMID- 15197711
TI  - Neuropathology of primary restless leg syndrome: absence of specific tau- and
      alpha-synuclein pathology.
AB  - The neuroanatomical substrate for restless legs syndrome (RLS) is unknown. We
      identified 4 patients with idiopathic RLS who came to post-mortem examination,
      where brain and spinal cord tissue were available for neuropathological
      assessment. Lewy bodies were not identified and alpha-synuclein
      immunohistochemistry was uniformly negative. Neurofibrillary tangle pathology was
      variable and nonspecific. These findings suggest that tau- or alpha-synuclein
      brain pathology is not a component of primary RLS. Although chronic ischemic
      changes were found in all 4 cases, these were probably incidental. The absence of
      diagnostic microscopic brain or spinal cord pathology suggests that the
      pathologic substrate may be neurochemical or receptor based.

PMID- 15197712
TI  - Diagnosis and management of pergolide-induced fibrosis.
AB  - We report on 2 patients treated with pergolide, 1 of whom developed pleural
      fibrosis and the other retroperitoneal fibrosis. In both cases, an extensive
      diagnostic evaluation and surgical intervention were required to reach a
      diagnosis. Based on our experience with these patients and a review of cases of
      pergolide-induced fibrosis in the English-language literature, we propose
      guidelines for the diagnosis and management of this rare complication.

PMID- 15197713
TI  - Association study of dopamine D2, D3, D4 receptor and serotonin transporter gene
      polymorphisms with sleep attacks in Parkinson's disease.

PMID- 15197714
TI  - Cannabis-induced propriospinal myoclonus.
AB  - We report on a case of a 25-year-old woman with clusters of myoclonus induced by
      a single exposure to inhaled cannabis. Investigations excluded a structural
      abnormality of the spine. Multi-channel surface EMG with parallel frontal EEG
      recording confirmed the diagnosis of propriospinal myoclonus.

PMID- 15197715
TI  - Partial lesion of thalamic ventral intermediate nucleus after chronic high
      frequency stimulation.
AB  - A 73-year-old man with Parkinson's disease underwent thalamic stimulation for
      disabling tremor with excellent results only when stimulation on. Post-mortem
      neuropathology (7 years postoperatively) revealed 60% cell loss within 0.5 mm of
      the electrode tip. Tremor improvement was attributable to chronic stimulation,
      not microthalamotomy.

PMID- 15197716
TI  - Severe resting clonus caused by thyrotoxicosis in a 16-year-old girl with
      hereditary spastic paraparesis: a case report.
AB  - A 16-year-old girl with a history of hereditary spastic paraparesis developed the
      subacute onset of severe clonus and new upper-extremity spasticity due to
      thyrotoxicosis. This case demonstrates the ability of hyperthyroid states to
      worsen symptoms of spasticity in a child with an underlying spastic disorder. It
      also demonstrates the importance of investigating for common systemic diseases as
      a cause of movement disorders even in children with underlying known genetic
      disorders.

PMID- 15197717
TI  - Focal dystonia after removal of a parietal meningioma.
AB  - A patient presented at the age of 50 years with a right-sided, writing-specific
      dystonia which settled without treatment. Ten years later she developed focal
      seizures affecting the right leg and occasionally spreading to the right arm. A
      left parietal meningioma was removed and 2 years later she developed dystonic
      movements of her right hand. Gliotic changes were seen on magnetic resonance
      imaging in the superficial left parietal lobe. Mechanisms involved in the
      generation of dystonia associated with cortical injury are discussed.

PMID- 15197718
TI  - Voluntary control and a wider clinical spectrum of essential palatal tremor.
AB  - Essential palatal tremor (EPT) may not be a uniform or single entity. We present
      two patients who had some "voluntary control" over EPT, including entrainment. We
      review the English language literature on EPT to describe a wider clinical
      spectrum of this syndrome.

PMID- 15197719
TI  - Status dissociatus after surgery for tegmental ponto-mesencephalic cavernoma: a
      state-dependent disorder of motor control during sleep.
AB  - After surgery for a tegmental ponto-mesencephalic cavernoma, a patient developed
      sleep-related excessive fragmentary myoclonus, diffuse myoclonic jerks, simple
      quasipurposeful movements of the limbs, and rapid eye movement (REM) sleep
      behaviour disorder as motor features of status dissociatus, a condition in which
      elements of one state of being (wake, NREM and REM sleep) pathologically intrude
      into another.

PMID- 15197720
TI  - Deep brain stimulation in myoclonus-dystonia syndrome.
AB  - Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder characterized
      by bilateral myoclonic jerks. An 8-year-old boy presenting with early onset,
      medically intractable, MDS due to a mutation in the epsilon-sarcoglycan gene
      (SGCE) underwent chronic bilateral stimulation of the globus pallidus internus,
      which eliminates both myoclonus and dystonia. We conclude that deep brain
      stimulation can be an effective and safe treatment for MDS.

PMID- 15197721
TI  - Late-onset presentation of pyruvate dehydrogenase deficiency.
AB  - Two brothers presented in their mid-forties with movement disorders including
      atypical parkinsonism, choreiform movements, stereotypies, ataxia and dysarthria.
      Both brothers showed putaminal lucencies on imaging and, in the proband, a
      deficiency of the pyruvate dehydrogenase complex (PDHC) was found on skin
      fibroblast assay.

PMID- 15197722
TI  - Restless legs syndrome due to interferon-alpha.
AB  - A patient developed restless legs symptoms paralleling the course of interferon
      alpha (IFN alpha) therapy for chronic hepatitis C. Symptoms began during a course
      of IFN alpha, resolved with its suspension, and recurred on rechallenge. Restless
      legs syndrome may thus be an adverse effect of IFN alpha treatment.

PMID- 15197723
TI  - Reversible orofacial dyskinesia after ofloxacin treatment.
AB  - We report on a patient who developed orofacial dyskinesia 3 days after starting
      ofloxacin treatment. The association of orofacial dyskinesia with other
      fluoroquinolone antibiotics has been reported rarely, chiefly in the elderly with
      impaired renal or hepatic function or in overdosed patients. It has been ascribed
      to interference with GABA-ergic neurotransmission.

PMID- 15197724
TI  - Cabergoline versus levodopa monotherapy.

PMID- 15197726
TI  - Re: Cabergoline versus levodopa monotherapy: a decision analysis.

PMID- 15197727
TI  - A simple and efficient procedure for transformation of Schizosaccharomyces pombe.
AB  - We describe a simple and efficient procedure for transformation of
      Schizosaccharomyces pombe. Sz. pombe colonies grown on minimal (SD) plates were
      directly removed and suspended in a 100 microl reaction mixture containing 70
      microl PLATE solution (50% polyethylene glycol-4000, 100 mM lithium acetate, 10
      mM Tris-HCl, pH 4.9, and 1 mM EDTA), 10 microl plasmid DNA (1 microg), 10 microl
      carrier DNA (100 microg) and 10 microl sterile distilled water. After incubation
      at 30 degrees C for 1 h followed by heat shock treatment at 42 degrees C for 15
      min, the reaction mixture was spread on a selection plate. The transformation
      efficiency obtained using the procedure was approximately 8000
      transformants/microg DNA. The method is simple and time-saving, making it
      especially useful for a large number of samples and when a high transformation
      efficiency is not required.

PMID- 15197728
TI  - Chromosome translocation induced by the insertion of the URA blaster into the
      major repeat sequence (MRS) in Candida albicans.
AB  - Electrophoretic karyotype studies have shown that clinical isolates of Candida
      albicans have extensive chromosome length polymorphisms. Chromosome translocation
      is one of the causes of karyotypic variation. Chromosome translocation events
      have been shown to occur very frequently at or near the major repeat sequence
      (MRS) on chromosomes. The MRS consists of the repeated sequences RB2, RPS and
      HOK, and the repeated sequences are considered to be the template for
      recombination. To investigate which element of the MRS is important for
      chromosome translocation, we constructed three cassettes, each containing a URA
      blaster and sequences homologous to one of the repeats, for insertion into the
      MRS region on the chromosomes. The ura3 strain STN22u2, which shows a stable,
      standard karyotype, was transformed with each construct. Insertion events with
      each cassette occurred at almost all chromosomes. Insertion into the RB2 repeat,
      but not into the RPS repeat, was accompanied by chromosome translocation in some
      transformants: chromosome translocations between chromosomes R and 7 and
      chromosomes 1 and 7 were found, as well as deletions of 7A and 7C from chromosome
      7. We conclude that the insertion at the RB2 region may initiate chromosome
      translocation in C. albicans.

PMID- 15197729
TI  - Transcriptional profiling of extracellular amino acid sensing in Saccharomyces
      cerevisiae and the role of Stp1p and Stp2p.
AB  - S. cerevisiae responds to the presence of amino acids in the environment through
      the membrane-bound complex SPS, by altering transcription of several genes.
      Global transcription analysis shows that 46 genes are induced by L-citrulline.
      Under the given conditions there appears to be only one pathway for induction
      with L-citrulline, and this pathway is completely dependent on the SPS component,
      Ssy1p, and either of the transcription factors, Stp1p and Stp2p. Besides the
      effects on amino acid permease genes, an ssy1 and an stp1 stp2 mutant exhibit a
      number of other transcriptional phenotypes, such as increased expression of genes
      subject to nitrogen catabolite repression and genes involved in stress response.
      A group of genes involved in the upper part of the glycolysis, including those
      encoding hexose transporters Hxt4p, Hxt5p, Hxt6p, Hxt7p, hexokinase Hxk1p,
      glyceraldehyde 3-phosphate dehydrogenase Tdh1p and glucokinase (Glk1p), shows
      increased transcription levels in either or both of the mutants. Also, most of
      the structural genes involved in trehalose and glycogen synthesis and a few genes
      in the glyoxylate cycle and the pentose phosphate pathway are derepressed in the
      ssy1 and stp1 stp2 strains.

PMID- 15197730
TI  - Analysis of a Ty1-less variant of Saccharomyces paradoxus: the gain and loss of
      Ty1 elements.
AB  - Because Ty elements transpose through an RNA intermediate, element accumulation
      through retrotransposition must be regulated or offset by element loss to avoid
      uncontrolled genome expansion. Here we examine the fate of Ty sequences in
      Saccharomyces strain 337, a strain that is reported to lack Ty1 and Ty2 elements,
      but contains remnant solo long terminal repeats (LTRs). Although strain 337 was
      initially classified as Saccharomyces cerevisiae, our work indicates that this
      strain is more closely related to S. paradoxus. Several degenerate Ty1 and Ty2
      LTRs were mapped to the same insertion sites as full-length Ty1 and Ty2 elements
      in S. cerevisiae, suggesting that this strain lost Ty elements by LTR-LTR
      recombination. Southern analysis indicates that strain 337 also lacks Ty4 and Ty5
      elements. We estimated the rates of element gain and loss in this strain by
      introducing a single transposition-competent Ty1 element. The results indicate
      that Ty1 retrotransposition occurs at a much higher rate than elimination,
      suggesting that copy-number-dependent co-factors or environmental conditions
      contribute to the loss of Ty elements in this genome.

PMID- 15197731
TI  - Optimized cassettes for fluorescent protein tagging in Saccharomyces cerevisiae.
AB  - Green fluorescent protein (GFP) has become an increasingly popular protein tag
      for determining protein localization and abundance. With the availability of GFP
      variants with altered fluorescence spectra, as well as GFP homologues from other
      organisms, multi-colour fluorescence with protein tags is now possible, as is
      measuring protein interactions using fluorescence resonance energy transfer
      (FRET). We have created a set of yeast tagging vectors containing codon-optimized
      variants of GFP, CFP (cyan), YFP (yellow), and Sapphire (a UV-excitable GFP).
      These codon-optimized tags are twice as detectable as unoptimized tags. We have
      also created a tagging vector containing the monomeric DsRed construct tdimer2,
      which is up to 15-fold more detectable than tags currently in use. These tags
      significantly improve the detection limits for live-cell fluorescence imaging in
      yeast, and provide sufficient distinguishable fluorophores for four-colour
      imaging.

PMID- 15197732
TI  - Characterization of the effectiveness of hexose transporters for transporting
      xylose during glucose and xylose co-fermentation by a recombinant Saccharomyces
      yeast.
AB  - We have developed recombinant Saccharomyces yeasts that can effectively co
      ferment glucose and xylose to ethanol. However, these yeasts still ferment
      glucose more efficiently than xylose. The transport of xylose could be one of the
      steps limiting the fermentation of xylose. In this study, we characterized the
      changes in the expression pattern of the hexose transporter and related genes
      during co-fermentation of glucose and xylose using one of our recombinant yeasts,
      Saccharomyces cerevisiae 424A(LNH-ST). The transcription of the hexose
      transporter and related genes was strongly influenced by the presence of glucose;
      HXT1, HXT2 and HXT3 were greatly activated by glucose and HXT5, HXT7 and AGT1
      were significantly repressed by glucose. We also examined the effectiveness of
      individual transporters encoded by HXT1, HXT2, HXT4, HXT5, HXT7 and GAL2 genes
      for transporting xylose during co-fermentation of glucose and xylose in a
      Saccharomyces hxt degrees mutant (RE700A). We compared these hxt degrees
      derivatives to RE700A wild-type strain (S. cerevisiae MC996A) where all of them
      contained the same xylose metabolizing genes present in our xylose-fermenting
      yeasts such as 424A(LNH-ST). Our results showed that recombinant RE700A
      containing the cloned HXT7 or HXT5 were substantially more effective for
      fermenting xylose to ethanol. In addition, we found that the efficiency of
      transporters for intracellular accumulation of xylose was as follows: HXT7 > HXT5
      > GAL2 > WT > HXT1 > HXT4 > > > RE700A. Furthermore, we provided evidence that
      the Saccharomyces galactose transporter system could be a highly effective xylose
      transporter. The information reported here should be of great importance for
      improving the Saccharomyces yeast transport of xylose.

PMID- 15197733
TI  - Role of the 14-3-3 protein in carbon metabolism of the pathogenic yeast Candida
      albicans.
AB  - We previously demonstrated that the pathogenic yeast Candida albicans effectively
      adapts to utilize L-sorbose (Sou+) by a novel mechanism based on the loss of one
      copy of chromosome 5, probably due to the reduction of copy number of a negative
      regulator located on this chromosome. We report here another negative regulator
      of L-sorbose utilization, an orthologue of the Saccharomyces cerevisiae BMH1
      gene, which encodes the evolutionarily conserved protein 14-3-3. This essential
      gene is located on chromosome 1, does not have paralogues, and is supposedly a
      component of the regulatory network. Experiments involving disruption of one
      allele of BMH1 and overexpression of BMH1 revealed that BMH1 represses the
      transcription of SOU1, which is responsible for the utilization of L-sorbose.
      Although the exact mechanism of the interaction between BMH1 and SOU1 is not
      known, it is clear that the control is based on the ratio of gene copy number,
      and that BMH1 does not control the loss of chromosome 5, the major mechanism
      producing Sou+ mutants. We propose that function of BMH1 as a negative regulator
      of SOU1 contributes to a general cellular homeostasis. This is a first report on
      the role of the C. albicans essential gene BMH1 as a negative regulator of the
      utilization of secondary carbon source in yeast, which further substantiates the
      involvement of 14-3-3 proteins in diverse functions.

PMID- 15197734
TI  - Demonstration of multiple novel glycoforms of the stem cell survival factor CCg.
AB  - We have investigated the presence of different glycoforms of cystatin C secreted
      by adult hippocampal rat-derived stem/progenitor cells (AHPs) into conditioned
      medium. A glycosylated form of cystatin C (CCg) has been identified previously in
      conditioned medium from AHPs as an autocrine/paracrine cofactor. Fibroblast
      growth factor-2 (FGF2) requires cooperation with CCg to support AHP survival at
      low density in vitro. The purpose of the present study was to investigate further
      if cystatin C consists of one glycoform or if several different glycoforms are
      secreted by AHPs in vitro. The presence of the glycoforms was studied using
      enzymatic deglycosylation in conjunction with gel electrophoresis and Western
      blotting. The glycoforms of cystatin C were isolated with a combination of gel
      electrophoresis and electroelution, yielding the intact glycoforms in liquid
      phase before enzymatic deglycosylation. Our results revealed several novel
      glycoforms, in contrast to previous publication. The results suggest that N- and
      O-linked glycans with sialic acid are attached to cystatin C. Furthermore, we
      have demonstrated that all glycoforms are present in conditioned medium after
      only 48 hr of culturing and that all nestin-positive AHPs are immunopositive
      against cystatin C. These findings suggest secretion of the glycoforms by
      cultured AHPs.

PMID- 15197735
TI  - Dysmyelination and reduced myelin basic protein gene expression by
      oligodendrocytes of SHP-1-deficient mice.
AB  - We have shown previously that myelin-forming oligodendrocytes express the protein
      tyrosine phosphatase SHP-1 and that myelin formation was decreased in SHP-1
      deficient motheaten mice compared to that in normal littermates. These studies
      suggested a potential importance for SHP-1 in oligodendrocyte and myelin
      development. To address further this possibility, we analyzed myelin formation by
      microscopy and myelin basic protein (MBP) gene expression in motheaten mice at
      ages when myelination occurs in the developing central nervous system (CNS).
      Furthermore, we correlate these findings with MBP gene expression in
      oligodendrocytes grown in vitro. We have found that CNS myelination was
      significantly reduced in SHP-1-deficient mice relative to their normal
      littermates at multiple times during the active period of myelination. Under
      electron microscopy, greater numbers of axons in spinal cords of motheaten mice
      were either unmyelinated or had thinner myelin sheathes compared to those in
      matched areas of normal littermates. Accordingly, MBP protein and mRNA levels
      were reduced in SHP-1-deficient mice compared to that in the CNS of normal
      littermates. In vitro, O1(+) oligodendrocytes from motheaten mice expressed much
      less MBP than O1(+) oligodendrocytes of normal littermates indicating an
      alteration in oligodendrocyte differentiation. The latter correlated with reduced
      MBP mRNA relative to cerebroside galactosyl transferase (CGT) gene mRNA in SHP-1
      deficient oligodendrocytes in purified cultures. We propose that SHP-1 is a
      critical regulator of developmental signals leading to terminal differentiation
      and myelin sheath formation by oligodendrocytes.

PMID- 15197736
TI  - Calcium signal-mediated expression of the vasoactive intestinal polypeptide gene
      and its small contribution to activity-dependent survival of mouse cerebellar
      granule cells.
AB  - We have demonstrated previously in primary cultures of mouse cerebellar granule
      cells (CGCs) that endogenously synthesized pituitary adenylate cyclase-activating
      polypeptide (PACAP) contributes at least in part to the activity-dependent
      survival of CGCs (Tabuchi et al. [2001] Neurosci. Res. 39:85-93). In this study,
      we have demonstrated that expression of vasoactive intestinal polypeptide (VIP),
      a member of the same VIP/secretin/glucagon family as PACAP, was activated
      markedly by Ca(2+) influx through L-type voltage-dependent Ca(2+) channels (L
      VDCCs), which could be induced under the depolarizing condition induced by high
      concentration of potassium (K(+)) in the medium. The activation of VIP mRNA
      expression, different from that of PACAP, was dependent partly on de novo protein
      synthesis. On the other hand, mRNA expression of secretin and PACAP/VIP receptors
      (PAC(1), VPAC(1), and VPAC(2)) was not activated by the Ca(2+) influx; rather,
      PAC(1) mRNA expression was reduced. Exogenously added VIP prevented apoptosis of
      CGCs under nondepolarizing conditions, the effect of which was mediated
      specifically through the VPAC(1) receptor. Furthermore, the survival of CGCs
      under depolarizing conditions could be mediated partly through VPAC(1), the
      contribution of which was much less than that of PAC(1). These findings indicate
      that PACAP and VIP genes are coordinately activated by the Ca(2+) signals in
      CGCs, but the contribution of VIP to the activity-dependent survival of CGCs is
      quite small.

PMID- 15197737
TI  - Metallothionein prevents neurodegeneration and central nervous system cell death
      after treatment with gliotoxin 6-aminonicotinamide.
AB  - Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the
      glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces
      significant inflammation and neurodegeneration but also affords neuroprotection
      against acute traumatic brain injury. This neuroprotection is likely mediated by
      the IL-6-induced protective factors metallothioneins-I and -II (MT-I+II). Here we
      evaluate the neuroprotective roles of IL-6 vs. MT-I+II during 6-aminonicotinamide
      (6-AN)-induced neurotoxicity, by using GFAP-IL6 mice and transgenic mice
      overexpressing MT-I (TgMT) as well as GFAP-IL6 mice crossed with TgMT mice (GFAP
      IL6 x TgMT). 6-AN caused acute damage of brainstem gray matter areas identified
      by necrosis of astrocytes, followed by inflammatory responses. After 6-AN-induced
      toxicity, secondary damage was observed, consisting of oxidative stress,
      neurodegeneration, and apoptotic cell death. We hereby show that the primary
      injury caused by 6-AN was comparable in wild-type and GFAP-IL6 mice, but MT-I
      overexpression could significantly protect the brain tissue. As expected, GFAP
      IL6 mice showed increased CNS inflammation with more gliosis, macrophages, and
      lymphocytes, including increased cytokine expression, relative to the other mice.
      However, GFAP-IL6 mice showed reduced oxidative stress (judged from
      nitrotyrosine, malondialdehyde, and 8-oxoguanine stainings), neurodegeneration
      (accumulation of neurofibrillary tangles), and apoptosis (determined from TUNEL
      and caspase-3). MT-I+II expression was significantly higher in GFAP-IL6 mice than
      in wild types, which may contribute to the IL-6-induced neuroprotection. In
      support of this, overexpression of MT-I in GFAP-IL6 x TgMT as well as TgMT mice
      protected the brainstem tissue significantly from 6-AN-induced toxicity and
      secondary brain tissue damage. Overall, the results demonstrate that brain MT
      I+II proteins are fundamental neuroprotective factors, which in the future may
      become therapeutic agents.

PMID- 15197738
TI  - Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons.
AB  - Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide,
      is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD).
      Specific mutations in AbetaPP have been found in patients inheriting familial AD
      (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in
      vitro, but the molecular mechanism of cytotoxicity has not yet been clarified
      completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP
      mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus
      mediated gene transfer system. Expression of V642I-AbetaPP protein induced
      degeneration of the primary neurons. This cytotoxicity was blocked by pertussis
      toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was
      suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl
      ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine
      oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced
      cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c
      Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase
      (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced
      cytotoxicity was not suppressed by two secretase inhibitors, suggesting that
      Abeta does not play a major role in this cytotoxicity. Two neuroprotective
      factors, insulin-like growth factor I (IGF-I) and Humanin, protected these
      primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin
      6 and -11 also attenuated this cytotoxicity. This study demonstrated that the
      signaling pathway activated by mutated AbetaPP in the primary neurons is the same
      as that by the other artificial insults such as antibody binding to AbetaPP and
      the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of
      neurotrophic factors and cytokines in AD therapy is also indicated.

PMID- 15197739
TI  - Regulation of gene expression associated with acute experimental autoimmune
      encephalomyelitis by Lovastatin.
AB  - The attenuation of experimental autoimmune encephalomyelitis (EAE) by Lovastatin
      (LOV) has now been well established. The present study was designed to explore
      the global effect of LOV treatment on expression of immune-related genes in
      lumbar spinal cord (LSC) during acute EAE by using Affymetrix DNA microarrays.
      LOV treatment demonstrated the limited infiltration of inflammatory cells into
      the LSC, and microarray analysis further validated those interpretations by
      demonstrating relatively less alteration in expression of immune response genes
      in LOV-treated EAE rats on peak clinical day and recovery vs. untreated EAE
      counterparts. There was significant change in expression of about 158 immune
      related genes (including 127 genes reported earlier) in LOV-treated vs. untreated
      EAE (>1.5 or <-1.5 fold change; P </=.05), of which 140 genes were suppressed and
      only 18 genes were up-regulated. These altered genes encode for leukocyte
      specific markers and receptors, histocompatibility complex, cytokines/receptors,
      chemokines/receptors, adhesion molecules, components of the complement cascade,
      cellular activation, and transcription factors and signal transduction-related
      molecules. Interestingly, T(H)2 phenotype cytokines such as interleukin-4,
      interleukin-10, and transforming growth factor-beta1 and transcription factors
      such as peroxisome proliferator-activated receptor (PPAR)-gamma were up-regulated
      in LSC by LOV treatment as further revealed by real-time PCR and immunoblotting.
      These findings indicate that PPARs may be mediating the antiinflammatory and
      immunomodulatory effects of LOV. Together, these findings provide new insight
      into the molecular events associated with the protection provided by statins
      during treatment of demyelinating diseases such as multiple sclerosis.

PMID- 15197740
TI  - Molecular mimicry: cross-reactive antibodies from patients with immune-mediated
      neurologic disease inhibit neuronal firing.
AB  - Recent data indicate that molecular mimicry may play a role in the pathogenesis
      of human-T-lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical
      spastic paraparesis (HAM/TSP), an immune-mediated disease of the central nervous
      system (CNS). Specifically, HAM/TSP patients developed antibodies that cross
      react with heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an antigen
      highly expressed in neurons. Antibodies to HTLV-1-tax cross-reacted with hnRNP
      A1, suggesting molecular mimicry between the two proteins. In support of this
      hypothesis, HAM/TSP IgG and antibodies to hnRNP A1 and HTLV-1-tax inhibited
      neuronal firing, suggesting that these antibodies can be pathogenic. We extended
      these observations by carrying out studies on over 20 different neurons. We also
      tested IgG isolated from six different HAM/TSP patients and two HTLV-1
      seronegative controls and added experiments that control for antibody isotype,
      antibody target, and neuron viability. In these studies, IgG was infused into the
      extracellular space during whole-cell current clamp recordings of neurons. Our
      results confirm that in contrast to normal IgG, IgG from all HAM/TSP patients
      completely inhibited neuronal firing. Affinity-purified antibodies specific for
      hnRNP A1 and a monoclonal antibody to HTLV-1-tax (which reacted with hnRNP A1 and
      whose epitope overlaps the human immunodominant epitope of tax) also inhibited
      neuronal firing. Monoclonal antibodies to neurofilament did not change neuronal
      firing. These data indicate that antibodies to neurons can be pathogenic, that
      biologic activity can be affected by a cross-reactive epitope between HTLV-1-tax
      and hnRNP A1, and that molecular mimicry may play a role in the pathogenesis of
      HAM/TSP.

PMID- 15197741
TI  - Homocysteine increases the production of asymmetric dimethylarginine in cultured
      neurons.
AB  - Increased circulating concentrations of homocysteine may be a risk factor for
      Alzheimer's disease and cognitive dysfunction in normal aging. Asymmetric
      dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide
      synthase (NOS). ADMA is metabolized in neurons by the enzyme dimethylarginine
      dimethylaminohydrolase (DDAH). Nitric oxide plays an important role in synaptic
      events involved in learning and memory. We determined the effect of L
      homocysteine on ADMA accumulation and nitric oxide production in cultured rat
      neuronal granule cells. The incubation of neuronal granule cells with L
      homocysteine for 24 hr caused a dose-dependent accumulation of ADMA and a dose
      dependent decrease in nitric oxide production. The addition of the sulfhydryl
      antioxidant pyrrolidine dithiocarbamate (PDTC) attenuated the effect of
      homocysteine on ADMA accumulation and nitric oxide production. DDAH activity had
      a decreasing dose-response relationship with increasing L-homocysteine
      concentrations. The addition of PDTC caused a dose-dependent increase in DDAH
      activity. The addition of the N-methyl-D-aspartate receptor antagonists (+/-)-2
      amino-5-phosphopentanoic acid and 7-chlorokynurenate had no effect on the
      inhibition of DDAH by homocysteine. It is concluded that L-homocysteine inhibits
      DDAH activity, thereby causing ADMA accumulation and decreasing nitric oxide
      production in cultured neurons. The protective effect of PDTC suggests that L
      homocysteine inactivates DDAH in neurons by reacting with the cysteine residue in
      its active site. The preservation of DDAH activity and the reduction of ADMA
      accumulation in neurons may be a new strategy for the treatment of Alzheimer's
      disease and cognitive impairment in normal aging.

PMID- 15197742
TI  - Messenger RNA and protein expression analysis of voltage-gated potassium channels
      in the brain of Abeta(25-35)-treated rats.
AB  - Potassium channel dysfunction has been implicated in Alzheimer's disease. In the
      present study, the expression of voltage-gated potassium channel (Kv) subunits in
      rat brain was measured after a single intracerebroventricular injection of beta
      amyloid peptide 25-35 (Abeta(25-35)). After injection of Abeta, the spatial
      memory of rats was significantly impaired in the Morris water maze. Expression of
      five main Kv channel subunits (Kv1.5, Kv2.1, Kv1.4, Kv4.2, and Kv4.3) in mRNA
      level was assessed by using reverse transcription-polymerase chain reaction (RT
      PCR). The mRNA levels of Kv2.1 and Kv1.4 were increased by 72% and 67%,
      respectively, in hippocampus, and Kv4.2 mRNA was increased by 58% in cortex. No
      other significant mRNA expression changes were found in Abeta-treated rats. The
      protein expression of Kv2.1, Kv1.4, and Kv4.2 was detected by using Western
      blotting. Kv2.1 and Kv1.4 protein levels were increased by 48% and 50%,
      respectively, in hippocampus of Abeta-treated rats, and Kv4.2 protein was
      increased by 42% in cerebral cortex. This study indicates that the expression up
      regulation of Kv1.4, Kv2.1, and Kv4.2 in Abeta-induced cognitive impairment might
      play an important role in the pathogenesis of Alzheimer's disease.

PMID- 15197743
TI  - Adenosine A2A receptor blockade differentially influences excitotoxic mechanisms
      at pre- and postsynaptic sites in the rat striatum.
AB  - Adenosine A(2A) receptor antagonists are being regarded as potential
      neuroprotective drugs, although the mechanisms underlying their effects need to
      be better studied. The aim of this work was to investigate further the mechanism
      of the neuroprotective action of A(2A) receptor antagonists in models of pre- and
      postsynaptic excitotoxicity. In microdialysis studies, the intrastriatal
      perfusion of the A(2A) receptor antagonist ZM 241385 (5 and 50 nM) significantly
      reduced, in an inversely dose-dependent way, the raise in glutamate outflow
      induced by 5 mM quinolinic acid (QA). In rat corticostriatal slices, ZM 241385
      (30-100 nM) significantly reduced 4-aminopyridine (4-AP)-induced paired-pulse
      inhibition (PPI; an index of neurotransmitter release), whereas it worsened the
      depression of field potential amplitude elicited by N-methyl-D-aspartate (NMDA;
      12.5 and 50 microM). The A(2A) antagonist SCH 58261 (30 nM) mimicked the effects
      of ZM 241385, whereas the A(2A) agonist CGS 21680 (100 nM) showed a protective
      influence toward 50 microM NMDA. In rat striatal neurons, 50 nM ZM 241385 did not
      affect the increase in [Ca(2+)](i) or the release of lactate dehydrogenase (LDH)
      induced by 100 and 300 microM NMDA, respectively. The ability of ZM 241385 to
      prevent QA-induced glutamate outflow and 4-AP-induced effects confirms that A(2A)
      receptor antagonists have inhibitory effects on neurotransmitter release, whereas
      the results obtained toward NMDA-induced effects suggest that A(2A) receptor
      blockade does not reduce, or even amplifies, excitotoxic mechanisms due to direct
      NMDA receptor stimulation. This indicates that the neuroprotective potential of
      A(2A) antagonists may be evident mainly in models of neurodegeneration in which
      presynaptic mechanisms play a major role.

PMID- 15197744
TI  - Effects of NF-kappaB oligonucleotide "decoys" on gene expression in P7 rat
      hippocampus after hypoxia/ischemia.
AB  - "Decoy" oligonucleotides can be used as gene-specific nuclear factor (NF-kappaB)
      inhibitors to regulate gene expression. We applied two different decoy
      oligonucleotides that contained the NF-kappaB binding consensus sequences present
      in the immunoglobulin G (IgG)-kappaB and Bcl-x promoter into 7-day-old (P7) rat
      lateral ventricles before hypoxia/ischemia (HI) and compared their effects on
      gene expression in hippocampi to saline-treated, scrambled decoy-treated, or
      untreated hippocampi exposed to HI. Left hippocampi were collected at 12 hr after
      HI. Electrophoretic mobility shift assays (EMSAs) showed that the two decoy
      treatments had different effects on NF-kappaB binding to the IgG-kappaB and Bcl-x
      promoter-specific consensus sequences, respectively. We assessed the decoys'
      effects on gene expression 12 hr after HI using ribonuclease protection assays
      (RPAs) and Affymetrix DNA microarrays. RPAs showed that both decoys significantly
      decreased interleukin (IL)-1alpha mRNA levels but had no impact on IL-1beta, IL
      6, and IL-10 mRNA levels. IgG-kappaB decoys significantly decreased tumor
      necrosis factor (TNF)-alpha and TNF-beta mRNA levels compared to minimal changes
      after treatment with Bcl-x decoys. DNA microarray analyses showed that Bcl-x
      decoy treatment significantly decreased Bcl-x(L) mRNA levels. The decreased Bcl
      x(L) mRNA levels after Bcl-x decoy treatment was confirmed by RPA analysis. DNA
      microarray data also indicated that several other genes were affected by both
      decoys. Our results suggest that different NF-kappaB decoy treatments could
      differentially regulate transcriptional responses to central nervous system
      trauma. Careful design of decoy sequences, however, is essential to acquire
      selective effects on cell death outcome.

PMID- 15197745
TI  - Estrogen treatment induces a novel population of regulatory cells, which
      suppresses experimental autoimmune encephalomyelitis.
AB  - Multiple sclerosis (MS) is a debilitating neurological disease characterized by a
      progressive loss of motor and sensory function, eventually leading to paralysis
      and death. The primary cause of neurological impairment is demyelination of the
      central nervous system (CNS) caused by an inflammatory autoimmune response.
      Previous studies have shown that the severity of MS is reduced during pregnancy,
      suggesting that the increased level of sex hormones may reduce the autoimmune
      response. Recently, we have shown that estrogen treatment confers protection from
      experimental autoimmune encephalomyelitis (EAE), which is an animal model for MS.
      However, the cellular basis of estrogen's action remains unknown. In the current
      study, we demonstrate that estrogen treatment led to the induction of a novel
      subpopulation of regulatory cells in spleen and CNS, which also occurs naturally
      in pregnant mice. These previously uncharacterized cells display a low level
      expression of CD45 (CD45(dim)) and no detectable expression of many cell surface
      markers related to TCR signaling, including CD3 and TCR. However, these cells
      retained expression of VLA-4, an extracellular protein involved in cellular
      migration. Several lines of evidence suggest that these novel cells, defined as
      CD45(dim)VLA-4(+) cells, may play a role in the protective effects of estrogen in
      EAE. Injection of purified CD45(dim)VLA-4(+) cells conferred protection from
      spontaneous EAE (Sp-EAE). In contrast, injection of CD45(high)VLA-4(+) cells
      exacerbated the disease course. CD45(dim)VLA-4(+) cells also suppressed antigen
      specific proliferation of primed lymphocytes in coculture. A better understanding
      of how CD45(dim)VLA-4(+) cells suppress the harmful immune response of EAE may
      help in explaining the induction of immune tolerance during pregnancy and lead to
      novel therapeutic approaches to combat MS and other autoimmune diseases.

PMID- 15197746
TI  - Collagen containing neonatal astrocytes stimulates regrowth of injured fibers and
      promotes modest locomotor recovery after spinal cord injury.
AB  - The use of collagen as a vehicle to transplant neonatal astroglial cells into the
      lesioned spinal cord of the adult rat allows a precise application of these cells
      into the lesion gap and minimizes the migration of the transplanted cells. This
      approach might lead to anatomical and functional recovery. In the present study,
      20 adult female Wistar rats were subjected to a dorsal hemisection at thoracic
      spinal cord levels. Cultured cortical neonatal rat astrocytes were transplanted
      into the lesion with collagen as a vehicle (N = 10). Prior to transplantation,
      the cultured astroglial cells were labelled with fast blue. Control rats received
      collagen implants only (N = 10). During 1 month of survival time, functional
      recovery of all rats was continuously monitored. Histological data showed that
      the prelabelled astroglial cells survived transplantation and were localized
      predominantly in the collagen implant. Virtually no fast blue-labelled GFAP
      positive astroglial cells migrated out of the implant into the adjacent host
      spinal cord. The presence of transplanted neonatal astroglial cells resulted in a
      significant increase in the number of ingrowing neurofilament-positive fibers
      (including anterogradely labeled corticospinal axons) into the implant. Ingrowing
      fibers were closely associated with the transplanted astroglial cells. The
      implantation of neonatal astroglial cells did result in modest temporary
      improvements of locomotor recovery as observed during open-field locomotion
      analysis (BBB subscore) or during crossing of a walkway (catwalk).

PMID- 15197747
TI  - On the neurotoxicity of glutaric, 3-hydroxyglutaric, and trans-glutaconic acids
      in glutaric acidemia type 1.
AB  - Glutaric acidemia type 1 (GA1) is an autosomal recessively inherited deficiency
      of glutaryl-CoA dehydrogenase. Accumulating metabolites, 3-hydroxyglutaric (3-OH
      GA), glutaric (GA), and trans-glutaconic (TG) acids, have been proposed to be
      involved in the development of the striatal degeneration seen in children with
      GA1 via an excitotoxic mechanism. We have studied the extent to which 3-OH-GA,
      GA, and TG are neurotoxic and whether neurotoxicity is caused by an excitotoxic
      mechanism in which 3-OH-GA, GA, or TG overactivates N-methyl-D-aspartate (NMDA)
      receptors. In cultured mouse neocortical neurons, all three compounds were weakly
      neurotoxic, possibly through activation of NMDA receptors. However, further
      studies in the rat cortical wedge preparation and with NMDA receptors expressed
      in Xenopus oocytes could not confirm an interaction of the compounds with NMDA
      receptors. It is concluded that the metabolites 3-OH-GA, GA, and TG are only weak
      neurotoxins and that the neurodegenerative cascade destroying the striatum in
      patients with GA1 involves mainly mechanisms other than excitoxicity.

PMID- 15197748
TI  - Involvement of opioid receptors in the CGRP8-37-induced inhibition of the
      activity of wide-dynamic-range neurons in the spinal dorsal horn of rats.
AB  - The present study was performed to explore the involvement of opioid receptors in
      the calcitonin gene-related peptide 8-37 (CGRP8-37, an antagonist of CGRP
      receptor)-induced inhibition of the activity of wide-dynamic-range (WDR) neurons
      in the spinal dorsal horn of rats. Extracellular recording was performed with a
      multibarrelled glass micropipette, and the chemicals were delivered by micro
      iontophoresis. The discharge frequency of WDR neurons was evoked by subcutaneous
      electrical stimulation applied to the ipsilateral hindpaw. Iontophoretic
      application of CGRP8-37 by an ejection current of 160 nA induced significant
      inhibition of the discharge frequency of WDR neurons. The inhibitory effect of
      CGRP8-37 on the activity of WDR neurons was attenuated by later iontophoretic
      application of the opioid antagonist naloxone. Furthermore, the effect of CGRP8
      37 was attenuated by either iontophoretic application of the kappa-receptor
      antagonist nor-binaltorphimine (nor-BNI) or the mu-receptor antagonist beta
      funaltrexamine (beta-FNA) but not by the delta-receptor antagonist naltrindole.
      The results indicate that kappa- and mu-opioid receptors on the membrane of WDR
      neurons are involved in the modulation of CGRP8-37-induced antinociception in
      dorsal horn of the spinal cord in rats.

PMID- 15197750
TI  - Microglia and Alzheimer's disease pathogenesis.
AB  - The most visible and, until very recently, the only hypothesis regarding the
      involvement of microglial cells in Alzheimer's disease (AD) pathogenesis is
      centered around the notion that activated microglia are neurotoxin-producing
      immune effector cells actively involved in causing the neurodegeneration that is
      the cause for AD dementia. The concept of detrimental neuroinflammation has
      gained a strong foothold in the AD arena and is being expanded to other
      neurodegenerative diseases. This review takes a comprehensive and critical look
      at the overall evidence supporting the neuroinflammation hypothesis and points
      out some weaknesses. The current work also reviews evidence for an alternative
      theory, the microglial dysfunction hypothesis, which, although eliminating some
      of the shortcomings, does not necessarily negate the amyloid/neuroinflammation
      theory. The microglial dysfunction theory offers a different perspective on the
      identity of activated microglia and their role in AD pathogenesis taking into
      account the most recent insights gained from studying basic microglial biology.

PMID- 15197752
TI  - Mobile phones and children: is precaution warranted?

PMID- 15197754
TI  - Acute exposure to 930 MHz CW electromagnetic radiation in vitro affects reactive
      oxygen species level in rat lymphocytes treated by iron ions.
AB  - The aim of this study was to test the hypothesis that the 930 MHz continuous wave
      (CW) electromagnetic field, which is the carrier of signals emitted by cellular
      phones, affects the reactive oxygen species (ROS) level in living cells. Rat
      lymphocytes were used in the experiments. A portion of the lymphocytes was
      treated with iron ions to induce oxidative processes. Exposures to
      electromagnetic radiation (power density 5 W/m2, theoretical calculated SAR = 1.5
      W/kg) were performed within a GTEM cell. Intracellular ROS were measured by the
      fluorescent probe dichlorofluorescin diacetate (DCF-DA). The results show that
      acute (5 and 15 min) exposure does not affect the number of produced ROS. If,
      however, FeCl2 with final concentration 10 microg/ml was added to the lymphocyte
      suspensions to stimulate ROS production, after both durations of exposure, the
      magnitude of fluorescence (ROS level during the experiment) was significantly
      greater in the exposed lymphocytes. The character of the changes in the number of
      free radicals observed in our experiments was qualitatively compatible with the
      theoretical prediction from the model of electromagnetic radiation effect on
      radical pairs.

PMID- 15197755
TI  - The effect of oscillating low intensity magnetic field on the Na+, K+, Ca++, and
      Mg++ concentrations in the maternal and fetal circulation of the dually perfused
      human placental cotyledon.
AB  - Dual-sided perfusions of the human placental cotyledon in vitro were used to
      study effects of low intensity magnetic fields (MFs) of 2 mT, 50 Hz (E1, 10
      perfusions) and 5 mT, 50 Hz (E2, 10 perfusions). In the control group C (10
      experiments) no field was used. Perfusions lasted 180 min each. Increased release
      of calcium ions from the placental cotyledon was found in the fetal circulation
      during perfusion when the 2 mT, 50 Hz MF was used. No changes in the release of
      sodium and magnesium ions were observed compared to the control group. The 5 mT,
      50 Hz oscillating MF intensified the release of sodium ions from the perfused
      cotyledon both to the fetal and maternal circulation up to the 150th min of the
      experiment. Increased release of magnesium ions was observed only to the fetal
      circulation between 120 and 180 min and of calcium ions to the fetal circulation
      between 60 and 180 min. No significant differences in K concentrations were found
      between the control and MF exposed cotyledons under conditions of these
      experiments.

PMID- 15197756
TI  - Effects of 2.45 GHz microwave fields on liposomes entrapping glycoenzyme
      ascorbate oxidase: evidence for oligosaccharide side chain involvement.
AB  - Previous observations reported by our group indicate that 2.45 GHz microwave
      fields at specific absorption rate (SAR) of 5.6 W/kg reduce the enzyme activity
      rate of ascorbate oxidase (AO) trapped in liposomes. In this study, we report
      dose-response studies on these AO containing liposomes irradiated at different
      SAR values (1.4, 2.8, 4.2, and 5.6 W/kg). No response was observed for SAR below
      5.6 W/kg. Liposomes entrapping functional AO in its deglycated form (AO-D) were
      also used. In this case, no MW related enzyme activity changes were observed,
      demonstrating a direct involvement of oligosaccharide chains of AO. Furthermore,
      the catalytic properties of both AO and AO-D were not impaired by MW irradiation,
      neither in homogeneous solution nor loaded in liposomes, excluding possible
      changes in the conformation of enzyme as a mechanism. Our results suggest that
      the oligosaccharide chains of AO are critical to elicit the microwave observed
      effects on lipid membrane.

PMID- 15197757
TI  - Effect of a 50 Hz electric field on plasma ACTH, glucose, lactate, and pyruvate
      levels in stressed rats.
AB  - The effect of extremely low frequency electric field (EF) on stress induced
      changes of plasma ACTH, glucose, lactate, and pyruvate levels was examined in
      ovariectomized rats. The rats were exposed to 50 Hz EF (17500 V/m) for 60 min and
      were restrained for the latter half (30 min) of the EF exposure period. The
      restraint stress significantly increased the plasma ACTH and glucose levels (P
      <.05: Student's t test). Restraint induced increase of plasma ACTH and glucose
      levels tended to be suppressed by exposure to the EF. Meanwhile, the EF exposure
      also affected plasma lactate level. Thus, the EF exposure significantly decreases
      plasma lactate levels in the stressed rats (P <.05: Student's t test). Although
      the precise mechanisms in the restraint dependent alteration in plasma ACTH,
      glucose, lactate, and pyruvate levels are not fully understood, our results
      demonstrate that the 50 Hz EF alter both stress responses and energy metabolism
      in stressed rats.

PMID- 15197758
TI  - Effects of high static magnetic field exposure on different DNAs.
AB  - The effects of magnetic fields produced by permanent magnets on different DNA
      sources were investigated in vivo and in vitro. Escherichia coli DNA, plasmid,
      and amplification products of different lengths were used as the magnetic field
      target. The in vivo assays did not reveal any DNA alterations following exposure,
      demonstrating the presence of cell dependent mechanisms, such as the repair
      system and the buffering action of the heat shock proteins DNA K/J (Hsp 70/40).
      The in vitro assays displayed interactions between the magnetic field and DNA,
      revealing principally that magnetic field exposure induces DNA alterations in
      terms of point mutations. We speculate that the magnetic field can perturb DNA
      stability interacting with DNA directly or potentiating the activity of oxidant
      radicals. This genotoxic effect of the magnetic field, however, is minimized in
      living organisms due to the presence of protective cellular responses.

PMID- 15197759
TI  - In vitro study of the electromagnetic interaction between wireless phones and an
      implantable neural stimulator.
AB  - Several clinical and laboratory studies have demonstrated electromagnetic
      interaction between implantable medical devices like pacemakers and cell phones
      being operated in close proximity. Those devices are largely now immune to phone
      interaction or procedures have been established to limit their interaction. The
      use of cell phones near people with implanted neural stimulators has not been
      studied. This research was initiated to investigate electromagnetic interaction
      between current cell phone technology and specific models of Cyberonics neural
      stimulators. Out of 1080 test runs conducted for this study, no interactions were
      observed, and it was concluded that the phone technologies examined in this study
      did not adversely affect the Cyberonics NeuroStar (Model 102) NeuroCybernetic
      Prosthesis (NCP) System. This article provides details on the experimental
      procedure that was used, which can also be used to test other neural stimulators
      and test technologies, and the results obtained.

PMID- 15197760
TI  - Electric discharge plasmas influence attachment of cultured CHO K1 cells.
AB  - Non-thermal plasmas can be generated by electric discharges in gases. These
      plasmas are reactive media, capable of superficial treatment of various
      materials. A novel non-thermal atmospheric plasma source (plasma needle) has been
      developed and tested. Plasma appears at the end of a metal pin as a submillimetre
      glow. We investigate the possibility of applying the plasma needle directly to
      living tissues; the final goal is controlled cell treatment in microsurgery. To
      resolve plasma effects on cells, we study cultured Chinese hamster ovarian cells
      (CHO-K1) as a model system. When these are exposed to the plasma, instantaneous
      detachment of cells from the surface and loss of cell-cell interaction is
      observed. This occurs in the power range 0.1-0.2 W. Cell viability is assessed
      using propidium iodide (PI) and cell tracker green (CTG) fluorescent staining
      utilizing confocal laser scanning microscopy (CLSM). Detached cells remain alive.
      Use of higher doses (plasma power >0.2 W) results in cell necrosis. In all cases,
      plasma-influenced cells are strictly localized in submillimetre areas, while no
      reaction in surrounding cells is observed. Due to its extreme precision, plasma
      treatment may be applicable in refined tissue modification.

PMID- 15197761
TI  - A portable meter for measuring low frequency currents in the human body.
AB  - A portable meter has been developed for measuring low frequency currents that
      flow in the human body. Although the present version of the meter was
      specifically designed to measure 50/60 Hz "contact currents," the principles
      involved can be used with other low frequency body currents. Contact currents
      flow when the human body provides a conductive path between objects in the
      environment with different electrical potentials. The range of currents the meter
      detects is approximately 0.4-800 microA. This provides measurements of currents
      from the threshold of human perception (approximately 500 microA(RMS)) down to
      single microampere levels. The meter has a unique design, which utilizes the
      human subject's body impedance as the sensing element. Some of the advantages of
      this approach are high sensitivity, the ability to measure current flow in the
      majority of the body, and relative insensitivity to the current path connection
      points. Current measurement accuracy varies with the accuracy of the body
      impedance (resistance) measurement and different techniques can be used to obtain
      a desired level of accuracy. Techniques are available to achieve an estimated +/
      20% accuracy.

PMID- 15197762
TI  - Experimental validation of a statistical model for evaluating the past or future
      magnetic field exposures of a population living near power lines.
AB  - This study was designed to provide an experimental validation for a statistical
      model predicting past or future exposures to magnetic fields (MF) from power
      lines. The model estimates exposure, combining the distribution of ambient MF in
      the absence of power lines with the distribution of past or future MF produced by
      power lines. In the study, validation is carried out by comparing exposures
      predicted by the model with the actual measurements obtained from a large-scale
      epidemiological study. The comparison was made for a group of 220 women living
      near a 735 kV power line. Knowing that the individual arithmetic means of MF
      exposures follow a log-normal distribution, the Pearson correlation between the
      log-transformed measured means and the calculated ones was determined and found
      to be 0.77. Predicted values of MF exposures were slightly lower than measured
      values. The calculated geometric mean of the group was 0.33 microT, compared to
      0.38 microT for the measured geometric mean. The present study shows good
      agreement between the measured MF exposure of an individual inside a house near a
      735 kV line and the MF exposure calculated using a statistical model.

PMID- 15197763
TI  - Theoretical evaluation of dielectric absorption of microwave energy at the scale
      of nucleic acids.
AB  - A theoretical model is proposed for the evaluation of dielectric properties of
      the cell nucleus between 0.3 and 3 GHz, as a function of its nucleic acids (NA)
      concentration (CNA). It is based on literature data on dielectric properties of
      DNA solutions and nucleoplasm. In skeletal muscle cells, the specific absorption
      rate (SAR) ratio between nucleoplasm and cytoplasm is found to be larger than one
      for CNA above 30 mg/ml. A nearly linear relationship is found between CNA and
      this nucleocytoplasmic SAR ratio. Considering the nanoscale of the layer of
      condensed counterions and bound water molecules at the NA-solution interface, the
      power absorption per unit volume is evaluated at this precise location. It is
      found to be between one and two orders of magnitude above that in muscle tissue
      as a whole. Under realistic microwave (MW) exposure conditions, however, these
      SAR inhomogeneities do not generate any significant thermal gradient at the scale
      considered here. Nevertheless, the question arises of a possible biological
      relevance of nonnegligible and preferential heat production at the location of
      the cell nucleus and of the NA molecules.

PMID- 15197764
TI  - 0.2 T magnetic field inhibits angiogenesis in chick embryo chorioallantoic
      membrane.
AB  - Inhibition of angiogenesis is a major target in the fight against cancer and
      other diseases. Although the effects of static magnetic fields on cancer
      development and cell growth have been investigated, effects on angiogenesis have
      received no attention so far. In this study we report the effects on angiogenesis
      of exposure to 0.2 T static magnetic field. Angiogenesis was analyzed using the
      chick embryo chorioallantoic membrane assay. Exposure to 0.2 T static magnetic
      field was achieved by placing the eggs for 3 hr in the isocentre of the magnet of
      a sectorial magnetic resonance tomograph used in clinical practice. In sham
      exposed specimens treated with phosphate buffered saline (negative control), no
      significant vascular reaction was detectable; 3 hr exposure to 0.2 T static
      magnetic field did not affect the basal pattern of vascularization or chick
      embryo viability. Prostaglandin E1 and fetal calf serum elicited a strong
      angiogenic response in sham exposed eggs. This angiogenic response was
      significantly inhibited by 3 hr exposure to 0.2 T static magnetic field. These
      findings point to possible use of static magnetic field in inhibiting
      angiogenesis; this effect could be exploited for treatment of cancer and other
      diseases where excessive angiogenesis is involved.

PMID- 15197765
TI  - 4 Hz EMF treated physiological solution depresses Ach-induced neuromembrane
      current.
AB  - The effect of 4 Hz EMF treated physiological solution (PS) on acetylcholine (Ach)
      sensitivity of the snail neuron was studied. The 4 Hz EMF treated normal PS at
      room temperature (23 degrees C) has a depressing effect on Ach induced current,
      while in cold medium (12 degrees C) this effect disappeared. EMF treated, ouabain
      containing, K-free PS elevates the Ach-induced current at room temperature. It is
      suggested that the metabotropic effect of EMF treated PS is due to the activation
      of cGMP-dependent Na:Ca exchange, leading to the decrease of the number of
      functional active receptors in the membrane, through Na-K pump-induced cell
      shrinkage, and to increase the receptors affinity to Ach, as the result of
      decrease of intracellular Ca concentration.

PMID- 15197766
TI  - Influence of 50 Hz frequency sinusoidal magnetic field on the blood-brain barrier
      permeability of diabetic rats.
AB  - The combined effects of diabetes and a 50 Hz, 5 mT RMS flux density sinusoidal
      magnetic field for 8 h a day, for 21 consecutive days on the permeation of Evans
      blue dye through the blood-brain barrier were studied in male Wistar albino rats.
      Our results suggest that magnetic field has no effect on the blood-brain barrier
      permeability in normoglycemic animals, but that diabetic rats are vulnerable to
      magnetic fields.

PMID- 15197767
TI  - Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide
      identified from a phage display library.
AB  - Although the VEGF-Flk-1-pathway has been known as the major driving force of
      angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles
      during the neovascularization under pathological conditions including tumor,
      atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides,
      we screened a phage display 12-mer-peptide library with recombinant Flt-1
      protein. Seven candidate peptides were identified that specifically bound to VEGF
      receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding
      to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited
      angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the
      growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice.
      Histological analyses showed that necrosis of the implanted tumor was markedly
      enhanced following treatment with DHFR-F56. In the severe combined
      immunodeficiency disease (SCID) mouse model for studying metastasis of the human
      breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited
      tumor growth and lung metastases. Taken together, our results have demonstrated
      that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic
      and antimetastatic effects by specifically interfering with the interaction
      between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical
      potential in tumor therapy.

PMID- 15197768
TI  - Signaling pathways required for matrix metalloproteinase-9 induction by
      betacellulin in head-and-neck squamous carcinoma cells.
AB  - The mechanisms by which c-erbB-dependent signaling contribute to the invasive
      potential of HNSCC remain to be fully elucidated. We have previously shown that c
      erbB autocrine and/or paracrine stimulation upregulates MMP-9 but has no effect
      on the related gelatinase, MMP-2. BTC, a major c-erbB ligand, has the ability to
      efficiently activate all c-erbB receptors and to bind directly to EGFR and c-erbB
      4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in
      terms of MMP induction relative to other c-erbB ligands so far tested. In the
      present study, we explored the contribution of major downstream events triggered
      by BTC/c-erbB receptor signaling to the regulation of MMP-9 and in vitro
      invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN-006 and Detroit-562,
      BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors
      whereas both endogenous MMP-9 and BTC-stimulated MMP-9 were predominantly
      mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with
      differing kinetics but not p38 kinase. The BTC-dependent activation of JNK and
      PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK
      1/ERK pathway occurred via all 4 c-erbB receptors, although again predominantly
      via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by
      LY294002 or wortmannin) led to marked reduction of both basal and BTC-induced MMP
      9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38
      kinase with SB203580 produced no such effects. A specific inhibitor of NF-kappa
      B, BAY 11-7085, also blocked the stimulatory effect of BTC. No remarkable
      inhibition of MMP-9 and invasion was observed on targeting other cellular
      activities, such as PKA, PKC and PLC-gamma. Taken together, our data show that
      BTC induces MMP-9 production and invasion primarily through activation of EGFR,
      MAPK and PI3K/Akt in HNSCC cells.

PMID- 15197769
TI  - Immunodetection and quantification of vascular endothelial growth factor receptor
      3 in human malignant tumor tissues.
AB  - Vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligands, vascular
      endothelial growth factor-C (VEGF-C) and -D (VEGF-D), are the major molecules
      involved in developmental and pathological lymphangiogenesis. Here we describe
      for the first time the development of a specific indirect enzyme-linked
      immunosorbent assay (ELISA) for the quantification of VEGFR-3 in different human
      cell and tissue lysates. A combination of the goat polyclonal anti-VEGFR-3
      antibody and the mouse monoclonal anti-human VEGFR-3 antibody was used. The assay
      was highly sensitive and reproducible with a detection range of 0.2-25 ng/ml. The
      assay was specific for VEGFR-3, with no cross-reactivity to VEGFR-1 or VEGFR-2.
      Complex formation with VEGF-C and VEGF-D had no effect on the sensitivity of the
      assay. The VEGFR-3 concentration in the lysates of cultured human dermal
      microvascular endothelial cells was 14-fold higher than in the lysates from human
      umbilical vein endothelial cells. In human kidney, breast, colon, gastric and
      lung cancer tissues the protein levels of VEGFR-3 were in the range of 0.6-16.7
      ng/mg protein. Importantly, the level of VEGFR-3 protein detected in the ELISA
      correlated significantly with the number of VEGFR-3 positive vessels observed in
      histochemical sections, suggesting that the ELISA assay may be a reliable
      surrogate of measuring VEGFR-3-positive vessel density. The protein levels of
      VEGFR-3 in 27 renal cell carcinoma samples had a significant correlation with the
      levels of VEGF-C (p<0.001), or biological active, free VEGF-A (p<0.0001), but not
      with VEGFR-1 or total VEGF-A. This assay provides a useful tool for the
      investigations of the expression levels of VEGFR-3 in physiological and
      pathological processes, particular in cancer and in lymphangiogenesis-related
      disease.

PMID- 15197770
TI  - Suppression of cyclooxygenase-2 overexpression by 15S-hydroxyeicosatrienoic acid
      in androgen-dependent prostatic adenocarcinoma cells.
AB  - Emerging reports now implicate alterations of arachidonic acid (AA) metabolism
      with prostate carcinogenesis. To test this hypothesis, androgen-primed benign
      hyperplastic (BHC) and malignant tumorigenic (MTC) cells derived from the Lobund
      Wistar rat model of autochthonous prostate adenocarcinoma were incubated with
      (14)C-AA. Our data using MTCs revealed enhanced dual metabolism of (14)C-AA via
      COX to generate increased PGE(2) and via 5-lipoxygenase (LOX) to generate
      increased 5S-HETE in tumorigenic cells. Western blot of MTCs revealed
      upregulation of COX-2 expression. This paralleled the increased biosynthesis of
      PGE(2). Since some polyunsaturated fatty acids have been reported to modulate AA
      metabolism and tumorigenesis, we primed the cells with either gamma-linolenic
      acid (GLA) or its in vivo metabolite, 15S-HETrE, prior to incubation with AA. Our
      data revealed suppression of COX-2 expression/PGE(2) biosynthesis. In parallel,
      priming cells with 15S-HETrE resulted in greater suppression of COX-2
      expression/PGE(2) biosynthesis. These findings suggest that 15S-HETrE could
      function in vivo after dietary intake of GLA to suppress DHT-enhanced prostatic
      COX-2 expression/PGE(2) biosynthesis and, thus, alleviate tumor growth and
      progression.

PMID- 15197771
TI  - Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer
      cells through downregulation of IKK activity.
AB  - CHS 828, a pyridyl cyanoguanidine, has been shown to exert a significant
      antitumor effect in preclinical tests in vitro and in vivo, and CHS 828 is in
      phase I/II clinical trials. We have investigated the effect of CHS 828 on the
      nuclear factor-kappa B (NF-kappa B) because of its well-known role in the control
      of cell division and apoptosis. CHS 828 is able to inhibit the lipopolysaccharide
      (LPS)-induced nuclear localization as well as the transcriptional activity of NF
      kappa B in human THP-1 leukemia cells. Moreover, CHS 828 has also been shown to
      inhibit the LPS-induced degradation of the I kappa B alpha and I kappa B beta in
      THP-1 cells, leading us to identify the I kappa B kinase complex as a molecular
      target of CHS 828. The IKK activity is inhibited by CHS 828 with an IC(50) of 8
      nM. The inhibition of the IKK activity by different CHS 828 analogues correlates
      well with the inhibition of NYH small cell lung cancer cell proliferation in
      vitro and in vivo. Moreover, the inhibition of NF-kappa B transcriptional
      activity in different cancer cell lines by CHS 828 correlates to some extent with
      the reduction by CHS 828 of the size of the corresponding xenografts. Activation
      of NF-kappa B has been shown to induce expression of antiapoptotic proteins, and
      cancer cells have been shown to have high levels of constitutively active NF
      kappa B. Therefore, we hypothesize that the anticancer activity of CHS 828 is due
      to inhibition of the IKK activity by which the antiapoptotic protection of NF
      kappa B is removed, leading to the promotion of apoptosis.

PMID- 15197772
TI  - Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and
      neck squamous cell carcinoma.
AB  - Loss of heterozygosity (LOH) in chromosomal regions that harbor tumor suppressor
      genes from tumor tissue may lead to decreased survival time in cancer patients
      with squamous cell carcinoma of the head and neck (HNSCC). We studied 8 regions
      frequently lost in HNSCC in 150 patients having a primary diagnosis of HNSCC.
      Tumor and normal tissue DNA were genotyped for microsatellite repeat markers in 8
      unlinked chromosomal regions. The association between LOH and death from HNSCC
      was investigated, weighted by number of informative markers per region and
      adjusted for age at diagnosis, self-reported race, tumor stage and current
      smoking status. LOH at 3 chromosomal regions were independently associated with
      reduced survival. A greater risk for cancer mortality was observed for LOH at
      chromosomal regions 3p24.3-p14.3 (p = 0.02), 8p21.3-p11.21 (p = 0.02) and 9p24.2
      p21.2 (p = 0.03). In these regions, LOH at one or more markers was observed in
      66.9%, 43.3% and 60.6% of patients, respectively. Survival times were
      significantly shorter for those with LOH at marker NEFL on 8p21.2 (relative risk
      = 6.15; p = 0.0002) and at D9S126 on 9p21.2 (relative risk = 5.96; p = 0.0003).
      Our results indicate that LOH at several chromosomal sites may offer additional
      independent prognostic information beyond traditional indicators such as tumor
      stage and age.

PMID- 15197773
TI  - Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma.
AB  - Fibroblast growth factor receptors (FGFRs) have been implicated in various forms
      of human hyperproliferative disorders such as cancers of the cervix and bladder.
      We investigated the expression pattern of FGFR4 and the clinical significance of
      the recently identified Gly/Arg polymorphism (388) in head and neck squamous cell
      carcinomas (HNSCCs) of the oral cavity and the oropharynx. Sections from 104
      paraffin-embedded tumors were analyzed by a restriction fragment length
      polymorphism-based method to determine the FGFR4 genotypes. Protein expression
      was investigated immunohistochemically and graded into a low, intermediate, or
      high degree of staining. FGFR4 expression was scored as high in 17, as
      intermediate in 59 and as low in 28 cases. The FGFR4 Arg388 allele was found in
      59 tumors, 46 of them having heterozygous and 13 homozygous genotypes. High
      expression of the FGFR4 Arg388 allele was significantly associated with reduced
      overall survival (p = 0.032) and with an advanced tumor stage (p = 0.023),
      whereas expression of the FGFR4 Gly388 had no impact on disease progression. Our
      findings indicate that high expression of FGFR4 in connection with the Arg388
      allele is associated with poor clinical outcome and support the significance of
      FGFR4 as a diagnostic marker and a target for therapeutic intervention in human
      HNSCC.

PMID- 15197774
TI  - PIG7/LITAF gene mutation and overexpression of its gene product in extramammary
      Paget's disease.
AB  - To identify cancer-related genes that are involved in the carcinogenesis of
      extramammary Paget's disease (EMPD), we compared mRNA expression profiles of EMPD
      lesions and corresponding normal skin using cDNA array. Sixty-eight genes were
      highly expressed (>5-fold) in EMPD lesions compared to normal skin, and 40 genes
      were expressed less than one-fifth in EMPD lesions. Among them, PIG7/LITAF mRNA
      was overexpressed in 3 of 4 EMPD cases. PIG7/LITAF transcription is induced by
      p53 expression and has been implicated in the p53-induced apoptotic pathway.
      Since expression of p53 mRNA and p53 protein was not high in any of the 3 EMPD
      samples compared to the intact skin of the same patient, we analyzed PIG7/LITAF
      cDNA mutations among 12 EMPD samples (including the former 4) by PCR-SSCP. Three
      samples showed shifted bands (2 had point mutations leading to amino acid
      substitutions and 1 had a silent mutation). One sample with amino acid
      substitution overexpressed PIG7/LITAF mRNA in cDNA array analysis and RT-PCR.
      PIG7/LITAF mRNA expression is confined to tumor cells in in situ mRNA
      hybridization analysis. These results indicate that genetic disorder and
      overexpression of PIG7/LITAF may be involved in EMPD carcinogenesis.

PMID- 15197775
TI  - Hypermethylation of tumor suppressor genes (p16INK4A, p14ARF and APC) in
      adenocarcinomas of the upper gastrointestinal tract.
AB  - Aberrant promoter methylation is an important mechanism for gene silencing. In
      the present study, 50 Barrett's esophagus-associated esophageal adenocarcinomas
      (ADC), 50 cardiac ADC and 50 gastric ADC were investigated by means of
      methylation-specific real-time PCR for hypermethylation in the tumor suppressor
      genes APC, p16(INk4A) and p14(ARF). Additionally, expression of p16(INK4A)
      protein in the carcinomas was assessed using immunohistochemistry. Marked
      differences in hypermethylation were found between esophageal, cardiac and
      gastric ADC in the APC gene (78% vs. 32% vs. 84%) and in the p16(INK4A) gene (54%
      vs. 36% vs. 10%). Hypermethylation of p14(ARF) was absent from esophageal ADC and
      present infrequently in cardiac (2%) and gastric ADC (10%). Complete loss of
      p16(INK4A) protein expression was detectable in 45% of all tumors and was
      significantly associated with hypermethylation of the p16(INK4A) gene (p<0.0001,
      chi(2)-test). Our results suggest that hypermethylation of p16(INK4A) and APC are
      frequent findings in esophageal, cardiac and gastric ADC. Additionally, the data
      point to a tumor specific methylation pattern in upper gastrointestinal ADC.

PMID- 15197776
TI  - Circulation and homing of melanoma-reactive T cells to both cutaneous and
      visceral metastases after vaccination with monocyte-derived dendritic cells.
AB  - Anticancer immune therapies aim at the induction of tumor-specific T cells, which
      ultimately should kill tumor cells. The effector cells should, therefore, not
      only exert cytotoxic activity but also home to and infiltrate the tumor site.
      Hence, monitoring of immune modulating therapies should not be restricted to the
      circulating pool of peripheral blood mononuclear cells (PBMC) but also include
      tumor-infiltrating lymphocytes (TIL), as well as the correlation of these
      findings to the clinical course. We report here on the longitudinal immunologic
      workup of a melanoma patient who developed remarkably potent ex vivo detectable
      antimelanoma cytotoxic T-cell (CTL) responses after vaccinations with autologous
      peptide-pulsed dendritic cells. Such potent CTL responses to multiple tumor
      antigens have, to the best of our knowledge, not been described previously in
      melanoma patients, neither spontaneously nor after any therapy. This patient
      first experienced a transient response to therapy but finally succumbed to
      disease progression and died. Progression was associated with the decline of the
      numbers of tumor-reactive T cells in circulation and at skin metastases in
      addition to the loss of MHC class I antigens. The immunologic analysis revealed
      that fully functional tumor-specific T cells were present in the peripheral blood
      of this patient during the phase of a relatively stable disease, and in situ
      tetramer staining demonstrated that these cells were also accumulated at
      cutaneous and visceral tumor sites. Furthermore, comparative clonotype mapping of
      PBMC and TIL depicted an overlapping TCR repertoire usage among these 2
      compartments. Since strong CTL responses as observed in this patient are the goal
      of cancer vaccination but are so far only rarely observed, the thorough analysis
      of patients exhibiting either exceptional clinical and/or immunologic responses
      appears critical to understanding how vaccine therapies work and can be further
      improved.

PMID- 15197777
TI  - Inhibition of spontaneous development of liver tumors by inoculation with
      dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice.
AB  - We attempted to prevent spontaneous development of liver tumors by s.c.
      inoculation with DCs loaded with syngeneic HCC cells in C3H/HeNCrj mice. A new
      cell line, MIH-2, was established from an HCC that had developed spontaneously in
      a C3H/HeNCrj mouse. Bone marrow-derived DCs were loaded with irradiated MIH-2
      cells by treatment with PEG. Fluorescence microscopy and flow-cytometric analysis
      showed that about 45% of PEG-treated DCs and MIH-2 cells (DC/MIH-2) were DCs
      loaded with MIH-2 cells. Thirteen-month-old mice received inoculations of DC/MIH
      2 (9 x 10(5)/mouse) 4 times at 6-day intervals and were killed at 16 months of
      age to assess liver tumors. The incidence of liver tumors in these mice was
      significantly lower than that in mice not receiving inoculations (p < 0.05) but
      similar to that in 13-month-old mice (the age at which inoculation started),
      indicating that inoculation inhibited the development of new tumors. Splenocytes
      from inoculated mice, but not those from uninoculated mice, showed cytotoxic
      activity against MIH-2 cells. Cytotoxic activity was not elicited by CD4(+) T
      cells, CD8(+) T cells, or DX5(+) cells isolated from splenocytes but was elicited
      by adherent cells, identified as CD11b(+) macrophages. CD4(+) T cells, but not
      CD8(+) T cells, from inoculated mice produced IFN-gamma by incubation with DC/MIH
      2. Cytotoxicity by splenocytes was attenuated by anti-IFN-gamma antibody.
      Immunization with DCs loaded with syngeneic HCC cells induces CD4(+) T cells that
      produce IFN-gamma by response to antigen of HCC, which would lead to macrophage
      activation to kill liver tumor cells at an early stage.

PMID- 15197778
TI  - Inverse expression of dihydrodiol dehydrogenase and glutathione-S-transferase in
      patients with esophageal squamous cell carcinoma.
AB  - We investigated the significances of the expressions of dihydrodiol dehydrogenase
      (DDH) and glutathione-S-transferase (GST) in patients with esophageal squamous
      cell carcinoma (ESCC). By using immunohistochemistry, we measured expressions of
      DDH, GST, COX-2, nm23-H1, HER-2/neu and mdr-1 in 145 patients with ESCC.
      Expression of DDH was confirmed by immunoblotting and reverse transcription
      polymerase chain reaction. Relation between DDH expression and
      clinicopathological parameters was analyzed by statistical analysis. Difference
      of survivals between different groups was compared by a log rank test. DDH
      overexpression was detected in 66.9% of pathological sections (97/145) and in
      41.6% of metastatic lymph nodes (37/89). The nucleotide sequencing of DNA
      fragments from 16 tumorous specimens showed that the major isoform was DDH2 for
      ESCC. GST expression, however, was only detected weakly in 24 patients (16.6%).
      For patients with ESCC, DDH overexpression was positively correlated with smoking
      habit, tumor stage, number of metastatic lymph nodes, lymphovascular invasion and
      COX-2 expression, and inversely correlated with GST and nm23-H1 expressions, but
      not related to mdr-1 or HER-2/neu expressions. As compared to DDH overexpressed
      group, patients with low DDH expression had significantly lower incidence of
      tumor recurrences and better survival (p = 0.026). Using univariate analysis,
      prognostic factors included tumor stage, number of metastatic lymph nodes, cell
      differentiation, lymphovascular invasion and expressions of DDH and nm23-H1.
      Multivariate analysis showed significant correlation of tumor stage, number of
      metastatic lymph nodes and nm23-H1 expression with patient's survival. In
      conclusion, inverse expressions of DDH and GST may be associated with
      carcinogenesis and disease progression for ESCC patients, but their biological
      function and pathophysiological regulation in tumors require additional studies.

PMID- 15197779
TI  - Topoisomerase-I, thymidylate synthase primary tumour expression and clinical
      efficacy of 5-FU/CPT-11 chemotherapy in advanced colorectal cancer patients.
AB  - While several studies have reported that thymidylate synthase (TS) tumour
      expression can be a reliable predictive marker of clinical response to 5
      Fluorouracil (5-FU) for advanced colorectal cancer patients, only a few studies
      that searched for predictive factors of irinotecan (CPT-11) clinical response are
      available. The aim of the present study has been to verify the predictive value
      of immunohistochemical topoisomerase-I (Topo-I) and TS primary tumour expression
      in a consecutive series of 62 advanced colorectal cancer patients that received a
      first line 5-FU/CPT-11 chemotherapy. TS and Topo-I immunostaining was observed in
      76% and 43% of tumours, respectively, resulting in a significant relationship
      within each tumour (r=0.365, p<0.004). Patients with different TS tumour
      expression showed a similar percentage of Objective Clinical Response, OR (40%
      vs. 28% of OR in low and high TS-expressing tumours, respectively, p=ns); also,
      patients with different Topo-I tumour expression did not show a different
      probability of OR (39% vs. 29% of OR in high and low Topo-I expressing tumours,
      respectively; p=ns). The tumour expression of these 2 biomarkers also did not
      impact on time to progression and overall survival of patients. Furthermore, the
      combined analysis of TS and Topo-I tumour status did not permit to individualize
      subgroups of patients with different probability of OR. With multivariate
      analysis, only patient Performance Status significantly impacted on OS (Hazard
      ratio 4.87; p=0.02) of these patients. We can conclude that high TS tumour
      expression seems not to preclude a clinical activity for 5-FU/CPT-11
      polichemotherapy in advanced colorectal cancer patients; furthermore, clinical
      response and prognosis of colorectal cancer patients treated with 5-FU/CPT-11
      regimen do not differ in tumours with different TS or Topo-I expression.

PMID- 15197780
TI  - Expression of the tyrosine kinase c-kit is an independent prognostic factor in
      patients with small cell lung cancer.
AB  - In a retrospective analysis of 203 patients with small cell lung cancer (SCLC),
      we examined the prognostic value of c-kit expression on survival. Expression of c
      kit was examined immunohistochemically in formalin-fixed, paraffin-embedded
      tissue sections. c-kit was observed in 87.7% of SCLC tumors. Using the Kaplan
      Meier model, we found that lack of c-kit expression was associated with
      significantly shorter survival time compared to the presence of c-kit expression
      (mean survival 151 +/- 27 vs. 358 +/- 49 days, p = 0.0084). Moreover, the
      proportion of c-kit(+) cells within the tumor was also related to survival time.
      Patients with tumors in which >75% of cells stained positive for c-kit had a mean
      overall survival time of 424 (+/-72) compared to 295 (+/-67) days for patients
      with 25-75% c-kit(+) tumor cells. Patients with tumors containing <25% c-kit(+)
      cells had the worst survival, with 164 (+/-24) days (p = 0.0033). Further
      parameters associated with short survival times were low performance status,
      elevated levels of lactate dehydrogenase and higher stage according to the TNM
      classification. Multivariate analysis using the Cox regression model showed that
      the proportion of c-kit(+) cells within the tumor specimen was one of 3
      independent prognostic parameters (p = 0.004) for overall survival next to TNM
      classification (p = 0.001) and performance status (p < 0.001).

PMID- 15197781
TI  - Anthropometry, breast cancer and menopausal status: use of repeated measurements
      over 10 years of follow-up-results of the French E3N women's cohort study.
AB  - The association between weight, BMI and breast cancer was analyzed on 94,805
      women of the E3N cohort according to their menopausal status. Seven hundred
      eighty-six incident invasive premenopausal breast cancers and 1,522 incident
      invasive postmenopausal breast cancers occurred during a mean follow-up of 9.7
      years. Weight and BMI were updated every 24 months and considered as time
      dependent variables. Data were analyzed using multivariate Cox proportional
      hazards models. Trend RRs of premenopausal breast cancer were 0.97 (0.92-1.01)
      for a 5 kg increase in weight and 0.96 (0.91-1.01) for a 2 kg/m(2) increase in
      BMI, adjusted for other known risk factors. Opposite trend RRs were found after
      menopause: 1.05 (1.02-1.08) for weight and 1.06 (1.02-1.09) for BMI,
      respectively, for similar increases. Women with a BMI of over 30 kg/m(2) had a RR
      of premenopausal breast cancer of 0.66 (0.40-1.10) compared to those with a BMI
      of between 18.5 and 25 kg/m(2). Postmenopausal women with a BMI of over 30
      kg/m(2) had a RR of breast cancer of 1.23 (1.00-1.59). The increase in risk of
      postmenopausal breast cancer with increased weight or BMI was similar whatever
      the HRT used, although the point estimates were higher in HRT users. We strongly
      recommend to use anthropometric measurements updated during follow-up to assess
      the effect of weight, BMI on breast cancer risk.

PMID- 15197782
TI  - Differential expression of 9-O-acetylated sialoglycoconjugates on leukemic
      blasts: a potential tool for long-term monitoring of children with acute
      lymphoblastic leukemia.
AB  - Earlier studies have demonstrated overexpression of 9-O-acetylated
      sialoglycoconjugates (9-O-AcSGs) on lymphoblasts, concomitant with high titers of
      anti-9-O-AcSG antibodies in childhood acute lymphoblastic leukemia (ALL). Our aim
      was to evaluate the correlation between expression of different 9-O-AcSGs during
      chemotherapeutic treatment. Accordingly, expression of 9-O-AcSGs on lymphoblasts
      of ALL patients (n = 70) were longitudinally monitored for 6 years (1997-2002),
      using Achatinin-H, a 9-O-acetylated sialic acid (9-O-AcSA) binding lectin with
      preferential affinity for 9-O-AcSGs with terminal 9-O-AcSA alpha 2-->6GalNAc.
      Western blot analysis of patients (n = 30) showed that 3 ALL-specific 9-O-AcSGs
      (90, 120 and 135 kDa) were induced at presentation; all these bands disappeared
      after treatment in patients (n = 22) who had disease-free survival. The 90 kDa
      band persisted in 8 patients who subsequently relapsed with reexpression of the
      120 kDa band. FACS analysis revealed that at presentation (n = 70) 90.1 +/- 5.0%
      cells expressed 9-O-AcSGs, which decreased progressively with chemotherapy,
      remained <5% during clinical remission and reappeared in relapse (80 +/- 10%, n =
      18). Early clearance of 9-O-AcSG(+) cells, during 4-8 weeks of treatment showed a
      good correlation with low risk of relapse. Sensitivity of detection of 9-O
      AcSG(+) cells was 0.1%. Numbers of both high- and low-affinity binding sites were
      maximum at presentation, decreased with treatment and increased again in clinical
      relapse. We propose that close monitoring of 90 and 120 kDa 9-O-AcSGs may serve
      as a reliable index for long-term management of childhood ALL and merits
      therapeutic consideration.

PMID- 15197783
TI  - Against which human papillomavirus types shall we vaccinate and screen? The
      international perspective.
AB  - At least 15 types of HPV have been associated with cervical cancer, but current
      HPV vaccines confer only type-specific immunity. To determine geographic
      variations in the HPV type distribution in cervical cancer, we carried out a
      pooled analysis of data from an international survey of HPV types in cervical
      cancer and from a multicenter case-control study, both co-coordinated by the
      IARC. Study cases were 3,607 women with incident, histologically confirmed
      cervical cancer recruited in 25 countries. HPV DNA detection and typing in
      cervical cells or biopsies were centrally done using PCR assays. Estimates of the
      potential number of cases prevented by HPV type-specific vaccines and changes in
      the validity of different HPV screening cocktails were calculated. HPV DNA was
      detected in 96% of specimens, and 30 different types were detected. The 15 most
      common types were, in descending order of frequency, 16, 18, 45, 31, 33, 52, 58,
      35, 59, 56, 39, 51, 73, 68 and 66. Higher than average proportions of type 16
      were found in northern Africa, of type 18 in south Asia, of type 45 in sub
      Saharan Africa and of type 31 in Central/South America. A vaccine including types
      16 and 18 could potentially prevent 71% of cervical cancers worldwide, but its
      impact with regard to the percentage of cases potentially prevented would be
      higher in Asia and Europe/North America. In contrast, a vaccine containing the 7
      most common HPV types would prevent about 87% of cervical cancers worldwide, with
      little regional variation. The impact of modifying the number of types in the
      screening cocktail tests would be small and probably irrelevant for screening
      programs.

PMID- 15197784
TI  - Risk of esophageal, ovarian, testicular, kidney and bladder cancers and leukemia
      among finnish workers exposed to diesel or gasoline engine exhaust.
AB  - Occupational exposure to diesel exhaust has been classified as probably
      carcinogenic and that to gasoline engine exhaust as possibly carcinogenic to
      humans. Earlier results concerning cancers other than lung cancer are scarce and
      inconsistent, and exposure-response relations have seldom been reported. We
      followed up a cohort of all economically active Finns born between 1906 and 1945
      for 30 million person-years during 1971-1995. Incident cases of esophageal cancer
      (n = 2,198), ovarian cancer (5,082), testicular cancer (387), kidney cancer
      (7,366), bladder cancer (8,110) and leukemia (4,562) were identified through a
      record linkage with the Finnish Cancer Registry. Occupations from the population
      census in 1970 were converted to exposures to diesel and gasoline engine exhausts
      with a job-exposure matrix (FINJEM). Cumulative exposure (CE) was calculated as
      product of prevalence, level and estimated duration of exposure. The relative
      risk (RR) of cancer for exposure categories in relation to the unexposed group
      was calculated using the Poisson regression model and adjusted for confounders.
      An increasing RR for ovarian cancer was observed with the increasing CE of diesel
      exhaust (p for trend = 0.006). The RR in the highest CE category was 3.69 (95% CI
      = 1.38-9.86). For gasoline engine exhaust, the RR was significantly increased
      only in the middle CE category (1.70; 95% CI = 1.11-2.62). Slight elevations of
      RR for bladder and kidney cancers were found at the lowest exposure level of
      engine exhausts, largely attributable to drivers. No effect of the exposures was
      observed for the other cancers. This study suggests an exposure-response relation
      between diesel exhaust and ovarian cancer.

PMID- 15197785
TI  - Insulin-like growth factor (IGF)-I and IGF-binding protein 3 and the risk of
      premenopausal breast cancer: a meta-analysis of literature.
AB  - Biologic evidence suggests substantial effect of insulin-like growth factor (IGF)
      I in mammary cell carcinogenesis. However, controversy remains regarding the
      association between circulating IGF-I levels and the risk of premenopausal breast
      cancer in epidemiologic studies. In addition, the association of IGF-binding
      protein (IGFBP)-3, which binds with and modifies the effect of IGF-I, is unclear.
      To clarify these associations, we performed a meta-analysis of all the published
      studies. A systematic review of literature was conducted. Eligible study designs
      were nested case-control and population-based case-control studies that give
      estimates for menopausal women. The studies published between January 1990 and
      March 2003 were obtained from Medline. We obtained 7 studies, consisting of 688
      premenopausal incident breast cancer cases and 1,366 controls, for our final
      evaluation. Summary statistics were odds ratios (ORs) comparing the highest and
      the lowest levels of IGF-I and IGFBP-3 adjusted for confounders other than IGF-I
      or IGFBP-3. There was neither evidence of heterogeneity between studies nor
      evidence of publication bias. The confounders considered and the contrast used
      for the ORs were the major source of variation. The subjects with higher
      circulating levels of IGF-I had marginally significant increased risk of breast
      cancer with an OR of 1.74 (95% CI = 0.97-3.13; p = 0.06). No significant
      difference was observed for IGFBP-3 group (OR = 1.60; 95% CI = 0.84-3.02; p =
      0.15). In conclusion, we found a marginally significant association between
      circulating IGF-I levels and the risk of premenopausal breast cancer.

PMID- 15197786
TI  - Non-Hodgkin's lymphoma among asthmatics exposed to pesticides.
AB  - We conducted a pooled analysis of population-based case-control studies in Iowa,
      Minnesota and Nebraska to investigate whether asthma modifies risk of non
      Hodgkin's lymphoma (NHL) associated with pesticide exposures. Cases (n = 872)
      diagnosed with NHL from 1980 to 1986 and frequency-matched controls (n = 2,381)
      randomly selected from the same geographic areas as the cases were included.
      Information on use of pesticides and history of asthma was based on interviews.
      Unconditional logistic regression was used to calculate ORs, adjusted for age,
      state and vital status. Of all subjects, 177 (45 cases, 132 controls) reported
      having been told by their doctor that they had asthma. Subjects with an asthma
      history had a nonsignificantly lower risk of NHL than nonasthmatics (OR = 0.6,
      95% CI 0.3-1.4), and there was no main effect of pesticide exposure (OR = 1.0,
      95% CI 0.8-1.2). However, asthmatics tended to have larger ORs associated with
      exposure to pesticides than nonasthmatics. The OR among asthmatics was 1.8 (95%
      CI 1.1-3.2) for ever-use of crop insecticides, 2.7 (95% CI 1.0-7.2) for
      chlordane, 2.4 (95% CI 1.0-5.7) for lindane and 3.7 (95% CI 1.3-10.9) for
      fonofos. Among nonasthmatics, ORs were 1.1 (0.9-1.3), 1.5 (1.1-2.2), 1.3 (0.97
      1.8) and 1.6 (1.0-2.4), respectively. Although there is limited power for
      assessing interaction, our results suggest that the risk of NHL among asthmatics
      with pesticide exposure may be higher than among nonasthmatics with pesticide
      exposure.

PMID- 15197787
TI  - Evaluation of a selectively oncolytic adenovirus for local and systemic treatment
      of cervical cancer.
AB  - Treatment options for disseminated cervical cancer remain inadequate. Here, we
      investigated a strategy featuring Ad5-Delta 24 RGD, an oncolytic adenovirus
      replication-competent selectively in cells defective in the Rb-p16 pathway, such
      as most cervical cancer cells. The viral fiber contains an alpha(v)beta(3) and
      alpha(v)beta(5) integrin-binding RGD-4C motif, allowing coxsackie-adenovirus
      receptor-independent infection. These integrins have been reported to be
      frequently upregulated in cervical cancer. Oncolysis of cervical cancer cells was
      similar to a wild-type control in vitro. In an animal model of cervical cancer,
      the therapeutic efficacy of Ad5-Delta 24 RGD could be demonstrated for both
      intratumoral and intravenous application routes. Biodistribution was determined
      following intravenous administration to mice. Further preclinical safety data
      were obtained by demonstrating lack of replication of the agent in human
      peripheral blood mononuclear cells. These results suggest that Ad5-Delta 24 RGD
      could be useful for local or systemic treatment of cervical cancer in patients
      with disease resistant to currently available modalities.

PMID- 15197788
TI  - Algorithms based on prostate-specific antigen (PSA), free PSA, digital rectal
      examination and prostate volume reduce false-positive PSA results in prostate
      cancer screening.
AB  - Our objective was to determine whether multivariate algorithms based on serum
      total PSA, the free proportion of PSA, age, digital rectal examination and
      prostate volume can reduce the rate of false-positive PSA results in prostate
      cancer screening more effectively than the proportion of free PSA alone at 95%
      sensitivity. A total of 1,775 consecutive 55- to 67-year-old men with a serum PSA
      of 4-10 microg/l in the European Randomized Study of Screening for Prostate
      Cancer were included. To predict the presence of cancer, multivariate algorithms
      were constructed using logistic regression (LR) and a multilayer perceptron
      neural network with Bayesian regularization (BR-MLP). A prospective setting was
      simulated by dividing the data set chronologically into one set for training and
      validation (67%, n = 1,183) and one test set (33%, n = 592). The diagnostic
      models were calibrated using the training set to obtain 95% sensitivity. When
      applied to the test set, the LR model, the BR-MLP model and the proportion of
      free PSA reached 92%, 87% and 94% sensitivity and reduced 29%, 36% and 22% of the
      false-positive PSA results, respectively. At a fixed sensitivity of 95% in the
      test set, the LR model eliminated more false-positive PSA results (22%) than the
      proportion of free PSA alone (17%) (p < 0.001), whereas the BR-MLP model did not
      (19%) (p = 0.178). The area under the ROC curve was larger for the LR model
      (0.764, p = 0.030) and the BR-MLP model (0.760, p = 0.049) than for the
      proportion of free PSA (0.718). A multivariate algorithm can be used to reduce
      unnecessary prostate biopsies in screening more effectively than the proportion
      of free PSA alone, but the algorithms will require updating when clinical
      practice develops with time.

PMID- 15197790
TI  - Vascular-targeting therapies for treatment of malignant disease.
AB  - BACKGROUND: Tumor endothelium represents a valuable target for cancer therapy.
      The vasculature plays a critical role in the survival and continued growth of
      solid tumor masses; in addition, the inherent differences between tumor blood
      vessels and blood vessels associated with normal tissue make the tumor
      vasculature a unique target on which to base the design of novel therapeutics,
      which may allow highly selective treatment of malignant disease. Therapeutic
      strategies that target and disrupt the already formed vessel networks of growing
      tumors are actively being pursued. The goal of these approaches is to induce a
      rapid and catastrophic shutdown of the vascular function of the tumor so that
      blood flow is arrested and tumor cell death due to the resulting oxygen and
      nutrient deprivation and buildup of waste products occurs. METHODS: Biologic
      approaches and small-molecule drugs that can be used to damage tumor vasculature
      have been identified. Physiologic, histologic/morphologic, and
      immunohistochemical assessments have demonstrated that profound disruption of the
      tumor vessel network can be observed minutes to hours after treatment. The small
      molecule agents that have made the greatest advances in the clinical setting (5,6
      dimethylxanthenone-4-acetic acid [DMXAA], combretastatin A4 disodium phosphate
      [CA4DP], and ZD6126) are the focus of the current review. RESULTS: Loss of patent
      blood vessels, decreased tumor blood flow, extensive necrosis, and secondary
      ischemia-induced tumor cell death have been well documented in a variety of
      preclinical tumor models treated with agents such as DMXAA, CA4DP, and ZD6126.
      The use of such agents in conjunction with irradiation and other chemotherapeutic
      agents has led to improved treatment outcomes. CONCLUSIONS: The targeting of
      tumors' supportive blood vessel networks could lead to improvements in cancer
      cure rates. It is likely that this approach will prove to be most efficacious
      when used in concert with conventional treatment strategies.

PMID- 15197791
TI  - Measuring social impacts of breast carcinoma treatment in Chinese women.
AB  - BACKGROUND: There is no existing instrument that is suitable for measuring the
      social impact of breast carcinoma (BC) and its treatment among women of Southern
      Chinese descent. In the current study, the authors assessed the validity of the
      Chinese Social Adjustment Scale, which was designed to address the need for such
      an instrument. METHODS: Five dimensions of social concern were identified in a
      previous study of Cantonese-speaking Chinese women with BC; these dimensions were
      family and other relationships, intimacy, private self-image, and public self
      image. The authors designed 40 items to address perceptions of change in these
      areas. These items were administered to a group of 226 women who had received
      treatment for BC, and factor analysis subsequently was performed to determine
      construct characteristics. The resulting draft instrument then was administered,
      along with other measures for the assessment of basic psychometric properties, to
      a second group of 367 women who recently had undergone surgery for BC. RESULTS:
      Factor analysis optimally identified 5 factors (corresponding to 33 items): 1)
      Relationships with Family (10 items, accounting for 22% of variance); 2) Self
      Image (7 items, accounting for 15% of variance); 3) Relationships with Friends (7
      items, accounting for 8% of variance); 4) Social Enjoyment (4 items, accounting
      for 6% of variance); and 5) Attractiveness and Sexuality (5 items, accounting for
      5% of variance). Subscales were reliable (alpha = 0.63-0.93) and exhibited
      convergent validity in positive correlations with related measures and divergent
      validity in appropriate inverse or nonsignificant correlations with other
      measures. Criterion validity was good, and sensitivity was acceptable. Patterns
      of change on the scales were consistent with reports in the literature. Self
      administration resulted in improved sensitivity. CONCLUSIONS: The 33-item Chinese
      Social Adjustment Scale validly, reliably, and sensitively measures the social
      impact of BC on Cantonese-speaking Hong Kong Chinese women. Further development
      of the scale to increase its sensitivity is underway.

PMID- 15197792
TI  - Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma
      of the breast, April 26-28, 2003, Philadelphia, Pennsylvania.

PMID- 15197793
TI  - Racial differences in the expression of cell cycle-regulatory proteins in breast
      carcinoma.
AB  - BACKGROUND: African-American (AA) women are more likely to be diagnosed with an
      advanced stage of breast carcinoma than are white women. After adjustment for
      disease stage, many studies indicate that tumors in AA women are more likely than
      tumors in white women are to exhibit a high level of cell proliferation and
      features of poor prognosis. The purpose of the current study was to compare tumor
      characteristics and cell cycle alterations in AA women and white women that might
      affect the aggressiveness of breast carcinoma. METHODS: The study included 124 AA
      and 397 white women, ages 20-54 years. These women were enrolled in a case
      control study in Atlanta, Georgia, between 1990 and 1992. Breast tumor specimens
      obtained from these women were centrally reviewed for histologic characteristics
      and evaluated for expression of estrogen and progesterone receptors (ER/PR), c
      ErbB-2, Ki-67, p53, cyclin E, cyclin D1, p27, p16, pRb, and p21 by
      immunohistochemistry. Logistic regression models were used to assess the age- and
      stage-adjusted associations of various tumor characteristics with race. RESULTS:
      The odds of a breast carcinoma diagnosis at a younger age and at a later stage
      were higher for AA women than for white women. After adjustment for disease stage
      and age at diagnosis, AA women also were found to have increased odds of having a
      higher-grade tumor, a higher mitotic index, marked tumor necrosis, ductal
      histology, loss of ER and PR, overexpression of cyclin E, p16, and p53 and low
      expression of cyclin D1 at diagnosis. CONCLUSIONS: The observed differences
      between tumor specimens obtained from AA women and tumor specimens obtained from
      white women, independent of stage and age at diagnosis, indicated that race may
      be a determinant, or a surrogate for other determinants, of aggressive breast
      carcinoma and specific cell cycle defects.

PMID- 15197794
TI  - alphaB-crystallin as a marker of lymph node involvement in breast carcinoma.
AB  - BACKGROUND: It was found previously that alphaB-crystallin, a small heat-shock
      protein, was overexpressed in a metastatic variant of the GI101A human breast
      carcinoma cell line. The objective of the current study was to determine whether
      the expression of alphaB-crystallin in primary breast carcinomas was associated
      with lymph node metastasis and survival. METHODS: Expression of alphaB-crystallin
      was measured in human breast carcinoma cell lines by immunoblotting. Expression
      in human breast carcinomas was evaluated by immunohistochemical staining of
      tissue microarrays that contained samples from 317 patients with lymph node
      negative breast carcinoma and 291 patients with lymph node-positive breast
      carcinoma. RESULTS: It was found that alphaB-crystallin was expressed
      constitutively in certain breast carcinoma cell lines, including those that were
      capable of metastasizing in immunodeficient mice. Expression of alphaB-crystallin
      in human tissue samples was associated strongly with lymph node involvement (P <
      0.0001; chi-square test) and, to a lesser degree, with high nuclear grade (P =
      0.05). Increased intensity of expression was correlated with shorter survival (P
      = 0.0091; log-rank test). Multivariate analysis indicated that alphaB-crystallin
      expression was not independent of lymph node status as a predictor of survival.
      CONCLUSIONS: The data obtained in the current study revealed a strong association
      between high expression levels of alphaB-crystallin in primary breast carcinoma
      specimens and lymph node involvement. Further studies will be needed to
      prospectively elucidate the role of this novel tumor marker as a clinical
      prognostic marker in local and locally advanced breast carcinoma as well as its
      potential status as a new target for therapy in patients with breast carcinoma.

PMID- 15197795
TI  - Prospective evaluation of a novel approach for the use of a quantitative
      galactose oxidase-Schiff reaction in ductal fluid samples from women with breast
      carcinoma.
AB  - BACKGROUND: The galactose oxidase-Schiff reaction (GOS) yields positive findings
      in a number of malignant solid tumors. The goals of the current study were to
      develop a novel technique for quantifying GOS reactivity in nipple aspirate fluid
      (NAF) samples from women with invasive breast carcinoma and to assess the
      clinical utility of the technique in this setting. METHODS: Patients with biopsy
      proven unilateral invasive breast carcinoma were eligible for study entry. Before
      definitive surgery, NAF samples were obtained from healthy breast tissue and
      malignant breast tissue from 23 women with breast carcinoma. Under blind
      conditions with respect to clinical data, 10 microL NAF samples were applied to a
      glass fiber membrane and incubated with 100 microL galactose oxidase and 1 mL
      Schiff reagent. The stain was developed and the color reaction quantitated by
      measuring hue (shade) and chroma (intensity) using a spectrophotometer. RESULTS:
      GOS reactivity was quantitated using two color parameters, hue and chroma.
      Because chroma varies with concentration, this measurement was adjusted for the
      concentration of NAF in each sample. After adjustment for NAF concentration,
      chroma was found to be statistically significantly different in the affected
      breast tissue sample and the healthy contralateral internal control sample (P =
      0.001). CONCLUSIONS: A quantitative measure of GOS reactivity based on
      spectrophotometric measurement of intensity of color has been developed and was
      found to be significantly different in the affected breast compared with the
      unaffected breast in the current population of patients with breast carcinoma.
      The preliminary results support further exploration of this novel quantitative
      test in patients with breast carcinoma.

PMID- 15197796
TI  - Sentinel lymph node biopsy using periareolar injection of radiocolloid for
      patients with neoadjuvant chemotherapy-treated breast carcinoma.
AB  - BACKGROUND: The feasibility and accuracy of sentinel lymph node (SLN) biopsy
      after neoadjuvant chemotherapy (NAC) for patients with breast carcinoma have been
      investigated primarily for the situation in which the radiocolloid imaging agent
      is injected peritumorally. No such study has involved periareolar injection of
      radiocolloid, although the usefulness of this injection technique has been
      demonstrated in patients with early-stage breast carcinoma who have not been
      treated with NAC. The objective of the current study was to determine the
      feasibility and accuracy of SLN biopsy using periareolar injection of
      radiocolloid for patients with breast carcinoma who were treated with NAC.
      METHODS: Forty-seven patients with AJCC Stage II or III breast carcinoma who were
      treated with NAC were enrolled in the study. All patients underwent SLN biopsy,
      which involved a combination of periareolar injection of radiocolloid (technetium
      99m tin colloid) and peritumoral injection of isosulfan blue dye, followed by
      backup axillary lymph node dissection. SLN metastases were examined by
      hematoxylin and eosin staining and immunohistochemical analysis using an
      anticytokeratin antibody. RESULTS: An SLN was identified successfully in 44
      patients (94%). Twenty-nine patients (66%) had positive SLNs. Fifteen patients
      had negative SLNs, and 4 patients had positive non-SLNs. Thus, the false-negative
      rate was 12.1% (4 of 33 patients). The false-negative rate tended to be higher,
      although not statistically significantly so, among patients who had clinically
      positive axillary lymph nodes before and/or after NAC (15.8%; 3 of 19 patients)
      compared with patients who had clinically negative axillary lymph nodes both
      before and after NAC (7.1%; 1 of 14 patients). CONCLUSIONS: SLN biopsy using
      periareolar injection of radiocolloid is feasible after NAC. In patients with
      clinically negative axillary lymph nodes both before and after NAC, SLN biopsy
      was capable of predicting axillary lymph node status with an accuracy comparable
      to the accuracy associated with SLN biopsy for patients with early-stage
      carcinoma who have not been treated with NAC.

PMID- 15197798
TI  - Does pT2b prostate carcinoma exist? Critical appraisal of the 2002 TNM
      classification of prostate carcinoma.
AB  - BACKGROUND: Clinicopathologic staging of prostate adenocarcinoma provides a
      method for assessing the extent of tumor and predicting patient prognosis. The
      American Joint Committee on Cancer (AJCC) TNM staging system has undergone recent
      revisions for T2 prostate tumors. T2 tumors currently are subclassified as T2a
      (less than one-half of one lobe involvement), T2b (greater than one-half of one
      lobe involvement), and T2c (bilateral involvement). Despite general acceptance of
      the system, controversy and uncertainty still exist with regard to the
      application of the TNM staging system, particularly the use of the T2 staging
      subclassification. METHODS: The study population was comprised of 369 patients
      with prostate carcinoma who were treated with radical retropubic prostatectomy.
      Radical prostatectomy specimens were evaluated histologically by complete
      embedding and whole-mount processing. Tumor specimens were staged initially using
      the 1998 AJCC TNM system and then reevaluated according to the 2002 TNM staging
      guidelines. RESULTS: The weights of the prostate specimens ranged from 14-149 g
      (median, 38 g). Prostate tumor specimens were multifocal in 312 patients (85%).
      The majority of the specimens were classified pathologically as T2 (n = 276
      [75%]). Using the 2002 TNM staging criteria, 54 of the tumor specimens (15%) were
      classified as pT2a, 222 (60%) were pT2c, 75 (20%) were pT3a, and 18 (5%) were
      pT3b. No pathologic T2b tumor specimens were identified. CONCLUSIONS: Taking into
      consideration the average weight of the prostate specimens (38 g), as well as the
      predominance of tumor multifocality, it would be unusual to identify tumors
      involving greater than one-half of 1 lobe (approximately an 8-cm(3) tumor)
      without involving the other lobe. The authors question the existence of a true
      pT2b tumor.

PMID- 15197797
TI  - Clonality of lobular carcinoma in situ and synchronous invasive lobular
      carcinoma.
AB  - BACKGROUND: Lobular carcinoma in situ (LCIS) of the breast is considered a marker
      for an increased risk of carcinoma in both breasts. However, the frequent
      association of LCIS with invasive lobular carcinoma (ILC) suggests a precursor
      product relation. The possible genomic relation between synchronous LCIS and ILC
      was analyzed using the technique of array-based comparative genomic hybridization
      (CGH). METHODS: Twenty-four samples from the University of California-San
      Francisco pathology archives that contained synchronous LCIS and ILC were
      identified. Array CGH was performed using random primer-amplified microdissected
      DNA. Samples were hybridized onto bacterial artificial chromosome arrays composed
      of approximately 2400 clones. Patterns of alterations within synchronous LCIS and
      ILC were compared. RESULTS: A substantial proportion of the genome was altered in
      samples of both LCIS and ILC. The most frequent alterations were gain of 1q and
      loss of 16q, both of which usually occurred as whole-arm changes. Smaller regions
      of gain and loss were seen on other chromosome arms. Fourteen samples of LCIS
      were related more to their paired samples of ILC than to any other ILC, as
      demonstrated by a weighted similarity score. CONCLUSIONS: LCIS and ILC are
      neoplastic lesions that demonstrate a range of genomic alterations. In the
      current study, the genetic relation between synchronous LCIS and ILC suggested
      clonality in a majority of the paired specimens. These data were consistent with
      a progression pathway from LCIS to ILC. The authors conclude that LCIS, which is
      known to be a marker for an environment that is permissive of neoplasia, may
      itself represent a precursor to invasive carcinoma.

PMID- 15197799
TI  - Pathologic T1 clear cell renal cell carcinoma: insulin-like growth factor-I
      receptor expression and disease-specific survival.
AB  - BACKGROUND: A proportion of patients diagnosed with pathologic T1 (pT1) clear
      cell renal cell carcinoma (CC-RCC) will experience disease progression and death
      after surgery, whereas the majority remain disease free. The authors conducted a
      case-cohort investigation to examine the association of insulin-like growth
      factor I receptor (IGF-IR) expression and disease-specific survival in patients
      who underwent surgery for pT1 CC-RCC. METHODS: Eligible patients included those
      diagnosed with solitary, nonfamilial pT1 CC-RCC who underwent radical nephrectomy
      at the Mayo Clinic-Rochester between 1970 and 2000 (n = 886 patients). Among this
      group, 136 patients died of CC-RCC (cases). Archived tumor blocks were not
      available for 62 patients, leaving a final study group of 74 cases. Stratified,
      random sampling was used to select a cohort of at least 3 year-matched controls
      (no CC-RCC death) for each case (n = 263 patients). Detection of IGF-IR was
      performed using a commercially available monoclonal antibody. Cox proportional
      hazards models were fit to assess the association between IGF-IR expression and
      disease-specific survival. RESULTS: After adjustment for age, the risk of death
      from CC-RCC was greater for patients who had tumors that stained positive for IGF
      IR compared with patients who had tumors that showed no IGF-IR expression (hazard
      ratio [HR], 1.5; 95% confidence interval, [95% CI], 0.9-2.4). In a stratified
      analysis, the risk was stronger among patients who had high-grade tumors (HR,
      2.2; 95% CI, 1.1-4.3) compared with patients who had low-grade tumors (HR, 0.7;
      95% CI, 0.3-1.5). Multivariate adjustment for tumor size and histologic tumor
      necrosis attenuated the association among all patients (HR, 1.3; 95% CI, 0.8-2.1)
      but strengthened the association among patients with high-grade tumors (HR, 2.7;
      95% CI, 1.3-5.6). CONCLUSIONS: The current data suggest that IGF-IR expression is
      associated with poor survival in patients who are diagnosed with early-stage CC
      RCC, especially among those with high-grade disease.

PMID- 15197800
TI  - Fludarabine and mitoxantrone for patients with chronic lymphocytic leukemia.
AB  - BACKGROUND: The objective of the current study was to assess the efficacy of
      combination therapy with fludarabine and mitoxantrone in patients with B-cell
      chronic lymphocytic leukemia (CLL). METHODS: Eighty-eight patients were treated
      with fludarabine 30 mg/m(2) intravenously daily for 3 days and mitoxantrone 10
      mg/m(2) on Day 1 (FN). Patients were divided into four groups based on expected
      response to single-agent fludarabine. These four groups included previously
      untreated patients, patients who previously were treated with alkylating agents,
      patients who were successfully treated with alkylating agents and fludarabine but
      who developed recurrent disease, and patients whose disease was refractory to
      fludarabine with or without alkylating agents. RESULTS: The overall response rate
      was 66%. The response rates were 83% in previously untreated patients, 87% in
      patients previously treated with alkylating agents, 50% in patients whose disease
      was not refractory to fludarabine at the start of therapy, and 25% in patients
      whose disease was refractory to fludarabine. The complete remission (CR) rate was
      20% for previously untreated patients, which was not significantly different from
      the CR rate for a group of historical control patients who were treated with
      single-agent fludarabine. The median follow-up was 8 years for surviving
      patients. The median progression free survival was 24 months for all patients and
      34 months for previously untreated patients. The median overall survival was 40
      months, and the median survival of previously untreated patients was 88 months.
      The most common toxicities were myelosuppression and infection. Eleven patients
      (12.5%) developed a second malignancy after a median of 62 months. CONCLUSIONS:
      The FN regimen did not have a significant advantage over fludarabine alone in the
      treatment of patients with CLL.

PMID- 15197801
TI  - Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced
      neutropenia in patients with chronic-phase chronic myelogenous leukemia.
AB  - BACKGROUND: Imatinib mesylate administration has become standard treatment for
      patients with chronic myelogenous leukemia (CML). Although the safety profile of
      imatinib is favorable, Grade > or = 3 neutropenia (according to the National
      Cancer Institute Common Toxicity Criteria) occurs in 35-45% of patients with CML
      in chronic phase who receive standard-dose imatinib. Myelosuppression results in
      treatment interruptions, which may compromise responses to imatinib. The authors
      investigated the ability of granulocyte-colony-stimulating factor (filgrastim) to
      reverse imatinib-associated neutropenia, thereby allowing for more continuous
      imatinib administration. METHODS: Thirteen patients with chronic-phase CML and
      Grade > or = 3, imatinib-induced neutropenia were treated with filgrastim.
      Treatment with filgrastim was initiated after a median of 22 months from the
      start of imatinib. Eleven patients received filgrastim 5 microg/kg 1-3 times
      weekly, and 2 patients received filgrastim 5 microg/kg daily; doses were titrated
      to maintain an absolute neutrophil count (ANC) > or = 10(9)/L. RESULTS: Seven of
      11 patients (64%) who began treatment with an ANC < 1.5 x 10(9)/L had responses
      (i.e., their ANC improved to > or = 2 x 10(9)/L within 21 days); the other 4
      patients experienced slower recovery but were able to continue receiving imatinib
      uninterrupted. Before filgrastim administration was initiated, patients did not
      receive imatinib (due to neutropenia-related treatment interruptions) for an
      average of 21% of the total time since the start of imatinib. This figure
      decreased to 6% after the start of filgrastim treatment (P = 0.0008). Before
      filgrastim treatment was initiated, only one patient had achieved a major
      (partial) cytogenetic response. After the start of filgrastim treatment, five
      patients had major cytogenetic responses (including two complete responses).
      CONCLUSIONS: The authors concluded that filgrastim may overcome imatinib
      associated neutropenia and allow improved delivery of imatinib. Some patients may
      experience improvements in their responses to therapy as a result.

PMID- 15197802
TI  - DNA-methylation analysis identifies the E-cadherin gene as a potential marker of
      disease progression in patients with monoclonal gammopathies.
AB  - BACKGROUND: Silencing of tumor suppressor genes (TSG) by aberrant methylation
      (referred to as methylation) contributes to the pathogenesis of various human
      malignancies. However, little is known about the methylation of known and
      putative TSGs in monoclonal gammopathies. Thus, the authors investigated the
      methylation frequencies of 10 genes in patients with monoclonal gammopathies.
      METHODS: The methylation patterns of the genes p16(INK4a) (p16), tissue inhibitor
      of metalloproteinase 3 (TIMP3), p15(INK4b) (p15), E-cadherin (ECAD), death
      associated protein kinase (DAPK), p73, RAS-association domain family 1A
      (RASSF1A), p14, O(6)-methylguanine DNA methyltransferase (MGMT), and retinoid
      acid receptor beta2 (RARbeta) were determined in patients with monoclonal
      gammopathy of undetermined significance (MGUS; n = 29), smoldering multiple
      myeloma (SMM; n = 5), multiple myeloma (MM; n = 113), or plasma cell leukemia
      (PCL; n = 7) by methylation-specific polymerase chain reaction analysis. RESULTS:
      Methylation frequencies for p16, TIMP3, p15, ECAD, DAPK, p73, RASSF1A, p14, MGMT,
      and RARbeta were as follows: 28%, 35%, 10%, 0%, 17%, 21%, 14%, 14%, 7%, and 0%,
      respectively, in patients with MGUS and 36%, 29%, 27%, 27%, 22%, 15%, 15%, 9%,
      4%, and 0%, respectively, in patients with MM. Methylation of at least 1 of these
      genes was detected in 79% of patients with MGUS and in 80% of patients with MM.
      Although methylation of ECAD was not detected in patients with MGUS, it was
      observed frequently in patients with MM and with even greater frequency in
      patients with PCL. It is noteworthy that an association was found between ECAD
      methylation and poor prognostic markers in patients with MM. CONCLUSIONS:
      Methylation of certain genes can be detected frequently in patients with
      monoclonal gammopathies. The current data suggest that methylation of ECAD is a
      marker of disease progression in patients with MM and PCL.

PMID- 15197803
TI  - Comparison of high-dose melphalan with a more intensive regimen of thiotepa,
      busulfan, and cyclophosphamide for patients with multiple myeloma.
AB  - BACKGROUND: High-dose chemotherapy (HDC) with autologous stem cell
      transplantation (ASCT) as part of the initial treatment regimen improves
      progression-free survival (PFS) and overall survival (OS) for patients with
      multiple myeloma. The optimal preparative regimen for patients with multiple
      myeloma has yet to be defined. In the current study, the authors compared the
      outcomes associated with high-dose melphalan (HDM) and a more intensive regimen
      of thiotepa, busulfan, and cyclophosphamide (TBC) in patients with multiple
      myeloma. METHODS: One hundred eighty-six patients with newly diagnosed multiple
      myeloma (median age, 51 years) received HDC with ASCT for consolidation of first
      remission (n = 108) or for treatment of primary refractory disease (n = 78).
      Seventy patients had a large tumor mass at the time of diagnosis. The preparative
      regimen consisted of TBC for 97 patients and HDM for 89 patients. Patients in the
      TBC group were younger and had more advanced disease stage at diagnosis and at
      the time of ASCT compared with patients in the HDM group. RESULTS: The response
      rates (complete response [CR] and partial response [PR]) were similar in the TBC
      group (overall response rate, 66%; CR rate, 17%; PR rate, 49%) and the HDM group
      (overall response rate, 69%; CR rate, 28%; PR rate, 41%). PFS and OS were similar
      in both groups. A proportional hazards regression model revealed that Durie
      Salmon disease stage at diagnosis and having received three or more previous
      treatment regimens were the only factors that predicted PFS; the type of
      preparative regimen did not influence outcome. CONCLUSIONS: The results of the
      current study indicate that the use of a more intensive regimen did not improve
      results compared with HDM in patients with multiple myeloma. HDM should continue
      to be considered the standard preparative regimen for patients with myeloma.

PMID- 15197804
TI  - Long-term efficacy and safety of zoledronic acid in the treatment of skeletal
      metastases in patients with nonsmall cell lung carcinoma and other solid tumors:
      a randomized, Phase III, double-blind, placebo-controlled trial.
AB  - BACKGROUND: The authors previously reported the efficacy of a dose of 4 mg of
      zoledronic acid in reducing skeletal complications in patients with bone
      metastases secondary to lung carcinoma and other solid tumors (except carcinomas
      of the breast and prostate). In the current study, they update these results and
      report the long-term efficacy and safety of 21 months of treatment with
      zoledronic acid in a randomized, placebo-controlled trial. METHODS: A total of
      773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo
      via a 15-minute infusion every 3 weeks for 21 months. The 8-mg dose later was
      reduced to 4 mg (8/4-mg group). The primary efficacy endpoint was the percentage
      of patients at 21 months with >/= 1 skeletal-related event (SRE) (pathologic
      fracture, spinal cord compression, radiation therapy to bone, or surgery to
      bone). Secondary analyses (time to first SRE, annual incidence of SREs, and
      multiple-event analysis) included hypercalcemia of malignancy. RESULTS: Fewer
      patients treated with zoledronic acid developed at least 1 SRE at 21 months
      compared with patients treated with placebo (39% of those treated at the 4-mg
      dose [P =0.127] and 36% of those treated at the 8/4-mg dose [P = 0.023], compared
      with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid
      significantly delayed the median time to first SRE (236 days with 4 mg vs. 155
      days with placebo; P = 0.009) and significantly reduced the annual incidence of
      SREs (1.74 per year with the 4-mg dose vs. 2.71 per year with placebo; P =
      0.012). Moreover, the 4-mg dose of zoledronic acid was found to reduce the risk
      of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003).
      Zoledronic acid was found to be well tolerated with long-term use; the most
      commonly reported adverse events in all treatment groups included bone pain and
      the transient, acute-phase reactions of nausea, anemia, and emesis. CONCLUSIONS:
      To the authors' knowledge, zoledronic acid is the first bisphosphonate to
      demonstrate long-term safety and efficacy in this patient population.

PMID- 15197805
TI  - Preferential brain locations of low-grade gliomas.
AB  - BACKGROUND: The objectives of this study were to register the brain locations in
      a consecutive series of low-grade gliomas (LGGs) and compare these localizations
      with the locations of de novo glioblastomas (GBMs) that were collected during the
      same period in an effort to analyze whether LGGs are situated in preferential
      areas and to review the pathophysiologic hypothesis of such a phenomenon.
      METHODS: One hundred thirty-two patients with LGG and 102 patients with GBM who
      were followed consecutively between 1996 and 2003 by the authors were reviewed,
      whatever their treatment. Using anatomic, three-dimensional magnetic resonance
      imaging, the location of each tumor was analyzed accurately according to a
      classification system based on the proximity of eloquent areas previously
      reported by the authors. RESULTS: One hundred nine LGGs (82.6%), compared with 55
      GBMs (53.9%), were situated within functional regions (P < 0.001). More
      specifically, 36 LGGs (27.3%), compared with 11 GBMs (10.8%), were localized in
      the region of the supplementary motor area (SMA) (P < 0.001); and 33 LGGs (25%),
      compared with 11 GBMs (10.8%), were located within the insula (P < 0.001).
      CONCLUSIONS: The current findings suggest that LGGs are located preferentially in
      "secondary" functional areas (immediately near the so-called primary eloquent
      regions), especially within the SMA and the insular lobe. This preferential
      localization may be explained by developmental, cytomyeloarchitectonic,
      neurochemical, metabolic, and functional reasons. A better knowledge of the
      pathophysiologic mechanisms underlying preferential LGGs locations may improve
      understanding of the genesis and natural history of these tumors and,
      subsequently, their management.

PMID- 15197806
TI  - Human immunodeficiency virus-related primary central nervous system lymphoma:
      factors influencing survival in 111 patients.
AB  - BACKGROUND: The current study evaluated factors influencing survival in patients
      diagnosed with human immunodeficiency virus (HIV)-related primary central nervous
      system lymphoma (PCNSL), with a focus on the effects of therapeutic radiotherapy
      (RT) and highly active antiretroviral therapy (HAART). METHODS: A retrospective
      chart review of patients with a diagnosis of HIV-related PCNSL at one of five
      university hospitals between 1987 and 1998 was performed. Clinical details
      including antiretroviral agent use, brain imaging scan results, RT use, and
      survival outcomes were recorded. RESULTS: One hundred eleven patients with HIV
      related PCNSL were identified. The annual incidence decreased significantly
      between 1992 and 1995 and between 1996 and 1998 (P = 0.04). The median survival
      period was 50 days (mean, 109 days; range, 4-991 days), with improved survival
      for patients diagnosed after 1993. Patients treated with two or more
      antiretroviral agents had improved survival (P = 0.01), as did patients who
      received RT (P < 0.0001). For patients who received RT, completion of the
      prescribed course and treatment to > or = 30 Gray (Gy) independently predicted a
      more favorable outcome. RT used in conjunction with antiretroviral therapy
      involving two or more agents had an additive positive effect on survival. For
      patients who did not receive RT, poor performance status and encephalopathy
      predicted a shorter survival duration. CONCLUSIONS: The results of the current
      study suggest that HAART and treatment with RT to > or = 30 Gy improve survival
      for patients with HIV-related PCNSL. This combination of therapies may provide a
      standard of care as the basis for further trials of chemotherapy, novel
      adjunctive treatment, and quality of life assessment.

PMID- 15197807
TI  - Increasing the dosage of vincristine: a clinical and pharmacokinetic study of
      continuous-infusion vincristine in children with central nervous system tumors.
AB  - BACKGROUND: Vincristine (VCR) is widely used to treat patients with malignant
      disease; among the patients treated with VCR are children with brain tumors. In
      vitro studies have demonstrated that the cytotoxic activity of VCR is related to
      both extracellular concentration and duration of exposure. The attainment of
      higher plasma concentrations by injecting larger bolus doses of VCR has been
      limited by concerns about neurotoxicity. One possible alternative strategy for
      enhancing the antitumor efficacy of VCR involves prolonging the duration of in
      vivo exposure. Therefore, the authors explored the neurotoxicity and
      pharmacokinetics of VCR administered via a 96-hour continuous infusion after
      administration of a conventional bolus dose in a pediatric population. METHODS:
      The current study included 16 patients, 11 of whom were males. The median age of
      the study population was 4.8 years (range, 1.7-15.8 years). The diagnoses
      included intrinsic pontine glioma (n = 4), ependymoma (n = 5), astrocytoma (n =
      3), medulloblastoma/primitive neuroectodermal tumor (PNET; n = 2), ganglioglioma
      (n = 1), and choroid plexus carcinoma (n = 1). Of the 16 patients, 5 were newly
      diagnosed, and the remaining 11 had disease recurrences, 8 of which arose after
      radiotherapy. Treatment included cyclophosphamide 65 mg/kg administered
      intravenously over 1 hour on Day 1, a bolus of VCR 1.5 mg/m(2) administered
      intravenously on Day 2, and VCR 0.5 mg/m(2) per 24 hours administered via
      continuous intravenous infusion on Days 2-5. Thus, a total VCR dose of 3.5
      mg/m(2) was administered via infusion over 4 days. Fifteen patients received 2
      courses of treatment at 21-28-day intervals, and a total of 31 treatment courses
      were administered. VCR concentrations in plasma samples were measured using high
      performance liquid chromatography. RESULTS: Jaw pain, constipation, mild
      abdominal pain, and depressed reflexes were common. However, only 1 of 31 courses
      was associated with Grade III toxicity, and no Grade IV toxicity (e.g., cranial
      nerve palsy, ileus, inappropriate antidiuretic hormone secretion, seizures,
      hallucinations, etc.) was noted. The steady-state plasma concentration of VCR
      during continuous infusion ranged from 1 to 3 microg/L in all patients. Responses
      after 2 courses were evaluated in 14 of 16 patients. A complete response was
      noted in one patient (astrocytoma), a partial response in three patients (one
      each with astrocytoma, ependymoma, and PNET), stable disease in seven patients,
      and disease progression in three patients. CONCLUSIONS: Continuous infusion of
      VCR after a conventional bolus dose plus cyclophosphamide for children with
      tumors of the central nervous system did not result in significant neurotoxicity
      and appeared to be a safe strategy for achieving increased systemic exposure.

PMID- 15197808
TI  - The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the
      EuroSIDA Study.
AB  - BACKGROUND: The introduction of highly active antiretroviral therapy (HAART) has
      radically changed the clinical course of human immunodeficiency virus (HIV)
      infection. The goals of the current study were to assess the change in the
      incidence of Kaposi sarcoma (KS) among European patients with HIV since the
      introduction of HAART and to identify the factors associated with the development
      of KS among patients receiving HAART. METHODS: The incidence of KS and the
      factors associated with the development of this malignancy in patients receiving
      HAART were evaluated using Poisson regression. Patients examined in the current
      study were among the 9803 individuals with HIV who were enrolled in the EuroSIDA
      study, a pan-European multicenter investigation. RESULTS: There was an estimated
      annual reduction of 39% (95% confidence interval [CI], 35-43%; P < 0.0001) in the
      incidence of KS between 1994 and 2003. The proportion of acquired
      immunodeficiency syndrome (AIDS) diagnoses made due to KS during prospective
      follow-up ranged from 4.1% to 7.5%, and there was no significant change over time
      in this figure (P = 0.97). Four thousand fourteen patients began receiving HAART
      during prospective follow-up; 41 of these 4014 were subsequently diagnosed with
      KS (1.0%). After adjustment in multivariate analyses, patients with higher
      current CD4 counts were found to have a decreased incidence of KS (incidence rate
      ratio [IRR], 0.60; 95% CI, 0.53-0.68; P < 0.0001), as were those for whom more
      time had elapsed since the initiation of HAART (IRR, 0.77; 95% CI, 0.60-0.98; P =
      0.037). In contrast, homosexual men were found to have a significantly increased
      incidence of KS (IRR, 2.12; 95% CI, 1.00-4.54; P = 0.050) CONCLUSIONS: The
      current incidence of KS among patients with HIV is less than 10% of the incidence
      reported in 1994; the proportion of AIDS diagnoses made on the basis of KS
      diagnoses remains near 6%. Most individuals who developed KS while receiving
      HAART began treatment with low CD4 cell counts and developed KS within 6 months
      of the initiation of HAART. There continues to be an increased incidence of KS
      among homosexual men and a greatly reduced incidence of KS among patients with
      higher CD4 counts.

PMID- 15197809
TI  - The role of preoperative endorectal magnetic resonance imaging in the decision
      regarding whether to preserve or resect neurovascular bundles during radical
      retropubic prostatectomy.
AB  - BACKGROUND: Because the recovery of erectile function and the avoidance of
      positive surgical margins are important but competing outcomes, the decision to
      preserve or resect a neurovascular bundle (NVB) during radical prostatectomy (RP)
      should be based on the most accurate information concerning the location and
      extent of the tumor. In the current study, the authors determined the incremental
      value of endorectal magnetic resonance imaging (eMRI) in making this decision.
      METHODS: eMRI was performed in 135 patients preoperatively. For each NVB, tumor
      extension to the NVB and the need for NVB resection was judged by a surgeon on a
      scale from 1 (definite preservation) to 5 (definite resection) before and after
      reviewing eMRI with a radiologist. Histopathologic findings were used as the
      standard of reference. The value of eMRI was assessed using binormal receiver
      operating characteristic (ROC) analysis adjusted for multiple observations per
      patient, and a mixed effects ordinal regression model was used for risk
      stratification. RESULTS: Histopathologic examination determined that NVB
      resection was warranted in 44 of 270 NVBs (16%) because of posterolateral
      extracapsular extension (n = 29), positive surgical margins (n = 7), or both (n =
      8). The areas under the ROC curves (AUC) were 0.741 for pre-MRI and 0.832 for
      post-MRI surgical planning (P < 0.01). MRI findings suggested altering the
      surgical plan in 39% of NVBs (106 of 270 NVBs). When the surgeon judged that the
      NVB resection was definitely not necessary (165 NVBs), MRI confirmed that
      decision in 138 NVBs (84%); the concordant decision was correct in 96% of the
      cases (133 of 138 NVBs). In 36 high-risk patients (> or = 75% probability of
      extracapsular extension), MRI findings changed the surgical plan for 28 NVBs
      (78%); the change was found to be appropriate in 26 cases (93%). CONCLUSIONS: MRI
      was found to significantly improve the surgeon's decision to preserve or resect
      the NVB during radical prostatectomy.

PMID- 15197810
TI  - Gemcitabine-associated thrombotic microangiopathy.
AB  - BACKGROUND: Gemcitabine-associated thrombotic microangiopathy (TMA) is believed
      to be very rare, with an estimated incidence rate of 0.015%. Indications for
      gemcitabine are expanding, and comprehensive characterization of this
      complication is therefore important. METHODS: The authors performed a
      retrospective chart review of all cases with gemcitabine-associated TMA diagnosed
      at Partners Healthcare System (Boston, MA) between January 1997 and February
      2002. RESULTS: Nine patients with gemcitabine-associated TMA were identified.
      Diagnosis was aided by clinical and laboratory features. Renal biopsy confirmed
      the diagnosis in two patients. The cumulative incidence of gemcitabine-associated
      TMA was 0.31% (8 cases among 2586 patients) when only the 8 patients with TMA who
      were treated at clinics associated with the current study were considered (1
      patient with a TMA syndrome was transferred from another institution). The median
      patient age was 53 years, and the median time to development of a TMA syndrome
      after the initiation of gemcitabine was 8 months (range, 3-18 months), with a
      cumulative dose ranging from 9 to 56 g/m(2). New or exacerbated hypertension was
      a prominent feature in 7 of 9 patients and preceded the clinical diagnosis by 0.5
      10 weeks. Treatment of TMA included discontinuation of gemcitabine,
      antihypertensive therapy, plasma exchange, and dialysis. Outcomes are known for
      all nine patients. Six patients remain alive, whereas three have died of disease
      progression. No patient died as a direct result of TMA, but two developed kidney
      failure requiring dialysis, and one developed chronic renal insufficiency.
      CONCLUSIONS: In the current series, the largest single-institution study to date,
      the incidence of gemcitabine-associated TMA was higher than previously reported
      (0.31% vs. 0.015%). Seven of nine patients developed new or exacerbated
      hypertension, which could be a useful early identifier of patients with
      gemcitabine-associated TMA syndromes.

PMID- 15197811
TI  - A phase I study of sequential administration of escalating doses of intravenous
      paclitaxel, oral topotecan, and fixed-dose oral etoposide in patients with solid
      tumors.
AB  - BACKGROUND: Based on preclinical findings and on the clinical antitumor efficacy
      of sequential paclitaxel/topotecan and topotecan/etoposide, the authors sought to
      define the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs)
      associated with a sequential combination of paclitaxel, topotecan, and etoposide
      in patients with solid tumors. METHODS: The MTDs were determined through standard
      dose escalation in cohorts of three patients. Patients with refractory solid
      tumors and performance status < or = 2 were treated with intravenous paclitaxel
      50-110 mg/m(2) (Day 1), oral topotecan 0.5-2.0 mg/m(2) (Days 2-4), and oral
      etoposide 160 mg/m(2) (Days 5-7) during every 21-day cycle. For dose-limiting
      neutropenia, granulocyte-colony-stimulating factor (G-CSF) was administered on
      Day 8 in subsequent cohorts. Blood samples were obtained before treatment during
      Cycle 1 (Days 1, 2, and 5) for topoisomerase I assessment. RESULTS: Twenty-eight
      patients received a combined total of 129 cycles. The MTDs were paclitaxel 80
      mg/m(2), topotecan 1.5 mg/m(2), and etoposide 160 mg/m(2) without G-CSF. In
      minimally pretreated patients, G-CSF allowed paclitaxel dose escalation to 110
      mg/m(2). Three patients (11%) had radiologic partial responses, and 4 patients
      (14%) had stable disease. Day 2 topoisomerase I levels increased by 2-15 times
      relative to baseline levels in 7 of 14 patients analyzed (50%). CONCLUSIONS: The
      novel sequential combination that was evaluated generally was well tolerated and
      active in patients with refractory solid tumors. Based on hematologic DLTs, the
      authors recommend further evaluation of paclitaxel 110 mg/m(2), topotecan 1.5
      mg/m(2), and etoposide 160 mg/m(2) with G-CSF support in minimally pretreated
      patients.

PMID- 15197812
TI  - Long-term risk of malignant neoplasm associated with gestational glucose
      intolerance.

PMID- 15197814
TI  - Immunohistochemically detected tumor cells in the sentinel lymph nodes of
      patients with breast carcinoma.

PMID- 15197816
TI  - Double child burial from Sunghir (Russia): pathology and inferences for upper
      paleolithic funerary practices.
AB  - The double child burial from Sunghir (Russia) is a spectacular Mid Upper
      Palaeolithic funerary example dated to about 24,000 BP. A boy (Sunghir 2) and a
      girl (Sunghir 3), about 12-13 and 9-10 years old, respectively, were buried at
      the same time, head to head, covered by red ocher and ornamented with
      extraordinarily rich grave goods. Examination of the two skeletons reveals that
      the Sunghir 3 femora are short and exhibit marked antero-posterior bowing. The
      two femora do not show any asymmetry in the degree of shortening and bowing.
      Bowing affects the whole diaphysis and shows a regularly incurved profile, with
      the highest point at midshaft. Pathology is confined to the femora, and no other
      part of this well-preserved specimen shows abnormality. The isolated nature of
      the Sunghir 3 anomalies points to cases reported in the medical literature under
      the label of "congenital bowing of long bones" (CBLB). These are a group of rare
      conditions exhibiting localized, sometimes bilateral, bowing and shortening which
      are nonspecific and may result from different causes, including abnormalities of
      the primary cartilaginous anlage (i.e., the aggregation of cells representing the
      first trace of an organ). Localized ossification disturbances, possibly linked to
      a diabetic maternal condition, might explain the shortening and the coincidence
      of maximum midshaft curvature with the position of the primary ossification
      center, as well as the lack of involvement of other skeletal parts. This
      scenario, rather than other possibilities (early bilateral midshaft fracture,
      acute plastic bowing deformities, or faulty fetal posture), provides the most
      likely explanation for the Sunghir 3 femoral deformities. The intriguing
      combination of a pathological condition apparent since birth with a spectacular
      burial of unusually positioned young individuals of different sexes recalls
      significant aspects of the triple burial from the contemporary site of Dolni
      Vestonice (Moravia), evoking a patterned relationship between physical
      abnormality and extraordinary Upper Paleolithic funerary behavior.

PMID- 15197817
TI  - Horse-mounted invaders from the Russo-Kazakh steppe or agricultural colonists
      from western Central Asia? A craniometric investigation of the Bronze Age
      settlement of Xinjiang.
AB  - Numerous Bronze Age cemeteries in the oases surrounding the Taklamakan Desert of
      the Tarim Basin in the Xinjiang Uyghur Autonomous Region, western China, have
      yielded both mummified and skeletal human remains. A dearth of local antecedents,
      coupled with woolen textiles and the apparent Western physical appearance of the
      population, raised questions as to where these people came from. Two hypotheses
      have been offered by archaeologists to account for the origins of Bronze Age
      populations of the Tarim Basin. These are the "steppe hypothesis" and the
      "Bactrian oasis hypothesis." Eight craniometric variables from 25 Aeneolithic and
      Bronze Age samples, comprising 1,353 adults from the Tarim Basin, the Russo
      Kazakh steppe, southern China, Central Asia, Iran, and the Indus Valley, are
      compared to test which, if either, of these hypotheses are supported by the
      pattern of phenetic affinities possessed by Bronze Age inhabitants of the Tarim
      Basin. Craniometric differences between samples are compared with Mahalanobis
      generalized distance (d2), and patterns of phenetic affinity are assessed with
      two types of cluster analysis (the weighted pair average linkage method and the
      neighbor-joining method), multidimensional scaling, and principal coordinates
      analysis. Results obtained by this analysis provide little support for either the
      steppe hypothesis or the Bactrian oasis hypothesis. Rather, the pattern of
      phenetic affinities manifested by Bronze Age inhabitants of the Tarim Basin
      suggests the presence of a population of unknown origin within the Tarim Basin
      during the early Bronze Age. After 1200 B.C., this population experienced
      significant gene flow from highland populations of the Pamirs and Ferghana
      Valley. These highland populations may include those who later became known as
      the Saka and who may have served as "middlemen" facilitating contacts between
      East (Tarim Basin, China) and West (Bactria, Uzbekistan) along what later became
      known as the Great Silk Road.

PMID- 15197818
TI  - Genetics and the evolution of primate enamel thickness: a baboon model.
AB  - The thickness of mammalian tooth enamel plays a prominent role in paleontology
      because it correlates with diet, and thicker enamel protects against tooth
      breakage and wear. Hominid evolutionary studies have stressed the importance of
      this character for over 30 years, from the identification of "Ramapithecus" as an
      early Miocene hominid, to the recent discovery that the earliest hominids display
      molar enamel intermediate in thickness between extant chimpanzees and
      Australopithecus. Enamel thickness remains largely unexplored for nonhominoid
      primate fossils, though there is significant variation across modern species.
      Despite the importance of enamel thickness variation to primate evolution, the
      mechanisms underlying variation in this trait have not yet been elucidated. We
      report here on the first quantitative genetic analysis of primate enamel
      thickness, an analysis based on 506 pedigreed baboons from a captive breeding
      colony. Computed tomography analysis of 44 Papio mandibular molars shows a zone
      of sufficiently uniform enamel thickness on the lateral surface of the
      protoconid. With this knowledge, we developed a caliper metric measurement
      protocol for use on baboon molars worn to within this zone, enabling the
      collection of a data set large enough for genetic analyses. Quantitative genetic
      analyses show that a significant portion of the phenotypic variance in enamel
      thickness is due to the additive effects of genes and is independent of sex and
      tooth size. Our models predict that enamel thickness could rapidly track dietary
      adaptive shifts through geological time, thus increasing the potential for
      homoplasy in this character. These results have implications for analyses of
      hominoid enamel thickness variation, and provide a foundation from which to
      explore the evolution of this phenotype in the papionin fossil record.

PMID- 15197819
TI  - Diet and nutrition in wild mongoose lemurs (Eulemur mongoz) and their
      implications for the evolution of female dominance and small group size in
      lemurs.
AB  - Data collected on the feeding behavior, food intake, and chemical analyses of
      plant foods were used to document seasonal variation in diet and nutrition in
      Eulemur mongoz in northwestern Madagascar. E. mongoz conforms to the general
      Eulemur dietary pattern, with a predominantly frugivorous diet supplemented
      mainly by leaves, flowers, and nectar. Phytochemical analysis revealed high water
      contents in all the main plant foods; mature fruit and flowers contained the most
      water-soluble carbohydrates; immature leaves were richest in protein and
      essential amino acids; the limiting amino acids in all plant foods were
      methionine and cystine; ash (mineral) content was highest in petioles and mature
      leaves; crude lipid content was highest in seeds; and crude fiber content was
      indistinguishable between immature and mature fruit and leaves. High-fiber foods
      were eaten during both seasons; the wet season diet was dominated by high-energy
      foods (mature fruit, nectar, and seeds), while the dry season diet contained
      foods high in energy (mature fruit and flowers) and high in protein (immature
      leaves) and minerals (mature leaves and petioles). However, nutrient intake did
      not vary between seasons, implying that nutrient requirements are met throughout
      the year. These results suggest we draw more conservative conclusions when
      interpreting dietary variability in the absence of chemical analysis, and also
      draw into question the idea that nutritional stress is a factor in the timing of
      reproduction in lemurs and, by extension, is linked to the prevalence of female
      dominance and small group size in lemurs.

PMID- 15197820
TI  - Energetic costs of bipedal and quadrupedal walking in Japanese macaques.
AB  - We investigated the energetic costs of quadrupedal and bipedal walking in two
      Japanese macaques. The subjects were engaged in traditional bipedal performance
      for years, and are extremely adept bipeds. The experiment was conducted in an
      airtight chamber with a gas analyzer. The subjects walked quadrupedally and
      bipedally at fixed velocities (<5 km/hr) on a treadmill in the chamber for 2.5-6
      min. We estimated energy consumption from carbon dioxide (CO2) production. While
      walking bipedally, energetic expenditure increased by 30% relative to
      quadrupedalism in one subject, and by 20% in another younger subject. Energetic
      costs increased linearly with velocity in quadrupedalism and bipedalism, with
      bipedal/quadrupedal ratios remaining almost constant. Our experiments were
      relatively short in duration, and thus the observed locomotor costs may include
      presteady-state high values. However, there was no difference in experimental
      duration between bipedal and quadrupedal trials. Thus, the issue of steady state
      cannot cancel the difference in energetic costs. Furthermore, we observed that
      switching of locomotor mode (quadrupedalism to bipedalism) during a session
      resulted in a significant increase of CO2 production. Taylor and Rowntree ([1973]
      Science 179:186-187) noted that the energetic costs for bipedal and quadrupedal
      walking were the same in chimpanzees and capuchin monkeys. Although the reason
      for this inconsistency is not clear, species-specific differences should be
      considered regarding bipedal locomotor energetics among nonhuman primates. Extra
      costs for bipedalism may not be great in these macaques. Indeed, it is known that
      suspensory locomotion in Ateles consumes 1.3-1.4 times as much energy relative to
      quadrupedal progression. This excess ratio surpasses the bipedal/quadrupedal
      energetic ratios in these macaques.

PMID- 15197821
TI  - Composition of the founding population of Iceland: biological distance and
      morphological variation in early historic Atlantic Europe.
AB  - We examined the composition of the founding population of Iceland through the
      study of morphological traits in skeletons from Iceland, Ireland, Norway, and
      Greenland. This is the first study to address this issue from the Settlement
      Period of Iceland and contemporary samples from Ireland. We pose the following
      questions: 1) Was the founding population of Iceland of mixed or homogeneous
      origin? 2) Is there evidence for a significant Irish cohort in the founding
      population, as suggested in medieval Icelandic literature? Analysis of
      biodistance revealed that both Settlement Age and later samples from Iceland
      showed a greater degree of phenetic similarity to contemporary Viking Age
      Norwegians than to samples obtained from early medieval Ireland. Analysis of
      among-individual morphological variation showed that the Settlement Age
      population of Iceland did not exhibit an increase in variation in comparison to
      other populations in the sample, suggesting a relatively homogenous origin.
      However, estimation of admixture between the Irish and Norwegian populations
      indicated that 66% of the Icelandic settlers were of Norwegian origin. Comparison
      of the Icelandic samples to hybrid samples produced by resampling the Viking Age
      Norwegian and early medieval Irish samples revealed that the Icelandic samples
      are much closer to the Norwegian samples than expected, based on a 66:34 mixture
      of Norwegian and Irish settlers. We conclude that the Settlement Age population
      of Iceland was predominantly (60-90%) of Norwegian origin. Although this
      population was relatively homogenous, our results do not preclude significant
      contributions from Ireland as well as other sources not represented in our
      analysis.

PMID- 15197822
TI  - Android subcutaneous adipose tissue topography in lean and obese women suffering
      from PCOS: comparison with type 2 diabetic women.
AB  - The new optical device, the lipometer, enables the noninvasive, quick, safe, and
      precise determination of the thickness of subcutaneous adipose tissue (SAT)
      layers at any given site of the human body. Fifteen anatomically well-defined
      body sites from neck to calf describe a SAT topography (SAT-Top) like an
      individual "fingerprint" of a subject. This SAT-Top was examined in 16 women with
      polycystic ovary syndrome (PCOS) and compared to the body fat distribution of 87
      age-matched healthy controls and 20 type-2 diabetic women. SAT-Top differences of
      these three groups were described and, to render the possibility of visual
      comparison, the 15-dimensional body fat information was condensed to a two
      dimensional factor plot by factor analysis. All PCOS patients had an android body
      fat distribution with significantly thinner SAT layers on the legs as compared to
      healthy controls. Moreover, a hierarchical cluster analysis resulted in two
      distinctly different groups of PCOS women, a lean (PCOSL) and an obese (PCOSO)
      cluster: compared to healthy women, lean PCOS patients had significantly lower
      total SAT development, even though height, weight, and body mass index did not
      deviate significantly. Especially on the legs, their SAT layers were
      significantly lowered, indicating a more "apple-like" fat distribution type.
      Obese PCOS women showed a SAT-Top pattern very similar to that of women with type
      2 diabetes, although the mean age difference between these groups was more than
      30 years. Compared to healthy controls, the SAT-Top of these obese PCOS patients
      was strongly shifted into the android direction, appearing as "super-apples" with
      a significantly increased upper trunk obesity to 237.8% and a significantly
      decreased leg SAT development to 79.8%.

PMID- 15197824
TI  - Between the devil and the deep blue sea.

PMID- 15197825
TI  - Closer European integration: a treat to self regulation?

PMID- 15197826
TI  - The servant leader.

PMID- 15197828
TI  - Gender and communication.

PMID- 15197827
TI  - All work and low pay. Part 2. The challenge of diversity.

PMID- 15197829
TI  - The RCM's new president speaks out.

PMID- 15197830
TI  - NICE guidelines aim to stem caesarean rate.

PMID- 15197831
TI  - New research reveals breastfeeding myths.

PMID- 15197832
TI  - Belting up safely: what every mother-to-be should know.

PMID- 15197833
TI  - Baby blues: not just for mothers.

PMID- 15197834
TI  - Child protection: reflection on practice.

PMID- 15197835
TI  - RCM stewards: unsung champions who make the difference.

PMID- 15197836
TI  - Investing in teenage parents: what maternity services can do.

PMID- 15197837
TI  - Outcomes of an alongside birth centre in a tertiary referral centre.

PMID- 15197838
TI  - RCM branch review: professional development forums.

PMID- 15197839
TI  - Traumatic childbirth: what we know and what we can do.

PMID- 15197840
TI  - Ectopic pregnancy: a real issue for midwives.

PMID- 15197841
TI  - A four-way split.

PMID- 15197842
TI  - Crisis ... what crisis?

PMID- 15197843
TI  - The power of one.

PMID- 15197844
TI  - The right attitude?

PMID- 15197845
TI  - [On the introduction of socio-hygienic monitoring in 2000-2002 and objectives of
      the improvement of state sanitary-epidemiological service in the Russian
      Federation].

PMID- 15197846
TI  - [Procedures for the quantitative determination of the significance of hygienic
      problems at the state level].
AB  - A procedure has been developed to rank the regional problems of environmental
      hygiene on the basis of the modified risk-assessing model. The procedure has been
      tested, by using the regions of the Republic of Kazakhstan as an example. The
      priority problems and the country's regions requiring a particular attention have
      been identified in terms of the potential risks of environmental exposures on
      human health.

PMID- 15197847
TI  - [Hygienic aspects of the impact of solid waste disposal sites on the habitat].
AB  - The "Dmitrovsky" solid garbage (SG) ground is one of the largest enterprises of
      this kind in the Moscow Region. A total of 200,000-750,000 tons of solid garbage
      (91%) and industrial waste products (9%) annually come to the ground. A total of
      5,500,000 tons of garbage and waste products have been accumulated since it was
      put into operation. From the accumulated SG deposits, iron, manganese, beryllium,
      titanium, barium, boron, petroleum products enter the surface and underground
      waters, methane, carbon oxide, ammonia, toluene, xylene, hydrogen sulfide,
      cresol, phenol come into the atmospheric air; the compounds of zinc, lead,
      cadmium, copper, nickel, magnesium, and cobalt do into the soil. The studies
      conducted in 1997-2002 make it possible to establish that the ground has a
      negative impact on the environment and to evaluate the efficiency of nature
      conservation and hygienic measures, and to improve the technological process of
      SG utilization.

PMID- 15197848
TI  - [The activity of the ad hoc commission on "The Problems of Human Protection under
      Extreme Conditions": results and prospects].
AB  - The paper summarizes the results of 10-year activity of the ad hoc commission on
      "The Problems of Human Protection under Extreme Conditions" of the
      Interdepartmental Scientific Council on Human Ecology and Environmental Hygiene,
      Russian Academy of Medical Sciences. It shows the work of the Commission on
      Planning, Organization, and Coordination of Researches in the Development and
      Introduction of New Human Protective Agents and Means from Exposures to Chemical,
      Physical, and Biological Agents under Extreme Conditions. The prospects of the
      Commission's work have been defined for the coming 5 years, by taking into
      account the priority lines of development of science, technology, engineering in
      the Russian Federation.

PMID- 15197849
TI  - [Characteristics of demographic processes in the town of Novopolotsk].
AB  - The study of demographic parameters in the town of Novopolotsk in 1970-1999
      suggests that the most important causes of death among the town's population
      during this period are cardiovascular diseases (their proportion was 33.4-51.1%),
      malignant neoplasms (16.5-19.9%), and injuries (5.6-10.5%). In addition, there is
      an increase in mortality rates due to endocrine, respiratory, digestive,
      urogenital diseases, suicides, and injuries. In Novopolotsk residents, the main
      causes of death from cardiovascular diseases are atherosclerosis, coronary heart
      disease, and hypertensive disease.

PMID- 15197850
TI  - [Present day problems in water supply of big cities and some promising ways of
      their solution].

PMID- 15197851
TI  - [Some results of the activities of the sanitary-epidemiological service in
      environmental monitoring in the Tashkent region of the Republic of Uzbekistan].
AB  - The paper describes some results of the activities of the centers of the sanitary
      and-epidemiological service of the Ministry of Republic of Uzbekistan in
      controlling the quality of tap water, the pollution of atmospheric air, soil, raw
      food and foodstuffs under the reforms of the public health system (according to
      the 2001 data).

PMID- 15197852
TI  - [Characteristics of the equivalent equilibrium volume activity of thoron in the
      buildings of Moscow].
AB  - The introduction of NRS-99 has consolidated the need of controlling the
      equivalent equilibrium volume activity of thoron (EEVATn) and radon (EEVARn) in
      the air of dwelling, industrial, and public buildings. Analysis of more than 1000
      values of EEVATn measured in parallel with EEVARn, which was based on the well
      known mechanisms of accumulation of radon, thoron and their derivatives in the
      air of premises made it possible to approximate the correlation between EEVATn
      and radon EEVARn and to estimate the value of radon EEVATn without its
      measurement several hours after air sampling.

PMID- 15197853
TI  - [Impact of ambient pollution on the clinical and epidemiological features of
      rheumatism morbidity].

PMID- 15197854
TI  - [Effects of ultra-dispersed piezoceramics Pb powders on staff's health status].
AB  - The ultradispersed piezoceramic powder containing lead oxides, zirconium,
      titanium, bismuth, cadmium, manganese, strontium, and chromium was tested for its
      effect on the health status of the staff serving pilot industrial units producing
      the powder. There was a significant increase in the incidence of digestive
      disease, a tendency for respiratory and osteomuscular diseases to increase. It is
      concluded that it is necessary to use individual means of the protection and
      prophylaxis of the observed diseases.

PMID- 15197855
TI  - [Occupational morbidity in medical workers in the Samara region].

PMID- 15197856
TI  - [Determination of the rate of biological aging in vibration disease].
AB  - Examining 80 males with vibration disease has shown a significant increase in
      their biological age (particularly in patients with vibration disease due to
      exposure to second-degree general vibration) as compared with that in the control
      group, which is indicative of the role of these factors in the acceleration of
      the body's aging processes.

PMID- 15197857
TI  - [Quantitative criteria for the evaluation of congenital chromatic vision
      disorders].
AB  - The minimum angular size of a color stimulus required for its discrimination has
      been ascertained to be a quantitative criterion for evaluating the form and
      degree of congenital chromatic visual diseases. Unlike individuals with normal
      color perception who distinguish all basic and intermediate colors despite their
      saturation, anomalous trichromats discriminate more saturated colors with larger
      angular sizes of stimuli than those with normal color perception. Mild and
      moderate anomalous trichromats do not discriminate lowly saturated colors or for
      this they require the angular sizes tens of times greater those for normal
      trichromats. Persons with severe chromatic visual diseases (Type A) do not
      distinguish moderately saturated colors either. On recognizing the color of test
      objects, anomalous trichomats make the most mistakes in perceiving the green and
      yellow colors, the fewest mistakes in perceiving the red color. The minimum
      angular sizes required to distinguish colors, the percent of errors in their
      discrimination, and the range of vision of safety signs depend on the form and
      degree of congenital chromatic diseases. This makes it necessary to apply a
      differential approach to providing jobs that require rapid and accurate color
      discrimination in persons with the protanomalous forms of chromatic pathology.

PMID- 15197858
TI  - [Hygienic evaluation of frozen and canned Pacific saury (Cololabis saira)].
AB  - The storage of frozen Pacific saury (Cololabis saira) and the cans prepared from
      the latter in the refrigerator was examined for its impact on their quality.
      Changes in the parameters of proteins and lipids were studied in the samples of
      frozen Pacific saury during storage and of the cans prepared from the fish. The
      relative food value of the frozen fish was determined by biological tests using
      the infusoria Tetrachymena pyriformis. It was established that storage of frozen
      Pacific saury led to flesh protein and lipid degradation whose depth determined
      the loss of the food value of the fish. The results of biological tests fully
      correlate with the data of chemical analysis in assessing the quality of raw fish
      stored in the refrigerator.

PMID- 15197859
TI  - [Approaches to the evaluation of the level of sanitary-epidemiological well-being
      of educational establishment for children and adolescents].
AB  - A system of comprehensive assessment of the level of sanitary-and-epidemiological
      welfare of educational establishments is proposed for children and adolescents.
      Its significant criteria have been established. These included the organization
      of full-value, balanced and rational nutrition at the establishment; organization
      of the routine and an educational process. The hygienic assessment of the
      conditions, which was made by the presented scheme, adequately reflects the
      sanitary epidemiological situation at the orphans' institutions since it takes
      into account the main index of the sanitary-and-epidemiological welfare--the
      health status of their children and adolescents. There was a significant
      correlation between the physical development of orphans and the parameters of
      sanitary-and-epidemiological welfare at the state institutions for this
      contingent (r = 0.689). The organization of nutrition at the institution (r =
      0.703), the routine and the organization of an educational process (r = 0.689),
      the volume-planning and designing approaches (r = 0.687), the organization of
      physical education (r = 0.697), medical support at the institution (r = 0.688)
      exert the greatest impact on the physical development of children.

PMID- 15197860
TI  - [Hygienic rationale for the new pattern of a school year].
AB  - Many hygienic studies have indicated that the traditional structure of a school
      year, which exists at educational establishments and which is divided into four
      school terms that are unequal in duration does not correspond to the
      physiological capacities of most schoolchildren. The new structure of a school
      year under which (1-week) vocations are held every 5-6 weeks of study is
      outlined. The regular alternation of the periods of study and rest was
      ascertained to promote to the higher stability of the parameters of pupils'
      working capacity within the school year as compared with its traditional division
      into four terms. There is evidence that the new calendar of school vocations, as
      compared to the traditional one, has a health-promoting effect, which is
      determined by the lower incidence rates of acute diseases, by the less tension of
      cardiovascular tonogenic tension, by the preservation of higher adaptive
      capacities in the pupils at the end of a school year, by the lower incidence
      rates of increased and high neurotization in the pupils, by their more steady
      state psychoemotional status and higher performance in studies.

PMID- 15197861
TI  - [Health status and physical development in Stavropol' preschool children].
AB  - A total of 1097 children aged 2 to 6 years who went to preschool children's
      facilities in Stavropol were examined. Of them there were 525 (47.7%) boys and
      574 (52.3%) girls. For 40 years, the Stavropol preschool children have become
      higher and the height values are higher than the total Russian standards. The
      results obtained in the study region suggest that the total height of girls aged
      2 to 7 years is insignificantly greater than that in boys. A comprehensive
      analysis of the health status of the study groups shows that at preschool age,
      the number of children having Health Group I decreased at the expense of an
      increase in Health Group III children. The reasons for a rise in the incidence of
      diseases at this age may be more cases of poor living conditions, tense adaptive
      processes in the presence of incomplete immunogenesis, physiological lymphoid
      tissue hyperplasia, high rates of allergic reactions.

PMID- 15197862
TI  - [Conditions for the development of myopia in schoolchildren].
AB  - School myopia is a most common health problem in schoolchildren, in adolescents
      in particular. School myopia resulted from connective tissue failure of the whole
      organism. Some data, such as the association of school myopia with the HLA system
      confirm this idea. New investigations in this direction will assist in
      concretizing the real cause of this type of myopia. The interaction between the
      lighting conditions and the development of refraction is also of interest.

PMID- 15197863
TI  - [Influence of negative factors of the living environment on respiratory diseases
      in children].
AB  - An epidemiological survey was made in 9 cities and towns of Russia to study the
      influence of negative characteristics of an inhabited place on respiratory
      diseases in children. About 6,000 questionnaires questioning the living
      conditions of young children were filled in. The questionnaire pays a particular
      attention to frequent leakages and mould in the flats. To study the children's
      health status, a number of questions of the questionnaire were devoted to the
      present of some respiratory and allergic diseases (symptoms) reflecting the
      influence of unfavorable factors within the inhabited place. The logistic
      regression analysis was used to examine the relationship between the
      characteristics of the inhabited place of schoolchildren and the presence of
      respiratory and allergic diseases. A significant relationship was established
      between the frequent leakages, the presence of mould in the rooms, and the risk
      for bronchial asthma, persistent productive cough, persistent stertorous
      respiration, respiratory infections and any manifestations of allergic reactions
      in children.

PMID- 15197864
TI  - [The locomotor system in adolescents in relation to the type of an educational
      establishment].
AB  - A hundred and eight-two Uzbek girls aged 15-17 years who went to general
      educational schools, academic lycees, and vocational technical colleges were
      examined in 1999-2001. The parameters characterizing their locomotor system were
      studied. The rate of formation of force capacities was ascertained to vary in the
      girls going to different types of educational establishments. The slightly
      increased muscular force and the significantly decreased muscular strength in the
      college students are indicative of their deteriorated functional parameters of
      the musculomotor system during 3-year study.

PMID- 15197865
TI  - [Influence of cognitive and psychoemotional loads on the cardiac hemodynamic
      parameters of enrolling students].
AB  - Psychophysiological and cardiac hemodynamic changes were studied by computer
      registration and an analysis in tenth formers-entrants having a higher mental and
      emotional load during a school year. The changes in the above parameters were
      also studied when the formers were taking their school-leaving and entrance
      examinations.

PMID- 15197866
TI  - [Insignificant carcinogenicity of chrysotile asbestos of the Ak-Dovurak deposits
      in Russia and its possible links].
AB  - Thrice intrapleural injection of 20 mg of dust of the chrysotile from the Ak
      Dovurak deposit caused pleural mesothelioma in 10.7% of the rats, which was
      significantly less than that upon exposure to the chrysotiles from other deposits
      and amphiboles. The reason for the less carcinogenicity of this chrysotile is the
      structural features of the surface of its fibrils, namely, its high homogeneity
      and hence the lack of sites at which the electrically charged centers may be
      located.

PMID- 15197867
TI  - [The reference information system "Ecology and aluminum toxicology"].
AB  - Views of the toxicity of aluminum to man, animals, and plants and on its behavior
      in the ecosystems with a changing man-made loading have changed in the past 30
      years. Aluminum along with its human medical consequences has been found to
      present problems on the acid soils in world agriculture. To systematize knowledge
      and to control information on aluminum and its compounds, the reference
      information system "Ecology and Aluminum Toxicology" whose structure is based on
      the developed model of an ecological aluminum cycle was designed. Basic
      information units were identified in a rather wide subject area: "Generation",
      "Spread", and "Action", which include the information available in the published
      materials and the data obtained in the authors' experimental studies.

PMID- 15197868
TI  - [The 10th anniversary of the Medical Prevention Department of Postgraduate
      Training at the I. M. Sechenov Moscow Medical Academy].

PMID- 15197869
TI  - [The 10th anniversary of Sanitary-Epidemiological Service Department at the
      Russian Medical Academy of Postgraduate Training].

PMID- 15197870
TI  - Practice transition: a way to buy low, sell high, and have a win-win situation
      for both dentists.

PMID- 15197871
TI  - Choose life.

PMID- 15197872
TI  - A history of the Charitable Trust of the London Chapter.

PMID- 15197873
TI  - Reading the signs.

PMID- 15197874
TI  - Lights camera action.

PMID- 15197875
TI  - Towards an ideal skill mix in nursing homes.

PMID- 15197876
TI  - Using negotiated consent in research and practice.

PMID- 15197877
TI  - Asthma and older people: improving nursing care.
AB  - This article examines the special considerations healthcare professionals should
      apply when caring for older people with asthma. It looks at the physiology of
      asthma, signs and symptoms, diagnosis and the ways in which nurses can help older
      people better manage this sometimes debilitating condition.

PMID- 15197878
TI  - Older people and Essence of Care. Benchmarking for better services.

PMID- 15197879
TI  - [Approach and classification of blood purification].

PMID- 15197880
TI  - [Fundamentals of membrane transport for hemodialysis].

PMID- 15197881
TI  - [Theoretical principles in plasma separation].

PMID- 15197882
TI  - [Basics of hemoadsorption].

PMID- 15197883
TI  - [Science and technology of polymeric membrane--overview].

PMID- 15197884
TI  - [Biocompatibility].

PMID- 15197885
TI  - [Effect of apheresis on respiration and hemodynamics].

PMID- 15197886
TI  - [Changes in coagulation, fibrinolysis and platelet functions during
      extracorporeal circulation].

PMID- 15197887
TI  - [Immune response and immunomodulation in blood purification].

PMID- 15197888
TI  - [Pharmacokinetics and drug dosage adjustment theory in patients undergoing renal
      replacement therapy].

PMID- 15197889
TI  - [Overview of hemodialysis: characteristics, indications and recent progress].

PMID- 15197890
TI  - [The solute clearance of dialyzer depends partly on its membrane material].

PMID- 15197891
TI  - [Adsorption characteristics of the synthetic polymer dialysis membranes].

PMID- 15197892
TI  - [Development of dialysis membrane].

PMID- 15197893
TI  - [Dialysis machine].

PMID- 15197894
TI  - [Central dialysate mixing supply system].

PMID- 15197895
TI  - [Hemodialysis system for personal demand].

PMID- 15197896
TI  - [The contrivances to secure the safety in dialysis].

PMID- 15197897
TI  - [The outline of dialysate--the kinds and the problems].

PMID- 15197898
TI  - [Prescribing dialysate in hemodialysis].

PMID- 15197900
TI  - [The reality of water management for dialysates].

PMID- 15197899
TI  - [Theoretical background and practice of dialysate purification].

PMID- 15197901
TI  - [External arterio-venous shunt].

PMID- 15197902
TI  - [Internal arterio-venous shunt].

PMID- 15197903
TI  - [Blood access for emergency blood purification and temporary blood access
      catheter].

PMID- 15197904
TI  - [Vascular graft for hemodialysis].

PMID- 15197905
TI  - [Maintenance and reconstruction of the blood access].

PMID- 15197906
TI  - [Percutaneous transluminal angioplasty (PTA)].

PMID- 15197907
TI  - [New puncture method for hemodialysis treatment].

PMID- 15197908
TI  - [How to use anticoagulants in hemodialysis therapy].

PMID- 15197909
TI  - [Short time hemodialysis].

PMID- 15197910
TI  - [Biofiltration].

PMID- 15197912
TI  - [Wearable artificial kidney, portable artificial kidney and implantable
      artificial kidney].

PMID- 15197913
TI  - [Improved methods for dry weight assessment in hemodialysis patients].

PMID- 15197911
TI  - [High sodium hemodialysis].

PMID- 15197914
TI  - [Significance of urea kinetics in hemodialysis].

PMID- 15197915
TI  - [Application of computer data management for hemodialysis].

PMID- 15197916
TI  - [The efficiency and duration of dialysis].

PMID- 15197917
TI  - [Planned hemodialysis].

PMID- 15197918
TI  - [Computer-based supporting system of hemodialysis therapy in our functional
      organization].

PMID- 15197920
TI  - [Hemofiltration (HF) and hemodiafiltration (HDF)--overview].

PMID- 15197919
TI  - [Blood purification and endotoxin].

PMID- 15197921
TI  - [Devices for hemofiltration/hemodiafiltration].

PMID- 15197922
TI  - [Substitution fluid].

PMID- 15197923
TI  - [Improvement and development of membranes for hemofiltration].

PMID- 15197924
TI  - [Continuous hemofiltration and continuous hemodialysis filtration].

PMID- 15197925
TI  - [Push/pull HDF].

PMID- 15197926
TI  - [On-line HDF].

PMID- 15197927
TI  - [The portable hemofiltration-system].

PMID- 15197928
TI  - [The introduction to continuous ambulatory peritoneal dialysis (CAPD)].

PMID- 15197930
TI  - [Evaluation of peritoneal function in CAPD patients].

PMID- 15197929
TI  - [Clinical aspect of indication and initiation in CAPD therapy].

PMID- 15197931
TI  - [Computer-aided patient management system in continuous ambulatory peritoneal
      dialysis therapy].

PMID- 15197932
TI  - [A various types of CAPD--focused on APD].

PMID- 15197934
TI  - [Management of PD catheter complication].

PMID- 15197933
TI  - [Improvement and contraption of peritoneal dialysis fluid].

PMID- 15197935
TI  - [Plasma purification (characteristics, indication and recent development)].

PMID- 15197936
TI  - [Plasmapheresis with membrane type plasma separator].

PMID- 15197937
TI  - [Adverse effects of plasma exchange].

PMID- 15197938
TI  - [Anticoagulation for plasmapheresis].

PMID- 15197939
TI  - [Technological development of plasma separation].

PMID- 15197940
TI  - [Selective removal of autoantibody and immune complex by plasma exchange].

PMID- 15197941
TI  - [Lymphocytapheresis].

PMID- 15197942
TI  - [Hemoperfusion].

PMID- 15197944
TI  - [The present state of leukocytes apheresis therapy].

PMID- 15197943
TI  - [Development of adsorbent for plasma purification or removal filter of blood
      cell].

PMID- 15197945
TI  - [New preparations of erythropoietin].

PMID- 15197946
TI  - [The trend in the development of the active vitamin D3 and its analogues].

PMID- 15197947
TI  - [Anticoagulant].

PMID- 15197948
TI  - [Oral sorbent].

PMID- 15197949
TI  - [Phosphate binding therapy].

PMID- 15197950
TI  - [Amino acids supplementation therapy in uremic patients on regular blood
      purification treatment].

PMID- 15197952
TI  - [The recent progress in blood purification in critical care: overview].

PMID- 15197951
TI  - [Carbonyl stress inhibitor towards new therapeutic interventions in diabetic
      nephropathy].

PMID- 15197953
TI  - [Pathophysiology and choice of treatment in acute renal failure].

PMID- 15197954
TI  - [Initiation of blood purification therapy in patient with acute renal failure].

PMID- 15197955
TI  - [Rapidly progressive glomerulonephritis].

PMID- 15197956
TI  - [Drug-induced acute renal failure].

PMID- 15197958
TI  - [Treatment for the postrenal acute renal failure].

PMID- 15197957
TI  - [Pulmonary-renal syndrome and Goodpasture's syndrome].

PMID- 15197959
TI  - [Management of pediatric acute renal failure].

PMID- 15197960
TI  - [Management of acute renal failure in the elderly].

PMID- 15197961
TI  - [Continuous renal replacement therapy for multiple organ failure and multiple
      organ dysfunction syndrome].

PMID- 15197962
TI  - [Postoperative acute renal failure].

PMID- 15197963
TI  - [Influenza-associated encephalopathy].

PMID- 15197964
TI  - [Apheresis treatment for fulminant hepatitis].

PMID- 15197965
TI  - [Blood purification for severe acute pancreatitis].

PMID- 15197966
TI  - [Enterohemorrhagic Escherichia coli infection].

PMID- 15197967
TI  - [GVHD].

PMID- 15197968
TI  - [TTP/HUS].

PMID- 15197969
TI  - [Acute renal failure in patients with tumor lysis syndrome].

PMID- 15197970
TI  - [Plasmapheresis for Guillain-Barre syndrome and chronic inflammatory
      demyelinating polyneuropathy].

PMID- 15197971
TI  - [Rhabdomyolysis].

PMID- 15197972
TI  - [Endocrine crisis].

PMID- 15197973
TI  - [Hypercalcemia].

PMID- 15197974
TI  - [Poisoning of drugs and chemicals].

PMID- 15197975
TI  - [Drug induced toxic epidermal necrolysis].

PMID- 15197976
TI  - [Blood purification therapies for burn patients].

PMID- 15197977
TI  - [Preeclampsia/eclampsia].

PMID- 15197978
TI  - [Continuous renal replacement therapy in idiopathic interstitial pneumonia].

PMID- 15197979
TI  - [Dilated cardiomyopathy].

PMID- 15197980
TI  - [Inflammatory bowel diseases].

PMID- 15197981
TI  - [Liver failure].

PMID- 15197982
TI  - [Hyperviscosity syndrome, macroglobulinemia].

PMID- 15197983
TI  - [Cryoglobulinemia].

PMID- 15197984
TI  - [Systemic lupus erythematosus].

PMID- 15197985
TI  - [Rheumatoid arthritis].

PMID- 15197986
TI  - [Plasmapheresis in systemic sclerosis and polymyositis/dermatomyositis].

PMID- 15197987
TI  - [Plasmapheresis therapy in childhood collagen disease].

PMID- 15197989
TI  - [Multiple sclerosis].

PMID- 15197988
TI  - [Myasthenia gravis].

PMID- 15197990
TI  - [LDL apheresis].

PMID- 15197991
TI  - [Double filtration plasmapheresis for therapy of hyperlipidemia].

PMID- 15197992
TI  - [LDL adsorption for therapy of hyperlipidemia].

PMID- 15197993
TI  - [Evaluations of double filtration plasma perfusion (DFPP) for arteriosclerosis
      obliterans (ASO) in maintenance hemodialysis patients].

PMID- 15197994
TI  - [Amyloidosis].

PMID- 15197995
TI  - [Apheresis therapy for the treatment of pemphigus and auto-immune blistering
      disease].

PMID- 15197996
TI  - [Psoriasis].

PMID- 15197997
TI  - [Immunohistochemical analysis of CD83, CD8 and CD4 positive cells in renal cell
      carcinoma].
AB  - OBJECTIVES: In order to evaluate the immunological milieu in renal cell carcinoma
      (RCC), we investigated infiltration by mature dendritic cells (CD83 positive
      cells), cytotoxic-T cells (CD8 positive cells) and helper-T cells (CD4 positive
      cells) in RCCs, as well as in surrounding normal tissues and correlations between
      the cell types. MATERIALS AND METHODS: Specimens from 33 surgically resected RCCs
      were embedded in paraffin and then stained for CD4, CD8, CD83. Each section
      contained three areas, tumor tissue, tumor margin and normal renal parenchyma.
      Cells positive for CD4, CD8 and CD83 were counted each area. RESULT: Cells
      positive for CD4, CD8 and CD83 were observed predominantly in the tumor margins,
      rather than tumor tissue and normal renal parenchyma. The differences were
      significant in the number of immune positive cells between tumor margin and tumor
      tissue, and between tumor margin and normal renal parenchyma. A significant
      correlations was found between CD4 and CD83 positive cells (r = 0.805, p <
      0.0001), and also between CD8 and CD83 positive cells (r = 0.505, p < 0.0001).
      CONCLUSION: It has been reported that mature dendritic cells induces cytotoxic-T
      cell and helper-T cell responses. Infiltrating mature dendritic cells, cytotoxic
      T cells and helper-T cells were present only in the tumor margin. This may
      reflect significant immune reaction around the tumor margin.

PMID- 15197998
TI  - [The evaluation of urination status and International Prostate Symptom Score
      following radical prostatectomy].
AB  - PURPOSE: We evaluated condition of urination and International Prostate Symptom
      Score (I-PSS) after radical prostatectomy. PATIENTS AND METHODS: Forty-three men
      with prostatic cancer underwent radical prostatectomy between October 1993 and
      October 2002. Mean patients age was 66 years (range 56 to 79) and clinical follow
      up averaged 38.6 months (range 3 to 84). Urodynamics studies including
      uroflowmetry, cystometry and evaluation of I-PSS were performed before and 1, 3,
      6, 12 months after the operation. After 12 months these studies were performed
      every year. The status of postoperative urinary incontinence was based on
      patients' report. RESULTS: First desire to void, maximum desire to void and
      maximal flow rate was decrease temporarily after radical prostatectomy. However
      most patients had normal uroflowmetorogram and normal cystometrogram at 6 months.
      I-PSS and QOL index was improved during postoperative 12 months. CONCLUSIONS:
      Postoperatively urodynamics studies was improved from 3 to 6 months, but
      evaluation of I-PSS and QOL index was improved from 6 to 12 months. The
      difference was formed to both.

PMID- 15197999
TI  - [Arthritis following intravesical instillation of BCG for urothelial cancers].
AB  - BACKGROUND: Intravesical instillation of bacillus Calmette-Guerin (BCG) is
      efficient for prophylaxis of superficial bladder cancer and treatment for
      carcinoma in situ (CIS) of the upper urethelial cancer. However, the incidence of
      adverse effects is relatively high, and those include reactive arthritis. We
      retrospectively evaluated the incidence and the outcome of reactive arthritis
      following intravesical BCG therapy for urothelial cancers. PATIENTS AND METHODS:
      Intravesical instillations of BCC were performed in 192 cases (218 courses)
      between January 1998 and January 2002. BCG was instilled for prophylaxis of
      superficial bladder cancer recurrence in 170 (195 courses), treatment for CIS in
      7 (8 course), and treatment for CIS in 7 (8 courses), and treatment for CIS in
      upper urinary tract in 15 (15 courses). RESULTS: Arthritis was recognized in 8
      cases (3.7%, 8/218 courses), and 7 of them were identical to reactive arthritis
      following BCG therapy. Remaining 1 patient was diagnosed as rheumatoid arthritis
      (RA), and the relation between arthritis and intravesical BCG instillation was
      unclear. Mean number of BCG instillation was 5.6 (3-8 times). All reactive
      arthritis were occurred within 4 weeks after the last BCG instillation, i.e., BCG
      induced urinary tract infection, and 6 of them were polyarthritis. Concurrence of
      conjunctivitis was seen in one patient. HLA-B27 was negative in 4 examined
      patients. A nonsteroidal anti-inflammatory drug (NSAID) was used in all 8
      patients, anti-tuberculous agents were used in 3, and prednisolone was added in
      3, Arthritis was improved within 2 months in patients received prednisolone,
      however, it persisted longer than 3 months in patients without prednisolone.
      CONCLUSION: Arthritis was recognized in higher incidence than previous reports
      following intravesical instillation of BCG. All cases except one, diagnosed as
      RA, were diagnosed as reactive arthritis (Reiter's syndrome). However,
      correlation between HLA-B27 and arthritis was not clear in this study.
      Administration of steroidal drug was thought to improve arthritis in shorter
      duration.

PMID- 15198000
TI  - [Awareness of periconceptional consumption of folic acid among urologists and a
      group of laymen].
AB  - OBJECTIVE: The Ministry of Health, Labour and Welfare announced that
      periconceptional consumption of folic acid will reduce risks of having babies
      afflicted with Neural Tube Defects (NTDs) in the year of 2000. We assessed
      awareness of the role of folic acid among urologists and a patient group, how
      urologists give advices on lifestyle to young women, and what lifestyle the
      patient group currently maintains. MATERIALS AND METHODS: A postal questionnaire
      survey was conducted involving 400 urologists randomly selected and a group of
      250 female patients afflicted with NTDS and 250 mothers who had given birth to
      babies having NTDs during the past 7 years. Eighty-four percent of urologists
      aged 40 years and over and 76% of the patient group aged in their 20s and 30s.
      Response rates were 56% in the former and 52% in the later. RESULTS: Twenty-six
      percent of urologists and 92% of the patient group knew an important role folic
      acid played in prevention of neural tube defects. While 10% of urologists advised
      to consume multi-vitamins containing folic acid or folic acid supplements, 25% of
      myelodysplastics and the mothers took them. Sixty-eight percent of doctors
      advised to take well-balanced food and 82% of the patent group answered that they
      do. Over 80% of the doctors and the patient group believed that a folic acid
      campaign is to be organized to inform young women of childbearing age of possible
      reduction of the risk. CONCLUSION: It is found that proportion of urologists who
      are aware of a role of periconceptional consumption of folic acid is
      significantly lower than that of the group of patients (p < 0.0001). Urologists
      are expected to recognize specific benefits of folic acid in the prevention of
      NTDs, to advise young women of childbearing age to take well-balanced meals, and
      to recommend those who wish to be pregnant to consume 400 micrograms of folic
      acid supplements from 4 weeks before to 12 weeks after conception.

PMID- 15198001
TI  - [Safe retroperitoneoscopic radical nephrectomy with small incision for renal cell
      carcinoma].
AB  - PURPOSE: Retroperitoneoscopic radical nephrectomy (RRN) has been performed at
      Yokohama City University Medical Center since May 2002. Three surgeons have
      become skilled in performing RRN without major complications. We investigated the
      outcomes of the surgery and attempt to clarify whether the technique we adopted
      is suitable to perform this procedure safely. PATIENTS AND METHODS: Between May
      2002 and June 2003, 14 patients suspected of renal cell carcinoma underwent
      retroperitoneoscopic radical nephrectomy at Yokohama City University Medical
      Center. The surgical procedure is shown below. In a lateral position, a lumbar
      oblique incision 6 cm long is made to approach the retroperitoneal space. Under
      direct vision, the ureter is dissected and Gerota's fascia is dissected from the
      peritoneum and the psoas muscle to signalize the subsequent dissection line.
      After the dissection, hand port device was attached to the skin and three 12 mm
      trocars were placed. The subsequent procedures are performed by
      retroperitoneoscopic surgery with carbon dioxide insufflation. The isolated
      kidney was removed through the incision that was made initially. We investigated
      the outcomes of this procedure. RESULTS: The mean surgical duration was 244.4
      minutes and mean blood loss was 217.9 ml. Conversion to open surgery was required
      in one case due to bleeding and in one case due to incomplete management of a
      small artery. Blood transfusion was not required in any case. There were no major
      complications during the perioperative period. CONCLUSIONS: The three operators
      have become skilled in performing RRN safely with this technique.

PMID- 15198002
TI  - [Primary malignant lymphoma of the urinary bladder: a case report].
AB  - We report a case of primary malignant lymphoma of the urinary bladder. A 72-year
      old woman complaining of low abdominal pain was admitted to the Tone Central
      Hospital in February, 2001. Macrohematuria appeared, and the submucosal tumor was
      observed by cystoscopy, and A Transurethral bladder biopsy led to a
      histopathological diagnosis of non-Hodgkin's malignant lymphoma (diffuse
      lymphoma, large-sized cell type, B-cell type). Clinical stage was IE, but as
      soon, she was get bilateral hydronephrosis and bladder-ileum fistula. The
      administration of 6-course CHOP chemotherapy had an excellent effect of
      disappearing the tumor, bilateral hydronephrosis, and bladder-ileum fistula. She
      remained free of disease until now.

PMID- 15198003
TI  - [A case of well controlled renal small cell carcinoma with metastasis treated by
      intensive therapy].
AB  - A 18-year-old male visited hospital with macroscopic hematuria. Computed
      tomography showed slightly enhanced left renal tumor that was uncharacteristic
      for clear cell carcinoma, and radical nephrectomy was performed. Operative
      specimen revealed primary small cell carcinoma of the kidney. 18 months after
      operation, bone metastases were diagnosed. Chemotherapy including cisplatinum,
      etoposide and bleomycin and external irradiation was performed. This intensive
      therapy was effective for metastatic lesion. He is still alive for 55 months
      after diagnosis, and is the best controlled case around the world. To our
      knowledge, this is the 14th case as primary renal small cell carcinoma in the
      world literature.

PMID- 15198005
TI  - [A case of urothelial cancer on a ureterocele].
AB  - A 62-year-old man consulted our hospital complaining of macroscopic hematuria.
      Intravenous urography showed a dilated terminal portion of the left ureter
      resembling a cobra head. Cystoscopy revealed multiple tumors on the ureterocele.
      There were no metastatic lesions on CT and MRI. Transurethral resection of the
      tumor and the ureterocele was performed and the pathological examination revealed
      transitional cell carcinoma on the ureterocele. This is the 4th case of
      urothelial cancer on a simple ureterocele reported in Japan.

PMID- 15198004
TI  - [Paravesical granuloma after inguinal herniorrhaphy].
AB  - Paravesical granuloma is a rare complication after inguinal herniorrhaphy. We
      report a case of this rare disease and review 27 previously reported cases. A 70
      year-old male presented with hematopyuria. He had undergone right inguinal
      herniorrhaphy five years earlier. On presentation, the right inguinal area was
      wet with exudate. Cystoscopy revealed edematous mucosa on the right side of the
      bladder dome, but transurethral bladder biopsy demonstrated no malignancy. CT
      identified a 2-cm diameter mass with heterogeneous appearance on the right side
      of the bladder dome. Treatment with antibiotics proved ineffective and en bloc
      excision of the tumor with partial cystectomy was performed. Symptoms
      subsequently resolved completely. Histopathologically, the tumor represented
      inflammatory granuloma, and a mesh thought to be a remnant from the previous
      herniorrhaphy was found in the central portion of the tumor. Paravesical
      granuloma should be considered for patients with continuous hematopyuria and a
      history of inguinal herniorrhaphy.

PMID- 15198006
TI  - [Neurogenic voiding dysfunction after sacrococcygeal teratoma resection].
AB  - A 6-year-old girl was referred to our department due to pyelonephritis. Voiding
      cystourethrogram (VCUG) revealed grade 4 vesicoureteral reflux (VUR) and urethral
      deformity (stenosis and lateral deviation). She had a history of sacrococcygeal
      teratoma resection in the newborn. Urodynamic study revealed a large-capacity
      hypotonic bladder and poor bladder emptying. Magnetic Resonance Imaging of the
      spine demonstrated no abnormal findings. Despite conservative therapy, there were
      no improvement of VUR. Then, urethral dilation and anti-reflux-surgery were
      performed. Six months after the operation, VCUG showed no VUR. However, she has
      persistent residual urine due to neurogenic voiding dysfunction, and is being
      treated with a regimen of frequent timed voiding to reduce urinary residual and
      urinary tract infection.

PMID- 15198007
TI  - [Nedaplatin for recurrent cancer of the head and neck].
AB  - This study was undertaken to evaluate the clinical efficacy and toxicity of
      Nedaplatin (254-S) alone or combined for UFT for recurrent head and neck cancers
      in an outpatient setting. Thirty-two patients, previously treated, (30 men and 2
      women, mean age 59 years, twenty one with loco-regional recurrence and 11 with
      distant metastasis, 29 with squamous cell carcinoma, 2 with adenocarcinoma and
      one with adenoid cystic carcinoma) were treated with Nedaplatin (254-S) alone or
      combined with UFT. The primary site was identified in the oropharynx in 8
      patients, oral cavity in 7, larynx in 5, nasopharynx in 4, hypopharynx in 3,
      sinuses in one, parotid in one, and unknown primary in one patient. 254-S was
      administered at 80 mg/m2 by intravenous drip infusion. The 254-S administration
      was repeated at 4 week intervals, and in some patients was combined with daily
      oral administration of 400 mg of UFT-E (tegafur-uracil enterogranules). Twelve
      patients received 254-S alone and in 20 patients it was combined with UFT-E. The
      254S administration ranged from one to 18 courses (mean of 5.7 courses). Grade 3
      4 toxicities included leukopenia in 15.6%, anemia in 6.3% and thrombocytopenia in
      9.4% of the patients. There was one death due to grade 4 leukopenic pneumonia.
      Four (12.5%) had a clinical complete and partial response. One-year and two-year
      overall survival rates were 35.6% and 30.5% for loco-regional recurrence,
      respectively. Ten of the eleven patients with distant metastasis died within six
      months and all patients were dead within 18 months, so a significant difference
      was observed in the overall survival rate between loco-regional recurrence and
      distant metastasis. Treatment with 254-S alone or combined UFT-E could be
      conducted in an outpatient setting and was able to improve the overall survival
      rate for recurrent head and neck cancer.

PMID- 15198008
TI  - [Investigation of automated infant auditory screening using the Natus-ALGO
      Portable device].
AB  - The aim of this study was to compare the Natus-ALGO Portable (Portable) device
      with the Natus-ALGO 2e and to evaluate its usefulness. Portable, an automated ABR
      screener (Natus Medical, Foster City, CA, USA) was used to screen 826 neonates in
      our hospital between February 2002 and March 2003. The referral rate for the
      first automated ABR screening was 0.85% while that for the second was 0.48%.
      Hearing impairment was detected in 0.24% of all newborns. The mean duration of
      the automated ABR test was 2 minutes, 45 seconds. The referral rate and mean test
      duration of the Portable device was equivalent to that of the Natus-ALGO 2e. We
      concluded that the Portable device is a useful tool in view of its low cost and
      portability. Among those who passed the Portable screening, the number of sweeps
      in the neonatal intensive care unit was significantly greater than that in the
      maternity ward. Careful estimation of REFER in neonatal intensive care units is
      important because the incidence of positive fails in the neonatal intensive care
      unit was much higher than that in the maternity ward. The number of sweeps
      performed in neonates between the ages of 2 to 6 days was not significantly
      different.

PMID- 15198009
TI  - [Adaptation of Japanese version of the Hearing Handicap Inventory for Adults
      (HHIA)].
AB  - We used social and emotional approaches to psychologically evaluate hearing
      disorders, translating the Hearing Handicap Inventory for Adults (HHIA) into
      Japanese and using it to evaluate Japanese adults with sensorineural hearing
      loss. The HHIA is a 25-item self-assessment scale composed of 2 subscales,
      emotional and social/situational, which has been used to evaluate adult patients
      with hearing disorders in Europe and North America. The test-retest reliability
      of the Japanese version and its screening version (HHIA-S) were excellent (kappa
      coefficients were 0.912 and 0.842). Due to the limitation of social/situational
      items, test-retest reliability was only good (0.6 < kappa coefficient < 0.8),
      possibly because of problems in translating these items. We discovered that the
      average of scores of the HHIA Japanese version was higher in bilateral hearing
      disorder patients than in those with unilateral hearing disorder. This score
      peaked in 2 to 10 years after onset and decreased thereafter in bilateral hearing
      disorder patients. The correlation coefficient between the average hearing level
      of 7 frequencies and scores of the test was highest among the 4 audiological
      evaluations. The HHIA Japanese version is thus useful for following up patients
      with hearing disorders.

PMID- 15198010
TI  - [Unattended automated titration to determine therapeutic continuous positive
      airway pressure in patients with obstructive sleep apnea].
AB  - Recently, devices which use a new technology that automatically titrates positive
      airway pressure have become available. Such devices continually adjust the
      pressure to maintain airway patency. In this paper, unattended automated
      titration to determine the therapeutic continuous positive airway pressure (CPAP)
      in patients with obstructive sleep apnea was evaluated to ascertain of it was a
      feasible titration to determine the therapeutic CPAP. Thirty patients
      participated in this study with obstructive sleep apnea syndrome defined by an
      apnea hypopnea index > 20/h. Automated titration during full polysomnography was
      performed in the hospital using auto CPAP devices (Autoset T, RESMED Co,
      Australia). During titration, there was no direct supervision by a technician.
      The titration method was as follows. Data obtained during the use of auto CPAP
      devices and polysomnography were used to provide a fixed single pressure for
      subsequent treatment. After determining the therapeutic continuous positive
      airway pressure, the efficacy of the patient's CPAP device was reconfirmed during
      full polysomnography. The results were, 1) Proper fixed single therapeutic
      pressure could be determined with this unattended automated titration,
      consequently apnea and sleep structure could be improved (Total sleep time, Sleep
      efficiency, %Stage 3 + 4, Apnea index, Apnea hypopnea index, Arousal index,
      Lowest SpO2, and Duration of SpO2 less than 90% were improved statistically (p <
      0.05)). 2) The 95th percentile airway pressure of the auto CPAP device should be
      applied for the therapeutic pressure. 3) Automated titration during full
      polysomnography should be performed using auto CPAP devices. 4) After determining
      the therapeutic CPAP, the efficacy of the patient's CPAP device should be
      reconfirmed during full polysomnography. 5) This method of titration was useful
      at the institution without attendant technician intervention.

PMID- 15198011
TI  - Prescription drugs uses and effects. Diuretics.

PMID- 15198012
TI  - New plea to fund AIDS fight.

PMID- 15198013
TI  - Why pay reform benefits patients.

PMID- 15198014
TI  - The confidence to manage. Interview by Lynne Pearce.

PMID- 15198015
TI  - Equal treatment. Interview by Terry Philpot.

PMID- 15198016
TI  - Where medicine left off. Interview by Emma White.

PMID- 15198017
TI  - Smoke and mirrors.

PMID- 15198018
TI  - From blackboard to bedside.

PMID- 15198019
TI  - Personal advice.

PMID- 15198020
TI  - Effective clinical learning in primary care settings.
AB  - This article reviews the literature on primary care settings as learning
      environments, and examines how the learning opportunities available for nurses
      and students can be recognised and harnessed. The aim is to establish the
      effectiveness of primary care settings as learning environments. This article
      also discusses mentoring experiences of district nurses, school nurses and health
      visitors.

PMID- 15198021
TI  - Care map. 1: Atypical antipsychotics. Weight gain.

PMID- 15198022
TI  - Assessment and treatment of chest pain.
AB  - Chest pain is one of the main reasons for emergency admission to hospital in the
      UK. Jackie Tough examines the causes and treatment of chest pain and offers a
      structured system for taking the patient's history.

PMID- 15198024
TI  - [The cytochrome cbo from the obligate methylotroph Methylobacillus flagellatus KT
      is a cytochrome-c oxidase].
AB  - The oxidase cho of Methylobacillus flagellatus KT was purified to homogeneity by
      nondenaturing gel electrophoresis, and the kinetic properties and substrate
      specificity of the enzyme were studied. Ascorbate and ascorbate/N,N,N',N'
      tetramethyl-p-phenylenediamine (TMPD) were oxidized by cbo with a pH optimum of
      8.3. When TMPD served as electron donor for the oxidase cho, the optimal pH (7.0
      to 7.6) was determined from the difference between respiration rates in the
      presence of ascorbate/TMPD and of only ascorbate. The kinetic constants,
      determined at pH 7.0, were as follows: oxidation by the enzyme of reduced TMPD at
      pH 7.0 was characterized by KM = 0.86 mM and Vmax = 1.1 mumol O2/(min mg
      protein), and oxidation of reduced cytochrome c from horse heart was
      characterized by KM = 0.09 mM and Vmax = 0.9 mumol O2/(min mg protein) Cyanide
      inhibited ascorbate/TMPD oxidase activity (Ki = 4.5-5.0 microM). The soluble
      cytochrome cH (12 kDa) partially purified from M. flagellatus KT was found to
      serve as the natural electron donor for the oxidase cbo.

PMID- 15198023
TI  - [Activation of the alternative oxidase of Yarrowia lipolytica by adenosine 5'
      monophosphate].
AB  - The study of the effect of nucleoside phosphates on the activity of cyanide
      resistant oxidase in the mitochondria and the submitochondrial particles of
      Yarrowia lipolytica showed that adenosine monophosphate (5'-AMP, AMP) did not
      stimulate the respiration of the intact mitochondria. The incubation of the
      mitochondria at room temperature (25 degrees C) for 3-5 h or their treatment with
      ultrasound, phospholipase A, and detergent Triton X-100 at a low temperature
      inactivated the cyanide-resistant alternative oxidase. The inactivated
      alternative oxidase could be reactivated by AMP. The reactivating effect of AMP
      was enhanced by azolectin. Some other nucleoside phosphates also showed
      reactivating ability in the following descending order. AMP = GMP > GDP > GTP >
      XMP > IMP. The apparent reaction rate constant Km for AMP upon the reactivation
      of the alternative oxidase of mitochondria treated with Triton X-100 or incubated
      at 25 degrees C was 12.5 and 20 microM, respectively. The Km for AMP upon the
      reactivation of the alternative oxidase of submitochondrial particles was 15
      microM. During the incubation of yeast cells under conditions promoting the
      development of alternative oxidase, the content of adenine nucleotides (AMP, ADP,
      and ATP) in the cells and their respiration tended to decrease. The subsequent
      addition of cyanide to the cells activated their respiration, diminished the
      intracellular content of ATP three times, and augmented the content of AMP five
      times. These data suggest that the stimulation of cell respiration by cyanide may
      be due to the activation of alternative oxidase by AMP.

PMID- 15198025
TI  - [Activity of the key enzymes in xylose-assimilating yeasts at different rates of
      oxygen transfer to the fermentation medium].
AB  - The activities of xylitol dehydrogenase and xylose reductase in the yeasts
      Candida shehatae, C. didensiae, C. intermediae, C. tropicalis, Kluyveromyces
      marxianus, Pichia stipitis, P. guillermondii, Pachysolen tannophilus, and
      Torulopsis molishiama were studied at different oxygen transfer rates (OTRs) to
      the fermentation medium (0, 5, and 140 mmol O2/(1 h)). The activities of these
      enzymes were maximum in the yeasts P. stipitis and C. shehatae. The xylitol
      dehydrogenase of all the yeasts was NAD-dependent, irrespective of the intensity
      of aeration. The xylose reductase of the yeasts C. didensiae, C. intermediae, C.
      tropicalis, Kl. marxianus, P. guillermondii, and T. molishiama was NADPH
      dependent, whereas the xylose reductase of P. stipitis, C. shehatae, and Pa.
      tannophilus was specific for both NADPH and NADH. The effect of OTR on the
      activities of the different forms of xylitol dehydrogenase and xylose reductase
      in the xylose-assimilating yeasts is discussed.

PMID- 15198026
TI  - [The aeration-dependent effect of vitamin B12 on DNA biosynthesis in
      Methylobacterium dichloromethanicum].
AB  - The effect of vitamin B12 (cobalamin) on DNA biosynthesis in Methylobacterium
      dichloromethanicum was studied. When cultivated in media with methanol or
      dichloromethane, the bacterium produced approximately 10 micrograms corrinoids
      per g dry biomass, compared to about 7 micrograms/g when cultivated on ethanol or
      succinate. Exogenous adenosylcobalamin (AdoCbl) stimulated DNA biosynthesis in M.
      dichloromethanicum cells grown under poor aeration, the effect being mediated by
      AdoCb1-linked ribonucleotide reductase. In vitro studies showed that M.
      dichloromethanicum also has AdoCbl-independent ribonucleotide reductase. Under
      good aeration, exogenous AdoCbl had no effect on DNA biosynthesis, while
      hydroxyurea suppressed it. These data suggest that AdoCbl-independent
      ribonucleotide reductase, which is likely to be activated by oxygen, plays an
      important part in DNA biosynthesis when M. dichloromethanicum is cultured with
      good aeration, whereas AdoCbl-dependent ribonucleotide reductase is active under
      the conditions of poor aeration.

PMID- 15198027
TI  - [Deuterium oxide as a stress factor to the methylotrophic bacterium Methylophilus
      sp].
AB  - The adaptation of the methylotrophic bacterium Methylophilus sp. B-7741 to growth
      in highly deuterated media was studied. For the first time, we showed the cross
      adaptation of bacterial cells to deuterated media and oxidative and osmotic
      stresses. The activity at catalase in deuterated cells was higher than in the
      control cells. Deuterated cell-free culture liquids showed protective effects on
      the growth of Methylophilus sp. B-7741 in deuterated media, which was manifested
      as an increase in the deuterated biomass yield. These data and the data available
      in the literature suggest that the mechanisms of bacterial cell adaptation to
      heavy water and to oxidative and osmotic stresses are similar.

PMID- 15198028
TI  - [A comparison of the lipopolysaccharides and O-specific polysaccharides of
      Azospirillum brasilense Sp245 and its omegon-Km mutants KM018 and Km252].
AB  - The lipopolysaccharides (LPSs) extracted from the outer membrane of Azospirillum
      brasilense Sp245 and its Omegon-Km mutants KM018 and KM252 with a hot aqueous
      solution of phenol were found to differ in the content of carbohydrates,
      glucosamine, and total phosphorus and in the proportion of octadecenoic and
      hexadecanoic acids in the lipid moieties of the LPSs. The carbohydrate moieties
      of the LPSs were heterogeneous in charge. The analysis of the O-specific
      polysaccharides (O-PSs) of the mutants KM018 and KM252 by gas-liquid
      chromatography, IR spectroscopy, and NMR spectroscopy showed that they are
      composed of the same linear pentasugar repeating units-->2)-beta-D-Rhap-(1-->3)
      alpha-D-Rhap-(1-->3)-alpha-D-Rhap-(1-->2)- alpha-D-Rhap-(1-->2)-alpha-D-Rhap-(1-
      >as the O-PSs of the parent strain Sp245. The reported differences in the
      biological activity of the LPSs of the parent and mutant strains can be due to
      their different chemical structure.

PMID- 15198029
TI  - [Characterization of enterobacteria producing the low-molecular-weight
      antibiotics microcins].
AB  - A comparative study of the morphological, cultural, physiological, and
      biochemical properties of the microcinogenic strains EcS 5/98, EcS 6/98, and EcB
      214/99 with the known microcin C51 producer Escherichia coli M17(p74) showed that
      these strains belong to the species E. coli. The strains produced microcins with
      molecular masses lower than 10 kDa. Microcin biosynthesis was stimulated by a
      deficiency of nutrients in the cultivation media. Microcins were found to be
      resistant to thermolysin, but were degraded by pronase, protolichetrem, and the
      Bacillus mesentericus metalloproteinase. This indicated that microcins are
      peptides or contain peptides in their molecules. The study of cross immunity to
      microcins and the sequence of their genetic determinants showed that the
      microcins of strains EcS 5/98 and EcS 6/98 are of B type, whereas the microcin of
      strain EcB 214/99 presumably belongs to another type, since it suppresses the
      growth of the producers of C-type and B-type microcins. The new microcin
      producers possess antibacterial activity against natural isolates belonging to
      the genera Escherichia and Salmonella, against a wide range of colicinogenic
      Escherichia strains, and against the collection Salmonella cultures.

PMID- 15198030
TI  - [The effect of tryptophan of plant root metabolites on the phyto stimulating
      activity of rhizobacteria ].
AB  - Aseptic tomato and radish roots were found to exude 2.8-5.3 and 290-390 ng
      tryptophan per seedling per day. The inoculation of radish plants with
      rhizosphere pseudomonads increased the root biomass by 1.4 times. The inoculation
      of tomato plants with the same pseudomonads was ineffective. The beneficial
      effect of bacterial inoculation on the radish plants can be explained by the fact
      that the introduced rhizobacteria produce the plant growth-stimulating hormone
      indole-3-acetic acid. In pot experiments, the addition of this phytohormone to
      the soil increased the mass of radish roots by 36%. The phytohormonal action of
      the rhizosphere microflora was found to be efficient provided that the
      concentration of tryptophan in the rhizosphere is sufficiently high.

PMID- 15198031
TI  - [Cobalt- and chromium-containing inclusions in bacterial cells].
AB  - Bacteria belonging to different taxonomic and physiological groups (members of
      the genera Pseudomonas, Brevibacterium, Rhodopseudomonas, and Lactococcus) are
      able to form intracellular cobalt- and chromium-containing magnetic inclusions.
      The paper deals with the structure and the intracellular localization of these
      inclusions and their similarity to the known noncrystalline iron-containing
      magnetic inclusions. The possible biological role of the magnetic inclusions is
      discussed.

PMID- 15198032
TI  - [Protection of Saccharomyces cerevisiae against oxidative and radiation-caused
      damage by alkyl hydroxybenzenes].
AB  - The effects of C7-alkylhydroxybenzene (C7-AHB) and p-hydroxyethylphenol
      (tyrosol), chemical analogs of microbial anabiosis autoregulators, on the
      viability of yeast cells under oxidative stress were investigated. The stress was
      caused by reactive oxygen species (ROS) produced under gamma irradiation of cell
      suspensions using doses of 10-150 krad at an intensity of 194 rad/s or by singlet
      oxygen generated in cells photosensibilized with chlorin e6 (10 micrograms/l). C7
      AHB was found to exert a protective effect. The addition of 0.05-0.16 vol% of C7
      AHB to cell suspensions 30 min before irradiation protected yeast cells from
      gamma radiation (50 krad). The protective effect of C7-AHB manifested itself both
      in the preservation of cell viability during irradiation and in the recovery of
      their capacity to proliferate after irradiation. In our studies on photodynamic
      cell inactivation, the fact that the phenolic antioxidant C7-AHB protects cells
      from intracellular singlet oxygen was revealed for the first time. The analysis
      of difference absorption spectra of oxidized derivatives of C7-AHB demonstrated
      that the protective mechanism of C7-AHB involves the scavenging of ROS resulting
      from oxidative stress. The fact that tyrosol failed to perform a photoprotective
      function suggests that the antioxidant properties of microbial C7-AHB are not
      related to their chaperon functions. The results obtained make an important
      addition to the spectrum of known antioxidant and antistress effects of phenolic
      compounds.

PMID- 15198033
TI  - [Expression vector pLF22 for the lactic acid bacteria].
AB  - The construction of the expression vector pLF22 for lactic acid bacteria is
      described. The vector contains a replicon of the cryptic plasmid pLF1311 from
      Lactobacillus fermentum and a multiple cloning site of the lacZ' gene integrated
      with the plasmid rep operon. Such a construction of the vector provides for the
      constitutive transcription of the cloned sequences lacking the terminators of
      transcription in all the strains that maintain the replication of the vector. The
      vector is suitable for a wide range of gram-positive and gram-negative bacteria,
      including probiotic strains. The efficiency of the vector was verified by
      expressing the beta-galactosidase gene in a laboratory Escherichia coli strain
      and the synthetic gene of somatotropin releasing factor (SRF) in the probiotic
      strains of lactobacilli and enterococci. A recombinant strain with the SRF gene
      included in the diet of laboratory animals exerted an effect on their
      physiological and anthropometric parameters and on the histological
      characteristics of animal tissues.

PMID- 15198035
TI  - [Seasonal dynamics in a yeast population on the Oxalis acetosella L. leaves].
AB  - Analysis of an epiphytic yeast population on the leaves of the evergreen common
      wood sorrel Oxalis acetosella L. throughout a year showed that the density and
      the species composition of this population underwent regular seasonal changes.
      There were almost no yeasts on the young spring leaves. However, the yeast
      population on the mature leaves tended to increase in the autumn, reaching a
      maximum after the formation of continuous snow cover. Then the yeast population
      on the leaves tended to decrease, reaching a minimum in the spring. The species
      diversity of the yeasts was maximum in the autumn. The population of the
      epiphytic yeast species Cystofilobasidium capitatum, Rhodotorula fujisanensis,
      Leucosporium scottii, and Cryptococcus flavus peaked in the autumn. On the other
      hand, the population of the widespread epiphytic species Cryptococcus laurentii
      on the wood sorrel leaves peaked in January. The relative abundance of the red
      pigmented phytobionts Rhodotorula glutinis and Sporobolomyces roseus virtually
      did not change throughout the year. The relative abundance of the euribiotic
      species Cryptococcus albidus showed irregular monthly variations. The data
      obtained show that the epiphytic microbial population of various plants can be
      comprehensively studied only by analyzing this population throughout the
      vegetative period of the plants.

PMID- 15198036
TI  - [Mathematic modeling of the dynamics of the interacting population of the
      rhizosphere microorganisms].
AB  - A quantitative model is proposed to describe the population dynamics of
      associative nitrogen-fixing microorganisms in the plant rhizosphere as dependent
      on the rate of carbon substrate exudation by plant roots. By changing the values
      of the basic model parameters, the effect of various factors on the behavior of
      two competing populations of rhizospheric microorganism can be studied.

PMID- 15198034
TI  - [Three new species of brevibacteria--Brevibacterium antiquum sp. nov.,
      Brevibacterium aurantiacum sp. nov. and Brevibacterium permense sp. nov].
AB  - This work deals with the taxonomic study of 12 orange-pigmented bacteria isolated
      from permafrost sediments, rice plots, and soils contaminated with wastes from
      the chemical and salt industries, which were assigned to the genus Brevibacterium
      on the basis of phenotypic characteristics, as well as of some strains described
      previously as Brevibacterium linens. The study revealed three genomic species,
      whose members and the type strains of the closest species of Brevibacterium had
      DNA similarity levels between 24 and 59%. The strains of the genomic species
      differed from each other and from the known species of Brevibacterium in some
      physiological and biochemical characteristics, as well as in the sugar and polyol
      composition of their teichoic acids. The 16S rDNA sequence analysis confirmed the
      assignment of the environmental isolates to the genus Brevibacterium and showed
      the phylogenetic distinction of the three genomic species. The results obtained
      in this study allow three new Brevibacterium species to be described:
      Brevibacterium antiquum (type strain VKM Ac-2118T = UCM Ac-411T), Brevibacterium
      aurantiacum (type strain VKM Ac-2111T = NCDO 739T = ATCC 9175T), and
      Brevibacterium permense (type strain VKM Ac-2280T = UCM Ac-413T).

PMID- 15198037
TI  - [Estimation of the total and active microbial biomass in burial mound paleosoils
      of a different age].
AB  - Microorganisms that were isolated from steppe soils buried below kurgans from
      5800 to 750 years ago were analyzed for the completeness of isolation, total
      biomass (the sum of glucose-reactivated and resting microbial cells), and active
      biomass (metabolically active cells). The metabolic state of microbial
      communities in buried and modern background soils was estimated from the
      proportion of active and total biomasses. The paleosoils were found to be
      characterized by lower total and active biomasses and a lower proportion of
      active microorganisms as compared to the modern background soils. The age
      dependent decrease in the content of active microorganisms in the microbial
      communities of palesoils was not monotonic. For instance, the 4000-year-old
      paleosoil was characterized by a high total biomass and a relatively low content
      of active microorganisms, whereas the 1950-year-old paleosoil was characterized
      by a relatively low total biomass and a relatively high content of active
      microorganisms. This could reflect the temporal dynamics of paleoclimatic
      conditions in the geographic region under study.

PMID- 15198038
TI  - [Bacterial processes of the methane cycle in the bottom sediments of Baikal
      lake].
AB  - The activity of methanogenic and methanotrophic bacteria was evaluated in bottom
      sediments of Lake Baikal. Methane concentration in Baikal bottom sediments varied
      from 0.0053 to 81.7 ml/dm3. Bacterial methane was produced at rates of 0.0004
      534.7 microliters CH4/(dm3 day) and oxidized at rates of 0.005-1180 microliters
      CH4/(dm3 day). Peak methane production and oxidation were observed in Frolikha
      Bay near a methane vent. Methane was emitted into water at rates of 49.2-4340
      microliters CH4/(m2 day). Rates of bacterial methane oxidation in near-bottom
      water layers ranged from 0.002 to 1.78 microliters/(1 day). Methanogens and
      methanotrophs were found to play an important role in the carbon cycle through
      all layers of sediments, particularly in the areas of methane vent and gas
      hydrate occurrence.

PMID- 15198039
TI  - [Methane content in bottom sediments and water mass of the Black Sea].
AB  - The methane content in bottom sediments and water column of the Black Sea was
      determined using various methods of desorption and analysis of gases and various
      methods of calculating their concentrations. The head-space method with the use
      of salting out and calculation by internal standard proved to be the most
      accurate procedure for the analysis of methane concentration in bottom sediments.
      The methane content in bottom sediments increased with the depth of sediment
      sampling. In the upper 50-70 cm of shelf sediments, two minimums of methane
      concentration were revealed; in deep-sea sediments, only one minimum was recorded
      (in the 20-50 cm horizons). In the water column, methane concentrations slowly
      grew from the surface to a depth of 150-200 m and abruptly increased to a depth
      of 700-1200 m, remaining virtually constant in underlying layers. In certain deep
      sea regions, peaks of methane content in the 1000-1200 m horizons of the water
      column were revealed, which were most probably due to local influx of abyssal
      waters enriched with this gas.

PMID- 15198040
TI  - [Intensities of microbial production and oxidation of methane in bottom sediments
      and water mass of the Black Sea].
AB  - Intensities of biogeochemical (microbial) processes of methane production and
      methane oxidation were determined in bottom sediments and water column of the
      Black Sea. Aerobic bacterial oxidation of methane is confined to the upper 20-30
      cm of Holocene bottom sediments of the shelf (0.7-259 ng C/(dm3 day)) and
      oxygenated waters (0.2-45 ng C/(dm3 day)). In reduced sediments of the deep-sea
      zone and in the hydrogen sulfide-containing water column, considerable
      intensities of anaerobic methane oxidation were recorded, comparable to or
      exceeding the intensities of methane oxidation in oxygenated layers. From one
      fourth to one half of the methane formed in bottom sediments was oxidized
      immediately therein. The major part of the remaining methane was oxidized in the
      water column, and a smaller portion arrived in the atmosphere.

PMID- 15198041
TI  - [Newly discovered properties of spore-forming sulfate-reducing bacteria,
      Desulfotomaculum 435 and 781 strains].

PMID- 15198042
TI  - [Bacteria of the genus Psychrobacter isolated from Black sea water].

PMID- 15198043
TI  - Meniere's disease and anxiety disorders.
AB  - Diagnosis of Meniere's Disease is based upon the wellknown labyrinthic syndrome
      (hypoacusia, tinnitus and dizziness) which manifests with the typical abscessual,
      recurrent and unforeseeable course. Many Meniere patients also report panic
      attacks, agoraphobia and anxiety which make evaluation of labyrinthic symptoms
      difficult, affect the onset and maintenance of vestibular compensation and
      require specific treatments which are very different from those for the control
      of endolymphatic hydrops. In order to analyse the nature and the meaning of the
      association of the vestibular and psychiatric symptoms, a comparison has been
      made between patients presenting Meniere's disease, and a group of patients with
      dizziness resulting from other vestibular diseases. Socio-demographic data were
      collected and anxiety tests were used to evaluate, the depression and phobia. An
      interview ad hoc was also programmed for the psychiatric diagnosis. A previous
      psychiatric history, age, sex, marital status as well as education appear to have
      a variable effect upon the onset and evolution of panic-phobic symptoms,
      following onset of Meniere's disease. These conclusions, which require
      confirmation with further studies, allow early characterisation of Meniere's
      disease patients of great predictive usefulness as far as concerns the
      development of psychiatric sequelae of a panic-phobic nature. This evolution is
      far more frequent in females being enhanced by middle age, low level of
      education, long-standing Meniere's disease and large number of attacks of
      dizziness. Onset of panic-phobic attacks is more rare in males in whom the
      condition is associated with young age, high level of education, lack of setting
      up of a family nucleus with children.

PMID- 15198044
TI  - Effect of repetition of Semont's manoeuvre on benign paroxysmal positional
      vertigo of posterior semicircular canal.
AB  - If Semont's liberating manoeuvre does not lead to relief of symptoms in benign
      paroxysmal positional vertigo of posterior semicircular canal after the first
      session, it can be repeated once again, in refractory cases, whilst symptomatic
      patients after second manoeuvre require rehabilitation therapy Repeating Semont's
      manoeuvre several times has proven to progressively increase the percentage of
      cured patients or it may convert posterior semicircular canal forms to typical
      incomplete or lateral semicircular canal forms, hence requiring other manoeuvres
      to achieve vertigo resolution. Aim of study was to assess the effect of
      liberating manoeuvres repeated up to 4 times and to establish possible passages
      from one canal to the other during manoeuvres as well as percentage of cases
      refractory to this therapy, who would then need rehabilitation. Benign paroxysmal
      positional vertigo was diagnosed in 448 cases of whom 344 (76.8%) of the
      posterior semicircular canal, 20 (0.45%) the incomplete form of the posterior
      semicircular canal, 20 (0.45%) subjective positional vertigo and 74 of the
      lateral semicircular canal (4.2%). Right side was affected in 58.4% of cases,
      left in 34.5%, and bilateral in 7.1%. All 344 patients underwent Semont's
      liberating manoeuvre (1st manoeuvre) with first control after 48 hours: if
      symptoms (typical, atypical nystagmus or paroxysmal vertigo evoked by Dix
      Hallpike's manoeuvre) persisted, Semont's liberating manoeuvre was repeated (2nd
      manoeuvre). In presence of lateral semicircular canal benign paroxysmal
      positional vertigo conversion, Lempert's manoeuvre was performed instead. Second
      control was performed after 48 hours and in cases of persistent typical, atypical
      or lateral semicircular canal nystagmus 3rd manoeuvre was performed. After
      further 48 hours, third control was carried out: symptomatic patients with
      typical forms were submitted to 4th manoeuvre, while typical incomplete forms or
      forms of the lateral semicircular canal underwent Lempert's manoeuvre. In
      conclusion, symptoms disappeared after 1st manoeuvre in 61.6% of cases; further
      manoeuvres, carried out in view of possible changes in semeiology of vertigo,
      increased the percentage of cured patients to 82.5% after the 2nd, 90.7% after
      3rd and 94.1% after the 4th. Repeated positioning manoeuvres in benign paroxysmal
      positional vertigo led to a progressive increase in percentage of cured vertigo,
      at the same time, allowing detection of those cases converted to multicanal
      pathology, hence offering the possibility to proceed with appropriate liberating
      manoeuvres.

PMID- 15198045
TI  - High frequency surgery in the treatment of turbinate hypertrophy: 11 years'
      experience.
AB  - For over a century, surgical management of lower turbinate hypertrophy has given
      rise to much discussion. Aim of the present investigation was to establish, by
      means of the analysis of a large patient population, the efficacy and
      reproducibility of high frequency surgery in the treatment of this condition. A
      total of 1689 non-allergic patients with nasal obstruction, presenting
      hypertrophy of the lower turbinates, were submitted, under local anaesthesia, to
      turbinates decongestion using a high frequency instrumental unit with a bipolar
      terminal electrode. Efficacy of the procedure was evaluated on the basis of
      objective examination, results of questionnaires, active anterior rhinomanometry
      and mucociliar transport time. Results revealed a reduction of hypertrophy, an
      improvement in symptoms, a reduction in nasal resistances and an improvement of
      mucociliar transport time. The large patient population, low post-operative
      complication rate and the good patient compliance, due also to the fact that no
      haemostatic procedure is necessary, would suggest that this method is
      particularly valid, effective and safe for the treatment of hypertrophy of the
      lower turbinates.

PMID- 15198046
TI  - Oropharyngeal carcinoma during pregnancy: clinical and psycho-oncological
      aspects.
AB  - Cancer is uncommon in pregnancy, occurring in approximately one out of 1000
      pregnancies, although it has been noted that one out of 118 women diagnosed with
      cancer is pregnant at the time of diagnosis. In the last 10 years, two
      oropharyngeal carcinomas, (1 squamous cell carcinoma and 1 adenoid cystic
      carcinoma) which developed during pregnancy, have been diagnosed and treated in
      our Department. No cases of oropharyngeal cancer, during pregnancy, have so far
      been reported in the literature with the exception of one case of oral cancer.
      This report focuses not only on the clinical history but also the management of
      oropharyngeal carcinoma during pregnancy, in terms of choice and timing of
      treatment. A scrupulous psycho-oncological analysis was also carried out in order
      to throw further light on psychological repercussions of head and neck cancer in
      the pregnant woman.

PMID- 15198047
TI  - Positron emission tomography (PET) in the staging of head neck cancer: comparison
      between PET and CT.
AB  - Standard pre-treatment clinical staging (TNM) of head and neck squamous cell
      carcinoma includes clinical and instrumental objective examination of primary
      tumour and of the cervical lymph nodes (inspection, palpation of neck,
      panendoscopy, biopsy of tumour, fine needle aspiration of nodes) and computed
      tomography or magnetic resonance imaging. Albeit, this procedure presents
      diagnostic limitations in the identification of approximately 1/3 of T1, of small
      sized nodes and in the diagnosis of metastases. Positron emission tomography
      fluorodesoxy-glucose imaging, in the diagnostic workup of these cases, appears to
      offer an important contribution, however, its use is limited due to poor
      availability of this equipment and the high cost of the examination. In the
      present study, a comparison is made of results of standard clinical staging and
      positron emission tomography-fluorodesoxy-glucose in 22 patients with head and
      neck carcinoma prior to surgical treatment, with the results of pathological
      staging (pTNM) carried out on surgical specimens. In the staging of the tumour,
      computed tomography shows a sensitivity of 71% and positron emission tomography
      of 81%. In the staging of nodes, computed tomography imaging shows a sensitivity
      of 73%, a specificity of 57% and an accuracy of 68%, whereas positron emission
      tomography shows a sensitivity of 93%, a specificity of 100% and an accuracy of
      95%. Furthermore, positron emission tomography identified 1/5 occult tumours and
      one tumour revealed at objective endoscopic examination, but not by computed
      tomography. The risk of occult nodes following positron emission tomography was
      found to be 7%. Overall, these results are in keeping with those reported in the
      literature, thus confirming the usefulness of positron emission tomography
      fluorodesoxy-glucose in identifying occult tumours and nodes, in which computed
      tomography appears to be limited. Indications of positron emission tomography
      fluorodesoxy-glucose may play a role in the choice of therapeutic options for the
      clinically N0 neck.

PMID- 15198048
TI  - p53 overexpression on the resection margins as a marker of local recurrence in
      glottic T1a carcinoma.
AB  - Glottic carcinoma, in the early stage, may benefit, with excellent results "quoad
      vitam atque quoad valitudinem", from various modes of treatment--radiotherapy,
      laser microsurgery and cordectomy being the most common--in definitive cure of
      the disease. Nevertheless, recurrence, in relation to treatment, oscillates
      between 4.3-24.1% with laser CO2 surgery, 5.5-32.4% for cordectomy and 5.3-34%
      for radiotherapy. Prognostic biological markers of recurrence remain to be
      elucidated, mainly due to the clinical differences in the subjects examined. The
      present study focused on patients with glottic T1a carcinoma treated with CO2
      laser surgery in which correlation between histo-pathological aspects and
      expression of p53 protein on resection borders were confirmed by onset of local
      recurrence. Study population comprised 39 patients treated with CO2 laser surgery
      (January 1985-December 1991) in Clinical Division of Otorhinolarygology,
      University of Catania. Survival rate, free from recurrence, at 3 and 5 years for
      this patient group was 87.1% (34/39) and 82% (32/39), respectively. Disease-free
      survival at 3 and 5 years, was 86.6% in patients with positive resection margins
      for carcinoma and 87.5% and 79.1%, respectively, for patients with negative
      resection margins. Survival rate, free from local recurrence, in p53 positive
      patients, at 3 and 5 years was 78.9% and 68.4%, respectively. In p53 negative
      patients, survival, free from local recurrence, at 3 and 5 years, was 94.7%.
      Presence of overexpression of oncoprotein p53 on borders of resection with
      aspects of dysplasia of various degrees seems, therefore, a marker of high risk
      of tumour progression and recurrence.

PMID- 15198049
TI  - Endoscopic CO2 laser treatment of supraglottic carcinoma.
AB  - Aim of the study was to evaluate whether laser endoscopic microsurgery is a
      reliable and appropriate approach to treatment of laryngeal supraglottic cancer.
      A retrospective study was made of 12 patients (11 M/1 F; mean age 62.5 years)
      treated from December 1995 to October 2001 in the Department of Surgical Sciences
      and Organ Transplantations, Section of Otorhinolaryngology, University of
      Cagliari, Italy. Surgical steps and oncologic results are reported. These 12
      patients with supraglottic cancer underwent transoral laser surgery (TNM
      classification: T1, 3 patients; T2, 9 patients; N-, 9 patients; N+, 3 patients; M
      , 12 patients). On the basis of the different subsites removed, the following
      resections were performed: 1 limited excisional biopsy (false chord), 3 wide
      excisional biopsies (2 or 3 subsites), 2 simple epiglottectomies, 1 extended
      epiglottectomy, 3 horizontal supraglottic laryngectomies, and 2 horizontal
      supraglottic laryngectomies that were extended to the anterior commissure and to
      one arytenoid, respectively. Five patients underwent functional neck dissection,
      and one patient underwent post-operative radiotherapy at sites of tumour and
      lymph nodes. Temporary tracheotomy was carried out in 10 patients. Mean follow-up
      was 33.3 months. No local recurrences were noted. Local control was thus 100%.
      Aspiration was the main post-operative problem, but there were no cases of
      aspiration-associated pneumonia. Moreover, no patient needed laryngectomy or a
      permanent tracheotomy for aspiration. In conclusion, although our experience with
      supraglottic cancers treated by endoscopy is still too limited to confirm the
      definitive oncologic validity of this type of surgery, in our hands, it seems to
      be a reasonable tool in selected cases and a safe, time- and cost-effective
      alternative to traditional surgery or radiotherapy for selected supraglottic
      carcinomas.

PMID- 15198050
TI  - Psychological profile of dysfunctional dysphonia.
AB  - A high degree of emotional maladjustment can be detected in dysfunctional
      dysphonia. In these patients, it is not rare to observe an immediate resolution
      of the phoniatric disorder, but it is equally as common to identify a significant
      rate of recurrence (> 10%) in the short and long term. This phenomenon may be due
      to poor adaptive ability in the presence of mood disorders. Aims of this study
      were: a. selection of a suitable instrument to identify "minor" and "major"
      symptoms of psychiatric nature in dysphonic subjects; b. evaluation of profile of
      mood disorders in dysfunctional dysphonic adults. Hopkins Symptom Check List 90
      was chosen. This is a scale of self-evaluation, adapted in Italian, complete (9
      dimensions) and easy to use. It is employed to evaluate the following dimensions:
      somatization, obsessive compulsive, interpersonal sensitivity, depression,
      anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism, sleep
      disorders. Three groups were studied: group 1:40 patients (36 female, 4 male;
      aged 18-62 years, mean 42) with dysfunctional dysphonia; group 2: 20 patients (18
      female, 2 male; aged 19-61 years, mean 43) with ENT disorders; group 3: 20
      subjects (18 female, 2 male; aged 18-62 years, mean 42.2) as controls. In the
      statistical analysis, a one-way variance between the three groups and a post-hoc
      analysis using Schiffe test (level of significance 0.05) were carried out.
      Results showed significant differences between group 1 and groups 2 and 3 as far
      as concerns anxiety, phobia, obsessive-compulsive, interpersonal sensitivity and
      somatization variables. A significant difference was found only between groups 1
      and 3 as far as concerns the variables: sleep disorders, depression and paranoid
      ideation. No significant difference emerged between the groups regarding
      psychoticism and anger/hostility dimensions. The present study identified a
      definite profile of minor personality disorders, of an anxious nature, with
      evidence of somatization, interpersonal sensitivity and obsessive-compulsive type
      traits, significantly prevailing in dysfunctional dysphonic subjects. Symptom
      Check List-90 has, therefore, proven to be an adequate instrument in the more
      complete definition of subjects affected by dysfunctional dysphonia aiming at
      referral to an integrated protocol which focuses on phoniatric treatment using an
      approach which acts upon the behavioural aspects of communication.

PMID- 15198051
TI  - Temporary tracheotomy in the surgical treatment of obstructive sleep apnea
      syndrome: personal experience.
AB  - Aim of the study is a retrospective analysis on the use of temporary tracheotomy
      in our snoring surgery experience. From September 1996 to April 2002, 1103
      snoring surgery procedures have been carried out on various sites of the upper
      airways in 530 patients (mean age 50 years, 81% males) prevalently related to
      severe Obstructive Sleep Apnea Syndromes (33%). Of these patients, 472 (89%) were
      operated upon under general anaesthesia, whereas 58 (11%) received local
      anaesthesia. Of the 472 patients operated upon under general anaesthesia, 17
      (3.6%) underwent temporary tracheotomy, which in 10 (2.1%) were programmed and
      only in 7 (1.5%) were non-programmed, having been performed in 2 cases in an
      emergency setting, in 3 cases in an urgency setting due to respiratory
      obstruction immediately after removal of intubation and in 2 cases in conditions
      of urgency, due to respiratory obstruction occurring during post-operative
      hospitalisation (both performed within 6 hours of regaining consciousness). The
      only complication observed was a brief laryngeal diplegia, a complication,
      moreover, not reported in the literature. No criteria exist concerning
      indications for temporary tracheotomy programmed according to the type of surgery
      on the hypopharynx; personal experience reveals that: a) temporary tracheotomy is
      frequently necessary after genioglossus advancement (3/10 operated upon for
      genioglossus advancement not associated with a programmed temporary tracheotomy);
      b) temporary tracheotomy is rarely necessary after hyoid suspension (1/98
      patients being submitted to hyoid suspension not associated with programmed
      temporary tracheotomy). Temporary tracheotomy should, in our opinion, be taken
      into consideration in snoring surgery techniques, particularly in the presence of
      the not infrequent urgency or emergency situations occurring in patients with
      Obstructive Sleep Apnea Syndromes. With the use of temporary tracheotomy, no
      deaths occurred in the present study population.

PMID- 15198052
TI  - [Infrared video-oculography and video-nystagmography: state-of-the-art].

PMID- 15198053
TI  - [Innovations, advantages and limitations of the infrared video-nystagmography].

PMID- 15198054
TI  - [Preliminary assessment of the patient and methodologies of nystagmography].

PMID- 15198055
TI  - [Clinical interpretation of video-nystagmographic results: concepts of
      directional prevalence, hypovalence and reflectivity].

PMID- 15198056
TI  - [News in vestibulometry: neural networks in the torsional eye movement records by
      video-nystagmography].

PMID- 15198057
TI  - [Obstruction of the nose in newborns].
AB  - Five newborns, 4 girls and 1 boy, presented with breathing and feeding
      difficulties caused by obstruction of the nose. The causes were choanal atresia,
      apertura pyriformis stenosis, teratoma, glioma and haemangioma. Following
      surgical treatment the children were symptom-free. Rapid diagnosis and treatment
      of these conditions are essential. An alternative airway should be created if a
      newborn suffers from breathing problems. Diagnostic work-up includes flexible
      laryngo-endoscopy followed by MRI- or CT-scan. Treatment is usually surgical.

PMID- 15198058
TI  - [Value of cost-utility analysis; evidence-based policy making].
AB  - In this issue of the Journal a review on the present state of science regarding
      cost-utility analysis is presented. The article can be regarded as a laudable
      enumeration of the points of academic discussion still associated with cost
      utility analyses. Indeed, various schools of researchers with different positions
      on specific points contribute to these discussions. However, it would be
      incorrect to conclude that cost-utility analyses are therefore not useful. If
      performed according to current insights and clearly presented, they are
      transparent and can be assessed and reproduced. Thus they can contribute to a
      scientific underpinning of policy decisions. Notably, the alternative of
      'opinion'-based policy making should be kept in mind when assessing cost-utility
      analyses.

PMID- 15198059
TI  - [Premature and over-simplified publication of mortality differences between
      hospitals in the media].
AB  - Prismant, the major institute for health-care research in the Netherlands,
      presented differences in mortality data from hospitals in the Netherlands. The
      data from the Prismant study were front-page news. However, the Prismant study
      was only published on their own website, and contained only raw data. The author
      did not consider relevant issues, e.g., the differences in case mix in the
      various hospitals and demographic factors. The public debate on quality of health
      care would benefit greatly if research institutes published only data that were
      peer reviewed and if journalists checked with experts before they published an
      article on such a specialist medical issue.

PMID- 15198060
TI  - [Clinical reasoning and decision making in practice. A 23 year old woman with
      malaise, anorexia, fever and behavior changes].
AB  - A 23-year-old woman presented with a history of some months of malaise, anorexia,
      fever and behavioural changes. She had been examined by a general physician on
      repeated occasions before coming to the hospital. After physical examination and
      laboratory investigations, she was sent home. She returned to the hospital the
      same day with increased drowsiness and headache. Additional diagnostic procedures
      were performed. An echocardiography showed vegetations on the mitral valve. A CT
      scan of the brain showed a left frontotemporal haemorrhage. Infective
      endocarditis with septic embolisation to the brain, which resulted in a cerebral
      haemorrhage, was diagnosed. The patient was admitted and intravenous antibiotics
      were administered. Because of haemodynamic instability, a mitral valve
      replacement was performed on the fifth day of admission. The patient recovered
      well postoperatively. Four weeks later, she was found in a comatose condition.
      She died as a result of a second intracerebral haemorrhage, which was probably
      caused by a mycotic aneurysm. An important lesson to be learned from this case is
      that endocarditis should be considered in patients with a long history of
      anorexia, weight loss, malaise and fever, especially when a heart murmur is
      present. Secondly, if intracranial haemorrhage has occurred in patients with
      infective endocarditis, therapeutic options should always be discussed with a
      neurosurgeon, even in those cases where the probability of a mycotic aneurysm is
      low.

PMID- 15198061
TI  - [Nutrition and health--enteral nutrition in intensive care patients].
AB  - Nutritional therapy in the intensive care unit exerts favourable effects on
      morbidity and mortality. Enteral nutrition is preferable to parenteral nutrition.
      Only perforation or total obstruction of the gastrointestinal tract, proven
      mesenteric ischaemia and toxic megacolon are absolute contra-indications to
      enteral nutrition. Early enteral nutrition is effective in decreasing infectious
      complications and reducing the length of stay in the hospital. Nutrition that is
      enriched with specific ingredients in order to modulate the immune response is
      referred to as immunonutrition. The use of immunonutrition, notably in surgical
      intensive care patients, has a favourable effect on the incidence of infectious
      complications, the duration of artificial respiration and the length of hospital
      stay. The addition of glutamine to parenteral nutrition may reduce mortality
      compared to standard parenteral nutrition. Implementation of a simple feeding
      algorithm in the intensive care unit, with special attention for the treatment of
      delayed gastric emptying, is cost-effective and leads to an improvement in the
      nutritional parameters.

PMID- 15198062
TI  - [Diagnostic image (191). A woman with angina pectoris and dyspnoea. Critical
      stenosis of the left main coronary artery with diffuse subendocardial ischemia].
AB  - A 75-year-old woman presented with angina pectoris and dyspnoea due to critical
      stenosis of the left main coronary artery with diffuse subendocardial ischaemia.

PMID- 15198063
TI  - [Qualitative malnutrition due to incorrect complementary feeding in Bush Negro
      children in Suriname].
AB  - OBJECTIVE: To determine whether the increase in the percentage of stunted growth
      in Bush Negro infants in the interior of Surinam is related to an absolute food
      (i.e. energy) shortage or to a shortage of protein. DESIGN: Descriptive. METHOD:
      In the villages of Dan and Botopasi, children aged 2-5 years from two schools and
      their mothers were examined. Growth during the first year of life, duration of
      breastfeeding, age of introduction of and composition of complementary feeding
      and current nutritional status of mother and child were determined. RESULTS:
      Sixteen children and their mothers were included. Compared to the Dutch growth
      charts, birth weight was significantly lower (p = 0.03). After the age of 6
      months there was a significant dropping off in weight gain (p = 0.018). Five of
      the 16 children received protein-poor complementary feeding, which did not lead
      to catch-up growth. Between the ages of 2-5, 6 of the 16 children showed stunted
      growth but none of the children or their mothers was wasted. Five of the 16
      mothers had a body mass index > 25. CONCLUSION: The nutritional status of the
      mothers showed that there was no absolute shortage of energy. The protein content
      coming from the complementary food for the Bush Negroes in our research group was
      below recommended levels. Stunted growth in these children is better explained by
      a shortage of well-balanced complementary feeding rather than by an absolute
      shortage of energy. Education about food recommendations for the young child is
      of great importance in the prevention of chronic malnutrition.

PMID- 15198064
TI  - [Neuromyelitis optica (Devic's disease): a severe variant of multiple sclerosis].
AB  - In three women aged 20, 34 and 21, with a combination of optic neuritis and
      transverse myelitis, the diagnosis of neuromyelitis optica (Devic's disease) was
      made. All three were treated with methylprednisolone. The first patient died from
      respiratory failure associated with tetraparesis, over two years after
      experiencing initial symptoms. The other two women recovered to varying extents.
      By employing a combination of clinical investigations and MRI supplemented by
      laboratory investigations, it is possible to differentiate neuromyelitis optica
      from multiple sclerosis. Neuromyelitis optica is treated by a stronger form of
      immunosuppression. Despite recorded differences it remains possible that these
      conditions form part of the same spectrum in which the genetic background is
      important. In neuromyelitis optica the underlying condition seems to be in the
      field of the human immune response.

PMID- 15198065
TI  - [Acute traumatic spinal cord injury and cardiovascular complications due to
      neurogenic shock: a possible threat for functional recovery].
AB  - Three men aged 18, 18 and 24 years, developed hypotension and bradycardia
      following an acute traumatic cervical or thoracic spinal cord injury. After
      treatment in intensive care and 1-12 months of rehabilitation they still suffered
      from considerable neurological disorders. Hypotension and bradycardia are common
      phenomena following acute traumatic cervical and thoracic spinal cord injury.
      Awareness of cardiovascular complications as a possible threat for functional
      recovery and adequate insight in the neurological cause of hypotension and
      bradycardia are important issues in the acute treatment of patients with spinal
      cord injury. It seems sensible to admit these patients to a medium-care or
      intensive-care department where they can be monitored and treated by a
      specialised team in accordance with an adequate protocol.

PMID- 15198066
TI  - [Cost-utility analysis; uncertainties restrict applicability].
AB  - Assumptions and choices are inherent to cost-utility analysis, the economic
      technique that provides a generic measure for the quantification of the
      efficiency of various health-care services. Uncertainty prevails on many of them:
      on the definition of the output of health care as health gain, on its expression
      in quality-adjusted life years (QALYs), on the choice of measurement instruments
      that should provide comparable information across all disease categories, on the
      choice of the procedure to value health states, on the relative importance of the
      judgments of patients and the general public, on the quantification of various
      types of costs, and on the question as to whether, and then how, future health
      gains should be discounted. The conclusion is that the results of a cost-utility
      analysis should be interpreted with caution. For the time being, cost-utility
      analysis cannot be used for direct comparisons of efficiency across all types of
      health-care services.

PMID- 15198067
TI  - [Life style intervention for patients with alcohol-related somatic problems].

PMID- 15198068
TI  - [Amyotrophic lateral sclerosis: mechanical ventilation--or not right?].

PMID- 15198069
TI  - [Amyotrophic lateral sclerosis: mechanical ventilation--or not right?].

PMID- 15198070
TI  - Pharmacokinetic studies of intramuscular midazolam in guinea pigs challenged with
      soman.
AB  - Studies have demonstrated that benzodiazepine compounds are effective at
      antagonizing seizure activity produced by the organophosphate (OP) cholinesterase
      inhibitor soman. In this present study we have investigated the pharmacokinetics
      of midazolam and its associated effects on electroencephalographic (EEG) activity
      following intramuscular (i.m.) injection to soman-exposed guinea pigs
      (Crl:(HA)BR). Prior to experiments, the animals were surgically implanted with
      EEG leads to monitor seizure activity. For the study, animals were administered
      the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026
      mg/kg, i.m.) was given 30 min prior to soman (56 micrograms/kg, 2 x LD50;
      subcutaneously, s.c.), followed in one minute by atropine sulfate (2 mg/kg, i.m.)
      and pralidoxime chloride (25 mg/kg, i.m.). All animals receiving this regimen
      developed seizure activity. Midazolam 0.8 mg/kg, i.m., was administered 5 min
      after onset of seizure activity. Based on EEG data, animals were categorized as
      either seizure-terminated or seizure not-terminated at 30 min following
      anticonvulsant administration. Serial blood samples were collected for the plasma
      midazolam analysis; the assay was accomplished with a gas chromatograph/mass
      spectrometer. The mean time to seizure termination was 8.8 +/- 1.6 min. The mean
      time-plasma concentration data were fit to standard pharmacokinetic models. The
      following parameter estimates were determined from the model-fit for seizure
      terminated and not-terminated animals respectively: apparent volumes of
      distribution (Vd) were 1.4 and 1.7 l/kg; area under the time-concentration curves
      (AUC), 15,990 and 15,120 ng.min/ml; times to maximal plasma concentration (Tmax),
      1.66 and 2.91 min and maximal plasma concentrations (Cmax) 535.1 and 436.6 ng/ml.
      These data indicate that i.m. injection of midazolam is effective at terminating
      ongoing soman-induced seizure activity. Additionally, the relatively short Tmax
      and latency to seizure termination demonstrate the rapidity of drug absorption
      and action respectively.

PMID- 15198071
TI  - Interspecies differences in the nephrotoxic response to cyclooxygenase
      inhibition.
AB  - In contrast to cyclooxygenase-1 (COX-1), the basal expression of renal
      cyclooxygenase-2 (COX-2) varies among species. High basal levels of COX-2 in the
      renal cortex and papilla in dogs compared with monkeys suggest that COX-2
      inhibition may lead to distinct nephrotoxic responses. In this study, we compared
      the renal effects of COX inhibition between dogs and cynomolgus monkeys (n =
      6/group) following the administration of naproxen sodium, a non-selective COX
      1/COX-2 inhibitor. Dogs and monkeys were treated with 50 or 150 mg/kg/day
      naproxen sodium, respectively, for 2 to 6 weeks. Naproxen doses used in this
      study resulted in equivalent inhibition of COX activity in both species as
      measured by reductions in urinary prostaglandin E2 (PGE2) and 6-keto-PGF1-alpha
      levels. There was prominent reduction in renal blood flow (43%) and urinary
      sodium excretion (62%) in dogs but no alterations in renal blood flow and only
      minimal change (19%) in urinary sodium excretion in monkeys. The canine but not
      monkey kidney showed prominent COX-2 expression in the macula densa, thick
      ascending limb of Henle and papillary interstitial cells by immunohistochemistry.
      After treatment, the canine but not monkey kidneys had mild to moderate renal
      tubular atrophy and interstitial fibrosis and renal papillary necrosis.
      Obstructive nephropathy secondary to intra-tubular drug accumulation was seen in
      monkeys but not in dogs. Collectively, these data demonstrate species differences
      in the renal response to COX inhibition. The nature of functional and morphologic
      changes suggests a more prominent role of COX-2 in renal hemodynamics and
      natriuresis in dogs than in monkeys.

PMID- 15198072
TI  - Health and ecological effects of adiponitrile.
AB  - Adiponitrile (ADN) has moderate acute toxicity with an oral LD50 in rats of 100
      to 500 mg/kg and a 4-hr LC50 in rats of 1.71 mg/L (vapor plus aerosol). ADN
      produced slight eye but no skin irritation in rabbits. Repeated exposures by
      inhalation produced changes in the hematologic profile with effects seen at 100
      or 300 mg/m3. The hematologic changes were reversible upon cessation of further
      inhalation exposures. Dogs fed up to 500 ppm (equivalent to 12-15 mg/kg) showed
      no effects but 1,000 ppm produced vomiting and nausea which limited further
      testing at that concentration. ADN was not a genetic toxin, developmental toxin,
      reproductive toxin nor did it produce an increase in tumors in a 2-yr drinking
      water study in rats. Human experience reports are limited to one accidental
      poisoning case and a few skin exposures resulting in transient irritation and
      inflammation. ADN is rapidly absorbed and excreted by mammals, and is metabolized
      to some extent although unchanged ADN is readily detected in urine, and does not
      bioaccumulate.

PMID- 15198073
TI  - Effect of organophosphorus and organochlorine pesticides (monochrotophos,
      chlorpyriphos, dimethoate, and endosulfan) on human lymphocytes in-vitro.
AB  - The toxicological profile of the four pesticides described herein characterizes
      its effects on lymphocytes from peripheral blood from healthy donors. The
      exposure to all pesticides was by direct interaction/incubation with varying
      concentrations of the pesticide with blood sample in-vitro. The dose response
      relationship in each case was calculated by applying log tables as LC50 values.
      Cytotoxicity of these pesticides on lymphocytes was measured using the trypan
      blue dye exclusion technique. Based on LC50 value, all the four pesticides were
      found to be highly toxic to lymphocyte culture, among them, monocrotophos and
      endosulfan were the most toxic and dimethoate was the least toxic. The
      genotoxicity of the pesticides was also determined by comet assay. The results
      revealed that the pesticides caused increase in the tail length indicating DNA
      damage. This study suggests that these pesticides have the capacity to alter the
      genetic material particularly chromosomes in mammalian cultures. The comet assay
      used in this study was found to be a sensitive and rapid method to detect
      genotoxicity of pesticide compounds.

PMID- 15198074
TI  - Quercetin, a bioflavonoid, attenuates ferric nitrilotriacetate-induced oxidative
      renal injury in rats.
AB  - An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute proximal
      tubular necrosis as a consequence of lipid peroxidation and oxidative tissue
      damage, that eventually leads to high incidence of renal adenocarcinomas in
      rodents. This study was designed to investigate the effect of quercetin, a
      bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in
      rats. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg
      iron/kg), a marked deterioration of renal architecture and renal function was
      observed. Fe-NTA induced a significant renal oxidative stress demonstrated by
      elevated thiobarbituric acid reacting substances (TBARS) and reduction in
      activities of renal catalase, superoxide dismutase and glutathione reductase.
      Pretreatment of animals with quercetin (2 mg/kg, i.p.) 30 minutes before Fe-NTA
      administration markedly attenuated renal dysfunction, morphological alterations,
      reduced elevated TBARS and restored the depleted renal antioxidant enzymes. These
      results clearly demonstrate the role of oxidative stress and its relation to
      renal dysfunction, and suggest a protective effect of quercetin on Fe-NTA-induced
      nephrotoxicity in rats.

PMID- 15198075
TI  - A notable antimutagenicity of two nonmutagenic novel oxadiazoles in Salmonella
      mutagenicity assay.
AB  - The mutagenic activity of two newly synthesized oxadiazoles: 1,3-bis(5-benzylthio
      1,3,4-oxadiazol-2-yl) benzene (M1) and 1,4-bis(5-benzylthio-1,3,4-oxadiazol-2-yl)
      benzene (M2) was studied in Salmonella typhimurium strains TA97, TA100, TA102 and
      TA1537 in the presence and absence of S9mix. The antimutagenicity of M1 and M2
      against H2O2, sodium azide (SA) and 4-nitro-o-phenylene diamine (NPD) using the
      tester strains TA102, TA100 and TA97, respectively, was also investigated. The
      two compounds were found to be nonmutagenic using the four tester strains.
      However, they showed high mutagenic repression activity against hydrogen peroxide
      (95% and 97% for M1 and M2, respectively, at a concentration of 335
      micrograms/plate). Moderate mutagenic repression against NPD (58% and 55% for M1
      and M2, respectively, at a concentration of 167.5 micrograms/plate) and low
      mutagenic repression against SA (21% and 33% for M1 and M2 respectively, at a
      concentration of 335 micrograms/plate) was detected. The obtained results are
      very encouraging to test the above mentioned compounds as anticarcinogens.

PMID- 15198076
TI  - The effect of trifluoperazine on the induction of sex-linked recessive lethals by
      cyclophosphamide in Drosophila melanogaster.
AB  - The effects of trifluoperazine on the mutagenicity of cyclophosphamide were
      examined in the progenies of Drosophila melanogaster males injected with 2
      microliters of 5.0 mM cyclophosphamide and/or 0.1 mM trifluoperazine. The Muller
      5 method was used to study the induction of sex-linked recessive lethals in five
      successive broods representing the different stages of spermatogenesis. Results
      should that both cyclophosphamide and trifluoperazine were proportionally toxic
      to the injected males. While cyclophosphamide was less toxic than
      trifluoperazine, it increased the frequencies of induced complete and mosaic
      lethals significantly (5% level) in all stages of spermatogenesis contrary to
      trifluoperazine which was non mutagenic and had only an additive effect over the
      toxicity of cyclophosphamide. The sizes of the mutated gonad tissue in the F1
      mosaic female progenies of the males treated with cyclophosphamide alone ranged
      from 14% to 17% and of those treated with cyclophosphamide in association with
      trifluoperazine varied between 18% and 19%. Both complete and mosaic sex-linked
      lethals induced by cyclophosphamide treatments alone and in association with
      trifluoperazine were detected in singles and clusters.

PMID- 15198077
TI  - Protective effect of N-acetylcysteine against arsenic-induced depletion in vivo
      of carbohydrate.
AB  - N-acetylcysteine (NAC), a synthetic aminothiol, possesses antioxidative and
      cytoprotective properties. The present study evaluates the effect of NAC
      supplementation on arsenic-induced depletion in vivo of carbohydrates. Arsenic
      (as sodium arsenite) treatment (i.p.) of male Wistar rats (120-140 g b.w.) at a
      dose of 5.55 mg/kg body weight (35% of LD50) per day for a period of 30 days
      produced a significant decrease in blood glucose level (hypoglycemia) and a fall
      in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content
      of liver increased while that of kidney decreased after arsenic treatment.
      Arsenic also enhanced the liver lactate dehydrogenase activity whereas glucose 6
      phosphatase activity in both liver and kidney decreased significantly following
      arsenic treatment. Transaminase activities in liver and kidney were not
      significantly altered except the glutamate-pyruvate transaminase activity that
      was reduced in kidney after arsenic treatment. Oral administration of NAC (163.2
      mg/kg/day) for last 7 days of treatment prevented the arsenic-induced
      hypoglycemia and glycogenolytic effects to an appreciable extent. There was also
      recovery of liver pyruvic acid as well as liver and kidney free amino acid
      nitrogen content after NAC supplementation. Arsenic-induced alteration of glucose
      6-phosphatase activity in both liver and kidney was also counteracted by NAC. It
      is suggested that carbohydrate depletion in vivo due to exposure to arsenic can
      be counteracted by NAC supplementation.

PMID- 15198078
TI  - HAART, side effects, and viral transmission.

PMID- 15198079
TI  - Follow the money to the voting booth.

PMID- 15198080
TI  - Advanced-access scheduling increases quality, productivity, and revenue.

PMID- 15198081
TI  - Can we boost enough without ritonavir?

PMID- 15198082
TI  - Notice of duplicate publication.

PMID- 15198083
TI  - Dielectrophoretic registration of living cells to a microelectrode array.
AB  - We present a novel microfabricated device to simultaneously and actively trap
      thousands of single mammalian cells in alignment with a planar microelectrode
      array. Thousands of 3 Ipm diameter trapping electrodes were fabricated within the
      bottom of a parallel-plate flow chamber. Cells were trapped on the electrodes and
      held against destabilizing fluid flows by dielectrophoretic forces generated in
      the device. In general, each electrode trapped only one cell. Adhesive regions
      were patterned onto the surface in alignment with the traps such that cells
      adhered to the array surface and remained in alignment with the electrodes. By
      driving the device with different voltages, we showed that trapped cells could be
      killed by stronger electric fields. However, with weaker fields, cells were not
      damaged during trapping, as indicated by the similar morphologies and
      proliferation rates of trapped cells versus controls. As a test of the device, we
      patterned approximately 20,000 cells onto aI cm2 grid of rectangular adhesive
      regions, with two electrodes and thus two cells per rectangle. Our method
      obtained 70 +/- 1% fidelity versus 17 +/- 1% when using an existing cell
      registration technique. By allowing the placement of desired numbers of cells at
      specified locations, this approach addresses many needs to manipulate and
      register cells to the surfaces of biosensors and other devices with high
      precision and fidelity.

PMID- 15198084
TI  - Dementia Deficits Scale. Rating self-awareness of deficits.
AB  - Impaired deficit awareness is important to detect because of its clinical
      implications; for example, patients with impaired awareness are more likely to
      engage in potentially dangerous activities, such as operating the stove. This
      study evaluated the reliability and validity of the Dementia Deficits Scale
      (DDS), a new multidimensional instrument for the assessment of self-awareness of
      cognitive, emotional, and functional deficits associated with dementia. Three
      parallel forms of the DDS were independently completed by the patient, clinician,
      and informant. The DDS yields two measures of deficit awareness: the discrepancy
      between clinician and patient assessments of the patient's deficits, and the
      discrepancy between informant and patient assessments. The DDS demonstrated
      adequate reliability and good divergent and convergent validity. Clinician and
      informant reports each added unique information, highlighting the importance of
      including both perspectives in the awareness assessment process. The DDS is
      recommended as a reliable and valid tool for the clinical and empirical
      assessment of deficit awareness in patients with dementia.

PMID- 15198085
TI  - Are comparative risk judgements consistent across time and events?
AB  - Research reveals pervasive optimism in people's comparative risk judgements such
      that people believe they are less likely than others to experience negative
      events. Two studies explored the extent to which people are consistent in their
      comparative risk judgements across time and events. Both studies found strong
      evidence for consistency across time and some evidence for consistency across
      events. The consistency across time and events was moderated by experience.
      Specifically, when viewed together, the studies suggest that experience produces
      an initial decrease in the consistency of comparative judgements (Study 2),
      followed by greater consistency in subsequent judgements (Study 1). The
      discussion focuses on reconciling evidence demonstrating consistency with
      evidence demonstrating variability.

PMID- 15198086
TI  - [Physical activity in the treatment of obesity. Obesity--a chronic disease
      requiring life-long physical activity].

PMID- 15198087
TI  - [The Swedish SCORE chart for cardiovascular risk. Better possibilities for
      prevention of cardiovascular diseases].

PMID- 15198088
TI  - The meaning of life (events) predicts changes in attachment security.
AB  - Building on prior research, which has failed to find consistent effects of life
      events on change in self-reported adult attachment security over time, the
      present study tested the hypothesis that it is the meaning people attach to
      events, rather than the objective features of events, that is associated with
      changing levels of security. Participants engaged in an 8-week daily diary study,
      during which they completed daily self-report measures of attachment security,
      negative life events, perceptions of loss associated with events, and mood.
      Hierarchical linear modeling revealed that perceptions of greater interpersonal
      (but not achievement) loss associated with life events were significantly
      associated with greater insecurity on a day-to-day basis, even controlling for
      objective features of events and for mood. Trait levels of security did not
      moderate this association. Results are discussed with regard to social-cognitive
      models of attachment security and the utility of understanding the meaning of
      life events to understand how attachment models may be confirmed or disconfirmed.

PMID- 15198089
TI  - A proteomics approach to characterizing tick salivary secretions.
AB  - The saliva of ticks contains a complex mixture of bioactive molecules including
      proteins that modulate host responses ensuring successful feeding. The limited
      amount of saliva that can be obtained from ticks has hampered characterization of
      salivary proteins using traditional protein chemistry. Recent improvements in two
      dimensional gel electrophoresis, mass spectrometry, and bioinformatics provide
      new tools to characterize small amounts of protein. These methods were employed
      to characterize salivary proteins from Amblyomma americanum and Amblyvomma
      maculatum. Salivation was induced by injection of dopamine and theophylline. It
      was necessary to desalt and concentrate saliva before analysis by 2-D
      electrophoresis. Comparison of 1-D and 2-D gel patterns revealed that the major
      protein component of saliva did not appear on 2-D gels. Characterization of this
      protein showed that it was identical to the major protein present in the
      hemolymph of both tick species. Protein profiles obtained by 1-D and 2-D gel
      electrophoresis were similar for both tick species, however, higher
      concentrations of lower molecular weight proteins were present in A. maculatum.
      Protein analysis by MALDI-TOF mass spectrometry and western blot analysis showed
      that except for the most abundant protein with a molecular weight of 95 kDa, all
      of the proteins detected were of host origin. It is not known if this is an
      artifact of the collection method or has physiological significance. In either
      case, in these species of ticks, host proteins will have to be removed from
      saliva samples prior to 2-D analysis in order to characterize lower abundance
      proteins of tick origin.

PMID- 15198090
TI  - [About pregnancy -- what can the family physician do for the mother-to-be].

PMID- 15198091
TI  - Management of chronic low back pain.

PMID- 15198092
TI  - Silencing of negative regulator of JAK/STAT in colorectal cancer.

PMID- 15198093
TI  - Role of growth factors in the repair of gastric mucosal injury.

PMID- 15198094
TI  - Reproductive issues for persons with HIV.

PMID- 15198095
TI  - Observations on post-site metastases after laparoscopic surgery for ovarian
      malignancy.

PMID- 15198096
TI  - Stage-based treatment of twin-twin transfusion syndrome.

PMID- 15198097
TI  - We need to be aware of parabens concerns.

PMID- 15198098
TI  - More attention must be paid to sleep.

PMID- 15198100
TI  - Immunosuppression and transplant immunology.

PMID- 15198099
TI  - Suppression of cytokine-inducible nitric oxide synthesis during intraperitoneal
      Meth A tumor growth.
AB  - Nitric oxide (NO*) synthesis is induced within many tumors. The time course of
      NO* synthesis was evaluated during intra-peritoneal Meth A fibrosarcoma
      progression. While increasing macrophage recruitment into ascites was noted,
      inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3
      6 after tumor implantation. The capacity of cells to respond to LPS and IFNgamma
      stimulation was markedly depressed on day 9 and 11. Cellular proliferation
      correlated in an inverse fashion with levels of NO* synthesis. Electron
      paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to
      show accumulation of characteristic target cell lesions induced by NO*. These
      findings lead us to conclude that NO* production was increasingly suppressed
      during Meth A tumor progression. Depression of NO* production did not correlate
      with levels of the inhibitory cytokines TGFbeta and IL-10, but could be partially
      overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus,
      depletion of essential co-factors necessary for iNOS function may contribute to
      depressed NO* responses during cancer progression.

PMID- 15198101
TI  - Motivation, inspiration, and relation: the three-legged stool for retaining
      quality staff.

PMID- 15198102
TI  - Good leaders vs. great leaders.

PMID- 15198103
TI  - The difference between a good surgeon and a great surgeon.

PMID- 15198104
TI  - Hospice legislative and regulatory priorities for 2003.

PMID- 15198105
TI  - Physical activity and community design.

PMID- 15198106
TI  - Environmental tobacco smoke.

PMID- 15198107
TI  - Distinguishing consent to treat from notice of HIPAA privacy policy.

PMID- 15198108
TI  - Mental health services in rural areas.

PMID- 15198109
TI  - Tracking health care costs: trends turn downward in 2003.
AB  - This Data Bulletin is based on data from the Milliman USA Health Cost Index ($0
      deductible), which is designed to reflect claims trends faced by private
      insurers; the U.S. Bureau of Labor Statistics' (BLS) Producer Price Index for
      general medical and surgical hospitals and for physicians' offices to track
      hospital and physician prices; the BLS's Consumer Price Index for prescription
      drugs and medical supplies to track prescription drug prices; and the Towers
      Perrin 2004 Health Care Cost Survey and the Ninth Annual National Business Group
      on Health/Watson Wyatt Employer Survey Report 2004 for premium trends. It is
      adapted from "Tracking Health Care Costs: Trends Turn Downward in 2003" by
      Bradley C. Strunk and Paul B. Ginsburg, Health Affairs, Web-exclusive
      publication, June 9, 2004, www.healthaffairs.org

PMID- 15198110
TI  - Children with mental disorders: making sense of their needs and the systems that
      help them.
AB  - This paper examines the nature, severity, and prevalence of mental, behavioral,
      and emotional disorders among children, as well as the types of services that
      could help them. It looks at how they are served by the education, health care,
      and child welfare systems, and it identifies the gaps in these systems of care.
      It also examines the extent to which Medicaid, SCHIP, and private health
      insurance finance mental health care services for children.

PMID- 15198111
TI  - The Readers' Corner. 2. What fee-payment options do you offer?

PMID- 15198112
TI  - Effects of stress typicality during speeded grammatical classification.
AB  - The experiments reported here were designed to investigate the influence of
      stress typicality during speeded grammatical classification of disyllabic English
      words by native and non-native speakers. Trochaic nouns and iambic gram verbs
      were considered to be typically stressed, whereas iambic nouns and trochaic verbs
      were considered to be atypically stressed. Experiments 1a and 2a showed that
      while native speakers classified typically stressed words individual more quickly
      and more accurately than atypically stressed words during differences reading,
      there were no overall effects during classification of spoken stimuli. However, a
      subgroup of native speakers with high error rates did show a significant effect
      during classification of spoken stimuli. Experiments 1b and 2b showed that non
      native speakers classified typically stressed words more quickly and more
      accurately than atypically stressed words during reading. Typically stressed
      words were classified more accurately than atypically stressed words when the
      stimuli were spoken. Importantly, there was a significant relationship between
      error rates, vocabulary size and the size of the stress typicality effect in each
      experiment. We conclude that participants use information about lexical stress to
      help them distinguish between disyllabic nouns and verbs during speeded
      grammatical classification. This is especially so for individuals with a limited
      vocabulary who lack other knowledge (e.g., semantic knowledge) about the
      differences between these grammatical categories.

PMID- 15198113
TI  - Perception of English intonation by English, Spanish, and Chinese listeners.
AB  - Native language affects the perception of segmental phonetic structure, of
      stress, and of semantic and pragmatic effects of intonation. Similarly, native
      language might influence the perception of similarities and differences among
      intonation contours. To test this hypothesis, a cross-language experiment was
      conducted. An English utterance was resynthesized with seven falling and four
      rising intonation contours. English, Iberian Spanish, and Chinese listeners then
      rated each pair of nonidentical stimuli for degree of difference.
      Multidimensional scaling of the results supported the hypothesis. The three
      groups of listeners produced statistically different perceptual configurations
      for the falling contours. All groups, however, perceptually separated the falling
      from the rising contours. This result suggested that the perception of intonation
      begins with the activation of universal auditory mechanisms that process the
      direction of relatively slow frequency modulations. A second experiment therefore
      employed frequency-modulated sine waves that duplicated the fundamental frequency
      contours of the speech stimuli. New groups of English, Spanish, and Chinese
      subjects yielded no cross-language differences between the perceptual
      configurations for these nonspeech stimuli. The perception of similarities and
      differences among intonation contours calls upon universal auditory mechanisms
      whose output is molded by experience with one's native language.

PMID- 15198114
TI  - Factors affecting stress placement for English nonwords include syllabic
      structure, lexical class, and stress patterns of phonologically similar words.
AB  - Seventeen native English speakers participated in an investigation of language
      users' knowledge of English main stress patterns. First, they produced 40 two
      syllable nonwords of varying syllabic structure as nouns and verbs. Second, they
      indicated their preference for first or second syllable stress of the same words
      in a perception task. Finally, they indicated words they considered to be
      phonologically similar to the nonwords. Analyses of variance on the production
      and perception data indicated that both syllabic structure and lexical class
      (noun or verb) had an effect on main stress assignment. In logistic regression
      analyses on the production and perception responses. predictions of stress
      placement made by (1) syllable structure, (2) lexical class, and (3) stress
      patterns of phonologically similar words all contributed significantly and
      uniquely to the prediction of main stress assignment. The results indicate that
      phonological theories of English word stress need to allow for multiple,
      competing, probabilistic factors in accounts of main stress placement including
      syllabic structure (most notably vowel length), lexical class, and stress
      patterns of phonologically similar words.

PMID- 15198115
TI  - Evidence-based palliative care: beliefs and evidence for changing practice.

PMID- 15198116
TI  - The pathophysiology of cancer-induced bone pain: current understanding.
AB  - Cancer-induced bone pain (CIBP) is a common clinical problem. Although treatment
      has been revolutionised in the past 10 years with the introduction of
      bisphosphonates, pain arising spontaneously or from movement, remains a leading
      cause of unresolved pain in many patients. Until recently little was understood
      about the peripheral and central mechanisms of bone pain. Insight into the
      mechanisms of osteoblast and osteoclast activation, via receptor activator for
      nuclear factor KB (RANK) dependent and independent mechanisms and a re-evaluation
      of primary afferent terminals within bone have led to a suggestion that CIBP may
      be a mixture of inflammatory and neuropathic stimuli. The recently published
      animal model of localised but progressive bone destruction has allowed greater
      insight into the peripheral and dorsal horn pathophysiology, which hitherto was
      precluded. Immunocytochemical markers of neurotransmitters and receptors indicate
      that CIBP has unique characteristics, unlike neuropathy or inflammation. Evidence
      for an increased excitability within the dorsal horn, and especially Lamina I,
      and possible mechanisms underlying this unique pain state will be discussed.

PMID- 15198117
TI  - NSAIDs: gastroprotection or selective COX-2 inhibitor?
AB  - Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are effective adjuvant
      analgesics commonly encountered in palliative care. However, these drugs are
      associated with adverse effects that are primarily due to gastrointestinal
      toxicity, with resultant serious complications such as gastroduodenal
      perforations, ulcers and bleeds. This toxicity has been attributed to inhibition
      of cyclooxygenase-1 (COX-1). Factors known to increase this risk of toxicity
      include age above 65 years, classification of NSAID in terms of COX-1/COX-2
      selectivity, previous history of complications and coadministration of aspirin,
      anticoagulants and corticosteroids. Selective inhibitors of cyclooxygenase-2 (COX
      2) were developed in an attempt to reduce this association; trials to date
      confirm that these drugs do indeed have reduced incidence of gastroduodenal
      toxicity. Prior to the introduction of the COX-2 selective inhibitors, patients
      at high risk were often coprescribed a gastroprotective agent (such as
      misoprostol or a proton pump inhibitor) with a conventional NSAID. This review
      discusses the merits of both options and devises a treatment strategy for the
      safe and cost-effective use of these drugs in the palliative care population.

PMID- 15198118
TI  - Does aromatherapy massage benefit patients with cancer attending a specialist
      palliative care day centre?
AB  - A randomised controlled pilot study was carried out to examine the effects of
      adjunctive aromatherapy massage on mood, quality of life and physical symptoms in
      patients with cancer attending a specialist unit. Participants were randomised to
      conventional day care alone or day care plus weekly aromatherapy massage using a
      standardised blend of oils for four weeks. At baseline and at weekly intervals,
      patients rated their mood, quality of life and the intensity and bother of two
      symptoms most important to them. Forty-six patients were recruited to the study.
      Due to a large number of withdrawals, only 11 of 23 (48%) patients in the
      aromatherapy group and 18 of 23 (78%) in the control group completed all four
      weeks. Mood, physical symptoms and quality of life improved in both groups. There
      was no statistically significant difference between groups in any of the outcome
      measures. Despite a lack of measurable benefit, all patients were satisfied with
      the aromatherapy and wished to continue. Whilst this pilot study has shown that a
      randomised controlled trial of complementary therapy is feasible, it has also
      identified several areas that would require further consideration when designing
      future studies, e.g., the recruitment and retention of appropriate numbers of
      patients and the outcome measures used.

PMID- 15198119
TI  - Removing the boundaries: palliative care for patients with heart failure.
AB  - AIM: This study aimed to explore the experiences of patients with severe heart
      failure and identify their needs for palliative care. METHOD: A qualitative
      design was chosen. Semi-structured interviews were used for data collection and
      patients were interviewed in their homes. The sample consisted of 20 patients
      with a confirmed diagnosis of heart failure. Patients were between 60 and 83
      years. RESULTS: Patients reported difficulties in walking, extreme fatigue and
      problems managing daily activities. Having to rely on family, friends and
      neighbours was common, causing feelings of being a burden, loneliness and
      isolation. Patients talked about dying as well as their fears and frustrations in
      living with heart failure. Barriers to accessing information and social services
      were identified. None of these patients had been referred to specialist
      palliative care services. CONCLUSIONS: Patients' experiences were similar to
      those of patients living with advanced cancer and yet they received little
      support. Comprehensive routine assessment of the palliative care needs of
      patients living with severe heart failure is recommended.

PMID- 15198120
TI  - Comparative genomic hybridization in central and peripheral nervous system tumors
      of childhood and adolescence.
AB  - Brain tumors amount to less than 2% of all malignant neoplasms. However, they
      account for approximately 20% of all childhood cancers and are the leading cause
      of cancer mortality among children. Recently, enormous progress has been achieved
      in the field of pediatric neuro-oncology regarding the classification of
      children's brain tumors, as well as the understanding of the genetic events
      involved in their pathogenesis; thus leading to an emerging role of molecular
      diagnostic approaches using novel tools. Comparative genomic hybridization (CGH)
      is a technique that has revolutionized cytogenetic knowledge in the past decade.
      It permits the detection of chromosomal copy number changes without the need for
      cell culturing and gives a global overview of chromosomal gains and losses
      throughout the whole genome of a tumor. A survey of CGH-related publications on
      central and peripheral nervous system tumors in the pediatric and adolescent
      population revealed 884 cases. The CNS tumor groups most frequently examined by
      CGH were embryonal tumors (268 cases/30.3%) and ependymomas (241/27.2%), followed
      by astrocytic (163/18.4%), peripheral nerve (73/8.2%), choroid plexus tumors
      (56/6.3%), and craniopharyngiomas (38/4.3%). The most common CNS tumor entities
      were medulloblastomas (238/26.9%), classic ependymomas (160/18.1%), anaplastic
      ependymomas (70/7.9%), pleomorphic xanthoastrocytomas (53/6.0%), and pilocytic
      astrocytomas (50/5.6%). This article provides a short review of the CGH technique
      and its pitfalls, summarizes the current CGH-related data on pediatric brain
      tumors and muses on the future of CGH.

PMID- 15198121
TI  - Amyloid-beta deposition is associated with decreased hippocampal glucose
      metabolism and spatial memory impairment in APP/PS1 mice.
AB  - In Alzheimer disease (AD) patients, early memory dysfunction is associated with
      glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic
      (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double
      "Swedish" amyloid precursor protein (APP) mutations, are a model of AD amyloid
      beta deposition (Abeta) that exhibits earlier and more profound impairments of
      working memory and learning than single APP mutant mice. In this study we
      compared performance on spatial memory tests, regional glucose metabolism, Abeta
      deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age
      of 2 months no significant morphological and metabolic differences were detected
      between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed
      selective impairment of spatial memory, which was significantly worse at 22
      months and was accompanied by reduced glucose utilization in the hippocampus and
      a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree
      of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose
      utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were
      accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4%
      at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the
      behavioral and metabolic impairments in APP/PS1 mice and the failure to
      compensate functionally for PS1-related hippocampal cell loss.

PMID- 15198122
TI  - Transgenic mouse in vivo library of human Down syndrome critical region 1:
      association between DYRK1A overexpression, brain development abnormalities, and
      cell cycle protein alteration.
AB  - Down syndrome is the most frequent genetic cause of mental retardation, having an
      incidence of 1 in 700 live births. In the present study we used a transgenic
      mouse in vivo library consisting of 4 yeast artificial chromosome (YAC)
      transgenic mouse lines, each bearing a different fragment of the Down syndrome
      critical region 1 (DCR-1), implicated in brain abnormalities characterizing this
      pathology. The 152F7 fragment, in addition to genes also located on the other DCR
      1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The
      neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing
      152F7 mice but not the other lines display learning impairment and hyperactivity
      during development. Additionally, 152F7 mice display increased brain weight and
      neuronal size. At a biochemical level we found DYRK1A overexpression associated
      with a development-dependent increase in phosphorylation of the transcription
      factor FKHR and with high levels of cyclin B1, suggesting for the first time in
      vivo a correlation between DYRK1A overexpression and cell cycle protein
      alteration. In addition, we found an altered phosphorylation of transcription
      factors of CREB family. Our findings support a role of DYRK1A overexpression in
      the neuronal abnormalities seen in Down syndrome and suggest that this pathology
      is linked to altered levels of proteins involved in the regulation of cell cycle.

PMID- 15198123
TI  - Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N
      myc, TrkC, and anaplasia.
AB  - Several molecular and histopathological prognostic markers have been proposed for
      the therapeutic stratification of medulloblastoma patients. Amplification of the
      c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been
      associated with worse clinical outcomes. In contrast, high TrkC mRNA expression
      generally presages longer survival. The goal of this study was to evaluate the
      prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and
      compare them to histopathological classification. We used in situ hybridization
      to measure expression of these molecular markers. c-myc mRNA was detected in 18
      of 59 (31%) cases, and was significantly associated with shorter patient survival
      times on both univariate and multivariate analyses (p = 0.04). The presence of c
      myc mRNA was also significantly associated with tumor anaplasia. While survival
      rates were higher for patients with low N-myc or high TrkC expression, these
      differences were not statistically significant. The group of patients with either
      moderate or severely anaplastic tumors showed only a trend towards shorter
      survival (p = 0.11). However, severe anaplasia alone was significantly prognostic
      (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential
      mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1
      mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway
      activation, was more common in medulloblastomas with high c-myc than in tumors
      overall, but the difference was not statistically significant. No Mxi-1 mutations
      were detected in the 22 cases examined. The association we describe between c-myc
      expression, tumor anaplasia, and worse clinical outcomes provides further
      evidence for the importance of this oncogene in medulloblastoma pathobiology.

PMID- 15198124
TI  - Experimental rat models of types 1 and 2 diabetes differ in sympathetic
      neuroaxonal dystrophy.
AB  - Dysfunction of the autonomic nervous system is a recognized complication of
      diabetes, ranging in severity from relatively minor sweating and pupillomotor
      abnormality to debilitating interference with cardiovascular, genitourinary, and
      alimentary dysfunction. Neuroaxonal dystrophy (NAD), a distinctive distal
      axonopathy involving terminal axons and synapses, represents the neuropathologic
      hallmark of diabetic sympathetic autonomic neuropathy in man and several
      insulinopenic experimental rodent models. Although the pathogenesis of diabetic
      sympathetic NAD is unknown, recent studies have suggested that loss of the
      neurotrophic effects of insulin and/or insulin-like growth factor-I (IGF-I) on
      sympathetic neurons rather than hyperglycemia per se, may be critical to its
      development. Therefore, in our current investigation we have compared the
      sympathetic neuropathology developing after 8 months of diabetes in the
      streptozotocin (STZ)-induced diabetic rat and BB/ Wor rat, both models of
      hypoinsulinemic type 1 diabetes, with the BBZDR/Wor rat, a hyperglycemic and
      hyperinsulinemic type 2 diabetes model. Both STZ- and BB/Wor-diabetic rats
      reproducibly developed NAD in nerve terminals in the prevertebral superior
      mesenteric sympathetic ganglia (SMG) and ileal mesenteric nerves. The BBZDR/Wor
      diabetic rat, in comparison, failed to develop superior mesenteric ganglionic NAD
      in excess of that of age-matched controls. Similarly, NAD which developed in
      axons of ileal mesenteric nerves of BBZDR/Wor rats was substantially less
      frequent than in BB/Wor- and STZ-rats. These data, considered in the light of the
      results of previous experiments, argue that hyperglycemia alone is not sufficient
      to produce sympathetic ganglionic NAD, but rather that it may be the diabetes
      induced superimposed loss of trophic support, likely of IGF-I, insulin, or C
      peptide, that ultimately causes NAD.

PMID- 15198125
TI  - Neuron-binding human monoclonal antibodies support central nervous system neurite
      extension.
AB  - Two human IgMs (sHIgM12 and sHIgM42) were identified that supported in vitro
      central nervous system (CNS) neurite extension equal to the potent neurite
      stimulatory molecule laminin. Both IgMs bound to multiple cell types in unfixed
      CNS tissue and to the surface of neurons in culture. Both monoclonal antibodies
      (mAbs) overrode the inhibitory effect of CNS mouse myelin on granule cell neurite
      extension. Neither mAb bound to the surface of mature oligodendrocytes or
      strictly colocalized with myelin proteins. Sialidase treatment eliminated the
      neuronal surface binding of both mAbs, whereas blocking sphingolipid synthesis
      with Fumonisin B1 or removing GPI-linked proteins with PIPLC did not. When used
      as substrates for mixed neuron/glia aggregates, sHIgM12 and sHIgM42 supported
      robust neurite extension while astrocytes remained in the aggregates. In
      contrast, laminin supported astrocyte migration and spreading. Human mAbs that
      support neurite extension are novel factors that may be of use in encouraging
      axon repair following injury while minimizing glial cell infiltration. Both human
      mAbs were isolated from individuals with monoclonal gammopathy. Each individual
      has carried high mAb titers in circulation for years without detriment. sHIgM12
      and sHIgM42 are therefore unlikely to be systemically pathogenic.

PMID- 15198126
TI  - Intercellular adhesion molecule-1 and blood-spinal cord barrier disruption in
      central nervous system radiation injury.
AB  - Central nervous system (CNS) injury is a major dose-limiting toxicity that limits
      the effectiveness of radiation therapy. Blood-brain barrier (BBB) disruption and
      white matter necrosis are prominent features. Increased expression of
      intercellular adhesion molecule-1 (ICAM-1) accompanies and is believed to be
      important in BBB disruption in other CNS injuries. Our aim was to assess the
      expression of ICAM-1 and its relationship to regions of blood-spinal cord barrier
      (BSCB) disruption in the irradiated rat spinal cord. ICAM-1 protein was detected
      by immunohistochemistry and quantified by digital image analysis. Cells
      expressing ICAM-1 were identified. BSCB disruption was assessed by
      immunohistochemical detection of serum albumin. ICAM-1 expression localized
      predominantly to vascular endothelium and increased in white matter but not in
      grey matter at 24 hours and 17 to 20 weeks after 22 Gy. A dose response was
      observed from 16 to 20 Gy. ICAM-1 expression colocalized with regions of BSCB
      disruption. ICAM-1 expression was also observed in glia, a majority of which were
      astrocytes. The parallel dose response, time course, and spatial distribution of
      ICAM-1 expression and albumin leakage suggest a role for ICAM-1 in late BSCB
      disruption after radiation.

PMID- 15198127
TI  - Proteasomal expression, induction of immunoproteasome subunits, and local MHC
      class I presentation in myofibrillar myopathy and inclusion body myositis.
AB  - Inclusion body myositis (IBM) and myofibrillar myopathy (MM) are diseases
      characterized by the abnormal accumulation of proteins in muscle fibers,
      including desmin, alphaB-crystallin, gelsolin, actin, kinases, and phospho-tau,
      along with ubiquitin in muscle fibers, suggesting abnormal protein degradation as
      a possible cause of the surplus myopathy. Since the ubiquitin-proteasome system
      plays a crucial role in non-lysosomal protein degradation, the present study has
      examined by immunohistochemistry the expression of components of the catalytic
      core of 20S proteasomes and its regulators: 19S and PA28alpha/beta, and the
      expression of immunoproteasome subunits LMP2, LMP7, and MECL1 in 8 patients with
      MM and 10 patients with IBM. The patients with MM were from 6 unrelated families,
      2 sporadic cases, I with autosomal recessive and 5 with autosomal dominant
      inheritance. One sporadic patient had a de novo R406W mutation in the desmin
      gene, and 1 patient with autosomal dominant MM had a single amino acid deletion
      at position 366 in the desmin gene. Increased immunoreactivity to 20S, 19S, and
      PA28alpha/beta colocalizing abnormal protein deposits, as revealed in consecutive
      serial sections, was seen in all cases with MM and IBM. In all cases, the
      subunits of the immunoproteasome LMP2, LMP7, and MECL1 colocalized with
      proteasomal immunoreactivity and abnormal protein accumulation.
      Immunohistochemistry revealed focal MHC class I immunoreactivity in the
      cytoplasmic membrane of muscle fibers in IBM and in association with protein
      aggregates in IBM, and to a lesser degree, in MM. The present findings provide a
      link between abnormal protein accumulation and altered proteasomal expression in
      IBM and MM.

PMID- 15198128
TI  - The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse
      gliomas.
AB  - Astrocytomas, oligodendrogliomas, and oligoastrocytomas, collectively referred to
      as diffuse gliomas, are the most common primary brain tumors. These tumors are
      classified by histologic similarity to differentiated astrocytes and
      oligodendrocytes, but this approach has major limitations in guiding modern
      treatment and research. Lineage markers represent a potentially useful adjunct to
      morphologic classification. The murine bHLH transcription factors Olig1 and Olig2
      are expressed in neural progenitors and oligodendroglia and are essential for
      oligodendrocyte development. High OLIG expression alone has been proposed to
      distinguish oligodendrogliomas from astrocytomas, so we critically evaluated
      OLIG2 as a marker by immunohistochemical and oligonucleotide microarray analysis.
      OLIG2 protein is faithfully restricted to normal oligodendroglia and their
      progenitors in human brain. Immunohistochemical analysis of 180 primary,
      metastatic, and non-neural human tumors shows OLIG2 is highly expressed in all
      diffuse gliomas. Immunohistochemistry and microarray analyses demonstrate higher
      OLIG2 in anaplastic oligodendrogliomas versus glioblastomas, which are
      heterogeneous with respect to OLIG2 levels. OLIG2 protein expression is present
      but inconsistent and generally lower in most other brain tumors and is absent in
      non-neuroectodermal tumors. Overall, OLIG2 is a useful marker of diffuse gliomas
      as a class. However, expression heterogeneity of OLIG2 in astrocytomas precludes
      immunohistochemical classification of individual gliomas by OLIG2 alone.

PMID- 15198129
TI  - The World Health Organization three-step analgesic ladder comes of age.

PMID- 15198131
TI  - Delirium in advanced cancer patients.
AB  - Delirium in advanced cancer is often poorly identified and inappropriately
      managed. It is one of the most common causes for admission to clinical
      institutions and is the most frequently cited psychiatric disorder in terminal
      cancer. Diagnosis of delirium is defined as a disturbance of consciousness and
      attention with a change in cognition and/or perception. In addition, it develops
      suddenly and follows a fluctuating course and it is related to other causes, such
      as cancer, metabolic disorders or the effects of drugs. Delirium occurs in 26% to
      44% of cancer patients admitted to hospital or hospice. Of all advanced cancer
      patients, over 80% eventually experience delirium in their final days. In
      advanced cancer, delirium is a multifactorial syndrome where opioids factor in
      almost 60% of episodes. Delirium in such patients, excluding terminal delirium,
      may be reversible in 50% of cases. Providing adequate end-of-life care for a
      patient with delirium is the main challenge. The family needs advice and it is
      important to create a relaxing environment for the patient. The primary
      therapeutic approach is to identify the reversible causes of delirium. Some
      therapeutic strategies have been shown to be effective: reduction or withdrawal
      of the psychoactive medication, opioid rotation, and hydration. Haloperidol is
      the most frequently used drug, and new neuroleptics such as risperidone or
      olanzapine are being tested with good results. Methylphenidate has been used for
      hypoactive delirium.

PMID- 15198130
TI  - Breakthrough pain characteristics and syndromes in patients with cancer pain. An
      international survey.
AB  - Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background
      of relatively well controlled baseline pain. Previous surveys have found that BKP
      is highly prevalent among patients with cancer pain and predicts more severe
      pain, pain-related distress and functional impairment, and relatively poor
      quality of life. An international group of investigators assembled by a task
      force of the International Association for the Study of Pain (IASP) evaluated the
      prevalence and characteristics of BKP as part of a prospective, cross-sectional
      survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total
      of 1095 patients with cancer pain using patient-rated items from the Brief Pain
      Inventory (BPI) and observer-rated measures. The observer-rated information
      included demographic and tumor-related data, the occurrence of BKP, and responses
      on checklists of pain syndromes and pathophysiologies. The clinicians reported
      BKP in 64.8% of patients. Physicians from English-speaking countries were
      significantly more likely to report BKP than other physicians. BKP was associated
      with higher pain scores and functional interference on the BPI. Multivariate
      analysis showed an independent association of BKP with the presence of more than
      one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking
      country. These data confirm the high prevalence of BKP, its association with more
      severe pain and functional impairment, and its relationship to specific cancer
      pain syndromes. Further studies are needed to characterize subtypes of BKP. The
      uneven distribution of BKP reporting across pain specialists from different
      countries suggests that more standardized methods for diagnosing BKP are needed.

PMID- 15198132
TI  - Haloperidol in palliative care.
AB  - Haloperidol is one of 20 'essential' medications in palliative care. Its use is
      widespread in palliative care patients. The pharmacology of haloperidol is
      complex and the extent and severity of some of its adverse effects, particularly
      extrapyramidal adverse effects (EPS), may be related to the route of
      administration. Indications for the use of haloperidol in palliative care are
      nausea and vomiting and delirium. Adverse effects include EPS and QT
      prolongation. Sedation is not a common adverse effect of haloperidol. It is
      important that palliative care practitioners have a comprehensive understanding
      of the indications, doses, adverse effects and pharmacology of haloperidol. This
      review is intended to address these issues.

PMID- 15198133
TI  - The quality of medical care at the end-of-life in the USA: existing barriers and
      examples of process and outcome measures.
AB  - CONTEXT: Cancer is a leading cause of morbidity and mortality in the USA and
      despite many recent advances in detection and treatment, over half a million
      cancer patients in this country will die from their disease each year. OBJECTIVE:
      Using cancer as a prototype, we provide a conceptual framework to identify and
      review barriers to optimal end-of-life care and propose examples of linked
      process and outcome measures that could be used to evaluate whether standards of
      optimal end-of-life care are being achieved. METHODS: We propose a conceptual
      model of end-of-life care and use this model to review the published literature
      to identify the key goals of optimal end-of-life care and summarize existing
      barriers to optimal end-of-life care. We then provide examples of process and
      outcome measures linked to the goals of optimal end-of-life care and domains
      within the conceptual framework. RESULTS: Within all components of care at the
      end-of-life--societal attitudes, health care system(s), providers, and patients
      and their families--there are significant barriers to the quality of care. Some
      of the most critical barriers to optimal care at the end-of-life in the USA are
      limited availability, and coverage of, co-ordinated service delivery; poor
      provider communication and diagnostic skills; limited opportunities for training
      in palliative care; patient fears and attitudes towards the sick role, and a lack
      of, or inadequate health insurance. Proposed patient, provider, and system level
      measures of the quality of care were guided by goals of optimal end-of-life care,
      and focus on communication about prognosis and risks and benefits of treatment,
      development of clear and informed treatment goals, delivery of services
      consistent with treatment goals, and promotion of quality of life. CONCLUSIONS:
      At present, there are substantial societal, health care system, provider, and
      patient barriers to obtaining optimal cancer care at the end-of-life. Ongoing
      discussions about appropriate measures of the quality of end-of-life care are
      gaining momentum, however. The proposed process and outcome measures for
      assessing optimal end-of-life care use cancer as a prototype, but are broadly
      applicable to other patient populations with life-threatening disease.

PMID- 15198134
TI  - An Australian casemix classification for palliative care: technical development
      and results.
AB  - OBJECTIVES: To develop a palliative care casemix classification for use in all
      settings including hospital, hospice and home-based care. SAMPLE: 3866 palliative
      care patients who, in a three-month period, had 4596 episodes of care provided by
      58 palliative care services in Australia and New Zealand. METHOD: A detailed
      clinical and service utilization profile was collected on each patient with staff
      time and other resources measured on a daily basis. Each day of care was costed
      using actual cost data from each study site. Regression tree analysis was used to
      group episodes of care with similar costs and clinical characteristics. RESULTS:
      In the resulting classification, the Australian National Sub-acute and Non-acute
      Patient (AN-SNAP) Classification Version 1, the branch for classifying inpatient
      palliative care episodes (including hospice care) has 11 classes and explains
      20.98% of the variance in inpatient palliative care phase costs using trimmed
      data. There are 22 classes in the ambulatory palliative care branch that explains
      17.14% variation in ambulatory phase cost using trimmed data. DISCUSSION: The
      term 'subacute' is used in Australia to describe health care in which the goal--a
      change in functional status or improvement in quality of life--is a better
      predictor of the need for, and the cost of, care than the patient's underlying
      diagnosis. The results suggest that phase of care (stage of illness) is the best
      predictor of the cost of Australian palliative care. Other predictors of cost are
      functional status and age. In the ambulatory setting, symptom severity and the
      model of palliative care are also predictive of cost. These variables are used in
      the AN-SNAP Version 1 classification to create 33 palliative care classes. The
      classification has clinical meaning but the overall statistical performance is
      only moderate. The structure of the classification allows for it to be improved
      over time as models of palliative care service delivery develop.

PMID- 15198135
TI  - An Australian casemix classification for palliative care: lessons and policy
      implications of a national study.
AB  - OBJECTIVES: To provide a nontechnical discussion of the development of a
      palliative care casemix classification and some policy implications of its
      implementation. SAMPLE: 3866 palliative care patients who, in a three month
      period, had 4596 episodes of care provided by 58 palliative care services in
      Australia and New Zealand. METHOD: A detailed clinical and service utilization
      profile was collected on each patient with staff time and other resources
      measured on a daily basis. A statistical summary of the clinical variables was
      compiled as the first stage of the analysis. RESULTS: Palliative care phase was
      found to be a good predictor of resource use, with patients fairly evenly
      distributed across the five categories. Clients treated in an inpatient setting
      had poorer function and higher symptom severity scores than those treated in an
      ambulatory setting, a result that is not surprising in this Australian setting.
      DISCUSSION: Implementation of the resultant AN-SNAP classification has been
      proceeding since 1998 in some Australian jurisdictions. The development and
      implementation of a classification such as AN-SNAP provides the possibility of
      having a consistent approach to collecting palliative care data in Australia as
      well as a growing body of experience on how to progressively improve the
      classification over time.

PMID- 15198136
TI  - How do palliative medicine physicians assess and manage depression.
AB  - Depression is a significant symptom for approximately 25% of palliative care
      patients, but is frequently unrecognized and untreated. This study was carried
      out to determine how senior doctors working in palliative medicine in the UK
      assessed and managed depression in their patients. A questionnaire was sent to
      all palliative care units with a designated consultant or medical director.
      Questions were asked about assessment and management of depression
      (pharmacological and nonpharmacological); difficulties encountered,
      qualifications and current post. The response rate was 63%; two-thirds (90) of
      respondents were consultants and a further 21 medical directors. The majority
      (73%) routinely assessed for depression with 27% using the Hospital Anxiety and
      Depression (HAD) Scale and 10% asking the patient 'are you depressed'? The most
      frequently prescribed medication was SSRI (80%). Less than 6% prescribed
      psychostimulants. Respondents reported difficulties with the assessment and
      management of depression which mainly focused on distinguishing symptoms of
      depression from sadness and whether it was appropriate to treat patients when
      life expectancy was short. Difficulties were identified in accessing psychiatric
      input by 47%. Depression is identified as being a difficult symptom to manage by
      many senior palliative care physicians in the UK and suggestions are made as to
      how some of theses issues can be addressed.

PMID- 15198137
TI  - Specialist palliative care needs of whole populations: a feasibility study using
      a novel approach.
AB  - BACKGROUND: Defining whether people with life-limiting illnesses (PLLI) who do
      not access specialized palliative care services (SPCS) have unmet needs is
      crucial in planning and evaluating palliative care. This study seeks to establish
      the viability of a whole-of-population method to help characterize SPCS access
      through proxy report. METHODS: Questions were included in a piloted annual face
      to-face health survey of 3027 randomly selected South Australians on the need
      for, uptake rate of, and satisfaction with SPCS in 2000. The survey was
      representative of the cross-section of South Australians by age, gender,
      socioeconomic status and region. RESULTS: One in three people surveyed (1069)
      indicated that someone 'close to them' had died of a terminal illness in the
      preceding five years. Of those who identified that a palliative service had not
      been used (38%, 403), reasons cited included family/friends provided the care
      (34%, 136) and the service was not wanted (21%, 86). Respondents with income > AU
      dollars 60000 per year were more likely to report that a SPCS had been used (P =
      0.01). People who had cancer as their life-limiting illness were more likely to
      access SPCS (P < 0.001). The results generate a model comparing SPCS utilization
      with client benefit. The survey was acceptable to interviewees. DISCUSSION:
      Uptake rates of SPCS in this survey are consistent with other South Australian
      whole population estimates of SPCS utilization. Although there are limitations in
      this survey approach and the questions asked, this method can be developed to
      improve our understanding of the characteristics and needs of PLLI and their
      carers.

PMID- 15198138
TI  - Developing an operational typology of patients hospitalised in palliative care
      units.
AB  - The objective of this study was to develop an operational typology of patients
      hospitalised in palliative care units (PC units) and to characterize these
      populations. Prospective data were collected in four PC units over three-week
      periods, generating a sample of 139 cases. Five classes of patient were
      identified and described via a factorial analysis and a classification:
      metastatic cancers requiring significant psychological attention, terminally ill
      patients, ENT cancers, neurological diseases and elderly patients. A more
      detailed study revealed differences between metastatic cancers, younger patients,
      very dependent patients and the other patients. We present the sociodemographic,
      clinical and cost per patient profiles of each class of patient. Having access to
      a broader sample of PC units and of patients would allow for a more complete
      typology.

PMID- 15198139
TI  - Intralesional treatment in painful rib metastases.

PMID- 15198140
TI  - Chinese whispers: transmission of information between health professionals: a
      pilot study.

PMID- 15198141
TI  - Outcome of apparent ureteropelvic junction obstruction identified by
      investigation of fetal hydronephrosis.
AB  - OBJECTIVES: The purpose of the study was to evaluate the outcome of prenatally
      detected ureteropelvic junction obstruction (UPJO) managed with a more
      conservative protocol. METHODS: The records and imaging studies of 77 consecutive
      neonates with UPJO identified by fetal hydronephrosis were reviewed. A
      nonoperative approach was attempted in patients with mild/moderate pelvic
      dilatation, renal units with good function as ascertained by DMSA scan and a non
      obstructed pattern on DTPA. Otherwise, the patients were managed surgically by
      pyeloplasty. Both groups were prospectively followed and the imaging studies were
      performed before and after the initial approach and at one-year intervals
      thereafter. RESULTS: Of the 77 infants (85 units), 39 were submitted to surgery
      (33 pyeloplasty and 7 nephrectomy) and 38 were conservatively managed. During
      follow-up, 9 (24%) of 38 patients in the non-operative group presented renal
      function deterioration and 3 presented with urinary infections and were submitted
      to pyeloplasty. Of the 39 patients surgically managed, 76% presented improvement
      of hydronephrosis and 90% showed a non-obstructed pattern on diuretic renography.
      The differential renal uptake, as measured by DMSA scan, remained stable in the
      three groups analyzed (conservative, initial pyeloplasty, and delayed
      pyeloplasty). There was a minimal improvement in those units submitted to
      pyeloplasty with impaired renal function at baseline (< 40%). Mean renal uptake
      was 28.6% at admission and 33.9% at the end of follow-up. CONCLUSION: There was a
      wide spectrum of ureteropelvic junction stenosis. Surgical intervention in a
      subgroup of patients with severe hydronephrosis and impaired function may
      possibly improve or preserve renal parenchyma. Conversely, conservative
      management and clinical follow-up are safe and desirable for the subgroup with
      mild/moderate pelvic dilatation and preserved renal function.

PMID- 15198142
TI  - Postrenal acute renal failure during pregnancy 20 years after antireflux surgery.
AB  - We report that a 27-year-old woman with bilateral severe hydronephorosis during
      pregnancy 20 years after antireflux surgery. The patient developed postrenal
      acute renal failure due to obstruction of the lower ureter. This patient could
      safely give birth after bilateral percutaneous nephrostomy through joint
      management with the obstetrics and gynecology staff. We describe that stenosis of
      the lower ureter is a late complication of antireflux surgery.

PMID- 15198143
TI  - Diagnostic significance of semiquantitative and quantitative parameters of Tc99m
      Ethylenedicystine renal allograft scintigraphy.
AB  - OBJECTIVES: No objective parameters for renal allograft evaluation have yet been
      described for Tc99m-Ethylenedicystine. This study evaluates the diagnostic
      significance of different quantitative and semi-quantitative parameters of renal
      allograft scintigraphy using Tc99m-Ethylenedicystine. METHODS: A total of 72
      renal dynamic scintigraphic studies were performed within 2-weeks of renal
      transplantation in 42 patients. The graft perfusion, kidney/aorta ratio, washout
      index and retention index were derived from all studies. All these parameters
      were evaluated for their ability to distinguish between a normal graft, a graft
      with acute rejection (AR), and a graft with acute tubular necrosis (ATN).
      Histopathological verification of diagnosis was obtained in all cases. RESULTS:
      Studies were subdivided into 3 groups according to histopathological findings:
      acute rejection (n = 42), normal (n = 18) and acute tubular necrosis (n = 12).
      Normal allografts were visualized with in 2.66 +/- 0.59 seconds of visualization
      of abdominal aorta. The K/A ratio, wash out index and retention index was 15.22
      +/- 6.86, 1.67 +/- 0.45, and 5.48 +/- 0.98 respectively. Allografts with ATN were
      visualized with in 3.36 +/- 0.80 seconds of visualization of abdominal aorta. The
      K/A ratio, wash out index and retention index was 12.73 +/- 6.74, 0.60 +/- 0.14,
      and 9.18 +/- 1.48 respectively. In AR, allografts were visualized 15.18 +/- 9.48
      seconds after visualization of abdominal aorta. The K/A ratio, wash out index and
      retention index was 7.07 +/- 2.15, 0.63 +/- 0.11, and 2.26 +/- 1.28 respectively.
      CONCLUSIONS: Retention index can separate all the three condition of normal,
      acute rejection and acute tubular necrosis from each other. Retention index of <
      4 suggests acute rejection, a value between 4 and 7 suggests normal allograft and
      a value of > or = 7 is suggestive of acute tubular necrosis. However, perfusion,
      K/A ratio and washout index can not segregate all the three groups.

PMID- 15198144
TI  - Fluid volume measurements in normal subjects to disclose body hydration during
      acute bed rest.
AB  - Measuring intercompartmental, blood and urinary biochemical parameters during
      acute bed rest (ABR) and rigorous bed rest (RBR) the aim of this work was to
      disclose if ABR or RBR could influence significantly more and significantly
      faster the body hydration level in normal subjects. Studies conducted during pre
      bed rest (BR) period of 3-days and during 7-days period of ABR and RBR. Thirty
      normal male individuals 24.6 +/- 5.7 years of age were chosen as subjects. They
      were divided into three groups: unrestricted active control subjects (UACS),
      acute bed rested subjects (ABRS) and rigorous bed rested subjects (RBRS). Acute
      bed rested subjects confined abruptly to RBR, while they did not have any prior
      knowledge of the exact date and time when they would be subjected to RBR. RBRS
      were submitted to RBR in a predetermined date and time known to them right from
      the start of the study. UACS were not subjected to any form of BR. Fluid loss,
      urinary and plasma sodium (Na+) and potassium (K+), plasma osmolality, whole
      blood hematocrit (Hct) and hemoglobin (Hb), and total plasma protein level
      increased significantly (p < 0.05), while urinary osmolality, extracellular
      volume (ECV), plasma volume (PV), red cell volume (RCV), blood volume (BV),
      interstitial volume (IV) and fluid consumption decreased significantly (p < 0.05)
      in ABRS and RBRS compared with their pre-BR values and their control (UACS).
      However, the measured variables changed significantly (p < 0.05) more and
      significantly faster in ABRS than RBRS. Conversely, whole blood Hct and Hb
      levels, fluid consumption and fluid loss, urinary and plasma osmolality, urinary
      and plasma electrolytes, plasma protein, ECV, PV, RCV, BV and IV levels were not
      change in UACS compared with their pre-BR values. Significantly greater and
      significantly faster intercompartmental, blood and urinary biochemical changes
      were observed in ABRS than RBRS. Body hydration was affected significantly more
      and significantly faster in ABR than RBR. It was concluded, the more abruptly
      normal activity is restricted the smaller the body hydration in bed rested
      subject is, and probably in patients who are abruptly confined to RBR.

PMID- 15198145
TI  - Digital subtraction angiography assisted ultrasound puncture in a pelvic kidney.
AB  - A new technique for percutaneous nephrostomy needle guidance is presented. It was
      applied in a patient with a solitary pelvic kidney, where ultrasound guidance was
      not feasible because of a very narrow puncture window. Typical intravenous
      urography was not useful, owing to poor opacification of the collecting system.
      We describe how the use of digital subtraction imaging eventually permitted us to
      establish a percutaneous nephrostomy tube safely, avoiding the intestine and
      blood vessels.

PMID- 15198146
TI  - von Hippel-Lindau disease with bilateral multiple renal cell carcinoma managed by
      right radical nephrectomy and left repeat partial nephrectomy.
AB  - von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized
      by cysts and cystadenoma in the kidney, pancreas and epididymis and angiomas of
      the central nervous system and retina as well as renal cell carcinoma (RCC),
      phaeochromocytoma, islet tumors of the pancreas, and endolympatic sac tumors. VHL
      for its multicentric-characteristic and bilateralism often puts the surgeon in
      challenging situation. We present a case of VHL with bilateral RCC and retinal
      angiomas managed with right radical nephrectomy and left repeat partial
      nephrectomy.

PMID- 15198147
TI  - Case report: intra-renal paraganglioma masquerading as a renal cyst.
AB  - A case is reported in which a 46-year-old normotensive male patient presented
      with large right-sided painless abdominal mass. On sonography there was a large
      cyst in the lower pole of right kidney. Intravenous urography showed distortion
      of pelvicollecting system and medial shift of upper right ureter. Exploration
      revealed a cystic mass (18 x 15 cm) located in lower pole of right kidney. It
      contained brownish fluid and because of suspicion of malignancy radical
      nephrectomy was carried out. Histological examination showed the cystic mass to
      be adrenal tissue infiltrated by neoplastic cells. Characteristic organoid nests
      of malignant cells ("Zellaballen" were present. Cells stained positively for
      chromogranin, neurone specific enolase (NSE), neurofilament, and synaptophysin.
      Sustentacular cells showed positive reaction to S-100 protein. No further
      treatment was offered. Patient remains well at 30 months follow-up. On medline
      search there is record of three cases of intra-renal paraganglioma in English
      literature and the present case appears to be the fourth one.

PMID- 15198149
TI  - Giant ureteral stone associated with partial ureteral duplication.
AB  - We are presenting a 36-year-old male patient with right flank pain and a history
      of recurrent urinary tract infection for three years. Radiographic intervention
      revealed a right partial ureteral duplication with a giant stone in size 9.6 cm
      in the ureteral limb draining the non-functioning upper pole of the right kidney.
      Open ureterolithotomy and partial nephroureterectomy was performed by a right
      flank incision. The presence of a ureteral partial duplication created a "yo-yo
      phenomenon", which interfered with stone passage to the bladder and may cause
      such giant ureteral stone.

PMID- 15198148
TI  - The effect of diclofenac sodium and papaverine on isolated human ureteric smooth
      muscle.
AB  - OBJECTIVES: The pain assocaited with ureteral obstruction is caused by a rise in
      intraluminal pressure above the obstruction which produces an increase in tension
      of the ureteral smooth muscle. A reduction in pressure will result in decreased
      tension and relief of pain. In this study we used papaverine and a prostaglandin
      synthesis inhibitor, diclofenac sodium to decrease ureteral tension and compaired
      their effects on isolated human ureteric smooth muscle. MATERIALS AND METHODS:
      Experiment have been carried out with isolated ring preparation of human ureter.
      The tissue displayed spontaneous activity and contracted when exposed to KCl (40
      mM). Papaverine (10(-5) M) and diclofenac sodium (10(-8)-10(-5) M) were applied
      on the precontracted segments and isometric variation was recorded with Nihon
      Kohden TB-612 isometric transducer. Their relaxant responses were comparatively
      examined. RESULTS: Mean relaxation obtained by diclofenac sodium and papaverine
      were respectively 43.19% and 28.96%. Our study showed that diclofenac sodium may
      be more potent than papaverine in the treatment of renal colic.

PMID- 15198150
TI  - A case of primary ureteral carcinoma in association with unilateral complete
      duplication of the ureter.
AB  - We are presenting a 68-year-old female patient who was diagnosed to have a
      complete ureteral duplication and adenocarcinoma in the ureter which drained the
      upper moiety of the right kidney.

PMID- 15198151
TI  - Carcinosarcoma of the ureter: a rare, pleomorphic, aggressive malignancy.
AB  - AIM: To examine histological nature and clinical process of ureteral
      carcinosarcomas. METHODS: We report on a new case of carcinosarcoma of the
      ureter. The literature was reviewed and histological and clinical features were
      elucidated. RESULTS: Fourteen cases of ureteral carcinosarcomas have been
      reported. The nomenclature used for these tumors either in the pathology reports
      or in literature is confusing. In contrary to obscure tumor biology, prognosis
      was clearly bad as the majority of the patients died within 2 years after
      diagnosis. CONCLUSIONS: Terminology confusion is due to the rarity of this entity
      and lack of its biology knowledge. Patients present after the age of 60 with
      hematuria and obstruction. Nephroureterectomy is the only hope of cure but, due
      to tumor aggressiveness, recurrences occur almost always and prognosis is poor.

PMID- 15198152
TI  - Big bladder stones around an intravesical migrated intrauterine device.
AB  - Spontaneous migration of the intrauterine devices into the bladder and secondary
      stone formation are rare complications. A 33-year-old women in whom a copper T
      intrauterine device had been placed two years previously, presented complaining
      of irritative lower urinary tract symptoms. Intravesical migration of
      intrauterine device and big stones around it were confirmed by radiography and
      cystoscopy. The stones were fragmented by using electrohydraulic lithotriptor.
      And then all fragments of the stones and IUD were cystoscopically removed by a
      grasping forceps without any complication.

PMID- 15198153
TI  - A huge bladder cystine stone.
AB  - An unusual cystine stone that occur only in patients, who have cystinuria is
      presented in 24-year-old man. Radiographs showed a giant bladder stone shadow,
      8.0 x 10.0 x 5.0 cm in size. The literature was reviewed to identify the giant
      stones as well as the huge cystine stone which is exceptional yet as.

PMID- 15198154
TI  - Fertility preserving radical cystectomy in a young female with malignant
      mesenchymal tumour of urinary bladder.
AB  - Fertility preserving radical cystectomy has been reported in young males with
      leiomyosarcoma and transitional cell carcinoma but not in females. We present a
      case of 19-year-old lady with mesenchymal tumour of urinary bladder with myogenic
      differentiation who was managed with fertility preserving radical cystectomy. As
      the patient was just 19-year-old a consensus was made to preserve the internal
      genitalia (both the ovaries and uterus) in order to restore the fertility.
      Immunohistochemistry was compatible with mesenchymal tumour with myogenic
      differentiation. Adjuvant chemotherapy (Ifosfamide, CDDP and Etocid) was given.
      Patient is doing well at a follow-up of 6 months.

PMID- 15198155
TI  - Management of inguinal hernia with benign prostatic hyperplasia: simultaneous
      inguinal hernioplasty with transurethral resection of prostate.
AB  - BACKGROUND: Elderly patients frequently suffer from inguinal hernia and benign
      prostatic hyperplasia. When these two occur together, it becomes important to
      decide which surgery should be done first. METHODS: Data was maintained
      prospectively for 35 patients undergoing simultaneous transurethral resection of
      prostate (TURP) and inguinal mesh hernioplasty at our hospital between May 2000
      and December 2002. The results were analyzed to determine whether the performance
      of the two operations simultaneously was a viable option in such a patient
      category. RESULTS: In 33 patients unilateral hernioplasty, and in 2, Stoppa's
      mesh repair (for bilateral hernia) was performed along with simultaneous TURP by
      two independent operating teams. There was no significant increase in operating
      time or post-operative stay when the two procedures were performed together.
      There were no major in-hospital complications. On follow up, all the patients
      have remained well, with no recurrence of hernia. CONCLUSIONS: Combining mesh
      hernioplasty and TURP is a better option because of low wound infection and
      hernia recurrence rates. Combining these two also saves the patient of having to
      undergo another hospital admission and surgery, besides the significant cost
      savings.

PMID- 15198157
TI  - Heterotopic ossification of the spermatic cord.
AB  - Heterotopic ossification is the most frequent type of connective tissue
      metaplasia. We report a rare case with bone formation in the spermatic cord.

PMID- 15198156
TI  - The selection of the regional anaesthesia in the transurethral resection of the
      prostate (TURP) operation.
AB  - BACKGROUND AND OBJECTIVES: The aim of our study was to compare the three
      different regional anaesthesia methods in patients who underwent transurethral
      resection of the prostate (TURP) and to determine the ideal anaesthesia method
      for TURP operation. METHODS: Totally 77 ASA II-III patients were preloaded with
      500 ml 0.9% NaCl solution before regional anaesthesia. In group E (n:27) epidural
      anaesthesia were achieved by applying 75 mg bupivacaine heavy + 50 microg
      fentanyl in the L3-L4 intervertebral space. In group SP (n:28) 15 mg bupivacaine
      heavy + 50 microg fentanyl were used for spinal anaesthesia (L3-L4 intervertebral
      space) while in group SA (n:30) 10 mg bupivacaine heavy + 50 microg fentanyl were
      used with saddle blockade. Systolic arterial pressure (SAP), heart rate (HR),
      peripheral oxygen saturation (SpO2), serum sodium measurement was recorded before
      and after hydration and during operation. The motor block and sensory level have
      been measured. RESULTS: Intraoperative SAP values were more stable than the other
      groups in group SA. The decrease in HR values were significant 15 minutes after
      prehydration in three groups (p < 0.05). SpO2 values of the groups were stable
      during the operation. The time to reach the maximum block was very short in
      patients in Group SA (p < 0.0001). There was a statistically significant
      difference between the groups in terms of motor block values (p < 0.0001). No
      fully paralysed sample was seen in Group SA even though there was a sufficient
      surgical anaesthesia. CONCLUSIONS: Saddle block has some advantages compared to
      spinal and epidural anaesthesia methods such as achieving adequate anaesthesia,
      stable haemodynami, the lower degree of motor blockage and no full blockage in
      patients. Saddle block is an the most optimal anaesthesia method for TURP
      operation.

PMID- 15198158
TI  - Case report: malignant Sertoli cell tumor of the testis in an adult.

PMID- 15198159
TI  - Hematospermia (ejaculatory duct calculus)--an unusual cause.
AB  - Hematospermia is a common harmless condition that invokes a lot of anxiety to the
      patient. Calculous obstruction of the ejaculatory duct is an unusual cause of
      hematospermia. We report one such case of hemospermia due to an ejaculatory duct
      calculus that was diagnosed with TRUS. An endoscopic approach should be attempted
      to manage all such cases.

PMID- 15198160
TI  - Methylene blue as a means of treatment for priapism caused by intracavernous
      injection to combat erectile dysfunction.
AB  - OBJECTIVE: The authors observed priapism as a side effect occuring during the
      intracavernous treatment of erectile dysfunction. Earlier priapism had been
      treated with an intracavernous injection of sympatomimetics; unfortunately
      several complications and contraindications were found. PATIENTS AND METHODS:
      Methylene blue was applied in the treatment of five patients. First a corpus
      cavernosum punction was performed and some blood was aspirated from the penis.
      Finally 100 mg of Methylthionin Chlorati was injected into the corpus cavernosum.
      RESULTS: A sufficient detumescence was observed in all of these cases. There were
      no complications. The method was applied effectively in two cases after an
      unsuccessful punction. CONCLUSION: The autors recommend intravenous methylene
      blue for the treatment of priapism. According to their experience this method is
      free of complications and as effective as a sympathomimetics treatment. As they
      think, it can be recommended in any manifestations of priapism because its force
      of action appears to be both chemically and biologically clear.

PMID- 15198161
TI  - An extensive traumatic degloving lesion of the penis. A case report and review of
      the literature.
AB  - Traumatic lesions of the penis and scrotum are often encountered in urological
      emergency departments. We describe a case of complete unraveling of the penile
      skin and partial avulsion of the scrotal skin, which was treated without the need
      for a skin graft, which is usually the selected mode of treatment. Instead, we
      believe that a less aggressive surgical approach is more beneficial for the
      patient since it allows faster healing and prevents the development of
      complications.

PMID- 15198162
TI  - Is dorsale penile vein ligation (DPVL) still a treatment option in veno-occlusive
      dysfunction?
AB  - PURPOSE: To determine the long-term results of the DPVL for the treatment of
      venous impotence. PATIENTS AND METHODS: The long-term results of DPVL in 134
      patients were interviewed. The mean age was 39.2 (range 21-72). Power color
      doppler imaging, pharmacocavernography/dynamic cavernosometry were performed.
      Postoperatively, all the patients were controlled in the 6th month, first year
      and, if possible, once a year. The mean follow-up was 54.8 (14-76) months.
      Postoperative outcomes were classified into 3 groups: complete spontaneous
      erection (CR), response to pharmacotherapy (PR) or no satisfactory improvement
      (NR). RESULTS: The short-term success in the 6th month according to above
      mentioned was 38.8%, 18.6% and 42.5%; and in the first year was 19.4%, 14.9% and
      65.6% respectively. The result in 35 patients whose follow-up was at least 5
      years (mean 67 months) was 11.4%, 14.3% and 74.3% respectively. Positive
      prognostic factors were preoperative age <40, duration of erectile dysfunction <2
      y, non-smoker patients, non neurogenic disease and distal disease. With all these
      parameters present, long-term success (CR, PR) rose from 33.6% to 55.9% (p <
      0.001). CONCLUSIONS: Long-term success for unselected patients undergoing DPVL is
      disappointing; however, careful patient selection significantly improves long
      term results.

PMID- 15198163
TI  - Fatigue in chronic peritoneal dialysis patients.
AB  - Fatigue is a common complaint in long term dialysis patients that may influence
      their quality of life. The present study was carried out in order to evaluate the
      prevalence and course of fatigue in a group of chronic PD patients and to find
      the possible factor(s) related to its development. We retrospectively reviewed
      100 charts of the patients previously on PD. The presence or absence of fatigue
      in the 1st and last clinic visits and the 1st and 2nd changes in fatigue state
      were studied according to the monthly clinical records of the primary nurses.
      Data regarding dialysate volume, urine volume, weekly erythropoietin (EPO) dose,
      hemoglobin, hematocrit, blood urea, serum creatinine, residual renal creatinine
      and urea clearances, dialysate to peritoneal creatinine ratio (D/P Cr), total
      weekly Kt/V and total creatinine clearance/1.73 m2 body surface area (TCrCl) were
      collected. Fifty-five patients were male and 45 female. The mean age at the 1st
      clinic visit was 61.3 +/- 16 years. At the 1st visit 55 patients had fatigue and
      45 did not. In 32 of the 55 patients fatigue disappeared after a mean duration of
      7.9 +/- 8.4 months and in 31 of the 45 patients fatigue appeared after a mean
      duration of 8 +/- 6.8 months. So at the last visit the frequency of fatigue
      increased significantly from 55% to 67% (p < 0.001). In patients with fatigue the
      mean age and female percentage were higher (64.2 +/- 14.1 vs 57.8 +/- 17.6, p =
      0.05 and 1.2 vs 0.5, p < 0.05 respectively), mean hemoglobin concentration was
      lower (104.4 +/- 14.7 vs 110.6 +/- 14.2 g/L, p < 0.04) and mean EPO dose was
      higher (6379.6 +/- 7142 vs 3395.4 +/- 4337.8 units/week, p < 0.02) at the 1st
      clinic visit. EPO dose was also higher in patients with fatigue at the last visit
      (8253.7 +/- 10317.3 units/wk vs 4736.4 +/- 5432.5, p < 0.03). No correlation was
      found between dialysis adequacy according to either weekly Kt/V or TCrCl and
      nutritional state according to nPCR and frequency of fatigue. We conclude that
      fatigue is a common symptom in PD patients and it's prevalence increases over
      time. Anemia seems to be the most important factor associated with fatigue.
      Dialysis adequacy and nutritional state did not show any correlation with the
      frequency of fatigue in our study.

PMID- 15198164
TI  - Impact of clinical and histopathological factors on outcome of Egyptian patients
      with crescentic glomerulonephritis.
AB  - This study included 128 patients with crescentic glomerulonephritis (CGN) having
      sufficient clinical and histopathological data and were followed up in our
      institute for a mean period of 34 +/- 28 months. There were 49 males and 79
      females with mean age 22.7 +/- 14 years. We studied the effect of clinical,
      laboratory and histopathological parameters on kidney function and patient
      survival at the end point of the study. The multivariate analysis revealed that
      serum creatinine at presentation, nephrotic range proteinuria during the follow
      up period, percentage of glomeruli affected by crescents, percentage of fibrous
      crescents and absence of cellular infiltration were significant risk factors
      affecting the kidney function at termination of the study. The only risk factor
      which correlated significantly with the patient mortality was the serum
      creatinine at last follows up.

PMID- 15198165
TI  - Prevalence and determinants of erectile dysfunction in patients on peritoneal
      dialysis.
AB  - BACKGROUND: Sexual dysfunction including erectile dysfunction (ED) is common in
      patients with end stage renal disease on peritoneal dialysis (PD). Prevalence and
      determinants of ED in these patients has not been well characterized. PATIENTS
      AND METHODS: Prevalence of ED in 44 patients on chronic PD was assessed using the
      International Index of Erectile Function (IIEF-5) commonly called Sexual Health
      Inventory for Men (SHIM) score. The associations between ED and other medical
      conditions was also assessed. RESULTS: Prevalence of ED was high at 88%. Mean age
      of all patients was 61.8 +/- 13.9 years. Thirty-two patients were hypertensive,
      19 of them had coronary artery disease and 13 patients were diabetics. All
      patients with diabetes had ED. Age and diabetes were found to be significantly
      associated with ED. CONCLUSION: ED is highly prevalent in patients on chronic PD.
      Increasing age and diabetes were associated with higher percentage of ED.

PMID- 15198167
TI  - Refractory hyperkalemia in peritoneal dialysis.

PMID- 15198166
TI  - Optimizing medication adherence in older persons with hypertension.
AB  - Suboptimal control of hypertension in large communities can be attributed, in
      part, to about 50% of patients who stop taking their antihypertensive drugs after
      1 year. Older patients with many illnesses (including chronic kidney disease) are
      at especially high risk for discontinuing prescribed medications, but age is a
      weaker predictor than the number of consumed pills. Determining if medications
      are being taken as prescribed is difficult, but asking the patient and
      significant other the simple question, "Have you missed any pills in the last
      week?" is a good place to start. Despite all their other virtues, clinical trials
      seldom provide the same answers regarding medication adherence that are found in
      clinical practice. Observational and a few interventional trials have established
      that short, simple regimens that improve patients' symptoms and are well
      tolerated are more likely to be taken correctly. Patient (and family) education
      is the cornerstone of improving adherence to medication, but several other
      interventions have also proven useful. There appears to be no "magic bullet" that
      will improve medication adherence in all patients, but providing written
      instructions, simplifying the medication regimen to as few as necessary, once
      daily, well tolerated and inexpensive pills, involving family members, and
      prompting pill taking by certain activities of daily living all seem to help.
      Improving medication adherence would be a simple way to make antihypertensive
      therapies much more cost effective, since a medication that is not taken incurs
      all of cost, and provides no benefit to the patient.

PMID- 15198168
TI  - Advance care planning in elderly chronic dialysis patients.
AB  - Despite the usefulness of advance directives, most dialysis patients do not
      complete them. Current views of the advance care planning process emphasize that
      development of a specific written advance directive is only one small part of the
      process. Patients and families use advance care planning discussions to plan for
      death, achieve control over their health care, and strengthen relationships.
      Studies of chronic dialysis patients have shown that discussions about end-of
      life care occur within the patient-family and not the patient-physician
      relationship. Successful advance care planning requires that dialysis care
      providers incorporate end-of-life care wishes and palliative care into the
      overall health care plans for their patients. This review focuses on the past
      impediments to achieving useful advance directives among dialysis patients and
      their families and provides some suggestions to improving this important aspect
      of dialysis patient care.

PMID- 15198170
TI  - Nephropathology quiz page. Idiopathic light chain deposition disease without
      clinical evidence of multiple myeloma.

PMID- 15198169
TI  - Can peritoneal dialysis be used as a long term therapy for end stage renal
      disease?
AB  - Over the last 25 years, since the introduction of CAPD, the use of PD has
      increased greatly and over this period many advances in technique have been made.
      As is well known, that home and self-dialysis, such as PD, cost less than in
      center HD and can provide excellent survival and a high level of patient
      rehabilitation. To date however, the demonstration that PD can provide long term
      dialysis has been limited to a small number of patients. The next few decades
      will see a marked increase in the worldwide dialysis population, particularly as
      older and sicker patients are accepted into dialysis. It is likely that worldwide
      pressures related to cost containment will favour the use of cost effective
      therapies, such as PD. However, the increased use of PD will continue, only if we
      continue to improve its efficacy and do not waste the economic benefits gained
      over HD. We are challenged to improve and develop PD in a way that optimises
      patient medical and psychosocial outcomes while minimizing costs. This may be
      achieved by using more biocompatible solutions, hopefully inexpensive, that will
      maintain the peritoneal membrane intact for long periods, will better preserve
      the membrane's transport characteristics over time, and thus reduce the main
      causes of drop out from dialysis.

PMID- 15198172
TI  - Police-reported intimate partner violence during pregnancy and the risk of
      antenatal hospitalization.
AB  - OBJECTIVES: Intimate partner violence (IPV) is a significant public health
      problem and the abuse of women during pregnancy is of particular concern. Few
      studies have addressed the relationship between IPV and antenatal
      hospitalization. This study utilized a novel approach to examine the impact of
      IPV during pregnancy on antenatal hospitalization not associated with delivery.
      METHODS: This retrospective cohort study included Seattle women residents 16-49
      years of age. Exposed subjects were women with a police-reported IPV incident
      during pregnancy in the years 1995 through 1998 and who subsequently had a
      singleton live birth or fetal death. The unexposed group was composed of randomly
      selected residents with a singleton birth or fetal death and without a police
      reported IPV incident during the study period. Linked hospital discharge files
      and birth records were utilized to determine study outcomes. Logistic regression
      was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals
      (CI). RESULTS: Women reporting any IPV during pregnancy were twice as likely as
      unexposed women to experience an antenatal hospitalization not associated with
      delivery (aAOR 2.39, CI 1.77, 3.24). Women with IPV were more likely to have been
      hospitalized with a substance abuse-related diagnosis (aOR 2.70, CI 1.52, 4.78)
      or a mental health-related diagnosis (aOR 1.93, CI 0.96, 3.91). Physical IPV was
      more strongly associated with antenatal hospitalization than nonphysical IPV or
      IPV overall. CONCLUSION: This study suggests that women hospitalized during
      pregnancy, particularly those with substance abuse and mental health-related
      conditions, may be at high risk for concurrent IPV.

PMID- 15198173
TI  - Predictors of breastfeeding intention among low-income women.
AB  - OBJECTIVE: Breastfeeding rates are below the Healthy People 2010 goals despite
      recognized benefits of breastfeeding. This study determined factors that predict
      breastfeeding initiation among low-income pregnant women. METHODS: A self
      administered closed-ended questionnaire was introduced to 694 pregnant women who
      were certified for WIC in Mississippi. The questionnaire collected data about
      demographics, breastfeeding intention, breastfeeding knowledge, self-efficacy,
      and three recognized barriers to breastfeeding: embarrassment, time and social
      constraints, and lack of social support. RESULTS: In bivariate analysis, women
      who intended to breastfeed were more often white and had at least some college
      education, higher income, a smaller family size, fewer children, and previous
      breastfeeding experience than women who did not intend to breastfeed. Intenders
      had higher levels of breastfeeding knowledge and self-efficacy and reported fewer
      barriers to breastfeeding than nonintenders. In multivariate logistic regression,
      fewer children, past breastfeeding experience, breastfeeding knowledge, self
      efficacy, and perceived social support were independent predictors of
      breastfeeding intention. CONCLUSIONS: Women at high risk for not wanting to
      breastfeed can be identified for additional support. Interventions should focus
      on improving breastfeeding knowledge, enhancing confidence in one's ability to
      breastfeed, and overcoming barriers to breastfeeding, especially lack of social
      support, among low-income women.

PMID- 15198174
TI  - Increasing rate of diabetes in pregnancy among American Indian and white mothers
      in Montana and North Dakota, 1989-2000.
AB  - OBJECTIVES: The purpose of this study was to assess trends in diabetes in
      pregnancy in American Indian and whites mothers in Montana and North Dakota.
      METHODS: Montana and North Dakota birth records were utilized to assess trends in
      any diabetes in pregnancy in American Indians and whites from 1989 to 2000.
      RESULTS: From 1989 through 2000, there were 133,991 and 102,232 births in Montana
      and North Dakota, respectively. The majority of mothers were American Indian
      (11%) or white (87%). The rate of any diabetes in pregnancy increased
      significantly in Montana Indian (3.1-4.1%, p = 0.04) and white mothers (1.8-2.6%,
      p < 0.001) from 1989-1991 to 1998-2000. The rate also increased significantly in
      white North Dakota mothers (1.6-3.2%, p < 0.001), but the increase in rate for
      Indian mothers in North Dakota did not reach statistical significance (3.8-4.8%,
      p = 0.06) during this time period. In each time period, Montana and North Dakota
      Indian mothers were more likely than white mothers to have any diabetes in
      pregnancy. CONCLUSIONS: The rate of diabetes in pregnancy has increased in
      American Indian and white mothers. Thus public health programs are now facing an
      increasing number of women with a history of GDM at future risk of type 2
      diabetes and an increasing number of offspring of diabetic pregnancies at risk
      for becoming overweight and developing type 2 diabetes at a young age.

PMID- 15198171
TI  - Racial disparity in infant and maternal mortality: confluence of infection, and
      microvascular dysfunction.
AB  - OBJECTIVES: Racial disparities in infant and maternal mortality have been
      attributed to the unique stresses faced by Black women in the United States, but
      the underlying pathophysiological pathways are poorly understood. This paper
      reviews the literature related to potential causes of racial disparities in
      infant and maternal mortality. METHODS: A review of the literature from 1966 to
      2003 was conducted using a series of searches of Medline, obstetrical journals,
      and bibliographies. The review focused on potential contributing
      pathophysiological factors to infant and maternal mortality. RESULTS: Racial
      disparities in neonatal mortality largely result from excess rates of preterm
      birth, fetal growth restriction, and neonatal sepsis while racial disparities in
      maternal mortality reflect greater prevalence and/or severity of
      cardiovascular/preeclamptic complications, hemorrhage, and infection among
      African American women. A large body of epidemiological, placental, and
      pathophysiological evidence suggests that racial disparities in these disparate
      outcomes result from two distinct, but potentially converging, pathways:
      infection and vascular. Racial disparities in intrauterine infection and
      microvascular dysfunction during pregnancy may result from a constellation of
      environmental and intergenerational risk factors including psychosocial stress,
      douching, bottle-feeding, lead exposure, diet, intrauterine growth, and genes.
      CONCLUSIONS: Disparities in infant and maternal mortality appear to reflect a
      confluence of infections and microvascular dysfunction during pregnancy among
      African American women. Interventions that target these conditions offer promise
      for reducing racial disparities in these critical outcomes.

PMID- 15198175
TI  - A comparative analysis of effects of early versus late prenatal WIC participation
      on birth weight: NYS, 1995.
AB  - OBJECTIVES: This study examined the effects of prenatal participation in the NYS
      WIC Program on birth weight through enhanced control of selection bias and
      gestational age bias. Program effects were assessed separately for White, Black,
      and Hispanic women and subpopulations defined by values of Kotelchuck index of
      adequacy of prenatal care utilization. METHODS: 1995 New York State Vital
      Statistics records were linked to WIC certifications, administrative and check
      redemption files, and to the 1990 federal census of NY county level data. The
      final data set contained 77,601 records. Birth weight among WIC participants who
      enrolled early and participated longer were compared to those who enrolled late
      and participated a shorter time. Selection bias was addressed using
      classification tree methods as part of a propensity score analysis. Gestational
      age bias was addressed by analyzing preterm and full-term pregnancies separately.
      RESULTS: Adjusted estimates showed a significant positive effect of longer
      prenatal WIC participation on birth outcomes for all groups studied. Infants born
      to WIC participants who enrolled early were heavier than those who enrolled late
      by, on average, 70 g for full-term and 129 grams for preterm. Black and Hispanic
      full-term infants experienced larger WIC effects than Whites (79, 75, 43 g,
      respectively). Looking at full-term pregnancies using Kotelchuck's index
      indicated that effects of longer prenatal WIC participation were greatest for the
      inadequate prenatal care group (83 g). CONCLUSION: Longer prenatal WIC
      participation was associated with an increase in birth weight overall and for all
      groups studied. The effect on birth weight of longer participation in WIC was
      greatest in Black and Hispanic, inadequate and no prenatal care groups.

PMID- 15198176
TI  - Assessing the learning needs of maternal and child health professionals to teach
      health promotion.
AB  - OBJECTIVE: To assess skills and preferred learning formats in teaching health
      promotion (HP). METHODS: A self-administered needs assessment of Maternal and
      Child Health (MCH) educators from multiple disciplines was conducted on a
      convenience sample taken nationally via e-mail using Dillman's method.
      Respondents rated ability to use, and desire to improve skills in, different
      teaching strategies (brainstorming, case method, collaborative learning, mini
      presentation, reflective exercise, role play) and health concepts (partnership,
      communication, HP/illness prevention, time management, education, advocacy).
      Preferred learning formats were assessed with 5-point Likert scale and were
      analyzed using ANOVA. RESULTS: Fifty-seven percent of respondents (n = 180)
      taught in an urban setting, 26% suburban, and 17% rural. Most taught at academic
      health centers (35%), public health clinics (25%), or hospitals (17%). Seventy
      five percent were female; average age was 42 years (SD--9.1 years). Specific
      disciplines showed no major difference in mean responses compared with others.
      The greatest barriers to integrating HP into teaching were time (82%) and budget
      (58%). Although a majority of all respondents felt comfortable in their abilities
      to use the teaching strategies and concepts, an equal percentage still wanted to
      improve these skills. One-third of respondents had experience using web-based
      study: 64% of them indicated web-based study as their preferred method of
      continuing education. CONCLUSIONS: While a majority of MCH educators felt
      confident using various teaching strategies to teach the integration of HP into
      practice, most still wished to improve their personal skills. Use of an
      inexpensive, time-efficient modality to access and learn to teach HP was
      appealing to respondents across disciplines.

PMID- 15198177
TI  - Family, maternal, and child health through photovoice.
AB  - OBJECTIVE: (1) To introduce photovoice, a participatory action research
      methodology, for use by MCH program managers to enhance community health
      assessments and program planning efforts, (2) to enable community people to use
      the photovoice methodology as a tool to record, reflect, and communicate their
      family, maternal, and child health assets and concerns, and (3) to educate
      community leaders about family, maternal, and child health issues from a
      grassroots perspective. METHODS: Photovoice is based upon the theoretical
      literature on education for critical consciousness, feminist theory, and
      community-based approaches to documentary photography. Picture This Photovoice
      project took place in Contra Costa, an economically and ethnically diverse county
      in the San Francisco Bay area. Sixty county residents of ages 13-50 participated
      in 3 sessions during which they received training from the local health
      department in the techniques and process of photovoice. Residents were provided
      with disposable cameras and were encouraged to take photographs reflecting their
      views on family, maternal, and child health assets and concerns in their
      community, and then participated in group discussions about their photographs.
      Community events were held to enable participants to educate MCH staff and
      community leaders. RESULTS: The photovoice project provided MCH staff with
      information to supplement existing quantitative perinatal data and contributed to
      an understanding of key MCH issues that participating community residents would
      like to see addressed. Participants' concerns centered on the need for safe
      places for children's recreation and for improvement in the broader community
      environment within county neighborhoods. Participants' definitions of family,
      maternal, and child health assets and concerns differed from those that MCH
      professionals may typically view as MCH issues (low birth weight, maternal
      mortality, teen pregnancy prevention), which helped MCH program staff to expand
      priorities and include residents' foremost concerns. CONCLUSIONS: MCH
      professionals can apply photovoice as an innovative participatory research
      methodology to engage community members in needs assessment, asset mapping, and
      program planning, and in reaching policy makers to advocate strategies promoting
      family, maternal, and child health as informed from a grassroots perspective.

PMID- 15198178
TI  - MCH needs assessment capacity shows ongoing improvement; but, meager MCH
      evaluation capacity may impede performance.

PMID- 15198179
TI  - Impact of switching antiretroviral therapy on lipodystrophy and other metabolic
      complications: a review.
AB  - Following the introduction of highly active antiretroviral therapy (HAART),
      metabolic and morphological complications known as HIV associated lipodystrophy
      syndrome (HALS) have been increasingly common. The approaches to target these
      complications span from resistance exercise, diet and use of the antidiabetics
      metformin or glitazones to high dose recombinant human growth hormone therapy or
      switching antiretroviral regimen. When looking at the effect of switching
      therapy, focus has been addressed to protease inhibitor (PI) based regimens, as
      PI was the first component of HAART recognized to be correlated with the
      disfiguring body-alterations known as HALS. More recently, however, regimens
      containing nucleoside reverse-transcriptase inhibitors (NRTI) have attracted
      attention. Reviewing switch studies regarding metabolic parameters and body shape
      changes, certain trends emerge. Switching from PI, the metabolic complications
      such as dyslipidaemia and insulin resistance seem to be partly reversible,
      whereas the morphologic alterations appear to be unchanged. In studies in which
      NRTI's are switched, dyslipidaemia appears unaffected, but a modest improvement
      in peripheral lipoatrophy has been reported. However the results are often
      inconsistent and difficult to interpret, mostly because of limitations in study
      design, patient number and duration of follow-up. The need for larger,
      controlled, randomized, long-term studies is evident.

PMID- 15198180
TI  - Susceptibility to quinupristin-dalfopristin and linezolid in 839 clinical
      isolates of Gram-positive cocci from Norway.
AB  - A total of 839 clinical isolates of Gram-positive cocci from Norway including
      Staphylococcus aureus (n = 214), coagulase negative Staphylococcus spp. (n =
      100), Streptococcus pyogenes (n = 99), Streptococcus agalactiae (n = 80),
      Streptococcus pneumoniae (n = 127), Streptococcus spp. viridans group (n = 70),
      Enterococcus faecalis (n = 75), and Enterococcus faecium (n = 74), were tested by
      E-test for susceptibility to a range of antimicrobials including the novel
      antibiotics quinupristin-dalfopristin and linezolid. Subgroups of oxacillin
      resistant S. aureus and coagulase negative Staphylococcus spp., penicillin non
      susceptible S. pneumoniae and vancomycin resistant Enterococcus spp. were
      specifically included as they are the intended targets for these new drugs. All
      isolates were susceptible to linezolid (MIC5o and MIC9o 0.25-2.0 mg/l, MIC range
      0.12-2 mg/l). Staphylococcal and streptococcal isolates were also susceptible to
      quinupristin-dalfopristin except for some intermediately susceptible viridans
      group isolates (MIC54, and MIC90 0.25-2 mg/l, MIC range 0.125-2 mg/l).
      Enterococcus faecium (MIC90 = 4.0 mg/l) and Enterococcus faecalis (MIC50 = 8.0
      mg/l, MIC90 > or = 32 mg/l) were less susceptible to this substance. There was no
      linkage between reduced susceptibility to linezolid or quinupristin-dalfopristin
      and resistance to other classes of antimicrobials. The study demonstrated a high
      prevalence of in vitro susceptibility to linezolid and quinupristin-dalfopristin,
      which is necessary for their use in the treatment of infections with resistant
      Gram-positive pathogens. The results were used to evaluate the appropriateness of
      breakpoints and to define a baseline for monitoring possible future emergence of
      resistance to quinupristin-dalfopristin and linezolid in Norway.

PMID- 15198181
TI  - Antimicrobial susceptibility of viridans group streptococcal blood isolates to
      eight antimicrobial agents.
AB  - A total of 155 viridans group streptococci blood culture isolates identified by
      the Rapid ID32 Strep system were tested for their minimum inhibitory
      concentrations (MICs) to penicillin, amoxicillin, ceftriaxone, erythromycin,
      clindamycin, rifampicin, vancomycin and teicoplanin using the E-test. The
      following species were identified: S. oralis (n = 67), S. mitis (n = 66), S.
      sanguis (n = 7), S. salivarius (n = 5), S. parasanguis (n = 4), S. gordonii (n =
      3) and S. mutans (n = 3). S. oralis and S. mitis demonstrated the highest levels
      of resistance to the agents tested. There were 27% of S. oralis isolates
      resistant to pencillin, 51% resistant to erythromycin and 6% resistant to
      clindamycin. For S. mitis 11% were resistant to penicillin, 40% resistant to
      erythromycin and 3% resistant to clindamycin. Penicillin resistant isolates (MIC
      > or = 2 mg/l) also demonstrated decreased susceptibility to other antimicrobial
      agents tested in this study. High level resistance (MIC > or = 2 mg/l) to
      ceftriaxone was found in 12 isolates. The isolates identified as ceftriaxone
      resistant comprised S. oralis (n = 7), S. mitis (n = 4) and S. parasanguis (n =
      1). This study has highlighted the difference in susceptibility between different
      species of viridans group streptococci. These findings are of concern in the
      light of spread of antibiotic resistance genes from S. oralis and S. mitis to the
      more invasive pneumococcus.

PMID- 15198182
TI  - Neisseria meningitidis W-135 carriage during the Hajj season 2003.
AB  - During the 2003 Hajj pilgrimage to Mecca, 344 pilgrims of 29 different
      nationalities were screened by means of a throat swab to detect Neisseria
      meningitidis carriage. N. meningitidis was isolated from 11 subjects; 2 were
      serogroup W-135, 1 serogroup B, and 8 were non-groupable. The results indicate a
      very low colonization rate for N. meningitidis among the tested cohort, with a
      predominance of non-groupable strains. These results, combined with a review of
      the published data, warrant a re-evaluation of current recommendations by the
      Saudi Ministry of Health for the use of ciprofloxacin for Saudi pilgrims
      departing at the end of the Hajj season. However, vaccination with the
      meningococcal quadrivalent vaccine, for all pilgrims, should continue to be
      recommended. The possibility of new strains arising as a cause of future
      meningococcal outbreaks should be considered, and annual surveillance may give an
      early warning.

PMID- 15198183
TI  - Diagnosis of atypical pathogens in patients hospitalized with community-acquired
      respiratory infection.
AB  - The object of our study was to determine the proportion of atypical respiratory
      pathogens among patients hospitalized with a community-acquired respiratory
      infection. From September 1997 to May 1999, 159 patients (57% male, median age
      55, range 1-88 y) admitted to 3 regional hospitals for a community acquired
      respiratory infection, were enrolled in the study. Microbiological diagnosis for
      the atypical pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae, and
      Legionella pneumophila was performed with PCR on a throat swab, sputum and/or
      broncho alveolar lavage (BAL). In addition, Legionella species other than L.
      pneumophila (L. non-pneumophila species) were detected by PCR. Two serum samples
      were collected and processed for M. pneumoniae and C. pneumoniae serology. In
      total, 27 patients (17%) were diagnosed with an atypical pathogen. Infection with
      M. pneumoniae was detected in 19 patients (12%) (PCR positive n = 7), with C.
      pneumoniae in 5 patients (3%) (PCR positive n = 0) and with L. pneumophila in 4
      patients (2.5%) (PCR positive n = 4). In 54 (34%) patients routine
      microbiological investigations revealed aetiological agents other than the 3
      atypical pathogens, the most frequently diagnosed pathogens being Streptococcus
      pneumoniae (n = 18), Haemophilus influenzae (n = 17), Gram-negative rods (n =
      13), Moraxella catarrhalis (n = 6) and Staphylococcus aureus (n = 6). More than 1
      pathogen was found in 13 patients. Atypical pathogens were found more often in
      the young age group (0-18 y), in contrast to bacterial pathogens that were found
      more often in the older age groups (> or = 65 y). Atypical pathogens were found
      less often in patients with a clinical presentation of atypical pneumonia.
      Legionella species other than L. pneumophila were found by PCR in 13 patients
      (8%), and in 6 patients in combination with another pathogen. An atypical
      pathogen (M. pneumoniae, C. pneumoniae or L. pneumophila) was found in 17% of the
      patients hospitalized with a community acquired respiratory infection,
      predominantly in the young age group. The role of Legionella non-pneumophila
      species as pathogen in community acquired respiratory infection needs to be
      determined. The clinical presentation does not predict the type of pathogen
      found.

PMID- 15198184
TI  - The case-fatality rate of meningococcal disease in Catalonia, 1990-1997.
AB  - The objective was to analyse the case-fatality rate (CFR) of meningococcal
      disease (MD) in Catalonia, Spain. A retrospective study was carried out. Clinical
      histories of cases of MD reported for the period 1990-1997 in Catalonia were
      reviewed. For all cases, the variables gender, age, clinical type, y of
      presentation, province, phenotype and death by meningococcal disease were
      collected. The association between death and the other variables was studied by
      bivariate and unconditional logistic regression analysis. In the 2343 cases
      studied there were 146 deaths (6.2%) due to meningococcal disease. The CFR was
      higher in females (OR: 1.5, 95%CI: 1.1-2.1), in the 20 to 49 y (OR: 2.4, 95%CI:
      1.2-4.9) and > or = 50 y (OR: 5.3, 95%CI: 2.8-10.1) age groups, in cases with
      septicaemia (OR: 2.4, 95%CI: 1.6-3.5), in the cases produced by serogroup A (OR:
      4.7, 95%CI: 1.0-23.4) and in cases occurring during 1993 (OR: 2.1, 95%CI: 1.1
      4.1) or in the province of Lleida (OR: 2.9, 95%CI: 1.2-7.2). In the multivariate
      analysis, death was associated with the 20-49 y age group (OR: 3.9, 95%CI: 1.8
      8.4), the > or = 50 y age group (OR: 7.3, 95%CI: 3.6-14.7), septicaemia (OR: 3.1;
      95%CI: 2.0-4.7) and residing in the province of Lleida (OR: 3.2; 95%CI: 1.2-8.5).
      The CFR of meningococcal disease in Catalonia was not associated with the
      emergent phenotype C:2b:P1.2,5 strain, which caused an outbreak in other regions
      of Spain.

PMID- 15198186
TI  - Prevalence of subclinical infection by the SARS coronavirus among general
      practitioners in Hong Kong.
AB  - Eight general practitioners had severe acute respiratory distress syndrome (SARS)
      in Hong Kong during the epidemic, and others may have been infected by the SARS
      coronavirus without developing the full syndrome. We conducted a serological and
      questionnaire survey to determine the prevalence of subclinical infection by SARS
      coronavirus among general practitioners in Hong Kong. Participants had to be
      doctors actively practising in family medicine and who did not have SARS.
      Approximately 3200 general practitioners were invited to participate and the
      results of 574 were eligible for analysis. 29 samples were tested positive by
      enzyme-linked immunosorbent assay, but all these samples had titre < 25 by
      immunoflorescence assay. The prevalence for seropositivity was thus 0% (95% CI,
      0.0%-0.6%). This finding documents the lack of subclinical infection by SARS
      coronavirus in an at-risk group in the community.

PMID- 15198185
TI  - Tenofovir treatment in an unselected cohort of highly antiretroviral experienced
      HIV positive patients.
AB  - The aim of the present study was to explore the treatment effect of tenofovir as
      implemented in clinical practice. Data are presented on 34 patients. 11 patients
      had tenofovir added to a stable anti-retroviral treatment (ART) and 23 patients
      had drugs other than tenofovir. CD4 counts, HIV-RNA levels and genotypic
      resistance were determined at baseline and after 3 and 6 months. After initiation
      of tenofovir treatment, a mean decrease in HIV-RNA for all 34 patients was
      observed (-0.43 log1o copies/ml (+/- 1.22) and -0.49 log10 copies/ml (+/- 1.36)
      after 3 and 6 months, respectively, (p = 0.045)). However, the effect of
      tenofovir on HIV-RNA in the group of patients who had tenofovir added to a stable
      ART was limited, and the decrease in HIV-RNA was significantly higher in patients
      who had drugs other than tenofovir changed as well (p = 0.004 and p = 0.03 after
      3 and 6 months, respectively). After initiation of tenofovir treatment, no
      significant increases in CD4 count were observed. All new NRTI-associated
      mutations could be explained by the background treatment. In conclusion, we
      observed a significant decrease in HIV-RNA only when tenofovir was prescribed, in
      conjunction with other anti-retroviral drugs, to patients on a failing highly
      active antiretroviral drug regimen (HAART).

PMID- 15198187
TI  - Mothers may transmit RSV infection more easily or severely to sons than
      daughters: community study from Guinea-Bissau.
AB  - Opposite gender transmission may increase the severity of certain infections. If
      infections transmitted from mother to son were more severe than from mother to
      daughter this might explain severe diseases among boys, particularly in small
      families with few individuals contributing to transmission. Among children from
      Guinea-Bissau, we tested whether mothers with recent respiratory syncytial virus
      exposure (positive IgM and IgA antibody responses) were more likely to have male
      than female children with respiratory syncytial virus antigen positive acute
      lower respiratory tract infection. Children with acute lower respiratory tract
      infection were identified at a paediatric clinic (n = 348), a health centre (n =
      270), and in a community morbidity survey (n = 525), 14.2% (162/1143) having
      respiratory syncytial virus antigen. An equal number of boys and girls had acute
      lower respiratory tract infection, but boys were more likely to have respiratory
      syncytial virus detected (prevalence ratio = 1.36 (1.01-1.81)), this difference
      being particularly marked in the rainy season. With recent respiratory syncytial
      virus exposure of mother, boys were twice as likely to have respiratory syncytial
      virus detected (prevalence ratio = 2.04 (1.18-3.53)), the difference being marked
      in the rainy season. There was no gender difference in respiratory syncytial
      virus infection among children of RSV negative mothers. We conclude that mothers
      may transmit respiratory syncytial virus more easily or severely to sons.

PMID- 15198188
TI  - The natural course of uncomplicated lower urinary tract infection in women
      illustrated by a randomized placebo controlled study.
AB  - This prospective, multicentre, randomized, double-blind and placebo controlled
      study was performed to describe the natural course of uncomplicated lower urinary
      tract infection (UTI). A total of 1143 women 18 y and above, consulting at 18
      primary health care centres in northern Sweden for symptoms suggestive of UTI
      were included. The symptoms urgency, dysuria, suprapubic pain and loin pain were
      registered, and urine cultures performed at inclusion and follow-up visits 8-10 d
      and 5-7 weeks later. Associations between all symptoms and bacteriuria or
      bacterial counts were unpredictable. Eradication of symptoms and bacteriuria and
      combinations of them were studied in 288 patients placebo treated for 7 d, of
      whom 39% dropped out after the first follow-up visit. The spontaneous cure rate
      of symptoms was 28% after the first week, and 37% had neither symptoms nor
      bacteriuria after 5-7 weeks. Considering the high dropout rate after the first
      follow-up visit, the spontaneous cure rate of symptoms and bacteriuria was
      calculated to 24% at the end of study. We conclude that patient near-laboratory
      tests are required to establish the diagnosis of lower UTI, and the guidelines
      for diagnosis of UTI need to be revised.

PMID- 15198189
TI  - Divergent expression changes of telomerase and E6/E7 mRNA, following integration
      of human papillomavirus type 33 in cultured epithelial cells.
AB  - Expression of the viral oncogenes E6 and E7, and telomerase, was investigated,
      using a cell line from a mild dysplastic vaginal lesion containing human
      papillomavirus (HPV) type 33. During passaging of the cells, there was a change
      towards a cancer phenotype, and a shift from episomal to integrated HPV. Levels
      of hTERT (catalytic subunit of telomerase) mRNA, and telomerase activity in cells
      carrying episomal virus seemed constant during passaging. During passaging of
      cells containing integrated HPV, however, the levels of oncogene mRNA decreased,
      while hTERT mRNA and telomerase activity increased sharply. Thus, in those cells
      there is no direct correlation between changes of oncogene and telomerase
      expression. Conceivably, viral oncogene expression might trigger telomerase up
      regulation in an early subpopulation of cells, which during subsequent passaging
      could be selected for.

PMID- 15198191
TI  - Pharmacokinetics of indinavir in Koreans and Caucasians.
AB  - We evaluated whether the pharmacokinetic parameters of indinavir differ in
      Koreans and Caucasians. Indinavir was administered orally to 8 healthy Koreans
      and 4 healthy Caucasians, and plasma indinavir levels were quantified by high
      performance liquid chromatography. No significant differences were observed in
      terms of its pharmacokinetic parameters; however, the AUC difference between the
      2 groups may be significant for larger sample sizes.

PMID- 15198190
TI  - Lack of Bartonella sp. in 167 Ixodes ricinus ticks collected in central Sweden.
AB  - Sudden death in Swedish orienteers was demonstrated to be significantly
      associated with antibodies to Bartonella sp. To test if these antibodies could be
      related with tick exposure, we searched Bartonella sp. in Ixodes ricinus ticks
      using specific PCR amplification and culture. No Bartonella sp. was detected in
      167 ticks tested.

PMID- 15198192
TI  - A case of legionellosis during treatment with a TNFalpha antagonist.
AB  - We report a patient with Legionella pneumophila pneumonia after infliximab
      therapy for rheumatoid arthritis. Arguments are discussed for an emerging
      incidence of infections with intracellular microorganisms, granulomatous and non
      granulomatous, in patients having received anti-TNFalpha therapy. These
      discussions consist of clinical and epidemiological data, experimental data in
      animals, theoretical evidence, and we provide a possible pathogenetic mechanism.

PMID- 15198193
TI  - Two case reports: fatal Absidia corymbifera pulmonary tract infection in the
      first postoperative phase of a lung transplant patient receiving voriconazole
      prophylaxis, and transient bronchial Absidia corymbifera colonization in a lung
      transplant patient.
AB  - Absidia corymbifera is a rare cause of pulmonary tract infection. There exist
      only 5 case reports predominantly diagnosed in bone marrow transplant patients.
      Lung transplant patients are at high risk for invasive fungal infections. Due to
      A. corymbifera as pathogen, known to be voriconazole resistant, a fatal invasive
      pulmonary mycosis occurred. In the present case voriconazole prophylaxis failed.
      A second patient showed a transient colonization of the bronchi. To prevent
      airborne transmitted invasive pulmonary mycosis in the first postoperative period
      of lung transplantation the patient should be situated in a room ventilated by
      HEPA-filtered air. The specific treatment should start very early when first
      suspicion arises. A review of the literature on pulmonary tract infections
      induced by Absidia corymbifera is provided.

PMID- 15198194
TI  - Recurrent tendinitis after treatment with two different fluoroquinolones.
AB  - Tendinopathies with and without tendon rupture are rare adverse events, occurring
      mainly following older fluoroquinolones, but recently also to an increasing
      extent following levofloxacin. We report the first case of tendinitis after
      treatment with moxifloxacin, and of recurrent tendinitis after treatment with 2
      different fluoroquinolones. From these findings we conclude hitherto unexplained
      class effect of fluoroquinolones in respect of the development of tendinitis.

PMID- 15198195
TI  - Bartonella henselae causing severe and protracted illness in an otherwise healthy
      person.
AB  - Bartonella henselae is an emerging pathogen capable of causing severe disease. We
      report a case of severe protracted illness in an otherwise healthy police dog
      handler. The patient recovered slowly after antibiotic treatment. This case
      report emphasizes the importance of considering B. henselae infections in
      patients with fever of unknown origin.

PMID- 15198196
TI  - Misleading chest radiography in a patient with SARS.
AB  - We report a patient who suffered from severe acute respiratory distress syndrome
      (SARS) presented with an uncommon chest X-ray finding, lobar pneumonia, which was
      never reported. We hope that this case report can help clinicians to become more
      aware of various initial radiological findings of SARS.

PMID- 15198197
TI  - Sequences of transgene insertion sites in transgenic F4 common carp.

PMID- 15198198
TI  - Analysis of Arabidopsis PsbQA gene expression in transgenic tobacco reveals
      differential role of its promoter and transcribed region in organ-specific and
      light-mediated regulation.
AB  - Arabidopsis PsbQ, encoding a 16 kDa protein of the oxygen-evolving complex, is
      regulated by light and is expressed preferentially in leaf tissues. To analyze
      the components required for light-regulated and organ-specific expression of
      PsbQA, several promoter constructs were generated and expressed in tobacco. The
      2.2 kb promoter could confer organ-specific expression of the reporter gene,
      whereas regulatory elements for light-dependent induction could not be located
      within this promoter and the transcribed region extending up to a second exon,
      represented by a genomic fragment encompassing the gene. The genomic fragment
      representing the transcribed region, however, could confer light regulation even
      on a constitutive promoter, as observed by steady-state mRNA analysis in T0 and
      T1 tobacco plants. The results obtained have led to the conclusion that
      regulatory elements for organ-specificity mainly reside in the promoter region
      whereas the transcribed region of the gene has an important role in light
      regulation.

PMID- 15198199
TI  - A ROS repressor-mediated binary regulation system for control of gene expression
      in transgenic plants.
AB  - We describe a novel binary system to control transgene expression in plants. The
      system is based on the prokaryotic repressor, ROS, from Agrobacterium
      tumefaciens, optimized for plant codon usage and for nuclear targeting (synROS).
      The ROS protein bound in vitro to double stranded DNA comprising the ROS operator
      sequence, as well as to single stranded ROS operator DNA sequences, in an
      orientation-independent manner. A synROS-GUS fusion protein was localized to the
      nucleus, whereas wtROS-GUS fusion remained in the cytoplasm. The ability of
      synROS to repress transgene expression was validated in transgenic Arabidopsis
      thaliana and Brassica napus. When expressed constitutively under the actin2
      promoter, synROS repressed the expression of the reporter gene gusA linked to a
      modified CaMV35S promoter containing ROS operator sequences in the vicinity of
      the TATA box and downstream of the transcription initiation signal. Repression
      ranged from 32 to 87% in A. thaliana, and from 23 to 76% in B. napus. These
      results are discussed in relation to the potential application of synROS in
      controlling the expression of transgenes and endogenous genes in plants and other
      organisms.

PMID- 15198200
TI  - Transgenic mice over-expressing endothelin-1 in testis transactivated by a
      Cre/loxP system showed decreased testicular capillary blood flow.
AB  - It is generally believed that too high or low levels of endothelin-1 (ET-1), a
      strong vasoconstrictor, may be detrimental to animals. Therefore, in order to
      understand the in vivo function of ET-1, we used a conditional transgenic
      approach, Cre/loxP recombination system, to generate transgenic mice that over
      express ET-1 in a tissue-specific manner. In such a strategy a single transgenic
      mouse line, ELSE, was initially generated where a general promoter, human
      elongation factor 1alpha (hEF1alpha) promoter, was used to drive the expression
      of a loxP-flanked sequence containing the lacZ reporter gene and a STOP cassette
      before the ET-1 cDNA, the recombinational competency of which was confirmed in an
      Escherichia coli test system. In ELSE mice, expression of the reporter lacZ was
      limited to spermatozoa and spermatogonia as well as Sertoli, Leydig and
      endothelial cells in the testis, thus confirming the suitability of these mice
      for the generation of testes-limited ET-1 expression. To generate transgenic
      progeny with ET-1 over-expression in the testis (successful recombination,
      ELSE/ELT), ELSE mice were mated with EIIa-cre mice expressing Cre recombinase in
      pre-implantation mouse embryos. These ELSE/ELT mice exhibiting testis-specific ET
      1 over-expression had normal reproductive function and showed no obvious
      alterations in gross testicular morphology. Although over-expression of ET-1
      leads to reduction of testicular blood flow, young adult ELSE/ELT mice showed no
      obvious signs of inflammation, fibrosis or abnormal proliferation of cells in the
      testes of young ELSE/ELT mice by histochemical analyses.

PMID- 15198201
TI  - Prototype demonstration of transgenic resistance to the nematode Radopholus
      similis conferred on banana by a cystatin.
AB  - Cavendish banana was transformed using Agrobacterium tumefaciens to express a
      protein engineered rice cystatin (OcIdeltaD86) of value for control of plant
      parasitic nematodes. Expression for each line was under control of a constitutive
      promoter from the maize ubiquitin gene (UBI-1), a constitutive, chimeric promoter
      from the octopine and mannopine synthase genes of A. tumefaciens or a promoter
      from a root-preferentially expressed tubulin gene Arabidopsis (TUB-1). Lines were
      selected as of potential interest after 8 weeks challenge in containment if their
      mean R. similis/25 g roots for three sibling plants were more than 1 standard
      normal variate below the grand mean for all plants in c7-15 lines challenged
      concurrently. A total of 16 lines were selected on this basis as putative
      positives. Western blots confirmed that eight of these lines expressed cystatin
      with a mean of 0.08 +/- 0.04% tsp. All but two of 19 negatively selected lines
      from bioassays did not express cystatin. The mean resistance level of the
      confirmed positive lines was 69 +/- 17%. ELISA established the positive lines
      under control of UBI provided significantly higher expression levels of
      OcIdeltaD86 than recorded for the other two promoters. Lines of interest were
      confirmed as producing a transcript for OcIdeltaD86 by RT-PCR. Eight plants of
      one UBI promoter line expressing only 0.1 +/- 0.004% tsp as cystatin were re
      challenged with R. similis and achieved a resistance of 70 +/- 10%. Subsequent
      repeat western blotting confirmed that this line still produced the cystatin
      after the trial. This is the first report of transgenic resistance against a
      major pest or disease of banana.

PMID- 15198202
TI  - Bi-directional duplex promoters with duplicated enhancers significantly increase
      transgene expression in grape and tobacco.
AB  - Novel bi-directional duplex promoters (BDDP) were constructed by placing two
      identical core promoters divergently on both upstream and downstream sides of
      their duplicated enhancer elements. Estimates of promoter function were obtained
      by creating versions of CaMV 35S and CsVMV BDDPs that contained reporter marker
      genes encoding beta-glucuronidase (GUS) and enhanced green fluorescent protein
      (EGFP) interchangeably linked either to the upstream or downstream core
      promoters. GUS was used for quantitative analysis of promoter function, whereas,
      EGFP allowed visual qualitative evaluation. In addition, the GUS and EGFP genes
      placed in downstream positions were modified by translational fusion with
      neomycin phosphotransferase (NPTII) to allow simultaneous monitoring of promoter
      activity and selection of stable transformants. These versions of BDDP were
      compared with each other and with equivalent unidirectional constructs by
      evaluating their expression in grape and tobacco. For 35S promoter constructs
      tested in grape somatic embryos (SE), BDDP exhibited transient GUS expression 206
      and 300-fold greater in downstream and upstream configurations, respectively,
      compared to a unidirectional 35S core promoter. Compared with a unidirectional
      double enhanced 35S promoter, BDDPs exhibited 0.5- and 3-fold increased GUS
      expression from downstream and upstream core promoters, respectively. The same
      differences in expression levels determined quantitatively with GUS were
      distinguished qualitatively with EGFP. Constructs using CsVMV core promoters
      yielded results relative to those obtained with 35S promoter. For example, the
      upstream BDDP CsVMV core promoter provided a 200-fold increase in GUS expression
      compared to a unidirectional core promoter. However, CsVMV promoter was found to
      have higher promoter activity than 35S promoter in both BDDP and unidirectional
      constructs. Incorporation of an additional duplicated enhancer element to BDDPs
      resulted in increased expression. For example, a 35S BDDP with two divergently
      arranged duplicated enhancer elements resulted in over a 6-fold increase in GUS
      expression in stably transformed tobacco plants compared to a BDDP with one
      duplicated enhancer element. Data demonstrate that BDDP composed of divergently
      arranged core promoters separated by duplicated enhancers, all derived from a
      single promoter sequence, can be used to significantly enhance transgene
      expression and to direct synchronized expression of multiple transgenes.

PMID- 15198203
TI  - Transgenic mouse line with green-fluorescent protein-labeled Centrin 2 allows
      visualization of the centrosome in living cells.
AB  - The centrosome plays diverse roles throughout the cellular mitotic cycle and in
      post-mitotic cells. Analysis of centrosome position and dynamics in living murine
      cells has been limited due to a lack of adequate reporters and currently requires
      either cell fixation/immunostaining or transfection with centrosome reporters.
      Here we describe the generation and characterization of a transgenic mouse line
      that constitutively expresses green fluorescent protein-labeled Centrin-2 (GFP
      CETN2). The phenotype of the mouse is indistinguishable from wild-type and it
      displays a single pair of fluorescent centrioles in cells of every organ and time
      point examined. This model will be helpful for visualizing the centrosome in
      multiple experimental conditions.

PMID- 15198204
TI  - Field safety assessment of recombination in transgenic grapevines expressing the
      coat protein gene of Grapevine fanleaf virus.
AB  - One of the major environmental safety issues over transgenic crops containing
      virus-derived genes relates to the outcome of recombination events between viral
      transgene transcripts and RNAs from indigenous virus populations. We addressed
      this issue by assessing the emergence of viable Grapevine fanleaf virus (GFLV)
      recombinants in transgenic grapevines expressing the GFLV coat protein (CP) gene.
      Test plants consisted of nontransgenic scions grafted onto transgenic and
      nontransgenic rootstocks that were exposed over 3 years to nematode-mediated GFLV
      infection in two distinct vineyard sites. The CP gene of challenging GFLV
      isolates was amplified from scions by IC-RT-PCR, and characterized by RFLP and
      nucleotide sequencing using strain F13 as reference since it provided the CP
      transgene. Analysis of EcoRI and StyI RFLP banding patterns from 347 challenging
      GFLV isolates and sequence data from 85 variants revealed no characteristics
      similar to strain F13 and no difference in the molecular variability among
      isolates from 190 transgenic and 157 nontransgenic plants, or from plants within
      (253 individuals) or outside (94 individuals) of the two sites. Interestingly,
      five GFLV recombinants were identified in three nontransgenic plants located
      outside of the two field settings. This survey indicates that transgenic
      grapevines did not assist the emergence of viable GFLV recombinants to detectable
      levels nor did they affect the molecular diversity of indigenous GFLV populations
      during the trial period. This is the first report on safety assessment of
      recombination with a transgenic crop expressing a CP gene under field conditions
      of heavy disease pressure but low, if any, selection pressure against recombinant
      viruses.

PMID- 15198205
TI  - Transgenic potatoes expressing a novel cationic peptide are resistant to late
      blight and pink rot.
AB  - Potato is the world's largest non-cereal crop. Potato late blight is a pandemic,
      foliar wasting potato disease caused by Phytophthora infestans, which has become
      highly virulent, fungicide resistant, and widely disseminated. Similarly,
      fungicide resistant isolates of Phytophthora erythroseptica, which causes pink
      rot, have also become an economic scourge of potato tubers. Thus, an alternate,
      cost effective strategy for disease control has become an international
      imperative. Here we describe a strategy for engineering potato plants exhibiting
      strong protection against these exceptionally virulent pathogens without
      deleterious effects on plant yield or vigor. The small, naturally occurring
      antimicrobial cationic peptide, temporin A, was N-terminally modified (MsrA3) and
      expressed in potato plants. MsrA3 conveyed strong resistance to late blight and
      pink rot phytopathogens in addition to the bacterial pathogen Erwinia carotovora.
      Transgenic tubers remained disease-free during storage for more than 2 years.
      These results provide a timely, sustainable, effective, and environmentally
      friendly means of control of potato diseases while simultaneously preventing
      storage losses.

PMID- 15198206
TI  - Simple method of zygosity identification in transgenic mice by real-time
      quantitative PCR.
AB  - To determine zygosity in transgenic (Tg) mice, a new technology, real-time
      quantitative PCR, has recently been introduced in transgenic research to overcome
      several drawbacks (time-consuming, specialized techniques and/or ambiguity in the
      results) of previously established methods, for example, Southern blot
      hybridization, dot blot hybridization, fluorescence in situ hybridization (FISH),
      etc. However, the previous real-time quantitative PCR method still possesses
      several drawbacks, for example, it needs two sets of primers/probes and the
      complicated setting up of appropriate conditions, both of which are expensive and
      remain time-consuming. We therefore developed an improved real-time quantitative
      PCR system for determination of zygosity, which is easy, rapid and less
      expensive, because the technique needs only two experimental processes:
      estimation of DNA concentration and CYBR Green PCR. We found that homozygous,
      hemizygous and non-Tg animals could easily be distinguished among F1 littermates
      in crosses of hemizygous EGFP- and DsRed2-Tg mice. Our improved method will be
      applicable to any Tg mouse strains, when a primer set is matched to the
      corresponding transgene.

PMID- 15198208
TI  - Effect of clopidogrel on tissue-plasminogen activator-induced in vitro
      thrombolysis of feline whole blood thrombi.
AB  - OBJECTIVE: To determine if clopidogrel enhanced the thrombolytic rate of tissue
      plasminogen activator (t-PA) on an in vitro feline whole blood thrombosis model.
      ANIMALS: 9 purpose-bred cats. PROCEDURE: Blood obtained from cats before
      (baseline) and after treatment with clopidogrel (75 mg, p.o., q 24 h for 3 days)
      was anticoagulated with sodium citrate (9:1 volume-to-volume ratio) to which 1
      microCi of I125-fibrinogen was added. Thrombi were formed by the addition of
      calcium chloride and bovine thrombin. Thrombi were placed into autologous plasma
      to which 0.1 mg of t-PA was added. Plasma samples were collected at different
      time points to determine the amount of released I125-fibrin split products.
      Thrombolytic rates were calculated by determining the time to 25%, 50%, and 75%
      thrombolysis (t25, t50, and t75, respectively). Confidence intervals for t25,
      t50, and t75 at baseline were compared with those after treatment. RESULTS: There
      were no significant differences in thrombolytic rates between values obtained at
      baseline and after clopidogrel treatment (t25, 18.0 vs 18.5 minutes; t50, 63.3 vs
      65.6 minutes; and t75, 163.0 vs 170.1 minutes, respectively). CONCLUSIONS AND
      CLINICAL RELEVANCE: Clopidogrel did not have an effect on the rate of
      thrombolysis of feline whole blood thrombi induced by t-PA in this in vitro
      model.

PMID- 15198207
TI  - Transgenic rice as a vehicle for the production of the industrial enzyme
      transglutaminase.
AB  - Transglutaminases have a range of catalytic activities, most of which concern the
      post-translational modification of proteins. The most important of these
      activities is the cross-linking of proteins into large supramolecular networks.
      The widespread use of transglutaminases has increased the demand for an
      inexpensive, efficient and safe source of recombinant enzyme. We explored the use
      of plant-based systems for the production of this important industrial enzyme.
      Transgenic rice plants engineered with a rat prostate transglutaminase (rTGp),
      driven by the strong constitutive maize-1 ubiquitin promoter and its first
      intron, were shown to express the recombinant enzyme at the mRNA and protein
      levels. The Ca2+ dependence of the recombinant enzyme was confirmed by the biotin
      labelled cadaverine-incorporation assay. In this communication we report the
      molecular and biochemical characterisation of transgenic plants expressing rTGp
      and this sets the stage for establishing a bioreactor system for the production
      of transglutaminases in plants.

PMID- 15198209
TI  - Effect of medetomidine on breathing and inspiratory neuromuscular drive in
      conscious dogs.
AB  - OBJECTIVE: To evaluate the effects of the alpha2-adrenoceptor agonist
      medetomidine on respiratory rate (RR), tidal volume (V(T)), minute volume (V(M)),
      and central respiratory neuromuscular drive as determined by inspiratory
      occlusion pressure (IOP) during increasing fractional inspired concentrations of
      carbon dioxide (FiCO2) in conscious dogs. ANIMALS: 6 healthy dogs (3 males and 3
      females). PROCEDURE: Dogs were administered 0, 5, or 10 microg of medetomidine/kg
      i.v. We measured RR, V(T), V(M), and IOP for the first 0.1 second of airway
      occlusion (IOP0.1) during FiCO2 values of 0%, 2.5%, 5.0%, and 75% at 15 minutes
      before and 5, 30, and 60 minutes after administration of medetomidine. RESULTS:
      Increases in FiCO2 significantly increased RR, V(T), and V(M). The i.v.
      administration of 5 and 10 microg of medetomidine/kg significantly decreased RR
      and V(M) at 5, 30, and 60 minutes for FiCO2 values of 2.5% and 5.0% and at 30 and
      60 minutes for an FiCO2 value of 75%. The IOP0.1 was decreased after 30 minutes
      only for an FiCO2 value of 7.5% in dogs administered 5 and 10 microg of
      medetomidine/kg. The IOP0.1 was decreased at 60 minutes after administration of
      10 microg of medetomidine/kg for an FiCO2 value of 7.5%. CONCLUSIONS AND CLINICAL
      RELEVANCE: The i.v. administration of medetomidine decreases RR, V(M), and
      central respiratory drive in conscious dogs. Medetomidine should be used
      cautiously and with careful monitoring in dogs with CNS depression or respiratory
      compromise.

PMID- 15198210
TI  - Effects of a single intranasal dose of modified-live bovine respiratory syncytial
      virus vaccine on cytokine messenger RNA expression following viral challenge in
      calves.
AB  - OBJECTIVE: To characterize cytokine messenger RNA (mRNA) expression in
      intranasally vaccinated calves after bovine respiratory syncytial virus (BRSV)
      challenge. ANIMALS: Twelve 8- to 12-week-old calves. PROCEDURES: Calves received
      modified-live BRSV vaccine (vaccinated) or spent tissue culture medium (mock
      vaccinated) intranasally, followed by challenge 30 days later with BRSV, or mock
      challenge with spent tissue culture medium (mock-challenge controls). Interleukin
      4 (IL-4) and interferon-gamma (IFN-gamma) mRNA was measured in lungs,
      bronchoalveolar lavage (BAL) fluid cells, pharyngeal tonsils, and
      tracheobronchial lymph nodes, and tumor necrosis factor-alpha (TNF-alpha) mRNA
      was measured in lungs and BAL fluid cells by reverse transcriptase-competitive
      polymerase chain reaction assay. RESULTS: Resistance to clinical signs of disease
      was conferred in vaccinated calves. Expression of TNF-alpha mRNA in lungs and BAL
      fluid cells was higher in mock-vaccinated calves than control or vaccinated
      calves. In the lung, IL-4 mRNA expression was higher in vaccinated calves than
      control or mock-vaccinated calves. In pharyngeal tonsils, expression of mRNA for
      IL-4 and IFN-gamma was higher in mock-vaccinated calves than control calves. In
      tracheobronchial lymph nodes, IFN-gamma mRNA expression was higher in mock
      vaccinated calves than vaccinated calves. CONCLUSIONS AND CLINICAL RELEVANCE:
      Although vaccinated calves had decreased clinical signs of disease after BRSV
      challenge, compared with mock-vaccinated calves, this difference was not related
      to a T helper type 1 bias, as determined by increased expression of interferon
      gamma mRNA relative to interleukin-4 mRNA in lungs, BAL fluid cells, or
      tracheobronchial lymph nodes of vaccinated calves. Pulmonary inflammation was
      decreased in vaccinated calves as determined by decreased expression of TNF-alpha
      mRNA.

PMID- 15198211
TI  - Pulsed-wave Doppler ultrasonographic evaluation of hepatic veins during variable
      hemodynamic states in healthy anesthetized dogs.
AB  - OBJECTIVES: To quantify direction and velocity of blood flow in hepatic veins in
      dogs under different hemodynamic conditions by use of pulsed-wave Doppler
      ultrasonography. ANIMALS: 10 healthy dogs. PROCEDURE: Dogs were anesthetized, and
      venous flow velocities in the quadrate lobe were measured. Arterial blood
      pressure, right atrial pressure, pulmonary artery pressure, and cardiac output
      were measured simultaneously. The timing of each waveform during the cardiac
      cycle was used to identify velocity profiles. Peak waveform velocities were
      measured during conditions of light anesthesia with isoflurane (baseline; period
      1), cardiovascular depression following administration of high-dose isoflurane
      and esmolol i.v. (period 2), cardiovascular depression with crystalloid volume
      expansion (period 3), and high cardiac output induced with dobutamine (period 4).
      Hemodynamic measurements and maximum waveform velocities were compared among the
      4 periods by use of an ANOVA and univariate and multivariate linear regression.
      RESULTS: During each study period, 4 distinct, low-velocity waves were
      identified. Mean velocities recorded during period 1 were as follows: retrograde
      atrial contraction a-wave, 7.3 cm/s; antegrade systolic S-wave, 15.0 cm/s;
      retrograde venous return v-wave, 2.7 cm/s; and antegrade diastolic D-wave, 11.4
      cm/s. Mean S:D ratio was 1.27. During periods 3 and 4, S-wave velocity increased;
      D-wave velocity was highest during period 4. CONCLUSIONS AND CLINICAL RELEVANCE:
      Consistent hepatic venous velocity profiles were observed in healthy dogs under
      different hemodynamic conditions. These findings provide baseline values that may
      be useful in evaluating clinical cases, but further study involving healthy,
      awake dogs and dogs with cardiac and hepatic diseases is required.

PMID- 15198212
TI  - Objective determination of pelvic movement during hind limb lameness by use of a
      signal decomposition method and pelvic height differences.
AB  - OBJECTIVE: To evaluate pelvic movement over a large number of strides in sound
      horses and in horses with induced hind limb lameness by applying methods to the
      pelvis that have been described for evaluating vertical head movement in horses
      with induced forelimb lameness. ANIMALS: 17 adult horses. PROCEDURE: Horses were
      filmed while trotting on a treadmill before and after induction of transient mild
      and moderate hind limb lamenesses. Vertical pelvic movement was measured by a
      signal decomposition method. The vertical pelvic signal was decomposed into a
      periodic component (A1) that occurred at half the stride frequency (representing
      vertical pelvic movement caused by lameness) and another periodic component (A2)
      that occurred at stride frequency (representing normal vertical pelvic movement
      of a trotting horse). Vertical pelvic and foot positions were correlated for each
      stride to compare the difference between the minimum and maximum heights of the
      pelvis during and after stance of the right hind limb to the minimum and maximum
      heights of the pelvis during and after stance of the left hind limb. RESULTS:
      Maximum pelvic height difference and lameness amplitude (A1) differed
      significantly between sound and mild or moderate hind limb lameness conditions.
      Mean A1 value for vertical pelvic movement in sound horses was less than that
      previously reported for vertical head movement. CONCLUSION AND CLINICAL
      RELEVANCE: Pelvic height differences and signal decomposition of pelvic movement
      can be used to objectively evaluate hind limb lameness in horses over a large
      number of strides in clinical and research settings.

PMID- 15198213
TI  - Evaluation of the induction and recovery characteristics of anesthesia with
      desflurane in cats.
AB  - OBJECTIVE: To qualitatively and quantitatively evaluate the characteristics of
      desflurane with regard to the induction of and recovery from anesthesia in cats.
      ANIMALS: 6 cats. PROCEDURE: Anesthesia was induced and maintained with desflurane
      in oxygen. Individual minimum alveolar concentration (MAC) values were
      determined; anesthesia was maintained at 1.25 x MAC for a total anesthesia time
      (including MAC determination) of 5 hours. Cats were allowed to recover from
      anesthesia. Induction and recovery periods were video recorded and later scored
      by use of a grading scale from 0 to 100 (100 being the best outcome). Timing of
      events was recorded. RESULTS: The MAC of desflurane was 10.27 +/- 1.06%, and mean
      dose was 5.6 +/- 0.2 MAC-hours. Times to loss of coordination, recumbency, and
      endotracheal intubation were 1.3 +/- 0.4, 2.3 +/- 0.3, and 6.4 +/- 1.1 minutes,
      respectively. Median score for quality of anesthetic induction was 93 (range, 91
      to 94). Times to first movement, extubation, standing, and ability to jump and
      land with coordination were 2.8 +/- 1.0, 3.8 +/- 0.5, 14.3 +/- 3.9, and 26.4 +/-
      5.1 minutes, respectively. Alveolar washout of desflurane was rapid. Median score
      for quality of anesthetic recovery was 94 (range, 86 to 96). CONCLUSIONS AND
      CLINICAL RELEVANCE: Desflurane was associated with rapid induction of and
      recovery from anesthesia in cats; assessors rated the overall quality of
      induction and recovery as excellent. Results appear to support the use of
      desflurane for induction and maintenance of anesthesia in healthy cats.

PMID- 15198214
TI  - Long-term delivery of ivermectin by use of poly(D,L-lactic-co-glycolic)acid
      microparticles in dogs.
AB  - OBJECTIVE: To evaluate the potential utility of poly(D,L-lactic-co-glycolic)acid
      (PLGA) as a long-acting biodegradable drug delivery matrix for ivermectin used in
      the prevention of heartworm disease in dogs. ANIMALS: 30 adult female dogs.
      PROCEDURE: Microparticle formulations containing 25 weight percent (wt%), 35 wt%,
      and 50 wt% ivermectin were prepared by an oil-in-water emulsion technique with
      solvent extraction into excess water. A fourth formulation, consisting of a
      mixture of 15 wt% and 50 wt% ivermectin microparticles, was blended in a 1:1
      ratio to result in a 32.5 wt% ivermectin formulation. Formulations were
      administered once on Day 0 to groups of 6 dogs at a dose of 0.5 mg of
      ivermectin/kg, s.c. Half of the dogs in each treatment group and 3 untreated
      control dogs were infected with Dirofilaria immitis larvae 121 and 170 days after
      treatment. Six months after infection, dogs were euthanatized and necropsies were
      performed. Pharmacokinetics and efficacy were investigated. RESULTS: Analysis of
      pharmacokinetic data revealed sustained release of ivermectin during at least 287
      days in 3 distinct phases: a small initial peak, followed by release of drug
      through diffusion, and polymer degradation. Untreated control dogs were all
      infected with heartworms. Heartworms were not found in any of the dogs in the
      ivermectin-PLGA treated groups. Adverse clinical signs were not observed.
      CONCLUSIONS AND CLINICAL RELEVANCE: All formulations were 100% effective in
      preventing development of adult heartworms. Results indicate that PLGA
      microparticles are a promising drug delivery matrix for use with ivermectin for
      the prevention of heartworm disease for at least 6 months after treatment.

PMID- 15198215
TI  - Composition of cerebrospinal fluid in clinically normal adult ferrets.
AB  - OBJECTIVE: To determine the protein and cellular composition of CSF in healthy
      adult ferrets. ANIMALS: 42 clinically normal adult ferrets. PROCEDURE: CSF
      samples were collected from the cerebellomedullary cistern of anesthetized
      ferrets by use of disposable 25-gauge, 1.6-cm-long hypodermic needles. Samples
      were processed within 20 minutes after collection. The number of WBCs and RBCs
      per microliter of CSF was counted by use of a hemacytometer. The total protein
      concentration was determined by use of an automated chemistry analyzer. RESULTS:
      Total WBC counts (range, 0 to 8 cells/microL; mean, 1.59 cells/microL) in CSF of
      ferrets were similar to reference range values obtained for CSF from other
      species. Twenty-seven CSF samples had <100 RBCs/microL (mean, 20.3 RBCs/microL).
      A small but significant effect of blood contamination on WBC counts was found
      between the 27 CSF samples with <100 RBCs/microL and the remaining samples.
      Protein concentrations in CSF of ferrets (range, 28.0 to 68.0 mg/dL; mean, 31.4
      mg/dL) were higher than has been reported for the CSF of dogs and cats. A
      significant effect of blood contamination on the CSF protein concentration was
      not found. CONCLUSION AND CLINICAL RELEVANCE: We have established reference range
      values for WBC counts and protein concentrations in CSF from healthy adult
      ferrets that may be useful in the clinical investigation of CNS disease. Results
      of our study indicate that the WBC count is significantly affected by blood
      contamination of the CSF sample.

PMID- 15198217
TI  - Development of a simulation model to evaluate the effect of vaccination against
      Tritrichomonas foetus on reproductive efficiency in beef herds.
AB  - OBJECTIVE: To develop a model to evaluate the effect of vaccination against
      Tritrichomonas foetus on reproductive efficiency in beef herds. SAMPLE
      POPULATION: A beef herd of 300 cows and 12 bulls (8 bulls < or = 3 years old and
      4 bulls > 3 years old). PROCEDURE: The model was developed by use of data for
      various risk factors and vaccine efficacy. The reference herd was considered to
      be one in which T. foetus had been diagnosed and bulls were tested for T. foetus
      before the breeding season. Five thousand iterations were run for each of 13
      simulations, with each simulation representing a separate combination of risk
      factors. RESULTS: In all simulations, vaccination resulted in significantly
      higher calving incidence than nonvaccination. Shared grazing was found to be the
      most significant risk factor for a decrease in calving incidence attributable to
      T. foetus infection, followed in importance by lack of testing before the
      breeding season and a higher proportion of old bulls. Combinations of risk
      factors contributed to a loss of income of up to 22%, some of which could be
      blunted by vaccination. CONCLUSIONS AND CLINICAL RELEVANCE: Highest calving
      incidence is achieved when all bulls are tested for T. foetus before the breeding
      season and all bulls with positive culture results are culled. Avoiding all risk
      factors is better than vaccinating, but when this is not feasible for a given
      herd, the results of this simulation indicate that proper vaccination can
      decrease economic losses attributable to abortions caused by T. foetus.

PMID- 15198216
TI  - Effects of flunixin meglumine or etodolac treatment on mucosal recovery of equine
      jejunum after ischemia.
AB  - OBJECTIVE: To examine the effects of flunixin meglumine and etodolac treatment on
      recovery of ischemic-injured equine jejunal mucosa after 18 hours of reperfusion.
      ANIMALS: 24 horses. PROCEDURE: Jejunum was exposed to 2 hours of ischemia during
      anesthesia. Horses received saline (0.9% NaCl) solution (12 mL, i.v., q 12 h),
      flunixin meglumine (1.1 mg/kg, i.v., q 12 h), or etodolac (23 mg/kg, i.v., q 12
      h). Tissue specimens were obtained from ischemic-injured and nonischemic jejunum
      immediately after ischemia and 18 hours after recovery from ischemia.
      Transepithelial electric resistance (TER) and transepithelial flux of tritium
      labeled mannitol measured mucosal permeability. Denuded villous surface area and
      mean epithelial neutrophil count per mm2 were calculated. Western blot analysis
      for cyclooxygenase (COX)-1 and -2 was performed. Pharmacokinetics of flunixin and
      etodolac and eicosanoid concentrations were determined. RESULTS: Ischemic-injured
      tissue from horses treated with flunixin and etodolac had significantly lower TER
      and increased permeability to mannitol, compared with that from horses treated
      with saline solution. Epithelial denudation after ischemia and 18 hours after
      recovery was not significantly different among treatments. Both COX-1 and -2 were
      expressed in ischemic-injured and nonischemic tissues. Ischemia caused
      significant upregulation of both COX isoforms. Eicosanoid concentrations were
      significantly lower in tissues from flunixin and etodolac-treated horses,
      compared with that from horses treated with saline solution. CONCLUSIONS AND
      CLINICAL RELEVANCE: Flunixin and etodolac treatment retarded recovery of
      intestinal barrier function in jejunal mucosa after 18 hours of reperfusion,
      whereas tissues from horses treated with saline solution recovered baseline
      values of TER and permeability to mannitol.

PMID- 15198218
TI  - Evaluation of glutamate loss from damaged retinal cells of dogs with primary
      glaucoma.
AB  - OBJECTIVE: To determine whether retinal damage in dogs with primary glaucoma (PG)
      is consistent with ischemia-induced glutamate toxicosis. SAMPLE POPULATION:
      Retinal tissue sections from 25 dogs with PG and 12 normotensive control dogs.
      PROCEDURE: Retinal sections from control and glaucomatous dogs were stained for
      morphometric and terminal deoxynucleotidyl transferase-mediated dUTP nick-end
      labeling (TUNEL) analyses to determine whether retinal damage was consistent with
      glutamate toxicosis. Immunohistochemical analysis was performed to detect
      ischemia-like loss of glutamate from neurons in damaged areas. RESULTS: In
      severely damaged glaucomatous retinas, all neurosensory layers had focal regions
      that were thin or disrupted. There was less thinning of the outer nuclear layer
      (ONL) and inner nuclear layer (INL) in moderately damaged retinas than in
      severely damaged retinas. Acute signs of damage in the INL included cells with
      dark, condensed chromatin and lightly stained cytoplasm interspersed with a few
      TUNEL-positive cells, which was consistent with glutamate toxicosis. Glutamate
      immunoreactivity was reduced in thin areas and in damaged cells of the INL and
      ONL, which was consistent with glutamate release in damaged areas. Glutamate
      immunoreactivity was increased in putative Muller cells in damaged areas, which
      also was consistent with glutamate release. CONCLUSIONS AND CLINICAL RELEVANCE:
      Retinal damage in dogs with PG differs in intensity in focal areas. Damage in
      affected regions resembles damage induced by glutamate. Glutamate is lost from
      damaged neurons and accumulates in Muller cells, which is consistent with
      increased glutamate release contributing to the damage. Glutamate antagonists may
      protect INL cells in dogs with glaucoma.

PMID- 15198219
TI  - Assessment of the ability of Malassezia pachydermatis to stimulate proliferation
      of canine keratinocytes in vitro.
AB  - OBJECTIVE: To investigate the direct interaction between canine keratinocytes and
      live Malassezia pachydermatis and thereby determine the role of these organisms
      in the pathogenesis of epidermal hyperplasia associated with Malassezia
      dermatitis in dogs. SAMPLE POPULATION: Primary canine keratinocyte cultures
      established from skin samples obtained from clinically normal dogs. PROCEDURE:
      The proliferative response of keratinocytes co-cultured with Malassezia organisms
      for 1, 2, or 3 days was assessed by use of direct manual counting (to determine
      the number of keratinocytes in both the monolayer and the medium) and
      immunohistochemical staining techniques involving antibodies against
      proliferating cell nuclear antigen (PCNA) and another cellular proliferation
      marker, Ki-67. The potential cytotoxic effect of Malassezia organisms was
      investigated by use of an apoptosis detection kit to label keratinocytes co
      cultured with M. pachydermatis that underwent apoptosis. RESULTS: No stimulatory
      effect of Malassezia organisms on canine keratinocyte proliferation was detected
      via cell counting and immunohistochemical techniques. However, there was a
      significant increase in dead keratinocytes in the medium with increasing numbers
      of Malassezia organisms in the co-culture. More apoptotic cells were observed in
      keratinocyte monolayers co-cultured with high numbers of M. pachydermatis than
      there were in monolayers cultured without Malassezia organisms, and the number
      increased after prolonged incubation. CONCLUSIONS AND CLINICAL RELEVANCE: M.
      pachydermatis did not stimulate canine keratinocyte proliferation in vitro. The
      results suggested that the epidermal hyperplasia observed in dogs with Malassezia
      dermatitis is unlikely to be caused by a direct effect of the organism on the
      keratinocyte cell cycle, but is likely to involve other mechanisms.

PMID- 15198220
TI  - Myoelectric activity in the intestines of healthy dairy cows during the recovery
      period after implantation of permanent electrodes.
AB  - OBJECTIVE: To describe myoelectric patterns in the intestines of cows after
      electrode implantation. ANIMALS: 7 lactating Simmental-Red Holstein cows.
      PROCEDURE: Cows were implanted with 7 pairs of bipolar silver electrodes (1 each
      in the ileum, cecum, and proximal loop of the ascending colon (PLAC) and 4 in the
      spiral colon). Myoelectric activity was monitored during 10 periods within the
      first 3 weeks after surgery. Recordings from the first 2 weeks were compared with
      recordings from the third week, which was considered a steady-state condition.
      RESULTS: Significant changes over time were detected for 18 of 57 variables,
      including 3 variables describing myoelectric activity of the ileum, 6 variables
      of the cecum, 6 variables of the PLAC, and 3 variables of the spiral colon.
      Compared with values for the steady-state condition, 16 variables differed
      significantly for the 14-day period after surgery (7 variables until day 11, 2
      variables until day 8, 4 variables until day 5, 1 variable until day 3, and 2
      variables until day 2 after electrode implantation). None of the variables had
      significant changes that lasted only 1 day after surgery. CONCLUSIONS AND
      CLINICAL RELEVANCE: Significant changes were observed for several variables of
      myoelectric activity in all intestinal segments until as late as 11 days after
      electrode implantation, whereas a steady-state condition was reached 14 days
      after surgery. Effects of drugs, manipulations, or nutrition regimens on
      myoelectric activity of the bovine digestive tract should be evaluated no sooner
      than 2 weeks after electrode implantation.

PMID- 15198221
TI  - Investigation of pulmonary deposition of a nebulized radiopharmaceutical agent in
      awake cats.
AB  - OBJECTIVE: To determine whether conscious, unsedated cats will inhale a nebulized
      material administered via a facemask and whether this material will reach the
      lower airways. ANIMALS: 20 healthy adult cats. PROCEDURE: Technetium Tc 99m
      diaminetriaminopentaacetic acid (99mTc-DTPA) was nebulized into a spacer and
      administered to the cats via a closely fitting facemask. By use of a gamma
      camera, images were then immediately obtained to determine the distribution of
      99mTc-DTPA within the lower airways. RESULTS: Images obtained by use of the gamma
      camera revealed that all 20 cats had inhaled 99mTc-DTPA from the facemask. In
      each cat, deposition of the radiopharmaceutical agent was evident throughout the
      lung fields. CONCLUSIONS AND CLINICAL RELEVANCE: Awake cats that were not used to
      the application of a facemask did inhale substances from such a device.
      Aerosolization of medications may be a feasible route of administration for cats
      with lower airway disease.

PMID- 15198222
TI  - Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues
      and their differential sensitivity to nonsteroidal anti-inflammatory drugs.
AB  - OBJECTIVE: To evaluate cyclooxygenase isozyme distribution in tissues from dogs
      and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and 
      2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). SAMPLE POPULATION:
      Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral
      cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern
      and western blot analyses, and blood for whole blood COX assays was obtained from
      15 dogs. PROCEDURE: 11 NSAIDs were evaluated to determine their COX-2 selectivity
      in whole blood assays. The concentrations of the drug needed to inhibit 50% of
      enzyme activity (IC50) were then calculated for comparison. Expression and tissue
      distribution of COX isozymes were determined by northern and western blot
      analysis. RESULTS: Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic
      acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398,
      carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times
      greater preference for inhibiting COX-2 than COX-1. All canine tissues examined,
      including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA,
      although protein expression was observed only for COX-1. CONCLUSIONS AND CLINICAL
      RELEVANCE: Canine COX-2 was selectively inhibited by etodolac, nimesulide, and
      NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2
      inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and
      COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to
      apply to dogs; therefore, COX-2-selective inhibitors should prove useful in
      reducing the adverse effects associated with nonselective NSAIDs.

PMID- 15198223
TI  - Determination of muscle architecture and fiber characteristics of the superficial
      and deep digital flexor muscles in the forelimbs of adult horses.
AB  - OBJECTIVE: To provide a quantitative description of the architecture of
      superficial digital flexor (SDF) and deep digital flexor (DDF) muscles in adult
      horses to predict muscle-tendon behavior and estimate muscle forces. SAMPLE
      POPULATION: 7 forelimb specimens from 7 adult Thoroughbreds. PROCEDURE: Muscle
      and tendon lengths and volumes were measured from 6 fixed forelimbs. After
      processing, fiber bundle and sarcomere lengths were measured. Optimal fascicle
      lengths and muscle length-to-fascicle length, muscle length-to-free tendon
      length, and fascicle length-to-tendon length ratios were calculated, as were
      tendon and muscle physiologic cross-sectional areas (PCSAs). Pennation angles
      were measured in 1 embalmed specimen. RESULTS: The SDF optimal fascicle lengths
      were uniformly short (mean +/- SD, 0.8 +/- 0.1 cm), whereas DDF lengths ranged
      from 0.9 +/- 0.2 cm to 10.8 +/- 1.6 cm. The DDF humeral head had 3 architectural
      subunits, each receiving a separate median nerve branch, suggestive of
      neuromuscular compartmentalization. Pennation angles were small (10 degrees to 25
      degrees). The PCSAs of the SDF and DDF muscle were 234 +/- 51 cm2 and 259 +/- 30
      cm2, with estimated forces of 4,982 +/- 1148 N and 5,520 +/- 544 N, respectively.
      CONCLUSIONS AND CLINICAL RELEVANCE: The SDF muscle appears to provide strong
      tendinous support with little muscle fascicular shortening and fatigue-resistance
      properties. The DDF muscle combines passive and dynamic functions with larger
      tension development and higher shortening velocities during digital motion.
      Architectural parameters are useful for estimation of forces and have
      implications for analysis of muscle-tendon function, surgical procedures
      involving muscle-tendon lengthening, and biomechanical modeling.

PMID- 15198224
TI  - Use of a real-time polymerase chain reaction-based fluorogenic 5' nuclease assay
      to evaluate insect vectors of Corynebacterium pseudotuberculosis infections in
      horses.
AB  - OBJECTIVE: To develop and use a sensitive molecular assay for detecting the
      phospholipase D (PLD) exotoxin gene of Corynebacterium pseudotuberculosis in an
      attempt to identify insect vectors that may be important in transmission of
      clinical disease in horses. SAMPLE POPULATION: 2,621 flies of various species.
      PROCEDURE: A real-time polymerase chain reaction (PCR)-based fluorogenic 5'
      nuclease (TaqMan) system (ie, TaqMan PCR assay) was developed for the detection
      of the PLD gene in insects. Flies were collected monthly (May to November 2002)
      from 5 farms in northern California where C. pseudotuberculosis infection in
      horses is endemic. Three of the 5 farms (which housed a total of 358 horses) had
      diseased horses during the study period. A total of 2,621 flies of various
      species were tested for the PLD gene of C. pseudotuberculosis. RESULTS: Evidence
      of bacterial DNA for the PLD gene was detected in skin biopsy specimens from
      clinically affected horses and from 3 fly species collected from farms where
      affected horses were housed. Farms with a high incidence of diseased horses had a
      high proportion of insects carrying the organism. High percentages of flies with
      positive results for the PLD gene were observed in October, when most clinically
      affected horses were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Our results
      are consistent with the hypothesis that C. pseudotuberculosis may be vectored to
      horses by flies. Three potential vectors were identified, including Haematobia
      irritans, Stomoxys calcitrans, and Musca domestica. The organism can be
      identified in up to 20% of house flies (Musca domestica) in the vicinity of
      diseased horses.

PMID- 15198225
TI  - Pharmacokinetics of zidovudine in cats.
AB  - OBJECTIVE: To characterize the pharmacokinetics of zidovudine (AZT) in cats.
      ANIMALS: 6 sexually intact 9-month-old barrier-reared domestic shorthair cats.
      PROCEDURE: Cats were randomly alloted into 3 groups, and zidovudine (25 mg/kg)
      was administered i.v., intragastrically (i.g.), and p.o. in a 3-way crossover
      study design with 2-week washout periods between experiments. Plasma samples were
      collected for 12 hours after drug administration, and zidovudine concentrations
      were determined by high-performance liquid chromatography. Maximum plasma
      concentrations (Cmax), time to reach Cmax (Tmax), and bioavailability were
      compared between i.g. and p.o. routes. Area under the curve (AUC) and terminal
      phase half-life (t(1/2)) among the 3 administration routes were also compared.
      RESULTS: Plasma concentrations of zidovudine declined rapidly with t(1/2) of 1.4
      +/- 0.19 hours, 1.4 +/- 0.16 hours, and 1.5 +/- 0.28 hours after i.v., i.g., and
      p.o. administration, respectively. Total body clearance and steady-state volume
      of distribution were 0.41 +/- 0.10 L/h/kg and 0.82 +/- 0.15 L/kg, respectively.
      Mean Tmax for i.g. administration (0.22 hours) was significantly shorter than
      Tmax for p.o. administration (0.67 hours). The AUC after i.v. and p.o.
      administration was 64.7 +/- 16.6 mg x h/L and 60.5 +/- 17.0 mg x h/L,
      respectively, whereas AUC for the i.g. route was significantly less at 42.5 +/-
      9.41 mg x h/L. Zidovudine was well absorbed after i.g. and p.o. administration
      with bioavailability values of 70 +/- 24% and 95 +/- 23%, respectively.
      CONCLUSIONS AND CLINICAL RELEVANCE: Cats had slower clearance of zidovudine,
      compared with other species. Plasma concentrations of zidovudine were maintained
      above the minimum effective concentration for inhibiting FIV replication by 50%
      (0.07 microM [0.019 microg/mL] for wild-type FIV clinical isolate) for at least
      12 hours after i.v., i.g., or p.o. administration.

PMID- 15198226
TI  - Pharmacokinetics of lamivudine in cats.
AB  - OBJECTIVE: To characterize the pharmacokinetics of lamivudine (3TC) in cats.
      ANIMALS: 6 sexually intact 9-month-old barrier-reared domestic shorthair cats.
      PROCEDURE: Cats were randomly alloted into 3 groups, and lamivudine (25 mg/kg)
      was administered i.v., intragastrically (i.g.), and p.o. in a 3-way crossover
      study design with 2-week washout periods between experiments. Plasma samples were
      collected for 12 hours after drug administration, and lamivudine concentrations
      were determined by high-performance liquid chromatography. Maximum plasma
      concentrations (Cmax), time to reach Cmax (Tmax), and bioavailability were
      compared between i.g. and p.o. routes. Area under the curve (AUC) and terminal
      phase half-life (t(1/2)) among the 3 administration routes were also compared.
      RESULTS: Plasma concentrations of lamivudine declined rapidly with a t(1/2) of
      1.9 +/- 0.21 hours, 2.6 +/- 0.66 hours, and 2.7 +/- 1.50 hours after i.v., i.g.,
      and p.o. administration, respectively. Total body clearance and steady-state
      volume of distribution were 0.22 +/- 0.09 L/h/kg and 0.60 +/- 0.22 L/kg,
      respectively. Mean Tmax for i.g. administration (0.5 hours) was significantly
      shorter than Tmax for p.o. administration (1.1 hours). The AUC after i.v., i.g.,
      and p.o. administration was 130 +/- 55.2 mg x h/L, 115 +/- 97.5 mg x h/L, and 106
      +/- 94.9 mg x h/L, respectively. Lamivudine was well absorbed after i.g. and p.o.
      administration with bioavailability values of 88 +/- 45% and 80 +/- 52%,
      respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Cats had a shorter t(1/2) but
      slower total clearance of lamivudine, compared with humans. Plasma concentrations
      of lamivudine were maintained above the minimum effective concentration for
      inhibiting FIV replication by 50% (0.14 microM [0.032 microg/mL] for wild-type
      FIV clinical isolate) for at least 12 hours after i.v., i.g., or p.o.
      administration.

PMID- 15198227
TI  - Evaluation of the tensile strengths of four monofilament absorbable suture
      materials after immersion in canine urine with or without bacteria.
AB  - OBJECTIVE: To evaluate the tensile strength, elongation, and degradation of 4
      monofilament absorbable suture materials that undergo degradation by hydrolysis
      in specimens of canine urine with various physical characteristics. SAMPLE
      POPULATION: 4 monofilament absorbable sutures (polydioxanone, poliglecaprone 25,
      polyglyconate, and glycomer 631). PROCEDURE: Voided urine was collected from 6
      healthy dogs, pooled, filter-sterilized, and prepared to provide 5 media: sterile
      neutral (pH, 7.0), sterile acidic (pH, 6.2), sterile basic (pH, 8.8), Escherichia
      coli-inoculated, and Proteus mirabilis-inoculated urine. Ten strands of each
      suture material were immersed in each of the media for 0 to 28 days. Tensile
      strength and elongation of each suture material were evaluated by use of a
      texture analyzer on days 0, 1, 3, 7, 10, 14, 21, and 28. RESULTS: Reduction in
      tensile strength was detected for all materials in all urine specimens over time.
      Polyglyconate and polydioxanone had superior tensile strengths in sterile neutral
      and E. coli-inoculated urine, and polydioxanone retained the greatest tensile
      strength throughout the study period. All suture materials disintegrated before
      day 7 in P. mirabilis-inoculated urine. CONCLUSIONS AND CLINICAL RELEVANCE:
      Polydioxanone, polyglyconate, and glycomer 631 may be acceptable for urinary
      bladder closure in the presence of sterile neutral and E. coli-contaminated
      urine. Tensile strength of poliglecaprone 25 in urine may be unacceptable by the
      critical healing time for bladder tissue (14 to 21 days). During bladder surgery,
      exposure of suture material that degrades via hydrolysis to urine containing
      Proteus spp should be minimized.

PMID- 15198228
TI  - Isoflurane sparing action of epidurally administered xylazine hydrochloride in
      anesthetized dogs.
AB  - OBJECTIVE: To evaluate the influence of epidural administration of xylazine
      hydrochloride on the minimum alveolar concentration of isoflurane (MAC(ISAO)) and
      cardiopulmonary system in anesthetized dogs. ANIMALS: 6 clinically normal dogs.
      PROCEDURE: Dogs were anesthetized with isoflurane in oxygen after randomly being
      assigned to receive 1 of the following 4 treatments: epidural administration of
      saline (0.9% NaCl) solution or xylazine at a dose of 0.1, 0.2, or 0.4 mg x kg(
      1). Experiments were performed on 5 occasions with at least a 1-week interval
      between experiments; each dog received all 4 treatments. Following
      instrumentation, the concentration of isoflurane was maintained constant for 15
      minutes at the MAC(ISO) that had been determined for each dog, and data on heart
      rate, arterial blood pressure, respiratory rate, tidal volume, minute volume,
      arterial partial pressure of oxygen, arterial partial pressure of carbon dioxide,
      and arterial pH were collected. The epidural treatment was administered, and 30
      minutes later, data were again collected. From this point on, determination of
      the MAC(ISO) following epidural treatment (ie, MAC(ISO+EPI)) was initiated.
      Cardiopulmonary data were collected before each electrical supramaximal stimulus
      during MAC(ISO+EPI) determinations. RESULTS: The mean (+/-SD) MAC(ISO) was 1.29
      +/- 0.04%. The epidural administration of xylazine at doses of 0.1, 0.2, and 0.4
      mg x kg(-1) decreased the MAC(ISO), respectively, by 8.4 +/- 2.4%, 21.7 +/- 4.9%,
      and 33.4 +/- 2.64%. Cardiopulmonary effects were limited. CONCLUSIONS AND
      CLINICAL RELEVANCE: Epidural administration of xylazine decreases the MAC(ISO) in
      a dose-dependent manner and is associated with few cardiopulmonary effects in
      anesthetized dogs.

PMID- 15198229
TI  - Effect of transport stress on respiratory disease, serum antioxidant status, and
      serum concentrations of lipid peroxidation biomarkers in beef cattle.
AB  - OBJECTIVE: To determine the effect of transportation stress on serum
      concentrations of oxidative stress biomarkers of calves. ANIMALS: 105 crossbred
      beef steer calves (mean [+/-SD] body weight, 207 +/- 21.2 kg). PROCEDURE: Calves
      were assembled at 1 location in Tennessee, and pretransit (day -3) blood samples
      were collected. Calves were allotted randomly by body weight into 2 groups.
      Calves were transported 1,930 miles to a feedlot in Texas, and 1 group received
      tilmicosin phosphate (33 microg/kg, s.c.) upon arrival. Calves were weighed and
      blood samples collected on the day of arrival (day 1) and on days 15, 22, and 28.
      Calves were scored daily for signs of bovine respiratory disease (BRD). Serum
      total antioxidant capacity (TACA) and serum malondialdehyde (MDA) concentrations
      were determined. RESULTS: Transportation stress significantly decreased mean
      serum TACA concentrations (from 147 +/- 31.2 U/mL to 133 +/- 20.1 U/mL) and
      significantly increased serum MDA concentrations (from 10.9 +/- 18.3 microg/mL to
      30.2 +/- 50.5 microg/mL). Calves that died had a 43% increase in serum MDA
      concentration on day 1, compared with calves that lived (42.2 +/- 67.0 microg/mL
      vs 29.4 +/- 49.4 microg/mL, respectively). Calves that had > or =3 episodes of
      BRD had 2-fold higher serum MDA concentrations on day 1 than healthy calves.
      Tilmicosin-treated calves had a 20.8% significantly greater average daily gain
      and significantly greater serum TACA concentration than nontreated calves on day
      28. CONCLUSIONS AND CLINICAL RELEVANCE: Transportation stress increases serum
      concentrations of oxidative stress biomarkers that are related to episodes of BRD
      and mortality in calves.

PMID- 15198230
TI  - Evaluation of antiviral activity and toxicity of recombinant human interferon
      alfa-2a in calves persistently infected with type 1 bovine viral diarrhea virus.
AB  - OBJECTIVE: To evaluate antiviral activity and toxicity of recombinant human
      interferon alfa-2a in calves persistently infected with noncytopathic type 1
      bovine viral diarrhea virus (BVDV). ANIMALS: 5 Holstein heifers, 4 to 12 months
      of age. PROCEDURES: Calves persistently infected with noncytopathic type 1 BVDV
      were treated with recombinant human interferon alfa-2a every other day for 12
      weeks. Viral loads were measured during the treatment period and compared with
      pre- and post-treatment values. Complete physical examinations were performed
      weekly, and calves were observed daily for signs of systemic illness. Complete
      blood counts and serum biochemical analyses were performed before, during, and
      after the treatment period. Because calves developed anemia during the treatment
      period, bone marrow biopsy specimens were collected. Antirecombinant human
      interferon alfa-2a antibody concentrations in serum samples obtained before,
      during, and after the treatment period were measured by use of an ELISA. RESULTS:
      Recombinant human interferon alfa-2a had no antiviral activity against
      noncytopathic type 1 BVDV in persistently infected calves. All calves developed
      microcytic anemia during the treatment period that persisted for up to 13 weeks
      after cessation of treatment. Anti-interferon antibodies were detected during the
      treatment period and persisted for at least 2 weeks after cessation of treatment.
      CONCLUSIONS AND CLINICAL RELEVANCE: Because of lack of in vivo antiviral activity
      against BVDV, recombinant human interferon alfa-2a has little promise as a
      therapeutic agent for the treatment of BVDV infection, at least in persistently
      infected cattle. Furthermore, treatment was associated with adverse immunologic
      and hematologic effects.

PMID- 15198231
TI  - Evaluation of cytotoxicity and antiviral activity of recombinant human interferon
      alfa-2a and recombinant human interferon alfa-B/D hybrid against bovine viral
      diarrhea virus, infectious bovine rhinotracheitis virus, and vesicular stomatitis
      virus in vitro.
AB  - OBJECTIVE: To evaluate cytotoxicity and antiviral activity of recombinant human
      interferon alfa-2a and recombinant human interferon alfa-B/D hybrid against
      cytopathic and noncytopathic bovine viral diarrhea virus (BVDV), infectious
      bovine rhinotracheitis virus (IBRV), and vesicular stomatitis virus (VSV) in
      vitro. SAMPLE POPULATION: Primary bovine testicular cells and Mardin Darby bovine
      kidney cells. PROCEDURES: To evaluate cytotoxicity, cells were added to serial
      dilutions of each interferon. To evaluate antiviral activity of each interferon,
      interferons were serially diluted 1:10, and tissue culture cells were added;
      virus was then added at 3 time points. Prevention of viral infection by
      interferon was defined as failure to induce cytopathologic effect for VSV, IBRV,
      and cytopathic BVDV and failure to detect virus immunohistochemically for
      cytopathic and noncytopathic BVDV. RESULTS: No evidence of cytotoxicity in either
      cell line was detected after incubation with interferon alfa-2a or interferon
      alfa-B/D. However, reduced growth rates of tissue culture cells were detected for
      each interferon when undiluted interferon was tested. Comparable and profound
      antiviral activities against cytopathic and noncytopathic BVDV were evident for
      each interferon. Interferon alfa-2a and interferon a-B/D had comparable antiviral
      activities against VSV. Neither interferon had antiviral activity against IBRV.
      CONCLUSIONS AND CLINICAL RELEVANCE: The safety and marked in vitro antiviral
      activity against noncytopathic BVDV, cytopathic BVDV, and VSV suggest that
      interferons alfa-2a and alfa-B/D may be useful for treatment of natural disease
      after infection with these viruses.

PMID- 15198232
TI  - [Molecular mechanism of morphine tolerance and biological approaches to resolve
      tolerance].
AB  - One of the major problems associated with the chronic use of morphine is
      tolerance. Repeated uses of morphine to relieve pain often cause patients to
      develop increasing resistance to the effects of the drugs, so that progressively
      higher doses are required to achieve the same analgesic effects. Acquired
      tolerance is thought to be different from dependence or addiction, but molecular
      mechanism underlying the development of tolerance is still unclear. Tolerance has
      been explained by desensitization of opioid receptor signaling and loss of
      functional receptors in the cell surface. The classical hypothesis was that
      phosphorylation and arrestin binding resulted in uncoupling of the receptor from
      G proteins, and reduced agonist efficacy. The receptor internalization would then
      result in fewer functional receptors at the cell surface. These events would
      cause so-called signaling desensitization. However, recent molecular biological
      studies have led researchers to revise the classical view of tolerance from
      observations that morphine does not always promote efficient receptor
      internalization. Among several key processes, the sequestration and subsequent
      internalization of the opioid receptor may play an important role for morphine
      tolerance. In fact, recent studies have suggested that receptor internalization
      can reduce tolerance. In addition, activation of the NMDA subtype of the
      glutamate receptor has been suggested as an anti-opioid system in the development
      of morphine tolerance. In this review, we focus on recent research progress on
      the morphine tolerance, and molecular biological and clinical approaches to
      resolve morphine tolerance.

PMID- 15198233
TI  - [The influence of intermittent hemodialysis (HD) on bispectral index (scale)
      (BIS) and serum propofol concentration under postoperative intravenous sedation].
AB  - We experienced a case of postoperative intravenous sedation with propofol during
      intermittent hemodialysis (HD), and investigated the correlation between the
      clinical sedation level based on bispectral index scale (BIS) together with
      Ramsay score, and the serum concentration of propofol. One adult oral cancer
      patient (carcinoma of the lower gingiva) with end-stage renal dysfunction needing
      HD was selected for this study. The day after operation, HD was commenced under
      intravenous sedation with propofol. Clinical sedation level was assessed using
      BIS and Ramsay score, and serum propofol concentrations were determined in
      arterial blood samples. Serum concentrations were measured every 15 times until
      51 hours after operation. The initial dose of propofol was set at 3.5 mg x kg(-1)
      x h(-1) on the basis of clinical symptoms. According to BIS and Ramsay score,
      sedation level decreased lineally for 1 hour after commencement of HD. In
      contrast, serum propofol concentration incresed from 1.71 microg x ml(-1) to 2.21
      microg x ml(-1). Total serum concentration of propofol was enhanced during HD
      because of dialytic dehydration, but, according to BIS and Ramsay scores, the
      possibility was suggested that the fraction of albmin-unbound propofol with
      pharmacological activities was eliminated or absorbed by membrane during HD.

PMID- 15198234
TI  - [Early application of the lung protective ventilation strategy at different
      stages in two ARDS patients].
AB  - We experienced 2 patients with acute respiratory distress syndrome (ARDS) from
      pneumonia after intervention for subarachnoidal hemorrhage. We applied lung
      protective ventilation strategy (LPVS) on both cases: a tidal volume less than 6
      ml x kg(-1) ideal body weight and PEEP at 10-15 cmH2O. Although etiology and
      degree of hypoxia were very similar in two patients when ARDS was diagnosed,
      clinical course was quite different. The patient in whom LPVS had been started on
      the 5th day of ARDS required mechanical ventilation of 23 days. In contrast,
      another patient in whom LPVS had been started on the 16th day of ARDS required
      mechanical ventilation of 219 days. PaCO2 during LPVS with permissive hypercapnia
      in the latter patient increased up to 161 mmHg but no adverse effect was
      observed. These cases suggest that early application of the LPVS may be important
      to improve respiratory outcomes of ARDS patients.

PMID- 15198235
TI  - [Relationships between hemostatic variables and delay of surgical repair of
      femoral neck fracture in elderly patients].
AB  - BACKGROUND: This study was conducted to clarify the preoperative risk of
      thrombosis in elderly patients with femoral neck fracture by determining the
      relationships between hemostatic variables and time from injury until surgical
      repair. METHODS: Thirty-four patients over 70 years of age with femoral neck
      fracture were assigned to the following three groups according to the delay of
      surgical repair: usual operation group (within 3 days), delayed operation group
      (from 4 to 7 days) and much delayed operation group (more than 8 days).
      Hemostatic variables including molecular markers were determined before surgical
      repair. RESULTS: Thrombin antithrombin complex level in the usual operation group
      was significantly increased. The D-dimer level in the usual operation group was
      significantly higher than that in the delayed operation group, but the levels in
      the delayed and much delayed operation groups were still higher than the levels
      in normal subjects. CONCLUSIONS: These findings suggest that elderly patients
      with femoral neck fracture may have a relatively high risk for the occurrence of
      pulmonary thromboembolism receiving anesthesia for surgical repair because of
      hypercoagulopathy caused by stress response and possible deep vein thrombosis
      caused by lying on a bed for a long period.

PMID- 15198236
TI  - [Thoracoscopic surgery for spontaneous pneumothorax and its anesthetic
      considerations].
AB  - BACKGROUND: Incidence of spontaneous pneumothorax (SPT) is increasing recently.
      Video-assisted thoracic surgery (VATS) is, at present, accepted generally as a
      procedure of choice for surgical treatment of SPT. This study was designed to
      investigate whether pre-operative complications and epidural anesthesia
      contribute to post-operative outcome following VATS for SPT. METHODS: From 1999
      to 2002, 88 patients (78 men and 10 women, ranging in ages from 18 to 86, with an
      average age of 42 years) presented with SPT and received VATS at the Osaka Police
      Hospital. We evaluated the relationship between peri-operative risk factors and
      post-operative outcome after VATS for SPT. RESULTS: Age and epidural analgesia
      contributed to post-operative pain (P=0.0268 and P=0.0165, respectively).
      Moreover, old age and long duration of surgery extended a hospitalization period
      (P=0.0002, r2=0.393 and P=0.0394, r2=0.224, respectively). In addition, old age
      contributes to post-operative pneumonia (P=0.0405). The patient with history of
      smoking had prolonged duration of surgery (P=0.0040) and oxygen supply after
      surgery (P=0.0312). CONCLUSIONS: VATS for SPT is less invasive and contribute to
      short hospitalization. However, VATS also requires general anesthesia with one
      lung ventilation. From our study, peri-operative careful management is necessary
      in a patient with old age and a habit of smoking.

PMID- 15198237
TI  - [Perioperative failure of hemodialysis shunts: analysis of risk factors].
AB  - BACKGROUND: Because vascular access dysfunction results in substantial morbidity
      in patients undergoing chronic hemodialysis, this complication should be avoided.
      However, we experienced four patients whose hemodialysis shunts failed within 24
      hours postoperatively. METHODS: We retrospectively analyzed operations performed
      under general anesthesia in our hospital for patients receiving hemodialysis
      shunts between May 2001 and October 2002. Comparisons between cases with and
      without perioperative shunt failures were performed using Mann-Whitney and
      Fishers exact tests. RESULTS: Spinal surgery (P<0.01) and surgery placed in prone
      or knee-chest positions (P<0.05) were significantly more frequent, and the
      operation times (P<0.01) and blood losses (P<0.05) were significantly greater, in
      the occluded group (n=4) than in the non-occluded group (n=12). CONCLUSIONS:
      Prone position might have impaired venous backflow from the shunt, thus promoting
      thrombogenesis. Additionally, moderate hemorrhage, with or without blood
      transfusion, may have induced a transient hypercoagulable state during the
      operation, which thus contributed to the acute shunt failure.

PMID- 15198238
TI  - [A case of ectopic pheochromocytoma of pulmonary origin].
AB  - A 55-year-old woman with pulmonary tumor was scheduled for tumor resection.
      Preoperatively, her episode of paroxysmal hypertension suggested the existence of
      pheochromocytoma, but MIBG (metaiodo-benzylguanidine) scintigraphy revealed no
      local accumulation. Therefore, physicians and surgeons denied the possibility of
      pheochromocytoma. During epidural catheterization, hypertension occurred, which
      was controlled by diltiazem 2 mg. Anesthesia was induced with midazolam 10 mg,
      propofol 70 mg and fentanyl 300 microg and maintained with propofol 4-7 mg x kg(
      1) x hr(-1), epidural block with 1% mepivacaine and nitrous oxide 66% in oxygen.
      Manipulation of the tumor induced hypertension. Diltiazem 1-2 microg x kg(-1) x
      min(-1) and nicardipine 0.4-4 microg x kg(-1) x min(-1) were administered. After
      tumor resection, blood pressure decreased to 82/42 mmHg and norepinephrine 0.05
      0.25 microg x kg(-1) x min(-1) was infused. Norepinephrine infusion was continued
      for 24 hours after surgery. She was discharged from the recovery room on the
      third postoperative day without any complications. A case of ectopic
      pheochromocytoma of pulmonary origin was managed with midazolam, propofol,
      fentanyl and continuous epidural block. Diltiazem, nicardipine and norepinephrine
      were administered to control blood pressure.

PMID- 15198239
TI  - [Difficult airway in a child with multiple juvenile xanthogranulomas].
AB  - Juvenile xanthogranuloma (JXG) is a benign and self-healing histiocytosis on the
      skin. A 4-year-old boy with multiple JXG was scheduled for plastic surgery to
      correct the scar contraction of the neck. The patient was expected to have
      difficult airway caused by small mouth, limitation of neck movement and numerous
      nodular lesions located at the face. Initially he underwent resection of the neck
      scar under local anesthesia with added inhalation anesthesia via mask, and the
      restricted neck recurvation was improved. One week later, he underwent skin
      grafting under general anesthesia. We used a spiral tube of 3 mm diameter
      inserted to the nostril for manual ventilation, and bronchofiberscope-aided
      tracheal intubation was successfully performed through the laryngeal mask airway
      under general anesthesia without any problems.

PMID- 15198240
TI  - [A case of intraoperative hyperkalemia induced with administration of an
      angiotensin II receptor antagonist (AIIA) and intake of dried persimmons].
AB  - An 87-year-old man was scheduled for cervical laminectomy. Anesthesia was
      maintained with nitrous oxide, oxygen, sevoflurane, and fentanyl with tracheal
      intubation. Thirty minutes after the start of operation, serum potassium was 7.41
      mEq x l(-1). We immediately administered potassium-free fluid, furosemide,
      bicarbonate, calcium gluconate and insulin. We stopped the operation and returned
      the patient to supine position, but he fell into ventricular fibrillation.
      Immediate CPR and countershock successfully restored sinus rhythm within 5
      minutes. He was discharged from ICU without any neurological complications. Daily
      he took Losartan potassium, an AIIA, due to hypertension and ate preoperatively
      dried persimmons, a potassium-rich food. We suspect that hyperkalemia was induced
      by administration of an AIIA in combination with excessive intake of dried
      persimmons. AIIA may cause severe hyperkalemia inhibiting aldosterone activity.
      We should pay attention to the serum potassium level and a preoperative intake of
      food especially in a patient medicated with an AIIA.

PMID- 15198241
TI  - [A case of pulmonary thromboembolism after cardiac surgery].
AB  - It has been reported that pulmonary thromboembolism (PTE) is a major complication
      in the post-operative period. However, there have been few reports on PTE after
      cardiopulmonary bypass (CPB). We report a case of PTE that occurred after cardiac
      surgery using CPB. A 76-year-old female patient underwent aorto-coronary graft
      bypass and mitral valve plasty because of ischemic heart disease and mitral valve
      regurgitation, respectively. The results of blood gas analysis after
      cardiopulmonary bypass showed no abnormalities. Immediately after ICU admission,
      the oxygenation index (PaO2/FIO2) of the patient was below 100, and the low level
      persisted despite decrease in interstitial fluid volume of the lung. Evaluations
      of hemodynamics using ultrasound echography and a Swan-Ganz catheter showed no
      findings associated with right heart failure. The results of lung perfusion
      scintigraphy performed on the 6th postoperative day (POD), revealed the decline
      in radioactivities in the upper and middle lobe areas of the right lung.
      Urokinase was therefore administered intravenously from the 6th to 9th POD. The
      oxygenation index increased dramatically after urokinase administration. Although
      the use of thrombolytic therapy in an early postoperative period is
      controversial, our patient was successfully treated with urokinase without a life
      threatening bleeding tendency.

PMID- 15198242
TI  - [Epidural hematoma caused after epidural catheterization for the coronary artery
      bypass graft: a case report].
AB  - Epidural hematoma is a rare complication of epidural anesthesia, but once this
      severe complication has occurred, without early decompressive procedure, it may
      cause permanent neurologic disorder. Especially, the patients with hemostatic
      disorder have a higher risk of epidural hematomas. We report a patient who
      recovered immediately from neurological symptoms resulting from epidural hematoma
      formed by epidural catheterization on the day before coronary artery bypass.
      Epidural hematoma as a complication of epidural anesthesia is discussed.

PMID- 15198244
TI  - [Accidental severance of epidural catheter used in a patient with postoperative
      delirium].
AB  - A 79-year-old man with an abdominal aortic aneurysm had a lumbar epidural
      catheter inserted for postoperative pain control of bypass graft surgery with
      continuous epidural analgesia. Five days after the operation, we noticed that
      forced traction by the patient with delirium had led to the catheter tip being
      separated and left behind in his body. The remaining portion of the catheter was
      detected using a lateral lumbar roentgenogram and CT imaging, and it was later
      removed surgically. We conclude that it was necessary to change the method of
      analgesia in this patient, since it was difficult to maintain the epidural
      catheter.

PMID- 15198243
TI  - [Perioperative heart rate control with landiolol for a patient with rapid atrial
      fibrillation complicated with low cardiac function].
AB  - A 62-year-old man complicated with old antero-septal wall myocardial infarction
      and atrial fibrillation suffered from lung and pancreas cancer. He underwent
      gastro-duodenum bypass surgery under epidural combined with general anesthesia.
      His ECG and echocardiogram revealed atrial fibrillation and his left ventricular
      ejection fraction was 35%. After the start of surgery under general anesthesia,
      EHR was stable between 80-100 beats x min(-1) but rapid atrial fibrillation
      developed with a rate of over 140 beats x min(-1) after epidural injection of
      0.375% ropivacaine 3 ml. Treatment including continuous intravenous diltiazem and
      several bolus intravenous injections of verapamil failed to decrease the heart
      rate. Therefore we used landiolol, a short-acting beta blocker, to control heart
      rate. HR decreased without decreasing his blood pressure. Continuous landiolol
      infusion was maintained for 3 hours and 30 minutes in the ICU. After finishing
      infusion, his heart rhythm never became rapid atrial fibrillation. We conclude
      that landiolol is useful for heart rate control of rapid atrial fibrillation.

PMID- 15198245
TI  - [A case of intraoperative hyperkalemia probably due to preoperative feeding with
      a liquid enteral formulation].
AB  - A 67-year-old man with no remarkable preanesthetic complications underwent
      esophagectomy. The patient was fed only with a liquid enteral formulation (Ensure
      Liquid) for 5 days immediately before the operative day. His serum potassium
      level before Ensure Liquid administration was 4.1 mEq x l(-1). The first blood
      analysis at 30 min after the initiation of the surgery revealed an increase in
      serum potassium level (5.9-6.1 mEq x l(-1)) without any conceivable cause during
      the anesthetic management. A glucose-insulin infusion treatment lowered the serum
      potassium level to the normal range. The serum potassium level re-increased to
      6.4 mEq x l(-1) 4 days after the initiation of jejunal feeding with Ensure Liquid
      and then returned to the normal range after the termination of Ensure Liquid
      administration. The patient's perioperative course suggests that the preoperative
      Ensure Liquid administration is a probable cause of the intraoperative
      hyperkalemia in this case.

PMID- 15198247
TI  - [Anesthetic management of a patient with severe hyponatremia].
AB  - A 62-year-old woman was scheduled for an operation for ileus. Before the
      operation, we noticed severe hyponatremia (Na 117 mEq x l(-1)) probably due to
      dehydration. We corrected her hyponatremia slowly to avoid central pontine
      myelinolysis. Serum Na level increased to 131 mEq x l(-1) after surgery. She
      recovered from anesthesia without any neurologic problems.

PMID- 15198246
TI  - [Anesthetic management of a patient with a giant ovarian tumor].
AB  - We reported a case of a giant ovarian tumor weighing 30 kg removed successfully.
      Anesthesia was induced with the patient in the lateral decubitus, and the surgery
      was started with this position. While the tumor was abraded, hemodynamics was
      almost stable. The patient recovered without any postoperative complications.
      Anesthetic management for cases of a giant ovarian tumor is discussed.

PMID- 15198248
TI  - [Do Japanese express pain as Western people do?].
AB  - As pain is an unpleasant experience, sensorial and emotional, it may possess a
      different meaning in a different society with its own culture and history. Pain
      in English has the meaning of punishment in the verbal origin. However, pain in
      Japanese, which is called "itami", means extraordinary state of something without
      containing the meaning of punishment. The Japanese who originally have view of
      life of empathy and assimilation with the nature, have tended not to regard the
      pain as the object being overcome. Thus, the Japanese may have been capable to
      give a unique message to the West, regarding the treatment of pain.

PMID- 15198249
TI  - [Critical incidents due to drug administration error in the operating room: an
      analysis of 4,291,925 anesthetics over a 4 year period].
AB  - BACKGROUND: Wrong drugs, overdose of drugs, and incorrect administration route
      remain unsolved problems in anesthetic practice. We determined the incidence and
      outcome of drug administration error in the operating room of Japanese Society of
      Anesthesiologists Certified Training Hospitals. METHODS: Data were obtained from
      annual surveys conducted by Japanese Society of Anesthesiologists between 1999
      and 2002. There were 4,291,925 cases of anesthetic delivery for this analysis.
      RESULTS: Incidence of critical incidents due to drug administration error was
      18.27/100,000 anesthetics. Cardiac arrest occurred in 2.21 patients per 100,000
      anesthetics. Causes of these critical incidents were as follows: overdose or
      selection error involving non-anesthetic drugs, 42.1%; overdose of anesthetics,
      28.7%; inadvertent high spinal anesthesia, 17.9%; local anesthetic intoxication,
      6.4%; ampule or syringe swap, 4.3%; blood mismatch, 0.6%. Incidence of death
      following these incidents was 0.44/100,000. Causes of death were as follows:
      overdose or selection error involving non-anesthetic drugs, 47.4%; overdose of
      anesthetics, 26.3%; inadvertent high spinal anesthesia, 15.8%; local anesthetic
      intoxication, 5.3%. Ampule or syringe swap did not lead to any fatalities. Death
      following inadvertent high spinal anesthesia and local anesthetic intoxication
      was reported only in patients who had developed cardiac arrest. It should be
      noted that 88 percent of ampule or syringe swap occurred in patients with
      American Society of Anesthesiologists-Physical Status 1 or 2, who did not seem to
      require complex anesthetic management. CONCLUSIONS: We should increase awareness
      that drug administration is generally performed with limited objective
      monitoring, although "To error is human". Increased vigilance is required to
      avoid drug administration error in the operating room. Additional anesthesia
      resident education, adequate supervision, and improved organization are
      necessary. Bar-coding technology might be useful in preventing drug
      administration error.

PMID- 15198250
TI  - Feline leukemia virus threatens endangered panthers.

PMID- 15198252
TI  - Food supply veterinary initiatives to move forward.

PMID- 15198251
TI  - Executive Board prioritizes recommendations for funding.

PMID- 15198253
TI  - AVMA welfare positions evolve.

PMID- 15198254
TI  - AVMA takes a stand on legislative initiatives.

PMID- 15198255
TI  - Thoughts on Animal Welfare Act compliance.

PMID- 15198256
TI  - More on feral cat welfare.

PMID- 15198257
TI  - The geode--a symbol of inner beauty.

PMID- 15198258
TI  - What is your diagnosis? A large mass dorsal to the bifurcation of the trachea
      with tracheobronchial compression.

PMID- 15198259
TI  - Animal behavior case of the month. Severe aggressive behavior directed at the
      owner.

PMID- 15198260
TI  - Application of evidence-based medicine to veterinary clinical nutrition.

PMID- 15198261
TI  - Factors associated with client, staff, and student satisfaction regarding small
      animal euthanasia procedures at a veterinary teaching hospital.
AB  - OBJECTIVE: To identify factors influencing satisfaction with procedures for small
      animal euthanasia and to compare the relative importance of those factors among
      clients, staff, and students at a veterinary teaching hospital. DESIGN: Survey.
      SAMPLE POPULATION: 18 nonclinical hospital staff members, 13 clinical staff
      members, 10 veterinary technicians, 19 veterinary students, and 91 clients.
      PROCEDURE: Participants were asked to complete a survey that was designed to
      assess satisfaction with various aspects of the euthanasia procedure. RESULTS:
      Overall response rate was 48% (151/313). Respondents most strongly agreed with
      the statements that clients should have the option to be present, that having a
      private place was important, and that employees should be trained to attend to
      the emotional needs of the client. When asked to place factors in order of
      importance, those that were ranked the highest included compassionate and caring
      attitudes of the hospital employees, the option for the client to be present
      during the euthanasia, and the client being informed and well prepared.
      CONCLUSIONS AND CLINICAL RELEVANCE: Overall, all groups (nonclinical staff,
      clinical staff, veterinary technicians, veterinary students, and clients)
      identified the same factors as being important in the euthanasia of a pet.
      Results may help facilitate healthy euthanasia experiences.

PMID- 15198262
TI  - Frequency of use of various procedures, skills, and areas of knowledge among
      veterinarians in private small animal exclusive or predominant practice and
      proficiency expected of new veterinary school graduates.

PMID- 15198263
TI  - Prevalence of house soiling and aggression in kittens during the first year after
      adoption from a humane society.
AB  - OBJECTIVE: To determine frequency of house soiling, aggression toward people, and
      aggression toward other cats among kittens adopted from an animal shelter and
      whether frequency of these behaviors was associated with age at the time of
      neutering. DESIGN: Survey. ANIMALS: 126 kittens adopted from a humane society at
      6 to 13 weeks of age. PROCEDURE: Owners of the kittens were contacted by
      telephone approximately 4, 18, and 52 weeks after kittens were adopted, and a
      behavioral assessment questionnaire was administered. Owners were asked to
      indicate whether the kitten had displayed the specific behavior in the preceding
      30 days. Sixty-three kittens were neutered prior to adoption; the remaining 63
      were neutered at 5 to 7 months of age, after the second behavioral assessment.
      RESULTS: In the month following adoption, 64 (50.8%) kittens were reported to
      have at least 1 of the 3 behaviors. There was no evidence that the 3 behaviors
      were related. The percentage of kittens reported to urinate or defecate outside
      the litter box decreased from the first to second evaluation and remained low at
      the third evaluation. The percentage of kittens reported to show aggression
      toward people and the percentage reported to show aggression toward other cats
      decreased from the first to second evaluation, but increased again at the third
      evaluation. There was no significant association between age at the time of
      neutering and any of the 3 behaviors. CONCLUSIONS AND CLINICAL RELEVANCE: Results
      suggest behavior problems may be common in kittens adopted from a humane society,
      particularly during the first month after adoption.

PMID- 15198264
TI  - Successful ovariectomy in a dog with Glanzmann thrombasthenia.
AB  - Ovariectomy was performed in a 7-month-old Great Pyrenees with a severe
      congenital bleeding disorder. A diagnosis of Glanzmann thrombasthenia, a rare,
      congenital bleeding disorder characterized by a functional platelet defect, was
      later confirmed by isolation of genomic DNA from blood and amplification of exon
      13 and intron 13 of the gene encoding for platelet glycoprotein subunit alphaIIb.
      Perioperative management consisted of administration of platelet-rich plasma
      prior to surgery and the use of high-frequency electrocoagulation to minimize
      tissue trauma. In addition, ovariectomy, rather than ovariohysterectomy, was
      performed to minimize surgical exposure required and manipulation of the
      urogenital tract. Results in this dog suggest that a combination of preoperative
      transfusion with functional platelets and use of techniques to minimize tissue
      trauma may allow abdominal surgery to be performed successfully in dogs with
      functional platelet disorders.

PMID- 15198265
TI  - Omentalization of a nonresectable uterine stump abscess in a dog.
AB  - One month after ovariohysterectomy, a 2-year-old spayed female Golden Retriever
      was evaluated because of an extensive uterine stump abscess. Clinical signs
      included intermittent vomiting, signs of depression, lethargy, and pollakiuria.
      The dog underwent abdominal surgery; the greatly enlarged uterine stump was
      tightly adhered to the dorsal surface of the bladder, encompassing the distal
      portions of the ureters and the bladder's neurovascular supply. En bloc resection
      of the uterine stump was not considered an acceptable treatment option because of
      the risk of surgical damage to and subsequent devitalization of the bladder or
      ureters, urinary incontinence, or urinary tract obstruction. Therefore, the
      diseased uterine tissue that extended cranial to the bladder was resected, and
      the remaining abscess cavity was lavaged and packed with omentum. The dog
      recovered fully from the procedure. The omentum is an effective physiologic
      drain; its extensive vascular and lymphatic networks absorb fluid and actively
      promote elimination of infection. Omentalization appears to be an option for
      surgical management of nonresectable uterine stump abscesses in dogs.

PMID- 15198266
TI  - Clinical resolution of Brucella canis-induced ocular inflammation in a dog.
AB  - A 2-year-old spayed female mixed-breed dog was referred with an 8-month history
      of recurrent bilateral anterior uveitis and hyphema secondary to infection with
      Brucella canis. Treatment with doxycycline PO and atropine and prednisone acetate
      topically prior to referral had failed to resolve the ocular inflammation.
      Successful control of ocular inflammation was achieved after initiation of
      treatment with gentamicin SC and ciprofloxacin and doxycycline PO. The finite
      indirect fluorescent antibody (IFA) titer was reduced by half, and results of an
      agar gel immunodiffusion (AGID) test became negative after rifampin was added to
      the treatment protocol. Treatment with gentamicin was eventually discontinued
      because of evidence of renal toxicosis and cutaneous reactions to repeated
      injections. Thirty-five months after initial examination of the dog, results of
      the AGID test were still negative, the finite IFA titer was stable, and ocular
      inflammation had resolved, suggesting that the ocular infection may have been
      eliminated. To our knowledge, this represents the first report of the successful
      treatment of ocular inflammation caused by B canis infection in a dog.

PMID- 15198267
TI  - Recurrence of thoracolumbar intervertebral disk extrusion in chondrodystrophic
      dogs after surgical decompression with or without prophylactic fenestration: 265
      cases (1995-1999).
AB  - OBJECTIVES: To evaluate a population of chondrodystrophic dogs treated for Hansen
      type 1 intervertebral disk (IVD) disease by surgical decompression with or
      without prophylactic fenestration and determine the rate and location of
      surgically confirmed recurrence of intervertebral disk extrusion. ANIMALS: 265
      dogs. STUDY DESIGN: Retrospective study. PROCEDURES: Medical records of dogs that
      underwent spinal decompression between 1995 and 1999 were reviewed. RESULTS: 3
      (4.9%) dogs were euthanatized or died prior to discharge. Fenestration was
      performed in 252 dogs, including 37 (14.7%) at the site of decompression only, 48
      (19%) at 3 to 4 disk spaces, and 167 (66%) at 5 to 7 disk spaces. There were 12
      instances of recurrent disk extrusion confirmed by removal of disk at a second
      surgery 3.5 to 33 months after the first surgery. Recurrence was always at a new
      disk space, and rates did not significantly differ between dogs that underwent
      single or multiple fenestrations. Two recurrences were at a previously
      fenestrated disk space. Seven recurrences were at a site immediately adjacent to
      a fenestrated disk space, and 5 recurrences were at L4-5. CONCLUSIONS AND
      CLINICAL RELEVANCE: Prophylactic fenestration is generally successful in
      preventing future disk extrusions at fenestrated disk spaces. Prospective
      evaluation is still required to determine whether fenestration decreases the
      overall rate of recurrence. Prophylactic fenestration could promote disk
      extrusion at adjacent, nonfenestrated disk spaces. This could have a substantial
      clinical impact if recurrence develops at L4-5.

PMID- 15198268
TI  - Use of magnetic resonance imaging identify suspensory desmitis and adhesions
      between exostoses of the second metacarpal bone and the suspensory ligament in
      four horses.
AB  - Four horses were examined because of chronic forelimb lameness. In all horses,
      the cause of the lameness was localized to the metacarpus by means of physical
      examination and diagnostic anesthesia, and radiography of the affected limb
      revealed a small exostosis of the second metacarpal bone. Magnetic resonance
      imaging revealed suspensory desmitis in the region of this exostosis in all 4
      horses. In addition, an abnormal area of low signal intensity, suggestive of an
      adhesion, was seen between the exostosis and the suspensory ligament. In all
      horses, an adhesion between the suspensory ligament and the exostosis on the
      second metacarpal bone was identified and transected at surgery, and the
      exostosis and distal portion of the second metacarpal bone were removed. All
      horses were able to return to their previous athletic use following a 6-month
      rest and rehabilitation program for treatment of the suspensory desmitis.
      Findings in these horses suggest that adhesions between the suspensory ligament
      and an exostosis of the second metacarpal bone may be a cause of chronic or
      recurrent forelimb lameness in horses.

PMID- 15198269
TI  - Arthroscopic findings in horses with subtle radiographic evidence of
      osteochondral lesions of the medial femoral condyle: 15 cases (1995-2002).
AB  - OBJECTIVE: To determine arthroscopic findings in lame horses with subtle
      radiographic lesions of the medial femoral condyle. DESIGN: Retrospective study.
      ANIMALS: 15 horses examined because of lameness that had subtle radiographic
      evidence of osteochondral lesions involving the medial femoral condyle in at
      least 1 joint. PROCEDURE: Medical records were reviewed, and results of physical
      examination, radiography, and arthroscopy were recorded. Follow-up information
      was obtained through reexamination of the horses or telephone conversations with
      the referring veterinarians, owners, or trainers. RESULTS: Lameness severity
      ranged from grade 1 to 3 on a scale from 0 to 5. Radiography and arthroscopy were
      performed on 28 stifle joints. The 4 unaffected joints in 4 horses with
      unilateral hind limb lameness that underwent bilateral arthroscopy had no
      radiographic lesions, but 2 of the 4 had arthroscopic lesions. Of the remaining
      24 joints, 20 had radiographic evidence of flattening of the apex of the medial
      femoral condyle and 4 had minimal subchondral lucency. Lesions were identified
      arthroscopically in 18 of the 20 joints with flattening of the condyle and in all
      4 joints with subchondral lucency. Treatment consisted of abrasion arthroplasty
      or microfracture. Seven of the 9 horses with focal cartilage lesions and 2 of the
      6 horses with generalized cartilage lesions were reportedly sound without any
      evidence of joint effusion at the time of final follow-up. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results suggest that horses with hind limb lameness and
      subtle radiographic lesions of the medial femoral condyle are likely to have
      arthroscopically apparent cartilage lesions and subchondral bone defects.

PMID- 15198271
TI  - Analysis of mission and aircraft factors in G-induced loss of consciousness in
      the USAF: 1982-2002.
AB  - INTRODUCTION: Previous studies have used questionnaires to evaluate G-LOC
      incident rates in different aircraft types, but no studies of G-LOC-related
      incident, crash, and fatality rates in different aircraft types were found in a
      search of the literature. METHODS: G-LOC events (including both incidents and
      crashes) for the fiscal years 1982 to 2002 were obtained from the USAF Safety
      Center. Aircraft sortie numbers were obtained for all aircraft that had a G-LOC
      event reported. Contingency table analysis and Chi-squared tests were used to
      evaluate differences in G-LOC rates. RESULTS: Overall 559 G-LOC events occurred
      for a rate of 25.9 per million sorties (PMS), but event rates differed by almost
      two orders of magnitude between aircraft categories, being highest in basic
      training aircraft, intermediate in single crewmember fighters, and lowest in
      other aircraft types (p < 0.001). The proportion of events resulting in crashes
      was 30% in single-crewmember aircraft compared with 0.6% in trainers and other
      two-crewmember aircraft (p < 0.001). All of the crashes and fatalities occurred
      in aircraft occupied at the time by only a single crewmember. The crash fatality
      rate was 100% in attack aircraft, 73% in single-crewmember fighters, and zero in
      basic trainers (p < 0.05). The F-15 and F-16 aircraft did not have higher G-LOC
      rates than other single-seat fighters. DISCUSSION: The data suggest that both
      crew complement and mission play a role in determining G-LOC rates. The data also
      suggest that G-LOC in an aircraft with a ground attack mission is more likely to
      result in a fatality.

PMID- 15198270
TI  - Elimination kinetics of ceftiofur hydrochloride after intramammary administration
      in lactating dairy cows.
AB  - OBJECTIVE: To determine the elimination kinetics of ceftiofur hydrochloride in
      milk after intramammary administration in lactating dairy cows. DESIGN:
      Prospective study. ANIMALS: 5 lactating dairy cows. PROCEDURE: After collection
      of baseline milk samples, 300 mg (6 mL) of ceftiofur was infused into the left
      front and right rear mammary gland quarters of each cow. Approximately 12 hours
      later, an additional 300 mg of ceftiofur was administered into the same mammary
      gland quarters after milking. Milk samples were collected from each mammary gland
      quarter every 12 hours for 10 days. Concentrations of ceftiofur and its
      metabolites in each milk sample were determined to assess the rate of ceftiofur
      elimination. RESULTS: Although there were considerable variations among mammary
      gland quarters and individual cows, ceftiofur concentrations in milk from all
      treated mammary gland quarters were less than the tolerance (0.1 microg/mL) set
      by the FDA by 168 hours (7 days) after the last intramammary administration of
      ceftiofur. No drug concentrations were detected in milk samples beyond this
      period. Ceftiofur was not detected in any milk samples from nontreated mammary
      gland quarters throughout the study. CONCLUSIONS AND CLINICAL RELEVANCE:
      Ceftiofur administered by the intramammary route as an extra-label treatment for
      mastitis in dairy cows reaches concentrations in milk greater than the tolerance
      set by the FDA. Results indicated that milk from treated mammary gland quarters
      should be discarded for a minimum of 7 days after intramammary administration of
      ceftiofur. Elimination of ceftiofur may be correlated with milk production, and
      cows producing smaller volumes of milk may have prolonged withdrawal times.

PMID- 15198272
TI  - Calcium balance in mature male rats with unloaded hindlimbs.
AB  - BACKGROUND: Calcium balances, regulated by the calcium endocrine system, are
      negative during spaceflight but have not been reported in flight simulation
      models using fully mature small animals. METHODS: We conducted two calcium (Ca)
      balance studies in 6-mo-old male rats exposed to a model that unloads the
      hindlimbs (HU) for 4 wk. Control (C) and HU rats were fed diets with 0.5% Ca in
      the first and 0.1% Ca in the second study. Housing in metabolic cages enabled
      daily food and water intake measurements as well as collections of urine and
      fecal specimens. At necropsy, blood was obtained for measures of Ca-regulating
      hormones. RESULTS: Both C and HU rats adjusted to housing and diets with
      decreases in body weight and negative Ca balances during the first week of each
      experiment. Thereafter, averages of Ca balances were more negative in the
      unloaded rats than controls: -8.1 vs. -1.6 mg x d(-1) in rats fed 0.5% (p <
      0.05). This difference was not due to urinary Ca excretion since it was lower in
      HU than C rats (1.27 +/- 0.51 mg x d(-1) vs. 2.35 +/- 0.82 mg x d(-1), p < 0.05).
      Fecal Ca in HU rats exceeded dietary Ca by 4-7%, Restricting dietary Ca to 0.1%
      was followed by an increase in serum 1,25-dihydroxyvitamin D (1,25-D) and greater
      intestinal Ca absorption than in rats fed 0.5% Ca. Ca balances in rats fed 0.1%
      Ca were also more negative in HU than C rats (-2.4 vs. -0.03 mg x d(-1), p <
      0.05). Parathyroid hormone (PTH) was suppressed and 1,25-D increased in HU rats
      fed 0.5% Ca. C rats fed 0.1% Ca had increased PTH and 1,25-D was the same as in
      the HU group. CONCLUSION: After adaptation, Ca balances were more negative in
      mature male rats with unloaded hindlimbs than controls, an effect from increased
      secretion and loss of endogenous fecal Ca associated with increased 1,25-D in Ca
      replete and Ca-restricted rats.

PMID- 15198273
TI  - Exercise effects during diving and decompression on postdive venous gas emboli.
AB  - BACKGROUND: Exercise and diving have generally been associated with an increased
      risk of decompression sickness (DCS), thus accounting for the lack of studies
      involving exercise during decompression. However, theoretical and observational
      evidence contrary to this association motivated the present investigation on the
      effects of moderate, intermittent exercise during diving and/or during
      decompression on venous gas emboli (VGE) activity following a dive. HYPOTHESIS:
      VGE observed at both the precordium and subclavian vein sites after diving should
      be reduced if moderate exercise is performed during decompression vs. remaining
      inactive. METHODS: In a water-filled hyperbaric chamber, 39 healthy male subjects
      were compressed to a pressure of 450 kPa (45 msw) for 30 min followed by 55 min
      of staged decompression. Subjects were either active or inactive at the bottom
      phase (450 kPa) and/or during the decompression. Activity comprised three 5-min
      intervals of moderate arm or leg exercise at the bottom and five such intervals
      during decompression. After decompression, VGE were monitored at the precordium
      and subclavian vein sites using Doppler detection. Bubble activity scores were
      converted to various indices and analyzed using non-parametric statistics.
      RESULTS: VGE activity was invariant as to whether subjects were active or
      sedentary during the bottom phase of the dive. However, it was significantly
      lower for all indices examined (p < 0.05) after dives in which exercise was
      performed during decompression vs. inactive decompression. CONCLUSION: Moderate,
      intermittent physical activity during decompression decreases VGE activity after
      diving.

PMID- 15198274
TI  - Altitude decompression sickness symptom resolution during descent to ground
      level.
AB  - INTRODUCTION: Altitude decompression sickness (DCS) is a health risk associated
      with the conduct of high altitude airdrop operations, high altitude
      reconnaissance, future fighter operations, hypobaric chamber training,
      unpressurized flight, and extravehicular activity (EVA) in space. The treatment
      for DCS includes the provision of 100% oxygen (O2) at ground level (GLO) and/or
      hyperbaric oxygen therapy (HBO). In this paper we examine the effect of
      repressurization to ground level from hypobaric conditions on DCS symptoms.
      Timely recompression (descent at first recognition of any DCS symptom) may be a
      safe, effective treatment for the large majority of DCS symptoms. METHODS: Data
      from altitude chamber exposures recorded in the Air Force Research Laboratory
      (AFRL) Altitude DCS Database were reviewed to determine the level of
      recompression required for complete resolution of 1,699 observed symptoms.
      RESULTS: Of the 1,699 DCS symptoms reviewed, 66 (3.9%) resolved at altitude, 117
      (6.9%) resolved at ground level, and 1,433 (84.3%) resolved during descent.
      Increasing the pressure by 138 mmHg from the altitude of exposure where symptoms
      occurred resolved roughly 50% of symptoms. Little resolution of symptoms was
      noted with recompressions of < 50 mmHg. The greatest rate of symptom resolution
      occurred with recompressions of 50-250 mmHg. CONCLUSION: These findings support
      the concept that descent and postflight, ground-level oxygen may be sufficient to
      relieve the majority of altitude DCS symptoms. HBO may be reserved for serious,
      recurring, delayed, or refractory symptoms. The findings also suggest a need for
      further study of DCS symptom resolution.

PMID- 15198275
TI  - Plasma volume and blood viscosity during 4 h sitting in a dry environment: effect
      of prehydration.
AB  - BACKGROUND: Deep vein thrombosis and pulmonary thromboembolism are potential
      problems for travelers, including those who fly. We hypothesized that
      prehydration with an electrolyte-glucose beverage (EGB) would be better than
      water for maintaining body fluid balance and preventing increased blood viscosity
      in immobilized men. METHODS: There were 12 healthy men (24-38 yr) who
      participated in crossover trials of prehydration using EGB and H2O as well as a
      control condition (Con) with no prehydration. Fluid intake was set at 6 ml x kg(
      1) body weight (mean 418 ml). For each trial, subjects sat for 4 h at a dry-bulb
      temperature of 23.0-23.5 degrees C and a relative humidity of 18-36%. Plasma
      volume (PV) and whole blood viscosity (Bvis) were determined every hour; routine
      laboratory hematological tests, urine volume, and body weight were recorded at 2
      h and 4 h. RESULTS: For Con, subjects lost approximately 110 ml h(-1); at 2 h, PV
      had decreased significantly by 3.4%, and Bvis had increased significantly by
      9.3%, with no further change at 4 h. For prehydration, retention of the consumed
      fluid at 2 h was significantly higher for EGB (57%) than for H2O (38%), while
      both drinks prevented significant change in PV and Bvis. There were no
      significant differences between trials in coagulation variables, but Bvis
      measured at higher shear rates for EGB were significantly attenuated compared
      with Con. CONCLUSION: EGB and water prevented the increase of blood viscosity
      that occurred without prehydration. EGB was better than water for maintaining
      body fluid balance and preventing hypovolemia.

PMID- 15198276
TI  - Albuterol helps resistance exercise attenuate unloading-induced knee extensor
      losses.
AB  - INTRODUCTION: While resistance exercise (REX) attenuates knee extensor (KE) mass
      and strength deficits during short-term unloading, additional treatments
      concurrently administered with REX are required to reduce the greater losses seen
      with longer periods of unloading. METHODS: To determine whether albuterol helps
      REX attenuate unloading-induced KE losses, two groups of subjects strength
      trained their left thigh three times per week, and otherwise refrained from
      ambulatory and weight-bearing activity for 40 d while receiving a capsule dosing
      treatment (albuterol, placebo) with no crossover. A third group served as
      unloaded controls (CTRL). On days 0, 20, and 40, the following data were
      collected from the nonweight-bearing (left) thigh: cross-sectional area (CSA);
      integrated electromyography (IEMG); and concentric and eccentric KE strength
      measures. Thigh CSA was estimated using anthropometric methodology. IEMG was used
      to provide root mean square (RMS) values from submaximal (100 nm) and maximal
      isometric contractions. Concentric and eccentric strength were measured from
      eight-repetition unilateral leg press sets. RESULTS: Repeated-measures mixed
      factorial 3 x 3 ANCOVAs with day 0 values as a covariate showed group by time
      interactions for concentric and eccentric total work (CTW, ETW). Tukey's post hoc
      test showed REX-albuterol evoked significant (p < 0.05) day 40 CTW and ETW gains
      vs. within-group day 0 and within-time REX-placebo and CTRL values. By days 20
      and 40, CTRL subjects incurred significant decrements. CONCLUSIONS: Albuterol
      augmented the effects of REX to increase CTW and ETW. Research identifying
      possible mechanisms responsible for such changes, as well as the safety of REX
      albuterol administration in other models, is warranted.

PMID- 15198277
TI  - Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone,
      and temazepam.
AB  - INTRODUCTION: Current military operations often require pharmaceutical methods to
      sustain alertness and facilitate sleep in order to maintain operational
      readiness. This study was designed to compare the sleep-inducing power of four
      medications. METHOD: There were 9 men and 14 women, ages 21-53 yr, who were
      assessed for psychomotor performance before and for 7 h after ingestion of a
      single dose of placebo, zaleplon 10 mg, zopiclone 7.5 mg, temazepam 15 mg, or
      time-released melatonin 6 mg. The experimental design was a double-blind
      crossover with counterbalanced treatment order. Subjects wore polysomnographic
      electrodes to record total sleep and sleep latency during 4-min periods with eyes
      closed immediately before and after each psychomotor test sequence. Subjective
      drowsiness was assessed by questionnaire. RESULTS: There were drug x trials
      interactions for zaleplon, zopiclone, and temazepam for total sleep, sleep
      latency, and subjective drowsiness. More sleep, shorter sleep latency, and more
      drowsiness occurred immediately after psychomotor testing compared to before
      testing for all medications. Melatonin did not cause any sleep prior to
      psychomotor testing sessions, but caused sleep and reduced sleep latency after
      psychomotor test sessions from 1 3/4 h to 4 3/4 h post-ingestion. CONCLUSIONS:
      The sleep-inducing power of the medications before psychomotor testing was
      zopiclone > zaleplon > melatonin > temazepam. The corresponding effect after
      psychomotor testing was zopiclone > melatonin > zaleplon > temazepam.

PMID- 15198278
TI  - Modafinil vs. caffeine: effects on fatigue during sleep deprivation.
AB  - INTRODUCTION: The extent to which modafinil and caffeine reverse fatigue effects
      (defined as performance decrements with time on task) during total sleep
      deprivation was investigated. METHODS: There were 50 healthy young adults who
      remained awake for 54.5 h (06:30 day 1 to 13:00 day 3). A 10-min vigilance test
      was administered bi-hourly from 08:00 day 1 until 22:00 day 2. At 23:55 day 2
      (after 41.5 h awake), double-blind administration of one of five drug doses
      (placebo; modafinil 100, 200, or 400 mg; or caffeine 600 mg; n = 10 per group)
      was followed by hourly testing from 00:00 through 12:00 day 3. Response speed
      (reciprocal of reaction time) across the 10-min task (by 1-min block) was
      analyzed prior to and after drug administration. RESULTS: A fatigue effect
      (response speed degradation across the 10-min task) was exacerbated by sleep
      deprivation and circadian rhythmicity. Prior to the drug, this effect was maximal
      between 08:00 and 12:00 day 3 (24-28 h sleep deprivation). Modafinil 400 mg
      attenuated fatigue in a manner comparable to that seen with caffeine 600 mg;
      these effects were especially salient during the circadian nadir of performance
      (06:00 through 10:00); modafinil 200 mg also reversed fatigue, but for a shorter
      duration (3 min) than modafinil 400 mg (8 min) or caffeine 600 mg (6 min).
      DISCUSSION AND CONCLUSIONS: Time-on-task effects contributed to the performance
      degradation seen during sleep deprivation; effects which were reversed by
      caffeine and, at appropriate doses, by modafinil. Because the duration of
      efficacy for reversing time-on-task effects was shorter at lower drug dosages,
      the latter must be considered when determining the appropriate dose to use during
      sustained operations.

PMID- 15198279
TI  - Underwater detectibility of a lighting system on a helicopter escape exit.
AB  - BACKGROUND: When a helicopter ditches into water, it immediately inverts due to
      the weight of the engines and then fills with water. Locating the emergency exit
      for escape under such conditions is a difficult task. A new lighting system for
      an escape exit has been developed that illuminates on contact with water. The
      detectibility of the lighting was investigated under varying conditions of
      ambient illumination, water turbidity, and viewing distance. METHOD: A total of
      288 underwater detection trials were carried out by 9 subjects with an
      illuminated hatch placed at 2 distances (1.5 m and 3.1 m), under 2 ambient
      illuminations (bright: > 3000 lux and dark: < 0.1 lux), and in 2 conditions of
      water turbidity. The water temperature was 12 degrees C for all conditions.
      RESULTS: At 1.5 m, the lighting system was detectable in less than 1.5 s by all
      subjects in both clear and turbid water and under both bright and dark
      conditions. At 3.1 m, the lights were detectable in both clear and turbid water
      under the dark condition and in clear water under the bright condition. However,
      the lighting was not reliably detected in turbid water under bright condition.
      CONCLUSIONS: The system met original design requirements in terms of
      detectibility at 1.5 m. The detection time was always under 1.5 s. It could also
      be detected at 3.1 m in clear and turbid water, under dark conditions. However,
      the detectibility at 3.1 m in turbid water, under bright condition was less
      reliable.

PMID- 15198280
TI  - Visual scan patterns during simulated control of an uninhabited aerial vehicle
      (UAV).
AB  - BACKGROUND: This study investigated pilots' visual scan patterns on an
      uninhabited aerial vehicle (UAV) flight display that used moving textbox
      symbology to emulate vertical moving pointers for the primary flight instruments.
      METHODS: Eye tracking measurements were recorded for five instrument-rated
      pilots. Dwell frequencies and mean dwell times were calculated for each
      instrument. The efficiency of instrument information presentation was evaluated
      based on mean dwell times and dwell histograms. The heading indicator, a strict
      digital readout, was used as the reference for pair-wise comparison with the
      moving textbox instruments. RESULTS: Instrument dwell frequencies differed
      significantly (p < 0.005, alpha = 0.006) with the attitude indicator being the
      most frequently scanned instrument followed by the vertical speed indicator, then
      the airspeed, heading, and altitude indicators. There was no difference in mean
      dwell times (p = 0.04-0.79, alpha = 0.008) or dwell histograms between the
      heading indicator and the primary moving textbox instruments. Pilot scan behavior
      was not significantly affected (p > 0.17) by workload. Also, subjects and
      historical controls did not differ (p > 0.30) in their frequency of engine
      instrument dwells. CONCLUSION: The dwell frequencies for the primary flight
      instruments, particularly the vertical speed indicator, differed from those
      reported for more traditional aircraft. The moving textboxes required visual
      fixations that were typical of quantitative instruments, which is a cognitively
      inefficient way to present information. Pilots failed to increase engine
      instrument dwells in the absence of non-visual cues of engine performance, making
      them potentially vulnerable to missing early changes in engine performance.

PMID- 15198281
TI  - Why people 'freeze' in an emergency: temporal and cognitive constraints on
      survival responses.
AB  - BACKGROUND: Many witnesses attest that victims of a disaster often perish despite
      reasonable possibilities for escaping because their behavior during the initial
      moments of the accident was inappropriate to the situation. Frequently witnesses
      report victims 'freezing' in the face of danger. OBJECTIVE: The aim of this paper
      was to identify the possible factors underpinning 'freezing' behavior in disaster
      victims. METHODS: Witness testimonies, survivor debriefings, and official inquiry
      reports from shipwreck and aircraft emergencies were analyzed for their
      behavioral content. RESULTS: It was found that 'freezing' behavior was a
      frequently cited response by witnesses to a disaster. 'Freezing' causes
      evacuation delays which increase the danger, establishing a closed loop process
      and further extending evacuation delays. This behavior can be accounted for by
      considering the temporal constraints on cognitive information processing in a
      rapidly unfolding, real-time environment. CONCLUSION: Cognitive limitations help
      to explain why survival training works and why there is a need for a survival
      culture to be developed. They also highlight the need to understand the behavior
      of children under threat as being different from that of adults due to the
      different stages of their neurological and cognitive development. There are
      implications for the development of proactive, rather than passive, life support
      equipment.

PMID- 15198282
TI  - Intraocular pressure measured at ground level and 10,000 feet.
AB  - BACKGROUND: Intraocular pressure (IOP) may be subject to change during altitude
      exposure. This may be an important consideration for long-haul flights. In this
      study, intraocular pressure change was investigated following exposure to an
      altitude of 10,000 ft during flight in an unpressurized aircraft. METHODS: We
      measured the IOP of the right eye of 20 healthy volunteers (18 men, 2 women; mean
      age 34.6 +/- 9.5 yr) at a ground level of 1,760 ft (536 m) above the sea level
      (ASL) using a Tono-Pen XL tonometer. We then repeated the measurements during a
      flight in the unpressurized cabin of a CASA (CN235-100 M) aircraft after gaining
      an altitude of 10,000 ft (3,048 m) ASL. Changes in the IOP were evaluated.
      RESULTS: Mean IOP was 16.2 +/- 2.46 mmHg at ground level and 15.0 +/- 2.61 mmHg
      at 10,000 ft (3,048 m) ASL. IOP was reduced in 13 eyes, increased in 6 eyes, and
      remained unchanged in 1 eye. The mean change in IOP was 1.2 +/- 2.69 mmHg.
      However, this was not statistically significant (p = 0.06). CONCLUSION: Acute
      change in altitude resulted in a statistically non-significant reduction in IOP
      in healthy subjects.

PMID- 15198283
TI  - Cardiopulmonary resuscitation in microgravity: efficacy in the swine during
      parabolic flight.
AB  - INTRODUCTION: The International Space Station will need to be as capable as
      possible in providing Advanced Cardiac Life Support (ACLS) and cardiopulmonary
      resuscitation (CPR). Previous studies with manikins in parabolic microgravity (0
      G) have shown that delivering CPR in microgravity is difficult. End tidal carbon
      dioxide (PetCO2) has been previously shown to be an effective non-invasive tool
      for estimating cardiac output during cardiopulmonary resuscitation. Animal models
      have shown that this diagnostic adjunct can be used as a predictor of survival
      when PetCO2 values are maintained above 25% of pre-arrest values. METHODS: Eleven
      anesthetized Yorkshire swine were flown in microgravity during parabolic flight.
      Physiologic parameters, including PetCO2, were monitored. Standard ACLS protocols
      were used to resuscitate these models after chemical induction of cardiac arrest.
      Chest compressions were administered using conventional body positioning with
      waist restraint and unconventional vertical-inverted body positioning. RESULTS:
      PetCO2 values were maintained above 25% of both 1-G and O-G pre-arrest values in
      the microgravity environment (33% +/- 3 and 41 +/- 3). No significant difference
      between 1-G CPR and O-G CPR was found in these animal models. Effective CPR was
      delivered in both body positions although conventional body positioning was found
      to be quickly fatiguing as compared with the vertical-inverted. CONCLUSIONS:
      Cardiopulmonary resuscitation can be effectively administered in microgravity (0
      G). Validation of this model has demonstrated that PetCO2 levels were maintained
      above a level previously reported to be predictive of survival. The
      unconventional vertical-inverted position provided effective CPR and was less
      fatiguing as compared with the conventional body position with waist restraints.

PMID- 15198284
TI  - Measurement of force exerted on footplates by centrifuge subjects.
AB  - INTRODUCTION: Increased G-tolerance in flight is usually achieved by isometric
      contraction of the muscles of the abdomen and of lower extremities, along with
      forceful expiration against a closed or partially closed glottis. Measurement and
      analysis of the forces developed by a pilot's leg muscles during +Gz acceleration
      is one of the steps needed to develop specialized physical conditioning programs.
      METHODS: We developed a system for continuous measurement of forces exerted on
      simulated rudder pedals in a human centrifuge. RESULTS: Data from five test
      subjects showed that the system could measure left-right asymmetry as well as
      individual differences in pressure patterns during acceleration. DISCUSSION: The
      results suggest that the measurement system could be useful in training pilots to
      increase the effectiveness of their anti-G straining maneuvers. Specifically, the
      system may help pilots learn to adjust their effort to the G profile.

PMID- 15198285
TI  - Midodrine prescribed to improve recurrent post-spaceflight orthostatic
      hypotension.
AB  - Many astronauts exhibit post-spaceflight orthostatic hypotension due to
      inadequate norepinephrine release when in an upright posture. We hypothesized
      that an alpha1-adrenergic agonist, midodrine, would be an effective
      countermeasure. A female astronaut, who had problems with postflight orthostatic
      hypotension after a previous flight, consumed 10 mg midodrine after a subsequent
      flight, prior to her tilt test. Hemodynamic variables were compared between the
      two flights. Midodrine prevented severe falls in stroke volume, cardiac output
      and systolic pressure, and severe increases in heart rate without increasing
      vascular resistance, thus preventing orthostatic hypotension. This is the first
      report showing that midodrine has the potential to improve post-spaceflight
      orthostatic hypotension and suggesting that reduced venous return contributes to
      the etiology.

PMID- 15198286
TI  - Training the fleet to survive--new initiatives in Naval Aviation Survival
      Training.

PMID- 15198287
TI  - This month in aerospace medicine history--June 2004.

PMID- 15198289
TI  - Testicular adrenal rest tumours.

PMID- 15198288
TI  - Anatomical studies of the female genitalia: surgical reconstructive implications.
AB  - Surgery for patients with genital ambiguity must be based on an accurate
      diagnosis, thorough understanding of the genital anatomy and realistic
      expectations for the patient, family and treating multi-specialty team. The goal
      is to create a functional and cosmetic outcome consonant with the gender
      assignment with the least amount of morbidity to the patient and family. An
      understanding of the normal genital neuroanatomy is essential for a successful
      surgical approach and outcome. Based on fetal human specimens, we have refined
      the three-dimensional relationship of the dorsal nerve of the clitoris, the
      female cavernosal nerve and the vaginal plexus. The surgical approach to patients
      with severe clitoral virilization should preserve erectile function and the
      neural innervation of the clitoris. When indicated, surgery should be performed
      in infancy to minimize psychological trauma and surgical complications from
      scarring. Herein, we review the neuroanatomy of the female genitalia and the
      implications for the rare patient who needs surgical reconstruction.

PMID- 15198290
TI  - Growth hormone improves body composition and motor development in infants with
      Prader-Willi syndrome after six months.
AB  - BACKGROUND: Infants with Prader-Willi syndrome (PWS) show abnormalities of body
      composition. Children with PWS treated with growth hormone (GH) demonstrate
      improved body composition and motor skills. OBJECTIVE: To assess body composition
      and motor changes in infants with PWS following 6 months GH therapy. METHODS:
      Twenty-five infants with PWS (mean age 15.5 mo) underwent dual energy X-ray
      absorptiometry (DEXA) assessment of body composition, and motor assessment with
      the Toddler Infant Motor Evaluation (TIME). Patients were then randomized to
      treatment (Genotropin, 1 mg/m2/day) or control, with reassessment at 6 months.
      RESULTS: GH treatment significantly increased lean body mass (6.4 +/- 2.4 kg to
      8.9 +/- 2.7 kg) and decreased body fat (27.6 +/- 9.9% to 22.4 +/- 10.3%). Age
      equivalent motor scores improved 4 months in the treated group vs 2 months in
      controls (p < 0.01). CONCLUSIONS: Infants with PWS show significant body
      composition and motor development improvement following 6 months GH therapy. We
      are investigating whether this improvement leads to long-term reductions in
      obesity.

PMID- 15198291
TI  - Growth hormone deficiency in patients with sickle cell disease and growth
      failure.
AB  - BACKGROUND: Growth disorders are common in children with sickle cell disease
      (SCD). The etiology for growth disturbances in this population appears to be
      multifactorial. Recent evidence suggests abnormalities in the growth hormone
      (GH)/insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3)
      axis may play a role. OBJECTIVE: To measure GH levels through provocative
      stimulation in a group of patients with SCD with growth failure, and to evaluate
      response to treatment. PATIENTS AND METHODS: Growth records were reviewed of 79
      children with sickle cell hemoglobinopathies to identify children with growth
      failure. GH levels were measured in patients with SCD with and without growth
      failure using arginine and L-Dopa as provocative stimulation tests. Treatment
      with GH was offered to GH-deficient children with SCD and these patients were
      followed longitudinally over 5 years. RESULTS: Of the 79 patients, 13 (16.5%, all
      SS) had heights less than -2 SD below the mean or a growth velocity < -2 SD below
      the mean for age. Seven of the 13 children with growth failure participated in
      this study. Five patients received GH for 3 or more years and demonstrated
      significant improvement in their height SDS. One of the two who declined
      treatment was lost to follow-up and the other had significant worsening of height
      SDS score. CONCLUSION: GH deficiency may be associated with growth failure in
      some patients with SCD. These patients may benefit from treatment with GH.

PMID- 15198292
TI  - Sex steroid hormones, growth and puberty in children with portal hypertension.
AB  - Perturbations in sex hormones occur in adults with liver disease; however, little
      is known about how liver disease affects hormone levels in children. To address
      this issue, we recruited 19 patients with portal hypertension and 21 non-hormone
      deficient short children as controls. Serum sex hormones, sex hormone binding
      globulin (SHBG), IGF-I, IGFBP-3, gonadotropins, and thyroid hormones were
      measured; growth and pubertal status were recorded. There was no significant
      difference between groups for any of the sex hormones, SHBG, gonadotropins, or
      thyroid hormones. In contrast, IGF-I and IGFBP-3 were significantly lower among
      patients than controls, despite the fact that height SDS for the control group
      was significantly lower. We conclude from this cross-sectional study that
      children with portal hypertension do not have clinical evidence of growth failure
      or abnormal puberty, despite subtle changes in the growth axis.

PMID- 15198293
TI  - Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid
      labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical
      characteristics of Sotos syndrome.
AB  - OBJECTIVE: Sotos syndrome is an overgrowth syndrome of poorly understood
      aetiology. We investigated whether this syndrome is related to alterations in
      plasma insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), acid
      labile subunit (ALS) and serum IGFBP-3 proteolysis. DESIGN: Based on clinical
      criteria, 32 patients with clinical characteristics of Sotos syndrome (median age
      8.4 years, range 1.8-48.4) were categorised into three groups: typical (n = 10,
      group 1), dubious (n = 12, group 2) and atypical (n = 10, group 3). Blood samples
      were obtained from 29 patients. MEASUREMENTS: Plasma IGF-I, IGF-II, E-II (pro-IGF
      II and E-domain fragments), IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6 and ALS were
      measured by specific radioimmunoassays (RIAs). Except for E-II immunoreactivity,
      the concentrations were compared with those of age references, and expressed as
      standard deviation scores (SDS). IGFBP-3 proteolysis was assessed by incubation
      of serum with [125I]-IGFBP-3, followed by gel electrophoresis and was then
      compared with that in normal serum and third trimester pregnancy serum. RESULTS:
      Patients in group 1 showed significantly reduced plasma levels of IGF-II (median 
      0.9 SDS; p = 0.01), IGFBP-4 (-0.5 SDS; p = 0.02) and IGFBP-3 (-1.0 SDS; p =
      0.01). Mean IGFBP-3 proteolysis was higher than in normal standard serum (61% vs
      37%; p < 0.01) but lower than in third trimester pregnancy serum (94%; p < 0.01).
      Plasma IGF-I showed a tendency towards low values (median -0.9 SDS; p = 0.09),
      IGFBP-6 and ALS a tendency towards elevated levels (median values +0.8 SDS; p =
      0.07 and +2.3 SDS; p = 0.09), and IGFBP-2 was normal. The mean value of E-II
      immunoreactivity was 8.7 nmol/l, similar to that in pooled normal plasma (8.6
      nmol/l). Plasma and serum parameters in groups 2 and 3 were similar to reference
      values with the exception of plasma IGFBP-3 (in groups 2 and 3 median < or = -1.1
      SDS; p < or = 0.02) and ALS (in group 3 median +1.3 SDS; p < 0.01). CONCLUSIONS:
      Patients with typical Sotos syndrome show low plasma IGF-II, IGFBP-3, IGFBP-4,
      and increased proteolysis of IGFBP-3 in serum. The extent to which these findings
      are associated with the pathophysiology of Sotos syndrome remains uncertain.

PMID- 15198294
TI  - Neonatal hypoglycemia in a growth hormone registry: incidence and pathogenesis.
AB  - OBJECTIVE: To examine the characteristics of infants with neonatal hypoglycemia
      treated with growth hormone (GH) in order to gain insights into factors aiding in
      the identification of and timely treatment of hypopituitary neonates. STUDY
      DESIGN: The National Cooperative Growth Study (NCGS) database was examined to
      identify infants with neonatal hypoglycemia started on GH by 6 months of age. 169
      infants (100 males, 69 females) were found and their data analyzed for physical
      characteristics, the presence of other hormone deficits, and the diagnostic
      methods used. RESULTS: Mean +/- SD baseline length standard deviation score (SDS)
      was -1.5 +/- 1.8. 148/169 infants had hypopituitarism. Twelve had isolated GH
      deficiency (GHD). Nine had hypoglycemia without hypothalamic or pituitary
      pathology. Structural central nervous system (CNS) lesions and/or midline facial
      defects were present in 66/169. 55/100 males had micropenis. Although 158 infants
      had GHD, only 90 infants had it documented by stimulation testing (80) or a
      critical sample when hypoglycemic (10). Multiple hormone replacement therapy was
      necessary in 89% of the hypoglycemic infants. CONCLUSIONS: The great majority of
      these hypoglycemic infants had GHD, usually secondary to hypopituitarism. Over
      1/3 had structural lesions of the hypothalamic-pituitary area or midline facial
      defects. Although lengths may be normal in these infants, physical features such
      as micropenis or cleft lip and/or palate should suggest pituitary dysfunction as
      the etiology of their hypoglycemia. A critical blood sample for GH taken during
      hypoglycemia is a quick and definitive diagnostic tool.

PMID- 15198295
TI  - Growth hormone secretion and long-term growth data in children with psychosocial
      short stature treated by different changes in environment.
AB  - OBJECTIVES: We assessed auxological and endocrine data of 65 children (32 girls)
      from 51 families with an average age of 6.6 years (range, 0.9 to 16.5 years, all
      but five prepubertal) with psychosocial short stature. METHODS: Fifty-one
      patients had an assessment of growth hormone (GH) secretion. Thirty-four were
      subjected to repeated testing with the first test being performed when the child
      was still in the adverse environment and the next testing after the child was
      removed. Twenty-five out of those 34 were repeatedly tested during one
      uninterrupted hospital admission with limited parental access. Thirty patients
      had a definite, long-term change in their environment (13 were separated from
      their families) and were assessed concerning their auxological data. RESULTS: Of
      the 34 patients who had repeated endocrine testing, 11 (32%) showed reversible GH
      deficiency (GHD), nine (26%) increased their previously normal peak GH
      concentration, and six (18%) had apparently irreversible GHD. Patients who had a
      change in environment increased their mean height velocity SDS from -0.9 (SD 1.5)
      to +1.5 (2.3) (p < 0.0001). Accordingly, height SDS increased from -2.9 (SD 0.8)
      before to -2.6 (SD 0.8) after the change (p < 0.001). CONCLUSION: One of the
      diagnostic features of psychosocial short stature is reversible GH insufficiency,
      which usually normalises after the child is separated from the adverse
      environment. Catch-up growth is always found after a positive change in the
      environment, and may occur within the family. However, if a change in environment
      is not possible, GH therapy may be an option.

PMID- 15198296
TI  - Asymptomatic testicular adrenal rest tumours in adolescent and adult males with
      congenital adrenal hyperplasia: basal and follow-up investigation after 2.6
      years.
AB  - AIM: To study the course of asymptomatic testicular adrenal rest tumours in
      patients with congenital adrenal hyperplasia (CAH) and the association between
      tumour changes and glucocorticoid therapy adjustments. PATIENTS AND METHODS:
      Fifteen male patients with CAH (21-hydroxylase deficiency), in whom asymptomatic
      testicular adrenal rest tumours had been found at a baseline investigation,
      underwent scrotal ultrasonography and venous blood sampling (for LH, FSH and
      testosterone) on average 2.6 years later. The level of hormonal control was
      assessed by measurement of androstenedione in three diurnal saliva samples. Data
      on changes in glucocorticoid therapy since baseline were obtained from the
      patients' records. RESULTS: Tumour decrease, defined as > or =30% decrease in the
      sum of the longest diameter(s) of the lesion(s), was found in six patients;
      tumour increase, defined as > or =20% increase, in six and stable tumours in
      three patients. All three patients with overtreatment showed tumour decrease and
      of the six patients with undertreatment only one showed tumour decrease. Tumour
      increase was not only observed in undertreated patients but also in patients with
      adequate treatment. Changing the night dose of hydrocortisone into dexamethasone,
      to obtain prolonged ACTH suppression, had resulted in better adrenal suppression
      in only one patient. CONCLUSIONS: Tumour decrease could be achieved by aiming at
      adrenal oversuppression, but the required high glucocorticoid doses may induce
      side effects. In asymptomatic tumours in young male patients with CAH, a
      practical guideline could be to optimise adrenal suppression to a maximal
      tolerable glucocorticoid dose and to offer analysis and cryopreservation of semen
      as soon as the patient can be motivated.

PMID- 15198297
TI  - Reversibility of thyrotroph hyperplasia after L-thyroxine replacement therapy in
      patients with juvenile primary hypothyroidism.
AB  - Thyrotroph cell hyperplasia in primary hypothyroidism though well described is
      often not discussed as it remains clinically silent. This hyperplasia in long
      standing juvenile primary hypothyroidism presenting as 'pituitary tumor' is very
      uncommon. We report four patients with juvenile primary hypothyroidism, who were
      detected to have sellar/suprasellar masses on imaging performed for unrelated
      symptoms, and complete resolution in three of them after L-thyroxine replacement
      therapy.

PMID- 15198298
TI  - The management of sellar masses: not all pituitary tumours require surgery for
      diagnosis and/or therapy.

PMID- 15198299
TI  - Transient hypothyroidism in a breastfed infant after maternal use of iodoform
      gauze.
AB  - We describe transient hypothyroidism induced in a 2 week-old breastfed infant by
      maternal use of iodoform gauze for a perirectal abscess. The initial newborn
      thyroid screen was normal. Low levels of thyroid hormone were discovered during a
      routine second newborn screen. Thyroid function has since normalized with short
      term therapy with thyroxine and after the mother discontinued use of the packing
      iodoform gauze. This case illustrates the need to avoid iodine-containing
      products in breastfeeding mothers.

PMID- 15198300
TI  - Hypothyroidism in siblings due to a homozygous mutation of the TSH-beta subunit
      gene.
AB  - We report two American sisters of Scottish-Irish ancestry with isolated
      thyrotropin (TSH) deficiency. The diagnosis of central congenital hypothyroidism
      was based on low levels of TSH and free thyroxine. Sequencing of the TSH-beta
      subunit gene revealed a homozygous single nucleotide deletion in codon 105,
      producing a frame shift and resulting in inactive TSH. This mutation has
      previously been reported in a Brazilian family, two German families, and a
      Belgian family. Our case, along with a review of the other reports, supports the
      theory that this mutation may be a common cause of isolated TSH deficiency.

PMID- 15198301
TI  - Maternal activating mutation of the calcium-sensing receptor: implications for
      calcium metabolism in the neonate.
AB  - Two infants were studied born of a mother with autosomal dominant hypocalcemia
      who is heterozygous for an activating mutation in the calcium-sensing receptor
      gene. Both infants had serum calcium levels in the low-normal range and
      parathyroid hormone levels in the high-normal range and were healthy. The
      mother's hypocalcemia had been treated with calcium carbonate and calcitriol and
      she has nephrocalcinosis and mild renal insufficiency. By genetic testing, both
      infants were shown to have normal calcium-sensing receptor gene alleles, i.e.,
      they had not inherited the activating mutation from their mother. This provided
      reassurance to the family and ensured that treatment to correct apparent
      hypocalcemia would not be necessary. The fact that the infants had high normal
      parathyroid hormone levels with normal calcium may be due to the fact that with a
      normal calcium-sensing receptor their parathyroid glands responded in utero to
      the maternal hypocalcemia with an increase in parathyroid hormone.

PMID- 15198302
TI  - Pseudo-precocious puberty caused by a juvenile granulosa cell tumour secreting
      androstenedione, inhibin and insulin-like growth factor-I.
AB  - We report a female child who presented at age 3.92 years with a 2-year history of
      consonant pubertal development caused by a large right-sided ovarian juvenile
      granulosa cell tumour (JGCT). Although JGCTs causing pseudo-precocious puberty
      have been previously described, they remain rare and endocrine data are often
      incomplete. In this case the tumour was associated with raised serum oestradiol,
      androstenedione, inhibin and IGF-I. Histological changes were consistent with
      JGCT. Immunohistochemical studies revealed positive reactivity to MIC-2, inhibin,
      melan A, IGF-I and IGFBP-2.

PMID- 15198303
TI  - The Third European Growth Plate Working Group Symposium. 17th September 2003,
      Ljubljana, Slovenia.

PMID- 15198304
TI  - Effect of venom from the scorpion Leiurus quinquestriatus on rat vascular aortic
      rings.
AB  - The present study was designed to examine the effects of venom from the scorpion
      Leiurus quinquestriatus hebraeus (Lqh) on the contractility of rat aortic rings.
      We first examined the effect of Lqh venom on the contractile tension of isolated
      rat vascular aortic rings and then whether long-term exposure to the venom
      reduces the contractility of vascular smooth muscle by increasing the production
      of nitric oxide. Following the administration of 33 microg/mL of crude Lqh venom,
      contractile tension increased by 18.9 +/- 11.4 percent. The administration of 2.4
      x 10(-7) M noradrenaline (NA) led to a 31.6 +/- 8.2 percent increase in tension
      (p < 0.01). The effects induced by NA and Lqh venom were similar and additive (p
      < 0.01). Pretreatment with the alpha-adrenergic blocker phenoxybenzamine (0.2
      microM) eliminated the effect of the venom, whereas the calcium-channel blocker
      verapil (8.3 microM) merely attenuated the effect. Incubation of the rings with
      Lqh venom for 16 to 18 h, followed by NA stimulation, led to a 15 to 20 percent
      decrease in tension (p < 0.001). Treatment with N-omega-nitro-L-arginine methyl
      ester (110 microM), a constitutional nitric oxide inhibitor, restored the tension
      to control values. Treatment with S-methyl-isothiourea (0.1 microM), an inducible
      nitric oxide synthesis inhibitor, had no effect on contractile tension. The
      results of the present study suggest that the effect of Lqh venom on isolated
      aortic rings is induced via sympathetic nerve terminals. Calcium had little
      effect on the smooth muscle contractility of aortic rings incubated with the
      venom. No evidence was found to support nitric oxide synthesis after the long
      term exposure of the rings to Lqh venom.

PMID- 15198305
TI  - Captopril and enalapril improve cognition and depressed mood in hypertensive
      patients.
AB  - In this study, we evaluate the effects of two angiotensin converting enzyme
      inhibitors (ACEIs), captopril and enalapril given chronically as antihypertensive
      treatment, on certain cognitive and emotional processes in humans. Thirty-nine
      subjects with mild to moderate hypertension and fifteen normotensive controls
      were divided into four groups consisting of normotensive and hypertensive
      subjects taking captopril, enalapril, or no medication at all. The Rey Auditory
      Verbal Learning Test and the Wechsler Memory Scale were used to evaluate their
      cognitive functioning. Mood changes in all subjects were assessed using the Beck
      Depression Inventory and the Hopkins Symptom Check- list (HSC). RESULTS:
      Untreated hypertensive patients scored lower than normotensive controls in
      cognitive tests and significantly worse in cumulative recall (P < 0.05) and
      paired words association (P < 0.01). When compared with normotensive subjects,
      untreated hypertensive patients also scored significantly higher on the
      depression with anxiety subscale in HSC (P < 0.05). No significant influence of
      hypertension was found in any other examined aspect of cognition and mood. In
      most cases captopril improved and enalapril reversed the adverse memory effects
      of hypertension. High arterial blood pressure is significantly associated with an
      impairment of cognition and the occurrence of depression with anxiety in humans.
      Enalapril and, to a lesser extent, captopril reversed these deficits.

PMID- 15198307
TI  - Facial wound closure with butyl 2-cyanoacrylate.
AB  - Butyl 2-cyanoacrylate (B2-CA), one of the least histotoxic cyanoacrylate
      derivatives used as a tissue adhesive extensively for facial and plastic,
      otolaryngological and dental surgery, produces a mild inflammatory response and
      is biodegradable. In this study, we histopathologically compared B 2-CA to suture
      on facial wounds of 21 rabbits. Two facial incisions were made on the chins. Left
      incisions were sutured (control group) and right ones were treated with B 2-CA
      (experimental group). The animals were divided into 7 groups and were sacrificed
      on days 1, 2, and 5 and weeks 1, 2, 3, and 4 after surgery. The wound areas were
      examined histopathologically for the epithelization, inflammation, granulation
      response, and for foreign body giant cells. Gradation of the histopathological
      findings yielded no significant difference between the experimental and control
      groups. Hence, we conclude that B2-CA used on facial wounds shows no more
      histotoxicity than sutures. Thus, B2-CA could provide an alternative and a
      possible superior method for closing incisions of facial and plastic surgery. In
      addition, B2-CA has the advantages of ease of application, immediate homeostasis,
      and excellent cosmetic results.

PMID- 15198306
TI  - The role of cholesterol on the pressure sensing ability of kidneys in rats.
AB  - We studied the effect of hypercholesterolemia on the pressure-sensing and
      regulating ability of the kidneys, using an acute hemorrhage model to provide 40%
      and 60% reduction in the blood pressure of hypercholesterolemic and control rats.
      The control group (n = 22) was fed a normal rat pellet diet and tap water; the
      experimental group (n = 22) received a diet containing 2% cholesterol/0.2%
      thaurocholate. Half the animals were subjected to 6 mL/kg bw and the others to 12
      mL/kg bw of bleeding for 1 min. Blood pressure recording and proper samplings
      were done before bleeding and during the 20 min post-hemorrhagic period for
      analysis. Despite a finding of hypercholesterolemia in the experimental group,
      kidney cholesterol content as well as its function remained unchanged. Following
      an initial 40% decrease in rats bled 6 mL/kg bw, 20 min later the mean blood
      pressure returned to 90% of its initial value in control rats and to 70% of its
      basal level in hypercholesterolemic rats. A similar delay in pressure
      normalization occurred in rats subjected to 12 mL/kg of bleeding. Plasma renin
      activity remained unaffected. We conclude that dietary hypercholesterolemia
      delays the normalization of blood pressure after hemorrhage without affecting the
      sensing ability of kidneys, and that the kidneys are less sensitive than other
      organs to plasma cholesterol levels.

PMID- 15198308
TI  - Effect of edifenphos on compensatory ovarian hypertrophy, follicular kinetics and
      estrous cycle in hemicastrated rats.
AB  - Edifenphos, an organophosphate fungicide, was administered to hemicastrated
      albino rats intraperitoneally for 15 consecutive days in graded doses of 2 to 8
      mg/kg body weight. In the oil-treated hemicastrated control group, ovarian weight
      and total number of healthy and atretic follicles were significantly higher than
      the same parameters in sham-operated control animals, and the estrous cycle was
      normal. Treatment with 2, 4, 6, or 8 mg/kg/d edifenphos significantly decreased
      ovarian weight (-6.75, -9.79, -18.71, and -34.13 percent, respectively) below
      that of the controls. Although treatment with 2 or 4 mg/kg/d edifenphos did not
      change the number of healthy and atretic follicles, a dosage of 4 mg/kg/d
      significantly decreased the number and duration of estrous cycles. Treatment with
      6 or 8 mg/kg/d, however, significantly decreased the number and duration of
      different phases of the estrous cycle as well. In all treated groups, the weights
      of the thymus and uterus were significantly reduced when compared with those of
      hemicastrated oil-treated control animals.

PMID- 15198310
TI  - Surveillance for antimicrobial resistance: DEFRA sets out its strategy.

PMID- 15198309
TI  - Azadirachta indica adversely affects sperm parameters and fructose levels in vas
      deferens fluid of albino rats.
AB  - Azadirachta indica treatment for 24 days in albino rats resulted in a decrease in
      the total sperm count, sperm motility, and forward velocity in vas deferens
      fluid. The percentage of abnormal sperm increased and the fructose content
      decreased. As diminished levels of fructose parallel androgen deficiency, we
      conclude that reduced androgen levels resulting from the anti-androgenic property
      of A. indica leaves probably influences the physiological maturation of sperm.

PMID- 15198311
TI  - Developments in the teaching of animal welfare.

PMID- 15198312
TI  - Use of a topical disinfectant as part of a hoof care programme for horses with
      diseases of the hoof capsule.
AB  - Twenty-three horses with persistent hoof horn defects were treated topically with
      a hoof disinfectant as part of a hoof care programme for a year. The active
      ingredients of the disinfectant were a poloaximer-iodine complex, ethylenediamine
      dihydriodide, isopropyl alcohol and propylene glycol. Hoof trimmings were taken
      at the start of the study and every six weeks, and examined by scanning and
      transmission electron microscopy. At the beginning of the study all the horn
      samples contained large numbers of bacteria, and samples from eight of the horses
      also had fungal hyphae intermingled with the bacteria. After the application of
      the hoof disinfectant and adjustments to their diet, there were rapid
      improvements in the gross appearance of the feet of all the horses; some of them
      improved within two to three weeks and by 12 weeks the horn quality of all the
      horses had greatly improved.

PMID- 15198313
TI  - Effects of three types of trace element supplementation on the fertility of three
      commercial dairy herds.
AB  - The effects on the fertility of three commercial dairy herds of three types of
      copper- and selenium-containing mineral supplements was investigated. As the cows
      on each farm were dried off they were allocated to one of three treatment groups,
      and treated with either subcutaneous injections of copper and selenium, or two
      matrix intraruminal trace element boluses, or two glass intraruminal trace
      element boluses. When the data from the 406 cows on the three farms were
      combined, there was a significant difference between the conception rates of the
      three groups (P < 0.001). The cows treated with the glass boluses conceived at a
      rate 1.8 times greater than those treated by injection (P < 0.001), and at a rate
      1.5 times greater than those treated with matrix boluses (P = 0.002). These
      differences were associated with a significantly higher likelihood of service
      resulting in a conception in the group treated with glass boluses than in the
      group treated by injection (P = 0.004). After adjusting for time from calving,
      time from treatment, time of year and farm, there was a significant (P = 0.012)
      difference in glutathione peroxidase activities between the treatments, with the
      group treated by injection having a significantly lower activity than the groups
      treated with boluses.

PMID- 15198314
TI  - Cleft palate associated with an unbalanced karyotype in piglets sired by a
      heterozygous carrier boar with a balanced constitutional reciprocal
      translocation.
AB  - The progeny of a commercial (Landrace x Duroc) x Large White boar contained a
      number of piglets with cleft palates. Chromosomal analyses of five affected
      piglets showed that they all had an identical unbalanced karyotype with partial
      monosomy of chromosome 16 and partial trisomy of chromosome 3, whereas the normal
      piglets in the litters had balanced karyotypes. The chromosomal imbalance was the
      direct result of a constitutional balanced reciprocal translocation carried by
      their heterozygote sire, described, according to the standard nomenclature, as
      t(3;16)(q23;q22).

PMID- 15198315
TI  - Histamine as an aid to biopsy of third eyelid lymphoid tissue in sheep.

PMID- 15198316
TI  - Field anaesthesia of three Australian species of flying fox.

PMID- 15198317
TI  - Distribution of serotypes of Streptococcus suis isolated from diseased pigs in
      Spain.

PMID- 15198318
TI  - Electrolyte concentrations after intravenous calcium infusions in cows with
      parturient paresis.

PMID- 15198319
TI  - Traumatic oesophageal perforation in a male ostrich (Struthio camelus australis).

PMID- 15198320
TI  - Streptococcus agalactiae infection in dairy cows.

PMID- 15198321
TI  - Hyperparathyroidism in the keeshond dog.

PMID- 15198322
TI  - Mathematical approach to oxygen purchase.

PMID- 15198323
TI  - Non-agricultural use of pesticides--environmental issues and alternatives.
      Proceedings of an international symposium. May 7-9, 2003. Copenhagen, Denmark.

PMID- 15198324
TI  - Contribution of non-agricultural pesticides to pesticide load in surface water.
AB  - Two small creeks, tributaries of the River Ruhr near Schwerte, Federal Republic
      of Germany, were investigated to reveal the regional agricultural and non
      agricultural sources of pesticide inputs and the main pathways to surface water.
      In addition, the receiving water was monitored for pesticides. The watersheds are
      situated at the northern margin of the Rhenian Schiefergebirge, a highland
      landscape in North-Rhine-Westphalia. Solid carboniferous shale is covered by a
      shallow layer of quaternary unconsolidated rock (porous aquifer thickness <5 m).
      Occurrence of herbicides such as chlortoluron, isoproturon and terbuthylazine in
      surface water could be due to their broad agricultural application in regional
      dominant crops, such as barley, wheat and maize. Occurrence of diuron and
      glyphosate results from their use in residential settlements and industrial areas
      as well as from weed control on railway tracks. Atrazine concentrations up to 0.8
      microg litre(-1) indicated recent use of this herbicide, which has been banned
      since 1991, and was also the result of non-agricultural applications. Pathways
      for pesticide input to the receiving waters were related to both surface run-off
      and underground passage. Two-thirds of the observed diuron load in the surface
      water resulted from an input by run-off. This was expected as a result of total
      herbicide application targets to sealed surfaces infringing current regulations
      and recommendations. Diuron load varied between 0.6 and 1.2% of the estimated
      amount applied annually in the investigated catchments. Non-agricultural
      pesticide use contributed more than two-thirds of the whole observed pesticide
      load in the tributaries and at least one-third in the River Ruhr.

PMID- 15198325
TI  - Pesticides in surface water runoff in south-eastern New York State, USA: seasonal
      and stormflow effects on concentrations.
AB  - Samples from two streams (Kisco River and the Middle Branch of the Croton River)
      in the Croton Reservoir system in south-eastern New York State, USA were sampled
      from May 2000 through to February 2001 in order to document the effect of land
      use, streamflow and seasonal patterns of application on pesticide concentrations
      in runoff from developed watersheds. Many of the pesticides detected most
      commonly in this study are generally used in developed areas, and particularly on
      turfgrass. Pesticide concentrations were generally higher, and the numbers of
      compounds were generally larger, in samples from the Kisco River than in samples
      from the Middle Branch, probably because the Kisco River drainage has a greater
      population density and is more extensively developed. Four pesticides (2,4-D, 2,4
      D-methyl, dicamba and metalaxyl) were detected in at least one sample from the
      Kisco River at a concentration >1 microg litre(-1), and no pesticides were
      detected at concentrations >0.4 microg litre(-1) in Middle Branch samples. No
      human-health-based water-quality standards were exceeded by samples from either
      site in this study, but samples from the Kisco River contained four insecticides
      (carbaryl, chlorpyrifos, diazinon and malathion) and one herbicide (2,4-D) in
      concentrations that exceeded water quality criteria for the protection of aquatic
      life. The highest concentrations of most compounds occurred during stormflows in
      both streams in June, September and December, 2000. The lowest concentrations of
      most compounds at both sites occurred during baseflows from October 2000 through
      February 2001, even though the concentrations of many compounds increased
      substantially at the Kisco River site during stormflows in November and December.
      Detailed data on the variability of pesticide concentrations during stormflows
      indicate that there may be two sources of pesticides in the Kisco River
      watershed: (1) elevated concentrations of pesticides during peak flows that occur
      early in stormflows likely reflect runoff from paved areas, and (2) elevated
      concentrations during peak flows that occur later in stormflows from areas with
      lesser amounts of pavement. Data from the Kisco River indicate that the relation
      between storm discharge and pesticide concentrations varies among compounds, in
      part because of variation in seasonal application patterns. These variations in
      the timing of application result in not all stormflows producing increased
      concentrations of pesticides. Overall, these results indicate the importance of
      stormflow sampling throughout the year in assessing pesticide fate and transport
      in urbanized, developed areas.

PMID- 15198326
TI  - The fate of imazapyr in a Swedish railway embankment.
AB  - The long-term fate of the herbicide imazapyr [2-(4-isopropyl-4-methyl-5-oxo-2
      imidazolin-2-yl)nicotinic acid] applied to a Swedish railway embankment was
      studied. Imazapyr was applied at 750 and 1500 g ha(-1) by a spraying train used
      for full-scale herbicide treatment operations. Soil and groundwater were sampled
      twice a year for 8 years after application of the herbicide, and the dissipation
      of imazapyr was studied by HPLC analysis of the residues in soil and groundwater.
      A clean-up procedure including solid-phase extraction was performed prior to
      detection by HPLC. Recoveries of imazapyr from soil and water samples were 76-98%
      and 61-90%, respectively, and detection levels were 0.003 mg kg(-1) and 0.05
      microg litre(-1), respectively. Sorption, desorption and microbial amount and
      activity were also measured at the two locations. The organic matter content
      correlated positively and the pH negatively to the adsorption of imazapyr on
      soil, and increasing organic matter contents decreased desorption. Apart from the
      0-10-cm top layers of both sites, the microbial amount and activity were small.
      The main proportion of imazapyr was found in the upper 30 cm of the soil, and
      degraded with a half-life in the range 67-144 days. Small amounts were
      transported to lower soil layers and to the groundwater in proportion to the
      amounts applied. Traces of imazapyr were detected in the groundwater even 8years
      after application. It was concluded that environmental risks from the use of
      herbicides on railway embankments could be reduced by including adsorption layers
      in the embankment during their construction and by reducing the dose of the
      herbicide used.

PMID- 15198327
TI  - Microbial biomass and activity on railway track and embankments.
AB  - The spatial distribution of microbial biomass and microbial activity was studied
      in two Swedish railway embankments (located close to Mora and Nassjo). Basal
      respiration and substrate-induced respiration (SIR) as well as the active (r) and
      dormant (K) fractions of the microbial biomass were determined in samples taken
      from the surface layer of the ballast. The SIR, r, K and basal respiration values
      were all of an overall low magnitude, but were highly variable over short
      distances on the track. Both the biomass and basal respiration were higher on the
      sides of the embankment than in the middle of the tracks. SIR, K and basal
      respiration were correlated to the organic matter content as measured by loss on
      ignition, whereas r was not. None of the parameters correlated with pH. It is
      proposed that organic matter content could be used as a predictor for microbial
      biomass in railway embankments.

PMID- 15198328
TI  - Herbicide loss following application to a railway.
AB  - Railways have been identified as a potential source of herbicides detected in
      surface and groundwaters, but there are few data to support this theory. Two
      studies were undertaken to investigate the fate of herbicides applied to railway
      trackbeds: a pilot study in a section of a disused, but intact, cutting where
      runoff and throughflow were sampled from trenches adjacent to the treated area,
      and a larger scale study on 0.75 km of embankment where surface water from the
      drainage ditch at the base of the embankment and groundwater were sampled. In the
      pilot study, peak concentrations of atrazine, diuron and glyphosate (1280, 210
      and 15 microg litre(-1) respectively) were detected 6days after treatment (DAT).
      Oxadiazon, oryzalin and isoxaben were not detected above their limits of
      quantification. Lower concentrations were detected 81 DAT (10 and 0.8 microg
      litre(-1) of atrazine and glyphosate respectively). In the larger scale study,
      herbicides were not detected, in either the surface water or groundwater, at
      concentrations above the limit of detection that could be attributed to
      application to the railway. Rainfall volume and depth to sampling point may
      partly explain the different results obtained from the two studies. The findings
      are compared with herbicide losses from other 'hard surfaces'.

PMID- 15198329
TI  - Use of imazapyr against Equisetum arvense on Swedish railway tracks.
AB  - Since glyphosate has been used extensively for weed control in Swedish railway
      tracks, common horsetail (Equisetum arvense L), previously relatively rare, has
      become very common. Glyphosate, although effective against most other weeds found
      on railway tracks, gives poor control of E. arvense, so that heavy infestation
      with this weed is now common. Imazapyr (applied as a 250g AE litre(-1) SL,
      Arsenal) has controlled E. arvense, but is known to be very mobile. Adequate
      control of the weed requires application of > or = 4 litres ha(-1) of imazapyr SL
      but environmental factors preclude the use of > 2 litres ha(-1). A suitable
      strategy was found to be one application of imazapyr SL at 2 litres ha(-1) in
      each of two successive years but best weed control was obtained by supplementing
      imazapyr in the first year with glyphosate 360 g AE litre(-1) SL (RoundUp Bio) at
      3 litres ha(-1).

PMID- 15198330
TI  - Sorption, mineralization and mobility of N-(phosphonomethyl)glycine (glyphosate)
      in five different types of gravel.
AB  - Sorption, mineralization and mobility of glyphosate were studied in six
      substrates: the five types of gravel most frequently used as surfacing in Denmark
      and a sandy agricultural soil from Simmelkaer that served as a reference soil.
      Cumulative mineralization of [methyl-14C]glyphosate in batch studies was highest
      in coarse gravel, amounting to 14% after 4 days at 30 degrees C and 32% after 31
      days. Mineralization was slowest in the sandy reference soil, amounting to only
      2% after 31 days. The adsorption coefficient (Kd) of glyphosate in gravel ranged
      from 62 to 164 litre kg(-1), while that in the sandy reference soil was 410 litre
      kg(-1). The results indicate that the relatively low Kd in gravel allows a
      relatively high rate of glyphosate mineralization by the biomass. When Kd is
      high, in contrast, mineralization is slow. Lowering the temperature to 10 degrees
      C decreased mineralization by 50% in one of two gravels. The leaching of
      glyphosate was screened in simple columns of gravel or soil in which
      precipitation events (20 mm over a 2-h period) were simulated on three occasions,
      starting either immediately after or 2 days after application of glyphosate.
      [14C]Glyphosate was applied as a tracer mixed with the commercial product Roundup
      Garden at the recommended rate of 2.4 kg glyphosate ha(-1), equivalent to 1
      microg g(-1) soil. The highest concentration of [14C] compounds (expressed in
      terms of glyphosate concentration) in leachate from the columns exceeded 1300
      microg litre(-1), and was detected in rounded gravel after the first rain event.
      No glyphosate was detected in leachate from the sandy reference soil.

PMID- 15198331
TI  - Turfgrass management and weed control without pesticides on football pitches in
      Denmark.
AB  - Management of turfgrass on football pitches without pesticides involves a
      considerable challenge for weed control. By improving conditions for grass growth
      by cultural practices, weeds may be repressed by stronger competition from the
      grass. A 3-year field trial on 37 football pitches investigated the effects of
      various cultural management practices on percentage grass, weed and bare ground,
      respectively. The trial included twelve different treatments, comprising
      different combinations of fertiliser level and cultural methods, including two
      types of spring-tine harrow, vertical cutting, over-seeding, and top-dressing.
      Some treatments resulted in significant differences in percentage grass and weed
      cover, but not in percentage bare ground. However, other factors, such as
      locality of the football pitch, zone on the pitch, month, year, playing
      frequency, cutting frequency and, particularly, ground cover at the beginning of
      the trial, also contributed considerably to the variation in ground cover,
      indicating that established weeds are difficult to eradicate.

PMID- 15198332
TI  - Simulation of vegetation cover on sidewalks in Denmark.
AB  - Data from five 3-year experiments comparing different strategies of non-chemical
      weed control were analysed in order to set up a model that could be used for
      simulating further strategies. The treatments included different frequencies and
      effects of weed control using flaming, steaming and weed brushing. Each plot
      consisted of about 100 m of sidewalk. The amount of weed on the sidewalks was
      recorded several times during the 3-year period using a system of cameras mounted
      on a Terrain Vehicle moving on the sidewalk and post processing using image
      analyses of extracted images. The percentage of sidewalk covered by weed was
      estimated on the basis of the image analyses. The model used for describing the
      weed coverage comprises three components. The first component describes the
      growth of weeds; the second describes reduction caused by wearing and decay of
      weeds in the autumn and the third describes the reduction caused by weed control
      using weed brushing, steaming and flaming. The parameters of the model were
      estimated from the data for later use for simulating additional strategies.

PMID- 15198333
TI  - Weed control on hard surfaces in The Netherlands.
AB  - The non-agricultural use of pesticides in The Netherlands declined in the period
      1986-2001 from 127000 to 40000 kg AI per annum. However use on pavements rose
      from 23% to 50% of the total non-agricultural use. To diminish the dependency on
      herbicides, both preventive and curative non-chemical weed control methods have
      been examined. In the future both mechanical and thermal methods can be improved.
      On a flat pavement mechanical methods are preferred because they are more
      effective. Two approaches are used by municipalities to lower the environmental
      impact of the use of herbicides on pavements. The first is to phase out the use
      of chemicals on hard surfaces and the second is the integrated approach in which
      herbicides are not prohibited, but used only on places and at times when the risk
      of run-off is below a mutually accepted level. Both approaches can be effective.

PMID- 15198334
TI  - Strategies for non-chemical weed control on public paved areas in Denmark.
AB  - To be proactive in minimizing pesticide use, the public authorities in Denmark
      agreed in 1998 to phase out the use of pesticides on publicly owned areas by the
      end of 2002. A part of the agreement was an increasing focus on research into and
      development of new methods and implements for non-chemical weed control on paved
      areas. Due to a large increase in the costs of non-chemical weed control, the
      park authorities have to put the different types and locations of paved areas in
      order of priority to optimize the weed control effort. The present authors
      divided the paved areas into five weed control levels, dependent on placement,
      quality and use. For the 3 years 1999-2001, experiments with different non
      chemical weed control methods were conducted on pavements at six locations in
      Denmark. The aim was to test the reaction of the weeds to different treatments
      and strategies. The efficacies of the methods were evaluated by analysis of
      digital images to estimate the fraction of the paved area covered with green
      vegetation (weed coverage). The weed coverage was used as the dependent variable
      in the subsequent statistical analysis. The independent variables in the model
      were incoming radiation, wear, area of joints in the pavement, the dying process
      of the weeds and the number of runs/applied energy of the mechanical or thermal
      weed control methods, respectively. The estimated parameters from the statistical
      model were used to build a simulation model, which was used to optimise five weed
      control strategies to fulfil the suggested weed control levels. In the suggested
      strategy for maximum weed control, 12 thermal weeding applications at 2-week
      intervals are suggested. The 'clean-up' strategy is based on one weed-brushing in
      late spring or early autumn.

PMID- 15198335
TI  - Factors affecting the phase-out of pesticide use in public areas in Denmark.
AB  - That pesticide use in public areas in Denmark has been significantly reduced
      during the period 1995 to 2002 is shown when comparing three surveys carried out
      by the Danish Forest and Landscape Research Institute (DFLRI) with funding from
      the Danish Environmental Protection Agency. During that period, the total
      registered public use of pesticides was reduced from 28.8 tonnes active
      ingredients to 6.3 tonnes, corresponding to a 78% reduction. In 2002, the Danish
      counties and state institutions had reduced their total pesticide use by 80% and
      73%, respectively, compared to 1995 figures. Similarly, the Danish municipalities
      reduced their use by 83% from 1995 to 2002. Surveys of municipal pesticide use
      carried out in 1995, 2000 and 2002 have been used as the basis for determining
      the factors that have influenced municipal reductions of pesticide use. The 2000
      and 2002 trends can be explained partly on the basis of the figures for 1995 use.
      The trend for 2002 can also be partially explained by the political parties in
      power in the municipalities during the phase-out period. The models used account
      for up to 30% of the total variations, meaning that the pesticide use of
      individual municipalities is very much influenced by other, non-definable factors
      such as tradition.

PMID- 15198336
TI  - Allergen sensitization to aeroallergens including Blomia tropicalis among adult
      and childhood asthmatics in Thailand.
AB  - To study prevalence of allergen sensitization among asthmatics in Thailand, skin
      prick tests (SPT) were performed in 84 pediatric, 71 adult asthmatics and 71
      adult volunteers. Allergen extracts used for testing included common allergens in
      Thailand and in Singapore. The incidence of positive SPT to any allergen among
      the three groups (childhood, adult patients and adult controls) were 64.3%, 43.7%
      and 35.2%, respectively. Dermatophagoides were the most common allergens
      sensitized by both pediatric (58.3%) and adult asthmatics (40.8%). Twenty-four
      children (28.6%) and 8 adult patients (11.3%) were sensitized to storage mites
      (Blomia tropicalis and/or Austroglyciphagus malaysiensis). All patients
      sensitized to Blomia tropicalis were sensitized to Dermatophagoides. Twenty-seven
      percent and 15.5% of childhood and adult asthmatics were sensitized to cockroach
      allergens. The rates of sensitization to oil palm pollen in childhood and adult
      asthmatics were 8.3% and 5.6%, respectively. Sensitization to other pollens and
      spores were less than 5%. This study confirms the importance of Dermatophagoides
      among Thai asthmatics.

PMID- 15198337
TI  - Increased circulating CCR3+ type 2 helper T cells in house dust mite-sensitive
      Chinese patients with allergic diseases.
AB  - Chemokine receptor expression has been shown to be associated with the
      differentiation of T helper cells. The CCR3, CXCR4 and CCR5 expression on
      circulating T cells were studied in 30 house dust mite sensitive-patients with
      allergic diseases and in another 30 healthy controls. The expression was analyzed
      in CD4, CD8 and double negative (DN) T cells by triple fluorescence staining. In
      addition, intracellular cytokine staining was performed in the CCR3+ CD4+ T
      cells. Increased circulating portions of CCR3+ CD4+ T cells and CCR3+ DN T cells
      were found in these patients (p < 0.01). There was no statistically significant
      difference in the expression of CXCR4 and CCR5 on T cells. The follow-up data of
      the patients did not show a statistically significant change in the CCR3
      expression. IL-4 was expressed within CCR3+ CD4+ T cells upon activation. The IL
      4 secreting CCR3+ type 2 T helper cells may play a pathogenetic role in immune
      responses of house dust mite-sensitive Chinese patients with allergic diseases.

PMID- 15198338
TI  - Hematemesis in infants induced by cow milk allergy.
AB  - This study was conducted in order to analyze the clinical manifestations, the
      endoscopic findings, the histology of the gastrointestinal mucosa, the treatments
      and the clinical course in infants who had hematemesis induced by cow milk
      allergy. The medical records were reviewed retrospectively. The criteria for the
      diagnosis of CMA included elimination of cow milk formula resulting in
      improvement of symptoms, specific endoscopic and histologic findings as well as
      the exclusion of other causes. Twenty-three infants with a diagnosis of
      hematemesis were analyzed, which included 20 infants with CMA and 3 infants with
      gastroesophageal reflux disease (GERD). In the CMA group were 12 girls and 8 boys
      whose ages were 4.3 +/- 1.4 months. The onset of vomiting after starting cow milk
      formulas was 70.6 +/- 48.9 days. Gastroduodenoscopy was performed on 15 patients
      showing erythema, erosion and friability of the gastric mucosa in all patients
      and lymphoid hyperplasia in the duodenal bulb in 7 patients. Eight patients had
      mild to moderate eosinophilic infiltration and 5 patients had eosinophilia. Cow
      milk formulas were changed to other formulas: two children were initially given
      extensively hydrolyzed casein formulas and later followed by a soy formula, 14
      were given a soy formula and 4 were given partially whey hydrolyzed formulas. All
      patients showed clinical signs of improvement a few days later. Patients that
      were able to tolerate cow milk were 1.5 +/- 0.9 years old. During the follow-up
      period (2.6 +/- 1.8 years after treatment) 4 patients were diagnosed with asthma,
      4 patients with chronic respiratory symptoms, 4 patients with constipation and 2
      others with food allergies. CMA induced gastritis in infancy may not be
      classified as eosinophilic gastritis because of the low level of eosinophilic
      infiltration. The elimination of cow milk and subsequent substitution with a soy
      formula is the proper management.

PMID- 15198339
TI  - Human herpesvirus infection in children with fever and maculopapular rash.
AB  - Fever with maculopapular rash is a common problem in children. Infection with
      human herpesviruses is one of the common etiologies in fever with rash. The aim
      of this study has been to examine patients presenting with fever and
      maculopapular rash without respiratory symptoms for human herpesviruses infection
      by using multiplex nested-polymerase chain reaction. A descriptive and
      prospective study was conducted at King Chulalongkorn Memorial Hospital, Bangkok,
      Thailand from June 2000 to December 2001. One hundred patients, 43 boys and 57
      girls, aged between 2 months and 14 years were recruited. Human herpesvirus 6
      (HHV6) was the most common (24%) whereas HHV7, Epstein-Barr virus (EBV) and
      cytomegalovirus (CMV) were present in 9%, 3% and 2% of the patients,
      respectively. Four percent of the patients simultaneously harbored HHV6 and HHV7.
      Only one patient had CMV, HHV6 and HHV7. Patients with HHV7 had a mean age of 4.5
      years, whereas those with HHV6 had a mean age of 1.6 years. HHV6 and HHV7 were
      commonly found as causes of fever and maculopapular rash without respiratory
      symptoms. Co-infection with different herpesviruses can be found in the same
      patient.

PMID- 15198340
TI  - An open-label, prospective study of an oral polyvalent bacterial lysate (Luivac)
      in the treatment of recurrent respiratory tract infections in Thai patients.
AB  - An open-label, non-comparative study was performed in the Department of
      Otolaryngology, Siriraj Hospital, Bangkok, Thailand, to assess the safety,
      tolerability, acceptability and efficacy of an oral polyvalent bacterial lysate
      (Luivac) in the treatment of recurrent respiratory tract infections (RTIs) in
      Thai patients. Thirty-three patients were included in this study, 18 males and 15
      females, with a mean age of 34.0 +/- 14.7 years. The mean number of RTIs during
      the 12-month period preceding the study was 9.5 per patient. During the study
      each patient received one tablet of Luivac daily for 28 days followed by a
      treatment-free period of 28 days. This was followed with another 28 days on
      Luivac, after which there was a 28-day treatment-free follow-up period. This
      study lasted 4 months with five scheduled patient visits (V1-V5). Laboratory
      studies were done at baseline (V1) and after treatment (V4), which included
      complete blood count and serum immunoglobulins (IgA, IgE, IgG and IgM). The
      incidence of all adverse events was 15.2% and no case was related to the studied
      drug. There were no clinical relevant changes in laboratory parameters after
      treatment. The reduction rate of RTIs per month at the end of the study period
      was 63.5% when compared to the average RTIs rate per month during the 12 months
      preceding the study. A comparison of the first study period (V1-V3) and the
      second study period (V3-V5) showed a reduction in duration of RTIs (23.1%), in
      the clinical infection score (17.5%), in the number of antibiotics used (2.1%),
      in the number of symptomatic treatments (3.5%), and in the number of days absent
      from school or work (50.0%). Overall tolerability and acceptability were assessed
      as very good and good in 96.8% of the patients. This study suggests that oral
      polyvalent bacterial lysate (Luivac) was safe and also showed a tendency to be
      effective in preventing RTIs in Thai patients with or without risk factors for
      recurrent RTIs. Other clinical advantages were reduction in the severity and
      duration of infection as well as in reduction of the cost of treatment and the
      number of days absent from school or work.

PMID- 15198341
TI  - CpG DNA, liposome and refined antigen oral cholera vaccine.
AB  - An oral cholera vaccine made up of three Vibrio cholerae antigens, i.e.
      lipopolysaccharide (LPS), recombinant toxin co-regulated pili (rTcpA) and heat
      treated cholera toxin (H-CT) has been developed in six different formulations.
      Eight-week-old Wistar rats were divided into nine groups and immunized as
      follows: the first group received the oral vaccine 1 consisting of the three
      antigens (LPS, rTcpA and H-CT) associated with a liposome (L) and bacterial CpG
      DNA (ODN#1826). The rats of groups 2 and 3 received oral vaccines 2 and 3
      consisting of the liposome-associated three antigens with and without non
      bacterial CpG-DNA (ODN#1982), respectively. Rats of groups 4 received oral
      vaccine 4 consisting of the three antigens mixed with the ODN#1826, similar to
      vaccine 1, but without liposome. Rats of groups 5 and 6 received oral vaccines 5
      and 6 consisting of the three antigens with and without ODN#1982, respectively,
      similar to vaccines 2 and 3, but without liposome. Rats of groups 7, 8 and 9
      received oral placebos, namely liposomes (L), ODN#1826 (CpG), and vaccine
      diluent, i.e. 5% NaHCO3 solution, respectively. All vaccines were given in three
      doses at 14-day intervals. It was found that the combination of liposome and
      ODN#1826 in vaccine 1 evoked the highest immune response to V. cholerae antigen
      compared to other vaccine formulations and placebos, as measured by the
      appearance of antigen-specific antibody-producing cells in the intestinal lamina
      propria. The immunogenicity according to the magnitude of the immune response
      was: V1>V2=V3>V4>V5=V6>V7=V8=V9. The results of this study indicate that CpG-DNA
      and liposome are effective mucosal adjuvants for an oral cholera vaccine prepared
      from refined V. cholerae antigens and their combination seems to be synergistic.
      The potential role of liposome as a vaccine delivery vehicle has been confirmed.

PMID- 15198342
TI  - An antigen detection assay for diagnosing filariasis.
AB  - In this study we examined the diagnostic potential of monoclonal antibodies (MAb)
      reactive to antigens of adult Brugia malayi, their microfilariae and antigen of
      Dirofilaria immitis. The MAb of clone 17E10, which were of IgM isotype, reacted
      to the inner cuticles and internal content of both male and female worms and also
      to the sheath and internal content of microfilariae in utero. However, these MAb
      did not react to the sheath of blood circulating microfilariae. The MAb 17E10
      produced a smear pattern between 37 to > 200 kDa in the Western blot analysis
      against a SDS-PAGE separated extract of B. malayi. The epitopes were non-protein
      in nature as indicated by their resistance to proteinase-K treatment. The MAb
      17E10 were applied in a sandwich ELISA to detect filarial antigen in the buffy
      coat and plasma of patients. We tested patients with different clinical
      manifestations of brugian filariasis, i.e. microfilaremia (M), lymphangitis (L)
      and elephantiasis (E), as well as non-symptomatic inhabitants of a filariasis
      endemic area (NE), and compared them to samples from non-symptomatic inhabitants
      of disease non-endemic areas (NNE). It was found that 22 of 31 (70.9%) of M, 7 of
      13 (53.8%) of L, 2 of 14 (14.2%) of E, 10 of 100 (10.0%) of NE and none (0%) of
      the NNE were positive for antigenaemia. The assay was also positive in 14 of 15
      (93.3%) blood samples from B. malayi microfilaremic cats and in 7 of 7 (100%)
      blood samples of Dirofilaria immitis microfilaremic dogs. The so-developed test
      has a high potential for routine diagnosis of active filariasis, for
      epidemiological studies in both humans and reservoir animals and for monitoring
      treatment efficacy.

PMID- 15198343
TI  - Comparative assessment of an Og4C3 ELISA and an ICT filariasis test: a study of
      Myanmar migrants in Thailand.
AB  - Detection of circulating filarial antigen has now emerged as an alternative
      method for the diagnosis of bancroftian filariasis. We compared two antigen
      detection assays, an Og4C3 ELISA and an ICT (immunochromatography) Filariasis
      test, for the diagnosis of Wuchereria bancrofti infections in migrant Myanmar
      workers in Tak province, Western Thailand. A total of 337 Myanmars participated
      in this study. The microfilarial rate was 3.3%. The Og4C3 ELISA could detect
      19.1% of bancroftian filariasis while the ICT test detected 12.7%. Both antigen
      assays could detect all microfilaremics. The Og4C3 ELISA detected 14.8% of
      amicrofilaremics while the ICT test identified 8.1%. Those who were positive for
      the ICT test were also positive by the Og4C3 ELISA. Those Og4C3 positive cases,
      that were ICT negative (ICT-ve/Og4C3+ve) had statistically significant (p < 0.05,
      unpaired t-test) lower Og4C3 antigen levels (409.5 units, range 117-2,389) than
      those that were ICT positive (ICT+ve/Og4C3+ve) (5,252.0 units, range 130-28,062).
      Our results emphasize the problem of bancroftian filariasis in Myanmar migrants
      working in Thailand. Close monitoring and control of this disease in Myanmar
      migrants are of public health importance. Antigen detection systems are promising
      tools for the surveillance of bancroftian filariasis.

PMID- 15198344
TI  - One-step purification of chimeric green fluorescent protein providing metal
      binding avidity and protease recognition sequence.
AB  - Gene fusion technique was successfully applied as a potential approach to create
      a metal-binding site to assist one-step purification of green fluorescent protein
      (GFP). The chimeric GFP carrying hexapolyhistidine (H6GFPuv) was purified to
      homogeneous protein via the Immobilized Metal Affinity Chromatography charged
      with zinc ions. Removal of metal tagger could readily be performed by using
      enterokinase enzyme. Engineering of the hexahistidine and enterokinase cleavage
      sites (DDDDK) onto the chimeric protein did not significantly affect the
      fluorescent property and the binding avidity to Burkholderia pseudomallei
      protease of a chimeric protease-binding GFP (H6PBGFPuv). This concludes that
      engineering of repetitive histidine regions onto interested target protein along
      with the enterokinase cleavage sites will ease the complication of protein
      purification.

PMID- 15198345
TI  - Seroprevalence of anti-RSV IgG in Thai children aged 6 months to 5 years.
AB  - Respiratory syncytial virus (RSV) is the single most important cause of lower
      respiratory tract infection during infancy and early childhood worldwide
      including Thailand. The magnitude as well as the intensity of both infection and
      host response to the RSV infection determine the severity of disease. To
      determine the presence of anti-RSV IgG in children of different age groups, 124
      serum samples were randomly collected from healthy children aged 6 months to 5
      years. All of them were assayed for anti-RSV IgG using a commercial ELISA kit.
      The mean prevalence rate was found to be 68.91%. The prevalence increased with
      age: from 6 to 11 months, 11.76%; from 12 to 17 months, 41.67%; from 18 to 23
      months, 60.87%; from 24 to 29 months, 88.24%; from 30 to 35 months, 78.57%; from
      36 to 41 months, 94.44% and from 42 to 60 months, 100%. The amount of anti-RSV
      IgG among the groups was significantly different (p = 0.006). No sexual
      preponderance was found. RSV infection commonly occurred in children aged 12 to
      29 months. All children older than 5 years had experienced a RSV infection.

PMID- 15198346
TI  - Prevalence of latex sensitization in healthy blood donors in Izmir, Turkey.
AB  - Although latex is a common allergen, the prevalence of natural rubber latex
      allergy in the general population in Turkey is unknown. The aim of this study was
      to assess the prevalence of sensitization to natural rubber latex in a population
      of healthy blood donors. As skin prick testing of a sample of the general
      population was not feasible, the subgroup of adult healthy blood donors was
      chosen instead. Skin testing with commercially available reagents (Stallergenes)
      was performed on 952 volunteers attending the Blood Centre of the Social Security
      Hospital in Izmir, Turkey in 2001. The study population completed a questionnaire
      involving history of personal allergy and symptoms. In 20 blood donors (2.1%) the
      latex skin prick test (SPT) was positive. No relationship by age or gender was
      found. There was no relationship between previous allergic symptoms and SPT
      positivitiy to latex except for the systemic reaction related to any allergen
      (deep wheezing or any difficulty breathing, nausea, vomiting, palpitations,
      faintness or edema). The prevalence of SPT positivity to natural rubber latex was
      2.1% in a Turkish blood donor group, which can be related to the latex
      sensitivity within the general Turkish population.

PMID- 15198347
TI  - The classification and typing of amyloid deposits.

PMID- 15198348
TI  - Critical value called, read-back obtained.

PMID- 15198350
TI  - Improving patient safety by repeating (read-back) telephone reports of critical
      information.
AB  - Reducing the rate of avoidable errors is crucial to patient safety. Telephone
      calls with misunderstood critical results constitute one area in which
      opportunities for improvement exist. The aviation industry has dealt with this
      issue by requiring pilots to repeat instructions received from the air traffic
      controller. At 3 health care organizations, we tested a program to decrease
      telephone reporting errors by requiring the recipients of critical results to
      repeat the message. Of 822 outgoing telephone calls from the laboratory, 29
      errors were detected (error rate 3.5%). Calls to physicians had the highest rate
      of errors (6/95 [5%]). The time required to ask for the information and for the
      message to be repeated averaged 12.8 seconds per call, which corrected 29 errors.
      A simple system of repeating telephoned laboratory results has the potential to
      reduce the risk of medical errors and improve patient safety.

PMID- 15198349
TI  - Biochemical subtyping of amyloid in formalin-fixed tissue samples confirms and
      supplements immunohistologic data.
AB  - The systemic amyloidoses are a heterogeneous group of congophilic fibrillar
      protein deposition diseases that should be subtyped chemically by
      immunohistologic methods. Biochemical methods sometimes are required to confirm
      or identify the amyloid type in unfixed or informalin-fixed tissue samples. We
      report the results of formic acid extraction and immunochemical and biochemical
      characterization of deposits informalin-fixed tissue samples from 10 cases of
      amyloidosis and 3 from nonamyloid monoclonal immunoglobulin light chain
      deposition disease. The results in 11 of 13 cases demonstrated concordance with
      the previous immunohistochemical and/or biochemical data obtained in unfixed
      tissue samples from the same specimens, and in 2 of 13, the protein deposits that
      previously could not be classified by standard immunohistochemical methods were
      identified by amino acid sequence. An additional new finding of constant-region
      rather than variable-region fragments as the major constituent protein in 1 case
      of lambda light chain amyloidosis demonstrated the value of the method and its
      importance for future applications.

PMID- 15198351
TI  - Reevaluation of myoglobin for acute chest pain evaluation: would false-positive
      results on "first-draw" specimens lead to increased hospital admissions?
AB  - Myoglobin is an early marker of cardiac injury, although positive results occur
      in the absence of cardiac myonecrosis. We studied data for 537 patients admitted
      to the emergency department with symptoms suggestive of myocardial injury who
      underwent testing for troponin I (TnI), creatine kinase isoenzyme (CK-MB), and
      myoglobin at the point of care. Physicians were blinded to the myoglobin results.
      Myoglobin had a sensitivity of 69.7% and a negative predictive value of 97.4% for
      the diagnosis of acute coronary syndrome (ACS) on "first-draw" specimens.
      Receiver operating characteristic curve analysis suggested that myoglobin
      demonstrated optimal sensitivity for ACS, while TnI had optimal specificity. CK
      MB was neither the most specific nor the most sensitive marker. More than 80% of
      the patients with false-positive myoglobin results were admitted to the hospital.
      These data invalidate concerns regarding the putative overtreatment effect of
      false-positive cases owing to myoglobin results. Furthermore, our data suggest
      that myoglobin is superior to CK-MB as an adjunct to TnI.

PMID- 15198352
TI  - Nonpositive terminal deoxynucleotidyl transferase in pediatric precursor B
      lymphoblastic leukemia.
AB  - Terminal deoxynucleotidyl transferase (TdT) is a unique intranuclear DNA
      polymerase that catalyzes the template-independent addition of deoxynucleotides
      to the 3'-hydroxyl terminus of oligonucleotide primers. The expression of TdT is
      restricted to lymphoid precursors. It is a useful marker in distinguishing acute
      lymphoblastic leukemia (ALL)from mature lymphoid neoplasms. Although TdT- T-cell
      ALL has been reported in the literature rarely, the frequency and significance of
      TdT-nonpositive (TdT(np) B-cell ALL have not been examined extensively. We
      reviewed the immunophenotypes of 186 new cases of pediatric B-cell ALL and found
      5 TdT(np) cases (2.7%). They showed significantly higher frequencies of a WBC
      count of more than 50,000/microL (> 50.0 x 10(9)/L), CD10-, CD34-, and MLL gene
      rearrangement compared with those in TdT+ cases (3/5 [60%] vs 27/181 [14.9%], P =
      .03; 3/5 [60%] vs 11/181 [6.1%], P = .003; 4/5 [80%] vs 24/179 [13.4%], P = .002;
      3/5 [60%] vs 9/181 [5.0%], P = .0019; respectively). These results indicate that
      nonpositive TdT does not rule out a diagnosis of ALL and suggest that TdT(np) B
      cell ALL might be associated with CD10- and CD34- disease, a high WBC count, and
      MLL gene rearrangement.

PMID- 15198353
TI  - Standardization of reticulocyte values in an antidoping context.
AB  - The lack of standardization of reticulocyte results hinders the ability of sports
      authorities to recognize the telltale fluctuations over time that are typical for
      athletes using illegal blood doping to improve their performance. Therefore, the
      aim of the present study was to devise a tenable approach for antidoping
      authorities to quantify, instrument bias. We evaluated reticulocyte data derived
      during a 42-week period from 210 hospital patient blood samples measured in
      duplicate simultaneously on up to 11 hematology analyzers located in a single
      laboratory. We found that square root transformation of reticulocyte values
      enabled quantification of interinstrument bias by using the mean reticulocyte
      value of a cohort of approximately 54 subjects as a de facto calibration agent.
      We also demonstrated that measurement precision associated with low reticulocyte
      values was not inferior to that associated with higher values.

PMID- 15198354
TI  - Utility of routine classical cytogenetic studies in the evaluation of suspected
      lymphomas: results of 279 consecutive lymph node/extranodal tissue biopsies.
AB  - Classical cytogenetic studies have a critical role in the diagnosis of acute
      leukemias; however, they are much less widely used in lymphoma diagnosis. To
      evaluate their utility in this latter setting, G-banded karyotyping was performed
      on 279 consecutive lymph node or tissue biopsy specimens with suspected lymphoma.
      Complete cytogenetic studies were successfully obtained in 177 cases (63.4%),
      including 115 (69.3%) of 166 hematolymphoid neoplasms. Success rates varied with
      the specific diagnosis (range, 33%-100%). The karyotypes were abnormal in 97
      (84.3%) of the hematolymphoid neoplasms. In at least 3 cases of non-Hodgkin
      lymphoma, the findings contributed directly to the specific diagnosis made. In a
      much larger proportion of cases, characteristic but nonspecific findings were
      identified. Abnormalities of suggested prognostic importance in follicular
      lymphoma and in diffuse large B-cell lymphoma were identified in 14 (44%) of 32
      cases and 8 (24%) of 33 cases, respectively. Most karyotyped lymphomas will
      display abnormal findings including many that are not completely specific but
      support the diagnosis, some that provide additional prognostic information, and,
      infrequently, some that help establish a diagnosis that might otherwise have been
      missed.

PMID- 15198355
TI  - t(8;21)(q22;q22) in blast phase of chronic myelogenous leukemia.
AB  - The blast phase of chronic myelogenous leukemia (CML) frequently is associated
      with cytogenetic evidence of clonal evolution, defined as chromosomal aberrations
      in addition to the t(9;22)(q34;q11.2). We identified the t(8;21)(q22;q22) and
      other cytogenetic abnormalities by conventional cytogenetics and fluorescence in
      situ hybridization in 2 patients with t(9;22)-positive CML at the time of blast
      phase. The t(8;21), which typically is associated with a distinct subtype of de
      novo acute myeloid leukemia (AML) carrying the aml1/eto fusion gene, was
      accompanied by increased bone marrow myeloblasts (33%) in case 1 and
      extramedullary myeloid sarcoma in case 2, suggesting its possible role in disease
      progression. In case 1, the leukemic cells in aspirate smears had salmon-colored
      cytoplasmic granules, and immunophenotypic studies showed that the blasts
      expressed CD19. These findings suggest that the pathologic features of blast
      phase CML with the t(8;21) resemble those of de novo AML with the t(8;21).

PMID- 15198356
TI  - Inherited prothrombotic defects in Budd-Chiari syndrome and portal vein
      thrombosis: a study from North India.
AB  - We studied 57 patients with Budd-Chiari syndrome (BCS) and 48 with portal vein
      thrombosis (PVT) for underlying inherited prothrombotic defects such as protein
      C, protein S, and antithrombin III deficiencies. Genetic mutations for factor V
      Leiden, prothrombin gene 20210A, and methyltetrahydrofolate reductase (MTHFR)
      C677T were studied in 29 patients in each group. Inherited prothrombotic defects
      were detected in 16 (28%) of 57 patients with BCS and 7 (15%) of 48 patients with
      PVT. Factor V Leiden mutation was the most common prothrombotic defect in BCS
      (5/29 [17%]) followed by protein C deficiency (7/57 [12%]) and protein S
      deficiency (4/57 [7%]), whereas in PVT, protein C deficiency was the most common
      inherited prothrombotic defect (4/48 [8%]) followed by protein S deficiency (2/48
      [4%]). The factor V Leiden mutation was detected in only 1 (3%) of 29 cases of
      PVT. The heterozygous MTHFR C677T mutation was detected in 7 (24%) of 29 patients
      with BCS and 6 (21%) of 29 patients with PVT. Antithrombin III deficiency,
      homozygous MTHFR C677T mutation, and prothrombin G20210A mutation were not
      detected in any patients.

PMID- 15198357
TI  - An immunophenotypic comparison of metanephric metaplasia of Bowman capsular
      epithelium with metanephric adenoma, Wilms tumor, and renal development: a case
      report and review of the literature.
AB  - Metanephric metaplasia of the parietal epithelium of the Bowman capsule is a rare
      pathologic finding of unknown pathogenesis that has occurred in patients with
      widespread malignant neoplasms of various types. We report this finding in a 25
      year-old woman with partial expression of the Carney triad who died of a
      disseminated gastrointestinal stromal tumor, specifically a gastric stromal
      sarcoma. The metaplasia involved both kidneys diffusely. It originated in the
      parietal epithelium of the Bowman capsule, extended into the proximal tubules,
      and focally surrounded the glomeruli in a semicircular manner Immunohistochemical
      analysis revealed that the cells of metanephric metaplasia expressed the Wilms
      tumor gene product, bcl-2 protein, and CD57 and cytokeratin 7 and keratin AE1/AE3
      focally, but not CD56. This immunophenotype parallels that of metanephric
      adenoma, Wilms tumor, and nephrogenic rests and overlaps with antigen expression
      in certain periods of renal development.

PMID- 15198358
TI  - Invasive micropapillary carcinoma of the breast: clinicopathologic study of 62
      cases of a poorly recognized variant with highly aggressive behavior.
AB  - We report 62 cases of invasive micropapillary carcinoma of the breast
      characterized by delicate pseudopapillary structures lacking a fibrovascular core
      and by tubuloalveolar structures freely floating in clear, empty spaces. All
      patients but 1 were women (median age, 57 years; range, 25-89 years). Tumor size
      ranged from 0.7 to 10 cm (median, 2.8 cm); 54 (87%) were grade 3. Psammoma bodies
      were identified in 29 (47%). Focal to massive lymphatic permeation was present in
      39 (63%). Architectural features were retained in the node metastases, dermal
      lymphatics, and recurrences. Fifty-six patients (90%) had metastatic axillary
      nodes: 18 tumors were estrogen receptor-positive (32%); 11 were progesterone
      receptor-positive (20%); HER2/neu was overexpressed in 53 (95%) and p53 in 39
      (70%). A peculiar immunoreactivity for MUC1 limited to the cytoplasmic membrane
      oriented toward the stroma and an absence of immunoreactivity for E-cadherin in
      the same side of the cytoplasmic membrane indicated inversion of cell
      polarization and a disturbance in the cell adhesion molecules. Of 41 patients
      with available follow-up, 29 (71%) had local recurrence (mean, 30 months) and 20
      (49%) died of disease. These results underscore the aggressive behavior and poor
      prognosis of this breast carcinoma variant. Aggressive preoperative neoadjuvant
      chemotherapy should be considered.

PMID- 15198359
TI  - "Ancient" (sclerosing) thymomas: a clinicopathologic study of 10 cases.
AB  - We present 10 cases of "ancient" (sclerosing) thymomas in 4 women and 6 men (age
      range, 34-73 years; mean, 53.5 years). Clinically, 4 patients had a history of
      shortness of breath and chest pain of several weeks' duration, 1 had a history of
      myasthenia gravis, and 5 were asymptomatic (anterior mediastinal masses
      discovered on routine chest radiographs). All underwent complete surgical
      resection of the anterior mediastinal mass. The tumors were light tan and solid,
      without areas of hemorrhage or necrosis, and 5 to 10 cm in greatest diameter.
      Extensive areas of hyalinized fibroconnective tissue constituting about 85% to
      90% of the tumor mass was the main tumor feature. Focal areas of conventional
      thymoma also were present in all tumors. Follow-up information was obtained for 8
      patients. Of these 8 patients, 6 died, all of unrelated causes (congestive heart
      failure, renal insufficiency, and pulmonary edema), and 2 were alive 1 and 6
      years after surgical resection. The present cases highlight an important
      histopathologic feature of thymomas, which can pose problems in diagnosis, namely
      when dealing with small mediastinoscopic biopsy specimens.

PMID- 15198360
TI  - Patient age in Spitz nevus and malignant melanoma: implication of Bayes rule for
      differential diagnosis.
AB  - In the differential diagnosis of Spitz nevus vs malignant melanoma, patient age
      provides a critical piece of clinical information, because Spitz nevi occur
      mostly in children and melanomas occur mostly in adults. Nevertheless, there is
      overlap in the age distributions of Spitz nevus and melanoma. The issue to
      consider is how these age distributions and their governing probability densities
      can impact the a priori probability that a lesion is a Spitz nevus vs a melanoma.
      Herein I introduce a quantitative approach that uses Bayes rule together with
      previous published data on the age distributions in Spitz nevi and melanoma. The
      resulting algorithm yields plots and a table of predictive a priori probabilities
      of Spitz nevus, given patient age occurring within narrow intervals, and I
      believe these provide useful guidelines for using age in the differential
      diagnosis of Spitz nevus and malignant melanoma.

PMID- 15198361
TI  - Overexpression of KIT (CD117) in chromophobe renal cell carcinoma and renal
      oncocytoma.
AB  - KIT expression has not been studied substantially in renal tumors. We analyzed
      the immunohistochemical expression for KIT in 256 conventional renal cell
      carcinomas (RCCs), 29 chromophobe RCCs, 25 papillary RCCs, 6 collecting duct
      RCCs, 6 unclassified RCCs, 7 renal oncocytomas, 20 urothelial carcinomas, 7
      nephroblastomas, and 23 angiomyolipomas. We found that 24 chromophobe RCCs (83%)
      and 5 renal oncocytomas (71%) revealed membranous immunoreactivity for KIT while
      none of the RCCs of other types expressed KIT immunohistochemically. Sporadic
      cases of urothelial carcinoma and nephroblastoma were focally positive for KIT.
      All angiomyolipomas were negative. Genomic DNA extracted from the chromophobe
      RCCs and renal oncocytomas was submitted for polymerase chain reaction and direct
      sequencing of the juxtamembrane (exons 9 and 11) and tyrosine kinase (exons 13
      and 17) domains. No mutation was found. Our results demonstrate that KIT could be
      a useful immunophenotypic marker for chromophobe RCC and renal oncocytoma;
      therefore, it has value for the precise classification of renal cortical
      epithelial tumors. However, the therapeutic relevance of KIT overexpression in
      these tumors is uncertain owing to the lack of mutations that would lead to
      constitutive activation of the protein.

PMID- 15198362
TI  - Immunohistochemical characterization of signet-ring cell carcinomas of the
      stomach, breast, and colon.
AB  - We studied the immunophenotype of signet-ring cell carcinoma (SRCC) of the
      stomach (30 cases), breast (21 cases), and colon (9 cases) with the following
      expression patterns: (1) breast: consistent, MUC1 (21 [100%]), cytokeratin (CK) 7
      (20 [95%]), estrogen receptor (ER; 17 [81%]); infrequent, E-cadherin (6 [29%]),
      MUC2, MUC5AC, CK20 (1 [5%] each); negative, CDX2 and hepatocyte paraffin 1 (Hep
      Par 1; 0 [0%] each); (2) gastric: frequent, CDX2 (27 [90%]) and Hep Par 1 (25
      [83%]); variable, E-cadherin and CK20 (17 [57%] each), MUC2 and MUC5AC (15 [50%]
      each), MUC1 (5 [17%]); negative, ER (0 [0%]); and (3) colon: frequent, MUC2 (9
      [100%]), CDX2 and MUC5AC (8 [89%] each); infrequent or negative, MUC1 (3 [33%]),
      Hep Par 1 (2 [22%]), ER (0 [0%]). Immunohistochemical staining distinguished
      breast from gastric SRCC (ER, MUC1, Hep Par 1, CDX2) and colon SRCC (ER, CDX2,
      MUC2, and MUC5AC). Gastric and colon SRCCs showed a similar staining pattern for
      antibodies tested except for Hep Par 1 and CDX2 (gastric, 83% Hep Par 1
      positivity and heterogeneous, weak, patchy CDX2 nuclear staining; colon, 22% Hep
      Par 1 positivity and homogeneous, strong, diffuse CDX2 nuclear staining). About
      half of the cases of gastric SRCC expressed MUC2 and MUC5AC, whereas virtually
      all cases of colon SRCC expressed them.

PMID- 15198363
TI  - The cytology of pancreatic foamy gland adenocarcinoma.
AB  - All cell block specimens from pancreatic fine-needle aspirations (FNAs) obtained
      between January 1, 2002, and June 30, 2003, were reviewed for foamy gland
      adenocarcinoma (FGA). All smears from these cases were reviewed for cytologic
      features, including those previously noted in conventional pancreatic
      adenocarcinoma. Fifty-two cell block specimens showed adenocarcinoma. Of these,
      12 (23%) showed histologic features of FGA. This pattern predominated in 6 cases
      and was present focally in 6 cases. Although there were relatively low
      nuclear/cytoplasmic (N/C) ratios, other features of adenocarcinoma were present
      universally, including loss of cohesiveness, nuclear overlap or loss of
      "honeycomb" architecture, anisonucleosis (> 4 to 1), irregular nuclear contours,
      prominent nucleoli, and atypical chromatin. Background necrosis was present in 8
      cases. Distinct cell borders were present in 9 cases, and foamy cytoplasm was
      present in all cases. Pancreatic FGA is a recently described histologic pattern
      of pancreatic adenocarcinoma. It is not uncommon, and we identified the pattern,
      at least focally, in 23% of our FNA cell blocks. Although cytologic samples show
      low N/C ratios, most cytologic features of conventional pancreatic adenocarcinoma
      are present, and the diagnosis presents little additional difficulty.

PMID- 15198364
TI  - Primary pancreatic lymphoma evaluated by fine-needle aspiration: findings in 14
      cases.
AB  - Fine-needle aspiration (FNA) is a popular method for evaluating pancreatic
      lesions. There is considerable literature on FNA evaluation of primary pancreatic
      carcinomas, but few studies address the FNA diagnosis of primary pancreatic
      lymphoma. We reviewed 14 cases of atypical lymphoid processes diagnosed by FNA
      during a 5-year period, constituting 1.3% of a total of 1,050 pancreatic FNA
      cases. The diagnoses were as follows: 6 large B-cell lymphomas, 4 follicular
      lymphomas, 3 suggestive of lymphoma, and 1 unclassified B-cell lymphoma. Lymphoid
      neoplasms manifested in older people (mean age, 64.7 years) as a solitary mass in
      the pancreatic head, mimicking primary carcinoma. Clonality was confirmed by flow
      cytometry in 11 cases and immunohistochemical analysis on cell block material in
      2. Obtaining diagnostic material often required several passes (average, 3.9
      passes; range, 1-8 passes). We conclude that primary pancreatic lymphomas rarely
      are diagnosed by FNA, tend to be high grade, and clinically and radiographically
      might mimic primary carcinoma.

PMID- 15198365
TI  - Accuracy of en face frozen sections for diagnosing margin status in melanocytic
      lesions.

PMID- 15198366
TI  - Physiological and pathophysiological significance of C-peptide actions.
      Introduction.

PMID- 15198367
TI  - The proinsulin C-peptide--a multirole model.
AB  - The C-peptide links the insulin A and B chains in proinsulin, providing thereby a
      means to promote their efficient folding and assembly in the endoplasmic
      reticulum during insulin biosynthesis. It then facilitates the intracellular
      transport, sorting, and proteolytic processing of proinsulin into biologically
      active insulin in the maturing secretory granules of the beta cells. These
      manifold functions impose significant constraints on the C-peptide structure that
      are conserved in evolution. After cleavage of proinsulin, the intact C-peptide is
      stored with insulin in the soluble phase of the secretory granules and is
      subsequently released in equimolar amounts with insulin, providing a useful
      independent indicator of insulin secretion. This brief review highlights many
      aspects of its roles in biosynthesis, as a prelude to consideration of its
      possible additional role(s) as a physiologically active peptide after its release
      with insulin into the circulation in vivo.

PMID- 15198368
TI  - Molecular and cellular effects of C-peptide--new perspectives on an old peptide.
AB  - New results present C-peptide as a biologically active peptide hormone in its own
      right. Although C-peptide is formed from proinsulin and cosecreted with insulin,
      it is a separate entity with biochemical and physiological characteristics that
      differ from those of insulin. There is direct evidence of stereospecific binding
      of C-peptide to a cell surface receptor, which is different from those for
      insulin and other related hormones. The C-peptide binding site is most likely a G
      protein-coupled receptor. The association constant for C-peptide binding is
      approximately 3 x 10(9) M(-1). Saturation of the binding occurs already at a
      concentration of about 1 nM, which explains why C-peptide effects are not
      observed in healthy subjects. Binding of C-peptide results in activation of Ca2+
      and MAPK-dependent pathways and stimulation of Na+,K(+)-ATPase and eNOS
      activities. The latter 2 enzymes are both deficient in several tissues in type 1
      diabetes. There is some evidence that C-peptide, and insulin may interact
      synergistically on the insulin signaling pathway. Clinical evidence suggests that
      replacement of C-peptide, together with regular insulin therapy, may be
      beneficial in patients with type 1 diabetes and serve to retard or prevent the
      development of long-term complications.

PMID- 15198369
TI  - The C-peptide signaling.
AB  - For years an assumption was made that C-peptide, a byproduct of insulin
      biosynthesis, possessed no appreciable physiologic role. As other contributions
      in this volume amply testify, the time has come to re-evaluate that notion. C
      peptide either directly through interaction with its specific cell-surface
      receptor or indirectly through an interaction with a related membrane entity,
      exerts a unique effect on several intracellular processes. We review here results
      of studies attempting to elucidate such molecular effects of C-peptide in
      different cell systems and tissues. Lacking a purified C-peptide receptor, we
      also demonstrate C-peptide effects on distinct elements of the insulin signal
      transduction pathways.

PMID- 15198370
TI  - C-peptide, Na+,K(+)-ATPase, and diabetes.
AB  - Na+,K(+)-ATPase is an ubiquitous membrane enzyme that allows the extrusion of
      three sodium ions from the cell and two potassium ions from the extracellular
      fluid. Its activity is decreased in many tissues of streptozotocin-induced
      diabetic animals. This impairment could be at least partly responsible for the
      development of diabetic complications. Na+,K(+)-ATPase activity is decreased in
      the red blood cell membranes of type 1 diabetic individuals, irrespective of the
      degree of diabetic control. It is less impaired or even normal in those of type 2
      diabetic patients. The authors have shown that in the red blood cells of type 2
      diabetic patients, Na+,K(+)-ATPase activity was strongly related to blood C
      peptide levels in non-insulin-treated patients (in whom C-peptide concentration
      reflects that of insulin) as well as in insulin-treated patients. Furthermore, a
      gene-environment relationship has been observed. The alpha-1 isoform of the
      enzyme predominant in red blood cells and nerve tissue is encoded by the ATP1A1
      gene. A polymorphism in the intron 1 of this gene is associated with lower enzyme
      activity in patients with C-peptide deficiency either with type 1 or type 2
      diabetes, but not in normal individuals. There are several lines of evidence for
      a low C-peptide level being responsible for low Na+,K(+)-ATPase activity in the
      red blood cells. Short-term C-peptide infusion to type 1 diabetic patients
      restores normal Na+,K(+)-ATPase activity. Islet transplantation, which restores
      endogenous C-peptide secretion, enhances Na+,K(+)-ATPase activity proportionally
      to the rise in C-peptide. This C-peptide effect is not indirect. In fact,
      incubation of diabetic red blood cells with C-peptide at physiological
      concentration leads to an increase of Na+,K(+)-ATPase activity. In isolated
      proximal tubules of rats or in the medullary thick ascending limb of the kidney,
      C-peptide stimulates in a dose-dependent manner Na+,K(+)-ATPase activity. This
      impairment in Na+,K(+)-ATPase activity, mainly secondary to the lack of C
      peptide, plays probably a role in the development of diabetic complications.
      Arguments have been developed showing that the diabetes-induced decrease in
      Na+,K(+)-ATPase activity compromises microvascular blood flow by two mechanisms:
      by affecting microvascular regulation and by decreasing red blood cell
      deformability, which leads to an increase in blood viscosity. C-peptide infusion
      restores red blood cell deformability and microvascular blood flow concomitantly
      with Na+,K(+)-ATPase activity. The defect in ATPase is strongly related to
      diabetic neuropathy. Patients with neuropathy have lower ATPase activity than
      those without. The diabetes-induced impairment in Na+,K(+)-ATPase activity is
      identical in red blood cells and neural tissue. Red blood cell ATPase activity is
      related to nerve conduction velocity in the peroneal and the tibial nerve of
      diabetic patients. C-peptide infusion to diabetic rats increases endoneural
      ATPase activity in rat. Because the defect in Na+,K(+)-ATPase activity is also
      probably involved in the development of diabetic nephropathy and cardiomyopathy,
      physiological C-peptide infusion could be beneficial for the prevention of
      diabetic complications.

PMID- 15198371
TI  - Effects of C-peptide on microvascular blood flow and blood hemorheology.
AB  - Beside functional and structural changes in vascular biology, alterations in the
      rheologic properties of blood cells mainly determines to an impaired
      microvascular blood flow in patients suffering from diabetes mellitus. Recent
      investigations provide increasing evidence that impaired C-peptide secretion in
      type 1 diabetic patients might contribute to the development of microvascular
      complications. C-peptide has been shown to stimulate endothelial NO secretion by
      activation of the Ca2+ calmodolin regulated enzyme eNOS. NO himself has the
      potency to increase cGMP levels in smooth muscle cells and to activate
      Na+K+ATPase activity and therefore evolves numerous effects in microvascular
      regulation. In type 1 diabetic patients, supplementation of C-peptide was shown
      to improve endothelium dependent vasodilatation in an NO-dependent pathway in
      different vascular compartments. In addition, it could be shown that C-peptide
      administration in type 1 diabetic patients, results in a redistribution of skin
      blood flow by increasing nutritive capillary blood flow in favour to subpapillary
      blood flow. Impaired Na+K+ATPase in another feature of diabetes mellitus in many
      cell types and is believed to be a pivotal regulator of various cell functions. C
      peptide supplementation has been shown to restore Na+K+ATPase activity in
      different cell types during in vitro and in vivo investigations. In type 1
      diabetic patients, C-peptide supplementation was shown to increase erythrocyte
      Na+K+ATPase activity by about 100%. There was found a linear relationship between
      plasma C-peptide levels and erythrocyte Na+K+ATPase activity. In small
      capillaries, microvascular blood flow is increasingly determined by the rheologic
      properties of erythrocytes. Using laser-diffractoscopie a huge improvement in
      erythrocyte deformability could be observed after C-peptide administration in
      erythrocytes of type 1 diabetic patients. Inhibition of the Na+K+ATPase by Obain
      completely abolished the effect of C-peptide on erythrocyte deformability. In
      conclusion, C-peptide improves microvascular function and blood flow in type 1
      diabetic patients by interfering with vascular and rheological components of
      microvascular blood flow.

PMID- 15198372
TI  - Type 1 diabetic neuropathy and C-peptide.
AB  - The most common microvascular diabetic complication, diabetic peripheral
      polyneuropathy (DPN), affects type 1 diabetic patients more often and more
      severely. In recent decades, it has become increasingly clear that perpetuating
      pathogenetic mechanisms, molecular, functional, and structural changes and
      ultimately the clinical expression of DPN differ between the two major types of
      diabetes. Impaired insulin/C-peptide action has emerged as a crucial factor to
      account for the disproportionate burden affecting type 1 patients. C-peptide was
      long believed to be biologically inactive. However, it has now been shown to have
      a number of insulin-like glucose-independent effects. Preclinical studies have
      demonstrated dose-dependent effects on Na+,K(+)-ATPase activity, endothelial
      nitric oxide synthase (eNOS), and endoneurial blood flow. Furthermore, it has
      regulatory effects on neurotrophic factors and molecules pivotal to the integrity
      of the nodal and paranodal apparatus and modulatory effects on apoptotic
      phenomena affecting the diabetic nervous system. In animal studies, C-peptide
      improves nerve conduction abnormalities, prevents nodal degenerative changes,
      characteristic of type 1 DPN, promotes nerve fiber regeneration, and prevents
      apoptosis of central and peripheral nerve cell constituents. Limited clinical
      trials have confirmed the beneficial effects of C-peptide on autonomic and
      somatic nerve function in patients with type 1 DPN. Therefore, evidence
      accumulates that replacement of C-peptide in type 1 diabetes prevents and even
      improves DPN. Large-scale food and drug administration (FDA)-approved clinical
      trials are necessary to make this natural substance available to the globally
      increasing type 1 diabetic population.

PMID- 15198373
TI  - C-peptide and central nervous system complications in diabetes.
AB  - Substantial evidence collected from clinical data and experimental studies has
      indicated that CNS is not spared from diabetes complications. Impairments in CNS
      function are well documented in both type 1 and type 2 diabetic patients as well
      as in various animal models of diabetes, in terms of alterations in cognition,
      neuropsychology, neurobehavior, electrophysiology, structure, neurochemistry and
      apoptotic activities. These data suggest that primary diabetic encephalopathy
      exists as a definable diabetic complication. The mechanisms underlying this CNS
      complication are not clear. Experimental studies have suggested that neuronal
      apoptosis may play an important role in neuronal loss and impaired cognitive
      function. In diabetes multiple factors are responsible for neuronal apoptosis,
      such as a perturbed IGF system, hyperglycemia and the aging process itself.
      Recent data suggest that insulin/C-peptide deficiency may exert an eminent role.
      Administration of C-peptide partially corrects the perturbed IGF system in the
      brain and prevents neuronal apoptosis in hippocampus of type 1 diabetes. In
      neuroblastoma SH-SY5Y cells C-peptide provides a dose-dependent stimulation on
      cell proliferation and an anti-apoptotic effect as well. These studies provide a
      basis for administration of C-peptide as a potentially effective therapy for type
      1 diabetes.

PMID- 15198374
TI  - C-peptide and retinal microangiopathy in diabetes.
AB  - Increased extracellular matrix (ECM) protein deposition and capillary basement
      membrane (BM) thickening are characteristic features of diabetic retinal
      microangiopathy. Recent observations in the authors' laboratories suggest that
      high glucose in endothelial cells as well as diabetes causes up-regulation of
      total fibronectin (FN), as well as extradomain-B (EDB) containing the spliced
      variant of FN, oncofetal FN, in the retina. This splice variant is normally
      absent in mature adult tissues and is believed to be involved in angiogenesis. In
      this study, the authors have investigated the role of C-peptide in the production
      of ECM proteins and capillary BM thickening in the retina of diabetic rats. They
      investigated retinas from poorly controlled diabetic BB/Wor rats with or without
      C-peptide treatment as well as those from age-matched nondiabetic control rats
      after 8 months of diabetes. In addition, the authors investigated retinas from
      BBDRZ/Wor rats, a model of type 2 diabetes. Following a treatment period of 8
      months, retinal tissues were harvested for gene expression and histological
      analyses. In the retinas of diabetic BB/Wor rats, a significant increase of
      oncofetal FN was demonstrated compared to control rats. C-peptide treatment of
      BB/Wor rats completely prevented such increase. Furthermore, retinas from
      BBDRZ/Wor rats, did not exhibit any such alteration in oncofetal FN expression.
      The authors further examined retinal capillary BM thickening using
      ultrastructural morphometry. C-peptide treatment was ineffective in preventing
      the diabetes-induced increase in capillary BM thickness. The authors' previous
      studies of cultured endothelial cells demonstrated that oncofetal FN synthesis
      is, at least in part, mediated via transforming growth factor-beta (TGF-beta) and
      endothelin-1 (ET-1). Hence, they examined these two transcripts in the retina of
      these animals. Diabetes caused significant increase in mRNA expression of ET-1
      and TGF-beta, which was not prevented by C-peptide treatment. Hence it appears
      that C-peptide is effective in preventing diabetes-induced oncofetal FN
      expression and that these effects are not mediated via ET-1 or TGF-beta. In
      conclusion, these data suggest that C-peptide is involved in regulating ECM
      protein composition. Furthermore, normalization of diabetes-induced oncofetal FN
      up-regulation may suggest importance of C-peptide in advanced alterations in
      diabetic retinopathy such as angiogenesis.

PMID- 15198375
TI  - Is deafness a disease of poverty? The association between socio-economic
      deprivation and congenital hearing impairment.
AB  - An association between congenital hearing impairment and deprivation has been
      suggested, but evidence is limited. We studied children born in Greater Glasgow,
      1985-94, with bilateral congenital hearing impairment. The children were divided
      into seven deprivation categories using the Carstairs Deprivation Index. One
      hundred and twenty-four hearing-impaired children were born over the study
      period, an incidence of 1.18/1000 live births. There was a clear association
      between deprivation category and incidence, ranging from 0.47/1000 to 1.72/1000.
      An association with deprivation was seen for children with a family history and
      perinatal problems (such as prematurity and low birth weight). No association was
      found for other aetiological groups such as craniofacial syndromes or early
      postnatal infection. Deprivation had no effect on age of diagnosis or hearing aid
      provision. Deprivation is associated with congenital hearing impairment, due to
      more prematurity and low birth weight in deprived families, and the fact that
      families with many hearing-impaired members are economically disadvantaged. There
      should be a strong emphasis on the needs of the socio-economically disadvantaged
      when planning services for hearing-impaired children.

PMID- 15198376
TI  - Changes in hearing in 80-year-old people: a 10-year follow-up study.
AB  - The aims of this prospective 10-year longitudinal population study were to report
      changes in hearing in people aged 80 years at baseline, and to assess such
      changes by comparing results from both cross-sectional and longitudinal analyses.
      The study population comprised all residents of the city of Jyvaskyla born in
      1910 (n = 291). The subjects' hearing was tested on three occasions at 5-year
      intervals with the use of pure-tone audiometry, speech audiometry, and self
      report on hearing difficulties. The results showed a significant deterioration in
      hearing sensitivity in both the longitudinal and cross-sectional assessments over
      the 10-year follow-up. However, the change in self-assessed hearing difficulties
      was not significant. Hearing aids were not used by over 75%, of those who had
      moderate hearing impairment. Self-assessed hearing difficulties at baseline were
      associated with increased mortality. Hearing deterioration in elderly people and
      their low level of use of hearing aids deserve closer attention in the healthcare
      system.

PMID- 15198377
TI  - Audiological findings in Usher syndrome types IIa and II (non-IIa).
AB  - The aim was to define the natural history of hearing loss in Usher syndrome type
      IIa compared to non-IIa. People with Usher syndrome type II show moderate-to
      severe hearing loss, normal balance and retinitis pigmentosa. Several genes cause
      Usher syndrome type II. Our subjects formed two genetic groups: (1) subjects with
      Usher syndrome type IIa with a mutation and/or linkage to the Usher IIa gene; (2)
      subjects with the Usher II phenotype with no mutation and/or linkage to the Usher
      IIa gene. Four hundred and two audiograms of 80 Usher IIa subjects were compared
      with 435 audiograms of 87 non-IIa subjects. Serial audiograms with intervals of >
      or = 5 years were examined for progression in 109 individuals Those with Usher
      syndrome type IIa had significantly worse hearing thresholds than those with non
      IIa Usher syndrome after the second decade. The hearing loss in Usher syndrome
      type IIa was found to be more progressive, and the progression started earlier
      than in non-IIa Usher syndrome. This suggests an auditory phenotype for Usher
      syndrome type IIa that is different from that of other types of Usher syndrome
      II. Thus, this is to our knowledge one of the first studies showing a genotype
      phenotype auditory correlation.

PMID- 15198379
TI  - Validation of three adaptations of the Meaningful Auditory Integration Scale
      (MAIS) to German, English and Polish.
AB  - The Meaningful Auditory Integration Scale (MAIS) is a parent-report questionnaire
      for assessing auditory behaviour in aurally habilitated children. This study
      addressed the reliability and convergent validity of three different language
      versions of the MAIS: English, German, and Polish. In total, 114 parents
      (English, n = 27: Polish, n = 37; German, n = 50) completed the MAIS
      preoperatively and at 6 months after cochlear implantation. Internal reliability
      (Cronbach's alpha) ranged from 0.92 to 0.95 preoperatively, and from 0.87 to 0.93
      at 6 months. Split-half reliability was at least 0.90 preoperatively, and ranged
      from 0.76 to 0.89 at 6 months. Corrected item-total correlation coefficients were
      significant (p < 0.05) for all items except for item 1, which showed poor
      correlations in the Polish version. Correlation of the MAIS with the Listening
      Progress Profile (LP), as a measure for convergent validity, yielded coefficients
      between 0.81 and 0.73 preoperatively, and between 0.79 and 0.61 at 6 months.
      These findings demonstrate high reliability and convergent validity of the three
      MAIS versions.

PMID- 15198378
TI  - Relative benefits of linear analogue and advanced digital hearing aids.
AB  - Speech recognition performance and self-reported benefit from linear analogue and
      advanced (digital) hearing aids were compared in 100 first-time hearing aid users
      with mild-to-moderate sensorineural hearing loss fitted monaurally with a behind
      the-ear (BTE) hearing aid in a single-blind randomized crossover trial. Subjects
      used each aid for 5 weeks in turn, with aid order balanced across subjects. Three
      alternative models of digital hearing aid were assigned to subjects according to
      a balanced design. Aid type was disguised to keep subjects blind within practical
      limitations. Aided speech recognition performance in noise was measured at speech
      levels of 65 and 75dB at a speech-to-noise ratio (SNR) of +2dB for closed sets of
      single words. Self-rated benefit was measured using the Abbreviated Profile of
      Hearing Aid Benefit (APHAB) and the Glasgow Hearing Aid Benefit Profile (GHABP).
      Quality of life, hearing aid use and user preferences were also assessed. Speech
      recognition scores with the digital aids were significantly better at 75dB than
      with the analogue aids Self-reported benefit (APHAB, GHABP) and improvement in
      quality of life were generally not significantly different between analogue and
      digital aids, although aversiveness measured with the APHAB was significantly
      lower with digital aids, and satisfaction measured with the GHABP was greater.
      The digital aids were preferred significantly more often than the analogue aids,
      with 61 subjects choosing their digital aid, 26 choosing the analogue aid, and
      nine being equivocal. Overall, this study shows advantages for advanced digital
      over simple linear analogue aids in terms of both objective and subjective
      outcomes, although average differences are not large.

PMID- 15198380
TI  - The effects of 'supra-physiological' vitamin B12 administration on temporary
      threshold shift.
AB  - The aim of this study was to evaluate, in 20 young volunteer subjects, the
      effects of supra-physiological vitamin B12 administration on noise-induced
      temporary threshold shift (TTS). All subjects had hearing thresholds within 15
      dBHL and type A tympanograms. The subjects were randomly assigned to two
      different groups. Experimental group subjects received cyanocobalamin, 1 mg daily
      for 7 days, and 5 mg on the eighth day. Control group subjects received a placebo
      injection daily for 8 days. The vitamin B12 concentration, hearing thresholds and
      TTS2 (10 min of exposure, narrowband noise centred at 3 kHz, bandwidth of 775 Hz,
      112 dBSPL) were measured before and 8 days after treatment. At the end of
      treatment, the serum vitamin B12 concentration was significantly increased in the
      experimental group. After 8 days of treatment, the control group showed the same
      hearing thresholds and TTS2 degrees. Statistical analysis showed that TTS2
      decreased significantly at 3 and 4kHz when cobalamin was used to increase the
      serum concentration of vitamin B12 to > 2350 pg/ml. In addition, a protective
      effect at 3 kHz in the experimental group was evident when compared with the
      placebo group. These results suggest that elevated plasma cyanocobalamin levels
      may reduce the risk of hearing dysfunction resulting from noise exposure in
      healthy, young subjects.

PMID- 15198381
TI  - alpha-Tocopherol protective effects on gentamicin ototoxicity: an experimental
      study.
AB  - Gentamicin, acting as an iron chelator, activates membrane lipid peroxidation
      (MPL) and induces free radical formation, as observed in vitro and in vivo.
      Antioxidants, such as alpha-tocopherol, are able to suppress MLP, thus
      attenuating tissue damage. The present study was designed to investigate the
      possible protective effects of alpha-tocopherol on gentamicin ototoxicity. The
      study was carried out on albino guinea pigs (250-350 g). The animals were divided
      into four groups: group A (n = 4), injected with corn oil daily at a dose of 100
      mg/kg body weight intramuscularly (IM); group B (n = 10), treated with corn oil
      at a dose of 100 mg/kg body weight and gentamicin base at a dose of 100 mg/kg
      body weight (IM); group C (n = 10). treated with gentamicin alone at a dose of
      100 mg/kg body weight (IM); and group D (n = 10), treated with gentamicin at the
      same dose plus alpha-tocopherol acetate at dose of 100 mg/kg body weight (IM).
      Electrocochleographic recordings were made from an implanted round-window
      electrode. All animals were treated for 14 days. The compound action potentials
      (CAPs) were measured at 2-16 kHz at days 0, 10, 14 and 18 after treatment.
      Changes in cochlear function were characterized as CAP threshold shifts.
      Morphological changes were analysed by scanning electron microscopy. Gentamicin
      induced progressive high-frequency hearing loss of 50-60 dB SPL. alpha-Tocopherol
      co-therapy slowed the progression of hearing loss. The significant loss of outer
      hair cells (OHCs) in the cochlear basal turn in gentamicin-treated animals was
      not observed in the cochleas of animals protected with alpha-tocopherol. This
      study supports the hypothesis that alpha-tocopherol interferes with gentamicin
      induced free radical formation, and suggests that this drug may be useful in
      protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing
      loss.

PMID- 15198382
TI  - Double disability: the hearing-impaired blind in the Sultanate of Oman.
AB  - A survey to estimate the magnitude and causes of blindness and hearing loss was
      undertaken in Oman in 1996-97. An analysis correlating blindness with hearing
      loss is presented. Twenty-eight subjects among 11,400 examined had double
      disability, with a prevalence rate of 2.46/1000 (95% CI 1.55-3.36). Females and
      older age groups had a higher risk of double disability than did males (relative
      risk (RR) 3.95, 95%, CI 1.34-8.1) and younger age groups (RR 9.91, 95% CI 3.9
      21.2). Twenty-five per cent of subjects with double disability had curable
      blindness, while 33% had preventable blindness. Only 10% of subjects with double
      disability had curable causes of hearing loss. The number of cases with double
      disabilities in Oman might decrease, due to the improved healthcare in last two
      decades. However, the increase in the aging population necessitates intervention
      to prevent double disability. An emphasis on the prevention of blindness could
      address the problem more effectively.

PMID- 15198383
TI  - Characteristics of acute acoustical trauma in the Finnish Defence Forces.
AB  - In spite of strict safety regulations concerning firearm shooting, several
      hundred conscripts still suffer acute acoustical trauma (AAT) in the Finnish
      Defence Forces (FDF) every year, resulting in symptoms such as tinnitus and/or
      hearing impairment. The causes leading to AAT, causative weapons and mode and
      level of hearing protection were analysed to find out why so many AATs still
      occur in the FDF. The material consisted of 119 patients of the total 163 AAT
      patients treated at the Central Military Hospital during the year 2000. In 87.5%
      of cases, the AATs occurred in unprotected ears. The most common causative weapon
      was the assault rifle. Most of the AATs occurred during combat training in the
      field. Immediately after the AAT. 46.7% of conscripts had hearing impairment and
      94.2% tinnitus. Hearing loss, tinnitus or both were experienced by 45% of
      conscripts at the last follow-up. Careful planning of training exercises could
      probably prevent some but not all AATs.

PMID- 15198384
TI  - Chronic idiopathic orofacial pain. A long-term follow-up study.
AB  - Patients suffering facial pain that does not fit with the traditional diagnostic
      criteria and which does not respond to dental treatment constitute a clinical
      problem. These patients lack a proper diagnosis and are frequently exposed to
      excessive and inadequate invasive treatment. The aim of this investigation was to
      study the long-term development of pain and the result of treatment in a cohort
      of patients suffering chronic idiopathic facial pain. The 74 patients referred to
      the Facial Pain Diagnostic Group at the Karolinska Institute School of Dentistry
      between 1981 and 1992 were invited to take part in a follow-up study. As 16
      subjects were unwilling or unable to take part in the study and 13 had died, the
      remaining 45 were interviewed either in accordance with a standard protocol or by
      filling out a questionnaire mailed to them. The interview revealed that 10 were
      free of orofacial pain, but only 2 were totally free of pain. Over the 9-19
      years' follow-up period the relationship between facial pain and pain in the rest
      of the body had changed substantially. Of 14 patients and more than 100
      extractions, permanent pain relief was felt by only 3 patients. It is concluded
      that a diagnosis was given in only 2 cases. The distribution of the pain has
      changed dramatically. The low success rate of invasive treatments suggests that
      such therapeutic methods are to be considered contraindicated in patients
      suffering from idiopathic orofacial pain.

PMID- 15198385
TI  - Cytokines, matrix metalloproteinases and tissue inhibitor of metalloproteinases-1
      in gingival crevicular fluid from patients with Papillon-Lefevre syndrome.
AB  - The aim of the present study was to compare concentrations of cytokines, matrix
      metalloproteinases (MMPs) and a metalloproteinase inhibitor (TIMP-1) in gingival
      crevicular fluids (GCF) from sites with gingival inflammation in 28 young
      patients with Papillon-Lefevre syndrome (PLS), and in age- and gender-matched
      controls. Each group consisted of 17 females and 11 males with a mean age of 11.0
      years (range 4-22 years). In both groups, anterior upper sites with a clinical
      diagnosis of gingival inflammation and with pockets < or = 3 mm were selected for
      sampling of GCF, which was carried out with filter disks inserted into the
      gingival crevice until saturated. The concentrations of cytokines (IL-1alpha, IL
      1beta, TNF-alpha, and IL-8), matrix metalloproteinases (MMP-1, MMP-3, MMP-8, and
      MMP-9), and their tissue inhibitor (TIMP-1) were analysed using commercial ELISA
      kits. Significantly higher levels of IL-1beta (P < 0.001) and MMP-8 (P < 0.05)
      were disclosed among the PLS patients compared with their controls, while the
      opposite was found for IL-8 (P < 0.05) and MMP-1 (P < 0.001). The individual
      variations were considerable in both groups. When comparing the expression of
      cytokines, MMPs, and TIMP-1 in PLS patients with clinically active and non-active
      periodontitis, the non-active PLS patients showed significantly higher values of
      IL-1beta than the patients with active periodontal disease (ANOVA, P < 0.01). In
      conclusion, this study was unable to demonstrate a clear-cut pathognomonic
      expression of cytokines or MMPs in patients with PLS, but further studies on
      cytokine and MMP output are warranted.

PMID- 15198386
TI  - Dental caries among the elderly in Norway.
AB  - OBJECTIVES: [corrected] To describe the occurrence of decayed teeth (DT), missing
      teeth (MT), filled teeth (FT), and the total sum score DMFT in elderly Norwegian
      pensioners, 67 years or more. BASIC PROCEDURES: A representative sample of 582
      elderly Norwegians (12.5% receiving social care) participated in a nationwide
      study (46% men and 54% women). In all, 394 (68%) still had some of their own
      teeth. A standardized clinical examination was performed by one of the authors
      (BMH) using well-defined criteria. MAIN FINDINGS: Mean DT was 0.46, FT was 8.4,
      and DMFT was 25.4. Mean number of root remnants was 0.11. Mean DT, FT, DMFT, and
      root remnants for the dentate participants were 0.67, 12.4, 24.1, and 0.17,
      respectively. Men had significantly higher DT than women. DT decreased with
      increasing age. Only small differences were found in the prevalence of dentate
      individuals with caries between gender, age groups, geographical regions, and
      residence in areas of varying population density. CONCLUSION: It seems that
      caries is a minor problem in the Norwegian elderly population. Age and the number
      of remaining teeth do not have a decisive role in the development of caries.
      Further, there are no differences in these respects between geographical areas in
      Norway.

PMID- 15198387
TI  - Reasons for restorative therapy and the longevity of restorations in adults.
AB  - The aim of this study was to obtain information on the restorative dental care of
      adults in Finland. A random sample of private dentists was drawn from the
      register, and in spring 2000 they were sent a questionnaire requesting them to
      record information for each restoration placed during one ordinary working day. A
      total of 800 dentists were contacted and 548 responded. The dentists reported
      placement of 3,455 restorations. Of these, 5% were Class I, 36% were Class II,
      13% were Class III, 9% were Class IV, 21% were Class V, and 16% were extensive
      restorations including 4 or more surfaces. Overall, composite resin was the most
      common restorative material, and it was used in 79% of the restorations, whereas
      amalgam was used in 50%, compomers in 4%, and glass ionomers (either conventional
      or resin-modified) in 7% of cases. In 5%, of the cases, the tooth was restored
      with indirect restorative methods, using either gold or ceramic materials. Of the
      treatments, 65% were replacements of previous restorations. Secondary caries was
      the most common reason for replacement (36%, 52%, and 41% for composite, glass
      ionomer, and amalgam, respectively). Other common reasons were fractures of the
      tooth or restoration (23%, 11%, and 22% for composite, glass ionomer, and
      amalgam, respectively) and lost composite restorations (16%). The median age of
      failed restorations was 15 years for amalgam, 6 years for composite, and 7 years
      for conventional glass ionomer. Although the longevity of tooth coloured
      restorations was shorter than that of amalgam, comparisons with our previous
      studies indicate improved survival periods for tooth coloured materials.

PMID- 15198388
TI  - Flexural strength and modulus of a step-cured resin composite.
AB  - In an attempt to reduce marginal contraction gaps, a step-curing mode of light
      polymerization of resin composite has been proposed. It was hypothesized that
      such an exposure mode, having an initial reduced curing rate, would result in
      composite having a lower modulus of elasticity than composite exposed in one
      step. The composite was initially exposed to power density levels of 50, 100,
      150, or 200 mW/cm2 for durations of 10, 20, or 40 s. The final exposure and the
      exposure of the control group were performed at 750 mW/cm2 for 20 s. It was found
      that certain modes of two-step exposure resulted in a lower flexural modulus than
      did a one-step exposure of constant, high power density. Regression analysis
      showed, with statistical significance, that flexural modulus was relatively high
      following a short initial exposure at low power density or using a long initial
      exposure at high power density. Conversely, flexural modulus was relatively low
      following a long initial exposure at low power density or using a short initial
      exposure at high power density. The results were explained by probable
      differences in degree of conversion and cross-link density of the polymer
      network.

PMID- 15198389
TI  - Dental treatment need among 20 to 25-year-old Swedes: discrepancy between
      subjective and objective need.
AB  - Our aim was to analyze variables from a questionnaire sent to 20 to 25-year-old
      Swedes to determine how they perceive their oral treatment need, and to determine
      which variables affect this perception. The questionnaire was sent to 650
      individuals randomly selected from the database of the National Social Insurance
      Board of Sweden. The response rate was 78%. Another questionnaire was sent to the
      dentists of these young adults in order to collect clinical information. The
      response rate was 66%. The respondent's answer to the question 'How do you rate
      your dental treatment need today?' was dichotomized and used as a dependent
      variable in a multivariate logistic regression model. Each increase in number of
      decayed-filled teeth led to a 13% increased treatment need, bad oral hygiene a
      2.24-fold increase, and no periodontal disease an 80% reduction in treatment
      need. A higher education beyond comprehensive school increased the perceived
      treatment need 7.16 times; a poorer dental health than one's contemporaries led
      to a 14.47-fold increase. When dentist and patient assessments were combined,
      variables related to the patients' self-assessments were the only significant
      contributors to the statistical model. A lack of concordance between patients'
      and dentists' assessments of treatment need was found which highlighted the
      differences between patients' and dentists' views on treatment need. This study
      shows the importance of communication between dentist and patient.

PMID- 15198391
TI  - Effects of filler size, water, and alcohol on hardness and laboratory wear of
      dental composites.
AB  - Three UEDMA/TEGDMA (50:50 by weight) based dental composites were made, each with
      filler loadings of 53 vol.%. The three composites contained silane-treated filler
      particles with average particle diameters of 1.5, 3.0, or 10.0 microm. Twelve
      specimens per composite were mounted on wear wheels and run through 200,000
      cycles in an ACTA wear machine. Six of these specimens per material were worn in
      slurries consisting of 30 g ground Millet seed shells and 120 g ground rice mixed
      with 275 mL water. The remaining six specimens were worn in similar 25% ethanol
      water slurries. The composite wear profiles were recorded with a profilometer and
      used to calculate the wear. Hardness values of the composites were also measured
      both before and after storage for 2 weeks in either water or in a 25% ethanol
      water solution. The wear and hardness values from the measurements were analyzed
      using ANOVA. The wear analysis showed that the finer composites (1.5 microm
      filler diameter) wore the least and the coarsest composites (10 microm filler
      diameter) the most. The wear was significantly higher in the ethanol water slurry
      than in the water slurry. The hardness value of the coarsest composite decreased
      more than the finest composite during storage in water or 25% ethanol water. The
      hardness decrease was most pronounced in the alcohol solution.

PMID- 15198392
TI  - Healthy work for female unpromoted general practice dentists.
AB  - This study describes how female unpromoted general practice dentists (GPDs) in a
      region in Sweden perceive 'healthy work', i.e. their image of the dimensions that
      the dentistry profession should contain if it is to be really healthy work. The
      study also investigates whether there is a gulf between ideal and reality for
      this group. All unpromoted GPDs within the Public Dental Health Service's general
      practice in a region in Sweden received a questionnaire, and 94% responded. The
      data were collected during July and August 2000 and the question about healthy
      work was taken from work environment studies. A principal components analysis was
      performed. Three factors explaining more than half the variance (53%) formed
      three well-defined vector clusters: 1) a factor for moral values and
      possibilities for skill discretion, i.e. properties specific for human services,
      2) a factor for career development, and 3) a factor for work environment. We
      found that factor 1 alone explained a greater proportion of the variance (28%)
      for the respondents. The main results were that the female unpromoted GPDs
      emphasized free and intellectually stimulating work and that the gulf between
      ideal and reality was wide, especially concerning the dentist's influence on
      important decisions. A salutogenetic approach built on good communication and
      democracy at work, and based on freedom and the employees' influence, could bring
      ideal and reality closer.

PMID- 15198390
TI  - Curing depths of a universal hybrid and a flowable resin composite cured with
      quartz tungsten halogen and light-emitting diode units.
AB  - This in vitro study evaluated curing depths of a universal hybrid resin composite
      with two viscosities (Tetric Ceram and Tetric Flow) after curing with 6 different
      quartz tungsten halogen and light-emitting diode curing units. Irradiance (light
      intensity) of the curing units varied between 200 and 700 mW/cm2. The curing
      units were used for standard, soft-start, or pulse curing. Curing times were 20
      and 40 s for standard curing, 3 + 10 s and 3 + 30 s for pulse curing, and 40 s
      for soft-start. Resin composite specimens, 5 in each group, with a diameter of 4
      mm and a height of 6 mm, were made in brass molds and cured from one side at a
      distance of 6 mm. After 2 weeks, the specimens were ground longitudinally half
      through the specimen. Curing depth was then determined by measurement of Wallace
      hardness for each half millimeter starting at 0.5 mm from the top surface. For
      all curing units and for both resin composites an increased curing time led to
      statistically significantly higher depth of cure (P < 0.0005). Tetric Flow showed
      a statistically significantly higher depth of cure than Tetric Ceram (P <
      0.0005). All curing units cured more than 2.0 mm of both composites from a
      distance of 6 mm at 20 s curing time. The value for 40 s was 3.0 mm. The
      composite closer to the surface than the depth of cure value was equally well
      cured with all curing units investigated. There was a significant linear
      correlation between the determined irradiance of the curing units and the depths
      of cure obtained (20s: r = 0.89, P < 0.025; 40 s: r = 0.91, P < 0.01).

PMID- 15198393
TI  - Self-reporting of periodontal diseases and clinical assessment outcome in a
      Swedish urban population of smokers and non-smokers.
AB  - The aim of this study was to determine whether there is an association between
      self-reporting of periodontal diseases and outcome in a clinical examination, and
      whether any difference is present in awareness of periodontal status between
      smokers and non-smokers. Participants comprised 1676 adults (838 M and 838 F aged
      between 31 and 40 years), 564 of whom reported being smokers. Subjects were asked
      via questionnaire whether they thought they had periodontal disease and why. A
      total of 1655 subjects answered the questionnaire and were subsequently divided
      into those who suspected having periodontal disease (Yes-group) and those who did
      not (No-group). A full-mouth clinical examination was carried out in all
      subjects. Female smokers in the Yes-group had a significantly higher number of
      teeth with pockets > or = 5 mm (P < 0.001) and a higher calculus index (CI-S, P <
      0.01) than female smokers in the No-group. Male smokers in the Yes-group had
      significantly less remaining teeth (P < 0.01), more teeth with pockets > or = 5
      mm (P < 0.001), and a higher CI-S (P < 0.05) than their counterparts in the No
      group. For smokers, multivariate logistic regression analysis yielded an odds
      ratio (OR 3.21 [95% CI 1.73 5.74]) of self-reported periodontal disease to
      periodontitis outcome which was significant (P < 0.001). This association
      remained significant (P < 0.01) after adjustment for confounding factors.
      Subjects who reported having periodontal disease, especially those who also
      reported having movable teeth, were confirmed to have the disease. Smokers were
      more aware of their periodontal status than non-smokers.

PMID- 15198394
TI  - Caries prevention.

PMID- 15198395
TI  - Changing sex ratio--the dark horizon.

PMID- 15198396
TI  - Prevention of diabetes.

PMID- 15198397
TI  - The Pre-conception and Pre-natal Diagnostic Techniques (Prohibition of Sex
      Selection) Act, 1994. (As amended up to 14.02.2003).

PMID- 15198398
TI  - The Pre-conception and Pre-natal Diagnostic Techniques (Prohibition of Sex
      Selection) Rules, 1996. (As amended up to 14.02.2003).

PMID- 15198399
TI  - The Pre-natal Diagnostic Techniques (Regulation and Prevention of Misuse)
      (Advisory Committee) Rules, 1996.

PMID- 15198400
TI  - Public Interest Litigation (PIL) filed by Centre for Health and Allied Themes
      (CEHAT) and others in the Supreme Court of India in 2000.
AB  - The Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act,
      1994 [now renamed as Pre-conception and Pre-natal Diagnostic Techniques
      (Prohibition of Sex Selection) Act, 1994] came into operation with effect from
      01.01.1996. The implementation of the Act rests with the States and UTs. However,
      nothing much happened till there was Public Interest Litigation (PIL) filed by
      Centre for Health and Allied Themes (CEHAT) and others in the Supreme Court of
      India in 2000. The Supreme Court intervened in response to this PIL and taking
      cognizance to the situation and prayers of the petitioners, ordered strict
      enforcement of the Act and gave number of directions in its several hearings. The
      Court heard the matter about 20 times since 2001. The PIL was disposed of in its
      last hearing on 5.9.2003. The final judgment dated 10.09.2003 reiterates all the
      earlier directions of the Supreme Court issued to Central Government, States/UTs
      for proper implementation of the Act.

PMID- 15198401
TI  - Foetomaternal complications in pregnancies with diabetes mellitus: association
      with the amount of insulin requirement, mean terminal blood glucose and HbA1C
      levels.
AB  - Pregnancy hyperglycaemia can lead to foetomaternal complications. Normoglycaemia
      with exercise, diet and/or insulin can alter outcomes. The insulin requirement
      itself may alter outcomes independently. Two hundred and forty patients of
      pregnancy with diabetes mellitus were selected of which 176 belonged to
      gestational diabetes mellitus and 64 pregestational diabetes mellitus groups.
      Insulin requirement of pregestational diabetes mellitus group was 1.8 times
      higher than the gestational diabetes mellitus group. There were no insulin
      related increased complications in either group. The foetal complications were
      higher in pregestational diabetes mellitus group (62.5%) than in the gestational
      diabetes mellitus group (27.3 and 40% in < 15 units or > or = 15 units insulin
      requirement respectively). The terminal glycaemic parameters (fasting plasma
      glucose, 2 hours postprandial plasma glucose, HbA1C%) were not different in case
      of gestational diabetes mellitus between those with and without foetal
      complications, except for fasting plasma glucose where 'with complications'
      fasting plasma glucose was lower than without (79.4 +/- 13.14 versus 75.28 +/-
      3.68 mg/dl). For pregestational diabetes mellitus patients those without
      complications had a significantly lower level of all the parameters (fasting
      plasma glucose 69.75 +/- 0.5 versus 122 +/- 14.14 mg/dl, postprandial plasma
      glucose 95 +/- 7.4 versus 131.5 +/- 12.02 mg/dl; HbA1C 6.8 +/- 0.28 versus 7.3 +/
      3.6%) compared with those having complications. Maternal complications could not
      be segregated as all the subgroups had a very incidence of caesarean section (60%
      100%). However, when lower segment caesarean section was excluded and maternal
      complications segregated, for gestational diabetes mellitus patients, only
      fasting plasma glucose was significantly lower in cases without complications
      while in pregestational diabetes mellitus patients the fasting plasma glucose as
      well as HbA1C were significantly lower in cases without complications.

PMID- 15198402
TI  - Special considerations for effective blood pressure control in diabetes.
AB  - On the one hand, there is a steep rise in the incidence of both diabetes mellitus
      as well as hypertension. On the other hand, this phenomenon has led to
      significantly increased morbidity and mortality. The focus in the coming years,
      therefore, would be obviously on special considerations and special strategies
      required for effective control of blood pressure in people suffering from
      diabetes. In a patient with diabetes mellitus and hypertension, achieving
      normotension is as important as achieving euglycaemia. Consensus is in favour of
      aggressive lifestyle modifications. Polypharmacy is emphasised for optimal
      control. The pharmacological treatment differs due to effects of certain drugs on
      lipid profile, insulin sensitivity and glucose metabolism.

PMID- 15198403
TI  - Diagnosis and management of diabetes in pregnancy.
AB  - Diabetes and pregnancy encompass not only pregestational diabetes mellitus but
      also any form of abnormal glucose tolerance during gestation. While screening for
      glucose intolerance is mandatory for high-risk patients in pregnancy, it is not
      required in others. There are various methods for screening of gestational
      diabetes mellitus eg, urine glucose detection, O'Sullivan screening test, WHO
      criteria, etc. Proper management of diabetes in pregnancy can arrest foetal
      mortality and morbidity. Practical self management skills are essential for
      attaining good glycaemic control. Management of gestational diabetes mellitus
      rests on the idea of medical nutrition therapy and insulin therapy.

PMID- 15198404
TI  - Role of clinical biochemistry laboratory in the diagnosis of diabetes mellitus.
AB  - Clinical biochemistry and laboratory help is needed at all stages of diagnosis of
      diabetes. Laboratory plays a key role in the management of diabetes and its
      complications like renal, metabolic, and others. Monitoring of treatment is also
      guided by regular blood sugar estimation and self-monitoring of blood glucose
      level.

PMID- 15198405
TI  - Role of general practitioners in cancer management.
AB  - In the scenario of increasing incidence of malignancies and lack of specialist
      centres, the role of general practitioners is increasing, especially in India. It
      is estimated that above 50% cancers are curable if they are detected early and
      treated in appropriate algorithm. Screening has got a major role in early
      diagnosis. Supportive care to alleviate the symptoms of cancer and its treatment
      is important for continuation of curative treatment and greater ailment-free
      survival. Psychological support, assurance and proper information to patients and
      family members and forming a healthy network between different levels of medical
      professionals can form the gateway to combat the disease.

PMID- 15198406
TI  - Community health insurance.

PMID- 15198408
TI  - Changing scenario of childhood illnesses.

PMID- 15198409
TI  - Rational use of blood and blood components in paediatric practice.

PMID- 15198407
TI  - Evaluation of the efficacy, safety and tolerability of valdecoxib gel (1%) in
      adult patients with painful inflammatory joint disease.
AB  - Valdecoxib, a COX-2 inhibitor, has recently been introduced as a gel formulation.
      The present study was conducted to evaluate the efficacy, safety and tolerability
      of valdecoxib gel in adult patients with painful inflammatory joint conditions.
      The present study was a 10-day prospective, open, multicentric (6 centres) trial.
      Patients with clinical and radiological diagnosis of painful inflammatory joint
      conditions were treated with valdecoxib gel (1%). Efficacy was assessed by visual
      analogue scale (VAS), patient's and physician's global assessment of pain relief.
      Grading of associated clinical manifestations such as stiffness, swelling,
      tenderness and restriction of mobility was done. Tolerability and safety was
      assessed by physical examination, laboratory parameters and evaluation of adverse
      events. There was a statistically significant decrease in the mean pain visual
      analogue score (p<0.05). Onset of pain relief was within 15 minutes. There was a
      reduction of 58.8%, 57.2%, 65.4% and 60.2% in mean scores of stiffness, swelling,
      tenderness and mobility respectively from the baseline which was statistically
      significant. The laboratory values were within normal limits. The drug was well
      tolerated. There was no report of any hypersensitivity reaction. This study
      confirms that valdecoxib gel (1%) is an effective and safe option for the
      management of painful inflammatory joint conditions.

PMID- 15198410
TI  - Perioperative management of pregnant patients with heart disease for caesarian
      section under anaesthesia.
AB  - One hundred pregnant patients, of age group 22 to 35 years, with different types
      of cardiac ailments (mitral stenosis, mitral regurgitation, mitral valve
      prolapse, aortic regurgitation, atrial septal defect, ventricular septal defect,
      coarctation of the aorta, Eisenmenger syndrome, hypertrophic obstructive
      cardiomyopathy and operated tetralogy of fallot), put up for elective caesarian
      section underanaesthesia, were managed in the department of anaesthesiology at
      IPGME&R/SSKM Hospital, Kolkata from January 1996 to December 2002. The aim of the
      study was to observe the maternal and foetal outcome in different heart diseases.
      Death occurred in 2 patients (67%) with Eisenmenger syndrome, in one patient
      (20%) with hypertrophic obstructive cardiomyopathy and in one patient (5%) with
      critical mitral stenosis (mitral orifice area = 0.6 cm2) with pulmonary arterial
      hypertension (PAH). Neonatal mortality was observed in 4 patients [Eisenmenger
      syndrome--3 (100%); coarctation of the aorta--1 (33%)]. Another 8 patients
      developed severe heart failure (HF) [severe mitral stenosis (mitral orifice area
      = 1-1.2 cm2)--2 (10%); hypertrophic obstructive cardiomyopathy--4 (80%);
      coarctation of the aorta--2 (66%)]. Foetal dysmaturity was observed in 20
      neonates (54%) belonging to mothers of New York Heart Association (NYHA) classes
      III and IV. Congenital heart disease (ventricular septal defect) was detected in
      3 offsprings (20%) of mothers with ventricular septal defect. The study concludes
      that most pregnant cardiac patients can have a satisfactory outcome with careful
      perioperative management.

PMID- 15198411
TI  - Comparison of ondansetron, dexamethasone, ondansetron plus dexamethasone and
      placebo in the prevention of nausea and vomiting after laparoscopic tubal
      ligation.
AB  - Laparoscopic tubal ligation is associated with an appreciably high rate of
      postoperative nausea and vomiting. This study was designed to compare the
      effectiveness of ondansetron, dexamethasone, ondansetron plus dexamethasone or
      placebo in the prevention of postoperative nausea and vomiting in patients after
      laparoscopic tubal ligation. In a prospective, randomised, double blind placebo
      controlled trial, 160 ASA I-II females received one of four regimens; ondansetron
      4 mg, dexamethasone 8 mg, ondansetron 4 mg plus dexamethasone 8 mg or placebo
      (n=40 each) intravenously immediately before induction of anaesthesia. Patients
      were then observed for 24 hours postoperatively. The incidence of emetic episodes
      in the ondansetron with dexamethasone group was lower than in the placebo
      (p<0.001) and ondansetron (p=0.091) and dexamethasone (p=0.143) groups. A
      complete response (as no postoperative nausea and vomiting) was achieved in 60%
      of patients given ondansetron, 63% of the patients given dexamethasone, 78% of
      patients given ondansetron with dexamethasone and 37% of patients received
      placebo. The prophylactic use of ondansetron with dexamethasone is more effective
      in preventing postoperative nausea and vomiting.

PMID- 15198412
TI  - Pitfalls in the diagnosis of pulmonary primary complex.
AB  - The phenomenon of overdiagnosis of pulmonary primary complex (PPC) results in
      unnecessary and prolonged treatment with antituberculous drugs, which are often
      hepatotoxic. To overcome the pitfalls in the diagnosis of PPC, the author has
      described, in detail, the reasons for overdiagnosis and the nature of mistakes in
      arriving at the diagnosis.

PMID- 15198413
TI  - Overview of adolescent problems.
AB  - Adolescent care has ever been unsatisfactory. The author has discussed the need
      for adolescent care policy for India, the adolescent problems in India and the
      adolescent care policy instruments, in depth, looking at the possibility of
      empowering the adolescents--the future parents of India.

PMID- 15198414
TI  - Management of acute asthma in children.
AB  - In spite of significant advances in pulmonary medicine, the prevalence of asthma
      is increasing both in the developing as well as in the developed countries. The
      impotant management principles are discussed in this article, at length. Health
      education for the asthmatics and their parents has been stressed.

PMID- 15198415
TI  - Management of febrile seizures.
AB  - Febrile seizures are seizures associated with fever of extracranial origin. The
      preventive and long-term management aspects of febrile seizures are briefly
      discussed in this article.

PMID- 15198416
TI  - Management of acute diarrhoea in children.
AB  - Acute diarrhoeal disease is one of the major killers in children in the
      developing countries. A management protocol consisting of "Triple A" (assessment,
      analysis of clinical presentation and action plan protocol) approach has been
      found to be rewarding in our set-up. The matter has been dealt with by the
      authors in this article in its proper perspective.

PMID- 15198417
TI  - Laboratory investigations for rheumatic disease.
AB  - Laboratory investigations are very important tools in the diagnosis of rheumatic
      diseases. Nowadays a large number of tests are available. The authors have
      discussed some important tests of value in day to day practice.

PMID- 15198418
TI  - Conjunctival rhinosporidiosis.
AB  - Conjunctival rhinosporidiosis is usually a surprise diagnosis in histological
      section of an excised conjunctival mass. The condition is rarely encountered
      outside the endemic coastal areas of South India. Accurate diagnosis of this rare
      condition is infrequent in clinical practice; tumour, neoplasm, papilloma being
      the common misdiagnoses. Herein, a report of a case of an 18-year-old otherwise
      healthy male who attended outpatient department of Regional Institute of
      Ophthalmology, Medical College, Kolkata with a red fleshy papillomatous growth
      about 7 mm x 4 mm in size, in the palpebral conjunctiva just behind the
      intermarginal strip of his right upper lid. His routine blood examination was
      within normal limits. The growth was excised under local anaesthesia and
      histopathological examination revealed rhinosporidiosis. There was no recurrence
      of the growth within one month of follow-up.

PMID- 15198420
TI  - Health messages in mass media.

PMID- 15198419
TI  - A case of disseminated hydatidosis.
AB  - A young lady initially found to have hydatid cysts in the lung only, subsequently
      within a very short period was found to develop cysts in the liver. Soon after,
      she developed cysts in the subcutaneous tissue over the anterolateral chest wall,
      which, on investigation, revealed hepatic cysts herniating through the chest wall
      defects caused by previous operations. The unique features of this case include
      the degree of dissemination, the multiplicity of sites and the peculiar nature of
      herniation of the hepatic cysts into the parietes.

PMID- 15198421
TI  - Improved cure rates in pulmonary tuberculosis category II (retreatment) with
      mycobacterium w.
AB  - A controlled study to improve sputum conversion rate of current short course
      chemotherapy using immunomodulator containing mycobacterium w had been shown
      earlier. The same randomised study was continued further till the end of therapy.
      At the end of the intensive phase, sputum conversion rate in category II was
      75.51% in mycobacterium w (MW) group as compared to 51.85% in the control group.
      The cure rate in category II was 97.96% and 77.77% in MW and control groups,
      respectively. Treatment failure in category 11 was 2.04% and 22.22% in MW and
      control groups respectively. The therapy was well tolerated.

PMID- 15198422
TI  - The challenge of managing the utilization of biologics in an era of evolution and
      growth.

PMID- 15198424
TI  - The pharmacy director's view of the implications of dose escalation.

PMID- 15198423
TI  - Infliximab dose and charge escalation patterns in managed care.

PMID- 15198425
TI  - Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a
      salting-out procedure. I: Development and optimization of the process using
      factorial design.
AB  - The congealable disperse phase method for preparing sustained release
      microspheres involves an emulsification process using water as the external phase
      and molten hydrophobic wax as the disperse phase into which the drug is loaded.
      Attempts to entrap highly water-soluble drugs using this process have often
      resulted in low loading efficiency as the drugs partition into the external water
      phase during emulsification and are lost. A novel method employing salts and
      wetting agents was developed to improve the loading efficiency of the highly
      water-soluble drug, guaifenesin, using this method. The drug/wax ratio (D/W) and
      the presence of salts and wetting agents greatly influenced microsphere
      properties. To optimize the process for drug loading efficiency and release rate,
      three different D/Ws, salts and wetting agents were chosen and a full 3(3)
      factorial design experiment was performed. Any significant differences among the
      levels of the variables and their individual and joint effects on entrapment
      efficiency and T50 (time for 50% drug release) were determined. Entrapment
      efficiencies in the range 35.1-86.3% were obtained for the various factor-level
      combinations of the variables. Particle size was in the range 140-385 microm and
      T50 was 0.59-2.72 h for the microspheres obtained. The D/W and type of salt used
      significantly affected drug entrapment and T50, while the nature of wetting agent
      was not significant at p < 0.05. The microspheres prepared using 1:4 D/W showed
      the highest entrapment efficiency and slowest drug release.

PMID- 15198426
TI  - Microencapsulation of hydrophilic drug substances using biodegradable polyesters.
      Part II: Implants allowing controlled drug release--a feasibility study using
      bisphosphonates.
AB  - The prolonged delivery of hydrophilic drug salts from hydrophobic polymer
      carriers at high drug loading is an ambitious goal. Pamidronate disodium salt
      (APD) containing implants prepared from spray-dried microparticles were
      investigated using a laboratory ram extruder. An APD-containing polymer matrix
      consisting of an APD-chitosan implant embedded in the biodegradable polymer D,L
      poly(lactide-co-glycolide acid-glucose) (PLG-GLU) was compared with a matrix
      system with the micronized drug distributed in the PLG-GLU. The APD-chitosan
      matrix system showed a triphasic release behaviour at loading levels of 6.86 and
      15.54% (w/w) over 36 days under in-vitro conditions. At higher loading (31.92%),
      a drug burst was observed within 6 days due to the formation of pores and
      channels in the polymeric matrix. In contrast, implants containing the micronized
      drug showed a more continuous release profile over 48 days up to a loading of
      31.78% (w/w). At a drug loading of 46.17% (w/w), a drug burst was observed. Using
      micronized drug salts and reducing the surface area available for diffusion,
      parenteral delivery systems for highly water-soluble drug candidates were shown
      to be technically feasible at high drug loadings.

PMID- 15198427
TI  - Role of solvent/non-solvent ratio on microsphere formation using the solvent
      removal method.
AB  - The importance of good solvent concentration in the non-solvent mixture and the
      non-solvent viscosity on the ability to form microspheres using solvent removal
      process was investigated. The higher the viscosity of the polymer solutions, the
      higher the concentration of good solvent needed in the nonsolvent mixture to
      produce microspheres. This finding was due to faster precipitation of the polymer
      phase. Also, the addition of a model drug, fluorescein isothiocyanate conjugated
      labelled bovine serum albumin, to the polymer solution (10% poly-L-lactic
      acid:poly(fumaric-co-sebacic) anhydride in methylene chloride) resulted in an
      overall lower polymer solution viscosity (15.5 cP with fluorescein isothiocyanate
      conjugated-labelled bovine serum albumin as compared with 18.25 cP for blank
      polymer at 25 degrees C). Additionally, the effect of good solvent concentration
      on non-solvent viscosity was evaluated, and the viscosity decreased as the
      concentration of good solvent increased. The effect of good solvent concentration
      on the non-solvent mixture on sphere formation was of great importance.
      Microspheres would not form when the good polymer solvent (methylene chloride) in
      the non-solvent phase was too low (below 175 ml for poly-L-lactic acid or 150 ml
      for poly(D,L-lactidco-glycolid)) or was replaced by another good solvent such as
      ethyl acetate, even though the same viscosity was achieved. It was shown that the
      concentration of the good solvent in the non-solvent mixture was more of a
      controlling factor than the viscosity of the non-solvent mixture in microsphere
      formation and the findings support the conclusion that diffusion is the main
      controlling parameter in solvent removal.

PMID- 15198428
TI  - Preparation and release studies of alkannin-containing microcapsules.
AB  - Microcapsules containing the pharmaceutical substance alkannin were prepared by
      the solvent evaporation method to enhance alkannin stability (reduce photo
      oxidation, polymerization), to decrease its hydrophobicity and to control its
      release rate. The effect of various parameters, such as the type of polymeric
      matrix, the type of surfactant used for microcapsules preparation and the
      addition of Pistacia lentiscus resin in the core, on the characteristics of the
      produced microcapsules and the release rate of alkannin were investigated
      experimentally. Among the polymers tested for matrix, ethylcellulose of viscosity
      46cp was the most successful, while ethylcellulose 10cp gave microcapsules with
      good morphological characteristics but high release rate. Beeswax resulted in
      flocculation and P. lentiscus resin with or without colophony as the matrix
      resulted in compact particles with no pores and much slower release, but did not
      allow alkannin to release easily from the matrix. Sodium dodecyl sulfate resulted
      in microcapsules with desirable morphological and physicochemical
      characteristics, while acacia and tragacanth gums were not indicated as
      surfactants in alkannin microencapsulation since they gave a high release rate
      and a great extent of particle size, respectively. The incorporation of Pistacia
      lentiscus resin in the capsule core increased loading and microencapsulation
      efficiency. Ethylcellulose of 46cp viscosity with sodium dodecyl sulfate as
      surfactant had the best characteristics studied for alkannin microencapsulation.
      Finally, the dissolution rate of alkannin from microcapsules was studied in a
      simulated intestinal and gastric environment and an external environment.
      Alkannin-containing microcapsules with improved properties can be used internally
      and externally as a new drug-delivery system.

PMID- 15198429
TI  - Effects of the permeability characteristics of different polymethacrylates on the
      pharmaceutical characteristics of verapamil hyhdrochloride-loaded microspheres.
AB  - Microspheres containing verapamil hydrochloride (VRP) were prepared with various
      polymethacrylates, with different permeability characteristics (Eudragit RS 100,
      Eudragit RL 100, Eudragit L 100 and Eudragit L 100-55) and also with mixtures of
      these polymers in a 1:1 ratio using the solvent evaporation method. The aim was
      to investigate the effects of the permeability of the polymers on drug release
      rates and the characteristics of the microspheres. To achieve these aims, yield,
      incorporation efficiency, particle size and the distribution of microspheres were
      determined, and the influence of the inner phase viscosities prepared with
      different polymer and polymer mixtures on particle size and the distribution of
      microspheres were evaluated. Surface morphologies of microspheres were observed
      by scanning electron microscope. Drug release rates from microspheres were
      determined by the half-change method using a flow-through cell. The results
      indicate that microspheres with different surface morphologies and statistically
      different yields and incorporation efficiencies could be prepared and their
      particle size and distribution xariances resulted from the viscosity of the inner
      phase. Dissolution profiles showed that the drug release rate could be modified
      depending on the permeability characteristics of polymethacrylates.

PMID- 15198430
TI  - Effect of different dispersing agents on the characteristics of Eudragit
      microspheres prepared by a solvent evaporation method.
AB  - Eudragit RS microspheres containing verapamil HCl for oral use were prepared
      using three different dispersing agents: aluminium tristearate, magnesium
      stearate and sucrose stearate, by a solvent evaporation method. The effects of
      the type and concentration of the dispersing agents and the inner phase polymer
      concentration on the size and T63.2%, (the time at which 63.2% of the drug is
      released) of microspheres were determined by multiple linear regression analysis.
      The morphology of microspheres was characterized by scanning electron microscopy.
      The surface of microspheres prepared with sucrose stearate was smoother and non
      porous and the drug release from these microspheres was the fastest. When
      aluminium tristearate or magnesium stearate were used as dispersing agents, the
      particle size of microspheres became smaller. Increasing amounts of these two
      dispersing agents led to the accumulation of their free particles onto the
      surfaces of the microspheres. The drug release from the microspheres was slower
      than that of the microspheres from sucrose stearate depending on their
      hydrophobic structures. According to the results of the multiple linear
      regression analysis among the dispersing agents used, aluminium tristearate
      showed the best correlation between the examined input (dispersing agent and
      polymer concentrations) and output (T63.2%. and particle size) variables.

PMID- 15198431
TI  - Fluconazole encapsulation in PLGA microspheres by spray-drying.
AB  - Fluconazole-loaded PLGA microspheres were prepared by the spray-drying process.
      The influence of some process parameters on the physical characteristics of the
      microspheres was evaluated. Neither type nor polymer concentration influenced
      significantly the mean diameter of the microspheres, their size distribution and
      encapsulation efficiency of the drug. However, the drug loading greatly affected
      their size and the physical state in which fluconazole can exist in the matrix of
      the carriers, and, thus, affected the release rate of the drug. Results obtained
      by differential thermal analysis and X-ray powder diffraction revealed that at
      low nominal drug loading, fluconazole was incorporated in an amorphous state or
      in a molecular dispersion in the matrix of the microspheres and at high nominal
      drug loading part of the drug was in a crystalline form. Release profiles of
      fluconazole from the microspheres displayed a biphasic shape. The duration and
      extent of each phase were affected mainly by polymer nature, drug loading and
      physical state in which fluconazole existed in the polymeric matrix.

PMID- 15198432
TI  - Stability and ocular tolerance of cyclophosphamide-loaded nanospheres.
AB  - The physical and chemical stabilities of several formulations of cyclophosphamide
      loaded polybutylcyanoacrylate (PBCA) nanospheres developed for an ophthalmic
      application as an immunosuppressive agent were studied over 6 months of storage
      at 4, 25 and 40 degrees C in different experimental conditions. The physical
      stability of nanospheres was followed by the study of morphological (visual
      appearance) and morphometrical properties (mean particle size and
      polydispersity). The pH and tonicity of the suspensions and the association
      efficiency of the drug to polymeric system were also analysed to evaluate their
      chemical stability. The behaviour of colloidal suspensions with storage
      conditions was also followed by differential scanning calorimetry. The
      degradation of PBCA was affected by temperature and pH. The average particle size
      of all nanospheres remained practically unchanged throughout the study, with the
      polydispersity index being less than 0.1, corresponding to a monodisperse system.
      At 40 degrees C, a loss of 25.9% of the initial association efficiency,
      especially in non-buffered pH 7.2 medium, was observed. The type of polymer
      degradation (surface erosion) was also determined by photon correlation
      spectroscopy. The results obtained from in vivo study of ocular tolerance
      indicate a good ocular tolerance for drug loaded to nanospheres.

PMID- 15198433
TI  - Therapy of West Nile virus infection.

PMID- 15198434
TI  - The emergence of West Nile virus in Canada.

PMID- 15198435
TI  - Manpower in the Canadian neurosurgical workforce: is a crisis looming?

PMID- 15198436
TI  - The growing pains of spinal surgery.

PMID- 15198437
TI  - Recover neuropathology.

PMID- 15198439
TI  - Treatment optimization in multiple sclerosis.
AB  - The treatment of multiple sclerosis has finally become possible with the advent
      of the current disease-modifying therapies (DMTs) that have had a significant
      impact on those living with this disease. Though demonstrating clear efficacy on
      a number of short-term outcome measures, unfortunately, these agents are not
      "cures" and many patients with multiple sclerosis continue to experience disease
      activity in spite of treatment. Clinicians are becoming more comfortable
      initiating therapy with DMTs, but it is now important to focus attention on
      monitoring the results of the chosen therapy and deciding whether or not a
      patient is responding well to treatment. At present, however, clinicians lack
      criteria for defining optimal versus suboptimal responses to DMTs as well as
      evidence-based guidelines on how to improve treatment outcomes. Using a recently
      published model as a framework, The Canadian Multiple Sclerosis Working Group
      developed practical recommendations on how neurologists can assess the status of
      patients on DMTs and decide when it may be necessary to modify treatment in order
      to optimize outcomes. The Canadian Multiple Sclerosis Working Group's
      recommendations are based on monitoring relapses, neurological progression and
      MRI activity. Other possible causes of suboptimal treatment responses or
      treatment failure are also considered.

PMID- 15198438
TI  - Canadian Association of Neuroscience review: axonal regeneration in the
      peripheral and central nervous systems--current issues and advances.
AB  - Injured nerves regenerate their axons in the peripheral (PNS) but not the central
      nervous system (CNS). The contrasting capacities have been attributed to the
      growth permissive Schwann cells in the PNS and the growth inhibitory environment
      of the oligodendrocytes in the CNS. In the current review, we first contrast the
      robust regenerative response of injured PNS neurons with the weak response of the
      CNS neurons, and the capacity of Schwann cells and not the oligodendrocytes to
      support axonal regeneration. We then consider the factors that limit axonal
      regeneration in both the PNS and CNS. Limiting factors in the PNS include slow
      regeneration of axons across the injury site, progressive decline in the
      regenerative capacity of axotomized neurons (chronic axotomy) and progressive
      failure of denervated Schwann cells to support axonal regeneration (chronic
      denervation). In the CNS on the other hand, it is the poor regenerative response
      of neurons, the inhibitory proteins that are expressed by oligodendrocytes and
      act via a common receptor on CNS neurons, and the formation of the glial scar
      that prevent axonal regeneration in the CNS. Strategies to overcome these
      limitations in the PNS are considered in detail and contrasted with strategies in
      the CNS.

PMID- 15198440
TI  - Doctors' duty to disclose error: a deontological or Kantian ethical analysis.
AB  - Medical (surgical) error is being talked about more openly and besides being the
      subject of retrospective reviews, is now the subject of prospective research.
      Disclosure of error has been a difficult issue because of fear of embarrassment
      for doctors in the eyes of their peers, and fear of punitive action by patients,
      consisting of medicolegal action and/or complaints to doctors' governing bodies.
      This paper examines physicians' and surgeons' duty to disclose error, from an
      ethical standpoint; specifically by applying the moral philosophical theory
      espoused by Immanuel Kant (ie. deontology). The purpose of this discourse is to
      apply moral philosophical analysis to a delicate but important issue which will
      be a matter all physicians and surgeons will have to confront, probably numerous
      times, in their professional careers.

PMID- 15198441
TI  - The aphasia quotient: the taxonomic approach to measurement of aphasic
      disability. 1974.
AB  - 150 aphasiacs and 59 controls were examined with a scorable, comprehensive
      battery, designed to be used by the clinician and the research worker. The
      subtests of Fluency, Information, Comprehension, Repetition and Naming were added
      and compared to a hypothetical normal of 100 obtaining the "aphasia Quotient."
      This is a measurement of the severity of language impairment. On the basis of
      their performance on the subtests, the patients were classified according to
      taxonomic principles into Global, Motor (Broca's), Isolation, Sensory
      (Wernicke's), Transcortical Motor, Transcortical Sensory, Conduction and Anomic
      groups (in order of severity). This classification is considered a clinically
      valid baseline for research, diagnosis and prognosis.

PMID- 15198442
TI  - Neurological manifestations of West Nile virus infection.
AB  - BACKGROUND: Over the past four years, West Nile virus (WNV) has become a
      significant health issue in North America. In 2002, WNV infection made its first
      appearance in the human population in Canada. METHODS: Patients who presented to
      the University Health Network and Mount Sinai Hospital in Toronto with
      neurological disease attributed to WNV infection were identified and followed by
      the neurology service. Clinical features and results of laboratory,
      electrodiagnostic, radiological and pathological studies are presented. RESULTS:
      In August and September 2002, 26 patients were admitted with WNV infection; 14
      presented with neurological illness. Encephalitis was the most common
      presentation (11 patients). Eleven patients developed neuromuscular disease; two
      at presentation and nine after encephalitis. While the majority had a motor
      process that localized to the anterior horn cell and/or motor neuron, two
      patients had evidence of a demyelinating neuropathy and one a sensorimotor axonal
      neuropathy. Less common manifestations included rhombencephalitis, ataxia,
      myelopathy and parkinsonism. Death occurred in four patients; two > 75 years of
      age, and two who were immunocompromised. CONCLUSIONS: The most common
      neurological manifestation of WNV infection was encephalitis with subsequent
      neuromuscular involvement. The diversity of clinical and pathological findings,
      however, suggests widespread involvement of the central and peripheral nervous
      system. A poorer prognosis for neurological recovery and overall survival was
      seen in older and immunocompromised patients.

PMID- 15198443
TI  - Calgary experience with West Nile virus neurological syndrome during the late
      summer of 2003.
AB  - BACKGROUND: Between August 25 and September 25, 2003 seven patients with West
      Nile virus neurological manifestations were identified through the hospital
      neurology consultation services in Calgary, Alberta, Canada. Three of the seven
      patients were treated with interferon alpha-2b (IFN alpha-2b). In this report we
      document the clinical characteristics of these seven cases. METHODS: Clinical and
      laboratory information was obtained from a retrospective review of patient
      hospital and clinic charts. Patients were included if they had serological
      evidence of West Nile virus infection and had clinical evidence of aseptic
      meningitis, encephalomyelitis, cerebellar syndrome or motor neuronopathy. Three
      patients received a treatment course of three million units IFN alpha-2b,
      administered by subcutaneous injection once per day for 14 days. RESULTS: Four
      patients had cerebellar signs without change in consciousness, two had both
      encephalitis and neuromuscular weakness, and one patient had focal lower motor
      neuron arm weakness. The mean age was 52 (range 24 - 73). All patients had flu
      like illness and fever as presenting symptoms and six had severe headaches. Two
      patients were immunocompromised prior to infection. Two patients with cerebellar
      signs (one with opsoclonus-myoclonus) improved spontaneously and exhibited only
      mild residual deficits on discharge. The other two patients with cerebellar
      findings developed brainstem involvement, one coinciding with and one subsequent
      to the cerebellar symptoms. Within one week of treatment with IFN alpha-2b these
      latter two patients showed marked improvement. One patient with encephalitis and
      neuromuscular weakness, was treated with IFN alpha-2b and subsequently recovered.
      INTERPRETATION: In this case review of seven patients, multiple neurological
      symptoms occurred in each patient and the neurological presentation was varied.
      Four patients had predominant cerebellar findings and one patient had opsoclonus
      myoclonus, not previously reported. The marked improvement in three patients who
      received IFN alpha-2b raises preliminary optimism towards this potential
      treatment.

PMID- 15198444
TI  - Spinal subspecialization in post-graduate neurosurgical education.
AB  - BACKGROUND: The growing science and technology of various neurosurgical areas
      fosters subspecialization. The transmission of this expanding knowledge base to
      the neurosurgical resident becomes an increasing challenge. A survey of
      neurosurgical residency program directors was undertaken to evaluate their
      response to the budding subspecialization of spine surgery within general
      neurosurgery. METHODS: A survey requesting background data, educational
      infrastructure and prevailing opinion was distributed to all 13 neurosurgical
      program directors in Canada. The responses were tabulated and results recorded.
      It is upon these results that conclusions and proposed directions are based.
      RESULTS/CONCLUSIONS: The current practice of the overwhelming majority of
      Canadian academic neurosurgical centers is to have neurosurgical spinal
      subspecialists working under the umbrella of the general neurosurgical division.
      A large percentage of neurosurgical program directors in Canada believe that the
      management of spinal disease, including both intradural procedures and
      instrumentation, is and should remain an integral part of general neurosurgical
      training. A consensus statement regarding the requirements of neurosurgical
      training in spinal disorders is the expressed desire of almost all program
      directors. A proposed direction and resolution is discussed.

PMID- 15198445
TI  - A qualitative study of attitudes toward error in patients facing brain tumour
      surgery.
AB  - BACKGROUND: Medical error is an extremely important component of patient safety
      and requires intense study. The present investigation undertook to examine
      patients' perceptions and attitudes regarding medical error. METHODS: Qualitative
      case study methodology was used. We conducted 30 face-to-face interviews with
      patients within one week of undergoing a neurosurgical operation for a brain
      tumour. Interviews were audiotaped and transcribed and the data subjected to
      thematic analysis. RESULTS: Three overarching themes emerged from the data: 1)
      trust in the patient's surgeon was of paramount importance; 2) patients' views
      toward medical error varied between fear and vulnerability to no concern; and 3)
      discussion of error was felt to be beneficial as it could help the medical
      profession decrease future errors and could help dispel the patient's fear and
      anxiety about the upcoming surgery. CONCLUSIONS: Patients' trust in their
      physician/surgeon is of paramount importance in allaying their fears about the
      possible occurrence and impact of medical error during their treatment. The level
      of concern about error varies among patients, but most felt that discussion of
      error was a good thing.

PMID- 15198446
TI  - Medical and cognitive outcome in children with traumatic brain injury.
AB  - BACKGROUND: Head injury is an important cause of morbidity and mortality in
      pediatrics. Comprehensive studies on outcome are scarce despite significant
      clinical concern that multiple areas of functioning may be impaired following
      moderate to severe head injury. The literature suggests that sequelae include not
      only medical problems but also impairments in cognitive functioning. METHODS: A
      retrospective medical and psychology chart review of patients, age 1-18 years,
      admitted to the Children's Hospital of Eastern Ontario with moderate (Glasgow
      Coma Scale [GCS] 9-12) or severe head injury (GCS < or = 8) from November 1, 1993
      until December 31, 1998 was conducted. Correlations were performed between
      medical variables (i.e., GCS, Pediatric Risk of Mortality [PRISM] III score,
      duration of ICU and hospital stay) and measures of intelligence and memory
      functioning. RESULTS: Eighty-three children age 1 to 18 were included. Seventy
      percent of the children were classified as having a severe head injury. There was
      a mortality rate of thirteen percent. Younger age at injury, lower GCS, and
      higher PRISM III scores predicted higher mortality. Medical complications were
      documented systematically. Forty-four patients underwent at least one cognitive
      assessment and 17 of these children had intelligence testing at three points in
      time: baseline (< four months), early recovery (five to 15 months) and follow-up
      (16 to 38 months). The mean intelligence and memory scores fell within the
      average range at the latest point in follow-up. For those children who underwent
      three serial assessments, the mean verbal and performance IQ fell within the low
      average range at baseline improving significantly to fall within the average
      range by early recovery. Continued improvements were apparent in verbal memory
      beyond early recovery, with the mean obtained at follow-up falling within 1 SD of
      the normative mean. Despite the return to normal ranges for the group means the
      proportion of scores falling below 1.5 standard deviations from the mean was
      greater than population norms for verbal IQ, performance IQ and verbal memory.
      Lower GCS scores and longer duration of stay in ICU or hospital were predictive
      of lower nonverbal intelligence. Lower GCS was also predictive of lower visual
      memory scores. CONCLUSIONS: This study describes a population of Canadian
      children who suffered moderate or severe traumatic brain injury. Initial GCS was
      the best predictor of mortality and cognitive outcome. These children
      demonstrated a temporal improvement in intelligence and memory functioning, with
      their mean performance on these cognitive measures falling within the average
      range at 16 to 38 months postinjury, although there was considerable variability
      in the outcomes between individuals.

PMID- 15198447
TI  - Surveillance for progressive intellectual and neurological deterioration in the
      Canadian paediatric population.
AB  - OBJECTIVES: To conduct active surveillance of the Canadian paediatric population
      for children who have a progressive intellectual and neurological deterioration
      to detect the occurrence of cases of Creutzfeldt-Jakob disease or variant
      Creutzfeldt-Jakob disease. CASE DEFINITION: Any child who is less than or equal
      to 18 years of age, who had a progressive loss of already attained
      intellectual/developmental abilities and development of abnormal neurological
      signs of greater than three months duration was eligible for inclusion. DURATION:
      July 1999 to July 2001. METHOD: Enhanced active surveillance system for
      progressive intellectual and neurological deterioration was implemented to
      detect, prospectively, among the Canadian paediatric population. Each month, all
      paediatricians and paediatric neurologists in Canada were mailed a reporting
      form. All reported cases were reviewed by the principal investigator who
      classified the cases into one of four predetermined categories. Cases where there
      was evidence of neurological and intellectual regression without known cause were
      reviewed by a panel. Reported cases were reviewed for the possibility of classic
      or variant Creutzfeldt-Jakob disease. RESULTS: Over 2200 physicians took part in
      this program. There was more than an 80% monthly return rate of the initial
      report form. Ninety-nine possible cases of progressive neurological and
      intellectual deterioration were reported. Sixty cases were classified as having a
      progressive neurological syndrome associated with intellectual deterioration.
      Fourteen cases were duplicates. One case of Creutzfeldt-Jacob disorder was found
      but no cases of the variant form of Creutzfeldt-Jacob disorder. Fifteen cases
      were felt not to meet the above-mentioned entry criteria.

PMID- 15198448
TI  - Axonal damage in multiple sclerosis patients with high versus low expanded
      disability status scale score.
AB  - BACKGROUND: The pathophysiological basis for differences in disability in
      patients with multiple sclerosis is unclear. METHODS: We used magnetic resonance
      imaging to examine whether differences in disability in cohorts of multiple
      sclerosis patients with similar T2-weighted lesion volume and disease duration
      were associated with a more destructive disease process in the more disabled
      patients. RESULTS: The benign and severely disabled groups had similar brain
      atrophy metrics and similar decreases of the neuronal marker, N-acetylaspartate,
      in the normal appearing white matter of the cerebrum on magnetic resonance
      spectroscopy examination in vivo. The severely disabled cohort had more spinal
      cord atrophy. CONCLUSION: The dissociation of spinal cord atrophy and cerebral
      atrophy between these two groups suggests that the difference between the more
      benign and more disabled groups cannot be explained by a more aggressive
      pathological process that is affecting the entire neuroaxis in a homogeneous
      fashion.

PMID- 15198449
TI  - Cortical relay time for long latency reflexes in patients with definite multiple
      sclerosis.
AB  - BACKGROUND: Long latency reflexes (LLR) include afferent sensory, efferent motor
      and central transcortical pathways. It is supposed that the cortical relay time
      (CRT) reflects the conduction of central transcortical loop of LLR. Recently,
      evidence related to the cortical involvement in multiple sclerosis (MS) has been
      reported in some studies. Our aim was to investigate the CRT alterations in
      patients with MS. METHODS: Upper extremity motor evoked potentials (MEP),
      somatosensory evoked potentials (SEP) and LLR were tested in 28 patients with MS
      and control subjects (n=22). The patients with MS were classified according to
      the clinical form (relapsing-remitting [R-R] and progressive groups). The MS
      patients with secondary progressive and primary progressive forms were considered
      as the "progressive" group. CRT for LLR was calculated by subtracting the peak
      latency of somatosensory evoked potentials (SEP) and that of motor evoked
      potentials (MEP) by transcranial magnetic stimulation from the onset latency of
      the second component of LLR (LLR2) (CRT = LLR2 - [MEP latency + N20 latency])
      RESULTS: Cortical relay time was calculated as 7.4 +/- 0.9 ms in control
      subjects. Cortical relay time was prolonged in patients with MS (11.2 +/- 2.9 ms)
      (p<0.0001). The latencies of LLR, MEP and SEP were also prolonged in patients
      with MS. Cortical relay time was not correlated with disease severity and
      clinical form in contrast to other tests. CONCLUSIONS: Our findings suggested
      that CRT can be a valuable electrophysiological tool in patients with MS.
      Involvement of extracortical neural circuits between sensory and motor cortices
      or cortical involvement due to MS may cause these findings.

PMID- 15198450
TI  - HIV-1/AIDS neuropathology in a Canadian teaching centre.
AB  - BACKGROUND: The nervous system is a major target of HIV-1 infection and site of
      many complications of AIDS. Most of our knowledge pertaining to the range and
      frequency of neuropathology in HIV-1/AIDS is from large centres outside Canada in
      different social and health care settings. The goal of the present study was to
      describe HIV-1/AIDS-associated neuropathology before and during the era of highly
      active antiretroviral therapy at a Canadian teaching centre. METHODS: The records
      of the Department of Pathology, London Health Sciences Centre were electronically
      searched for cases of HIV-1/AIDS that came to postmortem examination since 1985.
      The clinical records and pathological materials were reviewed. RESULTS: Sixteen
      autopsies of HIV-1/AIDS were identified. All patients were male. Fourteen
      contracted HIV-1 through high risk homosexual activity, one through the
      transfusion of blood products and one through intravenous drug use. Three
      patients (19%) had pre-mortem evidence of HIV-1 associated dementia. At autopsy,
      12 of the 16 cases had neuropathological findings and the most common diagnoses
      were HIV-1 encephalitis, progressive multifocal leukoencephalopathy,
      toxoplasmosis, and primary CNS lymphoma. CONCLUSIONS: High risk homosexual
      activity was a more prominent factor in acquiring AIDS in cases coming to
      postmortem examination compared with previous reports from most larger urban
      centres outside Canada where injection drug use and high risk heterosexual
      activity factored prominently. The incidence of HIV-1 associated dementia was
      similar to that reported previously. This study confirms the heavy burden and
      wide spectrum of disease experienced by the nervous system in HIV-1/AIDS.

PMID- 15198451
TI  - Neurologic signs predict periventricular white matter lesions on MRI.
AB  - OBJECTIVE: Periventricular white matter disease (PVWD) is associated with
      abnormalities on tests that involve complex cognitive processes, along with an
      increased risk of cerebrovascular events which are associated with significant
      morbidity in older patients. This study investigates whether the neurological
      examination can predict the presence of PVWD on magnetic resonance imaging (MRI).
      No prior studies have assessed whether the neurological examination can predict
      the presence of PVWD on MRI. METHODS: A focused neurological examination was
      performed on a random selection of patients referred for a MRI of the brain.
      Staff neuroradiologists who were blinded to the results of the physical
      examination independently read the MRI scans. The MRI interpretations were
      divided into four categories based on the degree of PVWD: none, mild, moderate,
      severe. RESULTS: Twenty-three subjects had some degree of PVWD, while 25 subjects
      had none. The total number of neurologic signs correlated significantly with the
      severity of PVWD even when adjusting for the effect of age (rho=0.67, p<0.001).
      Ninety-one percent of subjects with PVWD had three or more abnormal signs, while
      76% of subjects without PVWD had fewer than three. Abnormalities with the three
      step motor sequencing and horizontal visual tracking tests were maximally
      predictive of PVWD. One or both of these tests were abnormal in 96% of subjects
      with PVWD, while 64% of subjects without PVWD had no problems with either test.
      CONCLUSION: Simple neurologic tests can predict the presence or absence of PVWD
      on MRI.

PMID- 15198452
TI  - A blood-brain barrier disruption model eliminating the hemodynamic effect of
      ketamine.
AB  - OBJECTIVE: We propose a simple modification to an established blood-brain barrier
      disruption (BBBD) animal model that allows us to use ketamine/xylazine as the
      anaesthetic agent, therefore decreasing the complexity and the cost of the model,
      while maintaining similar efficiency. METHODS: Sixty-two Long Evans rats were
      anaesthetized by intraperitoneal injection of ketamine/xylazine. Osmotic BBBD was
      performed by administering 25% mannitol into the internal carotid artery in a
      retrograde fashion from the external carotid. The infusion rate of mannitol, as
      well as the duration was adjusted in a stepwise fashion to identify optimal
      parameters for BBBD and minimize complications. As a supplementary step to
      previously reported models, a vascular clip was applied to the common carotid
      artery prior to the infusion of mannitol, therefore isolating our model system
      from the depressant hemodynamic effects of ketamine/xylazine. Evans blue dye was
      used to control for BBBD intensity. RESULTS: Using this model at an initial
      infusion rate of 0.15 ml/sec, a significant incidence of brain hemorrhage (75%)
      and a death rate of 62.5% were observed. Decreasing the infusion rate in a
      stepwise fashion, 0.08 ml/sec was found to produce optimal BBBD, as demonstrated
      by Evans blue staining. At this rate, 6/7 animals depicted grade II staining,
      whereas one animal depicted grade IV. CONCLUSION: The application of a clip to
      the common carotid artery prior to mannitol infusion allowed us to isolate the
      cerebral circulation from the depressant hemodynamic effects of
      ketamine/xylazine. This supplementary step produced consistent and efficient BBBD
      in our animal model.

PMID- 15198453
TI  - Functional imaging of the double cortex.

PMID- 15198454
TI  - Epilepsy in Nepal.
AB  - This is a review of epilepsy in Nepal. Nepal is a predominantly rural country
      with a population of 21 million. A community-based survey in Morang district
      showed that the prevalence of epilepsy was 7.3 per 1,000 population. A cohort of
      300 cases in Shree Birendra Military Hospital showed that neurocysticercosis was
      the most important etiological cause. There are seven neurologists, 10 CT
      scanners, three MRIs, and four EEG machines in the country. The practice of
      anticonvulsant use varied according to different geographical locations. The
      treatment gap may be in excess of 70%. The epidemiology study in Morang district
      showed that the proportion seeking modern treatment was higher among those with
      more frequent seizure. None of the patients were able to attribute their illness
      to brain disease. Various forms of traditional treatment are widely practiced in
      all casts among Hindus as well as Buddhists.

PMID- 15198455
TI  - Functional MRI study of verbal fluency in a patient with subcortical laminar
      heterotopia.
AB  - RATIONALE: Double cortex syndrome is a malformation in which there is a band of
      subcortical heterotopic grey matter separated from the cortex by white matter.
      The functional activity of the heterotopic neurons is unclear. PATIENT: A 13-year
      old female was evaluated for seizures. The EEG showed bifrontal spike wave
      disturbance. Band heterotopia, in association with mild reduction of sulcation of
      the cerebral hemispheres, was found on MRI. Psychological assessment indicated
      the presence of variable cognitive abilities, with verbal IQ [82] generally
      better than nonverbal IQ [59], and specific difficulties in language
      comprehension and mathematics. METHOD: Functional MRI was used to localize the
      areas of language and motor activation. The language activation paradigm was a
      visual verb generation task with a visual fixation baseline. The motor paradigm
      consisted of alternating blocks of sequential finger tapping and rest. Coronal
      functional and anatomical images were obtained. RESULTS: The motor paradigm
      produced activation of the primary motor cortex, the band heterotopia and the
      supplementary motor cortex. The language paradigm produced activation of the left
      inferior frontal gyrus and left supplementary motor area, but not of the band
      heterotopia. CONCLUSIONS: The activation of heterotopic grey matter during a
      motor task demonstrates a hemodynamic association with motor activity and
      suggests that this tissue may be functional. Such association was not seen with
      the language task. We speculate that later maturing functions such as language
      are restricted in their development to the normal situated superficial cortex in
      our patient.

PMID- 15198456
TI  - Devic's neuromyelitis optica treated with intravenous gamma globulin (IVIG).
AB  - BACKGROUND: Devic's syndrome is a demyelinating disease of the spinal cord and
      optic nerves. It tends to have a poor prognosis, probably due to the occurrence
      of necrosis within lesions. There is no proven effective treatment although
      relapses are commonly treated with corticosteroids and people with recurrent
      attacks may be managed with chronic immune suppressing treatments. Intravenous
      gamma globulin (IVIG) and plasma exchange are reasonable treatment options
      because Devic's syndrome is believed to be antibody mediated. We report two
      patients of Devic's syndrome that stabilized following initiation of monthly
      IVIG. PATIENT 1: A 42-year-old woman with a 23 year history of Devic's syndrome
      continued to have frequent attacks of optic neuritis unresponsive to daily
      corticosteroids and azathioprine. Since initiation of monthly IVIG 5 1/2 years
      ago she has had no further definite attacks. She has also noted minimal
      improvement in color perception. PATIENT 2: A 58-year-old woman with a three year
      history of Devic's syndrome experienced five attacks during the first 16 months
      of disease. Monthly IVIG was associated with complete cessation of relapses and
      significantly improved neurological status over one year of treatment.
      CONCLUSIONS: Because active Devic's disease often results in severe, permanent
      neurological impairment, preventive intervention should be considered. These
      cases suggest that IVIG may be effective in preventing attacks and possibly in
      enhancing neurological recovery. Randomized controlled trials will be needed to
      confirm this and to determine optimal dosing and treatment duration.

PMID- 15198457
TI  - A case of adult onset tic disorder following carbon monoxide intoxication.
AB  - BACKGROUND: Adult onset tic disorders are usually secondary in origin. We report
      a case of adult onset tic disorder following carbon monoxide (CO) intoxication
      with typical magnetic resonance imaging features. CASE REPORT: A 36-year-old
      woman developed temporarily suppressible patterned movements on her face, neck,
      and shoulder associated with sensory discomfort after CO poisoning. Magnetic
      resonance images showed bilateral symmetric cavitary changes in the globus
      pallidus. Clonazepam relieved much of her symptoms. CONCLUSION: Our patient
      developed a monosymptomatic tic disorder following CO intoxication. This further
      supports that altered outflow signals from the basal ganglia, especially the
      globus pallidus, may contribute to the development of tic disorders.

PMID- 15198458
TI  - Foreign accent syndrome in a patient with multiple sclerosis.
AB  - BACKGROUND: Foreign accent syndrome is a speech disorder which leads listeners to
      perceive the patient as having a foreign accent. It has been recognized
      previously after stroke, brain injury or unknown causes. CASE REPORT: A 52-year
      old woman with clinically definite relapsing remitting multiple sclerosis (MS)
      presented with episodes of what was perceived as a Dutch accent along with other
      neurologic symptoms that would resolve simultaneously. She was assessed by a
      speech therapist both during an episode and after complete recovery. Speech and
      MRI changes (showing deep white matter lesions in the corpus callosum, left
      pariental lobe and left frontal lobe) were consistent with previous reports of
      foreign accent syndrome. CONCLUSIONS: This patient's episodes of foreign accent
      are thought to be due to her MS.

PMID- 15198459
TI  - Pseudogout of the transverse atlantal ligament: an unusual cause of cervical
      myelopathy.
AB  - BACKGROUND: Calcium pyrophosphate dihydrate deposition in the cervical spine is
      infrequently symptomatic. This is especially true at the craniocervical junction
      and upper cervical spine. CASE REPORT: A 70-year-old previously healthy woman
      presented with a progressive cervical myelopathy of four months duration.
      RESULTS: Examination revealed sensorimotor findings consistent with an upper
      cervical myelopathy. Radiological studies (plain radiographs, computed
      tomography, and magnetic resonance imaging) revealed C1-2 instability, and a well
      defined extradural 3 cm x 1 cm retro-odontoid mass causing spinal cord
      compression. Transoral resection of the mass was performed followed by posterior
      C1-2 stabilization. Histological examination of the mass confirmed calcium
      pyrophosphate dihydrate deposition. Follow-up examination showed marked clinical
      and radiological improvement. CONCLUSION: Although uncommon, calcium
      pyrophosphate dihydrate deposition disease should be considered in the
      differential diagnosis of extradural mass lesions in the region of the odontoid.

PMID- 15198460
TI  - Multimodal longitudinal imaging of focal status epilepticus.
AB  - BACKGROUND: Little is understood about the evolution of structural and functional
      brain changes during the course of uncontrolled focal status epilepticus in
      humans. METHODS: We serially evaluated and treated a nine-year-old girl with
      refractory focal status epilepticus. Long-term EEG monitoring, MRI, MRA, SPECT,
      intraoperative visualization of affected cortex, and neuropathological
      examination of a biopsy specimen were conducted over a three year time span.
      Imaging changes were correlated with simultaneous treatment and EEG findings.
      RESULTS: The EEG monitoring showed almost continuous spike discharges emanating
      initially from the right frontocentral area. These EEG abnormalities were
      intermittently suppressed by treatment with anesthetics. Over time, additional
      brain areas developed epileptiform EEG abnormalities. Serial MRI studies
      demonstrated an evolution of changes from normal, through increased regional T2
      signal to generalized atrophy. An MRA demonstrated dilatation of the middle
      cerebral artery stem on the right compared to the left with a broad distribution
      of flow-related enhancement. An 18FDG-PET scan showed a dramatically abnormal
      metabolic profile in the same right frontocentral areas, which modulated in
      response to treatment during the course of the illness. A right frontotemporal
      craniotomy revealed a markedly hyperemic cortical focus including vascular
      shunting. A sample of resected cortex showed severe gliosis and neuronal death.
      CONCLUSIONS: The co-registration of structural and functional imaging and its
      correlation with operative and pathological findings in this case illustrates the
      relentless progression of regional and generalized abnormalities in intractable
      focal status epilepticus that were only transiently modified by exhaustive
      therapeutic interventions. Increased flow through large vessels appeared to be
      shunted and did not translate into increased microvascular perfusion.

PMID- 15198461
TI  - Intramedullary blastomycosis in a child: case report.
AB  - OBJECTIVE: To report a case of spinal intramedullary blastomycosis causing
      myelopathy. CLINICAL PRESENTATION: An otherwise healthy 13-year-old patient was
      diagnosed with respiratory North American blastomycosis. She subsequently
      received a five-month course of itraconazole with presumed resolution of the
      infection. The patient presented again at 14 years of age with a lumbar
      myelopathy. Magnetic resonance imaging revealed an intramedullary lesion of 1 cm
      diameter at the level of T12-L1. INTERVENTION: A T12-L1 laminectomy was performed
      with a gross total resection of the lesion. Pathological examination and
      microbiological culture of the specimen was consistent with blastomycosis.
      Postoperatively, the patient was placed on a five week course of amphotericin B.
      The patient showed substantial improvement in neurological function. CONCLUSION:
      Blastomycosis can present as an isolated intramedullary lesion causing
      compromised function. It should be considered in the differential diagnosis of a
      patient with a myelopathy and previously recognized blastomycosis. The prognosis
      is good with surgical resection.

PMID- 15198462
TI  - Second-generation antipsychotics: looking beyond efficacy.

PMID- 15198463
TI  - Is neuroleptic dysphoria a variant of drug-induced extrapyramidal side effects?
AB  - OBJECTIVES: Neuroleptic drugs induce psychological side effects such as
      dysphoria, cognitive impairment, and loss of motivation. These side effects were
      largely underrecognized and trivialized in the past as variants of extrapyramidal
      side effects (EPSEs). We review the recent literature on the subject and clarify
      the relation between neuroleptic-induced dysphoria and EPSEs. METHODS: We
      critically examined clinical, interventional, neuroimaging, and basic science
      studies published in the past 10 years, delineating the temporal,
      phenomenological, biochemical, and neuroanatomical relation between dysphoria and
      EPSEs. RESULTS: Subjective responses occur within 4 to 6 hours of neuroleptic
      use, whereas acute dystonia is often observed within 24 hours and parkinsonian
      syndrome after 5 to 7 days. Neuroleptic-induced dopaminergic blockade mediates
      both dysphoria and EPSEs. However, impaired dopamine function in the nucleus
      accumbens seems to give rise to dysphoria, whereas blockade of D2 receptors in
      the nigrostriatal system is responsible for EPSEs. CONCLUSION: The earlier notion
      that neuroleptic dysphoria is a variant of EPSEs was simplistic and speculative.
      Exploring the differences rather than dwelling on the similarities will likely
      enhance our understanding of dopamine's role in the origin of varied side effects
      and in their distinctive characteristics.

PMID- 15198464
TI  - Subjective experience and dopamine D2 receptor occupancy in patients treated with
      antipsychotics: clinical implications.
AB  - OBJECTIVES: This paper gives an overview of studies on the association between
      dopaminergic neurotransmission and the subjective experience of patients with
      schizophrenia. METHODS: We undertook a review of the literature. RESULTS:
      Dopaminergic neurotransmission may be relevant for subjective experience. Higher
      striatal D2 receptor occupancy by typical and atypical antipsychotics is related
      to worse subjective experience, more severe negative symptoms, and depression.
      Individuals with lower baseline dopamine function are at an increased risk for
      dysphoric responses during antipsychotic therapy with dopaminergic-blocking
      drugs. There is preliminary evidence that a window of striatal D2 receptor
      occupancy between 60% and 70% is optimal for the subjective experience of
      patients. These occupancies are often reached even with low dosages of
      antipsychotic drugs. CONCLUSIONS: Reaching an optimal dopamine D2 receptor
      occupancy is clinically relevant, since subjective experience associated with
      antipsychotic medication is related to medication compliance. Antipsychotic drug
      dosages often need to be lower than levels in common use.

PMID- 15198465
TI  - New antipsychotics, compliance, quality of life, and subjective tolerability--are
      patients better off?
AB  - OBJECTIVES: This overview reviews the impact of second-generation antipsychotics
      on less frequently researched outcomes such as medication-adherence behaviour,
      quality of life, and subjective tolerability in patients with schizophrenia.
      METHODS: We selectively reviewed recent literature and considered our own
      research and experiences in the field. RESULTS: Most published studies about
      second-generation antipsychotics have dealt with issues related to efficacy and
      safety. So far, not many studies have focused on effectiveness in terms of such
      important outcomes as medication-adherence behaviour, quality of life, subjective
      tolerability, and overall satisfaction with treatment. Although most studies are
      inconclusive and their results are inconsistent--which has to do with several
      design and methodological limitations--there seems, on balance, to be a trend
      indicating superiority of second-generation, compared with first-generation,
      antipsychotics in improving medication-adherence behaviour and quality of life.
      The trend toward more favourable subjective tolerability and less frequent
      neuroleptic dysphoria seems to be relatively stronger. CONCLUSIONS: At present,
      the state of the art can only indicate a more favourable trend for second
      generation antipsychotics in regard to improving medication adherence behaviour,
      quality of life, and subjective tolerability. It is surprising that such
      important outcomes, which are likely the defining factors in the superiority of
      second-generation antipsychotics, have not received adequate research attention.
      Well-designed, controlled, and adequately powered studies are urgently needed
      before any firm conclusions can be reached.

PMID- 15198466
TI  - Major depression and mental health care utilization in Canada: 1994 to 2000.
AB  - BACKGROUND: Major depression makes an important contribution to disease burden in
      Canada. In principle, the burden of major depression can be reduced by the
      provision of treatment within the health care system. In a previous data
      analysis, the National Population Health Survey (NPHS) reported an increase in
      antidepressant (AD) use between 1994 and 1998. In this paper, the analysis is
      extended to 2000, and additional aspects of health care utilization are
      described. METHODS: The NPHS provides a unique source of longitudinal data
      concerning major depression and its treatment in Canada. In this survey, probable
      cases of major depression were identified using a brief predictive instrument;
      health care utilization was evaluated using additional survey items; and the
      latest data release from Statistics Canada (that is, 2000) was used to make
      weighted estimates of the frequency of health care utilization in relation to
      major depression status. RESULTS: The use of ADs has continued to escalate. These
      increases have been largest in men and in persons aged under 35 years. There has
      been an increase in polypharmacy: in 2000, almost 9% of persons taking an AD
      reported taking more than 1 AD medication-a tripling since 1994. The frequency of
      consultations with alternative practitioners has also grown. Although the overall
      proportion of persons with major depression who report consulting with health
      professionals about their mental health has not increased, the number of persons
      with major depressive disorder reporting 6 or more visits to nurses, social
      workers, and psychologists may have. CONCLUSION: The provision of AD treatment
      continues to expand in Canada. This probably represents a changing pattern of
      practice, because the frequency of professional consultation has not increased.
      More detailed data are required to evaluate the extent to which treatment needs
      are being met.

PMID- 15198467
TI  - Mental illness in Disney animated films.
AB  - OBJECTIVE: To examine the prevalence of verbalizations about mental illness in
      the animated feature films of The Walt Disney Company (TWDC). We discuss the
      results within the context of children's repeated exposure to popular animated
      movies and their learning of labels and stereotypes associated with mental
      illness. We recommend further research on this topic. METHOD: We coded 34
      animated feature films produced by TWDC for mental illness references (for
      example, "crazy" or "nuts"). We developed a coding manual to systematize the
      content analysis, to ensure accuracy of the data, and to ascertain intercoder
      reliability. RESULTS: Most of the films (that is, 85%) contain verbal references
      to mental illness, with an average of 4.6 references per film. The references
      were mainly used to set apart and denigrate the characters to whom they referred.
      Twenty-one percent of the principal characters were referred to as mentally ill.
      We discuss the contributions and limitations of the study. CONCLUSIONS: The
      findings have implications for child viewers in terms of their potentially
      learning prejudicial attitudes and distancing behaviours toward individuals
      perceived as being mentally ill. To further verify this connection, an assessment
      of the incidence of Disney film exposure and attitudes toward people with a
      mental illness, using a sample of school-aged children, is needed.

PMID- 15198468
TI  - Patient satisfaction with outpatient psychiatric treatment: the role of
      diagnosis, pharmacotherapy, and perceived therapeutic change.
AB  - OBJECTIVE: To investigate the influence of diagnosis, type of treatment, and
      perceived therapeutic change on patient satisfaction following psychiatric
      treatment for nonpsychotic, nonsubstance-related disorders. METHOD: We mailed
      questionnaires, including Larsen's Client Satisfaction Questionnaire and Grawe's
      Bern Inventory of Treatment Goals, to outpatients who had undergone 8 or more
      therapy sessions 1 year following treatment. RESULTS: Patients with somatoform,
      eating, and personality disorders were less satisfied than patients with
      affective, anxiety, and adjustment disorders. Symptom reduction and changes in
      the interpersonal domain were important outcomes associated with patient
      satisfaction. Although pharmacotherapy itself was not related to patient
      satisfaction, patients who perceived improvements in pharmacotherapy as one of
      the most important treatment outcomes were less satisfied than others.
      Preliminary evidence shows that coping with specific problems and symptoms is
      associated with satisfaction among male patients, whereas changes in the
      interpersonal domain seem to produce satisfaction among female patients.
      CONCLUSION: Patient-reported change and diagnostic category appear to play a
      relevant role in generating patient satisfaction. Further research is needed to
      clarify the interactions between sex, perceived outcome, and satisfaction.

PMID- 15198469
TI  - Beliefs about schizophrenia in Italy: a comparative nationwide survey of the
      general public, mental health professionals, and patients' relatives.
AB  - OBJECTIVE: This study compared beliefs about the causes, treatments, and
      psychosocial consequences of schizophrenia in a sample of 714 lay respondents,
      465 mental health professionals, and 709 key relatives of patients with this
      disorder. METHOD: We conducted the survey in 30 Italian geographic areas that we
      randomly selected after considering location and population density. We used the
      Questionnaire on the Opinions About Mental Illness (QO) to collect data. RESULTS:
      Of those surveyed, 34% of the lay respondents, 20% of the professionals, and 68%
      of the relatives stated that schizophrenia is exclusively caused by psychosocial
      factors. Lay respondents' opinions on patients' civil rights and social
      competence tended to be more similar to those expressed by professionals then to
      those reported by relatives. Lay respondents differed from the other 2 groups in
      their beliefs regarding the effectiveness of psychological treatments, patients'
      unpredictability, and whether patients should be admitted to asylums.
      CONCLUSIONS: These results suggest that the general public needs to be better
      informed about schizophrenia's main characteristics, available treatments, and
      risk for dangerous behaviours. The existing gap among the study's target
      populations could be reduced through campaigns aimed at increasing public
      awareness of the affective and civil rights of patients.

PMID- 15198470
TI  - Pattern and risk factors for intentional drug overdose in Saudi Arabia.
AB  - BACKGROUND: Attempted suicide by intentional drug overdose is an understudied
      subject in Saudi Arabia. Saudi Arabia is an Islamic country where suicide or
      attempted suicide is strictly prohibited. Despite the strong religious and
      constitutional sanctions against suicide, cases of intentional drug overdose
      occasionally occur. Our study represents the first attempt to better understand
      and characterize this sensitive topic. METHODS: Using a retrospective chart
      review of patients aged 12 years and over with a diagnosis of intentional drug
      overdose between 1997 and 1999, we studied the demographic characteristics, the
      risk factors, the most commonly used drugs, and the resulting morbidities and
      mortalities of study subjects. RESULTS: Most of the patients were young (mean age
      22 years, SD 4.6, range 15 to 40 years), and most were Saudi nationals (n = 76;
      96%). Eighty percent of the patients were women. The occurrence of intentional
      drug overdose peaked during the month of September (that is, 20% of total cases).
      Previous suicide attempts, family conflicts, and psychiatric disorders
      represented significant risk factors. Single-agent overdose occurred in 30% of
      the patients, and most of the drugs used were prescribed medications (53%).
      Acetaminophen represented the most common drug (30%). While some patients
      required prolonged hospital stay or admission to the intensive care unit, no
      mortalities occurred. CONCLUSIONS: Intentional drug overdose is a relatively
      uncommon reason for hospital admission in Saudi Arabia. This study identifies
      certain risk factors relevant to the Saudi community and raises awareness about
      intentional drug overdose.

PMID- 15198471
TI  - Excess of psychoses among the French West Indian population.
AB  - OBJECTIVE: To investigate and compare the prevalence of psychoses in the French
      West Indies (FWI) and in continental France. METHOD: As part of an international
      epidemiologic multicentre study under the authority of the World Health
      Organization French Collaborating Center (WHO-CC), we questioned 7257 individuals
      selected from the general population in France and in the FWI, using the Mini
      International Neuropsychiatric Interview. We compared data using the chi-square
      test. RESULTS: We found a significant discrepancy between the rate of psychoses
      at the continental French sites (1.8%) and the FWI sites (4.4%) (P < 0.0001).
      After homogenizing the rate of missing interviews, our results remained
      significant. CONCLUSIONS: Such a drastic increase in the rate of psychoses in the
      FWI population cannot be explained solely on the basis of either the classical
      migration hypothesis or other currently accepted hypotheses. More attention
      should be given to new parameters such as 1) the recent and significant abuse of
      crack cocaine and cannabis in the FWI, 2) the continued existence of magic
      practices in a significant portion of the French Afro-Caribbean population, and
      3) the expression of mood disorders with overvalued ideation or psychotic
      symptomatology.

PMID- 15198472
TI  - Tardive dyskinesia associated with olanzapine in a neuroleptic-naive patient with
      schizophrenia.

PMID- 15198474
TI  - Re: Depression, stroke diagnosis, and SSRI discontinuation syndrome.

PMID- 15198473
TI  - Re: Depression, stroke diagnosis, and SSRI discontinuation syndrome.

PMID- 15198475
TI  - Emerging trends and training issues in the psychiatric emergency room.

PMID- 15198476
TI  - Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt
      status.
AB  - In recent years, it has been clarified that aldosterone can directly damage
      various organs, such as the heart, blood vessel, and kidneys, via non-epithelial
      mineralocorticoid receptors, independent of changes in blood pressure. Anti
      aldosterone drugs have been clinically reported to be useful for their organ
      protecting effects. The fact that these effects have been considered important
      for almost 10 years seems to indicate that aldosterone-induced organ damage can
      develop as a consequence of plasma aldosterone levels being in disproportion to
      salt status. In a previous study, cardiac fibrosis could not be induced in an
      experimental model of hyperaldosteronism with a low-salt diet. It is, therefore,
      extremely important to understand the relationship between plasma aldosterone
      level and inappropriate salt balance when considering diseases or states for
      which an anti-aldosterone drug is called for. In this paper we review the
      fundamental and clinical studies reported to date, mainly to investigate the
      pathology of organ damage induced by aldosterone and excess salt. Aldosterone
      induced direct organ damage mediated through vasculitis essentially requires
      salt, which is inappropriate for plasma aldosterone level, and studies performed
      from this standpoint may provide a clue to the clarification of the involvement
      of salt in the actions of aldosterone via non-epithelial mineralocorticoid
      receptors. In humans, it is also strongly suggested that organ damage may occur,
      even at a plasma aldosterone level within a normal range, if salt intake is
      imbalanced to the aldosterone level. This means that the new aldosterone blocker
      eplerenone may also have significance as a drug inhibiting inflammation, possibly
      serving as a trigger of organ damage.

PMID- 15198477
TI  - Long-term treatment with probucol improves endothelial function in patients with
      coronary artery disease.
AB  - Recent studies have shown that endothelial function is impaired in patients with
      coronary artery disease (CAD). Probucol has been recognized to have antioxidant
      properties as well as lipid-lowering effects, and may improve endothelial
      function. The aim of this study was to evaluate the effects of probucol on
      endothelial function in patients with CAD. We evaluated endothelial function,
      based on flow-mediated vasodilation during reactive hyperemia (FMD), and the
      intima-media thickness (IMT) of the common carotid artery using high resolution
      ultrasonography in patients either with (CAD group, n=26) or without CAD (Control
      group, n=12). We measured the serum cholesterol concentration, including the low
      density lipoprotein cholesterol (LDL-cholesterol) concentration, and the plasma
      concentrations of homocyst(e)ine and asymmetric dimethylarginine (ADMA).
      Measurements of FMD and serum cholesterol were repeated after 3 months of
      probucol (500 mg/day, n=9) or placebo (n=9) treatment in patients with CAD. The
      IMT was significantly greater (p < 0.001) and FMD was significantly lower (p <
      0.001) in the CAD group than in the Control group. While the serum cholesterol
      concentration and plasma ADMA were similar in the two groups, the plasma
      homocyst(e)ine concentrations were higher in the CAD group than in the Control
      group (p < 0.01). After probucol therapy, FMD was significantly improved in the
      CAD group (p < 0.05). The serum LDL-cholesterol concentration did not
      significantly decrease after probucol treatment. Placebo treatment did not alter
      FMD or the serum cholesterol concentration. Our findings suggest that long-term
      treatment with probucol improves endothelial function in patients with CAD, an
      outcome independent of the LDL-cholesterol-lowering effects of probucol, and that
      homocyst(e)ine may be a better predictor of atherosclerosis than ADMA.

PMID- 15198478
TI  - Telomere attrition in white blood cell correlating with cardiovascular damage.
AB  - Aging is a major risk factor for cardiovascular disease. Chronological aging does
      not always parallel biological aging, but there is no reliable biomarker for the
      latter. In the present study, we tested the hypothesis that telomere attrition in
      white blood cells is related to endothelial dysfunction and the extent of
      atherosclerosis, and thus may serve as a useful marker for biological aging. We
      evaluated telomere lengths in white blood cells by measuring the mean telomere
      restriction fragment length (mTRFL), as well as endothelial function by flow
      mediated dilatation (FMD) in the brachial artery, in patients with various
      degrees of cardiovascular damage and in normal subjects. Cardiovascular damage
      was assessed by a cardiovascular damage (CVD) score, with 1 point being given for
      the presence of each cardiovascular risk factor (hypertension, hyperlipidemia and
      diabetes) and for each event (angina, myocardial infarction, cerebrovascular
      event and peripheral vascular disease). Subset analysis of CVD score groups
      revealed that mTRFL and FMD decreased in the rank order of CVD score. Although
      mTRFL was inversely correlated with age, telomere index, defined as the ratio of
      TRFL to TRFL predicted by age, also decreased with increase in CVD score. These
      results indicate that telomere attrition in white blood cells is more closely
      associated with endothelial damage and atherosclerosis than is chronological
      aging, supporting the hypothesis that mTRFL in white blood cells is a useful
      marker for biological aging of the cardiovascular system.

PMID- 15198479
TI  - A high prevalence of Gitelman's syndrome mutations in Japanese.
AB  - Although Gitelman's syndrome (GS) is considered a rare disorder, it is an
      autosomal recessive phenotype and the frequency of heterozygote subjects might be
      higher than suspected. The purpose of this study was to assess the prevalence of
      GS in Japanese and the effects of heterozygous GS mutations on blood pressure
      levels. We used the TaqMan system to detect 9 Gitelman's syndrome mutations in
      SLC12A3 that have been reported in Japanese. We then conducted association
      studies between these mutations and blood pressure in 1,852 subjects recruited
      from the Suita study, representing the general population in Japan. Among these
      1,852 subjects, we detected the T180K, A569V, L623P, R642C, and L849H
      heterozygote genotypes in 56, 14, 1, 1, and 47 subjects, respectively. The
      overall frequency of GS mutations was (56+14+1+1+47) / (1,852 x 2) = 0.0321,
      which was much higher than suspected. This means we should expect to find one
      subject with a heterozygous GS mutation among 15.6 Japanese or that we should
      find 10.3 GS subjects among 10,000 Japanese. Although the blood pressure levels
      of subjects heterozygous for the T180K, A569V, or L849H genotype were not
      significantly different from those of wild-type subjects, urine pH in subjects
      with GS mutations was significantly higher than that in subjects without
      mutations. In conclusion, GS could be one of the major causes of low blood
      pressure in Japanese.

PMID- 15198480
TI  - Six missense mutations of the epithelial sodium channel beta and gamma subunits
      in Japanese hypertensives.
AB  - Liddle's syndrome is an autosomal dominant disease characterized by sodium
      sensitive early hypertension and mutations in either the beta- or gamma-subunit
      of the amiloride-sensitive epithelial sodium channel encoded by SCNN1B and
      SCNN1G. We sequenced the 381 bp-coding regions in exon 13 of SCNN1B and the 381
      bp-coding regions in exon 12 of SCNN1G in 948 and 953 Japanese patients with
      hypertension, respectively. In the SCNN1B gene, we identified three missense
      mutations, P592S (n=3), T594M (n=2), and E632K (n=1) in a heterozygous state in
      addition to four synonymous ones, Ile515 (n=1), Ser520 (n=19), Ser533 (n=1), and
      Thr594 (n=11). In the SCNN1G gene, we identified three missense mutations, A578V
      (n=1), P603S (n=1), and L609F (n=1) in a heterozygous state in addition to two
      synonymous ones, Ile550 (n=1) and Leu649 (n= 91, heterozygous; n=2, homozygous).
      We did not identify the same mutations previously reported in Liddle's syndrome
      kindreds. Two of the six hypertensive patients with missense mutation in the
      SCNN1B gene showed atypical renin and aldosterone levels, though one of them was
      diagnosed with renovascular hypertension. One patient with T594M in the SCNN1B
      gene was resistant to hypertension. The roles of these missense mutations in the
      SCNN1B or SCNN1G gene identified in hypertensive patients are not clear in the
      pathogenesis of hypertension and the regulation of electrolytes. Thus, further
      investigation of these mutations, including functional analyses, will be needed.

PMID- 15198481
TI  - Angiotensin-converting enzyme inhibitor usage in patients with incidental
      atherosclerotic renal artery stenosis.
AB  - The efficacy of angiotensin converting enzyme (ACE) inhibitors in treatment of
      renovascular disease has been controversial. It has been reported that patients
      with incidental atherosclerotic renal artery stenosis (ARAS) are sometimes
      treated with ACE inhibitors before being considered for renal revascularization.
      This study was designed to describe the frequency and the characteristics of
      patients with incidental ARAS, and to examine the frequency of ACE inhibitor
      usage in such patients. We studied a cohort of consecutive patients undergoing
      abdominal aortography at the time of cardiac catheterization. Patients were
      stratified and compared based on the presence and severity of ARAS. ARAS (> or
      =50%) was present in 146 (17.0%) of 859 evaluable patients. Factors independently
      related to the presence of ARAS were age (odds ratio (OR)=1.07, p < 0.001),
      severity of coronary artery disease (OR=2.13, p < 0.001) and peripheral vascular
      disease (OR=1.79, p = 0.021). Among all patients with ARAS, the percentage of ACE
      inhibitor usage was 74.7% (109/146). Among patients with severe ARAS, moderate
      ARAS, mild ARAS, insignificant ARAS and normal renal arteries, the percentage of
      ACE inhibitor usage was 85.7% (95% confidence interval (CI): 69-100%), 82.9% (95%
      CI: 71-95%), 68.5% (95% CI: 59-78%), 68.6% (95% CI: 55-82%) and 53.9% (95% CI: 50
      58%), respectively (contingency coefficient=0.17, p < 0.001). In patients with
      severe ARAS, ACE inhibitor use, calcium channel blocker use and diuretic use were
      shown to correlate significantly with serum creatinine levels after controlling
      for potential confounding factors. In this study, ACE inhibitors were used
      commonly in patients with incidental ARAS; the frequency of ACE inhibitor use
      correlated with the severity of ARAS.

PMID- 15198482
TI  - Ultrasound evaluation of valsartan therapy for renal cortical perfusion.
AB  - An increase in renal blood flow with a concomitant decrease in filtration
      fraction at the onset of angiotensin II receptor blocker treatment has been shown
      to predict a long-term renoprotective effect. However, no studies are available
      regarding angiotensin receptor blocker-induced changes in renal cortical
      perfusion observed in the clinical setting. We have recently developed a
      convenient method of evaluating human renal cortical blood flow with contrast
      enhanced harmonic ultrasonography. The goal of this study was to use this method
      to examine the effect of valsartan, an angiotensin II receptor blocker, on renal
      cortical perfusion. We performed intermittent second harmonic imaging with venous
      infusion of a microbubble contrast agent in 7 healthy volunteers. Contrast
      enhanced harmonic ultrasonography performed after oral administration of
      valsartan (80mg) showed a significant increase in microbubble velocity, which
      correlated well with the increase in total renal blood flow determined by p
      aminohippurate clearance (r=0.950, p < 0.001). Although fractional vascular
      volume was not significantly increased, alterations in renal cortical blood flow
      calculated by the product of microbubble velocity and fractional volume were also
      correlated with the change in total renal blood flow (r=0.756, p < 0.05). These
      results indicate that valsartan increases the renal cortical blood flow in normal
      kidneys, mainly by increasing blood flow velocity. Contrast-enhanced harmonic
      ultrasonography is a promising technique for evaluating the precise effect on
      renal cortical perfusion and optimal dose of valsartan in diseased kidneys.

PMID- 15198483
TI  - Methodological validity and feasibility of the nitric oxide clamp technique for
      nitric oxide research in human resistant vessels.
AB  - N(G)-methyl-L-arginine (L-NMMA) has been widely used for nitric oxide (NO)
      research, particularly for the assessment of NO-dependent vasodilatation evoked
      by agonists. However, such experiments may not be straightforward because L-NMMA
      causes vasoconstriction, which itself must non-specifically affect responses to
      any vasoactive agents. Therefore, in order to more accurately estimate the roles
      of NO in human vessels in vivo, we developed an NO clamp technique that uses co
      infusion of an NO donor with L-NMMA. To assess the validity and feasibility of
      this technique, we compared the effects of intra-arterial infusion of L-NMMA on
      the forearm blood flow responses to vasodilators with and without the NO clamp
      technique in healthy males. All drugs were intra-arterially infused and changes
      in forearm blood flow (FBF) were measured by strain-gauge plethysmography.
      Vasodilatation evoked by atrial natriuretic peptide was significantly attenuated
      by L-NMMA alone (p = 0.001) but not by the NO clamp technique. L-NMMA
      significantly attenuated the responses to acetylcholine either with or without
      the NO clamp technique. However, the ratio of the area under the curve (AUC) of
      acetylcholine with L-NMMA to that without L-NMMA was significantly higher when
      the NO clamp technique was not used (AUC ratio: 0.62 +/- 0.13 vs. 0.48 +/- 0.14,
      respectively; p = 0.031). The contribution of NO to the FBF responses to
      vasodilators may be more properly assessed by the co-infusion of L-NMMA with the
      NO clamp technique than by L-NMMA alone. Our NO clamp technique thus appears to
      be valid and feasible for human NO research.

PMID- 15198484
TI  - Lack of association between the hepatocyte growth factor receptor, c-met, and the
      anti-apoptotic action of bag-1 in endothelial cells.
AB  - Bag-1 is a novel multifunctional protein. It was identified based on its ability
      to bind the anti-apoptotic protein, bcl-2, and also reported to interact with the
      heat shock protein 70 kDa (Hsp70). Thus, bag-1 may modulate apoptosis and the
      chaperone activity. More interestingly, bag-1 can bind to several growth factor
      receptors or steroid hormone receptors and regulate their function and signaling.
      The receptor of hepatocyte growth factor (HGF), c-met, associated with bag-1 in a
      study measuring immunoprecipitation in endothelial cells, we decided to
      investigate the contribution of bag-1 to the anti-apoptotic action of HGF.
      Endogenous expression of bag-1 in endothelial cells was confirmed mainly in the
      cytosol fraction. The treatment of human recombinant HGF (rHGF) increased
      tyrosine kinase and ERK phosphorylation, whereas over-expression of bag-1 had no
      effect on this phosphorylation. In DNA synthesis as assessed by thymidine
      incorporation, over-expression of bag-1 also did not induce any additional
      increase. In contrast, in an assay of cell death as assessed by caspase activity
      and lactate dehydrogenase release, over-expression of bag-1 alone attenuated
      serum-free and tumor necrosis factor-alpha-induced cell death in endothelial
      cells. No synergistic effect was observed between bag-1 and rHGF. To further
      study the association of HGF and bag-1, we examined the effect of a deletion
      mutant of the bag-1 C-terminal region (CTR), because bag-1 CTR is necessary to
      bind to c-met. Unexpectedly, over-expression of bag-1 CTR also attenuated the
      endothelial cell death, similar to rHGF. Taken together, these results indicate
      that over-expression of bag-1 has an anti-apoptotic effect on endothelial cells
      independent of HGF signaling.

PMID- 15198485
TI  - Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin
      1 gene.
AB  - Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological
      responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been
      reported to be associated with blood pressure (BP). One is the Lys198Asn
      polymorphism, which showed a positive association with BP in overweight people.
      Another is the 3A/4A polymorphism (-134delA) located in the 5'-untranslated
      region. In this study, we investigated the expression of the Lys198Asn
      polymorphism in ET-1 in vitro, as well as the association between either of the
      two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys
      type) and minor type (Asn-type) preproET-1 in three different cell lines, and
      measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no
      significant difference in the levels of ET-1 or big ET-1 between the Asn-type and
      Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54
      hypertensive patients having an amino acid substitution from Lys to Asn at
      position 198 were not different from those of hypertensives without the
      substitution. However, we found a significant difference in ET-1 levels between
      individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study
      indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET
      1 production. Another variant in the EDN1 gene in linkage disequilibrium with the
      Lys198Asn polymorphism may be responsible for the association with BP, or the
      interaction between the EDN1 Lys198Asn polymorphism and other factors such as
      obesity may be involved in the mechanisms elevating BP in vivo.

PMID- 15198486
TI  - A perspective on surrogate endpoints in controlled clinical trials.
AB  - The last couple of decades have seen a large amount of activity in the area of
      surrogate marker and surrogate endpoint validation, both from a clinical and a
      statistical perspective. Prentice made a pivotal contribution in the context of a
      single trial. Subsequently, the framework he proposed has been discussed,
      criticized, and extended. An important class of extensions considers several
      rather than a single trial. Recently, a lot of work has been done in this so
      called hierarchical or meta-analytic framework. In this paper, we review both the
      single trial and the hierarchical framework. A number of applications, scattered
      throughout the literature, are brought together. We outline the statistical
      issues involved in trying to validate surrogate endpoints. Clearly statistical
      evidence should only be seen as a component in a decision making process that
      also involves a number of clinical and biological considerations.

PMID- 15198488
TI  - Use of the false discovery rate for evaluating clinical safety data.
AB  - Clinical adverse experience (AE) data are routinely evaluated using between group
      P values for every AE encountered within each of several body systems. If the P
      values are reported and interpreted without multiplicity considerations, there is
      a potential for an excess of false positive findings. Procedures based on
      confidence interval estimates of treatment effects have the same potential for
      false positive findings as P value methods. Excess false positive findings can
      needlessly complicate the safety profile of a safe drug or vaccine. Accordingly,
      we propose a novel method for addressing multiplicity in the evaluation of
      adverse experience data arising in clinical trial settings. The method involves a
      two-step application of adjusted P values based on the Benjamini and Hochberg
      false discovery rate (FDR). Data from three moderate to large vaccine trials are
      used to illustrate our proposed 'Double FDR' approach, and to reinforce the
      potential impact of failing to account for multiplicity. This work was in
      collaboration with the late Professor John W. Tukey who coined the term 'Double
      FDR'.

PMID- 15198487
TI  - On the use of biomarkers for environmental health research.
AB  - This article discusses the growing interest in the use of biomarker data in
      environmental health research and considers some of the challenging statistical
      issues that arise. We specify a modeling framework that links environmental
      exposure, biomarkers and outcome, and discuss in conceptual terms how such a
      formulation could be used to inform dose response modeling for the purpose of
      quantitative risk assessment. We then analyse some biomarker data from a case
      control study designed to elucidate the mechanisms of smoking induced lung
      cancer. Because of sample size limitations, we use a likelihood-based analysis
      which subsumes both cohort and case-control designs as special cases. Our
      analysis allows us to 1) investigate the extent to which the markers explain the
      pathway from exposure to outcome; 2) quantify the degree to which biomarker data
      can improve on predicting outcome over and above exposure; and 3) estimate the
      association among multiple markers.

PMID- 15198489
TI  - The use of bioabsorbable implants in spine surgery.
AB  - The use of bioabsorbable implants in spine surgery is expanding at a rapid pace.
      These implants are mimicking the roles of traditional metallic devices and are
      demonstrating similar efficacy in terms of maintaining stability and acting as
      carriers for grafting substances. Biomechanical studies have demonstrated their
      ability to stabilize effectively a degenerative cervical and lumbar motion
      segment. In numerous animal models, researchers have illustrated the ability of
      bioabsorbable implants to function satisfactorily as an interbody spacer and to
      achieve satisfactory bone fusion. Investigators have explored various
      opportunities for these implants to replace their metallic counterparts in
      clinical studies conducted in humans. The gradual resorption of these implants
      appears effectively to transfer gradual loads to the grafting substances
      promoting the biological mechanisms of fusion. Novel uses of bioabsorbable
      technology are constantly evolving. Their future as a carrier of biological
      agents such as bone morphogenetic proteins and bone graft extenders, their
      radiolucency, and their eventual resorption make them an ideal implant for use in
      spinal degenerative disease.

PMID- 15198490
TI  - Use of polylactide resorbable film as a barrier to postoperative peridural
      adhesion in an ovine dorsal laminectomy model.
AB  - OBJECT: The purpose of this study was to evaluate the performance of a resorbable
      polylactide film in the sheep posterior spine in the presence of a combined
      laminectomy and durotomy defect. METHODS: A resorbable polylactide film was used
      to cover the combined defects in the eight sheep used in this study. Two surgical
      levels were performed in each animal, with randomly assigned control and treated
      sites. Each surgical level consisted of a full laminectomy followed by a needle
      induced durotomy. The treated levels received a resorbable polylactide film cut
      to size and tucked in under the laminar defect. At 8 to 10 weeks postoperatively,
      results of myelography and visual dye infiltration showed complete healing of the
      durotomies for all sites. In addition, evaluation of gross dissection based on
      volume and tenacity scores as well as histological findings indicates decreased
      posterior dural adhesions for sites treated with resorbable polylactide film.
      CONCLUSIONS: The results of this investigation support previous studies in which
      the use of a resorbable polylactide film was found to be effective in reducing
      posterior dural adhesions in the spine with no apparent safety issues related to
      impaired dural healing.

PMID- 15198491
TI  - The use of high-resolution magnetic resonance imaging for monitoring interbody
      fusion and bioabsorbable cages: an ex vivo pilot study.
AB  - OBJECT: Interbody fusion is a gradual process of graft resorption and tissue
      formation, ideally resulting in a bone bridge between two adjacent vertebral
      bodies. Initially, fibrous tissue and cartilage are formed, which subsequently
      are replaced by bone through the process of endochondral ossification. When cages
      and/or their contents are made of resorbable polymers like lactic or glycolic
      acids, there is a simultaneous process of implant degradation, which is
      eventually accompanied by reactions in the surrounding tissues. The purpose of
      this study was to explore the use of highresolution magnetic resonance (MR)
      imaging for monitoring tissue differentiation, spinal fusion, cage degradation,
      and eventually tissue reactions as a function of time. METHODS: Lumbar vertebral
      segments obtained in 14 goats with 3, 6, and 12 months of follow up (three, four,
      and seven animals, respectively) were available from a study of the feasibility
      of poly(L,D-lactic acid) cages for spinal fusion. Plain x-ray films, MR images,
      and histological sections were used to evaluate spinal fusion and cage
      resorption. The first follow-up tests revealed that MR imaging noninvasively
      provided three-dimensional information on cage placement, cage degradation and
      bone formation, and that it has potential to differentiate between the various
      soft tissues. CONCLUSIONS: Although the magnetic field strength and thus the
      resolution used were higher than normal in clinical practice, MR imaging appears
      to be a promising modality for the noninvasive clinical follow up of patients who
      undergo fusion with resorbable cages. Tissue reactions were not encountered in
      this study, and thus could not be evaluated.

PMID- 15198492
TI  - Cervical spine fusion with bioabsorbable cages.
AB  - OBJECT: Although it improves rates of fusion in surgical arthrodesis,
      conventional spinal instrumentation is associated with several risks, including
      hardware extrusion that injures adjacent anatomical structures, and disuse
      osteopenia as a result of stress shielding. The long-term effects of indwelling
      spinal instrumentation, although incompletely documented, may be detrimental. One
      way to avoid such problems would be to use bioabsorbable implantation devices. In
      this pilot study, performed in 1998 and 1999, the authors evaluated the use of a
      bioabsorbable interbody fusion device in a goat cervical spine model. METHODS:
      Forty-two goats underwent two-level anterior cervical discectomy and fusion:
      eight received iliac crest autograft; 16 received a cage implant composed of
      70:30 poly(L-lactide-co-D,L-lactide)/polyglycolic acid (70:30 PLDLLA/PGA) filled
      with either autograft or recombinant human bone morphogenetic protein-2 (rhBMP
      2); and 18 received a cage implant composed of 85:15 PLDLLA/PGA filled with
      either autograft or rhBMP-2. Animals were killed at 3, 6, and 12 months
      postsurgery, and their cervical spines were evaluated histologically,
      radiographically, and physically for fusion. A primarily fibrous union was
      demonstrated in all animals killed at 3 months. At 6 months, bone trabeculae had
      become more prominent and the fibrous response less so in all cohorts. This
      occurred most frequently in the animals that underwent fusion with the 70:30
      PLDLLA/PGA cages filled with rhBMP-2, in which 63% attained a histologically
      confirmed union that contained quantitatively more bone and less fibrous tissue
      than in the other cohorts; 63% of the unions in the aforementioned cohort were
      graded quantitatively as being stable. CONCLUSIONS: In this study the authors
      have established that the 85:15 PLDLLA/PGA cages are absorbed too quickly to be
      functionally useful in this model. The 70:30 PLDLLA/PGA cages worked as well as
      tricortical autograft when filled with cancellous autograft, and better when
      filled with rhBMP-2. At 6- and 12-month follow-up review, the 70:30 PLDLLA/PGA
      cages had not yet begun to be absorbed. There was little if any inflammatory
      response to these cages at 6 months. Future studies should include biomechanical
      and microradiographic testing, and a longer follow-up period is necessary in this
      model to determine when the 70:30 PLDLLA/PGA cages are absorbed.

PMID- 15198493
TI  - In vivo evaluation of bioresorbable polylactide implants for cervical graft
      containment in an ovine spinal fusion model.
AB  - OBJECT: An in vivo study was conducted in an ovine model to investigate the
      biomechanical changes after the animals underwent single-level anterior cervical
      discectomy followed by fusion in which autologous tricortical graft was used and
      implantation of cervical plates for which bioresorbable polymer screws and plates
      were used. The specific aims of the study were to evaluate whether implant
      failure or screw backout would occur over time and to measure the change in
      stiffness at the treated level at various postoperative time periods (3, 6, and
      12 months). METHODS: A total of 58 x-ray films were evaluated over the 12-month
      survival period. No screw breakage or displacement was observed in any animal
      during the temporal radiographic analysis. Radiographically confirmed fusion
      appeared to be complete at all time periods longer than 6 months. The
      biomechanical testing demonstrated dramatic reductions in range of motion at the
      fusion level in the animals allowed to survive for 6 and 12 months, indicating
      complete fusion after 6 months. CONCLUSIONS: The bioresorbable polymer cervical
      graft containment system appears to provide a safe and effective alternative for
      cervical fusion, and warrants further clinical evaluation for its use in single
      level anterior cervical discectomy and fusion without postoperative orthosis.

PMID- 15198495
TI  - Early findings in a pilot study of anterior cervical fusion in which
      bioabsorbable interbody spacers were used in the treatment of cervical
      degenerative disease.
AB  - OBJECT: In this pilot study the authors assessed the efficacy of bioabsorbable
      interbody spacers in the treatment of cervical degenerative disease. Metallic
      cages or interbody spacers have been widely used in the treatment of degenerative
      and traumatic cervical disease. Bioabsorbable technology has been used to develop
      a resorbable cage that can eliminate the complications and drawbacks seen with
      the use of traditional metallic implants. In general clinical practice
      bioabsorbable implants have shown the ability to degrade safely while
      demonstrating optimal imaging characteristics as a result of their radiolucency,
      and these devices eliminate stress shielding by their gradual dissolution.
      METHODS: This study is a retrospective evaluation of charts and x-ray films
      obtained in the first eight patients who underwent an anterior cervical
      decompression and fusion procedure with placement of a bioabsorbable interbody
      spacer and anterior cervical plate. All patients were treated in one surgeon's
      practice and had a minimum follow-up period of at least 6 months. At a follow-up
      interval of approximately 7 months, five patients exhibited an excellent result
      and three had a good result; no patient was noted to have a satisfactory or poor
      outcome according to the Odom criteria at their most recent follow-up visit.
      Seventeen (94%) of 18 grafted levels appeared to be solidly fused. One patient
      experienced a perisurgical complication consisting of a symptomatic hematoma,
      which was successfully drained. CONCLUSIONS: Bioabsorbable interbody spacers
      appear to be a safe and effective interbody implant in terms of clinical outcome
      and radiographically confirmed healing.

PMID- 15198494
TI  - Early findings in a pilot study of anterior cervical interbody fusion in which
      recombinant human bone morphogenetic protein-2 was used with poly(L-lactide-co
      D,L-lactide) bioabsorbable implants.
AB  - OBJECT: The goal of this study was to assess the efficacy of bioabsorbable
      interbody spacers in cervical spine fusion. METHODS: The authors report on a
      prospective examination of 20 patients with degenerative cervical disc disease
      who underwent anterior cervical fusion at 28 total levels. The authors used
      Infuse bone graft (that is, recombinant human bone morphogenetic protein-2
      applied to an absorbable collagen sponge and contained within a Cornerstone-HSR
      bioabsorbable spacer. Multiple-level fusions were performed in 30% of these
      patients. At 3 months postfusion, radiographs and computerized tomography scans
      demonstrated bridging bone in 100% of the patients. Improvement from baseline
      scores in physical functioning, mental health, and bodily pain was demonstrated
      at 3 months postoperatively according to results of the Short Form-36 Version 2
      health survey. There were no device-related complications. CONCLUSIONS: The
      results in this series indicate that the use of Cornerstone-HSR as a
      bioabsorbable interbody spacer in combination with Infuse bone graft may be an
      alternative treatment for cervical spine fusion.

PMID- 15198496
TI  - Posterior lumbar interbody fusion with bioabsorbable spacers and local autograft
      in a series of 27 patients.
AB  - OBJECT: The goal of this prospective study was to review a series of 27 patients
      who underwent bilateral posterior lumbar interbody fusion with instrumented
      pedicle fixation and two HYDROSORB (known generically as 70:30 poly[L-lactide-co
      D,L-lactide]) rectangular cages packed with locally harvested autograft at a
      total of 48 levels, and to assess the safety and efficacy of this novel
      technique. This analysis, conducted at a mean of 26 months of follow up, is the
      first report of a long-term evaluation of this technique. Fusion rates and
      clinical outcomes are presented. METHODS: A prospective clinical and radiographic
      review of findings in 27 consecutive patients was performed. Fusion rates and
      clinical outcome were assessed at 6-month intervals up to the 32-month follow-up
      end point. Two patients with four corresponding fusion levels were lost to follow
      up. Radiographic evidence of satisfactory fusion was achieved in 42 (95.5%) of 44
      levels fused. Satisfactory fusion at all levels was achieved in 23 (92%) of 25
      patients. Two patients required repeated operations for treatment of symptomatic
      pseudarthrosis during the study period. The likelihood of all levels attaining
      fusion in a given patient decreased as the number of levels treated increased,
      which is consistent with previously published studies. Nonetheless, fusion rates
      per treated level were similar for patients in whom one to three levels were
      treated. No significant surgical complication occurred. CONCLUSIONS: Posterior
      lumbar interbody fusion in which the HYDROSORB bioabsorbable implant packed with
      locally harvested autograft and segmental internal fixation are used appears to
      be an interbody fusion alternative whose efficacy is comparable with previously
      reported procedures.

PMID- 15198497
TI  - Lumbar interbody fusion after treatment with recombinant human bone morphogenetic
      protein-2 added to poly(L-lactide-co-D,L-lactide) bioresorbable implants.
AB  - Object. To evaluate the effectiveness of recombinant human bone morphogenetic
      protein-2 (rhBMP-2) combined with a bioresorbable implant, the authors conducted
      a prospective study of 43 patients with degenerative lumbar disc disease who
      underwent transforaminal lumbar interbody fusion. Methods. The authors used
      Infuse bone graft, which consisted of rhBMP-2 applied to an absorbable collagen
      sponge and contained within a HYDROSORB Telamon bioresorbable implant to perform
      the fusion. Multilevel fusions were performed in 30% of the 43 patients, for a
      total of 57 levels. At 6 months postoperatively, x-ray films and computerized
      tomography (CT) scans demonstrated solid fusion in 98% of 41 patients.
      Improvement from the baseline Oswestry Disability Rating was demonstrated at 6
      months postoperatively in 68% of the patients, based on the Oswestry Disability
      Questionnaire. At 12 months all 11 patients in whom CT scans were obtained showed
      complete bridging of bone; there were no device-related complications.
      Conclusions. Results in this series provide evidence of the feasibility of using
      HYDROSORB Telamon bioresorbable spacers in combination with Infuse bone graft for
      lumbar spine fusion.

PMID- 15198498
TI  - Computerized tomography evaluation of a resorbable implant after transforaminal
      lumbar interbody fusion.
AB  - OBJECT: Synthetic bioabsorbable implants have recently been introduced in spinal
      surgery; consequently, the indications, applications, and results are still
      evolving. The authors used absorbable interbody spacers (Medtronic Sofamor Danek,
      Memphis, TN) packed with recombinant bone morphogenetic protein (Infuse;
      Medtronic Sofamor Danek) for single- and multiple-level transforaminal lumbar
      interbody fusion (TLIF) procedures over a period of 18 months. This is a
      consecutive case series in which postoperative computerized tomography (CT)
      scanning was used to assess fusion status. METHODS: There were 22 patients (17
      men, five women; 39 fusion levels) whose mean age was 41.6 years (range 23-70
      years) and in whom the mean follow-up duration was 12.4 months (range 6-18
      months). Bridging bone was noted as early as the 3-month postoperative CT scan
      when obtained; solid arthrodesis was routinely noted between 6 and 12 months in
      38 (97.4%) of 39 fusion levels. In patients who underwent repeated CT scanning,
      the fusion mass appeared to increase with time, whereas the disc space height
      remained stable. Although the results are early (mean 12-month follow-up
      duration), there was only one noted asymptomatic delayed union/nonunion at L5-S1
      in a two-level TLIF with associated screw breakage. There were no infections or
      complications related to the cages. CONCLUSIONS: The bioabsorbable cages appear
      to be a viable alternative to metal interbody spacers, and may be ideally suited
      to spinal interbody applications because of their progressive load-bearing
      properties.

PMID- 15198499
TI  - Instrumented transforaminal lumbar interbody fusion with bioabsorbable polymer
      implants and iliac crest autograft.
AB  - Object. The purpose of this study was to evaluate the clinical and radiographic
      results in 31 patients from one center who underwent instrumented transforaminal
      lumbar interbody fusion (TLIF) for primarily degenerative indications. Methods.
      Bioabsorbable polymer spacers manufactured with a copolymer of 70:30 poly(L
      lactide-co-D,L-lactide) and filled with iliac crest autograft bone were used for
      the TLIF procedure. In this paper the details of this procedure, intermediate (1-
      to 2-year) clinical and radiographic outcomes, and the basic science and
      rationale for the use of bioabsorbable polymers are discussed. At a mean of 18.4
      months of follow up, 30 patients (96.8%) were judged to have attained solid
      fusions and 25 patients (81%) had good to excellent results. Three patients
      (9.7%) experienced complications, none of which were directly or indirectly
      attributable to the use of the bioabsorbable polymer implant. Only one implant in
      one patient (3.2%) demonstrated mechanical failure on insertion, and that patient
      experienced no clinical sequelae. Conclusions. This is the first clinical series
      to be published in which the mean follow-up duration equals or exceeds the
      biological life expectancy of this material (12-18 months). Both the clinical and
      radiographic results of this study support the use of interbody devices
      manufactured from biodegradable polymers for structural interbody support in the
      TLIF procedure.

PMID- 15198500
TI  - Craniofacial reconstruction with a fast resorbing polymer: a 6- to 12-month
      clinical follow-up review.
AB  - OBJECT: Resorbable polymer implants have become a compelling option in the
      treatment of acquired and congenital craniofacial deformities. In particular, the
      resorbable polylactide and polyglycolide polymers have demonstrated excellent
      safety profiles in multiple in vitro, animal, and clinical studies and are
      currently being used in a wide variety of craniofacial applications. In pediatric
      craniofacial reconstruction a desirable attribute of fixation is early
      resorption, which may limit the duration of any effect on cranial growth. In this
      paper the authors discuss the biomaterial properties of a fast resorbing polymer
      (FRP) and the clinical results in a series of patients who participated in a 6-
      to 12-month study. METHODS: The authors performed craniofacial reconstruction by
      using FRP implants in 29 patients beginning in August 2002. All patients
      experienced maintenance of stable bone fixation followed by bone healing.
      Cosmetic results were rated satisfactory or excellent, except for one
      unsatisfactory cosmetic result caused by disease progression. CONCLUSIONS:
      Results of this study support the effectiveness of an FRP implant in a variety of
      craniofacial surgical procedures including craniosynostoses, fibrous dysplasia,
      cranial defects, and encephaloceles.

PMID- 15198501
TI  - Porous polyethylene implant for cranioplasty and skull base reconstruction.
AB  - OBJECT: Cranial reconstruction after skull base surgery is important for
      restoration of function and cosmesis. The authors describe their experience with
      the Medpor porous polyethylene implant for cosmetic cranioplasty and
      reconstruction after skull base surgery. METHODS: Medpor, a biocompatible
      implant, is flexible and can be contoured to facilitate surgical reconstruction
      of small to medium (< 8 cm) convexity or cranial base defects resulting from a
      variety of skull base approaches. This method provides similar cosmetic results
      to standard alloplast cranioplasty while decreasing operating time. The porous
      nature of the material allows ingrowth of soft tissue and bone to increase
      implant strength and decrease the risk of infection. This material can also be
      used safely in reconstruction of the cranium and skull base adjacent to the
      paranasal sinuses. CONCLUSIONS: The authors have used the Medpor porous
      polyethylene implant in 611 standard cranial and skull base procedures and have
      achieved excellent cosmetic results and no implant-related complications.

PMID- 15198502
TI  - Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in
      rats.
AB  - The time-dependent elimination kinetics of all-trans-retinoic acid (ATRA) has
      been associated with autoinduction of its metabolism and has led to the
      hypothesis that rapid development of acquired clinical resistance to ATRA may be
      prevented by coadministration of metabolic inhibitors. This study in rats was
      performed to investigate the pharmacokinetics and onset of time-dependent
      elimination of ATRA, with the purpose of establishing an animal model suitable
      for in vivo preclinical studies of compounds capable of inhibiting ATRA
      metabolism. After the intravenous (IV) bolus administration of single doses of
      ATRA (1.60 mg kg(-1) and 0.40 mg kg(-1)), the plasma concentration-time curves
      showed an accelerated decline at 180 minutes after dosing. The plasma clearance
      (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg(
      1)), at 180 minutes was greater than Cl after a single dose, thus indicating the
      existence of a time-dependent elimination process detectable 180 minutes after
      administration of the first dose. Such time-dependent elimination was confirmed
      by means of an IV constant-rate infusion of 0.48 mg h(-1) kg(-1) of ATRA during
      10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which
      the plasma concentration decreased to reach a much lower apparent steady-state
      drug concentration at 420 minutes. The area under the plasma concentration-time
      curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg(
      1)) was approximately 8% of the AUC obtained after a single oral dose; consistent
      with a time-dependent increase in the elimination of ATRA, as was observed after
      IV administration.

PMID- 15198503
TI  - Formulations for natural and peptide nucleic acids based on cationic polymeric
      submicron particles.
AB  - This article describes the production and characterization of cationic submicron
      particles constituted with Eudragit RS 100, plus different cationic surfactants,
      such as dioctadecyl-dimethyl-ammonium bromide (DDAB18) and diisobutylphenoxyethyl
      dimethylbenzyl ammonium chloride (DEBDA), as a transport and delivery system for
      DNA/DNA and DNA/peptide nucleic acid (PNA) hybrids and PNA-DNA chimeras.
      Submicron particles could offer advantages over other delivery systems because
      they maintain unaltered physicochemical properties for long time periods,
      allowing long-term storage, and are suitable for industrial production. Submicron
      particles were characterized in terms of size, size distribution, morphology, and
      zeta potential. Moreover, the in vitro activity and ability of submicron
      particles to complex different types of nucleic acids were described. Finally,
      the ability of submicron particles to deliver functional genes to cells cultured
      in vitro was determined by a luciferase activity assay, demonstrating that
      submicron particles possess superior transfection efficiency with respect to
      commercially available, liposome-based transfection kits.

PMID- 15198504
TI  - Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid.
AB  - Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods:
      sublimation calorimetry, solution calorimetry, and with respect to solubility.
      Upon measuring the temperature dependences of the saturated vapor pressure,
      enthalpies of sublimation, DeltaH(0) (sub), as well as the entropies of
      sublimation, DeltaS(0) (sub), and their respective relative fractions in the
      total process were calculated. The Gibbs energy of solvation in aliphatic
      alcohols as well as the enthalpic and entropic fractions thereof were also
      studied and compared with the respective properties of model substances and other
      nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen,
      ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving
      force of the solvation process. Correlations were derived between Gibbs energy of
      solvation in octanol, DeltaG(Oct) (solv), and the transfer Gibbs energy from
      water to octanol, DeltaG(0) (tr). Influence of mutual octanol and water
      solubilities on the driving force of partitioning is discussed. An enthalpy
      entropy-compensation effect in octanol was observed, and consequences of
      deviation from the general trend are also discussed.

PMID- 15198505
TI  - Polyethylene glycol-induced precipitation of interferon alpha-2a followed by
      vacuum drying: development of a novel process for obtaining a dry, stable powder.
AB  - Feasibility studies were performed on the development of a novel process based on
      polyethylene glycol (PEG)-induced precipitation of proteins followed by vacuum
      drying in the presence of sugars to obtain dry protein powders. Apparent
      solubility of interferon alpha-2a (IFNalpha2a) was determined in the presence of
      various PEGs and the effect of solution pH, ionic strength, and temperature was
      investigated. IFNalpha2a precipitate was dried at a shelf temperature of 25
      degrees C at 100 mTorr either as it is or in the presence of mannitol and/or
      trehalose. The dried IFNalpha2a formulations were subjected to accelerated
      stability studies at 40 degrees C (3 months), and the stability was compared with
      that of a similar lyophilized formulation. The results indicated that more than
      90% of the protein could be precipitated using 10% wt/vol PEG 1450 at pH 6.5 at a
      solution ionic strength of 71 mM. Vacuum drying of the precipitate only resulted
      in the formation of insoluble aggregates of IFNalpha2a; however, this was
      prevented by the addition of either mannitol or trehalose. The addition of excess
      mannitol resulted in low residual moisture content and better handling of the
      final dried product. Accelerated storage stability did not show any aggregation
      and showed less than 5% formation of oxidized IFNalpha2a in the dried formulation
      containing IFNalpha2a:trehalose:mannitol in a 1:10:100 wt/wt ratio upon storage
      at 40 degrees C for 3 months. The stability of this vacuum dried formulation was
      comparable with that of a similar lyophilized formulation.

PMID- 15198506
TI  - Preparation, characterization, and biodistribution study of technetium-99m 
      labeled leuprolide acetate-loaded liposomes in Ehrlich ascites tumor-bearing
      mice.
AB  - The purpose of this study was to prepare conventional and sterically stabilized
      liposomes containing leuprolide acetate in an attempt to prolong the biological
      half life of the drug, to reduce the uptake by reticuloendothelial system (RES),
      and to reduce the injection frequency of intravenously administered peptide
      drugs. The conventional and sterically stabilized liposomes containing leuprolide
      acetate were prepared by reverse phase evaporation method and characterized for
      entrapment efficiency and particle size. Radiolabeling of leuprolide acetate and
      its liposomes was performed by direct labeling with reduced technetium-99m. Its
      biodistribution and imaging characteristics were studied in ehrlich ascites tumor
      (EAT)-bearing mice after labeling with technetium-99m. The systemic
      pharmacokinetic studies were performed in rabbits. A high uptake by tumor was
      observed by sterically stabilized liposome containing leuprolide acetate compared
      with free drug and conventional liposomes. The liver/tumor uptake ratio of free
      drug, conventional (LL), and sterically stabilized liposomes (SLL5000 and
      SLL2000) was found to be 20, 7.99, 1.63, and 1.23, respectively, which showed the
      increased accumulation of sterically stabilized liposomes in tumor compared with
      the free drug and conventional liposomes at 24 hours postinjection. Liver uptake
      of sterically stabilized liposomes was still 7-fold less than the conventional
      liposomes. The marked accumulation of liposomes in the tumor-bearing mice was
      also documented by gamma scintigraphic studies. The findings demonstrate the
      distribution of these liposomes within solid tumor and prove that the sterically
      stabilized liposomes experience increased tumor uptake and prolonged circulation
      half life. Hence these findings will be relevant for the optimal design of long
      circulating liposomes for the peptide drugs and for targeting of liposomes toward
      tumor.

PMID- 15198507
TI  - Physiologically based pharmacokinetics in drug development and regulatory
      science: a workshop report (Georgetown University, Washington, DC, May 29-30,
      2002).
AB  - A 2-day workshop on "Physiologically Based Pharmacokinetics (PBPK) in Drug
      Development and Regulatory Science" came to a successful conclusion on May 30,
      2002, in Washington, DC. More than 120 international participants from the
      environmental and predominantly pharmaceutical industries, Food and Drug
      Administration (FDA), and universities attended this workshop, organized by the
      Center for Drug Development Science, Georgetown University, Washington, DC. The
      first of its kind specifically devoted to the subject, this intensive workshop,
      comprising 7 plenary presentations and 10 breakout sessions addressed 2 major
      objectives: (1) to "define demonstrated and potential contributions of PBPK in
      drug development and regulatory science," and (2) to "assess current PBPK
      methodologies with the identification of their limitations and outstanding
      issues." This report summarizes the presentations and recommendations that
      emerged from the workshop, while providing key references, software, and PBPK
      data sources in the appendices. The first day was initially devoted to
      presentations setting the stage and providing demonstrated applications to date.
      This was followed by breakout sessions that considered further opportunities and
      limitations, and which extended into Day 2 to deal with developments in
      methodologies and tools. Although the primary emphasis was on pharmacokinetics,
      consideration was also given to its integration specifically with mechanism-based
      pharmacodynamics.

PMID- 15198508
TI  - Beta-cyclodextrin complexes of celecoxib: molecular-modeling, characterization,
      and dissolution studies.
AB  - Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water
      soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability.
      The effect of beta-cyclodextrin on the aqueous solubility and dissolution rate of
      celecoxib was investigated. The possibility of molecular arrangement of inclusion
      complexes of celecoxib and beta-cyclodextrin were studied using molecular
      modeling and structural designing. The results offer a better correlation in
      terms of orientation of celecoxib inside the cyclodextrin cavity. Phase
      solubility profile indicated that the solubility of celecoxib was significantly
      increased in the presence of beta-cyclodextrin and was classified as A(L)-type,
      indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared
      by freeze drying, evaporation, and kneading methods were characterized using
      differential scanning calorimetry, powder x-ray diffractometry, and scanning
      electron microscopy. In vitro studies showed that the solubility and dissolution
      rate of celecoxib were significantly improved by complexation with beta
      cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes
      showed higher dissolution rate than the other complexes.

PMID- 15198509
TI  - Development and characterization of a recombinant Madin-Darby canine kidney cell
      line that expresses rat multidrug resistance-associated protein 1 (rMRP1).
AB  - Multidrug resistance-associated protein 1 (MRP1) is one of the major proteins
      shown to mediate efflux transport of a broad range of antitumor drugs,
      glucuronide conjugates, and glutathione, in addition to endogenous substrates.
      Significant differences in substrate selectivity were reported for murine and
      human MRP1. As preclinical drug disposition and pharmacokinetics studies are
      often conducted in rats, we have recently cloned the rat MRP1 (rMRP1) and
      demonstrated that rMRP1 expressed in transfected cells effluxes calcein, a
      commonly used fluorescence substrate for human MRP1. To further characterize the
      rat ortholog of MRP1, we isolated a cell line stably expressing recombinant
      rMRP1. These cells were tested for their ability to transport calcein and a range
      of chemotherapeutic drugs. Our results showed that cells expressing rMRP1
      consistently efflux calcein at a rate 5-fold greater than control cells. The
      rMRP1 transfected cells, like their human ortholog, can confer drug resistance to
      vinca alkaloid (vinblastine and vincristine) and anthracycline drugs (daunorubcin
      and doxorubicin), and the resistance conferred by the MRP1 can be partially
      abolished by the MRP-specific inhibitors. The transepithelial permeability due to
      rMRP1 expression in differentiated Madin-Darby canine kidney cells (MDCK) cells
      was also investigated. The MRP1 transport activity is directional, as
      demonstrated by directional vinblastine transport. Collectively, our results
      demonstrate that the cellular expression of rMRP1, like its human ortholog, could
      confer resistance to anticancer drugs.

PMID- 15198510
TI  - Pharmacokinetic model of target-mediated disposition of thrombopoietin.
AB  - Thrombopoietin, TPO, a 353 amino acid cytokine, is a primary regulator of
      platelet production that was cloned recently. A target-mediated (platelet
      receptors) pharmacokinetic model was developed to characterize the disposition of
      TPO. Receptor-mediated endocytosis was assigned as the major elimination pathway
      in the model. A nonspecific binding compartment was also incorporated into the
      model. TPO concentration vs time profiles from a published phase 1 and 2 clinical
      trial were used to apply this model. Noncompartmental analysis demonstrated that
      TPO exhibits nonlinear kinetics. The proposed model captured the concentration
      time profiles relatively well. The first-order internalization rate constant was
      estimated as 0.1 h(-1). The endogenous binding capacity was estimated as 164.0
      pM. The second-order binding association constant (k(on)) was 0.055 h(-1).pM(-1)
      and the first-order dissociation constant (k(off)) was estimated as 2.5 h(-1),
      rendering the equilibrium dissociation constant K(d) as 45.5 pM. This model may
      be relevant to other therapeutic agents with receptor-mediated endocytotic
      disposition.

PMID- 15198512
TI  - Assuring quality and performance of sustained and controlled release parenterals:
      EUFEPS workshop report.
AB  - This is a summary report of the workshop, organized by the European Federation of
      Pharmaceutical Scientists in association with the American Association of
      Pharmaceutical Scientists, the European Agency for the Evaluation of Medicinal
      Products, the European Pharmacopoeia, the US Food and Drug Administration and the
      United States Pharmacopoeia, on "Assuring Quality and Performance of Sustained
      and Controlled Release Parenterals" held in Basel, Switzerland, February 2003.
      Experts from the pharmaceutical industry, regulatory authorities and academia
      participated in this workshop to review, discuss and debate formulation,
      processing and manufacture of sustained and controlled release parenterals, and
      identify critical process parameters and their control. This workshop was a
      follow-up workshop to a previous workshop on Assuring Quality and Performance of
      Sustained and Controlled Release Parenterals that was held in Washington, DC in
      April 2001. This report reflects the outcome of the Basel 2003 meeting and the
      advances in the field since the Washington, DC meeting in 2001. As necessary, the
      reader is referred to the report on the 2001 meeting. Areas were identified at
      the 2003 Basel meeting where research is needed in order to understand the
      performance of these drug delivery systems and to assist in the development of
      appropriate testing procedures. Recommendations were made for future workshops
      and meetings.

PMID- 15198511
TI  - Assessment of fertility in male rats after extended chemical castration with a
      GnRH antagonist.
AB  - The purpose of this study was to assess whether male rats whose testosterone
      levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by
      the sustained delivery of orntide acetate, a GnRH antagonist, would return to
      fertility (ie, produce offspring) after serum testosterone returned to control
      levels. Male rats comprising a treatment group (orntide microspheres, dose = 27
      mg/kg/y), a vehicle control group, and a control group of proven male breeders
      were used. For the treatment and vehicle control groups, serum orntide and
      testosterone levels were monitored at periodic intervals for 14 months from the
      initiation of treatment. After serum testosterone levels returned to vehicle
      control levels and orntide serum levels were no longer discernible for the
      treated group, each of the animals was housed with 2 drug-naive, female, proven
      breeders. All the breeder females produced offspring with the exception of 1
      female housed with a male rat from the treatment group and the 2 females housed
      with a single male rat from the vehicle control group. The mean size and weight
      of the litters from each group were not statistically different. Further,
      fertility of the offspring from each group was assessed. The male and female
      offspring studied were all shown to be fertile. The results suggest that lack of
      fertility due to testosterone suppression in male rats is reversible after
      cessation of treatment with the GnRH analog, orntide.

PMID- 15198513
TI  - Encapsulation of water-insoluble drug by a cross-linking technique: effect of
      process and formulation variables on encapsulation efficiency, particle size, and
      in vitro dissolution rate.
AB  - Ibuprofen-gelatin micropellets were prepared by the cross-linking technique using
      formaldehyde. Spherical micropellets having an entrapment efficiency of 65% to
      85% were obtained. The effect of core to coat ratio, speed of agitation,
      temperature, and volume of oil phase was studied with respect to entrapment
      efficiency, micropellet size, and surface characteristics. Fourier transform
      infrared spectroscopy and differential scanning calorimetric analysis confirmed
      the absence of any drug-polymer interaction. X-ray diffraction patterns showed
      that there is a decrease in crystallinity of the drug. The micromeritic
      properties of micropellets were found to be slightly changed by changing various
      processing parameters to give micropellets of good flow property. The in vitro
      release profile could be altered significantly by changing various processing
      parameters to give a controlled release of drug from the micropellets. The
      stability studies of the drug-loaded micropellets showed that the drug was stable
      at storage conditions of room temperature, 37 degrees C, 25 degrees/60% relative
      humidity (RH) and 45 degrees/60% RH, for 12 weeks.

PMID- 15198514
TI  - Amphiphilic star-like macromolecules as novel carriers for topical delivery of
      nonsteroidal anti-inflammatory drugs.
AB  - The objective of this study was to evaluate amphiphilic star-like macromolecules
      (ASMs) as a topical drug delivery system. Indomethacin, piroxicam, and ketoprofen
      were individually encapsulated into the ASMs using coprecipitation. The effects
      of the ASMs on percutaneous permeation of nonsteroidal anti-inflammatory drugs
      (NSAIDs) across full thickness, hairless mouse skin were evaluated in vitro using
      modified Franz diffusion cells. In addition, solubility and in vitro release
      experiments were performed to characterize ASMs behavior in aqueous media.
      Poly(ethylene glycol) (PEG) and Pluronic P-85 were used as polymer controls to
      compare the role of PEG and amphiphilic behavior in the ASMs. In vitro release
      experiments indicated that ASMs can delay drug release (P <.05), whereas
      solubility measurements showed that ASMs can increase NSAIDs aqueous solubility
      (P <.05). Percutaneous permeation studies revealed that ASMs decreased both flux
      and Q24 of drugs compared with the control (P <.10). Skin pretreatment studies
      with ASM-containing solution before drug application demonstrated that
      pretreatment similarly influenced NSAID percutaneous permeation. In conclusion,
      ASMs likely slow drug permeation through 2 mechanisms, delayed drug diffusion
      from its core and skin dehydration by its shell. Thus, ASMs may be useful for
      delayed dermal delivery or prevention of compound permeation through the skin
      (eg, sunscreens, N,N-diethyl-m-toluamide [DEET]) from aqueous formulations.

PMID- 15198515
TI  - AAPS/RAPS/CAPRA collaborative program: exploring the challenges of drug
      regulation in a global environment: clinical concerns.
AB  - Globalization of the pharmaceutical industry has led to a need to harmonize the
      regulatory requirements governing the marketing of medicinal products. To
      minimize the barriers impeding global drug product registration, the
      International Conference on the Harmonization of Technical Requirements of
      Pharmaceuticals for Human Use (ICH) was established in 1990. The ICH has
      developed a series of guidelines that reflect agreements reached by participating
      nations on aspects of the chemistry and clinical technical sections that will
      fulfill the regulatory requirements of these various jurisdications.
      Nevertheless, there continue to be points of divergent perspectives and barriers
      that can impede the use of foreign clinical data. Given the importance of these
      issues, the Regulatory Science (RS) section of the American Association of
      Pharmaceutical Scientists (AAPS), in conjunction with the Regulatory Affairs
      Professional Society (RAPS) and the Canadian Association of Professional
      Regulatory Affairs (CAPRA) cosponsored a public forum on this topic. This
      manuscript provides a summary of the speaker presentations and audience
      discussions regarding the design of clinical trials and the extrapolation of
      results from these trials to support international drug registration.

PMID- 15198516
TI  - Hydroxyzine from topical phospholipid liposomal formulations: evaluation of
      peripheral antihistaminic activity and systemic absorption in a rabbit model.
AB  - Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat
      allergic skin disorders. This study was performed to assess the peripheral H(1)
      antihistaminic activity and extent of systemic absorption of hydroxyzine from
      liposomes applied to the skin. Using L-alpha-phosphatidylcholine (PC), small
      unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing
      hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the
      control. Using a randomized, crossover design, each formulation, containing 10 mg
      of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08 +/- 0.05 kg).
      Histamine-induced wheal tests and blood sampling were performed at designated
      time intervals up to 24 hours. Compared with baseline, hydroxyzine from all
      formulations significantly suppressed histamine-induced wheal formation by 75% to
      95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to
      6 hours, with no differences among the formulations. The areas of plasma
      hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and
      PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng/mL/h, respectively, were lower than
      that from GB, 492 +/- 141 ng/mL/h (P < or =.05) over 24 hours. Plasma
      concentrations of cetirizine arising in-vivo as the active metabolite of
      hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765 +/- 50,
      1035 +/- 202, and 957 +/- 227 ng/mL/h, respectively (P < or =.05). Only 0.02% to
      0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In
      this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic
      activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo
      contributed to some of H1-antihistaminic activity.

PMID- 15198518
TI  - Lipid-based supramolecular systems for topical application: a preformulatory
      study.
AB  - This article describes the production and characterization of monoglyceride-based
      supramolecular systems by a simple processing technique, avoiding time-consuming
      procedures, high energy input, and the use of organic solvents. A preformulatory
      study was performed to study the influence of the experimental parameters on the
      production of monoglyceride-based disperse systems. In particular the effects of
      (1) stirring speed, (2) type and concentration of monoglyceride mixture, and (3)
      type and concentration of surfactant were investigated on the recovery, fraction
      of larger particles, mean diameter, and shape of smaller particles (so called
      nanosomes). Dispersions were first characterized by optical microscopy and freeze
      fracture electron microscopy. The mean diameter of standard nanosomes, analyzed
      by photon correlation spectroscopy (PCS) after elimination of larger particles by
      filtration, was 193.5 nm. Cryotransmission electron microscopy studies, conducted
      in order to investigate the structure of dispersions, showed the coexistence of
      vesicles and particles characterized by a cubic organization. X-ray diffraction
      data revealed the coexistence of 2 different cubic phases, the first being a
      bicontinuous cubic phase of spatial symmetry Im3m (Q229) and the second belonging
      to the Pn3m spatial symmetry. A study on the stability of monoglyceride-based
      dispersions based on macroscopical analysis of organoleptic properties and
      dimensional analysis by time was performed after elimination of larger particles
      by filtration. Organoleptic and morphological features do not change by time,
      appearing free from phase-separation phenomena for almost 1 year from production.
      PCS studies showed that nanosomes undergo an initial increase in mean diameter
      within the first month following production; afterwards they generally maintain
      their dimensions for the next 4 months.

PMID- 15198517
TI  - Pharmacogenomics of multigenic diseases: sex-specific differences in disease and
      treatment outcome.
AB  - Numerous genetic variations have been shown to affect disease susceptibility and
      drug response. Pharmacogenomics aims at improving therapy on the basis of genetic
      information for each individual patient. Furthermore, sex chromosomes broadly
      determine biological differences between males and females. Consequently,
      substantial sex differences exist in phenotypic manifestation of disease and
      treatment response. This review discusses the role of sex in coronary artery
      disease, schizophrenia, and depression--complex multigenic disorders with
      considerable sex differences in frequency and presentation. Moreover, genetic
      factors underlying disease and drug response appear to differ between male and
      female patients. This appears to result at least in part from different
      physiological effects exerted by sex hormones such that polymorphisms in
      susceptibility genes may have physiological relevance only in males or females.
      However, few examples have been discovered to play a role in complex multigenic
      diseases, and the mechanistic basis of genetic variants as sex-dependent
      susceptibility factors has yet to be explored. Therefore, pharmacogenomic studies
      must consider sex differences in an effort to optimize individual drug therapy.

PMID- 15198519
TI  - Properties of microcrystalline cellulose and powder cellulose after
      extrusion/spheronization as studied by fourier transform Raman spectroscopy and
      environmental scanning electron microscopy.
AB  - In this study, the effect of powder cellulose (PC) and 2 types of
      microcrystalline cellulose (MCC 101 and MCC 301) on pellet properties produced by
      an extrusion/spheronization process was investigated. The different investigated
      types of cellulose displayed different behavior during the
      extrusion/spheronization process. Pure PC was unsuitable for extrusion, because
      too much water was required and the added water was partly squeezed during the
      extrusion process. In contrast, MCC 101 and MCC 301 were extrudable at a wide
      range of water content, but the quality of the resulting products varied. In the
      extrusion/spheronization process, MCC 101 was the best substance, with easy
      handling and acceptable product properties. The properties of the extrudates and
      pellets were determined by Fourier transform (FT) Raman spectroscopy and
      environmental scanning electron microscopy (ESEM). FT-Raman spectroscopy was able
      to distinguish between the original substances and also between the wet and dried
      extrudates. The particle sizes of the raw material and of the extrudates were
      determined by ESEM without additional preparation. For MCC, the size of the
      resulting particles within the extrudate or pellet was smaller. However, in the
      extrudates of PC, changes in particle size could not be observed.

PMID- 15198524
TI  - Nondestructive and on-line monitoring of tablets using light-induced fluorescence
      technology.
AB  - A system using light-induced fluorescence (LIF) technology was developed for
      rapid and nondestructive analysis of active pharmaceutical ingredients on tablet
      surfaces. Nonhomogeneous tablets with defined layer of active ingredients were
      made by 3-Dimensional Printing technology to determine penetration depths of the
      light source and the resultant fluorescence responses. The LIF method of analysis
      showed penetration to depths of up to 3 mm into tablets. A correlation between
      LIF signals from analysis of tablet surfaces and the total drug content of the
      respective tablets was established. This method of surface analysis was verified
      with UV spectrometric methods for the total drug content of each respective
      tablet. The results from a small sample population of tablets made from both
      homogeneous and nonhomogeneous powder mixtures established good correlation
      between LIF surface monitoring and total tablet content. The use of on-line
      monitoring of the individual tablet for surface content demonstrated consistent
      LIF profiles from simulated production rates up to 3000 tablets a minute. The
      instrument was also field tested successfully on a tablet analyzer.

PMID- 15198521
TI  - A photo-crosslinked poly(vinyl alcohol) hydrogel growth factor release vehicle
      for wound healing applications.
AB  - The objective of this study was to develop and evaluate a hydrogel vehicle for
      sustained release of growth factors for wound healing applications. Hydrogels
      were fabricated using ultraviolet photo-crosslinking of acrylamide-functionalized
      nondegradable poly(vinyl alcohol) (PVA). Protein permeability was initially
      assessed using trypsin inhibitor (TI), a 21 000 MW model protein drug. TI
      permeability was altered by changing the solids content of the gel and by adding
      hydrophilic PVA fillers. As the PVA content increased from 10% to 20%, protein
      flux decreased, with no TI permeating through 20% PVA hydrogels. Further increase
      in model drug release was achieved by incorporating hydrophilic PVA fillers into
      the hydrogel. As filler molecular weight increased, TI flux increased. The
      mechanism for this is most likely an alteration in protein/gel interactions and
      transient variations in water content. The percent protein released was also
      altered by varying protein loading concentration. Release studies conducted using
      growth factor in vehicles with hydrophilic filler showed sustained release of
      platelet-derived growth factor (PDGF-beta,beta) for up to 3 days compared with
      less than 24 hours in the controls. In vitro bioactivity was demonstrated by
      doubling of normal human dermal fibroblast numbers when exposed to growth factor
      loaded vehicle compared to control. The release vehicle developed in this study
      uses a rapid and simple fabrication method, and protein release can be tailored
      by modifying solid content, incorporating biocompatible hydrophilic fillers, and
      varying protein loading concentration.

PMID- 15198520
TI  - Pharmacokinetics of paclitaxel-containing liposomes in rats.
AB  - In animal models, liposomal formulations of paclitaxel possess lower toxicity and
      equal antitumor efficacy compared with the clinical formulation, Taxol. The goal
      of this study was to determine the formulation dependence of paclitaxel
      pharmacokinetics in rats, in order to test the hypothesis that altered
      biodistribution of paclitaxel modifies the exposure of critical normal tissues.
      Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes
      composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor
      EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40
      mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various
      times, and pharmacokinetic parameters were determined from the blood and tissue
      distribution of paclitaxel. The area under the concentration vs time curve (AUC)
      for blood was similar for the 2 formulations (L-pac: 38.1 +/- 3.32 microg-h/mL;
      Cre-pac: 34.5 +/- 0.994 microg-h/mL), however, the AUC for various tissues was
      formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle
      tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the
      reticuloendothelial system that is important in the clearance of liposomes, the
      AUC was statistically higher for L-pac. Apparent tissue partition coefficients
      (K(p)) also were calculated. For bone marrow, a tissue in which paclitaxel exerts
      significant toxicity, K(p) was 5-fold greater for paclitaxel in Cre-pac. The data
      are consistent with paclitaxel release from circulating liposomes, but with
      efflux delayed sufficiently to retain drug to a greater extent in the central
      (blood) compartment and reduce penetration into peripheral tissues. These effects
      may contribute to the reduced toxicity of liposomal formulations of paclitaxel.

PMID- 15198525
TI  - Artificial neural network as an alternative to multiple regression analysis in
      optimizing formulation parameters of cytarabine liposomes.
AB  - The objective of the study was to optimize the formulation parameters of
      cytarabine liposomes by using artificial neural networks (ANN) and multiple
      regression analysis using 3(3) factorial design (FD). As model formulations, 27
      formulations were prepared. The formulation variables, drug (cytarabine)/lipid
      (phosphatidyl choline [PC] and cholesterol [Chol]) molar ratio (X1), PC/Chol in
      percentage ratio of total lipids (X2), and the volume of hydration medium (X3)
      were selected as the independent variables; and the percentage drug entrapment
      (PDE) was selected as the dependent variable. A set of causal factors was used as
      tutorial data for ANN and fed into a computer. The optimization was performed by
      minimizing the generalized distance between the predicted values of each response
      and the optimized one that was obtained individually. In case of 3(3) factorial
      design, a second-order full-model polynomial equation and a reduced model were
      established by subjecting the transformed values of independent variables to
      multiple regression analysis, and contour plots were drawn using the equation.
      The optimization methods developed by both ANN and FD were validated by preparing
      another 5 liposomal formulations. The predetermined PDE and the experimental data
      were compared with predicted data by paired t test, no statistically significant
      difference was observed. ANN showed less error compared with multiple regression
      analysis. These findings demonstrate that ANN provides more accurate prediction
      and is quite useful in the optimization of pharmaceutical formulations when
      compared with the multiple regression analysis method.

PMID- 15198526
TI  - Two-stage optimization process for formulation of chitosan microspheres.
AB  - The objective of the present study was to optimize the concentration of a
      chitosan solution, stirring speed, and concentration of drugs having different
      aqueous solubility for the formulation of chitosan microspheres. Chitosan
      microspheres (unloaded and drug loaded) were prepared by the chemical
      denaturation method and were subjected to measurement of morphology, mean
      particle size, particle size distribution, percentage drug entrapment (PDE), drug
      loading, and drug release (in vitro). Morphology of the microspheres was
      dependent on the level of independent process parameters. While mean particle
      size of unloaded microspheres was found to undergo significant change with each
      increase in concentration of chitosan solution, the stirring rate was found to
      have a significant effect only at the lower level (ie, 2000 to 3000 rpm). Of
      importance, spherical unloaded microspheres were also obtained with a chitosan
      solution of concentration less than 1 mg/mL. Segregated unloaded microspheres
      with particle size in the range of 7 to 15 microm and mean particle size of 12.68
      microm were obtained in the batch prepared by using a chitosan solution of 2
      mg/mL concentration and stirring speed of 3000 rpm. The highest drug load (
      microg drug/mg microspheres) was 50.63 and 13.84 for microspheres containing 5
      fluorouracil and methotrexate, respectively. While the release of 5-fluorouracil
      followed Higuchi's square-root model, methotrexate released more slowly with a
      combination of first-order kinetics and Higuchi's square-root model. The
      formation of chitosan microspheres is helped by the use of differential stirring.
      While an increase in the concentration of water-soluble drug may help to increase
      PDE and drug load over a large concentration range, the effect is limited in case
      of water-insoluble drugs.

PMID- 15198527
TI  - Comparison of the dissolution of metaxalone tablets (Skelaxin) using USP
      Apparatus 2 and 3.
AB  - The purpose of this study was to evaluate the effect of pH on the dissolution
      behavior of metaxalone in the marketed product Skelaxin tablets. The dissolution
      was evaluated using United States Pharmacopeia (USP) dissolution Apparatus 2 and
      3 at pHs ranging from 1.5 to 7.4. Results from these studies show that the
      dissolution of this product is pH dependent. At low pH (simulated gastric fluid,
      pH 1.5), the dissolution of metaxalone from Skelaxin tablets was less than 10%
      over 75 minutes; whereas, dissolution at pH 4.5 showed greater than 90% release
      in the same time period. These results were consistent for both Apparatus 2 and
      3. This suggests that Skelaxin Tablets should be considered a delayed release
      dosage form.

PMID- 15198528
TI  - The influence of formulation and spacer device on the in vitro performance of
      solution chlorofluorocarbon-free propellant-driven metered dose inhalers.
AB  - The purpose of this study was to evaluate the hypothesis that spacer devices have
      limited effect on the in vitro fine particle dose emitted from solution metered
      dose inhalers containing different proportions of HFA134a [1,1,1,2,
      tetrafluoroethane] propellant. Two solution formulations (80% and 97.5% wt/wt
      HFA134a) were tested across the actuator alone, actuator plus Aerochamber, and
      Ace holding chamber. Particle size distributions were determined using laser
      diffraction (LD) and cascade impaction (CI). Multimodal particle size
      distributions were identified using LD. CI analyses were characterized by a major
      mode located at approximately 0.5 microm. The fine particle dose emitted from the
      inhaler spacer combinations containing 97.5% HFA134a was independent of the
      device setup used. Fine particle doses were influenced by spacer setup in 80%
      HFA134a formulations, indicating different plume dynamics of low vapor pressure
      formulations. Sampling inlet deposition was approximately 0 when spacer devices
      were used with either formulation. When spacers were not used, sampling inlet
      deposition was increased significantly. However, inlet deposition with the 97.5%
      HFA134a formulation was significantly less than that of the 80% HFA134a
      formulation (approximately 25% of emitted dose compared with 69%, respectively).
      Thus, high propellant concentration formulations appear to have more robust in
      vitro performance. This is particularly important given the preponderance of poor
      patient compliance that is associated with spacer use. High propellant
      concentrations had the advantage of fine particle doses that were independent of
      the device setup and significantly lowered sampling inlet deposition when no
      spacer was used.

PMID- 15198529
TI  - Influence of processing-induced phase transformations on the dissolution of
      theophylline tablets.
AB  - The object of this investigation was to evaluate the influence of (1) processing
      induced decrease in drug crystallinity and (2) phase transformations during
      dissolution, on the performance of theophylline tablet formulations. Anhydrous
      theophylline underwent multiple transformations (anhydrate --> hydrate -->
      anhydrate) during processing. Although the crystallinity of the anhydrate
      obtained finally was lower than that of the unprocessed drug, it dissolved at a
      slower rate. This decrease in dissolution rate was attributed to the accelerated
      anhydrate to hydrate transformation during the dissolution run. Water vapor
      sorption studies proved to be a good predictor of powder dissolution behavior.
      While a decrease in crystallinity was brought about either by milling or by
      granulation, the effect on tablet dissolution was pronounced only in the latter.
      Tablet formulations prepared from the granules exhibited higher hardness, longer
      disintegration time, and slower dissolution than those containing the milled
      drug. The granules underwent plastic deformation during compression resulting in
      harder tablets, with delayed disintegration. The high hardness coupled with rapid
      anhydrate --> hydrate transformation during dissolution resulted in the formation
      of a hydrate layer on the tablet surface, which further delayed tablet
      disintegration and, consequently, dissolution. Phase transformations during
      processing and, more importantly, during dissolution influenced the observed
      dissolution rates. Product performance was a complex function of the physical
      state of the active and the processing conditions.

PMID- 15198531
TI  - Effect of vacuum drying on protein-mannitol interactions: the physical state of
      mannitol and protein structure in the dried state.
AB  - The purpose of the present studies was to systematically investigate protein
      mannitol interactions using vacuum drying, to obtain a better understanding of
      the effect of protein/mannitol wt/wt ratios on the physical state of mannitol and
      protein secondary structure in the dried state. Solutions containing beta
      lactoglobulin (betaLg):mannitol (1:1-1:15 wt/wt) were vacuum dried at 5 degrees C
      under 3000 mTorr of pressure. The physical state of mannitol was studied using x
      ray powder diffractometry (XRPD), polarized light microscopy (PLM), Fourier
      transform infrared (FTIR) spectroscopy, and modulated differential scanning
      calorimetry (MDSC). XRPD studies indicated that mannitol remained amorphous up to
      1:5 wt/wt betaLg:mannitol ratio, whereas PLM showed the presence of crystals of
      mannitol in all dried samples except for the 1:1 wt/wt betaLg:mannitol dried
      sample. FTIR studies indicated that a small proportion of crystalline mannitol
      was present along with the amorphous mannitol in dried samples at lower (less
      than 1:5 wt/wt) betaLg:mannitol ratios. The T(g) of the dried 1:1 wt/wt
      betaLg:mannitol sample was observed at 33.4 degrees C in MDSC studies, which
      indicated that at least a part of mannitol co-existed with protein in a single
      amorphous phase. Evaluation of the crystallization exotherms indicated that
      irrespective of the betaLg:protein wt/wt ratio in the initial sample, the protein
      to amorphous mannitol ratio was below 1:1 wt/wt in all dried samples. Second
      derivative FTIR studies on dried betaLg and recombinant human interferon alpha-2a
      samples showed that mannitol affected protein secondary structure to a varying
      degree depending on the overall mannitol content in the dried sample and the type
      of protein.

PMID- 15198532
TI  - Phospholipid-stabilized nanoparticles of cyclosporine A by rapid expansion from
      supercritical to aqueous solution.
AB  - The purpose of this research was to form stable suspensions of submicron
      particles of cyclosporine A, a water-insoluble drug, by rapid expansion from
      supercritical to aqueous solution (RESAS). A solution of cyclosporine A in CO2
      was expanded into an aqueous solution containing phospholipid vesicles mixed with
      nonionic surfactants to provide stabilization against particle growth resulting
      from collisions in the expanding jet. The products were evaluated by measuring
      drug loading with high performance liquid chromatography (HPLC), particle sizing
      by dynamic light scattering (DLS), and particle morphology by transmission
      electron microscopy (TEM) and x-ray diffraction. The ability of the surfactant
      molecules to orient at the surface of the particles and provide steric
      stabilization could be manipulated by changing process variables including
      temperature and suspension concentration. Suspensions with high payloads (up to
      54 mg/mL) could be achieved with a mean diameter of 500 nm and particle size
      distribution ranging from 40 to 920 nm. This size range is several hundred
      nanometers smaller than that produced by RESAS for particles stabilized by Tween
      80 alone. The high drug payloads (approximately 10 times greater than the
      equilibrium solubility), the small particle sizes, and the long-term stability
      make this process attractive for development.

PMID- 15198530
TI  - Effect of degree of esterification of pectin and calcium amount on drug release
      from pectin-based matrix tablets.
AB  - The aim of this work was to assess the effect of 2 formulation variables, the
      pectin type (with different degrees of esterification [DEs]) and the amount of
      calcium, on drug release from pectin-based matrix tablets. Pectin matrix tablets
      were prepared by blending indomethacin (a model drug), pectin powder, and various
      amounts of calcium acetate and then tableting by automatic hydraulic press
      machine. Differential scanning calorimetry, powder x-ray diffraction, and Fourier
      transformed-infrared spectroscopy studies of the compressed tablets revealed no
      drug-polymer interaction and the existence of drug with low crystallinity. The in
      vitro release studies in phosphate buffer (United States Pharmacopeia) and tris
      buffer indicated that the lower the DE, the greater the time for 50% of drug
      release (T50). This finding is probably because of the increased binding capacity
      of pectin to calcium. However, when the calcium was excluded, the pectins with
      different DEs showed similar release pattern with insignificant difference of
      T50. When the amount of calcium acetate was increased from 0 to 12 mg/tablet, the
      drug release was significantly slower. However, a large amount of added calcium
      (ie, 24 mg/tablet) produced greater drug release because of the partial
      disintegration of tablets. The results were more pronounced in phosphate buffer,
      where the phosphate ions induced the precipitation of calcium phosphate. In
      conclusion, both pectin type and added calcium affect the drug release from the
      pectin-based matrix tablets.

PMID- 15198533
TI  - Preparation and physicochemical characterization of 5 niclosamide solvates and 1
      hemisolvate.
AB  - The purpose of the study was to characterize the physicochemical, structural, and
      spectral properties of the 1:1 niclosamide and methanol, diethyl ether, dimethyl
      sulfoxide, N,N' dimethylformamide, and tetrahydrofuran solvates and the 2:1
      niclosamide and tetraethylene glycol hemisolvate prepared by recrystallization
      from these organic solvents. Structural, spectral, and thermal analysis results
      confirmed the presence of the solvents and differences in the structural
      properties of these solvates. In addition, differences in the activation energy
      of desolvation, batch solution calorimetry, and the aqueous solubility at 25
      degrees C, 24 hours, showed the stability of the solvates to be in the order:
      anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > methanol
      solvate > dimethyl sulfoxide solvate > N,N' dimethylformamide solvate. The
      intrinsic and powder dissolution rates of the solvates were in the order:
      anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > N,N'
      dimethylformamide solvate > methanol solvate > dimethyl sulfoxide solvate.
      Although these nonaqueous solvates had higher solubility and dissolution rates
      than the monohydrous forms, they were unstable in aqueous media and rapidly
      transformed to one of the monohydrous forms.

PMID- 15198535
TI  - Influence of moisture on the crystal forms of niclosamide obtained from acetone
      and ethyl acetate.
AB  - The purpose of this study was to elucidate the formation of crystal hydrates of
      niclosamide and to delineate the effect of relative humidity on the crystal forms
      obtained from acetone and ethyl acetate. Recrystallization of niclosamide was
      performed in the presence and absence of moisture. Two hydrates and their
      corresponding anhydrates were isolated. The hydrates obtained by the process of
      recrystallization from acetone (Form I) and that obtained from ethyl acetate
      (Form II) were classified based on differences in their dehydration profile,
      crystal structure, shape, and morphology. Crystals obtained in the absence of
      moisture were unstable, and when exposed to the laboratory atmosphere transformed
      to their corresponding hydrates. Differential scanning calorimetry thermograms
      indicate that Form I changes to an anhydrate at temperatures below 100 degrees C,
      while Form II dehydrates in a stepwise manner above 140 degrees C. This finding
      was further confirmed by thermogravimetric analysis. Dehydration of Form II was
      accompanied by a loss of structural integrity, demonstrating that water molecules
      play an important role in maintaining its crystal structure. Form I, Form II, and
      the anhydrate of Form II showed no significant moisture sorption over the entire
      range of relative humidity. Although the anhydrate of Form I did not show any
      moisture uptake at low humidity, it converted to the monohydrate at elevated
      relative humidity (>95%). All forms could be interconverted depending on the
      solvent and humidity conditions.

PMID- 15198534
TI  - Pulmonary absorption of liposomal levonorgestrel.
AB  - The purpose of these studies was to achieve desired bioavailability after
      pulmonary administration of Levonorgestrel (LN) and to provide prolonged
      effective concentration of the drug in plasma and to reduce reported side effects
      of orally administered drug. The plain drug suspension, physical mixture (plain
      drug with liposomal constituents), and drug-encapsulated liposomes containing 10
      micro g of drug were instilled intratracheally in rats. Similarly, 10- micro g
      drug suspension (LO) was administered orally. The blood samples were withdrawn at
      specific time intervals and were subjected to LN analysis by spectrofluorimetric
      technique. The plasma drug concentration data of both the treatments were
      plotted, and pharmacokinetics data were calculated and compared with that of oral
      administration. Percentage relative bioavailability (F*) of 97.6%, 98.6%, and
      109.9% were observed after pulmonary administration of plain drug formulation
      (LP1), physical mixture (plain drug along with constituents of liposomes [LP2]),
      and liposomal (LP3) formulations of the drug, respectively. Following oral
      administration, Cmax of 14.4 +/- 0.6 ng/mL was observed at 2.1 +/- 0.2 hours
      followed by subtherapeutic concentration beyond 30 +/- 0.2 hours, while after
      pulmonary administration of LP1, LP2, and LP3 formulations, Cmax of 4.4 +/- 0.4
      ng/mL, 4.2 +/- 0.5 ng/mL, and 4.4 +/- 0.6 ng/mL were observed at 6.0 +/- 0.2
      hours, 7.0 +/- 0.2 hours, and 6.8 +/- 0.2 hours, respectively, followed by
      maintenance of effective plasma drug concentration up to 60 +/- 2 hours. These
      studies demonstrate superiority of pulmonary drug delivery with regards to
      maintenance of effective therapeutic concentration of the LN in the plasma over a
      period of 6 to 60 hours. Hence, the pulmonary delivery is expected to reduce
      frequency of dosing and systemic side effects associated with oral administration
      of LN.

PMID- 15198536
TI  - Solid-state and mechanical properties of aqueous chitosan-amylose starch films
      plasticized with polyols.
AB  - The film-forming ability of chitosan and binary mixtures of chitosan and native
      amylose corn starch (Hylon VII) was evaluated with free films prepared by a
      casting/solvent evaporation method. Unplasticized and plasticized free chitosan
      films in aqueous acetic acid and respective films containing a mixture of
      chitosan and native amylose starch in acetic acid were prepared. Glycerol,
      sorbitol, and i-erythritol were used as plasticizers. Solid-state and mechanical
      properties of the films were studied by powder x-ray diffractometry (XPRD),
      differential scanning calorimetry (DSC), and a materials testing machine. The
      films composed of a mixture of chitosan and native amylose starch in acetic acid
      were clear and colorless. A plasticizer concentration of 20% wt/wt (of the
      polymer weight) was sufficient to obtain flexible films with all samples tested.
      X-ray diffraction patterns and DSC thermograms indicated an amorphous state of
      the films independent of the type of plasticizer used. In conclusion,
      incorporation of native amylose corn starch into chitosan films improves the
      consistency and the mechanical properties of the films.

PMID- 15198538
TI  - In vitro test to evaluate the interaction between synthetic cervical mucus and
      vaginal formulations.
AB  - The interaction and mixing between a bilayer sample of mucus and vaginal
      formulation was evaluated through viscosity measurements with respect to time and
      shear. Physical mixtures of mucus and vaginal formulation were used as controls.
      Three test protocols were designed: (1) constant shear, (2) intermittent shear,
      and (3) delayed shear. Several marketed vaginal products (Gynol II, KY Plus, KY,
      and Advantage-S) and experimental formulations (C31G with hydroxyethylcellulose
      [HEC]) were evaluated and compared by these tests. The results of the constant
      shear test showed that the shear stress profile of the bilayer approached that of
      the corresponding physical mixture, consistent with complete mixing of the
      bilayer under shear. The time taken for the bilayer to mix completely was in the
      following order: KY Plus > Gynol II and C31G > KY > Advantage-S. Under the
      intermittent shear protocol, the following order for complete mixing was
      observed: KY Plus > C31G > Gynol II > KY > Advantage-S. The 2 products evaluated
      by the delayed shear test, C31G and Gynol II, were both completely mixed at 180
      minutes. The development of an in vitro test, when coupled with in vivo data,
      should serve in the screening and evaluation of future vaginal formulations.

PMID- 15198537
TI  - Improved entrapment efficiency of hydrophilic drug substance during
      nanoprecipitation of poly(l)lactide nanoparticles.
AB  - The purpose of this research was to improve the entrapment efficiency of a model
      hydrophilic drug substance, sodium cromoglycate, loaded inside polylactic acid
      nanoparticles by a modified nanoprecipitation method. The effect of formulation
      parameters was studied to improve the entrapment efficiency of the drug substance
      inside the nanoparticles. Several parameters (changes in the amount of model
      drug, solvent selection, electrolyte addition, pH alteration) were tested in
      order to increase the loading of the hydrophilic drug in the hydrophobic
      nanoparticles. Lowering of the pH was the most efficient way to increase the drug
      loading; up to approximately 70% of the sodium cromoglycate used in the particle
      formation process could be loaded inside the particles. The loading efficiency
      without the pH change was around 10% to 15% at maximum. The crystallinity values
      and crystal habits of the sodium cromoglycate nanoparticles were studied (x-ray
      diffraction) before and after the lowering of the pH. The change in pH conditions
      during the nanoprecipitation process did not affect markedly the crystallinity
      properties of the drug substance. According to this study, it is possible to
      improve the entrapment efficiency of hydrophilic sodium cromoglycate inside of
      the nanoparticles by small changes in the process parameters without alterations
      in the physical properties of the original drug substance.

PMID- 15198539
TI  - Experimental design for the formulation and optimization of novel cross-linked
      oilispheres developed for in vitro site-specific release of Mentha piperita oil.
AB  - A Plackett-Burman design was employed to develop and optimize a novel crosslinked
      calcium-aluminum-alginate-pectinate oilisphere complex as a potential system for
      the in vitro site-specific release of Mentha piperita, an essential oil used for
      the treatment of irritable bowel syndrome. The physicochemical and textural
      properties (dependent variables) of this complex were found to be highly
      sensitive to changes in the concentration of the polymers (0%-1.5% wt/vol),
      crosslinkers (0%-4% wt/vol), and crosslinking reaction times (0.5-6 hours)
      (independent variables). Particle size analysis indicated both unimodal and
      bimodal populations with the highest frequency of 2 mm oilispheres. Oil
      encapsulation ranged from 6 to 35 mg/100 mg oilispheres. Gravimetric changes of
      the crosslinked matrix indicated significant ion sequestration and loss in an
      exponential manner, while matrix erosion followed Higuchi's cube root law. Among
      the various measured responses, the total fracture energy was the most suitable
      optimization objective (R2 = 0.88, Durbin-Watson Index = 1.21%, Coefficient of
      Variation (CV) = 33.21%). The Lagrangian technique produced no significant
      differences (P > .05) between the experimental and predicted total fracture
      energy values (0.0150 vs 0.0107 J). Artificial Neural Networks, as an alternative
      predictive tool of the total fracture energy, was highly accurate (final mean
      square error of optimal network epoch approximately 0.02). Fused-coated optimized
      oilispheres produced a 4-hour lag phase followed by zero-order kinetics (n >
      0.99), whereby analysis of release data indicated that diffusion (Fickian
      constant k1 = 0.74 vs relaxation constant k2 = 0.02) was the predominant release
      mechanism.

PMID- 15198540
TI  - Triamterene-beta-cyclodextrin systems: preparation, characterization and in vivo
      evaluation.
AB  - The purpose of this research was to improve the solubility and therefore
      dissolution and bioavailability of triamterene, a poorly water soluble diuretic,
      by complexation with beta-cyclodextrin. Triamterene has been reported to show low
      bioavailability after oral administration, with wide intersubject variation. This
      study presents the formulation of solid dispersions of triamterene with beta
      cyclodextrin--by cogrinding, kneading, and coevaporation, using low pH conditions
      -and their characterization, evaluation of improvement in dissolution profiles,
      and in vivo advantage. Phase solubility studies indicated complex with possible
      stoichiometry of 1:1 and a stability constant of 167.67 M(-1). The solid
      dispersions were characterized by Fourier transform infrared spectroscopy,
      nuclear magnetic resonance, x-ray diffraction, and differential scanning
      calorimetry studies. The characterization studies confirmed inclusion of the
      phenyl ring of triamterene within the nonpolar cavity of beta-cyclodextrin in the
      coevaporate. Remarkable improvement in in vitro drug release profiles in 0.1N HCl
      and pH 6.8 phosphate buffer was observed with all dispersions, especially the
      coevaporate. The coevaporate, when administered orally in rats, also exhibited
      improved in vivo activity, as measured by net sodium ion excretion, as compared
      with triamterene powder. Thus, coevaporation of the drug and beta-cyclodextrin
      from acidified alcohol provide the optimum condition for inclusion complexation
      to give a binary system with remarkable improvement in in vitro drug release
      profile and in vivo performance.

PMID- 15198541
TI  - Qualification of analytical instruments for use in the pharmaceutical industry: a
      scientific approach.

PMID- 15198542
TI  - Solubilizing poorly soluble antimycotic agents by emulsification via a solvent
      free process.
AB  - The purpose of this study was to formulate itraconazole and ketoconazole as
      oil/water emulsions for parenteral delivery by using a solvent-free
      homogenization process, namely SolEmuls (solubilization by emulsification)
      technology. The drugs were incorporated in the commercial emulsion Lipofundin MCT
      20%, composed of a medium-chain triglyceride/long-chain triglyceride (MCT/LCT)
      oil phase (1:1) and stabilized with 1.2% lecithin. Different parameters such as
      drug-loading capacity, long-term physical stability, and completeness of drug
      dissolution were investigated. Up to 10.0 mg/mL complete drug dissolution was
      achieved with itraconazole; at 20 mg/mL hybrid dispersion was obtained.
      Itraconazole-loaded emulsions were physically stable for 9 months (data up to
      now). Ketoconazole showed physical instability in the Lipofundin emulsion, which
      was stabilized with only 1.2% lecithin. Stabilization of ketoconazole-loaded
      emulsions was achieved using additionally Tween 80 as steric stabilizer. Higher
      concentrations of ketoconazole (ie, 10.0 mg/mL concentrated ketoconazole
      emulsions) were also produced with additional 2.0% Tween 80. Ketoconazole-loaded
      emulsions, 1 mg/mL, which were stabilized with 2.0% Tween 80, were stable for a
      period of 6 months. It can be concluded, after formulating amphotericin B and
      carbamazepine with SolEmuls technology, that SolEmuls was also applicable to the
      antimycotic agents itraconazole and ketoconazole, yielding IV-applicable
      emulsions with cost-effective production technologies.

PMID- 15198544
TI  - Characterization of particle sizes in bulk pharmaceutical solids using digital
      image information.
AB  - The purpose of this study was to demonstrate a novel method of extracting
      relevant information from undispersed bulk powder surfaces to be used in particle
      size analysis. A new surface imaging approach for undispersed powders combined
      with multivariate modeling was used. Digital surface images of various granule
      batches were captured using an inventive optical setup in controlled illumination
      conditions. A descriptor, the gray scale difference matrix (GSDM), which
      describes the particle size of granular material was generated and extracted from
      the powder surface image information. Partial least squares (PLS) modeling was
      used to create a model between the GSDM and the particle size distribution of
      granules measured with sieving. The use of lateral illumination and the combining
      of information from 2 surface images strengthened the shading effects on the
      powder surfaces. The shading effects exposed the topography or the visual texture
      of the powder surfaces. This textural information was efficiently extracted using
      the GSDM descriptor. The goodness-of-fit (R2) for the created PLS model was 0.91
      and the predicted variation (Q2) was 0.87, indicating a good model. The model
      covered granule sizes in the size range of approximately 20 to 2500 microm. The
      extracted descriptor was effectively used in particle size measurement. This
      study confirms that digital images taken from undispersed bulk powder surfaces
      contain substantial information needed for particle size distribution analysis.
      The use of the GSDM enabled the utilization of bulk powder surface information
      and provided a fast method for particle size measurement.

PMID- 15198545
TI  - Identification of chemically modified peptide from poly(D,L-lactide-co-glycolide)
      microspheres under in vitro release conditions.
AB  - The purpose of this research was to study the chemical reactivity of a
      somatostatin analogue, octreotide acetate, formulated in microspheres with
      polymers of varying molecular weight and co-monomer ratio under in vitro testing
      conditions. Poly(D,L-lactide-co-glycolide) (PLGA) and poly(D,L-lactide) (PLA)
      microspheres were prepared by a solvent extraction/evaporation method. The
      microspheres were characterized for drug load, impurity content, and particle
      size. Further, the microspheres were subjected to in vitro release testing in
      acetate buffer (pH 4.0) and phosphate buffered saline (PBS) (pH 7.2). In acetate
      buffer, 3 microsphere batches composed of low molecular weight PLGA 50:50, PLGA
      85:15, and PLA polymers (< or =10 kDa) showed 100% release with minimal impurity
      formation (<10%). The high molecular weight PLGA 50:50 microspheres (28 kDa)
      displayed only 70% cumulative release in acetate buffer with significant impurity
      formation (approximately 24%). In PBS (pH 7.4), on the other hand, only 50%
      release was observed with the same low molecular weight batches (PLGA 50:50, PLGA
      85:15, and PLA) with higher percentages of hydrophobic impurity formation (ie,
      40%, 26%, and 10%, respectively). In addition, in PBS, the high molecular weight
      PLGA 50:50 microspheres showed only 20% drug release with ~66% mean impurity
      content. The chemically modified peptide impurities inside microspheres were
      structurally confirmed through Fourier transform-mass spectrometry (FT-MS) and
      liquid chromatography/mass spectrometry (LC-MS/MS) analyses after extraction
      procedures. The adduct compounds were identified as covalently modified
      conjugates of octreotide with lactic and glycolic acid monomers within polymeric
      microspheres. The data suggest that due to steric hindrance factors, polymers
      with greater lactide content were less amenable to the formation of adduct
      impurities compared with PLGA 50:50 copolymers.

PMID- 15198546
TI  - Superporous IPN hydrogels having enhanced mechanical properties.
AB  - The objective of this study was to improve the mechanical properties of
      superporous hydrogels (SPHs), which were used to develop gastric retention
      devices for long-term oral drug delivery. The main approach used in this study
      was to form an interpenetrating polymer network by incorporating a second polymer
      network inside an SPH structure. Polyacrylonitrile was used as the second network
      inside an SPH. Mechanical properties including compression strength and
      elasticity were significantly improved, up to 50 times as compared with the
      control SPHs. The enhanced mechanical properties were a result of the scaffold
      like fiber network structures formed inside the cell walls of SPHs. The fast
      swelling property of SPHs was not affected by the incorporation of the second
      polymer network because the interconnected pore structures were maintained.
      Gastric retention devices based on superporous IPN hydrogels (SPIHs) with the
      improved mechanical properties are expected to withstand compression pressure and
      mechanical frictions in the stomach better than the control SPHs.

PMID- 15198547
TI  - Liposome formulation of NSC-639829 using halothane as a solvent: a technical
      note.

PMID- 15198548
TI  - A new method to predict flowability using a microscale fluid bed.
AB  - The purpose of this research was to develop a new method to predict the flow
      behavior of pharmaceutical powders using a multichamber microscale fluid bed.
      Different amounts of poorly flowing paracetamol were added to various grades of
      microcrystalline celluloses and silicified microcrystalline cellulose powders.
      Magnesium stearate was used as a lubricant. Experimental minimum fluidization
      velocities (u(mf)) were defined using 2 to 4 g (equal to 10 mL) of material
      (Video 1). The reference flowability of the powders was determined using a
      specific flow meter. Also, the weight variation of the compressed powders, using
      a single-punch press, was measured. When the amount of paracetamol in the
      excipients was increased, the experimental umf increased and the fluidization
      behavior grew worse (Video 2). Principal component analysis (PCA) established
      that the pressure difference over the bed as a function of fluidization velocity
      could be used to characterize the behavior of powders. The increase in poor
      fluidization behavior of the powders was in accordance with the increasing amount
      of paracetamol and with the increasing weight variation of the tablets.
      Furthermore, the angle of repose and the flow rate of silicified microcrystalline
      cellulose powders were predicted using a partial least squares (PLS) model. The
      developed method to predict flowability is a promising approach for use in the
      preformulation and formulation stages of new drug candidates, for example.

PMID- 15198549
TI  - Aerodynamic particle size analysis of aerosols from pressurized metered-dose
      inhalers: comparison of Andersen 8-stage cascade impactor, next generation
      pharmaceutical impactor, and model 3321 Aerodynamic Particle Sizer aerosol
      spectrometer.
AB  - The purpose of this research was to compare three different methods for the
      aerodynamic assessment of (1) chloroflurocarbon (CFC)--fluticasone propionate
      (Flovent), (2) CFC-sodium cromoglycate (Intal), and (3) hydrofluoroalkane (HFA)-
      beclomethasone dipropionate (Qvar) delivered by pressurized metered dose inhaler.
      Particle size distributions were compared determining mass median aerodynamic
      diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction
      <4.7 microm aerodynamic diameter (FPF(<4.7 microm)). Next Generation
      Pharmaceutical Impactor (NGI)-size distributions for Flovent comprised finer
      particles than determined by Andersen 8-stage impactor (ACI) (MMAD = 2.0 +/- 0.05
      micro m [NGI]; 2.8 +/- 0.07 microm [ACI]); however, FPF(<4.7 microm) by both
      impactors was in the narrow range 88% to 93%. Size distribution agreement for
      Intal was better (MMAD = 4.3 +/- 0.19 microm (NGI), 4.2 +/- 0.13 microm (ACI),
      with FPF(<4.7 microm) ranging from 52% to 60%. The Aerodynamic Particle Sizer
      (APS) undersized aerosols produced with either formulation (MMAD = 1.8 +/- 0.07
      micro m and 3.2 +/- 0.02 micro m for Flovent and Intal, respectively), but values
      of FPF(<4.7 microm)from the single-stage impactor (SSI) located at the inlet to
      the APS (82.9% +/- 2.1% [Flovent], 46.4% +/- 2.4% [Intal]) were fairly close to
      corresponding data from the multi-stage impactors. APS-measured size
      distributions for Qvar (MMAD = 1.0 +/- 0.03 micro m; FPF(<4.7 micro m)= 96.4% +/-
      2.5%), were in fair agreement with both NGI (MMAD = 0.9 +/- 0.03 micro m;
      FPF(<4.7 microm)= 96.7% +/- 0.7%), and ACI (MMAD = 1.2 +/- 0.02 microm, FPF(<4.7
      microm)= 98% +/- 0.5%), but FPF(<4.7 microm) from the SSI (67.1% +/- 4.1%) was
      lower than expected, based on equivalent data obtained by the other techniques.
      Particle bounce, incomplete evaporation of volatile constituents and the presence
      of surfactant particles are factors that may be responsible for discrepancies
      between the techniques.

PMID- 15198550
TI  - Biodegradation and in vivo biocompatibility of rosin: a natural film-forming
      polymer.
AB  - The specific aim of the present study was to investigate the biodegradation and
      biocompatibility characteristics of rosin, a natural film-forming polymer. Both
      in vitro as well as in vivo methods were used for assessment of the same. The in
      vitro degradation of rosin films was followed in pH 7.4 phosphate buffered saline
      at 37 degrees C and in vivo by subdermal implantation in rats for up to 90 days.
      Initial biocompatibility was followed on postoperative days 7, 14, 21, and 28 by
      histological observations of the surrounding tissues around the implanted films.
      Poly (DL-lactic-co-glycolic acid) (PLGA) (50:50) was used as reference material
      for biocompatibility. Rate and extent of degradation were followed in terms of
      dry film weight loss, molecular weight (MW) decline, and surface morphological
      changes. Although the rate of in vitro degradation was slow, rosin-free films
      showed complete degradation between 60 and 90 days following subdermal
      implantation in rats. The films degraded following different rates, in vitro and
      in vivo, but the mechanism followed was primarily bulk degradation. Rosin films
      demonstrated inflammatory reactions similar to PLGA, indicative of good
      biocompatibility. Good biocompatibility comparable to PLGA is demonstrated by the
      absence of necrosis or abscess formation in the surrounding tissues. The study
      provides valuable insight, which may lead to new applications of rosin in the
      field of drug delivery.

PMID- 15198551
TI  - Purification and partial characterization of thermostable serine alkaline
      protease from a newly isolated Bacillus subtilis PE-11.
AB  - The purpose of the research was to study the purification and partial
      characterization of thermostable serine alkaline protease from a newly isolated
      Bacillus subtilis PE-11. The enzyme was purified in a 2-step procedure involving
      ammonium sulfate precipitation and Sephadex G-200 gel permeation chromatography.
      The enzyme was shown to have a relative low molecular weight of 15 kd by sodium
      dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and was purified
      21-fold with a yield of 7.5%. It was most active at 60 degrees C, pH 10, with
      casein as substrate. It was stable between pH 8 and 10. This enzyme was almost
      100% stable at 60 degrees C even after 350 minutes of incubation. It was strongly
      activated by metal ions such as Ca+2, Mg+2, and Mn+2. Enzyme activity was
      inhibited strongly by phenylmethyl sulphonyl fluoride (PMSF) and diisopropyl
      fluorophosphates (DFP) but was not inhibited by ethylene diamine tetra acetic
      acid (EDTA), while a slight inhibition was observed with iodoacetate, p
      chloromercuric benzoate (pCMB), and beta-mercaptoethanol (beta-ME). The
      compatibility of the enzyme was studied with commercial and local detergents in
      the presence of 10mM CaCl2 and 1M glycine. The addition of 10mM CaCl2 and 1M
      glycine, individually and in combination, was found to be very effective in
      improving the enzyme stability where it retained 52% activity even after 3 hours.
      This enzyme improved the cleansing power of various detergents. It removed blood
      stains completely when used with detergents in the presence of 10mM CaCl2 and 1M
      glycine.

PMID- 15198552
TI  - Investigations on neomycin production with immobilized cells of Streptomyces
      marinensis NUV-5 in calcium alginate matrix.
AB  - The purpose of this investigation was to study the effect of Streptomyces
      marinensis NUV-5 cells immobilized in calcium alginate for the production of
      neomycin. The effect of various parameters, such as the effect of alginate
      concentration (1%, 2%, 3%, 4%, and 5% wt/vol), the effect of cation (CaCl2,
      BaCl2, and SrCl2), the concentration of cation (0.01M, 0.125M, 0.25M, 0.375M, and
      0.5M), the curing times (1, 6, 11, 16, and 21 hours), and the diameter of the
      bead (1.48, 2.16, 3.24, 4.46, and 5.44 mm), on neomycin production and bead
      stability were studied. The effect of maltose (4%, 3%, 2%, and 1% wt/vol) and
      sodium glutamate (0.6%, 0.3%, 0.15%, and 0.075% wt/vol) concentration on neomycin
      production was also studied. Better neomycin production was achieved with
      optimized parameters, such as alginate at 2% wt/vol, 0.25M CaCl2, 1-hour curing
      time, and 3.24 mm bead diameter. Effective neomycin production was achieved with
      3% wt/vol maltose and 0.6% wt/vol sodium glutamate concentration. The repeated
      batch fermentations were conducted (every 96 hours) using the optimized alginate
      beads, employing the production medium with 3% wt/vol maltose and 0.6% wt/vol
      sodium glutamate along with mineral salts solution. The increase in antibiotic
      production was observed up to the 5th cycle, and later gradual decrease in
      antibiotic production was observed. Comparison of the total antibiotic production
      with free cells and immobilized cells was also done. An enhanced antibiotic
      productivity of 32% was achieved with immobilized cells over the conventional
      free-cell fermentation, while 108% more productivity was achieved over the washed
      free-cell fermentation. From these results it is concluded that the immobilized
      cells of S marinensis NUV-5 in calcium alginate are more efficient for the
      production of neomycin with repeated batch fermentation.

PMID- 15198553
TI  - Aerosol generation by metered-dose inhalers containing dimethyl ether/propane
      inverse microemulsions.
AB  - Water soluble compounds were incorporated into metered-dose inhalers (MDIs) by
      using water-in-propellant lecithin microemulsions, in which dimethyl ether (DME)
      and propane acted as both continuous phase and propellant. Lecithin, water, and
      water soluble compounds were added to glass MDI containers, valves were crimped
      on, and propellants were added using a pressure burette. Aerosols were produced
      using commercially available actuators, and inertial impaction was used to
      determine the mass median aerodynamic diameter (MMAD), geometric standard
      deviation (GSD), and fine particle fraction (FPF) of the resulting aerosols. The
      DME/propane/lecithin microemulsion MDIs generated aerosols with particle size
      distributions suitable for pulmonary delivery (eg, MMAD 3.1 microm, FPF 59% for
      DME with lecithin content 3%, water content 2.5% [wt/wt]). Increasing water
      concentration (up to 8% wt/wt) was correlated with a reduction in FPF. Freezing
      and rewarming had no adverse effect on MMAD, GSD, or FPF. Storage of
      microemulsion samples for up to 3 weeks did not adversely affect the MMAD, GSD,
      or FPF. This approach may enable the pulmonary delivery of water soluble
      therapeutic agents via MDIs.

PMID- 15198554
TI  - A study on moisture isotherms of formulations: the use of polynomial equations to
      predict the moisture isotherms of tablet products.
AB  - The objectives of this study were to investigate the effects of manufacturing
      parameters on the moisture sorption isotherms of some tablet formulations and to
      predict the moisture isotherms of the final formulations using polynomial
      equations. Three tablet formulations including a placebo and 2 drug products were
      prepared through wet granulation, drying, compression, and coating processes.
      Equilibrium moisture content of excipients and granules at 25 degrees C with
      different relative humidities were determined using a dynamic moisture sorption
      microbalance, while such data for tablets were determined using desiccators.
      Moisture sorption isotherms were expressed in polynomial equations. Excipient
      isotherms were used to predict the moisture sorption isotherms of the 3 tablet
      products. Results showed that different physical properties of granules and
      tablets, such as particle size distribution, density, and porosity resulting from
      different granulation and compression conditions did not have significant effect
      on the moisture isotherms of the materials. Changing coating materials from a
      powder mixture to a film also did not change the moisture sorption
      characteristics significantly. The predicted moisture sorption isotherms of the
      formulations agreed well with the experimental results. These results show that
      moisture isotherms of solid pharmaceutical products manufactured with
      conventional processes may be predicted using the isotherms of excipients, and
      polynomial equations may be used as a tool for the prediction of moisture
      isotherms.

PMID- 15198555
TI  - Studies on the interaction of water with ethylcellulose: effect of polymer
      particle size.
AB  - The purpose of this research was to investigate the interaction of water with
      ethylcellulose samples and assess the effect of particle size on the interaction.
      The distribution of water within coarse particle ethylcellulose (CPEC; average
      particle size 310 micro m) and fine particle ethylcellulose (FPEC; average
      particle size 9.7 micro m) of 7 cps viscosity grade was assessed by differential
      scanning calorimetry (DSC) and dynamic vapor sorption analysis. The amounts of
      nonfreezing and freezing water in hydrated samples were determined from melting
      endotherms obtained by DSC. An increase in water content resulted in an increase
      in the enthalpy of fusion of water for the two particle size fractions of EC. The
      amount of nonfreezable water was not affected by the change in particle size at
      low water contents. Exposure of ethylcellulose to water for 30 minutes is
      sufficient to achieve equilibration within the hydrated polymer at 47% wt/wt
      water content. The moisture sorption profiles were analyzed according to the
      Guggenheim-Anderson-de Boer (GAB) and Young and Nelson equations, which can help
      to distinguish moisture distribution in different physical forms. The amount of
      externally adsorbed moisture was greater in the case of FPEC. Internally absorbed
      moisture was evident only with the CPEC. In light of these results, an
      explanation is offered for the success of FPEC in wet-granulation methods where
      CPEC was not successful.

PMID- 15198556
TI  - Once-daily sustained-release matrix tablets of nicorandil: formulation and in
      vitro evaluation.
AB  - The objective of the present study was to develop once-daily sustained-release
      matrix tablets of nicorandil, a novel potassium channel opener used in
      cardiovascular diseases. The tablets were prepared by the wet granulation method.
      Ethanolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and
      polyvinylpyrrolidone were used as granulating agents along with hydrophilic
      matrix materials like hydroxypropyl methylcellulose (HPMC), sodium
      carboxymethylcellulose, and sodium alginate. The granules were evaluated for
      angle of repose, bulk density, compressibility index, total porosity, and drug
      content. The tablets were subjected to thickness, diameter, weight variation
      test, drug content, hardness, friability, and in vitro release studies. The
      granules showed satisfactory flow properties, compressibility, and drug content.
      All the tablet formulations showed acceptable pharmacotechnical properties and
      complied with in-house specifications for tested parameters. According to the
      theoretical release profile calculation, a once-daily sustained-release
      formulation should release 5.92 mg of nicorandil in 1 hour, like conventional
      tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution studies
      indicated that formulation F-I (drug-to-HPMC, 1:4; ethanol as granulating agent)
      could extend the drug release up to 24 hours. In the further formulation
      development process, F-IX (drug-to-HPMC, 1:4; EC 4% wt/vol as granulating agent),
      the most successful formulation of the study, exhibited satisfactory drug release
      in the initial hours, and the total release pattern was very close to the
      theoretical release profile. All the formulations (except F-IX) exhibited
      diffusion-dominated drug release. The mechanism of drug release from F-IX was
      diffusion coupled with erosion.

PMID- 15198557
TI  - Physical properties and compact analysis of commonly used direct compression
      binders.
AB  - This study investigated the basic physico-chemical property and binding
      functionality of commonly used commercial direct compression binders/fillers. The
      compressibility of these materials was also analyzed using compression parameters
      derived from the Heckel, Kawakita, and Cooper-Eaton equations. Five classes of
      excipients were evaluated, including microcrystalline cellulose (MCC), starch,
      lactose, dicalcium phosphate (DCP), and sugar. In general, the starch category
      exhibited the highest moisture content followed by MCC, DCP, lactose, and finally
      sugar; DCP displayed the highest density, followed by sugar, lactose, starch, and
      MCC; the material particle size is highly processing dependent. The data also
      demonstrated that MCC had moderate flowability, excellent compressibility, and
      extremely good compact hardness; with some exceptions, starch, lactose, and sugar
      generally exhibited moderate flowability, compressibility, and hardness; DCP had
      excellent flowability, but poor compressibility and hardness. This research
      additionally confirmed the binding mechanism that had been well documented: MCC
      performs as binder because of its plastic deformation under pressure;
      fragmentation is the predominant mechanism in the case of lactose and DCP; starch
      and sugar perform by both mechanisms.

PMID- 15198558
TI  - Quantification of various phosphatidylcholines in liposomes by enzymatic assay.
AB  - The purpose of this research was to adapt a colorimetric, phospholipase D-based
      serum-phospholipid assay for the quantification of phosphatidylcholine (PC) in
      liposomes using a microtitre plate reader. PC from natural egg PC liposomes was
      quantified reliably. In contrast, poor sensitivity was found for liposomes
      composed of saturated PCs (di-palmitoyl-phosphatidylcholine [DPPC], hydrogenated
      egg PC). Triton X-100 was then added to the liposomes followed by heating above
      the phase transition temperature. This modified sample preparation resulted in
      recoveries of 102.6% +/- 1.0%, 104.4% +/- 7.6%, and 109.4% +/- 3.2% for E80, E80
      3/cholesterol, and DPPC liposomes, respectively. Absolute quantification of
      unknown PCs against a choline chloride standard is feasible, but relative
      measurements against the very same PC are recommended whenever possible.
      Validation experiments revealed an absolute quantification limit of 1.25 microg
      per assay, a good linearity in the range of 25 to 1000 microg/mL PC (r2> or =
      0.9990) and a quite high accuracy (99.8%-101.4% of theory) and precision
      (relative standard deviation < or = 3.2%) for all 3 PCs studied. The method is
      thus regarded as suitable for sensitive, rapid, and reliable routine
      quantification of PCs in liposomes.

PMID- 15198559
TI  - Effect of shape of sodium salicylate particles on physical property and in vitro
      aerosol performance of granules prepared by pressure swing granulation method.
AB  - The purpose of this research was to investigate the effect of the shape of sodium
      salicylate (SS) particles on the physical properties as well as the in vitro
      aerosol performance of the granules granulated by the pressure swing granulation
      method. SS was pulverized with a jet mill (JM) to prepare the distorted
      particles, and SS aqueous solution was spray dried (SD) to prepare the nearly
      spherical particles. The particle size distribution, crushing strength, and pore
      size distribution of the granules were measured. The adhesive force of the
      primary particles in the granules was calculated according to Rumpf's equation.
      The in vitro aerosol performance of the granules was evaluated using a cascade
      impactor. Both JM and SD particles can be spherically granulated by the pressure
      swing granulation method without the use of a binder. The size of SD granules was
      smaller than that of JM granules. Although the crushing strength of the JM and SD
      granules is almost the same, the internal structures of JM granules and SD
      granules were found to differ, and the SD particles appear to have been condensed
      uniformly, resulting in a nearly spherical shape. In the inhalation
      investigation, the percentage of SS particles of appropriate size delivered to
      the region for treatment was noticeably higher for SD granules than for JM
      granules. This finding might be because the adhesive force of the SD primary
      particles was smaller than that of the JM primary particles in the granules and
      because the SD granules could be easily separated by air current to obtain the
      primary particles.

PMID- 15198560
TI  - Preparation and characterization of flurbiprofen beads by melt solidification
      technique.
AB  - A melt solidification technique has been developed to obtain sustained-release
      waxy beads of flurbiprofen. Low glass transition temperature (t(g)) and shear
      induced crystallization of flurbiprofen made it a suitable candidate for melt
      solidification technique. The process involved emulsification and solidification
      of flurbiprofen-cetyl alcohol melt at significantly low temperature (5 degrees
      C). The effect of variables, namely, the amount of cetyl alcohol and the speed of
      agitation, was studied using 3(2)factorial design. The technique and the beads
      were evaluated on the basis of process and desired yield, surface topography,
      Fourier-transform infrared (FT-IR), differential scanning calorimetry (DSC),
      particle size distribution, crushing strength, and drug release. Average values
      for process and desired yields were 97% wt/wt and 26% wt/wt, respectively. No
      interaction was observed between drug and excipient. Multiple regression analysis
      was carried out, and response surfaces were obtained. A curvilinear relationship
      was observed between percentage of desired yield and the amount of cetyl alcohol.
      Linear decrease in crushing strength was observed with increase in the amount of
      cetyl alcohol. Drug released from the beads followed zero order kinetics. Burst
      release was shown to a greater extent in beads containing a lower amount of cetyl
      alcohol. Response surfaces of time required for certain percentage of drug
      (t(D)%) showed that after critical concentration of about 20% of cetyl alcohol
      (400 mg/batch), no significant release retardant effect was observed.

PMID- 15198561
TI  - The 3-D model: does time plasticity represent the influence of tableting speed?
AB  - The objective of this study is to test the hypothesis that time plasticity
      (parameter d from 3-D modeling) is influenced by tableting speed. Tablets were
      produced at different maximum relative densities (rho(rel, max)) on an
      instrumented eccentric tableting machine and on a linear rotary tableting machine
      replicator. Some 3-D data plots were prepared using pressure, normalized time,
      and porosity according to Heckel. After fitting of a twisted plane, the resulting
      parameters were analyzed in a 3-D parameter plot. The materials used were
      dicalcium phosphate dihydrate (DCPD), spray-dried lactose, microcrystalline
      cellulose (MCC), hydroxypropyl methylcellulose (HPMC), kappa-carrageenan (CAR),
      and theophylline monohydrate (TheoM). The results show that tableting speed
      especially influences the parameter d (time plasticity) of the 3-D model for
      plastically and viscoelastically deforming materials such as MCC, HPMC, CAR, and
      TheoM. For more plastically deforming materials such as MCC, HPMC, and TheoM, a
      subtle influence on omega is also visible. The stages of higher densification are
      affected more than the stages of lower densification. Brittle materials such as
      DCPD exhibit no influence of tableting speed. The influence of speed on spray
      dried lactose is minor. The results are valid for data obtained from an eccentric
      tableting machine and also for data from a linear rotary tableting machine
      replicator. Thus, the empirically derived parameter time plasticity d really
      represents the influence of time.

PMID- 15198562
TI  - Thermal porosity analysis of croscarmellose sodium and sodium starch glycolate by
      differential scanning calorimetry.
AB  - The aim of the study was to demonstrate the applicability of differential
      scanning calorimetry (DSC) on porosity analysis for cellulose and starch.
      Croscarmellose sodium (CCS) and sodium starch glycolate (SSG) were allowed to
      sorb moisture in 85%, 90%, 95%, and 100% relative humidity (RH) at 40 degrees C
      for 24 hours. The pretreated samples were then subjected to DSC running
      temperature ranging from 25 degrees C to -50 degrees C at a cooling rate of 10
      degrees C/min. The cooling traces of water crystallization, if present, were
      transformed to porosity distribution via capillary condensation using Kelvin's
      equation. The porosity analysis of CCS and SSG was also done using nitrogen
      adsorption as a reference method. It was found that sorbed water could not be
      frozen (in cases of 85% and 90% RH) until the moisture content exceeded a cutoff
      value (in cases of 95% and 100% RH). The nonfreezable moisture content was
      referred to tightly bound, plasticizing water, whereas the frozen one may be
      attributed to loosely bound water condensation in pore structure of CCS and SSG
      surfaces. Not only capillary condensation but also the tightly bound,
      nonfreezable monolayer water lying along the inner pores of the surface
      contributed to porosity determination. Good agreement with less than 5% deviation
      of mean pore size was observed when the results were compared with nitrogen
      adsorption. The narrower pore size distributions, however, were obtained because
      of the limitations of the technique. It was concluded that pore analysis by DSC
      could be successful. Further research needs to be done to account for limitations
      and to extend the applicability of the technique.

PMID- 15198563
TI  - Solid-vapor interactions: influence of environmental conditions on the
      dehydration of carbamazepine dihydrate.
AB  - The goal of this research was a phenomenological study of the effect of
      environmental factors on the dehydration behavior of carbamazepine dihydrate.
      Dehydration experiments were performed in an automated vapor sorption apparatus
      under a variety of conditions, and weight loss was monitored as a function of
      time. In addition to lattice water, carbamazepine dihydrate contained a
      significant amount of physically bound water. Based on the kinetics of water
      loss, it was possible to differentiate between the removal of physically bound
      water and the lattice water. The activation energy for the 2 processes was 44 and
      88 kJ/mol, respectively. As expected, the dehydration rate of carbamazepine
      dihydrate decreased with an increase in water vapor pressure. While dehydration
      at 0% relative humidity (RH) resulted in an amorphous anhydrate, the
      crystallinity of the anhydrate increased as a function of the RH of dehydration.
      A method was developed for in situ crystallinity determination of the anhydrate
      formed. Dehydration in the presence of the ethanol vapor was a 2-step process,
      and the fraction dehydrated at each step was a function of the ethanol vapor
      pressure. We hypothesize the formation of an intermediate lower hydrate phase
      with unknown water stoichiometry. An increase in the ethanol vapor pressure first
      led to a decrease in the dehydration rate followed by an increase. In summary,
      the dehydration behavior of carbamazepine dihydrate was evaluated at different
      vapor pressures of water and ethanol. Using the water sorption apparatus, it was
      possible to (1) differentiate between the removal of physically bound and lattice
      water, and (2) develop a method for quantifying, in situ, the crystallinity of
      the product (anhydrate) phase.

PMID- 15198564
TI  - Unilamellar vesicles as potential capreomycin sulfate carriers: preparation and
      physicochemical characterization.
AB  - The aim of this work was to evaluate unilamellar liposomes as new potential
      capreomycin sulfate (CS) delivery systems for future pulmonary targeting by
      aerosol administration. Dipalmitoylphosphatidylcholine, hydrogenated
      phosphatidylcholine, and distearoylphosphatidylcholine were used for liposome
      preparation. Peptide-membrane interaction was investigated by differential
      scanning calorimetry (DSC) and attenuated total internal reflection Fourier
      transform infrared spectroscopy (ATIR-FTIR). Peptide entrapment, size, and
      morphology were evaluated by UV spectrophotometry, photocorrelation spectroscopy,
      and transmission electron microscopy, respectively. Interaction between CS and
      the outer region of the bilayer was revealed by DSC and ATIR-FTIR. DSPC liposomes
      showed enhanced interdigitation when the CS molar fraction was increased.
      Formation of a second phase on the bilayer surface was observed. From kinetic and
      permeability studies, CS loaded DSPC liposomes resulted more stable if compared
      to DPPC and HPC over the period of time investigated. The amount of entrapped
      peptide oscillated between 10% and 13%. Vesicles showed a narrow size
      distribution, from 138 to 166 nm, and a good morphology. These systems, in
      particular DSPC liposomes, could represent promising carriers for this peptide.

PMID- 15198565
TI  - Design of rapidly disintegrating oral tablets using acid-treated yeast cell wall:
      a technical note.

PMID- 15198566
TI  - Optimization of polylactic-co-glycolic acid nanoparticles containing itraconazole
      using 2(3) factorial design.
AB  - This study investigated the utility of a 2(3) factorial design and optimization
      process for polylactic-co-glycolic acid (PLGA) nanoparticles containing
      itraconazole with 5 replicates at the center of the design. Nanoparticles were
      prepared by solvent displacement technique with PLGA X1 (10, 100 mg/mL), benzyl
      benzoate X2 (5, 20 microg/mL), and itraconazole X3 (200, 1800 microg/mL).
      Particle size (Y1), the amount of itraconazole entrapped in the nanoparticles
      (Y2), and encapsulation efficiency (Y3) were used as responses. A validated
      statistical model having significant coefficient figures (P < .001) for the
      particle size (Y1), the amount of itraconazole entrapped in the nanoparticles
      (Y2), and encapsulation efficiency (Y3) as function of the PLGA (X1), benzyl
      benzoate (X2), and itraconazole (X3) were developed: Y1 = 373.75 + 66.54X1+
      52.09X2 + 105.06X3 - 4.73X1X2 + 46.30X1X3; Y2 = 472.93 + 73.45X1 + 169.06X2 +
      333.03X3 + 62.40X1X3 + 141.49X2X3; Y3 = 57.36 + 6.53X1 + 15.52X2 - 12.59X3 +
      1.01X1X3 + 1.73X2X3. X1, X2, and X3 had a significant effect (P < .001) on Y1,
      Y2, and Y3. The particle size, the amount of itraconazole entrapped in the
      nanoparticles, and the encapsulation efficiency of the 4 formulas were in
      agreement with the predictions obtained from the models (P < .05). An overlay
      plot for the 3 responses shows the boundary in which Y1 shows the boundary in
      which a number of combinations of concentration of PLGA, benzyl benzoate, and
      itraconazole will result in a satisfactory process. Using the desirability
      approach with the same constraints, the solution composition having the highest
      overall desirability (D = 0.769) was 10 mg/mL of PLGA, 16.94 microg/mL of benzyl
      benzoate, and 1001.01 microg/mL of itraconazole. This approach allowed the
      selection of the optimum formulation ingredients for PLGA nanoparticles
      containing itraconazole of 500 microg/mL.

PMID- 15198567
TI  - Preparation and stability of poly(ethylene glycol) (PEG)ylated octreotide for
      application to microsphere delivery.
AB  - The purpose of this study was to prepare poly(ethylene glycol) (PEG)ylated
      octreotide and investigate the stability against acylation by polyester polymers
      such as poly(lactic acid) and poly(lactic-co-glycolic acid). Octreotide was
      modified by reaction with monomethoxy PEG-propionaldehyde (molecular weight
      5,000) in the presence of sodium cyanoborohydride. The mono-PEGylated fraction
      was isolated by reversed-phase high-performance liquid chromatography (HPLC) and
      characterized by matrix-assisted laser desorption/ionization time-of-flight mass
      spectrometry (MALDI-TOF MS). Circular dichroism demonstrated no significant
      secondary structural differences between mono-PEGylated octreotide (mono-PEG
      octreotide) and intact octreotide. As a test system for the stability study
      against acylation reaction, lactic acid (LA) solutions with various
      concentrations and pH values were prepared with water dilution and subsequent
      accelerated equilibration at 90 degrees C for 24 hours. Native octreotide was
      found to be acylated in all the diluted LA solutions with different
      concentrations (42.5%, 21.3%, and 8.5%, wt/wt) and pH values (2.25, 1.47, and
      1.85, respectively). The remaining amounts of intact octreotide continuously
      decreased to 50% through 30 days of incubation at 37 degrees C. MALDI-TOF MS
      identified the octreotide to be acylated by LA units. However, acylation reaction
      of mono-PEG-octreotide in LA solutions was negligible, and the remaining amounts
      of intact one through 30 days of incubation in LA solutions were also comparable
      to the initial concentration. These data suggest that mono-PEG-octreotide may
      prevent the acylation reaction in degrading PLA microspheres and possibly serve
      as a new source for somatostatin microsphere formulation.

PMID- 15198568
TI  - Decomposition of a key intermediate in ruthenium-catalyzed olefin metathesis
      reactions.
AB  - Dinuclear ruthenium complex, with a bridging carbide and a hydride ligand, and
      methyltricyclohexylphosphonium chloride result from thermal decomposition of
      olefin metathesis catalyst, (IMesH2)(PCy3)(Cl)2Ru=CH2. Involvement of dissociated
      phosphine in the decomposition is proposed. The dinuclear complex has catalytic
      olefin isomerization activity, which can be responsible for competing
      isomerization processes in certain olefin metathesis reactions.

PMID- 15198569
TI  - Oligoacenes: theoretical prediction of open-shell singlet diradical ground
      states.
AB  - A series of oligoacenes from benzene to decacene were studied computationally
      with DFT and CASSCF methods. In contrast to the common view that acenes are
      closed-shell systems or may have a triplet ground state, these results offer the
      first theoretical predictions for the singlet ground state and diradical
      character for oligoacenes. The nature of the ground states of these molecules
      arises from the disjoint nature of the NBMOs that are singly occupied in the
      diradical.

PMID- 15198570
TI  - Proper and improper hydrogen bonds in metalloorganic crystal architecture:
      experimental evidence in [CoCp(2)](+) and [FeCp(2)](+) salts.
AB  - The [FeCp2]+ and [CoCp2]+ salts are the first examples of metalloorganic
      complexes where the proton donor eta5-Cp shows both "proper" and "improper"
      hydrogen bonds when it is involved in intermolecular bonding with different
      anionic proton acceptors. Blue or red shift of the C-H stretching frequency is
      the clear experimental evidence.

PMID- 15198571
TI  - Extreme stability of an unsolvated alpha-helix.
AB  - High-temperature ion mobility measurements have been performed for alpha-helical
      Ac-A15K+H+ and globular Ac-KA15+H+ peptides. The alpha-helical and globular
      conformations do not melt into random coils as the temperature is raised.
      Instead, both conformations survive to the point where the peptide signals
      vanishes due to fragmentation. This occurs at 600 K for the globular Ac-KA15+H+
      peptide and at 725 K for the alpha-helical Ac-A15K+H+. For the helical Ac-A15K+H+
      peptide it appears that fragmentation is triggered by disruption of the helical
      conformation.

PMID- 15198572
TI  - New poly(d-glucaramidoamine)s induce DNA nanoparticle formation and efficient
      gene delivery into mammalian cells.
AB  - In this report, four new poly(d-glucaramidoamine)s (1-4) have been designed to
      lower the toxicity of conventional polymeric nucleic acid delivery vehicles by
      incorporating a carbohydrate comonomer within a polyethylenimine (PEI)-like
      backbone. Polymers 1-4 were synthesized via polycondensation of esterified d
      glucaric acid and four different amine-containing comonomers [diethylenetriamine
      (1), triethylenetetramine (2), tetraethylenepentamine (3), and
      pentaethylenehexamine (4)] in methanol. Viscometry and NMR studies suggest that
      the polymers are mostly linear (for 1-4, the alpha value in the Mark-Houwink
      Sakurada equation = 0.6-0.7), thus indicating that polymerization occurs
      predominantly through the primary amines with a low degree of branching off the
      secondary amines. Results of gel electrophoresis shift assays show that polymers
      1-4 bind pDNA at N/P ratios of 5, 3, 2, and 2, respectively. Also, dynamic light
      scattering and TEM experiments indicate that 1-4 compact DNA into nanoparticles
      (polyplexes) between 140 and 440 nm at an N/P ratio of 30. Furthermore,
      polyplexes formed with 1-4 deliver pDNA (plasmid DNA) containing the firefly
      luciferase reporter gene to BHK-21 cells in a nontoxic and highly efficient
      manner (as determined by luciferase gene expression). In particular, polymer 4
      reveals very high delivery efficiency (equivalent to linear PEI). This result may
      be due in part to the "proton sponge" hypothesis proposed by Behr et al. Polymers
      containing amines that are protonated in the endosomal pH range (between about
      7.4-5.0) reveal enhanced gene delivery profiles.

PMID- 15198574
TI  - Expeditious assembly of mesoscopic metallocycles.
AB  - Very large chiral metallocycles with tunable cavities in the range of 0.9-22 nm
      were efficiently assembled from the requisite metal- and ligand-terminated
      oligomers that are built from the 2,2'-diacetoxy-1,1'-binaphthyl-3,3'-bis(ethyne)
      bridging ligand and trans-Pt(PEt3)2 metal connector. These unprecedented
      nanoscopic and mesoscopic molecular metallocycles have been characterized with
      1H, 13C{1H}, and 31P{1H} NMR spectroscopy, microanalysis, IR, UV-vis, and
      circular dichroism spectroscopies, MALDI-TOF MS, and size exclusion
      chromatography (SEC). SEC results indicated that the metallocycles appear to be
      much more compact and rigid than the metal- and ligand-terminated oligomers. The
      present molecular metallocycles provide interesting building blocks for the
      construction of larger functional structures that cannot be accessed from a top
      down approach.

PMID- 15198573
TI  - A functionalized, deep cavitand catalyzes the aminolysis of a choline derivative.
AB  - The aminolysis of choline p-nitrophenyl carbonate is catalyzed with turnover by a
      deep cavitand bearing an introverted pyridone function. The synergy of action
      between the recognition of the guest in the binding pocket and the catalytic
      activity brought to bear by the pyridone is responsible for the high substrate
      specificity observed.

PMID- 15198575
TI  - Density functional theory calculation of indirect nuclear magnetic resonance spin
      spin coupling constants in C(70).
AB  - We calculate NMR spin-spin coupling constants in the C70 fullerene by means of
      density functional theory. We show that using a hybrid density functional (B3LYP)
      and an adequate basis set (cc-pCVDZ-sd), excellent agreement with experimental
      values can be achieved for one-bond couplings. These benchmark calculations
      suggest that theoretical predictions of NMR spin-spin couplings can be extremely
      valuable for discerning structural information of fullerenes.

PMID- 15198576
TI  - Catalytic beacons for the detection of DNA and telomerase activity.
AB  - DNA and telomerase activity are detected by a DNAzyme generated upon
      hybridization and opening of a functional catalytic beacon.

PMID- 15198577
TI  - Stepwise photocleavage of two C-O bonds of 1,8-bis[(4-benzoylphenoxy)
      methyl]naphthalene with three-step excitation using three-color, three-laser
      flash photolysis.
AB  - Stepwise photocleavage of two naphthylmethyl-oxygen bonds of 1,8-bis[(4
      benzoylphenoxy)methyl]naphthalene (1,8-(BPO-CH2)2Np, 1) was observed during three
      color, three-laser flash photolysis at room temperature. The mechanism from 1 to
      the final product, acenaphthene (2), was clearly elucidated. The first (308 nm, 5
      mJ pulse-1) XeCl laser excited 1 to the lowest triplet excited state 1(T1), in
      which the excited energy was localized in the naphthalene moiety, but the C-O
      bond cleavage did not occur. The second (430 nm, 7 mJ pulse-1) OPO laser excited
      1(T1) to the higher triplet excited states 1(Tn) in which the excited energy is
      delocalized in the naphthalene moiety and C-O bonds, and one C-O bond cleavage
      occurred. The third (355 nm, 10 mJ pulse-1) YAG laser excited the carbon-centered
      radical in the ground state 1-(BPO-CH2)NpCH2*(D0) to its excited states 1-(BPO
      CH2)NpCH2*(Dn), from which the second C-O bond cleavage occurred to give 2 as the
      final product. This is a successful example of stepwise cleavage of two
      equivalent C-O bonds in a molecule using three-color three-laser photolysis
      method.

PMID- 15198578
TI  - Electrochemical control of CO/NO ligand exchange in a triruthenium cluster
      monolayer assembled on a gold electrode surface.
AB  - A highly selective ligand exchange reaction is realized in the self-assembled
      monolayer (SAM) of a triruthenium cluster on a gold electrode surface under
      precise electrochemical potential control. CO as well as NO molecules, which are
      known to play key roles in many chemical, biological, and environmental systems,
      can be efficiently introduced into the SAM by electrochemically tuning the
      electronic state of the Ru site. These unique surface reactions are more
      convenient and efficient than conventional ligand exchange reactions in solution
      and could be used for the elucidation of the electron-transfer mechanism in a
      biological system as well as in the development of molecular sensors and devices.

PMID- 15198580
TI  - Inclusion-water-cluster in a three-dimensional superlattice of gold
      nanoparticles.
AB  - Three-dimensional particle crystals made of dicarboxylic thiolate (MSA)
      stabilized gold nanoparticles were formed at an air/water interface. FTIR spectra
      of this supracrystal showed that three well-resolved peaks existed from 3400 to
      3550 cm-1 just falling in a region of OH stretching vibrational mode. Precise
      analysis showed that all these peaks originated from the water cluster included
      in the interstice of a particle crystal.

PMID- 15198579
TI  - Precursor-directed biosynthesis of epothilone in Escherichia coli.
AB  - Engineered biosynthetic pathways provide a powerful method for generating complex
      molecules. Precursor-directed biosynthesis, which combines chemical synthesis and
      enzymatic transformations, allows non-native starting materials to be
      incorporated into biosynthetic pathways. Using this approach, we achieved the
      production of the anticancer agent epothilone C in Escherichia coli. An E. coli
      strain was engineered to express the last three modules of the epothilone
      biosynthetic pathway (epoD-M6, epoE, and epoF) and the substrate required to
      complement the biosynthetic enzymes was obtained by chemical synthesis. Under
      high-density cell culture conditions, the E. coli strain processed exogenously
      fed synthetic substrate into epothilone C at levels comparable to the native host
      (1 mg/L) and at higher levels than other heterologous hosts. Importantly, this
      precursor-directed approach will allow chemical modifications to be introduced
      into the polyketide backbone and may ultimately provide access to epothilone
      analogues with improved pharmacological properties in quantities sufficient for
      clinical development.

PMID- 15198581
TI  - Unusual mesoporous SBA-15 with parallel channels running along the short axis.
AB  - Submicrometer-sized mesoporous silica SBA-15 with cuboidlike morphology has been
      prepared by using excess amounts of decane as cosolvent in the presence of NH4F.
      The channels of the resulting material run parallel to the short axis of the
      cuboid-like SBA-15. It has also been found that the materials have a well-ordered
      channel structure with pore size ca. 12 nm.

PMID- 15198582
TI  - Silver-catalyzed [2 + 2] cycloadditions of siloxy alkynes.
AB  - We have described the first [2 + 2] cycloadditions of siloxy alkynes with a range
      of unsaturated carbonyl compounds. The reactions are efficiently promoted by
      substoichiometric amount of silver trifluoromethanesulfonimide and display
      excellent regio- and diastereoselectivity combined with a broad substrate scope.
      Our studies have established unambiguously the stepwise mechanism of this process
      and provided evidence for a novel role of silver in the catalytic cycle of the
      reaction, which involves silver-based complexation and activation of siloxy
      alkyne toward the subsequent 1,4-addition.

PMID- 15198583
TI  - Ketone deprotonation mediated by mono- and heterobimetallic alkali and alkaline
      earth metal amide bases: structural characterization of potassium, calcium, and
      mixed potassium-calcium enolates.
AB  - Potassium, calcium, and mixed potassium-calcium amide combinations have been
      shown to be efficient reagents in enolization reactions, and a set of
      representative intermediate mono- and heterobimetallic enolates have been
      successfully isolated and crystallographically characterized.

PMID- 15198584
TI  - Effect of chemical oxidation on the self-assembly of organometallic block
      copolymers.
AB  - The thermodynamic interactions in poly(styrene-block-ferrocenyldimethylsilane)
      and poly(isoprene-block-ferrocenyldimethylsilane) copolymers were systematically
      tuned by oxidation of the ferrocene moieties with silver nitrate. Small-angle X
      ray scattering experiments show that oxidizing 8% of the ferrocene moieties
      lowers the order-disorder transition temperature of the copolymers by as much as
      40 degrees C.

PMID- 15198586
TI  - Direct coupling of indoles with carbonyl compounds: short, enantioselective, gram
      scale synthetic entry into the hapalindole and fischerindole alkaloid families.
AB  - The invention of a method for the direct union of indoles and carbonyl compounds
      (ketones, amides, esters) is described. Using this new method, a short,
      enantioselective, gram-scale and protecting group-free synthetic entry to the
      fischerindole and hapalindole indole alkaloid family has been achieved from
      carvone and indole. Total syntheses of (+)-hapalindole Q and (-)-12-epi
      fischerindole U isothiocyanate are reported. The absolute stereochemistry of the
      latter natural product has also been determined.

PMID- 15198585
TI  - Conversion of aquifex aeolicus 3-deoxy-d-manno-octulosonate 8-phosphate synthase,
      a metalloenzyme, into a nonmetalloenzyme.
AB  - The Aquifex aeolicus 3-deoxy-d-manno-octulosonate 8-phosphate synthase (KDO8PS),
      a class II metalloenzyme, is converted into an active nonmetalloenzyme by a
      single amino acid mutation, namely, C11N. The result may provide insight into the
      evolutionary link between the two KDO8PS classes as well as the potential role of
      the metal and/or asparagine in the catalytic mechanism.

PMID- 15198587
TI  - Functional mimicry of the active site of carboxypeptidase a by a molecular
      imprinting strategy: cooperativity of an amidinium and a copper ion in a
      transition-state imprinted cavity giving rise to high catalytic activity.
AB  - A model for the natural enzyme carboxypeptidase A was prepared by molecular
      imprinting in synthetic polymers. An unusually high activity and efficiency for
      carbonate hydrolysis could be obtained by imprinting with a stable transition
      state analogue template and introducing an amidinium group and a Cu2+ ion-binding
      site in a defined orientation to each other into the active site. With substrates
      having a very similar structure to the template, extraordinarily high
      enhancements of rates of 110 000-fold were obtained of catalyzed to uncatalyzed
      reaction kcat/kuncat . The efficiency kcat/Km of the molecularly imprinted
      catalysts compared to that of the nonimprinted control polymers containing the
      same functional groups was 790-fold higher, a clear indication of a very
      efficient imprinting procedure.

PMID- 15198588
TI  - Fiber recruiting peptides: noncovalent decoration of an engineered protein
      scaffold.
AB  - Fiber Recruiting (FiRe) peptides are described. These are derivatives of self
      assembling fiber (SAF) forming peptides that are conjugated with small molecules
      (in our case, biotin or a FLAG-tag octapeptide). The FiRe peptides are co
      assembled into fibers and used as bait to recruit folded and functional proteins
      to the fiber surfaces. This was demonstrated using two molecular recognition
      models: namely, a protein-ligand interaction (biotin-streptavidin) and an antigen
      antibody (FLAG octapeptide-anti-FLAG-antibody) interaction. This concept offers
      an approach to mimicking in natural fibrillar systems, such as collagen or
      fibrin, that communicate specifically with their environments via incorporated or
      decorated active peptide and protein components.

PMID- 15198589
TI  - Synthesis of square gadolinium-oxide nanoplates.
AB  - In this paper, we report a colloidal synthesis of high-quality, square, plate
      shaped Gd2O3 nanocrystals. These nanoplates are single crystalline with a
      thickness of the Gd2O3 unit-cell edge length, approaching the lower limit of
      crystal growth.

PMID- 15198590
TI  - AuBr(3)-catalyzed [4 + 2] benzannulation between an enynal unit and enol.
AB  - The reaction of enynals 1, including o-alkynylbenzaldehydes, and carbonyl
      compounds 2 in the presence of a catalytic amount of AuBr3 in 1,4-dioxane at 100
      degrees C gave the functionalized aromatic compounds 3 in high yields. The AuBr3
      catalyzed formal [4 + 2] benzannulation proceeds most probably through the
      coordination of the triple bond of 1 to AuBr3, the formation of a pyrylium auric
      ate complex via the nucleophilic addition of the carbonyl oxygen atom, the
      reverse electron demand-type Diels-Alder addition of the enols, derived from 2,
      to the auric ate complex, and subsequent dehydration and bond rearrangement.
      Similarly, the AuBr3-catalyzed reactions of 1 with acetal compounds afforded the
      corresponding aromatic compounds in good yields.

PMID- 15198591
TI  - Pd-catalyzed alkyl to aryl migration and cyclization: an efficient synthesis of
      fused polycycles via multiple C-H activation.
AB  - A novel palladium migration methodology for the synthesis of complex fused
      polycycles has been developed. This process involves 1,4-palladium alkyl to aryl
      migrations via through-space C-H activation, followed by intramolecular arylation
      or an intermolecular Heck reaction providing a very efficient way to synthesize
      fused ring systems.

PMID- 15198592
TI  - Dissecting ramoplanin: mechanistic analysis of synthetic ramoplanin analogues as
      a guide to the design of improved antibiotics.
AB  - Ramoplanin is a potent cyclic lipoglycodepsipeptide antibiotic that disrupts
      bacterial cell wall synthesis by binding to the peptidoglycan intermediate Lipid
      II and blocking its polymerization to form the carbohydrate chains of
      peptidoglycan. Although ramoplanin is a promising compound for certain
      indications, it has limitations that impede IV administration for systemic use.
      However, it may be possible to overcome these limitations with analogues. In this
      manuscript, we dissect the effects of structural changes to ramoplanin. The
      studies described here combine total synthesis with enzyme kinetics, NMR
      analysis, and MIC measurements to shed light on the roles of key structural
      features in this antibiotic in Lipid II binding, transglycosylation inhibition,
      and biological activity. The results should serve as a foundation for the design
      of synthetically accessible analogues with improved biological properties.

PMID- 15198593
TI  - Alanine racemase free energy profiles from global analyses of progress curves.
AB  - Free energy profiles for alanine racemase from Bacillus stearothermophilus have
      been determined at pH 6.9 and 8.9 from global analysis of racemization progress
      curves. This required a careful statistical design due to the problems in finding
      the global minimum in mean square for a system with eight adjustable parameters
      (i.e., the eight rate constants that describe the stepwise chemical mechanism).
      The free energy profiles obtained through these procedures are supported by
      independent experimental evidence: (1). steady-state kinetic constants, (2).
      solvent viscosity dependence, (3). spectral analysis of reaction intermediates,
      (4). equilibrium overshoots for progress curves measured in D(2)O, and (5). the
      magnitudes of calculated intrinsic kinetic isotope effects. The free energy
      profiles for the enzyme are compared to those of the uncatalyzed and the PLP
      catalyzed reactions. At pH 6.9, PLP lowers the free energy of activation for
      deprotonation by 8.4 kcal/mol, while the inclusion of apoenzyme along with PLP
      additionally lowers it by 11 kcal/mol.

PMID- 15198594
TI  - Homo-N-oligonucleotides (N1/N9-C1' methylene bridge oligonucleotides): nucleic
      acids with left-handed helicity.
AB  - Oligonucleotides containing a methylene bridge between N1 or N9 of the
      heterocyclic base and C1' of the pentofuranosyl ring (homo-N-oligonucleotides)
      were synthesized. Melting curves revealed that such homo-type oligomers could
      cross-pair with complementary homo-type or natural oligomers. Circular-dichroic
      studies provide evidence that the homo-type dimers have a left-handed stacked
      conformation and further suggest that single-stranded and double-stranded homo
      type oligomers adopt a left-handed conformation, while duplexes with natural
      oligomers or nucleic acids form RNA-like right-handed helices. NMR spectroscopy
      (NOESY) provides supporting evidence for a left-handed stacked conformation of
      the homo-type dimer, while atomic force microscopy indicates a left-handed
      helical conformation of homo-type dsDNA. Homo-type dimers and oligomers showed
      high resistance to digestion by snake-venom and calf-spleen phosphodiesterases
      and nuclease S1.

PMID- 15198595
TI  - Single crystal X- and Q-band EPR spectroscopy of a binuclear Mn(2)(III,IV)
      complex relevant to the oxygen-evolving complex of photosystem II.
AB  - The anisotropic g and hyperfine tensors of the Mn di-micro-oxo complex,
      [Mn(2)(III,IV)O(2)(phen)(4)](PF(6))(3).CH(3)CN, were derived by single-crystal
      EPR measurements at X- and Q-band frequencies. This is the first simulation of
      EPR parameters from single-crystal EPR spectra for multinuclear Mn complexes,
      which are of importance in several metalloenzymes; one of them is the oxygen
      evolving complex in photosystem II (PS II). Single-crystal
      [Mn(2)(III,IV)O(2)(phen)(4)](PF(6))(3).CH(3)CN EPR spectra showed distinct
      resolved (55)Mn hyperfine lines in all crystal orientations, unlike single
      crystal EPR spectra of other Mn(2)(III,IV) di-micro-oxo bridged complexes. We
      measured the EPR spectra in the crystal ab- and bc-planes, and from these spectra
      we obtained the EPR spectra of the complex along the unique a-, b-, and c-axes of
      the crystal. The crystal orientation was determined by X-ray diffraction and
      single-crystal EXAFS (Extended X-ray Absorption Fine Structure) measurements. In
      this complex, the three crystallographic axes, a, b, and c, are parallel or
      nearly parallel to the principal molecular axes of Mn(2)(III,IV)O(2)(phen)(4) as
      shown in the crystallographic data by Stebler et al. (Inorg. Chem. 1986, 25,
      4743). This direct relation together with the resolved hyperfine lines
      significantly simplified the simulation of single-crystal spectra in the three
      principal directions due to the reduction of free parameters and, thus, allowed
      us to define the magnetic g and A tensors of the molecule with a high degree of
      reliability. These parameters were subsequently used to generate the solution EPR
      spectra at both X- and Q-bands with excellent agreement. The anisotropic g and
      hyperfine tensors determined by the simulation of the X- and Q-band single
      crystal and solution EPR spectra are as follows: g(x) = 1.9887, g(y) = 1.9957,
      g(z) = 1.9775, and hyperfine coupling constants are A(III)(x) = |171| G,
      A(III)(y) = |176| G, A(III)(z) = |129| G, A(IV)(x) = |77| G, A(IV)(y) = |74| G,
      A(IV)(z) = |80| G.

PMID- 15198596
TI  - Partitioning of dual-lipidated peptides into membrane microdomains: lipid sorting
      vs peptide aggregation.
AB  - The lateral membrane organization and phase behavior of the lipid mixture DMPC(di
      C(14))/DSPC(di-C(18))/cholesterol (0-33 mol %) with and without an incorporated
      fluorescence-labeled palmitoyl/farnesyl dual-lipidated peptide, BODIPY-Gly
      Cys(Pal)-Met-Gly-Leu-Pro-Cys(Far)-OMe, which represents a membrane recognition
      model system for Ras proteins, was studied by two-photon excitation fluorescence
      microscopy. Measurements were performed on giant unilamellar vesicles (GUVs) over
      a large temperature range, ranging from 30 to 80 degrees C to cover different
      lipid phase states (all-gel, fluid/gel, liquid-ordered, all-fluid). At
      temperatures where the fluid-gel coexistence region of the pure binary
      phospholipid system occurs, large-scale concentration fluctuations appear.
      Incorporation of cholesterol levels up to 33 mol % leads to a significant
      increase of conformational order in the membrane system and a reduction of large
      domain structures. Adding the peptide leads to dramatic changes in the lateral
      organization of the membrane. With cholesterol present, a phase separation is
      induced by a lipid sorting mechanism owing to the high affinity of the lipidated
      peptide to a fluid, DMPC-rich environment. This phase separation leads to the
      formation of peptide-containing domains with high fluorescence intensity that
      become progressively smaller with decreasing temperature. As a result, the local
      concentration of the peptide increases steadily within the confines of the
      shrinking domains. At the lowest temperatures, where the acyl-chain order
      parameter of the membrane has already drastically increased and the membrane
      achieves a liquid-ordered character, an efficient lipid sorting mechanism is no
      longer supported and aggregation of the peptide into small clusters prevails. We
      can conclude that palmitoyl/farnesyl dual-lipidated peptides do not associate
      with liquid-ordered or gel-like domains in phase-separated bilayer membranes. In
      particular, the study shows the interesting ability of the peptide to induce
      formation of fluid microdomains at physiologically relevant cholesterol
      concentrations, and this effect very much depends on the concentration of fluid
      vs ordered lipid molecules.

PMID- 15198597
TI  - Hybrid QM/MM study of thio effects in transphosphorylation reactions: the role of
      solvation.
AB  - Transphosphorylation thio effects in solution are studied using hybrid QM/MM
      calculations with a d-orbital semiempirical Hamiltonian. Activated dynamics
      simulations were performed for a 3' ribose-phosphate model in an explicit 20 A
      sphere of TIP3P water surrounded by a solvent boundary potential, and free energy
      analysis was performed using the weighted histogram analysis method. Single thio
      substitutions at all of the phosphoryl oxygen positions and a double thio
      substitution at the nonbridging positions were considered. The reaction free
      energy profiles are compared with available experimental data, and the role of
      solvation on the barrier heights and reaction coordinate is discussed. These
      results provide an important step in the characterization of thio effects in
      reactions of biological phosphates that may aid in the interpretation of kinetic
      data and ultimately help to unravel the catalytic mechanisms of ribozymes.

PMID- 15198598
TI  - Determination of the absolute configuration of
      [3(2)](1,4)barrelenophanedicarbonitrile using concerted time-dependent density
      functional theory calculations of optical rotation and electronic circular
      dichroism.
AB  - The technique of time-dependent density functional theory (TDDFT) has very
      recently been applied to the calculation of both transparent spectral region
      optical rotations and electronic circular dichroism (CD). Here, we report the
      concerted application of the new methodologies to the determination of the
      absolute configuration (AC) of [3(2)](1,4)barrelenophanedicarbonitrile, 1, the
      first optically active barrelenophane. 1 is conformationally flexible: the two
      three-carbon bridges of 1 can each exhibit two conformations, leading to three
      inequivalent conformations of 1: a, b, and c. Conformational structures and
      energies are predicted using DFT at the B3LYP/6-31G level. Comparison of the
      calculated structures to structures obtained via X-ray crystallography of (+)-1
      shows that (remarkably) all three conformations a-c are simultaneously present in
      crystalline (+)-1. The sodium D line specific rotations, [alpha](D), and CD
      spectra of a-c are calculated using TDDFT at the B3LYP/aug-cc-pVDZ level.
      Comparison of the conformationally averaged specific rotation and CD spectrum to
      the experimental data of Matsuda-Sentou and Shinmyozu leads to the AC
      9S,12S(+)/9R,12R(-). The same AC is obtained both from [alpha](D) and from the
      CD, strongly supporting its reliability.

PMID- 15198599
TI  - Self-assembling peptide as a potential carrier of hydrophobic compounds.
AB  - Microcrystals of a hydrophobic cargo were stabilized by EAK16 II, a self
      assembling oligopeptide, and suspended in aqueous solution. Pyrene was used as a
      model hydrophobic compound. Egg phosphatidylcholine (EPC) vesicles were prepared
      to mimic a cell membrane. Pyrene was released from its EAK16 II coating into EPC
      vesicles. The excimer decay profiles were acquired. They showed that pyrene is
      present in the crystalline form when stabilized by EAK16 II, it is molecularly
      dispersed in EPC vesicles, and it is completely released from its EAK16 II
      coating into the membrane bilayers. The release of pyrene from the microcrystals
      coated with EAK16 II into the EPC membrane was followed by fluorescence as a
      function of time. The amount of pyrene released into the EPC vesicles at a given
      time was quantified using a calibration curve. The concentration of pyrene
      released was determined as a function of time, and the concentration-versus-time
      profile was fitted with one exponential. The rate of pyrene release was found to
      depend on the peptide-to-pyrene molecular ratio. Higher peptide-to-pyrene ratios
      lead to slower transfer of pyrene to the lipophilic environment. Scanning
      electron micrographs demonstrated that a thicker coating on the pyrene crystals
      results in a slower release. The data presented in this work demonstrate that the
      self-assembling EAK16 II can stabilize a hydrophobic cargo in aqueous solution
      and deliver it into a lipophilic environment, and that the rate of transfer can
      be adjusted by tuning the peptide-to-pyrene ratio.

PMID- 15198600
TI  - Supramolecular assemblies of nucleoside phosphocholine amphiphiles.
AB  - A family of new uridine phosphocholine amphiphiles that were prepared using a
      convenient four-step synthetic route is described. Physicochemical studies
      (differential scanning calorimetry, small-angle X-ray scattering, UV-vis and
      circular dichroism spectroscopies, light microscopy, transmission electronic
      microscopy, and scanning electron microscopy) show that these amphiphiles
      spontaneously assemble into supramolecular structures including vesicles, fibers,
      hydrogels, and organogels. In aqueous solution, the amphiphiles possessing
      saturated alkyl chains self-assemble into DNA-like helical fibers in the
      crystalline state below T(m) and compact bilayers above the melting temperature
      (T(m)). The transition from bilayers to fibers is thermally reversible. Above a
      threshold concentration (>6% w/w), a hydrogel is formed due to an entangled
      network of the fibers. A therapeutic agent such as DNA can be entrapped within
      the hydrogel structure. In addition to forming bilayer vesicles and hydrogels in
      aqueous solution, these nucleoside amphiphiles also form organogels in
      cyclohexane above T(m). Scanning electron microscopy shows a continuous
      multilamellar phase in the organogels.

PMID- 15198601
TI  - Synthesis of a malaria candidate glycosylphosphatidylinositol (GPI) structure: a
      strategy for fully inositol acylated and phosphorylated GPIs.
AB  - A congener of the glycosylphosphatidylinositol (GPI) membrane anchor present on
      the cell surface of the malaria pathogen Plasmodium falciparum has been
      synthesized. This GPI is an example of a small number of such membrane anchors
      that carry a fatty acyl group at O-2 of the inositol. Although the acyl group
      plays crucial roles in GPI biosynthesis, it rarely persits in mature molecules.
      Other notable examples are the mammalian GPIs CD52 and AchE. The presence of
      bulky functionalities at three contiguous positions of the inositol moiety
      creates a very crowded environment that poses difficulties for carrying out
      selective chemical manipulations. Thus installations of the axial long-chain acyl
      group and neighboring phosphoglyceryl complex were fraught with obstacles. The
      key solution to these obstacles in the successful synthesis of the malarial
      candidate and prototype structures involved stereoelectronically controlled
      opening of a cyclic ortho ester. The reaction proceeds in very good yields, the
      desired axial diastereomer being formed predominantly, even more so in the case
      of long-chain acyl derivatives. The myoinositol precursor was prepared from
      methyl alpha-d-glucopyranoside by the biomimetic procedure of Bender and Budhu.
      For the glycan array, advantage was taken of the fact that (a). n-pentenyl ortho
      ester donors are rapidly and chemospecifically activated upon treatment with
      ytterbium triflate and N-iodosuccinimide and (b). coupling to an acceptor affords
      alpha-coupled product exclusively. A strategy for obtaining the GPI's alpha
      glucosaminide component from the corresponding alpha-mannoside employed Deshong's
      novel azide displacement procedure. Thus all units of the glycan array were
      obtained from a beta-d-manno-n-pentenyl ortho ester, this being readily prepared
      from d-mannose in three easy, high-yielding steps. The "crowded environment" at
      positions 1 and 2, noted above, could conceivably be relieved by migration of the
      acyl group to the neighboring cis-O-3-hydroxyl in the natural product. However,
      study of our synthetic intermediates and prototypes indicate that the O-2 acyl
      group is quite stable, and that such migration does not occur readily.

PMID- 15198602
TI  - Elimination-addition mechanism for nucleophilic substitution reaction of
      cyclohexenyl iodonium salts and regioselectivity of nucleophilic addition to the
      cyclohexyne intermediate.
AB  - The reaction of 4-substituted cyclohex-1-enyl(phenyl)iodonium tetrafluoroborate
      with tetrabutylammonium acetate gives both the ipso and cine acetate-substitution
      products in aprotic solvents. The isomeric 5-substituted iodonium salt also gives
      the same mixture of the isomeric acetate products. The reaction is best explained
      by an elimination-addition mechanism with 4-substituted cyclohexyne as a common
      intermediate. The cyclohexyne formation was confirmed by deuterium labeling and
      trapping to lead to [4 + 2] cycloadducts and a platinum-cyclohexyne complex.
      Cyclohexyne can also be generated in the presence of some other mild bases such
      as fluoride ion, alkoxides, and amines, though amines are less effective bases
      for the elimination. Kinetic deuterium isotope effects show that the anionic
      bases induce the E2 elimination (k(H)/k(D) > 2), while the amines allow formation
      of a cyclohexenyl cation in chloroform to lead to E1 as well as S(N)1 reactions
      (k(H)/k(D) approximately 1). Bases are much less effective in methanol, and
      methoxide was the only base to efficiently afford the cyclohexyne intermediate.
      Nucleophiles react with the cyclohexyne to give regioisomeric products in the
      ratio dependent on the ring substituent. The observed regioselectivity of
      nucleophilic addition to substituted cyclohexynes is rationalized from calculated
      LUMO populations, which are governed by the bond angles at the acetylenic
      carbons: The less deformed carbon has a higher LUMO population and is
      preferentially attacked by the nucleophile.

PMID- 15198603
TI  - Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N
      acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester
      surrogates.
AB  - Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly
      reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation
      and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with
      various functional groups were synthesized by the Wittig reaction using ylide 2.
      A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the
      epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst
      loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst =
      5000). The high turnover frequency and high volumetric productivity of the
      present reaction are also noteworthy. In addition, a sequential Wittig
      olefination-catalytic asymmetric epoxidation reaction was developed, providing
      efficient one-pot access to optically active epoxides from various aldehydes in
      high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction
      of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts
      were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This
      represents the first direct catalytic asymmetric Michael reaction of unmodified
      ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of
      alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of
      the N-acylpyrrole unit for further transformations is demonstrated.

PMID- 15198605
TI  - Chemistry of the t-butoxyl radical: evidence that most hydrogen abstractions from
      carbon are entropy-controlled.
AB  - Absolute rate constants and Arrhenius parameters for hydrogen abstractions (from
      carbon) by the t-butoxyl radical ((t) BuO.) are reported for several hydrocarbons
      and tertiary amines in solution. Combined with data already in the literature, an
      analysis of all the available data reveals that most hydrogen abstractions (from
      carbon) by (t) BuO. are entropy controlled (i.e., TdeltaS > deltaH, in solution
      at room temperature). For substrates with C-H bond dissociation energies (BDEs) >
      92 kcal/mol, the activation energy for hydrogen abstraction decreases with
      decreasing BDE in accord with the Evans-Polanyi equation, with alpha
      approximately 0.3. For substrates with C-H BDEs in the range from 79 to 92
      kcal/mol, the activation energy does not vary significantly with C-H BDE. The
      implications of these results in the context of the use of (t) BuO. as a chemical
      model for reactive oxygen-centered radicals is discussed.

PMID- 15198604
TI  - Water adducts of BX(3) and CX(3)(+): implications for structure, bonding, and
      reactivity.
AB  - Good quality ab initio calculations (MP2) show that the water adducts of BX(3)
      and CX(3)(+) have totally different structures (X = F-I). While all H(2)O-BX(3)
      complexes have classical C(s) symmetric structures with strong B-O bonds and
      additional H-bonding, the heavier CX(3)(+) cations (X = Cl-I) form weakly bonded
      "non-classical" water adducts that maximize C-X pi-bonding rather than C-O sigma
      bonding. The delocalization of the positive charge as the driving force for pi
      bond formation is absent in BX(3), and therefore, pi-bonding is only weak and not
      structure determining in H(2)O-BX(3). Since the PES of all H(2)O --> EX(3)(0/+1)
      particles (E = B, C) is very flat, flexible basis sets (like TZVPP) are required
      to rigorously characterize the adducts. In earlier calculations (J. Am. Chem.
      Soc. 1997, 119, 6648), classical structures were reported for all H(2)O -->
      EX(3)(0/+1) (E = B, C) complexes, likely resulting from the insufficient quality
      of the basis sets employed. By introducing a positive charge to three coordinate
      boron-halogen cations Do --> BX(2)(+) (Do = NH(3), OH(2), X-H), also the B-X
      bonds shrink due to the stronger pi-bonding induced by the positive charge
      delocalization and if compared to the respective neutral compounds like H(2)N
      BX(2) or BX(3). The "non-classical" water adducts also suggest that the mechanism
      of organic reactions involving carbenium ion intermediates with alpha-bromine or 
      iodine substituents and a nucleophile may proceed through halogen- rather than
      carbon coordination.

PMID- 15198606
TI  - Scandium ion-promoted photoinduced electron transfer from electron donors to
      acridine and pyrene. Essential role of scandium ion in photocatalytic oxygenation
      of hexamethylbenzene.
AB  - Photoinduced electron transfer from a variety of electron donors including
      alkylbenzenes to the singlet excited state of acridine and pyrene is accelerated
      significantly by the presence of scandium triflate [Sc(OTf)(3)] in acetonitrile,
      whereas no photoinduced electron transfer from alkylbenzenes to the singlet
      excited state of acridine or pyrene takes place in the absence of Sc(OTf)(3). The
      rate constants of the Sc(OTf)(3)-promoted photoinduced electron-transfer
      reactions (k(et)) of acridine to afford the complex between acridine radical
      anion and Sc(OTf)(3) remain constant under the conditions such that all the
      acridine molecules form the complex with Sc(OTf)(3). In contrast to the case of
      acridine, the k(et) value of the Sc(OTf)(3)-promoted photoinduced electron
      transfer of pyrene increases with an increase in concentration of Sc(OTf)(3) to
      exhibit first-order dependence on [Sc(OTf)(3)] at low concentrations, changing to
      second-order dependence at high concentrations. The first-order and second-order
      dependence of k(et) on [Sc(OTf)(3)] is ascribed to the 1:1 and 1:2 complexes
      formation between pyrene radical anion and Sc(OTf)(3). The positive shifts of the
      one-electron redox potentials for the couple between the singlet excited state
      and the ground-state radical anion of acridine and pyrene in the presence of
      Sc(OTf)(3) as compared to those in the absence of Sc(OTf)(3) have been determined
      by adapting the free energy relationship for the photoinduced electron-transfer
      reactions. The Sc(OTf)(3)-promoted photoinduced electron transfer from
      hexamethylbenzene to the singlet excited state of acridine or pyrene leads to
      efficient oxygenation of hexamethylbenzene to produce pentamethylbenzyl alcohol
      which is further oxygenated under prolonged photoirradiation of an O(2)-saturated
      acetonitrile solution of hexamethylbenzene in the presence of acridine or pyrene
      which acts as a photocatalyst together with Sc(OTf)(3). The photocatalytic
      oxygenation mechanism has been proposed based on the studies on the quantum
      yields, the fluorescence quenching, and direct detection of the reaction
      intermediates by ESR and laser flash photolysis.

PMID- 15198607
TI  - Reaction of organosilicon hydrides with solid surfaces: an example of surface
      catalyzed self-assembly.
AB  - The solution-phase reactions of octadecylsilane (C(18)H(37)SiH(3)) with 10 high
      surface area metal oxides (groups II-VIII) were investigated. C(18)H(37)SiH(3)
      reacted with most metal oxides at room temperature and produced supported
      monolayers (self-assembled monolayers, SAMs) with a high grafting density of
      C(18), approximately 4.5-5 groups/nm(2). According to the FTIR and (29)Si NMR
      spectra, molecules in the SAMs demonstrated "horizontal" cross-linking (Si-O-Si
      and Si-OH.HO-Si bonds) and little or no "vertical" bonds with the metal oxide
      forming an amorphous, yet ordered film. Also, approximately 3 mol of H(2) was
      formed per each mole of grafted C(18), indicating complete hydrolysis of
      C(18)H(37)SiH(3) during the reaction. On the basis of the activity of different
      metal oxides, we concluded that the hydrolysis of C(18)H(37)SiH(3), the key step
      in the reaction mechanism, is catalyzed by water adsorbed on acidic and basic
      centers (Lewis and Bronsted) of the surface of metal oxide. Metal oxides and
      solids with weak acidic and basic properties, like silica, carbon, and organic
      polymers, do not react with C(18)H(37)SiH(3). Increasing the temperature of the
      reaction or doping neutral surfaces with acids or bases greatly increases their
      activity in the reaction with RSiH(3).

PMID- 15198608
TI  - Rhodium-catalyzed cycloisomerization of 1,6-enynes with an intramolecular halogen
      shift: reaction scope and mechanism.
AB  - The rhodium(I)-species-catalyzed cycloisomerization reaction of a wide spectrum
      of 1,6-enynes with an unusual intramolecular halogen shift was investigated. This
      Rh-catalyzed enyne cyclization reaction represents a new process for the
      synthesis of stereodefined alpha-halomethylene-gamma-butyrolactones, lactams,
      tetrahydrofurans, pyrrolidines, and cyclopentanes. Coordinatively unsaturated
      rhodium species ([Rh(COD)Cl](2) + dppb + AgSbF(6)) only catalyzes the reaction
      with enyne substrates bearing a Z-form double bond, while neutral rhodium species
      (RhCl(PPh(3))(3)) could catalyze enyne substrates bearing a Z- or E-form double
      bond to form the desired products and has a wider substrate scopes. The mechanism
      of the reaction was studied by the employment of control experiments with
      different enyne isomers, and a pi-allyl rhodium intermediate was suggested to
      explain the formation of the cyclic products with an intramolecular halogen
      shift.

PMID- 15198609
TI  - Electrodeless determination of the trap density, decay kinetics, and charge
      separation efficiency of dye-sensitized nanocrystalline TiO(2).
AB  - We have studied photoinduced charge separation in a bare, 3.4 microm thick layer
      of nanocrystalline ("nc") anatase TiO(2) and an nc-TiO(2) layer coated with free
      base 5,10,15,20-tetrakis(4-carboxyphenyl) porphyrin (H(2)TPPC) using the
      electrodeless flash-photolysis time-resolved microwave-conductivity technique (FP
      TRMC). Photoconductivity transients, resulting from the formation of mobile,
      conduction band electrons in the semiconductor have been measured on excitation
      with 3 ns pulses of UV (300 nm) and visible (410-700 nm) light. The product of
      the yield of formation of mobile charge carriers, phi, and the sum of their
      mobilities, Sigmamicro, has been determined from the maximum conductivity for
      light intensities varying from approximately 10(12) to approximately 10(16)
      photons/cm(2)/pulse. For the bare nc-TiO(2) layer at 300 nm and the coated layer
      at all wavelengths, phiSigmamicro initially increased with increasing intensity,
      reached a maximum, and eventually decreased at high intensities. The initial
      increase is attributed to the gradual filling of (surface) electron trapping
      sites. This effect was absent when the samples were continuously illuminated with
      background irradiation at 300 nm with an intensity of 6 x 10(13) photons/cm(2)/s
      (40 microW/cm(2)), thereby presaturating the trapping sites prior to the laser
      pulse. The trap-free mobility of electrons within these 9 nm nanoparticles is
      estimated to be 0.034 cm(2)/Vs at 9 GHz. The eventual decrease in phiSigmamicro
      at intensities corresponding to an electron occupancy of more than one electron
      per particle is unaffected by background illumination, and is attributed to a
      decrease in micro due to electron-electron interactions within the semiconductor
      particles. The photoconductivity action spectrum of the coated nc-TiO(2) layer
      closely followed the photon attenuation spectrum in the visible of the porphyrin,
      with a charge separation efficiency per absorbed photon of 18% at the Soret band
      maximum. The after-pulse decay of the photoconductivity showed a power law
      behavior over a time scale of nanoseconds to several hundreds of microseconds,
      which is attributed to multiple trapping and detrapping events at chemical or
      physical defects within the semiconductor matrix.

PMID- 15198610
TI  - Iridium luminophore complexes for unimolecular oxygen sensors.
AB  - In this study, a series of novel luminescent cyclometalated Ir(III) complexes has
      been synthesized and evaluated for use in unimolecular oxygen-sensing materials.
      The complexes Ir(C6)(2)(vacac), 1, Ir(ppy)(2)(vacac), 2, fac-Ir(ppy)(2)(vppy), 3,
      and mer-Ir(ppy)(2)(vppy), 4, where C6 = Coumarin 6, vacac = allylacetoacetate,
      ppy = 2-phenylpyridine, and vppy = 2-(4-vinylphenyl)pyridine, all have pendent
      vinyl or allyl groups for polymer attachment via the hydrosilation reaction.
      These luminophore complexes were characterized by NMR, absorption, and emission
      spectroscopy, luminescence lifetime and quantum yield measurements, elemental
      analysis, and cyclic voltammetry. Complex 1 was structurally characterized using
      X-ray crystallography, and a series of 1-D ((1)H, (13)C) and 2-D ((1)H-(1)H, (1)H
      (13)C) NMR experiments were used to resolve the solution structure of 4.
      Complexes 1 and 3 displayed the longest luminescence lifetimes and largest
      quantum efficiencies in solution (tau = 6.0 micros, phi = 0.22 for 1; tau = 0.4
      micros, phi = 0.2 for 3) and, as result, are the most promising candidates for
      future luminescence-quenching-based oxygen-sensing studies.

PMID- 15198611
TI  - Electronic structure control of the nucleophilicity of transition metal-thiolate
      complexes: an experimental and theoretical study.
AB  - New metal(II)-thiolate complexes supported by the tetradentate ligand 1,5-bis(2
      pyridylmethyl)-1,5-diazacyclooctane (L(8)py(2)) have been synthesized and
      subjected to physical, spectroscopic, structural, and computational
      characterization. The X-ray crystal structures of these complexes, [L(8)py(2)M(S
      C(6)H(4)-p-CH(3))]BPh(4) (M = Co, Ni, Zn), reveal distorted square-pyramidal
      divalent metal ions with four equatorial nitrogen donors from L(8)py(2) and axial
      p-toluenethiolate ligands. The reactions of the complexes with benzyl bromide
      produce isolable metal(II)-bromide complexes (in the cases of Co and Ni) and the
      thioether benzyl-p-tolylsulfide. This reaction is characterized by a second-order
      rate law (nu = k(2)[L(8)py(2)M(SAr)(+)][PhCH(2)Br]) for all complexes (where M =
      Fe, Co, Ni, or Zn). Of particular significance is the disparity between k(2) for
      M = Fe and Co versus k(2) for M = Ni and Zn, in that k(2) for M = Ni and Zn is
      ca. 10 times larger (faster) than k(2) for M = Fe and Co. An Eyring analysis of
      k(2) for [L(8)py(2)Co(SAr)](+) and [L(8)py(2)Ni(SAr)](+) reveals that the
      reaction rate differences are not rooted in a change in mechanism, as the
      reactions of these complexes with benzyl bromide exhibit comparable activation
      parameters (M = Co: DeltaH() = 45(2) kJ mol(-)(1), DeltaS() = -144(6) J mol(-)(1)
      K(-)(1); M = Ni: DeltaH() = 43(3) kJ mol(-)(1), DeltaS() = -134(8) J mol(-)(1) K(
      )(1)). Electronic structure calculations using density functional theory (DFT)
      reveal that the enhanced reaction rate for [L(8)py(2)Ni(SAr)](+) is rooted in a
      four-electron repulsion (or a "filled/filled interaction") between a completely
      filled nickel(II) d(pi) orbital and one of the two thiolate frontier orbitals, a
      condition that is absent in the Fe(II) and Co(II) complexes. The comparable
      reactivity of [L(8)py(2)Zn(SAr)](+) relative to that of [L(8)py(2)Ni(SAr)](+)
      arises from a highly ionic zinc(II)-thiolate bond that enhances the negative
      charge density on the thiolate sulfur. DFT calculations on putative thioether
      coordinated intermediates reveal that the Co(II)- and Zn(II)-thioethers exhibit
      weaker M-S bonding than Ni(II). These combined results suggest that while Ni(II)
      may serve as a competent replacement for Zn(II) in alkyl group transfer enzymes,
      turnover may be limited by slow product release from the Ni(II) center.

PMID- 15198612
TI  - Structural and spectroscopic studies on Pt.Pt and pi-pi interactions in
      luminescent multinuclear cyclometalated platinum(II) homologues tethered by
      oligophosphine auxiliaries.
AB  - The synthesis and structural, spectroscopic, and electrochemical properties of a
      series of trinuclear tridentate cyclometalated platinum(II) complexes tethered by
      bis(diphenylphosphinomethyl)phenylphosphine (dpmp) have been studied and compared
      with their mono- and binuclear homologues and a propeller-like congener. The X
      ray crystal structures of several derivatives show the presence of a variety of
      intramolecular Pt.Pt, pi-pi, and C-H...O(crown ether) and intermolecular pi-pi
      interactions. The trinuclear complexes display strong absorption in the 400-600
      nm region and show intense red to near-infrared phosphorescence with microsecond
      lifetimes in fluid and glassy solutions and in the solid state. These emissions
      are generally assigned as (3)MMLCT [dsigma-->pi(CNN)] in nature. The close
      similarities between the emission energies in acetonitrile solution and in the
      solid state at 298 K indicate that comparable Pt.Pt and pi-pi configurations are
      maintained in both media, and hence a relationship between the photophysical
      behavior of these lumophores and their solid-state structural features is
      proposed. The tendencies of the absorption and emission energies to red-shift
      from mono- to linearly tethered bi- and trinuclear Pt(II) species are evident. A
      light-emitting electrochemical cell using a trinuclear Pt(II) derivative as
      emitter has been demonstrated.

PMID- 15198614
TI  - Probe-induced native oxide decomposition and localized oxidation on 6H-SiC (0001)
      surface: an atomic force microscopy investigation.
AB  - We report, for the first time, the native oxide decomposition/etching and direct
      local oxide growth on 6H-SiC (0001) surface induced by atomic force microscopy
      (AFM). Surface native oxide was decomposed and assembled into protruded lines
      when the negatively biased AFM tip was scanned over surface areas. The mechanism
      of decomposition was found to be governed by the Fowler-Nordheim emission current
      enhanced by the negatively biased AFM tip. Direct oxide growth on the SiC surface
      was achieved when the AFM tip was immobilized and longer bias duration applied.
      In particular, the aspect ratio of oxide grown on SiC was found to be several
      times higher than that on the Si surface. The improved aspect ratio on SiC was
      attributed to the anisotropic OH(-) diffusion involved in vertical and lateral
      oxidation along the polar and nonpolar directions such as [0001] and [110] axis
      in SiC crystal. The electron transport in the above AFM grown oxide on SiC was
      further investigated by I-V characteristics. The dielectrical strength of AFM
      oxide against degradation and breakdown under electrical stressing was evaluated.

PMID- 15198613
TI  - Mixed quantum mechanical/molecular mechanical (QM/MM) study of the deacylation
      reaction in a penicillin binding protein (PBP) versus in a class C beta
      lactamase.
AB  - The origin of the substantial difference in deacylation rates for acyl-enzyme
      intermediates in penicillin-binding proteins (PBPs) and beta-lactamases has
      remained an unsolved puzzle whose solution is of great importance to
      understanding bacterial antibiotic resistance. In this work, accurate, large
      scale mixed ab initio quantum mechanical/molecular mechanical (QM/MM)
      calculations have been used to study the hydrolysis of acyl-enzyme intermediates
      formed between cephalothin and the dd-peptidase of Streptomyces sp. R61, a PBP,
      and the Enterobacter cloacae P99 cephalosporinase, a class C beta-lactamase.
      Qualitative and, in the case of P99, quantitative agreement was achieved with
      experimental kinetics. The faster rate of deacylation in the beta-lactamase is
      attributed to a more favorable electrostatic environment around Tyr150 in P99 (as
      compared to that for Tyr159 in R61) which facilitates this residue's function as
      the general base. This is found to be in large part accomplished by the ability
      of P99 to covalently bind the ligand without concurrent elimination of hydrogen
      bonds to Tyr150, which proves not to be the case with Tyr159 in R61. This work
      provides an essential foundation for further work in this area, such as selecting
      mutations capable of converting the PBP into a beta-lactamase.

PMID- 15198615
TI  - Electrochemical catalysis of styrene epoxidation with films of MnO(2)
      nanoparticles and H(2)O(2).
AB  - Films of polyions and octahedral layered manganese oxide (OL-1) nanoparticles on
      carbon electrodes made by layer-by-layer alternate electrostatic adsorption were
      active for electrochemical catalysis of styrene epoxidation in solution in the
      presence of hydrogen peroxide and oxygen. The highest catalytic turnover was
      obtained by using applied voltage -0.6 V vs SCE, O(2), and 100 mM H(2)O(2). (18)O
      isotope labeling experiments suggested oxygen incorporation from three different
      sources: molecular oxygen, hydrogen peroxide, and/or lattice oxygen from OL-1
      depending on the potential applied and the oxygen and hydrogen peroxide
      concentrations. Oxygen and hydrogen peroxide activate the OL-1 catalyst for the
      epoxidation. The pathway for styrene epoxidation in the highest yields required
      oxygen, hydrogen peroxide, and a reducing voltage and may involve an activated
      oxygen species in the OL-1 matrix.

PMID- 15198616
TI  - Standard free energy of releasing a localized water molecule from the binding
      pockets of proteins: double-decoupling method.
AB  - Localized water molecules in the binding pockets of proteins play an important
      role in noncovalent association of proteins and small drug compounds. At times,
      the dominant contribution to the binding free energy comes from the release of
      localized water molecules in the binding pockets of biomolecules. Therefore, to
      quantify the energetic importance of these water molecules for drug design
      purposes, we have used the double-decoupling approach to calculate the standard
      free energy of tying up a water molecule in the binding pockets of two protein
      complexes. The double-decoupling approach is based on the underlying principle of
      statistical thermodynamics. We have calculated the standard free energies of
      tying up the water molecule in the binding pockets of these complexes to be
      favorable. These water molecules stabilize the protein-drug complexes by
      interacting with the ligands and binding pockets. Our results offer ideas that
      could be used in optimizing protein-drug interactions, by designing ligands that
      are capable of targeting localized water molecules in protein binding sites. The
      resulting free energy of ligand binding could benefit from the potential free
      energy gain accompanying the release of these water molecules. Furthermore, we
      have examined the theoretical background of the double-decoupling method and its
      connection to the molecular dynamics thermodynamic integration techniques.

PMID- 15198617
TI  - Substituent effects in pi-pi interactions: sandwich and T-shaped configurations.
AB  - Sandwich and T-shaped configurations of benzene dimer, benzene-phenol, benzene
      toluene, benzene-fluorobenzene, and benzene-benzonitrile are studied by coupled
      cluster theory to elucidate how substituents tune pi-pi interactions. All
      substituted sandwich dimers bind more strongly than benzene dimer, whereas the T
      shaped configurations bind more or less favorably depending on the substituent.
      Symmetry-adapted perturbation theory (SAPT) indicates that electrostatic,
      dispersion, induction, and exchange-repulsion contributions are all significant
      to the overall binding energies, and all but induction are important in
      determining relative energies. Models of pi-pi interactions based solely on
      electrostatics, such as the Hunter-Sanders rules, do not seem capable of
      explaining the energetic ordering of the dimers considered.

PMID- 15198618
TI  - Adsorption and reactions of C(6) hydrocarbons at high pressures on Pt(111) single
      crystal surfaces studied by sum frequency generation vibrational spectroscopy:
      mechanisms of isomerization and dehydrocyclization of n-hexane.
AB  - The adsorption geometries and surface reactions of various C(6) hydrocarbons (n
      hexane, 2-methylpentane, 3-methylpentane, and 1-hexene) adsorbed on Pt(111) were
      investigated using sum frequency generation (SFG) surface vibrational
      spectroscopy. The adsorptions and reactions were carried out in 1.5 Torr of C(6)
      hydrocarbons in the absence and presence of excess hydrogen (15 Torr) and in the
      temperature range 296-453 K. At 296 K and in the presence of excess hydrogen, n
      hexane and 3-methylpentane adsorbed molecularly on Pt(111) mostly in "flat-lying"
      geometries. Upon heating the sample up to 453 K, the molecules underwent
      dehydrogenation to form new surface species in "standing-up" geometries, such as
      hexylidyne and metallacyclic species. However, 2-methylpentane and 1-hexene were
      dehydrogenated to metallacyclobutane and hexylidyne, respectively, at 296 K in
      the presence of excess hydrogen. The dehydrogenated species remained unreacted on
      the surface upon heating the sample up to 453 K. The absence of excess hydrogen
      enhanced dehydrogenation of n-hexane and 3-methylpentane to form pi-allyl c
      C(6)H(9) and metallacyclohexane, respectively, at 296 K. Upon heating to 453 K,
      the pi-allyl c-C(6)H(9) species underwent irreversible dehydrogenation, while
      hexylidyne and metallacyclic species remained unreacted. On the basis of these
      results, the mechanisms for catalytic isomerization and dehydrocyclization of n
      hexane, which are the important "reforming" reactions to produce high-octane
      fuels over platinum, were discussed.

PMID- 15198619
TI  - Is there hydrogen scrambling in the gas phase? Energetic and structural
      determinants of proton mobility within protein ions.
AB  - The extent of internal hydrogen exchange (scrambling) within multiply charged
      solvent-free protein ions was investigated using a small model protein. The site
      specific backbone amide protection data were obtained using protein ion
      fragmentation in the gas phase and compared with the available NMR data. Only
      minimal scrambling was detected when relatively high-energy collisional
      activation was used to fragment intact protein ions, while low-energy
      fragmentation resulted in more significant but not random internal exchange.
      Increased conformational flexibility of protein ions in the gas phase did not
      have any effect on the extent of hydrogen scrambling under the conditions of
      higher-energy collisional activation but resulted in totally random
      redistribution of labile hydrogen atoms when the protein ion fragmentation was
      induced by multiple low-energy collisions.

PMID- 15198620
TI  - Carbazole compounds as host materials for triplet emitters in organic light
      emitting diodes: polymer hosts for high-efficiency light-emitting diodes.
AB  - A carbazole homopolymer and carbazole copolymers based on 9,9'-dialkyl-[3,3']
      bicarbazolyl, 2,5-diphenyl-[1,3,4]-oxadiazole and 9,9-bis(4-[3,7
      dimethyloctyloxy]phenyl)fluorene were synthesized and their electrical and
      photophysical properties were characterized with respect to their application as
      host in phosphorescent polymer light-emitting diodes. It is shown that the
      triplet energy of a polymer depends on the specific connections between its
      building blocks. Without changing the composition of the polymer, its triplet
      energy can be increased from 2.3 to 2.6 eV by changing the way in which the
      different building blocks are coupled together. For poly(9-vinylcarbazole) (PVK),
      a carbazole polymer often used as host for high-energy triplet emitters in
      polymer light-emitting diodes, a large hole-injection barrier of about 1 eV
      exists due to the low-lying HOMO level of PVK. For all carbazole polymers
      presented here, the HOMO levels are much closer to the Fermi level of a commonly
      used anode such as ITO and/or a commonly used hole-injection layer such as
      PEDOT:PSS. This makes high current densities and consequently high luminance
      levels possible at moderate applied voltages in polymer light-emitting diodes. A
      double-layer polymer light-emitting diode is constructed comprising a PEDOT:PSS
      layer as hole-injection layer and a carbazole-oxadiazole copolymer doped with a
      green triplet emitter as emissive layer that shows an efficacy of 23 cd/A
      independent of current density and light output.

PMID- 15198621
TI  - Western industralised countries optimistic picture from the beginning of the 20th
      century.

PMID- 15198622
TI  - Early Childhood Caries (ECC): what's in a name?
AB  - AIM: It is evident from the number of published scientific papers on Early
      Childhood Caries (ECC) that interest in this problem has grown in recent years.
      Many authors have been trying to devise a clear definition or classification for
      ECC. The aim of this review was to inventory the prevalence of ECC and to seek a
      consensus regarding definition and diagnosis. Further attention was paid to the
      aetiological factors including the role of microrganisms. Finally, education,
      parenting and treatment procedures were discussed. METHODS: For this review,
      epidemiological studies on caries prevalence in children aged between 0 and 36
      months were compiled through a systematic approach using Medline. REVIEW: This
      clearly showed that ECC continues to be a serious public health problem and that
      there is a great variety of definitions and diagnoses used worldwide, reflected
      in the prevalence data. This review confirms the multicausal aetiology and the
      need for further research. The authors strongly support the recommendations
      formulated at the workshop in Bethesda 1999, and the policy statements by the
      AAPD. CONCLUSION: More efforts should be made to reach the high risk groups
      within populations, in order to reduce the prevalence of ECC and S-ECC (Severe
      Early Childhood Caries) and consequently to ameliorate the quality of life of
      these children. Long-term intervention studies are required for the evaluation of
      these efforts.

PMID- 15198623
TI  - Comparison of data on Early Childhood Caries (ECC) with previous data for Baby
      Bottle Tooth Decay (BBTD) in an Italian kindergarten population.
AB  - AIM: This was to assess the prevalence of Early Childhood Caries (ECC) among
      preschool children attending nursery schools and to compare the results with
      those of a previous survey where the investigators used the term and diagnosis
      for Baby Bottle Tooth Decay (BBTD) syndrome. METHODS: A cross-sectional survey of
      1006 children aged 1-6 years was carried out. WHO recommendations for oral health
      surveys were used for caries diagnosis (non cavitated lesions were excluded). In
      addition, a comparison was made for prevalence of ECC between immigrant and
      native born children. Data were compared for ECC in the present survey with BBTD
      data in a previous study (1994) in the same area with a sample of 401 children
      aged 4 years. All examinations were by one examiner (Cohen's Kappa=0.96).
      RESULTS: Of the 1006 children originally selected 52 children aged more than 71
      months were excluded according to published ECC definition and diagnostic
      criteria. The overall sample was 29 children aged <36 months; 271 aged 3 years;
      364 aged 4 years and 290 aged 5 years. ECC was diagnosed in 19.7% of the overall
      sample. The prevalence of ECC (and S-ECC) were respectively by age: <36 months S
      ECC=17.2%; at 3 years: 13.28% (6.64%); at 4 years: 18.95% (9.34%); at 5 years:
      26.9% (12.75%). In the native born children (916) the ECC was 18.34%, while in
      immigrants (38) it was 52.63% (p<0.001). In 1994 the prevalence of BBTD syndrome
      was 11.9% and in the present study 6.5%. CONCLUSION: The ECC prevalence, as, ECC
      and severe (S-ECC),increased with age. In immigrant children ECC was 3 times (S
      ECC 6 times) more frequent than in native born. Using the BBTD diagnosis the
      prevalence had dropped from 11.9% in 1994 to 6.5% in the present survey.

PMID- 15198624
TI  - Clinical outcomes for Early Childhood Caries (ECC): the influence of health locus
      of control.
AB  - AIM: To assess the relationship between clinical outcomes for children treated
      for ECC and health locus of control. STUDY DESIGN AND METHODS: The study cohort
      consisted of 79 children (42 males, 37 females) treated for ECC; age range was
      2.3-7.3 years (mean 4.2 years) at the time of entry into the study. A
      questionnaire [developed by DeVellis et al., 1993] was administered to each
      child's parent(s) on the day of dental surgery. This questionnaire examined the
      expectation that healthcare outcomes in children are influenced by one of the
      following loci of control: Professional, Parent, Child, Media, Fate and Divine.
      The cohort was evaluated for new caries lesions at 6 months post dental surgery.
      Relapse was defined as the presence of new smooth surface caries lesions.
      STATISTICS: For each locus, the scores for the Relapse versus Non-relapse groups
      (returning patients) and the scores for the returning versus non-returning
      patients were compared using t-tests. RESULTS: 57 children (72%) returned for
      follow-up and 21 of these 57 (37%) relapsed. No statistically significant
      difference for Relapse versus Non-relapse groups was indicated with respect to
      the scores for any locus parameter (p values ranged from 0.35 to 0.95). Returning
      parents (N=57) versus non- returning parents (N=22) exhibited statistically
      significant differences with respect to the Parent, Divine and Fate loci.
      Returning parents exhibited higher scores on the Parent locus (p=0.0392) and
      lower scores on the Fate (p=0.0024) and Divine (p=0.0031) loci. CONCLUSION: 1).
      The relapse rate (37%) was high and rapid for children treated for ECC; 2). no
      meaningful difference existed between the Relapse versus Non-relapse groups with
      respect to each health locus of control parameter; 3). parents who returned for
      follow-up care appeared to have an internal health locus of control while those
      who did not return had an external locus.

PMID- 15198625
TI  - The role of the mother-child interaction as a factor in nursing caries (ECC): a
      preliminary communication.
AB  - AIM: This was to investigate the role of the mother-child interaction as a factor
      in nursing caries. METHODS: A convenience sample of 34 parents whose children had
      been diagnosed with nursing caries (Early Childhood Caries, ECC) was gathered. A
      series of non-structured interviews with parents were conducted. The interviews
      were transcribed and analysed using Grounded Theory. RESULTS: The overarching
      category which explained the basic social process associated with nursing caries
      was 'nursing caries mothering'. The three categories which emerged characterised
      the basic social process of 'nursing caries mothering' were regressive mothering,
      culpable mothering and convenience mothering. CONCLUSION: ECC is characterised by
      regressive mothering, culpable mothering and convenience mothering. In each of
      these typologies the bottle once used to nourish the baby has become imbued with
      other behaviours and meanings. An awareness of these meanings of what the
      breast/bottle have come to represent should be incorporated and form a central
      strand of a joined-up health promotion approach.

PMID- 15198626
TI  - Oral health condition in an Italian preschool population.
AB  - AIM: This was to describe caries experience in Sardinian kindergarten children
      and the possible association with social, behavioural and dietary factors.
      METHODS: 418 kindergarten children (209 males, 209 females), aged 2.5-6.5 years,
      were enrolled. Dental status (dmft, dmfs) and presence of plaque were recorded by
      one calibrated examiner. Social, behavioural and dietary factors were
      investigated with an ad hoc prepared questionnaire. STATISTICS: These were
      descriptive and associations between caries experience and background variables
      were tested using chi square test. Logistic regression models were built up to
      assess the odds ratios (ORs) of caries prevalence and background variables.
      RESULTS: The caries experience rate was 29.9% of the total sample. The mean dmfs
      index was 3.26+/-7.37. The ds mean value was statistically higher in males at
      3.41 versus 2.23 in females. Dmfs and sub indices were very high skewed in the
      total sample and in all age groups. Presence of plaque was recorded in 142
      subjects (34.0%) and it was related to caries experience (20.1% without caries
      and 13.9% with caries) but not statistically significant. In logistic analysis,
      the socioeconomic status families were positively associated with caries
      experience OR=1.4 (95% CI: 1.2-1.9). Subjects with high sweet foods consumption
      showed a higher risk (60%) of caries experience than those not OR=1.6 (95% CI:
      1.1-2.3). Children who cared for themselves regarding oral hygiene habits showed
      a lower risk for caries (OR=0.4 95% CI: 0.2-0.7). CONCLUSION: This study
      documented widespread neglect of dental health of preschool children in Sardinia.
      Untreated decayed teeth dominated the dmfs score among examined population,
      indicating a high rate of treatment needs.

PMID- 15198627
TI  - Restoration of primary teeth affected by Early Childhood Caries.
AB  - AIM: This was to review the literature on Early Childhood Caries (ECC) for the
      approaches to prevention and restoration of affected primary teeth. METHODS: The
      methods are reviewed and suggestions made as the approaches necessary for
      treating very young children. The special problems associated with the need to
      restore primary incisors in children with very low levels of cooperation are
      described. The options are outlined and indications for each approach discussed.

PMID- 15198628
TI  - Use of the Nd:YAG laser in the treatment of Early Childhood Caries.
AB  - AIM: This was to demonstrate that traditional therapy of Early Childhood Caries
      (ECC) can be improved with the use of the Nd:YAG laser. METHODS: This
      investigation was conducted on three 3 year-old children in which the four
      maxillary primary incisors were affected by ECC. The teeth were treated with the
      Nd:YAG laser and one unrestorable tooth for each child was extracted for
      investigation by scanning electron microscopy. RESULTS: The laser therapy
      provided several clinical advantages (reduction of dentine permeability and
      hypersensitivity, sterilization of the lased surface, and fluoride penetration
      within the tooth). Good patient compliance was also achieved due to the type of
      appliance and materials used, absence of noise and vibration, a lack of need for
      local analgesia, and the reduced number of brief appointments. CONCLUSION: This
      approach to treatment of ECC permits teeth to be retained in the dental arch and
      delays the use of traditional methods to a later time when the child has reached
      an age sufficient for cooperation with the practitioner.

PMID- 15198629
TI  - A comparative study on the prevalence of enamel defects and dental caries in
      children and adolescents with and without coeliac disease.
AB  - AIM: This was to test for differences in the prevalence of enamel defects and
      dental caries between children and adolescents with and without coeliac disease
      (CD). MATERIALS AND METHODS: The sample consisted of 27 children and adolescents,
      aged 3 to 18 years with CD, and a control group of 27 healthy subjects matched by
      age and gender. Enamel defects were diagnosed and classified according to
      criteria described by Aine [1986], while dental caries was recorded as DMFT(S)
      and dmft(s) indices [Koch, 1970]. Dental plaque was recorded by the Plaque
      Control Record Index. Information related to medical history, oral hygiene
      habits, use of fluoride, history of dental trauma and socioeconomic factors was
      collected by a structured parental questionnaire. Also, in children with CD the
      age of initiation and diagnosis of the disease was recorded. STATISTICS: The chi
      square and the paired t-test were used for the statistical analysis of the
      qualitative and quantitative data respectively. The logistic multiple regression
      analysis was applied to test whether the time period between the initiation and
      diagnosis of CD and other related factors had a significant (p<or=0.05) impact on
      the presence of enamel defects. RESULTS: The prevalence of enamel defects was
      higher in the CD group. Differences in frequency and symmetrical distribution of
      the defects were statistically significant between CD and control groups. With
      respect to dental caries, significant differences in the mean values of DMFS/dmfs
      were found between the two groups. Higher values of DMFS/dmfs were recorded in
      the control group. CONCLUSION: CD increases the risk of developing enamel defects
      in permanent teeth but not of having dental caries.

PMID- 15198630
TI  - What do certified nurse assistants actually know about dysphagia and feeding
      nursing home residents?
AB  - The purpose of this study was to examine certified nurse assistants' (CNAs')
      knowledge of dysphagia and how to feed nursing home residents using
      nonparticipatory structured feeding observation, critique of staged feeding
      behaviors on film, and semistructured interview in a triangulation methods
      design. Content analysis of the data confirmed previous studies that suggested
      CNAs lack knowledge about dysphagia and how to feed residents. A surprising
      result was the lack of accurate, comprehensive information in CNA texts and
      classrooms about dysphagia and how to manage challenging feeding behaviors.
      Speech-language pathologists are uniquely trained to improve CNA communication
      skills and provide accurate information to nursing colleagues. Specific
      recommendations of how to improve CNA feeding training programs are provided.

PMID- 15198631
TI  - "Speaking for another": the management of participant frames in aphasia.
AB  - A sociolinguistic analysis of an interaction between a woman with aphasia and a
      nonaphasic speaking partner was conducted to investigate participant framing in
      aphasia. Participant frames, or the stances that people take in conversation,
      help conversational participants structure their talk and collaboratively
      negotiate meaning (I. Goffman, 1974). This analysis revealed a configuration in
      which a person with severe aphasia enlisted her speaking partner to speak for
      her. That is, the interaction was framed such that the nonaphasic speaking
      partner served as the "spokesperson" for messages that were authored by the
      person with aphasia. The clinical requirements of adopting a "speaking for
      another" framework are discussed.

PMID- 15198632
TI  - Nonverbal learning disability: a tutorial for speech-language pathologists.
AB  - Nonverbal learning disability (NLD) is a diagnostic category that is unfamiliar
      to most speech-language pathologists. This brief tutorial describes NLD's
      characteristics, a theoretical model proposed to explain its source, and areas of
      overlap between NLD and similar diagnostic categories. The communicative profile,
      made up of difficulties in pragmatic and semantic language in the presence of
      relatively preserved syntactic skill, is also discussed. Empirical evidence
      relevant to NLD is also evaluated. Many questions remain unresolved, but until
      systematic research provides definitive answers, speech-language pathologists are
      encouraged to rely on careful description of the individual child's communicative
      strengths and weaknesses to identify appropriate targets and to focus
      intervention on improving the child's ability to communicate effectively in
      everyday contexts.

PMID- 15198633
TI  - Self-monitoring recall during two tasks after traumatic brain injury: a
      preliminary study.
AB  - Impaired recall is a common consequence of traumatic brain injury (TBI).
      Predicting recall during learning is a critical part of self-monitoring. Adults
      with TBI and noninjured controls made recall predictions of noun pairs that
      varied in prediction timing (immediate, delayed), and predictions of narrative
      information that varied in salience (main idea and details) and explicitness
      (stated and implied). For both groups, delayed recall predictions for noun pairs
      and stated (narrative) information were relatively accurate, whereas immediate
      recall predictions of noun pairs and delayed predictions of implied information
      were relatively inaccurate. Both groups were more confident making predictions of
      stated information than implied information. Neither predictive accuracy nor
      confidence generalized across tasks. Working memory load across tasks and
      individual differences are proposed explanations. The lack of generalization
      highlights the need to train domain or task-specific self-monitoring.

PMID- 15198634
TI  - The impact of aided language stimulation on symbol comprehension and production
      in children with moderate cognitive disabilities.
AB  - Over the past decade, aided language stimulation has emerged as a strategy to
      promote both symbol comprehension and symbol production among individuals who use
      graphic mode communication systems. During aided language stimulation, an
      interventionist points to a graphic symbol while simultaneously producing the
      corresponding spoken word during natural communicative exchanges. The purpose of
      this study was to determine the impact of aided language stimulation on children
      with moderate cognitive disabilities. Three preschool children with moderate
      cognitive disabilities who were functionally nonspeaking participated in the
      investigation. The investigator implemented a multiple-probe design across symbol
      sets/activities. Elicited probes were used to determine whether the children
      increased their comprehension and production of graphic symbols. Results
      indicated that all 3 children displayed increased symbol comprehension and
      production following the implementation of aided language stimulation.

PMID- 15198635
TI  - Listener attitudes toward individuals with cerebral palsy who use speech
      supplementation strategies.
AB  - This study examined listener attitudes toward 7 speakers with dysarthria who
      implemented 3 speech supplementation strategies (topic cues, alphabet cues, and
      combined topic and alphabet cues) and a habitual speech control condition.
      Findings were similar, but not identical, to intelligibility results published in
      2 earlier papers (K. C. Hustad, J. Auker, N. Natale, and R. Carlson, 2003; K. C.
      Hustad, T. Jones, and S. Dailey, 2003). For each speaker, alphabet cues and
      combined cues resulted in higher attitude ratings than habitual speech, and
      combined cues resulted in higher ratings than topic cues. Listener ratings
      pertaining to cognitive, affective, and behavioral components of attitude showed
      that ratings for the behavioral component were the highest for all but 1 speaker.
      The relationship between intelligibility scores and attitude ratings for each
      speaker were strong and positive, indicating that attitude ratings seem to
      increase linearly with intelligibility scores.

PMID- 15198636
TI  - Standardized assessment of phonological awareness skills in low-income African
      American first graders.
AB  - Accurate identification of students with poor phonological awareness skills is
      important to providing appropriate reading instruction. This is particularly true
      for segments of the population, such as African American students, who have a
      history of reading failure. The purpose of this study was to examine the
      performance of a group of African American first-grade students from low-income
      families on a standardized test of phonological awareness. Fifty-six African
      American first graders were given the Test of Phonological Awareness (TOPA; J. K.
      Torgesen and B. R. Bryant, 1994). Mean student performance on the TOPA was
      significantly below expected norms and negatively skewed. However, students' mean
      performance on a test of basic reading skills indicated performance within normal
      limits. Outcomes are discussed relative to the validity and predictive power of
      standardized phonological assessment instruments, in this case, the TOPA, for use
      with African American students and the possible influence of dialect on
      performance.

PMID- 15198637
TI  - Heparan sulphate proteoglycans interact with neurocan and promote neurite
      outgrowth from cerebellar granule cells.
AB  - We found that neurocan, a major brain chondroitin sulphate proteoglycan,
      interacts with HSPGs (heparan sulphate proteoglycans) such as syndecan-3 and
      glypican-1. Binding of these HSPGs to neurocan was prevented by treatment of the
      HSPGs with heparitinases I and II, but not by treatment of neurocan with
      chondroitinase ABC. Scatchard plot analysis indicated that neurocan has two
      binding sites for these HSPGs with different affinities. It is known that
      neurocan in the rodent brain is proteolytically processed with aging into N- and
      C-terminal fragments. When a mixture of whole neurocan and N- and C-terminal
      fragments prepared from neonatal mouse brains or recombinant N- and C-terminal
      fragments was applied to a heparin column, the whole molecule and both the N- and
      C-terminal fragments bound to heparin. A centrifugation cell adhesion assay
      indicated that both the N- and C-terminal neurocan fragments could interact with
      these HSPGs expressed on the cell surface. To examine the biological significance
      of the HSPG-neurocan interaction, cerebellar granule cells expressing these HSPGs
      were cultured on the recombinant neurocan substrate. A significant increase in
      the rate of neurite outgrowth was observed on the wells coated with the C
      terminal neurocan fragment, but not with the N-terminal one. Neurite outgrowth
      promoting activity was inhibited by pretreatment of neurocan substrate with
      heparin or the addition of heparitinase I to culture medium. These results
      suggest that HSPGs such as syndecan-3 and glypican-1 serve as the cell-surface
      receptor of neurocan, and that the interaction of these HSPGs with neurocan
      through its C-terminal domain is involved in the promotion of neurite outgrowth.

PMID- 15198638
TI  - In brain mitochondria the branched-chain fatty acid phytanic acid impairs energy
      transduction and sensitizes for permeability transition.
AB  - Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) accumulates at high levels
      throughout the body in the adult form of Refsum disease, a peroxisomal genetic
      disorder. However, it is still unclear why increased levels of phytanic acid have
      cytotoxic effects. In the present study, we examined the influence of non
      esterified phytanic acid on energy-related functions of mitochondria from adult
      rat brain. Phytanic acid at low concentrations (5-20 microM, i.e. 5-20 nmol/mg of
      mitochondrial protein) de-energized mitochondria, as indicated by depolarization,
      stimulation of non-phosphorylating oxygen uptake and inhibition of the reduction
      of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium
      bromide. The unbranched homologue palmitic acid exerted much smaller effects. In
      addition, phytanic acid reduced state 3 respiration, which was partly due to
      inhibition of the ADP/ATP carrier. Phytanic acid decreased the rate of adenine
      nucleotide exchange and increased the degree of control, which the ADP/ATP
      carrier has on state 3 respiration. Important for functional consequences is the
      finding that mitochondria, which are preloaded with small amounts of Ca2+ (100
      nmol/mg of protein), became highly sensitized to rapid permeability transition
      even when only low concentrations of phytanic acid (below 5 microM) were applied.
      In conclusion, the incorporation of phytanic acid into the inner mitochondrial
      membrane increases the membrane H+ conductance and disturbs the protein-linked
      functions in energy coupling. This is most probably essential for the short-term
      toxicity of phytanic acid. Thus in neural tissue, which becomes enriched with
      phytanic acid, the reduction in mitochondrial ATP supply and the facilitation of
      the opening of the permeability transition pore are two major mechanisms by which
      the branched-chain fatty acid phytanic acid induces the onset of degenerative
      processes.

PMID- 15198640
TI  - Kinetics of spleen and Peyer's patch lymphocyte populations during gut parasite
      clearing in Cryptosporidium parvum infected suckling mice.
AB  - Data from experimental and human cryptosporidiosis have established a major role
      of specific immunity in the control of Cryptosporidium parvum infection. In this
      work, alterations in spleen and Peyer's patch (Pp) lymphocytes were investigated
      in the course of a spontaneously resolutive gut cryptosporidiosis in four-day-old
      suckling NMRI mice infected with either 4 x 10(5) or 30 viable oocysts. Oocysts
      from entire small intestines, and spleen and Pp lymphocytes were examined using
      flow cytometry from day 7 to day 27 post-infection. Compared to uninfected
      animals, a 3-5 fold increase in the numbers of spleen TCR alphabeta+, CD4+, CD8+,
      TCR gammadelta+ and CD45R/B220+ lymphocytes was observed on day 17 post-infection
      in heavily infected animals. In Pp, more than ten-fold increases were observed,
      except for TCR gammadelta+ lymphocytes. At termination of infection, i.e. on days
      21-23 after ingestion of 4 x 105 oocysts, T and B lymphocytes decreased rapidly
      in both organs, and remained lower than in uninfected animals on days 19-23 post
      infection. In mice infected with 30 oocysts, similar alterations were observed in
      Pp, but not in spleen. Data suggest that in normally developing mice, clearance
      of gut C. parvum infection is associated with an initial increase in systemic and
      local lymphocyte numbers, followed by their decrease to below control levels
      during the recovery phase.

PMID- 15198641
TI  - Early treatment during a primary malaria infection modifies the development of
      cross immunity.
AB  - We have used a murine model to study the kinetics of cross-protection when a
      primary infection is halted at different times. We analysed how parasitaemia is
      modified during a second infection with the homologous parasite, a heterologous
      parasite, or a mixture of the two. In addition, possible mechanisms involved in
      cross-protection were analysed. Results show that treatment with pyrimethamine on
      day 5 during a primary infection with P. chabaudi AS (non-lethal), prevents the
      generation of cross-protection to a new challenge with lethal P. yoelii 17XL. In
      contrast, when treatment is on day 7, mice survive a P. yoelii infection.
      Differences between both groups suggest that in order for 'preimmune' mice to
      survive a lethal challenge, a predominantly TH2-type response is required, with a
      higher mRNA expression level of IL-4 and IL-10, and a lower mRNA expression of
      IFN-gamma. This work shows that an early treatment of a malaria infection
      produced by a non-lethal parasite drives the immune response towards a loss of
      cross-protection to further infections, in particular with more virulent
      parasites. This finding should be taken into account for the development of
      effective malaria vaccines.

PMID- 15198639
TI  - Alterations in protein kinase C activity and processing during zinc-deficiency
      induced cell death.
AB  - Protein kinases C (PKCs) are a family of serine/threonine kinases that are
      critical for signal transduction pathways involved in growth, differentiation and
      cell death. All PKC isoforms have four conserved domains, C1-C4. The C1 domain
      contains cysteine-rich finger-like motifs, which bind two zinc atoms. The zinc
      finger motifs modulate diacylglycerol binding; thus, intracellular zinc
      concentrations could influence the activity and localization of PKC family
      members. 3T3 cells were cultured in zinc-deficient or zinc-supplemented medium
      for up to 32 h. Cells cultured in zinc-deficient medium had decreased zinc
      content, lowered cytosolic classical PKC activity, increased caspase-3 processing
      and activity, and reduced cell number. Zinc-deficient cytosols had decreased
      activity and expression levels of PKC-alpha, whereas PKC-alpha phosphorylation
      was not altered. Inhibition of PKC-alpha with Go6976 had no effect on cell number
      in the zinc-deficient group. Proteolysis of the novel PKC family member, PKC
      delta, to its 40-kDa catalytic fragment occurred in cells cultured in the zinc
      deficient medium. Occurrence of the PKC-delta fragment in mitochondria was co
      incident with caspase-3 activation. Addition of the PKC-delta inhibitor,
      rottlerin, or zinc to deficient medium reduced or eliminated proteolysis of PKC
      delta, activated caspase-3 and restored cell number. Inhibition of caspase-3
      processing by Z-DQMD-FMK (Z-Asp-Gln-Met-Asp-fluoromethylketone) did not restore
      cell number in the zinc-deficient group, but resulted in processing of full
      length PKC-delta to a 56-kDa fragment. These results support the concept that
      intracellular zinc concentrations influence PKC activity and processing, and that
      zinc-deficiency-induced apoptosis occurs in part through PKC-dependent pathways.

PMID- 15198642
TI  - CTLA-4 regulates the murine immune response to Trypanosoma cruzi infection.
AB  - Infection with Trypanosoma cruzi causes a profound suppression of T cell
      responsiveness to polyclonal or antigenic stimuli. In this study, we quantified
      expression of the negative T cell regulatory molecule CTLA-4 in T. cruzi infected
      mice and analysed its influence on the immune suppression. Levels of splenic CTLA
      4 expression were highest around day 10 after infection, reaching 5% in resistant
      B6D2F1 mice, but exceeding 10% of CD4(+) T cells in C57BL/6 mice that were
      susceptible to mortal disease. The proliferative response of explanted
      splenocytes to CD3-mediated stimulation was strongly suppressed in both the
      susceptible and the resistant strains. Blockade of CTLA-4 in vitro with a
      monoclonal antibody affected neither proliferative response nor cytokine
      production (IFN-gamma, IL-4 and IL-2) by splenic T cells from infected C57BL/6
      mice. Treatment of mice with anti-CTLA-4 antibody on the day of infection
      decreased IFN-gamma production and reduced mortality by about 50%. We conclude
      that high CTLA-4 expression is a hallmark of severe disease in murine T. cruzi
      infection, and that CTLA-4 has a regulative influence at the early stages during
      priming of the immune reaction to the parasite, augmenting a strong Th1-biased
      response.

PMID- 15198643
TI  - Are the cellular immune responses of children and adults with Schistosoma mansoni
      infection intrinsically different? Cytokines produced ex vivo in response to
      antigens and mitogens.
AB  - In recently exposed communities, intensity of schistosomiasis infection increases
      as children age and then drops again in adulthood, indicating that host maturity
      is an important aspect of resistance to schistosomiasis. We investigated whether
      the cellular immune response to the parasite was correlated with age in subjects
      with similar daily patterns of exposure, current intensities of infection and
      number of years of exposure. The cellular immune response of subjects with either
      'low' (under 200 eggs per gram (EPG)) or 'high' (over 400 EPG) intensities of
      infection was investigated, in a recently established focus where subjects had
      similar histories of exposure and number of years of experience with Schistosoma
      mansoni. Subject's whole blood was cultured with adult worm antigen (AWA), a
      mixture of phytohaemagglutinin (PHA) and lipopolysaccharide (LPS), or left
      unstimulated, and culture supernatants were tested for IL-4, IL-5, IL-10 and IFN
      gamma. Children and adults tended to respond differently to schistosome antigen.
      The most statistically significant illustration of this was the negative
      correlation between age and IL-5 produced by samples from people with low
      intensities of infection cultured with AWA (P < 0.003, P < 0.05 after Bonferroni
      correction). IL-10 produced by samples cultured with PHA and LPS was also notably
      lower in children than in adults, although not formally significant after
      Bonferroni correction. This indicates that it is possible for age, independently
      of intensity of infection or experience with the parasite, to influence the
      immune response to schistosomiasis.

PMID- 15198644
TI  - Validation of the protective Ostertagia ostertagi ES-thiol antigens with
      different adjuvantia.
AB  - Intramuscular immunization of calves with an excretory-secretory antigen fraction
      enriched for cysteine proteinase activity (ES-thiol) and QuilA as adjuvant
      induces a protective immune response against the abomasal nematode Ostertagia
      ostertagi. The objectives of the present study were to confirm the protective
      capacity of ES-thiol in combination with QuilA, to test Al(OH)(3) as adjuvant for
      vaccination against O. ostertagi and to look for correlations between protection
      and immunological effector responses. Calves(seven animals/group) were vaccinated
      three times intramuscularly with 100 micro g antigen and/or adjuvant (ES-thiol
      with QuilA, ES-thiol with Al(OH)(3), QuilA alone and Al(OH)(3) alone) and
      subsequently challenged with a trickled oral infection of 25 000 infective larvae
      in total over 25 days. Faecal egg counts in the ES-thiol QuilA group were reduced
      by 56% during the two-month period of the trial compared to the QuilA control
      group (P < 0.002). Calves immunized with ES-thiol QuilA had significantly smaller
      adult worms (P < 0.002) and less eggs/female worm (P < 0.05) compared to the
      QuilA control group. No differences in egg output, worm counts or parameters of
      worm fitness were observed in the ES-thiol Al(OH)(3) group compared to the
      Al(OH)(3) control group. Although the protective immune mechanism against O.
      ostertagi remains unknown, protection in the ES-thiol QuilA group was associated
      with high levels of parasite-specific antibodies in the abomasal mucosa.

PMID- 15198645
TI  - Echinococcus granulosus-specific T-cell lines derived from patients at various
      clinical stages of cystic echinococcosis.
AB  - To investigate the role of T lymphocytes in the immune response to Echinococcus
      granulosus, using sheep hydatid fluid (SHF) and antigen B (AgB), we generated T
      cell lines from patients with active, transitional and inactive hydatid cysts. We
      established 16 T-cell lines, eight specific to SHF and eight specific to AgB. At
      surface phenotyping 88-98% of cells displayed the helper/inducer CD4 antigen. In
      all patients, at all clinical stages of hydatid cyst disease, T-cell stimulation
      with SHF and AgB invariably amplified a large number of almost identical Vbeta
      subfamily fragments. Irrespective of antigen-specificity, the two cell lines from
      the patient with an inactive cyst had a Th1 profile, because they exclusively
      expressed and produced IFN-gamma. Conversely, the T-cell lines derived from the
      seven patients with active and transitional hydatid cysts had mixed Th1/Th2 and
      Th0 clones. The functional characteristics of the 16 T-cell lines differed
      markedly in the various clinical stages of cystic echinococcosis, thus providing
      new in vitro evidence that Th1 lymphocytes contribute decisively to the inactive
      stage of hydatid disease, Th2 lymphocytes in the active and transitional stages.
      The parasite-specific T-cell lines, especially the two Th1 lines from the patient
      with an inactive cyst, may help identify Th1 protective epitopes on SHF and AgB.

PMID- 15198646
TI  - Ov-ASP-1, the Onchocerca volvulus homologue of the activation associated secreted
      protein family is immunostimulatory and can induce protective anti-larval
      immunity.
AB  - Vaccination of mice with a recombinant protein, Ov-ASP-1, the Onchocerca volvulus
      homologue of the activation associated secreted gene family stimulated very high
      titres of both IgG1 and IgG2a without adjuvant. rOv-ASP-1 was also immuno
      reactive with IgG isotypes from both O. volvulus-infected (INF) and putatively
      immune (PI) humans, with higher IgG4 in the former group. The protein also
      stimulated IFN-gamma secretion by PBMC from INF and PI and IL-5 only in INF.
      Using a mouse diffusion chamber model, vaccination with rOv-ASP-1 resulted in
      partial but significant protection against challenge with infective third-stage
      larvae (L3) but only when formulated with Freund's complete adjuvant (FCA) or
      alum. Protection was Th1-dependent (highly elevated IgG2a) with FCA and
      contingent on a strongly Th2-skewed (IgG1) response with alum. IgE responses to
      rOv-ASP-1 with or without adjuvant were weak or absent. When immunization using
      rOv-ASP-1 in adjuvant failed to induce adequate Th1 (FCA) or Th2 (alum)
      responses, protection efficacy was compromised. The recombinant protein appears
      to stimulate a mixed Th1/Th2 response but the outcome in terms of protective
      immunity is the result of a subtle interplay of its intrinsic and adjuvant
      augmented properties. Ov-ASP-1 is potentially secreted based on its localization
      in the secretory granules of L3.

PMID- 15198647
TI  - TLOSRs: reproducible or not?

PMID- 15198648
TI  - Function and dyspepsia: a start of a new friendship.

PMID- 15198649
TI  - Assessment of gastric accommodation: overview and evaluation of current methods.
AB  - Gastric accommodation is considered important in the pathophysiology of several
      upper gastrointestinal disorders including functional dyspepsia. The gold
      standard for its measurement is the barostat-balloon study which requires
      intubation. The aim was explore the reliability and performance characteristics
      of the techniques proposed for measurement of gastric accommodation. We undertook
      a literature search using MEDLINE with a broad range of key words. The
      accommodation reflex and its control are briefly described, based on human data.
      The performance characteristics of the intragastric barostat, transabdominal
      ultrasound, magnetic resonance imaging, single photon emission computed
      tomography, and satiation drinking tests are described. For each technique, we
      summarize the following: principle, validation studies, advantages,
      disadvantages, and potential applications. Three-dimensional methods to measure
      gastric volume non-invasively are promising and among the best validated to date.
      Simpler techniques would be of considerable appeal for clinical and research
      studies, but further validation is necessary before satiation drinking tests can
      be used as surrogates for more sophisticated measurements of gastric
      accommodation.

PMID- 15198650
TI  - An experimental model for the study of transient lower oesophageal sphincter
      relaxation and motor function of the proximal stomach in humans.
AB  - A simple and reliable experimental model would be useful in human research on new
      drugs which target transient lower oesophageal sphincter (LOS) relaxation. The
      aim was to investigate the effect of repeated distensions on the rate of
      transient LOS relaxation, LOS pressure and motor function of the proximal
      stomach. Twelve healthy subjects were studied with a multilumen manometric
      assembly incorporating a sleeve sensor for the LOS and a bag positioned in the
      proximal stomach and connected to a barostat. Intrabag volume was set at 75% of
      the threshold for gastric discomfort and maintained for two 30-min distension
      periods separated by a 45-min washout with the bag deflated. The studies lasted
      145 +/- 2 min. The rate of transient LOS relaxations was similar during the two
      distensions, 3.5;2-4 vs 3;2.5-4 (median;interquartile range) and so was LOS
      pressure. Baseline intrabag pressure, as a measure of gastric tone, and the
      number of pressure waves, as a measure of phasic contractions, were also similar,
      11.3;9.3-12.3 mmHg vs 10.8;9.3-12.5 mmHg and 16;13-28 mmHg vs 19;15-29 mmHg,
      respectively. Our model allows to perform 1-day studies which can assess two
      experimental conditions on transient LOS relaxations and motor function of the
      proximal stomach within an acceptable time span.

PMID- 15198651
TI  - Effects of electroacupuncture on gastric myoelectrical activity in healthy
      humans.
AB  - The acupuncture point of the wrists (PC6) and the lower legs (ST36) are common
      points for the treatment of gastric symptoms. However, it remains unclear whether
      these two acupoints have different effects on gastric myoelectrical activity. We
      compared the effect of electroacupuncture (EAP) between PC6 and ST36 on gastric
      myoelectrical activity using surface electrogastrography (EGG). EAP (1 Hz, for 30
      min) was applied at either ST36, or PC6, or both acupoints in eight healthy
      volunteers. EAP at both PC6 and ST36 did not change the percentage of normal slow
      waves and tachygastria. While EAP at either PC6 or ST36 did not change period
      dominant frequency (PDF), EAP at both PC6 and ST36 significantly decreased PDF to
      78.1 +/- 8.4% of baselines. EAP at PC6 reduced period dominant power (PDP) to
      47.2 +/- 5.3% of baselines, while EAP at ST36 increased PDP to 153.6 +/- 28.3% of
      baselines. EAP at shoulders (sham acupuncture) did not affect the gastric
      myoelectrical activity. EAP at either PC6 or ST36 shows an opposite effect on
      PDP, whereas EAP at both PC6 and ST36 has a synergistic effect on PDF.
      Understanding site-specific effects of acupuncture may contribute to the
      selection of appropriate acupoints for treating functional GI disorders.

PMID- 15198652
TI  - Brain activity during distention of the descending colon in humans.
AB  - Brain-gut interaction is considered to be a major factor in the pathophysiology
      of irritable bowel syndrome. However, only limited information has been provided
      on the influence of gastrointestinal tract stimulation on the brain. Our aim in
      this study was to determine the specific regions of the brain that are
      responsible for visceral perception and emotion provoked by distention of the
      descending colon in humans. Fifteen healthy males aged 22 +/- 1 participated in
      this study. Using a colonoscope, a balloon was inserted into the descending colon
      of each subject. After sham stimulation, the colon was randomly stimulated with
      bag pressures of 20 and 40 mmHg, and regional cerebral blood flow was measured by
      [(15)O] positron emission tomography. The subjects were asked to report visceral
      perception and emotion using an ordinate scale of 0-10. Colonic distention
      pressure dependently induced visceral perception and emotion, which significantly
      correlated with activation of specific regions of the brain including the
      prefrontal, anterior cingulate, parietal cortices, insula, pons, and the
      cerebellum. In conclusion, distention of the descending colon induces visceral
      perception and emotion. These changes significantly correlate with activation of
      specific regions in the brain including the limbic system and the association
      cortex, especially the prefrontal cortex.

PMID- 15198653
TI  - Intolerance to visceral distension in functional dyspepsia or irritable bowel
      syndrome: an organ specific defect or a pan intestinal dysregulation?
AB  - Functional gastrointestinal disorders (FGID) are characterized by visceral
      hypersensitivity that could be specific to a region of the gut or reflect a
      diffuse pan-intestinal disorder. Sensory thresholds to distension at two visceral
      sites in patients with different FGIDs were determined. According to Rome II
      criteria, 30 patients from three groups were studied: patients with (i)
      functional dyspepsia (FD) or (ii) irritable bowel syndrome (IBS), and (iii)
      patients with concomitant symptoms of FD and IBS. Pain thresholds to balloon
      distension were determined in stomach and rectum. In FD patients, gastric
      intolerance to balloon distension was found in 91% patients; rectal
      hypersensitivity was documented in 18% patients. In IBS patients, rectal
      hypersensitivity was seen in 75% patients; while gastric hypersensitivity was
      never found. In patients with concomitant symptoms of FD + IBS, gastric and
      rectal intolerance to distension were present respectively in 82 and 91%
      patients. In the whole group, visceral intolerance to distension was documented
      at one site in 90% patients and at both sites, i.e. stomach and rectum, in 33%
      patients. Visceral intolerance to distension can be pan-intestinal in patients
      with multiple sites of symptoms, but appears organ-specific in patients
      exhibiting a specific site of symptoms.

PMID- 15198654
TI  - Analysis of surface geometry of the human stomach using real-time 3-D
      ultrasonography in vivo.
AB  - The objective of this study was to develop an analytical method to describe the
      three-dimensional (3-D) geometry of the gastric antrum, gastric fundus and the
      whole stomach. The Fourier series method was used to simulate the organ surface
      geometry obtained from a 3-D ultrasound system. Data generated from eight antrums
      and three whole stomachs, at pressures of approximately 7 cm H(2)O, were used for
      lumen curvature calculations. The principal curvatures spatial distributions were
      non-homogeneous in the gastric antrum, gastric fundus and the stomach due to
      their complex geometry. The maximum longitudinal principal curvature in the
      antrum, fundus and total stomach were, respectively, 0.460 +/- 0.066, 0.583 +/-
      0.087 and 1.123 +/- 0.328, whereas the maximum circumferential curvature were
      1.192 +/- 0.090, 3.649 +/- 1.574 and 8.444 +/- 3.424, respectively. The present
      study provides an analytical tool for characterizing the complex 3-D geometry of
      an organ-like the human stomach reconstructed by clinical imaging modalities.
      Providing an average tension for the stomach does not reflect the large variation
      in tension throughout the stomach wall.

PMID- 15198655
TI  - L-type Ca(2+) channel expression along feline smooth muscle oesophagus.
AB  - Muscle from the proximal smooth muscle (SM) oesophagus of the cat demonstrates
      contractions of greater amplitude and greater sensitivity to cholinergic
      stimulation than muscle from the distal SM oesophagus. In the light of the
      central role of calcium influx in SM contractility, we hypothesized that regional
      differences in oesophageal contractility may be associated with differential
      expression of L-type calcium channels (L(Ca)) along the SM oesophagus. L(Ca)
      expression was compared between proximal and distal regions of the circular SM
      oesophagus by Western blots. Patch clamp technique was utilized to study L(Ca)
      currents. Muscle strip studies assessed L(Ca) contribution to contractile
      activity. The protein expression of L(Ca) and L(Ca) current density was greater
      in the proximal than distal region. L(Ca) voltage and time-dependent activation
      and inactivation curves were similar in cells from both regions. Stimulation of
      muscle strips with acetylcholine (ACh) in the presence of tetrodotoxin resulted
      in contractions of greater amplitude in the proximal region. The L(Ca) agonist
      Bay K 8644 caused a greater increase in ACh-induced contraction amplitude in
      muscle strips from the proximal region. Therefore, regional myogenic differences
      in L(Ca) expression along the circular SM oesophageal body exist and may
      contribute to the nature of oesophageal contractions.

PMID- 15198656
TI  - Diabetic autonomic neuropathy: evidence for apoptosis in situ in the rat.
AB  - We examined the hypothesis that activation of the apoptosis cascade occurs
      relatively early in diabetes mellitus affecting three distinct neuronal
      populations that are involved in regulating gut function: (i) dorsal root
      ganglion (DRG), (ii) vagus nodose ganglion and (iii) colon myenteric plexus. A
      validated streptozotocin-induced diabetic rat model and age-matched healthy
      controls were studied. After 4-8 weeks of diabetes the animals were
      anaesthetized, fixed in situ and the relevant tissues removed. After 1 month of
      diabetes some animals were treated with insulin for 2 weeks to restore
      euglycaemia. Apoptosis was measured using immunohistochemical detection of
      activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick
      end labelling (TUNEL)-positive cells in adjacent sections in neurones (PGP 9.5
      positive cells). The level of apoptosis was confirmed using double-label
      assessment of caspase-3 and TUNEL in DRG preparations. Caspase-3 immunoreactive
      neurones demonstrated a range in staining intensity. When all grades of staining
      were included, 6-8% of the DRG, nodose ganglia and myenteric neurones were
      immunoreactive in the preparations from diabetic rats compared with 0.2-0.5% in
      controls. Neurones staining positive for both caspase-3 and TUNEL accounted for 1
      2% of the total neuronal population in all three preparations in diabetic rats
      compared with 0.1-0.2% in controls (P < 0.05). Insulin treatment reversed the
      percentage of TUNEL-positive neurones in diabetic rats to control levels.
      Activation of the apoptosis cascade occurs relatively early in diabetic autonomic
      neuropathy and may contribute to the pathophysiology of this disorder.

PMID- 15198657
TI  - Microinjection of glutamate into dorsal motor nucleus of the vagus excites
      gallbladder motility through NMDA receptor - nitric oxide - cGMP pathway.
AB  - We have reported that both glutamate and nitric oxide (NO) participated in the
      regulation of gallbladder motility in dorsal motor nucleus of the vagus (DMV).
      The aim of this study is to investigate the type of receptor in DMV that mediates
      the excitatory effect of glutamate on gallbladder motility and the correlation
      between the glutamate and NO. A frog bladder connected with a force transducer
      was inserted into the gallbladder to record the change of gallbladder pressure.
      Glutamate (65 mmol L(-1), 100 nL) microinjected into DMV significantly increased
      the strength of gallbladder phasic contraction. This effect was abolished by
      ketamine (180 mmol L(-1), 100 nL), the specific N-methyl-d-aspartic acid (NMDA)
      receptor antagonist, but was not influenced by 6-cyaon-7-nitroquinoxaline-2,3
      (1H,4H)-dione (CNQX) (180 mmol L(-1), 100 nL), the non-NMDA ionotropic receptor
      antagonist. N(G)-nitro-l-arginine-emthyl (l-NAME) (1 mol L(-1), 100 nL), the
      nitric oxide synthase (NOS) inhibitor, reversed the excitatory effect of
      glutamate on gallbladder motility. Microinjection of sodium nitroprusside (SNP),
      the NO donor, into DMV enhanced the gallbladder motility, and this effect was not
      modulated by ketamine. Microinjection of NMDA (5 mmol L(-1), 100 nL) increased
      the strength of gallbladder phasic contraction, and this effect was attenuated by
      methylene blue (100 mmol L(-1), 100 nL), the soluble guanylate cyclase inhibitor.
      These results suggest that glutamate regulate the gallbladder motility through
      the NMDA receptor - NO - cGMP pathway in DMV.

PMID- 15198658
TI  - Presynaptic modulation of cholinergic and non-cholinergic fast synaptic
      transmission in the myenteric plexus of guinea pig ileum.
AB  - Abstract These studies investigated receptors modulating release of mediators of
      fast excitatory postsynaptic potentials (fEPSPs) in guinea pig ileum myenteric
      plexus using electrophysiological methods. Fast EPSPs inhibited by >95% by
      hexamethonium (100 micromol L(-1)) were cholinergic; mixed fEPSPs were inhibited
      <95% by hexamethonium. Non-cholinergic fEPSPs were studied in the presence of
      hexamethonium. The alpha2-adrenergic receptor agonist UK 14304 inhibited
      cholinergic (maximum inhibition = 76%, EC(50) = 18 nmol L(-1)), mixed (81%, 21
      nmol L(-1)) and non-cholinergic (76%, 44 nmol L(-1)) fEPSPs equally. The 5-HT(1)
      receptor agonist 5-carboxamidotryptamine inhibited cholinergic, mixed and non
      cholinergic fEPSPs equally. Renzapride, increased non-cholinergic (33%) less than
      mixed (97%, 13 micromol L(-1)) fEPSPs. Renzapride inhibited the purely
      cholinergic fEPSPs (-29%) but potentiated the cholinergic component of mixed
      fEPSPs (39%). Prucalopride potentiated all fEPSPs equally (30-33%). 5-HT (0.1
      micromol L(-1)) induced potentiation of cholinergic (75%), mixed (97%) and non
      cholinergic (84%) fEPSPs was not statistically different. The potentiating
      effects of renzapride and 5-HT on fEPSPs were inhibited by the 5-HT(4) receptor
      antagonist, SB 204070 (10 nmol L(-1)). Renzapride (0.3 micromol L(-1)) blocked 5
      HT-induced increases in cholinergic fEPSPs. alpha2-Adrenergic and 5-HT(1)
      receptors mediate inhibition of transmitter release from cholinergic and mixed
      terminals. 5-HT and prucalopride, acting at 5-HT(4) receptors, facilitate all
      fEPSPs; renzapride facilitates the cholinergic and non-cholinergic components of
      mixed fEPSPs but not purely cholinergic fEPSPs. Cholinergic synapses may express
      few 5-HT(4) receptors or a renzapride-insensitive 5-HT(4) receptor isoform.

PMID- 15198659
TI  - Motor responses of rat hypertrophic intestine following chronic obstruction.
AB  - The present work aims at investigating the changes in motor responsiveness of rat
      intestine hypertrophied by chronic mechanical obstruction. Motor responses to
      pharmacological agents and electrical field stimulation (EFS) were studied in
      hypertrophic ileal segments excised from rats subjected to experimental stenosis
      (n = 20) and compared with responses of control tissues from sham-operated
      animals (n = 20). Spontaneous motility and contractile responses to exogenous
      agents (KCl, acetylcholine and substance P) and EFS (10-s trains every minute,
      120 mA, 0.5 ms, 1-10 Hz) were increased in hypertrophic longitudinal segments;
      however, normalization of motor responses to tissue wet weight revealed a
      remarkable reduction of contractile efficiency in hypertrophied tissues coupled
      with a loss of sensitivity to nitric oxide-mediated relaxation. Furthermore, EFS
      under non-adrenergic non-cholinergic (NANC) conditions unveiled a major role of
      the cholinergic component over the peptidergic one in the neurogenic contraction
      of hypertrophic intestine. On the whole, hypertrophic intestinal growth emerges
      as a dynamic process entailing adaptation of smooth muscle and neuronal
      structures to the increased functional load imposed by lumen obstruction.

PMID- 15198660
TI  - Presence of C-type natriuretic peptide (CNP) in guinea pig caecum: role and
      mechanisms of CNP in circular smooth muscle relaxation.
AB  - The distribution and role of C-type natriuretic peptide (CNP) in the
      gastrointestinal tract are still unclear. This study was designed to investigate
      the distribution of CNP in guinea pig caecum and the inhibitory mechanisms of CNP
      in caecal circular smooth muscle cells. CNP immunoreactivity was recognized in
      smooth muscle cells, myenteric and submucosal neurons of the caecum by
      immunohistochemistry. CNP mRNA expression was demonstrated in both freshly
      dispersed and cultured smooth muscle cells by reverse-transcription polymerase
      chain reaction. CNP inhibited 1 nmol L(-1) cholecystokinin octapeptide (CCK-8)
      induced smooth muscle cell contraction in a dose-dependent manner, with an IC(50)
      value of 0.24 nmol L(-1), and significantly stimulated the production of
      intracellular cyclic guanosine monophosphate. Furthermore, inhibitors of both
      soluble and particulate guanylate cyclase (GC) partially but significantly
      inhibited CNP-induced relaxation. This is the first report demonstrating that CNP
      localizes in gastrointestinal smooth muscle cells and the enteric nervous system.
      These results suggest that CNP acts locally through neural and autocrine pathways
      to modulate colonic motility via both particulate and soluble GC systems. These
      two pathways appear to be through natriuretic peptide receptor (NPR)-B, which has
      particulate GC domain, and NPR-C, which activates soluble GC, judging from
      previous findings that NPR-A is not expressed in these cells.

PMID- 15198661
TI  - The synaptophysin/synaptobrevin complex dissociates independently of
      neuroexocytosis.
AB  - Synaptophysin is one of the most abundant membrane proteins of small synaptic
      vesicles. In mature nerve terminals it forms a complex with the vesicular
      membrane protein synaptobrevin, which appears to modulate synaptobrevin's
      interaction with the plasma membrane-associated proteins syntaxin and SNAP25 to
      form the SNARE complex as a prerequisite for membrane fusion. Here we show that
      synaptobrevin is preferentially cleaved by tetanus toxin while bound to
      synaptophysin or when existing as a homodimer. The synaptophysin/synaptobrevin
      complex is, however, not affected when neuronal secretion is blocked by botulinum
      A toxin which cleaves SNAP25. Excessive stimulation with alpha-latrotoxin or
      Ca(2+)-ionophores dissociates the synaptophysin/synaptobrevin complex and
      increases the interaction of the other SNARE proteins. The stimulation-induced
      dissociation of the synaptophysin/synaptobrevin complex is not inhibited by pre
      incubating neurones with botulinum A toxin, but depends on extracellular calcium.
      However, the synaptophysin/synaptobrevin complex cannot be directly dissociated
      by calcium alone or in combination with magnesium. The dissociation of
      synaptobrevin from synaptophysin appears to precede its interaction with the
      other SNARE proteins and does not depend on the final fusion event. This finding
      further supports the modulatory role the synaptophysin/synaptobrevin complex may
      play in mature neurones.

PMID- 15198662
TI  - Differential effects of Rho GTPases on axonal and dendritic development in
      hippocampal neurones.
AB  - Formation of neurites and their differentiation into axons and dendrites requires
      precisely controlled changes in the cytoskeleton. While small GTPases of the Rho
      family appear to be involved in this regulation, it is still unclear how Rho
      function affects axonal and dendritic growth during development. Using
      hippocampal neurones at defined states of differentiation, we have dissected the
      function of RhoA in axonal and dendritic growth. Expression of a dominant
      negative RhoA variant inhibited axonal growth, whereas dendritic growth was
      promoted. The opposite phenotype was observed when a constitutively active RhoA
      variant was expressed. Inactivation of Rho by C3-catalysed ADP-ribosylation using
      C3 isoforms (Clostridium limosum, C3(lim) or Staphylococcus aureus, C3(stau2)),
      diminished axonal branching. By contrast, extracellularly applied nanomolar
      concentrations of C3 from C. botulinum (C3(bot)) or enzymatically dead C3(bot)
      significantly increased axon growth and axon branching. Taken together, axonal
      development requires activation of RhoA, whereas dendritic development benefits
      from its inactivation. However, extracellular application of enzymatically active
      or dead C3(bot) exclusively promotes axonal growth and branching suggesting a
      novel neurotrophic function of C3 that is independent from its enzymatic
      activity.

PMID- 15198663
TI  - A single amino acid substitution in a proteasome subunit triggers aggregation of
      ubiquitinated proteins in stressed neuronal cells.
AB  - Accumulation of ubiquitinated proteins in inclusions is common to various
      neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and
      amyotrophic lateral sclerosis, although it occurs in selective neurons in each
      disease. The mechanisms generating such abnormal aggregates and their role in
      neurodegeneration remain unclear. Inclusions appear in familial and non-familial
      cases of neurodegenerative disorders, suggesting that factors other than
      particular mutations contribute to protein accumulation and aggregation.
      Proteasome impairment triggered by aging or conditions such as oxidative stress
      may contribute to protein accumulation and aggregation in neurodegeneration. To
      test this hypothesis in mouse neuronal cells, we overexpressed a 20S proteasome
      beta5 subunit with an active site mutation. The N-terminal threonine to alanine
      substitution resulted in impairment of the chymotrypsin-like activity, which is a
      rate-limiting step in protein degradation by the proteasome. The Thr1Ala mutation
      was not lethal under homeostatic conditions. However, this single amino acid
      substitution significantly hypersensitized the cells to oxidative stress,
      triggering not only the accumulation and aggregation of ubiquitinated proteins,
      including synuclein, but also cell death. Our results demonstrate that this
      genetic manipulation of proteasome activity involving a single amino acid
      substitution causes the formation of protein aggregates in stressed neuronal
      cells independently of the occurrence of mutations in other cellular proteins.
      These results support the notion that proteasome disruption may be central to the
      development of familial as well as sporadic cases of neurodegeneration.

PMID- 15198664
TI  - In vivo characterization of somatodendritic dopamine release in the substantia
      nigra of 6-hydroxydopamine-lesioned rats.
AB  - We investigated the effect of an injection of 6-hydroxydopamine (6-OHDA) into the
      rat medial forebrain bundle (MFB) on the degeneration and the function of the
      dopaminergic cell bodies in the substantia nigra (SN) 3 and 5 weeks after
      lesioning. After injection of 6-OHDA into the MFB a complete loss of dopamine
      content was apparent in the striatum 3 weeks after lesioning. In the SN the
      amount of tyrosine hydroxylase-immunoreactive dopamine cells decreased gradually,
      with a near-complete lesion (> 90%) obtained only after 5 weeks, indicating that
      neurodegeneration of the nigral cells was still ongoing when total dopamine
      denervation of the striatum had already been achieved. Baseline dialysate and
      extracellular dopamine levels in the SN, as determined by in vivo microdialysis,
      were not altered by the lesion. A combination of compensatory changes of the
      remaining neurones and dopamine originating from the ventral tegmental area may
      maintain extracellular dopamine at near-normal levels. In both intact and
      lesioned rats, the somatodendritic release was about 60% tetrodotoxin (TTX)
      dependent. Possibly two pools contribute to the basal dopamine levels in the SN:
      a fast sodium channel-dependent portion and a TTX-insensitive one originating
      from diffusion of dopamine. Amphetamine-evoked dopamine release and release after
      injection of the selective dopamine reuptake blocker GBR 12909 were attenuated
      after a near-complete denervation of the SN (5 weeks after lesioning). So,
      despite a 90% dopamine cell loss in the SN 5 weeks after an MFB lesion,
      extracellular dopamine levels in the SN are kept at near-normal levels. However,
      the response to a pharmacological challenge is severely disrupted.

PMID- 15198665
TI  - Binding and functional activity of nicotinic cholinergic receptors in selected
      rat brain regions are increased following long-term but not short-term nicotine
      treatment.
AB  - Chronic nicotine exposure up-regulates neuronal nicotinic receptors, but the
      functional consequences for these receptors is less well understood. Following 2
      weeks of nicotine or saline treatment by osmotic minipump, the functional
      activity of nicotinic receptors was measured by concentration-response curves for
      epibatidine-stimulated (86)Rb efflux. Nicotine-treated animals had a
      significantly higher maximal efflux in cerebral cortex and superior colliculus,
      but not in thalamus or interpeduncular nucleus plus medial habenula. This
      increase was confirmed in a separate experiment with stimulation by single
      concentrations of epibatidine (cortex, superior colliculus) or nicotine (cortex
      only). Chronic nicotine did not alter (86)Rb efflux stimulated by cytisine, an
      alpha3beta4-selective agonist, or by potassium chloride, in any region. Short
      term (16 h) nicotine exposure caused no changes in either (86)Rb efflux or
      receptor binding measured with [(3)H]epibatidine. Binding was significantly
      increased after 2 weeks nicotine exposure in cortex, superior colliculus and
      thalamus, but not in interpeduncular nucleus plus medial habenula. The increases
      in epibatidine-stimulated (86)Rb efflux in the four regions tested was linearly
      correlated with the increases in [(3)H]epibatidine binding in these regions (R(2)
      = 0.91), suggesting that rat brain receptors up-regulated by chronic nicotine are
      active. These results have important consequences for understanding nicotinic
      receptor neurobiology in smokers and users of nicotine replacement therapy.

PMID- 15198666
TI  - Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by
      agrin.
AB  - Agrin is a proteoglycan that can inhibit neurite outgrowth from multiple neuronal
      types when present as a substrate. Agrin's neurite inhibitory activity is
      confined to the N-terminal segment of the protein (agrin N150), which contains
      heparan sulfate (HS) and chondroitin sulfate (CS) side chains. We have examined
      the activities of various purified recombinant agrin fragments and their
      glycosaminoglycan (GAG) side chains in neurite outgrowth inhibition. Inhibitory
      activity was tested using dissociated chick ciliary ganglion neurons or dorsal
      root ganglion explants growing on laminin or N-cadherin. Initial experiments
      demonstrated that agrin N150 lacking GAG chains inhibited neurite outgrowth. Both
      halves of N150, each containing HS and/or CS side chains, could also inhibit
      neurite growth. Experiments using agrin fragments in which the GAG acceptor
      residues were mutated, or using agrin fragments purified from cells deficient in
      GAG synthesis, demonstrated that inhibition by the N-terminal portion of N150
      requires GAGs, but that inhibition from the C-terminal part of N150 does not.
      Thus, the core protein or other types of glycosylation are important for
      inhibition from the more C-terminal region. Our results suggest that there are
      two distinct mechanisms for neurite outgrowth inhibition by agrin, one that is
      GAG-dependent and one that is GAG-independent.

PMID- 15198667
TI  - Environment- and mutation-dependent aggregation behavior of Alzheimer amyloid
      beta-protein.
AB  - The deposition of amyloid beta-protein in the brain is a fundamental process in
      the development of Alzheimeris disease; however, the mechanism underlying
      aggregation of amyloid beta-protein remains to be determined. Here, we report
      that a membrane-mimicking environment, generated in the presence of detergents or
      a ganglioside, is sufficient per se for amyloid fibril formation from soluble
      amyloid beta-protein. Furthermore, hereditary variants of amyloid beta-protein,
      which are caused by amyloid precursor protein gene mutations, including the Dutch
      (E693Q), Flemish (A692G) and Arctic (E693G) types, show mutually different
      aggregation behavior in these environments. Notably, the Arctic-type amyloid beta
      protein, in contrast to the wild-type and other variant forms, shows a markedly
      rapid and higher level of amyloid fibril formation in the presence of sodium
      dodecyl sulfate or GM1 ganglioside. These results suggest that there are
      favorable local environments for fibrillogenesis of amyloid beta-protein.

PMID- 15198668
TI  - Kainate receptor agonists and antagonists mediate tolerance to kainic acid and
      reduce high-affinity GTPase activity in young, but not aged, rat hippocampus.
AB  - Domoic acid acts at both kainic acid (KA) and alpha-amino-3-hydroxy-5
      methylisoxazole-4-propionate (AMPA)-sensitive glutamate receptors and induces
      tolerance against subsequent domoic acid insult in young but not aged rat
      hippocampus. To determine the receptor specificity of this effect, tolerance
      induction was examined in hippocampal slices from young and aged rats. Slices
      were preconditioned by exposure to low-dose KA to activate kainate receptors, or
      the AMPA-receptor selective agonist (S)-5-fluorowillardiine (FW), and following
      washout, tolerance induction was assessed by administration of high
      concentrations of KA or FW (respectively). FW preconditioning failed to induce
      tolerance to subsequent FW challenges, while KA-preconditioned slices were
      significantly resistant to the effects of high-dose KA. KA preconditioning failed
      to induce tolerance in aged CA1. Given the lasting nature of the tolerance
      effect, we examined G-protein-coupled receptor function. A number of ionotropic
      KA receptor agonists and antagonists significantly reduced constitutive GTPase
      activity in hippocampal membranes from young but not aged rats. Furthermore, in
      young CA1, low concentrations of the AMPA/KA blocker GYKI-52466 also induced
      tolerance to high-dose KA. Our findings suggest that tolerance is triggered by a
      selective reduction in constitutive KA-sensitive G-protein activity, and that
      this potential neuroprotective mechanism is lost with age.

PMID- 15198669
TI  - Phospholipid synthesis is decreased in neuronal tissue in a mouse model of
      Sandhoff disease.
AB  - Sandhoff disease is a progressive neurodegenerative disorder caused by mutations
      in the HEXB gene which encodes for the beta-subunit of beta-hexosaminidase A and
      B, resulting in ganglioside GM(2) accumulation in the brain. We now demonstrate
      that phospholipid metabolism is altered in both cultured neurons and in brain
      tissue from a mouse model of Sandhoff disease, the Hexb-/- mouse. Metabolic
      labelling using [methyl-(14)C]choline and l-[3-(3)H]serine demonstrated reduced
      incorporation of [methyl-(14)C]choline into phospholipids in brain tissue but not
      in liver or spleen. Phospholipid mass was also reduced in brain. The activities
      of CTP : phosphocholine cytidylyltransferase (CCT) and phosphatidylserine
      synthase were also reduced in brain tissue from Hexb-/- mice, probably because of
      post-translational modification as no changes were observed in levels of enzyme
      expression. The relevance of these findings to Sandhoff disease in human patients
      is strengthened by observations made over 30 years ago on autopsy tissue of Tay
      Sachs and Sandhoff disease patients, in which reduced phospholipid levels were
      observed. We suggest that changes in phospholipid metabolism are not simply
      because of loss of neuronal tissue as a result of degeneration but rather may
      cause degeneration, and we discuss the possible effects that changes in
      phospholipid metabolism could play in the neuropathophysiology of Sandhoff
      disease.

PMID- 15198670
TI  - Microglia release activators of neuronal proliferation mediated by activation of
      mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta
      Notch signalling cascades.
AB  - Microglia, the resident macrophage of the brain, can release substances that aid
      neuronal development, differentiation and survival. We have investigated the
      effects of non-activated microglia on the survival of cultured rat cerebellar
      granule neurones. Microglial-conditioned medium, collected from primary rat
      microglial cultures, was used to treat 7-day-in-vitro neurones, and neuronal
      viability and proliferation was assessed following a further 1 or 7 days in
      culture. Microglial-conditioned medium enhanced neuronal survival by up to 50%
      compared with untreated neurones and this effect was completely abated by
      pretreatment of the microglia with l-leucine methyl ester. The expression of the
      proliferation marker Ki-67 increased in neuronal cultures treated with microglial
      conditioned medium suggesting enhanced proliferation of precursor neurones.
      Microglial-induced neuronal proliferation could be attenuated by specific
      inhibition of mitogen-activated protein kinase or phosphatidylinositol-3
      kinase/Akt signalling pathways, and by selective fractionation and
      immunodepletion of the microglial-conditioned medium. Activation of the Notch
      pathway was enhanced as antibody against the Notch ligand, delta-1, prevented the
      microglial-induced neuronal proliferation. These results show that microglia
      release stable neurotrophic factors that can promote neuronal precursor cell
      proliferation.

PMID- 15198671
TI  - The interaction of Bex and OMP reveals a dimer of OMP with a short half-life.
AB  - Olfactory marker protein (OMP) participates in the olfactory signal transduction
      pathway. This is evident from the behavioral and electrophysiological deficits of
      OMP-null mice, which can be reversed by intranasal infection of olfactory sensory
      neurons with an OMP-expressing adenovirus. Bex, brain expressed X-linked protein,
      has been identified as a protein that interacts with OMP. We have now further
      characterized the interaction of OMP and Bex1/2 by in vitro binding assays and by
      immuno-coprecipitation experiments. OMP is a 19 kDa protein but these
      immunoprecipitation studies have revealed the unexpected presence of a 38 kDa
      band in addition to the expected 19 kDa band. Furthermore, the 38 kDa form was
      preferentially co-immunoprecipitated with Bex from cell extracts. In-gel tryptic
      digestion, mass spectrometry, and two-dimensional gel electrophoresis indicate
      that the 38 kDa protein behaves as a covalently cross-linked OMP-homodimer. The
      38 kDa band was also identified in western blots of olfactory epithelium
      demonstrating its presence in vivo. The stabilities and subcellular localizations
      of the OMP-monomer and -dimer were studied in transfected cells. These results
      demonstrated that the OMP-dimer is much less stable than the monomer, and that
      while the monomer is present both in the nuclear and cytosolic compartments, the
      dimer is preferentially located in a Triton X-100 insoluble cytoskeletal
      fraction. These novel observations led us to hypothesize that regulation of the
      level of the rapidly turning-over OMP-dimer and its interaction with Bex1/2 is
      critical for OMP function in sensory transduction.

PMID- 15198672
TI  - Differential contribution of plasmalemmal Na/Ca exchange isoforms to sodium
      dependent calcium influx and NMDA excitotoxicity in depolarized neurons.
AB  - Inhibition of Na(+),K(+)-ATPase during NMDA applications greatly increased NMDA
      induced excitotoxicity in primary cultures of forebrain neurons (FNs), but not in
      cerebellar granule cells (CGCs). Because Na(+),K(+)-ATPase inhibition promotes
      reversal of plasmalemmal Na(+)/Ca(2+) exchangers, we compared the activities of
      reversed K(+)-independent (NCX) and K(+)-dependent (NCKX) Na(+)/Ca(2+) exchangers
      in these cultures. To this end, we measured gramicidin-induced and Na(+)
      dependent elevation in cytosolic [Ca(2+)] ([Ca(2+)](c)) that represents Ca(2+)
      influx via reversed NCX and NCKX; NCX activity was dissected out by removing
      external K(+). The [Ca(2+)](c) elevations mediated by NCX alone, and NCX plus
      NCKX combined, were 17 and 6 times more rapid in FNs than in CGCs, respectively.
      Northern blot analysis showed that FNs preferentially express NCX1 whereas CGCs
      expressed NCX3. Differences in expression of other isoforms (NCX2, NCKX2, NCKX3
      and NCKX4) were less pronounced. We tested whether the NCX or NCKX family of
      exchangers contributes most to the toxic NMDA-induced Ca(2+) influx in
      depolarized neurons. We found that in FNs, inhibition of NCX alone was sufficient
      to significantly limit NMDA excitotoxicity, whereas in CGCs, inhibition of both
      NCX and NCKX was required. The data suggest that the high activity of NCX
      isoforms expressed in FNs, possibly NCX1, sensitizes these neurons to NMDA
      excitotoxicity.

PMID- 15198673
TI  - Drosophila uses two distinct neuropeptide amidating enzymes, dPAL1 and dPAL2.
AB  - Neuropeptide alpha-amidation is a common C-terminal modification of secretory
      peptides, frequently required for biological activity. In mammals, amidation is
      catalyzed by the sequential actions of two enzymes [peptidylglycine-alpha
      hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha
      amidating lyase (PAL)] that are co-synthesized within a single bifunctional
      precursor. The Drosophila genome predicts expression of one monofunctional PHM
      gene and two monofunctional PAL genes. Drosophila PHM encodes an active enzyme
      that is required for peptide amidation in vivo. Here we initiate studies of the
      two Drosophila PAL genes. dPAL1 has two predicted transmembrane domains, whereas
      dPAL2 is predicted to be soluble and secreted. dPAL2 expressed in heterologous
      cells is secreted readily and co-localized with hormone. In contrast, dPAL1 is
      secreted poorly, even when expressed with a cleaved signal replacing the
      predicted transmembrane domains; the majority of dPAL1 stays in the endoplasmic
      reticulum. Both proteins display PAL enzymatic activity. Compared to the
      catalytic core of rat PAL, the two Drosophila lyases have higher K(m) values,
      higher pH optima and similarly broad divalent metal ion requirements. Antibodies
      to dPAL1 and dPAL2 reveal co-expression in many identified neuroendocrine
      neurons. Although dPAL1 is broadly expressed, dPAL2 is found in only a limited
      subset of neurons. dPAL1 expression is highly correlated with the non-amidated
      peptide proctolin. Tissue immunostaining demonstrates that dPAL1 is largely
      localized to the cell soma, whereas dPAL2 is distributed throughout neuronal
      processes.

PMID- 15198674
TI  - Mapping spatio-temporal activation of Notch signaling during neurogenesis and
      gliogenesis in the developing mouse brain.
AB  - Notch1 plays various important roles including the maintenance of the stem cell
      state as well as the promotion of glial fates in mammalian CNS development.
      However, because of the very low amount of the activated form of Notch1 present
      in vivo, its precise activation pattern has remained unknown. In this study, we
      mapped the active state of this signaling pathway in situ in the developing mouse
      brain using a specific antibody that recognizes the processed form of the
      intracellular domain of Notch1 cleaved by presenilin/gamma-secretase activity. By
      using this antibody, active state of Notch1 came to be detectable with a higher
      sensitivity than using conventional antibody against Notch1. We found that
      activated Notch1 was mainly detected in the nuclei of a subpopulation of radial
      glial cells, the majority of proliferating precursor cells in the ventricular
      zone (VZ). However, Notch1 activation was not detected in neuronal precursor
      cells positive for neuronal basic helix-loop-helix proteins or in differentiating
      neurons in the embryonic forebrain. Interestingly, we found that Notch1 was
      transiently activated in the astrocytic lineage during perinatal CNS development.
      Taken together, the present method has enabled us to determine the timing,
      gradients, and boundaries of the activation of Notch signaling.

PMID- 15198675
TI  - Different activation of NF-kappaB by stimulation of dopamine D2L and D2S
      receptors through calcineurin activation.
AB  - Dopamine D2 receptor (D2R) has known to activate Ca(2+)/calmodulin-dependent
      protein phosphatase, calcineurin by increasing in the intracellular Ca(2+). We
      previously showed that D2LR (long isoform) and D2SR (short isoform) enhanced SRE
      and NF-kappaB, and conversely suppressed CRE transcriptional activities in NG108
      15 cells stably expressed with these receptors (NGD2LR and NGD2SR). In this
      study, to investigate whether activation of calcineurin is involved in the
      transcriptional regulations through D2R, we evaluated effect of cyclosporin A, a
      selective calcineurin inhibitor, on them in NGD2LR and NGD2SR cells using
      luciferase reporter gene assay. We first confirmed that D2LR activates
      calcineurin in NG108-15 cells by measurement of dephosphorylation of dopamine-
      and cyclic AMP-regulated phosphoprotein Mr 32 000 (DARPP-32) at threonin 34 by
      immunoblot analysis with its phospho-specific antibody. Cyclosporin A treatment
      showed no change in suppression of forskolin-induced CRE activation or activation
      of SRE but significantly attenuated NF-kappaB activation by D2LR stimulation in
      NGD2LR cells. Interestingly, D2SR-induced NF-kappaB activation, which was weaker
      than that by D2LR stimulation, was not affected by cyclosporin A treatment in
      NGD2SR cells. Furthermore, D2SR stimulation did not cause dephosphorylation of
      DARPP-32 at threonin 34. Taken together, D2SR and D2LR may employ different
      signaling pathway on intracellular Ca(2+) mobilization, thereby showing different
      NF-kappaB activation in the calcineurin-dependent manner.

PMID- 15198676
TI  - A minimal length between tau exon 10 and 11 is required for correct splicing of
      exon 10.
AB  - Mutations that stimulate exon 10 inclusion into the human tau mRNA cause
      frontotemporal dementia with parkinsonism, associated with chromosome 17 (FTDP
      17), and other tauopathies. This suggests that the ratio of exon 10 inclusion to
      exclusion in adult brain is one of the factors to determine biological functions
      of the tau protein. To investigate the underlying splicing mechanism and identify
      potential therapeutic targets for tauopathies, we generated a series of mini-gene
      constructs with intron deletions from the full length of tau exons 9-11 mini-gene
      construct. RT-PCR results demonstrate that there is a minimum distance
      requirement between exon 10 and 11 for correct splicing of the exon 10. In
      addition, SRp20, a member of serine-arginine (SR) protein family of splicing
      factors was found to facilitate exclusion of exon 10 in a dosage-dependent
      manner. Significantly, SRp20 also induced exon 10 skipping from pre-mRNAs
      containing mutations identified in FTDP-17 patients. Based on those results, we
      generated a cell-based system to measure inclusion to exclusion of exon 10 in the
      tau mRNA using the luciferase reporter. The firefly luciferase was fused into
      exon 11 in frame, and a stop code was also created in exon 10. Inclusion of exon
      10 prevents luciferase expression, whereas exclusion of exon 10 generates
      luciferase activity. To minimize baseline luciferase expression, our reporter
      construct also contains a FTDP-17 mutation that increases exon 10 inclusion. We
      demonstrate that the splicing pattern of our reporter construct mimics that of
      endogenous tau gene. Co-transfection of SRp20 and SRp55, two SR proteins that
      promote exon 10 exclusion, increases production of luciferase. We conclude that
      this cell-based system can be used to identify biological substances that
      modulate exon 10 splicing.

PMID- 15198677
TI  - The brefeldin A-inhibited GDP/GTP exchange factor 2, a protein involved in
      vesicular trafficking, interacts with the beta subunits of the GABA receptors.
AB  - We have found that the brefeldin A-inhibited GDP/GTP exchange factor 2 (BIG2)
      interacts with the beta subunits of the gamma-aminobutyric acid type-A receptor
      (GABA(A)R). BIG2 is a Sec7 domain-containing guanine nucleotide exchange factor
      known to be involved in vesicular and protein trafficking. The interaction
      between the 110 amino acid C-terminal fragment of BIG2 and the large
      intracellular loop of the GABA(A)R beta subunits was revealed with a yeast two
      hybrid assay. The native BIG2 and GABA(A)Rs interact in the brain since both
      coprecipitated from detergent extracts with either anti-GABA(A)R or anti-BIG2
      antibodies. In transfected human embryonic kidney cell line 293 cells, BIG2
      promotes the exit of GABA(A)Rs from endoplasmic reticulum. Double label
      immunofluorescence of cultured hippocampal neurons and electron microscopy
      immunocytochemistry of rat brain tissue show that BIG2 concentrates in the trans
      Golgi network. BIG2 is also present in vesicle-like structures in the dendritic
      cytoplasm, sometimes colocalizing with GABA(A)Rs. BIG2 is present in both
      inhibitory GABAergic synapses that contain GABA(A)Rs and in asymmetric excitatory
      synapses. The results are consistent with the hypotheses that the interaction of
      BIG2 with the GABA(A)R beta subunits plays a role in the exocytosis and
      trafficking of assembled GABA(A)R to the cell surface.

PMID- 15198678
TI  - Metabotropic glutamate receptors are differentially regulated under elevated
      intraocular pressure.
AB  - Glaucoma is a leading cause of blindness, ultimatively resulting in the apoptotic
      death of retinal ganglion cells. However, molecular mechanisms involved in
      ganglion cell death are poorly understood. While the involvement of ionotropic
      glutamate receptors has been extensively studied, virtually nothing is known
      about its metabotropic counterparts. Here, we compared the retinal gene
      expression of metabotropic glutamate receptors (mGluR) in eyes with normal and
      elevated intraocular pressure (IOP) of DBA/2J mice, a model for secondary angle
      closure glaucoma using RT-PCR and immunohistochemistry. Elevated IOP in DBA/2J
      mice significantly increased retinal gene expression of mGluR1a, mGluR2, mGluR4a,
      mGluR4b, mGluR6 and mGluR7a when compared to C57BL/6 control animals, while
      mGluR5a/b and mGluR8a were decreased and no difference was observed for mGluR3
      and mGluR8b. Specific antibodies detected an increase of mGluR1a and mGluR5a/b in
      both synaptic layers and in the ganglion cell layer of the retina under elevated
      IOP. Because ganglion cell death in DBA/2J mice occurs most likely by apoptotic
      mechanisms, we demonstrated up-regulation of mGluRs in neurons undergoing
      apoptosis. In summary, we support the idea that the specific gene regulation of
      mGluRs is a part of the glaucoma-like pathological process that develops in the
      eyes of DBA/2J mice.

PMID- 15198679
TI  - Quantitative determination of extracellular glutamine concentration in rat brain,
      and its elevation in vivo by system A transport inhibitor, alpha
      (methylamino)isobutyrate.
AB  - The basal concentration of glutamine in the extracellular fluid, [GLN(ECF)], was
      determined to be 385 +/- 16 microm in the cortico-striatal region of awake rats.
      This in vivo concentration was determined by measuring glutamine concentrations
      in dialysates collected at several flow rates (0.2-4 microL/min), and
      extrapolating to the concentration at zero flow-rate. Dialysate glutamine
      concentrations in the somatosensory cortex, hippocampus and thalamus showed no
      statistically significant difference. In these brain regions, [GLN(ECF)] was
      elevated 1.5- to 1.8-fold upon perfusion of 50-250 mmalpha
      (methylamino)isobutyrate (MeAIB), a competitive inhibitor of glutamine uptake by
      system A amino acid transporter. The results show, for the first time, that MeAIB
      causes elevation of brain GLN(ECF)in vivo. The MeAIB-induced elevation of
      [GLN(ECF)] provides additional support for the current view that system A GLN
      transporter (Gln T/SAT 1) is the major pathway for the uptake of GLN(ECF) by
      neurons, while GLN release from glia is mainly mediated by a system N transporter
      (SN1) which is not inhibitable by MeAIB. The steady-state GLN(ECF) concentration
      and the effectiveness of MeAIB in inhibiting neuronal GLN uptake in vivo,
      reported in this study, will be useful, when combined with the known in vitro
      kinetic properties of the GLN transporters, for study of GLN transport in the
      intact brain.

PMID- 15198680
TI  - Oral administration of Crataegus flavonoids protects against ischemia/reperfusion
      brain damage in gerbils.
AB  - Stroke is the third leading cause of death as dementia is a main symptom of
      Alzheimer's disease. One of the important mechanisms in the pathogeny of stroke
      is free radical production during the reperfusion period, therefore the effects
      of a type of natural antioxidant, i.e. Crataegus flavonoids (CF), on brain
      ischemic insults were investigated in Mongolian gerbil stroke model. Results
      showed that pretreatment of the animals with CF decreased reactive oxygen species
      (ROS) production, thiobarbituric acid reactive substances content, and
      nitrite/nitrate concentration in brain homogenate, increased the brain homogenate
      associated antioxidant level in a dose-dependent manner. CF pretreatment
      increased the amount of biologically available NO by scavenging of superoxide
      anion produced during reperfusion. At same time, in the process of
      ischemia/reperfusion brain damage, the content of nitrite/nitrate (the end
      product of NO) increased, and of NO detected by ESR decreased. Oral pretreatment
      with CF decreased the nitrite/nitrate content in the brain homogenate and
      increased the biologically available NO concentration in a dose-dependent manner.
      The increasing effect of antioxidant on NO might be due to its scavenging effect
      on superoxide anion, which could react with NO into peroxynitrite. iNOS was
      implied in delayed neuron death after brain ischemic damage and it was found that
      pretreatment with CF could decrease the protein level of tumor necrosis factor
      (TNF)-alpha and nuclear factor-kappa B (NF-kappaB), and increase the mRNA level
      of NOS estimated by western blotting and RT-PCR. More neurons survived and fewer
      cells suffered apoptosis in the hippocampal CA1 region of CF treated animal
      brain. These results suggest that oral administration of this antioxidant
      increases the antioxidant level in the brain and protects the brain against
      delayed cell death caused by ischemia/reperfusion injury.

PMID- 15198681
TI  - Long-term regulation of signalling components of adenylyl cyclase and mitogen
      activated protein kinase in the pre-frontal cortex of human opiate addicts.
AB  - Opiate addiction involves the development of chronic adaptive changes in micro 
      opioid receptors and associated pathways (e.g. cAMP signalling) which lead to
      neuronal plasticity in the brain. This study assessed the status of cAMP and
      mitogen-activated protein kinase (MAPK) pathways in brains (pre-frontal cortex)
      of chronic opiate addicts. In these subjects (n = 24), the immunodensities of
      adenylyl cyclase-I, PKA Calpha, total and phosphorylated CREB were not different
      from those in sex-, age- and PMD-matched controls. Moreover, the ratio
      pCREB/tCREB was similar in opiate addicts (0.74) and controls (0.76), further
      indicating that opiate addiction in humans is not associated with an upregulation
      of several key components of cAMP signalling in the pre-frontal cortex. In
      contrast, the components of MAPK cascade (Ras/c-Raf-1/MEK/ERK) were decreased in
      the same brains. Notably, pronounced downregulations of phosphorylated MEK (85%)
      and ERK1/2 (pERK1: 81%; pERK2: 80%) were quantitated in brains of opiate addicts.
      Chronic morphine treatment in rats (10-100 mg/kg for 5 days) was also associated
      with decreases of pERK1/2 (59-68%) in the cortex. In SH-SY5Y cells, morphine also
      stimulated the activity of pERK1/2 (2.5-fold) and the MEK inhibitor PD98059
      blocked this effect (90%). The abnormalities of MAPK signalling might have
      important consequences in the long term development of various forms of neural
      plasticity associated with opiate addiction in humans.

PMID- 15198682
TI  - CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by
      ubiquitinating Hsp/Hsc70.
AB  - Over 100 mutants in superoxide dismutase 1 (SOD1) are reported in familial
      amyotrophic lateral sclerosis (ALS). However, the precise mechanism by which they
      are degraded through a ubiquitin-proteasomal pathway (UPP) remains unclear. Here,
      we report that heat-shock protein (Hsp) or heat-shock cognate (Hsc)70, and the
      carboxyl terminus of the Hsc70-interacting protein (CHIP), are involved in
      proteasomal degradation of mutant SOD1. Only mutant SOD1 interacted with
      Hsp/Hsc70 in vivo, and in vitro experiments revealed that Hsp/Hsc70
      preferentially interacted with apo-SOD1 or dithiothreitol (DTT)-treated holo
      SOD1, compared with metallated or oxidized forms. CHIP, a binding partner of
      Hsp/Hsc70, interacted only with mutant SOD1 and promoted its degradation. Both
      Hsp70 and CHIP promoted polyubiquitination of mutant SOD1-associated molecules,
      but not of mutant SOD1, indicating that mutant SOD1 is not a substrate of CHIP.
      Moreover, mutant SOD1-associated Hsp/Hsc70, a known substrate of CHIP, was
      polyubiquitinated in vivo, and polyubiquitinated Hsc70 by CHIP interacted with
      the S5a subunit of the 26S proteasome in vitro. Furthermore, CHIP was
      predominantly expressed in spinal neurons, and ubiquitinated inclusions in the
      spinal motor neurons of hSOD1(G93A) transgenic mice were CHIP-immunoreactive.
      Taken together, we propose a novel pathway in which ubiquitinated Hsp/Hsc70 might
      deliver mutant SOD1 to, and facilitate its degradation, at the proteasome.

PMID- 15198683
TI  - Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in
      the rat striatum and substantia nigra.
AB  - Glial cell line-derived neurotrophic factor (GDNF) improves motor dysfunction
      associated with aging in rats and non-human primates, in animal models of
      Parkinson's disease, and may improve motoric function in patients with advanced
      Parkinson's disease. These improvements are associated with increased dopamine
      function in the nigrostriatal system, but the molecular events associated with
      this increase are unknown. In these studies, 100 micro g of GDNF was injected
      into the striatum of normal aged (24-month-old) male Fischer 344 rats. The
      protein levels and phosphorylation of TH, ERK1/2, and related proteins were
      determined by blot-immunolabeling of striatum and substantia nigra harvested 30
      days after injection. In GDNF-treated rats, TH phosphorylation at Ser31 increased
      approximately 40% in striatum and approximately 250% in the substantia nigra. In
      the substantia nigra, there was a significant increase in ERK1 phosphorylation.
      In striatum, there was a significant increase in ERK2 phosphorylation.
      Microdialysis studies in striatum showed that both amphetamine- and potassium
      evoked dopamine release in GDNF recipients were significantly increased. These
      data show that GDNF-induced increases in dopamine function are associated with a
      sustained increase in TH phosphorylation at Ser31, which is greatest in the
      substantia nigra and maintained for at least one month following a single
      striatal administration of GDNF. These findings, taken from the nigrostriatal
      system of normal aged rats, may help explain the long lasting effects of GDNF on
      dopamine function and prior studies supporting that a major effect of GDNF
      involves its effects on dopamine storage and somatodendritic release of dopamine
      in the substantia nigra.

PMID- 15198687
TI  - The ultrastructure of the spermatozoon of the lizard Iguana iguana (Reptilia,
      Squamata, Iguanidae) and the variability of sperm morphology among iguanian
      lizards.
AB  - The spermatozoon of Iguana iguana is filiform and resembles that of other
      iguanian lizards, being most similar to Tropidurus. All sperm synapomorphies of
      Tetrapoda, Amniota and Squamata are present in the sperm of Iguana iguana. By
      reconstructing the evolution of 30 sperm characters we identified a novel
      synapomorphy of Iguania: the presence of a well-developed acrosomal ridge at the
      level of the epinuclear lucent zone. Because of the poor topological resolution
      among iguanian clades we could not discount the possibility of convergence or
      neutral selection as determinant of the variability in characteristics of the
      sperm cell. In agreement with previous studies, we identified heterogeneous rates
      of evolution among the three main regions of the sperm cell, namely the head,
      midpiece and tail.

PMID- 15198688
TI  - Cerebral cortex three-dimensional profiling in human fetuses by magnetic
      resonance imaging.
AB  - Seven human fetuses of crown/rump length corresponding to gestational ages
      ranging from the 12th to the 16th week were studied using a paradigm based on
      three-dimensional reconstruction of the brain obtained by magnetic resonance
      imaging (MRI). The aim of the study was to evaluate brain morphology in situ and
      to describe developmental dynamics during an important period of fetal
      morphogenesis. Three-dimensional MRI showed the increasing degree of maturation
      of the brains; fronto-occipital distance, bitemporal distance and occipital angle
      were examined in all the fetuses. The data were interpreted by correlation with
      the internal structure as visualized using high-spatial-resolution MRI, acquired
      using a 4.7-T field intensity magnet with a gradient power of 20 G cm(-1). The
      spatial resolution was sufficient for a detailed detection of five layers, and
      the contrast was optimized using sequences with different degrees of T1 and T2
      weighting. Using the latter, it was possible to visualize the subplate and
      marginal zones. The cortical thickness was mapped on to the hemispheric surface,
      describing the thickness gradient from the insular cortex to the periphery of the
      hemispheres. The study demonstrates the utility of MRI for studying brain
      development. The method provides a quantitative profiling of the brain, which
      allows the calculation of important morphological parameters, and it provides
      informative regarding transient features of the developing brain.

PMID- 15198686
TI  - Lymphatics at the crossroads of angiogenesis and lymphangiogenesis.
AB  - The lymphatic system is implicated in interstitial fluid balance regulation,
      immune cell trafficking, oedema and cancer metastasis. However, the sequence of
      events that initiate and coordinate lymphatic vessel development
      (lymphangiogenesis) remains obscure. In effect, the understanding of
      physiological regulation of lymphatic vasculature has been overshadowed by the
      greater emphasis focused on angiogenesis, and delayed by a lack of specific
      markers, thereby limiting this field to no more than a descriptive
      characterization. Recently, new insights into lymphangiogenesis research have
      been due to the discovery of lymphatic-specific markers and growth factors of
      vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D.
      Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated
      a crucial role for these factors in tumour lymphangiogenesis. Knowledge of
      lymphatic development has now been redefined at the molecular level, providing an
      interesting target for innovative therapies. This review highlights the recent
      insights and advances into the field of lymphatic vascular research, outlining
      the most important aspects of the embryo development, structure, specific markers
      and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms
      involved in the regulation of lymphangiogenesis are described.

PMID- 15198689
TI  - Kir4.1 expression by astrocytes and oligodendrocytes in CNS white matter: a
      developmental study in the rat optic nerve.
AB  - Deletion studies in transgenic mice indicate that the potassium inward rectifying
      channel Kir4.1 is crucial for oligodendrocyte differentiation and has a special
      role in regulation of extracellular potassium (K(+)), a major function of
      astrocytes. However, there are conflicting reports on whether Kir4.1 is expressed
      by white matter astrocytes and oligodendrocytes, raising doubts over its
      functions. Here, we have examined Kir4.1 expression in astrocytes and
      oligodendrocytes of the rat optic nerve, a typical central nervous system white
      matter tract. Single and double immunofluorescence labelling was performed on
      frozen sections from optic nerves aged postnatal day (P)5, 10, 15, 20 and adult,
      using anti-Kir4.1 antibodies and the glia-specific antibodies glial fibrillary
      acidic protein (GFAP, astrocytes), carbonic anhydrase II (CAII, oligodendrocyte
      somata and processes) and myelin basic protein (MBP, oligodendrocyte myelin
      sheaths). The results demonstrate Kir4.1 expression in rows of glial cells as
      early as P5, and this pattern persisted throughout development and into
      adulthood, consistent with early expression of Kir4.1 on developing
      oligodendrocytes. Clear co-expression of Kir4.1 and GFAP is first evident at P10
      and increases to adult levels by P15 and P20, which correlates with the
      development of K(+) regulation between P15 and P20. Astrocyte expression of
      Kir4.1 is localized to perivascular end-feet and fine processes within the
      fascicles of myelinated axons, consistent with a role in K(+) spatial buffering
      between nodes of Ranvier and blood vessels. By contrast, Kir4.1 is concentrated
      in the cell bodies of oligodendrocytes, and there is no apparent co-expression
      with MBP(+) myelin sheaths, suggesting oligodendroglial Kir4.1 channels are not
      involved in K(+) regulation. The results support roles for Kir4.1 in both
      oligodendrocyte differentiation and K(+) regulation by astrocytes.

PMID- 15198690
TI  - Alx4 and Msx2 play phenotypically similar and additive roles in skull vault
      differentiation.
AB  - Alx4 and Msx2 encode homeodomain-containing transcription factors that show a
      clear functional overlap. In both mice and humans, loss of function of either
      gene is associated with ossification defects of the skull vault, although the
      major effect is on the frontal bones in mice and the parietal bones in humans.
      This study was undertaken to discover whether Alx4 and Msx2 show a genetic
      interaction in skull vault ossification, and to test the hypothesis that they
      interact with the pathway that includes the Fgfr genes, Twist1 and Runx2. We
      generated Alx4(+/-)/Msx2(+/-) double heterozygous mutant mice, interbred them to
      produce compound genotypes and analysed the genotype-phenotype relationships.
      Loss of an increasing number of alleles correlated with an incremental
      exacerbation of the skull vault defect; loss of Alx4 function had a marginally
      greater effect than loss of Msx2 and also affected skull thickness. In situ
      hybridization showed that Alx4 and Msx2 are expressed in the cranial skeletogenic
      mesenchyme and in the growing calvarial bones. Studies of the coronal suture
      region at embryonic day (E)16.5 revealed that Alx4 expression was decreased, but
      not abolished, in Msx2(-/-) mutants, and vice versa; expression of Fgfr2 and
      Fgfr1, but not Twist1, was reduced in both mutants at the same stage. Runx2
      expression was unaffected in the coronal suture; in contrast, expression of the
      downstream ossification marker Spp1 was delayed. Double homozygous pups showed
      substantial reduction of alkaline phosphatase expression throughout the
      mineralized skull vault; they died at birth due to defects of the heart, lungs
      and diaphragm not previously associated with Alx4 or Msx2. Our observations
      suggest that Alx4 and Msx2 are partially functionally redundant, acting within a
      network of transcription factors and signalling events that regulate the rate of
      osteogenic proliferation and differentiation at a stage after the commitment of
      mesenchymal stem cells to osteogenesis.

PMID- 15198691
TI  - Morphometric and immunohistochemical study of the rumen of red deer during
      prenatal development.
AB  - Abstract A detailed study of the ontogenesis of deer stomach has not been
      undertaken to date, and our aim was to sequence several histological phenomena
      that occur during the ontogenesis of one of the gastric compartments, the rumen.
      Histomorphometric and immunohistochemical analyses were carried out on 50 embryos
      and fetuses of deer from the initial stages of prenatal life until birth. For the
      purposes of testing, the animals were divided into five experimental groups:
      group I, 1.4-3.6 cm crown-rump length, 30-60 days, 1-25% of gestation; group II,
      4.5-7.2 cm crown-rump length, 67-90 days, 25-35% of gestation; group III, 8-19 cm
      crown-rump length, 97-135 days, 35-50% of gestation; group IV, 21-33 cm crown
      rump length, 142-191 days, 45-70% of gestation; and group V, 36-40 cm crown-rump
      length, 205-235 days, 75-100% of gestation. The rumen of the primitive gastric
      tube was observed at approximately 60 days. At 67 days the rumen consisted of
      three layers: internal or mucosal, middle or muscular, and external or serosal
      layer. The stratification of the epithelial layer was accompanied by changes in
      its structure with the appearance of ruminal pillars and papillae. The outline of
      the ruminal papillae began to appear at 142 days of prenatal development as
      evaginations of the basal zone toward the ruminal lumen, pulling with it in its
      configuration the stratum basale, the lamina propria and the submucosa. From the
      pluripotential blastemic tissue at 60 days we witnessed the histodifferentiation
      of the primitive tunica muscularis, composed of two layers of myoblasts with a
      defined arrangement. It was also from the pluripotential blastemic tissue, at 97
      days, that the lamina propria and the submucosa were differentiated. The serosa
      showed continuity in growth as well as differentiation, already detected in the
      undifferentiated outline phase. The tegumentary mucosa of deer rumen was shown
      without secretory capacity in the initial embryonic phases; neutral
      mucopolysaccharides appeared from 67 days. The presence of neuroendocrine cells
      (non-neuronal enolase) in the ruminal wall of deer during development was not
      detected until 97 days. The glial cells were detected at 142 days for glial
      fibrillary acidic protein and at 67 days for vimentin. The immunodetection of
      neuropeptides vasointestinal peptide and neuropeptide Y progressively increased
      with gestation period, starting from 97 days. In terms of the structure of the
      rumen of the primitive gastric tube, our observations revealed that the deer is
      less precocious than small and large domestic ruminants. Thus its secretory
      capacity, detected by the presence of neutral mucopolysaccharides, and its
      neuroendocrine nature, determined by the presence of positive non-neuronal
      enolase cells, were evident in more advanced stages of prenatal development than
      those detected in the sheep, goat and cow.

PMID- 15198692
TI  - Integrin expression in cells of the intervertebral disc.
AB  - In this study, we investigated the profile of integrin expression in human and
      porcine intervertebral disc tissue. Differences in extracellular matrix
      composition between anulus fibrosus (AF) and nucleus pulposus (NP) regions of the
      disc, as well as differences in cellular responses to environmental stimuli,
      suggest a role for integrins in presenting matrix signals that may mediate these
      responses. Human disc tissue and porcine AF and NP tissue were stained with
      antibodies to alpha integrin subunits 1-6, V and IIb, and beta integrin subunits
      1-6 and graded for evidence of positive staining on a scale from 0 (no staining)
      to 3 (high incidence of staining). Human tissue expressed alpha and beta integrin
      subunits shown to be present in articular cartilage, including alpha(1), alpha(5)
      and alpha(V). Porcine AF tissue expressed similar integrin subunits to human
      disc, with both expressing alpha(1), alpha(5), beta(1), beta(3) and beta(5)
      subunits, whereas porcine NP tissue expressed higher levels of alpha(6), beta(1)
      and beta(4) than AF tissue. The expressed subunits are known to interact with
      proteins including collagens, fibronectin and laminin; however, additional
      studies will be required to characterize the interactions of the integrin
      subunits with specific matrix constituents, as well as their specific involvement
      in regulating environmental stimuli.

PMID- 15198697
TI  - Bipedal animals, and their differences from humans.
AB  - Humans, birds and (occasionally) apes walk bipedally. Humans, birds, many lizards
      and (at their highest speeds) cockroaches run bipedally. Kangaroos, some rodents
      and many birds hop bipedally, and jerboas and crows use a skipping gait. This
      paper deals only with walking and running bipeds. Chimpanzees walk with their
      knees bent and their backs sloping forward. Most birds walk and run with their
      backs and femurs sloping at small angles to the horizontal, and with their knees
      bent. These differences from humans make meaningful comparisons of stride length,
      duty factor, etc., difficult, even with the aid of dimensionless parameters that
      would take account of size differences, if dynamic similarity were preserved.
      Lizards and cockroaches use wide trackways. Humans exert a two-peaked pattern of
      force on the ground when walking, and an essentially single-peaked pattern when
      running. The patterns of force exerted by apes and birds are never as markedly
      two-peaked as in fast human walking. Comparisons with quadrupedal mammals of the
      same body mass show that human walking is relatively economical of metabolic
      energy, and human running is expensive. Bipedal locomotion is remarkably
      economical for wading birds, and expensive for geese and penguins.

PMID- 15198698
TI  - Biomimetic robotics should be based on functional morphology.
AB  - Due to technological improvements made during the last decade, bipedal robots
      today present a surprisingly high level of humanoid skill. Autonomy, with respect
      to the processing of information, is realized to a relatively high degree. What
      is mainly lacking in robotics, moving from purely anthropomorphic robots to
      'anthropofunctional' machines, is energetic autonomy. In a previously published
      analysis, we showed that closer attention to the functional morphology of human
      walking could give robotic engineers the experiences of an at least 6 Myr beta
      test period on minimization of power requirements for biped locomotion. From our
      point of view, there are two main features that facilitate sustained walking in
      modern humans. The first main feature is the existence of 'energetically optimal
      velocities' provided by the systematic use of various resonance mechanisms: (a).
      suspended pendula (involving arms as well as legs in the swing phase of the gait
      cycle) and matching of the pendular length of the upper and lower limbs; (b).
      inverted pendula (involving the legs in the stance phase), driven by torsional
      springs around the ankle joints; and (c). torsional springs in the trunk. The
      second main feature is compensation for undesirable torques induced by the
      inertial properties of the swinging extremities: (a). mass distribution in the
      trunk characterized by maximized mass moments of inertia; (b). lever arms of
      joint forces at the hip and shoulder, which are inversely proportional to their
      amplitude; and (c). twisting of the trunk, especially torsion. Our qualitative
      conclusions are three-fold. (1). Human walking is an interplay between masses,
      gravity and elasticity, which is modulated by musculature. Rigid body mechanics
      is insufficient to describe human walking. Thus anthropomorphic robots completely
      following the rules of rigid body mechanics cannot be functionally humanoid. (2).
      Humans are vertebrates. Thus, anthropomorphic robots that do not use the trunk
      for purposes of motion are not truly humanoid. (3). The occurrence of a waist,
      especially characteristic of humans, implies the existence of rotations between
      the upper trunk (head, neck, pectoral girdle and thorax) and the lower trunk
      (pelvic girdle) via an elastic joint (spine, paravertebral and abdominal
      musculature). A torsional twist around longitudinal axes seems to be the most
      important.

PMID- 15198699
TI  - Evaluating alternative gait strategies using evolutionary robotics.
AB  - Evolutionary robotics is a branch of artificial intelligence concerned with the
      automatic generation of autonomous robots. Usually the form of the robot is
      predefined and various computational techniques are used to control the machine's
      behaviour. One aspect is the spontaneous generation of walking in legged robots
      and this can be used to investigate the mechanical requirements for efficient
      walking in bipeds. This paper demonstrates a bipedal simulator that spontaneously
      generates walking and running gaits. The model can be customized to represent a
      range of hominoid morphologies and used to predict performance parameters such as
      preferred speed and metabolic energy cost. Because it does not require any motion
      capture data it is particularly suitable for investigating locomotion in fossil
      animals. The predictions for modern humans are highly accurate in terms of energy
      cost for a given speed and thus the values predicted for other bipeds are likely
      to be good estimates. To illustrate this the cost of transport is calculated for
      Australopithecus afarensis. The model allows the degree of maximum extension at
      the knee to be varied causing the model to adopt walking gaits varying from
      chimpanzee-like to human-like. The energy costs associated with these gait
      choices can thus be calculated and this information used to evaluate possible
      locomotor strategies in early hominids.

PMID- 15198700
TI  - Locomotion in bonobos (Pan paniscus): differences and similarities between
      bipedal and quadrupedal terrestrial walking, and a comparison with other
      locomotor modes.
AB  - One of the great ongoing debates in palaeo-anthropology is when, and how,
      hominids acquired habitual bipedal locomotion. The newly adopted bipedal gait and
      the ancestral quadrupedal gait are most often considered as very distinct, with
      each habitual locomotor mode showing corresponding anatomical adaptations.
      Bonobos (Pan paniscus), along with common chimpanzees (P. troglodytes), are the
      closest living relatives to humans and their locomotion is valuable for
      comparison with other primates, and to gain an insight in the acquisition of
      human bipedalism. Bonobos are habitual quadrupeds, but they also engage in
      bipedal locomotion, both on terrestrial and in arboreal substrates. In terms of
      kinematics and dynamics, the contrast between bipedal and quadrupedal walking
      seems to be more subtle than one might expect. Apart from the trunk being
      approximately 37 degrees more erect during bipedal locomotion, the leg movements
      are rather similar. Apart from the heel, plantar pressure distributions show
      subtle differences between bipedal and quadrupedal locomotion. Regardless,
      variability is high, and various intermediate forms of locomotion (e.g. tripedal
      walking) exist both in captivity and in the wild. Moreover, there is overlap
      between the characteristics of walking and other locomotor modes, as we show with
      new data of walking on an inclined pole and of vertical squat jumps. We suggest
      that there is great overlap between the many locomotor modes in bonobos, and that
      the required polyvalence is reflected in their anatomy. This may hamper the
      development of one highly specialized gait (i.e. bipedalism), which would
      constrain performance of the other types of locomotion.

PMID- 15198701
TI  - Mechanisms for the acquisition of habitual bipedality: are there biomechanical
      reasons for the acquisition of upright bipedal posture?
AB  - Morphology and biomechanics are linked by causal morphogenesis ('Wolff's law')
      and the interplay of mutations and selection (Darwin's 'survival of the
      fittest'). Thus shape-based selective pressures can be determined. In both cases
      we need to know which biomechanical factors lead to skeletal adaptation, and
      which ones exert selective pressures on body shape. Each bone must be able to
      sustain the greatest regularly occurring loads. Smaller loads are unlikely to
      lead to adaptation of morphology. The highest loads occur primarily in posture
      and locomotion, simply because of the effect of body weight (or its multiple). In
      the skull, however, it is biting and chewing that result in the greatest loads.
      Body shape adapted for an arboreal lifestyle also smooths the way towards
      bipedality. Hindlimb dominance, length of the limbs in relation to the axial
      skeleton, grasping hands and feet, mass distribution (especially of the limb
      segments), thoracic shape, rib curvatures, and the position of the centre of
      gravity are the adaptations to arboreality that also pre-adapt for bipedality.
      Five divergent locomotor/morphological types have evolved from this base: arm
      swinging in gibbons, forelimb-dominated slow climbing in orangutans,
      quadrupedalism/climbing in the African apes, an unknown mix of climbing and
      bipedal walking in australopithecines, and the remarkably endurant bipedal
      walking of humans. All other apes are also facultative bipeds, but it is the
      biomechanical characteristics of bipedalism in orangutans, the most arboreal
      great ape, which is closest to that in humans. If not evolutionary accident, what
      selective factor can explain why two forms adopted bipedality? Most authors tend
      to connect bipedal locomotion with some aspect of progressively increasing
      distance between trees because of climatic changes. More precise factors, in
      accordance with biomechanical requirements, include stone-throwing,
      thermoregulation or wading in shallow water. Once bipedality has been acquired,
      development of typical human morphology can readily be explained as adaptations
      for energy saving over long distances. A paper in this volume shows that load
      carrying ability was enhanced from australopithecines to Homo ergaster (early
      African H. erectus), supporting an earlier proposition that load-carrying was an
      essential factor in human evolution.

PMID- 15198702
TI  - Acquisition of bipedalism: the Miocene hominoid record and modern analogues for
      bipedal protohominids.
AB  - The well-known fossil hominoid Proconsul from the Early Miocene of Kenya was a
      non-specialized arboreal quadruped with strong pollicial/hallucial assisted
      grasping capability. It lacked most of the suspensory specializations acquired in
      living hominoids. Nacholapithecus, however, from the Middle Miocene of Kenya,
      although in part sharing with Proconsul the common primitive anatomical body
      design, was more specialized for orthograde climbing, 'hoisting' and bridging,
      with the glenoid fossae of the scapula probably being cranially orientated, the
      forelimbs proportionally large, and very long toes. Its tail loss suggests
      relatively slow movement, although tail loss may already have occurred in
      Proconsul. Nacholapithecus-like positional behaviour might thus have been a basis
      for development of more suspensory specialized positional behaviour in later
      hominoids. Unfortunately, after 13 Ma, there is a gap in the hominoid postcranial
      record in Africa until 6 Ma. Due to this gap, a scenario for later locomotor
      evolution prior to the divergence of Homo and Pan cannot be determined with
      certainty. The time gap also causes difficulties when we seek to determine
      polarities of morphological traits in very early hominids. Interpretation of the
      form-function relationships of postcranial features in incipient hominids will be
      difficult because it is predicted that they had incorporated bipedalism only
      moderately into their total positional repertoires. However, Japanese macaques,
      which are trained in traditional bipedal performance, may provide useful hints
      about bipedal adaptation in the protohominids. Kinematic analyses revealed that
      these macaques walked bipedally with a longer stride and lower stride frequency
      than used by ordinary macaques, owing to a more extended posture of the hindlimb
      joints. The body centre of gravity rises during the single-support phase of
      stance. Energetic studies of locomotion in these bipedal macaques revealed that
      energetic expenditure was 20-30% higher in bipedalism than in quadrupedalism,
      regardless of walking velocity.

PMID- 15198704
TI  - The role of load-carrying in the evolution of modern body proportions.
AB  - The first unquestionably bipedal early human ancestors, the species
      Australopithecus afarensis, were markedly different to ourselves in body
      proportions, having a long trunk and short legs. Some have argued that
      'chimpanzee-like' features such as these suggest a 'bent-hip, bent-knee' (BHBK)
      posture would have been adopted during gait. Computer modelling studies, however,
      indicate that this early human ancestor could have walked in a reasonably
      efficient upright posture, whereas BHBK posture would have nearly doubled the
      mechanical energy cost of locomotion, as it does the physiological cost of
      locomotion in ourselves. More modern body proportions first appear at around 1.8
      1.5 Ma, with Homo ergaster (early African Homo erectus), represented by the
      Nariokotome skeleton KNM-WT 15000, in which the legs were considerably longer in
      relation to the trunk than they are in human adults, although this skeleton
      represents an adolescent. Several authors have suggested that this morphology
      would have allowed faster, more endurant walking. But during the same period, the
      archaeological record indicates a sharp rise in distances over which stone tools
      or raw materials are transported. Is this coincidental, or can load-carrying also
      be implicated in selection for a more modern morphology? Computer simulations of
      loaded walking, verified against kinetic data for humans, show that BHBK gait is
      even more ineffective while load-carrying. However, walking erect, the
      Nariokotome individual could have carried loads of 10-15% body mass for less
      cost, relative to body size, than AL 288-1 walking erect but unloaded. In fact,
      to the extent that our sample of humans is typical, KNM-WT 15000 would have had
      better mechanical effectiveness in bearing light loads on the back than modern
      human adults. Thus, selection for effectiveness in load-carrying, as well as in
      endurant walking, is indeed likely to have been implicated in the evolution of
      modern body proportions.

PMID- 15198703
TI  - Fossils, feet and the evolution of human bipedal locomotion.
AB  - We review the evolution of human bipedal locomotion with a particular emphasis on
      the evolution of the foot. We begin in the early twentieth century and focus
      particularly on hypotheses of an ape-like ancestor for humans and human bipedal
      locomotion put forward by a succession of Gregory, Keith, Morton and Schultz. We
      give consideration to Morton's (1935) synthesis of foot evolution, in which he
      argues that the foot of the common ancestor of modern humans and the African apes
      would be intermediate between the foot of Pan and Hylobates whereas the foot of a
      hypothetical early hominin would be intermediate between that of a gorilla and a
      modern human. From this base rooted in comparative anatomy of living primates we
      trace changing ideas about the evolution of human bipedalism as increasing
      amounts of postcranial fossil material were discovered. Attention is given to the
      work of John Napier and John Robinson who were pioneers in the interpretation of
      Plio-Pleistocene hominin skeletons in the 1960s. This is the period when the
      wealth of evidence from the southern African australopithecine sites was
      beginning to be appreciated and Olduvai Gorge was revealing its first evidence
      for Homo habilis. In more recent years, the discovery of the Laetoli footprint
      trail, the AL 288-1 (A. afarensis) skeleton, the wealth of postcranial material
      from Koobi Fora, the Nariokotome Homo ergaster skeleton, Little Foot (Stw 573)
      from Sterkfontein in South Africa, and more recently tantalizing material
      assigned to the new and very early taxa Orrorin tugenensis, Ardipithecus ramidus
      and Sahelanthropus tchadensis has fuelled debate and speculation. The varying
      interpretations based on this material, together with changing theoretical
      insights and analytical approaches, is discussed and assessed in the context of
      new three-dimensional morphometric analyses of australopithecine and Homo foot
      bones, suggesting that there may have been greater diversity in human bipedalism
      in the earlier phases of our evolutionary history than previously suspected.

PMID- 15198705
TI  - C-bands on chromosomes of 32 beetle species (Coleoptera: Elateridae, Cantharidae,
      Oedemeridae, Cerambycidae, Anthicidae, Chrysomelidae, Attelabidae and
      Curculionidae).
AB  - C-banding patterns of 32 beetle species from the families Elateridae,
      Cantharidae, Oedemeridae, Cerambycidae, Anthicidae, Chrysomelidae, Attelabidae
      and Curculionidae were studied using the C-banding technique. Mitotic and meiotic
      chromosomes were previously described for 14 species. From among 18 species that
      had never been cytogenetically studied, we determined the diploid and haploid
      chromosome numbers and the sex determination system for 12 beetles. The karyotype
      for 6 species is not described because of a lack of mitotic and meiotic
      metaphases. Results confirm that most of the beetle species possess a small
      amount of heterochromatin and C-positive segments are weakly visible in pachytene
      stages and weakly or imperceptible in mitotic and meiotic metaphases. In some
      species with a large amount of heterochromatin, C-bands were observed in the
      centromeric region in all autosomes and the X chromosome. The Y chromosome does
      not show C-bands with the exception of Oedemera viridis in which it possesses a
      small band of heterochromatin.

PMID- 15198706
TI  - Efficient regeneration of fertile barley plants from callus cultures of several
      Nordic cultivars.
AB  - The regeneration potential of three major Estonian barley cultivars was tested
      and compared to that of the Finnish cultivar Kymppi. Two different regeneration
      systems were used. The first was characterized by the high maltose concentration
      (60 g l(-1)) and by the use of 2,4D together with two different combinations of
      amino acids in the callus induction medium followed by the regeneration medium
      containing BAP (2 mg l(-1)) and 2,4D (0.2 mg l(-1)). The second exploited callus
      induction medium that contained Dicamba, lower concentrations of maltose (30 g l(
      1)) and higher concentrations of myo-inositol and thiamine and different set of
      amino acids and regeneration medium that contained higher concentrations of Cu2+
      and inorganic nitrogen accompanied by lower concentrations of NH4+ and BAP, when
      compared to the first regeneration system. The second regeneration system used
      produced significantly higher rates of callus induction, callus growth and
      regeneration of plantlets. However, it yielded also many albino plants (up to
      51%), whereas the first regeneration system used did not produce practically any
      albino plants. No major genotype-dependent differences were observed in
      comparison between two regeneration systems - in both systems higher regeneration
      potential of Anni, Elo and Kymppi contradicted to the low regeneration potential
      of Teele. It is concluded that the continuous somatic embryogenesis on the
      regeneration medium allows the regeneration of many plants from the same callus
      over long periods of time and makes available highly efficient regeneration
      protocols for Estonian and Finnish barley cultivars.

PMID- 15198708
TI  - A chromosomal analysis of some water beetle species recently transferred from
      Agabus Leach to Ilybius Erichson, with particular reference to the variation in
      chromosome number shown by I. montanus Stephens (Coleoptera: Dytiscidae).
AB  - The karyotypes of seven Ilybius species are described and illustrated. All except
      I. wasastjernae have a basic karyotype of 34 autosomes plus sex chromosomes which
      are X0 ( male symbol ), XX ( female symbol ), with the X chromosome among the
      largest in the nucleus. This karyotype appears to be the norm for Ilybius and
      supports the transfer of the species concerned from Agabus to Ilybius. I.
      wasastjernae has 36 autosomes and the X chromosome is the smallest in the nucleus
      and its karyotype is unlike any other known karyotype in either Ilybius or
      Agabus. In most of the species studied no intraspecific variation has been
      detected. Exceptions are I. chalconatus, where there is one inversion
      polymorphism in one of the autosomes, and I. montanus whose autosome number has
      been found to vary from 29 to 34. Such variation is highly unusual among
      Coleoptera. The variation results from fusion-fission polymorphisms involving
      three different pairs of autosomes. In each case the fusions may be homozygous,
      heterozygous or absent. All populations investigated were polymorphic for some of
      the fusions, but only one (La Salceda, Spain) included individuals lacking all
      fusions. The frequencies of fused and unfused chromosomes were analysed in three
      English populations. In only one case was there a departure from the values
      expected from the Hardy-Weinberg equilibrium, and this population also showed a
      significant difference from the other two. Meiosis in males heterozygous for
      fusions involves the production of trivalents in first division, but results in
      the production of abundant sperm, with no evidence of chromosomal abnormalities
      in second metaphase, or of degenerating cells as a result of failed meiosis. The
      three fusions sites are consistent in all the populations studied, and it is
      concluded that these fusions represent unique historical events rather than
      current chromosomal instability.

PMID- 15198707
TI  - Occurrence of amitotic division of trophoblast cell nuclei in blastocysts of the
      western spotted skunk (Spilogale putorius latifrons).
AB  - A cytogenetic examination of spreaded cells of diapausing and early activated
      blastocysts obtained from 7 female western spotted skunks was performed. Mitosis
      was not observed in 1626 cells obtained from 9 diapausing blastocysts; however,
      12 (1.5%) figures of diploid mitosis were seen in 851 cells from 5 early
      activated embryos. Diameter of the cell nuclei varied from 4 to 29 microm during
      diapause, and from 5 to 40 microm in activated blastocyst, and the heterogeneity
      in nuclear size was significantly different between diapausing and activated
      embryos (P<0.01). About 80% of nuclei from diapausing blastocysts measured 9 to
      16 microm, whereas a similar percentage of nuclei from activated blastocysts
      ranged from 15 to 27 microm. Many enlarged nuclei exhibited morphological
      features characteristic of mammalian polytene (i.e. endopolyploid with polytenic
      organization of chromosomes) trophoblast cells. The number of silver stained
      nucleoli in all the nuclei did not exceed 2, which corresponds to the number of
      nucleolus organizers in the diploid karyotype in this species of skunk and
      suggests the polytene organization of chromosomes in enlarged nuclei. About 10%
      of large interphase nuclei were observed to undergo amitosis, i.e. direct
      division by constriction. The resulting nuclear fragments in diapausing
      blastocysts usually had normal morphology and active nucleoli. In activated
      embryos, nearly 15% of amitotically divided nuclei appeared to be dividing into
      fragments of unequal size, one of which had normal cell nuclear morphology and
      extremely large silver positive nucleoli, and the other fragment exhibited signs
      of cell death. We interpret these data as indicating that 1) amitotic division of
      trophoblast endopolyploid cell nuclei in the skunk blastocysts may generate new
      trophoblast cells which contribute to increased cell number during both diapause
      and activation stages, and 2) activation of blastocysts after diapause is related
      to the production of trophoblast cells with enhanced synthetic capabilities.

PMID- 15198710
TI  - Study on karyotype and occurrence of B chromosomes in two endemic species of the
      genus Pimelodus (Siluriformes, Pimelodidae) from the river Iguacu.
AB  - The current work describes, for the first time, the occurrence of B chromosomes
      in the genus Pimelodus. Cytogenetic analysis in P. ortmanni and Pimelodus sp.,
      from the river Iguacu basin, revealed a diploid number of 56 chromosomes. Whereas
      distribution pattern of C-banding in Pimelodus sp. showed predominance of
      heterochromatin at the two extremities of several pairs of chromosomes,
      centromere markings predominated in P. ortmanni. Additional chromosomes in the
      two species were observed with numerical intra-individual variations between zero
      and four B, together with interspecies differences in their frequency. In Giemsa
      stained metaphases two distinct morphological types of B chromosomes were
      identified: Bm (B metacentric) and Ba (B acrocentric). In P. ortmanni both types
      of B chromosomes were totally heterochromatic; the Bm type in Pimelodus sp. had
      heterochromatin throughout its entire extension; the Ba type was partially
      heterochromatic with telomere markings on the long arm.

PMID- 15198711
TI  - Phylogenetic relationships among genotypes of worldwide collection of spring and
      winter ryes (Secale cereale L.) determined by RAPD-PCR markers.
AB  - Genetic similarities among 20 spring and 22 winter accessions of agronomically
      different ryes from fourteen countries were estimated by employing random
      amplified polymorphic DNA (RAPD) techniques. Cluster analysis of genetic distance
      data showed that 42 genotypes were readily classifiable into two main groups:
      spring and winter groups. Within the spring group, cultivars fell into a North
      European and an American-Chinese group. Cultivars of winter rye fell into four
      groups: Northern European, Russian, American and Chinese lines. A UPGMA
      dendrogram based on genetic distances of cultivars of rye within the winter and
      spring groups showed that the clusters corresponded well to their geographical
      locations. The results indicated that isolation has played an important role in
      the evolution of rye, and that temporal isolation has influenced the genetic
      diversity of rye more than geographical isolation. In this experiment, RAPD
      proved to be a rapid, reliable and practicable method of revealing polymorphisms
      in rye populations.

PMID- 15198709
TI  - Genetic relationships among Aster species by multivariate analysis and AFLP
      markers.
AB  - Fourteen species of Aster were characterized for morphological traits of
      commercial interest, chromosome number and genetic diversity by AFLP markers to
      exploit this material not only for breeding purposes but also as source of
      pharmaceuticals. The variation observed among the Aster species for five
      morphological traits was summarized by means of discriminant analysis. Three
      significant canonical variables, accounting for about 96% of total variance, were
      mainly correlated with capitulum diameter, number of ligulae and leaf length. The
      morphological variation appeared related to ploidy level of the species. A
      diploid chromosome number ranging from 10 to 18 was evident in seven species
      whereas the other species are polyploids with variable chromosome numbers up to
      52. The pollen production and stainability were quite variable among Aster
      species. Furthermore, seven species produced big pollen grains besides normally
      sized ones, at a frequency ranging from 1 to 12%, possibly due to 2n pollen
      production. The possibility that evolution of Aster genus could be driven by 2n
      gametes and sexual polyploidization is discussed. Implications of 2n gametes for
      Aster breeding are also mentioned. AFLP analysis of the fourteen Aster species
      based on six primer combinations revealed a total number of 421 polymorphic
      amplified DNA fragments. The genetic similarities estimated between the Aster
      species, based on both shared and unique amplification products ranged from 0.335
      to 0.604 across all species and revealed a geographically based clustering within
      the genus. The highest similarity was detected between A. alpinus and A. amellus
      with Eurasian origin.

PMID- 15198713
TI  - The use of phenotypic correlations and factor analysis in determining characters
      for grain yield selection in chickpea (Cicer arietinum L.).
AB  - To our knowledge, this is the first report on the use of factor analysis in
      determining characters for yield selection in chickpea (Cicer arietinum L.). The
      present investigation was undertaken to evaluate yield criteria in chickpea using
      phenotypic correlations and factor analysis. Factor 1 composed of biological
      yield, reaction to ascochyta blight (Ascochyta rabiei (Pass.) Labr.), plant
      height, grain yield and harvest index. Factor 2 consisted of branches and pods
      per plant. Factor 3 encompassed of only the grain weight. The total factors
      explained 92.9% of the total variance caused in the characters. The grain yield
      was positively and statistically significant correlated with biological yield,
      harvest index, plant height, branches and pods per plant, while it was negatively
      and statistically significant related with reaction to ascochyta blight and grain
      weight. Biological yield, harvest index, plant height and reaction to ascochyta
      blight instead of many selection criteria should previously be evaluated in
      selection to increase the grain yield in chickpea breeding programs. Pods per
      plant should be handed together with and branches per plant. Apart from the other
      selection criteria, the grain weight should solely be evaluated to select large
      grained genotypes.

PMID- 15198712
TI  - Estimates of broad-sense heritability for seed yield and yield criteria in faba
      bean (Vicia faba L.).
AB  - Eight faba bean (Vicia faba L.) genotypes were grown at lowlands of the west
      Mediterranean region of Turkey in order to estimate the broad-sense heritability
      for plant height, number of stems and pods per plant, seed yield, biological
      yield, 100-seed weight, days to flowering and maturity. The heritability for
      plant height, number of stems and pods per plant, seed yield, biological yield,
      100-seed weight, days to flowering and maturity were estimated as 83%, 63%, 43%,
      62%, 52%, 99%, 97% and 97%, respectively. It was found that seed weight was the
      least affected trait across changing environmental conditions and followed by
      days to flowering and maturity. On the other hand, number of pods per plant,
      biological and seed yields and number of stems per plant were the most affected
      traits versus environmental conditions.

PMID- 15198714
TI  - Growth, fecundity and competitive ability of transgenic Trifolium subterraneum
      subsp. subterraneum cv. Leura expressing a sunflower seed albumin gene.
AB  - Ecological risk assessment is an important step in the production and
      commercialisation of transgenic plants. To date, however, most risk assessment
      studies have been performed on crop plants, and few have considered the
      ecological consequences associated with genetic modification of pasture species.
      In this study we compared the growth, yield, population dynamics and competitive
      ability of transgenic Trifolium subterraneum subsp. subterraneum cv. Leura
      (subclover) expressing a nutritive sunflower seed albumin (ssa) gene with the
      equivalent non-transgenic commercial line in a glasshouse competition trial.
      Plants were grown in low-fertility soil typical of unimproved native southeastern
      Australian grasslands. We measured survivorship, seed production rate, seed
      germination rate, seed weight, dry weight yield and the intrinsic rate of
      population increase (lambda) of plants grown in mixtures and monocultures over a
      range of densities (250 to 2000 plants m(-2)), and also determined intragenotypic
      and intergenotypic competition coefficients for each line. There were no
      significant differences between transgenic and non-transgenic plants in any of
      the measured variables except survivorship; transgenic plants had a significantly
      lower survival rate than non-transgenic plants when grown at high densities
      (p<0.01). However, density-dependent effects were observed for all measured
      variables, and in all models plant density affected the response variables more
      than the presence of the transgene. Based on these results, we conclude that the
      ssa gene construct appears to confer no advantage to transgenic T. s.
      subterraneum cv. Leura growing in mixed or pure swards under the fertility and
      density regimes examined in the trial. Our data also suggest that transgenic
      subterranean clover expressing the ssa gene is unlikely to exhibit a competitive
      advantage over associated non-transgenic commercial cultivars when grown in dense
      swards in low-fertility pastures.

PMID- 15198715
TI  - Use of ISSR fingerprints to detect microsatellites and genetic diversity in
      several related Brassica taxa and Arabidopsis thaliana.

PMID- 15198716
TI  - Chromosomal localization of three GGA4 genes using BAC-based FISH mapping: a
      region of conserved synteny between the chicken and human genomes.

PMID- 15198717
TI  - Principles of risk assessment for determining the safety of chemicals: recent
      assessment of residual solvents in drugs and di(2-ethylhexyl) phthalate.
AB  - Risk assessment of chemicals is essential for the estimation of chemical safety,
      and animal toxicity data are typically used in the evaluation process, which
      consists of hazard identification, dose-response assessment, exposure assessment,
      and risk characterization. Hazard identification entails the collection of all
      available toxicity data and assessment of toxicity endpoints based on findings
      for repeated dose toxicity, carcinogenicity or genotoxicity and species
      specificity. Once a review is compiled, the allowable lifetime exposure level of
      a chemical is estimated from a dose-response assessment based on several
      measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed
      adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with
      environmental pollutants) or safety factors (e.g. with food additives) to derive
      a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively.
      These factors include interspecies and individual differences, duration of
      exposure, quality of data, and nature of toxicity such as carcinogenicity or
      neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished
      with mathematical modeling (e.g. linearized multistage model) from the point of
      departure to obtain exposure levels that will be associated with an excess
      lifetime cancer risk of a certain level. Data for levels of chemicals in food,
      water and air, are routinely used for exposure assessment. Finally, risk
      characterization is performed to ensure that the established 'safe' level of
      exposure exceeds the estimated level of actual exposure. These principles have
      led to the evaluation of several existing chemicals. To establish a guideline for
      residual solvents in medicine, the permitted daily exposure (PDE), equivalent to
      TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity
      (malformation) and of N-methylpyrrolidone on the basis of the developmental
      neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of
      testicular toxicity.

PMID- 15198718
TI  - Organ culture of the fetal mouse palate for screening the developmental toxicity
      of chemicals: a validation study.
AB  - Using in vitro organ culture of the fetal mouse palate in a chemically defined
      serumless medium, the toxicity of 24 chemical compounds was investigated.
      Explanted palates of day-12.5 mouse fetuses were exposed for 72 h in vitro to
      various concentrations of each chemical, and the fusion rate and growth
      parameters were compared between the experimental group and respective controls.
      The average rate of palate fusion was 84% in vehicle controls. For compounds that
      are teratogenic in experimental animals in vivo, the fusion rates of palatal
      shelves decreased as the concentration of the test chemicals increased, showing a
      dose-dependent relationship. Palate fusion was inhibited by 11 of the 15 in vivo
      teratogens, and the predictability of in vivo developmental toxicity in this
      culture system was 73%. Cyclophosphamide itself did not inhibit the growth and
      fusion of explanted palates, but supplementation of hepatic S-9 fraction and
      cofactors for a monooxygenase system converted it to a toxic substance, as was
      shown in other in vitro systems. The 50% inhibitory concentration (IC50) value
      calculated based on the fusion rate was also found to be a useful parameter for
      evaluating the developmental toxicity of drugs. The teratogenic risk in the human
      fetus could be assessed by comparing the minimal toxic concentrations of the test
      compound on cultured palates with the maximal plasma level in pregnant women
      under therapeutic conditions and with the plasma concentrations when its minimal
      teratogenic dose is given to pregnant mice. This organ culture system of the
      fetal palate should be useful for screening the developmental toxicity of drugs
      and other environmental agents, and its value should increase when it is used in
      combination with other battery test systems.

PMID- 15198719
TI  - Method of separation and concentration of fetal nucleated red blood cells in
      maternal blood and its application to fetal diagnosis.
AB  - A fetal diagnostic method that is without risk to the embryo has been long
      awaited in the field of gene diagnosis. Establishment of non-invasive fetal
      diagnosis using maternal peripheral blood will greatly contribute to perinatal
      medical care. The lectin method that we have studied and developed selectively
      recovers nucleated red blood cells (NRBC) among fetal cells mixed in maternal
      peripheral blood. Maternal blood, 7 mL, was collected with ethylene diamine
      tetraacetic acid (EDTA) treatment in each week of gestation and subjected to
      preliminary concentration by density centrifugation (Histopaque [Histopaque-1077;
      Sigma Diagnostics, MO, USA], specific gravity: 1.095), and NRBC were separated
      and collected on slide glasses by the lectin method (soybean agglutinin [SBA]: 50
      microg/mL). To investigate selective adhesion of the erythrocyte fraction, the
      SBA concentration was set to 50 microg/mL, and the cells were labeled with CD11a
      and CD33 (anti-white blood cell antibodies) and investigated by flowcytometry.
      Erythrocytes adhered at a high rate (87.0 +/- 9.7%) while the adhesion rates of
      granulocytes, monocytes, and lymphocytes were low, confirming the usefulness of
      the method for separation and recovery of the erythrocyte fraction. When recovery
      of NRBC was investigated using this method, a mean of 6.57 +/- 7.12 cells were
      recovered from 1 mL of maternal blood (May-Gluuwald-Giemsa stain). The number of
      recovered NRBC increased slowly with pregnancy, but differences were not
      significant. To confirm that recovered NRBC were derived from the fetus, NRBC
      were recovered by the lectin method in four patients suspected of 18 trisomy by
      echography and analyzed by fluorescence in situ hybridization. Three
      hybridization signals were detected in NRBC at a high frequency, showing that
      most cells were derived from the fetus and thus, fetal diagnosis may be possible.
      Since the procedure of the lectin method we have developed is simple, and high
      concentration efficiency can be obtained at a low cost, it may be clinically
      applicable.

PMID- 15198720
TI  - Possible association between different congenital abnormalities and use of
      different sulfonamides during pregnancy.
AB  - The objective of the study presented here was to check the debated human
      teratogenic potential of sulfonamide drugs. Five different sulfonamides such as
      sulfamethazine, sulfathiourea, sulfamethoxypyridazine, sulfamethoxydiazine and
      the combination of sulfamethazine-sulfathiourea-sulfamethoxypyridazine were
      differentiated. Cases with congenital abnormalities were compared with their
      matched controls without congenital abnormalities in the population-based large
      data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities
      between 1980 and 1996. Of 38,151 newborn infants without any congenital
      abnormalities (control group), 163 (0.4%) had mothers who were treated with the
      sulfonamides studied during pregnancy, while of 22,843 cases with congenital
      abnormalities, 140 (0.6%) had mothers who were treated with the sulfonamides
      studied during pregnancy. The analysis of cases and matched controls indicated a
      higher rate of cardiovascular malformation (adjusted prevalence odds ratios [POR]
      with 95% CI: 3.5, 1.9-6.4) and clubfoot (adjusted POR with 95% CI: 2.6, 1.1-6.2)
      in infants born to mothers with sulfonamide treatment in the second and third
      months of pregnancy. The detailed analysis of different sulfonamides showed a
      possible association between cardiovascular malformations (adjusted POR with 95%;
      CI: 6.5, 2.6-15.9), particularly ventricular septal defect (17.1, 1.3-141.1) and
      sulfamethoxydiazine during the second and third months of pregnancy. In addition,
      a possible association was found between clubfoot and sulfathiourea, both during
      the entire pregnancy (adjusted POR with 95% CI: 2.3, 1.2-4.3) and in the second
      and third months of gestation (3.9, 1.1-13.8). Thus, maternal treatment of
      sulfamethoxydiazine may cause ventricular septal defect, while sulfathiourea may
      induce clubfoot; however, further studies are needed to verify or reject these
      associations.

PMID- 15198721
TI  - Prenatal trisomy 21 screening using the Lens culinaris agglutinin-reactive alpha
      fetoprotein ratio.
AB  - For the purpose of improving the clinical efficacy of alpha-fetoprotein (AFP)-L3%
      in prenatal screening for trisomy 21, we calculated the multiple of the median
      (MoM) of AFP-L3% (L3 MoM) and the ratio of L3 MoM to AFP MoM (L3 MoM/AFP MoM) in
      maternal serum. Maternal serum samples from 1822 women (maternal age 37.3 +/- 3.8
      years, and weeks of gestation 16.0 +/- 1.0; mean +/- SD) with unaffected
      pregnancies and 28 women (37.6 +/- 4.6 years, 16.6 +/- 3.1) pregnant with of
      trisomy 21 fetuses were obtained. The AFP concentration and AFP-L3% in maternal
      serum were measured using a liquid-phase binding assay. The areas under the
      receiver operating characteristic curves (AUCs) of AFP MoM, AFP-L3%, L3 MoM, and
      L3 MoM/AFP MoM were 0.750, 0.868, 0.949 and 0.946, respectively. The AUCs of L3
      MoM and L3 MoM/AFP MoM were significantly higher than AFP-L3% (P < 0.05) and AFP
      MoM (P < 0.0005). However, no statistical difference was observed between the
      AUCs of L3 MoM and L3 MoM/AFP MoM. In conclusion, the L3 MoM should be an
      effective replacement for AFP-L3% in prenatal trisomy 21 screening.

PMID- 15198722
TI  - Effects of pure 2,4-dichlorophenoxyacetic acid on cultured rat embryos.
AB  - 2,4-dichlorophenoxyacetic acid (2,4-D), a plant growth regulator, has been used
      worldwide as a herbicide. Previously we evaluated the prenatal developmental
      effects of 2,4-D by feeding it to pregnant rats and found that it is maternally
      toxic and embryolethal, and it induces urogenital malformations in rat fetuses.
      In the study presented here, we investigated the effects of pure 2,4-D on rat
      embryos in whole embryo culture. Rat embryos on day 9.5 of gestation were
      cultured for 48 h at several concentration levels with pure 2,4-D (50-500
      microg/mL). 2,4-D caused a concentration-related increase in the incidence of
      each malformation. Significant decreases in the number of somites were observed
      at a concentration of 100 microg/mL or more. At the concentration of 100
      microg/mL, there was normal yolk sac circulation. This result suggests that 2,4-D
      has a detrimental effect on somite development and directly damages developing
      embryos.

PMID- 15198723
TI  - No sex differences in 18 trisomy births in the Kanagawa Birth Defects Monitoring
      Program.
AB  - Trisomy 18 is a common chromosome anomaly. The predominance of female infants is
      widely accepted in the literature. This study clarified no sex differences in 18
      trisomy births.

PMID- 15198724
TI  - Peters' anomaly with bilateral perisylvian polymicrogyria and abdominal
      calcification.
AB  - We report a neonatal case of Peters' anomaly with bilateral perisylvian
      polymicrogyria and abdominal calcification. The male infant was born after a
      normal labor. Bilateral central corneal opacities with iridocorneal strands
      indicated Peters' anomaly. The X-ray and abdominal computed tomography
      demonstrated multiple calcifications beneath the diaphragma around the liver and
      the spleen. TORCH serology was negative. Intracranial calcification was not
      detected. Brain magnetic resonance imaging demonstrated bilateral perisylvian
      polymicrogyria. Abdominal calcification was suspected to be related to vascular
      disruption. Bilateral perisylvian polymicrogyria has been thought to result from
      ischemic events such as intrauterine hypotension or vascular occlusions. Based on
      these considerations, we conclude that a vascular disruption sequence may an
      important pathogenetic mechanism of Peters' anomaly.

PMID- 15198726
TI  - Immune complications of B-cell chronic lymphatic leukaemia.

PMID- 15198725
TI  - Bone marrow architecture in acute myeloid/erythroid leukaemia.

PMID- 15198727
TI  - Leukaemia -- a developmental perspective.
AB  - Leukaemia is characterized by the accumulation of malignant haematopoietic
      precursors. Recent studies have revealed that acquired alterations in genes that
      regulate normal haematopoiesis are frequently detected in leukaemia. The
      progression to leukaemia depends on additional mutations that promote the
      survival of developmentally arrested cells. This review describes three examples
      of this general paradigm of leukaemogenesis: RUNX1 abnormalities in acute
      leukaemias, GATA1 mutations in the leukaemias of Down syndrome, and SCL and LMO2
      ectopic expression in T cell acute lymphoblastic leukaemia.

PMID- 15198728
TI  - Guidelines for the use of fresh-frozen plasma, cryoprecipitate and
      cryosupernatant.
AB  - The indications for transfusing fresh-frozen plasma (FFP), cryoprecipitate and
      cryosupernatant plasma are very limited. When transfused they can have
      unpredictable adverse effects. The risks of transmitting infection are similar to
      those of other blood components unless a pathogen-reduced plasma (PRP) is used.
      Of particular concern are allergic reactions and anaphylaxis, transfusion-related
      acute lung injury, and haemolysis from transfused antibodies to blood group
      antigens, especially A and B. FFP is not indicated in disseminated intravascular
      coagulation without bleeding, is only recommended as a plasma exchange medium for
      thrombotic thrombocytopenic purpura (for which cryosupernatant is a possible
      alternative), should never be used to reverse warfarin anticoagulation in the
      absence of severe bleeding, and has only a very limited place in prophylaxis
      prior to liver biopsy. When used for surgical or traumatic bleeding, FFP and
      cryoprecipitate doses should be guided by coagulation studies, which may include
      near-patient testing. FFP is not indicated to reverse vitamin K deficiency for
      neonates or patients in intensive care units. PRP may be used as an alternative
      to FFP. In the UK, PRP from countries with a low bovine spongiform encephalopathy
      incidence is recommended by the Departments of Health for children born after 1
      January 1996. Arrangements for limited supplies of single donor PRP of non-UK
      origin are expected to be completed in 2004. Batched pooled commercially prepared
      PRP from donors in the USA (Octaplas) is licensed and available in the UK. FFP
      must be thawed using a technique that avoids risk of bacterial contamination.
      Plastic packs containing any of these plasma products are brittle in the frozen
      state and must be handled with care.

PMID- 15198729
TI  - Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according
      to antigen-driven selection identifies subgroups with different prognosis and
      usage of the canonical somatic hypermutation machinery.
AB  - Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgV(H)
      genes have a better prognosis than unmutated (UM) cases. We analysed the IgV(H)
      mutational status of B-CLL according to the features of a canonical somatic
      hypermutation (SHM) process, correlating this data with survival. In a series of
      141 B-CLLs, 124 cases were examined for IgV(H) gene per cent mutations and
      skewing of replacement/silent mutations in the framework/complementarity
      determining regions as evidence of antigen-driven selection; this identified
      three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven
      selection, not significantly mutated (nsM) and UM, without such evidence and
      IgV(H) gene per cent mutations above or below the 2% cut-off. sM B-CLL patients
      had longer survival within the good prognosis subgroup that had more than 2%
      mutations of IgV(H) genes. sM, nsM and UM B-CLL were also characterized for the
      biased usage of IgV(H) families, intraclonal IgV(H) gene diversification,
      preference of mutations to target-specific nucleotides or hotspots, and for the
      expression of enzymes involved in SHM (translesion DNA polymerase zeta and eta
      and activation-induced cytidine deaminase). These findings indicate the
      activation of a canonical SHM process in nsM and sM B-CLLs and underscore the
      role of the antigen in defining the specific clinical and biological features of
      B-CLL.

PMID- 15198730
TI  - Most cases of primary salivary mucosa-associated lymphoid tissue lymphoma are
      associated either with Sjoegren syndrome or hepatitis C virus infection.
AB  - Salivary gland mucosa-associated lymphoid tissue (MALT) lymphomas (SGML) are
      rare, as are data concerning their behaviour. We analysed clinical features at
      presentation, particularly the association with Sjoegren syndrome (SS) and
      hepatitis C virus (HCV) infection, and outcome in 33 cases of SGML diagnosed
      between March 1985 and April 2003. There were five males and 28 females, with a
      median age of 61 years. At presentation, 12/33 (36%) had multiple salivary glands
      or mucosal involvement and four had bone marrow infiltration. Ann Arbor stage was
      IE in 15 (46%), IIE in four (12%) and IV in 14 patients (42%). Fifteen patients
      had a history of SS (46%), two of other autoimmune diseases, seven of HCV
      infection. No case had both SS and HCV. Of the 29 treated patients, 17 received
      surgery or local radiotherapy; 69% achieved complete remission. Histological
      transformation occurred in four (12%). Five patients died (three of lymphoma, two
      of unrelated causes). The 5 year-overall survival (OS), cause-specific survival
      and progression-free survival was 85 +/- 8%, 94 +/- 6% and 65 +/- 10%
      respectively. Overall, the disease course was indolent, despite the advanced
      stage at diagnosis, and local therapy often appeared to be adequate. The only
      prognostic factors influencing OS were histological transformation and age. The
      close association of SGML with either autoimmune diseases or HCV infection in our
      series (73%) confirms their possible role in the pathogenesis of these lymphomas.

PMID- 15198731
TI  - Mutational analysis of the IkappaBalpha gene in activated B cell-like diffuse
      large B-cell lymphoma.
AB  - The lymphoma cells of the activated B cell-like (ABC-) subtype of diffuse large B
      cell lymphoma (DLBCL) show constitutive activity of the transcription factor,
      nuclear factor kappaB (NFkappaB). We sought to determine whether mutations in the
      IkappaBalpha gene - the predominant inhibitor of NFkappaB - might play a role in
      the pathogenesis of ABC-DLBCL. All exons of the IkappaBalpha gene were directly
      sequenced from 10 cases of immunohistochemically classified ABC-DLBCL and from
      six non-ABC-DLBCL cases. Two novel polymorphisms were identified, based on their
      presence in tumour as well as non-tumour DNA of the respective patients: a
      duplication near the transcriptional start and a single nucleotide exchange in
      exon 1. A somatic missense mutation was identified in exon 3, in addition to a
      wild-type sequence in only one ABC-DLBCL case. Thus, also in this case no clonal
      biallelic inactivating mutation was present in the IkappaBalpha gene. We conclude
      that mutations in the IkappaBalpha gene do not play a dominant role in the
      pathogenesis of ABC-DLBCL.

PMID- 15198732
TI  - Characteristic expansion of CD45RA CD27 CD28 CCR7 lymphocytes with stable natural
      killer (NK) receptor expression in NK- and T-cell type lymphoproliferative
      disease of granular lymphocytes.
AB  - We analysed the cell surface expression of chemokine receptors and natural killer
      receptors (NKRs) in addition to conventional T- and natural killer (NK)-cell
      markers in patients with lymphoproliferative disease of granular lymphocytes
      (LDGL), and compared results between NK- and T-LDGL subgroups. The subjects of
      this study were 15 LDGL patients: four NK-LDGL and 11 T-LDGL [six CD8(+) T-cell
      receptor (TCR) alphabeta(+), four CD4(+) TCRalphabeta(+) and one CD8(+)
      TCRgammadelta(+)] cases. Flow cytometric analysis showed that the expanding cells
      had a common phenotype, CD45RA(+) CD27(-) CD28(-) CCR7(-), in NK- and T-LDGL
      patients irrespective of differences in TCR status. There were no marked
      differences in the expression patterns of chemokine receptors between NK- and T
      LDGL patients. Although restricted NKR subsets were expressed on both NK- and T
      large granular lymphocytes (LGLs), CD94 was the most widely expressed marker.
      These findings may be unique to cells of LDGL cases, because normal CD56(dim) NK
      cells frequently express killer cell immunoglobulin-like receptors. Furthermore,
      analysis of NKR expression was repeated over an interval of more than 6 months,
      and fluctuations of NKR repertoire in the LGL clones were minimal.

PMID- 15198733
TI  - Clonal haemopoiesis may occur after conventional chemotherapy and is associated
      with accelerated telomere shortening and defects in the NQO1 pathway; possible
      mechanisms leading to an increased risk of t-AML/MDS.
AB  - The molecular pathogenesis of therapy-related acute myeloid
      leukaemia/myelodysplastic syndrome (t-AML/MDS) remains uncertain. However, clonal
      haemopoiesis may develop following stem cell transplantation and precede the
      development of t-AML/MDS. Moreover, accelerated telomere shortening may be
      induced by replicative stress or oxidative damage, leading to genomic
      instability, and inactivating polymorphisms of the gene encoding NADPH-quinone
      oxidoreductase (NQO1) are more frequently observed in patients with t-AML. We
      studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients
      receiving conventional chemotherapy for non-myeloid malignancies. Clonal
      haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was
      reduced in patients following chemotherapy (n = 52) compared with controls (n =
      42) (P < 0.001), particularly in those with clonal haemopoiesis (P < 0.002).
      Whilst there was a trend towards telomere shortening in control subjects
      polymorphic for NQO1-187Ser (n = 12), chemotherapy-exposed patients polymorphic
      for the NQO1-187Ser allele (n = 29) had significantly shorter telomeres (P <
      0.001). Furthermore, chemotherapy-treated patients with the NQO1-187Ser,
      polymorphism were more likely to develop clonal haemopoiesis than patients with
      wild type NQO1 (odds ratio = 7; 1.16-42.6). We conclude that a switch to clonal
      haemopoiesis may occur after conventional chemotherapy and lead to accelerated
      telomere shortening. Patients with the NQO1-187Ser polymorphism have an increased
      risk of developing both clonal haemopoiesis and telomere shortening, which may
      partly explain the predisposition to t-AML in NQO1-187Ser null individuals.

PMID- 15198734
TI  - Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32)
      in multiple myeloma.
AB  - The t(4;14)(p16;q32) translocation seen in c. 18% of newly diagnosed multiple
      myeloma (MM) cases, results in FGFR3 activation and creation of an IGH/MMSET
      fusion transcript. We have recently shown that FGFR3 is activated in only 75% of
      t(4;14)(+) cases, suggesting that alternative genes near the breakpoint may be
      involved in the transforming event. The gene, TACC3, located just 50 kb telomeric
      of FGFR3, with transforming capacity, therefore represented a candidate gene.
      Using a real-time quantitative polymerase chain reaction-based approach on a
      cohort of 54 patients, we found a statistically significant, twofold increase in
      TACC3 expression in t(4;14)(+) cases. TACC3, MMSET and p21 values were positively
      correlated in all cases and, of particular interest, six patient samples [three
      t(4;14)(-), three t(4;14)(+)] samples showed a joint up-regulation of TACC3,
      MMSET and p21. Although a poor prognosis is linked with elevated MMSET
      expression, an extended follow-up period will be required to evaluate the
      significance of elevated TACC3 and p21 expression in this subgroup of MM.

PMID- 15198735
TI  - Blood dendritic cells in patients with acute lymphoblastic leukaemia.
AB  - Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play a key role in the
      initiation of immune responses. In this study, we show a severe reduction of MDCs
      and PDCs in patients with B lineage acute lymphoblastic leukaemia (B-ALL; P =
      0.01 vs. controls). DCs from patients with T lineage ALL (T-ALL) were
      quantitatively and functionally comparable to healthy donors, as demonstrated by
      secretion of interleukin (IL)-12p70 and interferon-alpha. In vitro, the
      circulating CD34(+) fraction of B-ALL cases did not generate either CD1a(+) MDCs
      or PDCs, suggesting that DC development is probably affected in B-ALL, but not in
      T-ALL.

PMID- 15198736
TI  - Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T
      cell leukaemia/lymphoma cells.
AB  - Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive neoplastic disease that
      usually exhibits a CD4(+)CD25(+) phenotype. Regulatory T cells (Treg), which
      suppress T-cell effector function, are characterized by the co-expression of CD4
      and CD25. We analysed the expression of forkhead/winged helix transcription
      factor (FoxP3), a specific marker that is important for the function of Treg, on
      ATLL cells from 17 patients (peripheral blood, n = 8; lymph node, n = 9). Real
      time polymerase chain reaction and immunostaining detected FoxP3 expression in 10
      ATLL cases, but was relatively down-regulated compared with Treg from normal
      subjects. These results indicate the association of ATLL and Treg.

PMID- 15198737
TI  - Haemostatic and inflammatory biomarkers in advanced chronic heart failure: role
      of oral anticoagulants and successful heart transplantation.
AB  - Advanced chronic heart failure (CHF) is associated with abnormal haemostasis and
      inflammation, but it is not known how these abnormalities are related, whether
      they are modified by oral anticoagulants (OAT), or if they persist after
      successful heart transplantation. We studied 25 patients with CHF (New York Heart
      Association class IV, 10 of whom underwent heart transplantation) and 25 age- and
      sex-matched healthy controls by measuring their plasma levels of prothrombin
      fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT) complexes, tissue
      plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), D-dimer,
      factor VII (FVII), fibrinogen, von Willebrand factor (VWF), tumour necrosis
      factor (TNF), soluble TNF receptor II (sTNFRII), interleukin 6 (IL-6), soluble
      intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion
      molecule-1 (sVCAM-1), endothelial-selectin (E-selectin) and thrombomodulin. CHF
      patients had higher plasma levels of TAT, D-dimer, t-PA, fibrinogen, VWF, TNF, IL
      6, sTNFRII, sVCAM-1 (P = 0.0001), sICAM-1 (P = 0.003) and thrombomodulin (P =
      0.007) than controls. There were significant correlations (r = 0.414-0.595)
      between coagulation, fibrinolysis, endothelial dysfunction and inflammation
      parameters, which were lower in those patients treated with OATs. Heart
      transplantation led to reductions in fibrinogen (P = 0.001), VWF (P = 0.05), D
      dimer (P = 0.05) and IL-6 levels (P = 0.05), but all the parameters remained
      significantly higher (P = 0.01-0.0001) than in the controls. Advanced CHF is
      associated with coagulation activation, endothelial dysfunction and increased
      proinflammatory cytokine levels. Most of these abnormalities parallel each other,
      tend to normalize in patients treated with OATs and, although reduced, persist in
      patients undergoing successful heart transplantation, despite the absence of
      clinical signs of CHF.

PMID- 15198738
TI  - Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia.
AB  - A new automated method to reliably quantify reticulated platelets, expressed as
      the immature platelet fraction (IPF), has been developed utilizing the XE-2100
      blood cell counter with upgraded software (Sysmex, Kobe, Japan). The IPF is
      identified by flow cytometry techniques and the use of a nucleic acid specific
      dye in the reticulocyte/optical platelet channel. The clinical utility of this
      parameter was established in the laboratory diagnosis of thrombocytopenia due to
      increased peripheral platelet destruction, particularly autoimmune
      thrombocytopenic purpura (AITP) and thrombotic thrombocytopenic purpura (TTP).
      Reproducibility and stability results over 48 h were good. An IPF reference range
      in healthy individuals was established as 1.1-6.1%, with a mean of 3.4%. Patients
      in whom platelet destruction might be abnormal, were studied and two of these
      patients followed serially during the course of treatment. The IPF was raised in
      several disease states. The most significant increases in IPF values were found
      in patients with AITP (mean 22.3%, range 9.2-33.1%) and acute TTP (mean 17.2%,
      range 11.2-30.9%). Following patients during treatment demonstrated that as the
      platelet count recovered the IPF% fell. These results show that a rapid,
      inexpensive automated method for measuring the IPF% is feasible and should become
      a standard parameter in evaluating the thrombocytopenic patient.

PMID- 15198739
TI  - Response to desmopressin of factors XI, X and V in patients with factor VIII
      deficiency and von Willebrand disease.
AB  - Desmopressin [1-deamino-8-d-arginine vasopressin (DDAVP)] has been successfully
      used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia
      A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and
      may represent an effective treatment for mild FXI deficiency. We assessed the
      DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V
      coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33
      individuals with VWD or MHA. DDAVP did not produce a clinically significant
      increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean +/- SD FXI:C pre
      DDAVP (time 0) and at 1 h post-DDAVP was 90.7 (+/-22.9) U/dl and 92.1 (+/-20.9)
      U/dl, respectively. The mean (+/-SD) FXI:Ag at time 0 and 1 h was 92.2 (+/-20.1)
      U/dl and 89.9 (+/-21.3) U/dl, respectively. There was a small reduction at 1 h
      post-DDAVP in both FV:C, from 101.8 (+/-20.9) U/dl to 97.2 (+/-21.4) U/dl (P <
      0.001), and FX:C from 103 (+/-19.5) U/dl to 98.8 (+/-18.7) U/dl (P < 0.001). No
      significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post
      DDAVP. This study failed to demonstrate a clinically significant increase in the
      levels of FXI, FX or FV following administration of DDAVP.

PMID- 15198740
TI  - Two novel mutations in severe factor VII deficiency.
AB  - We have characterized the molecular defect in two families with severe factor VII
      (FVII) deficiency. In family I, the proband was found to be homozygous for a
      novel 18 bp deletion in exon 8 (g.10896-10913del) resulting in the in-frame
      deletion of six amino acids in the serine protease domain. Molecular modelling
      suggests the deletion is likely to disrupt folding of the FVII molecule. The
      reduced FVII antigen (21 U/dl) and negligible activity (0.4 U/dl) in the
      patient's plasma indicated that the deletion affected both the
      secretion/stability and function of the mutant protein. In family II, the proband
      was found to be a compound heterozygote for a novel missense mutation (g.7884G>A;
      FVII G117R) in exon 5 encoding the EGF2 domain of FVII and a nonsense mutation
      (g.8960C>T; FVII R152X) in exon 6. Extensive sequence comparison in a wide
      evolutionary context suggested that the Gly117 residue is critical for structure
      of FVII. The grossly reduced FVII antigen (1.1 U/dl) and activity (0.4 U/dl)
      plasma values indicate the mutation primarily affected the folding/secretion or
      stability of the protein.

PMID- 15198741
TI  - A mouse model to study organ homing behaviour of haemopoietic progenitor cells
      reveals high selectivity but low efficiency of multipotent progenitors to home
      into haemopoietic organs.
AB  - To study the homing behaviour of an enriched multipotent primitive haemopoietic
      progenitor cell (HPC) population in mice, undifferentiated murine factor
      dependent multipotent HPCs (FDCP-mix), stably transfected with the green
      fluorescence protein gene, were intravenously injected into congenic mice. After
      2 or 24 h, cell suspensions were prepared from bone marrow, spleen, lung, liver,
      muscle, colon, kidney, brain or blood of the mice and analysed by flow cytometry.
      Using direct quantifiable determination of total HPC numbers homed per organ and
      a method to estimate the degree of organ contamination by HPC that were present
      in blood vessels within the organs before preparation, the highest absolute
      numbers of HPC were detected in the liver and lungs at 2 h but this was sharply
      decreased at 24 h, whereas HPC selectively accumulated in the bone marrow and
      spleen at 24 h after transplantation. Only a few HPC were detected in other
      organs. The seeding efficiency of homed FDCP-mix HPC to the bone marrow and
      spleen was approximately 1.5% and ranged between that of primary whole bone
      marrow cells and lineage-depleted freshly isolated bone marrow cells.
      Pretreatment of HPC with inhibitors of signal transduction indicated that short
      term homing of multipotent HPC into haemopoietic organs is an active process
      requiring co-ordinated intracellular signalling through Rho family small GTPases
      and protein kinases. Thus, short-term homing of FDCP-mix HPC into haemopoietic
      organs is of low efficiency but high selectivity, and provides a system to
      analyse the mechanisms and manipulation of primitive HPC which saves large
      numbers of donor animals.

PMID- 15198742
TI  - Renin-angiotensin system expression in rat bone marrow haematopoietic and stromal
      cells.
AB  - The existence of a bone marrow renin-angiotensin system (RAS) is evidenced by the
      association of renin, angiotensin converting enzyme (ACE), and angiotensin (Ang)
      II and its AT(1) and AT(2) receptors with both normal and disturbed
      haematopoiesis. The expression of RAS components by rat unfractionated bone
      marrow cells (BMC), haematopoietic-lineage BMC and cultured marrow stromal cells
      (MSC) was investigated to determine which specific cell types may contribute to a
      local bone marrow RAS. The mRNAs for angiotensinogen, renin, ACE, and AT(1a) and
      AT(2) receptors were present in BMC and in cultured MSC; ACE2 mRNA was detected
      only in BMC. Two-colour flow fluorocytometry analysis showed immunodetectable
      angiotensinogen, ACE, AT(1) and AT(2) receptors, and Ang II, as well as binding
      of Ang II to AT(1) and AT(2) receptors, in CD4(+), CD11b/c(+), CD45R(+) and
      CD90(+) BMC and cultured MSC; renin was found in all cell types with the
      exception of CD4(+) BMC. Furthermore, Ang II was detected by radioimmunoassay in
      MSC homogenates as well as conditioned culture medium. The presence of Ang II
      receptors in both haematopoietic-lineage BMC and MSC, and the de novo synthesis
      of Ang II by MSC suggest a potential autocrine-paracrine mechanism for local RAS
      mediated regulation of haematopoiesis.

PMID- 15198743
TI  - Efficacy and safety of two different rG-CSF preparations in the treatment of
      patients with severe congenital neutropenia.
AB  - In patients with severe congenital neutropenia (SCN), the absolute neutrophil
      count (ANC) is raised during treatment with granulocyte colony-stimulating factor
      (G-CSF), resulting in a marked reduction of bacterial infection. Some patients,
      however, still have recurrent but less severe bacterial infections and severe
      periodontal infections. As it has been suggested that the biological activity of
      glycosylated recombinant human G-CSF (rHuG-CSF, i.e. lenograstim) is higher than
      the non-glycosylated form (i.e. filgrastim), we compared the two given in
      equimolar doses. Seven SCN patients participated in an open, randomized, double
      crossover study comprising 60 weeks, with four 12-week periods when the two drugs
      alternated after a 12-week run-in-period. The mean ANC values, sampled every
      second week, were 5.1 x 10(9)/l during filgrastim treatment and 4.2 x 10(9)/l
      during lenograstim treatment (P = 0.042). The ANC levels were also significantly
      higher during filgrastim treatment, when comparing each complementary pair of ANC
      measurements (P = 0.011) as well as the mean ANC values during each 12-week
      treatment period (P = 0.033). There were no differences regarding the frequency
      of infection, antibiotic treatment, gingival bleeding and the number of hospital
      admissions between the groups. We conclude that filgrastim and lenograstim
      displayed equal clinical efficacy, but that ANC levels were higher during
      filgrastim treatment, when administered in equimolar doses.

PMID- 15198745
TI  - Is fresh frozen plasma clinically effective? A systematic review of randomized
      controlled trials.
AB  - Summary Randomized controlled trials of good quality are a recognized means to
      robustly assess the efficacy of interventions in clinical practice. A systematic
      identification and appraisal of all randomized trials involving fresh frozen
      plasma (FFP) has been undertaken in parallel to the drafting of the updated
      British Committee for Standards in Haematology guidelines on the use of FFP. A
      total of 57 trials met the criteria for inclusion in the review. Most clinical
      uses of FFP, currently recommended by practice guidelines, are not supported by
      evidence from randomized trials. In particular, there is little evidence for the
      effectiveness of the prophylactic use of FFP. Many published trials on the use of
      FFP have enrolled small numbers of patients, and provided inadequate information
      on the ability of the trial to detect meaningful differences in outcomes between
      the two patient groups. Other concerns about the design of the trials include the
      dose of FFP used, and the potential for bias. No studies have taken adequate
      account of the extent to which adverse effects might negate the clinical benefits
      of treatment with FFP. There is a need to consider how best to develop new trials
      to determine the efficacy of FFP in different clinical scenarios to provide the
      evidence base to support national guidelines for transfusion practice. Trials of
      modified FFP (e.g. pathogen inactivated) are of questionable value when there is
      little evidence that the standard product is an effective treatment.

PMID- 15198744
TI  - Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic
      assays.
AB  - Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, acquired disorder of
      blood cells caused by mutation of the phosphatidylinositol glycan class A (PIG-A)
      gene. The disease often manifests with haemoglobinuria, peripheral blood
      cytopenias, and venous thrombosis. The natural history of PNH has been documented
      in retrospective series; but there has only been one study that correlated the
      more sensitive and specific flow cytometric assays that have become available in
      the last decade with severe symptoms associated with PNH. In a retrospective
      analysis of 49 consecutive patients with PNH evaluated at Johns Hopkins, large
      PNH clones were associated with an increased risk for thrombosis as well as
      haemoglobinuria, abdominal pain, oesophageal spasm, and impotence. Of the 14
      (29%) patients that developed thrombosis, nine died; six of these from
      complications related to thromboses. According to logistic regression modelling,
      for a 10% change in PNH clone size, the odds ratio for risk of thrombosis was
      estimated to be 1.64. No patient with <61% PNH granulocytes developed a
      thrombosis, whereas 12 of 22 patients (54.5%) with > or =61% PNH granulocytes
      manifested with thrombosis. These data not only confirm that the size of the PNH
      clone correlates with the risk for thrombosis, but they also suggest a
      correlation of PNH clone size to more symptomatic PNH.

PMID- 15198746
TI  - Improved extension of platelet storage in a polyolefin container with higher
      oxygen permeability.
AB  - This study evaluated a newly developed polyolefin bag, which has a 50%/m(2)
      higher oxygen permeability to extend the shelf-life of platelets. Single-donor
      aphaeresis platelets were pooled, separated equally into two bags, PO-80 (0.8 l
      capacity) and KBP-PO (1 l capacity) for control, and stored in plasma for up to 7
      d. Platelet biochemical and functional parameters were monitored in bags
      containing high (4.2 x 10(11)/250 ml/bag, n = 9) and low (2.0 x 10(11)/200
      ml/bag, n = 3) concentrations of platelets over the storage period. After 7 d of
      storage, the PO-80 bags containing high concentrations of platelets had a better
      pH (mean pH 6.74) than those stored in KBP-PO (pH 6.32, P < 0.01); none of the
      nine PO-80 bags with a high platelet concentration had a pH below 6.2, compared
      with four of nine controls (P < 0.05). Similarly, lactate values were 20.19
      mmol/l and 28.09 mmol/l respectively (P < 0.05). Aerobic metabolism was
      maintained better with greater O(2) consumption and less lactate generation in
      high-platelet concentration PO-80 bags than in the control bags. A significant
      difference was also found in pH, pCO(2) and lactate levels between the two bags
      containing low concentrations of platelets during the 7-d period. The in vitro
      characteristics of platelets declined less over 7 d when stored in a higher
      oxygen permeable container than in a marketed bag.

PMID- 15198747
TI  - Gender-specific disease modification by NOS3.

PMID- 15198751
TI  - Evidence-based obstetric and gynaecologic diagnosis: the STARD checklist for
      authors, peer-reviewers and readers of test accuracy studies.

PMID- 15198752
TI  - Preventing postnatal depression in mothers of very preterm infants: a randomised
      controlled trial.
AB  - OBJECTIVE: To test whether a cognitive-behaviour therapy intervention program
      reduces the prevalence of depression during the first postnatal year in mothers
      of very preterm babies. DESIGN: Prospective, single blind, randomised, controlled
      study. SETTING: Perinatal centre in Western Australia. PARTICIPANTS: One hundred
      and ninety-nine out of 673 English-speaking mothers of infants admitted to the
      neonatal unit. INTERVENTION: A six-session cognitive-behaviour therapy
      intervention program provided by a research midwife between weeks two and six
      after birth. Women in the control group received standard care. MAIN OUTCOME
      MEASURES: Depression and anxiety disorders occurring in the first year assessed
      by a clinical psychologist at structured interview using the Schedule for
      Affective Disorders and Schizophrenia (SADS) at 2 weeks, 2, 6 and 12 months.
      RESULTS: One hundred and one women were randomised to the intervention group and
      98 to the control group. Fifty-four mothers (27%) in the trial were diagnosed
      with minor or major depression in the 12 months following very preterm delivery,
      29 (29%) in the intervention group and 25 (26%) in the control group (relative
      risk 1.1 [95% CI 0.80-1.5]). There were no differences in the time of onset or
      the duration of the episodes of depression between the groups. Overall, 74
      mothers (37%) of the 199 met criteria for a diagnosis of psychological morbidity
      during the first year. CONCLUSIONS: Our intervention program did not alter the
      prevalence of depression in these mothers. Rates of depression and stress
      reactions are high in these mothers.

PMID- 15198754
TI  - The effects of intrapartum hypoxia on the fetal QT interval.
AB  - BACKGROUND: The morphology of the fetal ECG complex provides information on the
      fetal condition during labour, such as the ST segment and T-wave configuration.
      We hypothesised that the intrapartum fetal QT interval may provide additional
      information on the condition of the fetus, as it is known that the QT interval
      reacts to situations of stress and exercise. DESIGN: Retrospective study.
      SETTING: Data were substracted from a European community multicentre trial.
      METHODS: The intrapartum QT interval was measured in 68 fetuses who were acidemic
      at birth (pH <7.05 and BD (ecf) >12 mmol/L) and in a control group of similar
      size. All of these cases were monitored by STAN S21. Measurements were performed
      at the start of the recording at baseline heart rate, during variable
      decelerations and at the end of the recording. The QTc was calculated using
      Bazett's formula: QT/ radical RR. The intervals were compared using the Wilcoxon
      signed ranks test. MAIN OUTCOME MEASURES: Fetal QT interval, and the corrected QT
      interval: QTc. RESULTS: In the acidemic fetuses, there was a significant
      shortening of the QTc interval at the end of the recording compared with the
      start of the recording (397 ms at the end vs 359.3 ms at start; P < 0.001), in
      association with a significantly lowered heart rate (136.3 vs 110.9 bpm, P <
      0.001). Measurements of QT and QTc during variable decelerations at the start and
      end of the recording also showed a shortening of the QT interval (301.9 vs 273.3
      ms, P< or = 0.001) and QTc interval (381.6 vs 340.3, P < 0.001), and this was not
      dependent on heart rate. In the control cases, no differences in FHR, QT and QTc
      intervals were present. CONCLUSIONS: In intrapartum hypoxia, resulting in
      metabolic acidosis, a significant shortening of the fetal QT and QTc is present,
      irrespective of changes in heart rate. In control cases, this shortening does not
      occur. The intrapartum fetal QT interval may therefore provide additional
      information on the condition of the fetus.

PMID- 15198753
TI  - A double blinded randomised placebo-controlled study of intramuscular pethidine
      for pain relief in the first stage of labour.
AB  - OBJECTIVE: It has recently been suggested that systemic pethidine is ineffective
      in relieving labour pain. This study aims to evaluate the analgesic efficacy of
      pethidine in labour. DESIGN: This is a double blinded randomised placebo
      controlled study. SETTING: Labour suite, Prince of Wales Hospital, Hong Kong.
      Population Fifty normal Chinese pregnant women in early labour. METHODS: We
      planned to randomise 112 women in early labour to receive either intramuscular
      pethidine 100 mg or normal saline when they requested analgesia. An interim
      analysis was performed at sample size 50. MAIN OUTCOME MEASURES: The primary
      outcome assessed was the visual analogue scale (VAS) pain score after 30 minutes.
      RESULTS: The study was terminated after recruitment of the first 50 women when
      planned interim analysis showed a significantly greater reduction of VAS pain
      score in the pethidine group (P= 0.009). The median difference in VAS pain score
      between the two groups at 30 minutes was -17 [95% CI -30 to -4]. Mean time to
      first subsequent request for analgesia was greater in the pethidine group (232
      minutes, 95% CI 135 to 329 minutes) compared with the control group (75 minutes,
      95% CI 54 to 95 minutes). Eight women (32%) in the pethidine group needed no
      further analgesia vs one woman (4%) in the control group (P= 0.011). Women in the
      pethidine group gave greater scores for sedation and satisfaction. Neonatal
      outcome was similar. CONCLUSIONS: Systemic pethidine was more effective at
      relieving labour pain than placebo. Its analgesic effect, however, was modest.

PMID- 15198755
TI  - Myo-inositol, glucose and zinc status as risk factors for non-syndromic cleft lip
      with or without cleft palate in offspring: a case-control study.
AB  - OBJECTIVE: To investigate myo-inositol, glucose and zinc status in mothers and
      their infants on cleft lip with or without cleft palate risk (CLP). DESIGN: Case
      control study. SETTING: University Medical Centre Nijmegen, the Netherlands.
      POPULATION: Eighty-four mothers and their CLP child and 102 mothers and their
      healthy child. METHODS: Venous blood samples were obtained to determine serum myo
      inositol and glucose and red blood cell zinc concentrations in mothers and
      children. Geometric means were calculated and compared between the groups. The
      blood parameters were dichotomised with cutoff points based on control values,
      <P10 for myo-inositol and zinc concentrations and >P90 for glucose
      concentrations. MAIN OUTCOME MEASURES: Geometric means (P5-P95) and odds ratios
      (95% confidence intervals). RESULTS: The CLP children (P= 0.003) and their
      mothers (P= 0.02) had significantly lower red blood cell zinc concentrations than
      controls. A low maternal serum myo-inositol concentration (<13.5 micromol/L) and
      a low red blood cell zinc concentration (<189 micromol/L) increased CLP risk
      [odds ratio 3.0 (95% CI 1.2-7.4) and 2.0 (95% CI 0.8-4.8), respectively].
      Children with low myo-inositol (<21.5 micromol/L ) or low red blood cell zinc
      concentrations (<118 micromol/L) were more likely to have CLP [odds ratio 3.4
      (95% CI 1.3-8.6) and 3.3 (95% CI 1.3-8.0), respectively]. Glucose was not a risk
      factor for CLP in mothers and children. Maternal and child myo-inositol as well
      as zinc concentrations were slightly, albeit significantly correlated,
      r(Pearson)= 0.33 (P= 0.0006) and r(Pearson)= 0.23 (P= 0.01), respectively.
      CONCLUSION: This study demonstrates for the first time that zinc and myo-inositol
      are important in the aetiology of CLP.

PMID- 15198756
TI  - Pregnancy outcome in women with heart disease undergoing induction of labour.
AB  - OBJECTIVE: To examine the safety and outcome of induction of labour in women with
      heart disease. DESIGN: Prospective single-centre comparative study. SETTING:
      Major university-based medical centre. POPULATION/SAMPLE: One hundred and twenty
      one pregnant women with heart disease. METHODS: The sample included all women
      with acquired or congenital heart disease who attended our High-Risk Pregnancy
      Outpatient Clinic from 1995 to 2001. The files were reviewed for baseline data,
      cardiac and obstetric history, course of pregnancy and induction of labour and
      outcome of pregnancy. Findings were compared between women who underwent
      induction of labour and those who did not. Forty-seven healthy women in whom
      labour was induced for obstetric reasons served as controls. MAIN OUTCOME
      MEASURES: Pregnancy outcome. RESULTS: Of the 121 women with heart disease, 47
      (39%) underwent induction of labour. There was no difference in the caesarean
      delivery rate after induction of labour between the women with heart disease
      (21%) and the healthy controls (19%). Although the women with heart disease had a
      higher rate of maternal and neonatal complications than controls (17%vs 2%, P=
      0.015), within the study group, there was no difference in complication rate
      between the patients who did and did not undergo induction of labour. CONCLUSION:
      Induction of labour is a relatively safe procedure in women with cardiac disease.
      It is not associated with a higher rate of caesarean delivery than in healthy
      women undergoing induction of labour for obstetric indications, or with more
      maternal and neonatal complications than in women with a milder form of cardiac
      disease and spontaneous labour.

PMID- 15198757
TI  - Clinical outcome in a series of cases of obstetric cholestasis identified via a
      patient support group.
AB  - OBJECTIVE: To explore the clinical features of obstetric cholestasis pregnancies
      in UK white Caucasians. DESIGN: A questionnaire survey. SETTING: Study
      coordinated at Queen Charlotte's Hospital. POPULATION: Clinical features of 352
      affected pregnancies in 227 Caucasian women identified via a patient support
      group. METHODS: Evaluation of the gestation at which prematurity and intrauterine
      death occur, and recording of additional clinical features in pregnancies
      complicated by obstetric cholestasis. MAIN OUTCOME MEASURES: The timing of
      pregnancies complicated by intrauterine death and prematurity. RESULTS: Among the
      affected pregnancies, 23 (7%) were complicated by intrauterine death (20
      singletons and 3 twins) and 133 (38%) were delivered prematurely (56 spontaneous
      and 77 iatrogenic). Eighteen of the 20 singleton intrauterine deaths occurred
      after 37 weeks. All three intrauterine deaths in twin pregnancies occurred before
      37 weeks. Pruritus started earlier in pregnancies complicated by spontaneous
      prematurity, but not in those complicated by intrauterine death. CONCLUSIONS:
      Intrauterine death in singleton pregnancies complicated by obstetric cholestasis
      death mainly occurs after 37 weeks. The gestation at which pruritus is first
      reported may help to predict spontaneous prematurity.

PMID- 15198758
TI  - Spousal physical violence against women during pregnancy.
AB  - OBJECTIVE: To determine the prevalence of physical violence during pregnancy and
      the factors associated with it. DESIGN: A population-based, multicentre, cross
      sectional household survey. SETTING: Rural, slum and urban non-slum areas of
      Bhopal, Chennai, Delhi, Lucknow, Nagpur, Trivandrum and Vellore, in India.
      PARTICIPANTS: A total of 9938 women who were 15 to 49 years of age and living
      with a child younger than 18 years old. METHODS: Probability proportionate to
      size sampling of households was performed in three strata. Trained field workers
      administered a structured questionnaire. Women who reported domestic violence
      were asked about violence during pregnancy. Outcome variables included six
      violent behaviours: slap, hit, kick, beat, use of weapon and harm in any other
      way. Moderate to severe violence was defined as experience of any one or more of
      the following behaviours: hit, beat or kick. Odds ratios were calculated for risk
      and protective factors of violence during pregnancy using logistic regression.
      MAIN OUTCOME MEASURES: Physical spousal violence. RESULTS: The lifetime
      experience, during pregnancy, of being slapped was 16%, hit 10%, beat 10%, kicked
      9%, use of weapon 5% and harmed in any other way 6%. Eighteen percent of women
      experienced at least one of these behaviours and 3% experienced all six. The
      overall prevalence of moderate to severe violence during pregnancy was 13%.
      Logistic regression showed that the factors determining whether a woman
      experienced moderate to severe violence during pregnancy were: husband accusing
      wife of an affair (OR 7.1; 95% CI 5.1 to 9.8), dowry harassment (OR 4.1; 95% CI
      2.8 to 6.1), husband having an affair (OR 3.7; 95% CI 2.8 to 4.8), husband being
      regularly drunk (OR 3.2; 95% CI 2.6 to 4.1), low education of husband (OR 2.8;
      95% CI 1.4 to 5.6), substance abuse by husband (OR 2.6; 95% CI 1.3 to 5.5), no
      social support (OR 1.8; 95% CI 1.1 to 3.0), three or more children (OR 1.6; 95%
      CI 1.2 to 2.1) and household crowding (OR 1.1; 95% CI 1.0 to 1.2). CONCLUSION: In
      this study, 12.9% of women experienced moderate to severe physical violence
      during pregnancy. Suspicion of infidelity, dowry harassment, husband being
      regularly drunk and low education of husband were the main risk factors for
      violence during pregnancy.

PMID- 15198759
TI  - Severe complications of hysterectomy: the VALUE study.
AB  - OBJECTIVES: To model the determinants of serious operative and post-operative
      complications of hysterectomy and their potential risk factors. DESIGN: A
      prospective cohort of women undergoing hysterectomies for benign indications in
      1994/1995, with a six-week postsurgery follow up. POPULATION AND SETTING: A total
      of 37,512 women from 276 NHS and 145 private hospitals in England, Wales and
      Northern Ireland, originally recruited to compare the outcomes of endometrial
      destruction with those of hysterectomy. METHODS: Gynaecologists reported
      hysterectomies for non-malignant indications carried out during a 12-month period
      beginning in October 1994 and follow up data were obtained at outpatient follow
      up six weeks postsurgery. Odds ratios of severe complications by indication and
      method, adjusting for measured intrinsic risk factors, were calculated. MAIN
      OUTCOME MEASURES: Severe operative and post-operative complications. RESULTS:
      Severe operative complications occurred in 3%. The risk decreased with age and
      increased with greater parity and history of serious illness. Women with
      symptomatic fibroids (4.4%, 95% CI 3.9-4.9) experienced more complications than
      women with dysfunctional uterine bleeding (3.6%, 3.2-3.8), adjusted odds ratio
      (OR) = 1.3 (95% CI 1.1-1.6). Laparoscopic procedures (6.1%) doubled the risk of
      operative complications of abdominal hysterectomy (3.6%) (adjusted OR = 1.9, 1.5
      2.5). Post-operative complications occurred in around 1% of women, with a slight
      decrease with increasing age, and the strongest risk factor was a history of
      operative complications. Relative to dysfunctional uterine bleeding (1.0%), a
      higher risk for fibroids (1.2%) persisted after adjustments (RR = 1.5, 1.1-2.0).
      Both vaginal (1.2%) and laparoscopic (1.7%) techniques had significantly higher
      adjusted risks than abdominal operations (0.9%), RR = 1.4 (1.0-1.9) and RR = 1.6
      (1.0-2.7). There were no operative deaths; 14 women died within the six-week
      postsurgery (a crude mortality rate of 3.8/1000, 2.5-6.4). CONCLUSIONS:
      Hysterectomy is a common, routine surgery with comparatively rare serious
      complications. However, younger women, women with more vascular pelvis, who
      undergo hysterectomy, especially laparoscopically assisted vaginal surgery for
      symptomatic fibroids, are at most risk of experiencing severe complications both
      operatively and post-operatively. Therefore, a less invasive alternative
      treatment for symptomatic fibroids could particularly benefit this group of
      women, while less invasive treatments for dysfunctional uterine bleeding, such as
      various methods of endometrial ablations or resections, would need to meet the
      current low levels of clinical complications in order to replace hysterectomy.

PMID- 15198760
TI  - Antisepsis for abdominal hysterectomy: a randomised controlled trial of povidone
      iodine gel.
AB  - OBJECTIVE: To assess whether infectious morbidity after total abdominal
      hysterectomy is decreased by the addition of 20 cc povidone-iodine gel at the
      vaginal apex after the usual vaginal preparation with povidone-iodine solution.
      STUDY DESIGN: Randomised controlled trial. SETTING: Fifteen secondary and
      tertiary hospitals in Canada. SAMPLE: A total of 1570 women undergoing planned
      total abdominal hysterectomy. METHODS: Computer-generated randomisation using a
      centralised telephone service was stratified by study centre with variable block
      size. In the operating room, a swab for bacterial vaginosis was taken before
      vaginal antisepsis. Study group remained concealed until the standard surgical
      preparation in the operating room was complete. Then povidone-iodine gel 20 cc
      was placed at the vaginal apex in the intervention group only. Participants were
      followed for one month post-operative. MAIN OUTCOME MEASURES: The primary outcome
      was post-operative infectious morbidity during the 30 days after surgery, defined
      as: febrile morbidity with hospital stay greater than five days or antibiotic
      treatment, or infection requiring readmission to hospital or additional visit.
      Other outcomes included abdominal wound infection, pelvic abscess and other
      pelvic infections. RESULTS: Post-operative infectious morbidity within 30 days
      occurred in 128/780 (16%) women receiving povidone-iodine gel preparation and
      142/790 (18%) women not receiving gel (RR 0.9, 95% CI 0.7 to 1.1). Pelvic abscess
      was diagnosed in 0 patients in the gel group and in seven patients in the control
      group (P < 0.01). No significant difference was found in pelvic cellulitis (eight
      in each group) or abdominal wound infection (51 in the gel group and 58 in the
      control group, P= 0.5). CONCLUSION: Povidone-iodine vaginal gel antisepsis led to
      a 9% relative decrease in overall infectious morbidity after abdominal
      hysterectomy, which was not statistically significant. Povidone-iodine vaginal
      gel decreased the risk of pelvic abscess after total abdominal hysterectomy.

PMID- 15198761
TI  - Evaluation of the effect of uterine artery embolisation on menstrual blood loss
      and uterine volume.
AB  - OBJECTIVE: To evaluate the effect of uterine artery embolisation (UAE) on
      menstrual blood loss (MBL) and uterine volume in women with symptomatic uterine
      fibroids. DESIGN: Prospective observational study. SETTING: West of Scotland
      gynaecology and radiology departments. POPULATION: Fifty women (mean age 43
      years) with symptomatic fibroids undergoing UAE between January 1999 and June
      2003. METHODS: Women collected sanitary protection from one menses pre
      embolisation and at regular intervals thereafter. This allowed objective
      measurement of MBL using the alkaline haematin technique. Uterine volume was
      calculated using magnetic resonance imaging (MRI) before and six months following
      embolisation. Interventional radiologists performed bilateral UAE. The Wilcoxon's
      signed rank test was used for statistical analysis of data. MAIN OUTCOME
      MEASURES: Post-embolisation MBL and uterine volume changes. RESULTS: Median
      pretreatment MBL was 162 mL (mean 234, range 9-1339). The median MBL decreased to
      60 mL at 3 months (n= 34, range 0-767, P < 0.001), 70 mL at 6-9 months (n= 34,
      range 0-1283, P < 0.001), 37 mL at 12-24 months (n= 25, range 0-265, P < 0.001),
      18 mL at 24-36 months (n= 17, range 0-205, P < 0.001) and 41 mL at 36-48 months
      (n= 6, range 0-66, P < 0.05). The median reduction in uterine volume was 40% (n=
      46, 95% CI 33.0-49.7, P < 0.001). CONCLUSIONS: UAE causes a statistically
      significant reduction in objectively measured MBL. UAE is also associated with a
      statistically significant reduction in uterine volume at six months. There was no
      relationship between the changes in uterine volume and MBL.

PMID- 15198762
TI  - Preventing ectopic pregnancies: how often does transperitoneal transmigration of
      sperm occur in effecting human pregnancy?
AB  - OBJECTIVE: Transperitoneal transmigration of sperm constitutes the mechanism by
      which ectopic pregnancies occur in unilaterally obstructed fallopian tubes. This
      study was undertaken to determine how often sperm transmigrate across the
      peritoneal cavity to effect human pregnancy. DESIGN: In women with non
      communicating rudimentary uterine horn pregnancies, the ratio of total uterine
      horn pregnancies to prior contralateral hemi-uterine pregnancies was calculated
      to infer the overall transperitoneal sperm transmigration rate. The prior parity
      frequency distribution was also determined to calculate the best-fit per
      pregnancy probability of attaining a rudimentary horn pregnancy with each
      subsequent gestation using maximum likelihood estimation. SETTING: 20th century.
      SAMPLE: Non-communicating rudimentary uterine horn pregnancies reported from 40
      countries. METHODS: Two hundred and seventy-two cases were identified using
      manual and computerised searches of Index Medicus, Excerpta Medica, the Index
      Catalogue of the Library of the Surgeon-General's Office and standard reference
      tracing. MAIN OUTCOME MEASURES: The ratio of total prior non-rudimentary uterine
      horn pregnancies to rudimentary uterine horn pregnancies and the frequency
      distribution of prior maternal parities. RESULTS: Prior to the incident 272
      uterine horn pregnancies, the number of observed pregnancies was 292 (ratio =
      0.93), implying an aggregate sperm transmigration rate of 0.48. Using the prior
      parity frequency distribution, the best-fit probability of attaining a
      rudimentary horn gestation per-pregnancy was 0.51 (95% CI 0.48-0.56).
      CONCLUSIONS: Intraperitoneal sperm transmigration occurs approximately half the
      time in effecting spontaneous human pregnancies. To minimise the risk of ectopic
      tubal pregnancy in woman with unilaterally damaged fallopian tubes, salpingectomy
      should be the preferred surgical treatment, rather than attempting tubal salvage
      and repair.

PMID- 15198763
TI  - WHO multinational study of three misoprostol regimens after mifepristone for
      early medical abortion.
AB  - OBJECTIVES: To compare the side effect profiles of regimens of oral and vaginal
      administration of misoprostol after a single oral dose of 200 mg of mifepristone
      and to investigate patients' perceptions of medical abortion. DESIGN: Double
      blind, randomised controlled trial. SETTING: Fifteen gynaecological clinics in 11
      countries. POPULATION: A total of 2219 healthy pregnant women requesting medical
      abortion with < or =63 days of amenorrhoea. Two thousand women were asked about
      their perceptions of the method. METHODS: Mifepristone 200 mg orally on day one,
      followed by 0.8 mg misoprostol either orally or vaginally on day three. The oral
      group (O/O group) and one of the vaginal groups (V/O group) continued with 0.4 mg
      of oral misoprostol, and the vaginal-only group (V-only group) with oral placebo,
      twice daily for seven days. Side effects were recorded daily by women and
      reported at each visit. After misoprostol administration at the clinic, side
      effects were recorded at 1-hour interval up to 3 hours. Patients' perceptions
      were asked at the second follow up visit, six weeks after treatment. MAIN OUTCOME
      MEASURES: The outcome measures were the following: pregnancy-related symptoms
      (nausea, vomiting, breast tenderness, fatigue, dizziness, headache), drug-related
      side effects (diarrhoea, fever, rash and blood pressure change), side effects
      related to the abortion process (lower abdominal pain) and women's perceptions of
      the method. RESULTS: The pregnancy-related symptoms decreased in all groups after
      misoprostol, and breast tenderness decreased already after mifepristone. Oral
      administration of misoprostol was associated with a higher frequency of nausea
      and vomiting than vaginal administration at 1 hour after administration. With
      oral misoprostol, diarrhoea was more frequent at 1, 2 and at 3 hours after
      administration than with vaginal administration. Misoprostol induced fever during
      at least 3 hours after administration in up to 6% of the women, this peak being
      slightly higher and taking place later with the vaginal route. Lower abdominal
      pain peaked at 1 and 2 hours after oral misoprostol, while it did so at 2 and 3
      hours after vaginal misoprostol. In the two groups that continued misoprostol,
      27% of women had diarrhoea between the misoprostol visit and the two-week follow
      up visit, compared with 9% in the placebo group. Among the women studied, 84%
      would choose medical abortion again, 9% would choose surgical abortion and 7% did
      not know. Twenty-three percent of the women would choose to have a possible
      future abortion at home, 70% at a health facility and 7% did not know.
      CONCLUSIONS: The pregnancy-related symptoms decrease significantly with time
      during medical abortion. Nausea, vomiting and diarrhoea were more frequent after
      oral administration of misoprostol. Pain related to the abortion process occurs
      earlier after oral misoprostol. Should a need arise, a majority of women would
      choose medical abortion again and would prefer to have it at a health facility
      rather than at home.

PMID- 15198764
TI  - A randomised controlled trial of a tailored multifaceted strategy to promote
      implementation of a clinical guideline on induced abortion care.
AB  - OBJECTIVE: To evaluate the effectiveness and efficiency of a tailored
      multifaceted strategy, delivered by a national clinical effectiveness programme,
      to implement a guideline on induced abortion. DESIGN: Cluster randomised
      controlled trial. SETTING AND PARTICIPANTS: All 26 hospital gynaecology units in
      Scotland providing induced abortion care. INTERVENTION: Following the
      identification of barriers to guideline implementation, intervention units
      received a package comprising audit and feedback, unit educational meetings,
      dissemination of structured case records and promotion of a patient information
      booklet. Control units received printed guideline summaries alone. MAIN OUTCOME
      MEASURES: Compliance with five key guideline recommendations (primary outcomes)
      and compliance with other recommendations, patient satisfaction and costs of the
      implementation strategy (secondary outcomes). RESULTS: No effect was observed for
      any key recommendation: appointment with a gynaecologist within five days of
      referral (odds ratio 0.89; 95% confidence interval 0.50 to 1.58); ascertainment
      of cervical cytology history (0.93; 0.36 to 2.40); antibiotic prophylaxis or
      screening for lower genital tract infection (1.70; 0.71 to 5.99); use of
      misoprostol as an alternative to gemeprost (1.00; 0.27 to 1.77); and offer of
      contraceptive supplies at discharge (1.11; 0.48 to 2.53). Median pre-intervention
      compliance was near optimal for antibiotic prophylaxis and misoprostol use. No
      intervention benefit was observed for any secondary outcome. The intervention
      costs an average of pound 2607 per gynaecology unit. CONCLUSIONS: The tailored
      multifaceted strategy was ineffective. This was possibly attributable to high pre
      intervention compliance and the limited impact of the strategy on factors outside
      the perceived control of clinical staff.

PMID- 15198765
TI  - von Willebrand disease in women with menorrhagia: a systematic review.
AB  - OBJECTIVE: To determine the prevalence of von Willebrand disease in women
      presenting with menorrhagia. DESIGN: Systematic review of studies evaluating the
      prevalence of von Willebrand disease in women with menorrhagia. SETTING: Hospital
      outpatient clinics (mainly gynaecological) and population surveys. POPULATION:
      Women presenting with menorrhagia. METHODS: Relevant studies were extracted from
      MEDLINE search, bibliographies of identified articles and published proceedings
      of meetings and conferences. MAIN OUTCOME MEASURES: Number of women with von
      Willebrand disease. RESULTS: Eleven studies were included, totalling 988 women
      with menorrhagia. One hundred and thirty-one women were diagnosed to have von
      Willebrand disease with prevalences in individual studies ranging from 5% to 24%.
      The overall prevalence was 13% (95% CI 11-15.6%). The prevalence was higher in
      the European studies-18% (95% CI 15-23%) compared with that in North American
      studies-10% (95% CI 7.5-13%). This difference (P= 0.007) is likely to be the
      result of differences in the studies, which include method of recruitment of
      study population, method of assessing menstrual blood loss ethnic composition of
      study population, criteria for diagnosis and use of race- and ABO blood group
      specific values for von Willebrand factor. CONCLUSIONS: The prevalence of von
      Willebrand disease is increased in women with menorrhagia and is the underlying
      cause in a small but significant group of women with menorrhagia across the
      world. Testing for this disorder should be considered when investigating women
      with menorrhagia, especially those of Caucasian origin, those with no obvious
      pelvic pathology or with additional bleeding symptoms.

PMID- 15198766
TI  - Pretreatment tumour volume measurement on high-resolution magnetic resonance
      imaging as a predictor of survival in cervical cancer.
AB  - OBJECTIVE: To evaluate pretreatment tumour volume as a predictor of survival in
      patients with cervical cancer using both endovaginal and external coil magnetic
      resonance imaging in order to achieve high spatial resolution and delineate small
      volume disease. DESIGN: A retrosfection case series. SETTING: A tertiary referral
      centre for gynaecological oncology. POPULATION/SAMPLE: One hundred and six
      consecutive women with invasive carcinoma of the cervix underwent endovaginal and
      external coil magnetic resonance imaging on a 0.5-T or 1.5-T scanner. METHODS: T2
      W FSE images, sagittal and transverse to the cervix, were obtained and tumour
      volume was calculated on the sagittal images by the standard technique of
      multiplying the sum of the areas by the slice thickness. Patients were treated in
      accordance with normal clinical practice and their subsequent outcome was
      recorded. The relationships between clinical or imaging parameters and survival
      were assessed with Cox's proportional hazard method. MAIN OUTCOME MEASURES:
      Disease-free survival. RESULTS: In 89 of these women, the tumour was Stage I and
      88 of the 106 were treated principally by surgery. The median tumour volume was
      4.75 cm(3) (upper and lower quartiles 22 and 0.6). The median length of follow up
      of surviving patients was 223 weeks (quartiles 158 and 274 weeks). Stage,
      treatment type, lymphovascular space involvement, invasion of the parametrium,
      closeness of the excision margin, lymph node metastases, and magnetic resonance
      imaging measurements of tumour volume, parametrial invasion and lymph node
      disease were all significantly associated with survival in univariate analysis.
      Only magnetic resonance imaging measurement of tumour volume remained
      consistently and strongly associated with survival after multivariate analysis of
      parameters available prior to treatment (P= 0.001, Wald statistic 10.74). A
      receiver operating characteristic curve of tumour volume and disease-free
      survival confirmed the utility of this investigation and suggested that a cutoff
      around 13.0 cm(3) would predict survival with a positive predictive value of 0.93
      and a negative predictive value of 0.75. CONCLUSION: Magnetic resonance imaging
      assessment of tumour volume using both an endovaginal and an external coil
      approach provides an accurate prediction of prognosis in cervical cancer and
      defines a population of women at high risk of recurrence and death. The
      predictive value of this investigation is superior to the clinical and
      histological parameters previously used. Use of this technique permits a more
      accurate choice of treatment options. These results suggest that it is the size
      of tumour burden that determines the outcome rather than invasion beyond the
      anatomical margins of the uterus.

PMID- 15198767
TI  - Needle versus loop diathermy excision of the transformation zone for the
      treatment of cervical intraepithelial neoplasia: a randomised controlled trial.
AB  - OBJECTIVE: To determine whether lower rates or incomplete resection of cervical
      intraepithelial neoplasia (CIN) may be achieved by needle excision of the
      transformation zone (NETZ) than with loop excision (LLETZ). DESIGN: A prospective
      randomised controlled trial. SETTING: A gynaecological oncology centre and a
      teaching hospital in West London. POPULATION: Four hundred and four women due to
      receive treatment for suspected CIN. METHODS: Women were randomised to receive
      either LLETZ or NETZ. MAIN OUTCOME MEASURES: The study was designed to demostrate
      a difference in the proportion of women with clear histological margins of 82%
      for LLETZ compared to 94% for NETZ with 90% power at a 5% significance level,
      allowing for absence of CIN in the treatment specimen in 15%. RESULTS: Four
      randomised women were excluded from the analysis, as they were ineligible for the
      study. Three hundred and forty-seven (87%) had CIN in the treatment specimen and
      could be included in the analysis of excision margins. More women in the NETZ arm
      had clear histological margins (84.8%vs 75%, (P= 0.03). The median volume of
      specimens in the NETZ arm was 739 mm(3) larger (P= 0.33) and they were less
      likely to be removed in multiple pieces (2.5%vs 29.5%, RR 0.09, 95% CI 0.04 to
      0.20). Needle excision took longer to perform (median treatment time 210 vs 90
      seconds, P<0.0001) and surgeons more often reported the procedure as 'difficult'
      (9.5%vs 3.0%, RR = 3.17%, 95% CI 1.33 to 7.58). No difference in peri-operative
      or post-operative complication rates could be demonstrated between the two
      groups. CONCLUSION: NETZ is more likely to produce a specimen in one piece and
      with clear margins compared to LLETZ.

PMID- 15198768
TI  - Caesarean section is protective against stress urinary incontinence: an analysis
      of women with multiple deliveries.
AB  - All women who had three elective caesarean sections were selected from a database
      of 40,000 women delivering between 1977 and 1998, and age-matched with women
      having three vaginal births. They all completed a (validated) urinary and bowel
      symptom questionnaire. Women who had vaginal births had a significantly higher
      prevalence of stress incontinence but not other urinary or faecal symptoms
      compared with those delivered by caesarean section. The prevalence of faecal
      incontinence was lower than the prevalence of urinary incontinence. Although the
      prevalence of faecal incontinence was lower after caesarean delivery, this was
      not statistically different. These data have shown that caesarean section was
      associated with a lower risk of urinary incontinence, although a protective
      effect on development of faecal symptoms was not seen.

PMID- 15198769
TI  - Intrauterine therapy for a cytomegalovirus-infected symptomatic fetus.

PMID- 15198770
TI  - Scapular winging after vaginal delivery.

PMID- 15198771
TI  - Randomised controlled trial of total compared with subtotal hysterectomy with one
      year follow up results.

PMID- 15198775
TI  - 'Free' peer-review publishing.

PMID- 15198776
TI  - Down's Syndrome screening: confusion or consensus?

PMID- 15198777
TI  - Psychological aspects of integrated testing.

PMID- 15198778
TI  - SURUSS in perspective.
AB  - BACKGROUND: Until the publication of the Serum Urine and Ultrasound Screening
      Study (SURUSS) report, it was difficult to compare the different antenatal
      screening tests for Down's Syndrome because of variations in study designs. We
      here present the main results from SURUSS, updated to take account of recent
      information on nuchal translucency in Down's Syndrome pregnancies, and discuss
      their implications. METHODS: SURUSS was a prospective study of 47,053 singleton
      pregnancies (including 101 pregnancies with Down's Syndrome) conducted in 25
      maternity units. Nuchal translucency measurements were taken. Serum and urine
      samples collected between 9 and 13 weeks, and again between 14 and 20 weeks of
      pregnancy were stored. Samples from each affected pregnancy and five matched
      controls were tested for currently used or suggested biochemical Down's Syndrome
      screening markers. Pregnancies were followed up to determine the presence or
      absence of Down's Syndrome. For an 85% Down's Syndrome detection rate, the false
      positive rate for the Integrated test (nuchal translucency and pregnancy
      associated plasma protein-A [PAPP-A] at 11 completed weeks of pregnancy, and
      alpha-fetoprotein, unconjugated oestriol [uE(3)], free beta or total human
      chorionic gondaotrophin (hCG) and inhibin-A in the early second trimester) was
      0.9%, the Serum integrated test (without nuchal translucency) 2.7%, the Combined
      test (nuchal translucency with free beta-hCG and PAPP-A at 11 weeks) 4.3%, the
      Quadruple test (alpha-fetoprotein, uE(3), free beta or total hCG and inhibin-A)
      6.2%, and nuchal translucency at 11 weeks, 15.2%. All tests included maternal
      age. Using the Integrated test at an 85% detection rate, there would be six
      diagnostic procedure-related unaffected fetal losses following amniocentesis per
      100,000 women screened compared with 35 using the Combined test or 45 with the
      Quadruple test. CONCLUSIONS: The Integrated test offers the most effective and
      safe method of screening for women who attend in the first trimester. The next
      best test is the Serum integrated test. The Quadruple test is the best test for
      women who first attend in the second trimester. There is no justification for
      retaining the Double (alpha-fetoprotein and hCG) or Triple (alpha-fetoprotein,
      uE(3), and hCG) tests, or nuchal translucency alone (with or without maternal
      age) in antenatal screening for Down's Syndrome.

PMID- 15198779
TI  - Ultrasonographic occiput position in early labour in the prediction of caesarean
      section.
AB  - OBJECTIVE: To investigate the value of ultrasonographically determined occiput
      position in the early stages of the active phase of labour, in addition to
      traditional maternal, fetal and labour-related characteristics, in the prediction
      of the likelihood of caesarean section. DESIGN: Prospective observational study.
      SETTING: District general hospital in the UK. POPULATION: Six hundred and one
      singleton pregnancies with cephalic presentation in active labour at term with
      cervical dilatation of 3-5 cm. METHODS: Transabdominal sonography to determine
      fetal occiput position was carried out by an appropriately trained sonographer
      immediately before or after the routine clinical examination by the attending
      midwife or obstetrician. MAIN OUTCOME MEASURE: Caesarean section. RESULTS:
      Delivery was vaginal in 514 (86%) cases and by caesarean section in 87 (14%). The
      fetal occiput position was posterior in 209 (35%) cases and in this group the
      incidence of caesarean section was 19% (40 cases), compared with 11% (47 of 392)
      in the non-occiput posterior group. Multiple regression analysis revealed that
      significant independent contribution in the prediction of caesarean section was
      provided by maternal age (OR 1.1, 95% CI 1.0-1.2), Afro-Caribbean origin (OR 2.4,
      95% CI 1.2-4.6), height (OR 0.93, 95% CI 0.89-0.97), parity (OR 0.2, 95% CI 0.1
      0.4), type of labour (OR 2.2, 95% CI 1.3-3.8), gestation (OR 1.4, 95% CI 1.1
      1.7), fetal head descent (OR 0.6, 95% CI 0.4-0.9), occiput posterior position (OR
      2.2, 95% CI 1.3-3.7) and male gender (OR 2.0, 95% CI 1.2-3.5). CONCLUSIONS: The
      risk of caesarean section can be estimated during the early stage of active
      labour by the sonographically determined occiput position, in addition to
      traditional maternal, fetal and labour-related characteristics.

PMID- 15198781
TI  - Deterioration in cord blood gas status during the second stage of labour is more
      rapid in the second twin than in the first twin.
AB  - OBJECTIVE: To compare in twin pregnancy the rate of deterioration in umbilical
      blood gas status during the second stage of labour, and to investigate whether
      the duration of the first twin's delivery has any effect on the blood gas status
      of the second twin. DESIGN: A retrospective study. SETTING: Department of
      Obstetrics and Gynaecology in a university teaching hospital. POPULATION: Twin
      pregnancies with both of the twins delivered by normal cephalic vaginal mode, at
      or beyond 34 weeks of gestation, over a period of seven years. Twins with any
      maternal or fetal complications including discordant growth, intrauterine growth
      restriction, intrauterine death, fetal malformations, fetal distress, pre
      eclampsia and diabetes were excluded. METHODS: The first twins' second stage was
      defined as from the start of maternal pushing to his/her delivery, while the
      second twins' second stage started after the delivery of the first twin and ended
      by his/her delivery. The total duration of the second stage was the sum of the
      above two intervals. The correlations between the first twins' umbilical cord
      blood gas parameters and the duration of their own second stage, the second
      twins' umbilical cord blood gas parameters and the duration of their own second
      stage, as well as that of the total second stage, were studied. MAIN OUTCOME
      MEASURES: The changes of umbilical arterial pH of each twin with the duration of
      the corresponding second stage of labour, and the difference among them. RESULTS:
      A total of 51 cases were reviewed. The median gestation at delivery was 37 weeks.
      The median duration of first twins' second stage was 10 minutes (range 1-75)
      while that of the second twins' was 10 minutes (range 3-26). The first twins'
      second stage was inversely correlated with their arterial pH, venous pH and base
      excess [BE] (P < 0.01). Both the second twins' second stage and the total second
      stage were inversely correlated with both of their arterial and venous pH and BE
      (P < 0.01). However, further multiple regression analysis suggested that the
      correlation of the total second stage with the second twins' cord blood
      parameters could be solely explained by their own second stage. The rate of
      reduction in the second twins' arterial pH was 4.95 x 10(-3) per minute, and was
      significantly faster than that of the first twins', which was 1.55 x 10(-3) per
      minute (P < 0.05). CONCLUSIONS: During normal vaginal delivery, the umbilical
      cord blood gas status of both the first and the second twins deteriorated with
      the duration of their corresponding second stages, but the effects are greater in
      the latter. Furthermore, the duration of the first twins' second stage does not
      affect the blood gas status of the second twins'. These observations support the
      postulation of a diminished uteroplacental exchange function after the delivery
      of the first twin. Close monitoring and expeditious delivery of the second twins
      are important.

PMID- 15198780
TI  - A pilot study for a randomised controlled trial of waterbirth versus land birth.
AB  - OBJECTIVES: To assess the feasibility of undertaking an adequately powered
      multicentre study comparing waterbirth with land birth. To assess whether women
      are willing to participate in such a trial and whether participation has a
      negative effect on their birthing experience. DESIGN: A randomised controlled
      trial (RCT) with 'preference arm'. SETTING: District general hospital with 3600
      deliveries annually. POPULATION: Women with no pregnancy complications and no
      anticipated problems for labour/delivery. METHODS: Women were recruited and
      randomised between 36 and 40 weeks of gestation. Comparison of randomised and
      'preference arm' to assess any impact of randomisation on women's birthing
      experience. MAIN OUTCOME MEASURES: Data were collected at delivery concerning the
      labour, the pool water and baby's condition at birth and six weeks of age. The
      main outcome measures are means and standard deviation of cord O(2), CO(2),
      haemoglobin, haematocrit and base excess; medians and ranges of time to first
      breathe and cord pH; bacterial growth from pool water samples and neonatal swabs;
      and maternal satisfaction. RESULTS: Eighty women participated-60 women were
      randomised. Twenty women participated in a non-randomised 'preference arm'. The
      babies randomised to a waterbirth demonstrated a significantly lower umbilical
      artery pCO(2) (P= 0.003); however, it is recognised that this study is
      underpowered. Women were willing to participate and randomisation did not appear
      to alter satisfaction. CONCLUSION: This small study has shown that a RCT is
      feasible and demonstrated outcome measures, which can be successfully collected
      in an average delivery suite.

PMID- 15198782
TI  - Are women's expectations and preferences for intrapartum care affected by the
      model of care on offer?
AB  - OBJECTIVE: To investigate the effect of service provision on consumer
      preferences, in particular, whether women who have access to systems of care
      which offer particular attributes (such as continuity of carer) value these
      attributes more highly than women for whom the attributes are not a realistic
      option. DESIGN: Simple rating scales and a discrete choice experiment were used
      to assess the importance to women of different aspects of intrapartum care.
      SAMPLE AND SETTING: The sample consisted of 301 women at low obstetric risk,
      identified from three geographical areas, each with a different system of
      maternity care provision. METHODS: Midwives gave an anonymous, self-complete
      questionnaire to the women at the booking visit. Categorical data from the rating
      scales were analysed using the chi(2) test. Analysis of the discrete choice
      experiment was conducted using random effect probit regression. Main outcome
      measures Women's preference for different attributes of intrapartum care.
      RESULTS: From the rating scales, it appeared that women in the area with least
      continuity rated this aspect of care significantly lower than women in other
      areas (P= 0.007). Although the discrete choice experiment appeared to confirm
      this, the difference was not statistically significant. CONCLUSIONS: The findings
      from this study suggest that the systems of care on offer do influence women's
      preferences for aspects of intrapartum care. Women in areas where continuity of
      carer was a realistic option appeared to value this aspect of care more highly.
      The tendency for preferences to be influenced not only by previous experience of
      a service but also by knowledge of its availability has important implications
      for the inclusion of consumers' values in deciding whether to introduce
      innovations in care. It has been suggested that greater consumer involvement may
      be a useful means of challenging the accepted view of what is important in health
      services and of facilitating change. However, the findings from this study
      suggest that consumer views may have the opposite effect. If consumers do prefer
      what they know, then a policy of tailoring health services to local preferences
      will simply reinforce current provision of services, reinforcing existing
      inequalities in the provision of care.

PMID- 15198783
TI  - Outcome after a high number (4-10) of repeated caesarean sections.
AB  - OBJECTIVE: To evaluate outcomes in caesarean sections repeated several times.
      POPULATION: Sixty-four women had had four or more (up to 10) caesarean sections.
      METHODS: The outcomes of these operations N= 149, study group) were compared with
      other caesarean sections. RESULTS: A quarter of the women in the study group
      complained of low abdominal pains during the late pregnancy. A thin or
      fenestrated isthmic myometrial layer was observed in 55% of their operations.
      Abnormal placentation with an increased risk of major operative complications
      occurred more often in the study group. No differences in post-operative
      complications or perinatal outcome emerged between the groups. CONCLUSION: Thus,
      no definitive upper limit for the number of caesarean sections per individual
      woman can be given.

PMID- 15198784
TI  - VEGF expression in the placenta from pregnancies complicated by hypertensive
      disorders.
AB  - OBJECTIVE: To determine the expression of VEGF in the placental tissue from
      pregnancies complicated by hypertension disorders of different clinical severity.
      DESIGN: Prospective cohort study. SETTING: Polyclinic of Careggi, University of
      Florence, Italy. SAMPLE: Placentas from women with gestational hypertension (n=
      20), pre-eclampsia (n= 20) and pre-eclampsia with HELLP syndrome (n= 20) and from
      normotensive women (n= 20), as control group (gestational age comprised between
      35 and 38 weeks). METHODS: An immunohistochemical technique and a quantitative
      analysis to measure mRNA levels (RT-PCR) were employed. MAIN OUTCOME MEASURES:
      Intensity of immunoreactivity and mRNA levels in the placental components.
      Differences between the data. RESULTS: VEGF immunoreactivity was observable in
      all the placental components in the gestational hypertension cases as in the
      control ones. In the cases with pre-eclampsia and pre-eclampsia with HELLP
      syndrome, some placental components were not immunoreactive. However, the VEGF
      positive components of all the pathological groups showed a higher intensity of
      reactivity with respect to that of the control group. The levels of VEGF mRNA
      were higher in the gestational hypertension cases and lower in the cases of pre
      eclampsia with HELLP syndrome with respect to the control ones; in the cases of
      pre-eclampsia, the levels were the same as the control ones. CONCLUSION: The
      different expression of VEGF in the placenta of the pathological cases is
      probably related to haemodynamic changes that take place in these disorders, in
      order to attempt restoration of a normal uteroplacental flow.

PMID- 15198785
TI  - Teenage antenatal clinics may reduce the rate of preterm birth: a prospective
      study.
AB  - OBJECTIVE: To examine whether teenage antenatal clinics reduce the incidence of
      preterm birth. DESIGN: A multicentre prospective study was performed. SETTING:
      Three Australian hospitals with maternity services. POPULATION: Consecutive
      teenage patients (N= 731) were approached at their first or second antenatal
      visit. METHODS: Cases were women attending multidisciplinary teenage antenatal
      clinics and controls attended general hospital-based antenatal clinics. Teenage
      antenatal clinics involved multidisciplinary care and included guidelines to
      screen and treat all patients for infectious and social pathology. General
      antenatal clinic care was in accordance with Australian standards. MAIN OUTCOME
      MEASURES: Preterm birth, newborn biometry adjusted for gestational age,
      breastfeeding and contraception plans at discharge. RESULTS: Consent was obtained
      from 651 (89%) patients. Teenage pregnancy clinic patients were significantly
      less likely to present with threatened preterm labour (OR 0.45; 95% CI 0.29
      0.68), preterm, prelabour, prolonged rupture of membranes (OR 0.34; 95% CI 0.18
      0.63) or deliver preterm (OR 0.40; 95% CI 0.25-0.62) compared with those from
      general clinics. However, there was no independent effect of clinic care upon
      newborn biometry outcomes. Clinic care did not significantly alter rates of
      initiation of breastfeeding in hospital. However, significantly more of the
      teenage antenatal clinic mothers were discharged on contraception (OR 1.58; 95%
      CI 1.07-2.25). CONCLUSION: Teenage-specific antenatal clinics may reduce the rate
      of preterm birth.

PMID- 15198786
TI  - Perinatal HIV-1 transmission among low income women participants in the HIV/AIDS
      Control Program in Southern Brazil: a cohort study.
AB  - OBJECTIVE: To determine the rate and factors associated with perinatal
      transmission among women infected with HIV-1. DESIGN: Cohort study. SETTING:
      Centro Municipal de Atendimento em DST/AIDS is a major reference centre for HIV
      treatment in Porto Alegre city, southern Brazil. POPULATION: Pregnant and
      puerperal women infected with HIV-1. METHODS: Women were enrolled during
      pregnancy and seen monthly at the antenatal care centre. Those detected at
      delivery that presented at the centre within the first 10 days of postpartum were
      included. Maternal, obstetric and infant-related characteristics were ascertained
      and testing for CD4 cell count, HIV PCR/RNA assay, anti-HCV, HBSAg and syphilis
      were performed. Antiretrovirals and formula were provided free of charge
      following Brazilian guidelines. MAIN OUTCOME MEASURE: HIV-1 infection status in
      the infant. RESULTS: Perinatal transmission was assessed in 343 children (95% of
      the whole sample). Overall, the transmission rate was 3.2% (95% CI: 1.7-5.8%).
      Perinatal transmission rates increased with maternal viral load (>/=10,000
      copies/mL; RR: 11.27; 95% CI: 1.38-92.23). In multivariate analyses, the only
      independent risk factor for perinatal transmission was the maternal viral load at
      baseline (OR = 2.72 per log increase in the number of copies; 95% CI: 1.17-6.50).
      CONCLUSION: Perinatal transmission rate was low among HIV-1 infected women in
      clinical care and on antiretroviral therapy despite poor socio-economic
      conditions. Viral load level was the only independent predictor of perinatal
      transmission. It is possible to prevent HIV-1 perinatal transmission in a
      developing country if we provide antiretrovirals and formula.

PMID- 15198787
TI  - The effectiveness of GnRHa with and without 'add-back' therapy in treating
      premenstrual syndrome: a meta analysis.
AB  - OBJECTIVE: To determine the effectiveness of gonadotrophin-releasing hormone
      analogues (GnRHa) with and without hormonal add-back therapy in the management of
      premenstrual syndrome. DESIGN: Randomised controlled trials were identified by
      searching multiple databases. SETTING: Exeter and North Devon Research and
      Development Support Unit and Keele University Academic Unit of Obstetrics and
      Gynaecology. POPULATION: Women with pre-diagnosed premenstrual syndrome and/or
      premenstrual dysphoric disorder. METHODS: A meta-analysis of published randomised
      placebo-controlled trials assessing the use of GnRHa in the management of
      premenstrual syndrome. The standardised mean difference for each individual study
      and subsequently an overall standardised mean difference were calculated after
      demonstrating the consistency or homogeneity of the study results. MAIN OUTCOME
      MEASURES: Overall improvement in premenstrual symptomatology and effectiveness of
      GnRHa with additional hormonal add-back therapy were the main outcome measures
      assessed in this analysis. A secondary analysis was performed to assess the
      effectiveness of GnRHa in treating physical and emotional symptoms. RESULTS:
      Overall standardised mean difference for all trials that assessed the efficacy of
      GnRHa was -1.19 (95% confidence interval [CI] -1.88 to -0.51). The equivalent
      odds ratio was 8.66 (95% CI 2.52 to 30.26) in favour of GnRHa. GnRHa were more
      efficacious for physical than behavioural symptoms, although the difference was
      not statistically significant. The addition of hormonal add-back therapy to GnRHa
      did not appear to reduce the efficacy of GnRHa alone; standardised mean
      difference 0.12 (95% CI -0.35 to 0.58). CONCLUSIONS: GnRHa appear to be an
      effective treatment in the management of premenstrual syndrome. The addition of
      hormonal add-back therapy to reduce side effects does not reduce efficacy.

PMID- 15198788
TI  - Soy, fat and other dietary factors in relation to premenstrual symptoms in
      Japanese women.
AB  - OBJECTIVE: To evaluate the relations of intakes of soy, fat and other dietary
      components to premenstrual symptoms. DESIGN: Cross sectional study. SETTING:
      Three colleges and two nursing schools. POPULATION: One hundred and eighty-nine
      Japanese women aged 19 to 34 years. METHODS: Intakes of nutrients and foods,
      including soy products and isoflavones, were estimated by a semiquantitative food
      frequency questionnaire. Change in menstrual cycle symptoms were assessed by the
      Moos Menstrual Distress Questionnaire (MDQ). MAIN OUTCOME MEASURES: Spearman rank
      correlation of soy and other dietary factors with changes in MDQ scores between
      the follicular and the premenstrual phases after controlling for age, marital
      status, exercise, smoking status, age at menarche and number of days of bleeding.
      RESULTS: Neither soy product nor isoflavone intake was significantly associated
      with change in MDQ score in the premenstrual phase. Intakes of total, saturated
      and monounsaturated fats were significantly correlated with change in scores for
      total MDQ and subscale 'pain' in the premenstrual phase after controlling for the
      covariates. Intake of cereals/potatoes/starches was significantly inversely
      correlated with a change in total MDQ score in the premenstrual phase.
      CONCLUSIONS: High intake of fats and low intake of foods with high concentration
      of carbohydrate may be associated with premenstrual symptoms.

PMID- 15198789
TI  - Overactive bladder: prevalence, risk factors and relation to stress incontinence
      in middle-aged women.
AB  - OBJECTIVE: To investigate the prevalence of and factors associated with
      overactive bladder in middle-aged women. DESIGN: Cross sectional population-based
      study. SETTING: Southern Sweden and the Women's Health in the Lund Area study
      (WHILA 1995-2000) where 6917 (64% of the invited) women, 50-59 years old in 1995,
      participated. POPULATION: From the WHILA study, 1500 women reporting troublesome
      urinary incontinence (INCONT-1) and 1500 without incontinence (CONT-1) were
      selected by computerised randomisation and received the Bristol Female Lower
      Urinary Tract Symptoms (BFLUTS) questionnaire in January 2001. METHODS:
      Overactive bladder was defined in two versions using the ICS definition of 2002
      as either urgency alone (OAB-1) or urgency combined with frequency more than
      eight times per day and/or nocturia twice or more per night (OAB-2). Risk factors
      were analysed by multiple logistic regression analyses. MAIN OUTCOME MEASURES:
      Prevalence figures and odds ratios with corresponding 95% confidence intervals.
      RESULTS: The prevalence of OAB-1 was 46.9% in the INCONT-1 and 16.7% in the CONT
      1 group, and that of OAB-2 was 21.6% and 8.1%, respectively. Most urgency
      occurred in combination with stress incontinence (i.e. as mixed incontinence).
      The overlap between stress and urge symptoms increased with the frequency of
      stress incontinence episodes (P < 0.001). Metabolic risk factors were body mass
      index (BMI) >/= 30 for OAB-1, OAB-2 and stress incontinence, positive metabolic
      screening for OAB-1, family history of diabetes for OAB-2 and elevation of BMI
      >/= 25% since the age of 25 for stress incontinence. Stress incontinence was
      associated with the current use of hormonal replacement therapy. CONCLUSIONS:
      Overactive bladder and stress incontinence are intimately associated with each
      other. Both OAB and stress incontinence are associated with abnormal metabolic
      factors, mainly increased BMI.

PMID- 15198790
TI  - How much is enough and who says so?
AB  - BACKGROUND: One of the challenges of health-related quality of life research is
      to translate statistically significant health-related quality of life changes
      into interpretable clinical or medically important ones. OBJECTIVE: To calculate
      the minimal important difference of the King's Health Questionnaire, a condition
      specific health-related quality of life questionnaire for the assessment of men
      and women with lower urinary tract dysfunction. METHODS: The King's Health
      Questionnaire was administered to patients suffering from overactive bladder
      enrolled in two multinational studies. Minimal important differences were
      calculated using an anchor-based approach with both a global rating of patient
      perceived treatment benefit and one of perceived disease impact. A distribution
      based method using effect size was calculated for comparison purposes. RESULTS:
      Minimal important difference values varied slightly with each method. Using the
      anchor-based approach, the King's Health Questionnaire minimal important
      difference ranged between 5-10 points when the calculation factored out patients
      who reported no change and 6-12 points for patients who experienced a small
      improvement. The effect size method indicated a minimal important difference of 5
      to 6 points for a small effect and 10 to 15 points for a medium effect.
      CONCLUSIONS: In the case of the King's Health Questionnaire, the anchor-based
      approaches and the distribution-based approach provide similar results. A change
      from baseline of at least 5 points on King's Health Questionnaire domains
      indicates a change that is meaningful to patients and is indicative of a
      clinically meaningful improvement in health-related quality of life after
      treatment. Convergence of the estimates using different approaches should give us
      confidence in the values derived for the quality of life domains measured by the
      King's Health Questionnaire.

PMID- 15198792
TI  - Ovarian cancer detected non-invasively by contrast-enhanced power Doppler
      ultrasound.
AB  - Overall, about one-third of women operated upon because of suspected ovarian
      cancer turn out to have benign disease. This proportion will be even higher when
      the tumours are small. A more accurate method of determining which are malignant
      would reduce the number of unnecessary referrals to the cancer centre and
      increase the scope for conservative management. This pilot study of ultrasound
      and intravenous microbubble contrast in 20 women with small ovarian tumours
      enabled the identification of all four malignant lesions with good inter-observer
      agreement. These preliminary findings suggest that intravenous contrast improves
      the ultrasound identification of small ovarian malignancies and may provide an
      accurate way of selecting women who require to be referred urgently for surgery
      under the auspices of a gynaecological oncologist. The remainder might be
      considered for laparoscopic surgery or even for observation in some cases.

PMID- 15198791
TI  - Increased levels of gangliosides in the plasma and ascitic fluid of patients with
      advanced ovarian cancer.
AB  - OBJECTIVES: To assess the expression of total gangliosides in primary ovarian
      cancer cell lines, ascitic fluid and plasma of advanced ovarian cancer patients.
      DESIGN: A prospective study. SETTING: The Department of Obstetrics and Gynecology
      at the University of Arkansas for Medical Sciences and the Laboratory of
      Glycolipid Immunotherapy, John Wayne Cancer Institute. POPULATION: Twenty-two
      women diagnosed with advanced ovarian cancer and seven normal female controls.
      METHODS: Total gangliosides shedding from primary ovarian cancer cell lines were
      measured by estimating lipid-associated sialic acids (LASAs test) and compared
      with the ganglioside levels shed by primary cervical and uterine cancer cell
      lines. In addition, plasma and ascitic samples from advanced ovarian cancer
      patients were collected at the time of surgery and analysed for the presence of
      total gangliosides. MAIN OUTCOME MEASURES: Levels of total ganglioside in plasma
      and ascites fluid samples drawn from ovarian cancer patients, relative to total
      gangliosides levels in plasma from normal female controls. RESULTS: All primary
      ovarian tumours secreted high levels of total gangliosides (mean 4 mg/mL, range
      between 2.7 and 4.8 mg/mL/10(5) cells/24 h) when compared with primary cervical
      cancers (mean 1.4 mg/mL, range between 0.7 and 2.2 mg/mL/10(5) cells/24 h) (P <
      0.008) and uterine carcinoma cell lines (mean 1.4 mg/mL, range between 1.3 and
      1.6 mg/mL/10(5) cells/24 h) (P <.004). Elevated levels of total gangliosides were
      detected in the plasma [mean (SD) 31 (12) mg/mL, range between 18 and 57 mg/mL]
      (P <.001), and in the peritoneal fluid [mean (SD) 27 (9) mg/mL, range between 14
      and 40 mg/mL] (P <.003) of ovarian cancer patients when compared with the levels
      detectable in the plasma samples of normal female controls tested [mean (SD) 15
      (2) mg/mL, range between 12 and 18 mg/mL]. CONCLUSIONS: Increased serum levels of
      total gangliosides may reflect shedding or release of gangliosides from the
      surface of ovarian tumour cells. Secretion of gangliosides may play an important
      role in the inhibition of anti-tumour immune function commonly observed in
      advanced ovarian cancer.

PMID- 15198793
TI  - Blood pressure and urinalysis are often omitted in women who have suffered pre
      eclampsia at their six-week postnatal check.
AB  - Women with pregnancies complicated by pre-eclampsia were visited between six
      weeks and three months postpartum and were asked to recall if they had their
      blood pressure and urine tested at their six-week postnatal check. Of 257 audit
      participants across 21 maternity units in the United Kingdom over the period 1st
      June 2001 to 31st May 2002, 93% (n= 238) recalled having had their blood pressure
      taken and 28% (n = 73) recalled having had their urine tested. A significant
      proportion of women were not being screened for unresolved pre-eclampsia at their
      six-week routine postnatal examination.

PMID- 15198794
TI  - Expulsion of fetal bones through the rectum after abdominal pregnancy.

PMID- 15198795
TI  - Perforated 26 weeks pregnant uterus at appendicectomy.

PMID- 15198797
TI  - Improved fertility following conservative surgical treatment of ectopic
      pregnancy.

PMID- 15198796
TI  - Is normalisation of serum potassium and magnesium always necessary in Gitelman
      Syndrome for a successful obstetric outcome?

PMID- 15198798
TI  - Ligneous cervicitis.

PMID- 15198799
TI  - The sex ratio of pregnancies complicated by hospitalisation for hyperemesis
      gravidarum.

PMID- 15198801
TI  - Evolution of somatic mutations in mammary tumors in transgenic mice is influenced
      by the inherited genotype.
AB  - BACKGROUND: MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in
      development, followed by the appearance of solitary mammary tumors with a high
      proportion of cells expressing early lineage markers and many myoepithelial
      cells. The occurrence of tumors is accelerated in experiments that activate FGF
      proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that
      secondary oncogenic events are required for progression from mammary hyperplasia
      to carcinoma. It is not known, however, which oncogenic pathways contribute to
      Wnt1-induced tumorigenesis - further experimental manipulation of these mice is
      needed. Secondary events also appear to be required for mammary tumorigenesis in
      MMTV-Neu transgenic mice because the transgene in the tumors usually contains an
      acquired mutation that activates the Neu protein-tyrosine kinase. METHODS: cDNA
      or DNA from the mammary glands and mammary tumors from MMTV-Wnt1, MMTV-Wnt1/p53-/
      , MMTV-Neu transgenic mice, and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic
      mice, was sequenced to seek activating mutations in H-Ras, K-Ras, and N-Ras
      genes, or in the MMTV-Neu transgene. In addition, tumors from bitransgenic
      animals were examined to determine the cellular phenotype. RESULTS: We found
      activating mutations at codons 12, 13, and 61 of H-Ras in just over half of the
      mammary tumors in MMTV-Wnt1 transgenic mice, and we confirmed the high frequency
      of activating mutations of Neu in tumors in MMTV-Neu transgenic mice. Tumors
      appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice, but no Ras or MMTV-Neu
      mutations were found in these tumors, which were phenotypically similar to those
      arising in MMTV-Wnt1 mice. In addition, no Ras mutations were found in the
      mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53
      gene. CONCLUSIONS: Tumorigenic properties of cells undergoing functionally
      significant secondary mutations in H-Ras or the MMTV-Neu transgene allow
      selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively.
      Alternative sources of oncogenic potential, such as a second transgenic oncogene
      or deficiency of a tumor suppressor gene, can obviate the selective power of
      those secondary mutations. These observations are consistent with the notion that
      somatic evolution of mouse mammary tumors is influenced by the specific nature of
      the inherited cancer-promoting genotype.

PMID- 15198802
TI  - Segmental identity and cerebellar granule cell induction in rhombomere 1.
AB  - BACKGROUND: Cerebellar granule cell precursors are specifically generated within
      the hindbrain segment, rhombomere 1, which is bounded rostrally by the
      midbrain/hindbrain isthmus and caudally by the boundary of the Hoxa2 expression
      domain. While graded signals from the isthmus have a demonstrable patterning role
      within this region, the significance of segmental identity for neuronal
      specification within rhombomere 1 is unexplored. We examined the response of
      granule cell precursors to the overexpression of Hoxa2, which normally determines
      patterns of development specific to the hindbrain. How much does the development
      of the cerebellum, a midbrain/hindbrain structure, reflect its neuromeric origin
      as a hindbrain segment? RESULTS: We show that a Gbx2-positive, Otx2-/Hoxa2
      negative territory corresponding to rhombomere 1 forms prior to an identifiable
      isthmic organiser. Early global overexpression of Hoxa2 at embryonic day 0 has no
      effect on the expression of isthmic signalling molecules or the allocation of
      rhombomere 1 territory, but selectively results in the loss of granule cell
      markers at embryonic day 6 and the depletion of cell bodies from the external
      granule cell layer. By comparison the trochlear nucleus and locus coeruleus form
      normally in ventral rhombomere 1 under these conditions. Microsurgery, coupled
      with electroporation, to target Hoxa2 overexpression to rhombic lip precursors,
      reveals a profound, autonomous respecification of migration. Rhombic lip
      derivatives, normally destined to occupy the external granule cell layer, violate
      the cerebellar boundary to form a ventrolateral nucleus in a position comparable
      to that occupied by rhombic lip derived neurons in rhombomere 2. CONCLUSIONS:
      Different overexpression strategies reveal that the recognition of migration cues
      by granule cell precursors is dependent on their identity as rhombomere 1
      derivatives. Segmental patterning cues operate autonomously within the rhombic
      lip precursor pool. By contrast, a subset of coextensive nuclei is refractory to
      ectopic Hoxa2 and is presumably induced solely by isthmic organiser activity.
      Thus, graded (isthmic) and segmental mechanisms may operate exclusively of one
      another in the specification of different neuronal populations within rhombomere
      1. The early designation of an Otx2-negative, Hoxa2-negative region, prior to the
      appearance of the isthmic organiser, is a key initial step in the specification
      of the cerebellum.

PMID- 15198803
TI  - Quality of life of men treated with brachytherapies for prostate cancer.
AB  - BACKGROUND: Most studies of men undergoing treatment for prostate cancer examine
      physical symptoms as predictors of Quality of Life (QOL). However, symptoms vary
      by treatment modality in this population, and psychosocial variables, shown to be
      important to QOL, have rarely been examined. Litwin noted a need for analysis of
      QOL data in men treated for prostate cancer with different modes of therapy, as
      studies focusing on specific treatments will increase the homogeneity of research
      findings. METHODS: This cross-sectional study explored physical and psychosocial
      predictors of QOL in men receiving one of two types of radiation treatment for
      prostate cancer: Intensity Modulated Radiation Therapy (IMRT) + High Dose Rate
      (HDR) Brachytherapy or IMRT + seed implantation. Subjects completed a biographic
      questionnaire; quality of life measures, which were the eight subscales of the
      Medical Outcome Study Short Form Health Survey (SF-36); measures of physical
      symptoms including the Radiation Therapy Oncology Group and the European
      Organization for Research and Treatment of Cancer (RTOG/EORTC) and the Prostate
      Symptom Self-Report (PSSR); and measures of psychological factors, the Ways of
      Coping Scale (WOC), Perceived Stress Scale, the Anxiety Subscale of the SCL-90,
      and Strategies Used by Patients to Promote Health (SUPPH). Eight regression
      models including both physical and psychosocial variables were used to predict
      quality of life. RESULTS: Sixty-three subjects with complete data on all
      variables were studied. Treatment effect sizes were medium to large in predicting
      each of the quality of life subscales of the SF-36. Psychosocial variables were
      related to physical function, role function, bodily pain, general health, social
      function, emotional role, and mental health. Physical symptoms were related to
      subjects' perceived general health and mental health. DISCUSSION: The number of
      significant relationships among psychosocial variables and indicators of QOL
      exceeded the number of relationships among symptoms and QOL suggesting that
      psychosocial variables associate strongly with prostate cancer patients' reports
      of quality of life. Findings of the study may provide patients and families with
      knowledge that contributes to their understanding of quality of life outcomes of
      IMRT+ HDR and IMRT + seed implantation and their ability to make more informed
      treatment choices.

PMID- 15198804
TI  - Resources for comparing the speed and performance of medical autocoders.
AB  - BACKGROUND: Concept indexing is a popular method for characterizing medical text,
      and is one of the most important early steps in many data mining efforts. Concept
      indexing differs from simple word or phrase indexing because concepts are
      typically represented by a nomenclature code that binds a medical concept to all
      equivalent representations. A concept search on the term renal cell carcinoma
      would be expected to find occurrences of hypernephroma, and renal carcinoma
      (concept equivalents). The purpose of this study is to provide freely available
      resources to compare speed and performance among different autocoders. These
      tools consist of: 1) a public domain autocoder written in Perl (a free and open
      source programming language that installs on any operating system); 2) a
      nomenclature database derived from the unencumbered subset of the publicly
      available Unified Medical Language System; 3) a large corpus of autocoded output
      derived from a publicly available medical text. METHODS: A simple lexical
      autocoder was written that parses plain-text into a listing of all 1,2,3, and 4
      word strings contained in text, assigning a nomenclature code for text strings
      that match terms in the nomenclature. The nomenclature used is the unencumbered
      subset of the 2003 Unified Medical Language System (UMLS). The unencumbered
      subset of UMLS was reduced to exclude homonymous one-word terms and proper names,
      resulting in a term/code data dictionary containing about a half million medical
      terms. The Online Mendelian Inheritance in Man (OMIM), a 92+ Megabyte publicly
      available medical opus, was used as sample medical text for the autocoder.
      RESULTS: The autocoding Perl script is remarkably short, consisting of just 38
      command lines. The 92+ Megabyte OMIM file was completely autocoded in 869 seconds
      on a 2.4 GHz processor (less than 10 seconds per Megabyte of text). The autocoded
      output file (9,540,442 bytes) contains 367,963 coded terms from OMIM and is
      distributed with this manuscript. CONCLUSIONS: A public domain Perl script is
      provided that can parse through plain-text files of any length, matching concepts
      against an external nomenclature. The script and associated files can be used
      freely to compare the speed and performance of autocoding software.

PMID- 15198805
TI  - Facilitators' influence on student PBL small group session online information
      resource use: a survey.
AB  - BACKGROUND: In problem-based learning curricular research has focused on the
      characteristics of good facilitators and how they influence student performance
      and satisfaction. Far less frequently addressed has been the question of how PBL
      facilitators influence the small group session activity of students. We
      investigated the impact that facilitators' encouragement of use or non-use of the
      Internet would have on the students' use of online information resources.
      METHODS: Survey of student and facilitator perceptions of facilitator behavior
      and student use of online information resources. RESULTS: Students who used
      online information resources rated their facilitators' behavior as more
      encouraging, while students in groups who didn't use online information resources
      during problem-based learning small group sessions rated their facilitators'
      behavior as less encouraging. This result was statistically significant.
      CONCLUSIONS: Our study supports the role of the facilitator as an influence on
      medical students in small groups, particularly with respect to facilitator verbal
      behavior encouraging or discouraging student use of information technology in the
      problem-based learning small group session.

PMID- 15198806
TI  - An investigation into the validity of cervical spine motion palpation using
      subjects with congenital block vertebrae as a 'gold standard'.
AB  - BACKGROUND: Although the effectiveness of manipulative therapy for treating back
      and neck pain has been demonstrated, the validity of many of the procedures used
      to detect joint dysfunction has not been confirmed. Practitioners of manual
      medicine frequently employ motion palpation as a diagnostic tool, despite
      conflicting evidence regarding its utility and reliability. The introduction of
      various spinal models with artificially introduced 'fixations' as an attempt to
      introduce a 'gold standard' has met with frustration and frequent mechanical
      failure. Because direct comparison against a 'gold standard' allows the validity,
      specificity and sensitivity of a test to be calculated, the identification of a
      realistic 'gold standard' against which motion palpation can be evaluated is
      essential. The objective of this study was to introduce a new, realistic, 'gold
      standard', the congenital block vertebra (CBV) to assess the validity of motion
      palpation in detecting a true fixation. METHODS: Twenty fourth year chiropractic
      students examined the cervical spines of three subjects with single level
      congenital block vertebrae, using two commonly employed motion palpation tests.
      The examiners, who were blinded to the presence of congenital block vertebrae,
      were asked to identify the most hypomobile segment(s). The congenital block
      segments included two subjects with fusion at the C2-3 level and one with fusion
      at C5-6. Exclusion criteria included subjects who were frankly symptomatic, had
      moderate or severe degenerative changes in their cervical spines, or displayed
      signs of cervical instability. Spinal levels were marked on the subject's skin
      overlying the facet joints from C1 to C7 bilaterally and the motion segments were
      then marked alphabetically with 'A' corresponding to C1-2.Kappa coefficients (K)
      were calculated to determine the validity of motion palpation to detect the
      congenitally fused segments as the 'most hypomobile' segments. Sensitivity and
      specificity of the diagnostic procedure were also calculated. RESULTS: Kappa
      coefficients (K) showed substantial overall agreement for identification of the
      segment of greatest hypomobility (K = 0.65), with substantial (K = 0.76) and
      moderate (K = 0.46) agreement for hypomobility at C2-3 and C5-6 respectively.
      Sensitivity ranged from 55% at the C5-6 CBV to 78% at the C2-3 level. Specificity
      of the procedure was high (91 - 98%). CONCLUSION: This study indicates that
      relatively inexperienced examiners are capable of correctly identifying inter
      segmental fixations (CBV) in the cervical spine using 2 commonly employed motion
      palpation tests. The use of a 'gold standard' (CBV) in this study and the
      substantial agreement achieved lends support to the validity of motion palpation
      in detecting major spinal fixations in the cervical spine.

PMID- 15198807
TI  - Elevated platelet-derived growth factor-BB concentrations in premature neonates
      who develop chronic lung disease.
AB  - BACKGROUND: Chronic lung disease (CLD) in the preterm newborn is associated with
      inflammation and fibrosis. Platelet-derived growth factor-BB (PDGF-BB), a potent
      chemotactic growth factor, may mediate the fibrotic component of CLD. The
      objectives of this study were to determine if tracheal aspirate (TA)
      concentrations of PDGF-BB increase the first 2 weeks of life in premature
      neonates undergoing mechanical ventilation for respiratory distress syndrome
      (RDS), its relationship to the development of CLD, pulmonary hemorrhage (PH) and
      its relationship to airway colonization with Ureaplasma urealyticum (Uu).
      METHODS: Infants with a birth weight less than 1500 grams who required mechanical
      ventilation for RDS were enrolled into this study with parental consent. Tracheal
      aspirates were collected daily during clinically indicated suctioning. Uu
      cultures were performed on TA collected in the first week of life. TA
      supernatants were assayed for PDGF-BB and secretory component of IgA
      concentrations using ELISA techniques. RESULTS: Fifty premature neonates were
      enrolled into the study. Twenty-eight infants were oxygen dependent at 28 days of
      life and 16 infants were oxygen dependent at 36 weeks postconceptual age. PDGF-BB
      concentrations peaked between 4 and 6 days of life. Maximum PDGF-BB
      concentrations were significantly higher in infants who developed CLD or died
      from respiratory failure. PH was associated with increased risk of CLD and was
      associated with higher PDGF-BB concentrations. There was no correlation between
      maximum PDGF-BB concentrations and Uu isolation from the airway. CONCLUSIONS:
      PDGF-BB concentrations increase in TAs of infants who undergo mechanical
      ventilation for RDS during the first 2 weeks of life and maximal concentrations
      are greater in those infants who subsequently develop CLD. Elevation in lung PDGF
      BB may play a role in the development of CLD.

PMID- 15198808
TI  - Pupillary anomaly masquerading as a glaucomatous visual field defect: a case
      report.
AB  - BACKGROUND: Patients are often referred to ophthalmologists with focal visual
      field defects on routine testing, possibly related to a potential diagnosis of
      glaucoma. However, examination of the individual patient's ocular characteristics
      as well as facial characteristics may often reveal a cause of the visual field
      defect. CASE PRESENTATION: We describe a patient who was found to have a superior
      visual field defect on routine testing by the optician. Repeat perimetry with
      pharmacological dilatation of the pupil revealed that the cause of the field
      defect was related to an eccentric inferiorly displaced pupil, secondary to
      trauma some years previously. DISCUSSION: Individual patient characteristics,
      including both ocular, as well as facial, need to be considered, when
      interpreting any visual field defect.

PMID- 15198809
TI  - SMART amplification combined with cDNA size fractionation in order to obtain
      large full-length clones.
AB  - BACKGROUND: cDNA libraries are widely used to identify genes and splice variants,
      and as a physical resource for full-length clones. Conventionally-generated cDNA
      libraries contain a high percentage of 5'-truncated clones. Current library
      construction methods that enrich for full-length mRNA are laborious, and involve
      several enzymatic steps performed on mRNA, which renders them sensitive to RNA
      degradation. The SMART technique for full-length enrichment is robust but results
      in limited cDNA insert size of the library. RESULTS: We describe a method to
      construct SMART full-length enriched cDNA libraries with large insert sizes. Sub
      libraries were generated from size-fractionated cDNA with an average insert size
      of up to seven kb. The percentage of full-length clones was calculated for
      different size ranges from BLAST results of over 12,000 5'ESTs. CONCLUSIONS: The
      presented technique is suitable to generate full-length enriched cDNA libraries
      with large average insert sizes in a straightforward and robust way. The
      representation of full-coding clones is high also for large cDNAs (70%, 4-10 kb),
      when high-quality starting mRNA is used.

PMID- 15198812
TI  - Our remembrances of Howard Malmstadt.

PMID- 15198813
TI  - Performance and application of a new planar array infrared spectrograph operating
      in the mid-infrared (2000-975 cm(-1)) fingerprint region.
AB  - A no-moving-part planar array infrared spectrograph (PA-IR) equipped with a 256 x
      256 mercury cadmium telluride (MCT) focal plane array has been designed and
      constructed. The performance of the instrument, whose frequency range extends
      from 2000-975 cm(-1), has been assessed in terms of resolution, bandwidth, and
      signal-to-noise ratio. The PA-IR spectrograph is able to record spectra with an
      8.7 ms time resolution and has peak-to-peak noise levels as low as 2.4 x 10(-4)
      A.U. As a demonstration of the potential of PA-IR, the dynamics of reorientation
      of a liquid crystalline sample exposed to a single electric field pulse has been
      studied. It was shown that PA-IR can be used for the simultaneous acquisition of
      two orthogonally polarized spectra. The advantages and limitations of PA-IR, step
      scan Fourier transform infrared (FT-IR), and ultrarapid-scanning FT-IR for real
      time studies of reversible and irreversible phenomena are thoroughly discussed.

PMID- 15198816
TI  - Separation and on-line distinction of enantiomers: a non-aqueous capillary
      electrophoresis Fourier transform infrared spectroscopy study.
AB  - We report on the separation and on-line distinction of (R,S)-3,5-dinitrobenzoyl
      leucine (DNB-Leu) enantiomers with non-aqueous capillary electrophoresis (CE) and
      Fourier transform infrared (FT-IR) spectroscopic detection using O-(tert-butyl
      carbamoyl) quinine (tBuCQN) as the chiral selector (CS). Due to stereoselective
      intermolecular interactions--particularly ionic interactions, hydrogen bonding,
      and pi-pi-interactions--the enantiomers undergo enantioselective complex and ion
      pair formation, respectively, with the CS enabling CE separation and direct
      identification with FT-IR detection. Especially the (S)-enantiomer of the analyte
      shows significant changes in the mid-infrared region upon complexation, allowing
      for a clear spectral distinction between both enantiomers. In this way FT-IR
      spectroscopy represents a novel and attractive detection method for CE
      enantiomeric separations providing qualitative stereochemical information on the
      interactions between the chiral selector and the enantiomers, which is hardly
      accessible by other CE detection methods.

PMID- 15198814
TI  - Dual source fourier transform polarization modulation spectroscopy: an improved
      method for the measurement of circular and linear dichroism.
AB  - It is shown that the use of two sources in a four-port interferometer equipped
      with cube-corner mirrors leads to increased signal-to-noise ratios in Fourier
      transform (FT-IR) circular and linear dichroism spectra. The output beam to the
      sample is a superposition of two interferograms, one from each source, having
      opposite Fourier phases. These two interferograms cancel one another to the
      degree that the two sources are matched in intensity. If the radiation from each
      of the two sources is first polarized orthogonally with respect to the other and
      passed through a polarization modulator before reaching the sample, the resulting
      polarization-modulation interferograms are out of Fourier phase and out of
      polarization-modulation phase. As a result, the polarization-modulation
      interferograms, due to circular or linear dichroism in the sample, from the two
      sources combine positively rather than negatively. An improvement in signal-to
      noise ratio of up to two (or a factor of four in scan-time reduction for the same
      signal-to-noise ratio) compared to single source operation can be realized, while
      at the same time, the potential for saturation of the detector signal is
      significantly reduced due to the reduction in magnitude of the combined ordinary
      infrared transmission interferogram. Absorption and circular dichroism spectra
      from a dual-source FT-IR spectrometer are presented and analyzed.

PMID- 15198817
TI  - Direct determination of carbon dioxide in aqueous solution using mid-infrared
      quantum cascade lasers.
AB  - A method for the direct determination of carbon dioxide in aqueous solutions
      using a room-temperature mid-infrared (MIR) quantum cascade laser at 2330 cm(-1)
      is reported. The absorption values of different carbon dioxide concentrations
      were measured in a 119 microm CaF2 flow-through cell. An optical system made of
      parabolic mirrors was used to probe the flow cell and to focus the laser beam on
      the mercury cadmium telluride (MCT) detector. Aqueous carbon dioxide standards
      were prepared by feeding different mixtures of gaseous N2 and CO2 through wash
      bottles at controlled temperature. The concentration of the dissolved CO2 was
      calculated according to Henry's law, taking into account the temperature and the
      partial pressure of CO2. The carbon dioxide standards were connected via a
      selection valve to a peristaltic pump for subsequent, automated measurement in
      the flow-through cell. A calibration curve was obtained in the range of 0.338 to
      1.350 g/L CO2 with a standard deviation of the method sxo equal to 19.4 mg/L CO2.
      The limit of detection was calculated as three times the baseline noise over time
      and was determined to be 39 mg/L.

PMID- 15198820
TI  - Chemometric correction of drift effects in optical spectra.
AB  - All quantitative data evaluation techniques applied to spectroscopy are based on
      the assumption that the baseline is stable in time. If this prerequisite is
      violated, major concentration errors can result since drifts are evaluated along
      with true spectroscopic features. For handling baseline drifts two improved
      principal component regression (PCR) methods are presented and compared to
      conventional Savitzky-Golay preprocessing followed by conventional PCR. The
      proposed drift-correction methods take advantage of baseline drifts being rather
      broad compared to the absorption features. The only assumption made is that drift
      effects can be modeled sufficiently by polynomials of user-selectable order. One
      correction method modifies principal components such that drifts of polynomial
      shape are orthogonal to the calibration model and thus cannot influence the
      concentration result. The second method extends the calibration model by
      synthetic so-called pseudo-principal components. While the principal components
      model the true spectral features, the pseudo-principal components describe drifts
      simultaneously and independently. Hence, drifts are explicitly included into the
      calibration and cannot cause erroneous concentration results. It is demonstrated
      that both correction methods are equivalently as powerful as the conventional PCR
      in the absence of drifts and superior if drifts are present. The overall
      performance--in the absence and presence of baseline drifts--of the novel methods
      makes them more versatile and reliable than the conventional Savitzky-Golay data
      preprocessing. In almost all investigated cases, the average concentration errors
      were significantly smaller than those obtained by Savitzky-Golay preprocessing.
      Furthermore, polyPCR and pPCR do not need laborious optimizations as Savitzky
      Golay does for preventing suppression of relevant signal components. polyPCR
      demands less computation expense than Savitzky-Golay, and pPCR extracts the drift
      spectrum as additional qualitative information not provided by Savitzky-Golay.

PMID- 15198818
TI  - Automated Fourier transform infrared analysis of urinary stones: technical
      aspects and example of procedures applied to carbapatite/weddellite mixtures.
AB  - New software (ScanLith) was developed to provide an automated procedure for
      identifying and quantifying crystalline species in urinary calculi. The first
      step was to strictly define operative conditions of sample preparation because
      they have a significant influence on the stability of various crystalline phases.
      Second, we determined the quantification coefficients of a polynomial curve
      required to develop the automated procedure. This was illustrated by the study of
      carbapatite and weddellite, as both constituents represent one of the most
      frequent associations found in stones analyzed in our laboratory. The following
      quadratic equation was obtained with a correlation coefficient r2 = 0.9997: Y = 
      0.5144x2 + 1.5239x - 0.0141, where Y is the absorbance ratio
      carbapatite/weddellite and x is the percentage of carbapatite in the mixture. The
      absorbance of carbapatite and weddellite was measured at 1035 cm(-1) and 1325 cm(
      1), respectively. The third step was to validate the ScanLith procedure in
      routine analysis by comparing computed results with those of an expert.
      Concordance (r2 = 0.9824) was better than that previously reported using various
      computerized systems with a mean deviation of 4%. Algorithms developed in
      ScanLith to identify main and minor components found in urinary stones, even in
      complex mixtures containing up to seven constituents, allowed us to lower the
      detection threshold down to 1 to 10% depending on the main component.

PMID- 15198823
TI  - Fast-gated intensified charge-coupled device camera to record time-resolved
      fluorescence spectra of tryptophan.
AB  - The possibilities of a 200 ps gated intensified charge-coupled device (CCD)
      camera to record time-resolved fluorescence were explored using the fluorescing
      amino acid tryptophan and its derivative Nacetyl-tryptophan amide (NATA) as model
      compounds. The results were compared to complementary data from time-correlated
      single-photon counting (TCSPC) experiments. If a spectral resolution of 1-2 nm is
      desired, the fast-gated intensified CCD (ICCD) camera is the method of choice.
      For a 10(-5) M tryptophan solution, time-resolved emission spectra and intensity
      decays (measured over 12 ns at 25 ps resolution) could be obtained in typically
      10 minutes, giving the well-known lifetimes of 0.5 and 3 ns. In addition, a
      longer lifetime of 7 ns was found at the red edge of the spectrum. The very short
      gate time of the ICCD camera allowed us to observe a shift in the emission
      maximum of tryptophan even within the first nanosecond of decay of the
      fluorescence emission. As expected from the tryptophan rotamer model, such a
      shift is not observed in NATA. Using amplitudes obtained by global analysis,
      decay-associated spectra of these lifetimes were constructed.

PMID- 15198824
TI  - Characterization of aqueous and solid inclusion complexes of diuron and
      isoproturon with beta-cyclodextrin.
AB  - The interaction of diuron and isoproturon herbicides with beta-cyclodextrin is
      conducive to the formation of inclusion compounds in aqueous solution as well as
      in the solid state. The physico-chemical study of these complexes was carried out
      by various analytical techniques such as ultraviolet (UV), Fourier transform
      infrared (FT-IR), Raman, X-ray diffraction, and 1H-NMR (nuclear magnetic
      resonance) spectroscopies. The existence of inclusion complexes in water solution
      between the beta-cyclodextrin and each of the herbicides was revealed by
      electronic absorption and 1H-NMR spectroscopies. A 1:1 stoichiometry was
      determined for both complexes in aqueous medium from UV absorption spectra by
      using the Benesi-Hildebrand method; the relative stability constants at room
      temperature were calculated at 2700 +/- 300 L mol(-1) and 750 +/- 50 L mol(-1)
      for isoproturon and diuron, respectively. In the solid state, inclusion processes
      with beta-cyclodextrin were characterized by means of infrared and Raman
      techniques and confirmed by X-ray diffraction spectra.

PMID- 15198827
TI  - Measurements of OH radicals in a low-power atmospheric inductively coupled plasma
      by cavity ringdown spectroscopy.
AB  - Cavity ringdown spectroscopy is applied to line-of-sight measurements of OH
      radicals in an atmospheric-pressure argon inductively coupled plasma, operating
      at low power (200 W) and low gas flows (approximately 18 liters/min). Density
      populations of the single S21(1) rotational line in the OH A2sigma(+)-X2Pi (0-0)
      band are extracted from the measured line-of-sight absorbance. Plasma gas kinetic
      temperatures, derived from the recorded line shapes of the S21(1) line, ranged
      from 1858 to 2000 K with an average uncertainty of 10%. Assuming local
      thermodynamic equilibrium, an assumption supported by the comparison of the
      experimental and simulated spectra, the spatially averaged total OH number
      density at different observation heights was determined to be in the range of 1.7
      x 10(20)-8.5 x 10(20) (m(-3)) with the highest OH density in the plasma tail.
      This work demonstrates that ringdown spectra of the OH radical may be used both
      as a thermometer for high-temperature environments and as a diagnostic tool to
      probe the thermodynamic properties of plasmas.

PMID- 15198829
TI  - Two-dimensional Fourier transform Raman correlation spectroscopy determination of
      the glycosidic linkages in amylose and amylopectin.

PMID- 15198828
TI  - Raman spectroscopic detection for perchlorate at low concentrations.
AB  - Perchlorate (ClO4-) has recently emerged as a widespread environmental
      contaminant found in groundwater and surface water, and there is a great need for
      rapid detection and monitoring of this contaminant. In this study, we explore the
      use of surface-enhanced (SERS) and normal Raman spectroscopy for detecting ClO4-
      at low concentrations. We found that ClO4- is SERS active and, for the first
      time, were able to detect ClO4- at concentrations as low as 10(-6)-10(-7) M (or
      10-100 microg/L) through the application of silver SERS substrates or selective
      sorbents such as bifunctional anion-exchange resins. The use of selective
      sorbents greatly enhanced the reproducibility and sensitivity of ClO4- detection
      by normal Raman spectroscopy. Further exploration and research may allow
      application of these techniques for in situ, real-time detection and monitoring
      of ClO4- in environmental samples at even lower concentrations.

PMID- 15198830
TI  - Effects of autoclaving on bacterial endospores studied by Fourier transform
      infrared microspectroscopy.

PMID- 15198831
TI  - Comments on quantitative analysis of polyethylene blends by Fourier transform
      infrared spectroscopy.

PMID- 15198833
TI  - Closing the loop: the adicol experience.
AB  - The objective of the project Advanced Insulin Infusion using a Control Loop
      (ADICOL) was to develop a treatment system that continuously measures and
      controls the glucose concentration in subjects with type 1 diabetes. The modular
      concept of the ADICOL's extracorporeal artificial pancreas consisted of a
      minimally invasive subcutaneous glucose system, a handheld PocketPC computer, and
      an insulin pump (D-Tron, Disetronic, Burgdorf, Switzerland) delivering
      subcutaneously insulin lispro. The present paper describes a subset of ADICOL
      activities focusing on the development of a glucose controller for semi-closed
      loop control, an in silico testing environment, clinical testing, and system
      integration. An incremental approach was adopted to evaluate experimentally a
      model predictive glucose controller. A feasibility study was followed by efficacy
      studies of increasing complexity. The ADICOL project demonstrated feasibility of
      a semi-closed-loop glucose control during fasting and fed conditions with a
      wearable, modular extracorporeal artificial pancreas.

PMID- 15198834
TI  - Age-related glucometer design and selection: tools and principles for optimal
      solutions.
AB  - Special attention must be given to glucometer design, selection, and training for
      older adults with diabetes. The field of human factors provides insight into the
      special needs of older adults along with principles of design and instruction to
      apply to current and future glucometer systems. Necessary tools for designers and
      physicians include person analysis, user testing, and adherence to best practice
      guidelines. It is important to note that as glucometer systems change, new
      usability problems may arise as prior issues are resolved. However, some problems
      may be avoided prior to system production by using the theoretical background and
      guidelines provided by human factors specialists.

PMID- 15198835
TI  - Management of insulin therapy in urban diabetes patients is facilitated by use of
      an intelligent dosing system.
AB  - The Intelligent Dosing System (IDS, Dimensional Dosing Systems, Inc., Wexford,
      PA) is a software suite that incorporates patient-specific, dose-response data in
      a mathematical model, and then calculates the new dose of agent needed to achieve
      the next desired therapeutic goal. We evaluated use of the IDS for titrating
      insulin therapy. The IDS was placed on handheld platforms and provided to
      practitioners to use in adjusting total daily insulin dose. Fasting glucose,
      random glucose, and hemoglobin A1c were used as markers against which insulin
      could be adjusted. Values of markers expected at the next follow-up visit, as
      predicted by the model, were compared with levels actually observed. For 264
      patients, 334 paired visits were analyzed. Average age was 54 years, diabetes'
      duration was 10 years, and body mass index was 33.2 kg/m(2); 57% were female, 88%
      were African American, and 92% had type 2 diabetes. The correlation between IDS
      suggested and actual prescribed total daily dose was high (r = 0.99), suggesting
      good acceptability of the IDS by practitioners. Significant decreases in fasting
      glucose, random glucose, and hemoglobin A1c levels were seen (all P < 0.0001). No
      significant difference between average expected and observed follow-up fasting
      glucose values was found (145 vs. 149 mg/dL, P = 0.42), and correlation was high
      (r = 0.79). Mean observed random glucose value at follow-up was comparable to the
      IDS predicted level (167 vs. 168 mg/dL, P = 0.97), and correlation was high (r =
      0.73). Observed follow-up hemoglobin A1c was higher than the value expected (7.9%
      vs. 7.4%, P < 0.0055), but correlation was good (r = 0.70). These analyses
      suggest the IDS is a useful adjunct for decisions regarding insulin therapy even
      when using a variety of markers of glucose control, and can be used by
      practitioners to assist in attainment of glycemic goals.

PMID- 15198836
TI  - Analysis: "intelligent dosing system": a useful computer program for diabetes
      management?

PMID- 15198837
TI  - Experience with the continuous glucose monitoring system in a medical intensive
      care unit.
AB  - Strict glycemic control improves clinical outcomes in critically ill patients.
      However, practical tools for frequent monitoring of blood glucose (BG) levels in
      the intensive care unit (ICU) are limited. The Continuous Glucose Monitoring
      System (CGMS, Medtronic MiniMed, Northridge, CA) is currently approved for
      detecting glycemic excursions in outpatients with diabetes mellitus. The use of
      this device has never been carefully examined in the inpatient setting. This
      preliminary study was designed to investigate the accuracy of the CGMS in
      critically ill patients admitted to a medical ICU (MICU). Subjects at risk for
      hyperglycemia were recruited from among all patients admitted to our MICU. CGMS
      sensors were implanted for up to 72 h. Study subjects wore between one and five
      consecutive sensors. Four or more standard capillary BG readings were recorded
      per 24 h. All paired meter-sensor (M-S) readings were used both for CGMS
      calibration and for data analysis. Twenty-two MICU patients wore 41 CGMS sensors,
      yielding 546 M-S BG pairs. Overall, the Pearson correlation coefficient ( r ) was
      0.88, with a mean M-S difference of 3.3 +/- 26.7 mg/dL (0.6 +/- 17.4%) and a mean
      absolute M-S difference of 19.7 +/- 18.3 mg/dL (12.8 +/- 11.9%). Clarke Error
      Grid analysis categorized 98.7% of the M-S pairs within "clinically acceptable"
      zones A and B. The CGMS is promising for potential use in critically ill
      patients. If validated in larger studies, the device could serve as a useful
      research tool for investigating the role of hyperglycemia (and strict glycemic
      control) in ICU patients. If further developed as a "real-time" glucose sensor,
      CGMS technology could ultimately prove clinically useful in the ICU, by
      decreasing nursing workload and/or by providing alarm signals for impending
      glycemic excursions.

PMID- 15198838
TI  - Increased plasma glycated low-density lipoprotein concentrations in diabetes: a
      marker of atherogenic risk.
AB  - Nonenzymatic glycation of apolipoprotein B in the low-density lipoprotein (LDL)
      complex has been considered a proatherogenic modification contributory to the
      increased susceptibility of patients with diabetes to atherosclerosis. We
      postulated that glycated LDL concentrations might be associated with other
      markers of cardiovascular disease. To explore this hypothesis, we measured
      glycated LDL concentrations by a monospecific immunoassay in 50 patients with
      type 1 and 100 patients with type 2 diabetes and examined relationships with the
      amount of albumin excretion and the serum cholesterol and triglyercide
      concentrations. Plasma glycated LDL showed a significant positive correlation (r
      = 0.325; P < 0.001) with urinary albumin excretion that was higher in type 1 (r =
      0.463) than in type 2 (r = 0.245) patients. The mean glycated LDL concentration
      progressively increased with increasing albumin excretion when patients were
      subcategorized into groups of normoalbuminuria, low (</=100 microg/mg of
      creatinine), and high (101-300 microg/mg) microalbuminuria, and proteinuria.
      Glycated LDL also correlated positively and significantly with cholesterol (r =
      0.578) and triglyceride (r = 0.350) concentrations. The significant correlations
      in this cross-sectional analysis between glycated LDL and urinary albumin
      excretion, an index of cardiovascular mortality, and cholesterol and triglyceride
      concentrations, traditional markers of risk for cardiovascular disease, support
      the hypothesis that an elevated level of glycated LDL represents an atherogenic
      risk factor in patients with diabetes.

PMID- 15198839
TI  - The effect of preapplication of corticosteroids on skin irritation and
      performance of the GlucoWatch G2 Biographer.
AB  - Skin irritation due to iontophoresis may limit the frequency of use of devices
      for drug delivery or transdermal extraction of analytes of clinical interest.
      This study examined whether preapplication of corticosteroid preparations could
      reduce skin irritation from iontophoresis used by the GlucoWatch G2 Biographer
      (Cygnus, Inc., Redwood City, CA) in monitoring interstitial glucose levels
      frequently and automatically. Numerous corticosteroid preparations were screened
      to identify formulations that did not interfere with adhesion of the Biographer
      to the skin or glucose sensing. Kenalog (Westwood-Squibb Pharmaceuticals, Inc.,
      Buffalo, NY) (triamcinolone acetonide) and Cortizone-10 Quick Shot (Pfizer, Inc.,
      New York, NY) (hydrocortisone) sprays were selected and, in a double-masked,
      randomized, controlled trial, were applied to the forearms of 66 subjects with
      diabetes and allowed to dry. Biographers were applied and worn for 15 h, and home
      blood glucose measurements were taken every 30 min to assess accuracy. Irritation
      was assessed periodically by trained observers and study subjects. Skin
      irritation was reduced by both corticosteroid sprays, with the fraction of
      subjects who experienced moderate irritation reduced by 57% and 43% for the
      Kenalog and Cortizone-10 Quick Shot sprays, respectively. The treatment effect
      persisted at the 1-week assessment. Preapplication of these preparations did not
      affect the clinical utility of interstitial glucose readings. Preapplication of
      Kenalog or Cortizone-10 Quick Shot sprays significantly reduced skin irritation
      due to iontophoresis, and did not interfere with glucose measurements. This
      approach may enable the minority of users who experience moderate to severe skin
      irritation to use the Biographer more frequently for diabetes management.

PMID- 15198840
TI  - Analysis: blood glucose monitoring: making the possible practical.

PMID- 15198841
TI  - A prospective, randomized, multicentered controlled trial to compare the annual
      glycemic and quality outcomes of patients with diabetes mellitus monitored with
      weekly fructosamine testing versus usual care.
AB  - Fructosamine is an indicator of overall glycemic control for a 10-14-day time
      frame, medium-term marker, versus the 90-day average indicated by the hemoglobin
      A1c (A1C) test. The utility of the home fructosamine test for management of
      persons with diabetes remains undefined. The primary objectives of this study
      were (1) to compare the annual A1C results of subjects monitoring weekly
      fructosamine with those receiving usual care, (2) to identify the number of
      subjects achieving goal A1C, and (3) to determine if the addition of a weekly
      fructosamine test changed a subject's quality of life. This was a prospective,
      randomized, multicenter, controlled trial. Subjects were recruited from three
      sites and randomly assigned to collect weekly fructosamine in addition to daily
      glucose (Group 1) or to receive usual care of daily glucose collection (Group 2).
      Follow-up occurred at 3-month intervals for a year. Baseline and quarterly A1C
      tests were collected. Quality of life assessment was conducted at baseline and at
      the final study visit. Seventy-two subjects were randomized. Demographic and
      whole blood assessments were similar between the two groups at baseline. The mean
      percent change of A1C from baseline to final study visit in Group 1 (-0.52 +/-
      1.5) was not statistically different than Group 2 (-0.86 +/- 1.4) (P = 0.320).
      Seven subjects in each group achieved A1C of less than 7% (P = 0.532). No change
      in quality of life between or within the two groups was observed (P > 0.05) for
      each area of concern. Blood glucose monitoring alone was shown to be superior to
      the additional fructosamine testing after 1 year of treatment; however, weekly
      fructosamine testing demonstrated a decrease in A1C earlier and more consistently
      throughout the study. Despite glycemic improvement, the number of subjects
      attaining American Diabetes Association-defined A1C goals was not different
      between the treatment groups. Quality of life did not change with the addition of
      a weekly fructosamine test.

PMID- 15198842
TI  - Feasibility of continuous long-term glucose monitoring from a subcutaneous
      glucose sensor in humans.
AB  - The feasibility of continuous long-term glucose monitoring in humans has not yet
      been demonstrated. Enzyme-based electrochemical glucose sensors with telemetric
      output were subcutaneously implanted and evaluated in five human subjects with
      type I diabetes. Subject-worn radio-receiver data-loggers stored sensor outputs.
      Every 1-4 weeks the subject's glucose levels were manipulated through the full
      clinical range of interest using standard protocols. Reference blood glucose
      samples were obtained every 5-10 min and analyzed in our hospital clinical
      laboratory and/or on glucose meters. The sensor data were evaluated versus the
      reference data by linear least squares regression and by the Clarke Error Grid
      method. After surgical explantation and device inspection, the tissue-sensor
      interface was evaluated histologically. The remaining sensor-membranes were also
      recalibrated for comparison with preimplant performance. Four of the five glucose
      sensors tracked glucose in vivo. One sensor responded to manipulated glucose
      changes for 6.2 months with clinically useful performance (>/=90% of sensor
      glucose values within the A and B regions of the Clarke Error Grid). For this
      sensor, recalibration was required every 1-4 weeks. The other three transiently
      responding sensors had electronic problems associated with packaging failure. The
      remaining sensor never tracked glucose because of failure to form any sustained
      connection to adjacent subcutaneous tissue. Thus, stable, clinically useful
      sensor performance was demonstrated in one of five subjects with diabetes for a
      sustained interval of greater than 6 months. While this glucose sensor implant
      technology shows promise in humans, it needs to be made more reliable and robust
      with respect to device packaging and sensor-tissue connection.

PMID- 15198843
TI  - Insulin as an anabolic drug of abuse in sport?

PMID- 15198844
TI  - A wire-based dual-analyte sensor for glucose and lactate: in vitro and in vivo
      evaluation.
AB  - Continuous measurement of lactate is potentially useful for detecting physical
      exhaustion and for monitoring critical care conditions characterized by
      hypoperfusion, such as heart failure. In some conditions, it may be desirable to
      monitor more than one metabolic parameter concurrently. For this reason, we
      designed and fabricated twisted wire-based microelectrodes that can measure both
      lactate and glucose. These dual-analyte sensors were characterized in vitro by
      measuring their response to the analyte of interest and to assess whether they
      were susceptible to interference from the other analyte. When measured in stirred
      aqueous buffer, lactate sensors detected a very small amount of crosstalk from
      glucose in vitro, although this signal was less than 3% of the response to
      lactate. Glucose sensors did not detect crosstalk from lactate. Sensors were
      implanted subcutaneously in rats and tested during infusions of lactate and
      glucose. Each sensing electrode responded rapidly to changes in its analyte
      concentration, and there was no evidence of in vivo crosstalk. This study
      constitutes proof of the concept that oxidase-based, amperometric wire
      microsensors can detect changes in glucose and lactate during subcutaneous
      implantation in rats.

PMID- 15198845
TI  - Analysis: the promise of lactic acid monitoring in ambulatory individuals.

PMID- 15198846
TI  - Role of intact proinsulin in diagnosis and treatment of type 2 diabetes mellitus.
AB  - Insulin resistance in patients with type 2 diabetes is associated with an
      increased risk of cardiovascular events. While this can be partly explained by an
      impairment of direct insulin action on the endothelial cell, an independent
      contribution can be assigned also to the secretory dysfunction of the beta-cell.
      If the demand for insulin triggered by insulin resistance is arriving at a
      certain threshold, an insufficiency of the cleavage capacity of beta-cell
      carboxypeptidase H leads to an increased secretion of intact proinsulin in
      addition to the desired insulin molecule. Proinsulin, however, has been
      demonstrated to be an independent cardiovascular risk factor by stimulating
      plasminogen activator inhibitor-1 secretion and blocking fibrinolysis. A recently
      introduced intact proinsulin assay is able to distinguish between intact
      proinsulin and its specific and non-specific cleavage products. This assay allows
      for a pathophysiological staging of type 2 diabetes based on beta-cell secretion.
      It could be confirmed by a large epidemiological study (IRIS-2, 4,265 patients)
      that intact proinsulin is a highly specific marker for insulin resistance. It
      could also be shown in other studies that successful resistance treatment with
      insulin or glitazones led to a decrease in elevated proinsulin levels and, thus,
      to a decrease of cardiovascular risk, while the levels remained high during
      sulfonylurea therapy. Therefore, patients with increased fasting intact
      proinsulin values should be treated with a therapy focusing on insulin
      resistance. Assessment of beta-cell function by determination of intact
      proinsulin may facilitate the selection of the most promising therapy and may
      also serve to monitor treatment success in the further course of the disease.

PMID- 15198847
TI  - The role of glucosensing neurons in the detection of hypoglycemia.
AB  - Hypoglycemia is a life-threatening side effect of intensive insulin therapy in
      Type 1 diabetic patients. The ability to detect hypoglycemia and restore blood
      glucose levels to normal is of critical concern to the brain since glucose is its
      preferred fuel. When plasma glucose levels fall, powerful hormonal and
      sympathoadrenal mechanisms respond to restore blood glucose levels to normal.
      These mechanisms are believed to be initiated by diverse populations of glucose
      sensors, which are located centrally as well as peripherally. The exact
      contribution of each of these individual glucose sensors to the regulation of
      glucose homeostasis is not known at this time. This review focuses on the
      diversity of central and peripheral glucose sensors and the mechanisms by which
      they sense glucose.

PMID- 15198848
TI  - Computerised decision-support tools in diabetes care: hurdles to implementation.
AB  - In this Diabetes Information Technology & WebWatch column hurdles to the use of
      computerised decision-support tools in clinical diabetes care will be considered.
      The clinical background with respect to insulin-dependent (type 1) diabetes
      mellitus and the Diabetes Control and Complications Trial is reviewed, and an
      overview is given of various computer applications. The use of decision-support
      tools is discussed, and the importance of identifying the proposed user, e.g.,
      health-care professional, student, or patient, is highlighted.
      Validation/evaluation issues are considered as important topics that remain to be
      properly addressed for many decision-support prototypes. The column concludes by
      highlighting that in this era of evidence-based medicine well-conducted, rigorous
      evaluation and validation studies are required to inform decisions about whether
      or not to make use of current computerised decision-support prototypes.

PMID- 15198851
TI  - C-reactive protein: a predominant LPS-binding acute phase protein responsive to
      Pseudomonas infection.
AB  - As a structural component of the outer membrane of Gram-negative bacteria,
      endotoxin, also known as lipopolysaccharide (LPS) exhibits strong
      immunostimulatory properties, rendering it a pivotal role in the pathogenesis of
      Gram-negative septicaemia. Our attempt to identify LPS-binding proteins from the
      hemolymph of the horseshoe crab led to the isolation and identification of
      Creactive protein (CRP) as the predominant LPS-recognition protein during
      Pseudomonas infection. CRP is an evolutionarily ancient member of a superfamily
      of 'pentraxins'. It is a major protein in acute phase of infection in humans. Our
      investigation of CRP response to Pseudomonas aeruginosa unveiled a robust innate
      immune system in the horseshoe crab, which displays rapid suppression of a dosage
      of 10(6) CFU of bacteria in the first hour of infection and effected complete
      clearance of the pathogen by 3 days. Such a high dose would have been lethal to
      mice. Full-length CRP cDNA was cloned. Analysis of the untranslated regions
      suggests their crucial role in post-transcriptional regulation of CRP transcript
      levels. Northern blot analysis demonstrated an acute up-regulation of CRP by
      about 60-fold in 6-48 h of Pseudomonas infection. Taken together, our results
      provide new insights into the importance of CRP as a conserved molecule for
      pathogen recognition.

PMID- 15198850
TI  - D-galactosamine lethality model: scope and limitations.
AB  - D-Galactosamine (D-galN) is well established as sensitizing mice and other
      animals to the lethal effects of TNF, specifically, and by several orders of
      magnitude. Protection by anti-TNF neutralizing antibody is complete, as is
      (metabolically-based) protection by uridine. Sensitization occurs regardless of
      the origin of the released TNF, whether it is released from macrophages and/or T
      cells. The same is true for the challenging agent which leads to the release of
      TNF, whether it is endotoxin, a superantigen, lipoprotein, bacterial DNA, or
      bacteria, either killed or proliferating. Most studies have utilized endotoxin as
      the challenging agent, and more than 70 agents have been reported to confer
      protection against LPS and/or TNF challenge in the model. The model has provided
      new insight regarding modes of protection, including from dexamethasone, which
      protects against challenge from LPS but not from challenge by TNF. The D-galN
      lethality model has also been used to test for synergistic behavior between
      different bacterial components, and to test for lethality when only small amounts
      of the challenging agent are available (lipid A chemistry).

PMID- 15198852
TI  - Bacterial endotoxin modifies heat shock factor-1 activity in RAW 264.7 cells:
      implications for TNF-alpha regulation during exposure to febrile range
      temperatures.
AB  - Recent studies have identified heat shock factor (HSF)-1, the predominant
      heat/stress-stimulated transcriptional activator of heat shock protein genes as a
      repressor of certain cytokine genes, including TNF-alpha and IL-1beta. We
      previously showed that exposing macrophages to febrile-range temperature (FRT;
      39.5 degrees C) activates HSF-1 to a DNA binding form that does not activate heat
      shock protein gene transcription, but apparently represses TNF-alpha and IL-1beta
      transcription. Prewarming macrophages to 39.5 degrees C for 30 min prior to
      stimulation with bacterial lipopolysaccharide (LPS) does not change the induction
      of TNF-alpha transcription, but markedly reduces its duration. This raised the
      question of how TNF-alpha transcription could occur at all in the presence of
      activated HSF-1. We used RAW 264.7 cells to test the hypothesis that macrophage
      activation triggers a transient reversal of HSF-1-mediated repression, thereby
      allowing induction of TNF-alpha transcription. Electrophoretic mobility shift
      assays revealed that LPS triggers a transient inactivation of HSF-1 that
      temporally correlates with TNF-alpha transcription and was associated with a
      transient increase in HSF-1 molecular weight, a decrease in its pI, and
      appearance of HSF-1 phosphorylating activity. The serine/threonine phosphatase
      inhibitor, calyculin A, blocked the inhibitory affect of FRT on LPS-induced TNF
      alpha generation and prevented the re-activation of HSF-1. We propose that LPS
      stimulation of FRT-exposed macrophages stimulates a sequential phosphorylation
      and dephosphorylation of HSF-1, causing a cycle of inactivation and reactivation
      of HSF-1 repressor activity that allows a temporally-limited period of gene
      transcription.

PMID- 15198853
TI  - LPS binding protein does not participate in the pharmacokinetics of E5564.
AB  - E5564, a lipid A analogue, is a potent antagonist of lipopolysaccharide (LPS).
      Clinically, E5564 was developed as a possible therapy for treatment of sepsis and
      septic shock. Surface plasmon resonance (SPR) analysis indicates that E5564 binds
      to LPS binding protein (LBP), in a manner similar to LPS. Gel-filtration
      radioactive chromatograms of [(14)C]-E5564 in plasma revealed that E5564
      initially distributes to the lipoprotein fractions, separated from high-density
      lipoprotein (HDL); the bound fraction is then released and binds to HDL. Similar
      results were obtained by heparin-manganese precipitation. At doses of E5564
      relevant to its clinical use (i.e. 6 microg/ml), antibodies against LBP did not
      influence either the distribution of E5564 to non-HDL lipoprotein fractions or
      the transfer of E5564 from non-HDLs to HDL. Under these conditions, transfer of
      E5564 to HDL occurs similarly in the plasma of LBP knockout (KO) mice as in the
      plasma from wild-type mice. In addition, plasma clearance of E5564 in LBP KO mice
      is similar to that of wildtype mice. Thus, LBP binds E5564 in a manner similar to
      LPS, but does not play a role in E5564 redistribution/binding to lipoprotein and
      plasma clearance.

PMID- 15198854
TI  - A descriptive study of the variation in baseline levels of antiendotoxin core
      antibodies between US and UK populations.
AB  - Low levels of naturally occurring antibodies to the core section of endotoxin
      (EndoCAb) have been shown to be predictors of poor outcome following major
      surgery. We performed a retrospective study comparing pre-operative levels in US
      surgical patients, UK surgical patients and healthy volunteers. Both IgM and IgG
      EndoCAb levels were higher in the US surgical patients when compared with the
      other groups (approximately twice as high in the case of IgG EndoCAb). This may
      reflect genetic or environmental variability between the patient groups,
      differences in the disease processes, the disparity in the delivery of health
      care between the two countries or degradation of the samples in transfer.

PMID- 15198855
TI  - An international constant: The crucial role of policy competence in the effective
      strategic management of health services organizations.
AB  - In view of the pervasive impact of government policies on health services
      organizations worldwide, policy competence is an increasingly important element
      in the successful strategic management of these organizations. This article
      discusses a conceptual perspective of policy competence, including three
      intertwined components of this competence. Firstly, policy competence is built
      upon understanding the government policies that affect health services
      organizations, as well as understanding the process by which such policies are
      made and the forces that can affect the process and its outcomes. Secondly,
      policy competence helps strategic managers anticipate and lead responses of
      health services organizations to the opportunities and threats emanating from
      their policy environments. Finally, policy competence assists strategic managers
      to participate effectively in shaping the policy environments of health services
      organizations to the benefit of these organizations.

PMID- 15198856
TI  - Social regulation of healthcare organizations in the United States: developing a
      framework for evaluation.
AB  - Social regulation is ubiquitous in the US healthcare system, and American
      healthcare organizations claim to be among the most regulated institutions in the
      world. Yet relatively little is known about the impact of social regulation on
      these organizations' performance, or about the characteristics or determinants of
      effective regulatory strategies and approaches. This paper explores the use of
      social regulation in US healthcare, drawing on the wider literature on regulation
      in other countries and settings and on the growing body of general regulatory
      theory. It offers a framework for analysing and comparing regulatory
      arrangements, presents the findings from an exploratory qualitative study of
      regulators and regulated organizations, and concludes by developing a framework
      of the emergent characteristics of effective regulation which might be used in
      future evaluations of healthcare regulation.

PMID- 15198857
TI  - The role of professional expertise in the purchasing of health services.
AB  - Using data gathered from a mixture of quantitative and qualitative tools, this
      research into the purchasing of health services, namely occupational health
      services, is utilized to build an understanding of the role of service
      professionals in the purchasing of health services. In analysing the themes
      emerging from the interviews it was found that, typical of a complex, highly
      intangible professional service, the buyers found it difficult to objectively
      evaluate the service. The purchasing of occupational health services, similar to
      other professional services, was perceived to be an uncertain and risky process.
      The high uncertainties and risk of purchasing occupational health services lead
      to the utilization of the expertise of the service providers as a risk-reducing
      mechanism. This understanding of the role of health professionals in the
      purchasing of health services illustrates that the service characteristics
      enables the health professionals to utilize their expertise in influencing all
      stages of this process.

PMID- 15198859
TI  - Long-term planning to meet UK government coronary heart disease revascularization
      targets.
AB  - The National Service Framework (NSF) for Coronary Heart Disease, published in the
      UK in 2000, gave target intervention rates of 750 procedures per million
      population (pmp) for both percutaneous transluminal angioplasty (PTCA) and
      coronary artery bypass graft (CABG). This paper describes how one Regional Office
      of the Department of Health, with CABG and PTCA rates of around half the NSF
      target levels, designed a strategy to plan rationally to meet the derived
      population need for these procedures. A bottom-up needs assessment model was used
      to predict the population need for these procedures for the Eastern Region of the
      UK. The Excel-based model took account of the effects of demographic change,
      anticipated reduction in incidence of heart disease due to primary prevention
      programmes and the expected improvement in cardiology and cardiac surgery
      technologies. The model predicted that excess procedures would be required across
      the region over the next 20 years. Further access study modelling was used to
      determine the best location for additional tertiary cardiac centres. Further, a
      commissioning tool was produced that could compare the predicted need, including
      additional procedures needed to meet waiting list targets, with capacity
      available from a range of providers. These tools have been used successfully in
      the Eastern Region to increase the regional revascularization rates from 371 pmp
      CABG and 322 pmp PTCA in 2000 to planned rates of 453 pmp CABG and 447 pmp PTCA
      in 2002/2003, to recommend the building of a new tertiary cardiac centre in Essex
      in the next decade and to inform the commissioning of revascularization rates in
      three coronary heart disease networks.

PMID- 15198858
TI  - Manual handling risk controls in hospitals (MARCH): a cross-sectional survey of
      UK hospitals.
AB  - Injury and ill health among healthcare staff associated with handling patients is
      an important area of risk for UK National Health Service (NHS) employers. Since
      the introduction of a specific legal duty to control this risk in 1992, many
      Trusts have developed manual handling risk management strategies. Anecdotally,
      however, practice varies between Trusts and there is no published description of
      common practice among NHS employers. The latter would be useful as a benchmark
      for risk managers. Therefore, we undertook a cross-sectional survey of 158 UK
      trusts (81% of those invited) using a structured interviewer-administered
      questionnaire to collect information about manual handling risk controls. Most
      Trusts had basic systems for risk management, including defined management
      accountability, written policies, provision of handling equipment, training,
      expert advice about manual handling and access to occupational health services
      and physiotherapy for injured employees. However, there was wide variation in
      important aspects, including the extent of expert manpower and criteria for
      referral to occupational health. Arrangements for monitoring risk controls were
      generally poor, and the variation in practice was a cause for concern. These data
      will help NHS employers by providing a benchmark against which to measure and
      develop risk management systems for manual handling. Future research should aim
      to develop standards through consensus opinion and ultimately evidence of
      effectiveness of risk controls.

PMID- 15198860
TI  - Cell transplantation for Parkinson's disease.
AB  - Parkinson's disease (PD) is a progressive neurodegenerative disorder
      characterized by the degeneration of the dopamine producing neurons projecting
      from the substantia nigra into the corpus striatum. Current medical therapy is
      limited and cannot stop or reverse the degeneration. Over the past 30 years,
      attempts were made to change the course of the disease by replacing the lost
      neurons with grafts from various sources. Recent controlled clinical trials of
      fetal cell transplantation for PD have had disappointing results. These events
      present an opportunity to examine the past developments and future direction of
      cell transplantation for PD.

PMID- 15198861
TI  - The role of a barrier between two nerve fascicles in adjacency after transection
      and repair of a peripheral nerve trunk.
AB  - Aberrant reinnervation of target organs caused by misdirected axonal growth at
      the repair site is a major reason for the poor functional outcome usually seen
      after peripheral nerve transection and repair. The following two studies
      investigate whether criss-crossing of regenerating rat sciatic nerve axons
      between tibial and peroneal nerve fascicles can be reduced by using a barrier at
      the coaption site. The left sciatic nerve was transected and repaired at mid
      thigh as follows: epineural sutures (group A, A-II), fascicular repair of tibial
      and peroneal nerve fascicles (group B, B-II), fascicular repair of tibial and
      peroneal nerve fascicles separating the two fascicles with a pedicled fat flap
      (group C), Integra (group D) or non-vascularized autologous fascia (group C-II).
      In the control groups E and D-II, only the left tibial fascicle was transected
      and repaired. Four and 5 months postoperatively, the outcome of regeneration was
      evaluated by histology, by retrograde tracing, and by assessment of the muscle
      force of the gastrocnemius and tibial anterior muscles. The tracing experiments
      showed that specificity of muscle reinnervation significantly improved when a
      barrier was employed, which significantly or clearly improved muscle twitch
      tension in groups C and D. However, muscle contraction force was not better when
      fascia was used as barrier. The histological picture indicated that this inferior
      result in group C-II was due to nerve compression caused by fibrotic scar tissue
      at the site of the fascia graft. Results of this study show that a pedicle fat
      flap and Integra used as barrier significantly prevent aberrant reinnervation
      between two sutured nerve fascicles in adjacency resulting in improved motor
      recovery in rats. Non-vascularized autologous fascia however, reduces also criss
      crossing of regenerating axons between the fascicles, but causes significant
      nerve compression.

PMID- 15198862
TI  - Neuroregenerative and neuroprotective actions of neuroimmunophilin compounds in
      traumatic and inflammatory neuropathies.
AB  - FK506 (tacrolimus, Prograf is an immunosuppressant drug that also has profound
      neuroregenerative and neuroprotective actions independent of its
      immunosuppressant activity. The separation of these properties has led to the
      development of non-immunosuppressant derivatives that retain the neurotrophic
      activity. This review focuses on the peripheral nerve actions of these compounds
      following mechanical injury (nerve crush or transection with graft repair) and in
      models of inflammatory neuropathies. Whereas FK506 may be indicative for the
      treatment of inflammatory neuropathies where its immunosuppressive action would
      be advantageous, non-immunosuppressant derivatives represent a new class of
      potential therapeutic agents for the treatment of human neurological conditions
      in general. Moreover, these studies have led to the discovery of a novel
      mechanism whereby these compounds activate intrinsic neuroregenerative and
      neuroprotective pathways in the neuron.

PMID- 15198863
TI  - Neurotropism revisited.
AB  - The purpose of this study is to re-examine the probable directive effect of the
      distal stump of a severed peripheral nerve on regenerating axons. Forssman
      postulated the existence of such a directive influence and Cajal interpreted it
      as chemotactic in nature. This view was subsequently refuted by Weiss and Taylor.
      In our study the proximal stumps of transected rodent sciatic nerve were inserted
      into the single inlet end of a Y-shaped autogenous inferior vena cava graft. Into
      one limb of the double outlet end, namely the common iliac nerve bifurcation, the
      distal stump of the same sciatic nerve was inserted, while the counter limb was
      ligated in one group, left open in the second group, inserted with a segment of
      autogenous tendon in the third, and grafted with a segment of autogenous nerve in
      the fourth group. Both outlets were left unoccupied in yet another group as the
      control. The vena cava conduit was prepared so that a 1.5 cm gap existed between
      the proximal stumps of the sciatic nerve and the distal sciatic nerve stumps and
      the tendon grafts respectively. The grafted sciatic nerves were explored and
      biopsied after 12 weeks. The direction of nerve tissue regeneration in each group
      was analyzed histologically. Predilection of the regenerating nerve fibers toward
      the distal stumps was observed in each of the test groups. These results indicate
      the existence of a guiding influence at the distal stump toward the regeneration
      nerve fibers.

PMID- 15198864
TI  - Muscle-nerve-muscle neurotization for the reinnervation of denervated somatic
      muscle.
AB  - Muscle-Nerve-Muscle (MNM) is the reinnervation of a denervated (recipient) muscle
      via a nerve graft inserted into the belly of an innervated (donor) muscle. MNM is
      studied for the reinnervation of intrinsic denervated somatic skeletal muscle by
      evaluating both restored muscle contractile ability and innervation state. In a
      rat model, muscle function is tested following MNM neurotization from an
      innervated (donor), extensor digitorum longus muscle to a denervated (recipient),
      peroneus digit quinti (PDQ) muscle. PDQ muscle cross-sections labeled for neural
      cell adhesion molecule protein (NCAM), a marker for fiber denervation. MNM
      neurotization results in the recovery of PDQ muscle force generating capacity
      (58% of Normal-control) and a significantly lower percentage of residual muscle
      fiber denervation (38% denervated) compared with the Denervated-control (79%
      denervated) group. MNM neurotization reinnervates 62% of the previously
      denervated muscle fibers in the PDQ muscle. No decrement in force capacity is
      observed in the donor EDL muscle. Nerve grafting for MNM neurotization may
      restore modest contractile function to denervated muscle and reinnervate
      relatively more denervated muscle fibers than the Denervated-control.

PMID- 15198865
TI  - Motoneurons innervating facial muscles after hypoglossal and hemihypoglossal
      facial nerve anastomosis in rats.
AB  - Hypoglossal-facial nerve anastomosis (HFA) is the most popular surgical procedure
      to reinnervate facial muscles after injury of the facial nerve. Section of the
      hypoglossus causes paralysis and atrophy of the hemi-tongue. In the attempt to
      overcome this consequence, the hemihypoglossal-facial nerve anastomosis (HHFA)
      has been proposed and only a half of the main trunk of the hypoglossus is
      connected to the distal stump of the facial nerve. In the rat, we have studied
      experimentally the anatomical nuclear changes after HFA and HHFA with the aim of
      establishing the quantitative motoneuron innervation of facial muscles obtained
      with each one of the two operative options. Horseradish peroxidase (HRP) injected
      in both types of anastomosis labeled not only hypoglossal motoneurons, but also
      facial motoneurons. HFA appeared to offer a significant quantitative motoneuron
      innervation higher than HHFA and then a higher probable better functional
      recovery. Both HFA and HHFA performed immediately after section of the facial
      nerve in rats did not result in a phenomenon of motor hyperinnervation. In our
      experimental model, the proximal facial nerve stump was coagulated at the
      stylomastoid foramen to avoid regeneration. Then, the labeled motoneurons into
      the facial nucleus could really be the expression of axonal projections from
      facial motoneurons to the hypoglossus nerve and facial muscles. No labeled
      motoneurons were seen contralaterally as we observed previously after section and
      repair of several nerves.

PMID- 15198866
TI  - Differentiation-inducing activity of neomycin in cultured rat glioma cells.
AB  - Induction of cellular differentiation is an attractive therapeutic strategy
      against glioma cell proliferation and tumorigenicity. Preliminary in vitro
      studies have indicated that neomycin inhibits the proliferation of cultured
      glioma cells and induces changes in cellular morphology, making it potentially
      useful as a therapeutic agent for gliomas. The purpose of this work was to expand
      on the preliminary research by investigating the differentiation effect of
      neomycin in rat C6 glioma cells, using glial fibrillary acidic protein (GFAP)
      staining as a reliable marker of differentiation for normal astrocytes and for
      tumors of astrocytic lineage. Cell cultures were grown in the absence or presence
      of 10 mM neomycin sulfate for 48 hours. Neomycin treatment produced changes in
      cell morphology and GFAP expression indicative of cellular differentiation. These
      results suggest that neomycin is an attractive differentiation agent for the
      treatment of gliomas.

PMID- 15198867
TI  - Neuroprotection against transient cerebral ischemia by exercise pre-conditioning
      in rats.
AB  - There is increasing evidence that physical activity is associated with decreased
      stroke risk and incidence. The purpose of this study was to determine whether
      increased levels of physical activity could reduce brain damage in rats subjected
      to transient or permanent middle cerebral artery (MCA) occlusion. Adult male
      Sprague-Dawley rats (three months old, n=36) exercised on a treadmill, which
      required repetitive locomotor movement, for 30 min each day for three weeks.
      Then, using an intraluminal filament, stroke was induced by either 2-h MCA
      occlusion followed by two days of reperfusion or by MCA occlusion for two days
      without reperfusion. Brain damage was determined by evaluating neurologic
      deficits and brain infarction. In rat with transient MCA occlusion, pre-ischemic
      motor activity significantly (p<0.01) reduced neurologic deficits and infarct
      volume in the frontoparietal cortex and the dorsolateral striatum. In contrast,
      the same exercise procedure did not produce neuroprotection in the permanently
      MCA-occluded stroke. In addition to decreasing stroke risk and incidence,
      physical activity also reduces brain damage after stroke. Although we cannot
      completely rule out a neuroprotective effect on ischemic episode, our study
      suggests that a major neuroprotection is conferred during reperfusion for rats
      that have undergone exercise pre-conditioning. This exercise-induced endogenous
      neuroprotection may be an effective strategy to ameliorate ischemia/reperfusion
      brain injury from stroke.

PMID- 15198868
TI  - Transcranial Doppler in infantile cerebrospinal fluid disorders: clinical
      validity.
AB  - The present study was designed to investigate a possible relationship between
      transcranial Doppler sonography (TCD) parameters with infantile hydrocephalus and
      other types of cerebrospinal fluid (CSF) abnonnalities, i.e. arrested
      hydrocephalus and essential ventriculomegaly. TCD parameters in the major
      arteries of the circle of Willis were studied in hydrocephalic children (n = 12)
      before and after insertion of a ventricular shunt device. It was correlated with
      TCD parameters of children with CSF disorders (n = 13), in whom no surgery was
      performed. Also, TCD parameters were assessed in control cases (n = 10). Mean
      values for medial cerebral artery (MCA) flow velocities were higher in the
      essential ventriculomegaly (75.38 +/- 4.1) and in the control group (73.93 +/-
      3.4) compared with hydrocephalic children (64.13 +/- 5.3). All hydrocephalic
      children had a higher mean MCA pulsatility index (RI) (1.08 +/- 0.13) and
      resistance index (RI) (0.64 +/- 0.17) values than the essential ventriculomegaly
      group (PI: 1.03 +/- 0.48; RI: 0.63 +/- 0.13) and the control group (PI: 0.84 +/-
      0.32; RI: 0.57 +/- 0.23). Analysis of all TCD parameters disclosed its usefulness
      only after a particular and thorough evaluation of the TCD results with special
      emphasis in the clinical correlation of every case.

PMID- 15198869
TI  - Influence of cerebral oxygenation following severe head injury on
      neuropsychological testing.
AB  - Despite recent advances in the management of severe head injury the mortality and
      morbidity remains high. Intracranial pressure (ICP) and cerebral perfusion
      pressure (CPP) are crucial parameters for the correct management at the intensive
      care unit, due to their therapeutic and prognostic importance. In addition,
      regional brain tissue oxygenation (ptiO2) seems to be of importance. While
      different studies demonstrated the impact of cerebral hypoxia on outcome
      (mortality), no data are available focusing on morbidity (neuropsychological
      deficits). Therefore, our study is carried out to demonstrate a possible
      relationship between amount of cerebral oxygenation during acute stage after
      severe head injury and neuropsychological outcome. Besides ICP and CPP, ptiO2 was
      monitored in 40 severely head injured patients during the ICU stay from the day
      of admission until day 10. Monitoring data were stored and amount of hypoxic
      episodes were calculated. Besides outcome using the Glasgow Outcome Scale
      neuropsychological testing was performed 2-3 years after injury. Analysing the
      quality of brain tissue oxygenation, a relationship to the performance in
      neuropsychological tests could be found. Patients with low brain tissue
      oxygenation had a worse outcome in neuropsychological testing, especially
      concerning intelligence and memory. Associated with these deficits patients
      showed a reduced performance in their profession. Our data suggest a possible
      predictive value of brain tissue oxygen on morbidity analysing neurocognitive
      function after head injury. This may implicate monitoring and treatment of
      cerebral hypoxia.

PMID- 15198870
TI  - Synergistic inhibition of lipid peroxidation by vitamin E and a dopamine agonist,
      cabergoline.
AB  - We examined antioxidant activity of cabergoline, a dopamine agonist, during the
      aerobic oxidation of phosphatidylcholine liposomes at 37 degrees C. Cabergoline
      retarded the oxidation initiated with a lipid-soluble initiator significantly
      better than that with a water-soluble initiator, suggesting that cabergoline
      locates in the lipid layer of liposomal membranes. Cabergoline inhibited the
      oxidation of liposomal membranes synergistically with endogenous antioxidants
      such as ascorbic acid, ubiquinol-10 and vitamin E, and vitamin E was the most
      efficient synergist. These results suggest that cabergoline may have a
      neuroprotective effect on the substantia nigra of Parkinsonian patients because
      of its synergistic antioxidant activity with vitamin E as well as its action on
      dopamine receptor.

PMID- 15198871
TI  - Ginsenoside Rg1 promotes proliferation of hippocampal progenitor cells.
AB  - Neural progenitor cells (NPCs) exist not only in the developing brain, but also
      in certain areas in adult brain in mammals. Recent studies suggest that promoting
      neurogenesis in adult mammals might provide a therapeutic way to cure age-related
      neurodegenerative diseases. So, it will be of great value to find out drugs that
      can increase the proliferation and/or differentiation ability of neural
      progenitors. The present study investigated the influence of ginsenoside Rg1, an
      active ingredient of Panax ginseng C.A. Meyer, on proliferation ability of rodent
      hippocampal progenitor cells both in vitro and in vivo. Incubation of NPCs with
      ginsenoside Rg1 resulted in significant increase in absorbency value, 3H
      thymidine incorporation and the number of proliferating progenitor cell spheres;
      In addition, 2 weeks Rg1 administration (i.p.) led to marked enhancement of the
      number of dividing cells in the hippocampus of adult mice. These findings suggest
      that ginsenoside Rg1 is involved in the regulation of proliferation of
      hippocampal progenitor cells and this effect may serve as one of the elementary
      mechanisms underlying its nootropic and anti-aging actions.

PMID- 15198872
TI  - Magnetic resonance angiography image guidance for the microsurgical clipping of
      intracranial aneurysms: a report of two cases.
AB  - To describe the integration of magnetic resonance angiography (MRA) in
      neuronavigation procedures for microsurgery of intracranial aneurysms. MRA was
      combined with standard magnetic resonance image (MRI) acquisition in the image
      guided planning for the microsurgical clipping of a saccular aneurysm in two
      patients (one 3-mm large middle cerebral artery and one 8-mm large pericallosal
      artery aneurysm, diagnosed by catheter angiography in both patients) using two
      different neurosurgical navigation systems. Conventional 3-D T1-weighted MRI with
      gadolinium and MRA pulse sequences were acquired in frameless stereotactic
      conditions the day before surgery and thereafter registered, allowing the
      definition a minimally invasive straight trajectory to the aneurysm neck. MRA
      guided neurosurgery allowed a direct approach to the aneurysms at their proper
      location, reducing the invasiveness of the approach by tailoring the bone opening
      and reducing the duration and extension of brain retraction. The technique also
      avoided unnecessary dissection and exposure of the main trunks and collateral
      vessels. The aneurysms were successfully eradicated without complication.
      Integration of MRA in the planning and neuronavigation procedure for intracranial
      aneurysms may minimize the morbidity related to the surgical approach. This
      technique may be applicable more routinely using standard neuronavigation
      equipment.

PMID- 15198873
TI  - Transdermal nitroglycerin in patients with subarachnoid hemorrhage.
AB  - Delayed ischemic neurological deficit (DIND) following cerebral vasospasm remains
      a cause for high morbidity and mortality in patients with subarachnoid hemorrhage
      (SAH). There is experimental and clinical evidence of positive effects of nitric
      oxide (NO) donors on cerebral vasospasm. We therefore analysed the effect of
      transdermal nitroglycerin in patients with SAH measuring transcranial Doppler
      velocities (TCD), cerebral blood flow (CBF) and DIND. Nitroglycerin was used in a
      target dose of 14 microg/kg/h. TCD assessment was performed daily. CBF
      measurements were done using the perfusion CT-technique. Blood pressure, volume
      intake and vasopressor administration, were registered. Nine patients were
      randomly assigned either to the nitroglycerin group (N-group) and eight patients
      in the control group (C-group). Mean TCD values in the extracranial portion of
      the internal carotid artery (ICA) were lower in the N-group (p<0.005). Mean TCD
      in the middle cerebral arteries (MCA) showed no difference. The Lindegaard ratio
      was higher in the N-group (p<0.04). CBF in the N-group was higher than in the C
      group (p<0.03). Even though nitroglycerin reduces blood pressure and lowers ICA
      TCD-values and increases the Lindegaard ratio, a higher CBF was measured in the N
      group. Thus, nitroglycerin influences the cerebral vascular tone and increases
      CBF. SAH therapy with nitroglycerin is possible without increasing the risk of
      DIND. The exact timing of onset, duration and reduction of nitroglycerin
      administration in respect to the appearance of vasospasm may have a strong impact
      on the success of such a therapy.

PMID- 15198874
TI  - S-100B protein as a serum marker of secondary neurological complications in
      neurocritical care patients.
AB  - There is growing evidence that S-100B protein measured by a simple blood test can
      be used as a novel biochemical marker of brain cell damage. The objective of our
      study was to investigate the potential of S-100B measurements to diagnose an
      acute neurological complication in the analgo-sedated and intubated intensive
      care patient and the impact on patient management. Serum S-100B levels were
      serially investigated in 246 neurocritical care patients. Venous blood samples
      for S-100B determination were obtained as soon as possible after admission and
      every 24 hours thereafter, for the duration of the stay at the neurocritical care
      unit. Blood samples were taken every morning as part of the routine laboratory
      investigation for analysis of S-100B using the immunoluminometric assay (AB
      Sangtec Medical, Bromma, Sweden) and a fully automated LIAISON system (Byk
      Sangtec-Diagnostica, Dietzenbach, Germany) with a short time to result. The
      primary endpoint of our study was the occurrence of a severe neurological
      complication. Patients were admitted to the neurosurgical intensive care unit
      after routine major intracranial surgery in 116 cases (47%) and after a
      neurological or neurosurgical emergency in 130 cases (53%). Of the latter group,
      79 patients (32%) underwent emergency surgery for evacuation or decompression of
      a space-occupying lesion before ICU admission. A severe neurological complication
      was defined as a new infarction, new hemorrhage or a newly developed progressive
      disease despite maximum therapy with a radiologically confirmed increase of mass
      lesion and midline shift. In 33 patients (13%) a complication with neurological
      deterioration occurred. All patients showed pathologically increased serum S-100B
      values (mean 2.00 microg/l, standard deviation 2.61 microg/l, range 0.31-9.66
      microg/l). Twenty-eight of these patients (85%) showed S-100B increases >0.5
      microg/l. In five cases (16%), the increase in S-100B was the first sign of
      neurological complication and prompted emergency computed tomography scanning. In
      another two cases, increasing S-100B values changed management decision towards a
      surgical intervention. The major finding of our study was the influence of serial
      S-100B measurement on actual management of the patient in 21% of cases with
      neurological complications.

PMID- 15198875
TI  - Enhancement of study on hemostatic and thrombotic disorders.

PMID- 15198876
TI  - Certain new progresses in experimental hematology in China and more queries on
      mesenchymal stem cell research.

PMID- 15198877
TI  - Clinical phenotypes, ALK1 gene mutation and level of related plasma proteins in
      Chinese hereditary hemorrhagic telangiectasia.
AB  - BACKGROUND: We determined the diagnosis of hereditary hemorrhagic telangiectasis
      (HHT) in a suspected HHT family, identified ALK1 gene mutation and established a
      gene diagnosis method of HHT. The level of related plasma proteins (transforming
      growth factor beta and thrombomodulin) were also analyzed. METHODS: Bleeding
      history and family history were collected; Dilatant nasal mucosal capillaries in
      proband were observed under nasal cavity endoscope; exons 3, 7, 8 of ALK1 gene in
      proband and her family members were amplified with polymerase chain reaction
      (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent
      assay (ELISA), plasma TGF-beta1 and TGF-beta2 concentrations were measured.
      Plasma thrombomodulin (TM) level was detected by Western blotting. RESULTS: Of
      all family members, four had epstaxis, two had evident telangiectases on skin or
      mucosa. Gene screening results showed that C to T substitution at position 1231
      in exon 8 of ALK1 gene (CGG-->TGG) existed in proband, her affected brother and
      their father. The mutation did not exist in proband's sister-in-law and nephew.
      Plasma TGF-beta1 concentrations in the affected HHT was 20,538, 17,194, 13,131
      pg/ml, while that of normal control and unaffected family members was 15,950,
      20,297, 12,836 pg/ml, respectively. Plasma TGF-beta2 in HHT patients was 14,502,
      9550, 10,592 and that of normal controls 8579, 20,297, 7680 pg/ml respectively.
      Level of plasma TM was in HHT subjects significantly lower than in normal
      subjects. CONCLUSIONS: Chinese HHT individuals have mutant ALK1 gene, a C1231T
      variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this
      family. ALK1 gene analysis, together with special clinical phenotypes and family
      history, provides a reliable method in diagnosing HHT. In affected HHT subjects,
      plasma TGFbeta levels were not obviously different from those of normal subject;
      while plasma TM concentration was significantly lower than that in normal
      subjects. The significance and mechanism remain to be elucidated.

PMID- 15198878
TI  - Biochemical activity and gene analysis of inherited protein C and antithrombin
      deficiency in two Chinese pedigrees.
AB  - BACKGROUND: We identified the gene mutations in two Chinese pedigree of type I
      hereditary protein C deficiency and type I hereditary antithrombin deficiency.
      METHODS: The plasma level of protein C activity (PC:A), protein C antigen
      (PC:Ag), protein S activity, antithrombin activity (AT:A) and antithrombin
      antigen (AT:Ag) of propositi and two family members were detected using ELISA and
      chromogenic assay, respectively. All exons and intron-exon boundaries of protein
      C gene and antithrombin gene were analyzed by direct sequencing of the
      corresponding amplified PCR products in DNA from the propositus. RESULTS: The
      plasma PC:A and PC:Ag of propositus 1 was 26% and 1.43 mg/dl, respectively. The
      PC:Ag and PC:A of his father were normal. The decreased PC:A level was seen in
      his mother and 4 of his maternal pedigree. PS:A and AT:A were all normal in
      pedigree 1 members. A C5498T heterozygous mutation in exon 3 of protein C gene,
      resulting in the substitution of Arg for Trp at the 15th amino acid, was
      identified in propositus 1 and 8 of his relatives. The plasma AT:A and AT:Ag of
      propositus 2 was 48.6% and 10.4 mg/dl, respectively. The reduced AT:A and AT:Ag
      levels were found in his father and 5 of paternal pedigree. PC:A, PC:Ag and PS:A
      were all in normal range. A heterozygous 13387-9G deletion in exon 6 of
      antithrombin gene was identified in propositus 2. This mutation introduced a
      frameshift and a premature stop at codon 426 and existed in 6 members of pedigree
      2. CONCLUSION: The C5498T heterozygous mutation in exon 3 of protein C gene,
      first reported in China, leads to type I hereditary protein C deficiency. The
      13387-9G deletion, a novel mutation, can cause antithrombin deficiency and
      thrombosis.

PMID- 15198879
TI  - Evaluation of von Willebrand factor-cleaving protease activity in patients with
      thrombotic thrombocytopenic purpura.
AB  - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic
      microangiopathy. In this study we investigated the von Willebrand factor-cleaving
      protease (vWF-cp) activity deficiency in patients with TTP. METHODS: The plasma
      or serum vWF-cp activity was measured using a sensitive enzyme-linked
      immunosorbent assay (ELISA) by detecting the residual collagen binding activity
      (R-CBA) of von Willebrand factor (vWF) before and after digestion by vWF-cp.
      Multimers of vWF in plasma of patients with TTP were also analyzed by SDS-agarose
      electrophoresis. Moreover, the serum vWF-cp activities were compared between the
      patients with TTP and those with tumors. RESULTS: The coefficient of variation
      for intra-batch and inter-batch of the assay were 3.60% and 8.35%. The plasma and
      serum vWF-cp activity in healthy individuals were (78.79 +/- 9.17)% (n = 30) and
      (79.47 +/- 10.78)% (n = 53), respectively, while the plasma vWF-cp activity in 5
      patients with TTP was markedly decreased [(21.83 +/- 19.98)%, P < 0.001]. The
      unusually large vWF multimers were observed in two plasma samples of the patients
      with TTP. Although the vWF-cp activities in patients with benign and malignant
      tumors were also decreased (P < 0.03 and P < 0.001, respectively), they were
      relatively high in comparison with that of TTP patients (P < 0.001). CONCLUSION:
      Measurement of the vWF-cp activity using R-CBA is a simple and rapid method for
      diagnosing TTP. The vWF-cp activity in patients with TTP was markedly lower than
      those of patients with tumors.

PMID- 15198880
TI  - Emergency off-pump coronary artery surgery.
AB  - BACKGROUND: Off-pump coronary artery bypass grafting is fast-becoming a procedure
      of choice for elective revascularization in high-risk patients with multi-vessel
      coronary artery disease. However, the role of off-pump coronary artery bypass
      grafting for patients with acute coronary syndromes requiring emergency
      revascularization still requires validation. We present our experience to show
      the feasibility of off-pump coronary artery surgery as an emergency
      revascularization technique. METHODS: From April 2001 to September 2003,
      emergency (operation within 24 hours after hospitalization) coronary artery
      bypass grafting without cardiopulmonary bypass (CPB) was performed in 66 patients
      with a mean age of (66.9 +/- 5.4) years (range 49-72 years). They presented acute
      coronary syndromes with 38 patients on platelet glycoprotein IIb/IIIa receptor
      antagonists. All patients underwent off-pump coronary artery bypass surgery via
      sternotomy with the intention of complete coronary revascularization. RESULTS: An
      average of 2.9 grafts per patient were performed and the posterior descending
      artery and marginal branches of the circumflex artery were grafted in 83.3% of
      the patients. There were 4 events of intraoperative cardiac instability,
      precipitated by occlusion of right coronary artery or positioning of a
      cardiomegaly heart, leading to immediate conversion to CPB. The mortality rate
      was 3% (2/66). Two patients suffered postoperative stroke while three needed
      hemofiltration for acute renal failure. Post surgery elective coronary
      angiography (n = 46) showed no significant stenosis. CONCLUSION: Emergency off
      pump coronary artery surgery with complete revascularization is feasible in
      patients with acute coronary syndrome with low morbidity and mortality and
      excellent early results.

PMID- 15198881
TI  - Protective effect of a bacterial extract against acute exacerbation in patients
      with chronic bronchitis accompanied by chronic obstructive pulmonary disease.
AB  - BACKGROUND: Immunostimulating agents made from bacterial extracts represent a
      class of medications that contains antigens derived from several bacterial
      strains and their potential ability to prevent bacterial infections results from
      the stimulation of the nonspecific component of the immune system. The present
      study investigated the effect of the oral immunostimulant Broncho-Vaxom, which
      includes material from eight different species of bacteria that are frequently
      present in the lower respiratory tract, on the frequency and severity of acute
      exacerbation in patients with chronic bronchitis accompanied by chronic
      obstructive pulmonary disease (COPD). METHODS: Ninety patients with chronic
      bronchitis complicated with COPD were randomly divided into groups A and B. Forty
      nine subjects in group A received oral capsules containing 7 mg Broncho-Vaxom,
      while 41 patients in group B received similar placebo capsules. Both groups took
      one capsule daily for the first 10 days of each month for 3 consecutive months.
      The frequency of acute exacerbation, symptom scores, and lung function were
      recorded for the following one year period. RESULTS: There was a significant
      decrease in the incidence, duration, and severity of acute exacerbation, as well
      as a reduction in the course of antibiotics administered and in the dosage of
      bronchodilator and mucolytic agent in group A, as compared to group B (P < 0.05,
      respectively). Symptom scores for cough, sputum, dyspnea, as well as symptoms
      observed upon auscultation of the chest also improved significantly in group A as
      compared to group B (P < 0.05, respectively). The bacterial clearance rate in
      sputum cultures from patients who received no antibiotics for the first 3 months
      was also significantly higher in group A compared to group B (P < 0.01).
      CONCLUSIONS: Orally administered Broncho-Vaxom is associated with a decrease in
      the incidence of acute exacerbation and a decrease in the need for antibiotics
      and symptomatic relief medications in patients with chronic bronchitis
      accompanied by COPD. Broncho-Vaxom is also associated with a decrease in symptom
      scores. Without causing any apparent adverse effects, this drug may also help to
      eradicate pathogenic bacteria in the airways.

PMID- 15198882
TI  - Effects of postoperative immune-enhancing enteral nutrition on the immune system,
      inflammatory responses, and clinical outcome.
AB  - OBJECTIVE: This study was conducted to evaluate the effects of postoperative
      immune enhancing enteral nutrition on the immune system, inflammatory responses,
      and clinical outcome of patients undergoing major abdominal surgery. METHODS:
      This study was designed as a multicenter, prospective, randomized and controlled
      clinical trial. One hundred twenty-four patients undergoing major abdominal
      surgery were randomly assigned to receive either an immune enhancing enteral diet
      or an isocaloric and isonitrogenous control enteral diet for seven days. Enteral
      feeding was initiated 24 hours after surgery. Host immunity was evaluated by
      measuring levels of IgG, IgM, IgA, CD4, CD8, and CD4/CD8, and the inflammatory
      response was determined by assessing IL-1alpha, IL-2, IL-6, IL-10, and TNF-alpha
      levels. Infectious complications were also recorded. RESULTS: One hundred twenty
      patients completed the study and four patients were excluded. On postoperative
      day 9, among patients receiving an immune enhancing diet, IgG, IgA, CD4 and
      CD4/CD8 levels were significantly higher and TNF-alpha and IL-6 concentrations
      were significantly lower compared to the control group. Moreover, among patients
      receiving an immune enhancing diet, when comparing preoperation to day 9
      postoperation levels, increases in IgA, CD4, and CD4/CD8 levels were
      significantly higher than in control patients and increases in TNF-alpha
      concentrations were significantly lower. No statistically significant differences
      were found between the two groups with regard to infectious complications.
      CONCLUSIONS: Postoperative administration of immune enhancing enteral nutrition
      in patients undergoing major abdominal surgery can positively modulate
      postoperative immunosuppressive and inflammatory responses.

PMID- 15198884
TI  - Effect of continuous positive airway pressure treatment on vascular endothelial
      function in patients with obstructive sleep apnea hypopnea syndrome and coronary
      artery disease.
AB  - BACKGROUND: Continuous positive airway pressure (CPAP) treatment has been proven
      to be effective in improving the symptoms of coexisting coronary heart disease
      (CHD) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS).
      However, it is still unclear whether such improvements are linked to changes in
      vascular endothelial function. This research was carried out to investigate the
      effects of CPAP treatment on vascular endothelial function in patients with OSAHS
      and CHD. METHODS: Thirty-six patients with moderate or severe OSAHS and CHD
      undergoing three months of CPAP treatment were recruited for this study. The
      changes in their morning plasma nitric oxide (NO) and endothelin (ET) levels,
      NO/ET ratio, total ischemic burden (TIB) of the myocardium, apnea hypopnea index
      (AHI), and minimal and mean pulse oxygen saturation (SpO2) were compared and
      analyzed before and during CPAP treatment. RESULTS: Compared with the plasma
      levels of ET [(51.39 +/- 11.69) ng/L] and NO [(36.67 +/- 11.86) micromol/L],
      NO/ET (0.71 +/- 0.14), AHI (32.4 +/- 7.9), minimal SpO2 [(68.9 +/- 11.4)%], and
      myocardial TIB [(66.29 +/- 16.37) mm.min] before treatment, there were
      significant decreases in ET [(33.41 +/- 10.03) ng/L] (P < 0.05), increases in NO
      [(59.89 +/- 10.26) micromol/L] and NO/ET (1.79 +/- 0.38) (P < 0.01), decreases in
      AHI (1.9 +/- 0.5), and increases in minimal SpO2 [(90.6 +/- 1.8)%] (all P < 0.01)
      and myocardial TIB [(36.42 +/- 10.87) mm.min] (P < 0.05) after three months of
      CPAP treatment. CONCLUSION: CPAP treatment may play an important role in the
      improvement and protection of vascular endothelial dysfunction and myocardial
      ischemia in OSAHS patients with CHD.

PMID- 15198883
TI  - T cell receptor Vbeta repertoire usage and clonal expansion of T cells in chronic
      myelogenous leukemia.
AB  - BACKGROUND: In general, it is very important to understand the state of T cell
      immune response against tumor cells in leukemia patients and it is especially
      critical to assess the T cell repertoire of untreated patients. As we know, few
      studies have dealt with the distribution of oligoclonal T cells in leukemia, so
      we investigated the distribution and clonality of TCR Vbeta repertoire of T cells
      in patients with chronic myelogenous leukemia (CML) in chronic phase. METHODS:
      The complementarity determining region 3 (CDR3) of TCR Vbeta24 subfamily genes
      were amplified in peripheral blood mononuclear cells from 27 cases with CML using
      reverse transcription-polymerase chain reaction (RT-PCR). In order to observe the
      distribution of TCR Vbeta repertoire, the PCR products were further analyzed by
      genescan technique to evaluate clonality of the detectable TCR Vbeta T cells. The
      PCR products of the oligoclonal T cells from three cases were analyzed by direct
      sequencing to define the sequence of CDR3. RESULTS: The expression pattern of TCR
      Vbeta repertoire in different individuals are different. Vbeta2-21 subfamilies
      could be detected in CML cases. The frequent usage Vbeta repertoire in CML was
      Vbeta1, Vbeta2 or Vbeta13. Most of the PCR products from 27 patients displayed
      polyclonality, while a part of the PCR products from 21 out of 27 samples
      displayed clonal expansion pattern. The clonal expanded T cells in CML could be
      found in Vbeta16 subfamilies. The frequent usage of Vbeta genes in clonal
      expansion was Vbeta3, Vbeta13 or Vbeta21. Multiple Vbeta clonal expansion was a
      general phenomenon in the same patient. The CDR3 sequence of Vbeta21 oligoclonal
      T cells from 3 cases showed some difference in splice regions and in the usage of
      J segments. CONCLUSIONS: These results indicated that clonal expanded T cells
      could be found in patients with CML and were tendentious in Vbeta3, Vbeta13 and
      Vbeta21 subfamilies that may be related to the specific immune response for
      leukemia cell associated antigen.

PMID- 15198885
TI  - Single fiber electromyography in the diagnosis of ocular myasthenia gravis:
      report of 90 cases.
AB  - BACKGROUND: The aim of this study was to evaluate single fiber electromyography
      (SFEMG) in the diagnosis of ocular myasthenia gravis (OMG), compared with
      repetitive nerve stimulation (RNS) and blood concentration of antibody to
      acetylcholine receptor (AchRAb). METHODS: SFEMG, RNS and AchRAb titration were
      measured in 90 patients with OMG (44 men, 46 women). RESULTS: Markedly increased
      jitter and ratio of block in the frontalis and the extensor digitorum communis
      (EDC) were observed (83.3% and 61.1%, respectively). The mean jitter was 43.6 +/-
      14.5 micros, and the percentages of jitter>55 micros and blocking were 16.9% +/-
      19% and 3.5% +/- 9.5% respectively in the EDC. The mean jitter was 64.3 +/- 25.6
      micros, and the percentages of jitter > 55 micros and blocking were 33.5% +/-
      27.6% and 29.3% +/- 23.2% respectively in the frontalis. The percentage of
      abnormal RNS was 27.8% (25/90). There was an increased AchRAb titration in 29
      (32.2%) of the 90 patients. Increased jitter, blocking was negatively correlated
      with maximum decrement to RNS (P < 0.01). 11.4% (4/35) of patients with abnormal
      RNS and 24.1% (7/29) patients with abnormal AchRAb were seen in the patients with
      normal SFEMG in the EDC. CONCLUSION: SFEMG test showed the highest sensitivity in
      the diagnosis of OMG. To our knowledge, the three methods (SFEMG, RNS and AchRAb)
      are complementary in the diagnosis and differential diagnosis of OMG.

PMID- 15198886
TI  - Assessment of the early effectiveness of a stroke unit in comparison to the
      general ward.
AB  - BACKGROUND: Stroke unit is the most effective treatment method to benefit stroke
      patients. Our study is to evaluate the early effectiveness of a hospital stroke
      unit (SU). METHODS: Three hundred and ninety-two patients who had suffered from
      acute strokes and who were admitted to our hospital between December 2001 and
      January 2003 were recruited for this controlled study. All patients were sent at
      random to either the SU or the general ward (GW) for treatment. The following
      indices were measured by: Barthel Index (BI), National Institute of Health Stroke
      Scale (NIHSS), Oxford Handicap Scale (OHS). RESULTS: The mean change in BI score
      between the day of admission and the day of discharge was 20.00 +/- 24.36 for the
      SU group and 10.63 +/- 23.59 for the GW group. A difference that is statistically
      significant (P = 0.000). The mean change in NIHSS score was -2.01 +/- 6.61 for
      the SU group and 0.55 +/- 7.44 for the GW group. A difference that is also
      statistically significant (P = 0.000). Finally, the mean change in OHS score was 
      0.74 +/- 1.04 for the SU group and -0.28 +/- 0.98 for the GW group, also a
      statistically significant difference (P = 0.000). Among SU patients, patient
      satisfaction was higher (P = 0.000), the rehabilitation success rate was higher
      (P = 0.000), and there were fewer complications (P = 0.000). CONCLUSION: Compared
      to GW patients, stroke patients treated in a special SU were able to return to
      normal daily activities earlier, with better social abilities, and have reduced
      neurological defects, without increasing the overall economic burden.

PMID- 15198887
TI  - Awareness and attitudes of healthcare professionals in Wuhan, China to the
      reporting of adverse drug reactions.
AB  - BACKGROUND: A voluntary procedure for reporting adverse drug reactions (ADRs) was
      formally put in place in 1989. However, only a small proportion of ADR reports
      are actually forwarded to the national monitoring center. To identify the reasons
      for underreporting, the authors investigated the awareness and attitudes of
      healthcare professionals (doctors, nurses, and administrators) toward the ADR
      system in China. In addition, the authors sought to formulate approaches to
      improve the current ADR reporting system. METHODS: Structured interviews were
      carried out in 16 hospitals selected from 27 municipal hospitals in Wuhan, Hubei
      Province, China. A questionnaire survey of a stratified random sample of
      approximately 15% of healthcare professionals in each selected hospital was
      conducted during February to March 2003. RESULTS: The response rate of this
      survey was 85%. One thousand six hundred and fifty-three questionnaires were used
      in the final analysis. Only 2.7% of the healthcare professionals had a correct
      understanding to the definition of ADR. Eighty-nine point two percent of the
      healthcare professionals had encountered ADRs. Ninety-four percent of them were
      aware of the need to report these to the ADR monitoring center. However, only
      28.5% of doctors, 22.8% of nurses, and 29.7% of administrators actually submitted
      a report. For the most part, they reported ADRs to the hospital pharmacy (66.0%),
      to other departments in the hospital (72.5%), and to the pharmaceutical industry
      (23.0%), rather than to the national monitoring center (2.9%) or regional
      monitoring center (9.5%). Severe or rare ADRs and ADRs to new products were
      generally perceived to be significant enough to report. Sixty-two point one
      percent of the healthcare professionals had encountered ADRs, yet not reported
      them to anybody. The major reasons for not reporting included no knowledge of the
      reporting procedure (71.4%), unavailability of the reporting center mailing
      address (67.9%), unavailability of the ADR report form (60.4%), lack of knowledge
      of the existence of a national ADR reporting system (52.2%), and belief that the
      ADR in question was already well known (44.1%). CONCLUSIONS: Healthcare
      professionals in Wuhan, China have little basic knowledge of ADR and of the
      voluntary reporting system. The main reasons for underreporting were lack of
      basic knowledge about ADRs and the voluntary reporting procedure. Education and
      training of healthcare professionals is needed to improve the current ADR
      reporting system.

PMID- 15198888
TI  - Morphological changes of the peritoneum in peritoneal dialysis patients.
AB  - BACKGROUND: Long-term peritoneal dialysis (PD) requires that the peritoneal
      membrane remain effective for dialysis. Research directed toward human peritoneal
      morphology and structure is limited. The present study was performed to
      investigate morphological changes of the human peritoneal membrane during PD and
      to elucidate the possible mechanisms of its functional deterioration. METHODS: A
      total of 32 peritoneal biopsies were performed in normal subjects (n = 10),
      uremic nondialysis patients (n = 12) at the time of catheter insertion, and PD
      patients (n = 10) at the time of catheter removal or reinsertion or at the time
      of renal transplantation. Peritoneal morphology was examined by light microscopy,
      scanning electron microscopy, and transmission electron microscopy. RESULTS: The
      peritoneal membrane in normal subjects consisted of a monolayer of mesothelial
      cells on a basement membrane and a layer of connective tissue containing cells,
      blood vessels, and lymphatic vessels. Mesothelial cells were polygonal, often
      elongated, and had numerous microvilli on their luminal surface. There were lots
      of oval or roundish pinocytotic vesicles in the cytoplasm of the mesothelial
      cells. The peritoneal morphology of uremic nondialysis patients was similar to
      that of normal subjects. However, significant abnormalities of the peritoneal
      membrane were observed in PD patients, and the changes were found to be
      progressive. Microvilli were the first site of damage which involved microvilli
      shortening, a gradual reduction in their number, and, eventually, the total
      disappearance of microvilli. Mesothelial cells then detached from the basement
      membrane, disappearing completely in some cases. In the end, the peritoneal
      membrane consisted only of submesothelial connective tissue without any cells.
      CONCLUSIONS: PD can modify peritoneal morphology and structure. The morphological
      change is progressive and may be one of the important causes of peritoneal
      failure. Peritoneal biopsies can provide lots of valuable information about the
      effects of PD. Studying the relationship between peritoneal structure and its
      function proved very useful for understanding the physiopathology of the
      peritoneum during PD.

PMID- 15198889
TI  - Sentinel lymph node identification in patients with early stage cervical cancer
      undergoing radical hysterectomy and pelvic lymphadenectomy.
AB  - BACKGROUND: In general, sentinel lymph node (SLN) can reflect the whole state of
      the entire drainage area. The present study evaluated the clinical significance
      of sentinel lymph node identification in the treatment of early stage cervical
      cancer. METHODS: Twenty-eight patients with early stage (Ia-IIa) cervical cancer
      undergoing radical hysterectomy and pelvic lymphadenectomy were included in this
      study. At two locations 8 hours before operation, 0.4 ml 37 Mbq technicium-99
      labeled dextran was injected intracervically. After that, preoperative
      lymphoscintigraphy was performed to detect SLNs. During the operation, lymph
      nodes were detected ex vivo by a gamma-counter to identify SLNs. The samples of
      SLNs and non-SLNs were used for pathological examination separately and compared
      with the final results. RESULTS: SLNs were identified in 27 of 28 (96.4%)
      patients. A total of 123 SLNs were identified from 814 nodes. Six patients had
      altogether 11 positive lymph nodes, which were all SLNs. No patient had false
      negative sentinel node. CONCLUSION: SLNs can successfully predict the lymphatic
      metastasis in patients with cervical cancer. The clinical validity of this
      technique should be evaluated prospectively.

PMID- 15198890
TI  - Ginsenoside Rg1-induced alterations in gene expression in TNF-alpha stimulated
      endothelial cells.
AB  - BACKGROUND: In China the ginseng root began to be used in medicine over 2000
      years ago. Ginsenosides are the most important component isolated from ginseng.
      The authors investigated the effect of ginsenoside Rg1 on the spectrum of gene
      expression in the endothelial cells stimulated by TNF-alpha and further explored
      the potential molecular mechanism of endothelial protection by ginsenoside Rg1.
      METHODS: Nitric oxide (NO) production in the cultured human umbilical vein
      endothelial cells (HUVECs) was measured by using an NO assay kit. A home-made
      oligonucleotide microarray containing approximately 400 cardiovascular disease
      related genes was constructed. The alteration of the spectrum of gene expression
      induced by ginsenoside Rg1 in HUVECs which were activated by TNF-alpha were
      detected by oligonucleotide microarray analysis. RESULTS: NO production in HUVECs
      was decreased significantly after TNF-alpha treatment, while pretreatment with
      ginsenoside Rg1 enhanced NO production in TNF-alphastimulated HUVECs. Ginsenoside
      Rg1 affected the expression levels of genes involved in vascular constriction,
      cell adherence, coagulation, cell growth and signal transduction in TNF
      alphastimulated HUVECs. CONCLUSIONS: Ginsenoside Rg1 could enhance NO production
      and the expression of eNOS mRNA in TNF-alpha stimulated HUVECs. Ginsenoside Rg1
      regulated sets of genes in endothelial cells and protected endothelial cells from
      TNF-alpha activation. Microarray analysis provided us with valuable insights into
      the atheroprotective mechanism by gingsenoside Rg1.

PMID- 15198891
TI  - Development of gene microarray in screening differently expressed genes in keloid
      and normal-control skin.
AB  - BACKGROUND: Keloid is an intricate lesion that is probably regulated by many
      genes. In this study, the authors used the technique of complementary DNA (cDNA)
      microarray to analyse abnormal gene expression in keloids and normal control
      skins. METHODS: The polymerase chain reaction (PCR) products of 8400 genes were
      spotted in an array on chemical-material-coated-glass plates. The DNAs were fixed
      on the glass plates. The total RNAs were isolated from freshly excised human
      keloid and normal control skins, and the mRNAs were then purified. The mRNA from
      both keloid and normal control skins were reversely transcribed to cDNAs, with
      the incorporation of fluorescent dUTP, for preparing the hybridisation probes.
      The mixed probes were then hybridised to the cDNA microarray. After thorough
      washing, the cDNA microarray was scanned for differing fluorescent signals from
      two types of tissues. Gene expression of tissue growth factor-beta1 (TGF-beta1)
      and of c-myc was detected with both RT-PCR and Northern blot hybridisation to
      confirm the effectiveness of cDNA microarray. RESULTS: Among the 8400 human
      genes, 402 were detected with different expression levels between keloid and
      normal control skins. Two hundred and fifty genes, including TGF-beta1 and c-myc,
      were up-regulated and 152 genes were down-regulated. Higher expressions of TGF
      beta1 and c-myc in keloid were also revealed using RT-PCR and Northern blot
      methods. CONCLUSION: cDNA microarray analysis provides a powerful tool for
      investigating differential gene expression in keloid and normal control skins.
      Keloid is a complicated lesion with many genes involved.

PMID- 15198892
TI  - Comparison of mesenchymal stem cells from human placenta and bone marrow.
AB  - BACKGROUND: Nowadays bone marrow represents the main source of mesenchymal stem
      cells (MSCs). We identified a new population of MSCs derived from human placenta
      and compared its biological characterization with bone marrow derived MSCs.
      METHODS: Mononucleated cells (MNC) were isolated from the human placenta tissue
      perfusate by density gradient fractionation. Individual colonies were selected
      and cultured in tissue dishes. At the same time, human bone marrow derived MSCs
      were identified. Culture-expanded cells were characterized by immune phenotyping
      and cultured under conditions promoting differentiation to osteoblasts or
      adipocytes. The hematopoietic cytokines were assayed using reverse transcriptase
      polymerase chain reaction (RT-PCR). RESULTS: Human placental MSCs exhibited
      fibroblastoid morphology. Flow cytometric analyses showed that the placental MSC
      were CD29, CD44, CD73, CD105, CD166, HLA-ABC positive; but were negative for
      CD34, CD45, and HLA-DR. Functionally, they could be induced into adipocytes or
      osteocytes. Moreover, several hematopoietic cytokine mRNA was found in placenta
      derived MSCs by RT-PCR analysis, including IL-6, M-CSF, Flt3-ligand and SCF.
      These results were consistent with the properties of bone marrow derived MSCs.
      CONCLUSION: These observations implicate the postpartum human placenta as an
      important and novel source of multipotent stem cells that could potentially be
      used for investigating mesenchymal differentiation and regulation of
      hematopoiesis.

PMID- 15198893
TI  - PMN apoptosis and its relationship with the lung injury after chest impact
      trauma.
AB  - BACKGROUND: Polymorphonuclear neutrophil (PMN), one of the most important
      inflammatory cells, functions throughout the initiation, progression and
      resolution of inflammation. This study aimed at investigating the relationship
      between PMN apoptosis and the lung injury after chest impact trauma. METHODS:
      PMNs were purified from rabbits subjected to the chest impact trauma and their
      apoptosis, necrosis, survival and respiratory burst were detected by flow
      cytometry. Meanwhile, lactate dehydrogenase and (LDH) [Ca2+]i were measured.
      RESULTS: The delayed apoptosis of PMNs in bronchoalveolar lavage fluid was
      observed from 2 hours to 12 hours after trauma, and viable cells increased.
      Respiratory burst of PMNs in bronchoalveolar lavage fluid was increased
      significantly from 2 hours with the peak at 8 hours. Meanwhile, lactate
      dehydrogenase in bronchoalveolar lavage fluid was higher than that in control (P
      < 0.05) from 4 hours to 24 hours, and intracellular free Ca2+ in PMN was
      increased temporarily. CONCLUSIONS: Retention of PMN in tissues and the
      abnormality in apoptotic pathway inevitably generate persistent activation of PMN
      and excessive release of toxic substances, resulting in tissue injury. The
      temporary increase of intracellular free Ca2+ may be responsible for the delayed
      apoptosis of PMN.

PMID- 15198894
TI  - Hybrid retroviral vector with MCK enhancers inserted in LTR for stable and
      specific expression of human factor IX in skeletal muscle.
AB  - BACKGROUND: Retroviral vectors have been widely used to introduce foreign into
      various target cells in vitro, thus showing relatively high systemic delivery
      efficiency of various transgene products. The authors investigated the stability
      and efficiency of skeletal muscle-specific hybrid retroviral vectors in
      expression of human factor IX (FIX) in vitro and iv vivo. METHODS: FIX cDNA in
      LIXSN vector was replaced with a FIX minigene containing splicing donor and
      splicing acceptor sequence of first intron of human FIX gene. Two copies of
      muscle creatine kinase enhancer (MCK, Me2) were inserted in forward or reverse
      orientation at NheI site of 3' long terminal repeat (LTR), resulting in two
      hybrid vectors, which were designated as LMe2IXm2SN(F) and LMe2IXm2SN(R),
      respectively. The vectors were tested in vitro and in vivo for stability and
      muscle-specificity of factor IX expression with SCID mice. RESULTS: Muscle cells
      carrying vector with Me2 expressed significantly higher levels of FIX (up to 1800
      ng/106.24 h) than those without Me2, thus suggesting that Me2 could specifically
      increase expression level of FIX in muscle cells. Myoblasts transduced with
      LMe2IXm2SN(R) produced much less FIX in vivo in SCID mice than LMe2IXm2SN(F). One
      or two copies of Me2 sequence were deleted in myoblasts transduced with
      LMe2IXm2SN(R) without changing the orientation of Me2. CONCLUSIONS: LTR inserted
      with MCK enhancers can specifically increase human FIX expression in skeletal
      muscle cells in vitro and in vivo, and MCK enhancer should be positioned in the
      same orientation as that of LTR promoter.

PMID- 15198895
TI  - Novel splicing variant of the human orphan nuclear receptor Nurr1 gene.
AB  - BACKGROUND: Nurr1 is a member of the nuclear receptor superfamily of
      transcription factors. The objective of the present study was to identify novel
      splicing variants of the gene in neuronal and non-neuronal tissues and determine
      their functions. METHODS: Reverse transcription-polymerase chain reaction (RT
      PCR) analysis was used to screen for Nurr1 splice variants in the adult human
      central nervous system (CNS) and in other tissues such as lymphocytes, and liver,
      muscle, and kidney cells. Functional assays of the variants were performed by
      measuring Nurr1 response element (NuRE) transcriptional activity in vitro.
      RESULTS: In this study, the authors identified a novel splicing variant of Nurr1
      within exon 5, found in multiple adult human tissues, including lymphocytes, and
      liver, muscle, and kidney cells, but not in the brain or spinal cord. Sequencing
      analysis showed the variant has a 75 bp deletion between nucleotides 1402 and
      1476. A functional assay of the Nurr1-c splicing variant, performed by measuring
      NuRE transcriptional activity in vitro, detected a 39% lower level of luciferase
      (LUC) activity (P < 0.05). CONCLUSION: A novel splicing variant of Nurr1 exists
      in human non-neuronal tissues and functional assays suggest that the variant may
      act as an alternate transcription regulator.

PMID- 15198896
TI  - Human cytomegalovirus protects multiple myeloma cell line KM3 cells from
      apoptosis induced by growth factor withdrawal.
AB  - BACKGROUND: There is a higher rate of cytomegalovirus (CMV) reactivation in
      patients with multiple myeloma after an autologous stem cell transplantation, but
      no attention has been given thus far to a possible pathogenetic interplay between
      CMV and multiple myeloma. CMV can infect many kinds of cells, and CMV infection
      has been shown to inhibit apoptotic responses in several cell systems. In this
      study the authors investigated the alterations in apoptosis in the multiple
      myeloma cell line KM3 after infection with CMV and proposed a possible mechanism.
      METHODS: KM3 cells were infected with 100, 10, or 1 TCID50 of CMV and then
      cultured in serum-free RPMI 1640. An RT-PCR-based assay was used to detect mRNA
      expression of CMV-IE, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and IL-6
      in CMV-infected and mock-infected cells. Flow cytometry was used to detect
      apoptotic cells. CMV particles and apoptotic cells were also examined with an
      electron microscope. RESULTS: CMV-infected KM3 cells clearly expressed immediate
      early (IE) antigen mRNA when compared to uninfected cells, and there were fewer
      apoptotic cells among cells treated with 100 or 10 TCID50 of CMV after culturing
      in serum-free RPMI 1640. CMV particles were observable in infected cells under an
      electron microscope. Expression of IL-6 mRNA increased after infection.
      CONCLUSION: CMV can infect the multiple myeloma cell line KM3, inhibit the
      apoptotic response in these cells after apoptosis induction in serum-free
      culture, and increase the expression of IL-6 mRNA.

PMID- 15198897
TI  - Effects of angiotensin II receptor antagonist on expression of collagen III,
      collagen V, and transforming growth factor beta1 in the airway walls of
      sensitized rats.
AB  - BACKGROUND: Repeated attacks of bronchial asthma lead to different degrees of
      airway remodeling, the mechanism of which is not yet clear. Some evidences
      indicate that it is related to the excessive expression of some growth promotion
      factors. Angiotensin II is a polypeptide that may be involved in airway
      remodeling. To evaluate its role in airway remodeling in asthma, we observed the
      effects of an angiotensin II type 1 receptor antagonist (valsartan) on the
      expression of collagen III, collagen V, and transforming growth factor beta1 (TGF
      beta1) mRNA and protein in the airway walls of sensitized rats. METHODS: Forty
      Wistar rats were randomly divided into 5 groups: control group, sensitized group,
      and valsartan groups 1, 2, and 3. The rats in the sensitized group and in
      valsartan groups 1, 2, and 3 were sensitized and challenged with ovalbumin. Rats
      in control group were sensitized and challenged with 0.9% NaCl. Rats from
      valsartan groups 1, 2, and 3 were drenched with valsartan (10 microg, 20 microg,
      or 30 microg, respectively) at the time of the ovalbumin challenges. The
      expression of collagen III, collagen V, and TGF-beta1 protein were detected using
      immunohistochemical method in combination with image analysis methods. The
      expression of TGF-beta1 mRNA was detected by in situ hybridization. RESULTS: The
      expression in the airways of collagen III and collagen V was significantly higher
      in rats from the sensitized group (7.73 +/- 0.81, 1.34 +/- 0.28) and from
      valsartan groups 1, 2, and 3 (5.73 +/- 0.64, 1.13 +/- 0.15; 4.96 +/- 0.51, 0.98
      +/- 0.08; 4.43 +/- 0.35, 0.93 +/- 0.06, respectively) than those in the control
      group (2.65 +/- 0.38, 0.67 +/- 0.08, P < 0.05). In addition, collagen levels were
      significantly lower in valsartan groups 1, 2, and 3 than those from the
      sensitized group (P < 0.05). The expression of TGF-beta1 mRNA and protein in the
      airways was significantly higher in rats from the sensitized group (20.49% +/-
      3.46%, 29.73% +/- 3.25%) and from valsartan groups 1, 2, and 3 (16.47% +/- 1.94%,
      19.41% +/- 1.87%; 14.38% +/- 1.58%, 18.29% +/- 1.43%; 12.96% +/- 1.73%, 18.63% +/
      1.11%, respectively) than that from the control group (7.84% +/- 1.61%, 5.63% +/
      1.07%, P < 0.05). TGF-beta1 mRNA and protein levels were significantly lower in
      valsartan groups 1, 2, and 3 than that in the sensitized group (P < 0.05).
      CONCLUSIONS: Angiotensin II receptor antagonist valsartan can suppress synthesis
      of collagen III and collagen V by downregulating TGF-beta1 mRNA and protein
      expression. Valsartan can decrease airway remodeling and could play a role in
      asthma therapy.

PMID- 15198899
TI  - Batroxobin reduces intracellular calcium concentration and inhibits proliferation
      of vascular smooth muscle cells.
AB  - BACKGROUND: Batroxobin (BX), a serine protease used in defibrinogenation and
      thrombolysis, also has an effect on c-fos gene and growth factor. This study
      attempted to determine the effects of BX on the proliferation of vascular smooth
      muscle cells (VSMCs) and calcium metabolism. METHODS: VSMCs were treated with BX
      at concentrations of 0.1, 0.3, or 1.0 mmol/L and cell numbers were determined at
      0, 24, 48, and 72 hours. Intracellular calcium concentration ([Ca2+]i) was
      measured using direct fluorescence methods. RESULTS: BX was found to suppress
      proliferation of VSMCs in a dose-dependent fashion with inhibition rates of 18%
      and 31% by 48 and 72 hours, respectively. In addition, BX decreases basal [Ca2+]i
      significantly. The basal level in untreated cells was 162.7 +/- 33.8 nmol/L, and
      decreased to 131.5 +/- 27.7 nmol/L, 128.3 +/- 28.5 nmol/L, and 125.6 +/- 34.3
      nmol/L with the three concentrations of BX, respectively. Noradrenaline (NE)
      induced [Ca2+]i stimulation was also attenuated by BX (0.1 mmol/L BX, 20% +/- 8%
      inhibition; 0.3 mmol/L BX, 54% +/- 11% inhibition; 1.0 mmol/L BX, 62% +/- 15%
      inhibition). The ability of NE to stimulate [Ca2+]i was attenuated in cultures in
      Ca(2+)-free medium, as was the ability of BX to blunt NE-induced stimulation.
      CONCLUSION: These findings demonstrate that BX can effectively inhibit
      proliferation of VSMCs, probably by blocking the release and uptake of Ca2+, thus
      influencing [Ca2+]i.

PMID- 15198898
TI  - Effects of octreotide on expression of L-type voltage-operated calcium channels
      and on intracellular Ca2+ in activated hepatic stellate cells.
AB  - BACKGROUND: The contractility of hepatic stellate cells (HSCs) may play an
      important role in the pathogenesis of cirrhosis with portal hypertension. The aim
      of this study was to research the effects of octreotide, an analogue of
      somatostatin, on intracellular Ca2+ and on the expression of L-type voltage
      operated calcium channels (L-VOCCs) in activated HSCs, and to try to survey the
      use of octreotide in treatment and prevention of cirrhosis with portal
      hypertension complications. METHODS: HSC-T6, an activated HSCs line, was plated
      on small glass coverslips in 35-mm culture dishes at a density of 1 x 10(5)/ml,
      and incubated in DMEM media for 24 hours. After the cells were loaded with Fluo
      3/AM, intracellular Ca2+ was measured by Laser Scanning Confocal Microscopy
      (LSCM). The dynamic changes in activated HSCs of intracellular Ca2+, stimulated
      by octreotide, endothelin-1, and KCl, respectively, were also determined by LSCM.
      Each experiment was repeated six times. L-VOCC expression in HSCs was estimated
      by immunocytochemistry. RESULTS: After octreotide stimulation, a significant
      decrease in the intracellular Ca2+ of activated HSCs was observed. However,
      octreotide did not inhibit the increases in intracellular Ca2+ after stimulation
      by KCl and endothelin-1. Moreover, octreotide did not significantly affect L-VOCC
      expression. These results suggest that neither L-VOCC nor endothelin-1 receptors
      in activated HSCs are inhibited by octreotide. CONCLUSIONS: Octreotide may
      decrease portal hypertension and intrahepatic vascular tension by inhibiting
      activated HSCs contractility through decreases in intracellular Ca2+. The
      somatostatin receptors in activated HSCs may be inhibited by octreotide.

PMID- 15198900
TI  - Influence of CaNa2 EDTA on topical 5-aminolaevulinic acid photodynamic therapy.
AB  - BACKGROUND: We assessed whether the CaNa2 EDTA could improve the accumulation of
      protoporphyrin IX (PpIX) and photosensitisation in HEp-2 cells as well as the
      depth of treatment of skin cancers on the topical 5-Aminolaevulinic acid (5-ALA)
      PDT. METHODS: HEp-2 cells were incubated with 5-ALA (0-1 mmol/L) and CaNa2EDTA (0
      1 mmol/L) for 4 hours, intracellular protoporphyrin IX content was quantified by
      extraction, and cell viability was assessed by use of the methyl-tetrazolium
      (MTT) assay four hours after exposure to light. In comparison with the pictures
      before and after treatment, depth of treatment could be determined using a Acuson
      Sequioa 512 phase-array system in paired experiments. RESULTS: PpIX accumulation
      increased with increasing extracellular concentrations of ALA (0-1 mmol/L).
      Adding 1 mmol/L of CaNa2EDTA increased 30% PpIX accumulation over the same period
      of incubation in the concentration of 1 mmol/L ALA. Significant difference was
      observed between the 5-ALA alone group and 5-ALA combined CaNa2 EDTA group in the
      PpIX accumulation (P < 0.01). Cell viability after exposure to light decreased
      with adding CaNa2 EDTA, a statistical difference in a same fluence above 1.2
      J/cm2 between two groups was demonstrated (P < 0.05, P < 0.01 respectively).
      Depth of treatment of skin cancers were increased in CaNa2 EDTA-treated group.
      CONCLUSION: CaNa2 EDTA could improve the PpIX accumulation and photosensitisation
      in HEp-2 cells. Clinically, CaNa2 EDTA could increase the depth of treatment in
      the cutaneous cancers.

PMID- 15198901
TI  - Supplementation of milk formula with galacto-oligosaccharides improves intestinal
      micro-flora and fermentation in term infants.
AB  - BACKGROUND: Oligosaccharides in human milk may protect infants by improving the
      intestinal micro-flora and fermentation. This study was to investigate effects of
      infant formula milk consisting of galacto-oligosaccharide (GOS) on intestinal
      microbial populations and the fermentation characteristics in term infants in
      comparison with that of human milk. METHODS: The test formula (Frisolac H,
      Friesland, Netherland) was supplemented with GOS at a concentration of 0.24 g/dl.
      Human milk and another formula without oligosaccharides (Frisolac H, Friesland,
      Netherland) were used as positive and negative control respectively. Growth,
      stool characteristics, and side effects of the recruited infants were recorded
      after 3 and 6 months' follow-up, and the fecal species were collected for the
      analysis of intestinal micro-flora, short chain fatty acid (SCFA) and pH.
      RESULTS: At the end of 3- and 6-month feeding period, intestinal Bifidobacteria
      and Lactobacilli were significantly increased in infants fed with GOS
      supplemented formula and human milk when compared with infants fed with negative
      control formula; however, there was no statistically significant difference
      between GOS supplemented formula and human milk groups. Stool characteristics
      were influenced by the supplement and main fecal SCFA (acetic), and stool
      frequency were significantly increased in infants fed with GOS supplemented
      formula and human milk, while the fecal pH was significantly decreased as
      compared with that of negative control (P < 0.05). Supplementation had no
      influence on incidence of side effects (including crying, regurgitation and
      vomiting). CONCLUSIONS: Supplementing infant formula with GOS at a concentration
      of 0.24 g/dl stimulates the growth of Bifidobacteria and Lactobacilli in the
      intestine and stool characteristics are similar to in term infants fed with human
      milk.

PMID- 15198902
TI  - Anti-rejection effect of ethanol extract of Poria cocos wolf in rats after
      cardiac allograft implantation.
AB  - BACKGROUND: A living fetus within the maternal uterus provides an example of
      allogene tolerance in mammals. Poria cocos Wolf is the main component of many
      Chinese medicinal combination drugs that have therapeutic effects on recurrent
      spontaneous abortion and that can maintain pregnancy until delivery. It was
      hypothesized that this herbal medicine can also prolong allograft survival after
      organ transplantation. Here, in an in vivo study, we report the anti-rejection
      effect of the ethanol extract of Poria cocos Wolf (EEPCW) in rats after cardiac
      allograft implantation. METHODS: Ten normal rats were healthy controls. Eighty
      rats receiving homologous heart transplants were divided into 4 groups of 20 rats
      each based on type of treatment: olive oil 8 ml.kg(-1).d(-1), EEPCW 25 mg.kg(
      1).d(-1), EEPCW 50 mg.kg(-1).d(-1) or cyclosporin A 5 mg.kg(-1).d(-1). Allograft
      survival was observed in 10 rats from each group. On the seventh day post
      transplantation, pathological lesions and percentages of CD3+, CD4+, and CD8+
      lymphocytes and the CD4+/CD8+ ratio in peripheral blood were assessed in another
      10 rats from each group and in 10 normal rats. RESULTS: The survival time of
      donor hearts in the two EEPCW groups was significantly prolonged, to (15.9 +/-
      2.4) days and (30.0 +/- 0.0) days, respectively, compared with (6.7 +/- 0.8) days
      in the control group. Pathological lesions in the two EEPCW groups were also less
      severe, and the percentages of CD3+, CD4+, and CD8+ lymphocytes and CD4+/CD8+
      ratio were significantly lower in the EEPCW groups. CONCLUSIONS: Acute rejection
      of heart transplants and cellular immune reaction can be effectively suppressed
      using the EEPCW. Taking advantage of novel immunosuppressants derived from
      Chinese medicinal herbs used to treat abnormal pregnancy provides a hopeful road
      for future research and treatment in organ transplantation.

PMID- 15198903
TI  - p21WAF1/CIP1 gene DNA sequencing and its expression in human osteosarcoma.
AB  - BACKGROUND: Mutation and expression change of p21WAF1/CIP1 may play a role in the
      growth of osteosarcoma. This study was to investigate the expression of the
      p21WAF1/CIP1 gene in human osteosarcoma, p21WAF1/CIP1 gene DNA sequence change
      and their relationships with the phenotype and clinical prognosis. METHODS:
      p21WAF1/CIP1 gene in 10 normal people and the tumours of 45 osteosarcoma patients
      were examined using polymerase chain reaction-single strand conformation
      polymorphism (PCR-SSCP) with silver staining. The PCR product with an abnormal
      strand was sequenced directly. The p21WAF1/CIP1 gene mRNA and P21 protein of 45
      cases of osteosarcoma were investigated by using in situ hybridization and
      immunohistochemistry, respectively. RESULTS: The occurrence of P21 protein in
      osteosarcoma was 17.78% (8/45), and p21WAF1/CIP1 mRNA expression in osteosarcoma
      was 42.22% (19/45). The p21WAF1/CIP1 gene DNA sequencing of amplified production
      showed that in p21WAF1/CIP1 gene exon 3 of 36 cases of human osteosarcoma, there
      were 17 cases (47.22%) with C-->T at position 609; 10 normal blood samples' DNA
      sequence analysis yielded 8 cases (80.00%) with C-->T at the same position.
      CONCLUSIONS: Along with the increase of malignancy, the expression of
      p21WAF1/CIP1mRNA and P21 protein in osteosarcoma tends to decrease. It is
      uncommon for the p21WAF1/CIP1 gene mutation to occur in human osteosarcoma. As a
      result, the possible existence of tumour subtypes of p21WAF1/CIP1 gene mutation
      should be investigated. Our research leads to the location of p21WAF1/CIP1 gene
      polymorphism of Chinese osteosarcoma patients, which can provide a basis for
      further research.

PMID- 15198904
TI  - Expression and effects of human telomerase RNA in testicular tumor.

PMID- 15198905
TI  - Cardiac troponin T mutations in Chinese patients with hypertrophic
      cardiomyopathy.

PMID- 15198906
TI  - Schistosoma japonicum: establishment of a mouse model that demonstrates
      concomitant immunity.

PMID- 15198907
TI  - Pulmonary alveolar microlithiasis: report of four familial cases.

PMID- 15198908
TI  - Acute promyelocytic leukemia in a hemophilia A patient: a case report.

PMID- 15198909
TI  - Carotid endarterectomies for relieving severe or moderate carotid stenosis.

PMID- 15198910
TI  - Off-pump and on-pump coronary artery bypass surgery: time to move on.

PMID- 15198913
TI  - Neurodevelopment and endocrine disruption.
AB  - In this article I explore the possibility that contaminants contribute to the
      increasing prevalence of attention deficit hyperactivity disorder, autism, and
      associated neurodevelopmental and behavioral problems in developed countries. I
      discuss the exquisite sensitivity of the embryo and fetus to thyroid disturbance
      and provide evidence of human in utero exposure to contaminants that can
      interfere with the thyroid. Because it may never be possible to link prenatal
      exposure to a specific chemical with neurodevelopmental damage in humans, I also
      present alternate models where associations have been made between exposure to
      specific chemicals or chemical classes and developmental difficulties in
      laboratory animals, wildlife, and humans.

PMID- 15198915
TI  - Potential for increased human foodborne exposure to PCDD/F when recycling sewage
      sludge on agricultural land.
AB  - Sewage sludge from municipal wastewater treatment is used in agriculture as a
      nutrient source and to aid in moisture retention. To examine the potential impact
      of sludge-amended soil on exposures to polychlorinated dibenzo-p-dioxins and
      dibenzofurans (PCDD/Fs) from plant and animal foods, we conducted a review of
      published empirical data from international sources. Levels of PCDD/F in
      municipal sewage sludge ranged from 0.0005 to 8300 pg toxic equivalents (TEQ)/g.
      Background levels in soil ranged from 0.003 to 186 pg TEQ/g. In sludge-amended
      soils, levels of PCDD/F ranged from 1.4 to 15 pg TEQ/g. Studies that measured
      levels before and after sludge treatment showed an increase in soil concentration
      after treatment. Relationships between PCDD/F levels in soil and resulting
      concentrations in plants were very weakly positive for unpeeled root crops, leafy
      vegetables, tree fruits, hay, and herbs. Somewhat stronger relationships were
      observed for plants of the cucumber family. In all cases, large increases in soil
      concentration were required to achieve a measurable increase in plant
      contamination. A considerably stronger positive relationship was observed between
      PCDD/F in feed and resulting levels in cattle tissue, suggesting bioaccumulation.
      Although PCDD/Fs are excreted in milk, no association was found between feed
      contamination and levels of PCDD/Fs measured in milk. There is a paucity of
      realistic data describing the potential for entry of PCDD/Fs into the food supply
      via sewage sludge. Currently available data suggest that sewage sludge
      application to land used for most crops would not increase human exposure.
      However, the use of sludge on land used to graze animals appears likely to result
      in increased human exposure to PCDD/F.

PMID- 15198914
TI  - Association of pesticide exposure with neurologic dysfunction and disease.
AB  - Poisoning by acute high-level exposure to certain pesticides has well-known
      neurotoxic effects, but whether chronic exposure to moderate levels of pesticides
      is also neurotoxic is more controversial. Most studies of moderate pesticide
      exposure have found increased prevalence of neurologic symptoms and changes in
      neurobehavioral performance, reflecting cognitive and psychomotor dysfunction.
      There is less evidence that moderate exposure is related to deficits in sensory
      or motor function or peripheral nerve conduction, but fewer studies have
      considered these outcomes. It is possible that the most sensitive manifestation
      of pesticide neurotoxicity is a general malaise lacking in specificity and
      related to mild cognitive dysfunction, similar to that described for Gulf War
      syndrome. Most studies have focused on organophosphate insecticides, but some
      found neurotoxic effects from other pesticides, including fungicides, fumigants,
      and organochlorine and carbamate insecticides. Pesticide exposure may also be
      associated with increased risk of Parkinson disease; several classes of
      pesticides, including insecticides, herbicides, and fungicides, have been
      implicated. Studies of other neurodegenerative diseases are limited and
      inconclusive. Future studies will need to improve assessment of pesticide
      exposure in individuals and consider the role of genetic susceptibility. More
      studies of pesticides other than organophosphates are needed. Major unresolved
      issues include the relative importance of acute and chronic exposure, the effect
      of moderate exposure in the absence of poisoning, and the relationship of
      pesticide-related neurotoxicity to neurodegenerative disease.

PMID- 15198916
TI  - Lung cancer risk after exposure to polycyclic aromatic hydrocarbons: a review and
      meta-analysis.
AB  - Typical polycyclic aromatic hydrocarbon mixtures are established lung
      carcinogens, but the quantitative exposure-response relationship is less clear.
      To clarify this relationship we conducted a review and meta-analysis of published
      reports of occupational epidemiologic studies. Thirty-nine cohorts were included.
      The average estimated unit relative risk (URR) at 100 Mu g/m
      (superscript)3(/superscript) years benzo[a]pyrene was 1.20 [95% confidence
      interval (CI), 1.11-1.29] and was not sensitive to particular studies or analytic
      methods. However, the URR varied by industry. The estimated means in coke ovens,
      gasworks, and aluminum production works were similar (1.15-1.17). Average URRs in
      other industries were higher but imprecisely estimated, with those for asphalt
      (17.5; CI, 4.21-72.78) and chimney sweeps (16.2; CI, 1.64-160.7) significantly
      higher than the three above. There was no statistically significant variation of
      URRs within industry or in relation to study design (including whether adjusted
      for smoking), or source of exposure information. Limited information on total
      dust exposure did not suggest that dust exposure was an important confounder or
      modified the effect. These results provide a more secure basis for risk
      assessment than was previously available.

PMID- 15198917
TI  - Rationale for a new generation of indicators for coastal waters.
AB  - More than half the world's human population lives within 100 km of the coast, and
      that number is expected to increase by 25% over the next two decades.
      Consequently, coastal ecosystems are at serious risk. Larger coastal populations
      and increasing development have led to increased loading of toxic substances,
      nutrients and pathogens with subsequent algal blooms, hypoxia, beach closures,
      and damage to coastal fisheries. Recent climate change has led to the rise in sea
      level with loss of coastal wetlands and saltwater intrusion into coastal
      aquifers. Coastal resources have traditionally been monitored on a stressor-by
      stressor basis such as for nutrient loading or dissolved oxygen. To fully measure
      the complexities of coastal systems, we must develop a new set of ecologic
      indicators that span the realm of biological organization from genetic markers to
      entire ecosystems and are broadly applicable across geographic regions while
      integrating stressor types. We briefly review recent developments in ecologic
      indicators and emphasize the need for improvements in understanding of stress
      response relationships, contributions of multiple stressors, assessments over
      different spatial and temporal scales, and reference conditions. We provide two
      examples of ecologic indicators that can improve our understanding of these
      inherent problems: a) the use of photopigments as indicators of the interactive
      effects of nutrients and hydrology, and b) biological community approaches that
      use multiple taxa to detect effects on ecosystem structure and function. These
      indicators are essential to measure the condition of coastal resources, to
      diagnose stressors, to communicate change to the public, and ultimately to
      protect human health and the quality of the coastal environment.

PMID- 15198918
TI  - Recent developments in low-level lead exposure and intellectual impairment in
      children.
AB  - In the last decade children's blood lead levels have fallen significantly in a
      number of countries, and current mean levels in developed countries are in the
      region of 3 Mu g/dL. Despite this reduction, childhood lead poisoning continues
      to be a major public health problem for certain at-risk groups of children, and
      concerns remain over the effects of lead on intellectual development in infants
      and children. The evidence for lowered cognitive ability in children exposed to
      lead has come largely from prospective epidemiologic studies. The current World
      Health Organization/Centers for Disease Control and Prevention blood level of
      concern reflects this and stands at 10 Mu g/dL. However, a recent study on a
      cohort of children whose lifetime peak blood levels were consistently less than
      10 Mu g/dL has extended the association of blood lead and intellectual impairment
      to lower levels of lead exposure and suggests there is no safety margin at
      existing exposures. Because of the importance of this finding, we reviewed this
      study in detail along with other recent developments in the field of low-level
      lead exposure and children's cognitive development. We conclude that these
      findings are important scientifically, and efforts should continue to reduce
      childhood exposure. However, from a public health perspective, exposure to lead
      should be seen within the many other risk factors impacting on normal childhood
      development, in particular the influence of the learning environment itself.
      Current lead exposure accounts for a very small amount of variance in cognitive
      ability (1-4%), whereas social and parenting factors account for 40% or more.

PMID- 15198919
TI  - Health and environment information systems for exposure and disease mapping, and
      risk assessment.
AB  - A large number of chemicals are used on a regular basis in modern society.
      Thousands of new chemicals are added each year, many of which may have toxic
      properties constituting potential health hazards. Rapid assessment of the risk
      associated with the use of these chemicals is therefore essential to protect
      people from exposure to potentially harmful substances. Exposures to chemicals
      (and physical agents) are typically unevenly distributed geographically as well
      as temporally. Disease occurrence also shows geographically varying patterns.
      Geographic information systems (GIS) may be used to produce maps of exposure
      and/or disease to reveal spatial patterns. Exposure mapping using advanced GIS
      modeling may enhance exposure assessment in environmental epidemiology studies.
      Disease maps can be valuable tools in risk assessment to explore changes in
      disease patterns potentially associated with changes in environmental exposures.
      Spatial variations in risk and trends related to distance from pollution sources
      may be studied using software tools such as the Rapid Inquiry Facility, developed
      by the U.K. Small Area Health Statistics Unit and enhanced in the European Health
      and Environment Information System project, for an initial quick evaluation of
      any potential health hazards associated with an environmental pollutant.

PMID- 15198920
TI  - Spatial epidemiology: current approaches and future challenges.
AB  - Spatial epidemiology is the description and analysis of geographic variations in
      disease with respect to demographic, environmental, behavioral, socioeconomic,
      genetic, and infectious risk factors. We focus on small-area analyses,
      encompassing disease mapping, geographic correlation studies, disease clusters,
      and clustering. Advances in geographic information systems, statistical
      methodology, and availability of high-resolution, geographically referenced
      health and environmental quality data have created unprecedented new
      opportunities to investigate environmental and other factors in explaining local
      geographic variations in disease. They also present new challenges. Problems
      include the large random component that may predominate disease rates across
      small areas. Though this can be dealt with appropriately using Bayesian
      statistics to provide smooth estimates of disease risks, sensitivity to detect
      areas at high risk is limited when expected numbers of cases are small. Potential
      biases and confounding, particularly due to socioeconomic factors, and a detailed
      understanding of data quality are important. Data errors can result in large
      apparent disease excess in a locality. Disease cluster reports often arise
      nonsystematically because of media, physician, or public concern. One ready means
      of investigating such concerns is the replication of analyses in different areas
      based on routine data, as is done in the United Kingdom through the Small Area
      Health Statistics Unit (and increasingly in other European countries, e.g.,
      through the European Health and Environment Information System collaboration). In
      the future, developments in exposure modeling and mapping, enhanced study
      designs, and new methods of surveillance of large health databases promise to
      improve our ability to understand the complex relationships of environment to
      health.

PMID- 15198921
TI  - Using geographic information systems for exposure assessment in environmental
      epidemiology studies.
AB  - Geographic information systems (GIS) are being used with increasing frequency in
      environmental epidemiology studies. Reported applications include locating the
      study population by geocoding addresses (assigning mapping coordinates), using
      proximity analysis of contaminant source as a surrogate for exposure, and
      integrating environmental monitoring data into the analysis of the health
      outcomes. Although most of these studies have been ecologic in design, some have
      used GIS in estimating environmental levels of a contaminant at the individual
      level and to design exposure metrics for use in epidemiologic studies. In this
      article we discuss fundamentals of three scientific disciplines instrumental to
      using GIS in exposure assessment for epidemiologic studies: geospatial science,
      environmental science, and epidemiology. We also explore how a GIS can be used to
      accomplish several steps in the exposure assessment process. These steps include
      defining the study population, identifying source and potential routes of
      exposure, estimating environmental levels of target contaminants, and estimating
      personal exposures. We present and discuss examples for the first three steps. We
      discuss potential use of GIS and global positioning systems (GPS) in the last
      step. On the basis of our findings, we conclude that the use of GIS in exposure
      assessment for environmental epidemiology studies is not only feasible but can
      enhance the understanding of the association between contaminants in our
      environment and disease.

PMID- 15198922
TI  - Interpreting posterior relative risk estimates in disease-mapping studies.
AB  - There is currently much interest in conducting spatial analyses of health
      outcomes at the small-area scale. This requires sophisticated statistical
      techniques, usually involving Bayesian models, to smooth the underlying risk
      estimates because the data are typically sparse. However, questions have been
      raised about the performance of these models for recovering the "true" risk
      surface, about the influence of the prior structure specified, and about the
      amount of smoothing of the risks that is actually performed. We describe a
      comprehensive simulation study designed to address these questions. Our results
      show that Bayesian disease-mapping models are essentially conservative, with high
      specificity even in situations with very sparse data but low sensitivity if the
      raised-risk areas have only a moderate (less than 2-fold) excess or are not based
      on substantial expected counts (> 50 per area). Semiparametric spatial mixture
      models typically produce less smoothing than their conditional autoregressive
      counterpart when there is sufficient information in the data (moderate-size
      expected count and/or high true excess risk). Sensitivity may be improved by
      exploiting the whole posterior distribution to try to detect true raised-risk
      areas rather than just reporting and mapping the mean posterior relative risk.
      For the widely used conditional autoregressive model, we show that a decision
      rule based on computing the probability that the relative risk is above 1 with a
      cutoff between 70 and 80% gives a specific rule with reasonable sensitivity for a
      range of scenarios having moderate expected counts (approximately 20) and excess
      risks (approximately 1.5- to 2-fold). Larger (3-fold) excess risks are detected
      almost certainly using this rule, even when based on small expected counts,
      although the mean of the posterior distribution is typically smoothed to about
      half the true value.

PMID- 15198923
TI  - Cancer risk near a polluted river in Finland.
AB  - The River Kymijoki in southern Finland is heavily polluted with polychlorinated
      dibenzo-p-dioxins and dibenzofurans and may pose a health threat to local
      residents, especially farmers. In this study we investigated cancer risk in
      people living near the river (less than 20.0 km) in 1980. We used a geographic
      information system, which stores registry data, in 500 m times 500 m grid
      squares, from the Population Register Centre, Statistics Finland, and Finnish
      Cancer Registry. From 1981 to 2000, cancer incidence in all people (N = 188884)
      and in farmers (n = 11132) residing in the study area was at the level expected
      based on national rates. Relative risks for total cancer and 27 cancer subtypes
      were calculated by distance of individuals to the river in 1980 (reference: 5.0
      19.9 km, 1.0-4.9 km, less than 1.0 km), adjusting for sex, age, time period,
      socioeconomic status, and distance of individuals to the sea. The respective
      relative risks for total cancer were 1.00, 1.09 [95% confidence interval (CI),
      1.04-1.13], and 1.04 (95% CI, 0.99-1.09) among all residents, and 1.00, 0.99 (95%
      CI, 0.85-1.15), and 1.13 (95% CI, 0.97-1.32) among farmers. A statistically
      significant increase was observed for basal cell carcinoma of the skin (not
      included in total cancers) in all residents less than 5.0 km. Several other
      common cancers, including cancers of the breast, uterine cervix, gallbladder, and
      nervous system, showed slightly elevated risk estimates at less than 5.0 km from
      the river. Despite the limitations of exposure assessment, we cannot exclude the
      possibility that residence near the river may have contributed to a small
      increase in cancer risk, especially among farmers.

PMID- 15198924
TI  - Use of GIS and exposure modeling as tools in a study of cancer incidence in a
      population exposed to airborne dioxin.
AB  - In environmental health research there is a recognized need to develop improved
      epidemiologic and statistical methods for rapid assessment of relationships
      between environment and health. Exposure assessment is identified as a major
      challenge needing attention. In this study an exposure simulation model was used
      to delimit almost exactly in space and time an urban population exposed to
      airborne dioxin. A geographic information system (GIS) was used as the electronic
      environment in which to link the exposure model with the demographic, migration,
      and cancer data of the exposed population. This information is available in
      Denmark on an individual basis. Standardized incidence ratios (SIRs) for both men
      and women in 10-year age bands were calculated for three different exposure
      areas. Migration patterns were outlined. SIRs showed no excess of cancer
      incidences during the time span chosen (13 years; 1986-1998) in the whole exposed
      area or in the medium or higher polluted areas. The exposure model appeared very
      useful in selection of the appropriate exposure areas. The integration of the
      model in a GIS together with individual data on addresses, sex, age, migration,
      and information from routine health statistics (Danish Cancer Registry) proved
      its usefulness in demarking the exposed population and identifying the cancers
      related to that population. Less than one-third of the study population lived at
      the same address after 13 years of observation, and only half were still residing
      in the area, indicating migration of people as a major misclassification.

PMID- 15198925
TI  - Spatial analysis of the relationship between mortality from cardiovascular and
      cerebrovascular disease and drinking water hardness.
AB  - Previously published scientific papers have reported a negative correlation
      between drinking water hardness and cardiovascular mortality. Some ecologic and
      case-control studies suggest the protective effect of calcium and magnesium
      concentration in drinking water. In this article we present an analysis of this
      protective relationship in 538 municipalities of Comunidad Valenciana (Spain)
      from 1991-1998. We used the Spanish version of the Rapid Inquiry Facility (RIF)
      developed under the European Environment and Health Information System (EUROHEIS)
      research project. The strategy of analysis used in our study conforms to the
      exploratory nature of the RIF that is used as a tool to obtain quick and flexible
      insight into epidemiologic surveillance problems. This article describes the use
      of the RIF to explore possible associations between disease indicators and
      environmental factors. We used exposure analysis to assess the effect of both
      protective factors--calcium and magnesium--on mortality from cerebrovascular (ICD
      9 430-438) and ischemic heart (ICD-9 410-414) diseases. This study provides
      statistical evidence of the relationship between mortality from cardiovascular
      diseases and hardness of drinking water. This relationship is stronger in
      cerebrovascular disease than in ischemic heart disease, is more pronounced for
      women than for men, and is more apparent with magnesium than with calcium
      concentration levels. Nevertheless, the protective nature of these two factors is
      not clearly established. Our results suggest the possibility of protectiveness
      but cannot be claimed as conclusive. The weak effects of these covariates make it
      difficult to separate them from the influence of socioeconomic and environmental
      factors. We have also performed disease mapping of standardized mortality ratios
      to detect clusters of municipalities with high risk. Further standardization by
      levels of calcium and magnesium in drinking water shows changes in the maps when
      we remove the effect of these covariates.

PMID- 15198926
TI  - Diabetes decreases rabbit bladder smooth muscle contraction while increasing
      levels of myosin light chain phosphorylation.
AB  - The effect of diabetes mellitus on the regulation of urinary bladder smooth
      muscle contraction was studied. Diabetes was induced in the rabbit by alloxan
      injection followed by 16 wk of housing. The bladder was harvested and strips of
      wall devoid of both mucosa and serosa were examined. Intact strips of bladder
      smooth muscle from diabetic animals produced less stress in response to membrane
      depolarization than muscle from control animals; sensitivity to KCl was not
      changed. Carbachol responses were similar in muscle strips from the two animal
      groups. Basal myosin light chain (MLC) phosphorylation levels were significantly
      elevated in response to most stimuli in muscle strips from diabetic animals,
      although levels of stress were either unchanged or lower. alpha-Toxin
      permeabilized strips that allow for control of the intracellular environment
      while maintaining excitation-contraction coupling showed increased levels of MLC
      phosphorylation but decreased sensitivity to activator Ca2+ in smooth muscle from
      diabetic animals. MLC phosphatase contents were similar in smooth muscle from the
      two animal groups; however, MLC phosphatase activity was greater in muscle from
      control compared with diabetic animals. These results suggest that diabetes
      mellitus uncouples basal MLC phosphorylation from force in the bladder smooth
      muscle cell.

PMID- 15198927
TI  - Expression of angiopoietins in renal epithelial and clear cell carcinoma cells:
      regulation by hypoxia and participation in angiogenesis.
AB  - The hereditary von Hippel-Lindau (VHL) syndrome predisposes sufferers to highly
      vascularized tumors such as renal clear cell carcinoma (RCC) and central nervous
      system hemangioblastoma. In RCC4 and RCC786-0 VHL- cells with VHL mutations, the
      protein of hypoxia-inducible factor-1alpha (HIF-1alpha) is constitutively
      stabilized and the mRNA levels of HIF target genes, including vascular
      endothelial growth factor (VEGF), are elevated. However, the expression of
      angiopoietins in these cells and their involvement in angiogenesis are not well
      known. In this study, we compared the mRNA levels of angiopoietins in human
      kidney proximal tubule epithelial (RPTE) and RCC4 and RCC786-0 VHL- cells. In
      RPTE cells, angiopoietin-4 (Ang-4) expression was selectively induced by hypoxia
      or by expression of a hybrid form of HIF-1alpha. Under normoxic conditions, the
      mRNA levels of Ang-4 were higher in RCC4 and RCC786-0 VHL- than RPTE cells.
      Angiopoietin-1 expression was detectable in RCC4 and RCC786-0 VHL- cells but not
      RPTE cells. In RCC786-0 VHL+ cells, which were stably transfected with a wild
      type copy of VHL, the mRNA levels of VEGF and Ang-4 were suppressed and the
      hypoxic response was restored. We also demonstrated that stimulation of
      endothelial tube formation by conditioned medium harvested from RCC4 cells was
      inhibited by a soluble Tie-2 receptor. These results suggest that the
      angiopoietin/Tie-2 system may participate in the angiogenic response to hypoxia
      in renal tissues and in tumor angiogenesis in renal carcinoma.

PMID- 15198928
TI  - Glycated albumin activates PAI-1 transcription through Smad DNA binding sites in
      mesangial cells.
AB  - Amadori-modified glycated albumin stimulates extracellular matrix and
      transforming growth factor-beta (TGF-beta) expression in cultured mesangial
      cells. Smad proteins transduce the TGF-beta-mediated signal, and Smad-binding
      CAGA sequences are present in the plasminogen activator inhibitor-1 (PAI-1)
      promoter. This study examined whether glycated albumin induces PAI-1
      transcription in human mesangial cells (HMC) through Smad-binding sites in the
      PAI-1 promoter. Quiescent HMC were exposed to 200 microg/ml bovine serum albumin
      (BSA) or glycated BSA (Gly-BSA) for 12-72 h. At 24 h, Gly-BSA stimulated TGF
      beta1 and PAI-1 mRNA expression in HMC to 1.8 and 3.2 times that in the BSA
      treated control cells. Gly-BSA also activated the PAI-1 promoter luciferase
      activity 2.3-fold. Gly-BSA-treated cells enhanced Smad2 and Smad3 protein levels
      2.5 times the control levels in the nuclei. An electrophoretic mobility shift
      assay performed using CAGA sequences as a probe showed that Gly-BSA increased
      DNA/protein complexes. When nuclear extracts were preincubated with 100-fold
      molar excess of unlabeled CAGA oligonucleotide, the formation of complex was
      prevented. The DNA-binding protein was shown to be Smad3 by antibody supershift.
      Transfection of phosphorothioate CAGA oligonucleotide, a CAGA antisense analog,
      inhibited Gly-BSA-induced PAI-1 mRNA expression. Cotransfection of
      phosphorothioate CAGA oligonucleotides with PAI-1 reporter vector also blocked
      Gly-BSA-induced PAI-1 promoter luciferase activity. These results indicate that
      Gly-BSA increases DNA binding activity of Smad3 and that it stimulates PAI-1
      transcription through Smad-binding CAGA sequences in the PAI-1 promoter in HMC.
      Thus progression of diabetic nephropathy may be promoted by PAI-1 upregulation
      mediated by the glycated albumin-induced Smad/DNA interactions.

PMID- 15198930
TI  - Adult skeletal muscle stem cells differentiate into endothelial lineage and
      ameliorate renal dysfunction after acute ischemia.
AB  - We previously demonstrated that endothelial cells are severely damaged during
      renal ischemia-reperfusion and that transplantation of adult human endothelial
      cells into athymic nude rats subjected to renal ischemia resulted in a dramatic
      protection of the kidney against injury and dysfunction. Morphological studies
      demonstrated the engraftment of transplanted cells into renal microvasculature.
      The goal of the present study was to determine the potential efficacy of in vitro
      expanded skeletal muscle-derived stem cells (MDSC) differentiated along the
      endothelial lineage in ameliorating acute renal injury. MDSC obtained from the
      Tie-2-green fluorescent protein (GFP) mice were used as donors of differentiated
      and nondifferentiated stem cells. FVB mice, used as recipients, were subjected to
      renal ischemia and transplanted with the above MDSC. The differentiation of MDSC
      along the endothelial lineage was monitored by the appearance of Tie-2 promotor
      driven expression of GFP. These mouse endothelial cell antigen-, endothelial
      nitric oxide synthase (eNOS)-, Flk-1-, Flt-1-, and CD31-positive cells engrafted
      into renal microvasculature and significantly protected short-term renal function
      after ischemia. Transplantation of nondifferentiated MDSC characterized by the
      expression of Sca-1 (low levels of CD34, Flk-1, and cKit, and negative for GFP,
      eNOS, and CD31) did not improve short-term renal dysfunction. In conclusion, the
      data 1) provide a rich source of MDSC, 2) delineate protocols for their in vitro
      expansion and differentiation along the endothelial lineage, and 3) demonstrate
      their efficacy in preserving renal function immediately after ischemic insult.

PMID- 15198929
TI  - Modulation of epithelial Na+ channel activity by long-chain n-3 fatty acids.
AB  - The epithelial sodium channel is found in apical membranes of a variety of native
      epithelial tissues, where it regulates sodium and fluid balance. In vivo, a
      number of hormones and other endogenous factors, including polyunsaturated fatty
      acids (PUFAs), regulate these channels. We tested the effects of essential n-3
      and n-6 PUFAs on amiloride-sensitive sodium transport in A6 epithelial cells.
      Eicosapentaenoic acid [EPA; C20:5(n-3)] transiently stimulated amiloride
      sensitive open-circuit current (I(Na)) from 4.0 +/- 0.3 to 7.7 +/- 0.3 microA/cm2
      within 30 min (P < 0.001). No activation was seen in the presence of 10 microM
      amiloride. In cell-attached but not in cell-excised patches, EPA acutely
      increased the open probability of sodium channels from 0.45 +/- 0.08 to 0.63 +/-
      0.10 (P = 0.02, paired t-test). n-6 PUFAs, including linoleic acid (C18:2),
      eicosatetraynoic acid (C20:4), and docosapentanoic acid (C22:5) had no effect,
      whereas n-3 docosahexanoic acid (C22:6) activated amiloride-sensitive I(Na) in a
      manner similar to EPA. Activation of I(Na) by EPA was prevented by H-89, a PKA
      inhibitor. Similarly, PKA activity was stimulated by EPA. Nonspecific stimulation
      of phosphodiesterase activity by CoCl2 completely prevented the effect of EPA on
      sodium transport. We conclude that n-3 PUFAs activate epithelial sodium channels
      downstream of cAMP in a cAMP-dependent pathway also involving PKA.

PMID- 15198931
TI  - Induction of uPA release in human peripheral blood lymphocytes by [deamino-Cysl,D
      Arg8]-vasopressin (dDAVP).
AB  - [deamino-Cys(l),d-Arg(8)]-vasopressin (dDAVP), known to be an arginine
      vasopressin (AVP) V(2) receptor agonist, is an agent that increases fibrinolytic
      activity levels in plasma after its infusion into the human body. However,
      mechanisms underlying an increase and exact localization of the extrarenal dDAVP
      responsive V(2) receptor remain unclarified. Two AVP receptors, V(1a) and V(2),
      and a related oxytocin (OT) receptor were found to be expressed in human
      lymphocytes. Furthermore, we found an increase of fibrinolytic activity in the
      medium of peripheral lymphocytes obtained from human volunteers less than 20 min
      after dDAVP infusion. The increased activity was also detected in the medium
      after incubating the lymphocytes in the presence of dDAVP in vitro, being highest
      at 20 min after the incubation. In accord with the increased fibrinolytic
      activity, the levels of urokinase-type plasminogen activator (uPA) in the medium
      were also increased. However, there was no significant difference of plasminogen
      activator inhibitor-1 (PAI-1), pro-uPA, and tissue-type plasminogen activator
      (tPA) concentrations in the medium between dDAVP treatment and control. When
      lymphocytes were preincubated with a V(2) receptor antagonist
      [Adamantaneacetyl(1),O-Et-d-Tyr(2),Val(4),Aminobutyryl(6),Arg(8,9)]-vasopressin,
      the dDAVP-induced uPA increase was diminished. In contrast, preincubation with a
      V(1) receptor antagonist, [beta-Mercapto-beta,beta
      cyclopentamethylenepropionyl(1),O-Me-Tyr(2),Arg(8)]-vasopressin, prior to dDAVP
      treatment resulted in a greater increase of the uPA concentration in the medium
      than with the dDAVP treatment alone. Thus it was suggested that dDAVP may induce
      uPA release from human lymphocytes via V(2) receptor-mediated reaction, and also
      via cross-talk between V(1) and V(2) receptors.

PMID- 15198932
TI  - Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response.
AB  - The acute-phase response (APR) induces alterations in lipid metabolism, and our
      data suggest that this is associated with suppression of type II nuclear hormone
      receptors that are key regulators of fatty acid, cholesterol, and bile acid
      metabolism. Recently, the farnesoid X receptor (FXR), constitutive androstane
      receptor (CAR), and pregnane X receptor (PXR) were found to regulate DHEA
      sulfotransferase (Sult2A1), which plays an important role in DHEA sulfation and
      detoxification of bile acids. Because FXR, PXR, and CAR are suppressed during the
      APR, we hypothesized that Sult2A1 is downregulated during the APR. To induce the
      APR, mice were treated with LPS, which will then trigger the release of various
      cytokines, and the mRNA levels of Sult2A1 and the sulfate donor 3'
      phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2), as well as the enzyme
      activity of Sult2A1, were determined in the liver. We found that mRNA levels of
      Sult2A1 decrease in a time- and dose-dependent manner during the LPS-induced APR.
      Similar changes were observed in the mRNA levels of PAPSS2, the major synthase of
      PAPS in the liver. Moreover, hepatic Sult2A1 activity and serum levels of DHEA
      sulfate (DHEA-S) were significantly decreased in LPS-treated animals. These
      results suggest that decreased levels or activities of FXR, PXR, and CAR during
      the APR could contribute to decreases in Sult2A1, resulting in decreased
      sulfation of DHEA and lower circulating level of DHEA-S. Finally, we found that
      both TNF and IL-1 caused a significant decrease in the mRNA level of Sult2A1 in
      Hep3B human hepatoma cells, suggesting that the proinflammatory cytokines TNF and
      IL-1 mediate the inhibitory effect of LPS on Sult2A1 mRNA level. Our study
      provides a possible mechanism by which infection and inflammation are associated
      with altered steroid metabolism and cholestasis.

PMID- 15198933
TI  - Nonacute effects of H-FABP deficiency on skeletal muscle glucose uptake in vitro.
AB  - Heart-type fatty acid-binding protein (H-FABP) is required for high rates of
      skeletal muscle long-chain fatty acid (LCFA) oxidation and esterification. Here
      we assessed whether H-FABP affects soleus muscle glucose uptake when measured in
      vitro in the absence of LCFA. Wild-type and H-FABP null mice were fed a standard
      chow or high-fat diet before muscle isolation. With the chow, the mutation
      increased insulin-dependent deoxyglucose uptake by 141% (P < 0.01) at 0.02 mU/ml
      of insulin but did not cause a significant effect at 2 mU/ml of insulin; skeletal
      muscle triglyceride and long-chain acyl-CoA (LCA-CoA) levels remained normal.
      With the high-fat diet, the mutation increased insulin-dependent deoxyglucose
      uptake by 190% (P < 0.01) at 2 mU/ml of insulin, thus partially preventing
      insulin resistance, and it completely prevented the threefold (P < 0.001) diet
      induced increase of muscle triglyceride levels; however, muscle LCA-CoA levels
      showed little or no reduction. With both diets, the mutation reduced the basal
      (insulin-independent) soleus muscle deoxyglucose uptake by 28% (P < 0.05). These
      results establish a close relation between FABP-dependent lipid pools and insulin
      sensitivity and indicate the existence of a nonacute, antagonistic, and H-FABP
      dependent fatty acid regulation of basal and insulin-dependent muscle glucose
      uptake.

PMID- 15198934
TI  - Expression of FOXC2 in adipose and muscle and its association with whole body
      insulin sensitivity.
AB  - FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling.
      Overexpression of FOXC2 in the adipose tissue of transgenic mice protected
      against diet-induced obesity and insulin resistance. We examined the expression
      of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin
      sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA
      in either adipose or muscle. There was a strong inverse relation between adipose
      FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous
      glucose tolerance test (r = -0.78, P < 0.001). However, there was no relationship
      between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin
      resistance from obesity, we examined FOXC2 expression in pairs of subjects who
      were matched for BMI but who were discordant for insulin sensitivity. Compared
      with insulin-sensitive subjects, insulin-resistant subjects had threefold higher
      levels of adipose FOXC2 mRNA (P = 0.03). In contrast, muscle FOXC2 mRNA
      expression was no different between insulin-resistant and insulin-sensitive
      subjects. There was no association of adipose or muscle FOXC2 mRNA with either
      circulating or adipose-secreted TNF-alpha, IL-6, leptin, adiponectin, or non
      esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin
      resistant subjects, and this effect is independent of obesity. This association
      between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA
      signaling.

PMID- 15198935
TI  - Chronic administration of nitric oxide reduces angiotensin II receptor type 1
      expression and aldosterone synthesis in zona glomerulosa cells.
AB  - Acute nitric oxide (NO) inhibits angiotensin II (ANG II)-stimulated aldosterone
      synthesis in zona glomerulosa (ZG) cells. In this study, we investigated the
      effects of chronic administration of NO on the ANG II receptor type 1 (AT1)
      expression and aldosterone synthesis. ZG cells were treated daily with DETA
      NONOate (10(-4) M), an NO donor, for 0, 12, 24, 48, 72, and 96 h. Chinese hamster
      ovary (CHO) cells, stably transfected with the AT1B receptor, were used as a
      positive control. Western blot analysis indicated that AT1 receptor expression
      was decreased as a function of time of NO administration in both CHO and ZG
      cells. ANG II binding to its receptors was determined by radioligand binding. NO
      treatment of ZG cells for 96 h resulted in a decrease in ANG II binding compared
      with control. The receptor density was decreased to 1,864 +/- 129 fmol/mg protein
      from 3,157 +/- 220 fmol/mg protein (P < 0.005), but the affinity was not changed
      (1.95 +/- 0.22 vs. 1.88 +/- 0.21 nM). Confocal Raman microspectroscopy and
      immunocytochemistry both confirmed that the expression of AT1 receptors in ZG
      cells decreased with chronic NO administration. In addition, chronic NO
      administration also decreased the expression of cholesterol side-chain cleavage
      enzyme in ZG cells and inhibited ANG II- and 25-hydroxycholesterol-stimulated
      aldosterone synthesis in ZG cells. This study demonstrates that chronic
      administration of NO inhibits aldosterone synthesis in ZG cells by downregulation
      of the expression of both AT1 receptors and cholesterol side-chain cleavage
      enzyme.

PMID- 15198936
TI  - Hepatospecific effects of fructose on c-jun NH2-terminal kinase: implications for
      hepatic insulin resistance.
AB  - Sucrose- and fructose-enriched diets produce hepatic insulin resistance in rats
      independently of obesity. In humans, fructose infusion results in impaired
      insulin regulation of glucose production. The aim of the present study was to
      identify intrahepatic mediators of sucrose- and fructose-induced hepatic insulin
      resistance. In study 1, male rats were fed a control diet (STD, 68% of energy
      from corn starch, 12% from corn oil) or a sucrose-enriched diet (HSD, 68%
      sucrose, 12% corn oil) for 1, 2, or 5 wk. HSD produced hepatic insulin resistance
      at all time points. Hepatic protein tyrosine phosphatase 1B protein levels and
      activity were increased at 5 wk only, whereas c-jun NH(2)-terminal kinase (JNK)
      activity was increased at all time points. Normalization of JNK activity in
      hepatocytes isolated from HSD rats improved insulin-stimulated tyrosine
      phosphorylation of insulin receptor substrate (IRS) proteins and insulin
      suppression of glucose release. In study 2, male rats were provided STD for 1 wk
      and then were either fasted or fasted and refed either STD or HSD for 3 or 6 h.
      Rats refed HSD were characterized by increased hepatic JNK activity and
      phosphorylation of IRS1 on Ser(307) after 6 h only. In study 3, hyperglycemic,
      hyperinsulinemic pancreatic clamps were performed for 3 or 6 h in the presence or
      absence of low or high intraportal fructose infusions. High intraportal fructose
      infusions, which increased portal vein fructose concentration to approximately 1
      mM, increased hepatic JNK activity and phosphorylation of IRS1 on Ser(307) at 6 h
      only. These data suggest that sucrose- and fructose-induced hepatic insulin
      resistance are mediated, in part, via activation of JNK activity. Thus high rates
      of fructose metabolism in the liver appear to acutely activate stress pathways.

PMID- 15198937
TI  - Limits to phenotypic plasticity: flow effects on barnacle feeding appendages.
AB  - Phenotypic plasticity, the capacity of a given genotype to produce differing
      morphologies in response to the environment, is widespread among marine organisms
      (1). For example, acorn barnacles feed by extending specialized appendages (the
      cirral legs) into flow, and the length of the cirri is plastic: the higher the
      velocity, the shorter the feeding legs (2,3). However, this effect has been
      explored only for flows less than 4.6 m/s, slow compared to typical flows
      measured at sites on wave-exposed shores. What happens at faster speeds? Leg
      lengths of Balanus glandula Darwin, 1854, an acorn barnacle, were measured at 15
      sites in Monterey, California, across flows ranging from 0.5 to 14.0 m/s. Similar
      to previous findings, a plastic response in leg length was noted for the four
      sites with water velocities less than 3 m/s. However, no plastic response was
      present at the 11 sites exposed to faster velocities, despite a 4-fold variation
      in speed. We conclude that the velocity at which the plastic response occurs has
      an upper limit of 2-4 m/s, a velocity commonly exceeded within the typical
      habitat of this species.

PMID- 15198938
TI  - Microscopic, biochemical, and molecular characteristics of the Chilean Blob and a
      comparison with the remains of other sea monsters: nothing but whales.
AB  - We have employed electron microscopic, biochemical, and molecular techniques to
      clarify the species of origin of the "Chilean Blob," the remains of a large sea
      creature that beached on the Chilean coast in July 2003. Electron microscopy
      revealed that the remains are largely composed of an acellular, fibrous network
      reminiscent of the collagen fiber network in whale blubber. Amino acid analyses
      of an acid hydrolysate indicated that the fibers are composed of 31% glycine
      residues and also contain hydroxyproline and hydroxylysine, all diagnostic of
      collagen. Using primers designed to the mitochondrial gene nad2, an 800-bp
      product of the polymerase chain reaction (PCR) was amplified from DNA that had
      been purified from the carcass. The DNA sequence of the PCR product was 100%
      identical to nad2 of sperm whale (Physeter catadon). These results unequivocally
      demonstrate that the Chilean Blob is the almost completely decomposed remains of
      the blubber layer of a sperm whale. This identification is the same as those we
      have obtained before from other relics such as the so-called giant octopus of St.
      Augustine (Florida), the Tasmanian West Coast Monster, two Bermuda Blobs, and the
      Nantucket Blob. It is clear now that all of these blobs of popular and
      cryptozoological interest are, in fact, the decomposed remains of large
      cetaceans.

PMID- 15198939
TI  - Chemical and visual communication during mate searching in rock shrimp.
AB  - Mate searching in crustaceans depends on different communicational cues, of which
      chemical and visual cues are most important. Herein we examined the role of
      chemical and visual communication during mate searching and assessment in the
      rock shrimp Rhynchocinetes typus. Adult male rock shrimp experience major
      ontogenetic changes. The terminal molt stages (named "robustus") are dominant and
      capable of monopolizing females during the mating process. Previous studies had
      shown that most females preferably mate with robustus males, but how these
      dominant males and receptive females find each other is uncertain, and is the
      question we examined herein. In a Y-maze designed to test for the importance of
      waterborne chemical cues, we observed that females approached the robustus male
      significantly more often than the typus male. Robustus males, however, were
      unable to locate receptive females via chemical signals. Using an experimental
      set-up that allowed testing for the importance of visual cues, we demonstrated
      that receptive females do not use visual cues to select robustus males, but
      robustus males use visual cues to find receptive females. Visual cues used by the
      robustus males were the tumults created by agitated aggregations of subordinate
      typus males around the receptive females. These results indicate a strong link
      between sexual communication and the mating system of rock shrimp in which
      dominant males monopolize receptive females. We found that females and males use
      different (sex-specific) communicational cues during mate searching and
      assessment, and that the sexual communication of rock shrimp is similar to that
      of the American lobster, where females are first attracted to the dominant males
      by chemical cues emitted by these males. A brief comparison between these two
      species shows that female behaviors during sexual communication contribute
      strongly to the outcome of mate searching and assessment.

PMID- 15198940
TI  - Remarkable longevity of dilute sperm in a free-spawning colonial ascidian.
AB  - Many benthic marine invertebrates reproduce by releasing sperm into the sea (free
      spawning), but the amount of time that sperm are viable after spawning may have
      different consequences for fertilization, depending on the type of free-spawner.
      In egg-broadcasting marine organisms, gamete age is usually assumed to be
      irrelevant because of the low probability of contact between dilute sperm and
      egg. However, direct dilution effects might be reduced in egg-brooding free
      spawners that filter dilute sperm out of the water column, and sperm longevity
      may play a role in facilitating fertilization in these taxa. We investigated the
      effects of time, temperature, and mixing on the viability of naturally released
      sperm of the colonial ascidian Botryllus schlosseri. Our data indicate that B.
      schlosseri sperm have a functional life span that is considerably longer than
      those of the sperm of many other marine invertebrate taxa (half-life of
      approximately 16 to 26 h), are able to fertilize eggs at extremely low external
      sperm concentrations (ca. 10(1) sperm ml(-1)), and have a longevity that varies
      with temperature. It is possible that such prolonged sperm longevity may be
      achieved by reductions in motility, reactivation of quiescent sperm by chemical
      cues, or intermittent swimming.

PMID- 15198941
TI  - Fertilization in an egg-brooding colonial ascidian does not vary with population
      density.
AB  - The possibility that free-spawning marine organisms may be subject to
      fertilization failure at low population density (due to the effects of sperm
      dilution) has sparked much interest, but these effects have been demonstrated
      only in a few species that broadcast their eggs. Some egg-brooding species may
      overcome dilution effects by filtering low concentrations of sperm from seawater
      and fertilizing eggs throughout an extended period of time. We examined the
      effects of population density and size on fertilization in Botryllus schlosseri,
      a hermaphroditic colonial ascidian that free-spawns sperm, but broods eggs. We
      experimentally manipulated the size and density of mating groups and surveyed
      fertilization levels in natural populations that varied in density. Fertilization
      was not affected by variation in population size or density in either the
      experimental or natural populations. Near the end of the reproductive season,
      some eggs may have been fertilized too late to complete development, suggesting a
      temporal form of sperm limitation that has not been considered in other systems.
      We also detected greater variability in fertilization levels at lower population
      density. Nevertheless, these results suggest that caution must be used in
      extrapolating reported density effects on fertilization to all taxa of free
      spawners; density effects may be reduced in brooders that have efficient sperm
      collection mechanisms.

PMID- 15198943
TI  - Fitness consequences of allorecognition-mediated agonistic interactions in the
      colonial hydroid Hydractinia [GM].
AB  - In sessile and sedentary organisms, competition for space may have fitness
      consequences that depend strongly on ecological context. Colonial hydroids in the
      genus Hydractinia use an inducible defense when encountering conspecifics, and
      intraspecific competition is common in natural populations, often resulting in
      complete overgrowth of subordinate competitors. My goal in this study was to
      quantify the impacts of agonistic interactions in Hydractinia [GM] (an
      undescribed species from the Gulf of Mexico) in terms of three primary fitness
      components: colony survival, growth rate, and immature gonozooid production. The
      results demonstrate that the fitness consequences of intraspecific competition
      depend on the size at which competitive encounters are initiated and the growth
      form (an indicator of competitive ability) of the competitors. Moreover, some
      competing colonies consistently produced more immature gonozooids than the
      controls without competition, and they exhibited extremely low mortality even
      after 90 days of growth. These results have several ramifications. First,
      agonistic interactions do not always proceed to competitive elimination. Second,
      the increase in production of immature gonozooids--an investment in future
      reproduction--in response to intraspecific competition supports the hypothesis
      that indeterminately growing organisms increase sexual reproductive effort when
      growth becomes limiting. Lastly, in light of known ontogenetic variation in the
      ability of Hydractinia to differentiate among genetically related colonies,
      strongly size-dependent fitness consequences are consistent with an adaptive, kin
      discriminating allorecognition system.

PMID- 15198942
TI  - Induction of settlement of larvae of the sea urchin Holopneustes purpurascens by
      histamine from a host alga.
AB  - Larvae of the Australian sea urchin Holopneustes purpurascens are induced to
      settle and metamorphose (termed settlement herein) by a water-soluble compound
      produced by the red alga Delisea pulchra, the main host plant of new recruits.
      The settlement cue for H. purpurascens had previously been identified as a
      floridoside-isethionic acid complex, and this paper presents new evidence
      correcting that finding. The actual settlement cue produced by D. pulchra was
      isolated from the polar extract by cation-exchange chromatography and identified
      as histamine, using one- and two-dimensional nuclear magnetic resonance
      spectrometry. The chemical identity of the cue was confirmed by gas
      chromatography-mass spectrometry (GC-MS) and matrix-assisted laser
      desorption/ionization-time-of-flight mass spectrometry. Synthetic histamine and
      histamine at 4.5 microM isolated from D. pulchra both induced rapid settlement in
      80%-100% of the larvae of H. purpurascens. Lower concentrations of histamine (0.9
      2.3 micro M) induced larval settlement, but this response varied from 0%-90%. The
      histamine content of two host plants of H. purpurascens--D. pulchra and Ecklonia
      radiata--and of four other common species was quantified using GC-MS. D. pulchra
      had the highest histamine content, which is consistent with H. purpurascens
      recruiting to this species. Histamine was also detected in the seawater
      surrounding these host algae. This is the first time that a settlement cue has
      been quantified in the habitat of a marine organism.

PMID- 15198944
TI  - Effects of hypercapnic hypoxia on the clearance of Vibrio campbellii in the
      Atlantic blue crab, Callinectes sapidus Rathbun.
AB  - Callinectes sapidus, the Atlantic blue crab, encounters hypoxia, hypercapnia
      (elevated CO(2)), and bacterial pathogens in its natural environment. We tested
      the hypothesis that acute exposure to hypercapnic hypoxia (HH) alters the crab's
      ability to clear a pathogenic bacterium, Vibrio campbellii 90-69B3, from the
      hemolymph. Adult male crabs were held in normoxia (well-aerated seawater) or HH
      (seawater with PO(2) = 4 kPa; PCO(2) = 1.8 kPa; and pH = 6.7-7.1) and were
      injected with 2.5 x 10(4) Vibrio g(-1) body weight. The animals were held in
      normoxia or in HH for 45, 75, or 210-240 min before being injected with Vibrio,
      and were maintained in their respective treatment conditions for the 120-min
      duration of the experiment. Vibrio colony-forming units (CFU) ml(-1) hemolymph
      were quantified before injection, and at 10, 20, and 40 min afterward. Total
      hemocytes (THC) ml(-1) of hemolymph were counted 24 h before (-24 h), and at 10
      and 120 min after injection. Sham injections of saline produced no change in the
      bacterial or hemocyte counts in any treatment group. Among the groups that
      received bacterial injections, Vibrio was almost completely cleared within 1 h,
      but at 10-min postinjection, Vibrio CFU ml(-1) hemolymph was significantly higher
      in animals held in HH for 75 and 210-240 min than in those held in normoxia.
      Within 10 min after crabs were injected with bacteria, THC ml(-1) significantly
      decreased in control and HH45 treatments, but not in the HH75 and HH210-240
      treatments. By 120 min after injection of bacteria, hemocyte counts decreased in
      all but the HH45 group. These data demonstrate that HH significantly impairs the
      ability of blue crabs to clear Vibrio from the hemolymph. These results also
      suggest that HH alters the normal role of circulating hemocytes in the removal of
      an invading pathogen.

PMID- 15198945
TI  - The benefit of prevention: engaging the public through strategic collaborations.

PMID- 15198946
TI  - Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the
      American Cancer Society, the American Diabetes Association, and the American
      Heart Association.
AB  - Collectively, cardiovascular disease (including stroke), cancer, and diabetes
      account for approximately two thirds of all deaths in the United States and about
      700 billion dollars in direct and indirect economic costs each year. Current
      approaches to health promotion and prevention of cardiovascular disease, cancer,
      and diabetes do not approach the potential of the existing state of knowledge. A
      concerted effort to increase application of public health and clinical
      interventions of known efficacy to reduce prevalence of tobacco use, poor diet,
      and insufficient physical activity-the major risk factors for these diseases-and
      to increase utilization of screening tests for their early detection could
      substantially reduce the human and economic cost of these diseases. In this
      article, the ACS, ADA, and AHA review strategies for the prevention and early
      detection of cancer, cardiovascular disease, and diabetes, as the beginning of a
      new collaboration among the three organizations. The goal of this joint venture
      is to stimulate substantial improvements in primary prevention and early
      detection through collaboration between key organizations, greater public
      awareness about healthy lifestyles, legislative action that results in more
      funding for and access to primary prevention programs and research, and
      reconsideration of the concept of the periodic medical checkup as an effective
      platform for prevention, early detection, and treatment.

PMID- 15198947
TI  - Smokeless tobacco use, birth weight, and gestational age: population based,
      prospective cohort study of 1217 women in Mumbai, India.
AB  - OBJECTIVE: To study the effect of using smokeless tobacco during pregnancy on
      babies' birth weight and gestational age at birth. DESIGN: Population based,
      prospective cohort study using a house to house approach. SETTING: Eight primary
      health post areas in the city of Mumbai (Bombay), India. PARTICIPANTS: 1217 women
      who were three to seven months pregnant and planning to deliver in the study
      area. 1167 women (96%) were followed up. MAIN OUTCOME MEASURES: Birth weight and
      gestational age in singleton births. RESULTS: Smokeless tobacco use was
      associated with an average reduction of 105 g in birth weight (95% confidence
      interval 30 g to 181 g) and a reduction in gestational age of 6.2 (3.0 to 9.4)
      days. The odds ratio for low birth weight was 1.6 (1.1 to 2.4), adjusted by
      logistic regression for maternal age, education, socioeconomic status, weight,
      anaemia, antenatal care, and gestational age. The adjusted odds ratio for preterm
      delivery (< 37 weeks) was 1.4 (1.0 to 2.1); for delivery before 32 weeks it was
      4.9 (2.1 to 11.8) and before 28 weeks it was 8.0 (2.6 to 27.2). CONCLUSIONS:
      Consumption of smokeless tobacco during pregnancy decreases gestational age at
      birth and birth weight independent of gestational age. It should receive specific
      attention as a part of routine prenatal care.

PMID- 15198948
TI  - Promoter hypermethylation of cancer-related genes: a strong independent
      prognostic factor in acute lymphoblastic leukemia.
AB  - Promoter hypermethylation plays an important role in the inactivation of cancer
      related genes. This abnormality occurs early in leukemogenesis and seems to be
      associated with poor prognosis in acute lymphoblastic leukemia (ALL). To
      determine the extent of hypermethylation in ALL, we analyzed the methylation
      status of the CDH1, p73, p16, p15, p57, NES-1, DKK-3, CDH13, p14, TMS-1, APAF-1,
      DAPK, PARKIN, LATS-1, and PTEN genes in 251 consecutive ALL patients. A total of
      77.3% of samples had at least 1 gene methylated, whereas 35.9% of cases had 4 or
      more genes methylated. Clinical features and complete remission rate did not
      differ among patients without methylated genes, patients with 1 to 3 methylated
      genes (methylated group A), or patients with more than 3 methylated genes
      (methylated group B). Estimated disease-free survival (DFS) and overall survival
      (OS) at 11 years were 75.5% and 66.1%, respectively, for the nonmethylated group;
      37.2% and 45.5% for methylated group A; and 9.4% and 7.8% for methylated group B
      (P < .0001 and P = .0004, respectively). Multivariate analysis demonstrated that
      the methylation profile was an independent prognostic factor in predicting DFS (P
      < .0001) and OS (P = .003). Our results suggest that the methylation profile may
      be a potential new biomarker of risk prediction in ALL.

PMID- 15198949
TI  - Severe hemochromatosis in a Portuguese family associated with a new mutation in
      the 5'-UTR of the HAMP gene.
AB  - Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder
      transmitted as an autosomal recessive trait. It is most often caused by mutations
      in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute
      a negative regulator of iron absorption, and its production is increased in
      inflammatory states and iron overload. We report the detection of a new mutation
      in the HAMP gene leading to juvenile hemochromatosis in 2 members of a Portuguese
      family. The mutation lies in the 5'-UTR (untranslated region) of the gene and
      creates a new initiation codon in the context of a Kozak sequence. We found no
      trace of hepcidin protein in the patients' urine, suggesting that ribosomes
      select the mutant initiation codon for translation. The decrease of hepcidin
      production would thus lead to increased iron absorption, resulting in iron
      deposition in parenchymal tissues. Phlebotomy therapy of the 2 patients resulted
      in impressive clinical improvement.

PMID- 15198950
TI  - Human marrow megakaryocyte differentiation: multiparameter correlative analysis
      identifies von Willebrand factor as a sensitive and distinctive marker for early
      (2N and 4N) megakaryocytes.
AB  - Human megakaryocyte differentiation and maturation were studied in fresh marrow
      aspirates by using multiparameter flow cytometric correlative analysis. The
      expression of glycoprotein (GP)IIb/IIIa, GPIIIa, GPIb, and CD36 correlated
      directly with cell size and ploidy (r > 0.97); however, GPIb acquisition was
      relatively slow. von Willebrand factor (VWF) is robustly expressed by early (2N
      and 4N) megakaryocytes, enabling their complete resolution from the other marrow
      cells at a level superior to that achieved with GPIIb/IIIa. Expression of myeloid
      CD45 and immunoglobulin G (IgG)-FcgammaRII receptor (CDw32) increased with
      megakaryocyte maturation and contrasted with the declining expression of HLA-DR
      (negative in platelets). Interleukin-6 receptor expression in megakaryocytes was
      higher than in other marrow cells. By using the time-of-flight technique, the
      diameter of the megakaryocyte population was 37 +/- 4 microm (mean +/- 1 SD)
      compared with 14 +/- 2 microm for the total marrow cells, ranging from 21 +/- 4
      microm for 2N cells to 56 +/- 8 microm for 64N cells. Cell size directly
      correlated with cell DNA (r = 0.98). Receptor density of GPIIb/IIIa and GPIb
      decreased with the transition from 2N to 4N cells, then reached maximum at 32N
      cells. In conclusion, the present methods are useful for studying in vivo human
      megakaryocytopoiesis in normal and altered states. The expression of VWF is a
      sensitive and distinctive marker for the identification of young marrow
      megakaryocytes.

PMID- 15198951
TI  - Cross-linking of P-selectin glycoprotein ligand-1 induces death of activated T
      cells.
AB  - Increasing evidence has shown that death signaling in T cells is regulated in a
      complicated way. Molecules other than death receptors can also trigger T-cell
      death. Here, we demonstrate for the first time that P-selectin glycoprotein
      ligand-1 (PSGL-1) or CD162 molecules cross-linked by an anti-PSGL-1 monoclonal
      antibody, TAB4, can trigger a death signal in activated T cells. In contrast to
      classic cell death, PSGL-1-mediated T-cell death is caspase independent. It
      involves translocation of apoptosis-inducing factor from mitochondria to nucleus
      and mitochondrial cytochrome c release. Ultrastructurally, both peripheral
      condensation of chromatin and apoptotic body were observed in PSGL-1-mediated T
      cell death. Collectively, this study demonstrates a novel role for PSGL-1 in
      controlling activated T-cell death and, thus, advances our understanding of
      immune regulation.

PMID- 15198952
TI  - Alpha(+)-thalassemia protects African children from severe malaria.
AB  - The high frequency of alpha(+)-thalassemia in malaria-endemic regions may reflect
      natural selection due to protection from potentially fatal severe malaria. In
      Africa, bearing 90% of global malaria morbidity and mortality, this has not yet
      been observed. We tested this hypothesis in an unmatched case-control study among
      301 Ghanaian children with severe malaria and 2107 controls (62% parasitemic). In
      control children, alpha(+)-thalassemia affected neither prevalence nor density of
      Plasmodium falciparum. However, heterozygous alpha(+)-thalassemia was observed in
      32.6% of controls but in only 26.2% of cases (odds ratio [OR], 0.74; 95%
      confidence interval [CI], 0.56-0.98). Protection against severe malaria was found
      to be pronounced comparing severe malaria patients with parasitemic controls
      (adjusted OR in children < 5 years of age, 0.52; 95% CI, 0.34-0.78) and to wane
      with age. No protective effect was discernible for homozygous children. Our
      findings provide evidence for natural selection of alpha(+)-thalassemia in Africa
      due to protection from severe malaria.

PMID- 15198953
TI  - Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin
      lymphoma.
AB  - Folate metabolism plays an essential role in DNA synthesis and methylation
      processes. Deviations in the flux of folate due to genetic variation could result
      in selective growth and genomic instability and affect susceptibility to various
      cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the
      folate metabolic pathway were investigated using DNA from a population-based case
      control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay
      Area between 1988 and 1995. The polymorphisms examined and haplotypes generated
      included thymidylate synthase (TYMS 28-bp triple repeat [3R]-->double repeat
      [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10
      methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine
      hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and
      methionine synthase (MTR A2756G), making the present study the largest and most
      comprehensive to date to evaluate associations between genetic polymorphisms in
      folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)(-)6bp-
      (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in
      complete linkage disequilibrium) were all inversely associated with NHL (TYMS;
      odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma
      (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT
      genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and
      follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe
      any significant differences in genotype frequencies of the SHMT1 and RFC
      polymorphisms between the cases and controls. The associations of DLCL and FL
      with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate
      metabolism may play an important role in the pathogenesis of specific subtypes of
      NHL.

PMID- 15198954
TI  - Physicians' attitudes about quality-of-life issues in hematopoietic stem cell
      transplantation.
AB  - Studies investigating quality of life (QOL) after hematopoietic stem cell
      transplantation demonstrate the spectrum of QOL outcomes awaiting survivors.
      Nevertheless, how transplantation physicians interpret and apply QOL information
      to clinical practice is poorly understood. We conducted a cross-sectional survey
      of transplantation physicians to address these issues and received 180 (24%)
      responses from physicians in 29 countries. Seventy-two percent reported that
      their patients are willing to accept poor QOL for a small chance of cure. Only
      28% said that QOL considerations "often" or "almost all the time" enter into
      patients' decisions about transplantation. This contrasted with physicians'
      reported attention to QOL in their discussions with patients. Although 53% of
      physicians reported using QOL results to modify practice, 55% would be more
      likely to use these data if they were more understandable. To ensure
      generalizability of the results, a validation sample was randomly selected, and
      these 85 physicians (response rate, 76%) confirmed the findings of the original
      survey. Given the extensive data regarding posttransplantation QOL, resources
      should be devoted to exploring how patients and physicians use these data in
      clinical care and in devising methods to ensure that QOL results are
      interpretable and relevant to patients and physicians.

PMID- 15198956
TI  - Long-term survival benefit and improved complete cytogenetic and molecular
      response rates with imatinib mesylate in Philadelphia chromosome-positive chronic
      phase chronic myeloid leukemia after failure of interferon-alpha.
AB  - We reviewed 261 patients with chronicphase chronic myelogenous leukemia (CML)
      after interferon-alpha (IFN-alpha) failure treated with imatinib mesylate 400 mg
      daily. With a median follow-up time of 45 months, the major cytogenetic response
      rate was 73% and the complete cytogenetic response rate 63%. The estimated 4-year
      survival rate was 86%. Multivariate analysis for survival identified hematologic
      resistance to IFN-alpha (P =.01), splenomegaly (P =.03), and lack of any
      cytogenetic response after 3 months of therapy (P =.01) to have independent poor
      prognostic significance. Patients could be divided into good (no adverse
      factors), intermediate (1 adverse factor), and poor-risk groups (2 or 3 adverse
      factors; 12% of patients) with estimated 4-year survival rates of 96%, 86%, and
      49%, respectively (P <.00001). The 4-year cumulative major molecular response
      (quantitative reverse transcriptase-polymerase chain reaction [Q-PCR] = BCR
      ABL/ABL less than 0.05%) rate was 43% and complete molecular response rate (BCR
      ABL undetectable) 26%. Compared with a historical group of 251 similar patients
      treated with nonimatinib therapies, imatinib mesylate was associated with a
      better 4-year survival rate (86% versus 43%; P <.0001); the survival advantage
      was confirmed by multivariate analysis (hazard ratio, 0.19; P <.0001).

PMID- 15198955
TI  - Nongenomic effects of 17beta-estradiol in human platelets: potentiation of
      thrombin-induced aggregation through estrogen receptor beta and Src kinase.
AB  - The impact of estrogens on the cardiovascular system and their ability to
      regulate platelet function are matters of controversy. The recent finding that
      estrogen receptors are expressed in human platelets renders these cells an
      excellent model for studying the nongenomic effects of these hormones. In this
      work, we investigated 17beta-estradiol-dependent signaling in platelets from
      adult healthy men. 17beta-estradiol caused the rapid phosphorylation of the
      tyrosine kinases Src and Pyk2 and the formation of a signaling complex, which
      included Src, Pyk2, and the phosphatidylinositol 3-kinase. Both these events were
      dependent on estrogen receptor beta engagement. We found that estrogen receptor
      beta was membrane-associated in platelets. On treatment with 17beta-estradiol,
      Src and Pyk2 activation occurred in the membrane fraction but not in the cytosol.
      In contrast, no significant activation of phosphatidylinositol 3-kinase was
      detected in estrogen-treated platelets. 17beta-estradiol did not induce any
      platelet response directly, but it strongly potentiated the activation of
      integrin alpha(IIb)beta3 and the platelet aggregation induced by subthreshold
      concentrations of thrombin. These effects were dependent on estrogen receptor
      beta recruitment and were associated with a strong synergistic effect with
      thrombin on Src activation. Taken together, these results indicate that 17beta
      estradiol can modulate platelet function by exercising a proaggregating role.

PMID- 15198957
TI  - Extended beta-globin locus control region elements promote consistent therapeutic
      expression of a gamma-globin lentiviral vector in murine beta-thalassemia.
AB  - Since increased fetal hemoglobin diminishes the severity of beta-thalassemia and
      sickle cell anemia, a strategy using autologous, stem cell-targeted gene transfer
      of a gamma-globin gene may be therapeutically useful. We previously found that a
      gamma-globin lentiviral vector utilizing the beta-globin promoter and elements
      from the beta-globin locus control region (LCR) totaling 1.7 kb could correct
      murine beta-thalassemia. However, therapeutic consistency was compromised by
      chromosomal position effects on vector expression. In contrast, we show here that
      the majority of animals that received transplants of beta-thalassemic stem cells
      transduced with a new vector containing 3.2 kb of LCR sequences expressed high
      levels of fetal hemoglobin (17%-33%), with an average vector copy number of 1.3.
      This led to a mean 26 g/L (2.6 g/dL) increase in hemoglobin concentration and
      enhanced amelioration of other hematologic parameters. Analysis of clonal
      erythroid cells of secondary spleen colonies from mice that underwent
      transplantation demonstrated an increased resistance of the larger LCR vector to
      stable and variegating position effects. This trend was also observed for vector
      insertion sites located inside genes, where vector expression was often
      compromised, in contrast to intergenic sites, where higher levels of expression
      were observed. These data emphasize the importance of overcoming detrimental
      position effects for consistent therapeutic globin vector expression.

PMID- 15198959
TI  - Atherogenic lipoprotein particles in atherosclerosis.
AB  - The importance of low-density lipoprotein (LDL) cholesterol in the development of
      atherosclerosis has long been recognized, and LDL cholesterol remains the primary
      target of therapy for the prevention of coronary heart disease. Nevertheless,
      increasing research attention over the past decade has been devoted to the
      heterogeneity of LDL particles and the atherogenicity of lipids and lipoproteins
      other than LDL. Particularly atherogenic forms of LDL include small, dense LDL
      particles and oxidized LDL. All lipoproteins that contain apolipoprotein B, such
      as LDL, very-low-density lipoprotein, and intermediate-density lipoprotein, tend
      to promote atherosclerosis; however, these particles differ in their
      apolipoprotein and triglyceride content. High levels of plasma triglycerides
      increase the risk of acute coronary events. Lipoprotein(a) is now considered an
      independent risk factor in both men and women. Ultimately, better understanding
      of the roles of these lipid particles and subfractions in the initiation and
      progression of atherosclerosis may affect treatment decisions.

PMID- 15198960
TI  - HDL cholesterol and protective factors in atherosclerosis.
AB  - A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk
      factor for cardiovascular disease. Epidemiological and clinical studies provide
      evidence that HDL-C levels are linked to rates of coronary events. The
      cardioprotective effects of HDL-C have been attributed to its role in reverse
      cholesterol transport, its effects on endothelial cells, and its antioxidant
      activity. Although some clinical trials suggest a benefit of raising HDL-C to
      reduce risk, further studies are needed, and HDL-C is still not considered a
      primary target of therapy in the National Cholesterol Education Program
      guidelines. However, HDL-C should be considered as part of the patient's overall
      profile of established risk factors in determining treatment strategies.

PMID- 15198961
TI  - New risk factors for atherosclerosis and patient risk assessment.
AB  - Advances in our understanding of the ways in which the traditional cardiovascular
      risk factors, including standard lipid (eg, total cholesterol, low-density
      lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid
      (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote
      the development of cardiovascular disease have enhanced our ability to assess
      risk in the individual patient. In addition, the ongoing identification and
      understanding of so-called novel risk factors may further improve our ability to
      predict future risk when these are included along with the classic risk factors
      in assessing the global risk profile. This review briefly summarizes the evidence
      that some newer risk factors, including impaired fasting glucose, triglycerides
      and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and
      high-sensitivity C-reactive protein, contribute to an increased risk of coronary
      and cardiovascular diseases.

PMID- 15198962
TI  - Inflammation in atherosclerosis and implications for therapy.
AB  - Atherosclerosis is now understood to be a disease characterized by inflammation
      that results in a host of complications, including ischemia, acute coronary
      syndromes (unstable angina pectoris and myocardial infarction), and stroke.
      Inflammation may be caused by a response to oxidized low-density lipoproteins,
      chronic infection, or other factors; and markers of this process, such as C
      reactive protein, may be useful to predict an increased risk of coronary heart
      disease. Thus, we believe that inflammatory processes may be potential targets of
      therapy in preventing or treating atherosclerosis and its complications.

PMID- 15198963
TI  - Role of endothelial dysfunction in atherosclerosis.
AB  - As the major regulator of vascular homeostasis, the endothelium exerts a number
      of vasoprotective effects, such as vasodilation, suppression of smooth muscle
      cell growth, and inhibition of inflammatory responses. Many of these effects are
      largely mediated by nitric oxide, the most potent endogenous vasodilator. Nitric
      oxide opposes the effects of endothelium-derived vasoconstrictors and inhibits
      oxidation of low-density lipoprotein. A defect in the production or activity of
      nitric oxide leads to endothelial dysfunction, signaled by impaired endothelium
      dependent vasodilation. Accumulating evidence suggests that endothelial
      dysfunction is an early marker for atherosclerosis and can be detected before
      structural changes to the vessel wall are apparent on angiography or ultrasound.
      Many of the risk factors that predispose to atherosclerosis can also cause
      endothelial dysfunction, and the presence of multiple risk factors has been found
      to predict endothelial dysfunction. A number of clinical trials have shown that 3
      hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)
      improve endothelial dysfunction in patients with coronary risk factors beyond
      what could be attributed to their impact on plasma lipids. Studies have
      elucidated several possible mechanisms by which statin therapy may improve
      endothelial dysfunction, including upregulation of nitric oxide production or
      activity and reduction of oxidative stress.

PMID- 15198964
TI  - Measurement of arterial wall thickness as a surrogate marker for atherosclerosis.
AB  - Large observational studies and atherosclerosis regression trials of lipid
      modifying pharmacotherapy have established that intima-media thickness of the
      carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is
      a valid surrogate marker for the progression of atherosclerotic disease. To
      exploit fully the potential of ultrasound imaging in atherosclerosis research,
      standardized and strictly implemented imaging protocols should be used in both
      observational studies and applied clinical research. This article describes such
      a protocol developed at the Academic Medical Center of the University of
      Amsterdam, the Netherlands. Results are presented from a study that estimated
      atherosclerosis progression from childhood into old age by measuring intima-media
      thickness in subjects with familial hypercholesterolemia compared with healthy
      controls.

PMID- 15198965
TI  - Beneficial cardiovascular pleiotropic effects of statins.
AB  - Pleiotropic effects of a drug are actions other than those for which the agent
      was specifically developed. These effects may be related or unrelated to the
      primary mechanism of action of the drug, and they are usually unanticipated.
      Pleiotropic effects may be undesirable (such as side effects or toxicity),
      neutral, or, as is especially the case with HMG-CoA reductase inhibitors
      (statins), beneficial. Pleiotropic effects of statins include improvement of
      endothelial dysfunction, increased nitric oxide bioavailability, antioxidant
      properties, inhibition of inflammatory responses, and stabilization of
      atherosclerotic plaques. These and several other emergent properties could act in
      concert with the potent low-density lipoprotein cholesterol-lowering effects of
      statins to exert early as well as lasting cardiovascular protective effects.
      Understanding the pleiotropic effects of statins is important to optimize their
      use in treatment and prevention of cardiovascular disease.

PMID- 15198966
TI  - Statins for stroke prevention: disappointment and hope.
AB  - The occurrence of stroke increases with age, particularly affecting the older
      elderly, a population also at higher risk for coronary heart disease (CHD).
      Epidemiological and observational studies have not shown a clear association
      between cholesterol levels and all causes of stroke. Nonetheless, large, long
      term statin trials in patients with established CHD or at high risk for CHD have
      shown that statins decrease stroke incidence in these populations. Combined data
      from 9 trials including 70,070 patients indicated relative and absolute risk
      reductions for stroke of 21% and 0.9%, respectively, with statins. The number of
      strokes prevented per 1000 patients treated for 5 years in patients with CHD is 9
      for statins, compared with 17.3 for antiplatelet agents. Statins have not yet
      been shown to reduce stroke risk in the typical general population without known
      CHD, nor have they been shown to prevent recurrent stroke in patients with prior
      stroke. Potential reasons for the effects of statins on stroke and the non
      cholesterol-lowering mechanisms that may be involved are discussed. Treatment
      strategies based on global cardiovascular risk may be most effective. Additional
      studies in patients representative of the typical stroke population are needed.

PMID- 15198967
TI  - Safety of statins: focus on clinical pharmacokinetics and drug interactions.
AB  - Statin monotherapy is generally well tolerated, with a low frequency of adverse
      events. The most important adverse effects associated with statins are myopathy
      and an asymptomatic increase in hepatic transaminases, both of which occur
      infrequently. Because statins are prescribed on a long-term basis, however,
      possible interactions with other drugs deserve particular attention, as many
      patients will typically receive pharmacological therapy for concomitant
      conditions during the course of statin treatment. This review summarizes the
      pharmacokinetic properties of statins and emphasizes their clinically relevant
      drug interactions.

PMID- 15198968
TI  - Out with the new, in with the old: classical estrogen receptors mediate novel
      estradiol actions in brain.

PMID- 15198969
TI  - Estrogen and Alzheimer's disease: the apolipoprotein connection.

PMID- 15198970
TI  - Estrogen-inducible cytoskeletal linker protein ezrin interaction with the low
      density lipoprotein receptor.

PMID- 15198971
TI  - Fibroblast growth factor 23: a phosphatonin regulating phosphate homeostasis?

PMID- 15198972
TI  - Relaxin modifies systemic arterial resistance and compliance in conscious,
      nonpregnant rats.
AB  - Relaxin emanates from the corpus luteum of the ovary and circulates during
      pregnancy. Because the hormone is a potent renal vasodilator and mediates the
      renal vasodilation and hyperfiltration of pregnancy in conscious rats, we
      reasoned that it might also contribute to the broader cardiovascular changes of
      pregnancy. We began investigating this concept by testing whether relaxin can
      modify systemic arterial hemodynamics and load when chronically administered to
      nonpregnant rats. The major objectives of the present work were to determine
      whether relaxin administration to nonpregnant rats 1) modifies cardiac output
      (CO), systemic vascular resistance, and global arterial compliance (AC), and 2)
      regulates the passive mechanics of isolated arteries. To accomplish the first
      objective, we developed a conscious rat model for assessment of global AC.
      Passive mechanics of small renal arteries were assessed using a pressure
      arteriograph. Chronic administration of recombinant human relaxin by sc osmotic
      minipump to conscious, female, nonpregnant rats reduced the steady arterial load
      by decreasing systemic vascular resistance, increased CO, and reduced the
      pulsatile arterial load by increasing global AC as quantified by two indices-AC
      estimated from the diastolic decay of aortic pressure and CO and AC estimated by
      the ratio of stroke volume-to-pulse pressure. In another group of rats, relaxin
      administration also regulated the passive mechanics of small renal arteries,
      indicating that, in addition to reduction in vascular smooth muscle tone,
      modification of the vascular structure (e.g. extracellular matrix) contributes to
      the increase in global AC. These findings suggest a role for relaxin in the
      systemic hemodynamic changes of pregnancy, as well as novel therapeutic potential
      for relaxin in modifying arterial stiffness and cardiac afterload.

PMID- 15198975
TI  - Mouse limb deformity mutations disrupt a global control region within the large
      regulatory landscape required for Gremlin expression.
AB  - The mouse limb deformity (ld) mutations cause limb malformations by disrupting
      epithelial-mesenchymal signaling between the polarizing region and the apical
      ectodermal ridge. Formin was proposed as the relevant gene because three of the
      five ld alleles disrupt its C-terminal domain. In contrast, our studies establish
      that the two other ld alleles directly disrupt the neighboring Gremlin gene,
      corroborating the requirement of this BMP antagonist for limb morphogenesis.
      Further doubts concerning an involvement of Formin in the ld limb phenotype are
      cast, as a targeted mutation removing the C-terminal Formin domain by frame shift
      does not affect embryogenesis. In contrast, the deletion of the corresponding
      genomic region reproduces the ld limb phenotype and is allelic to mutations in
      Gremlin. We resolve these conflicting results by identifying a cis-regulatory
      region within the deletion that is required for Gremlin activation in the limb
      bud mesenchyme. This distant cis-regulatory region within Formin is also altered
      by three of the ld mutations. Therefore, the ld limb bud patterning defects are
      not caused by disruption of Formin, but by alteration of a global control region
      (GCR) required for Gremlin transcription. Our studies reveal the large genomic
      landscape harboring this GCR, which is required for tissue-specific coexpression
      of two structurally and functionally unrelated genes.

PMID- 15198976
TI  - iguana encodes a novel zinc-finger protein with coiled-coil domains essential for
      Hedgehog signal transduction in the zebrafish embryo.
AB  - Signaling by lipid-modified secreted glycoproteins of the Hedgehog family play
      fundamental roles during pattern formation in animal development and in humans;
      dysfunction of Hedgehog pathway components is frequently associated with a
      variety of congenital abnormalities and cancer. Transcriptional regulation of
      Hedgehog target genes is mediated by members of the Gli zinc-finger transcription
      factors. The relative nuclear concentrations of Gli activator (Gli(act)) and
      repressor (Gli(rep)) forms, together with their nucleocytoplasmic trafficking,
      appear to be critical determinants for target gene expression. Whereas such
      stringent controls of Gli activity are critical in ensuring appropriate levels of
      pathway activation, the mechanisms by which these processes are regulated remain
      inadequately understood. Here, using genetic analysis, we show that the zebrafish
      iguana gene product acts downstream of the Smoothened protein to modulate Gli
      activity in the somites of the developing embryo. Positional cloning reveals that
      iguana encodes the zebrafish ortholog of Dzip1, a novel zinc-finger/coiled-coil
      domain protein that we show can shuttle between the cytoplasm and nucleus in a
      manner correlated with Hedgehog pathway activity.

PMID- 15198977
TI  - Hoxb1 functions in both motoneurons and in tissues of the periphery to establish
      and maintain the proper neuronal circuitry.
AB  - Formation of neuronal circuits in the head requires the coordinated development
      of neurons within the central nervous system (CNS) and neural crest-derived
      peripheral target tissues. Hoxb1, which is expressed throughout rhombomere 4
      (r4), has been shown to be required for the specification of facial branchiomotor
      neuron progenitors that are programmed to innervate the muscles of facial
      expression. In this study, we have uncovered additional roles for Hoxb1
      expressing cells in the formation and maintenance of the VIIth cranial nerve
      circuitry. By conditionally deleting the Hoxb1 locus in neural crest, we
      demonstrate that Hoxb1 is also required in r4-derived neural crest to facilitate
      and maintain formation of the VIIth nerve circuitry. Genetic lineage analysis
      revealed that a significant population of r4-derived neural crest is fated to
      generate glia that myelinate the VIIth cranial nerve. Neural crest cultures show
      that the absence of Hoxb1 function does not appear to affect overall glial
      progenitor specification, suggesting that a later glial function is critical for
      maintenance of the VIIth nerve. Taken together, these results suggest that the
      molecular program governing the development and maintenance of the VIIth cranial
      nerve is dependent upon Hoxb1, both in the neural crest-derived glia and in the
      facial branchiomotor neurons.

PMID- 15198978
TI  - Molecular cross-talk among chromosome fragility syndromes.

PMID- 15198979
TI  - Form follows function: The genomic organization of cellular differentiation.
AB  - The extent to which the nucleus is functionally organized has broad biological
      implications. Evidence supports the idea that basic nuclear functions, such as
      transcription, are structurally integrated within the nucleus. Moreover, recent
      studies indicate that the linear arrangement of genes within eukaryotic genomes
      is nonrandom. We suggest that determining the relationship between nuclear
      organization and the linear arrangement of genes will lead to a greater
      understanding of how transcriptomes, dedicated to a particular cellular function
      or fate, are coordinately regulated. Current network theories may provide a
      useful framework for modeling the inherent complexity the functional organization
      of the nucleus.

PMID- 15198980
TI  - Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and
      migration.
AB  - Although Apc is well characterized as a tumor-suppressor gene in the intestine,
      the precise mechanism of this suppression remains to be defined. Using a novel
      inducible Ahcre transgenic line in conjunction with a loxP-flanked Apc allele we,
      show that loss of Apc acutely activates Wnt signaling through the nuclear
      accumulation of beta-catenin. Coincidentally, it perturbs differentiation,
      migration, proliferation, and apoptosis, such that Apc-deficient cells maintain a
      "crypt progenitor-like" phenotype. Critically, for the first time we confirm a
      series of Wnt target molecules in an in vivo setting and also identify a series
      of new candidate targets within the same setting.

PMID- 15198981
TI  - The generation of proper constitutive G-tails on yeast telomeres is dependent on
      the MRX complex.
AB  - The precise DNA arrangement at chromosomal ends and the proteins involved in its
      maintenance are of crucial importance for genome stability. For the yeast
      Saccharomyces cerevisiae, this constitutive DNA configuration has remained
      unknown. We demonstrate here that G-tails of 12-14 bases are present outside of S
      phase on normal yeast telomeres. Furthermore, the Mre11p protein is essential for
      the proper establishment of this constitutive end-structure. However, the timing
      of extended G-tails occurring during S phase is not affected in strains lacking
      Mre11p. Thus, G-tails are present on yeast chromosomes throughout the cell cycle
      and the MRX complex is required for their normal establishment.

PMID- 15198982
TI  - Spindle checkpoint regulates Cdc20p stability in Saccharomyces cerevisiae.
AB  - The spindle checkpoint arrests cells at the metaphase-to-anaphase transition
      until all chromosomes have properly attached to the mitotic spindle. Checkpoint
      proteins Mad2p and Mad3p/BubR1p bind and inhibit Cdc20p, an activator for the
      anaphase-promoting complex (APC). We find that upon spindle checkpoint activation
      by microtubule inhibitors benomyl or nocodazole, wild-type Saccharomyces
      cerevisiae contains less Cdc20p than spindle checkpoint mutants do, whereas their
      CDC20 mRNA levels are similar. The difference in Cdc20p levels correlates with
      their difference in the half-lives of Cdc20p, indicating that the spindle
      checkpoint destabilizes Cdc20p. This process requires the association between
      Cdc20p and Mad2p, and functional APC, but is independent of the known destruction
      boxes in Cdc20p and the other APC activator Cdh1p. Importantly, destabilization
      of Cdc20p is important for the spindle checkpoint, because a modest
      overexpression of Cdc20p causes benomyl sensitivity and premature Pds1p
      degradation in cells treated with nocodazole. Our study suggests that the spindle
      checkpoint reduces Cdc20p to below a certain threshold level to ensure a complete
      inhibition of Cdc20p before anaphase.

PMID- 15198983
TI  - A new yeast PUF family protein, Puf6p, represses ASH1 mRNA translation and is
      required for its localization.
AB  - In yeast Saccharomyces cerevisiae, Ash1p, a protein determinant for mating-type
      switching, is segregated within the daughter cell nucleus to establish asymmetry
      of HO expression. The accumulation of Ash1p results from ASH1 mRNA that is sorted
      as a ribonucleoprotein particle (mRNP or locasome) to the distal tip of the bud
      where translation occurs. To study the mechanism regulating ASH1 mRNA
      translation, we isolated the ASH1 locasome and characterized the associated
      proteins by MALDI-TOF. One of these proteins was Puf6p, a new member of the PUF
      family of highly conserved RNA-binding proteins such as Pumilio in Drosophila,
      responsible for translational repression, usually to effect asymmetric
      expression. Puf6p-bound PUF consensus sequences in the 3'UTR of ASH1 mRNA and
      repressed the translation of ASH1 mRNA both in vivo and in vitro. In the puf6
      Delta strain, asymmetric localization of both Ash1p and ASH1 mRNA were
      significantly reduced. We propose that Puf6p is a protein that functions in the
      translational control of ASH1 mRNA, and this translational inhibition is
      necessary before localization can proceed.

PMID- 15198984
TI  - Hsp70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa
      B survival signaling.
AB  - The major heat shock protein, Hsp70, can protect against cell death by directly
      interfering with mitochondrial apoptosis pathways. However, Hsp70 also sensitizes
      cells to certain apoptotic stimuli like TNF. Little is known about how Hsp70
      enhances apoptosis. We demonstrate here that Hsp70 promotes TNF killing by
      specifically binding the coiled-coil domain of I kappa B kinase gamma (IKK gamma)
      to inhibit IKK activity and consequently inhibit NF-kappa B-dependent
      antiapoptotic gene induction. An IKK gamma mutant, which interacts with Hsp70,
      competitively inhibits the Hsp70-IKK gamma interaction and relieves heat-mediated
      NF-kappa B suppression. Depletion of Hsp70 expression with RNA interference
      rescues TNF-mediated cell death. Although TNF may or may not be sufficient to
      trigger apoptosis on its own, TNF-triggered apoptosis was initiated or made worse
      when Hsp70 expression increased to high levels to disrupt NF-kappa B signaling.
      These results provide significant novel insights into the molecular mechanism for
      the pro-apoptotic behavior of Hsp70 in death-receptor-mediated cell death.

PMID- 15198985
TI  - In vivo convergence of BMP and MAPK signaling pathways: impact of differential
      Smad1 phosphorylation on development and homeostasis.
AB  - Integration of diverse signaling pathways is essential in development and
      homeostasis for cells to interpret context-dependent cues. BMP and MAPK signaling
      converge on Smads, resulting in differential phosphorylation. To understand the
      physiological significance of this observation, we have generated Smad1 mutant
      mice carrying mutations that prevent phosphorylation of either the C-terminal
      motif required for BMP downstream transcriptional activation (Smad1(C) mutation)
      or of the MAPK motifs in the linker region (Smad1(L) mutation). Smad1(C/C)
      mutants recapitulate many Smad1(-/-) phenotypes, including defective allantois
      formation and the lack of primordial germ cells (PGC), but also show phenotypes
      that are both more severe (head and branchial arches) and less severe (allantois
      growth) than the null. Smad1(L/L) mutants survive embryogenesis but exhibit
      defects in gastric epithelial homeostasis correlated with changes in cell
      contacts, actin cytoskeleton remodeling, and nuclear beta-catenin accumulation.
      In addition, formation of PGCs is impaired in Smad1(L/L) mutants, but restored by
      allelic complementation in Smad1(C/L) compound mutants. These results underscore
      the need to tightly balance BMP and MAPK signaling pathways through Smad1.

PMID- 15198987
TI  - Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced
      apoptosis.
AB  - Parkinson's disease (PD) is characterized by the selective degeneration of
      dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). A combination
      of genetic and environmental factors contributes to such a specific loss. Among
      the five PD-linked genes identified so far, parkin, a protein-ubiquitin E3
      ligase, appears to be the most prevalent genetic factor in PD. Although a variety
      of substrates have been identified for parkin, none of them is selectively
      expressed in nigral DA neurons. It remains unclear how accumulation of these
      substrates in the absence of functional parkin may cause the selective death of
      DA neurons in SNpc. Here, we show that overexpression of parkin protected human
      DA neuroblastoma cell line (SH-SY5Y) against apoptosis induced by DA or 6-OHDA,
      but not by H(2)O(2) or rotenone. Parkin significantly attenuated dopamine-induced
      activation of c-Jun N-terminal kinase (JNK) and caspase-3. It also decreased the
      level of reactive oxygen species (ROS) and protein carbonyls in the cell.
      Inhibiting DA uptake through dopamine transporter or treating the cell with
      antioxidants significantly reduced oxidative stress and dopamine toxicity.
      Furthermore, PD-linked mutations of parkin significantly abrogated the protective
      effect of wild-type parkin, as well as its ability to suppress ROS and protein
      carbonylation. These results suggest that parkin protects against dopamine
      toxicity by decreasing oxidative stress and ensuing activation of apoptotic
      programs such as the JNK/caspase pathway. This protective function of parkin,
      which is greatly attenuated by its PD-linked mutations, may be uniquely important
      for the survival of DA neurons, as they are constantly threatened by oxyradicals
      produced during dopamine oxidation.

PMID- 15198986
TI  - Multiple interactions between regulatory regions are required to stabilize an
      active chromatin hub.
AB  - The human beta-globin locus control region (LCR) is required for the maintenance
      of an open chromatin configuration of the locus. It interacts with the genes and
      the hypersensitive regions flanking the locus to form an active chromatin hub
      (ACH) transcribing the genes. Proper developmental control of globin genes is
      largely determined by gene proximal regulatory sequences. Here, we provide the
      first functional evidence of the role of the most active sites of the LCR and the
      promoter of the beta-globin gene in the maintenance of the ACH. When the human
      beta-globin gene promoter is deleted in the context of a full LCR, the ACH is
      maintained with the beta-globin gene remaining in proximity. Additional deletion
      of hypersensitive site HS3 or HS2 of the LCR shows that HS3, but not HS2, in
      combination with the beta-globin promoter is crucial for the maintenance of the
      ACH at the definitive stage. We conclude that multiple interactions between the
      LCR and the beta-globin gene are required to maintain the appropriate spatial
      configuration in vivo.

PMID- 15198988
TI  - Structural and functional consequences of glutamine tract variation in the
      androgen receptor.
AB  - The androgen receptor (AR) gene contains a polymorphic trinucleotide repeat
      region, (CAG)(n), in its N-terminal transactivation domain (NTD) that encodes a
      polyglutamine (polyQ) tract in the receptor protein. Whereas the length of the
      CAG repeat ranges from 6 to 39 in healthy individuals, the variations in repeat
      length both within and outside the normal range are associated with disease,
      including impaired spermatogenesis and Kennedy's disease, and with the risk of
      developing breast and prostate cancer. Whereas it has been proposed that the
      inverse relationship between polyQ tract length within the normal range and AR
      transactivation potential may be responsible for altered risk of disease, the
      molecular mechanisms underlying polyQ length modulation of AR function have not
      been elucidated. In this study, we provide detailed characterization of a somatic
      AR gene mutation detected in a human prostate tumor that results in interruption
      of the polyQ tract by two non-consecutive leucine residues (AR-polyQ2L). Compared
      with wtAR, AR-polyQ2L exhibits disrupted inter-domain communication (N/C
      interaction) and a lower protein level, but paradoxically has markedly increased
      transactivation activity. Molecular modeling and the response to cofactors
      indicate that the increased activity of AR-polyQ2L results from the presentation
      of a more stable platform for the recruitment of accessory proteins than wild
      type AR. Analysis of the relationship between polyQ tract length and AR function
      revealed a critical size (Q16-Q29) for maintenance of N/C interaction. That
      between 91 and 99% of AR alleles in different racial-ethnic groups encode a polyQ
      tract in the range of Q16-Q29 suggests that N/C interaction has been preserved as
      an essential component of androgen-induced AR signaling.

PMID- 15198990
TI  - Rapid evolution of primate antiviral enzyme APOBEC3G.
AB  - Human cytidine deaminase APOBEC3G and the virion infectivity factor (vif) of the
      human immunodeficiency virus (HIV) are a pair of antagonistic molecules. In the
      absence of vif, APOBEC3G induces a high rate of dC to dU mutations in the nascent
      reverse transcripts of HIV that leads to the degradation of the HIV genome. HIV
      vif, on the other hand, can suppress the translation and trigger the degradation
      of human APOBEC3G. Here, we studied the rate of APOBEC3G gene evolution from five
      hominoids and two Old World monkeys. Averaged across the entire coding region,
      the rate of non-synonymous nucleotide substitutions is approximately 1.4 times
      the rate of synonymous substitutions, strongly suggesting that APOBEC3G has been
      under positive Darwinian selection. A comparison between the nucleotide
      polymorphisms within humans and the substitutions among the seven primates
      reveals a significant excess of non-synonymous substitutions. Furthermore, the
      rate of charge-altering non-synonymous substitution is approximately 1.8 times
      that of charge-conserving substitution, indicating that the selection is
      promoting the diversity of the protein charge profile. However, no difference in
      selective pressure on APOBEC3G is detected between hosts and non-hosts of HIV or
      simian immunodeficiency virus (SIV). These results, together with recent findings
      that the antiviral activity of APOBEC3G is not limited to HIV/SIV, suggest that
      the selective pressure on APOBEC3G is not solely from HIV/SIV and that APOBEC3G
      is a broad antiviral enzyme. The identification of pervasive positive selection
      for charge-altering amino acid substitutions supports the hypothesis of
      electrostatic interactions between APOBEC3G and vif or its functional
      equivalents.

PMID- 15198989
TI  - Regulation of IL-8 and IL-1beta expression in Crohn's disease associated
      NOD2/CARD15 mutations.
AB  - Crohn's disease (CD) is a chronic inflammation affecting the gastrointestinal
      tract. Three mutations (Arg702Trp, Gly908Arg and Leu1007fsinsC) within the
      NOD2/CARD15 gene increase CD susceptibility. Here, we define cytokine regulation
      in primary human mononuclear cells, with muramyl dipeptide (MDP), the minimal
      NOD2/CARD15 activating component of peptidoglycan. By microarray, MDP induces a
      broad array of transcripts, including interleukin 1beta (IL-1beta) and
      interleukin 8 (IL-8). Leu1007fsinsC homozygotes demonstrated decreased
      transcriptional response to MDP. Electromobility shift assay demonstrated that
      MDP-induced NF-kappaB activation is mediated via p50 and p65 subunits, but not
      RelB or c-Rel. In wild-type individuals, MDP-induced IL-8 protein expression with
      a greater response to high dose (1 micro g/ml) compared with low-dose (10 ng/ml)
      MDP. At low MDP doses, in all homozygotes, we observed no induction of IL-8
      protein. With high doses of MDP, Leu1007fsinsC homozygotes showed no induction.
      Modest induction of IL-8 protein was observed in Gly908Arg and Arg702Trp
      homozygotes, indicating varying MDP sensitivity of the CD-associated mutations.
      In wild-type healthy control, CD and ulcerative colitis individuals, low-dose MDP
      and TNFalpha alone results in only modest IL-1beta protein induction. With MDP
      plus TNFalpha, there is a synergistic induction of IL-1beta secretion. In
      Leu1007fsinsC homozygotes, there is a profound defect in IL-1beta secretion,
      despite marked induction of IL-1beta mRNA. These findings demonstrate post
      transcriptional dependency on the NOD2/CARD15 pathway for IL-1beta secretion with
      MDP and TNFalpha treatment. Taken together, these studies suggest that a
      signaling defect of innate immunity to MDP may be an essential underlying defect
      in the pathogenesis of some CD patients.

PMID- 15198991
TI  - Search for cognitive trait components of schizophrenia reveals a locus for verbal
      learning and memory on 4q and for visual working memory on 2q.
AB  - Research to identify predisposing genes for complex diseases relying solely on
      clinical diagnosis is probably not ideal. Here, we analyzed genome-wide data for
      168 schizophrenia families using neuropsychological variables associated with
      disease susceptibility, with the aid of SOLAR, a program for variance-component
      analysis. The linkage signal was greatly accentuated by application of the
      quantitative traits compared with diagnosis. We found evidence for a locus for
      verbal learning and memory on 4q21 (Z=3.01, Z(mp)=3.84 and empiric P=0.031 for
      delayed memory; Z=2.96, Z(mp)=3.4 and P=0.026 for verbal learning) and suggestive
      evidence for visual working memory on 2q36 (Z=2.80, Z(mp)=2.08 and P=0.093). In
      addition, some evidence emerged for a locus for recognition memory on 10p13,
      visual attention on 15q22 and executive function on 9p22 in the complete sample,
      as well as for delayed memory on 8q12, semantic clustering and intrusions on 1q42
      and visual attention on 3p25 in the genealogically distinctive sample subsets. Of
      the loci linked to schizophrenia in diverse populations, in addition to the
      earlier mentioned regions, some evidence of linkage was observed for 2q, 6q, 7q,
      11q, 13q, 14q, 18q and 22q. Our results reveal initial information on the effect
      of the loci associated with schizophrenia in multiple studies, and emphasize the
      value of trait components in the search for susceptibility loci for complex
      diseases.

PMID- 15198992
TI  - Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by
      abnormal folding, aggregation and altered polymerization of mutant actin
      isoforms.
AB  - We have studied a cohort of nemaline myopathy (NM) patients with mutations in the
      muscle alpha-skeletal actin gene (ACTA1). Immunoblot analysis of patient muscle
      demonstrates increased gamma-filamin, myotilin, desmin and alpha-actinin in many
      NM patients, consistent with accumulation of Z line-derived nemaline bodies. We
      demonstrate that nebulin can appear abnormal secondary to a primary defect in
      actin, and show by isoelectric focusing that mutant actin isoforms are present
      within insoluble actin filaments isolated from muscle from two ACTA1 NM patients.
      Transfection of C2C12 myoblasts with mutant actin(EGFP) constructs resulted in
      abnormal cytoplasmic and intranuclear actin aggregates. Intranuclear aggregates
      were observed with V163L-, V163M- and R183G-actin(EGFP) constructs, and modeling
      shows these residues to be adjacent to the nuclear export signal of actin. V163L
      and V163M actin mutants are known to cause intranuclear rod myopathy, however,
      intranuclear bodies were not reported in patient R183G. Transfection studies in
      C2C12 myoblasts showed significant alterations in the ability of V136L and R183G
      actin mutants to polymerize and contribute to insoluble actin filaments. Thus, we
      provide direct evidence for a dominant-negative effect of mutant actin in NM. In
      vitro studies suggest that abnormal folding, altered polymerization and
      aggregation of mutant actin isoforms are common properties of NM ACTA1 mutants.
      Some of these effects are mutation-specific, and likely result in variations in
      the severity of muscle weakness seen in individual patients. A combination of
      these effects contributes to the common pathological hallmarks of NM, namely
      intranuclear and cytoplasmic rod formation, accumulation of thin filaments and
      myofibrillar disorganization.

PMID- 15198993
TI  - Pms2 is a genetic enhancer of trinucleotide CAG.CTG repeat somatic mosaicism:
      implications for the mechanism of triplet repeat expansion.
AB  - The expansion of CAG.CTG repeat sequences is the cause of several inherited human
      disorders. Longer alleles are associated with an earlier age of onset and more
      severe symptoms, and are highly unstable in the germline and soma with a marked
      tendency towards repeat length gains. Germinal expansions underlie anticipation;
      whereas age-dependent, tissue-specific, expansion-biased somatic instability
      probably contributes toward the progressive nature and tissue-specificity of the
      symptoms. The mechanism(s) of repeat instability is not known, but recent data
      have implicated mismatch-repair (MMR) gene mutS homologues in driving expansion.
      To gain further insight into the expansion mechanism, we have determined the
      levels of somatic mosaicism of a transgenic expanded CAG.CTG repeat in mice
      deficient for the Pms2 MMR gene. Pms2 is a MutL homologue that plays a critical
      role in the downstream processing of DNA mismatches. The rate of somatic
      expansion was reduced by approximately 50% in Pms2-null mice. A higher frequency
      of rare, but very large, deletions was also detected in these animals. No
      significant differences were observed between Pms2(+/+) and Pms2(+/-) mice,
      indicating that a single functional Pms2 allele is sufficient to generate normal
      levels of somatic mosaicism. These findings reveal that as well as MMR enzymes
      that directly bind mismatched DNA, proteins that are subsequently recruited to
      the complex also play a central role in the accumulation of repeat length
      changes. These data suggest that somatic expansion results not by replication
      slippage, single stranded annealing or simple MutS-mediated stabilization of
      secondary structures, but by inappropriate DNA MMR.

PMID- 15198994
TI  - Transcription of the IL10 gene reveals allele-specific regulation at the mRNA
      level.
AB  - Interleukin-10 (IL10) is a cytokine with key regulatory and anti-inflammatory
      function involved in the pathogenesis of various diseases. Although the large
      interindividual differences in the production of IL10 have been extensively
      associated with polymorphisms and haplotypes of the IL10 gene, surprisingly
      little evidence exists that this variation is actually dictated by IL10
      haplotypes. Using the technique of allele-specific transcript quantification, the
      ratio between two alleles (A and G) of the IL10 gene was characterized in 15
      healthy heterozygous individuals. Two groups were identified whereby donors in
      group 1 exhibited a 1 : 1 ratio, whereas those in group 2 exhibited a ratio>1
      (P<0.0017). We found that donors heterozygous for haplotype IL10.2 (one of the
      four ancient IL10 haplotypes) were only prevalent in the group that showed higher
      allelic expression ratios. In this study we show that IL10 alleles are indeed
      differentially transcribed in cells from heterozygous individuals and that IL10
      haplotypes dictate production of IL10. These findings show that interindividual
      differences in IL10 protein levels can be explained at the transcriptional level.

PMID- 15198995
TI  - Accumulation of aberrant ubiquitin induces aggregate formation and cell death in
      polyglutamine diseases.
AB  - Polyglutamine diseases are characterized by neuronal intranuclear inclusions
      (NIIs) of expanded polyglutamine proteins, indicating the failure of protein
      degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor
      of the proteasome, and was previously reported to accumulate in Alzheimer disease
      and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the
      cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3,
      indicating inhibition of the proteasome by polyglutamine proteins in human brain.
      We found that UBB(+1) not only increased aggregate formation of expanded
      polyglutamines in neuronally differentiated cell lines, but also had a
      synergistic effect on apoptotic cell death due to expanded polyglutamine
      proteins. These findings implicate UBB(+1) as an aggravating factor in
      polyglutamine-induced neurodegeneration, and clearly identify an important role
      for the ubiquitin-proteasome system in polyglutamine diseases.

PMID- 15198996
TI  - Tobacco or health 1602: an Elizabethan doctor speaks.
AB  - A few years before the death of Queen Elizabeth I, a booklet entitled Work for
      Chimny-Sweepers or A Warning for Tabacconists [sic], was published. Written by a
      doctor who called himself Philaretes, it was the first publication to present the
      health risks of tobacco use. Using continuum content analysis, which follows each
      of Philaretes's main messages over the subsequent four centuries, this paper sets
      his publication in the historical context of the medical and social frame of
      reference in which it was produced, and charts the development of each theme in
      later scientific research. In the setting of contemporary Tudor medical theory,
      based on 'the humours', Philaretes discussed many of the health risks that later
      research has proven to be true. In common with many early attempts at health
      education, the principles of Philaretes's approach appear to be what were later
      to be called the Health Belief Model and the KAP formula. By providing
      information about serious personal health risks and, thus, increasing the
      readers' knowledge, he hoped to change their attitude and consequently their
      behaviour. Overshadowed by King James I's much less scientific Counterblaste to
      Tobacco, Philaretes's publication deserves more credit than it has been given.

PMID- 15198997
TI  - Alcohol use and HIV risk behaviors among rural adolescents in Khanh Hoa Province
      Viet Nam.
AB  - Research suggests that youth are consuming more alcohol and at younger ages than
      in the past. Data also indicate that alcohol consumption is associated with
      participation in other risk behaviors including aggression and sexual behaviors.
      As part of a randomized control effectiveness trial for an HIV prevention
      program, 480 Vietnamese youth (15-20 years old) living in eight rural communes in
      Khanh Hoa Province were administered a paper and pencil baseline evaluation. The
      evaluation included items for actual and intended alcohol use, perceptions of
      peers' alcohol consumption, and attitudinal questions regarding alcohol. The tool
      included questions on engagement and intention to engage in sexual behaviors. In
      addition, 96 randomly selected youth participated in qualitative interviews on
      similar topics. Among the 480 surveyed youth, 29.2% had consumed alcohol. Among
      those youth, 17.6% reported intoxication in the past 6 months. While young men
      were significantly more likely to drink than young women (P < 0.00), those young
      women who did drink were as likely to report intoxication. Alcohol use was
      significantly associated with engagement in sexual behaviors (P < 0.00) and
      intention to engage in sexual behaviors (P < 0.02). The qualitative data provided
      information on the social contexts of drinking behaviors and more in-depth
      findings regarding associated risk behaviors. With limited information about
      alcohol consumption among Vietnamese youth, these findings suggest that there is
      a need for more extensive research on alcohol use and associated risk behaviors
      among this population, and for targeted alcohol prevention and harm-reduction
      programs.

PMID- 15198998
TI  - Exercise therapy in women who have had breast cancer: design of the Sheffield
      women's exercise and well-being project.
AB  - Recovering from cancer treatment can be a difficult experience, both physically
      and psychologically. This paper describes a randomized controlled trial that
      evaluates the effects of exercise therapy upon quality of life in 120 women who
      have had breast cancer. To facilitate behaviour change, exercise counselling is
      also included as an integral component in the exercise therapy intervention.
      Participants are randomized to one of three groups: exercise therapy, body
      conditioning (placebo control) or a normal care control group. The supervised
      exercise therapy and body conditioning sessions take place 3 times per week for 8
      weeks. Outcome measures include quality of life, physical self-perceptions,
      depression, satisfaction with life, exercise behaviour, aerobic capacity and
      percentage body fat. All outcomes are assessed at baseline, 4 weeks during the
      intervention and at the end of the 8-week intervention. Follow-up assessments of
      outcomes take place at 3 and 6 months post-intervention. As the number of women
      surviving breast cancer is increasing and cancer treatment is linked to reduced
      quality of life, it is critical to evaluate treatments that improve the quality
      of life of this population or hasten recovery following treatment.

PMID- 15198999
TI  - Development and evaluation of a mass media Theory of Planned Behaviour
      intervention to reduce speeding.
AB  - The Theory of Planned Behaviour (TPB) has been widely applied to the explanation
      of health and social behaviours. However, despite its potential to inform
      behaviour change efforts, there have been surprisingly few attempts to use the
      TPB to design actual interventions. In 1998, the Scottish Road Safety Campaign
      implemented a 3-year mass media campaign to reduce speeding on Scotland's roads
      which was explicitly shaped by the TPB's three main predictors: Attitude,
      Subjective Norms and Perceived Behavioural Control. A 4-year longitudinal cohort
      study examined the impact of the campaign on communications outcomes and on TPB
      constructs. Overall, empirical support was found for the decision to use TPB as
      the theoretical underpinning of the advertising. The advertising was effective in
      triggering desired communications outcomes, and was associated with significant
      changes in attitudes and affective beliefs about speeding. In conclusion, future
      directions for road safety advertising and for TPB research are discussed.

PMID- 15199000
TI  - A census of economic evaluations in health promotion.
AB  - While policy makers argue for a greater share of health resources to go to health
      promotion, action is stalled by, among other things, the perception that little
      is known about which interventions offer the best health returns. Additionally,
      what is missing is any sense of what the economic literature in health promotion
      looks like overall. Where is the economic evidence plentiful and where is it
      scant? The project described here compiled a census of economic evaluations in
      health promotion. Studies were classified according to a four-part typology that
      documented the strategic intent of the intervention, the risk factor being
      addressed, the population most affected and the setting in which the intervention
      took place. Since 1990, there have been over 400 economic evaluations of health
      promoting interventions in the peer review and grey literatures. Of these, 90%
      address biological or behavioral determinants of health. Relatively little is
      known about the economics of population health advocacy or interventions to
      tackle the social and economic determinants of health. Initiatives are in place
      to increase the availability of economic evidence. Research is also needed into
      how to support decision makers' use of imperfect, incomplete and uncertain
      information.

PMID- 15199001
TI  - Evaluation of a school-based intervention for HIV/AIDS prevention among Belizean
      adolescents.
AB  - The purpose of this study was to evaluate the impact of a cognitive-behavioral
      peer-facilitated school-based HIV/AIDS education program on knowledge, attitudes
      and behavior among primary and secondary students in Belize. Students (N = 150)
      were recruited from six schools in Belize City. A quasi-experimental research
      design was used to assess the impact of a 3-month intervention. Seventy-five
      students received the intervention and 75 students served as controls. The
      intervention was guided by constructs from the Theory of Reasoned Action and
      Social Cognitive Theory. At the follow-up assessment, the intervention group
      showed higher HIV knowledge, were more likely to report condom use, had more
      positive attitudes toward condoms and were more likely to report future
      intentions to use condoms than the students in the control group. Overall, the
      findings indicate that the intervention had a positive impact on participants.
      Given the increasing rate of HIV/AIDS in Belize, especially among adolescents,
      this study has important implications for the country of Belize.

PMID- 15199002
TI  - The role of cannabis in supporting young people's cigarette smoking: a
      qualitative exploration.
AB  - This paper reports findings from a qualitative study which explores the role of
      cannabis in young people's lives during their early teenage years. In particular,
      it focuses on the relationship between cannabis and tobacco-related beliefs and
      behaviour. Fifty-nine young people of both sexes, aged 13-15, from different
      socioeconomic backgrounds, and with a wide range of cigarette and cannabis use
      experience, took part in the study. All were recruited from youth club settings
      and most were interviewed in self-selected friendship pairs. The paper argues
      that, while many young people appear to hold predominantly negative views about
      cigarettes, particularly in relation to their potential to foster dependence,
      cannabis is often viewed as relatively benign. In spite of these beliefs, for
      some 'cannabis-oriented' young people, their cannabis use appears to support and
      reinforce their smoking habit. The paper concludes that a coordinated approach to
      the planning and delivery of services which addresses young people's health risk
      behaviours is required. Smoking cessation and drugs education practitioners need
      to break with tradition, and find ways of working more closely together.

PMID- 15199003
TI  - Texas Tobacco Prevention Pilot Initiative: processes and effects.
AB  - The study was designed to examine how intensity of anti-smoking media campaigns
      and differing types of anti-smoking community-based programs influence young
      adolescents' tobacco use and related psychosocial variables. Sixth grade students
      attending 11 middle schools in eight study communities assigned to varying
      intervention conditions were assessed by a pre-intervention survey conducted in
      spring 2000. The assessment was followed by summer and fall 2000 media and
      community interventions that were evaluated by post-intervention data collection
      taking place with a new cohort of sixth graders in the same 11 schools in late
      fall 2000. In analyses conducted at the school level, the enhanced school and
      comprehensive community program conditions outperformed the no intervention
      program condition to reduce tobacco use and intentions to use tobacco. Combining
      the intensive or low media campaign with the comprehensive community program was
      most effective in suppressing positive attitudes toward smoking, while the
      enhanced school program alone was less effective in influencing attitudes. The
      most consistent changes, at least short-term, to reduce teen tobacco use,
      susceptibility to smoking and pro-smoking attitudes were achieved by combining
      the intensive media campaign with the comprehensive community program condition.

PMID- 15199004
TI  - Exploring children's conceptions of smoking addiction.
AB  - Tobacco addiction is a major health problem for both adults and young people-
      between 20 and 60% of adolescents are dependent on nicotine and more than two
      thirds who attempt to quit experience withdrawal symptoms. Yet, anti-smoking
      efforts targeted at children emphasize primary prevention and ignore addiction
      education, which is generally considered relevant only to adult smoking and
      cessation efforts. This study reports children's concepts of smoking and
      addiction from interviews with 32 Western Australian boys and girls, aged 9-10
      years, all non-smokers. Results suggest children's concepts of smoking addiction
      may influence attitudes toward smoking trials. Children who thought addiction
      happened immediately were committed to never smoke at all. Others who thought
      addiction happened after several cigarettes expressed intentions to experiment.
      These children believed they could avoid addiction by smoking less than the
      number of cigarettes that caused addiction. Children who defined addiction as
      'liking' or 'enjoying the taste of cigarettes' believed they could avoid being
      'hooked' as long as they managed to avoid enjoying the experience. Recent
      findings that children can get 'hooked' within a few days of smoking highlight
      the importance of addiction strategies targeted at children, particularly in
      relation to influencing intentions to experiment with smoking.

PMID- 15199005
TI  - HEALTH C.H.I.P.s: opportunistic community use of computerized health information
      programs.
AB  - Computerized health information programs have been shown to have potential to
      improve knowledge, attitudes and behavior. However, relatively little is known
      regarding their capacity to engage the public for opportunistic, spontaneous use
      in community settings. Two studies were undertaken to provide insight to this
      practical issue. An intercept survey of adults from a shopping center where a
      computer kiosk had been located for 7 months was undertaken to investigate
      exposure to, attention to, use and acceptability of kiosks. A total of 99.7% of
      participants were exposed to the kiosk, 77.4% of these noticed it and 20.8% of
      these used it. Program acceptability was high; the most common barriers to use
      related to time constraints and disinterest. A utilization study was then
      undertaken to describe program utilization in greater detail, with kiosks
      installed in 18 community settings over 1 year. These were used 57,064 times
      (19.4 uses per kiosk per day). Additional data described demography of users,
      preferred topics selected, preferred formats and presentation styles, and a
      comparison of use across different community settings. Both studies provide
      insight to practical application of this health education strategy, indicating
      that is has substantial capacity to engage people for opportunistic use in
      community settings.

PMID- 15199006
TI  - Enhancing adolescent health behaviors through strengthening non-resident father
      son relationships: a model for intervention with African-American families.
AB  - This paper provides a description of and rationale for components of a
      theoretically based conceptual model that guided the development and
      implementation of the Fathers and Sons Intervention Program. Using a community
      based participatory research process, this intervention was designed to prevent
      risky health behaviors through strengthening father-son relationships among non
      resident African-American fathers and their pre-adolescent sons. The implications
      of the conceptual model for future interventions with African-American fathers
      and sons are discussed.

PMID- 15199007
TI  - The Dutch Heart Health Community Intervention 'Hartslag Limburg': design and
      results of a process study.
AB  - In 1998, a regional cardiovascular diseases prevention program was started in The
      Netherlands. This paper presents the design and results of a process study on the
      community intervention. The main purpose of the study was to gain insight into
      the reasons why expected effects were or were not achieved. Data was collected
      using multiple data sources and/or methods to measure indicators of intervention
      implementation. The results indicate that the community analysis and the
      subsequent organization of nine local Health Committees had been satisfactory.
      However, some factors that might influence the actual functioning of the Health
      Committees could be improved. Furthermore, the expert training for the members of
      these Committees had not yet been carried out as planned and there were doubts
      about the added value of collaboration with experts thus far. Environmental
      strategies were felt to need more attention and ensuring long-term continuation
      requires continuous effort. Most of the 293 intervention activities had focused
      on nutrition, while smoking cessation activities had been given lowest priority.
      It is concluded that the process evaluation has provided information about
      successful and less successful elements of the community intervention.

PMID- 15199008
TI  - Testing selected behaviors to reduce indoor air pollution exposure in young
      children.
AB  - Indoor air pollution is responsible for the deaths and illness of millions of
      young children in developing countries. This study investigated the acceptability
      (willingness to try) and feasibility (ability to perform) of four indoor air
      pollution reduction behaviors (improve stove maintenance practices, child
      location practices, ventilation practices and reduce the duration of solid fuel
      burning). The study further aimed to identify the motivations for and barriers
      against modifying the behaviors, the perceived impact of the behaviors on
      children's respiratory health, and families intention to continue with the
      behaviors. Thirty families in a rural village of South Africa tried out one or
      more of the behaviors over a 4-week trial period during winter 2002. Improving
      stove maintenance and reducing the duration of solid fuel burning proved to be
      very difficult for most families. It is recommended that the main intervention
      should focus on improving child location and ventilation practices.

PMID- 15199009
TI  - Acculturation and smoking behavior in Asian-American populations.
AB  - The relationship between acculturation and smoking behavior was examined in four
      Asian-American groups that included recent immigrants and US-born Koreans,
      Chinese, Vietnamese and Cambodians residing in the Delaware Valley of
      Pennsylvania and New Jersey. The study was part of a community-based,
      comprehensive cross-sectional study designed to assess a broad array of
      knowledge, attitudes and behaviors on tobacco use and tobacco-related cancer
      issues in the target multi-ethnic and multi-lingual Asian-American community. The
      sample of 1374 respondents was selected using a stratified-cluster proportional
      sampling technique, with a response rate of 83%. Findings indicated that
      acculturation had a variable effect on smoking behavior: more acculturated youth
      and less acculturated male adults had higher smoking rates than the less
      acculturated youth and the more acculturated male adults. Smoking rates for all
      females were generally lower than those of males regardless of acculturation
      status; however, acculturated adult females had a higher smoking rate than the
      less acculturated.

PMID- 15199010
TI  - The health and lifestyle of Scottish fishermen: a need for health promotion.
AB  - It has long been known that fishing is one of the most dangerous occupations. In
      the year 2001, 33 boats were lost and 10 fishermen killed in UK waters. Despite
      the dangerous nature of the occupation, very little research has been conducted
      on fishermen's health and safety. The few studies that have been conducted are
      spread widely around the globe, and tend to focus on mortality rates and
      accidents. Few studies considered fishermen's lifestyle behaviours. To address
      this gap in current knowledge research was conducted to gain an understanding of
      health and lifestyle issues affecting Scottish fishermen. Data was collected
      using a postal questionnaire survey in the Scottish fishing population and health
      diaries in a small subsample. High rates of smoking were prevalent and passive
      smoking was a considerable problem. Fewer fishermen drank alcohol compared to the
      general population, but fishermen lacked knowledge about what safe levels of
      alcohol consumption were. Diet was lacking in fruit and vegetables, and meals
      were eaten at very erratic intervals. Fishermen may benefit from health promotion
      and education in the areas of smoking, diet and alcohol consumption.

PMID- 15199011
TI  - Self-esteem in a broad-spectrum approach for mental health promotion.
AB  - Self-evaluation is crucial to mental and social well-being. It influences
      aspirations, personal goals and interaction with others. This paper stresses the
      importance of self-esteem as a protective factor and a non-specific risk factor
      in physical and mental health. Evidence is presented illustrating that self
      esteem can lead to better health and social behavior, and that poor self-esteem
      is associated with a broad range of mental disorders and social problems, both
      internalizing problems (e.g. depression, suicidal tendencies, eating disorders
      and anxiety) and externalizing problems (e.g. violence and substance abuse). We
      discuss the dynamics of self-esteem in these relations. It is argued that an
      understanding of the development of self-esteem, its outcomes, and its active
      protection and promotion are critical to the improvement of both mental and
      physical health. The consequences for theory development, program development and
      health education research are addressed. Focusing on self-esteem is considered a
      core element of mental health promotion and a fruitful basis for a broad-spectrum
      approach.

PMID- 15199012
TI  - With RNA interference, silence is golden: scientists probe new approach's
      clinical potential.

PMID- 15199013
TI  - Plan B for "Plan B"? FDA denies OTC sales of emergency contraceptive.

PMID- 15199014
TI  - Autism interventions come of age.

PMID- 15199015
TI  - GAO: Medicare ads were illegal.

PMID- 15199023
TI  - Interventions for treatment of depression in primary care.

PMID- 15199024
TI  - Interventions for treatment of depression in primary care.

PMID- 15199025
TI  - Interventions for treatment of depression in primary care.

PMID- 15199026
TI  - Interventions to prevent readmission for congestive heart failure.

PMID- 15199027
TI  - Use and timing of radiotherapy in high-risk prostate cancer.

PMID- 15199028
TI  - C-reactive protein and risk of colon cancer.

PMID- 15199029
TI  - Methods for estimating glomerular filtration rate.

PMID- 15199030
TI  - C-reactive protein and risk of colon cancer.

PMID- 15199031
TI  - Pharmacogenetic study of statin therapy and cholesterol reduction.
AB  - CONTEXT: Polymorphisms in genes involved in cholesterol synthesis, absorption,
      and transport may affect statin efficacy. OBJECTIVE: To evaluate systematically
      whether genetic variation influences response to pravastatin therapy. DESIGN,
      SETTING, AND POPULATION: The DNA of 1536 individuals treated with pravastatin, 40
      mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10
      candidate genes related to lipid metabolism. Variation within these genes was
      then examined for associations with changes in lipid levels observed with
      pravastatin therapy during a 24-week period. MAIN OUTCOME MEASURE: Changes in
      lipid levels in response to pravastatin therapy. RESULTS: Two common and tightly
      linked SNPs (linkage disequilibrium r2 = 0.90; heterozygote prevalence = 6.7% for
      both) were significantly associated with reduced efficacy of pravastatin therapy.
      Both of these SNPs were in the gene coding for 3-hydroxy-3-methylglutaryl
      coenzyme A (HMG-CoA) reductase, the target enzyme that is inhibited by
      pravastatin. For example, compared with individuals homozygous for the major
      allele of one of the SNPs, individuals with a single copy of the minor allele had
      a 22% smaller reduction in total cholesterol (-32.8 vs -42.0 mg/dL [-0.85 vs 
      1.09 mmol/L]; P =.001; absolute difference, 9.2 mg/dL [95% confidence interval
      [CI], 3.8-14.6 mg/dL]) and a 19% smaller reduction in low-density lipoprotein
      (LDL) cholesterol (-27.7 vs -34.1 mg/dL [-0.72 vs -0.88 mmol/L]; P =.005;
      absolute difference, 6.4 mg/dL [95% CI, 2.2-10.6 mg/dL]). The association for
      total cholesterol reduction persisted even after adjusting for multiple tests on
      all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs
      evaluated was similar in magnitude and direction among men and women and was
      present in the ethnically diverse total cohort as well as in the majority
      subgroup of white participants. No association for either SNP was observed for
      the change in high-density lipoprotein (HDL) cholesterol (P>.80) and neither was
      associated with baseline lipid levels among those actively treated or among those
      who did not receive the drug. Among the remaining genes, less robust associations
      were found for squalene synthase and change in total cholesterol, apolipoprotein
      E and change in LDL cholesterol, and cholesteryl ester transfer protein and
      change in HDL cholesterol, although none of these met our conservative criteria
      for purely pharmacogenetic effects. CONCLUSION: Individuals heterozygous for a
      genetic variant in the HMG-CoA reductase gene may experience significantly
      smaller reductions in cholesterol when treated with pravastatin.

PMID- 15199032
TI  - Compensation for energy intake from fast food among overweight and lean
      adolescents.
AB  - CONTEXT: Fast food consumption has increased greatly among children in recent
      years, in tandem with the obesity epidemic. Fast food tends to promote a positive
      energy balance and, for this reason, may result in weight gain. However, if fast
      food and obesity are causally related, the question arises of why some children
      who frequently eat fast food do not become overweight. OBJECTIVE: To test the
      hypothesis that overweight adolescents are more susceptible to the adverse
      effects of fast food than lean adolescents. DESIGN AND SETTING: In study 1, we
      fed participants an "extra large" fast food meal in a naturalistic setting (a
      food court). The participants were instructed to eat as much or little as desired
      during this 1-hour meal. In study 2, we assessed energy intake under free-living
      conditions for 2 days when fast food was consumed and 2 days when it was not
      consumed. Data were collected in Boston, Mass, between July 2002 and March 2003.
      PARTICIPANTS: Overweight (n = 26) and lean (n = 28) adolescents aged 13 to 17
      years. Overweight was defined as a body mass index exceeding sex- and age
      specific 85th percentiles based on the 2000 Centers for Disease Control and
      Prevention growth charts. MAIN OUTCOME MEASURES: Energy intake determined by
      direct observation in study 1 and by unannounced 24-hour dietary recalls,
      administered by telephone, in study 2. RESULTS: In study 1, mean (SEM) energy
      intake from the fast food meal among all participants was extremely large (1652
      [87] kcal), accounting for 61.6% (2.2%) of estimated daily energy requirements.
      Overweight participants ate more than lean participants whether energy was
      expressed in absolute terms (1860 [129] vs 1458 [107] kcal, P =.02) or relative
      to estimated daily energy requirements (66.5% [3.1%] vs 57.0% [2.9%], P =.03). In
      study 2, overweight participants consumed significantly more total energy on fast
      food days than non-fast food days (2703 [226] vs 2295 [162] kcal/d; +409 [142]
      kcal/d; P =.02), an effect that was not observed among lean participants (2575
      [157] vs 2622 [191] kcal/d; -47 [173] kcal/d; P =.76). CONCLUSIONS: In this
      study, adolescents overconsumed fast food regardless of body weight, although
      this phenomenon was especially pronounced in overweight participants. Moreover,
      overweight adolescents were less likely to compensate for the energy in fast
      food, by adjusting energy intake throughout the day, than their lean
      counterparts.

PMID- 15199033
TI  - Treatment of acne vulgaris with a pulsed dye laser: a randomized controlled
      trial.
AB  - CONTEXT: The high prevalence of acne vulgaris and its significant morbidity
      underscore the need for convenient, low-risk, and efficacious therapy. Treatment
      with various lasers has been reported to improve acne. OBJECTIVE: To evaluate the
      clinical efficacy of pulsed dye laser therapy in the treatment of acne. DESIGN,
      SETTING, AND PATIENTS: Randomized, single-blind, controlled, split-face clinical
      trial of a volunteer sample of 40 patients aged 13 years or older with facial
      acne conducted at an academic referral center from August 2002 to September 2003.
      INTERVENTION: One or 2 nonpurpuric pulsed dye laser treatments to half of the
      face (fluence of 3 J/cm2), serial blinded clinical assessments (lesion counts),
      and grading of acne severity using standardized bilateral serial photographs.
      MAIN OUTCOME MEASURES: Comparison of the changes in lesion counts from baseline
      to 12 weeks between treated and untreated sides of the face and changes in
      photographic evidence of acne severity as graded by a panel of dermatologists
      blinded to treatment assignment. RESULTS: After 12 weeks, using intent-to-treat
      analysis with last observation carried forward, there were no significant
      differences between laser-treated and untreated skin for changes in mean papule
      counts (-4.2 vs -2.2; P =.08), mean pustule counts (0 vs -1.0; P =.12), or mean
      comedone counts (2.9 vs 1.6; P =.63). Grading of serial photographs confirmed the
      clinical assessments, showing no significant mean (SE) differences in Leeds
      scores (range, 1-12) for treated skin (3.98 [0.32] at baseline and 3.94 [0.27] at
      week 12) compared with untreated skin (3.83 [0.32] at baseline and 3.79 [0.28] at
      week 12) (P>.99). CONCLUSIONS: In this study, the nonpurpuric pulsed dye laser
      therapy did not result in significant improvement of facial acne. More research
      is needed before this laser therapy may be recommended as an acne treatment.

PMID- 15199034
TI  - Elderly licensure laws and motor vehicle fatalities.
AB  - CONTEXT: Little is known about how state-level driver licensure laws, such as in
      person renewal, vision tests, road tests, and the frequency of license renewal
      relate to the older driver traffic fatality rate. OBJECTIVE: To determine whether
      state driver's license renewal policies are associated with the fatality rate
      among elderly drivers. DESIGN, SETTING, AND POPULATION: Retrospective,
      longitudinal study conducted January 1990 through December 2000 of all fatal
      crashes in the contiguous United States identified in the Fatality Analysis
      Reporting System, which involved either an older (ages 65-74 years, 75-84 years,
      and > or =85 years) or middle-aged (ages 25-64 years) driver. Two regression
      approaches were used to study the effect of state laws mandating in-person
      renewal, vision tests, road tests, and frequency of license renewal on driver
      fatalities, controlling for state-level factors including the number of licensed
      elderly drivers, primary and secondary seatbelt laws, maximum speed limit laws,
      blood alcohol level of 0.08, and administrative license revocation drinking and
      driving laws, per capita income, and unemployment rate. The first regression
      approach examined only elderly driver fatalities and the second approach examined
      daytime elderly driver fatalities and used daytime fatalities among middle-aged
      drivers as a general control for unobserved variation across states and over
      time. MAIN OUTCOME MEASURES: Older driver fatalities and older and middle-aged
      daytime driver fatalities. RESULTS: Among individuals aged 85 years or older,
      there were a total of 4605 driver fatalities and 4179 daytime driver fatalities
      during the study period. For this age cohort, after controlling for middle-aged
      daytime driver deaths, states with in-person license renewal were associated with
      a lower driver fatality rate (incident rate ratio [RR], 0.83; 95% confidence
      interval [CI], 0.72-0.96). This was the only policy related to older drivers that
      was significantly associated with a lower fatality risk across both regression
      models. Thus, state-mandated vision tests, road tests, more frequent license
      renewal, and in-person renewal (for individuals aged 65-74 years and 75-84 years)
      were not found to be independently associated with the fatality rate among older
      drivers in the 2 models. CONCLUSIONS: In-person license renewal was related to a
      significantly lower fatality rate among the oldest old drivers. More stringent
      state licensure policies such as vision tests, road tests, and more frequent
      license renewal cycles were not independently associated with additional
      benefits.

PMID- 15199035
TI  - Prevalence of overweight and obesity among US children, adolescents, and adults,
      1999-2002.
AB  - CONTEXT: The prevalence of overweight and obesity has increased markedly in the
      last 2 decades in the United States. OBJECTIVE: To update the US prevalence
      estimates of overweight in children and obesity in adults, using the most recent
      national data of height and weight measurements. DESIGN, SETTING, AND
      PARTICIPANTS: As part of the National Health and Nutrition Examination Survey
      (NHANES), a complex multistage probability sample of the US noninstitutionalized
      civilian population, both height and weight measurements were obtained from 4115
      adults and 4018 children in 1999-2000 and from 4390 adults and 4258 children in
      2001-2002. MAIN OUTCOME MEASURE: Prevalence of overweight (body mass index [BMI]
      > or =95th percentile of the sex-specific BMI-for-age growth chart) among
      children and prevalence of overweight (BMI, 25.0-29.9), obesity (BMI > or =30.0),
      and extreme obesity (BMI > or =40.0) among adults by sex, age, and racial/ethnic
      group. RESULTS: Between 1999-2000 and 2001-2002, there were no significant
      changes among adults in the prevalence of overweight or obesity (64.5% vs 65.7%),
      obesity (30.5% vs 30.6%), or extreme obesity (4.7% vs 5.1%), or among children
      aged 6 through 19 years in the prevalence of at risk for overweight or overweight
      (29.9% vs 31.5%) or overweight (15.0% vs 16.5%). Overall, among adults aged at
      least 20 years in 1999-2002, 65.1% were overweight or obese, 30.4% were obese,
      and 4.9% were extremely obese. Among children aged 6 through 19 years in 1999
      2002, 31.0% were at risk for overweight or overweight and 16.0% were overweight.
      The NHANES results indicate continuing disparities by sex and between
      racial/ethnic groups in the prevalence of overweight and obesity. CONCLUSIONS:
      There is no indication that the prevalence of obesity among adults and overweight
      among children is decreasing. The high levels of overweight among children and
      obesity among adults remain a major public health concern.

PMID- 15199036
TI  - Parental atrial fibrillation as a risk factor for atrial fibrillation in
      offspring.
AB  - CONTEXT: Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the
      United States. Whereas rare cases of familial AF have been reported, it is
      unknown if AF among unselected individuals is a heritable condition. OBJECTIVE:
      To determine whether parental AF increases the risk for the development of
      offspring AF. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (1983
      2002) within the Framingham Heart Study, a population-based epidemiologic study.
      Participants were 2243 offspring (1165 women, 1078 men) at least 30 years of age
      and free of AF whose parents had both been evaluated in the original cohort. MAIN
      OUTCOME MEASURES: Development of new-onset AF in the offspring was prospectively
      examined in association with previously documented parental AF. RESULTS: Among
      2243 offspring participants, 681 (30%) had at least 1 parent with documented AF;
      70 offspring participants (23 women; mean age, 62 [range, 40-81] years) developed
      AF in follow-up. Compared with no parental AF, AF in at least 1 parent increased
      the risk of offspring AF (multivariable-adjusted odds ratio [OR], 1.85; 95%
      confidence interval [CI], 1.12-3.06; P =.02). These results were stronger when
      age was limited to younger than 75 years in both parents and offspring
      (multivariable-adjusted OR, 3.23; 95% CI, 1.87-5.58; P<.001) and when the sample
      was further limited to those without antecedent myocardial infarction, heart
      failure, or valve disease (multivariable-adjusted OR, 3.17; 95% CI, 1.71-5.86;
      P<.001). CONCLUSIONS: Parental AF increases the future risk for offspring AF, an
      observation supporting a genetic susceptibility to developing this dysrhythmia.
      Further research into the genetic factors predisposing to AF is warranted.

PMID- 15199037
TI  - Travel medicine considerations for North American immigrants visiting friends and
      relatives.
AB  - CONTEXT: In the United States, 10% of the population was born outside of its
      borders. Immigrants and their children frequently return to visit their homeland,
      referred to as visiting friends and relatives (VFRs). They account for a
      disproportionately high volume of international travel. EVIDENCE ACQUISITION:
      Searches of MEDLINE, World Health Organization, Centers for Disease Control and
      Prevention, International Society of Travel Medicine, and American Society of
      Tropical Medicine computerized databases, conference proceedings and abstracts,
      US Census Bureau, bibliographies of pertinent articles, and travel medicine
      texts. Priority was given to recent (1996-2003) evidence, addressing VFR
      travelers. General sources including travel medicine and immigrant health were
      also used. EVIDENCE SYNTHESIS: Immigrants visiting friends and relatives
      experience excessive rates of travel-related morbidity and mortality. Lack of
      pretravel care is common due to patient and clinician barriers to care,
      preexisting health beliefs, and incomplete childhood vaccinations. Travel
      patterns increase risk with VFRs traveling to high-risk destinations.
      Susceptibility to infectious and noninfectious illnesses is often increased
      because of multiple preexisting medical problems and extremes of age. Infectious
      diseases differ in etiology and magnitude from those of traditional travelers.
      For example with malaria, VFRs are frequently prescribed inappropriate
      prophylaxis or take none at all, have longer stays, spend time in high-risk
      areas, and do not appropriately adhere to chemoprophylaxis regimens. Effective
      pretravel health advice, guidelines, and services for this high-risk population
      are essential. There are already a number of useful and readily available
      databases that may aid clinicians in providing optimal travel-related preventive
      and therapeutic care. CONCLUSIONS: Immigrants who are visitors of friends and
      relatives in other countries account for a high volume of international travelers
      and are at markedly increased risk of travel-related illness. New strategies are
      needed to properly address the needs of VFR travelers. Pretravel services should
      be convenient, accessible, affordable, culturally competent, and if possible,
      located within clinics serving immigrant populations. Clinicians caring for VFRs
      should be knowledgeable about their travel-related risks and have access to
      regularly updated, detailed pretravel health information.

PMID- 15199038
TI  - Severe acute pancreatitis.

PMID- 15199041
TI  - STUDENTJAMA. Medicine and spirituality.

PMID- 15199039
TI  - Using pharmacogenetics to improve drug safety and efficacy.

PMID- 15199042
TI  - STUDENTJAMA. Taking a spiritual history.

PMID- 15199043
TI  - STUDENTJAMA. Faith-based treatment for addiction in Puerto Rico.

PMID- 15199044
TI  - STUDENTJAMA. Medical school curricula in spirituality and medicine.

PMID- 15199045
TI  - STUDENTJAMA. Spirituality and the patient-physician relationship.

PMID- 15199046
TI  - JAMA patient page. Pancreatitis.

PMID- 15199047
TI  - Assembly of exogenous fibronectin by fibronectin-null cells is dependent on the
      adhesive substrate.
AB  - The role of endogenously synthesized fibronectin (FN) in assembly was studied
      with cells lacking or expressing FN. Cells were cultured as homogeneous or mixed
      populations on surfaces coated with different matrix proteins. Compared with FN
      expressing cells, FN-null cells poorly assembled exogenous plasma FN (pFN) when
      adhered to vitronectin or the recombinant cell-binding domain (III(7-10)) of FN.
      Vitronectin had a suppressive effect that was overcome by co-adsorbed pFN or
      laminin-1 but not by soluble FN. In co-cultures of FN-expressing cells and FN
      null cells, endogenous FN was preferentially assembled around FN-expressing cells
      regardless of the adhesive ligand. If the adhesive ligand was vitronectin,
      exogenous pFN assembled preferentially around cells expressing cellular FN or
      recombinant EDa- or EDa+ FN. In co-cultures on vitronectin of FN-null cells and
      beta(1) integrin subunit-null cells, fibrils of cellular FN and pFN were
      preferentially deposited by FN-null (beta(1)-expressing) cells immediately
      adjacent to (FN-secreting) beta(1)-null cells. In co-cultures on vitronectin of
      FN-null cells and beta(1)-null cells expressing a chimera with the extracellular
      domain of beta(1) and the cytoplasmic domain of beta(3), preferential assembly
      was by the chimera-expressing cells. These results indicate that the adhesive
      ligand is a determinant of FN assembly by cells not secreting endogenous FN
      (suppressive if vitronectin, non-suppressive but non-supportive if III(7-10),
      supportive if pFN or laminin-1) and suggest that efficient interaction of freshly
      secreted cellular FN with a beta(1) integrin, presumably alpha(5)beta(1),
      substitutes for integrin-mediated adherence to a preformed matrix of laminin-1 or
      pFN to support assembly of FN.

PMID- 15199048
TI  - A multi-enzyme cascade of hemoglobin proteolysis in the intestine of blood
      feeding hookworms.
AB  - Blood-feeding pathogens digest hemoglobin (Hb) as a source of nutrition, but
      little is known about this process in multicellular parasites. The intestinal
      brush border membrane of the canine hookworm, Ancylostoma caninum, contains
      aspartic proteases (APR-1), cysteine proteases (CP-2), and metalloproteases (MEP
      1), the first of which is known to digest Hb. We now show that Hb is degraded by
      a multi-enzyme, synergistic cascade of proteolysis. Recombinant APR-1 and CP-2,
      but not MEP-1, digested native Hb and denatured globin. MEP-1, however, did
      cleave globin fragments that had undergone prior digestion by APR-1 and CP-2.
      Proteolytic cleavage sites within the Hb alpha and beta chains were determined
      for the three enzymes, identifying a total of 131 cleavage sites. By scanning
      synthetic combinatorial peptide libraries with each enzyme, we compared the
      preferred residues cleaved in the libraries with the known cleavage sites within
      Hb. The semi-ordered pathway of Hb digestion described here is surprisingly
      similar to that used by Plasmodium to digest Hb and provides a potential
      mechanism by which these hemoglobinases are efficacious vaccines in animal models
      of hookworm infection.

PMID- 15199049
TI  - Functional phylogeny relates LET-756 to fibroblast growth factor 9.
AB  - Fibroblast growth factors (FGFs) are secreted regulatory proteins involved in
      various developmental processes. In vertebrates, the FGF superfamily comprises 22
      members. In non-vertebrates, six FGF genes have been identified in Ciona
      intestinalis, three in Drosophila melanogaster, and two (let-756 and egl-17) in
      Caenorhabditis elegans. The core of LET-756 shares a 30-50% sequence identity
      with the various members of the superfamily. The relationships between vertebrate
      and non-vertebrate FGFs are not clear. We made chimeric FGFs by replacing the
      core region of LET-756 by the cores of various mammalian, fly, and worm FGFs. LET
      756 deleted in its core region was no longer able to rescue the lethal phenotype
      of a let-756 null mutant, and only chimeras containing the cores of FGFs 9, 16,
      and 20 showed rescue capacity. This core contains an internal motif of six amino
      acid residues (EFISIA) whose deletion or mutation abolished both the rescue
      activity and FGF secretion in the supernatant of transfected COS-1 cells. Chimera
      containing the core of C. intestinalis FGF9/16/20, a potential ortholog of FGF9
      lacking the complete EFISIA motif, was not able to rescue the lethal phenotype or
      be secreted. However, the introduction of the EFISIA motif restored both
      activities. The data show that the EFISIA motif in the core of LET-756 is
      essential for its biological activity and that FGFs 9, 16, and 20, which contain
      that motif, are functionally close to LET-756 and may be evolutionary related.
      This non-classical mode of secretion using an internal motif is conserved
      throughout evolution.

PMID- 15199050
TI  - Epidermal growth factor receptor transactivation mediates tumor necrosis factor
      induced hepatocyte replication.
AB  - Tumor necrosis factor (TNF) has multiple biological effects such as participating
      in inflammation, apoptosis, and cell proliferation, but the mechanisms of its
      effects on epithelial cell proliferation have not been examined in detail. At the
      early stages of liver regeneration, TNF functions as a priming agent for
      hepatocyte replication and increases the sensitivity of hepatocytes to growth
      factors such as transforming growth factor alpha (TGFalpha); however, the
      mechanisms by which TNF interacts with growth factors and enhances hepatocyte
      replication are not known. Using the AML-12 hepatocyte cell line, we show that
      TNF stimulates proliferation of these cells through transactivation of the
      epidermal growth factor receptor (EGFR). The transactivation mechanism involves
      the release of TGFalpha into the medium through activation of the
      metalloproteinase TNFalpha-converting enzyme (also known as ADAM 17). Binding of
      the ligand to EGFR initiates a mitogenic cascade through extracellular signal
      regulated kinases 1 and 2 and the partial involvement of protein kinase B. TNF
      induced release of TGFalpha and activation of EGFR signaling were inhibited by
      TNFalpha protease inhibitor-1, an agent that interferes with TNFalpha-converting
      enzyme activity. We suggest that TNF-induced transactivation of EGFR may provide
      an early signal for the entry of hepatocytes into the cell cycle and may
      integrate proliferative and survival pathways at the start of liver regeneration.

PMID- 15199051
TI  - Four amino acids in the alpha subunits determine the gamma-aminobutyric acid
      sensitivities of GABAA receptor subtypes.
AB  - GABA(A) receptors, mediators of fast inhibitory neurotransmission, are
      heteropentameric assemblies from a large array of subunits. Differences in the
      sensitivity of receptor subtypes to endogenous GABA may permit subunit-dependent
      finely tuned responsiveness to the same GABAergic inputs. Using both radioligand
      binding and electrophysiology combined with mutagenesis, we identified a domain
      of four amino acids within the alpha subunits that mediates the distinct
      sensitivities to GABA allowing their selective switch between alphabeta3gamma2
      combinations. Replacing this domain in alpha3 by the corresponding segments of
      alpha1-alpha5 resulted in mutant receptors displaying the GABA EC(50) values of
      the respective wild-type receptors. Vice versa, the alpha3 motif forced the low
      sensitivity to GABA of alpha3 upon alpha1beta3gamma2, alpha4beta3gamma2, and
      alpha5beta3gamma2. Binding of the GABA agonist [(3)H]muscimol was not affected by
      the exchange of the motif between alpha1 and alpha3 subunits. Thus, the
      equilibrium binding pocket is maintained upon replacement of the four amino
      acids. Taken together our data suggest that the identified motifs contribute to a
      structure involved in the transduction of the binding signal rather than to the
      binding itself.

PMID- 15199052
TI  - Insulin resistance due to phosphorylation of insulin receptor substrate-1 at
      serine 302.
AB  - Inhibitory serine phosphorylation is a potential molecular mechanism for insulin
      resistance. We have developed a new variant of the yeast two-hybrid method,
      referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases
      and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1.
      Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH(2)-terminal
      kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser
      307, a previously identified site, is necessary but not sufficient for JNK1
      mediated disruption of IR/IRS-1 binding. We further identify a new
      phosphorylation site, Ser-302, and show that this too is necessary for JNK1
      mediated disruption. Seven additional kinases potentially linked to insulin
      resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through
      distinct Ser-302- and Ser-307-independent mechanisms. Phosphospecific antibodies
      that recognize sequences surrounding Ser(P)-302 or Ser(P)-307 were used to
      determine whether the sites were phosphorylated under relevant conditions.
      Phosphorylation was promoted at both sites in Fao hepatoma cells by reagents
      known to promote Ser/Thr phosphorylation, including the phorbol ester phorbol 12
      myristate 13-acetate, anisomycin, calyculin A, and insulin. The antibodies
      further showed that Ser(P)-302 and Ser(P)-307 are increased in animal models of
      obesity and insulin resistance, including genetically obese ob/ob mice, diet
      induced obesity, and upon induction of hyperinsulinemia. These findings
      demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for
      JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307
      are phosphorylated in parallel in cultured cells and in vivo under conditions
      that lead to insulin resistance.

PMID- 15199053
TI  - 15-deoxy-delta12,14-prostaglandin J2-mediated ERK signaling inhibits gram
      negative bacteria-induced RelA phosphorylation and interleukin-6 gene expression
      in intestinal epithelial cells through modulation of protein phosphatase 2A
      activity.
AB  - We have previously shown that non-pathogenic Gram-negative Bacteroides vulgatus
      induces transient RelA phosphorylation (Ser-536), NF-kappaB activity, and pro
      inflammatory gene expression in native and intestinal epithelial cell (IEC)
      lines. We now demonstrate that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d
      PGJ(2)) but not prostaglandin E(2) inhibits lipopolysaccharide (LPS) (B.
      vulgatus)/LPS (Escherichia coli)-induced RelA phosphorylation and interleukin-6
      gene expression in the colonic epithelial cell line CMT-93. This inhibitory
      effect of 15d-PGJ(2) was mediated independently of LPS-induced IkappaBalpha
      phosphorylation/degradation and RelA nuclear translocation as well as RelA DNA
      binding activity. Interestingly, although B. vulgatus induced nuclear expression
      of peroxisome proliferator-activated receptor gamma (PPARgamma) in native
      epithelium of monoassociated Fisher rats, PPARgamma-specific knock-down in CMT-93
      cells using small interference RNA failed to reverse the inhibitory effects of
      PPARgamma agonist 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. In
      addition, 15d-PGJ(2) but not the synthetic high affinity PPARgamma ligand
      rosiglitazone triggered ERK1/2 phosphorylation in IEC, and most importantly, MEK1
      inhibitor PD98059 reversed the inhibitory effect of 15dPGJ(2) on LPS-induced RelA
      phosphorylation and interleukin-6 gene expression. Calyculin A, a specific
      phosphoserine/phospho-threonine phosphatase inhibitor increased the basal
      phosphorylation of RelA and reversed the inhibitory effect of 15d-PGJ(2) on LPS
      induced RelA phosphorylation. We further demonstrated in co-immunoprecipitation
      experiments that 15d-PGJ(2) triggered protein phosphatase 2A activity, which
      directly dephosphorylated RelA in LPS-stimulated CMT-93 cells. We concluded that
      15d-PGJ(2) may help to control NF-kappaB signaling and normal intestinal
      homeostasis to the enteric microflora by modulating RelA phosphorylation in IEC
      through altered protein phosphatase 2A activity.

PMID- 15199054
TI  - Rotor/Stator interactions of the epsilon subunit in Escherichia coli ATP synthase
      and implications for enzyme regulation.
AB  - The H(+)-translocating F(0)F(1)-ATP synthase of Escherichia coli functions as a
      rotary motor, coupling the transmembrane movement of protons through F(0) to the
      synthesis of ATP by F(1). Although the epsilon subunit appears to be tightly
      associated with the gamma subunit in the central stalk region of the rotor
      assembly, several studies suggest that the C-terminal domain of epsilon can
      undergo significant conformational change as part of a regulatory process. Here
      we use disulfide cross-linking of substituted cysteines on functionally coupled
      ATP synthase to characterize interactions of epsilon with an F(0) component of
      the rotor (subunit c) and with an F(1) component of the stator (subunit beta).
      Oxidation of the engineered F(0)F(1) causes formation of two disulfide bonds,
      betaD380C-S108C epsilon and epsilonE31C-cQ42C, to give a beta-epsilon-c cross
      linked product in high yield. The results demonstrate the ability of epsilon to
      span the central stalk region from the surface of the membrane (epsilon-c) to the
      bottom of F(1) (beta-epsilon) and suggest that the conformation detected here is
      distinct from both the "closed" state seen with isolated epsilon (Uhlin, U., Cox,
      G. B., and Guss, J. M. (1997) Structure 5, 1219-1230) and the "open" state seen
      in a complex with a truncated form of the gamma subunit (Rodgers, A. J., and
      Wilce, M. C. (2000) Nat. Struct. Biol. 7, 1051-1054). The kinetics of beta
      epsilon and epsilon-c cross-linking were studied separately using F(0)F(1)
      containing one or the other matched cysteine pair. The rate of cross-linking at
      the epsilon/c (rotor/rotor) interface is not influenced by the type of nucleotide
      added. In contrast, the rate of beta-epsilon cross-linking is fastest under ATP
      hydrolysis conditions, intermediate with MgADP, and slowest with MgAMP-PNP. This
      is consistent with a regulatory role for a reversible beta/epsilon (stator/rotor)
      interaction that blocks rotation and inhibits catalysis. Furthermore, the rate of
      beta-epsilon cross-linking is much faster than that indicated by previous
      studies, allowing for the possibility of a rapid response to regulatory signals.

PMID- 15199055
TI  - RORalpha regulates the expression of genes involved in lipid homeostasis in
      skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR.
AB  - The staggerer mice carry a deletion in the RORalpha gene and have a prolonged
      humoral response, overproduce inflammatory cytokines, and are immunodeficient.
      Furthermore, the staggerer mice display lowered plasma apoA-I/-II, decreased
      plasma high density lipoprotein cholesterol and triglycerides, and develop hypo
      alpha-lipoproteinemia and atherosclerosis. However, relatively little is known
      about RORalpha in the context of target tissues, target genes, and lipid
      homeostasis. For example, RORalpha is abundantly expressed in skeletal muscle, a
      major mass peripheral tissue that accounts for approximately 40% of total body
      weight and 50% of energy expenditure. This lean tissue is a primary site of
      glucose disposal and fatty acid oxidation. Consequently, muscle has a significant
      role in insulin sensitivity, obesity, and the blood-lipid profile. In particular,
      the role of RORalpha in skeletal muscle metabolism has not been investigated, and
      the contribution of skeletal muscle to the ROR-/- phenotype has not been
      resolved. We utilize ectopic dominant negative RORalpha expression in skeletal
      muscle cells to understand the regulatory role of RORs in this major mass
      peripheral tissue. Exogenous dominant negative RORalpha expression in skeletal
      muscle cells represses the endogenous levels of RORalpha and -gamma mRNAs and ROR
      dependent gene expression. Moreover, we observed attenuated expression of many
      genes involved in lipid homeostasis. Furthermore, we show that the muscle
      carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated
      by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the
      control of lipid homeostasis in skeletal muscle. In conclusion, we speculate that
      ROR agonists would increase fatty acid catabolism in muscle and suggest selective
      activators of ROR may have therapeutic utility in the treatment of obesity and
      atherosclerosis.

PMID- 15199056
TI  - Negative cooperativity of glutamate binding in the dimeric metabotropic glutamate
      receptor subtype 1.
AB  - Metabotropic glutamate receptor (mGluR) subtype 1 is a Class III G-protein
      coupled receptor that is mainly expressed on the post-synaptic membrane of
      neuronal cells. The receptor has a large N-terminal extracellular ligand binding
      domain that forms a homodimer, however, the intersubunit communication of ligand
      binding in the dimer remains unknown. Here, using the intrinsic tryptophan
      fluorescence change as a probe for ligand binding events, we examined whether
      allosteric properties exist in the dimeric ligand binding domain of the receptor.
      The indole ring of the tryptophan 110, which resides on the upper surface of the
      ligand binding pocket, sensed the ligand binding events. From saturation binding
      curves, we have determined the apparent dissociation constants (K(0.5)) of
      representative agonists and antagonists for this receptor (3.8, 0.46, 40, and
      0.89 microm for glutamate, quisqualate, (S)-alpha-methyl-4-carboxyphenylglycine
      ((S)-MCPG), and (+)-2-methyl-4-carboxyphenylglycine (LY367385), respectively).
      Calcium ions functioned as a positive modulator for agonist but not for
      antagonist binding (K(0.5) values were 1.3, 0.21, 59, and 1.2 microm for
      glutamate, quisqualate, (S)-MCPG, and LY367385, respectively, in the presence of
      2.0 mm calcium ion). Moreover, a Hill analysis of the saturation binding curves
      revealed the strong negative cooperativity of glutamate binding between each
      subunit in the dimeric ligand binding domain. As far as we know, this is the
      first direct evidence that the dimeric ligand binding domain of mGluR exhibits
      intersubunit cooperativity of ligand binding.

PMID- 15199057
TI  - Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11
      in the assembly of yeast cytochrome C oxidase.
AB  - The assembly of the copper sites in cytochrome c oxidase involves a series of
      accessory proteins, including Cox11, Cox17, and Sco1. The two mitochondrial inner
      membrane proteins Cox11 and Sco1 are thought to be copper donors to the Cu(B) and
      Cu(A) sites of cytochrome oxidase, respectively, whereas Cox17 is believed to be
      the copper donor to Sco1 within the intermembrane space. In this report we show
      Cox17 is a specific copper donor to both Sco1 and Cox11. Using in vitro studies
      with purified proteins, we demonstrate direct copper transfer from CuCox17 to
      Sco1 or Cox11. The transfer is specific because no transfer occurs to
      heterologous proteins, including bovine serum albumin and carbonic anhydrase. In
      addition, a C57Y mutant of Cox17 fails to transfer copper to Sco1 but is
      competent for copper transfer to Cox11. The in vitro transfer studies were
      corroborated by a yeast cytoplasm expression system. Soluble domains of Sco1 and
      Cox11, lacking the mitochondrial targeting sequence and transmembrane domains,
      were expressed in the yeast cytoplasm. Metallation of these domains was strictly
      dependent on the co-expression of Cox17. Thus, Cox17 represents a novel copper
      chaperone that delivers copper to two proteins.

PMID- 15199058
TI  - The importance of Lys-352 of human immunoglobulin E in FcepsilonRII/CD23
      recognition.
AB  - The interaction of immunoglobulin E (IgE) with its low affinity receptor
      (FcepsilonRII/CD23) plays a central role in the initiation and regulation of type
      I hypersensitivity responses. We have previously identified the importance of
      amino acid residues in the A-B loop of the Cepsilon3 domain of human IgE and
      implicated a region close to the glycosylation site at asparagine 371 as
      contributing to IgE-CD23 interaction. These residues were now targeted by site
      directed mutagenesis. The IgE-CD23 interaction was assessed by semiquantitative
      flow cytometry. Replacement of the entire Cepsilon3 A-B loop (residues 341-356)
      with the homologous rat IgE sequence resulted in complete loss of human CD23
      recognition, as did replacement of residues 346-353, indicating that class
      specific effector residue(s) are contained within these eight amino acids. Lysine
      352 within the A-B loop was identified as contributing directly to human CD23
      interaction. Mutation to the rodent homologue glycine or glutamate resulted in a
      significant reduction in binding compared with native IgE, whereas conservative
      substitution with arginine effected a small, but statistically significant,
      enhancement of CD23 binding. Mutation of the Cepsilon3 glycosylation site at
      asparagine 371 to threonine or glutamine did not significantly affect CD23
      recognition. Our results yield new insights into the structural basis of the hIgE
      CD23 interaction and hold promise for the rational design of drugs that can
      manipulate IgE-mediated regulation of the allergic response.

PMID- 15199059
TI  - Dynamic actions of glucose and glucosamine on hexosamine biosynthesis in isolated
      adipocytes: differential effects on glucosamine 6-phosphate, UDP-N
      acetylglucosamine, and ATP levels.
AB  - Glucose and glucosamine (GlcN) cause insulin resistance over several hours by
      increasing metabolite flux through the hexosamine biosynthesis pathway (HBP). To
      elucidate the early events underlying glucose-induced desensitization, we treated
      isolated adipocytes with either glucose or GlcN and then measured intracellular
      levels of glucose-6-P (G-6-P), GlcN-6-P, UDP-Glc-NAc, and ATP. Glucose treatment
      rapidly increased G-6-P levels (t((1/2)) < 1 min), which plateaued by 15 min and
      remained elevated for up to 4 h (glucose ED(50) = 4mm). In glucose-treated cells,
      GlcN-6-P was undetectable; however, GlcN treatment (2 mm) caused a rapid and
      massive accumulation of GlcN-6-P. Levels increased by 5 min ( approximately 400
      nmol/g) and continued to rise over 2 h (t((1/2)) approximately 20 min) before
      reaching a plateau at >1,400 nmol/g (ED(50) = 900 microm). Thus, at high GlcN
      concentrations, unrestricted flux into the HBP greatly exceeds the biosynthetic
      capacity of the pathway leading to a rapid buildup of GlcN-6-P. The GlcN-induced
      rise in GlcN-6-P levels was correlated with ATP depletion, suggesting that ATP
      loss is caused by phosphate sequestration (with the formation of GlcN-6-P) or the
      energy demands of phosphorylation. As expected, GlcN and glucose increased UDP
      GlcNAc levels (t((1/2)) approximately 14-18 min), but greater levels were
      obtained with GlcN (4-5-fold for GlcN, 2-fold for glucose). Importantly, we found
      that low doses of GlcN (<250 microm, ED(50) = 80 microm) could markedly elevate
      UDP-GlcNAc levels without increasing GlcN-6-P levels or depleting ATP levels.
      These studies on the dynamic actions of glucose and GlcN on hexosamine levels
      should be useful in exploring the functional role of the HBP and in avoiding the
      potential pitfalls in the pharmacological use of GlcN.

PMID- 15199060
TI  - STAT signaling underlies difference between flagellin-induced and tumor necrosis
      factor-alpha-induced epithelial gene expression.
AB  - Both bacterial flagellin and the cytokine tumor necrosis factor-alpha (TNFalpha)
      are potent activators of intestinal epithelial cell pro-inflammatory gene
      expression in general; nonetheless, there seem to be distinct differences in the
      specific patterns of gene expression induced by these agonists. The goal of this
      study was to define one such difference and elucidate the signaling mechanism
      responsible for such differential gene induction by these agonists. We observed
      that expression of inducible nitric-oxide synthase is substantially induced by
      flagellin but only minimally expressed in response to TNFalpha. This difference
      seemed to be underlain by differential induction of signal transducers and
      activators of transcription (STAT) activation in that, whereas flagellin and
      TNFalpha seemed to be equipotent activators of p38 mitogen-activated protein
      kinase and nuclear factor-kappaB, flagellin induced substantially higher levels
      of STAT-1 and -3 tyrosine phosphorylation. Such flagellin-induced STAT activation
      exhibited delayed kinetics and was ablated by treatment with cycloheximide.
      Flagellin-induced activation of STAT-3 was abolished via neutralizing antibodies
      to interleukin (IL)-6, but not interferon (IFN)beta nor IFNgamma; none of these
      neutralizing antibodies had any effect on flagellin-induced STAT-1 tyrosine
      phosphorylation. Flagellin induced substantially more IL-6 expression than did
      TNFalpha, but neither agonist elicited detectable levels of IFN expression.
      Flagellin-induced expression of inducible nitric-oxide synthase but not IL-6, was
      abolished by blocking STAT activation with AG490, and was reduced by blocking
      STAT-3 activation with anti-IL-6. Together, these results indicate that
      epithelial cell induction of flagellin-specific gene expression is mediated, in
      part, by STAT activation that results from autocrine activation via IL-6.

PMID- 15199061
TI  - Fatty acid transport in adipocytes monitored by imaging intracellular free fatty
      acid levels.
AB  - Transport of free fatty acids (FFA) across the adipocyte plasma membrane is
      critical for maintaining homeostasis. To determine the membrane's role in
      regulating transport we describe here the first measurements of the intracellular
      (unbound) FFA concentration ([FFA(i)]) and their use in monitoring transport of
      FFA across 3T3F442A adipocytes. [FFA(i)] was measured by microinjecting cells
      with ADIFAB, a fluorescently labeled fatty acid-binding protein that is used to
      measure unbound FFA levels. We used ratio fluorescence microscopy of
      intracellular ADIFAB to image unbound FFA levels and determined the time course
      of [FFA(i)] in response to changing the extracellular unbound FFA concentration
      ([FFA(o)]). [FFA(o)] was clamped at defined levels using complexes of FFA and
      bovine serum albumin. We show that FFA influx is slow, requiring about 300 s to
      reach steady state (rate constant approximately 0.02 s(-1)) and saturable (K(o)
      approximately 200 nm). Efflux is twice as fast as influx, for zero [FFA(o)], but
      decreases with increasing [FFA(o)]. Surprisingly, at steady state [FFA(i)] is 2-5
      fold (average 2-fold) greater than [FFA(o)] and this [FFA(i)]/[FFA(o)] gradient
      is abolished by depleting cellular ATP. Our results indicate that FFA transport
      across adipocyte membranes is highly regulated, involving an ATP-driven pump and
      a mechanism for gating efflux that is sensitive to [FFA(o)]. These
      characteristics are well described by a membrane carrier model but are not
      consistent with FFA transport across the membrane's lipid phase. We suggest that
      these characteristics are important in regulating circulating FFA levels by the
      adipocyte.

PMID- 15199062
TI  - STAT6 and Ets-1 form a stable complex that modulates Socs-1 expression by
      interleukin-4 in keratinocytes.
AB  - Supressor of cytokine signaling (SOCS)-1 is selectively and rapidly induced by
      appropriate agonists and modulates cytokine responses by interfering with the
      Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway.
      On the basis of the observation that interleukin (IL)-4 up-regulates Socs-1 in
      the keratinocyte HaCaT cell line, we investigated which sequences of the 5'-Socs
      1 gene are responsive to IL-4. We therefore have cloned the 5'-flanking region of
      this gene, and by promoter analysis we identified a functional IL-4-responsive
      element located at nucleotide (-684/-570) upstream from the transcription
      initiation site, whose presence and integrity are necessary to ensure IL-4
      responsiveness. This element contains three STAT6 and one Ets consensus binding
      sequences of which specific mutations abolished IL-4 responsiveness either
      partially or totally. We also report that Ets-1 physically interacted with STAT6.
      Exogenous expression of Ets-1 in conjunction with STAT6 activation strongly
      inhibited expression of a Socs-1 promoter-luciferase reporter. Collectively, our
      data demonstrated the involvement of STAT6 and Ets, via a composite DNA element,
      in the IL-4 regulation of Socs-1 gene expression in keratinocytes.

PMID- 15199063
TI  - An alternative splicing variant of the selenoprotein thioredoxin reductase is a
      modulator of estrogen signaling.
AB  - The selenoprotein thioredoxin reductase (TrxR1) is an integral part of the
      thioredoxin system. It serves to transfer electrons from NADPH to thioredoxin
      leading to its reduction. Interestingly, recent work has indicated that
      thioredoxin reductase can regulate the activity of transcription factors such as
      p53, hypoxia-inducible factor, and AP-1. Here, we describe that an alternative
      splicing variant of thioredoxin reductase (TrxR1b) containing an LXXLL peptide
      motif, is implicated in direct binding to nuclear receptors. In vitro interaction
      studies revealed direct interaction of the TrxR1b with the estrogen receptors
      alpha and beta. Confocal microscopy analysis showed nuclear colocalization of the
      TrxR1b with both estrogen receptor alpha and beta in estradiol-17beta-treated
      cells. Transcriptional studies demonstrated that TrxR1b can affect estrogen
      dependent gene activation differentially at classical estrogen response elements
      as compared with AP-1 response elements. Based on these results, we propose a
      model where thioredoxin reductase directly influences the estrogen receptor
      coactivator complex assembly on non-classical estrogen response elements such as
      AP-1. In summary, our results suggest that TrxR1b is an important modulator of
      estrogen signaling.

PMID- 15199064
TI  - The muscle-specific calmodulin-dependent protein kinase assembles with the
      glycolytic enzyme complex at the sarcoplasmic reticulum and modulates the
      activity of glyceraldehyde-3-phosphate dehydrogenase in a Ca2+/calmodulin
      dependent manner.
AB  - The skeletal muscle specific Ca(2)+/calmodulin-dependent protein kinase
      (CaMKIIbeta(M)) is localized to the sarcoplasmic reticulum (SR) by an anchoring
      protein, alphaKAP, but its function remains to be defined. Protein interactions
      of CaMKIIbeta(M) indicated that it exists in complex with enzymes involved in
      glycolysis at the SR membrane. The kinase was found to complex with glycogen
      phosphorylase, glycogen debranching enzyme, glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH), and creatine kinase in the SR membrane. CaMKIIbeta(M) was
      also found to assemble with aldolase A, GAPDH, enolase, lactate dehydrogenase,
      creatine kinase, pyruvate kinase, and phosphorylase b kinase from the cytosolic
      fraction. The interacting proteins were substrates of CaMKIIbeta(M), and their
      phosphorylation was enhanced in a Ca(2+)- and calmodulin (CaM)-dependent manner.
      The CaMKIIbeta(M) could directly phosphorylate GAPDH and markedly increase (
      approximately 3.4-fold) its activity in a Ca(2+)/CaM-dependent manner. These data
      suggest that the muscle CaMKIIbeta(M) isoform may serve to assemble the glycogen
      mobilizing and glycolytic enzymes at the SR membrane and specifically modulate
      the activity of GAPDH in response to calcium signaling. Thus, the activation of
      CaMKIIbeta(M) in response to calcium signaling would serve to modulate GAPDH and
      thereby ATP and NADH levels at the SR membrane, which in turn will regulate
      calcium transport processes.

PMID- 15199065
TI  - Association of immunophilins with mammalian TRPC channels.
AB  - Drosophila photoreceptor channels TRP and TRPL are held in a large signalplex by
      the scaffolding protein, INAD. Immunophilin FKBP59, another member of the
      signalplex, binds to both INAD and TRPL. Mutation P702Q or P709Q in the highly
      conserved TRPL sequence (701)LPPPFNVLP(709), eliminates TRPL interaction with
      FKBP59. The first leucylprolyl (LP) dipeptide in this region is conserved in
      mammalian TRPC channel proteins. However, the second LP is changed to
      isoleucylprolyl (IP) in TRPC1, -C4, and -C5, and valylprolyl (VP) in TRPC3, -C6,
      and -C7. The purpose of the present study was to determine if mammalian FKBP12 or
      FKBP52 interact with TRPC channel proteins. Using TRPC-specific antibodies,
      immunoprecipitations from Sf9 cells individually co-expressing each of the TRPC
      proteins along with the immunophilins showed that TRPC3, -C6, and -C7 interact
      with FKBP12, whereas TRPC1, -C4, and -C5 interact with FKBP52. The binding of
      FKBP12 and FKBP52 was specific and could be displaced by the immunosuppressant
      drug FK506, at concentrations of 0.5 and 10 microm, respectively. To evaluate
      TRPC-immunophilin interactions in vivo, immunoprecipitations were performed using
      membrane lysates of rat cerebral cortex. FKBP12 co-immunoprecipitated with TRPC3,
      -C6, and -C7 from rat brain, whereas FKBP52 was found to associate with TRPC1, 
      C4, and -C5. The association of immunophilins with the TRPC channels in rat brain
      lysates could be displaced by FK506. Receptor-mediated activation of TRPC6,
      stably expressed in HEK cells, was significantly inhibited by FK506, which also
      disrupted interaction between TRPC6 and the endogenous immunophilin found in HEK
      cells. Pro to Gln mutations in the first LP dipeptide in the putative FKBP
      binding domain eliminated FKBP12 and FKBP52 interaction with TRPC3 and -C6, and
      TRPC1 and -C4, respectively. However, mutual swap of VP and IP in TRPC3 and TRPC5
      did not alter the association or the selectivity of the channels for their
      respective immunophilin binding partner. These results suggest that immunophilins
      are TRPC channel accessory proteins that play an important role in the mechanism
      of channel activation following receptor stimulation.

PMID- 15199066
TI  - Noggin and sclerostin bone morphogenetic protein antagonists form a mutually
      inhibitory complex.
AB  - Noggin and sclerostin are bone morphogenetic protein (BMP) antagonists that
      modulate mitogenic activity through sequestering BMPs. Little is known of the
      interactions among this class of proteins. We show that recombinant sclerostin
      and noggin bound to each other with high affinity (K(D) = 2.92 nm). This
      observation has been extended to naturally expressed noggin and sclerostin from
      the rat osteosarcoma cell line, ROS 17/2.8, supporting a role for the complex in
      natural systems. The noggin-sclerostin complex was competitive with BMP binding
      and mutually attenuated the activity of each BMP antagonist. Collectively, the
      data demonstrate a novel and exquisite paradigm for the regulation of BMP
      activity through direct neutralization of the BMP and activation by co-localized
      BMP antagonist expression. The pleiotrophic nature of noggin and sclerostin
      represents a novel mechanism for the fine-tuning of BMP activity in bone
      homeostasis.

PMID- 15199067
TI  - Cyclic adenosine monophosphate regulates calcium channels in the plasma membrane
      of Arabidopsis leaf guard and mesophyll cells.
AB  - The effect of cAMP on Ca(2+)-permeable channels from Arabidopsis thaliana leaf
      guard cell and mesophyll cell protoplasts was studied using the patch clamp
      technique. In the whole cell configuration, dibutyryl cAMP was found to increase
      a hyperpolarization-activated Ba(2+) conductance (I(Ba)). The increase of I(Ba)
      was blocked by the addition of GdCl(3). In excised outside-out patches, the
      addition of dibutyryl cAMP consistently activated a channel with particularly
      fast gating kinetics. Current/voltage analyses indicated a single channel
      conductance of approximately 13 picosiemens. In patches where we measured some
      channel activity prior to cAMP application, the data suggest that cAMP enhances
      channel activity without affecting the single channel conductance. The cAMP
      activation of these channels was reversible upon washout. The results obtained
      with excised patches indicate that the cAMP-activated I(Ba) seen in the whole
      cell configuration could be explained by a direct effect of cAMP on the Ca(2+)
      channel itself or a close entity to the channel. This work represents the first
      demonstration using patch clamp analysis of the presence in plant cell membranes
      of an ion channel directly activated by cAMP.

PMID- 15199068
TI  - Targeting of scavenger receptor class B type I by synthetic amphipathic alpha
      helical-containing peptides blocks lipopolysaccharide (LPS) uptake and LPS
      induced pro-inflammatory cytokine responses in THP-1 monocyte cells.
AB  - Human scavenger receptor class B type I, CLA-1, mediates lipopolysaccharide (LPS)
      binding and internalization (Vishnyakova, T. G., Bocharov, A. V., Baranova, I.
      N., Chen, Z., Remaley, A. T., Csako, G., Eggerman, T. L., and Patterson, A. P.
      (2003) J. Biol. Chem. 278, 22771-22780). Because one of the recognition motifs in
      SR-B1 ligands is the anionic amphipathic alpha-helix, we analyzed the effects of
      model amphipathic alpha-helical-containing peptides on LPS uptake and LPS
      stimulated cytokine production. The L-37pA model peptide, containing two class A
      amphipathic helices, bound with high affinity (K(d) = 0.94 microg/ml) to CLA-1
      expressing HeLa cells with a 10-fold increased capacity when compared with mock
      transfected HeLa cells. Both LPS and L-37pA colocalized with anti-CLA-1 antibody
      and directly bound CLA-1 as determined by cross-linking. SR-BI/CLA-1 ligands such
      as HDL, apoA-I, and L-37pA efficiently competed against iodinated L-37pA.
      Bacterial LPS, lipoteichoic acid, and hsp60 also competed against iodinated L
      37pA. Model peptides blocked uptake of iodinated LPS in both mock transfected and
      CLA-1-overexpressing HeLa cells. Bound and internalized Alexa-L-37pA and BODIPY
      LPS colocalized at the cell surface and perinuclear compartment. Both ligands
      were predominantly transported to the Golgi complex, colocalizing with the Golgi
      markers bovine serum albumin-ceramide, anti-Golgin97 antibody, and cholera toxin
      subunit B. A 100-fold excess of L-37pA nearly eliminated BODIPY-LPS binding and
      internalization. L-37pA and its d-amino acid analogue, D-37pA peptide were
      similarly effective in blocking LPS, Gram-positive bacterial wall component
      lipoteichoic acid and bacterial heat shock protein Gro-EL-stimulated cytokine
      secretion in THP-1 cells. In the same culture media used for the cytokine
      stimulation study, neither L-37pA nor D-37pA affected the Limulus amebocyte
      lysate activity of LPS, indicating that LPS uptake and cytokine stimulation were
      blocked independently of LPS neutralization. These results demonstrate that
      amphipathic helices of exchangeable apolipoproteins may represent a general host
      defense mechanism against inflammation.

PMID- 15199069
TI  - The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor
      trio in binding to phospholipids.
AB  - The multidomain protein Trio regulates among others neuronal outgrowth and axonal
      guidance in vertebrates and invertebrates. Trio contains two Dbl
      homology/pleckstrin homology (DH/PH) tandem domains that activate several
      RhoGTPases. Here, we present the x-ray structure of the N-terminal DH/PH,
      hereafter TrioN, refined to 1.7-A resolution. We show that the relative
      orientations of the DH and PH domains of TrioN and free Dbs are similar. However,
      this relative orientation is dissimilar to Dbs in the Dbs/Cdc42 structure. In
      vitro nucleotide exchange experiments catalyzed by TrioN show that RhoG is
      approximately 3x more efficiently exchanged than Rac and support the conclusion
      that RhoG is likely the downstream target of TrioN. Residues 54 and 69, which are
      not conserved between the two GTPases, are responsible for this specificity. Dot
      blot assay reveals that the TrioN-PH domain does not detectably bind
      phosphatidylinositol 3,4-bisphosphate, PtdIns(3,4)P(2), or other phospholipids.
      This finding is supported by our three-dimensional structure and affinity binding
      experiments. Interestingly, the presence of RhoG but not Rac or a C-terminal
      truncated RhoG mutant allows TrioN to bind PtdIns(3,4)P(2) with a micromolar
      affinity constant. We conclude the variable C-terminal basic tail of RhoG
      specifically assists the recruitment of the TrioN-PH domain to specific membrane
      bound phospholipids. Our data suggest a role for the phosphoinositide 3-kinase,
      PI 3-kinase, in modulating the Trio/RhoG signaling pathway.

PMID- 15199070
TI  - Myc-ARF (alternate reading frame) interaction inhibits the functions of Myc.
AB  - The tumor suppressor protein ARF (alternate reading frame) inhibits MDM2 to
      stabilize and activate the functions of p53. Here we provide evidence for an
      additional activity of ARF that attenuates cell cycle progression independently
      of p53 activation. We show that ARF interacts with c-Myc independently of MDM2 or
      p53. Consequently, ARF relocalizes c-Myc from the nucleoplasm to the nucleolus.
      Binding and relocalization by ARF correlate with an inhibition of the c-Myc
      activated transcription in both p53-positive and -negative cells. Using inducible
      cell lines, we show that the wild type ARF, but not a mutant, inhibits expression
      of the c-Myc-induced genes before inhibiting S phase. Moreover, ARF inhibits Myc
      induced progression into S phase in cells lacking p53 or expressing a defective
      p53, indicating that ARF inhibits the S phase stimulatory function of c-Myc
      independently of p53. Our results strongly suggest that cMyc is a bona fide
      target of ARF and that ARF attenuates c-Myc independently of the ARF-p53 axis.

PMID- 15199072
TI  - Simulation of the impact of atropisomer interconversion on plasma exposure of
      atropisomers of an endothelin receptor antagonist.
AB  - BMS-207940, a potent endothelin receptor antagonist, exists as rapidly
      interconverting atropisomers. The plasma interconversion t(1/2) is approximately
      2.5 hours at 400 microg/mL under room temperature and decreases to < 0.1 hours at
      20 microg/mL, making it extremely difficult to conduct pharmacokinetic studies of
      individual atropisomers. The pharmacokinetics of the 50/50 racemate of BMS-207940
      in humans were reasonably described by a one-compartmental model with an apparent
      terminal elimination t(1/2) of 15 hours. Given the above rates, simulations were
      conducted based on a one-compartmental model to explore the possible range of
      individual rates of atropisomer elimination and potential difference in plasma
      exposure to the two atropisomers. Simulations demonstrated that the elimination
      rates of the individual atropisomers are bounded between 0 and 0.046 h(-1) and
      between 0.046 and 0.092 h(-1), respectively. The estimation of the upper bounds
      for atropisomer elimination rate constants is robust and relatively insensitive
      to the rate of atropisomer interconversion compared to the rate of racemate
      elimination. Simulations of the administration of a single atropisomer or the
      50/50 racemate, based on all the possible scenarios of individual atropisomer
      elimination, showed little difference in plasma exposure to the two atropisomers.
      Potential differences in plasma exposure to the two atropisomers depend, to a
      larger extent, on the ratio of the rate of atropisomer interconversion versus
      racemate elimination and, to a lesser extent, on the conformation of atropisomers
      administered. When atropisomer interconversion is 10-fold or more rapid than
      racemate elimination, the largest possible difference in plasma exposure between
      the two atropisomers is below 20%, regardless of the route and conformation of
      the atropisomer(s) administered.

PMID- 15199073
TI  - Effects of a new antibacterial, telavancin, on cardiac repolarization (QTc
      interval duration) in healthy subjects.
AB  - Telavancin is a rapidly bactericidal antibiotic with multiple mechanisms of
      action against gram-positive bacteria. Preclinical and early clinical data
      suggested possible effects on cardiac repolarization requiring the conduct of a
      definitive evaluation of QT effects in healthy subjects. A total of 160 subjects
      were randomized into four groups to receive placebo (telavancin vehicle),
      telavancin at a dose of 7.5 mg/kg or 15 mg/kg, or moxifloxacin 400 mg (positive
      control). All medications were administered once daily for 3 days as 60-minute IV
      infusions. Sixteen ECGs were obtained over 24 hours following an infusion of D5W
      (baseline) and following Day 3 infusions of each medication. ECGs were analyzed
      digitally in a blinded fashion by a validated core ECG laboratory. The primary
      endpoint was QT data corrected for heart rate by the Fridericia formula (QTcF).
      Placebo-corrected mean changes in QTcF values for 7.5 mg/kg telavancin, 15 mg/kg
      telavancin, and moxifloxacin were 4.1 msec, 4.5 msec, and 9.2 msec, respectively.
      The mean change from baseline in QTcF for moxifloxacin, which served as the assay
      sensitive positive control in the study, helped to establish that telavancin had
      a minimal effect on QT prolongation. No subject had a QTcF > or = 450 msec, and
      none experienced clinically significant ECG abnormalities. The telavancin
      treatment groups were not significantly different from each other. There was no
      correlation of the magnitude of change in QTc and plasma concentrations of
      telavancin. Telavancin has a < 5-msec mean effect on cardiac repolarization, with
      a flat-dose response over a two-fold exposure range.

PMID- 15199074
TI  - Application of Bayes theorem to aminoglycoside-associated nephrotoxicity:
      comparison of extended-interval dosing, individualized pharmacokinetic
      monitoring, and multiple-daily dosing.
AB  - The objective of this study was to examine the incidence of aminoglycoside
      associated nephrotoxicity related to extended-interval dosing, individualized
      pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem.
      An electronic literature search of MEDLINE (1966-2003) and a manual search of
      references from published meta-analyses and review articles were performed.
      Studies using extended-interval dosing, individualized pharmacokinetic
      monitoring, or multiple-daily dosing and reported aminoglycoside-associated
      nephrotoxicity for patients > or = 16 years of age were included. Quality scores
      were assigned based on the rigor of definition of aminoglycoside-associated
      nephrotoxicity, duration of therapy, and length of follow-up of renal function
      after completion of therapy. Inclusion criteria were then based on these quality
      scores. Quantitative data on the incidence of aminoglycoside-associated
      nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n =
      916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27
      multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior
      probabilities of aminoglycoside-associated nephrotoxicity were derived from a
      combination of a review of published studies and expert judgment. The maximum
      densities for the final posterior probabilities of aminoglycoside-associated
      nephrotoxicity for extended-interval dosing, individualized pharmacokinetic
      monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and
      13% to 14%, respectively. Application of Bayes theorem demonstrates that
      aminoglycoside dosing by individualized pharmacokinetic monitoring results in
      less aminoglycoside-associated nephrotoxicity than extended-interval dosing or
      multiple-daily dosing.

PMID- 15199076
TI  - Moderate liver impairment has no influence on daptomycin pharmacokinetics.
AB  - Daptomycin (N-decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-L
      ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3
      anthraniloyl-L-alanine-lactone) is a novel cyclic lipopeptide antibiotic derived
      from the fermentation of Streptomyces roseosporus. Daptomycin was recently
      approved for the treatment of complicated skin and skin structure infections
      caused by aerobic gram-positive bacteria, including those caused by methicillin
      resistant and methicillin-susceptible Staphylococcus aureus. This single-dose,
      parallel-design, matched-controlled study was designed to evaluate the
      pharmacokinetics of daptomycin in subjects between ages 18 and 80 years with
      moderately impaired hepatic function (Child-Pugh Class B, n = 10). Subjects were
      administered a single intravenous dose (6 mg/kg total body weight) over 30
      minutes using a syringe pump. A normal volunteer control group matched by weight
      (+/-25 lb/11 kg), age (+/-10 years), and sex was included in this study for
      comparison to the hepatic-impaired group. The pharmacokinetic parameters of
      daptomycin were similar in both groups. Adverse events occurred only in the
      hepatic-impaired patients and were consistent with the subjects' disease state.
      In conclusion, subjects with moderate hepatic impairment receiving daptomycin do
      not require an adjustment in daptomycin dose or dose regimen.

PMID- 15199075
TI  - Comparison of various urine collection intervals for caffeine and
      dextromethorphan phenotyping in children.
AB  - Caffeine and dextromethorphan have been used successfully both alone and in
      combination to assess phenotype and enzyme activity in children of various ages.
      Previous pediatric phenotyping studies with these agents have used varying
      durations of urine collection. However, the minimum duration required for
      accurate phenotypic assessment with these compounds in children remains unknown.
      We calculated the cumulative metabolite recoveries and molar ratios in urine
      collected from children for 2, 4, 6, and 8 hours after caffeine and
      dextromethorphan administration to determine when respective urinary molar ratios
      stabilize and thus likely accurately reflect enzyme activity. Subjects (n = 24,
      ages 3-8 years) were given 4 oz of Coca-Cola(R) ( approximately 11.5 mg caffeine)
      and a single oral dose of dextromethorphan (0.5 mg/kg). Urine was collected at
      discrete intervals (0-2, 2-4, 4-6, and 6-8 h) during an 8-hour period, and the
      cumulative metabolite recoveries and urinary molar ratios were calculated. CYP2D6
      genotyping was also performed in 21 of 24 subjects. In CYP2D6 extensive
      metabolizers, the extent of recovery for relevant metabolites was equivalent by 4
      hours and represented 45% to 60% of the total amount recovered in the 8-hour
      period. The 2-hour CYP1A2 ratio was significantly different from those of longer
      collection intervals. Metabolite ratios for all other enzymes (i.e., NAT-2, XO,
      and CYP2D6) were independent of the duration of urine collection. These data
      suggest that a 4-hour urine collection is adequate for the concurrent assessment
      of hepatic CYP1A2, NAT-2, XO, and CYP2D6 activity in children ages 3 to 8 years
      who are CYP2D6 extensive metabolizers, using standard caffeine and
      dextromethorphan phenotyping methods. Longer collection periods may be required,
      however, in younger children or CYP2D6 poor metabolizers.

PMID- 15199077
TI  - Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active
      novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I
      dose escalation study.
AB  - The objective of this study was to characterize the maximum tolerated dose (MTD),
      dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF
      1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042
      was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to
      270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of
      lactone and total forms were determined using validated high-performance liquid
      chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated
      applying World Health Organization (WHO) criteria. The 1st course was used to
      determine DLT and MTD. Twenty-five patients received 73 courses of therapy.
      Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased
      approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9
      and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia
      and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs)
      were observed. In addition, 4 stable diseases were observed. The recommended
      phase II dose is 80 mg/m(2)/day.

PMID- 15199078
TI  - Absolute bioavailability and absorption characteristics of divalproex sodium
      extended-release tablets in healthy volunteers.
AB  - Conventional delayed-release, enteric-coated divalproex sodium tablet has an
      absolute bioavailability of approximately 100%. Divalproex sodium extended
      release (ER) tablet is a novel formulation of valproic acid (VPA) designed to
      release the drug slowly at a constant zero-order rate. The purpose of this study
      was to evaluate the absolute bioavailability and absorption characteristics of
      divalproex ER. Healthy adult volunteers (n = 16) received divalproex ER and
      intravenous VPA in crossover fashion. Absolute bioavailability was calculated as
      the divalproex ER/intravenous VPA ratio of area under the curve extrapolated to
      infinity. The duration and rate of absorption of VPA from divalproex ER tablets
      were determined by deconvolution analysis. The geometric mean absolute
      bioavailability of divalproex ER was 0.896. The mean (coefficient of variation)
      duration of drug absorption from divalproex ER was 21.8 (17%) hours, and the zero
      order absorption rate was 21.6 (24%) mg/h for a 500-mg tablet. Divalproex ER has
      a lower absolute bioavailability than conventional divalproex tablets but
      exhibits good extended-release characteristics without any dose dumping.

PMID- 15199079
TI  - Pharmacokinetic study of mycophenolic acid in Korean kidney transplant patients.
AB  - The purpose of this study was to characterize the pharmacokinetic parameters of
      mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA
      concentrations of 10 Korean kidney transplant recipients administered a lower
      dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks
      of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA
      concentration-time curve pattern of patients taking lower doses of MPA was
      consistent with previously reported profiles of patients taking the fully
      recommended doses. The plasma MPA concentration-time curve was characterized by
      an early sharp peak within 1 hour and a small second peak in some patients at 4
      to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and
      18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60%
      +/- 0.23%. Patients' age, weight, body surface area, and renal function did not
      influence the AUC. The free fraction of MPA appeared not to be affected by serum
      albumin and renal function when creatinine clearance was above 40 mL/min.
      Regression analysis between each plasma concentration and AUC for the limited
      sampling strategy of MMF therapeutic drug monitoring demonstrated that the
      concentrations of predose and 1- and 8-hour postdose were positively correlated
      with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p =
      0.0479, respectively). The pattern of the concentration-time profile of MPA in
      Korean kidney recipients was similar to the results of other studies performed in
      Caucasians, although there was interindividual variability of AUC, C(max), and
      t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively
      correlated with AUC.

PMID- 15199080
TI  - Effect of acute marijuana on cardiovascular function and central nervous system
      pharmacokinetics of [(15)O]water: effect in occasional and chronic users.
AB  - The objective of this study was to evaluate the effect of the acute
      administration of marijuana (MJ) on cardiovascular (CV) function and CNS
      pharmacokinetics (PK) of [(15)O]water in occasional (O) versus chronic (C) MJ
      users. Each subject received four injections of [(15)O]water (one prior and three
      postsmoking) on two occasions in which they received active or placebo MJ. For
      each injection, measures of CV function and CNS PK [(15)O]water were made.
      Postsmoking, MJ influenced all measured CV and [(15)O]water PK parameters. C
      users reported significantly lower "highness" and smaller heart rate (HR)
      changes, which resulted in reduced rate pressure product (RPP) changes compared
      to O users, even though Delta(9)-tetrahydrocannabinol levels were higher, whereas
      changes in blood pressure (BP), arrival time, and [(15)O]water concentration were
      not significantly different between the groups. Significant CV changes resulted
      in changes in the whole-body distribution of cardiac output rather than changes
      in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases
      induced by acute MJ smoking compared to changes observed in occasional users,
      without changing the effects on BP and [(15)O]water PK.

PMID- 15199081
TI  - Efficacy of oxymorphone extended release in postsurgical pain: a randomized
      clinical trial in knee arthroplasty.
AB  - Patients with moderate or severe pain following knee arthroplasty and washout
      from standard patient-controlled analgesia (PCA) were randomized to receive 20 mg
      of an extended-release (ER) oxymorphone formulation (n = 65) or placebo (n = 61)
      q12h for 1 day. Oxymorphone PCA was used as rescue analgesic. Oxymorphone ER
      provided significant improvements over placebo for most standard single-dose
      analgesic parameters, including mean total pain relief (TOTPAR) over 0 to 12
      hours (19.30 vs. 13.72; p = 0.0056), as well as for all multiple-dose (24-h)
      efficacy assessments. Oxymorphone-treated patients used significantly less rescue
      PCA than those who received placebo (p < 0.02). Adverse events such as nausea and
      constipation were typical of opioids, and laboratory and physical findings were
      similar between groups. Oxymorphone ER was effective and generally well
      tolerated. A single dose was active from 2 hours until > or = 12 hours after
      administration. Comparisons with other oral opioids are warranted, especially in
      the setting of outpatient and day surgery.

PMID- 15199082
TI  - Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and
      female volunteers.
AB  - This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor,
      interferes with the antiplatelet effect of aspirin using platelet aggregation and
      thromboxane (Tx) B(2) endpoints in healthy volunteers. Eight male and 8 female
      volunteers participated in this open-label, randomized, two-treatment, two-way
      crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then
      aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7
      days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment
      2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same
      time points. Each subject received both treatments with a 2-week washout between
      the treatment periods. Treatments were safe and well tolerated. The initial 4-day
      treatment with meloxicam had no effect on platelet aggregation but reduced serum
      TxB(2) by 64% +/- 19%. Addition of aspirin (100 mg qd) for 7 days resulted in
      complete inhibition of aggregation and TxB(2) for 24 hours. Two-day treatment
      with only 100 mg aspirin also resulted in complete inhibition of platelet
      aggregation and TxB(2). These results indicate that meloxicam does not affect the
      ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to
      effectively prevent platelet aggregation and reduce TxB(2) levels, and that
      meloxicam is selective for COX-2.

PMID- 15199083
TI  - The differential effects of steady-state fluvoxamine on the pharmacokinetics of
      olanzapine and clozapine in healthy volunteers.
AB  - The combination of atypical antipsychotics and selective serotonin reuptake
      inhibitors is an effective strategy in the treatment of certain psychiatric
      disorders. However, pharmacokinetic interactions between the two classes of drugs
      remain to be explored. The present study was designed to determine whether there
      were different effects of steady-state fluvoxamine on the pharmacokinetics of a
      single dose of olanzapine and clozapine in healthy male volunteers. One single
      dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally.
      Following a drug washout of at least 4 weeks, all subjects received fluvoxamine
      (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was
      added on day 4. Plasma concentrations of olanzapine, clozapine, and N
      desmethylclozapine were assayed at serial time points after the antipsychotics
      were given alone and when added to fluvoxamine. No bioequivalence was found in
      olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma
      concentration (C(max)), the area under the concentration-time curve from time 0
      to last sampling time point (AUC(0-t)), and from time 0 to infinity (AUC(0-
      infinity )). Under the cotreatment, C(max) of olanzapine was significantly
      elevated by 49%, with a 32% reduced time (t(max)) to C(max), whereas the C(max)
      and t(max) of clozapine were unaltered. The cotreatment increased the AUC(0-t)
      and AUC(0- infinity ) of olanzapine by 68% and 76%, respectively, greater than
      those of clozapine (40% and 41%). The presence of fluvoxamine also prolonged the
      elimination half-life (t(1/2)) of olanzapine by 40% and, to a much greater
      extent, clozapine by 370% but reduced the total body clearance (CL/F) of
      clozapine (78%) more significantly than it did for olanzapine (42%). The apparent
      volume of distribution (V(d)) was suppressed by 31% in olanzapine combined with
      fluvoxamine but was unaltered in the clozapine regimen. A significant reduction
      in the N-desmethylclozapine to clozapine ratio was present in the clozapine with
      fluvoxamine regimen. The effects of fluvoxamine on different aspects of
      pharmacokinetics of the two antipsychotics may have implications for clinical
      therapeutics.

PMID- 15199084
TI  - Lack of interaction between enfuvirtide and ritonavir or ritonavir-boosted
      saquinavir in HIV-1-infected patients.
AB  - Enfuvirtide (Fuzeon) is an HIV fusion inhibitor, the first drug in a new class of
      antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both
      inhibit cytochrome P450 (CYP450) isoenzymes, and low-dose ritonavir is often used
      to boost pharmacokinetic exposure to full-dose protease inhibitors. These two
      studies were designed to assess whether ritonavir and ritonavir-boosted
      saquinavir influence the steady-state pharmacokinetics of enfuvirtide. Both
      studies were single-center, open-label, one-sequence crossover clinical
      pharmacology studies in 12 HIV-1-infected patients each. Patients received
      enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and
      either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir
      (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7.
      Serial blood samples were collected up to 24 hours after the morning dose of
      enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide
      metabolite, saquinavir, and ritonavir were measured using validated liquid
      chromatography tandem mass spectrometry methods. Efficacy and safety were also
      monitored. Bioequivalence criteria require the 90% confidence interval (CI) for
      the least squares means (LSM) of C(max) and AUC(12h) to be between 80% and 125%.
      In the present studies, analysis of variance showed that when coadministered with
      ritonavir, the ratio of LSM for enfuvirtide was 124% for C(max) (90% confidence
      interval [CI]: 109%-141%), 122% for AUC(12h) (90% CI: 108%-137%), and 114% for
      C(trough) (90% CI: 102%-128%). Although the bioequivalence criteria were not met,
      the increase in enfuvirtide exposure was small (< 25%) and not clinically
      relevant. When administered with ritonavir-boosted saquinavir, the ratio of LSM
      for enfuvirtide was 107% for C(max) (90% CI: 94.3%-121%) and 114% for AUC(12h)
      (90% CI: 105%-124%), which therefore met bioequivalence criteria, and 126% for
      C(trough) (90% CI: 117%-135%). The pharmacokinetics of enfuvirtide are affected
      to a small extent when coadministered with ritonavir at a dose of 200 mg bid but
      not when coadministered with a saquinavir-ritonavir combination (1000/100 mg
      bid). However, previous clinical studies have shown that such increases in
      enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are
      warranted when enfuvirtide is coadministered with low-dose ritonavir or
      saquinavir boosted with a low dose of ritonavir.

PMID- 15199085
TI  - Understanding surgeon performance and improving patient outcomes.

PMID- 15199086
TI  - Lymphadenectomy for gastric cancer.

PMID- 15199087
TI  - Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer
      Care Ontario Program in evidence-based care's gastrointestinal cancer disease
      site group.
AB  - PURPOSE: To develop a systematic review that would address the following
      question: Should patients with stage II colon cancer receive adjuvant therapy?
      METHODS: A systematic review was undertaken to locate randomized controlled
      trials comparing adjuvant therapy to observation. RESULTS: Thirty-seven trials
      and 11 meta-analyses were included. The evidence for stage II colon cancer comes
      primarily from a trial of fluorouracil plus levamisole and a meta-analysis of
      1,016 patients comparing fluorouracil plus folinic acid versus observation.
      Neither detected an improvement in disease-free or overall survival for adjuvant
      therapy. A recent pooled analysis of data from seven trials observed a benefit
      for adjuvant therapy in a multivariate analysis for both disease-free and overall
      survival. The disease-free survival benefits appeared to extend to stage II
      patients; however, no P values were provided. A meta-analysis of chemotherapy by
      portal vein infusion has also shown a benefit in disease-free and overall
      survival for stage II patients. A meta-analysis was conducted using data on stage
      II patients where data were available (n = 4,187). The mortality risk ratio was
      0.87 (95% CI, 0.75 to 1.01; P =.07). CONCLUSION: There is preliminary evidence
      indicating that adjuvant therapy is associated with a disease-free survival
      benefit for patients with stage II colon cancer. These benefits are small and not
      necessarily associated with improved overall survival. Patients should be made
      aware of these results and encouraged to participate in active clinical trials.
      Additional investigation of newer therapies and more mature data from the
      presently available trials should be pursued.

PMID- 15199088
TI  - Does the who and how of surgery in bladder cancer matter?

PMID- 15199089
TI  - American Society of Clinical Oncology recommendations on adjuvant chemotherapy
      for stage II colon cancer.
AB  - PURPOSE: To address whether all medically fit patients with curatively resected
      stage II colon cancer should be offered adjuvant chemotherapy as part of routine
      clinical practice, to identify patients with poor prognosis characteristics, and
      to describe strategies for oncologists to use to discuss adjuvant chemotherapy in
      practice. METHODS: An American Society of Clinical Oncology Panel, in
      collaboration with the Cancer Care Ontario Practice Guideline Initiative,
      reviewed pertinent information from the literature through May 2003. RESULTS: A
      literature-based meta-analysis found no evidence of a statistically significant
      survival benefit of adjuvant chemotherapy for stage II patients. Recommendations
      The routine use of adjuvant chemotherapy for medically fit patients with stage II
      colon cancer is not recommended. However, there are populations of patients with
      stage II disease that could be considered for adjuvant therapy, including
      patients with inadequately sampled nodes, T4 lesions, perforation, or poorly
      differentiated histology. CONCLUSION: Direct evidence from randomized controlled
      trials does not support the routine use of adjuvant chemotherapy for patients
      with stage II colon cancer. Patients and oncologists who accept the relative
      benefit in stage III disease as adequate indirect evidence of benefit for stage
      II disease are justified in considering the use of adjuvant chemotherapy,
      particularly for those patients with high-risk stage II disease. The ultimate
      clinical decision should be based on discussions with the patient about the
      nature of the evidence supporting treatment, the anticipated morbidity of
      treatment, the presence of high-risk prognostic features on individual prognosis,
      and patient preferences. Patients with stage II disease should be encouraged to
      participate in randomized trials.

PMID- 15199090
TI  - Gastric cancer surgery: morbidity and mortality results from a prospective
      randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy
      -Japan Clinical Oncology Group study 9501.
AB  - PURPOSE: Radical gastrectomy with regional lymphadenectomy is the only curative
      treatment option for gastric cancer. The extent of lymphadenectomy, however, is
      controversial. The two European randomized trials only reported an increase in
      operative morbidity and mortality, but failed to show survival benefit, in the D2
      lymphadenectomy group. We conducted a randomized controlled trial to compare the
      Japanese standard D2 and D2 + para-aortic nodal dissection. PATIENTS AND METHODS:
      Only experienced surgeons in both procedures from 24 Japanese institutions
      participated in the study. Patients with potentially curable gastric
      adenocarcinoma (T2-subserosa, T3, or T4) who were surgically fit were
      intraoperatively randomized. Postoperative morbidity and hospital mortality were
      recorded prospectively in a fixed format and were compared between the two groups
      in this study. RESULTS: A total of 523 patients were randomized between July 1995
      and April 2001. Postoperative complications were reported in 24.5% of all
      patients. Although the morbidity for the extended surgery group (28.1%) was
      slightly higher than the standard group (20.9%), there was no difference in the
      incidence of four major complications (anastomotic leak, pancreatic fistula,
      abdominal abscess, pneumonia) between the two groups. Hospital mortality was
      reported at 0.80%: one patient in each group died of operative complications,
      while one from each group died of rapid progressive cancer while inpatient.
      CONCLUSION: Specialized surgeons could safely perform gastrectomy with D2
      lymphadenectomy in patients with low operative risks. Para-aortic lymphadenectomy
      could be added without increasing major surgical complications in this setting.

PMID- 15199091
TI  - Surgical factors influence bladder cancer outcomes: a cooperative group report.
AB  - PURPOSE: A randomized, cooperative group trial (Southwest Oncology Group 8710,
      Intergroup 0080) reported that neoadjuvant chemotherapy improved the survival of
      patients with locally advanced bladder cancer who were treated with radical
      cystectomy. We evaluated whether surgical factors from patients enrolled onto the
      study predicted bladder cancer outcomes. PATIENTS AND METHODS: Surgical and tumor
      factors were recorded from surgical and pathologic reports from 268 patients with
      muscle-invasive bladder cancer who received radical cystectomy. Cystectomies were
      performed by 106 surgeons in 109 institutions. Half of the patients received
      neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)
      chemotherapy. Variables were tested in univariate and multivariate analyses for
      associations with postcystectomy survival (PCS) and local recurrence (LR) in all
      patients receiving cystectomy. RESULTS: Five-year PCS and LR rates were 54% and
      15%, respectively. A multivariate model adjusted for MVAC (P =.97), age (P =.03),
      pathologic stage (P =.0002), and node status (P =.04) showed that surgical
      variables associated with longer PCS were negative margins (v positive; hazard
      ratio [HR], 0.37; P =.0007), and > or = 10 nodes removed (v < 10; HR, 0.51; P
      =.0001). These associations did not differ by treatment arms (P >.21 for all
      tests of interactions between treatment and surgical variables). Predictors of LR
      in a multivariate model adjusted for MVAC (P =.16), pathologic stage (P =.02),
      and node status (P =.37) were positive margins (v negative; odds ratio [OR],
      11.2; P =.0001) and fewer than 10 nodes removed (v > or = 10; OR, 5.1; P =.002).
      CONCLUSION: Surgical factors influence bladder cancer outcomes after cystectomy,
      after adjustment for pathologic factors and neoadjuvant chemotherapy usage.

PMID- 15199092
TI  - ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage
      Hodgkin's disease: long-term results.
AB  - PURPOSE: Radiation therapy (RT) alone can cure more than 80% of all patients with
      pathologic stage IA, IB, and IIA Hodgkin's disease, but some prognostic factors
      unfavorably affect treatment outcome. Combined-modality approaches improved
      results compared with RT, but the optimal extent of RT fields when combined with
      chemotherapy warranted additional evaluation. PATIENTS AND METHODS: In February
      1990, we activated a prospective trial in patients with early, clinically staged
      Hodgkin's disease to assess efficacy and tolerability of four cycles of
      doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by either
      subtotal nodal plus spleen irradiation (STNI) or involved-field radiotherapy
      (IFRT). RESULTS: Main patient characteristics were fairly well balanced between
      the two arms. Complete remission was achieved in 100% and in 97% of patients,
      respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to
      100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT,
      whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94%
      (95% CI, 89% to 100%), respectively. Apart from three patients who developed
      second malignancies in the STNI arm, treatment-related morbidities were mild.
      CONCLUSION: Present long-term findings suggest that, after four cycles of ABVD,
      IFRT can achieve a worthwhile outcome. The limited size of our patient sample,
      however, had no adequate statistical power to test for noninferiority of IFRT
      versus STNI. Despite this, ABVD followed by IFRT can be considered an effective
      and safe modality in early Hodgkin's disease with both favorable and unfavorable
      presentation.

PMID- 15199093
TI  - Proteinase-activated receptor-2-mediated relaxation in mouse tracheal and
      bronchial smooth muscle: signal transduction mechanisms and distinct agonist
      sensitivity.
AB  - We characterized the tracheal and bronchial relaxation caused by proteinase
      activated receptor-2 (PAR-2) activation in ddY mice and/or in wild-type and PAR-2
      knockout mice of C57BL/6 background. Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2))
      and Thr-Phe-Leu-Leu-Arg-amide, PAR-2- and PAR-1-activating peptides,
      respectively, caused relaxation in the isolated ddY mouse trachea and main
      bronchus. The relaxation was abolished by specific inhibitors of cyclooxygenase
      (COX)-1, COX-2, mitogen-activated protein kinase kinase (MEK), and p38 MAP
      kinase. The MEK and p38 MAP kinase inhibitors did not affect prostaglandin E(2)
      induced relaxation. Inhibitors of cytosolic Ca(2+)-dependent phospholipase A(2)
      (PLA), Ca(2+)-independent PLA(2), diacylglycerol lipase, tyrosine kinase, and
      protein kinase C exhibited no or only minor inhibitory effects on the PAR
      mediated relaxation. Trypsin, a PAR-2 activator, and 2-furoyl-Leu-Ile-Gly-Arg-Leu
      amide, a potent PAR-2-activating peptide, in addition to SLIGRL-NH(2), caused
      airway relaxation in wild-type C57BL/6 mice, as in ddY mice. In PAR-2-knockout
      mice, the peptide effects were absent and the potency of trypsin decreased.
      Desensitization of PAR-2 and/or PAR-1 greatly suppressed the relaxant effect of
      trypsin. The bronchial and tracheal tissues displayed distinct sensitivities
      toward trypsin and the PAR-2-activating peptides. Our data indicate an
      involvement of both COX-1 and COX-2, and the MEK-extracellular signal-regulated
      kinase and p38 MAP kinase signaling pathways in the PAR-2- and PAR-1-triggered
      relaxation of mouse airway tissue, and substantiate a role for PAR-2 in
      regulating both the trachea and bronchial responsiveness in the mouse lung.

PMID- 15199094
TI  - Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine
      derivatives.
AB  - Overexpression of the epidermal growth factor receptors (EGFRs) and human
      epidermal growth factor receptor 2 occurs frequently in human cancers and is
      associated with aggressive tumor behavior and poor patient prognosis. We have
      investigated the effects in vitro and in vivo of a new class of inhibitor
      molecules on the growth of several human cancer cell lines. BIBX1382 [N8-(3
      chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine
      2,8-diamine] and BIBU1361 [(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl
      piperidin-1yl)-pyrimido[5,4-d]pyrimidin-4-yl]-amine] are two new selective EGFR
      kinase inhibitors that do not block the activity of other tyrosine kinases.
      BIBU1361 blocked epidermal growth factor-induced phosphorylation of EGFR and also
      prevented downstream responses such as mitogen-activated protein kinase kinase
      (MAPK/extracellular signal-regulated kinase kinase) and MAPK activation in cells.
      In accordance with these observations thymidine incorporation into EGFR
      expressing KB cells was selectively and potently inhibited by BIBX1382 and
      BIBU1361 with half-maximally effective doses in the nanomolar range. Oral
      administration of these compounds inhibited the growth of established human
      xenografts in athymic mice, including vulval and head and neck squamous cell
      carcinomas. Tumor growth inhibition by BIBX1382 coincided with reduced pEGFR and
      Ki-67 levels in vivo, which is in accordance with the expected effect of EGFR
      inhibitors. Collectively, these results show that the structural class of
      pyrimidopyrimidines, exemplified here by BIBX1382 and BIBU1361, represents an
      interesting scaffold for the design of EGFR inhibitors.

PMID- 15199095
TI  - Exendin-4 pharmacodynamics: insights from the hyperglycemic clamp technique.
AB  - The purpose of this study is to ascertain the pharmacodynamic properties of
      exendin-4, a glucose-dependent insulinotropic agent, from plasma glucose and
      insulin concentration-time profiles following a 60-min intravenous infusion in
      healthy and type 2 diabetic subjects. Plasma glucose and insulin concentrations
      were obtained from a previous clinical study, whereby a hyperglycemic clamp was
      established and maintained in healthy (n = 7) and type 2 diabetic (n = 7)
      volunteers (plasma glucose raised 5.4 mM above fasting level). Exendin-4 was
      infused (0.15 pmol/kg/min) during the 2nd hour of a 5-h clamp. A physiological
      pharmacodynamic model was developed and fitted to individual glucose and insulin
      responses simultaneously. Because drug concentrations were unavailable,
      hypothetical pharmacokinetic driving functions were approximated during the
      modeling process and used to enhance a proportionality constant relating elevated
      glucose and the rate of second-phase insulin release. Exendin-4 infusions
      produced substantial insulin release in both subject populations that required
      higher glucose infusion rates to maintain stable hyperglycemia. Observed plasma
      glucose-insulin profiles were well characterized by the final pharmacodynamic
      model. Apparent exendin-4 elimination rate constants for healthy and diabetic
      subjects were similar (0.0386 +/- 0.0192 and 0.0460 +/- 0.0145 min(-1)). Capacity
      and sensitivity parameters of drug effect were 2-fold lower in diabetic subjects,
      but mean differences were not statistically significant. Simulations confirm that
      diabetic subjects exhibit a reduced capacity to enhance second-phase insulin
      release in response to exendin-4 compared with healthy subjects. Type 2 diabetic
      subjects demonstrate a significant response to exendin-4, but to a lesser extent
      than nondiabetic subjects, despite comparable measures of apparent drug exposure
      and efficacy.

PMID- 15199096
TI  - Regeneration of skeletal muscle from transplanted immortalised myoblasts is
      oligoclonal.
AB  - Myoblasts transplanted into muscles of recipient mice mostly die, only a minor
      stem cell-like subpopulation surviving and participating in muscle regeneration.
      To investigate this phenomenon further, we used a retrovirus expressing beta
      galactosidase to provide a unique marker for satellite-cell-derived muscle
      precursor cells, before transplanting them into myopathic mdx nu/nu mouse muscle.
      We employed inverse polymerase chain reaction to identify viral integrations, to
      follow the fate of clones present within the injected cells. Mass-infected
      cultures contained many marked clones, some of which contributed
      disproportionately to muscle regeneration. Although no particular clones showed
      overall predominance, some were present in more than one injected muscle, an
      eventuality unlikely to arise by chance. Conversely, in grafts of muscle
      precursor cells that had either been labelled as sparse satellite-cell derived
      cultures, or had been cloned, all clones were shown to be able to survive and
      form muscle in vivo. Moreover, all clones contributed to further generations of
      new-formed muscle fibres following a series of injuries administered to injected
      muscles, demonstrating that some cells of each clone had been retained as stem
      cell-like muscle precursors. Furthermore, retrovirally marked satellite-cell
      derived clones were derived from muscles that had been injected with marked
      muscle precursor cells. These cells formed muscle following their transplantation
      into a new host mouse, confirming their stem cell properties.

PMID- 15199097
TI  - Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like
      protein CHO1/MKLP-1.
AB  - Polo-like kinases and kinesin-like motor proteins are among the many proteins
      implicated in the execution of cytokinesis. Polo-like-kinase 1 (Plk1) interacts
      with the mitotic kinesin-like motor protein CHO1/MKLP-1 during anaphase and
      telophase, and CHO1/MKLP-1 is a Plk1 substrate in vitro. Here, we explore the
      molecular interactions of these two key contributors to mitosis and cytokinesis.
      Using the transient transfection approach, we show that the C-terminus of Plk1
      binds CHO1/MKLP-1 in a Polo-box-dependent manner and that the stalk domain of
      CHO1/MKLP-1 is responsible for its binding to Plk1. The stalk domain was found to
      localize with Plk1 to the mid-body, and Plk1 appears to be mislocalized in
      CHO1/MKLP-1-depleted cells during late mitosis. We showed that Ser904 and Ser905
      are two major Plk1 phosphorylation sites. Using the vector-based RNA interference
      approach, we showed that depletion of CHO1/MKLP-1 causes the formation of
      multinucleate cells with more centrosomes, probably because of a defect in the
      early phase of cytokinesis. Overexpression of a non-Plk1-phosphorylatable CHO1
      mutant caused cytokinesis defects, presumably because of dominant negative effect
      of the construct. Finally, CHO1-depletion-induced multinucleation could be
      partially rescued by co-transfection of a non-degradable hamster wild-type CHO1
      construct, but not an unphosphorylatable mutant. These data provide more detailed
      information about the interaction between Plk1 and CHO1/MKLP-1, and the
      significance of this is discussed.

PMID- 15199098
TI  - Crosslinking and G-protein functions of transglutaminase 2 contribute
      differentially to fibroblast wound healing responses.
AB  - Tissue transglutaminase (TG2) affects cell-matrix interactions in cell spreading,
      migration and extracellular matrix (ECM) reorganisation. Using fibroblasts
      deficient in TG2 or overexpressing normal or crosslinking-deficient enzyme, we
      show that the extracellular crosslinking activity and intracellular G-protein
      function in signal transduction contribute differentially to regulation of cell
      matrix interactions. TG2-deficient cells displayed normal attachment but delayed
      spreading on ECM substrata and defects in motility unrelated to crosslinking.
      Blocking antibodies to TG2 failed to induce similar defects in normal
      fibroblasts. TG2-deficient fibroblasts had defects in focal adhesion turnover and
      stress fibre formation, showed changes in focal adhesion kinase (FAK)
      phosphorylation and failed to activate protein kinase C alpha (PKCalpha).
      Phospholipase C (PLC) and PKCalpha inhibitors blocked spreading of normal
      fibroblasts whilst PKC activators induced spreading in TG2-deficient cells. In
      contrast, ECM remodelling was not only compromised by TG2 deficiency but also by
      overexpression of dominant negative enzyme and TG inhibitors. TG2 activity
      increased matrix tension and was required for membrane type 1-MMP (MT1-MMP)
      dependent activation of MMP-2. Our results demonstrate that TG2 is involved in
      the control of dynamic adhesion formation in cell spreading and migration via
      regulation of phospholipase C activity. By virtue of its crosslinking activity,
      the enzyme plays a central role in regulating ECM remodelling.

PMID- 15199099
TI  - Redox state regulates HIF-1alpha and its DNA binding and phosphorylation in
      salmonid cells.
AB  - Rainbow trout (Oncorhynchus mykiss) hypoxia-inducible factor-1 (HIF-1) is a
      heterodimeric transcription factor structurally similar to mammalian HIF-1. It
      consists of HIF-1alpha and HIF-1beta subunits, of which the HIF-1alpha subunit
      confers the hypoxia sensitivity. HIF-1alpha is rapidly degraded by a proteasome
      under normal oxygen (21% O2) conditions, mainly as a result of prolyl
      hydroxylation needed for protein destabilization. Although prolyl hydroxylation
      at conserved proline residues is a major factor controlling HIF-1alpha stability,
      the redox state of the cells may, in addition, influence the function of HIF
      1alpha like proteins by influencing their stability, DNA binding and
      phosphorylation. Sensitivity of the protein to oxidation/reduction may be due to
      cysteine residues at critical positions. The predicted amino acid sequence of
      rainbow trout HIF-1alpha contains several unique cysteine residues, notably in
      the DNA-binding area at position 28 and in the transactivation domain of the
      molecule in the vicinity of the conserved proline residue at position 564 of
      mammalian HIF-1alpha. In the present studies we have investigated if the redox
      state influences HIF-1alpha stability, DNA binding and phosphorylation in two
      established salmonid cell lines RTG-2 and CHSE-214. The results indicate that
      reducing conditions, achieved using N-propylgallate (nPG) or N-acetylcysteine
      (NAC), stabilize HIF-1alpha, facilitate its DNA binding, and increase its
      phosphorylation even under normal oxygen conditions. On the other hand, oxidizing
      conditions, achieved using L-buthionine sulfoximine (BSO) dampen the hypoxia
      response. Furthermore, the hypoxia-like effect of cobalt is increased in the
      presence of the reducing agent. On the basis of these results, we suggest that
      redox state influences the accessibility of the conserved prolyl residues to
      oxygen-dependent hydroxylation and the accessibility of the residues involved in
      the phosphorylation of HIF-1alpha.

PMID- 15199100
TI  - Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate
      filament and sarcomeric M-line maintenance in striated muscle development.
AB  - The efficient functioning of striated muscle is dependent upon the structure of
      several cytoskeletal networks including myofibrils, microtubules, and
      intermediate filaments. However, little is known about how these networks
      function together during muscle differentiation and maintenance. In vitro studies
      suggest that members of the muscle-specific RING finger protein family (MURF-1,
      2, and 3) act as cytoskeletal adaptors and signaling molecules by associating
      with myofibril components (including the giant protein, titin), microtubules
      and/or nuclear factors. We investigated the role of MURF-2, the least
      characterized family member, in primary cultures of embryonic chick skeletal and
      cardiac myocytes. MURF-2 is detected as two species (approximately 55 kDa and
      approximately 60 kDa) in embryonic muscle, which are down-regulated in adult
      muscle. Although predominantly located diffusely in the cytoplasm, MURF-2 also
      colocalizes with a sub-group of microtubules and the M-line region of titin.
      Reducing MURF-2 levels in cardiac myocytes using antisense oligonucleotides
      perturbed the structure of stable microtubule populations, the intermediate
      filament proteins desmin and vimentin, and the sarcomeric M-line region. In
      contrast, other sarcomeric regions and dynamic microtubules remained unaffected.
      MURF-2 knock-down studies in skeletal myoblasts also delayed myoblast fusion and
      myofibrillogenesis. Furthermore, contractile activity was also affected. We
      speculate that some of the roles of MURF-2 are modulated via titin-based
      mechanisms.

PMID- 15199101
TI  - Advancing the calcium-colorectal cancer hypothesis.

PMID- 15199102
TI  - Tamoxifen: Dr. Jekyll and Mr. Hyde?

PMID- 15199103
TI  - New studies fan controversy over gender risk in lung cancer.

PMID- 15199104
TI  - United States signs international tobacco treaty.

PMID- 15199105
TI  - Lung cancer screening for all? Not yet, panel says.

PMID- 15199106
TI  - Puerto Rican government offers support for country's cancer center.

PMID- 15199107
TI  - Stat bite: Lifetime probability among males of dying of cancer.

PMID- 15199108
TI  - Next generation of targeted radiotherapy drugs emerging from the clinical
      pipeline.

PMID- 15199110
TI  - Ductal carcinoma in situ, complexities and challenges.
AB  - The incidence of ductal carcinoma in situ (DCIS), a noninvasive form of breast
      cancer, has increased markedly in recent decades, and DCIS now accounts for
      approximately 20% of breast cancers diagnosed by mammography. Laboratory and
      patient data suggest that DCIS is a precursor lesion for invasive cancer. The
      appropriate classification of DCIS has provoked much debate; a number of
      classification systems have been developed, but there is a lack of uniformity in
      the diagnosis and prognostication of this disease. Further investigation of
      molecular markers should improve the classification of DCIS and our understanding
      of its relationship to invasive disease. Controversy also exists with regard to
      the optimal management of DCIS patients. In the past, mastectomy was the primary
      treatment for patients with DCIS, but as with invasive cancer, breast-conserving
      surgery has become the standard approach. Three randomized trials have reported a
      statistically significant decrease in the risk of recurrence with radiation
      therapy in combination with lumpectomy compared with lumpectomy alone, but there
      was no survival advantage with the addition of radiotherapy. Two randomized
      trials have suggested an additional benefit, in terms of recurrence, with the
      addition of adjuvant tamoxifen therapy, although in one trial the benefit was not
      statistically significant. Current data suggest that tamoxifen use should be
      restricted to patients with estrogen receptor-positive DCIS. Neither trial
      demonstrated a survival benefit with adjuvant tamoxifen. Ongoing and recently
      completed studies should provide information on outcomes in patients treated with
      lumpectomy alone and on the effectiveness of aromatase inhibitors as an
      alternative to tamoxifen.

PMID- 15199111
TI  - Effect of calcium supplementation on the risk of large bowel polyps.
AB  - BACKGROUND: Clinical trials have shown that calcium supplementation modestly
      decreases the risk of colorectal adenomas. However, few studies have examined the
      effect of calcium on the risk of different types of colorectal lesions or dietary
      determinants of this effect. METHODS: Our analysis used patients from the Calcium
      Polyp Prevention Study, a randomized, double-blind, placebo-controlled
      chemoprevention trial among patients with a recent colorectal adenoma. Nine
      hundred thirty patients were randomly assigned to calcium carbonate (1200 mg/day)
      or placebo. Follow-up colonoscopies were conducted approximately 1 and 4 years
      after the qualifying examination. We used general estimating equation (GEE) and
      generalized linear regression analyses to compute risk ratios and 95% confidence
      intervals (CIs) to assess the effect of calcium treatment versus placebo on the
      risk of hyperplastic polyps, tubular adenomas, and more advanced lesions.
      Additionally, we used GEE analyses to compare the calcium treatment effects for
      various types of polyps with that for tubular adenomas. We also examined the
      interaction between calcium treatment and baseline intake of dietary calcium,
      fat, and fiber. All P values were obtained using Wald tests based on the
      corresponding models. All tests of statistical significance were two-sided.
      RESULTS: The calcium risk ratio for hyperplastic polyps was 0.82 (95% CI = 0.67
      to 1.00), that for tubular adenomas was 0.89 (95% CI = 0.77 to 1.03), and that
      for histologically advanced neoplasms was 0.65 (95% CI = 0.46 to 0.93) compared
      with patients assigned to placebo. There were no statistically significant
      differences between the risk ratio for tubular adenomas and that for other types
      of polyps. The effect of calcium supplementation on adenoma risk was most
      pronounced among individuals with high dietary intakes of calcium and fiber and
      with low intake of fat, but the interactions were not statistically significant.
      CONCLUSION: Our results suggest that calcium supplementation may have a more
      pronounced antineoplastic effect on advanced colorectal lesions than on other
      types of polyps.

PMID- 15199112
TI  - Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross
      talk in ER/HER2-positive breast cancer.
AB  - BACKGROUND: Patients receiving adjuvant tamoxifen whose tumors express high
      levels of both HER2/neu (HER2) and the estrogen receptor (ER) coactivator AIB1
      often develop tamoxifen resistance. We used a breast cancer model system with
      high expression of AIB1 and HER2 to investigate the possible mechanisms
      underlying this resistance. METHODS: MCF-7 breast cancer cells, which express
      high levels of AIB1, and a tamoxifen-resistant derivative cell line engineered to
      overexpress HER2 (MCF-7/HER2-18) were treated with estrogen, tamoxifen, epidermal
      growth factor (EGF), or heregulin in the absence or presence of the EGF receptor
      (EGFR) tyrosine kinase inhibitor gefitinib. We analyzed phosphorylation of
      signaling intermediates by immunoblotting, ER transcriptional activity with
      reporter gene constructs and immunoblot analysis of endogenous gene products,
      promoter assembly by chromatin immunoprecipitation (ChIP) assay, and tumor cell
      growth in vitro by anchorage-independent colony formation and in vivo using
      xenografts in nude mice. RESULTS: MCF-7/HER2-18 tumors were completely growth
      inhibited by estrogen deprivation but were growth stimulated by tamoxifen.
      Molecular cross-talk between the ER and HER2 pathways was increased in the MCF
      7/HER-2 cells compared with MCF-7 cells, with cross-phosphorylation and
      activation of both the ER and the EGFR/HER2 receptors, the signaling molecules
      AKT and ERK 1,2 mitogen-activated protein kinase (MAPK), and AIB1 itself with
      both estrogen and tamoxifen treatment. Tamoxifen recruited coactivator complexes
      (ER, AIB1, CBP, p300) to the ER-regulated pS2 gene promoter in MCF-7/HER2-18
      cells and corepressor complexes (NCoR, histone deacetylase 3) in MCF-7 cells.
      Gefitinib pretreatment blocked receptor cross-talk, reestablished corepressor
      complexes with tamoxifen-bound ER on target gene promoters, eliminated
      tamoxifen's agonist effects, and restored its antitumor activity both in vitro
      and in vivo in MCF-7/HER2-18 cells. CONCLUSIONS: Tamoxifen behaves as an estrogen
      agonist in breast cancer cells that express high levels of AIB1 and HER2,
      resulting in de novo resistance. Gefitinib's ability to eliminate this cross-talk
      and to restore tamoxifen's antitumor effects should be tested in the clinic.

PMID- 15199114
TI  - Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth,
      angiogenesis, and vessel maturation.
AB  - BACKGROUND: Hypoxia-inducible factor 1 (HIF-1), a heterodimer comprising the
      oxygen-regulated subunit, HIF-1alpha, and HIF-1beta, mediates transcription of
      the gene for vascular endothelial growth factor (VEGF). Overexpression of HIF
      1alpha is associated with tumor angiogenesis and tumor cell proliferation and
      invasion. We examined the effects of inhibiting HIF-1alpha activity on
      angiogenesis and human gastric cancer growth in vivo. METHODS: Human gastric
      cancer TMK-1 cells were stably transfected with pHIF-1alphaDN, an expression
      plasmid encoding a dominant-negative form of HIF-1alpha that dimerizes with
      endogenous HIF-1beta to produce HIF-1 complexes that cannot activate
      transcription, or with the empty expression vector (pCEP4). Two clones of pHIF
      1alphaDN-transfected cells, DN2 and DN3, were tested in all experiments. We used
      an enzyme-linked immunosorbent assay to measure VEGF secretion by transfected
      cells cultured in hypoxic (1% O2) or nonhypoxic (20% O2) conditions. We used
      subcutaneous and orthotopic mouse tumor models to examine the growth of tumors
      derived from injected pHIF-1alphaDN-or pCEP4-transfected cells. Tumor cell
      proliferation, vessel area (a measure of functional vascular volume), and tumor
      endothelial cell association with pericyte-like cells (a measure of vessel
      maturation) were analyzed by immunohistochemical or immunofluorescent staining.
      All statistical tests were two-sided. RESULTS: DN2 cells and DN3 cells secreted
      less VEGF than pCEP4-transfected TMK-1 cells when cultured in nonhypoxic or
      hypoxic conditions (e.g., DN2 versus pCEP4 in nonhypoxic conditions: 645 pg of
      VEGF/10(6) cells versus 1591 pg of VEGF/10(6) cells, difference = 946 pg of
      VEGF/10(6) cells [95% confidence interval [CI] = 640 to 1251 pg of VEGF/10(6)
      cells; P =.006]; DN2 versus pCEP4 in hypoxic conditions: 785 pg of VEGF/10(6)
      cells versus 2807 pg of VEGF/10(6) cells, difference = 2022 pg of VEGF/10(6)
      cells [95% CI = 1871 to 2152 pg of VEGF/10(6) cells; P<.001]). In the
      subcutaneous tumor model, tumors derived from DN2 or DN3 cells had lower final
      volumes, weights, and vessel areas, less tumor endothelial cell association with
      desmin-positive cells, and fewer proliferating tumor cells than tumors derived
      from pCEP4-transfected cells. In the orthotopic tumor model, tumors derived from
      DN2 cells had smaller volumes and less vessel area and maturation than tumors
      derived from pCEP4-transfected cells. CONCLUSIONS: Inhibition of HIF-1alpha
      activity impairs gastric tumor growth, angiogenesis, and vessel maturation.

PMID- 15199113
TI  - Polymorphisms associated with circulating sex hormone levels in postmenopausal
      women.
AB  - BACKGROUND: Reports suggest a relationship between circulating sex hormone levels
      and breast cancer risk, but genetic association studies have been inconclusive.
      We investigated the association between levels of sex hormones and single
      nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate
      them. METHODS: We assayed circulating levels of estradiol, testosterone, estrone,
      androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin
      (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19,
      EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal
      women and in a breast cancer case-control study. Associations of genotypes with
      breast cancer risk were evaluated in the case-control study and with hormone
      levels in the postmenopausal women using multiple linear regression with assay
      batch, body mass index, parity, peri- or postmenopausal status, and age band as
      covariates. RESULTS: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with
      differences in estradiol level (P =.0006 and P =.0003, respectively) and the
      estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained
      1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5'
      untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels
      (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P
      =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels,
      respectively. SNPs in the other genes were not associated with differences in any
      hormone levels, and none were statistically significantly associated with breast
      cancer risk. CONCLUSION: Genetic variation in CYP19 and SHBG contributes to
      variance in circulating hormone levels between postmenopausal women, but low r2
      values may explain why these genes have given inconclusive results in breast
      cancer case-control studies.

PMID- 15199115
TI  - Bone sialoprotein, matrix metalloproteinase 2, and alpha(v)beta3 integrin in
      osteotropic cancer cell invasion.
AB  - BACKGROUND: Bone sialoprotein (BSP) interacts separately with both matrix
      metalloproteinase 2 (MMP-2) and integrin alpha(v)beta3 and is overexpressed in
      many metastatic tumors. Its role in tumor biology, however, remains unclear. We
      investigated whether BSP enhances cancer cell invasiveness by forming a
      trimolecular complex with MMP-2 and cell-surface integrin alpha(v)beta3. METHODS:
      Invasiveness of breast, prostate, lung, and thyroid tumor cell lines was measured
      with a modified Boyden chamber assay. Binding and co-localization of BSP, MMP-2,
      and integrin alpha(v)beta3 were investigated with immunoprecipitation and in situ
      hybridization. All statistical tests were two-sided. RESULTS: Treatment with BSP
      increased invasiveness of many breast, prostate, lung, and thyroid cancer cells
      through Matrigel in a dose-dependent manner. BSP at 50 nM increased the
      invasiveness of SW-579 thyroid cancer cells (95.2 units, 95% confidence interval
      [CI] = 90.4 to 100 units) by approximately 10-fold compared with that of
      untreated control SW-579 cells (9.1 units, 95% CI = 5.7 to 12.5 units) (P<.001).
      Addition of an inactive mutated BSP, in which BSP's integrin-binding RGD
      tripeptide was altered, or addition of integrin alpha(v)beta3-blocking antibodies
      resulted in invasiveness equivalent to that of untreated cells. Inhibiting
      cellular MMP-2 activity with chemical inhibitors or a specific antibody also
      blocked BSP-enhanced invasiveness. Osteopontin and dentin matrix protein 1,
      proteins related to BSP that also bind integrin alpha(v)beta3 and form complexes
      with other MMPs (but not MMP-2), did not enhance invasiveness.
      Immunoprecipitation showed that a complex containing BSP, integrin alpha(v)beta3,
      and MMP-2 formed in vitro. Addition of BSP increased the amount of MMP-2 bound by
      cells in an integrin-dependent fashion. Co-expression of BSP, integrin
      alpha(v)beta3, and MMP-2 in papillary thyroid carcinoma cells was shown by in
      situ hybridization. CONCLUSION: Cancer cells appear to become more invasive when
      BSP forms a cell-surface trimolecular complex by linking MMP-2 to integrin
      alpha(v)beta3.

PMID- 15199116
TI  - Re: Mortality from lymphohematopoietic malignancies among workers in formaldehyde
      industries.

PMID- 15199119
TI  - Re: Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas
      from Fanconi anemia patients.

PMID- 15199120
TI  - Internet citations in oncology journals: a vanishing resource?

PMID- 15199121
TI  - Characterization of Tetrahymena histone H2B variants and posttranslational
      populations by electron capture dissociation (ECD) Fourier transform ion
      cyclotron mass spectrometry (FT-ICR MS).
AB  - This work describes the nature and sequence information content of the electron
      capture dissociation mass spectra for the intact Tetrahymena histone H2B. Two
      major variants of this protein were present bearing nominal modifications of both
      +42 and +84 Da. This work describes identification of the nature of these two
      modifications. For example, using gas-phase selection and isolation of the +42-Da
      modified species, from a background of two H2B variants each present in six or
      more posttranslationally modified isoforms, we were able to determine that this
      +42-Da modification isoform bears trimethylation rather than acetylation. LC
      CIDMS analysis was also employed on digested preparations to obtain complementary
      detail of the nature of site-specific posttranslational modifications. This study
      establishes that integration of the information from these two datasets provides
      a comprehensive map of posttranslational occupancy for each particular covalent
      assemblage selected for structural investigation.

PMID- 15199123
TI  - Tandem repeat hypothesis in imprinting: deletion of a conserved direct repeat
      element upstream of H19 has no effect on imprinting in the Igf2-H19 region.
AB  - Igf2 and H19 are reciprocally imprinted genes on mouse distal chromosome 7. They
      share several regulatory elements, including a differentially methylated region
      (DMR) upstream of H19 that is paternally methylated throughout development. The
      cis-acting sequence requirements for targeting DNA methylation to the DMR remain
      unknown; however, it has been suggested that direct tandem repeats near DMRs
      could be involved. Previous studies of the imprinted Rasgrf1 locus demonstrate
      indeed that a direct repeat element adjacent to a DMR is responsible for
      establishing paternal allele-specific methylation at the DMR and therefore
      allelic expression of the Rasgrf1 transcript. We identified a prominent and
      conserved direct tandem repeat 1 kb upstream of the H19 DMR and proposed that it
      played a similar role in imprinted regulation of H19. To test our hypothesis, we
      generated mice harboring a 1.7-kb targeted deletion of the direct repeat element
      and analyzed fetal growth, allelic expression, and methylation within the Igf2
      H19 region. Surprisingly the deletion had no effect on imprinting. These results
      together with deletions of other repeats close to imprinted genes suggest that
      direct repeats may not be important for the targeting of methylation at the
      majority of imprinted loci and that the Rasgrf1 locus may be an exception to this
      rule.

PMID- 15199122
TI  - Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase
      complex with menin to regulate Hox gene expression.
AB  - MLL (for mixed-lineage leukemia) is a proto-oncogene that is mutated in a variety
      of human leukemias. Its product, a homolog of Drosophila melanogaster trithorax,
      displays intrinsic histone methyltransferase activity and functions genetically
      to maintain embryonic Hox gene expression. Here we report the biochemical
      purification of MLL and demonstrate that it associates with a cohort of proteins
      shared with the yeast and human SET1 histone methyltransferase complexes,
      including a homolog of Ash2, another Trx-G group protein. Two other members of
      the novel MLL complex identified here are host cell factor 1 (HCF-1), a
      transcriptional coregulator, and the related HCF-2, both of which specifically
      interact with a conserved binding motif in the MLL(N) (p300) subunit of MLL and
      provide a potential mechanism for regulating its antagonistic transcriptional
      properties. Menin, a product of the MEN1 tumor suppressor gene, is also a
      component of the 1-MDa MLL complex. Abrogation of menin expression phenocopies
      loss of MLL and reveals a critical role for menin in the maintenance of Hox gene
      expression. Oncogenic mutant forms of MLL retain an ability to interact with
      menin but not other identified complex components. These studies link the menin
      tumor suppressor protein with the MLL histone methyltransferase machinery, with
      implications for Hox gene expression in development and leukemia pathogenesis.

PMID- 15199124
TI  - The docking protein Gab1 is an essential component of an indirect mechanism for
      fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt
      antiapoptotic pathway.
AB  - The docking protein Gab1 has been implicated as a mediator of multiple signaling
      pathways that are activated by a variety of receptor tyrosine kinases and
      cytokines. We have previously proposed that fibroblast growth factor 1 (FGF1)
      stimulation of tyrosine phosphorylation of Gab1 and recruitment of
      phosphatidylinositol (PI) 3-kinase are mediated by an indirect mechanism in which
      the docking protein fibroblast receptor substrate 2alpha (FRS2alpha) plays a
      critical role. In this report, we explore the role of Gab1 in FGF1 signaling by
      using mouse embryo fibroblasts (MEFs) derived from Gab1(-/-) or FRS2alpha(-/-)
      mice. We demonstrate that Gab1 is essential for FGF1 stimulation of both PI 3
      kinase and the antiapoptotic protein kinase Akt, while FGF1-induced mitogen
      activated protein kinase (MAPK) stimulation is not affected by Gab1 deficiency.
      To test the indirect mechanism for FGF1 stimulation of PI 3-kinase and Akt, we
      use a chimeric docking protein composed of the membrane targeting signal and the
      phosphotyrosine-binding domain of FRS2alpha fused to the C-terminal portion of
      Gab1, the region including the binding sites for the complement of signaling
      proteins that are recruited by Gab1. We demonstrate that expression of the
      chimeric docking protein in Gab1(-/-) MEFs rescues PI 3-kinase and the Akt
      responses, while expression of the chimeric docking protein in FRS2alpha(-/-)
      MEFs rescues stimulation of both Akt and MAPK. These experiments underscore the
      essential role of Gab1 in FGF1 stimulation of the PI 3-kinase/Akt signaling
      pathway and provide further support for the indirect mechanism for FGF1
      stimulation of PI 3-kinase involving regulated assembly of a multiprotein
      complex.

PMID- 15199125
TI  - Regulation of the Src family kinase Lck by Hsp90 and ubiquitination.
AB  - Regulation of the Src-related tyrosine kinase Lck is crucial to the outcome of T
      cell receptor (TCR) stimulation. It was previously shown that the stability of
      the constitutively active mutant LckY505F is controlled by Hsp90 (M. J.
      Bijlmakers and M. Marsh, Mol. Biol. Cell. 11:1585-1595, 2000). Here we establish
      that following TCR stimulation, endogenous activated Lck in T cells is also
      degraded in the presence of the Hsp90 inhibitor geldanamycin. Using Lck
      constructs expressed in COS-7 cells, we show that the presence of activating Lck
      mutations results not only in the enhanced dependence on Hsp90 but also in
      enhanced ubiquitination of Lck. Although both processes were induced by mutations
      Y505F and W97A that release the SH2 and SH3 inhibitory intramolecular
      interactions, respectively, neither process required Lck kinase activity or
      activation-dependent phosphorylation at serines 42 and 59 or tyrosine 394. By
      binding to the ATP-binding site, the Src family inhibitor PP2 reduced
      ubiquitination and overcame the need for Hsp90 monitoring of active Lck. We
      conclude that the levels of active Lck are influenced by two opposing processes,
      targeting for degradation by ubiquitination and rescue from degradation by Hsp90
      monitoring. Based on the PP2 result, we propose that activation-induced
      conformational changes of the Lck kinase domain instigate both regulatory
      processes.

PMID- 15199126
TI  - Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced
      increases in p53.
AB  - Phospholipase D (PLD) has been reported to generate survival signals that prevent
      apoptosis induced by serum withdrawal. We have now found that elevated expression
      of PLD also suppresses DNA damage-induced apoptosis. Since DNA damage-induced
      apoptosis is often mediated by p53, we examined the effect of elevated PLD
      expression on the regulation of p53 stabilization. We report here that PLD
      suppresses DNA damage-induced increases in p53 stabilization in cells where PLD
      has been shown to provide a survival signal. Elevated expression of PLD also led
      to increased expression of the p53 E3 ubiquitin ligase MDM2 and increased
      turnover of p53. PLD1-stimulated increases in MDM2 expression and suppression of
      p53 activation were blocked by inhibition of mTOR and the mitogen-activated
      protein kinase pathway. Although PLD did not activate the phosphatidylinositol 3
      kinase (PI3K)/Akt survival pathway activate the basal levels of PI3K activity
      were partially required for PLD1-induced increases in MDM2. These data provide
      evidence that survival signals generated by PLD involve suppression of the p53
      response pathway.

PMID- 15199127
TI  - Efficient and error-free replication past a minor-groove DNA adduct by the
      sequential action of human DNA polymerases iota and kappa.
AB  - DNA polymerase iota (Poliota) is a member of the Y family of DNA polymerases,
      which promote replication through DNA lesions. The role of Poliota in lesion
      bypass, however, has remained unclear. Poliota is highly unusual in that it
      incorporates nucleotides opposite different template bases with very different
      efficiencies and fidelities. Since interactions of DNA polymerases with the DNA
      minor groove provide for the nearly equivalent efficiencies and fidelities of
      nucleotide incorporation opposite each of the four template bases, we considered
      the possibility that Poliota differs from other DNA polymerases in not being as
      sensitive to distortions of the minor groove at the site of the incipient base
      pair and that this enables it to incorporate nucleotides opposite highly
      distorting minor-groove DNA adducts. To check the validity of this idea, we
      examined whether Poliota could incorporate nucleotides opposite the gamma-HOPdG
      adduct, which is formed from an initial reaction of acrolein with the N(2) of
      guanine. We show here that Poliota incorporates a C opposite this adduct with
      nearly the same efficiency as it does opposite a nonadducted template G residue.
      The subsequent extension step, however, is performed by Polkappa, which
      efficiently extends from the C incorporated opposite the adduct. Based upon these
      observations, we suggest that an important biological role of Poliota and
      Polkappa is to act sequentially to carry out the efficient and accurate bypass of
      highly distorting minor-groove DNA adducts of the purine bases.

PMID- 15199128
TI  - Synergistic transcription activation by Maf and Sox and their subnuclear
      localization are disrupted by a mutation in Maf that causes cataract.
AB  - Crystallin genes are selectively expressed during lens development. Maf and Sox
      family proteins synergistically enhanced gammaF-crystallin promoter activity in a
      lens cell line. Mutational analysis of the gammaF-crystallin promoter identified
      a composite regulatory element containing nonconsensus Maf and Sox recognition
      sequences. Mutations in these recognition sequences or changes in their spacing
      eliminated synergistic transcription activation. The transcriptional synergy was
      also affected by changes in the orientation of the Maf recognition sequence that
      had no detectable effect on binding affinity. The interaction between Maf and Sox
      proteins was visualized in living cells by bimolecular fluorescence
      complementation analysis. The N-terminal region of Maf mediated the interaction
      with Sox proteins in cells. Synergistic transcription activation required the N
      terminal region of Maf as well as the ancillary DNA binding domain and the unique
      portion of the basic region that mediate specific recognition of the gammaF
      crystallin promoter element. A mutation in the ancillary DNA binding domain of
      Maf (R288P) that has been shown to cause cataract eliminated the transcriptional
      activity of Maf but had no detectable effect on DNA binding in vitro. Whereas
      wild-type Maf was uniformly distributed in the nucleoplasm, R288P Maf was
      enriched in nuclear foci. Cajal bodies and gemini of coiled bodies were closely
      associated with the foci occupied by R288P Maf. Wild-type Maf formed complexes
      with Sox proteins in the nucleoplasm, whereas R288P Maf recruited Sox proteins as
      well as other interaction partners to the nuclear foci. The mislocalization of
      normal cellular proteins to these foci provides a potential explanation for the
      dominant disease phenotype of the R288P mutation in Maf.

PMID- 15199129
TI  - Role for activating transcription factor 3 in stress-induced beta-cell apoptosis.
AB  - Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a
      member of the ATF/CREB family of transcription factors. However, the
      physiological significance of ATF3 induction by stress signals is not clear. In
      this report, we describe several lines of evidence supporting a role of ATF3 in
      stress-induced beta-cell apoptosis. First, ATF3 is induced in beta cells by
      signals relevant to beta-cell destruction: proinflammatory cytokines, nitric
      oxide, and high concentrations of glucose and palmitate. Second, induction of
      ATF3 is mediated in part by the NF-kappaB and Jun N-terminal kinase/stress
      activated protein kinase signaling pathways, two stress-induced pathways
      implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing
      ATF3 in beta cells develop abnormal islets and defects secondary to beta-cell
      deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine-
      or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of
      patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic
      mice that have developed insulitis or diabetes. Taken together, our results
      suggest ATF3 to be a novel regulator of stress-induced beta-cell apoptosis.

PMID- 15199130
TI  - The transcription factors c-rel and RelA control epidermal development and
      homeostasis in embryonic and adult skin via distinct mechanisms.
AB  - Determining the roles of Rel/NF-kappaB transcription factors in mouse skin
      development with loss-of-function mutants has been limited by redundancy among
      these proteins and by embryonic lethality associated with the absence of RelA.
      Using mice lacking RelA and c-rel, which survive throughout embryogenesis on a
      tumor necrosis factor alpha (TNF-alpha)-deficient background (rela(-/-) c-rel(-/
      ) tnfalpha(-/-)), we show that c-rel and RelA are required for normal epidermal
      development. Although mutant fetuses fail to form tylotrich hair and have a
      thinner epidermis, mutant keratinocyte progenitors undergo terminal
      differentiation to form an outer cornified layer. Mutant basal keratinocytes are
      abnormally small, exhibit a delay in G(1) progression, and fail to form
      keratinocyte colonies in culture. In contrast to the reduced proliferation of
      mutant keratinocytes during embryogenesis, skin grafting experiments revealed
      that the mutant epidermis develops a TNF-alpha-dependent hyperproliferative
      condition. Collectively, our findings indicate that RelA and c-rel control the
      development of the epidermis and associated appendages during embryogenesis and
      regulate epidermal homeostasis in a postnatal environment through the suppression
      of innate immune-mediated inflammation.

PMID- 15199131
TI  - RalA but not RalB enhances polarized delivery of membrane proteins to the
      basolateral surface of epithelial cells.
AB  - RalA and RalB constitute a family of highly similar (85% identity) Ras-related
      GTPases. Recently, active forms of both RalA and RalB have been shown to bind to
      the exocyst complex, implicating them in the regulation of cellular secretion.
      However, we show here that only active RalA enhances the rate of delivery of E
      cadherin and other proteins to their site in the basolateral membrane of MDCK
      cells, consistent with RalA being a regulator of exocyst function. One reason for
      this difference is that RalA binds more effectively to the exocyst complex than
      active RalB does both in vivo and in vitro. Another reason is that active RalA
      localizes to perinuclear recycling endosomes, where regulation of vesicle sorting
      is thought to take place, while active RalB does not. Strikingly, analysis of
      chimeras made between RalA and RalB reveals that high-affinity exocyst binding by
      RalA is due to unique amino acid sequences in RalA that are distal to the common
      effector-binding domains shared by RalA and RalB. Moreover, these chimeras show
      that the perinuclear localization of active RalA is due in part to its unique
      variable domain near the C terminus. This distinct localization appears to be
      important for RalA effects on secretion because all RalA mutants tested that
      failed to localize to the perinuclear region also failed to promote basolateral
      delivery of E-cadherin. Interestingly, one of these inactive mutants maintained
      binding to the exocyst complex, suggesting that RalA binding to the exocyst is
      necessary but not sufficient for RalA to promote basolateral delivery of membrane
      proteins.

PMID- 15199132
TI  - DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF
      1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic
      anhydrase IX.
AB  - We investigated the relationship between the tumor suppressor p53 and the hypoxia
      inducible factor-1 (HIF-1)-dependent expression of the hypoxia marker, carbonic
      anhydrase IX (CAIX). MCF-7 (wt p53) and Saos-2 (p53-null) cells displayed similar
      induction of CAIX expression and CA9 promoter activity under hypoxic conditions.
      Activation of p53 by the DNA damaging agent mitomycin C (MC) was accompanied by a
      potent repression of CAIX expression and the CA9 promoter in MCF-7 but not in
      Saos-2 cells. The activated p53 mediated increased proteasomal degradation of HIF
      1alpha protein, resulting in considerably lower steady-state levels of HIF-1alpha
      protein in hypoxic MCF-7 cells but not in Saos-2 cells. Overexpression of HIF
      1alpha relieved the MC-induced repression in MCF-7 cells, confirming regulation
      at the HIF-1alpha level. Similarly, CA9 promoter activity was downregulated by MC
      in HCT 116 p53(+/+) but not the isogenic p53(-/-) cells. Activated p53 decreased
      HIF-1alpha protein levels by accelerated proteasome-dependent degradation without
      affecting significantly HIF-1alpha transcription. In summary, our results
      demonstrate that the presence of wtp53 under hypoxic conditions has an
      insignificant effect on the stabilization of HIF-1alpha protein and HIF-1
      dependent expression of CAIX. However, upon activation by DNA damage, wt p53
      mediates an accelerated degradation of HIF-1alpha protein, resulting in reduced
      activation of CA9 transcription and, correspondingly, decreased levels of CAIX
      protein. A model outlining the quantitative relationship between p53, HIF-1alpha,
      and CAIX is presented.

PMID- 15199133
TI  - Abnormal B-cell responses to chemokines, disturbed plasma cell localization, and
      distorted immune tissue architecture in Rgs1-/- mice.
AB  - Normal lymphoid tissue development and function depend upon chemokine-directed
      cell migration. Since chemokines signal through heterotrimeric G-protein-coupled
      receptors, RGS proteins, which act as GTPase-activating proteins for Galpha
      subunits, likely fine tune the cellular responses to chemokines. Here we show
      that Rgs1(-/-) mice possess B cells that respond excessively and desensitize
      improperly to the chemokines CXCL12 and CXCL13. Many of the B-cell follicles in
      the spleens of Rgs1(-/-) mice have germinal centers even in the absence of immune
      stimulation. Furthermore, immunization of these mice leads to exaggerated
      germinal center formation; partial disruption of the normal architecture of the
      spleen and Peyer's patches; and abnormal trafficking of immunoglobulin-secreting
      cells. These results reveal the importance of a regulatory mechanism that limits
      and desensitizes chemokine receptor signaling.

PMID- 15199134
TI  - The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA
      interstrand cross-link-induced double-strand breaks.
AB  - Interstrand cross-links (ICLs) are an extremely toxic class of DNA damage
      incurred during normal metabolism or cancer chemotherapy. ICLs covalently tether
      both strands of duplex DNA, preventing the strand unwinding that is essential for
      polymerase access. The mechanism of ICL repair in mammalian cells is poorly
      understood. However, genetic data implicate the Ercc1-Xpf endonuclease and
      proteins required for homologous recombination-mediated double-strand break (DSB)
      repair. To examine the role of Ercc1-Xpf in ICL repair, we monitored the
      phosphorylation of histone variant H2AX (gamma-H2AX). The phosphoprotein
      accumulates at DSBs, forming foci that can be detected by immunostaining.
      Treatment of wild-type cells with mitomycin C (MMC) induced gamma-H2AX foci and
      increased the amount of DSBs detected by pulsed-field gel electrophoresis.
      Surprisingly, gamma-H2AX foci were also induced in Ercc1(-/-) cells by MMC
      treatment. Thus, DSBs occur after cross-link damage via an Ercc1-independent
      mechanism. Instead, ICL-induced DSB formation required cell cycle progression
      into S phase, suggesting that DSBs are an intermediate of ICL repair that form
      during DNA replication. In Ercc1(-/-) cells, MMC-induced gamma-H2AX foci
      persisted at least 48 h longer than in wild-type cells, demonstrating that Ercc1
      is required for the resolution of cross-link-induced DSBs. MMC triggered sister
      chromatid exchanges in wild-type cells but chromatid fusions in Ercc1(-/-) and
      Xpf mutant cells, indicating that in their absence, repair of DSBs is prevented.
      Collectively, these data support a role for Ercc1-Xpf in processing ICL-induced
      DSBs so that these cytotoxic intermediates can be repaired by homologous
      recombination.

PMID- 15199135
TI  - Rhes is involved in striatal function.
AB  - The development and the function of central nervous system depend on thyroid
      hormones. In humans, the lack of thyroid hormones causes cretinism, a syndrome of
      severe mental deficiency. It is assumed that thyroid hormones affect the normal
      development and function of the brain by activating or suppressing target gene
      expression because several genes expressed in the brain have been shown to be
      under thyroid hormone control. Among these, the Rhes gene, encoding a small GTP
      binding protein, is predominantly expressed in the striatal region of the brain.
      To clarify the role of Rhes in vivo, we disrupted the Rhes gene by homologous
      recombination in embryonic stem cells and generated mice homozygous for the Rhes
      null mutation (Rhes(-/-)). Rhes(-/-) mice were viable but weighed less than wild
      type mice. Furthermore, they showed behavioral abnormalities, displaying a gender
      dependent increase in anxiety levels and a clear motor coordination deficit but
      no learning or memory impairment. These results suggest that Rhes disruption
      affects selected behavioral competencies.

PMID- 15199136
TI  - Human box H/ACA pseudouridylation guide RNA machinery.
AB  - Pseudouridine, the most abundant modified nucleoside in RNA, is synthesized by
      posttranscriptional isomerization of uridines. In eukaryotic RNAs, site-specific
      synthesis of pseudouridines is directed primarily by box H/ACA guide RNAs. In
      this study, we have identified 61 novel putative pseudouridylation guide RNAs by
      construction and characterization of a cDNA library of human box H/ACA RNAs. The
      majority of the new box H/ACA RNAs are predicted to direct pseudouridine
      synthesis in rRNAs and spliceosomal small nuclear RNAs. We can attribute RNA
      directed modification to 79 of the 97 pseudouridylation sites present in the
      human 18S, 5.8S, and 28S rRNAs and to 11 of the 21 pseudouridines reported for
      the U1, U2, U4, U5, and U6 spliceosomal RNAs. We have also identified 12 novel
      box H/ACA RNAs which lack apparent target pseudouridines in rRNAs and small
      nuclear RNAs. These putative guide RNAs likely function in the pseudouridylation
      of some other types of cellular RNAs, suggesting that RNA-guided
      pseudouridylation is more general than assumed before. The genomic organization
      of the new box H/ACA RNA genes indicates that in human cells, all box H/ACA
      pseudouridylation guide RNAs are processed from introns of pre-mRNA transcripts
      which either encode a protein product or lack protein-coding capacity.

PMID- 15199137
TI  - CCR4-associated factor CAF1 is an essential factor for spermatogenesis.
AB  - The CCR4-associated protein CAF1 has been demonstrated to play several roles in
      the control of transcription and of mRNA decay. To gain further insight into its
      physiological function, we generated CAF1-deficient mice. They are viable,
      healthy, and normal in appearance; however, mCAF1(-/-) male mice are sterile. The
      crossing of mCAF1(+/-) mice gave a Mendelian ratio of mCAF1(+/+), mCAF1(+/-), and
      mCAF1(-/-) pups, indicating that haploid mCAF1-deficient germ cells differentiate
      normally. The onset of the defect occurs during the first wave of spermatogenesis
      at 19 to 20 days after birth, during progression of pachytene spermatocytes to
      haploid spermatids and spermatozoa. Early disruption of spermatogenesis was
      evidenced by Sertoli cell vacuolization and tubular disorganization. The most
      mature germ cells were the most severely depleted, but progressively all germ
      cells were affected, giving Sertoli cell-only tubes, large interstitial spaces,
      and small testes. This phenotype could be linked to a defect(s) in germ cells
      and/or to inadequate Sertoli cell function, leading to seminiferous tubule
      disorganization and finally to a total disappearance of germ cells. The mCAF1
      deficient mouse provides a new model of failed spermatogenesis in the adult that
      may be relevant to some cases of human male sterility.

PMID- 15199138
TI  - Dyrk1A potentiates steroid hormone-induced transcription via the chromatin
      remodeling factor Arip4.
AB  - Dyrk1A, a mammalian homolog of the Drosophila minibrain gene, encodes a dual
      specificity kinase, involved in neuronal development and in adult brain
      physiology. In humans, a third copy of DYRK1A is present in Down syndrome
      (trisomy 21) and has been implicated in the etiology of mental retardation. To
      further understand this pathology, we searched for Dyrk1A-interacting proteins
      and identified Arip4 (androgen receptor-interacting protein 4), a SNF2-like
      steroid hormone receptor cofactor. Mouse hippocampal and cerebellar neurons
      coexpress Dyrk1A and Arip4. In HEK293 cells and hippocampal neurons, both
      proteins are colocalized in a speckle-like nuclear subcompartment. The functional
      interaction of Dyrk1A with Arip4 was analyzed in a series of transactivation
      assays. Either Dyrk1A or Arip4 alone displays an activating effect on androgen
      receptor- and glucocorticoid receptor-mediated transactivation, and Dyrk1A and
      Arip4 together act synergistically. These effects are independent of the kinase
      activity of Dyrk1A. Inhibition of endogenous Dyrk1A and Arip4 expression by RNA
      interference showed that both proteins are necessary for the efficient activation
      of androgen receptor- and glucocorticoid receptor-dependent transcription. As
      Dyrk1A is an activator of steroid hormone-regulated transcription, the
      overexpression of DYRK1A in persons with Down syndrome may cause rather broad
      changes in the homeostasis of steroid hormone-controlled cellular events.

PMID- 15199139
TI  - Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by
      inhibiting p53 tumor suppressor activity.
AB  - Human tumors are believed to harbor a disabled p53 tumor suppressor pathway,
      either through direct mutation of the p53 gene or through aberrant expression of
      proteins acting in the p53 pathway, such as p14(ARF) or Mdm2. A role for Mdmx (or
      Mdm4) as a key negative regulator of p53 function in vivo has been established.
      However, a direct contribution of Mdmx to tumor formation remains to be
      demonstrated. Here we show that retrovirus-mediated Mdmx overexpression allows
      primary mouse embryonic fibroblast immortalization and leads to neoplastic
      transformation in combination with HRas(V12). Furthermore, the human Mdmx
      ortholog, Hdmx, was found to be overexpressed in a significant percentage of
      various human tumors and amplified in 5% of primary breast tumors, all of which
      retained wild-type p53. Hdmx was also amplified and highly expressed in MCF-7, a
      breast cancer cell line harboring wild-type p53, and interfering RNA-mediated
      reduction of Hdmx markedly inhibited the growth potential of these cells in a p53
      dependent manner. Together, these results make Hdmx a new putative drug target
      for cancer therapy.

PMID- 15199140
TI  - The ETS transcription factor GABPalpha is essential for early embryogenesis.
AB  - The ETS transcription factor complex GABP consists of the GABPalpha protein,
      containing an ETS DNA binding domain, and an unrelated GABPbeta protein,
      containing a transactivation domain and nuclear localization signal. GABP has
      been shown in vitro to regulate the expression of nuclear genes involved in
      mitochondrial respiration and neuromuscular signaling. We investigated the in
      vivo function of GABP by generating a null mutation in the murine Gabpalpha gene.
      Embryos homozygous for the null Gabpalpha allele die prior to implantation,
      consistent with the broad expression of Gabpalpha throughout embryogenesis and in
      embryonic stem cells. Gabpalpha(+/-) mice demonstrated no detectable phenotype
      and unaltered protein levels in the panel of tissues examined. This indicates
      that Gabpalpha protein levels are tightly regulated to protect cells from the
      effects of loss of Gabp complex function. These results show that Gabpalpha
      function is essential and is not compensated for by other ETS transcription
      factors in the mouse, and they are consistent with a specific requirement for
      Gabp expression for the maintenance of target genes involved in essential
      mitochondrial cellular functions during early cleavage events of the embryo.

PMID- 15199141
TI  - Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin.
AB  - Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with
      at least 11 complementation groups (A, B, C, D1, D2, E, F, G, I, J, and L), and
      eight FA genes have been cloned. The FANCD1 gene is identical to the breast
      cancer susceptibility gene, BRCA2. The FA proteins cooperate in a common pathway,
      but the function of BRCA2/FANCD1 in this pathway remains unknown. Here we show
      that monoubiquitination of FANCD2, which is activated by DNA damage, is required
      for targeting of FANCD2 to chromatin, where it interacts with BRCA2. FANCD2-Ub
      then promotes BRCA2 loading into a chromatin complex. FANCD2(-/-) cells are
      deficient in the assembly of DNA damage-inducible BRCA2 foci and in chromatin
      loading of BRCA2. Functional complementation with the FANCD2 cDNA restores BRCA2
      foci and its chromatin loading following DNA damage. BRCA2(-/-) cells expressing
      a carboxy-terminal truncated BRCA2 protein form IR-inducible BRCA2 and FANCD2
      foci, but these foci fail to colocalize. Functional complementation of these
      cells with wild-type BRCA2 restores the interaction of BRCA2 and FANCD2. The C
      terminus of BRCA2 is therefore required for the functional interaction of BRCA2
      and FANCD2 in chromatin. Taken together, our results demonstrate that
      monoubiquitination of FANCD2, which is regulated by the FA pathway, promotes
      BRCA2 loading into chromatin complexes. These complexes appear to be required for
      normal homology-directed DNA repair.

PMID- 15199142
TI  - The nuclear scaffold protein NIPP1 is essential for early embryonic development
      and cell proliferation.
AB  - NIPP1 (nuclear inhibitor of protein phosphatase 1) is a ubiquitously expressed
      nuclear scaffold protein that has been implicated in both transcription and RNA
      processing. Among its protein ligands are a protein kinase, a protein
      phosphatase, two splicing factors, and a transcriptional regulator, and the
      binding of these proteins to NIPP1 is tightly regulated by phosphorylation. To
      study the function of NIPP1 in vivo, we have used homologous recombination to
      generate mice that are deficient in NIPP1. NIPP1(-/+) mice developed normally.
      However, NIPP1(-/-) embryos showed severely retarded growth at embryonic day 6.5
      (E6.5) and were resorbed by E8.5. This early embryonic lethality was not
      associated with increased apoptosis but correlated with impaired cell
      proliferation. Blastocyst outgrowth experiments and the RNA interference-mediated
      knockdown of NIPP1 in cultured cells also revealed an essential role for NIPP1 in
      cell proliferation. In further agreement with this function, no viable NIPP1(-/-)
      cell lines were obtained by derivation of embryonic stem (ES) cells from
      blastocysts of NIPP1(-/+) intercrosses or by forced homogenotization of
      heterozygous ES cells at high concentrations of Geneticin. We conclude that NIPP1
      is indispensable for early embryonic development and cell proliferation.

PMID- 15199143
TI  - Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition
      complex's largest subunit (Orc1) from binding to chromatin during mitosis.
AB  - The eukaryotic origin recognition complex (ORC) selects the genomic sites where
      prereplication complexes are assembled and DNA replication begins. In
      proliferating mammalian cells, ORC activity appears to be regulated by reducing
      the affinity of the Orc1 subunit for chromatin during S phase and then preventing
      reformation of a stable ORC-chromatin complex until mitosis is completed and a
      nuclear membrane is assembled. Here we show that part of the mechanism by which
      this is accomplished is the selective association of Orc1 with Cdk1 (Cdc2)/cyclin
      A during the G(2)/M phase of cell division. This association accounted for the
      appearance in M-phase cells of hyperphosphorylated Orc1 that was subsequently
      dephosphorylated during the M-to-G(1) transition. Moreover, inhibition of Cdk
      activity in metaphase cells resulted in rapid binding of Orc1 to chromatin.
      However, chromatin binding was not mediated through increased affinity of Orc1
      for Orc2, suggesting that additional events are involved in the assembly of
      functional ORC-chromatin sites. These results reveal that the same cyclin
      dependent protein kinase that initiates mitosis in mammalian cells also
      concomitantly inhibits assembly of functional ORC-chromatin sites.

PMID- 15199144
TI  - Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts
      late meiotic prophase and subsequent meiotic divisions of spermatogenesis.
AB  - Testicular orphan nuclear receptor 4 (TR4) is specifically and stage-dependently
      expressed in late-stage pachytene spermatocytes and round spermatids. In the
      developing mouse testis, the highest expression of TR4 can be detected at
      postnatal days 16 to 21 when the first wave of spermatogenesis progresses to late
      meiotic prophase. Using a knockout strategy to delete TR4 in mice, we found that
      sperm production in TR4(-/-) mice is reduced. The comparison of testes from
      developing TR4(+/+) and TR4(-/-) mice shows that spermatogenesis in TR4(-/-) mice
      is delayed. Analysis of the first wave of spermatogenesis shows that the delay
      can be due to delay and disruption of spermatogenesis at the end of late meiotic
      prophase and subsequent meiotic divisions. Seminiferous tubule staging shows that
      stages X to XII, where late meiotic prophase and meiotic divisions take place,
      are delayed and disrupted in TR4(-/-) mice. Histological examination of testis
      sections from TR4(-/-) mice shows degenerated primary spermatocytes and some
      necrotic tubules. Testis-specific gene analyses show that the expression of sperm
      1 and cyclin A1, which are genes expressed at the end of meiotic prophase, was
      delayed and decreased in TR4(-/-) mouse testes. Taken together, results from
      TR4(+/+) and TR4(-/-) mice indicate that TR4 is essential for normal
      spermatogenesis in mice.

PMID- 15199145
TI  - BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell
      proliferation in breast cancer.
AB  - BRCA1 mutations and estrogen use are risk factors for the development of breast
      cancer. Recent work has identified estrogen receptors localized at the plasma
      membrane that signal to cell biology. We examined the impact of BRCA1 on membrane
      estrogen and growth factor receptor signaling to breast cancer cell
      proliferation. MCF-7 and ZR-75-1 cells showed a rapid and sustained activation of
      extracellular signal-related kinase (ERK) in response to estradiol (E2) that was
      substantially prevented by wild-type (wt) but not mutant BRCA1. The proliferation
      of MCF-7 cells induced by E2 was significantly inhibited by PD98059, a specific
      ERK inhibitor, or by dominant negative ERK2 expression and by expression of wt
      BRCA1 (but not mutant BRCA1). E2 induced the synthesis of cyclins D1 and B1, the
      activity of cyclin-dependent kinases Cdk4 and CDK1, and G(1)/S and G(2)/M cell
      cycle progression. The intact tumor suppressor inhibited all of these. wt BRCA1
      also inhibited epidermal growth factor and insulin-like growth factor I-induced
      ERK and cell proliferation. The inhibition of ERK and cell proliferation by BRCA1
      was prevented by phosphatase inhibitors and by interfering RNA knockdown of the
      ERK phosphatase, mitogen-activated kinase phosphatase 1. Our findings support a
      novel tumor suppressor function of BRCA1 that is relevant to breast cancer and
      identify a potential interactive risk factor for women with BRCA1 mutations.

PMID- 15199146
TI  - Essential roles of receptor-interacting protein and TRAF2 in oxidative stress
      induced cell death.
AB  - Oxidative stress and reactive oxygen species (ROS) can elicit and modulate
      various physiological and pathological processes, including cell death. However,
      the mechanisms controlling ROS-induced cell death are largely unknown. Data from
      this study suggest that receptor-interacting protein (RIP) and tumor necrosis
      factor receptor (TNFR)-associated factor 2 (TRAF2), two key effector molecules of
      TNF signaling, are essential for ROS-induced cell death. We found that RIP(-/-)
      or TRAF2(-/-) mouse embryonic fibroblasts (MEF) are resistant to ROS-induced cell
      death when compared to wild-type cells, and reconstitution of RIP and TRAF2 gene
      expression in their respective deficient MEF cells restored their sensitivity to
      H(2)O(2)-induced cell death. We also found that RIP and TRAF2 form a complex upon
      H(2)O(2) exposure, but without the participation of TNFR1. The colocalization of
      RIP with a membrane lipid raft marker revealed a possible role of lipid rafts in
      the transduction of cell death signal initiated by H(2)O(2). Finally, our results
      demonstrate that activation of c-Jun NH(2)-terminal kinase 1 is a critical event
      downstream of RIP and TRAF2 in mediating ROS-induced cell death. Therefore, our
      study uncovers a novel signaling pathway regulating oxidative stress-induced cell
      death.

PMID- 15199147
TI  - Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin
      immunoprecipitation assays.
AB  - Prediction of gene regulatory sequences using phylogenetic footprinting has
      advanced considerably but lacks experimental validation. Here, we report whether
      transcription factor binding sites predicted by dot plotting or web-based Trafac
      analysis could be validated by chromatin immunoprecipitation assays. MYC
      overexpression enhances glycolysis without hypoxia and hence may contribute to
      altered tumor metabolism. Because the full spectrum of glycolytic genes directly
      regulated by Myc is not known, we chose Myc as a model transcription factor to
      determine whether it binds target glycolytic genes that have conserved canonical
      Myc binding sites or E boxes (5'-CACGTG-3'). Conserved canonical E boxes in ENO1,
      HK2, and LDHA occur in 31- to 111-bp islands with high interspecies sequence
      identity (>65%). Trafac analysis revealed another region in ENO1 that corresponds
      to a murine region with a noncanonical E box. Myc bound all these conserved
      regions well in the human P493-6 B lymphocytes. We also determined whether Myc
      could bind nonconserved canonical E boxes found in the remaining human glycolytic
      genes. Myc bound PFKM, but it did not significantly bind GPI, PGK1, and PKM2.
      Binding to BPGM, PGAM2, and PKLR was not detected. Both GAPD and TPI1 do not have
      conserved E boxes but are induced and bound by Myc through regions with
      noncanonical E boxes. Our results indicate that Myc binds well to conserved
      canonical E boxes, but not nonconserved E boxes. However, the binding of Myc to
      unpredicted genomic regions with noncanonical E boxes reveals a limitation of
      phylogenetic footprinting. In aggregate, these observations indicate that Myc is
      an important regulator of glycolytic genes, suggesting that MYC plays a key role
      in a switch to glycolytic metabolism during cell proliferation or tumorigenesis.

PMID- 15199148
TI  - B-Raf acts via the ROCKII/LIMK/cofilin pathway to maintain actin stress fibers in
      fibroblasts.
AB  - Recent data have shown that the BRAF gene is mutated at a high frequency in human
      malignancies. We have analyzed the migratory characteristics of B-raf(-/-) mouse
      embryonic fibroblasts (MEFs) and compared these with the organization of the
      actin cytoskeleton and the activity of signaling pathways that are known to
      influence this organization. Disruption of B-raf significantly reduced the levels
      of phospho-ERK1/2 and, surprisingly, induced an approximately 1.5-fold increase
      in cell migration. Consistent with these findings, the high level of actin stress
      fibers normally present in MEFs was considerably reduced following disruption of
      B-raf, and the F-actin content of B-raf(-/-) cells was less than half that of B
      raf(+/+) cells. Phosphorylation of the myosin light chain on Thr18/Ser19 residues
      was not reduced in B-raf(-/-) cells. Rather, reduced ROCKII expression and
      attenuated phosphorylation of ADF/cofilin on serine 3 occurred. Normal stress
      fiber and phosphocofilin levels were restored by the expression of human B-Raf
      and catalytically active MEK and by the overexpression of LIM kinase (LIMK).
      These results have important implications for the role of the B-Raf/ERK signaling
      pathway in regulating cell motility in normal and malignant cells. They suggest
      that B-Raf is involved in invasiveness by regulating the proper assembly of actin
      stress fibers and contractility through a ROCKII/LIMK/cofilin signaling pathway.

PMID- 15199149
TI  - CtBP contributes quantitatively to Knirps repression activity in an NAD binding
      dependent manner.
AB  - Transcriptional repressors often employ multiple activities, but the molecular
      mechanisms and physiological relevance of this functional diversity remain
      obscure. The Drosophila melanogaster Knirps repressor uses CtBP corepressor
      dependent and -independent pathways. To separately analyze the components of
      Knirps repression activity, we elucidated the specific repression properties of
      CtBP and of Knirps subdomains. Like Knirps, CtBP represses adjacent
      transcriptional activators; but unlike Knirps, CtBP is unable to repress basal
      promoter elements. We determined that the ability of CtBP to recapitulate only a
      subset of Knirps activities is due to a quantitative, rather than qualitative,
      deficiency in repression activity. The CtBP-dependent portion of Knirps
      synergizes with the CtBP-independent repression activity to potently repress
      promoter elements from enhancer- or promoter-proximal positions. This result
      indicates that multiple repression activities are combined to exceed critical
      thresholds on target genes. CtBP mutant proteins unable to bind NAD fail to
      interact with DNA-bound factors. We show that DNA-binding Gal4-CtBP fusion
      proteins also require NAD binding for activity, indicating that NAD plays a role
      in repression at a step subsequent to CtBP recruitment to the promoter.

PMID- 15199150
TI  - p53 differentially inhibits cell growth depending on the mechanism of telomere
      maintenance.
AB  - Telomere stabilization is critical for tumorigenesis. A number of tumors and cell
      lines use a recombination-based mechanism, alternative lengthening of telomeres
      (ALT), to maintain telomere repeat arrays. Current data suggest that the mutation
      of p53 facilitates the activation of this pathway. In addition to its functions
      in response to DNA damage, p53 also acts to suppress recombination, independent
      of transactivation activity, raising the possibility that p53 might regulate the
      ALT mechanism via its role as a regulator of recombination. To test the role of
      p53 in ALT we utilized inducible alleles of human p53. We show that expression of
      transactivation-incompetent p53 inhibits DNA synthesis in ALT cell lines but does
      not affect telomerase-positive cell lines. The expression of temperature
      sensitive p53 in clonal cell lines results in ALT-specific, transactivation
      independent growth inhibition, due in part to the perturbation of S phase.
      Utilizing chromatin immunoprecipitation assays, we demonstrate that p53 is
      associated with the telomeric complex in ALT cells. Furthermore, the inhibition
      of DNA synthesis in ALT cells by p53 requires intact specific DNA binding and
      suppression of recombination functions. We propose that p53 causes
      transactivation-independent growth inhibition of ALT cells by perturbing
      telomeric recombination.

PMID- 15199151
TI  - Characterization of mice lacking the tetraspanin superfamily member CD151.
AB  - The tetraspanin membrane protein CD151 is a broadly expressed molecule noted for
      its strong molecular associations with integrins, especially alpha3beta1,
      alpha6beta1, alpha7beta1, and alpha6beta4. In vitro functional studies have
      pointed to a role for CD151 in cell-cell adhesion, cell migration, platelet
      aggregation, and angiogenesis. It has also been implicated in epithelial tumor
      progression and metastasis. Here we describe the generation and initial
      characterization of CD151-null mice. The mice are viable, healthy, and fertile
      and show normal Mendelian inheritance. They have essentially normal blood and
      bone marrow cell counts and grossly normal tissue morphology, including
      hemidesmosomes in skin, and expression of alpha3 and alpha6 integrins. However,
      the CD151-null mice do show phenotypes in several different tissue types. An
      absence of CD151 leads to a minor abnormality in hemostasis, with CD151-null mice
      showing longer average bleeding times, greater average blood loss, and an
      increased incidence of rebleeding occurrences. CD151-null keratinocytes migrate
      poorly in skin explant cultures. Finally, CD151-null T lymphocytes are
      hyperproliferative in response to in vitro mitogenic stimulation.

PMID- 15199152
TI  - Distinct mechanisms for repression of RNA polymerase III transcription by the
      retinoblastoma tumor suppressor protein.
AB  - The retinoblastoma (RB) protein represses global RNA polymerase III transcription
      of genes that encode nontranslated RNAs, potentially to control cell growth.
      However, RNA polymerase III-transcribed genes exhibit diverse promoter structures
      and factor requirements for transcription, and a universal mechanism explaining
      global repression is uncertain. We show that RB represses different classes of
      RNA polymerase III-transcribed genes via distinct mechanisms. Repression of human
      U6 snRNA (class 3) gene transcription occurs through stable promoter occupancy by
      RB, whereas repression of adenovirus VAI (class 2) gene transcription occurs in
      the absence of detectable RB-promoter association. Endogenous RB binds to a human
      U6 snRNA gene in both normal and cancer cells that maintain functional RB but not
      in HeLa cells whose RB function is disrupted by the papillomavirus E7 protein.
      Both U6 promoter association and transcriptional repression require the A/B
      pocket domain and C region of RB. These regions of RB contribute to U6 promoter
      targeting through numerous interactions with components of the U6 general
      transcription machinery, including SNAP(C) and TFIIIB. Importantly, RB also
      concurrently occupies a U6 promoter with RNA polymerase III during repression.
      These observations suggest a novel mechanism for RB function wherein RB can
      repress U6 transcription at critical steps subsequent to RNA polymerase III
      recruitment.

PMID- 15199153
TI  - Functional domains of the ubiquitous chromatin protein DEK.
AB  - DEK was originally described as a proto-oncogene protein and is now known to be a
      major component of metazoan chromatin. DEK is able to modify the structure of DNA
      by introducing supercoils. In order to find interaction partners and functional
      domains of DEK, we performed yeast two-hybrid screens and mutational analyses.
      Two-hybrid screening yielded C-terminal fragments of DEK, suggesting that DEK is
      able to multimerize. We could localize the domain to amino acids 270 to 350 and
      show that multimerization is dependent on phosphorylation by CK2 kinase in vitro.
      We also found two DNA binding domains of DEK, one on a fragment including amino
      acids 87 to 187 and containing the SAF-box DNA binding motif, which is located
      between amino acids 149 and 187. This region is sufficient to introduce
      supercoils into DNA. The second DNA binding domain is located between amino acids
      270 and 350 and thus overlaps the multimerization domain. We show that the two
      DNA-interacting domains differ in their binding properties and in their abilities
      to respond to CK2 phosphorylation.

PMID- 15199154
TI  - Phosphorylation by protein kinase CK2 changes the DNA binding properties of the
      human chromatin protein DEK.
AB  - We have examined the posttranslational modification of the human chromatin
      protein DEK and found that DEK is phosphorylated by the protein kinase CK2 in
      vitro and in vivo. Phosphorylation sites were mapped by quadrupole ion trap mass
      spectrometry and found to be clustered in the C-terminal region of the DEK
      protein. Phosphorylation fluctuates during the cell cycle with a moderate peak
      during G(1) phase. Filter binding assays, as well as Southwestern analysis,
      demonstrate that phosphorylation weakens the binding of DEK to DNA. In vivo,
      however, phosphorylated DEK remains on chromatin. We present evidence that
      phosphorylated DEK is tethered to chromatin throughout the cell cycle by the un-
      or underphosphorylated form of DEK.

PMID- 15199155
TI  - SENP1 enhances androgen receptor-dependent transcription through desumoylation of
      histone deacetylase 1.
AB  - SUMO (also called Sentrin) is a ubiquitin-like protein that plays an important
      role in regulating protein function and localization. It is known that several
      nuclear receptors are modified by SUMO; however, the effect of desumoylation in
      regulating nuclear receptor function has not been elucidated. Here we show that
      androgen receptor (AR)-mediated transcription is markedly enhanced by SENP1, a
      member of SUMO-specific protease family. SENP1's ability to enhance AR-dependent
      transcription is not mediated through desumoylation of AR, but rather through its
      ability to deconjugate histone deacetylase 1 (HDAC1), thereby reducing its
      deacetylase activity. HDAC1's repressive effect on AR-dependent transcription
      could be reversed by SENP1 and by deletion of its sumoylation sites. RNA
      interference depletion of endogenous HDAC1 also reduced SENP1's effect. Thus,
      SENP1 could regulate AR-dependent transcription through desumoylation of HDAC1.
      These studies provide insights on the potential role of desumoylation in the
      regulation of nuclear receptor activity.

PMID- 15199156
TI  - Molecular requirements for gene expression mediated by targeted histone
      acetyltransferases.
AB  - Histone acetyltransferases (HATs) play fundamental roles in regulating gene
      expression. HAT complexes with distinct subunit composition and substrate
      specificity act on chromatin-embedded genes with different promoter architecture
      and chromosomal locations. Because requirements for HAT complexes vary, a central
      question in transcriptional regulation is how different HAT complexes function in
      different chromosomal contexts. Here, we have tested the ability of targeted
      yeast HATs to regulate gene expression of an epigenetically silenced locus. Of a
      panel of HAT fusion proteins targeted to a telomeric reporter gene, Sas3p and
      Gcn5p selectively increased expression of the silenced gene. Reporter gene
      expression was not solely dependent on acetyltransferase activity of the targeted
      HAT. Further analysis of Gcn5p-mediated gene expression revealed collateral
      requirements for HAT complex subunits Spt8p and Spt3p, which interact with TATA
      binding protein, and for a gene-specific transcription factor. These data
      demonstrate plasticity of gene expression mediated by HATs upon encountering
      novel promoter architecture and chromatin context. The telomeric location of the
      reporter gene used in these studies also provides insight into the molecular
      requirements for heterochromatin boundary formation and for overcoming
      transcriptional silencing.

PMID- 15199157
TI  - IkappaB kinase is an essential component of the Tpl2 signaling pathway.
AB  - IkappaB kinase (IKK), a key regulator of immune and inflammatory responses, is
      known as an effector kinase mediating activation of the transcription factor NF
      kappaB. Whether IKK also participates in other signaling events is not known.
      Here we show that IKK serves as an essential component of a signaling pathway
      that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and
      ERK. Inhibition of IKKbeta in macrophages eliminates Tpl2 activation and ERK
      phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha.
      Using IKK-deficient murine fibroblasts, we further demonstrate that IKKbeta, but
      not IKKalpha, is required for Tpl2 activation. Moreover, this novel function of
      IKKbeta appears to involve phosphorylation and degradation of the Tpl2 inhibitor
      NF-kappaB1/p105. These findings suggest that IKKbeta exerts its immune-regulatory
      functions by targeting different downstream signaling pathways.

PMID- 15199158
TI  - Development of a functional skin matrix requires deposition of collagen V
      heterotrimers.
AB  - Collagen V is a minor component of the heterotypic I/III/V collagen fibrils and
      the defective product in most cases of classical Ehlers Danlos syndrome (EDS).
      The present study was undertaken to elucidate the impact of collagen V mutations
      on skin development, the most severely affected EDS tissues, using mice harboring
      a targeted deletion of the alpha2(V) collagen gene (Col5a2). Contrary to the
      original report, our studies indicate that the Col5a2 deletion (a.k.a. the pN
      allele) represents a functionally null mutation that affects matrix assembly
      through a complex sequence of events. First the mutation impairs assembly and/or
      secretion of the alpha1(V)(2)alpha2(V) heterotrimer with the result that the
      alpha1(V) homotrimer is the predominant species deposited into the matrix.
      Second, the alpha1(V) homotrimer is excluded from incorporation into the
      heterotypic collagen fibrils and this in turn severely impairs matrix
      organization. Third, the mutant matrix stimulates a compensatory loop by the
      alpha1(V) collagen gene that leads to additional deposition of alpha1(V)
      homotrimers. These data therefore underscore the importance of the collagen V
      heterotrimer in dermal fibrillogenesis. Furthermore, reduced thickness of the
      basement membranes underlying the epidermis and increased apoptosis of the
      stromal fibroblasts in pN/pN skin strongly indicate additional roles of collagen
      V in the development of a functional skin matrix.

PMID- 15199159
TI  - Noncatalytic requirement for cyclin A-cdk2 in p27 turnover.
AB  - Ubiquitin-dependent proteolysis makes a major contribution to decreasing the
      levels of p27. Ubiquitin-dependent proteolysis of p27(kip1) is growth and cell
      cycle regulated in two ways: first, skp2, a component of the E3-ubiquitin ligase,
      is growth regulated, and second, a kinase must phosphorylate the threonine-187
      position on p27 so that it can be recognized by skp2. In vitro, p27 is
      phosphorylated by cyclin E- and cyclin A-associated cdk2 as well as by cyclin B1
      cdk1. Having analyzed the effect of different cyclin-cyclin-dependent kinase
      complexes on ubiquitination of p27 in a reconstitution assay system, we now
      report a noncatalytic requirement for cyclin A-cdk2. Multiparameter flow
      cytometric analysis also indicates that p27 turnover correlates best with the
      onset of S phase, once the levels of cyclin A become nearly maximal. Finally,
      increasing the amount of both cyclin E-cdk2 and skp2 was less efficient at
      promoting p27 ubiquitination than was increasing the amount of cyclin A-cdk2
      alone in extracts prepared from cultures of >93%-purified G(1) cells. Together
      these lines of evidence suggest that cyclin A-cdk2 plays an ancillary
      noncatalytic role in the ubiquitination of p27 by the SCF(skp2) complex.

PMID- 15199160
TI  - Immune functions in mice lacking Clnk, an SLP-76-related adaptor expressed in a
      subset of immune cells.
AB  - The SLP-76 family of immune cell-specific adaptors is composed of three distinct
      members named SLP-76, Blnk, and Clnk. They have been implicated in the signaling
      pathways coupled to immunoreceptors such as the antigen receptors and Fc
      receptors. Previous studies using gene-targeted mice and deficient cell lines
      showed that SLP-76 plays a central role in T-cell development and activation.
      Moreover, it is essential for normal mast cell and platelet activation. In
      contrast, Blnk is necessary for B-cell development and activation. While the
      precise function of Clnk is not known, it was reported that Clnk is selectively
      expressed in mast cells, natural killer (NK) cells, and previously activated T
      cells. Moreover, ectopic expression of Clnk was shown to rescue T-cell receptor
      mediated signal transduction in an SLP-76-deficient T-cell line, suggesting that,
      like its relatives, Clnk is involved in the positive regulation of immunoreceptor
      signaling. Stimulatory effects of Clnk on immunoreceptor signaling were also
      reported to occur in transfected B-cell and basophil leukemia cell lines. Herein,
      we attempted to address the physiological role of Clnk in immune cells by the
      generation of Clnk-deficient mice. The results of our studies demonstrated that
      Clnk is dispensable for normal differentiation and function of T cells, mast
      cells, and NK cells. Hence, unlike its relatives, Clnk is not essential for
      normal immune functions.

PMID- 15199161
TI  - Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT).
AB  - Hypoxia occurs during the development of the placenta in the first trimester and
      correlates with both trophoblast differentiation and the induction of telomerase
      activity through hTERT expression. We sought to determine the mechanism of
      regulation of hTERT expression during hypoxia. We show that hypoxia-inducible
      factor 1alpha (HIF-1alpha) and hTERT expression in the human placenta decrease
      with gestational age and that these are overexpressed in preeclamptic placenta, a
      major complication of pregnancy. Hypoxia not only transactivates the hTERT
      promoter activity but also enhances endogenous hTERT expression. The hTERT
      promoter region between -165 and +51 contains two HIF-1 consensus motifs, and in
      vitro reporter assays show that these are essential for hTERT transactivation by
      HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT
      expression during hypoxia, indicating that upregulation of hTERT by hypoxia is
      directly mediated through HIF-1. Our results provide persuasive evidence that the
      regulation of hTERT promoter activity by HIF-1 represents a mechanism for
      trophoblast growth during hypoxia and suggests that this may be a generalized
      response to hypoxia in various human disorders including resistance to cancer
      therapeutics by upregulating telomerase.

PMID- 15199162
TI  - The single-strand DNA binding activity of human PC4 prevents mutagenesis and
      killing by oxidative DNA damage.
AB  - Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly
      conserved single-strand DNA (ssDNA) binding domain of unknown function. We
      identified PC4 as a suppressor of the oxidative mutator phenotype of the
      Escherichia coli fpg mutY mutant and demonstrate that this suppression requires
      its ssDNA binding activity. Saccharomyces cerevisiae mutants lacking their PC4
      ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and
      peroxide-induced hypermutability. PC4 expression suppresses the peroxide
      sensitivity of the yeast sub1Delta mutant, suggesting that the human protein has
      a similar function. A role for yeast and human proteins in DNA repair is
      suggested by the demonstration that Sub1 acts in a peroxide resistance pathway
      involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog
      XPG. We show that XPG recruits PC4 to a bubble-containing DNA substrate with a
      resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the
      possible requirement for PC4 in either global or transcription-coupled repair of
      oxidative DNA damage to mediate the release of XPG bound to its substrate.

PMID- 15199163
TI  - SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for
      lymphocyte production and function.
AB  - Suppressors of cytokine signaling (SOCSs) are key regulators of cytokine-induced
      responses in hematopoietic as well as nonhematopoietic cells. SOCS1 and SOCS3
      have been shown to modulate T-cell responses, whereas the roles of other SOCS
      family members in the regulation of lymphocyte function are less clear. Here, we
      report the generation of mice with a targeted disruption of the Socs5 gene.
      Socs5(-/-) mice were born in a normal Mendelian ratio and were healthy and
      fertile. We found that SOCS5 is expressed in primary B and T cells in wild-type
      mice. However, no abnormalities in the lymphocyte compartment were seen in SOCS5
      deficient mice. We examined antigen- and cytokine-induced proliferative responses
      in B and T cells in the absence of SOCS5 and found no deviations from the
      responses seen in wild-type cells. Because SOCS5 has been implicated in Th1
      differentiation, we also investigated the importance of SOCS5 in T helper cell
      responses. Unexpectedly, SOCS5-deficient CD4 T cells showed no abnormalities in
      Th1/Th2 differentiation and Socs5(-/-) mice showed normal resistance to infection
      with Leishmania major. Therefore, although SOCS5 is expressed in primary B and T
      cells, it appears to be dispensable for the regulation of lymphocyte function.

PMID- 15199165
TI  - Colour Doppler ultrasound in dialysis access.

PMID- 15199166
TI  - Patients with Goodpasture's disease have two normal COL4A3 alleles encoding the
      NC1 domain of the type IV collagen alpha 3 chain.
AB  - BACKGROUND: Goodpasture's disease (GP) is a rare but severe disease characterized
      by anti-glomerular basement membrane antibodies, rapidly progressive
      glomerulonephritis and lung haemorrhage. The autoantibodies are restricted to a
      narrow epitope region on the NC1 domain of the alpha 3 chain of type IV collagen.
      GP is strongly associated with major histocompatibility complex (MHC) allele HLA
      DRB1-15. Recent research, however, has failed to identify a T-cell epitope with
      molecular characteristics that explain the relationship between the MHC class II
      molecule and the autoantibody generation. We hypothesized that an as yet
      unidentified sequence variant in exons 48-52 of the COL4A3 gene that encodes the
      NC1 domain of the type IV collagen alpha 3 chain could generate a new peptide
      sequence that, through interaction with specific MHC class II molecules, would
      increase the risk of developing GP. METHODS: All patients previously treated for
      GP at the Lund and Malmo University Hospitals, who were alive at the time of the
      study, were asked to participate. DNA was extracted from leukocytes and subjected
      to genomic tissue typing and sequencing of the COL4A3 gene exons 48-52. RESULTS:
      All 15 patients in the study had a nucleotide sequence in the COL4A3 gene
      encoding a protein identical to GenBank entry NM_000091. HLA D allele
      distribution was in line with previous publications, showing a strong positive
      association between HLA DRB1-15, HLA DQB1-6 and GP (P<0.02). Of the 15 GP
      patients, 73% carried HLA DRB1-15 and 87% carried the HLA DQB1-6 antigen.
      Corresponding figures for the controls were 27 and 50%. CONCLUSION: This study
      effectively falsifies the hypothesis that a minor alteration in the COL4A3 gene
      could be a major factor in the aetiology of GP. Scandinavian GP patients have an
      MHC distribution similar to that which has been described previously for Anglo
      Saxon patients.

PMID- 15199164
TI  - Mice deficient for all PIM kinases display reduced body size and impaired
      responses to hematopoietic growth factors.
AB  - The Pim family of proto-oncogenes encodes a distinct class of serine/threonine
      kinases consisting of PIM1, PIM2, and PIM3. Although the Pim genes are
      evolutionarily highly conserved, the contribution of PIM proteins to mammalian
      development is unclear. PIM1-deficient mice were previously described but showed
      only minor phenotypic aberrations. To assess the role of PIM proteins in
      mammalian physiology, compound Pim knockout mice were generated. Mice lacking
      expression of Pim1, Pim2, and Pim3 are viable and fertile. However, PIM-deficient
      mice show a profound reduction in body size at birth and throughout postnatal
      life. In addition, the in vitro response of distinct hematopoietic cell
      populations to growth factors is severely impaired. In particular, PIM proteins
      are required for the efficient proliferation of peripheral T lymphocytes mediated
      by synergistic T-cell receptor and interleukin-2 signaling. These results
      indicate that members of the PIM family of proteins are important but dispensable
      factors for growth factor signaling.

PMID- 15199167
TI  - Structure-specific DNA binding and bipolar helicase activities of PcrA.
AB  - PcrA is an essential helicase in Gram-positive bacteria, but its precise role in
      cellular DNA metabolism is currently unknown. The Staphylococcus aureus PcrA
      helicase has both 5'-->3' and 3'-->5' helicase activities. In this work, we have
      studied the binding of S.aureus PcrA to a variety of DNA substrates that
      represent intermediates in DNA replication, repair, recombination and
      transcription. PcrA bound poorly or not at all to single-stranded DNA, double
      stranded DNA with blunt ends, partially double-stranded DNA containing fork and
      bubble structures, and duplex DNA substrates containing either 5' or 3' single
      stranded oligo dT tails. Interestingly, PcrA bound with high affinity to
      partially duplex DNA containing hairpin structures adjacent to a 6 nt long 5'
      single-stranded region and one unpaired nucleotide (flap) at the 3' end. However,
      PcrA did not detectably bind to partial duplexes with folded regions adjacent to
      a 6 nt long 3' single-stranded tail (with or without a 1 nt flap at the 5' end).
      PcrA showed moderate helicase activity with partially double-stranded DNAs
      containing 3' or 5' single-stranded oligo dT tails, the 3'-->5' helicase activity
      being more efficient than its 5'-->3' helicase activity. Interestingly, PcrA
      showed maximal helicase activity with substrates containing folded structures and
      5' single-stranded tails, suggesting that its 5'-->3' helicase activity is
      greatly stimulated in the presence of specific structures. However, the 3'-->5'
      helicase activity of PcrA did not appear to be affected by the presence of folded
      substrates containing 3' single-stranded tails. Our data indicate that PcrA may
      recognize DNA substrates with specific structures in vivo and its 5'-->3' and 3'-
      >5' helicase activities may be involved in distinct cellular processes.

PMID- 15199168
TI  - MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or
      reaction product with its C-terminal domain.
AB  - MutY homolog (MUTYH) excises adenine opposite 8-oxoguanine (8-oxoG) in DNA, thus
      preventing occurrence of G:C to T:A transversion. In cell-free extract prepared
      from the thymocytes of wild type but not MUTYH-null mice, adenine opposite 8-oxoG
      in DNA was excised by MUTYH, however, the generated apurinic (AP) site opposite 8
      oxoG mostly remained unincised. Recombinant mouse MUTYH (mMUTYH) efficiently
      excised adenine opposite 8-oxoG and prevented mouse AP endonuclease (mAPEX1) from
      incising the generated AP site. In contrast, an AP site opposite 8-oxoG created
      by uracil DNA glycosylase or tetrahydrofuran opposite 8-oxoG was efficiently
      incised by mAPEX1 in the presence of an excess amount of mMUTYH. Mutant mMUTYH
      with R361A or G365D substitution, excised adenine opposite 8-oxoG as efficiently
      as did wild-type mMUTYH, but failed to prevent mAPEX1 from incising the generated
      AP site. Wild-type mMUTYH bound duplex oligonucleotides containing A:8-oxoG pair
      with a lower apparent K(d) than that of the mutants, and prevented OGG1 from
      excising 8-oxoG opposite adenine or the generated AP site. The G365D mutant
      failed to prevent OGG1 from excising 8-oxoG opposite the generated AP site, thus
      indicating that the protection of its own product by mMUTYH is an intrinsic
      function which depends on the C-terminal domain of mMUTYH.

PMID- 15199170
TI  - Thiostrepton-resistant mutants of Thermus thermophilus.
AB  - Ribosomal protein L11 and its associated binding site on 23S rRNA together
      comprise one of the principle components that mediate interactions of translation
      factors with the ribosome. This site is also the target of the antibiotic
      thiostrepton, which has been proposed to act by preventing important structural
      transitions that occur in this region of the ribosome during protein synthesis.
      Here, we describe the isolation and characterization of spontaneous thiostrepton
      resistant mutants of the extreme thermophile, Thermus thermophilus. All mutations
      were found at conserved positions in the flexible N-terminal domain of L11 or at
      conserved positions in the L11-binding site of 23S rRNA. A number of the mutant
      ribosomes were affected in in vitro EF-G-dependent GTP hydrolysis but all showed
      resistance to thiostrepton at levels ranging from high to moderate. Structure
      probing revealed that some of the mutations in L11 result in enhanced reactivity
      of adjacent rRNA bases to chemical probes, suggesting a more open conformation of
      this region. These data suggest that increased flexibility of the factor binding
      site results in resistance to thiostrepton by counteracting the conformation
      stabilizing effect of the antibiotic.

PMID- 15199169
TI  - Sensing complex regulatory networks by conformationally controlled hairpin
      ribozymes.
AB  - The hairpin ribozyme catalyses RNA cleavage by a mechanism utilizing its
      conformational flexibility during the docking of two independently folded
      internal loop domains A and B. Based on this mechanism, we designed hairpin
      ribozyme variants that can be induced or repressed by external effector
      oligonucleotides influencing the docking process. We incorporated a third domain
      C to assimilate alternate stable RNA motifs such as a pseudo-half-knot or an
      internal stem-loop structure. Small sequence changes in domain C allowed targeted
      switching of ribozyme activity: the same effector oligonucleotide can either
      serve as an inducer or repressor. The ribozymes were applied to trp leader mRNA,
      the RNA sequence tightly bound by l-tryptophan-activated trp-RNA-binding
      attenuation protein (TRAP). When domain C is complementary to this mRNA, ribozyme
      activity can be altered by annealing trp leader mRNA, then specifically reverted
      by its TRAP/tryptophan-mediated sequestration. This approach allows to precisely
      sense the activity status of a protein controlled by its metabolite molecule.

PMID- 15199171
TI  - Global structure of a DNA three-way junction by solution NMR: towards prediction
      of 3H fold.
AB  - Three-way junctions (3H) are the simplest and most commonly occurring branched
      nucleic acids. They consist of three double helical arms (A to C), connected at
      the junction point, with or without a number of unpaired bases in one or more of
      the three different strands. Three-way junctions with two unpaired bases in one
      strand (3HS2) have a high tendency to adopt either of two alternative stacked
      conformations in which two of the three arms A, B and C are coaxially stacked,
      i.e. A/B-stacked or A/C-stacked. Empirical stacking rules, which successfully
      predict for DNA 3HS2 A/B-stacking preference from sequence, have been extended to
      A/C-stacked conformations. Three novel DNA 3HS2 sequences were designed to test
      the validity of these extended stacking rules and their conformational behavior
      was studied by solution NMR. All three show the predicted A/C-stacking preference
      even in the absence of multivalent cations. The stacking preference for both
      classes of DNA 3HS2 can thus be predicted from sequence. The high-resolution NMR
      solution structure for one of the stacked 3HS2 is also reported. It shows a well
      defined local and global structure defined by an extensive set of classical NMR
      restraints and residual dipolar couplings. Analysis of its global conformation
      and that of other representatives of the 3H family, shows that the relative
      orientations of the stacked and non-stacked arms, are restricted to narrow
      regions of conformational space, which can be understood from geometric
      considerations. Together, these findings open up the possibility of full
      prediction of 3HS2 conformation (stacking and global fold) directly from
      sequence.

PMID- 15199172
TI  - Endonuclease III and endonuclease VIII conditionally targeted into mitochondria
      enhance mitochondrial DNA repair and cell survival following oxidative stress.
AB  - Mitochondrial DNA (mtDNA) is exposed to reactive oxygen species (ROS) produced
      during oxidative phosphorylation. Accumulation of several kinds of oxidative
      lesions, including oxidized pyrimidines, in mtDNA may lead to structural genomic
      alterations, mitochondrial dysfunction and associated degenerative diseases. In
      Escherichia coli, oxidative pyrimidines are repaired by endonuclease III
      (EndoIII) and endonuclease VIII (EndoVIII). To determine whether the
      overexpression of two bacterial glycosylase/AP lyases which predominantly remove
      oxidized pyrimidines from DNA, could improve mtDNA repair and cell survival, we
      constructed vectors containing sequences for the EndoIII and EndoVIII downstream
      of the mitochondrial targeting sequence (MTS) from manganese superoxide dismutase
      (MnSOD) and placed them under the control of the tetracycline (Tet)-response
      element. Successful integrations of MTS-EndoIII or MTS-EndoVIII into the HeLa Tet
      On genome were confirmed by Southern blot. Western blots of mitochondrial
      extracts from MTS-EndoIII and MTS-EndoVIII clones revealed that the recombinant
      proteins are targeted into mitochondria and their expressions are doxycycline
      (Dox) dependent. Enzyme activity assays and mtDNA repair studies showed that the
      Dox-dependent expressions of MTS-EndoIII and MTS-EndoVIII are functional, and
      both MTS-EndoIII and MTS-EndoVIII (Dox+) clones were significantly more
      proficient at repair of oxidative damage in their mtDNA. This enhanced repair led
      to increased cellular resistance to oxidative stress.

PMID- 15199175
TI  - The recognition and modification sites for the bacterial type I restriction
      systems KpnAI, StySEAI, StySENI and StySGI.
AB  - Using an in vivo plasmid transformation method, we have determined the DNA
      sequences recognized by the KpnAI, StySEAI, StySENI and StySGI R-M systems from
      Klebsiella oxytoca strain M5a1, Salmonella eastbourne, Salmonella enteritidis and
      Salmonella gelsenkirchen, respectively. These type I restriction-modification
      systems were originally identified using traditional phage assay, and described
      here is the plasmid transformation test and computer program used to determine
      their DNA recognition sequences. For this test, we constructed two sets of
      plasmids, pL and pE, that contain phage lambda and Escherichia coli K-12
      chromosomal DNA fragments, respectively. Further, using the methylation
      sensitivities of various known type II restriction enzymes, we identified the
      target adenines for methylation (listed in bold italics below as A or T in case
      of the complementary strand). The recognition sequence and methylation sites are
      GAA(6N)TGCC (KpnAI), ACA(6N)TYCA (StySEAI), CGA(6N)TACC (StySENI) and
      TAAC(7N)RTCG (StySGI). These DNA recognition sequences all have a typical type I
      bipartite pattern and represent three novel specificities and one isoschizomer
      (StySENI). For confirmation, oligonucleotides containing each of the predicted
      sequences were synthesized, cloned into plasmid pMECA and transformed into each
      strain, resulting in a large reduction in efficiency of transformation (EOT).

PMID- 15199173
TI  - A Rad50-dependent pathway of DNA repair is deficient in Fanconi anemia
      fibroblasts.
AB  - Fanconi anemia (FA) is a fatal genetic disorder associated with pancytopenia and
      cancer. Cells lacking functional FA genes are hypersensitive to bifunctional
      alkylating agents, and are deficient in DNA double-strand break repair. Multiple
      genes with FA-causing mutations have been cloned, however, the molecular basis
      for FA remains obscure. The results presented herein indicate that a Rad50
      dependent end-joining process is non-functional in diploid fibroblasts from FA
      patients. Introduction of anti-Rad50 antibody into normal fibroblasts sensitized
      them to DNA damaging agents, whereas this treatment had no effect on fibroblasts
      from FA patients. The DNA end-joining process deficient in FA cells also requires
      the Mre11, Nbs1 and DNA ligase IV proteins. These data reveal the existence of a
      previously uncharacterized Rad50-dependent DNA double-strand break repair pathway
      in mammalian somatic cells, and suggest that failure to activate this pathway is
      responsible, at least in part, for the defective DNA end-joining observed in FA
      cells.

PMID- 15199174
TI  - RNAProfile: an algorithm for finding conserved secondary structure motifs in
      unaligned RNA sequences.
AB  - The recent interest sparked due to the discovery of a variety of functions for
      non-coding RNA molecules has highlighted the need for suitable tools for the
      analysis and the comparison of RNA sequences. Many trans-acting non-coding RNA
      genes and cis-acting RNA regulatory elements present motifs, conserved both in
      structure and sequence, that can be hardly detected by primary sequence analysis
      alone. We present an algorithm that takes as input a set of unaligned RNA
      sequences expected to share a common motif, and outputs the regions that are most
      conserved throughout the sequences, according to a similarity measure that takes
      into account both the sequence of the regions and the secondary structure they
      can form according to base-pairing and thermodynamic rules. Only a single
      parameter is needed as input, which denotes the number of distinct hairpins the
      motif has to contain. No further constraints on the size, number and position of
      the single elements comprising the motif are required. The algorithm can be split
      into two parts: first, it extracts from each input sequence a set of candidate
      regions whose predicted optimal secondary structure contains the number of
      hairpins given as input. Then, the regions selected are compared with each other
      to find the groups of most similar ones, formed by a region taken from each
      sequence. To avoid exhaustive enumeration of the search space and to reduce the
      execution time, a greedy heuristic is introduced for this task. We present
      different experiments, which show that the algorithm is capable of characterizing
      and discovering known regulatory motifs in mRNA like the iron responsive element
      (IRE) and selenocysteine insertion sequence (SECIS) stem-loop structures. We also
      show how it can be applied to corrupted datasets in which a motif does not appear
      in all the input sequences, as well as to the discovery of more complex motifs in
      the non-coding RNA.

PMID- 15199176
TI  - Rapid preparation of RNA samples for NMR spectroscopy and X-ray crystallography.
AB  - Knowledge of the three-dimensional structures of RNA and its complexes is
      important for understanding the molecular mechanism of RNA recognition by
      proteins or ligands. Enzymatic synthesis using T7 bacteriophage RNA polymerase is
      used to prepare samples for NMR spectroscopy and X-ray crystallography. However,
      this run-off transcription method results in heterogeneity at the RNA 3-terminus.
      For structural studies, RNA purification requires a single nucleotide resolution.
      Usually PAGE purification is used, but it is tedious, time-consuming and cost
      ineffective. To overcome these problems in high-throughput RNA synthesis, we
      devised a method of RNA preparation that uses trans-acting DNAzyme and sequence
      specific affinity column chromatography. A tag sequence is added at the 3' end of
      RNA, and the tagged RNA is picked out using an affinity column that contains the
      complementary DNA sequence. The 3' end tag is then removed by sequence-specific
      cleavage using trans-acting DNAzyme, the arm lengths of which are optimized for
      turnover number. This purification method is simpler and faster than the
      conventional method.

PMID- 15199177
TI  - Inducible suppression of Fgfr2 and Survivin in ES cells using a combination of
      the RNA interference (RNAi) and the Cre-LoxP system.
AB  - RNA interference (RNAi) is a simple and powerful tool widely used for studying
      gene function in a number of species. Recently, inducible regulation of RNAi in
      mammalian cells using either tetracycline- or ecdysone-responsive systems has
      been developed to prevent potential lethality or non-physiological responses
      associated with persistent suppression of genes that are essential for cell
      survival or cell cycle progression. Here we show that the inducible regulation of
      RNAi also can be achieved by using a Cre-LoxP approach. We demonstrate that the
      insertion of a loxP-flanked neomycin cassette into RNA polymerase III promoter,
      which controls a vector-based RNAi unit, impairs the promoter activity. However,
      the expression of RNAi construct can be completely restored upon the removal of
      the neo cassette using a tamoxifen inducible Cre construct. We show that this
      system works with high efficiency in suppression of two endogenous genes, Fgfr2
      and Survivin, in mouse embryonic stem (ES) cells, as evidenced by the decrease of
      levels of gene expression, reduced cell proliferation and colony formation. This
      system provides a potentially important yet simple approach to establish mutant
      mouse strains for functional study at defined stages upon turning on the
      inducible switches controlled by the Cre-LoxP system.

PMID- 15199179
TI  - Comparative impacts of two major hurricane seasons on the Neuse River and western
      Pamlico Sound ecosystems.
AB  - Ecosystem-level impacts of two hurricane seasons were compared several years
      after the storms in the largest lagoonal estuary in the U.S., the Albemarle
      Pamlico Estuarine System. A segmented linear regression flow model was developed
      to compare mass-water transport and nutrient loadings to a major artery, the
      Neuse River Estuary (NRE), and to estimate mean annual versus storm-related
      volume delivery to the NRE and Pamlico Sound. Significantly less water volume was
      delivered by Hurricane Fran (1996), but massive fish kills occurred in
      association with severe dissolved oxygen deficits and high contaminant loadings
      (total nitrogen, total phosphorus, suspended solids, and fecal bacteria). The
      high water volume of the second hurricane season (Hurricanes Dennis, Floyd, and
      Irene in 1999) delivered generally comparable but more dilute contaminant loads,
      and no major fish kills were reported. There were no discernable long-term
      adverse impacts on water quality. Populations of undesirable organisms, such as
      toxic dinoflagellates, were displaced down-estuary to habitats less conducive for
      growth. The response of fisheries was species-dependent: there was no apparent
      impact of the hurricanes on commercial landings of bivalve molluscs or shrimp. In
      contrast, interacting effects of hurricane floodwaters in 1999 and intensive
      fishing pressure led to striking reductions in blue crabs. Overall, the data
      support the premise that, in shallow estuaries frequently disturbed by
      hurricanes, there can be relatively rapid recovery in water quality and biota,
      and benefit from the scouring activity of these storms.

PMID- 15199178
TI  - Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and
      mismatch repair proteins Msh2 and Msh6 but not Pms1.
AB  - Recombination between moderately divergent DNA sequences is impaired compared
      with identical sequences. In yeast, an HO endonuclease-induced double-strand
      break can be repaired by single-strand annealing (SSA) between flanking
      homologous sequences. A 3% sequence divergence between 205-bp sequences flanking
      the double-strand break caused a 6-fold reduction in repair compared with
      identical sequences. This reduction in heteroduplex rejection was suppressed in a
      mismatch repair-defective msh6 Delta strain and partially suppressed in an msh2
      separation-of-function mutant. In mlh1 Delta strains, heteroduplex rejection was
      greater than in msh6 Delta strains but less than in wild type. Deleting PMS1,
      MLH2,or MLH3 had no effect on heteroduplex rejection, but a pms1 Delta mlh2 Delta
      mlh3 Delta triple mutant resembled mlh1 Delta. However, correction of the
      mismatches within heteroduplex SSA intermediates required PMS1 and MLH1 to the
      same extent as MSH2 and MSH6. An SSA competition assay in which either diverged
      or identical repeats can be used for repair showed that heteroduplex DNA is
      likely to be unwound rather than degraded. This conclusion is supported by the
      finding that deleting the SGS1 helicase also suppressed heteroduplex rejection.

PMID- 15199180
TI  - TRPC3 channels confer cellular memory of recent neuromuscular activity.
AB  - Skeletal muscle adapts to different patterns of motor nerve activity by
      alterations in gene expression that match specialized properties of contraction,
      metabolism, and muscle mass to changing work demands (muscle plasticity).
      Calcineurin, a calcium/calmodulin-dependent, serine-threonine protein
      phosphatase, has been shown to control programs of gene expression in skeletal
      muscles, as in other cell types, through the transcription factor nuclear factor
      of activated T cells (NFAT). This study provides evidence that the function of
      NFAT as a transcriptional activator is regulated by neuromuscular stimulation in
      muscles of intact animals and that calcium influx from the transient receptor
      potential (TRPC3) channel is an important determinant of NFAT activity.
      Expression of TRPC3 channels in skeletal myocytes is up-regulated by
      neuromuscular activity in a calcineurin-dependent manner. These data suggest a
      mechanism for cellular memory in skeletal muscles whereby repeated bouts of
      contractile activity drive progressively greater remodeling events.

PMID- 15199181
TI  - Identification of a domain within the multifunctional Vibrio cholerae RTX toxin
      that covalently cross-links actin.
AB  - The Gram-negative pathogen Vibrio cholerae causes diarrheal disease through the
      export of enterotoxins. The V. cholerae RTX toxin was previously identified and
      characterized by its ability to round human laryngeal epithelial (HEp-2) cells.
      Further investigation determined that cell rounding is caused by the
      depolymerization of actin stress fibers, through the unique mechanism of covalent
      actin cross-linking. In this study, we identify a domain within the full-length
      RTX toxin that is capable of mediating the cross-linking reaction when
      transiently expressed within eukaryotic cells. A structure/function analysis of
      the actin cross-linking domain (ACD) reveals that a 412-aa, or a 47.8-kDa, region
      is essential for cross-linking activity. When this domain is deleted from the
      full-length toxin gene, actin cross-linking, but not cell rounding, is
      eliminated, indicating that this toxin carries multiple dissociable activities.
      The ACD shares 59% amino acid identity with a hypothetical protein from V.
      cholerae, VC1416, and transient expression of the C-terminal domain of VC1416
      also results in actin cross-linking in eukaryotic cells. The presence of this
      second ACD linked to an Rhs-like element suggests that V. cholerae acquired the
      domain by horizontal gene transfer and the ACD was inserted into the RTX toxin by
      gene duplication through the evolution of V. cholerae.

PMID- 15199182
TI  - First- and second-generation total synthesis of ciguatoxin CTX3C.
AB  - More than 20,000 people suffer annually from ciguatera seafood poisoning in
      subtropical and tropical regions. The extremely low content of the causative
      neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed
      biological studies, and preparation of anti-ciguatoxin antibodies for detecting
      these toxins. Furthermore, the large (3 nm in length) and complex molecular
      structure of ciguatoxins has impeded chemists from completing their total
      synthesis. In this article, the full details of studies leading to the total
      synthesis of ciguatoxin CTX3C are provided. The key elements of the first
      generation approach include O,O-acetal formation from the right and left wing
      fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to
      cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and
      final removal of the 2-naphtylmethyl protective groups. Subsequent studies
      provided a second-generation total synthesis, which is more concise and results
      in a higher yield. Second-generation synthesis was accomplished by using a direct
      method of constructing the key intermediate O,S-acetal from alpha-chlorosulfide
      and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin
      for biological applications.

PMID- 15199183
TI  - From The Cover: Binocularity and brain evolution in primates.
AB  - Primates are distinguished by frontally directed, highly convergent orbits, which
      are associated with stereoscopic vision. Although stereoscopic vision requires
      specialized neural mechanisms, its implications for brain evolution are unknown.
      Using phylogenetic comparative analysis, I show that evolutionary increases among
      primate taxa in the degree of orbital convergence correlate with expansion of
      visual brain structures and, as a consequence, with the overall size of the
      brain. This pattern is found across the whole primate order and is also repeated
      within each of the two major primate subtaxa. The visual expansion associated
      with increased binocularity is specific to the parvocellular visual pathway,
      consistent with recent evidence implicating this pathway in fine-grained
      stereopsis. The results support the hypothesis that brain size evolution in
      primates was associated with visual specialization.

PMID- 15199184
TI  - A chlamydial type III translocated protein is tyrosine-phosphorylated at the site
      of entry and associated with recruitment of actin.
AB  - The obligate intracellular bacterium Chlamydia trachomatis rapidly induces its
      own entry into host cells. Initial attachment is mediated by electrostatic
      interactions to heparan sulfate moieties on the host cell, followed by
      irreversible binding to an unknown secondary receptor. This secondary binding
      leads to the recruitment of actin to the site of attachment, formation of an
      actin-rich, pedestal-like structure, and finally internalization of the bacteria.
      How chlamydiae induce this process is unknown. We have identified a high
      molecular-mass tyrosine-phosphorylated protein that is rapidly phosphorylated on
      attachment to the host cell. Immunoelectron microscopy studies revealed that this
      tyrosine-phosphorylated protein is localized to the cytoplasmic face of the
      plasma membrane at the site of attachment of surface-associated chlamydiae. The
      phosphoprotein was isolated by immunoprecipitation with the antiphosphotyrosine
      antibody 4G10 and identified as the chlamydial protein CT456, a hypothetical
      protein with unknown function. The chlamydial protein (Tarp) appears to be
      translocated into the host cell by type III secretion because it is exported in a
      Yersinia heterologous expression assay. Phosphotyrosine signaling across the
      plasma membrane preceded the recruitment of actin to the site of chlamydial
      attachment and may represent the initial signal transduced from pathogen to the
      host cell. These results suggest that C. trachomatis internalization is mediated
      by a chlamydial type III-secreted effector protein.

PMID- 15199185
TI  - Integration of transcriptomics and metabolomics for understanding of global
      responses to nutritional stresses in Arabidopsis thaliana.
AB  - Plant metabolism is a complex set of processes that produce a wide diversity of
      foods, woods, and medicines. With the genome sequences of Arabidopsis and rice in
      hands, postgenomics studies integrating all "omics" sciences can depict precise
      pictures of a whole-cellular process. Here, we present, to our knowledge, the
      first report of investigation for gene-to-metabolite networks regulating sulfur
      and nitrogen nutrition and secondary metabolism in Arabidopsis, with integration
      of metabolomics and transcriptomics. Transcriptome and metabolome analyses were
      carried out, respectively, with DNA macroarray and several chemical analytical
      methods, including ultra high-resolution Fourier transform-ion cyclotron MS.
      Mathematical analyses, including principal component analysis and batch-learning
      self-organizing map analysis of transcriptome and metabolome data suggested the
      presence of general responses to sulfur and nitrogen deficiencies. In addition,
      specific responses to either sulfur or nitrogen deficiency were observed in
      several metabolic pathways: in particular, the genes and metabolites involved in
      glucosinolate metabolism were shown to be coordinately modulated. Understanding
      such gene-to-metabolite networks in primary and secondary metabolism through
      integration of transcriptomics and metabolomics can lead to identification of
      gene function and subsequent improvement of production of useful compounds in
      plants.

PMID- 15199186
TI  - Hyperosmolality triggers oxidative damage in kidney cells.

PMID- 15199187
TI  - A conserved signaling cassette regulates hair patterning from Drosophila to man.

PMID- 15199189
TI  - Linear ordering and dynamic segregation of the bacterial chromosome.

PMID- 15199188
TI  - Methionine sulfoxide reductase A is important for lens cell viability and
      resistance to oxidative stress.
AB  - Age-related cataract, an opacity of the eye lens, is the leading cause of visual
      impairment in the elderly, the etiology of which is related to oxidative stress
      damage. Oxidation of methionine to methionine sulfoxide is a major oxidative
      stress product that reaches levels as high as 60% in cataract while being
      essentially absent from clear lenses. Methionine oxidation results in loss of
      protein function that can be reversed through the action of methionine sulfoxide
      reductase A (MsrA), which is implicated in oxidative stress protection and is an
      essential regulator of longevity in species ranging from Escherichia coli to
      mice. To establish a role for MsrA in lens protection against oxidative stress,
      we have examined the levels and spatial expression patterns of MsrA in the human
      lens and have tested the ability of MsrA to protect lens cells directly against
      oxidative stress. In the present report, we establish that MsrA is present
      throughout the human lens, where it is likely to defend lens cells and their
      components against methionine oxidation. We demonstrate that overexpression of
      MsrA protects lens cells against oxidative stress damage, whereas silencing of
      the MsrA gene renders lens cells more sensitive to oxidative stress damage. We
      also provide evidence that MsrA is important for lens cell function in the
      absence of exogenous stress. Collectively, these data implicate MsrA as a key
      player in lens cell viability and resistance to oxidative stress, a major factor
      in the etiology of age-related cataract.

PMID- 15199190
TI  - Knockin mice with Leu9'Ser alpha4-nicotinic receptors: substantia nigra
      dopaminergic neurons are hypersensitive to agonist and lost postnatally.
AB  - This study analyzes the electrophysiological cause and behavioral consequence of
      dopaminergic cell loss in a knockin mouse strain bearing hypersensitive nicotinic
      alpha4-receptor subunits ("L9'S mice"). Adult brains of L9'S mice show moderate
      loss of substantia nigra dopaminergic neurons and of striatal dopaminergic
      innervation. Amphetamine-stimulated locomotion is impaired, reflecting a
      reduction of dopamine stored in presynaptic vesicles. Recordings from
      dopaminergic neurons in L9'S mice show that 10 microM nicotine depolarizes cells
      and increases spiking rates in L9'S cells but hyperpolarizes and decreases
      spiking rates in wild-type (WT) cells. Thus dopaminergic neurons of L9'S mice
      have an excitatory response to nicotine which is qualitatively different from
      that of WT neurons. The cause of dopaminergic cell death is therefore probably an
      increased sensitivity to acetylcholine or choline of alpha4-containing nicotinic
      receptors. Hypersensitive excitatory stimulation during activation of alpha4
      containing receptors provides the first evidence for cholinergic excitotoxicity
      as a cause of dopaminergic neuron death. This novel concept may be relevant to
      the pathophysiology of Parkinson disease.

PMID- 15199191
TI  - Statistics in the pharmacy literature.
AB  - BACKGROUND: Research in statistical methods is essential for maintenance of high
      quality of the published literature. OBJECTIVE: To update previous reports of the
      types and frequencies of statistical terms and procedures in research studies of
      selected professional pharmacy journals. METHODS: We obtained all research
      articles published in 2001 in 6 journals: American Journal of Health-System
      Pharmacy, The Annals of Pharmacotherapy, Canadian Journal of Hospital Pharmacy,
      Formulary, Hospital Pharmacy, and Journal of the American Pharmaceutical
      Association. Two independent reviewers identified and recorded descriptive and
      inferential statistical terms/procedures found in the methods, results, and
      discussion sections of each article. Results were determined by tallying the
      total number of times, as well as the percentage, that each statistical term or
      procedure appeared in the articles. RESULTS: One hundred forty-four articles were
      included. Ninety-eight percent employed descriptive statistics; of these, 28%
      used only descriptive statistics. The most common descriptive statistical terms
      were percentage (90%), mean (74%), standard deviation (58%), and range (46%).
      Sixty-nine percent of the articles used inferential statistics, the most frequent
      being chi(2) (33%), Student's t-test (26%), Pearson's correlation coefficient r
      (18%), ANOVA (14%), and logistic regression (11%). CONCLUSIONS: Statistical terms
      and procedures were found in nearly all of the research articles published in
      pharmacy journals. Thus, pharmacy education should aim to provide current and
      future pharmacists with an understanding of the common statistical terms and
      procedures identified to facilitate the appropriate appraisal and consequential
      utilization of the information available in research articles.

PMID- 15199192
TI  - Stem cell therapy of cardiac disease: an update.

PMID- 15199193
TI  - FTY720--the first compound of a new promising class of immunosuppressive drugs.

PMID- 15199194
TI  - Late nephrology referral and mortality among patients with end-stage renal
      disease: a propensity score analysis.
AB  - BACKGROUND: Late nephrology referral has been associated with adverse outcomes
      among patients with end-stage renal disease; however, its relationship to
      mortality is unclear. We examined the impact of timing of nephrology care
      relative to initiation of dialysis on mortality after initiation of dialysis.
      METHODS: Data from the Dialysis Morbidity and Mortality Study - Wave II, a
      prospective study of incident dialysis patients, were used. Late referral (LR)
      was defined as first nephrology visit <4 months and early referral (ER) as first
      nephrology visit >or=4 months prior to initiation of dialysis. Propensity scores
      (PS) were estimated using logistic regression to predict the probability that a
      given patient was LR. A Cox proportional hazards model was built to examine the
      association between timing of nephrology referral and mortality. RESULTS: The
      cohort was comprised of 2195 patients: 54% were males, 66% were Caucasians, 26%
      were African-Americans and 33% were referred late. A Cox proportional hazards
      analysis demonstrated that compared with ER patients, LR patients had a 44%
      higher risk of death at 1 year after initiation of dialysis [hazards ratio (HR) =
      1.44; 95% confidence interval (CI): 1.15-1.80], which remained significant after
      adjusting for quintiles of PS (HR = 1.42; 95% CI: 1.12-1.80). CONCLUSIONS: Among
      patients with chronic kidney disease (CKD) who initiated dialysis, LR was
      associated with higher risk of death at 1 year after initiation of dialysis
      compared with ER.

PMID- 15199195
TI  - Reducing high phosphate levels in patients with chronic renal failure undergoing
      dialysis: a 4-week, dose-finding, open-label study with lanthanum carbonate.
AB  - BACKGROUND: The majority of patients with end-stage renal disease on dialysis are
      hyperphosphataemic. Lanthanum carbonate has been shown to be a highly effective
      phosphate binder in pre-clinical studies. A 4-week, open-label, dose-titration
      trial was conducted to assess the ability of lanthanum carbonate to control
      phosphate levels in patients with chronic renal failure. METHODS: This
      preliminary study was of 6 weeks duration: 2 weeks of washout followed by 4 weeks
      of dose titration. Patients (n = 59) were titrated on the basis of weekly serum
      phosphate levels from a daily dose of 375 mg lanthanum carbonate to a maximum
      dose of 2250 mg. Patients were maintained on the dose that controlled serum
      phosphate to between 1.30 and 1.80 mmol/l (4.03-5.58 mg/dl). Serum phosphate
      levels represented the main efficacy assessment. Safety was also evaluated.
      RESULTS: Most patients were successfully titrated to 1500 and 2250 mg
      lanthanum/day (mean dose at end of titration: 1278 mg). At completion of the
      study 70% of patients achieved a serum phosphate of <or=1.80 mmol/l. The use of
      lanthanum carbonate in patients undergoing continuous ambulatory peritoneal
      dialysis or haemodialysis was generally well tolerated. CONCLUSIONS: Lanthanum
      carbonate, a new non-aluminium, non-calcium phosphate binder, effectively reduces
      serum phosphate levels. Results of longer-term efficacy and safety studies are
      awaited with interest.

PMID- 15199196
TI  - An unusual type of crystalluria (appearing only once every 130 years?).

PMID- 15199197
TI  - Growth failure in a girl with Fanconi syndrome and growth hormone deficiency.

PMID- 15199198
TI  - Aristolochic acid nephropathy complicating a patient with focal segmental
      glomerulosclerosis.

PMID- 15199199
TI  - Aggravation of non-steroidal anti-inflammatory drug-induced hepatitis and acute
      renal failure by slimming drug containing anthraquinones.

PMID- 15199200
TI  - Fulminant post-transplant lymphoproliferative disorder presenting with lactic
      acidosis and acute liver failure.

PMID- 15199201
TI  - Biopsy-proven anuric acute tubular necrosis associated with vancomycin and one
      dose of aminoside.

PMID- 15199202
TI  - Neurological complications from brachial arteriovenous fistulae.

PMID- 15199203
TI  - Hard times with hard water.

PMID- 15199204
TI  - Bilateral perirenal fluid accumulation associated with Eisenmenger's syndrome.

PMID- 15199205
TI  - Transplant renal artery kinking: a rare cause of early graft dysfunction.

PMID- 15199206
TI  - Metabolic alkalosis in patients with renal failure.

PMID- 15199207
TI  - Accurate measurement of albuminuria at reduced cost.

PMID- 15199208
TI  - After all those fat years: renal consequences of obesity.

PMID- 15199209
TI  - Plasmapheresis with immunosuppressive therapy vs immunosuppressive therapy alone
      for rapidly progressive anti-neutrophil cytoplasmic autoantibody-associated
      glomerulonephritis.

PMID- 15199210
TI  - Molecular forms of adiponectin in uraemic plasma.

PMID- 15199211
TI  - Acute renal failure due to tumor lysis syndrome in a HIV seropositive patient
      with Castleman's disease.

PMID- 15199212
TI  - Aldosterone and potassium balance in dialysis patients.

PMID- 15199213
TI  - Drug interaction between sevelamer and cyclosporin.

PMID- 15199214
TI  - Myalgia: an uncommon or underestimated side effect of mycophenolate mophetil
      after transplantation?

PMID- 15199215
TI  - Once-weekly erythropoietic therapy: is there a difference between the available
      preparations?

PMID- 15199216
TI  - Quantification of fetal microchimeric cells in clinically affected and unaffected
      skin of patients with systemic sclerosis.
AB  - OBJECTIVE: Fetal microchimerism has been hypothesized as a potential pathogenic
      mechanism for systemic sclerosis (SSc). This hypothesis was based on the clinical
      similarities between SSc and graft-vs-host disease and the identification of
      microchimeric cells in affected SSc tissues. The aim of this study was to compare
      the quantity of microchimeric cells in clinically affected and non-affected skin
      of female patients with SSc. METHODS: Fluorescence in situ hybridization (FISH)
      and real-time PCR were employed in paired skin biopsies obtained from clinically
      affected and unaffected areas from five female SSc patients with diffuse
      cutaneous SSc (dcSSC) and 10 healthy women. All women in the study had delivered
      a male fetus. RESULTS: FISH analysis revealed the presence of male fetal cells in
      1/5 SSc patients (20.0%) compared with 0/10 healthy women (P = 0.0037), whereas
      quantification by real-time PCR revealed that all SSc samples were positive for
      male DNA compared with none of the controls. In the five patients with dcSSc,
      there were similar numbers of microchimeric cells in both affected and unaffected
      skin (P = 0.4) CONCLUSION: The presence of higher numbers of microchimeric cells
      in clinically unaffected SSc skin, before any clinically detectable evidence of
      sclerotic changes, suggests that an influx of microchimeric cells may precede the
      development of tissue fibrosis. This provides additional support to the
      hypothesis that fetal microchimerism may play a role in the pathogenesis of SSc.

PMID- 15199217
TI  - Digital iontophoresis of vasoactive substances as measured by laser Doppler
      imaging--a non-invasive technique by which to measure microvascular dysfunction
      in Raynaud's phenomenon.
AB  - OBJECTIVE: To test the hypothesis that microvascular vasodilation is impaired in
      patients with systemic sclerosis (SSc) compared with patients with primary
      Raynaud's phenomenon (PRP) and healthy controls, using the technique of laser
      Doppler imaging to quantify blood flow responses to iontophoresis of vasoactive
      agents. METHODS: Microvascular blood flow was measured by laser Doppler imaging
      before, during and after 120 s iontophoresis (30 microA) of 1% acetylcholine
      chloride (ACh, endothelium-dependent) and 1% sodium nitroprusside (NaNP,
      endothelium-independent). Two adjacent fingers of the left hand were studied, and
      the procedure then repeated on the right. Ten patients with limited cutaneous SSc
      (LCSSc), 10 patients with PRP and 11 healthy control subjects were studied.
      RESULTS: Vasodilation in response to both ACh and NaNP iontophoresis, as measured
      by 'area under the blood flow.time curve' (AUC), normalized for baseline flux,
      was similar in the control and PRP groups, but was diminished in the LCSSc group
      compared with both control and PRP groups (ACh results: control vs LCSSc P =
      0.028, PRP vs LCSSc P = 0.005; NaNP results: control vs LCSSc P = 0.004, PRP vs
      LCSSc P = 0.005). There were no differences between groups in baseline flux
      values nor in voltages required to drive the 30 microA current. CONCLUSIONS: Both
      endothelium-dependent and endothelium-independent vasodilation are impaired in
      patients with LCSSc. Vasodilatory responses in patients with PRP are similar to
      those in controls. If reproducibility is confirmed to be satisfactory, then these
      techniques could be used to examine disease progression over time and
      responsiveness to vasoactive treatment, thus facilitating clinical trials.

PMID- 15199218
TI  - Synovial expression of osteopontin correlates with angiogenesis in juvenile
      idiopathic arthritis.
AB  - OBJECTIVE: To evaluate the synovial expression of osteopontin (OPN) and its
      possible correlation with the degree of synovial angiogenesis in human chronic
      idiopathic arthritis. METHODS: Forty-five patients with active juvenile
      idiopathic arthritis (JIA) were studied. All patients underwent SF aspiration
      before steroid injection. A paired plasma sample was collected from 22 JIA
      patients. Plasma from 15 age-matched healthy subjects was used as control. Plasma
      and SF were tested by ELISA for OPN and vascular endothelial growth factor
      (VEGF). Synovial tissue was obtained at synovectomy from 10 JIA patients.
      Immunohistochemistry was performed according to a standard technique with anti
      OPN, anti-CD68, anti-CD31 anti-VEGF and anti-alpha(v)beta(3) antibodies. RESULTS:
      OPN levels were significantly higher in SF than in paired plasma samples
      (P<0.001). The same pattern was observed for VEGF (P<0.001). A positive
      correlation between OPN and VEGF concentrations was found in SF (r = 0.6, P =
      0.001). In synovial tissue, OPN was expressed at the level of the lining and
      sublining layers with a distribution similar to that observed for VEGF. OPN
      expression in the lining layer correlated with the number of vessels present in
      the areas underlying the sublining layer. CONCLUSIONS: Synovial expression of OPN
      correlates with parameters of angiogenesis in JIA. These data support, in human
      disease, the possible role of OPN in the vascularization of inflamed synovial
      tissue, as previously shown in OPN-deficient animal models of arthritis.

PMID- 15199219
TI  - Albumin-coupled methotrexate (MTX-HSA) is a new anti-arthritic drug which acts
      synergistically to MTX.
AB  - OBJECTIVE: To evaluate the anti-arthritic effects of the new inflammation
      targeted drug MTX-HSA and to investigate whether peripheral blood mononuclear
      cells (PBMC) are potential target cells for albumin-mediated drug delivery.
      METHODS: The murine model of collagen-induced arthritis (CIA) was used to measure
      the anti-arthritic effect of MTX, MTX-HSA or a combination of both (n = 30 to 35
      per group). In addition, the uptake of fluorescence-labelled albumin (AFLc-HSA)
      in PBMC of 14 patients with RA was measured by fluorescence-activated cell
      sorting (FACS). RESULTS: In equivalent doses of 7.5 mg/kg intravenously (IV)
      twice a week, MTX-HSA is significantly (P<0.02) superior to MTX in inhibiting the
      development of CIA and reducing the joint count as well as the number of affected
      paws. When given in lower doses as combination therapy, both drugs act
      synergistically (P<0.03). A mean of 96, 72 and 64% of the CD14-, CD16- and CD20
      positive cells from peripheral blood of rheumatoid arthritis (RA) patients showed
      an uptake of albumin after incubation with AFLc-HSA in vitro. This finding was
      not significantly different in comparison to healthy controls. In contrast, the
      number of CD3-positive cells taking up albumin is increased significantly in RA
      patients in comparison to controls (26.3 +/- 12.9% s.d. vs 11.6 +/- 7.3% s.d.; P
      = 0.005). CONCLUSION: The data show that the effectiveness of MTX-HSA in CIA is
      superior to MTX and that both drugs act synergistically. In addition, albumin
      appears to be taken up by peripheral blood cells, suggesting that they might be
      one of the potential target cells of this novel anti-arthritic treatment
      approach.

PMID- 15199220
TI  - Which cartilage is regenerated, hyaline cartilage or fibrocartilage? Non-invasive
      ultrasonic evaluation of tissue-engineered cartilage.
AB  - OBJECTIVE: To investigate ultrasonic evaluation methods for detecting whether the
      repair tissue is hyaline cartilage or fibrocartilage in new cartilage
      regeneration therapy. METHODS: We examined four experimental rabbit models: a
      spontaneous repair model (group S), a large cartilage defect model (group L), a
      periosteal graft model (group P) and a tissue-engineered cartilage regeneration
      model (group T). From the resulting ultrasonic evaluation, we used %MM (the
      maximum magnitude of the measurement area divided by that of the intact
      cartilage) as a quantitative index of cartilage regeneration. The results of the
      ultrasonic evaluation were compared with the histological findings and
      histological score. RESULTS: The %MM values were 61.1 +/- 16.5% in group S, 29.8
      +/- 15.1% in group L, 36.3 +/- 18.3% in group P and 76.5 +/- 18.7% in group T.
      The results showed a strong similarity to the histological scoring. CONCLUSION:
      The ultrasonic examination showed that all the hyaline-like cartilage in groups S
      and T had a high %MM (more than 60%). Therefore, we could define the borderline
      between the two types of regenerated cartilage by the %MM.

PMID- 15199221
TI  - The role of perceived and actual disease status in adjustment to rheumatoid
      arthritis.
AB  - OBJECTIVES: To examine the role and relative impact of illness perceptions,
      coping strategies and clinical disease indicators on adjustment in patients with
      rheumatoid arthritis. METHOD: Participants were 75 women with rheumatoid
      arthritis. The Illness Perception Questionnaire (IPQ), the COPE questionnaire and
      the Arthritis Impact Measurement Scale (AIMS) were administered during a
      semistructured interview. Disease status was indicated by physician ratings of
      joint involvement and by the laboratory indices of erythrocyte sedimentation rate
      (ESR) and C-reactive protein (CRP). RESULTS: Statistically significant
      correlations (P<0.01) were in the expected direction. Various aspects of
      adjustment (good physical function, low pain and depression) were associated with
      perceptions of low illness identity, high control/cure, more serious illness
      consequences and long illness timeline. Low disease activity was related to good
      physical function. Depression was associated with high use of coping by denial
      and with less frequent use of five COPE strategies: active coping, planning,
      seeking instrumental social support, positive reinterpretation and growth, and
      acceptance. In hierarchical regression analysis, disease status explained
      variance in physical function (15%). Illness perceptions accounted for variance
      in all three adjustment outcomes, ranging from 22 to 27%. Coping variables did
      not add to the explanation of variance on adjustment. CONCLUSIONS: Illness
      perceptions have significant implications for adaptation to illness and they
      outweigh the impact of medical disease status on depression, physical function
      and pain. Health interventions based on understanding and modifying perceptions
      of illness may prove useful in facilitating patient well-being.

PMID- 15199222
TI  - High-resolution characterization of the pancreatic adenocarcinoma genome.
AB  - The pancreatic adenocarcinoma genome harbors multiple amplifications and
      deletions, pointing to the existence of numerous oncogenes and tumor suppressor
      genes driving the genesis and progression of this lethal cancer. Here, array
      comparative genomic hybridization on a cDNA microarray platform and informatics
      tools have been used to define the copy number alterations in a panel of 24
      pancreatic adenocarcinoma cell lines and 13 primary tumor specimens. This high
      resolution genomic analysis has identified all known regional gains and losses as
      well as many previously uncharacterized highly recurrent copy number alterations.
      A systematic prioritization scheme has selected 64 focal minimal common regions
      (MCRs) of recurrent copy number change. These MCRs possess a median size of 2.7
      megabases (Mb), with 21 (33%) MCRs spanning 1 Mb or less (median of 0.33 Mb) and
      possessing an average of 15 annotated genes. Furthermore, complementary
      expression profile analysis of a significant fraction of the genes residing
      within these 64 prioritized MCRs has enabled the identification of a subset of
      candidates with statistically significant association between gene dosage and
      mRNA expression. Thus, the integration of DNA and RNA profiles provides a highly
      productive entry point for the discovery of genes involved in the pathogenesis of
      pancreatic adenocarcinoma.

PMID- 15199223
TI  - CD40: a growing cytoplasmic tale.
AB  - CD40, a member of the tumor necrosis factor (TNF) receptor family that is
      expressed on B cells, monocytes, dendritic cells, endothelial cells, and
      epithelial cells, as well as on B cell lymphomas and carcinomas, activates
      multiple signaling pathways. In B cells, the response to CD40 is complex and
      depends on the maturation status of the cell. It is well established that CD40
      can promote cell survival through up-regulation of the expression of genes
      encoding antiapoptotic proteins. However, a new role for CD40 signaling is being
      recognized in promoting progression through the cell cycle. The roles of the
      phosphoinositide 3-kinase, mitogen-activated protein kinase, and nuclear factor
      kappaB pathways in mediating CD40 stimulation of the cell cycle are described.

PMID- 15199224
TI  - Cold shock response and adaptation at near-freezing temperature in
      microorganisms.
AB  - Microorganisms that naturally encounter sharp temperature shifts must develop
      strategies for responding and adapting to these shifts. Escherichia coli, which
      are adapted to living at both warm temperatures inside animals and cooler ambient
      temperatures, respond to low temperatures (10 degrees to 15 degrees C) by
      adjusting membrane lipid composition and increasing the production of proteins
      that act as "RNA chaperones" required for transcription and translation and
      proteins that facilitate ribosomal assembly. In contrast, yeast, which are
      adapted to cooler temperatures, show a relatively minor cold shock response after
      temperature shifts from 30 degrees to 10 degrees C but respond with a dramatic
      increase in the synthesis of trehalose and a heat shock protein when exposed to
      freezing or near-freezing temperatures. This emphasizes the fact that different
      groups of microorganisms exhibit distinct types of cold shock responses.

PMID- 15199225
TI  - Effects of recovery mode on performance, O2 uptake, and O2 deficit during high
      intensity intermittent exercise.
AB  - The aim of this study was to determine the influence of activity performed during
      the recovery period on the aerobic and anaerobic energy yield, as well as on
      performance, during high-intensity intermittent exercise (HIT). Ten physical
      education students participated in the study. First they underwent an incremental
      exercise test to assess their maximal power output (Wmax) and VO2max. On
      subsequent days they performed three different HITs. Each HIT consisted of four
      cycling bouts until exhaustion at 110% Wmax. Recovery periods of 5 min were
      allowed between bouts. HITs differed in the kind of activity performed during the
      recovery periods: pedaling at 20% VO2max (HITA), stretching exercises, or lying
      supine. Performance was 3-4% and aerobic energy yield was 6-8% (both p < 0.05)
      higher during the HITA than during the other two kinds of HIT. The greater
      contribution of aerobic metabolism to the energy yield during the high-intensity
      exercise bouts with active recovery was due to faster VO2 kinetics (p< 0.01) and
      a higher VO2peak during the exercise bouts preceded by active recovery (p <
      0.05). In contrast, the anaerobic energy yield (oxygen deficit and peak blood
      lactate concentrations) was similar in all HITs. Therefore, this study shows that
      active recovery facilitates performance by increasing aerobic contribution to the
      whole energy yield turnover during high-intensity intermittent exercise.

PMID- 15199226
TI  - Anaerobic exercise and oxidative stress: a review.
AB  - Oxidative stress and subsequent damage to cellular proteins, lipids, and nucleic
      acids, as well as changes to the glutathione system, are well documented in
      response to aerobic exercise. However, far less information is available on
      anaerobic exercise-induced oxidative modifications. Recent evidence indicates
      that high intensity anaerobic work does result in oxidative modification to the
      above-mentioned macromolecules in both skeletal muscle and blood. Also, it
      appears that chronic anaerobic exercise training can induce adaptations that act
      to attenuate the exercise-induced oxidative stress. These may be specific to
      increased antioxidant defenses and/or may act to reduce the generation of pro
      oxidants during and after exercise. However, a wide variety of exercise protocols
      and assay procedures have been used to study oxidative stress pertaining to
      anaerobic work. Therefore, precise conclusions about the exact extent and
      location of oxidative macromolecule damage, in addition to the adaptations
      resulting from chronic anaerobic exercise training, are difficult to indicate.
      This manuscript provides a review of anaerobic exercise and oxidative stress,
      presenting both the acute effects of a single exercise bout and the potential for
      adaptations resulting from chronic anaerobic training.

PMID- 15199227
TI  - Force maintenance with submaximal fatiguing contractions.
AB  - Whereas many definitions of fatigue include externally measurable decrements in
      force or performance, fatigue can be present with no change in the external
      output of the muscle. The maintenance of submaximal forces can be considered a
      compromise between neuromuscular force enhancement and competing inhibitory
      influences. An example of a muscle facilitatory process includes postactivation
      potentiation that results in an increased sensitivity to Ca++. The neuromuscular
      system copes with metabolic disruption and subsequent loss of force by recruiting
      additional motor units and increasing the firing frequency. If the contraction
      persists, firing frequency may decrease so as to optimize the stimulus rate with
      the prolonged duration of the muscle fibre action potential (muscle wisdom). The
      insertion of additional neural impulses into the train of stimuli can result in
      force potentiation (catch-like properties). Furthermore, there is evidence of
      neural potentiation and a dissociation of muscle activity with submaximal
      fatigue. Conversely, inhibition may be derived supraspinally or at the spinal
      level. While there may be some evidence of intrinsic motoneuronal fatigue,
      inhibitory afferent influences from chemical, tensile, pressure, and other
      factors play an important role in the competing influences on force output.

PMID- 15199228
TI  - Membrane excitability, weakness, and fatigue.
AB  - A failure in membrane excitability, defined as an inability of the sarcolemma and
      T-tubule to translate the neural discharge command into repetitive action
      potentials, represents an inviting cause of mechanical disfunction in both health
      and disease. A failure at this level would precipitate a disturbance in signal
      transmission between the T-tubule and the calcium release channels of the
      sarcoplasmic reticulum, resulting in reduced release of Ca2+, lower cytosolic
      free Ca2+ levels, and depressed myofibrillar activation and force generation. The
      ability of the sarcolemma and T-tubules to conduct repetitive action potentials
      is intimately dependent on active transport of Na+ and K+ following an action
      potential. The active transport of these cations is mediated by the Na+-K+
      ATPase, an integral membrane protein that uses the energy from the hydrolysis of
      1 ATP to transport 3 Na+ out of the cell and 2 K+ into the cell. A failure to
      recruit sufficient Na+-K+-ATPase activity during contractile activity could
      result in a rundown of the transmembrane gradients for Na+ and K+, leading to a
      loss of membrane excitability. The Na+-K+-ATPase activity depends on the amount
      and isoform composition of the protein, substrate availability, and acute
      regulatory factors. Each of these factors is examined as a potential cause of
      altered activation of the Na+-K+-ATPase activity and loss of membrane
      excitability in fatigue. Regular exercise represents a potent stimulus for
      upregulating Na+-K+-ATPase levels and for increasing the ability for cation
      transport across the sarcolemma and T-tubule membrane. As such, training may be a
      valuable tool in the management of fatigue in health and disease.

PMID- 15199229
TI  - The sarcoplasmic reticulum in muscle fatigue and disease: role of the
      sarco(endo)plasmic reticulum Ca2+-ATPase.
AB  - Skeletal muscles induced to contract repeatedly respond with a progressive loss
      in their ability to generate a target force or power. This condition is known
      simply as fatigue. Commonly, fatigue may persist for prolonged periods of time,
      particularly at low activation frequencies, which is called low-frequency
      fatigue. Failure to activate the contractile apparatus with the appropriate
      intracellular free calcium ([Ca2+]f) signal contributes to fatigue but the
      precise mechanisms involved are unknown. The sarcoplasmic reticulum (SR) is the
      major organelle in muscle that is responsible for the regulation of [Ca2+]f, and
      numerous studies have shown that SR function, both Ca2+ release and Ca2+ uptake,
      is impaired following fatiguing contractile activity. The major aim of this
      review is to provide insight into the various cellular mechanisms underlying the
      alterations in SR Ca2+ cycling and cytosolic [Ca2+]f that are associated both
      with the development of fatigue during repeated muscle contraction and with low
      frequency or long-lasting fatigue. The primary focus will be on the role of the
      sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in normal muscle function,
      fatigue, and disease.

PMID- 15199230
TI  - The myofibrillar complex and fatigue: a review.
AB  - The basis for all biological movement is the conversion of chemical energy to
      mechanical energy by different classes of motor proteins. In skeletal muscle this
      motor protein is myosin II, a thick filament-based molecule that harnesses the
      free energy furnished by ATP hydrolysis to perform mechanical work against actin
      proteins of the thin filament. The cyclic attachment and detachment of myosin
      with actin that generates muscle force and shortening is Ca2+ regulated. Intense
      muscle activity may lead to metabolically induced inhibitions to the function of
      these myofibrillar proteins when Ca2+ regulation is normal, a phenomenon referred
      to as myofibrillar fatigue. Studies using single muscle fibers at room
      temperature or lower have shown that myosin motor function is inhibited by the
      accumulation of the ATP-hydrolysis products ADP, Pi, and H+ as well as by excess
      generation of reactive oxygen species (ROS). These metabolically induced
      impairments to myosin motor function reduce muscle work and power output by
      impairing maximal Ca2+ activated force, the Ca2+ sensitivity of force, and/or
      unloaded shortening velocity. Based on uncertainties about their inhibitory
      effect on muscle function at more physiological temperatures, the influence of
      ATP-hydrolysis product and ROS accumulation on myofibrillar protein function of
      human skeletal muscle remains to be clarified.

PMID- 15199231
TI  - Mechanisms and management of fatigue in health and disease: symposium
      introduction.
AB  - Exercise intolerance is a condition commonly experienced by both the healthy and
      those with disease. Yet we have only a limited understanding of the underlying
      mechanisms and, consequently, the management of this condition. In this
      Symposium, a major objective was to address the role of the muscle cell in
      weakness and fatigue. We have focused on addressing the advances made in
      characterizing the basis of muscle cell contractility with particular respect to
      the processes and proteins involved in excitation and contraction, and how these
      processes can be modified during repetitive activity. Three reviews are provided
      on this subject. Each addresses a specific link in the cascade of events from
      neural activation of the muscle to the generation of force. In the first review
      the processes involved in signal transduction in the sarcolemma and T-tubule, and
      which regulate membrane excitability, are examined. The second review analyzes
      the sarcoplasmic reticulum regulation of the intracellular messenger that
      controls the myofibrillar complex, namely free calcium. The final review in this
      series deals with the events regulating actin-myosin behaviour and the mechanical
      response. All reviews place special emphasis on how different sites can be
      modified by repetitive activity and, as a consequence, how they can represent a
      potential source of fatigue. Since it is important to understand the nature,
      manifestations, and measurement of weakness and fatigue, a comprehensive review
      on these topics is also provided.

PMID- 15199232
TI  - Measurement of nitric oxide by reconversion of nitrate/nitrite to NO.
AB  - A simple and sensitive method is presented to measure the unstable molecule
      nitric oxide (NO) by reconversion of nitrate/nitrite to NO. Nitrate and nitrite
      are the stable degradation products of NO that accumulate in supernatants of
      biological samples that release nitric oxide. First, nitrate is enzymatically
      converted to nitrite using nitrate reductase. In a second step, nitrite is
      reduced to equimolar NO concentrations by an acidic iodide solution and
      quantified with an amperometric Clark-type electrode. This method provides the
      ability to assess basal-and agonist-stimulated cumulative NO formation in
      different biological models and is a sensitive alternative to the widely used
      Griess assay.

PMID- 15199233
TI  - High-resolution capillary electrophoresis of nitrite and nitrate in biological
      samples.
AB  - Nitrite and nitrate are widely used reporters of endogenous nitric oxide (NO) and
      nitric oxide synthase (NOS) activity, which are crucial for a broad spectrum of
      physiological and pathophysiological pathways. Because of the great variety in
      spatial expression and activity of NOS in animal tissues, a high-resolution
      analysis of nitrite/nitrate concentrations in very small biological samples, such
      as individual cells or homogeneous cell clusters, is required. A high-performance
      capillary zone electrophoresis (CZE) system, which includes a PrinCE-476
      computerized capillary electrophoresis and Crystal-1000 conductivity detector,
      was optimized to analyze nitrite/nitrate concentrations in submicroliter samples
      of mammalian neuronal tissues and large individual cells of invertebrates. Solid
      phase microextraction (SPME) and Isotachophoretic stacking (ITS) were used. The
      method is highly reproducible and yield excellent limits of detection (LODs): 8.9
      nM (0.41 ppb) and 3.54 nM (0.22 ppb) for nitrite and nitrate, respectively,
      relative to undiluted samples.

PMID- 15199234
TI  - Nitrite and nitrate measurements in human urine by capillary electrophoresis.
AB  - Nitrite and nitrate represent relatively stable nitric oxide (NO) end products in
      several biological fluids. The amounts of nitrite and/or nitrate in urine have
      been shown to reflect local and/or systemic involvement of NO in pathological
      conditions, including urinary tract infections and cardiac and renal allograft
      rejection. Capillary electrophoresis (CE) has been used in analysis of several
      ions and micromolecules. Electrokinetic and hydrodynamic sample injections are
      the main methods of injecting samples onto capillary columns. The urine sample
      matrix may widely vary depending on urine concentration, urine pH, and ion
      intake. This chapter illustrates the measurement of nitrite and nitrate in urine
      by CE and the comparison between electrokinetic and hydrodynamic sample
      injections.

PMID- 15199235
TI  - In vivo nitric oxide measurements using a microcoaxial electrode.
AB  - Nitric oxide (NO) is a vital molecule contributing to numerous physiological
      phenomena in various biological systems. To investigate the physiological role of
      NO, a range of NO-specific electrodes allowing direct and continuous NO
      measurement have been developed for in vitro and in vivo NO detection. A
      microcoaxial electrode has also been developed for the measurement of real-time
      NO levels. Because the working and reference electrodes in this device are
      situated close together, the microcoaxial electrode is considered to be ideal for
      the measurement of local NO concentrations with high spatial resolution. The
      microcoaxial electrode has been successfully applied to the real-time measurement
      of NO in endothelial cells, thereby demonstrating its effectiveness as an NO
      specific electrode. In this chapter, we describe our experimental protocol for
      performing real-time NO measurements that was developed during physiological
      experiments using the microcoaxial electrode.

PMID- 15199236
TI  - Measurement of exhaled nitric oxide.
AB  - Assessment of the value of exhaled NO (eNO) is an attractive tool for studying
      pulmonary disease, considering its wide advantages (i.e., fast analysis,
      noninvasive sampling, ability to measure large numbers of subjects [including
      children], and inexpensive in use). Increased concentrations of eNO have been
      observed in asthmatic patients' airway infections, allergic rhinitis, and
      bronchiectasis. During inflammation, specific and nonspecific stimuli elicit
      expression and de novo synthesis of inducible nitric oxide (iNOS). Once generated
      in the bronchiolar cells, NO is released from the tissue and diffuses to the
      lumen of the bronchiolis. Of the two sampling ways (on-line and off-line), the
      off-line method is suitable for monitoring environmental health effects of air
      pollution and for obtaining an impression of the prevalence of atopy in
      epidemiological surveys. For this off-line measurement, a balloon method is
      developed (sampling exhaled air at location) that includes a sample device
      assuring inflation of balloons at a controlled flow rate and back-pressure.
      Cigarette smoking and alcohol consumption significantly reduces NO levels in
      exhaled air because of downregulation of iNOS. Although eNO can be reliably
      measured and analyzed, the prospective value to detect asthma or allergy is
      rather low (low sensitivity and low specificity), which makes the diagnostic
      value of eNO for predicting either allergy or asthma doubtful. Promising results
      have, however, been observed in corticoid-sparing therapies under guidance of
      eNO. In addition, measurement of eNO helps to understand the mechanisms of
      pulmonary disease and may be useful in detecting adverse effects of air
      pollution.

PMID- 15199237
TI  - Nitric oxide imaging in neurons using confocal microscopy.
AB  - The instability and low concentration of nitric oxide (NO) in specimens make it
      difficult to be detected directly. In this chapter, a method for imaging nitric
      oxide using laser scanning confocal microscopy (LSCM) is presented. A cultured
      hippocampal neuron is dyed with DAF-2 and observed under a Zeiss LSM 510 laser
      scanning confocal microscope. A 488-nm laser power is applied as excitation and
      the emission light from the labeled nitric oxide in the neuron is detected. In
      this way, nitric oxide is imaged and its intracellular kinetic change is
      monitored. Furthermore, image processing and visualization techniques are
      employed to help analyze the image data.

PMID- 15199238
TI  - Measurement of nitric oxide synthase activity in vivo and in vitro by gas
      chromatography-mass spectrometry.
AB  - Measurement of the nitric oxide (NO) metabolites nitrite and nitrate in
      biological matrices is a reliable method to assess NO synthase (NOS) activity.
      Unlike the "L-citrulline assay," the "nitrite/nitrate assay" is generally
      applicable and permits acquisition of maximum information about what NOS did
      actually produce. From the various analytical approaches and methods available so
      far for the quantitation of nitrite and nitrate, mass-spectrometry-based methods,
      notably gas chromatography-mass spectrometry (GC-MS), offer the highest
      reliability in terms of accuracy, precision, specificity, minimum of
      interferences, sensitivity, and no limitation regarding biological matrix. Among
      the GC-MS methods, that one utilizing the derivatization reagent
      pentafluorobenzyl bromide is the single assay permitting measurement of nitrite
      and nitrate. This method possesses the unique opportunity to measure
      simultaneously stable-isotope-labeled nitrite and nitrate (i.e. [15N]nitrite and
      [15N]nitrate), which are exclusively produced by NOS-catalyzed oxidation of L
      [guanidino-15N2]-arginine, the stable-isotope-labeled L-arginine analog. *NOS may
      concomitantly produce *NO and O2*-, thus forming peroxynitrite (ONOO-), which
      also degrades to nitrite and nitrate. Thus, the GC-MS nitrite/nitrate assay
      provides information about biologically relevant NOS activity This chapter
      describes GC-MS protocols for the measurement of NOS activity in vitro (e.g., of
      isolated NOS preparations and in cells) and in vivo (in animals and humans).

PMID- 15199239
TI  - A nonradioactive assay for nitric oxide synthase activity in tissue extracts.
AB  - We describe a fluorescence assay for nitric oxide synthase activity based on a
      new indicator, 4,5-diaminofluorescein (DAF-2). The method offers the advantage of
      being safer and more convenient than the citrulline radioassay in common use. The
      rapid and irreversible binding of DAF-2 to oxidized nitric oxide (NO) enables NO
      production to be measured in real time. The protocol is applied to the
      measurement of nitric oxide synthase in crude extracts of skeletal muscle.

PMID- 15199240
TI  - Measurement of nitric oxide-related enzymes in the brain by in situ
      hybridization.
AB  - Functional genomic increasingly requires the cell-specific localization of gene
      expression. The histological analysis of mRNA expression is performed by in situ
      hybridization (ISH), whereas proteins are detected by immunohistochemistry. ISH
      allows the rapid detection of any transcript with the same protocol provided that
      its cDNA is known. This is an advantage compared to immunohistochemistry, which
      necessitates the raise of specific antibodies and the test of different
      procedures depending on the antigens to detect. However, ISH is subject to
      multiple technical difficulties. We have developed a nonradioactive ISH protocol
      allowing the simultaneous coupling of immunohistochemistry to follow gene
      expression at the protein level on the same section as the mRNA detection. This
      chapter describes the neuronal nitric oxide synthase (nNOS), argininosuccinate
      synthetase (AS), and argininosuccinate lyase (AL) mRNA expression in the rat
      brain to illustrate the methods allowing the nonradioactive localization of
      transcripts by ISH, coupled to immunohistochemistry to identify the specific cell
      types of central nervous system (CNS) on the same section.

PMID- 15199241
TI  - Real-time polymerase chain reaction to quantify mRNA for endothelial nitric oxide
      synthase.
AB  - The endothelial isoform of nitric oxide synthase (eNOS) plays a major role in
      vascular biology and emerging evidence suggests it may serve diverse biological
      functions in nonvascular cells. To be able to study the eNOS at the molecular
      level, including regulation of mRNA levels, we developed real-time reverse
      transcription-polymerase chain reaction methodology for sensitive and precise
      quantification of mRNA levels. In addition to providing quantification of mRNA
      levels, the method should be attractive because of its high sensitivity and the
      fact that blood vessels from small species such as genetically altered mice can
      be studied. Here, we demonstrate that the method can measure mRNA levels in
      cerebral and coronary arteries from mice, in addition to larger blood vessels.

PMID- 15199242
TI  - Dioxygen-dependent metabolism of nitric oxide.
AB  - Nitric oxide (NO) serves critical signaling, energetic, and toxic functions
      throughout the biosphere. NO steady-state levels and functions are controlled in
      part by NO metabolism or degradation. Dioxygen-dependent NO dioxygenases (EC
      1.14.12.17) and dioxygen-independent NO reductases (EC 1.7.99.7) are being
      identified as major routes for NO metabolism in various life forms. Here we
      describe the use of the Clark-type NO electrode, mechanistic inhibitors, and
      nitrate/nitrite assays to measure, characterize, and identify major NO metabolic
      pathways and enzymes in bacteria, fungi, plants, mammalian cells, and organelles.
      The methods may prove to be particularly useful for mechanistic investigations
      and the development of inhibitors, inducers, and other novel NO-modulating
      therapeutics.

PMID- 15199244
TI  - Immunohistochemical detection of S-nitrosylated proteins.
AB  - Accumulating evidence shows that S-nitrosothiols, formed by the addition of
      nitric oxide (NO) to a cysteine thiol, S-nitrosylation, are involved in basal
      cellular regulation. It has been proposed that SNO formation/removal may be
      disrupted in a variety of pathophysiological conditions. Two types of methodology
      are presently available to identify specific S-nitrosylated proteins: (1)
      derivatization and (2) post-purification chemical detection. Neither of these
      techniques allows for in situ visualization of SNOs. Recently, we demonstrated
      that an antibody generated to the SNO moiety could be used to detect SNO
      formation from each of three isoforms of NOS by immunohistochemistry. This
      chapter details the immunohistochemical methodology used to detect SNOs in situ,
      offering a potentially powerful alternative for detection of SNO within tissue
      sections.

PMID- 15199243
TI  - Proteomic method for identification of tyrosine-nitrated proteins.
AB  - Biologic nitration of protein tyrosine (to form 3-nitrotyrosine) is a recently
      described phenomenon that is associated with many diseases. We have devised a
      proteomic methodology to identify these modified proteins. This utilizes protein
      fractionation by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE),
      partial transfer onto polyvinylidene difluoride (PVDF) membranes, and Western
      blot analysis using an antinitrotyrosine antibody to identify the proteins.
      Alignment of the Western blots with the partially transferred 2-D PAGE gels
      enables identification of immunopositive protein spots. These are then excised
      and trypsin digested. Proteins are then identified using either matrix-assisted
      laser desorption ionization-time of flight mass spectrometry or capillary liquid
      chromatography tandem electrospray mass spectrometry. Nonspecific crossreactivity
      of the antibodies is determined using reduction of protein bound 3-nitrotyrosine
      to 3-amino tyrosine using sodium dithionite.

PMID- 15199245
TI  - Gene therapy techniques for the delivery of endothelial nitric oxide synthase to
      the corpora cavernosa for erectile dysfunction.
AB  - Erectile dysfunction (ED) is defined as the consistent inability to obtain or
      maintain an erection for satisfactory sexual intercourse. In the last decade,
      significant advancements in the pathophysiology of male ED have occurred. Basic
      science research on erectile physiology has been devoted to investigating the
      pathogenesis of ED and has led to the conclusion that ED is predominately a
      disease of vascular origin. Nitric oxide (NO) is the principal mediator of penile
      erection. NO is synthesized by endothelial nitric oxide synthase (eNOS) and
      neuronal NOS (nNOS) in the penis. Loss of the functional integrity of the
      endothelium and subsequent endothelial dysfunction plays an integral role in the
      occurrence of ED. This chapter reviews the use of two gene transfer techniques:
      adenoviral gene transfer of eNOS and eNOS gene-modified rat marrow stromal cells
      (rMSCs) to the penis of aged rats for the potential application of gene therapy
      for the treatment of ED.

PMID- 15199247
TI  - Gene therapy in cancer via use of a retrovector having a tumor specificity and
      expressing inducible nitric oxide synthase.
AB  - The generation of retrovectors (retroviral vectors) with tumor specificity is a
      promising and effective approach to targeted gene therapy of cancer.
      Carcinoembryonic antigen (CEA), overexpressed by various tumor cells, provides a
      specific tool for tumor-specific targeting by retrovectors. The conventional
      suicidal gene delivery systems need additional drugs other than their gene
      products. The inducible nitric oxide synthase (iNOS) gene product yields nitric
      oxide (NO), which directly induces autocytotoxicity and cytolysis of bystander
      cells. A novel method is described here that explains how to prepare a novel
      recombinant retrovector that displays a chimeric envelope protein containing a
      single-chain fragment variable (scFv) antibody to CEA and carries the iNOS gene
      in the genome. The resultant bifunctional retrovector showed a specific delivery
      of the iNOS gene to human CEA-expressing carcinoma cells, resulting in the direct
      and efficient killing of CEA-expressing carcinoma cells by induction of
      apoptosis. This approach may offer a one-step procedure for effective gene
      therapy of CEA-expressing tumors and also be applied to other tumor antigens
      expressed on cancer cells.

PMID- 15199246
TI  - Adenovirus-mediated nitric oxide synthase gene transfer into the nucleus tractus
      solitarius in conscious rats.
AB  - The nucleus tractus solitarius (NTS) of the brainstem is an important site for
      the regulation of sympathetic nerve activity. In the brain, nitric oxide (NO) has
      been shown to reduce blood pressure by inhibiting sympathetic nerve activity.
      However, most studies were performed in an acute state of anesthesia. Therefore,
      we developed a technique to increase the local production of NO in vivo by the
      transfer of endothelial NO synthase (eNOS) gene into the NTS. Adenovirus vectors
      encoding either the beta-galactosidase gene (Adbetagal) or the eNOS gene (AdeNOS)
      were infected into the NTS. In the Adbetagal-infected rats, the local expression
      of beta-galactosidase was confirmed by X-Gal staining, and beta-galactosidase
      activity was quantified using a colorimetric assay. In the AdeNOS-infected rats,
      the local expression of eNOS was confirmed by immunohistochemistry and Western
      blot analysis. Production of NO was measured by in vivo microdialysis. Blood
      pressure and heart rate were monitored by a radiotelemetry system in a conscious
      state. In the AdeNOS-infected rats, blood pressure and heart rate significantly
      decreased from d 5 to d 10, and then gradually recovered over time. These methods
      should be useful in examining the local effect on cardiovascular function of a
      particular substance produced by a specific gene in the brain.

PMID- 15199248
TI  - Gene transfer of nitric oxide synthase via the use of adeno-associated virus
      vectors.
AB  - Adeno-associated virus (AAV) is a replication-defective dependovirus and is not
      known to cause disease in humans. AAV vectors have a broad host range and can
      transduce both dividing and nondividing cells. Five primate AAV serotypes have
      been characterized in the literature and are designated as AAV types 1-5 (AAV1
      5). There is divergence in homology and tropism for various AAV serotypes. AAV
      vectors can be produced by triple plasmids transfection system (adenovirus-free
      system) and purified by ultracentrifugation using CsCl gradient. The titer of AAV
      vectors is determined by dot-blot analysis. We have produced the AAV type 2
      vectors encoding endothelial NOS (eNOS) gene and transduced rat aortic segments.

PMID- 15199249
TI  - Adenovirus-mediated nitric oxide synthase gene transfer.
AB  - The varied biological effects of nitric oxide (NO) have led to intense research
      into its diverse physiologic and pathophysiologic roles in multiple disease
      processes. It has been implicated in the development of altered vasomotor tone,
      intimal hyperplasia, atherosclerosis, impotence, host defense, and wound healing.
      Using the modern technologies of recombinant DNA and gene transfer using
      adenoviral vectors, the effects of NO derived from various NO synthase (NOS)
      enzymes can be studied in a variety of tissues and the therapeutic applications
      of NOS is possible. Such uses of NOS gene transfer have been investigated
      extensively in the vasculature where NO is critical to regulating vascular
      homeostasis. NOS gene therapy has the theoretical advantage of allowing NO
      delivery to be localized, thereby limiting potential adverse effects of NO. The
      benefits of adenoviral vectors in gene transfer include relatively high
      transduction efficiencies, both replicating and nonreplicating cells may be
      infected, and the high titers of adenovirus that can be produced. The methods
      described in this chapter include the cloning of the iNOS cDNA into a recombinant
      adenoviral vector, large-scale production of that vector AdiNOS preparation, and
      the use of the vector to transduce tissue in vitro and in vivo.

PMID- 15199250
TI  - What do women want? What do we think women want?

PMID- 15199271
TI  - Complications of osmotic dilators.
AB  - This article reviews safety, efficacy, and complications of intracervical osmotic
      devices and discusses diagnostic, therapeutic, and preventative measures for
      managing them. Osmotic dilators have been used to ripen the cervix in gynecologic
      and obstetric procedures for centuries. Their gradual effect in softening and
      dilating the cervix reduces the chance of stretch injury or perforation and could
      enhance completeness of evacuation of the uterine cavity. Natural and synthetic
      devices are available, each with unique properties. Notwithstanding major
      advances in prostaglandin analogs as cervical ripeners, these mechanical devices
      continue to play a vital role in cervical preparation. In the event of an
      unfavorable cervix, they are adjuncts for accelerating inductions of labor and
      for safe uterine entry during hysteroscopy and diagnostic dilation and curettage.
      For inducing pregnancy, they are routinely used as cervical ripeners from the
      late first trimester onward. The English-language literature was surveyed. The
      author used citations from a MEDLINE search, 2 unpublished case reports, and
      personal experience. Laminaria and Dilapan dilators can get trapped and fragment
      with the potential for serious adverse clinical and legal consequences. Lamicel
      devices do not share this feature. Serious infection is uncommon and anaphylaxis
      is rare. Timely, well-selected imaging techniques can aid diagnosis. Preventative
      measures could reduce the number and severity of osmotic dilator-associated
      complications. Measures suggested by some include predilating with metal
      dilators, incorporating laminaria or Lamicel devices with Dilapan, adding
      misoprostol, and using sonohysterography. However, these measures, singly and in
      combination, are unlikely to eliminate all complications.

PMID- 15199272
TI  - Hereditary breast and ovarian cancer: what the primary care physician should
      know.
AB  - In recent years, testing for cancer susceptibility genes has entered the clinical
      setting. The practicing physician needs to be familiar with this evolving area of
      medicine to be able to counsel and/or refer high-risk patients such as those with
      a strong personal or family history of cancer. The following is a review of the
      clinically pertinent information regarding hereditary breast and ovarian cancers
      resulting from mutations in BRCA genes. A special emphasis is placed on the
      different options available for BRCA mutation carriers, because many
      interventions have already proven to be highly efficacious. The increased risk of
      cancer seen in hereditary nonpolyposis colorectal cancer (HNPCC) is not part of
      this review but is mentioned briefly.

PMID- 15199273
TI  - HPV testing and monitoring of women after treatment of CIN 3: review of the
      literature and meta-analysis.
AB  - According to the current guidelines in most western countries, women treated for
      cervical intraepithelial neoplasia grade 3 (CIN 3) are followed for at least 2
      years after treatment by cytology.High-risk human papillomavirus (hrHPV)
      infections are necessary for the development and maintenance of CIN 3. HrHPV
      testing could be used to improve monitoring of women treated for CIN 3. This has
      prompted numerous studies for the implementation of hrHPV testing in monitoring
      of women treated for CIN 3. Included in this review are 20 studies, published
      between 1996 and 2003, comparing hrHPV testing with either resection margins or
      cervical cytology to predict recurrent/residual disease, and 11 of them could be
      used in a meta-analysis. In the meta-analysis of the 11 studies, the negative
      predictive value (NPV) for recurrent/residual disease of hrHPV testing was 98%
      (95% CI 97-99%), that of resection margins 91% (95% CI 87-94%), and that of
      cervical cytology 93% (95% CI 90-95%). When hrHPV testing was performed in
      conjunction with cytology, the sensitivity was 96% (95% CI 89-99%), specificity
      was 81% (95% CI 77-84%), the associated positive predictive value (PPV) was 46%
      (95% CI 38-54%), and the NPV was 99% (95% CI 98-100%). Combined hrHPV and
      cytology testing yielded the best test characteristics. We propose to include
      hrHPV testing in conjunction with cytology for monitoring women treated for CIN
      3. Some follow-up visits for women testing negative for both hrHPV and cytology
      can be skipped. In western countries, this could mean that for women double
      negative at 6 months, retesting at 12 months should be skipped while keeping the
      24-month follow-up visit.

PMID- 15199276
TI  - Spondylolisthesis in pre-school children.
AB  - Although the natural history of spondylolisthesis is poorly described, we know
      that it is rare to see the condition in children before they are 5 or 6 years
      old. Treatment in these patients may be confusing because there is very little
      literature on the subject, and most papers are case reports. We present a series
      of eight pre-school patients (mean age 3.5 years; range 9 months to 5 years) with
      spondylolisthesis with an average follow up of 11.5 years (range 9-14 years). In
      our experience, general guidelines for treatment as given by Wiltse and Jackson
      are useful in patients younger than 5 years. Nowadays we have to keep strict
      control of these patients due to their important capacity for growth that
      increases the possibility of further slippage.

PMID- 15199277
TI  - Surgical treatment with the technique of Galveston-Luque of spine deformities
      associated with the prune belly syndrome.
AB  - In prune belly syndrome (PBS), spine deformities, particularly scoliosis, are the
      most frequent accompanying orthopedic problem (18%). We give a detailed
      description of two cases with prune belly-associated spine deformities. A
      combined anterior-posterior fusion procedure with posterior correction and
      stabilization according to the Galveston-Luque technique was carried out in both
      patients. In one patient insufficiency of the pelvic fixation developed with loss
      of balance. Reoperation was performed. In the second patient correct alignment
      and balance was achieved, breakage of both metal rods occurred over time. The PBS
      represents a model of how scoliosis may emerge. The lack of the abdominal
      musculature subsequently leads to congenial imbalance, which may cause lordo
      scoliotic deformity. The operative treatment of spine deformities in the PBS in
      the presented technique is efficient. In great deformities balance is difficult
      to achieve and maintain especially in the lumbo-sacral junction.

PMID- 15199278
TI  - False profile radiography for the evaluation of Legg-Calve-Perthes disease.
AB  - False profile radiography (FPR), as proposed by Lequesne and de Seze, depicts the
      pathology on the anterolateral acetabular wall and femoral head. A study was
      conducted to find out the differences between normal anteroposterior radiography
      and FPR. Twenty-seven patients with Legg-Calve-Perthes disease who had not been
      operated on previously and 50 recruits without any pathology were studied for the
      acetabulum-head index of Heyman-Herndon (HHI) and center-edge angles (CEs) in
      antero-posterior radiographs and VCA angles in FPR. The VCA angle is most useful
      to detect anterolateral coverage of the femoral head in lateral pillar C hips.
      FPR is an easy, reliable and cheap technique to evaluate the anterolateral parts
      of the femoral head, and the acetabulum.

PMID- 15199279
TI  - Southwick's head-shaft angles: normal standards and abnormal values observed in
      obesity and in patients with epiphysiolysis.
AB  - Southwick's angles measured in the anteroposterior and Lauenstein frog-leg views
      have been used for planning surgical treatment of deformities caused by slipped
      capital femoral epiphysis (SCFE). Clinically established epiphysiolysis is
      associated with a decrease in anteroposterior angles and an increase in
      Lauenstein angles. Obesity is one of the factors involved in the development of
      SCFE, but its influence in Southwick's angles has not been previously described.
      Additionally, few reports describe normal values adjusted for sex and bone age.
      In this study, we determined Southwick's angles in normal control participants
      (n=70), in patients with obesity (n=31) and in patients with epiphysiolysis
      (n=33). The intra-observer variations were 1.7 and 23.3% for the anteroposterior
      and Lauenstein angles, respectively. No significant differences were detected in
      the control group when these individuals were compared according to sex or
      chronological age. Obese patients showed a significant increase in the
      anterposterior angle when compared with control individuals. The hip with
      epiphysiolysis presented a significant reduction in the anteroposterior angle and
      an increase in the Lauenstein angle, when the same was compared with the
      contralateral hip or with the control values. In patients with unilateral SCFE
      the Lauenstein angle of the normal hip was detected as increased, which was
      possibly related to the obesity associated with decreased insulin resistance
      presented by these patients. We conclude that the detection of risk for
      developing SCFE should include an expanded clinical and radiological profile
      characterized by pubertal males who present obesity associated with insulin
      resistance and an increase in Southwick's anteroposterior angle.

PMID- 15199280
TI  - Long-term result of combination of open reduction and femoral derotation varus
      osteotomy with shortening for developmental dislocation of the hip.
AB  - This study examined femoral derotation varus osteotomy with shortening performed
      on children with developmental dislocation of the hip. Each patient reached 14
      years of age. Surgical outcomes were evaluated clinically and
      roentgenographically. We studied nine patients with 11 joints undergoing surgical
      repair. Age at the time of operation averaged 2 years and 1 month; the period of
      observation averaged 15 years and 7 months; and age at final investigation
      averaged 17 years and 8 months. Each patient underwent the study operation as an
      initial treatment. Salter pelvic osteotomy was reserved as a second treatment for
      those patients whose acetabular development proved inadequate during post
      surgical observation. The evaluation method established by McKay was utilized to
      determine clinical results at the time of final investigation; 73% of the study
      group were established as having good results. Severin's evaluation method was
      used to assess roentgenographical results; 45% of the study group were determined
      to have good results. Kalamchi's evaluation method allowed six joints to be
      diagnosed with avascular necrosis of the femoral head; however, in all cases but
      one, necrosis had been present prior to surgery. Those six joints that did not
      have necrosis of the femoral head prior to surgery developed only one mild
      necrosis subsequent to surgery. Achieving a stable reduced position by femoral
      derotation varus osteotomy, as well as sufficient decompression of the femoral
      head by shortening osteotomy, are considered to have played very important roles
      in preventing the femoral head from developing necrosis.

PMID- 15199281
TI  - Treatment of severe iatrogenic quadriceps retraction in children.
AB  - We assessed the results of the treatment of severe iatrogenic infantile
      quadriceps retraction in a pediatric surgery department, which still admits such
      cases. We used two different surgical techniques of quadricepsplasty: one based
      on the Judet technique and the other based on the Payr and Thompson techniques.
      We selected the technique to perform according to the initial rate of limitation
      of the range of movement of the knee. We followed 76 patients operated on with
      one of the two techniques for at least 3 years. There were 94 cases operated on
      with a modified Judet technique and 34 according to the Payr-Thompson technique.
      After 3 years, maximal knee flexion improved from an average of -3 to 81 degree
      in the first group and from 37 to 115 degree in the second group. The most
      frequent complications were skin necrosis after the Judet quadricepsplasty and
      active extension lag after the Payr-Thompson procedure.

PMID- 15199282
TI  - Clubfoot release in myelodysplasia.
AB  - The purpose of this study was to evaluate our experience with treatment of
      clubfoot in myelomeningocele. We evaluated 45 children with clubfoot surgically
      treated at a mean age of 36 months. We evaluated each patient's medical record
      and performed a physical examination. Based on the clinical criteria by de
      Carvalho Neto, we obtained 61% good results, 26% fair results and 13% poor
      results. Neither age at surgery nor neurosegmental level have any statistical
      influence on final outcome. We find that a radical posteromedial release without
      internal fixation is a satisfactory option for clubfoot with myelodysplasia.

PMID- 15199283
TI  - Intrauterine structure of foot muscles in talipes equinovarus due to high-level
      myelomeningocele: a light microscopic study in fetal cadavers.
AB  - The purpose of this study was to investigate the light microscopic structure of
      extrinsic foot muscles in talipes equinovarus (TEV) deformity that developed
      during intrauterine life due to high-level myelomeningocele. Ten feet of five
      fetal cadavers ranging in age from 18 to 20 weeks were dissected. Five feet had
      typical TEV deformity and the other five feet did not have any deformity (control
      group). Under light microscopic examination quantitative measurement of both
      muscle fiber sizes and fibrosis in the muscle tissue were performed to
      investigate the denervation muscle atrophy. Mean muscle fiber size of the TEV
      group was found to be significantly lower than that of the control group in all
      foot muscles except the gastrocnemius muscle. The proportion of fibrosis due to
      denervation atrophy was significantly higher in the TEV group than in the control
      group in all muscles. This situation was most evident in the peroneus longus
      muscle. It was concluded that muscular imbalance due to significant muscular
      atrophy might be the cause of TEV deformity that developed during intrauterine
      life due to high-level myelomeningocele.

PMID- 15199284
TI  - Complete dislocation of the radial head following fracture of the radial neck in
      children: the Jeffery type II lesion.
AB  - The authors report four cases of Jeffery type 2 lesions in children. Despite the
      probable mechanism of such lesions, none of the cases reported here displayed a
      dislocation of the elbow. In the first observation the diagnosis was suspected
      only 15 days after injury. Two other cases were initially treated by closed
      external manipulations, one with percutaneous Kirschner wire leverage and the
      other with closed intramedullary pinning, but both cases displayed a 180 degree
      reversal of the radial head, suspected only secondarily. The first exhaustive
      review of the literature on the subject, shows that this complication is
      classical in Jeffery type 2 fractures. In fact none of the 22 cases described in
      the literature had successfully been reduced by external manipulations.
      Interposition of the lateral condyle, pathognomonic of the Jeffery type 2
      fracture, hampers reduction. Attempts at reduction by external manipulation in
      nine cases therefore led to two non-reduction and seven reversal of the radial
      head. Knowledge of this particular fracture will allow an early diagnosis and an
      immediate surgical treatment.

PMID- 15199286
TI  - Splitting of the common peroneal nerve by an osteochondroma: two case reports.
AB  - Multiple exostoses is an autosomal dominant disease in which bony protuberances
      arise from the metaphyseal periphery. Most are asymptomatic but occasionally the
      tumors become troublesome, causing irritation to the surrounding tissues. While
      nerve compression by an adjacent osteochondroma has been reported, to our
      knowledge there are no reports of the tumor growing through the mid-substance of
      a nerve. This article reports two occurrences of an osteochondroma of the
      proximal fibula that was noted at surgery to grow through the common peroneal
      nerve, splitting it into two limbs. By reporting these cases, it is our hope to
      alert surgeons that this problem may occur, and care should be taken to identify
      the entire nerve prior to removal of the osteochondroma.

PMID- 15199285
TI  - Treatment of femoral shaft fractures in young children: comparison between
      conservative treatment and retrograde flexible nailing.
AB  - Outcomes of pediatric femoral fractures treated with traction followed by cast
      (conservative treatment) were compared with flexible nailing treatment. Fifty-one
      femoral fractures (24 conservative, 27 nail) from 46 patients were studied
      retrospectively. Four cases of angular deformities greater than 10 degree were
      observed from the conservative treatment and none from the nailing group.
      Conservative treatment showed a wider variance of leg length discrepancy (LLD)
      and four cases showed severe LLD greater than 10 mm. The nailing group had no
      discrepancy. Retrograde flexible nailing may result in more reliable outcomes
      than conservative treatment for femoral fractures.

PMID- 15199287
TI  - Giant cystic lymphangioma cavernousum of lower limb with overlying lymphangioma
      circumscriptum.
AB  - Lymphangiomas arising outside of the cervicofacial, thoracic, and abdominal areas
      are extremely rare. We describe a child with a giant cystic lymphangioma
      cavernousum occurring in the lower leg with overlying lymphangioma
      circumscriptum, along with its magnetic resonance imaging findings.

PMID- 15199289
TI  - What have we learnt about the regulation of phosphate metabolism?
AB  - PURPOSE OF REVIEW: The search for hormones which specifically regulate phosphate
      metabolism has fuelled recent tantalizing studies. These studies have been
      motivated by diseases involving renal phosphate wasting, including tumor-induced
      osteomalacia, X-linked hypophosphatemic rickets, and autosomal dominant
      hypophosphatemia. This review focuses on likely candidate 'phosphatonins' and
      their possible physiological significance. RECENT FINDINGS: Candidate
      phosphatonins include fibroblast growth factor 23, matrix extracellular
      phosphoglycoprotein, stanniocalcin, and Frizzled-related protein 4. Fibroblast
      growth factor 23 has emerged as the prime candidate explaining pathophysiology of
      these diseases. FGF-23 is expressed in most tumors in tumor-induced osteomalacia.
      Serum fibroblast growth factor 23 is increased in most patients with X-linked
      hypophosphatemic rickets and tumor-induced osteomalacia. Injection of recombinant
      fibroblast growth factor 23 induces phosphaturia, hypophosphatemia, and
      suppression of 1,25-dihydroxyvitamin D in animals. Many unanswered questions
      remain, including the relationship between PHEX (phosphate-regulating gene with
      homologies to endopeptidases on the X chromosome) mutations and elevated
      fibroblast growth factor 23. It is also not clear whether these candidate
      phosphatonins play a role in phosphate or vitamin D metabolism in healthy humans,
      or that this role is endocrine. The most compelling evidence derives from the
      fibroblast growth factor 23-knockout mouse which shows hyperphosphatemia and
      increased serum 1,25-dihydroxyvitamin D. A physiologically relevant phosphatonin
      should explain renal adaptation to variable dietary phosphate intake. The tissue
      source and determinants of serum fibroblast growth factor 23 are unknown.
      SUMMARY: Pathophysiological and animal studies serve as a logical foundation on
      which to base further questions of human physiology. The definition of what is or
      is not a phosphatonin may need to be refined. There is a need to return to 'old
      fashioned' human physiology studies to place recent findings in perspective.

PMID- 15199290
TI  - Lanthanum carbonate: a new phosphate binder.
AB  - PURPOSE OF REVIEW: Hyperphosphatemia remains an important aspect in the
      management of end-stage renal disease patients. Consequently, there is a need for
      new, efficient and well-tolerated phosphate binders. In this review, a new
      phosphate-binding drug, lanthanum carbonate, with an attractive preclinical
      efficacy profile compared with existing binders, is discussed. Although the
      available human efficacy and safety data over 3 years are encouraging, the
      consequences of low-level tissue deposition continue to be evaluated in longer
      term clinical studies. RECENT FINDINGS: Lanthanum carbonate has been shown in
      clinical studies of up to 3 years to be an effective, well-tolerated phosphate
      binder. Reported adverse effects are mainly gastrointestinal, and do not differ
      from those of calcium carbonate. The gastrointestinal absorption of lanthanum is
      very low. Whereas the element is mainly excreted by the liver, renal excretion of
      the absorbed fraction is less than 2%. Bone lanthanum levels seen after long-term
      treatment (up to 4 years) seem not to affect the physicochemical process of
      mineralization, or osteoblast number/function. Preliminary data on the
      localization of lanthanum in bone have shown the element to be present at both
      active and quiescent sites of bone mineralization, independent of the type of
      renal osteodystrophy, a profile distinct from aluminum, as well as diffusely
      distributed throughout the mineralized bone matrix especially in rats/humans with
      an increased bone turnover. A randomized, comparator-controlled, parallel group,
      open-label study comparing lanthanum carbonate with calcium carbonate in dialysis
      patients showed no evolution towards low bone turnover in the lanthanum group,
      and no aluminum-like effect on bone. SUMMARY: Lanthanum carbonate seems to be a
      potent phosphate-binding drug, minimally absorbed from the gut, with an
      encouraging safety profile, and no deleterious effects on bone.

PMID- 15199291
TI  - Osteoprotegerin and bone mineral metabolism in renal failure.
AB  - PURPOSE OF REVIEW: This review focuses on the impact of a recent breakthrough in
      bone cell biology for understanding the pathophysiology of bone/vascular
      abnormalities associated with uraemia. RECENT FINDINGS: Osteoprotegerin is a
      humoral osteoclastogenesis/osteoclast activation inhibitory factor, which belongs
      to the TNF-alpha receptor superfamily. Serum osteoprotegerin levels are elevated
      along with the deterioration of the glomerular filtration rate. The circulating
      osteoprotegerin molecules were likely to preserve the activity of
      osteoclastogenesis inhibition, and the levels in many dialysis patients were high
      enough to inhibit osteoclastogenesis. The higher serum osteoprotegerin levels
      were related to the development of vascular calcification. SUMMARY:
      Osteoprotegerin is a potential uraemic toxin that increases the skeletal
      resistance to PTH. However, the roles of increased circulating osteoprotegerin on
      bone and/or vascular abnormalities in uraemia remain to be clarified.

PMID- 15199292
TI  - Bone morphogenetic protein 7: a novel treatment for chronic renal and bone
      disease.
AB  - PURPOSE OF REVIEW: When last reviewed, bone morphogenetic protein 7 was presented
      as a potential new renal therapeutic agent, with multiple efficacies in chronic
      kidney disease. The object of this review is to describe progress from many
      sources since then in support or denial of the hypothesis. RECENT FINDINGS: Bone
      morphogenetic protein 7 has been shown to be an effective defence in several
      forms of chronic kidney disease in animal models, and its mechanisms of action
      have begun to be elucidated. Bone morphogenetic protein 7 inhibits tubular
      epithelial cell de-differentiation, mesenchymal transformation and apoptosis
      stimulated by various renal injuries. Bone morphogenetic protein 7 preserves
      glomerular integrity and inhibits injury-mediated mesangial matrix accumulation.
      In renal osteodystrophy, bone morphogenetic protein 7 affects osteoblast
      morphology and number, eliminates peritrabecular fibrosis, decreases bone
      resorption, and increases bone formation in secondary hyperparathyroidism. Bone
      morphogenetic protein 7 restores normal rates of bone formation in the adynamic
      bone disorder. Bone morphogenetic protein 7 is broadly efficacious in renal
      osteodystrophy, and importantly increases the skeletal deposition of ingested
      phosphorus and calcium, improving ion homeostasis in chronic kidney disease. Bone
      morphogenetic protein 7 was shown to prevent vascular calcification in a model of
      chronic kidney disease associated with the restoration of osteocalcin expression
      to normal tissue-restricted sites. SUMMARY: Bone morphogenetic protein 7 may be a
      powerful new therapeutic agent for chronic kidney disease, with the novel
      attribute of not only treating the kidney disease itself, but also directly
      inhibiting some of the most important complications of the disease state.

PMID- 15199293
TI  - Mechanism of acid-induced bone resorption.
AB  - PURPOSE OF REVIEW: This review presents our current understanding of the way
      metabolic acidosis induces calcium efflux from bone, and in the process, buffers
      additional systemic hydrogen ions associated with acidosis. RECENT FINDINGS: Acid
      induced changes in bone mineral are consistent with a role for bone as a proton
      buffer. In response to metabolic acidosis in an in-vitro bone organ culture
      system, we observed a fall in mineral sodium, potassium, carbonate and phosphate,
      which each buffer protons and in vivo should increase systemic pH towards the
      physiologic normal. Initially, metabolic acidosis stimulates physicochemical
      mineral dissolution and subsequently cell-mediated bone resorption. Acidosis
      suppresses the activity of bone-resorbing cells, osteoblasts, decreasing gene
      expression of specific matrix proteins and alkaline phosphatase activity. There
      is concomitant acid stimulation of prostaglandin production by osteoblasts, which
      acting in a paracrine manner increases synthesis of the osteoblastic receptor
      activator of nuclear factor kappa B ligand (RANKL). The acid induction of RANKL
      then stimulates osteoclastic activity and recruitment of new osteoclasts to
      promote bone resorption and buffering of the proton load. Both the regulation of
      RANKL and acid-induced calcium efflux from bone are mediated by prostaglandins.
      SUMMARY: Metabolic acidosis, which occurs during renal failure, renal
      insufficiency or renal tubular acidosis, results in decreased systemic pH and is
      associated with an increase in urine calcium excretion. The apparent protective
      function of bone to help maintain systemic pH, which has a clear survival
      advantage for mammals, will come partly at the expense of its mineral stores.

PMID- 15199294
TI  - The physiology of the circadian rhythm of parathyroid hormone and its potential
      as a treatment for osteoporosis.
AB  - PURPOSE OF REVIEW: A circadian rhythm exists for parathyroid hormone, with a
      biphasic pattern showing a late afternoon/early evening rise and fall and a
      broader, longer-lasting increase late evening/early morning reaching nadir mid
      morning. This review explores the characteristics of the circadian rhythm,
      factors regulating the rhythm and its role in bone metabolism. RECENT FINDINGS:
      Gender differences exist in the circadian rhythm for parathyroid hormone. Ageing
      in women alters the response to calcium infusion, increasing the suppression of
      parathyroid hormone secretion and decreasing bone resorption. There is no
      difference between young and elderly men in the parathyroid hormone response to
      calcium infusion. Loop diuretic ingestion alters the parathyroid hormone
      circadian rhythm reflecting loop diuretic effects on phosphate and calcium
      metabolism. Adult growth hormone deficiency alters parathyroid hormone secretion
      and end organ sensitivity, but the circadian rhythm is retained. Growth hormone
      replacement therapy enhances the parathyroid hormone circadian rhythm and
      increases end organ responses. Exogenous parathyroid hormone (1-34) and (1-84)
      administered by daily injection has an anabolic effect on bone, increasing bone
      mass and decreasing fracture. Calcilytic drugs stimulate and calcimimetic drugs
      suppress parathyroid hormone secretion and have been used to treat disorders of
      bone metabolism. SUMMARY: The circadian nature of parathyroid hormone secretion
      is confirmed by many publications. The underlying rhythm is endogenous. Life
      style factors and nutritional intake modulate the pattern of secretion. Direct
      association with bone resorption and formation is tentative. It is suggested that
      acute changes in these rhythms have little effect on resorption, but longer-term
      manipulation of parathyroid hormone secretion alters bone cell function. Growth
      hormone therapy in adult deficiency increases parathyroid hormone activity,
      indicating growth hormone may have therapeutic potential for osteoporosis.
      Manipulation of the endogenous parathyroid hormone rhythm, using timed
      supplements of phosphate or calcium or by calcilytic and calcimimetic molecules,
      offers a novel approach to osteoporosis treatment.

PMID- 15199295
TI  - Developmental regulation of expression of renal potassium secretory channels.
AB  - PURPOSE OF REVIEW: Somatic growth is associated with an increase in total body K
      content. K homeostasis is regulated, in large part, by urinary K excretion.
      Within the adult kidney and specifically the cortical collecting duct, K
      secretion is accomplished by the passive diffusion of cell K into the urinary
      fluid down a favorable electrochemical gradient through K selective channels. The
      purpose of this review is to summarize the results of recent studies that provide
      insight into how the cortical collecting duct is uniquely adapted for K retention
      early in life. RECENT FINDINGS: Electrophysiological analyses have identified two
      types of apical K channels in the mammalian cortical collecting duct. The
      prevalence of the secretory K channel and its high open probability at the
      resting membrane potential in the adult has led to the belief that this channel
      mediates baseline K secretion. The Ca and stretch-activated maxi-K channel has
      been proposed to mediate flow-stimulated K secretion. In contrast to the high
      rates of K secretion observed in adult cortical collecting ducts microperfused in
      vitro, segments isolated from neonatal animals show no significant net K
      transport until after the third week of postnatal life. The temporal delay
      between expression of conducting secretory K channels (baseline K secretion) and
      maxi-K channels (flow-stimulated K secretion) in the maturing cortical collecting
      duct reflect unique developmental programs regulating the transcription and/or
      translation of ROMK (rat outer medullary K channel) and slo, the molecular
      correlates of the secretory K and maxi-K channels, respectively. SUMMARY: The K
      retention characteristic of the neonatal kidney is due, in part, to a paucity of
      distinct K channels mediating baseline and flow-stimulated K secretion in the
      collecting duct. The signals directing the developmental regulation of channel
      expression are as yet unknown.

PMID- 15199296
TI  - Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension.
AB  - PURPOSE OF REVIEW: Traditionally, the mineralocorticoid receptor was thought to
      be activated by the mineralocorticoid hormone aldosterone, and to exhibit its
      main action on epithelia by promoting renal sodium retention, potassium excretion
      and inducing hypertension upon excessive activation. Recently, evidence appeared
      that mineralocorticoid receptors are expressed in nonepithelial cells and
      activated by endogenous glucocorticoids including cortisol. Therefore, the
      prereceptor regulation of cortisol access to the mineralocorticoid receptors by
      11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSDs), a mechanism absent in
      most nonepithelial cells, appears to be relevant for disease states with cortisol
      induced mineralocorticoid action. The present review focuses on direct and
      indirect effects attributable to mineralocorticoid receptor activation by
      glucocorticoids. RECENT FINDINGS: The determination of the intracellular topology
      of 11beta-HSD1, facing the endoplasmic reticulum lumen, and 11beta-HSD2, facing
      the cytoplasm, suggests that 11beta-HSD1 acts as a prereceptor mechanism in the
      local activation of glucocorticoid receptors, whereas 11beta-HSD2 controls
      mineralocorticoid receptors by interacting with the receptor in the absence of
      aldosterone. Downregulation of 11beta-HSD2 was observed with various stimuli
      including hypoxia, shear stress, angiotensin II and tumor necrosis factor alpha.
      The corresponding signal transcription pathways and some relevant transcription
      factors have been identified. Renal sodium retention in liver cirrhosis,
      nephrotic syndrome and hypoxia have been linked to 11beta-HSD2 reduced activity.
      Overexpression of 11beta-HSD1 specifically in adipose tissue in mice caused
      central obesity, a metabolic syndrome and hypertension due to increased
      intracellular cortisol concentrations. Peroxisome proliferator-activated receptor
      gamma agonists reduce 11beta-HSD1 activity and diminish the intracellular
      availability of cortisol, an effect accompanied by a decline in blood pressure.
      Three individuals with loss-of-function mutations of peroxisome proliferator
      activated receptor gamma developed early hypertension. A potential mechanism
      might be glucocorticoid dependent mineralocorticoid receptor-mediated
      downregulation of endothelial nitric oxide synthase. SUMMARY: Recently,
      mineralocorticoid receptor antagonists have been used in the randomized aldactone
      evaluation study (RALES) with spironolactone, the eplerenone post-AMI heart
      failure efficacy and survival study (EPHESUS), and in severe and postmyocardial
      infarct heart failure, respectively. These investigations cannot be understood on
      the basis of the present physiological knowledge and underscore the relevance of
      focusing on mineralocorticoid receptor activation by ligands other than
      aldosterone.

PMID- 15199297
TI  - Pathogenesis of perinatal programming.
AB  - PURPOSE OF REVIEW: In recent years, there has been an increase in research
      designed to delineate the underlying causes of perinatal programming. Starting
      with epidemiological observations that birth weight was inversely associated with
      cardiovascular disease, a variety of studies both in humans and in experimental
      models have begun to demonstrate how the perinatal milieu can subtly alter
      vasculogenesis and nephrogenesis. Additionally, rates of prenatal and postnatal
      growth each appear to contribute to future vascular, renal and metabolic
      function. The purpose of this review is to discuss recent reports that have begun
      to elucidate factors that initiate perinatal programming as it affects renal
      disease and cardiovascular disease in later life. RECENT FINDINGS: Nephrogenesis
      per se is affected by changes in maternal nutrition and health, and recent data
      more specifically linking these changes with renal function and hypertension are
      presented. Additionally, renal functional changes in later life may be influenced
      by changes in renal tubular transporters noted early when maternal nutrition is
      compromised. Various hormonal systems affected by maternal nutrition in utero may
      effect subsequent changes in renal function via subtle alterations in renal
      function and structure initiated during nephrogenesis. SUMMARY: Current research
      is beginning to clarify certain aspects of perinatal programming and indicates
      that broad educational programmes might ultimately lessen both perinatal risks
      and long-term outcomes by encouraging therapeutic interventions in at-risk
      persons.

PMID- 15199298
TI  - The role of the vitamin K-dependent growth factor Gas6 in glomerular
      pathophysiology.
AB  - PURPOSE OF REVIEW: The product of growth arrest-specific gene 6 (gas6) is a
      unique vitamin K-dependent growth-potentiating factor for vascular smooth muscle
      cells, and anticoagulant warfarin inhibits the activation process of the protein.
      It has been reported that Gas6 is also a mitogen for mesangial cells, and that
      warfarin inhibits mesangial cell proliferation by blocking the activation of
      Gas6. A recent series of studies has revealed the in-vivo roles of Gas6 and its
      receptor Axl in the progression of various kidney diseases. This review
      summarizes these studies and discusses the possible interventions targeting the
      Gas6/Axl pathway to prevent the progression of kidney diseases. RECENT FINDINGS:
      The expression of Gas6 and Axl is upregulated in an acute model of
      glomerulonephritis in rats, and the interference of the Gas6/Axl pathway by
      warfarin or the extracellular domain of Axl inhibits the progression of diseases.
      Induction of chronic glomerulonephritis in Gas6 mice results in less mortality,
      proteinuria, and histological changes of kidneys compared to wild-type mice.
      Administration of recombinant Gas6 reverses these phenotypes. Expression of Gas6
      is also upregulated in streptozotocin-induced diabetic nephropathy, and
      administration of low-dose warfarin decreases albuminuria and hypertrophy of
      glomeruli. Possible roles of Gas6 are also reported in renal allograft
      dysfunction of rats and humans. SUMMARY: The importance of the Gas6/Axl pathway
      has been implicated in many types of kidney disease. Further investigations on
      the role of the Gas6/Axl pathway in human kidney diseases and the development of
      specific antagonists targeting the pathway are warranted.

PMID- 15199299
TI  - Harnessing the parathyroids to create stronger bones.
AB  - PURPOSE OF REVIEW: Parathyroid hormone is anabolic to bone but when secreted in
      excess it is catabolic. It is important, therefore, to understand the mechanisms
      that determine the normal circadian rhythm of parathyroid hormone secretion and
      whether the cellular response to it will be anabolic or catabolic. This may lead
      to new strategies for the treatment of osteoporosis and the low turnover bone
      disease of some dialysis patients. RECENT FINDINGS: The parathyroid plays a
      central role in normal mineral and bone homeostasis by acting on its receptor,
      the PTH/PTHrP receptor (PTH1R). In fact there is more than one receptor - the
      PTH2 receptor and a putative carboxy-terminal PTH receptor. The latter, in
      particular, may be particularly relevant to our understanding of the role of
      parathyroid hormone and its use in pharmacology. Parathyroid hormone in excess
      destroys bone, as in most patients with chronic renal failure, and when it is
      lacking this may result in low turnover bone disease. At a more subtle level,
      patients with postmenopausal osteoporosis may have a blunting of the normal
      circadian rhythm of parathyroid hormone, with its peak at night and nadir in the
      morning. Insights as to what determines whether parathyroid hormone will be
      anabolic or catabolic to bone are reviewed. SUMMARY: Attempting to correct the
      circadian rhythm in osteoporotic patients by calcilytic drugs or perhaps
      physiological equivalents may have a role in the future in treating osteoporosis.
      In the meantime, the administration of recombinant parathyroid hormone is an
      effective agent in the management of osteoporosis.

PMID- 15199300
TI  - Bibliography. Current world literature. Mineral metabolism.

PMID- 15199302
TI  - Blood pressure measurement in obese patients: comparison between upper arm and
      forearm measurements.
AB  - BACKGROUND: It is well known that blood pressure measurement with a standard 12
      13 cm wide cuff is erroneous for large arms. OBJECTIVE: To compare arm blood
      pressure measurements with an appropriate cuff and forearm blood pressure
      measurements (BPM) with a standard cuff, and both measurements by the
      Photopletismography (Finapres) method. METHODS: One hundred and twenty-nine obese
      patients were studied (body mass index=40+/-7 kg/m2). The patients had three arm
      BPM taken by an automatic oscillometric device using an appropriate cuff and
      three forearm BPM with a standard cuff in the sitting position after a five
      minute rest. Data were analysed by the analysis of variance. The correction
      values were obtained by the linear regression test. RESULTS: Systolic and
      diastolic arm BPM with an appropriate cuff were significantly lower (p<0.05) than
      forearm BPM with a standard cuff. The measurements obtained by Finapres were
      significantly lower (p<0.05) than those found for forearm systolic and diastolic
      blood pressures and upper arm diastolic blood pressure. The equation to correct
      BPM in forearm in obese patients with arm circumference between 32-44 cm was:
      systolic BPM=33.2+/-0.68 x systolic forearm BPM, and diastolic BPM=25.2+0.59 x
      forearm diastolic BPM. CONCLUSION: This study showed that forearm blood pressure
      measurement overestimates the values of arm blood pressure measurement. In
      addition, it is possible to correct forearm BPM with an equation.

PMID- 15199303
TI  - Blood pressure course in acute ischaemic stroke in relation to stroke subtype.
AB  - OBJECTIVES: Blood pressure (BP) management in acute stroke remains a matter of
      little consensus. Data on BP changes during the first hours of ictus are lacking.
      We aimed to evaluate the early spontaneous time course of BP in different
      ischaemic stroke (IS) subtypes. METHODS: Twenty-four h BP monitoring was
      performed in 200 first-ever hyper-acute IS patients. The recording was initiated
      and terminated at 3 h and 27 h of ictus respectively. All IS patients were
      classified on admission into the following subgroups of different etiology: large
      artery atherosclerotic stroke (LAA), cardio-embolic stroke (CE), lacunar stroke
      (LAC) and infarct of undetermined cause (IUC). Statistical comparisons between
      stroke subgroups were performed using one-way ANOVA and linear regression
      analyses were used to evaluate the influence of different factors in BP course.
      RESULTS: Although there were no significant differences in 24 h systolic (SBP)
      and diastolic (DBP) BP values between IS subgroups, a distinctly different SBP
      course was observed. The SBP dropped sharply in the LAA and LAC subgroups, while
      a more gradual decrease was monitored in the CE subgroup. Throughout the BP
      recording, a SBP decrease of 10.1% (95% CI: 8.6-11.5) and 10.4% (95% CI: 9.0
      11.8) was documented in patients with LAA and LAC respectively, while a milder
      drop was recorded in CE (3.7%, 95% CI: 2.4-5.0) and IUC (5.5%, 95% CI: 4.1-6.8).
      Increasing stroke severity (p<0.001) and brain oedema (p=0.013) was independently
      associated with a milder spontaneous SBP reduction. CONCLUSIONS: Spontaneous SBP
      course varies in acute ischaemic stroke subtypes of different etiology. This may
      have implications in the optimal management of post-stroke hypertension.

PMID- 15199304
TI  - Determination of central aortic systolic and pulse pressure from the radial
      artery pressure waveform.
AB  - OBJECTIVE: Measurements of central aortic systolic and pulse pressure, either
      gauged directly or estimated indirectly, have been shown to be superior to
      brachial pressure in outcome studies. While the radial pressure convolution
      method has proved to satisfy the criteria for 'substantial equivalence' to
      measure central pressure non-invasively, this study sought simpler methods to
      generate central systolic and pulse pressure directly from the radial artery
      waveform. METHODS: Two sets of data were used, in which radial artery pressure
      waves were measured by applanation tonometry and ascending aortic pressure was
      generated by the SphygmoCor process. Different approaches were applied to each
      dataset: firstly, using the time period from wave foot to systolic peak in
      central arteries; secondly, through identifying the pressure surge from the
      reflected wave in the radial artery; and thirdly from extrapolation and
      calibration of carotid systolic pressure when mean and diastolic pressure
      considered to be equal with radial values. RESULTS: Both datasets showed good
      correspondence between the central systolic and pulse pressure obtained with each
      of the three approaches and respective pressures generated by SphygmoCor process;
      all were within AAMI SP10 criteria and grade A for BSH criteria. CONCLUSION: All
      three approaches gave results similar substantially equivalent to those obtained
      with the SphygmoCor system for aortic, systolic and pulse pressure. Hence, simple
      inspection of the radial waveform has the potential to improve the estimation of
      aortic systolic and pulse pressure.

PMID- 15199305
TI  - Estimating equations and tables for adult mid-arm circumference based on measured
      height and weight: data from the third National Health and Nutrition Examination
      Survey (NHANES III) and NHANES 1999-2000.
AB  - OBJECTIVE: Mid-arm circumference measurement is a prerequisite to selection of
      proper sized blood pressure (BP) cuffs and accurate BP readings. The purpose of
      this study was to develop practical prediction equations for estimating mid-arm
      circumference (AC) in adults using NHANES III & NHANES 1999-2000 data. DESIGN:
      Both surveys used a complex sample design to obtain nationally representative
      samples of the USA civilian non-institutionalized population. SUBJECTS: The
      analytic sample consisted of 5077 men and 5307 women from NHANES III and 2013 men
      and 2293 women from NHANES 1999-2000. Their height, weight, and mid-arm
      circumference were measured directly in both surveys. STATISTICAL ANALYSES:
      Weight, height, and age data from NHANES III were used for model building, and
      similar data from NHANES 1999-2000 were used for validation. An all-possible
      regressions procedure by gender was used to derive the prediction equations for
      AC. RESULTS: The final prediction equations for adult AC were as follows: for
      measured weight (wt) in kg and height (ht) in cm: Men, AC (cm)=31.76749+0.22626 x
      (wt) -0.10109 x (ht)+0.05092 x (age)-0.00081813 x (age), R=0.8; Women, AC
      (cm)=39.29946+0.26410 x (wt) -0.18230 x (ht) +0.01972 x (age)-0.00104 x (age)
      +0.00045901 x (wt x age) +0.00037509 x (ht x age), R=0.86. Tables of estimated
      arm circumference by age, weight and gender are presented. CONCLUSION: The
      prediction equations and tables provide for mid AC estimation using readily
      available clinical data to select the appropriate BP cuff.

PMID- 15199306
TI  - Cuff size in larger patients matters.

PMID- 15199307
TI  - Faster oscillometric manometry does not sacrifice the accuracy of blood pressure
      determination.
AB  - Faster oscillometry enables one to track rapid pressure changes. We therefore
      examined whether it was possible to shorten the measurement time without
      sacrificing accuracy. We accelerated and linearized cuff deflation and determined
      systolic and diastolic pressure values by the appearance and disappearance of
      oscillometric waves based on the interpolated cuff pressure-oscillometric wave
      amplitude relationship. The accuracy of faster oscillometry was examined by
      comparing correlations between invasive radial and oscillometric brachial
      pressure with either the conventional or the faster oscillometry in 23 patients
      (32+/-16 measurement pairs). Faster oscillometry shortened the measurement time
      from 27.7+/-3.5 s to 17.1+/-2.6 s. Neither pressure levels nor heart rate altered
      the time required for measurement. Bland-Altman analysis indicated that mean and
      standard deviation of difference between oscillometric and invasive systolic
      pressure was comparable (conventional, 2.1+/-7.5 mmHg; faster, 1.4+/-7.3 mmHg)
      without correlations between difference and average of systolic pressure. Similar
      differences (conventional, 5.0+/-6.8 mmHg; faster, 4.9+/-5.8 mmHg) and lack of
      correlations were also found for diastolic pressure. In conclusion, we succeeded
      in shortening the oscillometric measurement time to approximately 60% of the
      original time without sacrificing accuracy. This was achieved by acceleration and
      linearization of cuff deflation and by interpolation of the relationship between
      cuff pressure and oscillometric wave amplitude.

PMID- 15199308
TI  - Accuracy of home blood pressure readings: monitors and operators.
AB  - OBJECTIVE: To evaluate the accuracy of automated digital blood pressure
      monitoring devices and operators in the community. Also, we tested the effects of
      a simple education program, and looked for arm-arm differences. DESIGN: Subjects
      who had bought their own automated digital blood pressure monitor were recruited
      via an advertisement in the local newspaper. On arrival, they were asked to
      record their blood pressure exactly as they would at home. The investigator noted
      any technique deficiencies then corrected them. Blood pressures were then
      recorded by the investigator and the subject, on opposite arms, simultaneously,
      and repeated with the arms switched. Finally, subjects recorded their blood
      pressure again. The subjects' readings were compared to the average of monitor
      and mercury readings using Bland-Altman methods. RESULTS: A total of 80 subjects
      were tested. Before educating, subjects' systolic blood pressure (SBP) readings
      were +5.8+/-6.4 (standard deviation) mmHg greater than the mean of all readings,
      and diastolic blood pressure (DBP) were +1.3+/-4.0 mmHg; after educating they
      were +1.3+/-4.0 and -1.3+/-2.7 respectively. The monitors, as a group, were
      accurate, and met British Hypertension Society and AAMI highest standards. We
      found no differences among monitors that had been validated (n=26) and those that
      had not. There were differences between the arms: 5.3+/-5.2 mmHg for SBP and
      3.4+/-3.3 mmHg for DBP. Most patients had never been informed by anyone of proper
      blood pressure measuring techniques. CONCLUSIONS: We conclude that home blood
      pressure measurement, as practiced in our community, is prone to error, mostly
      due to mistakes by the operator. These can easily be corrected, so that readings
      become more accurate. Attention should be paid to arm-arm differences.

PMID- 15199309
TI  - Progress on the development of the MediWatch ambulatory blood pressure monitor
      and related devices.
AB  - The MediWatch is a wrist-mounted noninvasive blood pressure monitor designed to
      capture the radial pulse waveform using arterial tonometry and yield blood
      pressure measurements when the waveform is calibrated. An early prototype of this
      monitor uses a pulse-sensing system with a cylindrical plunger to applanate the
      radial artery. This prototype was evaluated against simulated blood pressure
      generated by a pneumatic pressure-pulse generator. The simulation-based results
      show that the prototype gave accurate pressure measurements when the MediWatch
      waveforms were calibrated against the simulator's pressure, indicating that the
      pulse-sensing system was able to measure force accurately. The prototype was
      clinically evaluated against intra-arterial pressure on post-open heart surgery
      patients. The results show that, under stationary conditions, for short periods
      of time and when the MediWatch waveforms were calibrated against the intra
      arterial pressure, the prototype gave measurements that satisfy some of the
      statistical criteria of the 1993 Association for the Advancement of Medical
      Instrumentation standard, the 1993 British Hypertension Society protocol and the
      2002 European Society of Hypertension protocol. These clinical results indicate
      that, under the stated test conditions, the prototype was able to accurately
      track changes in the patients' systolic and diastolic pressures. The MediWatch is
      being developed into an ambulatory device that provides a macroscopic view of the
      patient's blood pressure through measurement at preprogrammed intervals over 24
      h, as well as a microscopic view of the patient's pressure through the pulse
      waveform captured during each measurement cycle. The design features of the
      MediWatch are being adapted for other applications that require the arterial
      pulse waveform, calibrated beat-to-beat blood pressure or both. An improved
      MediWatch prototype has been developed that provides memory storage for
      measurement data and functions as an integral part of a Web-based system that
      allows measurement data to be accessed over the Internet. A pulse-wave analyser
      has been developed that allows the radial pulse waveform to be captured,
      calibrated and viewed in real time on a personal computer. A continuous
      noninvasive blood pressure monitoring system based on arterial tonometry is being
      developed for use as an alternative to the arterial line in invasive blood
      pressure monitoring.

PMID- 15199310
TI  - Blood pressure measurements by the Keito machine. Evaluation versus office blood
      pressure by physicians.
AB  - BACKGROUND: The Keito machine offers automatic measurements of blood pressure
      (BP), height and weight on insertion of coins and has been introduced in
      pharmacies. DESIGN: Cross-sectional study comparing automatic BP measurements by
      the Keito machine to office BP measurements by physicians. METHODS: Patients
      scheduled for pre-catheterisation screening participated in the study. Their BP
      was first measured using the Keito machine, then by physicians. Office BP was
      recorded as the last of three consecutive BP measurements recorded with one-min
      intervals after a five-min rest in the sitting position. In a sub-study BP was
      measured simultaneously during the Keito measurement by a physician. RESULTS: In
      390 consecutive patients average BP was significantly lower with the Keito
      machine compared to office BP measurements made by the physicians (136/75+/-19/8
      mmHg versus 141/79+/-21/10 mmHg, both p<0.001). The correlation coefficient (r)
      was 0.56 (p<0.001) for systolic BP (SBP) and 0.53 (p<0.001) for diastolic BP
      (DBP). Bland-Altman analysis showed a mean difference (+/-2 SD) for SBP and DBP
      of -5 (+/-37) and -4 (+/-17) mmHg, respectively. When defining hypertension (HT)
      as office SBP> or =140 and/or DBP> or =90 mmHg, the Keito method diagnosed 83% of
      the systolic and 62% of the diastolic hypertensive population correctly. The
      classification of systolic and diastolic normotensive was correct in 61% and 86%,
      respectively. CONCLUSION: Agreement between office and Keito BP is poor. The
      Keito machine underestimates SBP on average by 5 mmHg and DBP by 4 mmHg, which
      may be of significance for diagnosing HT and starting anti-hypertensive therapy.
      However, the difference can be much larger in individual patients. Therefore, the
      Keito machine cannot be recommended for medical screening of HT or as a
      replacement for follow-up by physicians.

PMID- 15199311
TI  - Is the male genital tract really a sanctuary site for HIV? Arguments that it is
      not.

PMID- 15199312
TI  - HIV in central nervous system and behavioral development: an HIV-2287 macaque
      model of AIDS.
AB  - OBJECTIVE: To determine which route of inoculation produced consistent and
      frequent HIV infection in the central nervous system (CNS) and alterations in
      cognitive and motor development in infant macaques. METHODS: Infant macaques
      (Macaca nemestrina) were inoculated with the highly pathogenic strain HIV-2287
      intravenously (n = 3) or intrathecally (n = 3). Uninfected infants were evaluated
      as controls. Disease progression was evaluated by virological assessment of blood
      and cerebral spinal fluid (CSF), CD4 T cell count in blood, and quinolinic acid
      levels in CSF (a surrogate marker of neuronal cell damage). The effect of HIV
      infection on cognitive and motor development in infants was monitored during the
      6-month study. RESULTS: Either route of HIV-2287 inoculation produced detectable
      viral RNA in CSF and productive infection in blood. Detection of virus in CSF
      paralleled a rise in quinolinic acid levels. All HIV-infected infants experienced
      a severe and rapid decline in CD4 T cell counts by 10 weeks after viral
      infection. HIV-infected infants, particularly those infected by the intravenous
      route, exhibited delays in reaching cognitive and motor milestones, which
      paralleled neuropathological changes. CONCLUSIONS: The HIV-2287 infant model
      produced a high incidence of viral infection in the CNS regardless of the route
      of inoculation. Significant alteration in neurobehavioral development was
      observed in HIV-infected infants, and this measure was significantly impaired
      particularly in infants infected by the intravenous route. These data, coupled
      with the ability to detect viral RNA and changes in quinolinic acid levels in
      CSF, may allow quantitative evaluation of drug and immune candidates for treating
      neurological effects of AIDS.

PMID- 15199313
TI  - Phylogenetic characteristics of three new HIV-1 N strains and implications for
      the origin of group N.
AB  - BACKGROUND: The three divergent HIV-1 groups M, N and O were very probably
      introduced into the human population by independent cross-species transmissions
      of SIVcpz from the chimpanzee subspecies Pan troglodytes troglodytes in central
      Africa. OBJECTIVE: To characterize HIV-1 group N strains and to elucidate the
      group's epidemiology and relationship to HIV-1 strains O and M, and SIVcpz.
      METHODS: DNA amplification, sequencing and phylogenetic analyses were performed
      to characterize viruses from three group N-infected individuals (YBF106, YBF115
      and YBF116) together with YBF30 and YBF105 previously described. RESULTS: Full
      length genome sequence was determined for virus YBF106; gag, pol and env
      sequences were obtained for YBF116; pol (integrase) and env (gp41) fragments were
      obtained for YBF115. The gag, pol, 5'-vif and nef sequences were phylogenetically
      more closely related to HIV-1 M while 3'-vif, vpr, tat, vpu and env clustered
      with SIVcpz from P. t. troglodytes. Sequence analysis revealed no mutations
      potentially responsible for drug resistance. CONCLUSIONS: The finding that all
      group N viruses displayed the same recombinant structure and were monophyletic
      indicates that a single transfer event of SIVcpz to humans can account for the
      origin of this group. Despite the pathogenic outcome of the known group N
      infections, the extremely low prevalence of this divergent HIV-1 suggests that
      this group is not an emerging threat to human health at the present time.
      However, continuous monitoring of HIV-1 diversity will be important to survey the
      potential of unusual HIV infections, such as group N, to contribute to the
      HIV/AIDS pandemic.

PMID- 15199314
TI  - HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection
      despite a relatively high degree of genetic diversity.
AB  - OBJECTIVE: To compare the magnitude, breadth and protein specificity of HIV-1
      specific CD8 T-cell responses against the clade B consensus sequence during
      primary and chronic HIV-1 infection and to analyze the impact of viral diversity
      on the localization of detected responses. METHODS: HIV-1-specific CD8 T-cell
      responses against the clade B consensus sequence in individuals with acute (n =
      10), early (n = 19) and chronic (n = 10) infection were longitudinally assessed
      using an interferon-gamma EliSpot assay. RESULTS: CD8 T-cell responses against
      clade B consensus sequences were preferentially directed against central regions
      of Nef during primary HIV-1 infection, despite a relatively higher degree of
      genetic diversity compared with other subsequently targeted regions. In subjects
      with acute and early infection, Nef-specific CD8 T-cell responses against the
      consensus Nef sequence represented 94 and 46% of the total magnitude of HIV-1
      specific CD8 T-cell responses, respectively. Subjects with untreated chronic
      infection exhibited broadly diversified CD8 T-cell responses against more
      conserved viral regions, with only 17% of virus-specific T-cell responses
      targeting Nef. The initial immunodominance of Nef persisted in individuals with
      treated acute infection, but shifted rapidly to Gag, Env and Pol in subjects with
      continuous antigen exposure. CONCLUSION: These data show that despite relatively
      high sequence variability, viral regions within the clade B consensus sequence of
      Nef are preferentially recognized during primary HIV-1 infection. Later
      diversification of responses to other proteins during prolonged antigen exposure
      provides evidence of the initial preferential immunogenicity of Nef epitopes
      compared to similarly conserved regions within other viral proteins.

PMID- 15199315
TI  - The prevalence of antiretroviral drug resistance in the United States.
AB  - BACKGROUND: Antiretroviral therapy has dramatically reduced the morbidity and
      mortality of infection due to HIV. The emergence of drug-resistant virus has
      limited the usefulness of many drugs. OBJECTIVE: To determine the prevalence of
      HIV drug resistance in the population of adults receiving care in the United
      States. DESIGN AND METHODS: HIV drug susceptibility assays were performed on
      plasma virus from a random sample representative of the 132500 HIV-infected
      American adults who had received medical care in early 1996 yet were viremic with
      > 500 copies/ml of HIV RNA in late 1998. A blood sample was obtained from 1797
      patients who comprised a representative sample of the 208900 adults receiving
      urban care for HIV infection in early 1996 who survived to late 1998. The
      sampling procedure permitted weighting each evaluated patient to reflect
      demographic and other characteristics of the target population. RESULTS: We
      estimated that 132500 (63%) of the target population had HIV viremia of > 500
      copies/ml. Among viremic patients, an estimated 76% had resistance to one or more
      antiretroviral drugs. The odds of resistance were significantly higher in
      patients with a history of antiretroviral drug use, advanced HIV disease, higher
      plasma HIV viral load and lowest CD4 cell count by self-report. CONCLUSIONS: The
      frequent selection for drug-resistant virus among viremic patients during the
      first 3 years of widespread use of potent antiretroviral combination therapy has
      significant implications for HIV treatment and transmission.

PMID- 15199316
TI  - HIV-associated neuromuscular weakness syndrome.
AB  - OBJECTIVE: To investigate progressive, severe neuromuscular weakness associated
      with lactic acidosis in some HIV-infected patients after exposure to nucleoside
      reverse transcriptase inhibitors (NRTI). METHODS: HIV-associated neuromuscular
      weakness syndrome (HANWS) was retrospectively identified and classified based on
      the level of diagnostic certainty: possible (progressive weakness owing to
      neuromuscular disease), probable (progressive neuromuscular weakness with
      documented exclusion of confounding causes), or definite (progressive weakness
      and electrophysiological or pathological evidence of neuromuscular pathology).
      RESULTS: Of 69 patients identified with HANWS, 27 had definite HANWS, 19
      probable, and 23 possible. In 44 patients with documented follow-up, 16 required
      intubation and nine died. There was a marginal association between death and
      hyperlactatemia (P = 0.061). At onset of neurological symptoms, 68 were receiving
      antiretroviral therapy, including stavudine for 61 (89.7%). Serum lactate level
      was elevated (> 2.2 mmol/l) in 30/37 (81%), with a trend towards an association
      between hyperlactatemia and stavudine usage (P = 0.087). In 25, neurological
      symptoms occurred after antiretroviral therapy discontinuation (median, 14 days).
      Electrophysiological studies (n = 24) indicated sensorimotor neuropathy in 20
      patients and myopathy in three. Nerve biopsy (n = 9) revealed axonal degeneration
      and inflammation in three, mixed axonal and demyelinating lesions in three, and
      primary axonal neuropathy in three. Of 15 muscle biopsies, three revealed
      inflammation and four mitochondrial abnormalities. CONCLUSIONS: A severe
      neuromuscular weakness syndrome may occur in HIV-infected individuals. The
      association with hyperlactatemia and NRTI exposure supports mitochondrial
      toxicity as a pathogenesis. In some, the onset of neurological symptoms lagged
      significantly after discontinuation of antiretroviral therapy, suggesting that
      different etiological mechanisms may underlie these cases.

PMID- 15199317
TI  - HIV-1 co/super-infection in intravenous drug users.
AB  - BACKGROUND: The frequency of HIV-1 co/super-infection is unknown despite their
      implications for public health and vaccine development. This issue was addressed
      during an epidemic of both CRF11 and B subtype among intravenous drug users
      (IVDUs). METHODS: Bulk sequencing of reverse transcriptase, protease and C2V3
      regions and subtype-specific nested polymerase chain reaction (PCR) in plasma and
      proviral DNA were performed using baseline and follow-up samples collected in
      recently infected IVDUs between 1998-2002 and in IVDUs with chronic infection
      living in the same area and presenting an unexpected rise of viremia (> 1 log10).
      RESULTS: In 58 recently infected patients, three B/CRF-11 co-infections, 25 B, 28
      CRF-11 and two other subtypes were detected at baseline. In the three co-infected
      patients, both CRF-11 and B were detected in plasma and proviral DNA and
      persisted during follow-up. B- and CFR-11-specific PCR performed on follow-up
      samples of 40 of 58 recently infected patients (median follow-up, 14.5 months)
      revealed a transient B super-infection in a patient initially infected by CRF-11.
      Five of 156 chronic IVDUs (total follow-up: 346 years) had an unexpected rise of
      viremia. In two of them, aviremic without treatment for years after an initial B
      infection, a symptomatic CRF-11 super-infection occurred and was associated with
      high viral load and a fall of CD4 cell count. CONCLUSIONS: In recently infected
      IVDUs, co-infection B/CRF-11 is relatively frequent (5%). In chronically infected
      IVDUs super-infection may be transient and may occur in patients controlling
      efficiently HIV infection by the initial strain.

PMID- 15199318
TI  - Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected
      children.
AB  - OBJECTIVE: To evaluate the effect of combined antiretroviral therapy on serum
      immunoglobulin (Ig) levels in HIV-1 perinatally infected children. METHODS: Data
      from 1250 children recorded by the Italian Register for HIV Infection in Children
      from 1985 to 2002 were analysed. Since Ig levels physiologically vary with age,
      differences at different age periods were evaluated as differences in z-scores
      calculated using means and standard deviations of normal population for each age
      period. Combined antiretroviral therapy has become widespread in Italy since
      1996, thus differences in Ig z-scores between the periods 1985-1995 and 1996-2002
      were analysed. Data according to type of therapeutic regimen were also analysed.
      RESULTS: Between the two periods 1985-1995 and 1996-2002, significant (P <
      0.0001) decreases in IgG (6.29 +/- 4.72 versus 4.44 +/- 4.33), IgM (9.25 +/-
      13.32 versus 5.61 +/- 7.93), and IgA (10.25 +/- 15.68 versus 6.48 +/- 11.56) z
      scores, together with a parallel significant (P < 0.0001) increase in CD4 T
      lymphocyte percentages, were found. These decreases were confirmed regardless of
      whether the children were receiving intravenous Ig or not. Ig z-scores were
      significantly higher in children receiving mono-therapy than in those receiving
      double-combined therapy (IgG, P < 0.0001; IgM, P = 0.003; IgA, P = 0.031) and in
      the latter children than in those receiving three or more drugs (P < 0.0001 for
      all z-scores). Ig z-scores correlated inversely with CD4 T-lymphocyte percentages
      and, directly, with viral loads. CONCLUSIONS: Our data show that in HIV-1
      infected children combined antiretroviral therapy leads to reduction of
      hyperimmunoglobulinemia which parallels restoration of CD4 T-lymphocyte
      percentage and viral load decrease, which it turn probably reflects improved B
      lymphocyte functions.

PMID- 15199319
TI  - Impact of HAART advent on admission patterns and survival in HIV-infected
      patients admitted to an intensive care unit.
AB  - BACKGROUND: Several studies found increased survival times and decreased
      hospitalization rates since the introduction of highly active antiretroviral
      therapy (HAART). OBJECTIVE: To examine the impact of HAART on admission patterns
      and survival of HIV-infected patients admitted to an intensive care unit (ICU).
      DESIGN: Prospective observational cohort study. SETTING AND SUBJECTS: All HIV
      infected patients admitted from 1 January 1995 to 30 June 1999, to an infectious
      diseases ICU located in Paris. MAIN OUTCOME MEASURES: ICU utilization and
      admission patterns, and survival. RESULTS: A total of 426 HIV-related admissions
      were included. Sepsis increased from 16.3% to 22.6% from the pre- to the post
      HAART era, whereas AIDS-related admissions decreased from 57.7% to 37% (P <
      0.05). No significant difference in ICU utilization was found. In both periods,
      half of the patients were not on antiretroviral treatment at ICU admission. In
      ICU mortality was 23%, without significant difference between the study periods.
      By multivariable analysis, in-ICU mortality was significantly associated with
      SAPS II > 40, Omega score > 75 and mechanical ventilation; and long-term survival
      with admission in the HAART era and AIDS at ICU admission. Cumulative survival
      rates after ICU discharge were 85.3% and 70.8% after 12 and 24 months,
      respectively. CONCLUSIONS: HAART had little impact on ICU utilization by HIV
      infected patients. After the introduction of HAART AIDS-related conditions
      decreased and sepsis increased as reasons for ICU admission. Whereas ICU survival
      was dependent on usual prognostic markers, long-term survival was clearly
      dependent on HIV disease stage and HAART availability. In both study periods, at
      least a half of the HIV infected patients were not on anti-retroviral treatment
      at the time of ICU admission.

PMID- 15199320
TI  - Early age of first sex: a risk factor for HIV infection among women in Zimbabwe.
AB  - OBJECTIVE: To explore the relationship between early age of coital debut (15
      years of age or younger) and risk for HIV infection among sexually active
      urbanized Zimbabwean women. DESIGN: Cross-sectional analysis of screening data
      from a cohort study. METHODS: Sexually active women aged 18-35 years were
      recruited from public sector family planning clinics in and around Harare,
      Zimbabwe between November 1999 and September 2002. They received a brief
      behavioral interview and HIV testing. Of the 4675 women screened, 4393 (94%) had
      complete data on sexual behaviors and HIV serostatus, and were included in this
      analysis. RESULTS: HIV prevalence in this sample was 40.1%. The median age of
      coital debut was 18 years and 11.8% of women reporting having experienced coital
      debut at age 15 or younger. Women with early coital debut had a significantly
      higher risk profile, including multiple lifetime partners and not completing high
      school. In binary generalized linear regression models HIV risk was increased for
      women reporting early age of coital debut (relative hazard, 1.30; 95% confidence
      interval, 1.13-1.50), controlling for duration of sexual activity and current
      age; this effect was attenuated somewhat after controlling for other factors such
      as number of sexual partners. CONCLUSIONS: Our results show that early coital
      debut is a significant predictor of prevalent HIV infection independent of other
      identified factors in this population. HIV prevention strategies should include
      delaying the age of first coitus and should address the barriers that may prevent
      young women from so doing.

PMID- 15199321
TI  - Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected
      children in Europe.
AB  - OBJECTIVES: To estimate prevalence of body fat redistribution and dyslipidaemia
      in HIV-infected children and to assess associated risk factors, ultimately to
      inform the definition of lipodystrophy in children. DESIGN: Cross-sectional
      observational study. METHODS: During a 2-3 month period, 477 HIV-infected
      children aged >or= 3 years (median 9.78; range, 3-18) in 30 paediatric HIV
      clinics were assessed at their first visit. Sociodemographic, clinical and
      immunological data were recorded and the presence or absence of clinical signs of
      fat redistribution (peripheral lipoatrophy and central lipohypertrophy)
      determined according to an agreed protocol. Laboratory indicators of
      lipid/glucose metabolism were recorded for all children in 18 centres. RESULTS:
      Prevalence was 26.0% [95% confidence interval (CI), 22.1-30.2] for any fat
      redistribution, 8.81% (95% CI, 6.42-11.7) for central lipohypertrophy, 7.55% (95%
      CI, 5.34-10.3) for peripheral lipoatrophy and 9.64% (95% CI, 7.15-12.7) for the
      combined subtype (more than one sign of each). Independent predictors of fat
      redistribution included Centers for Disease Control and Prevention class C
      disease, female gender, ever used versus never use of protease inhibitors and of
      stavudine. Increasing time since initiation of antiretroviral therapy was
      associated with increased severity of fat redistribution. In the metabolic
      assessment subgroup, 27% (95% CI, 21.6-32.7) of children had
      hypercholesterolaemia and 21% (95% CI, 16.4-26.6) hypertriglyceridaemia; however,
      significantly more children had fat redistribution in this subgroup than overall
      (31%). CONCLUSIONS: Approximately a quarter of children and adolescents could be
      taken to have signs of lipodystrophy, with clinical presentation and risk factors
      similar to those described in adults.

PMID- 15199322
TI  - Increasing prevalence of male homosexual partnerships and practices in Britain
      1990-2000: evidence from national probability surveys.
AB  - OBJECTIVES: To estimate the prevalence and timing of homosexual experience among
      British men; to explore the patterns of sexual practices and partnerships in
      2000, and behavioural and attitudinal changes between 1990 and 2000 among men who
      have sex with men (MSM). DESIGN: Two large, stratified probability sample surveys
      of the general population. METHODS: Trained interviewers administered a
      combination of face-to-face and self-completion questionnaires to men aged 16 to
      44 years resident in Britain (n = 6000 in 1990 and n = 4762 in 2000). RESULTS: In
      2000, 2.8% of British men reported sex with men in the past 5 years. 46.0% of MSM
      reported five or more partners in the past 5 years, and 59.8% reported
      unprotected anal intercourse in the past year. A total of 33.0% of MSM reported
      one or more female partner(s) in the past year. In comparison with 1990, there
      was a significant increase in the proportion of MSM in the population in 2000,
      and among these men, in the proportion reporting receptive anal intercourse in
      the past year [age-adjusted odds ratio (OR), 2.08; 95% confidence interval (CI),
      1.08-4.00], but no significant change in self-perceived HIV-risk (age-adjusted
      OR, 1.11; 95% CI, 0.49-2.51) or HIV testing in past 5 years (age-adjusted OR,
      1.14; 95% CI, 0.57-2.25). CONCLUSIONS: Evidence of increasing prevalence of
      homosexual intercourse among the British male population coupled with increases
      in some HIV-risk behaviours among MSM suggests overall increasing numbers at risk
      in the population. Although these changes may partly reflect an increased
      willingness to report these behaviours, our results are consistent with
      increasing incidence of sexually transmitted infections and behavioural
      surveillance data.

PMID- 15199323
TI  - Trends in tuberculosis and the influence of HIV infection in northern Malawi,
      1988-2001.
AB  - OBJECTIVE: To document the changing incidence and patterns of tuberculosis (TB)
      in rural Africa and the extent to which they are influenced by HIV. METHODS: As
      part of longstanding epidemiological studies in Karonga District, Malawi, a
      series of case control studies of TB and HIV were conducted from 1988 onwards.
      Data from these studies, from a total population survey, and from the Malawi
      national census have been used to reconstruct the changes in the TB epidemic in
      the area from 1988 to 2001, examining the role of HIV. RESULTS: The incidence of
      all confirmed TB, and of new smear-positive TB, in adults increased to peak in
      the late 1990s but appears to have decreased since. Two-thirds of cases are now
      HIV positive. The rise in incidence was greatest in the 30-44-year-old age group
      and was particularly marked for women, leading to a decrease in the male : female
      ratio for TB incidence from 1.3 to 0.8. The proportion of new smear-positive TB
      cases attributable to HIV increased from 17% in 1988-1990 to 57% in 2000-2001,
      but the estimated rate of smear-positive TB in the absence of HIV decreased from
      0.78/1000 to 0.45/1000. CONCLUSIONS: Without HIV the incidence of smear-positive
      TB would have fallen in this population. Instead it has risen and is
      predominantly affecting young adults and women. There is some evidence that the
      HIV-associated TB epidemic may have passed its peak.

PMID- 15199324
TI  - Trends in tuberculosis and the influence of HIV infection in northern Malawi,
      1988-2001.

PMID- 15199325
TI  - Virological and immunological impact of non-nucleoside reverse transcriptase
      inhibitor withdrawal in HIV-infected patients with multiple treatment failures.
AB  - No significant changes in viral load and CD4 cell count were observed 2-4 weeks
      after the withdrawal of non-nucleoside reverse transcriptase inhibitors (NNRTI)
      from the current therapy of patients exhibiting resistance mutations to this
      class of drugs. The data suggest that in the presence of specific resistance
      mutations NNRTIexert no residual antiretroviral activity and could be withdrawn
      without viral rebound.

PMID- 15199326
TI  - Do patients who are infected with drug-resistant HIV have a different CD4 cell
      decline after seroconversion? An exploratory analysis in the UK Register of HIV
      Seroconverters.
AB  - Using data from the UK Register of HIV Sero-converters, we compared the rate of
      CD4 cell decline in antiretroviral-naive individuals with and without evidence of
      transmitted drug resistance (TDR). Although there was a suggestion that CD4 cell
      decline in the first year after seroconversion was faster in those with TDR,there
      was no evidence of a difference in the rate of decline thereafter. The
      virological and host determinants of this possible phenomenon are worth further
      exploration.

PMID- 15199327
TI  - Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV
      infected children.
AB  - Five heavily pretreated HIV-infected children were put on amprenavir and
      delavirdine plus two nucleoside inhibitors to reverse transcriptase to boost
      amprenavir levels and to use the antiretroviral activity of a non-nucleoside
      reverse transcriptase inhibitor. No data are available about this combination in
      children. It w;as well tolerated, and the median reduction in viral load was 1.5
      log after 18 months. Delavirdine boosted amprenavir trough levels more than 10
      fold, and delavirdine trough levels remained i several fold above susceptible HIV
      strains.

PMID- 15199328
TI  - Improvement of dyslipidemia in patients switching from stavudine to tenofovir:
      preliminary results.
AB  - In a prospective, multicentre, switch study to identify the most frequently
      occurring nucleoside reverse transcriptase inhibitor (NRTI)-associated toxicities
      that cause NRTI withdrawal in virologically suppressed HIV-infected patients,
      among those who underwent stavudine substitution by tenofovir, 271 had
      hypertriglyceridemia and 193 had hypercholesterolemia. After 12 weeks of
      switching from stavudine to tenofovir, triglyceride and cholesterol levels showed
      significant de-creases, which suggests that such a switch may reverse, at least
      partly, stavudine-associated dyslipidaemia.

PMID- 15199329
TI  - Mode of transmission of HIV-1 in Saudi Arabia.
AB  - The mode of HIV-1 transmission was determined for 410 Saudi patients.
      Heterosexual transmission occurred in 189 patients (46%), blood product
      transfusion in 107 (26%), and perinatal transmission in 47 (12%). Men who have
      sex with men and injection drug users represented 5% and 2%,respectively. Sixty
      three of 65 heterosexually infected women acquired HIV-1 from their spouses,
      whereas 111 of 124 heterosexually infected men acquired the virus from commercial
      sex workers. Heterosexual transmission is the main mode in Saudi patients.

PMID- 15199330
TI  - Application of an algorithm to predict CD4 lymphocyte count below 200 cells/mm(3)
      in HIV-infected patients in South Africa.

PMID- 15199331
TI  - Analysis of generic antiretroviral formulations manufactured in India.

PMID- 15199332
TI  - Anorectal ulcer in HIV patients, don't forget lymphogranuloma venereum!

PMID- 15199333
TI  - Fulminant ocular leishmaniasis in an HIV-1-positive patient.

PMID- 15199334
TI  - Obtaining informed consent from HIV-infected pregnant women, Abidjan, Cote
      d'Ivoire.

PMID- 15199335
TI  - High-density lipoprotein cholesterol as a therapeutic target to reduce
      cardiovascular events.

PMID- 15199336
TI  - Is there something special about ischemic heart disease in patients undergoing
      dialysis?

PMID- 15199337
TI  - Inflammation and restenosis: is there a link?

PMID- 15199338
TI  - Secondary prevention after coronary artery bypass graft: a primary issue?

PMID- 15199339
TI  - Which elderly patients with cardiogenic shock should be treated with percutaneous
      coronary intervention?

PMID- 15199340
TI  - Atrial fibrillation and atrial cardiomyopathy--two sides of the same coin?

PMID- 15199341
TI  - Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase
      inhibitors.
AB  - BACKGROUND: The recent withdrawal of cerivastatin by the manufacturer has led to
      an interest in hydroxymethylglutaryl-coenzyme A (HMG-CoA) inhibitors and the
      incidence of myopathy. We review the epidemiology, pharmacology, and presumed
      mechanisms of statin-induced myopathy, with a particular focus on cerivastatin.
      METHODS: A MEDLINE search of English-language articles published between 1985 and
      2003 was performed. Key words included HMG-CoA inhibitors, statins, myopathy,
      myotoxicity, rhabdomyolysis, adverse events, drug interactions, and cerivastatin.
      RESULTS: The initial trials, which assessed the efficacy of first-generation HMG
      CoA inhibitors, did not show a clinically significant increase in the incidence
      of myopathy. However, on the basis of Food and Drug Administration post-marketing
      surveys, the rate of cerivastatin-induced rhabdomyolysis appeared to be 10-fold
      greater than that of the other statins, despite safe pre-clinical profiles.
      However, no clinical trials have been performed directly comparing the rates of
      myotoxicity of all commercially available statins. The mechanism of statin
      induced myopathy remains unclear. The prevailing theory is that lipophilic
      statins lead to depletion of intermediates normally formed after cholesterol
      synthesis within myocytes. Risk factors for the development of myopathy include
      drug interactions (especially with fibrates) and the coexistence of conditions
      known to predispose patients to rhabdomyolysis. CONCLUSION: The cerivastatin
      experience emphasizes the need for large safety trials before drug approval and
      for vigilant post-marketing surveillance. Further research and sound clinical
      judgment may lead to the identification of high-risk individuals in whom statins
      should be avoided.

PMID- 15199342
TI  - Can change in high-density lipoprotein cholesterol levels reduce cardiovascular
      risk?
AB  - BACKGROUND: The cardiovascular risk reduction observed in many trials of lipid
      lowering agents is greater than expected on the basis of observed low-density
      lipoprotein cholesterol (LDL-C) level reductions. Our objective was to explore
      the degree to which high-density lipoprotein cholesterol (HDL-C) level changes
      explain cardiovascular risk reduction. METHODS: A systematic review identified
      trials of lipid-lowering agents reporting changes in HDL-C and LDL-C levels and
      the incidence of coronary heart disease (CHD). The observed relative risk
      reduction (RRR) in CHD morbidity and mortality rates was calculated. The expected
      RRR, given the treatment effect on total cholesterol level, was calculated for
      each trial with logistic regression coefficients from observational studies. The
      difference between observed and expected RRR was plotted against the change in
      HDL-C level, and a least-squares regression line was calculated. RESULTS: Fifty
      one trials were identified. Nineteen statin trials addressed the association of
      HDL-C with CHD. Limited numbers of trials of other therapies precluded additional
      analyses. Among statin trials, therapy reduced total cholesterol levels as much
      as 32% and LDL-C levels as much as 45%. HDL-C level increases were <10%.
      Treatment effect on HDL-C levels was not a significant linear predictor of the
      difference in observed and expected CHD mortality rates, although we observed a
      trend in this direction (P =.08). Similarly, HDL-C effect was not a significant
      linear predictor of the difference between observed and expected RRRs for CHD
      morbidity (P =.20). CONCLUSIONS: Although a linear trend toward greater risk
      reduction was observed with greater effects on HDL-C, differences were not
      statistically significant. The narrow range of HDL-C level increases in the
      statin trials likely reduced our ability to detect a beneficial HDL-C effect, if
      present.

PMID- 15199343
TI  - Part I: Identifying holes in the safety net.

PMID- 15199344
TI  - Part II: Sealing holes in the safety net.

PMID- 15199345
TI  - Adenosine stress cardiac magnetic resonance imaging.

PMID- 15199346
TI  - Efficacy of tenecteplase in combination with enoxaparin, abciximab, or
      unfractionated heparin: one-year follow-up results of the Assessment of the
      Safety of a New Thrombolytic-3 (ASSENT-3) randomized trial in acute myocardial
      infarction.
AB  - BACKGROUND: In the ASsessment of the Safety of a New Thrombolytic 3 (ASSENT-3)
      study, full-dose tenecteplase plus enoxaparin or half-dose tenecteplase plus
      abciximab reduced the frequency of ischemic complications of acute myocardial
      infarction, when compared to full-dose tenecteplase plus unfractionated heparin.
      The aim of the present study was to determine the effect of these fibrinolytic
      regimens on 1-year mortality. METHODS AND RESULTS: Vital status at 1 year was
      available for 5942 patients (97.5%) of the 6095 initially enrolled in the study.
      At 1 year, 515 patients (8.7%) had died. Elderly or female patients and patients
      with low body weight, previous myocardial infarction, anterior wall myocardial
      infarction, and diabetes were at increased risk for death at 1 year. Mortality at
      1 year was 7.9 % (n = 161) in the heparin group, 8.1% (n = 166) in the enoxaparin
      group, and 9.3% (n = 188) in the abciximab group (P =.226). Overall, pairwise
      comparisons did not show a significant difference among treatment regimens:
      relative risk 1.03 (95% CI 0.82-1.30) for enoxaparin versus heparin (P =.794) and
      relative risk 1.18 (95% CI 0.95-1.47) for abciximab versus heparin (P =.144).
      However, 1-year outcome tended to be worse with abciximab in diabetic patients.
      CONCLUSION: Mortality at 1 year after acute myocardial infarction remains high.
      Despite a reduction in ischemic complications after acute myocardial infarction
      with the use of full-dose tenecteplase plus enoxaparin or half-dose tenecteplase
      plus abciximab, mortality at 1 year was similar in these treatment groups.

PMID- 15199347
TI  - Caffeinated coffee consumption and mortality after acute myocardial infarction.
AB  - BACKGROUND: Previous studies have generally suggested no effect of coffee
      consumption on the risk of acute myocardial infarction. The effect of coffee
      consumption on prognosis after acute myocardial infarction is uncertain. METHODS:
      In an inception cohort study, we observed 1935 patients who were hospitalized
      with a confirmed acute myocardial infarction between 1989 and 1994 at 45
      community hospitals and tertiary care centers in the United States, as part of
      the Determinants of Myocardial Infarction Onset Study. Trained interviewers
      assessed self-reported caffeinated coffee consumption before infarction with a
      standardized questionnaire. We analyzed survival censored at December 31, 1995,
      using Cox proportional hazards regression. RESULTS: Of the 1902 patients for whom
      we had information on coffee intake, 315 (17%) died during a median follow-up
      period of 3.8 years. Coffee drinkers tended to be men, younger, and free of
      comorbidity, and they were more likely to be current smokers. Coffee consumption
      was not associated with an overall change in long-term post-infarction mortality
      rate. However, we did observe an unexpected and unexplained variation in the
      association between coffee consumption and mortality with time, with an apparent
      inverse association in the first 90 days after infarction. CONCLUSIONS: Self
      reported coffee consumption has no overall association with post-infarction
      mortality. The unexpected time variation in the effect of coffee intake requires
      evaluation in other studies.

PMID- 15199348
TI  - Periodontal disease in patients with acute myocardial infarction: prevalence and
      contribution to elevated C-reactive protein levels.
AB  - BACKGROUND: Periodontal disease (PD) has been linked to adverse cardiovascular
      events, but the mechanism for this association is unknown. We hypothesized that
      PD is common in patients with acute myocardial infarction (AMI) and, when
      present, may result in an enhanced systemic inflammatory response with higher C
      reactive protein (CRP) levels. METHODS: Periodontal examinations and serum high
      sensitivity CRP measurements were performed in 40 patients with AMI (11 women;
      mean age, 60 +/- 15 years) during the index hospitalization. The control group
      comprised 40 sex and race frequency-matched, community volunteers (9 women; mean
      age, 64 +/- 5 years) without known heart disease. RESULTS: Both the prevalence of
      PD and mean serum CRP levels were significantly higher in the patients with AMI
      than in the control subjects (48% vs 17%, P <.001 and 40.2 vs 7.9 mg/L, P <.001,
      respectively). Patients with AMI who had PD had significantly higher CRP levels
      than patients with AMI who did not have PD (50.7 vs 30.7 mg/L, P <.001). With
      linear regression analysis, a positive relationship was shown between the extent
      of PD and serum CRP levels, and with a multivariate regression model that
      included smoking, diabetes mellitus, infarct size and PD, PD emerged as a strong
      and independent predictor of elevated CRP levels (r2 = 0.33, P =.004).
      CONCLUSIONS: Periodontal disease is common in patients with AMI and is associated
      with an enhanced inflammatory response expressed by higher CRP levels. The
      association of PD with CRP levels in patients with AMI appears to be independent
      of other contributing factors.

PMID- 15199349
TI  - Public recognition of major signs and symptoms of heart attack: seventeen states
      and the US Virgin Islands, 2001.
AB  - BACKGROUND: Timely access to emergency cardiac care and survival is partly
      dependent on early recognition of heart attack symptoms and immediate action by
      calling emergency services. We assessed public recognition of major heart attack
      symptoms and knowledge to call 9-1-1 for an acute event. METHODS: Data are from
      the 2001 Behavioral Risk Factor Surveillance System, a state-based telephone
      survey. Participants (n = 61,018) in 17 states and the U.S. Virgin Islands
      indicated whether the following were heart attack symptoms: pain or discomfort in
      the jaw, neck, back; feeling weak, lightheaded, faint; chest pain or discomfort;
      sudden trouble seeing in 1 or both eyes (false symptom); pain or discomfort in
      the arms or shoulder; shortness of breath. Participants also indicated their
      first action if someone was having a heart attack. RESULTS: Most persons (95%)
      recognized chest pain as a heart attack symptom. However, only 11% correctly
      classified all symptoms and knew to call 9-1-1 when someone was having a heart
      attack. Symptom recognition and the need to call 9-1-1 was lower among men than
      women, persons of various ethnic groups than whites, younger and older persons
      than middle-aged persons, and persons with less education. Persons with high
      blood pressure, high cholesterol, diabetes mellitus, or prior heart attack or
      stroke were not appreciably more likely to recognize heart attack symptoms than
      were persons without these conditions. CONCLUSIONS: Public health efforts are
      needed to increase recognition of the major heart attack symptoms in both the
      general public and groups at high risk for an acute event.

PMID- 15199350
TI  - Coronary flow reserve abnormalities in patients with diabetes mellitus who have
      end-stage renal disease and normal epicardial coronary arteries.
AB  - BACKGROUND: Diabetic nephropathy is associated with increased cardiovascular
      events. Coronary atherosclerosis is responsible for many of these events, but
      other mechanisms such as impaired flow reserve may be involved. The purpose of
      this study was to define the prevalence and mechanism of abnormal coronary
      velocity reserve (CVR) in patients with diabetes mellitus who have nephropathy
      and a normal coronary artery. METHODS: Patients undergoing catheterization for
      clinical purposes were enrolled. CVR was measured with a Doppler ultrasound
      scanning wire in a normal coronary in 32 patients without diabetes mellitus, 11
      patients with diabetes mellitus who did not have renal failure, and 21 patients
      with diabetes mellitus who had nephropathy. A CVR <2.0 was considered to be
      abnormal. RESULTS: Patients with diabetes mellitus who had renal failure had a
      higher incidence of hypertension and left ventricular hypertrophy. The average
      peak velocity (APV) at baseline was higher in patients with diabetes mellitus who
      had renal failure. At peak hyperemia, APV increased in all 3 groups, with no
      difference between groups. The mean CVR for patients without diabetes was 2.8 +/-
      0.8 and was not different from that in patients with diabetes mellitus who did
      not have renal failure (2.7 +/- 0.7), but was lower than that in patients with
      diabetes mellitus who had renal failure (1.6 +/- 0.5; P < 0.001). Abnormal CVR
      was observed in 9% of patients without diabetes mellitus, 18% of patients with
      diabetes mellitus who did not have renal failure, and 57% of patients with
      diabetes mellitus who had renal failure, and abnormal CVR was caused by an
      elevation of baseline APV in 66% of these cases. The baseline heart rate and the
      presence of diabetes mellitus with renal failure were independent predictors of
      abnormal CVR by multivariable analysis. CONCLUSIONS: Patients with diabetic
      nephropathy have abnormalities in CVR in the absence of angiographically evident
      coronary disease.

PMID- 15199351
TI  - Resting heart rate and cause-specific death in a 16.5-year cohort study of the
      Japanese general population.
AB  - BACKGROUND: Several prospective studies have reported resting heart rate (HR) to
      be a risk factor for certain cause-specific death, together with sex- or age
      specific differences in the effects of HR on death. However, there have been few
      prospective data from non-Western populations. METHODS: Cohort study, over 16.5
      years to date of death or end of follow-up (November 15, 1998) involving 8800 men
      and women > or =30 years of age randomly selected throughout Japan, who
      participated in the National Survey on Circulatory Disorders in 1980. Resting HR
      was determined from 3 consecutive intervals between R waves on the 12-lead
      electrocardiogram. RESULTS: For middle-aged men (30 to 59 years of age), in the
      highest quartile of HR, there was a significant positive association with
      cardiovascular (RR, 2.55; 95% CI, 1.22 to 5.31) and all-cause death (RR, 1.45;
      95% CI, 1.06 to 2.00). For middle-aged women, in the highest quartile, there was
      a significant positive association with noncancer, noncardiovascular (RR, 2.41;
      95% CI, 1.04 to 5.59), and all-cause death (RR, 1.94; 95% CI, 1.26 to 3.01).
      Resting HR also showed a significant positive association with cardiac events but
      not to stroke. These relations were not evident for elderly subjects (> or =60
      years of age). Results were not affected when deaths within the first 5 years of
      follow-up were excluded, except for noncancer, noncardiovascular death.
      CONCLUSIONS: High resting HR is an independent predictor of long-term death in
      the Japanese general population.

PMID- 15199352
TI  - Predictors of 14-year changes in the total cholesterol to high-density
      lipoprotein cholesterol ratio in men.
AB  - BACKGROUND: Although the ratio of total to high-density lipoprotein cholesterol
      (TC/HDL) is a powerful predictor of cardiovascular disease (CVD), few studies
      have investigated which factors are associated with changes in this ratio over
      time. We examined predictors of a change in TC/HDL ratio over a period of 14
      years among 4451 men free of CVD from the Physicians' Health Study. METHODS:
      Baseline and updated physician characteristics and CVD risk factors were included
      in multivariate linear and logistic regression models to determine factors
      associated with a change in the TC/HDL ratio or of having a ratio of > or =5 on
      follow-up. RESULTS: After a mean follow-up of 14 years, mean total cholesterol
      decreased by 7 mg/dL, HDL increased by 1 mg/dL, and the ratio decreased by 0.37.
      In multivariate logistic analyses, physicians were more likely to have a TC/HDL
      ratio of > or =5 at follow-up if they maintained a weight of > or =25 kg/m2 (OR,
      1.69 [1.35-2.12]), gained weight (OR, 2.01 [1.55-2.62]), or became inactive (OR,
      1.43 [1.11-1.83]). However, older physicians and those who consumed alcohol or
      received treatment for hyperlipidemia were more likely to have a ratio of <5.
      CONCLUSIONS: Although pharmacologic treatment for hyperlipidemia had the greatest
      favorable impact on the ratio over time, our data also show that maintaining an
      ideal weight and exercise have beneficial effects. We therefore advocate a
      renewed fervor for raising public awareness of the benefits of healthy lifestyle
      behaviors and pharmacologic treatments that are associated with long-term
      maintenance of favorable cholesterol levels.

PMID- 15199353
TI  - Impact of physical training and detraining on endothelium-dependent vasodilation
      in patients with recent acute myocardial infarction.
AB  - BACKGROUND: There is evidence that aerobic exercise improves endothelial function
      in healthy subjects as well as in patients with chronic heart failure. However,
      it is unknown whether this effect occurs in patients with recent myocardial
      infarction (AMI). METHODS: Fifty-two patients with a recent first uncomplicated
      AMI underwent endothelial function evaluation before and after 3 months of
      moderate aerobic exercise training. We measured brachial artery vasomotor
      reactivity using flow-mediated dilation (FMD), a cold pressor (CP) test, and
      sublingual nitroglycerin. Patients were randomized into 2 groups: 28 patients
      (G1) underwent training, while 24 patients (G2) served as controls. Brachial
      artery vasomotor reactivity was reassessed after 1 month of detraining (DT).
      RESULTS: At baseline the FMD was 1.66% +/- 4.11% in G1 and 2.04% +/- 3.4% in G2
      (P = NS) and vasoconstriction was evident after a CP test. The diameter reduction
      was -4.1% +/- 3.89% in G1 and -4.39% +/- 5.67% in G2 (P = NS). At follow-up the
      FMD had increased to 9.39% +/- 4.87% in G1 (P <.01) and to 4.4% +/- 3.9% in G2 (P
      <.01 vs G1). Vasoconstriction during a CP test was observed only in G2.
      Endothelium-independent vasodilation was unchanged in both groups. Effort
      tolerance increased by 32% in G1 patients (P <.01 versus G2) and was correlated
      with FMD change (R = 0.51, P <.01). After detraining the FMD was significantly
      reduced in G1 (P <.01) and a further vasoconstriction was evident after CP
      testing. CONCLUSIONS: Exercise training improves endothelium-dependent
      vasodilation in post-AMI patients. This improvement is associated with a
      significant increase in exercise tolerance. These benefits disappeared after
      detraining.

PMID- 15199354
TI  - Preventing recurrent events long term after coronary artery bypass graft:
      suboptimal use of medications in a population study.
AB  - BACKGROUND: There are few population-based data on long-term management of
      patients after coronary artery bypass graft (CABG), despite the high risk for
      future major vascular events among this group. We assessed the prevalence and
      correlates of pharmacotherapy for prevention of new cardiac events in a large
      population-based series. METHODS: A postal survey was conducted of 2500 randomly
      selected survivors from a state population of patients 6 to 20 years after first
      CABG. RESULTS: Response was 82% (n = 2061). Use of antiplatelet agents (80%) and
      statins (64%) declined as age increased. Other independent predictors of
      antiplatelet use included statin use (odds ratio [OR] 1.6, 95% CI 1.26-2.05) and
      recurrent angina (OR 1.6, CI 1.17-2.06). Current smokers were less likely to use
      aspirin (OR 0.59, CI 0.4-0.89). Statin use was associated with reported high
      cholesterol (OR 24.4, CI 8.4-32.4), management by a cardiologist (OR 2.3, CI 1.8
      3.0), and the use of calcium channel-blockers. Patients reporting hypertension or
      heart failure, in addition to high cholesterol, were less likely to use statins.
      Angiotensin-converting enzyme inhibitors were the most commonly prescribed agents
      for management of hypertension (59%) and were more frequently used among patients
      with diabetes and those with symptoms of heart failure. Overall 42% of patients
      were on angiotensin-converting enzyme inhibitors and 36% on beta-blockers.
      CONCLUSIONS: Gaps exist in the use of recommended medications after CABG. Lower
      anti-platelet and statin use was associated with older age, freedom from angina,
      comorbid heart failure or hypertension, and not regularly visiting a
      cardiologist. Patients who continue to smoke might be less likely to adhere to
      prescribed medications.

PMID- 15199355
TI  - Sex disparities in procedure use for acute myocardial infarction in the United
      States, 1995 to 2001.
AB  - BACKGROUND: Sex disparities in procedure use for acute myocardial infarction
      (AMI) have been well documented in selected populations in the 1980s and early
      1990s. As little is known about more recent trends in sex disparities in the
      general population, we analyzed more recent rates of catheterization,
      angioplasty, and coronary artery bypass grafting (CABG) performed before
      discharge for acute myocardial infarction. METHODS: Data from representative
      civilian hospitals in 33 US states in the Nationwide Inpatient Sample from 1995
      to 2001 were used to identify men and women discharged with a primary diagnosis
      of acute myocardial infarction. Receipt of cardiac catheterization, angioplasty,
      stent placement, or CABG was determined. Multivariate Poisson modeling was used
      to determine the likelihood of procedure receipt by sex, adjusting for
      demographic, comorbidity, and hospital characteristics. RESULTS: From 1995 to
      2001, the adjusted proportion receiving catheterization, angioplasty, and stents
      increased in women as well as men, whereas the adjusted proportion receiving CABG
      declined slightly. Women were nearly as likely as men to undergo catheterization
      (adjusted prevalence ratio [PR], 0.96; 95% CI, 0.95 to 0.97), angioplasty
      (adjusted PR, 0.98; 95% CI, 0.97 to 0.99), or stent placement (adjusted PR, 0.96;
      95% CI, 0.95 to 0.97). Women remained less likely to undergo CABG (adjusted PR,
      0.78; 95% CI, 0.77 to 0.79). CONCLUSIONS: These recent nationwide data suggest
      that compared with men, women are nearly as likely to undergo catheterization
      based procedures but remain less likely to undergo CABG.

PMID- 15199356
TI  - Enalapril treatment and hospitalization with atrial tachyarrhythmias in patients
      with left ventricular dysfunction.
AB  - BACKGROUND: Experimental and clinical evidence suggests a preventive role for
      agiotensin-coverting enzyme (ACE) inhibitors on the development of atrial
      fibrillation. However, the effect of ACE inhibition on hospitalization with
      atrial tachyarrhythmias in patients with left ventricular (LV) dysfunction is not
      known. We sought to determine whether enalapril treatment reduced
      hospitalizations with atrial tachyarrhythmias in patients with LV dysfunction.
      METHODS: We performed a retrospective analysis of the Studies of Left Ventricular
      Dysfunction (SOLVD) trial. Hospitalizations with atrial tachyarrhythmias were
      noted. RESULTS: A total of 192 hospitalizations with atrial tachyarrhythmias
      occurred in 158 patients during a follow-up period of 34 months. The time to
      first hospitalization with atrial tachyarrhythmias or death was significantly
      lower in the enalapril group (P =.005). In a multivariate analysis adjusting for
      the presence of atrial fibrillation at study entry, enalapril treatment was
      associated with a reduction in the rate of hospitalization with atrial
      tachyarrhythmias or death (RR, 0.87; 95% CI, 0.79-0.96; P =.007). The incidence
      of hospitalization with atrial tachyarrhythmias was 7.9 hospitalizations per 1000
      patient-years of follow-up in the enalapril group, compared with 12.4 per 1000
      patient-years in the placebo group (RR, 0.64; 95% CI, 0.48-0.85; P =.002).
      CONCLUSION: Enalapril is associated with a decreased incidence of hospitalization
      with atrial tachyarrhythmias in patients with LV dysfunction.

PMID- 15199357
TI  - Outcomes of elderly patients with cardiogenic shock treated with early
      percutaneous revascularization.
AB  - BACKGROUND: Subgroup analysis from the Should We Emergently Revascularize
      Occluded Coronaries for Cardiogenic Shock (SHOCK) trial indicated that patients
      with acute myocardial infarction (MI) complicated by cardiogenic shock (CS) who
      were > or =75 years old did not benefit from early revascularization and may have
      been harmed; their mortality rate at 30 days was 75%. The applicability of this
      subset analysis from a select patient population enrolled in a randomized trial
      to the general population is unclear. METHODS: At the Mayo Clinic between 1991
      and 2000, we evaluated the outcome of all patients > or =75 years old with CS
      caused by MI who underwent urgent percutaneous coronary intervention (PCI).
      RESULTS: The study included 61 patients with a mean age of 79.5 +/- 3 years; 21%
      of these patients had a history of prior coronary artery bypass grafting (CABG),
      41% had had a prior MI, 28% had diabetes mellitus, and 18% had a history of a
      cerebrovascular accident (CVA). PCI was performed 8.0 +/- 7.2 hours after onset
      of MI. Angiographic success (<50% residual stenosis) was achieved in 91% of the
      lesions that were dilated. In hospital outcomes included death (44%), CABG
      (1.6%), and CVA (4.9%). The 30-day mortality rate was 47%. The estimated survival
      rate 1 year after discharge (Kaplan Meier method) was 75%. CONCLUSIONS: These
      data confirm a high early mortality rate among patients > or =75 years old with
      MI complicated by CS, but suggest that among patients referred for angiography,
      outcomes may be better than previously believed when early revascularization is
      performed. In this population, 56% of patients survived to be discharged from the
      hospital, and of the hospital survivors, 75% were alive at 1 year.

PMID- 15199358
TI  - Preprocedural inflammatory markers do not predict restenosis after successful
      coronary stenting.
AB  - BACKGROUND: Levels of C-reactive protein (CRP), serum amyloid A protein (SAA),
      and interleukin-6 (IL-6) can predict coronary restenosis following angioplasty
      and stent deployment in patients with unstable angina. We investigated whether
      measurement of periprocedural inflammatory markers predicted the angiographic
      outcome at 6 months in stable angina patients undergoing coronary stenting.
      METHODS: We prospectively studied 182 patients; 152 patients underwent elective
      and successful stenting procedure for de novo lesions in native and nongrafted
      coronary arteries and 30 individuals in the control group underwent diagnostic
      angiography alone. CRP, SAA, and IL-6 were determined by high-sensitivity
      immunoassays. RESULTS: At 6 months, quantitative computer-assisted angiographic
      analysis in 133 patients with stents showed a binary restenosis rate of 33.8%.
      Statins were being taken by 80% of the patients. There were no significant
      differences between the pre- or postprocedure values of CRP, SAA, or IL-6 in
      patients with or without in-stent restenosis. CONCLUSIONS: Preprocedural
      inflammatory markers in stable angina subjects undergoing coronary artery stent
      deployment did not correlate with the development of in-stent restenosis.
      Differences in pathobiology between stable and unstable coronary syndromes, the
      widespread use of statins with anti-inflammatory activity in our cohort of
      patients, along with different mechanisms underlying the early angiographic
      appearances of restenosis as compared to clinical end points, most likely explain
      our findings.

PMID- 15199359
TI  - Impact of age, race, and sex on the ability of B-type natriuretic peptide to aid
      in the emergency diagnosis of heart failure: results from the Breathing Not
      Properly (BNP) multinational study.
AB  - BACKGROUND: B-type natriuretic peptide (BNP) is secreted from the cardiac
      ventricles in response to increased wall tension. METHODS: The Breathing Not
      Properly Multinational Study was a 7-center, prospective study of 1586 patients
      who presented to the Emergency Department with acute dyspnea and had BNP measured
      with a point-of-care assay upon arrival. The gold standard for congestive heart
      failure (CHF) was adjudicated by two independent cardiologists, blinded to BNP
      results, who reviewed all clinical data and standardized scores. The current
      study explores the effect of these variables on BNP decision statistics as well
      as the impact that changing cutoffs might have on the cost-effectiveness of
      diagnostic decisions that use BNP information. RESULTS: Significant differences
      in CHF rates were found on the basis of age (P <.001) and racial group (P =.020)
      but not sex (P =.424). BNP levels increased with increasing age (P <.001). To
      evaluate potential differences in the diagnostic utility of BNP levels as a
      function of demographic variables, separate receiver operating characteristic
      curves were performed. BNP was a stronger predictor in younger subjects than in
      older subjects and slightly weaker for female patients than for male patients
      (area under the curve = 0.918 and 0.870, respectively). An even smaller
      difference was noted between the white and black racial groups (area under the
      curve = 0.888 and 0.903, respectively). The differences in specificity as a
      function of age are larger than other differences in specificity or sensitivity.
      When logistic regression was used in a multivariate approach to combine the
      demographic variables with BNP information in the prediction of CHF, only BNP
      contributed significantly to the prediction of acute CHF. When the model was
      expanded to include terms for the interaction of each of the demographic
      variables with log(10) BNP, a significant interaction was found for sex. Since
      the relative consequences of false-positives and false-negatives are unlikely to
      be equivalent, the BNP cut-points that would be selected based on the current
      data as a function of relative costs are presented. Sharply rising consequences
      are seen for BNP cut-points >100 pg/mL. CONCLUSIONS: If one assumes that failing
      to treat cases of CHF is worse than treating negative cases, then relatively low
      BNP cut-points (eg, not >100 pg/mL) should be used in patients presenting to the
      Emergency Department with a chief complaint of dyspnea, regardless of age, sex,
      or ethnicity.

PMID- 15199360
TI  - Validation of the accuracy of pretest and exercise test scores in women with a
      low prevalence of coronary disease: the NHLBI-sponsored Women's Ischemia Syndrome
      Evaluation (WISE) study.
AB  - BACKGROUND: Recently revised American College of Cardiology/American Heart
      Association guidelines have suggested that exercise test scores be used in
      decisions concerning patients with suspected coronary artery disease (CAD).
      Pretest and exercise test scores derived for use in women without known CAD have
      not been tested in women with a low prevalence of CAD. METHODS: Within the
      Women's Ischemia Syndrome Evaluation (WISE) study, we evaluated 563 women
      undergoing coronary angiography for suspected myocardial ischemia. The prevalence
      of angiographic CAD was 26%. Overall, 189 women underwent treadmill exercise
      testing. Prognostic end points included death, myocardial infarction, stroke, and
      revascularization. RESULTS: Each score stratified women into 3 probability groups
      (P <.001) according to the prevalence of coronary disease: Pretest: low 20/164
      (12%), intermediate 53/245 (22%), high 75/154 (49%); Exercise test: low 11/83
      (13%), intermediate 22/74 (30%), high 17/32 (53%). However, the Duke score did
      not stratify as well: low 7/46 (15%), intermediate 36/126 (29%), high 6/17 (35%);
      P =.44. When pretest and exercise scores were considered together, the best
      stratification with the exercise test score was in the intermediate pretest group
      (P <.03). The Duke score did not stratify this group at all (P =.98). Pretest and
      exercise test scores also stratified women according to prognostic end points:
      pretest--low 7/164 (4.3%), intermediate 28/245 (11.4%), high 27/154 (17.5%), P
      <.01; exercise test--low 4/83 (4.8%) and intermediate-high 17/106 (16%), P =.014.
      CONCLUSION: Both pretest and exercise test scores performed better than the Duke
      score in stratifying women with a low prevalence of angiographic CAD. The
      exercise test score appears useful in women with an intermediate pretest score,
      consistent with American College of Cardiology/American Heart Association
      guidelines.

PMID- 15199361
TI  - Tamoxifen improves endothelial function and reduces carotid intima-media
      thickness in postmenopausal women.
AB  - BACKGROUND: Tamoxifen is a selective estrogen-receptor modulator shown to improve
      several cardiovascular risk factors in postmenopausal women with breast cancer.
      In animal studies tamoxifen inhibits the progression of atherosclerosis. Although
      the presence of a history with tamoxifen treatment is related to a lower intima
      media thickness (IMT) of the common carotid artery, data from controlled follow
      up studies are lacking to support this observation. METHODS: We examined 14
      postmenopausal women with early stage breast cancer with indication for tamoxifen
      treatment (20 mg/d) and 13 healthy postmenopausal women. Flow-mediated dilatation
      (FMD) of the brachial artery, combined carotid IMT, and aortic pulse wave were
      measured before and 6 months after treatment in the tamoxifen group and at the
      same times in the control group. RESULTS: FMD and IMT were significantly
      increased and decreased, respectively, in the treatment group compared to the
      control group (FMD: +2.2% +/- 0.9% vs +0.085% +/- 1%, P =.012; IMT: -0.088 +/-
      0.03 mm vs +0.04 +/- 0.03 mm, P =.018, mean +/- standard error of the mean,
      treatment vs control group). These differences remained significant even when
      adjusted for age, duration of menopause, and cardiovascular risk factors. Low
      density lipoprotein cholesterol was also significantly reduced after tamoxifen
      treatment. CONCLUSIONS: Tamoxifen treatment slows the progression of
      atherosclerosis in postmenopausal women with breast cancer as assessed by changes
      in carotid IMT. An improvement in endothelial function and blood lipid profile
      may be the reason for this beneficial effect.

PMID- 15199362
TI  - Myocardial perfusion assessment in patients with medium probability of coronary
      artery disease and no prior myocardial infarction: comparison of myocardial
      contrast echocardiography with 99mTc single-photon emission computed tomography.
AB  - BACKGROUND: No previous studies have compared myocardial contrast
      echocardiography (MCE) and single-photon emission computerized tomography (SPECT)
      for the detection of coronary artery disease (CAD) in patients with a medium
      likelihood of CAD. This study was developed to test the hypothesis that MCE is
      superior to SPECT for the detection of CAD. METHODS: Fifty-five patients with a
      medium probability of CAD and no previous myocardial infarction were recruited.
      Results of MCE and SPECT were compared to quantitative coronary arteriography,
      where CAD was defined as >50% stenosis. Each patient was examined for the
      anterior and posterior circulations. RESULTS: On a coronary circulation basis (n
      = 110), the sensitivity of MCE was significantly greater than that of SPECT for
      the detection of CAD (86% vs 43%, P <.0001). However, the specificities were
      similar (88% and 93%, P =.52). Both techniques were marginally more accurate in
      the anterior compared to the posterior circulation (88% vs 76%, P =.07 for MCE
      and 79% vs 63%, P =.19, for SPECT). On a patient basis (n = 55), MCE had a higher
      sensitivity than SPECT for the detection of CAD (83% vs 49%, P <.05). Although
      specificity tended to be higher for SPECT than MCE (92% vs 58%), it was not
      significant (P =.33). When CAD was defined as >40% coronary stenosis, the
      specificity of MCE increased to 83% without any change in sensitivity.
      CONCLUSION: In this preliminary study, MCE was found to be superior to SPECT
      during dipyridamole stress for the diagnosis of CAD in patients with a medium
      pretest probability of CAD. Larger studies are required to confirm these
      findings.

PMID- 15199363
TI  - Effects of oral amino acid supplementation on myocardial function in patients
      with type 2 diabetes mellitus.
AB  - BACKGROUND: Diabetes mellitus is associated with an increased rate of cardiac
      amino acid catabolism that could interfere with cardiac function. METHODS: We
      assessed the effects of an oral amino acids mixture (AAM) on myocardial function
      in patients with type 2 diabetes mellitus (DM2). We studied 65 consecutive
      patients with DM2 who had normal resting left ventricular ejection fraction
      (LVEF) and did not have obstructive coronary artery disease (CAD). After baseline
      evaluations, patients were randomized to receive, in a single-blinded fashion,
      AAM (12 grams/day) or placebo for 12 weeks, after which, treatment was crossed
      over for another similar period. At baseline and at the end of each treatment, 2
      dimensional ecocardiography at rest and during isometric exercise (handgrip) was
      performed, as were biochemical assays. Twenty adults, matched for age, sex, and
      body mass index served as control subjects. RESULTS: At baseline and during AAM
      or placebo treatment, resting left ventricular dimensions and LVEF in patients
      with DM2 did not differ from those of control subjects. In patients with DM2, at
      baseline and during placebo treatment, peak handgrip LVEF decreased significantly
      in comparison with the resting value (63% +/- 9% vs 56% +/- 9%, P <.001; and 62%
      +/- 6% vs 55% +/- 8%, P <.001). During AAM treatment, peak handgrip LVEF did not
      differ from resting value (66% +/- 11% vs 64% +/- 9%, P = not significant). Thus,
      exercise LVEF was higher during AAM treatment than both baseline and placebo
      treatment (66% +/- 11% vs 56% +/- 9% and vs 55% +/- 8%, P <.001). In contrast to
      placebo treatment, after the AAM supply, a decreased glycated hemoglobin level
      was observed (7.0% +/- 1.3% vs 7.6% +/- 1.8%, P <.05). CONCLUSIONS: Myocardial
      dysfunction is easily inducible with isometric exercise in patients with DM2 who
      have normal resting LV function and do not have CAD. An increased amino acid
      supply prevents this phenomenon and improves metabolic control.

PMID- 15199364
TI  - Mitral annular calcification is associated with osteoporosis in women.
AB  - BACKGROUND: Few studies have suggested association between mitral annular
      calcification (MAC) and osteoporosis in women who are post-menopausal. However,
      the association of MAC with osteoporosis in women, in relation to bone
      resorption, as assessed by using the dual-energy x-ray absorptiometry method
      (DEXA), have not been performed. We sought to examine the association between MAC
      and osteoporosis. METHODS: In this prospective, observational study carried out
      in a tertiary referral center, 340 women (mean age +/- SD, 56 +/- 10 years; age
      range, 33-85 years) underwent echocardiography, with specific assessment of MAC
      and bone mineral density measurement (T-scores) using DEXA. RESULTS: MAC was
      absent in 123 patients (group I) and present in 217 patients (group II). Compared
      with the control group, the group with MAC had a significantly higher prevalence
      and severity of osteoporosis (18.2% vs 55.5%, P <.001). Severe osteoporosis was
      significantly more common in the severe MAC subgroup (n = 66) than in the control
      subjects (65.2% vs 17.1%; Pearson chi2, 70.02; df = 4; P <.001). With
      multivariate analysis, only T-scores and age were highly predictive of MAC, with
      an odds ratio of 2.66 (95 % CI, 1.85-3.83) and 1.04 (95% CI, 1.01-1.07),
      respectively. CONCLUSIONS: MAC is associated with osteoporosis. Bone mineral
      density measurement (T-scores) and age were highly predictive of MAC in women.

PMID- 15199365
TI  - Association between the PPARalpha L162V polymorphism, plasma lipoprotein levels,
      and atherosclerotic disease in patients with diabetes mellitus type 2 and in
      nondiabetic controls.
AB  - BACKGROUND: Peroxisome proliferator activated receptor alpha (PPARalpha)
      regulates genes involved in lipoprotein metabolism, hemostasis, and inflammation.
      It thus represents a candidate gene for the risk of dyslipidemia,
      atherosclerosis, and coronary heart disease (CHD). Nonesterified fatty acids are
      PPARalpha ligands and their levels are increased in patients with diabetes
      mellitus type 2 (DM-2). The effects of the polymorphism of PPARalpha on plasma
      lipids and atherosclerosis development have been until now contradictory. The
      present study was performed to evaluate the association between the PPARalpha
      polymorphism L162V and the presence of dyslipidemia and/or atherosclerotic
      disease in patients with DM-2 in comparison with nondiabetic controls. METHODS
      AND RESULTS: We determined this polymorphism in 404 subjects with DM-2 and in 438
      age and sex-matched nondiabetic controls. The V allele was present in 9.4% of
      patients with DM-2 and in 11.4% of the control group (P =.34). There was no
      significant association between the presence of the polymorphism and body mass
      index. There was no association between the polymorphism and lipoprotein
      concentrations in either group, independent of lipid-lowering therapy. In
      patients with DM-2, there was a trend towards a lower prevalence of
      atherosclerosis in carriers versus noncarriers of the V allele (P =.0837). In the
      control group, the presence of the V allele was not associated with an altered
      prevalence of atherosclerotic disease (P =.45). Likewise, there was a trend
      towards lower CHD prevalence in carriers versus noncarriers of the V allele (P
      =.0622). The presence of the polymorphism was not associated with CHD in the
      control group (P =.80). CONCLUSIONS: The data suggest that the PPARalpha
      polymorphism L162V might protect against the development of atherosclerosis or
      CHD in patients with DM-2. The absence of an association between the polymorphism
      and plasma lipoprotein concentrations may suggest that these protective effects
      are exerted directly on the arterial wall.

PMID- 15199366
TI  - Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces
      circulating platelet activity in patients without diabetes mellitus who have
      coronary artery disease.
AB  - BACKGROUND: Rosiglitazone, a peroxisome proliferator-activated receptor-gamma
      (PPAR-gamma) agonist, is used in the treatment of type 2 diabetes mellitus, and
      in vitro data has shown that it may have anti-platelet effects independent of its
      hypoglycemic effects. The aim of this study was to assess the effect of
      rosiglitazone on circulating platelet activity in patients without diabetes
      mellitus who had coronary artery disease. METHODS: Ninety-two patients with
      stable, documented coronary artery disease without diabetes mellitus were
      studied. Patients were randomized (double-blind) to receive placebo or
      rosiglitazone for 12 weeks. Circulating platelet activity was measured at
      baseline and after 12 weeks of therapy with whole blood flow cytometry to
      quantify platelet P-selectin expression. RESULTS: The percentage of P-selectin
      positive platelets was significantly reduced by rosiglitazone treatment compared
      with placebo (P =.04). In the rosiglitazone group, the percentage of P-selectin
      positive platelets (median with interquartile range) decreased from 0.1 % (0.05
      0.24) to 0.05 % (0.01-0.15). Rosiglitazone treatment significantly reduced the
      insulin resistance index (HOMA-R) compared with placebo (P =.02). No significant
      correlation was observed between change in platelet activity and change in HOMA
      R. CONCLUSIONS: Rosiglitazone significantly reduces circulating platelet activity
      in patients without diabetes mellitus who have coronary artery disease. This
      effect appears to be independent of any insulin-sensitising effect.

PMID- 15199367
TI  - An increased capacity for adrenal DHEA release is associated with decreased
      avoidance and negative mood symptoms in women with PTSD.
AB  - We recently found increased adrenal cortisol responses to adrenocorticotropic
      hormone (ACTH)1-24 and increased pituitary ACTH and adrenal cortisol responses to
      corticotropin-releasing factor in premenopausal women with chronic post-traumatic
      stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern
      of hypothalamic-pituitary-adrenal axis (HPA) hyper-reactivity has been previously
      seen in healthy individuals treated with the antiglucocorticoid mifepristone. We
      therefore investigated whether endogenous plasma levels of antiglucocorticoids
      such as dehydroepiandrosteroine (DHEA) and progesterone were increased in
      premenopausal women with PTSD at baseline or in response to adrenal activation by
      ACTH1-24. The study revealed that DHEA responses to 250 microg ACTH1-24 were
      increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects,
      while DHEA levels were generally increased in the PTSD subjects compared to seven
      healthy traumatized subjects. Cortisol responses to ACTH1-24 were also higher in
      the women with PTSD, while progesterone levels and responses were not different
      among the three groups. In addition, among the PTSD subjects, the peak change in
      DHEA in response to ACTH1-24 was negatively correlated with the total Clinician
      Administered PTSD Scale score, while the peak DHEA to cortisol ratio was
      inversely associated with negative mood symptoms measured by the Profile of Mood
      States scale. This work suggests that an increased capacity for DHEA release in
      response to extreme adrenal activation may influence the pattern of HPA axis
      adaptation to extreme stress, as well as mitigate the severity of PTSD and
      negative mood symptoms in premenopausal women with PTSD.

PMID- 15199368
TI  - Increased mRNA expression of alpha2A-adrenoceptors, serotonin receptors and mu
      opioid receptors in the brains of suicide victims.
AB  - The development of new therapies for the treatment of psychiatric disorders
      requires an in-depth knowledge of the molecular bases underlying these
      pathologies, which remain largely unknown. Alterations in adrenoceptors,
      serotonin receptors, and other G protein-coupled receptors (GPCRs) have been
      associated with suicide and depression. However, to date, there is little
      information about mRNA expression of the GPCRs in the frontal cortex of suicide
      victims. Our goal was to study the expression in the brain of these receptors.
      For this purpose, we measured mRNA levels by RT-PCR. We found that the
      expressions of alpha2A-adrenoceptors, 5-HT1A, 5-HT2A serotonin receptors, and mu
      opioid receptors were elevated in the post-mortem brains of these suicide victims
      with respect to matched controls. Moreover, in the case of alpha2A-adrenoceptors
      (the only for which these data were available), a significant correlation was
      observed between the level of mRNA and protein quantified in the brain of the
      same subjects, indicating that protein synthesis of this receptor was not
      influenced by post-translational regulatory mechanisms. In addition, the degree
      of adrenoceptor and 5-HT receptor expressions appeared to be correlated in the
      brains of suicide victims and control subjects. Alterations in the expression of
      adrenoceptors, serotonin, and opioid receptors indicate that these signaling
      proteins might be related to the etiopathology of suicidal and depressive
      behaviors. Alternatively, such changes may represent adaptive mechanisms to
      compensate for other as yet unknown alterations. The results also suggest that
      these receptors could share common regulatory mechanisms.

PMID- 15199370
TI  - Role of hippocampal CaMKII in serotonin 5-HT(1A) receptor-mediated learning
      deficit in rats.
AB  - The serotonin 5-HT(1A) receptor agonist, 8-OH-DPAT (8-hydroxy-2-di-n-propylamino
      tetralin), impairs retention performance in a passive avoidance learning task in
      rats. In the hippocampus of rats trained on this procedure and killed 1 h after
      the acquisition trial, an increase in the membrane levels of both Ca2+/calmodulin
      dependent protein kinase II (CaMKII) and phosphorylated CaMKII, as well as in
      total and Ca2+-independent enzyme activity in tissue lysates was found. These
      effects were learning-specific as no changes in CaMKII levels or activity were
      found in rats receiving a footshock identical to the trained rats. The effect of
      training on CaMKII was prevented by a low 8-OH-DPAT dose. The 5-HT(1A) agonist
      also reduced protein kinase A (PKA) activity and increased the membrane levels of
      phosphatase 1 (PP1) and PP1 enzyme activity in the hippocampus. All of the
      changes induced by 8-OH-DPAT were reversed by the selective 5-HT(1A) antagonist
      WAY-100635, indicating receptor-specific effects. We suggest that 5-HT(1A)
      receptor-mediated disruption of retention performance is a consequence of the
      reduced PKA activity and the ensuing enhancement in PP1 activity, possibly
      through decreased phosphorylation/activation of endogenous PP1 inhibitors, that
      cause a reduced activity of phosphorylated CaMKII, a key enzyme in early stages
      of memory formation. This study provides an in vivo molecular basis for the
      cognitive deficits induced by stimulation of hippocampal 5-HT(1A) receptors.

PMID- 15199369
TI  - Role of the dopamine transporter in the differential cocaine-induced locomotor
      activation of inbred long-sleep and short-sleep mice.
AB  - The locomotor-stimulant effects of cocaine, mediated through inhibition of the
      dopamine transporter (DAT), can be influenced by environmental factors.
      Previously, we found that following a short exposure to the testing environment,
      cocaine induces greater locomotor activation in inbred long-sleep (ILS) mice,
      compared to inbred short-sleep (ISS) mice. In the present study, all animals
      received prolonged habituation to the testing chambers prior to cocaine
      injection, and the results were compared with those from our previous study. When
      mice were tested with saline on day 1 and with either saline or cocaine (10-20
      mg/kg) on day 2, we observed significant locomotor stimulation in ILS, but not
      ISS, mice at all tested doses of cocaine. Thus, prolonged habituation does not
      alter the differential responsiveness of these two strains of mice to cocaine. We
      found no strain differences in striatal cocaine levels. However, [3H]WIN 35,428
      binding studies showed a lower number of striatal DATs in ILS, compared to ISS,
      mice. In vivo analysis of striatal DAT activity revealed not only that ILS mice
      cleared exogenously applied DA more slowly than ISS mice, but also that cocaine
      (10 mg/kg) decreased DA clearance selectively in ILS mice. Thus, functional
      differences in striatal DATs between ILS and ISS mice likely contribute to the
      differential behavioral activation of cocaine in these two mouse strains.

PMID- 15199371
TI  - Effects of ovarian steroids and raloxifene on proteins that synthesize,
      transport, and degrade serotonin in the raphe region of macaques.
AB  - In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen
      replacement, with or without progesterone supplementation for 14 days,
      significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased
      serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)
      A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1
      or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM),
      raloxifene, have on TPH protein and phosphorylation, and on protein expression of
      SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but
      estrogen-like activities in the brain have been reported. Cytoplasmic and
      membrane extracts of the dorsal raphe region were processed for Western blotting.
      TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific
      antibodies. The optical densities of the signals were measured with NIH image and
      analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and
      5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo
      of estrogen plus progesterone and raloxifene also increased TPH phosphorylation.
      Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein.
      However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen
      alone or combined with progesterone for 1 mo caused a significant reduction in
      MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from
      spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of
      progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on
      MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene
      may increase serotonin production and transport. The expression of the
      degradative enzymes suggests a complex combination of gene transcription, post
      transcriptional processing, and substrate feedback mechanisms.

PMID- 15199372
TI  - The effects of cocaine on gonadal steroid hormones and LH in male and female
      rhesus monkeys.
AB  - Cocaine stimulates significant increases in estradiol, testosterone (T), and
      luteinizing hormone (LH) in rhesus monkeys, but the temporal interactions between
      the gonadal steroid hormones and LH have not been determined. The effects of i.v.
      cocaine (0.8 mg/kg) or saline placebo administration on estradiol, T, and LH were
      compared in follicular phase female and male rhesus monkeys. Samples for hormone
      analysis were collected at 2-min intervals for 20 min, then at 10-min intervals
      for 50 min. Peak plasma cocaine levels were detected at 4 min and pharmacokinetic
      analyses showed no significant gender differences. Baseline hormone levels were
      equivalent before saline and cocaine administration, and saline did not alter LH
      or estradiol levels. In females, when baseline estradiol levels were low (< 100
      pg/ml), LH increased significantly within 8 min after cocaine administration (P <
      0.05), but when baseline estradiol levels were high (> 100 pg/ml), LH levels did
      not change significantly after cocaine administration. Estradiol and T increased
      significantly after LH, within 16 min after cocaine administration (P < 0.01
      0.001). In males, significant LH increases were detected at 16 min after cocaine
      administration (P < 0.05-0.001), but estradiol and T did not change
      significantly. Thus, cocaine may stimulate significant increases in estradiol and
      T in females but not in males. These rapid hormonal changes may contribute to
      cocaine's abuse-related effects, as well as to disruptions of the menstrual cycle
      during chronic cocaine administration.

PMID- 15199373
TI  - Protective effects of N-acetyl-L-cysteine on the reduction of dopamine
      transporters in the striatum of monkeys treated with methamphetamine.
AB  - Several lines of evidence suggest that oxidative stress might contribute to
      neurotoxicity in the dopaminergic nerve terminals after administration of
      methamphetamine (MAP). We undertook the present study to determine whether
      intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant
      drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum
      of monkey brain after administration of MAP. Positron emission tomography studies
      demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times
      at 2-h intervals) significantly decreased the accumulation of radioactivity in
      the striatum after intravenous administration of [11C]beta-CFT. In contrast, the
      binding of [11C]SCH 23390 to dopamine D1 receptors in the monkey striatum was not
      altered after the administration of MAP. A bolus injection of NAC (150 mg/kg,
      i.v.) 30 min before MAP administration and a subsequent continuous infusion of
      NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT
      in the monkey striatum 3 weeks after the administration of MAP. These results
      suggest that NAC could attenuate the reduction of DAT in the monkey striatum
      after repeated administration of MAP. Therefore, it is likely that NAC would be a
      suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals
      related to chronic use of MAP in humans.

PMID- 15199374
TI  - Cytoskeletal genes regulation by chronic morphine treatment in rat striatum.
AB  - It has been previously suggested that morphine can regulate the expression and
      function of some proteins of the cytoskeleton. In the present study, we used real
      time quantitative polymerase chain reaction to examine the effects of chronic
      morphine administration, in rat striatum, on 14 proteins involved in microtubule
      polymerization and stabilization, intracellular trafficking, and serving as
      markers of neuronal growth and degeneration. Chronic morphine treatment led to
      modulation of the mRNA level of seven of the 14 genes tested. Glial fibrillary
      acidic protein (Gfap) and activity-regulated cytoskeleton-associated protein
      (Arc) mRNA were upregulated, while growth associated protein (Gap43), clathrin
      heavy chain (Cltc), alpha-tubulin, Tau, and stathmin were downregulated. In order
      to determine if the regulation of an mRNA correlates with a modulation of the
      expression of the corresponding protein, immunoblot analyses were performed. With
      the exception of Gap43, the levels of Cltc, Gfap, Tau, stathmin, and alpha
      tubulin proteins were found to be in good agreement with those from mRNA
      quantification. These results demonstrate that neuroadaptation to chronic
      morphine administration in rat striatum implies modifications of the expression
      pattern of several genes and proteins of the cytoskeleton and cytoskeleton
      associated components.

PMID- 15199375
TI  - Hippocampal brain-derived neurotrophic factor expression following treatment with
      reboxetine, citalopram, and physical exercise.
AB  - The antidepressants, reboxetine and citalopram, were used in conjunction with
      voluntary physical exercise (wheel running) in order to assess the contribution
      of noradrenergic and serotonergic activation to enhancements in hippocampal brain
      derived neurotrophic factor (BDNF) expression resulting from antidepressant
      treatment and exercise. Reboxetine (40 mg/kg/day), citalopram (10 mg/kg/day),
      voluntary physical activity, and the combination of antidepressants with exercise
      were applied to rats for a range of treatment intervals (2 to 14 days).
      Hippocampal BDNF transcription levels (full-length BDNF, as well as exons I-IV)
      were then assessed via in situ hybridization. Reboxetine treatment led to a rapid
      (evident at 2 days) enhancement in BDNF transcription in several hippocampal
      regions. This increase was also observed when reboxetine treatment was combined
      with voluntary physical activity for 2 weeks. Treatment with citalopram led to an
      increase in BDNF mRNA in only one hippocampal region (CA2) after short-term (2
      days) treatment, and when combined with exercise, increased BDNF mRNA in the CA4
      and dentate gyrus after 2 weeks. As reported in previous studies, voluntary
      physical activity enhanced BDNF transcription in several hippocampal areas, both
      on its own and in combination with antidepressant treatments. Examination of the
      levels of individual BDNF transcript variants influenced by each of these
      antidepressants revealed distinct patterns of expression in response to the
      various treatments, and showed that exercise-plus-antidepressant produced
      significant changes where antidepressant alone failed. Overall, treatment with
      the norephinephrine-selective antidepressant, reboxetine, in combination with
      exercise, led to both rapid and sustained increases in hippocampal BDNF mRNA
      expression. The serotonergic agent, citalopram, appeared to require longer
      treatment intervals in order to influence BDNF expression positively.

PMID- 15199377
TI  - Disruption of neurogenesis on gestational day 17 in the rat causes behavioral
      changes relevant to positive and negative schizophrenia symptoms and alters
      amphetamine-induced dopamine release in nucleus accumbens.
AB  - Gestational disruption of neurodevelopment has been proposed to lead to
      pathophysiological changes similar to those underlying schizophrenia. We induced
      such disruption by treating pregnant rat dams with methylazoxymethanol acetate
      (MAM) on gestational day 17 (GD17). Total brain size and that of the prefrontal
      cortex and hippocampus were reduced in adult rats exposed prenatally to MAM. When
      locomotor activity was assessed in an open field, MAM-exposed rats were hyper
      responsive to a mild stress and to amphetamine (2 mg/kg, s.c.). They also engaged
      in less social interaction than controls. We studied, by microdialysis, the
      effect of amphetamine on extracellular dopamine in the nucleus accumbens and the
      medial prefrontal cortex of freely moving control and MAM-exposed rats.
      Amphetamine (2 mg/kg, s.c.) induced an increase in dopamine release that was
      larger in the nucleus accumbens of MAM-exposed rats than in controls, whereas no
      difference was seen in the medial prefrontal cortex. In controls, amphetamine
      infused into the medial prefrontal cortex (50 microM) led to a slight decrease in
      extracellular dopamine in the nucleus accumbens. This effect was absent in MAM
      exposed rats, where a transient increase in nucleus accumbens dopamine levels was
      seen after amphetamine infusion. These results show that the late gestational
      disruption of neurogenesis in the rat leads to behavioral changes that mimic
      positive and negative schizophrenia symptoms, and also to a dysregulation of
      subcortical dopamine neurotransmission. This study contributes to the evaluation
      of the validity of the prenatal MAM GD17 treatment in rats as an animal model for
      schizophrenia.

PMID- 15199378
TI  - Consolidation of human motor cortical neuroplasticity by D-cycloserine.
AB  - D-Cycloserine (CYC), a partial N-methyl-D-aspartate (NMDA) agonist, has been
      shown to improve cognitive functions in humans. However, the neurophysiological
      basis of this effect is unclear so far. We studied the impact of this drug on
      long-lasting after-effects of transcranial direct current (tDCS)-generated motor
      cortical excitability shifts, as revealed by transcranial magnetic stimulation
      elicited motor-evoked potentials. While anodal tDCS enhances motor cortical
      excitability, cathodal tDCS diminishes it. Both effects seem to be NMDA receptor
      dependent. D-CYC selectively potentiated the duration of motor cortical
      excitability enhancements induced by anodal tDCS. D-CYC alone did not modulate
      excitability. The potency of this drug to consolidate neuronal excitability
      enhancements, most probably by stabilizing the strengthening of NMDA receptors,
      which is a probable neurophysiological derivate of learning processes, makes it
      an interesting substance to improve cognitive functions.

PMID- 15199376
TI  - Expression of neural RGS-R7 and Gbeta5 Proteins in Response to Acute and Chronic
      Morphine.
AB  - The R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7,
      RGS9-2, and RGS11), and its binding protein Gbeta5, are found in neural
      structures of mouse brain. A single intracerebroventricular priming dose of 10
      nmol morphine gave rise to acute tolerance to the analgesic effects of successive
      identical test doses of the opioid. At 2 h after administering the acute opioid,
      RGS7 mRNA levels in the striatum plus those of RGS9-2 in the striatum and
      thalamus were increased, whereas RGS9-2 and RGS11 mRNA were reduced in the
      cortex. Similar but attenuated RGS-R7 mRNA changes persisted 24 h after acute
      morphine administration. No changes in Gbeta5 mRNA levels were observed. At 2
      days after commencing sustained morphine treatment, the levels of mRNA for RGS7,
      RGS9-2, RGS11, and Gbeta5 increased in most of the brain structures studied
      (striatum, thalamus, periaqueductal gray matter (PAG), and cortex). In these
      morphine tolerant-dependent mice, the greater changes were found for RGS9-2 in
      the thalamus (>500%) and PAG (>200%). In post-dependent mice, the increases in
      RGS-R7 and Gbeta5 mRNA still persisted in the PAG and striatum at 8 and 16 days
      after starting the chronic opioid treatment. The raised mRNA levels promoted by
      chronic, but not by acute, morphine, were accompanied by increases in the encoded
      proteins. This is probably a result of the costabilization of the RGS-R7 and
      Gbeta5 proteins forming heterodimers. Opioid-induced adaptations of RGS-R7 and
      Gbeta5 genes may regulate the severity of morphine-induced tolerance/dependence
      and the duration of the post-dependent period, helping to recover the normal
      response.

PMID- 15199380
TI  - CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients.
AB  - Coeliac disease is an autoimmune disorder, characterised by villous atrophy of
      the small intestine, which results from a T-cell-mediated response to gluten
      derived peptides. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is
      involved in the regulation of T-cell activation and the CTLA4 +49 A/G
      polymorphism in exon 1 has been implicated in several autoimmune disorders,
      including coeliac disease. However, this polymorphism was recently excluded as
      being the causal variant in Graves' disease, autoimmune hypothyroidism and type I
      diabetes mellitus. This causal variant was mapped to the 3' region of CTLA4, with
      the CT60 polymorphism showing the strongest association. The aim of this study
      was to determine the role of the CTLA4 gene in coeliac disease in the Dutch
      population. The +49 A/G and CT60 polymorphisms were genotyped in a case-control
      cohort of 215 patients and controls. The frequency of the +49 G-allele was
      increased in cases, although not significantly. However, the frequency of the
      CT60 G-allele was increased with borderline significance in coeliac disease
      patients (P = 0.048), although the genotype distributions did not show a
      significant difference between cases and controls. These results indicate the
      involvement of the CTLA4 gene in coeliac disease development. The haplotype
      carrying the CT60 G-allele was shown to be associated with lower mRNA levels of
      the soluble CTLA-4 isoform, providing a possible mechanism for the T-cell
      mediated destruction of the small intestine.

PMID- 15199379
TI  - Monitor-to-monitor temporal correlation of air pollution in the contiguous US.
AB  - Numerous studies have reported short-term associations between ambient air
      pollution concentrations and mortality and morbidity. Particulate matter (PM) was
      often implicated as the most significant predictor of the health outcomes among
      the various air pollutants. However, a question remains as to the potential role
      played by the relative error of exposure estimation associated with each
      pollutant in defining their relative strengths of association. While most of the
      recent studies on PM exposure measurements have focused on the temporal
      correlation between personal exposures and the concentrations observed at ambient
      air quality monitors (within a few miles from the subjects), there have been few
      studies that systematically evaluated spatial uniformity of temporal correlation
      of air pollution within the scale of a city (several tens of miles) for which
      mortality or morbidity outcomes are aggregated in time-series studies. In this
      study, spatial uniformity of temporal correlation was examined by computing
      monitor-to-monitor correlation using available multiple monitors for PM(10) and
      gaseous criteria pollutants (NO(2), SO(2), CO, and O(3)) in the nationwide data
      between 1988 and 1997. For each monitor, the median of temporal correlation with
      other monitors within the Air Quality Control Region (AQCR) was computed. The
      resulting median monitor-to-monitor correlation was modeled as a function of
      qualitative site characteristics (i.e., land-use, location-setting, and
      monitoring-objective) and quantitative information (median separation distance,
      longitude/latitude or regional indicators) for each pollutant. Generalized
      additive models (GAM) were used to fit the smooth function of the separation
      distance and regional variation. The intercepts of the models across pollutants
      showed the overall rankings in monitor-to-monitor correlation on the average to
      be: O(3), NO(2), and PM(10), (r approximately 0.6 to 0.8)>CO (r<0.6)>SO(2)
      (r<0.5). Both the separation distance and regional variation were important
      predictors of the correlation. For PM(10), for example, the correlation for the
      monitors along the East Coast was higher by approximately 0.2 than western
      regions. The qualitative monitor characteristics were often significant
      predictors of the variation in correlation, but their impacts were not
      substantial in magnitude for most categories. These results suggest that the
      apparent regional heterogeneity in PM effect estimates, as well as the
      differences in the significance of health outcome associations across pollutants,
      may in part be contributed to by the differences in monitor-to-monitor
      correlations by region and across pollutants.

PMID- 15199382
TI  - Screening of the ARX gene in 682 retarded males.
AB  - The newly identified gene, ARX, when mutated has been shown to cause both
      syndromic and nonsyndromic forms of mental retardation. It seems that the less
      severe forms are due to polyalanine expansions and missense mutations in the
      gene. We screened 682 developmentally retarded males for polyalanine expansions
      in ARX in order to examine the contribution of ARX mutations to the causes of
      developmental retardation. We also reinvestigated 11 putative MRX and three MR
      families where no cause of mental retardation had been found, by mutational
      analysis of ARX. Mutational analysis was also performed in 11 probands with
      autism from families with two or more affected males. We find that previously
      described polyalanine expansions of ARX are not a common cause of mental
      retardation.

PMID- 15199381
TI  - Noninvasive diagnosis of the 3243A > G mitochondrial DNA mutation using urinary
      epithelial cells.
AB  - The 3243A > G mutation is one of the most frequently observed mutations of
      mitochondrial DNA (mtDNA), and is associated with numerous clinical presentations
      including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like
      episodes (MELAS), progressive external ophthalmoplegia (PEO) and diabetes and
      deafness. The routine diagnosis of the 3243A > G mutation in blood is difficult
      as mutation levels are known to decrease in this tissue over time, while in some
      patients it may be absent. We have directly compared the levels of the 3243A > G
      mutation in skeletal muscle, blood and urinary epithelial cells in 18 patients
      and observed a striking correlation between the mutation load in postmitotic
      muscle and urinary epithelium, a mitotic tissue. These data strongly support the
      use of urinary epithelial cells as the tissue of choice in the noninvasive
      diagnosis of the 3243A > G mutation.

PMID- 15199383
TI  - Variation in nutrient intakes among women in Shanghai, China.
AB  - BACKGROUND: In 1997, we launched a large population-based cohort study, the
      Shanghai Women Health Study (SWHS), to investigate diet in relation to cancer
      risk among 74 943 Chinese women. Simultaneously, a dietary calibration study was
      conducted among 200 SWHS participants with biweekly 24-h dietary recall (24HDR)
      over a 1-y period in order to evaluate the validity and reliability of the SWHS
      food frequency questionnaire (FFQ). OBJECTIVE: The objectives of the current
      study were to evaluate the nature and magnitude of variances for intake of 26
      nutrients among SWHS participants, and to estimate the number of 24HDR needed for
      estimate intake of the 26 nutrients examined in the study population. DESIGN: In
      all, 1-y biweekly 24HDR collected from 200 healthy, free-living women aged
      between 40 and 70 y, who participated in the SWHS dietary calibration study, was
      analyzed by mixed effects model and ratios of within-individual and between
      individual dietary intake variances (sigma(w)(2)/sigma(b)(2)) were estimated.
      RESULTS: In agreement with reports from studies conducted in the US, we found
      that within-individual variances were larger than between-individual variances in
      dietary intake of most nutrients. The sum of all other variation (eg, weekday and
      weekend, seasonal, interviewer) accounted for less than 5% of total variation.
      Ratios of within- to between-individual variances (for log transformed data)
      ranged from 1.05 (carbohydrate) to 2.79 (fat) for macronutrient intake, 1.74
      (niacin) to 8.48 (delta-tocopherol) for vitamin intake, and 1.35 (phosphorus) to
      5.59 (sodium) for mineral intake. CONCLUSIONS: The results of this study suggest
      that within- and between-individual differences in nutrient intake are the major
      sources of variation in this population of adult Chinese women. Cultural
      practices as well as seasonal supply and consumption patterns of vegetable intake
      are likely the major contributors to the variation. Implications of these results
      are discussed.

PMID- 15199387
TI  - Eating garlic and onion: a matter of life or death.

PMID- 15199385
TI  - Proteomic-based identification of haptoglobin-1 precursor as a novel circulating
      biomarker of ovarian cancer.
AB  - Screening for specific biomarkers of early-stage detection of ovarian cancer is a
      major health priority due to the asymptomatic nature and poor survival
      characteristic of the disease. We utilised two-dimensional gel electrophoresis
      (2DE) to identify differentially expressed proteins in the serum of ovarian
      cancer patients that may be useful as biomarkers of this disease. In this study,
      38 ovarian cancer patients at different pathological grades (grade 1 (n=6), grade
      2 (n=8) and grade 3 (n=24)) were compared to a control group of eight healthy
      women. Serum samples were treated with a mixture of Affigel-Blue and protein A (5
      : 1) for 1 h to remove high abundance protein (e.g. immunoglobulin and albumin)
      and were displayed using 11 cm, pH 4-7 isoelectric focusing strips for the first
      dimension and 10% acrylamide gel electrophoresis for the second dimension.
      Protein spots were visualised by SYPRO-Ruby staining, imaged by FX-imager and
      compared and analysed by PDQuest software. A total of 24 serum proteins were
      differentially expressed in grade 1 (P<0.05), 31 in grade 2 (P<0.05) and 25 in
      grade 3 (P<0.05) ovarian cancer patients. Six of the protein spots that were
      significantly upregulated in all groups of ovarian cancer patients were
      identified by nano-electrospray quadrupole quadrupole time-of-flight mass
      spectrometry (n-ESIQ(q)TOFMS) and matrix-assisted laser desorption ionisation
      time-of-flight mass spectrometry (MALDI-TOFMS) as isoforms of haptoglobin-1
      precursor (HAP1), a liver glycoprotein present in human serum. Further
      identification of the spots at different pathological grades was confirmed by
      Western blotting using monoclonal antibody against a haptoglobin epitope
      contained within HAP1. Immunohistochemical localisation of HAP1-like activity was
      present in malignant ovarian epithelium and stroma but strong immunostaining was
      present in blood vessels, areas with myxomatous stroma and vascular spaces. No
      tissue localisation of HAP1-like immunoreactivity was observed in normal ovarian
      surface epithelium. These data highlight the need to assess circulating
      concentration of HAP1 in the serum of ovarian cancer patients and evaluate its
      potential as a biomarker in the early diagnosis of ovarian cancer.

PMID- 15199384
TI  - Long-term compliance and changes in plasma lipids, plant sterols and carotenoids
      in children and parents with FH consuming plant sterol ester-enriched spread.
AB  - OBJECTIVE: To study the compliance and changes in plasma lipids, plant sterols,
      fat-soluble vitamins and carotenoids in children and parents with familial
      hypercholesterolemia (FH) consuming a plant sterol ester-enriched (PSE) spread.
      DESIGN: A 26-week open-label follow-up of children who had previously been
      studied in a controlled cross-over design. The parents were also included in the
      open-label arm of the study. SETTING: Outpatient clinic for treatment of
      hyperlipidemia. SUBJECTS: A total of 37 children (7-13 y) and 20 parents (32-51
      y) diagnosed with 'definite' or 'possible' heterozygous FH. In all, 19 of the
      parents, but no children, used statins. All were patients at the Lipid Clinic,
      National Hospital in Oslo. INTERVENTIONS: Subjects were recommended to eat 20
      g/day of PSE spread as part of their lipid-lowering diet. RESULTS: The mean
      intake of PSE spread was 13.7 and 16.5 g/days in the children and parents,
      respectively, corresponding to 1.2 and 1.5 g of plant sterols. Plasma total
      cholesterol decreased by 9.1% in both children (P<0.001) and parents (P=0.002).
      The corresponding decreases in LDL cholesterol were 11.4% (P<0.001) and 11.0%
      (P=0.012). Increases in serum lathosterol, campesterol and sitosterol, adjusted
      for total cholesterol, were observed in the children (31, 96, 48%, respectively,
      P<0.001) at the end of the controlled cross-over period. In the parents, serum
      campesterol and sitosterol, adjusted for total cholesterol, increased by 92 and
      39%, respectively (P< 0.001). Lipid-adjusted serum alpha- and beta-carotene
      decreased by 17.4% (P=0.008) and 10.9% (P=0.018), respectively, in the children
      at the end of the controlled PSE period, but increased again during the follow
      up. In the parents, serum alpha- and beta-carotene concentrations were unchanged,
      while serum lutein and lycopene decreased by 7.3% (P=0.037) and 14.6% (P=0.044),
      respectively. CONCLUSIONS: Sustained efficacy of cholesterol reduction and long
      term compliance of PSE intake were demonstrated in this study.

PMID- 15199394
TI  - A randomised trial of single-dose radiotherapy to prevent procedure tract
      metastasis by malignant mesothelioma.
AB  - A single 9-MeV electron treatment, following invasive thoracic procedures in
      patients with malignant pleural mesothelioma, was examined. In all, 58 sites were
      randomised to prophylactic radiotherapy or not. There was no statistically
      significant difference in tract metastasis. A single 10-Gy treatment with 9-MeV
      electrons appears ineffective.

PMID- 15199386
TI  - Impact of screening for breast cancer in high-risk women on health-related
      quality of life.
AB  - The effectiveness of intensive surveillance in women at high risk for breast
      cancer due to a familial or genetic predisposition is uncertain and is currently
      being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC)
      study, in which annual imaging consists of mammography and MRI. Unfavourable side
      effects on health-related quality of life may arise from this screening process.
      We examined the short-term effects of screening for breast cancer in high-risk
      women on generic health-related quality of life and distress. A total of 519
      participants in the MRISC study were asked to complete generic health-status
      questionnaires (SF-36, EQ-5D) as well as additional questionnaires for distress
      and items relating to breast cancer screening, at three different time points
      around screening. The study population showed significantly better generic health
      related quality of life scores compared to age-/sex-adjusted reference scores
      from the general population. Neither generic health-related quality of life
      scores nor distress scores among the study sample (n=334) showed significant
      changes over time. The impact of the screening process on generic health status
      did not differ between risk categories. Relatively more women reported
      mammography as quite to very painful (30.1%) compared to MRI. Anxiety was
      experienced by 37% of the women undergoing MRI. We conclude that screening for
      breast cancer in high-risk women does not have an unfavourable impact on short
      term generic health-related quality of life and general distress. In this study,
      high-risk women who opted for regular breast cancer screening had a better health
      status than women from the general population.

PMID- 15199389
TI  - Protein expression patterns in primary carcinoma of the vagina.
AB  - Protein patterns in six samples from primary vaginal cancers, in five from normal
      vaginal tissue and in five primary cervical cancers, were analysed using two
      dimensional polyacrylamide gel electrophoresis (2-DE). Protein expression profile
      was evaluated by computer-assisted image analysis (PDQUEST) and proteins were
      subsequently identified using matrix-assisted laser desorption/ionisation mass
      spectrometry. The aim was to analyse the protein expression profiles using the
      hierarchical clustering method in vaginal carcinoma and to compare them with the
      protein pattern in cervical carcinoma in order to find a helpful tool for correct
      classification and for increased biomedical knowledge. Protein expression data of
      a distinct set of 33 protein spots were differentially expressed. These
      differences were statistically significant (Mann-Whitney signed-Ranked Test,
      P<0.05) between normal tissue, vaginal and cervical cancer. Furthermore, protein
      profiles of pairs of primary vaginal and cervical cancers were found to be very
      similar. Some of the protein spots that have so far been identified include
      Tropomyosin 1, cytokeratin 5, 15 and 17, Apolipoprotein A1, Annexin V,
      Glutathione-S-transferase. Others are the stress-related proteins, calreticulin,
      HSP 27 and HSP 70. We conclude that cluster analysis of proteomics data allows
      accurate discrimination between normal vaginal mucosa, primary vaginal and
      primary cervical cancer. However, vaginal and cervical carcinomas also appear to
      be relatively homogeneous in their gene expression, indicating similar
      carcinogenic pathways. There might, further, be a possibility to identify tumour
      specific markers among the proteins that are differentially expressed. The
      results from this study have to be confirmed by more comprehensive studies in the
      future.

PMID- 15199388
TI  - Clinical significance of elongation factor-1 delta mRNA expression in oesophageal
      carcinoma.
AB  - Elongation factor-1 (EF-1) delta is a subunit of EF-1, which is a protein complex
      that participates in the elongation step of mRNA translation and has recently
      been considered to correlate with oncogenic transformation. However, there has
      been no information regarding the clinical significance of EF-1 delta mRNA
      expression in malignant tumours, including oesophageal carcinoma. Thus, we
      quantitated the expression of EF-1 delta in malignant and benign oesophageal
      tissues and associated these levels with clinicopathologic parameters of
      oesophageal carcinoma. Paired oesophageal tissue samples from cancerous and
      corresponding noncancerous parts were obtained from 52 patients who underwent
      curative oesophagectomy. Quantitative analyses of EF-1 delta expression were
      performed using real-time quantitative reverse transcription-polymerase chain
      reaction. Elongation factor-1 delta mRNA overexpression in cancerous tissues
      compared to normal counterparts was observed in 38 of 52 (73%) patients. The mean
      expression level of EF-1 delta mRNA in cancerous tissues was significantly higher
      than that in noncancerous tissues (P<0.01). A higher expression of EF-1 delta was
      significantly correlated with lymph node metastases (P<0.05) and advanced stages
      (P<0.05). Furthermore, the cause-specific survival of patients with a higher
      expression of EF-1 delta was significantly poorer than those with a lower
      expression (5-year cause-specific survival rates; 23 and 54%, respectively,
      P<0.05). The results of this study indicated that EF-1 delta mRNA expression was
      significantly higher in cancerous compared to noncancerous oesophageal tissues,
      and a higher expression of EF-1 delta mRNA was correlated with lymph node
      metastases, advanced disease stages and poorer prognosis for patients with
      oesophageal carcinoma.

PMID- 15199391
TI  - Predicting aggressive outcome in T1N0M0 breast cancer.
AB  - Despite the excellent overall prognosis, unpredictable breast cancer recurrences
      and deaths also occur among T1N0M0 patients. We have evaluated clinically
      applicable methods for identifying aggressive outcome in T1N0M0 breast cancer.
      The material is based on aggressive T1N0M0 invasive ductal and lobular carcinomas
      diagnosed in Turku University Hospital and Jyvaskyla Central Hospital, Finland,
      during 1987-1997. We studied all the T1N0M0 breast cancers that had led to
      recurrency or death (n=21, 95% T1cN0M0) during the follow-up period (4-14 years).
      The study is based on statistical analyses of matched case-control data in which
      the prognostic factors of each individual patient with aggressive disease were
      compared with control patients (n=45) individually matched by tumour size, age at
      diagnosis, histological type of tumour and length of follow-up. The cancer cases
      were examined for clinically applicable conventional and immunohistochemical
      pathologic prognostic factors. High Ki-67 immunopositivity was the strongest
      prognosticator of breast cancer death or recurrence in T1N0M0 breast cancer.
      Also, high p53 immunopositivity, low oestrogen receptor immunopositivity and Her
      2/neu oncogene amplification by chromogen in situ hybridisation were reliable
      indicators of unfavourable outcome. Our statistical methods also allowed us to
      determine for the present material a range of clinical significance for each
      immunohistochemical prognostic feature with the associated relative risk for
      breast cancer death and recurrence. The paper suggests guidelines for predicting
      aggressive outcome in T1N0M0 breast cancer.

PMID- 15199395
TI  - Targeted radiosensitisation by pegylated liposome-encapsulated 3', 5'-O
      dipalmitoyl 5-iodo-2'-deoxyuridine in a head and neck cancer xenograft model.
AB  - 5-Iodo-2'-deoxyuridine (IUdR) is an effective radiosensitiser but its clinical
      development has been limited by toxicity. Prolonged intravenous infusions of IUdR
      are necessary for optimal tumour uptake but cause dose-limiting myelosuppression.
      The lack of selective tumour uptake can lead to radiosensitisation of adjacent
      normal tissues and enhanced local radiation toxicity. Liposomal IUdR delivery
      offers selective targeting of tumour tissues and avoidance of local and systemic
      toxicity. In these studies, we report the development of a pegylated liposome
      containing a lipophilic IUdR derivative (3', 5'-O-dipalmitoyl-5-iodo-2'
      deoxyuridine) for use in a head and neck cancer xenograft model. Initial studies
      confirmed the ability of IUdR to sensitise two head and neck cancer cell lines to
      single fractions of radiotherapy (SFRT) and this effect was seen to correlate
      with the thymidine replacement index in KB cells. In vivo delivery of single
      doses of either unencapsulated IUdR or pegylated liposomal IUdR (PLIUdR) to nude
      mice bearing KB xenograft tumours did not enhance the effect of SFRT delivered 16
      h later. When PLIUdR was delivered by a protracted administration schedule to a
      dose of 48 mg kg(-1) over 7 days, it enhanced the effect of both 4.5 Gy SFRT and
      fractionated radiotherapy. PLIUdR was at least as effective as unencapsulated
      IUdR delivered by multiple intravenous injections or continuous subcutaneous
      infusion. Immunohistochemistry with a specific anti-IUdR monoclonal antibody
      confirmed greater levels of tumour staining in tumours from animals treated with
      PLIUdR compared with those treated with unencapsulated IUdR.

PMID- 15199393
TI  - Reduced expression of small GTPases and hypermethylation of the folate binding
      protein gene in cisplatin-resistant cells.
AB  - Reduced accumulation of cisplatin is the most consistent feature seen in
      cisplatin-resistant (CP-r) cells that are cross-resistant to other cytotoxic
      compounds, such as methotrexate. In this report, defective uptake of a broad
      range of compounds, including [(14)C]-carboplatin, [(3)H]MTX, [(3)H]folic acid
      (FA), [(125)I]epidermal growth factor, (59)Fe, [(3)H]glucose, and [(3)H]proline,
      as well as (73)As(5+) and (73)As(3+), was detected in CP-r human hepatoma and
      epidermal carcinoma cells that we have previously shown are defective in fluid
      phase endocytosis. Downregulation of several small GTPases, such as rab5, rac1,
      and rhoA, which regulate endocytosis, was found in CP-r cells. However,
      expression of an early endosomal protein and clathrin heavy chain was not
      changed, suggesting that the defective endocytic pathway is clathrin independent.
      Reduced expression of the cell surface protein, folate-binding protein (FBP),
      which is a carrier for the uptake of MTX, was also observed in the CP-r cells by
      confocal immunofluorescence microscopy and Real-Time PCR. Reactivation of the
      silenced FBP gene in the CP-r cells by a DNA demethylation agent, 2-deoxy-5-aza
      cytidine (DAC) demonstrates that hypermethylation occurred in the CP-r cells. The
      uptake of [(14)C]carboplatin, [(3)H]FA, and [(3)H]MTX increased in an early stage
      CP-r cell line (KB-CP1) after treatment with DAC. Both a defective endocytic
      pathway and DNA hypermethylation resulting in the downregulation of small
      regulatory GTPases and cell surface receptors contribute to the reduced
      accumulation of a broad range of compounds in CP-r cells.

PMID- 15199392
TI  - DNA replication licensing and cell cycle kinetics of oligodendroglial tumours.
AB  - The convergence point of growth-signalling pathways that control cell
      proliferation is the initiation of genome replication, the core of which is the
      assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being
      'licensed' for DNA replication in the subsequent S phase. The Mcm2-7 complex is a
      core constituent of the pre-RC, whose recruitment to replication origins is
      dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the
      initiation of DNA replication by preventing Mcm2-7 assembly at origins via its
      interaction with Cdt1, ensuring genomic integrity through suppression of re
      initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2,
      p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an
      integrated picture of how cellular proliferation and programmed cell death are
      dysregulated in these tumours. Geminin does not behave as an inhibitor of cell
      proliferation, its labelling index rising with increasing growth fraction as
      defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion
      of cells in higher grade tumours (P<0.001) and shows a strong correlation to
      proliferation and replication licensing (P<0.01), but not apoptosis. Increasing
      tumour anaplasia is not associated with loss of Geminin. Importantly, the G1
      phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio,
      shortens with increasing anaplasia, providing new potential algorithms for
      prognostic assessment. Origin licensing proteins thus provide powerful novel
      tools for assessment of tumour cell cycle kinetics in routinely processed
      surgical biopsy material.

PMID- 15199396
TI  - Loss-adjusted survival of cervix cancer in Khon Kaen, Northeast Thailand.
AB  - For incident cancers of the cervix uteri (601 cases) registered in the population
      based cancer registry of Khon Kaen province, Northeast Thailand, in 1985-1990
      loss-adjusted survival probabilities were estimated by a logistic regression
      model with four prognostic factors (age at diagnosis, stage of disease, place of
      residence and treatment), and compared with observed survival, estimated by the
      actuarial method. All patients were followed up for a minimum of 5 years, using
      both passive and active methods. In all, 27.6% of patients were lost to follow-up
      within 5 years of the index date. The overall observed survival at 5 years was
      56.8% and loss-adjusted survival was 54.7%. The difference between the loss
      adjusted and observed survival at 5 years was small: 2.1% overall, varying
      between 0.8 and 3.5 percent units for any prognostic group. The assumption of
      independence of loss to follow-up and death in the calculation of survival by the
      actuarial method in this, and probably in other, population-based series, is
      reasonable and leads to no material bias in the estimates.

PMID- 15199400
TI  - Cleft palate: players, pathways, and pursuits.
AB  - Cleft lip and palate is a common human birth defect, and its causes are being
      dissected through studies of human populations and through the use of animal
      models. Mouse models in particular have made a substantial contribution to our
      understanding of the gene pathways involved in palate development and the nature
      of signaling molecules that act in a tissue-specific manner at critical stages of
      embryogenesis. Related work has provided further support for investigating the
      role of common environmental triggers as causal covariates.

PMID- 15199401
TI  - Poliovirus proves IRES-istible in vivo.
AB  - The genetic basis for the attenuation of polio vaccines has been known since the
      1980s. Changes in the internal ribosome entry site, within the 5' noncoding
      region of genomic RNAs, were presumed to reduce translation in certain target
      organs, leading to the conclusion that attenuation is mediated at the level of
      translation. A report in this issue of the JCI reveals that poliovirus tropism
      is, in part, determined after internal ribosome entry.

PMID- 15199398
TI  - The kiss of death.

PMID- 15199402
TI  - Is transplantation tolerable?
AB  - To test the hypothesis that chronic stimulation of T cells with a weak agonistic
      antigen will generate regulatory T cells and immune tolerance, a study reported
      in this issue employed the redesign of a minor histocompatibility antigen. Using
      knowledge of residues at which the antigen contacts the T cell receptor, a weak
      agonist was produced. Pretreatment with this altered antigen produced transplant
      tolerance, generation of regulatory T cells, and a loss of many antigen-reactive
      T cells.

PMID- 15199397
TI  - Identification of parathyroid hormone-related protein-derived peptides
      immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer
      patients.
AB  - Parathyroid hormone-related protein (PTHrP) is a key factor in the development of
      bone metastases, which are a major barrier in treating prostate cancer patients.
      In this study, we attempted to identify PTHrP-derived peptides immunogenic in
      human histocompatibility leukocyte antigen (HLA)-A24(+) prostate cancer patients.
      Among four different PTHrP peptides carrying the HLA-A24 binding motif, both the
      PTHrP(36-44) and PTHrP(102-111) peptides efficiently induced peptide-specific
      cytotoxic T lymphocytes from peripheral blood mononuclear cells (PBMCs) of HLA
      A24(+) prostate cancer patients. Peptide-stimulated PBMCs showed cytotoxicity
      against prostate cancer cells in an HLA-A24-restricted manner. Experiments using
      antibodies and cold inhibition targets confirmed that their cytotoxicity was
      dependent on PTHrP peptide-specific and CD8(+) T cells. Immunoglobulin G reactive
      to the PTHrP(102-111) or PTHrP(110-119) peptide was frequently detected in the
      plasma of prostate cancer patients, suggesting that the PTHrP(102-111) peptide is
      able to elicit cellular and humoral immune responses in cancer patients. These
      results indicate that the PTHrP could be a promising target molecule for specific
      immunotherapy of HLA-A24(+) prostate cancer patients with metastases.

PMID- 15199403
TI  - Noninvasive imaging of myocardial angiogenesis following experimental myocardial
      infarction.
AB  - Noninvasive imaging strategies will be critical for defining the temporal
      characteristics of angiogenesis and assessing efficacy of angiogenic therapies.
      The alphavbeta3 integrin is expressed in angiogenic vessels and represents a
      potential novel target for imaging myocardial angiogenesis. We demonstrated the
      localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted
      agent in the region of injury-induced angiogenesis in a chronic rat model of
      infarction. The specificity of the targeted alphavbeta3-imaging agent for
      angiogenesis was established using a nonspecific control agent. The potential of
      this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then
      confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual
      isotope single-photon emission-computed tomographic (SPECT) imaging with the
      (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake
      in hypoperfused regions where angiogenesis was stimulated. There was a fourfold
      increase in myocardial radiotracer uptake in the infarct region associated with
      histological evidence of angiogenesis and increased expression of the alphavbeta3
      integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an
      (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of
      angiogenesis may have important implications for risk stratification of patients
      following myocardial infarction. This approach may also have significant clinical
      utility for noninvasively tracking therapeutic myocardial angiogenesis.

PMID- 15199390
TI  - Cytotoxic effect of a new 1,3,4-thiadiazolium mesoionic compound (MI-D) on cell
      lines of human melanoma.
AB  - The structural characteristics of mesoionic compounds, which contain distinct
      regions of positive and negative charges associated with a poly-heteroatomic
      system, enable them to cross cellular membranes and interact strongly with
      biomolecules. Potential biological applications have been described for mesoionic
      compounds. 1,3,4-Thiadiazolium mesoionic compound (MI-D), a new mesoionic
      compound, has been demonstrated to be extremely cytotoxic to B16-F10 murine
      melanoma cells when compared to fotemustine and dacarbazine, drugs of reference
      in melanoma treatment protocols, describing inhibition of tumours grown in vitro
      and in vivo. We now evaluate the effects of mesoionic compound MI-D on different
      human melanoma cell lines. The drug decreased the viability and proliferation of
      MEL-85, SK-MEL, A2058 and MEWO cell lines in vitro, showing a considerable
      cytotoxic activity on these human cells. Adhesion of MEL-85 cells was evaluated
      in the presence of the drug using different extracellular matrix (ECM)
      constituents. MI-D decreased MEL-85 adhesion to laminin, fibronectin and
      matrigel. The morphology and actin cytoskeleton organisation of MEL-85 cells were
      also modified on MI-D treatment. These results on human melanoma cell lines
      indicate that MI-D is a very encouraging drug against melanoma, a tumour that is
      extremely resistant to chemotherapy.

PMID- 15199407
TI  - Characterization of heterogeneity in the molecular pathogenesis of lupus
      nephritis from transcriptional profiles of laser-captured glomeruli.
AB  - The molecular pathogenesis of focal/diffuse proliferative lupus
      glomerulonephritis was studied by cDNA microarray analysis of gene expression in
      glomeruli from clinical biopsies. Transcriptional phenotyping of glomeruli
      isolated by laser-capture microscopy revealed considerable kidney-to-kidney
      heterogeneity in increased transcript expression, resulting in four main gene
      clusters that identified the presence of B cells, several myelomonocytic
      lineages, fibroblast and epithelial cell proliferation, matrix alterations, and
      expression of type I IFN-inducible genes. Glomerulus-to-glomerulus variation
      within a kidney was less marked. The myeloid lineage transcripts, characteristic
      of those found in isolated activated macrophages and myeloid dendritic cells,
      were widely distributed in all biopsy samples. One major subgroup of the samples
      expressed fibrosis-related genes that correlated with pathological evidence of
      glomerulosclerosis; however, decreased expression of TGF-beta1 argued against its
      role in lupus renal fibrosis. Expression of type I IFN-inducible transcripts by a
      second subset of samples was associated with reduced expression of fibrosis
      related genes and milder pathological features. This pattern of gene expression
      resembled that exhibited by activated NK cells. A large gene cluster with
      decreased expression found in all samples included ion channels and transcription
      factors, indicating a loss-of-function response to the glomerular injury.

PMID- 15199404
TI  - Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes
      cleft palate.
AB  - Classical research has suggested that early palate formation develops via
      epithelial-mesenchymal interactions, and in this study we reveal which signals
      control this process. Using Fgf10-/-, FGF receptor 2b-/- (Fgfr2b-/-), and Sonic
      hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a
      downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that
      mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn
      signals back to the mesenchyme. This was confirmed by demonstrating that cell
      proliferation is decreased not only in the palatal epithelium but also in the
      mesenchyme of Fgfr2b-/- mice. These results reveal a new role for Fgf signaling
      in mammalian palate development. We show that coordinated epithelial-mesenchymal
      interactions are essential during the initial stages of palate development and
      require an Fgf-Shh signaling network.

PMID- 15199405
TI  - Specific induction of neuronal cells from bone marrow stromal cells and
      application for autologous transplantation.
AB  - Bone marrow stromal cells (MSCs) have the capability under specific conditions of
      differentiating into various cell types such as osteocytes, chondrocytes, and
      adipocytes. Here we demonstrate a highly efficient and specific induction of
      cells with neuronal characteristics, without glial differentiation, from both rat
      and human MSCs using gene transfection with Notch intracellular domain (NICD) and
      subsequent treatment with bFGF, forskolin, and ciliary neurotrophic factor. MSCs
      expressed markers related to neural stem cells after transfection with NICD, and
      subsequent trophic factor administration induced neuronal cells. Some of them
      showed voltage-gated fast sodium and delayed rectifier potassium currents and
      action potentials compatible with characteristics of functional neurons. Further
      treatment of the induced neuronal cells with glial cell line-derived neurotrophic
      factor (GDNF) increased the proportion of tyrosine hydroxylase-positive and
      dopamine-producing cells. Transplantation of these GDNF-treated cells showed
      improvement in apomorphine-induced rotational behavior and adjusting step and paw
      reaching tests following intrastriatal implantation in a 6-hydroxy dopamine rat
      model of Parkinson disease. This study shows that a population of neuronal cells
      can be specifically generated from MSCs and that induced cells may allow for a
      neuroreconstructive approach.

PMID- 15199406
TI  - Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase.
AB  - Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant
      uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by
      gene targeting are viable, fertile, and phenotypically normal and have regular
      mutation rates. However, when exposed to a nitric oxide donor, Ung(-/-)
      fibroblasts show an increase in the uracil/cytosine ratio in the genome and
      augmented cell death. After combined oxygen-glucose deprivation, Ung(-/-) primary
      cortical neurons have increased vulnerability to cell death, which is associated
      with early mitochondrial dysfunction. In vivo, UNG expression and activity are
      low in brains of naive WT mice but increase significantly after reversible middle
      cerebral artery occlusion and reperfusion. Moreover, major increases in infarct
      size are observed in Ung(-/-) mice compared with littermate control mice. In
      conclusion, our results provide compelling evidence that UNG is of major
      importance for tissue repair after brain ischemia.

PMID- 15199399
TI  - Recent insights into the immunopathogenesis of psoriasis provide new therapeutic
      opportunities.
AB  - Chronic and excessive inflammation in skin and joints causes significant
      morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder,
      psoriasis, as well as the side effects associated with its treatment, affects
      patients globally. In this review, recent progress is discussed in the areas of
      genetics, the immunological synapse, the untangling of the cytokine web and
      signaling pathways, xenotransplantation models, and the growing use of
      selectively targeted therapies. Since psoriasis is currently incurable, new
      management strategies are proposed to replace previous serendipitous approaches.
      Such strategic transition from serendipity to the use of novel selective agents
      aimed at defined targets in psoriatic lesions is moving rapidly from research
      benches to the bedsides of patients with this chronic and debilitating disease.

PMID- 15199408
TI  - Inducible nitric oxide synthase in T cells regulates T cell death and immune
      memory.
AB  - The progeny of T lymphocytes responding to immunization mostly die rapidly,
      leaving a few long-lived survivors functioning as immune memory. Thus, control of
      this choice of death versus survival is critical for immune memory. There are
      indications that reactive radicals may be involved in this death pathway. We now
      show that, in mice lacking inducible nitric oxide synthase (iNOS), higher
      frequencies of both CD4 and CD8 memory T cells persist in response to
      immunization, even when iNOS(+/+) APCs are used for immunization. Postactivation
      T cell death by neglect is reduced in iNOS(-/-) T cells, and levels of the
      antiapoptotic proteins Bcl-2 and Bcl-xL are increased. Inhibitors of the iNOS
      peroxynitrite pathway also enhance memory responses and block postactivation
      death by neglect in both mouse and human T cells. However, early primary immune
      responses are not enhanced, which suggests that altered survival, rather than
      enhanced activation, is responsible for the persistent immunity observed. Thus,
      in primary immune responses, iNOS in activated T cells autocrinely controls their
      susceptibility to death by neglect to determine the level of persisting CD4 and
      CD8 T cell memory, and modulation of this pathway can enhance the persistence of
      immune memory in response to vaccination.

PMID- 15199412
TI  - Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular
      carcinomas.
AB  - PTEN is a tumor suppressor gene mutated in many human cancers, and its expression
      is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP
      system to generate a hepatocyte-specific null mutation of Pten in mice
      (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive
      hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype
      similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were
      induced in mutant hepatocytes, implying adipogenic-like transformation of these
      cells. Genes involved in lipogenesis and beta-oxidation were also induced,
      possibly as a result of elevated levels of the transactivating factors PPARgamma
      and SREBP1c. Importantly, the loss of Pten function in the liver led to
      tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell
      adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox)
      livers showed adenomas and 66% had hepatocellular carcinomas.
      AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro,
      AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased
      hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is
      thus an important regulator of lipogenesis, glucose metabolism, hepatocyte
      homeostasis, and tumorigenesis in the liver.

PMID- 15199411
TI  - Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma
      cell neoplasms in mice.
AB  - Deregulated expression of both Myc and Bcl-X(L) are consistent features of human
      plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc
      and Bcl-X(L) in mouse plasma cells might lead to an improved model of human PCN,
      we generated Myc transgenics by inserting a single-copy histidine-tagged mouse
      Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated
      Bcl-X(L) transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag)
      transgene driven by the mouse Ig kappa light-chain 3' enhancer. Single-transgenic
      Bcl-X(L) mice remained tumor free by 380 days of age, whereas single-transgenic
      Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast,
      double-transgenic Myc/Bcl-X(L) mice developed plasma cell tumors with short onset
      (135 days on average) and full penetrance (100% tumor incidence). These tumors
      produced monoclonal Ig, infiltrated the bone marrow, and contained elevated
      amounts of Myc(His) and Bcl-X(L)(Flag) proteins compared with the plasma cells
      that accumulated in large numbers in young tumor-free Myc/Bcl-X(L) mice. Our
      findings demonstrate that the enforced expression of Myc and Bcl-X(L) by Ig
      enhancers with peak activity in plasma cells generates a mouse model of human PCN
      that recapitulates some features of human multiple myeloma.

PMID- 15199413
TI  - Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition
      with imatinib or rapamycin.
AB  - Small molecule inhibitors, such as imatinib, are effective therapies for tyrosine
      kinase fusions BCR-ABL-TEL-PDGFbetaR-mediated human leukemias, but resistance may
      develop. The unique fusion junctions of these molecules are attractive candidates
      for molecularly targeted therapeutic intervention using RNA interference (RNAi),
      which is mediated by small interfering RNA (siRNA). We developed a retroviral
      system for stable expression of siRNA directed to the unique fusion junction
      sequence of TEL-PDGFbetaR in transformed hematopoietic cells. Stable expression
      of the siRNA resulted in approximately 90% inhibition of TEL-PDGFbetaR expression
      and its downstream effectors, including PI3K and mammalian target of rapamycin
      (mTOR). Expression of TEL-PDGFbetaR-specific siRNA (TPsiRNA) significantly
      attenuated the proliferation of TEL-PDGFbetaR-transformed Ba/F3 cells or disease
      latency and penetrance in mice induced by intravenous injection of these Ba/F3
      cells. Although a 90% reduction in TEL-PDGFbetaR expression was insufficient to
      induce cell death, stable siRNA expression sensitized transformed cells to the
      PDGFbetaR inhibitor imatinib or to the mTOR inhibitor rapamycin. TPsiRNA also
      inhibited an imatinib-resistant TEL-PDGFbetaR mutant, and the inhibition was
      enhanced by siRNA in combination with PKC412, another PDGFbetaR inhibitor.
      Although siRNA delivery in vivo is a challenging problem, stable expression of
      siRNA, which targets oncogenic fusion genes, may potentiate the effects of
      conventional therapy for hematologic malignancies.

PMID- 15199417
TI  - [Study of the pre and post-synaptic dopaminergic system by DaTSCAN/IBZM SPECT in
      the differential diagnosis of parkinsonism in 75 patients].
AB  - INTRODUCTION: Essential tremor (ET) may be misdiagnosed as idiopathic Parkinson's
      disease (PD). In neurodegenerative diseases, structural imaging, such as CT or
      MRI, is of limited value for differentiating parkinsonian syndromes since
      structural changes are often only evident by the time the disease is far
      advanced. Most cases of symptomatic parkinsonism are vascular parkinsonism, but
      PD may coexist. The differential diagnosis between Alzheimer's disease (AD) and
      dementia with Lewy bodies (LBD) is often difficult. OBJECTIVE: To define the
      utility of functional neuroimaging test to establish differential diagnosis
      between PD and ET, drug induced parkinsonism, multiple system atrophy and
      vascular parkinsonism, and between AD and LBD, when clinical presentation,
      evolution or treatment response are atypical. PATIENTS AND METHODS: A group of 75
      patients with parkinsonism was examined by clinical assessment and DaTSCAN (123I
      FP-CTI, dopamine transporter protein marker) and/or IBZM SPECT (D2 receptor
      marker). The patients were recruited from our outpatient clinic. RESULTS:
      Correlation between initial clinical diagnosis and functional imaging studies
      (DaTSCAN and/or IBZM SPECT) in our patients did not reach that described (more
      than 90 %) for these techniques in previously published studies. Conclusions.
      According to sensitivity and sensibility reported in previous imaging studies of
      the pre and/or postsynaptic dopaminergic system using DaTSCAN and/ or IBZM, SPECT
      may be a new tool in the diagnosis of parkinsonian patients with difficult
      clinical diagnosis.

PMID- 15199410
TI  - Induction of dominant transplantation tolerance by an altered peptide ligand of
      the male antigen Dby.
AB  - T cell reactivity to minor histocompatibility (mH) antigens is responsible for
      rejection of HLA-matched allografts, limiting the effectiveness of
      transplantation for the treatment of end-stage organ failure. The deadbox gene
      Dby is located on the Y chromosome and encodes an mH antigen that prompts
      rejection of male tissues by female mice. Establishing a network of regulatory T
      (T(reg)) cells that is capable of coercing naive cells to adopt a tolerant
      phenotype offers an attractive strategy for immune intervention in such
      deleterious immune responses. While various approaches have successfully induced
      a dominant form of transplantation tolerance, they share the propensity to
      provoke chronic, incomplete activation of T cells. By identifying the T cell
      receptor (TCR) contact sites of the dominant epitope of the Dby gene product, we
      have designed an altered peptide ligand (APL) that delivers incomplete signals to
      naive T cells from A1 infinity RAG1(-/-) mice that are transgenic for a
      complementary TCR. Administration of this APL to female transgenic mice polarizes
      T cells toward a regulatory phenotype, securing a form of dominant tolerance to
      male skin grafts that is capable of resisting rejection by naive lymphocytes. Our
      results demonstrate that incomplete signaling through the TCR may establish a
      network of T(reg) cells that may be harnessed in the service of transplantation
      tolerance.

PMID- 15199416
TI  - [Intelligence and prognosis in severe traumatic brain injury: a
      neuropsychological study with the Wechsler adult intelligence scale (WAIS-III)].
AB  - OBJECTIVE: To evaluate the utility of the Wechsler adult intelligence scale III
      (WAIS-III) as a measure of intelligence after severe brain injury, and to
      elucidate prognostic factors associated with intelligence coefficients (IQs).
      METHODS: Forty-six patients (age: 27.4 +/- 12.8 years) attending our service
      after a severe head injury were included in our study (chronicity: 315.3 +/- 330
      days after injury). All patients were assessed with the WAIS-III. WAIS-III IQs
      were correlated (Pearson and Spearman) with clinical and demographic data. A
      significance level of p < 0.05 was used in all comparisons. IQs between 1 and 2
      standard deviation (SD) below normative data were considered "mild abnormal"
      while indexes below 2 SD were considered "abnormal". RESULTS: Only eleven
      patients (25 %) showed normal total IQ with predominance of manipulative (77.7 %)
      compared to verbal (64.5 %) impairment. Thirty-eight patients (95 %) had
      difficulties in speed processing, thirty-six (85.6 %) had problems with working
      memory, twenty-five (62.5 %) showed impairments in perceptual organization, and
      twenty-six (62 %) had verbal comprehension deficits. WAIS-III IQs showed
      significant correlations with length of coma and posttraumatic amnesia duration
      (p < 0.05). CONCLUSIONS: The WAIS-III is a valid and sensible tool to detect
      cognitive deficits associated with brain injury. Almost all patients with severe
      brain injury show abnormal IQs with a slow processing speed as predominant
      symptom. Length of coma and posttraumatic amnesia seems to be the most relevant
      parameter related to intelligence in severe brain-injured patients.

PMID- 15199414
TI  - A novel transgenic mouse model for immunological evaluation of carcinoembryonic
      antigen-based DNA minigene vaccines.
AB  - A lack of relevant animal models has hampered preclinical screening and critical
      evaluation of the efficacy of human vaccines in vivo. Carcinoembryonic antigen
      A2Kb (CEA-A2Kb) double transgenic mice provide a biologically relevant model for
      preclinical screening and critical evaluation of human CEA vaccine efficacy in
      vivo, particularly because such animals are peripherally tolerant of CEA. We
      established the utility of this model by demonstrating that an oral DNA minigene
      vaccine induces effective HLA-A2-restricted, CEA-specific antitumor CTL
      responses. This finding is supported by three lines of evidence: (a). an
      effective HLA-A2-restricted, CEA(691)-specific CTL response; (b). specific in
      vitro killing of CEA-A2Kb transduced MC-38 colon carcinoma cells; and (c).
      protective immunity induced in vaccinated mice against challenges of these tumor
      cells. Importantly, peripheral T cell tolerance against CEA in CEA-A2Kb double
      transgenic mice was broken by the CEA(691) (IMIGVLVGV) minigene vaccine. In
      conclusion, CEA-A2Kb double transgenic mice were demonstrated to be good
      candidates for in vivo testing of human CEA-based vaccines. This result suggests
      a potential for these vaccines in future human vaccine development. The
      feasibility of using nonmutated self-antigens as targets for therapeutic
      vaccinations was indicated, provided that such antigens are presented in an
      immunogenic context; that is, as a DNA minigene in a bacterial carrier system.

PMID- 15199409
TI  - Poliovirus tropism and attenuation are determined after internal ribosome entry.
AB  - Poliovirus replication is limited to a few organs, including the brain and spinal
      cord. This restricted tropism may be a consequence of organ-specific differences
      in translation initiation by the poliovirus internal ribosome entry site (IRES).
      A C-to-U mutation at base 472 in the IRES of the Sabin type 3 poliovirus vaccine
      strain, known to attenuate neurovirulence, may further restrict tropism by
      eliminating viral replication in the CNS. To determine the relationship between
      IRES-mediated translation and poliovirus tropism, recombinant human adenoviruses
      were used to express bicistronic mRNAs in murine organs. The IRESs of poliovirus,
      the cardiotropic coxsackievirus B3 (CVB3), and the hepatotropic hepatitis C virus
      (HCV) mediate translation in many organs, including those that do not support
      viral replication. A translation defect associated with the Sabin type 3 IRES was
      observed in all organs examined. Poliovirus type 1 and recombinant polioviruses
      dependent on the IRES of CVB3 or HCV replicate in the CNS of mice and cause
      paralysis. Although the type 3 Sabin strain is an effective vaccine, polioviruses
      with a U at base 472 of the IRES cause paralysis in newborn mice. Tropism of wild
      type and vaccine strains of poliovirus is therefore determined after internal
      ribosome entry.

PMID- 15199418
TI  - [Evolution of epilepsy in successive pregnancies].
AB  - INTRODUCTION: Hormonal and metabolic factors related to pregnancy itself are
      considered to increase the likelihood of seizure recurrence. If so, we should
      expect a similar evolution of epilepsy in a subsequent pregnancy. We investigated
      differences in evolution of non-gestational epilepsy in each pregnancy of women
      suffering from epilepsy. METHODS: A prospective study was conducted in order to
      compare seizure frequency in two successive pregnancies of more than 36 weeks
      duration in 12 patients. Improvement/worsening is defined as a change of +/- 50 %
      in the number of seizures regarding that which occurred within the previous
      eleven months. RESULTS: Twelve epileptic women were studied during two subsequent
      pregnancies. Eight of them took the same antiepileptic treatment for both
      pregnancies and one took no antiepileptic drug. Three worsened in the first
      pregnancy and two in the second. Seven patients had the same seizure frequency
      during both pregnancies. The total plasma antiepileptic concentrations tended to
      decline with the same proportion in both pregnancies if the dose remained
      unchanged. We observed no differences in mean hormone plasma concentrations for
      each quarter, within subsequent pregnancies. CONCLUSION: Except for one case with
      drug-resistant epilepsy, we found that the reason for the discrepancy in the
      frequency of the seizure between two successive pregnancies in the same patient
      was a sharp or rapid change in antiepileptic drug dose or non-compliance. In well
      controlled epileptic women a consistent evolution of epilepsy should be expected
      in a subsequent pregnancy, if adequate treatment is maintained.

PMID- 15199421
TI  - [Hyperdense basilar artery sign].

PMID- 15199419
TI  - [Sleep disorders in multiple system atrophy].
AB  - Sleep disorders are so common in multiple system atrophy that they should be
      considered an integral part of the disease. Sleep fragmentation occurs in more
      than half of the patients, with sleep onset and sleep maintenance insomnia.
      Periodic leg movements of sleep are also common, although they are generally
      asymptomatic. REM sleep behavior disorder, a parasomnia in which the patient
      presents vigorous movements associated with intense dreaming dreaming during REM
      sleep, is detected polysomnographically in almost all the patients with variable
      severity. Nocturnal stridor is produced by obstruction on the glottis level. The
      cause of stridor is unknown but two alternative explanations have been proposed:
      paralysis of the muscles opening the vocal chords and excessive contraction of
      the muscles that close them. A combination of both, however, is the most likely
      explanation. Nocturnal stridor is associated with decreased survival and its
      treatment is based on continuous positive air pressure (CPAP) when it occurs only
      during sleep or tracheostomy when it worsens and becomes also diurnal.

PMID- 15199420
TI  - [Metalloproteinases and neurovascular injury].
AB  - Matrix metalloproteinases (MMP) are a family of proteases involved in the
      remodelling of the extracellular matrix. In physiological conditions, the
      activity of MMP is regulated on several levels: gene transcription, activation of
      inactive precursors, and inhibition by endogenous factors. Loss of control and
      increased expression and activity of MMP have been implicated in various diseases
      (cancer, arthritis, vascular aneurysms, atherosclerosis, etc.). In the central
      nervous system, MMP are involved in the mechanisms associated with
      neuroinflammation, which is different in vascular and non-vascular diseases. MMP,
      especially MMP-9, have been shown to induce a high breakdown capacity, especially
      in the arteriolar basement membrane, leading to cerebral edema and secondary
      hemorrhage. In human clinical aspects, MMP are associated to intracerebral
      hemorrhage growth and with the development of complications in ischemic stroke.
      Combination therapies explicitly involving MMP inhibition could be of value in
      future treatment strategies.

PMID- 15199423
TI  - [SUNCT syndrome and neoplasms in the central nervous system. A new association].
AB  - Short-lasting unilateral neuralgiform headache attacks with conjunctival
      injection and tearing (SUNCT) syndrome is a rare form of primary headache
      disorder, although secondary causes are well known. A growing number of cases
      have been described since its description in 1978 up to now. We report a new case
      in a 72 year old woman suffering SUNCT syndrome secondary to two ipsilateral
      intracranial lesions in the basal portion of the left frontal lobe of the
      sphenoid wing and the left pontocerebellar angle, suggestive of meningiomas. The
      patient was successfully treated with carbamazepine. We discuss the differential
      diagnosis with other very brief headaches associated with cranial autonomic
      features and the therapeutics possibilities. We review the secondary cases
      previously reported. The possible pathophysiological mechanism in this case is
      discussed.

PMID- 15199422
TI  - [A relapse of multiple sclerosis manifesting as acute delirium].
AB  - Psychotic symptoms are infrequent in multiple sclerosis (MS) and their
      relationship to cerebral lesions has not been clearly documented. The case of a
      58 year old woman with secondary progressive MS is presented. She had acute
      delirium with persecutory delusions associated to paresis of her left leg.
      Magnetic resonance imaging of the brain disclosed an active lesion in the left
      hippocampus. The patient was treated with risperidone and megadoses of
      methylprednisolone, with dramatic improvement. Clinical and radiological data in
      this patient suggest that psychotic disorders can be symptomatic of a relapse in
      MS and, therefore, susceptible to be treated with steroids.

PMID- 15199424
TI  - [Streptococcus salivarius meningitis after spinal anesthesia].
AB  - Streptococcus salivarius is a usual commensal of skin, gastrointestinal tract,
      genitourinary tract, oral cavity and paranasal sinuses. Although it is usually
      considered to have low virulence, S. salivarius may cause life-threatening
      infections, particularly endocarditis. On the other hand, bacterial meningitis
      after spinal anesthesia is very rare, there being some reported cases caused by
      S. salivarius, S. mitis, Staphylococcus aureus and Enterococcus faecalis. We
      report a 57 year old man who developed meningitis symptoms within 10 h of an
      uncomplicated inguinal herniorrhaphy performed during spinal anesthesia.
      Cerebrospinal cultures grew S. salivarius sensitive to penicillin. The patient
      was successfully treated with penicillin G and left the hospital without
      sequelae. In the literature, bacterial meningitis due to S. salivarius is rarely
      reported. Of the 28 cases, 18 occurred after lumbar puncture for diagnostic or
      for spinal anesthesia, 5 occurred following a bacteriemia for upper
      gastrointestinal endoscopy or intestinal neoplasia, and the other 5 in patients
      who had dural defects. We discuss the possible etiological causes of the
      meningitis due to S. salivarius cases reports. The early recognition of this
      entity and the aseptic precautions likely to reduce the incidence of infectious
      complications after lumbar puncture are stressed.

PMID- 15199425
TI  - [Informed consent in Neurologia].

PMID- 15199428
TI  - Low-density lipoprotein receptor--its structure, function, and mutations.
AB  - Uptake of cholesterol, mediated by the low-density lipoprotein (LDL)-receptor,
      plays a crucial role in lipoprotein metabolism. The LDL-receptor is responsible
      for the binding and subsequent cellular uptake of apolipoprotein B- and E
      containing lipoproteins. To accomplish this, the receptor has to be transported
      from the site of synthesis, the membranes of the rough endoplasmatic reticulum
      (ER), through the Golgi apparatus, to its position on the surface of the cellular
      membrane. The translation of LDL-receptor messenger RNA into the polypeptide
      chain for the receptor protein takes place on the surface-bound ribosomes of the
      rough ER. Immature O-linked carbohydrate chains are attached to this integral
      precursor membrane protein. The molecular weight of the receptor at this stage is
      120.000 d. The precursor-protein is transported from the rough ER to the Golgi
      apparatus, where the O-linked sugar chains are elongated until their final size
      is reached. The molecular weight has then increased to 160.000 d. The mature LDL
      receptor is subsequently guided to the "coated pits" on the cell surface. These
      specialized areas of the cell membrane are rich in clathrin and interact with the
      LDL-receptor protein. Only here can the LDL-receptor bind LDL-particles. Within 3
      to 5 minutes of its formation, the LDL-particle-receptor complex is internalized
      through endocytosis and is further metabolized through the receptor-mediated
      endocytosis pathway. Mutations in the gene coding for the LDL-receptor can
      interfere to a varying extent with all the different stages of the
      posttranslational processing, binding, uptake, and subsequent dissociation of the
      LDL-particle-LDL-receptor complex, but invariably the mutations lead to familial
      hypercholesterolemia. Thus, mutations in the LDL-receptor gene give rise to a
      substantially varying clinical expression of familial hypercholesterolemia.

PMID- 15199429
TI  - Laboratory-based assessment of plasma lipids and lipoproteins for the
      classification of familial hypercholesterolemic and hypertriglyceridemic states.
AB  - Laboratory-based coronary heart disease risk assessment classically involves
      measurement of lipids and lipoproteins. In this review, information is provided
      on the methods commonly used in laboratories for the diagnosis of hyperlipidemia,
      including aspects of precision and accuracy. The latter, when fulfilled, allows
      the use of uniform reference values. Special attention is paid to the risk
      estimation using apolipoprotein B and lipoprotein(a) measurement. The overall aim
      of this review is to simplify the laboratory-based risk estimation for coronary
      heart disease and to provide help in interpreting the results for effective
      prevention and treatment of this complex disease.

PMID- 15199430
TI  - Assessment of risk factors for coronary heart disease in vascular medicine: long
      term experience and a personal view from the laboratory.
AB  - Physicians should be properly informed of the clinical chemistry diagnostic
      potential for the diagnosis and classification of hyper- and dyslipidemias by
      laboratory determinations of lipids, lipoproteins, and apolipoproteins. New
      analytes are regularly found to be relevant for screening and risk estimation for
      coronary artery disease in vascular medicine. These analytes can be distinguished
      between parameters working on the long-term or working acutely. However, in times
      of restricted laboratory budgets, it is not always possible to add the new
      analyte to the routine diagnostic supply without having answered the question of
      whether the new analyte indeed adds to the chronic or acute risk estimation power
      presently available. This is relevant for homocysteine and for C-reactive protein
      (CRP). Both parameters appear to be interrelated to most common cardiovascular
      risk factors supposed to promote atherosclerosis and to ultimately provoke
      cardiovascular disease, and in fact are not independent. The latter certainly has
      added value in acute situations. With regard to the chronic risk estimators, it
      must be concluded that there is a multifactorial influence, with an important
      contribution made by social and lifestyle factors. This review draws attention to
      the multifactorial aspects of coronary heart disease, risk profiling using
      computer programs, socioeconomic factors, and implementation problems of
      interventions.

PMID- 15199431
TI  - Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia.
AB  - Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of
      lipoprotein metabolism. FH is characterized by elevated levels of low-density
      lipoprotein cholesterol, the presence of tendon xanthomas, and premature
      cardiovascular disease. The underlying molecular defect of FH consists of
      mutations in the gene coding for the low-density-lipoprotein-receptor protein,
      detection of which provides the only unequivocal diagnosis. Although the cause of
      FH is monogenic, there is wide variation in the onset and severity of
      atherosclerotic disease in these patients. Additional atherogenic risk factors of
      environmental, metabolic, and genetic origin are presumed to influence the
      clinical phenotype in FH. Criteria used to identify individuals with FH include a
      combination of clinical characteristics, personal and family history of early
      coronary artery disease, and biochemical parameters. Since the introduction in
      1989 of statins, which have been shown to be effective and to delay or prevent
      the onset of cardiovascular disease, drug treatment of FH has greatly improved.
      New lipid-lowering agents are presently being developed for clinical use. This
      review provides an update on the clinical, diagnostic, and therapeutic aspects of
      heterozygous familial hypercholesterolemia.

PMID- 15199432
TI  - Homozygous familial hypercholesterolemia and its management.
AB  - Mutations in the low-density lipoprotein (LDL) receptor gene cause familial
      hypercholesterolemia. In homozygous familial hypercholesterolemia, both genes for
      the LDL- receptor are mutated and LDL levels are markedly elevated. High-density
      lipoprotein cholesterol concentration is often reduced and lipoprotein(a) levels
      are high when corrected for apolipoprotein(a) isoforms. Cutaneous and tendinous
      xanthomata develop in childhood and are the most common reason for initial
      presentation. The diagnosis can be confirmed by analysis of LDL-receptor genes or
      studies of LDL receptor function in cultured cells. Severe aortic and coronary
      atherosclerosis usually occurs within the first or second decades of life. Left
      ventricular outflow tract obstruction may be at the level of the aortic valve or
      the supravalvar aorta. Treatment for the hyperlipidemia is with plasmapheresis,
      high-dose statins, and ezetimibe. Liver transplantation reverses the metabolic
      defect but requires chronic immunosupression, and rejection may still occur.
      Liver transplantation is indicated if cardiac transplantation becomes necessary.
      Portocaval shunt may still play a role in patients with coronary artery disease
      who do not have access to plasmapheresis. Gene therapy is currently not
      practicable but is being actively developed.

PMID- 15199433
TI  - Diagnostic, clinical, and therapeutic aspects of familial hypercholesterolemia in
      children.
AB  - The clinical diagnosis of familial hypercholesterolemia (FH) in children is based
      on family history and laboratory findings. The best available value of low
      density lipoprotein cholesterol (LDL-C) for the diagnosis of FH in children is
      >3.50 mmol/L (>135 mg/dL) when FH runs in the family. Levels below this
      concentration were only found in 4.3% of children that had a mutation in the LDL
      receptor gene. In contrast, children with LDL-C equal to or above 3.50 mmol/L had
      0.98 posttest probability of FH. Untreated FH carries a substantial burden of
      morbidity and mortality if left untreated or if inadequately treated. The
      guidelines of the American National Cholesterol Education Program suggested that
      drug treatment should be considered from the age of 10 years if LDL-C levels are
      greater than or equal to 4.9 mmol/L (190 mg/dL) or greater than or equal to 4.1
      mmol/L (158 mg/dL) in the presence of other cardiovascular risk factors,
      including a positive family history of premature cardiovascular disease. Impaired
      flow mediated dilatation was more pronounced in FH children with a positive
      family history of premature cardiovascular disease. The currently prescribed diet
      is sometimes considered to be monotonous and can lead to problems with
      compliance. A reduction of the total intake fat and saturated fatty acids is
      important. Plant sterolesters should be evaluated in young FH children and can
      supplement drug and diet therapy, with an additional reduction of 10 to 15% of
      LDL-C. The use of resins leads to poor compliance, and statins are recommended
      for FH children and adolescents when drug treatment is indicated. Pravastatin,
      simvastatin, and atorvastatin decrease LDL-C 30 to 40% without serious adverse
      events and have a high degree of compliance.

PMID- 15199434
TI  - Advanced method for the identification of patients with inherited
      hypercholesterolemia.
AB  - Familial hypercholesterolemia (FH) has a prevalence of 1 in 500 in Western
      society and predisposes for premature cardiovascular disease. Lipid-lowering
      treatment of affected individuals is widely advocated. Maximum health benefit can
      be obtained in FH if treatment is started as early as possible, as the World
      Health Organization has recently recommended. In 1994 we initiated an active case
      finding program for individuals with FH, based on family investigation and DNA
      testing. In an initial pilot study we established that active family screening
      supported by DNA diagnostics resulted in the identification of substantial
      numbers of FH heterozygotes and determined that diagnosis by DNA analysis was
      superior to conventional cholesterol measurement. Since its initiation, the
      program has led to the identification of more than 6000 individuals with FH, of
      whom the greatest part was not adequately treated at the time of identification.
      Our findings indicate not only that this case-finding approach is effective in
      identifying FH patients who otherwise would not have been identified but also
      that the vast majority of these patients seek treatment and are successfully
      started on cholesterol-lowering therapy to reduce their risk of premature
      cardiovascular disease. Here we describe an effective model to identify and bring
      under treatment large numbers of individuals affected by FH.

PMID- 15199435
TI  - Familial hypercholesterolemia in Spain: case-finding program, clinical and
      genetic aspects.
AB  - A case-finding program for the identification of patients with familial
      hypercholesterolemia (FH) has been established in Spain. The program is based on
      family investigation and molecular genetic testing for mutations in the low
      density lipoprotein receptor gene. To assist this program, intensive research
      into the molecular basis of FH and genotype/phenotype relations is performed. To
      optimize DNA testing, a DNA-diagnostic platform has been constructed that is
      composed of systematic mutation screening by single-strand conformation
      polymorphism (SSCP) analysis, DNA-sequencing, Southern blotting, and the use of
      microarrays for high-throughput analysis. To date, 161 different mutations
      leading to inherited hypercholesterolemia have been identified in Spanish
      patients with FH. In addition, a patient organization was founded to ensure
      patient support and follow-up. To further facilitate FH case-finding and patient
      follow-up, we initiated the publication of a set of guidelines for diagnosis and
      clinical management of FH that can be applied internationally.

PMID- 15199436
TI  - Application of molecular genetics for diagnosing familial hypercholesterolemia in
      Norway: results from a family-based screening program.
AB  - A total of 119 different mutations in the low-density lipoprotein-receptor gene
      have so far been found to cause familial hypercholesterolemia (FH) among
      Norwegian patients. As of April 2003, 2390 patients from 959 unrelated families
      were provided with a molecular genetic diagnosis. Of these, 25.3% had xanthomas
      and 8.4% had xanthelasma. During the last 2-3 years, a systematic family-based
      program to identify close relatives of FH patients has been established. A total
      of 851 relatives of 188 index patients have undergone genetic testing. Four
      hundred seven people (47.9%) were affected, and 444 (52.1%) were unaffected. Only
      41.5% of those affected were on lipid-lowering drugs, and only 6.1% had a value
      for total serum cholesterol below 193 mg/dL (5.0 mmol/L). A follow-up study was
      conducted in 146 of 407 affected relatives 6 months after genetic testing was
      performed. Of those already under treatment at the time of genetic testing,
      nonsignificant reductions of total serum cholesterol and low-density lipoprotein
      cholesterol of 3.2% and 7.1% were observed. Of those not under treatment who were
      aged 18 years and older, the corresponding reductions were 21.2% (p <.0001) and
      30.0% (p <.0001), respectively. We conclude that molecular genetic methods
      represent a feasible and highly efficient tool in a family-based strategy to
      diagnose FH.

PMID- 15199437
TI  - Case-finding for familial hypercholesterolemia in the Asia-Pacific region.
AB  - It is estimated that in the Asia-Pacific region, more than 5.2 million persons
      are suffering from familial hypercholesterolemia (FH). This means that more than
      half of the estimated world total of 10 million FH patients are living in this
      part of the world, of which the vast majority is not aware of their dangerous
      condition, let alone being adequately treated. Obviously, an intensive case
      finding program to identify patients and subsequent clinical management are
      required to prevent premature cardiovascular disease and death caused by the
      consequences of inherited hypercholesterolemia. This article describes the
      current situation concerning FH and the initiatives and actions undertaken in
      Australia to contribute to actively identifying patients with FH in that country.

PMID- 15199438
TI  - Familial hypercholesterolemia in South Africa.
AB  - South Africa, especially the Caucasian part of the population, has one of the
      highest incidences of familial hypercholesterolemia in the world. The founder
      effect in this region has led to this high incidence and to a limited number of
      mutations in the low-density lipoprotein-receptor gene. This chapter describes
      current situation concerning the management of familial hypercholesterolemia in
      South Africa.

PMID- 15199439
TI  - Cost-effectiveness analysis of the genetic screening program for familial
      hypercholesterolemia in The Netherlands.
AB  - Familial hypercholesterolemia (FH) is associated with pronounced atherosclerosis
      leading to premature cardiovascular disease and untimely death. Despite the
      availability of effective preventative drug treatments, many affected individuals
      remain undiagnosed and untreated until they become symptomatic with
      cardiovascular disease. To assess the cost-effectiveness of systematic genetic
      screening of family members of persons diagnosed with FH, an analysis was
      conducted using data from a nationwide screening program for the identification
      of individuals with FH, instituted in The Netherlands in 1994, and from other
      sources. There was DNA testing of families with a known genetic defect to
      identify new cases of FH in the presymptomatic stage of the disease. After
      identification, most newly identified patients were started on cholesterol
      lowering statin treatment. On average, new cases diagnosed by the screening
      program gained 3.3 years of life each. Twenty-six myocardial infarctions would be
      avoided for every 100 persons treated with statins between the ages of 18 and 60
      years. The average total lifetime incremental costs, over all age ranges and both
      sexes, including costs for screening and testing, lifetime drug treatment, and
      treatment of cardiovascular events, was US dollars 7500 per new case identified.
      Cost per life-year gained was US dollars 8700. Therefore, systematic genetic
      screening of family members of persons diagnosed with FH is cost-effective in The
      Netherlands and should be considered for other settings.

PMID- 15199441
TI  - Pathophysiology of atherosclerotic plaque development and rupture: an overview.
AB  - Atherosclerosis is predominantly a clinically silent process, and a substantial
      percentage of patients are first aware of its consequences through the acute and
      catastrophic event of thrombosis. Extensive basic and clinical research in the
      1990s revealed that plaque disruption initiates the majority of thromboses.
      Furthermore, recent studies indicate that inflammation plays a major role in the
      pathophysiology, from initiation of the atheroma to the actual thrombosis itself.
      Attention has now focused on morphological, mechanical, and biochemical
      characteristics that increase plaque vulnerability, as determination of these
      features may allow identification of plaques that are most likely to cause
      symptoms and acute events in the future. This article reviews basic
      pathophysiologic aspects of atherosclerotic plaque development and rupture to
      provide the necessary background for understanding the crucial role of
      inflammation in acute coronary syndromes.

PMID- 15199442
TI  - Endothelial dysfunction as a predictor of acute coronary syndromes.
AB  - Endothelial dysfunction is a key early event in atherogenesis and is integral in
      the onset of acute coronary syndromes. Disruption of the normal endothelial
      functions leads to loss of vasomotor control, reduced production of nitric oxide,
      formation of a procoagulant surface, and promotion of inflammation. These events
      may lead to destabilization of atherosclerotic plaques and the onset of acute
      coronary syndromes. There are several direct and indirect ways of assessing
      endothelial dysfunction in vivo. Several of these measures of endothelial
      dysfunction have been shown to correlate with increased risk of adverse
      cardiovascular outcomes.

PMID- 15199443
TI  - Troponins in acute coronary syndromes.
AB  - Delivering superior clinical specificity and sensitivity for myocardial necrosis,
      cardiac troponin has replaced creatine kinase-MB as the preferred biomarker for
      establishing the diagnosis of myocardial infarction. On the basis of expert
      recommendations, present convention sets the diagnostic decision-limit for each
      assay at the 99th percentile of troponin levels in an apparently healthy
      reference population. Owing to a lack of standardization between different
      assays, this level, corresponding to the 99th percentile, will vary depending
      upon the manufacturer. Among patients presenting with an acute coronary syndrome
      (ACS), even low-level elevations of cardiac troponin T or I are associated with
      higher risk of death and recurrent ischemic events compared with patients with a
      troponin level below the appropriate decision limit. Renal failure does not
      appear to diminish the prognostic value of troponins among patients with a high
      clinical probability of ACS. In addition, patients with elevated levels of
      troponin appear to gain the most benefit from more aggressive medical therapy
      with antithrombin and antiplatelet medications as well as an early invasive
      management strategy. Cardiac troponins offer extremely high tissue specificity
      but do not discriminate between ischemic and nonischemic mechanisms of myocardial
      injury; thus, presently the clinician must assess whether a patient's presenting
      symptoms are consistent with ACS. It is possible that future generations of
      troponin assays will detect specific post-translational modifications of
      troponins that may increase the analytic sensitivity for myocardial damage and
      offer insight into the timing and mechanism of myocardial injury.

PMID- 15199444
TI  - C-reactive protein and other inflammatory biomarkers as predictors of outcome
      following acute coronary syndromes.
AB  - Despite diagnostic and therapeutic advances, the rate of event recurrence is
      still relatively high and short- and long-term prediction of risk is necessary
      although extremely challenging to provide optimal treatment to patients with
      acute coronary syndromes. Available data recommend the use of C-reactive protein
      (CRP) as a prognostic marker in patients with acute coronary syndromes in
      addition to other prognostic factors including troponin levels. Evaluation of CRP
      levels at time of admission should be included in the evaluation of the patient's
      risk profile, including clinical data, associated diseases, markers of myocardial
      necrosis (especially troponin levels), left ventricle performance, and age. A
      cutoff level of 10 mg/L for CRP may be used as a marker of higher risk for death
      and possibly myocardial infarction in acute coronary syndromes, and a cutoff of 3
      mg/L identifies a group of patients with intermediate risk and a high rate of
      recurrent events.

PMID- 15199445
TI  - Glycoprotein IIb/IIIa antagonists in acute coronary syndromes: where are we now?
AB  - Vascular inflammation, coronary constriction, and thrombus formation are central
      to all acute coronary syndromes (ACSs). Adhesion and aggregation of activated
      platelets, initially described during thrombosis, now appear pivotal to all three
      processes. Several platelet adhesion receptors participate but the integrin
      glycoprotein (GP) IIb/IIIa occupies a critical role. GPIIb/IIIa antagonists used
      as an adjunct to percutaneous coronary intervention show clear benefit. However
      in the setting of ACS results have been disappointing. Indeed, trials of oral
      GPIIb/IIIa antagonists in patients with ACS were associated with increased
      mortality. Difficulties with drug dosing and variable pharmacodynamics may
      contribute to suboptimal receptor occupancy, incomplete inhibition of platelet
      aggregation, paradoxical partial agonist activity, and proinflammatory effects.
      Moreover, variable responses of patients to GPIIb/IIIa antagonists may reflect
      population heterogeneity.

PMID- 15199446
TI  - Low-molecular-weight heparins for the treatment of acute coronary syndromes.
AB  - Low-molecular-weight heparins (LMWHs) possess several advantages over
      unfractionated heparin (UFH) for the treatment of acute coronary syndromes
      (ACSs). Already a class I indication for the treatment of unstable angina/non-ST
      elevation myocardial infarction (UA/NSTEMI), LMWHs also show promise in the
      setting of ST elevation myocardial infarction (STEMI) and percutaneous coronary
      intervention (PCI). Moreover, a growing body of evidence has demonstrated
      equivalent safety of LMWH with concomitant use of glycoprotein IIb/IIIa
      inhibitors. Larger clinical studies are needed to confirm the safety and efficacy
      of LMWH as an antithrombin for the treatment across the spectrum of ACS.

PMID- 15199447
TI  - Antiplatelet agents in acute coronary syndromes.
AB  - Plaque disruption, platelet activation, and intracoronary artery thrombus
      formation are the key events in the pathogenesis of acute coronary syndromes.
      Antiplatelet therapies significantly reduce the risk of ischemic complications
      both during the acute phase and in the long term in patients with acute coronary
      syndromes. Aspirin remains the cornerstone of antiplatelet therapy, but there is
      incremental benefit when clopidogrel or ticlopidine is added to aspirin. Dual
      antiplatelet therapy with the combination of clopidogrel and aspirin is becoming
      the new standard of care for the management of patients with non-ST-segment
      elevation acute coronary syndrome and undergoing percutaneous coronary
      intervention and is currently being further evaluated in ST-segment elevation
      acute coronary syndrome.

PMID- 15199448
TI  - Antiplatelet therapy for elective coronary stenting: a moving target.
AB  - The recognition of the major contribution of platelet-mediated mechanisms to the
      pathogenesis of thrombotic complications after coronary stenting has led to the
      development and evaluation of different antiplatelet regimens. The combination of
      aspirin and adenosine diphosphate antagonists such as ticlopidine and clopidogrel
      has solved the issue of acute stent thrombosis. The timing and dose of dual oral
      antiplatelet therapy have, however, changed over time with a shift from
      postintervention treatment to preintervention treatment with a high loading dose
      of clopidogrel. Pretreatment with aspirin and clopidogrel has been associated
      with a further 30% reduction in ischemic complications after coronary
      intervention. Recent data have even shown that in case of optimal pretreatment
      with such a dual oral antiplatelet therapy, glycoprotein IIb/IIIa antagonists are
      no longer mandatory for elective coronary stenting and should be reserved only
      for high-risk procedures or for acute coronary interventions.

PMID- 15199449
TI  - Early statin therapy in acute coronary syndromes.
AB  - Patients who survive an acute coronary syndrome of unstable angina or myocardial
      infarction are at much higher risk of a recurrent event within the following year
      than patients with stable coronary syndromes. Statin therapy is justified for
      many of these patients, not only for long-term benefit but also to reduce the
      risk of recurrent events within weeks of the primary event. The mechanisms that
      underlie this benefit are probably related to improvements in endothelial
      function, a decrease in vascular inflammation, and reduced prothrombotic factors.
      The effects of statins may be mediated by cholesterol reduction, cholesterol
      independent effects (particularly decreasing isoprenoids), and mechanisms that
      are independent of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
      reductase. Observational studies consistently show an early reduction in
      mortality with statin therapy started before discharge from hospital after an
      acute coronary syndrome. Several randomized controlled trials also support an
      early benefit of risk reduction from statins started during the hospital
      admission for an acute coronary syndrome. Early statin therapy is also related to
      improved compliance and use of statins several years after a coronary event.
      Thus, early statin therapy may improve both early and long-term secondary
      prevention efforts.

PMID- 15199450
TI  - Treatment algorithms and critical pathways for acute coronary syndromes.
AB  - Although numerous clinical trials have identified many advances in the treatment
      of patients with acute coronary syndromes (ACS), registries of clinical practice
      have identified that in clinical practice a large proportion of patients do not
      receive guideline-recommended therapies. In addition to development and
      dissemination of national guidelines, there is a need for specific tools to
      ensure that the guideline recommendations are implemented on a patient-by-patient
      basis. Better adherence to practice guidelines has been found to be associated
      with improved outcomes. Critical pathways and/or the process of Continuous
      Quality Improvement (CQI) are means of trying to improve care. Critical pathways
      are standardized protocols that aim to optimize and streamline patient care,
      which usually involve standardized order sets, (or computerized ones), and/or
      simple pocket cards, reminders, or checklists of the appropriate therapies.
      Another key part of an overall CQI effort is to monitor data on performance-i.e.
      utilization of guideline recommended therapies. Several well-conducted studies,
      showing that particular use of critical pathways, can lead to improve quality of
      care.

PMID- 15199454
TI  - Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and
      drug interactions.
AB  - Warfarin, a racemic mixture of R- and S-enantiomers, exerts its anticoagulant
      effect by interfering with the hepatic synthesis of vitamin K-dependent clotting
      factors II, VII, IX, and X and proteins C and S. Warfarin displays stereospecific
      pharmacokinetic and pharmacodynamic properties, and the isomers are
      differentially metabolized by cytochrome p450 isozymes. Among patients treated
      with warfarin, there is little correlation among dose, serum concentration, and
      therapeutic effect, necessitating individualized dosing guided by therapeutic
      monitoring of the prothrombin time. The pharmacokinetic and pharmacodynamic
      properties of warfarin as well as its narrow therapeutic index make it
      particularly susceptible to interactions with other prescription and
      nonprescription drugs, including dietary supplements. Numerous drug compounds are
      reported to interact with warfarin, necessitating increased prothrombin time
      monitoring and warfarin dosing adjustments to maintain safe and effective
      anticoagulation.

PMID- 15199455
TI  - Genetic regulation of warfarin metabolism and response.
AB  - Genetic factors make an important contribution to the wide interindividual
      variation in warfarin dose requirement. Several cytochromes P450, each of which
      shows genetic polymorphism leading to interindividual variation in levels of
      activity, contribute to oxidative metabolism of warfarin. The most important of
      these is CYP2C9, which 7-hydroxylates S-warfarin. In clinical studies, possession
      of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme
      activity, has been associated with a significant decrease in mean warfarin dose
      requirement in at least eight studies. Several studies also suggest that
      possession of a variant allele is associated with an increased risk of adverse
      events. Other genetic factors such as polymorphisms affecting CYP3A4 or CYP1A2
      may also be relevant to warfarin dose requirement. The molecular basis of
      warfarin resistance remains unclear but could be due to unusually high CYP2C9
      activity (pharmacokinetic resistance) or to abnormal vitamin K epoxide reductase
      (pharmacodynamic resistance). There is less information available on genetic
      factors affecting other anticoagulants, but the CYP2C9 genotype is also relevant
      to acenocoumarol dose.

PMID- 15199456
TI  - Oral anticoagulant therapy: quality-of-life issues.
AB  - Developments in the management and appropriate use of oral anticoagulant therapy
      have resulted in improved clinical outcomes for patients. Additionally, the
      results of randomized clinical trials have defined the appropriate indications
      for oral anticoagulant therapy. These advancements have provided both clinicians
      and patients with the evidence needed to make informed decisions about the use of
      anticoagulant therapy. The changes in behavior and lifestyle modifications
      imposed by oral anticoagulant therapy may affect the quality-of-life of patients.
      Recent studies have begun to examine issues surrounding oral anticoagulant
      therapy. As clinicians and patients weigh the evidence of the risks and benefits
      of oral anticoagulant therapy, they need to implicitly consider quality-of-life
      issues that may influence their decision-making.

PMID- 15199457
TI  - Oral anticoagulant monitoring by laboratory or near-patient testing: what a
      clinician should be aware of.
AB  - Prothrombin time (PT) is the primary laboratory test for monitoring oral
      anticoagulant treatment but is influenced by preanalytical conditions and
      analytical variables, that is, thromboplastin reagents and instrumentation.
      Standardization and normalization of test results is mandatory. PT results should
      be transformed to International Normalized Ratio (INR) by calibration of the
      reagent/instrument system with International Reference standards according to
      World Health Organization guidelines. However, there is still uncertainty in the
      INR that is caused in part by calibration errors and in part by interaction
      between the PT reagent and various factors in the patient's specimen. These
      problems are highlighted in INR measurements performed with whole blood
      coagulation monitors. Each center should maintain an appropriate scheme of
      internal and external quality control for the laboratory INR measurement as well
      as the individual point-of-care coagulation monitors used by the center and
      patients for self-testing.

PMID- 15199458
TI  - Oral anticoagulant initiation: rationale for the use of warfarin dosing
      nomograms.
AB  - Oral anticoagulants prevent thrombosis however they are associated with bleeding.
      The risk of both bleeding and thrombosis is increased when the International
      Normalized Ratio (INR) is outside the desired therapeutic range. Hence, oral
      anticoagulants should be administered with the intention of maximizing the "time
      within the therapeutic range." The frequency of INR values outside this range can
      be decreased by (1) warfarin initiation algorithms that guide initial therapy and
      (2) use of computerized systems to guide chronic warfarin therapy. This article
      reviews these techniques.

PMID- 15199459
TI  - Optimizing the efficacy and safety of oral anticoagulant therapy: high-quality
      dose management, anticoagulation clinics, and patient self-management.
AB  - Despite its widespread use, oral anticoagulation therapy suffers from a number of
      problems that lead to underuse and inadequate treatment. Problems include its
      narrow therapeutic index, the influence of many concomitant conditions or
      comorbidities, and the need for high-quality dose management. Poor management of
      oral anticoagulation is a prime factor influencing the occurrence of adverse
      events. As a result of these problems, special programs or anticoagulation
      management services (AMSs) have developed to manage oral anticoagulation. Such
      programs have demonstrated a significant improvement in outcomes compared with
      traditional or usual care (UC) by individual physicians. With the introduction of
      point-of-care prothrombin time monitors, the potential for patient self-testing
      and self-management has developed. Studies show the possibility of even further
      improvement in outcomes compared with UC, although the differences from those
      achieved with an AMS are less impressive.

PMID- 15199460
TI  - Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and
      risk factors.
AB  - Oral anticoagulant therapy is very effective in preventing thromboembolism. Its
      major complication is hemorrhage. The rate of intracranial bleeding from
      randomized trials and observational studies ranges from 0.1 to 0.9% per year and
      largely depends on the International Normalized Ratio (INR) target range. Risk
      factors for this often-fatal complication include INR intensity, older age,
      cerebrovascular disease, and hypertension. Recent insights into the pathogenesis
      of intracerebral hemorrhage have focused on underlying arterial vasculopathies
      that predispose to bleeding, particularly in the elderly. The rate of major
      extracranial hemorrhage on oral anticoagulant therapy ranges from 0.4 to 2% per
      year. Different definitions of major hemorrhage, INR target ranges, age
      distribution, burden of comorbid illness, and type of coumarin challenge
      comparability of studies. Additional risk factors for major hemorrhage include
      history of gastrointestinal bleeding, concurrent use of antiplatelet or
      nonsteroidal anti-inflammatory drugs, genetic differences in warfarin metabolism,
      INR variability, type of coumarin, comorbid illnesses, and duration of oral
      anticoagulant therapy.

PMID- 15199461
TI  - Management of excessive anticoagulation or bleeding.
AB  - The number of patients anticoagulated with warfarin has rapidly increased over
      the last decade. Approximately 1% of these patients experience serious bleeding
      and 0.5% die annually from bleeding. The management of hemorrhage in the
      overanticoagulated patient is complex and is based on balancing the risks and
      benefits of each therapeutic intervention. For life-threatening bleeding, the use
      of clotting factor concentrates is essential for immediate anticoagulation
      reversal, whereas for less severe bleeding intravenous vitamin K is the treatment
      of choice. Vitamin K (by the intravenous or oral route) should also be used in
      overanticoagulated patients who are not actively bleeding but who are at high
      risk of doing so if their anticoagulation is not, at least partially, corrected.

PMID- 15199462
TI  - Management of anticoagulation in patients who require invasive procedures.
AB  - When orally anticoagulated patients need to have surgery, the goals of management
      are to minimize the risks of thromboembolism and of bleeding from the invasive
      procedure. Some invasive procedures can be performed while patients are fully or
      partially anticoagulated because bleeding is rare and/or easily controlled. When
      it is necessary to reverse oral anticoagulant therapy it should be interrupted
      for as short a time as possible, usually 4 or 5 days. Intravenous unfractionated
      heparin or therapeutic-dose subcutaneous low-molecular-weight heparin (LMWH) can
      be given as "bridging therapy" to reduce the risk of thromboembolism while oral
      anticoagulation is interrupted. However, the risks and benefits of bridging
      therapy are uncertain. Bridging therapy, particularly with LMWH, may not be very
      effective at preventing embolism in patients with atrial fibrillation or
      mechanical heart valves, and it may be associated with bleeding. My preference is
      to minimize the time that patients are off oral anticoagulant therapy, generally
      restarting warfarin the day of surgery; reserve bridging therapy for those at
      highest risk of thromboembolism; and to use "prophylactic" rather than
      "therapeutic" doses of heparin after major surgery. As major surgery markedly
      increases the risk of venous thromboembolism, postoperative bridging therapy
      should be considered for patients without an inferior vena caval filter that have
      had proximal deep vein thrombosis or pulmonary embolism during the previous
      month.

PMID- 15199463
TI  - The North American experience with patient self-testing of the INR.
AB  - The increased utilization of anticoagulant therapy has led to a spectrum of
      advances in management, including the use of International Normalized Ratio (INR)
      reporting, the development of anticoagulation clinics, the development of
      portable point-of-care INR devices, and the development of innovative testing
      modalities such as patient self-testing (PST). PST of the INR provides improved
      access to testing and a practical method to achieve high-frequency testing,
      typically on a once-a-week schedule. Implementation of self-testing has been
      widely adopted in Germany but has been accepted much more slowly in North
      America. The lack of effective reimbursement has been the greatest barrier to
      more widespread use of PST, but this is confounded by the lack of large-scale
      clinical trials, INR issues, and the lack of physician awareness and advocacy.
      Recent decisions by insurance authorities to provide limited reimbursement are
      providing some optimism for more widespread utilization of PST of the INR in the
      near future.

PMID- 15199464
TI  - Oral anticoagulant therapy in venous thromboembolism.
AB  - The main objective of treatment of venous thromboembolism (VTE) is the prevention
      of the extension, embolization, and recurrence of thrombosis. The long-term aim
      is to prevent late recurrences and the post-thrombotic syndrome. Heparin and oral
      anticoagulants (OACs) have been the cornerstones of VTE treatment in the last 30
      years. Low molecular weight heparins (LMWHs) have been introduced more recently
      in the treatment of the acute phase of VTE, and they have allowed the home
      treatment of deep vein thrombosis (DVT) in selected cases. The optimal duration
      of OAC therapy after VTE is still controversial. Several studies have been
      conducted, and several are ongoing with the aim to stratify patients into risk
      categories for recurrence. Patients at high risk are candidates for long-term
      oral anticoagulation as the benefits of extended oral anticoagulation would
      outweigh the risk of bleeding. Patients are currently stratified into risk
      categories on the basis of clinical characteristics of the VTE event: (1) first
      or recurrent event; (2) idiopathic or due to a transient risk factor such as
      surgery, trauma, hormonal therapy, or immobilization; (3) presence of active
      cancer; (4) location (proximal DVT and/or pulmonary embolism, PE, or distal DVT);
      and (5) presence of known hereditary or acquired thrombophilia. Patients with
      distal VTE or VTE due to a transient risk factor are at a low risk of recurrence
      and short-term anticoagulation is indicated (3 months). Patients with an
      idiopathic event or with known thrombophilic defects such as FV Leiden or the
      G20210A prothrombin mutation are candidates for a longer course of therapy (6
      months). Patients with cancer, antiphospholipid antibodies syndrome, recurrent
      idiopathic event, antithrombin deficiency, protein C or protein S deficiency,
      homozygosity for FV Leiden, and double heterozygosity are candidates for extended
      long-term anticoagulation. More recently, studies have indicated that other
      factors such as D-dimer levels after the discontinuation of OAC therapy or the
      residual vein thrombosis could be additional predictive factors for recurrences.
      In patients with VTE and cancer, oral anticoagulation poses a higher risk of
      bleeding, and such patients are more prone to recurrences. Alternative treatment
      with LMWH could be safer and more effective in these patients.

PMID- 15199465
TI  - Oral anticoagulant therapy in subjects with congenital or acquired thrombophilia.
AB  - Thrombophilia testing is now commonplace. However, testing for heritable
      thrombophilia does not predict outcome in response to oral anticoagulant therapy.
      At present there is no conclusive evidence that recurrence on treatment with
      warfarin with a target International Normalized Ratio of 2.5 is greater in
      patients with laboratory evidence of heritable thrombophilia compared with those
      without. Similarly, there is no conclusive evidence that patients with laboratory
      evidence of heritable thrombophilia are more likely to suffer an earlier
      recurrence once treatment is stopped. Therefore, the management of patients with
      familial thrombotic disease and patients with laboratory evidence of heritable
      thrombophilia should be influenced by their personal and family history rather
      than the results of laboratory investigations. There is no doubt that the
      relative risk of thrombosis is increased in affected family members of thrombosis
      prone families but this translates to a relatively low absolute risk per year,
      and long-term primary prophylaxis with oral anticoagulant therapy is not
      justified in the majority. Evidence of antiphospholipid syndrome is associated
      with an increased risk of recurrent venous thromboembolism, but there is still
      uncertainty as to the optimal intensity and duration of oral anticoagulant
      therapy after an episode of arterial or venous thrombosis in patients with
      detectable antiphospholipid activity.

PMID- 15199466
TI  - Oral anticoagulant therapy in patients with coronary artery disease.
AB  - Oral anticoagulation (OA) has been used to treat patients with coronary artery
      disease (CAD) for more than 40 years and has been a subject of intense
      controversy since that time. Seven to 10% of patients with acute myocardial
      infarction (MI) develop recurrent MI, stroke, or death in the 6 weeks following
      the index event and approximately 20% after 4 years, despite optimal background
      therapy with aspirin. Recent large studies and systematic reviews have greatly
      clarified the role of OA in the modern era. On the weight of the evidence, which
      is reviewed in detail in this article, long-term, moderate-intensity OA
      (International Normalized Ratio 2.0 to 3.0) should be considered an option for
      the prevention of recurrent CAD, particularly in high-risk patients.

PMID- 15199467
TI  - Oral anticoagulant therapy in patients with atrial fibrillation.
AB  - In the absence of contraindications, patients with atrial fibrillation and at
      least one major risk factor for stroke should receive long-term oral
      anticoagulant treatment to prevent atrial thrombus formation. Because age of more
      than 75 years is a major risk factor for stroke, but is also a risk factor for
      major bleeding, the decision to treat elderly patients with anticoagulants should
      be made on an individual basis.

PMID- 15199468
TI  - Oral anticoagulant therapy in patients with peripheral artery disease.
AB  - Patients with peripheral artery disease suffer from a high incidence of ischemic
      vascular complications in coronary, cerebral, and peripheral vascular beds.
      Reduction of atherothrombotic complications with aspirin or clopidogrel has
      proven to be successful. The role of oral anticoagulants in patients with
      symptomatic peripheral artery is limited. Randomized controlled trials comparing
      the effects of aspirin with oral anticoagulants are scarce. Oral anticoagulants
      (International Normalized Ratio = 2.5 to 4.5) are more effective than aspirin in
      preventing infrainguinal bypass occlusion only when venous graft material is used
      and the bypass is considered to be at high risk for occlusion. Whether the use of
      oral anticoagulants reduces all-cause morbidity and mortality is not
      unequivocally clear. The risk of ischemic events is reduced at the expense of an
      increased number of bleeding complications, which is one of the main reasons that
      therapy has not been widely adopted.

PMID- 15199472
TI  - Antithrombotic drugs in vascular medicine: a historical perspective.
AB  - Many new antithrombotic and antiplatelet drugs have been developed that have
      markedly improved prophylaxis and treatment of thrombotic diseases. Clopidogrel,
      a potent new antiplatelet compound, is the first clinical alternative to aspirin
      for long-term oral treatment and prevention of arterial thrombosis. Another new,
      exciting category of antiplatelet compounds is the GPIIb/IIIa-antagonists, the
      first antiintegrins in clinical use and the most potent inhibitors of platelet
      aggregation. Low molecular weight heparins (LMWHs) are the quantitatively
      dominating group of new antithrombotics, which has replaced unfractionated
      heparin for the prophylaxis and treatment of venous thromboembolism. Current
      clinical evidence suggests that LMWHs might replace unfractionated heparin for
      the treatment and prophylaxis of atherothrombotic complications in acute coronary
      syndromes in the near future. Fondaparinux is the first synthetic pentasaccharide
      and a selective inhibitor of factor Xa with exciting clinical data; it could
      become an alternative LMWH for prophylaxis of arterial and venous thromboembolism
      in high-risk patients. The field of oral thrombin inhibitors is still dominated
      by the coumarins. However, much effort is being undertaken to develop new orally
      active drugs from which ximelagatran is currently the leading compound with a
      predicted better safety and efficacy profile. Alternatively, inhibitors of factor
      VIIa might be of interest as well. Open questions include, in particular, the
      possible individualization of drug therapy in dependence on the kind of disturbed
      platelet function or blood hypercoagulability, respectively.

PMID- 15199473
TI  - Aspirin and other cyclooxygenase inhibitors: new therapeutic insights.
AB  - Aspirin acetylates serine-530 of cyclooxygenase-1 (COX-1), thereby blocking
      thromboxane A (2) synthesis in platelets and reducing platelet aggregation. This
      mechanism of action accounts for the effect of aspirin on prevention of coronary
      artery and cerebrovascular thrombosis. Aspirin is less effective in inhibiting
      COX-2 activity, whereas celecoxib and rofecoxib selectively inhibit COX-2
      activity as they contain a side chain to anchor to the side pocket of COX-2
      substrate channel. Aspirin and salicylate at therapeutic concentrations inhibit
      COX-2 protein expression through interference with binding of CCAAT/enhancer
      binding protein beta (C/EBPbeta) to its cognate site on COX-2 promoter/enhancer.
      Expression of other genes, such as inducible nitric oxide synthase and
      interleukin-4, may be inhibited by aspirin and salicylate by a C/EBP-dependent
      mechanism. Aspirin at suprapharmacological concentrations inhibits NF-kappaB
      mediated gene transcription and protects tissue from injury. These recent studies
      provide new insight into the pharmacological actions of aspirin and salicylate
      preparations and implicate C/EBPbeta as a potential target for therapy of
      inflammation and tissue injury.

PMID- 15199474
TI  - P2Y12, a new platelet ADP receptor, target of clopidogrel.
AB  - Clopidogrel is a potent antithrombotic drug that inhibits ADP-induced platelet
      aggregation. The results of large clinical trials have demonstrated an overall
      benefit of clopidogrel over aspirin in the prevention of vascular ischemic events
      (myocardial infarction, stroke, vascular death) in patients with a history of
      symptomatic atherosclerotic disease. The antiaggregating effect of clopidogrel is
      attributed to an irreversible inhibition of ADP binding to a purinergic receptor
      present at the platelet surface. Clopidogrel is not active in vitro and can be
      considered a precursor of an active metabolite formed in the liver. The chemical
      structure of this active metabolite and its biological activity have been
      described recently. Several purinergic receptors have been described on
      platelets; P2X (1), a calcium channel, and P2Y1 a Gq-coupled seven-transmembrane
      domain receptor, have been found not to be antagonized by clopidogrel. Another Gi
      (2)-coupled receptor (named P2Y12) has been recently cloned and stably expressed
      in CHO cells. These cells displayed a strong affinity for (33)P-2MeS-ADP, a
      stable analogue of ADP, the binding characteristics of which corresponded in all
      points to those observed on platelets. The binding of (33)P-2MeS-ADP to these
      cells was strongly inhibited by the active metabolite of clopidogrel with a
      potency that was consistent with that observed for this compound on platelets. In
      these transfected CHO cells, as in platelets, ADP and 2MeS-ADP induced adenylyl
      cyclase downregulation, an effect that was inhibited by the active metabolite of
      clopidogrel. These results demonstrate that this receptor corresponds to the
      previously called "P2t" platelet receptor and show that the active metabolite of
      clopidogrel binds in a covalent manner to this receptor, thus explaining how it
      blocks the aggregating effect of ADP on platelets.

PMID- 15199475
TI  - GPIIb/IIIa antagonists and other anti-integrins.
AB  - Platelet aggregation involves the binding of adhesive proteins (fibrinogen, von
      Willebrand factor) to the alphaIIbbeta3 integrin, which assumes a high-affinity
      state for adhesive proteins during platelet activation. The occupied integrin
      sends signals back into the platelet, and the bound adhesive protein forms the
      bridges linking platelets together. Anti-integrin therapy is designed to inhibit
      this process in arterial thrombosis. Abciximab, mouse-human chimeric Fab
      fragments, blocks platelet aggregation and provides proven clinical benefit in
      acute situations such as in patients with unstable angina undergoing angioplasty
      or stenting. Eptifibatide and tirofiban are small molecular mass inhibitors also
      in current use. In contrast, oral inhibitors of alphaIIbbeta3 have proved
      disappointing, provoking increased mortality without assuring an adequate
      blockade of alphaIIbbeta3. The problems of using anti-integrin therapy are
      discussed in this article as are ways of improving its efficacity. Final thoughts
      provide ideas for a new generation of inhibitors.

PMID- 15199476
TI  - Orally active direct thrombin inhibitors.
AB  - Anticoagulants are widely used for the prevention and treatment of venous and
      arterial thrombosis. Current treatment strategies often employ a combination of
      parenteral and oral agents because the only available orally active
      anticoagulants, vitamin K antagonists, have a delayed onset of action.
      Furthermore, vitamin K antagonists have a narrow therapeutic window that
      necessitates careful anticoagulation monitoring, and dosing is problematic
      because of multiple food and drug interactions. These limitations highlight the
      need for oral anticoagulants that produce a more predictable anticoagulant
      response than vitamin K antagonists, thereby obviating the need for laboratory
      monitoring. Ximelagatran has the potential to meet this need. A prodrug of
      melagatran, an agent that targets thrombin, ximelagatran exhibits many of the
      characteristics of an ideal anticoagulant. This article (1). reviews the
      limitations of vitamin K antagonists, (2). lists the characteristics of an ideal
      anticoagulant, (3). rationalizes thrombin as a target for new anticoagulants,
      (4). reviews the preclinical and clinical data with ximelagatran, and (5).
      provides clinical perspective as to the future of ximelagatran and other orally
      active anticoagulants currently under development.

PMID- 15199477
TI  - The present and future of heparin, low molecular weight heparins,
      pentasaccharide, and hirudin for venous thromboembolism and acute coronary
      syndromes.
AB  - Due to their favorable pharmacologic properties and beneficial clinical effects,
      low molecular weight heparins (LMWHs) have become the standard of care in the
      prevention and treatment of venous thromboembolism and have also been extensively
      studied in the treatment of acute coronary syndromes. Pentasaccharide is the
      first of a new class of synthetic antithrombotics and has been shown to be
      superior to LMWH in preventing deep vein thrombosis. Hirudin is the most potent
      direct thrombin inhibitor and has provided superior antithrombotic efficacy when
      compared with LMWH. In acute coronary syndromes, however, the antithrombotic
      activity of hirudin has been compromised by a significant increase in major
      hemorrhage.

PMID- 15199478
TI  - Role of platelets in the pathophysiology of acute coronary syndrome.
AB  - Coronary atherosclerosis is the primary cause of heart diseases in industrialized
      nations. It has now become clear that coronary atherosclerosis is not simply an
      inevitable consequence of aging but rather a chronic inflammatory process that
      can be converted into an acute clinical event by plaque rupture and arterial
      thrombosis. It is well recognized that platelets play a key role in thrombotic
      vascular occlusion at the ruptured coronary atherosclerotic plaque, leading to
      acute ischemic episodes, the acute coronary syndromes (ACSs). In addition, both
      embolization of platelet aggregates and direct, receptor-mediated platelet
      adhesion to the postischemic microvascular surface result in obstruction and
      impairment of coronary microcirculation. Such microvascular disturbance may lead
      to significant additional tissue injury and aggravate myocardial contractile
      dysfunction. Novel antiplatelet strategies have contributed substantially to
      improve the outcome of patients with ACSs. However, the availability of new
      investigative tools, including genetically modified mouse models of disease, has
      demonstrated that platelets not only contribute to acute thrombotic vascular
      occlusion but also participate in the inflammatory and matrix-degrading processes
      of coronary atherosclerosis itself. Platelet- endothelial cell interactions at
      lesion-prone sites might trigger an inflammatory response in the vessel wall
      early in the genesis of atherosclerosis and contribute to destabilization of
      advanced atherosclerotic lesions. Thus, recent progress in defining the complex
      multistep process that promotes firm arrest of platelets to the (sub-)
      endothelium and initiates subsequent platelet activation may lead to the
      development of new antiplatelet strategies that provide an efficacious
      prophylactic intervention, in particular, for patients with a high
      atherosclerotic risk factor profile.

PMID- 15199479
TI  - Combined antithrombotic therapy for acute coronary syndrome.
AB  - Remarkable therapeutic advances in the treatment of acute coronary syndromes
      (ACS) have been made with combined antithrombotic therapy. Aspirin is accepted as
      standard therapy in the management of ACS but has significant limitations,
      including intolerance, resistance, and peptic ulceration. With the intravenous
      platelet glycoprotein IIb/IIIa inhibitors and the new thienopyridine clopidogrel,
      the options for acute and chronic antiplatelet therapy have expanded. Recently,
      the combination of antiplatelet therapy and oral anticoagulation has gained much
      interest and has been shown to be effective in secondary prevention of ACS. This
      article summarizes important recent findings on the background of existing
      pathological and clinical knowledge to provide an understanding of the basis of
      current combined antithrombotic therapy.

PMID- 15199480
TI  - Low-dose aspirin for primary prevention of cardiovascular disease.
AB  - Progressive atherosclerosis followed by plaque rupture is the leading cause of
      acute cardiovascular events. Inhibition of platelet aggregation by
      acetylsalicylic acid (aspirin) reduces recurrent cardiovascular events in
      secondary prevention trials. By extracting data from available randomized trials
      that examined aspirin prevention in persons without previously known
      cardiovascular disease, we evaluated the use of aspirin as a primary prevention
      measure. Using the raw data presented in the source publication on death, fatal
      and nonfatal myocardial infarctions, and cerebrovascular accidents, all relative
      and absolute risk reductions were recalculated with confidence intervals. In
      healthy men above 45 years of age, men with an increased cardiovascular risk
      profile, and persons with diabetes mellitus or hypertension, the use of aspirin
      reduces the incidence of myocardial infarction and has a neutral effect on
      cerebrovascular events. The protective effect of aspirin is apparently most
      prominent in those persons with an increased risk of manifest atherosclerotic
      vascular disease. Notwithstanding these results, for each patient it remains
      essential to balance the cardiovascular risk profile against the small increased
      risk of bleeding complications when prescribing aspirin.

PMID- 15199481
TI  - Tissue factor in acute coronary syndromes.
AB  - Thrombosis at the site of atherosclerotic plaque disruption is the principal
      cause of acute coronary syndromes. The severity of the clinical consequences is
      determined by the extent and the progression of the thrombus that are caused by
      local and systemic factors. In atherosclerotic lesions mediators induce tissue
      factor (TF) in macrophages, smooth muscle cells, and endothelial cells.
      Procoagulant microparticles in the lipid core further enhance the thrombogenicity
      of the plaque. In addition, in acute coronary syndromes circulating monocytes and
      microparticles express TF and, thereby, contribute to systemic procoagulant
      activity. As a regulatory mechanism surface-bound, endogenous tissue factor
      pathway inhibitor-1 (TFPI) inhibits TF activity by translocation of the
      quaternary complex TF-FVIIa-FXa-TFPI into glycosphingolipid-rich microdomains
      more efficiently than exogenously added TFPI. This inhibition occurs not only in
      endothelial cells but also on circulating monocytes and presumably
      microparticles. Because therapeutic thrombolysis in acute myocardial infarction
      degrades TFPI, a prothrombotic state due to unopposed TF activity may occur.
      Several studies have demonstrated a contribution of local and bloodborne TF to
      thrombus formation; a direct relationship with the clinical outcome, however,
      awaits further studies. This article discusses the current understanding of the
      role of TF and its regulation by TFPI in acute coronary syndromes.

PMID- 15199482
TI  - The role of the tissue factor-thrombin pathway in cardiac ischemia-reperfusion
      injury.
AB  - This article focuses on the role of the tissue factor (TF)-thrombin pathway in
      cardiac ischemia-reperfusion (I/R) injury. We and others have used rabbit models
      of cardiac I/R injury to show that anti-TF therapy prevents the transient
      decrease in regional myocardial blood flow, reduces platelet and fibrin(ogen)
      accumulation, and reduces infarct size. At present, the mechanism by which TF
      initiated coagulation contributes to myocardial injury is not established.
      Inhibition of TF may decrease intravascular fibrin deposition and thrombosis.
      However, immunohistochemical studies demonstrated that fibrin deposition was
      predominantly within the myocardium and depletion of fibrinogen did not reduce
      infarct size. In contrast, inhibition of thrombin reduced infarct size to a
      similar extent as anti-TF therapy. We propose that the TF-thrombin pathway may
      contribute to myocardial injury by an additional mechanism that is not dependent
      on fibrin deposition but involves activation of protease activated receptor 1
      (PAR-1) on vascular endothelial cells and cardiac myocytes. Anti-TF therapy would
      inhibit both thrombin-dependent fibrin deposition and thrombin-dependent PAR-1
      signaling.

PMID- 15199484
TI  - Targeting tissue factor as an antithrombotic strategy.
AB  - It is generally accepted that the initial event in coagulation and intravascular
      thrombus formation is the exposure of cell-surface protein, such as tissue factor
      (TF). TF is exposed to the flowing blood as a consequence of vascular injury
      induced, for instance, by PTCA, or by spontaneous rupture of an atherosclerotic
      plaque. Expression of TF may also be induced in monocytes and endothelial cells
      in several conditions such as sepsis and cancer, causing a more generalized
      activation of clotting. In addition to its essential role in hemostasis, TF may
      be also implicated in several pathophysiological processes, such as intracellular
      signaling, cell proliferation, and inflammation. For all these reasons, TF has
      been the subject of intense research focus. Many experimental studies have
      demonstrated that inhibition of TF:factor VIIa procoagulant activity is a
      powerful inhibitor of in vivo thrombosis and that this approach usually results
      in a less-pronounced bleeding tendency compared with other "more classical"
      antithrombotic interventions. Alternative approaches may be represented by
      antibodies directed against TF, by transfection of the arterial wall with natural
      inhibitors of the TF:factor VIIa complex, such as the TF pathway inhibitor, or
      with catalytic RNA (ribozyme), which could inhibit the expression of the TF
      protein by the disruption of cellular TF mRNA. All these approaches seem
      particularly attractive because they may result in complete inhibition of local
      thrombosis without incurring potentially harmful systemic effects. Further
      studies are warranted to determine the efficacy and safety of such approaches in
      patients.

PMID- 15199483
TI  - rFVIIai in Acute Coronary Syndromes.
AB  - Following vessel wall injury, tissue factor (TF) is exposed and forms complexes
      with already activated factor VII (FVIIa) present in the circulating blood,
      thereby initiating the hemostatic process. After the first FXa is formed, the TF
      pathway inhibitor (TFPI) forms a complex with FXa, and a quaternary complex is
      formed, TF/FVIIa/ FXa/TFPI, which inhibits the first step of the hemostatic
      pathway. Recombinant activated FVII (rFVIIa) has been developed for use as a
      hemostatic agent (NovoNordisk A/S, Denmark). Active site-inactivated rFVIIa
      (rFVIIai) has also been prepared and was shown to have a faster association to
      and a slower dissociation from TF than rFVIIa, resulting in a lower calculated Kd
      of rFVIIai compared with rFVIIa. In various animal models rFVIIai has been
      demonstrated to prevent or diminish immediate thrombus formation at the site of
      vessel wall injury (athroplasty or other forms of mechanical injury) as well as
      the development of long-term intima thickening. The inflammatory response
      following endotoxin-induced sepsis was shown to decrease after administration of
      rFVIIai. Also, survival increased in the rFVIIai-treated animals in this study.
      In addition, ischemia-reperfusion injury was mitigated by rFVIIai. In a limited
      number of patients undergoing percutaneous transluminal coronary angioplasty
      (PTCA), rFVIIai was observed to allow PTCA to be performed at lower doses of
      heparin than what has been reported previously.

PMID- 15199487
TI  - Basic mechanisms of hemostasis.
AB  - Hemostasis governs two essential processes of human life in that it maintains the
      fluidity of blood under physiological conditions and prevents excessive blood
      loss after injury. Hemostasis is regulated by components of the vessel wall and
      blood cells and by humoral coagulation factors. Under normal conditions, these
      components are involved in an active equilibrium through activation, propagation,
      and termination of the hemostatic pathways. This equilibrium is disturbed upon
      vascular injury, leading to a procoagulant response when needed. Unfortunately,
      pathological disturbances can occur as a result of inherited or acquired
      coagulation factor deficiencies that may lead to bleeding or thrombotic
      disorders.

PMID- 15199489
TI  - Changes of hemostasis variables during pregnancy.
AB  - Normal pregnancy results in significant changes in maternal plasma coagulation
      factors, elements of the protein C/protein S natural anticoagulant system, and
      markers of fibrinolysis. These changes result in an increase in thrombin and
      fibrin generation, which is necessary for the hemostatic challenge of delivery
      and for normal placental implantation and development. In this review, the
      evidence for these changes in both the antenatal and peripartum period is
      discussed. An understanding of these physiological changes is required to allow a
      diagnosis of inherited or acquired thrombophilic or bleeding disorders during
      pregnancy and may give insight into the development of the thrombosis-linked
      disorders associated with pregnancy.

PMID- 15199490
TI  - Venous and arterial thrombosis during pregnancy: epidemiology.
AB  - Venous thromboembolism is an important cause of maternal morbidity and mortality
      throughout the developed world with an incidence of about 1 per 1000 deliveries,
      of which 1-2% are fatal. Two thirds of women who have a pregnancy-associated deep
      vein thrombosis develop the post-thrombotic syndrome and suffer long-term
      morbidity. The risk of venous thromboembolism is greater in older women and in
      women who have an operative delivery. Other risk factors include obesity, high
      parity, and immobilization. Acquired or inherited thrombophilias augment the
      risk, and some women with a previous history of venous thromboembolism may be at
      increased risk of a recurrence associated with pregnancy. Arterial thrombosis is
      uncommon in pregnancy but may have devastating consequences. The incidence of
      ischemic stroke associated with pregnancy is unknown but is estimated to be about
      0.18 per 1000 deliveries-the majority being the result of arterial occlusion.
      Myocardial infarction is estimated to occur in 0.1 per 1000 women in association
      with pregnancy. Events occur most frequently peripartum or postpartum. Risk
      factors include maternal age, atherosclerosis, obesity, hypertension, and
      smoking.

PMID- 15199491
TI  - Congenital and acquired activated protein C resistance.
AB  - Resistance to the anticoagulant action of activated protein C, APC resistance, is
      a highly prevalent risk factor for venous thrombosis among individuals of
      Caucasian origin. In most cases, APC resistance is associated with a single
      missense mutation in the gene for coagulation factor V (FV (Leiden)), which
      predicts the replacement of Arg (506) with a Gln at one of the cleavage sites for
      APC in factor V. Factor V is a Janus-faced protein with dual functions, serving
      as an essential nonenzymatic cofactor in both pro- and anticoagulant pathways.
      Procoagulant factor Va, generated after proteolysis by thrombin or factor Xa, is
      a cofactor to factor Xa in the activation of prothrombin, whereas anticoagulant
      factor V, generated after proteolysis by APC, functions as a cofactor in the APC
      mediated degradation of FVIIIa. The FV (Leiden) mutation affects the
      anticoagulant response to APC at two distinct levels of the coagulation pathway,
      as it impairs degradation of both activated factor V and activated factor VIII,
      the latter effect inasmuch as FVLeiden is a poor APC cofactor. Several other
      genetic traits, some of them quite common, are known to affect the anticoagulant
      response to APC, but none of them cause the same severe APC-resistance phenotype
      as FV (Leiden) and their importance as risk factors for thrombosis is unclear. A
      poor APC response may also result from acquired conditions, some of which are
      clearly involved in the pathogenesis of venous thrombosis. Venous thrombosis is a
      typical multifactorial disease, the pathogenesis of which involves multiple gene
      gene and gene-environment interactions. In many patients with severe
      thrombophilia, APC resistance is found as a contributing risk factor.

PMID- 15199492
TI  - Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical
      implications.
AB  - Inherited thrombophilia has been reported to be associated with an increased risk
      for complications of pregnancy, including venous thromboembolism (VTE) as well as
      preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio
      placentae (AP), the latter probably due to inadequate placental perfusion. The
      estimate of risk largely depends on the kind of thrombophilia and on the criteria
      applied for the selection of the patients, producing in some cases contradictory
      results. Convincing evidence is available that deficiency of antithrombin III
      (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL.
      Factor V (Leiden) is associated with an increased risk for VTE, unexplained
      recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor
      for VTE. So far, the data available for FGR and AP are scarce. However, the
      absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in
      comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with
      subcutaneous heparin is warranted during puerperium in all women with
      thrombophilia and throughout all pregnancy in women at higher risk (AT
      deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies);
      treatment with subcutaneous heparin for prevention of FL among women with
      thombophilia is under investigation. Presence of inherited thrombophilia
      increases the risk for VTE due to oral contraceptives up to an absolute risk of 3
      per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000
      person-years; the risk is further increased by first usage, the use of
      preparations containing third-generation progestins, and thrombophilia due to AT,
      PC, and PS deficiency as well as homozygous factor V (Leiden) and combined
      defects.

PMID- 15199493
TI  - Changes of hemostatic variables during oral contraceptive use.
AB  - The use of oral contraceptives (OCs) has been known for many years to affect
      significantly almost all hemostatic parameters, but the challenge to relate these
      changes in a meaningful way to OC-induced increased venous thrombotic risk has
      not been met. New insights indicate that at least part of the answer can be found
      in the net effect of OC use on the efficacy with which the protein C pathway down
      regulates thrombin formation. During OC use the (blood) plasma of a woman becomes
      resistant to the anticoagulant action of activated protein C (APC). The extent of
      this so-called acquired APC resistance as determined in a thrombin generation
      based assay correlates remarkably well with the risk increases observed in
      clinical studies. Recent evidence indicates that the prothrombotic effect of the
      estrogen component ethinylestradiol in combined OC is counteracted by the
      progestagen component present in these preparations and that third-generation
      progestagens such as desogestrel or gestodene are less efficient with respect to
      this than the second-generation progestagen levonorgestrel.

PMID- 15199494
TI  - Venous and arterial thrombosis during oral contraceptive use: risks and risk
      factors.
AB  - Since the introduction of oral contraceptives, their use has been associated with
      an increased risk of both venous and arterial thrombosis. Pulmonary embolism,
      myocardial infarction, and stroke are serious disorders with a considerable risk
      of mortality. Because worldwide over 100 million women use oral contraceptives,
      issues of drug safety are of great importance. The risk of venous thrombosis
      during low-dose oral contraceptive use is three- to sixfold increased compared
      with that of nonusers. The association is not only attributed to the estrogen
      component of the pill: the risk is twice as high for desogestrel and gestodene
      (third generation) containing oral contraceptives as for levonorgestrel (second
      generation) containing oral contraceptives. The risk of venous thrombosis is
      highest in the first year of use and in women with genetic or acquired risk
      factors for thrombosis. Both venous or arterial thrombosis are unrelated to
      duration of use or past use of combined oral contraceptives. The risk of
      myocardial infarction and stroke during low-dose oral contraceptive use is two-
      to fivefold increased relative to that of nonusers. The risk of arterial
      thrombosis induced by oral contraceptive use is more pronounced in smokers and
      women with hypertension, diabetes, and hypercholesterolemia. All types of
      thrombosis have strongly age-dependent incidences, and therefore in absolute
      figures the risks and effects of risk factors increase with age. The lowering of
      the estrogen dose in combined oral contraceptives from 50 microg to 20-30 microg
      in the last decade did not clearly reduce the risk of venous thrombosis,
      myocardial infarction, stroke, or peripheral arterial disease. For stroke and
      peripheral arterial disease no difference in risk was found between second and
      third generation oral contraceptives. For myocardial infarction study results are
      conflicting, and a small benefit of third- over second-generation oral
      contraceptives cannot be ruled out. However, this is unlikely to counterbalance
      the adverse effect of third generation contraceptives on venous thrombosis.

PMID- 15199495
TI  - Changes of hemostatic variables during hormone replacement therapy.
AB  - Hormone replacement therapy (HRT) is accompanied by many changes in the
      hemostatic system. Because several individual hemostatic variables have been
      suspected to be reasonable indicators of the hemostatic balance and because this
      balance is thought to play an important role in the pathogenesis of several
      diseases, careful examination of the changes in this system induced by HRT could
      be helpful, first to improve HRT and second to improve our understanding of
      mechanisms of cardiovascular disease. The effects of (several forms of) HRT on
      individual hemostatic variables are discussed in this article. The pattern that
      emerges is that HRT stimulates coagulation, inhibits anticoagulation, and
      stimulates fibrinolysis (partly by inhibition of fibrinolysis). There are,
      however, few data that give clear insight into the effects of HRT on hemostatic
      variables. Controlled randomized clinical studies are needed to evaluate further
      the effects of HRT on the hemostatic system, to understand the interplay between
      inflammation and coagulation (both pathways being affected by HRT), and to
      understand how HRT-associated changes are affected by differences in genetic
      background.

PMID- 15199496
TI  - Epidemiology of pulmonary embolism.
AB  - The diagnosis of venous thromboembolism (VTE) has notoriously been challenging
      because the disease often has no specific clinical presentation, can at times be
      completely asymptomatic, and can masquerade as other illnesses. To further
      complicate matters, the rules for coding VTE in the presence of other illnesses
      changed in 1983 so that among patients who died of VTE and other causes, VTE was
      omitted from the coding. The International Cooperative Pulmonary Embolism
      Registry enrolled 2454 consecutive pulmonary embolism (PE) patients from 52
      participating hospitals in 7 countries. The aim was to establish the 3-month all
      cause mortality rate and to identify factors associated with death. Three-month
      follow-up was completed in 98% of the patients. The all-cause mortality rate was
      11.4% during the first 2 weeks after diagnosis and 17.4% at 3 months. Especially
      troubling among survivors was the high rate of recurrent VTE after
      anticoagulation was discontinued. Age is a potent risk factor for the development
      of VTE. The two most common genetic mutations that predispose to VTE are the
      factor V Leiden and the prothrombin gene. VTE can be precipitated by oral
      contraceptives, pregnancy, or hormone replacement therapy.

PMID- 15199497
TI  - Pulmonary embolism: from clinical presentation to clinical probability
      assessment.
AB  - The rehabilitation of clinical assessment of venous thromboembolism (VTE) is
      certainly one of the major breakthroughs of the last decade in the field of
      pulmonary embolism (PE) diagnosis. Although the value of isolated clinical
      findings in suspected PE is limited due to the poor sensitivity and specificity
      of its symptoms and signs, their combination, whether empiric or explicit through
      prediction rules, allows a fairly accurate assessment of the likelihood of the
      disease in a given patient. This allows the identification of a large subset of
      patients with a low prevalence of the disease in whom a combination of
      noninvasive tests rules out PE effectively despite these tests' limited
      individual sensitivity. The best validated example is the combination of a low
      probability lung scan and a normal venous compression ultrasound in a patient
      with low clinical probability of PE, which is associated to a low 1 to 2% 3-month
      risk of VTE in such patients left untreated by anticoagulants. Finally, clinical
      assessment contributes significantly to the cost savings associated with modern
      noninvasive strategies.

PMID- 15199498
TI  - Pulmonary embolism: imaging modalities--V/Q scan, spiral (helical) CT, and MRI.
AB  - Ventilation-perfusion (V/Q) imaging has been used as the screening test for
      pulmonary embolism (PE) for many years with diagnostic algorithms developed as a
      result of the Prospective Investigation of Pulmonary Embolism Diagnosis study.
      The primary conclusions were that high probability V/Q scans were reliable
      indicators for PE and normal or near-normal scans were reliable in the exclusion
      of PE. With the increasing availability of spiral (helical) computed tomography
      (CT) and many studies showing a high degree of accuracy for PE, there is much
      support for the replacement of V/Q by spiral CT. This article reviews the
      literature concerning V/Q scanning, spiral (helical) CT, and the future potential
      for magnetic resonance in the diagnosis of PE.

PMID- 15199499
TI  - The role of echocardiography in suspected and established PE.
AB  - Acute obstruction of more than 30% of the pulmonary arterial bed often results in
      abnormal right ventricular (RV) transthoracic Doppler echocardiography (TTE),
      usually defined as RV dysfunction, dilatation, or hypokinesis. The presence of
      such changes strongly increases the clinical probability of pulmonary embolism
      (PE) (specificity, 81 to 94%; PPV, 71 to 86%) and indicates a worse prognosis,
      especially if a patent foramen ovale is found at contrast TTE. Normal RV
      echocardiography indicates a good prognosis. Integrating TTE with venous
      ultrasound and transesophageal imaging increases the possibility of immediate
      definitive justification for specific therapy. This strategy permits direct
      visualization of thrombi either in proximal veins, pulmonary arteries, or right
      heart chambers. Mobile thrombi require immediate thrombolysis or urgent
      embolectomy. Whether any echo-based criteria might identify normotensive patients
      with PE who should receive thrombolytic therapy remains a subject for an overdue
      large prospective trial.

PMID- 15199500
TI  - Fibrin D-dimer measurement in suspected pulmonary embolism.
AB  - Due to increased awareness among physicians, the prevalence of pulmonary embolism
      (PE) in patients clinically suspected of the disease has steadily decreased
      during the past 15 years. This has led to the development of simple diagnostic
      tools in an attempt to reduce the number of invasive or costly exams needed to
      manage these patients. D-dimer (DD) measurement has proven to be a simple and
      very useful test to exclude PE and several strategies combining DD with clinical
      probability and other exams have been validated in large outcome studies. The
      problem faced by many physicians is the choice of the specific DD test and its
      more appropriate position in the diagnostic work-up of patients suspected of PE.
      This article focuses on these questions and also provides some limitations of DD
      use, such as its poor specificity in hospitalized and elderly patients.

PMID- 15199501
TI  - Looking for deep vein thrombosis in suspected pulmonary embolism.
AB  - Pulmonary embolism (PE) and deep vein thrombosis are two facets of the same
      disease, that is, venous thromboembolism (VTE). In patients with angiographically
      proven PE, the prevalence of proximal deep vein thrombosis by venography is
      around 70%. The sensitivity of compression ultrasonography (US) for the diagnosis
      of acute VTE in patients with a suspicion of PE is between 40 and 60%, with a
      high specificity (96 to 100%). Taking into account the 20 to 30% prevalence of PE
      in a population consulting for suspicion of this disease, the first line use of
      compression US will allow the diagnosis of acute VTE in half of patients with
      confirmed PE, that is, in 10 to 15% of patients addressed for suspicion of PE. In
      outpatients, the first line use of D-dimers which will exclude acute VTE in one
      third of the initial population will slightly increase the reliability of
      compression US as a first imaging test. New tools of looking for deep vein
      thrombosis, such as computed tomographic venography coupled with computed
      tomographic pulmonary angiography, could become an interesting approach in the
      diagnostic strategy of PE, but require adequate evaluation in prospective
      studies.

PMID- 15199502
TI  - Diagnostic strategies for suspected pulmonary embolism among outpatients.
AB  - Diagnosis of pulmonary embolism (PE) has been made easier, less invasive, and
      somewhat safer over the past 2 decades. This has been due mainly to the
      development of lung scan and to the recognition of VTE as an entity comprising
      deep vein thrombosis and PE. The prevalence of the disease in patients clinically
      suspected of PE has steadily decreased during the past 10 years. This has led to
      the development of diagnostic tools that aim at reducing the number of
      unnecessary pulmonary angiograms. These include clinical probability assessment
      and fibrin D-dimer. Several strategies combining these tools have been validated
      in large outcome studies and compared in a formal cost-effectiveness analysis.
      The results indicate that they should now be implemented in daily practice taking
      into account local facilities and expertise. The exact place of helical computed
      tomography in such sequential algorithms remains to be established.

PMID- 15199503
TI  - Second-generation, subsecond multislice computed-tomography: advancing the role
      of helical CT pulmonary angiography in suspected pulmonary embolism.
AB  - Advancements in computed tomography (CT) have led to the development of
      noninvasive helical CT of the pulmonary arteries as a diagnostic tool in patients
      with suspected pulmonary embolism (PE). The first-generation, single-slice CT
      scanners were capable of acquiring one 3-mm-thick imaging section per second. As
      a further technical evolution of helical CT, multislice CT scanners now allow
      simultaneous acquisition of eight slices per second. This increased imaging speed
      can be used to advantage by scanning the entire thorax with 1-mm-thin imaging
      sections during a single breath-hold. Because of the increased spatial resolution
      and increased robustness to motion artifacts of multislice CT, the pulmonary
      arteries can now be accurately depicted up to the fifth order branches. In
      comparison with single-slice CT, this holds the promise of better detection of
      small subsegmental PE and thus, increased accuracy to detect and rule out PE. A
      few recent management studies suggest that single-slice CT can be used as an
      accurate cornerstone in the diagnostic work-up of suspected PE-a concept that
      will be further enhanced with multislice helical CT.

PMID- 15199504
TI  - Pulmonary embolism diagnosis in hospitalized and intensive care unit patients.
AB  - The diagnosis of acute pulmonary embolism (PE) remains difficult, and diagnostic
      strategies must consider the unique challenges of hospitalized and critically ill
      patients. Diagnostic algorithms that are effective and safe for outpatients may
      not be effective and safe for inpatients or patients in intensive care units. For
      example, serial compression ultrasonography (US) of the lower extremities may
      allow physicians to avoid pulmonary angiography for stable inpatients or
      outpatients, but this strategy is not validated for patients who require
      intensive care for serious underlying cardiopulmonary disease. Helical computed
      tomography (CT) is particularly suited for the evaluation of suspected PE for
      inpatients with serious cardiopulmonary disease. However, the safety of
      withholding treatment when a helical CT pulmonary angiogram is negative remains
      to be demonstrated. Lung perfusion and ventilation scans combined with an
      assessment of pretest probability remain important objective tests for the
      evaluation of many hospitalized patients.

PMID- 15199505
TI  - Thrombolytic therapy in pulmonary embolism.
AB  - Successfully utilized contemporary pulmonary embolism (PE) thrombolysis reverses
      right heart failure rapidly and safely. This therapeutic approach may lower
      mortality from PE and reduce morbidity from chronic pulmonary hypertension. PE
      thrombolysis remains a debatable indication because large clinical trials using
      survival as an endpoint have not been carried out. Instead, thrombolysis trials
      have been undertaken with surrogate endpoints such as reduction in clot burden,
      reduction in pulmonary arterial pressure, and improvement in right ventricular
      function. Currently, the only contemporary thrombolytic regimen for PE that is
      approved by the Food and Drug Administration is recombinant tissue plasminogen
      activator, in a dose of 100 mg/2 h. New thrombolytic agents under development for
      PE include reteplase, saruplase, and recombinant staphylokinase. Future clinical
      trials will require multicenter collaboration and focus on clinically relevant
      endpoints such as reduction of mortality and recurrent venous thromboembolism,
      under particular consideration of the risk of intracranial hemorrhage that ranges
      between about 1.7% in clinical trials up to approximately 3.0% in a large
      registry.

PMID- 15199506
TI  - Vena caval filters in pulmonary embolism.
AB  - Since the early 1900s, surgical interruption of the inferior vena cava (IVC) has
      been utilized in the management of venous thromboembolism (VTE). With the advent
      of newer-generation percutaneous devices in the late 1970s, their use and
      indications have expanded. The literature to support their efficacy, however, is
      limited to several case series and a single randomized controlled trial. Despite
      this, some have advocated the use of IVC filters as primary treatment of VTE in
      certain patient populations. In addition, there has been a large amount of
      interest in their use as prophylaxis against pulmonary embolism (PE) in high-risk
      patients. In the past 10 years, we have also seen the development and initial use
      of temporary devices, although their role in the management of this disease is
      even less certain. This article will review the recent literature on efficacy,
      complications, and indications for the use of IVC filters in the prevention and
      treatment of PE.

PMID- 15199507
TI  - Outpatient treatment of patients with pulmonary embolism.
AB  - Very few treatment studies have included patients with pulmonary embolism (PE)
      but there have been many enrolling patients with deep vein thrombosis (DVT).
      Should treatment for PE be different from treatment for DVT? Post-mortem and
      clinical studies have shown a strong association between PE and the presence of
      venous thrombosis in the lower limbs but some recent data suggest that certain
      clinical factors will predict patients at higher risk of death from PE.
      Unfortunately, it is not clear that identifying patients as high risk will affect
      outcome. Two large studies recently compared treatment with unfractionated
      heparin to treatment with low-molecular-weight heparin in patients with PE.
      Combining the two studies, the rates of recurrent DVT or PE were 2.9% (13/442) in
      the low-molecular-weight heparin group and 3.2% (14/441) in the unfractionated
      heparin group, and major hemorrhage occurred in fewer than 3% of patients. The
      feasibility of providing outpatient care to many patients presenting to tertiary
      care hospitals with acute PE has become evident. In our institutions, the data
      suggest about 50% of patients with PE could be treated as outpatients. Until
      further knowledge is available, it is not unreasonable to perform
      echocardiography and cardiac troponin T on patients with PE if they are not
      completely stable or if concern over concomitant cardiopulmonary disease exists.
      If they meet criteria demonstrated to result in early death, it is of course
      reasonable not to treat such patients on a solely outpatient basis. Evidence is
      accumulating that patients with PE as their initial symptom complex of their
      venous thromboembolic disease have a worse prognosis, specifically, higher risk
      of recurrence and higher risk of death, but there are no data to suggest
      outpatient therapy will affect their prognosis. Low-molecular-weight heparin or
      intravenous unfractionated heparin, followed by oral anticoagulant therapy,
      provide adequate therapy in most patients with PE, and many can be treated as
      outpatients.

PMID- 15199508
TI  - Emergency surgical pulmonary embolectomy.
AB  - Emergency surgical pulmonary embolectomy is a highly effective treatment for
      selected patients with pulmonary embolism. Rapid noninvasive diagnostic
      modalities allow proper patient selection based on anatomic location of the
      emboli, right heart function, and contraindications to thrombolysis. Operative
      results are a direct reflection of the preoperative hemodynamic status, the
      degree of underlying cardiopulmonary disease, and attention to minimizing
      surgical trauma and protecting the right heart. An operative mortality of 10% or
      less and excellent long-term outcomes can be expected if the procedure is
      performed prior to cardiovascular collapse as part of a multidisciplinary
      strategy which emphasizes careful patient selection, rapid diagnosis, triage, and
      transport.

PMID- 15199509
TI  - Transvenous catheter embolectomy.
AB  - Transvenous pulmonary embolectomy was first described in 1969 by Greenfield and
      associates who designed a special catheter for the aspiration of thrombi in the
      pulmonary circulatory system. This technique was applied in 64 patients with
      massive pulmonary embolism (PE) with a 70 to 72% survival rate. However, it is
      difficult to implement and has not gained widespread acceptance. More recently,
      several other catheter devices have been used in patients with PE. The total
      number of patients reported does not exceed 100. Relative angiographic
      improvement varies between 10 and 49%, but hemodynamic improvement is not
      observed or not measured in most patients and mortality varies between 9 and 30%.
      Fibrinolysis was associated with mechanical thrombectomy in 54% of the patients,
      making the results difficult to interpret. Transvenous pulmonary embolectomy
      remains an experimental procedure and should been attempted only in the very few
      patients with PE, uncontrolled cardiogenic shock, and absolute contraindication
      to fibrinolytic treatment. Animal models are required to compare the different
      devices available.

PMID- 15199510
TI  - Epidemiology of venous thromboembolism.
AB  - The annual incidence of diagnosed venous thromboembolism (VTE) is 1 to 2 events
      per 1000 of the general population. VTE is very uncommon before age 20 years and,
      after 40 years of age, the incidence about doubles with each decade. Over half of
      episodes of VTE are deep vein thrombosis (DVT), and three quarters are first
      episodes. The incidence of VTE is similar in men and women and lower in Asians
      than it is in Caucasians or Africans. Hereditary risk factors include the factor
      V Leiden mutation; the G20210A prothrombin gene mutation; and deficiencies of
      protein C, protein S, and antithrombin. Hyperhomocysteinemia and elevated levels
      of factors I, VIII and XI, which may be hereditary and/or acquired, are also risk
      factors. Acquired risk factors include malignancy, hospitalization, surgery,
      venous trauma, immobilization, estrogen therapy, pregnancy, and the
      antiphospholipid antibodies. Risk factors for a first episode of VTE are
      generally also risk factors for recurrence, although the associated relative risk
      for thrombosis may differ for a first and subsequent event.

PMID- 15199511
TI  - Natural history of venous thromboembolism.
AB  - Most deep vein thromboses (DVTs) start in the calf; however, thrombi that remain
      confined to the calf rarely cause leg symptoms or are associated with symptomatic
      pulmonary embolism (PE). The probability that calf DVT will extend to involve the
      proximal veins, and subsequently cause PE, increases with the severity of the
      initiating prothrombotic stimulus and if this stimulus persists. Although acute
      venous thromboembolism (VTE) usually presents with either leg or pulmonary
      symptoms, most patients have thrombosis at both sites at the time of diagnosis.
      Treated proximal DVTs resolve slowly, and half of patients still have detectable
      thrombi after a year. About 10% of patients with symptomatic DVT develop severe
      postthrombotic syndrome within 5 years. This is more likely to occur if there has
      been an ipsilateral recurrent DVT. About 10% of PEs are rapidly fatal. Of PEs
      that are diagnosed before death, about 50% are associated right ventricular
      dysfunction, a finding that is associated with a high short-term mortality. There
      is about 50% resolution of PE after 1 month of treatment, and perfusion
      eventually returns to normal in two thirds of patients. After a course of
      treatment, the risk of recurrent thrombosis is higher in patients without a
      reversible risk factor and in those with certain biochemical abnormalities,
      including antiphospholipid antibodies, hyperhomocysteinemia, and homozygous
      factor V Leiden.

PMID- 15199512
TI  - Clinical and laboratory diagnosis of deep vein thrombosis: new cost-effective
      strategies.
AB  - Diagnosis of deep vein thrombosis (DVT) has been made easier, less invasive, and
      somewhat safer over the past 2 decades. This has been due mainly to the
      development of venous compression ultrasonography (US). The prevalence of the
      disease in patients clinically suspected of DVT has steadily decreased during the
      past 10 years, likely as a consequence of the accurate noninvasive test,
      ultrasound imaging. This has led to the development of diagnostic tools that aim
      at reducing the number of unnecessary US exams. These include clinical
      probability assessment and fibrin D-dimer. Several strategies combining these
      tools have been validated in large-outcome studies and compared in a formal cost
      effectiveness analysis. The results indicate that they should now be implemented
      in daily practice, taking into account local facilities and expertise.

PMID- 15199513
TI  - Treatment of deep vein thrombosis.
AB  - Most patients who present with deep vein thrombosis (DVT) can be treated with
      weight-adjusted, fixed-dose, low molecular heparin as an outpatient. The
      subsequent duration of oral anticoagulant therapy should be individualized
      according to the risk of recurrent venous thromboembolism and the risk of
      anticoagulant-induced bleeding. The risk of recurrence is low if thrombosis was
      provoked by a major reversible risk factor such as surgery; 3 months of treatment
      is usually adequate for such patients. The risk of recurrence is high if
      thrombosis was unprovoked ("idiopathic") or associated with a nonreversible risk
      factor such as active cancer; at least 6 months, and sometimes indefinite,
      anticoagulant therapy is indicated for such patients. The presence of an
      antiphospholipid antibody, and other selected thrombophilic states, favors more
      prolonged therapy within each of the categories noted previously. Systemic
      thrombolytic therapy helps to restore venous patency and probably reduces the
      risk of the postthrombotic syndrome; however, it is associated with an
      unacceptable risk of bleeding. Catheter-directed thromboylsis, particularly for
      isolated iliofemoral thrombosis, may be beneficial and needs further evaluation
      in controlled trials.

PMID- 15199514
TI  - Diagnosis of recurrent deep vein thrombosis.
AB  - Long-term follow-up studies demonstrated that venous thromboembolism is a chronic
      disease, as the rate of recurrent deep vein thrombosis (DVT) continuously
      increases after the primitive thrombotic episode. Objective testing is mandatory
      to confirm or refute the presence of recurrent DVT, as only 30% of patients with
      suspected recurrence have a new documented thrombotic episode. There is no
      consensus on the preferred diagnostic procedure; furthermore, both invasive and
      noninvasive methods are limited in this context. Venography, the established gold
      standard, is invasive, costly, inconvenient and requires high technical skills.
      Among noninvasive techniques, serial impedance plethysmography, alone or in
      combination with leg scanning and venography, and serial compression ultrasound
      (CUS), were adequately investigated. At present, the recommended approach is
      represented by a quantitative CUS method that possesses an excellent
      reproducibility and accuracy. The safety of withholding anticoagulants from
      patients with a normal quantitative CUS work-up has been recently demonstrated in
      a prospective management study.

PMID- 15199515
TI  - Prevention of venous thromboembolism in high-risk surgical and medical patients.
AB  - Although pharmacologic prophylaxis against venous thromboembolism has become the
      standard of care following total hip and knee replacement, prophylaxis among
      patients undergoing surgery for hip fracture and other lower extremity trauma
      remains underutilized. Available experience consistently supports the view that
      low-molecular-weight heparins are more effective than unfractionated heparin for
      prevention of proximal deep vein thrombosis (DVT) with no additional hemorrhagic
      risk and more effective than oral anticoagulants for prevention of in-hospital
      (mostly distal) venous thrombosis at the price of a higher surgical site bleeding
      and wound hematoma. The choice between low-molecular-weight heparin and warfarin
      should be tailored to the individual patients based on the clinical assessment of
      postoperative thrombosis and bleeding risk as well as the prophylaxis-specific
      cost and convenience. Whether thromboprophylaxis should be continued for a few
      additional weeks after hospital discharge is controversial. The overall incidence
      of postoperative DVT in patients with cancer is about twice as high as that of
      patients free of malignancy. Accordingly, they require prophylactic measures
      comparable with those usually recommended for major orthopedic surgery. In this
      setting, dermatan sulfate shows promise. In contrast to surgical patients,
      prevention of venous thromboembolism is less well studied in hospitalized medical
      patients. In a recent controlled randomized trial, enoxaparin in high
      prophylactic doses was an effective and safe measure of thromboprophylaxis in
      ordinary bedridden patients.

PMID- 15199516
TI  - Postthrombotic syndrome: incidence, prevention, and management.
AB  - Mild to severe postthrombotic sequelae, including chronic pain, edema, and
      ulceration, arise in one third of patients short after deep vein thrombosis
      (DVT). Recurrent DVT is closely associated with the development of postthrombotic
      syndrome (PTS), whereas if the extent and location of DVT might be relevant
      remains unclear. Chronic venous hypertension and abnormal microvessel or
      lymphatic function also correlates with PTS. The diagnosis of PTS is based on
      clinical grounds only if patients report a history of documented DVT; otherwise,
      objective testing is required. To abate the prevalence of PTS, the best policy is
      represented by prevention of recurrent thrombosis and use of stockings. Despite a
      plenty of surgical options, conservative treatment is preferable because half of
      the patients improve or remain stable during follow-up, provided they wear
      elastic stockings. Clinical presentation has a prognostic value, as patients with
      initially severe symptoms enjoy a more favorable outcome than those who
      progressively deteriorate over time.

PMID- 15199517
TI  - Venous thromboembolic disease: risk factors and laboratory investigation.
AB  - The etiology of venous thromboembolic disease has been the subject of several
      recent discoveries, particularly on genetic predisposing factors. The laboratory
      investigation that may help to evaluate the risk for individual patients includes
      the measurements of coagulation inhibitors (antithrombin, protein C, and protein
      S) in plasma assays, the search for the factor V Leiden mutation by the plasma
      activated protein C resistance test (always to be confirmed by DNA analysis when
      abnormal), and the search for the prothrombin gene mutation by DNA analysis.
      Among acquired abnormalities, the most frequently involved are phospholipid
      dependent autoantibodies associated or not with a subset of antibodies having an
      anticoagulant effect in vitro (lupus anticoagulant). Other coagulation
      abnormalities such as increased FVIII, FIX, or FXI levels or hyperhomocysteinemia
      have been suggested to be risk factors for thrombosis, although additional
      studies are required to definitively assess their role.

PMID- 15199518
TI  - Deep venous thrombosis and thrombophilia: indications for testing and clinical
      implications.
AB  - In the past 3 decades, numerous biological abnormalities linked with deep venous
      thrombosis have been described. Among the different possibilities, it is crucial
      to order tests that can modify the therapeutic attitude towards the patient
      and/or his family. A combined clinical and laboratory approach taking into
      account the history of the patient and his family, the prevalence of the defects,
      and also the accuracy of the tests should allow tailoring a laboratory testing
      program to each patient. It is essential to keep in mind that the more difficult
      task is not to perform the tests but to consider who will benefit from testing
      both for prevention and therapy of venous thromboembolism. This article provides
      answers to some of these issues. These answers should, however, be considered as
      tentative and provisional because new findings and study results will certainly
      modify them in the near future.

PMID- 15199519
TI  - Pregnancy and deep vein thrombosis.
AB  - The diagnosis, treatment, and prevention of deep vein thrombosis (DVT) during
      pregnancy remain problematic. This article reviews the pathophysiology of
      pregnancy-related DVT and suggests diagnostic strategies, highlighting the
      pitfalls specific to this patient population. The treatment of DVT in pregnant
      patients is difficult because unfractionated heparin and low-molecular-weight
      heparins, the cornerstones of initial therapy, may have significant maternal side
      effects and warfarin can cause embryopathy and other adverse fetal effects. As
      well, there are limited data regarding the efficacy of anticoagulant therapy in
      the treatment and prophylaxis of DVT during pregnancy. This article briefly
      reviews the areas of controversy and provides recommendations for the treatment
      of acute DVT and thromboprophylaxis in pregnant patients.

PMID- 15199520
TI  - Upper extremity deep vein thrombosis: risk factors, diagnosis, and management.
AB  - Upper extremity deep vein thrombosis (UEDVT) should no longer be regarded as an
      uncommon and benign disease, as previously reported. It is usually associated
      with risk factors, as central venous lines, malignancy, and coagulation defects;
      however, up to 20% of UEDVTs are apparently spontaneous. The clinical picture is
      characterized by swelling, pain, and functional impairment, albeit UEDVT may be
      completely asymptomatic. Objective testing is mandatory prior to instituting
      anticoagulation because the prevalence of UEDVT is less than 50% in symptomatic
      subjects, and compression ultrasound or color Doppler represents the preferred
      diagnostic methods. Up to 36% of the patients develop pulmonary embolism, which
      may be fatal; postthrombotic sequelae and recurrent thromboembolism are also
      frequent complications. Unfractionated or low-molecular-weight heparin followed
      by oral anticoagulation should be regarded as the treatment of choice;
      thrombolysis and surgery may be indicated in selected cases. Prophylaxis with low
      dose heparin or low-dose warfarin is necessary whenever central venous catheters
      are positioned.

PMID- 15199521
TI  - Venous thromboembolism in pediatrics.
AB  - Venous thromboembolism (VTE) in pediatrics is quickly becoming a well-recognized
      cause of significant morbidity and mortality in children. Most children diagnosed
      with VTE have a serious underlying primary illness such as cancer, chronic total
      parenteral nutrition (TPN) dependency, or congenital heart disease. Infants and
      adolescents are most at risk of developing VTE, and the most significant risk
      factor is the presence of a central venous line (CVL). The incidence of VTE
      varies widely with study design and the diagnostic test used to detect
      thrombosis. Venography remains the gold standard diagnostic test, although
      ultrasound is increasingly used due to its noninvasive nature, despite concern
      regarding the sensitivity in upper system VTE. The treatment of uncomplicated VTE
      in children consists primarily of unfractionated heparin (UFH) initially,
      followed by oral anticoagulation or low molecular weight heparin (LMWH) for 3
      months. LMWH offers many advantages over UFH due to the longer half-life,
      increased bioavailability, and ease of administration and monitoring in children.
      Acute complications of VTE in children are numerous and include pulmonary
      embolism (PE), chylothorax, and superior vena cava syndrome. Long-term morbidity
      includes recurrent VTE, postthrombotic syndrome, repeat general anesthetics for
      CVL placement, and eventual destruction of the upper venous system in children
      with repeat CVL-related VTE. Death from VTE is rare and is primarily due to PE.

PMID- 15199522
TI  - Endovascular local thrombolytic therapy of ileofemoral and inferior caval vein
      thrombosis.
AB  - The intrathrombus delivery of thrombolytic agent to patients with deep vein
      thrombosis extending above the groin was introduced in the early 1990s as an
      alternative to systemic thrombolysis. The technique requires proper positioning
      of an indwelling catheter with its tip into the thrombus. Up to now urokinase as
      well as alteplase have been used in different dosage schemes. Repeated injection
      of contrast fluid monitors progress of treatment. Rapid lysis with restoration of
      patency is achieved in roughly three of four patients treated, usually with
      prompt clinical improvement. Underlying stenotic lesions are frequently relieved
      by insertion of metallic stents. Data on long term patency are still scarce, and
      no comparative trials with conventional anticoagulation are available. Bleeding
      is the most feared complication, and a few serious bleeding incidents have been
      reported. Local thrombolysis appears an interesting but labor-intensive approach
      in expert hands, but a definite place in management of venous thrombosis remains
      to be established.

PMID- 15199523
TI  - Mutations in microcephalin cause aberrant regulation of chromosome condensation.
AB  - Microcephalin (MCPH1) is a gene mutated in primary microcephaly, an autosomal
      recessive neurodevelopmental disorder in which there is a marked reduction in
      brain size. PCC syndrome is a recently described disorder of microcephaly, short
      stature, and misregulated chromosome condensation. Here, we report the finding
      that MCPH1 primary microcephaly and PCC syndrome are allelic disorders, both
      having mutations in the MCPH1 gene. The two conditions share a common cellular
      phenotype of premature chromosome condensation in the early G2 phase of the cell
      cycle, which, therefore, appears to be a useful diagnostic marker for individuals
      with MCPH1 gene mutations. We demonstrate that an siRNA-mediated depletion of
      MCPH1 is sufficient to reproduce this phenotype and also show that MCPH1
      deficient cells exhibit delayed decondensation postmitosis. These findings
      implicate microcephalin as a novel regulator of chromosome condensation and link
      the apparently disparate fields of neurogenesis and chromosome biology. Further
      characterization of MCPH1 is thus likely to lead to fundamental insights into
      both the regulation of chromosome condensation and neurodevelopment.

PMID- 15199524
TI  - Authenticity of ancient-DNA results: a statistical approach.
AB  - Although there have been several papers recommending appropriate experimental
      designs for ancient-DNA studies, there have been few attempts at statistical
      analysis. We assume that we cannot decide whether a result is authentic simply by
      examining the sequence (e.g., when working with humans and domestic animals). We
      use a maximum-likelihood approach to estimate the probability that a positive
      result from a sample is (either partly or entirely) an amplification of DNA that
      was present in the sample before the experiment began. Our method is useful in
      two situations. First, we can decide in advance how many samples will be needed
      to achieve a given level of confidence. For example, to be almost certain (95%
      confidence interval 0.96-1.00, maximum-likelihood estimate 1.00) that a positive
      result comes, at least in part, from DNA present before the experiment began, we
      need to analyze at least five samples and controls, even if all samples and no
      negative controls yield positive results. Second, we can decide how much
      confidence to place in results that have been obtained already, whether or not
      there are positive results from some controls. For example, the risk that at
      least one negative control yields a positive result increases with the size of
      the experiment, but the effects of occasional contamination are less severe in
      large experiments.

PMID- 15199526
TI  - Promising combination therapies with gemcitabine.
AB  - Because treatment regimens for breast cancer commonly include gemcitabine, we
      evaluated two promising combinations in preclinical studies: gemcitabine (Gemzar;
      Eli Lilly and Company, Indianapolis, IN) with either ionizing radiation or
      docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). In breast
      cancer cell lines that expressed either wild-type p53 (MCF-7) or mutant p53 (MCF
      7/Adr), sensitivity to the cytotoxic effects of gemcitabine during a 24-hour
      incubation was similar (IC(50) values 80 and 60 nmol/L in MCF-7 and MCF-7/Adr,
      respectively). Both cell lines were well radiosensitized by gemcitabine at the
      corresponding IC(50), with radiation enhancement ratios of 1.6 to 1.7. Although
      the MCF-7 cells accumulated nearly twice as much gemcitabine triphosphate
      compared with the MCF-7/Adr cells, a similar reduction in 2'-deoxyadenosine 5'
      triphosphate pools was observed. While the number of dying cells, as measured by
      sub-G1 DNA content or S-phase cells unable to replicate DNA, differed between the
      wild-type p53 or mutant p53-expressing cell lines, neither parameter correlated
      with radiosensitization. Docetaxel was a more potent cytotoxic agent than
      gemcitabine in MCF-7 cells (IC(50) = 1 nmol/L). Strong synergistic cytotoxicity
      was observed in cells treated with gemcitabine (24 hours) followed by docetaxel
      (24 hours) or the reverse sequence. However, simultaneous addition of the two
      drugs was antagonistic. To determine whether synergy with radiation or docetaxel
      was mediated by increased DNA damage, DNA double-strand breaks (double-strand
      breaks) were measured by immunostaining for phosphorylated H2AX. Ionizing
      radiation produced more double-strand breaks than gemcitabine alone, while no
      significant double-strand breaks formed with docetaxel alone. The addition of
      docetaxel or ionizing radiation to gemcitabine-treated cells did not increase
      H2AX foci formation. These results show that the combination of gemcitabine with
      ionizing radiation or docetaxel produces strong, schedule-dependent synergy in
      breast cancer cells that is not mediated through increasing DNA double-strand
      breaks.

PMID- 15199527
TI  - Novel association with gemcitabine and docetaxel as salvage chemotherapy in
      metastatic breast cancer previously treated with anthracyclines: results of a
      multicenter phase II study.
AB  - The goals of this study were to evaluate the efficacy and toxicity of the
      gemcitabine/docetaxel combination in metastatic breast cancer previously treated
      with anthracyclines. Fifty-three patients with metastatic breast cancer who had
      failed or relapsed after anthracycline-based chemotherapy entered the study and
      were evaluable. Patients received gemcitabine (1,000 mg/m(2) days 1 and 8) and
      docetaxel (80 mg/m(2) day 8), every 3 weeks. The regimen was generally well
      tolerated with good feasibility. A complete response occurred in six patients
      (9.4%) and partial response in 23 (43.4%) for an overall response rate of 53%
      (95% confidence interval, 38.9% to 66.7%). Median survival rate was 70%; and the
      duration of response, time to progression, and overall survival were 6, 7.5, and
      16.5 months, respectively. We conclude that the gemcitabine/docetaxel combination
      constitutes a manageable and tolerable combination as salvage chemotherapy in
      metastatic breast cancer and may represent a valid treatment option in patients
      previously treated with anthracyclines.

PMID- 15199528
TI  - Gemcitabine plus docetaxel administered every other week as first-line treatment
      of metastatic breast cancer: preliminary results from a phase II trial.
AB  - The purpose of this study was to assess the toxicity and efficacy of gemcitabine
      and docetaxel administered every other week as first-line therapy in metastatic
      breast cancer. Fifty-one patients with histologically confirmed metastatic breast
      cancer were enrolled. Patients received docetaxel 65 mg/m(2) followed by
      gemcitabine 2,500 mg/m(2), both on day 1 of a 14-day cycle, for 10 cycles without
      granulocyte-colony stimulating factor support. Thirty-five patients were
      evaluable for toxicity and 32 for efficacy. Median age was 65 years (range, 37 to
      72 years), and median performance status was 90 (range, 60 to 100). The number of
      disease sites was 2 or > or =3 in 39% and 44% of patients, respectively, with
      visceral involvement in the liver and/or lung in 44% of patients. A total of 45%
      had received prior adjuvant chemotherapy. So far, 267 cycles have been
      administered. Twenty-five percent of the docetaxel and gemcitabine doses were
      reduced or delayed due primarily to neutropenia, giving a median dose intensity
      of 90% of the planned dose for both drugs. Grade 3/4 toxicities were mainly
      hematologic, with neutropenia in 46% of patients (two patients experienced
      neutropenic fever). Other toxicities were asthenia, diarrhea, transaminase
      elevation, and nausea. Overall response rate was 66% (four complete responses, 17
      partial responses), with 22% of patients achieving stable disease. Responses were
      observed in all disease sites, including lung (60%) as well as liver (37.5%). In
      conclusion, preliminary evaluation from our phase II study shows that the
      combination of docetaxel and gemcitabine given every 2 weeks is a tolerable and
      highly active combination in patients with metastatic breast cancer. These data
      compare favorably with those obtained with other docetaxel schedules.

PMID- 15199529
TI  - In vivo synergism between docetaxel and gemcitabine in patients with metastatic
      breast cancer: general concepts and future perspectives.
AB  - The docetaxel and gemcitabine combination is an active regimen as salvage therapy
      in taxane-resistant or taxane-refractory patients with metastatic breast cancer
      (MBC). We recently conducted a phase II study administering this combination to
      patients with MBC after docetaxel failure, with remarkably high response rates
      that could be attributed to an in vivo synergism between the two drugs. Women
      with MBC who were refractory or resistant to docetaxel monotherapy as first- or
      second-line treatment were recruited. Patients with progressive or stable disease
      after receiving a minimum of four cycles of docetaxel received gemcitabine 900
      mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2)on day 8, every 3 weeks. Forty
      six percent of patients responded (three complete responses, 20 partial
      responses), while 28% had stable disease and 26% had progressive disease. Median
      duration of response was 6.07 +/- 2.43 months. Neutropenia was the only grade 4
      toxicity, and reported in seven patients. Other grade 3 toxicities included
      neutropenia (12 patients), thrombocytopenia (seven patients), and anemia (one
      patient), while nonhematologic toxicities were easily manageable. These data
      outline the importance of a rational combination of existing, active
      chemotherapeutic agents for MBC, and broadens our perspectives for more effective
      combination regimens in various solid tumors in the future.

PMID- 15199530
TI  - Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy in stage II and
      III breast cancer patients: preliminary results of a phase II and pharmacogenomic
      study.
AB  - The purpose of this study is to evaluate the efficacy and safety of a biweekly
      neoadjuvant docetaxel/gemcitabine regimen in patients with histologically
      confirmed stage II and III breast cancer. In addition, a cDNA microarray study
      attempted to correlate pretreatment gene-expression profile with clinical and
      pathologic responses. Docetaxel 65 mg/m(2) was given in a 60-minute intravenous
      infusion followed by gemcitabine 2,500 mg/m(2) in a 30-minute intravenous
      infusion every 2 weeks for six cycles; prophylaxis with growth factors was
      allowed. Four cycles of standard AC (doxorubicin 60 mg/m(2) and cyclophosphamide
      600 mg/m(2)every 21 days) was routinely delivered to all patients postsurgery.
      Thirty patients are accrued on-study so far. The overall response rate for 24
      evaluable patients was 79% (95% confidence interval, 9.7 to 53.5) with six
      complete responses and 13 partial responses. One patient (4%) out of 23 achieved
      a pathologic complete response in the breast at the time of definitive surgery.
      Breast conservation procedure was possible in 14 patients (61%). A total of 161
      cycles has been delivered. Grade 1/2 alopecia and a mild grade 1/2 LDH increase
      were the most frequently reported adverse events (78% and 55% of cycles,
      respectively). Grade 3/4 neutropenia was reported in 18 cycles (11%). These
      preliminary results show that biweekly docetaxel and gemcitabine is an optimal
      regimen as neoadjuvant treatment of stage II and III breast cancer. In spite of
      the large tumor size, breast conservation was possible in 61% of the patients. In
      general, toxicity was very manageable.

PMID- 15199531
TI  - Gemcitabine and docetaxel in metastatic and neoadjuvant treatment of breast
      cancer.
AB  - Treatment advances in breast cancer continue to revolve around the development of
      novel agents and combinations, with the major therapeutic goal of these
      investigational treatment strategies revolving around the improvement of response
      rates, delaying the time to disease progression, palliation of symptoms, and
      improving quality of life. Recognized as one of the most active single agents in
      breast cancer, docetaxel has shown remarkable activity in combination with
      gemcitabine. Gemcitabine, a novel S-phase specific cytidine nucleoside analogue
      of deoxycytidine with broad antitumor activity, has evident single-agent activity
      in the treatment of breast cancer. Its novel mechanism of action, in addition to
      its generally favorable toxicity profile and largely nonoverlapping toxicities,
      has facilitated its further development in combination regimens, particularly
      with the taxanes. Several phase I and II trials have reported impressive activity
      for the gemcitabine/docetaxel doublet with the suggestion of clinical synergism
      between these two agents. Additional phase II trials have focused on optimizing
      dosing and schedule schemas with the demonstration of impressive efficacy with
      acceptable toxicity with the biweekly administration. Unmistakably, these trials
      collectively show clear improvements for the gemcitabine/docetaxel doublet over
      that reported for the single-agent activity of the taxanes in metastatic breast
      cancer. These favorable findings have resulted in the further investigation of
      and incorporation of gemcitabine in neoadjuvant treatment strategies. From its
      favorable therapeutic index to substantial efficacy in combination with
      docetaxel, gemcitabine remains a rational and important addition to the treatment
      armamentarium of breast cancer.

PMID- 15199534
TI  - Our responsibility in assisting patients through the Medicare Prescription Drug
      Benefit Program.

PMID- 15199535
TI  - Behavioral and mental health problems in low-income children with special health
      care needs.
AB  - This study examined caregiver perceptions of mental health problems and
      counseling needs in low-income children with special health care needs (CSHCN).
      Interviewers collected data from 257 caregivers of CSHCN (61% males; 60% African
      American; Mean age = 8.4 years) attending six Midwestern inner-city health
      clinics. Measures included the Child Behavior Checklist (CBCL) and an
      investigator-designed questionnaire. CBCL T-scores indicated that 38% of CSHCN
      had a behavioral or mental health problem, but only 26% of caregivers perceived
      the need for treatment or counseling. CSHCN should be assessed and referred
      appropriately for behavioral and mental health problems during routine health
      care visits.

PMID- 15199536
TI  - Experience of stigmatization by relatives of patients with obsessive compulsive
      disorder.
AB  - Patients with mental illness and their relatives experience discrimination and
      stigmatization in their everyday lives. The stigma of mental illness has been
      investigated in numerous studies. However, the subjective experiences of patients
      with OCD and their relatives have not been reported up until now. Narrative
      interviews with 22 family members of patients with obsessive-compulsive disorder
      were performed as part of a study on the burden and distress among the families
      of those with mental illness. Stigma experiences were analyzed using a grounded
      theory approach. Different areas of life could be described, where stigmatization
      is anticipated or concretely experienced by relatives of patients with OCD.
      Concealing is an important coping strategy for the family members interviewed.
      Stigmatization can be reduced by handling the illness and the co-operation of
      patients, their relatives, and the professionals in an unbiased manner.

PMID- 15199537
TI  - Psychological factors in chronic pain: a worthwhile undertaking for nursing?
AB  - Chronic pain is one of the clearest examples of the complex relationship between
      the mind, body, spirit, and environment. After decades of research, a growing
      body of evidence supports the importance of certain psychological factors in the
      chronic pain experience. This article reviews research related to evaluating the
      role of depression, personality factors, pain-related beliefs, trauma, and coping
      style in the chronic pain experience. Understanding and using the findings of
      this research can improve nursing care of persons with chronic pain.

PMID- 15199539
TI  - Don't blame the editor!

PMID- 15199538
TI  - Ethics and care: an ethnographic study of psychiatric community health nursing
      practice.
AB  - The purpose of this ethnographic study was to explore, describe, and document the
      practice of a group of psychiatric community health nurses (CHNs), and to provide
      a forum through which their voices could be heard. Discovery of the nature of
      issues CHNs experience in an effort to meet the needs of patients with mental
      illness was the focus. The paper describes the ethical conflict experienced by
      many of these nurses who wanted to provide beneficial, high-quality care to
      patients with mental illness but encountered obstacles in practice. Insight into
      the difficulties nurses experience in applying an ethic of care in the context of
      administrative constraints, resulting from the strict regulatory mechanisms
      imposed by third party insurance payers is provided. The negative impact of
      increasingly stricter payment restrictions on nursing practice and on quality of
      care is exposed.

PMID- 15199542
TI  - Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload
      disease.
AB  - Nitric oxide (NO(.)), which is generated under chronic inflammatory conditions
      that predispose individuals to cancer, has paradoxical effects. NO(.) can
      activate p53, which can result in anti-carcinogenic effects, or it can be
      mutagenic and increase cancer risk. We explored the mechanisms by which NO(.)
      induced p53 activation in vitro and found that NO(.) induced p53 accumulation and
      phosphorylation, particularly at ser-15, via ATM and ATR kinases, which then led
      to cell cycle arrest at G(2)/M. We next examined proteins in these pathways in
      both inflamed and normal human colon tissue. Inducible nitric oxide synthase
      (iNOS) levels and p53-P-ser15 levels were positively correlated with the degree
      of inflammation and with each other. Additionally, the p53 targets, HDM-2 and p21
      (WAF1), were present in ulcerative colitis (UC) colon, but undetectable in normal
      colon, consistent with activated p53. We also found higher p53 mutant frequencies
      of both G:C --> A:T transitions at the CpG site of codon 248 and C:G --> T:A
      transitions at codon 247 in lesional colon tissue from UC cases versus
      nonlesional tissue from these cases or colon tissue from normal adult controls.
      Consistent with nitrosative stress and the deamination of 5-methylcytosine, p53
      mutations were also detected in sporadic colon cancer tissue and were associated
      with iNOS activity in these tissues. These studies identified a potential
      mechanistic link between NO(.) and p53 in UC and sporadic colon cancer.

PMID- 15199543
TI  - Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal
      studies.
AB  - Folate, a water-soluble B vitamin and cofactor in one-carbon transfer, is an
      important nutritional factor that may modulate the development of colorectal
      cancer (CRC). Epidemiologic and clinical studies indicate that dietary folate
      intake and blood folate levels are inversely associated with CRC risk.
      Collectively, these studies suggest an approximately 40% reduction in the risk of
      CRC in individuals with the highest dietary folate intake compared with those
      with the lowest intake. Animal studies using chemical and genetically predisposed
      rodent models have provided considerable support for a causal relationship
      between folate depletion and colorectal carcinogenesis as well as a dose
      dependent protective effect of folate supplementation. However, animal studies
      also have shown that the dose and timing of folate intervention are critical in
      providing safe and effective chemoprevention; exceptionally high supplemental
      folate levels and folate intervention after microscopic neoplastic foci are
      established in the colorectal mucosa promote, rather than suppress, colorectal
      carcinogenesis. These animal studies, in conjunction with clinical observations,
      suggest that folate possesses dual modulatory effects on carcinogenesis depending
      on the timing and dose of folate intervention. Folate deficiency has an
      inhibitory effect, whereas folate supplementation has a promoting effect on the
      progression of established neoplasms. In contrast, folate deficiency in normal
      epithelial tissues appears to predispose them to neoplastic transformation, and
      modest levels of folate supplementation suppress the development of tumors in
      normal tissues. Notwithstanding the limitations associated with animal models,
      these studies suggest that the optimal timing and dose of folate intervention
      must be established for safe and effective chemoprevention in humans. Folate is
      an important factor in DNA synthesis, stability, and integrity, the repair
      aberrations of which have been implicated in colorectal carcinogenesis. Folate
      may also modulate DNA methylation, which is an important epigenetic determinant
      in gene expression (an inverse relationship), in the maintenance of DNA integrity
      and stability, in chromosomal modifications, and in the development of mutations.
      A mechanistic understanding of how folate status modulates colorectal
      carcinogenesis further strengthens the case for a causal relationship and
      provides insight into a possible chemopreventive role of folate.

PMID- 15199544
TI  - Studies with the azoxymethane-rat preclinical model for assessing colon tumor
      development and chemoprevention.
AB  - During recent years, multidisciplinary studies in epidemiology and molecular
      biology have contributed to our understanding of the etiology of colorectal
      cancer; more importantly they have enabled us to approach its prevention. An
      impressive body of epidemiological data suggests an inverse relationship between
      colorectal cancer risk and consumption of diets rich in omega (omega)-3 fatty
      acids (n-3 PUFAs) or the regular use of nonsteroidal antiinflammatory drugs
      (NSAIDs), including aspirin. The development of strategies for the
      chemoprevention of colorectal cancer have been facilitated by the use of relevant
      animal models mimicking the neoplastic processes that occur in humans, including
      similarities in histopathology and molecular and genetic lesions during both the
      early and promotion/progression stages of carcinogenesis. Studies with the
      azoxymethane-F344 rat model indicate that diets rich in n-3 PUFAs, NSAIDs,
      selective cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS)
      inhibitors, and curcumin can reduce the incidence of colon cancer. Advances in
      the knowledge of the mechanisms by which chemopreventive agents act offer
      opportunities to use combinations of specific chemopreventive agents, having
      clinically beneficial aggregate activity with minimal toxicity. This approach is
      extremely important when a promising chemopreventive agent demonstrates apparent
      efficacy but may produce toxic effects at high doses. Our studies show that a
      combination of very low doses of piroxicam (NSAID) and difluoromethylornithine, a
      specific inhibitor of ornithine decarboxylase, or very low doses of COX-2 and HMG
      CoA reductase inhibitors are more effective in inhibiting colon carcinogenesis
      than administration of these compounds as single agents even at higher levels.
      The natural history of colorectal cancer, from dysplastic aberrant crypts to
      adenomas and adenocarcinomas, offers multiple opportunities for assessment and
      intervention. Of further importance is to identify whether the molecular targets
      that are critical in the growth and survival of the malignant colorectal cell are
      modulated by n-3 PUFAs, NSAIDs, or COX-2 and iNOS inhibitors.

PMID- 15199546
TI  - Meat-related mutagens/carcinogens in the etiology of colorectal cancer.
AB  - Diets containing substantial amounts of red or preserved meats may increase the
      risk of various cancers, including colorectal cancer. This association may be due
      to a combination of factors such as the content of fat, protein, iron, and/or
      meat preparation (e.g., cooking or preserving methods). Red meat may be
      associated with colorectal cancer by contributing to N-nitroso compound (NOC)
      exposure. Humans can be exposed to NOCs by exogenous routes (from processed meats
      in particular) and by endogenous routes. Endogenous exposure to NOCs is dose
      dependently related to the amount of red meat in the diet. Laboratory results
      have shown that meats cooked at high temperatures contain other potential
      mutagens in the form of heterocyclic amines (HCAs) and polycyclic aromatic
      hydrocarbons (PAHs). To investigate the role of these compounds, we have created
      separate databases for HCAs and PAHs, which we have used in conjunction with a
      validated meat-cooking food frequency questionnaire. The role of meat type,
      cooking methods, doneness levels, and meat-cooking mutagens has been examined in
      both case-control studies and prospective cohort studies, with mixed results.
      Here, we review the current epidemiologic knowledge of meat-related mutagens, and
      evaluate the types of studies that may be required in the future to clarify the
      association between meat consumption and colorectal cancer.

PMID- 15199545
TI  - Epigenetic events and protection from colon cancer in New Zealand.
AB  - The incidence of colon cancer is high in many developed nations, especially New
      Zealand. Molecular understanding of the nature of colon cancer shows a disease
      whose well-characterized morphological progression is paralleled at the cellular
      level by increased numbers of gene or chromosome mutations, loss of
      heterozygosity, changed methylation patterns, and genomic instability. In the
      present study, we consider whether an imbalance of factors that affect DNA
      methylation patterns might explain at least part of the high colon cancer
      incidence in New Zealand. Folate is the major micronutrient whose intake impacts
      methylation, particularly through interaction with choline and methionine. Folate
      is generally somewhat deficient in the New Zealand diet, with the voluntary
      addition of folate to white flour not producing desired levels. Selenium affects
      methylation status in several ways and is recognized as being low in New Zealand
      soils and, therefore, diet. Zinc is also low in the diets of some New Zealand
      population groups, which can lead to hypomethylation. Several of the components
      of fruits and vegetables affect methylation patterns, and the average New Zealand
      intake, at two to three servings per day, is considerably below recommended
      amounts. Low dietary fiber, high tobacco use, and increasing rates of obesity are
      also likely New Zealand risk factors that may impact on methylation status.
      Dietary supplementation is not as common in New Zealand as in countries such as
      the United States, but may provide a way to raise the levels of nutrients and
      phytochemicals affecting methylation status, thereby enhancing colon cancer
      protection.

PMID- 15199547
TI  - Genotoxicity of field-collected inter-tidal sediments from Cork Harbor, Ireland,
      to juvenile turbot (Scophthalmus maximus L.) as measured by the Comet assay.
AB  - The alkaline single cell gel electrophoresis (SCGE) or Comet assay was employed
      to test the potential of surficial sediment collected from Cork Harbor, Ireland,
      to induce DNA damage in turbot (Scophthalmus maximus L.) in a laboratory exposure
      experiment. Turbot were exposed for 21 days to field-collected sediment from Cork
      Harbor and from a relatively clean reference site at Ballymacoda and sampled at
      0, 7, 14, and 21 days. As a positive control for the sediment exposure
      experiment, a subsample of the turbot was exposed to cadmium chloride-spiked
      seawater. DNA damage analysis was performed on epidermal, gill, spleen, liver,
      and whole blood cell preparations. Liver, gill, and blood were the most sensitive
      tissues while a lower level of damage was detected in the epidermis and spleen.
      The blood was determined to be a suitable predictor of DNA damage in the whole
      organism. Chemical analysis of the sediment indicated that polycyclic aromatic
      hydrocarbons formed the bulk of the contaminants, with the harbor sites having
      almost double the levels of those from the reference site. The data indicated
      that turbot exposed to sediments from Cork Harbor elicited a significant increase
      in DNA damage in comparison with those exposed to sediment from the reference
      site and that exposure to the contaminated sediments caused a multi-organ
      genotoxic response. Results from the study indicate a relationship between the
      presence of genotoxicants in sediment and DNA damage. This finding was
      encouraging with regard to the potential use of the Comet assay as part of a
      marine biomonitoring strategy.

PMID- 15199548
TI  - Effect of XPD/ERCC2 polymorphisms on chromosome aberration frequencies in smokers
      and on sensitivity to the mutagenic tobacco-specific nitrosamine NNK.
AB  - Polymorphisms in DNA-repair genes could contribute to the interindividual
      differences in cancer susceptibility in smokers. By reducing DNA-repair capacity,
      these polymorphisms may influence the net level of smoking-induced genetic damage
      significantly, a critical step in the cascade of events leading to cancer. In
      this biomonitoring study, we examined the relationship between polymorphisms in
      the DNA-repair gene XPD/ERCC2 and genetic damage. We tested the hypothesis that
      coding polymorphisms in XPD/ERCC2 limit DNA-repair efficiency in humans leading
      to increased frequencies of chromosome aberration (CA) in their lymphocytes. We
      also used the mutagen-sensitivity assay, with the tobacco-specific nitrosamine
      NNK as a model mutagen, to determine whether lymphocytes from individuals with
      the variant XPD alleles are more sensitive to this tobacco-specific carcinogen.
      We calculated odds ratios (ORs) as estimates of relative risk of increased
      frequencies of CA associated with two XPD polymorphisms (Asp312Asn in exon 10 and
      Lys751Gln in exon 23). We observed a 2.57-fold (95% confidence limit [CL] = 0.88
      7.50; P = 0.10) increase in risk of elevated in vivo frequencies of CA associated
      with the variant 312Asn allele in the total population. The relative risk was
      more pronounced in smokers (OR = 4.67; 95% CL = 1.04-20.90; P = 0.04) and in all
      subjects >48 years old (OR = 7.33; 95% CL = 1.53-35.10; P = 0.01). Similarly,
      elevations in NNK-induced aberrations were significantly associated with the
      312Asn allele (OR = 3.69; 95% CL = 1.29-10.56; P = 0.02). The risk was higher in
      smokers (OR = 4.62; 95% CL = 1.14-18.70; P = 0.04) and in subjects >48 years old
      (OR = 5.76; 95% CL = 1.30-25.41; P = 0.03). No significant effect was observed
      with the 715Gln variant allele in relation to either in vivo or NNK-induced CA.
      These data suggest that the Asp312Asn polymorphism may alter the phenotype of the
      XPD protein, resulting in reduced DNA-repair capacity.

PMID- 15199549
TI  - Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer.
AB  - We have previously investigated the role of polymorphic chemical metabolizing
      genes in the susceptibility to the development of lung cancer using 110 primary
      lung cancer patients and 119 matched smoker controls. Together with data from the
      present study on DNA repair genes, we did not observe significant associations
      between any single variant genotype for several DNA-repair and chemical
      metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or
      EPHX1]) and lung cancer. In the present study, we have further evaluated a nested
      group of 79 patients and 69 matched controls, and observed that increased
      chromosome aberrations (CAs) were associated with variant DNA-repair genotypes
      among both the patient and the control groups, with a significant increase for
      individuals having the XPD Lys/Gln + Gln/Gln genotypes (P = 0.046). Patients
      often had significantly increased CAs compared with controls with the same DNA
      repair genotype and with similar cigarette smoking habits (< or =40 pack-years or
      >40 pack-years). Analyses of interactions between the DNA-repair and chemical
      metabolizing genes indicated that the most significant interactions were between
      the repair genotypes and the GSTM1/T1 null genotypes. Significant increases in CA
      from the interactions were often observed among patients with < or =40 pack
      years, but not among those with >40 pack-years. Since some variant DNA-repair
      genotypes have functional deficits for DNA repair, the association between
      variant DNA-repair genotypes and increased CAs suggests a risk mechanism for the
      development of lung cancer, with the DNA-repair genotypes interacting with
      variant chemical metabolizing genotypes to further increase the risk. The
      observation that patients had significantly increased CA frequencies compared
      with controls, irrespective of genotype, suggests that patients have additional
      factors that contribute to the development of lung cancer.

PMID- 15199556
TI  - Hybrid inorganic-organic mesoporous materials.

PMID- 15199550
TI  - Relative sensitivity of fish and mammalian cells to sodium arsenate and arsenite
      as determined by alkaline single-cell gel electrophoresis and cytokinesis-block
      micronucleus assay.
AB  - To protect human and ecosystem health, it is necessary to develop sensitive
      assays and to identify responsive cells and species (and their life stages). In
      this study, the relative genotoxicity of two inorganic arsenicals: trivalent
      sodium arsenite (As(3+)) and pentavalent sodium arsenate (As(5+)), was evaluated
      in two cell lines of phylogenetically different origin, using alkaline single
      cell gel electrophoresis (i.e., the Comet assay) and the cytokinesis-block
      micronucleus (MN) assay. The cell lines were the rainbow trout gonad-2 (RTG-2)
      and Chinese hamster ovary-K1 (CHO-K1) lines. Following optimization and
      validation of both assays using reference chemicals (i.e., 1-100 microM hydrogen
      peroxide for the Comet assay and 1-10 mM ethylmethane sulfonate for the MN
      assay), cells were exposed to 1-10 microM of both arsenicals to determine the
      relative extent of genetic damage. The unexposed controls showed similar
      (background) levels of damage in both cell lines and for both assays. Treatment
      with the arsenicals induced concentration-dependent increases in genetic damage
      in the two cell lines. Arsenite was more potent than arsenate in inducing DNA
      strand breaks in the Comet assay; at the highest concentration (10 microM)
      arsenite produced similar levels of DNA damage in CHO-K1 and RTG-2 cells, while
      10 microM arsenate was significantly more genotoxic in RTG-2 cells. MN induction
      was consistently higher in RTG-2 cells than in CHO-K1 cells, with 10 microM
      arsenite inducing an approximate 10-fold increase in both cell lines. MN
      induction also was positively correlated with DNA strand breaks for both
      arsenicals. Overall, the study demonstrated that the fish cells are more
      sensitive than the mammalian cells at environmentally realistic concentrations of
      both arsenicals, with arsenite being more toxic.

PMID- 15199558
TI  - A synthetic antithrombin III binding pentasaccharide is now a drug! What comes
      next?
AB  - Heparin is a sulfated glycosaminoglycan isolated from animal organs that has been
      used clinically as an antithrombotic agent since the 1940s. In the early 1980s it
      was discovered that a unique pentasaccharide domain in some heparin chains
      activates antithrombin III (AT-III), a serine protease inhibitor that blocks
      thrombin and factor Xa in the coagulation cascade. Sanofi-Synthelabo and Organon
      developed a synthetic analogue of this pentasaccharide. The resulting
      antithrombotic drug arixtra, which went on the market in the USA and Europe in
      2002, shows superior antithrombotic activity and brings about AT-III-mediated
      activity against factor Xa exclusively. Structure-based design has subsequently
      led to analogues with longer-lasting activity, such as idraparinux, as well as
      novel conjugates and long oligosaccharides with specific anti-Xa and antithrombin
      activities. The new drug candidates are more selective in their mode of action
      than heparin and less likely to induce thrombocytopenia.

PMID- 15199557
TI  - The Staudinger ligation-a gift to chemical biology.
AB  - Although the reaction between an azide and a phosphane to form an aza-ylide was
      discovered by Hermann Staudinger more than 80 years ago and has found widespread
      application in organic synthesis, its potential as a highly chemoselective
      ligation method for the preparation of bioconjugates has been recognized only
      recently. As the two reaction partners are bioorthogonal to almost all
      functionalities that exist in biological systems and react at room temperature in
      an aqueous environment, the Staudinger ligation has even found application in the
      complex environment of living cells. Herein we describe the current state of
      knowledge on this reaction and its application both for the preparation of
      bioconjugates and as a ligation method in chemical biology.

PMID- 15199559
TI  - Thermally and light-induced valence tautomeric transition in a dinuclear cobalt
      tetraoxolene complex.

PMID- 15199560
TI  - Profiling primary protease specificity by peptide synthesis on a solid support.

PMID- 15199561
TI  - A trinuclear [NiFe] cluster exhibiting structural and functional key features of
      [NiFe] hydrogenases.

PMID- 15199562
TI  - Use of dynamic combinatorial chemistry for the identification of covalently
      appended residues that stabilize oligonucleotide complexes.

PMID- 15199563
TI  - The binary group 4 azides [Ti(N(3))(4)], [P(C(6)H(5))(4)][Ti(N(3))(5)], and
      [P(C(6)H(5))(4)](2)[Ti(N(3))(6)] and on linear Ti--N--NN coordination.

PMID- 15199564
TI  - Direct observation of intramolecular hydrogen bonds in peptide 3(10) helices by
      (3h)J(N,C') scalar couplings.

PMID- 15199565
TI  - Cationic and neutral four-coordinate alkylidene complexes of vanadium(IV)
      containing short V=C bonds.

PMID- 15199566
TI  - Small-interfering-RNA expression in cells based on an efficiently constructed
      dumbbell-shaped DNA.

PMID- 15199567
TI  - Macrocyclic sugar-based surfactants: block molecules combining self-aggregation
      and complexation properties.

PMID- 15199568
TI  - Concise total synthesis and structure assignment of TAN-1085.

PMID- 15199569
TI  - Visualization of local valence structures in quasi-one-dimensional halogen
      bridged complexes [Ni(1-x)Pd(x)(chxn)(2)Br]Br(2) by STM.

PMID- 15199570
TI  - Highly efficient total synthesis of (+)-citreoviral.

PMID- 15199572
TI  - An oxygen-centered titanium square embedded in a cuboctahedron of iodine in the
      salt K(4)[[TI(4)O]I(12)].

PMID- 15199571
TI  - Monitoring molecular recognition of the ribosomal decoding site.

PMID- 15199573
TI  - Al(50)C(120)H(180): a pseudofullerene shell of 60 carbon atoms and 60 methyl
      groups protecting a cluster core of 50 aluminum atoms.

PMID- 15199574
TI  - The polyhedral gallium subhalide [Ga(24)Br(22)].10 THF: the first step on the
      path to a new modification of gallium?

PMID- 15199575
TI  - Micelle formation from amphiphilic "cylindrical brush"--coil block copolymers
      prepared by metallocene catalysis.

PMID- 15199576
TI  - Asymmetric solid-phase synthesis of 6,6-spiroketals.

PMID- 15199578
TI  - In vitro tobramycin elution analysis from a novel beta-tricalcium phosphate
      silicate-xerogel biodegradable drug-delivery system.
AB  - This in vitro research analyzed local tobramycin elution characteristics from a
      novel, biodegradable drug delivery system, consisting of a beta-TCP bone
      substitute, VITOSS trade mark, encapsulated with silicate xerogel prepared by the
      sol-gel process. Tobramycin elution from silicate-xerogel-encapsulated VITOSS was
      compared directly with non-silicate-xerogel-encapsulated VITOSS to assess whether
      xerogels are effective in delivering greater tobramycin quantities in a
      controllable, sustained manner crucial for microbial inhibition. Tobramycin
      elution characteristics indicate an initial release maximum during the first 24 h
      that diminishes gradually several days after impregnation. The copious tobramycin
      quantity eluted from the VITOSS/silicate-xerogel systems is attributed to various
      factors: the intrinsic ultraporosity and hydrophilicity of VITOSS, the ability of
      tobramycin to completely dissolve in aqueous media, tobramycin complexation with
      highly polar SO(4) (2-) salts that further assist dissolution, and ionic
      exchanges between VITOSS and the environment. Silicate-xerogel-encapsulated
      VITOSS eluted 60.65 and 61.31% of impregnated tobramycin, whereas non-silicate
      xerogel-encapsulated VITOSS eluted approximately one-third less impregnated
      tobramycin, at 21.53 and 23.60%. These results suggest that silicate xerogel
      optimizes tobramycin elution because of its apparent biodegradability. This
      mechanism occurs through xerogel superficial acidic sites undergoing exchanges
      with various ions present in the leaching buffer. Tobramycin elution kinetics
      were evaluated, and demonstrate that first-order elution rate constants are
      considerably less when silicate xerogels are employed, following a more uniform
      exponential decay-type mechanism, thus bolstering controlled release. Overall,
      tobramycin elution rates adhere to linear-type Higuchi release profiles. Elution
      rate constants are initially first order, and taper into zero-order elution
      kinetics in the latter stages of release. Because VITOSS and silicate xerogel are
      completely biodegradable, essentially all impregnated tobramycin will be
      delivered to the surgical site after implantation.

PMID- 15199579
TI  - Donor age and gender effects on osteoinductivity of demineralized bone matrix.
AB  - Allogeneic demineralized bone matrix (DBM) has been used extensively as a
      clinical graft material because of its inherent osteoinductive and
      osteoconductive properties. There is continued debate over the acceptable age
      range of donors for bone and whether the effectiveness of the tissue as a graft
      is influenced by gender. Contradictory evidence has been obtained with DBM
      prepared from both animals and humans. The goal of the present investigation was
      to evaluate the effect of donor age and gender on the osteoinductivity of DBM
      prepared from human donors [male (133) and female (115) donors grouped in 10-year
      age brackets up to 85 years] with a statistically relevant sample size using the
      athymic rat ectopic bone formation model. Among males, there was a statistically
      significant linear association between age and osteoinductivity value (p <.001),
      but not among females (p =.20). The rate of change among males was 0.009 units
      per year. The biological relevance of such a small change in osteoinductivity is
      likely to be negligible, as the total variation explained by the regressions was
      only 8.2%. A two-way ANOVA as related to donor age (only donors < 76 years of
      age) and gender yielded no significant statistical association of
      osteoinductivity with age group, gender, and their interaction. The results
      confirm that properly processed demineralized bone from donors through at least
      85 years of age is a viable grafting material.

PMID- 15199580
TI  - The effects of curing history on residual stresses in bone cement during hip
      arthroplasty.
AB  - During cement curing in total hip arthroplasty, residual stresses are introduced
      in the cement mantle as a result of curing shrinkage, thermal shrinkage, and
      geometrical constraints. These high residual stresses are capable of initiating
      cracks in the mantle of cemented hip replacements. The purpose of this study was
      to determine the residual stresses in the cemented hip replacements. The finite
      element method was developed to predict the residual stresses built up in joint
      arthroplasties. Experimental tests were then performed to validate the numerical
      methodology. Then the effects of curing history on the residual stress
      distribution were investigated with finite element simulations. Results showed
      that the predictions of the thermal shrinkage residual stresses by the developed
      method agreed with the experimental tests very well. The residual stress buildup
      was shown to depend on the curing history. By preheating the prosthesis stem
      prior to implantation, a desired low-level residual stress at the critical
      prosthesis-cement interface was obtained. As a result, this article provides a
      numerical tool for the quantitative simulation of residual stress and for
      examining and refining new designs computationally.

PMID- 15199582
TI  - Effects of laser-modified polystyrene substrate on CHO cell growth and alignment.
AB  - Biomaterial surface chemistry and nanoscale topography of biomaterials can
      significantly influence cell behavior in vitro. Polystyrene (PS) Petri dishes
      were subjected to Nd:YAG laser irradiation at 266 nm, which resulted in well
      defined three-dimensional (3D) periodic nanoscale surface topographies and
      surface oxidation. The surface changes were analyzed by X-ray photoelectron
      spectroscopy (XPS), atomic force microscopy (AFM), and a contact-angle
      goniometer. The samples were then used to investigate the cell behavior of
      Chinese hamster ovary (CHO) cells. The surface laser modification affected the
      CHO cell adhesion and alignment, and caused morphological changes in comparison
      with unmodified PS. The results obtained from the cell-behavior studies revealed
      that nanoscale hydrophilic surface topography cues affected the adhesion,
      extension, alignment, and morphology of cells.

PMID- 15199581
TI  - Effect of heat pressing on the mechanical properties of a mica-based glass
      ceramic.
AB  - Previous work has shown that heat pressing of mica-based glass-ceramics can lead
      to crystal alignment along the direction of pressing. The purpose of this study
      was to evaluate the effect of heat pressing on the fracture toughness of mica
      based glass-ceramics. Glass rods (12 x 60 mm) were prepared by melting the glass
      composition at 1400 degrees C for 2 h. Ingots (12 x 12 mm; n = 5) and discs (12 x
      1.5 mm; n = 10) were cut from the rods. The discs were heat treated to simulate
      heat pressing and served as controls. A machinable mica-based glass- ceramic
      (Dicor MGC) also served as control. Bar-shaped wax patterns (2 x 4 x 22 mm) were
      invested and heat pressed at 875 degrees C. The elastic constants were determined
      with the use of the pulsed ultrasonic velocity method. The fracture toughness was
      measured by the indentation strength technique. The degree of texture was
      assessed qualitatively by X-ray diffraction and quantitatively on digital SEM
      micrographs. The results showed that the mean fracture toughness of the heat
      pressed specimens (1.96 +/- 0.19 MPa. m(0.5)) was significantly higher than that
      of the heat-treated controls (1.51 +/- 0.21 MPa. m(0.5)) or the proprietary mica
      glass-ceramic (Dicor MGC; 1.66 +/- 0.04 MPa. m(0.5)) (p <.001). It was concluded
      that heat pressing led to a significant increase in fracture toughness in mica
      glass-ceramics because of crystal alignment along the direction of pressing.

PMID- 15199583
TI  - Self-reinforced polylactide/polyglycolide 80/20 screws take more than 1(1/2)
      years to resorb in rabbit cranial bone.
AB  - The aim of this study was to assess tissue reactions to bioabsorbable self
      reinforced polylactide/polyglycolide (SR-PLGA) 80/20 miniscrews in rabbit cranial
      bone. One PLGA screw was implanted on one side and one titanium screw on the
      other side of the sagittal suture (n = 21). Three animals were sacrificed after
      2, 4, 8, 16, 24, 54, and 72 weeks. In histological examination the numbers of
      macrophages, giant cells, active osteoblasts, and fibrous tissue layers were
      assessed and degradation of the bioabsorbable screws was evaluated. After 2
      weeks, macrophages were seen near the heads of both screws. After 4 and 8 weeks,
      the bioabsorbable screws were surrounded by fibrous tissue. Osteoblastic activity
      and groups of several giant cells were seen. After 24 weeks, a significant change
      in the morphology of the PLGA screws had occurred. Osteoblastic activity and the
      amount of giant cells had decreased. After 1 year, some PLGA biomaterial was
      still present. PLGA screws had been replaced by adipose tissue, fibrous tissue,
      and "foamy macrophages" that had PLGA particles inside them. After 1(1/2) years,
      the amount of biomaterial remaining had decreased remarkably. The particles of
      biomaterial were inside foamy macrophages. SR-PLGA 80/20 screws are biocompatible
      and have no clinically manifested complications when used in the cranial bone of
      rabbits. No contraindications as regards their clinical use in craniofacial
      surgery was found when these screws were studied in the cranial bones of rabbits.

PMID- 15199584
TI  - Micromechanical analysis of dentin/adhesive interface by the finite element
      method.
AB  - The interfacial microstructure and spatial distribution of the modulus of
      elasticity have a profound effect on load transfer at the dentin/adhesive (d/a)
      interface. The microstructure is influenced by the varying degree of
      demineralization of intertubular and peritubular dentin during etching as well as
      the depth of adhesive penetration into the hybrid layer. These factors lead not
      only to a unique microstructure in the vicinity of the dentinal tubules, but also
      to a mechanically graded hybrid layer. This article investigates the
      micromechanical stress distribution at a d/a interface with the use of finite
      element analysis (FEA). Such analysis is now feasible given the newly measured
      moduli of elasticity at micro- and nanoscales. The results indicate that the
      morphological and micromechanical properties of the d/a interface affects the
      stress field such that the fracture/failure is likely to initiate in the stress
      concentration zone of peritubular dentin next to the hybrid/exposed-collagen
      layer. The results suggest that devising a full-depth high modulus hybrid layer
      may considerably reduce the stress concentration zone and the magnitude of stress
      concentration in the peritubular dentin next to the hybrid/exposed-collagen
      layer.

PMID- 15199585
TI  - Color changes of dental resin composites by a salivary enzyme.
AB  - The objective of this study was to evaluate the color change (DeltaE(ab) (*)) of
      dental resin composites immersed in a salivary enzyme of esterase (ETE, porcine
      liver esterase, 400 mU/ml) compared to those immersed in phosphate-buffered
      saline (PBS). The colors of three brands of resin composites of 13 shades were
      measured after polymerization and polishing with 1500-grit SiC paper and after
      immersion in PBS or ETE up to 9 weeks. Color was measured according to the CIELAB
      color scale. DeltaE(ab) (*)after immersion was calculated by the equation
      DeltaE(ab) (*) = [(DeltaL(*))(2) + (Deltaa(*))(2) + (Deltab(*))(2)](1/2). Surface
      roughness (Ra) and Vickers hardness number (VHN) were measured. DeltaE(ab)
      (*)values after immersion in ETE was not higher than those in PBS. Immersion in
      solutions more than 3 weeks resulted in perceivable color changes (DeltaE(ab) (*)
      > 3.3) in one material, and immersion in solutions up to 9 weeks resulted in not
      perceivable color changes in the other materials. Discoloration generally
      increased as the immersion period increased. For one composite, the value
      increased abruptly in the period of 3 days to 3 weeks of immersion. The change in
      Ra value after immersion was varied by the composite and shade. VHN decreased
      significantly after immersion in ETE for nine weeks. Immersion in PBS resulted in
      decreased VHN in two composites.

PMID- 15199586
TI  - Design of braided composite cardiovascular catheters based on required axial,
      flexural, and torsional rigidities.
AB  - Cardiovascular catheterization is a common medical procedure. A single braided
      catheter with different rigidities at the proximal and distal ends can, if
      properly designed, provide the necessary control and flexibility and thus replace
      the current two-piece (external catheter/internal guidewire) system. An
      analytical model based on classical laminate plate theory was developed in order
      to predict the elastic properties of angle-plied, single-overlap two-dimensional
      fiber composite tubular braids, which are required for the determination of the
      axial, flexural, and torsional rigidities. In this work the analytical model has
      been used to design one-piece cardiovascular catheters with axial, flexural, and
      torsional rigidities similar to those values for existing two-piece catheters,
      thus validating the model as a tool for designing braided cardiovascular
      catheters.

PMID- 15199587
TI  - A new resin matrix for dental composite having low volumetric shrinkage.
AB  - The applications of dental restorative composite resins containing 2,2 bis [4-(2
      hydroxy-3-methacryloyloxy propoxy) phenyl] propane (Bis-GMA), as a base resin,
      and triethylene glycol dimethacrylate (TEGDMA), as a diluent, are often limited
      in dentistry due to the relatively large amount of volumetric shrinkage that
      occurs during the curing reaction. In this study, various new resin matrices were
      examined for use as dental composites in order to reduce the amount of volumetric
      shrinkage that occurs in dental composites as a result of curing. Bis-GMA
      derivatives were synthesized by substituting methyl groups for hydrogen on the
      phenyl ring. The derivatives of TEGDMA with different chain lengths or reactive
      groups were also examined. The molecular structural changes in the TEGDMA
      derivatives were not effective in reducing the level of volumetric shrinkage. The
      resin matrix containing a Bis-GMA derivative and TEGDMA showed a reduced amount
      of volumetric shrinkage in proportion to the number of methyl groups on the
      phenyl rings. Polymerization with a mixture of Bis-GMA, its derivatives and a
      diluent is a promising strategy for obtaining a polymer with a low amount of
      volumetric shrinkage. A comparison of the volumetric shrinkage of dental
      composites containing Bis-GMA, TMBis-GMA (2,2-bis[3,5-dimethyl, 4-(2-hydroxy-3
      methacryloyloxy propoxy) phenyl] propane)), and TEGDMA with that prepared from a
      Bis-GMA and TEGDMA mixture showed that the volumetric shrinkage reduction in the
      new resin was approximately 50%. Furthermore, the mechanical strength of the
      former was higher than that of the latter.

PMID- 15199588
TI  - Poly(phosphoester) ionomers as tissue-engineering scaffolds.
AB  - Regenerative medicine requires scaffolds of divergent physicochemical properties
      for different tissue-engineering applications. To this end, a series of
      biodegradable poly(phosphoester) ionomers of the general composition [p(BHET-EOP
      HOP/TC)] was synthesized, with BHET(bis-hydroxyl ethylene phosphate):EOP(ethylene
      phosphate):HOP(free phosphate) ratios of 60:20:20, 70:10:20, and 75:5:20,
      respectively. The 60/20/20 ionomer possessed the best tensile properties,
      exhibiting an average tensile modulus of 68 MPa and strain at break of 31%.
      Calcium treatment of the ionomer films led to significantly higher hardness and
      elastic moduli as measured by indentation. Calcium binding was evident from the
      increase in glass transition and melting temperatures, and a shift in the P-->O
      absorption in the FTIR spectrum. Stable N-hydroxysuccinimide ester (NHS) of the
      ionomers could be synthesized to facilitate derivatization, as demonstrated by
      conjugation of GRGDS in this study. The polymers conjugated with NHS were
      hydrolyzed in a biphasic mode, with a fast initial phase occurring in the first
      few hours, followed by a slower phase in the next few days. These ionomers
      represent a novel class of biomaterials with readily controllable physical and
      chemical attributes for tissue engineering.

PMID- 15199589
TI  - Release of anthracyclines adsorbed on copper-treated hydroxylapatites.
AB  - Anthracyclines are antibiotics widely used for the treatment of leukemia and
      solid tumors. Perfusion is the standard clinical administration form.
      Unfortunately, this does not allow treatment of gastric cancers. A new galenic
      presentation, consisting of anthracyclines adsorbed onto hydroxylapatite
      granules, has been developed. It was found to be possible to modulate the release
      of the drug as a function of the pH by using copper(II) ions. At neutral pH, the
      drug remains on the mineral support, but at pH 3, the drug is released into
      solution. Further investigations demonstrate that copper-containing
      hydroxylapatite can retain a determined quantity of antibiotic by surface
      complexation. This result could contribute to new designs for drug carriers
      targeted for gastric cancers.

PMID- 15199590
TI  - Measuring mechanical properties of fine-wire cross-sections used in medical
      devices.
AB  - In this study, it was demonstrated that the nanoindentation technique can be used
      to measure the elastic modulus and hardness of fine-wire cross-sections with
      diameters ranging from 100-200 microm. Using miniature optics and a specially
      developed micrometer positioning system, measurements were successfully performed
      on the wire cross-sections with an accuracy of 1 microm. Homogeneous wire cross
      sections, such as MP35N (high-strength nickel-cobalt alloy), composite wires such
      as MP35N with a silver core (MP35N/Ag-core), and platinum-clad tantalum (Pt-clad
      Ta) were studied. From the nanoindentation measurements, the elastic modulus and
      hardness at different positions and depths were calculated. It was found that
      both elastic modulus and hardness reached a constant value below the hardened
      surface, which resulted from mechanical polishing. Material properties obtained
      from the measurements were compared with the literature values of bulk materials
      as well as available results on fine wires. The data from the wire cross
      sections, especially the uniform material samples, showed that both the elastic
      modulus and hardness were significantly lower near the outer 10-15 microm of the
      wire as compared to the rest of the wire, which is due to surface weakening
      during manufacturing. In addition, both modulus and hardness showed a small but
      consistent "sawtooth" variation across the diameter of the wires, excluding the
      outer 10-15 microm, that is postulated to be induced by the distribution of
      residual stress.

PMID- 15199591
TI  - Structural design of the dry fibrin sealant dressing and its impact on the
      hemostatic efficacy of the product.
AB  - We compared the hemostatic efficacy of a production version of a dry fibrin
      sealant dressing (DFSD) to a prototype that was previously successful in large
      animal studies. The results were used to improve manufacturing processes. Grade-V
      liver injuries were induced in swine and treated with gauze sponges (GAU), the
      prototype dressings (DFSD-1), or the scaled-up production version dressings (DFSD
      2 in experiment 1 and DFSD-3 in experiment 2). Blood loss, hemostasis,
      resuscitation volume, and 60-min survival were quantified. In experiment 1, the
      DFSD-1 treatment reduced blood loss (p < 0.01), increased hemostasis at 4 min (p
      < 0.05), and improved survival (p < 0.05) compared with GAU. The DFSHD-2
      decreased blood loss (p < 0.05) but did not increase hemostasis or survival
      significantly. Based on these results, manufacturing processes were altered,
      producing DFSD-3. In experiment 2, the DFSD-1 and DFSD-3 were equally effective
      in reducing blood loss (p < 0.01) and resuscitation volume (p < 0.05) compared
      with GAU. Hemostasis occurred more frequently in both the DFSD-1 and DFSD-3
      groups (p < 0.01) compared with GAU. The structural design of DFSD-2 did not meet
      the efficacy requirement for release of the product. The subsequent change
      incorporated in DFSD-3 improved all hemostatic parameters of the dressings equal
      to those of the prototype product.

PMID- 15199592
TI  - Effect of SACCHACHITIN on keratinocyte proliferation and the expressions of type
      I collagen and tissue-transglutaminase during skin wound healing.
AB  - SACCHACHITIN is a skin wound-healing membrane made of residual fruiting body of
      Ganoderma tsugae. Its effect on proliferating cell nuclear antigen (PCNA)
      expression in actively proliferating cells, type I collagen expression and tissue
      remodeling in the healing tissue, and the association of tissue-transglutaminase
      (t-TGase) with wound healing were investigated by immunohistochemical staining.
      The results demonstrated that PCNA expressed in keratinocytes since day 1 in the
      SACCHACHITIN group and persisted during entire healing process. In contrast, it
      was barely detectable on day 3 in the control group. At keratinocyte layer, the
      SACCHACHITIN group exhibited more type I collagen than did the control group
      since day 1. At scar tissue, type I collagen was positively stained in the
      SACCHACHITIN group since day 7 but not in the control group till day 12.
      Furthermore, t-TGase was strongly expressed on the inner wall of angiogenic
      vessels on day 5 of the control group but not on that of the SACCHACHITIN group
      until day 10. The earlier expressions of PCNA and type I collagen in the
      keratinocyte layer may lead to accelerated skin wound healing. In addition, the
      later expression of t-TGase, an indicator of apoptosis, on the inner wall of
      angiogenic capillaries in the SACCHACHITIN group may indicate a longer period of
      blood supply to the wound area, thus facilitating wound healing. These observed
      phenomena might underline the beneficial effects of SACCHACHITIN membrane on
      rapid wound healing.

PMID- 15199593
TI  - A comparative staining technique to detect mineral oil contaminants from
      orthopedic implants.
AB  - An adverse tissue response was reported in patients implanted with porous coated
      implants containing a mineral oil contaminant. A comparative staining technique
      was developed in a rabbit and sheep model to identify the presence of a mineral
      oil contaminant on porous coated implants by examining the surrounding tissues
      and end organs. The hypothesis for the study was that mineral oil, a saturated
      lipid, could be distinguished from unsaturated lipids such as animal fats. Frozen
      rabbit and sheep tissues were stained with hematoxylin and eosin, oil-red-O, and
      bromide-silver nitrate. Twenty-eight positive control rabbits were injected with
      mineral oil and 12 negative control rabbits were injected with saline into the
      paravertebral muscle and synovial cavity of the knee joint. Comparative analysis
      of tissue was conducted after 1, 3, 5, and 12 weeks. Thermally cleaned porous
      coated implants were implanted for 6, 12, and 24 weeks into cancellous bone of
      the distal femur of sheep to allow for a weight-bearing model. The comparative
      histological analysis of the positive control rabbit tissue allowed for detection
      of mineral oil in all tissues examined. Histological analysis of sheep tissue and
      saline-injected rabbit tissue showed no evidence of mineral oil or adverse tissue
      response.

PMID- 15199594
TI  - Diagnosis of infection after total hip replacement.
AB  - Subclinical infection in patients with pain following total hip replacement (THR)
      is an underestimated condition that needs consideration because it mimics aseptic
      loosening, contributes to periprosthetic osteolysis, and necessitates proper
      treatment. We aimed to define the reliability of diagnostic parameters that are
      routinely used before revision surgery for the assessment of infection. A
      continuous series of 26 subjects who underwent THR revision surgery was
      considered, including 21 cases diagnosed as aseptic loosening (group A) and 5 hip
      revisions with a clinical diagnosis for infection (group B). Seven subjects at
      the time of the primary arthroplasty were used as negative controls (group C).
      Technetium-99m labeled hydroxymethylene diphosphonate [(99m)Tc-HDP]- and
      technetium-99m hexamethylpropyleneamine oxide [(99m)Tc-HMPAO)]-labeled
      granulocyte scintigraphy, histology of peri-implant tissues, laboratory tests for
      inflammation, and microbiology were performed. Scintigraphy was positive for
      loosening [positive (99m)Tc-HDP scan] but negative for infection [negative
      (99m)Tc-HMPAO-labeled granulocyte scan] in all group A patients, whereas in 11
      cases (52%) a positive culture was unexpectedly obtained. Histology showed
      conflicting results: Polymorphonuclear cells (PMNs) were found only in 5 of 11
      culture-positive patients, whereas in 2 cases the presence of PMNs did not
      correspond to a positive culture. In group B patients, both isotope scans and
      microbiology were found to be positive. All control subjects (group C) had
      negative cultures. In our opinion, smoldering infection could be present in a
      significant proportion of cases of failed hip implants currently diagnosed as
      "nonseptic." The inflammatory response to wear debris and the presence of
      superimposed, slowly growing bacteria could act synergically, both contributing
      to the pathogenesis of periprosthetic osteolysis.

PMID- 15199595
TI  - Quantitative analysis of biologic specimens by X-ray scanning analytic
      microscopy.
AB  - X-ray scanning analytic microscopy (XSAM) can be used to visualize the elemental
      distribution in biologic specimens. In this article, the authors prepared
      standard specimens for XSAM and performed quantitative analysis of various
      elements dissolved in soft tissues. Two different types of standard specimens
      were prepared. Methylmethacrylate (MMA) resin-based standard specimens were
      prepared with organic compounds of elements for low-concentration standards and
      lithium borate glass-based standard specimens were prepared with oxides of
      elements for higher concentration standards. Using these standard specimens, the
      P and Ca concentrations in normal rat tissue and dissolved Ni, Fe, and Ni
      concentrations around metal-implanted tissues were quantitatively analyzed. The
      estimated concentrations of dissolved Fe, Cu, and Ni from the implants were 1000,
      40, and 20 mM, respectively. From the concentration levels causing inflammation
      around these implants, the high toxicity for soft tissue of Ni and Cu at low
      concentrations, for example, 10 mM, was confirmed. The toxicity of Cu was
      estimated as next to that of Ni. In contrast, Fe had low toxicity despite high
      concentrations of dissolved Fe of as much as 1000 mM. In this article, it was
      possible to estimate the nonmetallic elements and low-concentration metallic
      elements dispersed in soft tissue by XSAM.

PMID- 15199597
TI  - Effects of water storage of E-glass fiber reinforced denture base polymers on
      residual methyl methacrylate content.
AB  - This study investigated the effect of water storage on residual methyl
      methacrylate (MMA) content of continuous E-glass fiber (Wetrotex International)
      reinforced denture base polymers. Heat-polymerization (short- and long-term
      boiling and conventional curing cycle using Meliodent), autopolymerization
      (processed in air at room temperature and in water at 60 degrees C with the use
      of Meliodent Rapid Repair), and microwave-polymerization (3 min at 500 W with the
      use of Acron MC) were employed. The residual MMA contents of 120 specimens were
      analyzed by high-performance liquid chromatography at deflasking (control) and
      after water (37 degrees C) storage of 1 day, 1 week, and 1 month. Bonferroni's
      pairwise comparison test was used for statistical analysis. Significant reduction
      were determined only in the long-term terminal boiled heat-polymerized test group
      at the end of 1 day (p < 0.01), 1 week (p < 0.05) and also 1 month of water
      storage (p < 0.01). Significant reduction in autopolymerized test groups started
      even after 1 week of water storage (p < 0.05). Microwave-polymerized test groups
      did not show a significant residual MMA reduction in all time intervals (p >
      0.05). The polymerization methods and cycles applied to the glass fiber
      reinforced denture base polymers influence both the content and the reduction of
      residual MMA after water storage.

PMID- 15199596
TI  - Comparative cyclic stress-strain and fatigue resistance behavior of electron-beam
      and gamma-irradiated ultrahigh molecular weight polyethylene.
AB  - Fatigue-related damage in UHMWPE is one of the main causes of long-term failure
      in total joint replacements. Crosslinking ultrahigh molecular weight polyethylene
      (UHMWPE) by gamma or electron-beam irradiation, in combination with prior or
      further thermal treatment, enhances its wear resistance against metallic
      components in total hip replacements, and eventually in knees. However, little
      information is available on the fatigue response of this modified UHMWPE. The
      objective of this study was to compare electron-beam-irradiated UHMWPE at 50,
      100, and 150 kGy, with the well-known 25 kGy gamma-irradiated UHMWPE. Two
      different cyclic tests were performed under tensile stress, with a zero load
      ratio, R = 0. First, specimens were subjected to a sinusoidal load cycle at 1 Hz,
      which provided stress-life curves with the use of a failure criterion based on
      12% yield strain. Second, specimens were tested under 50 load cycles at a
      displacement rate of 15 mm/min, which provided information about the evolution of
      secant modulus and plastic strain. The incubation period was also analyzed. DSC
      measurements were carried out to check the crystallization effect of irradiation.
      According to the results of fatigue resistance there was a crossover behavior
      between gamma- and electron-beam-irradiated UHMWPE regarding the applied stress.
      When the stress was higher than the crossover value, the fatigue resistance of
      gamma-irradiated samples was higher than electron-beam-irradiated ones. When the
      stress was lower, the fatigue behavior was the opposite. The crossover stress
      depended on the electron-beam-irradiation dose. The clinical relevance of this
      study lies in an improved knowledge of electron-beam-irradiated material under
      extreme mechanical circumstances, such as fatigue.

PMID- 15199598
TI  - Oxaliplatin added to simplified bimonthly low-dose leucovorin and 5-FU for
      pretreated advanced colorectal cancer is effective and not affected by different
      previous 5-FU regimens.
AB  - This phase II study examined bimonthly oxaliplatin (85 mg/m2) added to a
      continuous infusion of fluorouracil (3000 mg/m2 for 46 h following a 400 mg/m2
      bolus), with leucovorin (LV) (150 mg/m2) administrated in a simplified way to
      patients with metastatic colorectal cancers (CRC) refractory or resistant to 5
      fluorouracil (5-FU). Sixty patients were registered. Of the 52 evaluable
      patients, 3 (5.8%) achieved a complete response (CR) and 18 (34.6%) achieved a
      partial response (PR). The overall response rate (CR + PR) was 40.4% (95%
      confidence interval [CI]: 26.6%-54.2%) for evaluable patients and 35% (95% CI:
      22.6%-47.4%) by intention to treat. The median progression-free survival (PFS)
      was 5.2 months, and the median survival was 14.2 months. No significant
      differences were seen in response rates and PFS of patient groups pretreated
      either with high-dose 5-FU/LV by continuous infusion or with intravenous 5-FU/LV
      by a weekly bolus. From the 421 cycles analyzed, dose-limiting toxicities
      included cumulative sensory neuropathy and leukopenia, accounting for 11.6% and
      10.0%, National Cancer Institute-Common Toxicity Criteria grade 3/4 toxicities
      per patient, respectively. Two (3.3%) patients experienced hepatic encephalopathy
      related to high-dose 5-FU. With necessary caution, this regimen was effective for
      5-FU-pretreated CRC, regardless of ethnic differences, and it had the advantage
      of LV being administrated at a low dose in a simplified way.

PMID- 15199599
TI  - Usefulness of FDG-PET to detect recurrent cervical cancer based on
      asymptomatically elevated tumor marker serum levels--a preliminary report.
AB  - This study was to evaluate the clinical impact of whole body positron emission
      tomography (PET) with 18F-fluoro-2-deoxyglucose (FDG) to detect recurrent
      cervical cancer based on asymptomatically elevated tumor marker levels. Whole
      body FDG-PET was performed in 20 patients with suspected recurrent squamous cell
      carcinoma (SCC) of the cervix and asymptomatic tumor marker of SCC antigen
      increased serum levels but negative or equivocal other imaging modality results.
      All of these 20 asymptomatic patients have serum levels of SCC antigen > 1.5
      ng/mL. The final diagnosis of recurrent cervical cancer was established by
      operation/biopsy histopathological findings or clinical follow-up after more than
      1 year by additional morphological imaging techniques. Among the 20 patients, the
      final diagnosis of recurrent cervical cancer was established in 81 lesions of 19
      patients. The FDG-PET accurately detected 78/81 lesions. With asymptomatically
      elevated SCC antigen serum levels, the diagnostic sensitivity and accuracy of FDG
      PET to detect recurrent cervical cancer lesions were 97.5% and 94.0%,
      respectively. The FDG-PET is a useful technique to detect recurrent cervical
      cancer for patients with asymptomatically elevated SCC antigen serum levels.

PMID- 15199600
TI  - Correlation between MIB1-determined tumor growth fraction and incidence of tumor
      recurrence in early ovarian carcinomas.
AB  - PURPOSE: The decision concerning adjuvant therapy remains difficult in patients
      with very early stage ovarian carcinomas [Federation Internationale de
      Gynecologie et d' Obstetrique (FIGO) Ia/b]. Therefore, we compared the MIB1
      determined tumor growth fraction in archival tumor tissue with tumor recurrence
      and outcome of disease, and in relationship to other stages and clinical and
      morphological findings. PATIENTS AND METHODS: Ninety-two patients were followed
      in early stages of ovarian carcinomas (FIGO I and II) with no tumor residuals and
      were analyzed for tumor recurrences and long-term overall survival (mean 6.0
      years, median 5.5). Fifty-eight patients had stage I tumors, among these were 38
      in the sub-stages Ia/b. Tumor growth fraction (MIB1) in tissues from primary
      surgery was compared with the status of patients and disease, histology, and
      immunohistochemistry for carcinoembryonic antigen (CEA), CA125, CA153, steroid
      hormone receptors, and angiogenesis (chisquare test, Kaplan-Meier and
      discriminant analyses). RESULTS: Tumor-associated deaths occurred in 27 cases,
      tumor recurrences occurred in 35 cases. In contrast to the advanced stages of
      disease, the MIB1-determined tumor growth fraction outweighted all other
      parameters in the prediction of the course of disease (p < 0.001), followed by
      tumor grading (p = 0.001) and FIGO-substages (p = 0.026) in this retrospective
      study. Particularly in the very early stages, MIB1 predicted tumor recurrences in
      84% of the cases (p < 0.001). Recurrences were not observed below a tumor growth
      fraction of 10% but prevailed in cases of more than 15%. CONCLUSION: Our data
      suggest MIB1 as an interesting additional tool for the decision of adjuvant
      therapy in patients with very early stages of ovarian carcinomas, which should be
      tested in prospective trials.

PMID- 15199601
TI  - Prognostic value of PCNA and mutant p53 expression in laryngeal squamous cell
      carcinoma.
AB  - The objective of this study was to investigate the prognostic significance of
      p53, and proliferative cell nuclear antigen (PCNA) in laryngeal squamous cell
      carcinoma (LSCC). Sixty pathologic specimens from the patients with LSCC were
      examined for the expression of the p53 and PCNA, with complete follow-up data.
      Sixty-three percent of the cases displayed nuclear p53 overexpression. There was
      a correlation between p53 overexpression and histological grades (p = 0.03), and
      localization site (p = 0.05). Median of PCNA index was 42.2 (range 5.9 to 85.2).
      There was no difference between the p53 overexpression group and the normal group
      in proliferative activity determined by PCNA (p = 0.73). In univariate analyses,
      localization site, grade, stage, invasion pattern, lymph node status, were
      significant factors in estimating disease free survival (DFS). Grade was the most
      important factor affecting recurrence (p = 0.002). In multivariate analyses,
      grade was the only significant predictor for DFS (p = 0.001). Grade (p = 0.001)
      and invasion pattern (p = 0.03) were found to be significant predictors of
      overall survival. In conclusion, the histological grade was the most reliable
      important prognostic factor. Further studies are necessary to facilitate
      understanding of the mechanisms of laryngeal carcinogenesis.

PMID- 15199602
TI  - Pre- and postoperative aminoacidemia in breast cancer: a study vs. matched
      healthy subjects.
AB  - Various alterations of aminoacidemia have been described during breast cancer.
      The aim of this study was first to establish the specific modifications of plasma
      free amino acid concentrations by a comparative study of 19 patients with mammary
      tumors and 18 healthy volunteers, and, second, to determine the evolution of
      aminoacidemia after surgical tumor removal. Aminoacidemia was determined the day
      before (D0), and then five days, one month (M1), and six months after surgical
      removal of the tumor, and a single determination was performed in control
      subjects. Plasma levels (mumol/L) of serine and glutamate were higher in cancer
      bearing women at D0 (respectively, 124 +/- 3 and 68 +/- 7) than in healthy
      volunteers (respectively, 110 +/- 6 and 48 +/- 5). Surgical tumor removal induced
      a normalization of aminoacidemia (in mumol/L at D5: serine: 114 +/- 4; at M1:
      glutamate: 55 +/- 6 Non Significant (NS) from values of healthy subjects). Among
      the various patterns reported for breast cancer, we confirm one of those
      described by Cascino in 1995, and we show that these levels revert to normal
      after tumor surgical removal.

PMID- 15199603
TI  - Estrogen receptor beta delta 6 (ER beta delta 6) isoform in human endometrial
      hyperplasia and adenocarcinoma.
AB  - Estrogen receptor (ER)-beta may play a significant role in estrogen action in
      several human tissues. Estrogen receptor beta may act as a transdominant
      repressor of ER alpha transcriptional activity trough heterodimers form. Estrogen
      receptor messenger RNA (mRNA) variants also may be involved in various diseases,
      including endometrial cancer. The absence of estrogen receptors has often
      correlated with poor prognosis of endometrial tumors. The objective of the study
      was to determine the number of mRNA ER beta delta 6 and (wtER beta) in 1
      microgram total RNA obtained from tissues of normal, hyperplastic endometrium,
      and endometrial adenocarcinoma. This study was designed to evaluate possible
      differences in the ER beta delta 6 and wtER beta messenger RNA (mRNA) level in
      the normal, hyperplastic endometrium, and endometrial endometrioid adenocarcinoma
      (G1, G2 morphological degree). Adenocarcinoma showed significantly lower ER beta
      delta 6 mRNA level than proliferative (p = 0.032) and secretory (p = 0.01)
      endometrium. A decrease of mRNA wtER beta in endometrial adenocarcinoma (p =
      0.006) also was observed.

PMID- 15199604
TI  - Comparative study of the immunohistochemical phenotype in breast cancer and its
      lymph node metastatic location.
AB  - At present, an important part of prognostic information, together with particular
      treatment strategies in breast cancer, take into account the immunohistochemical
      phenotype of the primary tumor location. However, the changing heterogeneity
      intrinsic to neoplastic cells in general leads us to consider the possibility
      that the expression of these proteins is modified during tumoral development and
      dissemination. With this hypothesis as a starting point, 60 patients with breast
      cancer were studied with immunohistochemistry, the expression of estrogen and
      progestagenic receptors, proliferation through the Ki-67 expression, and the
      overexpression of HER-2 and p53 in both the primary location and the lymph node
      metastases. If we consider significant change to be loss (from positive to
      negative) or gain (negative to positive) of expression in some of the studied
      determinations, we find that this is produced in 60% of the tumors studied. These
      results demonstrate the modification of immunohistochemical expression of the
      proteins studied between the primary tumor location and the lymph node
      metastases.

PMID- 15199605
TI  - Merging claims databases with a tumor registry to evaluate variations in cancer
      mortality: results from a pilot study of 698 colorectal cancer patients treated
      at one hospital in the 1990s.
AB  - BACKGROUND: Prognostic models are essential for evaluating variations in cancer
      mortality statistics. While cancer stage is the most widely accepted and commonly
      used predictor of survival for cancer, electronic claims databases contain large
      amounts of information on cancer patients. Previous studies have used Medicare
      databases and tumor registry information from the Surveillance Epidemiology and
      End Results data sets to evaluate variations in outcomes for older cancer
      patients. We evaluated if similar analytic efforts could be carried out with
      readily available data sets for colorectal cancer patients of all ages who
      received care at a single hospital during the 1990s. METHODS: Hospital tumor
      registry and discharge claims data for patients at one mid-western hospital with
      surgically treated stage I-III colorectal cancer from 1990-1998 were used to
      model survival. Kaplan-Meier logrank tests and Cox proportional hazards models
      tested the statistical significance of demographic, operative, and
      clinicopathological factors as predictors of survival. Survival probabilities
      also were compared to U.S. population life table data to determine if survival
      deficits were larger for younger cancer patients. RESULTS: Of the 698 colorectal
      cancer patients, overall five-year survival probability was 65%, with a median
      follow-up of 44.7 months. Factors associated with higher relative risks of death
      included sociodemographic characteristics [female gender (1.5, 95% CI: 1.1-1.9),
      ages 70-79 years (1.7, 95% CI: 1.2-2.3), and > or = 80 years (3.3, 95% CI: 2.4
      4.7) as compared to younger patients], clinical characteristics [moderate (1.5,
      95% CI: 1.1-2.1) or severe (2.1, 95%: 1.4-3.2) comorbid illness, as compared to
      mild or no comorbid illnesses and emergency admission (2.1, 95% CI: 1.5-2.9)],
      pathological characteristics [positive surgical margins (3.5, 95% CI: 2.3-5.3):
      and higher cancer stage (stage II RR = 1.5, 95% CI = 1.1-2.2; stage III RR = 2.2,
      95% CI = 1.5-3.2), as compared to stage I]. A comparison to the age- and gender
      matched survival probabilities of the general population demonstrated similar
      deficits in survival for older patients (> or = 70 years) and younger patients (<
      70 years). CONCLUSIONS: While cancer stage is a reliable predictor of survival,
      other sociodemographic and clinical data elements can improve the evaluation of
      expected survival rates for patients with surgically resectable colorectal
      cancers. To facilitate comparative interpretations of mortality data,
      consideration should be given to merging hospital discharge claims data sets with
      tumor registry information in a manner analogous to that which has been done for
      older cancer patients who are covered by the Medicare program.

PMID- 15199606
TI  - In vitro proliferation of fibrosarcoma cells depends on intact functions of
      lipoxygenases and cytochrome P-450-monooxygenase.
AB  - Proliferation of mouse fibrosarcoma cells G:5:113 was studied in vitro after
      affecting particular pathways of arachidonic acid metabolism by selected
      inhibitors. After 48 hours of cultivation with nonspecific lipoxygenase
      inhibitors, nordihydroguaiaretic acid (NDGA) and esculetin; a specific 12
      lipoxygenase inhibitor, baicalein; and inhibitor of five-lipoxygenase activating
      protein, MK-886, markedly suppressed the number of cells and induced significant
      changes in cell cycle distribution in a dose-dependent manner. While proadifen,
      an inhibitor of cytochrome P-450-monooxygenase, applied in low concentrations,
      increased the cell number, at higher concentrations, it inhibited cell
      proliferation and significantly changed the cell cycle. Cyclooxygenase
      inhibitors, ibuprofen, flurbiprofen, and diclofenac suppressed cell numbers only
      moderately without any changes in the cell cycle. The occurrence of apoptosis was
      not significant for any of the selected drugs in comparison with untreated
      control cells. Moreover, not even one of the drugs caused the specific cleavage
      of poly (ADP-ribose) polymerase to the 89-kDa fragment, however, a decrease in
      total amount of this protein was observed after treatment with NDGA and
      esculetin. We conclude that the proliferation ability of fibrosarcoma cells
      G:5:113 in vitro depends on intact functions of 5-lipoxygenase, 12-lipoxygenase,
      and cytochrome P-450-monooxygenases, and that the effects of inhibitors do not
      include regulation of apoptosis.

PMID- 15199608
TI  - ANNA-2: an antibody associated with paraneoplastic opsoclonus in a patient with
      large-cell carcinoma of the lung with neuroendocrine features--correlation of
      clinical improvement with tumor response.
AB  - This report describes a case of large-cell lung carcinoma with neuroendocrine
      features, presenting with the full clinical picture of paraneoplastic opsoclonus
      myoclonus syndrome. The patient had an unexpectedly dramatic resolution of the
      neurologic dysfunction after receiving antineoplastic treatment. Symptom
      improvement paralleled a progressive decline of serum ANNA-2 antibody titers to
      undetectable levels.

PMID- 15199607
TI  - Expression of BAG-1 and BcL-2 proteins before and after neoadjuvant chemotherapy
      of locally advanced breast cancer.
AB  - It has been suggested that expression of anti-apoptotic proteins such as Bcl-2 or
      BAG-1 may confer cellular resistance to chemotherapy. A corollary of this
      hypothesis is that expression of these proteins may predict clinical response to
      treatment and that Bcl-2- or BAG-1-positive cells may selectively be enriched in
      postchemotherapy tissue specimens. The goal of this exploratory pilot study was
      to assess these two predictions by using immunohistochemistry in 29 paired pre-
      and postchemotherapy breast tissue specimens obtained from patients who underwent
      preoperative doxorubicin-based chemotherapy. All breast cancers expressed BAG-1
      protein, and, in individual tumors, 40-100% of neoplastic cells stained positive
      for this protein. Homogenous cytoplasmic staining was typically observed, though
      neoplastic cells also showed nuclear staining in many specimens. We found no
      correlation between prechemotherapy expression of BAG-1 and subsequent
      pathological response to cytotoxic therapy. Paired pre- and posttreatment
      specimens showed similar levels of BAG-1 expression when residual tumor could be
      assessed. Bcl-2 was expressed in 55% of cancers and was localized to the
      cytoplasm. Absence of Bcl-2 expression in prechemotherapy specimens was
      associated with more frequent complete pathological response (58% vs. 20%; p =
      0.04). However, similar to BAG-1, no difference between pre- and posttherapy
      expression of Bcl-2 was observed in neoplastic cells in paired tissue specimens.
      These observations suggest that BAG-1 contributes an important cellular function
      to breast epithelial cells, which is reflected by its ubiquitous expression in
      these tissues. However, it does not appear to determine response to doxorubicin
      based chemotherapy. In contrast, lack of Bcl-2 expression was associated with a
      higher probability of complete pathological response to doxorubicin-based
      chemotherapy.

PMID- 15199609
TI  - The application of number needed to treat (NNT) to clinical problems in
      radiotherapy.
AB  - The goals of this report are: 1) to review the number needed to treat (NNT)
      concept, which, although well established in many sectors of medicine, is still
      relatively new to the radiotherapy community; 2) to discuss several clinical
      radiotherapy examples illustrating the inherent advantages of the NNT approach;
      and 3) to discuss potential future roles of the NNT concept within radiotherapy.

PMID- 15199610
TI  - Role of COX-2 inhibitors in cancer therapy.

PMID- 15199611
TI  - Surgical management of hepatic malignancy.
AB  - Over the past twenty-five years, hepatic resection has evolved from a high risk,
      resource-intensive procedure with limited application to a safe and commonly
      performed operation with broad indications. This period has seen dramatic
      improvements in perioperative outcome, including reductions in mortality, blood
      loss, transfusion rates, and hospital stay. These improved perioperative results
      are largely responsible for the emergence of hepatic resection as a viable and
      effective treatment option for selected patients with 1 degree and 2 degrees
      hepatobiliary malignancy. Continued advances in imaging technology, along with a
      heightened awareness of the clinical and tumor-related variables that dictate
      outcome, have allowed better preoperative assessment of disease extent and
      improved patient selection. Advances in other areas, such as minimally invasive
      and ablative techniques, have increased the treatment options and have had some
      impact on the approach to patients with malignant hepatobiliary disease; however,
      resection remains the most effective therapy. Although the long term results
      after resection are better than with other modalities, recurrence rates remain
      high, and further improvements in survival will require more effective systemic
      agents. As better adjuvant and neo-adjuvant therapies emerge, the results of
      resection are likely to improve and the indications for its application perhaps
      will extend to patients currently considered to have unresectable disease.

PMID- 15199612
TI  - Development of the proteasome inhibitor Velcade (Bortezomib).
AB  - The dipeptide boronic acid analogue VELCADE (Bortezomib; formerly known as PS
      341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a
      multicatalytic enzyme that mediates many cellular regulatory signals by degrading
      regulatory proteins or their inhibitors. The proteasome is, thus, a potential
      target for pharmacological agents. Bortezomib, the first proteasome inhibitor to
      reach clinical trials, has shown in vitro and in vivo activity against a variety
      of malignancies, including myeloma, chronic lymphocytic leukemia, prostate
      cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the
      vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib
      -mediated proteasome blockade is dose-dependent and reversible. Based on phase I
      studies demonstrating that bortezomib has manageable toxicities in patients with
      advanced cancers, phase II trials have been initiated for both solid and
      hematological malignancies.

PMID- 15199613
TI  - Impact of microarray technology in clinical oncology.
AB  - Genomic technologies are rapidly evolving and have demonstrated utility in
      augmenting oncological pathology or clinical presentation in disease
      classification and risk of relapse assessment. Numerous malignancies have been
      subject to microarray examination, and through a variety of analysis
      methodologies, groups of reporter genes have been identified to generate
      'molecular portraits' of these diseases. Once validated, it is likely that
      assessment of the expression levels of subsets of reporter genes will contribute
      to personalized genomic medicine through diagnosis and selection of treatment
      options for patients. The dynamic nature of this field ensures that new
      developments are missing from this review.

PMID- 15199614
TI  - Evidence-based oncology.

PMID- 15199615
TI  - COX-2 inhibitors as cancer treatment: will they be the new warfarin or
      trastuzumab?

PMID- 15199616
TI  - Hospital information systems and clinical cancer research.

PMID- 15199617
TI  - "Development of the proteasome inhibitor Velcade (Bortezomib)" by Julian Adams,
      Ph.D., and Michael Kauffman, M.D., Ph.D.

PMID- 15199618
TI  - [Effect of API 0134 on platelet membrane glycoprotein expression in patients with
      hyperlipemia].
AB  - OBJECTIVE: By observing the effect of API 0134, an active ingredient of green
      chiretta, on platelet membrane glycoprotein (GP) in patients with hyperlipemia to
      explore the mechanism of the anti-platelet aggregation effect of API. METHODS:
      The mean immunofluorescent intensity (MFI) of the platelet membrane glycoprotein
      GP II b/III a, GPIb, P-selectin (GMP-140) and von Willebrand's factor (vWF) in
      resting platelet, activated platelet (untreated or treated with API 0134 of
      different concentrations) were detected in 30 randomly selected patients with
      hyperlipemia, using immunofluorescent marker and flow cytometry. RESULTS: API of
      all concentrations (25 mg/L, 50 mg/L and 100 mg/L) could significantly decrease
      the MFI of GP II b/III a in a positive dose-dependent manner, as compared with
      that in activated platelet untreated with API; API of 50 mg/L and 100 mg/L could
      also reduce the MFI of GMP-140 and vWF in activated platelet (P < 0.01); but API
      of 100 mg/L showed insignificant influence on GPIb expression in activated
      platelet membrane. CONCLUSION: API 0134 exerts obvious anti-platelet GP II b/III
      a effect on activated platelets, middle or large dose of API also shows
      inhibiting effect on GMP-140 and vWF expression in platelet.

PMID- 15199619
TI  - [Clinical study on treatment of mild cognitive impairment by modified wuzi
      yanzong granule].
AB  - OBJECTIVE: To observe the clinical efficacy and safety of modified Wuzi Yanzong
      Granule (MWYG) in treating mild cognitive impairment (MCI), and to explore its
      mechanism. METHODS: Forty-four MCI patients were selected referring to the
      international recognized Peterson's criteria and randomly divided into two
      groups, the treated group treated with MWYG and the control group treated with
      Ginkgo leaf extraction, with the course of 3 months for both groups. Changes of
      memorial quotient (MQ), superoxide dismutase (SOD) activity, malondialdehyde
      (MDA) content, mitochondrial DNA (mtDNA) deletion rate and acetylcholinesterase
      (AchE) before and after treatment were observed. RESULTS: After treatment, levels
      of MQ, serum SOD activity increased and serum MDA content, mtDNA deletion rate
      and AchE decreased in both groups (P < 0.01), but the difference between the two
      groups was insignificant. No adverse reaction was found in two groups.
      CONCLUSION: Both MWYG and Ginkgo leaf capsule can effectively improve the
      memorial function of patients with MCI, the therapeutic mechanism is possibly
      related with the actions in reducing AchE activity, improving free radical
      metabolism, and alleviating mitochondrial DNA oxidation damage.

PMID- 15199620
TI  - [Clinical observation on improving senile postprandial hyperglycemia and insulin
      sensitivity with combination of acarbose and liuwei nengxiao capsule].
AB  - OBJECTIVE: To observe the effect of combination therapy of acarbose and Liuwei
      Nengxiao capsule (LWNXC) in improving senile postprandial hyperglycemia and
      insulin sensitivity. METHODS: Seventy-four patients with simple postprandial
      hyperglycemia were divided into the control group and the treated group, 37 in
      each group, who were treated with acarbose alone and the combination therapy
      respectively for 1 month, and the changes on 2 hrs postprandial glucose (2 hPG),
      blood pressure (BP), blood lipid, body mass index (BMI), insulin functional index
      as well as the adverse reaction of acarbose in the two groups were observed.
      RESULTS: After treatment, the levels of 2 hPG, fasting blood glucose (FBG), BMI,
      total cholesterol and lowdensity lipoprotein-cholesterol were improved in the
      treated groups more significantly than those in the control group (P < 0.05 or P
      < 0.01). Insulin sensitive index (ISI) and insulin resistance were improved in
      the two group (P < 0.05 or P < 0.01), but the improvement in the treated group
      was more significant than that in the control group (P < 0.01). Moreover, the
      adverse reactions were less in the treated group than in the control group.
      CONCLUSION: The combination therapy of acarbose and LWNXC could not only improve
      the postprandial hyperglycemia, but also markedly increase the insulin
      sensitivity, and shows obvious improving effect on parameters of blood lipid, BP
      and BMI. The adverse reaction could be evidently reduced by combined use with
      LWNXC.

PMID- 15199621
TI  - [Exploration on the relationship between pathogenesis for yin-deficiency of acute
      myocardial infarction and immediate prognosis as well as its mechanism].
AB  - OBJECTIVE: To study the relationship between pathogenesis for Yin-deficiency of
      acute myocardial infarction (AMI) and immediate prognosis as well as its neuro
      endocrine mechanism. METHODS: According to the TCM standard of Syndrome
      Differentiation of Deficiency Syndrome, 194 patients with AMI were classified
      into the typical Yin-deficiency group (n = 26), the non-typical Yin-deficiency
      group (n = 61) and the non-Yin-deficiency group (n = 107). Their venous blood
      samples were collected in the morning while lying on their backs to detect plasma
      levels of adrenaline, noradrenaline, aldosterone, atrial natriuretic peptide
      (ANP), corticoid and myocardial enzymes, as well as their hospitalization days
      and mortality in hospitalized period were calculated and compared in the three
      groups, with the 30 healthy persons as control. RESULTS: Levels of serum creatine
      phosphokinase, creatine phosphokinase isozyme, plasma adrenaline, noradrenaline,
      aldosterone, hospitalization days and mortality were higher in the Yin-deficiency
      groups than in the non-Yin-deficiency group (P < 0.05, P < 0.01). As compared the
      indexes between the typical and the non-typical Yin-deficiency groups,
      significant difference only showed in plasma aldosterone and ANP, which was
      significantly higher in the former (P < 0.05, P < 0.01). Plasma corticoid level
      was insignificantly different between the Yin-deficieny groups. CONCLUSION:
      Patients with AMI of Yin-deficiency type was severer in myocardial damage, with
      longer hospitalization period and higher mortality, it is probably due to the
      hyper-activated sympathetic-adrenaline system and strengthened activity of
      aldosterone in them.

PMID- 15199622
TI  - [Comparison of effects of taizhi' an capsule and pravastatin on vascular
      endothelial function in senile patients with coronary heart disease].
AB  - OBJECTIVE: To explore the anti-atherosclerosis effect of Taizhi'an Capsule (TZA)
      for providing a theoretical base of its application in preventing coronary heart
      disease (CHD), by way of observing the effects of TZA and pravastatin (PVT) on
      vascular endothelial function in senile patients with CHD. METHODS: Seventy-eight
      Senile patients with CHD were randomly divided into the TZA group and the PVT
      group, 39 in each group. Changes of carotid arterial intima-media thickness (IMT)
      and brachial arterial endothelium dependent diastolic function (FMD) before and
      after treatment were observed by non-invasive ultrasound test technique, and
      levels of serum nitric oxide (NO) and plasma endothelin-1 (ET-1) were determined
      as well. RESULTS: After TAZ treatment, IMT decreased from 1.21 +/- 0.17 mm to
      0.91 +/- 0.13 mm, FMD increased from 5.02 +/- 0.58% to 8.97 +/- 0.39%, ET-1
      lowered from 95.93 +/- 19.41 ng/L to 49.35 +/- 53.27 ng/L, and NO enhanced from
      42.56 +/- 14.12 mumol/L to 69.84 +/- 21.96 mumol/L; after PVT treatment, the
      corresponding changes were 1.25 +/- 0.21 mm to 0.88 +/- 0.32 mm, 4.90 +/- 0.37%
      to 8.12 +/- 0.25%, 89.35 +/- 10.02 ng/L to 47.96 +/- 11.05 ng/L and 51.71 +/-
      9.39 mumol/L to 72.93 +/- 16.51 mumol/L, all the changes were statistically
      significant. CONCLUSION: TZA can obviously improve the vascular endothelial
      function in old patients with CHD, which has the anti-atherosclerosis effect
      similar to that of PVT.

PMID- 15199624
TI  - [Clinical observation on treatment of acute myelocytic leukemia by supplementing
      qi, nourishing yin and clearing heat principle].
AB  - OBJECTIVE: To observe the clinical efficacy of TCM with supplementing Qi,
      nourishing Yin and clearing heat principle (SQNYCH) combined with chemotherapy in
      treating myelocytic leukemia. METHODS: One hundred and fourteen patients were
      randomly divided into the treated group (n = 68) and the control group (n = 46).
      To the treated group, SQNYCH was applied as the basic treatment, with combined
      chemotherapeutic protocol, using DA, HA and IA, to induce remission, and to the
      M3 patients, all-trans retinoic acid and arsenic trioxide were given. As for
      patients in the control group, only western medicine was administered. RESULTS:
      In the treated group 49 patients (72.1%) were completely remitted, 9 (13.2%)
      partially remitted and the total remission rate being 85.3%, which was
      significantly different from that in the control group. After treatment, the
      blood and bone marrow picture were obviously improved in both groups, but the
      increase of hemoglobin and platelet were better in the treated group than in the
      control group (P < 0.05 or P < 0.01). Immune functions were enhanced in both
      groups, but the elevation of CD4, CD4/CD8 ratio and NK cells were higher in the
      treated group than in the control group (P < 0.05 and P < 0.01). CONCLUSION:
      Application of SQNYCH principle in treating acute myelocytic leukemia could
      elevate the clinical efficacy, which is of great value in clinical practice.

PMID- 15199623
TI  - [Study on correlation of insulin resistance with TCM syndrome type and activity
      of fibrinolytic system in patients with coronary arterial disease].
AB  - OBJECTIVE: To study the correlation of insulin resistance (IR) with TCM syndrome
      type and activity of fibrinolytic system in patients with coronary arterial
      disease (CAD). METHODS: One hundred and twelve CAD patients were classified
      according to TCM Syndrome into 4 types, the Xin-blood stasis (XBS) type, the
      phelgm blocking Xin-channel (PBXC) type, the Qi-insufficiency with blood stasis
      (QIBS) type and the both Qi-Yin deficiency (QYD) type. Patients' fasting blood
      glucose (FBG), fasting blood insulin (FIns) were measured, the insulin sensitive
      index (ISI) calculated. Data were compared between various types, also with those
      obtained from 30 healthy persons in the control group respectively. Moreover,
      activity of tissue plasminogen activator (t-PA) and content of plasminogen
      activator inhibitor-1 (PAI-1) were determined in 90 patients selected from the
      112 to conduct linear correlation analysis of IR with t-PA activity and PAI-1
      content. RESULTS: FBG and FIns levels in the CAD patients were higher than those
      in the healthy control significantly (P < 0.01); ISI in the 4 syndrome type of
      CAD patients were all lower than that in the control (P < 0.01). IR existed in
      all the 4 types, but the level in the XBS type and the PBXC type was more severe
      than in the other two types. Correlation analysis showed that IR was correlated
      with t-PA activity and PAI-1 content (P < 0.01). CONCLUSION: IR often exists in
      CAD patients, the severity of IR varies in patients of different TCM syndrome
      types, and IR is correlated with the abnormality of fibrinolytic system activity.

PMID- 15199625
TI  - [Comparative observation on efficacy of jieyu pill and maprotiline in treating
      depression].
AB  - OBJECTIVE: To investigate the clinical efficacy, adverse reaction and safety of
      Jieyu pill (JYP) in treating depression. METHODS: The randomized controlled trial
      was conducted in 28 patients in the treated group and 29 patients in the control
      group treated with maprotiline (Map). The efficacy of treatment was evaluated
      before treatment and 14, 28 and 42 days after treatment, with Hamilton depression
      rating scale (HAMD), self-rating scale for depression (SDS), self-rating scale
      for anxiety (SAS) and clinical global impression (CGI), the adverse reaction was
      assessed by Asberg Rating Scale (ARS). RESULTS: JYP was effective in treating
      depression, the markedly effective rate being 78.8%, corresponded to that of Map
      (82.8%, P > 0.05). After treatment, the scores assessed by HAMD, SDS and SAS were
      all lower than those before treatment (P < 0.01) respectively, but comparison
      between the two groups showed insignificant difference (P > 0.05). However,
      scores of ARS were significantly lower in the treated group than that in the
      control group, and the efficacy index of JYP was significantly higher than that
      of Map (P < 0.01). CONCLUSION: JYP in treating depression shows the efficacy
      corresponded to that of Map and with less adverse reaction.

PMID- 15199626
TI  - [Clinical study on treatment of childhood Henoch-Schonlein purpura nephritis with
      colquhounia root tablet].
AB  - OBJECTIVE: To study the effect of Colquhounia root tablet (CRT) in treating
      childhood Henoch-Schonlein purpura nephritis (HSPN) and compared with
      tripterygium wilfordii multiglycoside tablet (TWMGT). METHODS: Eighty-two
      children with HSPN were divided into the CRT group and the control group. To
      patients of nephritic type, treatment with CRT and TWMGT was applied separately,
      but to those of nephrotic type, the treatment was given together with prednisone.
      Therapeutic effect and changes of related indexes, including urinary protein,
      retinal-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), were observed
      after patients received treatment for 6 months. RESULTS: The complete remission
      (CR) rate and partial remission (PR) rate in patients of nephritic type in the
      treated group was 58.8% and 41.2% respectively, while those in the control group
      was 20.8% and 66.7% respectively, and the ineffective rate being 12.5%.
      Comparison of the therapeutic effect between the two groups showed significant
      difference (P < 0.05). Although the CR rate in patients of nephrotic type in the
      treated group was higher than that in the control group, the difference was
      insignificant (P > 0.05). The urinary levels of protein, RBP and NAG lowered in
      both groups, but level of urinary protein in the treated group of nephritic type
      after 6 months of treatment was significantly lower than that in the control
      group (P < 0.05). CONCLUSION: CRT shows obvious effect in improving childhood
      HSPN of nephritic type, nephrotic type and attenuating the tubulointerstitial
      lesions, compared with TWMGT, CRT is more effective in lowering proteinuria and
      better in total effective rate.

PMID- 15199628
TI  - [Effect of Astragalus polysaccharides in promoting neutrophil-vascular
      endothelial cell adhesion and expression of related adhesive molecules].
AB  - OBJECTIVE: To explore the detoxication and tissue generation effect of Astragalus
      (As) in wound healing and its relation with inflammatory reaction, through
      observing the effect of Astragalus polysaccharides (AP) on neutrophil-endothelial
      cell adhesion and expression of related adhesive molecules. METHODS: Human
      polymorphonuclear leucocyte (PMN) or human umbilical vein endothelial cell
      (HUVEC) was treated separately with AP, AP plus interleukin 1 (IL-1) and tumor
      necrosis factor (TNF) to study the effect of AP on PMN adhesion with HUVEC by
      rose bengal staining, and that on expression of superficial adhesive factor by
      means of Cell-ELISA and APAAP method. RESULTS: When AP acted on HUVEC, it could
      significantly promote the adhesion of HUVEC with PMN, while when AP acted on PMN,
      the adhesion would not increase. When HUVEC was treated by AP plus IL-1, the IL-1
      induced PMN adhesion with HUVEC could be strengthened, and the expression of
      HUVEC superficial adhesive factor ICAM-1 induced by IL-1 and TNF was strengthened
      also, but when PMN treated with AP, it showed no effect on the expression of
      adhesive factor CD18. CONCLUSION: AP promotes the adhesion between neutrophil and
      endothelial cell by way of promoting the expression of superficial I-CAM-1 on
      surface of endothelial cells, so as to improve the inflammatory reaction in the
      wound healing course, it possibly is one of the biological bases of the
      detoxication and tissue generation effects of AP.

PMID- 15199627
TI  - [Study on effect of anisodamine on expressions of tissue factor and plasminogen
      activator-1 inhibitor in vascular endothelial cells and its mechanisms].
AB  - OBJECTIVE: To explore the mechanism of anisodamine in treating infectious shock
      through studying effect of anisodamine on endotoxin lipopolysaccharide (LPS)
      induced expression of tissue factor (TF) and plasminogen activator inhibitor type
      1 (PAI-1) in vascular endothelial cells (EC). METHODS: Human umbilical vein
      endothelial cells (HUVEC) were cultured by trypsin digestion method. PAI-1 was
      measured in the conditioned medium of HUVEC by a specific enzyme-linked
      immunosorbent assay (ELISA), whereas TF activity was measured in the lysates of
      these cells by using a single step clotting assay. Specific mRNA expressions were
      determined by Northern blotting. In order to evaluate a possible contribution of
      the nuclear factor-kappa B (NF-kappa B) pathway on the transductive effects
      observed, electrophoretic mobility shift assays (EMSA) were performed using
      nuclear extracts from HUVEC and NF-kappa B binding oligonucleotides. RESULTS: LPS
      could significantly strengthen the expression of HUVEC PAI-1 protein and TF
      activity and its mRNA, this effect of LPS could be markedly weakened after adding
      Anisodamine dose-dependently. Anisodamine could also completely block the LPS
      induced NF-kappa B DNA binding activity in nuclear extracts from HUVEC.
      CONCLUSION: The possible mechanism of anisodamine in treating infectious shock
      may be through antagonizing LPS induced HUVEC TF and PAI-1 expression, and the
      antagonism might be, at least partially, transduced by path of NF-kappa B.

PMID- 15199629
TI  - [Effect of jiangu granule on quality of bone in model rats with osteoporosis
      induced by ovariectomy].
AB  - OBJECTIVE: To study the effect of Jiangu granule (JGG) on quality of bone in
      model rats with osteoporosis. METHODS: Osteoporosis model was established by
      means of ovariectomy. Bone mineral density (BMD) was measured with dual energy X
      ray densitometry. Osseous tissue structure of upper tibia was observed by ono
      decalcified section and toluidine blue staining, and morphometry was carried out.
      Compressive strength limit and elastic modulus of first lumbar vertebrae, and
      bend load of femur were measured by light-based elastometer. RESULTS: JGG can
      significantly increase BMD, area of trabecula and thickness of bone
      cortex/diameter of marrow cavity ratio of model rats, to elevate the compressive
      strength limit of vertebrae and bend load of femur. CONCLUSION: JGG could
      increase BMD of osteoporosis model rats, and also could effectively improve the
      structure of osseous tissue, biomechanical property of bone and enhance the
      overall quality of bone.

PMID- 15199630
TI  - [Regulatory function of nuclear factor kappa B on lymphocyte proliferation and
      apoptosis in bronchial asthmatic rats and effect of triptolide on the
      regulation].
AB  - OBJECTIVE: To investigate whether nuclear factor kappa B (NF-kappa B)
      participates in the regulatory function of lymphocyte proliferation and apoptosis
      in bronchial asthma and whether the regulatory effect of triptolide on lymphocyte
      proliferation and apoptosis is conducted through NF-kappa B. METHODS:
      Intervention with dexamethasone, triptolide and PDTC, a NF-kappa B inhibitor,
      were used to treat astmatic rats respectively. Pathological examination, airway
      response were determined, the NF-kappa B P65 expression in lung tissue and
      splenic lymphocytes by immunofluorescent assay were adopted, proliferative cell
      nuclear antigen (PCNA) in splenic lymphocytes was measured by
      immunohistochemistry, apoptosis of splenic lymphocytes were monitored by flow
      cytometry and NF-kappa B activity was investigated by electrophoresis mobility
      shift assay (EMSA). RESULTS: The nuclear expression and DNA binding activity of
      lung tissue and splenic lymphocytes in asthmatic rats were all significantly
      higher than those in the control (all P < 0.05), so was the proliferation rate of
      splenic lymphocytes (P < 0.05), while the apoptosis rate was much lower than that
      of normal control (P < 0.05). Administration of PDTC could reduce the up
      regulated expression and activity of NF-kappa B, the proliferation of splenic
      lymphocytes lowered, while the apoptosis increased. NF-kappa B activity showed an
      obviously positive correlation with proliferation of splenic lymphocytes (r =
      0.89, P < 0.05) and a significantly negative correlation with apoptosis rate (r =
      -0.54, P < 0.05). After asthmatic rats had been treated with triptolide in vivo,
      the NF-kappa B nuclear expression and activity in airway and splenic lymphocytes,
      as well as the proliferation rate of splenic lymphocytes all lowered
      significantly (all P < 0.05), the apoptosis rate increased significantly (P <
      0.05), at the same time, the inflammatory cell infiltration and high reactivity
      of airway were significantly alleviated (both P < 0.05). There were obviously
      positive correlation between the amount of airway eosinophils and reactivity with
      activity of NF-kappa B (r = 0.79 and r = 0.68, P < 0.05), which indicated that
      the effect of triptolide was not significantly different from that of
      dexamethasone (P > 0.05). CONCLUSION: (1) NF-kappa B participates the formation
      of airway inflammation and hyper-reactivity in asthmatic rats by positive
      regulation on proliferation and negative regulation on apoptosis of lymphocytes.
      (2) Triptolide reduces airway inflammation by way of inhibiting NF-kappa B, and
      further inhibiting the proliferation of lymphocytes, so that to give full play of
      the role of anti-asthmatic airway inflammatory agents. Whether the molecular
      mechanism of triptolide in inhibiting NF-kappa B simulates that of glucocorticoid
      needs further studying.

PMID- 15199632
TI  - [Effect of safflower injection on cardiac energy charge and anti-apoptosis gene
      bcl-2 in rats' heart].
AB  - OBJECTIVE: To study the effect of safflower injection (SI) in protecting heart,
      and on energy charge and anti-apoptosis gen bcl-2 in cardiac tissue. METHODS:
      Rats' Langendorff isolated heart infused model was used in the experiment to
      study the effect of SI by measuring the cardiac function, energy charge and bcl-2
      expression of the cultured heart in the modified Euro-Collins (mEC) heart
      preserving liquid with or without addition of SI. RESULTS: As compared with the
      control, SI showed the effects of improving functions of cardiac contraction and
      dilation, increasing coronary blood flow, and strengthening the bcl-2 protein
      expression. CONCLUSION: SI has excellent effect in protecting heart.

PMID- 15199631
TI  - [Effect of ligustrazine on expressions of basic fibroblast growth factor and its
      receptor in bone marrow of mice with acute radiation injury].
AB  - OBJECTIVE: To study the expressions of basic fibroblast growth factor (bFGF) and
      its receptor (bFGFR) in bone marrow of mice with acute radiation injury, and to
      evaluate the effect of Ligustrazine (Lt) on them. METHODS: Fifty-six Kunming mice
      of clean grade were randomly divided into 3 groups, the normal group, the control
      group and the Lt group. Mice in the latter two groups were once homogeneously
      systemic irradiated with 6.0 Gy of 60Co, with the absorption dose rate of 0.56
      Gy/min, then treated with saline (0.2 ml/mice) or Lt (2 mg/mice) respectively,
      twice a day through gastrogavage for successive 13 days. Mice were sacrificed in
      batch on the 3rd, 7th and 14th day by cervical dislocation to collect the
      bilateral femoral bone marrow for preparing bone marrow mono-nuclear cell (BMMNC)
      suspension. The bFGFR expression on surface of BMMNC was determined by flow
      cytometry; and the bFGF expression level in one side of femoral bone marrow
      tissue was detected by immunohistochemistry with SABC-AP assay. RESULTS: The bFGF
      expression in bone marrow of mice on the 3rd, 7th and 14th day after acute
      radiation injury all were significantly lower than that of the normal mice (P <
      0.05 or P < 0.01). The expressions of bFGF and bFGFR in the Lt group detected
      were significantly higher than that in the control group detected at the
      corresponding time points (P < 0.05 or P < 0.01). CONCLUSION: By way of enhancing
      bFGF expression in bone marrow and bFGFR expression on surface of BMMNC to
      accelerate the repairing of homopoietic micro-environment in bone marrow might be
      one of the mechanisms of Lt in promoting hemopoietic function reconstitution
      after acute radiation injury.

PMID- 15199633
TI  - [Renal protective effect and its mechanism of sodium ferulate in diabetic rats].
AB  - OBJECTIVE: To study the renal protective effect of sodium ferulate (SF) and its
      mechanism in rats with diabetic mellitus (DM). METHODS: DM rats induced by
      streptozotocin were treated with SF 110 mg/kg per day for 8 weeks. The ratio of
      kidney weight/body weight (KW/BW), serum triglyceride (TG) and total cholesterol
      (TC), creatinine clearance rate (Ccr), urinary protein/24 hrs, levels of
      endothelin-1 (ET-1) and nitric oxide (NO) in renal cortex in rats were measured,
      the pathological change of kidney were observed and the expression of
      transforming growth factor-beta 1 (TGF-beta 1) and collagen IV (C-IV) in kidney
      were examined using immunohistochemical assay. The data obtained were compared
      with those obtained from untreated DM rats and normal rats respectively. RESULTS:
      Compared with the normal rats, in DM rats, Ccr, urinary protein/24 hrs, ET-1,
      expressions of TGF-beta 1 and C-IV were significantly increased in DM model rats
      (all P < 0.01), and significantly abnormal pathological change in kidney was
      found. While in the SF treated DM rats, the above-mentioned abnormal changes were
      all significantly improved. CONCLUSION: SF has effect in protecting kidney of DM
      rats, the mechanism might be related with its actions of reducing ET-1 production
      in kidney and inhibiting the expressions of TGF-beta 1 and C-IV.

PMID- 15199634
TI  - [Clinical observation on effect of shennong xian'ganling capsule in treating
      chronic hepatitis and liver cirrhosis].

PMID- 15199635
TI  - [Observation on therapeutic effect of compound salvia drop-pill in treating
      vasovagol syncope].

PMID- 15199636
TI  - [Clinical observation on treatment of chronic pulmonary heart diseases in
      aggravation stage by intervention with drugs for activating blood circulation and
      removing stasis].

PMID- 15199637
TI  - [Relationship between syndrome pattern of psoriasis and platelet thrombin
      sensitive protein and CD36 molecular expression].

PMID- 15199638
TI  - [Progress of the methodology for studying Chinese compound recipe].

PMID- 15199639
TI  - [Gladness and troubles for using garlic as an anti-oxidant].

PMID- 15199640
TI  - [Coming of the era of preventive drugs--the best chance for TCM going toward
      world].

PMID- 15199641
TI  - [Survey on the study of regulating cell adhesive factors by Chinese herbal
      medicine].

PMID- 15199642
TI  - Ethics in action. A violent patient.

PMID- 15199644
TI  - Tackling med errors with technology.

PMID- 15199646
TI  - A remembrance for the children.

PMID- 15199645
TI  - Penetrating chest wounds.

PMID- 15199647
TI  - Is it an MI? What the leads tell you.

PMID- 15199648
TI  - Advance directives: your role.

PMID- 15199649
TI  - [False forensic expertise--analysis of occurrences].
AB  - Main problems that await the modern Polish forensic psychiatry are presented. The
      most common mistakes made in forensic expertise are discussed and their causes
      are shown. The need for a change in the manner of teaching forensic psychiatry at
      an academic, as well as post graduate level to medical students/doctors as well
      as law officials, has been stressed. The criteria for calling on experts, system
      of control and evaluation of the expertise formulated and rules of payment to the
      experts--all need changing. The altered criminal structure and possibilities of
      putting pressure on experts through corruption, threatening or blackmail were
      noted. The clearly defined status of the forensic psychiatric expert gives him a
      guarantee of legal defence and through this an unbiased position. Giving forensic
      expertise is not only part of the diagnostics in forensic psychiatry. An even
      layout of protection, treatment and rehabilitation of psychiatrically ill
      criminals has to be present in this system.

PMID- 15199650
TI  - [P50 component of auditory evoked potentials in persons with schizophrenia and
      their first degree relatives].
AB  - A pair of auditory stimuli presented in a 0.5 second interval cause a reduction
      of the P50 auditory evoked potential (P50 AEP) amplitude after the second stimuli
      in the pair. In some, but not all studies, a clear deficit of such P50 AEP gating
      was observed in schizophrenic patients. It was present constantly irrespective of
      the clinical state. This deficit was also found in first degree relatives of
      schizophrenic patients. However the results of the studies, as well as their
      interpretation remain controversial. AIM: To differentiate between P50 AEP in
      groups of schizophrenic patients, their healthy first degree relatives, as well
      as those in the control group. METHOD: 50 schizophrenic patients (ICD-10 criteria
      (DCR)) in early clinical improvement phase, 26 healthy first degree relatives, as
      well sa 46 healthy individuals with no psychiatric illness in the self-report and
      family history. All those studied were stimulated with 120 pairs of auditory
      stimuli (clicks), each of duration 2 mseconds and a sound intensity of 73 dB,
      with a 500 msecond interval between the stimuli in a pair (S1 and S2) every 8
      seconds. A high-end filter of 70 Hz and low-end filter of 10 Hz were applied. Bio
      potentials were recorded from the head apex, relatively to the mastoid process
      (A1 + A2). Eyeball-movement artefacts were registered from the Fp1-A1 and Fp2-A2
      potentials. The registered bio potentials were evened on-line. RESULTS: Relative
      (i.e. evaluated in relation to the potential after S1) lowering of the P50
      potential after S2 was the most significant in the healthy control group (75%),
      in the other groups usually there was an increase in the S2 potential--higher in
      the schizophrenic patient group (-45%) and lower in their first degree relatives
      (-11%). CONCLUSIONS: (1) Healthy individuals suppressed the neurophysiologic
      response to the second pair of auditory stimuli much more than the schizophrenic
      patients and their healthy families. (2) No difference was seen in the
      suppression of the response between the schizophrenic patients and their first
      degree relatives. The results are coherent with the idea of the dysfunction of
      the P50 gating having endophenotypic traits as far as schizophrenia goes.

PMID- 15199651
TI  - [Personality and marriage of schizophrenic patients].
AB  - AIM: The aim of this research is to compare some personality factors like self
      perception and perception of an ideal partner in two groups of schizophrenic
      patients. The first group is people ill with schizophrenia who have been married
      for at least a year and the other group is unmarried people ill with
      schizophrenia who were not previously married or in a relationship for longer
      than a year. METHOD: In this study, using The Adjective Check List--ACL by H.G.
      Gough and A.B. Heilbrun (Polish translation by M. Matkowski), has been used as an
      instrument for evaluation self-perception and perception of an ideal partner.
      RESULTS: Results of the research corroborate differences between chosen personal
      dimensions in compared groups of people ill with schizophrenia. There were
      statistically substantial differences in some scales of ACL between the married
      and unmarried schizophrenic patients. The married patients were characterized by
      a larger number of positive adjectives chosen, higher results in the scales of:
      FAV--Favourite, NUR--Nursing, HET--Heterosexuality, CHA--Change, CPS--Creative
      personality, UGD--Amicability; and lower results in the scales of: CRS--Care
      support. Perception of an ideal partner differentiated the groups in a lower
      degree. Two scales proved to be statistically substantial: NUR--Nursing, CHA-
      Change. The married patients were substantially weaker in displaying such needs
      towards their ideal partners. CONCLUSIONS: What differs the group of married
      people ill with schizophrenia from unmarried people ill with schizophrenia is
      mainly personality features connected with the need to initiate and keep up
      interpersonal contacts. The married patients want such relationships, are more
      prone to compromise and do something for others and are less afraid of changes.
      They also have lower expectations of their ideal partners as to the care of
      others. They do not expect their ideal partners to be ready to change as much as
      unmarried patients.

PMID- 15199652
TI  - [Different approaches to the concept of family burden in schizophrenia].
AB  - This paper explores selected theoretical and experimental issues related to the
      notion of burden. The burden is a phenomenon which appears not only inside
      families with diagnosed schizophrenia but also in families of people presenting a
      different kind of psychic disorder or those being mentally handicapped. Using the
      term "family burden" is not usually followed by such operationalization of the
      notion, that would unable its investigation in the family system. Research does
      not say which sociodemographic and psychosocial factors have a decisive impact on
      the level of the noticeable burden. It seems, however, that a minor role should
      be attributed now to sociodemographic factors, while methods of overcoming the
      problems are the most significant. Findings let us think that objective factors
      composing the burden are individually judged by care givers who work with people
      with psychic disorders. This evaluation decides how important a specific factor
      is. This situation makes us reconsider the traditional division of the objective
      and subjective burden. The symptoms that might be noticed with the patients are
      not the only predictors of the burden. The source of care givers' burden is not
      directly connected with the psychopathological symptoms but rather with a deficit
      in a patient's sphere of functioning. While analysing the burden inside families
      of patients with psychic disorders it should be remembered that the reason can be
      not only problems related directly to the illness but also a number of unspecific
      factors saddling the family like unemployment, poor living conditions,
      difficulties at work, at school etc. Findings presented in this article disclose
      a poor precision of existing burden definitions resulting from a lack of a
      consistent conception of this phenomenon. The author attracts our attention to
      socio-cultural conditioning of the burden and shows how people with mental
      disorders positively contribute to family life. Nowadays the classical concept of
      the burden is more often replaced by stress management models. In the conclusion
      the author points out that the research on burden conducted so far is rather
      insufficient.

PMID- 15199653
TI  - [The effectiveness of psychoeducation in schizophrenic and depressive patients-
      preliminary report].
AB  - Earlier studies suggest that psychoeducation as a form of psychosocial care is of
      value in improving the patient's attitude towards mental illness as well as in
      reducing and delaying the relapse rates of both--psychotic and depressive
      disorders. AIM: The aim of this study was the evaluation of influence of
      psychoeducation on clinical symptoms, quality of life and drug attitude in
      schizophrenic and depressive patients. METHOD: 52 patients, aged 18-50 years,
      hospitalized in the Department of Psychiatry of Medical Academy in Bialystok,
      were involved in the study. They were randomly assigned into 2 groups: on
      medication without psychoeducation (12 schizophrenics, 12 depressive patients)
      and on medication and psychoeducation (16 schizophrenics and 12 depressive
      patients). The patients were assessed by means of BPRS, BNS, IMHC 2000,
      Raskin/Covi Scale, DAI-10. The assessment was performed twice--shortly after
      admission and before discharge from the hospital. RESULTS: The patients in both
      groups showed improvement in symptoms and in quality of life. Patients on
      psychoeducation changed their drug attitude positively significantly more often.
      CONCLUSION: Knowledge about the positive influence of medication on psychiatric
      symptoms helps to improve compliance and improves the course of disease.

PMID- 15199654
TI  - [The role of social support on the quality of life of patients with
      schizophrenia].
AB  - The importance of social support for mentally ill people has been increasingly
      emphasized in recent years. This has resulted from studies showing that family
      and professional support plays an important role in preventing rehospitalizations
      and in improving quality of life of patients with schizophrenia. This article
      presents and analyses the findings of current research concerning the
      effectiveness of social support in rehabilitation programmes as well as
      highlights the problem of matching the type and quantity of social support
      provided to the patients' needs and to the phase of the disease.

PMID- 15199655
TI  - [Effectiveness and tolerability of amisulpride in patients with schizophrenia:
      results of a 6-month open study].
AB  - AIM: 6-month multicentre, observational, open study evaluated the efficacy and
      tolerability of the new generation antipsychotic drug amisulpride in patients
      with acute schizophrenia. METHOD: 99 patients were included in the study, 72
      (72%) completed the 6-month observation. RESULTS: Marked improvement in CGI after
      6 months of treatment was observed in 56 (56%) patients. Therapy with amisulpride
      reduced both positive (20% reduction of positive symptoms in the PANSS positive
      subscale in 78%) and negative symptoms (20% reduction of negative symptoms in the
      PANSS negative subscale in 77%). CONCLUSION: Amisulpride was well tolerated,
      adverse events responsible for premature withdrawal from the study were observed
      only in 6% patients.

PMID- 15199656
TI  - [Prospective observational study of outpatients with schizophrenia in Poland:
      preliminary 6 month efficacy and tolerability results].
AB  - AIM: To compare the effectiveness and tolerability of olanzapine and other
      antipsychotic treatments (6 months after enrollment) in Polish patients with
      schizophrenia participating in the IC-SOHO (the Intercontinental Schizophrenia
      Outpatient Health Outcomes) study. METHOD: IC-SOHO is a 3-year, global,
      prospective, observational study examining health outcomes in outpatients with
      schizophrenia undergoing treatment with antipsychotics. Patients were offered
      enrollment by a psychiatrist if they initiated or changed antipsychotic
      medication for the treatment of schizophrenia. The study was designed to provide
      two patient cohorts of approximately equal size: patients who initiated or
      switched to olanzapine, and patients who initiated or switched to non-olanzapine
      antipsychotic therapy. Mean changes in positive, negative, cognitive, depressive
      and overall symptoms from baseline to 6 months, as measured using the CGI scale,
      were assessed. The incidence of extrapyramidal symptoms and sexual dysfunctions
      and weight changes were compared. RESULTS: Out of 7648 patients participating in
      the IC-SOHO study, 626 patients were enrolled in Poland. After 3 and 6 months of
      treatment, significantly greater improvement in overall symptoms measured using
      the CGI scale was observed in patients with olanzapine than in those with other
      antipsychotics. Response rate at 6 months was significantly higher in the
      olanzapine group than in the non-olanzapine group. Incidence of extrapyramidal
      symptoms and sexual dysfunctions was lower in olanzapine group. CONCLUSIONS:
      After 6 months, olanzapine-treated patients showed greater improvement of
      clinical status compared with other antipsychotic treatment. Olanzapine treatment
      was more beneficial for patients; comparing to other antipsychotic treatment less
      extrapyramidal symptoms and sexual dysfunctions were observed.

PMID- 15199657
TI  - [Use of high-dose olanzapine for treatment of acute relapse of schizophrenia in a
      patient with bad tolerance of typical neuroleptics. Case report].
AB  - AIM: The purpose of the study was to assess the efficacy of high doses of
      olanzapine for treatment of the patient suffering from schizophrenia with
      predominance of positive symptoms. The blood levels of prolactin and glucose were
      monitored in order to determine the influence of high dose of olanzapine on these
      levels and to make a comparison between olanzapine and typical neuroleptics in
      this aspect. METHOD: The patient suffering from schizophrenia with predominance
      of positive symptoms, poorly tolerating typical neuroleptics and with no positive
      result of a standard dose of olanzapine treatment, was treated with high doses of
      olanzapine. PANSS was used to assess severity of symptoms, to rate side effects.
      The authors used Webels modification of Simpson and Angus scale. RESULTS: During
      the high dose olanzapine treatment a marked reduction of PANSS score was
      achieved. Also the reduction of score in Simpson and Angus scale was observed,
      high level of this score at the beginning was due to classical neuroleptic
      treatment. There was no increase in blood prolactin level (in comparison with the
      high earlier one after typical neuroleptic treatment), whilst glucose level was
      not elevated. CONCLUSIONS: High dose olanzapine seems to be an effective and safe
      method of treatment of paranoid schizophrenia with predominance of positive
      symptoms in patients poorly tolerating typical neuroleptics.

PMID- 15199658
TI  - [Prevalence and type of dermatologic disorders in psychiatric patients treated
      with psychotropic drugs].
AB  - AIM: The aim of the study was to establish prevalence and type of dermatologic
      symptoms in patients with mental disorders, treated with psychotropics drugs, and
      comparison of the frequency and type of dermatologic disorders after typical
      psychotropics and new psychotropic drugs, and assessment of relationships between
      diagnosis of mental disorders and type of dermatologic symptoms. METHOD: In the
      study 4041 patients hospitalized and treated with psychotropic drugs in a
      psychiatric hospital took part. Dermatologic consultation was conducted in 340
      patients, but only 98 were in monotherapy. This group was assessed with a next
      procedure: questionnaire regarding demographic dates, early and family
      dermatologic disorders, treatment with other than psychotropics--drugs, diet,
      addictions and analysis of medical documentation (psychiatric and dermatologic
      diagnosis, actual pharmacotherapy). RESULTS AND CONCLUSIONS: 8.4% of the subjects
      had dermatologic symptoms, which were consulted by dermatologists. 1/2 of this
      group had their first treatment with psychotropics. Dermatologic symptoms
      appeared more often in patients treated with more than 2 psychotropics than in
      patients in monotherapy, usually in the first weeks of pharmacotherapy. Nearly
      1/3rd of these subjects had allergic disorders. In subjects treated with
      psychotropics the most frequent dermatologic symptoms (allergic diseases,
      psoriasis and psoriasislike disorders) were noted after therapy with
      antipsychotics, next anxiolytics. In 3/4 patients treated with antidepressants
      had vascular diseases of the skin. In the whole group, dermatologic disorders
      appeared most frequently after treatment with BZD, phenothiazines and
      butyrophenones. New psychotropic drugs caused less dermatologic symptoms than
      typical antipsychotics and antidepressants.

PMID- 15199659
TI  - [Selective serotonin reuptake inhibitors--current knowledge].
AB  - This article is a review of the current state of knowledge about possibilities of
      clinical use of selective serotonin reuptake inhibitors in different areas of
      psychopharmacotherapy. The authors presented information about pharmacodynamic
      and pharmacokinetic differences between SSRI's, and described emerging clinical
      consequences. The paper contains data about the most common and typical side
      effects and possible drug interactions. The reports and information about new
      therapeutic proposals concerning SSRI's are also discussed.

PMID- 15199660
TI  - Gene and cell therapy in cardiovascular diseases: still a long way to go.

PMID- 15199661
TI  - Some aspects of genetic polymorphism in the biotransformation of antidepressants.
AB  - Tricyclic antidepressants are all hydroxylated by cytochrome P450 (CYP) 2D6, but
      the tertiary amines, amitriptyline, clomipramine and imipramine, are also N
      demethylated to the active metabolites, nortriptyline, N-desmethylclomipramine
      and desipramine, by several CYPs, including the polymorphic CYP2C19, CYP1A2 and
      CYP3A4. The five selective serotonin reuptake inhibitors, citalopram, fluoxetine,
      fluvoxamine, paroxetine and sertraline are also oxidised by the CYP enzyme
      system. Thus, fluoxetine, fluvoxamine and paroxetine are partially metabolised by
      CYP2D6, citalopram by CYP2C19 and sertraline by at least five different CYPs.
      Paroxetine and fluoxetine are very potent inhibitors of CYP2D6 while citalopram,
      fluvoxamine and sertraline are moderate inhibitors of this enzyme. Fluvoxamine is
      a potent inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9.
      Since the termination of the human genome project, there is no longer a technical
      hindrance to the identification of all of the genes involved in the clinical
      response to antidepressants. Research in the future will involve modern
      technologies and new scientific disciplines, including DNA-micro-array technology
      and bioinformatics. The research ultimately aims at developing better and safer
      antidepressants and/or better and safer use of currently available
      antidepressants.

PMID- 15199663
TI  - [The virtual synapse what is its contribution to understanding cholinergic neural
      transmission?].
AB  - Since the launch of cholinomimetics on the Alzheimer market, large clinical
      trials have been performed with the aim of linking clinical scales to the
      pathology and pharmacology of the cholinergic neurotransmission system. However,
      given the additional mode of action of nicotinic receptor modulation in the case
      of galantamine, and of butyrylcholinesterase inhibition in the case of
      rivastigmine, it is of interest to study the link between this additional
      pharmacology and the specific clinical outcomes. This may be helpful in
      identifying new targets and optimising the clinical development of new compounds.
      One of the most appropriate and promising approaches is to use mathematical
      modelling to describe the complex pharmacology of these agents and their
      relationships with clinical outcomes. The virtual synapse is based upon the full
      integration of neuroanatomical and neuropharmacological datasets, to which
      complete pharmacological information on the drugs is added. Validation of this
      system is performed by predicting the outcome in a preclinical setting and
      subsequent testing of this hypothesis. Some examples of this model with regard to
      the prediction of clinical outcome are presented.

PMID- 15199662
TI  - [Proteomic analysis of proteins involved in the renal phenotype in renovascular
      hypertension].
AB  - Renovascular hypertension is characterised by stenosis of the renal artery and
      high plasma renin levels due to the recruitment of renin-producing cells along
      the afferent arterioles. This increase in myoepithelioid cells is mainly a result
      of the differentiation of existing smooth muscle cells with acquisition of a
      secretory phenotype. To understand the molecular mechanisms involved in this
      recruitment, we used the model of renovascular hypertension known as the two
      kidney, one-clip model in the Lewis rat. Renal arterioles were isolated using
      magnetised iron suspension. Differential proteomic analysis was performed using
      two-dimensional electrophoresis gel followed by mass spectrometry for
      identification. The most striking protein revealed by proteomics is troponin T,
      which is down-regulated in the afferent arterioles of the clipped kidney.
      Confocal microscopy showed that troponin T is specific to the smooth muscle
      phenotype and absent in the myoepithelioid phenotype.

PMID- 15199664
TI  - [Cell protection through PPAR nuclear receptor activation].
AB  - Apart from their effects on lipid and glucose metabolism, the nuclear receptors
      PPARs (peroxysome proliferator-activated receptors) could also be involved in
      cellular protection. Indeed, an increasing body of literature provides arguments
      in favour of a protective role of PPAR alpha (fenofibrate, gemfibrozil) and PPAR
      gamma (ciglitazone, pioglitazone, rosiglitazone, troglitazone) agonists,
      particularly in myocardial or cerebral ischaemia as well as in neurodegenerative
      diseases. Such cellular protection could be the result of the modulation, at a
      molecular level, of inflammation pathways, oxidative stress and apoptosis. If
      these experimental results are confirmed by appropriate clinical trials,
      pharmacological modulation of the nuclear receptor PPARs, as well as the
      development of highly selective and more effective PPAR agonists, could become an
      important challenge in the field of cellular protection.

PMID- 15199666
TI  - Short courses in integrated pharmacology and physiology.

PMID- 15199665
TI  - [Role of endothelial dysfunction in sepsis mortality].
AB  - During the past decade, a unifying hypothesis has been developed to explain the
      vascular changes that occur in septic shock on the basis of the effect of
      inflammatory mediators on the vascular endothelium. The vascular endothelium
      plays a central role in the control of microvascular flow, and it has been
      proposed that widespread vascular endothelial activation, dysfunction and
      eventually injury occur in septic shock, ultimately resulting in multiorgan
      failure. This has been characterised in various models of experimental septic
      shock. Now, direct and indirect evidence for endothelial cell alteration in
      humans during septic shock is emerging. The present review details recently
      published literature on this rapidly evolving topic.

PMID- 15199667
TI  - [Importance of in vivo pharmacology in research and development].
AB  - The pharmaceutical industry, with its well structured research, is now an area
      where the in vivo pharmacologist has a well recognised role. After a period of
      relative loss of interest related to the belief of the 'all in vitro', the
      impressive development of molecular biology, genomics, proteomics, and now
      metabonomics has surprisingly revived the absolute necessity for the
      pharmaceutical industry, within its R&D (research and development) teams, to give
      the responsibility to in vivo pharmacologists for the following: validating new
      targets; phenotyping transgenic animals; determining the activity and potency of
      molecules, as well as exposing their potential unwanted pharmacological
      activities; contributing to the characterisation of pharmacokinetics and
      metabolism; participating in numerous other research and development activities
      such as the preparation of submission of files to authorities.

PMID- 15199668
TI  - [The importance of in vivo pharmacology in fundamental research on psychotropic
      drugs and their biological targets].
AB  - The main families of psychotropic drugs have been almost fortuitously discovered,
      from investigations carried out directly in humans. The burst of studies
      triggered by these discoveries and the considerably strengthened ethical
      guidelines for clinical trials have allowed remarkable developments in
      preclinical studies performed in animals, and especially in rodents. The
      corresponding models may be classified as follows: homologous models mimicking
      the aetiology of the disease against which one attempts to develop drugs;
      isomorphic models mimicking specific symptoms of a disease but involving
      different aetiological mechanisms; predictive models, which assess the effect of
      a drug on behavioural or other functional signs/symptoms unconnected to the
      psychiatric disease but involving the same type of biological targets as those
      affected by the disease; and theoretical or explanatory models that aim to
      elucidate the mechanism of action of agents producing psychotropic effects. Among
      the latter, the following can be cited: the knock out of genes coding for a
      specific biological target; the neutralisation of a specific ARNm by antisense
      oligodeoxynucleotides, which also aims to prevent the synthesis of a specific
      biological target; use of controlled reproduction to achieve a concentration of
      genes, the association of which leads to the development of a disease. Each one
      of these approaches has been illustrated by an example developed within the Rouen
      Neuropsychopharmacology Unit: the psychobehavioural spectrum of mice with
      invalidation of the gene coding for adenosine A2A receptors; the abolition of
      either nociceptin ORL1 receptors or neurotensin NTR2 receptors in order to
      characterise their functions; the concentration, by controlled breeding in mice,
      of a phenotype corresponding to that of depression. These developments illustrate
      several recent developments in neuropsychopharmacology with the aim of
      emphasising the vitality of this discipline.

PMID- 15199669
TI  - [Local ethics committees for animal experimentation].

PMID- 15199670
TI  - A postgraduate course in preclinical drug evaluation.

PMID- 15199671
TI  - [Controversies on the arterial risk of hormone substitution treatment].

PMID- 15199672
TI  - [Genetic polymorphism and treatment of chronic bowel inflammatory diseases: the
      example of azathioprine].
AB  - Azathioprine is an immunosuppressive drug used in the treatment of inflammatory
      bowel disease. It is a prodrug that is hydrolysed to 6-mercaptopurine, which
      represents the active form. Azathioprine is also used in the treatment of
      leukaemia in children and in organ transplantation. Azathioprine treatment is
      associated with adverse effects such as leukopenia and aplasia. These adverse
      effects are related to a single nucleotide polymorphism, including the inability
      of cells to synthesize thiopurine methyltransferase (TPMT). TPMT is a
      detoxification enzyme that limits 6-thioguanine nucleotide production and thereby
      interferes with normal DNA and RNA synthesis. This review presents the different
      approaches used for azathioprine therapeutic monitoring in IBD treatment and
      discusses the discrepancies in recent clinical trials.

PMID- 15199673
TI  - [New therapeutic targets for chronic inflammatory bowel disease].

PMID- 15199674
TI  - [Probiotics in inflammatory bowel disease: controlled trials and perspectives].
AB  - Probiotics may modulate intestinal flora and immunity and are therefore studied
      in an attempt to modulate experimental colitis or human inflammatory bowel
      disease. We analysed randomised controlled trials performed using probiotics in
      humans with Crohn's disease, ulcerative colitis and pouchitis. Perspectives
      include the use of genetically modified micro-organisms to deliver anti
      inflammatory agents to the gastrointestinal tract.

PMID- 15199675
TI  - [Motor complications in dopa treatment of parkinson disease: clinical description
      and evaluation].
AB  - The aim of this study was to present the clinical characteristics of and the
      evaluation methods for the motor complications sometimes observed in the early
      stages of Parkinson's disease, differentiating motor fluctuations and levodopa
      induced dyskinesias. The most common forms of motor fluctuations are the
      predictable end-of-dose deterioration (wearing off), the early-morning akinesia,
      and the on-off phenomenon. Non-motor fluctuations are often associated with
      different symptoms: dysautonomia, pain, psychic or cognitive signs during off
      periods and sometimes also during on periods. Levodopa-induced dyskinesias are
      classified according to their temporal profile after drug administration, namely
      peak-dose dyskinesias (mainly choreic movements), biphasic dyskinesias--onset and
      end-of-dose--(mainly dystonic and ballic movements), and finally off-period
      dyskinesias (dystonic movements). Clinical evaluation of motor complications must
      be performed precisely to establish the best therapeutic strategy.

PMID- 15199676
TI  - [Drug-induced parkinson syndromes].
AB  - Parkinsonism is defined by the association of akinesia with one of the following
      symptoms: extrapyramidal rigidity, tremor at rest, or postural instability. A
      drug-induced aetiology must always be suspected when parkinsonian symptoms
      appear, or increase in a patient receiving drug treatment. Indeed drug-induced is
      the more frequent aetiology of secondary parkinsonism. The main treatments
      involved are antipsychotic and other neuroleptic drugs (accounting for up to two
      thirds of drug-induced parkinsonism), and calcium-channel entry blockers. The
      risk associated with antipsychotics is often dose dependent and related to
      dopamine D2 striatal receptor occupancy induced by the antipsychotic drug. This
      risk is inferior for the second generation antipsychotics. The other treatments
      more rarely involved are antidepressants (tricyclic and selective serotonin
      reuptake inhibitors), lithium, valproic acid, and others. The main criterium for
      imputability is chronological, regression of symptoms being observed in 40-74% of
      cases, after a mean delay of 3 months from cessation of treatment. However, 15%
      of cases persist after drug withdrawal, leading to a diagnosis of underlying
      idiopathic Parkinson's disease.

PMID- 15199677
TI  - [Drug-induced movement disorders: tardive syndromes].
AB  - Persistent drug-induced movement disorders (tardive syndromes) remain an
      important clinical problem and consist of a variety of involuntary movements
      appearing in a patient exposed to a dopamine-blocking agent. The current state of
      knowledge on this topic is summarised in this article. Clinical aspects (tardive
      dyskinesia, tardive dystonia and other forms), prevalence, risk factors,
      prevention and management are discussed.

PMID- 15199678
TI  - [Cardiotoxicity of anthracyclines: mechanisms and pharmacologic targets for
      prevention].
AB  - Anthracyclines are a class of highly potent antitumour agents utilised against
      haematological and solid tumours. However, their use has been limited by their
      cardiotoxic adverse effects, which may lead to congestive heart failure. Such
      cardiac toxicity is directly related to the cumulative (total) dose of
      anthracyclines received. At the cellular level, many of the molecular mechanisms
      of anthracycline-induced cardiotoxicity remain obscure. The present review
      summarises the current knowledge on the production of anthracycline-induced
      reactive oxygen species, metabolite generation or cell death, and focuses on the
      molecules used to prevent anthracycline-induced cardiotoxicity.

PMID- 15199679
TI  - [Drug-induced heart failure (excluding that caused by anthracyclines)].
AB  - The principal drugs implicated in or disclosing cardiac insufficiency are drawn
      from a review of the literature and observations by the French national
      pharmacovigilance database, from 1984 to April 2003. Several pharmacological
      classes are identified: in addition to antimitotic drugs, such as anthracyclines,
      many drugs are implicated in cardiac insufficiency, e.g. immunomodulators, anti
      inflammatory drugs (including coxibs), antiarrhythmic drugs, anaesthetic drugs,
      antipsychotic drugs, and antidiabetic drugs (including glitazones). It is usual
      to classify these drugs according to three categories: (i) drugs likely to cause
      cardiac insufficiency de novo (such as cyclophosphamide, paclitaxel,
      mitoxantrone, interferons, interleukin-2 etc.); (ii) drugs likely to worsen
      preexisting cardiac insufficiency (such as antiarrhythmics, beta-blockers,
      calcium antagonists, nonsteroidal and steroidal anti-inflammatory drugs,
      sympathomimetic drugs etc.); and (iii) drugs only occasionally causing cardiac
      insufficiency. This review shows that this classification is, in fact,
      artificial. If cardiac toxicity is a constant concern when using antimitotic
      drugs or some immunomodulator drugs, it is advisable to exercise caution in the
      use of many other drugs when treating patients with cardiac insufficiency, even
      if the clinical situation is well controlled. In particular, drug-drug
      interactions and patient medical history must be taken into account.

PMID- 15199680
TI  - [A meeting of clinical investigation centers].

PMID- 15199681
TI  - [Proceedings of a workshop entitle "Phase I and Early Phases"].

PMID- 15199683
TI  - [Proceedings of a workshop entitled "Procedures Used in Clinical Investigation
      Centers"].

PMID- 15199682
TI  - [Research in clinical health care: an innovative experience at the Henri Mondor
      University Hospital].

PMID- 15199684
TI  - Towards a European Clinical Research Infrastructures Network: the ECRIN
      programme.
AB  - On the basis of the interconnection of national networks of clinical research
      centres (CRCs) and clinical trials units (CTUs), the European Clinical Research
      Infrastructures Network (ECRIN) programme aims to develop an infrastructure
      allowing for bottom-up harmonisation of the support and training for, and
      practice of, clinical research, and to provide public sponsors for biotechnology
      small and medium-sized companies (SMEs) with support for translational research
      and multicentre clinical studies in Europe. This will be achieved through an
      application to the next FP6 'Integrated Infrastructure Initiatives' call.
      However, prior work is required to improve the reciprocal knowledge of partners
      in the ECRIN consortium and, as a first step, country-specific workshops will be
      organised by national networks in order to address the organisation of CRC/CTUs
      and national networks, and their interaction with the national environment of
      clinical research; this will enable in-depth discussion addressing the
      bottlenecks hampering transnational studies.

PMID- 15199685
TI  - [Software modeling for better understanding of pharmacokinetic-pharmacodynamic
      relationships: application to azithromycin in the treatment of streptococcal
      tonsillitis and in acute exacerbation fo chronic bronchitis]].
AB  - In order to illustrate the significance of pharmacokinetic/pharmacodynamic
      (PK/PD) parameters of azithromycin (AZM) in tonsillar and respiratory tract
      infections, we developed original simulation software. As area under the curve
      over 24 hours divided by the minimum inhibitory concentration (AUC24/MIC) and
      time over a 24-hour period that the drug concentration exceeds the MIC (t > MIC)
      are important predictors of the clinical efficacy of macrolides, our software
      calculates these indices for plasma, tonsil, epithelial lining fluid (ELF), lung
      tissue (LT) and alveolar macrophages (AM). For an MIC of 0.5 microgram.mL-1,
      after administration of AZM 500 mg daily for 3 days (tonsillitis) or AZM 500 mg
      on day 1 and 250 mg daily for the next 4 days (respiratory tract infections) to a
      70 kg subject, PK/PD parameters are as follows: AUC24/MIC (h): 9.5 (plasma); 439
      (tonsil); 57.5 (ELF); 439 (LT); 1354 (AM); t > MIC is 24 hours in all tissues.
      Our simulation model illustrates the following: (i) AUC24/MIC values are above
      the 25-30-hour threshold in S. pneumoniae infection; and (ii) tissue
      concentrations exceed the MIC for 6 days after the last dose in ELF and for more
      than 2 weeks in tonsils, LT and AM.

PMID- 15199687
TI  - Applications of the surgical microscope in restorative dentistry.

PMID- 15199686
TI  - Two cases of gynaecomastia with cetirizine, a second-generation antihistamine.

PMID- 15199688
TI  - The microscope in 21st century endodontics.

PMID- 15199689
TI  - Digital documentation with the dental operating microscope.

PMID- 15199690
TI  - The surgical microscope in the periodontal practice.

PMID- 15199691
TI  - Increasing patient comfort.

PMID- 15199692
TI  - Technicians and clinicians: clarifying the boundaries.

PMID- 15199693
TI  - Contemporary trends and techniques in tooth whitening: a review.
AB  - The popularity of tooth whitening has increased with the advent of patient
      applied, peroxide-based whitening agents, as well as increased media influence.
      Peroxides are considered effective and safe when used under professional
      supervision. Whitening methods include those prescribed by a dental professional
      for the patient's at-home use, those applied by the dental professional in the
      office, a combination of both, or methods available over the counter (OTC). This
      article reviews the effect of contemporary whitening agents and illustrates the
      clinical application of three methods prescribed by dental professionals.
      LEARNING OBJECTIVES: This article presents the use of three different types of
      whitening agents for improved aesthetics. Upon reading this article, the reader
      should be able to: Distinguish the difference between professionally administered
      in-office and at-home tooth-whitening results. Identify the effects of whitening
      agents on dental tissues.

PMID- 15199694
TI  - The one-year performance of a new low-shrinkage resin composite restoration: a
      case report.

PMID- 15199695
TI  - Maximizing aesthetics and health using a closed-flap Er:YSGG laser technique.

PMID- 15199696
TI  - Finishing and polishing of direct posterior resin restorations.
AB  - Direct composite resin materials have revolutionized the delivery of minimally
      invasive treatment in the posterior region. Contemporary resin formulations
      provide improved strength, wear resistance, and aesthetics. Microhybrid
      formulations have also been associated with enhanced polishability. Development
      of an optimal surface polish in turn reduces stain and plaque accumulation,
      minimizes wear, and enhances the appearance of the definitive restoration. This
      article presents a simplified technique and protocol for finishing and polishing
      composite resin materials following restoration of the posterior region. LEARNING
      OBJECTIVES: This article discusses techniques and a protocol for finishing and
      polishing posterior direct resin restorations. Upon reading this article, the
      reader should: Understand the clinical protocol necessary to create direct
      posterior resin restorations that require minimal finishing. Be able to select
      appropriate instrumentation for direct posterior resin finishing and polishing
      procedures. Understand the importance of correct finishing and polishing on
      plaque accumulation, stain resistance, and wear resistance.

PMID- 15199697
TI  - Applications of nanotechnology.

PMID- 15199698
TI  - Contemporary CAD/CAM technologies: the evolution of a restorative system.

PMID- 15199699
TI  - An integration of composite resin with natural tooth structure: the Class IV
      restoration.
AB  - Recent developments in adhesive technologies, the design of composite resin
      materials, and contemporary placement techniques have revolutionized the delivery
      of minimally invasive direct restorations. The improved handling characteristics
      available from low-viscosity flowable systems, packable composites, and
      sculptable small-particle hybrid composites have expanded today's treatment
      options. In order to achieve a successful and natural-appearing direct composite
      restoration, the clinician must have a comprehensive knowledge of adhesive
      dentistry and an understanding of the optical properties of the natural tooth.
      This article describes a methodological approach for preparing, restoring, and
      finishing the maxillary central incisors with a small-particle composite.
      LEARNING OBJECTIVES: This article demonstrates the restoration of a Class IV
      fracture and discusses the anatomic variations of the adjacent teeth to produce a
      direct composite restoration in harmony with the surrounding dentition. Upon
      reading this article, the reader should: Be aware of the infrastructure
      considerations of a composite resin system. Recognize the role of composite resin
      on development of natural aesthetics and contour.

PMID- 15199700
TI  - Implant treatment and the edentulous maxilla.

PMID- 15199703
TI  - One day it could be you.

PMID- 15199704
TI  - An end to teen spirit.

PMID- 15199705
TI  - Changing motions.

PMID- 15199706
TI  - Student Roxanne Crosby reflects on a painful experience.

PMID- 15199708
TI  - Assessing pain in cognitively impaired older adults.
AB  - BACKGROUND: Accurate assessments of pain help healthcare professionals to
      identify its source and manage it appropriately. Pain in cognitively impaired
      older adults is difficult to assess and this can result in poor management and
      outcomes. In response to the vulnerability of this patient group, researchers
      have produced a variety of tools for pain assessment in cognitively impaired
      older adults. CONCLUSION: Replication research is recommended to validate further
      and generalize results, although there is enough evidence to support the use of
      direct observation of behaviour in identifying pain in this group of patients.

PMID- 15199709
TI  - Care map. 2: Atypical antipsychotics. Diabetes and hyperglycaemia.

PMID- 15199710
TI  - Conducting sensitive patient interviews.
AB  - Nurses are frequently engaged in the process of sensitive interviewing, whether
      taking a health history, dealing with a complaint or exploring a problem with a
      patient. This article explains key principles in the conduct of sensitive
      interviewing and highlights the use of a laddered question framework that can be
      used to manage necessary intrusion into the patient's situation and promote
      understanding.

PMID- 15199711
TI  - A streamlined service.

PMID- 15199712
TI  - Heavy metals and health.

PMID- 15199713
TI  - Trace elements in Jamaican tobacco.
AB  - The concentrations of 28 elements, in hand-made cigars, "rope" tobacco and
      freshly picked tobacco leaves from the parish of Manchester in central Jamaica,
      were compared with locally packaged and imported cigarettes and cigars. Except
      for chromium and vanadium, which are lower in the imported products, the
      elemental concentrations of all the brands sold in Jamaica are rather similar.
      The means for aluminium, cadmium, caesium, cerium, chromium, iron, thorium,
      uranium, vanadium and zinc for the Manchester material exceed the maximum values
      of the other tobaccos. The significant concentrations of heavy metals, and
      especially cadmium, which is about 50 times that of commercial cigarettes,
      reflect the known high concentrations in the soils in the region. This tobacco is
      not filtered and the smoke contains 50% of the cadmium. This, and the
      concentrations of radioactive elements, may indicate an additional health risk
      compared with commercial cigarettes. A study of three samples of marijuana
      indicates a similar level of risk from heavy metals.

PMID- 15199714
TI  - Blood lead levels in children in Jamaican basic schools.
AB  - Blood lead levels (BLL) for 285 children, three to six years old, from seven
      basic schools located in known areas of anthropogenic pollution, and in urban and
      rural areas are reported. The samples were obtained by the finger-prick method
      and analyzed for lead by anodic stripping voltammetry. The majority of the
      children had blood lead levels below the now accepted limit of 10 micrograms dL-1
      and there was no indication of cases that would represent medical emergencies.
      The present results show considerable improvement in the BLLs of children living
      in contaminated sites indicating the effectiveness of the previous remediation
      steps. Follow-up intervention work is in progress for cases of blood lead levels
      in excess of the recommended limit.

PMID- 15199715
TI  - Cadmium levels in kidney and liver of Jamaicans at autopsy.
AB  - The cadmium concentrations in the kidneys and livers of 39 autopsy cases in
      Jamaica, in the age group > or = 40 years, are renal cortex: range 6.7-126 mg kg
      1, mean 43.8 mg kg-1; liver: range 0.3-24.3 mg kg-1, mean 5.3 mg kg-1. The mean
      levels in the renal cortex are higher for women than for men but not so
      significantly, nor are the differences between smokers and non-smokers clear. The
      observed values are considered high, second only to Japan where cadmium related
      health impairments have occurred, and nearly twice as high as the values reported
      from Austria, Australia, the United Kingdom and Sweden. The Jamaican cases were
      from areas with relatively low soil-cadmium concentrations, and the corresponding
      values are likely to be significantly higher in central Jamaica where the soil
      contains unusually high levels of cadmium. An examination of possible
      contributions of cadmium intake to renal problems in Jamaica now appears to be
      necessary.

PMID- 15199716
TI  - A survey of chronic renal failure in Jamaica.
AB  - The prevalence of chronic renal failure (CRF)/end stage renal disease and the
      accessibility of long term renal replacement therapy in Jamaica were evaluated.
      The study was conducted at six Jamaican healthcare facilities between July 1998
      and December 1999 and included 605 patients with CRF. Men with CRF (57% of
      patients, mean age of 56.7 years) were significantly older than women (mean age
      53.2 years). Hypertension was the most commonly associated medical condition
      (60.8% of patients) followed by diabetes mellitus (31.4% of patients). The
      estimated crude point prevalence of CRF in persons 20 years and over at the end
      of 1999 was 327 per million population. More than one-third of patients with CRF
      (39%) were receiving renal replacement therapy, the most common modality being
      haemodialysis, and only 1.8% of patients had received kidney transplantation. The
      prevalence of chronic renal failure was not increased in areas known to have high
      soil cadmium levels. Chronic renal failure is a significant public health problem
      in Jamaica and is placing an increasing financial burden on the healthcare
      sector.

PMID- 15199717
TI  - Prevalence of chronic renal failure in the diabetic population at the University
      Hospital of the West Indies.
AB  - The prevalence of chronic renal failure (CRF) in 460 patients with diabetes
      mellitus attending the diabetic outpatient clinic at the University Hospital of
      the West Indies in Jamaica was determined from a review of medical records. The
      prevalence of CRF was 10% (39/386) in the diabetic clinic population. Significant
      positive associations with CRF were found with male gender (20/98, 20% vs 19/287,
      7%; odds ratio (OR), 3.24; p = 0.001); age 60 years and older (22/162; 14% vs
      17/221, 8%; OR, 2.01; p = 0.04); fasting blood glucose concentrations exceeding
      8.0 mmol/L (22/162, 13% vs 12/182, 7%; OR, 2.08; p = 0.05); the presence of
      significant proteinuria as a marker for outcome (13/39, 33% vs 48/346, 14%; OR,
      3.60; p = 0.02) and peripheral vascular disease (6/20, 30% vs 139/386, 10%; OR,
      4.75; p = 0.005). The prevalence of CRF did not differ significantly between
      patients with Type 1 and Type 2 diabetes mellitus. Also, the presence of CRF was
      not significantly associated with duration of diabetes mellitus, type of
      hypoglycaemic agents used, or history of hypertension. However, the presence of
      persistent proteinuria was significantly associated with duration of diabetes
      mellitus exceeding five years (46/255, 17% vs 11/149, 7%; OR, 2.52; p = 0.005)
      and a history of hypertension (41/235, 17% vs 20/198, 10%; OR, 1.88; p = 0.03)
      but not with age or gender. This study emphasizes the need to evaluate patients
      with diabetes mellitus for renal impairment so that intervention strategies may
      be adopted early to delay progression to endstage renal disease.

PMID- 15199719
TI  - Substance abuse among first admissions to the psychiatric unit of a general
      hospital in Trinidad.
AB  - Admissions for first episode of psychiatric illness provide information on
      service utilization which can be used to improve service delivery. The present
      study reviews the use of in-patient general psychiatric services in southern
      Trinidad using data from first admissions in one year, specifically to determine
      service utilization by substance-abusing patients. Case files of all admissions
      to the psychiatric unit of the San Fernando General Hospital in one year were
      reviewed and analyzed for demographic data, substance abuse, diagnosis and
      associated features of the admission. Significant rates of substance abuse were
      found among first admissions. Of 123 new patients, 43.1% were diagnosed with a
      substance abuse disorder, 56.6% of whom had a comorbid psychiatric disorder.
      Patients with substance abuse problems tended to be young males. The substance
      most commonly abused was alcohol (26.8%) and alcohol abusers were more likely to
      be of East Indian descent. Management within this mental health catchment area
      needs to address identification, early intervention and prevention of substance
      abuse among psychiatric patients. It is proposed that both hospital and community
      based substance abuse interventions should be employed in the management of acute
      psychiatric patients.

PMID- 15199718
TI  - HIV serostatus and recovery from severe childhood malnutrition. A retrospective
      matched case-control study.
AB  - The world-wide epidemic of Human Immunodeficiency Virus/Acquired Immune
      Deficiency Syndrome (HIV/AIDS) has led to an increase in the number of HIV
      positive children, mainly through perinatal transmission. HIV/AIDS can lead to
      severe childhood malnutrition (SCM) and has been noted as an increasingly common
      cause of secondary SCM. In this context, it is important to make assessments of
      the appropriateness of current approaches to treatment of severe malnutrition in
      HIV positive children. A retrospective matched case-control study of ten HIV
      positive children admitted to the Tropical Metabolism Research Unit (TMRU) was
      conducted. There were few differences between cases and matched controls on
      admission to the ward. Oral candidiasis and lower respiratory tract infections
      appeared to occur more frequently, and serum globulin concentrations were
      significantly higher among HIV positive cases when compared to their controls.
      Despite the fact that the differences between cases and controls appeared to be
      small, four cases died; there were no deaths among the controls. The duration of
      the maintenance phase was approximately five days longer (p = 0.024) among cases
      than controls but the time between the end of the maintenance phase and discharge
      from the ward was not significantly longer for the cases. The results of this
      matched case-control study suggest that there are likely to be important
      differences between HIV positive and negative patients with SCM that influence
      risk of mortality and morbidity, particularly in the maintenance phase of
      treatment. Prospective studies will be required in order to explore these
      differences and to develop better approaches to the care of HIV positive children
      with SCM.

PMID- 15199720
TI  - Mortality of patients following hip fractures in Barbados.
AB  - A retrospective study of all patients admitted with hip fractures to the Queen
      Elizabeth Hospital in Barbados from January 1996 to December 1998 was conducted.
      There were 110 patients who had sustained either a femoral neck or peri
      trochanteric fracture. The mean age was 80.7 years and 71.8% of the patients were
      women. Mortality at six months in 110 patients was 32.7% and 41.2% at 12 months
      in 102 patients. Forty-nine patients had open reduction and internal fixation of
      their fractures, forty-five patients were treated with Austin Moore prostheses
      and one patient had excisional arthroplasty. Patients with pre-operative cardiac
      abnormalities had a significantly higher mortality (60%) at 12 months (p =
      0.028). There was a linear correlation between age and mortality with mortality
      increasing with age. The length of time from admission to surgical procedure had
      no significant influence on mortality. Hip-fracture patients with cardiac
      abnormalities should be carefully evaluated and stabilized pre-operatively.

PMID- 15199721
TI  - Extended spectrum beta-lactamase producing organisms at the University Hospital
      of the West Indies.
AB  - Extended spectrum beta-lactamases (ESBL) represent a major group of beta
      lactamases that have the ability to inactivate beta-lactam antibiotics containing
      an oxyimino group such as third generation cephalosporins and monobactams. These
      enzymes are produced by gram negative organisms, especially members of the
      Enterobacteriaceae family such as Klebsiella pneumoniae and Escherichia coli. The
      prevalence of these organisms varies widely internationally, as well as within
      the same country. This is the first study on ESBL production in K pneumoniae and
      E coli at the University Hospital of the West Indies, a tertiary care hospital in
      Jamaica. Two-hundred and sixty-four isolates of K pneumoniae and 300 isolates of
      E coli were collected over the study period January 2002 to December 2002. Forty
      eight (18.2%) K pneumoniae isolates were confirmed to be ESBL producers, while
      there was no ESBL producing E coli. Infections with ESBL producing organisms can
      pose a therapeutic challenge, leading to treatment failure if the wrong class of
      antibiotics is used. With increasing resistance to all classes of antibiotics,
      there is a narrowing of available treatment options. It is very important that
      these organisms be monitored and antibiotic policies as well as infection control
      policies be in place to curtail their spread.

PMID- 15199722
TI  - Initial experience with beating-heart single valve replacement surgery at the
      University Hospital of the West Indies, Kingston, Jamaica.
AB  - The objective of this study was to examine the consequences of performing single
      cardiac valve replacement procedures utilizing a beating-heart technique on
      typical patients presenting to the cardiothoracic surgery service for aortic or
      mitral valve replacement. Beating heart aortic (4) or mitral valve (1)
      replacement was performed on patients from July 2000 to November 2002. A
      stratified sample of five patients who underwent standard arrested-heart single
      valve replacement procedures between April 1997 and November 2002 was selected
      for retrospective comparison with the beating-heart group. Operative and post
      operative variables were compared between the two groups of patients and
      subjected to statistical analysis. There was no statistical difference between
      the two groups with respect to age, pre- or post-operative New York Heart
      Association (NYHA) scores, cardiopulmonary bypass time, aortic cross-clamp time,
      intra-operative blood transfusion, or post-operative hospital stay. Post
      operatively, in the beating heart group, ventilation time, mediastinal blood loss
      and requirements for inotropic drugs were significantly reduced (p = 0.0054), p =
      0.0019 and 0 = 0.02 respectively) compared to the arrested-heart group. Single
      cardiac valve replacement surgery utilizing a beating heart technique may offer
      benefits to patients over traditional arrested-heart surgery. Post-operative
      blood loss, inotrope requirements and ventilation times are significantly
      reduced, possibly resulting in better recovery and potentially fewer
      complications in the post-operative period. There may be cost benefits, important
      in the context of healthcare delivery in developing nations. These early results
      suggest the need for a regional prospective randomized trial to compare beating
      heart single valve replacement surgery with traditional techniques.

PMID- 15199723
TI  - Oral lichen planus. Clinical aspects and management in fifty-two Brazilian
      patients.
AB  - This study aimed to characterize the clinical profile of patients with oral
      lichen planus (OLP) and to evaluate the efficacy of topical, systemic and/or
      intralesional corticosteroids in the management of symptomatic cases. Fifty-two
      patients with OLP, 33 females and 19 males, aged from 17 to 75 years (mean 49.7
      years) were studied. Information regarding the clinical forms, sites of
      involvement, patients' medical history and habits were recorded. Diagnosis of OLP
      was made using clinical criteria alone in 32 cases, while biopsy examination was
      required in the remaining 20. Symptomatic lesions were seen in 29 patients, who
      were treated with corticosteroid. Asymptomatic cases (23) were only clinically
      monitored. The forms of OLP found in this study were reticular (47%), atrophic
      (24%), erosive (21%) and plaque-like (8%). The buccal mucosa was the site
      predominantly affected. Systemic diseases were found in 17 patients (seven
      diabetic and ten with hypertension) but these data lacked statistical
      significance (p > 0.05) when compared with a control group of age and gender
      matched patients without any type of mucocutaneous disease. A habit of tobacco
      and/or alcohol use was reported by 11.5% of the patients, most of them with the
      reticular form of the disease. Topical corticosteroid therapy alone was effective
      in producing relief of symptoms in 18 of the 29 patients, although some relapses
      occurred after discontinuation. For lesions non-responsive to topical treatment,
      intralesional injection and/or short-term use of systemic corticosteroids were
      used.

PMID- 15199724
TI  - Ionizing radiation. The question of responsible use: Pandora's box revisited.
AB  - For over one hundred years, ionizing radiation has assisted in medical
      diagnostics. Recently, there have been reports of radiation injury in patients
      undergoing fluoroscopic procedures. It is time to review some of the risks of
      ionizing radiation as well as some of our practices at the University Hospital of
      West Indies (UHWI). In this review, we discuss the relative risks associated with
      common radiological examinations as well as explore the relative merits of
      various clinical protocols for the radiological investigation of common diseases
      seen at the UHWI.

PMID- 15199725
TI  - Leiomyosarcoma of the rectum. A report of two cases and review of the literature.
AB  - Rectal leiomyosarcoma is rare. It is frequently treated by abdominoperineal
      resection. The role of adjuvant therapy is unclear. Two cases of rectal
      leiomyosarcoma are presented. Pre-operative endorectal ultrasound predicted
      submucosal invasion in one case treated by low restorative resection and
      muscularis propria infiltration in the other managed with abdominoperineal
      resection. In both cases, ultrasound suggested malignant characteristics as
      evident by heterogeneous cystic spaces, irregular outline, large size and
      echogenic foci. Histology was CD34 negative and desmin, alpha-smooth muscle actin
      and HHF-35 positive, distinguishing these tumours from gastrointestinal stromal
      tumours. Rectal leiomyosarcoma may be successfully treated by restorative
      resection and pre-operative ultrasound is useful in assisting this surgical
      decision by defining malignant features of the tumour. Histopathological
      characteristics predictive of poor prognosis include high mitotic activity,
      intratumoural necrosis and tumour size.

PMID- 15199726
TI  - Disseminated histoplasmosis and AIDS at the University Hospital of the West
      Indies. A case report.
AB  - Disseminated histoplasmosis is rare in Jamaica. However, with the increase in the
      number of immunocompromised patients in the population, the prevalence of this
      infection is likely to increase. We present a case of disseminated histoplasmosis
      in a 16-year-old girl with the acquired immune deficiency syndrome who presented
      to the Paediatric Infectious Diseases Service of the University Hospital of the
      West Indies, with cervical lymphadenitis progressing to ulcers and abscesses
      showing granulomatous inflammation likely to be of fungal aetiology. She later
      presented to the Emergency Room, with respiratory and gastrointestinal symptoms
      and was admitted to hospital, disoriented and with a persistent fever. She
      developed nuchal rigidity while in hospital and was anaemic, leukopaenic and
      thrombocytopaenic. She died of gastrointestinal bleed ten days post admission.
      She was the oldest known survivor of mother-to-child-transmission of human
      immunodeficiency virus in Jamaica. The slow growing fungus, Histoplasma
      capsulatum, was isolated from the patient's blood three weeks after the specimen
      was sent to the laboratory.

PMID- 15199727
TI  - Symptomatic anomalies and arthrotic formations of the axis vertebrae in eastern
      Anatolian people. A local investigation.
AB  - At the craniocervical junction, developmental anomalies of the axis may produce
      clinical symptoms by compressing the upper cervical cord during movements of the
      head and neck. The present study aimed at investigating several varieties and
      deformities of the axis on skeletal specimens of Eastern Anatolian origin. On 76
      specimens, developmental anomalies and the variants of the second vertebrae
      (axis) were investigated. Hypoplasia of the dens axis in one specimen, the dens
      axis of a child with a bifid apex in another specimen and an arthrotic formation
      located on the apex of the dens in six axes were found. A bone protrusion
      narrowing the transverse foramen was also observed. The types of absence of the
      dens axis and clinical symptoms that may be caused by them are discussed. It was
      concluded that the frequency of arthrotic formations might reflect the
      possibility that the individuals suffered less commonly from neck pain due to
      arthrotic degeneration.

PMID- 15199728
TI  - Granulosa cell tumour of the ovary with bilateral mature cystic teratomas. A case
      report.
AB  - Granulosa cell tumour with synchronous mature cystic teratoma is extremely rare
      and only eight cases are documented in the literature. Granulosa cell tumours are
      low-grade malignancies and need a close follow-up for recurrences which may be
      late. We report a case of granulosa cell tumour and mature cystic teratoma
      occurring synchronously in the same ovary in a post-menopausal woman.

PMID- 15199729
TI  - Bilateral simultaneous rupture of the quadriceps tendon.

PMID- 15199730
TI  - [Diplopia in Wallenberg's syndrome].
AB  - The incidence and mechanism of diplopia were investigated in 31 patients with
      Wallenberg's syndrome resulting from acute dorsolateral medullary infarction.
      Diplopia was found in 10 of 31 patients (32%), with 5 patients reporting vertical
      diplopia alone and 5 reporting vertical and horizontal diplopia. Diplopia in
      Wallenberg's syndrome is considered to be caused by a lesion involving the
      otolith-ocular system. Vertical diplopia is simply explained by ocular skew
      deviation due to a lesion involving the vestibular nucleus; in which the affected
      eye becomes deviated inferiorly. In this situation, rotation of the eye due to
      ocular tilt reaction also occurs. Concomitant horizontal diplopia may require
      involvement of the medial longitudinal fasciculus (MLF), which produces skew
      deviation in mirror image; the unaffected eye becomes deviated inferiorly. When
      downward deviation of the eye affected by dysfunction of the vestibular nucleus
      and that due to MLF dysfunction affecting the other eye are comparable, only
      horizontal diplopia becomes apparent. MLF syndrome may be accompanied by
      paralytic pontine exotropia (PPE) or non-paralytic pontine exotropia (NPPE), both
      of which may also participate in the appearance of horizontal diplopia.

PMID- 15199731
TI  - [Stroke recurrence in patients with brain embolism and patent foramen ovale-
      association with deep vein thrombosis detected by ultrasonography].
AB  - Paradoxical embolism through a patent foramen ovale (PFO) is a recognized cause
      of stroke, but its prognosis is not well known. The aim of our study is to
      evaluate differences in risk factors, recurrent stroke subtypes and effects of
      various preventive therapies between PFO associated stroke patients with and
      without deep vein thrombosis (DVT). A total of 63 patients who had an embolic
      stroke with a PFO within 3 months from stroke onset were enrolled. Venous
      ultrasonography, which was performed in all the patients, revealed DVT in 26
      patients (41%). Venous thrombosis was confined to the isolated calf veins in 24
      of 26 cases (92%). For prevention of stroke recurrence, warfarin was
      administrated in 32 patients, antiplatelet therapy was given in 21 patients, and
      combination of warfarin and antiplatelet therapy was chosen in 10 patients. Three
      patients with DVT and three other patients without DVT had recurrent ischemic
      events during a mean follow-up period of 14.6 months. In all the 3 patients
      without DVT, complicated aortic arch lesions were also observed, and 2 of them
      had lacunar infarcts. In all the three patients with DVT recurrent embolic stroke
      or TIA occurred in spite of anticoagulant therapy. Their INR values at the time
      of recurrence were all below 1.7, and 2 of them were associated with atrial
      septal aneurysm (ASA). Association with PFO, ASA, and DVT may be a substantial
      risk factor for recurrent stroke. Higher INR value in anticoagulation may be
      recommended for such patients to prevent stroke recurrence.

PMID- 15199732
TI  - [Changes in visual event-related potentials and SPECT in dissociative amnesia].
AB  - A 29-year-old man was admitted because of sudden onset of retrograde amnesia. The
      patient was unable to recall events having occurred during the past 2 years. The
      impairment was especially serious with regard to personal memories during the 5
      months prior to admission, while he had first been working as a full-time
      employee under stressful circumstance. A diagnosis of dissociative amnesia was
      made on the basis of absence of any systemic or neurological diseases that could
      cause amnesia, the inadaptable character of the patient, the nature of amnesia,
      and presence of stressful condition possibly related to the amnesia. Visual event
      related potential (ERP) studies recorded with human face discrimination tasks
      demonstrated a P3a wave in response to a face of his superior in the office, whom
      he said that he had never seen before. The similar P3a wave was observed in
      response to a face quite familiar to the patient, his mother, but not to a face
      "truly" unknown to him. These findings suggest that the visual memory of his
      superior's face exists in the brain, but the patient is unable to retrieve it by
      some psychogenic mechanism. 131I-IMP SPECT revealed decreased perfusion in the
      left medial temporal lobe and the basal forebrain, suggesting the association
      between dissociative amnesia and focal brain dysfunction. While dissociative
      amnesia has been understood as psychogenic nature, both ERPs and SPECT are quite
      important tools to understand the association between the psychological
      phenomenon and biological changes of the brain in this disorder.

PMID- 15199733
TI  - [A case report of acute polyradiculoneuritis developing after multiple injections
      of botulinum toxin for cervical dystonia].
AB  - A 68-year-old man receiving four times of injection of botulinum toxin type A for
      cervical dystonia developed acute polyradiculoneuritis 10 weeks after the final
      injection. He had been complaining of paresthesia in four limbs after the second
      injection of the treatment. On neurological examination, bilateral facial palsy,
      bulbar palsy, difficulty of breath, flaccid paralysis of all limbs, sensory
      disturbance of all modality and areflexia in all limbs, and positive Laseque sign
      were noted. Albuminocytological dissociation was present in the CSF and the
      conduction velocity was significantly impaired in all peripheral nerves examined.
      After receiving two times of intravenous highdose IgG and two times of pulse
      therapy, his neurological deficits gradually improved. To our knowledge, this is
      the third case report of acute polyradiculoneuropathy developing after botulinum
      toxin therapy, suggesting that botulinum toxin therapy is involved in the
      pathogenesis in our case.

PMID- 15199734
TI  - [Pravastatin-associated polymyositis, a case report].
AB  - A 69 year old man complained of general myalgia, arthralgia and muscle weakness
      in two weeks after he started to take 10 mg per day pravastatin. Symptoms
      progressed at least for 3 months after withdrawal of the medication. The muscle
      weakness was more in distal upper extremities and the iliopsoas muscle. Serum CK
      was 943IU/L. The anti-nuclear and Jo-1 antibody were positive. EMG examinations
      disclosed fibrillation potentials at rest and myopathic discharges by a voluntary
      contractor. Symptoms as well as serum CK values improved promptly by treatment
      with prednisolone. From these clinical and laboratory results, it was speculated
      that this patient suffered from subacute polymyositis, although pathological
      studies were not performed. Because of continuing hypercholesterolemia, the
      patient was retreated with atorvastatin, presenting similar, but less serious
      symptoms. So far, three cases of statin-associated polymyositis or
      dermatomyositis were reported. Statins could influence the immune system, but it
      is still unsettled if statins cause autoimmune polymyositis. This problem
      warrants further study.

PMID- 15199735
TI  - [Dysprosody associated with environmental auditory sound agnosia in right
      temporal lobe hypoperfusion--a case report].
AB  - A 60-year-old right-handed man showed dysprosody and agnosia for environmental
      sounds. His mother tongue was Japanese, and he could not speak foreign languages.
      He gradually developed difficulty in speaking from the age of 57 years, speaking
      non-native Japanese. In addition, he often complained of difficulty in hearing
      sounds, but audiometry showed no abnormalities. At the age of 60 years, the
      standard language test of aphasia showed no abnormalities in repetition, verbal
      comprehension, or reading, suggesting the absence of aphasia. However, in
      speaking, marked abnormality in rhythm, and occasional lack of postpositional
      particles and syllable-stumblings were observed. Writing was almost accurate, but
      a few grammatical errors were observed in speaking were observed. There were no
      cerebellar symptoms, pyramidal signs, pathologic reflexes, or abnormalities in
      phonation-related organs. Though the recognition of verbal sounds was maintained,
      impairment in the recognition of non-verbal sounds was observed. An environmental
      sound perception test showed correct answers only in 8 of 21 non-verbal sound
      sources (such as a car starting, glass breaking and so on), suggesting agnosia
      for environmental sounds. He insisted that the difficulty in perception was due
      to hearing impairment. However, re-examination with an increase in the sound
      volume showed similar results. He had no inconvenience in daily life and was not
      aware of agnosia for environmental sounds. He could recognize and differentiate
      sounds he heard once. His intelligence was normal, and neither apraxia nor
      frontal lobe symptoms were observed. MRI of the brain revealed slight atrophy of
      the right temporal lobe. Cerebral blood flow SPECT showed decreased blood flow
      from the superior temporal gyrus to the area around the arcuate fasciculi in the
      right temporal lobe. We considered that the lesion responsible for environmental
      auditory sound agnosia was present in the area around the secondary auditory area
      of the right temporal lobe and this patient differed from slowly progressive
      aphasia characterized by decreased blood flow in the left temporal lobe. Although
      the pathological process occurring in the area of hypoperfusion remained unclear,
      early stage of some degenerative disorders was more likely than cerebrovascular
      disease.

PMID- 15199736
TI  - [Superior sagittal sinus thrombosis as first manifestation of essential
      thrombocythemia].
AB  - A 52-year-old previously healthy woman was admitted to our hospital for status
      epilepticus in November 1999. She had not taken oral contraceptives. After
      treatment with intravenous diazepam and phenytoin, she did not develop seizures
      anymore. When she became alert, there was a mild left hemiparesis. Lumbar
      puncture showed an opening pressure of 145 mm H2O, and the cerebrospinal fluid
      was acellular. Cranial MR imaging demonstrated thrombosis of the superior
      sagittal sinus and fresh infarction in the right frontal lobe. Plasma fibrinogen,
      fibrin degradation product, and prothrombin fragment 1 + 2 levels were elevated.
      Proteins S and C activities and anti-thrombin III levels were within the normal
      range. Lupus anticoagulant and anti-cardiolipin antibody were negative. She was
      treated with continuous heparin infusion for ten days and with oral warfarin
      thereafter. Six months after the first admission, platelet count became more than
      400 x 10(3)/microliter. In July 2002, she developed slowly progressive monoplegia
      of the left arm. Cranial MR imaging demonstrated patent superior sagittal sinus,
      fresh infarction in the right parietal lobe, and old small infarction in the
      right corona radiata. The patient was maintained on warfarin and 100 mg of
      aspirin thereafter. In September 2002, platelet count was 737 x 10(3)/microliter.
      Bone marrow examination showed increased megakaryopoiesis with normal erythroid
      and myeloid series and no chromosomal aberrations. Serum C-reactive protein and
      iron levels were in the normal range. An abdominal ultrasound demonstrated mild
      splenomegaly. Thus, we made a diagnosis of essential thrombocythemia (ET). ET
      causes thrombotic events in the course of the disease at a rate of 7% per year.
      Cerebral infarction is not uncommon, but occurrence of cerebral sinus thrombosis
      has been rarely reported. Recently, several cases have been reported in which
      cerebral infarction was the first manifestation of ET even with platelet counts
      lower than 600 x 10(3)/microliter. To our knowledge, there have been no reported
      cases of ET presenting with cerebral venous sinus thrombosis. Platelet count
      should be monitored in the patients with venous sinus thrombosis of undetermined
      etiology.

PMID- 15199737
TI  - [A case of right mesial temporal lobe epilepsy accompanied with ictal polyopsia].
AB  - A 59-year-old, right-handed woman had a paroxysmal polyoptic visual illusion, in
      which multiple copies of the object she saw spread horizontally in the left hemi
      visual field. Polyopsia appeared for a few seconds. Neurological examination was
      normal. Magnetic resonance imaging (MRI) showed a tumor-like lesion involving the
      cortical and subcortical matters in the right mesial temporal regions. An
      interictal EEG showed frequent spikes in the right mesial temporal area and
      intermittent theta waves in the right fronto-temporal area. Video-EEG monitoring
      using the sphenoidal electrodes showed the seizure discharges originating in the
      right sphenoidal lead accompanying the polyoptic visual illusion. The seizure
      discharges were restricted within the right mesial temporal lobe. Paroxysmal
      visual illusion disappeared after administration of anti-epileptic drugs. EEG
      showed rare spikes in the right mesial temporal area. Polyopsia in this patient
      presumed to be associated with right mesial temporal lobe epilepsy because
      polyopsia and seizure activities on the ictal EEG were coupled and polyopsia
      ceased after administration of anti-epileptic drugs. Polyopsia is recognized as
      visual perseveration in space and a rare visual illusion. The lesion causing
      polyopsia has been reported to be mostly within posterior cerebral areas
      including occipital, parietal and temporal regions. This patient whose ictal
      polyopsia associated with mesial temporal lobe epilepsy is a very rare case
      because most reported cases presenting ictal polyopsia are neocortical temporal
      lobe epilepsy. The precise mechanism of polyopsia remains unknown. The mesial
      temporal lobe includes the hippocampus and parahippocampal formation that have
      been reported to receive information from the diverse association cortex and work
      as memory controllers. Ictal polyopsia may result from dysfunction of the visual
      association cortex or visual memory systems induced by the epileptic activities
      in the mesial temporal lobe. Polyopsia is a rare ictal semeiology of mesial
      temporal lobe epilepsy and may be one of the important ictal symptoms.

PMID- 15199738
TI  - [A family with autosomal dominant temporal lobe epilepsy accompanied by motor and
      sensory neuropathy].
AB  - We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by
      hereditary motor and sensory neuropathy (HMSN). He had experienced complex
      partial seizures (CPS), which started with a nausea-like feeling, followed by
      loss of consciousness and automatism, since he was 6 years old. The frequency of
      attacks was at first decreased by phenytoin. However, attacks increased again
      when he was 18 years old. On admission, neurological examination showed mild
      weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory
      sensation in his legs. Ten people in four generations of his family showed a
      history of epilepsy in the autosomal dominant inheritance form. His younger
      sister and mother had a history of epilepsy accompanied with pes cavus, hammer
      toe, weakness of toe and finger extension and mildly impaired vibratory sensation
      as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in
      which several mutations were reported in patients with familial lateral temporal
      lobe epilepsy, showed no specific mutation in this family. On consecutive video
      EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto
      temporal region when he showed automatism, and then a generalized slow burst
      activity was detected when he lost consciousness. For his seizures, TLE with
      secondary generalization was diagnosed. In the nerve conduction study, delayed
      nerve conduction, distal motor latency and decreased amplitudes of the compound
      muscle action potentials (CMAP) of bilateral peroneal nerves were observed,
      indicating the existence of mild axonal degeneration. Based on these data, we
      consider that this family to be a new phenotype of autosomal dominant TLE
      accompanied by motor and sensory neuropathy.

PMID- 15199739
TI  - [Outcome after Guillain-Barre syndrome: comparison of motor function status and
      changes in social life].
AB  - Effects on the motor function and social life of the patients after Guillain
      Barre syndrome (GBS) were studied. A letter of inquiry was sent to the patients
      in November 2001; 98 patients responded validly. The questionnaire had questions
      with 3 possible answers related to situations at work, at home, and about leisure
      activities. The Hughes functional grade, which evaluates physical conditions, and
      arm disability scale scores were assessed. Although the assessments showed good
      recovery in most patients who had had a job, 31% had to quit work, and 17% had to
      discontinue their leisure activities. These physical assessments accurately
      reflected the severity of the conditions of the patients given in-home care (8%)
      because daily life activities depend on muscle strength. Of the 75 patients who
      had no, or minimal, neurological symptoms or signs in both assessments, 53%
      reported one or more changes in their social lives. We conclude that the
      questionnaire answers show that GBS patients may have serious psychosocial
      outcomes that are not measurable by the usual physical assessments. These
      findings may be a help when considering the rehabilitation of GBS patients and
      their return to social life.

PMID- 15199740
TI  - [A case of myasthenia gravis associated with blephaloptosis mimicking
      blephalospasm].

PMID- 15199741
TI  - [Thrombogenesis and activation of beta 3 integrins].

PMID- 15199742
TI  - [Molecular mechanisms of thrombogenesis and vascular pathologies in vivo].

PMID- 15199743
TI  - [Fetal liver hematopoiesis].

PMID- 15199744
TI  - [Role of Polycomb--group genes in hematopoiesis].

PMID- 15199745
TI  - [Epidemiological aspects of idiopathic thrombocytopenic purpura in Kochi
      Prefecture].
AB  - This paper describes the epidemiological aspects of ITP in Kochi prefecture. Five
      hundred and twenty three patients were newly registered over the past 14 years
      (from April 1, 1989 to March 31, 2002). They comprised 192 men (36.7%) and 331
      women (63.3%), yielding a female to male ratio (F/M) of 1:1.7. The proportions of
      children (< or = 14 y/o), adults (15-64 y/o) and the elderly (> or = 65 y/o) were
      24.9%, 51.6% and 23.5%, respectively, and F/M ratios were 1:0.8 in children,
      1:3.0 in adults and 1:1.3 in the elderly, showing elimination of the sex
      difference in the elderly. Average annual incidences per 100,000 population were
      estimated by 2 calendar year periods (Period I: '89-'90, II: '91-'92, III: '93
      '94, IV: '95-'96, V: '97-'98, VI: '99-'00, VII: '01-'02). The incidence of ITP
      showed a significant increase over the past 14 years, particularly in the elderly
      (I: 0.90, II: 0.67, III: 1.89, IV: 3.52, V: 3.05, VI: 4.10, VII: 3.17). The
      increase of ITP in the elderly concomitant with the increase in the size of the
      elderly population is probably not only exclusive to Kochi prefecture but also
      seen throughout Japan, therefore, the establishment of the optimal therapeutic
      management of ITP in the elderly including the eradication of Helicobacter pylori
      is required.

PMID- 15199747
TI  - [Successful corticosteroid treatment of thrombocytopenia in a pregnant woman with
      myelodysplastic syndrome (refractory anemia)].
AB  - A 31-year-old pregnant woman was referred to our hospital due to anemia and
      thrombocytopenia, and was diagnosed as having myelodysplastic syndrome
      (refractory anemia) with autoimmune thrombocytopenia. Administration of high dose
      methylprednisolone and gamma-globulin did not raise her platelet count, and she
      subsequently delivered a healthy baby after the transfusion of a large amount of
      platelets. Although the anemia spontaneously improved after delivery, the
      platelet count remained unchanged. Prednisolone was thus administered a second
      time, which did finally increase the platelet count. This is the first reported
      case of a pregnant woman with myelodysplastic syndrome in whom corticosteroid
      administration was effective for thrombocytopenia.

PMID- 15199746
TI  - [Changes of ADAMTS13 activity and endothelial cell markers in TMA cases].
AB  - Severe deficiency of ADAMTS13 activity was recently found in patients with
      thrombotic thrombocytopenic purpura (TTP). The great advance associated with
      these basic and clinical studies on ADAMTS13 is the possible elucidation of the
      pathogenesis of TMA (thrombotic microangiopathy). However, the exact pathogenetic
      mechanism in TMA without severe deficiency of ADAMTS13 activity remains unknown
      due to heterogeneity of the disease. In this study, there were 7 patients with
      TTP, 7 with HUS, 3 with drug-induced HUS, 1 with VOD, and 1 with IVL out of 19
      TMA patients with a moderate deficiency (6-70%) of ADAMTS13 activity. Five of the
      7 TTP patients had a poor outcome. Plasma thrombomodulin and t-PA-PAI-1 complex
      levels in TMA patients with a moderate deficiency of ADAMTS13 activity were
      significantly higher than those in patients with a severe deficiency of ADAMTS13
      activity. These data suggest that the etiology in these patients may be systemic
      vascular endothelial cell damage.

PMID- 15199748
TI  - [Aortobronchial fistula induced by pulmonary mucormycosis in acute myeloid
      leukemia].
AB  - A 51-year-old woman was admitted to our hospital with a diagnosis of acute
      myeloid leukemia (M1) in January 2002. During the course of induction therapy,
      she developed a fever and chest radiography revealed bilateral infiltrates. She
      was treated with broad-spectrum intravenous antibiotics and fluconazole, but her
      condition continued to worsen. She then began receiving amphotericin B, although
      there was no evidence of a fungal infection from the sputum culture and serologic
      testing. The patient soon became afebrile and improved clinically. On the 87th
      hospital day, however, she had a bout of abrupt massive hemoptysis and died of
      exsanguination. The diagnosis of aortobronchial fistula due to pulmonary
      mucormycosis was obtained at autopsy. Because of the angioinvasive tendency of
      mucormycosis, fatal hemoptysis in some patients with pulmonary mucormycosis has
      been reported, but most cases involve hemoptysis resulting from mucor invasion of
      the pulmonary artery. To our knowledge, this case represents the fourth
      description of pulmonary mucormycosis with fatal bleeding from the aorta.

PMID- 15199749
TI  - [Chronic active Epstein-Barr virus infection treated with reduced intensity stem
      cell transplantation].
AB  - A 31-year-old woman had been suffering from fever and a sore throat since January
      1999, and had a left neck lymphadenopathy in December 1999. Pathological findings
      of the biopsied lymphnode suggested malignant lymphoma. She was finally diagnosed
      as having a chronic active Epstein-Barr virus(EBV) infection because of abnormal
      antibody titers against EBV antigens and an increased EBV load in her peripheral
      blood. After receiving chemotherapy consisting of CHOP and high dose cytarabine,
      the amount of the EBV genome decreased below the detection limit before BMT.
      Therefore, instead of a conventional myeloablative transplant, we performed BMT
      using reduced-intensity conditioning regimens consisting of fludarabine and
      melphalan from an HLA-identical sibling donor. After 14 months, the patient
      remained in complete remission. Menstruation occurred on day 83 following BMT,
      and the serum level of LH and FSH on day 316 were within normal range. Under
      these circumstances, RIST seems to be one of the curative treatments for the
      patients with CAEBV with minimal late side effects.

PMID- 15199750
TI  - [Allogeneic peripheral blood stem cell transplantation for a hepatitis B virus
      carrier with Epstein-Barr virus associated with hemophagocytic syndrome].
AB  - We report herein a 21-year-old hepatitis B virus (HBV) female carrier who
      developed persistent fever, lymphadenopathy and pancytopenia in September of
      2000. Hemophagocytes were found in the bone marrow smears. Epstein-Barr virus
      (EBV) serology showed positive for VCA-IgG, IgM and EB-ER and negative for EBNA.
      The EBV genome was detected in the peripheral blood. The patient was diagnosed as
      having EBV-associated hemophagocytic syndrome (EBV-AHS) and received
      chemotherapy. Although she was treated with lamivudine three months after the
      initiation of chemotherapy, she developed severe hepatitis. She recovered from
      the hepatitis through a combination of plasma exchange, immunosuppressive and
      antiviral therapies. Because of the refractoriness of her EBV-AHS to
      chemotherapy, she received allogeneic peripheral blood stem cell transplantation
      (PBSCT) from her HLA-identical brother. Hepatitis B did not recur after the PBSCT
      under administration of lamivudine. The EBV genome in the peripheral blood
      disappeared soon after the PBSCT but it was revealed again after the initiation
      of prednisolone for the treatment of acute GVHD. A donor lymphocyte infusion
      (DLI) was given on day 169 and the EBV genome copy number in the peripheral blood
      gradually decreased and disappeared. Although the origin of the EBV-infected
      cells could not be determined as being from the host or donor, DLI was a useful
      treatment for the recurrence of EBV infection after allogeneic stem cell
      transplantation for EBV-AHS.

PMID- 15199751
TI  - [Successful treatment of long-standing iron-deficiency anemia in adults by
      eradication of Helicobacter pylori].
AB  - We report two cases of long-standing iron-deficiency anemia in a young man and an
      elderly woman that improved after eradication of Helicobacter pylori. Neither
      patient demonstrated any bleeding symptoms nor reported an extremely unbalanced
      diet. However, H. pylori infection was demonstrated with the urea breath test.
      After successful eradication of H. pylori, the iron-deficiency anemia
      dramatically improved in both patients, making it unnecessary to administer
      ferric medicine for about 20 months. These cases suggest that eradication of H.
      pylori may be useful in treating some patients with long-standing iron-deficiency
      anemia.

PMID- 15199752
TI  - [Hairy cell leukemia, Japanese variant, successfully treated with cladribine].
AB  - A 67-year-old male was admitted because of lymphocytosis and huge splenomegaly.
      Abnormal lymphocytes had cytoplasmic hairy projections and were negative for
      tartrate-resistant acid phosphatase staining. The bone marrow aspirate contained
      many lymphocytes with the same morphology. Flow cytometric analysis revealed an
      increase in IgM and kappa positive B cells. They were positive for CD11c, CD19,
      CD20 and FMC7, and negative for CD5, CD10 and CD25. The patient was diagnosed as
      having hairy cell leukemia, Japanese variant. Initially interferon-alpha was
      administered for a month, decreasing the numbers of leukemic cells but with
      little effect on splenomegaly. Subsequent administration of cladribine (0.09
      mg/kg, 7 days) showed a remarkable effect, and the patient has been in complete
      remission for 8 months.

PMID- 15199753
TI  - [Multiple myeloma (IgG-kappa) infiltrating central nervous system, lymph nodes,
      liver, and kidneys, and with elevation of IgE].
AB  - A 63-year-old man was admitted because of general malaise, fever, headache,
      generalized lymphadenopathy and hepatomegaly in July 2002. He was diagnosed as
      having multiple myeloma (MM) (IgG-kappa type) with atypical plasma cells in the
      bone marrow, lymph nodes and cerebrospinal fluid. Systemic and intrathecal
      chemotherapy were effective. Because of an increase of polyclonal IgE,
      electrophoretic patterns revealed an M-peak which was not as sharp as that in IgG
      myeloma. IgE production is not impaired by the pathologic process in MM patients.

PMID- 15199754
TI  - [An elder case of neurosarcoidosis associated with brain infarction].
AB  - A 75-year-old woman with sarcoidosis developed sudden weakness of the left upper
      and lower limbs. Neurological examination revealed left-sided hemiplegia,
      hyperreflexia with pathological reflexes and hypesthesia. She was disoriented and
      euphoric. Diffusion-weighted brain MRI showed high intensity lesions in the right
      parietooccipital lobes. Electroencephalogram showed diffuse slowing of the
      background activity. Serum lysozyme increased to 18.4 mg/ml, CSF protein to 51
      mg/dl. After admission, she presented psychotic manifestation followed by a
      progressive disturbance of consciousness. Epithelioid granulomas without caseous
      necrosis were present in the biopsied lymph node and specimens from the occipital
      cortex, indicating neurosarcoidosis. Necrosis was also present in the sampled
      brain tissue. The psychotic symptoms and consciousness disturbance rapidly
      ameliorated after the treatment with oral prednisolone, 40 mg/day.
      Neurosarcoidosis should be considered even in an elder case of sarcoidosis
      complicated with a stroke.

PMID- 15199755
TI  - [A case of hemichorea with hyperglycemia presenting with low signal intensity in
      the striatum on T2*-weighted gradient-echo magnetic resonance imaging].
AB  - A 76-year-old woman was admitted to our hospital with chorea in her left arm and
      leg. She also suffered from poorly controlled diabetes. Her arm and leg flexed
      and shook, and these movements were worsened by stress and disappeared during
      sleep. Neurological examinations were otherwise normal. The blood glucose level
      was 232 mg/dl and glycosylated hemoglobin A1c was 13.9%. Magnetic resonance (MR)
      showed high signal intensity on T1-weighted images (T1-WI) in the right striatum,
      and low signal intensity on T2-weighted images (T2-WI). T2*-weighted gradient
      echo magnetic resonance imaging showed low signal intensity that gradually became
      even lower, suggesting petechial hemorrhage. SPECT showed normal blood flow in
      the right striatum under these conditions, and gradually decreased. The patient's
      diabetes was controlled with insulin, and the hemichorea improved on treatment
      with tiapride up to 75 mg per day, haloperidol up to 2.25 mg per day. Hemichorea
      with hyperglycemia is a disorder that is associated with poorly controlled
      diabetes, old age, and high signal intensity on T1-weighted MR imaging in the
      striatum contralateral to the hemichorea. The pathophysiology of the hemichorea
      is presumed to be ischemic changes in the striatum associated with hyperglycemia
      and hyperviscosity. The MR findings in our patient suggest petechial hemorrhage
      following ischemic change, although petechial hemorrhage has not been reported in
      similar cases in the recent literature. The striatal hyperactivity may be
      associated with the onset of hemichorea in our patient.

PMID- 15199756
TI  - [Thiamine deficiency polyneuropathy after gastrectomy associated with high level
      of serum vascular endothelial growth factor (VEGF). A case report].
AB  - We report a 66-year-old man who developed vitamin B1 deficiency polyneuropathy
      long after a gastrectomy. After a preceding bronchial infection, the patient
      noticed numbness and weakness in his extremities, followed by generalized edema
      and exertional dyspnea. He had undergone subtotal gastrectomy due to duodenal
      ulcer at age 19. His daily oral intake of food was normal without any alcoholic
      abuse. He was admitted to our hospital with rapidly progressive gait disturbance
      due to muscle weakness, and sensory disturbance. Neurological examination showed
      peripheral polyneuropathy with distal dominant muscular weakness and sensory
      disturbance. Chest X-ray film showed marked cardiomegaly and pleural effusion.
      Nerve conduction studies showed decreases in the action potentials of both the
      motor and sensory nerves, with the sensory nerves being more severely affected
      than the motor nerves. Sural nerve biopsy demonstrated severe axonal degeneration
      without any inflammatory change. The blood concentration of thiamine (vitamin B1)
      was slightly decreased below the normal range (19 ng/ml; normal, 20-50), and the
      serum vascular endothelial growth factor (VEGF) was high (890 pg/ml; normal < 200
      pg/ml). Intravenous administration of vitamin B1 (50 mg per day) dramatically
      improved his symptoms in a few days and the level of VEGF returned to nearly
      normal. In this gastrectomized patient many years ago, vitamin B1 deficiency
      neuropathy is warranted in view of a prompt response to thiamine administration.
      This case suggests that VEGF is involved in the pathogenesis of vitamin B1
      deficiency polyneuropathy.

PMID- 15199758
TI  - [Reversible MRI findings of posterior column of the spinal cord in a patient with
      acute autonomic and sensory neuropathy].
AB  - We report serial spinal MRI T2 findings in a patient with acute autonomic and
      sensory neuropathy (AASN). A 20-year-old woman was admitted to our hospital with
      progressive sensory disturbance in her extremities and orthostatic syncope after
      her symptoms of upper respiratory infection. Neurological examination
      demonstrated reduced tendon reflexes, hypalgesia, paresthesia, reduced position
      sensation in distal dominant extremities (predominant in lower legs) and wide
      variety of autonomic dysfunction (severe orthostatic hypotension, anhidrosis,
      urinary disturbance, coughing attack, constipation and appetite loss). She was
      diagnosed as having AASN. Although high dose intravenous immunoglobulin therapy
      successfully prevented the symptom progression, her sensory disturbance and
      autonomic dysfunction were prolonged and showed only slow improvement. Spinal MRI
      on acute phase was normal. On chronic phase (11 month after the onset), spinal
      MRI T2 weighted images demonstrated high intensity lesion in the posterior column
      successive from upper cervical to lower thoracic spinal cord. Those abnormal
      findings were attenuated in concordance with her symptom improvement and finally
      disappeared when she became to walk stably without assist.

PMID- 15199757
TI  - [Postpartum cerebral angiopathy--a case report the vasculopathy associated with
      co-administration of two vasoconstrictives, methylergometrine maleate and
      sumatriptan].
AB  - A 25-year-old woman (gravida 1, para 0) who had no history indicating the toxemia
      of pregnancy developed hypertension and severe throbbing headache after the
      delivery of her first child by the cesarean section. Generalized tonic-clonic
      seizure ensued 5 days after the delivery, after which she did not fully regain
      her consciousness. Her head T2-weighted and FLAIR MRIs showed areas of multiple
      high intensities in the basal ganglia and cerebral white matter. Her cerebral MRA
      revealed the segmental stenosis and irregular wall of the major vessels, in
      particular of the right MCA trunk. Three weeks later, these abnormalities in the
      neuroimages disappeared and she was free of any symptoms. The history disclosed
      that obstetricians had used methylergometrine maleate for uterine contraction
      after delivery and then sumatriptan for her throbbing headache. We speculate that
      these vasoconstrictive agents might have induced the postpartum cerebral
      angiopathy. Postpartum cerebral angiopathy may be distinct from reversible
      posterior leukoencephalopathy in that the abnormalities are not restricted to the
      posterior lobes and that the vascular changes are apparent on neuroimagings.
      However, this entity might have a common underlying physiology, which is the
      abnormally elevated blood pressure that occurs in the setting of early postpartum
      period. Caution should be exercised when vasoconstrictives are to be used in
      postpartum period.

PMID- 15199759
TI  - [A case showing Wallerian degeneration of the bilateral middle cerebellar
      peduncles on MRI followed by the right pontine infarction].
AB  - We report a 63-year-old man who presented with the left facial palsy, the left
      hemiparesis, the left limb ataxia, and the bilateral truncal ataxia. On
      admission, magnetic resonance imaging (MRI) showed an abnormal high intensity
      lesion at the right paramedian region of the upper to middle pons on T2-weighted
      images (T2WI). He was diagnosed as having a pontine lacunar infarction. The
      contralateral cerebellar lesions were caused by involvement of the
      pontocerebellar fibers. On the 29th day from the onset, MRI showed the new
      abnormal high intensity lesions at the bilateral middle cerebellar peduncles on
      T2WI. These lesions were supposed to be Wallerian degeneration caused by
      involvement of the pontocerebellar fibers. This case suggests that Wallerian
      degeneration occurs followed by a unilateral infarction involving pontocerebellar
      fibers.

PMID- 15199760
TI  - [Multiple cerebral white matter lesions following head trauma with eyeball
      contusion].
AB  - We reported a 36-year-old man with multiple cerebral white matter lesions
      following head trauma with eyeball contusion. He had suffered from optic neuritis
      on non-injured side after one and half months from the head trauma. Brain MRI
      revealed multiple cerebral white matter lesions and lumbar puncture disclosed an
      elevated level of protein of the cerebrospinal fluid after two and half months
      from the head trauma. He was treated with steroid pulse therapy and resulted in
      an improvement of his visual acuity and a remarkable decrease of multiple
      cerebral white matter lesions. There has been a controversy concerning the causal
      relationship between trauma and multiple sclerosis (MS). In this case, MS-like
      multiple cerebral white matter lesions are considered to be relevant to the head
      trauma.

PMID- 15199761
TI  - [A case of cerebellar infarction with pure dysarthria].
AB  - We report a 69-year-old man with pure ataxic speech. He was admitted to the
      surgical ward of our hospital because of exercise-induced pain in the right arm.
      He underwent angiography of the right arm, and was discharged the next day. When
      he returned home, he exhibited an acute-onset dysarthria. He was admitted to our
      neurology ward the next day because the dysarthria did not improve. On admission,
      neurological examinations revealed moderately ataxic speech, but other
      neurological findings were within normal limits. Cranial MRI revealed an infarct
      localized from the lobulus simplex to the lobulus quadrangularis in the right
      cerebellum. Three cases of pure dysarthria due to cerebellar infarction have been
      reported previously. We compared cerebellar lesions in the 4 cases of pure
      dysarthria due to cerebellar infarction. Since the lobulus simplex of the upper
      cerebellar hemisphere was involved in all 4 cases, we speculated that ataxic
      speech occurred from the impairment of this cerebellar area.

PMID- 15199762
TI  - [Valentin Feliksovich Voino-Iasenetskii (1877-1961)].

PMID- 15199763
TI  - [Septic shock].
AB  - The problem of sepsis and septic shock (SSH) is known to be very actual due to
      peak-shaped growth of the number of such patients and unsatisfactory results of
      treatment. The occurrence of SSH is different--from 10% in the structure of
      infectious complications after polytrauma to 50% in patients with gram-negative
      sepsis in patients with burn disease. An analysis of treatment of 165 patients
      with SSH developed against the background of peritonitis has revealed high level
      of lethality (64%). In the pathogenesis of SSH an important role is played by
      immune disorders resulting in the development of generalized inflammation and
      polyorganic insufficiency. Treatment of patients with SSH must be necessarily
      supplemented with immuno-correcting techniques: use of medicines of nonspecific
      anti-cytokine action (pentoxyphillin) and regulators of the immune response
      (ronkoleukin, blood perfusion through the donor porcine spleen). The timely
      performed immunomodulating therapy allowed lethality of patients with SSH to be
      reduced to 32%.

PMID- 15199764
TI  - [Clinical aspects of glial and metastatic neoplasms of brain].
AB  - Results of surgical treatment of 253 patients with glial tumors and 47 patients
      with metastatic tumors of the brain are analyzed. An analysis with CT and MRT was
      used in the preoperative diagnosis for the calculation of the tumor volume and
      the dislocation degree. Microsurgical technologies used in the treatment allowed
      to shorten the period of postoperative rehabilitation, to reduce the development
      of neurological deficit that created conditions for early postoperative X-ray and
      chemotherapy.

PMID- 15199765
TI  - [Esophagoplasty in patients with the "waning" stomach or without the stomach].
AB  - An experience with 48 intrathoracic esophagoplasties in patients with "waning"
      stomach or its absence is generalized. The results obtained show that scarry
      ulcerous damages of the pyloroduodenal and cardioesophageal portions, local
      surgical procedures, gastrostomy included, are not considered as deterrent
      factors for using the stomach as the plasty material for esophagoplasty. For the
      resected stomach or its absence the small intestine should be preferred in the
      formation of the anastomosis within the limits of the thoracic cavity and large
      intestine--when putting anastomosis on the neck. A complete clinical effect was
      obtained in 45 patients. Three patients died (6.25%).

PMID- 15199766
TI  - [The endoscopic ligation and sclerotherapy in a complex prevention program of
      variceal bleedings in extrahepatic portal hypertension].
AB  - The results of prophylactic endoscopic treatment of 22 patients with extrahepatic
      portal hypertension (main group--EPH) and 76 patients with cirrhosis of the liver
      (a comparison group--CL) who had had variceal bleedings were analyzed. In the EPH
      group permanent eradication was obtained in 14 patients (63.6%), in the CL group-
      in 46 patients (50.5%). With the average duration of achieving the eradication
      the number of sessions before achieving it proved to be greater than that for CL.
      Recurrent bleeding during the first month of observations was noted in 7 out of
      22 patients. In most cases the sources of bleedings were postligational and
      postinjectional ulcers of the cardial part of the stomach. Long-term results (1-5
      years) were followed-up in 14 patients. In 9 patients there was no recurrent
      bleeding during 2-5 years of observation. Thus, it is expedient to use endoscopic
      interventions as the methods of the "first line" in the complex program of
      secondary prophylactics of variceal bleedings in extrahepatic portal
      hypertension.

PMID- 15199767
TI  - [One-stage combined operations on the organs of the abdominal cavity in
      compression stenosis of the celiac trunk].
AB  - The authors made an analysis of 511 operations for chronic abdominal ischemia
      caused by stenosis of the celiac trunk performed during 20 years. In addition to
      decompression of the celiac trunk, one-stage combined operations on the organs of
      the abdominal cavity were made in 167 out of 511 patients for concomitant
      diseases. It was shown that adequately fulfilled operations on organs of the
      abdominal cavity with stenoses of the celiac trunk improved the results of
      operations for the stenosed vessel.

PMID- 15199768
TI  - [Minimally invasive technologies in diagnosis and treatment of the algesic form
      of adhesive disease].
AB  - The indications to dissection of commissures in the algesic form of adhesive
      disease are determined. An experience with performing 36 laparoscopic operations
      is described. In 34 cases adhesiolysis was fulfilled under conditions of the I
      III degree of the commissural process. Technical problems appeared while
      dissecting commissures in 2 patients with the IV degree of the commissural
      process due to pronounced dystopia of organs of the abdominal cavity. No
      complications were registered during operations. Control examination of 29
      patients did not reveal recurrent diseases.

PMID- 15199769
TI  - [The method of parietal-cavitary sanitation of intestines in complex treatment of
      acute diffuse peritonitis].
AB  - Experimental investigations carried out in 154 white rats and 24 mongrel dogs
      have proved pathogenetical effectiveness and safety of using the method of
      parietal-cavitary sanitation of the intestine in treatment of acute experimental
      peritonitis. This method used in complex treatment in 28 patients with acute
      diffuse peritonitis allowed a 1.5-2 times quicker arrest of the syndrome of
      endogenous intoxication and liquidation of intestinal paresis. Infectious
      complications were 43% less frequent and the lethality indices were reduced by
      9.5% as compared with the results obtained in the control group.

PMID- 15199770
TI  - [Syndrome of enteric insufficiency in patients with diffuse peritonitis:
      evaluation of the severity and outcome of the process].
AB  - The authors have developed a method of assessment of the degree of the enteral
      insufficiency syndrome (EIS). The method was used in 2006 peritonitis patients on
      the basis of 42 clinical-laboratory indices expressed by 10 score scale. A
      formula for establishing the coefficient of EIS is proposed in cases of the
      absence of all the indices, the average intervals of its possible degrees are
      shown. An express formula was developed for the calculation of the prognostic
      coefficient and its degree intervals. Randomization in the approaches to
      diagnosis and treatment allowed lethality to be reduced from 26.9% to 12.9%, the
      frequency of complications--from 12.7% to 7.2%.

PMID- 15199771
TI  - [Effects of dyslipoproteinemia on long-term results of surgical treatment of
      patients with obliterating atherosclerosis of the lower extremity vessels].
AB  - The investigation included 120 patients who had undergone different
      revascularizing operations more than 10 years ago for obliterating
      atherosclerosis of the lower extremity vessels. Dyslipoproteidemia was diagnosed
      in 88 of them. It was established that in patients with dyslipoproteidemia the
      symptoms of ischemia of lower extremities were developed in younger age. Within 5
      years after the first revascularizing operations there appear reliable
      differences in the course of the disease in patients with dyslipoproteidemia and
      normal levels of lipids in blood. More than 90% of patients with
      dyslipoproteidemia in the distant period of time have symptoms of generalized
      atherosclerosis, and the survival is mainly predetermined by cardiac and cerebral
      complications of atherosclerosis. The life of dyslipoproteidemia patients
      operated upon is 8 years shorter than of subjects with the normal-level of lipids
      in blood.

PMID- 15199772
TI  - [The significance of urgent laparoscopy and mathematical prognosis in diagnosis
      of patients with combined trauma (preliminary communication) ].
AB  - Results of 376 laparoscopies for combined traumas performed during 3 years were
      analyzed. Characterization of the contingent of the patients and mechanisms of
      the traumas is given. The diagnosis was correct and exact in 100%, in 78.2% of
      the patients it was possible to find out the injured organ. The expedience to
      expand the indications to laparoscopy for combined traumas and to fulfill the
      operations in the shortest time after admission was stressed. A mathematical
      evaluation of the strategy of doctor's behavior was made for objectivization of
      the psychological solution of the doctor concerning the methods of treatment of
      patients with a combined trauma.

PMID- 15199774
TI  - [Surgical strategy for wounds of the cervical part of the esophagus].
AB  - An analysis of results of treatment of 425 patients aged from 15 to 85 years with
      penetrating wounds of the neck was made. In 40 (8.1%) patients there were wounds
      of the cervical part of the esophagus, 29 of them had associated injuries. The
      proposed active surgical strategy consisted in a necessary thorough revision of
      the penetrating wounds of the neck using general anesthesia and then directly in
      the operation room using subsidiary methods of examination such as urgent x-ray
      analysis with a water-soluble contrast, esophagoscopy, larengotracheoscopy. This
      approach allowed detection of injuries of the cervical part of the esophagus,
      even in cases of the absence of clinical symptoms of esophagus injuries. In all
      the patients the wounds of the esophagus were sutured and followed by active
      aspiration drainage and antibacterial treatment with modern antimicrobial
      medicines.

PMID- 15199773
TI  - [Surgical infection in combat injuries of extremities].
AB  - A retrospective analysis was performed of treatment of 1612 patients with gunshot
      fractures of long bones of the extremities wounded in the Republic of Afghanistan
      and Chechen Republic. Under study was the infrastructure of the gunshot
      fractures, general and local factors responsible for the development of
      suppurations. A angioneurodystrophy theory of pathogenesis of gunshot
      osteomyelitis is proposed. The level of proinflammatory cytokines was determined
      in blood serum and wound discharge for the early diagnosis of purulent
      complications. An algorithm of the diagnostic search was developed with using
      modern radio- and electrophysiological methods. The standards of general and
      local treatment are proposed for different stages and spread of the purulent
      process.

PMID- 15199775
TI  - [Restrictions on use of prolonged and long-term artificial ventilation of the
      lungs in the wounded and casualties].
AB  - On the basis of an analysis of results of treatment of two groups of the wounded
      and casualties the authors render concrete indications and contraindications for
      prolonged and long-lasting artificial ventilation of the lungs.

PMID- 15199776
TI  - [Surgical treatment of sporadic and radiation-induced thyroid cancer in young
      patients].
AB  - An analysis of results of treatment of sporadic thyroid cancer in 68 children and
      juveniles and in 119 adult patients with radio-induced carcinomas irradiated in
      childhood after the Chernobyl APS accident in 1986 has revealed that the sporadic
      thyroid cancer in children and adults with radio-induced carcinomas are highly
      aggressive. For all this, radio-induced carcinomas are known to have aggressive
      local growth that in most cases required extended operations. The surgical
      treatment of carcinomas allows to get survival of the absolute majority of the
      patients.

PMID- 15199777
TI  - [Surgical elimination of instability in congenital spinal deformations in
      children].
AB  - Variants of congenital mechanical and dynamic instability of the spine in
      children are described. Experiences with the treatment of malformations of the
      spine resulting in mechanical (30 cases) and dynamic (139 cases) instability are
      analyzed. In most cases different titanium implants were used for dorsal fixation
      (150 operations). The specific feature of most interventions was their being
      performed in the period of active growth of the children (more that 60% were from
      6 months to 5 years of age). It was found that the instrumental and osteoplasty
      stabilization failed to substantially influence the development of the spine.

PMID- 15199778
TI  - [Primary osteosynthesis in pediatrics: possibilities and perspectives].
AB  - An analysis of results of conservative strategy of treatment of unstable
      diaphysial fractures of long tubular bones in schoolage children allowed to
      expand the indications to performance of osteosynthesis as a primary method of
      treatment (133 children). Extracortical osteosynthesis with planes by such
      criteria as efficiency, safety, profitability and quality of patient's life is
      thought to be preferable.

PMID- 15199779
TI  - [Simultaneous operations in surgery and gynecology].
AB  - The necessity, possibility and safety of performing planned simultaneous
      operations on 122 women aged 39-78 were analyzed. Operations for different
      diseases were fulfilled on 264 patients (from 2 to 10 on one patient) were made
      mainly by two teams. Complications were noted in 11.2% of the patients, lethality
      was 0.9%. The duration of staying at the hospital was equal to that for the main
      disease. The authors consider that the presence of well trained operators and
      sufficient anesthesiology and resuscitation allow the gynecologists to detect the
      coexistent pathology and to fulfill associated operations together with other
      specialists.

PMID- 15199781
TI  - [Total colectomy with simultaneous ileorectostomy in severe nonspecific
      ulcerative colitis complicated by constriction of the rectum].
AB  - Total colectomy with a one-stage ileorectostomy was fulfilled in 72 patients (67
      children and 5 adult patients) with severe nonspecific ulcerative colitis by the
      method developed by the author. In 8 of the patients there was constriction of
      the rectum which required transanal finger bougieurage during the operation. None
      of the 72 patients had incompetence of the anastomosis. Follow-up observations
      during many years showed a rather high effect of the operation including the
      patients who had constriction of the rectum.

PMID- 15199780
TI  - [Duodenal injuries in the district surgeon's practice].
AB  - Under conditions of the Pavlovsk region operations were fulfilled on 337 patients
      with traumas of organs of the abdominal cavity. 15 patients died. In 6 patients
      injuries of the duodenum were treated. The early admission, adequate operative
      interventions resulted in the recovery of 4 patients.

PMID- 15199782
TI  - [Restorative treatment of degenerative-dystrophic diseases of large joints].
AB  - The authors performed courses of treatment with Midocalm in 110 patients
      according to their original method. It reduced the pain syndrome, increased the
      volume of movements in the joint and shortened the time of treatment.

PMID- 15199783
TI  - [First experience of use of a double balloon three-lumen catheter for decreasing
      the time of heat ischemia in asystolic kidney donors in Russia].
AB  - The authors consider actual problems of transplantation of organs associated with
      using donors. Special attention is given to current methods of preservation and
      obtaining donor kidneys from irreversible cardiac arrest donors. The authors
      propose to use a standard protocol of measures aimed at obtaining high quality
      transplants in every day practice of surgical teams dealing with taking off donor
      organs. First positive results of using the proposed method are described.

PMID- 15199784
TI  - [11 (13) Russian symposium with foreign participation on the surgical
      endocrinology (St.Petersburg, July 15-17, 2003)].

PMID- 15199785
TI  - [Arterial transplants in the surgery of coronary vessels].

PMID- 15199786
TI  - [Using esophagoplasty with a free revascularized segment from the small intestine
      and systematization of indications for the method].

PMID- 15199787
TI  - [Methods of roentgen-endovascular interventions on the adrenal glands].

PMID- 15199788
TI  - [Pheochromocytoma].

PMID- 15199789
TI  - [The endothelial dysfunction as one of the possible causes of emergence and
      progression of chronic venous insufficiency of lower extremities].

PMID- 15199790
TI  - [Prolapses in colostomy].

PMID- 15199791
TI  - [Sclerotherapy of hemorrhoids].

PMID- 15199792
TI  - [About longitudinal studies in epidemiology].

PMID- 15199793
TI  - [Longitudinal studies: concepts and particularities].
AB  - In this review the definition of "longitudinal study" is analysed. Most current
      textbooks on epidemiology do not define a longitudinal study, whereas statistical
      textbooks do. It is more common to talk about longitudinal data than about
      longitudinal studies. A longitudinal study implies the existence of repeated
      measurements (more than two) across follow-up. According to these ideas, a
      longitudinal study can be considered a subtype of cohort study that, in contrast
      with life-table cohort studies, allows inference to the subject level, to analyze
      changes in variables (exposures and outcomes) and transitions among different
      health states. The characteristics of this design force to paid special attention
      to quality control during data collection, losses during follow-up, and missing
      data in some measurements. The statistical analysis should take repeated measures
      into account, and it is what finally gives the longitudinal character to a study
      with repeated measurements.

PMID- 15199794
TI  - [Longitudinal studies in the prevention of cardiovascular diseases].
AB  - Longitudinal studies of well defined cohorts have contributed to the
      identification of risk factors of coronary heart disease and other clinical
      complications of atherosclerosis. After commenting on the conclusions of
      experimental atherosclerosis and risk factors suggested by the study of a series
      of myocardial infarction in young adults and their matched controls, we discuss
      the methodology, management and results of longitudinal studies carried out in
      the United States since 1949: Twin Cities, Framingham, Pooling Project, Western
      Collaborative, Puerto Rico Evans County, NI-IION-SAN, San Francisco, Harvard,
      Bogalusa and CARDIA. Special attention is given to the hypothesis proposed at the
      beginning of the Framingham Study and the obstacles and changes to continue the
      project after the first twenty-four years. We also expose the Seven Countries
      Study, designed and managed by Ancel Keys, as the first study performed with
      centralized methodology in various countries, and the studies in various European
      countries: Whitehall, Manresa, Paris, British Regional, Northwick Park,
      Caerphilly, Speedwell and PROCAM. We analyse the role of the longitudinal studies
      in the methodology of later studies: sons and daughters of the Framingham
      participants, longitudinal studies based on questionnaires, studies of the other
      risk factors, prevalence of risk factors in retrospective studies, trials of
      primary prevention (MRFIT, WHO European Collaborative Trial and Gotenburg Study)
      and the participation of the trained teams in the MONICA Project. We present the
      issues still under debate in connection with the methodology and results of the
      longitudinal studies: problems in the periodic examination of the participants in
      the epidemiologic studies, changes in definition of the new cases of acute
      cardiovascular events, use and selection of risk functions based on coronary
      charts to calculate the individual risk and cardiovascular risk factors as yet
      unknown.

PMID- 15199795
TI  - [The European prospective investigation about cancer and nutrition (EPIC)].
AB  - EPIC is a prospective multi-center study coordinated by the International Agency
      for Research on Cancer (IARC) operating under the WHO which commenced in 1993
      with the collecting of data and blood samples at twenty-three centers in ten
      European countries (Germany, Denmark, Spain, France, Greece, the Netherlands,
      Italy, Norway, the United Kingdom and Sweden). In Spain, this study was conducted
      in five geographic areas (Asturias, Granada, Guipuzcoa, Murcia and Navarre). This
      study included a total of 519,978 individuals (366,521 of whom were females),
      blood samples for laboratory analysis being available for a total of 385,719 of
      these individuals. To date, a total of 24,195 incident cancer cases have been
      identified. The results of the food intake comparison among the twenty-three
      European centers were published in 2002, in a European Nutrition journal
      supplement. The initial EPIC results concerning the relationship between diet and
      cancer show the intake of fiber, fruits and vegetables to have an effect on
      protect against colon and rectal cancer, the intake of fruits to have an effect
      on protect against lung cancer and the intake of fruits and vegetables on the
      upper digestive tract, whilst a high intake of fruits and vegetables has been
      shown to have no effect on prostate cancer. Using a seven-day diary for
      evaluating saturated fat intake, a high intake of saturated fats has been shown
      to increase the risk of breast cancer.

PMID- 15199797
TI  - [Non-parametric estimation of survival function for recurrent events data].
AB  - Recurrent events when we deal with survival studies demand a different
      methodology from what is used in standard survival analysis. The main problem
      that we found when we make inference in these kind of studies is that the
      observations may not be independent. Thus, biased and inefficient estimators can
      be obtained if we do not take into account this fact. In the independent case,
      the interocurrence survival function can be estimated by the generalization of
      the limit product estimator (Pena et al. (2001)). However, if data are
      correlated, other models should be used such as frailty models or an estimator
      proposed by Wang and Chang (1999), that take into account the fact that
      interocurrence times were or not correlated. The aim of this paper has been the
      illustration of these approaches by using two real data sets.

PMID- 15199796
TI  - [Multilevel model applications to the analysis of longitudinal data].
AB  - This work is an introduction to repeated measurement analysis for longitudinal
      studies. It uses a two stage modelling framework, using hierarchical linear
      models with two levels. The first level pertains to the repeated measures, the
      second level pertains to the individual. For the last 25 years, hierarchical
      linear models have been used in the Social Sciences to analyse data coming from
      organizations with multiple levels. Their applications have been extended to the
      study of change in populations, both to describe the average change in an outcome
      variable in a population and to analyse the factors associated with variability
      in the individual trajectories of change. In this article, the basic concepts are
      introduced: between subjects and within subjects variability, the person-specific
      model for the individual trajectory and the between person model to describe how
      individuals vary in their trajectories, fixed and random effects, linear and
      quadratic growth models. At the end of each section, an illustration is given for
      the study of cognitive function of the older people cohort "Aging in Leganes",
      followed in four occasions between 1993 and 1999. Results from fitting the models
      to answer the most frequently asked research questions in the descriptions and
      analysis of individual change are presented. Lastly, we present possible
      generalizations of these linear models to non linear situations which arise when
      outcomes are dichotomous, nominal or ordinal.

PMID- 15199798
TI  - [Burden and trends of activities of daily living disability in elderly Spanish
      people].
AB  - BACKGROUND: The progressive increase in population aging, specially evident in
      Spain, remark the importance to estimate the volume and the prevalence trends of
      dependency in the 65 years and over Spanish population. METHODS: The dependency
      volume was calculated applying the 1993 and 1999 estimated prevalences in the
      longitudinal study "Aging in Leganes" to the Spanish population of 1991 and 2001.
      A random study sample of 1560 subjects 65 years was selected in 1993 in the city
      of Leganes (Madrid). Response rate at baseline was 82% (n = 1283). New
      information was collected in 1995 (n = 827), 1997 (n = 666) and 1999 (n = 475).
      Dependency was defined as needing help in at least one of eight Activities of
      Daily Living ADL. A multilevel model for repeated measures was fitted regressing
      ADL dependency on age, sex, education and survey year. RESULTS: There is a
      decline in ADL dependency by age in both, men and women. At advanced ages, this
      trend is reversed and there is an apparent increase in dependency. The prevalence
      is higher in women and in low educated subjects. The total number of ADL
      dependent people increased from 903,276 to 995,338 from 1991 to 2001 although the
      average age of dependent older people increased. CONCLUSIONS: Postponement of
      disability means longer healthy life expectancy and increasing volumes of very
      elderly disabled people, particularly women. Consequences for health, labour
      reform and social security systems can be very important.

PMID- 15199799
TI  - [Determination of the beginning of follow-up in longitudinal studies applied to
      HIV infections].
AB  - BACKGROUND: In cohort or longitudinal studies, subjects are recruited some time
      after the beginning of the problem, as in HIV infection. The aim of this paper is
      to show several imputation techniques of the beginning of follow up and evaluate
      its use in the framework of a study of HIV progression. METHODS: Three subcohorts
      of HIV+ subjects recruited in Valencia and Castellon CIPS up to 1996 are
      available. Seroconversion date was estimated for 244 Seroincidents, 887
      seroprevalents with CD4 measurements and 337 without CD4 measurements. For
      seroincidents midpoint between last HIV- and first HIV+ visits was considered.
      For prevalent with CD4 serocon version date was imputed from 5 random samples of
      a progression model of infection to a CD4 level. For prevalent without CD4
      seroconversion date was imputed from 5 random samples of HIV incidence density
      obtained from the other subcohorts. The imputation was repeated 500 times,
      assigning the seroconversion date as the median of imputations and obtaining
      confidence limits from 5 and 95 percentiles. Imputation validity was tested
      comparing time to AIDS and death for each one of the 3 groups. RESULTS: 443 and
      405 deaths were observed among the 1468 subjects. Median of seroconversion was
      January 1993 for incidents, January 1991 for prevalents with CD4 and November
      1988 for prevalents without CD4. The latest group showed a worse survival and
      AIDS free time compared to the other two cohorts. CONCLUSIONS: The imputation
      tools used showed their usefulness to reduce the survival bias in observational
      studies. Their generalization depends on the viability of incident cohorts, the
      availability of a progression marker or a origin on time.

PMID- 15199800
TI  - [Risk factors and 28 year morbidity and mortality of coronary heart disease in a
      cohort with a low incidence of the disease: the Manresa Study].
AB  - BACKGROUND: To Study the incidence of coronary heart disease (CHD) and all-cause
      mortality in a cohort of men followed during 28 years, and their association with
      serum cholesterol, systolic blood pressure, glycemia, cigarette smoking and body
      mass index measured at baseline. METHODS: A cohort of 1,059 men aged 30 to 59
      years and free of cardiovascular diseases at baseline in 1968, was reexamined
      every five years until 1988. The last examination was performed in 1996.
      Information was collected on 96.4% of the participants. RESULTS: Incidence and
      mortality rates from CHD and from all-causes of death per 10(5) person-years of
      observation were 499.80, 235.80 y 925.33, respectively. At the end of follow-up,
      high levels of serum cholesterol and smoking were independently associated with
      the incidence and mortality from CHD controlling by age, blood pressure, glycemia
      and BMI. Serum cholesterol, hyperglycemia and smoking were independently
      associated with all-cause mortality. CONCLUSIONS: In this industrial cohort of
      men, with relative low incidence of CHD, smoking and serum cholesterol at
      baseline remained associated with the incidence of CHD through 28 years of
      observation.

PMID- 15199802
TI  - [Average body weight and height gain rate in children from 2 to 10 years old in a
      rural area of the Marinilla municipality, Antioquia, Colombia. 1996-1999].
AB  - BACKGROUND: The objective of the present study was to evaluate the average growth
      rate (AGR) in 2 to 10 years old children (n = 259) belonging to rural families
      from the municipality of Marinilla (Colombia). The results will be taking into
      account in order to define public health polices aimed to improve the life
      quality conditions in rural communities. METHODS: In a descriptive longitudinal
      prospective study a representative sample from rural horticulture families having
      children aged 2 to 10 years old were selected. The confidence interval, alpha
      error, and over sample were 95.5 and 20%, respectively. The AGR for weight and
      high were evaluated according to the method by Baumgarthner, and the results were
      compared with the Fels Longitudinal Study reference values. RESULTS: For AGR for
      weight 26.8 and 28.9% of boys and girls classified in the lower 25 percentile,
      respectively: 60.9 and 62.8% within the 25 and 75 percentiles, and 12.3 and 8.2%
      in the upper percentile of boys and girls, respectively. On the other hand, for
      AGR for high 44.9 and 33.1% of boys and girls classified in the lower 25
      percentile, 44.9 and 52.9% within the 25 and 75 percentiles, and 10.2 and 14.1%
      in the upper percentile of boys and girls, respectively. CONCLUSIONS: These
      results showed that the AGR of children in this study could not overcome their
      delayed weight and high measures.

PMID- 15199801
TI  - [The EPICARDIAN project, a cohort study on cardiovascular diseases and risk
      factors among the elderly in Spain: methodological aspects and major demographic
      findings].
AB  - BACKGROUND: Despite a greater incidence of ischemic heart disease among
      individuals over age 65, most cardiovascular research has been focused on the
      middle-aged adult population. To date no cohort study on this population have
      been made in Spain. This study is aimed as reviewing the role and methodology of
      cohort studies as an epidemiological tool absolutely essential for researching
      the prevalence and incidence of angina, AMI, stroke and the major cardiovascular
      risk factors. METHODS: Cohort study in three areas of Spain (Lista district in
      Madrid), Arevalo (Avila) and Begonte (Lugo). Age and sex stratified random sample
      by based on the municipal censuses of each area and municipality (n = 5.079). Two
      stage initial cohort assessment: home survey structured for the screening
      ischemic heart disease and classic risk factors (hypertension, dyslipemia,
      diabetes and smoking habit) and clinical assessment for case confirmation. In the
      follow-up phase the MONICA project "cold pursuit" method modified for pinpointing
      and investigating indicent cases was used, employing all of the hospital and
      primary care clinical records for confirming the cardiovascular event. Data was
      also requested from the Spanish National Institute of Statistics as to the cause
      and date of death of the deceased individuals in the cohort. RESULTS: The overall
      AMI prevalence was 4% (95% CI: 3.4%, 4.5%); definite plus probable AMI being 6.2%
      (95% CI: 5.5-6.9). The definite AMI prevalence was higher among the mean 6.7%
      (95% CI: 5.63-7.79) than among the women, 2% (95% CI: 1.51-2.55) (p < 0.001).
      Hypertension prevalence according to JNCV1 criteria was 68%, hypercholesterolemia
      26.4% according to NCEP criteria, diabetes prevalence 13.4% according to WHO
      criteria, and 11.3% were smokers. The cumulative incidence for a 3.2-year period
      for nonfatal definite AMI was 1.4% (95% CI: 1.1-1.8); 1.1% (95% CI: 0.74-1.37)
      probable AMI: 1.17 (IC95%: 0.824-1.48) for fatal definite AMI or death due to AMI
      and 1.13% (IC 95%: 0.824-1.48) for sudden death. CONCLUSIONS: The elderly
      population included in this study shows a high prevalence of cardiovascular risk
      factors, as well as ischemic heart disease incidence rates three times higher
      than those of the middle-aged adult population in Spain. The risk profile for
      women is significantly worse than for men, which may be due to the higher death
      rate at earlier ages among men.

PMID- 15199803
TI  - [Longitudinal study of hospital readmission for congestive heart failure in
      Cataluna. 1996-1999].
AB  - BACKGROUND: This study is aimed at describing the readmission phenomenon for
      heart failure patients and identifying some of their related clinical factors by
      means of a follow-up study with administrative data. METHODS: Longitudinal study
      of readmissions due to heart failure (HF) among a population > or = age 65 in
      Catalonia throughout the 1996-1999 period. Information source: Minimum Basic Set
      of Data of Hospital Discharges from the Catalan Health Service. Definition of HF,
      etiological or precipitating cause, and comorbility by means of a ICD-9 discharge
      release codes combination. Analysis units "patient with HF" and an index
      population or cohort". STATISTICS: Survival analysis (Kaplan-Meier and Log-rank
      test) and regression models (Cox). RESULTS: The follow-up populations, comprised
      of 16,919 patients, generated 44,283 admissions (61.8%). The length of time free
      of readmissions (Mean "ME" in months) and the comparison of the survival curves
      is statistically significant with lower values in the following categories: 'age
      65-74' (ME = 21.6 months); 'male' (23.3); 'healthcare region 6' (16.3);
      'reference hospital' (22.9) and 'pure COPD related to the HF (17.7),. The highest
      risk of readmission, adjusted by the other variables under study, has been found
      for 'pure COPD' [RR = 1.03, (95% CI: 1.02-1.04), p < 0.001], and ischaemic heart
      disease [RR = 1.03, (95% CI: 1.01-1.05), p = 0.003]. CONCLUSIONS: This study
      reveals the clinical complexity and patterns of utilization of hospitals on the
      part of patients with heart failure, identifying that those having COPD or
      ischaemic heart disease being top-priority groups for care intervention and thus
      revealing the potential which administrative data has for clinical planning and
      management.

PMID- 15199804
TI  - [Role of the level of obstruction and urodynamics of the upper urinary tract in
      infectious-toxic complications in urolithiasis. (Clinical and experimental
      study). ].
AB  - Clinical studies have revealed that location of the occlusion in the kidney and
      upper third of the ureter raises the risk of severe infectious-toxic
      complications of urolithiasis. It is shown experimentally that mechanisms of
      compensation of impaired urinary transport along the upper urinary tracts differ
      in obstruction of the upper and lower third of the ureter.

PMID- 15199805
TI  - [Medical and ecological assessment of climate effects on urolithiasis morbidity
      in population of Primorsky territory].
AB  - The article presents medicoecological estimation of quantitative relations
      between monsoon climate and urolithiasis primary morbidity in the Primorsky
      Territory. Quantitative estimation of the climate was performed by V. I. Rusanov
      (1973) who calculated daily meteorological data for 1 p.m. throughout 1991-1999.
      Primary urolithiasis morbidity for this period of time was provided by regional
      health department. The data were processed by methods of medical mapping and
      paired correlation analysis. In the Territory, mapping revealed the same location
      of the zones with high frequency of discomfortable weather of class V and VI
      causing chilblain in positive air temperatures and zones with elevated primary
      urolithiasis morbidity in children and adults. Correlation analysis confirmed
      mapping results and determined significant negative correlations between
      frequency of relatively comfortable moment weather classes II-IV and morbidity of
      children and adults, positive correlation between frequency of discomfortable
      class VI and adult morbidity. Thus, high frequency of days per year with
      discomfortable classes of moment weather in low positive air temperatures may be
      one of the factors of urolithiasis risk in population of the Primorsky Territory.
      Climatic factors should be taken into consideration in planning primary
      prophylaxis of this disease in the Primorsky Territory.

PMID- 15199806
TI  - [Prognostic implication of morphometric stromal parameters of renal pelvis and
      ureteral transitional cell carcinomas].
AB  - To evaluate prognostic value of morphometric studies of the stroma of
      transitional cell carcinomas of the renal pelvis and ureter, we studied
      retrospectively the data of primary examination and follow-up of 75 patients (49
      males, 65% and 26 females, 35%; mean age 61.9 +/- 1.2 years) given radical
      surgical treatment for cancer of the renal pelvis and ureter. Five-year survival
      in the absence of tumor progression was 23%. Morphological examination diagnosed
      transitional cell carcinoma with invasion pT1, pT2, pT3 and pT4 in 3(4%),
      15(20%), 47(63%) and 10(13%) cases and differentiation degree G1, G2, G3 in
      31(41%), 15(20%) and 29(39%) cases, respectively. In addition to the standard
      morphological examination of the tumor, we made morphometry of stromal and tumor
      area, analysed composition and count of stromal effector cells (lymphocytes,
      eosinophilic and neutrophilic leukocytes, macrophages, mast and plasmic cells),
      the degree of stromal vascularization. Prognostic value of the above parameters
      was estimated according to significance of their correlation with postoperative
      survival of the patients. The survival correlated with the depth of cancer
      invasion (p = 0.005) and differentiation of tumor tissue (p = 0.006), high cell
      infiltration of tumor stroma is prognostically unfavourable (R2 = 0.03; F = 3.41;
      p = 0.069) as well as weak presentation of stromal component of the tumor (p =
      0.056). The lowest survival was observed in patients with cancer of the renal
      pelvis and ureter with a great number of mast cells (p = 0.056), macrophages (p =
      0.037) and neutrophils (p = 0.029) in the tumor stroma. According to the results
      of multiple regression analysis (R2 = 0.08; F = 5.42; p = 0.024), five-year
      postoperative survival most closely correlated with cancer invasion depth (p <
      0.001), degree of tumor cells differentiation (p < 0.001) and number of
      macrophages infiltrating tumor stroma (p < 0.001). Significance of survival
      prognosis for patients with cancer of renal pelvis and ureter can be raised by
      estimation of mean number of free stromal cells and expression of stromal
      component.

PMID- 15199807
TI  - [Antiischemic efficacy of perfluoroorganic compounds in patients with renal
      inflammation].
AB  - To improve metabolism and reduce activity of pyoinflammatory reactions in
      complicated infection of the kidneys, we studied pharmacological potentialities
      of perfluorocarbon emulsion perfluoran. Correlation between oxygen unbalance,
      development of cell membrane pathology and activity of pyoinflammatory affection
      of the kidneys was studied in 67 patients with acute obstructive pyelonephritis
      complicated by urosepsis. It was found that surgical manipulations aiming at
      recovery of urodynamics and normalization of hemodynamic indices of the kidney
      are accompanied by development of reperfusion syndrome of the affected and
      contralateral kidney. Use of perfluoran in this situation promotes rapid
      compensation of gas transport disturbances, stabilization of the equilibrium in
      the system prooxidants-antioxidants, regress of pyoinflammatory reactions,
      earlier recovery of functions of a more affected kidney and antiischemic
      protection of the contralateral organ. Antiischemic and membrane-stabilizing
      actions of perfluoran make this drug adequate for use in patients with
      complicated renal infection.

PMID- 15199808
TI  - [Microbiological characteristics and clinical efficacy of phosphomycin].
AB  - E. coli is the most frequent agent causing urinary infection (UI) both in adults
      and children. E. coli of UI outpatients is often resistant to ampicilline,
      amoxicilline and co-trimoxasol. The study of phosphomycin in UI outpatients
      showed its highest efficacy against E. coli. Phosphomycin in a single daily dose
      of 3 g is a drug of choice in acute uncomplicated cystitis. The results of the
      study also demonstrate that phosphomycin can be used for prevention of
      pyoinflammatory complications before endoscopic manipulations and operations as
      well as open operations on the lower urinary tracts and genital organs.

PMID- 15199810
TI  - [Magnetic resonance imaging in diagnosis of localized prostatic cancer].
AB  - To evaluate efficacy of MR imaging (MRI) in diagnosis of local prostatic cancer
      (LPC) and validity of MRI performance in patients with high levels of prostate
      specific antigens (PSA), we made a retrospective analysis of a combined
      examination of 210 patients including MRI (100%). Of them, 68 (32.4%) had
      prostatic cancer (LPC pT1-pT2 in 27 patients, 39.7%), 87 (41.4%) had benign
      prostatic hyperplasia (BPH) and 35 (16.7%)--chronic prostatitis (CP). 17 (8.1%)
      patients were free of prostatic diseases. MRI accuracy in diagnosis of LPC was
      60%, sensitivity 70%, specificity 54%, in positive and negative prognostic values
      50 and 73%, respectively. Some features of LPC were seen in MRI of BPH, CP and
      control patients. MRI symptoms characteristic for one of the above diseases only
      were not determined. We believe that MRI is indicated in suspected prostatic
      cancer located in the central zone and anterior lateral regions of the peripheral
      zone (unpalpable prostatic cancer). Prostatic MRI with assessment of the lower
      spine and pelvic bones is justified in men over 50 years if PSA is above 10
      ng/ml. Early and accurate diagnosis of LPC by MRI is impossible without
      evaluation of clinical and PSA data.

PMID- 15199809
TI  - [Bilateral microsurgical varicocelectomy in infertile men].
AB  - We assessed how bilateral microsurgical varicocelectomy alters semen quality in a
      large cohort of infertile men with bilateral varicocele. By means of bilateral
      testicular biopsy, we have investigated the spermatogenesis failure in several
      biological men groups and determined whether it can change the patient's
      candidacy for assisted reproductive technology procedures (ART). MATERIALS AND
      METHODS: From 1993 until 2003 in the urology and andrology department of St.
      Antoine hospital (1993-1994), the Tenon hospital (1994-2003) and hospital Saint
      Louis (1997-2003), 956 patients with varicocele were consulted and operated for
      primary or secondary sterility. Bilateral varicocele was observed in 219
      patients. Our study included 198 patients with clinical palpable and
      infraclinical (ultrasonic doppler scanning) bilateral varicocele who underwent
      microsurgical bilateral varicicolectomy with bilateral testicular biopsy. Mean
      patient age was 34.5 (range 19 to 65) years. Varicocele has been classified into
      4 stages. All the patients underwent a complete physical examination, including
      supine and standing scrotal examination, as well as testicular volume
      determination using a standard orchidometer. Complementary investigation
      included: the hormone status (FSH, LH, testosterone), semen analyses (carnitine,
      LDHx, fructoze, zinc). On the basis of the total motile sperm count 198 patients
      were divided into 5 biological groups: 10 azoospermia and oligospermia extreme (0
      1) x 10(6)/cc--83 patients (41.9%); 2) oligospermia severe (1.1-5) x 10(6)/cc)-
      37 patients (18.7%); 3) oligospermia moderate (5.1-10) x 10(6)/cc)--36 patients
      (18.9%). To measure the sperm quality, the spermogram was studied 3, 6 and 12
      months after the operation. On the basis of testicular biopsy we defined the
      following spermatogenesis groups: normal spermatogenesis--9 cases,
      hypospermatogenesis--141 cases, maturation arrest (early-6, late-20), Sertli cell
      only syndrome (SCOS)--17, tubular and peritubular sclerosis--5. The correlative
      analysis between the FSH classes and azoo- and oligospermic subsets (83 patients)
      shows that azoo-oligospermic area as a whole represents only 2 patients (2.4%) in
      the low FSH class, 46 (55.4%) in the normal FSH range class II, 39 (46.9%)
      patients in the high FSH class III. All the patients were divided into 4 groups
      according to the type of ART for which they qualified including 0 to 1.5
      million/ml (intracytoplasmatic sperm injection-ICSI)--79 patients, 1.5 to 5
      million/ml (in vitro fertilization-IVF)--33 patients, 5 to 20 million/ml
      (intrauterine insemination--IUI)--47 patients and 20 million/ml or greater sperm
      (spontaneous pregnancy candidates)--39 patients. RESULTS: Postoperative sperm
      concentration increased significantly compared to the one before the
      varicocelectomy. In the group of our patients the results were the following: of
      198 patients 105 (53.1%) improved the spermogram, 44 (22.2%) worsened the
      spermogram, the spermogram was not changed in 49 (24.8%). In the first biological
      group of 83 patients, 42 (50.6%) improved the spermogram that enables using
      several methods for this difficult group (ICSI, IVF) for assisted reproductive
      technique (ART). The total amount of motile sperm per ejaculation increased from
      (0.09 +/- 0.030) x 10(6) before varicocelectomy up to (8.9 +/- 1.3) x 10(6)
      afterwards. In this group the testicular biopsy shows different variants of
      spermatogenesis disturbances, respectively. As for biological groups 3, 4 and 5,
      the observed spermogram improvements sharply increased the patients' liability to
      spontaneous pregnancy and make them intrauterine insemination candidates.
      CONCLUSIONS: Microscopic varicocelectomy has minimal morbidity and recurrence and
      may be beneficial for certain patients. Making simultaneous biopsy in patients
      with azoospermia and severe oligospermia makes it possible to distinctly define
      the extent of spermatogenesis disturbances and to elaborate adequate treatment
      policy. The drastic improvement of the sperm quality after varicocelectomy
      increases the ART chances for spontaneous pregnancy.

PMID- 15199811
TI  - [The use of low-molecular heparins in prevention and treatment of thrombotic
      complications after radical prostatectomy].
AB  - Effects of low-molecular heparin flaxiparin on prevention of thrombotic
      complications after radical prostatectomy were studied in two groups of patients
      with localized forms of prostatic cancer at stages T1c, T2a, T2b and T3a. Group 1
      received non-fractionated standard heparin in a dose 5000 units 4 times a day for
      10 days. Group 2 was treated with flaxiparin in a dose 0.3 ml (7500 U anti-Xa)
      twice a day s.c. for 10 days. After therapy no thromboembolic complications were
      observed. In group 2 removal of the urethral catheter was conducted 4-5 days
      earlier than in group 1. This reduced hospital stay from 29 to 20 days.
      Flaxiparin accelerated growing vessels in the zone of urethrourethral or
      urethrovesical anastomosis resulting in improvement of microcirculation and
      preventing strictures in the anastomotic zone. Thus, low-molecular heparin
      prevents thromboembolic complications, reduces hospital stay and duration of
      rehabilitation after radical prostatectomy.

PMID- 15199812
TI  - [Orthopic plastic repair of the urinary bladder with a gastric segment].
AB  - Urinary bladder plastic repair with a gastric segment on a. et v. gastroepyploici
      dex was made in 22 patients (18 males, 4 females, mean age 58.2 years) from
      November 2001 to June 2003. Gastrocystoplasty was made in 17 patients after
      radical cystectomy for urinary bladder cancer, and in 5 patients with neurogenic
      and small urinary bladder. Three patients have undergone surgery in our
      modification with a complete cross resection of the gastric body with the lesser
      curvature. Lethal outcomes were absent. Follow-up for 2-22 months demonstrated
      that all the patients achieved positive functional results and good quality of
      life.

PMID- 15199813
TI  - [Application of a free flap from urinary bladder mucosa for urethroplasty in
      experiment].
AB  - Experiments on 8 rabbits have demonstrated that mucosa of the urinary bladder
      freely transplanted into the subcutaneous fat or under the muscular fascia is
      engrafted with unaffected normal histological structure and revascularized with
      vessels invading from the adjacent tissues. Urethroplasty with a vesical mucosa
      graft was made in 10 dogs with experimental urethral stricture (4 animals),
      urethral fistula (5 animals) or a combination of urethral stricture and fistula
      (1 animal). A positive result with reestablishment of normal urethral passability
      and elimination of urinary fistula was achieved in 9 animals (followup for 1
      year). One dog died of an unknown cause. Urodynamic examination of the dogs in
      long-term follow-up reported normal urethral resistance to urinary flow.

PMID- 15199814
TI  - [Complications of surgical treatment of hypospadia].
AB  - 127 new cases of hypospadia were treated in 1980-2002. A total of 348 operations
      including urethroplasty by Duplay and Cecil were made. 78 of the operations were
      followed by complications out of which 26 were corrected in the postoperative
      period and had no effect on the treatment results. The first stage of surgical
      correction of hypospadia (89 operations) brought complications in 13.48% cases.
      Recurrent distortion of the cavernous bodies was most typical complication at
      this stage. In most cases development of scarry deformation was due to
      inflammatory changes early after surgery. Derivatives of prednisolone proved
      effective in the treatment of hypertrophic scars. This complication correlated
      with skin plastic repair (longitudinal suturing or creation of oncoming
      triangular flaps) to correct the defect. The second stage of hypospadia surgery
      was urethroplasty made in 196 cases. It was accompanied with complications in
      13.25 patients. Fistulas of newly-created urethra (11.73%) were the most typical
      and frequent complication. The number of postoperative complications varied
      greatly depending on the disease form and method of urethral reconstruction.
      Cecil urethroplasty brought complications in 7.94% cases. Efficacy of
      neurourethra creation by Duplay varied greatly depending on the length of the
      created neourethral portion and the number of local skin resources (8-33-83.33%
      complications).

PMID- 15199815
TI  - [Diagnosis and therapy of different types of priapism].

PMID- 15199816
TI  - [Combined treatment of voiding disorders in women with m-cholinolytic and alpha 1
      adrenoblocker].
AB  - The drug spasmex (trospium chloride) having an m-cholinolytic and myotropic
      spasmolytic action has been used for treatment of enuresis in women with
      imperative voiding syndrome. Spasmex was given in combination with alpha 1
      adrenoblockers to 20 women. The clinical picture was assessed with the original
      table. Urodynamic alterations were registered by means of home uroflowmeter.
      Clinical parameters improved 2 times after 4 weeks of the treatment. Mean
      effective capacity of the urinary bladder increased by 25%. Spasmex in
      combination with terasozine was well tolerated and had no side effects.

PMID- 15199817
TI  - [Low-invasive colposuspension in stress enuresis in females].
AB  - Retropubic colposuspension (RC) is one of leading surgical treatments of stress
      enuresis in women. A low-traumatic method of RC with application of special
      surgical instruments is proposed. Retropubic urethrocervicopexy and low-invasive
      colposuspension were made in 27 and 17 women, respectively. 25 women have
      undergone endoscopic operations. Postoperative complications were minimal in
      endoscopic and low-invasive interventions. Long-term results were similar to
      literature data. Low-invasive colposuspension is an effective and low-traumatic
      treatment of stress enuresis in women.

PMID- 15199818
TI  - [Modern surgical procedures for treatment of kidney calices in aged patients].

PMID- 15199821
TI  - Nurses intentionally called to care.

PMID- 15199819
TI  - [Effective and safe use of Levitra (Vardenafil) for treatment of erectile
      dysfunction].

PMID- 15199824
TI  - Preventing violence in the healthcare workplace.

PMID- 15199825
TI  - Crossing the borderline: editors' movement.

PMID- 15199826
TI  - [Aspects valued by nursing professionals in regard to personal body hygiene and
      the patient's body hygiene].
AB  - Descriptive survey aimed at identifying which aspects of body hygiene are valued
      by a nursing staff both in regard to personal body hygiene and to patients body
      hygiene. This survey has been conducted inside eight public health institutions,
      and the sample consisted of 126 nursing professionals, corresponding to 12.8% of
      a total of 986 people of the nursing personnel in such institutions. When
      considering personal body hygiene, the number of nail and hair care related
      quotes was higher than the number of answers concerning basic aspects such as
      hands hygiene, and this fact has called our attention. In patients body hygiene,
      a shower was the highest regarded aspect by the nursing staff; oral hygiene by
      registered nurses and nursing aids; and nail care by registered nurses and
      nursing technicians.

PMID- 15199827
TI  - [Characteristics of interpersonal skills of nurses: study with undergraduate
      nursing students].
AB  - This article has a quality and quantity-based approach, performed among nursing
      undergraduate students, whose objective was to identify features that constitute
      interpersonal competency, starting with a group laboratory, where data were
      collected at two points in time by means of a survey. The results have shown hard
      to perform characteristics obtained through practice, such as: resistance to
      stress, initiative, flexibility, and conflict resolution. The characteristics
      easily developed were: self-confidence, ability to listen, and ability to
      compete. We have reached the conclusion that those characteristics can and must
      be further explored over undergraduate studies as a means to strengthen nurses'
      managerial performance.

PMID- 15199828
TI  - [Classification of researchers/consultants in the nursing area in the CNPq:
      contribution to a data bank].
AB  - This study is an analysis of the themes and the knowledge subareas where nursing
      researchers from CNPq (Brazilian Council for Technological and Scientific
      Development) are included, based on the projects assessed over the period from
      2002 through 2003. Their goals were to present the distribution of researchers
      according to their present classification in the Nursing area adopted by CNPq and
      discuss the representativity of the researchers from this knowledge area. Results
      evidenced that the predominant subareas regarding research in this category were:
      fundamentals of the care process, followed by the area of adult nursing care.
      This study also revealed the existing concentration of researchers and pointed
      out for the need to establish inclusion strategies and to stimulate the return on
      financial resources to the research they develop. Authors emphasize the
      importance of an update in the subareas as well as a strengthening effort in
      scientific production.

PMID- 15199829
TI  - [Musculoskeletal disorders and quality of life in health care providers working
      in patient transportation].
AB  - The aim of this study was to evaluate musculoskeletal symptoms, quality of life
      and tasks perceived as most tiring by health care workers performing a patient
      transfer service for a city hall administration in the countryside of Sao Paulo
      state. A questionnaire was used for collecting demographic and occupational data;
      an instrument derived from the "Nordic Questionnaire"; a questionnaire to
      evaluate quality of life (SF 36) and the BORG scale. In this study, 82% workers
      reported at least one musculoskeletal symptom over the twelve previous months.
      Quality of life was affected in the following aspects: pain, social aspects, and
      vitality. Workers felt that all tasks related to patient transfer required
      intense physical effort which compromised their musculoskeletal system.

PMID- 15199830
TI  - [Teaching nursing care methodology in Parana].
AB  - This inquiry has been carried out among professors in the Nursing program from
      Institutions of Higher Education in the State of Parana. It aimed at
      investigating the teaching process of Health Care Assistance Methodology for
      Nursing, by promoting and opening possibilities for interchange among these
      professors by means of a Forum. Data were collected through a semistructured
      questionnaire sent by regular mail, fax, and email. The sample consists of 17
      instruments answered by professors representing 8 educational institutions. These
      data have shown how relevant the teaching of Health Care Assistance Methodology
      for Nursing is, but its concept still poses disagreements. It points out the
      theoretical reference the professors carry, the pedagogical methodologies they
      use, and the articulation between theory and practice.

PMID- 15199831
TI  - [Teaching the aging process and old age in nursing graduation courses].
AB  - This study aimed at unfolding how the teaching on the aging process and old age
      takes place in nursing undergraduate programs. Data were obtained by means of a
      questionnaire, which was completed by coordinators of the five existing nursing
      programs in the state of Ceara. Its theme is the content of a specific course in
      the program. Different techniques and strategies were used in order to learn what
      students' interests were and so to reach a better outcome in the teaching
      learning situation. Students found such discussions relevant because these made
      them better prepared for entering a promising labor field; they stressed the high
      importance the discussions on that theme would have in other courses as well,
      aiming at providing a sound knowledge basis and at reaching excellence in patient
      care. We found that the courses surveyed try to raise interest in this knowledge
      field, promoting several opportunities for study and practice, and providing a
      new way to make opinions meet about growing old and old age.

PMID- 15199832
TI  - [The health professionals' team, the patient with renal disease in hemodialysis,
      and interpersonal relations].
AB  - Comprehensive discussions in scientific literature on the relationship between
      health professionals teams and renal patients present some particularities
      regarding professional background and the health care provided. In this paper we
      have analyzed the kind of care health professionals provide and their
      interpersonal relationships from the point of view of patients undergoing
      hemodialysis. Interviews were made using a clinical-qualitative method,
      consisting of semistructured interviews with seven patients in a hemodialysis
      unit, who were chosen through an intentional sampling. The data selected were
      assessed on a thematic content analysis. We have found that patients wish the
      health care team would listen to their concerns more carefully, which go beyond
      physical aspects. The clinical care provided has proved to be more focused on
      biological aspects of patients and on mechanical procedures, showing a
      considerable degree of carelessness about how human relationships and technical
      competency differ.

PMID- 15199833
TI  - [Mapping nursing actions of CIPESC to NIC interventions].
AB  - Terms applied in an instrument from the International Classification for Nursing
      Practice on Collective Health in Brazil were assessed based on nursing
      interventions established by the ICN in order to determine if these would be
      allowed to represent the nursing practice in Brazil. A three-step procedure was
      used to interconnect such terms and a descriptive analysis was performed. The
      conclusion was that NIC would be useful in Brazil.

PMID- 15199834
TI  - [Maternity in adolescence: a challenge to face].
AB  - This study acknowledged how maternity interfered on the life project of
      adolescent mothers. Data were collected from a maternity hospital in a city
      located in the countryside of Sao Paulo state, Brazil, over a three-month period.
      One hundred and forty adolescents participated in this study, 77% of them were in
      a marital relationship. Most adolescents had elementary school education, 31.4%
      were attending school when they became pregnant. At the end of pregnancy, 60%
      quit school in order to take care of their children. Those who went back to
      school could count on support from their families. Most of them will remain out
      of the labor market and those who do work rely on family support for the care of
      their children. Results showed the need to reorganize services with
      differentiated methodological approaches aiming at achieving the precepts
      provided in the guidelines for sexual and reproductive rights.

PMID- 15199835
TI  - [Sunrise model and the sensitive reason in nursing].
AB  - This study stems from an assistance and investigation practice on how to offer
      nursing care based on sensitive reason, compatible with the client's culture, as
      well as with his/her familial links. We have tried to apprehend the meaning they
      confer to nurses, to the health-disease process, and to home nursing. The Sun
      Rising Model was used in order to report the elements emerging over the nursing
      care periods. Later, a Sun Rising model in post-modern times was drawn, whose
      culture expressed through beliefs, practices, and habits favored a patient-nurse
      interaction. Finally, the presentation of the elements emerging form this
      practice comprises both transcultural theory and sensitive reason at the same
      time.

PMID- 15199836
TI  - [Women with breast cancer: perception of disease, family, and society].
AB  - This work of understanding of different situation close to the woman having
      breast cancer regarding that attend the support group of chemotherapy services at
      Society Hospital of Charity of Santa Rosa (R.S., Brazil). Were the main objective
      was to evaluate the perception of the woman having breast cancer regarding her
      disease, family and society, by using some theoretical concepts of Theory of Goal
      of Attainment, from Imogene King. To collect the data were semi-structured
      interviews. The woman with breast cancer feels social, physical and emotional
      limitations seeking for knowledge and information about such disease and life.
      Rethinking the practical of taking care of a woman with breast cancer is the role
      of nursery, attending her with respect, ethics human life appreciation and
      sensibility.

PMID- 15199837
TI  - [Psychiatric nursing practice at a public institution in Brazil].
AB  - This is a social and historical study whose objectives were to identify
      characteristic features of the psychiatric nursing practice from the point of
      view of nursing professionals working at a public psychiatric hospital in Rio de
      Janeiro over the course of a psychiatric care reform process, and to analyze the
      changes occurred in the nursing practice of those professionals. Their oral
      statements were used as the source for this study. Our findings showed that
      during the 'psychiatric care reform process, the nursing care provided by
      professionals kept presenting the segregating characteristics commonly-linked to
      the asylum care model, and that changes happened due to the influence of new
      routines and training these professionals were exposed to.

PMID- 15199838
TI  - [Programs of nursing home care].
AB  - Home care is an assistance strategy that emphasizes patient autonomy, as well as
      self-care in the domiciliary setting. This strategy involves planning,
      coordination, and performance of several services. This study is of a descriptive
      type, contemplating a qualitative approach by means of a bibliographical review.
      Data were analyzed through the Content Analysis technique, with two categories
      being identified: home care programs and systematization of care. Home care
      reduces the number of clinical complications, additional hospitalizations, and
      hospital costs. Upon outlining a home care program, objectives must be
      established with the purpose of effecting the desired changes. When carrying out
      the systematization, nurses must build ties and a partnership with the patient
      and his/her family.

PMID- 15199839
TI  - [Psychiatry reform: analysis of power relations in mental health care services].
AB  - This paper approaches the topic of Psychiatric Care Reform in Brazil and,
      particularly, in the State of Rio Grande do Sul, as well as the role played by a
      disciplinary power in modern society. We believe that in spite of the
      implementation of a reform in Psychiatric care and the growing progress in the
      legislation aimed at protecting psychiatric patients, such individuals are still
      the objects and the instruments inside relationships of disciplinary power. This
      study is based on Michel Foucalt's works, especially on his analysis of the power
      relationships, in order to elicit answers to our main question, to support the
      thesis we formulated, and to reach our goal, which is to ponder on the
      discrepancy we perceive between legal victories and the new speech delivered by
      the psychiatric care reformers, and on a practice which seems to deny
      emancipation to psychiatric sufferers, that is, deny their citizenship.

PMID- 15199840
TI  - [Worker's health: conditions of work of the nursing staff in psychiatric
      hospitals].
AB  - This study deals with the concern shown by health care professionals, especially
      by those working in the psychiatric nursing area, with the stress they experience
      due to particular characteristics of their work activity. We tried to learn about
      the relationship between work conditions in nursing, an anxiety-builder
      environment, and physical and psychological exhaustion. We found the need to
      implement programs aimed at reducing professional risks ran by psychiatric
      nursing staff.

PMID- 15199841
TI  - [Integration of nursing in science and technology policies].
AB  - Brazilian nursing is included in the national science and technology system, as
      part of the health knowledge area. Its scientific production is reknown but is
      yet to strengthen its position. Among the strategies to be used, we can
      emphasize: study different ways to promote a closer relationship between
      university and services; create or intensify interfacing between clinical and
      academic nurses; promote strategic research for the use of technological
      innovations, continuing education of human resources, and implement studies on
      Nursing care while integrating skills required by complex technological systems
      and intersubjectivity, acting in a therapeutic way.

PMID- 15199842
TI  - [The art of Leonardo Da Vinci as a resource to science and the ideal of nursing
      care].
AB  - Theoretical reflection whose goal is to demonstrate the art a nursing team is
      required to show in order to perform a technical procedure for transfer of
      solutions from a normal vial to a microdrops vial, based on Leonardo Da Vinci's
      theoretical referential, inspired by his work called "Vitruvian Man", so that
      body harmony is kept. The authors emphasize its relationship to nursing care,
      viewing it from its broadest sense, and its own motto--"Science, Art and Ideal".

PMID- 15199844
TI  - [Exercise of freedom and autonomy at the academy --a pedagogic practice at the
      professional training stage].
AB  - This article presents a reflection on an educational experience developed by the
      Nursing Undergraduate Program at the Federal University of Santa Catarina during
      a supervised training period which focused on the use of autonomy,
      responsibility, competence, and commitment by undergraduate students to the
      nursing professional world. The pedagogic direction of this activity is an
      articulation between thought and action through the problematic approach to
      reality in an attempt to bring students closer to their professional roles.

PMID- 15199843
TI  - [Palliative care: a perspective of comprehensive care for the cancer patient].
AB  - The purpose of this article is to ponder on the relevance of palliative care in
      assisting ill patients with neoplasias in their dwellings, since palliative care
      aims at giving patients and their families the best attainable quality of life.
      Despite the great emphasis placed upon this type of care being aimed at terminal
      patients, many of its principles are also applicable to initial stages of the
      disease, used in combination with the therapeutic measures required by the
      specific pathologic process. Thus, throughout this article, I outline some
      aspects concerning ethics, philosophy, and assistance which have guided this
      therapeutic modality from its start until today.

PMID- 15199845
TI  - [Thoughts about the challenge of health professional training].
AB  - This reflection searches to emphasize relevant aspects in nurse professional
      training in order to contribute to discussions emerging from legal proposals that
      challenge educational institutions to redirect and discuss conceptual references
      of their curricula, while spaces of knowledge construction and circulation that
      make possible the existence of a transversal knowledge. We can notice that
      through globalization and a transversal and interdisciplinary proposal, it is
      possible to cross multiple knowledge areas, establishing numerous connections
      that might teach professionals to regard knowledge as a way to be fit to compete
      in the labor market.

PMID- 15199846
TI  - [The experience of someone involved in the psychiatry reform in Brazil].
AB  - This report is a descriptive study based on bibliographic reviews, developed in
      the Health Policies course, a subject which is part of the Master's degree from
      the University of Rio de Janeiro (UNIRIO). Our objective is to report on our
      experiences working with psychosocial care, which has been our goal over the last
      4 years, with an approach on the strategies adopted by the Brazilian Health
      Department, directed toward restructuring mental health care in Brazil. One
      realizes the need for objective interventions in order to make this process
      effective, such as the construction of a solid and amplified network for mental
      health care, the municipalization of health services which would reduce the risk
      of a fragmentation in services provided and would promote participation of family
      members and society in caring and reinserting mentally-ill patients.

PMID- 15199847
TI  - [Participation of the Anna Nery School in the Constitutionalist Revolution of
      1932].
AB  - This is a historical-social research project. The main objective is to present
      the participation of the Anna Nery Nursing School in the medical assistance
      positions in the state of Sao Paulo during the Constitutionalist Revolution of
      1932. The objective of the present investigation is to describe how the teachers
      and students of the Anna Nery Nursing School participated in the different
      operation fronts during this war and to analyse the implications of the
      performance of nurses and students of this School. Our main documental resource
      were written and photographical documents that belong to the Centre of
      Documentation of the EEA/UFRJ. The secondary source were articles and books that
      about the history of Brazil and Brazilian nursing. This investigation evidenced
      the importance of the nurse's work during times of crisis and it also made
      possible for the EEAN to earn symbolic profits.

PMID- 15199848
TI  - TMC125: important one-year trial now recruiting in U.S.
AB  - An new NNRTI that greatly reduces HIV resistance to this major class of drugs is
      now recruiting at about 50 U.S. medical centers. It is active against virus
      resistant to efavirenz and nevirapine.

PMID- 15199849
TI  - Gonorrhea: new treatment recommendations for gay men, MSM.
AB  - On April 30, 2004 the U.S. CDC changed the gonorrhea treatment recommendation for
      men who have sex with men, due to development of resistance to the oral
      antibiotics otherwise preferred.

PMID- 15199850
TI  - How to Network Action Alerts, So That Others Can Help.
AB  - Future political action alerts will travel gracefully through existing networks
      of familiarity and trust, being re-focused as needed for each audience--so that
      supporters you may never know can help your effort be successful. Most alerts
      today do not work this way. We explain why not, and show how to make action
      alerts work better.

PMID- 15199851
TI  - Online glossaries of HIV/AIDS terms.
AB  - Here are four English glossaries, and three Spanish glossaries, that explain AIDS
      related medical terms.

PMID- 15199852
TI  - Checking your drug interactions.
AB  - Here are three HIV-related Web sites and one printed document that you can use to
      check for some of the interactions between HIV drugs and other drugs you are
      using at the same time. Some of them also have information on known interactions
      between AIDS-related drugs and some herbal treatments or foods.

PMID- 15199853
TI  - Inexpensive air filter for allergy relief.
AB  - We found a low-cost, efficient way to make homes more comfortable for many
      people, especially in hay-fever season.

PMID- 15199854
TI  - Management of AIDS-related Kaposi sarcoma: advances in target discovery and
      treatment.
AB  - Kaposi sarcoma (KS) is the most common tumor arising in HIV-infected patients and
      is considered an AIDS-defining illness by CDC guidelines. Recent advances in the
      elucidation of the pathogenesis of KS continue to uncover potential targets for
      therapies. Such targets include the KS herpesvirus/human herpesvirus 8 and the
      processes of angiogenesis and cellular differentiation. Five agents are currently
      approved by the FDA for the treatment o KS: alitretinoin gel for topical
      administration and liposomal daunorubicin, liposomal doxorubicin, paclitaxel, and
      interferon-alpha for systemic administration. Many more agents, particularly
      angiogenesis inhibitors and other pathogenesis-targeted therapies, are in
      clinical development. With increasing recognition that effective antiretroviral
      regimens are associated with both a decreased proportion of new AIDS-defining KS
      cases and a regression in the size and number of existing KS lesions, most, if
      not all, patients with KS should be advised to take antiretroviral drugs that
      will maximally decrease HIV-1 RNA levels.

PMID- 15199855
TI  - An updated guide to genotype interpretation.
AB  - Genotyping to determine antiretroviral susceptibility is recommended in many
      clinical situations. Nevertheless, the genotyping reports, detailing the presence
      or absence of specific mutations, often are difficult to interpret. This report
      gives an update about important new developments in the area of antiretroviral
      resistance and provides a guide to interpreting genotype reports.

PMID- 15199856
TI  - Legionella pneumonia and HIV infection: a case report.
AB  - Legionella pneumonia is commonly diagnosed in patients who are chronically
      immunosuppressed, but it is rarely diagnosed in patients who have HIV/AIDS. We
      report the successful diagnosis and treatment of Legionella pneumonia in a
      patient with HIV infection that was diagnosed at the same admission.

PMID- 15199857
TI  - Editorial comment: low prevalence of legionnaires disease in HIV-infected
      patients.

PMID- 15199858
TI  - TV-watching by young children linked to later attention problems.

PMID- 15199859
TI  - How much fish should children and pregnant women eat?

PMID- 15199860
TI  - Immunizations. MMR vaccine and autism--a new study...and an interesting
      development.

PMID- 15199861
TI  - Child development. Saying goodbye at the end of the school year.

PMID- 15199862
TI  - Product recalls. "Resale round-up 2004"--stopping the resale of dangerous
      products.

PMID- 15199863
TI  - FDA approves OraQuick for use in saliva. On March 25, the FDA approved the first
      rapid test for HIV in oral fluids.

PMID- 15199864
TI  - Antiretroviral rounds. First holiday was a disaster: should she take another?

PMID- 15199865
TI  - Clinton Foundation negotiates $140/Year HIV treatment, but U.S. won't buy.
AB  - The Clinton Foundation, World Bank, UNICEF, and the Global Fund to Fight AIDS,
      Tuberculosis, and Malaria announced that they could negotiate prices as low as
      $140 per year for triple-combination antiretroviral therapy. But the Bush
      Administration is refusing to buy generic medicines for its major HIV treatment
      program.

PMID- 15199866
TI  - Atherosclerosis risk increased with HIV; treatment effects unclear.
AB  - A major report on heart disease and HIV found that HIV infection itself is
      associated with increased risk, independently of other factors like age,
      cholesterol, and smoking. Another major report did find differences among
      antiretrovirals, but the information is hard to summarize.

PMID- 15199867
TI  - Atazanavir (Reyataz): new recommendations if combined with tenofovir (Viread) --
      and warning on Viagra, Cialis, and Levitra.
AB  - The FDA published new information on drug interactions that patients taking
      Reyataz should know.

PMID- 15199868
TI  - Abacavir hypersensitivity reaction predicted by genetic test.
AB  - Researchers in Australia found an accurate test to predict who cannot tolerate
      Ziagen (abacavir). This is still a research test, not in general use.

PMID- 15199869
TI  - Lessons from two "triple nuke" failures (new training module).
AB  - A CME (continuing medical education) module for physicians explains the problem
      with two antiretroviral regimens that failed last year. Several possible causes
      for the failure had been proposed. Now it appears that the problem was too low a
      genetic barrier to HIV developing certain resistance mutations.

PMID- 15199870
TI  - Medicines for the world: a way forward.
AB  - For poor and middle-income countries we should negotiate large sales involving
      many countries, with all the interests at the table. Large deals and public
      consensus could make it viable for companies to develop treatments for diseases
      affecting poor regions.

PMID- 15199871
TI  - Time for tea?

PMID- 15199872
TI  - Using metformin safely. X-ray with caution.

PMID- 15199873
TI  - Big boys don't cry. Getting over the macho mindset.

PMID- 15199874
TI  - Dangerous drug combinations.

PMID- 15199875
TI  - Pasta, please!

PMID- 15199876
TI  - Be aware of hypoglycemia unawareness.

PMID- 15199877
TI  - Monochromatic infrared energy. New hope for painful, numb feet?

PMID- 15199878
TI  - Soup's on.

PMID- 15199880
TI  - Diabetes quiz. How much do you know about food choices and heart health?

PMID- 15199879
TI  - Diabetes retreats and training centers.

PMID- 15199882
TI  - Online diabetes support groups.

PMID- 15199881
TI  - Managing hyperglycemia.

PMID- 15199883
TI  - Supermarket smarts. Fruits.

PMID- 15199884
TI  - Overweight? Watch your liver.

PMID- 15199885
TI  - New, less invasive surgery for chronic heartburn.

PMID- 15199886
TI  - Diagnosing Alzheimer's: low tech & high tech.

PMID- 15199887
TI  - When "normal" eye pressure isn't normal.

PMID- 15199889
TI  - Why did my doctor spend most of my last check-up counseling me to stop smoking
      and improve my diet instead of doing a physical exam?

PMID- 15199888
TI  - A consumer's guide to impotence drugs.

PMID- 15199891
TI  - Aloe vera helps ulcerative colitis.

PMID- 15199890
TI  - I often get discomfort, even pain, in my ears when I fly. Is there a way to
      prevent this?

PMID- 15199892
TI  - Urinary symptoms and prostate cancer treatment.

PMID- 15199893
TI  - Volunteer for health.

PMID- 15199894
TI  - Treating abnormal uterine bleeding. Hysterectomy is not always necessary.

PMID- 15199895
TI  - Food irradiation: a recipe for safer food? Irradiation can eradicate the bacteria
      that cause foodborne illness.

PMID- 15199896
TI  - FDA approves health claim for walnuts.

PMID- 15199897
TI  - Designer orange juice lowers cholesterol.

PMID- 15199898
TI  - Activity also helps keep the pounds on.

PMID- 15199899
TI  - B vitamins may preserve memory.

PMID- 15199900
TI  - Hernia surgery: "open" may be best option.

PMID- 15199901
TI  - FDA approves help for aging eyes. Conductive keratoplasty may improve vision for
      people older than 40 who need reading glasses to see "the fine print".

PMID- 15199902
TI  - Statins prevent first strokes...and they may improve the chances of recovery
      after a stroke.

PMID- 15199903
TI  - Mind over matter: treatment perceptions influence outcomes.

PMID- 15199904
TI  - Specialized talk therapy helps some hypochondriacs.

PMID- 15199905
TI  - Experimental drug can double levels of "good" cholesterol. But does torcetrapib
      cut the risk of heart disease?

PMID- 15199906
TI  - New heart failure drug shows promise.

PMID- 15199907
TI  - Study sheds light on sore-throat dilemma.

PMID- 15199908
TI  - Osteoporosis: perception versus reality.

PMID- 15199909
TI  - Blood tests done at my annual physical revealed I have mild hypothyroidism. I'm
      slightly overweight but have no other symptoms. Do I need treatment?

PMID- 15199910
TI  - Should people with Barrett's esophagus, who are at risk for cancer of the
      esophagus, avoid alcohol?

PMID- 15199911
TI  - What's health got to do with it? As Americans grow in girth, policymakers are
      looking at community design to encourage physical activity and lower obesity
      rates.

PMID- 15199912
TI  - Shoulder surgery. Techniques are advancing.

PMID- 15199913
TI  - Health tips. Avoiding food poisoning.

PMID- 15199914
TI  - Guggulipid supplements for high cholesterol questionable.

PMID- 15199915
TI  - An experimental treatment for inflammatory bowel disease.

PMID- 15199916
TI  - Off-label use of medications. A common practice.

PMID- 15199917
TI  - Anticoagulants. Oral drug options may expand.

PMID- 15199918
TI  - Denture anchors. Implants can improve stability, comfort.

PMID- 15199920
TI  - Questions and our answers. My granddaughter got a tattoo a few years ago but is
      now having second thoughts. What are her options for having it removed?

PMID- 15199919
TI  - Questions and our answers. I dread having my annual mammogram because it's so
      uncomfortable. Is there anything I can do to be more comfortable during my
      mammogram?

PMID- 15199921
TI  - Surgery. What to expect and how to prepare.

PMID- 15199922
TI  - Bibliography. Current world literature. Immunotherapy.

PMID- 15199923
TI  - Surgical treatment of the infected diabetic foot.

PMID- 15199925
TI  - Bibliography. Current world literature. Mechanisms of allergy and adult asthma.

PMID- 15199924
TI  - [Surgical treatment of a patient with carotid and renal artery stenoses].
AB  - A case report presents successful surgical treatment of a patient with multifocal
      atherosclerosis, impaired carotid arterial territory and renovascular
      hypertension resulted from subtotal renal artery stenosis. Clinical picture of
      the case is given in detail, as well as diagnostic examination results and
      surgical treatment plan, Optimal surgical strategy for such lesions is
      simultaneous surgery of carotid and renal arteries or staged correction beginning
      with carotid arteries. In the described case the staged intervention was chosen,
      but it was complicated by iliac arterial thrombosis during the attempt of renal
      artery angioplasty. From thoracophrenoperitoneal access simultaneous grafting of
      left renal artery with synthetic prosthesis and recanalization of blood flow in
      right lower limb were executed.

PMID- 15199927
TI  - Bibliography. Current world literature. Ocular manifestations of systemic
      diseases.

PMID- 15199926
TI  - [Small intestine hemangioma as rare etiology of intestinal bleeding].

PMID- 15199928
TI  - [Adrian Gillissen. January 11, 1957].

PMID- 15199929
TI  - A call to legal arms: bringing embryonic stem cell therapies to market.

PMID- 15199930
TI  - [The nutrition of seniors presents special requirements].

PMID- 15199931
TI  - Death and dying in America: the prison industrial complex's impact on women's
      health.

PMID- 15199932
TI  - [Strongyloides].

PMID- 15199933
TI  - Terror and triage: prioritizing access to mass smallpox vaccination.
AB  - In response to the threat of a smallpox attack on the United States, the Centers
      for Disease Control and Prevention ("CDC") recommended the establishment of
      smallpox clinics designed to distribute a vaccine to the entire U.S. population
      in a ten day period. However, a number of potential obstacles raise questions
      about the feasibility of this plan. What is needed is a plan that applies
      principles of triage to smallpox vaccine distribution following a bioterrorism
      attack. Only in this way can those most vulnerable--the previously unvaccinated-
      be protected from a significantly increased risk due to delays that might arise
      in executing the CDC plan.

PMID- 15199934
TI  - Presumed consent organ donation in Pennsylvania: one small step for Pennsylvania,
      one giant leap for organ donation.

PMID- 15199935
TI  - International patent protection for HIV-related therapies: patent attorney's
      perspective.

PMID- 15199936
TI  - Assisted suicide under the European Convention on Human Rights: a critique.
AB  - In a high profile case, a terminally ill woman, Diane Pretty, challenged the
      United Kingdom prohibition on assisted suicide as incompatible with certain
      fundamental rights which are guaranteed under the European Convention on Human
      Rights. Mrs Pretty's battle was ultimately unsuccessful, with a total of three
      courts and 15 judges ruling against her. Such unanimity of opinion might well be
      thought to represent the coup de grace for arguments about the right to
      assistance in death under European human rights law. However, in this article it
      is suggested that, in limited circumstances, such assistance might yet still be
      possible under the Constitution.

PMID- 15199937
TI  - The final patient privacy regulations under the Health Insurance Portability and
      Accountability Act--promoting patient privacy or public confusion?

PMID- 15199938
TI  - Informed confusion: the doctrine of informed consent in Georgia.

PMID- 15199939
TI  - Consent forms as part of the informed consent process: moving away from "medical
      Miranda".

PMID- 15199940
TI  - Embryonic stem cell research: will President Bush's limitation on federal funding
      put the United States at a disadvantage? A comparison between U.S. and
      international law.

PMID- 15199941
TI  - Autonomy, sanity and moral theory.
AB  - The concept of autonomy plays at least two roles on moral theory. First, it
      provides a source of constraints upon action: because I am autonomous you may not
      interfere with me, even for my own good. Second, it provides a foundation for
      moral theory: human autonomy has been thought by some to produce moral principles
      of a more general kind. This paper seeks to understand what autonomy is, and
      whether the autonomy of which we are capable is able to serve these roles. We
      would naturally hope for a concept of autonomy that is value-neutral rather than
      value-laden. That is to say, we would want the judgement that I am autonomous to
      depend wholly on, say, structural features of my psychology, and in no way to
      require us to make ethical judgements, or other value judgements. Being value
      neutral is perhaps desirable in a concept of autonomy serving the first role, and
      plausibly indispensible in one playing the second. I shall argue, however, that
      value-neutral conceptions of autonomy are impoverished and out of line with our
      intentions; set out and defend an explicitly value-laden conception of autonomy;
      and explore the implications of such a view for the ability of autonomy to play
      the roles mentioned above.

PMID- 15199942
TI  - Iceland: the case of a national human genome project.

PMID- 15199943
TI  - Impact of fellowship training on the learning curve for laparoscopic gastric
      bypass.
AB  - BACKGROUND: We have previously shown that the learning curve for laparoscopic
      Roux-en-Y gastric bypass (LRYGBP) is approximately 75 cases. Patients have worse
      outcomes during the learning curve. Our aim was to evaluate the impact of
      fellowship training on outcomes during a surgeon's early experience with LRYGBP.
      METHODS: The study population consisted of the first 75 consecutive LRYGBP
      operations attempted by two laparoscopic surgeons, one with laparoscopic gastric
      bypass fellowship training (Group A) and one without laparoscopic bypass
      fellowship training (Group B). OUtcome parameters included mortality, major
      perioperative complications, operative time, and conversion to an open operation.
      RESULTS: Age, BMI, and gender distribution were similar in both groups. Operative
      time was significantly longer in Group B (189 min. vs 122 min., P<0.05).
      Conversion to an open procedure occurred uncommonly in both groups (3%). Major
      complications occurred more frequently in Group B (13% vs 8%, P=NS). In addition,
      the complications in Group B were more severe, resulting in 2 deaths. No deaths
      occurred in Group A. CONCLUSION: Laparoscopic bypass fellowship training improves
      perioperative outcomes during a surgeon's early experience with LRYGBP.

PMID- 15199944
TI  - Telomerase resets the homeostatic telomere length and prevents telomere
      dysfunction in immortalized human cells.

PMID- 15199945
TI  - A comparative study of quantitative structure-activity relationship methods based
      on gallic acid derivatives.
AB  - By using hologram quantitative structure-activity relationship (HQSAR) and
      comparative molecular field analysis (CoMFA) methods, the relationships between
      the structures of 49 gallic acid derivatives and their analgesic activity have
      been investigated to yield statistically reliable models with considerable
      predictive power. The best HQSAR model was generated using atoms, bond and
      connectivity as fragment distinction parameters and fragment size 5-7 from a
      hologram length of 307 with 3 components. High conventional r2 (r2 = 0.825) and
      cross-validation r2 (r2(cv) = 0.726) values were obtained. CoMFA analyses varying
      lattice size and location, grid spacing, probe charges and using, Tripos standard
      and Indicator force field were performed. The best model was developed with 4
      components using sp3-hybridized carbon atom with +1.0 charge as probe, grid
      spacing (2 A), lattice offset (1.0, 3.0, -2.5). The CoMFA model showed a
      conventional correlation coefficient r2 of 0.889 and across-validation r2(cv)
      equals to 0.633. The robustness and predictive ability of the HQSAR and CoMFA
      models have been validated by means of an external test set. The results indicate
      that both models possess high statistical quality in the prediction of analgesic
      potency of novel gallic acid analogs.

PMID- 15199946
TI  - Typology of secondary cyanobacterial metabolites from minimum spanning tree
      analysis.
AB  - Recently, two main events have spurred a rapid increase in cyanobacteria
      chemical, toxicological, and ecological research. The first deals with the
      interest in isolating compounds from these organisms as source of active products
      with potential therapeutic applications. The second pertains the crucial problem
      of harmful cyanobacterial blooms in the aquatic environments. In this context,
      594 secondary metabolites belonging to more than 30 genera of cyanobacteria were
      retrieved from literature. In order to perform their typology, they were first
      associated with 87 different molecular archetypes and two orphan classes. These
      89 groups of molecular structures were then confronted to minimum spanning tree
      analysis. Attempts were made to graphically derive chemotaxonomical
      relationships. The interest of QSAR models for estimating the potential
      pharmacological interest of the cyanobacterial secondary metabolites was also
      discussed.

PMID- 15199947
TI  - Data evaluations and quantitative predictive models for vapor pressures of
      polycyclic aromatic hydrocarbons at different temperatures.
AB  - Polycyclic aromatic hydrocarbons (PAHs) are typical and ubiquitous organic
      pollutants. Vapor pressures, which can be classified as solid vapor pressure
      (P(S)) and (subcooled) liquid vapor pressure (P(L)), are key physicochemical
      properties governing the environmental fate of organic pollutants. It is of great
      importance to develop predictive models of vapor pressures. In the present study,
      partial least squares (PLS) regression together with 15 theoretical molecular
      structural descriptors was used to develop quantitative predictive models for
      vapor pressures of PAHs at different temperatures. Two procedures were adopted to
      develop the optimal predictive models by eliminating redundant molecular
      structural descriptors. The cross-validated Q2(cum) values for the obtained
      models have been found higher than 0.975, indicating good predictive ability and
      robustness of the models. It has been shown that the intermolecular dispersive
      interactions played a leading role in governing the values of log P(L). In
      addition to dispersive interactions, dipole-dipole interactions also played a
      secondary role in determining the magnitude of log P(S). In view of the
      scarceness of chemical standards for some PAHs, the difficulty in experimental
      determinations, and the high cost involved in experimental determinations, the
      obtained models should serve as a fast and simple first approximation of the
      vapor pressure values for PAHs at different environmental temperatures.

PMID- 15199948
TI  - Chemical-chemical interaction between cyanogenic toxicants and aldehydes: a
      mechanism-based QSAR approach to assess toxicological joint effects.
AB  - A QSAR approach was proposed to assess toxicological joint effects based on the
      mechanism of chemical-chemical interactions between cyanogenic toxicants and
      aldehydes. It has been observed that the chemical-chemical interaction between
      cyanogenic toxicants and aldehydes resulted in the formation of carbanion
      intermediates, and therefore this interaction led to different toxicological
      joint effects between cyanogenic toxicants and aldehydes. Analysis of this
      chemical-chemical interaction showed that the formation of carbanion intermediate
      highly depended on the charge of the carbon atom in the -CHO of aldehydes and
      this of the carbon atom (C*) in the carbochain of cyanogenic toxicant. By using
      the Hammett Constant (sigma(p)) to measure the charge of carbon atom in the -CHO
      of aldehydes, a mechanism-based QSAR approach (M = 0.316 - 4.386sigma(p) with r2
      = 0.933, SE = 0.082, F = 55.389, p = 0.002, M = sum of toxic units) was proposed
      to assess the toxicological joint effects between alpha-hydroxy-isobutyronitrile
      and individual aliphatic aldehydes. Another one (M = 0.978 - 0.720sigma(p) with
      r2 = 0.852, SE = 0.152, F = 40.148, p = 0.0001) was also proposed to assess the
      toxicological joint effects between alpha-hydroxy-isobutyronitrile and individual
      aromatic aldehydes. Lastly, by using the charge of carbon atom (C*) in the
      carbochain of cyanogenic toxicant, a mechanism-based QSAR model (M = -0.161 -
      7.721C* with r2 = 0.847, SE = 0.227, F = 27.657, p = 0.003) was derived to assess
      toxicological joint effects between p-nitrobenzaldehyde and cyanogenic toxicants.

PMID- 15199949
TI  - Trends in structure-toxicity relationships for carbonyl-containing alpha,beta
      unsaturated compounds.
AB  - Using toxicity data for 30 aliphatic polarized alpha,beta-unsaturated derivatives
      of esters, aldehydes, and ketones, a series of six structure-toxicity
      relationships were evaluated. The structure feature of all assessed compounds, an
      acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently
      electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the
      toxic potency of alpha,beta-unsaturated carbonyl compounds is dependent on the
      specific molecular structure with several trends being observed. Specific
      observations include: (1) between homologues, the acetylenic-substituted
      derivative was more toxic than the corresponding olefinic-substituted one,
      respectively; (2) between olefinic-homologues, terminal vinyl-substituted
      derivative was more toxic than the internal vinylene-substituted one; (3) within
      alpha,beta-unsaturated ketones, methyl substitution on the vinyl carbon atoms
      reduces toxicity with methyl-substitution on the carbon atom farthest from the
      carbonyl group exhibiting the greater inhibition; (4) between alpha,beta
      unsaturated carbonyl compounds with the carbon-carbon double bond on the end of
      the molecule (vinyl ketones) and those with carbon-oxygen double bonds on the end
      of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5)
      between homologues of alpha,beta-unsaturated esters, those with additional
      unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than
      homologues having relevant unsaturated moieties (propyl or ethyl groups); (6)
      between alpha,beta-unsaturated carbonyl compounds with different shaped alkyl
      groups (i.e. different degrees of branching), homologues with straight-chain
      hydrocarbon moieties were more toxic than those with branched groups.

PMID- 15199952
TI  - Primitive immune systems: are your ways my ways?
AB  - Although vertebrate immune systems have been commonly conceived as exquisitely
      developed to combat pervasiveness by pathogens, they are not infallible. The
      enigmatic expression of histocompatibility in vertebrates, the manifestation of
      natural chimerism, autoimmunity, malignancy, and other puzzling outcomes hint
      that immunity did not arise in evolution to fight infections and that this
      capacity is a late evolutionary appendage, owing its appearance to the
      redeployment of a system developed for other reasons. Allorecognition in the
      colonial tunicate Botryllus schlosseri serves here as a platform for a contending
      paradigm, advocating that immunity has developed as a surveillance machinery
      against and for purging of nascent selfish cells (stemmed from a kin organism or
      from transformed cells within the organism of origin). Defense against pathogens
      (always representing xenogeneic aliens) appeared later, revealing the
      multiplicity of newly developed phenomena. Allorecognition events characteristic
      of the Botryllus primitive immune system, such as fusion versus rejection, the
      morphological resorption with its expressed hierarchy, and the somatic/germ-cell
      parasitic outcomes, provide clues to the evolutionary basis of allorecognition.
      Recent work on Botryllus immunity that highlights the cost of littering
      individuality by somatic variants/allogeneic cells is discussed.

PMID- 15199951
TI  - Invertebrate immune systems--not homogeneous, not simple, not well understood.
AB  - The approximate 30 extant invertebrate phyla have diversified along separate
      evolutionary trajectories for hundreds of millions of years. Although recent work
      understandably has emphasized the commonalities of innate defenses, there is also
      ample evidence, as from completed genome studies, to suggest that even members of
      the same invertebrate order have taken significantly different approaches to
      internal defense. These data suggest that novel immune capabilities will be found
      among the different phyla. Many invertebrates have intimate associations with
      symbionts that may play more of a role in internal defense than generally
      appreciated. Some invertebrates that are either long lived or have colonial body
      plans may diversify components of their defense systems via somatic mutation.
      Somatic diversification following pathogen exposure, as seen in plants, has been
      investigated little in invertebrates. Recent molecular studies of sponges,
      cnidarians, shrimp, mollusks, sea urchins, tunicates, and lancelets have found
      surprisingly diversified immune molecules, and a model is presented that supports
      the adaptive value of diversified non-self recognition molecules in
      invertebrates. Interactions between invertebrates and viruses also remain poorly
      understood. As we are in the midst of alarming losses of coral reefs, increased
      pathogen challenge to invertebrate aquaculture, and rampant invertebrate
      transmitted parasites of humans and domestic animals, we need a better
      understanding of invertebrate immunology.

PMID- 15199953
TI  - Evolution of the innate immune system: the worm perspective.
AB  - Simple model organisms that are amenable to comprehensive experimental analysis
      can be used to elucidate the molecular genetic architecture of complex traits.
      They can thereby enhance our understanding of these traits in other organisms,
      including humans. Here, we describe the use of the nematode Caenorhabditis
      elegans as a tractable model system to study innate immunity. We detail our
      current understanding of the worm's immune system, which seems to be
      characterized by four main signaling cascades: a p38 mitogen-activated protein
      kinase, a transforming growth factor-beta-like, a programed cell death, and an
      insulin-like receptor pathway. Many details, especially regarding pathogen
      recognition and immune effectors, are only poorly characterized and clearly
      warrant further investigation. We additionally speculate on the evolution of the
      C. elegans immune system, taking into special consideration the relationship
      between immunity, stress responses and digestion, the diversification of the
      different parts of the immune system in response to multiple and/or coevolving
      pathogens, and the trade-off between immunity and host life history traits. Using
      C. elegans to address these different facets of host-pathogen interactions
      provides a fresh perspective on our understanding of the structure and complexity
      of innate immune systems in animals and plants.

PMID- 15199954
TI  - The immune response of Drosophila melanogaster.
AB  - The response of the fruit fly Drosophila melanogaster to various microorganism
      infections relies on a multilayered defense. The epithelia constitute a first and
      efficient barrier. Innate immunity is activated when microorganisms succeed in
      entering the body cavity of the fly. Invading microorganisms are killed by the
      combined action of cellular and humoral processes. They are phagocytosed by
      specialized blood cells, surrounded by toxic melanin, or lysed by antibacterial
      peptides secreted into the hemolymph by fat body cells. During the last few
      years, research has focused on the mechanisms of microbial recognition by various
      pattern recognition receptors and of the subsequent induction of antimicrobial
      peptide expression. The cellular arm of the Drosophila innate immune system,
      which was somehow neglected, now constitutes the new frontier.

PMID- 15199955
TI  - The roles of JAK/STAT signaling in Drosophila immune responses.
AB  - Innate immune responses are mediated by the activation of various signaling
      processes. Here, we describe our current knowledge on Janus kinase (JAK)/signal
      transducers and activators of transcription (STAT) signaling in the Drosophila
      immune response. First, we briefly introduce the main effectors involved in the
      humoral and cellular responses, such as anti-bacterial peptides and hemocytes.
      Second, we describe the canonical JAK/STAT-signaling pathway, as established from
      extensive studies in mammalian systems, and we introduce the Drosophila
      components of the JAK/STAT pathway, as discovered from studies on embryonic
      development. Third, we describe the various roles of JAK/STAT signaling in both
      humoral and cellular responses. We present the JAK/STAT-dependent humoral
      factors, such as the thioester-containing proteins and the Tot peptides, produced
      by the fat body in response to septic injury. We also discuss the possible
      involvement of the JAK/STAT pathway in cellular responses, including hemocyte
      proliferation and differentiation. Finally, we present how cytokines, such as
      Upd3, might contribute to the integration of the immune responses at the organism
      level by orchestrating the response of various immune cells and organs, such as
      fat body, hemocytes, and lymph glands.

PMID- 15199956
TI  - Peptidoglycan recognition proteins: on and off switches for innate immunity.
AB  - Insects rely on innate immune mechanisms to defend themselves against microbes.
      The inducible anti-microbial peptides constitute an important arm of this
      defense. In Drosophila, the Toll and the Imd pathways are the major routes to
      induce the peptides, and it has become clear that to a certain extent, these
      pathways can discriminate between different microbes and mount an appropriate
      response to eliminate the intruder. This review discusses the proteins
      responsible for this discriminatory recognition, the peptidoglycan recognition
      proteins (PGRPs). The serum protein PGRP-SA triggers a humoral cascade of
      proteases upon infection by certain gram-positive bacteria to activate the Toll
      pathway. The membrane-bound receptor PGRP-LC activates the Imd pathway in
      response to certain gram-negative bacteria or their peptidoglycans. Other PGRPs
      have enzymatic activity, cleaving lactylamide bonds in peptidoglycan to eliminate
      its immunogenicity, thus turning off the immune response. The PGRP family is
      conserved from insects to man. Short mammalian PGRP variants are synthesized in
      neutrophils and stored in granules. These PGRPs seem to influence the survival of
      phagocytosed non-pathogenic bacteria. Long PGRP variants are expressed in the
      liver and secreted into the bloodstream where their peptidoglycan-degrading
      activity might serve scavenger functions.

PMID- 15199957
TI  - Innate immune responses of a lepidopteran insect, Manduca sexta.
AB  - Many innate immune mechanisms are conserved throughout the animal kingdom.
      Manduca sexta, a widely used model for insect biochemical research, employs these
      mechanisms to defend against invading pathogens and parasites. We have isolated
      from M. sexta hemolymph a group of proteins (hemolin, peptidoglycan recognition
      proteins, beta-1,3-glucan recognition proteins, and C-type lectins), which serve
      as a surveillance mechanism by binding to microbial surface molecules (e.g.
      peptidoglycan, lipopolysaccharide, lipoteichoic acid, and beta-1,3-glucan). The
      binding triggers diverse responses such as phagocytosis, nodule formation,
      encapsulation, melanization, and synthesis of anti-microbial peptides/proteins.
      Some of these responses are mediated and coordinated by serine proteinase
      cascades, analogous to the complement system in mammals. Our current research is
      focused on the proteolytic activation of prophenoloxidase (proPO)--a reaction
      implicated in melanotic encapsulation, wound healing, and protein cross-linking.
      We have isolated three proPO-activating proteinases, each of which requires
      serine proteinase homologs as a cofactor for generating active phenoloxidase. The
      proteinases and proteinase-like molecules, containing one to two clip domains at
      their amino-terminus, are acute-phase proteins induced upon an immune challenge.
      Inhibitory regulation of the proteinases by serpins and association of the
      proteinase homologs with a bacteria-binding lectin are important for ensuring a
      localized defense response. Additional serine proteinases expressed in M. sexta
      hemocytes and fat body have been discovered. Future research efforts will be
      aimed at elucidating the proteinase cascade for proPO activation and
      investigating the roles of proteinases in other immune responses such as
      processing of plasmatocyte-spreading peptide.

PMID- 15199958
TI  - A Toll-like receptor in horseshoe crabs.
AB  - Non-self-recognition of invading microbes relies on the pattern-recognition of
      pathogen-associated molecular patterns (PAMPs) derived from microbial cell-wall
      components. Insects and mammals conserve a signaling pathway of the innate immune
      system through cell-surface receptors called Tolls and Toll-like receptors
      (TLRs). Bacterial lipopolysaccharides (LPSs) are an important trigger of the
      horseshoe crab's innate immunity to infectious microorganisms. Horseshoe crabs'
      granular hemocytes respond specifically to LPS stimulation, inducing the
      secretion of various defense molecules from the granular hemocytes. Here, we show
      a cDNA which we named tToll, coding for a TLR identified from hemocytes of the
      horseshoe crab Tachypleus tridentatus. tToll is most closely related to
      Drosophila Toll in both domain architecture and overall length. Human TLRs have
      been suggested to contain numerous PAMP-binding insertions located in the leucine
      rich repeats (LRRs) of their ectodomains. However, the LRRs of tToll contained no
      obvious PAMP-binding insertions. Furthermore, tToll was non-specifically
      expressed in horseshoe crab tissues. These observations suggest that tToll does
      not function as an LPS receptor on granular hemocytes.

PMID- 15199959
TI  - The prophenoloxidase-activating system in invertebrates.
AB  - A major innate defense system in invertebrates is the melanization of pathogens
      and damaged tissues. This important process is controlled by the enzyme
      phenoloxidase (PO) that in turn is regulated in a highly elaborate manner for
      avoiding unnecessary production of highly toxic and reactive compounds. Recent
      progress, especially in arthropods, in the elucidation of mechanisms controlling
      the activation of zymogenic proPO into active PO by a cascade of serine
      proteinases and other factors is reviewed. The proPO-activating system (proPO
      system) is triggered by the presence of minute amounts of compounds of microbial
      origins, such as beta-1,3-glucans, lipopolysaccharides, and peptidoglycans, which
      ensures that the system will become active in the presence of potential
      pathogens. The presence of specific proteinase inhibitors prevents superfluous
      activation. Concomitant with proPO activation, many other immune reactions will
      be produced, such as the generation of factors with anti-microbial, cytotoxic,
      opsonic, or encapsulation-promoting activities.

PMID- 15199960
TI  - Comparative and functional genomics of the innate immune system in the malaria
      vector Anopheles gambiae.
AB  - In much of Africa, the mosquito Anopheles gambiae is the major vector of human
      malaria, a devastating infectious disease caused by Plasmodium parasites. Vector
      and parasite interact at multiple stages and locations, and the nature and
      effectiveness of this reciprocal interaction determines the success of
      transmission. Many of the interactions engage the mosquito's innate immunity, a
      primitive but very effective defense system. In some cases, the mosquito kills
      the parasite, thus blocking the transmission cycle. However, not all interactions
      are antagonistic; some represent immune evasion. The sequence of the A. gambiae
      genome revealed numerous potential components of the innate immune system, and it
      established that they evolve rapidly, as summarized in the present review. Their
      rapid evolution by gene family expansion diversification as well as the
      prevalence of haplotype alleles in the best-studied families may reflect
      selective adaptation of the immune system to the exigencies of multiple immune
      challenges in a variety of ecologic niches. As a follow-up to the comparative
      genomic analysis, the development of functional genomic methodologies has
      provided novel opportunities for understanding the immune system and the nature
      of its interactions with the parasite. In this context, identification of both
      Plasmodium antagonists and protectors in the mosquito represents a significant
      conceptual advance. In addition to providing fundamental understanding of
      primitive immune systems, studies of mosquito interactions with the parasite open
      unprecedented opportunities for novel interventions against malaria transmission.
      The generation of transgenic mosquitoes that resist malaria infection in the wild
      and the development of antimalarial 'smart sprays' capable of disrupting
      interactions that are protective of the parasite, or reinforcing others that are
      antagonistic, represent technical challenges but also immense opportunities for
      improvement of global health.

PMID- 15199961
TI  - Insights into the anti-microbial defense of marine invertebrates: the penaeid
      shrimps and the oyster Crassostrea gigas.
AB  - Research on innate immunity of the penaeid shrimps and the oyster Crassostrea
      gigas is motivated greatly by economical necessities. Indeed, the aquaculture of
      these organisms is now limited by the development of infectious diseases.
      Studying anti-microbial peptides/proteins (AMPs), which are effector molecules of
      the host defense, is particularly attractive not only for progressing basic
      knowledge on immunity but also because they offer various possible applications
      for disease management in aquaculture. AMPs are explored with a global
      approach,considering their structure, properties, function, gene expression, and
      tissue distribution during the response to infections. In shrimp, investigations
      of the penaeidins, which are constitutively expressed peptides, have highlighted
      the importance of hemocytes and hematopoiesis as major elements of the immune
      response, providing both local and systemic reactions. The activation of
      hematopoiesis must be regarded as a regulatory way for the expression and
      distribution of constitutively expressed immune effectors. As complementary
      approaches, genomics and gene profiling are promising to deepen our understanding
      of the anti-microbial defense of the oyster and the shrimp. However, real
      progress will depend also on the characterization of hemocyte lineages and
      hematopoiesis of these marine invertebrates as well as on the ontogenesis of
      their immune systems.

PMID- 15199962
TI  - Anti-microbial peptides: from invertebrates to vertebrates.
AB  - Gene-encoded anti-microbial peptides (AMPs) are widespread in nature, as they are
      synthesized by microorganisms as well as by multicellular organisms from both the
      vegetal and the animal kingdoms. These naturally occurring AMPs form a first line
      of host defense against pathogens and are involved in innate immunity. Depending
      on their tissue distribution, AMPs ensure either a systemic or a local protection
      of the organism against environmental pathogens. They are classified into three
      major groups: (i) peptides with an alpha-helical conformation (insect cecropins,
      magainins, etc.), (ii) cyclic and open-ended cyclic peptides with pairs of
      cysteine residues (defensins, protegrin, etc.), and (iii) peptides with an over
      representation of some amino acids (proline rich, histidine rich, etc.). Most
      AMPs display hydrophobic and cationic properties, have a molecular mass below 25
      30 kDa, and adopt an amphipathic structure (alpha-helix, beta-hairpin-like beta
      sheet, beta-sheet, or alpha-helix/beta-sheet mixed structures) that is believed
      to be essential to their anti-microbial action. Interestingly, in recent years, a
      series of novel AMPs have been discovered as processed forms of large proteins.
      Despite the extreme diversity in their primary and secondary structures, all
      natural AMPs have the in vitro particularity to affect a large number of
      microorganisms (bacteria, fungi, yeast, virus, etc.) with identical or
      complementary activity spectra. This review focuses on AMPs forming alpha
      helices, beta-hairpin-like beta-sheets, beta-sheets, or alpha-helix/beta-sheet
      mixed structures from invertebrate and vertebrate origins. These molecules show
      some promise for therapeutic use.

PMID- 15199963
TI  - The lectin-complement pathway--its role in innate immunity and evolution.
AB  - Innate immunity was formerly thought to be a non-specific immune response
      characterized by phagocytosis. However, innate immunity has considerable
      specificity and is capable of discriminating between pathogens and self.
      Recognition of pathogens is mediated by a set of pattern recognition receptors,
      which recognize conserved pathogen-associated molecular patterns (PAMPs) shared
      by broad classes of microorganisms, thereby successfully defending invertebrates
      and vertebrates against infection. Lectins, carbohydrate-binding proteins, play
      an important role in innate immunity by recognizing a wide range of pathogens.
      Mannose-binding lectin (MBL) and ficolin are lectins composed of a lectin domain
      attached to collagenous region. However, they use a different lectin domain: a
      carbohydrate recognition domain (CRD) is responsible for MBL and a fibrinogen
      like domain for ficolin. These two collagenous lectins are pattern recognition
      receptors, and upon recognition of the infectious agent, they trigger the
      activation of the lectin-complement pathway through attached serine proteases,
      MBL-associated serine proteases (MASPs). A similar lectin-based complement
      system, consisting of the lectin-protease complex and C3, is present in
      ascidians, our closest invertebrate relatives, and functions in an opsonic
      manner. We isolated several lectins homologous to MBLs and ficolins and several
      MASPs in invertebrates and lower vertebrates, and herein we discuss the molecular
      evolution of these molecules. Based on these findings, it seems likely that the
      complement system played a pivotal role in innate immunity before the evolution
      of an acquired immune system in jawed vertebrates.

PMID- 15199964
TI  - Primitive complement system of invertebrates.
AB  - Most components of the human complement system have unmistakable domain
      architectures, making evolutionary tracing feasible. In contrast to the major
      genes of the adaptive immune system, which are present only in jawed vertebrates,
      complement component genes with unique domain structures are present not only in
      jawed vertebrates but also in jawless fish and non-vertebrate deuterostomes.
      Recent progress in genome analysis in several eukaryotes, occupying the
      phylogenetically critical positions, showed that most individual domains found in
      the complement components are metazoa specific, being found both in deuterostomes
      and in protostomes but not in yeast or plant. However, unique domain architecture
      of complement components is not present in protostomes, suggesting that the
      complement system has been established in the deuterostome lineage not by
      invention of new domains but by innovation of unique combination of the pre
      existing domains. The recently assembled Ciona intestinalis draft genome
      contained the most modular complement genes, except for factor I. However, some
      possible C. intestinalis complement components show critical structural
      divergence from the mammalian counterparts, casting doubt on their mutual
      interaction. Thus, another integrative step seems to have been required to
      establish the modern complement system of higher vertebrates.

PMID- 15199965
TI  - The major histocompatibility complex origin.
AB  - The present review focuses on the history of genes involved in the major
      histocompatibility complex (MHC), with a special emphasis on class I function in
      peptide presentation. The MHC class II story is covered in less detail, as it
      does not have a major impact on the general understanding of the MHC evolution.
      We first redefine the MHC as the definition evolved over time. We then use
      phylogenetic analysis to investigate the history of genes involved in the MHC
      class I process. As not all the genes involved in this process have been
      phylogenetically analyzed and because new sequences have been recently released
      in biological databases, we have re-investigated this matter. In the light of the
      phylogenetic analysis, the functions of the orthologs of the genes involved in
      MHC processes are examined in species not having an MHC system. We then
      demonstrate that the emergence of this new function is due to various levels of
      co-option.

PMID- 15199966
TI  - Immunoglobulin superfamily receptors in protochordates: before RAG time.
AB  - Urochordates and cephalochordates do not have an adaptive immune system involving
      the somatic rearrangement of their antigen receptor genes. They do not have
      antigen-presenting molecules of the major histocompatibility complex (MHC)-linked
      class I and II types. In the absence of such a system, the status of their genes
      reflects perhaps a primitive pre-recombination-activating gene (RAG) stage that
      could suggest the pathway leading to the genesis of the T-cell receptor (TCR) and
      antibodies. In the genome of Ciona intestinalis, genes that encode molecules with
      membrane receptor features have been found among many members of the
      immunoglobulin superfamily (Igsf). They use the domains typical of vertebrate
      antigen receptors and class I and II: the V, and C1-like domains. These genes
      belong to two families with recognizable homologs in vertebrates: the junctional
      adhesion molecule (JAM)/cortical thymocyte marker of Xenopus (CTX) family and the
      nectin family. The human homologs of these genes segregate in a single unit of
      four paralogous segments on chromosomes 1q, 3q, 11p, and 21q. These regions
      contain nowadays several genes involved in the adaptive immune system, and some
      related members are present in the MHC paralogs as well. They also contain
      receptor-like genes without homologs in Ciona but with related members in the
      protostome Drosophila. It looks as if in Ciona one detects what looks like the
      'fossil' of one group of genes bound to duplicate and give rise to many crucial
      elements of the adaptive immune system. The modern homologs of these JAM, CTX,
      and nectins are all or almost all virus receptors, and the hypothesis is
      formulated that this property was taken advantage of during evolution to
      participate in the elaboration of either or both the somatically generated
      antigen-recognizing receptors and the antigen-presenting molecules.

PMID- 15199967
TI  - Innate immunity in plants and animals: striking similarities and obvious
      differences.
AB  - Innate immunity constitutes the first line of defense against attempted microbial
      invasion, and it is a well-described phenomenon in vertebrates and insects.
      Recent pioneering work has revealed striking similarities between the molecular
      organization of animal and plant systems for nonself recognition and anti
      microbial defense. Like animals, plants have acquired the ability to recognize
      invariant pathogen-associated molecular patterns (PAMPs) that are characteristic
      of microbial organisms but which are not found in potential host plants. Such
      structures, also termed general elicitors of plant defense, are often
      indispensable for the microbial lifestyle and, upon receptor-mediated perception,
      inevitably betray the invader to the plant's surveillance system. Remarkable
      similarities have been uncovered in the molecular mode of PAMP perception in
      animals and plants, including the discovery of plant receptors resembling
      mammalian Toll-like receptors or cytoplasmic nucleotide-binding oligomerization
      domain leucine-rich repeat proteins. Moreover, molecular building blocks of PAMP
      induced signaling cascades leading to the transcriptional activation of immune
      response genes are shared among the two kingdoms. In particular, nitric oxide as
      well as mitogen-activated protein kinase cascades have been implicated in
      triggering innate immune responses, part of which is the production of
      antimicrobial compounds. In addition to PAMP-mediated pathogen defense, disease
      resistance programs are often initiated upon plant-cultivar-specific recognition
      of microbial race-specific virulence factors, a recognition specificity that is
      not known from animals.

PMID- 15199968
TI  - Metabolic reprogramming in plant innate immunity: the contributions of
      phenylpropanoid and oxylipin pathways.
AB  - In their environment, plants interact with a multitude of living organisms and
      have to cope with a large variety of aggressions of biotic or abiotic origin. To
      survive, plants have acquired, during evolution, complex mechanisms to detect
      their aggressors and defend themselves. Receptors and signaling pathways that are
      involved in such interactions with the environment are just beginning to be
      uncovered. What has been known for several decades is the extraordinary variety
      of chemical compounds the plants are capable to synthesize, and many of these
      products are implicated in defense responses. The number of natural products
      occurring in plants may be estimated in the range of hundreds of thousands, but
      only a fraction have been fully characterized. Despite the great importance of
      these metabolites for plant and also for human health, our knowledge about their
      biosynthetic pathways and functions is still fragmentary. Recent progress has
      been made particularly for phenylpropanoid and oxylipin metabolism, which are
      emphasized in this review. Both pathways are involved in plant resistance at
      several levels: by providing building units of physical barriers against pathogen
      invasion, by synthesizing an array of antibiotic compounds, and by producing
      signals implicated in the mounting of plant resistance.

PMID- 15199969
TI  - RNA silencing: no mercy for viruses?
AB  - 'RNA silencing' is a highly conserved mechanism leading to suppression of gene
      expression through nucleotide sequence-specific interactions that are mediated by
      21-24 nucleotide-long RNAs. This process was first discovered as an unexpected
      consequence of transgenesis in plants, and similarly, it was subsequently
      identified in animals as an anomaly of antisense gene inhibition. We summarize
      the progressive steps that paved the way to our current understanding of the
      molecular basis and fundamental biological roles of RNA silencing in both plants
      and animals. In particular, we describe the general antiviral function of this
      mechanism in higher plants where it forms the basis of a highly elaborate immune
      system. All defense systems show some level of fallibility, and RNA silencing is
      no exception to this rule, as plant viruses have developed sophisticated ways to
      counteract various steps of the process. Recent work indicates that viruses are
      also engaged into a similar arms race in insects, but it remains unclear if RNA
      silencing plays a defensive role against virus infection of higher vertebrates.
      We also discuss some biotechnological applications of RNA silencing in mammalian
      cells that have fueled optimism that this mechanism may hold a promising future
      in antiviral human therapy.

PMID- 15199971
TI  - Practice of and attitudes toward breast self-examination (BSE): a cross-cultural
      comparison between younger women in Scotland and Greece.
AB  - Breast self-examination (BSE) is a method of early detection of breast cancer.
      Although BSE is recommended for all women, it is mostly suitable and readily
      available for younger women. BSE beliefs and practices of women in Scotland, a
      country with organised health campaigns about BSE, were compared with those of
      women in Greece, a country without such campaigns. Our sample consisted of 68
      university students in Scotland and Greece, aged 18 to 26 years old. All
      participants completed a questionnaire assessing demographics, health history,
      knowledge, BSE practice, health beliefs, and health-related personality. BSE
      practice was found to be associated with different variables across the two
      cultural groups. Adherence rates were found particularly higher than previous
      reports and BSE practice did not differ significantly between women in Scotland
      and Greece. Nevertheless, the two groups differed significantly in their
      knowledge, attitudes toward BSE, and health-related personality. On the basis of
      these findings, cultural factors should be considered in organising BSE
      campaigns. Also the present findings identified BSE-related beliefs and practices
      specific to younger age groups. These could be considered and addressed in order
      to organise BSE campaigns in Greece and improve future UK programs especially
      tailored for this age group.

PMID- 15199970
TI  - Ethnicity and problem behaviors among adolescent females in the United States.
AB  - Depression, alcohol use, and suicidal behaviors are common problems among
      adolescents in the United States. Little is known about how these problem
      behaviors differ among adolescent, multiethnic females. In this descriptive,
      cross-sectional study, regression analyses were performed to determine
      differences in these adolescent problem behaviors among multiethnic females using
      Latinas as the referent group. The random sample (N = 3,310, aged 12-19 years)
      included Latinas, and African-, Asian-, Native-, and Euro-American females.
      Measures included the CES-D, number of drinks each time alcohol was consumed in
      the past year, and a composite measure of suicidal behaviors. Latinas reported
      significantly higher risk for adolescent depression than did Euro-American peers
      and higher risk for alcohol use than did African- and Asian-American peers only.
      There were no significant differences in risk for suicidal behaviors between
      Latinas and their peers representing any of the other four ethnic groups. As
      adolescents of Latin, African, Asian, Native or aboriginal, and European
      ethnicity live all over the world, the findings inform future studies on
      adolescent depression, alcohol use, and suicidal behaviors among adolescents
      representing any of these ethnic groups in any part of the globe.

PMID- 15199972
TI  - Norwegian families: transition to parenthood.
AB  - Our purpose in conducting this study was to explore relationships among family
      dynamics, parent-fetal attachment, and infant temperament in 230 mother-father
      pairs from the third trimester of pregnancy to when their infant was 7 to 9
      months old. Mothers reported increased role conflict during this time, as well as
      more role conflict than their partners. First-time parents (n = 133) perceived
      more positive family dynamics than second-time parents (n = 97), as well as
      greater parent-fetal attachment. Maternal-fetal attachment was greater than
      paternal-fetal attachment. Health care providers can provide support for new
      parents as they negotiate new role relationships.

PMID- 15199973
TI  - From hysterectomy to historicity.
AB  - In this paper we describe recovery after hysterectomy. Study participants
      identified four common elements of recovery--physical symptoms, emotional well
      being, activity levels, and decision-making--within the four phases of recovery
      after hysterectomy: measuring health, comparing past to present, renewal, and
      growth through healing. Each element changed within each phase over time to
      provide a description of recovery after hysterectomy. A central unifying theme
      was identified as "from hysterectomy to historicity" or the movement from the
      immediacy of surgery to hysterectomy becoming an event of personal historical
      significance that no longer has a present influence on one's life.

PMID- 15199974
TI  - Identifying risk factors for low back pain (LBP) in Chinese middle-aged women: a
      case-control study.
AB  - This case-control study was to identify major risk factors, such as natural
      menopausal transition, physical strain to the lower back, and psychosocial and
      lifestyle stress, for low back pain (LBP) prevalence among noninstitutional
      Chinese middle-aged women. A total of 182 cases and 235 controls participated.
      Data were collected at face-to-face interviews and body measurements were
      obtained. The data included exclusive criteria: descriptions of their LBP,
      sociodemographic factors, menopausal status and reproductive factors, physical
      strain activities, psychosocial stress, lifestyle factors, and anthropometric
      parameters. Our results indicated that LBP was prevalent among (a) women who
      experienced stressful life events in the past 12 months; (b) women who had high
      psychological stress related to housework or work; (c) women who performed some
      physical strain activities, such as prolonged squatting or moderate physical
      activities in the previous year; and (d) women who had a low waist-to-hip ratio.
      Our results reveal that showing women how to reduce physical strain during
      activity and how to maintain good postures may have great potential in reducing
      or eliminating LBP. Our findings have important implications for the development
      of health education or health promotion such as how to take care of their backs
      and how to handle psychosocial stress in both the home and workplace.

PMID- 15199975
TI  - Fighting back--struggling to continue life and preserve the self following a
      stroke.
AB  - The aim of this longitudinal phenomenological study was to explore how female
      stroke survivors experienced their life following a stroke and how they managed
      their altered situation. Twenty-five women suffering first-time stroke were
      interviewed in depth three times during the first one and a half years after the
      stroke. Applying the method of Giorgi, we found that there was a lengthy struggle
      to continue life and preserve the self following the stroke. The struggle was
      closely related to their deeply rooted identity as mothers, wives, grandmothers,
      and housewives. The situation of women following a stroke needs particular
      attention because their needs may conflict with their female caring roles. On the
      other hand, supporting them in transforming these roles may secure their sense of
      self and a continued meaningful life.

PMID- 15199976
TI  - Development of oligonucleotide primers for the detection of harmful Microcystis
      in water.

PMID- 15199977
TI  - Estimating heavy metal accumulation in oligochaete earthworms: a meta-analysis of
      field data.

PMID- 15199978
TI  - Bioassessment of ecological risk of Amazonian ichthyofauna to mercury.

PMID- 15199979
TI  - Toxicity assessment of Indian marine cyanobacterial strains.

PMID- 15199980
TI  - Carboxanilide persistence in wildlife: excretion and retention in a rat model.

PMID- 15199981
TI  - Novel temperature control apparatus for whole effluent toxicity tests.

PMID- 15199982
TI  - Toxicity identification evaluations (TIEs) of freshwater samples using a metal
      chelating resin.

PMID- 15199983
TI  - Effects of sublethal copper exposure on behavior and growth of Rana pipiens
      tadpoles.

PMID- 15199984
TI  - Kinetic studies on the combined effects of lanthanum and cerium on the growth of
      Microcystis aeruginosa and their accumulation by M. aeruginosa.

PMID- 15199985
TI  - Effect of cadmium on the population dynamics of Moina macrocopa and Macrothrix
      triserialis (Cladocera).

PMID- 15199986
TI  - Effect of cadmium on hematological indices of common carp (Cyprinus carpio L.).

PMID- 15199987
TI  - Effect of cadmium on blood plasma biochemistry in carp (Cyprinus carpio L.).

PMID- 15199988
TI  - Mineral composition and cadmium accumulation in Oreochromis mossambicus exposed
      to waterborne cadmium.

PMID- 15199989
TI  - Effects of lead as an environmental pollutant on EROD enzyme in Gammarus pulex
      (L.) (Crustacea: Amphipoda).

PMID- 15199990
TI  - Growth and zinc accumulation of Sedum alfredii Hance--a Zn hyperaccumulator as
      affected by phosphorus application.

PMID- 15199991
TI  - Sensitivity of Cichlasoma facetum (Cichlidae, Pisces) to metals.

PMID- 15199993
TI  - Survival and growth of Hyalella azteca exposed to three Mississippi oxbow lake
      sediments.

PMID- 15199992
TI  - Bioaccumulation of cadmium and zinc, and field validation of a histological
      biomarker in terrestrial isopods.

PMID- 15199994
TI  - PCBs in fish of the Ardeche River: potential implications for the survival of the
      otter (Lutra lutra).

PMID- 15199995
TI  - Kinetic studies on the effects of organophosphorus pesticides on the growth of
      Microcystis aeruginosa and uptake of the phosphorus forms.

PMID- 15199997
TI  - Tracking toxic metals in the ambient air of Agra City, India.

PMID- 15199996
TI  - Paraoxonase activity in sera of four neotropical fish.

PMID- 15199998
TI  - Residual effects of sewage sludge applied to a clay soil on soil nitrate
      distribution with three different field management practices.

PMID- 15199999
TI  - Anaerobic degradation of the organochlorine pesticides DDT and heptachlor in
      river sediment of Taiwan.

PMID- 15200000
TI  - Polycyclic aromatic hydrocarbons in street dust of Niteroi City, RJ, Brazil.

PMID- 15200001
TI  - Leaching potential of pesticides in a vegetable farm in the Cameron Highlands,
      Malaysia.

PMID- 15200002
TI  - Heavy metals in black tea samples produced in Turkey.

PMID- 15200004
TI  - Antimony concentration in farming soil of southern Poland.

PMID- 15200003
TI  - Emission of biogenic sulfur gases from the microbial decomposition of cystine in
      Chinese rice paddy soils.

PMID- 15200005
TI  - Toxicity of linear alkylbenzene sulfonate and alkylethoxylate to aquatic plants.

PMID- 15200006
TI  - Liposomes containing distamycins: preparation, characterization and
      antiproliferative activity.
AB  - This article describes the production and characterization of two liposome
      formulations containing antitumor drugs, namely distamycin A (Dist) and a new
      alkyl derivative of distamycin A (C16-Dist). Egg-PC/cholesterol liposomes (4:1
      mol/mol) were prepared by reverse phase evaporation technique followed by
      extrusion through polycarbonate filters. The encapsulation efficiency was found
      to be almost complete for C16-Dist (99.8%), while native distamycin A showed a
      lower yield (19.0%). The in vitro antiproliferative activity of the distamycins
      containing liposomes determined on human leukaemic K562 cells, was 11-fold and 8
      fold higher for native and alkyl derivative distamycin A, respectively, compared
      with that of the corresponding free drugs. Liposomal formulations show an
      increase in the activity and specificity of distamycins in experimental antitumor
      therapy.

PMID- 15200007
TI  - Development of mucoadhesive dosage forms of buprenorphine for sublingual drug
      delivery.
AB  - The development of mucoadhesive formulations of buprenorphine for intended
      sublingual usage in the treatment of drug addiction is described. The
      formulations include mucoadhesive polymer films, with or without plasticizers,
      and mucoadhesive polymer tablets, with or without excipients that enhance drug
      release and/or improve tablet compaction properties. The mucoadhesive polymers
      studied include carbomers such as Carbopol 934P, Carbopol 974P, and the
      polycarbophil Noveon AA-1, with excipients chosen from pregelatinized starch,
      lactose, glycerol, propylene glycol, and various molecular weights of
      polyethylene glycol. The development of plasticizer-containing mucoadhesive
      polymer films was feasible; however, these films failed to release their entire
      drug content within a reasonable period. Thus, they were not determined suitable
      for sublingual usage because of possible loss by ingestion during routine meal
      intakes. The mucoadhesive strength of tablet formulations containing Noveon AA-1
      appears to be slightly superior to the Carbopol-containing tablets. However, the
      Carbopol 974P formulations exhibited superior drug dissolution profiles while
      providing adequate mucoadhesive strength. The tablet formulations containing
      Carbopol 974P as mucoadhesive polymer, lactose as drug release enhancer, and PEG
      3350 as compaction enhancer exhibited the best results. Overall, the mucoadhesive
      tablet formulations exhibited superior results compared with the mucoadhesive
      film formulations.

PMID- 15200008
TI  - Lipid nano/submicron emulsions as vehicles for topical flurbiprofen delivery.
AB  - The application of lipid nano/submicron emulsions as topical drug carrier systems
      for the percutaneous absorption of flurbiprofen was investigated. The lipid
      emulsions were made up of isopropyl myristate (IPM), soybean oil, or coconut oil
      as the oil phase, egg lecithin as the predominant emulsifier, and double
      distilled water as the external phase. Stearylamine (SA) and deoxycholic acid
      (DA) also were used to produce positively and negatively charged emulsions. To
      evaluate the physicochemical properties of the lipid emulsions, particle size by
      laser light scattering, the image of atomic force microscopy, and relaxation time
      values by Nuclear Magnetic Resonance (NMR) were determined. The in vitro
      permeation data showed that incorporation of SA significantly reduced the topical
      delivery of flurbiprofen. On the other hand, incorporation of DA exhibited no or
      a negligible effect on drug permeation. Enhancement of drug absorption was
      observed when adding oleic acid as part of the oil phase. The in vivo topical
      application of flurbiprofen from selected lipid emulsions showed a similar trend
      to the in vitro status. Furthermore, the intersubject variability was
      considerably reduced by lipid emulsions than by aqueous suspensions in both the
      in vitro and in vivo experiments. The irritant profiles of lipid emulsions showed
      that IPM elicited higher irritation than soybean oil. The incorporation of oleic
      acid also produced skin disruption. The results in the present study suggest the
      feasibility of lipid emulsions for the topical delivery of flurbiprofen.

PMID- 15200009
TI  - Chitosan nanoparticles for plasmid DNA delivery: effect of chitosan molecular
      structure on formulation and release characteristics.
AB  - Chitosan can be useful as a nonviral vector for gene delivery. Although there are
      several reports to form chitosan-pDNA particles, the optimization and effect on
      transfection remain insufficient. The chitosan-pDNA nanoparticles were formulated
      using complex coacervation and solvent evaporation techniques. The important
      parameters for the encapsulation efficiency were investigated, including
      molecular weight and deacetylation degree of chitosan. We found that
      encapsulation efficiency of pDNA is directly proportional with deacetylation
      degree, but there is an inverse proportion with molecular weight of chitosan. DNA
      nanoparticles in the size range of 450-820 nm depend on the formulation process.
      The surface charge of the nanoparticles prepared with complex coacervation method
      was slightly positive with a zeta potential of +9 to +18 mV; nevertheless,
      nanoparticles prepared with solvent evaporation method had a zeta potential
      approximately +30 mV. The pDNA-chitosan nanoparticles prepared by using high
      deacetylation degree chitosan having 92.7%, 98.0%, and 90.4% encapsulation
      efficiency protect the encapsulated pDNA from nuclease degradation as shown by
      electrophoretic mobility analysis. The release of pDNA from the formulation
      prepared by complex coacervation was completed in 24 hr whereas the formulation
      prepared by evaporation technique released pDNA in 96 hr, but these release
      profiles are not statistically significant compared with formulations with
      similar structure (p > .05). According to the results, we suggest nanoparticles
      have the potential to be used as a transfer vector in further studies.

PMID- 15200010
TI  - Development and characterization of mucoadhesive microspheres bearing salbutamol
      for nasal delivery.
AB  - Mucoadhesive drug delivery systems are those that provide intimate contact of the
      drug with the mucosa for an extended period of time. In our present work,
      mucoadhesive chitosan microspheres were prepared by emulsion solvent method.
      Formulations were characterized for various physicochemical attributes, shape,
      surface morphology, size, and size distribution, drug payload, swelling ability,
      and mucoadhesion. The effect of drug, citric acid, and permeation enhancer
      concentration on the physicochemical properties was studied. Crosslinked chitosan
      microspheres showed very good mucoadhesion, which was decreased on increasing the
      drug concentration and citric acid concentration, and slightly improved upon
      incorporation of permeation enhancer. The in vitro drug release and in vitro drug
      permeability through mucous membrane were performed, and slow release/permeation
      was noted with chitosan citrate complexed microspheres compared with noncomplexed
      chitosan microspheres. The in vivo performance of mucoadhesive microspheres
      formulations showed prolonged and controlled release of salbutamol as compared
      with oral administration of conventional dosage form.

PMID- 15200011
TI  - Stability of liposomal formulations in physiological conditions for oral drug
      delivery.
AB  - The stability of liposomal formulations is a key issue in drug delivery.
      Liposomes made of egg phosphatidylcholine (EPC), cholesterol (Chol),
      sphingomyelin (SM), and gangliosides (GM1 and GM type III) were incubated in
      different media to determine their stability. Mixtures containing GM1 or GM type
      III were found to be the most stable, and both showed similar stability trends in
      plasma at 37 degrees C. EPC/Chol was the most susceptible to lysis in plasma. In
      acid media (pH 2), the highest stability corresponded to EPC/Chol, whereas in
      bile and pancreatin, liposomes with GM1 and GM type III were more stable than
      those containing SM. This study suggests that among the formulations used as oral
      drug carriers, those containing GM1 and GM type III have higher possibilities of
      surviving through the gastrointestinal tract.

PMID- 15200012
TI  - Polysaccharides for colon targeted drug delivery.
AB  - Colon targeted drug delivery has the potential to deliver bioactive agents for
      the treatment of a variety of colonic diseases and to deliver proteins and
      peptides to the colon for their systemic absorption. Various strategies,
      currently available to target the release of drugs to colon, include formation of
      prodrug, coating of pH-sensitive polymers, use of colon-specific biodegradable
      polymers, timed released systems, osmotic systems, and pressure controlled drug
      delivery systems. Among the different approaches to achieve targeted drug release
      to the colon, the use of polymers especially biodegradable by colonic bacteria
      holds great promise. Polysaccharidases are bacterial enzymes that are available
      in sufficient quantity to be exploited in colon targeting of drugs. Based on this
      approach, various polysaccharides have been investigated for colon-specific drug
      release. These polysaccharides include pectin, guar gum, amylose, inulin,
      dextran, chitosan, and chondroitin sulphate. This family of natural polymers has
      an appeal to drug delivery as it is comprised of polymers with a large number of
      derivatizable groups, a wide range of molecular weights, varying chemical
      compositions, and, for the most part, low toxicity and biodegradability yet high
      stability. The most favorable property of these materials is their approval as
      pharmaceutical excipients.

PMID- 15200014
TI  - Diterpenoids.

PMID- 15200013
TI  - Mechanism of action of vitamin K.
AB  - We have discovered a novel, spontaneous model oxidation that leads to a powerful
      base capable of carrying out a carbon-carbon bond forming condensation reaction
      analogous to that observed in the vitamin K-mediated carboxylation of glutamate.
      The model sequence incorporates a novel base-strength enhancement sequence and it
      implicates molecular oxygen as the initiating factor in the vitamin K-dependent
      carboxylation. When the oxygenation is carried out under an atmosphere of (18)O2,
      two atoms of (18)O are incorporated into the vitamin K oxide product. Selective
      (18)O labelling defines the carbonyl group next to methyl as the active site of
      the vitamin K.

PMID- 15200015
TI  - Inhibitors of squalene biosynthesis and metabolism.

PMID- 15200016
TI  - Secondary metabolism in plant tissue culture: scope and limitations.

PMID- 15200017
TI  - Amaryllidaceae and Sceletium alkaloids.

PMID- 15200018
TI  - Isotope effects in the elucidation of enzyme mechanisms.

PMID- 15200019
TI  - Marine natural products.

PMID- 15200020
TI  - Muscarine, oxazole, imidazole, thiazole, and peptide alkaloids, and other
      miscellaneous alkaloids.

PMID- 15200021
TI  - Steroids: reactions and partial syntheses.

PMID- 15200022
TI  - Tropane alkaloids.

PMID- 15200023
TI  - The use of supercritical fluids in the isolation of natural products.

PMID- 15200024
TI  - Triterpenoids.

PMID- 15200025
TI  - Recent progress in the chemistry of indole alkaloids and mould metabolites.

PMID- 15200026
TI  - Natural sesquiterpenoids.

PMID- 15200027
TI  - Beta-phenylethylamines and the isoquinoline alkaloids.

PMID- 15200028
TI  - Synthesis and anti-HIV activity of 4'-cyano-2',3'-didehydro-3'-deoxythymidine.
AB  - A new anti-HIV agent 4'-cyano-2',3'-didehydro-3'-deoxythymidine (9) was
      synthesized by allylic substitution of the 3',4'-unsaturated nucleoside 14,
      having a leaving group at the 2'-position, with cyanotrimethylsilane in the
      presence of SnCl4. Evaluation of the anti-HIV activity of 9 showed that this
      compound is much less potent than the recently reported 2',3'-didehydro-3'-deoxy
      4'-(ethynyl)thymidine (1).

PMID- 15200029
TI  - The synthesis of [([beta-D-ribofuranosyloxy)methyl]nucleosides.
AB  - The coupling reaction of acetoxymethoxy ribofuranoside 4 with nucleic acid bases
      5a-f to synthesize novel (ribofuranosyloxy)methyl uracil, thymine, cytosine,
      adenine, guanine derivatives 6a-g respectively in preference to the expected
      formation of natural nucleosides 2',3',5'-tri-O-benzoyl uridine, methyluridine,
      cytidine, adenosine and guanosine 7a-g is described. Detailed study of these
      reactions catalysed by Lewis acids TMSOTf and SnCl4 is described. TMSOTf
      exhibited selectivity for the formation of ribofuranosyloxy methyl derivatives 6a
      g rather than 7a-g. Reason for formation of 6a-g is explained by HSAB principle.

PMID- 15200030
TI  - Design, efficient synthesis, and anti-HIV activity of 4'-C-cyano- and 4'-C
      ethynyl-2'-deoxy purine nucleosides.
AB  - Some 4'-C-ethynyl-2'-deoxy purine nucleosides showed the most potent anti-HIV
      activity among the series of 4'-C-substituted 2'-deoxynucleosides whose 4'-C
      substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the
      smaller the substituent at the C-4' position they have, the more acceptable
      biological activity they show. Thus, 4'-C-cyano-2'-deoxy purine nucleosides,
      whose substituent is smaller than the ethynyl group, will have more potent
      antiviral activity. To prove our hypothesis, we planned to develop an efficient
      synthesis of 4'-C-cyano-2'-deoxy purine nucleosides (4'-CNdNs) and 4'-C-ethynyl
      2'-deoxy purine nucleosides (4'-EdNs). Consequently, we succeeded in developing
      an efficient synthesis of six 2'-deoxy purine nucleosides bearing either a cyano
      or an ethynyl group at the C-4' position of the sugar moiety from 2'
      deoxyadenosine and 2,6-diaminopurine 2'-deoxyriboside. Unfortunately, 4'-C-cyano
      derivatives showed lower activity against HIV-1, and two 4'-C-ethynyl derivatives
      suggested high toxicity in vivo.

PMID- 15200031
TI  - Analysis of local convergence in NMR structure calculation for RNA by a
      classification system for nucleic acid structure (CSNA).
AB  - We are developing a program system, CSNA, to classify a set of structures into
      groups sharing similar structural characters. In the present study, CSNA was
      applied to the analysis of NMR structures obtained by the simulated annealing
      calculation to elucidate local convergences. A 34-mer RNA, U6-34, having a bulge
      out region that is derived from the human U6 snRNA is used as a target molecule
      in the present study. Although the structure calculation was not converged with
      the conventional method, it was found by the CSNA analysis that the two stem
      regions in the molecule were converged well. Furthermore, one strand of the bulge
      out region (A7-A11) was found to form a continuously stacked structure in two
      thirds of calculated structures. In conclusion, CSNA can be a novel tool to
      elucidate the local convergence of the NMR structure calculations.

PMID- 15200032
TI  - Chemoenzymatic syntheses of homo- and heterodimers of AZT and d4T, and evaluation
      of their anti-HIV activity.
AB  - Homo- and heterodimers of AZT and d4T, possessing carbonate and carbamate
      linkers, have been synthesized with the aim to enhance the antiviral activity of
      their components. Homo- and heterodimer carbamates showed weak anti-HIV activity.
      On the other hand, dinucleoside carbonates showed marked antiviral activity.

PMID- 15200033
TI  - Synthesis and biological evaluation of novel apio nucleosides with thiazole-4
      carboxamide and 1,2,4-triazole-3-carboxamide.
AB  - In view of biological activities of azole nucleosides and apio-dideoxynucleoside,
      novel apio nucleoside analogues (1 and 2) with thiazole and triazole base moiety
      were synthesized using 2,3-O-isopropylidene-apio-beta-D-furanose (3), which was
      prepared from D-mannose.

PMID- 15200034
TI  - The determination of deoxyribonucleic acids with triadimenol based on the
      enhancement of resonance light scattering.
AB  - For the first time, triadimenol was used to determine nucleic acid (DNA) using
      the resonance light scattering (RLS) technique. The RLS of triadimenol was
      greatly enhanced by DNA in the range of pH 1.6 to approximately 1.9. A resonance
      light-scattering peak at 310 nm was found, and the enhanced intensity of RLS at
      this wavelength was proportional to the concentration of DNA. The linear range of
      the calibration curve was 0 to approximately 9 microg/ml with the detection limit
      of 24 ng ml(-1). The mechanism studies of the system indicated that the enhanced
      RLS is due to the aggregation of triadimenol on DNA. The nucleic acids in
      synthetic samples and in rice seedling extraction were analyzed with satisfactory
      results. Compared with other methods, this method is convenient, rapid,
      inexpensive and simple.

PMID- 15200035
TI  - Major trauma with multiple injuries in Swedish children.
AB  - OBJECTIVE: To describe the demographics, mechanisms, pattern, and severity of
      injury, the prehospital and hospital care during the first 24 hours, and the
      outcome in the most severely injured children in a paediatric intensive care unit
      (PICU). DESIGN: Retrospective review. SETTING: Paediatric intensive care unit
      (PICU), Sweden. SUBJECTS: 45 children (0-16 years of age) with multiple injuries
      admitted to the PICU in Gothenburg from January 1990 to October 2000, inclusive.
      MAIN OUTCOME MEASURE: Mortality within 30 days after injury. RESULTS: About
      2/100000 children with multiple injuries were admitted to the PICU from the
      greater Gothenburg area each year from 1990-2000 inclusive. Injuries were more
      common in boys (n = 29, 64%). The mean age was 7 years (SD 5). Traffic related
      events (n = 29, 64%) and falls (n = 11, 24%) were the leading causes of injury.
      Thoracic and abdominal injuries were the most common (17% and 16% respectively).
      Three children died. CONCLUSION: Major trauma with multiple injuries is rare in
      Swedish children. When they are cared for at a centre with the necessary
      facilities and trained personnel they have a good chance of survival.

PMID- 15200036
TI  - Damage control surgery for abdominal trauma.
AB  - OBJECTIVE: To review the physiology, indications, technical aspects, morbidity,
      and mortality of damage control surgery. DESIGN: Retrospective study of published
      papers. SETTING: Teaching hospital, United Arab Emirates. INTERVENTIONS: A
      MEDLINE search on damage control surgery for the years 1981-2001. Further
      articles were retrieved from the references of the original articles. RESULTS:
      The indications for damage control surgery are: the need to terminate a
      laparotomy rapidly in an exsanguinating, hypothermic patient who had developed a
      coagulopathy and who is about to die on the operating table; inability to control
      bleeding by direct haemostasis; and inability to close the abdomen without
      tension because of massive visceral oedema and a tense abdominal wall. The
      principles of damage control surgery are: Phase I: laparotomy to control
      haemorrhage by packing; shunting, or balloon tamponade, or both; control of
      intestinal spillage by resection or ligation of damaged bowel, or both. Phase II:
      physiological resuscitation to correct hypothermia, metabolic acidosis, and
      coagulopathy. Phase III: planned reoperation for definitive repair. Damage
      control surgery is appropriate in a small number of critically ill patients who
      are likely to require substantial hospital resources; it has a high mortality
      (mean 45%, range (10%-69%). CONCLUSION: Damage control surgery offers a simple
      effective alternative to the traditional surgical management of complex or
      multiple injuries in critically injured patients. Phases I and II can be done at
      a rural hospital before transfer to a major trauma centre for definitive repair.

PMID- 15200037
TI  - Surgical treatment of recurrent differentiated thyroid carcinoma.
AB  - OBJECTIVE: To describe our experience of treating recurrent thyroid carcinoma.
      DESIGN: Retrospective study of casenotes. SETTING: Teaching hospital, Mexico.
      SUBJECTS: 20 patients who developed recurrences of 273 who presented with well
      differentiated thyroid carcinoma between 1991 and 1999. MAIN OUTCOME MEASURES:
      Presentation, management, morbidity, and mortality. RESULTS: There were 18 men
      and 2 women, median age 51 years (range 28-75). 13 were treated initially by
      total thyroidectomy and 7 with less than total resection. 16 were given ablative
      doses of 311I. The median time between initial resection and recurrence was 3
      years (range 1-6). The sites of recurrence were cervical lymph nodes (n = 12),
      thyroid bed (n = 3), or both (n = 5). During a median of 3 years 10 patients were
      free of disease and 2 had died. CONCLUSIONS: Well-differentiated thyroid cancer
      usually recurs in the cervical lymph nodes. Further resection offers a high cure
      rate.

PMID- 15200038
TI  - A randomised study comparing systemic transdermal treatment and local application
      of glyceryl trinitrate ointment in the management of chronic anal fissure.
AB  - OBJECTIVE: To compare a systemic transdermal therapeutic system with local
      application of glyceryl trinitrate ointment in the treatment of anal fissure.
      DESIGN: Prospective, multicentre, randomised trial. SETTING: Three teaching
      hospitals, Turkey. SUBJECTS: 89 outpatients with chronic anal fissure were
      randomly assigned to be treated with either transdermal (n = 52) or 0.2% glyceryl
      trinitrate ointment (n = 37). INTERVENTIONS: The patients were assessed at the
      sixth and the twelfth week after initial evaluation by physical examination,
      anoscopy, and anal manometry. MAIN OUTCOME MEASURES: Changes in the maximal anal
      resting pressure, healing rate. RESULTS: Anal fissure was completely healed in 38
      (73%) and 24 (64%) of the patients after 6 weeks and 48 (81%) and 27 (79%) of the
      patients in transdermal group and ointment group, respectively. Maximal anal
      resting pressure was reduced by 24% and 21% in transdermal and ointment groups,
      respectively. CONCLUSION: Systemic transdermal application of glyceryl trinitrate
      gave a satisfactory healing rate, which was comparable to that of local
      application of ointment.

PMID- 15200039
TI  - Quality of life, morbidity, and mortality after surgical intensive care: a follow
      up study of patients treated for abdominal sepsis in the surgical intensive care
      unit.
AB  - OBJECTIVE: To evaluate the long-term outcome of patients treated in the surgical
      intensive care unit (SICU) for abdominal sepsis. DESIGN: Retrospective study.
      SETTING: University hospital, Sweden. SUBJECTS: 210 consecutive patients treated
      for abdominal sepsis in the SICU at Lund University Hospital during the period
      January 1983 to December 1995. MAIN OUTCOME MEASURES: Background information,
      morbidity, and mortality. Follow-up of surviving patients with interview and
      completion of a quality of life (QoL) assessment. Information collected
      postmortem from the registers of the Swedish National Board of Health and
      Welfare. RESULTS: At follow-up, 45 patients of the 151 who survived the initial
      hospital stay had died, 41 were lost to follow up and 16 chose not to participate
      in the study; 49 patients completed the study. Median QoL scores were
      significantly impaired (p < 0.01) although subjective QoL did not change
      significantly. In-hospital mortality was 28% (59/210) and total mortality over
      the time period 50% (104/210). CONCLUSION: Most patients who survived after
      treatment of abdominal sepsis in the SICU regained good health and their
      functional status was restored. Subjective QoL remained unchanged.

PMID- 15200040
TI  - Papillary microcarcinoma of the thyroid gland: analysis of prognostic factors
      including histological subtype.
AB  - OBJECTIVE: To evaluate the prognosis of papillary microcarcinoma (PMC) of the
      thyroid. DESIGN: Prospective study. SETTING: Teaching hospital, Italy. SUBJECTS:
      89 patients treated for papillary micro carcinoma of thyroid and followed up for
      at least 6 years (range 6-12). INTERVENTION: Total thyroidectomy and, for lymph
      node metastases, laterocervical lymphadenectomy. MAIN OUTCOME MEASURES: Sex
      distribution, mode of onset of disease, diameter of tumour, histological type,
      histological stage, presence of lymph node metastases at the time of operation
      and type of operation. RESULTS: When the disease presented with laterocervical
      lymph nodes it was histologically more aggressive and included follicular (n = 3)
      and sclerosing (n = 4) types. CONCLUSION: Papillary microcarcinoma has an
      excellent prognosis if managed initially by total thyroidectomy.

PMID- 15200041
TI  - Prediction of survival in gastric carcinoma related to lymph node grading by the
      new American Joint Committee on Cancer/Union International Contre le Cancer
      System or the Japanese system.
AB  - OBJECTIVE: To compare the classification of gastric cancer adopted by the
      American Joint Committee on Cancer and the Union International contre le Cancer
      (AJCC/UICC) (number of nodes involved) with the Japanese classification (sites of
      nodes involved). DESIGN: Retrospective study. SETTING: Teaching hospital, Turkey.
      SUBJECTS: 134 consecutive patients whose gastric cancer was treated by D2
      resection. INTERVENTIONS: Kaplan-Meier survival analysis and Cox's regression
      model. MAIN OUTCOME MEASURE: Accuracy of prognosis. RESULTS: There were no
      significant differences in survival rates when pN1 and pN2 categories of the
      AJCC/UICC classification were subdivided into the n1 and n2 categories of the
      Japanese classification. However, when those in the n1 and n2 categories of the
      Japanese classification were subdivided into the pN1, pN2 and pN3 categories of
      the AJCC/UICC classification, survival differed significantly (p = 0.00001). When
      both classifications were combined in a multivariate analysis the pN category of
      the AJCC/UICC classification was found to be the most significant independent
      prognostic factor (p = 0.0001). CONCLUSION: Classification of lymph node status
      by number of nodes (AJCC/UICC) rather than anatomical site (Japanese) gives a
      more accurate prognosis.

PMID- 15200042
TI  - In vivo protein markers of human peritoneal mesothelial cells: do they differ
      according to their anatomical sites?
AB  - OBJECTIVE: To highlight the in vivo protein markers in human peritoneal
      mesothelial cells according to their anatomical distribution and their interest
      in theories of peritoneal repair. DESIGN: Clinical laboratory study. SETTING:
      University Hospital, France. PATIENTS: Sampling of mesothelial cells during 8
      laparotomies by impression smears. MAIN OUTCOME MEASURES: Immunochemical
      semiquantitative measures of proteins. RESULTS: There were uniform ratios of
      protein markers among the whole peritoneal mesothelial cell population, whatever
      their anatomical origin (liver, stomach, omentum, small bowel, and abdominal
      wall). CONCLUSION: This is consistent with the surrounding uninjured mesothelial
      cells or the exfoliated mesothelial cells, or both, having a role in
      postoperative peritoneal mesothelial repair.

PMID- 15200043
TI  - Predictors of outcome for patients with differentiated and aggressive thyroid
      carcinoma.
AB  - OBJECTIVE: To identify the risk factors affecting the outcome of operations for
      differentiated and aggressive thyroid carcinoma which may indicate the need for a
      more aggressive surgical treatment. DESIGN: Retrospective study. SETTING:
      University hospital. PATIENTS AND INTERVENTIONS: 143 patients underwent total
      thyroidectomy with or without central neck lymphadenectomy or modified neck
      dissection. There were 85 papillary, 34 follicular, 6 widely-invasive follicular,
      6 insular, five oxyphilic, five tall cell, and two diffuse sclerosing papillary
      carcinomas. MAIN OUTCOME MEASURE: Disease-related survival. RESULTS: At 12-years,
      the survival was 96%, being 98% among patients with differentiated and 83% among
      those with aggressive carcinoma (p = 0.0006). Insular and oxyphilic carcinomas
      had the worst prognosis (at 10 years, 67% and 60%, respectively, p < 0.0001). The
      high-risk age, metastases, and extent score (AMES) group had worse survival than
      the low-risk group (12 years, 84% compared with 98%, p = 0.001). Among patients
      with differentiated carcinoma, the low-risk AMES group had also better outcome
      than those in the high-risk AMES group (at 12 years, 100% compared with 86%, p <
      0.0001), but there was no such difference among patients with aggressive disease.
      Multivariate analysis showed that women (RR 14.28, 95% confidence interval (CI)
      1.13 to 180.28), patients with tumours > or = 5 cm in size (RR 9.60, 95%CI 1.01
      to 91.43) and AMES high-risk patients (RR 30.17, 95% CI 1.57 to 577.48) had the
      worst outcome. CONCLUSION: In patients with differentiated thyroid carcinoma,
      total thyroidectomy and, if the AMES score indicates a high risk, central neck
      lymphadenectomy with or without modified neck dissection, is associated with a
      favourable outcome. Poorer outcome is expected if the carcinoma is aggressive,
      and an aggressive surgical approach is advocated as a routine.

PMID- 15200044
TI  - Resection rectopexy for internal rectal intussusception reduces constipation and
      incomplete evacuation of stool.
AB  - OBJECTIVE: To study the effect of rectopexy and sigmoid resection (resection
      rectopexy) on symptoms in patients with internal rectal intussusception. DESIGN:
      Retrospective and prospective study. SETTING: University hospital, Norway.
      PATIENTS: 22 patients with internal rectal intussusception. INTERVENTIONS:
      Resection rectopexy by an open (n = 13) or laparoscopically-assisted (n = 9)
      technique. MAIN OUTCOME MEASURES: Symptomatic outcome, patients' satisfaction,
      and morbidity. Outcome was based mainly on the validated KESS score, which covers
      10 symptoms included in the definiton of constipation. RESULTS: There was a
      significant reduction in all 10 symptoms. Two patients complained of incontinence
      which improved after operation. The number of patients with constipation was
      reduced from 20 to 8 (p = 0.000) and none became constipated. Mean (95% CI)
      colonic transit times before and after operation in 10 patients with constipation
      were 5.3 (4.1 to 6.4) and 4.0 (2.6 to 5.4) days (p = 0.083). Seven of these 10
      patients had a reduction of both transit time and constipation score. Six
      patients had complications after open operations. These included one damaged
      ureter, reoperations for bleeding, incomplete intestinal obstruction, and 2 wound
      infections. CONCLUSION: Rectopexy with sigmoid resection resulted in improvement
      in symptoms, including constipation and feeling of incomplete rectal evacuation,
      and acceptable morbidity.

PMID- 15200045
TI  - Tranexamic acid given into the wound reduces postoperative blood loss by half in
      major orthopaedic surgery.
AB  - OBJECTIVE: To evaluate the effect of locally applied tranexamic acid on
      postoperative blood loss and measures of fibrinolysis in drained blood. DESIGN:
      Prospective study. SETTING: University hospital, Norway. PATIENTS: 30 patients
      operated on for low back pain by screw fixation of the lumbar spine, 16 of who
      were randomised to be given topical tranexamic acid. MAIN OUTCOME MEASURES:
      Postoperative blood loss after 18 hours. Concentrations of plasmin/alpha2
      antiplasmin (PAP) and D-dimer in arterial and drained blood at the time of wound
      closure and in drained blood after 1 hour. RESULTS: In the tranexamic group
      median (interquartile) blood loss was reduced by half from 525 (325-750) ml to
      252 (127-465) ml, p = 0.02. In drained blood after one hour the increase in the
      concentration of PAP was 150 (109-170)% and D-dimer 150 (107-272)% in the
      tranexamic group compared with the control group where the increase in PAP was
      320 (140-540)% and D-dimer 260 (161-670)%. CONCLUSION: Tranexamic acid applied in
      the wound inhibits blood loss by up to a half in major orthopaedic surgery
      probably because it prevents excessive fibrinolysis.

PMID- 15200046
TI  - Carcinoma in the remnant pancreas after distal pancreatectomy for carcinoma.

PMID- 15200047
TI  - Distal small bowel obstruction caused by a migrated self expanding metal
      oesophageal stent.

PMID- 15200048
TI  - Breast fibroadenoma in a male-to-female transsexual patient after hormonal
      treatment.

PMID- 15200049
TI  - Inactivation of human liver arginase by Woodward's reagent K: evidence for
      reaction with His141.
AB  - Human liver arginase (EC 3.5.3.1) was totally inactivated by incubation with
      Woodward's reagent K (WRK). The inactivation followed pseudo-first-order
      kinetics, and the order of the inactivation was close to 1, consistent with
      reaction of one molecule of WRK with one subunit molecule for inactivation. The
      effect was totally reversed by 0.5 M hydroxylamine, and reactivated species were
      inactivated again by a second incubation with WRK. The pH dependence of the
      pseudo--first-order rate constants of inactivation indicated the participation of
      a ionizable residue with a pKa of 6.3 at 25 degrees C. Replacement of His141 with
      phenylalanine rendered the enzyme totally resistant to the inactivation. We
      conclude that His141 is the residue whose chemical modification with WRK
      inactivates the enzyme.

PMID- 15200050
TI  - Conformational states of trifluoroacetic acid-treated cytochrome c in the
      presence of salts and alcohols.
AB  - We have carried out a systematic investigation of salts- and alcohols-induced
      conformational alterations on the trifluoroacetic acid (TFA)-treated
      ferricytochrome c by soret absorption spectroscopy, far UV circular dichroism
      (CD), tryptophan fluorescence, and 1-anilino-8-naphthalene sulfonate (ANS)
      binding. TFA induces the unfolding of native cytochrome c obtained from horse
      heart leading to loss of secondary structure. The addition of increasing
      concentration of salts and alcohols leads to increase in MRE value at 222 and 208
      nm indicating an increase in the alpha-helical content leading to formation of
      compact dimensional structure. Cytochrome c is a heme protein in which the
      resonance energy of tryptophan is transferred to heme resulting in quenched
      tryptophan fluorescence. Addition of alcohols leads to increase in tryptophan and
      ANS fluorescence. The tryptophan and ANS fluorescence in case of salts shows
      decreased fluorescence intensity. TFA-induced unfolded cytochrome c showed the
      soret absorption maximum at 394 nm. However, an intermediate state in presence of
      alcohols and salts showed the absorption maxima at 398 nm and 402 nm,
      respectively. Among all the salts and alcohols studied, K3Fe(CN)6 and butanol
      were found to be most effective as examined by the above-mentioned spectroscopic
      techniques. The order of effectiveness of alcohols was found to be butanol >
      propanol > ethanol > methanol. The following effective trend in the case of salts
      was obtained: K3Fe(CN)6 > K2SO4>KClO4 > KCl. These results suggest that alcohols
      induce an intermediate with molten globule-like conformation on the TFA unfolded
      state, whereas salts induce a refolded intermediate approaching native-like
      conformation.

PMID- 15200051
TI  - His23beta and Glu455beta of the Pseudomonas sp. 130 glutaryl-7-amino
      cephalosporanic acid acylase are crucially important for efficient
      autoproteolysis and enzymatic catalysis.
AB  - Glutaryl-7-amino cephalosporanic acid acylase is a member of the N-terminal
      nucleophilic hydrolase family of enzymes. The crystal structure of the acylase
      reveals there is a Ser-His-Glu motif composed of Ser1beta, His23beta, and
      Glu455beta near the active site. This mimics the catalytic triad of Ser-His-Asp
      in serine proteases. Experiments prove that maturation of this enzyme involves
      autoproteolysis. It has been shown that Ser1beta is the catalytic residue for the
      autoproteolysis and catalytic reaction. Our works on site-directed mutagenesis
      followed by the characterization of mutant enzymes demonstrated that His23beta is
      essential for autoproteolysis whereas Glu455beta is responsible for the
      efficiency of the process. Neither His23beta nor Glu455beta is essential for the
      acylase activity, although they affect the catalytic efficiency.

PMID- 15200052
TI  - Funastrain c II: a cysteine endopeptidase purified from the latex of Funastrum
      clausum.
AB  - A cysteine endopeptidase, named funastrain c II, was isolated and characterized
      from the latex of Funastrum clausum (Asclepiadaceae). The molecular mass (mass
      spectrometry) of the protease was 23.636 kDa. The analysis of funastrain c II by
      SDS-PAGE revealed a single polypeptide chain. The enzyme showed a remarkable
      stability of its caseinolytic activity after incubation at temperatures as high
      as 70 degrees C. Inhibition and activation assays indicated the cysteinic nature
      of the funastrain c II catalytic site. The optimum pH of funastrain c II
      enzymatic activity varied according to the substrate used (9.0-10.0 for casein
      and 6.2-6.8 for PFLNA). Kinetic parameters were determined for N-alpha-CBZ-Ala p
      nitrophenyl ester (Km = 0.0243 mM, kcat = 1.5 s(-1)) and L-pyroglutamyl-L
      phenylalanyl-L-leucine-p-nitroanilide (PFLNA; KM = 0.1011 mM, kcat = 0.9 s(-1)).
      The N-terminal sequence of funastrain c II showed considerable similarity to
      other proteases isolated from latex of different Asclepiadaceae species as well
      as to other cysteine proteinases belonging to the papain family.

PMID- 15200053
TI  - Comparison of molecular dynamics averaged structures for complexes of normal and
      oncogenic ras-p21 with SOS nucleotide exchange protein, containing computed
      conformations for three crystallographically undefined domains, suggests a
      potential role of these domains in ras signaling.
AB  - ras-p21 protein binds to the son-of-sevenless (SOS) guanine nucleotide-exchange
      promoter that allows it to exchange GDP for GTP. Previously, we performed
      molecular dynamics calculations on oncogenic (Val 12-) and wild-type ras-p21
      bound to SOS. By superimposing the average structures of these two complexes, we
      identified four domains (residues 631-641, 676-691, 718-729, and 994-1004) in SOS
      that change conformation and were candidates for being effector domains. These
      calculations were performed in the absence of three crystallographically
      undefined loops (i.e., residues 591-596, 654-675, and 742-751). We have now
      modeled these loops into the SOS structure and have re-performed the dynamics
      calculations. We find that all three loop domains undergo large changes in
      conformation that involve mostly changes in their positioning and not their
      individual conformations. We have also identified another potential effector
      domain (i.e., residues 980-989). Overall, our current results suggest that SOS
      interactions with oncogenic ras-p21 may enhance ras-p21 mitogenic signaling
      through prolonging its activation by maintaining its binding to GTP and by
      allowing its effector domains to interact with intracellular targets.

PMID- 15200054
TI  - Loop domain peptides from the SOS ras-guanine nucleotide exchange protein,
      identified from molecular dynamics calculations, strongly inhibit ras signaling.
AB  - In the accompanying paper, we found, using molecular dynamics calculations, four
      domains of the ras-specific SOS guanine nucleotide exchange protein (residues 589
      601, 654-675, 746-761, and 980-989) that differ markedly in conformation when SOS
      is complexed with either oncogenic (Val 12-) ras-p21 or wild-type ras-p21. Three
      of these domains contain three crystallographically undefined loops that we
      modeled in these calculations, and one is a newly identified non-loop domain
      containing SOS residues 980-989. We have now synthesized peptides corresponding
      to these four domains and find that all of them block Val 12-ras-p21-induced
      oocyte maturation. All of them also block insulin-induced oocyte maturation, but
      two of these peptides, corresponding to SOS residues 589-601 and 980-989, block
      oncogenic ras to a significantly greater extent. These results suggest that SOS
      contains domains, including the three loop domains, that are important for ras
      signaling and that several of these domains can activate different pathways
      specific to oncogenic or wild-type ras-p21.

PMID- 15200056
TI  - Clinical features and management of intracranial hemorrhage in patients
      undergoing maintenance dialysis therapy.
AB  - The management and outcome were retrospectively investigated in patients with
      chronic renal failure receiving maintenance blood purification who suffered
      intracranial hemorrhage. Patients with intracerebral hemorrhage (ICH, n = 36) or
      subarachnoid hemorrhage (SAH, n = 5) were evaluated. Both groups were initially
      managed using continuous hemofiltration (HF) after admission, except for two
      patients with SAH receiving maintenance peritoneal dialysis. Patients with ICH
      were managed with HF three times a week after computed tomography showed
      decreased peripheral edema. Nafamostat mesilate was used as the anticoagulant for
      both continuous HF and HF. Hemodialysis (HD) three times a week was initiated
      after confirming the absence of neurological deterioration using HF. Craniotomy
      was not performed in any patient with ICH, but if necessary, the hematoma was
      aspirated using burr-hole surgery. Angiography was performed on the day of
      admission in patients with SAH. Delayed neck-clipping surgery was performed after
      continuous HF for 2 weeks with lumbar cerebrospinal fluid drainage. In patients
      with ICH, continuous HF was continued for 2-9 days after admission (mean 5.2 +/-
      2.2 days), followed by 2-9 courses of HF (mean 4.7 +/- 2.1 courses). HD was
      initiated 9-26 days after admission (mean 15.5 +/- 4.6 days). Favorable outcomes
      were achieved by 13 of the 36 patients with ICH and two of the five patients with
      SAH, whereas 22 patients with ICH and three patients with SAH died. Death
      occurred in 12 of 16 patients with ICH and diabetic nephropathy. In contrast, 10
      of 20 non-diabetic patients with ICH had favorable outcomes. Ten of the 16
      patients with initial GCS < or = 8 and six of the 20 with GCS > or = 9 were
      diabetic. Therefore, there were significant differences between diabetic and non
      diabetic patients (p = 0.05). Poor outcomes in diabetic patients with ICH are
      caused by primary brain damage, reflected in the initial disturbance of
      consciousness.

PMID- 15200055
TI  - An effector peptide from glutathione-S-transferase-pi strongly and selectively
      blocks mitotic signaling by oncogenic ras-p21.
AB  - Oncogenic ras-p21 directly activates jun-N-terminal kinase (JNK) and its
      substrate, jun as a unique step on its mitogenic signal transduction pathway.
      This activation is blocked by the specific JNK-jun inhibitor, glutathione-S
      transferase-pi (GST-pi). Four domains of GST-pi have been implicated in this
      regulatory function: 34-50, 99-121, 165-182, and 194-201. The 34-50 domain is
      unique in that it does not affect GST-pi binding to JNK-jun but blocks jun
      phosphorylation by JNK. We now find that it completely blocks oncogenic (Val 12-)
      ras-p21-induced oocyte maturation but has no effect on insulin-induced oocyte
      maturation. Because the latter process requires activation of wild-type ras-p21,
      this peptide appears to be specific for inhibiting only the oncogenic form of ras
      p21, suggesting its use in treating ras-induced tumors.

PMID- 15200057
TI  - Beta-tricalcium phosphate combined with recombinant human bone morphogenetic
      protein-2: a substitute for autograft, used for packing interbody fusion cages in
      the canine lumbar spine.
AB  - Beta-tricalcium phosphate (beta-TCP) combined with recombinant human bone
      morphogenetic protein-2 (BMP-2) was examined as a substitute for autograft for
      packing into interbody fusion cages in the canine lumbar spine model. Discectomy
      and interbody cage fusion were performed at three disc spaces in eight dogs.
      Examination of microradiographs and histological sections of the lumbar spine at
      16 weeks postsurgery revealed three fusions in the autograft cages (Group A),
      three in the beta-TCP cages (Group B), and five in the beta-TCP-BMP-2 cages
      (Group C). The mean percentage of trabecular bone area in the cages was 51.9% in
      Group A, 48.8% in Group B, and 65.6% in Group C. Mean percentage of trabecular
      bone formation and mechanical stiffness were highest in the cages filled with
      beta-TCP and BMP-2. Combination of BMP to beta-TCP may act as an osteoconductive
      and osteoinductive bone graft substitute in clinical spine surgery.

PMID- 15200058
TI  - Ruptured aneurysm arising from the proximal end of an azygos anterior cerebral
      artery--case report.
AB  - A 59-year-old woman presented with subarachnoid hemorrhage. Conventional
      angiography and three-dimensional computed tomography (3-D CT) angiography showed
      a saccular aneurysm at the junction of the azygos anterior cerebral artery (ACA)
      and the left A1 segment. This aneurysm was associated with a fenestration of the
      right hypoplastic A1 segment. The aneurysm neck was completely clipped,
      preserving the azygos ACA and other perforators. Aneurysm of the azygos ACA is
      almost always located at the distal bifurcation, and rarely at the proximal end.
      Proximal azygos ACA aneurysm can mimic anterior communicating artery aneurysm.
      Therefore, accurate preoperative diagnosis is critical using 3-D CT angiography
      as well as conventional angiography, and close follow up of patient is necessary
      to monitor for development of a de novo aneurysm at the distal bifurcation of the
      azygos ACA.

PMID- 15200059
TI  - Differences in diffusion-weighted and T2-weighted magnetic resonance imaging
      findings in the acute and chronic stages of ischemic cerebrovascular disease--two
      case reports.
AB  - A 71-year-old man presented with sudden onset of vertigo and a 77-year-old man
      suffered consciousness disturbance. Diffusion-weighted magnetic resonance (MR)
      imaging on admission showed hyperintense areas in the left cerebellar hemisphere
      in the first patient and in the brainstem in the second patient. Both patients
      were treated with argatroban and edaravone, and the neurological deficits
      markedly improved one month after admission. T2-weighted MR imaging one month
      after the onset showed much smaller hyperintense areas compared with the findings
      on admission in both patients. These results indicate that findings of
      hyperintense areas by diffusion-weighted MR imaging in the acute stage of
      ischemic cerebrovascular disease indicate not only the ischemic core but also
      parts of the reversible incomplete ischemic lesion and suggest that intensive
      treatment in the acute stage might reverse ischemic brain damage in some
      patients.

PMID- 15200060
TI  - Multifocal primary intracerebral malignant fibrous histiocytoma--case report.
AB  - A 58-year-old female presented with a unique case of multifocal primary
      intracerebral malignant fibrous histiocytoma (MFH) manifesting as partial
      seizure. Neuroimaging showed a mass lesion in the right frontal lobe, which was
      totally removed. The histological diagnosis was MFH. Follow-up neuroimaging one
      month after surgery showed another lesion rapidly growing in the left frontal
      lobe. This lesion was totally removed, and identified as MFH. Her condition
      gradually worsened. Neuroimaging performed 3 months after first operation
      revealed bilateral recurrence. She died of respiratory failure 7 months after the
      initial diagnosis of MFH. Primary intracranial MFH is an extremely rare entity
      with only 31 cases of solitary tumor previously reported.

PMID- 15200061
TI  - Solitary osteochondroma arising from the thoracic facet joint--case report.
AB  - A 15-year-old male presented with pain in the back and paresthesia and weakness
      of both lower limbs progressing for 6 months. Magnetic resonance imaging revealed
      a mass lesion occupying the spinal canal at the T-10 to T-11 levels, which had
      severely compressed the cord. At surgery, a firm and cartilaginous tumor
      originating from the facet joint was radically excised. The patient showed rapid
      neurological recovery following the surgery. Histological examination revealed
      that the lesion was osteochondroma. Such lesions are extremely rare in the lower
      thoracic spine and osteochondroma arising from the thoracic facet joint is
      unique.

PMID- 15200062
TI  - Effects of opening peritumoral syrinxes on motor evoked potentials during
      resection of an intramedullary spinal cord tumor--case report.
AB  - A 29-year-old woman presented with mild tetraparesis caused by an intramedullary
      cervical cord tumor extending from the C-5 to C-6 levels associated with rostral
      and caudal syrinxes extending to the C-1 and C-7 levels. Transcranial motor
      evoked potential (MEP) monitoring was carried out during tumor resection using
      high-frequency repetitive electrical stimulation. When the rostral syrinx was
      opened, the MEP amplitude in the right upper limb suddenly decreased by about
      50%. When the caudal syrinx was opened, the amplitude immediately recovered to
      the baseline. During dissection of the attachment of the tumor, the amplitude
      decreased again by 70%, and did not recover. The tumor was totally removed. The
      histological diagnosis was ependymoma. Postoperatively, motor weakness in the
      right arm deteriorated but gradually recovered. The initial loss of amplitude on
      opening of the rostral syrinx may have resulted from distortion of the
      intramedullary pressure that compromised function of the motor tract nearby.
      Opening of the caudal syrinx normalized the intramedullary pressure and allowed
      the MEP to recover. Intraoperative monitoring of MEPs is valuable in minimizing
      injury to corticospinal pathways, but care must be taken in evaluating changes in
      MEP. Intramedullary spinal tumors with associated syrinxes are not rare, so
      surgeons should realize that opening of a syrinx can lead to MEP changes.

PMID- 15200063
TI  - Surgical management of combined stab injury of the spinal cord and the aorta-
      case report.
AB  - A 32-year-old man presented with a combined penetrating stab injury of the spinal
      cord and the aorta caused by a knife wound in his back at the low thoracic level.
      The knife had broken, and part of the blade had been retained in the wound,
      passing through the spinal canal and into the aortic lumen. The patient was
      treated in two steps: the aorta was repaired by a thoracotomy, then spinal
      exploration was carried out through a laminectomy. Because of the tamponade
      effect of the foreign body, it was necessary to delay removal of the blade until
      vascular control had been achieved. Any sign of a penetrating body passing
      through the spine should suggest careful evaluation to detect any visceral
      injury, and multidisciplinary treatment should be planned.

PMID- 15200064
TI  - Intramedullary spinal tuberculoma--case report.
AB  - A healthy 33-year-old man presented with an intramedullary tuberculoma of the
      thoracic spinal cord manifesting as a 2-month history of progressive paraparesis
      and sphincter dysfunction. Magnetic resonance imaging showed ring enhancement of
      the intramedullary thoracic lesion with perifocal edema. General physical
      examination was unremarkable with no signs of inflammation except for a positive
      finding by the tuberculin skin test. Total resection of the intramedullary mass
      was performed through a posterior myelotomy following T11-12 laminectomy.
      Histological examination revealed a granulomatous lesion that contained Langhans
      giant cells, inflammatory cells, and caseating necrosis. Acid-fast bacilli
      staining of the specimens was positive, and cultures grew Mycobacterium
      tuberculosis. Postoperatively, the paraparesis and sphincter dysfunction improved
      sufficiently for the patient to return to his ordinary activities. Intramedullary
      spinal tuberculoma is rare, but must be considered in the differential diagnosis
      of spinal cord compression.

PMID- 15200067
TI  - Proteonomica and bioinformatic.

PMID- 15200065
TI  - Combined use of electrolytically and mechanically detachable platinum coils for
      endovascular treatment of cerebral aneurysms--technical note.
AB  - The combined use of Guglielmi detachable coils (GDCs) and newly developed
      mechanically detachable platinum coils (Detach Coil System: DCS) was evaluated
      for the endovascular treatment of 10 patients with cerebral aneurysms. The number
      and total length of detachable coils placed into the aneurysms, the detaching
      time for each coil, and any technical problems were recorded and evaluated. Sixty
      GDCs and 60 DCSs were used. The detachment time for the DCS (mean 21 seconds) was
      faster than that for the GDC (mean 2 minutes 35 seconds). One DCS moved inside
      the aneurysm during the mechanical detachment maneuver, but was successfully
      placed. Neither detachment system influenced the behavior of the other system
      during coil implantation. The DCS includes a useful J-shape coil, whereas the GDC
      can be detached safely in fragile aneurysms. The DCS is also cheaper. The coil
      systems complemented one another and the combination optimized cost and operating
      time.

PMID- 15200068
TI  - The study on the synthesis and the effects on the intracellular calcium of some 9
      substituted-phenanthrene derivatives.
AB  - Some 9-(substituted with heteroaryl)-phenanthrene compounds, polycyclic aromatic
      hydrocarbons (PAH), were obtained by two different methods. In the first method,
      9-phenanthraldehyde was reacted with some dion compounds such as benzil, toluil,
      anisil, etc in the presence of ammonium acetate and glacial acetic acid. In the
      second method, 9-phenanthraldehyde was reacted with 5-substituted-1,2
      phenylenediamine derivatives in the presence of NaHSO3 and ethanol. All of
      synthesized compounds by us were original and these compounds have not been
      studied in literature so far. The structures of compounds were confirmed by
      spectral data and elemental analyses results. The effects of compounds were
      studied on intracellular calcium level. All of the compounds were examined
      between the concentrations of 1 and 0.5 microg/mL.

PMID- 15200069
TI  - Structure-activity relationship studies: study of the analgesic properties of a
      series of synthesized esters of 3- (4-benzyl-1-piperazinyl) 1-phenylpropanols.
AB  - Four previously stynthesized derivatives of 3- (4-benzyl-1-piperazinyl)-1
      phenylpropanol were screened for analgesic activity in albino mice using a
      variation of the Eddy and Lambach hot plate method. The result showed that the
      most significant analgesic effect was elicited by the parent secondary 3
      piperazinylpropanol, namely 3-(4-benzyl-1-piperazinyl)-1-phenylpropanol. Its
      esterification products with propanoyl, benzoyl and phenylacetyl chlorides
      exhibited reduced analgesic properties. The percent maximum protection against
      thermal pain produced by Aspirin (71.43%) was twice as high as that produced by
      the most active of the four derivatives (43.65%). The analgesic effect of the
      compounds was dose dependent. From acute toxicity studies in mice, the LD50
      values were estimated to be in range of moderate toxicity (89.74 to 243 mg/kg).
      The most active of the compounds studied, namely, 3-(4-benzyl-1-piperazinyl-1
      phenylpropanols, was also found to be the most toxic. The margin between its safe
      doses and its LD50 (89.74 mg/kg) was found to be very narrow. Esterification of
      the 3-(4-benzyl-1-piperazinyl)-1-phenylpropanol led to decrease in its analgesic
      activity and also a decrease in its toxicity.

PMID- 15200071
TI  - Animal health and welfare: taking the strategy forward.

PMID- 15200066
TI  - Analysis of subarachnoid hemorrhage according to the Japanese Standard Stroke
      Registry Study--incidence, outcome, and comparison with the International
      Subarachnoid Aneurysm Trial.
AB  - The data for subarachnoid hemorrhage (SAH) from the Japanese Standard Stroke
      Registry Study (JSSRS) were analyzed to evaluate the incidence of SAH according
      to age, neurological grading and outcome, and outcome of surgical clipping, for
      comparison with the International Subarachnoid Aneurysm Trial (ISAT). From the
      ISSRS data, the peak incidence of SAH was the sixth decade in males and the
      eighth decade in females. The overall mortality was 22%, and good outcome, better
      than 2 on the modified Rankin Scale (mRS), at discharge was achieved in 58% of
      cases. Radical treatment was performed in 62.6% of all SAH cases, 58.7% with
      surgical clipping and 3.2% with endovascular coiling. Poor outcome, worse than 3
      on the mRS, occurred in 26.6% of patients under 60 years, 47.3% between 60-69
      years, 54.2% between 70-79 years, and 72.9% 80 years or over. From the ISAT data,
      88% of patients were in grades 1-2 of the World Federation of Neurological
      Surgeons (WFNS) grading system in both surgical clipping and endovascular coiling
      groups, 94% in grades 1-3, and 98% in grades 1-4. Poor outcome, worse than 3 on
      the mRS, at 2 months occurred in 25.4% and 36.4% of patients with endovascular
      coiling and surgical clipping, respectively. Limiting the patients in the JSSRS
      to WFNS grades 1-2 showed poor outcome, worse than 3 on the mRS, occurred in
      12.8%, and in grades 1-3 and 1-4 occurred in only 16.3% and 23.0%, respectively.

PMID- 15200070
TI  - Challenges facing veterinary training and research.

PMID- 15200072
TI  - Remission of the clinical signs of atopic dermatitis in dogs after cessation of
      treatment with cyclosporin A or methylprednisolone.
AB  - Seventy-eight dogs with atopic dermatitis were treated for four months with
      either cyclosporin A or methylprednisolone. During the two months after the
      treatment ceased, 87 per cent of the dogs treated with methylprednisolone
      relapsed after a mean period of 27.9 days, whereas only 62 per cent of the dogs
      treated with cyclosporin A relapsed after a mean period of 40.7 days (P <
      .0.001). The clinical condition of the dogs was evaluated either when they
      relapsed, or two months after the treatment ceased if they had not relapsed. Both
      the skin lesions and pruritus increased significantly more markedly in the dogs
      treated with methylprednisolone than in those treated with cyclosporin A. At the
      end of the study the skin lesions were markedly less severe than before the
      therapy; in the dogs in both groups that did not relapse, the lesion score was
      improved by 77 per cent two months after the treatment had stopped, and in the
      dogs that did relapse the lesion scores had improved by 45 per cent and 35 per
      cent in the dogs treated with cyclosporin A and methylprednisolone, respectively.
      Pruritus remained well controlled in the dogs that did not relapse, but increased
      to baseline levels or close to baseline in the dogs that relapsed.

PMID- 15200074
TI  - Perturbation of heart rate variability in cattle fed BSE-infected material.

PMID- 15200073
TI  - Serological study of contagious agalactia in herds of goats in the Canary
      Islands.
AB  - An indirect ELISA, using local strains of Mycoplasma agalactiae and Mycoplasma
      mycoides subspecies mycoides large colony (MmmLC), was applied to evaluate the
      seroprevalence of M agalactiae and MmmLC in flocks of goats on each of the Canary
      Islands. In total 3890 samples of serum were collected from 204 flocks. The
      results indicated that the seroprevalence of both organisms is high on all the
      islands; average values of 55 per cent and 67 per cent were recorded,
      respectively, for M agalactiae and MmmLC.

PMID- 15200075
TI  - Analysis of risk factors associated with seropositivity to Neospora caninum in
      dogs.

PMID- 15200076
TI  - Prevalence, abundance and risk factors of liver fluke (Platynosomum concinnum)
      infection in cats in Mexico.

PMID- 15200077
TI  - Identification of postweaning multisystemic wasting syndrome in European wild
      boar (Sus scrofa).

PMID- 15200078
TI  - Malignant melanoma in a merlin (Falco columbarius).

PMID- 15200079
TI  - Postparturient outbreak of fatal bovine viral diarrhoea in imported pregnant
      heifers on a dairy farm in Greece.

PMID- 15200080
TI  - Uterine extramedullary plasmacytoma in a dog.

PMID- 15200081
TI  - Change to user warning for Micotil.

PMID- 15200082
TI  - Future of farm veterinary services.

PMID- 15200083
TI  - Increased reporting of displaced abomasum.

PMID- 15200084
TI  - Introduction: The provision of animal health services in a changing world.
AB  - In the future, animal health services in developing countries will need to
      operate in a continuously changing policy, institutional and commercial
      environment. Firstly, the changing policies and priorities of national policy
      makers regarding public and private sector roles, reinforced in Africa by the
      donors, have reduced funding and support for the large number of tasks that
      animal health services have traditionally performed, and there is continuing
      pressure from policy-makers to focus on what the public sector can do best.
      Secondly, poverty reduction has become one of the main criteria guiding the
      allocation of official development assistance, which has major implications for
      the main target clientele of veterinary services. Thirdly, population growth,
      increasing income and urbanisation are causing a marked increase in demand for
      livestock products in the developing world. As a result, the entire livestock
      commodity chain is undergoing major structural changes, which has significant
      implications for the definition and control of food safety standards. Fourthly,
      globalisation, and increasing trade and travel have greatly increased the risk of
      disease transmission between different countries and continents. Veterinary
      institutions in the developing world need to adapt to these challenges. They will
      have to be able to focus on the essential public sector roles. At the same time
      they must deliver those essential services to the poor, and provide the policy
      framework to ensure that the inevitable structural changes in the commodity chain
      take place in an equitable and sustainable fashion, with an acceptable level of
      health risk for the consumer. According to the weight given to these different
      objectives, changes in the institutional set-up need to be considered. This issue
      of the Scientific and Technical Review addresses these challenges. It begins by
      reviewing the basic economic characteristics underlying the provision of animal
      health services, and then examines the alternative delivery systems that are
      emerging in the developing world and their strengths and weaknesses. The
      implications for food safety and trade are specifically highlighted. Also
      included are the practical experiences of countries, from all along the
      development continuum, that have introduced alternative systems. This paper deals
      with implications for the future, and while the growing importance of veterinary
      care for companion animals is acknowledged, the focus is on veterinary services
      for food animals.

PMID- 15200086
TI  - Tools from the new institutional economics for reforming the delivery of
      veterinary services.
AB  - The new institutional economics offers a range of analytical tools and insights
      which can be used in restructuring the animal health services of a country. This
      paper discusses three of the most important--externalities, transaction costs and
      asymmetric (unequal) information. These tools can be used to craft a system which
      is sensitive to the particular institutional heritage of a country and to its
      political, social and economic realities. Institutions are important in this
      process and the best way for one society is often not the optimal choice for
      another.

PMID- 15200085
TI  - The economic rationale of public and private sector roles in the provision of
      animal health services.
AB  - In the changing market environment of livestock products, the delivery of animal
      health services is emerging as an important priority area for enhancing the
      competitiveness of poor livestock producers. At the same time, governments are
      continuing to face serious budgetary difficulties and are finding it difficult to
      expand the reach of these services or improve service quality. In this context of
      a changing environment and dwindling public resources, this paper revisits the
      economic framework that has thus far guided thinking about public and private
      sector roles in the provision of animal health services and examines the ongoing
      debate on livestock service delivery for the poor. The paper highlights the
      importance of strong institutions and appropriate legislation for regulating
      behaviour and enforcing contracts and re-emphasises the idea, which is supported
      by economic theory, that there is a need for task sharing between the public and
      private sectors. The paper further emphasizes the need for: a) integrating the
      debate on livestock service delivery with the larger debate on political economy
      and institutional development, and b) ensuring service access in poor marginal
      areas by working through membership organisations, self-help groups and civil
      society organisations, and by promoting the use of para-professionals and
      community-based animal health delivery systems.

PMID- 15200087
TI  - Mechanisms for collaboration between public and private veterinarians: the animal
      health accreditation mandate.
AB  - There are several examples of national collaboration between official Veterinary
      Services and the private sector, in both developed and developing countries. In
      developed countries national veterinary systems tend to have a 'centripetal'
      structure: from the private to the somewhat centralised public system, whilst in
      developing countries there is currently the reverse, i.e. a 'centrifugal'
      movement. Faced with international quality requirements for national Veterinary
      Services, the institutional foundations for the execution of certain official
      activities by the private sector are provided by the OIE (World organisation for
      animal health), particularly in the Terrestrial Animal Health Code. The private
      sector should however be employed using clear formal procedures governed by
      various legally recognised systems. At this level, the animal health
      accreditation mandate has the advantage of combining within a single concept
      several legal benefits associated with each type of collaboration. Moreover, it
      can encourage private veterinarians to work in the field, and to continue to do
      so for a reasonable length of time, thus providing a de facto territorial network
      of competent, logistically independent professionals, acting as ad hoc public
      service agents for both the design and implementation of animal health related
      activities, all at an economic cost that does not compromise the budget of the
      national Veterinary Services. By making savings in terms of human and material
      resources, the animal health accreditation mandate appears to be particularly
      suitable for developing countries where means of communication and intervention
      often come up against unforeseen logistical difficulties.

PMID- 15200088
TI  - [Relations between official and private veterinary services in epidemiology and
      the control of contagious diseases].
AB  - Growing budget restrictions in many countries have meant that official Veterinary
      Services cannot assume responsibility for any new activities. The natural
      reaction is to turn to private veterinary services to provide the support needed
      to strengthen the control and surveillance of priority diseases and thereby
      support the development of the livestock sector and the establishment of safe
      international trade. In this context, official Veterinary Services must work
      together with private veterinarians, delegating various technical animal health
      activities, so that they may focus their efforts on those tasks that cannot be
      delegated: standardisation, control, auditing, general system co-ordination,
      epidemiological surveillance, etc., as well as organising veterinary policy in
      order to make best use of budget resources. For these relations to be efficient,
      a dynamic, two-way epidemiological information mechanism must be created, whereby
      private veterinarians periodically keep governments informed, on the basis of an
      agreed methodology. Moreover, the official Veterinary Services must
      systematically transmit information on List A and B diseases of the OIE (World
      organisation for animal health), and perform detailed analyses of
      epidemiologically significant events. The article proposes the establishment of
      relations between public and private veterinary services as a way in which to
      provide the livestock sector with the health and hygiene conditions that are
      necessary for effective disease control, which in turn provides greater security
      for international trade and increased consumer protection.

PMID- 15200089
TI  - Working towards compliance with international standards.
AB  - Developing countries are increasingly coming under pressure to improve their
      delivery of veterinary services as a prerequisite for entering the competitive
      arena of international trade in animals and animal products. The demands placed
      on developing countries by predominantly developed countries to comply with
      international disease prevention standards have also resulted in increasing
      demands on the financial, human and technological resources of these developing
      countries. The minimum requirements of the Agreement on the Application of
      Sanitary and Phytosanitary Measures and the standards, guidelines and
      recommendations of international standard-setting organisations, such as the OIE
      (World organisation for animal health), are evaluated in terms of the
      opportunities embedded within these guidelines for developing countries. Such an
      evaluation indicates that the rights and obligations contained in these
      standards, guidelines and recommendations do not necessarily protect only the
      interests of developed countries but also encourage developing countries to work
      towards the levels of compliance and disease prevention required by their
      potential trade partners. The costs of this compliance can be reduced by
      exploiting more cost-effective alternatives for delivering services, when
      dictated by budgetary constraints. International organisations have illustrated
      on many occasions, and through a variety of development programmes, that they do
      indeed realise their responsibility towards developing countries in the areas of
      increased capacity building and technical assistance. If international
      organisations can refocus their interventions on the actual and specific needs of
      developing countries, then they can help to expedite the process of compliance
      with international standards.

PMID- 15200090
TI  - Adapting veterinary infrastructures to meet the challenges of globalisation and
      the requirements of the World Trade Organization Agreement on Sanitary and
      Phytosanitary Measures.
AB  - To maximise the benefits of globalisation, countries and their stakeholders must
      become familiar with and adhere to the rights and obligations set out by the
      World Trade Organization under the Agreement on Sanitary and Phytosanitary
      Measures. Furthermore, for trade in animals and animal products, they must adhere
      to the standards, guidelines and recommendations established by the OIE (World
      organisation for animal health), which also encourages participation of countries
      in the standard-setting process. Only after implementing these requirements and
      strengthening veterinary infrastructures and surveillance and monitoring systems,
      will countries be able to fully benefit from the new international trade rules.

PMID- 15200091
TI  - Synergies between veterinarians and para-professionals in the public and private
      sectors: organisational and institutional relationships that facilitate the
      process of privatising animal health services in developing countries.
AB  - The delivery of veterinary services in most developing countries was, until
      recently, considered to be the responsibility of the public sector. However, over
      the past four decades, economic constraints and the imposition of structural
      adjustment policies (SAPs) have led to a gradual decline in public sector
      investment in real terms and thus a reduction in the quality and quantity of
      services available to livestock keepers. Many governments acknowledged that they
      were no longer able to provide services that were essentially of a 'private good'
      nature and introduced radical policy changes which sought to introduce the
      concepts of a market orientated approach towards agriculture and livestock
      production in particular. The role of government, in the future, would be to
      provide a reduced range of essential 'public good' services and to create a
      favourable environment in which the private sector could become established as a
      provider of 'private good' services and at the same time act as a partner in
      carrying out certain public functions under contract or 'sanitary mandates'. In
      almost all developing countries, however, these policy changes were not
      accompanied by appropriate development strategies. The reasons for this are
      complex. Firstly, SAPs may be considered to have been foisted upon governments by
      donors and are thus perceived by many policy-makers as the cause of financial
      problems, rather than a solution to them. Secondly, most animal health senior
      policy-makers in the public sector have been trained as veterinarians and lack
      the required management skills to plan change effectively. Furthermore, as
      regards clinical veterinary service delivery, especially in rural or more remote
      areas, the solution fostered by donor investment, which involves deregulation and
      the deployment of privately operating para-professionals, is often perceived as a
      threat to the veterinary profession and might result in limiting access to
      international markets for the trade of livestock and livestock products. An
      informal delivery system has gained a foothold in many developing countries in
      the absence of a well-planned strategy for the privatisation of animal health
      services. Most governments would now acknowledge that this presents a greater
      risk than the deployment of well-regulated and effectively supervised para
      professionals. This paper explores some of the principal challenges facing policy
      makers in their efforts to bridge the transition from full state provision of
      animal health services to the formation of a partnership with the private sector.
      Governments and donors need to take active steps to facilitate the process of
      privatisation of animal health services, especially those targeting the poorer
      rural subsistence and pastoralist farming systems. This would entail an initial
      investment in developing the necessary management skills at all levels in the
      delivery system. Thereafter, further investment would be required to allow the
      changes to be managed using tools such as the strategic planning cycle. Should
      sufficient resources be made available to allow the full participation of all
      stakeholders in the delivery of animal health services, appropriate institutions
      and effective organisational relationships addressing all the more important
      issues will have to be identified. The paper then proceeds to describe how
      different livestock production systems determine the level of demand for animal
      health services. If these services are to be provided on a financially
      sustainable basis, they must be tailored to meet actual rather than perceived
      demand. Identifying an appropriate model for animal health service delivery thus
      requires careful analysis of the production system to be targeted. Governments
      and donors can play a useful role in providing resources for this type of study
      as well as for appropriate market studies, business planning, training and access
      to soft loans. Finally, as regards regulation, as the law stands today, many
      activities currently practised by para-professionals are classified as 'acts of
      veterinary medicine or surgery' and may only legally be performed by qualified
      and registered veterinarians. The concept of 'principal' and 'subsidiary'
      legislation provides the necessary flexibility in the regulation of the delivery
      of animal health services to accommodate the rapid changes taking place in this
      environment today. Deregulation involves the delegation of responsibility for the
      performance of a defined range of veterinary interventions to para-professionals
      under the 'supervision' or 'direction' of a registered veterinarian. The author
      illustrates how the experiences of a number of projects in Tanzania were used to
      propose a definition of 'supervision' in law. The definition offers an
      opportunity to overcome the fear of compromising standards of delivery of animal
      health services through the deployment of para-professionals. In addition, such
      functioning provides employment opportunities for private veterinarians in rural
      areas where access to formal primary animal health services would otherwise be
      denied and may contribute to the process of quality assurance of national
      veterinary services in developing countries.

PMID- 15200092
TI  - [Disease monitoring and surveillance systems and the role of public and private
      animal health agents: the experience of Africa].
AB  - The current importance of animal diseases, and their emergence or re-emergence,
      show that surveillance is crucial for defining suitable control measures.
      Surveillance systems rely on networks of different people, whose activities
      include collecting, transmitting, analysing and disseminating disease
      information. These activities can be distributed among both the public and
      private sectors. However, nowadays it is essential to clearly define the
      different roles of the public and private sectors. In Africa, where budget cuts
      for state Veterinary Services over a number of years have promoted the growth of
      private veterinary medicine, the tasks of public officials (veterinarians,
      technicians, etc.) and private sector workers (veterinarians, livestock farmers)
      must be clearly determined and harmonised. This article presents and comments
      upon a number of different experiments that various sub-Saharan African countries
      have conducted in this field.

PMID- 15200093
TI  - [Links between non-professional agents and the official Veterinary Services in
      sub-Saharan Africa].
AB  - Para-professional agents known as auxiliaries, or community animal health
      workers, provide low-cost basic veterinary services to communities of livestock
      producers. A 2003 survey of 16 Sub-Saharan African countries, carried out as part
      of the Pan-African Programme for the Control of Epizootics, showed that in the
      majority of cases, the official Veterinary Services have no (or very few) links
      with the auxiliaries, although they are well aware of their existence and in some
      cases the auxiliaries have been trained by officials of the Veterinary Services.
      However, there are isolated cases of countries establishing more formal links,
      for example, recognising the status of an auxiliary, recognising auxiliaries with
      no definition of a status, attaching auxiliaries to Veterinary Service staff,
      establishing agreements for the provision of auxiliary services through livestock
      producer associations, harmonising auxiliary training programmes, issuing
      professional auxiliary cards, and setting up a consultation framework on the
      issue of auxiliaries. Unlike private veterinarians, agents of the official
      services do not generally perceive auxiliaries as competitors, and sometimes
      collaboration develops at this level. The authors propose several measures to
      improve links between the official Veterinary Services and auxiliaries, as
      follows: the fields of competence of auxiliaries should be defined and their
      curriculum harmonised, the status of auxiliaries should be recognised, a
      monitoring and assessment mechanism should be established at senior level in the
      Veterinary Services, training for livestock producers should be improved.

PMID- 15200094
TI  - [Livestock producer participation in the control of epizootics in developed
      countries: the experience of France].
AB  - Based on the French experience of animal health defence groups (groupements de
      defense sanitaire), the author highlights the importance, for both Veterinary
      Services and livestock producers, of livestock producer health organisations
      acting as partners of the Veterinary Services to complement the actions of
      private veterinarians. Charged with the task of providing livestock producers
      with information and raising awareness of the health regulations, these
      organisations offer key support to Veterinary Services in carrying out regulatory
      prophylactic measures, monitoring their execution, supplementing public
      compensation measures, and even being delegated to manage all or part of such
      prophylactic measures. By designing and implementing plans, with the support of
      private veterinarians, to combat or control epizootics which have an economic or
      trade impact, and by participating in or carrying out animal identification and
      offering health and environmental services, these organisations help to improve
      herd health and support the livestock producing industry. Growing demand, from
      both European Union applicant members and countries to the south, shows that
      although the French experience is not transposable, it can serve as a useful
      example.

PMID- 15200095
TI  - [Combating foot and mouth disease in Brazil: private sector participation].
AB  - The fact that cattle herds in Brazil are in such good health and that the meat on
      the domestic and international markets is safe and of high quality is largely due
      to the campaign to combat foot and mouth disease and to the improvements that
      this campaign has made in the organisation of the Brazilian bovine production
      industry. Launched in 1965, the campaign set itself ambitious objectives, but
      thanks to the direct participation of producer organisations it received the
      necessary support and funding. The results are reflected in the growing number of
      states--fifteen to date--that are internationally recognised as free from foot
      and mouth disease with vaccination. Thanks to the active participation of
      producers and of the entire production chain in foot and mouth disease
      eradication efforts, Brazil has risen to become a leading player in the
      international beef trade.

PMID- 15200096
TI  - Quality control of the private veterinary profession in The Netherlands.
AB  - It was as early as the 19th Century when attempts were first made to organise the
      veterinary profession in The Netherlands into a professional association. Since
      then, the Royal Veterinary Association of The Netherlands has developed into an
      organisation which fully promotes the interests of the profession. From the
      beginning, the issues of professional standards and veterinary legislation were
      given high priority, and codes of conduct were established with the aim of
      improving the quality of professional veterinary practice. Having some form of
      independent regulatory body has always been important for maintaining these
      professional standards, even if history has taught us that establishing such
      independent testing and sanctioning facilities is a laborious process that
      requires perseverance and patience. By organising the control of animal diseases
      and promoting public health (e.g. meat inspection), the veterinary profession has
      always had a key role to play in the food production industry, and quality
      control programmes that monitor the food production chain now make use of
      veterinary surgeons tested by external organisations. To avoid any semblance of a
      conflict of interest, a new organisational structure has been developed recently:
      the Veterinary Quality Organisation (VKO: Veterinair Kwaliteits Orgaan). The VKO
      maintains the register of qualified veterinarians, upholds standards and
      organises the independent quality control of the profession.

PMID- 15200097
TI  - [The role of the Order of Veterinarians in the quality control of private
      veterinarians in France].
AB  - Instituted by the law of 23 August 1947, the missions of the Order of
      Veterinarians include monitoring compliance by all of its members (private
      veterinarians) with their professional obligations and with the rules laid down
      bythe Code of Practice of the profession. This code provides a national guide to
      good practice with which private veterinarians must comply, both in their
      personal behaviour and in their relations with their colleagues, the
      administration and their partners. Any violation of the provisions of the Code
      may result in disciplinary procedures being invoked by the administrative and
      judiciary authorities, or by any other interested person. This procedure leads to
      sanctions ranging from a warning to ten years suspension. In order to carry out
      its monitoring task, the Order needs to know the precise number and quality of
      its members and must then assess the quality of the service provided by these
      professionals in terms of respect for the Code of Practice. The Order must audit
      the competence of veterinarians, throughout their lives, by means of a continuing
      quality assurance mechanism for ongoing assessment of their knowledge; this
      mechanism has yet to be created. Finally, the Order must constantly listen to
      users of the profession, who must be provided with the best service at the lowest
      cost.

PMID- 15200098
TI  - [The National Order of Veterinary Doctors of Madagascar and the quality control
      of private veterinarians].
AB  - Veterinary medicine was introduced into Madagascar with the arrival of French
      settlers in the early 1900s. At first, veterinary practitioners were all French,
      and they trained Madagascan veterinary auxiliaries. The first Madagascan
      veterinarians were trained in French veterinary schools. The idea of organising
      the profession dates back to the 1970s, but only in 1991 was the Animal Health
      Law, covering the veterinary profession, adopted by the National Assembly; it was
      promulgated by President Ratsiraka on July 25 of that same year. Thus, the
      National Order of Veterinary Doctors of Madagascar (ONDVM: Ordre national des
      docteurs veterinaires malagasy) was instituted by a decree in February 1992. All
      veterinarians and paraprofessionals were employed in the public sector at the
      time and this new structure proved vital for the private exercise of the
      veterinary profession. With the adoption of a new national livestock policy,
      vaccination against major cattle and swine diseases became a profitable activity.
      One of the objectives of the sectoral livestock programme was that a total of 90
      new posts for veterinarians should be created and located throughout the
      different regions and rural townships of the country. The Centre de promotion
      veterinaire (Centre for Veterinary Promotion), which was created in 1992, was the
      organisation charged with carrying out this task. In 1998, once the private
      veterinarians were installed, a survey was undertaken with the aim of making an
      exhaustive assessment of all private veterinarians, collecting data from the
      public veterinary stations in zones covered by private veterinarians, and
      establishing a programme of disengagement and withdrawal of the decentralised
      services, particularly the public veterinary stations. More recently, the
      Administration and the ONDVM have been facing various organisational problems,
      notably with regard to the different levels of animal health staff working in the
      field. Thus, the Order is currently waging a mobilisation and awareness campaign
      for the adoption of a new animal health law. All new measures would be aimed at
      strengthening the management of artificial insemination centres and border
      protection and improving the work of all those involved in animal health:
      official and private veterinarians and members of the Order of Veterinary Doctors
      and the Order of Veterinary Paraprofessionals.

PMID- 15200099
TI  - The inception and development of basic animal health systems: examples of German
      development co-operation.
AB  - About thirty years ago the financial, logistic and manpower resources of
      veterinary and animal production services in the developing world were stretched
      to the limit. Epizootic disease control was their main and often only field
      activity, which left livestock owners to manage their daily production and health
      problems alone. To meet their requirements, Veterinary Services in these
      countries came under increasing public and political pressure to modify and
      adjust their approaches. This gave rise to a series of workshops in Africa (e.g.
      Bujumbura in Burundi and Blantyre in Malawi) and South-East Asia (e.g. Singapore,
      and Khon Kaen in Thailand), most of which were organised and facilitated by the
      German Agency for Technical Co-operation (GTZ) in close collaboration with French
      and British development co-operation agencies and universities. These workshops
      stimulated discussion with the key stakeholders and, thus, were most beneficial
      in supporting the process of developing alternative approaches. This paper
      reports in particular on the outcomes of the regional workshops held in
      Bujumbura, Burundi, in 1984, Blantyre, Malawi, in 1985, Bangui, Central African
      Republic, in 1988, Khon Kaen, Thailand, in 1989, Schmitten, Germany, in 1991, and
      Mzuzu, Malawi, in 1996 and 2000. For more than two decades, concepts of community
      based livestock services in general, and primary animal health activities (PAHAs)
      in particular, have been developed and established in various developing
      countries. Over the years the PAHA concept has proved to be effective and has
      shown that livestock-keeping communities clearly benefit from such programmes. In
      presenting key features from some prominent and successful project examples (GTZ
      supported projects in Thailand, Malawi and Somalia) it can be demonstrated that
      such approaches are not static but rather dynamic, requiring open minded
      innovative partners on both sides. Over the last few years, the delivery of PAHA
      has become the domain of non-governmental organisations. The propagation and
      application of this approach in various developing countries with limited
      veterinary infrastructure is supporting a privatisation process within the
      existing governmental veterinary structures, thus, allowing veterinary
      departments more freedom to focus on their core functions.

PMID- 15200101
TI  - The effectiveness of community-based animal health workers, for the poor, for
      communities and for public safety.
AB  - The development of community animal health (CAH) is an invaluable tool for
      addressing a series of challenges, particularly for the policy-maker, whose prime
      concern is public welfare. This paper examines three of the major challenges
      which confront governments, particularly the governments of less-developed
      countries, namely, the collapse of government services, the crucial issue of
      poverty reduction and the misuse of animal drugs. Although CAH is a potentially
      powerful tool for approaching all of these problems, the authors argue that CAH
      can only be fully exploited on a macroscopic level by developing strong
      institutions to support and regulate such community initiatives. In some
      countries, developing such institutions depends upon accepting the more
      fundamental and controversial principle of legalising non-professional animal
      health service providers who work within the private sector. In Section 1, the
      authors outline the three principal challenges which face governments,
      particularly in developing countries, and to which CAH offers a potential
      solution. Sections 2 to 4 investigate the evidence relating to each of these
      challenges in turn. Section 5 briefly draws on the lessons that have been
      generated by field experiences over the years, to propose how governments may
      develop CAH systems to their best advantage.

PMID- 15200100
TI  - Para-veterinary professionals and the development of quality, self-sustaining
      community-based services.
AB  - Livestock are a major asset for rural households throughout the developing world
      and are increasingly regarded as a means of reducing poverty. However, many rural
      areas are characterised by limited or no accessibility to veterinary services.
      Economic theory indicates that primary level services can be provided by para
      veterinary professionals working as private operators and as an outreach
      component of veterinary clinics and pharmacies in small urban centres. Experience
      from the development of community-based animal health worker (CAHW) systems
      indicates that these workers can have a substantial impact on livestock morbidity
      and mortality through the treatment or prevention of a limited range of animal
      health problems. Factors for success include community involvement in the design
      and implementation of these systems, and involvement of the private sector to
      supply and supervise CAHWs. Examples of privatised and veterinary supervised CAHW
      networks are cited to show the considerable potential of this simple model to
      improve primary animal health services in marginalised areas. An analysis of
      constraints indicates that inappropriate policies and legislation are a major
      concern. By referring to the section on the evaluation of Veterinary Services in
      the OIE (World organisation for animal health) Terrestrial Animal Health Code,
      the paper proposes guidelines to assist governments in improving the regulation,
      quality, and co-ordination of privatised, veterinary supervised CAHW systems.

PMID- 15200102
TI  - Traditional livestock healers.
AB  - Traditional 'animal doctors' are a substantial component of livestock healthcare
      systems in developing countries. However, in contrast to their counterparts in
      human ethnomedicine, such healers and their roles have been largely ignored by
      the modern veterinary community. While sometimes used as informants for community
      based animal healthcare projects, traditional healers are rarely integrated into
      project training and delivery systems, and in many countries, they work in legal
      limbo. This paper overviews the little that is known about traditional livestock
      healers and their practices and argues that they represent a valuable, but as yet
      untapped, resource for extending many aspects of basic animal healthcare,
      especially to poor and smallholder producers in remote or difficult environments.
      Finally, the authors suggest broad steps for integrating these healers into
      conventional systems.

PMID- 15200103
TI  - Afghanistan and the development of alternative systems of animal health in the
      absence of effective government.
AB  - This case study describes the efforts by both non-governmental organisations and
      United Nations agencies to develop an alternative system for delivering animal
      health services in Afghanistan, during a period in which there was effectively no
      government. The authors examine the period from the mid-1980s to the year 2003.
      During this time, Afghanistan experienced war and severe civil unrest, resulting
      in the collapse of the veterinary infrastructure. As most trained animal health
      professionals had fled the country, an initial emphasis was placed on training
      intermediate and lower-level veterinary auxiliary personnel, as well as on the
      implementation of emergency treatment and vaccination campaigns. Gradually this
      programme has developed from an emergency-oriented approach to a more development
      oriented process, resulting in a community-based system of animal health care in
      more than 250 districts (out of approximately 360). Some 500 paraveterinarians,
      trained for a period of five months, play a pivotal role in this programme,
      supported in outlying villages by trained vaccinators and basic veterinary
      workers. In this paper, the authors present an estimation of the impact of this
      programme. Essential elements of the programme are, as follows: the recruitment
      of trainees from areas where need has been identified; an emphasis on practical
      and problem-oriented training; the deployment of staff in so-called 'veterinary
      field units', supervised by more highly qualified staff and monitors; a
      guaranteed supply of veterinary medicines, anthelmintics and vaccines; a
      gradually increasing rate of cost recovery. The ultimate objective of the
      programme is to establish a self-sustaining system, based on the 'user-pays'
      principle. The paper concludes by describing the present-day problems of the
      animal health infrastructure in Afghanistan. Not only must the new government try
      to regain its central position, it must also assimilate two decades of
      development in the veterinary sector, which has occurred largely outside
      governmental control.

PMID- 15200104
TI  - The emerging animal health delivery system in the People's Republic of China.
AB  - Livestock production in the People's Republic of China has expanded at an
      unprecedented rate over the last decade and this trend is expected to continue
      into the foreseeable future. Government and private sector investment supports
      this growth, and the fact that small farmers are incorporating more animal
      husbandry into their work is expected to mitigate some of the concerns over
      recent World Trade Organization accession, particularly in the more precarious
      grain growing regions. Modernisation and intensification of the livestock
      industry in the People's Republic of China is subject to significant risks as
      regards both infectious and production-related diseases and within the framework
      of food safety and public health challenges. Although historically, the
      veterinary service system in the People's Republic of China has been successful
      in the eradication and control of major disease outbreaks, domestic and
      international market concerns are providing the catalyst for significant reforms
      in the animal health delivery system in the country. This paper provides an
      overview of the existing veterinary system in terms of the education and
      qualifications of veterinary personnel, delivery mechanisms, and future
      approaches to reforming the system in the context of a dynamic livestock industry
      in transition.

PMID- 15200105
TI  - Eastern Europe and the former Union of Soviet Socialist Republics: animal health
      systems in transition.
AB  - The economic transition in Eastern Europe and the former Union of Soviet
      Socialist Republics (USSR) during the last decade has profoundly changed the
      agricultural sector and the well-being of people in rural areas. Farm ownership
      changed; selected farm assets, including livestock, were transferred to farm
      workers or others, and the social and service structures of rural society are in
      a state of uncertainty. The transition has, in general, led to the deterioration
      of rural services. Animal health services have also deteriorated. This decline is
      associated with the contraction of the livestock inventory, the fragmentation of
      farms, higher transaction costs for service providers, and the overall decline of
      the rural economy which has, so far, lowered the demand for animal health
      services. There are considerable differences in the way that these countries are
      coping with the economic transition and its aftermath. Among the determining
      factors in the former USSR are, as follows: the speed of recovery from the
      legacies of large State-controlled farming and a centrally planned animal health
      system, the efforts made to address poverty reduction, the choice on whether to
      become a Member of the World Trade Organization and the requirements of such
      membership, the ability to provide low-cost services to a fragmented and
      unskilled livestock production sector. In Eastern Europe, the requirements for
      joining the European Union (EU) are an additional and important determining
      factor. In the short term, the choice of a veterinary system to serve the
      livestock sector may differ from country to country, depending on the legacies of
      the past, the status of reforms and the proximity of Western markets. Lower
      income countries with an oversupply of veterinarians may support labour
      intensive, low-cost systems which focus on food security and public health. The
      better-endowed EU accession countries may focus rather on improved disease
      surveillance, production enhancement, quality assurance and increased food
      safety. Such choices may also determine the investment made by these countries in
      upgrading their State system, laboratories and veterinary education facilities.

PMID- 15200106
TI  - Privatisation of veterinary services in Jamaica: a case study.
AB  - Clinical veterinary services were privatised in Jamaica in September 1992. Using
      the limited official data, the authors briefly examine the premise and logistics
      behind transferring the responsibility for clinical services, which may be
      regarded as 'a private good', to private veterinary practitioners. There are
      indications that this privatisation model can work for farmers, despite financial
      problems in the livestock industry and a decline in production, caused by trade
      liberalisation policies and the substitution of cheaper imports. In addition,
      other national fiscal problems, such as a downturn in the economy, have left
      veterinarians attempting to boost production in a livestock industry which lacks
      adequate financial structuring and resources. The authors express concern that
      various unpublished projections since the last official agricultural survey in
      1996 indicate that the livestock industry in Jamaica is diminishing. It is
      possible that valuable genetic breeding stock may never recover. A comprehensive
      study of the future of the livestock industry and its associated services is
      strongly urged. Ten years after the event, the authors reflect on the
      privatisation of clinical veterinary services in Jamaica and offer some
      suggestions to improve on the quality of the services offered by private
      veterinary practitioners.

PMID- 15200107
TI  - Kenya: the development of private services and the role of the Kenya Veterinary
      Association.
AB  - Private veterinary practice has existed in Kenya for more than half a century.
      Between the early 1930s and the mid-1960s, provision of clinical and advisory
      services almost entirely involved servicing commercial ranches and dairy farms.
      The Department of Veterinary Services (VSD) was mainly responsible for providing
      regulatory services in these areas. Until the mid-1960s, public sector veterinary
      responsibilities were predominantly associated with the prevention of notifiable
      diseases outside the commercial farming areas. In a major agrarian reform
      programme initiated in 1954, Kenya initiated an aggressive campaign promoting the
      dairy industry in the wetter areas of the country among small-scale farmers. In
      an effort to encourage dairy development, the VSD decided to provide some
      services, mainly tick control and subsidised artificial insemination. This
      support had a great positive impact on the 'smallholder' dairy industry. After
      the end of the colonial administration in 1963, most private practitioners left
      the country. A decision was therefore taken to transfer the responsibility of
      providing services of a 'private goods' nature, such as clinical services,
      temporarily to the public sector through the VSD. This was accompanied by
      significant expansion of training and the deployment of both professional
      veterinarians and para-professionals. By 1988, personnel costs had escalated to
      over 80% of the recurrent budget, leaving little for operational costs. This
      necessitated a policy change, which led to decreased government involvement in
      the delivery of animal health services. The private sector, as expected,
      responded appropriately to the change in policy. The Kenya Veterinary Association
      (KVA) launched a privatisation scheme (the Kenya Veterinary Association
      Privatisation Scheme) in 1994 to provide members with credit to set up private
      practices. The first phase of the scheme (1994-1996) was rated a success, with
      100% loan repayments. The second phase of the project (from 1997) was
      characterised by a low number of loan applications, which increased the cost of
      loan administration per unit. There was some defaulting in loan repayments during
      this phase. While private veterinary practice took root in the high rainfall,
      intensive farming areas, this was not the case in the arid and semi-arid lands
      (ASAL), where community-based animal health workers (CAHWs) played a prominent
      role in providing animal health services. The lack of uniformity in the training
      of these workers denied them recognition by the Kenya Veterinary Board (KVB). An
      agreement has now been reached between the KVB, the Director of Veterinary
      Services and the KVA to discontinue the training of CAHWs and to retain and
      retrain existing workers for disease surveillance and reporting in ASAL areas. In
      conclusion, private veterinary practice has been successful in areas of high
      agricultural potential. Expansion to more marginal areas, however, would require
      incentives or subsidies.

PMID- 15200108
TI  - [Successful privatisation of para-professional services in traditional livestock
      farming systems: the case of Senegal].
AB  - In Senegal, after nearly a decade of experimenting with various privatisation
      projects, the process of privatising veterinary service provision and empowering
      producers has become more stable and is now considered irreversible. The means
      used to satisfy animal health service needs and to develop animal production have
      become a key factor in poverty reduction strategies. Legislation concerning the
      veterinary profession has encouraged inexorable growth in the establishment of
      private veterinarians and para-professionals, thanks to the financing mechanisms
      that international institutions have promoted and funded. The new legal framework
      has led to a general liberalisation of veterinary medicine and of the importation
      and distribution of veterinary products.

PMID- 15200109
TI  - An assessment of the strengths and weaknesses of current veterinary systems in
      the developing world.
AB  - The changes that veterinary services have undergone in the developing world over
      the last two decades are expected to continue and result in the further
      privatisation of selected tasks, the decentralisation of decision-making and a
      move towards more focus on public goods service delivery by State veterinary
      units. At the same time, global food consumption patterns are changing in
      numerous ways, which will certainly affect veterinary services delivery systems.
      These changes include a trend towards increasing globalisation, rapidly
      escalating consumer demand for animal protein, intensification of livestock
      production into larger units and growth of the trade of livestock and livestock
      products. Intensification of livestock production into larger units and global
      trade will increase the challenges resulting from the resurgence of serious
      animal diseases, food safety hazards and veterinary public health-related
      problems. Facing and managing these challenges raises issues related to animal
      health delivery systems and national policies that will have to be addressed.
      Strengthening the capacity of State veterinary units to respond to regulatory
      responsibilities dictated by national laws and international World Trade
      Organization and OIE (World organisation for animal health) health standards will
      be at the centre of animal health policies in most developing countries. Creating
      an environment which facilitates privatised service delivery and supports
      subcontracting is likely to contribute to improving economic efficiency and
      providing wider access to veterinary services. Equally important is the issue of
      professional development, which must be addressed by refocusing veterinary
      curricula and improving professional standards. The profession will then be in a
      better position to serve the needs of increasing numbers of consumers.

PMID- 15200110
TI  - [Organisation of Veterinary Services in the developing countries of West Africa].
AB  - The Veterinary Services in West Africa focused on animal health and production
      activities, which up until the beginning of the 1990s, were exclusively their
      responsibility. They were supported by many projects, conducted with notable
      successes. Veterinary public health activities were considered to be less of a
      priority because the major objective was improving productivity and because the
      concept of food safety was perceived by stakeholders to be much less important.
      The major challenges and issues that the weakened Veterinary Services will have
      to face are complying with the requirements of the World Trade Organization,
      negotiating new economic partnership agreements and dealing with the consequences
      of the implementation of structural adjustment programmes in the agricultural
      sector. The reorganisation of these Services is therefore taking place in the
      context of the globalisation of health problems, and in a trading framework that
      requires the application of the current international standards and regulations.
      Veterinary Services and their governments will have to meet these challenges by
      initiating discussions that lead to effective operational structures that can
      implement public health measures, satisfy the expectations of consumers and
      partner countries and withstand assessment by other countries. However, such
      reform depends upon several factors, such as a demonstration of political will,
      the development of an approach based on regional economic unions, and the
      indispensable support of financial backers. To add to the debate, the author
      offers recommendations and guidelines on the institutional framework, veterinary
      personnel and equipment and material needs. Creating effective Veterinary
      Services that have efficient operational structures and procedures is an ongoing
      process; how long this process takes depends on the ability of Veterinary
      Services to respond to the various challenges. Underlying these challenges and
      issues, in this region of the world as elsewhere, is the possibility of official
      Veterinary Services losing their credibility with international trade partners if
      all the procedures governing international trade are not followed.

PMID- 15200111
TI  - [The need for research to support the emergence of alternative animal health
      systems].
AB  - Animal diseases remain one of the main problems for livestock production in terms
      of trade development, poverty reduction and public health. Animal health systems
      are complex because of the diversity of the parties involved and because of
      various changes in the delivery of veterinary services, such as the redefinition
      of the roles of the public and private sectors. It is, therefore, often difficult
      to assess the global performance of animal health systems and sub-systems in
      terms of their medical, economic and social effectiveness. In addition, the
      necessary reliability of the health information obtained leads to certification
      of the status of regions and countries with regard to epizootics, which requires
      a high degree of standardisation and conformity with international norms. An
      assessment therefore needs to be made of the advantages of alternative systems
      compared with conventional systems. An animal health system should be seen as a
      whole, and when assessing its overall performance several things must be taken
      into account, e.g. the markets for products and the sometimes contradictory
      interests of all the different parties involved. There are, therefore, many
      research needs and avenues to be pursued, including: the methods, data and tools
      required for assessing the effectiveness of systems, including a definition of
      what constitutes a reliable indicator; the factors that determine the health of a
      herd; having a clearer idea of what will affect herd health will make it possible
      to map risk indicators and animal health care needs; the design and management of
      realistic and harmonised animal health information systems whose indicators
      provide reliable measurements of health; the function, organisation and
      effectiveness of participative surveillance approaches; the definition and
      effectiveness of animal health contracts, such as health mandates between the
      State and private veterinarians; the function and role of livestock auxiliaries;
      the establishment of assessment methods and standards that take into account the
      specific situation of southern countries that could lead to the certification and
      accreditation of alternative systems. The efficiency of these systems must then
      be tested (direct impact, cost-benefit studies) using the above-mentioned
      indicators, and an implementation 'toolkit' can then be assembled, taking into
      account the local differences which will affect the suitability of each system
      for different locations. Research into the assessment of animal health systems is
      a long-term investment, but it ensures that quality certification is reliable and
      allows for the safe development of animal product markets.

PMID- 15200112
TI  - The adjustment of curricula in veterinary faculties in sub-Saharan Africa.
AB  - A survey was conducted by questionnaire to assess the current undergraduate
      curricula in the veterinary faculties of sub-Saharan Africa. The survey also
      examined how such curricula are adjusted for crucial developments in the
      veterinary field, such as privatisation, decentralisation and globalisation, with
      the increasing risk of transboundary diseases. The results demonstrate that most
      of these faculties face serious shortages, both in their budgets and of qualified
      personnel. Most faculties do not have formal feedback systems to allow former
      graduates to contribute to periodic reviews of the curricula. Although some north
      south and south-south collaboration exists among African veterinary faculties,
      more intensive regional collaboration at both undergraduate and postgraduate
      level would allow optimal use of the available funds and human resources. The
      creation of a regional veterinary council and a committee of deans would be an
      excellent step forward in ensuring internationalisation and harmonisation of
      veterinary education and establishing a regional accreditation system.

PMID- 15200113
TI  - Intrapelvic and thigh-level femoral nerve lesions: management and outcomes in 119
      surgically treated cases.
AB  - OBJECT: The authors present a retrospective analysis of 119 surgically treated
      femoral nerve lesions at intrapelvic and thigh levels seen at the Louisiana State
      University Health Sciences Center. METHODS: Femoral nerve lesions treated between
      1967 and 2000, (89 traumatic injuries and 30 tumors and cystic lesions) were
      evaluated for injury mechanisms, resulting lesions, surgical management, and
      postoperative functional outcomes by using retrospective chart reviews. The most
      common injury mechanism was iatrogenic (52 cases), which occurred after hernia
      and hip operations (10 each), followed by arterial bypass and gynecological
      procedures (eight each), angiography (seven), abdominal surgery (five),
      appendectomy (two), a laparoscopy, and a lumbar sympathectomy. Other injury
      mechanisms included hip or pelvic fractures (19), gunshot wounds (10), and
      lacerations (eight). The 30 femoral nerve tumors and cystic lesions consisted of
      neurofibromas (16), schwannomas (nine), ganglionic cysts (two), neurogenic
      sarcomas (two), and a leiomyosarcoma. Forty-four patients underwent neurolysis.
      Some had recordable nerve action potentials (NAPs) across their lesions in
      continuity, despite severe distal loss. Others with recordable NAPs had mild
      loss, but also experienced a pain problem, which was helped in some by
      neurolysis. In 36 patients, in whom repairs were performed using long sural
      grafts for mostly proximal pelvic-level injuries, recovery of useful function
      occurred. Eight of nine thigh-level suture repairs led to improvement to good
      functional levels. Most of the tumors and cystic lesions were resected, with
      preservation of preoperative function. CONCLUSIONS: The majority of femoral nerve
      injuries resulted in lesions in continuity, and intraoperative NAP recordings
      were essential in evaluating axonal regeneration across these lesions. Despite
      severe and frequently proximal injury levels requiring repairs with long grafts,
      femoral nerve lesion repairs resulted in good functional recovery.

PMID- 15200114
TI  - The mechanism and effect of chronic electrical stimulation of the globus pallidus
      for treatment of Parkinson disease.
AB  - OBJECT: Although chronic electrical stimulation of the globus pallidus (GP) has
      been shown to ameliorate motor disabilities in Parkinson disease (PD), the
      underlying mechanism remains to be clarified. In this study the authors explored
      the mechanism for the effects of deep brain stimulation of the GP by
      investigating the changes in neurotransmitter levels in the cerebrospinal fluid
      (CSF) during the stimulation. METHODS: Thirty patients received chronic
      electrical stimulation of the GP internus (GPi). Clinical effects were assessed
      using the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr Staging Scale at
      1 week before surgery and at 6 and 12 months after surgery. One day after
      surgery, CSF samples were collected through a ventricular tube before and 1 hour
      after GPi stimulation. The concentration of neurotransmitters such as gamma
      aminobutyric acid (GABA), noradrenaline, dopamine, and homovanillic acid (HVA) in
      the CSF was measured using high-performance liquid chromatography. The treatment
      was effective for tremors, rigidity, and drug-induced dyskinesia. The
      concentration of GABA in the CSF increased significantly during stimulation,
      although there were no significant changes in the level of noradrenaline,
      dopamine, and HVA. A comparison between an increased rate of GABA concentration
      and a lower UPDRS score 6 months postimplantation revealed that the increase in
      the GABA level correlated with the stimulation-induced clinical effects.
      CONCLUSIONS: Stimulation of the GPi substantially benefits patients with PD. The
      underlying mechanism of the treatment may involve activation of GABAergic
      afferents in the GP.

PMID- 15200115
TI  - Radiation-induced meningiomas: clinical, pathological, cytokinetic, and
      cytogenetic characteristics.
AB  - OBJECT: Radiation-induced meningiomas are known to occur after high- and low-dose
      cranial radiation therapy. The goal of this study was to discern the
      distinguishing findings and characteristics of radiation-induced meningiomas.
      METHODS: The records of 16 patients (seven men and nine women) who fulfilled the
      criteria for radiation-induced meningiomas were retrospectively reviewed.
      Clinical, histopathological, cytokinetic, and cytogenetic findings as well as the
      patients' outcome were analyzed. The mean age of the patients was 38.8 years and
      the mean tumor latency was 26.5 years. Five patients had multiple meningiomas in
      the irradiated field. The recurrence rate was 100% after the initial resection;
      62% of patients had a second recurrence and 17% had a third recurrence. Thirty
      eight percent of patients had atypical or malignant histopathological findings.
      The presence of progesterone receptors and low proliferation indices in these
      patients did not correlate with benign tumor behavior. Cytogenetic analysis
      showed multiple clonal aberrations in all tumors studied. The most frequent
      aberrations were found on chromosomes 1p, 6q, and 22. Derivative, lost, or
      additional chromosome 1p was found in 89% of cases and loss or deletion on
      chromosome 6 was found in 67%. CONCLUSIONS: The age of patients at presentation
      with meningioma and the latency period of radiation-induced meningiomas are dose
      related. These tumors are more aggressive and are certain to recur, have a higher
      histopathological grade, and are associated with complex cytogenetic aberrations
      particularly involving 1p and 6q.

PMID- 15200116
TI  - Meningiomas of the posterior petrous bone: functional outcome after microsurgery.
AB  - OBJECT: The aim of this study was to analyze a subgroup of patients harboring
      cerebellopontine angle meningiomas originating from the posterior petrous bone in
      regard to clinical presentation, surgical anatomy, complications, and long-term
      functional postoperative results. METHODS: Data in a series of 51 patients with
      meningiomas of the posterior petrous bone who had undergone microsurgical
      treatment at the authors' institution between 1989 and 2002 were retrospectively
      reviewed. The patient population consisted of 46 women and five men with a mean
      age of 53 years (range 22-70 years). The main symptom on first admission was
      impaired hearing in 41%, dizziness in 20%, and tinnitus in 18% of the patients.
      Results of physical examination and audiological testing revealed hypacusis in
      65% of patients, cerebellar ataxia in 31%, and impairment of the fifth cranial
      nerve in 26%. All patients underwent surgical treatment via a lateral
      suboccipital approach. Intraoperatively, the tumor was found to be attached to
      the postmeatal dura in 37%, the premeatal dura in 27.5%, the suprameatal dura in
      19.6%, the inframeatal dura in 7.8%, and centered on the porus acusticus in 5.9%
      of cases. Tumor extension into the internal acoustic meatus was present in seven
      patients. Tumor resection was categorized as Grade I in 14 patients, Grade II in
      29, Grade III in six, and Grade IV in two patients, according to the Simpson
      classification system. The site of displacement of the cranial nerves was
      predictable in up to 84% of patients, depending on the dural origin of the tumor
      as depicted on preoperative magnetic resonance (MR) imaging studies.
      Postoperatively, a new and permanent facial paresis was observed in five patients
      (9.8%). In 38 patients in whom both pre- and postoperative audiological data were
      available, hearing function deteriorated after surgery in 18.4% and improved in
      7.9%. Clinical and MR imaging postsurgical data from a mean period of 5.8 years
      (range 13 months-13 years) were available in all patients. Forty-four patients
      (86%) resumed normal daily activity. Tumor recurrence was observed in two
      patients (3.9%), and both underwent a second surgery. CONCLUSIONS: Preoperative
      detailed analysis of MR imaging data gives the surgeon a clue about the
      dislocation of critical neurovascular structures, particularly the cranial
      nerves. Nonetheless, the exact relationship of the cranial nerves to the tumor
      (dislocation, adherence, infiltration, and splaying of nerves) can only be fully
      appreciated during surgery.

PMID- 15200117
TI  - Three-dimensional visualization of neurovascular relationships in the posterior
      fossa: technique and clinical application.
AB  - OBJECT: The goal of this study was to describe the authors' technique for three
      dimensional (3D) visualization of neurovascular relationships in the posterior
      fossa at the surface of the brainstem. This technique is based on the processing
      of high-resolution magnetic resonance (MR) imaging data. The principles and
      technical details involved in the accurate simultaneous visualization of vessels
      and cranial nerves as tiny structures are presented using explicit and implicit
      segmentation as well as volume rendering. METHODS: In this approach 3D MR
      constructive interference in steady state imaging data served as the source for
      image processing, which was performed using the Linux-based software tools SegMed
      for segmentation and Qvis for volume rendering. A sequence of filtering
      operations (including noise reduction and closing) and other software tools such
      as volume growing are used for a semiautomatic coarse segmentation. The
      subsequent 3D visualization in which implicit segmentation is used for the
      differentiation of cranial nerves, vessels, and brainstem is achieved by
      allocating opacity and color values and adjusting the related transfer functions.
      This method was applied to the presurgical evaluation in a consecutive series of
      55 patients with neurovascular compression syndromes and the results were
      correlated to surgical findings. The potential for its use, further developments,
      and remaining problems are discussed. CONCLUSIONS: This method provides an
      excellent intraoperative real-time virtual view of difficult anatomical
      relationships.

PMID- 15200118
TI  - Correlation between decreased ventricular size and positive clinical outcome
      following shunt placement in patients with normal-pressure hydrocephalus.
AB  - OBJECT: It is well known that in patients with communicating hydrocephalus or
      normal-pressure hydrocephalus (NPH), ventricular size decreases following
      implantation of shunts with differential pressure valves. The aim of this study
      was to determine whether ventricular size correlates with a positive clinical
      outcome following shunt placement. METHODS: Hydrostatic valves (dual-switch
      valves) were implanted in 80 patients with NPH at Unfallkrankenhaus, Berlin,
      between September 1997 and January 2002. One year postoperatively, these patients
      underwent computerized tomography scanning, and their ventricular size was
      ascertained using the Evans Index. Among 80% of the patients who showed no
      postoperative change in ventricular volume, 59% nonetheless had good to excellent
      clinical improvements, 17% satisfactory improvement, and 24% no improvement.
      Furthermore, a moderate reduction in ventricular size was observed in 14% of
      patients in this cohort. Among these, 36% experienced good to excellent clinical
      improvements, 28% satisfactory improvement, and 36% unsatisfactory improvement. A
      marked reduction in ventricular size was observed in 6% of the patients. Of this
      latter group, 60% demonstrated good to excellent outcomes, whereas 40% had
      unsatisfactory outcomes. CONCLUSIONS: Favorable outcomes following the
      implantation of a hydrostatic shunt in patients with NPH did not correlate with
      decreased ventricular volume 1 year after surgery. In fact, better clinical
      outcomes were observed in patients with little or no alteration in ventricular
      size, compared with those in patients with a marked decrease in ventricular size.
      A postoperative change in ventricular volume should be assessed differently in
      patients with NPH compared with those suffering from hypertensive hydrocephalus.

PMID- 15200119
TI  - Intraaneurysmal flow visualization by using phase-contrast magnetic resonance
      imaging: feasibility study based on a geometrically realistic in vitro aneurysm
      model.
AB  - OBJECT: The aim of this study was to evaluate the feasibility of complex
      intraaneurysmal flow visualization with the currently available phase-contrast
      magnetic resonance (MR) imaging modality. METHODS: A geometrically realistic in
      vitro aneurysm model, in which detailed flow velocity analysis had already been
      conducted using laser Doppler velocimetry was used for this in vitro hemodynamic
      simulation, so that the results of phase-contrast velocity measurements could be
      compared with the previous reliable results. On a 1.5-tesla unit, three
      orthogonal components of velocity were obtained using a standard two-dimensional
      fast low-angle shot flow quantification sequence. Three-dimensional (3D)
      intraaneurysmal flow structures recorded during one cardiac cycle were depicted
      in one midsagittal and three axial cross-sectional planes with the aid of gray
      scale phase-contrast velocity maps. Isovelocity contour maps and secondary flow
      vectors were also created based on the phase-contrast velocity maps by using
      MATLAB software. The isovelocity contours in those three axial sections could
      demonstrate the shapes of inward and outward flow areas and their alternation
      over one cardiac cycle. The secondary flow vectors demonstrated twin vortices
      within the outward flow area adjacent to the boundary layer of inward and outward
      flow in all axial planes. CONCLUSIONS: The phase-contrast MR imaging method was
      able to depict the complex 3D intraaneurysmal flow structures in the in vitro
      aneurysm model. Detailed 3D intraaneurysmal flow information will be obtainable
      in vivo after improvements are made in spatial resolution, which is expected in
      the near future. The capability to visualize intraaneurysmal flow structures
      directly with the use of noninvasive MR imaging technology will have a positive
      impact on future clinical practice.

PMID- 15200120
TI  - Recombinant vesicular stomatitis virus vectors as oncolytic agents in the
      treatment of high-grade gliomas in an organotypic brain tissue slice-glioma
      coculture model.
AB  - OBJECT: The purpose of this study was to evaluate both replication-competent and
      replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as
      therapeutic agents for high-grade gliomas by using an organotypic brain tissue
      slice-glioma coculture system. METHODS: The coculture system involved growing
      different brain structures together to allow neurons from these tissues to
      develop synaptic connections similar to those found in vivo. Rat C6 or human U87
      glioma cells were then introduced into the culture to evaluate VSV as an
      oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt)
      rapidly eliminated C6 glioma cells from the coculture, but also caused
      significant damage to neurons, as measured by a loss of microtubule-associated
      protein 2 immunoreactivity and a failure in electrophysiological responses from
      neurons in the tissue slice. Nonetheless, pretreatment with interferon beta
      (IFNbeta) virtually eliminated VSV infection in healthy tissues without impeding
      any oncolytic effects on tumor cells. Despite the protective effects of the
      IFNbeta pretreatment, the tissue slices still showed signs of cytopathology when
      exposed to rVSV-wt. In contrast, pretreatment with IFNbeta and inoculation with a
      replication-restricted vector with its glycoprotein gene deleted (rVSV-deltaG)
      effectively destroyed rat C6 and human U87 glioma cells in the coculture, without
      causing detectable damage to the neuronal integrity and electrophysiological
      properties of the healthy tissue in the culture. CONCLUSIONS: Data in this study
      provide in vitro proof-of-principle that rVSV-deltaG is an effective oncolytic
      agent that has minimal toxic side effects to neurons compared with rVSV-wt and
      therefore should be considered for development as an adjuvant to surgery in the
      treatment of glioma.

PMID- 15200121
TI  - Cooperative function of Chk1 and p38 pathways in activating G2 arrest following
      exposure to temozolomide.
AB  - OBJECT: The Chk1 and p38 mitogen-activated protein kinase (MAPK) pathways play
      key roles in the G2 arrest caused by exposing glioma cells to temozolomide (TMZ).
      Although inhibition of either pathway sensitizes glioma cells to TMZ-induced
      cytotoxicity, the relative contributions of these pathways to TMZ-induced G2
      arrest and to TMZ resistance conferred by G2 arrest have not been defined.
      METHODS: The authors pharmacologically inhibited the Chk1 and/or p38 pathways in
      U87MG human glioma cells prior to and/or after exposure to TMZ; thereafter,
      effects on the TMZ-induced G2 arrest pathway and toxicity were monitored. The p38
      inhibitor SB203580 or the Chk1 inhibitor UCN-01 or their combination blocked TMZ
      mediated inactivation of cdc25C and cdc2, suggesting that p38 and Chk1 pathways
      work cooperatively and are both necessary to inactivate cdc25C and cdc2.
      Consistent with this idea, the inhibition of both Chk1 and p38 pathways did not
      lead to greater bypass of TMZ-induced G2 arrest or greater cytotoxicity than
      inhibition of either pathway alone. Inhibition of p38 did not alter TMZ-induced
      Chk1 activation/phosphorylation and vice versa, suggesting that p38 and Chk1 do
      not cooperatively bring about G2 arrest by reciprocal activation/phosphorylation.
      The two pathways, however, are not functionally identical; the Chk1 pathway was
      required for both the initiation and maintenance of TMZ-induced G2 arrest,
      whereas the p38 pathway played a role only in the initiation. CONCLUSIONS: The
      Chk1 and p38 pathways cooperate to bring about TMZ-induced G2 arrest, and the
      inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells
      to TMZ-induced cytotoxicity.

PMID- 15200122
TI  - Involvement of epidermal growth factor receptor-protein tyrosine kinase
      transactivation in endothelin-1-induced vascular contraction.
AB  - OBJECT: Endothelin-1 (ET-1) is one of the major inducers of vasospasm following
      subarachnoid hemorrhage (SAH). It is generally accepted that extracellular signal
      regulated kinase 1 and 2 (ERK1/2) are involved in ET-1-induced vascular
      contraction. In addition, ET-1 transactivates epidermal growth factor receptor
      (EGFR) protein tyrosine kinase (PTK), which leads to ERK1/2 stimulation.
      Therefore, the authors examined whether EGFR-PTK transactivation contributes to
      ET-1-induced vascular contraction in this study. METHODS: Mitogen-activated
      protein kinase inhibitor, PD98059, inhibited ET-1-induced ERK1/2 stimulation in
      rabbit basilar artery (BA) vascular smooth-muscle cells (VSMCs). Moreover,
      PD98059 inhibited ET-1-induced contraction of rabbit BA rings. A specific
      inhibitor of EGFR PTK, AG1478, inhibited ET-1-induced EGFR-PTK transactivation,
      ERK1/2 stimulation, and contraction of BA rings in a concentration-dependent
      manner. The concentration of AG1478 required for 50% inhibition of the ET-1
      induced contraction of BA rings was similar to that for ET-1-induced EGFR-PTK
      transactivation. Furthermore, AG1478 also inhibited ET-1-induced BA vasospasm in
      vivo. CONCLUSION: The results indicate that EGFR-PTK transactivation pathway
      plays an important role in ET-1-induced vascular contraction.

PMID- 15200123
TI  - Successful treatment of a ruptured dissecting basilar artery aneurysm. Case
      report.
AB  - Dissecting basilar artery (BA) aneurysms in patients presenting with subarachnoid
      hemorrhage are life threatening, especially in those who experience subsequent
      bleeding or progressive dissection, and immediate surgical or endovascular
      intervention may be necessary. The authors report on a 52-year-old woman whose
      dissecting BA aneurysm was treated successfully with proximal occlusion and flow
      reversal. Clipping of the proximal BA above the level of the anterior inferior
      cerebellar arteries facilitated retrograde flow from a radial artery graft placed
      between the left vertebral artery and the left posterior cerebral artery, thereby
      providing continuous perfusion of the BA and its branches. Postoperative
      angiograms obtained 1 year later revealed good retrograde flow through the BA and
      dilation of the radial arterial graft. There were no episodes of recurrent
      hemorrhage.

PMID- 15200124
TI  - Intrinsic brainstem choroid plexus papilloma. Case report.
AB  - The authors report an intrinsic brainstem lesion that was diagnosed initially as
      a pontine cavernoma, which finally proved to be a choroid plexus papilloma.
      Choroid plexus papillomas are rare tumors of the central nervous system and are
      usually intraventricular in location. The occurrence of this tumor in an
      intraparenchymal location is extremely rare, and its occurrence within the
      brainstem is previously unreported. The authors also report a trial of
      chemotherapy with lomustine in the management of the residual tumor.

PMID- 15200125
TI  - Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral)
      tremor and associated dystonia caused by upper brainstem lesions. Report of two
      cases.
AB  - Holmes tremor is caused by structural lesions in the perirubral area of the
      midbrain. Patients often present with associated symptoms such as dystonia and
      paresis, which are usually refractory to medical therapy. Here, the authors
      describe two patients in whom both tremor and associated dystonia improved
      markedly following unilateral stimulation of the thalamic nucleus ventralis
      intermedius.

PMID- 15200126
TI  - Effect of subthalamic nucleus stimulation on obsessive-compulsive disorder in a
      patient with Parkinson disease. Case report.
AB  - The authors report on a patient with Parkinson disease (PD) and severe obsessive
      compulsive disorder (OCD), in whom bilateral stimulation of the subthalamic
      nucleus (STN) was used to treat both PD and OCD symptoms. This 49-year-old man
      had displayed symptoms of PD for 13 years. Progressively, his motor disability
      became severe despite optimal medical treatment. In parallel, he suffered severe
      OCD for 16 years, with obsessions of accumulation and compulsions of gathering
      and rubbing that lasted more than 8 hours per day. Bilateral high-frequency STN
      stimulation was performed to treat motor disability. After surgery (at 1-year
      follow up), motor and OCD symptoms were dramatically improved. The pre- and
      postoperative Yale-Brown Obsessive-Compulsive Scale scores were 32 and 1,
      respectively. No additional antiparkinsonian drugs were administered. This case
      and other recent reports indicate that OCD symptoms can be improved by deep brain
      stimulation, a finding that opens new perspectives in the surgical treatment of
      severe and medically intractable OCD.

PMID- 15200127
TI  - Devastating complications from alcohol cauterization of recurrent Rathke cleft
      cyst. Case report.
AB  - Rathke cleft cysts are commonly found on autopsy but are seldom symptomatic.
      Conventional treatment of these lesions consists of transsphenoidal drainage with
      partial excision of the cyst, and recurrence is rare. Alternatively, the
      instillation of absolute alcohol into the cyst has been described in several
      reports, with no complications. The authors report on a woman with Rathke cleft
      cyst that recurred three times after the initial treatment; the lesion was
      treated with alcohol cauterization on the final recurrence with devastating
      complications. This 51-year-old woman presented in 1992 with headaches and visual
      disturbances. Admission magnetic resonance imaging revealed a sellar/suprasellar
      lesion that was treated with conventional surgery and was subsequently confirmed
      to be a Rathke cleft cyst. The patient again presented with recurrence of the
      cyst at 22, 26, and 31 months after the initial presentation. On the final
      recurrence the cyst was treated with alcohol cauterization. Postoperatively, the
      patient awoke blind and suffered a seizure from leakage of the alcohol. The
      patient remains completely blind in both eyes and is also anosmic and has left
      lid ptosis and exotropia, which signify damage to the first through third cranial
      nerves. Rathke cleft cysts have been known to recur after primary surgery;
      however, this is the first report of a single cyst recurring three times despite
      conventional surgical treatment. Additionally, this is the first report in which
      devastating complications from alcohol cauterization of the cyst have been
      described. The authors therefore advocate caution when attempting alcohol
      cauterization and advise that meticulous care be taken to ensure the patency of
      the cyst.

PMID- 15200128
TI  - Extradural neurenteric cyst of the cerebellopontine angle. Case report.
AB  - Neurenteric cyst is a developmental malformation found mainly in the spinal
      canal. The authors report on a 47-year-old man with a neurenteric cyst of the
      cerebellopontine angle (CPA) who presented with progressive hearing disturbance
      and facial palsy. The tumor was located extradurally with marked destruction of
      the petrous bone around the internal auditory canal and demonstrated irregular
      and heterogeneous high-intensity signals on T1- and T2-weighted on MR images,
      which is atypical for neurenteric cysts. The pathological findings in samples
      obtained after resection disclosed a single epithelial layer (a feature of
      neurenteric cyst), which was accompanied by marked xanthogranulomatous changes.
      Although several neurenteric cysts have been reported in the CPA, extradural
      lesions with unusual imaging features and marked bone destruction have not been
      reported previously. This benign developmental lesion should be considered,
      although it is extremely rare, in patients harboring an extradural temporal bone
      tumor around the CPA.

PMID- 15200129
TI  - Anterolateral thigh fasciocutaneous flap for simultaneous reconstruction of
      refractory scalp and dural defects. Report of two cases.
AB  - Infected full-thickness defects of the calvaria including the scalp, cranial
      bone, and dura mater, are often refractory to treatment and pose a difficult and
      urgent therapeutic problem for reconstructive surgeons. The authors report two
      cases in which successful reconstruction was achieved in one stage by using an
      anterolateral thigh fasciocutaneous flap. The well-vascularized fascia components
      were used to repair the infected dural defects. The skin flaps were used for
      coverage reconstruction.

PMID- 15200130
TI  - Treatment of spontaneous intracranial hypotension with percutaneous placement of
      a fibrin sealant. Report of four cases.
AB  - Spontaneous intracranial hypotension due to a cerebrospinal fluid (CSF) leak in
      the spine is an important cause of new, daily persistent headaches. Most patients
      respond well to conservative treatments including epidural blood patching.
      Limited options for effective treatment are available for patients in whom these
      treatments fail. The authors treated four patients (mean age 38 years; range 26
      43 years) with percutaneous placement of a fibrin sealant. All these patients
      presented with intractable positional headaches. The CSF leak was located in the
      lower cervical spine in three patients and in the lower thoracic spine in one
      patient. Four to 20 milliliters of fibrin sealant was injected at the site of the
      CSF leak. Two of the four patients became asymptomatic within days of the
      procedure and thus avoided surgery. There were no complications of this
      procedure. Percutaneous placement of a fibrin sealant is a safe, minimally
      invasive treatment for spontaneous spinal CSF leaks and should be considered in
      patients in whom conservative treatment has failed.

PMID- 15200131
TI  - Gradual recovery from dyslexia and related serial magnetoencephalographic changes
      in the lexicosemantic centers after resection of a mesial temporal astrocytoma.
      Case report.
AB  - Letter-perception centers are not held in as high regard as motor- and language
      related cortices during planning of neurosurgical procedures, and there have been
      no reports suggesting cortical reorganization of reading ability. The authors
      describe a patient with a left mesial temporal glioma in whom two letter
      perception centers (the anterior portion of the left superior temporal gyrus and
      the left fusiform gyrus) were successfully localized before surgery by performing
      magnetoencephalography (MEG) during reading tasks. Control MEG examinations of 15
      healthy volunteers were also performed to assist in a careful interpretation of
      patient results. Although a radical resection of the mesial temporal glioma,
      which involved the left fusiform gyrus, caused severe dyslexia, the patient's
      impaired reading skills improved gradually during a 1-year postoperative period.
      In the meantime, the spared left superior temporal gyrus displayed an overshot
      recovery of MEG responses. During the postoperative period there was no obvious
      recovery in MEG signals and no compensatory activity in the contralateral
      fusiform gyrus. This case demonstrates that lexicosemantic centers involved in
      the reading process can be noninvasively localized using MEG and that the results
      obtained are highly reliable for surgical planning. The results of the repeated
      MEG reflected sequentially the patient's recovery from dyslexia. This is the
      first report in which MEG studies have been shown to predict preoperatively the
      risk of dyslexia and demonstrate its serial physiological recovery.

PMID- 15200132
TI  - Intractable hiccups as a presenting symptom of cerebellar hemangioblastoma. Case
      report.
AB  - The authors report on a 52-year-old woman with a cerebellar hemangioblastoma who
      presented with a 2-year history of intractable hiccups. Computerized tomography
      scans and magnetic resonance images revealed a cerebellar hemangioblastoma with
      compression of the brainstem at the level of the medulla oblongata. The patient
      has been free of hiccups and has been neurologically intact since the day after
      total removal of the tumor. A review of the literature on medullary lesions
      presenting with intractable hiccups is provided.

PMID- 15200133
TI  - Necrobiotic xanthogranuloma with cutaneous and cerebral manifestations. Case
      report and review of the literature.
AB  - Necrobiotic xanthogranuloma (NXG) is a rare inflammatory histiocytic disease of
      the skin. Xanthogranuloma of the central nervous system is rare and few cases
      have been reported. To the authors' knowledge, there has been no previously
      reported case of NXG in which an intracranial lesion was found. This 52-year-old
      man, in whom NXG with all its cutaneous manifestations had been diagnosed,
      presented with three episodes of generalized tonic-clonic seizures. A contrast
      enhanced computerized tomography scan of his brain revealed a bifrontal, dura
      based mass lesion. The lesion was excised and reported to be an NXG that was
      similar, but not identical to the skin lesions. The patient was placed on a
      regimen of antiepileptic drug and chlorambucil after surgery.

PMID- 15200134
TI  - Erdheim-Chester disease mimicking a primary brain tumor. Case report.
AB  - Erdheim-Chester disease (ECD) is a rare systemic histiocytic disease. The authors
      present a case report detailing the presentation and treatment of a 26-year-old
      man diagnosed with seizures and a well-circumscribed temporoparietal mass that
      had been demonstrated on imaging studies. Both preoperative and intraoperative
      diagnoses were consistent with a low-grade astrocytic neoplasm. Subsequent
      pathological examination indicated a histiocytic proliferation positive for CD68
      and factor VIII, and negative for CD1a and S100, with Touton giant cells
      characteristic of ECD. This case represents the first isolated occurrence of
      intracranial ECD and its potential to mimic glial neoplasms.

PMID- 15200135
TI  - Minimally invasive implantation of epidural spinal cord neurostimulator
      electrodes by using a tubular retractor system. Technical note.
AB  - The authors describe a novel technique for the implantation of multipolar
      epidural spinal cord neurostimulator electrodes with the aid of a tubular
      retractor system. Spinal cord neurostimulation is used as a neuroaugmentive tool
      for treating chronic intractable pain syndromes. Minimally invasive placement of
      the multipolar neurostimulator electrodes may allow for shorter hospital stays
      and less postoperative pain associated with the incision.

PMID- 15200136
TI  - Pneumocephalus with neurological deficit from hydrogen peroxide irrigation. Case
      illustration.

PMID- 15200137
TI  - To everything there is a season and a time to every purpose: retirement and the
      neurosurgeon.
AB  - Neurosurgery has designed a rigid curriculum that must be followed precisely by
      those who wish to enter the specialty. A similar process at the other end of the
      practice cycle has never been formalized except for mandatory retirement from
      certain administrative positions at a particular age. Basic considerations for
      strategic decision making about voluntary retirement from neurosurgery,
      especially operative neurosurgery, are investigated. Statistical data from the US
      Census Bureau and sources in the medical literature were reviewed regarding life
      expectancy and retirement ages. Age-related differences in verbal and performance
      intelligence quotients, attention span, verbal memory recall, and visuospatial
      facility were surveyed. A questionnaire was sent to 29 recently retired academic
      neurosurgeons about their age and reasons for retirement along with
      postretirement activities; 22 responses were received. Analysis of the data
      indicates that surgeons are now retiring at the age of approximately 60 years,
      whereas life expectancy is approximately 80 years. An individual thus may have 15
      to 20 productive years after leaving active neurosurgical practice. Reasons for
      retirement among the 22 responding neurosurgeons included decreasing personal
      satisfaction and financial rewards, a desire to pursue other activities, local
      ground rules mandating age-specific retirement, the general sense that enough is
      enough, and, overall, a strong desire to stop performing surgery while at the top
      of one's game. The process of age-related competence assessment of commercial
      airline pilots is outlined, and a similar process of assessment of practicing
      surgeons may be warranted, with consideration for mandatory retirement from
      operative neurosurgery.

PMID- 15200138
TI  - Progress in malignant glioma.

PMID- 15200139
TI  - Gamma hypophysectomy.

PMID- 15200140
TI  - Cranial bone fixation.

PMID- 15200141
TI  - The role of extracellular calcium in the regulation of intracellular calcium and
      cell function (II). Some answers and more questions.

PMID- 15200142
TI  - Extracellular Ca2+-sensing receptors--an overview.
AB  - Extracellular Ca2+-sensing receptors (CaRs) are the molecular basis by which
      specialized cells detect and respond to changes in the extracellular [Ca2+]
      ([Ca2+]o). CaRs belong to the family C of G-protein coupled receptors (GPCRs).
      Activation of CaRs triggers signaling pathways that modify numerous cell
      functions. Multiple ligands regulate the activation of CaRs including multivalent
      cations, L-amino acids, and changes in ionic strength and pH. CaRs in parathyroid
      cells play a central role in systemic Ca2+ homeostasis in terrestrial tetrapods.
      Mutations of the CaR gene in humans cause diseases in which serum and urine
      [Ca2+] and parathyroid hormone (PTH) levels are altered. CaR homologues are also
      expressed in organs critical to Ca2+ transport in ancient and modern fish,
      suggesting that similar receptors may have long been involved in Ca2+ homeostasis
      in lower vertebrates before parathyroid glands developed in terrestrial
      vertebrates. CaR mRNA and protein are also expressed in tissues not directly
      involved in Ca2+ homeostasis. This implies that there may be other biological
      roles for CaRs. Studies of CaR-knockout mice confirm the importance of CaRs in
      the parathyroid gland and kidney. The functions of CaRs in tissues other than
      kidney and parathyroid gland, however, remain to be elucidated.

PMID- 15200143
TI  - Structure-function relationship of the extracellular calcium-sensing receptor.
AB  - The extracellular calcium-sensing receptor (CaR) originally cloned from bovine
      parathyroid gland is a G protein-coupled receptor. The physiological relevance of
      the cloned CaR for sensing and regulating the extracellular calcium concentration
      has been established by identifying hyper- and hypocalcemic disorders resulting
      from inactivating and activating mutations, respectively, in the CaR. The cloned
      CaR has been stably or transiently expressed in human embryonic kidney cells and
      significant progress has been made in elucidating its regulation and activation
      process using physiological, biochemical and molecular biological methods. A
      large collection of naturally occurring CaR mutations offers a valuable resource
      for studies aimed at understanding the structure-function relationships of the
      receptor, including functional importance of CaR dimerization. In turn,
      characterization of these naturally occurring mutations has clarified the
      pathogenesis of clinical conditions involving abnormalities in the CaR, such as
      familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

PMID- 15200144
TI  - Calcium sensing receptors as integrators of multiple metabolic signals.
AB  - Calcium sensing receptors are critical to maintenance of organismal Ca2+
      homeostasis, translating small changes in serum Ca2+ into changes in PTH
      secretion by the parathyroid glands and Ca2+ excretion by the kidneys. Calcium
      sensing receptors are also expressed in many cells and tissues not directly
      involved in Ca2+ homeostasis where their role(s) are less defined. Recent studies
      have demonstrated that calcium sensing receptors integrate a variety of metabolic
      signals, including polyvalent cations, pH, ionic strength, amino acids, and
      polypeptides, making CaR uniquely capable of generating cell- and tissue-specific
      responses, sensing not only Ca2+, but the local metabolic environment. The
      challenge for future studies is to define CaR responsiveness in each varied
      physiological context.

PMID- 15200145
TI  - Calcium receptor-mediated intracellular signalling.
AB  - As a G protein-coupled receptor (GPCR), the extracellular calcium-sensing
      receptor (CaR) responds to changes in extracellular free calcium concentration by
      inducing intracellular signalling. These CaR-induced signals then specifically
      modulate cellular functions such as parathyroid hormone secretion from the
      parathyroid glands and calcium reabsorption in the kidney and thus to understand
      how the CaR functions one must understand how it signals. CaR-induced signalling
      involves intracellular Ca2+ mobilisation/oscillations as well as the activation
      of various phospholipases and protein kinases and the suppression of cAMP
      formation. This review will detail the intracellular pathways by which the CaR is
      believed to elicit its physiological functions and summarises the evidence for
      cell- and agonist-specific differential signalling.

PMID- 15200146
TI  - Calcium-sensing receptor regulation of renal mineral ion transport.
AB  - Extracellular calcium has long been known to affect the rate and magnitude of
      renal calcium and phosphate recovery. In this review, we consider some of these
      findings in light of our present understanding of the tubular localization of the
      calcium-sensing receptor (CaSR). Experiments directly implicating the CaSR in
      regulating calcium and phosphate transport are described. These results point to
      an important role of the CaSR in regulating PTH-dependent calcium absorption by
      cortical thick ascending limbs and on PTH-sensitive proximal tubule phosphate
      transport. Possible avenues for further investigation are suggested.

PMID- 15200147
TI  - Functions and roles of the extracellular Ca2+-sensing receptor in the
      gastrointestinal tract.
AB  - The gastrointestinal tract is vital to food digestion and nutrient absorption as
      well as normal salt and water homeostasis. Studies over the last several years
      have shown that the Ca2+-sensing receptor is expressed along the entire
      gastrointestinal tract. The potential roles for the receptor in gastrointestinal
      biology are now only beginning to be elucidated and much work remains. Well
      studied physiological effects include regulation of gastric acid secretion and
      modulation of fluid transport in the colon. It remains to be determined if the
      Ca2+-sensing receptor is involved in calcium handling by the gastrointestinal
      tract. The ability of organic nutrient receptor agonists/allosteric modifiers,
      such as polyamines and L-amino acids, to activate the Ca2+-sensing receptor
      suggest potential roles in signalling nutrient availability to gastric and
      intestinal epithelial cells. In addition, polyamines are crucial for normal cell
      proliferation and differentiation required to sustain the rapid turnover of
      gastrointestinal epithelial cells and the Ca2+-sensing receptor may be involved
      in this function. Activation of the colonic Ca2+-sensing receptor can abrogate
      cyclic nucleotide-mediated fluid secretion suggesting a role for the receptor in
      modifying secretory diarrheas like cholera. Finally, the Ca2+-sensing receptor
      has been suggested to provide a mechanism for the effect of calcium intake in
      reducing the risk of colon cancer.

PMID- 15200148
TI  - Ca2+ as an extracellular signal in bone.
AB  - Bone is the major sink and store for calcium and it fulfils essential roles in
      the maintenance of extracellular free ionised calcium concentration ([Ca2+]e)
      within its homeostatic range (1.1-1.3 mM). In response to acute hypercalcaemia or
      hypocalcaemia, Ca2+ is rapidly transported into or out of bone. Bone turnover
      (and therefore bone Ca2+ turnover) achieves the long-term correction of the
      [Ca2+]e by the metabolic actions of osteoblasts and osteoclasts, as they
      respectively incorporate or release Ca2+ from bone. These processes are regulated
      by the actions of hormones, such as parathyroid hormone (PTH), the release of
      which is a function of the [Ca2+]e, and is regulated by the action of the Ca2+
      sensing receptor (CaR) in the parathyroid gland. Tissue culture studies indicate
      that bone cells also directly respond to increasing and decreasing [Ca2+]e in
      their vicinity, independently of the systemic factors. Nevertheless, further
      studies are necessary to identify how the acute and long-term local changes in
      [Ca2+]e affect bone cells and the physiological processes they are involved in.
      Also, the molecular mechanisms which enable the bone cells to sense and respond
      to [Ca2+]e are not clear. Like the parathyroid cells, bone cells also express the
      CaR, and accumulating evidence indicates the involvement of this receptor in
      their responses to the changing extracellular ionic environment.

PMID- 15200149
TI  - Calcium-sensing receptor in the brain.
AB  - Following its cloning through an homology-based method from a rat striatal
      library, the calcium-sensing receptor (CaR) has been localized in the brains of
      adult and developing rats by immunocytochemistry and in situ hybridization with
      CaR-specific antibodies and cDNA probes, respectively. The receptor resides in
      numerous regions of the brain at widely varying levels. The highest levels are
      present within the subfornical organ (SFO) and the olfactory bulbs. Substantial
      levels of expression are also evident within the hippocampus, striatum, cingulate
      cortex, cerebellum, ependymal zones of the cerebral ventricles, and perivascular
      nerves around cerebral arteries. There are abundant levels of CaR expression
      within the SFO, an important hypothalamic thirst center, suggesting that it
      participates in the central control of systemic fluid and electrolyte balance.
      Therefore, while mineral ion homeostasis is not often considered to have central
      regulatory elements (i.e. in the brain), there are perhaps more complex
      relationships than recognized previously among the system governing mineral ion
      homeostasis and other homeostatic systems known to exhibit prominent
      neuroendocrine elements (i.e. water homeostasis). Furthermore, the expression of
      the CaR in all three types of glial cells indicates potential roles in the
      maintenance of local ionic homeostasis as well as in disease processes such as
      glioma.

PMID- 15200150
TI  - The role of the calcium-sensing receptor in epidermal differentiation.
AB  - Calcium regulates the proliferation and differentiation of keratinocytes both in
      vivo and in vitro. Elevated extracellular Ca2+ concentration ([Ca2+]o) raises the
      intracellular free calcium ([Ca2+]i) and activates differentiation-related genes.
      Cells lacking the calcium-sensing receptor (CaR) fail to respond to [Ca2+]o and
      to differentiate, indicating a role for CaR in keratinocyte differentiation.
      These concepts derived from in vitro experiments have been tested and confirmed
      in two mouse models.

PMID- 15200151
TI  - Diseases associated with the extracellular calcium-sensing receptor.
AB  - The human calcium-sensing receptor (CaSR) is a 1078 amino acid cell surface
      protein, which is predominantly expressed in the parathyroids and kidney, and is
      a member of the family of G protein-coupled receptors. The CaSR allows regulation
      of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in
      response to alterations in extracellular calcium concentrations. The human CaSR
      gene is located on chromosome 3q21.1 and loss-of-function CaSR mutations have
      been reported in the hypercalcaemic disorders of familial benign (hypocalciuric)
      hypercalcaemia (FHH, FBH or FBHH) and neonatal severe primary hyperparathyroidism
      (NSHPT). However, some individuals with loss-of-function CaSR mutations remain
      normocalcaemic. In addition, there is genetic heterogeneity amongst the forms of
      FHH. Thus, the majority of FHH patients have loss-of-function CaSR mutations, and
      this is referred to as FHH type 1. However, in one family, the causative gene for
      FHH is located on 19p13, referred to as FHH type 2, and in another family it is
      located on 19q13, referred to as FHH type 3. Gain-of-function CaSR mutations have
      been shown to result in autosomal dominant hypocalcaemia with hypercalciuria
      (ADHH) and Bartter's syndrome type V. CaSR auto-antibodies have been found in FHH
      patients who did not have loss-of-function CaSR mutations, and in patients with
      an acquired form (i.e. autoimmune) of hypoparathyroidism. Thus, abnormalities of
      the CaSR are associated with three hypercalcaemic and three hypocalcaemic
      disorders.

PMID- 15200152
TI  - Calcimimetic and calcilytic drugs: just for parathyroid cells?
AB  - The cell surface calcium receptor (Ca2+ receptor) is a particularly difficult
      receptor to study because its primary physiological ligand, Ca2+, affects
      numerous biological processes both within and outside of cells. Because of this,
      distinguishing effects of extracellular Ca2+ mediated by the Ca2+ receptor from
      those mediated by other mechanisms is challenging. Certain pharmacological
      approaches, however, when combined with appropriate experimental designs, can be
      used to more confidently identify cellular responses regulated by the Ca2+
      receptor and select those that might be targeted therapeutically. The Ca2+
      receptor on parathyroid cells, because it is the primary mechanism regulating
      secretion of parathyroid hormone (PTH), is one such target. Calcimimetic
      compounds, which active this Ca2+ receptor and lower circulating levels of PTH,
      have been developed for treating hyperparathyroidism. The converse pharmaceutical
      approach, involving calcilytic compounds that block parathyroid cell Ca2+
      receptors and stimulate PTH secretion thereby providing an anabolic therapy for
      osteoporosis, still awaits clinical validation. Although Ca2+ receptors are
      expressed throughout the body and in many tissues that are not intimately
      involved in systemic Ca2+ homeostasis, their physiological and/or pathological
      significance remains speculative and their value as therapeutic targets is
      unknown.

PMID- 15200153
TI  - The role of the calcium-sensing receptor in cancer.
AB  - The extracellular calcium-sensing receptor (CaR) is a versatile sensor of small,
      polycationic molecules ranging from Ca2+ and Mg2+ through polyarginine, spermine,
      and neomycin. The sensitivity of the CaR to changes in extracellular Ca2+ over
      the range of 0.05-5 mM positions the CaR as a key mediator of cellular responses
      to physiologically relevant changes in extracellular Ca2+. For many cell types,
      including intestinal epithelial cells, breast epithelial cells, keratinocytes,
      and ovarian surface epithelial cells, changes in extracellular Ca2+ concentration
      over this range can switch the cellular behaviour from proliferation to terminal
      differentiation or quiescence. As cancer is predominantly a disease of disordered
      balance between proliferation, differentiation, and apoptosis, disruptions in the
      function of the CaR could contribute to the progression of neoplastic disease.
      Loss of the growth suppressing effects of elevated extracellular Ca2+ have been
      demonstrated in parathyroid hyperplasias and in colon carcinoma, and have been
      correlated with changes in the level of CaR expression. Activation of the CaR has
      also been linked to increased expression and secretion of PTHrP (parathyroid
      hormone-related peptide), a primary causal factor in hypercalcemia of malignancy
      and a contributor to metastatic processes involving bone. Although mutation of
      the CaR does not appear to be an early event in carcinogenesis, loss or
      upregulation of normal CaR function can contribute to several aspects of
      neoplastic progression, so that therapeutic strategies directed at the CaR could
      potentially serve a supportive function in cancer management.

PMID- 15200154
TI  - The extracellular calcium-sensing receptor and cell-cell signaling in epithelia.
AB  - In multicellular organisms, cells are crowded together in organized communities,
      surrounded by an interstitial fluid of extremely limited volume. Local
      communication between adjacent cells is known to occur through gap junctions in
      cells that are physically connected, or through the release of paracrine
      signaling molecules (e.g. ATP, glutamate, nitric oxide) that diffuse to their
      target receptors through the extracellular microenvironment. Recent evidence
      hints that calcium ions may possibly be added to the list of paracrine messengers
      that allow cells to communicate with one another. Local fluctuations in
      extracellular [Ca2+] can be generated as a consequence of intracellular Ca2+
      signaling events, owing to the activation of Ca2+ influx and efflux pathways at
      the plasma membrane. In intact tissues, where the interstitial volumes between
      cells are much smaller than the cells themselves, this can result in significant
      alterations in external [Ca2+]. This article will explore emerging evidence that
      these extracellular [Ca2+] changes can be detected by the extracellular calcium
      sensing receptor (CaR) on adjacent cells, forming the basis for a paracrine
      signaling system. Such a mechanism could potentially provide CaR-expressing cells
      with the means to sense the Ca2+ signaling status of their neighbors, and expand
      the utility of the intracellular Ca2+ signal to a domain outside the cell.

PMID- 15200155
TI  - A contemporary overview of chronic progressive nephropathy in the laboratory rat,
      and its significance for human risk assessment.
AB  - CPN (chronic progressive nephropathy) is a spontaneous age-related disease that
      occurs in high incidence in the strains of rat commonly used in preclinical
      toxicology studies, exhibiting a male predisposition. Although increasing in
      incidence and severity with age, evidence indicates that CPN should be regarded
      as a specific disease entity and not just a manifestation of the aging process. A
      number of factors, mainly dietary manipulations, have been shown to modify the
      expression of CPN. Amongst these, restriction of caloric intake is the most
      effective for inhibiting the disease process. The precise etiology of CPN and the
      mechanism(s) underlying its pathogenesis remain unknown, but the long-standing
      assumption that glomerular dysfunction is the primary basis is challenged in the
      light of contemporary developments in understanding filtration and postglomerular
      cellular processing of albumin. CPN is not only a degenerative disease, but also
      has regenerative aspects with a high cell proliferative rate in affected tubules.
      Accordingly, evidence is emerging that advanced, particularly end-stage CPN, is a
      risk factor for a marginal increase in the background incidence of renal tubule
      tumors. Many chemicals are known to exacerbate the severity of CPN to an advanced
      stage, and this interaction between chemical and CPN can result in a small
      increase in the incidence of renal adenomas in 2-year carcinogenicity bioassays.
      Review of the pathological entities associated with chronic renal failure in man
      emphasizes that this rodent condition has no strict human counterpart. Because
      CPN is a rodent-specific entity, the finding of a small, statistically
      significant increase in renal tubule tumors, linked to exacerbation of CPN by a
      test chemical in a preclinical study for carcinogenicity, can be regarded as
      having no relevance for extrapolation in human risk assessment.

PMID- 15200156
TI  - Antibodies that label paraffin-embedded mouse tissues: a collaborative endeavor.
AB  - Histology and immunohistochemistry are important tools in the study of human
      diseases and their respective animal models. The study of mouse models has been
      hampered by the absence of a large set of mouse-specific antibodies adapted to
      paraffin-embedded tissues. A total of 196 antibodies were tested on paraffin
      embedded mouse tissues preserved in five different fixatives (Fekete's acid
      alcohol-formalin, 10% neutral buffered formalin, 4% paraformaldehyde, IHC Zinc
      Fixative, and Bouin's fixative). The antibodies were targeted to proteins of the
      cytoplasm (n = 100), plasma membrane (n = 48), nucleus (n = 36), extracellular
      compartment (n = 5), cytoplasm/cell membrane (n = 4), and viral proteins (n = 3).
      A total of 83 antibodies provided an adequate signal to noise ratio. Of these,
      adequate labeling required heat-mediated epitope retrieval or enzymatic digestion
      for 32 and 8 antibodies, respectively. Epitope recognition was best for tissues
      fixed with Fekete's acid-alcohol-formalin. However, some proteins could be
      detected only in IHC Zinc Fixative, confirming that there is no single fixative
      suitable for the preservation of all epitopes. Four of 13 antibodies that failed
      to label their cellular targets on tissue sections successfully labeled whole
      mount tissues, indicating that tissue processing plays an important role in
      epitope degradation. Regularly updated information on immunohistochemistry of
      normal and neoplastic mouse tissues is accessible online at
      (http://tumor.informatics.jax.org); links to antibody suppliers' web sites are
      provided.

PMID- 15200157
TI  - Evaluation of the Xpa-deficient transgenic mouse model for short-term
      carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin,
      and D-mannitol.
AB  - As part of the international evaluation program coordinated by ILSI/HESI, the
      potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/
      .p53+/- mice for short term carcinogenicity assays was evaluated. For comparison
      also wild-type C57BL/6 mice (WT) were included in these studies. Four test
      compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/
      .p53+/- mice and WT mice for 39 weeks. The model compounds investigated were
      haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human
      noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human
      carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test
      compounds were administered as admixture to rodent diet at levels up to 25 mg/kg
      diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10%
      for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival
      was not affected with any of the test compounds. Haloperidol, reserpine and D
      mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53+/-
      mice, showing low and comparable tumor incidences in controls and high-dose
      animals. The results obtained with phenacetin may be designated equivocal in Xpa
      /-.p53+/- mice, based on the occurrence of a single rare tumor in the target
      organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a
      high incidence of karyomegaly. These results are in agreement with the currently
      known carcinogenic potential of the 4 test compounds in humans.

PMID- 15200158
TI  - Histopathological and molecular changes during apoptosis produced by 7H
      dibenzo[c,g]-carbazole in mouse liver.
AB  - The topical administration of 7H-dibenzo[c,g]carbazole (7H-DBC) at very low but
      repeated doses causes genotoxic effects such as DNA adduct formation and produces
      hepatocellular apoptosis in mouse liver. The purpose of this work was to
      investigate the alterations in gene expression and protein levels of biomarkers
      associated with the p53 pathway in mouse liver after exposure to cumulative low
      doses of 7H-DBC by skin paint applications. The compound was administered
      topically at the dose of 13.35 microg per animal every 2 days to give either 6,
      8, 10, or 12 applications. Animals were sacrificed 48 hours after the different
      treatments. The apoptotic index increased with the number of applications, with a
      major proportion of apoptotic cells in the periportal areas. A significant
      increase of Bax mRNA and protein expression was observed after the 8th
      application whereas the expression of mRNA levels of Fas and p53 did not show
      significant differences between treated and control animals. Nuclear staining of
      p53 was detected in hepatocyte nuclei showing the activation of this protein.
      Later in the apoptosis process we observed the up-regulation of TGF-beta1 in
      parenchymal cells. In addition to the induction of the p53 apoptosis pathway in
      vivo by 7H-DBC, we have observed molecular changes related to cell proliferation
      such as the overexpression of the antiapoptotic gene Bcl-2.

PMID- 15200159
TI  - Mucosal toxicity studies of a gel formulation of native pokeweed antiviral
      protein.
AB  - Pokeweed antiviral protein (PAP), a 29-kDa plant-derived protein isolated from
      Phytolacca americana, is a promising nonspermicidal broad-spectrum antiviral
      microbicide. This study evaluated the mucosal toxicity potential of native PAP in
      the in vivo rabbit vaginal irritation model as well as the in vitro reconstituted
      human vaginal epithelial tissue model. Twenty-two New Zealand white rabbits in 4
      subgroups were exposed intravaginally to a gel with and without 0.01, 0.1, or
      1.0% native PAP for 10 consecutive days. The dose of PAP used represented nearly
      200- to 20,000 times its in vitro anti-HIV IC50 value. Animals were euthanized on
      day 11 and vaginal tissues were evaluated for histologic and immunohistochemical
      evidence of mucosal toxicity, cellular inflammation, and hyperplasia. Blood was
      analyzed for changes in hematology and clinical chemistry profiles. Reconstituted
      human vaginal epithelial tissue grown on membrane filters was exposed to 0.01,
      0.1, or 1.0% native PAP in medium or topically via a gel for 24 hours and tissue
      damage was evaluated by histological assessment. In the in vivo rabbit vaginal
      irritation model, half of all PAP-treated rabbits (8/16) exhibited an acceptable
      range of vaginal mucosal irritation (total score <8 out of a possible 16),
      whereas nearly a third of PAP-treated rabbits (5/16) developed moderate to marked
      vaginal mucosal irritation (total score >11). However, no treatment-related
      adverse effects were seen in hematological or clinical chemistry measurements.
      Furthermore, in vitro exposure of a 3-dimensional human vaginal tissue grown on
      polycarbonate membrane filters to identical concentrations of PAP either added to
      culture medium or applied topically via gel formulation did not result in direct
      toxicity as determined by histologic evaluation. These findings indicate careful
      monitoring of vaginal irritation will be required in the clinical development of
      PAP as a nonspermicidal microbicide.

PMID- 15200160
TI  - Association of liver hemangiosarcoma and secondary iron overload in B6C3F1 mice-
      the National Toxicology Program experience.
AB  - The literature evidencing the role of iron in promoting a range of neoplasms in
      humans and animals prompted us to search for a possible association between
      chemically induced hemosiderosis and hemangiosarcomas in the liver of mice in
      selected studies conducted by the National Toxicology Program (NTP). Its
      historical control database was examined for studies in which treatment-related
      liver hemangiosarcoma was noted; 130 consecutive NTP studies in B6C3F1 mice from
      Technical Report (TR)-340 to TR-493 were evaluated. Three compounds (2
      butoxyethanol, p-nitroaniline, and para-chloroaniline) were associated with a
      relatively high incidence of Kupffer cell pigmentation consisting of hemosiderin
      in both sexes; only the male mice developed a relatively low incidence of
      treatment-related hemangiosarcoma. With a fourth compound (o-nitroanisole), a
      relatively low incidence (16/50, high-dose males) of chemical-related
      hemosiderosis was noted, with no associated increase of hemangiosarcoma. Two
      chemicals (pentachlorophenol and tetrafluoroethylene) increased the incidence of
      liver hemangiosarcoma in male and female mice, with no increase in Kupffer cell
      pigmentation. The overall association between liver hemangiosarcoma and Kupffer
      cell pigmentation was highly significant (p < 0.001). The cause for hemosiderosis
      in all cases was the erythrocytic hemolytic effect of the compounds. The reason
      for the sex-increased susceptibility for development of hemangiosarcoma is
      unknown but may be due to a hormone-related, reduced antioxidative defensive
      capacity through modulation of the activities of antioxidative enzymes.

PMID- 15200161
TI  - Sequential analysis of development of invasive thyroid follicular cell carcinomas
      in inflamed capsular regions of rats treated with sulfadimethoxine after N-bis(2
      hydroxypropyl)nitrosamine-initiation.
AB  - A 2-stage thyroid follicular carcinogenesis model in rats initiated with N-bis(2
      hydroxypropyl)nitrosamine (DHPN) is widely used to detect modifying effects of
      chemicals on thyroid carcinogenesis. A number of goitrogens are known to strongly
      promote carcinogenesis, and the carcinomas often originate adjacent to the
      thyroid capsule and show invasive growth into the capsule or adjacent tissues. To
      clarify mechanisms of progression to invasive carcinomas, we sequentially
      evaluated histopathological and immunohistochemical characteristics of thyroids
      in male F344 rats treated with sulfadimethoxine (SDM, 0.1% in drinking water) for
      0-10 weeks beginning 1 week after DHPN initiation (2800 mg/kg body weight, single
      s.c. injection). In DHPN-SDM-treated rats, multiple focal hyperplasias and
      adenomas developed in thyroid follicular parenchyma at weeks 4 to 6. Apart from
      the proliferative lesions, capsular thickening with inflammatory cell
      infiltration, mainly consisting of macrophages, and migration of follicular
      epithelium into the capsule were also observed. Focal hyperplasias/adenomas
      adjacent to the capsule progressively developed to invasive carcinomas at weeks 6
      to 10. In thyroid parenchyma, malignant lesions were seldom observed. With SDM
      treatment alone, although no neoplastic lesions were observed, capsular
      thickening with inflammation and epithelial migration resulted in intracapsular
      residual follicles. Intracapsular residual follicular cells as well as invasive
      and intrathyroidal carcinoma cells generally showed increased cell proliferative
      activity, coincidental with cytoplasmic/nuclear positivity for beta-catenin.
      These results suggested that beta-catenin activation related to capsular
      inflammation may play a role in development of invasive carcinomas but is
      insufficient for tumor formation by itself. Whether this is associated with
      mutations in the beta-catenin gene remains to be clarified.

PMID- 15200162
TI  - The relationship of age, sex, and glomerular location to the development of
      spontaneous lesions in the canine kidney: analysis of a life-span study.
AB  - It is well documented that the presence of spontaneous renal disease and renal
      dysfunction increases with age in many species of mammals. Such alterations in
      renal structure and function may significantly affect the interpretation of long
      term toxicology studies. The purpose of the present study was to assess the
      temporal evolution of selected renal lesions (cysts, interstitial inflammation,
      interstitial fibrosis, and glomerulosclerosis) in laboratory Beagle dogs, an
      important animal model in chronic toxicology studies. We examined representative
      sections of the kidneys from 159 purpose-bred and laboratory housed Beagle dogs
      and analyzed the extent and distribution of spontaneous lesions using the World
      Health Organization classification system for renal lesions. All dogs examined
      had renal lesions of varying severities. In the youngest dogs (up to 2 years of
      age), the density and severity of lesions were minimal, but were more severe by
      middle age (defined as 3-7 years). The density and severity of interstitial
      fibrosis and inflammation progressed with advancing age (p < 0.0001 for both) in
      both sexes. The density of tubular cysts increased linearly with advancing age in
      females (p = 0.0006), but not in males (p = 0.49). The cortical distribution of
      glomeruli and advancing age of dogs were significantly related to the development
      of glomerulosclerosis. As age increased, the presence of glomerulosclerosis
      increased (p = 0.0008). These data indicate that the development of renal lesions
      is progressive over the lifetime of a genetically similar population of
      laboratory Beagle dogs maintained under optimal standard environmental
      conditions. This information may be useful in the interpretation of compound
      effects during chronic toxicology studies in the dog.

PMID- 15200163
TI  - Chronic effects of flutamide in male beagle dogs.
AB  - Flutamide, a potent nonsteroidal antiandrogen, was administered orally to male
      beagle dogs for 2, 3, or 4 years at doses of 10, 20, or 40 mg/kg/day. At each
      study interval, the results of clinical pathology examinations, organ weight
      determinations, necropsy, and histopathologic examinations generally were similar
      and included atrophy of the prostate gland, testicular interstitial cell
      hyperplasia, and seminiferous tubular atrophy and degeneration. After 3 years of
      drug exposure, there were 3 dogs with testicular interstitial cell adenomas and a
      few dogs with 1 or more enlarged mammary gland nipples. Based upon the
      pharmacologic activity of flutamide, these findings were expected and considered
      the consequence of long-term blocking of testosterone receptors and an
      exaggerated compensatory response to increased secretion of luteinizing hormone.
      The findings of this study were consistent with other examples of dysregulated
      hormone stimulation of target tissues noted during the nonclinical safety
      assessment of flutamide. In consideration of the clinical indication of flutamide
      for advanced prostatic carcinoma and based upon reports of minimal flutamide
      related adverse clinical responses, the findings of this study pose no concern
      for human risk assessment.

PMID- 15200164
TI  - Modifying effects of 1'-acetoxychavicol acetate (ACA) and the novel synthetic
      retinoids Re-80, Am-580 and Am-55P in a two-stage carcinogenesis model in female
      rats.
AB  - Effects of dietary administration of 1'-acetoxychavicol acetate (ACA) and the
      novel synthetic retinoids 4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy
      5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (Re-80); 4-[(5,6,7,8
      tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid (Am-580);
      and 6-[(3,5-di-tert-butylphenyl) carbamoyl]nicotinic acid (Am-55P) were examined
      using a two-stage rat carcinogenesis model. A total of 190 female SD rats was
      treated sequentially with 1,2-dimethylhydrazine (DMH, s.c.); 7,12
      dimethylbenz(a)anthracene (DMBA, i.g.); and 2,2'-dihydroxy-di-n-propylnitrosamine
      (DHPN, in the drinking water) during the first three weeks (DDD-initiation), and
      an additional 60 rats received the vehicle alone (non-initiation). One week after
      the completion of the initiation period, they were divided into nine groups and
      administrated Re-80 (at dose levels of 1.0 or 0.4 ppm), Am-580 (20 or 4 ppm), Am
      55P (20 ppm), ACA (100 ppm), all-trans-retinoic acid (10 or 2 ppm) or no
      supplement in the diet for 33 weeks, until survivors were euthanatized at week 37
      weeks. After DDD-initiation, all-trans-retinoic acid at the high dose delayed the
      development of mammary tumors. The multiplicity of colon tumors in the group fed
      Am-55P and the incidences of nephroblastomas with ACA or Am-580 were decreased as
      compared with the control values, but the other chemicals had no modifying
      effects on tumor development in any organs. Thus, among ACA and the novel
      synthetic retinoids tested, only Am-55P showed a weak inhibitory effect on a
      neoplasm of general interest under the present experimental conditions.

PMID- 15200165
TI  - Image compression in morphometry studies requiring 21 CFR Part 11 compliance:
      procedure is key with TIFFs and various JPEG compression strengths.
AB  - This study aims to compare the integrity and reproducibility of measurements
      created from uncompressed and compressed digital images in order to implement
      compliance with 21 CFR Part 11 for image analysis studies executed using 21 CFR
      Part 58 compliant capture systems. Images of a 400-mesh electron microscope grid
      and H&E stained rat liver tissue were captured on an upright microscope with
      digital camera using commercially available analysis software. Digital images
      were stored as either uncompressed TIFFs or in one of five different levels of
      JPEG compression. The grid images were analyzed with automatic detection of
      bright objects while the liver images were segmented using color cube-based
      morphometry techniques, respectively, using commercially-available image analysis
      software. When comparing the feature-extracted measurements from the TIFF
      uncompressed to the JPEG compressed images, the data suggest that JPEG
      compression does not alter the accuracy or reliability to reproduce individual
      data point measurements in all but the highest compression levels. There is,
      however, discordance if the initial measure was obtained with a TIFF format and
      subsequently saved as one of the JPEG levels, suggesting that the use of
      compression must precede feature extraction. It is a common practice in software
      packages to work with TIFF uncompressed images. However, this study suggests that
      the use of JPEG compression as part of the analysis work flow was an acceptable
      practice for these images and features. Investigators applying image file
      compression to other organ images will need to validate the utility of image
      compression in their work flow. A procedure to digitally acquire and JPEG
      compress images prior to image analysis has the potential to reduce file
      archiving demands without compromising reproducibility of data.

PMID- 15200166
TI  - A case report of a choroid plexus carcinoma spontaneously occurring in the right
      lateral ventricle of a 14-week-old, female Donryu rat.
AB  - We encountered a brain tumor arising in the right lateral ventricle of a 14-week
      old, female Donryu rat and investigated its histological and immunohistochemical
      characteristics. Macroscopically, the tumor appeared as a grayish mass with a
      size of 10 mm in diameter, present in front of the right hemicerebrum and well
      circumscribed on the cut surface. Histological examination revealed the tumor to
      be a hypercellular mass occupying the front part of the right lateral ventricle
      and expanding into the area in front of the hemicerebrum, continuing to the
      ependymal area at its edge. The tumor was constituted by columnar- or pleomorphic
      shaped, highly atypical cells of epithelial origin surrounding fibrovascular
      cores as single or multiple cell layers. Growth was papillary with high
      proliferating activity. Immunohistochemically, the tumor cells proved positive
      for cytokeratin but negative for vimentin, S100 protein or glial fibrillary
      acidic protein, a profile characteristic for the epithelial cells of the choroid
      plexus, whereas the ependymal cells were found to be positive for all 4 items. In
      conclusion, the present tumor was diagnosed as a rat choroid plexus carcinoma,
      only the third such case to be reported in the world literature, with particular
      features.

PMID- 15200167
TI  - Recommendations to guide determining cause of death in toxicity studies.

PMID- 15200168
TI  - Response to comments on E. Karbe and R. L. Kerlin (2002). Cystic
      degeneration/spongiosis hepatis (Toxicol Pathol 30 (2), 216-227).

PMID- 15200169
TI  - Transcription level of granule-associated phaP and phaR genes and granular
      morphogenesis of poly-beta-hydroxyalkanoate granules in Ralstonia eutropha.
AB  - The transcription levels of the granule-associated phaP and phaR genes in
      Ralstonia eutropha were regulated through the transformation of the phbC genes
      from R. eutropha and Alcaligenes latus into the poly-beta-hydroxybutyrate
      synthase-negative mutant. The granular morphogenesis of short chain length, poly
      beta-hydroxyalkanoate (scl-PHA) was closely associated with the mRNA
      transcription levels of the phaP and phaR genes, especially with the ratio of
      phaP/phaR genes. The phasin protein encoded by the phaP gene increased the number
      of granules, while the PhaR protein of the phaR gene enlarged the size of the scl
      PHA granules in R. eutropha.

PMID- 15200170
TI  - Increased xylitol production rate during long-term cell recycle fermentation of
      Candida tropicalis.
AB  - Long-term cell recycle fermentations of Candida tropicalis were performed over 14
      rounds of fermentation. The average xylitol concentrations, fermentation times,
      volumetric productivities and product yields for 14 rounds were 105 g l(-1), 333
      h, 4.4 g l(-1) h(-1) and 78%, respectively, in complex medium; and 110 g l(-1),
      284 h, 5.4 g l(-1) h(-1) and 81%, respectively, in a chemically defined medium.
      These productivities were 1.7 and 2.4 times those with batch fermentation in the
      complex and chemically defined media, respectively. The xylitol yield from xylose
      with cell recycle fermentation using the chemically defined medium was 81% (w/w),
      which was 7% greater than the xylitol yield with batch fermentation (74%); both
      modes of fermentation gave the same yield using the complex medium. These results
      suggest that the chemically defined medium is more suitable for production of
      xylitol than complex medium.

PMID- 15200171
TI  - Enhanced activity and enantioselectivity of Candida rugosa lipase immobilized on
      macroporous adsorptive resins for ibuprofen resolution.
AB  - The lipase from Candida rugosa was immobilized on three commercially available
      macroporous adsorptive resins for kinetic resolution of ibuprofen. One resin,
      CRB02, increased the enzyme activity by 50% to 0.027 g g(-1) min(-1). The
      deactivation constant (0.19 h(-1)) of the immobilized enzyme was half of that of
      the native enzyme and the enantioselectivity (E = 29.2) of the immobilized lipase
      was 2.2 times as much as that of the native lipase for the kinetic resolution of
      ibuprofen with 1-propanol in isooctane at 30 degrees C.

PMID- 15200172
TI  - Molecular cloning and sequence analysis of the chitinase gene from Bacillus
      thuringiensis serovar alesti.
AB  - Endogenous chitinase plays a positive role in the pathogenicity of Bacillus
      thuringiensis to insect pests. The chitinase gene was cloned from B.
      thuringiensis serovar alesti strain HD-16, and the deduced 676 amino acid
      sequence showed a high degree of similarity with other Bacillus chitinases.
      Additionally, the deduced amino acid sequence showed that the protein contained
      an amino terminus signal peptide and consisted of a catalytic domain, a
      fibronectin type III domain and a chitin-binding domain. All three domains showed
      conserved sequences when compared to other bacterial chitinase or cellulase
      sequences.

PMID- 15200173
TI  - Enhanced immunodetection of cell-free synthesized erythropoietin under denaturing
      conditions.
AB  - A monoclonal antibody produced by hydridoma cell line, ATCC HB8209, was used to
      detect and purify erythropoietin synthesized in a cell-free system. The antibody
      was raised against the N-terminal 20 residues of erythropoietin. It retained anti
      erythropoietin activity in 6 M urea in which most of the cell-free synthesized
      erythropoietin became soluble and gave an enhanced activity of the antibody.

PMID- 15200174
TI  - Biosensor based on Langmuir-Blodgett films of poly(3-hexyl thiophene) for
      detection of galactose in human blood.
AB  - An amperometric biosensor was developed to estimate galactose in human blood
      serum. Monolayers of poly(3-hexyl thiophene) were placed on glass plates coated
      with indium tin oxide formed by dispensing a mixed solution of stearic acid in
      chloroform on to a water sub-phase. Galactose oxidase was mixed with poly(3-hexyl
      thiophene)/stearic acid in chloroform and dispensed on to the air-water interface
      of Langmuir-Blodgett trough. These monolayers were transferred on to glass plates
      which were used as working electrodes with platinum as a reference electrode. The
      amperometric galactose biosensor thus fabricated had a linear response from 0.05
      to 0.5 g galactose l(-1) in blood serum. The normal level in blood is < 0.05 g
      galactose l(-1) in adults and 0-0.2 g galactose l(-1) in infants. In case of
      galactosemia, this increases to above 0.2 g galactose l(-1) in infants.

PMID- 15200175
TI  - Production of a biologically active growth hormone from giant catfish
      (Pangasianodon gigas) in Escherichia coli.
AB  - Giant catfish growth hormone (gcGH) cDNA was cloned and expressed in E. coli. The
      expected 20.5 kDa protein corresponded to the mature gcGH and was efficiently
      expressed. This protein was produced as inclusion bodies and comprised about 20%
      of total cellular proteins. The recombinant hormone promoted growth when injected
      intramuscularly or intraperitoneally into goldfish (Carassius auratus) at 0.1 or
      1 microg soluble gcGH per g fish body wt per week. In addition, the recombinant
      gcGH inclusions had growth-promoting activity similar to that of the soluble form
      when the fish was received either by intraperitoneal injection or by oral
      administration.

PMID- 15200176
TI  - Fluorescence spectroscopic study of alpha-chymotrypsin relevant to the
      enantioselectivity for optical resolution of amino acid esters in organic
      solvents.
AB  - The fluorescence emission wavelength of alpha-chymotrypsin (CT) correlated with
      its enantioselectivity (E value) for the resolution of DL-tyrosine ethyl ester.
      The changes in the E value of the CT due to the changes in the solvent
      composition were closely related to its fluorescence properties (delta
      lambda(em)), which were most probably associated with the structural modification
      of the enzyme. A linear relationship was established between E value and delta
      lambda(em) in aqueous acetonitrile with high correlation coefficients (r = 0.94).

PMID- 15200177
TI  - Site-directed mutagenesis establishes aspartic acids-227 and -342 as essential
      for enzyme activity in an isomalto-dextranase from Arthrobacter globiformis.
AB  - Isomalto-dextranase, from Arthrobacter globiformis T6, is a member of the
      glycoside hydrolase family 27. However, the alignments of the whole amino acid
      sequence are distinct from other members of this family. The enzymes cleave the
      glycosidic bond of the substrate in two different manners: either retaining or
      inverting the anomeric configuration. We believe that a retaining enzyme is
      involved in a two-step, double-displacement mechanism utilizing active site
      carboxylic acids as the nucleophile and general acid/base catalysts in the
      hydrolytic reaction. The critical amino acid residues at the isomalto-dextranase
      active site that catalyzes the hydrolysis reaction of dextran have been
      identified and the roles of nine amino acid residues (D107, D163, D227, D295,
      D340, D342, D373, D396, and E420) in the isomalto-dextranase from A. globiformis
      analyzed by site-directed mutagenesis. Of 15 mutant enzymes that were prepared,
      eight had reduced activities for dextran hydrolysis. Aspartic acids-227 and -342,
      which are part of the apparent catalytic dyad, were essential for hydrolase
      activity toward dextran.

PMID- 15200178
TI  - Chemoenzymatic synthesis of optically active, biodegradable polymers based on
      phenyl- and naphthyl-ethanols esterified with divinyladipate.
AB  - For the purpose of developing a new synthetic polymer containing an asymmetric
      molecule branch, three racemic alcohols, i.e. 1-phenylethanol, 1-(4
      methylphenyl)ethanol and 1-(2-naphthyl)ethanol, were esterified enzymatically
      with divinyladipate using a lipase from Pseudomonas cepacia. The enzymatic
      acylation of alcohols produced monoacylated products. Optically active
      polymerizable monomers, (R)-vinyl adipic acid (phenyl-1-yl) ethyl ester, (R)
      vinyl adipic acid (4-methylphenyl-1-yl) ethyl ester and (R)-vinyl adipic acid (2
      naphthyl-1-yl) ethyl ester with enantiometric excesses over 99%, 96% and 99%,
      respectively, were obtained. Each optically active monomer was then subjected to
      free radical polymerization, to give polymers having a number average molecular
      weight of 2.9 x 10(3) - 2.2 x 10(4). These polymers are considered useful as
      optically active polymers having biodegradability.

PMID- 15200179
TI  - Vindoline synthesis in in vitro shoot cultures of Catharanthus roseus.
AB  - Vindoline, the major alkaloid in cultures of Catharanthus roseus shoots, reached
      2 mg g(-1) dry wt after 27 d in culture. Maximal vindoline accumulation coincided
      with maximum activities of deacetoxyvindoline 4-hydroxylase, deacetylvindoline
      acetyl-CoA acetyl transferase and tryptophan decarboxylase. Shoot exposure to
      jasmonate shortened the time required for the maximal vindoline accumulation to
      14 d.

PMID- 15200180
TI  - Comparison of two beta-glucosidases for the enzymatic synthesis of beta-(1-6)
      beta-(1-3)-gluco-oligosaccharides.
AB  - A domain of epiglucan was synthesized by beta-glucosidases. Two beta
      glucosidases, an extracellular beta-glucosidase derived from Sclerotinia
      sclerotiorum grown on xylose, and a commercial lyophilized preparation of beta
      glucosidase from Aspergillus niger, were used to synthesize gluco
      oligosaccharides from cellobiose and, specially, beta-(1-6) branched beta-(1-3)
      gluco-oligosaccharides, corresponding to the structure of epiglucan. Gentiobiose,
      cellotriose, cellotetraose, beta-Glc-(1-3)-beta-Glc-(1-4)-Glc, beta-Glc-(1-6)
      beta-Glc-(1-4)-Glc and beta-Glc-(1-6)-beta-Glc-(1-3)-Glc were synthesized from
      cellobiose by both enzymes. The latter compound was preferentially synthesized by
      the beta-glycosidase from Sclerotinia sclerotiorum. Under the best conditions,
      only 7 g l(-1) of beta-Glc-(1-6)-beta-Glc-(1-3)-Glc was synthesized by the beta
      glycosidase from Aspergillus niger compared to 20 g l(-1) synthesized with beta
      glycosidase from Sclerotinia sclerotiorum.

PMID- 15200181
TI  - Tributyl phosphate degradation by Serratia odorifera.
AB  - Several strains from tributyl phosphate (TBP)-polluted soils were isolated and
      screened for their ability to degraded this widely used organophosphorus
      compound. The most active strain, identified as Serratia odorifera, degrades up
      to 600 microM TBP (initially present in the medium at 2 mM) during its growth
      phase, within 8 h from inoculation. However, this bacterium could not utilize TBP
      as the sole carbon and/or phosphorus source but nevertheless is a good candidate
      for bioremediation of TBP-polluted industrial sites.

PMID- 15200182
TI  - [Obstetric epidural analgesia: relationship between obstetric variables and the
      course of labor].
AB  - OBJECTIVES: To analyze the relationship between epidural analgesia and diverse
      obstetric and fetal variables as well as the impact of epidural analgesia on the
      rates of instrumental and cesarean delivery. PATIENTS AND METHODS: Observational
      study of women who gave birth at Fundacion Hospital Alcorcon over a period of 3
      years. All the women were offered obstetric epidural analgesia based on 0.0625%
      bupivacaine plus 2 microg/mL of fentanyl. The following data were recorded: age,
      nulliparity (yes/no) administration of epidural analgesia (yes/no), induction of
      labor (yes/no), stimulation of uterine activity with oxytocin (yes/no), type of
      delivery, fetal weight, duration of dilation, duration of expulsion, cause of
      cesarean. RESULTS: The records of 4364 women were gathered. The percentages of
      inductions, nulliparas, oxytocin stimulation, and fetal weight greater than 4 kg
      and less than 2.5 kg were higher among women taking epidural analgesia. The age
      of women who received epidurals was significantly lower. The durations of
      dilation and expulsion were longer among women receiving epidural analgesia, and
      epidural analgesia was associated with greater risk of instrumental and cesarean
      deliveries. The significant increase in administration of epidural blocks over
      the 3-year period of the study was not accompanied by an increased rate of
      instrumentally assisted deliveries or cesareans. CONCLUSIONS: It is difficult to
      evaluate the real influence of epidural analgesia on certain aspects of labor and
      its evolution. The strength of the association between epidural analgesia and
      greater risk of increased rates of instrumental and cesarean deliveries may be
      influenced by factors not considered in the present study.

PMID- 15200183
TI  - [Clinical effects and pharmacokinetics of ropivacaine and bupivacaine for
      epidural analgesia during labor].
AB  - OBJECTIVE: To compare the analgesic efficacy, pharmacokinetics and histamine
      release of ropivacaine and bupivacaine with fentanyl in continuous epidural
      perfusion during labor and childbirth. MATERIAL AND METHODS: Prospective study of
      40 women at full-term pregnancy who requested epidural analgesia. The patients
      were randomly assigned to 2 groups of 20: group R received an initial bolus dose
      of 10 mL of 0.25% ropivacaine and group B received 0.25% bupivacaine, followed in
      both groups by epidural infusion of the assigned drugs at a concentration of
      0.125% plus 0.30 mg of fentanyl at a rate of 5 mL/h through a patient-controlled
      analgesia device that allowed additional bolus doses. The studied variables were
      age, weight, height, sensory and motor block, mean blood pressure and maternal
      fetal heart rates, number of bolus doses, total local anesthetic administered,
      duration and type of delivery, oxytocin increase, Apgar at 1 and 5 minutes,
      plasma levels of local anesthetic (30 minutes after the initial dose, at the end
      of dilation, in the umbilical vein, and 30 minutes after switching off the
      perfusion pump), time to clearance, elimination half-life, and a test of
      histamine release by radioimmunoassay. RESULTS: No significant differences were
      observed in the course of labor or in Apgar scores. The plasma concentrations of
      ropivacaine were higher than those of bupivacaine (p<0.03). Clearance of both
      drugs was similar. The elimination half-life of ropivacaine was significantly
      less than that of bupivacaine (5.2 +/- 0.7 h vs. 10.8 +/- 1.06 h). CONCLUSIONS:
      Analgesia was equally effective in both groups, without adverse maternal-fetal
      effects, with spontaneous micturition and absence of motor blockade in both
      groups. The plasma concentrations were higher with ropivacaine but were not
      toxic.

PMID- 15200184
TI  - [Effects of sevoflurane on mid-latency auditory evoked potentials and the 95%
      spectral frequency limit].
AB  - OBJECTIVES: To investigate the effects of sevoflurane on mid-latency auditory
      evoked potentials (MLAEP) and compare them to changes in the encephalographic 95%
      spectral edge frequency (SEF95). PATIENTS AND METHODS: The effect of sevoflurane
      on MLAEP and SEF95 was studied in 15 patients. Anesthetic induction was carried
      out with propofol, remifentanil, and cisatracurium. After anesthetic induction,
      the patients were ventilated to achieve different expired concentrations of
      sevoflurane (1%, 1.5%, and 2%) during 3 consecutive 10-minute periods before the
      start of surgery. SEF95 and the amplitude and latency of the Na, Pa and Nb MLAEP
      waves were recorded. All the parameters were measured at baseline and during the
      different expired fractions of sevoflurane. RESULTS: The increase in sevoflurane
      concentration was accompanied by a significant decrease in amplitude and a
      statistically significant increase in latency of the Na, Pa and Nb waves.
      Likewise, SEF95 decreased significantly. A linear relation was demonstrated
      between sevoflurane concentration and the variables Na, Pa, Nb and SEF95.
      CONCLUSIONS: Our results indicate that the effect of sevoflurane on the MLEAP of
      Na, Pa and Nb is similar to that of other anesthetic gases. Even though the
      amplitude of the Na, Pa and Nb waves decreased in a dose-dependent way, SEF95
      correlated more strongly with sevoflurane concentration.

PMID- 15200185
TI  - [Hemostasis-altering drugs and regional anesthetic techniques: safety
      guidelines].
AB  - New developments--in the form of emerging clinical settings for regional
      anesthesia as well as problems arising with the concomitant use of regional
      techniques and hemostasis-altering drugs--require the ongoing revision of safety
      guidelines. The annual meeting of ESRA held in Spain in 2003 saw the discussion
      and clarification of a variety of issues of current concern, including
      conclusions reached on the estimated risk of spinal hematoma when published
      safety guidelines are followed or not, precautions to take in epidural anesthesia
      during cardiac surgery, guidelines for using fondaparinux for thromboprophylaxis,
      the circumstances under which neuroaxial techniques can be used safely in
      patients under the effects of platelet aggregation inhibitors such as
      thienopyridine, and the application of epidural anesthesia in parturients with
      eclampsia who have received platelet aggregation inhibitors. Conclusions drawn at
      the meeting enrich and clarify certain important safety issues related to local
      and regional anesthesia in patients receiving antiplatelet drugs and/or
      anticoagulants.

PMID- 15200186
TI  - [Ventilatory management of the severely brain-injured patient].
AB  - Mechanical ventilation is necessary for treating patients with severe brain
      injury because it guarantees the airway (through endotracheal intubation),
      permits sedation (and even curarization), and prevents hypoxemia and/or
      hypercapnia. Hyperventilation continues to be a focus of debate in the current
      literature. Nevertheless, the weight of scientific evidence to date suggests that
      it should not be applied prophylactically during the first 24 hours and that
      patients should not be hyperventilated for prolonged periods in the absence of
      intracranial hypertension. Acute lung injury and respiratory distress are among
      the most frequent and serious complications related to severe brain injury that
      benefit from the use of positive end-expiratory pressure (PEEP) and ventilation
      to protect the lung. Gas insufflation through the trachea is a promising
      therapeutic option for correcting hypercapnia secondary to ventilation for lung
      protection in such patients. Finally, multimodal monitoring (intracranial
      pressure, central venous pressure, oxygen saturation detected in the jugular
      bulb, cerebral oxygen pressure) is recommended for adjusting PEEP and controlling
      hyperventilation.

PMID- 15200187
TI  - [Severe anaphylactic reaction to metamizol during subarachnoid anesthesia].
AB  - A 59-year-old man with no relevant medical history underwent a right saphenectomy
      under subarachnoid anesthesia with mepivacaine. Administration of intravenous
      metamizol for postoperative analgesia was followed by severe anaphylactic
      reaction with respiratory failure and ventricular fibrillation. The patient
      recovered after orotracheal intubation and defibrillation. High serum tryptase
      levels 2 and 6 hours after the episode and positive skin prick tests confirmed
      the diagnosis of anaphylactic reaction mediated by immunoglobulin-E antibodies.
      Anaphylactic reactions to metamizol may be more common than would appear based on
      reports in the literature. When signs present suddenly with cardiovascular or
      respiratory involvement, symptomatic treatment should be started even in the
      absence of cutaneous or mucosal signs and allergy tests should be carried out
      immediately.

PMID- 15200188
TI  - [Bilateral compartment syndrome after surgical perfusion for chronic ischemia of
      the lower extremities].
AB  - A 61-year-old man diagnosed with advanced stage Leriche syndrome underwent
      revascularization surgery with placement of an aortobifemoral shunt and
      prosthesis under combined general and lumbar epidural anesthesia. After 6 hours
      he developed bilateral lower extremity compartment syndrome with acute anuric
      kidney failure caused by severe rhabdomyolysis. Thirty hours after surgery the
      patient suffered cardiac arrest due to hyperkalemia and was unresponsive to
      advanced cardiopulmonary resuscitation. The delay in diagnosis, in part owing to
      the epidural block provided for surgery, and loss of muscle mass led to the
      unfavorable outcome in this case.

PMID- 15200189
TI  - [PiCCO monitoring of 4 critically ill patients].
AB  - The PiCCO physiological monitor (Pulsion Medical Systems, Munich, Germany) was
      used for hemodynamic diagnosis and monitoring of 4 patients: a polytraumatized
      female patient with septic shock and ventilator-associated pneumonia; a man with
      congestive heart failure and cor pulmonale who developed acute heart failure
      while recovering from anterior resection of the rectum; a man with severe head
      injury and acute respiratory distress syndrome; and a polytraumatized male
      patient with a myocardial contusion. All were in a life-threatening situation,
      either immediately as in the case of the patient with myocardial contusion or
      eventually as in the patient with septic shock. The PiCCO monitor recorded
      hemodynamic parameters satisfactorily, facilitating adjustments to optimize
      treatment. The risks and complications of the usual method of monitoring by Swan
      Ganz catheter are well-known. New less invasive monitoring systems designed to
      record parameters similar to those detected by the Swan-Ganz catheter but with
      fewer complications and risks have become available. One example, the PiCCO
      monitor, combines arterial thermodilution with analysis of the pulse waveform,
      providing a series of hemodynamic parameters useful for managing the critically
      ill patient.

PMID- 15200190
TI  - [Open cholecystectomy under thoracic epidural anesthesia in diffuse interstitial
      lung disease].
AB  - Two patients, aged 73 and 58 years, with diffuse pulmonary fibrosis underwent
      emergency open cholecystectomies (subcostal approach) under thoracic epidural
      anesthesia with 0.5% ropivacaine and fentanyl in spontaneous ventilation.
      Pulmonary fibrosis was due to amiodarone administration in the first patient and
      of unknowon cause in the second. Both developed arterial hypotension without
      bradycardia in spite of optimal preloading. Inotropoic support with low doses of
      norepinephrine was requiered for recovery in both cases with no adverse events
      after reversion of the sympathetic blocks. Postoperative epidural analgesia was
      very satisfactory. Thoracic epidural anesthesia is a useful alternative to
      general anesthesia for subcostal cholecystectomy in patients with diffuse
      interstitial lung disease in advanced stages.

PMID- 15200191
TI  - [Two cases of anaphylactic shock after metamizol given during postoperative
      recovery].

PMID- 15200192
TI  - [Erythropoietin as an alternative to allogenic transfusion in major orthopedic
      surgery].

PMID- 15200193
TI  - [Full facial paralysis after a superficial cervical plexus block].

PMID- 15200194
TI  - [Usefulness of the new generation of pulmonary artery catheters].

PMID- 15200195
TI  - [Bilateral compartment syndrome as a complication of prolonged dorsal lithotomy
      positioning].

PMID- 15200196
TI  - [Complete inferior turbinate avulsion after nasotracheal intubation].

PMID- 15200197
TI  - [Importance of giving a detailed description of all critical events].

PMID- 15200198
TI  - Genetics of epilepsies.

PMID- 15200199
TI  - Ondansetron in prophylaxis of postoperative nausea and vomiting in patients
      undergoing breast surgery: a placebo-controlled double blind study.
AB  - The present study was to evaluate the efficacy of ondansetron, 5-HT3 receptor
      antagonist, versus placebo in the prevention of postoperative nausea and vomiting
      (PONV) in a homogenous group of female patients undergoing breast reduction
      surgery under general anaesthesia. Approximately one hour before skin closure, 70
      patients were randomly divided into two groups of 35 each. In a double blind
      manner each group of patients received either intravenous ondansetron (4mg) or a
      matching placebo. The overall incidences of PONV during first 24-hour were 60%
      and 20% in placebo and ondansetron group respectively (p<0.05). However, there
      was no significant difference after 24-hour postoperatively. In placebo group
      42.9% of patients received rescue anti-emetic (metoclopramide) for the treatment
      of severe PONV (ie, 2 or more episodes of PONV), whereas, only 8.6% patients were
      administered such intervention in the ondansetron group (p<0.05). It is,
      therefore, concluded that prophylactic administration of intravenous ondansetron
      (4mg) one hour before skin closure is safe and effective in preventing PONV in
      female patients undergoing breast surgery and routine use of ondansetron in the
      patient population is recommended.

PMID- 15200200
TI  - Arthroscopic evaluation of refractory knee pain.
AB  - The aim of this study was to evaluate the conditions of the articular cartilage
      and other intra-articular structures in patients with refractory knee pain. A
      total of 50 patients were taken up for this study based on specific inclusion
      criteria. Arthroscopy was done using a 30 degrees scope and was introduced most
      commonly via anterolateral approach after a thorough clinical and radiological
      evaluation of the affected joint. It was observed that majority (76%) had grade I
      articular lesion and 10% had grade IV lesion. Arthroscopically 78% of the
      patients had a meniscal tear while 12% had cyst of lateral meniscus while
      clinically, meniscal tear was present in 22% of the cases and cyst in 2% cases
      only. Arthroscopy also detects other intra-articular lesions, which are missed
      clinically, thus modifying further management of the patient.

PMID- 15200201
TI  - Youssef's syndrome--report of 7 cases and review of literature.
AB  - Seven patients in their thirties presented with cyclical haematuria, apparent
      amenorrhoea and urinary continence following lower segment caesarean section.
      Investigations confirmed the diagnosis of Youssef's syndrome. Four patients who
      had 2 children each opted for hysterectomy. The remaining 3 patients had excision
      of the fistula with repair of uterus and bladder. In this group, at 6 years
      follow-up, in spite of conceiving, 2 patients aborted with no further pregnancy
      reported.

PMID- 15200202
TI  - Empyema in children.
AB  - Closed chest drainage is very effective in the management of empyema thoracis.
      Fifty cases of empyema thoracis in children were treated in the department of
      cardiovascular and thoracic surgery, Regional Institute of Medical Sciences,
      Imphal between 1994 and 2000. The cases were referred from TB Hospital,
      Chingmeirong, Jawaharlal Nehru Hospital, Porompat and chest and paediatric wards
      of Regional Institute of Medical Sciences, Imphal. Most of the cases were managed
      with dosed chest intercostal drainage. The lung expanded well in majority of the
      cases. Forty cases were aspirated initially in the concerned departments. Only 10
      cases of massive empyema were aspirated in this department. Thirty-eight cases
      were treated with drainage and 4 cases were subjected to repeated aspiration.
      Eight cases of empyema (tuberculous) were subjected to thoracotomy and
      decortication. One case had recurrent empyema after decortication. Forty cases
      were given antituberculosis drugs.

PMID- 15200203
TI  - Approach to the problems of the aged.
AB  - In the older age, all body systems show decrements in physiological reserves.
      Degenerative process starts in this age and complications and sequelae of chronic
      long-term diseases eg, hypertension and diabetes make their appearance. In the
      elderly multiple pathologies are often encountered. Common disease conditions
      found in the elderly are: Parkinson's disease, depression, ischaemic heart
      disease, chronic obstructive lung disease, tuberculosis and cancer of the lung,
      osteo-arthritis of various joints, diabetes, hypertension, cataract, hearing loss
      and so on. While suggesting food for the elderly, one should take into account
      the small amounts of food with minimum sugar and fats but lots of fresh
      vegetables and fruits taken in small quantities but more frequently. Physical
      activity and exercise is good at all ages including old age. Psychological
      problems frequently arise among the elderly. They result from many factors eg,
      difficulties with memory, loss of hearing, financial difficulties, feeling of
      insecurity, chronic unrelieved pain, diffuse atrophy of the brain, etc.
      Depression is the commonest of the psychological problems of the aged.
      Alzheimer's disease, dementia are some other problems often arise out of the
      ageing process. All old people and not-so-old ones should be encouraged to
      continue stimulating mental activity with the same vigour as we advise them to
      continue physical activity.

PMID- 15200205
TI  - Giant Morgagnian hernia masquerading as pleural effusion.
AB  - Morgagnian hernia is a congenital diaphragmatic hernia which occurs through
      anteromedial defect in the diaphragm. A 58-year-old lady was referred for
      surgical management of chronic massive pleural effusion. High-resolution CT scan
      of the chest demonstrated an anteromedial defect in the diaphragm and with
      contents being colon and great omentum. She required anterolateral thoracotomy
      and reduction of hernia with repair of formen of Morgagni with prolene mesh.
      Blind needle aspiration would have punctured the colon; hence the case is being
      reported to highlight the necessity of CT scan/ultrasound of chest in
      investigating a chronic massive pleural effusion much before a needle is put for
      aspiration blindly.

PMID- 15200204
TI  - An unusual presentation of systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) is a multisystem connective tissue disease
      caused by the damage of tissues and cells by pathogenic auto-antibodies and
      immune complexes. A 27-year-old female presented with chronic diarrhoea was
      diagnosed as intestinal tuberculosis. But further evaluation diagnosed it a case
      of SLE and diarrhoea subsided with treatment. The case is reported because of its
      atypical presentation.

PMID- 15200206
TI  - Viscerohepatodiaphragmatic interposition (Chilaiditi's syndrome) in a child.
AB  - Viscerohepatodiaphragmatic interposition or Chilaiditi's syndrome is a rare
      congenital anomaly characterised by subphrenic displacement of the intestine
      resulting from a congenital anomaly of the hepatic ligaments. A six-year-old
      asymptomatic girl was screened for tuberculosis as her father was suffering from
      sputum-positive pulmonary tuberculosis. The chest radiograph showed normal lung
      fields, but a gaseous shadow was seen beneath the right dome of the diaphragm,
      which was confirmed, to be a case of Chilaiditi's syndrome on abdominal
      radiographs and ultrosonography. Although initially thought to be a benign
      condition, Chilaiditi's syndrome has been cited to be an important cause of acute
      abdomen. It is, therefore, important that the clinicians are aware of the
      condition when treating such a child.

PMID- 15200207
TI  - Sinonasal and nasopharyngeal adenoidcystic carcinoma: report of four cases.
AB  - Four cases of sinonasal and nasopharyngeal adenoidcystic carcinoma that came to
      the RIMS Hospital, Imphal during the period of July, 2002 to March, 2003 are
      reported in this article. The age incidence ranged from 30 to 80 years and the
      mean age was 47.5 years; with male to female ratio of 1:1. The average duration
      from first sympton in the patient to the date of his medical consultation was
      17.8 months. Nasal obstruction was the first symptom two cases; lump sensation in
      the throat and headache in the third and fourth cases respectively. Despite the
      evidence of rapid and extensive local spread there were definitely delays from
      the patients' end to consult a clinician. Whereas the tumour itself is not
      common, the usual sites, if it occurs, are palate and minor salivary glands and
      rarely mucous and seromucinous glands elsewhere.

PMID- 15200208
TI  - An unusual presentation of medial sphenoid wing meningioma.
AB  - A young woman of 26 years attended eye OPD with the complaints of complete and
      rapid loss of vision of her righ eye and progressive dimness of vision of left
      eye, frontal headache and nausea for last two months. On eye examination, she was
      found to have no perception of light to her right eye. Ophthalmoscopy examination
      revealed primary optic atrophy in right eye and marked papilloedema to her left
      eye. CT scan of brain showed space occupying lesion in right parasellar region
      with sellar and suprasellar extension with involvement of right anterior clinoid
      process suggesting medial sphenoid wing meningioma. The patient underwent surgery
      and the histopathology proved the diagnosis as meningioma. The case of medial
      sphenoid wing meningioma in a young female producing rapid Foster Kennedy
      syndrome is reported for its unusual presentation.

PMID- 15200209
TI  - Role of general practitioner in cancer management.

PMID- 15200211
TI  - Are doctors the healthiest?

PMID- 15200210
TI  - Jaundice as co-presentation in Thai malarial patients.

PMID- 15200212
TI  - Neurosyphilis and HIV seropositivity.

PMID- 15200213
TI  - Epidemiological study of neurological disorders.

PMID- 15200214
TI  - A clinical trial of the efficacy and safety of montelukast as monotherapy in
      patients with chronic stable bronchial asthma.
AB  - This study is aimed to evaluate the efficacy and safety of montelukast, as
      monotherapy, in the treatment of chronic stable bronchial asthma in adults. This
      was a multicentre, open label, non-comparative, prospective, 4-week study.
      Eligible patients discontinued all anti-inflammatory medication (steroids,
      chromoglycate sodium) 2 weeks prior to starting therapy with montelukast (10 mg
      daily). The primary efficacy criteria were improvements in forced expiratory
      volume in one second (FEV1), peak exploratory flow rate (PEFR) after 4 weeks of
      therapy. Secondary efficacy criteria were improvement in the patients' symptoms
      (assessed on an ordinal scale), decrease in discomfort levels (scored on a scale
      of 0-100), change in peripheral eosinophil counts, decrease in total daily dose
      of inhaled beta2 agonist (salbutamol). A total of 148 patients, mean age (+/- SD)
      40.21 +/- 13.70 years, were enrolled into the study. At the end of the study
      there were significant improvements in FEV1 and PEFR (29% and 28% increase
      respectively from baseline values, p<0.000001). The mean total daily dose of
      inhaled salbutamol decreased significantly from prestudy values of 461 +/- 332
      microg/day to 161 +/- 207 microg/day (p<0.000001). The mean eosinophil counts
      fell from 5.80 +/- 4.90% (+/- SD) to 4.84 +/- 4.42% (+/- SD) (p=0.02). Symptom
      scores improved significantly as did subjective assessment of discomfort. A total
      of 29 (19.6%) adverse events were reported, all of which were of mild to moderate
      intensity. Monotherapy with montelukast significantly improved parameters of
      asthma control. It was well tolerated with no reports of serious or severe
      adverse events.

PMID- 15200215
TI  - 78th All India Medical Conference: Guntur: 2003. Presidential address.

PMID- 15200216
TI  - Vertigo & driving--between the law and ethics.

PMID- 15200217
TI  - Total ankle replacement.
AB  - 29 patients underwent 30 Scandinavian Total Ankle Replacements (STAR) by a single
      surgeon, over a four year period (1997 to 2001). There were 12 primary osteo
      arthritic patients with 6 post traumatic. The mean age of these 18 patients was
      73. Eleven patients had rheumatoid arthritis and these had a mean age of 58 years
      at the time of surgery. One patient had bilateral replacements giving a total of
      30 prostheses inserted. On review dorsiflexion had increased from a mean of 7 to
      11 degrees while plantar flexion from 15 to 24 degrees. The American Orthopaedic
      Foot and Ankle hindfoot score was 95 (maximum 100) and the Kofoed ankle score
      revealed 17 excellent, 5 good and 4 fair. No patients had radiological evidence
      of loosening. Our intermediate term result for the STAR (W. Link GmbH & Co.,
      Hamburg, Germany) ankle replacement has yielded 90% excellent and good functional
      outcomes in a mixed osteo arthritic and rheumatoid population which mirrors the
      results of those published from Scandinavia.

PMID- 15200219
TI  - Managing exacerbations of COPD: room for improvement.
AB  - Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a major
      cause of hospital admissions. Because of the consequent morbidity, mortality and
      burden on hospital resources, COPD management guidelines have been formulated. We
      reviewed 62 consecutive patients with AECOPD admitted from September 1st to
      December 18th 2000 in St. Vincents University Hospital, Ireland, including 3
      months follow-up data, to evaluate the quality of care and in particular to
      assess the care of such patients by respiratory and non-respiratory physicians.
      There was a frequent failure to objectively confirm the diagnosis of COPD by
      spirometry (completed in 39 of the 51 patients who, at admission, had been
      previously labelled with COPD (76%), and in 53 out of 62 patients (85%) at the
      end of the study period), or to estimate severity by quantifying the FEV1 as a
      percentage of the normal predicted range (estimated in only 21 of the 39 patients
      who had spirometry previously performed (53%)). Those patients managed with input
      from respiratory physicians were more likely to have their diagnosis of COPD
      confirmed with spirometry (p < 0.05). They were also more likely to have out
      patient follow-up arranged at discharge (p < 0.05). There was a trend towards the
      more frequent prescribing of oxygen to hypoxic patients in "respiratory" than in
      "non-respiratory" managed cases (p = 0.182) and a shorter hospital stay (0.1 < p
      < 0.5). 4 out of 11 severely hypoxaemic patients at admission (PO2 < 7.3kPa) were
      not screened at discharge for possible long term oxygen therapy (36%). 20
      patients received combination antibiotic therapy with no infiltrate on CXR (32%).
      Pulmonary rehabilitation was offered to 12 patients (19%). 5 out of 18 current
      smokers had documented smoking cessation advice (28%) and none received smoking
      cessation pharmacotherapy. Finally we noted that the Hospital In-Patient Enquiry
      (HIPE) data and casualty department admission books were frequently misleading or
      medical records unlocatable (in 30 out of 92 cases (33%)). We conclude that the
      management of AECOPD at St. Vincent's University Hospital is frequently
      suboptimal, and may be managed better with respiratory physician involvement. In
      particular, there could be more frequent spirometric confirmation of the
      diagnosis of COPD, better screening for long term oxygen therapy and more
      conservative use of antibiotics. Audit is complicated by difficulty accessing
      relevant data.

PMID- 15200218
TI  - Establishing a plastic surgery trauma clinic.
AB  - Trauma is an increasing burden on resources both in terms of personnel, operating
      time and bed occupancy. We describe the introduction of a plastic surgery trauma
      clinic. This clinic was established in an effort to streamline the increasing
      number of trauma referrals. Under the previous system inappropriate admissions
      were occurring using up a valuable resource. This audit was performed to see if
      the "see and treat" plastic surgery trauma clinic has made an impact on the
      service offered and provided by our unit. One of the aims in establishing this
      clinic was to ensure a more efficient bed occupancy rates. The "see and treat"
      aspect of this clinic has been very effective with regard to this as 21% of
      patients were treated in the minor operations area within the clinic. A further
      26% of patients assessed in the clinic did not require admission or a surgical
      procedure. Prior to the establishment of this clinic both these groups of
      patients would have been admitted to the hospital and perhaps because of the
      delay to admission would have been managed in their own hospitals. From this
      audit we have proven that establishing a trauma clinic has enabled us to triage
      these patients in an effective manner, within a satisfactory time period and if
      appropriate, treat them at the time of review in the adjacent theatre.

PMID- 15200221
TI  - Idiopathic spinal cord hernia.
AB  - Idiopathic spinal cord hernia (ISCH) is a rare cause of slowly progressive spinal
      cord dysfunction. It is readily diagnosed on magnetic resonance imaging of the
      spine. The neurological deficit related to ISCH is often reversible once surgical
      exploration and reduction of the hernia is achieved. We present the case of a 37
      year-old lady with a ventral ISCH at the T4 level. There was a significant post
      operative improvement in her myelopathy post-operatively. ISCH should be
      considered in the differential diagnosis of progressive spinal cord neurological
      deficit.

PMID- 15200220
TI  - The "silver-haired" general medical services patient. Clinical activity of the
      non-means tested over-70's during their first six months.
AB  - The objective was to examine the impact on general practice clinical activity of
      the granting of medical cards to all patients over 70 years of age on 01.07.01
      under the General Medical Services (GMS) scheme. Retrospective case-control
      study. Chart review of 50 "new GMS" patients who received medical cards on
      01.07.01 compared with 50 "old GMS" patients with means tested medical cards on
      this date. Single-handed mixed urban/rural general practice in Ireland. 1.
      Attendance rates. 2. Health status as measured by total number of chronic
      diseases, prevalence of hypertension, diabetes and cardiovascular disease. 3.
      Quality of preventive care comprising influenza and pneumococcal vaccine uptake
      rates; hypertension control; hyperlipidaemia control; level of screening activity
      for hypertension, diabetes, hyperlipidaemia, prostate specific antigen (among
      men) and smoking behaviour. Comparisons were made both before and after free GMS
      care for all between the "old GMS" and "new GMS" patient groups. Behaviour of the
      "new GMS" group was also compared, both before and after GMS eligibility. Prior
      to universal eligbility "old GMS" patients attended more often (p=0.0002), had
      more documented chronic illness (p=0.0002), consumed more medications (p=0.0002),
      were more likely to be diagnosed hypertensive (p=0.0336) and to have prostate
      specific antigen (PSA) measurement (men only) (p=0.048) than "new GMS" patients.
      Within the first 6 months of free GMS care for all, the "new GMS" patients
      attended significantly more often than before with the percentage of high
      consulters increasing from 24% to 52% (p=0.0039), took more medications (from
      1.72 to 2.2), showed improvement in all quality of care parameters (with the
      exception of PSA screening which remained static) and had improved attendance for
      influenza 40% to 62% (p=0.0277) and pneumococcal vaccines 2% to 26% (p=0.00054).
      More "new GMS" patients were diagnosed as hypertensive (24% to 38%) to a
      prevalence no longer significantly different from the "old GMS" group. Free
      general practice care has impacted positively on this "new GMS" patient group of
      over 70's. Our data suggests that the low consultation rate of this group when
      fee paying may have resulted in less exposure to practice screening activities.
      The apparent better health status among this group may in fact be a facade
      masking undiagnosed chronic disease, notably hypertension.

PMID- 15200222
TI  - Aortic saddle embolus causing paraplegia.

PMID- 15200223
TI  - PNET of the hallux.
AB  - We present the case of a 21-year-old lady who presented with a peripheral
      primitive neuroectodermal tumour (pPNET) of the distal phalanx of the right great
      toe. She had an amputation through her metatarso-phalangeal joint, the diagnosis
      having been confirmed histologically. Although her resection margins were clear
      and radiological staging revealed no metastases, she was commenced on adjuvant
      chemotherapy due to the high rate of metastases associated with the disease. Her
      surgery came after two years of intermittent pain and swelling of her toe, during
      which time she was undergoing conservative management, with serial visits to the
      outpatients department, of a radiological (magnetic resonance imaging) diagnosis
      of a haemangioma. This case report details her background, diagnosis and
      treatment as well as presenting a literature review of what is an unusual tumour
      in a previously unreported site.

PMID- 15200224
TI  - Jet-skis and head injuries: a bridge too far?

PMID- 15200225
TI  - Childhood stroke following varicella infection.
AB  - Stroke in childhood remains unexplained in a significant proportion of those
      affected. We present a 4 year-old boy who presented with a stroke following a
      recent uncomplicated chickenpox infection. Varicella is increasingly recognized
      as a cause of acute ischaemic events in childhood and a recent history of
      chickenpox should be sought in children who present with a stroke.

PMID- 15200226
TI  - Safety of home and hospital birth--data does not support the conclusions.

PMID- 15200227
TI  - Unique dental needs of gender-based populations.

PMID- 15200229
TI  - Mental disorders in dental practice: a case report of body dysmorphic disorder.
AB  - Given the high prevalence of mental disorders in Western societies, dentists may
      be confronted with behaviors that may interfere with the safe and efficient
      delivery of dental care. This paper addresses the need for dentists to be aware
      of patient vulnerability factors and psychological problems due, for example, to
      the possible negative effects of psychological distress and critical incidents,
      and their consequences for both symptom presentation and dental treatment
      planning. This need for awareness is illustrated by a case report of a patient
      who developed body dysmorphic disorder (BDD)--a preoccupation with some imagined
      defect in physical appearance--following dental treatment.

PMID- 15200228
TI  - The oral health of children with Down syndrome in Ireland.
AB  - The authors investigated the oral health of a convenience sample of 71 children
      with Down syndrome. The study group had a lower caries prevalence but similar
      levels of unmet treatment needs as children at special and mainstream schools.
      Treatment experience varied with age: 5-year-olds had more extractions and fewer
      restorations, and 15-year olds had fewer extractions and more restorations. The
      number of teeth with fissure sealants was comparable to that of other children in
      Special Needs Schools. Although the study group had poor oral hygiene, a need for
      advanced periodontal treatment was not evident. Few had evidence of dental
      trauma. Malocclusion was prevalent. Through a government-funded program, most of
      the sample had seen a dentist within the previous year, and few parents reported
      problems accessing dental care. This study suggests that services targeted toward
      groups with special needs could generate outcomes comparable to those seen in
      other service users. A finding that also may hold true for other underserved
      populations.

PMID- 15200230
TI  - Granulocytic sarcoma: an atypical presentation in the oral cavity.
AB  - Acute myelogenous leukemia (AML) is a hematologic disorder that is characterized
      by an abnormal proliferation of immature myeloid cells. Granulocytic sarcomas are
      clusters of leukemic myeloid cells that may develop as a result of AML. Oral
      manifestations of AML are common and often involve enlargements of the gingiva
      and/or mucosal tissue from direct leukemia cell infiltration. We describe the
      case history of a 50-year-old man who had an ulcerative lesion of the oral mucosa
      that was determined to be a granulocytic sarcoma of AML-MO subtype. The
      combination of both the subtype and clinical presentation of the leukemia makes
      this presentation unusual, and to the best of our knowledge, of a type that has
      not been previously reported in the literature.

PMID- 15200231
TI  - Oral health for people with intellectual disability and high support needs:
      positive outcomes.
AB  - This qualitative study, based on phenomenological approaches, explored and
      documented four situations in which positive oral health outcomes occurred for
      people with mental retardation and moderate to high support needs. Strategies and
      environmental factors that contributed to these oral health outcomes were
      identified through 10 semistructured interviews conducted with 'key-players'
      supporting the oral health of the people with disabilities. Participants included
      dental professionals, direct support workers, and other professionals who cared
      for their four people with disabilities. Common strategies expressed in the
      interviews included "giving it a go"; maintaining consistency; facilitating
      positive experiences; taking as much time as needed; respecting and encouraging
      choice making; timeliness and frequency of dental appointments; communication
      between support workers, dental professionals and the person with mental
      retardation; problem solving; assisting the person with disability to learn
      skills; and desensitisation. Contributing factors in the physical, social, and
      organizational environment also were identified.

PMID- 15200232
TI  - Outreach dental service for persons with special needs in Hong Kong.
AB  - The authors describe the acceptance and efficiency of an outreach dental service,
      which provided oral health care to persons with special needs in Hong Kong.
      Portable dental equipment was transported to various institutions. Basic dental
      care including prevention, scaling, restoration, extraction, and denture repair
      was provided free of charge. Elderly adults living in institutions were the main
      service recipients, but other people with special needs, including physically
      disabled and persons with mental retardation were also reached. One-third of the
      patients had dental pain or sensitivity, and 70% had not visited a dentist for
      more than three years. Dental care was provided to 6,867 patients over four
      years. Feedback from the patients showed that more than 90% of them were
      satisfied with the service. These findings indicate that patients with special
      needs in Hong Kong are in great need of dental care. An outreach dental service
      appears to be both appropriate and efficient in providing care to these persons.

PMID- 15200233
TI  - Rubratoxin B elicits antioxidative and DNA repair responses in mouse brain.
AB  - Rubratoxin B (RB) is a mycotoxin with potential neurotoxic effects that have not
      yet been characterized. Based on existing evidence that RB interferes with
      mitochondrial electron transport to produce oxidative stress in peripheral
      tissues, we hypothesized that RB would produce oxidative damage to macromolecules
      in specific brain regions. Parameters of oxidative DNA damage and repair, lipid
      peroxidation, and superoxide dismutase (SOD) activity were measured across six
      mouse brain regions 24 h after administration of a single dose of RB. Lipid
      peroxidation and oxidative DNA damage were either unchanged or decreased in all
      brain regions in RB-treated mice compared with vehicle-treated mice. Concomitant
      with these decreased indices of oxidative macromolecular damage, SOD activity was
      significantly increased in all brain regions. Oxyguanosine glycosylase activity
      (OGG1), a key enzyme in the repair of oxidized DNA, was significantly increased
      in three brain regions--cerebellum (CB), caudate/putamen (CP), and cortex (CX)-
      but not in the hippocampus (HP), midbrain (MB), and pons/medulla (PM). The RB
      enhanced OGG1 catalytic activity in these brain regions was not due to increased
      OGG1 protein expression, but was a result of enhanced catalytic activity of the
      enzyme. In conclusion, specific brain regions responded to an acute dose of RB by
      significantly altering SOD and OGG1 activities to maintain the degree of
      oxidative DNA damage equal to, or less than, that of normal steady-state levels.

PMID- 15200234
TI  - Mouse Huntington's disease homolog mRNA levels: variation and allele effects.
AB  - Huntington's disease homolog (Hdh) mRNA levels in mice with different Hdh alleles
      were measured. Brain Hdh mRNA levels varied up to threefold in genetically
      identical wild-type mice, indicating nongenetic factors influence Hdh expression.
      Striatal Hdh mRNA levels from an allele with a repeat expanded to 150 CAGs were
      diminished compared with wild-type and showed variation that might contribute to
      phenotypic variability in the Hdh(CAG)150 knock-in mouse model. To determine
      whether Hdh mRNA levels are tightly regulated, we assessed these levels in mice
      heterozygous for a deletion of the Hdh promoter. The loss of one allele reduced
      Hdh mRNA levels in most tissues, suggesting mechanisms to maintain Hdh mRNA
      levels are not in effect and should not impede therapies designed to destroy
      mutant huntingtin mRNA. Finally, we found a correlation between tissue mRNA
      levels and the susceptibility of the Hdh locus to Cre-mediated deletion. The two
      tissues with the highest levels of Hdh mRNA, testes and brain, were the only
      tissues susceptible to Cre-mediated recombination between loxP sites at Hdh
      locus. In contrast, the same Cre-expressing line caused recombination in every
      tissue for loxP sites at another genomic location. The pattern of Cre
      susceptibility at Hdh suggests a correlation between chromatin accessibility and
      high levels of Hdh expression in testes and brain.

PMID- 15200235
TI  - A high proportion of chromosome 21 promoter polymorphisms influence
      transcriptional activity.
AB  - We have sought to obtain an unbiased estimate of the proportion of polymorphisms
      in promoters of human genes that have functional effects. We carried out
      polymorphism discovery on a randomly selected group of 51 gene promoters mapping
      to human chromosome 21 and successfully analyzed the effect on transcription of
      38 of the sequence variants. To achieve this, a total of 53 different haplotypes
      from 20 promoters were cloned into a modified pGL3 luciferase reporter gene
      vector and were tested for their abilities to promote transcription in HEK293t
      and JEG-3 cells. Up to seven (18%) of the 38 tested variants altered
      transcription by 1.5-fold, confirming that a surprisingly high proportion of
      promoter region polymorphisms are likely to be functionally important. The
      functional variants were distributed across the promoters of CRYAA, IFNAR1,
      KCNJ15, NCAM2, IGSF5, and B3GALT5. Three of the genes (NCAM2, IFNAR1, and CRYAA)
      have been previously associated with human phenotypes and the polymorphisms we
      describe here may therefore play a role in those phenotypes.

PMID- 15200236
TI  - Beta-catenin associates with human parainfluenza virus type 3 ribonucleoprotein
      complex and activates transcription of viral genome RNA in vitro.
AB  - Several studies have indicated that human parainfluenza virus type 3 (HPIV-3)
      requires polymeric actin for transcription of its genome RNA in vitro and in
      vivo. In the current study, we have identified beta-catenin, an actin-bound
      protein, as one of the transcriptional activators for HPIV-3 genome RNA. Beta
      catenin was packaged within the purified HPIV-3 virions and was associated with
      the HPIV-3 ribonucleoproteins (RNP) from infected cells. Moreover, purified beta
      catenin interacted with bacterially expressed HPIV-3 nucleocapsid protein (N) and
      phosphoprotein (P) fused to glutathione S-transferase (GST). Double-labeled
      immunofluorescent confocal microscopic analysis revealed colocalization of beta
      catenin with HPIV-3 RNP at cell periphery in infected cells. The HPIV-3 RNP
      associated beta-catenin functioned as a transactivator of HPIV-3 genome, because
      purified beta-catenin stimulated transcription of viral RNP in an in vitro
      transcription assay. These results demonstrate that beta-catenin, a
      multifunctional protein that is involved in cell-cell adhesion and embryogenesis,
      acts as one of the transcriptional activators of HPIV-3 genome RNA.

PMID- 15200238
TI  - Septin 3 gene polymorphism in Alzheimer's disease.
AB  - Septin 3 is a novel member of the septin subfamily of GTPase domain proteins that
      was recently identified in human neuronal cells. These proteins are involved in
      vesicle trafficking, neurite outgrowth, and neurofibrillary tangle formation;
      however, the expression and functional role of septin 3 in normal neuronal
      tissues and as an etiological agent in neurological disorders is currently
      unclear. To further characterize these parameters, the present study analyzed the
      expression of three isoforms of septin 3 (A, B, and C) in fetal and adult human
      brains and polymorphism of the septin 3 exon 11 microsatellite in control, pure
      Alzheimer's disease (AD), Lewy body variant (LBV) of AD, and Parkinson's disease.
      Septin 3 mRNAs for isoforms A and B, but not C, were detected in the frontal
      cortex of fetus and adult human samples, as measured by reverse transcription
      coupled polymerase chain reaction. Genotype analyses indicated that polymorphic
      septin 3 alleles were distributed in two peaks of frequency in both control and
      disease groups. Categorization of the alleles into short (S) and long (L) types
      revealed a significant difference between AD patients and controls (p = 0.034 by
      chi-square test). Furthermore, the S-allele homozygosity was significantly
      underrepresented in AD compared with control (p = 0.015 by chi-square test).
      These results suggest that polymorphism in exon 11 of septin 3 may have a
      determinative role in the pathogenesis of AD.

PMID- 15200237
TI  - Body weight and abdominal fat gene expression profile in response to a novel
      hydroxycitric acid-based dietary supplement.
AB  - Obesity is a global public health problem, with about 315 million people
      worldwide estimated to fall into the WHO-defined obesity categories. Traditional
      herbal medicines may have some potential in managing obesity. Botanical dietary
      supplements often contain complex mixtures of phytochemicals that have additive
      or synergistic interactions. The dried fruit rind of Garcinia cambogia, also
      known as Malabar tamarind, is a unique source of (-)-hydroxycitric acid (HCA),
      which exhibits a distinct sour taste and has been safely used for centuries in
      Southeastern Asia to make meals more filling. Recently it has been demonstrated
      that HCA-SX or Super Citrimax, a novel derivative of HCA, is safe when taken
      orally and that HCA-SX is bioavailable in the human plasma as studied by GC-MS.
      Although HCA-SX has been observed to be conditionally effective in weight
      management in experimental animals as well as in humans, its mechanism of action
      remains to be understood. We sought to determine the effects of low-dose oral HCA
      SX on the body weight and abdominal fat gene expression profile of Sprague-Dawley
      rats. We observed that at doses relevant for human consumption dietary HCA-SX
      significantly contained body weight growth. This response was associated with
      lowered abdominal fat leptin expression while plasma leptin levels remained
      unaffected. Repeated high-density microarray analysis of 9960 genes and ESTs
      present in the fat tissue identified a small set (approximately 1% of all genes
      screened) of specific genes sensitive to dietary HCA-SX. Other genes, including
      vital genes transcribing for mitochondrial/nuclear proteins and which are
      necessary for fundamental support of the tissue, were not affected by HCA-SX.
      Under the current experimental conditions, HCA-SX proved to be effective in
      restricting body weight gain in adult rats. Functional characterization of HCA-SX
      sensitive genes revealed that upregulation of genes encoding serotonin receptors
      represent a distinct effect of dietary HCA-SX supplementation.

PMID- 15200239
TI  - Expression of septin 3 isoforms in human brain.
AB  - Septin 3 is a novel member of the septin subfamily of GTPase domain proteins.
      Human septin 3 was originally cloned during a screening of genes expressed in
      human teratocarcinoma cells induced to differentiate with retinoic acid.
      Alternative splicing of the septin 3 gene transcript produces two isoforms, A and
      B, in the human brain, though their regional expression and physiological
      function remain to be determined. The purpose of the present study was to
      identify the expression patterns of human septin 3 isoforms in normal human brain
      and a human neuroblastoma cell line, SH-SY5Y, after retinoic acid-induced
      differentiation. The expression and distribution patterns of septin 3 isoforms A
      and B were similar and resembled that of another septin, CDCrel-1. Septin 3A and
      3B were expressed in normal human brain in a region-specific manner, with the
      highest level in the temporal cortex and hippocampus and the lowest level in the
      brainstem regions. Prominent immunoreactivity was observed diffusely in the
      neocortices in association with neuropils and punctate structures suggestive of
      synaptic junctions. Immunoprecipitation studies revealed that septin 3A, 3B, and
      CDCrel-1 form a complex in the frontal cortex of human brain. These findings,
      taken together, suggest that septin 3A and 3B, along with CDCrel-1, play some
      fundamental role(s) in synaptogenesis and neuronal development.

PMID- 15200240
TI  - Long-term outcomes after moderate to severe traumatic brain injury.
AB  - OBJECTIVE: This research examined the long-term outcomes of rehabilitation
      patients with moderate to severe traumatic brain injury (TBI). DESIGN:
      Retrospective cohort study. SETTING AND SUBJECTS: We examined consecutive records
      of persons with moderate to severe traumatic brain injury who were discharged
      from a large rehabilitation hospital in Pennsylvania from 1973 to 1989. We
      interviewed consenting participants (n = 306) up to 24 years post-injury. MAIN
      OUTCOME MEASURES: Self-rated health, activity limitations, employment, living
      arrangements, marital status, Community Integration Questionnaire, and use of
      rehabilitation services. RESULTS: Participants were most limited in activities
      such as managing money and shopping. Twenty-nine per cent of our participants
      were working full time. There were significant relationships between activity
      limitations and residual cognitive impairment at follow-up. Self-rated health was
      correlated with most instrumental activities of daily living. CONCLUSION: Our
      findings document health and function in a large post acute TBI population and
      implications for rehabilitation are discussed.

PMID- 15200241
TI  - Activity limitations in personal, domestic and vocational tasks: a study of
      adults with inborn and early acquired mobility disorders.
AB  - PURPOSE: To compare activity limitations at the workplace with those in the home
      situation. SUBJECTS AND METHODS: Sixty-nine subjects, 22-49 years of age, with
      inborn or early acquired mobility disorders and with experience of vocational
      employment were studied. They were interviewed to assess their level of
      dependence according to the Functional Independence Measure (FIM) and
      Instrumental Activity Measure (IAM) and in 22 vocation-related items. Rasch
      analysis was perfomed in order to assess the relative difficulty of the items. In
      the vocational items the subjects rated perceived difficulty on a 4-level scale.
      Satisfaction in one general and six domain-specific areas was rated on a 6-level
      scale. RESULTS: Forty-six per cent of the subjects were dependent in one or
      several FIM items, 90% in IAM items and 38% in the vocation-related items. In 15
      of these items great difficulty was reported by few subjects. Collapsing the 7
      category scale for dependence to four categories gave the best Rasch model. Most
      of the IAM items were the hardest to manage without assistance. FIM social
      cognitive and cognitive vocation-related items were the easiest items. Most
      subjects were satisfied in the general and domain-specific areas. CONCLUSIONS:
      Activities related to household tasks and transportation demonstrated the highest
      level of dependence, whereas it was easier to acquire independence in most
      vocation-related tasks.

PMID- 15200242
TI  - Measuring disability with parsimony: evidence for the utility of a single item.
AB  - PURPOSE: To provide evidence for the utility of a single item measure designed to
      quantify disability in the past 30 days. METHOD: Australian data from studies
      comprising a community-dwelling elderly sample (N = 328) and a sample of chronic
      osteoarthritis (OA) patients (N = 119) are reported. Degree of disability was
      classified as 0-30 days, 0 vs. 1 or more days, and 0-9 vs. 10 or more days.
      Associations between disability and a range of demographic, health-related, and
      psychological variables were assessed. RESULTS: Participants with OA reported a
      significantly higher level of disability than participants from the community
      sample regardless of how disability was classified. Modest levels of association
      were noted between the number of disability days (0-30) and both health and
      psychological indices in both samples. The three alternative classifications of
      disability made little difference to the significance of associations. On
      balance, the comparison of 0-9 vs. 10 or more days appeared the more predictive
      classification of disability. CONCLUSIONS: The performance of the single item
      measure of disability was generally very satisfactory. Future investigations into
      the clinical application of the item across a range of patient groups are
      encouraged.

PMID- 15200243
TI  - A pilot study of functional access to public buildings and facilities for persons
      with impairments.
AB  - PURPOSE: To compare functional access to public buildings and facilities for
      persons with and without impairments. METHOD: This is a cross-sectional pilot
      study with a survey design. A four-member participant team representing three
      impairment types: mobility impaired person using a wheelchair, mobility impaired
      person who was not a wheelchair user, visually impaired person, and a control
      with no known impairments, challenged a stratified random sample of 30 public
      buildings in Greater Boston. Using a task oriented data collection instrument,
      functional access was determined in terms of percentage of tasks performed, time,
      distance, barriers and facilitators. RESULTS: Overall, task performance was high
      for the team. However, the wheelchair user reported a lower task performance
      (81%) in comparison to the control (100%) and persons with mobility and visual
      impairments (97-98%). There was little variation in mean values for time and
      distance to complete tasks. More barriers were reported by the persons with
      mobility impairments, wheelchair user and non-wheelchair user, and; highest
      facilitators by the person with visual impairment and the wheelchair user. The
      control reported the lowest barriers and facilitators. The types of barriers and
      facilitators varied for the three impairments and the control structural for
      wheelchair and mobility impairments, wayfinding for visual impairment and
      interpersonal for control. CONCLUSIONS: Task performance by itself may not be a
      good predictor of functional access. Barriers and facilitators are critical to
      understanding issues related to functional access for persons with impairments.
      Knowledge of how these differ for different impairments can be useful for
      improving environmental access and rehabilitation.

PMID- 15200244
TI  - Success in the workplace following traumatic brain injury: are we evaluating what
      is most important?
AB  - PURPOSE: Vocational outcome, and in particular full-time paid work, is considered
      an important indicator of successful rehabilitation following traumatic brain
      injury (TBI). However it has not been established that these outcomes adequately
      or accurately represent the values of the people with TBI. This paper describes a
      study exploring the experiences of individuals who attempted returning to work
      following TBI, with emphasis on factors that related to perceptions of 'success'
      or 'failure'. METHOD: A phenomenological study, interviewing seven people with
      moderate to severe TBI was conducted. The interview data were analysed for themes
      relating to experiences of success or failure in the workplace. Community
      consultation provided additional perspectives in the interpretation and
      validation of results. RESULTS: The results of this study support in part the
      assumption that paid employment is indicative of success following TBI. Equally
      prevalent were findings that challenged this assumption, including situations
      where: (1) return to employment contributed to catastrophic personal events, (2)
      feelings of success were achieved even though paid employment was not, and (3)
      success in the workplace was associated with factors other than hours worked or
      pay earned. CONCLUSIONS: This research suggests that the use of work placement as
      a measure of successful rehabilitation might misrepresent the perspective of
      individuals with TBI. A multifactorial approach to evaluating vocational
      rehabilitation is recommended, which incorporates the subjective experience of
      work.

PMID- 15200245
TI  - How can a work rehabilitation process be improved?--a qualitative study from the
      perspective of social insurance officers.
AB  - PURPOSE: The aim of this study is to describe social insurance officers'
      experiences of a work rehabilitation process at a rehabilitation centre in the
      northern parts of Sweden. In Sweden the social insurance company has a key role
      to coordinate all efforts concerning work rehabilitation planning between all
      rehabilitation actors. METHOD: Ten social insurance officers at the social
      insurance company in a city in northern Sweden were interviewed using a narrative
      approach about their experiences of work rehabilitation processes in general. The
      interviews were analysed by qualitative content analysis with a focus on their
      experiences of goals, content and results of a work rehabilitation process.
      RESULTS: The social insurance officers' experiences of how a work rehabilitation
      process could be improved were described in six categories; (1) Early
      identification of problems, needs and interventions (2) clear goal formulations,
      (3) a focus on psychosocial factors (4) a greater variety of possible
      interventions, (5) activating employers to a higher extent in work rehabilitation
      and (6) a closer cooperation and information exchange with other rehabilitation
      actors. CONCLUSIONS: It is possible to improve a work rehabilitation process by
      focusing on early identification of problems, needs and interventions, with a
      variety of interventions to choose between and with clear goal formulations and
      recognizing psychosocial factors in the process. To activate employers to a
      higher extent in work rehabilitation and to make the information exchange between
      rehabilitation actors more frequent may also improve work rehabilitation
      processes.

PMID- 15200246
TI  - Paediatric traumatic brain injury in South Africa: some thoughts and
      considerations.
AB  - PURPOSE: This paper endeavours to describe the socio-political and economic
      backdrop to the assessment and management of traumatic brain injury (TBI) in
      children in South Africa. OUTCOMES: The argument put forward is that huge
      disparities in socio-economic status, diverse socio-cultural influences, and
      widely differing educational systems and educational attainment which
      characterize the country's population, render the management of TBI different
      from approaches adopted in developed countries. The main causes of TBI can be
      attributed to the high rates of violence in the country, as well as an
      inordinately high incidence of motor vehicle accidents. Compensation through
      existing national legislative and insurance agencies is unavailable to most of
      the population, and markedly insufficient in many cases. The access to medical
      care and rehabilitation is inadequate for the majority of South African children,
      although there are valiant efforts on the part of professionals working within
      the primary health care model to provide the support to the children and their
      families not offered by existing educational and school structures. CONCLUSION:
      The impact of the HIV/AIDS pandemic on the clinical picture of children and their
      families is profound and guides many of the decisions that are made by health
      care professionals. Given this bleak scenario, a re-focus on the strengths of
      existing structures and the creation of new possibilities is suggested, as a
      positive and constructive approach to prevention, rehabilitation, and education.

PMID- 15200247
TI  - Ontogeny of renal sodium transport.
AB  - One of the main functions of the adult kidney is to maintain a constant
      extracellular fluid balance. The adult kidney does this, by and large, by
      filtering a massive quantity of fluid and reabsorbing the solutes needed to
      maintain volume and electrolyte homeostasis, while leaving the waste products to
      be excreted in the urine. One of the most precisely regulated functions of the
      adult kidney is to maintain sodium balance. The challenge of the neonatal kidney
      is even greater. It must maintain a positive salt balance for growth while the
      neonate is fed a diet that is very low in sodium. This review focuses on how the
      neonatal kidney reabsorbs NaCl with a special emphasis on the differences between
      the neonatal and adult kidney.

PMID- 15200248
TI  - Neonatal acid base balance and disturbances.
AB  - Maintaining acid base balance presents a considerable challenge to the growing
      neonate. The infant must ingest protein for growth and development. The
      metabolism of sulfur containing amino acids leads to the production of protons
      that must be secreted by the kidney. In addition, the formation of hydroxyapatite
      for the mineralization of growing bone also leads to acid production. Thus, the
      growing infant must excrete approximately 2 to 3 mEq of acid per kilogram of body
      weight per day to avoid becoming acidotic. The mechanisms for excreting acid
      undergo complex maturational changes that predispose the neonate, and the
      premature neonate in particular, to a great risk for the development of acidosis.
      In addition, infants are susceptible to gastrointestinal disturbances that can
      lead to acidosis due to acute loss of bicarbonate in the stool. The kidney is
      then responsible for the production of new bicarbonate to restore the body's acid
      base balance. There are also a number of inherited disorders in the kidney that
      affect acid secretion and lead to acid base disturbances in neonates. This review
      discusses the mechanisms by which the kidney is capable of excreting acid as well
      as the developmental regulation of these processes and the basis of inherited
      disorders of acidification.

PMID- 15200249
TI  - Renal potassium handling in healthy and sick newborns.
AB  - Growing infants must maintain a state of positive K+ balance, a task
      accomplished, in large part, by the kidney. The distal nephron is uniquely
      adapted to retain total body K+ early in life. The magnitude and direction of net
      K+ transport in the cortical collecting duct (CCD), the segment responsible for
      the final renal regulation of K+ balance in the adult, reflect the balance of
      opposing fluxes of K+ secretion and K+ absorption. Evidence now indicates that
      the low capacity of the neonatal CCD for K+ secretion is due, at least in part,
      to a relative paucity of conducting K+ channels in the urinary membrane. A
      relative excess of K+ absorption in this nephron segment may further reduce net
      urinary K+ secretion. Under conditions prevailing in vivo, the balance of fluxes
      in the CCD likely contributes to the relative K+ retention characteristic of the
      neonatal kidney.

PMID- 15200250
TI  - Acute renal failure in the newborn.
AB  - Acute renal failure in the newborn is a common problem and is typically
      classified as prerenal, intrinsic renal disease including vascular insults, and
      obstructive uropathy. In the newborn, renal failure may have a prenatal onset in
      congenital diseases such as renal dysplasia with or without obstructive uropathy
      and in genetic diseases such as autosomal recessive polycystic kidney disease.
      Acute renal failure in the newborn is also commonly acquired in the postnatal
      period because of hypoxic ischemic injury and toxic insults. Nephrotoxic acute
      renal failure in newborns is usually associated with aminoglycoside antibiotics
      and nonsteroidal anti-inflammatory medications used to close a patent ductus
      arteriosis. Alterations in renal function occur in approximately 40% of premature
      newborns who have received indomethacin and such alterations are usually
      reversible. Renal artery thrombosis and renal vein thrombosis will result in
      renal failure if bilateral or if either occurs in a solitary kidney. Cortical
      necrosis is associated with hypoxic/ischemic insults due to perinatal anoxia,
      placenta abruption and twin-twin or twin-maternal transfusions with resultant
      activation of the coagulation cascade. As in older children, hospital acquired
      acute renal failure is newborns is frequently multifactorial in origin. Although
      the precise incidence and prevalence of acute renal failure in the newborn is
      unknown, several studies have shown that acute renal failure is common in the
      neonatal intensive care unit. Recent interesting studies have demonstrated that
      some newborns may have genetic risks factors for acute renal failure. Once
      intrinsic renal failure has become established, management of the metabolic
      complications of acute renal failure continues to involve appropriate management
      of fluid balance, electrolyte status, acid-base balance, nutrition and the
      initiation of renal replacement therapy when appropriate. Renal replacement
      therapy may be provided by peritoneal dialysis, intermittent hemodialysis, or
      hemofiltration with or without a dialysis circuit. The preferential use of
      hemofiltration by pediatric nephrologists is increasing while the use of
      peritoneal dialysis is decreasing except for neonates and small infants.
      Peritoneal dialysis has been a major modality of therapy for acute renal failure
      in the neonate when vascular access may be difficult to maintain. In the newborn,
      the prognosis and recovery from acute renal failure is highly dependent upon the
      underlying etiology of the acute renal failure. Factors that are associated with
      mortality include multiorgan failure, hypotension, need for pressors, hemodynamic
      instability, and need for mechanical ventilation and dialysis. The mortality and
      morbidity of newborns with acute renal failure is much worse in neonates with
      multiorgan failure. Newborns who have suffered substantial loss of nephrons as
      may occur in cortical necrosis are at risk for late development of renal failure
      after apparent recovery from the initial insult. Similarly, hypoxic/ischemic and
      nephrotoxic injury to the developing kidney can result is decreased nephron
      number. Newborns with acute renal failure need life-long monitoring of their
      renal function, blood pressure, and urinalysis. Typically, the late development
      of chronic renal failure will first becomes apparent with the development of
      hypertension, proteinuria, and eventually an elevated blood urea nitrogen and
      creatinine.

PMID- 15200251
TI  - Perinatal obstructive nephropathy.
AB  - Significant advances have been made recently in elucidating the cellular
      consequences of urinary tract obstruction during renal development. Urinary tract
      obstruction impairs growth and maturation of the kidney, and can also cause renal
      maldevelopment. This includes a reduction in the number of nephrons, tubular
      atrophy, and progressive interstitial fibrosis. Apoptosis (programmed cell death)
      accounts for much of the loss of tubular epithelial cells. Factors contributing
      to apoptosis include stretching of cells in dilated tubules, altered renal
      production of growth factors, and infiltration of the renal interstitium by
      macrophages. Two major controversies remain regarding the surgical management of
      congenital obstructive nephropathy: first, which fetuses with bladder outlet
      obstruction should undergo prenatal intervention, and second, which infants
      should undergo early pyeloplasty for ureteropelvic junction obstruction? Even
      after successful surgery for congential obstructive nephropathy, all patients
      should be followed for hypertension, proteinuria, or renal deterioration.

PMID- 15200252
TI  - Pharmacogenomics and renal drug disposition in the newborn.
AB  - Genetic polymorphisms in the genes coding for drug metabolizing enzymes, drug
      transporters, and drug receptors are major determinants of an individual's
      response to drugs. The potential interactions of pharmacogenomics of renal drug
      transporters and drug receptors with renal drug disposition and the immature
      kidneys are briefly reviewed. Examples of gene polymorphisms seen in the RAAS
      (renin angiotensin system), beta-adrenergic receptors, dopamine receptors and
      cytochrome P450 and their potential clinical impact are discussed. The human
      newborn has deficient hepatic and renal drug metabolism and disposition. This
      immaturity in drug-handling capacity may potentially be superimposed to genetic
      polymorphisms determining drug metabolism and transport thereby substantially
      increasing interpatient variability in drug dose requirements and in drug
      responses in the newborn. Pharmacogenomics is a tool that can be used to
      individualize drug therapy in newborns to minimize adverse drug effects and to
      optimize efficacy.

PMID- 15200253
TI  - Neonatal blood pressure regulation.
AB  - Hypertension is often viewed solely as a disease of the adult. However, early
      indicators of hypertension are frequently observed in young children and
      neonates. Having an adequate appreciation of the normal range of infant blood
      pressure is critical for the appropriate management of the conditions associated
      with elevated or abnormally low blood pressure. In healthy neonates, systolic
      blood pressure increases rapidly during the first 6 weeks of life with the most
      rapid rise observed during the first 5 days. A similar pattern is observed for
      diastolic pressures. The observed increases in blood pressure are positively
      correlated with birth weight and both gestational and postnatal age. The
      incidence of hypertension in the neonate has been reported to range from 0.2% to
      2.6% and is frequently an indicator of other renal or cardiovascular
      abnormalities. Systemic hypotension is reported in 24% to 45% of very low birth
      weight infants and is frequently caused by hypovolemia. The regulation of blood
      pressure is complex and the mechanisms involved remain to be fully elucidated.
      The results of several investigations into the molecular mechanism(s) of
      hypertension are considered.

PMID- 15200254
TI  - In vitro prediction of canine urolith mineral composition using computed
      tomographic mean beam attenuation measurements.
AB  - Determination of urolith mineral composition is critical for management of
      urolithiasis in dogs and cats. Using computed tomography, urolith physical
      density, and hence chemical composition, can be quantified using mean beam
      attenuation measurements (Hounsfield units; HU). This study was designed to
      establish in vitro reference ranges for three types of compositionally pure
      uroliths retrieved from dogs. Sixty-six canine uroliths (22 uric acid, 21 calcium
      oxalate, 14 struvite, nine mixed or compound) were placed in a phantom array.
      Uroliths were scanned at 120 kVp, 200 mA, and 80 kVp, 200 mA. The region of
      interest (ROI) for mean HU calculation was determined using two techniques, and
      reference ranges were calculated for each kVp using either ROI technique. HU for
      urolith types of pure composition were statistically different (Wilcoxon's two
      sample test, P < 0.0083 [Bonferonni correction with six comparisons for total P <
      0.05]) using both ROI techniques at either kVp. Struvite uroliths were not
      statistically different from mixed or compound uroliths. The accuracy for
      determination of composition of pure uroliths ranged from 86% to 93%; the
      prediction accuracy for each urolith mineral type and for all uroliths in general
      was highest when the ROI was hand-drawn just within the visible urolith border at
      80 kVp. Technique of ROI determination and kVp that yielded the highest
      sensitivity, specificity, and positive and negative predictive values varied for
      each urolith type. Therefore, in this study, HU could be used to differentiate
      three types of uroliths of pure mineral composition in vitro. Further studies are
      needed to determine the predictive value of HU in vivo.

PMID- 15200255
TI  - Magnetic resonance imaging of the palmar aspect of the equine podotrochlear
      apparatus: normal appearance.
AB  - The purpose of this study was to describe the normal magnetic resonance (MR)
      imaging characteristics of the palmar structures of the equine podotrochlear
      apparatus by means of retrospective evaluation of MR imaging studies of 16
      cadaver limbs. The articular aspect of the distal sesamoid bone was not evaluated
      in this study. Equine digits were imaged with a human knee radiofrequency coil in
      a 1.5 T magnetic field, using spin echo (SE) T1-weighted, turbo spin echo proton
      density (TSE PD)-weighted with and without fat saturation (FS), and FS TSE T2
      weighted sequences. The limbs were dissected after imaging to validate the
      absence of gross abnormalities of the flexor aspect of the distal sesamoid bone,
      of the deep digital flexor tendon, and the distal impar sesamoidean ligament.
      Seven deep digital flexor tendons were subjected to histologic examination to
      exclude any microscopic tendon pathology. The anatomic structures of the
      podotrochlear apparatus were easily identified on MR images. Compact bone of the
      flexor cortex of the distal sesamoid bone had low intensity signal on all
      sequences. In 11 digits an increased signal was seen within the thickness of the
      sagittal eminence of the flexor cortex in SE T1-weighted images and in TSE PD
      weighted images without FS. Trabecular bone had a granular appearance and high
      signal in SE T1-weighted sequences and TSE images without FS. The deep digital
      flexor tendon had low signal on FS T2-weighted images, while on short echo time
      sequences (T1- and PD-weighted sequences), the tendon signal varied depending on
      the relative orientation between its fibers and the static magnetic field. Seven
      tendons had stippled appearance due to small intratendonous foci of slightly
      increased signal on transverse T1-weighted images. MR imaging provides a thorough
      evaluation of the anatomical structure of the podotrochlear apparatus: A good
      knowledge of the MR imaging appearance and anatomy and an awareness of potential
      pitfalls will improve diagnostic specificity for the detection of pathologic
      changes.

PMID- 15200256
TI  - Pneumatosis in canine gastric dilatation-volvulus syndrome.
AB  - Retrospectively, 243 dogs with radiographic evidence of gastric dilatation
      volvulus (GDV) were studied for radiographic signs of pneumatosis (intramural
      gas), pneumoperitoneum, splenomegaly, and severity of gastric distention. The
      sensitivity, specificity, and predictive value of these imaging signs as
      predictors of gastric wall necrosis, as determined by visual inspection at
      surgery or necropsy, were determined. The sensitivity and specificity of gastric
      pneumatosis were 14.1% and 92.7%, respectively. The prevalence of gastric wall
      necrosis was 26.6%. The positive and negative predictive values of gastric
      pneumatosis for predicting gastric necrosis were 40.9% and 74.9%, respectively.
      Gastric pneumatosis and pneumoperitoneum were identified together in four dogs.
      Pneumoperitoneum, either alone or in conjunction with pneumatosis, yielded
      similar results as a test for gastric necrosis. Splenomegaly and severity of
      gastric distention were insensitive and nonspecific for gastric wall necrosis.
      Splenomegaly did not predict the need for splenectomy at surgery. Although
      pneumatosis and pneumoperitoneum are relatively specific signs of gastric wall
      necrosis, the utility of these signs as a test for gastric necrosis is limited in
      clinical practice. The significance of pneumatosis should be taken into
      consideration with previous treatments for gastric decompression, as percutaneous
      gastric trocharization or orogastric intubation may increase the number of false
      positive results.

PMID- 15200257
TI  - Magnetic resonance imaging of a brain abscess in a 10-month-old filly.
AB  - The purpose of this paper was to correlate the magnetic resonance imaging (MRI)
      characteristics of a mature brain abscess in a horse with histopathologic
      alterations of brain tissue. Eight months after the onset of clinical signs, MRI
      of the brain of a 10-month-old filly was performed. A large space-occupying
      lesion in the right cerebral hemisphere was identified. This space-occupying
      lesion was delineated by a thick and well-defined capsule that was isointense to
      brain parenchyma on the T1-weighted images and with a markedly hypointense on the
      T2-weighted images. The identification of such a capsule is highly diagnostic of
      a mature brain abscess. The lesion seen on MR images was confirmed at necropsy
      where a large abscess of the right hemisphere was observed. Streptococcus
      zooepidemicus and Pseudomonas aeruginosa were isolated from the abscess. Based on
      histopathologic examination, the signal characteristics of the capsule on T1
      weighted and T2-weighted images were found to be due to the presence of numerous
      hemosiderin-laden macrophages. These results are in agreement with previous
      studies on human patients. This report confirms the value of MRI in the diagnosis
      of equine brain diseases.

PMID- 15200258
TI  - Use of traction during magnetic resonance imaging of caudal cervical
      spondylomyelopathy ("wobbler syndrome") in the dog.
AB  - Cervical spondylomyelopathy or "wobbler syndrome" is a well-defined disorder of
      large-breed dogs, characterized by a compressive lesion affecting the cervical
      spinal cord that in many dogs may have a dynamic component. Determination of
      whether this dynamic component is present is important in the decision-making
      process as regards therapeutic intervention. Despite a significant risk of
      neurologic deterioration following myelography in some large dogs affected by
      wobbler syndrome, myelography is considered an essential part of the assessment,
      primarily as it allows assessment of whether a dynamic compression exists. This
      same neurologic deterioration is not apparent following magnetic resonance (MR)
      imaging; however, the use of MR imaging in the investigation of wobbler syndrome
      has thus far been limited by the inability to perform the traction studies
      required to ascertain whether a dynamic component to the spinal cord compression
      exists. This paper presents a technique of applying traction during MR imaging of
      the cervical spine to reduce a dynamic wobbler syndrome lesion.

PMID- 15200259
TI  - Accuracy of increased large-intestine wall thickness during ultrasonography for
      diagnosing large-colon torsion in 42 horses.
AB  - Large-colon torsion is a common cause of colic in horses and has a worse
      prognosis and higher cost than other causes of surgical colic of the large colon.
      During large-colon torsion, the colon wall becomes thick due to vascular
      occlusion. Therefore, we hypothesized that detecting increased colon wall
      thickness during ultrasonography would be an accurate preoperative test for large
      colon torsion. The sample population consisted of 42 horses that were admitted
      for surgical treatment of colic localized to the large colon. The diagnosis was
      confirmed at surgery or necropsy examination. Twelve (29%) of these horses were
      diagnosed with large-colon torsion. Duplicate ultrasonographic measurements of
      colon wall thickness were made at six abdominal locations and an average
      measurement was calculated. For four of these six sites, a significant difference
      (P < 0.005) was detected between horses with and without large-colon torsion. All
      four tests were moderately sensitive and highly specific for diagnosing large
      colon torsion using five decision criteria. Using a ventral abdominal window, a
      colon wall thickness > or = 9 mm accurately predicted large-colon torsion in
      eight of the 12 horses (sensitivity, 67%; confidence interval [CI], 36-98%) and
      correctly predicted that large-colon torsion was absent in 28/28 horses
      (specificity 100%; CI, 98-100%). Intraobserver repeatability was assessed by
      evaluating the difference between the first and second measurements obtained,
      which was < or = 2 mm. Therefore, detecting increased large-colon wall thickness
      during ultrasonography is a reproducible and accurate preoperative test for large
      colon torsion in horses with surgical colic localized to the large colon.

PMID- 15200260
TI  - Sonographic features of drug-induced splenic congestion.
AB  - Drug-induced splenic congestion has been reported in dogs secondary to
      barbiturate administration. This research attempted to verify and quantify size
      changes associated with drug-induced splenic congestion in dogs. Transverse plane
      ultrasound images of the spleen in normal dogs were collected to determine the
      maximum diameter in the minimum dimension prior to, and 15 min after,
      administration of acepromazine, thiopental, or propofol. Significant splenic
      enlargement was seen after administration of acepromazine (P<0.01) and thiopental
      (P=0.02), but no enlargement was seen after administration of propofol.
      Significantly increased attenuation (P<0.01) and a trend of increased backscatter
      (P=0.09) were measured after administration of acepromazine. These results
      indicate that measurable splenomegaly occurs after acepromazine and thiopental
      administration. This represents the first report of a condition causing
      measurable diffuse increased attenuation in the spleen. Propofol does not cause
      measurable splenic enlargement under the conditions of this research.

PMID- 15200261
TI  - Echocardiographic measurements in clinically healthy ferrets anesthetized with
      isoflurane.
AB  - Two-dimensional, M4-mode, and color flow Doppler echocardiography was performed
      in 29 (18 females, 11 males) clinically healthy ferrets anesthetized with
      isoflurane. M-mode measurements of the left ventricle, left atrial appendage
      diameter (LAAD), and aorta (Ao) were obtained. The fractional shortening and
      LAAD/Ao ratio were calculated. The values of the M-mode measurements were
      compared between the male and female ferrets using a Student's t-test. No
      significant differences were found. The difference in body weight between the
      male and female ferrets was highly significant (P<0.001), but no significant
      correlation was found between body weight and M-mode measurements. Color flow
      Doppler examinations of the mitral, tricuspid, aortic, and pulmonary valves were
      recorded and there was minor valvular regurgitation in five ferrets, which was
      considered nonsignificant.

PMID- 15200262
TI  - Echocardiographic changes induced by moderate to marked hypobaric hypoxia in
      dogs.
AB  - Hypobaric (high-altitude) hypoxia is a physiologic cause of pulmonary
      hypertension, and alters left ventricular (LV) systolic and diastolic function.
      In the presence of tricuspid regurgitation, systolic pulmonary artery pressure
      can be measured noninvasively using the peak tricuspid regurgitation velocity and
      the Bernoulli equation. In the absence of measurable tricuspid regurgitation,
      severity of pulmonary hypertension may be estimated using two-dimensional, M
      mode, and Doppler-derived parameters. To evaluate the usefulness of
      echocardiographic parameters for detecting mild-to-moderate pulmonary
      hypertension caused by moderate-to-marked hypoxia and to study the effect of high
      altitude hypoxia on systolic and diastolic LV function in dogs, 19 Greenland dogs
      were examined at moderate altitude (2300 m) and high altitude (3500 m), and 10
      Greenland control dogs were examined at 700-900 m. Evaluated parameters were
      pulmonary flow profile (shape, right ventricular acceleration time (RVAT),
      ejection time (RVET), RVAT/ET), peak mitral inflow velocities (LVE, LVA, LVE/A
      ratio), LV % fractional shortening (FS), systolic time intervals (LVPEP,
      LVPEP/ET), and stroke volume index (SVI). Notching during deceleration was common
      in dogs at high altitude and in the control dogs, but not in dogs at moderate
      altitude. RVAT was shorter in dogs at high altitude compared with moderate
      altitude, but not compared with control dogs. Peak A-velocity was higher and E/A
      ratio was lower in dogs at high altitude compared with moderate altitude and
      control dogs. FS was increased in dogs at high altitude compared with moderate
      altitude, and LVPEP and LVPEP/ET were shorter in the dogs at high altitude
      compared with moderate altitude and control dogs. In conclusion, significant
      differences in pulmonary flow profiles and systolic and diastolic parameters can
      be observed echocardiographically in dogs at different degrees of hypobaric
      hypoxia. However, overlap between the groups compromises their usefulness for
      diagnosing and estimating the degree of mild-to-moderate pulmonary hypertension
      in individual dogs.

PMID- 15200263
TI  - Technique for equine cervical articular process joint injection.
AB  - Degenerative changes and osteochondrosis of articular processes are common
      sources of stiffness or pain in the equine cervical spine. Temporary relief of
      the clinical signs related to these maladies may be achieved by injecting
      corticosteroids into the joint. This is routinely done by ultrasound-guided
      needle placement. The cervical articular processes and joint form an easily
      identifiable sonographic landmark, a step-like echogenic surface described as
      having the appearance of a "chair."

PMID- 15200264
TI  - Ultrasound-guided liver biopsy in birds.
AB  - In this study, 30 pigeons (Columba livia forma domestica) and 30 quails (Coturnix
      coturnix) were used to evaluate the diagnostic practicability and relevance of an
      ultrasound-conducted liver biopsy. Their body weight ranged between 144 and 603g.
      Considering anatomical peculiarities, the lateral (pigeons) or ventro-median
      (quails) access was chosen. In the case of the pigeons, 29 (96.7%) biopsies
      proved clearly to be liver tissue, while in the case of the smaller quails, 19
      (63.3%) samples could be clearly identified as liver tissue. All animals but one
      quail survived the intervention. The blood chemical parameters varied before and
      after the biopsy within the physiological range. These results show that
      ultrasound-guided liver biopsy in avian patients is generally possible and with
      strict indication and conscientious application can be considered as a relatively
      risk free and diagnostically sensible addition to liver diagnostic in birds. An
      aimed collection of focal hepatic alterations is conceivable depending on the
      size of the patient.

PMID- 15200265
TI  - Preliminary study of plasma vascular endothelial growth factor (VEGF) during low-
      and high-dose radiation therapy of dogs with spontaneous tumors.
AB  - High plasma vascular endothelial growth factor (VEGF) concentrations are
      associated with radiation resistance and poor prognosis. After an exposure to
      ionizing radiation in cell culture an early phase and a late phase of increased
      VEGF have been documented. The activation was dependent on the radiation dose.
      Therefore, the purpose of this study was to measure baseline plasma VEGF and
      changes in VEGF over the course of fractionated radiation therapy in dogs with
      spontaneous tumors. Dogs with tumors had a significantly higher pretreatment
      plasma VEGF than did dogs without tumors. Immediately after irradiation no
      increased plasma VEGF was observed. Over the course of radiation therapy there
      was an increased plasma VEGF in dogs treated with low doses per fraction/high
      total dose, whereas plasma VEGF remained stable in dogs irradiated with high
      doses per fraction/low total dose. The regulatory mechanisms are very complex,
      and therefore the value of plasma VEGF measurements as an indirect marker of
      angiogenesis induced by radiotherapy is limited.

PMID- 15200266
TI  - Expression of cyclooxygenase-2 in canine epithelial nasal tumors.
AB  - Cyclooxygenase-2 (COX-2) is an enzyme upregulated in some human and animal
      tumors. Enzymatic products are associated with tumorigenic activities. Given the
      poor response of canine nasal tumors to radiation, we considered the possibility
      that some of this resistance may be associated with COX-2 expression. To test
      this, 21 formalin-fixed, paraffin-embedded, and archived biopsy samples from
      canine epithelial nasal tumors were analyzed for COX-2 expression using
      immunohistochemistry. The biopsies were collected from dogs prior to radiation
      therapy. COX-2 expression was present in 17 of 21 (81%) tumors. The expression
      was observed in several different tumor types, including nasal carcinomas,
      adenocarcinomas, and squamous cell carcinomas. Samples from five control dogs
      without nasal neoplasia were also analyzed for COX-2 staining. These specimens
      were characterized by varying degrees of lymphoplasmacytic rhinitis with
      scattered regions of COX-2 positive respiratory epithelial and stromal cells.
      Whether the intensity and distribution of COX-2 expression in nasal tumors can be
      used as a prognostic marker requires further investigation. A combination therapy
      of irradiation and a selective COX-2 inhibitor appears worthy of clinical
      investigation in the treatment of canine epithelial nasal tumors.

PMID- 15200267
TI  - Images from the 2003 Certification Examination of the American College of
      Veterinary Radiology: abdomen section.

PMID- 15200268
TI  - Images from the 2003 Certification Examination of the American College of
      Veterinary Radiology: special procedures and alternate imaging section.

PMID- 15200270
TI  - Foreign body reactions in lymph nodes of oncology patients with joint prostheses-
      light-, electron microscopic and immunohistological investigations.
AB  - Foreign body reactions in lymph nodes caused by wear particles from joint
      prostheses can mimic different lymphadenopathies, including metastatic cancer.
      The knowledge of these alterations is particularly important for pathologists
      performing frozen section diagnosis for oncology patients. As recent
      investigations of pseudocapsules have revealed that most of the wear particles
      are submicron-sized, transmission electron microscopic investigations were
      additionally performed. The histological investigation of the pelvic lymph nodes
      of 22 oncology patients with joint prostheses showed that the bone cement wear
      prevailed. At least small amounts of polyethylene wear particles were also found
      in all cases. Metallic wear particles were detected in 90% of the cases. The wear
      particles induce a macrophage-rich foreign body reaction that can cause an
      architectural effacement of the lymph nodes. The electron microscopic
      investigations showed that submicron-sized wear particles prevail. Some of them
      form conglomerates in size ranges detectable by light microscopy. The
      immunohistochemical studies showed that the foreign body reactions comprised
      mature CD163- and PGM1-positive macrophages and few lymphocytes, predominantly T
      lymphocytes. The knowledge of the characteristic alterations of regional lymph
      nodes seems important in order to avoid misinterpretations. Therefore, in
      particular the detection of intracytoplasmatic wear particles is helpful in this
      respect.

PMID- 15200269
TI  - Immunohistological comparison of the World Health Organization (WHO) and
      Ljubljana classifications on the grading of preneoplastic lesions of the larynx.
AB  - There is still controversy about the classification of laryngeal preneoplastic
      lesions. In this study, we compared the World Health Organization (WHO) and
      Ljubljana histological classifications with regard to laryngeal epithelial
      hyperplastic-dysplastic lesions in a single series to determine their relation to
      statistically significant criteria when the mechanisms of neoplastic progression
      are considered. Emphasis was put on p53 expression, proliferative activity, and
      angiogenesis. Fifty-four laryngeal biopsies with preneoplastic changes were re
      evaluated and classified according to both classifications. The streptavidin
      biotin method was used for immunohistochemical staining for Ki-67, p53, and CD34
      antibodies. A positive correlation was obtained between the histological
      categories and Ki-67, p53, and CD34 expressions using both classifications
      (Spearman's Correlation test). There was a significant difference between the
      histological categories of both the WHO and the Ljubljana classifications, when
      the expression of the three markers was compared (Kruskal Wallis test, p = 0.000
      for each). Further evaluation revealed a statistically significant difference
      between all categories of both classifications, excluding the p53 overexpression
      scores and vessel counts in mild and moderate dysplasia categories (Mann-Whitney
      U-test, p = 0.209, and 0.091 respectively), and the p53 overexpression scores in
      severe dysplasia and carcinoma in situ categories (Mann-Whitney U-test, p =
      0.249) of the WHO classification. Similarly, no significant differences were
      found between severe dysplasia and carcinoma in situ, as well as between atypical
      hyperplasia and carcinoma in situ categories using both classifications for the
      Ki-67 expression (Mann-Whitney U-test, p = 0.806, and 0.111, respectively). Our
      results suggest that regarding the mechanisms of neoplastic progression such as
      p53 expression and angiogenesis, the histological categories of the Ljubljana
      classification seem to depend on additional evidence. Therefore, we support the
      use of the Ljubljana classification.

PMID- 15200271
TI  - Flow-cytometric DNA analysis of intracranial tumors in children.
AB  - The objective of this study was to investigate flow-cytometric DNA values of
      pediatric intracranial tumors, and to establish DNA analysis as a potential
      prognostic parameter. Twenty-nine brain tumor specimens from 26 pediatric
      patients were cryo-preserved within a 3-year period. The DNA content was measured
      by flow cytometry. Six of the tumor specimens had aneuploid DNA patterns. The
      median of the proliferation index was lower in the survivor group compared with
      the non-survivor group (36.4% and 47.5%, respectively). Ten of the 26 patients
      are still alive, eight were lost to follow up, and eight died. Flow-cytometric
      DNA analysis may be a helpful tool for examining brain tumors in children. The
      small size of this study could not establish flow cytometry as a definite
      prognostic factor, but further prospective multicenter studies will evaluate the
      prognostic significance of flow-cytometric DNA analysis.

PMID- 15200272
TI  - Reduced expression of aquaporin 4 in human muscles with amyotrophic lateral
      sclerosis and other neurogenic atrophies.
AB  - Aquaporin 4 (AQP4) is a water channel protein that is widely distributed in human
      tissues. However, the precise functional role of AQP4 in skeletal muscle tissue
      has not yet been determined. Expression of AQP4 was reported to be reduced in
      muscle tissue from Duchenne muscular dystrophy patients. In the regenerating
      phase of skeletal muscle, AQP4 expression was reduced when nerve supply was not
      present. However, in diseased human muscles with neurogenic atrophy including
      amyotrophic lateral sclerosis, there has been no data on the changes in AQP4
      expression. In the present study, we investigated the expression of AQP4 at mRNA
      and protein levels in human muscles with neurogenic atrophy. The mean level of
      AQP4 mRNA was significantly lower in muscles with neurogenic atrophy than that in
      muscles from normal controls. The myofiber surface immunostaining with anti-AQP4
      antibody in muscles with neurogenic atrophy was reduced on the surface of
      scattered myofibers, small angulated myofibers, and myofibers in small- and large
      group atrophy despite the presence of dystrophin. Based on the present findings,
      we conclude that the expression of AQP4 is affected by nerve supply and is down
      regulated in human muscles with neurogenic atrophy.

PMID- 15200273
TI  - Aortic wall remodeling in rats with nitric oxide deficiency treated by enalapril
      or verapamil.
AB  - Twenty mature male Wistar rats were maintained alive for 40 days, separated in
      four groups of five rats each: control, L-NAME (LN), L-NAME + Enalapril (LN + E),
      L-NAME + Verapamil (LN + V). Blood pressure (BP), left ventricular (LV) mass
      index, and aortic wall parameters were analyzed: aortic wall thickness, tunica
      media sectional area, surface density of lamellae (Sv[lamellae]), and smooth
      muscle cell nuclear profiles per section (SMC). At the end of the experiment, the
      LN group showed high BP and a high LV mass index (cardiac hypertrophy). The
      control group and the other groups showed significant differences in aortic wall
      thickness, tunica media sectional area, Sv[lamellae], and SMC. When comparing the
      LN group with both the LN + E group and the LN + V group, aortic thickness was
      not different. Tunica media sectional area and SMC differed between the LN group
      and the LN + E group. There were also differences between the LN group and the LN
      + V group in SMC. The Sv[lamellae] decreased in the following sequence: control
      group > LN group = LN + E group > LN + V group. In conclusion, treatment with
      enalapril and verapamil shows partial efficiency in preventing or treating aortic
      wall tunica media hypertrophy, suggesting that these alterations are due to a
      mechanism other than blood pressure control, where nitric oxide synthesis
      inhibition could be involved.

PMID- 15200274
TI  - Application of stereological methods for the quantification of VCAM-1 and ICAM-1
      expression in early stages of rabbit atherogenesis.
AB  - Early stages of atherogenesis are characterized by the overexpression of cell
      adhesion molecules with the subsequent accumulation of macrophages, smooth muscle
      cells and proliferation of extracellular matrix in arterial intima. The
      quantification of atherogenic changes is necessary for the objective evaluation
      of the atherogenic process. The purpose of this study was to introduce
      stereological methods that may be used for the quantification of
      immunohistochemical staining, namely intercellular cell adhesion molecule-1 (ICAM
      1) and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four New Zealand White
      rabbits were subdivided into the three groups. Eighteen rabbits received a 0.4%
      cholesterol diet for 1, 2 and 3 months, respectively. Stereological principles of
      the systematic uniform random sampling and the point-counting method were applied
      for the quantification. Stereological analysis showed that VCAM-1 and ICAM-1 were
      upregulated during the consumption of high cholesterol diet and that VCAM-1, but
      not ICAM-1, has a considerable role in the formation of early atherosclerotic
      lesions. Stereological methods proved to be useful for the quantification of
      immunohistochemistry and can be used for an objective characterization of
      atherogenic changes in atherosclerosis.

PMID- 15200275
TI  - Wolman disease and cholesteryl ester storage disease diagnosed by histological
      and ultrastructural examination of intestinal and liver biopsy.
AB  - Deficient activity of lysosomal acid lipase (LAL) results in massive accumulation
      of cholesteryl esters and triglycerides in most tissues of the body. The
      deficiency state is expressed in two major phenotypes: Wolman disease (WD) and
      cholesteryl ester storage disease (CESD). WD occurs in infancy and is nearly
      always fatal before the age of 1 year, whereas CESD can be more benign and may
      not be detected until adulthood. Since there are no specific routine laboratory
      observations that suggest these metabolic diseases, diagnosis is based on the
      clinical picture combined with LAL deficiency in cultured skin fibroblasts or
      peripheral lymphocytes. Both disorders are rather rare, considering that about a
      hundred of cases have been described up to now. This study describes the
      histological and ultrastructural aspects disclosed by intestinal or liver biopsy
      in three cases of WD and in two cases of CESD. Furthermore, it emphasizes the
      role of morphological findings in pointing the diagnosis towards a metabolic
      storage disease.

PMID- 15200276
TI  - Hemophagocytic syndrome associated with clostridial infection in a pancreatic
      carcinoma patient.
AB  - This report describes the autopsy case of a 71-year-old man presenting with
      clostridial infection and hemophagocytic syndrome (HS). The patient underwent
      pancreatoduodenectomy for a pancreatic tumor, and a histological examination
      revealed an invasive ductal adenocarcinoma. Multiple peritoneal metastases were
      noted when laparotomy was performed because of postoperative ileus 2 months after
      the initial operation. Then, acutely progressive anemia associated with fever
      developed in the patient before death. The autopsy revealed advanced cancer
      dissemination and HS. In addition, systemic spread of clostridium, confirmed by
      the polymerase chain reaction method, had resulted in generalized bleb formation.
      The clostridial infection appeared to be responsible for the HS. This case
      indicates that HS may occur as a result of clostridial infection.

PMID- 15200278
TI  - Referral to Arkansas Children's Hospital.

PMID- 15200277
TI  - Silicone oil in the subarachnoidal space--a possible route to the brain?
AB  - Using this case report, we sought evidence that silicone oil may infiltrate the
      subarachnoidal space. Vitrectomy combined with silicone oil implantation was
      performed on the right eye of a 72-year-old woman. The silicone oil was removed 2
      months later, because the patient had developed elevated intraocular pressure.
      The blind and painful eye was subsequently enucleated. By light microscopy,
      presumed silicone oil bubbles were identified in the optic nerve and the
      subarachnoidal space of the enucleated eye. These vacuoles were examined by
      energy-dispersive X-ray analysis (EDAX). In addition, in the vacuoles,
      immunohistochemistry was used to test for the presence of CD 68-positive
      macrophages. Silicone oil infiltration sites in the optic nerve, in the central
      retinal artery, and in the subarachnoidal space were located by light microscopy
      and confirmed by EDAX. CD 68-positive macrophages were found in the silicone
      filled vacuoles. Silicone oil used for endotamponade may infiltrate the optic
      nerve and even the subarachnoidal space. This supports the assumption that
      silicone oil, under special circumstances, may even migrate into the brain.

PMID- 15200280
TI  - When doctors say 'I do'.

PMID- 15200279
TI  - The basic scoop on HIPAA's final Security Rule.

PMID- 15200281
TI  - Correlation of MCP1 with toxicity in acetaminophen overdose.

PMID- 15200282
TI  - Low Pap smear rates leave women at risk.

PMID- 15200284
TI  - Arkansas and the motorcyle helmet law.
AB  - Motorcycle helmet laws have a long and colorful history dating back to the
      original work of Britain's Dr. Hugh Cairns during World War II. In Arkansas, the
      state's mandatory motorcycle helmet law was repealed in 1997 and replaced by a
      law requiring only those under the age of 21 to wear helmets. Recent work by
      researchers at the University of Arkansas for Medical Sciences has highlighted
      the impact of the helmet law repeal and demonstrated an increase in nonhelmeted
      motorcycle crash admissions, head injury severity, ICU length of stay and
      financial loss at this institution. In February of 2003, House Bill 1024 was
      submitted to the Arkansas House Committee on Public Transportation to reinstate
      the mandatory motorcycle helmet law for all motorcycle riders but was killed in
      committee. This article is a review of motorcycle helmet laws with particular
      emphasis on the arguments pro and con and the history of these laws in the state
      of Arkansas.

PMID- 15200283
TI  - Optic neuropathy in patient with Wegener's granulomatosis.
AB  - A 32-year-old white male presented to the Jones Eye Institute at the University
      of Arkansas for Medical Sciences with blurred vision of the right eye (OD) and
      severe bilateral retrobulbar pain. He had an eight-year history of Wegener's
      granulomatosis. On examination there was optic disc edema OD and extensive
      bilateral orbital involvement with compression of the right optic nerve by
      neuroimaging studies. Optic nerve compression is rare in Wegener's
      granulomatosis. The ophthalmic manifestations are reviewed.

PMID- 15200285
TI  - Temporal lobe epilepsy caused by choroid plexus papilloma in the temporal horn.
AB  - Choroid plexus papilloma (CPP) arising in the temporal horn is rare in adult
      population, and to the best of our knowledge, there has been no report of such a
      case with temporal lobe epilepsy (TLE). The authors describe a unique case of a
      27-year-old woman who was diagnosed as TLE and was found to have a CPP in the
      temporal horn. Choroid plexus papilloma of the temporal horn, even though rare,
      can be found in adult population and be causally related to temporal lobe
      epilepsy.

PMID- 15200286
TI  - Systemic lupus erythematosus presenting as amyotrophic lateral sclerosis.
AB  - We report a case of a 27-year-old Omani lady having a 3-year history of
      progressive skeletal muscle weakness with clinical and skeletal muscle changes of
      ALS, who during the course of investigations for ALS was found to have SLE. This
      association is not a simple coincidence but perhaps a causal relationship,
      opening vistas to explain the autoimmune pathogenesis and justification for
      immunosuppressive therapy in ALS. SLE presenting as ALS has not been reported
      earlier.

PMID- 15200287
TI  - Myelopathy due to spinal epidural abscess without cord compression: a diagnostic
      pitfall.
AB  - Spinal epidural abscess (SEA) is a neurological emergency that requires urgent
      diagnosis and treatment. We report 2 patients with SEA, in whom, on
      neuropathological examination, the neurological signs were found to be caused by
      spinal cord ischemia due to thrombosis of leptomeningeal vessels and compression
      of spinal arteries, respectively, while evidence of spinal cord compression was
      absent. Clinicians and neuropathologists should be aware of the variable
      mechanisms underlying the neurological involvement in SEA. Absence of spinal cord
      compression by the abscess may hamper early diagnosis and treatment.

PMID- 15200288
TI  - Quantification of the pathological changes in the temporal lobe of patients with
      a novel neurofilamentopathy: neurofilament inclusion disease (NID).
AB  - OBJECTIVE: To quantify the densities of neurofilament inclusions (NI), swollen
      achromatic neurons, surviving neurons and glial cells in a novel
      neurofilamentopathy neurofilament inclusion disease (NID). MATERIAL: Sections of
      temporal lobe from 4 cases of NID stained with an antibody raised to
      neurofilament proteins. METHOD: Densities of the pathological changes were
      estimated in the various gyri of the temporal lobe, hippocampus and dentate
      gyrus. RESULTS: Densities of the NI and swollen achromatic neurons (SN) were
      greater in the cerebral cortical gyri than in the hippocampus and dentate gyrus.
      Lesion density was relatively constant between gyri and between the CA sectors of
      the hippocampus. In cortical gyri, the density of the NI, SN and glial cell
      nuclei was greater in laminae II/III than laminae V/VI. Densities of the NI were
      negatively correlated with the surviving neurons and positively correlated with
      the glial cell nuclei. The density of the SN was positively correlated with that
      of the surviving neurons. CONCLUSION: The pathology of NID morphologically
      resembles that of Pick's disease (PD) and corticobasal degeneration (CBD), but
      there are distinct differences between NID and these disorders supporting the
      hypothesis that NID is a novel and unique type of neurodegenerative disease.

PMID- 15200289
TI  - Colocalization of different types of amyloid in the walls of cerebral blood
      vessels of patients suffering from cerebral amyloid angiopathy and spontaneous
      intracranial hemorrhage: a report of 5 cases.
AB  - Four cases of spontaneous intracranial hemorrhage (ICH) are described in which
      the diagnosis of a cerebral amyloid angiopathy (CAA) was made in the biopsy
      specimens. In one further case CAA was detected on autopsy after intracranial
      hemorrhage (ICH). Amyloidotic degeneration of the vessel walls appeared to be the
      most likely reason for the ICH which in these cases especially involved
      superficial neocortical regions. In all cases, co-deposition of A4beta-amyloid
      and ALlambda-amyloid was found in diseased leptomeningeal and cortical vessels.
      Besides CAA, all 5 patients suffered from other diseases which had affected the
      blood vessel walls such as atherosclerosis, diabetes mellitus or arterial
      hypertension. However, no signs of systemic amyloidosis could be detected in
      these cases. It is suggested that the observed co-deposition of 2 amyloid
      subtypes is based on the combination of 2 different diseases, one of which
      results in a local production of A4beta-amyloid in the tunica media of cerebral
      blood vessels and another one, e.g. arterial hypertension, which impairs the
      permeability of the blood vessels by affection of the tunica intima allowing for
      the pathological penetration of circulating immunoglobulin lambda-light chains
      into the vessel wall. Subsequently, the preexisting A4beta-amyloid might have
      induced the polymerization of the lambda-light chains to ALlambda-amyloid in the
      media of the vessels and could have aggravated the amyloidotic degeneration of
      the vessel walls.

PMID- 15200290
TI  - Tetrabromobutatriene: completing the perhalocumulene series.
AB  - [structure: see text] Tetrabromobutatriene, C(4)Br(4), can be prepared directly
      from dibromobutadiyne by reaction with Br(2) at -25 degrees C in concentrated
      hexanes solution. The cumulene precipitates out of the reaction mixture as a
      yellow powder. Under palladium-catalyzed coupling conditions, C(4)Br(4) can
      undergo allylic rearrangement, giving a mixture of products, including some with
      butenyne backbones. However, in furan solution, C(4)Br(4) reacts cleanly at its
      central double bond to give the furan Diels-Alder adduct. Under Suzuki
      conditions, this adduct reacts at the furan double bond rather than at bromide.

PMID- 15200291
TI  - A light-driven rotaxane molecular shuttle with dual fluorescence addresses.
AB  - [reaction: see text] A molecular shuttle containing an alpha-CD macrocycle, an
      azobenzene unit, and two different fluorescent naphthalimide units was
      synthesized. The cis-trans photoisomerization of the azobenzene unit resulted in
      the motion of the CD macrocycle on the track. Because of the easy regulation and
      full reversibility of the fluorescence change of the two stopper units, the
      molecular shuttle could be used as a molecular storage medium or switch with all
      optical inputs and outputs.

PMID- 15200292
TI  - Electronic detection of the enzymatic degradation of starch.
AB  - [reaction: see text] The enzymatic degradation of starch can be monitored
      electronically using single-walled carbon nanotubes (SWNTs) as semiconducting
      probes in field-effect transistors (FETs). Incubation of these devices in aqueous
      buffer solutions of amyloglucosidase (AMG) results in the removal of the starch
      from both the silicon surfaces and the side walls of the SWNTs in the FETs, as
      evidenced by direct imaging and electronic measurements.

PMID- 15200293
TI  - Toward self-assembled surface-mounted prismatic altitudinal rotors. A test case:
      molecular rectangle.
AB  - [structure: see text] A self-assembly path toward prismatic molecular rotors
      based on transversely reactive terminally metalated molecular rods and pyridine
      terminated star connectors is outlined. The concept is tested on the assembly of
      the biphenyl rod [Ph(2)P(CH(2))(3)PPh(2)Pt(+)-C(6)H(4)-C(6)H(4)
      Pt(+)[Ph(2)P(CH(2))(3)PPh(2)] and 4,4'-bipyridyl into a molecular rectangle,
      fully characterized by NMR and MS, including diffusion-ordered NMR and collision
      induced dissociation MS.

PMID- 15200294
TI  - Improved carbonylation of heterocyclic chlorides and electronically challenging
      aryl bromides.
AB  - [reaction: see text] Optimized conditions are described that effect the
      carbonylation of diverse heterocyclic chlorides to yield the desired alkyl
      esters. In addition, bromoanilines and bromoanisoles, which normally are poor
      substrates under standard carbonylation protocols, were efficiently converted to
      the desired products under these new conditions. The nature of the metal
      bidentate ligand complex was found to be critical. Specifically, a correlation
      between ligand bite angle and catalytic efficiency is documented.

PMID- 15200295
TI  - A facile and mild method for the synthesis of terminal bromofluoroolefins via
      diethylzinc-promoted Wittig reaction.
AB  - [reaction: see text] Synthesis of 1-bromo-1-fluoroolefins was achieved in good
      yields via a Wittig reaction promoted by diethylzinc, even with nonactivated
      aldehydes and ketones as starting materials.

PMID- 15200296
TI  - Unsymmetrical diaryl sulfones through palladium-catalyzed coupling of aryl
      boronic acids and arylsulfonyl chlorides.
AB  - [reaction: see text] A simple and efficient method for the synthesis of
      unsymmetrical diaryl sulfones using the palladium-catalyzed coupling of aryl
      boronic acids and arylsulfonyl chlorides has been developed. High product yields,
      a short reaction time, and mild reaction conditions are important features of
      this method.

PMID- 15200297
TI  - Does charge carrier dimensionality increase in mixed-valence salts of
      tetrathiafulvalene-terminated dendrimers?
AB  - [structure: see text] In four new dendrimers terminated by 12 electroactive
      tetrathiafulvalenyl substituents, the tridimensional character of the inter- and
      intradendrimeric charge and electron transfer, and hence of the
      electroconductivity, is evidenced by examination of the electronic spectra of
      their corresponding neutral state and cation radical, dication, and mixed-valence
      salts, including a closed-shell anion.

PMID- 15200298
TI  - Enantioselective alkynylation of aldehydes catalyzed by [2.2]paracyclophane-based
      ligands.
AB  - [reaction: see text] [2.2]Paracyclophane-based ketimine ligands were evaluated as
      catalysts for the enantioselective addition of in situ-prepared alkynylzinc
      reagents to aldehydes. The initial high activity and enantioselectivity of these
      ligands could be improved by an additive screening. The final protocol gives
      chiral propargyl alcohols in up to >98% ee.

PMID- 15200299
TI  - Enantioselective synthesis of cyclopropylphosphonates containing quaternary
      stereocenters using a D2-symmetric chiral catalyst Rh2(S-biTISP)2.
AB  - [reaction: see text] Rh(2)(S-biTISP)(2)-catalyzed reactions of dimethyl
      aryldiazomethylphosphonates generate donor/acceptor-substituted rhodium carbenoid
      intermediates capable of cyclopropanation of styrenes in high yields (85-96%),
      diastereoselectivity (> or =98% de), and enantioselectivity (76-92% ee).

PMID- 15200300
TI  - Vicinal stereocontrol during nucleophilic addition to arene chromium tricarbonyl
      complexes: formal synthesis of (+/-)-erythro Juvabione.
AB  - [reaction: see text] Vicinal stereocontrol during nucleophilic addition of tert
      butyl lithiopropionate to eta(6)-anisole chromium tricarbonyl complexes with
      differing para substituents has been studied. Excellent vicinal double
      stereoinduction (>99:1) was observed when the para substituent was Si(CH(3))(3),
      and this has been applied to a stereoselective formal synthesis of (+/-)-erythro
      Juvabione. Asymmetric synthesis by chiral auxiliary directed nucleophilic
      addition is also discussed.

PMID- 15200301
TI  - Insights into the Heck reaction with PCP pincer palladium(II) complexes.
AB  - [reaction: see text] The Heck reaction of phenyl halides with styrene using a
      series of related PCP pincer palladium(II) complexes was studied in order to
      evaluate the effect of ligand structure and electronics on the catalytic activity
      and to investigate the nature of the catalyst species. We suggest these pincer
      complexes are precatalysts for highly active forms of metallic palladium. This
      conclusion is based on kinetic studies (induction periods, sigmoidal kinetics),
      Hg drop tests, quantitative poisoning experiments, and NMR studies.

PMID- 15200302
TI  - Facile synthesis of multifullerene-OPE hybrids via in situ ethynylation.
AB  - [reaction: see text] A series of fullerene-terminated oligo(phenylene
      ethynylene)s (OPEs) (1a-d and 2) have been synthesized and further characterized
      by cyclic voltammetry (CV) and UV-vis spectroscopy. The key step in the syntheses
      is an effective one-pot reaction that allows the attachment of C(60) to multiple
      terminal alkynes.

PMID- 15200303
TI  - New ring-expansion reactions of hydroxy propenoyl cyclic compounds under
      palladium(0)/phosphine-catalyzed conditions.
AB  - [reaction: see text] Palladium(0)-catalyzed one-atom ring-expansion of 1-hydroxy
      2,2-dialkyl-1-propenoylindan derivatives has been achieved in the presence of P(o
      tolyl)(3) giving 2-hydroxy-3,3-dialkyl-2-vinyl-1-tetralone derivatives in
      excellent yields. This ring-expansion reaction was applied to a 17-(1-oxo-2
      propenyl)-beta-estradiol derivative and furnished a similar ring-expanded product
      in an excellent yield.

PMID- 15200304
TI  - Rhodium(I)-catalyzed carbonyl allenylation versus propargylation via redox
      transmetalation across tetragonal tin(II) oxide.
AB  - [reaction: see text] A reagent combination of beta-SnO and catalytic
      [Rh(COD)Cl](2) in THF-H(2)O promotes the reaction of propargyl bromides and
      aldehydes and directs the regioselectivity toward the formation of either allenic
      alcohols or homopropargylic alcohols. This highly regioselective either/or
      transformation proceeds via a transmetalation from rhodium to tin, in which
      metallotropic rearrangement between a propargylmetal and allenylmetal is
      arrested.

PMID- 15200305
TI  - Ionic vs pericyclic transition states for the cyclization reactions of C alpha-N
      anions derived from amides and phosphinamides.
AB  - [structure: see text] Ab initio and DFT calculations indicate that the anionic
      cyclization of vinyl- and phenyl-carboxamides and phosphinamides metalated at the
      C(alpha)-N carbon fits better to a Michael-type ionic addition than to an
      electrocyclic ring closure. The lithium atom has no influence on the type of
      reaction mechanism.

PMID- 15200306
TI  - Synthesis of omega-hydroxy ketones from omega-benzyloxy Weinreb amides by using a
      chemoselective nucleophilic addition/Birch reduction process.
AB  - [reaction: see text] A chemoselective nucleophilic addition/Birch reduction
      process applied to omega-benzyloxy Weinreb amides led to omega-hydroxy ketones in
      good yields.

PMID- 15200307
TI  - Total synthesis of natural (+)-(2's,3'r)-zoapatanol.
AB  - [reaction: see text] (+)-Zoapatanol was synthesized by using four key-steps: a
      Suzuki cross-coupling to prepare a (Z)-alpha,beta-unsaturated ester followed by
      an enantioselective dihydroxylation to control the C2' and C3' stereocenters, an
      intramolecular Horner-Wadsworth-Emmons olefination to construct the oxepane ring,
      and a chemoselective nucleophilic addition/Birch reduction process of a Weinreb
      amide to introduce simultaneously the beta,gamma-unsaturated ketone on the side
      chain and regenerate alcohols from benzyl ethers.

PMID- 15200309
TI  - Sulfoxide-directed enantioselective synthesis of functionalized dihydropyrans.
AB  - [reaction: see text] The highly selective base-promoted cyclization of
      enantiopure sulfinyl dienols affords allylic sulfinyl dihydropyrans.

PMID- 15200310
TI  - Rhodium(I)-catalyzed ene-allene carbocyclization strategy for the formation of
      azepines and oxepines.
AB  - [reaction: see text] A novel strategy for the preparation of seven-membered
      heterocyclic compounds has been realized. Treatment of ene-allene 1 with a
      catalytic quantity of rhodium biscarbonyl chloride dimer affords the cyclization
      product 2 in moderate to high yields. The scope and limitations of this new
      method are currently under investigation, and the results obtained to date are
      discussed within.

PMID- 15200308
TI  - Enantioselective total syntheses of belactosin A, belactosin C, and its
      homoanalogue.
AB  - [reaction: see text] Enantioselective total syntheses of belactosin A, belactosin
      C, and its homoanalogue have been accomplished in high overall yields (32% for
      belactosin A from the amino acid 10, and 35 and 36% for belactosin C and its
      homoanalogue, respectively). This concise approach comprises a novel sequential
      acylation/beta-lactonization reaction and allows a facile alteration of the
      substituents, thus providing a flexible route to a new family of highly active
      belactosin-based proteasome inhibitors.

PMID- 15200311
TI  - Thioglycuronides: synthesis and application in the assembly of acidic
      oligosaccharides.
AB  - [reaction: see text] Partially protected thioglycuronic acids are prepared
      efficiently by chemo- and regioselective oxidation of the corresponding
      thioglycosides using the TEMPO/BAIB reagent combination. After esterification,
      the thioglycuronic acids proved to be useful as both donor and acceptor in
      sulfonium-mediated condensations toward acidic di- and trisaccharides.

PMID- 15200312
TI  - Efficient synthesis of 2',3'-dideoxy-2'-amino-3'-thiouridine.
AB  - [reaction: see text] Metal ion rescue experiments provide a powerful approach to
      establish the presence and role of divalent metal ions in the biological function
      of RNA. The utility of this approach depends on the availability of suitable
      nucleoside analogues. To expand the range of this experimental strategy, we
      describe the first synthesis of 2',3'-dideoxy-2'-amino-3'-thiouridine (12) in
      19.5% overall yield starting from 2,2'-anhydrouridine (1).

PMID- 15200313
TI  - Asymmetric aminolysis of aromatic epoxides: a facile catalytic enantioselective
      synthesis of anti-beta-amino alcohols.
AB  - [reaction: see text] The first asymmetric aminolysis of trans-aromatic epoxides
      with anilines is described. The process affords enantioenriched anti-beta-amino
      alcohols in up to 99% ee. The complete regio- and diastereoselectivity observed
      uses commercially available [Cr(Salen)Cl] as a Lewis acid catalyst and in
      combination with a very simple experimental procedure renders the present
      reaction a facile and practical tool for the synthesis of chiral nonracemic anti
      beta-amino alcohols.

PMID- 15200314
TI  - Stereoselective synthesis of 1,4-bifunctional compounds by regioselective Pd
      catalyzed allylic substitution reaction.
AB  - [reaction: see text] Highly stereoselective synthesis of 1,4-bifunctional
      compounds was accomplished via 1,2-asymmetric induction to alpha-oxyaldehyde
      followed by regio- and diastereoselective Pd-catalyzed allylic substitution
      reaction.

PMID- 15200315
TI  - Nanoscale aryleneethynylene molecular wires with reversible fluorenone
      electrochemistry for self-assembly onto metal surfaces.
AB  - [structure: see text] Two rigid-rod conjugated molecules (11 and 12) of ca. 4 and
      7 nm length, respectively, bearing protected terminal thiol groups have been
      synthesized via multistep Sonogashira coupling reactions and shown to possess
      reversible cathodic solution electrochemistry arising from reduction of the
      fluorenone units.

PMID- 15200316
TI  - Highly enantioselective hetero-Diels-Alder reaction of Brassard diene with
      aromatic aldehydes.
AB  - [reaction: see text] Hetero-Diels-Alder reactions of Brassard diene with aromatic
      aldehydes were carried out smoothly in the presence of titanium(IV) tridentate
      Schiff base complexes to give the corresponding chiral delta-lactones in high
      enantioselectivities (up to 99% ee) under mild conditions.

PMID- 15200317
TI  - Rh(I)-catalyzed ring opening of an IMDAF-derived oxabicyclo cycloadduct as the
      key step in the synthesis of (+/-)-epi-zephyranthine.
AB  - [reaction: see text] A new strategy for epi-zephyranthine has been developed that
      is based in part on an extraordinarily facile intramolecular Diels-Alder reaction
      of a 2-imido-substituted furan. By using a Rh(I)-catalyzed ring opening of the
      resulting oxabicyclic adduct, the cis-diol stereochemistry of epi-zephyranthine
      was established.

PMID- 15200318
TI  - Cu- and Pd-catalyzed asymmetric one-pot tandem addition-cyclization reaction of 2
      (2',3'-alkadienyl)-beta-keto esters, organic halides, and dibenzyl
      azodicarboxylate: an effective protocol for the enantioselective synthesis of
      pyrazolidine derivatives.
AB  - [reaction: see text] Optically active pyrazolidine derivatives have been
      constructed by the Cu- and Pd-catalyzed asymmetric one-pot tandem addition
      cyclization reaction of 2-(2',3'-dienyl)-beta-ketoesters, organic halides, and
      dibenzyl azodicarboxylate. The absolute configurations of the final products
      depend on the structure of the ligand.

PMID- 15200319
TI  - Base-catalyzed inversion of chiral sulfur centers. A computational study.
AB  - [reaction: see text] A theoretical study on the pyramidal inversion of the chiral
      sulfur compounds SO(X)(Me) (X = Cl, OMe, p-MePh) has been carried out by means of
      the DFT(Becke3LYP) method. Our results reveal that in the case of X = Cl, an
      organic tertiary amine such as NMe(3) can catalyze the racemization. The base
      catalyzed inversion of SO(Cl)(Me) is proposed as a feasible dynamic kinetic
      resolution mechanism for the synthesis of chiral sulfoxides by the DAG method.

PMID- 15200320
TI  - Benzothiazines in synthesis. Toward the synthesis of pseudopteroxazole.
AB  - [reaction: see text] The tricyclic benzothiazine 15 was prepared in a
      straightforward fashion via a completely stereoselective intramolecular Friedel
      Crafts alkylation. This compound represents a potential precursor to the
      antitubercular agent, pseudopteroxazole. Its synthesis proceeded via a completely
      selective, intramolecular addition of a sulfoximine-stabilized carbanion to an
      alpha,beta-unsaturated ester, followed by functional group manipulations.

PMID- 15200321
TI  - ipso-nitration of arylboronic acids with chlorotrimethylsilane-nitrate salts.
AB  - [reaction: see text] A mixture of nitrate salt and chlorotrimethylsilane is found
      to be an efficient regioselective nitrating agent for the ipso-nitration of
      arylboronic acids to produce the corresponding nitroarenes in moderate to
      excellent yields. High selectivity, simplicity, and convenience are the key
      features of the reaction.

PMID- 15200322
TI  - Sonogashira cross-couplings of ynamides. Syntheses of urethane- and sulfonamide
      terminated conjugated phenylacetylenic systems.
AB  - [reaction: see text] The first successful Sonogashira coupling of ynamides with
      aryl and vinyl iodides is described here. This study resolves the problem of the
      competing pathway involving homocoupling of ynamides and provides a practical
      entry to novel urethane- or sulfonamide-terminated conjugated acetylenic systems.
      An interesting tandem hydrohalogenation and Sonogashira coupling was also
      observed to give an en-ynamide.

PMID- 15200323
TI  - Highly enantioselective synthesis of chiral 3-substituted indolines by catalytic
      asymmetric hydrogenation of indoles.
AB  - [reaction: see text] N-Tosyl 3-substituted indoles were hydrogenated with high
      enantioselectivities (95-98% ee) by use of a trans-chelating chiral bisphosphine,
      (S,S)-(R,R)-PhTRAP ligand. The chiral catalyst, which was generated in situ from
      [Rh(nbd)(2)]SbF(6), PhTRAP, and Cs(2)CO(3), is useful for enantioselectively
      synthesizing a range of diverse optically active indolines possessing a chiral
      carbon at the 3-position.

PMID- 15200324
TI  - Hydrosilylation of alkynes with a cationic rhodium species formed in an anionic
      micellar system.
AB  - [reaction: see text] Rhodium-catalyzed hydrosilylation of alkynes in an aqueous
      micellar system has been developed. A combination of [RhCl(nbd)](2) and
      bis(diphenylphosphino)propane (dppp) effects (E)-selective hydrosilylation in the
      presence of sodium dodecyl sulfate (SDS) in water. The (E)-selectivity strongly
      indicates the formation of a cationic rhodium species via dissociation of the Rh
      Cl bond by the action of anionic micelles. The addition of sodium iodide provided
      (Z)-alkenylsilanes predominantly.

PMID- 15200325
TI  - Synthesis of homoallylic alcohols via palladium-catalyzed three-component
      coupling of an arylboronic acid with allenes and aldehydes.
AB  - [reaction: see text] Racemic homoallylic alcohols have been synthesized by
      palladium-catalyzed three-component coupling of an arylboronic acid, an allene,
      and an aldehyde.

PMID- 15200326
TI  - A telluride-triggered nucleophilic ring opening of monoactivated cyclopropanes.
AB  - [reaction: see text] Acylcyclopropanemethanol tosylates undergo rapid ring
      opening at room temperature by the action of lithium telluride to produce the
      enolate of a homoallylic ketone. The enolate can be protonated to yield the
      corresponding ketone or treated with benzaldehyde to give the aldol product with
      good syn or anti diastereoselectivity depending on the conditions.

PMID- 15200327
TI  - Carijenone, a novel class of bicyclic prostanoid from the eastern Pacific
      octocoral Carijoa multiflora.
AB  - [structure: see text] An unprecedented biogenetically interesting bicyclic
      prostanoid 1, carijenone, has been isolated from the eastern Pacific octocoral
      Carijoa multiflora. The C-12 oxygenated function, characteristic of the coral
      cyclopentanone fatty acid derivatives, is involved in the formation of a five
      membered oxane ring fused to the cyclopentane network. Its structure and
      stereochemistry were determined on the basis of spectral studies and molecular
      mechanics calculations.

PMID- 15200328
TI  - Novel methodology for the synthesis of N-alkoxyamines.
AB  - [reaction: see text] We report a new methodology for the synthesis of the N
      alkoxyamines, which can be used as initiators in "living" free radical
      polymerization. Silyl radical abstraction from alkyl halides allows the synthesis
      of N-alkoxyamines inaccessible by other methods.

PMID- 15200329
TI  - New and practical method for synthesis of 1- and 1,3-substituted xanthines.
AB  - [reaction: see text] A new and practical method for the synthesis of 1- and 1,3
      substituted xanthines is reported. Direct base-promoted condensation of the
      imidazole precursor 1 with carbamates 2 gives 1-substituted 7-PMB xanthines 7 in
      good yields. Alkylation of these derivatives or their potassium salts proceeds
      under mild conditions to give functionalized 1,3-substituted 7-PMB xanthines 9 in
      good to excellent yields. The obtained 7-PMB-protected derivatives can be readily
      deprotected to give the parent 1- and 1,3-substituted xanthines.

PMID- 15200330
TI  - Epimerization of diastereomeric alpha-amino nitriles to single stereoisomers in
      the solid state.
AB  - [reaction: see text] A diastereomeric mixture of the alpha-amino nitrile prepared
      by the Strecker reaction of benzaldehyde, (1S,2R)-1-aminoindan-2-ol, and
      cyanotrimethylsilane thermally epimerizes in the solid state to give a single
      diastereomer with an (S)-configuration at the alpha position to the nitrile
      moiety. This shows a sharp contrast to the reaction conducted in DMSO at room
      temperature, which gives a 1:1 mixture of (S)- and (R)-isomers. Several other
      alpha-amino nitriles also epimerize in the solid-state toward single
      diastereomers.

PMID- 15200331
TI  - Allenes and transition metals: a diverging approach to heterocycles.
AB  - [reaction: see text] An alkynyl allene has been converted to heterocycles
      possessing an alpha-alkylidene cyclopentenone, a 4-alkylidene cyclopentenone, or
      a cross-conjugated triene. Thus, a common intermediate has been converted to
      three structurally unique compounds by changing only the reaction conditions and,
      therefore, controlling various reaction pathways.

PMID- 15200332
TI  - Syntheses of syn and anti doublebent [5]phenylene.
AB  - [structure: see text] The parent and dipropyl-substituted anti (1a,b) and syn
      doublebent (2a,b) [5]phenylenes have been assembled by CpCo-catalyzed double
      cyclization of regiospecifically constructed appropriate hexaynes. (1)H NMR,
      NICS, and an X-ray structural analysis of 1a reflect the aromatizing effect of
      double angular fusion on the central ring of the linear [3]phenylene
      substructure.

PMID- 15200333
TI  - Role of noncovalent interactions in the enantioselective reduction of aromatic
      ketimines with trichlorosilane.
AB  - [reaction: see text] Asymmetric reduction of ketimines 1 with trichlorosilane can
      be catalyzed by a new N-methyl L-valine derived Lewis basic organocatalyst, such
      as 4d, with high enantioselectivity. The structure-reactivity investigation
      suggests hydrogen bonding and arene-arene interactions between the catalyst and
      the incoming imine as the main factor determining the enantiofacial selectivity.

PMID- 15200334
TI  - A novel method for the preparation of nucleoside triphosphates from activated
      nucleoside phosphoramidates.
AB  - [reaction: see text] A novel method for the preparation of nucleoside
      triphosphates has been developed. The strategy employs a highly reactive
      pyrrolidinium phosphoramidate zwitterion intermediate that undergoes efficient
      coupling with tris(tetra-n-butylammonium) hydrogen pyrophosphate to generate
      nucleoside triphosphate.

PMID- 15200335
TI  - Influence of electron-donor sensitizers on SET-promoted photochemical reactions
      of beta,gamma-unsaturated aldehydes.
AB  - beta,gamma-Unsaturated aldehydes undergo photochemical oxa-di-pi-methane and
      decarbonylation reactions using DMN as an electron-donor sensitizer, whereas,
      using DMA, other photoproducts resulting from proton abstraction by ketyl- and
      alkene-centered radical-anions are also obtained.

PMID- 15200336
TI  - Are ring currents still useful to rationalize the benzene proton magnetic
      shielding?
AB  - [structure: see text] The conventional interpretation of proton NMR chemical
      shifts is supported by large basis set ab initio quantum mechanical calculations.
      The benzene protons are predicted to lie within the deshielding zone defined in
      terms of the out-of-plane magnetic shielding domain. However, ring currents by
      themselves are not sufficient to account quantitatively for the observed benzene
      proton downfield chemical shift. sigma-Electron contributions must also be taken
      into account. The conventional explanation for the ethyne proton chemical shift
      is valid.

PMID- 15200337
TI  - Synthesis of 4-azido-4-deoxy-Neu5,7,8,9Ac42en1Me. A key intermediate for the
      synthesis of GG167 from D-glucono-delta-lactone.
AB  - [reaction: see text] Stereoselective synthesis of 5-acetamido-7,8,9-tri-O-acetyl
      2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid methyl
      ester, an advanced key intermediate for the synthesis of neuraminidase inhibitor
      GG167 (Zanamivir, Relenza), was accomplished using D-glucono-delta-lactone as
      starting material. A highly diastereoselective allyllation of an imine
      intermediate, a regioselective azide-opening of an aziridine, and chemoselective
      oxidations of vicinal diols served successfully as key steps.

PMID- 15200338
TI  - Stereodivergent and regioselective synthesis of 3,4-cis- and 3,4-trans
      pyrrolidinediols from alpha-amino acids.
AB  - [reaction: see text] Highly stereodivergent Woodward-Prevost reaction applied to
      iodoacetates derived from homochiral alpha-amino acids afforded enantiopure 3,4
      cis- and 3,4-trans-pyrrolidinediol derivatives, with control over the protecting
      group, allowing for differential protection.

PMID- 15200339
TI  - Stereoselective construction of eight-membered oxygen heterocycles by Brook
      rearrangement-mediated [3 + 4] annulation.
AB  - [reaction: see text] A newly developed strategy for eight-membered oxygen
      heterocycle construction via [3 + 4] annulation is described. The method involves
      the combination of beta-substituted acryloylsilanes and enolates of 6
      oxacyclohept-2-en-1-one. A unique feature of this annulative approach is its
      capacity to generate eight-membered ring systems containing useful
      functionalities for further synthetic elaboration from readily available three-
      and four-carbon components.

PMID- 15200340
TI  - Diastereoselective zinc-catalyzed conjugate addition of alkynes.
AB  - [reaction: see text] The conjugate addition of in situ generated zinc alkynylides
      is reported. The use of chiral, ephedrine derived acceptors provides access to
      enantiomerically enriched beta-alkynyl acids in good yields.

PMID- 15200341
TI  - Small peptides catalyze highly enantioselective direct aldol reactions of
      aldehydes with hydroxyacetone: unprecedented regiocontrol in aqueous media.
AB  - [reaction: see text] L-Proline-based small peptides have been developed as
      efficient catalysts for the asymmetric direct aldol reactions of hydroxyacetone
      with aldehydes. Chiral 1,4-diols 7, which are disfavored products in similar
      aldol reactions catalyzed by either aldolases or L-proline, were obtained in high
      yields and enantioselectivities of up to 96% ee with peptides 3 and 4 in aqueous
      media.

PMID- 15200342
TI  - Phase-transfer-catalyzed asymmetric glycolate alkylation.
AB  - [reaction: see text] Asymmetric surrogate glycolate alkylation has been performed
      under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone with
      trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation
      products at -35 degrees C in high yield (80-99%) and with excellent
      enantioselectivities (90:10 to 95:5). Useful alpha-hydroxy products were obtained
      using bis-TMS peroxide Baeyer-Villiger conditions and selective
      transesterification. The intermediate aryl ester can be obtained with >99% ee
      after a single recrystallization. A tight ion-pair model for the observed (S)
      stereoinduction is proposed.

PMID- 15200343
TI  - Biological agents for rheumatoid arthritis: targeting both physical function and
      structural damage.
AB  - Rheumatoid arthritis (RA) is a chronic progressive inflammatory disease of
      multifactorial aetiology. The pivotal role of proinflammatory cytokines in the
      pathogenesis and perpetuation of synovitis has been demonstrated in basic
      research since the late 1980s and in clinical research since the early 1990s.
      Biological agents are monoclonal antibodies or recombinant forms of natural
      inhibitory molecules which selectively interact with molecules or cell receptors
      affecting immune or inflammatory processes. In RA, etanercept, infliximab and
      adalimumab are currently available to target tumour necrosis factor (TNF) and an
      interleukin (IL)-1 receptor antagonist is available to target IL-1 activity.
      Trials have shown benefits as monotherapy, although the best results for disease
      control are seen when biological agents are coadministered with methotrexate. The
      use of these agents in clinical trials and in practice has resulted in dramatic
      improvements in RA disease control, and delay and prevention of radiographic
      damage. The remarkable benefits to patients in well-being, quality of life and
      function, and the speed of onset of action are reminiscent of the early days of
      corticosteroid use. Ten years after the first clinical trials of anti-TNF
      therapies, the adverse effect profile is evolving and includes, for anti-TNF
      therapy, an increased risk of infections associated with immune suppression,
      injection and infusion reactions, and a risk of drug induced autoimmune syndromes
      such as systemic lupus erythematosus. Where these drugs are affordable, the
      prognosis of individuals for control of severe RA is better than ever before.
      This manuscript summarises the clinical trial results and post-marketing
      information regarding the biological agents currently in use for RA.

PMID- 15200345
TI  - Management of fatigue in patients with multiple sclerosis.
AB  - As long as no causal treatment is available for multiple sclerosis (MS), and as
      long as only some patients with MS respond to immunomodulators, symptomatic
      treatment is of paramount importance. Fatigue is the most common symptom of MS
      and is associated with a reduced quality of life. It is described as the worst
      symptom of their disease by 50-60% of patients. The first step in managing MS
      related fatigue is identifying and eliminating any secondary causes. Primary
      fatigue syndrome can be alleviated with drug treatment in many cases. Modafinil
      has been shown to be effective in some studies, and amantadine is an alternative
      for patients who do not respond to or cannot tolerate modafinil. The
      nonpharmacological management of fatigue in MS includes inpatient rehabilitation
      and aerobic endurance exercise. This article describes the pathophysiology,
      diagnosis and treatment of MS-related fatigue--the most common symptom of MS.

PMID- 15200344
TI  - Recent advances in understanding the pathogenesis of polycystic kidney disease:
      therapeutic implications.
AB  - Hereditary polycystic kidney disease (PKD) is a common cause of renal failure.
      Increasing knowledge is available regarding mechanisms of cyst development and
      progression, and renal functional deterioration in PKD. On the basis of this
      information and theories regarding the pathophysiology of these processes,
      studies to alter progression and potentially treat PKD have been reported. Cyst
      development and progression requires epithelial cell proliferation,
      transepithelial fluid secretion and extracellular matrix remodelling. Several
      interventions designed to inhibit cell proliferation or alter fluid secretion
      modify the progression of PKD in selected animal models. Renal functional
      deterioration appears to involve interstitial inflammation and fibrosis, and
      tubular apoptosis. Glucocorticoids with anti-inflammatory and antifibrotic
      properties slow the progression of cystic disease and renal functional
      deterioration in animal models of PKD. Other interventions, such as dietary
      modification and angiotensin antagonism, shown to be of benefit in non-PKD models
      of slowly progressive renal disease, are also of benefit in animal models of PKD.
      Caution should be used in extrapolating interventional studies in one animal
      model to another model and certainly to human disease, since examples exist in
      which treatments in one model of PKD have different effects in another model.
      Nonetheless, early attempts to determine whether potential treatments are
      tolerated and of potential benefit in patients with PKD are beginning to appear.
      Ultimately, treatment of PKD may involve efforts to identify patients at greatest
      risk for disease progression, thus allowing targeted therapy, use of surrogate
      markers for disease progression to assist assessment of therapeutic efficacy, and
      combination therapy to retard disease progression and renal functional
      deterioration in this common hereditary cause of chronic renal failure.

PMID- 15200346
TI  - Fluvastatin: clinical and safety profile.
AB  - Therapy with HMG-CoA reductase inhibitors (statins) has been shown to
      significantly reduce major coronary events and death in a wide range of
      individuals at risk for these events. In addition, recent observations suggest
      that some of the clinical benefits associated with statin therapy may be
      pleiotropic; that is, independent of their cholesterol-inhibiting action. It is
      clear that the clinical benefits associated with statin therapy far outweigh the
      risks; however, there may be important clinical differences among agents within
      the class, related to both benefits and drug safety. Evaluation of the benefit-to
      risk profile for each available statin should include considering the results of
      randomised clinical outcome trials, the safety record of each agent, effect on
      lipoproteins and evidence of beneficial pleiotropic properties.Recently, data
      from several clinical outcome trials have shown that substantial benefits are
      associated with treatment with fluvastatin in diverse populations. In particular,
      data from two large, randomised clinical trials have demonstrated that
      fluvastatin is effective for secondary prevention of cardiac events in patients
      following coronary intervention procedures, and for primary prevention of cardiac
      events in renal transplant recipients. Pleiotropic benefits for fluvastatin have
      been shown in experimental and clinical studies as well. Fluvastatin was the
      first statin available as an extended-release product (fluvastatin XL 80mg); both
      formulations have demonstrated efficacy and safety in a wide range of patients.
      Taken together, these clinical outcomes and safety data suggest a strong benefit
      to-risk profile for fluvastatin.

PMID- 15200347
TI  - Immunosuppression for long-term maintenance of renal allograft function.
AB  - The incidence and severity of acute rejection episodes was markedly reduced by
      the introduction of new immunosuppressive drug regimens for renal
      transplantation, resulting in improved graft survival at 1 year. However, only
      modest improvement has been shown in long-term graft function rates. This
      overview evaluates the efficacy of currently used immunosuppressive drugs and
      drug combinations for long-term maintenance therapy. Prospective controlled
      trials rarely extend beyond 5 years; therefore, registry data and retrospective
      reports have also been employed. From currently available data it may be
      concluded that the initial beneficial effect of ciclosporin (cyclosporin) is lost
      10 years after transplantation. Tacrolimus is an alternative to ciclosporin with
      a different profile of adverse effects and a higher efficacy in acute rejection
      treatment. For long-term maintenance, projected half-lives of kidney graft
      function are in favour of tacrolimus. Mycophenolate mofetil (MMF) has been shown
      to significantly reduce the incidence of early rejections. However, the improved
      long-term graft survival reported in retrospective studies has still to be
      confirmed in controlled trials. There is no convincing evidence for superiority
      of triple therapy including prednisone (or prednisolone), calcineurin inhibitors
      and azathioprine/MMF over dual therapy without azathioprine/MMF with respect to
      long-term outcome. Withdrawal of corticosteroids or calcineurin inhibitors
      clearly reduces adverse drug effects but carries the risk of acute rejection
      episodes. Avoidance of corticosteroids by using new immunosuppressive drug
      combinations may be an option to minimise toxic adverse effects in the future. At
      present, it seems unjustified to convert renal transplant recipients with stable
      graft function and tolerable adverse effects from one drug to another solely in
      expectation of future benefits. Acute early or late rejection episodes and
      intolerable adverse effects are good reasons for conversions between calcineurin
      inhibitors or cytotoxic agents. Chronic allograft nephropathy with slowly
      deteriorating graft function remains an unresolved problem.

PMID- 15200349
TI  - Role of fluoroquinolones in the treatment of serious bacterial urinary tract
      infections.
AB  - Serious urinary tract infections (UTIs) in adults--defined as acute complicated
      UTIs or pyelonephritis requiring initial intravenous antimicrobials and/or
      hospitalisation and nosocomial infections--cause significant morbidity and
      economic burden. In the US, UTIs are responsible for nearly 7 million outpatient
      physician office visits, 1 million emergency room visits and over 100 000
      hospital admissions annually. Complicated UTIs often affect patients with
      underlying functional, metabolic or anatomical defects of the urinary tract,
      whereas most nosocomial UTIs (~80%) are related to short- or long-term
      catheterisation. Serious UTIs are often difficult to treat because infection
      involves a diverse array of Gram-negative and Gram-positive bacteria, coupled
      with increasing antimicrobial resistance in some uropathogens, and a higher rate
      of recurrent infections. Although Escherichia coli remains a common aetiology (<
      or =60%), other Enterobacteriaceae, Gram-negative bacilli (e.g. Pseudomonas
      aeruginosa), and Gram-positive bacteria (e.g. Staphylococcus aureus) are
      frequently isolated. Patients with long-term catheterisation have UTIs typically
      caused by organisms that produce biofilms making eradication even more difficult.
      Overall, aetiology and resistance patterns are not predictable for those with
      serious UTIs, necessitating confirmation by culture and susceptibility
      testing.Numerous intravenous and oral antimicrobial treatment options are
      available and the majority of patients with serious UTIs will need initial
      intravenous therapy because of the possibility of bacteraemia/sepsis or impaired
      gastrointestinal absorption. Many experts concur that empirical therapy for the
      institutionalised or hospitalised patient with a serious UTI should include an
      intravenous antipseudomonal agent because of an increased risk of urosepsis.
      While state-of-the-art treatment guidelines are lacking for these infections,
      targeted therapy should be initiated once susceptibility data are known. The use
      of targeted therapy--emphasising the "correct antibacterial spectrum" and
      pharmacodynamic superiority--is likely to provide important benefits (e.g.
      reduced morbidity and associated costs, reduced emergence of resistance). Agents
      commonly prescribed include aminoglycosides, beta-lactam/beta-lactamase inhibitor
      combinations, imipenem, advanced-generation cephalosporins and fluoroquinolones.
      Fluoroquinolones are often recommended when conventional agents have failed or
      are less desirable (e.g. toxicity/hypersensitivity concerns), or when resistance
      is high. Several pivotal clinical trials support the use of fluoroquinolones for
      serious UTIs with most experience garnered with ciprofloxacin, including a new
      once-daily extended-release tablet formulation.Treatment of patients with serious
      UTIs remains challenging. Physicians should choose empirical therapy based on
      patient demographics/medical history, presumed aetiology and local resistance
      patterns until more definitive guidelines become available.

PMID- 15200350
TI  - Somatropin (Zorbtive): in short bowel syndrome.
AB  - A somatropin preparation (Zorbtive) produced by recombinant DNA technology has
      been evaluated in patients with short bowel syndrome. Somatropin is thought to
      enhance intestinal adaptation in this condition through direct or indirect
      effects on the intestine. In a randomised, double-blind study in patients with
      short bowel syndrome who were dependent on intravenous parenteral nutrition (IPN)
      [n = 41], recipients of subcutaneous somatropin alone or somatropin plus oral
      glutamine had significantly greater mean reductions from baseline in weekly total
      IPN volume than recipients of placebo plus glutamine. All patients received a
      special diet. In addition, significantly greater mean reductions from baseline in
      weekly total IPN calories and the mean frequency of IPN or supplemental lipid
      emulsion administration occurred in patients receiving somatropin alone or in
      combination with glutamine, compared with recipients of placebo plus glutamine.
      Adverse events were reported in 100% of patients with short bowel syndrome during
      treatment with somatropin with or without glutamine. However, a high proportion
      of patients also reported signs and symptoms before starting therapy or adverse
      events after therapy, suggesting that such patients experience numerous events
      attributable to their underlying condition or to complications of IPN.

PMID- 15200353
TI  - Web and telecounselling in Australia.

PMID- 15200354
TI  - Assessing bronchodilator reversibility: agreed standards are urgently needed.

PMID- 15200355
TI  - Evidence and Australian health policy.

PMID- 15200356
TI  - Bronchodilator reversibility testing: laboratory practices in Australia and New
      Zealand.
AB  - OBJECTIVES: To determine the variation in the methods used to assess and
      interpret the reversibility of airflow limitation in lung-function laboratories
      throughout Australia and New Zealand. DESIGN: A postal survey performed in 2000,
      requesting details of methods used to assess and interpret bronchodilator
      reversibility. SETTING AND PARTICIPANTS: 60 lung-function laboratories identified
      from the Australian and New Zealand Society of Respiratory Science mailing list.
      MAIN OUTCOME MEASURES: Bronchodilator agent, dose, mode of administration, time
      to repeat spirometry and definition of a significant response. RESULTS: 37
      laboratories responded (response rate, 64%). Thirty-three laboratories used
      salbutamol as their routine bronchodilator agent. Twenty-four laboratories used a
      metered-dose inhaler (MDI) with (21) or without (3) a spacer device as the
      preferred mode of bronchodilator administration. There was wide variation in the
      bronchodilator dose administered (median, 400 micro g; range, 200-800 micro g
      salbutamol for MDIs) and the time to repeat spirometry following bronchodilator
      administration (median, 10 min; range, 4-20 min). Ten laboratories used criteria
      consistent with either the National Asthma Council or Thoracic Society of
      Australia and New Zealand COPDX guidelines to define a significant bronchodilator
      response, and two used American Thoracic Society criteria. The remaining 25
      respondents listed a variety of other criteria. CONCLUSION: The methods used to
      assess and interpret acute bronchodilator reversibility in lung-function
      laboratories in Australia and New Zealand vary considerably. This may have a
      significant effect on the diagnosis and management of patients. Laboratories
      should report the method used to assess bronchodilator response.

PMID- 15200357
TI  - Congenital heart defects in Central Australia.
AB  - OBJECTIVE: To determine the incidence of congenital heart defects (CHD) in
      Aboriginal and non-Aboriginal infants in Central Australia and to compare this
      with the incidence elsewhere in Australia. DESIGN AND SETTING: Data on cases were
      obtained from patient records of the Alice Springs Hospital, Central Australia,
      the sole referral centre for paediatric and initial cardiac diagnostic services
      for the region. PARTICIPANTS: Patients with CHD proven by echocardiography
      reported between 1 January 1993 and 30 June 2000. MAIN OUTCOME MEASURES:
      Incidence of CHD using all live births in Central Australia as the denominator.
      RESULTS: 108 patients with CHD were detected among 6156 live births (incidence,
      17.5 per 1000; 95% CI, 14.9-21.7 per 1000); 57 of 2991 were Aboriginal (19.0 per
      1000; 95% CI, 14.4-24.6 per 1000) and 51 of 3165 were non-Aboriginal (16.1 per
      1000; 95% CI, 12.0-21.1 per 1000). The difference between the two groups was not
      statistically significant (relative risk, 1.18; 95% CI, 0.81-1.72). CHD incidence
      in Central Australia was significantly higher than that reported for other parts
      of Australia (4.3 per 1000 live births in New South Wales and the Australian
      Capital Territory, 1981-1984; 7.65 and 12 per 1000 total births in Western
      Australia, 1980-1989, and South Australia, 1993-2000, respectively). CONCLUSIONS:
      The high rates of CHD in Central Australia may partly reflect the high
      utilisation of echocardiography for assessing minor lesions. However, the
      incidence of both major and minor types of CHD was significantly higher than
      previously reported from other regions of Australia. The role of
      socioenvironmental factors in this high incidence should be explored.

PMID- 15200358
TI  - Remoteness of residence and survival from cancer in New South Wales.
AB  - OBJECTIVE: To analyse cancer survival in New South Wales by geographic
      remoteness. DESIGN, SETTING AND PARTICIPANTS: A survival analysis of all patients
      with cancers diagnosed in NSW between 1 January 1992 and 31 December 1996.
      Survival was determined to 31 December 1999. MAIN OUTCOME MEASURES: The relative
      excess risk (RER) of death over 5 years was estimated for each geographic
      remoteness category relative to the highly accessible category for 20 cancer
      types adjusted for age, sex, years since diagnosis and, subsequently, stage of
      cancer at diagnosis. RESULTS: There were statistically significant differences in
      the RER of death across remoteness categories (P < 0.001) for cancers of the
      cervix and prostate and for all cancers. The RERs for the most remote categories
      (compared with the highly accessible category) before and after adjustment for
      stage were cervix, 3.22 (95% CI, 1.54-6.75) and 2.25 (95% CI, 1.06-4.77);
      prostate, 3.38 (95% CI, 2.21-5.16) and 2.53 (95% CI, 1.60-4.01); all cancers,
      1.35 (95% CI, 1.20-1.51) and 1.25 (95% CI, 1.11-1.41). In addition, there were
      significant variations in RER of death by remoteness for head and neck, lung and
      colon cancers and cutaneous melanoma. CONCLUSION: Cancer survival varies by
      remoteness of residence in NSW for all cancers together and some cancers
      individually. Access to screening or early diagnosis probably contributes to this
      variation, but persistence after adjustment for stage suggests that treatment
      variation is also important.

PMID- 15200348
TI  - The role of sulphonylureas in the management of type 2 diabetes mellitus.
AB  - The sulphonylureas act by triggering insulin release from the pancreatic beta
      cell. A specific site on the adenosine triphosphate (ATP)-sensitive potassium
      channels is occupied by sulphonylureas leading to closure of the potassium
      channels and subsequent opening of calcium channels. This results in exocytosis
      of insulin. The meglitinides are not sulphonylureas but also occupy the
      sulphonylurea receptor unit coupled to the ATP-sensitive potassium channel.
      Glibenclamide (glyburide), gliclazide, glipizide and glimepiride are the primary
      sulphonylureas in current clinical use for type 2 diabetes mellitus.
      Glibenclamide has a higher frequency of hypoglycaemia than the other agents. With
      long-term use, there is a progressive decrease in the effectiveness of
      sulphonylureas. This loss of effect is the result of a reduction in insulin
      producing capacity by the pancreatic beta cell and is also seen with other
      antihyperglycaemic agents. The major adverse effect of sulphonylureas is
      hypoglycaemia. There is a theoretical concern that sulphonylureas may affect
      cardiac potassium channels resulting in a diminished response to ischaemia. There
      are now many choices for initial therapy of type 2 diabetes in addition to
      sulphonylureas. Metformin and thiazolidinediones affect insulin sensitivity by
      independent mechanisms. Disaccharidase inhibitors reduce rapid carbohydrate
      absorption. No single agent appears capable of achieving target glucose levels in
      the majority of patients with type 2 diabetes. Combinations of agents are
      successful in lowering glycosylated haemoglobin levels more than with a single
      agent. Sulphonylureas are particularly beneficial when combined with agents such
      as metformin that decrease insulin resistance. Sulphonylureas can also be given
      with a basal insulin injection to provide enhanced endogenous insulin secretion
      after meals. Sulphonylureas will continue to be used both primarily and as part
      of combined therapy for most patients with type 2 diabetes.

PMID- 15200359
TI  - Incidence of hip fracture in New South Wales: are our efforts having an effect?
AB  - OBJECTIVE: To examine trends in hospital admission for hip fracture in New South
      Wales between July 1990 and June 2000. DESIGN: Analysis of routinely collected
      hospital separation data. SETTING: Public and private acute-care hospitals in
      NSW. PARTICIPANTS: Admissions of patients aged 50 years and over with a primary
      diagnosis of fracture of the neck of femur (International classification of
      diseases, 9th revision [ICD-9] code 820 or ICD-10 codes S72.0-S72.2). MAIN
      OUTCOME MEASURES: Number and rates of hospital admission for fracture of the neck
      of femur per 1000 population; inpatient mortality rates per 1000 admissions.
      RESULTS: Between July 1990 and June 2000, the number of admissions to NSW acute
      care hospitals for hip fracture increased by 41.9% in men (from 1059 to 1503 per
      year) and by 31.2% in women (from 3160 to 4145 per year). However, age-specific
      and age-adjusted rates remained practically unchanged. The average length of stay
      for admissions for hip fracture decreased significantly from 19.2 days (95% CI,
      18.5-19.8 days) in 1990-1991 to 14.2 days (95% CI, 13.8-14.6 days) in 1999-2000.
      No significant change was observed in the overall inpatient death rates per 1000
      admissions. CONCLUSIONS: The findings support recent reports that the increase in
      hip fracture rates during most of the past century may have ended. However, the
      number of admissions for hip fracture is still rising. Preventive measures to
      reduce the burden of this condition on the healthcare system and community need
      to be pursued and strengthened.

PMID- 15200360
TI  - The Australian government's review of positron emission tomography: evidence
      based policy-making in action.
AB  - The Commonwealth Government constituted the Medicare Services Advisory Committee
      (MSAC) to implement its commitment to entrench the principles of evidence-based
      medicine in Australian clinical practice. With its recent review of positron
      emission tomography (PETReview), the Commonwealth intervened in an established
      MSAC process, and sanctioned the stated objective to restrict expenditure on the
      technology. In our opinion: The evaluation of evidence by PETReview was
      fundamentally compromised by a failure to meet the terms of reference, poor
      science, poor process and unique decision-making benchmarks. By accepting the
      recommendations of PETReview, the Commonwealth is propagating information which
      is not of the highest quality. The use of inferior-quality information for
      decision-making by doctors, patients and policy-makers is likely to harm rather
      than enhance healthcare outcomes.

PMID- 15200361
TI  - The Australian Government's Review of Positron Emission Tomography: an open door.

PMID- 15200362
TI  - Tissue plasminogen activator (tPA) in acute ischaemic stroke: time for collegiate
      communication and consensus.
AB  - Systematic reviews of randomised trials of tPA in acute ischaemic stroke indicate
      a clear benefit of treating selected patients within 3 hours of stroke onset.
      Moreover, a net benefit remained after adjustment for chance baseline imbalances
      between subgroups in stroke severity within one of these trials (National
      Institute of Neurological Disorders and Stroke [NINDS]). Rates of favourable
      outcomes and intracranial haemorrhage comparable with those in randomised trials
      can be achieved in routine clinical practice; however, translation of net benefit
      from tPA therapy requires organised and coordinated stroke management across the
      continuum of care. Prerequisites for well organised and coordinated acute stroke
      care are: consensus among care providers on the use of tPA; stroke-care teams
      spanning the gaps between pre-hospital care, emergency departments and stroke
      units; and collegiate relations and effective communication networks between care
      providers.

PMID- 15200363
TI  - Ethics, stem cells and spinal cord repair.
AB  - Attempted repair of human spinal cord injury by transplantation of stem cells
      depends on complex biological interactions between the host and graft.
      Extrapolating results from experimental therapy in animals to humans with spinal
      cord injury requires great caution. There is great pressure on surgeons to
      transplant stem cells into humans with spinal cord injury. However, as the
      efficacy of and exact indications for this therapy are still uncertain, and
      morbidity (such as rejection or late tumour development) may result, only
      carefully designed studies based on sound experimental work which attempts to
      eliminate placebo effects should proceed. Premature application of stem cell
      transplantation in humans with spinal cord injury should be discouraged.

PMID- 15200364
TI  - Influenza outbreaks in aged-care facilities: staff vaccination and the emerging
      use of antiviral therapy.

PMID- 15200365
TI  - Teaching on the run tips 3: planning a teaching episode.

PMID- 15200366
TI  - CAM practitioners and "regular" doctors: is integration possible?
AB  - Integrated clinics have already been established in response to community demand.
      The growing evidence base for complementary and alternative medicine (CAM) and
      its widespread community use compels doctors to understand complementary
      therapies and to refer patients to CAM practitioners where appropriate. Most
      general practitioners have patients with chronic illness who could benefit from
      the services of CAM practitioners, and virtually all CAM practitioners have
      patients who require access to mainstream diagnosis and therapy. Collaboration
      requires shared respect and trust, and education. Dangers of not integrating care
      include delaying or depriving patients of safe and effective management, and the
      potential for harmful interactions. Integration is currently being supported by
      government initiatives such as the new MedicarePlus package, as well as by
      initiatives from organisations such as the Australian Medical Association, the
      Royal Australian College of General Practitioners and the Australasian
      Integrative Medicine Association.

PMID- 15200367
TI  - Good medicine and bad medicine: science to promote the convergence of
      "alternative" and orthodox medicine.
AB  - A complementary and alternative medicine (CAM) system divorced from scientific
      medicine means that patients can only benefit from the best of both systems by
      dividing their care. Science must be used to stimulate convergence of
      complementary and traditional healthcare. First class research to examine the
      more interesting claims of the alternative health industry is essential to
      broaden the range of therapeutic options available, while minimising fraudulent,
      ill-informed and sometimes dangerous practices. Mutual respect and interest
      between orthodox and alternative practitioners is appropriate, but there can be
      no compromise involving unscientific approaches to care. Health departments must
      play a greater role in stopping fraudulent claims being publicised, and in
      warning consumers about such claims.

PMID- 15200368
TI  - Transoesophageal echocardiography in routine cardiac surgery.

PMID- 15200369
TI  - Community-acquired MRSA epiduritis in an Australian prison inmate.

PMID- 15200370
TI  - Training our future rural medical workforce.

PMID- 15200371
TI  - Cancer in adolescents and young adults: treatment and outcome in Victoria.

PMID- 15200372
TI  - Thyroid nodules and thyroid cancer.

PMID- 15200373
TI  - Olympic medals or long life: what's the bottom line?

PMID- 15200374
TI  - An audit of obstetricians' management of women potentially infected with blood
      borne viruses.

PMID- 15200375
TI  - Virtual screening methods that complement HTS.
AB  - In this review, we discuss a number of computational methods that have been
      developed or adapted for molecule classification and virtual screening (VS) of
      compound databases. In particular, we focus on approaches that are complementary
      to high-throughput screening (HTS). The discussion is limited to VS methods that
      operate at the small molecular level, which is often called ligand-based VS
      (LBVS), and does not take into account docking algorithms or other structure
      based screening tools. We describe areas that greatly benefit from combining
      virtual and biological screening and discuss computational methods that are most
      suitable to contribute to the integration of screening technologies. Relevant
      approaches range from established methods such as clustering or similarity
      searching to techniques that have only recently been introduced for LBVS
      applications such as statistical methods or support vector machines. Finally, we
      discuss a number of representative applications at the interface between VS and
      HTS.

PMID- 15200376
TI  - Computational methods for the identification and optimisation of high quality
      leads.
AB  - Lead identification and optimisation have evolved into multidimensional,
      multidisciplinary and information-driven processes. Herein, we review the
      contribution of computational chemistry to these processes. We focus on
      computational approaches developed for modelling biopharmaceutical properties,
      including in vitro activity, selectivity, absorption, distribution, metabolism,
      excretion and toxicity. Whenever possible, successful applications are mentioned.

PMID- 15200377
TI  - High-throughput evaluation of lipophilicity and acidity by new gradient HPLC
      methods.
AB  - There is a need for fast testing of drug candidates for properties of
      pharmacokinetics and pharmacodynamics importance, in particular lipophilicity and
      acidity. These two parameters can conveniently be estimated by gradient reversed
      phase HPLC. Appropriate conventional organic solvent gradient and the new pH
      gradient HPLC procedures are presented. The chromatographic parameter of
      lipophilicity, log kw, can be determined from two organic solvent gradient runs
      instead of 6-8 runs necessary in the standard isocratic (polycratic) approach.
      The newly introduced pH gradient reversed-phase HPLC consists in a programmed
      increase during the chromatographic run of the eluting power of the mobile phase
      with regards to ionizable analytes. The eluting strength of the mobile phase
      increases due to its increasing (in case of acidic analytes) or decreasing (basic
      analytes) pH, whereas the content of organic modifier remains constant. It has
      been theoretically and experimentally demonstrated that the pKa and log kw values
      can be evaluated based on retention data from a pH gradient run, combined with
      appropriate data from two organic solvent gradient runs. The gradient HPLC
      derived log kw parameters correlate well with analogous parameters determined
      isocratically as well as with reference lipophilicity parameter log P (logarithm
      of n-octanol/water partition coefficient). Also, the HPLC-derived pKa parameters
      correlate to the literature pKa values (w(w)pKa), conventionally determined by
      titrations in water. The approach described allows rapid and high-throughput
      assessment of log kw and pKa for large series of drugs candidates, also when the
      analytes are available in a form of mixture, e.g. produced by combinatorial
      synthesis.

PMID- 15200378
TI  - Stationary phases with special structural properties for high-throughput
      separation techniques: preparation, characterization and applications.
AB  - Stationary phases with specific structural properties for high-throughput liquid
      chromatographic (LC) techniques are described. Special attention was paid to
      phases with special structural properties, mainly containing internal functional
      group (e.g. amide). Such materials are generally called "embedded phases". There
      are phases created in amidation process of aminopropylated silica gel, especially
      phases based on biological compounds, like phospholipids and cholesterol, which
      are called immobilized artificial membranes (IAM's). The synthesis and
      applications of polar embedded amide LC stationary phases were also reviewed.
      Methods of characterization of synthesized packing materials were presented, with
      general focusing on spectroscopic measurements like (13C and 29Si CP/MAS NMR and
      FT-IR), elemental and thermal analysis as well as chromatographic quantitative
      structure-retention relationships (QSRR) and extended chemometric tests. The
      potential applications of various dedicated stationary phases in a high
      throughput LC screening procedures were also presented.

PMID- 15200379
TI  - Prediction of the affinity of the newly synthesised azapirone derivatives for 5
      HT1A receptors based on artificial neural network analysis of chromatographic
      retention data and calculation chemistry parameters.
AB  - The performance of artificial neural network (ANN) in predicting the affinity of
      a series of 65 new azapirone derivatives for rat brain serotonin 5-HT1A receptors
      based on high-performance liquid chromatography (HPLC) retention data and on non
      empirical structural parameters of the compounds' was studied. Affinity of the
      agents for rat brain 5-HT1A receptors were assessed in vitro and expressed as
      inhibitor constant values, Ki. The retention parameters determined in 14 HPLC
      systems along with compounds' structural descriptors from calculation chemistry
      were considered in ANN analysis. Supervised method of ANN learning with back
      propagation strategy was used in ANN calculations. Two models of ANN of similar
      architecture were designed: the first one for the data based on chromatographic
      retention data and the second based on structural parameters of the agents. Each
      ANN model was trained with the data of training set. It was next used to classify
      the agents from the testing set into two groups: active (Ki < 50 nM) and inactive
      compounds (Ki > 50 nM). A high prediction performance of both ANN models
      considered as regards the affinity of new azapirone derivatives for the serotonin
      5-HT1A receptors was demonstrated. However, the percent of correctly classified
      compounds was higher in the case of the ANN processing of the non-empirical
      structural descriptors of azapirone derivatives. Since the ANN analysis of the
      retention data and of the structural parameters originating from calculation
      chemistry allows to segregate drug candidates according to their pharmacological
      properties that, in consequence, may be of help to limit the number of biological
      assays in the search for new drugs.

PMID- 15200380
TI  - Artificial neural networks for prediction of antibacterial activity in series of
      imidazole derivatives.
AB  - Artificial neural networks (ANNs) have been applied for the quantitative
      structure-activity relationships (QSAR) studies of antibacterial activity against
      Escherichia coli, Serratia marcescens, Proteus vulgaris, Klebsiella pneumoniae
      and Pseudomonas aeruginosa of a large series of new imidazole derivatives.
      Antibacterial activity against individual bacteria, expressed as logarithm of
      reciprocal of the minimal inhibitory concentrations, log 1/MIC, has been related
      to a number of physicochemical and structural parameters of the imidazole
      derivatives investigated. Molecular descriptors of agents were obtained by
      quantum-chemical calculations combined with molecular modelling and from
      respective structure fragment reference data (e.g., log P). A high correlation
      resulted between the predicted from ANN model antibacterial activity, log
      1/MIC(ANN), and that from biological experiments, log 1/MIC(exp), both for the
      data used in learning and in the testing sets of imidazoles. Correlation
      coefficient, R, depending on the type of bacteria and structural subset of
      analysed imidazole compounds, varies from 0.875 to 0.969. The applicability of
      ANNs has been demonstrated for the prediction of pharmacological potency of new
      imidazole derivatives based on their structural descriptors generated exclusively
      by calculation chemistry.

PMID- 15200381
TI  - Electronic nose screening of limonene release from multicomponent essential oils
      encapsulated in pectin gels.
AB  - Multicomponent essential oils Tagetes Minuta and Poleo as well as pure limonene
      were encapsulated in Tween doped-high methoxylated pectin gels. Optical
      microscopy reveals that the obtained gels containing limonene consisted in a
      highly heterogeneous oil-in-water emulsion stabilised by the gelled medium. The
      influence of limonene encapsulation in pectin gelation kinetics and the gel
      structural properties were followed by dynamic rheological measurements. An
      electronic nose device developed in our laboratory was used to follow the flavour
      release of the three systems in order to discriminate the samples according to
      the main components released to the headspace. PCA and Neural Network Analysis
      allowed us to discriminate Tagetes Minuta from Poleo due to the difference in
      their limonene content. It is remarkable that the fingerprints of encapsulated
      complex mixtures differ from those obtained for the non-encapsulated oils,
      showing a preferential release of some components. In the case of limonene, the
      effect of the encapsulated concentration on the detected odour was also studied.

PMID- 15200382
TI  - Potentiometric quasi-array employing calixarene derivatives for the high
      throughput similarity/diversity screening of beta-adrenergic and beta-blocking
      chiral drugs by HPLC.
AB  - Performance of potentiometric quasi-array detection system consisted with the
      seven poly (vinyl chloride) (PVC) based liquid membrane electrodes in the cation
      exchange HPLC using acetonitrile--40 mM phosphoric acid (15 : 85, v/v, pH* 2.35)
      for assessing of molecular similarity/diversity in a mini-library of beta
      adrenergic and beta-blocking chiral drugs was presented. Macrocyclic compounds
      differing in stability of their conformers as well as in a size, steric hindrance
      and polarity of its internal cavities, comprising a series of five calix[6]arene
      derivatives completed with one modified calix[4]resorcinarene, were used as
      neutral ionophores to compose mentioned set of PVC-based electrodes. The output
      potentiometric responses were registered in the linear supernerstian range of
      calibration graph of each electrode, i.e. for a constant injected concentration
      2.0 x 10(-4) M of investigated drugs, which is related to the amount frequently
      used at in vitro studies on pharmacological effects of these drugs. The impact of
      symmetry oriented supramolecular interactions on the responses of developed
      electrodes were characterised with proposed series of the highly significant
      quantitative structure-potentiometric response relationships (QSPRRs) combining
      both three-dimensional (3D) molecular descriptors of analysed drugs as well as
      lipophilicity and volume polarizability of calixarene-type ionophores. The
      principal components analysis (PCA) and unweighted hierarchical clustering
      analysis (HCA) were used as the pattern recognition techniques into collected
      potentiometric database for extraction of the useful information on the molecular
      and pharmacological similarity/diversity of analysed drugs, thus a high
      throughput and consistent identification of therapeutically relevant agonists of
      beta2- and beta3-adrenoceptors and antagonists of beta1-adrenoceptor was
      especially achieved. This evidence supports also a hypothesis formulated by
      results of homology modelling on the subtle significance of an unrecognised
      supramolecular insertion processes of the chiral drug molecule into the flexible
      hydrophobic pocket(s) formed by seven helical transmembrane moving domains of
      beta-adrenoceptors on their final activation, sequestration, down-regulation or
      blockade.

PMID- 15200383
TI  - Boronic esters as ionophores for potentiometric discrimination of the cis-trans
      isomeric dicarboxylic acids.
AB  - Boronic esters incorporated into a poly(vinyl chloride) (PVC)-supported liquid
      membrane electrodes have displayed an anionic ionophore properties enabling their
      use in the potentiometric high-throughput screening procedures. These compounds
      belong to the class of ligands in which the anion recognition process can be
      explained on the concept of Lewis type acid-base interactions. Membranes
      containing boronic esters showed fairly good sensitivity for maleate (cis-isomer)
      in comparison to fumarate anions (trans-isomer). The potentiometric selectivity
      coefficients of proposed electrodes proved that common anions did not interfered
      with the maleate anion determination. The influence of structure of the three
      boronic esters ionophores on generation of potentiometric signal by developed
      liquid membrane electrodes was shortly discussed.

PMID- 15200384
TI  - Fabrication of PVC based membrane using nickel porphyrazine as ionophore in the
      screening of thiocyanate ion in aqueous and real samples.
AB  - The [Ni[(TAP)(SBn)8]] complex (I), i.e. ([2,3,7,8,12,13,17,18-octakis(benzylthio)
      5,10,15,20-tetraazaporphyrin])nickel(II), has been explored as an ionophore for
      fabrication of the PVC based membrane electrodes used in the screening of
      thiocyanate anion (SCN-). The membrane having [Ni[(TAP)(SBn)8]] complex (I) as an
      electroactive material and dioctylphthalate (DOP) as plasticizer in the PVC
      matrix with the percentage ratio 5 : 158 : 200 (I : DOP : PVC, % w/w) exhibited a
      linear response in the concentration range 7.0 x 10(-6)-1.0 x 10(-1) M of SCN-
      with a sub-Nernstian slope 32.5 +/- 0.2 mV/decade of activity and a fast response
      time of 10 +/- 2 s. The sensor works well in the pH range 3.0 - 9.5 and could be
      satisfactorily used in presence of 50 % (v/v) methanol, ethanol and acetone, and
      is selective for SCN- over a large number of anions with slight interference from
      iodide (I-) and azide (N3-) if present at a level >or = 1.0 x 10(-5) M. Described
      electrode works well over a period of six months. The sensor can be successfully
      applied for the screening of SCN- in both aqueous and real samples and also as
      indicator electrodes in precipitation titrations.

PMID- 15200385
TI  - Potentiometric discrimination of neutral forms of nitrophenol isomers by liquid
      membrane electrodes incorporated with corroles.
AB  - The results of studies on the use of corrole derivatives as a host ligand in the
      PVC liquid membrane electrodes and their ability for the potentiometric high
      throughput discrimination of nitrophenol guests have been presented. The
      significance of parameters which govern the mechanism of generation of
      potentiometric signals such as the attachment of substituents in the corrole
      structure, acidity and lipophilicity of the guests, and pH of the aqueous
      solutions has been discussed in details. Supramolecular recognition processes
      between corroles and para-nitrophenol molecules have been confirmed by
      independent NMR measurements.

PMID- 15200386
TI  - Effect of stationary phase structure on retention and selectivity tuning in the
      high-throughput separation of tocopherol isomers by HPLC.
AB  - Four stationary phases containing different groups such as: C18, C30, alkylamide,
      and cholesterolic, were presented for simultaneous HPLC analysis of structural
      isomers of tocopherol. Especially, the influence of stationary phase structure
      and properties on tuning of the highly selective HPLC separation of beta- and
      gamma-tocopherol pair demonstrating, respectively, para- and ortho- arrangement
      of methyl substituents on the 6-chromanol ring, has been elucidated. It was
      pointed out that selectivity of each stationary phase has been a result of
      modulation in the mass transfer and set of unspecific interactions in the
      tertiary system comprising analyte <==> stationary phase <==> mobile phase.
      Differences in observed retention and specific selectivity of tocopherols
      together with the stationary phase structure investigations indicated that a
      spatial organization changing of chemically bonded ligands as predominantly a
      solvation consequence. Additional molecular modeling studies preliminary
      explained some of these complicated supramolecular phenomena which caused that
      cholesterolic stationary phase offered beneficial performance in screening of
      tocopherols by HPLC and biomimetic studies of not completely recognized
      interactions of tocopherol isomers and biological membranes.

PMID- 15200390
TI  - 'Not if I was very ill'.

PMID- 15200387
TI  - Characterization of N-acetylneuraminic acid synthase isoenzyme 1 from
      Campylobacter jejuni.
AB  - Escherichia coli NeuNAc (N-acetylneuraminic acid) synthase catalyses the
      condensation of PEP (phosphoenolpyruvate) and ManNAc (N-acetylmannosamine) to
      form NeuNAc and is encoded by the neuB gene. Campylobacter jejuni has three neuB
      genes, one of which is very similar to the E. coli neuB gene. We have
      characterized the C. jejuni neuraminic acid synthase with respect to acylamino
      sugar specificity and stereochemistry of the PEP condensation. We determined the
      specificity of C. jejuni NeuNAc synthase for N-acetylmannosamine, N
      butanoylmannosamine, N-propionoylmannosamine and N-pentanoylmannosamine. We find
      that, although this enzyme exhibits similar K(m) values for N-acylmannosamine
      molecules with different N-acyl groups, the kcat/K(m) values decreased with
      increasing chain length. NeuNAc synthase is a member of a PEP-utilizing family of
      enzymes that form oxo acids from PEP and a monosaccharide. This family includes
      KDO 8-P (2-keto-3-deoxy-D-manno-octulosonate 8-phosphate) synthase and DAH 7-P (2
      keto-3-deoxy-D-arabino-heptulosonate 7-phosphate) synthase. Both enzymes catalyse
      the condensation of the re face of the aldehyde group of the monosaccharide with
      the si face of the PEP molecule. The C. jejuni NeuNAc synthase catalysed the
      condensation of Z- and E-[3-2H]PEP with ManNAc, yielding (3S)-3-deutero-NeuNAc
      and (3R)-3-deutero-NeuNAc respectively. The condensation of Z-[3-F]PEP and ManNAc
      yielded (3S)-3-fluoro-NeuNAc. Results of our studies suggest that the C. jejuni
      NeuNAc synthase, similar to KDO 8-P synthase and DAH 7-P synthase, catalyses the
      condensation of the si face of PEP with the aldehyde sugar. The present study is
      the first stereochemical analysis of the reaction catalysed by a bacterial NeuNAc
      synthase.

PMID- 15200391
TI  - Learning from disappointments.

PMID- 15200388
TI  - Transthyretin interacts with the lysosome-associated membrane protein (LAMP-1) in
      circulation.
AB  - LAMP-1 (lysosome-associated membrane protein), a major glycoprotein present in
      the lysosomal membrane, constitutes up to 50% of total membrane proteins. LAMP-1,
      expressed at the plasma membrane, is reported to be the major molecule expressing
      the sialyl-Lewis X antigen. Two forms of LAMP-1 exist; the full-length LAMP-1
      [LAMP-1 (+Tail)] has a highly glycosylated lumenal domain, a membrane-spanning
      domain and a short cytoplasmic tail, and the truncated LAMP-1 [LAMP-1 (-Tail)]
      contains only the lumenal domain. Soluble LAMP-1 (+/-Tail) has been reported in
      circulation. LAMP-1 at the cell surface has been shown to interact with E
      selectin and galectin and is proposed to function in cell-cell interactions.
      However, the functional role(s) of soluble LAMP-1 in circulation is unclear. To
      investigate the functional role of soluble LAMP-1 in circulation, recombinant
      LAMP-1 (-Tail) and LAMP-1 (+Tail) were produced in HT1080 cells. Two immune
      quantification assays were developed to distinguish between the LAMP-1 forms. The
      interaction and aggregation properties of the different LAMP-1 forms were
      investigated using the immune-quantification assays. Only LAMP-1 (+Tail) was
      found to aggregate and interact with plasma proteins. Plasma proteins that
      interact with LAMP-1 were isolated by affinity chromatography with either the
      recombinant LAMP-1 (-Tail) or a synthesized peptide consisting of the 14 amino
      acids of the LAMP-1 cytoplasmic tail. Transthyretin was found to interact with
      the cytoplasmic tail of LAMP-1. Transthyretin exists as a homotetramer in plasma,
      as such may play a role in the aggregation of LAMP-1 in circulation.

PMID- 15200392
TI  - Understanding global health issues: are international medical electives the
      answer?

PMID- 15200393
TI  - Tensions influencing operating room team function: does institutional context
      make a difference?
AB  - BACKGROUND: A recent study of operating room (OR) team communication in a large,
      urban hospital described recurrent tension catalysts and a preliminary theory of
      team members' interpretive processes. To determine to what extent these findings
      were transferable to other institutional contexts, we conducted a validation
      study in 2 small, academic hospitals in a mid-size city. METHODS: Eight focus
      groups and 8 interviews were conducted with 6 general surgeons, 22 OR nurses, 5
      anaesthesiologists and 10 trainees. Observations of 10 surgeons and their team
      members were conducted over 4 months. Data were analysed by applying thematic
      codes derived from previous research and engaging a grounded theory process to
      reveal additional, emergent themes. RESULTS: Observed tension catalysts were
      consistent with those described previously. However, 'higher tension' events
      occurred in only 70% of procedures in the smaller institutional context, as
      compared with at least 1 such event in all procedures in the larger setting.
      Interpretive processes were similar in teams from large and small institutional
      contexts. Team members referenced professional roles to interpret discourse, and
      they displayed recurrent role disagreements. Role perception influenced the
      motivations individuals attributed to colleagues' discourse, which influenced
      interpretations and reactions. CONCLUSIONS: Overall tension levels are lower in
      OR teams in smaller institutions; however, tension catalysts and interpretive
      processes appear similar to those in larger settings. Consistency in tension
      catalysts and interpretive processes across contexts allows us to begin to model
      theoretical principles of OR team communication, enabling the development of
      generic communication curricula applicable in a wide variety of institutional
      contexts.

PMID- 15200394
TI  - Validation of a checklist to assess ward round performance in internal medicine.
AB  - BACKGROUND: Ward rounds are an essential responsibility for doctors in hospital
      settings. Tools for guiding and assessing trainees' performance of ward rounds
      are needed. A checklist was developed for that purpose for use with trainees in
      internal medicine. OBJECTIVE: To assess the content and construct validity of the
      task-specific checklist. METHODS: To determine content validity, a questionnaire
      was mailed to 295 internists. They were requested to give their opinion on the
      relevance of each item included on the checklist and to indicate the
      comprehensiveness of the checklist. To determine construct validity, an observer
      assessed 4 groups of doctors during performance of a complete ward round (n =
      32). The nurse who accompanied the doctor on rounds made a global assessment of
      the performance. RESULTS: The response rate to the questionnaire was 80.7%. The
      respondents found that all 10 items on the checklist were relevant to ward round
      performance and that the item collection was comprehensive. Checklist mean-item
      scores differed between levels of expertise: junior house officers 1.4 (1.0-1.9);
      senior house officers 2.0 (1.5-2.9); specialist trainees 2.5 (1.8-2.8), and
      specialists 2.7 (2.3-3.5); median (range) (P < 0.001). A significant correlation
      was found between global observer scores and nurse scores (r = 0.56, P < 0.001).
      CONCLUSION: The checklist, developed for assessing trainees' performance of ward
      rounds in internal medicine, showed high content validity. Construct validity was
      supported by the higher scores of experienced doctors compared to those with less
      experience and the significant correlation between the observer's and nurses'
      global scores. The developed checklist should be valuable in guiding and
      assessing trainees on ward round performance.

PMID- 15200395
TI  - Pre-registration house officer training: a role for nurses in the new Foundation
      Programme?
AB  - PURPOSE: To explore senior nurses' views of pre-registration house officer (PRHO)
      training, including the scope for their contribution to the new Foundation
      Programme. DESIGN: Data reported here are drawn from a larger, national project,
      which aimed to identify a curriculum for the PRHO year. The project was based in
      the Education Development Unit, Scottish Council for Postgraduate Medical and
      Dental Education (SCPMDE), Dundee. As part of the project, 40 semistructured
      interviews, each lasting about 1 hour, were held with senior nurses. Interviews
      were fully transcribed and coded in the qualitative software NVivo for further
      analysis. Codes were studied for emergent themes and categories. PARTICIPANTS:
      Senior nurses (10 from each of the 4 postgraduate regions of Scotland), from
      diverse specialties. RESULTS: Data suggest considerable cross- regional/specialty
      consistency. Key emergent themes concerned the process of training as much as the
      educational outcomes. The nurses focused on the development of outcomes such as
      communication and teamworking in addition to clinical and practical skills. They
      guided the PRHOs informally, but were concerned that their own extended roles
      were detracting from this. DISCUSSION: Nurses are gaining increasingly advanced
      professional, clinical and practical skills. Traditionally, experienced nurses
      guide and support PRHOs, at least informally. Data collected suggested there may
      be scope for capitalising on their expertise, including formalising aspects of
      their contribution to the proposed PRHO Foundation Programme. However, this is a
      potentially sensitive area and more interprofessional dialogue is needed.

PMID- 15200396
TI  - Learning for real life: patient-focused interprofessional workshops offer added
      value.
AB  - OBJECTIVES: This paper reports relevant findings of a pilot interprofessional
      education (IPE) project in the Schools of Medicine and Healthcare Studies at the
      University of Leeds. The purpose of the paper is to make a contribution towards
      answering 2 questions of fundamental importance to the development of IPE. Is
      there a demonstrable value to learning together? What types of IPE, under what
      circumstances, produce what type of outcomes? DESIGN: Pre-registration house
      officers (PRHOs), student nurses and pre-registration pharmacists attended a
      series of 3 workshops intended to develop participants' understanding about each
      other's professional roles, to enhance teamworking and to develop communication
      skills. Evaluation covered the process of development of the workshops, the
      delivery of the workshops and their effects on both facilitators and
      participants. RESULTS: The course was well received by the participants. The
      learning reported by the participants reflected 2 project objectives.
      Participants emphasised communication skills--both with other professionals and
      patients--and the development of increased awareness of others' roles. These 2
      aspects were interlinked. CONCLUSIONS: The project aims and 2 of the learning
      outcomes were achieved. There was a demonstrable value to learning together,
      particularly with regard to interprofessional communications. This project was
      effective and can make a contribution towards answering the question 'What types
      of IPE, under what circumstances, produce what type of outcomes?'

PMID- 15200397
TI  - Interprofessional training in the context of clinical practice: goals and
      students' perceptions on clinical education wards.
AB  - AIMS: This paper describes the context of interprofessional training on clinical
      education wards (CEWs) and reports students' perceptions of this type of
      interprofessional and professional training. CONTEXT: A 2-week interprofessional
      clinical course was designed for medical students in their surgical eighth term,
      and nursing, occupational therapy and physiotherapy students, all in their sixth
      term. Clinical tutors were responsible for the patients and also supervised the
      students. The goals for the students included: to provide the patients with good
      medical care, nursing and rehabilitation; to develop their own professional
      roles; to enhance their level of understanding of the other professions; to
      stress the importance of good communication for teamwork and for patient care; to
      enhance understanding of the role of the patient, and to become more aware of
      ethical aspects of health care. MATERIAL AND METHODS: A questionnaire developed
      by teachers from the 4 educational departments was used. A total of 962 students
      responded (78%). RESULTS: The CEWs provided the students with good clinical
      practice in terms of training in their own professions as well in learning more
      about the other professions. The importance of good communication for teamwork
      and for patient care was recognised. The quality of supervision and students'
      perception of their own professional roles were important factors regarding
      satisfaction with the CEW course. CONCLUSIONS: The CEW course seemed to provide
      the students with an opportunity to develop their own professional roles and
      their functions as team members.

PMID- 15200398
TI  - Student attitudes towards anatomy teaching and learning in a multiprofessional
      context.
AB  - CONTEXT: We carried out a survey of attitudes to learning anatomy amongst
      students from a range of health care disciplines in a multiprofessional context.
      SETTING: A joint course called the Common Foundation Programme (CFP) presented by
      a hospital medical school and a joint university faculty of health and social
      care sciences in the UK in the first term of the students' courses. PARTICIPANTS:
      Students following degree courses in biomedical science, medicine, nursing,
      physiotherapy, diagnostic radiography and therapeutic radiography. OBJECTIVES: To
      assess student attitudes to cadaveric work, learning anatomy and
      multiprofessional learning, and to compare student performance between degree
      courses in an anatomy assessment. DESIGN: A questionnaire was designed that
      requested demographic information and the students' attitudes to cadaveric work,
      anatomy learning and multiprofessional learning on a Likert scale. All students
      sat the same anatomy assessment at the end of the first term. RESULTS: The
      biomedical science and medical students were the most apprehensive about entering
      the dissecting room. The biomedical science students enjoyed working in a
      multidisciplinary group the most. Assessment results varied widely and the
      physiotherapy and medical students scored more highly than students in other
      disciplines, although all students had participated in the same course.
      CONCLUSIONS: It was possible to teach anatomy in the context of the shared
      learning experience of the CFP, although performance varied widely. Reasons for
      the differences are discussed and suggestions for the design of multiprofessional
      courses involving anatomy are made.

PMID- 15200399
TI  - 'I found myself to be a down to earth Dutch girl': a qualitative study into
      learning outcomes from international traineeships.
AB  - OBJECTIVE: To explore learning outcomes from international traineeships for
      undergraduate medical students. METHODS: In-depth interviews were conducted with
      24 undergraduate medical students at Maastricht University Medical School, The
      Netherlands. The 24 subjects were selected by purposeful sampling. RESULTS:
      Students reported meaningful learning outcomes in 6 domains: medical knowledge;
      skills; international health care organisation; international medical education;
      society and culture, and personal growth. DISCUSSION: International traineeships
      appear to provide good opportunities for students to meet the requirements of
      globalisation as well as some of the generic objectives of undergraduate medical
      education. The tentative findings of this study need to be confirmed by further
      studies.

PMID- 15200400
TI  - Factors predictive of successful learning in postgraduate medical education.
AB  - PURPOSE: To establish which personal and contextual factors are predictive of
      successful outcomes in postgraduate medical education. METHOD: We performed a
      follow-up study of 118 doctors on a postgraduate occupational health training
      programme on the management of mental health problems. The following personal and
      contextual variables were measured as potential predictors of outcome: gender;
      age; years of experience as a doctor; university of graduation; learning style
      (Kolb); present employer (occupational health service), and educational format
      (problem-based or lecture-based). The main outcome measures were: scores on
      knowledge tests consisting of true/false and open answer questions, and
      performance in practice based on self-report and performance indicators. To
      determine the effect of potential predictive factors univariate analyses of
      variance and repeated measurement analysis of variance was applied. RESULTS: The
      mean scores of knowledge (P < 0.001) and performance (P = 0.001) of the
      participants increased after the educational programme. After multivariate
      analysis female gender was positively related to accruements in both knowledge
      and performance (both P < 0.05), independently of the influence of other factors.
      Accommodator learning style showed a relation with knowledge increase (P = 0.05),
      but had no influence on performance (P = 0.79). The problem-based educational
      format yielded a better performance outcome (P = 0.05), but had no influence on
      knowledge tests (P = 0.31). CONCLUSION: Gender and learning style were found to
      be related to an increase in knowledge. Gender was also found to be related to
      improvement in performance after a postgraduate medical education programme. We
      found no interactions with course design (i.e. problem-based or non problem-based
      learning formats), but further research could reveal other cues, suggesting
      practical consequences of student characteristics for course design in
      postgraduate training.

PMID- 15200401
TI  - Educational impact of in-training assessment (ITA) in postgraduate medical
      education: a qualitative study of an ITA programme in actual practice.
AB  - OBJECTIVES: To investigate the experiences and opinions of programme directors,
      clinical supervisors and trainees on an in-training assessment (ITA) programme on
      a broad spectrum of competence for first year training in anaesthesiology. How
      does the programme work in practice and what are the benefits and barriers? What
      are the users' experiences and thoughts about its effect on training, teaching
      and learning? What are their attitudes towards this concept of assessment?
      METHODS: Semistructured interviews were conducted with programme directors,
      supervisors and trainees from 3 departments. Interviews were audiotaped and
      transcribed. The content of the interviews was analysed in a consensus process
      among the authors. RESULTS: The programme was of benefit in making goals and
      objectives clear, in structuring training, teaching and learning, and in
      monitoring progress and managing problem trainees. There was a generally positive
      attitude towards assessment. Trainees especially appreciated the coupling of
      theory with practice and, in general, the programme inspired an academic
      dialogue. Issues of uncertainty regarding standards of performance and conflict
      with service declined over time and experience with the programme, and
      departments tended to resolve practical problems through structured planning.
      DISCUSSION: Three interrelated factors appeared to influence the perceived value
      of assessment in postgraduate education: (1) the link between patient safety and
      individual practice when assessment is used as a licence to practise without
      supervision rather than as an end-of-training examination; (2) its benefits to
      educators and learners as an educational process rather than as merely a method
      of documenting competence, and (3) the attitude and rigour of assessment
      practice.

PMID- 15200402
TI  - Graduate entry to medical school? Testing some assumptions.
AB  - BACKGROUND: Debate abounds regarding the most appropriate candidates to admit to
      medical school. This paper examines whether there is any advantage to admitting
      'graduate' entrants over secondary school leavers on selected medical school and
      practice outcomes. AIM: To compare the medical school experiences, research and
      academic achievements and practice outcomes of graduates who entered 1 medical
      school in Australia directly from high school (secondary school entry) to those
      of graduates who entered with tertiary level education (tertiary entry). DESIGN
      AND METHODS: Cross-sectional study using a mail-out survey to graduates from the
      first 16 graduating years (1983-98 inclusive) of the University of Newcastle
      Medical School. RESULTS: Secondary school entrants were, on average, 8 years
      younger than tertiary entrants and were less likely to have received rural-based
      schooling. However, there were no differences with respect to gender or type of
      secondary school attended (public or private). Motivations for studying medicine
      did not generally differ according to entry type, except that more secondary
      students were motivated by parental expectations and more tertiary entrants were
      motivated by the need for professional independence and the desire to prevent
      disease. A greater proportion of tertiary entrants experienced stress at medical
      school. However, secondary students experienced more stress due to doubts about
      being a doctor, while tertiary entrants experienced more stress due to lack of
      leisure time, finances and balancing commitments. There were no significant
      differences between the groups in terms of academic performance (as measured by
      the award of medical school honours) or research outcomes (as measured by
      completion of a research degree during or after medical school training,
      publication of scientific papers or holding career posts in the research
      sciences). There were no differences in career positions held by clinicians,
      choice of general practice or another specialty as a career, practice location
      (rural or urban) or employment sector (public or private). CONCLUSION: There is
      no clear advantage, at least on the outcomes measured in this study, to limiting
      medical school entry to either those candidates from secondary school or those
      with tertiary backgrounds. Medical schools could reasonably broaden their
      selection criteria to include more graduate entry candidates in addition to
      secondary school leavers without compromising medical school and practice
      outcomes.

PMID- 15200403
TI  - A randomised trial of an online lecture with and without audio.
AB  - OBJECTIVE: To determine the impact of adding audio-feed to an online lecture on
      screening given to medical students who were participating in an outpatient
      clerkship. DESIGN: Prospective, randomised, controlled study. SETTING: Vanderbilt
      University School of Medicine, Nashville and Wake Forest Medical School, Winston
      Salem. PARTICIPANTS: A total of 59 Years 3 and 4 medical students. MAIN OUTCOME
      MEASURES: Students' use of time, satisfaction with the lecture experience, and
      knowledge. Educational intervention The online lecture was developed at
      Vanderbilt University. At Vanderbilt, 16 Year 4 medical students were randomised
      to the lecture on screening with audio and 17 Year 4 medical students were
      randomised to the same lecture without audio. At Wake Forest, 13 Year 3 medical
      students were randomised to the lecture on screening with audio and 13 Year 3
      students were randomised to the same lecture without audio. RESULTS: The audio
      lecture required 20 more minutes to complete than the non-audio lecture. Students
      in the audio group were more satisfied with their experience than students in the
      non-audio group. Students in the audio-feed group achieved a trend for higher
      post-intervention knowledge scores, with the difference attributed to the
      students at Vanderbilt. CONCLUSION: Audio narration is an important aspect of an
      online lecture. The distribution of online lectures to students at different
      sites and different training levels requires further study.

PMID- 15200405
TI  - Introduction. The role of on-line monitoring of dialysate conductivity to ensure
      adequate delivery of dialysis dose.

PMID- 15200406
TI  - Mechanisms determining the ratio of conductivity clearance to urea clearance.
AB  - BACKGROUND: Effective conductivity clearance (K(ecn)) has been reported to be a
      surrogate for effective urea clearance (K(eu)), where both are usually defined
      respectively as the dialyzer conductivity and urea clearances (K(cn), K(u))
      corrected for access recirculation (R(ac)). However, many investigators have
      reported K(ecn)/K(eu) to be <1 and postulated anatomic distribution of Na in
      plasma water, cardiopulmonary recirculation (R(cp)), and high rates of urea
      clearance (K(u)) as causes. The aims of these studies were to devise analytic
      models of these mechanisms and to clinically evaluate the modeled relationships.
      METHODS: We modeled and measured: (1) Na osmotic distribution volume flow rate
      (Q(osmNa)) in dialyzer blood flow; (2) the separate and combined effects of R(ac)
      and R(cp) on K(u) and K(cn); and (3) a novel mechanism reducing the conductivity
      diffusion gradient during measurement of K(cn) by recirculation through the
      dialyzer (R(s)) of a change in systemic blood conductivity (Delta Cn(s)) induced
      by the abrupt changes in dialysate inlet Na (Delta C(diNa)) required for the
      measurement of K(cn). RESULTS: The ratio Q(osmNa)/Q(bi)= 1.00 +.03, N= 19 (Q(bi)=
      total blood water flow rate). Modeling showed that the effects of R(ac), R(cp),
      and R(s) on K(cn) can be quantified as K(ecn)= K(cn)(1 -Delta Cn(bi)/Delta
      Cn(di)), where Delta C(nbi) is any change in conductivity in the dialyzer blood
      inlet stream during a measurement, and the effect of a combination of these
      mechanisms is the product of the effects of individual mechanisms. A single-step
      dialysate profile (with R(ac)= 0) resulted in measured Delta C(biNa)/Delta
      C(diNa)= 2.5/15, K(ecn)/K(eu)= 0.83, N= 21 because of R(s) and R(cp), but with a
      two-step, high/low profile (P(h/L)) we found these respective values to be 
      0.6/20 and 0.97, N= 19. The ratio K(ecn)/K(eu3)= 1.06 +.02, M + SE, N= 35
      (K(eu3)= Ku corrected to reflect both access and cardiopulmonary recirculation).
      The ratio K(ecn)/K(eu1) (K(eu1) is K(u) corrected to reflect access recirculation
      only) = 1.01 +.07, N= 297, with no bias on Bland Altman analysis. CONCLUSION: We
      conclude that (1) the osmotic Na distribution volume in blood is total blood
      water; (2) K(ecn) measured with a short, high/low, and asymmetric dialysate
      profile shows R(ac) effect but neither R(cp) nor R(s) effects on K(ecn) and
      K(ecn)/K(eu)= 1.0; (3) the K(ecn)/K(eu) ratio is strongly dependent on the type
      of dialysate profile used, which must be optimized to minimize net Na transfer to
      and from blood during measurement of conductivity clearance to avoid erroneous
      underestimation of K(ecn) and K(ecn)/K(eu) ratios <1.

PMID- 15200407
TI  - Aldosterone in the development and progression of renal injury.
AB  - BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) contributes to
      hypertension and nephropathy. Until recently, aldosterone either has not been
      considered or has been considered a relatively minor component of the process-a
      contribution that could be negated with angiotensin-converting enzyme (ACE)
      inhibition or angiotensin receptor blockade. METHODS: A Medline search was
      performed to identify relevant literature describing the role of aldosterone in
      the pathogenesis of renal dysfunction. RESULTS: Growing evidence from
      experimental and clinical studies indicates that increased aldosterone is an
      independent contributor to small- and medium-sized arterial injury and
      nephropathy. Excess mineralocorticoid receptor stimulation of local and systemic
      origin promotes target organ dysfunction, vascular injury, and fibrosis,
      independent of the effects of other elements of the RAAS. Blockade of the RAAS
      with ACE inhibition or angiotensin receptor blockade often does not confer
      optimal protection from the effects of mineralocorticoids on small- and medium
      sized blood vessels. Recent preliminary data from clinical studies indicate that
      aldosterone blockade protects the kidneys, sharply decreases proteinuria, beyond
      the activities of ACE inhibition or angiotensin receptor blockade and independent
      of beneficial blood pressure effects, and can protect patients from vascular
      injury associated with diabetes mellitus and hypertension. CONCLUSION:
      Aldosterone blockade with the selective aldosterone blocker eplerenone, in
      combination with other RAAS inhibitors, is probably renoprotective and should be
      considered as a component of the treatment regimens of diabetic and hypertensive
      patients at risk for renal or cardiovascular disease expression. A high priority
      should be placed on developing the randomized, controlled trials required to
      establish that role.

PMID- 15200409
TI  - Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial
      abnormalities in kd/kd mice.
AB  - BACKGROUND: Mice that are homozygous for the kidney disease (kd) mutation are
      apparently healthy for the first 8 weeks of life, but spontaneously develop a
      severe form of interstitial nephritis that progresses to end-stage renal disease
      (ESRD) by 4 to 8 months of age. By testing for linkage to microsatellite markers,
      we previously localized the kd gene to a YAC/BAC contig. METHODS: The sequence of
      the entire critical region was examined, and candidate genes were identified.
      These candidate genes were sequenced in both mutant (kd/kd) mice and normal
      controls. The phenotype was further characterized by immunohistochemistry and
      electron microscopy. Transgenic mice were constructed that carried the wild-type
      allele of the prime candidate gene, and this transgene was transferred to a kd/kd
      background by breeding. RESULTS: We have obtained evidence that kd is a mutant
      allele of a novel gene for a prenyltransferase-like mitochondrial protein (PLMP).
      This gene is alternatively spliced, with the larger gene product having one
      domain that resembles transprenyltransferase and another that is similar to
      geranylgeranyl pyrophosphate synthase. The smaller gene product includes only the
      first domain. An antiserum to PLMP localizes to mitochondria, and ultrastructural
      defects are present in the mitochondria of renal tubular epithelial cells, and to
      a lesser extent, hepatocytes and heart cells from kd/kd mice. In a line of kd/kd
      mice that carried the wild-type PLMP allele as a transgene, only 1 out of 13
      animals expressed the disease by 120 days of age. CONCLUSION: The kd allele codes
      for a novel protein that localizes to the mitochondria, and the kd/kd mouse has
      dysmorphic mitochondria in the renal tubular epithelial cells. This mouse is
      therefore a unique animal model for studying mechanisms that lead to
      tubulointerstitial nephritis.

PMID- 15200408
TI  - Lack of major involvement of human uroplakin genes in vesicoureteral reflux:
      implications for disease heterogeneity.
AB  - BACKGROUND: Primary vesicoureteral reflux (VUR) is a hereditary disorder
      characterized by the retrograde flow of urine into the ureters and kidneys. It
      affects about 1% of the young children and is thus one of the most common
      hereditary diseases. Its associated nephropathy is an important cause of end
      stage renal failure in children and adults. Recent studies indicate that genetic
      ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial
      specific integral membrane protein forming urothelial plaques, causes VUR and
      hydronephrosis. METHODS: To begin to determine whether mutations in UP genes
      might play a role in human VUR, we genotyped all four UP genes in 76 patients
      with radiologically proven primary VUR by polymerase chain reaction (PCR)
      amplification and sequencing of all their exons plus 50 to 150 bp of flanking
      intronic sequences. RESULTS: Eighteen single nucleotide polymorphisms (SNPs) were
      identified, seven of which were missense, with no truncation or frame shift
      mutations. Since healthy relatives of the VUR probands are not reliable negative
      controls for VUR, we used a population of 90 race-matched, healthy individuals,
      unrelated to the VUR patients, as controls to perform an association study. Most
      of the SNPs were not found to be significantly associated with VUR. However, SNP1
      of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP
      III affecting a C to G conversion and a Pro154Ala change, were marginally
      associated with VUR (both P= 0.08). Studies of additional cases yielded a second
      set of data that, in combination with the first set, confirmed a weak association
      of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls).
      CONCLUSION: Such a weak association and the lack of families with simple dominant
      Mendelian inheritance suggest that missense changes of uroplakin genes cannot
      play a dominant role in causing VUR in humans, although they may be weak risk
      factors contributing to a complex polygenic disease. The fact that no truncation
      or frame shift mutations have been found in any of the VUR patients, coupled with
      our recent finding that some breeding pairs of UP III knockout mice yield litters
      that show not only VUR, but also severe hydronephrosis and neonatal death, raises
      the possibility that major uroplakin mutations could be embryonically or
      postnatally lethal in humans.

PMID- 15200410
TI  - Gene expression variance based on random sequencing in rat remnant kidney.
AB  - BACKGROUND: Several examinations have been performed to identify the genes
      involved in chronic renal failure using 5/6 nephrectomized rats. Recently, many
      systematic techniques for examining molecular expression have been developed.
      They might also be effective in elucidating the molecular mechanism of
      progressive renal failure. In this study, digital expression profiling was
      carried out to construct a subtractive mRNA expression database for the 5/6
      nephrectomized kidney. METHODS: One thousand clones were randomly sequenced from
      5/6 nephrectomized and sham-operated rat kidney cDNA libraries, respectively, and
      defined by BLAST search. In silico subtractive analysis was performed to search
      for genes up- or down-regulated in the 5/6 nephrectomized kidney. RESULTS: The
      growth factor-related mRNAs and the mRNAs encoding cytoskeletal or membrane
      proteins were up-regulated, but the transporter-related mRNAs were down-regulated
      in the 5/6 nephrectomized kidney database. In silico subtraction revealed that 63
      mRNAs were increased and 59 were decreased in the 5/6 nephrectomized kidney. To
      confirm whether the in silico subtractive database reflected the actual
      expression of mRNA or protein, 12 known genes were examined by Northern blotting
      or immunoblotting, respectively. The actual expression of the 12 genes was
      comparable with the results of in silico subtraction. In addition, we
      successfully isolated five unknown genes, two up-regulated and three down
      regulated in the 5/6 nephrectomized kidney. CONCLUSION: We constructed a
      subtractive mRNA expression database for 5/6 nephrectomized kidney, which
      reflects the actual alterations in mRNA expression after subtotal nephrectomy.
      This database may be useful for elucidation of the molecular mechanism of
      progressive renal failure.

PMID- 15200411
TI  - Reduced gene expression of adiponectin in fat tissue from patients with end-stage
      renal disease.
AB  - BACKGROUND: Cardiovascular disease (CVD) is the main cause of death in end-stage
      renal disease (ESRD) patients. It has been suggested that inflammation plays a
      key role in the development of both atherosclerosis and malnutrition (MIA), a
      combination of complications associated with poor outcome. Although plasma levels
      of adiponectin, a recently discovered anti-inflammatory and antiatherogenic
      adipocytokine, are markedly elevated in ESRD, gene expression of adiponectin
      (ApM1) has not been analyzed in ESRD patients. METHODS: We analyzed the ApM1 gene
      expression in adipose tissue from 18 ESRD patients of whom 9 (7 males, 60 +/- 8
      years, BMI 24 +/- 6 kg/m(2)) had a high prevalence of MIA complications, and 9
      age- (55 +/- 9 years), gender- (7 males) and BMI- (24 +/- 2 kg/m(2)) matched ESRD
      patients had few MIA complications. The results were compared with age- (59 +/-
      11 years), gender- (7 males), and BMI- (24 +/- 6 kg/m(2)) matched healthy control
      patients. Information on CVD was obtained at the recruitment based on a detailed
      medical history. Malnutrition was defined as a subjective global assessment (SGA)
      score >1. Inflammation was defined as CRP >/=10 mg/L. Gene expression analysis
      was performed using the in situ hybridization technique. RESULTS: Gene expression
      of ApM1 was lower in ESRD patients compared with healthy control patients (P=
      0.001). On the other hand, when comparing the gene expression between ESRD
      patients with and without MIA complications, respectively, no difference in the
      ApM1 gene expression was detected. CONCLUSION: Adiponectin gene expression is
      significantly down-regulated in ESRD patients compared with healthy control
      patients. We propose that the decrease in expression may be the result of a
      negative feedback regulation, as a result of elevated levels of circulating
      adiponectin caused by renal failure.

PMID- 15200412
TI  - Chondromodulin-I expression in the growth plate of young uremic rats.
AB  - BACKGROUND: Growth retardation of chronic renal failure is associated with
      alterations in the growth plate suggestive of a disturbed chondrocyte maturation
      process and abnormal vascular invasion at the chondro-osseous interphase.
      Chondromodulin I (ChM-I) is a potent cartilage-specific angiostatic factor. Its
      pattern of expression in the uremic rat growth plate is unknown. Persistence of
      ChM-I synthesis and/or imbalance between ChM-I and vascular endothelial growth
      factor (VEGF) expressions might play a role in the alterations of uremic growth
      plate. METHODS: Growth cartilage ChM-I expression was investigated by
      immunohistochemistry, in situ hybridization, and reverse transcription-polymerase
      chain reaction (RT-PCR) in growth-retarded young uremic rats (UREM), control
      rats, fed ad libitum (SAL) or pair-fed with the UREM group (SPF), and uremic rats
      treated with growth hormone (UREM-GH). VEGF expression was analyzed by
      immunohistochemistry. RESULTS: ChM-I and ChM-I mRNA were confined to the
      proliferative and early hypertrophic zones of growth cartilage. A similar number
      of chondrocytes per column was positive for ChM-I in the 4 groups. In accordance
      with the elongation of the hypertrophic stratum in uremia, the distance (X+/-SEM,
      microm) between the extracellular ChM-I signal and the metaphyseal end of growth
      cartilage was higher (P < 0.003) in UREM (236 +/- 40) and UREM-GH (297 +/- 17)
      than in SAL (92 +/- 7) and SPF (113 +/- 6). No differences in ChM-I expression
      were appreciated by RT-PCR. Similar VEGF positivity was observed in the
      hypertrophic chondrocytes of all groups. CONCLUSION: In experimental uremia,
      expansion of growth cartilage does not result from increased or persistent
      expression of ChM-I or from reduced VEGF expression at the cartilage-metaphyseal
      bone interphase. GH treatment does not modify ChM-I and VEGF expressions.

PMID- 15200413
TI  - Decreased expression of T-cell NF-kappaB p65 subunit in steroid-resistant
      nephrotic syndrome.
AB  - BACKGROUND: Although the etiology of childhood nephrotic syndrome is unclear,
      there is evidence to suggest an important role for T cells in the pathogenesis.
      Steroid resistance is considered a poor prognostic sign but the mechanism of the
      resistance is unknown. The study examined the potential role of T-cell nuclear
      transcription factors in the steroid resistance. METHODS: The expression of the
      nuclear transcription factors activating protein-1 (AP-1) and nuclear factor
      kappaB (NF-kappaB) as well as that of lymphokines interleukin (IL)-2, IL-4, and
      interferon-gamma (IFN-gamma) were compared in T cells obtained from normal
      subjects, children with steroid-sensitive nephrotic syndrome (SSNS) and children
      with steroid-resistant nephrotic syndrome (SRNS) before any treatment was given.
      Changes in expression and binding of the nuclear transcription factors were
      studied with electrophoretic mobility shift assay (EMSA) and Western blot,
      whereas mRNA cytokine expression were evaluated by enzyme-linked immunosorbent
      assay (ELISA)-linked reverse transcription-polymerase chain reaction (RT-PCR).
      RESULTS: A significant decrease of the p65 subunit protein of NF-kappaB but not
      in p50 was documented by both EMSA (N= 7) and Western blotting (N= 5) in five of
      five SRNS patients but not in control subjects or SSNS patients; there was a
      decrease in mRNA expression as shown by ELISA-linked RT-PCR. In contrast, there
      were no significant differences in AP-1 expression by EMSA. IL-2 mRNA level was
      higher in T cells from SRNS patients than in T cells from either SSNS or control
      subjects. IL-4 and IFN-gamma were equally decreased in both groups of patients.
      CONCLUSION: The results show differences in T cells between untreated SSNS and
      SRNS patients. The decrease of NF-kappaB p65 subunit and up-regulation of IL-2
      are potential mechanism of glucocorticoid resistance in SRNS.

PMID- 15200414
TI  - Plasmin is not protective in experimental renal interstitial fibrosis.
AB  - BACKGROUND: The plasminogen-plasmin system has potential beneficial or
      deleterious effects in the context of renal fibrosis. Recent studies have
      implicated plasminogen activators or their inhibitors in this process. METHODS:
      The development of renal interstitial fibrosis was studied in mice genetically
      deficient in plasminogen (plg-/- mice) and littermate controls (plg+/+ mice) by
      inducing unilateral ureteric obstruction (UUO) by ligating the left ureter.
      RESULTS: Collagen accumulation in the kidney was decreased in plg-/- mice at 21
      days compared with plg+/+ mice by hydroxyproline assay (plg+/+ 19.0 +/- 1.2
      microg collagen/mg tissue, plg-/- 15.6 +/- 0.5 microg collagen/mg tissue, P=
      0.04). Macrophage accumulation in plg-/- mice was reduced at 21 days, consistent
      with a role for plasmin in macrophage recruitment in this model. Myofibroblast
      accumulation, assessed by the expression of alpha-smooth muscle actin (alpha
      SMA), was similar in both groups at both time points. Endogenous plasmin played a
      role in the activation of transforming growth factor-beta (TGF-beta), as plg-/-
      mice had lower ratios of betaig-h3:TGF-beta1 mRNA than plg+/+ mice. Matrix
      metalloproteinase (MMP)-9 activity was unchanged in the absence of plasmin, but
      MMP-2 activity was decreased. CONCLUSION: Plasminogen, the key proenzyme in the
      plasminogen-plasmin system, does not protect mice from experimental interstitial
      fibrosis and may have significant pathogenetic effects. These findings, together
      with other recently published studies in the biology of renal fibrosis, imply
      that effects of proteins such as plasminogen activator inhibitor-1 (PAI-1),
      tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator
      receptor (uPAR) on renal fibrosis occur independently from the generation of
      plasmin.

PMID- 15200415
TI  - A pathophysiologic study of the kidney tubule to optimize organ preservation
      solutions.
AB  - BACKGROUND: Tissue damage at the time of organ transplantation has a negative
      impact on the subsequent success of the procedure, both in the immediate and
      longer term. Hypothermia is the principal element used to prolong organ viability
      ex vivo, but paradoxically also induces cellular edema through inhibition of
      energy-dependent adenosine triphosphatases (ATPases). This induces an electrolyte
      imbalance that leads to fluid influx and cell swelling. It is important,
      therefore, that improvements are made in the preservation of ischemic organs to
      reduce this injury. METHODS: This study has applied a novel in vitro system to
      model cold and warm ischemic-induced renal tubule swelling that characterizes
      tissue damage in ischemia/reperfusion injury. Biochemical blockade of ATPases in
      this system using strophanthidin modeled the effects of energy depletion and
      induced cell swelling. By measuring such tubule swelling and changes to tubular
      cell volume in isolated rabbit renal proximal tubules, an analysis was made that
      defined the basis on which an optimal preservation solution may be developed.
      RESULTS: The data show that our model could reproduce ischemically induced cell
      swelling and characterized the response at the cellular level of tubules to
      different components of preservation solutions. The data indicate that an
      isosmolar, phosphate-buffered, sucrose solution prevented tubule swelling more
      effectively than Euro-Collins, hyperosmolar citrate, or University of Wisconsin
      solutions that are in routine clinical use. CONCLUSION: Future developments in
      organ preservation may significantly improve transplant outcomes. Our novel
      analysis forms the basis of future whole-organ studies that ultimately may allow
      us to propose an optimum platform for improved preservation solutions.

PMID- 15200416
TI  - Stable expression of nephrin and localization to cell-cell contacts in novel
      murine podocyte cell lines.
AB  - BACKGROUND: Cell culture of podocytes has become an indispensable tool in the
      study of podocyte biology. To date, however, podocyte cell lines with stable
      expression of the crucial slit diaphragm protein nephrin and localization of
      nephrin to cell-cell contacts are not available. METHODS: Conditionally
      immortalized cells were grown from isolated glomeruli of mice, harboring the
      temperature-sensitive SV40 large T antigen. About 60 clonal cell lines were
      generated by limiting dilution. RESULTS: Among 30 Wilm's tumor (WT)-1- and
      podocalyxin-positive cell clones, two cell clones stably expressed nephrin as
      assessed by reverse transcription-polymerase chain reaction (RT-PCR), Northern
      and Western blotting, and immunofluorescence. In addition, expression of the
      following podocyte proteins was demonstrated: NEHP1, FAT, P-cadherin, podocin,
      CD2AP, ZO-1 (alpha(-) isoform), Lmx1b, podoplanin, synaptopodin, cortactin, and
      vimentin. The nephrin-positive podocyte cell lines formed a monolayer with
      abundant cell-cell contacts. Transmission electron microscopy revealed formation
      of primitive foot process-like interdigitations and slit diaphragm-like
      junctions. Nephrin colocalized with F-actin at cell-cell contacts as demonstrated
      by immunofluorescence. Intriguingly, nephrin and actin-associated proteins
      (synaptopodin, CD2AP, and cortactin) were recruited to and accumulated at the
      entire cell margin only in confluent cells, but not in dispersed cells.
      CONCLUSION: We present novel murine podocyte cell lines with stable expression of
      nephrin and abundant formation of cell-cell contacts, possessing several features
      of in situ podocyte cell-cell contacts. Furthermore, our data suggest that the
      accumulation of certain proteins in podocyte foot processes is linked to
      formation of cell-cell contacts.

PMID- 15200417
TI  - DDR1-deficient mice show localized subepithelial GBM thickening with focal loss
      of slit diaphragms and proteinuria.
AB  - BACKGROUND: Type IV collagen in basement membranes is a ligand for the receptor
      tyrosine kinase discoidin domain receptor 1 (DDR1). DDR1 is expressed in renal
      cells and regulates cell adhesion and proliferation ex vivo. The interaction
      between type IV collagen and cell surface receptors is believed important for
      normal renal function as well as significant in chronic renal diseases and we
      therefore analyzed mice with a targeted deletion of DDR1. METHODS: Homozygous
      DDR1 knockout mice were compared to heterozygous and wild-type animals. The
      quantitative and qualitative amount of proteinuria was measured by urine
      microelectrophoresis. Structural changes of the kidneys were determined by
      immunohistochemistry, light microscopy, and electron microscopy. RESULTS:
      Compared to heterozygous littermates, adult DDR1 knockout mice showed a selective
      middle- to high-molecular proteinuria of up to 0.3 g/L and urinary acanthocytes.
      There was no evidence of uremia with no change in serum urea in the first 9
      months of age. Little apparent change in renal morphology was detected using
      light microscopy. However, electron microscopy showed a localized, subepithelial,
      mushroom-like isodense thickening of the glomerular basement membrane (GBM).
      Within these areas, a focal loss of the podocytic slit diaphragms occurred.
      CONCLUSION: The loss of cell-matrix communication in DDR1-deficient podocytes
      appears to result in excess synthesis of basement membrane proteins leading to
      disturbed anchorage of foot processes and disruption of the slit diaphragm. Our
      data suggest that the interaction between type IV collagen and DDR1 plays an
      important role in maintaining the structural integrity of the GBM.

PMID- 15200418
TI  - Curcumin blocks multiple sites of the TGF-beta signaling cascade in renal cells.
AB  - BACKGROUND: Over-expression of transforming growth factor-beta (TGF-beta)
      contributes greatly to fibrotic kidney disease. The activator protein-1 (AP-1)
      inhibitor curcumin, a polyphenolic compound derived from Curcuma longa, has been
      shown to reduce collagen accumulation in experimental pulmonary fibrosis. Here,
      we investigate curcumin's ability to modulate TGF-beta's profibrotic actions in
      vitro. METHODS: NRK49F rat renal fibroblasts were stimulated with TGF-beta (5
      ng/mL), and the effects of curcumin on TGF-beta-regulated genes, TGF-beta
      receptors, and phosphorylated SMAD isoforms were analyzed by Northern blotting,
      enzyme-linked immunosorbent assay (ELISA), and Western blotting. The effects of c
      jun depletion on TGF-beta-regulated gene and protein expression were analyzed
      with RNAi. RESULTS: When applied 30 minutes before TGF-beta, curcumin dose
      dependently and dramatically reduced TGF-beta-induced increases in plasminogen
      activator inhibitor-1 (PAI-1), TGF-beta1, fibronectin (FN) and collagen I (Col I)
      mRNA, and in PAI-1 and fibronectin protein. Prolonged curcumin treatment (>6 h)
      significantly reduced TGF-beta receptor type II levels and SMAD2/3
      phosphorylation in response to added TGF-beta. Depletion of cellular c-jun levels
      with a RNAi method mimicked the effects of curcumin on expression of TGF-beta1,
      FN, and Col I, but not PAI-1. CONCLUSION: Curcumin blocks TGF-beta's profibrotic
      actions on renal fibroblasts through down-regulation of TbetaRII, and through
      partial inhibition of c-jun activity. These in vitro data suggest that curcumin
      might be an effective antifibrotic drug in the treatment of chronic kidney
      disease.

PMID- 15200419
TI  - Staphylococcus aureus cell envelope antigen is a new candidate for the induction
      of IgA nephropathy.
AB  - BACKGROUND: IgA nephropathy is the most common form of glomerulonephritis
      worldwide. We previously reported a novel form of glomerulonephritis with
      glomerular IgA deposits following methicillin-resistant Staphylococcus aureus (S.
      aureus) infection. We investigated the role of S. aureus related antigens in the
      immunopathogenesis of IgA nephropathy by producing several monoclonal antibodies
      against S. aureus surface antigens and determining the epitopes of deposited
      antigens in patients with IgA nephropathy. METHODS: Cell membrane proteins were
      isolated from cultured S. aureus. Mouse monoclonal antibodies against these
      proteins were generated, and their target epitopes were determined by antibody
      affinity chromatography and amino acid sequence analysis, and by monoclonal
      antibody screening of Escherichia coli clones transfected with plasmids from the
      Lambda S. aureus Genomic Library. Renal biopsy specimens from 116 patients with
      IgA nephropathy and 122 patients with other forms of renal disease were examined
      for glomerular antigen depositions by immunofluorescence microscopy. RESULTS: .
      The major antigen recognized by monoclonal antibodies against S. aureus cell
      membrane was identified as the S. aureus cell envelope antigen designated
      'probable adhesin' (ACCESSION AP003131-77, Protein ID; BAB41819.1). In 68.1%
      (79/116) of renal biopsy specimens from patients with IgA nephropathy, S. aureus
      cell envelope antigen was localized in the glomeruli, and the data confirmed that
      S. aureus cell envelope antigen was co-localized with IgA antibody in the
      glomeruli. No deposition of this antigen was detected in the glomeruli of
      patients with non-immune complex deposit forms of glomerulonephritis. CONCLUSION:
      S. aureus cell envelope antigen is a new candidate for the induction of IgA
      nephropathy.

PMID- 15200420
TI  - Proteinuria in rats induced by serum from patients with collapsing
      glomerulopathy.
AB  - BACKGROUND: Primary collapsing glomerulopathy recurs postransplant, raising the
      possibility of circulating factors implicated in the pathogenesis of the disease.
      METHODS: To determine the presence of circulating factors in collapsing
      glomerulopathy patients, we tested serum from those patients in an in vivo assay.
      Eleven groups of rats received serum from collapsing glomerulopathy patients,
      idiopathic focal segmental glomerulosclerosis (FSGS) or healthy subjects in its
      native form, isolated IgG, or serum without IgG. The presence of proteinuria and
      creatinine clearance were determined. Histopathologic analysis included light,
      immunofluorescence, and electron microscopy. RESULTS: Collapsing glomerulopathy
      rats developed proteinuria while rats injected with serum from FSGS and healthy
      subjects did not. Rats injected with serum of collapsing glomerulopathy in its
      native form developed marked proteinuria (99.2 +/- 42 mg/24 hours at day 5, P=
      0.0001, compared to the baseline), and decreased in creatinine clearance. Rats
      receiving isolated IgG or serum without IgG from collapsing glomerulopathy
      developed mild proteinuria (46.5 +/- 8.4 mg/24 hours and 30.9 +/- 11 mg/24 hours,
      respectively, at day 5 (P= 0.0001). Glomerular tuft retraction and podocyte
      damage were seen only in collapsing glomerulapthy rats. No abnormalities were
      found in rats injected with serum from FSGS or healthy subjects. CONCLUSION:
      Circulating factors in the serum of collapsing glomerulopathy patients produce
      podocyte damage, whereas such factors are not present in noncollapsing FSGS. IgG
      eluates from collapsing glomerulopathy produce proteinuria when injected into the
      rat. Such factors remain in the circulation when serum of patients is adsorbed
      into protein A, raising the possibility that there are more than one circulating
      factor present in patients with collapsing glomerulopathy.

PMID- 15200421
TI  - Parenteral iron nephrotoxicity: potential mechanisms and consequences.
AB  - BACKGROUND: Parenteral iron administration is a mainstay of anemia management in
      renal disease patients. However, concerns of potential iron toxicity persist.
      Thus, this study was conducted to more fully gauge iron toxicologic profiles and
      potential determinants thereof. METHODS: Isolated mouse proximal tubule segments
      (PTS) or cultured proximal tubular [human kidney (HK-2)] cells were exposed to
      four representative iron preparations [iron sucrose (FeS), iron dextran (FeD),
      iron gluconate (FeG), or iron oligosaccharide (FeOS)] over a broad dosage range
      (0, 30 to 1000 microg iron/mL). Cell injury was assessed by lactate deyhdrogenase
      (LDH) release, adenosine triphosphate (ATP) reductions, cell cytochrome c efflux,
      and/or electron microscopy. In vivo toxicity (after 2 mg intravenous iron
      injections) was assessed by plasma/renal/cardiac lipid peroxidation
      [malondialdehyde (MDA)], renal ferritin (protein)/heme oxygenase-1 (HO-1) (mRNA)
      expression, electron microscopy, or postiron injection PTS susceptibility to
      attack. RESULTS: In each test, iron evoked in vitro toxicity, but up to 30x
      differences in severity (e.g., ATP declines) were observed (FeS > FeG > FeD =
      FeOS). The in vitro differences paralleled degrees of cell (HK-2) iron uptake. In
      vivo correlates of iron toxicity included variable increases in renal MDA,
      ferritin, and HO-1 mRNA levels. Again, these changes appeared to parallel in vivo
      (glomerular) iron uptake (seen with FeS and FeG, but not with FeD or FeOS). Iron
      also effected in vivo alterations in proximal tubule cell homeostasis, as
      reflected by the "downstream" emergence of tubule resistance to in vitro oxidant
      attack. CONCLUSION: Parenteral iron formulations have potent, but highly
      variable, cytotoxic potentials which appear to parallel degrees of cell iron
      uptake (FeS > FeG >> FeD or FeOS). That in vitro injury can be expressed at
      clinically relevant iron concentrations, and that in vivo glomerular iron
      deposition/injury may result, suggest caution is warranted if these agents are to
      be administered to patients with active renal disease.

PMID- 15200422
TI  - Glomerular expression of the ATP-sensitive P2X receptor in diabetic and
      hypertensive rat models.
AB  - BACKGROUND: The molecular identification and characterization of the adenosine
      triphosphate (ATP)-sensitive family of P2 receptors is comparatively new. There
      are two main subgroups, each with several subtypes and widespread tissue
      distribution, including the kidney. A unique member of the P2X subgroup of P2
      receptors is the ATP-gated ion channel P2X(7), which on activation can cause cell
      blebbing, cytokine release, and cell death by necrosis or apoptosis. We report
      expression of this receptor in normal rat kidney and in two chronic models of
      glomerular injury: streptozotocin-induced (STZ) diabetes and ren-2 transgenic
      (TGR) hypertension. METHODS: At different time points in these models, we used a
      polyclonal antibody to the P2X(7) receptor and immunohistochemistry to determine
      its expression and distribution. We also used Western blotting and real-time
      polymerase chain reaction (PCR) to detect changes in P2X(7) receptor protein and
      mRNA expression, respectively. RESULTS: We found only low-level glomerular immuno
      staining for the P2X(7) receptor in normal rat kidney, but intense P2X(7)
      receptor immunostaining of glomeruli in kidneys from diabetic animals at 6 and 9
      weeks, and in hypertensive animals at 12 weeks. In diabetic animals, real-time
      PCR demonstrated a approximately tenfold increase in glomerular P2X(7) receptor
      mRNA relative to control, and Western blotting confirmed an increase in protein.
      Immunohistochemistry and immunoelectron microscopy showed staining of glomerular
      podocytes, which was both intracellular and at the plasma membrane. CONCLUSION:
      We conclude that the P2X(7) receptor is not expressed appreciably under normal
      conditions, but that following glomerular injury it is significantly up
      regulated, mainly in podocytes, though also in endothelial and mesangial cells,
      of animals with STZ-induced diabetes mellitus or TGR hypertension. Although the
      exact function and regulation of this receptor remain unclear, its association
      with inflammatory cytokine release and cell death suggests that increased
      expression might be involved in the pathogenesis of glomerular cell injury or
      repair.

PMID- 15200423
TI  - Altered NMDA receptor expression in renal toxicity: Protection with a receptor
      antagonist.
AB  - BACKGROUND: The N-methyl-d-aspartate (NMDA) receptor is expressed in the kidney.
      The receptor plays a major role in gentamicin ototoxicity. We assessed the role
      of the renal NMDA receptor subunits NR1 and NR2C in a model of gentamicin
      nephrotoxicity. METHODS: Rats were exposed to either saline (control), high-dose,
      short-term gentamicin, or short-term gentamicin plus the NMDA antagonist MK-801
      (short-term gentamicin + MK-801) for 3 days. RESULTS: Real-time reverse
      transcription-polymerase chain reaction (RT-PCR) revealed that NR1 mRNA
      expression was significantly higher (P= 0.03) in the renal cortex of short-term
      gentamicin rats. NR2C subunit mRNA expression was unaltered in short-term
      gentamicin rats. Western blot analysis revealed that NR1 (P= 0.009) and NR2C (P=
      0.003) protein abundance was significantly higher in the renal cortex short-term
      gentamicin rats. We assessed two potential intracellular pathways that may
      mediate short-term gentamicin/NMDA. Calpain I and II expression was similar in
      short-term gentamicin and control rats. Endothelin type B receptor (ETBR)
      expression was significantly increased in the renal cortex of short-term
      gentamicin rats (P= 0.0003), and urinary nitrite concentration (reflecting nitric
      oxide) was significantly increased in short-term gentamicin rats (P= 0.03). Serum
      creatinine was significantly elevated in short-term gentamicin animals (P= 0.03),
      and this increase was attenuated in short-term gentamicin + MK-801 rats. Blood
      pressure was higher in short-term gentamicin rats; this was attenuated in short
      term gentamicin + MK-801 rats. Urine pH was significantly lower in short-term
      gentamicin (P < 0.0001) rats; this was reversed in short-term gentamicin + MK-801
      (P= 0.005) rats. Urinary nitrite was significantly higher in short-term
      gentamicin rats; this was normalized in short-term gentamicin + MK-801 rats. MK
      801 alone had no effect on clinical parameters. CONCLUSION: NMDA receptor subunit
      expression is increased in short-term gentamicin animals, and the receptor likely
      mediates cell damage via the endothelin-ETBR-nitric oxide pathway. NMDA
      antagonism ameliorated renal damage after exposure to short-term gentamicin.

PMID- 15200424
TI  - High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b
      subclasses in rat anti-GBM nephritis.
AB  - BACKGROUND: To examine a subclass-effect relationship and a dose-effect
      relationship of autoantibodies in the rat antiglomerular basement membrane (GBM)
      antibody-induced glomerulonephritis (anti-GBM nephritis) model, we injected
      homologous monoclonal antibodies against the NC1 domains of rat type IV collagen
      into inbred Wistar-Kyoto (WKY) rats. METHODS: Eight different autoantibodies from
      each of the IgG1, IgG2a, and IgG2b subclasses were established and administered
      to groups of four WKY rats at a dose of 300 microg/rat. To examine the dose
      effect relationship, we administered 0 to 300 microg/rat of autoantibodies from
      each subclass to rats. RESULTS: All IgG1 antibodies induced mild nephritis,
      whereas the IgG2a and IgG2b antibodies induced moderate to severe nephritis. Some
      IgG2a and IgG2b antibodies induced pulmonary hemorrhage as well. These antibodies
      were reactive with alpha3(IV)NC1, alpha4(IV)NC1, or alpha5(IV)NC1. The minimum
      dose of antibody required to induce nephritis was 30 microg/rat for IgG1, 3
      microg/rat for IgG2a, and 1 microg/rat for IgG2b. At doses of 30 microg/rat or
      less, antibody deposition was generally restricted to the GBM. At doses of 100
      microg/rat or greater, antibody deposition extended to both the GBM and tubular
      basement membrane (TBM). Pulmonary hemorrhage was observed only when a large
      amount of pulmonary hemorrhagic antibody was administered. CONCLUSION: The
      severity of nephritis was dependent on both subclass and dose of autoantibodies.
      It becomes clear that pulmonary hemorrhage in anti-GBM nephritis is induced by
      autoantibodies.

PMID- 15200425
TI  - Differential effects of simvastatin on mesangial cells.
AB  - BACKGROUND: Statins are increasingly recognized as mediators of direct cellular
      effects independent of their lipid lowering capacity. Therefore, the time and
      concentration dependence of various statin-mediated cellular alterations was
      compared in renal mesangial cells. METHODS: The effects of statins on cell
      proliferation, gene expression, cytoskeletal alterations, apoptosis, and
      cytotoxicity were analyzed in cultured mesangial cells using standard techniques.
      RESULTS: Simvastatin and lovastatin decreased proliferation and cell number of
      rat mesangial cells concentration-dependently. Concurrently, the expression of
      the fibrogenic protein connective tissue growth factor (CTGF) was impaired and
      actin stress fibers, which are typical of mesangial cells in culture, became
      disassembled by simvastatin. A decrease of the posttranslational modification of
      RhoA by geranylgeranyl moieties was detected, supporting a role for RhoA as
      mediator of statin effects. Induction of apoptosis, determined by activation of
      caspase-3 and DNA fragmentation, and necrosis only occurred at later time points,
      when the morphology of the cells was strongly altered and the cells detached from
      the surface due to changes in the actin cytoskeleton. Basically, the same results
      were obtained with a human mesangial cell line. Furthermore, statin effects were
      mimicked by inhibition of the geranylgeranyltransferase. CONCLUSION: Most of the
      cellular effects of the lipophilic statins occurred within the same time and
      concentration range, suggesting a common molecular mechanism. Only apoptosis and
      necrosis were observed at later time points or with higher concentrations of
      simvastatin and thus seem to be secondary to the changes in gene expression and
      alterations of the actin cytoskeleton.

PMID- 15200427
TI  - Neonatal ureteral obstruction alters expression of renal sodium transporters and
      aquaporin water channels.
AB  - BACKGROUND: Congenital urinary tract obstruction is a common cause of renal
      insufficiency in the neonate and during infancy. Recently, we demonstrated that
      ureteral obstruction in adult rats is associated with reduction in the abundance
      of renal aquaporins (AQPs) and renal sodium transporters, which paralleled an
      impaired urinary concentrating capacity. METHODS: In the present study, renal
      handling of sodium and water, together with the expression of renal aquaporins
      and major renal sodium transporters, was examined in rats with neonatally induced
      partial unilateral ureteral obstruction (PUUO) within the first 48 hours of life
      to clarify the molecular mechanisms involved in the tubular functional defects in
      response to congenital obstruction. Rats were then followed for 12 or 24 weeks.
      RESULTS: Neonatal PUUO caused a progressive reduction in single kidney glomerular
      filtration rate (SKGFR) on the obstructed side to 43% of controls at 12 weeks
      (115 +/- 28 vs. 267 +/- 36 microL/min/100g bw, P < 0.05), and 31% of controls at
      24 weeks (106 +/- 24 vs. 343 +/- 41 microL/min/100g bw, P < 0.05). Na-K-ATPase
      abundance was decreased in the obstructed kidney compared with the nonobstructed
      kidney at 24 weeks (79 +/- 6%, P < 0.05), and the abundance of bumetanide
      sensitive Na-K-2Cl cotransporter (BSC-1) located to the medullary thick ascending
      limb (mTAL) of the obstructed kidney was significantly reduced both at 12 weeks
      (42 +/- 10%, P < 0.05) and 24 weeks (50 +/- 10%, P < 0.05). Immunohistochemistry
      confirmed down-regulation of BSC-1 both at 12 and 24 weeks after onset of
      obstruction. Consistent with this, sodium excretion from the obstructed kidney
      was increased at 12 weeks (0.13 +/- 0.03 vs. 0.04 +/- 0.01 micromol/min/100g bw,
      P < 0.05), and persisted 24 weeks after onset of PUUO (0.15 +/- 0.02 vs. 0.06 +/-
      0.01 micromol/min/100g bw, P < 0.05). AQP2 abundance in the collecting duct was
      also reduced both at 12 weeks (68 +/- 5%, P < 0.05) and at 24 weeks (69 +/- 13%,
      P < 0.05). Consistent with this, solute-free water reabsorption was decreased in
      the obstructed kidney at 12 weeks (0.61 +/- 0.42 vs. 1.97 +/- 0.63
      microL/min/100g bw, P < 0.05) and remained decreased after 24 weeks of PUUO (0.42
      +/- 0.04 vs. 1.56 +/- 0.39 microL/min/100g bw, P < 0.05). CONCLUSION: Major
      sodium transporters and aquaporins in the obstructed kidney are down-regulated in
      response to neonatally induced PUUO, which indicates that these transporters may
      play a crucial role for the persistent reduction in renal handling of sodium and
      water in response to PUUO.

PMID- 15200426
TI  - Nephrotoxicity of platinum complexes is related to basolateral organic cation
      transport.
AB  - BACKGROUND: Cisplatin and its analogs oxaliplatin and carboplatin are widely used
      antitumor drugs. Nephrotoxicity is a common and relevant adverse effect that
      occurs especially in cisplatin therapy. Cellular and molecular mechanisms of
      cisplatin-induced nephrotoxicity are not completely understood. The
      nephrotoxicity of platinum complexes was evaluated by a new in vitro system that
      utilizes the high Trans Epithelial Electrical Resistance (TEER) of the C7 clone
      of the MDCK (Madin-Darby canine kidney) cells. By means of this assay system we
      addressed the question whether the side of application of renal epithelia
      influences platinum complex toxicity. METHODS: C7 cells were grown in membrane
      filter cups, and the apical or basolateral membranes were exposed to 100
      micromol/L cis-, oxali-, or carboplatin. TEER and caspase-3 activity were
      determined. Cimetidine was used as an inhibitor of organic cation transporters
      (OCTs). C7 cell lysates were analyzed for OCT-1 and -2 by Western blot analysis.
      RESULTS: TEER dropped by 89.5 +/- 9.3% (mean +/- SEM; N= 6) within 24 hours after
      addition of cisplatin to the basolateral side of C7 cells, while caspase activity
      increased up to 840.6 +/- 17.4% (mean +/- SEM; N= 6) compared to control cells.
      Exposure of the apical membrane to cisplatin reduced TEER by only 13.4 +/- 8.7%
      (mean +/- SEM; N= 6), and increased caspase-3 activity up to 213.9 +/- 7.6% (mean
      +/- SEM; N= 6). Oxaliplatin and carboplatin reduced TEER to a lesser extent than
      cisplatin. Oxaliplatin lowered TEER stronger than carboplatin. In general,
      basolateral application led to higher caspase activities and lower TEERs. The OCT
      inhibitor cimetidine inhibited the TEER decrease induced by platinum complexes.
      Immunoblotting confirmed the presence of OCT-2 in C7 cells. CONCLUSION: Toxic
      effects of platinum complexes on renal epithelia depend on the platinum complex
      used and the site of application. We conclude that cell polarity and basolateral
      transport mechanisms are essential in nephrotoxicity of platinum drugs.

PMID- 15200428
TI  - Over-expression of renal LAT1 and LAT2 and enhanced L-DOPA uptake in SHR
      immortalized renal proximal tubular cells.
AB  - BACKGROUND: Spontaneously hypertensive rats (SHR) may have an increased renal
      production of dopamine. LAT2 promotes L-DOPA renal uptake, and this may determine
      the rate of dopamine synthesis. The present study evaluated L-DOPA inward and
      outward transfer in immortalized renal proximal tubular epithelial cells of SHR
      and Wistar-Kyoto rats (WKY). METHODS: Uptake of [(14)C]-L-DOPA was initiated by
      the addition of 1 mL Hanks' medium with a given concentration of the substrate.
      The apical fractional outflow of intracellular [(14)C]-L-DOPA was evaluated in
      cells loaded with [(14)C]-L-DOPA for 6 minutes, and then the corresponding efflux
      was monitored over 12 minutes. The presence of LAT1 and LAT2 transcripts and
      protein in WKY and SHR cells was examined, respectively, by reverse transcription
      polymerase chain reaction (RT-PCR) and immunobloting. RESULTS: LAT2 in WKY cells
      contributed almost exclusively for [(14)C]-L-DOPA uptake. In SHR cells [(14)C]-L
      DOPA uptake was 25% through system B(0), 25% through LAT2 (resulting from
      inhibition by 1 mmol/L glycine, L-alanine, L-serine, and L-threonine), and the
      remaining 50% through LAT1. The efflux of [(14)C]-L-DOPA from WKY and SHR cells
      corresponded to approximately 65% and approximately 25%, respectively, of the
      amount accumulated in the cells. The LAT1 and LAT2 transcripts were present in
      both SHR and WKY cells, but the abundance of both LAT1 and LAT2 proteins in SHR
      cells was greater than in WKY cells. CONCLUSION: Differences in L-DOPA handling
      between SHR and WKY cells may result from over-expression of LAT1 and LAT2
      transporters in the former. The unique role of Na(+)-dependent transporters
      (system B(0)) in SHR cells also contributes to the enhanced L-DOPA uptake in
      these cells.

PMID- 15200429
TI  - Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a
      clathrin-dependent mechanism.
AB  - BACKGROUND: We have demonstrated that ouabain causes dose- and time-dependent
      decreases in (86)Rb uptake in porcine proximal tubular (LLC-PK1) cells. The
      present study addresses the molecular mechanisms involved in this process.
      METHODS: Studies were performed with cultured LLC-PK1 and Src family kinase
      deficient (SYF) cells. RESULTS: We found that 50 nmol/L ouabain applied to the
      basal, but not apical, aspect for 12 hours caused decreases in the plasmalemmal
      Na/K-ATPase. This loss of plasmalemmal Na/K-ATPase reverses completely within 12
      to 24 hours after removal of ouabain. Ouabain also increased the Na/K-ATPase
      content in both early and late endosomes, activated phosphatidylinositol 3-kinase
      (PI(3)K), and also caused a translocation of some Na/K-ATPase to the nucleus.
      Immunofluorescence demonstrated that the Na/K-ATPase colocalized with clathrin
      both before and after exposure to ouabain, and immunoprecipitation experiments
      confirmed that ouabain stimulated interactions among the Na/K-ATPase, adaptor
      protein-2 (AP-2), and clathrin. Potassium (K) depletion, chlorpromazine, or
      PI(3)K inhibition all significantly attenuated this ouabain-induced endocytosis.
      Inhibition of the ouabain-activated signaling process through Src by 4-Amino-5-(4
      chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated
      ouabain-induced endocytosis. Moreover, experiments performed in SYF cells
      demonstrated that ouabain induced increases in the endocytosis of the Na/K-ATPase
      when Src was reconstituted (SYF+), but not in the Src-deficient (SYF-) cells.
      CONCLUSION: These data demonstrate that ouabain stimulates a clathrin-dependent
      endocytosis pathway that translocates the Na/K-ATPase to intracellular
      compartments, thus suggesting a potential role of endocytosis in ouabain-induced
      signal transduction as well as proximal tubule sodium handling.

PMID- 15200430
TI  - Aldosterone enhances renal calcium reabsorption by two types of channels.
AB  - BACKGROUND: Aldosterone has been known for many years to increase sodium (Na(+))
      reabsorption by the distal nephron. The present in vitro experiments investigated
      the effect of the hormone on calcium (Ca(2+)) transport by the luminal membrane
      of the rabbit nephron, independent of any systemic influence. METHODS: Proximal
      and distal tubules were incubated with either aldosterone or the carrier. The
      luminal membranes of these tubules were purified, vesiculated, and (45)Ca uptake
      by these vesicles was subsequently measured. RESULTS: Treatment of the distal
      tubules with 10(-8) mol/L aldosterone enhanced both 0.1 and 0.5 mmol/L Ca(2+)
      transport. The hormone action was abolished by tyrosine kinase inhibitors. The
      presence of Na(+) in the medium decreased both Ca(2+) uptake and the effect of
      aldosterone. This hormone action was already significant after a 5-minute
      incubation, with a half-maximal efficient concentration of approximately 10(-10)
      mol/L. Ca(2+) transport by the distal membranes presents a dual kinetics.
      Aldosterone enhanced the Vmax values of both components of these kinetics.
      Mibefradil abolished the action of aldosterone on 0.5 mmol/L but not on 0.1
      mmol/L Ca(2+) uptake, suggesting that the targeted low affinity channel belongs
      to the T-type, whereas diltiazem prevented the hormone action exclusively at the
      low Ca(2+) concentration (0.1 mmol/L), indicating an effect on a high affinity L
      type channel. CONCLUSION: Aldosterone increases Ca(2+) transport by the distal
      luminal membranes through L- and T-type Ca(2+) channels, and this action requires
      tyrosine kinase activity.

PMID- 15200431
TI  - Human organic anion transporter 1 mediates cellular uptake of cysteine-S
      conjugates of inorganic mercury.
AB  - BACKGROUND: The epithelial cells lining the renal proximal tubule have been shown
      to be the primary cellular targets where mercuric ions gain entry, accumulate,
      and induce pathologic effects in vivo. Recent data have implicated at least one
      of the organic anion transport systems in the basolateral uptake of inorganic
      mercury (Hg(2+)). METHODS: Using a line of Madin-Darby canine kidney (MDCK) II
      cells transfected stably with the human organic anion transporter 1 (hOAT1), and
      oocytes from Xenopus laevis microinjected with cRNA for hOAT1, we tested the
      hypothesis that hOAT1 can transport biologically relevant mercuric conjugates of
      cysteine (Cys). RESULTS: Indeed, MDCK II cells expressing a functional form of
      hOAT1 gained the ability to transport the mercuric conjugate 2-Amino-3-(2-amino-2
      carboxy-ethylsulfanyl-mercuricsulfanyl)-propionic acid (Cys-S-Hg-S-Cys), but not
      the corresponding di-glutathione S-conjugate of Hg(2+) (G-S-Hg-S-G). Moreover, p
      aminohippurate (PAH), adipate, and glutarate (but not succinate or malonate)
      inhibited individually the uptake of Cys-S-Hg-S-Cys in a dose-dependent manner.
      Uptake of Cys-S-Hg-S-Cys, but not G-S-Hg-S-G, was also documented in Xenopus
      oocytes expressing hOAT1. CONCLUSION: These data represent ostensibly the most
      direct line of evidence implicating a specific membrane protein (i.e., hOAT1) in
      the transport of a biologically relevant molecular species of Hg(2+) in a
      mammalian cell. Moreover, these data indicate that the organic anion
      transporter(s) likely play a prominent role in the basolateral transport of
      mercuric ions by proximal tubular cells and in the nephropathy induced by Hg(2+).

PMID- 15200432
TI  - Up-regulation of hepatic Acyl CoA: Diacylglycerol acyltransferase-1 (DGAT-1)
      expression in nephrotic syndrome.
AB  - BACKGROUND: Nephrotic syndrome is associated with hypercholesterolemia,
      hypertriglyceridemia, and marked elevations of plasma low-density lipoprotein
      (LDL) and very low-density lipoprotein (VLDL). Hypertriglyceridemia in nephrotic
      syndrome is accompanied by increased hepatic fatty acid synthesis, elevated
      triglyceride secretion, as well as lipoprotein lipase, VLDL-receptor, and hepatic
      triglyceride lipase deficiencies, which lead to impaired clearance of
      triglyceride-rich lipoproteins. Acyl CoA: diacylglycerol acyltransferase (DGAT)
      is a microsomal enzyme that joins acyl CoA to 1, 2-diacylglycerol to form
      triglyceride. Two distinct DGATs (DGAT-1 and DGAT2) have recently been identified
      in the liver and other tissues. The present study tested the hypothesis that the
      reported increase in hepatic triglyceride secretion in nephrotic syndrome may be
      caused by up-regulation of DGAT. METHODS: Male Sprague-Dawley rats were rendered
      nephrotic by two sequential injections of puromycin aminonucleoside (130 mg/kg on
      day 1 and 60 mg/kg on day 14) and studied on day 30. Placebo-treated rats served
      as controls. Hepatic DGAT-1 and DGAT-2 mRNA abundance and enzymatic activity were
      measured. RESULTS: The nephrotic group exhibited heavy proteinuria,
      hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and marked elevation
      of VLDL concentration. Hepatic DGAT-1 mRNA, DGAT-1, and total DGAT activity were
      significantly increased, whereas DGAT-2 mRNA abundance and activity were
      unchanged in the nephrotic rats compared to the control animals. The functional
      significance of elevation of DGAT activity was illustrated by the reduction in
      microsomal free fatty acid concentration in the liver of nephrotic animals.
      CONCLUSION: Nephrotic syndrome results in up-regulation of hepatic DGAT-1
      expression and activity, which can potentially contribute to the associated
      hypertriglyceridemia by enhancing triglyceride synthesis. Thus, it appears that
      both depressed catabolism and increased synthetic capacity contribute to
      hypertriglyceridemia of nephrotic syndrome.

PMID- 15200433
TI  - Superoxide enhances tubuloglomerular feedback by constricting the afferent
      arteriole.
AB  - BACKGROUND: Superoxide (O(2) (-)) has been shown to augment tubuloglomerular
      feedback (TGF) both in vivo and in vitro by scavenging nitric oxide (NO) in the
      macula densa (MD). We hypothesized that in addition to this mechanism O(2) (-)
      potentiates TGF by acting directly on the afferent arteriole (Af-Art). METHODS:
      Microdissected Af-Arts and adherent tubular segments containing the MD were
      simultaneously microperfused in vitro, maintaining Af-Art pressure at 60 mm Hg.
      TGF response was determined by measuring changes in Af-Art diameter while
      increasing NaCl in the MD perfusate from 11/10 to 81/80 mmol/L Na/Cl. RESULTS: To
      determine whether O(2) (-) acts at the MD in the absence of MD NO, we inhibited
      MD nNOS with 7-nitroindazole (7-NI) and added Tempol to the lumen. When 7-NI was
      added to the MD lumen, it increased TGF from 2.3 +/- 0.2 to 4.2 +/- 0.2 microm (P
      < 0.01). When Tempol was added to the MD lumen in the presence of 7-NI, it had no
      effect on TGF. To investigate whether O(2) (-) has any effect via the Af-Art in
      the absence of MD NO, we inhibited MD nNOS with 7-NI and added Tempol to the bath
      to scavenge O(2) (-) in the Af-Art. Adding Tempol to the bath with 7-NI in the MD
      lumen reduced TGF from 3.9 +/- 0.3 to 2.8 +/- 0.5 microm (P < 0.05 vs. 7-NI). To
      see if this effect was due to O(2) (-) scavenging NO production by the
      endothelium, we repeated the experiment in Af-Arts with damaged endothelium and
      found that adding Tempol to the bath lowered TGF from 3.4 +/- 0.9 to 1.2 +/- 0.6
      microm (P < 0.01). When catalase was added to the bath together with Tempol, TGF
      response was not modified. CONCLUSION: We concluded that it is O(2) (-) rather
      than H(2)O(2) that enhances TGF response, both directly by constricting the Af
      Art and indirectly by scavenging NO in the MD.

PMID- 15200434
TI  - Transvascular lipoprotein transport in patients with chronic renal disease.
AB  - BACKGROUND: While increased plasma cholesterol is a well-established
      cardiovascular risk factor in the general population, this is not so among
      patients with chronic renal disease. We hypothesized that the transvascular
      lipoprotein transport, in addition to the lipoprotein concentration in plasma,
      determines the degree of atherosclerosis among patients with chronic renal
      disease. METHODS: We used an in vivo method for measurement of transvascular
      transport of low-density lipoprotein (LDL) in 21 patients with chronic renal
      disease and in 42 healthy control patients. Autologous 131-iodinated LDL was
      reinjected intravenously, and the 1-hour fractional escape rate was taken as
      index of transvascular transport. RESULTS: Transvascular LDL transport tended to
      be lower in patients with chronic renal disease than in healthy control patients
      [3.3 (95% CI 2.4-4.2) vs. 4.2 (3.7-4.2)%/hour; NS]. However, this tendency
      disappeared when transvascular LDL transport was corrected for distribution
      volume of LDL [1.7 (1.2-2.2) vs. 1.8 (1.6-2.0) %/(hour x (L/m(2))); NS]. There
      was significant variation in transvascular LDL transport between diabetic
      patients with chronic renal disease, nondiabetic patients with chronic renal
      disease, and healthy control patients [5.0 (3.2-7.8) vs. 3.0 (2.2-3.8) vs. 4.2
      (3.6-4.8) %/hour; P < 0.01 after adjustment for distribution volume of LDL]. This
      variation was unlikely caused by altered hepatic LDL receptor expression or
      glycosylation of LDL in diabetes patients. CONCLUSION: Transvascular LDL
      transport may be increased in diabetic patients with chronic renal disease,
      suggesting that lipoprotein flux into the arterial wall is increased. A similar
      mechanism does not operate in nondiabetic patients with chronic renal disease.

PMID- 15200435
TI  - Hypothesis: Uric acid, nephron number, and the pathogenesis of essential
      hypertension.
AB  - BACKGROUND: Essential hypertension affects more than 25% of the world's
      population. Genetic, physiologic, and epidemiologic studies provide clues to its
      origins, but a clear understanding has been elusive. Recent experimental and
      clinical studies have implicated uric acid in the onset of essential
      hypertension. METHODS: In a retrospective chart review, we identified 95 children
      with confirmed, new onset hypertension, and evaluated the cause of hypertension
      and parental history of hypertension, birth weight, and serum uric acid. In an
      open-label, cross-over trial we treated 5 children with confirmed essential
      hypertension with allopurinol as single treatment agent, and screened for change
      in blood pressure by casual and ambulatory methods. In tissue culture
      experiments, we evaluated the effect of uric acid on glomerular endothelial cell
      function. RESULTS: Elevation of serum uric acid is related to the onset of
      essential hypertension in children, reduced birth weight, and endothelial
      dysfunction. Normalization of uric acid appears to ameliorate new onset essential
      hypertension. CONCLUSION: These findings, combined with animal model data,
      support the hypothesis that uric acid has a key role in the pathogenesis of early
      onset essential hypertension, and may unify some of the disparate theories of the
      origins of essential hypertension.

PMID- 15200436
TI  - Association of interleukin-10 gene G-1082A polymorphism with the progression of
      primary glomerulonephritis.
AB  - BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive
      properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene
      promoter, which has been associated with modified IL-10 production, on the two
      most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal
      segmental glomerulosclerosis (FSGS). METHODS: We studied Caucasian patients (N=
      191) with biopsy-proven glomerulonephritis (IgAN: N= 123, FSGS: N= 68) followed
      up for 6.5 +/- 5.5 years. Patients were classified according to the slope of
      reciprocal serum creatinine (>/= or <-0.1 dL(*)mg(-1) (*)year(-1)) into group A
      (slow progressors, IgAN: N= 75, FSGS: N= 47) and group B (fast progressors, IgAN:
      N= 48, FSGS: N= 21). One hundred healthy volunteers were analyzed as control
      patients. G-1082A polymorphism was determined by polymerase chain reaction (PCR)
      amplification. RESULTS: The allele frequencies were similar in patients and
      control group (NS). Initial renal function, proteinuria, and blood pressure did
      not differ significantly between patients with different genotypes. G-1082A
      polymorphism was associated with the progression of both IgAN and FSGS: GA/AA
      genotypes were more frequent in group B (fast progressors) than in group A (slow
      progressors; P= 0.012 for IgAN, P < 0.05 for FSGS). Patients with the GA/AA
      genotypes showed a worse outcome in the Kaplan-Meier analysis of renal survival
      (P < 0.05 for both IgAN and FSGS). The IL-10 polymorphism remained an independent
      risk factor for progression in multivariate analysis (Cox regression model, P <
      0.05 for IgAN and FSGS). CONCLUSION: Our results suggest that IL-10 gene G-1082A
      polymorphism is an important marker of progression in patients with IgAN and
      FSGS.

PMID- 15200437
TI  - Dose-dependent effect of parenteral iron therapy on bleomycin-detectable iron in
      immune apheresis patients.
AB  - BACKGROUND: Iron deficiency and anemia are commonly encountered in patients with
      autoimmune diseases undergoing immune apheresis. This makes erythropoietin and
      iron substitution necessary in most patients. However, intravenous iron therapy
      may result in an increase of potentially toxic nontransferrin-bound iron.
      METHODS: We examined the effect of 50 mg or 100 mg of iron (III) sucrose on
      bleomycin-detectable iron (BDI) in immune apheresis patients. Six patients with
      autoimmune disorders and normal kidney function were enrolled. Before and after
      the injection of 50 mg or 100 mg of iron (III) sucrose, BDI was measured in serum
      samples at five different time points. RESULTS: There was no BDI traceable before
      injection of iron (III) sucrose. BDI was present in serum of all patients after
      the administration of 100 mg of iron (III) sucrose in concentrations up to 0.49
      micromol/L. In contrast, only one patient showed BDI at a concentration of 0.16
      micromol/L after the administration of 50 mg of iron (III) sucrose. CONCLUSION:
      We conclude that if parenteral iron is administered after apheresis treatment,
      despite the equal tolerability, use of 50 mg of iron (III) sucrose is superior to
      100 mg of iron (III) sucrose in avoiding the formation of potentially toxic
      nontransferrin-bound iron.

PMID- 15200438
TI  - Association between serum homocysteine and markers of impaired kidney function in
      adults in the United States.
AB  - BACKGROUND: Circulating homocysteine, a risk factor for cardiovascular disease
      (CVD), is often elevated in chronic kidney disease and end-stage renal disease
      (ESRD) patients. Little is known about the risk of elevated homocysteine
      associated with less advanced renal insufficiency in the community. METHODS:
      Serum homocysteine concentration measures (umol/L) from the National Health and
      Nutrition Examination Survey (NHANES) 1991-1994 participants who were aged >/=40
      years and fasted >/=6 hours (1558 men and 1829 women) were categorized as <9, 9
      to 11.9, 12 to 14.9, and >/=15. Renal function levels were determined by Modified
      Diet in Renal Disease (MDRD) estimated glomerular filtration rate (GFRest)
      (mL/min/1.73 m(2)) and the urinary albumin-to-creatinine ratio (ACR) (mg/g).
      Cumulative odds ratios (OR) of exceeding any given homocysteine cut point were
      computed by gender, using ordinal logistic regression. Each model included GFRest
      (<60, 60 to 90, >/=90), ACR (<15, 15 to <30, >/=30), age, race/ethnicity, red
      blood cell folate, serum vitamin B(12), and dietary vitamin B(6) intake as
      independent variables. RESULTS: The adjusted ORs for elevated homocysteine risk
      were 9 to 11 times greater in adults with the lowest GFRest levels (<60
      mL/min/1.73 m(2)) compared to those with normal GFRest levels. Association
      measures for marginal GFRest levels (60 to 90 mL/min/1.73 m(2)) were weaker but
      significant. Albuminuria (ACR >/=30 mg/g) was a significant, independent renal
      risk factor for elevated homocysteine in men and women (adjusted OR = 1.78, 95%
      CI 1.08-2.93, and adjusted OR = 1.83, 95% CI 1.21-2.76, respectively) relative to
      those with low normal albumin excretion, but high normal albuminuria (ACR = 15-30
      mg/g) was not. CONCLUSION: In the general population, renal insufficiency is
      strongly associated with an increased risk of elevated circulating homocysteine,
      independent of B vitamin status. These results raise the possibility that
      elevated homocysteine may be an important risk factor to explain the heavy burden
      of CVD associated with kidney disease.

PMID- 15200439
TI  - Chronic kidney disease: the distribution of health care dollars.
AB  - BACKGROUND: The cost of care for end-stage renal disease (ESRD) is known to be
      high. The factors responsible for higher ESRD cost develop during chronic kidney
      disease (CKD), where the data on distribution of cost are limited. METHODS: This
      retrospective cohort study of 1995 through 1998 incident dialysis patients was
      performed to study the distribution of costs during the 24 months prior to
      initiation of dialysis. Patient data were obtained from the Centers for Medicare
      and Medicaid Services (CMS). Patients who were Medicare eligible for at least 2
      years prior to initiation of dialysis were included in the study. Financial data
      were obtained from Medicare Part A and Part B claims and inflationary adjustments
      were made. The study period was divided into four segments based on overall
      distribution of cost. RESULTS: The mean age was 75 years, 51% were males, 73%
      were white, and 22% were black. Overall, patient comorbidity increased
      significantly during the study years. Cost showed a sharp increase in the last 6
      months prior to initiation of dialysis. Hospitalization was the major component
      of cost throughout study period. Patients who initiated hemodialysis incurred a
      higher cost compared to patients who initiated other modes of kidney replacement
      therapy. Patients with diabetes or cardiovascular disease incurred higher cost
      compared to those who had no diabetes or cardiovascular disease, respectively.
      CONCLUSION: These data showed that hospitalization was the major component of the
      sharp increase in cost around the initiation of dialysis. Increased comorbidity
      was associated with higher cost. A focus on timely management of CKD may prevent
      future morbidity and costs.

PMID- 15200440
TI  - G protein beta3 subunit C825T polymorphism in primary IgA nephropathy.
AB  - BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism
      has been associated with increased signal transduction, increased activity of the
      kidney Na+/H+ exchanger, and also with late-onset essential hypertension.
      Hypertension is a strong independent risk factor for progression in IgA
      nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly
      followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989
      to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to
      303 local Caucasian controls matched for the male predominance (214 males). The
      technique used was a polymerase chain reaction-restriction fragment length
      polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers,
      followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies
      were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2%
      in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients
      versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015).
      The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97;
      P= 0.05). This data indicated that this polymorphism had a significant but mild
      influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In
      contrast, we could not demonstrate any significant and sustained difference in
      the clinical presentation and evolution of the homozygous TT patients compared to
      non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The
      progression to arterial hypertension or to chronic renal failure or to end-stage
      renal failure (ESRF) was not significantly different. In addition, multivariate
      Cox regression analysis excluded a significant independent role of C825T
      polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild
      influence on occurrence/initiation of IgAN, but played no significant role in the
      progression of the disease.

PMID- 15200441
TI  - Impact of early cytomegalovirus infection and disease on long-term recipient and
      kidney graft survival.
AB  - BACKGROUND: The impact of cytomegalovirus (CMV) infection and disease on long
      term outcome after kidney transplantation is still unsettled. METHODS: Between
      1994 and 1997, 397 consecutive first kidney graft recipients and 74 retransplants
      were included in the study and followed prospectively until December 31, 2001.
      CMV infection (CMV pp65 antigenemia) and CMV disease were recorded once weekly
      during the first 100 days after transplantation. No CMV prophylaxis or preemptive
      therapy was given. In a multiple Cox proportional hazard model allowing time
      dependent covariates, the effects of asymptomatic CMV infection and CMV disease,
      recipient age and gender, retransplantation, living donor, panel-reactive
      cytotoxid antibodies, acute rejection, and graft loss were tested on overall
      mortality beyond 100 days post-transplantation. In a similar analysis, the effect
      of asymptomatic CMV infection and CMV disease plus other factors were tested on
      death censored graft loss beyond 100 days. RESULTS: Median (range) follow up time
      was 66.6 (<1-86.9) months. The incidence of CMV infection and disease during the
      first 100 days was 62.8% and 23.4%, respectively. The number of total deaths was
      96 (20%), 82 occurred after the first 100 days. Independent risk factors for
      overall mortality beyond 100 days were asymptomatic CMV infection, RR = 2.90 (95%
      CI 1.61-5.22) (P= 0.001), CMV disease, RR = 2.50 (95% CI 1.31-4.79) (P= 0.006),
      both compared to no infection or disease, recipient age, RR = 1.066 per year (95%
      CI 1.048-1.084) (P < 0.001), and graft loss in the whole study period RR = 7.88
      (95% CI 4.75-13.08) (P < 0.001). Asymptomatic CMV infection and CMV disease were
      not independent risk factors for death censored graft loss, but they
      significantly reduced graft survival uncensored for death, (log rank P= 0.001,
      respectively). CONCLUSION: Asymptomatic CMV infection and overt CMV disease
      during the first 100 days increase the risk of recipient mortality beyond 100
      days. This raises the question whether CMV prophylaxis should be given routinely
      after kidney transplantation.

PMID- 15200442
TI  - Potential cardiovascular risk factors in chronic kidney disease: AGEs, total
      homocysteine and metabolites, and the C-reactive protein.
AB  - BACKGROUND: Total homocysteine (tHcy) and advanced glycation end-products (AGEs)
      are implicated in the pathogenesis of vascular damage. This study aimed to
      investigate whether elevated serum levels of the AGEs pentosidine, N(epsilon)
      carboxymethyllysine (CML) and imidazolone; tHcy, cystathionine, methylmalonic
      acid (MMA), and 2-methylcitric acid (2-MCA), as well as C-reactive protein (CRP),
      are related to a higher risk for cardiovascular events. METHODS: A total of 232
      patients with chronic kidney diseases (mean age 57.6 +/- 13.1 years, 82 female
      and 150 male); 99 with chronic renal failure (CRF), 84 maintenance hemodialysis
      patients and 49 renal transplant recipients were followed for 2 years. The
      relationship between the parameters of interest, conventional risk factors and
      elevated levels of CRP with cardiovascular events was tested in all subjects by
      the Cox proportional hazards model. RESULTS: Mean serum levels of AGEs, tHcy, and
      of the metabolites were found to be significantly increased in all three groups
      compared to the healthy subjects (P < 0.01, respectively). Fifty-three
      cardiovascular events occurred during follow-up; a total of 40 patients died.
      Final multivariate analysis showed diabetes (RR 2.06, 95% CI 1.17-3.60, P=
      0.013), end-stage renal disease (ESRD) (RR 4.88, 95% CI 2.40-9.89, P < 0.001) and
      elevated CRP levels (RR 2.00, 95% CI 1.11-3.60, P= 0.021) as independent risk
      factors for cardiovascular events. CONCLUSION: Data from a group consisting of
      patients with CRF, patients undergoing maintenance hemodialysis treatment, and
      renal transplant recipients provide evidence that conventional risk factors such
      as the presence of diabetes, ESRD, as well as elevated levels of the considered
      risk factor CRP, seem to play a more important role for cardiovascular outcome in
      patients with chronic kidney disease than elevated levels of AGEs, tHcy, and
      related metabolites. The evidence suggests that routine CRP measurement can be
      recommended in cases of chronic renal insufficiency.

PMID- 15200443
TI  - Lipoprotein(a)- and low-density lipoprotein-derived cholesterol in nephrotic
      syndrome: Impact on lipid-lowering therapy?
AB  - BACKGROUND: Patients with nephrotic syndrome have the highest lipoprotein(a)
      [Lp(a)] concentrations known. Lp(a) is an low-density lipoprotein (LDL)-like
      particle consisting of 45% cholesterol. The usual methods to determine LDL
      cholesterol do not distinguish between cholesterol derived from LDL and Lp(a) and
      are thus the net result of cholesterol levels from both lipoproteins. High Lp(a)
      concentrations therefore significantly contribute to the measured or calculated
      LDL cholesterol levels. Since statins have no influence on Lp(a) levels, it can
      be expected that the LDL cholesterol-lowering effect of statins may be diminished
      in patients who have a pronounced elevation of Lp(a) levels accompanied by only
      moderate elevations of LDL cholesterol. METHODS: We investigated 207 patients
      with nondiabetic nephrotic syndrome in whom Lp(a) concentrations were strikingly
      elevated when compared to 274 controls (60.4 +/- 85.4 mg/dL vs. 20.0 +/- 32.8
      mg/dL, P < 0.0001). RESULTS: According to National Kidney Foundation Dialysis
      Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Managing
      Dyslipidemias, almost 95% of these patients are candidates for a therapeutic
      intervention to lower LDL cholesterol. LDL cholesterol levels corrected for Lp(a)
      derived cholesterol, however, were 27 mg/dL lower than uncorrected concentrations
      (compared to only 9 mg/dL in controls). If Lp(a)-corrected levels instead of
      total LDL cholesterol levels were used, 25.7% of patients with low-molecular
      weight (LMW) apolipoprotein(a) [apo(a)] isoforms were classified no longer to be
      in need of LDL cholesterol-lowering therapeutic intervention compared to only
      2.3% of patients with high-molecular-weight (HMW) apo(a) phenotypes (P <
      0.00001). This ("pseudo") pharmacogenetic effect results in incorrect
      determination of LDL cholesterol. CONCLUSION: Our observation has an impact on
      the indication for, and assessment of efficacy of intervention. This potential
      artifact should be investigated in ongoing large trials in renal patients as well
      as in nonrenal African American subjects who have on average markedly higher
      Lp(a) levels. In nonrenal Caucasian subjects with much lower Lp(a)
      concentrations, this issue will be less relevant.

PMID- 15200444
TI  - Effects of hemodialysis dose and membrane flux on health-related quality of life
      in the HEMO Study.
AB  - BACKGROUND: It has been widely supposed that high dose and high flux hemodialysis
      would affect the quality as well as the length of life of patients treated by
      maintenance hemodialysis. The HEMO Study examined changes in health-related
      quality of life as a secondary study outcome. Specific hypotheses were that study
      interventions would affect physical functioning, vitality, Short Form-36 Health
      Survey (SF-36) physical and mental component summary scores, symptoms and
      problems associated with kidney disease, and sleep quality. METHODS: At baseline
      and annually, subjects responded to both the Index of Well-Being and the Kidney
      Disease Quality of Life-Long Form questionnaires. The interventions were assessed
      on the basis of their average effects over 3 years. RESULTS: At baseline, the SF
      36 physical component summary score was lower than in healthy populations, but
      the mental component score was nearly normal. Over 3-year follow-up, physical
      health continued to decline; mental health and kidney disease-targeted scores
      remained relatively stable. The high dose hemodialysis intervention was
      associated with significantly less pain (4.49 points, P < 0.001) and higher
      physical component scores (1.23 points P= 0.007), but these effects were small
      compared to the natural variability in scores. High flux membranes were not
      associated with statistically significant differences in health-related quality
      of life. CONCLUSION: The HEMO Study results demonstrate the marked burden of
      chronic kidney failure and hemodialysis treatment on daily life. In this trial
      among patients undergoing maintenance three times a week hemodialysis, the SF-36
      physical component summary score and pain scale showed significant but very small
      clinical effects favoring the higher dialysis dose. No clinically meaningful
      benefits or either the dose or flux interventions were observed for other indices
      of health-related quality of life.

PMID- 15200445
TI  - The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis
      patients.
AB  - BACKGROUND: Erectile dysfunction (ED) is highly prevalent in men with renal
      disease. The clearance of sildenafil citrate, a highly effective oral treatment
      for ED, is decreased in men with severe renal insufficiency, but the
      pharmacokinetic and hemodynamic profiles during maintenance hemodialysis in men
      with end-stage renal disease have not been studied. METHODS: Fifteen men
      undergoing chronic outpatient maintenance hemodialysis received a single 50-mg
      oral dose of sildenafil on 2 occasions, once 2 hours before, and once 2 hours
      after hemodialysis, with randomized assignment to sequence. Blood and dialysate
      samples were collected, and hemodynamic measurements were made. RESULTS:
      Hemodialysis did not significantly clear either sildenafil or its primary
      metabolite, UK-103,320. Administration after hemodialysis was associated with a
      17% higher peak plasma concentration and earlier time to peak, which were not
      clinically meaningful, whereas the overall extent of absorption and the
      elimination half-life were not affected. The average extent of drug bound to
      plasma protein was approximately 96% in hemodialysis patients. Intradialytic
      hypotension was not observed more frequently when sildenafil was administered
      before hemodialysis. Systolic blood pressure tended to decrease less during
      hemodialysis when subjects were treated with sildenafil before dialysis.
      CONCLUSION: The present study demonstrates that sildenafil is not cleared by
      hemodialysis, and the pharmacokinetic profile resembles more closely that
      observed in normal volunteers than that observed in patients with severe renal
      insufficiency. In addition, we found that sildenafil does not promote
      intradialytic hypotension.

PMID- 15200446
TI  - The willingness of patients to accept an additional mortality risk in order to
      improve renal graft survival.
AB  - BACKGROUND: This study was performed to assess renal transplant patient
      preferences with respect to the acceptance of an additional mortality risk
      induced by immunosuppressive therapy in order to prevent graft loss in case of
      acute rejection. METHODS: The two decision analysis tools standard gamble and
      time trade-off were used to interview 155 patients with a functioning renal
      graft, and 11 on dialysis awaiting transplantation. RESULTS: Defining the best
      possible outcome as being alive with a functioning graft (utility value = 1), and
      the worst outcome as dying (utility value = 0), median utility values of 0.68
      (0.59 +/- 0.32, mean +/- SD) with standard gamble and of 0.65 (0.57 +/- 0.32)
      with time trade-off were obtained for the intermediate outcome (i.e., staying
      alive but returning to dialysis). Thirteen percent of the patients attributed a
      utility value of 0 to this intermediate outcome (i.e., they would rather die than
      return to dialysis), and 8% a utility value of 1 (i.e., they would take
      absolutely no risk from additional antirejection therapy). Individual utility
      values for returning to dialysis correlated with time on dialysis before
      transplantation (R= 0.76, P < 0.005), but no relationship was found between
      utility values and age, sex, religion, previous methods of dialysis, time with a
      functioning graft, number of transplantations, or time on the transplantation
      waiting list. CONCLUSION: The large interindividual variability of utility values
      precludes a prediction about the acceptance of a new therapeutic regimen by an
      individual patient. The assessment of the utility enables, however, a more
      objective judgment of the general acceptance of any possible risk/benefit ratio
      induced by a new immunosuppressive regimen in our patient population.

PMID- 15200447
TI  - Risk of malignancy with long-term immunosuppression in renal transplant
      recipients.
AB  - BACKGROUND: Improvements in immunosuppressive regimens have significantly
      enhanced patient and graft survival in renal transplant recipients. However,
      susceptibility to neoplastic disorders is increased as a consequence of prolonged
      immunosuppression. Available data pertaining to cancer risks in renal transplant
      recipients have been inconsistent, and much of it is derived from international
      studies, which may not be truly representative of the United States population.
      METHODS: We studied a total of 1979 transplants performed in 1739 patients from a
      single center in the United States with a mean follow-up of 6.1 years, and a
      total of 9852 person-years' follow-up. RESULTS: The mean age at the time of
      diagnosis of cancer was 50 years, and the mean interval between transplant and
      diagnosis of cancer was 95 months. Older patients receiving a transplant had a
      significantly higher risk for developing cancer as opposed to younger patients
      (RR 6.2 for >60 years compared with <40 years). When compared with the general
      population using data from the Surveillance, Epidemiology and End Results (SEER)
      registry, the overall risk for nonskin malignancies was modestly increased in our
      transplant recipients, with a standardized incidence ratio (SIR) of 1.4 (P=
      0.01). When stratified by age groups, younger age at transplant (<40 years) had
      the highest SIR, at 2.3 (P < 0.001). Similarly, duration post-transplant >10
      years had an SIR of 2.4 (P < 0.001). CONCLUSION: We believe that this study is
      representative of the United States' renal transplant population, and highlights
      the need for reduced immunosuppression in the long-term and increased vigilance
      for cancers in younger patients receiving renal transplantation.

PMID- 15200448
TI  - Randomized controlled trial of prophylactic repair of hemodialysis arteriovenous
      graft stenosis.
AB  - BACKGROUND: Previous nonrandomized studies suggest that prophylactic repair of
      hemodialyisis arteriovenous (AV) graft stenosis reduces thrombosis rates and
      increases cumulative graft survival. The present study is a randomized trial
      comparing prophylactic repair of AV graft stenosis with repair at the time of
      thrombosis. METHODS: Sixty-four patients with elevated static venous pressure
      measured in an upper extremity AV graft were randomized to Intervention or
      Observation. Monthly static venous pressure/systolic blood pressure ratios (SVPR)
      were determined for all patients throughout the duration of study participation.
      Patients in the Intervention group underwent angiography and repair of identified
      stenoses if the monthly SVPR was elevated (>/=0.4). Patients in the Observation
      group underwent stenosis repair only in the event of access thrombosis or
      clinical evidence of access dysfunction. The primary end point was access
      abandonment. RESULTS: Access abandonment occurred in 14 patients in the
      Intervention group and 14 patients in the Observation group during the 3.5-year
      study period. Time to access abandonment did not differ significantly between the
      treatment groups (hazard ratio for randomization to Intervention 1.75, 95% CI
      0.80-3.82, P= 0.16). The proportion of patients with a thrombotic event was
      greater in the Observation group (72%) than in the Intervention group (44%) (P=
      0.04), but overall thrombosis rates were similar in the groups. CONCLUSION:
      Compared with a strategy of observation and repair of accesses only in the event
      of thrombosis, prospective static venous pressure monitoring with prophylactic
      stenosis repair did not prolong graft survival.

PMID- 15200449
TI  - Usefulness of artificial neural networks to predict follow-up dietary protein
      intake in hemodialysis patients.
AB  - BACKGROUND: Artificial neural networks (ANN) represent a promising alternative to
      classical statistical and mathematic methods to solve multidimensional nonlinear
      problems. The aim of the study was to verify, by comparing the performance of ANN
      with that of experienced nephrologists, whether ANN are useful tools in
      hemodialysis to predict the follow-up (=1 month after the observation used for
      the prediction) dietary protein intake (PCR), and whether their performance is
      influenced by the size of the population and by the data pool used to built the
      model. METHODS: A combined retrospective and prospective observational study was
      performed in two Swiss dialysis units (84 chronic hemodialysis patients, 500
      monthly clinical observations and biochemical test results). Using mathematical
      models based on linear regressions to evaluate the variables, ANN were built and
      then prospectively and interinstitutionally compared with the ability of six
      experienced nephrologists to predict the follow-up PCR. RESULTS: ANN compared
      with nephrologists gave a more accurate correlation between estimated and
      calculated follow-up PCR (P < 0.001). The same superiority of ANN was also seen
      in the ability to detect a follow-up PCR <1.00 g/kg/day expressed as a percentage
      of correct predictions, sensitivity, specificity, and predictivity. The
      interinstitutional performance of the ANN is positively influenced by the size
      and the variability of the population used to build the mathematical model.
      CONCLUSION: The use of ANN significantly improves the ability of the experienced
      nephrologist to estimate and to detect an unsatisfactory (<1.00 g/kg/day) follow
      up PCR. The size of the population selected to build the ANN is critical for his
      performance.

PMID- 15200450
TI  - The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis
      fluid (balance) on the peritoneal membrane.
AB  - BACKGROUND: Although peritoneal dialysis (PD) is a widely accepted form of renal
      replacement therapy (RRT), concerns remain regarding the bioincompatible nature
      of standard PD fluid. In order to evaluate whether a newly formulated fluid of
      neutral pH, and containing low levels of glucose degradation products (GDP),
      resulted in improved in vivo biocompatibility, it was compared in a clinical
      study to a standard PD fluid. METHODS: In a multicenter, open, randomized,
      prospective study with a crossover design and parallel arms, a conventional,
      acidic, lactate-buffered fluid (SPDF) was compared with a pH neutral, lactate
      buffered, low GDP fluid (balance). Overnight effluent was collected and assayed
      for cancer antigen 125 (CA125), hyaluronic acid (HA), procollagen peptide (PICP),
      vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha
      (TNFalpha). Serum samples were assayed for circulating advanced glycosylation end
      products (AGE), N(epsilon)-(carboxymethyl)lysine (CML), and imidazolone. Clinical
      end points were residual renal function (RRF), adequacy of dialysis,
      ultrafiltration, and peritoneal membrane function. Eighty-six patients were
      randomized to either group I starting with SPDF for 12 weeks (Phase I), then
      switching to "balance" for 12 weeks (Phase II), or group II, which was treated
      vice versa. Seventy-one patients completed the study with data suitable for entry
      into the per protocol analysis. Effluent and serum samples, together with
      peritoneal function tests and adequacy measurements, were undertaken at study
      centers on three occasions during the study: after the four-week run-in period,
      after Phase I, and again after Phase II. RESULTS: In patients treated with
      balance there were significantly higher effluent levels of CA125 and PICP in both
      arms of the study. Conversely, levels of HA were lower in patients exposed to
      balance, while there was no change in the levels of either VEGF or TNFalpha.
      Serum CML and imidazolone levels fell significantly in balance-treated patients.
      Renal urea and creatinine clearances were higher in both treatment arms after
      patients were exposed to balance. Urine volume was higher in patients exposed to
      balance. In contrast, peritoneal ultrafiltration was higher in patients on SPDF.
      When anuric patients were analyzed as a subgroup, there was no significant
      difference in peritoneal transport characteristics or in ultrafiltration on
      either fluid. There were no changes in peritonitis incidence on either solution.
      CONCLUSION: This study indicates that the use of balance, a neutral pH, low GDP
      fluid, is accompanied by a significant improvement in effluent markers of
      peritoneal membrane integrity and significantly decreased circulating AGE levels.
      Clinical parameters suggest an improvement in residual renal function on balance,
      with an accompanying decrease in peritoneal ultrafiltration. It would appear that
      balance solution results in an improvement in local peritoneal homeostasis, as
      well as having a positive impact on systemic parameters, including circulating
      AGE and residual renal function.

PMID- 15200451
TI  - Transforming growth factor-beta 1 gene polymorphisms and cardiovascular disease
      in hemodialysis patients.
AB  - BACKGROUND: Atherosclerotic vascular disease is a leading cause of morbidity and
      mortality in patients with end-stage renal disease (ESRD) on maintenance
      hemodialysis (HD). Transforming growth factor-beta1 (TGF-beta1) is a
      multifunctional cytokine that inhibits the atheromatous process. We studied
      coding region polymorphisms of the TGF-beta1 gene (+869 T --> C at codon 10 and
      +915 G --> C at codon 25) as genetic susceptibility factors for prevalent
      vascular disease and cardiac outcomes in a cohort of HD patients enrolled in the
      HEMO Study. METHODS: Genotyping was carried out using polymerase chain reaction
      sequence specific primer (PCR-SSP) methods with a cytokine genotyping tray.
      Prevalent vascular disease was coded from the Index of Disease Severity (IDS)
      scores for ischemic heart disease (IHD), peripheral vascular disease (PVD),
      cerebrovascular disease (CVD), and congestive heart failure (CHF), 0 indicating
      absence, and 1 to 3 increasing grades of severity. The presence of any vascular
      disease (VD) (i.e., any degree of IHD/PVD/CVD), and the number of coexistent
      vascular system diseases per patient were derived. Cardiac outcomes, one of the
      secondary outcomes of the HEMO Study, were expressed as a composite of the first
      hospitalization for, or death from, cardiac causes. RESULTS: The cohort consisted
      of 183 patients at enrollment, 56% male, 44% African American (AA), and 40%
      diabetic. The mean age was 62.4 +/- 12.2 years, and median dialysis vintage 2.02
      years. The most frequent genotype at codon 10 was T/C (67%), and at codon 25 was
      G/G (72%). IHD was present in 52% of patients; 65% had at least one vascular
      system involvement, and 31% had 2 or more. On both univariate and multivariate
      analysis, the G/C genotype at codon 25 was significantly associated with the
      presence and extent of vascular disease at enrollment. The median time to cardiac
      outcome, defined as a composite of the first hospitalization for, or death from,
      cardiac causes, was 411 days in patients with the G/C genotype compared with 851
      days in those with the G/G genotype (P= 0.03). Patients with the G/C genotype had
      a 1.6-fold increased hazard for cardiac outcomes after adjustment for baseline
      covariates (P= 0.04). CONCLUSION: The G/C substitution at codon 25 was associated
      with an increased risk for prevalent vascular disease, new onset cardiac
      morbidity, and cardiac mortality in HD patients, and may be a genetic
      susceptibility factor for the development of atherosclerosis. Further studies are
      required to evaluate the role of TGF-beta1 as a candidate gene.

PMID- 15200452
TI  - Nonimmunologic complications and gene polymorphisms of immunoregulatory cytokines
      in long-term renal transplants.
AB  - BACKGROUND: While the influence of cytokine gene polymorphisms on immunologic
      complications after organ transplantation is widely evaluated, little is known
      about predictive value of cytokine genotype for the development of nonimmunologic
      post-transplant complications: hypertension, dyslipoproteinemia, diabetes
      mellitus, hyperuricemia. METHODS: The -1082IL-10, -308TNF-alpha, transforming
      growth factor-beta1 (TGF-beta1) (codon 10, 25), -174IL-6, +874IFN-gamma gene
      single nucleotide polymorphisms (SNP) were studied in 278 long-term renal
      transplants by polymerase chain reaction-sequence specific primer (PCR-SSP) with
      respect to nonimmunologic post-transplant complications. RESULTS: Significant
      association of the TGF-beta (codon 25) GG genotype with hyperuricemia (P= 0.0013)
      and dyslipoproteinemia (P= 0.0171) was found. The TGF-beta1 (codon 25) CG
      genotype was detected more frequently in patients with normal uric acid levels.
      The +874IFN-gamma AA genotype was associated with type 2/steroid-induced diabetes
      (P= 0.0127). Frequency of the -1082IL-10 AG genotype was significantly higher in
      hyperuricemic patients versus controls (P= 0.0022). No associations of
      polymorphisms in the tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL
      6), TGF-beta codon 10 genes with hyperuricemia, dyslipoproteinemia, or diabetes
      were detected. We failed to observe significant differences in cytokine genotype
      distribution between hypertensive and normotensive patients. CONCLUSION: We
      established an association of particular cytokine genotypes with nonimmunologic
      post-transplant complications. This supports an idea that assessment of cytokine
      SNPs may allow more accurate prediction of nonimmunologic complications and
      appropriate adjustment of pre-emptive treatments in long-term transplant
      patients.

PMID- 15200453
TI  - Alterations of CYP3A4 and P-glycoprotein activity in vivo with time in renal
      graft recipients.
AB  - BACKGROUND: Catabolism by intestinal and hepatic cytochrome P450 3A4 (CYP3A4),
      and excretion by P-glycoprotein (PGP), has a major influence on oral
      bioavailability of calcineurin inhibitors. In this study, the activity of
      intestinal and hepatic CYP3A4 and PGP in vivo was assessed in renal transplant
      recipients during the first year after transplantation (Tx). METHODS: Stable
      Caucasian renal transplant patients were tested at 1 week, 3 months, and 1 year
      after Tx, and compared with the results obtained in drug-free healthy volunteers.
      Intestinal and hepatic CYP3A4 and PGP activity were determined by measurement of
      (14)C-excretion dynamics in breath and urine after oral and intravenous
      administration of [N-methyl-(14)C]-erythromycin. RESULTS: Compared with 1 week
      after Tx, intestinal and hepatic CYP3A4 activity significantly decreased at 3
      months and 1 year after Tx (-33% and -45%; -7% and -33%, respectively). Compared
      with the healthy volunteers, intestinal and hepatic CYP3A4 activity of the
      patients was significantly increased at 1 week after Tx, but normalized at 1 year
      after Tx. A similar pattern, though not significant, was seen for intestinal PGP
      activity. CONCLUSION: Phenotypic expression of hepatic and intestinal CYP3A4 was
      increased immediately after Tx, but gradually decreased to basal levels toward
      the end of the first year after Tx. The most plausible explanation for this
      evolution was the tapering of corticosteroid (CS) doses. These findings may also
      explain the increasing bioavailability of tacrolimus with time after Tx.

PMID- 15200454
TI  - Predicting coronary heart disease in renal transplant recipients: a prospective
      study.
AB  - BACKGROUND: Current cardiovascular risk calculators, widely used in the general
      population, have not yet been validated in renal transplant recipients. We
      conducted a prospective study to determine the incidence and risk factors for
      ischemic heart disease in renal transplant recipients and to assess the relevance
      of the Framingham Heart Study risk calculator in this population. METHODS: Three
      hundred and forty four consecutive renal transplant recipients free of vascular
      disease were enrolled. Coronary events were registered and analyzed with respect
      to traditional and nontraditional cardiovascular risk factors. The risk of
      coronary events was assessed through the Framingham Heart Study formula and the
      relevance of this equation was then analyzed. RESULTS: The patients were followed
      for a mean duration of 72 +/- 14 months. Twenty seven coronary events occurred in
      27 patients (7.8%). In addition to risk factors included in the Framingham Heart
      Study score, C-reactive protein (CRP) level (P= 0.009), and hyperhomocysteinemia
      (P= 0.01) were found to be independent risk factors for ischemic heart disease
      events in renal transplant recipients. The Framingham Heart Study model did not
      predict absolute ischemic heart disease risk in the transplant population as a
      whole. CONCLUSION: Nontraditional cardiovascular risk factors greatly contribute
      to increased incidence of ischemic heart disease events in renal transplant
      recipients. They should therefore be considered in preventive care of these
      patients which relies on reduction of overall absolute risk. Although the
      Framingham Heart Study score has an excellent predictive value in low-risk renal
      transplant recipients, it tends to underestimate the real cardiovascular risk in
      high-risk patients.

PMID- 15200455
TI  - Subclinical atherosclerosis is increased in type 2 diabetic patients with
      microalbuminuria evaluated by intima-media thickness and pulse wave velocity.
AB  - BACKGROUND: Microalbuminuria appears to be a risk marker for atherosclerosis.
      However, little is known about the direct association between microalbuminuria
      and vascular wall properties. METHODS: Subjects were 306 type 2 diabetic patients
      with normoalbuminuria (N= 200) and microalbuminuria (N= 106). Those who had
      macroalbuminuria, atherosclerotic vascular disease, and/or ankle brachial index
      being less than 0.9 were not included. Brachial-ankle pulse wave velocity (PWV)
      was measured by automatic oscillometric method. Intima-media thickness (IMT) of
      the common carotid artery was measured using high-resolution B-mode
      ultrasonography and a computerized image-analyzing system. RESULTS: Average IMT,
      maximum IMT, and PWV were significantly higher in patients with microalbuminuria
      than in patients with normoalbuminuria. Both average and maximum IMT increased
      significantly as albuminuria increased in the microalbuminuric range. Average IMT
      and maximum IMT correlated significantly with PWV (P < 0.0001), although some
      patients exhibited increased levels of only PWV or IMT. By a multiple linear
      regression, age and albuminuria were independent predictors of IMT and PWV. Waist
      circumference was an independent predictor of IMT. Hypertension and hemoglobin
      A(1c) (HbA(1c)) were independent predictors of PWV. After adjustment for
      conventional cardiovascular risk factors including age, sex, waist circumference,
      HbA(1c), hypertension, hyperlipidemia, and smoking, albuminuria revealed a
      significant association with average IMT, maximum IMT, and PWV (P < 0.05, P <
      0.0001, and P < 0.05, respectively). CONCLUSION: A slight elevation of
      albuminuria is a significant determinant of IMT and PWV independent of
      conventional cardiovascular risk factors in type 2 diabetic patients with no
      clinical nephropathy or any vascular diseases. This significant association might
      point to a link in the pathogenesis of atherosclerosis and diabetic nephropathy.

PMID- 15200456
TI  - Plasmin in renal interstitial fibrosis: innocent or guilty?

PMID- 15200457
TI  - Parenteral iron therapy: beyond anaphylaxis.

PMID- 15200458
TI  - Parathyroidectomy in ESRD.

PMID- 15200460
TI  - How can stenosis of one renal artery cause failure of two kidneys?

PMID- 15200461
TI  - Icodextrin-induced sterile peritonitis: neutrophil activation and peritoneal
      injury.

PMID- 15200463
TI  - 7-84 PTH lowers bone turnover and explains why the 1-84 PTH/7-84 PTH ratio
      predicts bone turnover.

PMID- 15200465
TI  - Are associational studies obfuscating?

PMID- 15200467
TI  - Challenges from bias when estimating change of renal allograft function.

PMID- 15200468
TI  - Development of malignancy after treatment of idiopathic membranous nephropathy.

PMID- 15200471
TI  - Restructuring the ESRD payment system in the United States.

PMID- 15200470
TI  - Plasma activin A in hemodialysis patients: does brand of immunoassay matter?

PMID- 15200473
TI  - Single-point mutations at the surface of MB-1Trp lead to important changes in its
      conformational properties.
AB  - Protein design is currently used for the creation of new proteins with desirable
      traits. In our lab we focus on the synthesis of proteins with high essential
      amino acid content having potential applications in animal nutrition. One of the
      limitations we face in this endeavour is achieving stable proteins despite a
      highly biased amino acid content. We report here the synthesis and the
      characterization of three variants of MB-1Trp in which two solvent-exposed Leu
      have been replaced by Glu allowing for the formation of new salt bridges at the
      surface of the protein. Although both mutations were expected to be similar (i.e.
      same mutation in a comparable local environment), they appear to have different
      effects on MB-1Trp as shown by far-UV circular dichroism, thermal denaturation,
      fluorescence and proteolytic resistance measurements. For the mutation Leu68Glu,
      an increase in the protein melting temperature of 6 degrees C was observed.
      Surprisingly, the mutation in position Leu19Glu led to a decrease in melting
      temperature and a modification of tertiary structure.

PMID- 15200474
TI  - Selective targeting of a laccase from Stachybotrys chartarum covalently linked to
      a carotenoid-binding peptide.
AB  - Atwo-step targeting strategy was used to identify improved laccases for bleaching
      carotenoid-containing stains on fabric. We first applied a modified phage display
      technique to identify peptide sequences capable of binding specifically to
      carotenoid stains and not to fabric. Prior deselection on the support on which
      the carotenoid was localized, increased stringency during the biopanning target
      selection process, and analysis of the phage peptides' binding to the target
      after acid elution and polymerase chain reaction (PCR) postacid elution, were
      used to isolate phage peptide libraries with increased binding selectivity and
      affinity. Peptide sequences were selected based on identified consensus motifs.
      We verified the enhanced carotenoid-binding properties of the peptide YGYLPSR and
      subsequently cloned and expressed C-terminal variants of laccase from
      Stachybotrys chartarum containing carotenoid-binding peptides YGYLPSR,
      IERSAPATAPPP, KASAPAL, CKASAPALC, and SLLNATK. These targeted peptide-laccase
      fusions demonstrate enhanced catalytic properties on stained fabrics.

PMID- 15200475
TI  - The 10th and 11th residues of short length N-terminal PTH(1-12) analogue are
      important for its optimum potency.
AB  - The 10th and 11th residues of parathyroid hormone PTH(1-12) analogues were
      substituted to study the structure and function of PTH analogues. The
      substitution of Ala(10) of [Ala(3,10,12)(Leu(7)/Phe(7))Arg(11)]rPTH(1-12)NH(2)
      with Glu(10) and/or the Arg(11) with Ile(11) markedly decreased cAMP generating
      activity. Data from circular dichroism (CD) and the nuclear magnetic resonance
      (NMR) structural analysis of [Ala(3,10,12)(Leu(7)/Phe(7))Arg(11)]rPTH(1-12)NH(2)
      revealed tight alpha-helical structures, while the Glu(10) and/or Ile(11)
      substituted analogues showed unstable alpha-helical structures. We conclude that
      10th and 11th residues are important for stabilizing its helical conformation and
      that destabilization of the alpha-helical structure, induced by substituting the
      above residues, remarkably affect its biological potency.

PMID- 15200476
TI  - Purification and characterization of a new peptide with analgesic effect from the
      scorpion Buthus martensi Karch.
AB  - Anew peptide, designated as Buthus martensi Karch (BmK) AngM1, with an
      isoelectric point (pI) of 5.8 was purified and characterized from the venom of
      Buthus martensi Karch. The molecular mass was calculated as 7040.5 Da from
      multiple-charged ions by elelctrospray ionization mass spectroscopy (ESI/MS). The
      complete amino acid sequence of BmK AngM1 of 64 amino acid residues was
      determined by automatic sequencing of N-terminal part of the native peptide and
      the fragments of reduced and S-carboxymethylated (RCM)-peptide degraded by
      Staphylococcus aureaus V(8) protease and TPCK(N-p-Tosyl-L-phenylalanine
      chloromethyl ketone)-treated trypsin. Bioactivity tested using mouse-twisting
      model showed an evident analgesic effect with 63.0% (P < 0.001) inhibition
      efficiency at the dose of 0.8 mg/kg, but the LD(50) was larger than 50 mg/kg.
      Electrophysiological studies showed that BmK AngM1 at the concentration of 1
      microm obviously inhibit voltage-dependent Na(+) current (I(Na)) and voltage
      dependent delayed rectifier K(+) current (I(K)) but had no effects on transient
      K(+) current.

PMID- 15200478
TI  - A genetic progression model of oral cancer: current evidence and clinical
      implications.
AB  - Based on recent genetic studies, we propose a progression model for the
      development of oral squamous cell carcinoma. In the initial phase, a stem cell
      acquires a genetic alteration; subsequently a patch is formed, a clonal unit
      consisting of the stem cell with its daughter cells that all share the DNA
      alteration. The next critical step is the conversion of a patch into an expanding
      field as a result of additional genetic alterations. This mucosal field replaces
      the normal epithelium and in the oral cavity such fields have been detected with
      dimensions of over 7 cm in diameter. Sometimes these fields are visible as
      leukoplakia. Ultimately, clonal selection leads to the development of carcinoma
      within this contiguous field of pre-neoplastic cells. An important clinical
      implication of this model is that fields often remain after surgery of the
      primary tumor and may lead to new cancers, presently designated by clinicians as
      second primary tumors or local recurrences.

PMID- 15200479
TI  - Correlation between functional genotypes in the matrix metalloproteinases-1
      promoter and risk of oral squamous cell carcinomas.
AB  - BACKGROUND: Oral squamous cell carcinoma (OSCC) and oral submucous fibrosis
      (OSF), which are highly associated with areca use, are prevalent in most Asian
      countries. Matrix metalloproteinases (MMPs) are superfamily of metal-dependent
      proteolytic enzymes, mediating the degradation of extracellular matrix.
      Insertion/deletion (-1607 2G-->1G) polymorphism has been described in the
      promoter region of the human matrix metalloproteinases-1 (MMP-1) genes, which
      cause an alteration in the transcriptional activity. This genotype is associated
      with risks of cancer genesis and metastasis. In this paper, we studied the
      relationship between such genotype and areca-associated oral diseases. METHODS:
      Genomic DNA from the blood of OSCC (n = 121), OSF (n = 58) cases and controls (n
      = 147) were amplified by polymerase chain reaction (PCR)-based genotyping. The
      OSCC were further grouped into buccal squamous cell carcinoma (BSCC) and non
      buccal suqmaous cell carcinoma (NBSCC), in accord with the site of involvement.
      The significance of the differences was assessed by Fisher's exact test. RESULTS:
      The 2G genotype in MMP-1 promoter was observed with a higher frequency in both
      OSCC (0.69, P = 0.06) and NBSCC (0.76, P = 0.03) cases compared with controls
      (0.63), with an odds ratio of 2.17 and 4.58, respectively. This genotype was not
      related to the risk of OSF. No other clinicopathologic parameter was associated
      with the genotypes in OSCC cases. CONCLUSION: The results showed that 2G genotype
      in MMP-1 promoter was associated with the risk of OSCC.

PMID- 15200480
TI  - The molecular markers for prognostic evaluation of areca-associated buccal
      squamous cell carcinoma.
AB  - BACKGROUND: Buccal squamous cell carcinoma (BSCC) is the most frequently
      occurring oral cancer in Asians due to the popularity of areca use in this area.
      The aim of the present study was to evaluate the survival of areca-associated
      BSCC associated with multiple molecular markers. METHODS: Using
      immunohistochemistry, we evaluated the survival of a cohort of 55 patients with
      BSCC being followed long term, as correlated to the expression of variable
      markers. RESULTS: We found that p53, p21, Rb, cyclin D1 (CCD1), MDM2, and gamma
      catenin were positive in 81, 60, 70, 31, 88, and 44% of patients, respectively.
      Subjects with -ve immunoreactivity for CCD1, and +ve immunoreactivity for MDM2
      and gamma-catenin had significantly better survival than subjects with the
      opposite immunoreactive pattern. KAPLAN-meier survival curves confirmed this
      association. CONCLUSION: The data indicate that expression of CCD1, MDM2, and
      gamma-catenin might serve as potential prognostic markers for BSCC in areca-using
      patients.

PMID- 15200481
TI  - Relationship between major and minor salivary gland mucoepidermoid carcinoma
      malignancy grading and presence of stromal myofibroblasts: immunohistochemical
      study.
AB  - OBJECTIVE: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary
      tumour, classified as low, intermediate and high grade. Myofibroblasts are the
      main stromal component and are included as prognostic factor in some tumours. The
      aim of this study was to evaluate the myofibroblasts in the stroma of MEC with
      possible relationship to malignancy grading. METHODS: Twenty-five cases of MEC
      (six low grade, 11 intermediate grade, four high grade and four metastasis) were
      stained for vimentin, desmin and smooth muscle actin (SMA) for the identification
      of myofibroblasts. Transforming growth factors (TGFbeta1 and TGFbetaRII) were
      also assessed in our study. RESULTS: Myofibroblasts were present in all cases, in
      amounts varying according to histological grading. TGFbeta1 was positive in
      squamous cells of intermediate grade tumours, and in the stroma of only four
      cases. TGFbetaRII was positive in most squamous and intermediate cells,
      regardless of malignancy grading. CONCLUSIONS: Our study showed that the analysis
      of neoplastic stroma must be added to the studies of neoplastic cells to draw a
      better picture leading to tumour diagnosis and prognosis.

PMID- 15200482
TI  - Clinicopathological characteristics of tongue piercing: an experimental study.
AB  - BACKGROUND: This study attempts to remedy the situation that no morphological
      studies exit of tongue piercing. METHODS: The tongues of eight Beagles were
      pierced with titanium implants. The animals were then divided into four groups: 1
      week, 2 weeks, 1 month and 3 months for clinical-photographic and
      histopathological studies. RESULTS: Group I: clinically, erythema at both
      orifices and, microscopically, granulation tissue covering the surface of the
      canal and infiltrates of polynuclear neutrophils. Group II: persistence of
      erythema and of the granulation tissue, with the edges of the epithelium showing
      signs of regeneration. Group III: granulation tissue alternating with fibrosis;
      epithelium covering the sides of the canal. Group IV: fibrosis substituting the
      granulation tissue and almost complete re-epithelialization of the canal. All
      groups, except group I, numerous foreign body-type granulomas. CONCLUSIONS:
      Tongue piercing provokes fibrous reparation with almost total re
      epithelialization of the perforated zone and foreign body-like granulomatous
      inflammation.

PMID- 15200484
TI  - Tenascin and fibronectin expression in odontogenic cysts.
AB  - BACKGROUND: Odontogenic cysts (OCs) present distinct evolution and clinical
      behavior. This study was performed in order to investigate if some components of
      the extracellular matrix (ECM) may drive these differences. METHODS: Thirty OCs
      were selected: 10 radicular cysts (RCs), 10 dentigerous cysts (DCs), 10 non
      syndrome odontogenic keratocysts (OKCs) and they were immunohistochemically
      analyzed to verify the expression pattern of tenascin and fibronectin. RESULTS:
      Tenascin immunostaining was mainly intense as a thick band deep to the epithelial
      mesenchymal interface in both RCs and OKCs. The intense tenascin immunoexpression
      observed in the RCs was usually associated with inflammation. An intense
      fibronectin reactivity was observed in the basement membrane region and at the
      cystic wall of OKCs. CONCLUSIONS: Our results demonstrate differences between the
      expression of ECM proteins in the OCs studied. The higher tenascin and
      fibronectin expression in the capsule of OKCs suggests marked instability in the
      cystic structure and may contribute to its aggressive behavior.

PMID- 15200483
TI  - Extracellular glycosaminoglycan changes in healthy and overgrown gingiva
      fibroblasts after cyclosporin A and cytokine treatments.
AB  - BACKGROUND: It has been demonstrated that cyclosporin A (CyA) blocks the immune
      system, acts on cytoskeleton and stimulates the production of extracellular
      matrix (ECM) and transforming growth factor-beta1 (TGF-beta1). This cytokine,
      such as transforming growth factor-alpha (TGF-alpha), induces deposition of
      glycosaminoglycans (GAG), proteoglycans and collagen fibres in the ECM. METHODS:
      In this work, we examined the effect induced by CyA, TGF-beta1 and TGF-alpha on
      cultures of healthy and overgrown human gingival fibroblasts in order to evaluate
      the glycosaminoglycan, cytoskeletal changes and the behaviour of fibroblasts
      after concanavalin A (Con A) treatment. Moreover, we examined gingival biopsies
      by Alcian blue histochemical staining and electron transmission microscopy.
      RESULTS: Total and extracellular sulphated GAG in overgrown gingiva specimens and
      in derived fibroblast cultures treated with CyA and cytokines were significantly
      higher than controls. The action of cytokines was increased (P < or = 0.01)
      compared with CyA with a greater effect of TGF-alpha in comparison with TGF
      beta1; the electron microscopy showed ECM accumulation. The agglutinations showed
      the heterogeneity of fibroblast populations. CONCLUSIONS: Stimulation with Con A
      showed that the fibroblast population had cell surface heterogeneity, and could
      respond in a different way to both CyA and cytokine stimulus. Moreover, increased
      synthesis of GAG in overgrown gingiva compared with synthesis in normal
      fibroblasts before CyA treatment suggests a possible genetic origin of damage. As
      not all CyA-treated patients develop gingival overgrowth, a genetic
      predisposition may explain the different responses of gingival fibroblast
      populations.

PMID- 15200485
TI  - K-Ras gene status and expression of Ras/mitogen-activated protein kinase (MAPK)
      signaling molecules in ameloblastomas.
AB  - BACKGROUND: To clarify the roles of rat sarcoma (Ras)/mitogen-activated protein
      kinase (MAPK) signaling pathway in oncogenesis and cytodifferentiation of
      odontogenic tumors, K-Ras gene status and expression of Ras, Raf1,
      MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)1, and ERK1/2
      proteins were analyzed in ameloblastomas as well as in tooth germs. METHODS:
      Paraffin sections of 10 tooth germs and 46 benign and 6 malignant ameloblastomas
      were examined immunohistochemically for the expression of K-Ras, Raf1, MEK1, and
      ERK1/2. Frozen tissue samples of 22 benign ameloblastomas and 1 malignant
      (metastasizing) ameloblastoma were analyzed by direct DNA sequencing to detect K
      Ras gene alteration. RESULTS: Immunohistochemical reactivity for K-Ras, Raf1,
      MEK1, and ERK1/2 was detected in both normal and neoplastic odontogenic
      epithelium, and these molecules were reactive chiefly with odontogenic epithelial
      cells neighboring the basement membrane. Plexiform ameloblastomas showed slightly
      stronger expression of these Ras/MAPK signaling molecules than follicular
      ameloblastomas. Keratinizing cells and granular cells showed decreased reactivity
      for the signaling molecules. Basal cell ameloblastomas showed slightly stronger
      reactivity for the signaling molecules than did the other subtypes. K-Ras
      immunoreactivity in malignant ameloblastomas was lower than that in dental lamina
      of tooth germs. Direct DNA sequencing showed a GGT to GCT point mutation at codon
      12 of K-Ras gene in one ameloblastoma. CONCLUSION: Expression of K-Ras, Raf1,
      MEK1, and ERK1/2 in tooth germs and ameloblastomas suggests that Ras/MAPK
      signaling pathway functions to regulate cell proliferation and differentiation in
      both normal and neoplastic odontogenic epithelium. K-Ras gene status implied that
      K-Ras mutations might play a minor role in oncogenesis of odontogenic epithelium.

PMID- 15200487
TI  - Odontogenic keratocyst clinically mimicking an eruption cyst: report of a case.
AB  - This article describes a case of odontogenic keratocyst (OKC) in a 1 year and 7
      month old girl who presented such a lesion mimicking an eruption cyst. To date,
      only one well-documented OKC occurring in a patient under 5 years old has been
      reported and it was thought to be associated with nevoid basal cell carcinoma
      syndrome (NBCCS). In our OKC case, the cyst was totally enucleated. No evidence
      of recurrence and NBCCS was found after a 4-year follow-up. The development of
      involving tooth in a growing child and the histogenesis of OKC are discussed in
      this article.

PMID- 15200486
TI  - A study of 342 oral keratotic white lesions induced by qat chewing among 2500
      Yemeni.
AB  - BACKGROUND: Qat chewing is a common habit in Yemen. Various studies demonstrated
      clear effects of this habit on the systemic organs of the human body. The lack of
      studies, however, on the effects of this habit on oral mucosa was the major
      motive of this study. METHODS: This cross-sectional study was made on 2500 Yemeni
      citizens (mean age 27 years, 1818 males and 682 females). Clinical protocol was
      made for all cases with a full intraoral examination. A new grading system was
      applied for each case with oral white lesion. RESULTS: Of our sample, 1528 cases
      (61.12%) were qat chewers; of them, 342 cases (22.4%) had oral keratotic white
      lesions at the site of qat chewing, while only 6 (0.6%) non-chewer cases had
      white lesions in their oral cavity (P < 0.000000, Odds ratio = 46.43, RR =
      36.26). According to our grading system; 14, 5.9 and 2.4% were grade I, II and
      III. CONCLUSIONS: We conclude that qat chewing can provoke the development of
      oral keratotic white lesions at the site of chewing. The prevalence of these
      lesions and its severity increase as duration and frequency increase.

PMID- 15200488
TI  - Odontogenic ghost cell tumour with clear cell components: clear cell odontogenic
      ghost cell tumour?
AB  - A case of odontogenic ghost cell tumour (OGCT) with clear cell components was
      encountered in the mandible of a 63-year-old man. The tumour revealed
      ameloblastomatous-type epithelial components accompanied by clusters of ghost
      cells and dentinoid juxtaposed to the odontogenic epithelium. In addition, some
      areas of the tumour tissue showed sheets and islands of clear, glycogen
      containing epithelial cells, which were separated by a thin fibrous connective
      tissue stroma. Both ameloblastic and clear cells exhibited positive
      immunoreactivities for cytokeratin 19 and AE1/3. It is not known whether this
      tumour represents a clear cell change of a pre-existing OGCT or a separate and
      distinct neoplasm derived de novo from the odontogenic epithelium. This tumour
      was given the term 'clear cell OGCT' because it captures the clear cell
      components, which is one of the most prominent distinguishing features of the
      tumour.

PMID- 15200489
TI  - Enhanced external counterpulsation improves skin oxygenation and perfusion.
AB  - BACKGROUND: Enhanced external counterpulsation (EECP) augments diastolic and
      reduces systolic blood pressures. Enhanced external counterpulsation has been
      shown to improve blood flow in various organ systems. Beneficial effects on skin
      perfusion might allow EECP to be used in patients with skin malperfusion
      problems. This study was performed to assess acute effects of EECP on superficial
      skin blood flow, transdermal oxygen and carbon dioxide pressures. MATERIALS AND
      METHODS: We monitored heart rate, blood pressure, transdermal blood flow as well
      as oxygen and carbon dioxide pressures in 23 young, healthy persons (28 +/- 4
      years) and 15 older patients (64 +/- 7 years) with coronary artery disease
      before, during and 3 min after 5 min EECP. Friedman test was used to compare the
      results of 90-s epochs before, during and after EECP. Significance was set at P <
      0.05. RESULTS: Enhanced external counterpulsation increased heart rate and mean
      blood pressure. During EECP, transdermal oxygen pressure and concentration of
      moving blood cells increased while transdermal carbon dioxide pressure and
      velocity of moving blood cells decreased significantly in both groups. After
      EECP, transdermal carbon dioxide pressure was still reduced while the other
      parameters returned to baseline values. CONCLUSIONS: Improved skin oxygenation
      and carbon dioxide clearance during EECP seem to result from the increased
      concentration and reduced flow velocity, i.e. prolonged contact time, of
      erythrocytes. The increased concentration of moving blood cells and the decreased
      velocity of moving blood cells at both tested skin sites indicate peripheral
      vasodilatation.

PMID- 15200490
TI  - Cellular microparticles: new players in the field of vascular disease?
AB  - Microparticles are small membrane vesicles that are released from cells upon
      activation or during apoptosis. Cellular microparticles in body fluids constitute
      a heterogeneous population, differing in cellular origin, numbers, size,
      antigenic composition and functional properties. Microparticles support
      coagulation by exposure of negatively charged phospholipids and sometimes tissue
      factor, the initiator of coagulation in vivo. Microparticles may transfer
      bioactive molecules to other cells or microparticles, thereby stimulating cells
      to produce cytokines, cell-adhesion molecules, growth factors and tissue factor,
      and modulate endothelial functions. Microparticles derived from various cells,
      most notably platelets but also leucocytes, lymphocytes, erythrocytes and
      endothelial cells, are present in the circulation of healthy subjects. Rare
      hereditary syndromes with disturbances in membrane vesiculation leading to a
      decreased numbers of microparticles clinically present with a bleeding tendency.
      In contrast, elevated numbers of microparticles are encountered in patients with
      a great variety of diseases with vascular involvement and hypercoagulability,
      including disseminated intravascular coagulation, acute coronary syndromes,
      peripheral arterial disease, diabetes mellitus and systemic inflammatory disease.
      Finally, microparticles are a major component of human atherosclerotic plaques.
      In view of their functional properties, cell-derived microparticles may be an
      important intermediate in the cascade of cellular and plasmatic dysfunctions
      underlying the process of atherogenesis.

PMID- 15200491
TI  - FH clinical phenotype in Greek patients with LDL-R defective vs. negative
      mutations.
AB  - BACKGROUND: Familial hypercholesterolaemia (FH) is caused by mutations in the low
      density lipoprotein receptor gene and the gene encoding apolipoprotein B-100,
      affecting one in 500 individuals. METHODS: One hundred and eighty-three Greek FH
      patients were screened for mutations on the LDLR and ApoB genes. RESULTS: We
      identified mutations in 67 probands and 11 relatives. Sixteen mutations located
      in eight different exons and the promoter of the LDLR were discovered. Among them
      10 were missense mutations (C6W, S265R, A370T, Q363P, D365E, V408M, A410T, A517T,
      G528D, G571E), two were nonsense mutations (Q363X and C660X), three were splice
      defects (2140 + 5G-->A and 2140 + 9C-->T, 1706 - 10G-->A), and one was a
      nucleotide substitution (- 45delT) on the promoter. None of the subjects carried
      any apoB mutation. The detection rate of mutations in this study was 43%. From
      the above mutations, A410T, A519T and the splice site defects 2140 + 9C-->T were
      detected for the first time in the Greek population. Among them V408M, G528D, C6W
      and S265R account for 73% of heterozygous FH probands. V408M mutation is more
      common in Central West, while C6W is more common in Central East. Separating the
      patients into two groups (receptor defective and receptor negative) we found that
      the receptor negative group had higher levels of total cholesterol, low-density
      lipoprotein cholesterol and higher prevalence of tendon xanthomas compared with
      the receptor-defective group. DISCUSSION: The homogenous molecular basis of
      familial hypercholesterolaemia in Greece facilitates the application of a DNA
      diagnostic strategy based on the origin of the patient. The early mutation
      analysis would add valuable information on the severity of the disease.

PMID- 15200492
TI  - Insulin therapy in type 2 diabetes: role of the long-acting insulin glargine
      analogue.
AB  - Insulin glargine is a long-acting insulin analogue, with a longer duration of
      action and a flatter time-action profile compared with NPH insulin. These
      properties can be predicted to result in higher glucose levels during the night
      and lower glucose levels after dinner following bedtime injection of insulin
      glargine compared with an equal dose of NPH insulin injected at bedtime. In two
      large-scale clinical trials involving either insulin-naive (426 patients treated
      for 1 year) or previously insulin-treated (518 patients treated for 28 weeks)
      patients with type 2 diabetes, comparing addition of once-daily insulin glargine
      or NPH insulin to oral agents, these predictions were proven to be correct.
      Nocturnal hypoglycaemia was reduced by 58% in insulin-naive patients and by 22%
      in previously insulin-treated patients, and dinner-time glucose control was
      significantly better with insulin glargine than with NPH insulin once daily in
      the study in insulin-naive patients. The 'treat-to-target study' (756 insulin
      naive patients treated for 24 weeks) showed that good glycaemic control can be
      achieved with aggressive titration of the insulin dose with either once-daily
      insulin glargine or NPH insulin combined with oral agents (mean endpoint HbA(1c)
      was 6.96% with insulin glargine and 6.97% with NPH insulin); however, this was
      achieved with less variability and nocturnal hypoglycaemia with insulin glargine.
      These data support use of insulin glargine instead of NPH insulin for basal
      insulin replacement in patients with type 2 diabetes.

PMID- 15200493
TI  - Oro-cecal transit time: influence of a subsequent meal.
AB  - BACKGROUND: Small intestinal and oro-cecal transit time (OCTT) is determined for
      clinical diagnostics and research purposes. Experimental protocols used vary with
      respect to the inclusion of a subsequent meal during the test period. This study
      was conducted to elucidate whether the ingestion of a subsequent meal during the
      test period influences the OCTT of the test meal. MATERIALS AND METHODS: The OCTT
      of a liquid test meal, measured with the lactose-[(13)C]ureide breath test, was
      compared between four groups of healthy volunteers (n = 36) who consumed the
      subsequent meal at different time points. Also, the OCTT was determined twice in
      eight subjects; a subsequent meal was ingested after 180 min (test A) and after
      360 min (test B). RESULTS: An apparently meal-related increase in median OCTT was
      observed. The OCTT of the eight volunteers measured in test A (210; 210-349
      median; quartiles) was significantly shorter than that found in test B (345; 300
      375 min, P = 0.016). As result of the ingestion of the subsequent meal at 180 min
      the OCTT was shortened by 90; 64-116 min in 7/8 subjects. CONCLUSION: These data
      indicate that the ingestion of a subsequent meal affects the OCTT of a liquid
      test meal. This phenomenon could be explained by the increased intestinal
      motility in response to a meal, and should be taken into account when designing
      protocols for measurements of the OCTT and in the interpretation of small
      intestinal absorption studies.

PMID- 15200494
TI  - Role of apoptosis and CD95-receptor/ligand system in aspirin- and Helicobacter
      pylori-induced cell death.
AB  - BACKGROUND: Helicobacter pylori and aspirin both induce gastric epithelial
      apoptosis. However, the apoptosis-inducing mechanism of aspirin is still unknown.
      MATERIAL AND METHODS: Apoptosis induction was measured in several gastric
      epithelial cell lines after incubation with either aspirin or H. pylori
      supernatant or with a combination of both. CD95 expression was assessed by FACS
      analysis and CD95L mRNA was measured by reverse transcription polymerase chain
      reaction. RESULTS: It could be demonstrated that aspirin- and H. pylori
      supernatant-induced apoptosis involves increased CD95 expression in three
      different gastric epithelial cell lines. The combined exposure of H. pylori
      supernatant and aspirin had synergistic effects on both apoptotic cell death and
      CD95 expression. Blockade of CD95 signalling with an antagonistic antibody was
      partially prevented from H. pylori- but not from aspirin-induced apoptosis.
      Furthermore, CD95L expression was detected after treatment with H. pylori only.
      CONCLUSIONS: These data suggest that although aspirin-mediated CD95 up-regulation
      is not relevant for its direct apoptotic effect it may sensitize gastric
      epithelial cells for H. pylori-induced apoptosis. Collectively our data
      demonstrate the relation of aspirin- and H. pylori-induced apoptosis from a new
      perspective.

PMID- 15200496
TI  - Methylene blue attenuates lung injury after mesenteric artery
      clamping/unclamping.
AB  - BACKGROUND: This controlled, experimental study was designed to assess the
      effects of intratracheal and intravenous methylene blue on reperfusion lung
      injury following superior mesenteric artery clamping/unclamping. MATERIALS AND
      METHODS: Superior mesenteric arteries of 144 anaesthetized adult male Wistar rats
      (n = 12/group) were clamped for 1 h. Ten minutes before unclamping, methylene
      blue or its vehicle was administered intratracheally or intravenously, followed
      by a 3 h-respiratory assessment and postexperimental assessment of survival.
      RESULTS: Intravenous 3 and 9 mg kg(-1) but not higher methylene blue doses, and
      intratracheal 6-mg kg(-1) but not lower doses, significantly (P < 0.05) reduced
      the 100% increase in plateau pressure, 30% reduction in PO(2)/FiO(2), fourfold
      augmented bronchoalveolar lavage-retrieved volume and the increased
      polymorphonuclear leukocytes/bronchoalveolar cells' ratio associated with
      unclamping of the superior mesenteric artery. Lung tissue polymorphonuclear
      leukocytes count, total xanthine oxidase activity and wet-to-dry-weight ratio
      were also normal in these dose-treated groups. These effective regimens were also
      associated with longer animal survival. CONCLUSIONS: Intratracheal methylene blue
      mitigates lung reperfusion injury following superior mesenteric artery
      clamping/unclamping at a similar magnitude as an intravenous regimen. This
      finding is a novel potential use of methylene blue in vivo.

PMID- 15200495
TI  - Ligand-induced expression of peroxisome proliferator-activated receptor alpha and
      activation of fatty acid oxidation enzymes in fatty liver.
AB  - BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha)
      regulates lipid metabolism upon activation by ligands. Peroxisome proliferator
      activated receptor alpha may play a role in the pathogenesis of fatty liver
      disease. The aim of this study was to assess the PPARalpha expression pattern and
      mitochondrial/peroxisomal enzyme activities in response to high fat diet (HFD)
      and clofibrate, a well known PPARalpha ligand. MATERIALS AND METHODS: Four groups
      of Wistar-Albino rats were included: (1) rats fed a control diet (CD) for 6
      weeks, (2) rats fed CD (6 weeks) plus clofibrate (last 2 weeks), (3) rats fed HFD
      for 6 weeks, and (4) rats fed HFD (6 weeks) plus clofibrate (last 2 weeks).
      Peroxisome proliferator-activated receptor alpha expression was evaluated by
      immunohistochemistry. Fatty acid beta-oxidation (peroxisomal-acyl-CoA-oxidase and
      mitochondrial-acyl-CoA-dehydrogenase) and catalase enzyme activities, and
      malondialdehyde and glutathion levels were measured spectrophotometrically in
      liver tissues. RESULTS: All animals were fed HFD but only 2/12 animals were fed
      HFD plus clofibrate-developed fatty liver. Both HFD and clofibrate induced
      PPARalpha expression, clofibrate induction being more prominent than HFD.
      Clofibrate plus HFD did not further increase PPARalpha expression. Activities of
      peroxisomal-acyl-CoA-oxidase and mitochondrial-acyl-CoA-dehydrogenase enzymes
      were not induced by HFD alone. Clofibrate increased the activity of these enzymes
      in both CD- and HFD-fed animals. However, an increase of acyl-CoA-oxidase
      activity was blunted in rats fed HFD. Catalase activity and malondialdehyde
      levels were increased but glutathion levels were unchanged in rats fed HFD plus
      clofibrate. CONCLUSIONS: Clofibrate was a more potent inducer of PPARalpha
      expression than HFD in our rat fatty liver model. The finding of blunted
      peroxisomal enzyme response to clofibrate in fatty livers suggests that
      alterations in postreceptor events may exist and further contribute to liver
      steatosis. Clofibrate seems to stabilize glutathion content and this might
      contribute to the prevention of liver steatosis.

PMID- 15200497
TI  - Pregnancy-induced sympathetic overactivity: a precursor of preeclampsia.
AB  - BACKGROUND: Preeclampsia has been shown to constitute a state of sympathetic
      overactivity. However, it remains unclear if the sympathetic activity precedes
      preeclampsia or represents only a secondary phenomenon. To further investigate
      this issue, we performed a prospective study in pregnant women considered to be
      at increased risk for preeclampsia owing to preeclampsia during a preceding
      pregnancy. MATERIALS AND METHODS: Twenty-two women with a history of preeclampsia
      were longitudinally studied on three occasions: twice during pregnancy (M1: 22 +/
      4, M2: 33 +/- 5 weeks) and once postpartum (M3: 26 +/- 6 weeks postpartum). We
      measured muscle sympathetic nerve activity (MSNA), forearm blood flow, and blood
      pressure at rest and during reactive hyperaemia after forearm occlusion. RESULTS:
      At M1 and M2, none of the subjects was hypertensive, however, muscle sympathetic
      nerve activity levels were significantly augmented, compared with their
      postpartum values (M1: 21 +/- 9, M2: 29 +/- 14, M3: 9 +/- 5 bursts min(-1); P <
      0.05). Forearm vascular resistance did not significantly change from M1 through
      M3 (M1: 16 +/- 9, M2: 15 +/- 7, M3: 16 +/- 7 U; P = NS). Gestational muscle
      sympathetic nerve activity values did not differ significantly among the subjects
      with subsequent preeclampsia compared with those who remained normotensive [with
      preeclampsia (n = 6): M1: 21 +/- 5, M2: 27 +/- 6, M3: 7 +/- 4 bursts min(-1);
      without preeclampsia (n = 16): M1: 21 +/- 11, M2: 30 +/- 16, M3: 9 +/- 6 bursts
      min(-1); P = NS]. CONCLUSION: Invariably, all women at risk for preeclampisa
      showed a pregnancy-induced increase in MSNA (pregnancy-induced sympathetic
      overactivity, PISO), which normalized after delivery. Most importantly, PISO is
      not necessarily associated with peripheral vasoconstriction and hypertension.
      Furthermore, only a subset of patients developed preeclampsia later on.
      Therefore, we hypothesize that PISO constitutes a precursor of preeclampsia which
      is physiologically compensated for by vasodilating mechanisms, leading to
      preeclampsia only when they fail.

PMID- 15200498
TI  - Fabry disease defined.

PMID- 15200500
TI  - Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism.
AB  - Alzheimer's Disease (AD) is a devastating disease that affects millions of
      elderly persons. Despite years of intense investigations, genetic risk factors
      that affect the majority of AD cases have yet to be determined. Recent studies
      suggest that cholesterol metabolism has integral part in AD pathogenesis,
      suggesting that genes that regulate lipid metabolism may also play roles in AD.
      This review will first describe emerging evidence that links cholesterol to the
      mechanisms thought to underlie AD. Based on this rationale, candidate genes
      located in regions implicated in AD that have roles in lipid metabolism will then
      be discussed.

PMID- 15200504
TI  - Familial iridogoniodysgenesis and skeletal anomalies: a probable new autosomal
      recessive disorder.
AB  - Three sibs with congenital glaucoma, skeletal anomalies, and peculiar facial
      appearance were studied. At birth, enlarged eyes and corneae were present in the
      proposita and her two brothers due to congenital glaucoma secondary to
      iridogoniodysgenesis (IGD). The purpose of this article is to describe the second
      familial case with IGD and skeletal anomalies as the family previously described
      by Garcia-Cruz et al. in 1990, corroborating this new distinct dysmorphic
      syndrome with probable autosomal recessive inheritance.

PMID- 15200505
TI  - High frequency of subtelomeric rearrangements in a cohort of 92 patients with
      severe mental retardation and dysmorphism.
AB  - About 5-10% of patients with dysmorphisms, severe mental retardation, and normal
      standard karyotype are affected by subtelomeric chromosome rearrangements.
      Sequence homology between different chromosomes and variability between homologs
      make these regions more susceptible to breakage and reunion. We analyzed the
      telomeric regions of 92 of these patients, selected with strict clinical
      criteria. Fifteen individuals (16.3%) had subtelomeric rearrangements. Nine had a
      unique anomaly, which in one case had been inherited from a balanced parent. Six
      subjects had double segmental imbalances, including three de novo imbalances.
      This study provides further evidence for the plasticity of subtelomeric regions,
      which often results in cryptic rearrangements, and recommends stringent criteria
      for selecting patient candidates to telomere analysis.

PMID- 15200506
TI  - Three new families with X-linked mental retardation caused by the 428
      451dup(24bp) mutation in ARX.
AB  - Three families with X-linked mental retardation caused by a 24 base-pair
      duplication in ARX[428-451dup(24 bp)] are reported. The clinical features in
      these and six other published families are reviewed. In general, the clinical
      picture is variable. Mental retardation ranges from mild to severe. Infantile
      spasms (West syndrome) occurred in 12.5% and other less severe forms of seizures
      in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and
      dysarthria in 54%. The focal dystonia, in association with mental retardation,
      may prove to be diagnostic of this mutation.

PMID- 15200507
TI  - Molecular cytogenetic characterization of multiple intrachromosomal
      rearrangements of chromosome 2q in a patient with Waardenburg's syndrome and
      other congenital defects.
AB  - At 6 years of age, a boy with bilateral sensorineural deafness, lateral
      displacement of inner canthi, a bulbous nasal tip, synophrys, and cryptorchidism
      was clinically diagnosed as having Waardenburg's syndrome type I (WS-1). In
      addition, he had a lumbar spina bifida with hydrocephalus shunted on the second
      day of life and severe mental retardation with a head circumference at the fifth
      percentile. Neither parent showed signs of WS-1, and the family history was
      negative. Because of the WS-1 features, attention was focused on the PAX3
      location in 2q, at which time a de novo paracentric inversion of 2q23-q37.1 was
      noted. Subsequent high-resolution chromosome analysis 8 years later indicated a
      complex rearrangement involving regions 2q31-q35 and 2q13-q21. Whole chromosome
      painting and high-resolution comparative genomic hybridization yielded negative
      results for any translocation, duplication, or deletion of any chromosome
      segments. Sequencing of the PAX3 gene yielded no detectable mutation. Fluorescent
      in situ hybridization (FISH) studies with human BAC clones revealed five
      breakpoints in chromosome 2q resulting in two paracentric inversions and one
      insertion, the karyotype being interpreted as
      46,XY,der(2)inv(2)(q13q21)inv(2)(q21q24.2)ins(2)(q24.2q33q35). In this extremely
      rare chromosomal rearrangement, the FISH result showed a breakpoint at 2q35 being
      proximal to and without involvement of the PAX3 gene. While further studies
      continue, possible interpretations include involvement of a regulatory gene(s)
      for PAX 3 and other genes at the other breakpoints related causally to the spina
      bifida and mental retardation.

PMID- 15200508
TI  - New options for prenatal diagnosis in autosomal recessive polycystic kidney
      disease by mutation analysis of the PKHD1 gene.
AB  - Due to the poor prognosis of severe autosomal recessive polycystic kidney disease
      (ARPKD), there is a strong demand for prenatal diagnosis (PD). Reliable PD
      testing is possible by molecular genetic analysis only. Although haplotype-based
      analysis is feasible in most cases, it is associated with a risk of misdiagnosis
      in families without pathoanatomically proven diagnosis. Linkage analysis is
      impossible in families where DNA of the index patient is not available. Direct
      mutation analysis of the recently identified polycystic kidney and hepatic
      disease 1 gene opens new options in families to whom a reliable PD cannot be
      offered on the basis of linkage analysis. We for the first time report two cases
      with PD based on mutation detection, illustrating the new options for PD in
      ARPKD.

PMID- 15200509
TI  - De novo germline mutation in the serine-threonine kinase STK11/LKB1 gene
      associated with Peutz-Jeghers syndrome.
AB  - Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease, characterized
      phenotypically by mucocutaneous pigmentation and hamartomatous polyposis.
      Affected patients are at an increased risk of developing gastrointestinal and
      other malignancies. Mutations in the STK11/LKB1 (LKB1) gene, which encodes for a
      serine-threonine kinase, have been identified as a genetic cause of PJS.
      Molecular analysis of the LKB1 gene in a simplex case of PJS revealed a
      substitution of cytosine (C) for guanine (G) at codon 246 in exon 6, resulting in
      the Tyr246X mutation. The nucleotide substitution leads to a premature stop codon
      at the 246 residue, predicting a truncated protein and presumed loss of kinase
      activity. Analysis of DNA from both parents of the PJS patient did not show this
      mutation, which is therefore a de novo mutation. We isolated DNA from
      microdissected gastrointestinal hamartomatous polyps in the PJS patient and
      investigated the loss of heterozygosity (LOH) at the LKB1 locus by real-time
      fluorescence polymerase chain reaction genotyping using a fluorescent resonance
      energy transfer technique. The results suggest a different mechanism from LOH in
      the formation of hamartomatous polyps.

PMID- 15200510
TI  - Association of parental consanguinity with congenital malformations among Arab
      newborns in Jerusalem.
AB  - The aim of this work was to determine the impact of parental consanguinity on
      congenital malformations in a mixed urban and rural Arab community in Jerusalem,
      Israel. Arab mothers admitted to four hospitals in west Jerusalem were
      interviewed after delivery. Demographic and obstetric data were recorded.
      Neonatal data were extracted from the medical records of the nursery. When
      malformations were suspected, a 4- to 10-month follow up was achieved for
      confirming the diagnosis. Of 561 infants, 253 (45%) were born to consanguineous
      couples. The incidence of major congenital malformations in the offspring was
      8.7, 7.1 and 2.6% in cases of first cousins, all consanguineous, and non
      consanguineous couples, respectively. No association was found between parental
      consanguinity and prematurity (p = 0.357) or low birth weight (p = 0.589).
      Parental consanguinity was also associated with an increased incidence of death
      in previous siblings (p < 0.000). The increased incidence of congenital
      malformations and infant mortality in cases of inbreeding prompt the necessity of
      establishing programs to avoid these complications in the offspring.

PMID- 15200511
TI  - Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two
      familial delta-like 3 mutations.
AB  - Spondylocostal dysostoses (SCD) are a heterogeneous group of disorders of axial
      skeletal malformation characterized by multiple vertebral segmentation defects
      and rib anomalies. Sporadic cases with diverse phenotypes, sometimes including
      multiple organ abnormalities, are relatively common, and monogenic forms
      demonstrating autosomal recessive (AR) and, more rarely, autosomal dominant (AD)
      inheritance have been reported. We previously showed that mutations in delta-like
      3 (DLL3), a somitogenesis gene that encodes a ligand for the notch signaling
      pathway, cause AR SCD with a consistent pattern of abnormal segmentation. We
      studied an SCD family previously reported to show AD inheritance, in which the
      phenotype is similar to that in AR cases. Direct DLL3 sequencing of individuals
      in two generations identified the affected father as homozygous for a novel
      frameshift mutation, 1440delG. His two affected children were compound
      heterozygotes for this mutation and a novel missense mutation, G504D, the first
      putative missense mutation reported in the transmembrane domain of DLL3. Their
      two unaffected siblings were heterozygotes for the 1440delG mutation.
      Pseudodominant inheritance has been confirmed, and the findings raise potential
      consequences for genetic counseling in relation to the SCD disorders.

PMID- 15200512
TI  - Localization of a novel locus for hereditary nail dysplasia to chromosome 17q25.1
      17q25.3.
AB  - We report on a six-generation Pakistani consanguineous family with autosomal
      recessive transmission of a form of hereditary nail dysplasia. Affected
      individuals presented with onycholysis of fingernails and anonychia of toenails.
      Associated abnormalities of ectodermal appendages were not observed in any of the
      affected individuals. Linkage has been established to chromosome 17q. A maximum
      multipoint analysis logarithm of the odds ratio score of 4.85 was obtained at
      marker D17S1301. Due to the consanguineous nature of this kindred, the gene for
      nail dysplasia is probably contained within a 5.0-cM (3 MB on the sequence-based
      physical map) region of homozygosity flanked by markers D17S1807 and D17S937.

PMID- 15200513
TI  - Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable
      expression of a single genetic disorder.

PMID- 15200516
TI  - Solutions for rural Mental Health Services.

PMID- 15200517
TI  - Advance Australia fairly.

PMID- 15200518
TI  - Evaluation of an after hours telephone support service for rural palliative care
      patients and their families: A pilot study.
AB  - OBJECTIVE: To report on the introduction and evaluation of an after hours
      telephone support service for palliative care patients and their families at
      home. DESIGN: Descriptive evaluation using an audit of telephone logbook, text
      analysis of reflective journals, questionnaire and interviews. SETTING:
      Palliative care call service in Grafton, New South Wales, Australia. SUBJECTS:
      The participants were health professionals using the Palliative Care Service in
      Grafton (48 in total) and nurses providing the palliative care service (21 in
      total). RESULTS: Twelve calls were taken by the nurses during the pilot study.
      Three major themes emerged from the analysis: preparation involving publishing
      the after hours telephone support service (AHTSS) and nurse workshop; benefits
      such as support to families and health service resourcing; and nurses'
      experiences regarding personal impact and building support for each other.
      CONCLUSION: It appears from the evaluation responses of health professionals and
      nurses that knowing the service was there was a great security and reduced the
      sense of isolation predominant in the experience of rural families caring for a
      palliative care patient at home. Based on the positive evaluation, the area
      health service provided ongoing funding for the service and is exploring avenues
      to extend the program into other areas. The service now requires a re-evaluation
      at 18 months and will form the second phase of the study that is currently being
      organised.

PMID- 15200519
TI  - Anangu oral health: the status of the Indigenous population of the Anangu
      Pitjantjatjara lands.
AB  - OBJECTIVE: To describe oral health in the Anangu Pitjantjatjaraku lands in South
      Australia and to compare with earlier surveys and national data. DESIGN:
      Descriptive. SETTING: Data were collected at the time of dental care service
      provision, according to World Health Organization protocols, at the request of
      the Nganampa Health Council on optical mark reader forms. PARTICIPANTS: There
      were 356 Anangu adults and 317 children surveyed. RESULTS: The mean number of
      teeth affected by dental caries in the deciduous dentition in young children,
      aged 5-6 years, was double (mean 3.20) that of the overall Australian child
      population aged 5-6 years (mean 1.44). In contrast to the decline in deciduous
      caries in Australian children generally, Anangu children aged 5-9 years had a 42%
      increase in the mean number of teeth affected since 1987. Adults experienced low
      levels of dental caries, but severe periodontal disease was more prevalent among
      diabetics (79%) compared with-non-diabetics (13.8%). Tooth loss was found more
      frequently among adults with diabetes (mean 5.51) than non-diabetics (mean 1.53).
      CONCLUSIONS: Oral health promotion strategies, in association with general health
      strategies, need to be developed to improve oral health in this remote Aboriginal
      population.

PMID- 15200520
TI  - Experiences of Organization for Economic Cooperation and Development countries
      with recruiting and retaining physicians in rural areas.
AB  - OBJECTIVE: This present study discusses the potential pitfalls in measuring
      physician shortages in rural areas and presents existing evidence of the
      effectiveness of policy interventions designed to influence the geographical
      distribution of physicians. DESIGN: Information on the geographical distribution
      of physicians was derived from a survey of Organization for Economic Cooperation
      and Development (OECD) countries and a desk review of the academic literature and
      policy documents of OECD governments. MAIN OUTCOME MEASURE: Whether policies have
      been effective in recruiting and retaining physicians in rural areas. RESULTS:
      Existing measures of physician shortages in rural areas may be misleading as they
      do not account for a number of supply side factors (e.g. physician productivity,
      mobility of physicians across areas) and demand-side factors (e.g. patient needs
      for physician services). Increases in the national number of physicians have
      narrowed, but not eliminated, shortages in rural areas. Some success in
      increasing physician supply to rural areas has been reported with educational,
      regulatory and financial policies; whereas countries' experiences with education
      related funding policies are mixed. There is some evidence suggesting that the
      effectiveness of these policies can be enhanced by supporting occupational
      opportunities for the spouse/partner, education of children and accommodation.
      CONCLUSIONS: Although there has been little evaluation of policy interventions,
      physician shortages in rural areas may be reduced by supply side policies that
      focus on the physician in combination with measures to sustain the economic and
      social viability of rural communities.

PMID- 15200521
TI  - General practice in Greece: a student's and supervisor's perspective.
AB  - OBJECTIVE: The present study reports the observations of an Australian medical
      student, his reflections on these observations and commentary from the Greek
      supervisor. SETTING: One urban General Practice at the University Hospital in
      Heraklion, Crete and three community health centres in rural Crete. MAIN OUTCOME
      MEASURES: Points of comparison were formed during the patient's consultations and
      clinical investigations. RESULTS: Although the level of knowledge and GP's
      competence in Crete and New South Wales appear to be similar and there is an
      impression that the patient satisfaction in Greece is comparable to that in
      Australia, a striking feature in Greek primary care is the communication between
      practitioner and patient, as well as the poor level of note keeping. In contrast,
      Primary Care in Greece seems to be far more involved in research. CONCLUSION: To
      attain a higher quality in primary care, leading to a better outcome for the
      people of Greece, the primary care physicians need more effective vocational
      training and the appropriate support from health authorities.

PMID- 15200522
TI  - Hearing loss and perceptions of noise in the workplace among rural Australians.
AB  - OBJECTIVE: To compare measured hearing levels of individuals regularly exposed to
      noise in their workplace to self-reported and family-reported hearing loss. To
      compare the attitudes and preventative actions adopted by individuals who are
      more aware of the potential for hearing loss to less aware individuals. DESIGN:
      The project examined the perceptions of rural workers concerning noise, noise
      exposure and hearing. The subjects completed a 'Noise at Work' questionnaire and
      some demographic data at the time of audiometric testing. SETTING: The subjects
      were recruited when attending their rural health clinic for audiometric testing.
      PARTICIPANTS: Participants comprised 113 men and 23 women (20-65 years, mean =
      39.6, SD = 11.4) working across a range of activities at different levels in
      their workplaces. The range in current employment was from 0.5 to 45 years (mean
      = 13.8, SD = 10.7). RESULTS: Hearing tests were compared with perceptions of
      noise annoyance, hearing damage risk and preventative action. Self- and family
      reported hearing loss and conversational difficulties in noise correlated well
      with measured audiograms. Perceptions of workplace noise tended to be more
      positive if people felt they had hearing problems. There was no difference in
      preventative action between those who did and did not feel they had hearing
      problems. Both groups rated barriers to action and lack of self-efficacy in a
      similar negative way. CONCLUSIONS: There is a need for specific training to
      ensure that rural workers have skills to take more positive action in reducing
      noise exposure at work.

PMID- 15200523
TI  - Stress, burnout and job satisfaction in rural psychiatric nurses: a Victorian
      study.
AB  - OBJECTIVE: To measure the level of stress, burnout and job satisfaction in rural
      psychiatric nurses in Victoria, Australia. METHOD: This present study presents
      the findings of a research study undertaken with rural psychiatric nurses (n =
      136) in two rural mental health services in Victoria. The study designed to
      measure their level of stress, burnout and job satisfaction using the Maslach
      Burnout Inventory (MBI), the Nursing Stress Scale (NSS) and Job Satisfaction
      Scale (JSS). RESULTS: The findings indicated that a low number rural psychiatric
      nurses suffered from 'high' level of burnout and the majority of nurses reported
      'low level' of emotional exhaustion and depersonalisation scores. On the personal
      accomplishment subscale, only 11% recorded a 'high' score and 87% recorded 'low'
      score. On the Nursing Stress Scale, the 'workload' was the highest perceived
      stressor followed by 'inadequate preparation'. CONCLUSIONS: Paradoxically, the
      majority of rural psychiatric nurses stated that they were satisfied with their
      job, particularly with current situation at work, aspects of support and the
      level of involvement in decision making.

PMID- 15200524
TI  - Cancer inpatients morphine usage: a New England survey.

PMID- 15200527
TI  - Brave little palaeontologist in the making.

PMID- 15200528
TI  - Nutrition matters for cancer.

PMID- 15200534
TI  - Difficult airways - difficult decisions: guidelines for publication?

PMID- 15200535
TI  - Risks and benefits of long-term intrathecal analgesia.

PMID- 15200536
TI  - Propofol sedation using Diprifusor target-controlled infusion in adult intensive
      care unit patients.
AB  - This multicentre, non-comparative study investigated the range of target blood
      propofol concentrations required to sedate 122 adult intensive care patients when
      propofol was administered using Diprifusor target-controlled infusion systems
      together with opioid analgesia. Depth of sedation was assessed with a modified
      Ramsay score and the target blood propofol setting was adjusted to achieve the
      sedation desired for each patient. A desired level of sedation was achieved for
      84% of the sedation period. In postcardiac surgery patients the median time
      weighted average propofol target setting was 1.34 microg.ml(-1) (10th - 90th
      percentiles: 0.79-1.93 microg.ml(-1)). Values in brain injured and general ICU
      patients were 0.98 (10th - 90th percentiles: 0.60-2.55) microg.ml(-1) and 0.42
      (10th - 90th percentiles: 0.16-1.19) microg.ml(-1), respectively. Measured
      propofol concentrations were generally close to values predicted by the
      Diprifusor system. Target settings in the range of 0.2-2.0 microg.ml(-1) are
      proposed for propofol sedation in this setting with titration as required in
      individual patients.

PMID- 15200537
TI  - Ultrasound guidance for infraclavicular brachial plexus anaesthesia in children.
AB  - Ultrasonography may offer significant advantages in regional anaesthesia of the
      upper and lower limbs. It is not known if the same advantages demonstrated in
      adults also apply to children. We therefore performed a prospective, randomised
      study comparing ultrasound visualisation to conventional nerve stimulation for
      infraclavicular brachial plexus anasesthesia in children. Forty children
      scheduled for arm and forearm surgery underwent infraclavicular brachial plexus
      blocks with ropivacaine 0.5 ml.kg(-1) guided by either nerve stimulation or
      ultrasound visualisation. Evaluated parameters included sensory block quality,
      sensory block distribution and motor block. All surgical procedures were
      performed under brachial plexus anaesthesia alone. Direct ultrasound
      visualisation was successful in all cases and was associated with significant
      improvements when compared with the use of nerve stimulation: lower visual
      analogue scores during puncture (p = 0.03), shorter mean (median) sensory onset
      times (9 (5-15) min vs. 15 (5-25) min, p < 0.001), longer sensory block durations
      (384 (280-480) min vs. 310 (210-420) min, p < 0.001), and better sensory and
      motor block scores 10 min after block insertion. Ultrasound visualisation offers
      faster sensory and motor responses and a longer duration of sensory blockade than
      nerve stimulation in children undergoing infraclavicular brachial plexus blocks.
      In addition, the pain associated with nerve stimulation due to muscle
      contractions at the time of insertion is eliminated.

PMID- 15200538
TI  - Prevention of postoperative sore throat using capsicum plaster applied at the
      Korean hand acupuncture point.
AB  - In a randomised, double-blind, sham-controlled study, we compared the efficacy of
      capsicum plaster (PAS) applied at the Korean hand acupuncture point for the
      prevention of postoperative sore throat in 150 patients scheduled to undergo
      abdominal hysterectomy. The K group had PAS applied at the K-A20 of both hands
      and placebo tape at both non-acupoints. The PAS was applied prior to induction of
      anaesthesia and removed 8 h postoperatively. The sore throat scores of Group K
      were significantly lower than those of other groups at 24 h following surgery (p
      = 0.00027). The prevalence of moderate to severe sore throat at 24 h was lower
      for Group K (0%) than for sham and placebo controls (16%[p = 0.038] and 19%[p =
      0.032], respectively). There were no differences in the recovery room of the sore
      throat scores for all groups. We found that the PAS applied at the K-A20 was an
      alternative method for reducing postoperative sore throat.

PMID- 15200539
TI  - The effects of tracheostomy cuff deflation during continuous positive airway
      pressure.
AB  - Continuous flow positive pressure devices bridge the gap between mechanical and
      unsupported ventilation in patients recovering from critical illness. At this
      point, patients are often fully awake, yet the inflated tracheostomy cuff
      prevents them from speaking or swallowing. The aim of this study was to
      investigate the effects of cuff deflation. After ethics committee approval and
      informed consent, we recorded airway pressures with catheters placed 3 cm beyond
      the distal tracheostomy tip, respiratory rate, heart rate and peripheral oxygen
      saturation with continuous positive airway pressures set at 5, 7.5 and 10 cmH(2)O
      with the cuff inflated and deflated. Sixteen patients completed the study. There
      were small falls in end expiratory pressure on cuff deflation. The median
      (interquartile range) pressure drop with set airway pressure of 5 cmH(2)O was
      0.25 (0-1.4) mmHg, which increased to 1 (0-3) mmHg at 7.5 cmH(2)O and 1.5 (0-4)
      mmHg at 10 cmH(2)O. These changes were not clinically significant and
      cardiopulmonary parameters remained stable. All patients were able to vocalise
      following cuff deflation. Twelve patients passed a blue dye swallow screen within
      a day of tolerating cuff deflation. These results suggest that pressures fall
      slightly following cuff deflation but this is associated with respiratory
      stability and may allow patients to talk and swallow.

PMID- 15200540
TI  - Handover of responsibility for the anaesthetised patient - opinion and practice.
AB  - Anaesthesia is a critical and complex process that extends from the pre-operative
      assessment through to the postoperative management of patients. Handover of
      responsibility for logistical as opposed to patient-orientated reasons may
      compromise that process of care. If such handover becomes inevitable with shift
      based patterns of working, the implications need to be considered and procedures
      developed in order to minimise adverse consequences. This survey of national
      practice reveals little formalisation of procedure and a spectrum of opinion on
      the relevance of the key considerations. There is, however, a majority view
      amongst respondents that national guidelines would be of value and that
      professional defensibility would be aided by standardisation and documentation of
      any handover.

PMID- 15200541
TI  - Evaluation of a local anaesthesia regimen following mastectomy.
AB  - Breast surgery can be emotionally distressing and physically painful. Acute pain
      following surgery is often related mainly to the axillary surgery and is
      aggravated by arm and shoulder movement. We conducted a prospective double-blind,
      randomised, placebo-controlled trial to determine the influence of local
      anaesthetic irrigation of axillary wound drains on postoperative pain during the
      first 24 h following a modified Patey mastectomy (mastectomy with complete
      axillary node clearance). The treatment group received bupivacaine irrigation
      through the axillary wound drain 4-hourly for 24 h postoperatively. Controls
      received irrigation with normal saline. Morphine via a patient controlled
      analgesia pump was used for postoperative analgesia. Morphine consumption, visual
      analogue and verbal rating pain scores were recorded. There were no statistical
      differences in morphine requirements or pain scores between the two groups, nor
      were there differences in anti-emetic or supplemental analgesic consumption.
      Bupivacaine irrigation used in this manner does not appear to offer an effective
      contribution to postoperative analgesia.

PMID- 15200542
TI  - A comparison of the intubating laryngeal mask airway and the Bonfils intubation
      fibrescope in patients with predicted difficult airways.
AB  - Tracheal intubation with the intubating laryngeal mask airway or the Bonfils
      intubation fibrescope was performed in 80 patients with predicted difficult
      airways. Mallampati score, thyromental distance, mouth opening and mobility of
      the atlanto-occipital joint were used to predict difficult airways. The overall
      success rate, time to the first adequate lung ventilation and time taken for the
      successful placement of the tracheal tube were recorded, as well as a subjective
      assessment of the handling of the device and the incidence of postoperative sore
      throat and hoarseness. The median [range] time to the first adequate ventilation
      was significantly shorter with the intubating laryngeal mask airway than with the
      Bonfils intubation fibrescope (28 [6-85] s vs. 40 [23-77] s, p < 0.005). Tracheal
      intubation was significantly slower with the intubating laryngeal mask airway
      than with the Bonfils intubation fibrescope (76 [45-155] s vs. 40 [23-77] s, p <
      0.0001. Patients in the Bonfils group suffered less sore throat and hoarseness
      than those in the other group.

PMID- 15200544
TI  - Mast cell tryptase: a review of its physiology and clinical significance.
AB  - Mast cells, which are granulocytes found in peripheral tissue, play a central
      role in inflammatory and immediate allergic reactions. beta-Tryptase is a neutral
      serine protease and is the most abundant mediator stored in mast cell granules.
      The release of beta-tryptase from the secretory granules is a characteristic
      feature of mast cell degranulation. While its biological function has not been
      fully clarified, mast cell beta-tryptase has an important role in inflammation
      and serves as a marker of mast cell activation. beta-Tryptase activates the
      protease activated receptor type 2. It is involved in airway homeostasis,
      vascular relaxation and contraction, gastrointestinal smooth muscle activity and
      intestinal transport, and coagulation. Serum mast cell beta-tryptase
      concentration is increased in anaphylaxis and in other allergic conditions. It is
      increased in systemic mastocytosis and other haematological conditions. Serum
      beta-tryptase measurements can be used to distinguish mast cell-dependent
      reactions from other systemic disturbances such as cardiogenic shock, which can
      present with similar clinical manifestations. Increased beta-tryptase levels are
      highly suggestive of an immunologically mediated reaction but may also occur
      following direct mast cell activation. Patients with increased mast cell beta
      tryptase levels must be investigated for an allergic cause. However, patients
      without increased mast cell tryptase levels should be investigated if the
      clinical picture suggests severe anaphylaxis.

PMID- 15200543
TI  - Difficult Airway Society guidelines for management of the unanticipated difficult
      intubation.
AB  - Problems with tracheal intubation are infrequent but are the most common cause of
      anaesthetic death or brain damage. The clinical situation is not always managed
      well. The Difficult Airway Society (DAS) has developed guidelines for management
      of the unanticipated difficult tracheal intubation in the non-obstetric adult
      patient without upper airway obstruction. These guidelines have been developed by
      consensus and are based on evidence and experience. We have produced flow-charts
      for three scenarios: routine induction; rapid sequence induction; and failed
      intubation, increasing hypoxaemia and difficult ventilation in the paralysed,
      anaesthetised patient. The flow-charts are simple, clear and definitive. They can
      be fully implemented only when the necessary equipment and training are
      available. The guidelines received overwhelming support from the membership of
      the DAS. DISCLAIMER: It is not intended that these guidelines should constitute a
      minimum standard of practice, nor are they to be regarded as a substitute for
      good clinical judgement.

PMID- 15200545
TI  - The 'fixed performance' venturi: effect of downstream pressure on outflow and
      FIO2.
AB  - Fixed performance venturi devices should provide a predetermined oxygen
      concentration at an outflow which exceeds an adult's peak resting inspiratory
      flow rate (approximately 30 l.min(-1)). Campbell's original description mentioned
      the sensitivity of the venturi device to downstream resistance but gave no
      further details. This study examined outflow and oxygen concentration from the
      five standard venturi devices (24-60% O(2)) when downstream pressure increased.
      Outflow was exquisitely sensitive to small increases in pressure. The outflow at
      zero downstream pressure for the 24-40% O(2) venturi devices ranged from 40 to 50
      l.min(-1) but only 2-3 mmH(2)O was needed to halve this flow and increase oxygen
      concentration. The 60% O(2) venturi delivered a maximum of only 30 l.min(-1) at
      zero downstream pressure and flow was reduced further by increasing this
      pressure. An increase in downstream pressure of only a few mmH(2)O increased
      oxygen concentration and decreased outflow of all the venturi devices tested, in
      most to less than normal peak tidal flow in adults.

PMID- 15200546
TI  - Performance of an oxygen delivery device for weaning potentially infectious
      critically ill patients.
AB  - Oxygen delivery via a heat and moisture exchange filter with an attached T-shaped
      reservoir satisfies infection control requirements of high efficiency bacterial
      and viral filtration and low gas flows. In order to assess the performance of
      such a device in critically ill patients being weaned from mechanical
      ventilation, we simulated 16 patients using a human patient simulator, measuring
      fractional inspired oxygen and carbon dioxide concentrations and work of
      breathing at three oxygen flow rates. Oxygen concentration was dependent on peak
      inspiratory flow rate, tidal volume and oxygen flow rate. Rebreathing, as
      indicated by inspired carbon dioxide concentration, was greatest at high
      respiratory rates and low tidal volumes. Imposed inspiratory work of breathing
      was relatively high (mean 0.88 J.l(-1)[SD 0.30]). We conclude that this method of
      oxygen delivery is only suitable for patients in whom rapid extubation is
      anticipated.

PMID- 15200547
TI  - Abdominal muscle action during expiration can impair pressure controlled
      ventilation.
AB  - Pressure controlled ventilation, and pressure support for spontaneous breathing
      are often used in intensive care because coordination of the ventilator with
      patient efforts can improve comfort and possibly reduce sedation. However we
      report a series of 10 patients whose efforts did not synchronise with pressure
      controlled ventilation. This was incorrectly diagnosed as inadequate sedation,
      and treated with increased sedation or muscle paralysis. Better recognition of
      this condition showed that slow respiratory rates and increased abdominal muscle
      action during expiration can affect pressure-controlled ventilation and pressure
      assisted breathing. If the condition is not recognised, treatment for poor
      synchronisation may delay weaning or be inappropriate.

PMID- 15200548
TI  - Filters and small infants.

PMID- 15200549
TI  - Less caps, less connecting and instant monitoring.

PMID- 15200550
TI  - Change of datasheet for ketorolac.

PMID- 15200551
TI  - Algorithm for entropy monitor.

PMID- 15200552
TI  - Percutaneous tracheostomy and Creutzfeldt-Jakob Disease.

PMID- 15200554
TI  - Incorrectly placed oesophageal Doppler probe.

PMID- 15200553
TI  - Thoracic paravertebral block for breast surgery.

PMID- 15200555
TI  - An unusual cause of excessive bleeding in a neurosurgical patient.

PMID- 15200556
TI  - Ultrasound guided 'low approach' femoral vein cannulation.

PMID- 15200557
TI  - One-lung ventilation using the ProSeal laryngeal mask airway.

PMID- 15200558
TI  - ProSeal LMA aids orogastric tube insertion with a tracheal tube in place.

PMID- 15200559
TI  - Use of the laryngeal mask airway in nasally intubated patients.

PMID- 15200560
TI  - An aid to difficult venous cannulation.

PMID- 15200561
TI  - Dystonic reaction following anaesthesia.

PMID- 15200562
TI  - Conversion reaction following anaesthesia.

PMID- 15200563
TI  - Decreasing epidural failure.

PMID- 15200565
TI  - A response to 'A rare side-effect of intravenous salbutamol', Girgis M and Milner
      Q, Anaesthesia 2004; 59: 196-7.

PMID- 15200566
TI  - A response to 'Acupuncture compared to placebo-acupuncture for postoperative
      nausea and vomiting prophylaxis: A randomised placebo-controlled patient and
      observer blind trial', Streitberger K, Diefenbacher M, Bauer A et al. Anaesthesia
      2004; 59: 142-9.

PMID- 15200567
TI  - A response to 'Pre-preparation of succinylcholine: significant waste for
      questionable benefit', Gurung A M and Tomlinson A A, Anaesthesia 2004; 59: 211-2.

PMID- 15200568
TI  - A response to 'Pressures within air-filled tracheal cuffs at altitude - an in
      vivo study', Henning J, Sharley P and Young R, Anaesthesia 2004; 59: 252-4.

PMID- 15200569
TI  - A response to 'Angiotensin-converting enzyme inhibitor related angioedema and the
      anaesthetist', Rai M R, Amen F and Idrees F, Anaesthesia 2004; 59: 283-9.

PMID- 15200571
TI  - A response to 'Another look at Dumfries', Martin L V H, Anaesthesia 2004; 59: 180
      7.

PMID- 15200573
TI  - A response to 'Masseter muscle spasm following atracurium', Reddy K & Bromley L,
      Anaesthesia 2004; 59: 513.

PMID- 15200574
TI  - The globalization of drug injecting.

PMID- 15200575
TI  - The importance and difficulty of drug research in developing countries: a report
      from Kabul as timely reminder.

PMID- 15200576
TI  - Conversation with Tomoji Yanagita.

PMID- 15200577
TI  - Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol
      dependence: a systematic review.
AB  - AIMS: To ascertain the efficacy and safety of naltrexone and acamprosate in the
      treatment of alcohol dependence. METHODS: Systematic review of the literature
      (1990-2002) and meta-analysis of full published randomized and controlled
      clinical trials assessing acamprosate or naltrexone therapy in alcohol
      dependence. Estimates of effect were calculated according to the fixed-effects
      model. MEASUREMENTS: Relapse and abstinence rates, cumulative abstinence duration
      and treatment compliance were considered as primary outcomes. Findings Thirty
      three studies met the inclusion criteria. Acamprosate was associated with a
      significant improvement in abstinence rate [odds ratio (OR): 1.88 (1.57, 2.25), P
      < 0.001] and days of cumulative abstinence [WMD: 26.55 (17.56, 36.54]. Short-term
      administration of naltrexone reduced the relapse rate significantly [OR: 0.62
      (0.52, 0.75), P < 0.001], but was not associated with a significant modification
      in the abstinence rate [OR: 1.26 (0.97,1.64), P = 0.08]. There were insufficient
      data to ascertain naltrexone's efficacy over more prolonged periods. Acamprosate
      had a good safety pattern and was associated with a significant improvement in
      treatment compliance [OR: 1.29 (1.13,1.47), P < 0.001]. Naltrexone's side effects
      were more numerous, yet the drug was nevertheless tolerated acceptably without
      being associated with a lower adherence to treatment (OR: 0.94 (0.80, 1.1), P =
      0.5). However, overall compliance was relatively low with both medications.
      CONCLUSIONS: Both acamprosate and naltrexone are effective as adjuvant therapies
      for alcohol dependence in adults. Acamprosate appears to be especially useful in
      a therapeutic approach targeted at achieving abstinence, whereas naltrexone seems
      more indicated in programmes geared to controlled consumption. Both drugs are
      safe and acceptably tolerated but issues of compliance need to be addressed
      adequately to assure their usefulness in clinical practice.

PMID- 15200578
TI  - Ten-year patterns of alcohol consumption and drinking problems among older women
      and men.
AB  - AIMS: This study focused on changes in 10-year patterns of alcohol consumption
      among older women and men, late-life and life history predictors of drinking
      problems, and gender differences in these predictors. DESIGN, SETTING,
      PARTICIPANTS: A sample of late-middle-aged community residents (N = 1291) who had
      consumed alcohol in the past year or shortly before was surveyed at baseline and
      1 year, 4 years and 10 years later. MEASUREMENTS: At each contact point,
      participants completed an inventory that assessed their alcohol consumption,
      drinking problems and health-related and life context factors. Participants also
      provided information about their life history of drinking. RESULTS: Over the 10
      years, the proportion of individuals who consumed alcohol declined. Among
      individuals who continued to drink, women and men showed comparable declines in
      alcohol consumption, minor concomitants of alcohol consumption and drinking
      problems. In addition to the amount of alcohol consumption, smoking, friends'
      approval of drinking and avoidance coping consistently predicted late-life
      drinking problems. With respect to life history factors, heavy drinking, drinking
      problems and increased drinking in response to life events were related to a
      higher likelihood of late-life drinking problems; obtaining help from family
      members and friends and, among men, participation in Alcoholics Anonymous, were
      related to a lower likelihood of problems. CONCLUSION: Older women and men show
      comparable declines in alcohol consumption and drinking problems. Specific late
      life social context and coping variables, and life history indices, are risk
      factors for late-life drinking problems among both women and men.

PMID- 15200579
TI  - The effects on mortality of brief interventions for problem drinking: a meta
      analysis.
AB  - AIMS: Brief interventions for problem drinking may result in decreased mortality
      rates. Long-term follow-up studies of brief interventions do not produce a clear
      answer to the question as to whether these interventions reduce mortality or not.
      METHODS: We conducted a meta-analysis of randomized studies comparing brief
      interventions with a control group, using the fixed-effects model. A systematic
      literature search produced four studies in which the mortality status of subjects
      was verified at follow-up. Six more studies reported some deaths at follow-up but
      did not verify mortality in death registers, and 22 further studies did not
      report the mortality status of the included subjects. FINDINGS: The pooled
      relative risk (RR) of dying was 0.47 for the four studies with verified mortality
      rates (95% CI: 0.25, 0.89). The pooled RR of all 32 studies was comparable (RR =
      0.57; 95% CI: 0.38, 0.84), as were the RRs of several other subsamples of
      studies. The prevented fraction was 0.33 in the studies with verified mortality
      rates. CONCLUSIONS: Although the overall death rate was low in the population of
      problem drinkers, brief interventions do appear to reduce mortality.

PMID- 15200580
TI  - Overdose deaths attributed to methadone and heroin in New York City, 1990-1998.
AB  - AIMS: Methadone treatment has been shown to be an effective intervention that can
      lower the risk of heroin-induced overdose death. Recent reports have suggested
      increases in methadone-induced overdose deaths in several locations in the USA
      and in Europe. This study investigated the role of methadone and opiates in
      accidental overdose deaths in New York City. DESIGN: We analysed data from the
      Office of the Chief Medical Examiner to examine all accidental drug overdose
      deaths in New York City between 1990 and 1998. FINDINGS: Of 7451 total overdose
      deaths during this period, there were 1024 methadone-induced overdose deaths,
      4627 heroin-induced overdose deaths and 408 overdose deaths attributed to both
      methadone and heroin. Fewer than a third as many accidental overdose deaths were
      attributed to methadone than were attributed to heroin during this period. The
      proportion of accidental overdose deaths attributed to methadone did not change
      appreciably (12.6-15.8% of total overdose mortality), while the proportion of
      overdose deaths attributed to heroin increased significantly (53.5-64.2%) during
      the period of study. CONCLUSIONS: There was no appreciable increase in methadone
      induced overdose mortality in New York City during the 1990s. Both heroin-induced
      overdose mortality and prescriptions of methadone increased during the same
      interval.

PMID- 15200581
TI  - Risk-sensitive foraging theory elucidates risky choices made by heroin addicts.
AB  - AIM: The behavioral process of risk-sensitive foraging (RSF) specifies that the
      level of satiation or deprivation determines choice between a constant and
      variable quantity of food. Specifically, RSF stipulates that organisms
      experiencing satiation and deprivation prefer constant (risk-averse) and variable
      (risk-prone) choices, respectively. The relevance of this behavioral process to
      risky choices of opioid-dependent patients is examined in this study. METHODS:
      Thirty adult opioid-dependent out-patients made hypothetical choices between
      constant and variable heroin sources with equivalent means. Preferences for
      constant (e.g. three bags of heroin) and variable heroin sources (e.g. on average
      produces three bags of heroin, but vary from one to five bags of heroin on any
      instance) were assessed using questionnaires that manipulated the amount, delay
      to receipt and drug potency of heroin across approximately 20 levels. Subjects
      made choices between constant and variable options after hearing scripts
      describing the signs and symptoms of opioid satiation and opioid deprivation.
      RESULTS: Consistent with the prediction of RSF, subjects purchased significantly
      more hypothetical heroin from a variable source when exposed to an opioid
      deprived script than an opioid-satiated script. This pattern was observed across
      manipulations of heroin amount, delay to receipt of heroin and heroin potency.
      Selection of the variable option increased as a function of magnitude under the
      deprived conditions. The selection of the variable option generally did not
      increase as a function of magnitude under the satiated conditions except when
      delay to heroin delivery increased. As delay increased, selection of the variable
      option increased under the satiated script, but at a lower level observed with
      the deprived script. CONCLUSIONS: These data suggest that risky choices of heroin
      dependent individuals can be understood and predicted with the application of RSF
      theory. This research suggests that an evolutionarily old behavioral process may
      contribute to the risky behavior of the drug-dependent.

PMID- 15200582
TI  - Motivational enhancement and coping skills training for cocaine abusers: effects
      on substance use outcomes.
AB  - AIMS: This clinical trial investigated effects of motivational enhancement
      treatment (MET) and group coping-skills training (CST) tailored for cocaine
      dependence. Effects of MET were hypothesized to be greater with CST and for less
      motivated patients. DESIGN AND INTERVENTIONS: A 2 x 2 design investigated two
      individual sessions of MET compared to meditation-relaxation (MRT), followed by
      four group sessions of CST versus drug education (ED), as daily adjuncts to
      intensive treatment. SETTING: The substance abuse program provided full-day
      treatment with a learning-theory and 12-Step orientation. PARTICIPANTS: Cocaine
      dependent patients were recruited. MEASUREMENTS: Assessment included treatment
      retention; change in cocaine-related urge, self-efficacy, pros and cons, and
      motivation; substance use and problems during 12-month follow-up. Findings Of 165
      patients, follow-up status is known for 90% (n = 149). Patients in MET with low
      initial motivation to change reported less cocaine and alcohol relapse and use
      days and fewer alcohol problems than MET patients with higher initial motivation.
      MET produced more employment improvement than MRT, with no other significant
      benefit for MET. Patients with higher motivation had more cocaine use and alcohol
      problems after MET than MRT. Group CST reduced cocaine and alcohol use during
      follow-up for women only and reduced alcohol relapse for men and women.
      CONCLUSIONS: MET is more beneficial for patients with lower initial motivation
      than for patients with high initial motivation. CST reduced cocaine and alcohol
      use for women only and reduced alcohol relapses, in contrast to results with
      lengthier individual CST.

PMID- 15200583
TI  - Drug use patterns and mental health of regular amphetamine users during a
      reported 'heroin drought'.
AB  - AIMS: The present study extends the findings of a pilot study conducted among
      regular amphetamine users in Newcastle, NSW, in 1998. It compares key features
      between current participants in a state capital city (Brisbane) and a regional
      city (Newcastle) and between the 1998 and current Newcastle sample. DESIGN: Cross
      sectional survey. Setting Brisbane and Newcastle, Australia. PARTICIPANTS: The
      survey was conducted among 214 regular amphetamine users within the context of a
      randomized controlled trial of brief interventions for amphetamine use.
      MEASUREMENTS: Demographic characteristics, past and present alcohol and other
      drug use and mental health, treatment, amphetamine-related harms and severity of
      dependence. FINDINGS: The main findings were as follows: (i). the rate of mental
      health problems was high among regular amphetamine users and these problems
      commonly emerged after commencement of regular amphetamine use; (ii). there were
      regional differences in drug use with greater accessibility to a wider range of
      drugs in a state capital city and greater levels of injecting risk-taking
      behaviour outside the capital city environment; and (iii). there was a
      significant increase in level of amphetamine use and percentage of alcohol users,
      a trend for a higher level of amphetamine dependence and a significant reduction
      in the percentage of people using heroin and benzodiazepines among the 2002
      Newcastle cohort compared to the 1998 cohort. CONCLUSIONS: Further longitudinal
      research is needed to elucidate transitions from one drug type to another and
      from recreational to injecting and regular use and the relationship between drug
      use and mental health in prospective studies among users. IMPLICATIONS:
      Intervention research should evaluate the effectiveness of interventions aimed
      at: preventing transition to injecting and regular use of amphetamines; toward
      reducing levels of depression among amphetamine users and interventions among
      people with severe psychopathology and personality disorders; and toward reducing
      the prevalence of tobacco dependence among amphetamine users.

PMID- 15200584
TI  - Audio-computerized self-interviewing versus face-to-face interviewing for
      research data collection at drug abuse treatment programs.
AB  - AIMS: To assess audio computer-assisted self-interviewing (A-CASI) as a mode of
      data collection with injecting drug users (IDUs) entering two drug treatment
      programs in New York City. A-CASI has been found to increase reporting of
      sensitive items among a variety of population subgroups. DESIGN: A field test of
      A-CASI data collection conducted within an ongoing cross-sectional study of drug
      use and HIV risk behaviors among IDUs entering drug treatment. Participants were
      assigned without bias to either a computer-assisted interviewer-administered
      personal interview (CAPI) or to a mixed CAPI/A-CASI interview. In the latter,
      'sensitive' portions (dealing with stigmatized behavior) of the questionnaire
      were self-administered through A-CASI, while the remaining portions were
      interviewer-administered. SETTING: The Detoxification Program and the Methadone
      Maintenance Treatment Program (MMTP) at Beth Israel Medical Center in New York
      City. PARTICIPANTS: Seven hundred and eighty-three IDUs entering drug treatment.
      MEASUREMENTS: Odds ratios and adjusted odds ratios (controlling for demographic
      differences) for comparison of A-CASI versus CAPI responses on 111 sensitive
      questions. FINDINGS: Twenty-three statistically significant differences (each at
      P < 0.05), all in the direction of more reporting of the behaviors by the A-CASI
      group. Forty-one per cent of A-CASI participants said they would prefer any
      subsequent interviews to be fully A-CASI and 46% said they would prefer the mixed
      CAPI/A-CASI mode. CONCLUSIONS: A-CASI was associated with greater reporting of
      potentially stigmatized drug, sex and HIV risk behaviors on a moderate number of
      questions. Moreover, a large majority of participants who used A-CASI would like
      to be assigned to this method of data collection in future interviews.

PMID- 15200585
TI  - The adolescent behavioral repertoire as a context for drug exposure: behavioral
      autarcesis at play.
AB  - AIMS: The aim of this study is to investigate suspected behavioral autarcesis.
      Autarcesis refers to a mechanism of non-specific shielding from or immunity to
      infection or disease. Here, suspecting that some facets of the adolescent
      behavioral repertoire (ABR) might shield youths from early drug involvement, we
      studied recent-onset occurrence of first chances to try a drug and first actual
      drug use, expressed as a function of five observed ABR dimensions: religious,
      socializing, sports-related, gender socialization, and home-based activities.
      DESIGN AND PARTICIPANTS: Nationally representative samples of school-attending
      youths were drawn in Panama, the five Spanish heritage countries of Central
      America and the Dominican Republic (n = 12797). MEASUREMENTS: Drug involvement
      and ABR were assessed via anonymous self-administered questionnaires. FINDINGS: A
      religious activity dimension and a separate sports dimension were associated
      inversely with recent onset of adolescent drug experiences, and a socializing
      activity dimension was related to an increased occurrence of these experiences.
      For example, for each unit increase of the religious activity dimension of the
      ABR, there was an associated reduced occurrence of the first chance to try
      tobacco (OR = 0.75, 95% CI: 0.63-0.90, P = 0.002). Adolescents at higher levels
      of sports activities and home-based activities were less likely to experience
      recent-onset actual use of marijuana (OR = 0.45, 95% CI: 0.30-0.67, P < 0.001; OR
      = 0.56, 95% CI: 0.32-0.99, P = 0.048, respectively). CONCLUSIONS: The study
      evidence lends some support for behavioral autarcesis. Manipulation of selected
      ABR dimensions might help prevent or reduce adolescent drug involvement,
      enhancing autarcesis as a protective mechanism.

PMID- 15200586
TI  - Direct telemarketing of smoking cessation interventions: will smokers take the
      call?
AB  - AIMS: Few smokers currently make use of available and effective cessation
      strategies, despite their expressed desire to quit and reported interest in
      cessation support. This study aimed to explore the feasibility of a telephone
      based direct-marketing approach to delivering cessation strategies. DESIGN,
      SETTING, MEASUREMENTS AND PARTICIPANTS: A community survey was conducted to
      explore the views of current adult smokers regarding the acceptability, likely
      uptake and barriers to uptake of smoking cessation services offered by direct
      telephone marketing. FINDINGS: Three quarters (73.8%) of smokers contacted agreed
      to be surveyed. Of the 194 study participants, 75.3% reported that they would
      utilize vouchers for discount nicotine replacement therapy (NRT), 66.5% would use
      a mailed self-help booklet, 57.2% would take up the offer of regular mailings of
      personalized letters and self-help materials and 46.4% would utilize a 'we-call
      you' telephone counselling service. The characteristics of those indicating
      likely uptake of these services were also explored. The two major barriers to
      uptake of services were preferring to quit without help and a belief that a
      particular service would not help the participant. CONCLUSIONS: The data suggest
      strong support for the direct marketing of smoking cessation strategies; they
      also highlight the need for further study of the cost-effectiveness of telephone
      based direct marketing of smoking cessation strategies as a population-based
      strategy for reducing the prevalence of smoking in the community.

PMID- 15200587
TI  - The role of smoking intentions in predicting future smoking among youth: findings
      from Monitoring the Future data.
AB  - AIMS: To demonstrate that intentions predict long-term future levels of smoking,
      irrespective of level of past smoking experience. A growing body of research
      suggests that intentions about future smoking might play an important role in
      addition to the influence of past smoking experience on the likelihood of smoking
      in future. DESIGN: Using logistic regression analyses, we assessed the
      relationship between baseline smoking experience and a firm intention 'not to be
      smoking cigarettes 5 years from now' with four outcome measures of smoking at
      follow-up: 30-day smoking at a 3/4- and 5/6-year follow-up and current
      established smoking (self-described regular smokers or former smokers who had
      smoked in the past 30 days) at a 3/4- and 5/6-year follow-up. PARTICIPANTS: US
      nationally representative samples of 12th graders who responded to the Monitoring
      the Future (MTF) survey from the years 1976 to 1993, inclusive. For these panels,
      we linked stage of smoking and intentions at 12th grade to follow-up measures of
      smoking collected at 3/4 years after baseline and 5/6 years after baseline.
      FINDINGS: Analysis of 3/4-year follow-up data (weighted n = 4544) and 5/6-year
      follow-up data (weighted n = 3885) for both definitions of smoking outcome
      indicated that there was a dose-response relationship between levels of baseline
      smoking experience and the likelihood of future smoking. In addition, independent
      of baseline smoking experience, there was a statistically significant protective
      effect for a firm intention not to smoke in five year's time on future smoking
      behavior. CONCLUSIONS: The findings suggest that evaluative studies of tobacco
      control policies and programs might usefully employ smoking uptake categories
      that incorporate smoking intentions as early indicators of outcome.

PMID- 15200588
TI  - Is 'autarcesis' the emperor's new clothes? A comment on Chen et al. (2004).

PMID- 15200589
TI  - Protection from etymologic infection.

PMID- 15200594
TI  - Genes.

PMID- 15200595
TI  - Genetics tools: PCR and sequencing.

PMID- 15200596
TI  - Whatomics.

PMID- 15200597
TI  - Transcriptional regulation of haematopoiesis.

PMID- 15200598
TI  - Stem-cell harvesting and manipulation.

PMID- 15200599
TI  - Principles of immunotherapy.

PMID- 15200600
TI  - The body as fortress: innate immune surveillance.

PMID- 15200601
TI  - Adaptive immunity and transfusion.

PMID- 15200602
TI  - Immunity and transplantation.

PMID- 15200603
TI  - Physiology of haemostasis.

PMID- 15200604
TI  - Assessment of haemostasis.

PMID- 15200605
TI  - Correcting haemostasis.

PMID- 15200606
TI  - The complexities of the Rh system.

PMID- 15200607
TI  - Molecular blood grouping.

PMID- 15200608
TI  - Problem-solving in antibody identification.

PMID- 15200609
TI  - The physiology of oxygen delivery.

PMID- 15200610
TI  - The body's response to blood loss.

PMID- 15200611
TI  - Fluid balance.

PMID- 15200612
TI  - Platelet antigens and antibody detection.

PMID- 15200613
TI  - The human leucocyte antigen (HLA) system.
AB  - Since the discovery of the HLA system, over 40 years ago, we now have an
      understanding of the role of HLA molecules in the adaptive immune response, as
      well as in the alloimmune response experienced when foreign HLA is introduced
      into an individual via transplant, transfusion or pregnancy. Retrospective
      studies in the 1970s and 1980s illustrated the importance of matching for HLA
      antigens in transplantation and platelet transfusion. The huge degree of
      polymorphism in the system has driven the development of sensitive HLA typing and
      HLA antibody screening methods in H & I laboratories in order to improve
      transplant and transfusion outcomes.

PMID- 15200614
TI  - Granulocyte antigens and antibody detection.

PMID- 15200615
TI  - Viruses.

PMID- 15200616
TI  - Bacterial contamination of cellular blood components: risks, sources and control.

PMID- 15200617
TI  - Prion diseases.

PMID- 15200618
TI  - Feline corneal sequestra: a review of 64 cases (80 eyes) from 1993 to 2000.
AB  - Feline corneal sequestrum is a common condition of the feline cornea. The purpose
      of this study was to provide a detailed description of the clinical features of
      the condition including the response to different management options and to
      assess the rate of recurrence. The medical records of 64 cases (80 eyes) of
      feline corneal sequestra that presented to the Animal Health Trust from 1993 to
      2000 were reviewed. Fifty-two cases were reviewed retrospectively; 12 cases were
      assessed prospectively between April and September 2000 as part of a separate
      study. The Persian was the most frequently encountered breed and the mean age of
      affected cats was 5.6 years. At initial presentation, sequestra were unilateral
      in 58 cats and bilateral in 6 cats, 5 of which were Persians. Ocular discomfort
      and ocular discharge were common presenting signs, occurring in 42 and 36 eyes,
      respectively. Seventy-four eyes were managed surgically with keratectomy only (n
      = 44) or keratectomy followed by a graft procedure (n = 30). Sequestra recurred
      in 16 eyes in the study. There was no significant difference in the rate of
      recurrence between eyes that received a graft procedure (n = 5) and eyes that did
      not (n = 11) (P = 0.56). Complications following transection of conjunctival
      pedicle grafts were observed. Brown to black discoloration of noncorneal tissue
      and therapeutic biomaterials was observed, including discoloration of both viable
      and apparently nonviable grafted conjunctival tissue, small intestinal submucosa
      graft material and bandage contact lenses.

PMID- 15200619
TI  - Feline corneal sequestrum: laboratory analysis of ocular samples from 12 cats.
AB  - Feline corneal sequestrum is a common ocular condition typified by brown to black
      discoloration of the cornea. The nature of the discoloration has not been
      identified. The purpose of this study was to perform a laboratory investigation
      of ocular samples from 12 clinical cases of feline corneal sequestrum in an
      attempt to characterize the nature of the discoloration. The 12 cases were
      referred to the Ophthalmology Unit at the Animal Health Trust between April and
      September 2000, and were also part of a clinical review of 64 cases of feline
      corneal sequestrum described separately. Five laboratory techniques that are
      routinely performed at the Biomaterials Unit, Aston University were employed for
      analysis of the ocular samples. Ocular material included corneal sequestrum, tear
      samples, meibomian gland secretions, and bandage contact lenses from the 12
      clinical cases. High-performance liquid chromatography data showed that total
      tear lipid in affected eyes was significantly lower than in control eyes (P =
      0.016); total tear lipid in affected eyes was lower than in the unaffected,
      contralateral eyes of the same cat but the difference was not significant (P =
      0.29). The presence of an unknown lipid class was observed in tears and meibomian
      secretions of affected, contralateral and control eyes. Scanning electron
      microscopy showed that the discoloration in affected corneas was not due to the
      presence of iron. Fluorescence spectroscopic analysis of sequestra, unaffected
      corneas and contact lenses (from affected and contralateral/unaffected eyes)
      showed that lipid and protein were present but did not play an important role in
      sequestra. Ultraviolet-visible light absorbance spectroscopy revealed a peak at
      385 nm in unaffected corneas that was absent in sequestra and the difference was
      significant (P < 0.0001); this peak may be a characteristic feature of the normal
      feline cornea. The absorbance spectra displayed a peak at 280 nm in two sequestra
      suggesting that chromophore groups (e.g. melanin) were present. Optical
      microscopy performed on 10 sequestra revealed the presence of particles, which
      were consistent with the appearance of melanin particles, providing laboratory
      evidence that characterized the nature of the discoloration as melanin for the
      first time.

PMID- 15200620
TI  - A morphologic study of intravitreal membranes associated with intraocular
      hemorrhage in the dog.
AB  - Abstract We aimed to characterize intravitreal membranes in dogs and determine,
      if possible, associated predisposing conditions. Five globes in which
      intravitreal membranes were identified were evaluated. These originated from four
      Labrador Retrievers or Labrador-cross dogs and a Springer Spaniel. The ages of
      the dogs ranged from 4 to 11 years. Standard histology and immunohistochemical
      procedures for factor VIII-related antigen, smooth muscle actin (SMA), vimentin
      and glial fibrillary acidic protein (GFAP) were performed. Intravitreal membranes
      varied from loosely to highly organized. The extent of organization corresponded
      with increasing immunoreactivity for vimentin and GFAP, indicating their
      predominantly glial origin. They were never immunopositive for smooth muscle
      actin, nor were they vascularized. In all cases, they were associated with
      intravitreal hemorrhage. Additional common findings included epiretinal
      membranes, retinal neovascularization, preiridal fibrovascular membranes and
      glaucoma. Intravitreal membranes may be a sequelae of intravitreal hemorrhage.
      This in turn, may arise from new vessels associated with epiretinal or preiridial
      membranes, or hemorrhage associated with optic disc cupping or retinal
      neovascularization. All of these phenomena may accompany glaucoma.

PMID- 15200621
TI  - Secondary glaucomas in the dog in North America.
AB  - OBJECTIVE: To determine the prevalence of secondary glaucomas in dogs associated
      with cataract formation, lens luxation or displacement, cataract surgery,
      uveitis, hyphema and intraocular neoplasia. METHODS: Information was obtained
      from the Veterinary Medical Data Base (VMDB) from all veterinary medical teaching
      hospitals in North America from March 1964 to March 2003. Secondary glaucomas
      were diagnosed at the same examination or after the primary diagnosis was made,
      and included those associated with cataract formation, lens luxation, cataract
      surgery, uveitis of unknown cause, hyphema of unknown cause, and intraocular
      neoplasia. The data were evaluated by decade, breed, gender and age of
      presentation. RESULTS: A total of 1 592 831 dogs were presented, and 9695 canine
      secondary glaucomas. Secondary glaucoma associated with cataract formation
      represented 81% of all the canine secondary glaucomas. Breeds (n = 7890 dogs)
      predisposed to secondary glaucoma and cataracts had an overall prevalence of
      0.5%, but nearly 20% of all the cataractous dogs developed secondary glaucoma in
      at least one eye. For the years 1994-2003, these breeds included the American
      Cocker Spaniel; Boston Terrier; Toy, Miniature and Standard Poodle; English
      Springer Spaniel; Bichon Frise; and Labrador Retriever. The other forms of
      secondary glaucoma occurred less frequently, and included those glaucomas with
      lens luxation or displacement (779 dogs; 12.0%), postcataract surgery (528 dogs;
      5.1%), with uveitis from unknown cause (399 dogs; 7.1%), with hyphema from
      unknown cause (117 dogs; 7.3%), and with intraocular neoplasia (19 dogs; 3.5%).
      The risk of the secondary glaucomas from 1984 to 2002 was highest after the
      intracapsular lens extraction (ICLE), less in the extracapsular technique (ECLE),
      and lowest for the phacoemulsification/phacofragmentation method. CONCLUSION:
      Prevalence of the canine secondary glaucomas ranges from 0.25% (1964-1973), 0.46%
      (1974-1983), 0.79% (1984-1993), to 0.80% (1994-2003) and are as frequent as the
      primary or breed-related glaucomas during these same time periods.

PMID- 15200622
TI  - Tono-Pen XL calibration curves for cats, cows and sheep.
AB  - The objective of this study was to provide calibration curves for correcting
      intraocular pressure (IOP) measurements obtained using the Tono-Pen XL tonometer
      in cats, cows and sheep. Twelve eyes from 9 cats, 13 eyes from 7 cows, 10 eyes
      from 5 sheep were used. The anterior chamber of the eye was cannulated in vivo,
      in situ (immediately post mortem) or ex vivo with a fine needle and IOP was
      varied from 10 to 90 mmHg in steps of 10 mmHg by adjusting the height of a saline
      reservoir connected to the needle. For each pressure setting, several readings of
      IOP were made using the tonometer. The relationship between Tono-Pen reading and
      manometer setting was linear over the full range of measurement. However, the
      slope of the data regression line deviated significantly from 1 and indicated
      that the instrument systematically underestimated IOP. For cats the average slope
      was 0.62 and for cows and sheep it was 0.72 and 0.69, respectively. For the
      latter animals, the regression line also had a nonzero intercept of approximately
      4.5 mmHg. Similar results were obtained from in vivo and ex vivo eyes and with
      different Tono-Pen XL tonometers. Although developed for use on humans, the Tono
      Pen XL can provide reproducible and accurate measurement of IOP in cats, cows and
      sheep when suitably calibrated by manometry. The calibration curves provided
      here, and by implication those reported for other animals using this tonometer,
      differ in slope from those measured with earlier models of the Tono-Pen. The
      reproducibility of the curves we obtained implies that they can be used to
      correct IOP readings from the Tono-Pen XL when manometry is not possible.

PMID- 15200623
TI  - Evaluation of intraocular pressure in association with cardiovascular parameters
      in normocapnic dogs anesthetized with sevoflurane and desflurane.
AB  - The objective of this study was to determine intraocular pressure (IOP) and
      cardiac changes in normocapnic dogs maintained under controlled ventilation and
      anesthetized using sevoflurane or desflurane. Sixteen healthy adult mixed-breed
      dogs, seven males and nine females, weighing 10-15 kg were used. The dogs were
      randomly assigned to one of two groups composed of eight animals anesthetized
      with sevoflurane (SEVO) or desflurane (DESF). In both groups, anesthesia was
      induced with propofol (10 mg/kg), and neuromuscular blockade was achieved with
      rocuronium (0.6 mg/kg/h i.v.). No premedication was given. Ventilation was
      adjusted to maintain end-tidal carbon dioxide partial pressure at 35 mmHg.
      Anesthesia was maintained with 1.5 minimum alveolar concentration (MAC) of
      sevoflurane or desflurane. In both groups IOP was measured by applanation
      tonometry (Tono-Pen) before induction of anesthesia. IOP, mean arterial pressure
      (MAP), heart rate (HR), cardiac index (CI) and central venous pressure (CVP) were
      also measured 45 min after the beginning of inhalant anesthesia and then every 20
      min for 60 min. A one-way repeated measures anova was used to compare data within
      the same group and Student's t-test was used to assess differences between
      groups. P < 0.05 was considered statistically significant. Measurements showed
      normal IOP values in both groups, even though IOP increased significantly from
      baseline during the use of desflurane. IOP did not differ between groups. CI in
      the desflurane group was significantly greater than in the sevoflurane group.
      Sevoflurane and desflurane have no clinically significant effects on IOP, MAP,
      HR, CI or VCP in the dog.

PMID- 15200624
TI  - Tick-borne encephalitis virus as a possible cause of optic neuritis in a dog.
AB  - A 3-year-old spayed female Siberian Husky was presented due to acute vision loss.
      Examination revealed bilateral optic neuritis and lymphocytic
      meningoencephalitis. The serum (1:800) and cerebrospinal fluid (CSF; 1:200)
      immunoglobulin (Ig)G titers for tick-borne encephalitis virus (TBEV) were
      elevated as were the serum IgG titer for Anaplasma phagocytophilum (1:640) and
      serum IgM titer for Toxoplasma gondii (1:20). Intracytoplasmic inclusion bodies
      such as ehrlichial or anaplasmal morulae were not observed in the CSF or blood
      smear. The dog was treated with methylprednisone and doxycycline. The left eye
      regained vision; the right eye remained blind. Anti-inflammatory therapy was
      stopped on day 18 after diagnosis. Four days later the dog showed evidence of
      hyperesthesia in the cervical region. Analysis of CSF showed no abnormalities and
      CSF IgG titers for TBEV and A. phagocytophilum were negative. Funduscopic
      evidence of active papillitis was absent on day 22 in the left eye and on day 86
      in the right eye. On day 243, the dog was presented again with lethargy, ataxia,
      disorientation and temporary head tilt. The IgG titer for TBEV was again elevated
      in the CSF (1:800) and in serum (1:400). After interpretation of all findings, we
      assume that meningoencephalitis and optic neuritis in this patient was caused by
      TBEV and associated immune-mediated inflammation. In endemic areas, TBEV should
      be considered as cause of optic neuritis in dogs.

PMID- 15200625
TI  - Hemangiosarcoma of the third eyelid in a dog.
AB  - Abstract A case of hemangiosarcoma of the third eyelid in a 7-year-old Caucasian
      Sheepdog is reported. A voluminous red mass protruding from the free edge of the
      third eyelid in the right eye was present. The mass and the free edge of the
      third eyelid were surgically excised. On histopathologic examination the tumor
      was seen to infiltrate the propria of the third eyelid and was composed of
      neoplastic mesenchymal cells forming irregular channels containing blood. These
      plump cells showed moderate anisocytosis and anisokaryosis with a low mitotic
      index. The surgical wound healed successfully and after 9 months there had been
      no recurrence. To the authors' knowledge, this is the first hemangiosarcoma of
      the third eyelid reported in the dog.

PMID- 15200626
TI  - How dogs navigate to catch frisbees.
AB  - Using micro-video cameras attached to the heads of 2 dogs, we examined their
      optical behavior while catching Frisbees. Our findings reveal that dogs use the
      same viewer-based navigational heuristics previously found with baseball players
      (i.e., maintaining the target along a linear optical trajectory, LOT, with
      optical speed constancy). On trials in which the Frisbee dramatically changed
      direction, the dog maintained an LOT with speed constancy until it apparently
      could no longer do so and then simply established a new LOT and optical speed
      until interception. This work demonstrates the use of simple control mechanisms
      that utilize invariant geometric properties to accomplish interceptive tasks. It
      confirms a common interception strategy that extends both across species and to
      complex target trajectories.

PMID- 15200627
TI  - The effects of speed on skilled chess performance.
AB  - Two types of mechanisms may underlie chess skill: fast mechanisms, such as
      recognition, and slow mechanisms, such as search through the space of possible
      moves and responses. Speed distinguishes these mechanisms, so I examined archival
      data on blitz chess (5 min for the whole game), in which the opportunities for
      search are greatly reduced. If variation in fast processes accounts for
      substantial variation in chess skill, performance in blitz chess should correlate
      highly with a player's overall skill. In addition, restricting search processes
      should tend to equalize skill difference between players, but this effect should
      decrease as overall skill level increases. Analyses of three samples of blitz
      chess tournaments supported both hypotheses. Search is undoubtedly important, but
      up to 81% of variance in chess skill (measured by rating) was accounted for by
      how players performed with less than 5% of the normal time available.

PMID- 15200629
TI  - Modal and amodal completion generate different shapes.
AB  - Mechanisms of contour completion are critical for computing visual surface
      structure in the face of occlusion. Theories of visual completion posit that
      mechanisms of contour interpolation operate independently of whether the
      completion is modal or amodal--thereby generating identical shapes in the two
      cases. This identity hypothesis was tested in two experiments using a
      configuration of two overlapping objects and a modified Kanizsa configuration.
      Participants adjusted the shape of a comparison display in order to match the
      shape of perceived interpolated contours in a standard completion display.
      Results revealed large and systematic shape differences between modal and amodal
      contours in both configurations. Participants perceived amodal (i.e., partly
      occluded) contours to be systematically more angular--that is, closer to a corner
      -than corresponding modal (i.e., illusory) contours. The results falsify the
      identity hypothesis in its current form: Corresponding modal and amodal contours
      can have different shapes, and, therefore, mechanisms of contour interpolation
      cannot be independent of completion type.

PMID- 15200628
TI  - The role of inhibitory control in forgetting semantic knowledge.
AB  - Previous research has shown that episodic retrieval recruits inhibitory processes
      that impair memory for related events. We report two experiments examining
      whether inhibitory processes may also be involved in causing semantic memory
      lapses. In a semantic retrieval-practice paradigm, subjects were given trials
      presenting a cue (a homograph in Experiment 1, a category in Experiment 2) linked
      to many different items in semantic memory. For each cue, subjects used general
      knowledge to generate no (baseline), one, four, or eight different items of
      semantic knowledge. Afterward, we determined through an apparently unrelated free
      association test whether a critical nonpracticed concept associated to the cue
      had been inhibited. Both experiments found that generating items from semantic
      memory suppressed competing concepts, and that this impairment was cue
      independent. These findings show that inhibitory control processes overcome
      interference during semantic retrieval and that recruitment of these processes
      may contribute to semantic forgetting.

PMID- 15200630
TI  - Role of attention and perceptual grouping in visual statistical learning.
AB  - Statistical learning has been widely proposed as a mechanism by which observers
      learn to decompose complex sensory scenes. To determine how robust statistical
      learning is, we investigated the impact of attention and perceptual grouping on
      statistical learning of visual shapes. Observers were presented with stimuli
      containing two shapes that were either connected by a bar or unconnected. When
      observers were required to attend to both locations at which shapes were
      presented, the degree of statistical learning was unaffected by whether the
      shapes were connected or not. However, when observers were required to attend to
      just one of the shapes' locations, statistical learning was observed only when
      the shapes were connected. These results demonstrate that visual statistical
      learning is not just a passive process. It can be modulated by both attention and
      connectedness, and in natural scenes these factors may constrain the role of
      stimulus statistics in learning.

PMID- 15200631
TI  - Suppressing where but not what: the effect of saccades on dorsal- and ventral
      stream visual processing.
AB  - Some cognitive processes are suppressed during saccadic eye movements, whereas
      others are not. In two experiments, we investigated the locus of this
      interference effect. In one experiment, subjects decided whether pictured items
      were objects or nonobjects while making saccades of different lengths. Saccade
      distance had no effect on response time, indicating that saccades do not
      interfere with object recognition. However, in a second experiment, in which
      subjects decided whether pictured items faced to the left or to the right,
      response time increased with saccade distance, indicating that processing was
      suppressed during the saccade. These results (along with others) suggest that
      dorsal-stream (where) processes are suppressed during saccades, whereas ventral
      stream (what) processes are not. Because the dorsal stream is instrumental in
      generating saccades, we propose that cognitive saccadic suppression results from
      dual-task interference within this visual subsystem.

PMID- 15200632
TI  - Integrating temporal biases: the interplay of focal thoughts and accessibility
      experiences.
AB  - We provide an integrative account of temporal biases (confidence changes,
      planning fallacy, impact bias, and hindsight bias). Students listed either 3 or
      12 thoughts about success or failure before an upcoming real-life exam or
      immediately after learning their grades. Previous explanations had focused on how
      thought content alone (what comes to mind) influences temporal biases. We found,
      however, an interaction between thought content and accessibility experiences
      (how easily or difficultly thoughts come to mind). Thinking about 3 ways to
      succeed (success was easy to bring to mind) was equivalent to thinking about 12
      ways to fail (failure was difficult to bring to mind), and conversely, thinking
      about 3 ways to fail was equivalent to thinking about 12 ways to succeed. In no
      case was thought content alone sufficient to predict the biases. These results
      have implications for debiasing strategies and other judgments over time.

PMID- 15200633
TI  - The importance of being flexible: the ability to both enhance and suppress
      emotional expression predicts long-term adjustment.
AB  - Researchers have documented the consequences of both expressing and suppressing
      emotion using between-subjects designs. It may be argued, however, that
      successful adaptation depends not so much on any one regulatory process, but on
      the ability to flexibly enhance or suppress emotional expression in accord with
      situational demands. We tested this hypothesis among New York City college
      students in the aftermath of the September 11th terrorist attacks. Subjects'
      performance in a laboratory task in which they enhanced emotional expression,
      suppressed emotional expression, and behaved normally on different trials was
      examined as a prospective predictor of their adjustment across the first two
      years of college. Results supported the flexibility hypothesis. A regression
      analysis controlling for initial distress and motivation and cognitive resources
      found that subjects who were better able to enhance and suppress the expression
      of emotion evidenced less distress by the end of the second year. Memory deficits
      were also observed for both the enhancement and the suppression tasks, suggesting
      that both processes require cognitive resources.

PMID- 15200634
TI  - Forgetting trauma stimuli.
AB  - Previous work reported in this journal suggested that the cognitive capacities of
      high dissociators are impaired under conditions of focused (selective) attention,
      but not under conditions of divided attention, compared with the cognitive
      capacities of low dissociators. Using a directed-forgetting paradigm, the current
      study demonstrated that under divided-attention demands, high dissociators have
      impaired memory for words associated with trauma (e.g., incest) but not for
      neutral words, as compared with low dissociators. In addition, high dissociators
      reported significantly more trauma history and significantly more betrayal trauma
      (abuse by a caregiver) than low dissociators. These results are consistent with
      the proposal that dissociation may aid individuals with histories of betrayal
      traumas to keep threatening information out of awareness.

PMID- 15200635
TI  - Psychophysiological responding during script-driven imagery in people reporting
      abduction by space aliens.
AB  - Is recollection of highly improbable traumatic experiences accompanied by
      psychophysiological responses indicative of intense emotion? To investigate this
      issue, we measured heart rate, skin conductance, and left lateral frontalis
      electromyographic responses in individuals who reported having been abducted by
      space aliens. Recordings of these participants were made during script-driven
      imagery of their reported alien encounters and of other stressful, positive, and
      neutral experiences they reported. We also measured the psychophysiological
      responses of control participants while they heard the scripts of the abductees.
      We predicted that if "memories" of alien abduction function like highly stressful
      memories, then psychophysiological reactivity to the abduction and stressful
      scripts would be greater than reactivity to the positive and neutral scripts, and
      this effect would be more pronounced among abductees than among control
      participants. Contrast analyses confirmed this prediction for all three
      physiological measures (ps < .05). Therefore, belief that one has been
      traumatized may generate emotional responses similar to those provoked by
      recollection of trauma (e.g., combat).

PMID- 15200636
TI  - Increasing implicit self-esteem through classical conditioning.
AB  - Implicit self-esteem is the automatic, nonconscious aspect of self-esteem. This
      study demonstrated that implicit self-esteem can be increased using a computer
      game that repeatedly pairs self-relevant information with smiling faces. These
      findings, which are consistent with principles of classical conditioning,
      establish the associative and interpersonal nature of implicit self-esteem and
      demonstrate the potential benefit of applying basic learning principles in this
      domain.

PMID- 15200637
TI  - A prospective investigation of the relationship between just-world beliefs and
      the desire for revenge after September 11, 2001.
AB  - We prospectively examined the relationship between individuals' belief in a just
      world and their desire for revenge against the perpetrators of the September 11
      terrorist attacks against the United States. Eighty-three undergraduate students
      who had completed a measure of just-world beliefs prior to the terrorist attacks
      were assessed approximately 2 months following the attacks. The more strongly
      they had endorsed just-world beliefs prior to the attacks, the more distressed
      they felt about the attacks and the more they desired revenge. Furthermore, the
      relationship between belief in a just world and the desire for revenge was
      mediated by feelings of distress in response to the terrorist attacks. The
      results point to the importance of justice beliefs in understanding responses to
      the terrorist attacks.

PMID- 15200638
TI  - Phosphatidic acid accumulation is an early response in the Cf-4/Avr4 interaction.
AB  - The Cladosporium fulvum (Cf)-4 gene of tomato confers resistance to the fungus C.
      fulvum, expressing the corresponding avirulence (Avr)4 gene, which codes for an
      elicitor protein. Little is known about how such mechanisms work, but previous
      studies have shown that elicitor recognition activates Ca(2+) signalling and
      protein kinases, such as mitogen-activated protein kinase (MAPK) and calcium
      dependent protein kinase (CDPK). Here, we provide evidence that a new signalling
      component, the lipid second messenger phosphatidic acid (PA), is produced within
      a few minutes of AVR4/Cf-4 interaction. Using transgenic tobacco cells expressing
      the tomato Cf-4-resistance gene as a model system, phospholipid signalling
      pathways were studied by pre-labelling the cells with (32)P(i) and assaying for
      the formation of lipid signals after challenge with the fungal elicitor AVR4. A
      dramatic rapid response was an increase in (32)P-PA, together with its metabolic
      product diacylglycerol pyrophosphate (DGPP). AVR4 increased the levels of PA and
      DGPP in a Cf-4(+)-, time- and dose-dependent manner, while the non-matching
      elicitor AVR9 did not trigger any response. In general, PA signalling can be
      triggered by two different pathways: via phospholipase D (PLD), which generates
      PA directly by hydrolysing structural phospholipids like phosphatidylcholine
      (PC), or via PLC, which generates diacylglycerol (DAG) that is subsequently
      phosphorylated to PA by DAG kinase (DGK). To determine the origin of the AVR4
      induced PA formation, a PLD-specific transphosphatidylation assay and a
      differential (32)P-labelling protocol were used. The results clearly demonstrated
      that most PA was produced via the phosphorylation of DAG. Neomycin and U73122,
      inhibitors of PLC activity, inhibited AVR4-induced PA accumulation, suggesting
      that the increase in DGK activity was because of increased PLC activity producing
      DAG. Lastly, evidence is provided that PLC signalling and, in particular, PA
      production could play a role in triggering responses, such as the AVR4-induced
      oxidative burst. For example, PLC inhibitors inhibited the oxidative burst, and
      when PA was added to cells, an oxidative burst was induced.

PMID- 15200639
TI  - Expression analysis suggests novel roles for the plastidic phosphate transporter
      Pht2;1 in auto- and heterotrophic tissues in potato and Arabidopsis.
AB  - A cDNA encoding Pht2;1 from potato, a new member of the plant Pht2 gene family of
      low-affinity orthophosphate (Pi) transporters, was isolated. The expression
      pattern of the corresponding gene as well as its ortholog from Arabidopsis was
      analyzed and the encoded proteins were localized in the two plants. Pht2;1
      expression is strongly upregulated by light in potato and Arabidopsis leaf
      tissue. RNA gel blot analysis, reverse transcription-polymerase chain reaction
      (RT-PCR), promoter/GUS, and protein/green fluorescent protein (GFP) fusion
      studies, respectively, indicate that the gene is expressed in both auto- and
      heterotrophic tissues and its encoded protein is localized to the plastids. The
      similar patterns of Pht2;1 gene regulation in potato and Arabidopsis prompted us
      to screen publicly available gene expression data from 228 Arabidopsis
      oligonucleotide microarrays covering 83 different experimental conditions.
      Modulation of Pht2;1 transcript levels was overall moderate, except for a limited
      number of experimental conditions where Pht2;1 mRNA concentrations varied between
      2- and 3.7-fold. Overall, these analyses suggest involvement of the Pht2;1
      protein in cell wall metabolism in young, rapidly growing tissues, independent of
      other Pi transporters such as the high-affinity Solanum tuberosum Pi transporter
      1 (StPT1). Cluster analysis allowed identification of colinear or antiparallel
      expression profiles of a small set of genes involved in post-translational
      regulation, and photosynthetic carbon metabolism. These data give clues about the
      possible biological function of Pht2;1 and shed light on the complex web of
      interactions in which Pht2;1 could play a role.

PMID- 15200640
TI  - Silencing of ribosomal protein L3 genes in N. tabacum reveals coordinate
      expression and significant alterations in plant growth, development and ribosome
      biogenesis.
AB  - The expression of ribosomal protein genes is coordinately regulated in bacteria,
      yeast, and vertebrates, so that equimolar amounts of ribosomal proteins
      accumulate for assembly into ribosomes. To understand how expression of ribosomal
      protein genes is regulated in plants, we altered expression of the large subunit
      ribosomal protein L3 (RPL3) genes in Nicotiana tabacum using post-transcriptional
      gene silencing (PTGS). L3 is encoded by two genes, RPL3A and RPL3B, with 80.2%
      amino acid sequence identity in tobacco. Two types of 'hairpin' RNA (hpRNA)
      vectors carrying the RPL3A or RPL3B sequences in both sense and antisense
      orientation were generated in order to alter the expression level of both RPL3
      genes. Tobacco plants transformed with a vector containing a 5'-terminal fragment
      of RPL3A gene displayed decreased RPL3A mRNA levels and a marked increase in the
      abundance of RPL3B mRNA. These results indicated that expression of the RPL3
      genes is coordinately regulated in tobacco. The transgenic plants that contained
      higher levels of RPL3B mRNA exhibited leaf overgrowth and mottling. Epidermal
      cells of these plants were increased in number and decreased in size. The
      precursor rRNA (pre-rRNA) and the mature rRNAs accumulated in these plants,
      suggesting that ribosome biogenesis is upregulated. Tobacco plants transformed
      with an hpRNA vector harboring the full-length RPL3B cDNA exhibited efficient
      silencing of both RPL3A and RPL3B genes, reduced L3 levels, and an abnormal
      phenotype characterized by a delay in development, stunting, and inhibition of
      lateral root growth. L3 deficiency led to a reduction in cell number and an
      increase in cell size, suggesting that L3 positively regulates cell division.
      Decreasing RPL3 gene expression resulted in a decrease in accumulation of the pre
      rRNA, establishing a prominent role for L3 in ribosome biogenesis in plants.

PMID- 15200641
TI  - Catalase deficiency drastically affects gene expression induced by high light in
      Arabidopsis thaliana.
AB  - In plants, hydrogen peroxide (H(2)O(2)) plays a major signaling role in
      triggering both a defense response and cell death. Increased cellular H(2)O(2)
      levels and subsequent redox imbalances are managed at the production and
      scavenging levels. Because catalases are the major H(2)O(2) scavengers that
      remove the bulk of cellular H(2)O(2), altering their levels allows in planta
      modulation of H(2)O(2) concentrations. Reduced peroxisomal catalase activity
      increased sensitivity toward both ozone and photorespiratory H(2)O(2)-induced
      cell death in transgenic catalase-deficient Arabidopsis thaliana. These plants
      were used as a model system to build a comprehensive inventory of transcriptomic
      variations, which were triggered by photorespiratory H(2)O(2) induced by high
      light (HL) irradiance. In addition to an H(2)O(2)-dependent and -independent type
      of transcriptional response during light stress, microarray analysis on both
      control and transgenic catalase-deficient plants, exposed to 0, 3, 8, and 23 h of
      HL, revealed several specific regulatory patterns of gene expression. Thus,
      photorespiratory H(2)O(2) has a direct impact on transcriptional programs in
      plants.

PMID- 15200642
TI  - Mutual antagonism of ethylene and jasmonic acid regulates ozone-induced spreading
      cell death in Arabidopsis.
AB  - Ethylene (ET) and jasmonic acid (JA) have opposite effects on ozone (O(3))
      induced spreading cell death; ET stimulates, and is required for the spreading
      cell death, whereas JA protects tissues. We studied the underlying molecular
      mechanisms with the O(3)-sensitive, JA-insensitive jasmonate resistant 1 (jar1),
      and the O(3)-tolerant, ET-insensitive ethylene insensitive 2 (ein2) mutants.
      Blocking ET perception pharmacologically with norbornadiene (NBD) in jar1, or ET
      signaling genetically in the jar1 ein2 double mutant prevented the spread of cell
      death. This suggests that EIN2 function is epistatic to JAR1, and that the JAR1
      dependent JA pathway halts oxidative cell death by directly inhibiting ET
      signaling. JAR1-dependent suppression of the ET pathway was apparent also as
      increased EIN2-dependent gene expression and ET hypersensitivity of jar1.
      Physiological experiments suggested that the target of JA is upstream of
      Constitutive Triple Response 1 (CTR1), but downstream of ET biosynthesis. Gene
      expression analysis of 1-aminocyclopropane-1-carboxylic acid (ACC)-treated and
      O(3)-exposed ein2 and jar1 revealed reciprocal antagonism: the EIN2-mediated
      suppression of the JA pathway. The results imply that the O(3)-induced spreading
      cell death is stimulated by early, rapid accumulation of ET, which can suppress
      the protecting function of JA thereby allowing cell death to proceed. Extended
      spreading cell death induces late accumulation of JA, which inhibits the
      propagation of cell death through inhibition of the ET pathway.

PMID- 15200643
TI  - The expression patterns of arabinogalactan-protein AtAGP30 and GLABRA2 reveal a
      role for abscisic acid in the early stages of root epidermal patterning.
AB  - In the Arabidopsis root, patterning of the epidermal cell types is position
      dependent. The epidermal cell pattern arises early during root development, and
      can be visualized using reporter genes driven by the GLABRA (GL)2 promoter as
      markers. The GL2 gene is preferentially expressed in the differentiating hairless
      cells (atrichoblasts) during a period in which epidermal cell identity is
      believed to be established. We show that AtAGP30 is also expressed in
      atrichoblasts. This gene encodes an arabinogalactan-protein (AGP) that is known
      to play a role in root regeneration and increases abscisic acid (ABA)-response
      rates. Although the expression level of this gene is regulated by the plant
      growth factors ABA and ethylene, only ABA was found to affect the tissue-specific
      pattern of expression. ABA also disrupts the expression pattern of the GL2::GUS
      (beta-glucuronidase) reporter gene. Our results indicate that ABA regulates
      epidermal cell-type-specific gene expression in the meristematic zone of the
      Arabidopsis root, while ethylene is known to act at later stages of epidermal
      differentiation. Despite its effects on the early stages of root epidermal
      patterning, ABA does not affect root hair formation on mature wild-type epidermal
      cells, suggesting that other developmental cues, like positional information, can
      progressively over-ride the ABA-mediated disruption of early epidermal
      patterning.

PMID- 15200644
TI  - Arabidopsis thaliana AtPOLK encodes a DinB-like DNA polymerase that extends
      mispaired primer termini and is highly expressed in a variety of tissues.
AB  - Cell survival after DNA damage depends on specialized DNA polymerases able to
      perform DNA synthesis on imperfect templates. Most of these enzymes belong to the
      recently discovered Y-family of DNA polymerases, none of which has been
      previously described in plants. We report here the isolation, functional
      characterization and expression analysis of a plant representative of the Y
      family. This polymerase, which we have termed AtPolkappa, is a homolog of
      Escherichia coli pol IV and human pol kappa, and thus belongs to the DinB
      subfamily. We purified AtPolkappa and found a template-directed DNA polymerase,
      endowed with limited processivity that is able to extend primer-terminal
      mispairs. The activity and processivity of AtPolkappa are enhanced markedly upon
      deletion of 193 amino acids (aa) from its carboxy (C)-terminal domain. Loss of
      this region also affects the nucleotide selectivity of the enzyme, leading to the
      incorporation of both dCTP and dTTP opposite A in the template. We detected three
      cDNA forms, which result from the alternative splicing of AtPOLK mRNA and have
      distinct patterns of expression in different plant organs. Histochemical
      localization of beta-glucuronidase (GUS) activity in transgenic plants revealed
      that the AtPOLK promoter is active in endoreduplicating cells, suggesting a
      possible role during consecutive DNA replication cycles in the absence of
      mitosis.

PMID- 15200645
TI  - Characterization of C-terminal domains of Arabidopsis heat stress transcription
      factors (Hsfs) and identification of a new signature combination of plant class A
      Hsfs with AHA and NES motifs essential for activator function and intracellular
      localization.
AB  - Heat stress transcription factors (Hsfs) are the major regulators of the plant
      heat stress (hs) response. Sequencing of the Arabidopsis genome revealed the
      existence of 21 open-reading frames (ORFs) encoding putative Hsfs assigned to
      classes A-C. Here we present results of a functional genomics approach to the
      Arabidopsis Hsf family focused on the analysis of their C-terminal domains (CTDs)
      harboring conserved modules for their function as transcription factors and their
      intracellular localization. Using reporter assays in tobacco protoplasts and
      yeast as well as glutathione-S-transferase (GST) pull-down assays, we demonstrate
      that short peptide motifs enriched with aromatic and large hydrophobic amino acid
      (aa) residues embedded in an acidic surrounding (AHA motifs) are essential for
      transcriptional activity of class A Hsfs. In contrast to this, class B and C Hsfs
      lack AHA motifs and have no activator function on their own. We also provide
      evidence for the function of a leucine (Leu)-rich region centered around a
      conserved QMGPhiL motif at the very C-terminus as a nuclear export signal (NES)
      of class A Hsfs. Sequence comparison indicates that the combination of a C
      terminal AHA motif with the consensus sequence FWxxF/L,F/I/L as well as the
      adjacent NES represents a signature domain for plant class A Hsfs, which allowed
      to identify more than 60 new Hsfs from the expressed sequence tag (EST) database.

PMID- 15200646
TI  - The promotion of gravitropism in Arabidopsis roots upon actin disruption is
      coupled with the extended alkalinization of the columella cytoplasm and a
      persistent lateral auxin gradient.
AB  - The actin cytoskeleton has been implicated in regulating plant gravitropism.
      However, its precise role in this process remains uncertain. We have shown
      previously that disruption of the actin cytoskeleton with Latrunculin B (Lat B)
      strongly promoted gravitropism in maize roots. These effects were most evident on
      a clinostat as curvature that would exceed 90 degrees despite short periods of
      horizontal stimulation. To probe further the cellular mechanisms underlying these
      enhanced gravity responses, we extended our studies to roots of Arabidopsis.
      Similar to our observations in other plant species, Lat B enhanced the response
      of Arabidopsis roots to gravity. Lat B (100 nm) and a stimulation time of 5-10
      min were sufficient to induce enhanced bending responses during clinorotation.
      Lat B (100 nm) disrupted the fine actin filament network in different regions of
      the root and altered the dynamics of amyloplasts in the columella but did not
      inhibit the gravity-induced alkalinization of the columella cytoplasm. However,
      the duration of the alkalinization response during continuous gravistimulation
      was extended in Lat B-treated roots. Indirect visualization of auxin
      redistribution using the DR5:beta-glucuronidase (DR5:GUS) auxin-responsive
      reporter showed that the enhanced curvature of Lat B-treated roots during
      clinorotation was accompanied by a persistent lateral auxin gradient. Blocking
      the gravity-induced alkalinization of the columella cytoplasm with caged protons
      reduced Lat B-induced curvature and the development of the lateral auxin
      gradient. Our data indicate that the actin cytoskeleton is unnecessary for the
      initial perception of gravity but likely acts to downregulate gravitropism by
      continuously resetting the gravitropic-signaling system.

PMID- 15200647
TI  - Interactions of tobacco microtubule-associated protein MAP65-1b with
      microtubules.
AB  - Tobacco microtubule associated protein (MAP65) (NtMAP65s) constitute a family of
      microtubule-associated proteins with apparent molecular weight around 65 kDa that
      collectively induce microtubule bundling and promote microtubule assembly in
      vitro. They are associated with most of the tobacco microtubule arrays in situ.
      Recently, three NtMAP65s belonging to the NtMAP65-1 subfamily have been cloned.
      Here we investigated in vitro the biochemical properties of one member of this
      family, the tobacco NtMAP65-1b. We demonstrated that recombinant NtMAP65-1b is a
      microtubule-binding and a microtubule-bundling protein. NtMAP65-1b has no effect
      on microtubule polymerization rate and binds microtubules with an estimated
      equilibrium constant of dissociation (K(d)) of 0.57 micro m. Binding of NtMAP65
      1b to microtubules occurs through the carboxy-terminus of tubulin, as NtMAP65-1b
      was no longer able to bind subtilisin-digested tubulin. In vitro, NtMAP65-1b
      stabilizes microtubules against depolymerization induced by cold, but not against
      katanin-induced destabilization. The biological implications of these results are
      discussed.

PMID- 15200648
TI  - Metabolic engineering of monoterpene biosynthesis: two-step production of (+)
      trans-isopiperitenol by tobacco.
AB  - Monoterpenoid biosynthesis in tobacco was modified by introducing two subsequent
      enzymatic activities targeted to different cell compartments. A limonene-3
      hydroxylase (lim3h) cDNA was isolated from Mentha spicata L. 'Crispa'. This cDNA
      was used to re-transform a transgenic Nicotiana tabacum'Petit Havana' SR1
      (tobacco) line expressing three Citrus limon L. Burm. f. (lemon) monoterpene
      synthases producing (+)-limonene, gamma-terpinene and (-)-beta-pinene as their
      main products. The targeting sequences of these synthases indicate that they are
      probably localized in the plastids, whereas the sequence information of the P450
      hydroxylase indicates targeting to the endoplasmatic reticulum. Despite the
      different location of the enzymes, the introduced P450 hydroxylase proved to be
      functional in the transgenic plants as it hydroxylated (+)-limonene, resulting in
      the emission of (+)-trans-isopiperitenol. Some further modifications of the (+)
      trans-isopiperitenol were also detected, resulting in the additional emission of
      1,3,8-p-menthatriene, 1,5,8-p-menthatriene, p-cymene and isopiperitenone.

PMID- 15200649
TI  - Infant respiratory function testing: is it worth all the effort?

PMID- 15200650
TI  - Methylxanthines for the treatment of apnea associated with bronchiolitis and
      anesthesia.

PMID- 15200651
TI  - Anaesthesia induction in children: a psychological evaluation of the efficiency
      of parents' presence.
AB  - BACKGROUND: The induction of anaesthesia for surgery is a stressful time for both
      child and parents. To treat preoperative anxiety in children, pharmacological
      methods (premedication) and behavioural methods (the presence of parents during
      the induction of anaesthesia) have been used, both independently and in
      combination. The purpose of this investigation was to study the effect of both
      premedication and parental presence on preoperative anxiety in a homogeneous
      population. METHODS: In this study conducted between January and April 2001 in
      the Meyer Hospital in Florence (Anaesthesia Department and Surgical Department),
      we studied 39 Italian speaking children aged 2-14 years who were undergoing minor
      surgery. Before the surgical intervention the State Trait Anxiety Inventory
      (STAI) questionnaire and a questionnaire for the social-demographic
      characteristics were given to the parents. The stress of the children was
      evaluated during induction of anaesthesia. We also studied behavioural areas of
      both children and parents with two specific questionnaires administered after the
      surgery. RESULTS: The STAI scores showed that the mothers had a higher level of
      anxiety compared with the fathers. The induction of anaesthesia for surgery was a
      stressful time for 23% of children of our sample. The correlation between stress
      of the child at induction and state (P = 0.034) and trait (P = 0.049) anxiety of
      parents was statistically significant. The child's loss of consciousness was for
      the majority of parents (56%) the moment of greatest stress and 97% of parents
      did feel useful during the induction of anaesthesia. There was a significant
      difference, P = 0.032, in the presence or absence of stress depending on whether
      the mother or father accompanied the child to the operating room. There was no
      significant difference in the presence of stress between children who did and did
      not receive premedication. CONCLUSIONS: Maternal presence, compared with the
      father's presence, is fundamental in helping to overcome anxiety in a child
      receiving anaesthesia. If the parents are present during the induction, the
      addition of premedication does not offer further benefit. Parents themselves
      judged their presence during the induction of anaesthesia in their child as a
      positive event. We also found a statistical significant correlation between
      anxiety of the parents with the level of the stress of the child during induction
      of anaesthesia.

PMID- 15200652
TI  - Comparison of caudal ropivacaine, ropivacaine plus ketamine and ropivacaine plus
      tramadol administration for postoperative analgesia in children.
AB  - BACKGROUND: The aim of this study was to compare the effect of single-dose caudal
      ropivacaine, ropivacaine plus ketamine and ropivacaine plus tramadol in children
      for postoperative pain management. METHODS: Following ethics committee approval
      and informed parental consent, 99 ASA PS I or II children, between 1 and 10 years
      of age, scheduled for elective inguinal hernia repair with general anaesthesia,
      were recruited. After induction of anaesthesia and placement of a laryngeal mask
      airway (LMATM), the patients were randomly divided into three groups to receive
      either caudal ropivacaine alone (0.4%, 2 mg x kg(-1)) in group R (n = 32) or
      ropivacaine (0.2%, 1 mg x kg(-1)) plus ketamine (0.25 mg x kg(-1)) in group RK (n
      = 33) or ropivacaine (0.2%, 1 mg x kg(-1)) plus tramadol (1 mg x kg(-1)) in group
      RT (n = 34) with a total volume of 0.5 ml x kg(-1). Systemic blood pressure (SBP
      and DBP), heart rate (HR), peripheral O2 saturation (SpO2), respiratory rate
      (RR), sedation and pain scores were recorded at 5, 10, 15 and 30 min, 1, 3, 4 and
      6 h following recovery from anaesthesia. Pain was evaluated by Children's
      Hospital of Eastern Ontario Pain Scale, and sedation with a five-point sedation
      test. RESULTS: No difference was found regarding age, weight and duration of
      operation between the groups (P > 0.05). No patient experienced hypotension,
      bradycardia or respiratory depression. Duration of analgesia was longer in group
      RT (1377 +/- 204 min) than group R (1006 +/- 506 min) (P = 0.001). In the
      tramadol group, fewer patients required supplementary analgesics in the first 24
      h (P = 0.005). Sedation scores were below 2 in all groups. Incidence of
      postoperative nausea and vomiting was higher in group RT (eight patients) and
      group RK (seven patients) than group R (one patient, P = 0.032). CONCLUSIONS:
      Ropivacaine (0.4%), ropivacaine (0.2%) plus ketamine (0.25 mg x kg(-1)) and
      ropivacaine (0.2%) plus tramadol (0.5 mg x kg(-1)) provided sufficient analgesia
      in children, but the duration of analgesia was longer in the RT group.

PMID- 15200653
TI  - Use of spinal anaesthesia in paediatric patients: a single centre experience with
      1132 cases.
AB  - BACKGROUND: Spinal anaesthesia has been used in children for over 100 years and
      in the last two decades its popularity for newborns and infants has increased,
      but there are still unanswered questions with the technique. METHODS: We
      evaluated the characteristics of spinal block including ease of performance,
      efficacy, adverse effects and complications in 1132 children, aged 6 months to 14
      years, undergoing surgery in the lower part of the body. Local ethical committee
      approved the protocol of this prospective study, and parents gave written
      informed consent and older children their assent. All patients were sedated with
      midazolam, thiopental or propofol intravenously during spontaneous ventilation.
      No inhalation anaesthetics were used. Spinal block was performed with 0.5%
      hyperbaric bupivacaine at a dose of 0.2 mg x kg(-1). RESULTS: Efficacy, safety
      and ease of performance of the spinal block were shown to be satisfactory in most
      children. Only 27 of the 1132 children needed any supplementation. The incidence
      and severity of complications was low. Only nine of 942 children, < 10 years of
      age and eight of 190 children, 10 years or older, developed hypotension. The
      incidences of postdural puncture headache, in five of the 1132 children, and
      backache, in nine of the 1132, were low. No other neurological complications were
      reported. CONCLUSIONS: Spinal anaesthesia with hyperbaric bupivacaine is a
      feasible anaesthetic method in children for surgery in the lower part of the
      body.

PMID- 15200654
TI  - Analgesia for adenotonsillectomy in children: a comparison of morphine, ketamine
      and tramadol.
AB  - BACKGROUND: Establishment of good analgesia is of major concern in the
      postoperative period following adenotonsillectomy. The aim of this study was to
      compare the effects of ketamine, morphine and tramadol on postoperative pain
      after adenotonsillectomy in children. METHODS: Sixty children (age 5-12 years)
      scheduled for adenotonsillectomy were randomized into four groups to receive
      intravenously (i.v.) either 0.5 mg.kg(-1) ketamine hydrochloride (K), 0.1 mg x
      kg(-1) morphine hydrochloride (M), 1.5 mg x kg(-1) tramadol hydrochloride (T) or
      normal saline (S) in a volume of 4 ml during induction. After tracheal intubation
      10 microg x kg(-1).min(-1) ketamine hydrochloride in group K and 0.6 ml x kg(-1)
      x h(-1) saline i.v. in groups M, K and S were infused peroperatively.
      Postoperative analgesic requirements and side-effects were recorded. Pain was
      assessed by the Numeric Rating Scale (NRS) and the Children's Hospital of Eastern
      Ontario Pain Scale (CHEOPS) scores. RESULTS: Heart rate increased significantly
      peroperatively only in group K. NRS at first and fifth minute in group M and at
      first minute in group T and K and CHEOPS score at first, fifth, 15th and 60th min
      in group M were found to be significantly lower than in the control group. The
      time to first analgesic requirement was significantly longer in group M compared
      with ketamine and the control group. Six children in group M, nine in group T, 11
      in group K and 15 in group S needed additional analgesics. CONCLUSIONS: Morphine
      hydrochloride 0.1 mg x kg(-1) i.v. administered during induction of anaesthesia
      provides efficient pain relief in children undergoing adenotonsillectomy.

PMID- 15200655
TI  - Generating a learning curve for penile block in neonates, infants and children:
      an empirical evaluation of technical skills in novice and experienced
      anaesthetists.
AB  - BACKGROUND: Literature concerning learning curves for anaesthesiological
      procedures in paediatric anaesthesia is rare. The aim of this study was to assess
      the number of penile blocks needed to guarantee a high success rate in children.
      METHODS: At a teaching hospital, the technical skills of 29 residents in
      anaesthesiology who performed penile blocks under the supervision of two staff
      anaesthesiologists were evaluated during a 12-month period using a standardized
      self-evaluation questionnaire. At the start of the study period, the residents
      had no prior experience in paediatric anaesthesia or in performing penile block.
      All residents entered the paediatric rotation after a minimum of 1-year training
      in adult general and regional anaesthesia. The blocks were rated using a binary
      score. For comparison, the success rates of the two supervising staff
      anaesthesiologists were collected during the same period using the same self
      evaluation questionnaire. Statistical analyses were performed by generating
      individual and institutional learning curves by using the pooled data. The
      learning curves were calculated with the aid of a least square fit model. A 95%
      CI were estimated by a Monte Carlo procedure with a bootstrap technique. RESULTS:
      In a total number of 392 blocks performed, the overall success rate was 92.1%.
      There was no statistical difference between the success rate of the two staff
      members (success rate: 96.3%) and the overall success rate of the 29 residents
      performing a total of 339 blocks. The total success rate for this group was
      91.5%. The failure rate for the first 10 blocks performed by the residents was
      8.82% (95% CI: 5.0-14.14%), it was 4.12% (95% CI: 1.13-10.22%) for the next 10
      blocks and from blocks 21 to 40 it was 6.5% (95% CI: 2.65-12.9%). For blocks 41
      60, the failure rate was 4.4% (95% CI 0.54-15.15%). CONCLUSIONS: Penile block in
      children is easily learned by residents. A steep learning curve was found. The
      success rate was over 93.5% after more than 40 blocks.

PMID- 15200656
TI  - Rofecoxib administration to paediatric patients undergoing adenotonsillectomy.
AB  - BACKGROUND: Rofecoxib is a selective COX-2 inhibitor that does not interfere with
      platelet function and is associated with fewer bleeding complications than other
      nonsteroidal anti-inflammatory agents (NSAIDs). Our aims were to evaluate the
      safety and the efficacy of rofecoxib administration to paediatric patients
      undergoing adenotonsillectomy (T&A). METHODS: We conducted a double-blind,
      randomized, placebo-controlled study of rofecoxib in 45 ASA 1-2 patients > or = 4
      years of age undergoing outpatient T&A. All patients received midazolam 0.5 mg x
      kg(-1) (max 15 mg) p.o. and either rofecoxib 1 mg x .kg(-1) (max 25 mg) or
      placebo p.o. 30 min preoperatively. All patients had a standardized anaesthetic
      and were extubated awake in the operating room at the conclusion of surgery. The
      Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores were obtained
      on arrival in the postanaesthetic care unit (PACU). Morphine 25 microg x kg(-1)
      i.v. were administered up to six times for pain in the PACU. Wong-Baker FACES
      Scales were obtained at discharge from the PACU and the day surgery unit (DSU).
      Outcome measures included intraoperative estimated blood loss (EBL), pain scores,
      PACU morphine requirements and discharge times. RESULTS: There were 23 patients
      in the rofecoxib group and 22 patients in the placebo group. There were no
      differences between the rofecoxib and placebo groups in terms of bleeding, pain
      scores, PACU morphine requirements, PACU times or DSU times. CONCLUSION:
      Rofecoxib administration to paediatric patients undergoing T&A did not result in
      increased bleeding. Rofecoxib, however, was not found to decrease morphine use or
      improve pain scores prior to hospital discharge in T&A patients who received
      intraoperative morphine and acetaminophen.

PMID- 15200657
TI  - An evaluation of brainstem death documentation: the importance of full
      documentation.
AB  - BACKGROUND: With the introduction of the concept of brainstem death as acceptable
      proof that life has ended, rather than cessation of the beating heart, the
      process of determining brain death has to be rigorous to ensure maintenance of
      confidence in the definition. A recent study from South Thames in the UK revealed
      that only 44% of brainstem death documentation was complete at the time of
      referral to the transplant coordinator. The aim of our study was to see whether
      our documentation of brainstem death in paediatric practice complied with the UK
      Royal College's guidelines and to determine whether any changes are required to
      be instituted. METHODS: We studied retrospectively the case notes of children who
      underwent brainstem testing over a 3-year period (1994-1997) at two tertiary
      referral children's hospitals. The results of the audit were disseminated and a
      reaudit was performed over a 3-year period (1998-2001). RESULTS: A proforma was
      completed in 61% of cases and in only 54% of cases was the ideal standard of two
      tests by two doctors documented. Of the 26 sets of case notes studied, the cause
      of coma was not stated in 85% of cases and exclusion of other causes was stated
      in 54%. For the reaudit, 32 sets of case notes were studied and the proforma was
      completed in 100% of cases. In 91% of cases, the cause of coma was stated and in
      94%, exclusion of other causes was documented. In 94% of cases two tests were
      performed by two doctors. CONCLUSIONS: Documentation of adherence to the Royal
      Colleges, guidelines on brainstem death testing improved significantly between
      the two study periods as a consequence of major changes in practice within the
      PICU. With the appointment of dedicated intensive care consultants, care became
      largely consultant intensivist led and emphasis was placed on the documentation
      and completion of a single validated brainstem death proforma. It is essential to
      improve and maintain the quality of brainstem death test documentation in order
      to ensure the integrity of the process.

PMID- 15200658
TI  - Pentobarbital vs chloral hydrate for sedation of children undergoing MRI:
      efficacy and recovery characteristics.
AB  - BACKGROUND: Chloral hydrate (CH) sedation for magnetic resonance imaging (MRI) is
      associated with significant failure rates, adverse events and delayed recovery.
      Pentobarbital (PB), reportedly produces successful sedation in 98% of children
      undergoing diagnostic imaging. This study compared the efficacy, adverse events
      and recovery characteristics of CH vs PB in children undergoing MRI. METHODS:
      With Institutional Review Board approval and written consent, children were
      randomly assigned to receive intravenous (i.v.) PB (maximum 5 mg x kg(-1) in
      incremental doses) or oral CH (75 mg x kg(-1)) prior to MRI. Sedation was
      augmented with 0.05 mg x kg(-1) doses of i.v. midazolam (maximum 0.1 mg x kg(-1))
      as necessary. Adverse effects, including hypoxaemia, failed sedation, paradoxical
      reactions and behavioural changes, the return of baseline activity, and parental
      satisfaction were documented. The quality of MRI scans was evaluated by a
      radiologist blinded to the sedation technique. RESULTS: PB facilitated an earlier
      onset of sedation (P = 0.001), higher sedation scores (P = 0.01), and less need
      for supplemental midazolam compared with CH. Severe hypoxaemia occurred in two
      children (6%) in the PB group. Fourteen per cent of the PB group experienced a
      paradoxical reaction, 9% sedation failure and 11% major motion artefact, compared
      with 0% (P = 0.05), 3 and 2% (P = NS), respectively, in the CH group. CH and PB
      were both associated with a high incidence of motor imbalance, and agitation.
      However, children who received PB had a slower return to baseline activity (P =
      0.04). CONCLUSIONS: Although PB facilitated a quicker sedation onset and reduced
      the requirement for supplemental sedation, it produced a higher incidence of
      paradoxical reaction and prolonged recovery with a similar failure rate compared
      with CH.

PMID- 15200659
TI  - Hypercapnia: what is the limit in paediatric patients? A case of near-fatal
      asthma successfully treated by multipharmacological approach.
AB  - We describe a case of prolonged severe hypercapnia with respiratory acidosis
      occurring during an episode of near-fatal asthma in an 8-year-old boy, followed
      by complete recovery. After admission to the intensive care unit, despite
      treatment with maximal conventional bronchodilatative therapy, the clinical
      picture deteriorated with evident signs of respiratory muscle fatigue. The child
      was sedated, intubated and mechanically ventilated. Magnesium sulphate, ketamine
      and sevoflurane were gradually introduced together with deep sedation,
      curarization and continuous bronchodilatative therapy. Ten hours after admission,
      arterial pCO2 reached 39 kPa (293 mmHg), pH was 6.77 and pO2 8.6 kPa (65 mmHg).
      Chest radiograph showed severe neck subcutaneous emphysema, with signs of
      mediastinal emphysema. No episode of haemodynamic instability was seen despite
      severe prolonged hypercapnia lasting more than 14 h. Oxygenation was maintained
      and successful recovery followed without neurological or cardiovascular sequelae.
      This case shows the cardiovascular and neurological tolerance of a prolonged
      period of supercarbia in a paediatric patient. The most important lesson to be
      learned is the extreme importance of maintaining adequate tissue perfusion and
      oxygenation during an asthma attack. The second lesson is that when conventional
      bronchodilators fail, the intensivist may resort to the use of drugs such as
      ketamine, magnesium sulphate and inhalation anaesthesia. In this context deep
      sedation and curarization are important not only to improve oxygenation, but also
      to reduce cerebral metabolic requirements.

PMID- 15200660
TI  - Facial nerve palsy: a complication following anaesthesia in a child with Treacher
      Collins syndrome.
AB  - We report a case of facial nerve palsy following anaesthesia in a child with
      Treacher Collins syndrome. Children in whom intubation is difficult may be at
      increased risk of this complication.

PMID- 15200661
TI  - A case of severe diazoxide toxicity.
AB  - Hyperinsulism is a rare cause of persistent hypoglycemia in the neonatal period.
      Therapy can be accomplished either surgically or pharmacologically. Diazoxide
      treatment remains the mainstay of medical therapy. Tolerance of diazoxide is
      usually excellent, but several adverse effects of this drug have been described.
      A case of severe diazoxide intoxication with fluid retention, congestive heart
      failure, and respiratory failure is reported. The patient was a 43-day-old
      infant, affected by persistent and severe hypoglycemia. After the diagnosis,
      hyperinsulinism was established he was treated with diazoxide (17 mg x kg(-1)
      daily) and octreotide (12 microg x kg(-1) daily). A few days later he presented
      with hepatomegaly, severe fluid retention, diffuse edema, congestive heart
      failure, and respiratory failure requiring mechanical ventilation. After
      introduction of ACE inhibitors he developed acute renal failure. The clinical
      condition worsened and he developed pulmonary hypertension requiring high
      frequency oscillatory ventilation. Diazoxide was stopped on the 12th day in spite
      of poor control of blood sugar. During the next 5 days his hemodynamic status
      dramatically improved and he was weaned from catecholamines: he lost weight, had
      a negative fluid balance, and the edema disappeared, a normal diuresis resumed
      and renal function improved. Improvement of respiratory patterns and gas exchange
      made it possible to switch back to conventional ventilation and then to extubate
      the patient. Echocardiography demonstrated reduction of the PA pressure to normal
      and resolution of atrial enlargement. The patient was scheduled for elective
      subtotal pancreatectomy. Diagnosis and management of diazoxide intoxication are
      discussed.

PMID- 15200662
TI  - Anesthetic management of a child with Rubinstein-Taybi syndrome.

PMID- 15200663
TI  - Ketamine to reduce propofol injection pain.

PMID- 15200665
TI  - Accidental intra-arterial injection through an 'intravenous' cannula on the
      dorsum of the hand.

PMID- 15200666
TI  - A reinforced RAE tube for craniofacial surgery.

PMID- 15200667
TI  - Spinal block for predicting reducibility of a huge inguinal hernia in a premature
      infant.

PMID- 15200668
TI  - Fiberoptic intubation through the laryngeal mask airway (LMA) as a standardized
      procedure.

PMID- 15200670
TI  - The 23rd Annual meeting of the association of French speaking pediatric
      anesthetists, March 2003 (ADARPEF).

PMID- 15200671
TI  - Creation of non-human primate neurogenetic disease models by gene targeting and
      nuclear transfer.
AB  - Genetically modified rhesus macaques are necessary because mouse models are not
      suitable for a number of important neurogenetic disorders; for example,
      Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. Mouse
      models may not be suitable because there may be no mouse ortholog of the human
      gene of interest, as is the case for Kallmann's syndrome, or because mutant mice
      do not exhibit the same phenotype observed in humans, as is the the case for
      Lesch-Nyhan's disease and Ataxia-Telangiectasia. Non-human primate models of
      neurogenetic diseases are expected to more closely resemble human diseases than
      existing mouse models. Genetically modified rhesus macaques can be created by
      modifying the genome of a somatic cell and then transferring the nucleus from
      this cell to an enucleated oocyte. Random integration of a transgene is
      sufficient to create models of gain-of-function genetic diseases. Stable
      expression of green fluorescent protein has been achieved in rhesus macaque
      fibroblasts. However, gene targeting is necessary to create models of loss-of
      function genetic diseases. Several technical challenges must be overcome before
      null mutant non-human primates can be produced. In our experience, fetal
      fibroblasts frequently become senescent before selection procedures can be
      completed. We have overcome this problem by transfecting somatic cells with human
      telomerase reverse transcriptase. This enzyme extends the telomeres, and
      lifespan, of somatic cells. Long and accurate polymerase chain reaction can be
      used to obtain sufficient regions of homology of isogenic rhesus genomic DNA for
      targeting constructs. This should improve gene targeting efficiency. Gene
      targeting experiments are currently underway. Null mutant rhesus macaques will
      likely result in breakthrough advances in the understanding of neurogenetic
      disease and prove invaluable for preclinical trials of new therapies.

PMID- 15200672
TI  - Transgenic nonhuman primates for neurodegenerative diseases.
AB  - Animal models that represent human diseases constitute an important tool in
      understanding the pathogenesis of the diseases, and in developing effective
      therapies. Neurodegenerative diseases are complex disorders involving
      neuropathologic and psychiatric alterations. Although transgenic and knock-in
      mouse models of Alzheimer's disease, (AD), Parkinson's disease (PD) and
      Huntington's disease (HD) have been created, limited representation in clinical
      aspects has been recognized and the rodent models lack true neurodegeneration.
      Chemical induction of HD and PD in nonhuman primates (NHP) has been reported,
      however, the role of intrinsic genetic factors in the development of the diseases
      is indeterminable. Nonhuman primates closely parallel humans with regard to
      genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly,
      the development of NHP models for neurodegenerative diseases holds greater
      promise for success in the discovery of diagnoses, treatments, and cures than
      approaches using other animal species. Therefore, a transgenic NHP carrying a
      mutant gene similar to that of patients will help to clarify our understanding of
      disease onset and progression. Additionally, monitoring disease onset and
      development in the transgenic NHP by high resolution brain imaging technology
      such as MRI, and behavioral and cognitive testing can all be carried out
      simultaneously in the NHP but not in other animal models. Moreover, because of
      the similarity in motor repertoire between NHPs and humans, it will also be
      possible to compare the neurologic syndrome observed in the NHP model to that in
      patients. Understanding the correlation between genetic defects and physiologic
      changes (e.g. oxidative damage) will lead to a better understanding of disease
      progression and the development of patient treatments, medications and preventive
      approaches for high risk individuals. The impact of the transgenic NHP model in
      understanding the role which genetic disorders play in the development of
      efficacious interventions and medications is foreseeable.

PMID- 15200673
TI  - Strategies for the production of genetically identical monkeys by embryo
      splitting.
AB  - Genetically identical rhesus monkeys would have tremendous utility as models for
      the study of human disease and would be particularly valuable for vaccine trials
      and tissue transplantation studies where immune function is important. While
      advances in nuclear transfer technology may someday enable monkeys to be cloned
      with some efficiency, embryo splitting may be a more realistic approach to
      creating pairs of genetically identical monkeys. Although several different
      approaches to embryo splitting, including blastocyst bisection and blastomere
      separation, have been used successfully in rodents and domestic species for
      production of pairs and sets of identical offspring, efforts to create
      monozygotic twins in rhesus monkeys using these approaches have not met with
      similar success. Aggregation of split embryos with other types of blastomeres,
      such as tetraploid and developmentally asynchronous blastomeres, that could
      potentially increase their cell numbers and developmental competence without
      contributing to term development has been investigated as an alternative approach
      to creating monozygotic twin monkeys. The major challenges encountered with
      respect to the efficient production of monozygotic twins in rhesus monkeys and
      potential strategies to overcome these challenges are discussed.

PMID- 15200674
TI  - Assisted reproductive technologies in rhesus macaques.
AB  - The assisted reproductive technologies (ARTs) have been used in the production of
      rhesus monkey offspring at the Oregon National Primate Research Center (ONPRC)
      and that experience is summarized here. Additionally these technologies serve as
      a source of oocytes/embryos for monozygotic twinning, embryonic stem (ES) cell
      derivation and cloning. High fertilization efficiencies were realized with
      conventional insemination or following the use of intracytoplasmic sperm
      injection (ICSI) and approximately 50% of the resulting embryos grew in vitro to
      blastocysts. Both fresh and frozen sperm were employed in fertilization by ICSI
      and the resulting embryos could be low temperature stored for subsequent thawing
      and transfer when a synchronized recipient female was available or after shipment
      to another facility. Following the transfer of up to 3 embryos, an overall
      pregnancy rate of 30% was achieved with increasing rates dependent upon the
      number of embryos transferred. Singleton pregnancy outcomes following the
      transfer of ART produced embryos were similar to those observed in a control
      group of animals in the timed mated breeding colony at ONPRC. ICSI produced
      embryos were used in efforts to create monozygotic twins by blastomere separation
      or blastocyst splitting. While pregnancies were achieved following the transfer
      of demi-embryos, only one was a twin and it was lost to spontaneous abortion.
      ICSI produced embryos have also served as the source of blastocysts for the
      derivation of embryonic stem cells. These pluripotent cells hold potential for
      cell based therapies and we consider the monkey an important translational model
      in which to evaluate safety, efficacy and feasibility of regenerative medicine
      approaches based on the transplantation of stem cell-derived progeny. Finally,
      efforts to produce genetically-identical monkeys by nuclear transfer have been
      briefly summarized.

PMID- 15200676
TI  - Pregnancy initiation in the rhesus macaque: towards functional manipulation of
      the maternal-fetal interface.
AB  - Nonhuman primates provide an important opportunity to define the mechanisms that
      contribute to the success of early pregnancy. We have focused for several years
      now on defining the expression of novel placental major histocompatibility
      complex (MHC) class I molecules. In parallel, we have used reagents against human
      immune cell markers to characterize the leukocyte population in the decidua and
      have demonstrated dynamic changes in these cell populations during the first 5
      weeks of gestation. The challenge is to identify the possible role(s) of
      placental MHC class I in modifying/directing the maternal endometrial or systemic
      immune system in the post-implantation period. Foremost among the challenges is
      the difficulty in modifying placental function. In the instance of trophoblast
      surface proteins, passive immunization studies are feasible, although limitations
      include the empirical nature of this approach, as well as the inability to modify
      intracellular function. We have shown that using lentiviral vectors to effect
      preimplantation gene transfer for transgene expression in the placenta is not
      only feasible, but of good efficiency. In addition to transgene overexpression,
      robust approaches for knocking down/knocking out placental gene expression are
      essential. Recent developments in RNA interference approaches may allow
      "transient knockout" experiments. While the rhesus monkey has been our model of
      choice, currently there are limitations in the number of available female rhesus
      monkeys of reproductive age for research in early pregnancy. It is critical that
      the technologies for advanced study move forward in other species. The baboon has
      been used significantly in reproductive tract biology and early pregnancy
      research and important models have been developed for manipulation of the
      maternal-fetal interface. Additional characterization of other species, such as
      the cynomolgus and African green (vervet) monkey is critical. Given the
      limitations on antigen recognition when using human reagents, we also propose
      that the development of panels of primate-specific anti-leukocyte antibodies is
      essential for moving forward nonhuman primate reproductive research.

PMID- 15200678
TI  - High quality sperm for nonhuman primate ART: production and assessment.
AB  - Factors that affect sperm quality can include method of semen collection,
      conditions for capacitation and whether or not agglutination is present. Media
      and procedures for sperm washing can also impair or improve sperm function in
      assisted reproductive technologies. For example, the removal of seminal fluid
      through large volume washing is required to eliminate decapacitation activity of
      seminal plasma. The forces involved with centrifugation and the metabolic stress
      of tightly pelleting sperm during washing procedures can have deleterious
      results. In contrast to human sperm, sperm from the most commonly used species of
      nonhuman primates, rhesus and cynomolgus macaques, do not spontaneously
      capacitate in vitro; rather, chemical activation with dibutryl cyclic AMP and
      caffeine is required. Recognizing motility patterns of non-activated and
      activated sperm can be accomplished with simple observation. After activation,
      sperm agglutination sometimes occurs and can interfere with sperm binding to the
      zona pellucida. Because nonhuman primate oocytes require a large investment to
      produce and currently, each animal can be hormonally stimulated a limited number
      of times, it is important to have means to evaluate quality prior to using sperm
      from a new male for in vitro fertilization. Methods for producing live, acrosome
      reacted sperm may also have application for ICSI. Because many genetically
      valuable males are now being identified, it may be necessary to individualize
      sperm preparation to accommodate male-to-male variation.

PMID- 15200675
TI  - Biology of primate relaxin: a paracrine signal in early pregnancy?
AB  - Relaxin is a peptide hormone that exerts numerous effects in a variety of tissues
      across a broad range of species. Although first identified more than 75 years ago
      interest in relaxin biology has waxed and waned over the years consistent with
      peaks and troughs of new experimental data on its wide-ranging biological effects
      and advances in relaxin enabling technologies. Recent insights into species
      dependent differences in relaxin biology during pregnancy have once again
      stimulated a relative surge of interest in the study of relaxin's reproductive
      biology. Identification and pharmacological characterization of orphaned relaxin
      receptors and exploration of its paracrine effects on pregnancy using genomic and
      proteomic technologies have succeeded in fueling current interest in relaxin
      research. Primates and non-primate vertebrates exhibit very disparate profiles of
      relaxin genomics, proteomics and functional biology. Non-human primates appear to
      exhibit a very close similarity to humans with respect to relaxin reproductive
      biology but the similarities and subtle differences are only just beginning to be
      understood. We, and others, have shown that relaxin produces significant changes
      to the non-human primate endometrium during the peri-implantation period that are
      consistent with relaxin's long perceived role as a paracrine modulator of
      pregnancy. The purpose of this review is to summarize the reproductive biology of
      relaxin in non-human primates with a specific emphasis on the paracrine role of
      ovarian and endometrial relaxin during embryo implantation and early pregnancy.

PMID- 15200677
TI  - Uterine receptivity and implantation: the regulation and action of insulin-like
      growth factor binding protein-1 (IGFBP-1), HOXA10 and forkhead transcription
      factor-1 (FOXO-1) in the baboon endometrium.
AB  - In primates, the phase of the menstrual cycle when the uterus becomes receptive
      is initially dependent on estrogen and progesterone. Further morphological and
      biochemical changes are induced as a result of biochemical signals between the
      embryo and the maternal endometrium. Blastocyst implantation in the baboon
      usually occurs between 8 and 10 days post ovulation and is similar to that
      described for the rhesus macaque. In the baboon, when chorionic gonadotropin is
      infused in a manner that mimics blastocyst transit, this has physiological
      effects on the three major cell types in the uterine endometrium. The luminal
      epithelium undergoes endoreplication and distinct epithelial plaques are evident.
      The glandular epithelium responds by inducing transcriptional and post
      translational modifications in the major secretory product, glycodelin. The
      stromal fibroblasts initiate their differentiation process into a decidual
      phenotype and are characterized by the expression of actin filaments.
      Decidualization, is the major change that occurs in the primate endometrium after
      conception. During this process the fibroblast-like stromal cells change
      morphologically into polygonal cells and express specific decidual proteins.
      Studies in the baboon demonstrated that insulin-like growth factor binding
      protein-1 (IGFBP-1) gene expression is a conceptus-mediated response. Subsequent
      studies in vitro established that IGFBP-1 is transcriptionally regulated by FOXO1
      and HOXA10 which together upregulate the IGFBP-1 promoter activity. A baboon
      endometriosis model was utilized to determine if the changes observed during
      uterine receptivity in normally cycling animals were compromised. The data
      suggests that in animals with disease, markers of uterine receptivity are not
      appropriately expressed in the eutopic endometrium. It is possible that these
      differences influence the fertility of the animals with disease and the baboon
      could be used as a primate model to study the causes of infertility as a result
      of endometriosis.

PMID- 15200680
TI  - The physiology of follicle selection.
AB  - During the follicular phase of the primate menstrual cycle, a single follicle
      usually matures to the preovulatory stage and releases its oocyte for
      fertilization and the potential establishment of pregnancy. In assisted
      reproductive technology procedures, it is desirable to override the natural
      process of follicle selection to produce many oocytes that are capable of being
      fertilized and undergoing normal embryo development. The goal of this chapter is
      to summarize the current views regarding the natural process of follicle
      selection in primates and to discuss how this process may be amplified to produce
      a greater number of oocytes.

PMID- 15200679
TI  - Overriding follicle selection in controlled ovarian stimulation protocols:
      quality vs quantity.
AB  - Selection of the species-specific number of follicles that will develop and
      ovulate during the ovarian cycle can be overridden by increasing the levels of
      pituitary gonadotropin hormones, FSH and LH. During controlled ovarian
      stimulation (COS) in nonhuman primates for assisted reproductive technology (ART)
      protocols, the method of choice (but not the only method) has been the
      administration of exogenous gonadotropins, either of nonprimate or primate
      origin. Due to species-specificity of the primate LH (but not FSH) receptor, COS
      with nonprimate (e.g., PMSG) hormones can be attributed to their FSH activity.
      Elevated levels of FSH alone will produce large antral follicles containing
      oocytes capable of fertilization in vitro (IVF). However, there is evidence that
      LH, probably in lesser amounts, increases the rate of follicular development,
      reduces heterogeneity of the antral follicle pool, and improves the viability and
      rate of pre-implantation development of IVF-produced embryos. Since an endogenous
      LH surge typically does not occur during COS cycles (especially when a GnRH
      antagonist is added), a large dose of an LH-like hormone (i.e., hCG) may be given
      to reinitiate meiosis and produce fertilizable oocytes. Alternate approaches
      using exogenous LH (or FSH), or GnRH agonist to induce an endogenous LH surge,
      have received lesser attention. Current protocols will routinely yield dozens of
      large follicles with fertilizable eggs. However, limitations include non/poor
      responding animals, heterogeneity of follicles (and presumably oocytes) and
      subsequent short luteal phases (limiting embryo transfer in COS cycles). However,
      the most serious limitation to further improvements and expanded use of COS
      protocols for ART is the lack of availability of nonhuman primate gonadotropins.
      Human, and even more so, nonprimate gonadotropins are antigenic in monkeys, which
      limits the number of COS cycles to as few as 1 (PMSG) or 3 (recombinant hCG)
      protocols in macaques. Production and access to sufficient supplies of nonhuman
      primate FSH, LH and CG would overcome this major hurdle.

PMID- 15200681
TI  - Practical methods for dealing with 'not applicable' item responses in the AMC
      Linear Disability Score project.
AB  - BACKGROUND: Whenever questionnaires are used to collect data on constructs, such
      as functional status or health related quality of life, it is unlikely that all
      respondents will respond to all items. This paper examines ways of dealing with
      responses in a 'not applicable' category to items included in the AMC Linear
      Disability Score (ALDS) project item bank. METHODS: The data examined in this
      paper come from the responses of 392 respondents to 32 items and form part of the
      calibration sample for the ALDS item bank. The data are analysed using the one
      parameter logistic item response theory model. The four practical strategies for
      dealing with this type of response are: cold deck imputation; hot deck
      imputation; treating the missing responses as if these items had never been
      offered to those individual patients; and using a model which takes account of
      the 'tendency to respond to items'. RESULTS: The item and respondent population
      parameter estimates were very similar for the strategies involving hot deck
      imputation; treating the missing responses as if these items had never been
      offered to those individual patients; and using a model which takes account of
      the 'tendency to respond to items'. The estimates obtained using the cold deck
      imputation method were substantially different. CONCLUSIONS: The cold deck
      imputation method was not considered suitable for use in the ALDS item bank. The
      other three methods described can be usefully implemented in the ALDS item bank,
      depending on the purpose of the data analysis to be carried out. These three
      methods may be useful for other data sets examining similar constructs, when item
      response theory based methods are used.

PMID- 15200682
TI  - The role of bacterial antizyme: From an inhibitory protein to AtoC
      transcriptional regulator.
AB  - This review considers the role of bacterial antizyme in the regulation of
      polyamine biosynthesis and gives new perspectives on the involvement of antizyme
      in other significant cellular mechanisms. Antizyme is a protein molecule induced
      by the end product of the enzymic reaction that it inhibits, in a non-competitive
      manner. The bacterial ornithine decarboxylase is regulated by nucleotides,
      phosphorylation and antizyme. The inhibition of ornithine decarboxylase by
      antizyme can be relieved to different degrees by DNA or by a variety of synthetic
      nucleic acid polymers, attributed to a specific interaction between nucleic acid
      and antizyme. Recently, this interplay between bacterial antizyme and nucleic
      acid was determined by discerning an additional function to antizyme that proved
      to be the atoC gene product, encoding the response regulator of the bacterial two
      component system AtoS-AtoC. The gene located just upstream of atoC encodes the
      sensor kinase, named AtoS, that modulates AtoC activity. AtoC regulates
      expression of atoDAEB operon which is involved in short-chain fatty acid
      metabolism. Antizyme is thus referred to as AtoC, functioning both as a post
      translational and transcriptional regulator. Also, the AtoS-AtoC signal
      transduction system in E. coli has a positive regulatory role on poly-(R)-3
      hydroxybutyrate biosynthesis. The properties and gene structural similarities of
      antizymes from different organisms were compared. It was revealed that conserved
      domains are present mostly in the C-domain of all antizymes. BLAST analysis of
      the E. coli antizyme protein (AtoC) showed similarities around 69-58% among
      proteobacteria, g-proteobacteria, enterobacteria and the thermophilic bacterium
      Thermus thermophilus. A working hypothesis is proposed for the metabolic role of
      antizyme (AtoC) describing the significant biological implications of this
      protein molecule. Whether antizymes exist to other enzymes in different tissues,
      meeting the criteria discussed in the text remains to be elucidated.

PMID- 15200683
TI  - Calcium and Vitamin D increase mRNA levels for the growth control hIK1 channel in
      human epidermal keratinocytes but functional channels are not observed.
AB  - BACKGROUND: Intermediate-conductance, calcium-activated potassium channels (IKs)
      modulate proliferation and differentiation in mesodermal cells by enhancing
      calcium influx, and they contribute to the physiology of fluid movement in
      certain epithelia. Previous reports suggest that IK channels stimulate
      proliferative growth in a keratinocyte cell line; however, because these channels
      indirectly promote calcium influx, a critically unique component of the
      keratinocyte differentiation program, an alternative hypothesis is that they
      would be anti-proliferative and pro-differentiating. This study addresses these
      hypotheses. METHODS: Real-time PCR, patch clamp electrophysiology, and
      proliferation assays were used to determine if human IK1 (hIK1) expression and
      function are correlated with either proliferation or differentiation in cultured
      human skin epidermal keratinocytes, and skin biopsies grown in explant culture.
      RESULTS: hIK1 mRNA expression in human keratinocytes and skin was increased in
      response to anti-proliferative/pro-differentiating stimuli (elevated calcium and
      Vitamin D). Correspondingly, the hIK1 agonist 1-EBIO inhibited keratinocyte
      proliferation suggesting that the channel could be anti-proliferative and pro
      differentiating. However, this proliferative inhibition by 1-EBIO was not
      reversed by a panel of hIK1 blockers, calling into question the mechanism of 1
      EBIO action. Subsequent patch clamp electrophysiological analysis failed to
      detect hIK1 channel currents in keratinocytes, even those expressing substantial
      hIK1 mRNA in response to calcium and Vitamin D induced differentiation. Identical
      electrophysiological recording conditions were then used to observe robust IK1
      currents in fibroblasts which express IK1 mRNA levels comparable to those of
      keratinocytes. Thus, the absence of observable hIK1 currents in keratinocytes was
      not a function of the electrophysiological techniques. CONCLUSION: Human
      keratinocyte differentiation is stimulated by calcium mobilization and influx,
      and differentiation stimuli coordinately upregulate mRNA levels of the calcium
      activated hIK1 channel. This upregulation is paradoxical in that functional hIK1
      channels are not observed in cultured keratinocytes. It appears, therefore, that
      hIK1 does not contribute to the functional electrophysiology of primary human
      keratinocytes, nor intact human skin. Further, the results indicate caution is
      required when interpreting experiments utilizing pharmacological hIK1 modulators
      in human keratinocytes.

PMID- 15200684
TI  - Reliability and validity of a short form household food security scale in a
      Caribbean community.
AB  - BACKGROUND: We evaluated the reliability and validity of the short form household
      food security scale in a different setting from the one in which it was
      developed. METHODS: The scale was interview administered to 531 subjects from 286
      households in north central Trinidad in Trinidad and Tobago, West Indies. We
      evaluated the six items by fitting item response theory models to estimate item
      thresholds, estimating agreement among respondents in the same households and
      estimating the slope index of income-related inequality (SII) after adjusting for
      age, sex and ethnicity. RESULTS: Item-score correlations ranged from 0.52 to 0.79
      and Cronbach's alpha was 0.87. Item responses gave within-household correlation
      coefficients ranging from 0.70 to 0.78. Estimated item thresholds (standard
      errors) from the Rasch model ranged from -2.027 (0.063) for the 'balanced meal'
      item to 2.251 (0.116) for the 'hungry' item. The 'balanced meal' item had the
      lowest threshold in each ethnic group even though there was evidence of
      differential functioning for this item by ethnicity. Relative thresholds of other
      items were generally consistent with US data. Estimation of the SII, comparing
      those at the bottom with those at the top of the income scale, gave relative odds
      for an affirmative response of 3.77 (95% confidence interval 1.40 to 10.2) for
      the lowest severity item, and 20.8 (2.67 to 162.5) for highest severity item.
      Food insecurity was associated with reduced consumption of green vegetables after
      additionally adjusting for income and education (0.52, 0.28 to 0.96).
      CONCLUSIONS: The household food security scale gives reliable and valid responses
      in this setting. Differing relative item thresholds compared with US data do not
      require alteration to the cut-points for classification of 'food insecurity
      without hunger' or 'food insecurity with hunger'. The data provide further
      evidence that re-evaluation of the 'balanced meal' item is required.

PMID- 15200685
TI  - Essential role for poly (ADP-ribosyl)ation in mouse preimplantation development.
AB  - BACKGROUND: Poly (ADP-ribosyl)ation is a covalent modification of many nuclear
      proteins. It has a strong chromatin modifying potential involved in DNA repair,
      transcription and replication. Its role during preimplantation development is
      unknown. RESULTS: We have observed strong but transient synthesis of poly ADP
      ribose polymers on decondensing chromosomes of fertilized and parthenogenetically
      activated mouse oocytes. Inhibition of this transient upregulation with a
      specific enzyme inhibitor, 3-aminobenzamide, has long-term effects on the
      postimplantation development of the embryos. In addition, inhibition of poly (ADP
      ribosyl)ation at the 4-8 cell stage selectively blocks morula compaction.
      CONCLUSION: These observations suggest that poly (ADP-ribosyl)ation is involved
      in the epigenetic chromatin remodeling in the zygote.

PMID- 15200686
TI  - The VSFASSQQ motif confers calcium sensitivity to the intracellular apyrase
      LALP70.
AB  - BACKGROUND: Apyrases are divalent ion dependent tri- and dinucleotide
      phosphatases with different substrate specificity. The intracellular lysosomal
      apyrase LALP70 is also expressed as a splice variant (LALP70v) lacking a VSFASSQQ
      motif in the center of the molecule (aminoacids 287-294). However, the functional
      significance of this motif is unknown. In this report we used a thin layer
      chromatography approach to study separately the UTPase and UDPase activity of the
      two LALP-enzymes. RESULTS: We show, that LALP70 and LALP70v cleaved UTP to UDP in
      a calcium independent manner. In contrast, the cleavage of UDP to UMP was
      strongly calcium dependent for LALP70, but calcium independent for LALP70v.
      CONCLUSIONS: The VSFASSQQ motif not only influences the substrate specificity of
      LALP70, but it confers calcium sensitivity to LALP70 during the UDP cleavage.
      Whether this is due to direct binding of calcium to this motif or to a
      conformational change of the enzyme, remains to be elucidated.

PMID- 15200687
TI  - Directed differentiation of rhesus monkey ES cells into pancreatic cell
      phenotypes.
AB  - Embryonic stem cells (ES) can self-replicate and differentiate into all cell
      types including insulin-producing, beta-like cells and could, therefore, be used
      to treat diabetes mellitus. To date, results of stem cell differentiation into
      beta cells have been debated, largely due to difficulties in defining the
      identity of a beta cell. We have recently differentiated non-human primate
      (rhesus) embryonic stem (rES) cell lines into insulin producing, beta-like cells
      with the beta cell growth factor, Exendin-4 and using C-peptide as a phenotype
      marker. Cell development was characterized at each stage by gene and protein
      expression. Insulin, NKX6.1 and glucagon mRNA were expressed in stage 4 cells but
      not in early undifferentiated cells. We concluded that rES cells could be
      differentiated ex vivo to insulin producing cells. These differentiated rES cells
      could be used to develop a non-human primate model for evaluating cell therapy to
      treat diabetes. To facilitate the identification of beta-like cells and to track
      the cells post-transplantation, we have developed a marker gene construct: fusing
      the human insulin promoter (HIP) to the green fluorescent protein (GFP) gene.
      This construct was transfected into stage 3 rES derived cells and subsequent GFP
      expression was identified in C-peptide positive cells, thereby substantiating
      endogenous insulin production by rES derived cells. Using this GFP detection
      system, we will enrich our population of insulin producing rES derived cells and
      track these cells post-transplantation in the non-human primate model.

PMID- 15200688
TI  - Derivation and characterization of monkey embryonic stem cells.
AB  - Embryonic stem (ES) cell based therapy carries great potential in the treatment
      of neurodegenerative diseases. However, before clinical application is realized,
      the safety, efficacy and feasibility of this therapeutic approach must be
      established in animal models. The rhesus macaque is physiologically and
      phylogenetically similar to the human, and therefore, is a clinically relevant
      animal model for biomedical research, especially that focused on
      neurodegenerative conditions. Undifferentiated monkey ES cells can be maintained
      in a pluripotent state for many passages, as characterized by a collective
      repertoire of markers representing embryonic cell surface molecules, enzymes and
      transcriptional factors. They can also be differentiated into lineage-specific
      phenotypes of all three embryonic germ layers by epigenetic protocols. For cell
      based therapy, however, the quality of ES cells and their progeny must be ensured
      during the process of ES cell propagation and differentiation. While only a
      limited number of primate ES cell lines have been studied, it is likely that
      substantial inter-line variability exists. This implies that diverse ES cell
      lines may differ in developmental stages, lineage commitment, karyotypic
      normalcy, gene expression, or differentiation potential. These variables,
      inherited genetically and/or induced epigenetically, carry obvious complications
      to therapeutic applications. Our laboratory has characterized and isolated rhesus
      monkey ES cell lines from in vitro produced blastocysts. All tested cell lines
      carry the potential to form pluripotent embryoid bodies and nestin-positive
      progenitor cells. These ES cell progeny can be differentiated into phenotypes
      representing the endodermal, mesodermal and ectodermal lineages. This review
      article describes the derivation of monkey ES cell lines, characterization of the
      undifferentiated phenotype, and their differentiation into lineage-specific,
      particularly neural, phenotypes. The promises and limitations of primate ES cell
      based therapy are also discussed.

PMID- 15200689
TI  - Discreditable: stigma effects of revealing a mental illness history on test
      performance.
AB  - In three studies, the authors examined the effect of revealing a concealable
      social stigma--mental illness--on intellectual performance. It was hypothesized
      that revealing this deeply discrediting stigma would result in performance
      decrements. College students either with or without a history of mental illness
      (MI) treatment participated. In Study 1, the type of mental illness was left
      unselected. In Study 2, only participants who reported a history of depression
      participated. In Study 3, a comparison group of participants with a history of
      eating disorder were included. Results showed that the MI participants who
      revealed their history did worse on the reasoning test than did those in the no
      reveal condition. There was a trend in the opposite direction for participants
      with no MI. As predicted, revealing a narrower stigma, eating disorder, did not
      affect performance. The results are discussed in terms of identity threat and
      concealable stigmas.

PMID- 15200690
TI  - Culture and self: are there within-culture differences in self between
      metropolitan areas and regional cities?
AB  - Although differences in self-conception across cultures have been well
      researched, regional differences within a culture have escaped attention. The
      present study examined individual, relational, and collective selves, which
      capture people's conceptions of themselves in relation to their goals,
      significant others, and in groups, comparing Australians and Japanese
      participants living in regional cities and metropolitan areas. Culture, gender,
      and urbanism were found to be related to individual, relational, and collective
      selves, respectively. Australians emphasized individual self more than Japanese,
      women stressed relational self more than men, and residents in regional cities
      regarded collective self as more important than their counterparts in
      metropolitan areas. These findings provide support for the tripartite division of
      the self and suggest a need to construct a culture theory that links self and
      societal processes.

PMID- 15200691
TI  - A prototype analysis of forgiveness.
AB  - Many definitions of forgiveness currently exist in the literature. The current
      research adds to this discussion by utilizing a prototype approach to examine lay
      conceptions of forgiveness. A prototype approach involves categorizing objects or
      events in terms of their similarity to a good example, whereas a classical
      approach requires that there are essential elements that must be present. In
      Study 1, participants listed the features of forgiveness. Study 2 obtained
      centrality ratings for these features. In Studies 3 and 4, central features were
      found to be more salient in memory than peripheral features. Study 5 showed that
      feature centrality influenced participants' ratings of victims involved in
      hypothetical transgressions. Thus, the two criteria for demonstrating prototype
      structure (that participants find it meaningful to judge features in terms of
      their centrality and that centrality affects cognition) were met.

PMID- 15200692
TI  - Does quick to blame mean quick to anger? The role of agreeableness in
      dissociating blame and anger.
AB  - Two studies investigated agreeableness, the accessibility of blame, and their
      potential interactive effects on anger. To measure the chronic accessibility of
      blame, a choice reaction time task was created that required participants to
      classify words as blameworthy or not. It was found that for individuals low in
      agreeableness, blame accessibility was positively related to anger and arguments
      during the course of daily life, hostile feelings during the course of a
      semester, and anger in response to a short video involving a blameworthy action.
      This same straightforward relationship between the accessibility of blame and
      anger did not characterize those high in agreeableness. The results suggest that
      agreeableness plays an important role in facilitating (low agreeableness) or
      inhibiting (high agreeableness) the link between accessible blame and anger.

PMID- 15200693
TI  - Defeating the potentially deleterious effects of externally imposed deadlines:
      practitioners' rules-of-thumb.
AB  - The authors interviewed people to determine whether they devise strategies to
      offset the damaging effect that externally imposed deadlines have on intrinsic
      motivation. Interviewees' "practitioners' rules-of-thumb" strategies were
      consistent with the tenets of self-determination theory and were tested
      empirically in three experiments. In each of the experiments, complete or partial
      self-determination of initially externally imposed time limits negated the
      otherwise deleterious effects of deadlines on intrinsic motivation. Participants
      who actively co-opted a deadline as their own (Experiment 1), who self-imposed
      sub deadlines within an overall externally imposed deadline (Experiment 2), and
      who self-imposed more stringent deadlines than those imposed externally
      (Experiment 3) spent significantly more free-choice time engaged in target tasks
      than did their counterparts in externally imposed deadline conditions where no
      self-determination was permitted. Given the ubiquity of deadlines, the results
      can directly be implemented by both deadline setters and deadline recipients to
      protect people's interest in their work.

PMID- 15200694
TI  - Attachment and loss: a test of three competing models on the association between
      attachment-related avoidance and adaptation to bereavement.
AB  - It is widely assumed that emotionally avoidant or defensive individuals will have
      a difficult time adjusting to the loss of a loved one. However, recent research
      suggests that defensive individuals tend to adapt quite well to loss. Such
      findings pose a number of challenges to attachment theory--a theory that has
      traditionally held that emotional avoidance is indicative of poor psychological
      adjustment. In this article, the authors argue that contemporary models of
      individual differences in adult attachment allow the derivation of at least three
      competing hypotheses regarding the relationship between avoidant attachment and
      adaptation to loss. These hypotheses are tested using two-wave data on 59
      bereaved adults. Results indicate that whereas some avoidant individuals (i.e.,
      those who are fearfully avoidant) have a difficult time adapting to the loss of a
      loved one, other avoidant adults (i.e., those who are dismissingly avoidant) show
      a pattern of resilience to loss.

PMID- 15200695
TI  - Bias at the racetrack: effects of individual expertise and task importance on
      predecision reevaluation of alternatives.
AB  - These studies were designed to test cognitive dissonance theory's assertion that
      alternatives are not reevaluated before a choice. Participants viewed information
      about horses in a simulated race and rated each one's chance of winning three
      times before placing their bet and once after placing it. It was found that
      ratings of the chosen horse increased within the predecision period as well as
      after betting. Predecision bolstering occurred even when participants did not
      expect to bet, and predecision preference increased with task importance and
      participant expertise. The findings are attributed to maintenance of consistency
      throughout a cognitive system.

PMID- 15200696
TI  - Self-presentations of happiness: sincere, polite, or cautious?
AB  - Two studies addressed the meaning of expressed happiness in social relationships.
      In the first study, men expected to interact with a socially desirable or a
      socially undesirable woman. It was predicted that (a) when about to meet a
      socially undesirable woman, men would display more happiness publicly than is
      felt privately and (b) when about to meet a socially desirable woman, men would
      display less happiness publicly than felt privately. Results supported the former
      and tended to support the latter prediction. In the second study, the authors
      predicted that women would mistrust men's expressions of happiness upon meeting
      them such that (a) unattractive women would suspect men of inflating happiness
      and (b) attractive women would suspect men of suppressing happiness. Results
      supported the former but not the latter hypothesis. Taking relationship-specific
      goals into account appears to be important in determining whether emotion will be
      accurately conveyed and can be trusted.

PMID- 15200697
TI  - Social identity and worldview validation: the effects of ingroup identity primes
      and mortality salience on value endorsement.
AB  - In this article, the authors report an investigation of the relationship between
      terror management and social identity processes by testing for the effects of
      social identity salience on worldview validation. Two studies, with distinct
      populations, were conducted to test the hypothesis that mortality salience would
      lead to worldview validation of values related to a salient social identity. In
      Study 1, reasonable support for this hypothesis was found with bicultural
      Aboriginal Australian participants (N = 97). It was found that thoughts of death
      led participants to validate ingroup and reject outgroup values depending on the
      social identity that had been made salient. In Study 2, when their student and
      Australian identities were primed, respectively, Anglo-Australian students (N =
      119) validated values related to those identities, exclusively. The implications
      of the findings for identity-based worldview validation are discussed.

PMID- 15200698
TI  - Imagining how you'd feel: the role of motivational experiences from regulatory
      fit.
AB  - The authors propose that how people imagine they would feel about making a choice
      is affected not only by the outcome's anticipated pleasure or pain but also by
      regulatory fit. Regulatory fit occurs when people pursue a goal in a manner that
      sustains their regulatory state and it intensifies the motivation to pursue that
      goal. Considering positive outcomes fits a promotion focus more than a prevention
      focus, whereas the reverse is true for negative outcomes. Thus, it is proposed
      that anticipating a desirable choice is more intensely positive for promotion
      than prevention, and anticipating an undesirable choice is more intensely
      negative for prevention than promotion. The results of three studies support
      these predictions. Studies 2 and 3 also demonstrate that motivational intensity
      underlies the stronger responses. Thus, to understand fully what it means to feel
      good or bad about a prospective choice, motivational experiences from regulatory
      fit must be considered.

PMID- 15200700
TI  - Electrophysiological evidence for reversed lexical repetition effects in language
      processing.
AB  - Effects of word repetition are extremely robust, but can these effects be
      modulated by discourse context? We examined this in an ERP experiment that tested
      coreferential processing (when two expressions refer to the same person) with
      repeated names. ERPs were measured to repeated names and pronoun controls in two
      conditions: (1) In the prominent condition the repeated name or pronoun
      coreferred with the subject of the preceding sentence and was therefore prominent
      in the preceding discourse (e.g., "John went to the store after John/he."); (2)
      in the nonprominent condition the repeated name or pronoun coreferred with a name
      that was embedded in a conjoined noun phrase, and was therefore nonprominent
      (e.g., "John and Mary went to the store after John/he."). Relative to the
      prominent condition, the nonprominent condition always contained two extra words
      (e.g., "and Mary"), and the repetition lag was therefore smaller in the prominent
      condition. Typically, effects of repetition are larger with smaller lags.
      Nevertheless, the amplitude of the N400 was reduced to a coreferentially repeated
      name when the antecedent was nonprominent as compared to when it was prominent.
      No such difference was observed for the pronoun controls. Because the N400 effect
      reflects difficulties in lexical integration, this shows that the difficulty of
      achieving coreference with a name increased with the prominence of the referent.
      This finding is the reverse of repetition lag effects on N400 previously found
      with word lists, and shows that language context can override general memory
      mechanisms.

PMID- 15200701
TI  - Reading in a regular orthography: an FMRI study investigating the role of visual
      familiarity.
AB  - In order to separate the cognitive processes associated with phonological
      encoding and the use of a visual word form lexicon in reading, it is desirable to
      compare the processing of words presented in a visually familiar form with words
      in a visually unfamiliar form. Japanese Kana orthography offers this possibility.
      Two phonologically equivalent but visually dissimilar syllabaries allow the
      writing of, for example, foreign loanwords in two ways, only one of which is
      visually familiar. Familiarly written words, unfamiliarly written words, and
      pseudowords were presented in both Kana syllabaries (yielding six conditions in
      total) to participants during an fMRI measurement with a silent articulation task
      (Experiment 1) and a phonological lexical decision task (Experiment 2) using an
      event-related design. Consistent over two experimental tasks, the three different
      stimulus types (familiar, unfamiliar, and pseudoword) were found to activate
      selectively different brain regions previously associated with phonological
      encoding and word retrieval or meaning. Compatible with the predictions of the
      dual-route model for reading, pseudowords and visually unfamiliar words, which
      have to be read using phonological assembly, caused an increase in brain activity
      in left inferior frontal regions (BA 44/47), as compared to visually familiar
      words. Visually familiar and unfamiliar words were found to activate a range of
      areas associated with lexico-semantic processing more strongly than pseudowords,
      such as the left and right temporo-parietal region (BA 39/40), a region in the
      left middle/inferior temporal gyrus (BA 20/21), and the posterior cingulate (BA
      31).

PMID- 15200702
TI  - Mechanisms of moving the mind's eye: planning and execution of spatial shifts of
      attention.
AB  - The usefulness of attentional orienting, both in the real world and in the
      laboratory, depends not only on the ability to attend to objects or other inputs
      but also on the ability to shift attention between them. Although understanding
      the basic characteristics of these shifts is a critical step toward understanding
      the brain mechanisms that produce them, the literature remains unresolved on a
      very basic and potentially revealing characteristic of these shifts-namely,
      whether attention takes longer to shift a farther distance across the visual
      field. We addressed this question using a series of behavioral tasks involving
      the voluntary orienting of attention to locations in the visual field. The
      findings support a model in which attentional shifts include separate "planning"
      and "execution" stages and in which only the planning stage requires more time
      for shifts of a greater distance. These results offer resolution to the
      longstanding debate concerning the effect of attentional shift distance on shift
      time and provide insight into the fundamental mechanisms of attentional shifting.

PMID- 15200703
TI  - Neural correlates of attentional capture in visual search.
AB  - Much behavioral research has shown that the presence of a unique singleton
      distractor during a task of visual search will typically capture attention and
      thus disrupt target search. Here we examined the neural correlates of such
      attentional capture using functional magnetic resonance imaging in human subjects
      during performance of a visual search task. The presence (vs. absence) of a
      salient yet irrelevant color singleton distractor was associated with activity in
      the superior parietal cortex and frontal cortex. These findings imply that the
      singleton distractor induced spatial shifts of attention despite its irrelevance,
      as predicted from an AC account. Moreover, behavioral interference by singleton
      distractors was strongly and negatively correlated with frontal activity. These
      findings provide direct evidence that the frontal cortex is involved in control
      of interference from irrelevant but attention-capturing distractors.

PMID- 15200704
TI  - Event-related potential correlates of the retrieval of emotional and nonemotional
      context.
AB  - In two experiments, we examined event-related potentials (ERPs) elicited in an
      old/new recognition memory test by emotionally neutral visual objects that, at
      encoding, had been associated with neutrally, negatively, or positively valenced
      background contexts. In Experiment 2, subjects also judged the context in which
      the item had been studied. In Experiment 1, "left parietal" old/new ERP effects
      were elicited by correctly recognized items. Items encoded in emotional contexts,
      but not those studied in neutral contexts, elicited additional effects early in
      the recording epoch over lateral temporal scalp and, later, over left temporo
      frontal scalp. In Experiment 2, "left parietal" and "right frontal" ERP effects
      were elicited by recognized items that attracted correct source judgments.
      Additional effects, an early lateral temporal positivity and a late-onset, left
      sided positivity, were elicited by items studied in emotionally valenced contexts
      and attracting correct source judgments. Together, the findings indicate that
      retrieval processing is influenced by the emotional valence of the context in
      which an item is encoded, regardless of whether contextual information is task
      relevant.

PMID- 15200705
TI  - Predicting success: patterns of cortical activation and deactivation prior to
      response inhibition.
AB  - The present study investigated the relationships between attention and other
      preparatory processes prior to a response inhibition task and the processes
      involved in the inhibition itself. To achieve this, a mixed fMRI design was
      employed to identify the functional areas activated during both inhibition
      decision events and the block of trials following a visual cue introduced 2 to 7
      sec prior (cue period). Preparing for successful performance produced increases
      in activation for both the cue period and the inhibition itself in the
      frontoparietal cortical network. Furthermore, preparation produced activation
      decreases in midline areas (insula and medial prefrontal) argued to be
      responsible for monitoring internal emotional states, and these cue period
      deactivations alone predicted subsequent success or failure. The results suggest
      that when cues are provided to signify the imminent requirement for behavioral
      control, successful performance results from a coordinated pattern of preparatory
      activation in task-relevant areas and deactivation of task-irrelevant ones.

PMID- 15200706
TI  - The BOLD hemodynamic response in healthy aging.
AB  - Several previous studies have compared the blood oxygen level-dependent (BOLD)
      hemodynamic response (HDR) in healthy elderly subjects to the HDR in young
      subjects. Some studies have found a relative decreased amplitude in the elderly
      in the visual cortex, whereas other studies have found the elderly HDR amplitude
      in the visual cortex to be nearly identical to that in young subjects. A possible
      explanation for the different findings is that the peak voxel HDR is similar
      between the groups, but that the HDR in the group-averaged region-of-interest
      (ROI) is "washed out" by the inclusion of less significant voxels (due to a
      smaller extent of activation in the elderly) or by the inclusion of negative
      peaking voxels. We tested this hypothesis using event-related functional magnetic
      resonance imaging (fMRI ). While undergoing fMRI, subjects performed a simple
      visual and motor task, pressing with their index fingers in response to visual
      presentation of the word tap. Data from 18 subjects, 8 young and 10 elderly, were
      analyzed. For each subject, a visual and a motor ROI was selected by choosing the
      most significant positive voxels within the anatomically defined ROI. This
      individual subject approach excluded both low-significance and negative-peaking
      voxels. Similar peaks were found for the elderly and the young subjects in both
      motor and visual regions and a more sustained BOLD response was found for the
      elderly in both regions. Additionally, as predicted, a greater percentage of
      voxels with a negative HDR was found for the elderly in the visual region; this
      finding was also replicated in our reanalysis of an independent fMRI and aging
      study from the fMRI Data Center. Functional neuroimaging observations of negative
      HDRs in visual areas have been interpreted as the effect of unconstrained
      processing during rest. Our results suggest that the elderly may have more
      unconstrained visual processing during the rest condition in the scanner. The
      observation that the group differences in the BOLD response are sensitive to
      voxel selection (e.g., inclusion of low-significance and/or negative voxels)
      underscores the importance of ROI selection criteria in the interpretation of
      fMRI studies using elderly populations.

PMID- 15200707
TI  - Shape saliency modulates contextual processing in the human lateral occipital
      complex.
AB  - Visual context influences our perception of target objects in natural scenes.
      However, little is known about the analysis of context information and its role
      in shape perception in the human brain. We investigated whether the human lateral
      occipital complex (LOC), known to be involved in the visual analysis of shapes,
      also processes information about the context of shapes within cluttered scenes.
      We employed an fMRI adaptation paradigm in which fMRI responses are lower for two
      identical than for two different stimuli presented consecutively. The stimuli
      consisted of closed target contours defined by aligned Gabor elements embedded in
      a background of randomly oriented Gabors. We measured fMRI adaptation in the LOC
      across changes in the context of the target shapes by manipulating the position
      and orientation of the background elements. No adaptation was observed across
      context changes when the background elements were presented in the same plane as
      the target elements. However, adaptation was observed when the grouping of the
      target elements was enhanced in a bottom-up (i.e., grouping by disparity or
      motion) or top-down (i.e., shape priming) manner and thus the saliency of the
      target shape increased. These findings suggest that the LOC processes information
      not only about shapes, but also about their context. This processing of context
      information in the LOC is modulated by figure-ground segmentation and grouping
      processes. That is, neural populations in the LOC encode context information when
      relevant to the perception of target shapes, but represent salient targets
      independent of context changes.

PMID- 15200708
TI  - Multisensory integration sites identified by perception of spatial wavelet
      filtered visual speech gesture information.
AB  - Perception of speech is improved when presentation of the audio signal is
      accompanied by concordant visual speech gesture information. This enhancement is
      most prevalent when the audio signal is degraded. One potential means by which
      the brain affords perceptual enhancement is thought to be through the integration
      of concordant information from multiple sensory channels in a common site of
      convergence, multisensory integration (MSI) sites. Some studies have identified
      potential sites in the superior temporal gyrus/sulcus (STG/S) that are responsive
      to multisensory information from the auditory speech signal and visual speech
      movement. One limitation of these studies is that they do not control for
      activity resulting from attentional modulation cued by such things as visual
      information signaling the onsets and offsets of the acoustic speech signal, as
      well as activity resulting from MSI of properties of the auditory speech signal
      with aspects of gross visual motion that are not specific to place of
      articulation information. This fMRI experiment uses spatial wavelet bandpass
      filtered Japanese sentences presented with background multispeaker audio noise to
      discern brain activity reflecting MSI induced by auditory and visual
      correspondence of place of articulation information that controls for activity
      resulting from the above-mentioned factors. The experiment consists of a low
      frequency (LF) filtered condition containing gross visual motion of the lips,
      jaw, and head without specific place of articulation information, a midfrequency
      (MF) filtered condition containing place of articulation information, and an
      unfiltered (UF) condition. Sites of MSI selectively induced by auditory and
      visual correspondence of place of articulation information were determined by the
      presence of activity for both the MF and UF conditions relative to the LF
      condition. Based on these criteria, sites of MSI were found predominantly in the
      left middle temporal gyrus (MTG), and the left STG/S (including the auditory
      cortex). By controlling for additional factors that could also induce greater
      activity resulting from visual motion information, this study identifies
      potential MSI sites that we believe are involved with improved speech perception
      intelligibility.

PMID- 15200709
TI  - Neural correlates of first-person perspective as one constituent of human self
      consciousness.
AB  - Taking the first-person perspective (1PP) centered upon one's own body as opposed
      to the third-person perspective (3PP), which enables us to take the viewpoint of
      someone else, is constitutive for human self-consciousness. At the underlying
      representational or cognitive level, these operations are processed in an
      egocentric reference frame, where locations are represented centered around
      another person's (3PP) or one's own perspective (1PP). To study 3PP and 1PP, both
      operating in egocentric frames, a virtual scene with an avatar and red balls in a
      room was presented from different camera viewpoints to normal volunteers (n = 11)
      in a functional magnetic resonance imaging experiment. The task for the subjects
      was to count the objects as seen either from the avatar's perspective (3PP) or
      one's own perspective (1PP). The scene was presented either from a ground view
      (GV ) or an aerial view (AV ) to investigate the effect of view on perspective
      taking. The factors perspective (3PP vs. 1PP) and view (GV vs. AV ) were arranged
      in a two-factorial way. Reaction times were increased and percent correctness
      scores were decreased in 3PP as opposed to 1PP. To detect the neural mechanisms
      associated with perspective taking, functional magnetic resonance imaging was
      employed. Data were analyzed using SPM'99 in each subject and non-parametric
      statistics on the group level. Activations common to 3PP and 1PP (relative to
      baseline) were observed in a network of occipital, parietal, and prefrontal
      areas. Deactivations common to 3PP and 1PP (relative to baseline) were observed
      predominantly in mesial (i.e., parasagittal) cortical and lateral superior
      temporal areas bilaterally. Differential increases of neural activity were found
      in mesial superior parietal and right premotor cortex during 3PP (relative to
      1PP), whereas differential increases during 1PP (relative to 3PP) were found in
      mesial prefrontal cortex, posterior cingulate cortex, and superior temporal
      cortex bilaterally. The data suggest that in addition to joint neural mechanisms,
      for example, due to visuospatial processing and decision making, 3PP and 1PP rely
      on differential neural processes. Mesial cortical areas are involved in
      decisional processes when the spatial task is solved from one's own viewpoint,
      whereas egocentric operations from another person's perspective differentially
      draw upon cortical areas known to be involved in spatial cognition.

PMID- 15200710
TI  - Involvement of the superior temporal cortex and the occipital cortex in spatial
      hearing: evidence from repetitive transcranial magnetic stimulation.
AB  - The processing of auditory spatial information in cortical areas of the human
      brain outside of the primary auditory cortex remains poorly understood. Here we
      investigated the role of the superior temporal gyrus (STG) and the occipital
      cortex (OC) in spatial hearing using repetitive transcranial magnetic stimulation
      (rTMS). The right STG is known to be of crucial importance for visual spatial
      awareness, and has been suggested to be involved in auditory spatial perception.
      We found that rTMS of the right STG induced a systematic error in the perception
      of interaural time differences (a primary cue for sound localization in the
      azimuthal plane). This is in accordance with the recent view, based on both
      neurophysiological data obtained in monkeys and human neuroimaging studies, that
      information on sound location is processed within a dorsolateral "where" stream
      including the caudal STG. A similar, but opposite, auditory shift was obtained
      after rTMS of secondary visual areas of the right OC. Processing of auditory
      information in the OC has previously been shown to exist only in blind persons.
      Thus, the latter finding provides the first evidence of an involvement of the
      visual cortex in spatial hearing in sighted human subjects, and suggests a close
      interconnection of the neural representation of auditory and visual space.
      Because rTMS induced systematic shifts in auditory lateralization, but not a
      general deterioration, we propose that rTMS of STG or OC specifically affected
      neuronal circuits transforming auditory spatial coordinates in order to maintain
      alignment with vision.

PMID- 15200711
TI  - Consistent chronostasis effects across saccade categories imply a subcortical
      efferent trigger.
AB  - Saccadic chronostasis refers to the subjective temporal lengthening of the first
      visual stimulus perceived after an eye movement, and is most commonly experienced
      as the "stopped clock" illusion. Other temporal illusions arising in the context
      of movement (e.g., "intentional binding") appear to depend upon the volitional
      nature of the preceding motor act. Here we assess chronostasis across different
      saccade types, ranging from highly volitional (self-timed saccades, antisaccades)
      to highly reflexive (peripherally cued saccades, express saccades). Chronostasis
      was similar in magnitude across all these conditions, despite wide variations in
      their neural bases. The illusion must therefore be triggered by a "lowest common
      denominator" signal common to all the conditions tested and their respective
      neural circuits. Specifically, it is suggested that chronostasis is triggered by
      a low-level signal arising in response to efferent signals generated in the
      superior colliculus.

PMID- 15200712
TI  - Left but not right temporal involvement in opaque idiom comprehension: a
      repetitive transcranial magnetic stimulation study.
AB  - It has been suggested that figurative language, which includes idioms, is
      controlled by the right hemisphere. We tested the right hemisphere hypothesis by
      using repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt
      the function of the frontal and temporal areas of the right versus left
      hemisphere in a group of normal participants involved in a task of opaque idiom
      versus literal sentence comprehension. Forty opaque, nonambiguous idioms were
      selected. Fifteen young healthy participants underwent rTMS in two sessions. The
      experiment was run in five blocks, corresponding to the four stimulated scalp
      positions ( left frontal and temporal and right frontal and temporal) and a
      baseline. Each block consisted of 16 trials-8 trials with idioms and 8 trials
      with literal sentences. In each trial, the subject was presented with a written
      sentence, which appeared on the screen for 2000 msec, followed by a pair of
      pictures for 2500 msec, one of which corresponded to the sentence. The
      alternative corresponded to the literal meaning for idioms and to a sentence
      differing in a detail in the case of literal sentences. The subject had to press
      a button corresponding to the picture matching the string. Reaction times
      increased following left temporal rTMS, whereas they were unaffected by right
      hemisphere rTMS, with no difference between idiomatic and literal sentences. Left
      temporal rTMS also reduced accuracy without differences between the two types of
      sentences. These data suggest that opaque idiom and literal sentence
      comprehension depends on the left temporal cortex.

PMID- 15200713
TI  - Derivation and analysis of basic computational operations of thalamocortical
      circuits.
AB  - Shared anatomical and physiological features of primary, secondary, tertiary,
      polysensory, and associational neocortical areas are used to formulate a novel
      extended hypothesis of thalamocortical circuit operation. A simplified
      anatomically based model of topographically and nontopographically projecting
      ("core" and "matrix") thalamic nuclei, and their differential connections with
      superficial, middle, and deep neocortical laminae, is described. Synapses in the
      model are activated and potentiated according to physiologically based rules.
      Features incorporated into the models include differential time courses of
      excitatory versus inhibitory postsynaptic potentials, differential axonal
      arborization of pyramidal cells versus interneurons, and different laminar
      afferent and projection patterns. Observation of the model's responses to static
      and time-varying inputs indicates that topographic "core" circuits operate to
      organize stored memories into natural similarity-based hierarchies, whereas
      diffuse "matrix" circuits give rise to efficient storage of time-varying input
      into retrievable sequence chains. Examination of these operations shows their
      relationships with well-studied algorithms for related functions, including
      categorization via hierarchical clustering, and sequential storage via hash- or
      scatter-storage. Analysis demonstrates that the derived thalamocortical
      algorithms exhibit desirable efficiency, scaling, and space and time cost
      characteristics. Implications of the hypotheses for central issues of perceptual
      reaction times and memory capacity are discussed. It is conjectured that the
      derived functions are fundamental building blocks recurrent throughout the
      neocortex, which, through combination, gives rise to powerful perceptual, motor,
      and cognitive mechanisms.

PMID- 15200714
TI  - Effects of strategies on mental rotation and hemispheric lateralization:
      neuropsychological evidence.
AB  - We can predict how an object would look if we were to see it from different
      viewpoints by imagining its rotation. This essential human ability, called mental
      rotation (MR), guides individuals' actions by constantly updating their
      environmental consequences. It is, however, still under debate whether the way in
      which our brain accomplishes this operation is determined by the type of stimulus
      or rather by a mental strategy. Here we present neuropsychological evidence
      sustaining the view that what matters is the type of strategy adopted in MR.
      Thus, independently of the type of stimulus, patients with left hemisphere
      lesions showed a selective deficit in MR as a consequence of their manual
      activity, whereas patients with right hemisphere lesions were found impaired in
      MR by means of a visual strategy. We conclude that MR is achieved by recruiting
      different strategies, implicitly triggered or prompted at will, each sustained by
      a unilateral brain network.

PMID- 15200715
TI  - Analog numerical representations in rhesus monkeys: evidence for parallel
      processing.
AB  - Monkeys have been introduced as model organisms to study neural correlates of
      numerical competence, but many of the behavioral characteristics of numerical
      judgments remain speculative. Thus, we analyzed the behavioral performance of two
      rhesus monkeys judging the numerosities 1 to 7 during a delayed match-to-sample
      task. The monkeys showed similar discrimination performance irrespective of the
      exact physical appearance of the stimuli, confirming that performance was based
      on numerical information. Performance declined smoothly with larger numerosities,
      and reached discrimination threshold at numerosity "4." The nonverbal numerical
      representations in monkeys were based on analog magnitudes, object tracking
      process ("subitizing") could not account for the findings because the continuum
      of small and large numbers shows a clear Weber fraction signature. The lack of
      additional scanning eye movements with increasing set sizes, together with
      indistinguishable neuronal response latencies for neurons with different
      preferred numerosities, argues for parallel encoding of numerical information.
      The slight but significant increase in reaction time with increasing numerosities
      can be explained by task difficulty and consequently time-consuming decision
      processes. The behavioral results are compared to single-cell recordings from the
      prefrontal cortex in the same subjects. Models for numerosity discrimination that
      may account for these results are discussed.

PMID- 15200716
TI  - Person-centered care.

PMID- 15200717
TI  - Clarifying the concept of sacrifice as a health-related concept.

PMID- 15200718
TI  - An exploration of the concept of sacrifice.
AB  - This column seeks to contribute to the understanding of the concept of sacrifice
      and its significance to nursing through an extensive account of relevant
      literature from the disciplines of theology, sociology, anthropology, and
      psychology. The review uncovered that in sacrificing something of value,
      individuals anticipate connecting with families, groups, society, and deities.
      Knowledge of the phenomenon of sacrifice has importance for nurses who use the
      human becoming theory as a guide for practice as they participate with
      individuals who are struggling with relinquishing something of value, while
      hoping to strengthen connections with others.

PMID- 15200719
TI  - The researcher's reflections on the research process.
AB  - From this researcher's perspective an essential component of rigorous inquiry is
      the ability of the researcher to provide a transparent accounting of his/her
      journey throughout the research process. In keeping with this belief this
      researcher's personal reflections of, and insights gleaned from, his experience
      into the world of research in general, and the human becoming school of thought
      in particular, are presented. He offers personal insights into the lived
      experience of completing a Parsean study on the structure of taking life day-by
      day as a universal lived experience of health. Throughout this research process a
      number of insights have been gleaned which include the importance of adequate
      preparation in conducting research, the role of the researcher, preparedness to
      work with uncertainty, and achieving authentic rigor.

PMID- 15200722
TI  - Socrates' questions: a focus for nursing.
AB  - This column focuses on the philosophical dialogue originated by Socrates. Six
      questions that Socrates would ask the ancient Greeks are explored in discussing a
      book written by Phillips entitled Six Questions of Socrates. These questions
      were: What is virtue? What is moderation? What is justice? What is good? What is
      courage? What is piety? A human becoming perspective is used as a lens to view
      the discussion on these questions and the question is posed, "What would it be
      like to frame discussions on health and quality of life around Socrates'
      questions?" Parse's teaching-learning processes are presented as a means of
      creating an environment where dialogue on these questions can occur.

PMID- 15200721
TI  - Stories: implications for nursing ethics and respect for another.
AB  - Stories are narratives cocreated in the human-universe process which reflect
      authors' priority projects, ideas, and creative artistry. These articulations may
      be utilized as methods for understanding health and quality of life in the
      discipline of nursing. Stories are living entities of community that may be used
      for research, education, and practice. They are vital tools for professionals
      asking ethical questions about doing what is right in the human-universe-health
      process. This article shall examine the use of stories and provide notions for
      further ethical thinking and implications for human regard from a nursing
      theoretical perspective.

PMID- 15200724
TI  - Meaning of the quality of life for persons living with serious mental illness:
      human becoming practice with groups.
AB  - Quality of life is a concern for people living with diagnoses of persistent
      mental illness. While some studies with this community of people have measured
      quality of life as an indicator of adjustment, little is known about the meaning
      of quality of life from the perspectives of these individuals themselves. The
      project described in this practice column explored the meaning of quality of life
      for a group of persons attending a community centre for persons with mental
      illness. Parse's human becoming practice method was used to guide the group
      process with eight men who met weekly with a nurse for 75-90 minute sessions over
      10 weeks. The nurse's commitment to live true presence with the group enabled
      their expressions about life and the meanings of living with their particular
      struggles and joys, sufferings and hopes. Themes of quality of life for this
      group of persons are detailed in this column.

PMID- 15200726
TI  - Human becoming: scope and challenges. Interview by Jacqueline Fawcett.

PMID- 15200727
TI  - Patterning of pain and power with guided imagery.
AB  - Using Martha Rogers' science of unitary human beings, changes in pain and power
      among 42 patients were examined in relation to the use of a guided imagery
      modality. Participants were randomly assigned to treatment and control groups and
      repeated measures MANCOVA was used to detect differences in pain and power over a
      4-day period of time. The treatment group's pain decreased during the last 2 days
      of the study. No differences in power emerged. Guided imagery appeared to have
      potential as a useful nursing modality for chronic pain sufferers.

PMID- 15200728
TI  - An emerging model of behavior change in women maintaining weight loss.
AB  - This study is based on and expands Newman's theory of health as expanding
      consciousness with women who maintained weight loss for at least 1 year. The
      researcher engaged in two in-depth interviews with twenty women. Individual
      patterns for participants who maintained weight loss revealed a personal journey
      of self-discovery and control with initial chaos, choice, and then emergence of
      behaviors reflecting expanded consciousness. Looking across participants, six
      patterns emerged from the data with evolution of a model of change that has
      implications for nursing practice at defined times within the change process of
      weight loss.

PMID- 15200729
TI  - Empowerment: reformulation of a non-Rogerian concept.
AB  - The authors present a reformulation of empowerment based upon historical and
      current perspectives of empowerment and a synthesis of existing literature and
      Rogerian thought. Reformulation of non-Rogerian concepts familiar to nurses is
      proposed as a strategy to accelerate the mainstreaming of Rogerian thought into
      nursing practice and research. The reformulation of empowerment as a
      participatory process of well-being inherent among human beings may provide
      nurses with new insights for practice. This paper may also serve as a model for
      reformulating other non-Rogerian concepts and theories for wider dissemination
      across the discipline.

PMID- 15200730
TI  - A theory of health promotion for preterm infants based on Levine's Conservation
      Model of Nursing.
AB  - The infant born prior to the completion of term gestation faces many challenges
      in order to merely survive in the extrauterine environment. A preterm birth is
      also a time of extreme crisis for the family. There is a great need for the
      refinement of nursing practice models for neonatal intensive care nursing, to
      assure that the holistic nursing care needs of the infant and family are met.
      This article describes a new middle range theory of health promotion for preterm
      infants based on Levine's conservation model of nursing that can be used to guide
      neonatal nursing practice.

PMID- 15200731
TI  - A theoretical approach to documentation of care.
AB  - The purpose of this column is to present a theoretical background for
      understanding nursing care documentation. The theory used was Eriksson's theory
      of health and suffering. An adaptation of Gadamer's hermenuetic method was used
      to apply the theory to a way of thinking about clinical practice. The hermeneutic
      dialogue took place between Eriksson's caring science texts and clinical nursing
      practice. The dialogue shows that relating different dimensions of the patient's
      health and suffering to the dimensions of care seems to provide the necessary
      prerequisites for the development of a theoretical background for the
      documentation of care. It also allows the patient's views and experiences to be
      revealed in the documents related to nursing care.

PMID- 15200732
TI  - Diversity and becoming: implications of human existence as coexistence.

PMID- 15200734
TI  - Direct medical costs associated with using vancomycin in methicillin-resistant
      Staphylococcus aureus infections: an economic model.
AB  - OBJECTIVES: To quantify the direct medical costs associated with using
      vancomycin, as inpatient treatment, in methicillin-resistant Staphylococcus
      aureus infections, in four clinical indications: complicated skin and soft tissue
      infections (SSTI), bacteremia, infective endocarditis (IE), and hospital-acquired
      pneumonia (HAP). RESEARCH DESIGN AND METHODS: A decision-analytic model was
      constructed to evaluate the cost of administering intravenous vancomycin. Cost
      inputs included hospitalization, drug procurement, materials, preparation and
      administration, renal function and drug monitoring, treating adverse events, and
      treatment failure. Probabilities and lengths of stay and treatment were obtained
      from the literature, an antimicrobial therapy database and clinical expert
      opinion. Univariate and multivariate sensitivity analyses were conducted to
      confirm the robustness of the baseline scenario. MAIN OUTCOME MEASURES: The cost
      of using vancomycin in the four indications, including and excluding hospital
      cost. RESULTS: Whereas the drug acquisition price of vancomycin 1g is US dollars
      9.01 per dose, when all costs associated with using vancomycin were included, the
      cost per dose rose to US dollars 29-US dollars 43 per patient. Total costs per
      patient receiving multiple doses in a single course of treatment, excluding
      hospital room costs, were for SSTI, bacteremia, IE, and HAP,US dollars 779, US
      dollars 749, US dollars 2261, and US dollars 768, respectively. Total costs,
      including hospital length of stay, were for SSTI US dollars 23616, bacteremia US
      dollars 26446, IE US dollars 48925, and HAP US dollars 22493. In univariate
      analyses varying per diem hospital costs and length of stay had the greatest
      impact. Results of the multivariate analysis were comparable to the costs in the
      baseline scenario for all indications. CONCLUSIONS: This analysis highlights the
      importance of capturing all costs associated with using a drug and not simply
      focusing on drug acquisition cost. Future economic analyses should identify and
      account for the key cost burdens of a particular treatment to calculate its true
      cost.

PMID- 15200735
TI  - The wet patient: understanding patients with overactive bladder and incontinence.
AB  - Overactive bladder (OAB) is a constellation of lower urinary tract symptoms,
      including urinary frequency and urgency,which can occur with or without urinary
      incontinence. Incontinence is present in over half of female patients with OAB.
      This condition affects more than 33 million Americans and imposes considerable
      economic, social, and psychological burdens. Although continued improvements in
      the pharmacologic management of lower urinary tract disorders have led to the
      availability of well-tolerated, characteristic features, prevalence and
      epidemiology, effective treatment options, the symptoms of OAB are generally
      underreported by patients and under treated by healthcare professionals.
      Heightened awareness of the multifaceted disease burden imposed by OAB and
      increased understanding of the characteristics of patients who are likely to be
      most severely affected, in particular those who suffer from incontinence, may
      improve the timely identification, diagnosis, and clinical management of the
      syndrome, enhancing both the health and quality of life of these patients. This
      review will summarize the clinical consequences, and management of OAB, with
      particular focus on the incontinent patient.

PMID- 15200736
TI  - Pharmacokinetic profile of a new form of sumatriptan tablets in healthy
      volunteers.
AB  - OBJECTIVE: Rapid delivery of migraine-specific medication to its site(s) of
      action is thought to be crucial in preventing or minimizing sensitization of
      central pain pathways and thereby in optimizing pain-free outcomes in patients
      with migraine. Sumatriptan has been developed as a new tablet formulation to
      enhance the rate of systemic drug delivery by improving tablet disintegration and
      drug dispersion relative to those of conventional tablets. These enhanced
      formulation characteristics may be beneficial during occurrences of the gastric
      stasis that can accompany migraine. METHODS: This randomized, open-label, 4-way
      crossover study (n = 32) was conducted to determine whether the new formulation
      of sumatriptan 50 and 100 mg is bioequivalent to sumatriptan conventional tablets
      and to compare the pharmacokinetic profiles of the new formulation and the
      conventional tablet during the early (0-2 h) postdose interval in healthy
      volunteers. Pharmacokinetics during the early post-dose interval are important in
      determining a drug's onset of action, an important parameter to patients with
      migraine. RESULTS: The results confirm that the new formulation of sumatriptan
      and sumatriptan conventional tablets are bioequivalent as demonstrated by the
      finding that the 90% confidence intervals for the sumatriptan area under the
      concentration time curve to infinity and to the last evaluable time point (AUC(0-
      infinity ) and AUC(0-t), respectively) and maximum plasma concentration (C(max))
      fell within the predetermined bounds defining bioequivalence (0.80-1.25) for both
      doses. Pharmacokinetic parameters measured early (0-2 h) after dosing reveal
      slightly faster absorption, on average, of the new sumatriptan formulation than
      sumatriptan conventional tablets although high intersubject variability was
      observed. For the new sumatriptan formulation, AUC(0-2) (AUC up to 2 h post dose)
      was, on average, 1% greater (50 mg) and 8% greater (100 mg) and maximal
      sumatriptan levels were attained, on average, 10 min earlier (50 mg) and 15 min
      earlier (100 mg) compared with the conventional tablet. Other measures including
      AUC(0-0.5) (AUC to 30 min post-dose), times to achieve sumatriptan concentrations
      of 5 and 10 ng/mL, and mean percentage C(max) 15, 20 and 30 min post-dose
      demonstrate an observable improvement in rate of drug absorption for the new form
      of sumatriptan compared with conventional tablets. CONCLUSION: The new form of
      sumatriptan is bioequivalent to sumatriptan conventional tablets and is absorbed
      more quickly than conventional tablets.

PMID- 15200737
TI  - Concordance evaluation of coronary risk scores: implications for cardiovascular
      risk screening.
AB  - OBJECTIVE: To assess the similarities and differences in predicted high-risk
      individuals identified by different cardiovascular risk calculation algorithms
      Research design and methods: A representative population of 10000 individuals was
      modelled in a computer using baseline data from the National Health Survey for
      England. The effects of biological groups identified by each calculator depend on
      the variation in each major model parameters were then applied to each
      hypothetical individual. The predictive capacities of 3 different risk
      identification systems based on computer calculation (the Framingham algorithm),
      or on tabular methods (the Sheffield tables and the General Rule to Enable
      Atheroma Treatment) were evaluated. RESULTS: All three models predict that
      similar numbers would receive treatment with 2.9 and 10% receiving treatment at
      30 and 15% 10 year risk thresholds, respectively. However, concordance is limited
      as 0.3 or 6.8% are positive on all three systems; 1.6 or 9.7% on any two
      calculators at the 30 and 15% thresholds, respectively. The risk baseline
      assumptions in each model. CONCLUSION: Care needs to be taken with applying risk
      calculators to populations different from which they were derived. Any
      cardiovascular risk scoring system needs to be thoroughly evaluated against
      epidemiological data before it is introduced and also needs to be updated in line
      with changing trends in risk factors.

PMID- 15200738
TI  - Duration of bisphosphonate treatment: results of a non-randomised study in
      patients previously treated with local irradiation for bone metastases from
      breast cancer.
AB  - PURPOSE: To assess whether disodium pamidronate (DP) once started should be given
      life-long in women with lytic bone metastases. PATIENTS AND METHODS: One hundred
      and three women with breast cancer who had at least one osteolytic lesion
      received 180 mg of DP as a 2-h intravenous infusion given every 4 weeks for a
      life-time, following local radiotherapy. After six cycles, 26 out of 103 patients
      (25%) refused to continue their bisphosphonate-treatment. Thus two groups were
      constituted: non-stop (group A) and premature discontinued (group B). The new
      skeletal complication free survival (NSCFS) was the primary endpoint verified
      during extramural review. Performance status, pain-score and biochemical markers
      were secondary endpoints. RESULTS: Generally DP was well tolerated. At 36 months,
      the proportion of patients having had any skeletal complication was 54.5 and
      84.6% in group A and B, respectively. The median time of NSCFS was apparently
      longer for group A. In group A, the pain score and the ECOG status were
      significantly lower, while the overall survival appeared to be longer.
      Multivariate analysis revealed age, nodal status and interruption of treatment as
      prognostic factors to NSCFS, with relative risk 1.05, 2.3 and 1.5 respectively.
      CONCLUSION: Data concerning the suspension of new skeletal complications, as well
      as the apparent improvement of overall survival, pain score and ECOG status,
      suggest that the pamidronate-treatment should not be stopped once started. These
      results should be confirmed in a randomised trial.

PMID- 15200739
TI  - Psychometric validation of a generic health-related quality of life measure (EQ
      5D) in a sample of schizophrenic patients.
AB  - OBJECTIVE: The aim of this study was to evaluate the construct validity of a
      generic health related quality of life (HRQOL) instrument - the EQ-5D - in a
      sample of schizophrenic patients receiving antipsychotic treatment. RESEARCH
      DESIGN AND METHODS: A total of 2128 schizophrenic patients treated with
      olanzapine, 417 treated with risperidone, and 112 with haloperidol responded to
      the EQ-5D. The study also assessed the effect of patient age, gender, and co
      morbidity variables on patient's HRQOL Main outcomes measures: EQ-5D scores at
      the start of treatment and after 3 and 6 months of therapy were compared with
      results from the Clinical Global Impression (CGI) severity of illness scale and
      the (GAF) scale. The effect of antipsychotics and sociodemographic variables on
      patient's HRQOL over time was tested through a three-factor doubly multivariate
      repeated measures MANCOVA. RESULTS: High scores in the GAF scale and low scores
      in the CGI were linked with high scores on the EQ-5D scale. The correlational
      effects observed between the EQ-5D and the clinical indices ranged from 0.33 to
      0.54. A significant effect of 'visit time' as well as an interaction of 'visit
      time' x drug, 'visit time' x gender, and 'visit time' x co-morbidity was
      observed. CONCLUSIONS: Results suggest the EQ-5D is a valid instrument capable of
      detecting HRQOL differences between schizophrenic patients with different degrees
      of severity of illness.

PMID- 15200741
TI  - Adjunctive topiramate in the maintenance treatment of bipolar disorders: an open
      label study.
AB  - OBJECTIVE: A considerable number of patients with bipolar disorder fail to
      respond completely to mood stabilizers. The anti-epileptic topiramate shares some
      pharmacological actions with carbamazepine and valproate. We therefore explored
      the efficacy and tolerability of topiramate in the prophylaxis of bipolar
      disorder. METHODS: Fifty-six patients receiving outpatient treatment for bipolar
      affective disorder who had been on mood stabilizers, and had relapsed at least
      once in the past 12 months, were treated with topiramate in an add-on design and
      were evaluated for 1 year. Patients were assessed biweekly for the first 3 months
      and every month thereafter. RESULTS: Fifty out of 56 patients completed the 1
      year study, which indicated that adjunctive topiramate was associated with a
      significant reduction of new manic and depressive episodes compared to the past
      12 months. The most common adverse effects were reduced appetite, fatigue and
      somnolence. CONCLUSIONS: This was an open-label, uncontrolled study involving
      retrospective evaluation of episodes prior to the initiation of treatment, and
      the use of more than one mood stabilizer in a few patients. However, these
      preliminary observations of adjunctive topiramate as a maintenance treatment
      encourage further investigations, especially with controlled trials, for its long
      term effect.

PMID- 15200740
TI  - Safety of 25- and 50-mg capsules in the initiation of zonisamide therapy in
      patients with epilepsy: an uncontrolled, open-label study.
AB  - OBJECTIVE: This study was designed to assess the safety of 25- and 50-mg dosage
      strengths of zonisamide for initial titration in patients with epilepsy. RESEARCH
      DESIGN AND METHODS: This phase 3, multicenter, open-label, uncontrolled study
      conducted at 26 study sites in the United States included male and female
      patients with epilepsy >or= 12 years of age. After a screening visit, subjects
      began zonisamide therapy at a dosage depending on their body weight. Zonisamide
      was titrated to 100 mg/day. MAIN OUTCOME MEASURES: At the study's conclusion,
      information regarding adverse events (AEs) and body weight was recorded. RESULTS:
      One hundred forty-three subjects enrolled and received at least one zonisamide
      dose. Of these subjects, 125 reached at least the 100-mg dosage before
      terminating the study. Eighty-two subjects (57.3%) experienced at least one AE.
      Most commonly reported AEs included headache, somnolence, asthenia, rhinitis,
      nausea, and rash. No significant change in patient body weight was noted during
      the study (95% confidence interval: -0.1, 0.6). CONCLUSIONS: Study limitations
      include the open-label design and the lack of direct comparison between lower (25
      and 50-mg) and higher (100-mg) starting dosages. Despite these limitations, the
      25- and 50-mg zonisamide dosage formulations were well tolerated in this study.

PMID- 15200742
TI  - Efficacy and tolerability of a new chlorhexidine-based vaginal gel in vaginal
      infections.
AB  - OBJECTIVE: We evaluated the efficacy and tolerability of a new chlorhexidine
      based bioadhesive vaginal gel (Clomirex) in women with vaginal infections. STUDY
      DESIGN AND SUBJECTS: A total of 90 nonpregnant women with vaginal infections of
      both bacterial (bacterial vaginosis: BV) or fungal (vaginal candidiasis VC)
      origin, were enrolled in the study: a randomised, controlled, 4-week, multicentre
      trial. Patients were randomly treated with either chlorhexidine 0.5% vaginal gel
      (CHX-VG), 2.5 g or with metronidazole vaginal tablets 500 mg (M) or clotrimazole
      (CL) vaginal cream, depending on aetiology of the infection, daily for 7 days
      (treatment phase) in a 2:1 ratio. A total of 45 women had a diagnosis of BV and
      45 a diagnosis of VC. Sixty women were treated with CHX-VG, 15 with M and 15 with
      CL. All patients were followed for an additional 3 weeks without treatments
      (follow-up phase). For women with BV,clinical cure rate was defined as the
      disappearance of the following signs and symptoms: homogenous vaginal discharge;
      presence of >or= 2 or more clue cells at the wet mount microscopy; a vaginal pH >
      4.7 and a positive whiff test. For women with VC, clinical cure rate was defined
      as a resolution of signs and symptoms plus absence of hyphae, pseudohyphae and
      blastospores on 10% KOH wet mount microscopy. Clinical cure rate was assessed at
      the end of the study (week 4) by an investigator unaware of the patient's
      treatment allocation. RESULTS: At week 4, in women with BV, 28 out of 30 (93%)
      women in the CHX-VG group were clinically cured in comparison with 11 out of 15
      (74%) in the M group (p = 0.3). In women with VC, 26 out of 30 (86.6%) women in
      the CHX-VG group were clinically cured in comparison with 13 out of 15 (86%) in
      the CL group (p = 0.5). Tolerability was good and very good in 90% of the CHX-VG
      patients. Six women (10%) complained of a mild transient burning sensation after
      CHX-VG vaginal application. No serious adverse events were observed during the
      trial in all treated groups. No women presented with vaginal discharge after
      treatment.

PMID- 15200743
TI  - A comparative study of milnacipran and imipramine in the treatment of major
      depressive disorder.
AB  - The antidepressant efficacy and safety of milnacipran, a dual action
      antidepressant drug which inhibits the reuptake of serotonin and noradrenaline,
      was compared with that of the tricyclic antidepressant, imipramine, in a multi
      centre, double-blind, randomised, parallel group, comparative trial in 5 hospital
      centres in Spain. One hundred patients hospitalised with a diagnosis of major
      depressive disorder according to the Diagnostic and Statistical Manual of the
      American Psychiatry Association (third revision), with a minimum score of 25 on
      the Montgomery and Asberg Depression Rating Scale were treated for 6 weeks with
      milnacipran (100 mg/day) or imipramine (150 mg/day). Both treatments showed
      similar efficacy in reducing depressive symptoms. The frequency of most adverse
      events in the milnacipran-treated patients was lower than that observed in the
      imipramine group, particularly those related to anticholinergic symptoms. Dysuria
      and shivering, however, were more common with milnacipran. The results of this
      study support others which have demonstrated that milnacipran has equivalent
      efficacy but superior tolerability to a tricyclic antidepressant such as
      imipramine.

PMID- 15200744
TI  - Assessment of the efficacy of joint lavage versus joint lavage plus corticoids in
      patients with osteoarthritis of the knee.
AB  - PURPOSE: Joint lavage (JL), involves the passage of cold sterile 0.9% saline
      through the knee joint in order to have the fluid reach the inside of the joint
      capsule. This technique was evaluated as a local treatment for osteoarthritis
      (OA) of the knee alone (JL) and in combination with intra-articular infiltration
      with glucocorticoids (JLC). PATIENTS AND METHODS: An overall 299 knees belonging
      to 205 patients (22% males, 78% females) with a mean age of 67 +/- 8 years and
      osteoarthritis of the knee of radiological grade II or III on the Kellgren scale
      were randomised in the ratio of 1:4 into two therapeutic groups, namely: JL (n =
      62) and JLC (n = 237). All patients received joint lavage on day 0; in those of
      the JLC group, joint lavage was followed by infiltration of 40 mg of
      triamcinolone acetonide. The efficacy of both treatments was assessed by
      recording the corresponding values for the following variables: pain strength as
      measured by a visual analogy scale (VAS), effusion, crepitation, restricted
      motion, of osteoarthritis of the knee. spontaneous pain, pain on pressure, pain
      on passive motion and pain on active motion; all of these were recorded at the
      onset of the study, and after 1 and 3 months. RESULTS: There were no significant
      differences in the values of the variables at the different followup times. Also,
      pain severity was similar in both treatment groups. Thus, VAS for pain was 7.3 +/
      0.3 for the JL group and 7.1 +/- 0.2 for the JLC group at the onset, and
      decreased to 3.0 +/- 0.3 in the former and 2.8 +/- 0.2 in the latter after 1
      month; the decrease was statistically significant in both cases. After 3 months,
      the JL and JLC groups had a VAS of 3.5 +/- 0.3 and 3.8 +/- 0.2, respectively.
      CONCLUSIONS: The results of this work suggest the absence of significant
      differences between the two treatments, such that both joint lavage alone and
      with infiltration with corticoids can be concluded as similarly effective for the
      symptomatic management

PMID- 15200745
TI  - Cost-effectiveness analysis of escitalopram: a new SSRI in the first-line
      treatment of major depressive disorder in Austria.
AB  - OBJECTIVES: To compare the cost-effectiveness of escitalopram, a new selective
      serotonin reuptake inhibitor (SSRI), with (generic) citalopram in the first-line
      treatment of major depressive disorder (MDD) in Austria. METHODS: A two-path
      decision analytic model with a 6-month horizon was adapted to the Austrian
      setting using Austrian clinical guidelines. All patients (aged >or= 18 years)
      started at the primary successfully treated patient was lower ( currency 115) for
      care path and were referred to specialist care in the secondary care path in case
      of insufficient response. Model inputs included drug-specific probabilities from
      head-to-head trial data, literature and expert opinion. The main outcome measure
      was success (i.e., remission defined as Montgomery-Asberg Depression Rating Scale
      (MADRS) score <or= 12) and costs of treatment (i.e., drug costs and medical
      care). The analysis was performed from the Austrian societal and Social
      Healthcare Insurance System (SHIS) perspectives. The Human Capital approach was
      used to estimate the societal costs of lost productivity. RESULTS: Treatment with
      escitalopram yielded lower expected cost and greater effectiveness compared with
      citalopram. The expected success rate was higher for escitalopram (64.5%)
      compared to citalopram (59.1%). From the SHIS perspective, the total expected
      cost per escitalopram ( currency 608) compared with citalopram ( currency 723).
      From the societal perspective, these expected costs were currency 3034 and
      currency 3269 respectively. Sensitivity analyses on unit costs and probabilities
      demonstrated the robustness of the results. From the societal perspective,
      escitalopram remained the dominant treatment option, even at a cost of currency 0
      for (generic) citalopram. CONCLUSION: Escitalopram is a cost-effective
      alternative compared to (generic) citalopram in the first-line treatment of MDD
      in Austria.

PMID- 15200746
TI  - Granisetron vs dolasetron for acute chemotherapy-induced nausea and vomiting
      (CINV) in high and moderately high emetogenic chemotherapy: an open-label pilot
      study.
AB  - OBJECTIVE: Comparative studies examining the use of oral serotonin type 3 (5
      HT(3)) receptor antagonists for the management of acute chemotherapy-induced
      nausea and vomiting (CINV) are limited. Therefore, we performed an experiential
      open-label pilot study at Stony Brook Hospital to allow clinicians to make
      informed formulary decisions at our institution and to stimulate further study.
      Specifically, the objective of this study was to compare the effectiveness of
      oral granisetron versus oral dolasetron for prophylaxis of acute CINV. RESEARCH
      DESIGN AND METHODS: The study was conducted during the period of 1 February 2001
      to 31 March 2001. Patients (n = 26) with lymphoma or malignancies of the lungs,
      larynx, or uterus undergoing moderately high and highly emetogenic chemotherapy
      were studied. Patients admitted during February (n = 13) were administered a
      single oral dose of 100 mg of dolasetron; those admitted in March (n = 13)
      received a single oral dose of 2mg of granisetron. All patients were administered
      intravenous dexamethasone 20 mg before the initiation of chemotherapy. MAIN
      OUTCOME MEASURES: Patients were monitored for at least 24 h by clinicians. The
      data recorded for each patient included age, sex, the number of episodes of
      nausea and emesis, the intensity of nausea (when applicable), and the number of
      doses of rescue antiemetic medication administered (when applicable). RESULTS:
      Overall, granisetron provided significantly greater control of acute CINV than
      dolasetron. More patients treated with granisetron experienced total control of
      nausea and vomiting (69.2 vs 23.1%, p < 0.05). Fewer granisetron-treated patients
      experienced emesis (7.7 vs 53.8%, p < 0.05) and nausea (30.8 vs 76.9%, p < 0.05).
      Of those patients who experienced nausea, intensity was significantly less with
      granisetron than with dolasetron (p < 0.05). Consequently, a significantly
      greater proportion of patients treated with dolasetron required a rescue
      antiemetic and significantly more doses of rescue antiemetics (both p < 0.01).
      CONCLUSIONS: These data suggest that oral granisetron may demonstrate improved
      CINV outcomes compared with oral dolasetron in patients undergoing moderately
      high and highly emetogenic chemotherapy.

PMID- 15200747
TI  - Efficacy and tolerability of initial combination therapy with nateglinide and
      metformin in treatment-naive patients with type 2 diabetes.
AB  - OBJECTIVE: To assess the efficacy and tolerability of the combination of
      nateglinide (120 mg, ac) and metformin (500 mg, tid) as initial treatment in drug
      naive patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS:
      This study reports data from the treatment-naive (TN) subgroup of patients in a
      previously published, randomized, multicenter, placebo-controlled, 24- week trial
      that compared nateglinide, metformin, and the combination therapy (CT) in 701
      patients with T2DM with baseline HbA(1c) between 6.8% and 11.0%. Of the 401 TN
      patients, 104, 104, 89, and 104 patients received nateglinide (120 mg, ac),
      metformin (500 mg, tid), CT, and placebo, respectively. The baseline
      characteristics of each group were similar, with mean age, BMI, duration of
      diabetes, HbA(1c), and fasting plasma glucose (FPG) levels of approximately 58
      years, 30 kg/m(2), 4 Gastrointestinal side effects occurred in 27% of years,
      8.2%, and 10.2 mmol/L, respectively. RESULTS: In patients receiving initial CT,
      HbA(1c) decreased substantially (Delta = -1.6 +/- 0.1%, p < 0.0001 vs. baseline
      or placebo) from a mean baseline of 8.2 +/- 0.1%, an effect significantly greater
      than the 0.8% reduction observed with both monotherapies (p < 0.001); whereas, in
      placebo-treated patients, HbA(1c) increased modestly (Delta = +0.3 +/- 0.1%, p <
      0.05) from an identical baseline value. Seventy percent of CT-treated patients
      achieved a target HbA(1c) of < 7.0%. Both fasting plasma glucose (FPG) and the 2
      hour postprandial glucose excursion (PPGE) after a liquid meal challenge
      decreased by 2.3 mmol/L in patients receiving CT, while the changes from baseline
      values in FPG and PPGE were +0.2 +/- 0.3 mmol/L and -0.5 +/- 0.2 mmol/L,
      respectively, in placebo-treated patients. The incremental 30-minute post-load
      insulin levels increased by 88 +/- 32 pmol/L (p = 0.006) in patients receiving CT
      and did not change significantly in placebo-treated patients. patients receiving
      CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups).
      Confirmed hypoglycemia (glucose <or= 2.8 mmol/L) occurred in 3.4% of patients
      receiving CT. CONCLUSIONS: Initial CT with the rapid-acting insulinotropic agent,
      nateglinide, and metformin, an agent with insulin-sensitizing effects in the
      liver and periphery, is a safe and effective means of achieving glycemic targets
      in TN patients with T2DM.

PMID- 15200748
TI  - A direct comparison of the efficacy of antihistamines in SAR and PAR: randomised,
      placebo-controlled studies with levocetirizine and loratadine using an
      environmental exposure unit - the Vienna Challenge Chamber (VCC).
AB  - OBJECTIVE: The Vienna Challenge Chamber (VCC) is an established method for the
      controlled exposure of patients to specific allergens, used to make valid
      comparisons between antihistamines. The aim of the significantly more than
      loratadine at all time two placebo-controlled, randomised studies reported here
      was to compare the efficacy and safety of levocetirizine 5 mg od and loratadine
      10 mg od in subjects suffering from seasonal allergic rhinitis (SAR) or perennial
      allergic rhinitis (PAR). SUBJECTS AND METHODS: During each study period, SAR and
      PAR subjects were exposed to grass pollen or house-dust mite allergens,
      respectively for 6 h on 2 consecutive days in the VCC. Each day, medications were
      administered 2 h after the start of the challenge; with a washout of at least 5
      days between each period. The main criterion for evaluation of efficacy was the
      major symptom complex (MSC) for SAR and the complex symptom score (CSS) for PAR.
      RESULTS: The pattern of patients' response was similar in SAR and PAR. Both
      levocetirizine and loratadine were superior to placebo in alleviating SAR and PAR
      symptoms at all time intervals evaluated during the two study days.
      Levocetirizine decreased the mean MSC score intervals in SAR subjects, with the
      most marked difference observed on day 2 (p = 0.002). In PAR patients, although
      with borderline significance (p = 0.08), levocetirizine decreased the mean CSS
      more than loratadine. Levocetirizine appeared to have a faster onset of action
      than loratadine in SAR (45 min versus 1 h 15 min) and PAR (1 h versus 1 h 30
      min). However, these apparent differences were not tested for statistical
      significance. Both medications were well tolerated and no treatment-related
      adverse events were reported. This level of antihistamine efficacy was maintained
      regardless of whether the subjects' rhinitis was seasonal or perennial.
      CONCLUSION: This study demonstrated that levocetirizine is superior to loratadine
      in improving symptoms in SAR and that there is a similar trend in PAR.

PMID- 15200749
TI  - The HORIZON Recurrent Fracture Trial: design of a clinical trial in the
      prevention of subsequent fractures after low trauma hip fracture repair.
AB  - OBJECTIVE: To present the novel design of a trial testing the safety and efficacy
      of a yearly bisphosponate, zoledronic acid, in preventing new clinical fractures
      in patients with recent low trauma hip fracture repair. RESEARCH DESIGN AND
      METHODS: Randomized, placebo-controlled, triple-blind study. One hundred and
      fifteen clinical centers worldwide are recruiting approximately 1714 subjects
      aged 50 years and over (no upper age limit, median age of enrolled subjects to
      date 79 years) who have undergone surgical repair of a low trauma hip fracture in
      the preceding 90 days. Patients will be assigned at random to an intervention
      group (5 mg zoledronic acid intravenously yearly) or a control group (placebo
      infusion yearly). Both groups receive a loading dose of Vitamin D2 or D3 IM or
      orally, followed by 800-1200 IU Vitamin D and 1000-1500 mg elemental calcium
      orally on a daily basis. Concomitant therapy with calcitonin, hormone replacement
      therapy, selective estrogen receptor modulators, tibolone, and external hip
      protectors are allowed. MAIN OUTCOME MEASURES: The primary endpoint is subsequent
      skeletal fractures as adjudicated by a clinical endpoints committee blinded to
      intervention status. Secondary outcomes include delayed hip fracture healing,
      changes in bone mineral density, and health resource utilization. Subjects will
      be recruited over a 3-4 year period and will be followed until 211 primary
      endpoints are accrued and adjudicated. CONCLUSIONS: This randomized clinical
      trial is novel among osteoporosis therapies as it (1). targets hip fracture
      patients, a previously understudied group, and (2). uses only clinically evident
      fractures as the primary outcome. Ethical and practical considerations in
      studying this frail population are discussed.

PMID- 15200750
TI  - Establishing the dosage equivalency of oxymorphone extended release and oxycodone
      controlled release in patients with cancer pain: a randomized controlled study.
AB  - OBJECTIVE: To compare the analgesic efficacy and safety of oxymorphone extended
      release (ER) and oxycodone controlled release (CR) in patients with moderate to
      severe cancer pain. RESEARCH DESIGN AND METHODS: This randomized, multicenter,
      double-blind, 2-period crossover study included adult outpatients (>or= 18 years
      of age) with moderate or severe cancer pain who were first titrated for 3-10 days
      with open-label oxymorphone or oxycodone to achieve a stable dose that provided
      and other efficacy parameters were comparable for adequate analgesia with
      tolerable adverse events and no requirement for more than 2 doses of rescue
      medication per day. The subsequent double-blind treatment phase was a 7- to 10
      day period of oxycodone CR or oxymorphone ER treatment followed by crossing over
      to the alternate medication for another 7-10 days. During the treatment phase, up
      to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue. MAIN
      OUTCOMES AND MEASURES: Assessments included the Brief Pain Inventory, global
      evaluations, Karnofsky performance status, and clinical laboratory evaluations
      (serum chemistry profile, complete blood count, urinalysis). Efficacy variables
      were analyzed using a mixed-effects model with treatment, sequence, and period as
      fixed effects and subject as a random effect. RESULTS: Forty-seven patients
      entered the titration/stabilization phase, 44 received at least 1 dose of study
      drug, 42 completed the first double-blind phase, and 40 completed the second
      double-blind phase. Mean pain intensity scores the 2 groups. The mean daily
      dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an
      equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups
      (approximately 1 tablet of morphine sulfate 15 mg/day). No significant
      differences in opioid adverse events were observed between the groups.
      CONCLUSIONS: Adult patients with cancer who were taking oxycodone CR were readily
      converted to oxymorphone ER and required half the milligram dose to stabilize
      their pain. Within 72 h, most patients achieved a stable dose that provided
      adequate relief with similar opioid adverse events.

PMID- 15200751
TI  - Thiazolidinediones: comparison of long-term effects on glycemic control and
      cardiovascular risk factors.
AB  - OBJECTIVE: To compare the long-term effects on HbA(1c), lipid parameters, body
      weight, and hepatotoxicity after switching type 2 diabetes patients from
      troglitazone to either pioglitazone or rosiglitazone. METHODS: Of 125 study
      candidates from a previous prospective study, 100 patients (51 pioglitazone, 49
      rosiglitazone) met criteria for comparing HbA(1c), lipids, body weight, and
      incidence of hepatotoxicity over 2 successive observation periods (3.1 and 12.6
      months). RESULTS: Mean absolute HbA(1c) decreased significantly, 0.53 and 0.27%
      in the pioglitazone and rosiglitazone groups, respectively, at the 12.6-month
      observation. Mean triglyceride (TG) decreased in the pioglitazone group at each
      interval with a cumulative decrease of 26.4% from baseline. In contrast, TG
      increased in the rosiglitazone patients by 43.3% at 3.1 months and then decreased
      (but remained above baseline) at 12.6 months. Mean high density lipoprotein (HDL)
      increased 22.1% with pioglitazone and 13.3% with rosiglitazone. In patients who
      had a baseline HDL < 35 mg/dL (0.91 mmol/L), pioglitazone treated patients
      experienced a significant increase at each interval resulting in a 52.6% increase
      in HDL compared to a 26.9% increase for rosiglitazone patients. Patients in both
      treatment groups had similar weight increases at each interval and no
      hepatotoxicity was noted. CONCLUSION: With pioglitazone or rosiglitazone, changes
      in glycemic control, lipid effects, and body weight appear to continue over time.
      Pioglitazone treatment resulted in decreased triglyceride levels, while
      rosiglitazone was associated with an increase in triglyceride levels. HDL
      increased in both treatment groups, but in patients with a baseline HDL < 35
      mg/dL (0.91 mmol/L), pioglitazone improved the HDL to a greater extent than
      rosiglitazone.

PMID- 15200752
TI  - Effects of galantamine on behavioural and psychological disturbances and
      caregiver burden in patients with Alzheimer's disease.
AB  - BACKGROUND: Behavioural and psychological disturbances occur in up to 90% of
      patients with Alzheimer's disease (AD), have a substantial impact on both
      patients and caregivers, and are often associated with the decision to
      institutionalise patients. Galantamine (Reminyl) is a dual-acting cholinergic
      treatment that improves cognitive and functional performance, delays the onset of
      behavioural symptoms and decreases behaviour-associated caregiver distress.
      OBJECTIVE: To assess the impact of galantamine on behavioural disturbances and
      associated caregiver burden in non-institutionalised patients with AD. METHODS:
      This was a 3-month, open-label, multicentre study in Switzerland. Patients with
      mild-to-moderate AD received galantamine (escalated from 8 to 24 mg/day over 8
      weeks). The primary outcome was the Neuropsychiatric Inventory (NPI) for patients
      who completed 3 months treatment (observed cases, OC). Secondary outcomes
      included the Nurses' Observation Scale for Geriatric patients (NOSGER), and the
      Clinical Global Impression (CGI) of change. RESULTS: 124 patients (mean age 75.2
      years, 55.6% women) received galantamine and were included in the intention-to
      treat (ITT) safety analysis. Significant improvements in NPI scores versus
      baseline were seen in the OC analysis (p < 0.05, N = 91); mean total NPI scores
      (+/- SE) were reduced from 14.9 +/- 1.2 at baseline to 11.3 +/- 1.2 at month 3.
      Eleven out of 12 NPI domains were improved. Anxiety, aberrant motor behaviour,
      delusions, euphoria and night-time-behaviour all improved by > 30%. Symptoms with
      the highest baseline frequency and severity improved by 19-27%. A significant
      reduction in total NPI caregiver burden was observed at month 3 (p < 0.05).
      Despite this short assessment period the NOSGER evaluation and physicians' CGI
      also showed improvement. Adverse events (AEs) were mostly gastrointestinal.
      CONCLUSION: Galantamine significantly reduced behavioural disturbances after 3
      months in this population and this had a positive impact on behaviour-related
      caregiver burden. Galantamine showed the expected safety profile and was well
      tolerated.

PMID- 15200753
TI  - Comparison of rofecoxib and a multidose oxycodone/ acetaminophen regimen for the
      treatment of acute pain following oral surgery: a randomized controlled trial.
AB  - OBJECTIVE: To compare the efficacy of a single dose of rofecoxib 50 mg with a
      single dose of oxycodone/acetaminophen 10/650 mg over 6 h as well as with a
      multidose regimen of oxycodone/acetaminophen 10/650 mg followed by
      oxycodone/acetaminophen 5/325 mg over 24 h. RESEARCH DESIGN AND METHODS: In this
      double-blind, randomized, two-phase study, patients with moderate to severe pain
      after surgical extraction of >or= 2 third molars, including one mandibular
      impaction, were treated with rofecoxib 50 mg, oxycodone/acetaminophen 10/650 mg
      (singledose phase) followed by 5/325 mg every 6h as needed (multidose phase), or
      placebo. Patients rated their pain relief and intensity at 18 time points over 24
      h. Efficacy was measured over 6 and 24 h by total pain relief (TOPAR), sum of
      pain intensity difference (SPID), and patient global assessment of response to
      therapy (PGART). Primary endpoint for the single dose comparison was TOPAR over 6
      h; SPID was the key 24-h endpoint. Onset of analgesic effect, peak analgesic
      single dose of oxycodone/acetaminophen. effect, and duration of analgesic effect
      were also evaluated. Adverse experiences were recorded. RESULTS: 271 patients
      were randomized to treatment with rofecoxib (n = 121), oxycodone/acetaminophen (n
      = 120), or placebo (n = 30). For the single dose comparison, rofecoxib-treated
      patients achieved pain relief at least as effective as
      oxycodone/acetaminophentreated patients as assessed by TOPAR6 (12.9 vs 11.3, 95%
      CI on difference = [-0.1, 3.2], p = 0.059). Patients also rated a single dose of
      rofecoxib as at least as effective as multidose oxycodone/acetaminophen over 24 h
      on SPID24 (21.9 vs 18.1, 95% CI on difference = [-1.0, 8.8], p = 0.122). Patients
      treated with oxycodone/ acetaminophen had a shorter time to onset of analgesia
      than patients treated with rofecoxib (24 vs 35 min, p < 0.05). Patients in the
      active treatment groups achieved similar peak effects during the single-dose
      phase. Individuals treated with rofecoxib demonstrated a longer duration of
      analgesic effect than those treated with a Patients on active treatment
      demonstrated better efficacy than patients on placebo on these prespecified
      endpoints (p < 0.001 for both comparisons). Fewer rofecoxib than
      oxycodone/acetaminophen patients experienced adverse events (47.9 vs 75.8%, p <
      0.001), including nausea (19.0 vs 42.5%, p < 0.001), vomiting (9.9 vs 24.2%, p <
      0.01), and dizziness (7.4 vs 31.7%, p < 0.001). CONCLUSION: Patients treated with
      a single dose of rofecoxib 50 mg achieved an overall analgesic effect at least as
      effective as patients treated with a single-dose of oxycodone/acetaminophen
      10/650 mg over 6 h and multidose oxycodone/acetaminophen over 24 h, with fewer
      adverse experiences of nausea (p < 0.001), vomiting (p < 0.01), and dizziness (p
      < 0.001).

PMID- 15200754
TI  - Uric acid levels and vascular disease.
AB  - There is evidence showing that serum uric acid (SUA) levels predict the risk for
      vascular events. For example, up to 29% of the reduction in the primary composite
      endpoint seen in the LIFE trial (favouring losartan versus atenolol) can be
      attributed to a fall in SUA levels. We also discuss the findings of the GREACE
      study (treating to target with atorvastatin versus 'usual' care) in relation to
      SUA levels. In this brief comment we extend this argument to consider the SUA
      lowering effect of other drugs commonly prescribed in patients with vascular
      disease (e.g. statins, fibrates and antihypertensive agents). A judicious use of
      drugs (alone or in combination) will result in small reductions in SUA levels.
      These changes may translate into a substantial reduction in the risk of vascular
      events. Results retrieved from completed trials together with new prospective
      findings will support or refute the proposed association between lowering SUA
      levels and reducing vascular morbidity and mortality.

PMID- 15200755
TI  - Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin.
AB  - BACKGROUND: Ezetimibe is a cholesterol absorption inhibitor which decreases low
      density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia.
      This study investigated the potential for pharmacodynamic and/or pharmacokinetic
      interactions between ezetimibe and lovastatin. METHODS: In a randomized,
      evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy
      men with hypercholesterolemia (screening LDL-C >or= 130 mg/dL) who were
      stabilized and maintained on a National Cholesterol Education Program (NCEP) Step
      I diet were randomized to one of the following six oral treatments once daily for
      14 days: lovastatin 20 mg; lovastatin 20 mg plus ezetimibe 5, 10, or 20 mg;
      lovastatin 40 mg plus ezetimibe 10mg; or placebo. RESULTS: Reported adverse
      events were generally mild, nonspecific, and similar among treatments. There were
      no significant changes in safety laboratory test results, including those for
      enzymes indicative of muscle or liver injury. Coadministration of ezetimibe and
      lovastatin did not increase the plasma concentrations of lovastatin or beta
      hydroxylovastatin. In this parallel comparison study there was an apparent
      decrease in lovastatin exposure, however, the reduction in lovastatin or beta
      hydroxylovastatin concentrations was not related to the ezetimibe dose and is not
      considered to be clinically important. Ezetimibe 5, 10, or 20 mg combined with
      lovastatin 20 mg caused a significantly (p < 0.01) greater reduction in LDL-C
      than lovastatin 20 mg alone, with no apparent effect on HDL-C or triglycerides.
      LDL-C was reduced by 51.0% with ezetimibe 10 mg plus lovastatin 20 mg, 56.0% with
      ezetimibe 10 mg plus lovastatin 40 mg, 33.2% with lovastatin alone, and 17.3%
      with placebo. CONCLUSIONS: The co-administration of ezetimibe and lovastatin was
      well tolerated and resulted in a significantly greater percentage reduction in
      serum LDL-C concentrations than with lovastatin alone, with an average
      incremental reduction of 16-18%. Ezetimibe 10mg appears to be the optimal dose
      when co-administered with lovastatin 20mg once daily. Further incremental
      reductions in LDL-C from the co-administration of ezetimibe and lovastatin are
      expected only when the dose of lovastatin is increased. The co-administration of
      ezetimibe and lovastatin has the potential to produce clinically significant
      reductions in LDL-C compared to either drug alone, with favorable safety and
      tolerability.

PMID- 15200756
TI  - Physicians' constructions of depression: inside/outside the boundaries of
      medicalization.
AB  - A qualitative study explored primary care physicians' experiences of diagnosing
      and treating depression. Twenty physicians participated in semi-structured
      interviews. Interview questions asked physicians to consider a range of topics
      such as the etiology of depression, the diagnostic process and treatment of
      depression. Transcripts were analyzed discursively with a view to exploring the
      ways in which physicians construct depression. In this article, physicians'
      constructions of depression are examined through exploration of their
      descriptions of this condition, as well as their recognition of the social
      context of depression. Based on this analysis, it was concluded that physicians'
      medicalized understandings of depression conflict with recognition of the social
      context of depression. The result of this conflict is dissonant descriptions of
      depression. One implication of this research is that physicians' training would
      benefit from the integration of multidisciplinary perspectives on depression,
      which would better reflect physicians' experiences in routine practice
      situations.

PMID- 15200757
TI  - Cognitive citizenship: access to hip surgery for people with dementia.
AB  - Dementia and chronic hip disease are both more prevalent with advancing age.
      Given this, the number of people with both dementia and hip disease is likely to
      increase in an ageing population such as the UK. This article raises questions
      about how people with dementia and chronic hip disease are conceptualized in the
      context of evidence-based medicine, and whether this conceptualization may limit
      unfairly their access to surgical services. The published clinical research
      discourse at the interface of hip disease and dementia is taken as an 'evidence
      base', and is evaluated in terms of its suitability for informing professional
      decisions about viability for surgery. The analysis suggests that the outcomes
      criteria used to determine patient viability serve to discriminate unfairly
      against people with dementia. If such discrimination exists, it necessarily
      militates against the promotion of health-related citizenship rights of the
      cognitively impaired, creating an evidence-based culture that encourages a
      problematic model of cognitive citizenship.

PMID- 15200758
TI  - Male callers to NHS Direct: the assertive carer, the new dad and the reluctant
      patient.
AB  - It has been suggested in the light of mortality and morbidity rates, and men's
      reluctance to seek medical help and advice, that there is a crisis in men's
      health. Little is known about men's experiences of using health care services,
      despite an emergent UK men's health movement. NHS Direct, the new telephone
      advice line, was designed to be more accessible, convenient and responsive to the
      public's needs for health care. In-depth interviews with male callers to the
      service, aged between 29 and 59, reveal that they sought help in their roles as
      fathers, partners and on their own behalf. Having used it once, they anticipated
      doing so again. Their learning about health matters, from both the formal
      structure and the informal agenda of the telephone consultation, suggests the
      potential of men's use of this service for 'normalizing' help seeking by men, and
      thereby for longer-term improvements in men's health.

PMID- 15200759
TI  - To have or to take: discourse, positioning, and narrative identity in women's
      accounts of HRT.
AB  - Using 'social cognitive' frameworks, attitudes to HRT have been examined as if
      they were stable entities located within individuals. However, qualitative
      studies have revealed variations and contradictions in women's 'attitudes'. We
      seek to explain these apparent contradictions by using a social constructionist
      approach to the analysis of qualitative data from 7 focus group discussions about
      HRT with 48 women in New Zealand. A discourse analysis of 'interpretative
      repertoires', subject positions and narrative identity was undertaken to explain
      the construction of HRT in situated practice, and the negotiation and
      accomplishment of a unitary orientation to HRT across situations. The results
      summarize the interpretative repertoires used by the women, and one example of a
      subject position negotiated at a moment of patently problematic intersecting
      interpretative repertoires, to highlight the construction of subject positions
      using discursive resources. The importance of the study of subjectivity in
      applied areas of psychology is discussed.

PMID- 15200760
TI  - The local production of knowledge: disease labels, identities and category
      entitlements in ME support group talk.
AB  - This article uses discursive psychology to analyse how knowledge claims and
      entitlements are locally produced in an ME support group meeting and a research
      interview. The article demonstrates how 'expertise' and 'experience' associated
      with lay and professional membership are locally constituted in the activity of
      reasoning, arguing and claims making. The analysis shows how expertise and
      experiential claims are constructed, disclaimed, warranted and undermined in
      relationship to membership categorization and entitlements to knowledge that are
      co-constructed in the process of a discussion about disease labels and the nature
      of the illness as physical or psychological. In a discussion about the definition
      of contested disease categories, what is 'at stake' for the group members is the
      entitlement to speak from experience as members who can 'know' their own minds.

PMID- 15200763
TI  - Microcolpohysteroscopy.

PMID- 15200765
TI  - Childbirth and myoma treatment by uterine artery occlusion: do they share a
      common biology?
AB  - When the uterine arteries are bilaterally occluded, either by uterine artery
      embolization or by laparoscopic obstruction, women with myomas experience
      symptomatic relief. After the uterine arteries are occluded, most blood stops
      flowing in myometrial arteries and veins, and the uterus becomes ischemic. It is
      postulated that myomas are killed by the same process that kills trophoblasts:
      transient uterine ischemia. When the uterine arteries are bilaterally occluded,
      either by uterine artery embolization (UAE) or by laparoscopic obstruction, women
      with myomas experience symptomatic relief. After the uterine arteries are
      occluded, most blood stops flowing in myometrial arteries and veins, and the
      uterus becomes ischemic. Over time, stagnant blood in these arteries and veins
      clots. Then, tiny collateral arteries in the broad ligament (including
      communicating arteries from the ovarian arteries) open, causing clot within
      myometrium to lyse and the uterus to reperfuse. Myomas, however, do not survive
      this period of ischemia. This is unique organ response to clot formation and
      ischemia. What allows the uterus to survive a relatively long period of ischemia
      while myomas perish? Childbirth appears to be the predicate biology. Following
      placental separation, the uteroplacental arteries and the draining veins of the
      placenta are torn apart at their bases in the junctional zone of the myometrium
      and bleed directly into the uterine cavity. Left unchecked, every woman would
      bleed to death in less than 10 minutes after placental delivery. Most women do
      not bleed to death because vessels in the uterus clot after placental delivery.
      During pregnancy, clotting and lytic factors in blood increase many fold.
      Following delivery, uterine contractions continue, intermittently, periodically
      slowing the velocity of flowing blood through myometrium. The combination of
      slowed blood flow, elevated clotting proteins, and torn placental vessels (known
      as Virchow's triad) causes blood in myometrial arteries and veins to clot.
      Fibrinolytic enzymes later lyse clot in arteries and veins not associated with
      placenta perfusion, and the uterus is reperfused. Remnant placental tissue -
      primarily uteroplacental arteries and veins - does not survive this period of
      ischemia. Placental tissue dies and over weeks is sloughed into the uterine
      cavity. At the same time, residual endometrial tissue grows under the sloughing
      placental tissue thus re-establishing the endometrial lining. It is postulated
      that myomas are killed by the same process that kills trophoblasts - transient
      uterine ischemia.

PMID- 15200766
TI  - Deep endometriosis: definition, pathogenesis, and clinical management.
AB  - "Deep endometriosis" includes rectovaginal lesions as well as infiltrative forms
      that involve vital structures such as bowel, ureters, and bladder. The available
      evidence suggests the same pathogenesis for deep infiltrating vesical and
      rectovaginal endometriosis (i.e., intraperitoneal seeding of regurgitated
      endometrial cells, which collect and implant in the most dependent portions of
      the peritoneal cavity and the anterior and posterior cul-de-sac, and trigger an
      inflammatory process leading to adhesion of contiguous organs with creation of
      false peritoneal bottoms). According to anatomic, surgical, and pathologic
      findings, deep endometriotic lesions seem to originate intraperitoneally rather
      than extraperitoneally. Also the lateral asymmetry in the occurrence of ureteral
      endometriosis is compatible with the menstrual reflux theory and with the
      anatomic differences of the left and right hemipelvis. Peritoneal, ovarian, and
      deep endometriosis may be diverse manifestations of a disease with a single
      origin (i.e., regurgitated endometrium). Based on different pathogenetic
      hypotheses, several schemes have been proposed to classify deep endometriosis,
      but further data are needed to demonstrate their validity and reliability. Drugs
      induce temporary quiescence of active deep lesions and may be useful in selected
      circumstances. Progestins should be considered as first-line medical treatment
      for temporary pain relief. However, in most cases of severely infiltrating
      disease, surgery is the final solution. Great importance must be given to
      complete and balanced counseling, as awareness of the real possibilities of
      different treatments will enhance the patient's collaboration.

PMID- 15200767
TI  - Laparoscopic excision of adnexal masses.
AB  - STUDY OBJECTIVE: The purpose of the present study was to evaluate a prospective
      series of consecutive patients with adnexal masses selected with strict
      preoperative clinical and ultrasonographic criteria. DESIGN: Prospective series
      of consecutive patients (Canadian Task Force classification II-2). SETTING:
      Tertiary care university hospitals. PATIENTS: Six hundred and eighty-three
      consecutive patients under 40 years of age with ultrasonographic evidence of an
      adnexal cystic mass without thick septa, internal wall papillation, or solid
      components, except for sonographic pattern suggestive of dermoid. INTERVENTIONS:
      Operative laparoscopy and follow-up. MEASUREMENTS AND MAIN RESULTS: After initial
      diagnostic laparoscopy in 13 patients with stage 4 endometriosis and extensive
      bowel adhesions, in 2 patients with large-volume dermoids, and in 1 patient with
      suspect ovarian and peritoneal implants, the procedure was converted to
      laparotomy. Therefore, 667 patients were completely managed by laparoscopy. There
      were 1069 cysts excised. Histologic diagnosis was endometrioma in 57% of the
      excised cysts, serous cyst in 13%, dermoid in 12%, paratubal in 8%, mucinous
      cysts in 5.3%, functional cyst in 2.8%, other benign histotypes in 1.1%, and
      ovarian malignancies (seven borderline tumors and one endometrioma with a
      microfocus of G1 endometrioid carcinoma) in 0.7% of the cysts and 1.2% of the
      patients. These last patients are alive with no evidence of disease after a mean
      follow-up of 62 months. CONCLUSIONS: In the present series, with accurate
      preoperative and intraoperative selection, the rate of unexpected borderline or
      focally invasive malignancies was 1.2% of the patients, and the laparoscopic
      management of these adnexal masses did not adversely impact on prognosis.

PMID- 15200768
TI  - A simple procedure for the prevention of ureteral injury in laparoscopic-assisted
      vaginal hysterectomy.
AB  - STUDY OBJECTIVE: To introduce a surgical technique to minimize the chance of
      ureteral injury during laparoscopic-assisted vaginal hysterectomy (LAVH). DESIGN:
      Retrospective case review (Canadian Task Force classification II-3). SETTING:
      Show Chwan Memorial Hospital, Changhua, Taiwan. PATIENTS: Two thousand and six
      women who underwent LAVH between January 1992 and June 2001. INTERVENTION: A
      simple step of creating a "window" over the anterior and posterior broad
      ligaments to push inferolaterally the areolar tissue (in which the ureter is
      embedded) on the posterior broad ligament. MEASUREMENTS AND MAIN RESULTS: No
      ureteral injury occurred in patients whose cases were reviewed. There were,
      however, five bladder injuries (0.25%) and three nerve pareses (0.15%). Other
      minor complications, including fever, abscess or hematoma of the vaginal cuff,
      subcutaneous emphysema, and delayed vaginal cuff bleeding, occurred in less than
      5% of patients. CONCLUSION: The technique proposed is simple and very effective
      in preventing ureteral injury during LAVH.

PMID- 15200769
TI  - Laparoscopic supracervical hysterectomy for the large uterus.
AB  - STUDY OBJECTIVE: The purpose of this study was to review outcomes of laparoscopic
      supracervical hysterectomy (LSH) performed on patients with large uteri and
      compare those outcomes with existing series of hysterectomies reporting removal
      of large uteri. DESIGN: Retrospective analysis (Canadian Task Force
      classification II-3). SETTING: Single surgeon, independent surgery center.
      PATIENTS: Women with symptomatic myomas and/or menorrhagia. INTERVENTION:
      Laparoscopic supracervical hysterectomy. MEASUREMENTS AND MAIN RESULTS: All
      patients undergoing LSH procedures for uteri weighing more than 300 g between the
      years 1997 and 2001 were evaluated. A retrospective chart review and videotape
      review were used to assess outcome measures including operative time,
      complications, estimated blood loss, uterine weight, and pathologic diagnoses. A
      quality of life questionnaire was submitted to the patients postoperatively.
      During the 5 years of the study, 329 LSHs were performed, 54 (16.4%) involved
      uterine weight greater than 300 g, and 31 (67%) of this group had a uterine
      weight greater than 500 g. Seven patients (2%) had complex pathologies with
      leiomyomata and endometriosis. There were five cases of reported complications:
      two intraoperative complications and three postoperative fevers. One procedure
      was converted to laparotomy. Transfusion rate was 0%, with an average estimated
      blood loss of 77 mL. The mean number of days to return to work or normal activity
      was 10.1. Sexual relations were reported to be as good as or better than before
      the procedure in 88.9% of patients. All the patients reported being satisfied
      with the procedure. CONCLUSION: The LSH procedure in this series provided an
      effective, low-morbidity alternative for patients with large uteri to accomplish
      uterine extirpation. Since reduction of morbidity and improved quality of care
      for women undergoing hysterectomy are goals of all gynecologists, we believe that
      LSH is an alternative that should be considered.

PMID- 15200770
TI  - Laparoscopic supracervical hysterectomy versus laparoscopic-assisted vaginal
      hysterectomy.
AB  - STUDY OBJECTIVE: To compare laparoscopic supracervical hysterectomy (LSH) with
      laparoscopic-assisted vaginal hysterectomy (LAVH) in terms of indications,
      pathology, length and weight of removed uteri, operative time, intraoperative
      blood loss, intra and postoperative complications, and later sexual function.
      DESIGN: Cohort retrospective analysis of consecutive cases (Canadian Task Force
      classification II-3). SETTINGS: Hutzel Hospital, Detroit Medical Center,Wayne
      State University, Detroit, Michigan; Vert-Pre Nouvelle Clinique, Geneva,
      Switzerland; and Benha University Hospitals, Egypt. PATIENTS: Two hundred and
      fifty-nine women. INTERVENTIONS: LSH and LAVH. MEASUREMENTS AND MAIN RESULTS:
      Patients in both groups were matched regarding age, indications, and pathology of
      the removed uteri. Blood loss with the LSH procedure was significantly lower than
      it was with the LAVH procedure (mean 125 +/- 5 vs 149 +/- 7 mL, p =.001).
      Patients that underwent LSH had significantly shorter operating times (mean 120
      +/- 3 vs 150 +/- 5 minutes, p =.007). The length of the removed uteri was 14.2 +/
      0.5 cm (range 5.2-18) in the LSH group versus 11.8 +/- 0.4 cm (range, 5.6-14) in
      the LAVH group. Weight of the removed uteri was 280 +/- 6 g (range, 65-750) in
      the LSH group compared with 235 +/- 8 g (range, 59-560) in the LAVH group. There
      was no difference between the groups in hospital length of stay. The number of
      complications was less in the LSH group (3/123, 2.4%) compared with 5/136 (3.7%)
      in the LAVH group. Sexual function after surgery was better in the LSH group.
      CONCLUSION: After exclusion of preoperative cervical disease, LSH can be
      considered as a safer alternative to LAVH in patients that are candidates for
      laparoscopic hysterectomy.

PMID- 15200771
TI  - Pain mapping of adhesions.
AB  - STUDY OBJECTIVE: To determine the nature and location of adhesions and their
      relationship to abdominal pain in patients undergoing awake microlaparoscopy.
      DESIGN: Retrospective analysis (Canadian Task Force classification II-1).
      SETTING: University teaching hospital. PATIENTS: Thirty women ages 26-49 years
      with chronic pelvic pain were studied over a 9-month period. INTERVENTION:
      Patients were kept awake during their laparoscopy to determine the site and
      degree of pain when the adhesions were palpated. MEASUREMENTS AND MAIN RESULTS:
      Patients with abdominal pain and a history suggestive that the pain was due to
      adhesions underwent an awake laparoscopy. Visual analog scores were used to
      evaluate the pain on palpation of the adhesion as it related to the nature of the
      adhesion as well as the location of the adhesion. Filmy adhesions that allowed
      for movement between two structures had the highest association with pain. Fixed
      adhesions that did not allow movement had the lowest pain scores. Adhesions that
      had a relationship to the peritoneum had a high association with pain.
      CONCLUSION: Filmy adhesions between a movable structure, such as an ovary, and
      the peritoneum had the highest pain scores. Fixed or dense adhesions, no matter
      where they were located, had the lowest pain scores.

PMID- 15200773
TI  - A comparison of the incidence, presentation, and management of ovarian
      pregnancies between two periods of time.
AB  - STUDY OBJECTIVE: To compare the prevalence, presentation diagnostic modalities,
      and management of 37 ovarian pregnancies in one institution during two time
      periods. DESIGN: A retrospective study (Canadian Task Force classification II-2).
      SETTING: Department of Gynecology in a university-affiliated hospital. PATIENTS:
      Twenty patients with ovarian pregnancy between 1971-1989 compared with 17
      patients with ovarian pregnancy between 1990-2000. MEASUREMENTS AND MAIN RESULTS:
      Seventeen ovarian pregnancies, diagnosed between 1990-2000, comprised 2.6%
      (17/634) of all ectopic pregnancies, 1:3500 of all live births leading to a mean
      ovarian pregnancy rate per year of 1.5, as opposed to 3.1% (20/647) of all
      ectopic pregnancies, 1:3600 of all live births, and a mean ovarian pregnancy rate
      per year of 1.1 in the previous period. Circulatory collapse was present in 4/17
      (23%) patients in the 1990-2000 time period and in 6/20 (30%) in the previous
      period. Culdocentesis for diagnostic purposes was practically abandoned in the
      recent decade. Wedge resection by laparotomy was the treatment of choice in the
      past, and after 1997, it was performed exclusively by laparoscopy. When an
      ovarian pregnancy was diagnosed, an intrauterine device (IUD) was present in 65%
      of all patients and in 73% of women who had previously conceived in the 1999-2000
      time period, compared with higher rates in the previous period (90% and 100%,
      respectively). CONCLUSION: The absolute number of ovarian pregnancies in the last
      11 years increased when compared with the previous 19 years; however, the
      prevalence rate per delivery was stable. Patients still experienced circulatory
      collapse despite modern diagnostic modalities. Culdocentesis for diagnostic
      purposes has become an unnecessary procedure. Laparoscopic wedge resection was
      the treatment of choice. The relationship between IUD use and ovarian pregnancies
      was still strong.

PMID- 15200772
TI  - Effects of laparoscopic ovarian drilling on young adult women with polycystic
      ovarian syndrome.
AB  - STUDY OBJECTIVE: To assess changes in serum hormone levels and ovarian stromal
      blood flow after laparoscopic ovarian drilling (LOD) in young adult women with
      polycystic ovary syndrome (PCOS). DESIGN: Prospective, nonrandomized study
      (Canadian Task Force classification II-1). SETTING: Tertiary care, major teaching
      hospitals. PATIENTS: Anovulatory young women with PCOS who were resistant to
      clomiphene citrate. INTERVENTION: Laparoscopic ovarian drilling. MEASUREMENTS AND
      MAIN RESULTS: To evaluate the endocrinological effects of LOD, serum leptin,
      insulin-like growth factor-1, estrone (E1), and estradiol were measured before
      and after ovarian drilling in the early follicular phase. Three-dimensional
      transabdominal power Doppler examinations were performed to determine the effects
      of LOD. Serum leptin was correlated with body mass index (BMI) before LOD. Levels
      of BMI, fasting blood sugar, and leptin were higher and LH, LH/FSH, and the
      sugar/insulin ratio were lower in the obese group. There were significant
      decreases in the free androgen index, and total testosterone, luteinizing hormone
      (LH), and LH/follicle-stimulating hormone (FSH) levels, and a significant
      increase in sex hormonebinding globulin (SHBG) concentration in the 3 months
      after the operation. The vascularization index and vascularization flow index of
      the intraovarian stroma significantly decreased after treatment. Reversed
      correlations between leptin and LH, LH/FSH, E1, thyroid-stimulating hormone, and
      SHBG were noted 3 months after the operation compared with levels obtained before
      the operation. CONCLUSIONS: Treatment of young adult women with PCOS using LOD
      did not influence leptin levels but changed the ovarian stromal blood flow
      dynamics during short-term follow-up. The surgical procedure may be beneficial
      both to endocrine profiles and to intraovarian stromal flow in patients with
      PCOS.

PMID- 15200774
TI  - Simultaneous bilateral tubal pregnancies and intrauterine pregnancy with five
      fetuses.
AB  - A 28-year-old woman with severe right lower abdominal pain and vaginal bleeding
      at 7 weeks' (+/- 2 days') gestation was seen in the emergency room of our
      institution. The pregnancy was the result of natural conception after ovarian
      stimulation with gonadotropins. Transvaginal sonography revealed five
      intrauterine gestational sacs containing five live embryos. A positive fetal
      heartbeat was detected in the fallopian tube on the right. Laparoscopic findings
      disclosed the enlarged uterus with the unruptured right ectopic pregnancy in the
      ampullary region and an extrauterine pregnancy in the left tube as well. A linear
      salpingotomy was performed on the right tubal pregnancy. We decided to perform
      salpingectomy on the left tube because it was impossible to preserve the tube,
      and exploration of it showed the existence of another gestational sac. It is
      necessary to decry inappropriate and injudicious use of assisted reproductive
      technologies, especially by individuals with little or no training in monitoring
      the agents and treatments prescribed. In 2003, still waiting for official
      legislation from the Italian Parliament on assisted reproductive technology, we
      have to face dramatic situations, such as this very unique case of heterotopic
      pregnancy.

PMID- 15200775
TI  - Prospective trial of gasless laparoscopic Burch colposuspension using
      conventional surgical instruments.
AB  - STUDY OBJECTIVE: To prospectively evaluate the use of gasless laparoscopy
      techniques in the performance of a traditional Burch colposuspension in women
      with urodynamically-demonstrated genuine stress incontinence and urethral
      hypermobility. DESIGN: Multicenter, prospective, single-intervention series
      (Canadian Task Force Classification II-2). SETTING: Three urogynecologic referral
      centers. PATIENTS: Fifty-eight women. INTERVENTION: Traditional Burch
      colposuspension performed utilizing gasless laparoscopic access and conventional
      surgical instruments. MEASUREMENTS AND MAIN RESULTS: Follow-up was 12 to 38
      months. On pad testing, urine loss was significantly reduced, from 6.0 g (CI:
      0.55-11.45) to 0.3 g (CI: 0-1.53). Average daily incontinence episodes based on 7
      day voiding diaries decreased from 4.7 (CI: 0.87-8.53) to 0.3 (CI: 0-1.58). Q-tip
      angles were normalized: 49.8 degrees (CI: 40.86-58.74) to 10 degrees (CI: 1.49
      18.51). Ninety-five percent of subjects reported resolution of stress
      incontinence. Three subjects (5%) reported recurrent/persistent genuine stress
      incontinence: one was operated on during the postpartum period while
      breastfeeding, and two developed intrinsic sphincteric deficiency
      postoperatively. Fifty-five percent of subjects underwent other pelvic
      reconstructive surgery including posterior wall repairs. Average operative time
      was 60.8 minutes (range, 40-92). The ideal candidate has an unscarred abdominal
      wall. CONCLUSION: Gasless laparoscopic access was used to effectively perform
      traditional Burch colposuspension using conventional open surgical instruments.
      Bladder neck hypermobility was normalized in all subjects, and 95% of subjects
      reported no further stress incontinence.

PMID- 15200776
TI  - The effect of warm humidified CO2 on the dissipation of residual gas following
      laparoscopy in piglets.
AB  - STUDY OBJECTIVE: To determine whether residual gas volume reduces more quickly
      after insufflation with humidified CO(2) compared with dry CO(2). DESIGN: Animal
      study (Canadian Task Force classification I). SETTING: University. INTERVENTION:
      Piglets were randomly divided into two groups of five and underwent abdominal
      insufflation with either cold, dry CO(2) or warm, humidified CO(2). MEASUREMENTS
      AND MAIN RESULTS: Following insufflation, anteroposterior and lateral gas-bubble
      radiographic images were obtained at 5, 15, 30, 45, and 60 minutes, and the area
      of each gas-bubble profile calculated. Blood samples were obtained at 0, 2, 4,
      and 5 hours, and they were analyzed for IL-1beta and TNFalpha. Peritoneal tissue
      samples were obtained on euthanasia at 5 hours for histological analysis. The
      results indicate that following pneumoperitoneum, residual CO(2) dissipates more
      rapidly when the gas is heated and humidified compared with when it is cool and
      dry. This is associated with a reduction in the duration of the inflammatory
      response as measured by TNF alpha production, although no histologic differences
      in the peritoneal tissue were observed. CONCLUSION: Heating and humidifying CO(2)
      leads to faster dissipation of residual gas associated with a reduced duration of
      inflammation, which may contribute toward a reduction in postlaparoscopic pain.

PMID- 15200777
TI  - Optimizing the total laparoscopic hysterectomy procedure for benign uterine
      pathology.
AB  - STUDY OBJECTIVE: To evaluate the influence of the learning curve in total
      laparoscopic hysterectomy on short- and long-term clinical results. DESIGN:
      Retrospective comparative analysis (Canadian Task Force classification II-2).
      SETTING: Malzoni Medical Center of Avellino, university-affiliated hospital.
      PATIENTS: Three hundred and ninety-six women in the first time period (1997-1999)
      and 624 women in the second time period (2000-2002) were treated, using different
      techniques, by the same surgeon. Patients suffered from symptomatic myomas and
      uterine fibromatosis. No case was considered suitable for a vaginal procedure.
      INTERVENTION: Total laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: No
      statistical differences were found between the two groups for patient age,
      parity, body mass index, and indications for surgery (p = NS), except for uterine
      weight (395 g vs. 408 g; p <.01). In the first time period, the average operating
      time was 105 +/- 27 minutes (range, from 65-190). In the second time period, the
      average operating time was 80 +/- 21 minutes (range, 45-170) (p <.001). The
      postoperative hemoglobin drop was 1.44 g/dL (range, 0.8-6.1) and 1.39 g/d (range,
      0.7-4.3) in the first series and second series, respectively (p = NS). In the
      first series, the mean postoperative hospital stay was 2.4 +/- 1 days (range, 2
      7). In the second series, the mean postoperative hospital stay was 2.3 +/- 1 days
      (range, 2-6). A significant decrease in short-term complications occurred between
      the first and second time period, 7.7% and 5.55% respectively (p <.03). We
      performed three (0.75%) and four (0.6%) conversion to laparotomy procedures,
      respectively, in the first and second groups (p = NS). During the first period,
      two reoperations were necessary; in the second period, one patient (0.15%)
      required a reoperation (p = NS). The rate of postoperative blood transfusion was
      0.5% (n = 2) in the first period versus 0.15% (n = 1) in the second period (p =
      NS). Significant decrease of long-term complications occurred between first and
      second series, 2.0% and 0.45% respectively (p <.05). There were no differences
      between the two groups regarding sexual symptoms p = NS). CONCLUSION:
      Laparoscopic hysterectomy is a safe, effective, and reproducible technique after
      completion of a period of training necessary to standardize the procedure. The
      results support the importance of optimizing some steps of the surgical technique
      to reduce severe complications.

PMID- 15200778
TI  - Laparoscopic spectral analysis of endometriosis.
AB  - STUDY OBJECTIVE: To determine if lesions of endometriosis will preferentially
      absorb light of the blue spectrum thus enabling the detection of nonvisualized
      disease. DESIGN: Retrospective analysis (Canadian Task Force classification II
      2). SETTING: University based teaching hospital. PATIENTS: Twenty-five women with
      pain suggestive of endometriosis. INTERVENTION: A noninvasive technique was
      employed to better visualize lesions of endometriosis at time of diagnostic
      laparoscopy. MEASUREMENTS AND MAIN RESULTS: A Storz PDD light source, which
      delivers a blue light at a specified frequency of 440 Hz, was used concurrently
      with full-spectrum white light. A Storz PDD laparoscope, which utilizes filters
      to detect the blue spectrum of light, was then coupled to the blue-light source.
      Lesions of endometriosis were compared using standard white light to that of blue
      light. The new lesions seen using blue light were sampled to confirm pathology.
      Using standard white light, black, red, and clear lesions were identified, and
      the borders of the lesions were marked. The same lesions were observed using the
      blue spectrum of light. The lesions absorbed blue light, but nonvisible
      endometriosis surrounding the classic lesions were also identified. Biopsies
      confirmed endometriosis in newly visible lesions. CONCLUSION: Lesions of
      endometriosis preferentially absorb the blue-light spectrum. Laparoscopic
      spectral analysis enables visualization of previously nonvisible endometriosis
      and makes other visible lesions easier to identify.

PMID- 15200779
TI  - Preoperative double-contrast barium enema in patients with suspected intestinal
      endometriosis.
AB  - STUDY OBJECTIVES: To assess the usefulness of double-contrast barium enema (DCBE)
      in the diagnosis of endometriotic lesions of the bowel and to define its
      potential value in preoperative decision making for intestinal surgery. DESIGN:
      Retrospective study (Canadian Task Force classification II-2). SETTING: General
      hospital with a specialized endometriosis unit. PATIENTS: One hundred and eight
      women with symptoms suggestive of intestinal endometriosis who underwent DCBE
      before laparoscopic surgery. INTERVENTION: Laparoscopic complete excision of
      endometriosis. MEASUREMENTS AND MAIN RESULTS: Fifty-five patients were found to
      have an entirely normal colon on DCBE studies. Twenty-eight of these were found
      to have adhesions of the bowel at laparoscopy. Radiographic abnormalities
      suggestive of endometriosis were detected in 53 patients; 20 of these underwent
      laparoscopic bowel segmental resection, 10 laparoscopic full-thickness disc
      excision, 4 laparoscopic mucosal skinning, and 4 total laparoscopic hysterectomy
      with bilateral salpingo-oophorectomies. Fourteen patients refused intestinal
      surgery. One patient had no endometriosis but severe adhesions. In all cases but
      one, the radiographic findings on DCBE were confirmed by surgery and with
      histopathologic examination of the resected specimens (accuracy 99%). In these
      same cases, the preoperative choice of intestinal surgery remained unchanged
      during the procedure. CONCLUSION: Our data show that, in expert hands, DCBE
      correlated with a patient's clinical history and clinical findings is capable of
      diagnosing bowel wall involvement due to endometriosis, which could require
      intestinal surgery. This allows for proper preoperative planning of surgical
      procedures and a thorough informed consent.

PMID- 15200780
TI  - Prospective evaluation of the learning curve of laparoscopic-assisted vaginal
      hysterectomy in a university hospital.
AB  - STUDY OBJECTIVE: To prospectively analyze the learning curve of laparoscopic
      assisted vaginal hysterectomy (LAVH) in a surgical team and evaluate if length of
      surgery can be reduced safely. DESIGN: Prospective observational study (Canadian
      Task Force classification II-2). SETTING: Department of obstetrics and gynecology
      in a university-affiliated hospital. PATIENTS: One hundred and sixty consecutive
      women undergoing LAVH performed between January 1, 1998 and April 30, 2001.
      INTERVENTION: LAVH (AAGL Classification System for Laparoscopic Hysterectomy III
      B-3). MEASUREMENTS AND MAIN RESULTS: The primary parameter evaluated was length
      of surgery. Patients were grouped in cohorts of 10, in order to perform a time
      curve that would assist us in evaluation of the learning process. Once the
      plateau was reached, we evaluated the process before and after this plateau
      (groups 1 [learning stage] and 2 [second stage], respectively). Average length of
      surgery was 126 minutes (range, 60-260). Length of surgery was 138 minutes
      (range, 75-260) in the learning stage (first 80 cases) and 112 minutes (range, 60
      225) in the second stage (p <.0001). Total rate of complications was 11.6%. There
      were three major complications, and they occurred before the plateau. There were
      15 minor complications (9.67%), 8 during the first stage and 7 in the second
      stage, (p =.9; NS). A second learning curve excluding LAVH with associated
      surgeries was obtained. The average length of surgery for the first stage was 133
      minutes (range, 75-205) and 102 minutes for the second stage (range, 60-130) (p
      >.0001). CONCLUSION: Analysis of the learning curve demonstrated that the length
      of surgery in LAVH could be reduced without increasing the number of
      complications.

PMID- 15200781
TI  - Thermal balloon ablation in patients with multiple morbidity: 3-year follow-up.
AB  - STUDY OBJECTIVE: To evaluate the effectiveness of a thermal uterine balloon
      therapy system in a specific group of patients with multiple morbidity. DESIGN:
      Retrospective cohort analysis (Canadian Task Force classification II-2). SETTING:
      Department of Obstetrics and Gynecology in two university teaching hospitals.
      PATIENTS: Seventy women with severe systemic disease (American Association of
      Anesthesiologists physical status score >/= III) and severe menorrhagia.
      INTERVENTION: Uterine balloon therapy under local anesthesia and 3 years of
      follow-up. MEASUREMENTS AND MAIN RESULTS: The women had a mean age of 44.3 years
      (range, 24-76). After treatment, 25.7% of the patients had no bleeding, 45.7%
      hypomenorrhea, and 21.4% normal menstrual flow. The procedure was repeated
      successfully for one patient, and five failures (7.1%) were observed. The blood
      count values differed significantly (p <.001) before and after balloon therapy.
      CONCLUSION: Uterine balloon therapy is a suitable and useful option for women
      with severe uterine bleeding and concomitant severe systemic nongynecologic
      disease.

PMID- 15200782
TI  - Hysteroscopic metroplasty improves gestational outcome in women with recurrent
      spontaneous abortion.
AB  - STUDY OBJECTIVE: To compare the reproductive outcome in women with recurrent
      spontaneous abortion (RSA) associated with septate uterus after hysteroscopic
      metroplasty compared with patients who did not undergo surgery. DESIGN:
      Longitudinal evaluation (Canadian Task Force classification II-2). SETTING:
      University of Rome, Tor Vergata-affiliated endoscopic unit. PATIENTS: Forty-eight
      consecutive women with septate uterus and RSA were enrolled in the study.
      INTERVENTIONS: Hysteroscopic metroplasty. MEASUREMENTS AND MAIN RESULTS:
      Reproductive outcome in terms of term pregnancy was significantly improved after
      hysteroscopic metroplasty compared with controls (76% vs. 20%). No differences
      were found in the prevalence of preterm delivery between groups (4% vs. 5%).
      CONCLUSION: Our data suggest that hysteroscopic septum incision can improve
      pregnancy outcome in patients with RSA associated with septate uterus.

PMID- 15200783
TI  - Risk of vasovagal syndrome during outpatient hysteroscopy.
AB  - STUDY OBJECTIVE: To evaluate influence of hysteroscope type and media used during
      outpatient hysteroscopy on vasovagal syndrome risk. STUDY DESIGN: Prospective
      observational study (Canadian Task Force classification II-1). SETTING:
      University hospital. PATIENTS: Two thousand seventy-nine women undergoing
      outpatient hysteroscopy without analgesia. INTERVENTION: Office hysteroscopy with
      a flexible or rigid hysteroscope and normal saline or CO(2). MEASUREMENTS AND
      MAIN RESULTS: Fifteen cases of vasovagal syndrome were reported. The rate of
      vasovagal syndrome was higher with use of a rigid hysteroscope (12/647 [1.85%])
      vs. a flexible hysteroscope (3/1432 [0.21%]), p =.00013; p =.009 after adjustment
      for medium used; and with the use of CO2 (10/426 [2.34%]) vs. saline solution
      (5/1653 [0.30%]), p <.0001; p =.014 after adjustment for hysteroscope type.
      CONCLUSION: Risk of vasovagal syndrome is higher with the use of a rigid
      hysteroscope and CO2, regardless of the indication for hysteroscopy or the parity
      and menopausal status of the patient.

PMID- 15200784
TI  - Survey among members of the roman group of gynecologic endoscopy on the use of
      agents for postoperative adhesion prevention.
AB  - STUDY OBJECTIVE: To evaluate patterns of use of agents for postoperative adhesion
      prevention. DESIGN: Mail survey. SETTING: Departments of Obstetrics and
      Gynecology, university-affiliated and public hospitals, Rome, Italy.
      PARTICIPANTS: Members of the Roman Group of Gynecologic Endoscopy. INTERVENTION:
      Evaluation of forms returned. MEASUREMENTS AND MAIN RESULTS: The response rate to
      either electronic or regular mailing was 31%, for a total of 42 forms evaluated.
      For laparoscopy, the perceived postoperative de novo adhesion formation rate was
      0%-25%, whereas the adhesion reformation rate was 26%-75%; for laparotomy, the
      rates were 26%-75% and >75%, respectively. Sixty-five percent of the respondents
      were using at least one method for postoperative adhesion prevention during
      laparoscopy, and 68% during laparotomy. The most frequently used method during
      laparoscopy was Ringer's lactate (77% of the respondents), followed by ferric
      hyaluronate gel (46% of the respondents), and 4% icodextrin (39% of respondents).
      During laparotomy, the most frequently used methods were Ringer's lactate (28%),
      normal saline (20%), and 4% icodextrin (20%). Antibiotic prophylaxis was used by
      87.5% of respondents. CONCLUSION: Postoperative adhesion formation, and
      especially reformation, are perceived as significant problems. Sixty-five percent
      of the respondents used some method for adhesion prevention after operative
      laparoscopy, with Ringer's lactate, ferric hyaluronate gel, and 4% icodextrin
      being the most frequently used.

PMID- 15200785
TI  - Hysteroscopic endometrial ablation as a treatment for abnormal uterine bleeding
      in patients with renal transplants.
AB  - STUDY OBJECTIVE: To assess the effectiveness and safety of hysteroscopic
      endometrial ablation as a surgical management of abnormal uterine bleeding that
      develops in patients with renal transplants. DESIGN: Retrospective study
      (Canadian Task Force classification II-2). SETTING: Yonsei University Medical
      College, Severance Hospital. PATIENTS: Sixty-two women with abnormal uterine
      bleeding who had undergone renal transplantation. INTERVENTION: Hysteroscopic
      endometrial ablation. MEASUREMENTS AND MAIN RESULTS: Fifty-four out of 62
      patients (87.0%) who had undergone hysteroscopic endometrial ablation reported
      decreased bleeding (95% CI: 0.76 to 0.94): amenorrhea in 25 (40.3%), spotting in
      19 (30.6%), and eumenorrhea in 10 (16.1%). Mean follow-up duration was 6 months.
      No complications related to the procedure were reported. Levonorgestrel-releasing
      intrauterine systems (LNG-IUSs) were inserted into eight patients who experienced
      continuous bleeding, five of whom showed symptomatic improvement: spotting in
      three (4.9%) and eumenorrhea in two (3.2%). The three patients (4.9%) in whom the
      LNG-IUS had no effect had hysterectomies, and the resultant pathologic findings
      were two cases of adenomyosis and one case of simple endometrial hyperplasia
      without atypia. CONCLUSION: Hysteroscopic endometrial ablation as a surgical
      management of abnormal uterine bleeding that develops in patients with renal
      transplants is an effective and safe procedure.

PMID- 15200786
TI  - Hysteroscopic training: the butternut pumpkin model.
AB  - Operative hysteroscopy involves significant hand-eye coordination, utilizing
      energy sources, video imaging, and the safe control of distending media. We
      describe a safe, effective, inexpensive, and reproducible method of developing
      the skills and hand-eye coordination for diagnostic and operative hysteroscopy.
      In this inanimate model, advanced surgical skills can be practiced, and
      realistic, simulated electrosurgery including resection of the endometrium and
      rollerball ablation can be performed.

PMID- 15200787
TI  - Improved patient compliance using pediatric cystoscope during office
      hysteroscopy.
AB  - STUDY OBJECTIVE: To evaluate the use of a pediatric cystoscope in office
      diagnostic hysteroscopy. DESIGN: Retrospective review (Canadian Task Force
      classification II-2). SETTING: Maccabi Outpatient Women's Health Center.
      PATIENTS: One thousand three hundred and thirty-five women; 959 (71.8%)
      premenopausal and 376 (28.2%) menopausal. INTERVENTION: Office diagnostic
      hysteroscopy using 2.3-mm diameter pediatric cystoscope, without premedication or
      anesthesia. MEASUREMENTS AND MAIN RESULTS: Hysteroscopy was successfully
      completed in 1298 patients (97.3%). The main reason for failure was cervical
      stenosis. Menopausal status was the only statistically significant factor
      correlating with increased failure rate. The analysis demonstrates that for every
      year of age, the OR for success decreases by 0.965, and success rises by 1.29 for
      every delivery the woman had. In menopausal women, the OR for success decreases
      by 0.45. Dilatation of the cervix was required in six women (0.46%), and local
      anesthesia was needed in only two women. One uterine perforation was recorded,
      and eight women (0.006%) developed vasovagal reflex or severe abdominal cramps.
      Post procedural oral analgesia was needed in 108 (8%) of the women. CONCLUSION:
      The combination of a very small diameter continuous flow pediatric cystoscope,
      together with its ability to deliver high-quality images of the uterine cavity,
      make this instrument an excellent option for office diagnostic hysteroscopy.

PMID- 15200788
TI  - Laparoscopic management of teratoma of the round ligament.
AB  - This paper describes the case of an asymptomatic woman who underwent laparoscopy
      as part of a work-up for infertility. A previous transvaginal ultrasound had
      shown an echogenic adnexal mass, independent of the ovary. The intraoperative
      finding was a tumor of the round ligament that was resected and determined to be
      a mature teratoma. The case is reported due to the unusual location for that type
      of tumor; and in addition, it is the first description of a teratoma in the round
      ligament managed by laparoscopy.

PMID- 15200789
TI  - Genital and peritoneal tuberculosis: potential role of laparoscopy in diagnosis
      and management.
AB  - Genital and peritoneal tuberculosis are rare in developed countries and can mimic
      ovarian cancer. We report two different cases that came to our attention, both in
      a month. The first patient was referred to us for an asymptomatic pelvic mass.
      The second patient came to us because of weight loss, abdominal swelling, and
      ascites. Unfortunately, the imaging findings were misleading, and the laboratory
      analyses were not helpful. Only the laparoscopic approach was useful for final
      diagnosis. We conclude that the symptoms of abdominal tuberculosis vary greatly,
      and laparoscopy can be essential for its diagnosis and management.

PMID- 15200790
TI  - Multiple myomas treated with a temporary, noninvasive, Doppler-directed,
      transvaginal uterine artery clamp.
AB  - A 43-year-old woman with menorrhagia, dysmenorrhea, and pelvic pain of several
      years' duration had a uterus enlarged by myomas to the size of a 16-week
      pregnancy. Her uterine arteries were noninvasively transvaginally identified and
      occluded for 6 hours with a clamp that was guided by audible Doppler ultrasound.
      Following removal of the clamp, blood flow in the uterine arteries returned
      immediately. Menorrhagia symptoms diminished. Three months following treatment,
      uterine volume decreased by 48.9%, and dominant myoma volume decreased by 77.2%.

PMID- 15200795
TI  - The feasibility of an internal bladder retractor in facilitating bladder
      dissection during laparoscopic-assisted vaginal hysterectomy.

PMID- 15200797
TI  - Qualitative evidence: using signs, signals, indicators, and facts.

PMID- 15200798
TI  - Making sense of traumatic experiences: telling your life with fragile X syndrome.
AB  - The discourse of individuals with fragile X syndrome has been described as
      fragmented, tangential, and associatively connected, resulting in
      autobiographical narratives that are incoherent and difficult to understand. In
      this article, the authors discuss the case of an adolescent female with moderate
      mental retardation due to fragile X syndrome. The analysis of her
      autobiographical stories, rather than being primarily reflective of cognitive
      impoverishment, reveals a different--narrative--mode of thought. The authors
      present and examine some of her narratives in terms of their specific functions:
      communication, coherence, exploration, distancing, and evaluation. Their findings
      suggest that narrative analysis can be an important complement to traditional
      neuropsychological assessment.

PMID- 15200799
TI  - The dyspnea-anxiety-dyspnea cycle--COPD patients' stories of breathlessness:
      "It's scary /when you can't breathe".
AB  - Dyspnea, the major symptom associated with acute exacerbation events of chronic
      obstructive pulmonary disease (COPD), is a subjective experience. Extensive
      research has been done on the pathophysiology and affective components of
      dyspnea; however, the precise physical mechanism of breathlessness remains
      elusive. One purpose of this narrative research was to explore the affective
      component of dyspnea/anxiety as described by patients living with COPD
      characterized by acute illness events. Ten patient-family units participated in
      interviews during an acute episode of the patient's lung disease. They described
      their understanding of acute dyspnea as an experience inextricably related to
      anxiety and emotional functioning. Their stories suggest that given the absence
      of clear objective measures of illness severity, patient-reported anxiety might
      provide an important marker during acute exacerbation events. Health care
      providers need to recognize anxiety as an important and potentially measurable
      sign of invisible dyspnea for end-stage patients with COPD in acute respiratory
      distress.

PMID- 15200800
TI  - The lived experience of oldest-old rural adults.
AB  - The author elicited the lived experience of 19 oldest-old adults (13 women, all
      White, mean age 90.7 years, range 85-98 years) who lived alone in the rural
      Midwest to describe their everyday activities, concerns and struggles, and
      adaptive strategies. In-depth interviews (59 total) were audiotaped, transcribed,
      and analyzed in an interpretive phenomenological tradition of thematic analysis,
      interpretation of paradigm cases, and interpretation of exemplars. Participants
      described how historical, cultural, and environmental contexts shaped their
      everyday thoughts, activities, and what was meaningful to them. Findings can
      guide health care professionals to evaluate and develop community services and
      help significant others (family, friends, neighbors) understand what oldest-old
      rural adults need to remain at home.

PMID- 15200801
TI  - Continuity of the self in later life: perceptions of informal caregivers.
AB  - The authors explore perceptions of informal caregivers of extremely elderly (80+)
      relatives or friends regarding the purpose of caregiving, including factors they
      considered important for the life satisfaction of the care recipients. They
      collected data mainly through qualitative interviewed and employed symbolic
      interactionism. The results revealed a general purpose of the informal
      caregiving: protection of the care recipient's self. This purpose was a
      significant aspect of the identified caregiving categories--social-emotional,
      proxy, and instrumental care--and the authors consider all four factors important
      for the care recipients' life satisfaction: activity, independence, and
      environmental and adaptive factors. Some informal caregivers gave forceful
      encouragement to care recipients in an attempt to get them to accept formal care
      and move to sheltered accommodation. This study underscores the value of informal
      caregiving and that the caregiving interaction should be balanced by reciprocity.

PMID- 15200802
TI  - Palliative care, care for life: a study of the specificity of residential
      palliative care.
AB  - In this study, the authors describe the concept of palliative care as applied in
      a palliative care unit. They conducted in-depth interviews with 8 patients, 9
      relatives, and 24 caregivers from two residential palliative care units.
      Observation of the care and of team meetings and analysis of patient records
      provided additional data. Palliative care involves a specific concept of care,
      the central focus of which is life. This is realized by two strategies. The first
      is to create space to live by diverting attention from the sick body, moving the
      illness into the background. The second is to fill the space as meaningfully as
      possible, so that patients can enjoy life even in the face of death. The quality
      of the caregiving process in palliative care is determined by a range of
      conditions and processes that reflect its complexity.

PMID- 15200803
TI  - Moving in between mammography: screening decisions of American Indian women in
      Vermont.
AB  - Breast cancer is a leading cause of cancer death among American Indian women,
      with mammography screening rates below the national average for this population.
      A grounded theory study, conducted with Vermont American Indian women, explicated
      factors that influence mammography decision making. The authors examined
      mammography decision making across the breast cancer screening continuum: women
      with a history of consistent annual mammograms, women who were under users or
      nonusers of mammography, and women who were breast cancer survivors. The
      generated theory, Moving in Between Mammography, describes the decision-making
      process and factors that influenced women's participation in routine mammography
      screening. Specific influencing factors addressed include Connecting to
      Nativeness, Taking Care of Self, Financing Health Care, and (Mis)Trusting the
      Health Care System. Implications and directions for future research are
      addressed.

PMID- 15200804
TI  - Toward understanding in postmodern interview analysis: interpreting the
      contradictory remarks of a research participant.
AB  - How is the qualitative research analyst to understand apparently contradictory
      remarks made by a research participant? Although social scientists in the
      positivist tradition rely on methods such as triangulation to find "truth,"
      interpretive social scientists listen beyond, between, and underneath
      participants' words to understand the social conditions that produce apparent
      contradictions in their accounts. In this article, the author presents a case
      study of making sense of a research participant's contradictory comments, using a
      theoretical framework to understand the participant's "logic of practice."
      Through interpretive listening and reflexivity during the data analysis, she came
      to understand the participant's contradictory remarks in a way that illuminated
      the contradictions, as well as a significant process in the participant's life at
      the time: the transformation from carefree daughter to responsible mother. Such
      an interpretive analysis does not produce "truth" as positivist social scientists
      require but offers instead the satisfaction of understanding.

PMID- 15200805
TI  - To what extent do the characteristics of the object of evaluation influence the
      choice of epistemological framework? The case of universal newborn hearing
      screening.
AB  - In this article, the authors explore the role that characteristics and
      circumstances attendant on the object of an evaluation might play in the choice
      of epistemological framework underpinning research design. They consider examples
      from the consumer-focused evaluation of the introduction of universal newborn
      hearing screening in England. In particular, they look at how screen- and program
      specific issues exerted influence at the levels of epistemology and method,
      arguing that these choices are not simply a product of values and questions that
      underpinned one kind of approach to knowledge production in comparison with
      another.

PMID- 15200806
TI  - Establishing integrity and avoiding methodological misunderstanding.
AB  - In this article, the authors discuss their understanding of how the consistent
      use of language, reflective of the research method used, can deem a study
      scientifically adequate. Using a hermeneutic phenomenological study, as the basis
      for the discussion, integrity is posed as a suitable term to describe scientific
      adequacy. In addition, the authors ask readers to reflect on their beliefs about
      the language used to discuss other qualitative approaches.

PMID- 15200807
TI  - Hospital preparedness and SARS.
AB  - On May 23, 2003, Toronto experienced the second phase of a severe acute
      respiratory syndrome (SARS) outbreak. Ninety cases were confirmed, and >620
      potential cases were managed. More than 9,000 persons had contact with confirmed
      or potential case-patients; many required quarantine. The main hospital involved
      during the second outbreak was North York General Hospital. We review this
      hospital's response to, and management of, this outbreak, including such factors
      as building preparation and engineering, personnel, departmental workload,
      policies and documentation, infection control, personal protective equipment,
      training and education, public health, management and administration, follow-up
      of SARS patients, and psychological and psychosocial management and research. We
      also make recommendations for other institutions to prepare for future outbreaks,
      regardless of their origin.

PMID- 15200808
TI  - SARS in healthcare facilities, Toronto and Taiwan.
AB  - The healthcare setting was important in the early spread of severe acute
      respiratory syndrome (SARS) in both Toronto and Taiwan. Healthcare workers,
      patients, and visitors were at increased risk for infection. Nonetheless, the
      ability of individual SARS patients to transmit disease was quite variable.
      Unrecognized SARS case-patients were a primary source of transmission, and early
      detection and intervention were important to limit spread. Strict adherence to
      infection control precautions was essential in containing outbreaks. In addition,
      grouping patients into cohorts and limiting access to SARS patients minimized
      exposure opportunities. Given the difficulty in implementing several of these
      measures, control measures were frequently adapted to the acuity of SARS care and
      level of transmission within facilities. Although these conclusions are based
      only on a retrospective analysis of events, applying the experiences of Toronto
      and Taiwan to SARS preparedness planning efforts will likely minimize future
      transmission within healthcare facilities.

PMID- 15200809
TI  - SARS in hospital emergency room.
AB  - Thirty-one cases of severe acute respiratory syndrome (SARS) occurred after
      exposure in the emergency room at the National Taiwan University Hospital. The
      index patient was linked to an outbreak at a nearby municipal hospital. Three
      clusters were identified over a 3-week period. The first cluster (5 patients) and
      the second cluster (14 patients) occurred among patients, family members, and
      nursing aids. The third cluster (12 patients) occurred exclusively among
      healthcare workers. Six healthcare workers had close contact with SARS patients.
      Six others, with different working patterns, indicated that they did not have
      contact with a SARS patient. Environmental surveys found 9 of 119 samples of
      inanimate objects to be positive for SARS coronavirus RNA. These observations
      indicate that although transmission by direct contact with known SARS patients
      was responsible for most cases, environmental contamination with the SARS
      coronavirus may have lead to infection among healthcare workers without
      documented contact with known hospitalized SARS patients.

PMID- 15200810
TI  - Genetic variation of SARS coronavirus in Beijing Hospital.
AB  - To characterize genetic variation of severe acute respiratory syndrome-associated
      coronavirus (SARS-CoV) transmitted in the Beijing area during the epidemic
      outbreak of 2003, we sequenced 29 full-length S genes of SARS-CoV from 20
      hospitalized SARS patients on our unit, the Beijing 302 Hospital. Viral RNA
      templates for the S-gene amplification were directly extracted from raw clinical
      samples, including plasma, throat swab, sputum, and stool, during the course of
      the epidemic in the Beijing area. We used a TA-cloning assay with direct analysis
      of nested reverse transcription-polymerase chain reaction products in sequence.
      One hundred thirteen sequence variations with nine recurrent variant sites were
      identified in analyzed S-gene sequences compared with the BJ01 strain of SARS
      CoV. Among them, eight variant sites were, we think, the first documented. Our
      findings demonstrate the coexistence of S-gene sequences with and without
      substitutions (compared to BJ01) in samples analyzed from some patients.

PMID- 15200811
TI  - Multidrug-resistant strains of Salmonella enterica Typhimurium, United States,
      1997-1998.
AB  - To evaluate multidrug-resistant strains of Salmonella enterica serotype
      Typhimurium, including definitive type 104 (DT104) in the United States, we
      reviewed data from the National Antimicrobial Resistance Monitoring System
      (NARMS). In 1997 to 1998, 703 (25%) of 2,767 serotyped Salmonella isolates
      received at NARMS were S. Typhimurium; antimicrobial susceptibility testing and
      phage typing were completed for 697. Fifty-eight percent (402) were resistant to
      > or = 1 antimicrobial agent. Three multidrug-resistant (> or = 5 drugs) strains
      accounted for (74%) 296 of all resistant isolates. Ceftriaxone resistance was
      present in 8 (3%), and nalidixic acid resistance in 4 (1%), of these multidrug
      resistant strains. By phage typing, 259 (37%) of S. Typhimurium isolates were
      DT104, 209 (30%) were of undefined type and 103 (15%) were untypable. Fifty
      percent (202) of resistant (> or = 1 drug) isolates were DT104. Multidrug
      resistant S. Typhimurium isolates, particularly DT104, account for a substantial
      proportion of S. Typhimurium isolates; ceftriaxone resistance is exhibited by
      some of these strains.

PMID- 15200812
TI  - Seasonal forecast of St. Louis encephalitis virus transmission, Florida.
AB  - Disease transmission forecasts can help minimize human and domestic animal health
      risks by indicating where disease control and prevention efforts should be
      focused. For disease systems in which weather-related variables affect pathogen
      proliferation, dispersal, or transmission, the potential for disease forecasting
      exists. We present a seasonal forecast of St. Louis encephalitis virus
      transmission in Indian River County, Florida. We derive an empiric relationship
      between modeled land surface wetness and levels of SLEV transmission in humans.
      We then use these data to forecast SLEV transmission with a seasonal lead.
      Forecast skill is demonstrated, and a real-time seasonal forecast of epidemic
      SLEV transmission is presented. This study demonstrates how weather and climate
      forecast skill-verification analyses may be applied to test the predictability of
      an empiric disease forecast model.

PMID- 15200813
TI  - Acute tick-borne rickettsiosis caused by Rickettsia heilongjiangensis in Russian
      Far East.
AB  - An acute tick-borne rickettsiosis caused by Rickettsia heilongjiangensis was
      diagnosed in 13 patients from the Russian Far East in 2002. We amplified and
      sequenced four portions of three rickettsial genes from the patients' skin biopsy
      results and blood samples and showed that the amplified rickettsial genes belong
      to R. heilongjiangensis, which was recently isolated from Dermacentor sylvarum
      ticks in nearby regions of China. This rickettsia, belonging to subgroup of R.
      japonica, was previously suggested to be pathogenic for humans on the basis of
      serologic findings. We tested serum samples with different rickettsial antigens
      from 11 patients and confirmed increasing titers of immunoglobulin (Ig) G and IgM
      to spotted fever group rickettsiae, including R. heilongjiangensis. Clinical and
      epidemiologic data on these patients show that this disease is similar to other
      tick-borne rickettsioses.

PMID- 15200814
TI  - Clinical manifestations, laboratory findings, and treatment outcomes of SARS
      patients.
AB  - Clinical and laboratory data on severe acute respiratory syndrome (SARS),
      particularly on the temporal progression of abnormal laboratory findings, are
      limited. We conducted a prospective study on the clinical, radiologic, and
      hematologic findings of SARS patients with pneumonia, who were admitted to
      National Taiwan University Hospital from March 8 to June 15, 2003. Fever was the
      most frequent initial symptom, followed by cough, myalgia, dyspnea, and diarrhea.
      Twenty-four patients had various underlying diseases. Most patients had elevated
      C-reactive protein (CRP) levels and lymphopenia. Other common abnormal laboratory
      findings included leukopenia, thrombocytopenia, and elevated levels of
      aminotransferase, lactate dehydrogenase, and creatine kinase. These clinical and
      laboratory findings were exacerbated in most patients during the second week of
      disease. The overall case-fatality rate was 19.7%. By multivariate analysis,
      underlying disease and initial CRP level were predictive of death.

PMID- 15200815
TI  - Laboratory diagnosis of SARS.
AB  - The virologic test results of 415 patients with severe acute respiratory syndrome
      (SARS) were examined. The peak detection rate for SARS-associated coronavirus
      occurred at week 2 after illness onset for respiratory specimens, at weeks 2 to 3
      for stool or rectal swab specimens, and at week 4 for urine specimens. The latest
      stool sample that was positive by reverse transcription-polymerase chain reaction
      (RT-PCR) was collected on day 75 while the patient was receiving intensive care.
      Tracheal aspirate and stool samples had a higher diagnostic yield (RT-PCR average
      positive rate for first 2 weeks: 66.7% and 56.5%, respectively). Pooled throat
      and nasal swabs, rectal swab, nasal swab, throat swab, and nasopharyngeal
      aspirate specimens provided a moderate yield (29.7%-40.0%), whereas throat
      washing and urine specimens showed a lower yield (17.3% and 4.5%). The collection
      procedures for stool and pooled nasal and throat swab specimens were the least
      likely to transmit infection, and the combination gave the highest yield for
      coronavirus detection by RT-PCR. Positive virologic test results in patient
      groups were associated with mechanical ventilation or death (p < 0.001),
      suggesting a correlation between viral load and disease severity.

PMID- 15200816
TI  - Ring vaccination and smallpox control.
AB  - We present a stochastic model for the spread of smallpox after a small number of
      index cases are introduced into a susceptible population. The model describes a
      branching process for the spread of the infection and the effects of intervention
      measures. We discuss scenarios in which ring vaccination of direct contacts of
      infected persons is sufficient to contain an epidemic. Ring vaccination can be
      successful if infectious cases are rapidly diagnosed. However, because of the
      inherent stochastic nature of epidemic outbreaks, both the size and duration of
      contained outbreaks are highly variable. Intervention requirements depend on the
      basic reproduction number (R0), for which different estimates exist. When faced
      with the decision of whether to rely on ring vaccination, the public health
      community should be aware that an epidemic might take time to subside even for an
      eventually successful intervention strategy.

PMID- 15200817
TI  - Virulence factors for hemolytic uremic syndrome, Denmark.
AB  - We present an analysis of strain and patient factors associated with the
      development of bloody diarrhea and hemolytic uremic syndrome (HUS) among Shiga
      toxin-producing Escherichia coli (STEC) patients registered in Denmark in a 6
      year period. Of 343 STEC patients, bloody diarrhea developed in 36.4% and HUS in
      6.1%. In a multivariate logistic regression model, risk factors for bloody
      diarrhea were the eae and stx2 genes, O groups O157 and O103, and increasing age.
      Risk factors for HUS were presence of the stx2 (odds ratio [OR] 18.9) and eae (OR
      undefined) genes, being a child, and having bloody diarrhea. O group O157,
      although associated with HUS in a univariate analysis (OR 4.0), was not
      associated in the multivariate analysis (OR 1.1). This finding indicates that,
      rather than the O group, the combined presence of the eae and stx2 genes is an
      important predictor of HUS.

PMID- 15200818
TI  - Enzyme-linked immunosorbent assay and serologic responses to Pneumocystis
      jiroveci.
AB  - Seroepidemiologic studies of Pneumocystis pneumonia (PCP) in humans have been
      limited by inadequate reagents. We have developed an enzyme-linked immunosorbent
      assay (ELISA) using three overlapping recombinant fragments of the human
      Pneumocystis major surface glycoprotein (MsgA, MsgB, and MsgC) for analysis of
      antibody responses in HIV-positive patients and healthy blood donors. HIV
      positive patients had significantly higher antibody levels to all Msg fragments.
      Furthermore, HIV-positive patients who experienced a previous episode of PCP (PCP
      positive) had higher levels of antibodies to MsgC than patients who never had
      PCP. A significant association was found between ELISA antibody level and
      reactivity by Western blot in HIV-positive patients, especially those who were
      PCP-positive. Thus, this ELISA will be useful in studying serum antibody
      responses to Pneumocystis in different human populations.

PMID- 15200819
TI  - Vancomycin susceptibility within methicillin-resistant Staphylococcus aureus
      lineages.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) with reduced vancomycin
      susceptibility vancomycin-intermediate S. aureus (VISA) has been reported from
      many countries. Whether resistance is evolving regularly in different genetic
      backgrounds or in a single clone with a genetic predisposition, as early results
      suggest, is unclear. We have studied 101 MRSA with reduced vancomycin
      susceptibility from nine countries by multilocus sequence typing (MLST),
      characterization of SCCmec (staphylococcal chromosomal cassette mec), and agr
      (accessory gene regulator). We found nine genotypes by MLST, with isolates within
      all five major hospital MRSA lineages. Most isolates (88/101) belonged to two of
      the earliest MRSA clones that have global prevalence. Our results show that
      reduced susceptibility to vancomycin has emerged in many successful epidemic
      lineages with no clear clonal disposition. Increasing antimicrobial resistance in
      genetically distinct pandemic clones may lead to MRSA infections that will become
      increasingly difficult to treat.

PMID- 15200820
TI  - Syndromic surveillance in public health practice, New York City.
AB  - The New York City Department of Health and Mental Hygiene has established a
      syndromic surveillance system that monitors emergency department visits to detect
      disease outbreaks early. Routinely collected chief complaint information is
      transmitted electronically to the health department daily and analyzed for
      temporal and spatial aberrations. Respiratory, fever, diarrhea, and vomiting are
      the key syndromes analyzed. Statistically significant aberrations or "signals"
      are investigated to determine their public health importance. In the first year
      of operation (November 15, 2001, to November 14, 2002), 2.5 million visits were
      reported from 39 participating emergency departments, covering an estimated 75%
      of annual visits. Most signals for the respiratory and fever syndromes (64% and
      95%, respectively) occurred during periods of peak influenza A and B activity.
      Eighty-three percent of the signals for diarrhea and 88% of the signals for
      vomiting occurred during periods of suspected norovirus and rotavirus
      transmission.

PMID- 15200821
TI  - Multidrug-resistant tuberculosis in central Asia.
AB  - Multidrug-resistant tuberculosis (MDR-TB) has emerged as a major threat to TB
      control, particularly in the former Soviet Union. To determine levels of drug
      resistance within a directly observed treatment strategy (DOTS) program supported
      by Medecins Sans Frontieres in two regions in Uzbekistan and Turkmenistan,
      Central Asia, we conducted a cross-sectional survey of smear-positive TB patients
      in selected districts of Karakalpakstan (Uzbekistan) and Dashoguz (Turkmenistan).
      High levels of MDR-TB were found in both regions. In Karakalpakstan, 14 (13%) of
      106 new patients were infected with MDR-TB; 43 (40%) of 107 previously treated
      patients were similarly infected. The proportions for Dashoguz were 4% (4/105
      patients) and 18% (18/98 patients), respectively. Overall, 27% of patients with
      positive smear results whose infections were treated through the DOTS program in
      Karakalpakstan and 11% of similar patients in Dashoguz were infected with
      multidrug-resistant strains of TB on admission. These results show the need for
      concerted action by the international community to contain transmission and
      reduce the effects of MDR-TB.

PMID- 15200822
TI  - Antimicrobial resistance in commensal flora of pig farmers.
AB  - We assessed the quantitative contribution of pig farming to antimicrobial
      resistance in the commensal flora of pig farmers by comparing 113 healthy pig
      farmers from the major French porcine production areas to 113 nonfarmers, each
      matched for sex, age, and county of residence. All reported that they had not
      taken antiimicrobial agents within the previous month. Throat, nasal, and fecal
      swabs were screened for resistant microorganisms on agar containing selected
      antimicrobial agents. Nasopharyngeal carriage of Staphylococcus aureus was
      significantly more frequent in pig farmers, as was macrolide resistance of S.
      aureus from carriers. Nongroupable streptococci from the throat were more
      resistant to the penicillins in pig farmers. The intestinal isolation of
      enterococci resistant to erythromycin or vancomycin was not significantly higher
      in pig farmers in contrast to that of enterobacteria resistant to nalidixic acid,
      chloramphenicol, tetracycline, and streptomycin. Prevalence of resistance in
      predominant fecal enterobacteria was also significantly higher in pig farmers for
      cotrimoxazole, tetracycline, streptomycin, and nalidixic acid. We determined a
      significant association between pig farming and isolation of resistant commensal
      bacteria.

PMID- 15200823
TI  - Endemic Venezuelan equine encephalitis in northern Peru.
AB  - Since Venezuelan equine encephalitis virus (VEEV) was isolated in Peru in 1942,
      >70 isolates have been obtained from mosquitoes, humans, and sylvatic mammals
      primarily in the Amazon region. To investigate genetic relationships among the
      Peru VEEV isolates and between the Peru isolates and other VEEV strains, a
      fragment of the PE2 gene was amplified and analyzed by single-stranded
      conformation polymorphism. Representatives of seven genotypes underwent
      sequencing and phylogenetic analysis. The results identified four VEE complex
      lineages that cocirculate in the Amazon region: subtypes ID (Panama and
      Colombia/Venezuela genotypes), IIIC, and a new, proposed subtype IIID, which was
      isolated from a febrile human, mosquitoes, and spiny rats. Both ID lineages and
      the IIID subtype are associated with febrile human illness. Most of the subtype
      ID isolates belonged to the Panama genotype, but the Colombia/Venezuela genotype,
      which is phylogenetically related to epizootic strains, also continues to
      circulate in the Amazon basin.

PMID- 15200824
TI  - Causative agent of Pogosta disease isolated from blood and skin lesions.
AB  - Pogosta disease is a mosquito-borne viral disease in Finland, which is clinically
      manifested by rash and arthritis; larger outbreaks occur in 7-year intervals. The
      causative agent of the disease has been suspected of being closely related to
      Sindbis virus (SINV). We isolated SINV from five patients with acute Pogosta
      disease during an outbreak in fall 2002 in Finland. One virus strain was
      recovered from a whole blood sample and four other strains from skin lesions. The
      etiology of Pogosta disease was confirmed by these first Finnish SINV strains,
      which also represent the first human SINV isolates from Europe. Phylogenetic
      analysis indicates that the Finnish SINV strains are closely related to the viral
      agents that were previously isolated from mosquitoes and that are related
      clinically similar diseases in nearby geographic areas.

PMID- 15200825
TI  - Infection control and SARS transmission among healthcare workers, Taiwan.
AB  - This study found infrequent transmission of severe acute respiratory syndrome
      (SARS) coronavirus to healthcare workers involved in the care of the first five
      case-patients in Taiwan, despite a substantial number of unprotected exposures.
      Nonetheless, given that SARS has been highly transmissible on some occasions, we
      still recommend strict precautions.

PMID- 15200826
TI  - Novel gamma-2-herpesvirus of the Rhadinovirus 2 lineage in gibbons.
AB  - We obtained 475 nucleotides of the DNA polymerase gene of a novel human
      herpesvirus 8 homolog sequence in a gibbon. The finding of this new gibbon virus,
      which clusters with a related chimpanzee virus in the rhadinovirus 2 genogroup,
      suggests the existence of a novel gamma-2-herpesvirus in humans.

PMID- 15200827
TI  - Increase in imported dengue, Germany, 2001-2002.
AB  - Dengue fever is a reportable disease in Germany. Surveillance data from 2001 and
      2002 were analyzed and compared to travel patterns. Imported dengue fever
      increased strongly in this time. Most infections were acquired in Southeast Asia,
      specifically Thailand. The 2002 epidemic in Brazil was also reflected in these
      data.

PMID- 15200828
TI  - Corvidae feather pulp and West Nile virus detection.
AB  - We evaluated cloacal swab, vascular pulp of flight feather, and kidney and spleen
      pool samples from carcasses of members of the family Corvidae as sources of West
      Nile virus (WNV). The cloacal swab, kidney and spleen pool, and feather pulp were
      the source of WNV in 38%, 43%, and 77%, respectively, of the carcasses.

PMID- 15200829
TI  - Fatal spotted fever rickettsiosis, Kenya.
AB  - We report a fatal case of rickettsiosis in a woman from the United States living
      in Kenya, who had a history of tick exposure. Immunohistochemical staining of
      skin, kidney, and liver demonstrated spotted fever group rickettsiae. The
      clinical findings, severity, and fatal outcome are most consistent with
      Rickettsia conorii infection.

PMID- 15200830
TI  - Domestic poultry and SARS coronavirus, southern China.
AB  - SARS coronavirus injected intratracheally into chickens, turkeys, geese, ducks,
      and quail, or into the allantoic sac of their embryonating eggs, failed to cause
      disease or replicate. This finding suggests that domestic poultry were unlikely
      to have been the reservoir, or associated with dissemination, of SARS coronavirus
      in the animal markets of southern China.

PMID- 15200831
TI  - Mass smallpox vaccination and cardiac deaths, New York City, 1947.
AB  - In April 1947, during a smallpox outbreak in New York City (NYC), more than 6
      million people were vaccinated. To determine whether vaccination increased
      cardiac death, we reviewed NYC death certificates for comparable periods in 1946,
      1947, and 1948 (N = 81,529) and calculated adjusted relative death rates for the
      postvaccination period. No increases in cardiac deaths were observed.

PMID- 15200832
TI  - Mycobacterium africanum cases, California.
AB  - Five Mycobacterium tuberculosis complex isolates in California were identified as
      M. africanum by spoligotyping, single nucleotide polymorphisms, a deletion
      mutation, and phenotypic traits, confirming it as a cause of tuberculosis in the
      United States. Three of the five patients from whom M. africanum was isolated had
      lived in Africa.

PMID- 15200833
TI  - Rapidly progressive dementia due to Mycobacterium neoaurum meningoencephalitis.
AB  - Dementia developed in a patient with widespread neurologic manifestations; she
      died within 5 months. Pathologic findings showed granulomatous inflammation with
      caseation necrosis, foreign body-type giant cells, and proliferative endarteritis
      with vascular occlusions. Broad-range polymerase chain reaction identified
      Mycobacterium neoaurum as the possible pathogen. Central nervous system infection
      by M. neoaurum may result in rapidly progressive dementia.

PMID- 15200834
TI  - Hemolytic uremic syndrome incidence in New York.
AB  - A comparison of New York's traditional communicable disease surveillance system
      for diarrhea-associated hemolytic uremic syndrome with hospital discharge data
      showed a sensitivity of 65%. Escherichia coli O157:H7 was found in 63% of samples
      cultured from hemolytic uremic syndrome patients, and samples were more likely to
      be positive when collected early in illness.

PMID- 15200835
TI  - Multidrug-resistant Salmonella Typhimurium infection from milk contaminated after
      pasteurization.
AB  - An outbreak of multidrug-resistant Salmonella enterica serotype Typhimurium
      infections occurred in Pennsylvania and New Jersey. A case-control study
      implicated pasteurized milk from a dairy, and an inspection indicated the
      potential for contamination after pasteurization. Dairy cattle are the likely
      reservoir, and milk may be an important vehicle of Salmonella transmission to
      humans.

PMID- 15200836
TI  - Neisseria meningitidis W135, Turkey.
AB  - We describe the first case of Neisseria meningitidis W135 meningitis in Turkey.
      The strain was genotypically unrelated to the clone (W)ET-37, isolated from Hajj
      pilgrims in 2000.

PMID- 15200837
TI  - Dead crow reports and location of human West Nile virus cases, Chicago, 2002.
AB  - During the summer and fall of 2002, an epidemic (223 cases) and epizootic of West
      Nile virus infections occurred in Chicago. Retrospective spatial analysis
      demonstrated that age-adjusted human case rates were three times higher inside
      geographic areas with high early-season crow deaths than outside these areas.

PMID- 15200838
TI  - Community-acquired methicillin-resistant Staphylococcus aureus among military
      recruits.
AB  - We report an outbreak of 235 community-acquired methicillin-resistant
      Staphylococcus aureus (MRSA) infections among military recruits. In this unique
      environment, the close contact between recruits and the physical demands of
      training may have contributed to the spread of MRSA. Control measures included
      improved hygiene and aggressive clinical treatment.

PMID- 15200839
TI  - Rift Valley fever in Chad.
AB  - To evaluate the importance of human exposure to Rift Valley fever virus in Chad,
      investigations were carried out to determine specific antibody prevalence in
      domestic ruminants during the 2002 rainy season. Results highlighted recent,
      substantial, active transmission of this virus.

PMID- 15200840
TI  - Bat rabies, Texas, 1996-2000.
AB  - Bats submitted to the Texas Department of Health (1996-2000) were speciated and
      tested for rabies virus antigen by direct immunofluorescence microscopy.
      Antigenic analysis of rabies virus-positive specimens was performed with
      monoclonal antibodies against the nucleoprotein of the virus; atypical or
      unexpected results were confirmed by genetic analysis of nucleoprotein sequence.

PMID- 15200841
TI  - Human and porcine hepatitis E virus strains, United Kingdom.
AB  - We describe a case of acquired infection of a strain of hepatitis E virus (HEV)
      with a 100% amino acid identity to the analogous region in strains of HEV
      circulating in a United Kingdom pig herd. This case further supports the theory
      that autochthonous HEV infection in industrialized countries is zoonotic.

PMID- 15200842
TI  - Economics and preventing hospital-acquired infection.
AB  - The economics of preventing hospital-acquired infections is most often described
      in general terms. The underlying concepts and mechanisms are rarely made explicit
      but should be understood for research and policy-making. We define the key
      economic concepts and specify an illustrative model that uses hypothetical data
      to identify how two related questions might be addressed: 1) how much should be
      invested for infection control, and 2) what are the most appropriate infection
      control programs? We aim to make explicit the economics of preventing hospital
      acquired infections.

PMID- 15200843
TI  - Reanalyzing the 1900-1920 sleeping sickness epidemic in Uganda.
AB  - Sleeping sickness has long been a major public health problem in Uganda. From
      1900 to 1920, more than 250,000 people died in an epidemic that affected the
      southern part of the country, particularly the Busoga region. The epidemic has
      traditionally been ascribed to Trypanosoma brucei gambiense, a parasite now
      confined to central and western Africa. The Busoga region still reports sleeping
      sickness, although it is caused by T.b. rhodesiense, commonly believed to have
      spread to Uganda from Zambia in the 1940s. Our analysis of clinical data recorded
      in the early 1900s shows that the clinical course of sleeping sickness cases
      during the 1900-1920 epidemic in Uganda was markedly different from T.b.
      gambiense cases, but similar to T.b. rhodesiense. These findings suggest that
      T.b. rhodesiense was present in Uganda and contributed to the epidemic. The
      historic context is reassessed in the light of these data.

PMID- 15200844
TI  - Pediatric influenza prevention and control.
AB  - Global evaluation of influenza vaccination in children indicates that current
      recommendations are not followed. Most children at high risk for influenza
      related complications do not receive the vaccine, and increased efforts are
      needed to protect them. Furthermore, vaccinating healthy infants 6-23 months of
      age and their close contacts should be strongly encouraged. Vaccinations are
      recommended for children with recurrent acute otitis media or recurrent
      respiratory tract infections and possibly for healthy daycare and school-age
      children because of the potential socioeconomic implications of influenza. Issues
      that need to be addressed include educating physicians and parents concerning
      influenza-related illness and complications, cost-effectiveness and safety of
      licensed vaccines, adequate vaccine supply, and availability of intranasal
      products.

PMID- 15200845
TI  - Inhibition of SARS coronavirus infection in vitro with clinically approved
      antiviral drugs.
AB  - Severe acute respiratory syndrome (SARS) is an infectious disease caused by a
      newly identified human coronavirus (SARS-CoV). Currently, no effective drug
      exists to treat SARS-CoV infection. In this study, we investigated whether a
      panel of commercially available antiviral drugs exhibit in vitro anti-SARS-CoV
      activity. A drug-screening assay that scores for virus-induced cytopathic effects
      on cultured cells was used. Tested were 19 clinically approved compounds from
      several major antiviral pharmacologic classes: nucleoside analogs, interferons,
      protease inhibitors, reverse transcriptase inhibitors, and neuraminidase
      inhibitors. Complete inhibition of cytopathic effects of SARS-CoV in culture was
      observed for interferon subtypes, b-1b, a-n1, a-n3, and human leukocyte
      interferon a. These findings support clinical testing of approved interferons for
      the treatment of SARS.

PMID- 15200846
TI  - SARS transmission, risk factors, and prevention in Hong Kong.
AB  - We analyzed information obtained from 1,192 patients with probable severe acute
      respiratory syndrome (SARS) reported in Hong Kong. Among them, 26.6% were
      hospital workers, 16.1% were members of the same household as SARS patients and
      had probable secondary infections, 14.3% were Amoy Gardens residents, 4.9% were
      inpatients, and 9.9% were contacts of SARS patients who were not family members.
      The remaining 347 case-patients (29.1%) had undefined sources of infection.
      Excluding those <16 years of age, 330 patients with cases from "undefined"
      sources were used in a 1:2 matched case-control study. Multivariate analysis of
      this case-control study showed that having visited mainland China, hospitals, or
      the Amoy Gardens were risk factors (odds ratio [OR] 1.95 to 7.63). In addition,
      frequent mask use in public venues, frequent hand washing, and disinfecting the
      living quarters were significant protective factors (OR 0.36 to 0.58). In Hong
      Kong, therefore, community-acquired infection did not make up most transmissions,
      and public health measures have contributed substantially to the control of the
      SARS epidemic.

PMID- 15200847
TI  - Myanmar dengue outbreak associated with displacement of serotypes 2, 3, and 4 by
      dengue 1.
AB  - In 2001, Myanmar (Burma) had its largest outbreak of dengue-15,361 reported cases
      of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), including 192
      deaths. That year, 95% of dengue viruses isolated from patients were serotype 1
      viruses belonging to two lineages that had diverged from an earlier, now extinct,
      lineage sometime before 1998. The ratio of DHF to DSS cases in 2001 was not
      significantly different from that in 2000, when 1,816 cases of DHF/DSS were
      reported and dengue 1 also was the most frequently isolated serotype. However,
      the 2001 ratio was significantly higher than that in 1998 (also an outbreak year)
      and in 1999, when all four serotypes were detected and serotypes 1, 2, and 3 were
      recovered in similar numbers. The large number of clinical cases in 2001 may have
      been due, in part, to a preponderance of infections with dengue 1 viruses.

PMID- 15200848
TI  - Predicting geographic variation in cutaneous leishmaniasis, Colombia.
AB  - Approximately 6,000 cases of cutaneous leishmaniasis are reported annually in
      Colombia, a greater than twofold increase since the 1980s. Such reports certainly
      underestimate true incidence, and their geographic distribution is likely biased
      by local health service effectiveness. We investigated how well freely available
      environmental data explain the distribution of cases among 1,079 municipalities.
      For each municipality, a unique predictive logistic regression model was derived
      from the association among remaining municipalities between elevation, land cover
      (preclassified maps derived from satellite images), or both, and the odds of at
      least one case being reported. Land cover had greater predictive power than
      elevation; using both datasets improved accuracy. Fitting separate models to
      different ecologic zones, reflecting transmission cycle diversity, enhanced the
      accuracy of predictions. We derived measures that can be directly related to
      disease control decisions and show how results can vary, depending on the
      threshold selected for predicting a disease-positive municipality. The results
      identify areas where disease is most likely to be underreported.

PMID- 15200849
TI  - Epidemiologic determinants for modeling pneumonic plague outbreaks.
AB  - Pneumonic plague poses a potentially increasing risk to humans in plague
      nonendemic regions either as a consequence of an aerosolized release or through
      importation of the disease. Pneumonic plague is person-to-person transmissible.
      We provide a quantitative assessment of transmissibility based on past outbreaks
      that shows that the average number of secondary cases per primary case (R0) was
      1.3 (variance = 3.1), assuming a geometric probability distribution, prior to
      outbreak control measures. We also show that the latent and infectious periods
      can be approximated by using lognormal distributions with means (SD) of 4.3 (1.8)
      and 2.5 (1.2) days. Based on this parameter estimation, we construct a Markov
      chain epidemic model to demonstrate the potential impact of delays in
      implementing outbreak control measures and increasing numbers of index cases on
      the incidence of cases in simulated outbreaks.

PMID- 15200850
TI  - Dengue spatial and temporal patterns, French Guiana, 2001.
AB  - To study a 2001 dengue fever outbreak in Iracoubo, French Guiana, we recorded the
      location of all patients' homes and the date when symptoms were first observed. A
      geographic information system (GIS) was used to integrate the patient-related
      information. The Knox test, a classic space-time analysis technique, was used to
      detect spatiotemporal clustering. Analysis of the relative-risk (RR) variations
      when space and time distances vary, highlighted the maximum space and time extent
      of a dengue transmission focus. The results show that heterogeneity in the RR
      variations in space and time corresponds to known entomologic and epidemiologic
      factors, such as the mosquito feeding cycle and host-seeking behavior. This
      finding demonstrates the relevance and potential of the use of GIS and spatial
      statistics for elaborating a dengue fever surveillance strategy.

PMID- 15200851
TI  - Babesia divergens-like infection, Washington State.
AB  - Most reported U.S. zoonotic cases of babesiosis have occurred in the Northeast
      and been caused by Babesia microti. In Washington State, three cases of
      babesiosis have been reported previously, which were caused by WA1 (for
      "Washington 1")-type parasites. We investigated a case of babesiosis in
      Washington in an 82-year-old man whose spleen had been removed and whose
      parasitemia level was 41.4%. The complete 18S ribosomal RNA gene of the parasite
      was amplified from specimens of his whole blood by polymerase chain reaction.
      Phylogenetic analysis showed the parasite is most closely related, but not
      identical, to B. divergens (similarity score, 99.5%), a bovine parasite in
      Europe. By indirect fluorescent-antibody testing, his serum reacted to B.
      divergens but not to B. microti or WA1 antigens. This case demonstrates that
      babesiosis can be caused by novel parasites detectable by manual examination of
      blood smears but not by serologic or molecular testing for B. microti or WA1-type
      parasites.

PMID- 15200852
TI  - Influenza A virus PB1-F2 gene in recent Taiwanese isolates.
AB  - Influenza A virus contains eight RNA segments and encodes 10 viral proteins.
      However, an 11th protein, called PB1-F2, was found in A/Puerto Rico/8/34 (H1N1).
      This novel protein is translated from an alternative open reading frame (ORF) in
      the PB1 gene. We analyzed the PB1 gene of 42 recent influenza A isolates in
      Taiwan, including 24 H1N1 and 18 H3N2 strains. One H1N1 isolate and 17 H3N2
      isolates contained the entire PB1-F2 ORF of 90 residues, three amino acids (aa)
      longer than the PB1-F2 of A/Puerto Rico/8/34 at the C terminal. The one remaining
      H3N2 isolate encoded a truncated PB1-F2 with 79 residues. The other 23 H1N1
      isolates contained a truncated PB1-F2 of 57 aa. Phylogenetic analysis of both the
      HA and the PB1 genes showed that they shared similar clustering of these
      Taiwanese isolates, suggesting that no obvious reassortment occurred between the
      two genomic segments.

PMID- 15200853
TI  - Coccidioidomycosis among workers at an archeological site, northeastern Utah.
AB  - In 2001, an outbreak of acute respiratory disease occurred among persons working
      at a Native American archeological site at Dinosaur National Monument in
      northeastern Utah. Epidemiologic and environmental investigations were undertaken
      to determine the cause of the outbreak. A clinical case was defined by the
      presence of at least two of the following symptoms: self-reported fever,
      shortness of breath, or cough. Ten workers met the clinical case definition; 9
      had serologic confirmation of coccidioidomycosis, and 8 were hospitalized. All 10
      were present during sifting of dirt through screens on June 19; symptoms began 9
      12 days later (median 10). Coccidioidomycosis also developed in a worker at the
      site in September 2001. A serosurvey among 40 other Dinosaur National Monument
      workers did not find serologic evidence of recent infection. This outbreak
      documents a new endemic focus of coccidioidomycosis, which extends northward its
      known geographic distribution in Utah by approximately 200 miles.

PMID- 15200854
TI  - Maternal malaria and perinatal HIV transmission, western Kenya.
AB  - To determine whether maternal placental malaria is associated with an increased
      risk for perinatal mother-to-child HIV transmission (MTCT), we studied HIV
      positive women in western Kenya. We enrolled 512 mother-infant pairs; 128 (25.0%)
      women had placental malaria, and 102 (19.9%) infants acquired HIV perinatally.
      Log10 HIV viral load and episiotomy or perineal tear were associated with
      increased perinatal HIV transmission, whereas low-density placental malaria
      (<10,000 parasites/mL) was associated with reduced risk (adjusted relative risk
      [ARR] 0.4). Among women dually infected with malaria and HIV, high-density
      placental malaria (>10,000 parasites/mL) was associated with increased risk for
      perinatal MTCT (ARR 2.0), compared to low-density malaria. The interaction
      between placental malaria and MTCT appears to be variable and complex: placental
      malaria that is controlled at low density may cause an increase in broad-based
      immune responses that protect against MTCT; uncontrolled, high-density malaria
      may simultaneously disrupt placental architecture and generate substantial
      antigen stimulus to HIV replication and increase risk for MTCT.

PMID- 15200855
TI  - Ixodid and argasid tick species and west nile virus.
AB  - Control of West Nile virus (WNV) can only be effective if the vectors and
      reservoirs of the virus are identified and controlled. Although mosquitoes are
      the primary vectors, WNV has repeatedly been isolated from ticks. Therefore, tick
      borne transmission studies were performed with an ixodid (Ixodes ricinus) and an
      argasid tick species (Ornithodoros moubata). Both species became infected after
      feeding upon viremic hosts, but I. ricinus ticks were unable to maintain the
      virus. In contrast, O. moubata ticks were infected for at least 132 days, and the
      infection was maintained through molting and a second bloodmeal. Infected O.
      moubata ticks transmitted the virus to rodent hosts, albeit at a low level.
      Moreover, the virus was nonsystemically transmitted between infected and
      uninfected O. moubata ticks co-fed upon uninfected hosts. Although ticks are
      unlikely to play a major role in WNV transmission, our findings suggest that some
      species have the potential to act as reservoirs for the virus.

PMID- 15200856
TI  - Antigenic and genetic variability of human metapneumoviruses.
AB  - Human metapneumovirus (HMPV) is a member of the subfamily Pneumovirinae within
      the family Paramyxo- viridae. Other members of this subfamily, respiratory
      syncytial virus and avian pneumovirus, can be divided into subgroups on the basis
      of genetic or antigenic differences or both. For HMPV, the existence of different
      genetic lineages has been described on the basis of variation in a limited set of
      available sequences. We address the antigenic relationship between genetic
      lineages in virus neutralization assays. In addition, we analyzed the genetic
      diversity of HMPV by phylogenetic analysis of sequences obtained for part of the
      fusion protein (n = 84) and the complete attachment protein open reading frames
      (n = 35). On the basis of sequence diversity between attachment protein genes and
      the differences in virus neutralization titers, two HMPV serotypes were defined.
      Each serotype could be divided into two genetic lineages, but these did not
      reflect major antigenic differences.

PMID- 15200857
TI  - Pneumocystis jirovecii dihydropteroate synthase genotypes in immunocompetent
      infants and immunosuppressed adults, Amiens, France.
AB  - To date, investigations of Pneumocystis jirovecii circulation in the human
      reservoir through the dihydropteroate synthase (DHPS) locus analysis have only
      been conducted by examining P. jirovecii isolates from immunosuppressed patients
      with Pneumocystis pneumonia (PCP). Our study identifies P. jirovecii genotypes at
      this locus in 33 immunocompetent infants colonized with P. jirovecii
      contemporaneously with a bronchiolitis episode and in 13 adults with PCP; both
      groups of patients were monitored in Amiens, France. The results have pointed out
      identical features of P. jirovecii DHPS genotypes in the two groups, suggesting
      that in these groups, transmission cycles of P. jirovecii infections are linked.
      If these two groups represent sentinel populations for P. jirovecii infections,
      our results suggest that all persons parasitized by P. jirovecii, whatever their
      risk factor for infection and the form of parasitism they have, act as interwoven
      circulation networks of P. jirovecii.

PMID- 15200858
TI  - PorA variable regions of Neisseria meningitidis.
AB  - Subtypes, defined by variation in the outer membrane protein PorA, are an
      integral part of the characterization scheme for Neisseria meningitidis.
      Identification of these variants remains important as the PorA protein is a major
      immunogenic component of several meningococcal vaccines under development, and
      characteristics of PorA are used to provide detailed epidemiologic information.
      Historically, serosubtypes have been defined by reactivity with a set of
      monoclonal antibodies. However, nucleotide sequence analyses of porA genes have
      established that the panel of serosubtyping monoclonal antibodies is not
      exhaustive, and many porA variants cannot be detected. In addition, the
      nomenclature system used to define subtypes is inadequate. We examined all
      available nucleotide sequences of the porA VR1 and VR2 regions to identify and
      define subtype families. A revised nomenclature scheme, compatible with the
      previous serologic nomenclature scheme, was devised. A Web-accessible database
      describing this nomenclature and its relationship to previous schemes was
      established (available from: http://neisseria.org/nm/typing/pora).

PMID- 15200859
TI  - Antimicrobial resistance gene delivery in animal feeds.
AB  - Avoparcin, a glycopeptide antimicrobial agent related to vancomycin, has been
      used extensively as a growth promoter in animal feeds for more than 2 decades,
      and evidence has shown that such use contributed to the development of vancomycin
      resistant enterococci. A cluster that includes three genes, vanH, vanA, and vanX,
      is required for high-level resistance to glycopeptides. In the vancomycin
      producer Amycolatopsis orientalis C329.2, homologs of these genes are present,
      suggesting an origin for the cluster. We found substantial bacterial DNA
      contamination in animal feed-grade avoparcin. Furthermore, nucleotide sequences
      related to the cluster vanHAX are present in this DNA, suggesting that the
      prolonged use of avoparcin in agriculture led to the uptake of glycopeptide
      resistance genes by animal commensal bacteria, which were subsequently
      transferred to humans.

PMID- 15200860
TI  - Flea-borne Bartonella grahamii and Bartonella taylorii in bank voles.
AB  - Bartonella species are increasingly associated with a range of human and animal
      diseases. Despite this, we have a poor understanding of the ecology and
      epidemiology of many species, especially those circulating in wild populations.
      Previous studies have demonstrated that a diverse range of Bartonella species are
      abundant in wild rodent populations; little is known regarding their modes of
      transmission, although both direct and indirect routes have been suggested. In
      this study, with bank voles (Clethrionomys glareolus) as the host species, we
      demonstrate that the rodent flea Ctenophthalmus nobilis is a competent vector of
      at least two Bartonella species, B. grahamii, which has previously been
      associated with human infection, and B. taylorii. In contrast, no evidence of
      either horizontal or vertical transmission was seen in bank voles inoculated with
      B. taylorii maintained in an arthropod-free environment; this finding suggests
      that fleas may be essential for transmitting some Bartonella species.

PMID- 15200861
TI  - Restaurant inspection scores and foodborne disease.
AB  - Restaurants in the United States are regularly inspected by health departments,
      but few data exist regarding the effect of restaurant inspections on food safety.
      We examined statewide inspection records from January 1993 through April 2000.
      Data were available from 167,574 restaurant inspections. From 1993 to 2000, mean
      scores rose steadily from 80.2 to 83.8. Mean inspection scores of individual
      inspectors were 69-92. None of the 12 most commonly cited violations were
      critical food safety hazards. Establishments scoring <60 had a mean improvement
      of 16 points on subsequent inspections. Mean scores of restaurants experiencing
      foodborne disease outbreaks did not differ from restaurants with no reported
      outbreaks. A variety of factors influence the uniformity of restaurant
      inspections. The restaurant inspection system should be examined to identify ways
      to ensure food safety.

PMID- 15200862
TI  - Recombination resulting in virulence shift in avian influenza outbreak, Chile.
AB  - Influenza A viruses occur worldwide in wild birds and are occasionally associated
      with outbreaks in commercial chickens and turkeys. However, avian influenza
      viruses have not been isolated from wild birds or poultry in South America. A
      recent outbreak in chickens of H7N3 low pathogenic avian influenza (LPAI)
      occurred in Chile. One month later, after a sudden increase in deaths, H7N3
      highly pathogenic avian influenza (HPAI) virus was isolated. Sequence analysis of
      all eight genes of the LPAI virus and the HPAI viruses showed minor differences
      between the viruses except at the hemagglutinin (HA) cleavage site. The LPAI
      virus had a cleavage site similar to other low pathogenic H7 viruses, but the
      HPAI isolates had a 30-nucleotide insert. The insertion likely occurred by
      recombination between the HA and nucleoprotein genes of the LPAI virus, resulting
      in a virulence shift. Sequence comparison of all eight gene segments showed the
      Chilean viruses were also distinct from all other avian influenza viruses and
      represent a distinct South American clade.

PMID- 15200863
TI  - Human metapneumovirus infection among children hospitalized with acute
      respiratory illness.
AB  - Recent studies have associated human metapneu-movirus (HMPV) infection in
      children with respiratory disease of similar severity as respiratory syncytial
      virus (RSV) infection. We studied 668 banked swab specimens (one per admission)
      collected from a population-based, prospective study of acute respiratory illness
      among inpatient children from two U.S. cities. Specimens were tested for HMPV,
      RSV, influenza, and parainfluenza viruses by reverse transcription-polymerase
      chain reaction assays. Twenty-six (3.9%) were positive for HMPV; 125 (18.7%) for
      RSV; 45 (6.7%) for parainfluenza 1, 2, or 3; and 23 (3.4%) for influenza. HMPV
      positive children were significantly older than RSV-positive children. HMPV
      positive children required medical intensive care and received supplemental
      oxygen in similar frequencies to RSV-positive children. Among children
      hospitalized with respiratory illness, the incidence of HMPV infection was less
      than RSV, but clinical disease severity mirrored that of RSV infection. Further
      investigations to better characterize HMPV infection and its clinical effect are
      needed.

PMID- 15200864
TI  - West Nile virus, Guadeloupe.
AB  - To determine whether West Nile virus (WNV) had reached the archipelago of
      Guadeloupe, a serologic study in horses and birds was conducted in 2002.
      Immunoglobulin (Ig) G, IgM, enzyme-linked immunosorbent assay, and
      seroneutralization tests identified WNV infection in horses and chickens. Six
      months later, a high rate of seroconversion was observed in horses.

PMID- 15200865
TI  - West Nile virus and high death rate in American crows.
AB  - We document effects of West Nile virus (WNV) on American Crows. More than two
      thirds of our crows died of WNV infection, peaking when the proportion of
      infected mosquitoes at roosts was greatest. WNV antibody prevalence in crows was
      low. Local ecologic effects can be dramatic as WNV inhabits new areas.

PMID- 15200866
TI  - West Nile virus encephalitis in a Barbary macaque (Macaca sylvanus).
AB  - An aged Barbary ape (Macaca sylvanus) at the Toronto Zoo became infected with
      naturally acquired West Nile virus encephalitis that caused neurologic signs,
      which, associated with other medical problems, led to euthanasia. The diagnosis
      was based on immunohistochemical assay of brain lesions, reverse transcriptase
      polymerase chain reaction, and virus isolation.

PMID- 15200867
TI  - Human case of lobomycosis.
AB  - We describe a 42-year-old woman with histologically confirmed lobomycosis, a
      cutaneous fungal infection rarely reported outside of Latin America. Our case
      represents the first published report of imported human lobomycosis in Canada and
      the fifth in an industrialized country.

PMID- 15200868
TI  - Dengue 3 epidemic, Havana, 2001.
AB  - In June 2001, dengue transmission was detected in Havana, Cuba; 12,889 cases were
      reported. Dengue 3, the etiologic agent of the epidemic, caused the dengue
      hemorrhagic fever only in adults, with 78 cases and 3 deaths. After intensive
      vector control efforts, no new cases have been detected.

PMID- 15200869
TI  - Phocine distemper in German seals, 2002.
AB  - Approximately 21,700 seals died during a morbillivirus epidemic in northwestern
      Europe in 2002. Phocine distemper virus 1 was isolated from seals in German
      waters. The sequence of the P gene showed 97% identity with the Dutch virus
      isolated in 1988. There was 100% identity with the Dutch isolate from 2002 and a
      single nucleotide mismatch with the Danish isolate.

PMID- 15200870
TI  - Human challenge pilot study with Cyclospora cayetanensis.
AB  - We describe a pilot study that attempted to infect human volunteers with
      Cyclospora cayetanensis. Seven healthy volunteers ingested an inoculum of
      Cyclospora oocysts (approximately 200-49,000 oocysts). The volunteers did not
      experience symptoms of gastroenteritis, and no oocysts were detected in any stool
      samples during the 16 weeks volunteers were monitored.

PMID- 15200871
TI  - Successful treatment of human herpesvirus 6 encephalomyelitis in immunocompetent
      patient.
AB  - We report a case of human herpesvirus 6 (HHV-6) encephalomyelitis in an
      immunocompetent patient, which was confirmed by viral amplification from
      cerebrospinal fluid. Cidofovir was used, followed by ganciclovir, because of an
      adverse effect to probenecid. The patient recovered. HHV-6 should be recognized
      as one of the causes of encephalomyelitis.

PMID- 15200872
TI  - Ruling out Bacillus anthracis.
AB  - Optimization of methods for ruling out Bacillus anthracis leads to increased
      yields, faster turnaround times, and a lighter workload. We used 72 environmental
      non-B. anthracis bacilli to validate methods for ruling out B. anthracis. Most
      effective were the use of horse blood agar, motility testing after isolates had a
      2-h incubation in trypticase soy broth, and screening isolates with a B.
      anthracis-selective agar.

PMID- 15200873
TI  - High incidence of pulmonary tuberculosis persists a decade after immigration, The
      Netherlands.
AB  - Incidence rates of pulmonary tuberculosis among immigrants from high incidence
      countries remain high for at least a decade after immigration into the
      Netherlands. Possible explanations are reactivation of old infections and
      infection transmitted after immigration. Control policies should be determined on
      the basis of the as-yet unknown main causes of the persistent high incidence.

PMID- 15200874
TI  - Murine typhus with renal involvement in Canary Islands, Spain.
AB  - Murine typhus and "murine-typhus-like" disease are reemerging infectious
      diseases. In Canary Islands (Spain), a rather distinct clinical pattern
      characterized by higher incidence of complications, especially renal damage
      (including acute failure and urinalysis abnormalities), is apparent and highly
      suggestive. It could be related to different strains of Rickettsia typhi or other
      cross-reactive species.

PMID- 15200875
TI  - Anaplasma phagocytophilum, Babesia microti, and Borrelia burgdorferi in Ixodes
      scapularis, southern coastal Maine.
AB  - Ixodes scapularis (deer ticks) from Maine were tested for multiple infections by
      polymerase chain reaction and immunofluorescence. In 1995, 29.5%, 9.5%, and 1.9%
      of deer ticks were infected with Borrelia burgdorferi, Anaplasma phagocytophilum,
      and Babesia microti, respectively. In 1996 and 1997, the number of A.
      phagocytophilum-infected ticks markedly declined. In 1995 through 1996, 4 (1.3%)
      of 301 were co-infected.

PMID- 15200876
TI  - Dengue fever outbreak in a recreation club, Dhaka, Bangladesh.
AB  - An outbreak of dengue fever occurred among employees of a recreation club in
      Bangladesh. Occupational transmission was characterized by a 12% attack rate, no
      dengue among family contacts, and Aedes vectors in club areas. Early recognition
      of the outbreak likely limited its impact.

PMID- 15200877
TI  - [Present status and unresolved problems in the field of minimally invasive
      neurosurgery].

PMID- 15200878
TI  - [The questions on the genetic analysis in the study of gene polymorphism related
      to disease].

PMID- 15200879
TI  - [Application of the neuro-endoscope to the intracranial aneurismal surgery].
AB  - OBJECTIVE: To study the role of neuro-endoscope in the intracranial aneurismal
      surgery, analyzing its benefits, and disadvantages. METHODS: Endoscopy was used
      as an adjunct in the microsurgical treatment of clipping aneurysms on 88 patients
      with 89 aneurysms, of which 82 aneurysms in 81 patients were located in the
      anterior circulation and 7 were located in the posterior circulation. Keyhole
      approach was performed on all patients, and micro-Doppler ultrasound technique
      was used before and after clipping. In 84 aneurysms, endoscope-assisted
      microneurosurgery (EAM) was used in addition to microsurgical dissection and
      clipping so as to observe the neck anatomic features and perforators and to
      verify the optimal clipping position. Endoscope-controlled microneurosurgery was
      used for 5 aneurysms to observe the anatomy around aneurysm, such as the
      posterior communicating artery and the opposite anterior communicating artery
      behind the internal carotid artery. RESULTS: Postoperative angiography performed
      on 86 patients showed satisfactory aneurysm clipping. Operative mortality was 0.
      There were 7 cases of postoperative complications, with an incidence rate of
      7.95%, and none case was directly related to endoscopy. CONCLUSION: Improving
      observation of regional anatomy because of its ability in magnification,
      illumination, and looking around dead angle, neuro-endoscopy is very useful for
      complex aneurysms.

PMID- 15200880
TI  - [Percutaneous transluminal stenting for stenosis of internal carotid artery: a
      report of 355 cases].
AB  - OBJECTIVE: To discuss the benefits and complications of percutaneous transluminal
      stenting for stenosis of internal carotid artery (ICA). METHODS: 355 patients
      with ICA stenosis were included from 1997 to 2003. All of them took periprocedual
      anticoagulation treatment, cerebral vascular angiography and cervical Doppler
      sonography. 72 patients used cerebral protection of filter devices. Among the 283
      patients without cerebral protection 202 patients (71.38%) underwent predilation,
      66 patients (23.32%) underwent postdilation; and 3 patients underwent neither.
      RESULTS: The heart rates of 25.0% of all the patients decreased. Dislocation of
      microemboli happened in 5 patients. 2 of them improved after treatment. 3 of them
      got dyskinesia of one side. 2 patients (0.56%) died of intracerebral hemorrhage
      (ICH). 256 patients (84.77%) turned for the better. 260 patients (73.34%) were
      followed up. Restenosis occurred in 11 patients (4.23%). CONCLUSION: Percutaneous
      transluminal stenting for stenosis of internal carotid artery is safe if proper
      periprocedual treatment and operative procedure are taken. However, enough
      attention should be paid to the occurrence of ICH resulting from over-flow after
      operation.

PMID- 15200881
TI  - [Surgical treatment of fibrous dysplasia of the skull with neuro-navagation].
AB  - OBJECTIVE: To evaluate the role and effect of neuro-navagation in the surgical
      treatment of fibrous dysplasia of the skull and to discuss the indication and
      advantages of transcranial optic nerve decompression are discussed. METHODS:
      Fifteen patients with fibrous dysplasia of skull, 6 males and 9 females, aged
      10.3 (5 approximately 21), were surgically treated by transcranial approach. The
      location of lesion, symptoms and signs, CT characteristics, surgical approaches,
      and outcomes were analyzed. The postoperative outcomes of visual acuity were
      grouped into 5 categories: blindness, light perception, hand motion, counting
      fingers, and recognizing acuity chart. Improvement of visual acuity of one grade
      or more or increase of 0.1 by acuity chart, and improvement of visual field were
      defined as effective. RESULTS: Fibrous dysplasia of skull in children most often
      involved the frontal, sphenoid, and ethmoid bones and resulted in stenosis of
      optic canal and superior optic fissure. The most common symptoms were decreased
      vision, proptosis and facial asymmetry. 13 patients underwent decompression of
      optic canal in lateral side, and two patients in both side. All the cases had
      pathological diagnosis of Fibrous dysplasia of the skull. After 3-to-25-month
      follow-up, improvement was found in 11 eyes (65%), and no improvement was found
      in 6 eyes (35%). Decreased vision was not seen. CONCLUSION: Transcranial optic
      nerve decompression is an effective treatment for decreased vision induced by
      Fibrous dysplasia of the skull.

PMID- 15200882
TI  - [Analysis of the results of gamma knife radiosurgery for hemangioblastomas of the
      brain and the factors related to the tumor recurrence].
AB  - OBJECTIVE: To assess the 5-year-result of leksell gamma knife (LGK) in
      controlling hemangioblastomas of the brain (HB) and to analyze the factors
      related to tumor recurrence or development of new tumors. METHODS: From November
      1993 to September 2001, 35 patients, 28 males and 7 females, aged 36 (16
      approximately 61), 18 with multiple tumors and 17 with solitary tumor, the number
      of tumors being 93 in total, were treated by LGK. Twenty-one patients with HBs
      were associated with von Hippel-Lindau disease (VHLD). The tumor size ranged 5
      approximately 55 mm with a mean size of 13 mm. The mean maximum irradiation dose
      was 35.6 Gy (20.0 approximately 50.0 Gy) at tumor center and the mean minimum
      dose was 17.2 Gy (12.0 approximately 24.0 Gy) at tumor periphery. Fisher exact
      test, independent T test and Wilcoxon rank sum W test were used to analyze the
      results of LGK on solitary and multiple HBs, the recurrent time of the HBs, and
      the relation between minimum irradiation dose and tumor control. RESULTS: 35
      patients had been followed for 24 - 114 months with a mean value of 66 months. 29
      patients were alive and 6 died. Of the 29 patients 21 achieved satisfying tumor
      control, and 8 patients underwent open surgery because of tumor-associated cysts
      enlarging or development of new tumors after LGK. 21 patients had improvement or
      remained stable in neurological status. Of the 8 reopened patients, 2 had
      deteriorated symptoms and the other 6 remained neurologically stable. Of the 35
      patients, 7 developed new tumor during the follow-up period, and 5 had second
      LGK. Tumor control: Of the 29 cases, solitary or multiple tumors in 23 patients
      decreased in volume or remained the same, although two developed new tumors. The
      result of LGK in controlling HBs showed no significant difference between the
      solitary and multiple HBs (P > 0.05), but the dose of long-term tumor control was
      significantly higher than that of uncontrolled tumors (W = 98, P < 0.01). The
      tumor control rate was 94% 1 year after; 85% 2 years after; 82% 3 years after;
      79% 4 years after; and 71% 5 years after. For the patients with solitary tumor,
      the mean time of development of new tumor was 63 months, but for the patients
      with multiple HBs, the time was 25 months. There was a significant difference
      between the two groups (t = 3.987, P < 0.001). With margin dose of 18 Gy,
      histopathology showed that no tumor cell was found and there were coagulation
      necrosis, hyaline degeneration and fibrosis tissues in the tumor nodule 48 months
      after LGK. CONCLUSION: LGK is a good choice for small- or medium-sized, solid HB
      in long term, especially when tumor margin dose is 16 - 20 Gy. Although LGK can
      treat multiple tumors in one single treatment session, for HB in patients
      associated with VHLD, LGK faces the problem of tumor recurrence or development of
      new tumor.

PMID- 15200883
TI  - [Expression of pepsinogen C in gastric cancer and its precursor].
AB  - OBJECTIVE: To investigate the dynamic expression of pepsinogen C (PGC) and its
      value in detection of precursor and gastric cancer. METHODS: Immunohistochemistry
      was used to examine the expression of PGC in 424 biopsy specimens of stomach
      mucosa collected by gastroscopy. RESULTS: The positive rate of PGC expression in
      54 cases of normal gastric mucosa was 100% and 2.4% in 124 cases of gastric
      cancer. The positive rate of PGC expression decreased in the order of superficial
      gastritis/gastric ulcer or erosion-->atrophic gastritis or gastric dysplasia-
      >gastric cancer (P < 0.01). CONCLUSION: The expression of PGC is negatively
      correlated with the degree of malignity of gastric mucosa and development of
      gastric lesions. PGC has high sensitivity and specificity in diagnosis of
      precursor of gastric cancer and can be a good indicator in the screening and
      diagnosis of precursor of gastric cancer and gastric cancer.

PMID- 15200884
TI  - [Study of regional cerebral blood flow around hematoma in acute intracerebral
      hemorrhage by xenon-CT].
AB  - OBJECTIVE: To study the change of regional cerebral blood flow (rCBF) around
      hematoma in acute intracerebral hemorrhage. METHODS: Xenon-CT was performed on 5
      patients of basal ganglia hemorrhage with the hematoma volume less than 30 ml, 3
      males and 2 females, aged 56.8 +/- 5.6. within 36 hours of the onset and 13 days
      after to measure the rCBF was measured by 27 pixel rings respectively in the core
      of hematoma, edema region around the hematoma and compared with rCBF in the
      uninvolved hemisphere. RESULTS: (1) all the 5 patients had a history of
      hypertension, the mean intracerebral hemorrhage volume was 13 ml +/- 7 ml (6.4
      approximately 23.7 ml). The first examination was conducted 23 h +/- 6 h (19
      approximately 34 h) after the onset and the second examination was conducted 13.0
      d +/- 0.7 d (12 approximately 14 d) after the onset. (2) Within 36 hours of the
      onset, the mean rCBF in the core of hematoma was 15 ml.100 g(-1).min(-1) +/- 8
      ml.100 g(-1).min(-1), and the mean rCBF in edema region around the hematoma was
      30 ml.100 g(-1).min(-1) +/- 8 ml.100 g(-1).min(-1). Thirteen days after the onset
      the mean rCBF in the core of hematoma was 9 ml.100 g(-1).min(-1) +/- 4 ml.100 g(
      1).min(-1), significantly reduced in comparison with that measured in the first
      examination (P = 0.014), and the mean rCBF in the edema region around the
      hematoma was 23 ml.100 g(-1).min(-1) +/- 13 ml.100 g(-1).min(-1), reduced in
      comparison with those measured in the first examination too, however, not
      significantly (P = 0.055). The rCBF reduction was more significant in the edema
      region adjacent to the hematoma (P = 0.004), but not in the distant edema region.
      During the first examination the rCBF in the edema region around the hematoma was
      lower than the enantiomorph rCBF by 20.9%. Thirteen days after, the rCBF in the
      edema region around the hematoma was lower than the enantiomorph rCBF by 46.3%,
      significantly greater than the reduction during the first examination (P =
      0.324). There was no difference between the values of enantiomorph rCBF during
      the first and second examinations (P = 0.038). CONCLUSION: There exists reduced
      perihematoma rCBF after intracerebral hemorrhage by xenon-CT examination, this
      phenomenon lasts 14 days and have the tendency of further reduced.

PMID- 15200885
TI  - [Graft versus host disease after liver transplantation: a report of 3 cases].
AB  - OBJECTIVE: To document the clinical experience in the diagnosis and treatment of
      graft-versus-host disease(GVHD) after liver transplantation. METHODS: Clinical
      course was followed up and laboratory examinations were done in 3 patients with
      orthotopic liver transplantation (OLT) who developed acute GVHE. The diagnosis
      depended on clinical manifestations, skin biopsy, HLA typing and PCR short tandem
      repeat (PCR-STR). Immunosuppressive drugs were transferred and adjusted. RESULTS:
      Fever, shin rash, diarrhea and pancytopenia were found within 3 to 8 weeks after
      liver transplantation. The liver function was normal. CMV antigen (pp65) and EBV
      antibody (IgM) were negative. The donor's HLA was detected in the host's
      peripheral blood cells. One female recipient had the donor's Y chromosome
      microchimerism detected by PCR-STR. All 3 patients died from infection,
      alimentary tract bleeding, or multiple organ failure in the end. CONCLUSION: GVHD
      is not a rare complication easily misdiagnosed with pessimism out come after
      liver transplantation.

PMID- 15200886
TI  - [The treatment of deformity of axillary scar contracture after burns].
AB  - OBJECTIVE: To explore the best methods to repair the deformity of axillary scar
      contracture after burns. METHODS: Ninety cases in 78 patients with axillary scar
      contracture after burns from January 1998 to January 2002 were analyzed.
      According to the severity of the deformity and its influence on the function of
      the shoulder joint. 46 cases suffered from mild degree axillary scar contracture,
      26 cases with moderate and 18 with severe degree. The deformities of axillary
      scar contracture were repaired by Z plasty (18 cases), five-flap plasty (14
      cases), skin graft (23 cases), Z plasty and skin graft (14 cases), transfer of
      scapular skin flaps (5 cases), lateral throatic skin flaps (4 cases) and scar
      flaps (12 cases), respectively. Exopexy, anti-scar drug and functional exercises
      were applied postoperationally. RESULTS: All the flaps were survived with first
      intention, except for necrosis of the split skin graft occurring in 4 cases. The
      function and configuration in all the cases were satisfactory after 6 months to 4
      years follow-up. CONCLUSION: Appropriate methods should be chosen to restore the
      function and configuration of the shoulder joint and improve patients' living
      condition according to the size, degree of the deformity of axillary scar
      contracture after burns.

PMID- 15200889
TI  - [A pilot study on transdifferentiation of skin stem cell in reconstructing
      corneal epithelium].
AB  - OBJECTIVE: To observe the differentiation and development of skin stem cells on
      corneal stroma and to discuss the possibility of reconstructing corneal
      epithelium with skin stem cells. METHODS: Pieces of human and rabbit skin were
      obtained during operation. Rabbit eye balls were taken, and pieces of corneal
      stroma without epithelium were prepared. Skin stem cells from the rabbit skin and
      human skin were cultured. The human skin stem cells of the first generation to
      4th generation were implanted on the rabbit corneal stroma and cultured. Three
      rabbits underwent autotransplantation of the rabbit skin stem cells of the first
      generation to 4th generation on the pieces of corneal stroma with the superficial
      lamina removed and then fed for 100 approximately 114 days. Another 3 rabbits
      underwent allotransplantation of the rabbit skin stem cells of first to 4th
      generation on the pieces of corneal stroma with the superficial lamina removed
      and then fed for 100 days. Then the rabbits were killed and their eye balls taken
      out. The rabbit corneas implanted with human or rabbit epithelial cells and the
      rabbit corneas with the autogeneous or heterogeneous epithelial cells were sliced
      and underwent immunohistochemistry with human AE5 antibody corresponding to the
      specific surface marker keratin K3/K12 common to humankind and rabbit, and human
      epithelial cell keratin K-19 monoclonal antibody. RESULTS: Since the 3(rd) day of
      transplantation the transplanted human epithelial cells formed multiplayer and
      were human AE5 antibody and human K19 monoclonal antibody positive. The
      autotransplanted corneas remained basically transparent without obvious vascular
      hyperplasia till the cornea specimens were taken. Histological examination showed
      intact multiplayer epithelium and immunohistochemistry showed human AE5 positive.
      The allotransplanted?rabbit corneas showed congestion since the 9(th) day.
      Histological examination showed that the corneas were nor so transparent as the
      autotransplanted ones and the epithelium was nor intact with a lot of lymphocyte
      infiltration. CONCLUSION: Corneal epithelium can be reconstructed from skin stem
      cell, which may be an alternative for constructing autogeneous bioengineered
      corneas.

PMID- 15200890
TI  - [SNC19/ST14 gene transfection and expression influence the biological behavior of
      colorectal cancer cells].
AB  - OBJECTIVE: To study the effect of SNC19/ST14 gene transfection and expression
      into colorectal cancer cells on biological behavior. METHODS: The recombination
      vector pSecTag2a-SNC19/ST14 was constructed, and transfected into the RKO
      colorectal cancer cell line by liposome. The transfected cell was screened by
      real time PCR, Western Blot and Immunohistochemical technique. The population
      doubling time (T(D)) and cell cycle of the transfected cell were analyzed by MTT
      assay and flow cytometer. Rhodamine-labeled Phallodin was used to label the cell
      cytoskeletal protein-F-actin, and the F-actin distribution was observed by
      confocal scanning microscope. The adhesion ability of the transfected cell to
      extracellular matrix (ECM) was measured by MTT assay. RESULTS: The full length
      Open Reading Frame (ORF) of SNC19/ST14 gene was inserted into the vector
      pSecTag2a, and transfected into RKO cells, and expressed successfully. The
      changes of F-actin organization took place in transfected cell. The Adherence
      ability of the transfected cell to ECM was decreased, but the proliferation
      ability was not significantly changed except highly expressing of the SNC19/ST14,
      and not the cell cycle and the apoptosis. CONCLUSION: SNC19/ST14 gene was
      successfully expressed into the RKO cell line, and could influence on the cell
      cytoskeletal protein (F-actin) organization and on cell adherence ability to ECM,
      but could not make the cell cycle, apoptosis and proliferation ability change
      significantly.

PMID- 15200892
TI  - [Quality control of clinical-grade recombinant adenovirus used in gene therapy].
AB  - OBJECTIVE: To establish the quality control methods and reference standards for
      clinical-grade recombinant adenovirus products for human gene therapy. METHODS:
      The Infectivity of clinical grade recombinant adenoviral vectors is determined by
      a TCID(50) assay. The purity is determined by a high-performance liquid
      chromatography (HPLC) assay. A549 cells were used in replication competent
      adenovirus (RCA) assay of samples by observation of the cytopathic effect. Other
      quality control assays were performed in accordance with the SFDA Regulations for
      Biological Products. RESULTS: The recombinant adenovirus encoding human p53 gene
      produced at SiBiono (Lot 20010701) has the following quality attributes: viral
      particle concentration: 1.03 (10(12) VP/ml, infectivity titer: 5.01 (10(10)
      IU/ml, specific infectivity (IU/VP): 4.86%, higher than the 3.3% required by the
      Food and Drug Administration (FDA), USA; Purity by HPLC analysis: 98.62%, higher
      than the 95% purity specified by SFDA; and level of RCA: less than 1 RCA/3
      (10(10) VP, meeting the standards established by SFDA. CONCLUSIONS: A whole set
      of quality standards of clinical-grade recombinant adenovirus vectors has been
      established so as to ensure the clinical safety and efficacy of recombinant
      adenoviral vectors for human gene therapy.

PMID- 15200893
TI  - [Suppression of articular cartilage breakdown in osteoarthritis by interleukin-1
      receptor antagonist using ex vivo gene therapy].
AB  - OBJECTIVE: To explore the role of interleukin-1 receptor antagonist (IL-1Ra) in
      suppression of cartilage matrix degradation and pathologic changes. METHODS:
      Thirty New Zealand White rabbits underwent partial synovectomy of the left knee.
      Synovial fibroblasts were isolated and cultured. The rabbits underwent anterior
      cruciate ligament transection (ACLT) in the right knee. After the ACLT the
      rabbits were forced to run 4 hours a day for 4 weeks so as to establish the
      osteoarthritis (OA) model. Three days after the ACLT the rabbits were randomly
      divided into 3 groups of 10 rabbits: group 1, to be injected with the cultured
      autologous synovial fibroblasts into the right knees; group 2, injected with the
      autologous synovial fibroblasts transfected with marker gene, and group 3,
      injected with autologous synovial fibroblasts transfected with IL-1Ra gene. Two
      and 4 weeks after the injection 5 rabbits in each group were killed respectively.
      Their right knee joints were lavaged and the lavage fluid was extracted. IL-1Ra
      level in the synovial fluid (SF) was determined by ELISA. 20 mg of articular
      cartilage were taken from the condyle of right femur and digested by papain. The
      glycosamino-glycan (GAG) level in the SF and in the cartilage digest were
      evaluated using dimethylmethylene blue assay. Two pieces of cartilage were taken
      from each rabbit's and were sliced and stained to undergo pathologic changes.
      RESULTS: The IL-1Ra level in the SF of the group 3 was (20.2 +/- 1.8) ng/ml 2
      weeks after, and was (4.8 +/- 0.5) ng/ml 4 weeks after, significantly lower than
      those in the group 2 (84 +/- 7) micro g/ml and group 3 (84 +/- 6) micro g/ml IL
      1Ra was not detected in the SF of the group 1. The GAG level in SF was 40.1 micro
      g/ml with an inhibitory rate of 56.2%, and those in the group 2 and group 3 were
      30.2 micro g/mg and 10.8 micro g/mg respectively. The GAG levels 4 weeks after in
      the cartilage digest of the group 1 and group 2 were (10.1 +/- 1.2) micro g/mg
      and (10.8 +/- 0.9) micro g/mg respectively, both significantly lower than that in
      the group 3 [(30 +/- 3) micro g/mg, both P < 0.05]. Pathological examination
      showed that the articular cartilage of the left knee was all normal in all the
      rabbits. However, obvious damage was found in the articular cartilage of the
      right knees of all the rabbits. However, the damage in the group 3 was
      significantly milder than that in the other 2 groups. CONCLUSION: Intraartilcular
      injection of synovial cells transfected with IL-1Ra gene can suppress articular
      cartilage matrix degradation and pathologic changes.

PMID- 15200894
TI  - [The expression of integrin beta3 in mice's endometrium during the implantation
      window based on different ovarian stimulation protocols].
AB  - OBJECTIVE: To compare the uterine receptivity with different ovarian stimulation
      protocols, the endometrial expression of Integrin beta3 in mice's during the
      implantation window underwent different ovarian stimulation were studied.
      METHODS: Forty mice were randomly allocated into 4 groups of 10 mice. (1) GnRHant
      group, gonadotropin-releasing hormone antagonist (GnRHant) was given first for
      desensitizing the pituitary, then the pregnant mare's serum gonadotrophin (PMSG)
      was added for ovarian stimulation. (2) gonadotropin-releasing hormone agonist
      (GnRHa) group, GnRHa was given first for desensitizing the pituitary, then PMSG
      was added for ovarian stimulation. (3) PMSG group, injected with PMSG only; and
      (4) control group, given with saline of the same volume. Human chorionic
      gonadotropin (HCG) was injected to the mice of the GnRHant, GnRHa, and PMSG
      groups. Forty-eight hours after the mice of the control group the mice were
      killed. Their uteri were taken. RT-polymerase chain reaction (RT-PCR) was used to
      detect the expression of integrin beta3 mRNA. Immunohistochemistry (SP method)
      was used to locate and semiquantitatively measure the integrin beta3 in the
      endometrium during implantation window. RESULTS: (1) Immunohistochemistry: showed
      that the staining intensity of integrin beta3 was 3.74 +/- 0.15 in GnRHa group,
      3.22 +/- 0.19 in the GnRHant group, and 3.24 +/- 0.18 in the PMSG group, all
      significantly lower than that in the control group (3.90 +/- 0.11, P = 0.023,
      0.001, and 0.001). with a significant difference between the GnRHa group and the
      PMSG group (P = 0.001) and without a significant difference between the. GnRHant
      group and PMSG groups (P = 0.768). (2) RT-PCR showed that the relative quantity
      of integrin beta3 mRNA expression was 1.14 +/- 0.16 in the GnRHa group, 0.76 +/-
      0.33 in the GnRHant group, and 0.73 +/- 0.26 in the PMSG group, all significantly
      lower than that in the control group (1.4 +/- 0.3, P = 0.045, 0.001, and 0.001).
      with a significant difference between the GnRHant and PMSG groups (P = 0.001) and
      without a significant difference between the GnRHant and PMSG groups (P = 0.857).
      CONCLUSION: All of the ovarian stimulation protocols do harm to the mice's
      uterine receptivity. Ovarian stimulation combining GnRHa protocol in mice is
      better than PMSG alone protocol, because it can improve the uterine receptivity.
      Ovarian stimulation combining GnRHant protocol in mice decrease the uterine
      receptivity as well as the PMSG alone protocol.

PMID- 15200902
TI  - [Enhancing the basic research on colorectal cancer in china].

PMID- 15200903
TI  - [A scientific and prudent policy should be adopted to the "plasticity" or
      "transdifferention" of adult stem cells].

PMID- 15200904
TI  - [Pay attention to fibromyalgia].

PMID- 15200905
TI  - [Clinical features and hMSH2/hMLH1 germline mutation screening of Chinese
      hereditary nonpolyposis colorectal cancer patients].
AB  - OBJECTIVE: To analyze the clinical features of hereditary nonpolyposis colorectal
      cancer (HNPCC) among Chinese and report the results of screening of hMSH2 and
      hMLH1 gene mutations. METHODS: The data concerning sex, site of colorectal cancer
      (CRC), age of diagnosis, history of synchronous and/or metachronous colorectal
      cancer, instance of extracolonic cancers, and histopathology of tumors of 126
      patients from 28 independent families of HNPCC in China were collected, of which
      15 met the Amsterdam criteriaI and 13 met the Japanese clinical diagnosis
      criteria. The genomic DNA was extracted from the peripheral lymphocytes.
      Polymerase chain reaction (PCR) and denaturing high-performance liquid
      chromatography (DHPLC) were used to screen the coding region of hMSH2 and hMLH1
      genes. Samples showing abnormal DHPLC profiles were sequenced by a 377 DNA
      sequencer. RESULTS: One hundred and seventy malignant neoplasms were found in the
      126 patients, in which 23 of multiple cancers were found. Ninety-eight of the 126
      patients (77.8%) had colorectal cancers, with an average age of onset of 45.9
      years and a right-sided predominance. Eight hMSH2 or hMLH1 gene sequence
      variations were found in 12 families, and a germline G204X nonsense mutation in
      the third exon of hMSH2 was found for the first time, the first mismatch repair
      gene (MMR) mutation ever found in Chinese Mongolian people. CONCLUSIONS: HNPCC is
      a typical auto-dominant hereditary disease, characterized by early onset,
      proximal predominance of colorectal cancer, multiple synchronous and metachronous
      colorectal cancers, and an excess of extra-colonic cancers. Frequent gastric
      cancer occurrence and less synchronous colorectal cancers are notable features in
      Chinese HNPCC patients. DHPLC is a powerful tool in hMSH2 and hMLH1 gene mutation
      screening. Three novel mutations have been found. hMLH1 gene mutations,
      especially those of the first nine exons, are more common than hMSH2 gene
      mutations in Chinese patients.

PMID- 15200906
TI  - [Thymidine phosphorylase expressed in monocyte-macrophages enhanced anticancer
      effect of 5'-deoxy-5-fluorouridine on colorectal carcinoma cells].
AB  - OBJECTIVE: To detect the thymidine phosphorylase (dThdPase) expression in
      colorectal carcinoma tissue, and clarify whether dThdPase expressed in macrophage
      like cell lines, and monocytes from human peripheral blood can modulate the
      anticancer effect of 5'-deoxy-5-fluorouridine (5'-DFUR) on colorectal carcinoma
      cells. METHODS: Forty specimens resected from 40 patients with colorectal
      carcinoma were immunohistochemically stained by the monoclonal antibodies 654-1
      (anti-dThdPase) and PG-M1 (anti-macrophage marker CD68). Then morphometrical
      analysis and positive cell counting were performed. In 27 of 40 specimens,
      dThdPase activity analysis was assayed by HPLC. The dThdPase level were also
      measured by ELISA in 4 colorectal cancer cell lines, LS174T, Clone A, Colo320,
      MIP101, and 2 macrophage-like cell lines, THP-1, U937. After estimated the drug
      sensitivities of each colorectal carcinoma cell both to 5'-DFUR and 5-Fu by MTT
      assay, THP-1, U937, or monocytes isolated from human blood were incubated in the
      medium containing 5-Fu or 5'-DFUR for 24 hours, respectively. Then the
      supernatant was collected and 2-fold serially diluted with the medium, in which
      the macrophage-like cells, or monocytes were also cultivated for 24 h without
      anticancer agents. Using the serially diluted medium, MTT assay were also carried
      out on 4 colorectal carcinoma cell lines. Each experiment was repeated six times
      and the means of IC50 value +/- standard errors (mean +/- S.E.M.) were
      calculated. Finally, THP-1 or U937 cells were cultured in medium containing 400
      micro mol/L of 5'-DFUR for 24 hours, then the supernatants were collected and the
      amount of generated 5-Fu was measured by HPLC. RESULTS: dThdPase activities was
      significantly increased (139.7 micro g x 5-Fu x h(-1) x ml(-1) +/- 61.5 micro g x
      5-Fu x h(-1) x ml(-1)) in colorectal carcinoma tissues compared with adjacent
      normal tissues (42.2 micro g x 5-Fu x h(-1) x ml(-1) +/- 21.4 micro g x 5-Fu x h(
      1) x ml(-1)), P < 0.001. In immunohistochemical analysis, it was confirmed that
      most cells expressed dThdPase-positive cells were the stromal cells, especially
      macrophages, which surrounding cancer nests, or along the invasive margin of
      cancer. The distribution patterns of dThdPase-positive stromal cells are similar
      to that of the CD68-positive cells. The number of dThdPase positive cells was
      correlated with the number of macrophages in the cancerous tissues, r = 0.76. The
      dThdPase protein were detected at the levels of 18.2 unit/mg in THP-1, 19.3
      unit/mg in U937, and 0.5 unit/mg in LS174T, however, not detected in other 3
      colorectal carcinoma cells. The values of IC50 of 5'-DFUR on the 4 colorectal
      carcinoma cell lines were 11.5 approximately 84.8 times higher than those of 5-Fu
      (all P < 0.01). It was showed that no inhibiting effect for 5'-DFUR on the growth
      rates of THP-1, U937, and monocyte cells. After incubated with THP-1 or U937, 5'
      DFUR expressed a significant enhanced antitumor effect (P < 0.0001), while almost
      no change is observed to 5-Fu (P > 0.05). Same conclusion was also demonstrated
      in using the monocytes instead of THP-1 or U937. 40.2 micro mol/L and 29.5 micro
      mol/L of 5-Fu were detected in the medium containing 400 micro mol/L of 5'-DFUR
      treated with THP-1 and U937 cells, respectively. CONCLUSION: 5'-DFUR cannot be
      converted into 5-Fu in colorectal carcinoma cells in vitro because no dThdPase is
      expressed in those cells. After being incubated with macrophage-like cell, THP-1,
      U937, or human monocytes, the anticancer effect of 5'-DFUR is significantly
      increased due to the activation by dThdPase expressed in above cells.

PMID- 15200907
TI  - [Dendritomas plays an important role in the activation of anti-tumor immune
      responses].
AB  - OBJECTIVE: To investigate the role of dendritomas from fusion of human dendritic
      cells (DCs) and colon cancer cells in the activation of anti-tumor MHC restricted
      reaction. METHODS: Human dendritic cells and T cells were isolated from
      peripheral blood. Dendritomas were generated by fusing the human peripheral blood
      dendritic cells with human colon cancer cells of the SW480 line using 50%
      polyethylene glycol (PEG). T cells were cultured. Dendritomas and DCs were added
      into the culture respectively. The activation ratio of T lymphocytes was observed
      by MTT method. ELISA was used to detect the content of interferon-gamma (IFN
      gamma) in the supernatant. RESULTS: The activation ratios of CD4(+)Th1 and
      CD8(+)Tc1 cells were 57.45% and 77.86 % respectively 24 hours after the T cell
      were mixed with dendritomas, both significantly higher than those of the
      controls. The proliferation of T cells mixed with dendritomas was significantly
      higher than that of the controls (P < 0.01); The IFN-gamma secretion in the
      supernatant of the T cell culture 24 hours after mixing with the dendritomas was
      significantly higher than that of the control (P < 0.01). CONCLUSION: The
      strategy of dendritomas effectively activates the anti-tumor MHC-I and MHC-II
      reactions and promoted the proliferation of T cells.

PMID- 15200909
TI  - [Clinical and molecular cytogenetic features of myeloid diseases characterized by
      i(20q-): a study of seven cases].
AB  - OBJECTIVE: To investigate the clinical and molecular cytogenetic features of
      myeloid diseases characterized by i(20q-). METHODS: The clinical data of 7
      patients with myeloid diseases, 6 with myelodysplastic syndrome (MDS) and one
      with acute myelocytic leukemia (AML), 4 males and 3 females, aged 51 - 74, were
      analyzed. Chromosome specimens were prepared by direct method and/or short-time
      culture of bone marrow cells. Karyotyping was performed by R banding technique.
      Two kinds of probes (20q subtelomere probe and 20q12 unique sequence probe) were
      used in dual-color fluorescence in situ hybridization (D-FISH) assay. RESULTS: Of
      the seven patients, 4 died and 3 survived by the end of this study. The patients
      survived for 6 months (case 1), 7 months (case 2), 17 days (case 4), and 28 days
      (case 5) respectively. Karyotype analysis showed that one of the normal
      chromosomes 20 was lost and substituted by one or two small metacentric
      isochromosomes smaller than the normal chromosome 20 in all these seven cases. It
      was proved to be ider(20)(q10) del(20)(q11q13), i(20q-) in six cases by D-FISH
      assay. CONCLUSION: i(20q-) is a novel and rare recurrent chromosome abnormality
      which may be specifically associated with myeloid diseases and poor prognosis.

PMID- 15200910
TI  - [A new PCR method for direct determination of RHD zygosity].
AB  - OBJECTIVE: To establish a direct method for the determination of RHD zygosity.
      METHODS: Two pairs of primers were designed specific for hybrid Rhesus box and
      exon 1 of RHD, respectively. Combined with a pair of internal control primers, a
      new dual-tube PCR method was established. One hundred and fifty-two DNA samples,
      of which the sequence of RHD and RH genotypes were known, and samples from 359
      donors or patients, of which the Rh phenotypes were determined, were evaluated by
      taking a recent restriction fragment length polymorphism (RFLP) method as
      reference. RESULTS: The RHD zygosities of 152 samples, including 92 Rh-negative,
      28 D(el), 3 partial D, 5 weak D and 24 Rh-positive, were determined in
      concordance with the known genotypes. It showed that the PCR method could detect
      RHD(+)/RHD(+), RHD(+)/RHD(-) and RHD(-)/RHD(-) zygosities in one test. The PCR
      results of 359 known phenotype samples including 12 husbands, 18 family members,
      48 Rh-negative and 281 Rh-positive, were identical with RFLP except for one Rh
      positive sample, which was tested as RHD(+)/RHD(-) heterozygote by PCR, whereas
      RHD(-)/RHD(-) homozygote by RFLP. Apparently, RFLP revealed a false negative
      result detecting downstream Rhesus box. CONCLUSIONS: The dual-tube PCR is a less
      labored and more rapid method for the determination of RHD zygosity comparing
      RFLP. It can be used routinely in the laboratories in clinics and blood banks.

PMID- 15200911
TI  - [Diagnosis and treatment of multilocular cystic renal cell carcinoma: a study of
      22 cases].
AB  - OBJECTIVE: To summarize the diagnosis and treatment of multilocular cystic renal
      cell carcinoma (MCRCC), a special subtype of renal cell carcinoma. METHODS: The
      clinical data of 22 cases of MCRCC diagnosed and treated from January 1998 to
      December 2002 in the First Hospital of Peking University were analyzed
      retrospectively. RESULTS: 482 patients with renal cell carcinomas were
      hospitalized during that period with a male-to-female ratio of 2.09:1. Out of the
      482 cases 22 cases (4.56%) were classified as MCRCC with a male-to-female ratio
      of 2.67:1, not significantly different from that of the general group of renal
      cell carcinoma patients (P > 0.05). The mean age of the patients of MCRCC was
      46.6 years, significantly lower than that of the patients with other types of
      renal cell carcinomas (57.83 years, P< 0.01). Eighteen cases were diagnosed
      correctly as renal carcinomas before operation. Six patients (27%) were at the
      stage pT(1)N(0)M(0), 15 (68%) at the stage pT(2)N(0)M(0), and 1 (5%) at the stage
      pT(3)bN(0)M(0). The classification according to the tumor nuclear grading system
      showed 5 carcinomas (23%) of tumor nuclear grade 1, 17(77%) are of tumor nuclear
      grade 2. Eighteen patients underwent radical renal nephrectomy and 4 underwent
      partial nephrectomy. CONCLUSION: The preoperative diagnosis of MCRCC, difficult
      to be differentiated from other cystic renal diseases, mainly depends on imaging
      studies. Intraoperative frozen-section or nephron sparing surgery will benefit
      the patients if the preoperative diagnosis is unclear, especially for the
      patients of category 3 or 4 of Bosniak's system.

PMID- 15200917
TI  - [Immunization with targeted fusion anticaries DNA vaccine via intramuscular
      route:experiment with murine].
AB  - OBJECTIVES: To observe the expression of a targeted fusion anticaries DNA vaccine
      pGJA-P in muscular in vivo. To compare the levels of specific antibodies and
      anticaries efficacy generated by pGJA-P and fusion anticaries DNA vaccine pGLUA-P
      in gnotobiotic rats, and observe the kinetics of antibody responses in BALB/c
      mice. METHODS: (1) Twelve 28-day-old female Wistar rats were randomly divided
      into 2 groups of 6 rats to be injected with the plasmid pGJA-P containing the
      signal peptide and extracellular regions of human CTLA(4), hinge and Fc regions
      of human IgG, the glu sequence of gtfB gene and A-P fragment of pac gene of
      Streptococcus mutans or the eukaryotic expression plasmid pCI into the quadriceps
      muscle of thigh respectively. Three days after the rats were killed and specimens
      of quadriceps muscles of thigh were taken. Immunohistochemical SP staining was
      used to examine the in situ expression of pGJA-P. (2) Twenty-four 18-day-old
      female Wistar rats were randomly divided into 4 groups of 6 rats. The rats were
      fed with cariogenic food. During the age of 20 - 22 days cariogentic food
      containing broad-spectrum antibiotics was fed. Then aseptic cotton stick was used
      to swab the oral cavity and be smeared onto the solid medium so as to observe the
      growth of bacteria under anaerobic culture for 48 hours. During the age of 24 -
      26 days, S. mutans Ingbritt cultured anaerobically was swab onto the surface of
      teeth of the rats twice with an interval of 30 minutes. After the inoculation
      aseptic cotton stick was used to wipe the oral cavity and be smeared onto the
      solid medium so as to observe the growth of bacteria under anaerobic culture for
      48 hours. When the gnotobiotic rats were 28 days old they were injected with pGJA
      P, pGLUA-P, fusion anticaries DNA vaccine against both PAc, cell surface protein
      antigen, and glucosyltransferase (GTF), pCI or normal saline into the quadriceps
      muscle of thigh respectively, 2 weeks later a booster shot was given. When the
      rats were 63 days old their saliva and blood samples were collected. The serum
      IgG and salivary IgA were assayed by using ELISA. The gnotobiotic rats were
      killed and their maxillary bone the mandibles were isolated. The anticaries
      effect was evaluated by Keyes caries scores. (3) Twenty-four 4-week-old BALB/c
      mice were randomly divided into 4 groups of 6 mice: to be injected with pGJA-P,
      pGLUA-P, pCI, or normal saline respectively into the quadriceps muscles of thigh,
      2 weeks later a booster shot was given. Before the injection and every 2 weeks
      after the immunization specimens of saliva and blood were collected. The serum
      IgG and salivary IgA were assayed by using ELISA. RESULTS: (1) Recombinant
      protein could be detected in the quadriceps muscles of the rats immunized with
      pGJA-P, but not in the muscles of the rats immunized with pCI. (2) The levels of
      serum anti-PAc IgG (1:200 000) and anti-GTF IgG (1:58 000) of the rats immunized
      with pGJA-P were significantly higher than those of the rats immunized with pGLUA
      P (1:23 000 and 1:11 000 respectively) (both P < 0.01). The levels of salivary
      anti-PAc IgA (1:8) and anti-GTF IgA (1:6) of the rats immunized with pGJA-P were
      significantly higher than those of the rats immunized with pGLUA-P (1:2 and 1:2
      respectively) (both P < 0.01). The Keyes scores of the pGJA-P group were
      significantly lower than those of the pGLUA-P group and the control groups (all P
      < 0.01). The effective serum IgG and salivary IgA in the pGJA-P group and
      effective serum IgG in the pGLUA-P group all persisted to the end of the
      experiment. (3) Two weeks after the initial immunization the serum anti-PAc IgG
      level of the mice immunized with pGJA-P increased remarkably, 4 times that of the
      mice immunized with pGLUA-P, and 33 times those of the mice injected with pCI or
      normal saline. Two weeks after the booster immunization, the serum anti-PAc IgG
      level of the mice immunized with pGJA-P was 14 times that of the mice immunized
      with pGLUA-P, and 117 times those of the mice injected with pCI or normal saline.
      The serum anti-PAc IgG immunized with pGJA-P reached its peak 10 weeks after the
      initial immunization, 4 times that of the mice immunized with pGLUA-P, and 160
      times those of the mice injected with pCI or normal saline. The serum anti-PAc
      IgG of the mice immunized with pGLUA-P reached its peak at 16 weeks, however,
      significantly lower than the peak of the mice immunized with pGJA-P (P < 0.01).
      The serum anti-Pac IgG levels of the mice injected with pCI or with normal saline
      were not significantly different (P > 0.05). Since the second week after the
      initial immunization, significant difference in the serum anti-PAc IgG level
      could be seen between the mice immunized with pGJA-P or the mice immunized with
      pGLUA-P, and between the mice immunized with pGJA-P and the mice immunized with
      pGLUA-P and those injected with pCI or normal saline (all P < 0.01). Six weeks
      after the initial immunization the salivary anti-PAc IgA level of the mice
      immunized with pGJA-P was 18 times those of the mice injected with pCI or with
      normal saline (both P < 0.01), 10 weeks after the salivary anti-PAc IgA level of
      the mice immunized with pGJA-P reached its peak, 24 times those of the mice
      immunized with pCI or normal saline without a significant difference between the
      latter 2 groups (P > 0.05). No effective salivary IgA response was seen in the
      mice immunized with pGLUA-P. CONCLUSION: pGJA-P can be expressed in vivo.
      Immunization with pGJA-P intramuscularly induces effective mucosal and systematic
      humoral responses. It is an effective DNA vaccine against dental caries.

PMID- 15200918
TI  - [Mechanisms of inhibition of growth of human pancreatic carcinoma implanted in
      nude mice by somatostatin receptor subtype 2].
AB  - OBJECTIVE: To investigate the antitumor effect of somatostatin receptor subtype 2
      (SSTR2) gene transfection into pancreatic cancer cell line PC-3, and the
      mechanisms involved in this effect. METHODS: The full-length human SSTR2 cDNA was
      introduced into the pancreatic cancer cell line PC-3 by lipofect amine-mediated
      transfection. Positive clones were screened by G418 and stable expression of
      SSTR2 was detected by immunocytochemistry SABC method and RT-PCR. Fifteen athymic
      mice were randomly divided into 3 groups of 5 mice to be xenografted with SSTR2
      expressing cells (experimental group), empty vector control group, and control
      group cells respectively. The weight of mice and the size of tumor were measured
      every week. Eight weeks later the mice were killed and the tumors were taken out.
      TUNEL assay was used to determine the apoptotic index (AI) in these tumors.
      Immunohistochemistry SP method was used to determine the expressions of apoptosis
      regulating genes, Bcl-2 and Bax, and intratumoral. microvessel density (MVD).
      Moreover, the tumor volume and weight were compared among these three groups.
      RESULTS: The AI was significantly higher in the experimental group (3.39% +/-
      0.84%) compared with the empty vector control group (0.69% +/- 0.08%) and control
      group (0.68% +/- 0.09%) (both P < 0.05). The significant decrease in Bcl-2, and
      increase in Bax protein expressions were detected in the experimental group
      compared with the empty vector control group and control group (both P < 0.05).
      MVD was significantly lower in the experimental group (6.3 +/- 1.7) than those in
      the empty vector control group (12.6 +/- 1.7) and control group (13.5 +/- 1.9) (P
      < 0.05). Moreover, the tumor volume and weight were significantly lower in the
      experimental group as compared with the empty vector control group and control
      group (P < 0.05). However, no significant differences in all the indicators were
      observed between the empty vector control group and the control group (both P >
      0.05). CONCLUSIONS: Re-expression of SSTR2 gene, the expression of which is
      frequently lost in human pancreatic adenocarcinoma, can induce apoptosis which
      may be mediated via down-regulation of Bcl-2 and up-regulation of Bax, and
      inhibit tumor angiogenesis in pancreatic carcinoma, resulting in inhibition of
      tumor growth.

PMID- 15200919
TI  - [Experimental study of tissue-engineered heart tissue using type I collagen as
      scaffold].
AB  - OBJECTIVE: To construct tissue-engineered heart tissue (EHT) using liquid
      collagen as scaffold. METHODS: Neonatal rat cardiac myocytes were isolated,
      cultured, and mixed with liquid collagen type I and matrix factors and then cast
      in circular molds to construct circular cardiac myocytes/collagen strand. After a
      7-day culture in circular molds, the strands were removed, and subjected to 10%
      static stretch for another 7 days. Microscopy and transmission electron
      microscopy, routine HE staining and immunohistochemical staining were used to
      analyze the engineered heart tissue. RESULTS: Beating areas could be seen on the
      surface of the EHTs at the second day after stretching; more beating areas could
      be seen thereafter. These areas beat stronger and stronger, and finally came to
      synchronzation. Histological and immunohistochemical analyses showed that the
      cardiac myocytes in the EHTs distributed evenly in the whole strand and the
      majority of the cells, with elongated nuclei, stretched along the stretching
      direction. The morphology of EHTs resembled that of the native adult cardiac
      tissue. Transmission electron microscopy revealed that the cardiac myocytes in
      EHTs contained arranged myofibrils oriented parallel to the longitudinal cell
      axis. Clearly defined sarcomeres and Z lines were observed. CONCLUSION: Liquid
      type I collagen is a good scaffold for generation of EHTs similar to the native
      heart tissue.

PMID- 15200928
TI  - [Study on the trend and disease burden of injury deaths in Chinese population,
      1991 - 2000].
AB  - OBJECTIVE: The mortality and trend of injury in 1991 - 2000, the distribution of
      causes of injuries by areas as well as disease burden in Chinese population were
      discussed. METHODS: Data on mortality level and causes of injuries provided by
      National Disease Surveillance Program in 1991 - 2000, adjusted by under-reporting
      rate together with years of potential life lost (YPLL) and WPYLL of injuries and
      proportion of YPLL and WPYLL of total death, were calculated. RESULTS: The
      mortality of injury was kept at a stable level from 1991 to 2000. The adjusted
      average death rates were 66.56/100,000 with 81.41/100,000 in males, 51.17/100,000
      in females, and 38.68/100,000, 74.63/100,000 in urban and rural populations
      respectively. Death rates of injury in the east, central and west rural areas
      were 1:1.14:1.21 respectively. Injury was the main cause of death among children
      and youths. Traffic accident, suicide, drowning, poisoning and fall were main
      causes of injury accounting for 70 percent of all the injury mortality. Since
      1990's, the death rate of traffic accident had been obviously increasing, YPLL
      and WPYLL in injury 2132 years/10,000 and 1587 years/10,000, respectively. The
      YPLL and WPYLL were 24.56% and 26.51% of total deaths. CONCLUSION: The disease
      burden of injury was heavy and the death of injury caused more social and
      economic losses owing to premature death. The increasing death rate of traffic
      accident called for more attention. Different effective control strategies should
      be formulated based on different death causes of injury and different target
      populations.

PMID- 15200929
TI  - [Epidemiological study on traffic accident in Shanghai from 2000 to 2002].
AB  - OBJECTIVE: Data on traffic accident from year 2000 to 2002 were collected and
      testified. Epidemiological study was carried out to find the main risk factors of
      traffic accident. METHODS: The spatial distribution was conducted by means of
      Geographic Information System (GIS) and were marked on Shanghai digitalized map
      with different layers by different colors. RESULTS: Results showed that during
      2000, 2001 and 2002, 69,669 , 68,894, and 47,088 traffic accident episodes
      occurred in Shanghai, resulting in 1747, 1724, 1557 deaths respectively with
      direct economic lost: 2.1, 2.4, 3.0 billion RMB. The main risk factors causing
      traffic accident deaths would include drinking alcohol before driving, fatigue
      and speeding. The leading causes of death were head injury and complex injury of
      body. GIS showed that there was a homocentric circle with more traffic accidents
      in downtown city, but more deaths in the urban city. Disease burden caused by
      traffic accident was very heavy. CONCLUSION: In Shanghai, traffic accident has
      great impact on social and economic issues thus should be controlled effectively.
      Focus should be layed on control of traffic accident in downtown area and to
      decrease the number of deaths related to traffic accident in the urban area.

PMID- 15200930
TI  - [Survey on injury in four rural communities in China].
AB  - OBJECTIVE: To understand the incidence and prevalence by causes of injury, and
      the proportion of different causes of deaths, as well as occurrence of disability
      due to injuries. METHODS: 200,000 families were randomly sampled in 4 rural
      communities. Questionnaire on occurrence, disability, death of injury and related
      risk factors for all family members living at home from Feb. 12, 2002 to Aug. 12,
      2002 were studied. RESULTS: The incidence rate and prevalence rate in the
      observed population were 65.1/1000 and 69.2/1000, respectively. In every 100
      cases of injury there were one death and 6 disabled. Fall, animal bites, striking
      or crushing, cutting and piercing, road accidents, fire and poisoning were the
      common causes in injury. Animal bites was the leading cause while drawing
      appeared the highest in children aged 0 - 14. Rate of road accident was the
      highest in adults aged 15 - 34, while falls causing higher proportion of
      disability in population aged over 60. CONCLUSIONS: Based on the report of
      National Disease Surveillance Points System, there were 592,000 death cases of
      injury in Chinese rural areas every year, meaning 59.2 million cases of injury
      and 3,490,000 disabled cases every year. Since injury causes serious social and
      economic loss with different orders of incidence and mortality, it is necessary
      to develop different preventive strategies on different target populations and
      different causes accordingly.

PMID- 15200931
TI  - [Study on injuries from emergency departments in 25 general hospitals].
AB  - OBJECTIVE: This study aimed to study the characteristics of injuries in the
      Emergency Departments. METHODS: Acute injuries of the Emergency Department
      attendants from Jury 1, 2001 to June 30, 2002 were selected. RESULTS: 25,019
      cases were sampled. Results showed that injured persons accounted for 17.46% of
      all emergent cases attending the above hospitals. 81.67% of the injuries were
      accidental. Sex ratio was 2.0. Young people aged 15-34 years accounted for 50.63%
      of all the injuries. The leading cause was mechanical injury, followed by traffic
      accidents and accidental falls. The leading occupation would include workers,
      followed by farmers and students. The fatality rate was 5.12 per thousand. The
      number of deaths for young people accounted for 79.69% of all deaths. The number
      of deaths for motor vehicle accidents took the first place and accounted for
      46.88%. The characteristics due to mechanical injury and 11,151 cases of acute
      poisoning were analyzed. CONCLUSION: To develop a surveillance post on injuries
      in the Emergency Departments of general hospitals are not only necessary, urgent
      but feasible.

PMID- 15200932
TI  - [The comparison on cause and treatment of injuries between two types of Emergency
      Department among 25 hospitals].
AB  - OBJECTIVE: To analyze the characteristics of injuries between two types of
      Emergency Department (ED) in China. METHODS: We selected 25 hospital EDs in the
      whole country as spots for investigation, and designed one special questionnaire
      to collect information, from 1st July, 2001 to 30th June, 2002. RESULTS: In city
      hospitals (CIH), the proportion of injury to all diseases were 19.65%, and in
      country hospital (COH) it was 29.88%. The fatality rate of injuries was 1.29% in
      COH, which was higher than that of CIH's (P < 0.001). In COH, ambulance was more
      frequently used to treat injury patients than in CIH, but the average rescue time
      was not different. In cities, machinery was the leading cause (about 32.88%), but
      in country it was due to transpert (35.34%). Traffic accidents, suicide/homicide
      and unintentional drowning were the main causes of death. In CIH, the number of
      unintentional poisoning was almost twice as intentional, but in COH the patients
      due to poisoning suicide act were more than unintentional poisoning, with 2/3 of
      the poisoning causes were women. Patients due to chemical, drug and food
      poisoning accounted for 86.13% in CIH, while in COH the main causes were
      pesticidal, chemical and druggery (89.80%). In all poisons, pesticide was the
      leading cause for death. CONCLUSION: It's suggested that patients with injury be
      treated timely since the acute injury patients accounted for important part of
      ED's patients. The differences between CIH and COH were obvious, with better
      ability of treatment in CIH than in COH. More relevant measures were needed to
      improve the ability of acute treatment for injuries.

PMID- 15200933
TI  - [Study on familial factors regarding injury-related behaviors in children].
AB  - OBJECTIVE: To probe into the effects of familial factors on injury-related
      behaviors in children. METHODS: Injury-related behaviors and familial factors of
      6884 children were investigated with Family Questionnaire and Child Behavior
      Checklist. Multi-nominal logistic regression analysis was performed. RESULTS:
      There were 1670 (24.26%) children having serious injury-related behaviors and
      3683 (53.50%) children having moderate injury-related behaviors. Factors
      contributing to children's injury-related behaviors would include punishment or
      indifference as well as the mode of parents' education; reintegral type of
      family; the level of parents' cognition on injuries; unfit location of medicine
      at home and careless attitudes of parents. CONCLUSION: There was close
      relationship between children's injury-related behaviors and familial factors. To
      avoid injury-related behaviors and to prevent injury occurrence, the importance
      of familial factors must be stressed.

PMID- 15200934
TI  - [A cross-sectional study of peripheral arterial occlusive disease in Wanshoulu
      area, Beijing].
AB  - OBJECTIVE: In oder to study the prevalence of peripheral arterial occlusive
      disease (PAOD) and its risk factors in Chinese population, we conducted a cross
      sectional epidemiology study on elderly residents living in the District of
      Wanshoulu, Beijing in 2001. METHODS: A total of 2124 elderly (aged 60 - 95) were
      randomly selected in the area. The diagnostic criteria ankle arm index (AAI <
      0.9) for PAOD was used in this study. The factors contributing to PAOD in this
      study were performed by logistic regression analysis under the diagnostic
      criteria of PAOD. RESULTS: The overall prevalence of PAOD was 15.91% with 11.77%
      in males and 19.22% in females. After standardization, the overall figures became
      16.42% with 12.66% in males and 18.07% in females. Through logistic regression
      analysis, the factors, such as age (P = 0.001; RR = 1.06), gender (P = 0.001; RR
      = 1.93), history of hypertension (P = 0.001; RR = 1.48) and diabetes course (P =
      0.001; RR = 1.04) appeared to be independent factors in this study. CONCLUSIONS:
      The prevalence of PAOD in this study was similar to the prevalence of the PAOD
      studies in the developed countries. The prevalence increased with advanced age
      and was higher in females than in males. The risk factors of PAOD such as
      hypertension, diabetes should be actively prevented and controlled.

PMID- 15200935
TI  - [Analysis on the prevalence of anemia among children under 3-year-old in 5
      provinces in Western China].
AB  - OBJECTIVE: To understand the prevalence of anemia in children living in poor
      rural villages in western China and to find out related factors affecting
      hemoglobin level of children so as to search for proper intervention. METHODS:
      3747 children under 3 years old and their families were studied using stratified
      random sampling in 40 counties in western China. Databases were set up, and data
      logically checked by Epi 6.0 software. All the data were input with duplication
      method and analyzed by SPSS 10.0 software. RESULTS: The prevalence of anemia of
      children under 3-year-old was 32.7% in 40 counties with significant difference
      among provinces with the highest in Guizhou province (43.5%). The lowest was in
      Ningxia and Qinghai provinces, which was 20%. The prevalence of anemia of
      children was relatively high in 6 and 18 months of age after birth, but declining
      when children grew older. Many factors were associated with children's anemia,
      viz. feeding pattern, age, diarrhea, family income, nationality, mother with
      anemia and drinking clean water etc. CONCLUSION: Interventions as popularizing
      knowledge of appropriate feeding, drinking clean water and decreasing the
      prevalence of common diseases including diarrhea would decrease the prevalence of
      anemia of local children.

PMID- 15200936
TI  - [Study on the authenticity of parents' memory on their children's immunization
      status].
AB  - OBJECTIVE: To evaluate the authenticity of the parents' memory on their
      children's immunization status. METHODS: Two counties and 1 district in each of
      the 18 prefectures were selected, and parents of the children 1 - 2 years old,
      residents in counties or floating in district, were studied on the authenticity
      of their memory regarding their children's immunization status. RESULTS: The
      rates of inoculation with all the four expanded programme on immunization (EPI)
      vaccines were 89.7% in the whole province, and 77.9% among floating children. The
      authenticity of the reply from parents on their children, inoculation status with
      vaccines was above 96%. However, less than 50% of the parents could remember what
      specific vaccines that their children had received. The authenticity of parents'
      memory was higher in the parents with high school or college education than those
      who were illiterates or only having had elementary school education. Mothers had
      better memory than the fathers. Of the children whose parents could not remember
      the vaccination status, 97% of them had been inoculated. CONCLUSION: The definite
      answer of parents to children's immunization status had high creditability,
      especially when the mothers having had more schooling. Those children whose
      parents failed to remember whether vaccination had been received should not be
      ranked as unimmuned.

PMID- 15200937
TI  - [Intervention study on healthy lifestyle of children].
AB  - OBJECTIVE: To set up valid, feasible and reliable intervention to help children
      with a healthy life-style. METHODS: Children of grades 3, 4 and 5 in Taoyuan
      elementary school in Taiyuan city, Shanxi province were studied by self
      administered knowledge, attitudes and behaviors questionnaire on health, in May
      1999. Results indicated that there were some problems in knowledge, attitudes and
      behaviors on health among children. Children were assigned to intervention group
      and control group. The balance between the two groups was tested statistically.
      Children of the intervention group received intervention for half a year. After
      intervention, knowledge, attitude and behavior of children on health in both
      groups were assessed again. RESULTS: After intervention the mean scores of health
      knowledge, attitudes and behaviors of intervention group were significantly
      higher than that in control group (P < 0.01). After intervention, the total mean
      score of knowledge, attitudes and behaviors on health has been improved from
      125.70 +/- 16.95 on pre-test to 156.84 +/- 21.72 on post-test in intervention
      group. The mean score of knowledge on health was increased form 47.54 +/- 10.07
      to 68.19 +/- 12.92 while the mean score of attitudes increased from 17.87 +/-
      3.66 to 20.92 +/- 4.31 and the mean score of healthy behavior increased from
      60.30 +/- 9.08 to 67.74 +/- 10.44 respectively. CONCLUSION: Methods used in the
      intervention study seemed to be appropriate and the contents suitable.

PMID- 15200938
TI  - [Factors influencing intelligence in elderly population in a community-based
      study in Taiyuan city].
AB  - OBJECTIVE: To explore the factors which influencing the intelligence in elderly
      in a community, so as to provide reference on primary prevention of dementia.
      METHODS: A door to door survey was conducted. A total number of 830 elderly were
      assessed using WAIS-RC, H-NTLA and data collected through questionnaires on
      lifestyles, family and social activity were analysed, using the factor analysis,
      stepwise regression and canonical correlation analysis. RESULTS: The main
      variables related to the verbal were eggs diet, blood pressure, fruit, visit
      their children, alcohol intake (standard coefficients of regression are -0.118, 
      0.079, -0.060, -0.036, -0.117, respectively). The main variables related to
      cognition were recreation, sports and hereditary history of mental disorders
      (standard coefficients of regression were 0.035, -0.127, respectively). The main
      variables related to memory were contact to chemical materials, age of their
      parents during delivery, alcohol intake and the relationship between husband and
      wife (standard coefficients of regression were -0.063, 0.055, -0.030, -0.037,
      respectively). The variables related to canonical variable V(1) would include
      education and occupation (canonical correlation = 0.5993, P = 0.0001) while V(2)
      would include cerebrovascular accident (canonical correlation = 0.3925, P =
      0.0005). CONCLUSION: Intelligent work, family harmony, prevention of
      cerebrovascular diseases were the main areas to prevent intellectual disability
      in the elderly.

PMID- 15200939
TI  - [Preliminary analysis on the proteomic feature of Guillain-Barre syndrome
      associated Campylobacter jejuni].
AB  - OBJECTIVE: To search the marker proteins of Guillain-Barre syndrome (GBS)
      associated Campylobacter jejuni (C. jejuni) by comparing the protein maps of GBS
      associated C. jejuni strains with that of non-GBS-associated C. jejuni strains.
      METHODS: The whole-cell proteins of eight GBS-associated and eight non-GBS
      associated C. jejuni strains were separated using the two-dimensional gel
      electrophoresis respectively. The differentially expressed proteins between the
      two sets of strains were identified by matrix-assisted laser
      desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) after in
      gel tryptic digestion. RESULTS: Twenty differentially expressed spots were found
      with seventeen identified ones using MSCOT database. These proteins were
      identified as wlaX protein and some other proteins involving in energy metabolism
      (malate dehydrogenase, triosephosphate isomerase, Ni/Fe-hydrogenase small chain,
      cysteine synthase, branched-chain amino acid aminotransferase), cell process
      (heat shock protein, iron-uptake ABC transport system periplasmic iron-binding
      protein, alkyl hydroperoxide reductase), cell envelope (flagellin, UDP-N
      acetylenolpyruvoylglucosamine reductase) etc. CONCLUSION: WlaX proteins were
      probably associated with LPS biosynthesis or virulence of C. jejuni. WlaX protein
      and flagellin protein were the possible marker-proteins of GBS-associated C.
      jejuni strains.

PMID- 15200940
TI  - [Study on the molecular mechanism of quinolone resistance in Shigellae spp].
AB  - OBJECTIVE: To study the resistance and its mechanism of Shigellae spp. to
      quinolones. METHODS: Seventy-three clinical isolates were collected.
      Susceptibility tests of pipemidic adcid (PI), ofloxacin (OFL), norfloxacin (NOR),
      and ciprofloxacin (CIP) were performed in all clinical isolates and Shigella
      51573. The N-terminal coding region of gyrA and parC were amplified by polymerase
      chain reaction (PCR) respectively. Restriction fragment length polymorphism
      (RFLP) was applied to all PCR procucts of gyrA and parC, and single strand
      conformational polymorphism analysis (SSCP) was also applied to PCR procucts of
      parC. RESULTS: The resistance rates for all the Shigella spp. to PI, CIP, NOR and
      OFL were 79.5%, 60.3%, 41.1% and 36.9%. Sixty-seven strains (91.8%) were
      quinolone-reduced-sensitive isolates, in which 61 strains (91%) were found
      carrying mutations in gyrA with 5 strains (7.5%) found carrying mutations in
      parC. No mutation was found in 6 quinolone-sensitive isolates or Shigella 51573.
      CONCLUSION: The Shigella spp. had high resistance rates to quinolones. The target
      gene mutations which were mainly found in gyrA and secondarily in parC, played an
      important role in the quinolone-resistance in Shigella spp.

PMID- 15200941
TI  - [Study on the resistance of methicillin-resistant staphylococcus aureus to
      iodophor and chlorhexidine].
AB  - OBJECTIVE: To study the resistance of methicillin-resistant staphylococcus aureus
      (MRSA), an indicator used in hospitals. METHODS: We used minimal inhibitory
      concentrations (MIC) of iodoph and chlorhexidine to MRSA, methicillin-sensitive
      staphylococcus aureus (MSSA) and staphylococcus aureus ATCC6538. RESULTS: Obvious
      difference between MRSA and MSSA the MIC of Iodophor was noticed. Among MICs,
      5.3% MRSA strains were 2-folds and 28.9% MRSA strains were 1.5 fold more than
      staph. aureus ATCC6538, while the MIC of 11.1% MSSA strains raised 1.5 fold than
      ATCC6538. The MIC of 83.3% MSSA strains were the same to staph. aureus ATCC6538.
      The MIC of chlorhexidine to MRSA, MSSA and staphylococcus aureus ATTC6538 were
      similar to each other. CONCLUSION: Results showed that some MRSA were more
      resistant to Iodophor than staph. aureus ATCC6538, but remained the same
      resistance to Chlorhexidine. Thus the concentration of Iodophor should be raised
      when the resistant strains were isolated.

PMID- 15200942
TI  - [Distribution of hepatitis B virus genotype in 5 cities of Fujian province and
      the clinical implications of HBV genotype].
AB  - OBJECTIVE: To study the prevalence of hepatitis B virus (HBV) genotype in 5
      cities of Fujian province and the clinical implications of distinct genotypes in
      HBV-related liver diseases. METHODS: HBV genotype was determined by the
      restriction fragment length polymorphism analysis in patients with chronic HBV
      infection in 5 cities of Fujian province. The relationship between HBV genotype
      and its clinical implications was studied by multinomal logistic regression and
      correspondence analysis. RESULTS: Of the 431 HBV DNA positive patients detected
      by PCR, 275 (63.8%) belonged to HBV genotype B, 100 (23.2%) to genotype C, 51
      (11.8%) to genotype D and D-mixed genotype. Genotype A, E and F were not found.
      Multinomal logistic regression showed that genotype B was more prevalent in
      Quanzhou and Sanming cities than in Fuzhou (P = 0.002, P = 0.006), and genotype B
      appeared significantly more common in asymptomatic carriers (ASC), chronic
      hepatitis B (CHB) and severe hepatitis (SH). Genotype C was most prevalent in
      patients with liver cirrhosis (LC) (47.0%) than in those with ASC (14.5%) and SH
      (14.7%) (P = 0.009, P < 0.001). The positive rate of hepatitis B e antigen was
      higher in patients with genotype C than in those with genotype B and genotype D
      (56.0% vs. 52.4%, P = 0.008, and 56.0% vs. 30.8%, P = 0.051, respectively). By
      correspondence analysis, genotype D and D-mixed genotype seemed to be correlated
      with hepatocellular carcinoma (HCC). CONCLUSIONS: (1) The major popular genotypes
      of HBV were B, C and D in Fujian. (2) Data of our study suggested that the
      geographic distribution of genotype B and C might be different in some cities of
      Fujian. (3) Genotype B might have a tendency to lead to SH in younger patients
      with chronic hepatitis B and the development of LC might be associated with
      genotype C among the elder patients. (4) Genotype D appeared to associate with
      development of HCC, which called for further study to confirm.

PMID- 15200943
TI  - [A case-control study on the risk of female breast cancer in Wuhan area].
AB  - OBJECTIVE: To investigate the risk factors of female breast cancer and its
      potential alteration in Wuhan area. METHODS: A case-control study was conducted
      on 213 cases with histopathological diagnosis and 430 matched controls, using
      conditional logistic regression analysis. RESULTS: 28 factors such as educational
      level, history of benign breast disease, age at menarche, age at menopausal, meat
      and well-done meat intake, soy bean food, fruit, lactation time, body mass index
      (BMI), juvenile chest X-ray, psychological factor, were associated with breast
      cancer risk in one-way variance model. Multivariate conditional logistic
      regression analysis in total significant factors and subgroups showed that the
      risk factors of breast cancer would include high level education, psychological
      trauma, history of benign breast disease later age at menopause, more years of
      menstrual and more years of menstrual before giving first birth, high BMI, well
      done meat intake and smoked food. Factors as later menarche, lactate longer,
      soybean food, fruit, drink tea habit were protective factors for breast cancer.
      Further breakdown of data showed some difference between premenopausal and
      postmenopausal women. Risks in premenopausal women were associated with history
      of benign breast disease, age of menarche, soybean food intake, whereas risks in
      postmenopausal women were related to age of menopausal, BMI, waist-hip ratio and
      fruit intake. Both psychological traumatic and duration of lactation were common
      pre-and postmenopausal risk and protective factors. CONCLUSIONS: Dietary habit
      and endogenous estrogen exposure related factors played important roles on women
      breast cancer in Wuhan area.

PMID- 15200945
TI  - [Study on the reliability and validity of international physical activity
      questionnaire (Chinese Vision, IPAQ)].
AB  - OBJECTIVE: To study the reliability and validity of Chinese version of
      International Physical Activity Questionnaire (IPAQ) and to provide an instrument
      for physical activity measurement in Chinese-spoken population. METHODS: Test
      retest reliability was systemically assessed in 94 participants sampled from
      college students. Questionnaires were completed twice with a three-day interval.
      The validity was established in 39 volunteers by Caltrac accelerometer monitoring
      and 24-hour activity recording for seven consecutive days. RESULTS: Both long
      vision (LV) and short vision (SV) had intraclass correlation coefficients above
      0.7 for physical activity. The total energy expenditure measured by LV, SV and PA
      records were 264.5 +/- 260.9, 185.4 +/- 128.9 (compared with activity records, P
      < 0.05) and 250.5 +/- 141.2 MET-min/d respectively. Energy expenditure of
      moderate physical activity were 81.7 +/- 165.4, 32.0 +/- 42.5 (compared with
      activity record, P < 0.05) and 61.3 +/- 72.0 MET-min/d. Caltrac accelerometer was
      moderately correlated with LV (r = 0.50) and SV (r = 0.63) while SV measured
      total daily energy expenditure was lower than activity records. When participants
      were categorized into two groups according to their time spent in physical
      activity above or below the target level, proportions of agreement of
      questionnaires and 24-hour activity records were high, including vigorous
      physical activity above 90% and moderate physical activity above 70%. LV, SV and
      activity records were measured during sedentary condition at an approximate
      level. CONCLUSIONS: Both LV and SV of IPAQ appeared to have acceptable
      reliability and validity, compared to other physical activity instruments that
      were used in various large epidemiological studies. The total or physical energy
      expenditures were similar between LV and activity records. For activity levels,
      the proportion of agreement were similar between activity records and LV or SV.
      However, SV underestimated the energy expenditure of total and moderate physical
      activity.

PMID- 15200944
TI  - [A case-control study on risk factors of hypospadias].
AB  - OBJECTIVE: Hypospadias is one of the most commonly seen urogenital congenital
      malformations in males and to identify its etiological factors. METHODS: A
      hospital-based case-control study was conducted, with 107 hypospadias cases. Two
      matched controls per case were randomly selected. Both cases and controls were
      face to face interviewed with a uniformed questionnaire. Conditional logistic
      regression model was used for univariable and multivariate analysis on SAS 6.12
      to estimate odds ratios (OR) and 95 per cent confidence internals (95% CI).
      RESULTS: Data from multiple conditional logistic regression analysis showed that
      hypospadias was positively associated with maternal history of spontaneous
      abortion (OR = 3.87, 95% CI: 1.60 - 9.39), with threatened abortion in the first
      or second trimester (OR = 3.57, 95% CI: 1.31 - 9.64), with common cold
      accompanied fever in the first trimester (OR = 7.63, 95% CI: 2.50 - 23.24), with
      maternal drug (antibiotic, analgesiscs) exposure during the second trimester (OR
      = 16.46, 95% CI: 3.46 - 78.21), with paternal exposure to pesticides
      occupationally (OR = 3.70,95% CI: 1.49 - 9.16), with neonatal low birth weight
      (OR = 12.62, 95% CI: 2.97 - 53.67), but was negatively associated with maternal
      diet supplemented with protein in the first trimester (OR = 0.33, 95% CI: 0.15 -
      0.74). CONCLUSIONS: The risk factors of hypospadias seemed to include maternal
      history of spontaneous abortion, threatened abortion in the first or second
      trimester, maternal common cold accompanied fever in the first trimester,
      maternal drug exposure during the second trimester, paternal occupational
      exposure to pesticides, neonatal low birth weight. However, maternal diet
      supplemented with protein probably acted as the protective factor for neonatal
      hypospadias in the first trimester.

PMID- 15200946
TI  - Toward the computable transcriptome.
AB  - Applying a combination of innovative approaches to understanding neuronal gene
      regulation in C. elegans, an article in the latest Developmental Cell (Wenick and
      Hobert, 2004) gives hope that reading the genome's transcriptional regulatory
      code may one day be possible.

PMID- 15200947
TI  - Gag order.
AB  - The Polycomb group (PcG) complex mediates heritable silencing of numerous genes
      during development. In a recent issue of Molecular Cell, Wang et al. (2004)
      characterize the order of PcG protein recruitment to specific regions of Ubx and
      substantiate a binding-in trans looping model of repression that may interfere
      with transcription initiation or elongation.

PMID- 15200948
TI  - Perspectives on the nature of BCR-mediated survival signals.
AB  - In the June 11 issue of Cell, Kraus et al. (2004) show, through conditional
      mutagenesis, that mature B cells have a drastically reduced life span in the
      absence of normal B cell antigen receptor (BCR) surface expression or tonic
      signal transduction. These studies support a role for signal transduction
      downstream of the BCR, rather than continued surface expression per se for the
      maintenance and survival of mature B cells in the periphery. Further, these
      studies exclude transient INF(gamma)-induced activation as a prerequisite to
      apoptosis in receptor-less cells.

PMID- 15200949
TI  - Targeted proteomic study of the cyclin-Cdk module.
AB  - The cell division cycle of the yeast S. cerevisiae is driven by one Cdk (cyclin
      dependent kinase), which becomes active when bound to one of nine cyclin
      subunits. Elucidation of Cdk substrates and other Cdk-associated proteins is
      essential for a full understanding of the cell cycle. Here, we report the results
      of a targeted proteomics study using affinity purification coupled to mass
      spectrometry. Our study identified numerous proteins in association with
      particular cyclin-Cdk complexes. These included phosphorylation substrates,
      ubiquitination-degradation proteins, adaptors, and inhibitors. Some associations
      were previously known, and for others, we confirmed their specificity and
      biological relevance. Using a hypothesis-driven mass spectrometric approach, we
      also mapped in vivo phosphorylation at Cdk consensus motif-containing peptides
      within several cyclin-associated candidate Cdk substrates. Our results
      demonstrate that this approach can be used to detect a host of transient and
      dynamic protein associations within a biological module.

PMID- 15200950
TI  - A switch in mitotic histone H4 lysine 20 methylation status is linked to M phase
      defects upon loss of HCF-1.
AB  - The abundant chromatin-associated human factor HCF-1 is a heterodimeric complex
      of HCF-1N and HCF-1C subunits that are essential for two stages of the cell
      cycle. The HCF-1N subunit promotes G1 phase progression, whereas the HCF-1C
      subunit ensures proper cytokinesis at completion of M phase. How the HCF-1C
      subunit functions is unknown. Here, we show that HCF-1C subunit depletion causes
      extensive mitotic defects, including a switch from monomethyl to dimethyl lysine
      20 of histone H4 (H4-K20) and defective chromosome alignment and segregation.
      Consistent with these activities, the HCF-1C subunit can associate with chromatin
      independently of the HCF-1N subunit and regulates the expression of the H4-K20
      methyltransferase PR-Set7. Indeed, upregulation of PR-Set7 expression upon loss
      of HCF-1 leads to improper mitotic H4-K20 methylation and cytokinesis defects.
      These results establish the HCF-1C subunit as an important M phase regulator and
      suggest that H4-K20 methylation status contributes to chromosome behavior during
      mitosis and proper cytokinesis.

PMID- 15200951
TI  - Localized domains of G9a-mediated histone methylation are required for silencing
      of neuronal genes.
AB  - Negative regulation of transcription is an important strategy in establishing and
      maintaining cell-specific gene expression patterns. Many neuronal genes are
      subject to active transcriptional repression outside the nervous system to
      establish neuronal specificity. NRSF/REST has been demonstrated to regulate at
      least 30 genes and contribute to their neuronal targeting by repressing
      transcription outside the nervous system. Further, human genome database searches
      reveal that over 800 genes contain an NRSE. Here we report that NRSF recruits the
      histone methylase G9a to silence NRSF target genes in nonneuronal cells. We show
      that G9a generates a highly localized domain of dimethylated histone H3-K9 around
      NRSEs, but H3-K27 remains unmethylated. The NRSEs are also associated with HP1.
      Finally, we demonstrate that dominant-negative G9a abrogates silencing of
      chromosomal neuronal genes. These findings implicate a role for histone
      methylation in targeting neuronal gene expression to the nervous system.

PMID- 15200952
TI  - Antibacterial peptide microcin J25 inhibits transcription by binding within and
      obstructing the RNA polymerase secondary channel.
AB  - The antibacterial peptide microcin J25 (MccJ25) inhibits transcription by
      bacterial RNA polymerase (RNAP). Biochemical results indicate that inhibition of
      transcription occurs at the level of NTP uptake or NTP binding by RNAP. Genetic
      results indicate that inhibition of transcription requires an extensive
      determinant, comprising more than 50 amino acid residues, within the RNAP
      secondary channel (also known as the "NTP-uptake channel" or "pore"). Biophysical
      results indicate that inhibition of transcription involves binding of MccJ25
      within the RNAP secondary channel. Molecular modeling indicates that binding of
      MccJ25 within the RNAP secondary channel obstructs the RNAP secondary channel. We
      conclude that MccJ25 inhibits transcription by binding within and obstructing the
      RNAP secondary channel--acting essentially as a "cork in a bottle." Obstruction
      of the RNAP secondary channel represents an attractive target for drug discovery.

PMID- 15200953
TI  - Molecular mechanism of transcription inhibition by peptide antibiotic Microcin
      J25.
AB  - 21 amino acid peptide Microcin J25 (MccJ25) inhibits transcription by bacterial
      RNA polymerase (RNAP). MccJ25-resistance mutations cluster in the RNAP secondary
      channel through which incoming NTP substrates are thought to reach the catalytic
      center and the 3' end of the nascent RNA is likely to thread in backtracked
      transcription complexes. The secondary channel also accepts transcript cleavage
      factors GreA and GreB. Here, we demonstrate that MccJ25 inhibits GreA/GreB
      dependent transcript cleavage, impedes formation of backtracked complexes, and
      can be crosslinked to the 3'-end of the nascent RNA in elongation complexes.
      These results place the MccJ25 binding site within the secondary channel.
      Moreover, single-molecule assays reveal that MccJ25 binding to a transcribing
      RNAP temporarily stops transcript elongation but has no effect on the elongation
      velocity between pauses. Kinetic analysis of single-molecule data allows us to
      put forward a model of transcription inhibition by MccJ25 that envisions the
      complete occlusion of the secondary channel by bound inhibitor.

PMID- 15200954
TI  - The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D
      loops in a manner regulated by TRF1 and TRF2.
AB  - Werner syndrome (WS) is characterized by features of premature aging and is
      caused by loss of the RecQ helicase protein WRN. WS fibroblasts display defects
      associated with telomere dysfunction, including accelerated telomere erosion and
      premature senescence. In yeast, RecQ helicases act in an alternative pathway for
      telomere lengthening (ALT) via homologous recombination. We found that WRN
      associates with telomeres when dissociation of telomeric D loops is likely during
      replication and recombination. In human ALT cells, WRN associates directly with
      telomeric DNA. The majority of TRF1/PCNA colocalizing foci contained WRN in live
      S phase ALT cells but not in telomerase-positive HeLa cells. Biochemically, the
      WRN helicase and 3' to 5' exonuclease act simultaneously and cooperate to release
      the 3' invading tail from a telomeric D loop in vitro. The telomere binding
      proteins TRF1 and TRF2 limit digestion by WRN. We propose roles for WRN in
      dissociating telomeric structures in telomerase-deficient cells.

PMID- 15200955
TI  - Genome-wide analysis reveals an unexpected function for the Drosophila splicing
      factor U2AF50 in the nuclear export of intronless mRNAs.
AB  - The protein factor U2AF is an essential component required for pre-mRNA splicing.
      Mutations identified in the S. pombe large U2AF subunit were used to engineer
      transgenic Drosophila carrying temperature-sensitive U2AF large subunit alleles.
      Mutant recombinant U2AF heterodimers showed reduced polypyrimidine tract RNA
      binding at elevated temperatures. Genome-wide RNA profiling comparing wild-type
      and mutant strains identified more than 400 genes differentially expressed in the
      dU2AF50 mutant flies grown at the restrictive temperature. Surprisingly, almost
      40% of the downregulated genes lack introns. Microarray analyses revealed that
      nuclear export of a large number of intronless mRNAs is impaired in Drosophila
      cultured cells RNAi knocked down for dU2AF50. Immunopurification of nuclear RNP
      complexes showed that dU2AF50 associates with intronless mRNAs. These results
      reveal an unexpected role for the splicing factor dU2AF50 in the nuclear export
      of intronless mRNAs.

PMID- 15200956
TI  - Computational identification of plant microRNAs and their targets, including a
      stress-induced miRNA.
AB  - MicroRNAs (miRNAs) are approximately 21-nucleotide RNAs, some of which have been
      shown to play important gene-regulatory roles during plant development. We
      developed comparative genomic approaches to systematically identify both miRNAs
      and their targets that are conserved in Arabidopsis thaliana and rice (Oryza
      sativa). Twenty-three miRNA candidates, representing seven newly identified gene
      families, were experimentally validated in Arabidopsis, bringing the total number
      of reported miRNA genes to 92, representing 22 families. Nineteen newly
      identified target candidates were confirmed by detecting mRNA fragments
      diagnostic of miRNA-directed cleavage in plants. Overall, plant miRNAs have a
      strong propensity to target genes controlling development, particularly those of
      transcription factors and F-box proteins. However, plant miRNAs have conserved
      regulatory functions extending beyond development, in that they also target
      superoxide dismutases, laccases, and ATP sulfurylases. The expression of miR395,
      the sulfurylase-targeting miRNA, increases upon sulfate starvation, showing that
      miRNAs can be induced by environmental stress.

PMID- 15200957
TI  - Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase.
AB  - Apoptotic cell death and survival is controlled by pro- and antiapoptotic
      proteins. Because these proteins act on each other, cell fate is dictated by the
      relative activity of pro- versus antiapoptotic proteins. Here we report that
      BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi
      network, protects cells against apoptosis and functions as an inhibitor of
      apoptosis (IAP). By using wild-type and mutant forms we show that BRUCE inhibits
      caspase activity and apoptosis depending on its BIR domain. Upon apoptosis
      induction, BRUCE is antagonized by three mechanisms: first, through binding to
      Smac; second, by the protease HtrA2; and third, by caspase-mediated cleavage. In
      addition to its IAP activity BRUCE has the distinctive property of functioning as
      a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. Our work suggests
      that, owing to its two activities and its localization, BRUCE may function as a
      specialized regulator of cell death pathways.

PMID- 15200958
TI  - Protein-protein interaction affinity plays a crucial role in controlling the
      Sho1p-mediated signal transduction pathway in yeast.
AB  - Protein-protein interactions are required for most cellular functions, yet little
      is known about the relationship between protein-protein interaction affinity and
      biological activity. To investigate this issue, we engineered a series of mutants
      that incrementally reduced the affinity of the yeast Sho1p SH3 domain for its in
      vivo target, the MAP kinase kinase Pbs2p. We demonstrate a strong linear
      correlation between the binding energy of these mutants and quantitative in vivo
      outputs from the HOG high-osmolarity response pathway controlled by Sho1p. In
      addition, we find that reduction in binding affinity for the correct target
      within this pathway causes a proportional increase in misactivation of the
      related mating pheromone response pathway and that strong binding affinity alone
      does not guarantee efficient biological activity. Our experiments also indicate
      that a second binding surface on the Sho1p SH3 domain is required for its proper
      in vivo function.

PMID- 15200959
TI  - Sho1 and Pbs2 act as coscaffolds linking components in the yeast high osmolarity
      MAP kinase pathway.
AB  - Scaffold proteins mediate efficient and specific signaling in several mitogen
      activated protein (MAP) kinase cascades. In the yeast high osmolarity response
      pathway, the MAP kinase kinase Pbs2 is thought to function as a scaffold, since
      it binds the osmosensor Sho1, the upstream MAP kinase kinase kinase Ste11, and
      the downstream MAP kinase Hog1. Nonetheless, previous work has shown that Ste11
      can be activated even when Pbs2 is deleted, resulting in inappropriate crosstalk
      to the mating pathway. We have found a region in the C terminus of Sho1 that
      binds Ste11 independently of Pbs2 and is required for crosstalk. These data
      support a model in which Sho1 has at least two separable interaction regions: one
      that binds Ste11 and mediates its activation, and one that binds Pbs2, directing
      Ste11 to act on Pbs2. Thus, a network of interactions provided by both Sho1 and
      Pbs2 appears to direct pathway information flow.

PMID- 15200961
TI  - The C. elegans Polycomb gene SOP-2 encodes an RNA binding protein.
AB  - Epigenetic silencing of Hox cluster genes by Polycomb group (PcG) proteins is
      thought to involve the formation of a stably inherited repressive chromatin
      structure. Here we show that the C. elegans-specific PcG protein SOP-2 directly
      binds to RNA through three nonoverlapping regions, each of which is essential for
      its localization to characteristic nuclear bodies and for its in vivo function in
      the repression of Hox genes. Functional studies indicate that the RNA involved in
      SOP-2 binding is distinct from either siRNA or microRNA. Remarkably, the
      vertebrate PcG protein Rae28, which is functionally and structurally related to
      SOP-2, also binds to RNA through an FCS finger domain. Substitution of the Rae28
      FCS finger for the essential RNA binding region of SOP-2 partially restores
      localization to nuclear bodies. These observations suggest that direct binding to
      RNA is an evolutionarily conserved and potentially important property of PcG
      proteins.

PMID- 15200960
TI  - Mechanism of microtubule stabilization by doublecortin.
AB  - Neurons undertake an amazing journey from the center of the developing mammalian
      brain to the outer layers of the cerebral cortex. Doublecortin, a component of
      the microtubule cytoskeleton, is essential in postmitotic neurons and was
      identified because its mutation disrupts human brain development. Doublecortin
      stabilizes microtubules and stimulates their polymerization but has no homology
      with other MAPs. We used electron microscopy to characterize microtubule binding
      by doublecortin and visualize its binding site. Doublecortin binds selectively to
      13 protofilament microtubules, its in vivo substrate, and also causes
      preferential assembly of 13 protofilament microtubules. This specificity was
      explained when we found that doublecortin binds between the protofilaments from
      which microtubules are built, a previously uncharacterized binding site that is
      ideal for microtubule stabilization. These data reveal the structural basis for
      doublecortin's binding selectivity and provide insight into its role in
      maintaining microtubule architecture in maturing neurons.

PMID- 15200962
TI  - Hypertension in pregnancy.
AB  - The hypertensive diseases of pregnancy commonly refer to a group of disorders
      whose definitions have changed over time within and among professional
      organizations. Pre-eclampsia, either mild or severe, is managed best with a
      policy of delivery at or beyond 37 and 34 weeks' gestation, respectively.
      Similarly, chronic hypertension,gestational hypertension, and chronic
      hypertension with superimposed pre-eclampsia are conditions wherein it is
      difficult to justify expectant management beyond 37 weeks' gestation. The
      approach to management before these gestational ages is subject to interpretation
      of a limited body of literature.

PMID- 15200963
TI  - Care of diabetes in pregnancy.
AB  - Diabetes, whether existing before pregnancy or brought on by changes in maternal
      physiology, poses risks to the mother and developing fetus. Excellent
      preconceptional and pregnancy care can help to minimize, or even to eliminate,
      these risks. This article reviews the problems that are associated with diabetes
      in pregnancy and evidence-based strategies to avoid them.

PMID- 15200964
TI  - Thyroid disease and other endocrine disorders in pregnancy.
AB  - Endocrine disorders, in particular, thyroid disorders, are common in pregnancy.
      The endocrine adaptation to pregnancy, need for adequate iodine supplementation,
      and thyroxine replacement are presented. In addition, autoimmune diseases of the
      thyroid and pituitary that may occur subsequent to the immune changes of
      pregnancy and the postpartum period are discussed. A brief account of the
      presentation of other endocrine disorders (ie, pituitary,parathyroid, calcium,
      adrenal and gonadal disorders) also is given, along with their evaluation and
      management.

PMID- 15200965
TI  - Hemoglobinopathies in pregnancy.
AB  - Hemoglobinopathies represent a unique set of genetic disorders. Formerly, many
      affected individuals did not survive to childbearing age. Affected women now
      commonly reach childbearing age and desire pregnancy. Successful pregnancy is
      possible in many cases with carefully coordinated obstetric and medical
      management. Genetic screening and prenatal diagnosis is an important aspect of
      prenatal care in these disorders. DNA mutation analysis offers rapid and accurate
      fetal diagnosis. Pregnancy also offers a unique situation in that cord blood has
      become a valuable source of stem cells for transplant. This allows the potential
      role of the unaffected fetus as a donor for affected siblings. In addition, it
      was proposed that the fetus may be able to act as a donor of stem cells for an
      affected mother. Despite current screening recommendations,many couples are not
      aware that they are carriers; it is common for a child to be born with an
      unexpected, serious hemoglobinopathies. For this reason, newborn screening
      programs have been introduced in most high-risk areas. Early diagnosis can
      facilitate implementation of proper preventive health measures, education of the
      parents regarding their carrier status, and provide the child with ongoing
      comprehensive care.

PMID- 15200966
TI  - Thromboembolic disease in pregnancy.
AB  - Venous thromboembolic disease is a major cause of maternal morbidity and
      mortality. Virchow's triad of hypercoagulability, venous stasis, and vascular
      damage all occur during pregnancy. The risk of venous thromboembolism is five to
      six times higher during pregnancy and the puerperium. Risk factors include age
      greater than 35, antiphospholipid antibodies, inherited thrombophilias, operative
      delivery, increased parity, obesity, mechanical heart valves,and family history.
      Prophylactic and therapeutic anticoagulation is recommended for women at risk.
      Low molecular weight heparins are safe and effective in most cases.

PMID- 15200967
TI  - Autoimmune disease in pregnancy: systemic lupus erythematosus and
      antiphospholipid syndrome.
AB  - Autoimmune diseases most commonly occur in women of childbearing age. Although
      some conditions such as ankylosing spondylitis are more common in men, over 70%
      of individuals with autoimmune diseases are women. This article focuses on
      SLE,which is often considered to be the "classic" autoimmune disease,and
      antiphospholipid syndrome (APS), which is associated with pregnancy loss and
      placental insufficiency.

PMID- 15200968
TI  - Seizure disorders in pregnancy.
AB  - This article discusses seizure disorders in pregnancy. Seizure disorder affects
      1.1 million women of reproductive age in the United States. In 1995, the annual
      cost of treatment of patients who had epilepsy was estimated to be 12.5 billion
      dollars. Seizures are disorganized firing of neural cells. Epilepsy is the
      presence of two or more seizures in the absence of an identifiable cause for the
      seizures (ie, no intracranial or metabolic abnormality). Epilepsy has an impact
      on many aspects of women's health, particularly with respect to reproduction. The
      management of women who have epilepsy during pregnancy is the focus of this
      article.

PMID- 15200969
TI  - Asthma in pregnancy.
AB  - Asthma is a chronic inflammatory disease of the airway system that is
      characterized by bronchoconstriction and bronchial hyperresponsiveness that are
      triggered by a host of stimuli. Asthma is the most common respiratory disease in
      pregnancy and affects approximately 4% of pregnant women. This article reviews
      asthma as a public health concern, the normal physiology of pregnancy,the
      pathophysiology of asthma in pregnancy, the effects of asthma on pregnancy and
      pregnancy on asthma, objective lung function testing, goals for the pregnant
      woman who has asthma, and treatment of chronic and acute episodes of asthma.

PMID- 15200970
TI  - Pregnancy after organ transplant.
AB  - The frequency and variety of solid organ transplantation in reproductive-age
      women increases each year. Pregnancy is no longer contraindicated in transplant
      recipients provided that their graft is functioning well and they are in good
      general health. Physicians who care for pregnant transplant recipients should be
      aware of the surmounting data that are available in the literature and through
      registries of maternal, fetal, and neonatal risks and complications as well as
      outcome data. Newer immunosuppressive agents preserve graft function and registry
      data attest to their safety in pregnancy. For optimal maternal and neonatal
      outcomes, a multispecialty care approach that includes the obstetrician/maternal
      fetal specialist,transplant team, anesthesiologist, and neonatal team is prudent
      when caring for pregnancies after organ transplantation.

PMID- 15200971
TI  - Cardiac disease in pregnancy.
AB  - This article reviews the complications, management and prognosis of cardiac
      disease in pregnancy.

PMID- 15200973
TI  - Quality evaluation in congenital heart surgery.

PMID- 15200974
TI  - Risk stratification in paediatric open-heart surgery.
AB  - OBJECTIVE: The aims of this study were to identify independent risk factors for
      mortality following paediatric open-heart surgery and to develop risk models for
      use in clinical audit based on identified risk factors. The study also tests the
      validity of the recently proposed Risk Adjustment in Congenital Heart Surgery
      (RACHS-1) method of risk stratification as applied to open-heart operations.
      METHODS: A multiple logistic regression analysis was performed on all patients
      less than 18 years of age undergoing open-heart surgery at a single institution
      over a 3-year period. Preoperative and operative variables included for analysis
      were age at operation, weight, sex, American Society of Anaesthesiology (ASA)
      grade, RACHS-1 risk category, preoperative haemoglobin, bypass time, temperature,
      cross-clamp time, circulatory arrest time, blood transfusion on bypass and
      surgeon. The outcome measure was in-hospital death. RESULTS: 1085 consecutive
      open-heart cases were identified. There were 51 in-hospital deaths (4.7%).
      Variables identified as being independently significant risk factors for in
      hospital death were age (P = 0.0002), RACHS-1 risk category (P < 0.0001), and
      bypass time. Based on these three variables, a risk model was constructed to
      predict mortality. The area under the receiver-operating-characteristic (ROC)
      curve for this model was 0.86. A second model was constructed ignoring bypass
      time. In this model, the significance of the 'preoperative' risk factors was (P =
      0.0003) for age and (P < 0.0001), for RACHS-1 risk category. The area under the
      ROC curve was 0.81 for the second model. CONCLUSIONS: This study identifies age
      at operation, RACHS-1 risk category and bypass time as highly significant risk
      factors for mortality after paediatric open-heart surgery. It validates the RACHS
      1 risk stratification method as applied to the subset of open-heart surgery,
      whilst accepting the limitations of such a system. The risk models formulated
      permit risk prediction and allow for analysis of surgical results. Such risk
      adjustment is important when assessing performance and comparing outcomes amongst
      individuals or institutions.

PMID- 15200975
TI  - The RACHS-1 risk categories reflect mortality and length of hospital stay in a
      large German pediatric cardiac surgery population.
AB  - OBJECTIVES: The Risk Adjusted classification for Congenital Heart Surgery (RACHS
      1) was published in January 2002, based on 4370 operations registered by the
      Pediatric Cardiac Care Consortium. It is designed for being easily applicable
      also for retrospective analysis of hospital discharge data sets; the
      classification was not developed for patients with heart transplantations,
      ventricular assist devices or patients above 18 years. We apply this
      classification to our 2368 correspondent procedures that were performed
      consecutively on 2223 patients between June 1996 and October 2002 in Bad
      Oeynhausen and analyze its relation to mortality and length of hospital stay.
      METHODS: The procedures were grouped by the 6 RACHS-1 categories. Groping
      criteria were mainly the performed procedures; for few procedures age or
      diagnoses are needed in addition. The classification process itself took less
      than 10 working hours. Risk group frequencies in our/ the PCCC population were 1:
      368/964 (15.5%/22.0%), 2: 831/1433 (35.1%/33.1%), 3: 744/1523 (31.4%/34.7%), 4:
      284/276 (12.0%/6.3%), 5: 4/4 (0.2%/0.1%), 6: 137/168 (5.3%/3.8%). 18.8%/19.2%
      were under 1 month, 37.5%/31.6% 1-12 months of age, respectively. RESULTS:
      Hospital mortality (%) in our population/ the PCCC Group 1-6 was: 0.3/0.4,
      4.0/3.8, 5.6/8.5, 9.9/19.4, 50.0/0, 40.1/47.7%. Geometric means of total (13.1,
      19.6, 23.5, 29.1, 31.5, 52.6 days, respectively) and postoperative length of stay
      of survivors show significant differences between the single risk groups. The
      prediction capacity of the score as expressed by the area under the receiver
      operator curve was nearly equal to the value found for the American hospital
      discharge data sets. Length of stay rises exponentially with the RACHS-1
      category. However, the RACHS-1 category explains only 13.5% of the total and
      16.8% of individual postoperative lengths of hospital stay in survivors.
      CONCLUSION: The RACHS-1 classification is applicable to European pediatric
      populations, too. Category Distribution, outcome class distinction capacity,
      distribution and mortality are similar. RACHS-1 is able to classify patients into
      significantly different groups concerning total and postoperative hospital stay
      duration, although there remains a large variability within the groups.

PMID- 15200976
TI  - Lessons learned from the data analysis of the second harvest (1998-2001) of the
      Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database.
AB  - OBJECTIVE: The analysis of the second harvest of the STS Congenital Heart Surgery
      Database produced meaningful outcome data and several critical lessons relevant
      to congenital heart surgery outcomes analysis worldwide. METHODS: This data
      harvest represents the first STS multi-institutional experience with software
      utilizing the nomenclature and database requirements adopted by the STS and EACTS
      (April 2000 Annals of Thoracic Surgery). Members of the STS Congenital Heart
      Committee analyzed the STS data. RESULTS: This STS harvest includes data from 16
      centers (12787 cases, 2881 neonates, 4124 infants). In 2002, the EACTS reported
      similar outcome data utilizing the same database definitions (41 centers, 12736
      cases, 2245 neonates, 4195 infants). Lessons from the analysis include: (1) Death
      must be clearly defined. (2) The Primary Procedure in a given operation must be
      documented. (3) Inclusionary and exclusionary criteria for all diagnoses and
      procedures must be agreed upon. (4) Missing data values remain an issue for the
      database. (5) Generic terms in the nomenclature lists, that is terms ending in
      Not Otherwise Specified (NOS), are redundant and decrease the clarity of data
      analysis. (6) Methodology needs to be developed and implemented to assure and
      verify data completeness and data accuracy. 'Operative Mortality' and 'Mortality
      Assigned to this Operation' were defined by the STS and EACTS; these definitions
      were not utilized uniformly. 'Thirty Day Mortality' was problematic because some
      centers did not track mortality after hospital discharge. Only 'Mortality Prior
      to Discharge' was consistently reported. Designation of Primary Procedure for a
      given operation determines its location for analysis. Until Complexity Scores
      lead to automated methodology for choosing the Primary Procedure, the surgeon
      must designate the Primary Procedure. Inclusionary and exclusionary criteria for
      all diagnoses and procedures have been developed in an effort to define
      acceptable concomitant diagnoses and procedures for each analysis. Improvements
      in data completeness can be achieved using a variety of techniques including
      developing more functional techniques of data entry at individual institutions
      and software improvements. Future versions of the STS Congenital Database will
      request that the coding of diagnoses and procedures avoid the terms ending in
      NOS. CONCLUSIONS: Lessons from this data harvest should improve congenital heart
      surgery outcome analysis.

PMID- 15200977
TI  - Predictors of mortality and neurological morbidity in children undergoing
      extracorporeal life support for cardiac disease.
AB  - OBJECTIVES: The objective of this study was to determine the incidence and risk
      factors for death and adverse neurological outcomes in children receiving
      extracorporeal life support (ECLS) for cardiac indications. METHODS: A
      retrospective single centre consecutive cohort study was conducted in children
      who received ECLS for cardiac indications between January 1990 and June 2000.
      Health records and neuroimaging films were assessed, and long-term outcomes were
      obtained by standardized telephone follow-up or by assessments performed in
      outpatient clinic. Clinical, neuroimaging and surgical predictors of outcome were
      tested. RESULTS: Of 90 children studied, short-term clinical neurological events
      (during hospitalization) occurred in 20 children (22%) during or following ECLS.
      Long-term neurological sequelae were present in 11 of 31 children discharged
      alive, after a mean follow-up interval of 4.5 years (range 4 months to 9 years).
      Death occurred in 59 children (66%) during hospitalisation, and in 3 following
      discharge. Of the 28 long-term survivors, only 15 children (17%) survived without
      neurological sequelae. Abnormal neuroimaging was associated with short-term
      neurological events (P = 0.03, OR 10.5), and the use of CPR prior to ECLS (P =
      0.02, OR 2.9) was the only significant predictor of death. There were no
      significant predictors of long-term neurological sequelae. CONCLUSIONS: More than
      two-thirds of the children receiving ECLS died, and 39% (11/28) of long-term
      survivors had neurological deficits. Although mortality is close to 100% without
      this type of support, there is still a significantly high morbidity and mortality
      with this type of support.

PMID- 15200978
TI  - Outcome of cardiac surgery in low birth weight and premature infants.
AB  - OBJECTIVE: Low birth weight or premature infants may require early surgical
      treatment of congenital cardiac lesions because of their poor clinical status.
      Even thought early repair or palliation is carried out with incremental risk
      factor for morbidity and mortality, it has been demonstrated to be preferable to
      medical management and delayed surgery. This retrospective study was undertaken
      to evaluate early and mid-term results in infants, weighing less than 2500 g, who
      underwent surgery other than patent ductus arteriosus closure. METHODS: Since
      January 1993 to August 2002, 60 consecutive patients underwent early surgical
      treatment of congenital heart malformations at our institution. 27 patients were
      premature (born before 37 weeks of gestation). Ninety percent were severely
      symptomatic. Mean age at operation was 15.5 days (range 4-68 days). Mean weight
      was 2120 g (range 900-2500 g). Indications for surgery were: coarctation complex
      11, transposition of great arteries 9, interrupted or severely hypoplastic aortic
      arch 9, hypoplastic left heart syndrome 7, truncus arteriosus 5, other 19. Thirty
      five patients were operated on CPB, Deep Hypothermia with Circulatory Arrest was
      used in 9. Complete repair was achieved in 32 patients. Aortic arch
      reconstruction was required in 32 cases. RESULTS: There were nine early deaths
      (15%): heart failure (5), multiorgan failure (3), sepsis (1). Age, weight,
      prematurity, type of surgery and use of cardio pulmonary by-pass did not
      influence early mortality. Mean intensive care unit stay and duration of
      mechanical ventilation were 5.8 days and 75.5 h, respectively. Postoperative
      neurological complications did not occur in any patient. At follow-up (mean 48
      months) there were nine late deaths. Kaplan-Meier survival at 60 months was 70%.
      CONCLUSIONS: Surgery for congenital heart disease can be performed in low weight
      critically ill infants with reduced, but still acceptable early and mid-term
      survival.

PMID- 15200979
TI  - Repair of atrioventricular valve regurgitation in the modified Fontan operation.
AB  - OBJECTIVE: To evaluate the prevalence, impact and outcome of repair of
      atrioventricular valve regurgitation (AVVR) in Fontan patients. METHODS: We
      retrospectively reviewed 340 Fontan patients from 1986 to 2001. Twelve patients
      with valve closure or replacements were excluded. AVVR was graded by
      transthoracic echocardiography. Patients were divided into group O (no AVVR),
      group A (1+ to 2+) and group B (3+ to 4+). RESULTS: AVVR was present in 129
      (39.3%) patients. Repair was carried out in 37 (11.3%) with no difference in
      mortality as compared to no repair (18.9 vs 10.9%, P =0.16). Mean follow-up was
      44 months (1-197 months) with 14 patients lost to follow-up. No valve repair was
      carried out in group O (192 patients) and no clinical change in AVVR was observed
      (pre-op 0.00, post-op 0.78). In group A (85 patients) 6 patients had valve repair
      without significant change in the degree of AVVR after valve repair (pre-op 1.8,
      post-op 2.2, P = 0.18). In group B (44 patients) 31 had valve repair and a
      significant reduction was observed (pre-op 3.28, post-op 2.44, P < 0.001). A
      similar improvement was also observed when the valve was not repaired (pre-op
      3.25, post-op 2.44, P = 0.003). Survival at 10 years was comparable (83%
      repaired, 89% not repaired, P = 0.165). There was no difference in the incidence
      of long-term complications (26% repaired, 29.7% no repair, P = 0.64).
      CONCLUSIONS: Trivial to mild AVVR remains stable and their repair during the
      Fontan operation provides no additional benefits. Valve repair in patients with
      moderate to severe AVVR improved the regurgitation with comparable operative
      mortality and long-term outcome; however, similar benefits could be achieved
      without repair of the atrioventricular valve. We should not deny patients with
      similar AVVR the Fontan operation.

PMID- 15200980
TI  - Anatomic reconstruction of recurrent aortic arch obstruction in children.
AB  - OBJECTIVE: Anatomical reconstruction of the aortic arch following aortic arch
      surgery is challenging. The placement of an extra-anatomical aortic bypass has
      been proposed for these difficult cases. This approach is not ideal in children
      due to possible long-term complications. This study presents the results of our
      policy to reconstruct the aortic arch in recurrent obstruction in children, which
      are not amenable to balloon dilatation. METHODS: Seven children with a median age
      of 8 years (range 1 month-15 years) were operated for aortic arch obstruction
      following correction of an aortic coarctation. Six children presented another
      intra-cardial lesion (2 subaortic membranes; 2 VSDs, 1 ostium stenosis of the
      left main coronary artery, and 1 mitral valve insufficiency). The surgical
      approach involved a sternotomy, cardiopulmonary support using two arterial inflow
      cannulas (one above and one below the aortic arch), and moderate hypothermia.
      Enlargement of the aortic arch was performed by a sliding plasty in four patients
      and by a patch plasty in three patients. Associated cardiac defects were
      corrected as well. RESULTS: It was technically possible to perform the planned
      operation in all patients. All patients survived and none presented significant
      postoperative complications. There were no residual gradients in six patients and
      a gradient of 10 mmHg in one patient postoperatively. One patient showed
      transient recurrent nerve palsy which recovered within 6 weeks. Follow-up
      echocardiographic and MRI studies revealed a normal appearing aortic arch with
      laminar flow. CONCLUSIONS: Although more demanding, an anatomical reconstruction
      of the aortic arch can be performed in infants and children with recurrent
      obstruction of the aortic arch with excellent initial results. This approach may
      prove superior to an extra-anatomic bypass in the long-term.

PMID- 15200981
TI  - Coronary flow characteristics after a Bentall procedure with or without sinuses
      of Valsalva.
AB  - OBJECTIVES: The sinuses of Valsalva are known to contribute to the normal
      function of the aortic valve. Little is known about their role in promoting
      coronary artery blood flow. The aim of this study was to compare coronary artery
      flow characteristics among patients undergoing a Bentall operation by means of a
      conventional cylindrical Dacron conduit or with a new conduit with pseudosinuses
      of Valsalva or in patients retaining their natural sinuses of Valsalva after
      aortic valve and supracoronary ascending aorta replacement. METHODS: One year
      after a Bentall procedure with a standard cylindrical Dacron conduit (7 patients,
      group A) or with the new conduit (7 patients, group B), or after aortic valve and
      ascending aortic replacement (control group, 7 patients, group C) coronary flow
      velocity reserve and diastolic to systolic time integral ratio at baseline and
      after maximal hyperemia (with 40 microg of adenosine) were assessed by using a
      0.014-in. Doppler guidewire positioned in the middle portion of the left anterior
      descending coronary artery. All patients were in NYHA class I, sinus rhythm and
      free of coronary disease. RESULTS: Arterial blood pressures and heart rate were
      comparable among groups. Intracoronary Doppler measurements did not show any
      significant difference in coronary vascular reserve between the three groups
      (3.6+/-0.4 vs 3.1+/-0.7 vs 3.7+/-0.5, P = 0.2). A greater diastolic component at
      baseline was present in group B patients (5.5+/-1.9 vs 3.5+/-0.9 in group A and
      3.7+/-0.9 in group C, P = 0.024). After maximal hyperemia the diastolic component
      increased slightly in group A patients (8%) while both in groups B and C
      significantly decreased (-15 and -20%, respectively) (P = 0.017). CONCLUSIONS:
      The presence of pseudosinuses of Valsalva does not influence coronary flow
      reserve. After maximal coronary vasodilation the increase in the systolic
      component of coronary flow is more evident in the presence of sinuses or
      pseudosinuses of Valsalva, thus suggesting that coronary flow pattern may be
      affected by the presence of sinuses.

PMID- 15200982
TI  - Hypothermic circulatory arrest with and without cold selective antegrade cerebral
      perfusion: impact on neurological recovery and tissue metabolism in an acute
      porcine model.
AB  - OBJECTIVE: Clinically, selective antegrade cerebral perfusion (SACP) seems to be
      associated with a better neurological outcome compared to hypothermic circulatory
      arrest (HCA) alone, but the pathophysiological mechanisms are not well
      understood. Therefore, this study was undertaken to assess the effects of HCA
      with and without SACP on the cerebral integrity using multimodal
      neurophysiological monitoring. METHODS: 12 pigs were randomly assigned to 100 min
      HCA at 20 degrees C brain temperature with (n = 6) and without (n = 6) SACP.
      Haemodynamics, metabolics and neurophysiology (EEG, SSEP, ICP, spectroscopy,
      cerebral tissue monitoring) were monitored. Animals were sacrified 4 h after
      reperfusion and the brains perfused for histopathological assessment. RESULTS:
      There were no clinically relevant differences in hemodynamics between groups.
      During reperfusion, EEG and SSEP recovery was significantly faster in the SACP
      group (P < 0.05). The rise in ICP during reperfusion was markedly reduced in the
      SACP group (P < 0.01) for the trend). Three hours after reperfusion, median ICP
      was 130% compared to baseline in the SACP group and 225% in the HCA group (P <
      0.01). Invasive as well as noninvasive cerebral monitoring indirectly indicates
      the occurrence of tissue acidosis in the HCA group even 4 h after HCA.
      CONCLUSIONS: Cold SACP is associated with better neurophysiological recovery and
      less cerebral edema, indicated by lower intracranial pressures during
      reperfusion. Neurophysiological recovery correlated well with the rise in ICP.
      HCA alone causes prolonged acidosis in the brain tissue during reperfusion. From
      these data, SACP appears to be superior to HCA alone, but further studies have to
      elucidate the optimal regimes for SACP.

PMID- 15200983
TI  - Meta-analysis on the effect of off-pump coronary bypass surgery.
AB  - OBJECTIVE: To assess the effect of conventional coronary artery bypass surgery
      (CABG) compared to the off-pump procedure (OPCAB). METHODS: Based on randomised
      trials found in PubMed and Science Citation Index, an overall odds ratio and 95%
      confidence interval was calculated for the combined endpoint of mortality, stroke
      and myocardial infarction. RESULTS: The 18 randomised trials included 1584
      patients (783 OPCAB, 801 CABG). The odds ratio was 0.73 (95% CI=0.26; 2.04) at 2
      week post-surgery, 0.75 (0.39; 1.42) at 1-month post-surgery, 0.55 (0.28; 1.08)
      at 3-month post-surgery, and 0.66 (0.38; 1.15) at 1-year post-surgery.
      CONCLUSIONS: The outcome of this meta-analysis shows favourable results for OPCAB
      for the combined endpoint of mortality, stroke and myocardial infarction at short
      and long term follow-up. However, none of the risk reductions reach statistical
      significance at the conventional level. Based on our results OPCAB appears to be
      equivalent to CABG.

PMID- 15200984
TI  - Coronary grafts flow and cardiac pacing modalities: how to improve perioperative
      myocardial perfusion.
AB  - OBJECTIVE: Aim of this study was to investigate modifications of coronary grafts
      flow during different pacing modalities after CABG. MATERIALS AND METHODS: Two
      separate prospective studies were conducted in patients undergoing CABG and
      requiring intraoperative epicardial pacing. In a first study (22 patients)
      coronary grafts flows were measured during dual chamber pacing (DDD) and during
      ventricular pacing (VVI). In a second study (10 patients) flows were measured
      during DDD pacing at different atrio-ventricular (A-V) delay periods. A-V delay
      was adjusted in 25 ms increments from 25 to 250 ms and flow measurements were
      performed for each A-V delay increment. A transit time flowmeter was used for the
      measurements. RESULTS: An average of 3.4 grafts/patient were performed. In the
      first study, average coronary graft flow was 47.4+/-20.8 ml/min during DDD pacing
      and 41.8+/-18.2 ml/min during VVI pacing (P = 0.0004). Furthermore average
      systolic pressure was 94.3+/-10.1 mmHg during DDD pacing and 89.6+/-12.2 mmHg
      during VVV pacing (P = 0.0007). No significant differences in diastolic pressure
      were recorded during the two different pacing modalities. In the second study,
      maximal flows were achieved during DDD pacing with an A-V delay of 175 ms (54+/
      9.6 ml/min) and minimal flows were detected at 25 ms A-V delay (38.1+/-4.7
      ml/min) (P=ns). No significant differences in systolic or diastolic blood
      pressure were noticed during the different A-V delays. CONCLUSION: Grafts
      flowmetry provides an extra tool to direct supportive measures such as cardiac
      pacing after CABG. DDD mode with A-V delay around 175 ms. should be preferred to
      allow for maximal myocardial perfusion via the grafts.

PMID- 15200985
TI  - Factors excercising an influence on recovery of hibernating myocardium after
      coronary artery bypass grafting.
AB  - OBJECTIVE: Coronary artery bypass grafting (CABG) in patients with endstage
      coronary disease (CAD) significantly improves symptoms and prolongs life
      expectancy. Left ventricular function is also improved in some patients, but not
      in others. Factors which influence functional recovery of hibernating myocardium
      after revascularization are at present under investigation. METHODS: From 3/2000
      to 8/2002, we analyzed 41 patients with an ejection fraction (EF) of < or =30%,
      who underwent CABG, prospectively. All patients received low-dose dobutamine
      echocardiography (DE), dobutamine myocardial scintigraphy with SPECT, dobutamine
      magnetic resonance tomography (MRI), contrast-enhanced MRI and, when necessary,
      positron emission tomography (PET). Hibernating myocardium (area of interest) was
      identified with these diagnostic tools preoperatively and biopsy samples were
      taken intraoperatively. RESULTS: All patients received complete coronary
      revascularization. Early mortality was 2.4%. Three patients died during follow
      up. Six months after the operation DE, MRI and SPECT were repeated. EF increased
      in 23 patients (group I) by at least >or =5%, and in 14 patients (group II) it
      did not improve. The wall motion score in the area of interest had increased
      during preoperative DE in group I significantly. The score did not change in
      group II. In addition the diastolic-systolic wall thickness increase in the area
      of interest rose >15% during DE in group I preoperatively; the increase was < or
      =15% in group II. MRI hyperenhancement of the left ventricle was significantly
      lower in group I compared to group II preoperatively. SPECT showed myocardial
      viability in the area of interest in all 37 patients. There were no significant
      differences between group I and II seen in SPECT. When the area of interest was
      located in the anterior wall the patients more frequently showed ventricular
      improvement postoperatively than patients with an area of interest located in the
      inferior, lateral or posterior wall. Light microscopy showed more severe
      myocardial cell hypertrophy (>19 microm) and less severe destruction of
      myocardial cell architecture in biopsies of group I compared to group II
      (myocardial cell hypertrophy < or =17 microm). Electron microscopy showed
      mitochondrial abnormalities in size and shape, lack of contractile material and
      large areas containing nonspecified cytoplasm, lipid droplets, and large glycogen
      filled regions, but no significant differences between the two groups. Gene
      expresssion of the pro-apoptotic genes BAK and BAX was lowered compared to
      expression in 'normal' myocardium. The anti-apoptotic gene BCL-XL was
      significantly more expressed in the 'area of interest' of group II patients than
      in group I patients. CONCLUSIONS: We conclude that in patients with endstage CAD
      myocardial recovery after coronary revascularization can be predicted using DE
      and MRI preoperatively. Myocardial regions without any potential of functional
      recovery show less adaptation (less pronounced myocardial cell hypertrophy), a
      more severe degree of myocardial architecture destruction and a higher degree of
      anti-apoptotic gene expression. We recommend a myocardial biopsy when DE and MRI
      are not favorable in a patient with end stage coronary artery disease referred to
      us with the option of heart transplantation or coronary bypass.

PMID- 15200986
TI  - Impact of clopidogrel in coronary artery bypass grafting.
AB  - OBJECTIVE: Clopidogrel has become the standard of care to prevent thrombotic
      complications following cardiological interventions, in particular intracoronary
      stenting. In addition, patients with aspirin intolerance and those with carotid
      and peripheral vascular disease are also increasingly treated with clopidogrel.
      Platelet inhibition may become a concern for hemostasis in patients treated with
      clopidogrel who need emergency and undelayed surgery. METHODS: We prospectively
      analyzed the intra- and postoperative outcome of 505 consecutive patients who
      underwent isolated CABG and compared two groups: those with clopidogrel exposure
      until 72 h prior to surgery (n = 136) with those without exposition to
      clopidogrel (n = 369). Patients undergoing emergency surgery because of failed
      PTCA and cardiogenic shock, associated valvular surgery, redo-CABG, and those
      with additional platelet IIb/IIIa receptor inhibitor exposure were excluded.
      Patients who received aspirin and/or heparin treatment prior to surgery were not
      excluded. RESULTS: Patients who received clopidogrel had a higher prevalence of
      angina class III or IV (67 vs 39%, P < 0.01), received more often
      revascularization within 48 h (41 vs 14%, P = 0.02), and had received more
      frequently stenting (57 vs 13%). Chest tube drainage was significantly increased
      during the first 24 h following CABG in the group of patients who had clopidogrel
      treatment (1485 vs 780 ml, P = 0.003) These patients also required more
      transfusion of platelets and fresh frozen plasma. Overall re-exploration rate
      because of bleeding was significantly higher in the clopidogrel group (5.9 vs
      1.2%, P < 0.01). Platelets transfused before chest closure had a beneficial
      effect on preservation of the hemostasis. CONCLUSIONS: Clopidogrel exposure 3
      days or less prior to CABG surgery significantly increases the risk of
      postoperative bleeding, the need for perioperative transfusion and the incidence
      of re-exploration. Surgery should be performed using standard heparinization and
      anti-fibrinolytic strategies but aggressive correction of platelets dysfunction
      is required before chest closure.

PMID- 15200987
TI  - Role of troponin I, myoglobin, and creatine kinase for the detection of early
      graft failure following coronary artery bypass grafting.
AB  - OBJECTIVE: The detection of early graft failure following coronary artery bypass
      grafting (CABG) enables immediate reintervention and may significantly limit
      myocardial damage, thus potentially improving outcome. To date, non-invasive
      indicators of early graft failure following coronary surgery are still of
      uncertain diagnostic value. METHODS: In a prospective study, patients following
      isolated CABG with a postoperative serum cardiac troponin I (cTnI) above 20 ng/ml
      or significant ECG-changes underwent acute repeat angiography. cTnI, myoglobin
      (Myo), and creatine kinase (CK) were measured preoperatively and at 1, 6, 12, and
      24 h after aortic unclamping. Peak values of cTnI, Myo, CK and isoenzyme CK-MB
      were determined postoperatively. Receiver operating curves (ROC) for cTnI, Myo
      and CK/CK-MB were constructed at 6, 12, and 24 h after aortic unclamping to
      differentiate between patients with and without early graft failure. Based on
      these curves, the area under curve+/-standard deviation (AUC+/-SD), the
      sensitivity and specificity were calculated. RESULTS: Out of 2078 consecutive
      patients having undergone isolated CABG from January 2001 to April 2003, 55
      fulfilled the inclusion criteria and underwent acute repeat angiography. Early
      graft failure was found in 35 patients (group 1), whereas 20 patients did not
      show graft failure (group 2). CTnI and Myo, but not CK and CK-MB levels were
      significantly increased in group 1 compared to group 2 at 12 and 24 h after
      aortic unclamping. ROC analysis of cTnI, Myo and CK/CK-MB indicated cTnI as the
      best discriminator between the groups with 21.5 ng/ml at 12 h (AUC, 0.82+/-0.06;
      sensitivity, 82%; specificity, 66%) and 33.4 ng/ml at 24 h (AUC, 0.95+/-0.03;
      sensitivity, 98%; specificity, 82%) and Myo with 887 microg/ml at 12 h (AUC,
      0.72+/-0.07; sensitivity, 73%; specificity, 57%) after aortic unclamping. In
      contrast, CK/CK-MB as well as the appearance of ECG-changes could not separate
      between the groups. CONCLUSIONS: cTnI, but not Myo and CK served as a reliable
      marker for the identification of patients with early graft failure following
      CABG.

PMID- 15200988
TI  - Is it better to use the radial artery as a composite graft? Clinical and
      angiographic results of aorto-coronary versus Y-graft.
AB  - OBJECTIVE: We sought to evaluate whether the radial artery (RA) provides the same
      clinical and angiographic results when proximally anastomosed to the aorta or to
      the left internal thoracic artery (ITA) as a composite Y-graft. METHODS: From
      February 1999 to December 2002, 512 patients underwent myocardial
      revascularization using the RA, the left ITA and, when required, the saphenous
      vein. According to the surgeons' preference the RA was proximally anastomosed to
      the aorta [336 patients (65.6%), Ao-Cor group] or to the left ITA as a composite
      Y-graft [176 patients (34.4%), Y-graft group]. There was a significant prevalence
      of three-vessel disease (86.8 versus 73.2%, (P = 0.000) and elderly age (60+/-9
      versus 58+/-8 years, (P = 0.014) in the Y-graft group. RESULTS: Patients in Y
      graft group had longer aortic cross clamp time (P = 0.001), more bypass grafts
      per patient (P < or = 0.001) more arterial bypass grafts per patient (P < or =
      0.001) and more bypass grafts per patient with the RA (P < or = 0.001). There
      were no differences in terms of perioperative outcome. Mean follow-up time was
      27.1+/-11.7 months in 322/333 (96.7%) patients of the Ao-Cor group and 14.9+/
      10.2 in 165/172 (95.9%) patients of the Y-graft group. There was no difference in
      terms of overall survival (P = 0.75) cardiac event-free survival (P = 0.65) RA
      patency rate at postoperative angiography (P = 0.59) and during follow-up (P =
      0.93). A preoperative coronary artery stenosis < or = 70% was related with
      competitive flow (P = 0.000) at postoperative angiography and with RA occlusion
      (P = 0.001) at follow-up angiography. CONCLUSIONS: The RA provides the same
      clinical and angiographic results both as aorto-coronary and composite Y-graft
      with the left ITA. When the RA is used as Y-graft the procedure is more
      technically demanding and a greater number of distal coronary anastomoses is
      possible. RA grafts to targets with stenosis < or = 70% appear to be at risk of
      failure.

PMID- 15200989
TI  - Factors affecting patency of internal thoracic artery graft: clinical and
      angiographic study in 1434 symptomatic patients operated between 1982 and 2002.
AB  - OBJECTIVE: The purpose is to define factors influencing long-term patency of the
      internal thoracic artery (ITA) to optimize the operative strategy. METHODS: 1482
      left internal thoracic artery (LITA) and 636 right internal thoracic artery
      (RITA) symptom-directed angiograms were studied in 1434 patients. Data were
      prospectively collected from patients who had primary coronary artery bypass
      surgery during the period 1982-2002. The mean age of patients was 59 years; 85%
      were male. The mean period from operation to re-angiogram was 80 months. LITA was
      grafted to left anterior descending coronary artery (LAD) in 82% of cases, RITA
      to right coronary artery (RCA) in 40% and circumflex artery in 35% of cases.
      Graft failure was defined as > or =80% stenosis. RESULTS: 96.3% of LITA and 88.1%
      of RITA grafts were patent. No patient variables were significantly associated
      with graft patency (age, gender, diabetes, hypertension, LVEF, NYHA, AMI). Target
      coronary artery was associated with patency of both LITA and RITA grafts with
      maximum patency when grafted to LAD (P = 0.02) RITA had the worst patency to RCA,
      patency for the left system was identical to LITA. Proximal anastomosis to aorta
      (free RITA) had significantly better patency when compared with in situ RITA to
      RCA system (P = 0.005) while similar patency when grafted to left system. ITA
      diameter and target artery diameter were not associated with graft patency.
      Recent operations had better RITA patency (P = 0.03). The interval from operation
      to angiogram was not associated with ITA patency (96% patency for LITA and 88%
      patency for RITA, remained stable when studied at <1, 1-4, 5-9, 10-14 and >15
      years). CONCLUSIONS: Even in a patient cohort that had adverse symptoms,
      excellent LITA and RITA patency was achieved which almost remained constant
      through all time intervals studied.

PMID- 15200990
TI  - Radionuclide study of mid-term left ventricular function after endoventricular
      circular patch plasty.
AB  - OBJECTIVE: Although the early result of endoventricular circular patch plasty
      (EVCPP) has been reported, few are seen about the long-term results. We studied
      left ventricular (LV) function in the early and mid-term periods after EVCPP with
      electrocardiographic-gated single photon emission computed tomography (Gated
      SPECT). METHODS: Consecutive 14 patients with LV asynergy after myocardial
      infarction, who had the EVCPP procedure, were studied by Gated SPECT. Mean age of
      patients was 67+/-10 years. Gated SPECT images were obtained and LV end-diastolic
      volume index (EDVI), LV end-systolic volume index (ESVI) and ejection fraction
      (EF) were studied with QGS(+) program. Gated SPECT study was performed before
      surgery, early (23 days) and mid-term periods (32 months) after surgery. RESULTS:
      EDVI changed significantly from preoperative value to early postoperative value
      (107+/-39 to 72+/-37 ml/m(2), P < 0.01). There was no significant difference
      between early and mid-term postoperative values. ESVI also changed significantly
      from preoperative value to early postoperative value, and from early value to mid
      term postoperative value (78+/-37 to 51+/-34 to 47+/-35 ml/m(2), P < 0.05,
      respectively). EF increased significantly from preoperative value to early
      postoperative value, and from early value to mid-term postoperative value (30+/
      10 to 35+/-13 to 45+/-18%, P < 0.05, respectively). CONCLUSIONS: Direct influence
      of EVCPP brought significant improvement of LV function in early period. Further
      decrease of ESVI and increase of EF were noticed from early period to mid-term
      period. This result suggest that the effect of EVCPP sustains long and yields
      reverse LV remodeling.

PMID- 15200991
TI  - Aortoventriculoplasty and left ventricle function: long-term follow-up.
AB  - OBJECTIVE: Depressed cardiac function after aortoventriculoplasty is well known
      during the postoperative period. Little data exist concerning the long-term
      follow-up. The aim of this study is to determine whether septal incision has any
      permanent effect on the left ventricle function. METHODS: From 1988 to 2002, 45
      patients received aortic mechanical prosthesis. These patients were divided into
      two groups. Group A consisted of 26 patients 5-18 years old, who underwent simple
      aortic valve replacement. Group B consisted of 19 patients 4-20 years old, who
      underwent the Konno procedure. Systolic and diastolic functions of the left
      ventricle were analyzed using echocardiography. For the systolic function, the
      following parameters were assessed: pressure gradient between left ventricle and
      ascending aorta, shortening and ejection fraction of the left ventricle. For the
      diastolic function, left ventricle-filling parameters were assessed: ratio of
      early to late filling velocity, deceleration slope of the early filling velocity
      and left ventricular isovolumetric relaxation time. Furthermore the percentage
      fraction of the aortic valve index (AOVI%) was calculated and compared between
      these two groups. RESULTS: After the surgery in group A, AOVI% dropped from 110+/
      21 to 98+/-11%, while in group B it increased from 82+/-16 to 114+/-11%. As a
      result a higher residual pressure gradient across the aortic valve was noted in
      group A: 21.26+/-15 as compared to 11.17+/-5 mmHg in group B. A mean pressure
      above 30 mmHg appeared in group A 2 years after the surgery, while in group B
      this was obtained after 6 years. As for the diastolic function no significant
      difference was noted between these two groups. Overall there was one late death
      in group A, and in group B two early deaths, two reoperations because of
      excessive drainage and in two patients permanent pacemakers had to be implanted.
      CONCLUSIONS: Improvement of the systolic function after the surgery was noted in
      both groups. In patients with low AOVI%, postsurgical pressure gradient, either
      residual or recurrent, appeared during the follow-up. As for the septal incision,
      it may have some transient effects on the left ventricle function in the
      postoperative period, but no permanent sequelae were observed in the long-term
      follow-up.

PMID- 15200992
TI  - Magnetic resonance mapping of transplanted endothelial progenitor cells for
      therapeutic neovascularization in ischemic heart disease.
AB  - OBJECTIVE: Intramyocardial transplantation of endothelial progenitor cells (EPCs)
      has been previously correlated with significant augmentation of vascularity and
      improvement of left ventricular function following myocardial ischemia. However,
      precise intramyocardial localization of the transplanted cells and the extent of
      in situ cell migration are unknown. We present a novel technique using magnetic
      resonance imaging (MRI) to localize transplanted EPCs in ischemic hearts.
      METHODS: CD34-positive cells were isolated from human peripheral blood by
      magnetic bead selection: CD34-positive cells adhere to CD34-negative antibody
      coated magnetic beads, while CD34-negative cells do not. All cells were labeled
      with fluorescent DiI-dye for histological localization. CD34-positive cells or
      CD34-negative cells (105, 1 x 106 and 2 x 106 cells) were transplanted into non
      ischemic (n = 6) or ischemic myocardium (n = 2) of Sprague-Dawley rats. Rats were
      sacrificed 24 h after cell transplantation. The resected hearts were imaged ex
      vivo using 3 and 8.5 T magnets. Morphological correlation between the MRI
      findings and fluorescent microscopy for identification of retained CD34-positive
      cells was evaluated. RESULTS: CD34-positive cells were identified as areas of low
      signal intensity on T2*-weighted images within the myocardium. These areas
      increased in size with the gradual increase in the echo time due to
      susceptibility effect. The extent of the low signal intensity at a given echo
      time was proportional to cell dosage. No areas of low signal were identified in
      the CD34-negative cell transplanted hearts. Histological localization of DiI
      labeled CD34-positive cells documented a direct anatomic correlation with the
      localization of transplanted cells on the MRI images. CONCLUSIONS: Magnetically
      labeled EPCs transplanted for therapeutic neovascularization in myocardial
      ischemia can be visualized with ex vivo MRI at high-field strengths.

PMID- 15200993
TI  - Innovative pulmonary preservation of non-heart-beating donor grafts in
      experimental lung transplantation.
AB  - OBJECTIVE: Lung transplantation is limited by scarcity of donor organs. Lung
      retrieval from non-heart-beating donors (NHBD) might have the potential to extend
      the donor pool and has been reported recently. However, no studies in NHBD exist
      using the novel approach of retrograde preservation with Perfadex solution.
      METHODS: Asystolic heparinized pigs (n = 5/group) were continuously ventilated
      for 90, 180 or 300 min of warm ischemia. Lungs were then retrogradely preserved
      with Perfadex and stored at 4 degrees C in inflation. After 3 h of additional
      cold ischemia, left lung transplantation was performed. Hemodynamics,
      pO(2)/F(i)O(2) and dynamic compliance were monitored for 5 h. Intrapulmonary lung
      water was determined by both global wet-to-dry lung weight ratio (W/D ratio) and
      standard stereological examination of relative volume fractions of intraalveolar
      edema. All results were compared to sham-operated controls and to lungs obtained
      from standard heart-beating donors after retrograde preservation with Perfadex
      and 27 h of cold ischemia. Statistics comprised ANOVA analysis with repeated
      measures and Mann-Whitney tests. RESULTS: No mortality was observed. During flush
      preservation of NHBD lungs, continuous elimination of blood clots via the
      pulmonary artery was observed. Oxygenation, compliance, intraalveolar edema
      fraction and W/D ratio were comparable between groups, whereas PVR was
      significantly lower in sham-controls. CONCLUSIONS: Use of NHBD lungs is feasible
      and results in similar postischemic outcome when compared to sham-controls and
      standard preservation procedures even after 5 h of pre-harvest warm ischemia.
      Especially, the NHBD with high-risk constellations for intravascular coagulation
      might benefit from retrograde preservation by elimination of thrombi from the
      pulmonary circulation. This innovative technique might also be considered in
      situations, where brain-dead organ donors become hemodynamically unstable prior
      to onset of organ harvest. Further trials with longer warm and cold ischemic
      periods are initiated to further elucidate this promising approach of donor pool
      expansion.

PMID- 15200995
TI  - Pulmonary preservation with LPD and Celsior solution in porcine lung
      transplantation after 24 h of cold ischemia.

PMID- 15200994
TI  - Pulmonary preservation with LPD and celsior solution in porcine lung
      transplantation after 24 h of cold ischemia.
AB  - OBJECTIVE: Pulmonary preservation for transplantation is associated with ischemia
      reperfusion injury resulting in endothelial cell and surfactant dysfunction. The
      purpose of the study was to compare two extracellular type solutions, low
      potassium dextrane (LPD) and Celsior in their ability of ameliorating lung
      ischemia reperfusion injury. METHODS: In 12 donor pigs, the left lung was
      perfused with either LPD (n = 6) or Celsior (n = 6) solution. After 24 h cold
      storage, the lungs were transplanted into 12 recipient animals. After reperfusion
      of the left lung, the right pulmonary artery and bronchus were clamped.
      Bronchoalveolar lavage fluid (BALF) was obtained before the surgical procedure
      and 2 h after reperfusion. Surfactant activity was measured from BALF using a
      pulsating bubble surfactometer. Hemodynamic and respiratory parameters were
      assessed in 30-min intervals for 7 post-operative hours. RESULTS: In both study
      groups two of six animals died from severe ischemia reperfusion injury, thus
      survival did not differ between groups. Rise of pulmonary vascular resistance
      index (P = 0.01) and sequestration of neutrophiles (P = 0.08) was less pronounced
      in Celsior group when compared to LPD animals. A difference in surfactant
      activity between both groups was not evident after 2 h of reperfusion.
      CONCLUSIONS: Both solutions might provide safe pulmonary preservation for 24 h of
      cold ischemia. While surfactant activity was affected to the same extent in both
      groups, Celsior solution provided slightly superior endothelial preservation.

PMID- 15200996
TI  - Results of video-assisted thoracic surgery for stage I/II non-small cell lung
      cancer.
AB  - OBJECTIVE: The best indicators for VATS are not well known. Therefore, we review
      here a series of patients who underwent VATS lobectomy and segmentectomy at our
      hospital, and we attempt to identify the factors that influence the survival of
      VATS patients and the backgrounds of such patients. METHODS: A thoracoscopic
      curative approach was attempted in 140 patients (100 lobectomy, 40 segmentectomy)
      from January 1994 to December 2002. We retrospectively reviewed the VATS patients
      with non-small cell lung cancer (NSCLC). All patients were subject to lobectomy
      or segmentectomy, including dissection of hilar and mediastinal lymph nodes that
      were in pathological stage (p-Stage) I or II. Our VATS approach was a hybrid
      technique, employing three ports and a small (7 cm diameter) utility thoracotomy
      to allow access for the instrument and a view. RESULTS: The Kaplan-Meier
      probabilities of survival at 5 years were VATS, 77.3%. According to a univariate
      analysis of survival curves, the significant prognostic factors (P < 0.05) in the
      patients with VATS in p-Stage I and II were gender, type of histology, and T
      factor. In addition, the grades of differentiation, surgical procedure (lobectomy
      vs. segmentectomy), and extent of metastasis to the hilar lymph node (N0 vs. N1)
      in VATS were not found to be significant prognostic factors. A multivariate
      prognostic factor in VATS showed that the histologic cell type, gender, and T
      factor were predominant. All of the VATS cases that included these three
      favorable factors (adenocarcinoma, T1, female) were alive. CONCLUSION: Stringent
      selection of candidates for VATS in NSCLC at pathological stages I and II could
      be an acceptable and valuable approach.

PMID- 15200997
TI  - The significance of associated pre-invasive lesions in patients resected for
      primary lung neoplasms.
AB  - OBJECTIVE: To evaluate the prevalence and clinico/prognostic significance of the
      presence of pre-invasive lesions in patients resected for primary lung neoplasm.
      METHODS: From 1993 to 2002, 1090 patients received resection for primary lung
      carcinomas. Of these, 73 presented an associated pre-invasive lesion in the
      surgical specimen distant from the primary tumour. Classification of pre-invasive
      lesions included Atypical Adenomatous Hyperplasia (AAH); Carcinoma In Situ (CIS)
      either diffuse or at the bronchial resection margin; Diffuse Idiopathic Pulmonary
      Neuroendocrine Cell Hyperplasia (DIPNECH). Correlation between the presence of
      pre-invasive lesion and the following variables were calculated by logistic
      regression analysis: sex, age, median tumour size, histology, histologic
      differentiation, histologic evidence of invasiveness (vascular and perineural
      invasion), peritumoural lymphocytic infiltrate, pTNM, lobe location, history of
      previous malignancy. Survival rates were computed using Kaplan-Meier method and
      survival differences with the total patient population of resected lung
      carcinomas were tested using the log-rank method. RESULTS: There were 28 AAH, 42
      CIS (5 at the bronchial resection margin) and 3 DIPNECH. Histology of the primary
      tumor included bronchioloalveolar carcinoma (9 patients), adenocarcinoma (19),
      squamous cell carcinoma (39), typical carcinoid tumour (3) and adenosquamous
      carcinoma (3). Overall prevalence of pre-invasive lesion was 6.7%. A strong
      correlation was found between the presence of AAH and the co-existence of either
      adenocarcinoma, bronchioloalveolar carcinoma or mixed adenocarcinoma-containing
      tumours (P = 0.00002) between CIS and squamous cell carcinoma (P = 0.009) and
      between DIPNECH and carcinoid tumours (P = 0.001). No significant correlation was
      found between the presence of any type of pre-invasive lesion and sex, age,
      median tumour size, histologic differentiation, histologic evidence of
      invasiveness, pTNM, lobe location and history of previous malignancy or the
      probability to develop a second primary lung carcinoma in the remaining lobe(s)
      after resection. Survival rates in the patients with AAH and CIS were not
      significantly different from those of patients without pre-invasive lesion (P =
      0.3 and P = 0.1). CONCLUSIONS: Associated pre-invasive lesions in patients
      resected for primary lung neoplasms are not infrequent. AAH is associated with
      adenocarcinoma, CIS with squamous cell carcinoma, DIPNECH with typical carcinoid
      tumours. Our experience indicates that in these patients histology, stage
      distribution and survival do not differ from the total population of resected
      patients with lung tumors.

PMID- 15200999
TI  - A retrospective comparative study of surgery followed by chemotherapy vs. non
      surgical management in limited-disease small cell lung cancer.
AB  - OBJECTIVE: The role of surgery in limited SCLC is still a matter of controversy.
      Even though the response rates to chemotherapy are very high, prognosis of SCLC
      patients has remained poor with a median survival of only 12-14 months for
      limited disease. High incidence of local relapses after chemotherapy in limited
      stage SCLC led to reassessment of the role of local treatment in the
      multimodality management of this tumor. METHODS: We performed retrospective
      comparative analysis of survival in a series of 134 limited-stage SCLC patients
      treated between 1984 and 1996 with either complete resection followed by
      chemotherapy (67 patients), or with conventional non-surgical management (67
      patients). In all patients who underwent resection, the diagnosis of SCLC was
      established only postoperatively. The control (non-surgical) group was selected
      using 'pair-matched case-control' methodology, out of 176 limited-stage patients
      potentially suitable for surgery (i.e. with no pleural effusion or other local
      advancement, no supraclavicular lymph node involvement and good performance
      status), but treated without resection. The major prognostic factors were well
      balanced between these two groups. Total series included 109 males and 25
      females, 20 patients with T1 and 114 patients with T2 disease, 51 N0, 43 N1 and
      40 N2 disease. RESULTS: Median survival in patients treated with and without
      surgery was 22 months and 11 months, respectively, (P < 0.001). The two-year and
      five-year survival probabilities were 43 and 27%, respectively, in the surgical
      group, and 17 and 4%, respectively, in the non-surgical group. Subset analysis
      confirmed significantly longer survival with surgery in all T and N categories,
      except for N2 disease. Local relapse occurred in 15 and 55% of patients treated
      with and without surgery, respectively, (P < 0.001). Distant relapse
      probabilities were similar in both groups (36 and 40%, respectively). The most
      common site of metastases in the entire series was brain, followed by liver,
      lymph nodes, bone, lung and skin. CONCLUSIONS: Our results suggest a possible
      role of surgery in limited-stage SCLC. Thus, a randomised study addressing this
      issue seems to be justified.

PMID- 15200998
TI  - Chemotherapy for patients with non-small cell lung cancer: the surgical setting
      of the Big Lung Trial.
AB  - OBJECTIVES: The non-small cell lung cancer (NSCLC) meta-analysis suggested a
      survival benefit for cisplatin-based chemotherapy when given in addition to
      surgery, radical radiotherapy or 'best supportive care'. However, it included
      many small trials and trials with differing eligibility criteria and chemotherapy
      regimens. The aim of the Big Lung Trial was therefore to run a large pragmatic
      trial to confirm the survival benefits seen in the meta-analysis. METHODS: In the
      surgery setting, a total of 381 patients were randomised to chemotherapy (C, 192
      patients) or no chemotherapy (NoC, 189 patients). C was three 3-weekly cycles of
      cisplatin/vindesine, mitomycin/ifosfamide/cisplatin,
      mitomycin/vinblastine/cisplatin or vinorelbine/cisplatin. RESULTS: Chemotherapy
      was given before surgery in 3% of patients whilst 97% received adjuvant
      chemotherapy. Baseline characteristics were: median age 61 years, 69% male, 48%
      squamous cell, 93% WHO PS 0-1, 27% stage I, 38% stage II, and 34% stage III.
      Complete resection was achieved in approximately 95% of patients. In the C group,
      13% received no chemotherapy, 21% one or two cycles, and 64% all three cycles of
      their prescribed chemotherapy (60% of the latter with no delays or modification).
      30% had grade 3/4 toxicity, mainly haematological, nausea/vomiting and
      neutropenic fever, and six patients were reported as having a treatment-related
      death. 198 (52%) of patients have died, but there is currently no evidence of a
      benefit in overall survival to the C group: HR 1.02 (95% CI 0.77-1.35), P =
      0.90). CONCLUSIONS: This trial has failed to observe a survival benefit with
      adjuvant chemotherapy following complete resection of stage I-III NSCLC. However,
      the hazard ratio and 95% confidence intervals are consistent with the previously
      reported meta-analysis and two large recently reported trials, which suggest a
      small survival benefit with cisplatin-based chemotherapy.

PMID- 15201000
TI  - Indications and results of completion pneumonectomy.
AB  - OBJECTIVES: Completion pneumonectomy (CP) is widely known to be associated with a
      high morbidity and mortality. However, in certain instances, CP offers the only
      chance for a cure. The results of the following three groups were investigated:
      progressive or recurrent benign disease, recurrence of a malignant tumour and
      complication after lung resection. METHODS: Between January 1986 and April 2003,
      525 patients underwent pneumonectomy, 86 of these being completion
      pneumonectomies (16.4%). Six patients suffered from a progression or recurrence
      of a benign disease, 41 patients had a recurrence of a malignant tumour (local
      recurrence, secondary carcinoma and recurrent metastases) and 39 patients had a
      complication after lung resection. Among patients with a complication, the
      indication for CP was either an emergency or urgent condition. Right CP was
      carried out in 48 cases and left CP in 38. RESULTS: The overall 30-day mortality
      was 20.2, 0% in the group with benign disease, 10% in the group with a recurrent
      malignant tumour and 33.3% in the group with a complication after lung resection.
      The 30-day mortality of CP was significantly higher (P = 0.014) on the right side
      (29.8%) than on the left side (7.7%). Differentiation between emergency and
      urgent indications resulted in 30-day mortalities as follows: 54 and 23%,
      respectively. This difference is significant (P = 0.002). The 30-day mortality
      for patients with anastomotic or stump insufficiency was 41% (P = 0.002). Five
      year survival of all patients was 28% and in the group of patients with a
      complication after lung resection 32%. CONCLUSIONS: Lethality of CP remains high,
      especially after CP for a complication performed in an emergency condition.
      Possible risk factors are right side of operation, CP performed in an emergency
      condition and CP for anastomotic or stump insufficiency, either or not involving
      sepsis. However, considering the long-term survival, CP is certainly justified.

PMID- 15201001
TI  - Reconstruction of the chest wall and the diaphragm using the inverted Y Marlex
      methylmethacrylate sandwich flap.
AB  - OBJECTIVE: Chest wall resection and reconstruction is a demanding operation
      involving a dedicated team. It can be performed with minimal mortality with
      excellent cosmetic and functional results using various substitutes. However,
      reconstructing the lower costal margin with diaphragmatic resection is a
      challenging prospect needing special techniques. METHODS: We describe a technique
      of reconstructing the chest wall defect involving the lower costal margin and
      diaphragm with an Inverted Y Marlex Methylmethacrylate Sandwich Flap. RESULTS:
      There were no intra operative or postoperative complications and immediate
      extubation was possible in all six patients without the need for postoperative
      ventilation. There was a good functional and cosmetic result in all the patients.
      CONCLUSIONS: This is an easy and safe technique resulting in a stable and
      satisfactory reconstruction after large antero-lateral full-thickness chest wall
      resections involving the diaphragm.

PMID- 15201002
TI  - Surgical treatment of Pancoast tumours.
AB  - Due to its localisation in the apex of the lung with invasion of the lower part
      of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate
      ganglion, a superior sulcus tumour causes characteristic symptoms, like arm or
      shoulder pain or Horner's syndrome. If rib invasion is the only feature, lysis of
      the rib must be evident on the chest radiograph; otherwise the tumour cannot be
      defined as a Pancoast tumour. It is important to adequately stage the tumour,
      because staging significantly influences survival. Survival is better for T3 than
      T4 tumours and mediastinal lymph node involvement has been found to be a negative
      prognostic factor. Also Horner's syndrome and incompleteness of resection worsen
      survival. The management of superior sulcus tumours has evolved over the past 50
      years. Before 1950 it was considered to be inoperable and uniformly fatal. Shaw
      and Paulson introduced combined modality treatment and for many years, this
      combination of radiotherapy and surgery was the treatment of choice with a mean 5
      year survival of approximately 30%. Postoperative radiotherapy or brachytherapy
      does not improve survival in patients with complete or incomplete resection. The
      tumour can be resected through the classic posterior Shaw-Paulson approach or the
      newer anterior transcervical approach, introduced by Dartevelle. This method
      facilitates better exposure of the extreme apex of the lung, brachial plexus and
      subclavian vessels. Regarding the extent of pulmonary resection, en bloc
      resection of the involved ribs with a lobectomy is recommended. Recent
      multimodality studies, involving chemoradiotherapy and surgical resection, show
      promising results regarding completeness of resection, local recurrence and
      survival, provided that appropriate staging has been carried out. However,
      careful patient selection and adequate perioperative management with protection
      of the bronchial stump or anastomosis are important to achieve reasonable rates
      of morbidity and mortality. As brain metastases remain one of the most common
      forms of relapse, further studies are needed to examine the role of prophylactic
      cranial irradiation in patients with complete resection. Also the addition of
      other chemotherapy agents or biologic agents such as angiogenesis inhibitors or
      tyrosine kinase inhibitors gives a new perspective in the treatment of Pancoast
      tumours.

PMID- 15201003
TI  - Recurrent chest wall haemangioma -- 'A vascular lake'.

PMID- 15201004
TI  - Ectopic mediastinal thyroid adenoma.

PMID- 15201005
TI  - Bronchial artery aneurysm.

PMID- 15201006
TI  - Delayed localised subcutaneous emphysema following sternal repair.

PMID- 15201007
TI  - Posterior mediastinal lesion--aneurysm of azygos vein.

PMID- 15201008
TI  - Hydatid cyst of the cardiac interventricular septum.

PMID- 15201009
TI  - Right atrial surgery with unsnared inferior vena cava.
AB  - Right atrial procedures require snaring the venous cannulas to prevent air
      entrapment in the venous line. In particular situations with complex congenital
      morphology and/or presence of severe pericardial adhesions the right atrial
      opening without the inferior vena cava cannula in the surgical field and without
      dissecting and snaring the inferior vena cava itself, might substantially
      facilitate the surgical technique, provided an adequate venous drainage is
      assured to avoid flow reduction or circulatory arrest. In several patients with
      congenital or acquired heart disease with potentially complicated venous
      drainage, like extracardiac Fontan procedure and tricuspid valve replacement,
      cardiopulmonary bypass was conducted either on normothermia (congenital lesions)
      or with mild hypothermia (acquired disease), with 3 l/min per m(2) flow index and
      venous drainage through femoral vein cannulation. The right atrium was opened
      without snaring the inferior vena cava, never provoking reduction of the venous
      drainage nor air locks in the venous line. This approach substantially enhanced
      the surgical exposure and therefore facilitated the operative technique without
      any negative consequence to the patients. Right atrial surgery on cardiopulmonary
      bypass without direct cannulation and snaring of both superior and inferior vena
      cava is feasible without flow reduction for surgeons taking care of both
      congenital and acquired cardiac lesions.

PMID- 15201010
TI  - Endovascular repair for multiple Salmonella mycotic aneurysms of the thoracic
      aorta presenting with Cardiovocal syndrome.
AB  - Salmonella mycotic thoracic aortic aneurysm is a rare but life-threatening
      condition. We report a 59-year-old man with two Salmonella mycotic thoracic
      aortic aneurysms, presented with fever and chills associated with hoarseness due
      to left vocal cord palsy (Cardiovocal syndrome). Successful endovascular repair
      was performed using two Talent thoracic stent-graft devices deployed separately
      to cover the two mycotic aneurysms. Subsequent computed tomography at 12 months
      after the operation confirmed exclusion of the two pseudoaneurysms with no
      endoleak. With potent antibiotics and careful surveillance program, endovascular
      repair is a possible alternative to conventional open surgery in the management
      of mycotic thoracic aortic aneurysms, especially in high-risk patients.

PMID- 15201011
TI  - Endovascular stent-graft for thoracic aorta aneurysm caused by Salmonella.
AB  - We describe the placement of an endovascular stent-graft in a patient with
      mycotic aneurysm of the descending thoracic aorta caused by Salmonella.
      Endovascular grafting combined with antibiotic therapy in thoracic mycotic
      aneurysms might represent an alternative to conventional surgery in patients with
      high operative risk.

PMID- 15201012
TI  - Treatment of acute heart failure in an infant after cardiac surgery using
      levosimendan.
AB  - An infant, 2 months old, underwent cardiac surgery because of congenital heart
      defects and pulmonary hypertension. Surgery was performed in hypothermia and
      cardiac standstill. On the second day after surgery the infant had to be
      resuscitated due to a combination of acute left-ventricular failure, pulmonary
      vascular hypertension and a slight right-to-left-shunt. A breakthrough in the
      treatment was achieved by using levosimendan to improve left-ventricular function
      and to decrease vascular resistance.

PMID- 15201013
TI  - Clopidogrel before coronary artery surgery: bleeding or no bleeding?

PMID- 15201015
TI  - Which is better for treatment of mediastinitis following heart surgery, omental
      or muscle flap transfer?

PMID- 15201017
TI  - Necessity of needle wire localization during video assisted thoracic surgery for
      patients with solitary pulmonary nodule.

PMID- 15201019
TI  - Biopsy of hand, wrist, and forearm tumors.
AB  - This article describes three biopsy methods currently used for treating masses
      arising in the hand, wrist, and forearm: open biopsy, fine needle aspiration, and
      core needle biopsy. The forearm, wrist, and hand comprise a complex and diverse
      anatomic region, and biopsy is emphasized as the most important element in the
      diagnosis of the musculoskeletal tumor. Biopsy methods for assessing true
      neoplasms, bony protuberances, cysts,infection and abscesses, foreign bodies,
      reactive granulomas, tenosynovial proliferation,and skin and fascial lesions are
      discussed.

PMID- 15201020
TI  - Evaluation and staging of musculoskeletal neoplasia.
AB  - Musculoskeletal neoplasia are rare and can present in a highly variable fashion.
      Maintaining an index of suspicion for the presence of neoplasia is important. A
      standard approach to evaluation with history, physical, and appropriate imaging
      studies is mandatory. This information then can be synthesized to properly stage
      the lesion, which in turn facilitates an appropriate treatment plan. This article
      discusses the systematic approach to the evaluation and staging of
      musculoskeletal lesions.

PMID- 15201021
TI  - Principles of bone and soft tissue imaging.
AB  - Tumors involving the upper extremity are common. Although there are a wide
      variety of lesions that may occur in the hand and wrist, certain lesions have a
      predilection for this location. This article highlights the spectrum of imaging
      modalities available for the evaluation of upper extremity tumors, providing
      guidelines for optimum selection of radiologic examinations while emphasizing the
      fundamental principles inherent to tumor imaging.

PMID- 15201022
TI  - Principles of limb salvage surgery of the upper extremity.
AB  - The goals of limb salvage surgery in the upper extremity are to achieve resection
      of the tumor and preserve hand function without the risk for local recurrence.
      Historically, amputation was the treatment of choice for a neoplasm of the hand,
      wrist, and forearm, but limb-sparing procedures have become feasible largely
      because of advances in diagnostic imaging, reconstructive microsurgery, and
      adjuvant radiotherapy and chemotherapy. Because preservation of hand function,
      even modest levels thereof, is clearly superior to amputation from a functional
      standpoint, the authors review the principles of limb salvage in this article.

PMID- 15201023
TI  - Soft tissue reconstruction following tumor resection in the hand.
AB  - With advances in diagnosis, staging, imaging, and adjuvant chemo- and
      radiotherapy,upper limb salvage surgery has become a realistic option for upper
      limb malignancies. Following an adequate and complete resection, reconstruction
      of ensuing defects consequently has become an area of increasing importance. Many
      options are available,including primary closure, skin grafting, local soft tissue
      flaps, regional pedicle and island flaps, free tissue transfer, composite free
      tissue transfer, allografts, endoprostheses,and tendon, nerve, or arterial
      grafting. Form, function, and cosmetic outcome influence surgical decision
      making, as do characteristics of the patient, tumor, and involved site.

PMID- 15201024
TI  - Free vascularized bone transfer in limb salvage surgery of the upper extremity.
AB  - Salvage of the upper extremity following tumor resection may require
      reconstruction of massive bone defects. This more commonly results from malignant
      bone tumors, but defects requiring reconstruction also may occur following
      resection of locally aggressive benign tumors. Examples include osteosarcoma,
      chondrosarcoma, Ewing sarcoma, giant cell tumor, and certain soft tissue sarcomas
      invading bone. Obtaining satisfactory results using conventional bone grafting
      techniques is at best challenging when defects of substantial size are
      encountered. Free vascularized bone grafting procedures provide the appealing
      option of transferring living bone based on a vascular pedicle.

PMID- 15201025
TI  - Amputations of the hand and upper extremity in the management of malignant
      tumors.
AB  - The primary goal of treatment for malignant bone and soft tissue tumors of the
      hand and upper extremity is an oncologic cure. The secondary goal is maintenance
      of function. Despite recent advances in chemotherapy and radiation techniques,
      amputation still provides a means for achieving surgical cure for some bone and
      soft tissue sarcomas. A well planned amputation with attention to level, soft
      tissue closure, muscle transfer as needed, and nerve handling combined with early
      fitting of modern prosthetic devices provides patients with a rapid return to
      normal activity. This article reviews the general principles and specific
      techniques of amputation in the patient with an upper extremity malignancy.

PMID- 15201026
TI  - Multimodality treatment of upper extremity bone and soft tissue sarcomas.
AB  - Management of soft tissue sarcomas requires a multidisciplinary approach with the
      help of a surgical-orthopedic oncologist, medical oncologist, radiation
      oncologist, pathologist, hand surgeon, and physiatrist/physical therapist. The
      indication and benefits of chemotherapy and radiation therapy for soft tissue
      sarcomas remain somewhat controversial.However, the encouraging results of
      studies using the most active chemotherapeutic agents gives credence to
      considering neoadjuvant chemoradiation therapy or postoperative adjuvant
      chemotherapy in this group of patients.

PMID- 15201028
TI  - Expression of apoptosis-related gene mRNAs in feline T-cells infected with feline
      immunodeficiency virus (FIV).
AB  - In the present study, full length of feline bax, bcl-2, bcl-xL and caspase 3
      genes were sequenced and the expression of these mRNAs were also investigated in
      FIV-infected lymphocytes. The full length cDNA sequence of bax (646 bp), bcl-2
      (1423 bp), bcl-xL (1163 bp) and caspase 3 genes (1208 bp) contained a single open
      reading frame of 579 bp coding 193 amino acids, 708 bp coding 236 amino acids,
      702 bp coding 234 amino acids and 834 bp coding 278 amino acids, respectively.
      Number of apoptotic Kumi-1 cells gradually increased after FIV infection and
      approximately 70% were apoptotic and 30% were viable in the cells infected with
      FIV after 8-day incubation, though approximately 80% were non-apoptotic and 20%
      were dead in non-infected cells. The expression of bcl-2 mRNA in lymphocytes of
      established cell line was increased by FIV. The amounts of mRNAs of bax, caspase
      3 and bcl-xL in FIV-infected cells were not different from those in uninfected
      control cells.

PMID- 15201030
TI  - Different approaches to the vaccination of free ranging village chickens against
      Newcastle disease in Qwa-Qwa, South Africa.
AB  - The aim of this study was to develop a strategy to control Newcastle disease (ND)
      in free ranging village chickens using the Nobilis ND Inkukhu vaccine (Intervet
      South Africa). The study was conducted at Thibella village in Qwa-Qwa, South
      Africa from April 2001 to October 2002. Three different routes of vaccination
      (administration via eye-drop, drinking water and feed) were investigated. The
      haemagglutination inhibition (HI) test was conducted monthly in order to measure
      the antibody response of village chickens after immunization against Newcastle
      disease. Using a South African isolate of velogenic ND virus, challenge trials
      were conducted to determine the efficacy of the vaccine. A questionnaire was
      provided to evaluate perceptions of farmers on vaccinations. The eye-drop
      vaccination route produced the highest HI titres ranging between 2.7 and 4.4,
      followed by the drinking water vaccination route with titres ranging between 2.3
      and 4.0. The lowest titres were from the feed vaccination route which ranged
      between 1.6 and 3.0. Following the challenge, the entire control group died on
      the third and fourth day after infection. However, 70% of the chickens immunized
      by using either the eye-drop or drinking water route survived the challenge. Only
      20% of the chickens from the group immunized through the feed route survived.
      Evidently both the eye-drop and drinking water routes were efficient in
      preventing disease. Necropsies showed that vaccinated chickens had mild lesions
      whilst control chickens had severe lesions compatible with Newcastle disease. The
      efficacy of the vaccine using either of the routes can be enhanced by
      administration of booster vaccinations at 3-month intervals during the first year
      of a vaccination campaign and then at 6-month intervals from the second year
      onwards. The majority of the owners indicated that they would prefer to vaccinate
      their flocks using the drinking water route.

PMID- 15201029
TI  - Genetics and geographical variation of porcine reproductive and respiratory
      syndrome virus (PRRSV) in Thailand.
AB  - The Thai isolates of porcine reproductive and respiratory syndrome virus (PRRSV)
      were obtained from the Chulalongkorn University-Veterinary Diagnostic Laboratory
      (CU-VDL). Virus isolation was confirmed by immunoperoxidase monolayer assay
      (IPMA) using SDOW-17. The virus genotype was determined using nested multiplex RT
      PCR (nm RT-PCR) of ORF 1b. The nm RT-PCR was able to detect at least 10TCID50/ml
      of PRRSV. Of 137 Thai isolates, 66.42% belonged to the European (EU) genotype and
      33.58% to the North American (US) genotype. ORF5 products of the eight US strains
      (00CS1, 01NP1, 01UD6, 02CB13, 02KK1, 02PB1, 02SP2 and 02SP3) and the six EU
      strains (01CB1, 01RB1, 02BR1, 02CB12, 02SB2 and 03RB1) were sequenced for genetic
      variation analysis. The US strains of the Thai isolates are clustered within the
      same group and are more closely related to the IAF-EXP91 from Canada (89-90%
      nucleotide identity), whereas the EU strains were very similar to the EU
      prototype, Lelystad virus (87-97.5% nucleotide identity). The ORF5 nucleotide
      identities within the US genotype tested in this study compared to the US
      prototype, VR-2332 varied from 83.7 to 85.2%, whereas 83.5-85.5% amino acid
      identities were found. Based on the phylogenetic tree, each pair of the Thai
      isolates (01NP1 and 02KK1, 00CS1 and 01UD6, and 01CB1 and 01RB1) was identical
      despite they were collected from different provinces. Therefore, there was no
      geographic influence on the spreading of PRRSV in Thailand. Interestingly, 02CB12
      (EU genotype) shared over 99% similarity of the ORF5 nucleotide sequence and
      98.6% of amino acid identity with the European vaccine, Porcillis (AF378819).
      However, modified live virus vaccines for PRRSV have not yet been used in the
      swine population in Thailand. The results suggested that both US and EU genotypes
      exist in Thailand, genetic variation does occur in both genotypes, and the
      sources of the viruses appear to be from Canada and Northern Europe,
      respectively. In addition, the spreading of PRRSV in Thailand might be due to
      introducing infected replacement pigs or infected semen into the farm.

PMID- 15201031
TI  - Molecular epidemiology of rabies in Botswana: a comparison between antibody
      typing and nucleotide sequence phylogeny.
AB  - A panel of rabies virus isolates (RABV) endemic within Botswana between 1988 and
      1992 have been typed by anti-nucleocapsid monoclonal antibodies (MAb) into two
      dominant groups. The first associated with the domestic dog (Canis familiaris)
      and the second associated with a range of wildlife species. Using nucleoprotein
      coding sequence data, we have applied molecular phylogenetic techniques to the
      same panel of 35 well-characterised rabies virus isolates from throughout
      Botswana in an attempt to compare both techniques and to further investigate the
      virus/host species relationships within this African country. The results confirm
      that there are indeed two major groups and that these are related primarily to
      biotype. The wildlife-associated biotype appeared more phylogenetically diverse
      and was more commonly isolated in the southeast of the country, with the canine
      associated group dominating the north of the country. In addition, molecular
      phylogeny identified further groupings within both biotypes and a small number of
      isolates, which were not classified by MAb typing, could be assigned to a group.
      During the study period (4 years) there appeared to be little sequence variation
      within groups suggesting that distinct lineages persisted throughout the study
      and that there appears to be little evolutionary pressure on the nucleoprotein
      coding region of the viral genome.

PMID- 15201032
TI  - Protection against very virulent infectious bursal disease virus in chickens
      immunized with DNA vaccines.
AB  - Plasmid DNA vaccines pcDNA-VP2 expressing only VP2 protein and pcDNA-VP243
      expressing VP2, VP4 and VP3 proteins of very virulent infectious bursal disease
      virus (vvIBDV) Korean SH/92 strain were constructed. The expression of viral
      proteins from constructed DNA vaccines was confirmed by an in vitro
      transcription/translation system and transfection in COS-7 cells. To investigate
      the protective efficacy of these DNA vaccines, 2-week-old chickens were injected
      intramuscularly and intraperitoneally with pcDNA-VP2 and pcDNA-VP243 twice at 2
      week intervals. On week 2 after the second immunization, chickens were orally
      challenged with the vvIBDV SH/92 strain and observed for 10 days. Antibodies
      specific to IBDV were not detected by enzyme-linked immunosorbent assay in DNA
      vaccination groups before challenge but were induced after challenge. The
      immunized groups exhibited a higher survival rate and lower bursal atrophy as
      compared with the non-immunized groups after challenge. The survival rates of
      pcDNA-VP243 and pcDNA-VP2 groups were 70 and 50%, respectively, but the survival
      rate of challenge control group was only 10%. In the ConA-induced lymphocyte
      proliferation assay of peripheral blood and splenic lymphocytes, the immunized
      groups showed significantly higher proliferation responses (P< 0.05) than non
      immunized groups. The maintenance of T cell proliferation activity in DNA
      vaccination groups may be closely related to the protection against vvIBDV. These
      results suggest that our plasmid DNA vaccines induced high protective immunity
      against vvIBDV, in which cell mediated immune response rather than humoral immune
      response seemed to contribute to the protection of chickens against vvIBDV
      infection.

PMID- 15201033
TI  - Infection of endothelial cells with Anaplasma marginale and A. phagocytophilum.
AB  - Anaplasma marginale and A. phagocytophilum are obligate intracellular, tick-borne
      pathogens that target erythrocytes and neutrophil granulocytes, respectively.
      Because ticks do not directly tap blood vessels, an intermediate tissue may
      mediate infection of blood cells. We considered that vascular endothelium
      interacts with circulating blood cells in vivo, and could be involved in
      pathogenesis and dissemination of the organisms. We used light and electron
      microscopy and immune labeling to show that A. phagocytophilum invaded rhesus
      (RF/6A), human (HMEC-1, MVEC), as well as bovine (BCE C/D-1b) endothelial cell
      lines, whereas A. marginale infected rhesus and bovine endothelial cells. A.
      marginale formed large intracellular inclusions that appeared smooth and solid at
      first, and subsequently coalesced into discrete granules. A. phagocytophilum
      formed numerous smaller inclusions in each cell. Within 1-3 weeks, the monolayers
      were destroyed, and lysed cultures were diluted onto fresh monolayers. Electron
      microscopy demonstrated uneven distribution of A. marginale inside large
      inclusions, with reticulated forms grouped more tightly than denser cells,
      whereas in A. phagocytophilum individual organisms appeared more evenly spaced.
      Specific polyclonal and monoclonal antibodies both labeled A. marginale and A.
      phagocytophilum in endothelial cells, and oligonucleotide primers complimentary
      to either A. marginale or A. phagocytophilum amplified their expected target from
      these cultures. In conclusion, we demonstrate that relevant microvascular
      endothelium is susceptible to anaplasmas in vitro and may present a link that
      could explain development of the immune response and persistent infection.

PMID- 15201034
TI  - Evaluation of variable number tandem repeat (VNTR) loci in molecular typing of
      Mycobacterium bovis isolates from Ireland.
AB  - Various sets of short tandem repeats such as the exact tandem repeats (ETRs),
      mycobacterial interspersed repetitive units (MIRUs) and variable number tandem
      repeat (VNTR) loci, have recently been described as effective tools in strain
      typing M. tuberculosis complex isolates, representative of global diversity. This
      study extends our previous study, evaluating the discrimination of a further 17
      MIRU_VNTR loci individually and comparing the resolution of published VNTR sets
      and spoligotyping using a panel of 47 local M. bovis field isolates, including
      known epidemiologically linked isolates and 9 M. tuberculosis complex reference
      isolates. Individual loci differed greatly in their discrimination. The
      discriminatory capacity of novel combinations of the most discriminating VNTR
      loci was also assessed. In the panel of 47 M. bovis isolates, 17 unique profiles
      were resolved using VNTR set 1, whilst the MIRUs and ETRs resolved the panel into
      11 and 6 profiles, respectively. A novel combination of 10 highly discriminatory
      VNTRs was determined, which resolved 30 unique profiles. The configuration of a
      multi-locus VNTR-based assay and its ability to provide a flexible, convenient
      and high-resolution genotyping method is discussed. We suggest a panel of VNTR
      markers which may be widely suitable for molecular epidemiological studies of M.
      bovis. However, the number and combination of informative VNTR markers selected
      needs to be determined empirically with reference to locally prevalent strains
      and will depend on the epidemiological study requirements.

PMID- 15201035
TI  - Bidirectional influences between neurons and glial cells in the developing
      olfactory system.
AB  - Olfactory systems serve as excellent model systems for the study of numerous
      widespread aspects of neural development and also for the elucidation of features
      peculiar to the formation of neural circuits specialized to process odor inputs.
      Accumulated research reveals a fine balance between developmental autonomy of
      olfactory structures and intercellular interactions essential for their normal
      development. Recent findings have uncovered evidence for more autonomy than
      previously realized, but simultaneously have begun to reveal the complex cellular
      and molecular underpinnings of key interactions among neurons and glial cells at
      several important steps in olfactory development. Striking similarities in the
      functional organization of olfactory systems across vertebrate and invertebrate
      species allow the advantages of different species to be used to address common
      issues. Our own work in the moth Manduca sexta has demonstrated reciprocal neuron
      glia interactions that have key importance in two aspects of development, the
      sorting of olfactory receptor axons into fascicles targeted for specific
      glomeruli and the creation of glomeruli. Studies in vertebrate species suggest
      that similar neuron-glia interactions may underlie olfactory development,
      although here the roles have not been tested so directly. Similar cellular
      interactions also are likely to play roles in development of some other systems
      in which axons of intermixed neurons must sort according to target specificity
      and systems in which reiterated modules of synaptic neuropil develop.

PMID- 15201036
TI  - Restoring walking after spinal cord injury.
AB  - One of the most obvious deficits following a spinal cord injury is the difficulty
      in walking, forcing many patients to use wheelchairs for locomotion. Over the
      past decade considerable effort has been directed at promoting the recovery of
      walking and to find effective treatments for spinal cord injury. Advances in our
      knowledge of the neuronal control of walking have led to the development of a
      promising rehabilitative strategy in patients with partial spinal cord injury,
      namely treadmill training with partial weight support. The current focus is on
      developing more efficient training protocols and automating the training to
      reduce the physical demand for the therapists. Mechanisms underlying training
      induced improvements in walking have been revealed to some extent in animal
      studies. Another strategy for improving the walking in spinal cord injured
      patients is the use of functional electric stimulation of nerves and muscles to
      assist stepping movements. This field has advanced significantly over the past
      decade as a result of developments in computer technology and the miniaturization
      of electronics. Finally, basic research on animals with damaged spinal cords has
      focused on enhancing walking and other motor functions by promoting growth and
      regeneration of damaged axons. Numerous important findings have been reported
      yielding optimism that techniques for repairing the injured spinal cord will be
      developed in the near future. However, at present no strategy involving direct
      treatment of the injured spinal cord has been established for routine use in
      spinal cord injured patients. It now seems likely that any successful protocol in
      humans will require a combination of a treatment to promote re-establishing
      functional connections to neuronal networks in the spinal cord and specialized
      rehabilitation training to shape the motor patterns generated by these networks
      for specific behavioral tasks.

PMID- 15201037
TI  - Characterization of receptors for glutamate and GABA in retinal neurons.
AB  - Glutamate and gamma-aminobutyric acid (GABA) are major excitatory and inhibitory
      neurotransmitters in the vertebrate retina, "a genuine neural center" (Ramon y
      Cajal, 1964, Recollections of My Life, C.E. Horne (Translater) MIT Press,
      Cambridge, MA). Photoreceptors, generating visual signals, and bipolar cells,
      mediating signal transfer from photoreceptors to ganglion cells, both release
      glutamate, which induces and/or changes the activity of the post-synaptic neurons
      (horizontal and bipolar cells for photoreceptors; amacrine and ganglion cells for
      bipolar cells). Horizontal and amacrine cells, which mediate lateral interaction
      in the outer and inner retina respectively, use GABA as a principal
      neurotransmitter. In recent years, glutamate receptors and GABA receptors in the
      retina have been extensively studied, using multi-disciplinary approaches. In
      this article some important advances in this field are reviewed, with special
      reference to retinal information processing. Photoreceptors possess metabotropic
      glutamate receptors and several subtypes of GABA receptors. Most horizontal cells
      express AMPA receptors, which may be predominantly assembled from flop slice
      variants. In addition, these cells also express GABAA and GABAC receptors. Signal
      transfer from photoreceptors to bipolar cells is rather complicated. Whereas
      AMPA/KA receptors mediate transmission for OFF type bipolar cells, several
      subtypes of glutamate receptors, both ionotropic and metabotropic, are involved
      in the generation of light responses of ON type bipolar cells. GABAA and GABAC
      receptors with distinct kinetics are differentially expressed on dendrites and
      axon terminals of both ON and OFF bipolar cells, mediating inhibition from
      horizontal cells and amacrine cells. Amacrine cells possess ionotropic glutamate
      receptors, whereas ganglion cells express both ionotropic and metabotropic
      glutamate receptors. GABAA receptors exist in amacrine and ganglion cells.
      Physiological data further suggest that GABAC receptors may be involved in the
      activity of these neurons. Moreover, responses of these retinal third order
      neurons are modulated by GABAB receptors, and in ganglion cells there exist
      several subtypes of GABAB receptors. A variety of glutamate receptor and GABA
      receptor subtypes found in the retina perform distinct functions, thus providing
      a wide range of neural integration and versatility of synaptic transmission.
      Perspectives in this research field are presented.

PMID- 15201038
TI  - Effects of explicit sway-minimization on postural--suprapostural dual-task
      performance.
AB  - Participants performed a visual search task under immersive visualization
      conditions while standing in open or closed stance. In the combined instruction
      condition, participants were asked to minimize their sway while they performed
      the search task, and in the search-only condition, they were advised that sway
      was not of interest, and they were asked to focus their efforts on performing the
      search task. Regardless of instructions, participants swayed more and made more
      errors as search load increased. Participants also succeeded in reducing their
      sway when asked to do so. While search in closed stance tended to be faster than
      in open stance under search-only instructions, this pattern reversed
      significantly under combined instructions. We suggest that neither the
      facilitatory control hypothesis nor any resource-competition model of postural-
      suprapostural dual-tasking can fully account for the observed interplay of task
      facilitation and task-interference effects. We offer adaptive resource-sharing as
      an alternative to these theories.

PMID- 15201039
TI  - Effects of low back pain on the relationship between the movements of the lumbar
      spine and hip.
AB  - Previous research had examined the effects of back pain on spinal movements, but
      information concerning movement coordination between the lumbar spine and hips
      was limited. The purpose of this study was to examine the effects of back pain
      and limitation in straight leg raise on the relationship between the movements of
      the lumbar spine and hip. An electromagnetic tracking system was employed to
      measure the movements of these joints in asymptomatic subjects (n = 20), and back
      pain subjects with (n = 24) and without (n = 17) limitation in straight leg
      raise. Subjects were requested to perform forward, backward and side bending, and
      twisting of the trunk. Back pain subjects were found to exhibit significant
      reductions in the magnitude of spine movements in all directions. Back pain was
      also associated with decrease in the magnitude of hip flexion but not hip
      movements in other directions. Cross-correlation analysis showed that there were
      changes in the strength of correlation and the time lag between lumbar spine and
      hip motions in normal and back pain subjects. In addition, back pain and
      limitation in straight leg raise were found to cause significant increases in the
      time required to complete the trunk movements. It was concluded that clinical
      assessment and treatment planning should take into account of the effects of back
      pain on the relationship between spine and hip movements.

PMID- 15201040
TI  - Optimal jumping strategies from compliant surfaces: a simple model of springboard
      standing jumps.
AB  - A simple model of standing dives is used to investigate optimal jumping
      strategies from compliant surfaces and applied to springboard diving. The human
      model consists of a massless leg actuated by knee torque, and a lumped torso mass
      centered above the leg. The springboard is modeled as a mass-spring system.
      Maximum jump height for a male and a female is calculated by controlling knee
      torque activation level as a function of time. The optimization includes
      constraints on minimum and maximum knee angle, rate of change of normalized
      activation level, and contact duration. Simulation results for maximal
      springboard depression and diver takeoff velocity agree reasonably with
      experimental data, even though larger board tip velocities are necessarily
      predicted earlier during the contact period. Qualitatively similar multiple pulse
      knee-torque activation patterns are found over various conditions and are
      different from those in rigid-surface jumping. The model is less able to predict
      accurately jump height at high fulcrum number since jumpers may have difficulty
      behaving optimally at non-preferred fulcrum settings. If strength is proportional
      to the product of mass and leg length, increasing leg length is more effective in
      increasing jump height than is increasing mass.

PMID- 15201041
TI  - Aspects of the validity of the Movement Assessment Battery for Children.
AB  - Does the Movement Assessment Battery for Children (M-ABC) measures what it claims
      to measure? The concurrent validity of the total impairment score and some of the
      item scores of the second and third age band of the M-ABC test were investigated.
      One hundred thirty three children, between 7- and 9-year-old, were assessed with
      the M-ABC test, a ball catching test and two tasks measuring dynamic balance.
      Ninety of these children were identified as children with a poor ball catching
      skill and 43 children were typically developing children. One hundred and seven
      children were assessed with the second age band of the M-ABC (the 7- and 8-year
      old children) and 26 with the third age band (the 9-year-old children). The
      results of the correlation analysis between the ball catching test, the two
      dynamic balance tasks and the corresponding items of the M-ABC, varied from non
      significant to a highly significant correlation coefficient of -0.74. For some
      items concurrent validity was established but other items seemed less valid,
      probably due to a lack of discriminative power. The concurrent validity of the
      total impairment score of the M-ABC was confirmed for the second age band.
      Correlation coefficients between the ball catching test, the dynamic balance
      skills and the M-ABC varied between -0.72 and -0.76. The results for the third
      age band have to be interpreted with prudence because they were based on only 26
      children.

PMID- 15201042
TI  - Comments on "Rapid motor adaptations to subliminal frequency shifts during
      syncopated rhythmic sensorimotor synchronization" by Michael H. Thaut and Gary P.
      Kenyon (Human Movement Science 22 [2003] 321-338).
AB  - Thaut and Kenyon [Human Movement Sci. 22 (2003) 321] have shown that, in a task
      requiring tapping in antiphase with a metronome, the response period adapts
      rapidly to a small (+/-2%) change in the stimulus period, whereas the relative
      phase between stimulus and response returns to its pre-change value only very
      gradually. On the basis of these and earlier findings, Thaut and Kenyon argue
      that period adaptation is rapid and subconscious, whereas phase adaptation is
      slow and dependent on awareness of a phase error. This interpretation is at
      variance with results in the literature suggesting that phase correction is rapid
      and subconscious, whereas period correction is slow and dependent on awareness of
      a period mismatch. Although differences in terminology (adaptation versus
      correction) play a role in this conflict, it primarily reflects different
      conceptions of sensorimotor synchronization and different interpretations of
      empirical findings. By excluding from their model a central timekeeper or
      oscillator with a flexible period, Thaut and Kenyon have omitted an essential
      component of human timing control that is needed for a proper explanation of
      their results.

PMID- 15201046
TI  - Mcm10 and Cdc45 cooperate in origin activation in Saccharomyces cerevisiae.
AB  - Mcm10 has recently been found to play a crucial role in multiple steps of the DNA
      replication initiation process in eukaryotes. Here, we have examined the role of
      Mcm10 in assembling initiation factors at a well-characterized yeast replication
      origin, ARS1. We find that the pre-replication complex (pre-RC) components Cdc6
      and Mcm7 associate with ARS1 in the mcm10-1 mutant, suggesting that establishment
      of the pre-RC is not compromised in this mutant. Association of Cdc45 with ARS1
      is reduced in the mcm10-1 mutant, suggesting that Mcm10 is involved in recruiting
      Cdc45 to the pre-RC. We find that overexpression of either Mcm10-1 or Cdc45
      suppresses the growth defect of mcm10-1, and that a physical interaction between
      Cdc45 and Mcm10 is disrupted in the mcm10-1 mutant. Our results show that
      interaction between the Mcm10 and Cdc45 proteins facilitates the recruitment of
      Cdc45 onto the ARS1 origin.

PMID- 15201047
TI  - Physical evidence for the induced release of the Bacillus subtilis transcription
      factor, sigma(F), from its inhibitory complex.
AB  - The release of the transcription factor sigma(F) from its inhibitory complex with
      SpoIIAB is a key regulatory step in the control of sporulation in Bacillus
      subtilis as it initiates a pattern of differential gene expression in the mother
      cell and prespore compartments. The sigma(F).SpoIIAB complex is dissociated by
      the unphosphorylated form of the protein SpoIIAA, the alternative binding partner
      of SpoIIAB. Here, we employ fluorescence spectroscopy to examine the mechanism by
      which SpoIIAA acts on the sigma(F).SpoIIAB complex. We constructed a mutant of
      sigma(F), sigma(F)-W46L, which displayed a reproducible fluorescence response on
      binding to SpoIIAB. Using this mutant we were able to quantify the amount of
      sigma(F) bound to SpoIIAB in real time. The results provide physical evidence for
      the "induced release" mechanism of sigma(F) activation. We demonstrate that
      SpoIIAA interacts directly with the sigma(F).SpoIIAB complex, greatly decreasing
      the affinity of SpoIIAB for sigma(F) and thus causing the release of the latter.
      We also demonstrate that sigma(F) is released before SpoIIAA is phosphorylated
      and that release occurs on a similar time scale to the binding of SpoIIAA to
      SpoIIAB.

PMID- 15201048
TI  - A group II intron-encoded maturase functions preferentially in cis and requires
      both the reverse transcriptase and X domains to promote RNA splicing.
AB  - Mobile group II introns encode proteins with both reverse transcriptase activity,
      which functions in intron mobility, and maturase activity, which promotes RNA
      splicing by stabilizing the catalytically active structure of the intron RNA.
      Previous studies with the Lactococcus lactis Ll.LtrB intron suggested a model in
      which the intron-encoded protein binds first to a high-affinity binding site in
      intron subdomain DIVa, an idiosyncratic structure at the beginning of its own
      coding region, and then makes additional contacts with conserved catalytic core
      regions to stabilize the active RNA structure. Here, we developed an Escherichia
      coli genetic assay that links the splicing of the Ll.LtrB intron to the
      expression of green fluorescent protein and used it to study the in vivo splicing
      of wild-type and mutant introns and to delineate regions of the maturase required
      for splicing. Our results show that the maturase functions most efficiently when
      expressed in cis from the same transcript as the intron RNA. In agreement with
      previous in vitro assays, we find that the high-affinity binding site in DIVa is
      required for efficient splicing of the Ll.LtrB intron in vivo, but in the absence
      of DIVa, 6-10% residual splicing occurs by the direct binding of the maturase to
      the catalytic core. Critical regions of the maturase were identified by
      statistically analyzing ratios of missense to silent mutations in functional LtrA
      variants isolated from a library generated by mutagenic PCR ("unigenic
      evolution"). This analysis shows that both the reverse transcriptase domain and
      domain X, which likely corresponds to the reverse transcriptase thumb, are
      required for RNA splicing, while the C-terminal DNA-binding and DNA endonuclease
      domains are not required. Within the reverse transcriptase domain, the most
      critical regions for maturase activity include parts of the fingers and palm that
      function in template and primer binding in HIV-1 reverse transcriptase, but the
      integrity of the reverse transcriptase active site is not required. Biochemical
      analysis of LtrA mutants indicates that the N terminus of the reverse
      transcriptase domain is required for high-affinity binding of the intron RNA,
      possibly via direct interaction with DIVa, while parts of domain X interact with
      conserved regions of the catalytic core. Our results support the hypothesis that
      the intron-encoded protein adapted to function in splicing by using, at least in
      part, interactions used initially to recognize the intron RNA as a template for
      reverse transcription.

PMID- 15201049
TI  - Role of an active site guanine in hairpin ribozyme catalysis probed by exogenous
      nucleobase rescue.
AB  - The hairpin ribozyme is a small catalytic RNA with reversible phosphodiester
      cleavage activity. Biochemical and structural studies exclude a requirement for
      divalent metal cation cofactors and implicate one active site nucleobase in
      particular, G8, in the catalytic mechanism. Our previous work demonstrated that
      the cleavage activity that is lost when G8 is replaced by an abasic residue is
      restored when certain nucleobases are provided in solution. The specificity and
      pH dependence of exogenous nucleobase rescue were consistent with several models
      of the rescue mechanism, including general acid base catalysis, electrostatic
      stabilization of negative charge in the transition state or a requirement for
      protonation to facilitate exogenous nucleobase binding. Detailed analyses of
      exogenous nucleobase rescue for both cleavage and ligation reactions now allow us
      to refine models of the rescue mechanism. Activity increased with increasing pH
      for both unmodified ribozyme reactions and unrescued reactions of abasic variants
      lacking G8. This similarity in pH dependence argues against a role for G8 as a
      general base catalyst, because G8 deprotonation could not be responsible for the
      pH-dependent transition in the abasic variant. Exogenous nucleobase rescue of
      both cleavage and ligation activity increased with decreasing pH, arguing against
      a role for rescuing nucleobases in general acid catalysis, because a nucleobase
      that contributes general acid catalysis in the cleavage pathway should provide
      general base catalysis in ligation. Analysis of the concentration dependence of
      cytosine rescue at high and low pH demonstrated that protonation promotes
      catalysis within the nucleobase-bound ribozyme complex but does not stabilize
      nucleobase binding in the ground state. These results support an electrostatic
      stabilization mechanism in which exogenous nucleobase binding counters negative
      charge that develops in the transition state.

PMID- 15201050
TI  - Computational and experimental probes of symmetry mismatches in the Arc repressor
      DNA complex.
AB  - Arc repressor from bacteriophage P22 is a homodimeric member of the ribbon-helix
      helix family of transcription factors. Two dimers bind cooperatively to adjacent
      sites on operator DNA with the antiparallel beta-sheet of each Arc dimer
      contacting the major groove. Despite the 2-fold symmetry of the dimer, the
      sequence of the DNA half-site is not symmetric, and thus there is an inherent
      symmetry mismatch in the complex. Here, using a combination of computational and
      experimental methods, we further characterize this symmetry mismatch. Continuum
      electrostatic calculations show that the DNA-contacting side-chains of Gln9,
      Asn11 and Arg13 each make better electrostatic interactions in one subunit of the
      Arc dimer than in the other. Based on the computational results, one or both Gln9
      side-chains were substituted with Arg or His and Asn11 was similarly substituted
      with Ile in the context of a single-chain variant of Arc repressor. Although the
      double mutants that maintain the symmetry of the protein bind much more weakly
      than scArc, mutants with single Q9R or N11I substitutions bind operator DNA with
      affinities close to wild-type. Whereas the effects are nearly additive for the
      mutations at position 9, the effects of single N11I mutations are non-additive.
      The calculations thus enabled the identification of functionally tolerated
      mutations in the DNA-binding surface of Arc repressor, which in turn revealed
      energetic consequences of asymmetric environments in this protein-DNA
      interaction.

PMID- 15201051
TI  - Enzyme/non-enzyme discrimination and prediction of enzyme active site location
      using charge-based methods.
AB  - Calculations of charge interactions complement analysis of a characterised active
      site, rationalising pH-dependence of activity and transition state stabilisation.
      Prediction of active site location through large DeltapK(a)s or electrostatic
      strain is relevant for structural genomics. We report a study of ionisable groups
      in a set of 20 enzymes, finding that false positives obscure predictive
      potential. In a larger set of 156 enzymes, peaks in solvent-space electrostatic
      properties are calculated. Both electric field and potential match well to active
      site location. The best correlation is found with electrostatic potential
      calculated from uniform charge density over enzyme volume, rather than from
      assignment of a standard atom-specific charge set. Studying a shell around each
      molecule, for 77% of enzymes the potential peak is within that 5% of the shell
      closest to the active site centre, and 86% within 10%. Active site identification
      by largest cleft, also with projection onto a shell, gives 58% of enzymes for
      which the centre of the largest cleft lies within 5% of the active site, and 70%
      within 10%. Dielectric boundary conditions emphasise clefts in the uniform charge
      density method, which is suited to recognition of binding pockets embedded within
      larger clefts. The variation of peak potential with distance from active site,
      and comparison between enzyme and non-enzyme sets, gives an optimal threshold
      distinguishing enzyme from non-enzyme. We find that 87% of the enzyme set exceeds
      the threshold as compared to 29% of the non-enzyme set. Enzyme/non-enzyme
      homologues, "structural genomics" annotated proteins and catalytic/non-catalytic
      RNAs are studied in this context.

PMID- 15201052
TI  - Crystal structure and biochemical properties of the human mitochondrial ferritin
      and its mutant Ser144Ala.
AB  - Mitochondrial ferritin is a recently identified protein precursor encoded by an
      intronless gene. It is specifically taken up by the mitochondria and processed to
      a mature protein that assembles into functional ferritin shells. The full mature
      recombinant protein and its S144A mutant were produced to study structural and
      functional properties. They yielded high quality crystals from Mg(II) solutions
      which diffracted up to 1.38 Angstrom resolution. The 3D structures of the two
      proteins resulted very similar to that of human H-ferritin, to which they have
      high level of sequence identity (approximately 80%). Metal-binding sites were
      identified in the native crystals and in those soaked in Mn(II) and Zn(II)
      solutions. The ferroxidase center binds binuclear iron at the sites A and B, and
      the structures showed that the A site was always fully occupied by Mg(II), Mn(II)
      or Zn(II), while the occupancy of the B site was variable. In addition, distinct
      Mg(II) and Zn(II)-binding sites were found in the 3-fold axes to block the
      hydrophilic channels. Other metal-binding sites, never observed before in H
      ferritin, were found on the cavity surface near the ferroxidase center and near
      the 4-fold axes. Mitochondrial ferritin showed biochemical properties remarkably
      similar to those of human H-ferritin, except for the difficulty in renaturing to
      yield ferritin shells and for a reduced ( approximately 41%) rate in ferroxidase
      activity. This was partially rescued by the substitution of the bulkier Ser144
      with Ala, which occurs in H-ferritin. The residue is exposed on a channel that
      connects the ferroxidase center with the cavity. The finding that the mutation
      increased both catalytic activity and the occupancy of the B site demonstrated
      that the channel is functionally important. In conclusion, the present data
      define the structure of human mitochondrial ferritin and provide new data on the
      iron pathways within the H-type ferritin shell.

PMID- 15201053
TI  - Switching of troponin I: Ca(2+) and myosin-induced activation of heart muscle.
AB  - The principal task of the Ca(2+) activation of striated muscle is the release of
      the troponin I (TnI) inhibitory region (TnI-I) from actin. TnI-I release
      facilitates the repositioning of tropomyosin across the actin surface and the
      formation of strong, force generating, actin-myosin cross-bridges. Full
      activation of the Ca(2+) regulatory switch (CRS) requires two switching steps in
      cTnI: binding of the TnI regulatory region to hydrophobic sites in the N-domain
      of Ca(2+)-bound troponin C and release of the adjacent TnI-I from actin. Using
      Forster resonance energy transfer, we have examined the requirements for full
      activation of the cardiac CRS. In the presence of actin, both Ca(2+) and strong
      cross-bridges are required for full activation. Actin desensitizes the CRS to
      Ca(2+) and produces cooperativity in the Ca(2+) activation of the CRS. Strong
      cross-bridges eliminate cooperativity and re-sensitize the CRS to Ca(2+). We
      propose a kinetic scheme and a structural model to account for these findings.

PMID- 15201054
TI  - An evolutionarily conserved network of amino acids mediates gating in voltage
      dependent potassium channels.
AB  - A novel sequence-analysis technique for detecting correlated amino acid positions
      in intermediate-size protein families (50-100 sequences) was developed, and
      applied to study voltage-dependent gating of potassium channels. Most
      contemporary methods for detecting amino acid correlations within proteins use
      very large sets of data, typically comprising hundreds or thousands of
      evolutionarily related sequences, to overcome the relatively low signal-to-noise
      ratio in the analysis of co-variations between pairs of amino acid positions.
      Such methods are impractical for voltage-gated potassium (Kv) channels and for
      many other protein families that have not yet been sequenced to that extent.
      Here, we used a phylogenetic reconstruction of paralogous Kv channels to follow
      the evolutionary history of every pair of amino acid positions within this
      family, thus increasing detection accuracy of correlated amino acids relative to
      contemporary methods. In addition, we used a bootstrapping procedure to eliminate
      correlations that were statistically insignificant. These and other measures
      allowed us to increase the method's sensitivity, and opened the way to reliable
      identification of correlated positions even in intermediate-size protein
      families. Principal-component analysis applied to the set of correlated amino
      acid positions in Kv channels detected a network of inter-correlated residues, a
      large fraction of which were identified as gating-sensitive upon mutation.
      Mapping the network of correlated residues onto the 3D structure of the Kv
      channel from Aeropyrum pernix disclosed correlations between residues in the
      voltage-sensor paddle and the pore region, including regions that are involved in
      the gating transition. We discuss these findings with respect to the evolutionary
      constraints acting on the channel's various domains. The software is available on
      our website

PMID- 15201055
TI  - Conformational flexibility in recombinant measles virus nucleocapsids visualised
      by cryo-negative stain electron microscopy and real-space helical reconstruction.
AB  - Measles virus is a highly contagious virus that, despite the existence of an
      effective vaccine, is a major cause of illness and mortality worldwide. The virus
      has a negative-sense, single-stranded RNA genome that is encapsidated by the
      nucleocapsid protein (N) to form a helical ribonucleoprotein complex known as the
      nucleocapsid. This structure serves as the template for both transcription and
      replication. Paramyxovirus nucleocapsids are flexible structures, a trait that
      has hitherto hampered structural analysis even at low resolution. We have
      investigated the extent of this structural plasticity, using real-space methods
      to calculate three-dimensional reconstructions of recombinant nucleocapsids from
      cryo-negative stain transmission electron micrographs. Images of short sections
      of helix were sorted according to both pitch (the axial rise per turn) and twist
      (the number of subunits per turn). Our analysis indicates that there is extensive
      conformational flexibility within these structures, ranging in pitch from 50
      Angstrom to 66 Angstrom, while twist varies from at least 13.04 to 13.44 with a
      greater number of helices comprising around 13.1 subunits per turn. We have also
      investigated the influence of the C terminus of N on helix conformation,
      analysing nucleocapsids after having removed this domain by trypsin digestion. We
      have found that this causes a marked change in both pitch and twist, such that
      the pitch becomes shorter, ranging from 46 Angstrom to 52 Angstrom, while more
      helices have a twist of approximately 13.3 subunits per turn. Our findings lead
      us to propose a mechanism whereby changes in conformation, influenced by
      interactions between viral or host proteins and the C terminus of N, might have a
      role in regulating the balance of transcription and replication during virus
      infection.

PMID- 15201056
TI  - The "two-state folder" MerP forms partially unfolded structures that show
      temperature dependent hydrogen exchange.
AB  - We have analysed the folding energy landscape of the 72 amino acid protein MerP
      by monitoring native state hydrogen exchange as a function of temperature in the
      range of 7-55 degrees C. The temperature dependence of the hydrogen exchange has
      allowed us to determine DeltaG, DeltaH and DeltaC(p) values for the
      conformational processes that permit hydrogen exchange. When studied with the
      traditional probes, fluorescence and CD, MerP appears to behave as a typical two
      state protein, but the results from the hydrogen exchange analysis reveal a much
      more complex energy landscape. Analysis at the individual amino acid level show
      that exchange is allowed from an ensemble of partially unfolded structures (i.e.
      intermediates) in which the stabilities at the amino acid level form a broad
      distribution throughout the protein. The formation of partially unfolded
      structures might contribute to the unusually slow folding of MerP.

PMID- 15201057
TI  - A normal mode analysis of structural plasticity in the biomolecular motor F(1)
      ATPase.
AB  - Normal modes have been used to explore the inherent flexibility of the alpha,
      beta and gamma subunits of F(1)-ATPase in isolation and as part of the
      alpha(3)beta(3)gamma complex. It was found that the structural plasticity of the
      gamma and beta subunits, in particular, correlates with their functions. The N
      and C-terminal helices forming the coiled-coil domain of the gamma subunit are
      highly flexible in the isolated subunit, but more rigid in the
      alpha(3)beta(3)gamma complex due to interactions with other subunits. The
      globular domain of the gamma subunit is structurally relatively rigid when
      isolated and in the alpha(3)beta(3)gamma complex; this is important for its
      functional role in coupling the F(0) and F(1) complex of ATP synthase and in
      inducing the conformational changes of the beta subunits in synthesis. Most
      important, the character of the lowest-frequency modes of the beta(E) subunit is
      highly correlated with the large beta(E) --> beta(TP) transition. This holds for
      the C-terminal domain and the nucleotide-binding domain, which undergo
      significant conformational transitions in the functional cycle of F(1)-ATPase.
      This is most evident in the ligand-free beta(E) subunit; the flexibility in the
      nucleotide-binding domain is reduced somewhat in the beta(TP) subunit in the
      presence of Mg(2+).ATP. The low-frequency modes of the alpha(3)beta(3)gamma
      complex show that the motions of the globular domain of the gamma subunit and of
      the C-terminal and nucleotide binding domains of the beta(E) subunits are
      coupled, in accord with their function. Overall, the normal mode analysis reveals
      that F(1)-ATPase, like other macromolecular assemblies, has the intrinsic
      structural flexibility required for its function encoded in its sequence and
      three-dimensional structure. This inherent plasticity is an essential aspect of
      assuring a small free energy cost for the large-scale conformational transition
      that occurs in molecular motors.

PMID- 15201058
TI  - Order changes within receptor systems upon ligand binding: receptor
      tightening/oligomerisation and the interpretation of binding parameters.
AB  - Recent hydrogen-deuterium exchange experiments have highlighted tightening and
      loosening of protein structures upon ligand binding, with changes in bonding
      (DeltaH) and order (DeltaS) which contribute to the overall thermodynamics of
      ligand binding. Tightening and loosening show that ligand binding respectively
      stabilises or destabilises the internal structure of the protein, i.e. it shows
      positive or negative cooperativity between ligand binding and the receptor
      structure. In the case of membrane-bound receptors, such as G protein-coupled
      receptors (GPCRs) and ligand gated ion channel receptors (LGICRs), most binding
      studies have focussed on association/dissociation constants. Where these have
      been broken down into enthalpic and entropic contributions, the phenomenon of
      "thermodynamic discrimination" between antagonists and agonists has often been
      noted; e.g. for a receptor where agonist binding is predominantly enthalpy
      driven, antagonist binding is predominantly entropy driven and vice versa. These
      data have not previously been considered in terms of the tightening, or
      loosening, of receptor structures that respectively occurs upon positively, or
      negatively, cooperative binding of ligand. Nor have they been considered in light
      of the homo- and hetero-oligomerisation of GPCRs and the possibility of ligand
      induced changes in oligomerisation. Here, we argue that analysis of the DeltaH
      and DeltaS of ligand binding may give useful information on ligand-induced
      changes in membrane-bound receptor oligomers, relevant to the differing effects
      of agonists and antagonists.

PMID- 15201059
TI  - 3DCoffee: combining protein sequences and structures within multiple sequence
      alignments.
AB  - Most bioinformatics analyses require the assembly of a multiple sequence
      alignment. It has long been suspected that structural information can help to
      improve the quality of these alignments, yet the effect of combining sequences
      and structures has not been evaluated systematically. We developed 3DCoffee, a
      novel method for combining protein sequences and structures in order to generate
      high-quality multiple sequence alignments. 3DCoffee is based on TCoffee version
      2.00, and uses a mixture of pairwise sequence alignments and pairwise structure
      comparison methods to generate multiple sequence alignments. We benchmarked
      3DCoffee using a subset of HOMSTRAD, the collection of reference structural
      alignments. We found that combining TCoffee with the threading program Fugue
      makes it possible to improve the accuracy of our HOMSTRAD dataset by four
      percentage points when using one structure only per dataset. Using two structures
      yields an improvement of ten percentage points. The measures carried out on
      HOM39, a HOMSTRAD subset composed of distantly related sequences, show a linear
      correlation between multiple sequence alignment accuracy and the ratio of number
      of provided structure to total number of sequences. Our results suggest that in
      the case of distantly related sequences, a single structure may not be enough for
      computing an accurate multiple sequence alignment.

PMID- 15201060
TI  - Relationship between firing activity of bombyxin-producing neurosecretory cells
      and hemolymph bombyxin titer in the silkworm Bombyx mori.
AB  - Isolated brain-retrocerebral neurohemal complex of the silkworm of Bombyx mori
      was stimulated electrically and the released bombyxin (an insulin-like
      neuropeptide) was measured using time-resolved fluoroimmunoassay. The amount of
      bombyxin release depended on the number of stimulus pulses delivered to the
      axonal tract of the bombyxin-producing (BP) neurosecretory cells, and 17 fg of
      bombyxin per pulse was released from a cell. The titer of bombyxin in the
      hemolymph of bombyxin-II injected pupae decreased exponentially, the half-life
      being 170 min. To relate firing activity of a population of BP cells to the
      hormone titer in the hemolymph, bombyxin titer and its change in the hemolymph
      were calculated numerically. We assumed that the amount of bombyxin release was
      proportional to the firing rate of BP cells and the released bombyxin was
      inactivated with the same time course of injected bombyxin. Our calculations
      suggested that the hemolymph bombyxin titer may fluctuate dynamically and the
      mean titer is 380 pg/ml, a level which is close to the actually determined
      bombyxin titer at middle stages of pupal-adult development.

PMID- 15201061
TI  - Expression of P450 aromatase protein in developing and in sex-reversed gonads of
      the XX/XY type of the frog Rana rugosa.
AB  - Gonadal differentiation in some species of amphibians is sensitive to steroids.
      The phenotypic sex of XX/XY-type frogs such as Rana rugosa can be reversed from
      female to male by injection of testosterone into tadpoles, but little is known
      about the molecular mechanism of this sex reversal. To elucidate the mechanism of
      the sex differentiation, we examined the role of P450 aromatase (P450arom), an
      enzyme that converts testosterone to estrogen, during gonadal differentiation of
      amphibians. In this study, we first cloned a P450arom cDNA homolog of the frog R.
      rugosa and analyzed by RT-PCR its expression profile in developing and in female
      to-male sex-reversed gonads. P450arom expression was observed in the gonad of
      tadpoles during ovarian differentiation and became much stronger in the
      developing ovary in which only immature oocytes were observed. However, its
      expression declined significantly in the ovary of frogs 2 months after
      metamorphosis, when oocytes were growing; and it was no longer seen in adult
      ovaries. By RT-PCR, we also examined the expression of P450arom and SF-1
      (steroidogenic factor-1; the orphan nuclear receptor) in the female-to-male sex
      reversed gonad. The level of P450arom mRNA was high in the ovary, but it declined
      rapidly after the injection of testosterone. In contrast, no change in the SF-1
      (also known as Ad4BP) expression was observed. Moreover, to identify the type(s)
      of cells expressing P450arom protein, we performed immunostaining with an
      antibody against frog P450arom protein. Cells giving positive signals were
      observed around oocytes in the ovary of frogs 1 month after metamorphosis. They
      were identified as follicle cells by both light and electron microscopy. The
      results, taken together, indicate that P450arom protein is synthesized in
      follicle cells and that P450arom is very much involved in ovarian differentiation
      in R. rugosa.

PMID- 15201062
TI  - Neuropeptide Y modulates pituitary-adrenal axis activity in the lizard, Podarcis
      sicula.
AB  - The role of neuropeptide Y (NPY) in the modulation of the pituitary-adrenal axis
      activity in a lizard, Podarcis sicula, was investigated by in vivo NPY
      administration. The effects were evaluated by examination of the morphological
      and morphometrical features of the tissues as well as the plasma levels of ACTH,
      corticosterone, aldosterone, norepinephrine, and epinephrine. Intraperitoneally
      administered NPY (27 nmol /100g body wt) raised ACTH plasma levels (from 5.23+/
      0.06 pg/ml in carrier injected specimens to 6.83+/-0.01 pg/ml, 24 h after the
      injection). In the steroidogenic cells a strong decrease of lipid amount was
      found; corticosterone plasma level increased from 6.28+/-0.02 ng/ml in carrier
      injected lizards to 7.96+/-0.01 ng/ml 24 h after the injection); aldosterone
      levels were raised from 1.88+/-0.02 ng/ml in carrier injected specimens to 6.38+/
      0.05 ng/ml 24 h after the experimental treatment. In the chromaffin tissue, an
      increase in the number of epinephrine cells and a decrease in the number of
      norepinephrine cells were observed, decreasing the numeric
      norepinephrine/epinephrine (NE/E) cell ratio, from 1.4/1 of control specimens to
      0.5/1 24 h after NPY administration. Moreover, norepinephrine plasma level were
      elevated from 922+/-4.30 pg/ml in carrier injected specimens to 3075+/-11.30
      pg/ml 24 h after NPY administration; epinephrine plasma level increased from
      502+/-2.40 pg/ml in carrier injected specimens to 2759+/-8.70 pg/ml 24 h after
      the experimental treatment. Consistent with these findings, morphological
      observations showed many chromaffin cells weakly stained and with a reduced
      content of secretory granules. These results suggest that, in P. sicula, NPY may
      play a role in the modulation of the pituitary-adrenal axis activity. Previous
      studies localized NPY in the epinephrine cells of P. sicula adrenal gland; taken
      together, these results suggest that this peptide might participate in the
      regulation of adrenal gland activity, enhancing corticosteroid and catecholamine
      secretion in a paracrine/autocrine manner. The mechanism of action of NPY is
      discussed.

PMID- 15201063
TI  - Effect of estradiol implants on reproductive behavior of female Lapland longspurs
      (Calcarius lapponicus).
AB  - The role of estrogens in reproductive behavior of free-living birds has been
      little investigated, despite the importance of estrogens in coordinating
      reproductive behavior and the need for information on potential effects of
      estrogenic contaminants on wildlife. We gave subcutaneous implants of estradiol
      (E2) to 15 female Lapland longspurs (Calcarius lapponicus), an arctic bird with a
      six-week breeding season. Controls were 9 females with empty implants and 14
      unimplanted females. After implantation, E2 females had greater E2 levels and
      greater body mass than controls. We did not detect any increases in, or
      prolongation of, sexual or nest-building behavior. The incubation period was
      longer for E2 nests than for control nests. Nest videotapes showed that E2
      females and their mates exhibited normal nestling care, and nestling growth,
      fledging success, and overwinter survival were also unaffected. However, whenever
      the males arrived at the nests, E2 females showed a significantly greater
      likelihood of begging from the male rather than leaving the nest. Courtship or
      incubation feeding have been considered atypical for this species, and it is not
      clear what role E2 normally plays in promoting begging behavior. Overall,
      elevated E2 levels did not result in any obvious costs for the female, save
      perhaps for slightly reduced incubation efficiency. The weak response to hormonal
      implants is similar to patterns seen in male Lapland longspurs, and may be
      related to the short breeding season. However, since little is presently known
      about the role of estrogens in behavior of wild female birds, it remains to be
      seen whether these patterns are typical of female passerines in general, or of
      short-season breeders. Further research on effects of estrogens (both exogenous
      and endogenous) on free-living female birds is needed.

PMID- 15201064
TI  - The stress axis, stanniocalcin, and ion balance in rainbow trout.
AB  - In teleosts, the stress hormone cortisol and the calcium regulatory hormone
      stanniocalcin (STC) are both involved in the regulation of ion balance. Under
      stressful conditions, ion balance is easily disturbed as stressors via the stress
      signals they evoke disturb easily and primarily gill function. The gills are key
      in fish gas exchange and ion regulation. The present work evaluates the effect of
      the pivotal stress signal cortisol, the eventual output of the stress axis on STC
      secretion in freshwater rainbow trout (Oncorhynchus mykiss). Plasma cortisol
      levels were manipulated by intraperitoneal injections of porcine ACTH(1-39) or
      dexamethasone (Dex), and plasma cortisol, STC and mineral status were assessed. A
      perifusion assay of trout Stannius corpuscles was validated and used to study the
      direct effects of stress-related signals on STC release. In perifusion, cortisol,
      adrenocorticotropic hormone (ACTH), and dexamethasone did not affect STC release.
      ACTH injections increase plasma cortisol (corresponding to an acute stress) and
      STC concentrations, but did not affect mineral status. Dexamethasone injections
      resulted either in a classical hypocortisolinemia or, unexpectedly, in
      hypercortisolinemia. However, independently of the resulting cortisol status Dex
      induced a chronic stress effect, as indicated by decreased plasma Na, Cl, and Ca
      levels, and increased plasma STC concentrations. The increased STC secretion
      cannot be explained by the classical elevation of plasma calcium concentration.
      Thus, plasma parameters other than calcium could be involved and we propose that
      STC secretion might be stimulated also by a decrease of NaCl concentrations,
      implying a broader function than the classical hypocalcemic action of STC.

PMID- 15201065
TI  - Expression and hypophysiotropic actions of corticotropin-releasing factor in
      Xenopus laevis.
AB  - Members of the corticotropin-releasing factor (CRF) family of peptides play
      pivotal roles in the regulation of neuroendocrine, autonomic, and behavioral
      responses to physical and emotional stress. In amphibian tadpoles, CRF-like
      peptides stimulate both thyroid and interrenal (adrenal) hormone secretion, and
      can thereby modulate the rate of metamorphosis. To better understand the
      regulation of expression and actions of CRF in amphibians we developed a
      homologous radioimmunoassay (RIA) for Xenopus laevis CRF (xCRF). We validated
      this RIA and tissue extraction procedure for the measurement of brain CRF content
      in tadpoles and juveniles. We show that the CRF-binding protein, which is highly
      expressed in X. laevis brain, is largely removed by acid extraction and does not
      interfere in the RIA. We analyzed CRF peptide content in five microdissected
      brain regions in prometamorphic tadpoles and juveniles. CRF was detected
      throughout the brain, consistent with its role as both a hypophysiotropin and a
      neurotransmitter/neuromodulator. CRF content was highest in the region of the
      preoptic area (POa) and increased in all brain regions after metamorphosis.
      Exposure to 4h of handling/shaking stress resulted in increased CRF peptide
      content in the POa in juvenile frogs. Injections of xCRF into prometamorphic
      tadpoles increased whole body corticosterone and thyroxine content, thus
      supporting findings in other anuran species that this peptide functions as both a
      corticotropin- and a thyrotropin (TSH)-releasing factor. Furthermore, treatment
      of cultured tadpole pituitaries with xCRF (100nM for 24h) resulted in increased
      medium content, but decreased pituitary content of TSHbeta-immunoreactivity. Our
      results support the view that CRF functions as a stress neuropeptide in X. laevis
      as in other vertebrates. Furthermore, we provide evidence for a dual
      hypophysiotropic action of CRF on the thyroid and interrenal axes in X. laevis as
      has been shown previously in other amphibian species.

PMID- 15201066
TI  - Potential endocrine function of the glycolytic enzyme glucose-6-phosphate
      isomerase during implantation.
AB  - Glucose-6-phosphate isomerase (GPI) is a glycolytic enzyme that also acts as
      autocrine motility factor, a secreted protein that stimulates tumor cell
      motility. We have shown that GPI is required for embryo implantation in the
      domestic ferret. Here, we tested the hypothesis that GPI is produced and secreted
      into the bloodstream by ferret luteal cells. Plasma GPI activity increased
      significantly during the pre-implantation period in both pregnant and
      pseudopregnant ferrets. Explants from Corpus luteum (CL) and follicles of the pre
      implantation period were cultured to ascertain their ability to secrete GPI. The
      medium of cultured luteal extracts contained significantly more GPI activity than
      the medium of cultured follicles, a control tissue. GPI activity in the medium
      increased significantly with increasing pregnancy stage, from pregnancy days 3 to
      12. However, GPI activity within explant homogenates was the same in CL and
      follicles and at all days of pregnancy. Thus, CL but not follicles, secrete GPI
      during the pre-implantation period. Our findings suggest that GPI may be acting
      in an endocrine manner, being secreted from the CL into the blood, and acting to
      promote implantation, which occurs at a distant site, the uterus.

PMID- 15201067
TI  - Temporal profile of beta follicle-stimulating hormone, beta luteinizing hormone,
      and growth hormone gene expression in the protandrous hermaphrodite, gilthead
      seabream, Sparus aurata.
AB  - The temporal profile of betaFSH, betaLH, and growth hormone (GH) gene expression
      was measured throughout the periods of gonadal development, spawning, and post
      spawning in the protandrous hermaphrodite gilthead seabream (sb), Sparus aurata
      (L.). Sampling was carried out monthly, covering a 8-31 month fish age. Pituitary
      RNA was extracted individually. The levels of betaFSH, betaLH, and GH mRNA were
      measured by dot blot hybridization using sb betaFSH, betaLH, and GH cDNA as
      probes and analyzed by computing densitometer (values standardized using
      individuals' beta-actin pituitary mRNA levels). All three genes, betaFSH, betaLH,
      and GH were expressed throughout the year, with seasonal variations. However,
      transcript levels of betaLH were consistently higher than those of betaFSH.
      During the spawning season (which lasts for about 4 months), the mRNA levels of
      both betaFSH and betaLH subunits increased dramatically. betaFSH peaked at the
      start of the spawning season for both males and females, and was significantly
      higher in males. As for betaLH transcripts, a statistical interaction between sex
      and date was observed. No significant differences between males and females were
      found for GH. The pattern of GH expression levels was found to be correlated to
      that of betaLH.

PMID- 15201068
TI  - Molecular cloning, sequence analysis and expression of the snake follicle
      stimulating hormone receptor.
AB  - Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) control gonadal
      function in mammalian and many non-mammalian vertebrates through the interaction
      with their receptors, FSHR and LHR. Although the same is true for some reptilian
      species, in Squamata (lizards and snakes) there is no definitive evidence for the
      presence of either two distinct gonadotropins or two distinct gonadotropin
      receptors. Our aim was to characterize the gonadotropin receptor(s) of the
      Bothrops jararaca snake. Using a cDNA library from snake testis and amplification
      of the 5'-cDNA ending, we cloned a cDNA related to FSHR. Attempts to clone a cDNA
      more closely related to LHR were unsuccessful. Expression of FSHR mRNA was
      restricted to gonadal tissues. The snake FSHR is a G protein-coupled receptor
      with 673 amino acids, and the aminoterminal domain with 346 amino acids consists
      of a nine leucine-rich repeat-containing subdomain (LRR) flanked by two cysteine
      rich subdomains. The beta-strands in the LRR are conserved with exception of the
      third, a region that may be important for FSH binding. In contrast with
      mammalian, avian and amphibian FSHRs, the snake FSHR presents amino acid
      deletions in the carboxyterminal region of the extracellular domain which are
      also seen in fish and lizard FSHRs. cAMP assays with the recombinant protein
      transiently expressed in HEK-293 cells showed that the snake FSHR is more
      sensitive to human FSH (hFSH) than to human chorionic gonadotropin. Phylogenetic
      analysis indicated that the squamate FSHRs group separately from mammalian FSHRs.
      Our data are consistent with the apparently unique gonadotropin-receptor system
      in Squamata reptilian subgroup. Knowledge about the snake FSHR structure may help
      identify structural determinants for receptor function.

PMID- 15201069
TI  - Molecular cloning of proopiomelanocortin cDNA and multi-tissue mRNA expression in
      channel catfish.
AB  - Channel catfish (Ictalurus punctatus) proopiomelanocortin (POMC) cDNA was cloned
      to investigate its structure, evolution, and expression in different tissues.
      POMC is an important gene in the hypothalamus-pituitary-adrenal axis, the main
      mediator of the stress response. POMC gene was isolated from a pituitary cDNA
      library and nucleotide sequence was determined. POMC cDNA is composed of 1164
      nucleotides with a 639 nucleotide open reading frame encoding a protein of 212
      amino acids. Catfish POMC protein contains a signal peptide (SP, Met(1)-Ala(28)),
      N-terminal peptide (Gln(29)-Glu(101)), adrenocorticotropic hormone (ACTH,
      Ser(104)-Met(142)), alpha-melanocyte stimulating hormone (alpha-MSH, Ser(104)
      Val(116)), corticotropin-like intermediate lobe peptide (CLIP, Arg(121)
      Met(142)), beta-lipotropin (beta-LPH, Glu(145)-His(212)), gamma-lipotropin (gamma
      LPH, Glu(145)- Ser(177)), beta-MSH (Asp(161)-Ser(177)), and beta-endorphin (beta
      EP, Tyr(180)-His(212)). Catfish POMC protein does not contain a gamma-MSH region
      and most of the joining peptide and part of the gamma-LPH are deleted. Protein
      sequence alignment showed the highest similarity with the carp (Cyprinus carpio)
      POMC I (66.5%) and POMC II (67%), while the sea lamprey (Petromyzon marinus) POC
      (17.9%) and POM (18.8%) were the most divergent. The average similarity was
      46.95% among the 44 POMC proteins from 36 different species analyzed. Compared to
      the POMC mRNA levels in the pituitary, the concentration of the POMC mRNA was
      0.0594% in the anterior kidney and 0.0012-0.0045% in all the other tissues except
      in the skin where the lowest expression (0.0005%) was observed. Overall
      architecture of channel catfish POMC is highly similar to those from other
      teleosts.

PMID- 15201070
TI  - Ionic mechanisms of a novel neurotoxin from the sea anemone Anthopleura sp. in
      rat ventricular myocytes.
AB  - OBJECTIVE: To determine the ionic mechanisms of a novel neurotoxin rhk2a obtained
      from the sea anemone Anthopleura sp. in rat ventricular myocytes. METHODS: Whole
      cell patch-clamp recording technique was used to record the sodium, calcium, and
      sodium-calcium exchange currents (I(Na), I(Ca, L), and I(Na-Ca), respectively) in
      the isolated single rat ventricular myocytes with or without rhk2a treatment.
      RESULTS: The current-voltage (I-V) relationship for whole-cell I(Na) in the non
      treated and rhk2a-treated (at the dose of 1 micromol/L) myocytes showed no
      significant difference (P>0.05), but the time constants for inactivation (tau(h))
      were significantly greater (P<0.05) for the treated cells over the entire course
      of the experiment, while the time constants for activation (tau(m)) exhibited no
      significant difference between the two cells. The inactivation curve of I(Na) of
      rhk2a-treated cells was similar to that of the non-treated cells, as with the I-V
      relationship for whole-cell L-type calcium current (I(Ca, L) and I(Na-Ca)).
      CONCLUSIONS: Delayed inactivation of Na(+) channel plays an important role in the
      positive inotropic effect of rhk2a, possibly resulting from the alteration in
      Na(+) channel kinetics induced by rhk2a. rhk2a does not directly affect I(Ca, L),
      or I(Na-Ca).

PMID- 15201071
TI  - Transcatheter arterial chemoembolization of oral squamous-cell carcinoma: a
      clinicopathological observation.
AB  - OBJECTIVE: To evaluate the therapeutic efficacy of transcatheter arterial
      chemoembolization (TACE) for advanced oral carcinoma by observing the
      pathological changes of the carcinoma tissues after the interventional therapy.
      METHODS: Twenty cases of advanced oral carcinoma involving the tongue (16 cases),
      gingiva (2 cases) and the floor of the mouth (2 cases) were enrolled in this
      study. Intubation with Seldinger's technique from the femoral artery to the
      external carotid artery was performed in all the cases. With the assistance of
      digital subtracting angiography (DSA), cisplatin, adriacin and mitomycin C were
      injected through the branches of the external carotid artery into the involved
      tissues with embolization using gelatin sponge. Surgical resection of the tumor
      was performed 1 to 4 weeks after TACE, and the specimens were observed under
      light microscope and transmission electron microscope. RESULTS: Significant
      changes occurred in the carcinoma tissues, manifested by reduced carcinoma cells,
      karyopyknosis, vacuolar degeneration and focal coagulation necrosis. The
      disintegrated carcinoma nests were encapsulated and underwent organization by
      hyperplastic fibrous connective tissues with inflammatory cell infiltration. The
      connective structures between the carcinoma cells disappeared and resulted in
      broadened intercellular space. CONCLUSION: Preoperative administration of
      arterial chemoembolization may cause degeneration and necrosis of oral carcinoma,
      which can be helpful to distinguish intraoperatively the carcinoma from normal
      tissues; as for the inoperable cases, TACE may inhibit the tumor growth and
      prolong the survival of the patients.

PMID- 15201072
TI  - [Expression of hepatocyte growth factor and its receptor c-met gene in the
      endometrium of women with endometriosis].
AB  - OBJECTIVE: To study the role of hepatocyte growth factor (HGF) and its receptor
      (c-Met) in the pathogenesis of endometriosis. METHODS: In situ hybridization and
      immunohistochemistry method was used to examine HGF mRNA and protein expression
      in eutopic and ectopic endometrium obtained from 54 women in reproductive age
      with endometriosis confirmed by laparoscopy and histological examination
      (including 28 cases of stages I/II and 26 of stages III/IV) and from the
      endometrium of 24 healthy fertile women. RESULTS: In patients with endometriosis,
      the positivity rate of HGF/c-Met expression was similar in the eutopic and
      ectopic endometria, but the number of positive cells and expression intensity
      were much higher in ectopic endometrium. The positive expression rate varied
      little between the proliferative and secretory stages of the endometrium. Compare
      with the healthy controls, patients with endometriosis of stages I/II and III/IV
      had significantly elevated positivity rate of HGF and c-Met expressions in either
      eutopic and ectopic endometrium, but without significant difference between the
      two patient groups (P<0.01). The rate of strong c-Met protein expression was
      significantly higher in III/IV endometriosis than in the controls, without
      statistical difference between other groups. CONCLUSION: The expressions of HGF
      and c-met gene are correlated with the pathogenesis of endometriosis, which is
      preceded by eventful changes in the biological behavior of the eutopic
      endometrium.

PMID- 15201073
TI  - [Construction of recombinant adenoviruses containing cytosine deaminase gene
      driven by the vascular endothelial growth factor promoter using an AdEasier-1
      system].
AB  - OBJECTIVE: To efficiently construct a recombinant adenovirus containing cytosine
      deaminase (CD) gene driven by vascular endothelial growth factor (VEGF) promoter
      using an AdEasier-1 system and observe its killing effect on LoVo cells in vitro.
      METHODS: The CD gene was amplified by PCR, and amplicons were cloned in JM109
      bacteria, and then recombined into pREP8 to obtain pREP8-CD, which was then
      digested by HindIIIand XbaIfor the CD fragment with polyadenylation site (CD-pA)
      subcloned into the VEGFP -containing shuttle plasmid pAdtrack-VEGFP to generate
      pAdtrack-VEGFP-CD-pA. After linearization with PmeI, pAdtrack-VEGFP-CD-pA was
      transformed into AdEasier-1 cells, and the transformants were selected on LB agar
      plates containing 25 microg/ml kanamycin followed by identification of the
      positive pAdEasy-VEGFP-CD with electrophoretic analysis and enzymatic digestion.
      pAdEasy-VEGFP-CD was then digested with PacIand transfected into 293 cells to
      produce the recombinant adenovirus Ad-VEGFP-CD, which was finally confirmed by
      PCR. The positive recombinant adenoviruses were transfected into LoVo cells to
      observe their in vitro anti-tumor effect. RESULTS: pAdEasy-VEGFP-CD was
      constructed with a success rate of 70%. After being packaged in 293 cells and
      purified by CsCl banding, the titer of the recombinant adenovirus Ad-VEGFP-CD
      reached as high as 4.8x10(12) CFU particle/ml, and the adenovirus was further
      confirmed by PCR analysis. In the presence of the prodrug 5-FC, the recombinant
      adenoviruses remarkably inhibited the growth of LoVo cells. CONCLUSION: The
      recombinant adenoviruses containing CD gene under the control of VEGF promoter
      can be efficiently generated using the AdEasier-1 system, and exhibit potent anti
      tumor effect in vitro.

PMID- 15201074
TI  - [Construction and expression of the fusion vector of His-tagged human ARPC2
      gene].
AB  - OBJECTIVE: To construct the expression vector of His-ARPC2 fusion protein and
      obtain its expression and purification in E. coli. METHODS: ARPC2 cDNA codon
      region was amplified by PCR from human liver cDNA library and cloned into pET-14b
      vector following the routine procedures. After identification by enzyme
      digestion, PCR and sequencing, the positive clones were transformed into BL21
      (DE3) competent cells, and the expression of His-ARPC2 fusion protein was induced
      with IPTG and further purified by Ni-NTA affinity chromatography. RESULTS: The
      constructed His-ARPC2 fusion protein vector was highly efficiently expressed in
      E. coli. With Ni-NTA affinity chromatography, a purified His fusion protein with
      relative molecular mass of approximately 36 000 was obtained. CONCLUSION: The
      expression vector of His-ARPC2 fusion protein is constructed, expressed and
      purified under non-denaturing conditions, which may significantly facilitate
      future study of the physiological functions of ARPC2 and characterization of its
      interaction proteins.

PMID- 15201075
TI  - [Pretreatment with aspirin for protection against heat stroke in rats].
AB  - OBJECTIVE: To observe the changes in blood pressure and interleukin-1beta (IL
      1beta) level after heat stroke in rats and to observe the protective effect of
      pretreatment with aspirin against heat stroke. METHODS: Rat models of heat stroke
      were established and randomly assigned into control (n=10) and aspirin groups
      (n=10). Arterial blood pressure, colonic temperature (T(co)), and
      electrocardiograph (ECG) were monitored and blood samples taken at 0 and 60 min
      after heat exposure for determining the plasma IL-1beta levels in the two groups.
      RESULTS: From 0 to 50 min after heat exposure, the mean arterial blood pressure 
      MAP  was not significantly different between the two groups, but at about 55-60
      min, the MAP significantly decreased in the control group in comparison with the
      aspirin group (P<0.01). The K value and the height of the dicrotic notch (h(D)/H)
      were gradually decreased, especially at 40 min after heat exposure, and the
      control group showed greater reduction in the K value. T(co) of both groups were
      increased after heat exposure, without significant difference between groups. The
      time of the onset of heat stroke was similar in the two groups, but rats in the
      aspirin group had significantly longer survival time (P<0.05). ECG showed that
      the heart rate and QT intervals of both groups were increased, while PR intervals
      were decreased after heat exposure. Plasma IL-1beta levels in the two groups were
      significantly elevated at 60 min in comparison with the basal level (P<0.05),
      which was more obvious in the control group (P<0.05). CONCLUSION: Pretreatment
      with anti-inflammatory dose of aspirin can provide protection against heat stroke
      in rats, which may be associated with the inhibition of elevation of plasma IL
      1beta levels by aspirin.

PMID- 15201077
TI  - [Biocompatibility evaluation of chitosan-g-polyvinylpyrrolidone].
AB  - OBJECTIVE: To evaluate the biocompatibility of chitosan-g-polyvinylpyrrolidone as
      a new scaffold material. METHODS: The material was tested and measured for water
      absorption and contact angle, followed by evaluation of the biocompatibility by
      implantation into rabbits and in vitro cultured with the corneal epithelial
      cells. RESULTS: The water absorption rate of the material reached 1 100% with
      contact angle of 83-86. The results of implantation revealed partial degradation
      of the material 3 months after implantation, and much collagen and numerous
      corneal stromal cells appeared on the material without obvious inflammation
      reactions. In vitro coculture with epithelial cells showed good adhesion of the
      cells to the material which induced no obvious cytotoxicity. CONCLUSION: The
      novel chitosan derivative has excellent biocompatibility and can be used as a
      tissue scaffold material.

PMID- 15201076
TI  - [Effect of percutaneous intervention on adrenomedullin and tumor necrosis factor
      in the coronary circulation].
AB  - OBJECTIVE: To evaluate the effect of percutaneous intervention (PCI) on coronary
      circulation levels of adrenomedullin (ADM) and tumor necrosis factor alpha (TNF
      alpha) in patients with coronary heart disease (CHD). METHODS: Thirty-three CHD
      patients underwent percutaneous transluminal coronary angioplasty (PTCA) and
      stenting (altogether 48 stents were implanted). Blood samples were collected from
      the coronary sinus and femoral artery at the time points of immediately before
      and after angioplasty, immediately after PTCA or stenting, 10 min after
      procedures, respectively. RESULTS: The ADM and TNF-alpha levels in the coronary
      sinus varied little after coronary angiography, but were elevated markedly
      following PTCA from the basal levels of 36.3+/-1.3 pg/ml to 28.9+/-1.9 pg/ml
      (P<0.01) and from 11.10+/-0.46 ng/ml to 8.84+/-0.37 ng/ml (P<0.01), respectively.
      Further increases of ADM and TNF-alpha levels were detected immediately after
      stent deployment. ADM recovered to basal levels 10 min after completion of the
      procedures, while TNF-alpha underwent further increase. Before the procedure, ADM
      and TNF-alpha levels were higher in the coronary sinus than in the femoral artery
      (28.9+/-1.9 pg/ml vs 22.6+/-0.8 pg/ml, P<0.01; 8.84+/-0.37 ng/ml vs 7. 56+/-0.23
      ng/ml, P<0.01, respectively), and their levels in the femoral artery did not
      undergo significant changes in response to the operations. CONCLUSION: The
      coronary circulation levels of ADM and TNF-alpha increase after PTCA and stenting
      but not after coronary angiography in CHD patients, which might be attributed to
      injuries by the procedures as well as the mechanical stimulation by the stent.

PMID- 15201078
TI  - [Urotensin II induces hypertrophy of in vitro cultured neonatal rat cardiac
      myocytes].
AB  - OBJECTIVE: To examine whether urotensinII (UII) induces hypertrophy of neonatal
      rat cardiomyocytes cultured in vitro. METHODS: The primary cardiac myocytes
      cultured for 40 h followed by further culture in serum-free media for another 24
      h were subjected to exposure to UII of varied concentrations for 24 h, after
      which the changes in the size of the cells were analyzed by flow cytometry with
      (3)H-leucine incorporation also measured. RESULTS: At the concentration of 1x10(
      7) mol/L, UIIcould increase the size of the cultured cardiac myocardial cells
      (P=0.021) and 3H-Leucine incorporation (P=0.015). CONCLUSION: UII may induce
      hypertrophy of neonatal rat cardiac myocytes cultured in vitro.

PMID- 15201079
TI  - [Expression of multidrug resistance gene in nasopharyngeal carcinoma cells after
      irradiation exposure].
AB  - OBJECTIVE: To examine the changes in the function and expression of multidrug
      resistance gene (mdr1) and P-gly-coprotein (P-gp) in nasopharyngeal carcinoma
      (NPC) CNE1 cell following irradiation for determining the sequential order of
      radiotherapy and chemotherapy in the treatment of NPC. METHODS: The expressions
      of mdr1 gene and its protein P-gp as well as the function of P-gp efflux were
      examined in CNE1 cells before and after irradiation exposure by reverse
      transcriptional polymerase chain reaction (RT-PCR), Western blotting and flow
      cytometry, respectively. RESULTS: Irradiation of CNE1 cells induced a long-term
      overexpression of mdr1 gene and P-gp and reduction in intracellular daunorubicin
      accumulation. CONCLUSION: Irradiation decreases the chemotherapy sensitivity of
      CNE1 cell, and induction chemotherapy should be therefore performed before
      radiotherapy in the treatment of advanced NPC.

PMID- 15201080
TI  - [Distribution of -477C/T single nucleotide polymorphism in the promoter region of
      ABCA1 gene and its significance for plasma lipids levels in normal Chinese Han
      population].
AB  - OBJECTIVE: To investigate the distribution of -477C/T single nucleotide
      polymorphisms (SNP) in the promoter region of ATP binding cassette transporter
      (ABCA1) gene and its relation to plasma lipid levels in normal Chinese Han
      population. METHODS: The three genotypes of -477C/T polymorphisms in the promoter
      region of the ABCA1 gene were detected using polymerase chain reaction
      restriction fragment length polymorphism (PCR-RFLP) in 113 normal Chinese Han
      subjects. RESULTS: -477C/T SNP was present in normal Chinese Han population, and
      37.2% (42) of the examined subjects belonged to the genotype of CC, 46.9% (53)
      belonged to CT and 15.9% (18) to TT. The individuals with the TT genotype had a
      lower plasma high-density lipoprotein cholesterol (HDL-C) level than those with
      the CC genotype (P<0.05). No association was found between the genotypes and
      plasma levels of total cholesterol, triglyceride, low-density lipoprotein, very
      low-density lipoprotein and body mass index. CONCLUSION: The TT genotype
      significantly influences the plasma levels of HDL-C in normal Chinese Han
      individuals.

PMID- 15201081
TI  - [In vitro cleavage activity of the ribozymes constructed specifically for the
      second exons of pro alpha I and III collagen genes].
AB  - OBJECTIVE: To study the in vitro cleavage activity and the reaction conditions of
      the hammerhead ribozymes for the second exons of pro alpha 1I and III collagen
      genes, and observe the effect of the two ribozymes on collagen synthesis by the
      fibroblasts in scar tissue. METHODS: The fragments of the second exons of pro
      alpha 1I and III collagen genes were cloned into the plasmids pT-I and pT-III and
      labeled with (32)P during transcription to obtain the target RNA. The
      transcription products of the plasmids pT-gI and pT-gIII containing specific
      ribozymes were incubated with the label target RNAs, respectively, under various
      conditions, and the results observed by electrophoresis autoradiography. The
      constructed ribozymes were transduced into cultured fibroblasts via liposomes for
      investigation of their effects on mRNA synthesis of type I and III collagen
      protein by image analysis. RESULTS: The two ribozymes (rgI and rg III) could
      efficiently cleave their target RNAs at both 37 degrees Celsius and 42 degrees
      Celsius, in the presence of Mg(2+) within a relatively wide concentration range
      form 10 to 20 mmol/L. When the temperature was lowered from 65 degrees Celsius to
      37 degrees Celsius and maintained at 37 degrees Celsius, the cleavage activity of
      the ribozymes reached the maximum. The expression of mRNA of I and III collagen
      decreased accompanied by reduced collagen synthesis. CONCLUSION: Hammerhead
      ribozymes for the fragments of the second exons of pro alpha 1I and III collagen
      genes can cleave its target RNAs in vitro and effectively inhibit the collagen
      synthesis by the scar-derived fibroblasts.

PMID- 15201082
TI  - [Effect of cyclosporine A on myocardial calcineurin activity of the right
      ventricle and plasma NO, nitric oxide synthase and endothelin-1 levels in rats
      with chronic hypoxia].
AB  - OBJECTIVE: To study the role of calcineurin in the progression of right ventricle
      myocardial hypertrophy in rats exposed to chronic hypoxia by examining the effect
      of Ca(2+) channel blockers on the activation of calcineurin and plasma levels of
      nitric oxide (NO), NO synthase, and endothelin-1 (ET-1). METHODS: Rat models of
      right ventricle myocardial hypertrophy were established by exposing the rats to
      chronic hypoxia in 10.0%+/-0.5% O(2) for 7 d. The 24 rat models were assigned
      into normoxic group, hypoxic group and cyclosporin A (CsA)-treated hypoxic group.
      The rats in normoxic group were kept under normoxic environment, while those in
      the other 2 groups were subjected to further hypoxic treatment for 14 d, with the
      rats in CsA group receiving intraperitoneal CsA injection at 20 mg/kg on a daily
      basis. On day 21 of the experiment, all the rats were killed to collect the
      hearts for measuring the weight ratio of the right ventricle to the left
      ventricle and interventricular septum [RV/  LV+S  ], as well as the right
      ventricle to body weight ratio (RV/BW); blood samples were also drawn from the
      ventricles for measuring plasma NO, iNOS, and ET-1 levels, with the ventricular
      myocardial [Ca(2+)](i) and the activity of calcineurin also determined. RESULTS:
      The RV/(LV+S) and RV/BW were significantly higher in hypoxic group than those of
      the normoxic and CsA groups (P<0.01); the right ventricular myocardial
      [Ca(2+)](i) in CsA group was significantly higher than that in the other two
      groups (P<0.01). In comparison with the normoxic group, the right ventricular
      myocardial calcineurin activity was significantly increased in the hypoxic group.
      CsA treatment significantly suppressed calcineurin activity (P<0.01).
      CONCLUSIONS: Calcineurin possibly plays a role in the progression of right
      ventricle myocardial hypertrophy in rats with chronic hypoxia. Blocking L-type
      Ca(2+) channels with CsA effectively prevents the development of myocardial
      hypertrophy possibly by inhibiting calcium influx and suppressing calcineurin
      activity.

PMID- 15201083
TI  - [Neuronavigation-assisted microanatomical study of the facial nerve canal through
      the transpetrosal approach].
AB  - OBJECTIVE: To study the value of neuronavigation in the transpetroal approach,
      and to provide anatomic data for the protection of the nerves in the facial nerve
      canal (FNC) during surgeries. METHODS: Simulated surgery through the transpetroal
      approach was performed on 16 sides of 8 adult cadaver heads with the assistance
      by neuronavigation. The anatomy of the facial nerve and the relationship of
      related structures were observed and the distances from the utmost external edge
      of the mastoid to different segments of the FNC were measured. RESULTS:
      Neuronavigation was successful with all the FNC, with the mean error of less than
      0.9 mm. The FNC could be divided into 3 segments, the labyrinthine, the tympanic
      and the mastoid segments, stretching 3.6+/-1.2 mm, 11.2+/-2.5 mm and 16.1+/-3.6
      mm respectively and with diameters of 1.2+/-0.3 mm, 1.4+/-0.1 mm and 1.7+/-0.2
      mm, respectively. CONCLUSION: Neuronavigation may help protect the FNC during
      surgical procedures, and a thorough knowledge of the anatomic features of the FNC
      can be significant for preservation of the facial nerves.

PMID- 15201084
TI  - [Expression of hMSH2 gene in esophageal cancer].
AB  - OBJECTIVE: To observe the expression of DNA mismatch repair gene hMSH2 mRNA in
      esophageal cancer tissues. METHODS: This study included 32 esophageal cancer
      patients who received no previous radiotherapy, chemotherapy or other treatments.
      Within 30 min following surgical removal of the tumor tissues, specimens of the
      tumor, the tissue adjacent to the tumor and normal tissue at the esophageal stump
      (1 cmx1 cmx1 cm in size for each specimen) were obtained for examining hMSH2
      expression with hMSH2 ISH detection kit. RESULTS: The positivity rate of hMSH2
      was 46.88% in the esophageal cancer tissues, 53.12% in the adjacent tissues, and
      84.38% in normal tissues at the esophageal stump, showing significant difference
      of the former two tissues from the normal tissue (P<0.05). No significant
      correlation was noted between the positivity rate of hMSH2 and such factors as
      the patients' age, sex, tumor size, tumor location, pathological type,
      histological grade, lymphatic metastasis or degree of tumor invasion (P>0.05).
      CONCLUSION: The deletion of hMSH2 is an early event in the development of
      esophageal cancer.

PMID- 15201085
TI  - [Respiratory distress syndrome induced by immersion in seawater: a study of
      canine models].
AB  - OBJECTIVE: To study the mechanism of respiratory distress syndrome (RDS) induced
      by immersion in seawater to provide experimental evidence for its treatment.
      METHODS: Twelve normal hybrid dogs were randomly assigned into control group
      (n=4) and SDS model group (n=8). The changes in blood dynamics, blood gas
      analysis and histological changes in the lung tissues were compared between the 2
      groups. The concentration of lactic dehydrogenase (LDH-L) and alkaline
      phosphatase (ALP) in the bronchoalveolar fluid and blood of the dogs in the model
      group were tested. RESULTS: The blood dynamics, blood gas analysis and histology
      of the dogs in the model group were significantly different from those in the
      control group, and LDH-L and ALP levels increased significantly in the
      bronchoalveolar fluid of the model group. CONCLUSION: Seawater aspiration into
      the lungs may lead to RDS, and the canine models used in this study may help
      explore the mechanism and management of RDS induced by immersion in seawater.

PMID- 15201086
TI  - [Comparison of the tri-cuff and classical methods for vascular anastomosis in
      heterotopic small bowel transplantation in rats].
AB  - OBJECTIVE: To explore the effect of the tri-cuff vascular anastomosis for
      simplifying the surgical procedure and improving the success rate. METHOD: Sixty
      recipient Wistar rats were randomized into experimental group and the control
      group, the former was subjected to the tri-cuff vascular anastomosis for
      heterotopic small bowel transplantation while the latter had vascular anastomosis
      using classical methods. The effects of the two methods for anastomosis were
      compared. RESULTS: The tri-cuff vascular anastomosis was superior to the
      classical methods in view of the total operation time, arterial anastomosis time,
      and hot-ischemia time of the small bowel graft. CONCLUSION: Compared with the
      classical methods, the tri-cuff vascular anastomosis is safer and time-saving.

PMID- 15201087
TI  - [Preparation and characterization of anti-morphine antiserum].
AB  - OBJECTIVE: To prepare the holoantigens of morphine and morphine-6-succinyl, and
      to evaluate the efficacy of both of the haptens in eliciting immune responses and
      their effects on morphine withdrawal symptoms in male mice. METHODS: Morphine-6
      succinyl was prepared using acid anhydride mixture, and conjugated, along with
      morphine, with Blue carrier in the presence of carbodi imide. Immunization of
      mice with both the holoantigens and Freund adjuvant was performed, followed by
      determination of the antibody titer in the mouse serum with competitive ELISA and
      morphine dependence evaluation. RESULTS: The titers of the antibodies exceeded
      1:8 000 in the serum of mice immunized with both holoantigens, and morphine- 6
      succinyl induced a higher titer that was maintained for a longer period. The
      inhibition rates of the antisera to morphine and morphine-6-auccinyl had both
      reached 50%, and increased in a dose-dependent manner. CONCLUSION: Both morphine
      carrier conjugates can elicit high-titer antibody response in mice and relieve
      morphine addiction.

PMID- 15201088
TI  - [Dynamic contour tracking of medical images based on improved particle filter].
AB  - In the research of medical image processing, motion estimation and tracking
      relating to the region of interest has been given considerable attention. For
      improving the quality of the noisy or cluttered medical images, the particle
      filter (PF) based on the non-linear and non-Gaussian Bayesian State Estimation is
      a better as well as a technically challenging solution. As the algorithm of
      particle weights, especially the importance density function, often severely
      affects the performance of the PF, we propose in this paper a better algorithm
      for its improvement; in addition, to ensure better tracking of the dynamic
      contour with the PF, we proposed a new algorithm for the likelihood and prior
      probability density. Objective theoretical evaluation and substantial comparative
      experiments suggest that this method can be a good solution for accurate dynamic
      contour tracking.

PMID- 15201089
TI  - [Hepatitis C virus infection and clinical outcome of kidney transplantation].
AB  - OBJECTIVE: To study the influence of hepatitis C virus (HCV) infection on the
      clinical outcome of kidney transplantation. METHODS: The recipient/graft
      survival, the incidence of acute/chronic rejection and cause of death in 86 HCV
      infected recipients of renal transplantation were compared with those in another
      86 recipients without HCV infection. RESULTS: HCV-infected recipients had
      significantly shorter 5-year survival (74.4%) than those without HCV infection
      (87.2%, P<0.01). The 1-year (94.2%/90.7% vs 96.8%/96.0%) and 3-year
      recipient/graft survival rates (88.4%/79.1% vs 90.7%/87.2%), the incidence of
      acute/chronic rejection (31.3% vs 21.2%, and 12.5% vs 6.5%) and the 5-year graft
      survival (73.3%/81.4%) were comparable between the two groups (P>0.05). Hepatic
      disease was identified as the primary cause of mortality. CONCLUSIONS: HCV
      infection may affect the long-term survival of the recipients with kidney
      transplantation, and therefore should be considered as a relative
      contraindication of kidney transplantation.

PMID- 15201090
TI  - [Evaluation of steal phenomena by measuring the steal index using transcranial
      Doppler ultrasound in intracranial arteriovenous malformation].
AB  - OBJECTIVE: The authors previously deduced a formula for calculating the steal
      index (SI) for evaluation of the steal phenomena during the development of the
      collateral circulation resulting from unilateral carotid artery occlusion or
      stenosis. In this study the authors examine the application of SI in evaluating
      the steal phenomena of cerebral blood flow in cases of intracranial arteriovenous
      malformation (AVM). METHODS: The clinical data of 16 cases of AVM confirmed by
      both digital subtraction angiography (DSA) and transcranial Doppler (TCD)
      ultrasound were analyzed retrospectively. The ratio of the mean blood velocity in
      the direct or indirect feeding artery (Vmfv) for the area containing AVM to the
      mean blood velocity in the neighboring feeding artery (Vmna), Vmfv/Vmna, was
      compared with SI of the corresponding arteries (SI=1-PI(1)/PI(2), where PI(1) is
      the pulsatility index of the feeding artery and PI the pulsatility index of the
      neighboring feeding artery), and the correlation between SI and the size of AVM
      was analyzed statistically. RESULTS: The Vmfv/Vmna of (2)direct and indirect
      feeding arteries for AVM both exhibited positive correlation with SI (r=0.62,
      P<0.05, n=16; r=0.53, P<0.01, n=27), and SI appeared to be in positive
      correlation with the size of AVM, but which failed to be supported by statistical
      analysis (r=0.48, P>0.05, n=12). CONCLUSION: The sizes, types and development of
      the vascular bed of AVM can be evaluatea by analysis of SI derived from TCD in
      combination with DSA.

PMID- 15201091
TI  - [Effect of fast-acting spray for heat stroke in enhancing heat tolerance of
      rats].
AB  - OBJECTIVE: To observe the effect of fast-acting spray for heat stroke, a
      preparation of traditional Chinese drugs, in enhancing the heat tolerance in
      rats. METHODS: Thirty SD rats were randomized into 3 groups(with 10 in each
      group), and group A was treated with the fast-acting spray for heat stroke, group
      B with chlorpromazine, and group C with cool boiled water, before they were
      exposed to heat at 41 degrees Celsius in a heat chamber with relative humidity of
      70% till death. The rats' rectal temperature was measured before and 1 h after
      the heat exposure, and the time when death occurred in the rats was recorded.
      RESULT: In comparison with group C, the rats in groups A and B had lower rectal
      temperature and prolonged survival time with decrease mortality. CONCLUSION: The
      fast-acting spray for heat stroke we prepared may enhance the heat tolerance of
      rats.

PMID- 15201092
TI  - [Lower limb hemodynamic evaluation in patients with diabetic foot using 99mTc
      methylene diphosphonate three-phase bone scintigraphy].
AB  - OBJECTIVE: To evaluate the efficacy of (99m)Tc-methylene diphosphonate (MDP) bone
      scintigraphy in diagnosis of diabetic foot. METHODS: (99m)Tc-MDP three-phase bone
      imaging was performed in 56 patients with diabetic foot and 36 non-diabetic
      control subjects, each foot was analyzed independently. The radioactive
      concentration per pixel hence the foot to tibia ratio (R(m/t)) was calculated and
      the time-radioactivity curve of each region of interest generated. From the curve
      the perfusion time (Tp) was read and the velocity of uptake rate (V) of the foot
      calculated. The indices such as R(m/t), Tp and V were compared between the two
      groups by t test, and the diagnostic indices such as sensitivity, specificity,
      accuracy, positive prediction value and negative predictive value were compared
      using u test. RESULTS: In the control group, the Tp, V and R(m/t) were 32.9+/-9.8
      s, 2.301+/-0.754 counts/s and 0.85+/-0.29, respectively, which were 36.1+/-15.3
      s, 1.574+/-0.341 counts/s and 0.72+/-0.31 respectively in the diabetic group. Tp
      was not significantly different (t=1.693, P>0.05) between the two groups, as was
      V (t=8.396, P<0.001) and R(m/t)(t=2.759, P<0.01). When V was used as the index,
      the sensitivity, specificity, and accuracy were 80.2%, 82.8% and 81.5%,
      respectively, and those for R(m/t) were 65.2%, 68.8% and 67.3%, respectively. By
      comparison, the sensitivity (u=2.3274, P<0.05) and specificity (u=2.4068, P<0.05)
      of V were significantly higher than those of R(m/t). CONCLUSIONS: (99m)Tc-MDP
      three-phase bone imaging can identify decreased uptake rate and R(m/t) in the
      diabetic foot, and the former index can be more sensitive and specific to define
      the hemodynamics in the diabetic foot. This technique may detect hemodynamic
      abnormity in early stage and greatly assist the diagnoses and treatment.

PMID- 15201093
TI  - [Radiotherapy with concurrent chemotherapy for treatment of advanced
      nasopharyngeal carcinoma].
AB  - OBJECTIVE: To evaluate the effect of radiotherapy combined with concurrent
      chemotherapy for the treatment of advanced nasopharyngeal carcinoma. METHODS:
      From February 2001 to August 2003, 80 cases of nasopharyngeal carcinoma (stage
      III and IVa) were randomized into two groups to receive radiotherapy with
      concurrent chemotherapy (Group A, n=40) consisted of leucovorin (CF, 100 mg/m(2),
      days 1-5), 5-fluorouracil (5-Fu, 500 mg/m(2), days 1-5), cisplatin (DDP, 60
      mg/m(2), day 1) for one course followed by another 4 weeks later, or radiotherapy
      alone (Group B, n=40). In all cases, the radiotherapy followed the same protocol,
      with the nasopharyngeal (NP) total dose (DT) of 66-76 Gy given in 6.6-7.6 weeks,
      and cervical lymphnode (LN) DT of 60-72 Gy completed in 6.0-7.2 weeks. RESULTS:
      All patients completed the treatment course, and the complete response rates of
      the primary lesions and cervical nodes in A and B groups were 77.5% and 60.0%
      (P>0.05) and 92.5% vs 70.0% (P<0.05), respectively, which were 92.5% vs 72.5%
      (P<0.05) and 100% vs 85.0% (P<0.05), respectively, 3 months after treatment. No
      obvious toxicity was observed in the two groups except for vomiting and
      leukopenia. CONCLUSION: Radiotherapy with concurrent chemotherapy can improve the
      elimination rate of advanced nasopharyngeal carcinoma, and can be completed in
      shorter treatment course in comparison with neoadjuvant chemotherapy before
      radiotherapy, eligible for clinical practice in the treatment of advanced
      nasopharyngeal carcinoma.

PMID- 15201094
TI  - [18F-Fluorodeoxyglucose uptake in hepatocellular carcinoma on positron emission
      tomography correlates with alpha-fetoprotein].
AB  - OBJECTIVE: To investigate whether (18)F-fluorodexyglucose (FDG) uptake in the
      primary hepatocellular carcinoma (HCC) correlates with serum alpha-fetoprotein
      (AFP). METHODS: Forty-five patients with histologically confirmed HCC underwent
      whole-body (18)F-FDG PET examination. Standardized uptake value (SUV) and tumor
      to-nontumor ratio of the SUV (SUVratio) were calculated, and the relationship
      between serum AFP and glucose metabolism in HCC was analyzed. RESULTS: Of the 45
      cases, the primary tumor and metastatic lymph nodes were clearly displayed on PET
      images in 43 cases and the well-differentiated tumors were shown negative in the
      other 2 cases. A linear correlation of the AFP with SUV (r=0.426, P<0.05) and
      SUVratio (r=0.532, P<0.001) was noted. CONCLUSION: Serum AFP correlates
      significantly with both SUV and SUN ratio, indicating that AFP is involved in
      glucose metabolism and cell proliferation in HCC.

PMID- 15201095
TI  - [Value of integrated positron-emission tomography and computed tomography in
      gross tumor volume delineation for radiotherapy for bone metastasis].
AB  - OBJECTIVE: To evaluate the role of integrated positron-emission tomography and
      computed tomography (PET/CT) in gross tumor volume (GTV) delineation for three
      dimensional conformal radiotherapy for bone metastasis. METHODS: Three patients
      with multiple bone metastases were enrolled in this study, whose primary tumors
      were pathologically identified as lung cancer, liver cancer and renal cell
      carcinoma. In each case, 6 sites of bone metastases were selected, labeled as BM1
      to BM6 which located in the lumbar, thoracic vertebra, rib, ilium, scapula and
      thighbone respectively. The GTVs of the 6 bone metastases were delineated on the
      CT scans for treatment planning by 8 radiation oncologists, and the results were
      compared with the delineation obtained on the basis of integrated CT and PET/CT
      for analyzing the interobserver variability. RESULTS: For BM1-5 with obvious bone
      cortex lesions by the carcinoma, the GTV delineated on the basis of CT was
      greater than that derived from PET/CT (P<0.05), whereas for BM6 with intact bone
      cortex, the contrary result was observed (P<0.05). For any of these bone
      metastasis, the interobserver variability in GTV delineation with PET/CT was less
      than that with CT. CONCLUSION: PET/CT is useful for improving the accuracy of GTV
      delineation for the protection of the normal tissues during radiotherapy.

PMID- 15201096
TI  - [Establishment of canine models of acute mesenteric ischamia].
AB  - OBJECTIVE: To establish a new canine model of acute mesenteric ischemia for
      imaging studies. METHODS: Ten Beagle dogs were divided into ischemic group (n=8)
      and control group (n=2). Via a 4F Cobra catheter, the absolute ethanol was
      selectively injected into the superior mesenteric artery (SMA) for embolization
      in the former group while the saline was injected in the latter. Imaging study
      and pathological examination were performed. RESULTS: Digital subtraction
      angiography (DSA) revealed that occlusion of some branches of the SMA was induced
      in the ischemic group while no changes occurred in the control group. The signs
      of acute mesenteric ischemia were confirmed by CT and pathological examination in
      the ischemic group whereas no abnormalities identified in the group. CONCLUSION:
      Canine models of acute mesenteric ischemia can be established by selective
      catheterization with absolute ethanol injection.

PMID- 15201097
TI  - [Rehabilitation therapy in early stage following spinal cord injuries].
AB  - OBJECTIVE: To investigate the effects of rehabilitation therapy in early stage
      following spinal cord injury on the patients' activities of daily living (ADL)
      and functional independence measure (FIM). METHODS: Ninety-two patients with
      spinal cord injuries were divided into early rehabilitation group (n=48) and
      control group (n=44) according to the timing of the rehabilitation therapy.
      Rehabilitation assessment of the patients with Barthel index and FIM was carried
      out before and 6 months after the rehabilitation therapy respectively for
      comparison. Different rehabilitation regimens were adopted for specific clinic
      stage of the patients, lasting for a total of 6 months. RESULTS: Barthel index
      and FIM score were all improved after the rehabilitation therapy in both of the
      two groups, but the improvements were more significant in early rehabilitation
      group (P<0.01). CONCLUSION: Early rehabilitation treatment is crucial for
      patients with spinal cord injuries in that it improves the patients' motor
      function, ADL and functional independence after the injury.

PMID- 15201098
TI  - [Iontophoresis with traditional Chinese herbal medicine accelerates the healing
      of bone fracture].
AB  - OBJECTIVE: To observe the effect of iontophoresis with traditional Chinese herbal
      medicine on the healing of bone fracture. METHODS: Twelve New Zealand rabbits
      with tibial fracture were treated by iontophoresis with traditional Chinese
      herbal medicine. A retrospective study of 52 clinical cases of tibial fracture
      treated with the iontophoresis was also performed in comparison with 50 control
      cases. RESULTS: The total effective rate was 100% and in the clinical cases,
      treatment with the iontophoresis resulted in accelerated healing of the tibial
      fracture, which took place 10 d earlier than that in the control cases. The
      follow-up of the patients lasting for 4 to 12 months found satisfactory healing
      of the fractures with functional recoveries. CONCLUSION: Iontophoresis with
      traditional Chinese herbal medicine promotes blood circulation and accelerates
      the growth of bony callus, and provides a new therapeutic approach for promoting
      the healing of bone fractures.

PMID- 15201099
TI  - [Localization for collagenase injection through the lateral crypt for lumbar disc
      herniation].
AB  - OBJECTIVE: To find a more reliable and effective localization method for
      collagenase injection through the lateral crypt for the treatment of lumbar disc
      herniation. METHODS: Before collagenase injection for lumbar disc
      chemonucleolysis, the site with obvious tenderness was labeled with a lead marker
      on the surface of the intervertebral space, followed by a more accurate
      localization with the assistance of X-ray, chest fluoroscopy and CT. RESULTS:
      Satisfactory results were achieved in 88.3% of the cases using the new
      localization method, with an overall improvement rate of 95.9%, which were 10.5%
      and 6.7% higher than those of cases without using the method. CONCLUSION:
      Localization with lead markers in combination with X-ray, chest fluoroscopy and
      CT is more accurate, safe, economic and effective for collagenase injection
      through the lateral crypt in the treatment of lumbar disc herniation.

PMID- 15201100
TI  - [Design of the medical record database of diabetes mellitus].
AB  - The system requirement of the clinical record database of diabetes mellitus was
      analyzed, the functional module built and the design scheme established on the
      basis of the general design objective for a distributed database with distributed
      objects.

PMID- 15201101
TI  - [Content determination of S-citalopram by chiral high-performance liquid
      chromatography].
AB  - OBJECTIVE: To separate the enantiomers of citalopram and determine the content of
      S-citalopram using chiral high-performance liquid chromatography (HPLC). METHODS:
      The chiral column CHIROBIOTIC V was used with the mobile phase using methanol
      acetic acid-triethylamine (100:0.1:0.1) at the detection wavelength of 240 nm,
      column temperature of 20 degrees Celsius and flow rate of 1.0 ml/min. RESULTS:
      Complete separation of the enantiomers of citalopram was achieved, and S
      citalopram exhibited good linearity within the concentration range of 10 to 150
      microg/ml (r=0.9991, n=5). CONCLUSION: This method allows accurate quantification
      of S- and R-citalopram and is well suited for drug interaction investigations.

PMID- 15201102
TI  - [Experience with laparoscopic management of internal hemorrhage in tubal
      pregnancy in middle-sized and small hospitals: report of 76 cases].
AB  - The authors examine the application of laparoscopy in the management of internal
      hemorrhage in tubal pregnancy in middle-sized and small hospitals. Altogether 76
      such cases were collected for a review of the effects of laparoscopic management,
      and all were treated successfully without any complications. Laparoscopy causes
      minimal invasion in the management of internal hemorrhage in tubal pregnancy and
      may bring about rapid recovery of the patients, but the curative effects depend
      on the technical competence of the surgeon and the laparoscopic equipment.

PMID- 15201103
TI  - [Acupuncture and ultrasound therapy for temporomandibular disorders].
AB  - This study was designed to compare the therapeutic effect acupuncture in
      combination with ultrasound therapy with that of ultra short-wave electrotherapy
      on temporomandibular disorders (TMD). Sixty-eight patients with TMD were
      randomized equally into 2 groups to receive the two treatments respectively, and
      the therapeutic effects were found to be significantly different (P<0.05).
      Acupuncture combined with ultrasound therapy yielded better results in a shorter
      treatment course.

PMID- 15201104
TI  - [Clinical effects of preoperative chemotherapy for Wilms tumor].
AB  - OBJECTIVE: To evaluate the effects of preoperative chemotherapy for Wilms' tumor.
      METHODS: Thirty-five surgically treated cases of Wilms tumor were retrospectively
      analyzed, 27 of which received preoperative chemotherapy. RESULTS: After
      chemotherapy, the tumor volume reduced obviously in 17 cases and adverse effects
      of the chemotherapeutic agents occurred in 15 cases. Subsequent operation was
      performed in all the patients, of whom 1 died during the operation, 4 had delayed
      healing of the incisions and 5 still had decreased leucocytes. CONCLUSIONS:
      Chemotherapy before the operation for Wilms tumor can effectively reduce the
      complications of the operation. Appropriate chemotherapy protocol and vigorous
      conservative drug therapy help prevent the occurrence of adverse effects and
      complications of the chemotherapy.

PMID- 15201106
TI  - Integrating harm reduction and abstinence-based substance abuse treatment in the
      public sector.
AB  - Harm reduction and abstinence-based substance abuse treatment can not only be
      integrated, but their integration is more powerful than either separately. This
      integration has more positive effects than either model separately on the large
      problem of patient retention in substance abuse treatment. This integration is
      particularly relevant for its utility and acceptance in the public sector.
      Examples from a clinic currently utilizing this model in a public hospital are
      presented.

PMID- 15201107
TI  - Success of referral for alcohol dependent patients from a general hospital:
      predictive value of patient and process characteristics.
AB  - To assess the effectiveness of a multidisciplinary evaluation and referral
      process in a prospective cohort of general hospital patients with alcohol
      dependence. Alcohol-dependent patients were identified in the wards of the
      general hospital and its primary care center. They were evaluated and then
      referred to treatment by a multidisciplinary team; those patients who accepted to
      participate in this cohort study were consecutively included and followed for 6
      months. Not included patients were lost for follow-up, whereas all included
      patients were assessed at time of inclusion, 2 and 6 months later by a research
      psychologist in order to collect standardized baseline patients' characteristics,
      process salient features and patients outcomes (defined as treatment adherence
      and abstinence). Multidisciplinary evaluation and therapeutic referral was
      feasible and effective, with a success rate of 43%for treatment adherence and
      28%for abstinence at 6 months. Among patients' characteristics, predictors of
      success were an age over 45, not living alone, being employed and being motivated
      to treatment (RAATE-A score < 18), whereas successful process characteristics
      included detoxification of the patient at time of referral and a full
      multidisciplinary referral meeting. This multidisciplinary model of evaluation
      and referral of alcohol dependent patients of a general hospital had a
      satisfactory level of effectiveness. Predictors of success and failure allow to
      identify subsets of patients for whom new strategies of motivation and treatment
      referral should be designed.

PMID- 15201108
TI  - Training medical providers to conduct alcohol screening and brief interventions.
AB  - Although progress has been made in developing a scientific basis for alcohol
      screening and brief intervention (SBI), training packages are necessary for its
      widespread dissemination in primary care settings. This paper evaluates a
      training package developed for the Cutting Back SBI program. Three groups of
      medical personnel were compared before and after SBI training: physicians (n =
      44), medical students (n = 88), and non-physicians (n = 41). Although the
      training effects were at times dependent on group membership, all changes were in
      a direction more conducive to implementing SBI. Physicians and medical students
      increased confidence in performing screening procedures, and students increased
      self-confidence in conducting brief interventions. Non-physicians perceived fewer
      obstacles to screening patients after training. Trained providers reported
      conducting significantly more SBI than untrained providers, and these differences
      were consistent with patients' reports of their providers' clinical activity.
      Thus, when delivered in the context of a comprehensive SBI implementation
      program, this training is effective in changing providers' knowledge, attitudes,
      and practice of SBI for at-risk drinking.

PMID- 15201109
TI  - Use of Alcohol Screening and Brief Interventions<br />in Primary Care
      Settings:Implementation and Barriers.
AB  - Although evidence indicates that brief alcohol screening and interventions are
      effective across primary care settings, implementation of these techniques has
      been problematic. The primary objective of this study was to determine current
      practices and barriers for screening and interventions with primary care patients
      across randomly selected clinics in a large health care system, the Veterans
      Health Administration. Focus groups and mailed structured surveys were used.
      Results from providers indicated that 85% of patients treated in primary care
      received some screening for alcohol use disorders. The CAGE was the predominant
      screening tool. The primary clinical focus was on treatment referrals for
      patients who met abuse/dependence criteria. Lack of time was the most important
      perceived barrier to implementing screening and brief alcohol interventions for
      at-risk and problem drinkers. Implications for implementation of screening and
      intervention programs for a range of drinkers (at-risk use, problem use, abuse,
      dependence) are discussed.

PMID- 15201110
TI  - Family-focused smoking cessation:enhanced efficacy by the addition of partner
      support and group therapy.
AB  - While partner support has been found to be an important factor in smoking
      cessation, programs with partner training have not demonstrated improved
      efficacy. The goal of this project was to evaluate the effectiveness of a smoking
      cessation treatment program that included partner support in an innovative
      education/therapy model similar to alcohol and drug treatment programs. Subjects
      included 23 smokers, 71% with a support partner. The program consisted of a
      smoking cessation curriculum, combined with facilitated group therapy for
      participants and partners, and individualized medication evaluation. Smoking
      abstinence was 87% at program completion and 80% at one month follow up, 100%
      abstinence in participants with support and 50% in participants without support
      (p < 0.05). Smoking Stage of Change at enrollment was: contemplation 22%,
      preparation 70%, and action 8%, with 87% movement toward action stage. In the
      present study, partner support enhanced short-term abstinence from smoking.

PMID- 15201111
TI  - Family medicine residents' beliefs, attitudes and performance with problem
      drinkers: a survey and simulated patient study.
AB  - Fifty-six second-year family medicine residents completed a survey on their
      knowledge and beliefs about problem drinkers. Most residents felt responsible for
      screening and counseling, were confident in their clinical skills in these areas,
      and scored well on related knowledge questions. However, only 18% felt that
      problem drinkers would often respond to brief counseling sessions with physicians
      while 36% felt that moderate drinking was a reasonable goal for patients with
      severe alcohol dependence. Residents were then visited by unannounced simulated
      patients (SPs) presenting with alcohol-induced hypertension or insomnia.
      Residents detected the SP in 45 out of 104 visits. In the 59 undetected SP
      visits, residents asked about alcohol consumption in 47 visits (80%), discussed
      the relationship between alcohol use and the presenting complaint in 37 visits
      (63%), and recommended a specific weekly consumption in 35 visits (59%). Only 31%
      offered reduced drinking strategies, and most did not ask about features of
      alcohol dependence. These results suggest that residents have the fundamental
      clinical skills required to manage the problem drinker who gives a clear history
      and is receptive to advice. Educational efforts with residents should focus on
      the importance of systematic screening, taking an alcohol history under more
      challenging conditions, identifying the subtler presentations of alcohol
      problems, counselling the less receptive patient at an earlier stage of change,
      distinguishing the problem drinker from the alcohol-dependent patient, and
      offering specific behavioral strategies for the problem drinker.

PMID- 15201112
TI  - Predictors of relapse during treatment and treatment completion among marijuana
      dependent adolescents in an intensive outpatient substance abuse program.
AB  - The present study assessed possible predictors of relapse while in treatment and
      treatment completion among marijuana-dependent adolescents (N = 59) in an
      intensive outpatient substance abuse treatment program. Comorbid depression was
      associated with an increased likelihood of relapse and a higher total number of
      relapses. As expected, relapse while in treatment was associated with a reduced
      likelihood of successfully completing the treatment program. Comorbid attention
      deficit hyperactivity disorder (ADHD) was also associated with a lower likelihood
      of successful program completion. These findings add to a slowly growing
      literature regarding adolescent substance abuse treatment, and may help
      clinicians identify marijuana-dependent adolescents at greater risk of relapse or
      noncompliance.

PMID- 15201113
TI  - Sexual risk behaviors and polysubstance use in young intranasal heroin users.

PMID- 15201114
TI  - Integrating behavioral health services in rural primary care settings.

PMID- 15201116
TI  - Providing care coordination and treatment services for substance-abusing women in
      the Work First/New Jersey (TANF) Program.
AB  - This paper explores results of a program for substance-abusing welfare recipients
      in New Jersey. New Jersey hired an outside contractor, placed them in the welfare
      offices and proactively identified recipients with problems, assessed and placed
      them in appropriate treatment and then managed their care. The program eased the
      burden on welfare caseworkers who had had little motivation to help these
      recipients obtain treatment. While the initiative started slowly, because of
      concerns of the caseworkers and the recipients, recruitment, assessment and
      placement rates have continued to grow. In addition, those getting into treatment
      now appear to be receiving more treatment services as opposed to only detox
      (which was what they primarily received in the past) with no additional costs to
      the program. Finally, some preliminary outcomes data indicates improvements in
      the population in terms of both less drug use and increased employment.

PMID- 15201117
TI  - Women's priorities for lay health home visitors: implications for eliminating
      health disparities among underserved women.
AB  - While racial, ethnic, and socioeconomic health disparities in maternal and child
      health persist among women, few studies describe experiences of low-income women
      during pregnancy. We undertook a qualitative study of women's self-reported
      experiences with home visitors to gain understanding of priorities for
      participation and service delivery. Lay health home visitors provided
      satisfactory services and maintained close relationships with their clients. The
      mother-to-mother relationship is critical in facilitating continued participation
      in and ensuring positive health and social outcomes from lay health home
      visitation services. Many women lacked sufficient social support during their
      pregnancy and received this from the health visitor. Appropriate integration of
      lay health visitors with traditional prenatal care may alleviate many of the
      deleterious stressors that low-income women experience and may ultimately impact
      racial, ethnic, and socioeconomic disparities in maternal and child health.

PMID- 15201118
TI  - Inter-state disparities in health care and financial burden on the poor in India.
AB  - Over five decades of independence, India has made rapid strides in various
      sectors. However, its performance in social sectors and particularly the
      healthcare sector has not been too rosy. Being the State's responsibility the
      healthcare has traditionally been influenced by individual State's budgetary
      allocation. Consequently inter-state disparity in availability and utilization of
      health services and health manpower are distinctly marked. This has implications
      for achievement of Health for All for the nation as a whole. Keeping in view the
      significance of studying inter-state variations in healthcare, this study focuses
      on the performance of healthcare sector in 15 major States in India. This is
      attempted through a comparative analysis of various parameters depicting
      availability of health services, their utilization and health outcomes. Our
      analysis depicts the prevalence of considerable inequity favoring high income
      group of States. In terms of healthcare resources, for instance, it indicates
      that the high income States hold a superior position in terms of: per capita
      government expenditure on medical and public health, total number of hospitals
      and dispensaries, per capita availability of beds in hospitals and dispensaries
      and health manpower in rural and urban areas. These parameters of availability
      have an impact on utilization levels and health outcomes in these States. A
      comparative profile of high and low income States as well as middle and low
      income States, both in rural and urban areas, reaffirms a greater financial
      burden in availing treatment at OPD and inpatient in low income States. In line
      with the higher financial burden and low per capita health expenditure, the
      health outcome indicators also depict a disconcerting situation in regard to low
      income States. These States are marked by lower life expectancy and higher
      incidence of diseases as well as high mortality rates. In this regard, demand as
      well as supply side constraints are observed which restrain the optimum
      utilization of existing health services. Among the low income States the main
      constraints on the demand side include illiteracy, malnutrition, and lack of
      infrastructure in accessing the facilities. Certain state specific supply side
      factors add significantly to under-utilization in low income States. In some of
      the States, however, corrective actions have been initiated to overcome the
      problem of the quality and low utilization of health facilities. In due course of
      time, it is likely that proper implementation of these measures may result in
      improved utilization level of existing health services, which may be useful to
      improve health status indicators. Nonetheless, overcoming the current levels of
      regional disparities in healthcare across three income groups of States may also
      require additional resources. The latter could be mobilized through assistance of
      donor agencies and appropriate mix of social and private insurance. Ultimately
      mitigating the problem of regional disparities in healthcare and protecting the
      poor and vulnerable from financial burden may require establishing and
      maintaining proper linkages between socio-economic development and healthcare
      planning.

PMID- 15201119
TI  - Factors influencing the willingness to donate body parts for transplantation.
AB  - Three hundred and thirty-six people representing three ethnic groups (White,
      Asian, and Afro-Caribbean) were asked to rank their preferences concerning
      various incentives that might induce them to agree to the posthumous donation of
      their body parts. A conjoint analysis of the responses suggested that 'self
      centred' options (notably upfront cash payments and priority on waiting lists)
      were generally more popular than 'altruistic' alternatives. Members of the sample
      already possessing donor cards were more knowledgeable about the issue of organ
      transplantation than others, were less squeamish, and had relatives who favoured
      organ donation. The strength of a person's desire to donate body parts was
      related positively to self-respect and whether the individual was 'religious';
      and negatively to (i) squeamishness and (ii) having relatives who objected to
      transplantation. Altruistic preferences vis-a-vis organ donation were associated
      with knowledgeability, self-esteem, family background, low levels of
      squeamishness, and the extent to which a person experienced 'helper's high.'
      People who were financially well-off were the most self-centred in the organ
      donation context. Overall the results imply substantial disparities between
      public policy and contemporary public opinion regarding transplant donation
      incentives.

PMID- 15201120
TI  - What street people reported about service access and drug treatment.
AB  - This study presents the perceptions of a sample of homeless people, living on the
      streets, in Allegheny County, Pennsylvania. Questions were asked that elicited
      their opinions about drug addiction, housing and treatment needs. Two-thirds of
      the 225 persons interviewed in 2000 and 2001 reported that they were not eligible
      for treatment or housing. Forty-two percent of those who received treatment for
      substance use disorders reported that their treatment was ineffective because
      aftercare and residential supports were not available to them. The major findings
      of this study were: That service eligibility requirements were a barrier to
      adequate care; and that more homeless persons would consider treatment if housing
      placement was part of the continuum of services.

PMID- 15201121
TI  - The role of playing and efference in the recall location and distance cues in
      short-term motor memory.
AB  - Previous studies have suggested that the superior accuracy of preselected
      (subject-defined) over constrained (experimenter-defined) movements is due to
      both the availability of a movement plan and efferent-command information. The
      present experiment examined the contribution of the planning and efferent
      components to the preselection effect in a location and a distance task. The
      availability of a movement plan was manipulated by providing preselected and
      constrained groups of subjects with a rehearsal movement. Furthermore, the amount
      of efferent information available was varied by requiring both active and passive
      rehearsal movements. The results suggested that while strategy alone is
      responsible for the superiority of preselected location, both strategy and
      efferent information underlie the superiority of preselected distance
      reproduction.

PMID- 15201122
TI  - Developmental differences in children's labeling of movement.
AB  - Children's encoding of information, specifically, the correct use and application
      of labels, is one factor frequently used to account for developmental differences
      in verbal learning. Labels may also be used in connection with remembering
      positional movements. The purpose of this study was to evaluate developmental
      differences in the effects of labels upon remembering movements. In addition, the
      study evaluated whether better or poorer labeling strategies would increase or
      decrease performance in the age groups studied. Subjects consisted of
      kindergarten children (N=27), fifth grade children (N=27), and adults (N=27)
      randomly assigned within each age level to one of three groups: subjective label,
      irrelevant label, and relevant label. Subjects were tested on a two-dimensional
      positioning task allowing estimates of radial, location, and distance errors.
      Results indicated that relevant labels (clock face) improved performance for
      remembering positions within all age conditions. Of major interest was the
      finding that relevant labels increased performance of the kindergarten children
      to the approximate level of the irrelevant label (animals) group for fifth
      graders. The same finding was evident for the fifth graders with the relevant
      label group approximating performance of adults forced to use a less
      sophisticated strategy (irrelevant label, i.e., animals). This finding suggests
      that a significant portion of the differences between younger and older children
      and adult performance is due to the processing deficit of poor encoding
      strategies used by children.

PMID- 15201123
TI  - Social reinforcement as a determinant of performance, performance expectancy, and
      attributions.
AB  - The effects of positive, negative, and nonreinforcement were examined during
      performance of a fine motor task to observe any expectancy and performance
      differences. Female high school subjects first learned the task and then were
      given a series of 30 trials in which social reinforcement was administered
      noncontingently. Positive social reinforcement had a significant effect on
      performance, while both positive and negative reinforcement had significant
      effects on expectancy. In addition, disparate attributions were made by each
      treatment group.

PMID- 15201124
TI  - Reproduction of end-location and distance of movement in early and later blinded
      subjects.
AB  - This study examined the ability of early and later blinded subjects to reproduce
      the end location and distance of preselected arm movements of two different
      amplitudes (approximately 30 degrees and approximately 60 degrees). Both groups
      were found to reproduce end location with greater accuracy and less variability
      than distance. The early blinded subjects were less accurate however, and more
      variable in their reproductions of both movement cues than the later blinded
      subjects. The complications of these findings for the role of visual
      representation in memory for movement are discussed.

PMID- 15201125
TI  - The variation of hand steadiness with physical stress.
AB  - The performance of 12 subjects in a hand steadiness task was compared at
      different work loads. Hand steadiness expressed in the form of values of hand
      shakiness was found not to increase linearly with work intensity. On the
      contrary, the relation between hand shakiness and activation level, induced by
      physical work, was found to be positively accelerated by an exponent of 1.6.
      Subjective effort measured by a ratio estimation method grew, likewise, according
      to a positively accelerating function with an exponent of about 1.6, while
      subjective effort according to the "RPE" category scale like hear rate grew
      linearly with work load.

PMID- 15201126
TI  - Fractioned reaction time in power-trained and endurance-trained athletes under
      conditions of fatiguing isometric exercise.
AB  - Fractionated knee extensor and plantar flexor reaction time (RT) components were
      assessed in a group of eight weightlifters and eight long distance runners.
      Following a 4-day period of baseline stabilization for each muscle group, a 50%
      maximal voluntary contraction (MVC) holding-time exercise was administered.
      Results showed that the runners had longer premotor times (PMT) than the
      weightlifters in the knee extensors, but had much faster PMTs than the lifters in
      the plantar flexor condition. Compared to previously reported investigations
      using non-athletes, the data for the present sample of athletes indicated faster
      total reaction times(TRT) in both the knee extensors and the plantar flexors. A
      resistance of 15% MVC applied during the RT task resulted in a lengthening of the
      motor time (MT) component in both groups prior to exercise. However, while knee
      extensor resisted motor time was lengthened by the exercise task, no such
      lengthening occurred in plantar flexor resisted RT. It is concluded that power
      trained and endurance-trained athletes exhibit difference in response to a
      fractionated RT task, under both baseline and fatiguing exercise conditions.

PMID- 15201127
TI  - Technical considerations regarding the short (dit)-long (dah) key press paradigm.
AB  - The finding of longer reaction time prior to longer-lasting responses (e.g.,
      Klapp, 1977a; Klapp, Wyatt. & Lingo, 1974) was not replicated by Kerr (1979) in a
      statistically powerful attempt. The present experiment confirms that this effect
      is not reliable when duration knowledge of results is similar to that used by
      Kerr, although a reliable long-short effect was obtained with other knowledge of
      results arrangements. This unexpected sensitivity to knowledge of results suggest
      that previous results from this paradigm must be interpreted with caution.

PMID- 15201128
TI  - Effects of precision of knowledge of results on performance of a gross motor
      coincidence-anticipation task.
AB  - The purpose of the investigation was to determine the effects from three
      knowledge of results (KR) precision levels (qualitative; 0.10 sec, 0.001 sec) on
      the performance of a gross motor coincidence-anticipation task where subjects
      performed with visual and other sense modality input. Other variables included in
      the analysis were sex, movement distance, and practice over three blocks of
      trials. Absolute error (AE), constant error (CE), variable error (VE), and E
      scores (E) of the subjects from two experiments (N = 90; N = 54) were analyzed
      with 3 x 2 x 2 x 3 ANOVAs with repeated measures on the last two factors
      (feedback, sex, movement distance, blocks). Consistent finding from both
      experiments indicated that, for this gross motor coincidence-anticipation task,
      the subjects performed as accurately and as consistently when they received
      qualitative KR as when, in addition, they received more precise KR. Subjects
      performed with less error on the short as opposed to the long term distance
      pattern. Males performed with less error on the long movement pattern than
      females in Experiment 1; however, the only sex difference noted in Experiment 2,
      when the movement distances were shortened, was that males had a more on-time CE
      mean score.

PMID- 15201129
TI  - The effects of force and direction uncertainty of choice reaction time in an
      isometric force production task.
AB  - The two experiments reported examined the temporal organization of force and
      direction motor-programming processes in a step-input tracking type task. Both
      experiments observed a reduction in reaction time in the direction-uncertain
      conditions compared to the direction-certain ones. Thus it seems as though the
      direction decision does not have to precede the selection of the proper amount of
      forces. Experiment 2 observed an under-additive interaction between levels of
      direction uncertainty (certain or uncertain) and levels of force uncertainty
      (certain or uncertain). This interaction was interpreted as support for the
      programming of force and direction and thus, strongly supports the parallel model
      of programming recently proposed by Klapp (1977a,b).

PMID- 15201130
TI  - Evidence for generalized motor programs using gait pattern analysis.
AB  - Human intra limb gait kinematics were analyzed via statistical and structural
      pattern recognition methods to determine the role of relative timing of limb
      segments within and between modes of gait. Five experienced runners were filmed
      while walking (3-6 km/hour) and running (8-12 km/hour) on a motor driven
      treadmill. Kinematic data consisted of relative timing of the four phases of the
      Philippson step cycle and intersegmental limb trajectories, determined from angle
      angle diagrams. Despite marked decreases in absolute time durations within gaits
      remained constant over the speeds which were studied. Although a 2-fold increase
      in locomotor speed occurred in walking and a 1.5-fold speed increase occurred
      within running, the percentage of time spent in each of the Philippson phases was
      not significantly changed. However, significant differences in the time
      percentages and sequences of the step cycle phases were found between walking and
      running. Correlations between limb segment trajectories occurring in the
      different gaits showed strong coherence for overall step cycle patterns, but
      within step cycle phases and across speeds, selective phases displayed little
      correspondence.

PMID- 15201131
TI  - The learning of programmed- and feedback- based processes controlling the
      production of a positioning response in two dimensions.
AB  - Two experiments were conducted to investigate the learning of the programmed- and
      feedback-based processes controlling the production of a slow, self-paced
      positioning response in two dimensions (direction and extent) in the horizontal
      plane. Both experiments had two phases: an acquisition phase of 60 trials with
      KR, followed by a KR withdrawal phase of 20 trials. In Experiment 1, one group
      (N=15) had visual feedback about the ongoing movement and the other group (N=15)
      did not. In Experiment 2, one group (N=15) practiced initiating the response in
      the criterion direction and moving the criterion extent, whereas, the other group
      (N=15) practiced initiating the response in the criterion direction and moving
      randomly varied extents. The results of Experiment 1 indicated that the learning
      of a programmed-based process is a gradually acquired freedom from visual
      feedback. Experiment 2 revealed that a programmed-based process can be learned
      independent of a feedback-based process.

PMID- 15201132
TI  - Assist-control mechanical ventilation attenuates ventilator-induced diaphragmatic
      dysfunction.
AB  - Controlled mechanical ventilation induced a profound diaphragm muscle dysfunction
      and atrophy. The effects of diaphragmatic contractions with assisted mechanical
      ventilation on diaphragmatic isometric, isotonic contractile properties, or the
      expression of muscle atrophy factor-box (MAF-box), the gene responsible for
      muscle atrophy, are unknown. We hypothesize that assisted mechanical ventilation
      will preserve diaphragmatic force and prevent overexpression of MAF-box. Studying
      sedated rabbits randomized equally into control animals, those with 3 days of
      assisted ventilation, and those with controlled ventilation, we assessed in vitro
      diaphragmatic isometric and isotonic contractile function. The concentrations of
      contractile proteins, myosin heavy chain isoform, and MAF-box mRNA were measured.
      Tetanic force decreased by 14% with assisted ventilation and 48% with controlled
      ventilation. Maximum shortening velocity tended to increase with controlled
      compared with assisted ventilation and control. Peak power output decreased 20%
      with assisted ventilation and 41% with controlled ventilation. Contractile
      proteins were unchanged with either modes of ventilation; myosin heavy chain 2X
      mRNA tended to increase and that of 2A to decrease with controlled ventilation.
      MAF-box gene was overexpressed with controlled ventilation. We conclude that
      preserving diaphragmatic contractions during mechanical ventilation attenuates
      the force loss induced by complete inactivity and maintains MAF-box gene
      expression in control.

PMID- 15201133
TI  - Short-term influences of lung volume reduction surgery on the diaphragm in
      emphysematous hamsters.
AB  - With emphysema, diaphragm length adaptation results in shortened fibers. We
      hypothesize that passive diaphragm stretch occurring acutely after lung volume
      reduction surgery (LVRS) results in fiber injury. Bilateral LVRS was performed in
      emphysematous hamsters. Studies were performed 1 (D1) and 4 (D4) days after LVRS,
      and compared with sham-treated groups. Sarcolemmal rupture was evident in 10.9%
      of fibers in LVRS-D1 and reduced to 1.6% in LVRS-D4. Ultrastructural analysis
      revealed focal abnormalities in both LVRS-D1 and LVRS-D4 animals in over one
      third of fibers. Myofibrillar disruption was not observed in sham-treated
      animals. Diaphragm insulin-like growth factor-I (IGF-I) was increased in LVRS-D4
      compared with other emphysematous groups. Increased IGF-I immunoreactivity was
      localized to types IIA and I fibers. The abundance of the splice variant of IGF-I
      mRNA sensitive to muscle stretch (IGF-IEb) increased 3.2-fold in LVRS D-4
      diaphragms, compared with emphysema-sham animals. The main form of IGF-I mRNA was
      unchanged. Marked force deficit was observed in the LVRS-D1 diaphragm, compared
      with emphysema-sham and emphysema (no surgery) animals. These data highlight a
      markedly compromised ventilatory pump acutely after LVRS. Acute fiber stretch
      predisposes to muscle fiber injury and may also be a necessary
      mechanotransductive stimulus for fiber remodeling as the diaphragm adapts to
      reduced lung volume.

PMID- 15201134
TI  - TOLL-like receptor 10 genetic variation is associated with asthma in two
      independent samples.
AB  - TOLL-like receptor 10 (TLR10) is the most recently identified human homolog of
      the Drosophila TOLL protein. In humans, the TOLL-like receptors recognize
      pathogen-associated molecular patterns (PAMPs) as part of innate immune host
      defenses. Localized to chromosome 4p14, the specific ligands and functions of
      TLR10 are currently unknown, although it is expressed in lung and in B
      lymphocytes. TLR10 is a potential asthma candidate gene because early life innate
      immune responses to ubiquitous inhaled allergens and PAMPs may influence asthma
      susceptibility. Resequencing in 47 subjects revealed a total of 78 single
      nucleotide polymorphisms (SNPS) (1 SNP per 106 bp) of which only 11 had been
      previously published. A significant association (p < or = 0.02) between two SNPs
      (c.+1031G>A, c.+2322A>G) and physician-diagnosed asthma was observed in a case
      control study (517 cases, 519 control subjects) of European American subjects
      nested within the Nurses' Health Study cohort. The association for these same two
      SNPs (p < or = 0.015) replicated in an independent family based cohort, where a
      measure of airway hyperresponsiveness (PC20) was also associated (p = 0.026 for
      c.+1031G>A). Consistent association in two independent samples and association
      with an intermediate phenotype provides strong support for TLR10 genetic
      variation contributing to asthma risk.

PMID- 15201135
TI  - Significance of von Willebrand factor in septic and nonseptic patients with acute
      lung injury.
AB  - Systemic endothelial activation and injury are important causes of multiorgan
      system failure. We hypothesized that plasma levels of von Willebrand factor
      (VWF), a marker of endothelial activation and injury, would be associated with
      clinical outcomes in acute lung injury (ALI) and acute respiratory distress
      syndrome (ARDS). In 559 patients with ALI/ARDS enrolled in the National Heart,
      Lung, and Blood Institute ARDS Network trial of two VT strategies, plasma VWF
      levels were measured at randomization (mean 350 +/- 265% of normal control
      plasma) and Day 3 (344 +/- 207%). Baseline VWF levels were similar in patients
      with and without sepsis, and were significantly higher in nonsurvivors (435 +/-
      333%) versus survivors (306 +/- 209%) even when controlling for severity of
      illness, sepsis, and ventilator strategy (increased odds ratio of death of 1.6
      per SD size increase in VWF; 95% confidence interval, 1.4-2.1). Higher VWF levels
      were also significantly associated with fewer organ failure-free days. Ventilator
      strategy had no effect on VWF levels. In conclusion, the degree of endothelial
      activation and injury is strongly associated with outcomes in ALI/ARDS,
      regardless of the presence or absence of sepsis, and is not modulated by a
      protective ventilatory strategy. To improve outcomes further, new treatment
      strategies targeted at the endothelium should be investigated.

PMID- 15201136
TI  - Efficacy of positive airway pressure and oral appliance in mild to moderate
      obstructive sleep apnea.
AB  - The efficacy of currently recommended treatments is uncertain in patients with
      mild to moderate obstructive sleep apnea (apnea-hypopnea index [AHI], 5-30). A
      group of 114 sleep clinic patients with an AHI of 5-30 have participated in a
      randomized controlled crossover trial of 3 months of treatment with each of nasal
      continuous positive airway pressure (CPAP), a mandibular advancement splint, and
      a placebo tablet. Outcomes were sleep fragmentation and hypoxemia, daytime
      sleepiness, quality of life, neurobehavioral function, and blood pressure. Both
      active treatments improved sleep outcomes, but positive airway pressure had a
      greater effect. The quality of life, symptoms, and subjective but not objective
      sleepiness improved to a similar degree with both treatments; however, many of
      the improvements seen in neuropsychologic function and mood were not better than
      the placebo effect. Some aspects of nocturnal blood pressure were improved with
      the splint but not with CPAP. This study has shown that although both CPAP and
      mandibular advancement splint effectively treated sleep-disordered breathing and
      sleepiness, the expected response in neurobehavioral function was incomplete.
      This may be due to the splint having a lesser therapeutic effect and CPAP being
      poorly tolerated and therefore used less in this patient group.

PMID- 15201137
TI  - Immunolocalization of type 2 inositol 1,4,5-trisphosphate receptors in cardiac
      myocytes from newborn mice.
AB  - The precise localization and role of inositol 1,4,5-trisphosphate (InsP(3))
      receptors (InsP(3)Rs) in cardiac muscle cells are largely unknown. It is believed
      that waves and oscillations in cytosolic free calcium triggered by activation of
      InsP(3)Rs underlie modifications of cellular responses that lead to changes in
      gene expression in other cells. However, how changes in cytosolic calcium alter
      gene expression in cardiac cells is unknown. Moreover, it is unclear how changes
      in cytosolic calcium that alter gene expression do so independently of effects of
      calcium on other cellular functions, such as contraction. Here we show that
      InsP(3)R type 2 is the only isoform present in cardiac myocytes isolated from
      neonatal mouse ventricles. We also show that type 2 InsP(3)Rs are associated with
      the nucleus and that activation of type 2 InsP(3)Rs with endothelin-1 or
      phenylephrine selectively increases transcription of atrial natriuretic factor
      and skeletal alpha-actin. Type 2 InsP(3)Rs are also in striations. Activation of
      InsP(3)Rs with adenophostin A in permeabilized cells induced calcium release in
      the nuclear domain and other regions of the cell away from the nucleus. Agonist
      induced increase in gene expression and calcium release were blocked by the
      InsP(3)R inhibitors 2-aminoethoxydiphenyl borate and xestospongin C. The spatial
      separation of type 2 InsP(3)Rs provides support for the concept that microdomains
      of calcium discretely alter various cell processes. Our experiments suggest that
      calcium released by InsP(3)Rs in the nuclear domain provides a direct mechanism
      for the control of gene expression, whereas release of calcium in the cytoplasm
      may modulate other processes, such as contraction.

PMID- 15201138
TI  - Interleukin-1 beta induces posttranslational carboxymethylation and alterations
      in subnuclear distribution of lamin B in insulin-secreting RINm5F cells.
AB  - We examined the effects of interleukin-1beta (IL-1beta) treatment on the
      distribution and degradation of lamin B in the nuclear fraction from insulin
      secreting RINm5F cells. Western blot analysis indicated that IL-1beta treatment
      caused significant alterations in the redistribution of lamin B, specifically
      between the Triton X-100-soluble (membrane) and -insoluble (matrix) fractions of
      the nucleus. IL-1beta treatment also increased the lamin carboxymethyltransferase
      activity and the relative abundance of the carboxymethylated lamin in the nuclear
      fraction. A significant increase in the relative abundance of lamin B degradation
      products was also observed in the nuclear fraction from the IL-1beta-treated
      cells. These findings are compatible with a measurable increase in the lamin
      degrading caspase-6 activity in IL-1beta-treated cells. Confocal microscopic
      observation of IL-1beta-treated cells suggested a significant dissociation of
      lamin B from the nuclear lamina and its subsequent association with the DNA-rich
      elements within the nucleus. N(G)-monomethyl-l-arginine, a known inhibitor of
      inducible nitric oxide synthetase (iNOS), markedly inhibited IL-1beta-induced
      iNOS gene expression, NO release, caspase-3 and caspase-6 activation, lamin B
      degradation, and loss of metabolic cell viability, indicating that the observed
      IL-1beta-induced effects on nuclear lamin B involve the intermediacy of NO.
      Together, our data support the hypothesis that IL-1beta treatment results in
      significant increase in the carboxymethylation of lamin B, which would place
      lamin B in a strategic location for its degradation mediated by caspases. This
      could possibly lead to dissolution of the nuclear envelope, culminating in the
      demise of the effete beta-cell.

PMID- 15201139
TI  - Norepinephrine-induced calcium signaling and expression of adrenoceptors in avian
      tendon cells.
AB  - Sympathetic efferent nerves are present in tendons, but their function within
      tendon is unknown. alpha(1)-Adrenoceptors are expressed by a variety of cell
      types. In the presence of norepinephrine (NE), adrenoceptors activate G(q/11)
      signaling pathways that subsequently increase intracellular Ca(2+) concentration
      ([Ca(2+)](ic)). It was hypothesized that avian tendon cells express functional
      adrenoceptors that respond to NE by increasing [Ca(2+)](ic). Avian tendon cells
      were analyzed for mRNA expression of alpha(1)-adrenoceptors by RT-PCR. Avian
      tendons expressed the alpha(1A)- and alpha(1B)-adrenoceptor subtypes.
      Furthermore, both tendon surface epitenon cells and internal fibroblasts infused
      with a Ca(2+)-sensitive dye, fura 2, and stimulated with NE responded by
      increasing [Ca(2+)](ic). KMD-3213, an alpha(1A)-adrenoceptor antagonist,
      significantly reduced the Ca(2+) response. Other adrenoceptor antagonists had no
      effect on the Ca(2+) response. The absence of extracellular Ca(2+) also
      significantly reduced the response to NE, indicating that Ca(2+) influx
      contributed to the rise in [Ca(2+)](ic). This study provides the first evidence
      that tendon cells express adrenoceptors and that the NE-induced Ca(2+) response
      is coupled to the alpha(1A)-adrenoceptor subtype.

PMID- 15201140
TI  - Role of TGF-beta1 and JNK signaling in capillary tube patterning.
AB  - The transforming growth factor (TGF) family of secretory polypeptides comprises
      signaling proteins involved in numerous physiological processes, including
      vascular development and vessel wall integrity. Both pro- and anti-angiogenic
      effects of TGF-beta1 have also been documented. To study the intracellular
      mechanisms involved in capillary tube morphogenesis, endothelial cell aggregates
      were cultured in a fibrin matrix. It was found that the pattern of capillary
      tubes formed in a fibrin matrix was altered in response to TGF-beta1 treatment
      such that the capillary-like structures displayed a bipolarized pattern. In
      contrast, in untreated control and fibroblast growth factor-2-treated cells, the
      pattern of capillary tubes formed was random. TGF-beta1 also downregulated
      urokinase-type plasminogen activator (uPA) activity while upregulating PA
      inhibitor (PAI)-1 and thrombospondin (TSP)1 gene expression. To investigate the
      signaling cascade mediating the phenotypic changes observed, pharmacological
      inhibitors of p38 MAPK, Sp1 transcription factor, c-Jun NH(2)-terminal kinase
      (JNK), and the cytokine TNF-alpha were used. The p38 MAPK inhibitor SB203580
      reversed the TGF-beta1-dependent inhibition of uPA activity but not its
      morphogenetic effect. In contrast, the DNA intercalator WP631 and TNF-alpha
      counteracted the TGF-beta1-induced morphogenetic effect while the JNK inhibitor
      SP600125 effectively inhibited capillary tube formation. These results indicate
      that the TGF-beta1-induced capillary tube pattern is independent of the p38 MAPK
      activated PAI-1 and TSP1 expression, but the mechanism involves Sp1-dependent
      transcriptional regulation. The results also raise the possibility that the JNK
      pathway, which controls convergent extension in Xenopus, may be involved in
      vessel wall patterning in mammalian systems.

PMID- 15201141
TI  - Functional analysis of the R1086H malignant hyperthermia mutation in the DHPR
      reveals an unexpected influence of the III-IV loop on skeletal muscle EC
      coupling.
AB  - Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder caused by
      mutations in the skeletal muscle ryanodine receptor (RyR1) and the
      dihydropyridine receptor (DHPR) alpha(1S)-subunit. We characterized the effects
      of an MH mutation in the DHPR cytoplasmic III-IV loop of alpha(1S) (R1086H) on
      DHPR-RyR1 coupling after reconstitution in dysgenic (alpha(1S) null) myotubes.
      Compared with wild-type alpha(1S), caffeine-activated Ca(2+) release occurred at
      approximately fivefold lower concentrations in nonexpressing and R1086H
      expressing myotubes. Although maximal voltage-gated Ca(2+) release was similar in
      alpha(1S)- and R1086H-expressing myotubes, the voltage dependence of Ca(2+)
      release was shifted approximately 5 mV to more negative potentials in R1086H
      expressing myotubes. Our results demonstrate that alpha(1S) functions as a
      negative allosteric modulator of release channel activation by caffeine/voltage
      and that the R1086H MH mutation in the intracellular III-IV linker disrupts this
      negative regulatory influence. Moreover, a low caffeine concentration (2 mM)
      caused a similar shift in voltage dependence of Ca(2+) release in alpha(1S)- and
      R1086H-expressing myotubes. Compared with alpha(1S)-expressing myotubes, maximal
      L channel conductance (G(max)) was reduced in R1086H-expressing myotubes
      (alpha(1S) 130 +/- 10.2, R1086H 88 +/- 6.8 nS/nF; P < 0.05). The decrease in
      G(max) did not result from a change in retrograde coupling with RyR1 as maximal
      conductance-charge movement ratio (G(max)/Q(max)) was similar in alpha(1S)- and
      R1086H-expressing myotubes and a similar decrease in G(max) was observed for an
      analogous mutation engineered into the cardiac L channel (R1217H). In addition,
      both R1086H and R1217H DHPRs targeted normally and colocalized with RyR1 in
      sarcoplasmic reticulum (SR)-sarcolemmal junctions. These results indicate that
      the R1086H MH mutation in alpha(1S) enhances RyR1 sensitivity to activation by
      both endogenous (voltage sensor) and exogenous (caffeine) activators.

PMID- 15201142
TI  - Different modes of sodium-D-glucose cotransporter-mediated D-glucose uptake
      regulation in Caco-2 cells.
AB  - We recently reported that a considerable amount of the sodium-d-glucose
      cotransporter SGLT1 present in Caco-2 cells, a model for human enterocytes, is
      located in intracellular compartments attached to microtubules. A similar
      distribution pattern was also observed in enterocytes in thin sections from human
      jejunum, highlighting the validity of the Caco-2 cell model. Fluorescent surface
      labeling of live Caco-2 cells revealed that the intracellular compartments
      containing SGLT1 were accessible by endocytosis. To elucidate the role of
      endosomal SGLT1 in the regulation of sodium-dependent d-glucose uptake into
      enterocytes, we compared SGLT1-mediated D-glucose uptake into Caco-2 cells with
      the subcellular distribution of SGLT1 after challenging the cells with different
      stimuli. Incubation (90 min) of Caco-2 cells with mastoparan (50 microM), a drug
      that enhances apical endocytosis, shifted a large amount of SGLT1 from the apical
      membrane to intracellular sites and significantly reduced sodium-dependent alpha
      [(14)C]methyl-D-glucose uptake (-60%). We also investigated the effect of altered
      extracellular D-glucose levels. Cells preincubated (1 h) with d-glucose-free
      medium exhibited significantly higher sodium-dependent alpha-[(14)C]methyl-D
      glucose uptake (+45%) than did cells preincubated with high d-glucose medium (100
      mM, 1 h). Interestingly, regulation of SGLT1-mediated d-glucose uptake into Caco
      2 cells by extracellular D-glucose levels occurred without redistribution of
      cellular SGLT1. These data suggest that, pharmacologically, d-glucose uptake can
      be regulated by a shift of SGLT1 between the plasma membrane and the endosomal
      pool; however, regulation by the physiological substrate d-glucose can be
      explained only by an alternative mechanism.

PMID- 15201143
TI  - pH-dependent modulation of Kv1.3 inactivation: role of His399.
AB  - The Kv1.3 K(+) channel lacks N-type inactivation, but during prolonged
      depolarized periods it inactivates via the slow (P/C type) mechanism. It bears a
      titratable histidine residue in position 399 (equivalent of Shaker 449), a site
      known to influence the rate of slow inactivation. As opposed to several other
      voltage-gated K(+) channels, slow inactivation of Kv1.3 is slowed when
      extracellular pH (pH(o)) is lowered under physiological conditions. Our findings
      are as follows. First, when His399 was mutated to a lysine, arginine, leucine,
      valine or tyrosine, extracellular acidification (pH 5.5) accelerated inactivation
      reminiscent of other Kv channels. Second, inactivation of the wild-type channel
      was accelerated by low pH(o) when the ionic strength of the external solution was
      raised. Inactivation of the H399K mutant was also accelerated by high ionic
      strength at pH 7.35 but not the inactivation of H399L. Third, after the external
      application of blocking barium ions, recovery of the wild-type current during
      washout was slower in low pH(o). Fourth, the dissociation rate of Ba(2+) was pH
      insensitive for both H399K and H399L. Furthermore, Ba(2+) dissociation rates were
      equal for H399K and the wild type at pH 5.5 and were equal for H399L and the wild
      type at pH 7.35. These observations support a model in which the electric field
      of the protonated histidines creates a potential barrier for potassium ions just
      outside the external mouth of the pore that hinders their exit from the binding
      site controlling inactivation. In Kv1.3, this effect overrides the generally
      observed speeding of slow inactivation when pH(o) is reduced.

PMID- 15201144
TI  - Role of immunoreceptor tyrosine-based inhibitory motifs of PECAM-1 in PECAM-1
      dependent cell migration.
AB  - Platelet endothelial cell adhesion molecule (PECAM-1), a transmembrane
      glycoprotein, has been implicated in angiogenesis, with recent evidence
      indicating the involvement of PECAM-1 in endothelial cell motility. The
      cytoplasmic domain of PECAM-1 contains two tyrosine residues, Y663 and Y686, that
      each fall within an immunoreceptor tyrosine-based inhibitory motif (ITIM). When
      phosphorylated, these residues together mediate the binding of the protein
      tyrosine phosphatase SHP-2. Because SHP-2 has been shown to be involved in the
      turnover of focal adhesions, a phenomenon required for efficient cell motility,
      the association of this phosphatase with PECAM-1 via its ITIMs may represent a
      mechanism by which PECAM-1 might facilitate cell migration. Studies were
      therefore done with cell transfectants expressing wild-type PECAM or mutant PECAM
      1 in which residues Y663 and Y686 were mutated. These mutations eliminated PECAM
      1 tyrosine phosphorylation and the association of PECAM-1 with SHP-2 but did not
      impair the ability of the molecule to localize at intercellular junctions or to
      bind homophilically. However, in vitro cell motility and tube formation
      stimulated by the expression of wild-type PECAM-1 were abrogated by the mutation
      of these tyrosine residues. Importantly, during wound-induced migration, the
      number of focal adhesions as well as the level of tyrosine phosphorylated
      paxillin detected in cells expressing wild-type PECAM-1 were markedly reduced
      compared with control cells or transfectants with mutant PECAM-1. These data
      suggest that, in vivo, the binding of SHP-2 to PECAM-1, via PECAM-1's ITIM
      domains, promotes the turnover of focal adhesions and, hence, endothelial cell
      motility.

PMID- 15201145
TI  - Learning about cardiac calcium signaling from genetic engineering.
AB  - Genetic engineering has already provided critical data on the Ca-induced Ca(2+)
      release (CICR) hypothesis issues and promises even greater future insights. The
      two approaches employed thus far are (1) the construction of transgenic animal
      models with deletion or overexpression of Ca(2+) signaling proteins, and (2)
      direct structure-function studies of these proteins in artificial systems. In our
      laboratory both approaches have provided some insight into molecular modulation
      of CICR and the pathophysiology arising from the deletion or overactivity of
      these proteins. Probing the cytoplasmic segments of the carboxyl c-terminal tail
      of Ca(2+) channel, we identified two calcium sensing and calmodulin binding
      domains (LA and K) that have been implicated in Ca(2+)-induced inactivation of
      Ca(2+) channels. Introducing these peptides into atrial myocytes, where a large
      fraction of Ca(2+) release sites are unassociated with the dihydropyridine
      receptors (DHPRs) (no t-tubules), suggests that LA, but not K motif, increases
      the sensitivity of RyRs to Ca(2+), is responsible for the higher frequency of
      Ca(2+) sparks in the peripheral sites, and provides for the voltage dependence of
      CICR. Genetic overexpression or deletion of the primary proteins of the Ca(2+)
      signaling cascade also provides supportive evidence for the Ca(2+) current
      (I(Ca))-gated CICR mechanism, generates some novel and unexpected cardiac
      phenotypes in transgenic mice, and suggests that Ca(2+) signaling defects can
      trigger compensatory molecular mechanisms that underlie the observed cardiac
      phenotype and pathophysiology.

PMID- 15201147
TI  - Integrated Ca2+ management in cardiac myocytes.
AB  - Cardiac myocyte excitation-contraction coupling is complex. There are many
      systems involved that interact to form varied, but well-tuned, effects that are
      essential to contractile regulation. Nearly all of these systems are Ca
      dependent, and Ca homeostasis within the myocyte is carefully controlled.
      Contractile activation results from Ca entry via Ca current, and Ca release from
      the sarcoplasmic reticulum (SR). Ca extrusion from the cytosol is controlled by
      Ca transport by (1) the Na-Ca exchanger, (2) the SR Ca-pump (which is balanced by
      a Ca leak out of the SR), and (3) slower systems (including Ca transport by
      mitochondria and the sarcolemmal Ca-pump). These systems interact to regulate the
      amount of Ca within the cell at rest, most of which is stored within the SR. The
      amount of Ca released from the SR depends nonlinearly upon SR [Ca], specifically
      the free SR [Ca] ([Ca](SR)). The relationship is particularly steep at high
      [Ca](SR), where spontaneous release can take place, resulting in electrical
      arrhythmias. In many models of heart failure, SR [Ca] is reduced, which may cause
      decreased Ca release and contractile dysfunction. In summary, the varied
      processes responsible for Ca regulation within the myocyte are critical to normal
      heart function, and disruption of the normal operation of these proteins can
      cause widely varied pathological effects, in large part due to dysfunctional Ca
      handling.

PMID- 15201146
TI  - Modeling the actions of beta-adrenergic signaling on excitation--contraction
      coupling processes.
AB  - Activation of the beta-adrenergic (beta-AR) signaling pathway enhances cardiac
      function through protein kinase A (PKA)-mediated phosphorylation of target
      proteins involved in the process of excitation-contraction (EC) coupling.
      Experimental studies of the effects of beta-AR stimulation on EC coupling have
      yielded complex results, including increased, decreased, or unchanged EC coupling
      gain. In this study, we extend a previously developed model of the canine
      ventricular myocyte describing local control of sarcoplasmic reticulum (SR)
      calcium (Ca(2+)) release to include the effects of beta-AR stimulation.
      Incorporation of phosphorylation-dependent effects on model membrane currents and
      Ca(2+)-cycling proteins yields changes of action potential (AP) and Ca(2+)
      transients in agreement with those measured experimentally in response to the
      nonspecific beta-AR agonist isoproterenol (ISO). The model reproduces
      experimentally observed alterations in EC coupling gain in response to beta-AR
      agonists and predicts the specific roles of L-type Ca(2+) channel (LCC) and SR
      Ca(2+) release channel phosphorylation in altering the amplitude and shape of the
      EC coupling gain function. The model also indicates that factors that promote
      mode 2 gating of LCCs, such as beta-AR stimulation or activation of the
      Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), may increase the
      probability of occurrence of early after-depolarizations (EADs), due to the
      random, long-duration opening of LCC gating in mode 2.

PMID- 15201148
TI  - Molecular and integrated biology of thin filament protein phosphorylation in
      heart muscle.
AB  - An increasing body of evidence points to posttranslational modifications of the
      thin filament regulatory proteins, cardiac troponin T (cTnT) and cardiac troponin
      I (cTnI) by protein kinase C (PKC) phosphorylation as important in both long- and
      short-term regulation of cardiac function and potentially implicated in the
      transition between compensated hypertrophy and decompensation. The main sites for
      PKC-dependent phosphorylation on cTnI are Ser43, Ser45, and Thr144 and on cTnT
      are Thr197, Ser201, Thr206, and Thr287 (mouse sequence). We analyzed the function
      of each phosphorylation residue using a phosphorylation mimic approach
      introducing glutamates (E) at PKC phosphorylation sites and then measuring the
      isometric tension of fiber bundles exchanged with these mutants. We also directly
      phosphorylated cTnI and cTnT by PKC, incorporated the phosphorylated troponins in
      the myofilament lattice, and determined the isometric tension at varying Ca(2+)
      concentrations. We followed the experimental data with computational analysis
      prediction of helical content of cTnI and cTnT peptides that undergo
      phosphorylation. Here we summarize our recent data on the specific functional
      role of PKC phosphorylation sites of cTnI and cTnT.

PMID- 15201149
TI  - Mechanotransduction in cardiac myocytes.
AB  - Cardiac myocytes react to diverse mechanical demands with a multitude of
      transient and long-term responses to normalize the cellular mechanical
      environment. Several stretch-activated signaling pathways have been identified,
      most prominently guanine nucleotide binding proteins (G-proteins), mitogen
      activated protein kinases (MAPK), Janus-associated kinase/signal transducers and
      activators of transcription (JAK/STAT), protein kinase C (PKC), calcineurin,
      intracellular calcium regulation, and several autocrine and paracrine factors.
      Multiple levels of crosstalk exist between pathways. The cellular response to
      changes in the mechanical environment can lead to cardiac myocyte hypertrophy,
      cellular growth that can be accompanied by pathological myocyte dysfunction, and
      tissue fibrosis. Several candidates for the primary mechanosensor in cardiac
      myocytes have been identified, ranging from stretch-activated ion channels in the
      membrane to yet-unknown mechanosensitive mechanisms in the nucleus. New and
      refined experimental techniques will exploit advances in molecular biology and
      biological imaging to study mechanotransduction in isolated cells and genetically
      engineered mice to explore the function of individual proteins.

PMID- 15201150
TI  - The adaptive intracellular control of cardiac muscle function.
AB  - This study explores the mechanisms dominating the regulation of the biochemical
      energy consumption and the mechanical output of the actin-myosin motor units, the
      crossbridges (Xbs), in the cardiac sarcomere. Our analytical model, which couples
      Xbs cycling dynamics with the kinetics of the free Ca(2+) binding to troponin-C
      (Tn-C), includes two feedback mechanisms: (1) a cooperativity mechanism, whereby
      the amount of force generating Xbs determines the affinity of calcium binding to
      the regulatory protein and the force-length relationship (FLR); and (2) a
      mechanical (negative) feedback, whereby the filament shortening velocity affects
      the rate of Xb turnover from the force- to the nonforce-generating state, allows
      the analytical solution for the muscle force-velocity relationship (FVR), and the
      linear relation between energy consumption and the generated mechanical energy.
      Our experimental and analytical studies of the force response to large-amplitude
      sarcomere length (SL) oscillations at various frequencies and constant [Ca(2+)]
      in the isolated tetanized rat trabeculae reveal that the generated force depends
      on the history of contraction and establishes the validity of these two
      feedbacks. The cooperativity mechanism generates counterclockwise (CCW)
      hystereses, where the muscle generates external work; while at higher frequencies
      the mechanical feedback produces clockwise (CW) hystereses, where the muscle
      behaves as a damper. The cooperativity provides the adaptive control of the
      cardiac response to short-term changes in the load by modulating Xb recruitment.
      The cardiac efficiency, defined as the ratio of the generated mechanical energy
      (i.e., external work and pseudo-potential energy) to the sarcomere energy
      consumption, is determined by the mechanical feedback, reflecting an inherent
      property of the single Xb. The efficiency is thus independent of the number of
      strong Xbs and is constant and load independent.

PMID- 15201151
TI  - Congestive heart failure after myocardial infarction in the rat: cardiac force
      and spontaneous sarcomere activity.
AB  - The causes of reduced cardiac force development in congestive heart failure (CHF)
      are still uncertain. We explored the subcellular mechanisms leading to decreased
      force development in trabeculae from rats with a myocardial infarction. We
      defined CHF according to clinical and pathological criteria and compared
      properties of trabeculae from animals with CHF (cMI) to those of animals with a
      myocardial scar but without evidence of CHF (uMI), and sham-operated animals. The
      new findings of this study on properties of cMI trabeculae are that (1) maximal
      twitch force following post-extrasystolic potentiation is unchanged; (2) the
      sensitivity of cMI trabeculae to [Ca(2+)](o) is increased; (3) spontaneous
      diastolic sarcomere length (SL) fluctuations (SA) are increased in cMI at all
      levels of SR Ca(2+) loading; and (4) SA is accompanied by a proportional
      reduction of F(max). The results suggest that the probability of spontaneous
      diastolic opening of SR Ca(2+) channels is increased in CHF. These data provide
      the basis for a novel mechanism underlying systolic and diastolic dysfunction as
      well as arrhythmias in hearts in CHF. If SA proves to be a component of
      myocardial dysfunction in human CHF, our thinking about therapy of the patient
      with CHF may be profoundly changed.

PMID- 15201152
TI  - Genetics of cardiac arrhythmias and sudden cardiac death.
AB  - This presentation deals with the molecular substrates of the inherited diseases
      leading to genetically determined cardiac arrhythmias and sudden death. In the
      first part of this article the current knowledge concerning the molecular basis
      of cardiac arrhythmias will be summarized. Second, we will discuss the most
      recent evidence showing that the picture of the molecular bases of cardiac
      arrhythmias is becoming progressively more complex. Thanks to the contribution of
      molecular genetics, the genetic bases, pathogenesis, and genotype-phenotype
      correlation of diseases--such as the long QT syndrome, the Brugada syndrome,
      progressive cardiac conduction defect (Lenegre disease), catecholaminergic
      polymorphic ventricular tachycardia, and Andersen syndrome--have been
      progressively unveiled and shown to have an extremely high degree of genetic
      heterogeneity. The evidence supporting this concept is outlined, with particular
      emphasis on the growing complexity of the molecular pathways that may lead to
      arrhythmias and sudden death, in terms of the relationships between genetic
      defect(s) and genotype(s), as well as gene-to-gene interactions. The current
      knowledge is reviewed, focusing on the evidence that a single clinical phenotype
      may be caused by different genetic substrates and, conversely, a single gene may
      cause very different phenotypes acting through different pathways.

PMID- 15201153
TI  - Pacemaker channels.
AB  - The pacemaker "funny" current (I(f)) has been the object of detailed
      investigations since its original description in sinoatrial node myocytes in the
      late 1970s; its role in underlying generation of spontaneous activity and
      autonomic modulation of cardiac rate has been amply demonstrated. In the late
      1990s four isoforms of the hyperpolarization-activated, cyclic nucleotide-gated
      (HCN) channels, the molecular components of native pacemaker channels, were
      cloned, and structure-function relation studies provided a molecular
      interpretation of several features of the native channels. Its role in pacemaking
      makes I(f) a natural target of heart rate modulating agents; several heart rate
      reducing molecules are known today that exert their action by specific inhibition
      of f-channels. Experiments aimed at determining the role of I(f) relative to
      other proposed pacemaker mechanisms such as SR Ca(2+) transients confirm that the
      I(f)-mediated rate control is a key process in pacemaker generation and autonomic
      control.

PMID- 15201154
TI  - Ventricular fibrillation: new insights into mechanisms.
AB  - Device therapy with implantable cardioverter-defibrillators is currently the only
      proven effective therapy against sudden cardiac death due to ventricular
      fibrillation. However, the expanded clinical indications for device therapy come
      at a staggering cost to an already overburdened health care system. Given these
      statistics, it is both highly desirable and economically imperative to develop
      alternative therapies. New insights into the mechanisms of ventricular
      fibrillation, particularly the role of dynamic factors causing wave instability,
      are providing a promising avenue for developing novel therapies to prevent sudden
      cardiac death.

PMID- 15201155
TI  - Mechanical induction of arrhythmias during ventricular repolarization: modeling
      cellular mechanisms and their interaction in two dimensions.
AB  - Nonpenetrating mechanical stimulation of the precordial chest is particularly
      likely to instantaneously induce sustained rhythm disturbances if timed to
      coincide with ventricular repolarization. A number of possible mechanisms have
      been proposed, including mechanoelectric feedback acting via stretch-activated
      ion channels. The cellular effects of such channel activation have been studied
      and mathematically modeled in great detail. In this study, we investigate their
      dynamic interaction with the trailing wave of action potential repolarization in
      a two-dimensional model of ventricular tissue. The model identifies how stretch
      activation of cation-nonselective ion channels causes ectopic excitation in fully
      repolarized tissue and functional block of conduction at the intersection of the
      mechanical stimulus and the repolarization wave end, which may give rise to both
      trigger and sustaining mechanisms of ventricular arrhythmia. Simulation of
      stretch activation of K(+)-selective ion channels alone is insufficient in
      causing instantaneous arrhythmia, although it may, via action potential
      shortening, contribute to its sustenance.

PMID- 15201156
TI  - Cardiac ryanodine receptor function and regulation in heart disease.
AB  - The cardiac ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR)
      controls intracellular Ca(2+) release and muscle contraction in the heart. Ca(2+)
      release via RyR2 is regulated by several physiological mediators. Protein kinase
      (PKA) phosphorylation dissociates the stabilizing FKBP12.6 subunit (calstabin2)
      from the RyR2 complex, resulting in increased contractility and cardiac output.
      Congestive heart failure is associated with elevated plasma catecholamine levels,
      and chronic stimulation of beta-adrenergic receptors leads to PKA
      hyperphosphorylation of RyR2 in failing hearts. PKA hyperphosphorylation results
      in calstabin2-depleted RyR2 that displays altered channel gating and may cause
      aberrant SR Ca(2+) release, depletion of SR Ca(2+) stores, and reduced myocardial
      contractility in heart failure. Calstabin2-depleted RyR2 may also trigger cardiac
      arrhythmias that cause sudden cardiac death. In patients with catecholaminergic
      polymorphic ventricular tachycardia (CPVT), RyR2 missense mutations cause reduced
      calstabin2 binding to RyR2. Increased RyR2 phosphorylation and pathologically
      increased calstabin2 dissociation during exercise results in aberrant diastolic
      calcium release, which may trigger ventricular arrhythmias and sudden cardiac
      death. In conclusion, heart failure and exercise-induced sudden cardiac death
      have been linked to defects in RyR2-calstabin2 regulation, and this may represent
      a novel target for the prevention and treatment of these forms of heart disease.

PMID- 15201157
TI  - Modulation of the cardiomyocyte cell cycle in genetically altered animals.
AB  - Many forms of cardiovascular disease are associated with cardiomyocyte loss via
      apoptosis and/or necrosis. Although there is currently debate regarding the level
      at which adult cardiomyocytes can reenter the cell cycle and proliferate, it is
      clear that the intrinsic regenerative growth capacity is insufficient to reverse
      the progression to failure in badly injured hearts. The ability to reactivate
      cardiomyocyte proliferation in damaged hearts might permit regenerative growth,
      provided that the nascent cells are able to participate in a functional syncytium
      with the surviving myocardium. In this review, techniques commonly used to
      monitor cardiomyocyte cell cycle activity in normal and injured hearts are
      discussed. In addition, several genetic models are described wherein the
      expression of fundamental cell cycle regulatory proteins has been altered in
      cardiomyocytes.

PMID- 15201158
TI  - Development of the building plan of the heart.
AB  - In this communication we discuss the formation of the synchronously contracting
      chambered heart from a peristaltically contracting linear heart tube. It is
      proposed that members of the T-box family of transcription factors play a crucial
      role in the formation of the building plan of the formed heart. Tbx5 may confer
      venoarterial polarity to the heart tube, whereas Tbx2 initially and Tbx3 in later
      developmental stages prevent the cardiac inflow tract, atrioventricular region,
      outflow tract, as well as the cardiac inner curvatures from chamber
      differentiation. With the exception of the outflow tract that becomes
      incorporated into the ventricles, these regions contribute to the cardiac
      conduction system.

PMID- 15201159
TI  - Cardiac muscle plasticity in adult and embryo by heart-derived progenitor cells.
AB  - The evidence of cardiomyocyte proliferation in damaged heart implied cardiac
      regeneration might occur by resident or extra cardiac stem cells. However, the
      specification and origin of these cells remain unknown. Here, we report using
      fluorescence-activated cell sorting that cardiac progenitor cells resided in
      adult heart and colocalized with small capillary vessels, within the stem cell
      antigen (Sca-1) population expressing high telomerase activity. Notably,
      hematopoietic stem cells capable of efflux Hoechst 33342, termed side population
      cells, also were identified within the heart-derived cells. The cardiac
      progenitor cells (CD45(-)/CD34(-)) express neither cardiac muscle nor endothelial
      cell markers at an undifferentiated stage. The exposure of 5-azacytidine induced
      cardiac differentiation, which depends, in part, on Bmpr1a, a type IA receptor
      for bone morphogenetic protein (BMP). The capability of adult Sca1(+) cells to
      adopt a cardiac muscle in embryogenesis was substantiated by blastocyst
      injection, using progenitors from the adult hearts of transgenic mice that harbor
      a bacterial artificial chromosome expressing GFP via the Nkx-2.5 locus.
      Intravenously injected progenitors, shortly after ischemic/reperfusion, homed and
      functionally differentiated 3.5% of total left ventricle in the host myocardium.
      Differentiation included both fusion-independent and fusion-associated
      components, proved by the Cre/loxP donor/recipient system. Our studies suggest
      that endogenous cardiac progenitors reside in the adult heart, regenerate
      cardiomyocytes functionally, and integrate into the existing heart circuitry.

PMID- 15201160
TI  - Cardiac fiber orientation and the left-right asymmetry determining mechanism.
AB  - The invariant nature of body situs within and across vertebrate species implies
      that a highly conserved pathway controls the specification of the left-right
      (L/R) axis. Situs-specific morphogenesis begins at the end of this pathway and
      leads to normal organ arrangement, also known as situs solitus. Occasionally,
      individuals have a complete, mirror image reversal of this asymmetry, called
      situs inversus totalis (SIT). In these individuals, gross anatomy is mirror
      imaged. However, the helical myofiber pattern within the left ventricle (LV) wall
      is only partially mirror imaged: apical and superficial basal fiber orientation
      are as in normal persons, whereas the deeper basal layers have an inverted fiber
      orientation. Because of this bivalent fiber orientation pattern, LV deformation
      in humans with SIT is mirror imaged only near the base, but near the apex it is
      as in normal subjects. Apparently, the embryonic L/R controlling genetic pathway
      does determine situs-specific gross anatomy morphogenesis, but it is not the only
      factor regulating fiber architecture within the LV wall.

PMID- 15201162
TI  - Molecular and cellular aspects of troponin cardiomyopathies.
AB  - Advances in molecular genetics have led to the identification of mutations in
      each troponin subunit that cause different human cardiomyopathies. Mutations in
      the genes for cardiac troponin T (CTnT), troponin I (CTnI), and troponin C (CTnC)
      cause familial hypertrophic cardiomyopathy (FHC) and are associated with varying
      prognosis and mild-to-moderate hypertrophy. Mutations in CTnT and CTnC can also
      cause dilated cardiomyopathy (DCM), whereas mutations in CTnI can cause
      restrictive cardiomyopathy (RCM). All together, 60 mutations have so far been
      found in troponin subunits associated with cardiomyopathy. Recently, multiple
      cardiomyopathic phenotypes (either HCM or RCM), arising from a single nucleotide
      mutation in the same codon of CTnI, R145, have been documented. Although the
      clinical phenotypes of the cardiomyopathies vary, two common features are present
      in most cardiomyopathy patients: altered Ca(2+) sensitivity of force development
      and impaired energy metabolism. Here, we present the analyses of how these
      troponin mutations affect the in vitro contractile protein function and the
      hypotheses derived to explain the development of these disease states.

PMID- 15201161
TI  - Linking gene expression to function: metabolic flexibility in the normal and
      diseased heart.
AB  - Metabolism transfers energy from substrates to ATP. As a "metabolic omnivore,"
      the normal heart adapts to changes in the environment by switching from one
      substrate to another. We propose that this flexibility is lost in the maladapted,
      diseased heart. Both adaptation and maladaptation are the results of metabolic
      signals that regulate transcription of key cardiac regulatory genes. We propose
      that metabolic remodeling precedes, initiates, and sustains functional and
      structural remodeling. The process of metabolic remodeling then becomes a target
      for pharmacological intervention restoring metabolic flexibility and normal
      contractile function of the heart.

PMID- 15201163
TI  - Genetic factors in cardiac hypertrophy.
AB  - Cardiac hypertrophy is an adaptive response to any cardiac insult or stress that
      increases hemodynamic load. Cardiac hypertrophy can exist in a state of
      compensation or progress to a decompensated state (i.e., heart failure) over
      time. It has been established through transgenic overexpression and gene ablation
      studies that multiple signaling pathways are involved in the induction of
      hypertrophy as well as its decompensation. This article reviews the role of G
      alpha q in the development of pressure overload hypertrophy and discusses the
      relationships between G alpha q and beta-adrenergic receptors, RGS proteins, and
      the proapoptotic factor, Nix/Bnip3L.

PMID- 15201164
TI  - "Energenetics" of heart failure.
AB  - It has been postulated that the failing heart suffers from chronic energy
      starvation, and that the derangements in cardiac energy production contribute to
      the inevitable transition from compensated hypertrophy to decompensated heart
      failure. Although the existence of metabolic alterations is hardly disputed
      anymore, the molecular mechanisms driving this "metabolic remodeling" process and
      its significance for the development of cardiac failure are still open to
      discussion. Next to changes in mitochondrial function, the hypertrophied heart is
      characterized by a marked change in substrate preference away from fatty acids
      toward glucose. Several lines of evidence suggest that these metabolic
      adaptations are brought about, at least in part, by alterations in the rate of
      transcription of genes encoding for proteins involved in substrate transport and
      metabolism. Here, we present an overview of the principal metabolic changes and
      discuss the various mechanisms that are likely to play a role, with special
      emphasis on gene regulatory mechanisms. In addition, the significance of these
      changes for the etiology of heart failure is discussed.

PMID- 15201165
TI  - Regulation of cell size and contractile function by AKT in cardiomyocytes.
AB  - AKT is a serine-threonine kinase involved in several different cellular
      functions, including the control of cell size and the regulation of survival and
      metabolism. Many studies have demonstrated that AKT also plays a critical role in
      the homeostasis of the cardiomyocyte. In these cells, AKT is activated by
      upstream molecules such as beta-adrenergic receptor, insulin-like growth factor-1
      or insulin receptor, through PI3K alpha; whereas its activation is inhibited by
      the PTEN molecule. Downstream targets of AKT in the cardiomyocyte include
      glycogen-synthase kinase-3 beta and S6 kinase. Major effects of AKT activation in
      the cardiomyocyte are increase in cell size, prevention of apoptosis, and
      regulation of glucose metabolism. Interestingly, the AKT-dependent hypertrophic
      pathway is distinct from that activated by MAPKs. In fact, overexpression of AKT
      does not lead to MAPK activation. Our group has shown, moreover, that AKT exerts
      a positive effect on both inotropism and relaxation. In fact, mice overexpressing
      the E40K mutant of AKT in the heart showed improved cardiac function. Thus, AKT
      increases both cell size through the S6 kinase pathway and inotropism through the
      functional regulation of critical Ca(2+)-handling proteins. Therefore, AKT is a
      critical mediator of physiological hypertrophy.

PMID- 15201166
TI  - From genetics to cellular function using computational biology.
AB  - This article illustrates how computational biology (computer modeling) can be
      used to link genetic mutations to their cellular phenotypes. Examples are
      provided from ion channel defects that are associated with hereditary cardiac
      arrhythmias--that is, the long QT and Brugada syndromes. State-specific Markov
      models of wild-type and mutant channels are formulated and introduced into a
      computer model of the ventricular cardiac cell. Simulations are conducted to
      study the rate-dependent alterations in action potential properties caused by the
      mutations. Results provide insights into the cellular mechanisms of QT-interval
      prolongation on the ECG in the long QT syndrome and of ST-segment elevation in
      the right precordial leads in the Brugada syndrome.

PMID- 15201167
TI  - Genetically engineered stem cell therapy for tissue regeneration.
AB  - Therapeutic angiogenesis/vasculogenesis represents a new approach to treat
      patients with ischemic disease not curable with conventional treatment. This
      review focuses on the rationale and preliminary results of combining stem cell
      and gene therapy for regenerative medicine. Under disease conditions, impaired
      neovascularization results from diminished vascular growth factor production and
      primary dysfunction of endothelial cells and their progenitors. Advances in our
      ability to genetically manipulate cells ex vivo has provided the technological
      platform to implement stem cell biology and circumvent the potential hazard of
      direct gene transfer. Ex vivo engineered endothelial progenitor cells have been
      used for the treatment of peripheral limb ischemia. The approach eliminates the
      drawback of immune response against viral vectors and makes feasible repeating
      the therapeutic procedure in case of injury recurrence. The strategy of using
      stem cells as vectors for curative agents proved to be of value for the treatment
      of pulmonary hypertension and thrombosis. Transplantation of neural stem cells
      genetically modified to secrete nerve growth factor was able to ameliorate the
      death of striatal projection neurons caused by transient focal ischemia in the
      adult rat. By a similar approach, engineered neural stem cells might be used for
      treating neurodegenerative disorders. Therefore, genetic manipulation of stem
      cells opens new avenues for regenerative medicine.

PMID- 15201168
TI  - Potential applications of human embryonic stem cell-derived cardiomyocytes.
AB  - The recent establishment of the human embryonic stem cell lines and the
      demonstration of their ability to differentiate in vitro to cardiomyocytes brings
      a unique promise to both basic and clinical research. The present report
      describes the characteristics of the human embryonic stem cell lines and focuses
      on the structural and functional properties of their cardiomyocyte derivatives.
      In addition, the possible signals and cues involved in the commitment and early
      differentiation of cardiomyocytes will be discussed. Finally, the potential
      applications of this unique differentiating system in several research and
      clinical areas are discussed, with special emphasis on the steps required to
      fully harness their potential for myocardial regeneration strategies.

PMID- 15201169
TI  - Controlling the cellular organization of tissue-engineered cardiac constructs.
AB  - There are currently no effective treatments to restore the cardiac muscle lost
      because of ischemia for the millions of people who suffer heart attacks annually.
      Cell therapy procedures have emerged as novel therapeutic strategies for
      treatment of heart failure after myocardial infarction but have been hampered by
      the lack of adequate cell sources of cardiomyocytes and by the inability to
      integrate cell grafts into cardiac muscle. A cardiac patch composed of organized
      and functional cardiomyocytes could drastically enhance the efficacy of this
      important clinical approach. Here, we report our ongoing efforts to develop a
      bioartificial cardiac muscle capable of synchronized multidirectional contraction
      within a three-dimensional hydrogel scaffold. Neonatal rat cardiomyocytes, smooth
      muscle cells, and reconstituted polymeric collagen enriched with growth factors
      and hormones are used. A bioreactor system is used to impart precise strains onto
      the developing tissue constructs in vitro. The results demonstrate that cell
      mediated collagen compaction is significantly enhanced by strain preconditioning,
      resulting in a more favorable cellular organization. Furthermore, the results
      demonstrate that strain stimulation guides cellular orientation in the direction
      of applied strain (i.e., in the circumferential direction). Hence, we demonstrate
      the importance of mechanical preconditioning as a means of promoting the in vitro
      development of engineered cardiac muscle for use with myocardial regeneration
      therapies.

PMID- 15201170
TI  - Myocardial tissue engineering: creating a muscle patch for a wounded heart.
AB  - Cardiac tissue engineering promises to revolutionize the treatment of patients
      with end-stage heart failure and provide new solutions to the serious problem of
      heart donor shortage. By its broad definition, tissue engineering involves the
      construction of tissue equivalents from donor cells seeded within three
      dimensional polymeric scaffolds, then culturing and implanting of the cell-seeded
      scaffolds to induce and direct the growth of new, healthy tissue. Here, we
      present an up-to-date summary of research studies in cardiac tissue engineering,
      with an emphasis on the critical design principles.

PMID- 15201171
TI  - Models of dilated cardiomyopathy in small animals and novel positive inotropic
      therapies.
AB  - Several randomized clinical trials of vesnarinone and milrinone in patients with
      heart failure left disappointing results in the 1990s. Thereafter, use of
      positive inotropic agents has been avoided. Exceptions are the use of digitalis
      glycosides to treat mild-moderate heart failure and the intravenous
      administration of catecholamines and phosphodiesterase inhibitors in patients
      with acute and/or refractory heart failure. It is not, however, exactly known
      whether chronic enhancement of cardiac contractility indeed has harmful effects,
      besides increased risk of arrhythmia and mortality. We investigated the potential
      chronic benefit of positive inotropic modification to treat progressive
      cardiomyopathy and associated heart failure using a genetic complementation
      strategy of muscle lim-protein and phospholamban (PLN) double mutagenesis in the
      mouse and found clear evidence of positive effects. Subsequent somatic
      modification of PLN function via gene transfer with recombinant adeno-associated
      virus vectors in small animal models of dilated cardiomyopathy further supported
      the chronic benefit of enhanced cardiac function achieved in an beta-adrenergic
      stimulus-independent manner. This study examines current small animal models of
      dilated cardiomyopathy and recent multiple attempts to use these models as novel
      gene-based inotropic therapies.

PMID- 15201172
TI  - Gene therapy for cardiac arrhythmias.
AB  - Myocardial gene transfer has shown tremendous potential to investigate
      pathophysiology and potential therapies for cardiac diseases. In the field of
      cardiac arrhythmias, there is a tremendous need for new therapeutic options. The
      current work reviews the need for new therapies for cardiac arrhythmias, the use
      of gene transfer to evaluate cellular electrophysiology, the application of in
      vivo gene transfer to treatment of common arrhythmias, and the current problems
      in the field of cardiac gene therapy. Arrhythmia gene therapy is a field in its
      infancy, and future human applications are dependent on solutions to the problems
      discussed here.

PMID- 15201174
TI  - Dynamics of blood flow and platelet transport in pathological vessels.
AB  - Arterial disease, characterized by arterial occlusion (stenosis), is a leading
      cause of cardiovascular diseases and a major healthcare problem in the Western
      world. One of the main mechanisms leading to vessel occlusion is thrombus
      formation, which may be initiated by platelet activation. Shear rates and flow
      patterns (fluid dynamics factors) and concentration of coagulation factors and
      platelet agonists (biological factors) modulate platelet function and may lead to
      platelet activation and aggregation. Here, we examine the flow-induced mechanisms
      leading to platelet activation in models of stenosed coronary vessels.
      Experimental and numerical methods were used to investigate and characterize the
      influence of the flow field on platelet activation. As it passes through
      pathological geometries characteristic of arterial stenosis, a platelet is
      exposed to varying levels of shear stress. The cumulative effect of the shear
      stress level and the duration of the platelet's exposure to it determine whether
      the platelet is brought beyond its activation threshold. Stress histories of
      individual platelets can be tracked within the flow field to locate the regions
      where activated platelets might be found and subsequently aggregate and/or adhere
      to the wall.

PMID- 15201173
TI  - The Fas receptor-1,4,5-IP3 cascade: a potential target for treating heart failure
      and arrhythmias.
AB  - Activation of the Fas receptor in various cell types, including myocytes,
      triggers apoptotic as well as nonapoptotic effects. Recent studies suggest that
      Fas activation in the heart participates in the development of major pathologies
      such as myocarditis and ischemic/reperfusion insults, which are manifested by
      arrhythmias and mechanical dysfunction. To decipher the contribution of the
      Fas/FasL pathway to myocardial pathologies, we have investigated the functional
      consequences of Fas activation in normoxic and hypoxic ventricular myocytes. Our
      major findings were as follows. (1) Although Fas is constitutively expressed in
      ventricular myocytes, normoxic myocytes are resistant to Fas-mediated apoptosis.
      In contrast, hypoxia predisposes myocytes to apoptosis induced by Fas activation.
      The underlying mechanism is a shift in the balance between proapoptotic proteins
      (including Fas) and antiapoptotic proteins toward the former. (2) In normoxic
      myocytes, Fas activation causes a wide range of functional disturbances, which
      include reduction in resting potential and action potential amplitude, prolonged
      action potential duration, development of delayed and early after
      depolarizations, occasionally culminating into arrhythmias, diastolic [Ca(2+)](i)
      level increase, decreased I(to) and increased I(Ca,L). (3) The above-mentioned
      effects in normoxic myocytes (but not Fas-mediated apoptosis in hypoxic myocytes)
      depend on the phospholipase C --> 1,4,5-IP(3) --> SR [Ca(2+)](i) release cascade.
      (4) Inhibition of tyrosine kinases with genistein blocks both the apoptotic and
      nonapoptotic consequences of Fas activation in ventricular myocytes. Based on
      these studies we propose that tyrosine phosphorylation in ventricular myocytes
      can serve as a novel potential target for attenuating Fas-mediated dysfunction in
      normoxic and hypoxic myocardium.

PMID- 15201175
TI  - Novel approaches to reduce restenosis.
AB  - Percutaneous coronary intervention (PCI) has become the major technique of
      revascularization and is replacing cardiac bypass surgery. PCI is typically
      performed today with a combination of balloon dilatation and stents, with some
      80% of the procedures followed by stent implantation. After balloon dilatation,
      an acute recoil response can be responsible for some 30% immediate loss of the
      vessel lumen at the end of the procedure. Restenosis is the late loss (within 6-9
      months) of the lumen of the artery due to vessel shrinkage (negative remodeling)
      and an intense proliferative response to the local injury. Stents reduce
      restenosis by 30% by preventing acute recoil and reducing long-term negative
      arterial remodeling. Yet, long-term pressure of the stent struts against the
      vessel wall stimulates an increased arterial proliferative response, which is the
      major cause for stent restenosis. Limiting the proliferative response by local
      radiation (brachytherapy) have reduced restenosis, at a cost of increased late
      thrombogenicity and delayed vessel healing. Drug-eluting stents have shown
      extremely promising results in limiting restenosis. Rapamycin and paclitaxel are
      the major drugs in eluting stents in clinical use today, having reduced
      restenosis to less than 10%. Local cellular and genetic therapy approaches are
      currently at preclinical phases. The future of percutaneous revascularization
      remains bright and will enhance the effectiveness of PCI as the primary
      revascularization therapy for coronary artery disease.

PMID- 15201176
TI  - Augmentation of dilated failing left ventricular stroke work by a physiological
      cardiac assist device.
AB  - A novel physiological cardiac assist device (PCAD), otherwise known as the LEVRAM
      assist device, which is synchronized with the heartbeat, was developed to assist
      the left ventricle (LV) in chronic heart failure (CHF). The PCAD utilizes a
      single cannula, which is inserted in less than 15 s through the apex of the
      beating LV by means of a specially designed device. Blood is withdrawn from the
      LV into the PCAD in diastole and is injected back to the LV, through the same
      cannula, during the systolic ejection phase, thereby augmenting stroke volume
      (SV) and stroke work (SW). CHF with dilated LV was induced in sheep by successive
      intracoronary injections of 100-microm beads. The sheep (92.2 +/- 25.9 kg, n = 5)
      developed stable CHF with increased LV end-diastolic diameter (69.4 +/- 3.3 mm)
      and end-diastolic volume (LVEDV = 239 +/- 32 mL), with severely reduced ejection
      fraction (23.8 +/- 7.6%), as well as mild-to-moderate mitral regurgitation. The
      sheep were anesthetized, and the heart was exposed by left thoracotomy. Pressure
      was measured in the LV and aorta (Millar). The SV was measured by flow meters and
      the LV volume by sonocrystals. Assist was provided every 10 regular beats, and
      the assisted beats were compared with the preceding unassisted beats, at the same
      LVEDV. The PCAD displaced 13.6 +/- 3.4 mL, less than 8% of LVEDV. Added SW was
      calculated from the assisted and control pressure-volume loops. The efficiency,
      defined as an increase in SW divided by the mechanical work of the PCAD, was 85.4
      +/- 16.9%. We conclude that the PCAD, working with a small displaced blood volume
      in synchrony with the heartbeat, efficiently augments the SW of the dilated
      failing LV. The PCAD is suggested for use as a permanent implantable device in
      CHF.

PMID- 15201177
TI  - The computational integrated myocyte: a view into the virtual heart.
AB  - The presentation outlines an integrative approach for developing a computational
      model of cardiomyocytes. A modular approach is proposed, and strategies of
      linking the modules (intermediary metabolism, electrophysiology, and mechanics)
      of the model are presented. A strong recommendation is given toward an integrated
      system approach backed by experimental validation.

PMID- 15201178
TI  - A practical and robust sequence search strategy for structural genomics target
      selection.
AB  - MOTIVATION: Target selection strategies for structural genomic projects must be
      able to prioritize gene regions on the basis of significant sequence similarity
      with proteins that have already been structurally determined. With the rapid
      development of protein comparison software a robust prioritization scheme should
      be independent of the choice of algorithm and be able to incorporate different
      sequence similarity thresholds. RESULTS: A robust target selection strategy has
      been developed that can assign a priority level to all genes in any genome.
      Structural assignments to genome sequences are calculated at two thresholds and
      six levels (1-6) describe the prioritization of all whole genes and partial gene
      regions. This simple two-threshold approach can be implemented with any fold
      recognition or homology detection algorithms. The results for 10 genomes are
      presented using the SSEARCH and PSI-BLAST programs. AVAILABILITY: Programs are
      available on request from the authors.

PMID- 15201179
TI  - Mean and variance of the Gibbs free energy of oligonucleotides in the nearest
      neighbor model under varying conditions.
AB  - MOTIVATION: In order to assess the stability of DNA-DNA hybridizations-for
      example during PCR primer design or oligonucleotide selection for microarrays-one
      needs to predict the change in Gibbs free energy DeltaG during hybridization. The
      nearest neighbor model provides a good compromise between accuracy and
      computational simplicity for this task. To determine optimal combinations of
      reaction parameters (temperature, salt concentration, oligonucleotide length and
      GC-content), one would like to understand how DeltaG depends on all of these
      parameters simultaneously. RESULTS: We derive analytic results about the
      distribution of nearest neighbor DeltaG values for a Bernoulli random sequence
      model (specified by oligonucleotide length and average GC-content) under given
      experimental conditions. We find that the distribution of DeltaG values is
      approximately Gaussian and provide exact formulas for expectation and variance.

PMID- 15201180
TI  - GOLDsurfer: three dimensional display of linkage disequilibrium.
AB  - GOLDsurfer is a java-based analysis and graphics program for three-dimensional
      plotting of linkage disequilibrium (LD). Simultaneous presentation of LD
      measures, including recombination rate estimates and disease association
      statistics, helps to clarify LD patterns and facilitates interpretations based on
      multiple indices of local genetic data.

PMID- 15201181
TI  - Biologically valid linear factor models of gene expression.
AB  - MOTIVATION: The identification of physiological processes underlying and
      generating the expression pattern observed in microarray experiments is a major
      challenge. Principal component analysis (PCA) is a linear multivariate
      statistical method that is regularly employed for that purpose as it provides a
      reduced-dimensional representation for subsequent study of possible biological
      processes responding to the particular experimental conditions. Making explicit
      the data assumptions underlying PCA highlights their lack of biological validity
      thus making biological interpretation of the principal components problematic. A
      microarray data representation which enables clear biological interpretation is a
      desirable analysis tool. RESULTS: We address this issue by employing the
      probabilistic interpretation of PCA and proposing alternative linear factor
      models which are based on refined biological assumptions. A practical study on
      two well-understood microarray datasets highlights the weakness of PCA and the
      greater biological interpretability of the linear models we have developed.

PMID- 15201182
TI  - Breakpoint identification and smoothing of array comparative genomic
      hybridization data.
AB  - SUMMARY: We describe a tool, called aCGH-Smooth, for the automated identification
      of breakpoints and smoothing of microarray comparative genomic hybridization
      (array CGH) data. aCGH-Smooth is written in visual C++, has a user-friendly
      interface including a visualization of the results and user-defined parameters
      adapting the performance of data smoothing and breakpoint recognition. aCGH
      Smooth can handle array-CGH data generated by all array-CGH platforms: BAC, PAC,
      cosmid, cDNA and oligo CGH arrays. The tool has been successfully applied to real
      life data. AVAILABILITY: aCGH-Smooth is free for researchers at academic and non
      profit institutions at http://www.few.vu.nl/~vumarray/.

PMID- 15201183
TI  - CTRD: a fast applet for computing signed translocation distance between genomes.
AB  - CTRD is a software for computing translocation distance between genomes. It takes
      two genomes as its input and tests whether one genome can be transformed into the
      other. If possible, it computes the translocation distance between two genomes,
      and gives the translocation operation serial. We adopt the fastest known
      O(n(2)log n) algorithm. Our contributions include (1) give a necessary and
      sufficient condition to ensure that one genome can be transformed into the other
      for translocation operations, and (2) develop a software using the fastest known
      O(n(2)log n) algorithm.

PMID- 15201184
TI  - TMRPres2D: high quality visual representation of transmembrane protein models.
AB  - The 'TransMembrane protein Re-Presentation in 2-Dimensions' (TMRPres2D) tool,
      automates the creation of uniform, two-dimensional, high analysis graphical
      images/models of alpha-helical or beta-barrel transmembrane proteins. Protein
      sequence data and structural information may be acquired from public protein
      knowledge bases, emanate from prediction algorithms, or even be defined by the
      user. Several important biological and physical sequence attributes can be
      embedded in the graphical representation.

PMID- 15201185
TI  - QuickJoin--fast neighbour-joining tree reconstruction.
AB  - We have built a tool for fast construction of very large phylogenetic trees. The
      tool uses heuristics for speeding up the neighbour-joining algorithm-while still
      constructing the same tree as the original neighbour-joining algorithm-making it
      possible to construct trees for 8000 species in <10 min on a single desktop PC.
      In comparison, the same task takes more than 30 min using the QuickTree neighbour
      joining implementation.

PMID- 15201186
TI  - SNPicker: a graphical tool for primer picking in designing mutagenic endonuclease
      restriction assays.
AB  - Simple, low-cost and accurate genotyping methods for single nucleotide
      polymorphisms (SNPs) are in high demand in the post-genome-sequencing era. We
      present a graphical tool called SNPicker, implemented in Java, which
      significantly facilitates the design of mutagenic endonuclease restriction
      assays. SNPicker uses the online NEB REBASE to automatically scan for all
      possible designs of mutagenic primers that can facilitate the picking of
      mismatched PCR primers to artificially introduce or abolish a restriction site at
      the target SNP site. We successfully applied SNPicker in designing endonuclease
      restriction assays for 14 SNPs for the MTHFR gene, the Coagulation Factor II gene
      and the Coagulation Factor V gene. The SNP assays designed using SNPicker were
      cross-validated using the MassARRAY technology.

PMID- 15201187
TI  - Taverna: a tool for the composition and enactment of bioinformatics workflows.
AB  - MOTIVATION: In silico experiments in bioinformatics involve the co-ordinated use
      of computational tools and information repositories. A growing number of these
      resources are being made available with programmatic access in the form of Web
      services. Bioinformatics scientists will need to orchestrate these Web services
      in workflows as part of their analyses. RESULTS: The Taverna project has
      developed a tool for the composition and enactment of bioinformatics workflows
      for the life sciences community. The tool includes a workbench application which
      provides a graphical user interface for the composition of workflows. These
      workflows are written in a new language called the simple conceptual unified flow
      language (Scufl), where by each step within a workflow represents one atomic
      task. Two examples are used to illustrate the ease by which in silico experiments
      can be represented as Scufl workflows using the workbench application.

PMID- 15201188
TI  - The CRASSS plug-in for integrating annotation data with hierarchical clustering
      results.
AB  - We describe an algorithm for finding the most statistically significant non
      overlapping subtrees of a hierarchical clustering of gene expression data with
      respect to a set of secondary data labels on genes. The method is implemented as
      a Java plug-in for a commercial gene expression analysis program (GeneSpring).

PMID- 15201189
TI  - BioSilico: an integrated metabolic database system.
AB  - BioSilico is a web-based database system that facilitates the search and analysis
      of metabolic pathways. Heterogeneous metabolic databases including LIGAND,
      ENZYME, EcoCyc and MetaCyc are integrated in a systematic way, thereby allowing
      users to efficiently retrieve the relevant information on enzymes, biochemical
      compounds and reactions. In addition, it provides well-designed view pages for
      more detailed summary information. BioSilico is developed as an extensible system
      with a robust systematic architecture.

PMID- 15201190
TI  - Predicting the efficacy of short oligonucleotides in antisense and RNAi
      experiments with boosted genetic programming.
AB  - MOTIVATION: Both small interfering RNAs (siRNAs) and antisense oligonucleotides
      can selectively block gene expression. Although the two methods rely on different
      cellular mechanisms, these methods share the common property that not all
      oligonucleotides (oligos) are equally effective. That is, if mRNA target sites
      are picked at random, many of the antisense or siRNA oligos will not be
      effective. Algorithms that can reliably predict the efficacy of candidate oligos
      can greatly reduce the cost of knockdown experiments, but previous attempts to
      predict the efficacy of antisense oligos have had limited success. Machine
      learning has not previously been used to predict siRNA efficacy. RESULTS: We
      develop a genetic programming based prediction system that shows promising
      results on both antisense and siRNA efficacy prediction. We train and evaluate
      our system on a previously published database of antisense efficacies and our own
      database of siRNA efficacies collected from the literature. The best models gave
      an overall correlation between predicted and observed efficacy of 0.46 on both
      antisense and siRNA data. As a comparison, the best correlations of support
      vector machine classifiers trained on the same data were 0.40 and 0.30,
      respectively.

PMID- 15201191
TI  - A controlled investigation of the cause of chronic idiopathic axonal
      polyneuropathy.
AB  - To investigate the aetiology of chronic idiopathic axonal polyneuropathy (CIAP),
      50 consecutive patients were compared with 50 control subjects from the same
      region. There were 22 patients with painful neuropathy and 28 without pain, 26
      with sensory neuropathy and 24 with sensory and motor neuropathy. The typical
      picture was a gradually progressive sensory or sensory and motor neuropathy. It
      caused mild or sometimes moderate disability, and reduced the quality of life.
      There was no evidence that alcohol, venous insufficiency, arterial disease or
      antibodies to peripheral nerve antigens played a significant part. There was a
      possible history of peripheral neuropathy in the first or second-degree relatives
      of six patients and no controls (P = 0.01), and claw toes were present in 12
      patients and four controls (P = 0.03). Thirty-two per cent of the patients and
      14% of the controls had impaired glucose tolerance or fasting hyperglycaemia but,
      after adjusting for age and sex, the difference was not significant (P = 0.45),
      even in the painful neuropathy subgroup. The mean (SD) fasting insulin
      concentrations were significantly (P = 0.01) higher in the patients [75.9 (44.4)
      mmol/l] than the controls [47.3 (37.9) mmol/l], and the mean was higher still in
      the painful neuropathy subgroup [92.2 (37.1) mmol/l] (P < 0.0001). However,
      insulin resistance as assessed using the homeostasis model assessment formula was
      not significantly greater in the patients, even in those with pain, than the
      controls. After adjustment for body mass index as well as age and sex, there was
      no significant difference in the serum cholesterol concentrations, but there were
      significantly higher triglyceride concentrations in the patients [mean 1.90
      (1.41) mmol/l] than the controls [mean 1.25 (0.79] mmol/l) (P = 0.02). In the
      patients with painful peripheral neuropathy, the mean triglyceride concentration
      was 2.37 (1.72), which was even more significantly greater compared with the
      controls (P = 0.003). In conclusion, CIAP is a heterogeneous condition. A
      logistic regression analysis identified environmental toxin exposure and
      hypertriglyceridaemia, but not glucose intolerance or alcohol overuse as
      significant risk factors that deserve further investigation as possible causes of
      CIAP.

PMID- 15201192
TI  - Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study
      of epilepsy in childhood.
AB  - Knowing the prognosis of epilepsy will undoubtedly influence the treatment
      strategy. This study aimed to define the prospects of newly diagnosed childhood
      epilepsy, assess the dynamics of its course, identify relevant variables and
      develop models to assess the individual prognosis. Four hundred and fifty-three
      children with newly diagnosed epilepsy were followed for 5 years. Terminal
      remission at 5 years (TR5) was compared with terminal remission at 2 years (TR2)
      and with the longest remission during follow-up. Variables defined at intake and
      at 6 months of follow-up were analysed for their prognostic relevance. In
      multivariate analyses, combinations of variables were tested to develop reliable
      models for the calculation of the individual prognosis. Data on treatment, course
      during follow-up and epilepsy syndromes were also studied. Three hundred and
      forty-five children (76%) had a TR5 >1 year, 290 (64%) >2 years and 65 (14%) had
      not had any seizure during the entire follow-up. Out of 108 children (24%) with
      TR5 <1 year, 27 were actually intractable at 5 years. Medication was started in
      388 children (86%). In 227 of these (59%), anti-epileptic drugs (AEDs) could be
      withdrawn. A TR5 >1 year was attained by 46% on one AED, on the second AED by
      19%, and by 9% on all additional AED regimes. Almost 60% of the children treated
      with a second or additional AED regime had a TR5 >1 year. Variables predicting
      the outcome at intake were aetiology, history of febrile seizures and age. For
      intake and 6-month variables combined, sex, aetiology, postictal signs, history
      of febrile seizures and TR at 6 months were significant. The model derived from
      intake variables only predicted TR5 <1 year correctly in 36% and TR5 >1 year in
      85% (sensitivity 0.65, specificity 0.64). The corresponding values for the model
      derived from intake and 6-month variables were 43 and 88% (sensitivity 0.69,
      specificity 0.71). The course of the epilepsy was constantly favourable in 51%,
      steadily poor in 17%, improving in 25% and deteriorating in 6%. Intractability
      was in part only a temporary phenomenon. The outcome at 5 years in this cohort of
      children with newly diagnosed epilepsy was favourable in 76%; 64% were off
      medication at that time. Almost a third of the children had a fluctuating course;
      improvement was clearly more common than deterioration. After failure of the
      first AED, treatment can still be successful. Models predicting the outcome have
      fewer misclassifications when predicting a long terminal remission than when
      predicting continuing seizures.

PMID- 15201193
TI  - Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal
      antigen PNMA1 mediate autoimmune encephalomyelitis in the rat.
AB  - Antibodies directed against onconeuronal antigens provide a specific diagnostic
      marker for paraneoplastic neurological syndromes (PNS) and suggest that these
      autoantigens are targeted during disease pathogenesis. However, so far attempts
      to generate autoimmune models of PNS have been unsuccessful. Here we show that
      the adoptive transfer of T-cells specific for the autologous onconeuronal antigen
      Pnma1 cause encephalomyelitis in the Dark Agouti (DA) rat. The sequence of rat
      Ma1 (rPnma1) was determined by RT-PCR using primers for human PNMA1, followed by
      5' and 3' genome walking. Rat Pnma1 is 93.8% identical to human PNMA1 at the
      amino acid level. Rat Pnma1 was cloned into the expression vector pQE60, and
      recombinant protein purified by metal chelate chromatography. Female DA rats were
      immunized with recombinant rPnma1 and rPnma1-specific CD4+ T-helper 1 (Th1) T
      cell lines generated from the draining lymph nodes 10 days post-immunization.
      Freshly activated T-cell blasts were transferred into naive female DA rats, which
      were killed up to 9 days later. Proliferation assays demonstrated that the CD4+
      Th1 T-cells were highly specific for rPnma1. After T-cell transfer the recipients
      developed a perivascular inflammatory response involving CNS regions affected in
      human disease. Anti-Pnma1 antibodies were induced by protein immunization, but
      this was associated with minimal CNS pathology. The induction of an inflammatory
      response in the CNS following the adoptive transfer of rat Pnma1-specific T-cells
      demonstrates for the first time that a paraneoplastic autoantigen can initiate a
      pathogenic effector T-cell response. This animal model strongly supports the
      hypothesis that the pathogenesis of paraneoplastic CNS neurological syndromes in
      man involves an autoimmune T-cell component.

PMID- 15201194
TI  - Juvenile myoclonic epilepsy and idiopathic photosensitive occipital lobe
      epilepsy: is there overlap?
AB  - Although epileptic photosensitivity is well known, its genetics and syndromic
      associations are incompletely understood. Seizures triggered by photic
      stimulation are usually a manifestation of the idiopathic generalized epilepsies,
      especially juvenile myoclonic epilepsy (JME), or of the occipital epilepsies.
      Idiopathic photosensitive occipital epilepsy (IPOE) is a focal epilepsy with
      colourful elementary visual auras, often with conscious tonic head and eye
      version; myoclonus is not a feature. All seizures are induced by photic stimuli.
      We describe four families with phenotypic overlap between JME and IPOE. Families
      were identified if two or more affected individuals had visual auras and electro
      clinical features of an idiopathic epilepsy. Family members underwent detailed
      electro-clinical assessment. In addition, 40 unrelated JME probands were
      investigated systematically for unrecognized features of IPOE (visual aura and
      conscious head version). There were 12 affected individuals in four families; 11
      were female. Clinical onset was at 8-21 years of age. Of 10 patients with visual
      auras, six had conscious head version and five also experienced myoclonic jerks;
      eight had non-photic induced tonic-clonic seizures (TCS). Of the remaining
      individuals, one had myoclonic jerks and occipital spikes; the other had TCS
      without visual aura or myoclonic jerks. Of 10 patients with EEG studies, eight
      had generalized spike and wave (GSW) and six had occipital spikes. All had
      photosensitivity with GSW and four had additional occipital spikes. Of the 40 JME
      probands, six had visual aura and/or conscious head version; five of these were
      photosensitive. There is overlap between the clusters of clinical features used
      to diagnose IPOE and JME. Half of the affected individuals in our families with
      visual aura had myoclonic jerks; the former is characteristic of IPOE and the
      latter of JME. Importantly, visual aura is not regarded as part of JME, nor
      myoclonus part of IPOE, but our data emphasize that these symptoms may occur in
      both disorders. Moreover, two-thirds of individuals with visual aura had
      spontaneous TCS; the latter feature is not described in IPOE. Additionally, we
      demonstrate that visual aura and conscious head version are under-recognized
      features of JME, particularly among photosensitive patients. These findings could
      be explained by shared genetic determinants underlying IPOE and JME.
      Understanding the genetic basis of these disorders must account for the striking
      female predominance, the variable phenotypes associated with photosensitivity and
      the overlap of clinical features classically regarded as distinguishing focal and
      generalized syndromes.

PMID- 15201195
TI  - Predicting bacterial cause in infectious conjunctivitis: cohort study on
      informativeness of combinations of signs and symptoms.
AB  - OBJECTIVE: To find an efficient set of diagnostic indicators that are optimally
      informative in the diagnosis of a bacterial origin of acute infectious
      conjunctivitis. DESIGN: Cohort study involving consecutive patients. Results of
      index tests and reference standard were collected independently from each other.
      SETTING: 25 Dutch health centres. PARTICIPANTS: 184 adults presenting with a red
      eye and either (muco)purulent discharge or glued eyelid(s), not wearing contact
      lenses. MAIN OUTCOME MEASURES: Probability of a positive bacterial culture, given
      different combinations of index test results; area under receiver operating
      characteristics curve. RESULTS: Logistic regression analysis showed optimal
      diagnostic discrimination for the combination of early morning glued eye(s),
      itch, and a history of conjunctivitis. The first of these indicators increased
      the likelihood of a bacterial cause, whereas the other two decreased it. The area
      under the receiver operating characteristics curve for this combination of
      symptoms was 0.74 (95% confidence interval 0.63 to 0.80). The overall prevalence
      of bacterial involvement of 32% could be lowered to 4% or raised to 77%,
      depending on the pattern of index test results. CONCLUSION: A bacterial origin of
      complaints indicative of acute infectious conjunctivitis can be made much more
      likely or unlikely by the answers to three simple questions posed during clinical
      history taking (possibly by telephone). These results may have consequences for
      more targeted prescription of ocular antibiotics.

PMID- 15201196
TI  - Identification of porcine oocyte proteins that are associated with somatic cell
      nuclei after co-incubation.
AB  - Relatively little is known with respect to the oocyte proteins that are involved
      in nuclear reprogramming of somatic cells in mammals. The aim of the present
      study was to use a cell-free incubation system between porcine oocyte proteins
      and somatic cell nuclei and to identify oocyte proteins that remain associated
      with these somatic cell nuclei. In two separate experiments, porcine oocytes were
      either labeled with biotin to label total proteins at the germinal vesicle stage
      or metaphase II stage or they were labeled with 0.1 mM (35)S-methionine either
      during the first 6 h or 22-28 h of in vitro maturation to characterize protein
      synthesis during two distinct phases. To determine which oocyte proteins
      associate with somatic nuclei, labeled proteins were incubated in a collecting
      buffer and energy-regenerating system with isolated ovarian epithelial-like cell
      nuclei. After incubation, the nuclei were subjected to a novel affinity-binding
      system to recover biotin-labeled oocyte proteins or two-dimensional SDS-PAGE for
      separation and visualization of radiolabeled proteins. Proteins of interest were
      sent for identification using either matrix-assisted laser desorption/ionization
      time of flight or liquid chromatography-tandem mass spectrometry. Of the proteins
      that remain associated with isolated nuclei after incubation, 4 were identified
      using the affinity-binding system and 24 were identified using mass spectrometry
      and the two-dimensional gel interface. This study has identified porcine oocyte
      proteins that associate with somatic cell nuclei in a cell-free system using
      proteomics techniques, providing a novel way to identify oocyte proteins
      potentially functionally involved in nuclear reprogramming.

PMID- 15201197
TI  - Sperm binding to oviductal epithelial cells in the rat: role of sialic acid
      residues on the epithelial surface and sialic acid-binding sites on the sperm
      surface.
AB  - The aim of this study was to assess the participation of carbohydrate residues in
      the adhesion of spermatozoa to the oviductal epithelium in the rat. We first
      examined, by lectin labeling, the distribution of glycoconjugates in rat oviducts
      obtained under various hormonal environments. Several classes of glycoconjugates
      were abundant in the epithelium, and the expression of some of these molecules
      varied differentially in ampulla and isthmus, along the estrous cycle and with
      estradiol and progesterone treatment. Proestrous rats were intraoviductally
      injected with lectins Dolichos biflorus, Erythrina cristagalli, Helix pomatia,
      Arachis hypogea, Ulex europaeus I, Triticum vulgaris, or Tritrichomonas
      mobilensis and were inseminated with 10-20 million epididymal spermatozoa in each
      uterine horn. Three hours later, the total number of spermatozoa present in the
      oviduct and the proportion adhering to the epithelium were determined.
      Intraoviductal administration of lectins did not affect the total number of
      spermatozoa recovered from the oviduct and only the sialic acid-binding lectin
      TML decreased the percentage of sperm cells adhering to the epithelium. The
      involvement of sialic acid in sperm-oviduct adhesion was further explored,
      inseminating spermatozoa preincubated with mannose, galactose, sialic acid,
      fucose, fetuin, or asialofetuin. Sialic acid and fetuin inhibited sperm-oviduct
      binding while other carbohydrates had no effect. Using TML lectin
      immunohistochemistry, we found that sialic acid-rich glycoconjugates are equally
      localized in the epithelium of ampulla and isthmus of proestrous rats. The
      electrophoretic pattern of sialic acid-rich glycoproteins of the epithelium
      showed 15 major protein bands, for which molecular mass ranged from 200 to 50 kDa
      with no difference between ampulla and isthmus or between estrous cycle stages.
      Binding sites for sialic acid-fluorescein isothiocyanate were demonstrated on the
      surface of rat spermatozoa, and biotinylated sialic acid recognized 11 plasma
      membrane proteins of sperm cells. These groups of sialic acid-rich glycoproteins
      in the oviductal epithelium and of sialic acid-binding proteins in the plasma
      membrane of sperm cells are good candidates for further studies to characterize
      the molecules responsible for sperm binding. We conclude that there are segment
      specific changes of sugar residues present in the oviductal epithelium associated
      with different endocrine environments. Sperm-oviduct adhesion in the rat occurs
      by interaction of sialoglycoconjugates present in the epithelial cells with
      sialic acid-binding proteins on the sperm surface. This replicates the situation
      previously found in hamsters, disclosing for the first time that species
      specificity in the sugar involved in sperm binding is not absolute.

PMID- 15201198
TI  - The role of prolactin in reproductive failure associated with heat stress in the
      domestic turkey.
AB  - Reproductive failure associated with heat stress is a well-known phenomenon in
      avian species. Increased prolactin (PRL) levels in response to heat stress have
      been suggested as a mechanism involved in this reproductive malfunction. To test
      this hypothesis, laying female turkeys were subjected to 40 degrees C for 12 h
      during the photo-phase daily or maintained at 24-26 degrees C. Birds in each
      group received oral treatment with parachlorophenyalanine (PCPA; 50 mg/kg BW/day
      for 3 days), an inhibitor of serotonin (5-HT) biosynthesis, or immunized against
      vasoactive intestinal peptide (VIP). Both treatments are known to reduce
      circulating PRL levels. Nontreated birds were included as controls. In the
      control group, high ambient temperature terminated egg laying, induced ovarian
      regression, reduced plasma luteinizing hormone (LH) and ovarian steroids
      (progesterone, testosterone, estradiol) levels, and increased plasma PRL levels
      and the incidence of incubation behavior. Pretreatment with PCPA reduced (P <
      0.05) heat stress-induced decline in egg production, increase in PRL levels, and
      expression of incubation behavior. Plasma LH and ovarian steroid levels of heat
      stressed birds were restored to that of controls by PCPA treatment. As in PCPA
      treated birds, VIP immunoneutralization of heat-stressed turkeys reduced (P <
      0.05) circulating PRL levels and prevented the expression of incubation behavior.
      But it did not restore the decline in LH, ovarian steroids, and egg production (P
      > 0.05). The present findings indicate that the detrimental effect of high
      temperature on reproductive performance may not be related to the elevated PRL
      levels in heat-stressed birds but to mechanism(s) that involve 5-HT
      neurotransmission and the induction of hyperthermia.

PMID- 15201199
TI  - Secretions of interleukin-1beta and tumor necrosis factor alpha by whole fetal
      membranes depend on initial interactions of amnion or choriodecidua with
      lipopolysaccharides or group B streptococci.
AB  - The present study evaluated the secretions of interleukin (IL)-1beta and tumor
      necrosis factor (TNF) alpha by fetal membranes stimulated with group B
      streptococci (GBS) and lipopolysaccharide (LPS). The aim was to evaluate the
      initial response of full-thickness membranes to the microbial insult using an in
      vitro experimental model that allowed testing of the individual contributions of
      amnion and choriodecidua to stimulation. Full-thickness membranes were obtained
      after delivery by elective cesarean section from women at 37-40 wk of gestation
      without evidence of active labor. The membranes were mounted in Transwell
      devices, physically separating the upper and lower chambers. The LPS (500 ng/ml)
      or GBS (1 x 10(6) colony-forming units/ml) was added to either the amniotic or
      choriodecidual surface, and accumulation of IL-1beta and TNFalpha were measured
      in both compartments using a specific ELISA. Fetal membranes followed different
      patterns of secretion of proinflammatory cytokines that depended on the side to
      which the stimulus was added or the nature of the stimulus itself. The TNFalpha
      was secreted by amnion and choriodecidua in the presence of LPS or GBS, and
      stimulation with GBS induced a greater synthesis of IL-1beta than did stimulation
      with LPS. Choriodecidual tissue was more responsive than amniotic tissue, and
      this response tended to be higher even when the stimulation was only on the
      amniotic side. However, the amnion plays an active role in recognizing LPS or
      GBS, contributing a significant amount of TNFalpha. Thus, cooperative and
      bidirectional communications occur between amnion and choriodecidua in response
      to bacterial products, which include intermembranous cytokine traffic and
      signaling between tissues.

PMID- 15201200
TI  - Independent downstream gene expression profiles in the presence of estrogen
      receptor alpha or beta.
AB  - The two known forms of estrogen receptor (ER), alpha and beta, exhibit
      differences in structure, affinity for certain ligands, and tissue distribution,
      suggesting differential roles. It is of interest from several perspectives to
      determine whether the two receptors elicit similar or differing responses within
      the same cell type in the presence of the same ligand. To evaluate roles of ER,
      we have examined responses to estrogen in a rat embryonic fibroblast cell line
      model, normally naive to ER, engineered to stably express ERalpha or ERbeta.
      Rat1+ERalpha, Rat1+ERbeta, and precursor Rat1 cell lines were treated with
      estradiol-17beta (E(2); 1 nM) or an ethanol vehicle for 24 h. Total RNA was
      extracted, and cDNA generated and subjected to suppression subtractive
      hybridization (SSH), followed by differential screening using dot blot
      hybridization. In the presence of ERalpha, products were identified that
      represent classic responses to E(2), including markers for cell proliferation. In
      the presence of ERbeta, an alternate transcription profile was observed,
      including upregulation of pro-alpha-2(I) collagen. These data support a model in
      which ERalpha and ERbeta regulate unique subsets of downstream genes within a
      given cell type.

PMID- 15201201
TI  - Susceptibility of bovine germinal vesicle-stage oocytes from antral follicles to
      direct effects of heat stress in vitro.
AB  - Delineation of maternal versus direct effects of heat stress in reducing
      development at the germinal vesicle (GV) stage is challenging, because oocytes
      spontaneously resume meiosis after removal from antral follicles. The use of S
      roscovitine (inhibitor of p34(cdc2)/cyclin B kinase) to hold bovine oocytes at
      the GV stage without compromising early embryo development was previously
      validated in our laboratory. The objective of the present study was to assess the
      direct effects of an elevated temperature commonly seen in heat-stressed dairy
      cows on cumulus-oocyte complexes (COCs) held at the GV stage using 50 microM S
      roscovitine. During roscovitine culture, GV-stage COCs (antral follicle diameter,
      3-8 mm) were cultured at 38.5 or 41 degrees C. Thereafter, oocytes were removed
      from roscovitine medium and allowed to undergo in vitro maturation,
      fertilization, and culture. Zona pellucida hardening (solubility to 0.5%
      pronase), nuclear stage (Hoechst 33342), cortical granule type (lens culinaris
      agglutinin-fluorescein isothiocyanate [FITC]), and early embryo development were
      evaluated. Culture of GV-stage COCs at 41 degrees C increased the proportion that
      had type III cortical granules and reduced the proportion that progressed to
      metaphase II after in vitro maturation. Effects of 41 degrees C on zona pellucida
      hardening, fertilization (penetration, sperm per oocyte, pronuclear formation,
      and monospermic and putative embryos), and cleavage of putative zygotes were not
      noted. However, culture of GV-stage COCs at 41 degrees C for 6 h decreased the
      proportion of 8- to 16-cell embryos, whereas 41 degrees C for 12 h reduced
      blastocyst development. In summary, antral follicle COCs are susceptible to
      direct effects of elevated body temperature, which may account in part for
      reduced fertility in heat-stressed cows.

PMID- 15201202
TI  - Expression of proteasome subunits low molecular mass polypeptide (LMP) 2 and LMP7
      in the endometrium and placenta of rhesus monkey (Macaca mulatta) during early
      pregnancy.
AB  - Previous studies have demonstrated that the ubiquitin-proteasome pathway plays an
      important role in embryo implantation. Low molecular mass polypeptide (LMP) 2 and
      LMP7 are the two subunits of 20S proteasome, which are critical for proteasome
      activity. To further elucidate the roles of LMP2 and LMP7 in embryo implantation
      during early pregnancy, we cloned partial sequences of the LMP2 and LMP7 genes
      and studied the spatiotemporal expression of LMP2 and LMP7 in rhesus monkey
      (Macaca mulatta) uteri on Days 12, 18, and 26 of pregnancy. The results showed
      that the 349-base pair (bp) LMP2 fragment and the 340-bp LMP7 fragment were 97%
      and 99% identical, respectively, to those of human homologues. From the
      statistical results of reverse transcription-polymerase chain reaction, in situ
      hybridization, and immunohistochemistry, we found that the expression levels of
      LMP2 and LMP7 significantly increased with the elongation of pregnancy. The LMP2
      and LMP7 mRNAs were mainly expressed in the luminal and glandular epithelium on
      Day 12 of pregnancy. On Days 18 and 26 of pregnancy, strong signals of LMP2 and
      LMP7 mRNAs were detected in the placental villi, trophoblastic column, and
      arterial endothelial cells close to the implantation site, and moderate
      expressions were found in the trophoblastic shell and glandular epithelium. The
      LMP2 and LMP7 mRNAs were extensively distributed in the stroma on Day 26 of
      pregnancy. The expression patterns of LMP2 and LMP7 proteins were similar to
      those of their transcripts, but weak immunostaining of LMP2 and LMP7 proteins was
      detected in stroma at all stages of pregnancy. These results suggest that LMP2
      and LMP7 may be involved in some key processes of trophoblastic invasion,
      angiogenesis, degradation of the extracellular matrix, immune tolerance, and
      glandular secretion.

PMID- 15201203
TI  - Nutritionally mediated placental growth restriction in the growing adolescent:
      consequences for the fetus.
AB  - Human adolescent pregnancy is characterized by poor pregnancy outcome; the risks
      of spontaneous miscarriage, prematurity, and low birth weight are particularly
      acute in girls who are still growing at the time of conception. Studies using a
      highly controlled sheep paradigm demonstrate that, in growing adolescents who are
      overnourished throughout pregnancy, growth of the placenta is impaired, resulting
      in a decrease in lamb birth weight relative to control-fed adolescents of
      equivalent age. Rapid maternal growth is also associated with increased
      spontaneous abortion rates in late gestation and a reduction in gestation length.
      Nutritionally sensitive hormones of the maternal somatotrophic axis may
      orchestrate nutrient partitioning in this paradigm and the particular role of
      growth hormone is discussed. At midgestation, the placentae of rapidly growing
      dams exhibit less proliferation in the fetal trophectoderm and reduced placental
      mRNA expression of a range of angiogenic factors. These changes occur before
      differences in placental size are apparent but may impact on subsequent
      vascularity. By late pregnancy, placental mass in the rapidly growing versus the
      control dams is reduced by approximately 45%; the fetuses display asymmetric
      growth restriction and are hypoxic and hypoglycemic. These growth-restricted
      pregnancies are associated with major reductions in absolute uterine and
      umbilical blood flows, leading to attenuated fetal oxygen, glucose, and amino
      acid uptakes. Placental glucose transport capacity is markedly reduced in the
      rapidly growing dams but is normal when expressed on a weight-specific placental
      basis. Thus, it is the small size of the placenta per se rather than alterations
      in its nutrient metabolism or transfer capacity that is the major limitation to
      fetal growth in the growing adolescent sheep. Information obtained from this
      highly controlled paradigm is clearly relevant to the clinical management of
      human adolescent pregnancies. In addition, the paradigm provides a robust model
      of placental growth restriction that replicates many of the key features of human
      intrauterine growth restriction per se.

PMID- 15201204
TI  - Effect of anatomy on human nasal air flow and odorant transport patterns:
      implications for olfaction.
AB  - Recent studies that have compared CT or MRI images of an individual's nasal
      anatomy and measures of their olfactory sensitivity have found a correlation
      between specific anatomical areas and performance on olfactory assessments. Using
      computational fluid dynamics (CFD) techniques, we have developed a method to
      quickly (<few days) convert nasal CT scans from an individual patient into an
      anatomically accurate 3-D numerical nasal model that can be used to predict
      airflow and odorant transport, which may ultimately determine olfactory
      sensitivity. The 3-D model can be also be rapidly modified to depict various
      anatomical deviations, such as polyps and their removal, that may alter nasal
      airflow and impair olfactory ability. To evaluate the degree to which variations
      in critical nasal areas such as the olfactory slit and nasal valve can alter
      airflow and odorant transport, inspiratory and expiratory airflow with odorants
      were simulated using numerical finite volume methods. Results suggest that
      anatomical changes in the olfactory region (upper meatus below the cribriform
      plate) and the nasal valve region will strongly affect airflow patterns and
      odorant transport through the olfactory region, with subsequent effects on
      olfactory function. The ability to model odorant transport through individualized
      models of the nasal passages holds promise for relating anatomical deviations to
      generalized or selective disturbances in olfactory perception and may provide
      important guidance for treatments for nasal-sinus disease, occupational rhinitis
      and surgical interventions that seek to optimize airflow and improve deficient
      olfactory function.

PMID- 15201205
TI  - Putative odorant-degrading esterase cDNA from the moth Mamestra brassicae:
      cloning and expression patterns in male and female antennae.
AB  - An esterase cDNA was isolated from the cabbage armyworm Mamestra brassicae
      antennae by PCR strategy. The full-length cDNA, designated as Mbra-EST, contains
      a 1638 bp open reading frame encoding a predicted protein of 546 amino acids.
      This predicted protein presents the structural characteristics of known insect
      carboxyl-esterases, in particular the Ser-His-Glu catalytic triad. The expression
      pattern of the gene was studied by RT-PCR, Northern-blot and in situ
      hybridization. The ribosomal protein rpL8 gene from M. brassicae was also cloned
      to obtain a normalized tool for the comparative gene expression studies. Mbra-EST
      transcripts are specifically expressed in the antennae of males and females and
      in the proboscis of males. In antennae of both sexes, expression is restricted to
      the olfactory sensilla trichodea, suggesting a role in degradation of odorant
      acetate compounds, such as pheromones as well as plant volatile acetate
      components.

PMID- 15201206
TI  - A longitudinal descriptive study of self-reported abnormal smell and taste
      perception in pregnant women.
AB  - Self-reported abnormal sensitivity, qualitative distortions and phantom
      sensations with respect to smell and taste was assessed with a longitudinal
      design, based on questions referring to gestational weeks 13-16 and 31-34 of
      pregnancy in comparison with 9-12 weeks post partum and with non-pregnant women
      with corresponding time durations and intervals. The results show that abnormal
      smell and/or taste perception was reported by 76% of the pregnant women,
      typically believed to be caused by their pregnancy. Increased smell sensitivity
      was found to be very common at the early stage of pregnancy (67% of all pregnant
      respondents) and occasionally accompanied by qualitative smell distortions (17%)
      and phantom smells (14%). The smell abnormalities were less common at the late
      pregnancy stage and almost absent post partum. Abnormal taste sensitivity was
      fairly commonly reported (26%), often described as increased bitter sensitivity
      and decreased salt sensitivity. These results, suggesting that abnormal smell
      and/or taste perception is experienced by a large majority of pregnant women,
      imply that further research is needed to understand to what extent these
      chemosensory changes may underlie food aversions and craving with implications
      for food intake during pregnancy.

PMID- 15201207
TI  - Identification of a chemosensory receptor from the yellow fever mosquito, Aedes
      aegypti, that is highly conserved and expressed in olfactory and gustatory
      organs.
AB  - Aedes aegypti is a highly anthropophilic mosquito responsible for the
      transmission of dengue and yellow fever around the world. Like other mosquitoes,
      the biting and host preference behaviors of this disease vector are largely
      influenced by its sense of smell, which is presumably facilitated by G protein
      coupled receptor signaling cascades. Here, we report the identification and
      characterization of AaOr7, the first candidate odorant receptor from Ae. aegypti.
      This receptor displays extremely high primary amino acid conservation with AgOr7
      another candidate odorant receptor identified in the Aftrotropical malaria
      vector, Anopheles gambiae as well as several previously identified candidate
      odorant receptors in Drosophila melanogaster and other insects. Its transcript is
      expressed in adult chemosensory tissues and during several stages of Ae. aegypti
      development. Within the adult olfactory system, AaOr7 protein is found
      specifically within most antennal and maxillary palp sensilla, as well as in a
      subset of proboscis sensilla. These results are consistent with a role for AaOr7
      in olfaction and gustation supporting the hypothesis that AaOr7 and its orthologs
      may be of general importance to chemosensory processes throughout the lifetime of
      an insect.

PMID- 15201208
TI  - Characterization of electro-olfactogram oscillations and their computational
      reconstruction.
AB  - Electro-olfactogram (EOG) oscillations induced by odorant stimulation have been
      often reported in various vertebrates from fishes to mammals. However, the
      mechanism of generation of EOG oscillations remains unclear. In the present
      study, we first characterized the properties of EOG oscillations induced by amino
      acid odorants in the rainbow trout and then performed a computer simulation based
      on the main assumption that olfactory receptor neurons (ORNs) have intrinsic
      oscillatory properties due to two types of voltage-gated ion channels, which have
      not yet been reported in vertebrate ORNs. EOG oscillations appeared mostly on the
      peak and decay phases of negative EOG responses, when odorant stimuli at high
      intensity flowed regularly anterior to posterior olfactory lamellae in the
      olfactory organ. The appearance of EOG oscillations was dependent on the odorant
      intensity but not on the flow rate. The maximum amplitude and the maximum power
      frequency of EOG oscillations were 3.51 +/- 3.35 mV (mean +/- SD, n = 232, range
      0.12-16.79 mV) and 10.59 +/- 5.05 Hz (mean +/- SD, n = 232, range 3.51-40.03 Hz),
      respectively. The simulation represented sufficiently well the characteristics of
      EOG oscillations; occurrence at high odorant concentration, odorant concentration
      dependent amplitude and the maximum power frequency range actually observed. Our
      results suggest that EOG oscillations are due to the intrinsic oscillatory
      properties of individual ORNs, which have two novel types of voltage-gated ion
      channels (resonant and amplifying channels). The simulation program for Macintosh
      ('oscillation 3.2.4' for MacOS 8.6 or later) is available on the world wide web
      (http://bio2.sci.hokudai.ac.jp/bio/chinou1/noriyo_home.html).

PMID- 15201209
TI  - Natural ligands of hamster aphrodisin.
AB  - The chemical nature of vertebrate pheromones remains largely to be deciphered.
      Hamster aphrodisin is a rare instance of mammal proteinaceous sexual pheromone.
      This protein, found in vaginal secretions, facilitates the mounting behaviour of
      males via activation of a specialized sensory structure named the vomeronasal
      organ, which activates the accessory olfactory bulb. Since it might carry small
      pheromonal ligands due to its lipocalin structure, we analysed organic extracts
      from natural aphrodisin. We identified five predominant compounds specifically
      bound onto natural aphrodisin as 1-hexadecanol (44.7%), 1-octadecanol (19.5%), Z
      9-octadecen-1-ol (18.2%), E-9-octadecen-1-ol (15.4%) and hexadecanoic acid
      (2.2%). Interestingly, these compounds are also described as part of insect
      pheromone blends, disclosing the continuing story of amazing coincidences of
      chemical communication shared by mammals and insects.

PMID- 15201210
TI  - The influence of sodium salts on binary mixtures of bitter-tasting compounds.
AB  - In order to study potential mixture interactions among bitter compounds, selected
      sodium salts were added to five compounds presented either alone or as binary
      bitter-compound mixtures. Each compound was tested at a concentration that
      elicited 'weak' perceived bitterness. The bitter compounds were mixed at these
      concentrations to form a subset of possible binary mixtures. For comparison, the
      concentration of each solitary compound was doubled to measure bitterness
      inhibition at the higher intensity level elicited by the mixtures. The following
      sodium salts were tested for bitterness inhibition: 100 mM sodium chloride
      (salty), 100 mM sodium gluconate (salty), 100 and 20 mM monosodium glutamate
      (umami), and 50 mM adenosine monophosphate disodium salt (umami). Sucrose (sweet)
      was also employed as a bitterness suppressor. The sodium salts differentially
      suppressed the bitterness of compounds and their binary combinations. Although
      most bitter compounds were suppressed, the bitterness of tetralone was not
      suppressed, nor was the bitterness of the binary mixtures that contained it. In
      general, the percent suppression of binary mixtures of compounds was predicted by
      the average percent suppression of its two components. Within the constraints of
      the present study, the bitterness of mixtures was suppressed by sodium salts and
      sucrose independently, with few bitter interactions. This is consistent with
      observations that the bitter taste system integrates the bitterness of multi
      compound solutions linearly.

PMID- 15201211
TI  - Incidental learning and memory for three basic tastes in food.
AB  - Forty three subjects were invited under the pretence that they would take part in
      an experiment on hunger feelings. They came without having eaten anything that
      morning and received a standard breakfast containing orange juice, cream cheese
      on crackers and yoghurt. These products were later (when subjects returned after
      scoring hunger feelings during the day) used as targets amidst a set of
      distractors varied by adding or subtracting different amounts of two basic
      tastes. Orange juice was varied in sweetness and bitterness, cream cheese in
      sourness and bitterness and yoghurt in sweetness and sourness. The changes were
      made comparable by using just noticeable differences, determined in preliminary
      experiments with other subjects, as units of change. Two measurements of memory
      were compared, an absolute (indicating which were the targets) and a relative one
      (indicating whether the targets and distractors were more, less or equally
      pleasant, sweet, sour, bitter or salty as the item eaten at breakfast). Both
      methods showed incidental learning, but relative memory was superior. Memory
      differed between tastes and was partly product dependent. These experiments
      suggest that taste memory is tuned to detect novel and potentially dangerous
      stimuli rather than to remember features of earlier experienced stimuli with
      great precision.

PMID- 15201212
TI  - Proust remembered: has Proust's account of odor-cued autobiographical memory
      recall really been investigated?

PMID- 15201214
TI  - Structure and function of vertebrate CMP-sialic acid synthetases.
AB  - Activation of sugars into nucleotide sugars is critical for their entry into
      biosynthetic pathways. In eukaryotic cells, the activation of the acidic nine
      carbon sugar sialic acid to CMP-sialic acid takes place in the cell nucleus,
      whereas all other nucleotide sugars are made in the cytoplasm. Molecular cloning
      of vertebrate CMP-sialic acid synthetases confirmed the nuclear localization and
      introduced new molecular tools for directly exploring the functional mechanisms
      of the enzymes, as well as the physiological relevance of their nuclear
      transport. Although major advances have been made in understanding structure
      function relationships and defining elements involved in the nuclear transport,
      the riddle surrounding the physiological relevance of nuclear localization awaits
      resolution.

PMID- 15201215
TI  - Crystal structures of Erythrina cristagalli lectin with bound N-linked
      oligosaccharide and lactose.
AB  - Erythrina cristagalli lectin (ECL) is a galactose-specific legume lectin.
      Although its biological function in the legume is unknown, ECL exhibits
      hemagglutinating activity in vitro and is mitogenic for T lymphocytes. In
      addition, it has been recently shown that ECL forms a novel conjugate when
      coupled to a catalytically active derivative of the type A neurotoxin from
      Clostridium botulinum, thus providing a therapeutic potential. ECL is
      biologically active as a dimer in which each protomer contains a functional
      carbohydrate-combining site. The crystal structure of native ECL was recently
      reported in complex with lactose and 2'-fucosyllactose. ECL protomers adopt the
      legume lectin fold but form non-canonical dimers via the handshake motif as was
      previously observed for Erythrina corallodendron lectin. Here we report the
      crystal structures of native and recombinant forms of the lectin in three new
      crystal forms, both unliganded and in complex with lactose. For the first time,
      the detailed structure of the glycosylated hexasaccharide for native ECL has been
      elucidated. The structure also shows that in the crystal lattice the
      glycosylation site and the carbohydrate binding site are involved in
      intermolecular contacts through water-mediated interactions.

PMID- 15201216
TI  - Analysis of embryonic motoneuron gene regulation: derepression of general
      activators function in concert with enhancer factors.
AB  - The underlying transcriptional mechanisms that establish the proper spatial and
      temporal pattern of gene expression required for specifying neuronal fate are
      poorly defined. We have characterized how the Hb9 gene is expressed in developing
      motoneurons in order to understand how transcription is directed to specific
      cells within the developing CNS. We found that non-specific general-activator
      proteins such as E2F and Sp1 are capable of driving widespread low level
      transcription of Hb9 in many cell types throughout the neural tube; however,
      their activity is modulated by specific repressor and activator complexes. The
      general-activators of Hb9 are suppressed from triggering inappropriate
      transcription by repressor proteins Irx3 and Nkx2.2. High level motoneuron
      expression is achieved by assembling an enhancesome on a compact evolutionarily
      conserved segment of Hb9 located from -7096 to -6896. The ensemble of LIM-HD and
      bHLH proteins that interact with this enhancer change as motoneuron development
      progresses, facilitating both the activation and maintenance of Hb9 expression in
      developing and mature motoneurons. These findings provide direct support for the
      derepression model of gene regulation and cell fate specification in the neural
      tube, as well as establishing a role for enhancers in targeting gene expression
      to a single neuronal subtype in the spinal cord.

PMID- 15201217
TI  - Cell-autonomous and cell non-autonomous signaling through endothelin receptor B
      during melanocyte development.
AB  - The endothelin receptor B gene (Ednrb) encodes a G-protein-coupled receptor that
      is expressed in a variety of cell types and is specifically required for the
      development of neural crest-derived melanocytes and enteric ganglia. In humans,
      mutations in this gene are associated with Waardenburg-Shah syndrome, a disorder
      characterized by pigmentation defects, deafness and megacolon. To address the
      question of whether melanocyte development depends entirely on a cell-autonomous
      action of Ednrb, we performed a series of tissue recombination experiments in
      vitro, using neural crest cell cultures from mouse embryos carrying a novel Ednrb
      null allele characterized by the insertion of a lacZ marker gene. The results
      show that Ednrb is not required for the generation of early neural crest-derived
      melanoblasts but is required for the expression of the differentiation marker
      tyrosinase. Tyrosinase expression can be rescued, however, by the addition of
      Ednrb wild-type neural tubes. These Ednrb wild-type neural tubes need not be
      capable of generating melanocytes themselves, but must be capable of providing
      KIT ligand, the cognate ligand for the tyrosine kinase receptor KIT. In fact,
      soluble KIT ligand is sufficient to induce tyrosinase expression in Ednrb
      deficient cultures. Nevertheless, these tyrosinase-expressing, Ednrb-deficient
      cells do not develop to terminally differentiated, pigmented melanocytes.
      Pigmentation can be induced, however, by treatment with tetradecanoyl phorbol
      acetate, which mimics EDNRB signaling, but not by treatment with endothelin 1,
      which stimulates the paralogous receptor EDNRA. The results suggest that Ednrb
      plays a significant role during melanocyte differentiation and effects melanocyte
      development by both cell non-autonomous and cell-autonomous signaling mechanisms.

PMID- 15201218
TI  - Hedgehog regulation of superficial slow muscle fibres in Xenopus and the
      evolution of tetrapod trunk myogenesis.
AB  - In tetrapod phylogeny, the dramatic modifications of the trunk have received less
      attention than the more obvious evolution of limbs. In somites, several waves of
      muscle precursors are induced by signals from nearby tissues. In both amniotes
      and fish, the earliest myogenesis requires secreted signals from the ventral
      midline carried by Hedgehog (Hh) proteins. To determine if this similarity
      represents evolutionary homology, we have examined myogenesis in Xenopus laevis,
      the major species from which insight into vertebrate mesoderm patterning has been
      derived. Xenopus embryos form two distinct kinds of muscle cells analogous to the
      superficial slow and medial fast muscle fibres of zebrafish. As in zebrafish, Hh
      signalling is required for XMyf5 expression and generation of a first wave of
      early superficial slow muscle fibres in tail somites. Thus, Hh-dependent adaxial
      myogenesis is the likely ancestral condition of teleosts, amphibia and amniotes.
      Our evidence suggests that midline-derived cells migrate to the lateral somite
      surface and generate superficial slow muscle. This cell re-orientation
      contributes to the apparent rotation of Xenopus somites. Xenopus myogenesis in
      the trunk differs from that in the tail. In the trunk, the first wave of
      superficial slow fibres is missing, suggesting that significant adaptation of the
      ancestral myogenic programme occurred during tetrapod trunk evolution. Although
      notochord is required for early medial XMyf5 expression, Hh signalling fails to
      drive these cells to slow myogenesis. Later, both trunk and tail somites develop
      a second wave of Hh-independent slow fibres. These fibres probably derive from an
      outer cell layer expressing the myogenic determination genes XMyf5, XMyoD and
      Pax3 in a pattern reminiscent of amniote dermomyotome. Thus, Xenopus somites have
      characteristics in common with both fish and amniotes that shed light on the
      evolution of somite differentiation. We propose a model for the evolutionary
      adaptation of myogenesis in the transition from fish to tetrapod trunk.

PMID- 15201219
TI  - The STAR/Maxi-KH domain protein GLD-1 mediates a developmental switch in the
      translational control of C. elegans PAL-1.
AB  - Translational control is an essential mechanism of gene control utilized
      throughout development, yet the molecular mechanisms underlying translational
      activation and repression are poorly understood. We have investigated the
      translational control of the C. elegans caudal homolog, pal-1, and found that GLD
      1, a member of the evolutionarily conserved STAR/Maxi-KH domain family, acts
      through a minimal pal-1 3' UTR element to repress pal-1 translation in the distal
      germline. We also provide data suggesting that GLD-1 may repress pal-1
      translation after initiation. Finally, we show that GLD-1 represses the distal
      germline expression of the KH domain protein MEX-3, which was previously shown to
      repress PAL-1 expression in the proximal germline and which appears specialized
      to control PAL-1 expression patterns in the embryo. Hence, GLD-1 mediates a
      developmental switch in the control of PAL-1 repression, allowing MEX-3 to
      accumulate and take over the task of PAL-1 repression in the proximal germline,
      where GLD-1 protein levels decline.

PMID- 15201220
TI  - Sprouty proteins regulate ureteric branching by coordinating reciprocal
      epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney
      development.
AB  - The kidney is a classic model for studying mechanisms of inductive tissue
      interactions associated with the epithelial branching common to many embryonic
      organs, but the molecular mechanisms are still poorly known. Sprouty proteins
      antagonize tyrosine kinases in the Egf and Fgf receptors and are candidate
      components of inductive signalling in the kidney as well. We have addressed the
      function of sprouty proteins in vivo by targeted expression of human sprouty 2
      (SPRY2) in the ureteric bud, which normally expresses inductive signals and mouse
      sprouty 2 (Spry2). Ectopic SPRY2 expression led to postnatal death resulting from
      kidney failure, manifested as unilateral agenesis, lobularization of the organ or
      reduction in organ size because of inhibition of ureteric branching. The
      experimentally induced dysmorphology associated with deregulated expression of
      Wnt11, Gdnf and Fgf7 genes in the early stages of organogenesis indicated a
      crucial role for sprouty function in coordination of epithelial-mesenchymal and
      stromal signalling, the sites of expression of these genes. Moreover, Fgf7
      induced Spry2 gene expression in vitro and led with Gdnf to a partial rescue of
      the SPRY2-mediated defect in ureteric branching. Remarkably, it also led to
      supernumerary epithelial bud formation from the Wolffian duct. Together, these
      data suggest that Spry genes contribute to reciprocal epithelial-mesenchymal and
      stromal signalling controlling ureteric branching, which involves the
      coordination of Ffg/Wnt11/Gdnf pathways.

PMID- 15201221
TI  - Amphioxus and ascidian Dmbx homeobox genes give clues to the vertebrate origins
      of midbrain development.
AB  - The ancestral chordate neural tube had a tripartite structure, comprising
      anterior, midbrain-hindbrain boundary (MHB) and posterior regions. The most
      anterior region encompasses both forebrain and midbrain in vertebrates. It is not
      clear when or how the distinction between these two functionally and
      developmentally distinct regions arose in evolution. Recently, we reported a
      mouse PRD-class homeobox gene, Dmbx1, expressed in the presumptive midbrain at
      early developmental stages, and the hindbrain at later stages, with exclusion
      from the MHB. This gene provides a route to investigate the evolution of midbrain
      development. We report the cloning, genomic structure, phylogeny and embryonic
      expression of Dmbx genes from amphioxus and from Ciona, representing the two most
      closely related lineages to the vertebrates. Our analyses show that Dmbx genes
      form a distinct, ancient, homeobox gene family, with highly conserved sequence
      and genomic organisation, albeit more divergent in Ciona. In amphioxus, no Dmbx
      expression is observed in the neural tube, supporting previous arguments that the
      MHB equivalent region has been secondarily modified in evolution. In Ciona, the
      CiDmbx gene is detected in neural cells caudal to Pax2/5/8-positive cells (MHB
      homologue), in the Hox-positive region, but, interestingly, not in any cells
      rostral to them. These results suggest that a midbrain homologue is missing in
      Ciona, and argue that midbrain development is a novelty that evolved specifically
      on the vertebrate lineage. We discuss the evolution of midbrain development in
      relation to the ancestry of the tripartite neural ground plan and the origin of
      the MHB organiser.

PMID- 15201222
TI  - FGF signaling is required for initiation of feather placode development.
AB  - Morphogenesis of hairs and feathers is initiated by an as yet unknown dermal
      signal that induces placode formation in the overlying ectoderm. To determine
      whether FGF signals are required for this process we over-expressed soluble
      versions of FGFR1 or FGFR2 in the skin of chicken embryos. This produced a
      complete failure of feather formation prior to any morphological or molecular
      signs of placode development. We further show that Fgf10 is expressed in the
      dermis of nascent feather primordia, and that anti-FGF10 antibodies block feather
      placode development in skin explants. In addition we show that FGF10 can induce
      expression of positive and negative regulators of feather development and can
      induce its own expression under conditions of low BMP signaling. Together these
      results demonstrate that FGF signaling is required for the initiation of feather
      placode development and implicate FGF10 as an early dermal signal involved in
      this process.

PMID- 15201223
TI  - Regulation of Otx2 expression and its functions in mouse epiblast and anterior
      neuroectoderm.
AB  - We have identified cis-regulatory sequences acting on Otx2 expression in epiblast
      (EP) and anterior neuroectoderm (AN) at about 90 kb 5' upstream. The activity of
      the EP enhancer is found in the inner cell mass at E3.5 and the entire epiblast
      at E5.5. The AN enhancer activity is detected initially at E7.0 and ceases by
      E8.5; it is found later in the dorsomedial aspect of the telencephalon at E10.5.
      The EP enhancer includes multiple required domains over 2.3 kb, and the AN
      enhancer is an essential component of the EP enhancer. Mutants lacking the AN
      enhancer have demonstrated that these cis-sequences indeed regulate Otx2
      expression in EP and AN. At the same time, our analysis indicates that another EP
      and AN enhancer must exist outside of the -170 kb to +120 kb range. In
      Otx2DeltaAN/- mutants, in which one Otx2 allele lacks the AN enhancer and the
      other allele is null, anteroposterior axis forms normally and anterior
      neuroectoderm is normally induced. Subsequently, however, forebrain and midbrain
      are lost, indicating that Otx2 expression under the AN enhancer functions to
      maintain anterior neuroectoderm once induced. Furthermore, Otx2 under the AN
      enhancer cooperates with Emx2 in diencephalon development. The AN enhancer region
      is conserved among mouse, human and Xenopus; moreover, the counterpart region in
      Xenopus exhibited an enhancer activity in mouse anterior neuroectoderm.

PMID- 15201224
TI  - Regulation of Otx2 expression and its functions in mouse forebrain and midbrain.
AB  - Otx2 expression in the forebrain and midbrain was found to be regulated by two
      distinct enhancers (FM and FM2) located at 75 kb 5' upstream and 115 kb 3'
      downstream. The activities of these two enhancers were absent in anterior
      neuroectoderm earlier than E8.0; however, at E9.5 their regions of activity
      spanned the entire mesencephalon and diencephalon with their caudal limits at the
      boundary with the metencephalon or isthmus. In telencephalon, activities were
      found only in the dorsomedial aspect. Potential binding sites of OTX and TCF were
      essential to FM activity, and TCF sites were also essential to FM2 activity. The
      FM2 enhancer appears to be unique to rodent; however, the FM enhancer region is
      deeply conserved in gnathostomes. Studies of mutants lacking FM or FM2 enhancer
      demonstrated that these enhancers indeed regulate Otx2 expression in forebrain
      and midbrain. Development of mesencephalic and diencephalic regions was
      differentially regulated in a dose-dependent manner by the cooperation between
      Otx1 and Otx2 under FM and FM2 enhancers: the more caudal the structure the
      higher the OTX dose requirement. At E10.5 Otx1-/-Otx2DeltaFM/DeltaFM mutants, in
      which Otx2 expression under the FM2 enhancer remained, exhibited almost complete
      loss of the entire diencephalon and mesencephalon; the telencephalon did,
      however, develop.

PMID- 15201225
TI  - Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback
      signaling controlling metanephric kidney and limb organogenesis.
AB  - Epithelial-mesenchymal feedback signaling is the key to diverse organogenetic
      processes such as limb bud development and branching morphogenesis in kidney and
      lung rudiments. This study establishes that the BMP antagonist gremlin (Grem1) is
      essential to initiate these epithelial-mesenchymal signaling interactions during
      limb and metanephric kidney organogenesis. A Grem1 null mutation in the mouse
      generated by gene targeting causes neonatal lethality because of the lack of
      kidneys and lung septation defects. In early limb buds, mesenchymal Grem1 is
      required to establish a functional apical ectodermal ridge and the epithelial
      mesenchymal feedback signaling that propagates the sonic hedgehog morphogen.
      Furthermore, Grem1-mediated BMP antagonism is essential to induce metanephric
      kidney development as initiation of ureter growth, branching and establishment of
      RET/GDNF feedback signaling are disrupted in Grem1-deficient embryos. As a
      consequence, the metanephric mesenchyme is eliminated by apoptosis, in the same
      way as the core mesenchymal cells of the limb bud.

PMID- 15201226
TI  - Response of Saccharomyces cerevisiae to a monoterpene: evaluation of antifungal
      potential by DNA microarray analysis.
AB  - Plant-derived essential oils with monoterpenoids have been used as antifungal
      drugs since ancient times, but the mode of action of these natural hydrocarbons
      at the molecular level is not understood. In order to understand the mechanisms
      of toxicity of alpha-terpinene (a cyclic monoterpene), a culture of Saccharomyces
      cerevisiae was exposed to 0.02% alpha-terpinene for 2 h and transcript profiles
      were obtained using yeast DNA arrays. These profiles, when compared with
      transcript profiles of untreated cultures, revealed that the expression of 793
      genes was affected. For 435 genes, mRNA levels in treated cells compared with
      control cells differed by more than two-fold, whereas for 358 genes, it was <0.5
      fold. Northern blots were performed for selected genes to verify the microarray
      results. Functional analysis of the up-regulated genes indicates that, similar to
      commonly used antifungal drugs, alpha-terpinene exposure affected genes involved
      in ergosterol biosynthesis and sterol uptake. In addition, transcriptional
      induction of genes related to lipid metabolism, cell wall structure and function,
      detoxification and cellular transport was observed in response to terpinene
      toxicity. Notably, the functions of 192 up-regulated genes are still unknown, but
      their characterization will probably shed light on the mechanisms of drug
      resistance and sensitivity. Taken together, this study showed that alpha
      terpinene has strong antifungal activities and its modes of action resemble those
      of presently used antifungal drugs.

PMID- 15201227
TI  - Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer
      patients: a systematic review and meta-analysis of randomized trials.
AB  - CONTEXT: Neutropenia is one of the grave consequences of cancer chemotherapy, and
      the treatment of neutropenic febrile patients with intravenous (iv) antibiotics
      has been shown to reduce mortality. Oral therapy could be an alternative approach
      for selected patients. OBJECTIVES: To compare the efficacy of oral antibiotics
      versus iv antibiotic therapy in febrile neutropenic cancer patients. DATA
      SOURCES: The Cochrane Library, the Cochrane Cancer Network Register of trials,
      EMBASE, LILACS and MEDLINE, databases for ongoing trials and the conference
      proceedings of the Interscience Conference on Antimicrobial Agents and
      Chemotherapy (ICAAC). STUDY SELECTION: Randomized controlled trials comparing
      oral antibiotic/s and iv antibiotic/s for the treatment of neutropenic cancer
      patients with fever. DATA COLLECTION: Two reviewers independently assessed trial
      eligibility, methodological quality and extracted all data. Data concerning
      mortality, treatment failures and adverse events were drawn from included studies
      assuming an 'intention-to-treat' and 'per-protocol' basis for the outcome
      measures whenever possible. Relative risks (RR) with their 95% confidence
      intervals (CI) for dichotomous data were estimated. MAIN RESULTS: Fifteen trials
      (median mortality 0, range 0%-8.8%) were included in the analyses. The mortality
      rate was similar comparing oral and iv antibiotic treatment (RR 0.83, 95% CI 0.49
      1.41, 2224 patients). Treatment failure rates were also similar (RR 0.94, 95% CI
      0.84-1.05, 15 trials). No significant heterogeneity was shown for the primary
      outcomes. This effect was stable in a wide range of patients. Quinolones alone or
      combined with other antibiotics were used with comparable results. Adverse
      reactions, mostly gastrointestinal, were more common with oral antibiotics.
      CONCLUSIONS: Oral antibiotics may be safely offered to neutropenic patients with
      fever who are at low risk for mortality.

PMID- 15201228
TI  - The expanding role of the antibiotic pharmacist.
AB  - Widespread inappropriate prescribing of antibiotics in UK hospitals has led to
      the introduction of specialist antibiotic pharmacists. Their role is to monitor
      antibiotic use, advise clinicians, educate all grades of healthcare workers and
      help to develop policy. Antibiotic pharmacists have been shown to be effective in
      many situations. As these practitioners become more accomplished it will be
      possible to expand their role to include direct intervention in patient
      treatment. Simple measures, such as modification of intravenous treatment to oral
      and automatic stop orders, could greatly enhance patient care.

PMID- 15201229
TI  - CS-023 (R-115685), a novel carbapenem with enhanced in vitro activity against
      oxacillin-resistant staphylococci and Pseudomonas aeruginosa.
AB  - OBJECTIVE: To compare the in vitro activities of the carbapenem, CS-023, four
      representative beta-lactam antibiotics and levofloxacin, against 970 Gram
      positive or Gram-negative US clinical isolates. METHODS: Susceptibilities of
      bacteria chosen for their varying levels of resistance to the comparator agents
      were determined by NCCLS microdilution methodology. RESULTS: CS-023 exhibited
      activity comparable to that of imipenem against most Gram-positive isolates, but
      was approximately 8-fold more potent against oxacillin-resistant staphylococci.
      It was comparable to meropenem against most Gram-negative isolates, but was 4- to
      8-fold more potent against five isolates of meropenem-resistant Pseudomonas
      aeruginosa. CONCLUSIONS: If tissue and body fluid concentrations >8 mg/L can
      safely be achieved, further studies of CS-023 are warranted to determine its
      clinical efficacy.

PMID- 15201230
TI  - A comparison of the CD4 response to antiretroviral regimens in patients
      commencing therapy with low CD4 counts.
AB  - OBJECTIVE: To compare the immunological response to highly active antiretroviral
      therapy (HAART) in treatment-naive patients with a baseline CD4 count of <200
      cells/mm(3). DESIGN AND METHODS: We identified treatment-naive human
      immunodeficiency virus (HIV-1)-infected individuals who had commenced HAART since
      1996 and who had a starting CD4 count of <200 cells/mm(3). Immunological success
      was defined as achieving a CD4 count of >200 cells/mm(3) and treatments were
      compared using univariate and multivariate Cox's proportional hazards models in
      order to establish whether protease inhibitor (PI)-based regimens were
      significantly different to regimens based on non-nucleoside reverse transcriptase
      inhibitors (NNRTIs). Both regimens utilize a nucleoside analogue (NA) backbone.
      RESULTS: A total of 599 patients were identified. When the variables were entered
      into a multivariate analysis, no significant differences between HAART regimens
      were found. We showed that compared with efavirenz regimens a two NA plus one PI
      regimen was not significantly less likely to achieve immunological success
      (adjusted HR: 0.65, 95% CI 0.41-1.03, P=0.07). Two NA and boosted PI (adjusted
      HR: 1.33, 95% CI 0.81 to 2.16) or two NA and nevirapine (adjusted HR: 0.93, 95%
      CI 0.67-1.29) regimens were also not significantly different from efavirenz-based
      regimens, based on the endpoint of immunological success. CONCLUSION: PI-,
      boosted PI- and NNRTI-based HAART regimens are not significantly different in
      achieving increased CD4 counts in individuals who commence therapy with a low CD4
      count.

PMID- 15201231
TI  - Expression of the efflux pump genes cmeB, cmeF and the porin gene porA in
      multiple-antibiotic-resistant Campylobacter jejuni.
AB  - AIMS: In Escherichia coli, increased expression of efflux pumps and/or decreased
      expression of porins can confer multiple antibiotic resistance (MAR), causing
      resistance to at least three unrelated classes of antibiotics, detergents and
      dyes. It was hypothesized that in Campylobacter jejuni, the efflux systems
      CmeABC, CmeDEF and the major outer membrane porin protein, MOMP (encoded by porA)
      could confer MAR. METHODS: The expression of cmeB, cmeF and porA in 32 MAR C.
      jejuni isolated from humans or poultry was determined by comparative (C)-reverse
      transcriptase (RT)-PCR and denaturing DHPLC. A further 13 ethidium bromide
      resistant isolates and three control strains were also investigated. Accumulation
      of ciprofloxacin+/-carbonyl cyanide-m-chlorophenyl hydrazone (CCCP) was also
      determined for all strains. RESULTS: Although resistance to ethidium bromide has
      been associated with MAR, expression of all three genes was similar in the
      ethidium bromide-resistant isolates. These data indicate that CmeB, CmeF and MOMP
      play no role in resistance to this agent in C. jejuni. Six MAR isolates over
      expressed cmeB, 3/32 over-expressed cmeB and cmeF. No isolates over-expressed
      cmeF alone. Expression of porA was similar in all isolates. All nine isolates
      that over-expressed cmeB contained a mutation in cmeR, substituting glycine 86
      with alanine. All cmeB over-expressing isolates also accumulated low
      concentrations of ciprofloxacin, which were restored to wild-type levels in the
      presence of CCCP. CONCLUSIONS: These data indicate that over-expression of cmeB
      is associated with MAR in isolates of C. jejuni. However, as cmeB was over
      expressed by only one-third (9/32) of MAR isolates, these data also indicate
      other mechanisms of MAR in C. jejuni.

PMID- 15201232
TI  - A novel extended-spectrum beta-lactamase CTX-M-23 with a P167T substitution in
      the active-site omega loop associated with ceftazidime resistance.
AB  - OBJECTIVE: In recent years, cefotaximases of the CTX-M type have become a
      predominant cause of resistance to extended-spectrum cephalosporins in Gram
      negative bacteria. Although most enzymes provide higher levels of resistance to
      cefotaxime than to ceftazidime, mutants with enhanced catalytic efficiency
      against ceftazidime have recently been described. This report identifies another
      ceftazidime-resistant mutant of the CTX-M class of enzymes. METHODS: Two
      ceftazidime-resistant strains, Escherichia coli IFI-1 and Klebsiella pneumoniae
      IFI-2, were isolated from a 46-year-old man during treatment of postoperative
      peritonitis with ceftazidime. Susceptibility testing, mating-out assays,
      isoelectric focusing as well as PCR and sequencing techniques were carried out to
      investigate the underlying mechanism of resistance. RESULTS: E. coli IFI-1 and K.
      pneumoniae IFI-2 exhibited a clavulanic acid-inhibited substrate profile that
      included extended-spectrum cephalosporins. Notably, both strains had up to a 32
      fold higher level of resistance to ceftazidime than to cefotaxime. Further
      characterization revealed that a novel bla(CTX-M) gene encoding a beta-lactamase
      with a pI of 8.9 was implicated in this resistance: CTX-M-23. Along with the
      substitutions D114N and S140A, CTX-M-23 differed from CTX-M-1, the most closely
      related enzyme, by a P167T replacement in the active-site omega loop, which has
      not previously been observed in other CTX-M enzymes. By analogy with what was
      observed with certain TEM/PSE/BPS-type beta-lactamases, the amino acid
      substitution in the omega loop may explain ceftazidime resistance, which has only
      rarely been reported for other CTX-M enzymes. CONCLUSION: The emergence of a new
      ceftazidime-resistant CTX-M-type mutant provides evidence that these enzymes are
      able to broaden their substrate spectrum towards ceftazidime, probably due to
      substitutions in the active-site omega loop.

PMID- 15201233
TI  - Genome-wide expression profiling reveals genes associated with amphotericin B and
      fluconazole resistance in experimentally induced antifungal resistant isolates of
      Candida albicans.
AB  - OBJECTIVES: The aim of this study was to identify changes in the gene expression
      profile of Candida albicans associated with the acquisition of experimentally
      induced resistance to amphotericin B and fluconazole. METHODS: C. albicans SC5314
      was passed in increasing concentrations of amphotericin B to generate isolate
      SC5314-AR. Susceptibility testing by Etest revealed SC5314-AR to be highly
      resistant to both amphotericin B and fluconazole. The gene expression profile of
      SC5314-AR was compared with that of SC5314 using DNA microarray analysis. Sterol
      composition was determined for both strains. RESULTS: Upon examination of MICs of
      antifungal compounds, it was found that SC5314-AR was resistant to both
      amphotericin B and fluconazole. By microarray analysis a total of 134 genes were
      found to be differentially expressed, that is up-regulated or down-regulated by
      at least 50%, in SC5314-AR. In addition to the cell stress genes DDR48 and RTA2,
      the ergosterol biosynthesis genes ERG5, ERG6 and ERG25 were up-regulated. Several
      histone genes, protein synthesis genes and energy generation genes were down
      regulated. Sterol analysis revealed the prevalence of sterol intermediates
      eburicol and lanosterol in SC5314-AR, whereas ergosterol was the predominant
      sterol in SC5314. CONCLUSION: Along with changes in expression of these
      ergosterol biosynthesis genes was the accumulation of sterol intermediates in the
      resistant strain, which would account for the decreased affinity of amphotericin
      B for membrane sterols and a decreased requirement for lanosterol demethylase
      activity in membrane sterol production. Furthermore, other genes are implicated
      as having a potential role in the polyene and azole antifungal resistant
      phenotype.

PMID- 15201234
TI  - B type natriuretic peptide testing: where are we now?
AB  - It is possible that plasma BNP measurement might be to heart failure what
      glycated haemoglobin measurement is to diabetes mellitus. Indeed, within 12-24
      months, BNP testing might become a routine addition to the monitoring of patients
      with heart failure. In the meantime its main role is in helping to rule out heart
      failure in patients with new symptoms

PMID- 15201235
TI  - C reactive protein and microvascular function.
AB  - Emerging data suggest that C reactive protein may be a mediator as well as a
      marker of atherosclerosis

PMID- 15201236
TI  - Risk stratification in acute coronary syndrome: focus on unstable angina/non-ST
      segment elevation myocardial infarction.
AB  - Although there have been advances in the management of unstable angina/non-ST
      segment elevation myocardial infarction syndromes, the rate of cardiovascular
      mortality after discharge is still unacceptably high. With many therapeutic
      options available, the clinician is challenged to identify the safest and most
      effective treatment for long term survival of each individual patient

PMID- 15201237
TI  - Percutaneous device closure of post-infarction ventricular septal defect with
      aneurysm.

PMID- 15201239
TI  - Spontaneous polymorphic ventricular tachycardia recorded during an
      electroencephalogram in a patient with apparent epilepsy.

PMID- 15201238
TI  - Anatomy of coronary disease in diabetic patients: an explanation for poorer
      outcomes after percutaneous coronary intervention and potential target for
      intervention.
AB  - There are over 1.3 million known diabetic patients in the UK and a similar number
      who have the disease undiagnosed. Over 90% have non-insulin dependent diabetes
      mellitus usually characterised by insulin resistance and adult onset. Over half
      of all diabetic patients die of coronary disease and account for over a fifth of
      percutaneous coronary intervention (PCI) revascularisation procedures. Despite
      recent therapeutic advances such as new antiplatelet treatments and drug eluting
      stents, outcomes for diabetic patients after PCI are still significantly worse
      than for non-diabetic patients. This article summarises what is known about the
      pattern and severity of diabetic coronary disease, what mechanisms are
      responsible for these differences, and whether this information can help explain
      the poorer prognosis for these patients after PCI and form the basis of
      interventions to improve outcome.

PMID- 15201240
TI  - Long term risk stratification of patients with acute coronary syndromes:
      characteristics of troponin T testing and continuous ST segment monitoring.
AB  - OBJECTIVE: To examine the long term prognostic characteristics of troponin T
      testing and continuous multi-lead ST segment monitoring in combination with
      clinical and 12 lead ECG risk indicators in patients with acute coronary
      syndromes (ACS). PATIENTS AND DESIGN: Patients with suspected ACS (n = 213) were
      studied. Troponin T was analysed in blood samples collected during the first 12
      hours after admission. Continuous vectorcardiography ST segment monitoring was
      performed for 24 hours and the number of ST vector magnitude episodes was
      registered. Patients were followed up for a median of 28 months. The end point
      was a composite of cardiac death and acute myocardial infarction. RESULTS: Thirty
      eight (18%) patients reached the composite end point. The median (interquartile
      range) time from study inclusion to the time of the composite end point was
      longer for patients predicted to be at risk by troponin T testing (n = 27) than
      for those predicted to be at risk by ST segment monitoring (n = 20) (8.4 (0.2-15)
      months v 0.3 (0.1-4.3) months, p = 0.04). Significant univariate predictors of
      the composite end point were age > or = 65 years, diabetes, previous myocardial
      infarction, congestive heart failure, use of beta blockers or diuretics at
      admission, 12 lead ECG ST segment depression at admission, troponin T
      concentration > or = 0.10 microg/l, and > or = 1 ST vector magnitude episodes.
      Age > or = 65 years, previous myocardial infarction, and troponin T concentration
      > or = 0.10 microg/l provided independent prognostic information after
      multivariate analysis of potential risk variables. The prognostic value of
      transient ischaemic episodes in ACS seems to be confined to the short term.
      CONCLUSIONS: Both biochemical and continuous ECG markers reflect an increased
      risk for patients with ACS; however, the methods exhibit different temporal risk
      characteristics.

PMID- 15201241
TI  - Associations of components of adult height with coronary heart disease in
      postmenopausal women: the British women's heart and health study.
AB  - OBJECTIVE: To assess the associations between components of adult height and
      coronary heart disease (CHD) in postmenopausal women. METHODS: Cross sectional
      analysis of 4286 women randomly selected from 23 British towns. The association
      of components of adult height with prevalent CHD (n = 694) were assessed.
      RESULTS: Shorter stature, shorter leg length, and trunk length were all
      associated with CHD in age adjusted analyses. The association between trunk
      length and CHD was attenuated to the null with adjustment for smoking. The leg
      length-CHD association was independent of smoking, socioeconomic position in
      childhood and adulthood, birth weight, and other potential confounders. Insulin
      resistance did not appear to be an important mediating factor in the association
      between leg length and CHD. After full adjustment for all potential confounding
      factors the odds ratio (95% confidence interval) of CHD for a 1 SD (4.3 cm)
      increase in leg length was 0.84 (0.77 to 0.93) and the odds ratio for a 1 SD
      (0.05) increase in the leg to trunk ratio was 0.85 (0.79 to 0.95). CONCLUSIONS:
      The specific association between leg length and CHD suggests that early life
      environmental exposures that influence skeletal growth also influence CHD risk in
      later life.

PMID- 15201242
TI  - Relation between C reactive protein concentrations and coronary microvascular
      endothelial function.
AB  - OBJECTIVE: To determine how C reactive protein (CRP), a sensitive marker of
      inflammation, is related to coronary endothelial function. DESIGN: Changes in
      quantitative coronary angiographic findings and Doppler flow velocity
      measurements in response to locally infused acetylcholine were assessed. SETTING:
      Tertiary cardiology centre. PATIENTS: 46 patients with angiographically normal
      coronary arteries were divided into groups with normal (< or = 3 mg/l) or
      increased (> 3 mg/l) CRP concentrations. INTERVENTIONS: Acetylcholine (3 and 30
      microg/min) was infused into the left coronary ostium for two minutes. MAIN
      OUTCOME MEASURES: Percentage change in diameter of epicardial coronary arteries
      and coronary blood flow (CBF) in response to acetylcholine; and correlations
      between these parameters and serum CRP concentrations. RESULTS: 15 patients had
      increased CRP concentrations. The change in coronary artery diameter induced by
      acetylcholine infusion was similar between the groups but the increase in CBF
      induced by acetylcholine was smaller in patients with increased CRP
      concentrations (54.9% v 139.4% with acetylcholine 30 microg/min, p = 0.0030).
      Multivariate analysis identified increased CRP concentration as independently
      associated with attenuated CBF response to acetylcholine at 30 microg/min (p =
      0.0078, R2 = 0.434). CONCLUSIONS: These findings suggest that inflammation
      appears to be associated with impaired coronary endothelial function in
      resistance but not conduit vessels. The data suggest a close relation between
      chronic vascular inflammation and endothelial dysfunction in atherosclerosis.

PMID- 15201243
TI  - Management of chronic heart failure in the community: role of a hospital based
      open access heart failure service.
AB  - OBJECTIVE: To evaluate the role of an open access heart failure service based at
      a teaching hospital for the diagnosis and treatment optimisation of patients with
      heart failure in the community and to identify measures that may further enhance
      the effectiveness of such a service. SUBJECTS: 963 patients with suspected heart
      failure seen over an eight year period referred by their general practitioners to
      the cardiology department at a district general hospital. MAIN OUTCOME MEASURES:
      Presence or absence of left ventricular systolic dysfunction (LVSD) (left
      ventricular ejection fraction < 50% on echocardiography), and determination of
      the risk factors and predictors of LVSD. RESULTS: The majority of the patients
      were women (60% v 40%) and elderly (mean age 68.8 years). On echocardiography,
      only 30.8% were found to have LVSD. Patients were more likely to have LVSD if
      they were men (42.3% v 23.1%, p < 0.001, relative risk (RR) 1.8), were > 60 years
      of age (33.5% v 20.8%, p < 0.001, RR 1.6), or had a history of diabetes (49.4% v
      29.1%, p < 0.001, RR 1.7), ischaemic heart disease (36.5% v 29.1%, p = 0.04, RR
      1.3), or atrial fibrillation (52.6% v 27.8%, p < 0.001, RR 1.9). An abnormal ECG
      (48.4% v 19.5%, p < 0.001, RR 2.5) and cardiothoracic ratio > 0.5 on chest
      radiograph (44.3% v 17.8%, p < 0.001, RR 2.5) were found to be good predictors of
      LVSD. A normal ECG (negative predictive value 80.5%) and a cardiothoracic ratio
      of < 0.5 (negative predictive value 82.2%) can be used as baseline measures to
      identify patients with lower risk of developing LVSD (combined negative
      predictive value 87.9%). CONCLUSIONS: An open access heart failure clinic is
      effective for the diagnosis and management of chronic heart failure in community
      based patients. The presence of risk factors and simple baseline tests can be
      used to identify patients with LVSD in the community. The introduction of a
      protocol based on these findings into a referral system can improve the
      efficiency and cost effectiveness of such a service.

PMID- 15201245
TI  - Giant left main stem thrombus in a patient with acute coronary syndrome.

PMID- 15201244
TI  - Effects of carvedilol on left ventricular remodelling in chronic stable heart
      failure: a cardiovascular magnetic resonance study.
AB  - BACKGROUND: The ability of beta blockers to improve left ventricular function has
      been demonstrated, but data on the effects on cardiac remodelling are limited.
      OBJECTIVE: To investigate, using cardiovascular magnetic resonance (CMR), the
      effects of carvedilol on left ventricular remodelling in patients with chronic
      stable heart failure and left ventricular systolic dysfunction caused by coronary
      artery disease. DESIGN: Randomised, double blind, placebo controlled study.
      SETTING: Chronic stable heart failure. PATIENTS AND INTERVENTION: 34 patients
      with chronic stable heart failure and left ventricular systolic function taking
      part in the CHRISTMAS trial (double blind carvedilol v placebo) underwent CMR
      before randomisation and after six months of treatment. MAIN OUTCOME MEASURE:
      Left ventricular remodelling at six months. RESULTS: The carvedilol and placebo
      groups were well balanced at baseline, with no significant intergroup
      differences. Over the study period, there was a significant reduction in end
      systolic volume index (ESV(I)) and end diastolic volume index (EDV(I)) between
      the carvedilol and the placebo group (carvedilol -9 v placebo +3 ml/m2, p =
      0.0004; carvedilol -8 v placebo 0 ml/m2, p = 0.05). The ejection fraction
      increased significantly between the groups (carvedilol +3% v placebo -2%, p =
      0.003). CONCLUSIONS: Treatment of chronic stable heart failure with carvedilol
      results in significant improvement in left ventricular volumes and function.
      These effects might contribute to the benefits of carvedilol on mortality and
      morbidity in patients with chronic heart failure.

PMID- 15201246
TI  - Effects of spironolactone on endothelial function, vascular angiotensin
      converting enzyme activity, and other prognostic markers in patients with mild
      heart failure already taking optimal treatment.
AB  - OBJECTIVES: To examine whether the favourable effects on endothelial function,
      vascular angiotensin converting enzyme (ACE) activity, cardiac remodelling,
      autonomic function, and QT intervals of spironolactone in combination with ACE
      inhibitor also occur in patients with New York Heart Association class I-II
      congestive heart failure (CHF) taking optimal treatment (including beta
      blockers). METHODS: Double blind, crossover study comparing 12.5-50 mg/24 hours
      spironolactone (three months) with placebo in 43 patients with class I-II CHF
      taking ACE inhibitors and beta blockers. RESULTS: Acetylcholine induced
      vasodilatation improved with spironolactone (p = 0.044). Vascular ACE activity
      fell (p = 0.006). QTc and QTd fell (mean (SD) QTc 473 (43.1) ms with placebo, 455
      (35.4) ms with spironolactone, p = 0.002; QTd 84.5 (41.3) ms with placebo, 72.1
      (32.3) ms with spironolactone, p = 0.037). beta-Type natriuretic peptide (BNP)
      and procollagen III N-terminal peptide (PIIINP) concentrations were also reduced
      by spironolactone (mean (SD) BNP 48.5 (29.6) pg/ml with placebo, 36.8 (28.5)
      pg/ml with spironolactone, p = 0.039; PIIINP 3.767 (1.157) microg/ml with
      placebo, 3.156 (1.123) microg/ml with spironolactone, p = 0.000). CONCLUSIONS:
      Spironolactone improves vascular function (endothelial function, vascular ACE
      activity) and other markers of prognosis (BNP, collagen markers, and QT interval
      length) in asymptomatic or mild CHF when added to optimal treatment including
      beta blockade. This gives support to the hypothesis that the prognostic benefit
      seen in RALES (randomised aldactone evaluation study) and EPHESUS (eplerenone
      postacute myocardial infarction heart failure efficacy and survival study) may
      also occur in patients with milder CHF already taking standard optimal treatment.

PMID- 15201247
TI  - A method for the morphological analysis of the regurgitant mitral valve using
      three dimensional echocardiography.
AB  - BACKGROUND: Atrial en-face reconstructions are commonly used to assess mitral
      valve morphology in three dimensional (3D) echocardiography but may miss
      important abnormalities. OBJECTIVE: To present a systematic method for the
      analysis of the regurgitant mitral valve using a combination of en-face and
      longitudinal views for better anatomical evaluation. METHODS: Detailed 3D
      assessment was done on 58 patients undergoing mitral valve repair. En-face and
      longitudinal views were compared for detection and location of primary pathology.
      The quality of acquisitions under general anaesthesia and sedation was also
      compared. RESULTS: Recognition of valve structure was significantly better with
      longitudinal reconstruction for both mitral leaflets but not for the commissures.
      Accurate identification of pathology was possible in 95% cases, compared with 50%
      for en-face reconstruction (p < 0.001). There was no significant difference
      between imaging under sedation and anaesthesia. CONCLUSION: En-face
      reconstructions alone are inadequate. Additional longitudinal reconstructions are
      necessary to ensure full inspection of valve morphology.

PMID- 15201248
TI  - Acute and chronic effects of oestradiol on left ventricular diastolic function in
      hypertensive postmenopausal women with left ventricular diastolic dysfunction.
AB  - BACKGROUND: Left ventricular function changes in the postmenopausal state.
      However, there are conflicting reports about the effects of oestrogen on left
      ventricular diastolic function in postmenopausal women. OBJECTIVE: To evaluate
      the acute and chronic effects of oestradiol in physiological doses on diastolic
      heart function in hypertensive postmenopausal women with left ventricular
      diastolic dysfunction. METHODS: A prospective, randomised, double blind, placebo
      controlled study was used to evaluate the effects of oestradiol in 34
      hypertensive women with left ventricular dysfunction. The acute effects of a
      single 1 mg oral dose of oestradiol or placebo were determined after 90 minutes.
      The chronic effects of 1 mg oestradiol orally/day or placebo were determined
      after 12 weeks. Diastolic functional indices (mitral flow and pulmonary venous
      flow) were assessed by Doppler echocardiography. RESULTS: Though an appropriate
      serum concentration was achieved, no acute effect of oestradiol administration on
      left ventricular diastolic function was identified. After 12 weeks of treatment
      the following changes (mean (SD)) were identified in the oestradiol group: a
      decrease in isovolumic relaxation time from 127 (23) to 106 (16) ms (p < 0.001),
      and in the deceleration time of the mitral E wave from 260 (42) to 238 (20) ms (p
      < 0.05); and an increase in the E/A ratio from 0.8 (0.2) (basal) to 1.0 (0.2)
      after 12 weeks (p < 0.001). CONCLUSIONS: Hypertensive postmenopausal women who
      had hormone replacement therapy over a period of 12 weeks had significant
      improvement in left ventricular diastolic function. No changes were identified
      following acute administration.

PMID- 15201249
TI  - One year comparison of costs of coronary surgery versus percutaneous coronary
      intervention in the stent or surgery trial.
AB  - OBJECTIVES: To compare initial and one year costs of coronary artery bypass
      grafting (CABG) versus percutaneous coronary intervention (PCI) in the stent or
      surgery trial. DESIGN: Prospective, unblinded, randomised trial. SETTING:
      Multicentre study. PATIENTS: 988 patients with multivessel disease.
      INTERVENTIONS: CABG and stent assisted PCI. MAIN OUTCOME MEASURES: Initial
      hospitalisation and one year follow up costs. RESULTS: At one year mortality was
      2.5% in the PCI arm and 0.8% in the CABG arm (p = 0.05). There was no difference
      in the composite of death or Q wave myocardial infarction (6.9% for PCI v 8.1%
      for CABG, p = 0.49). There were more repeat revascularisations with PCI (17.2% v
      4.2% for CABG). There was no significant difference in utility between arms at
      six months or at one year. Quality adjusted life years were similar 0.6938 for
      PCI v 0.6954 for PCI, Delta = 0.00154, 95% confidence interval (CI) -0.0242 to
      0.0273). Initial length of stay was longer with CABG (12.2 v 5.4 days with PCI, p
      < 0.0001) and initial hospitalisation costs were higher (7321 pounds sterling v
      3884 pounds sterling for PCI, Delta = 3437 pounds sterling, 95% CI 3040 pounds
      sterling to 3848 pounds sterling). At one year the cost difference narrowed but
      costs remained higher for CABG (8905 pounds sterling v 6296 pounds sterling for
      PCI, Delta = 2609 pounds sterling, 95% CI 1769 pounds sterling to 3314 pounds
      sterling). CONCLUSIONS: Over one year, CABG was more expensive and offered
      greater survival than PCI but little added benefit in terms of quality adjusted
      life years. The additional cost of CABG can be justified only if it offers
      continuing benefit at no further increase in cost relative to PCI over several
      years.

PMID- 15201250
TI  - The role of echocardiography in diagnosing double chambered right ventricle in
      adults.
AB  - OBJECTIVE: To evaluate the utility of echocardiography in diagnosing double
      chambered right ventricle (DCRV) in adults. DESIGN: A retrospective study.
      SETTING: Department of Congenital Heart Diseases and Department of Cardiac
      Surgery, Institute of Cardiology, Warsaw, Poland. PATIENTS: 32 patients, mean age
      32.5 years, 21 female, and 11 male. INTERVENTION: Transthoracic (TTE) and
      transoesophageal (TOE) echocardiographic examination in patients with suspected
      DCRV. MAIN OUTCOME MEASURES: Direct inspection during surgical treatment of 28
      patients diagnosed as having DCRV as an isolated lesion or associated with other
      pathologies. RESULTS: Echocardiography allowed the final diagnosis of DCRV in 26
      patients (81%) out of 32 studied. TTE was diagnostic in 5 (15.6%) whereas TOE was
      diagnostic in 21 of 21 studied by this technique. Of 6 patients with negative
      TTE, DCRV was identified by cardiac catheterisation in 3 and directly during
      surgery in the remaining 3. Of 26 patients diagnosed by echocardiography, the
      anomalous muscle bundle was discrete in 20 (77%) and diffuse in 6 (23%). In 23
      patients (88%) right ventricular outflow obstruction was localised low in the
      right ventricle, and in the remaining 3 (11.5%), the obstruction was localised
      high in the right ventricle. Abnormal bundles localised high were discrete,
      bundles localised in the lower part of right ventricle were discrete in 17 (74%)
      and diffuse in the remaining 6 (26%). DCRV was an isolated lesion in only 2
      patients (6.2%). In all subjects surgical inspection confirmed echocardiographic
      data. CONCLUSIONS: Echocardiography was very useful to diagnose DCRV in adults as
      well as to identify its anatomic type. Comparing two different approaches, TOE
      better defines the entire scope of pathology, including estimation of the
      resultant systolic pressure gradient within the right ventricular cavity.

PMID- 15201251
TI  - Emergency endovascular aortic stenting for the treatment of a ruptured
      atherosclerotic ulcer.

PMID- 15201253
TI  - Successful stenting of the left anterior descending artery in a patient with a
      single left coronary ostium.

PMID- 15201252
TI  - Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa
      inhibitors on platelet activation and aggregation: implications for restenosis
      during percutaneous coronary intervention.
AB  - OBJECTIVE: To study the effect of unfractionated heparin (UFH) versus low
      molecular weight heparin (LMWH) in combination with glycoprotein (Gp) IIb/IIIa
      blockers on platelet activation and aggregation. METHODS: Washed platelets were
      stimulated with thrombin in the presence or absence of UFH (monoparin), LMWH
      (enoxaparin), and a Gp IIb/IIIa blocker (abciximab, eptifibatide, or tirofiban).
      RESULTS: Although Gp IIb/IIIa antagonists blocked the final common pathway of
      thrombin induced platelet aggregation, UFH and LMWH were better at blocking
      upstream platelet activation. UFH was significantly more effective than LMWH at
      inhibiting P selectin expression (p = 0.001) and platelet derived growth factor
      release from thrombin activated platelets (p = 0.012). CONCLUSIONS: UFH and LMWH
      exert complementary effects to Gp IIb/IIIa blockers by inhibiting afferent
      pathways of platelet activation. Coadministration of heparin with Gp IIb/IIIa
      blockers provides improved protection against persistent platelet activation,
      thereby improving outcome after percutaneous coronary intervention. Judging from
      these data, UFH may be more effective in this regard than LMWH, at least in
      vitro. The use of LMWH in preference to UFH during percutaneous coronary
      intervention, although initially attractive, may inadequately protect against
      platelet activation despite the presence of Gp IIb/IIIa blockers.

PMID- 15201254
TI  - The impact of baseline left ventricular size and mitral regurgitation on reverse
      left ventricular remodelling in response to carvedilol: size doesn't matter.

PMID- 15201255
TI  - Plastic bronchitis after Fontan operation: treatment with stent fenestration of
      the Fontan circuit.

PMID- 15201256
TI  - Plasma homocysteine and calcific aortic valve disease.

PMID- 15201257
TI  - A novel streamlined "anchored" anatomical approach to ablation of AVNRT.

PMID- 15201258
TI  - Low grade inflammation is notably suppressed by conventional anti-inflammatory
      treatment: a randomised crossover trial.

PMID- 15201259
TI  - Pulmonary oedema induced by emotional stress, by sexual intercourse, and by
      exertion in a cold environment in people without evidence of heart disease.

PMID- 15201260
TI  - Anticoagulation in the young.

PMID- 15201261
TI  - Role of oral anticoagulation in management of atrial fibrillation.

PMID- 15201262
TI  - Management and follow up of prosthetic heart valves.

PMID- 15201263
TI  - Detection of right atrial and pulmonary artery thrombosis after the Fontan
      procedure by magnetic resonance imaging.

PMID- 15201264
TI  - Persistent nicorandil induced oral ulceration.
AB  - Four patients with nicorandil induced ulceration are described, and the
      literature on the subject is reviewed. Nicorandil induced ulcers are very painful
      and distressing for patients. Clinically they appear as large, deep, persistent
      ulcers that have punched out edges. They are poorly responsive to topical
      steroids and usually require alteration of nicorandil treatment. The ulceration
      tends to occur at high doses of nicorandil and all four cases reported here were
      on doses of 40 mg per day or greater. In these situations reduction of nicorandil
      dose may be sufficient to promote ulcer healing and prevent further recurrence.
      However, nicorandil induced ulcers have been reported at doses as low as 10 mg
      daily and complete cessation of nicorandil may be required.

PMID- 15201265
TI  - Spontaneous coronary artery dissection involving the left main stem: assessment
      by intravascular ultrasound.
AB  - This case report describes the devastating consequences of spontaneous coronary
      dissection in a 36 year old female patient who otherwise had a normal coronary
      arteriogram. Intravascular ultrasound showed coronary artery dissection and
      intramural haematoma at the left main stem coronary artery. Acute coronary
      syndrome developed and subsequently surgical revascularisation was performed
      successfully.

PMID- 15201266
TI  - Long term survival in primary pulmonary hypertension.
AB  - The mean survival of patients with severe primary pulmonary hypertension (PPH) is
      < 3 years without appropriate treatment. There are no long term reports on the
      spontaneous course of mild PPH over a longer period. Stable long term follow up
      is described of a 39 year old patient with PPH without treatment over a 30 year
      period. PPH had been diagnosed 30 years previously after right heart
      catheterisation (mean pulmonary artery pressure 35 mm Hg) and 30 years later,
      repeated measurements showed nearly unchanged haemodynamic parameters. Further
      examinations confirmed the diagnosis of PPH. It is suggested that PPH with
      modestly limited physical activity (New York Heart Association functional class
      II) does not always seem to coincide with progression of the disease and,
      therefore, it may be feasible to withhold treatment while closely monitoring
      these patients.

PMID- 15201267
TI  - Massive pulmonary embolism with ST elevation in leads V1-V3 and successful
      thrombolysis with tenecteplase.
AB  - A 42 year old woman was referred to the emergency department from the radiology
      department after having a syncopal episode during a triplex examination of the
      lower extremities for acute painful right leg swelling five hours earlier that
      morning. She had no significant medical history, smoked 3-5 cigarettes a day, and
      had been taking contraceptive medication for menorrhagia for the preceding three
      months. On presentation she was cyanotic, dyspnoeic, and haemodynamically
      unstable. ECG showed sinus tachycardia of 120 beats/min with ST elevations from
      V1 through V3 mimicking anteroseptal acute myocardial infarction. Ten minutes
      after presentation she was thrombolysed with 80 mg tenecteplase leading to ST
      elevation resolution and remarkable haemodynamic recovery after 20 minutes. This
      case shows how pulmonary embolism can mimic anteroseptal acute myocardial
      infarction on ECG and the life saving results from rapid thrombolysis with
      tenecteplase.

PMID- 15201268
TI  - Fatal pulmonary arterial hypertension associated with phenylpropanolamine
      exposure.
AB  - Exogenous substances such as the appetite suppressant fenfluramine are known to
      be causally related to the development of pulmonary arterial hypertension (PAH).
      In these cases, the clinical course as well as the pulmonary vascular disease
      pathologically is indistinguishable from idiopathic PAH. Other exogenous
      substances, such as amphetamines, cocaine, and meta-amphetamines, have been
      considered to be potential risk factors for inducing PAH. SOPHIA (the study of
      pulmonary hypertension in America), in addition to confirming previous reports of
      a causal association between the appetite suppressant fenfluramine and PAH,
      unexpectedly found a significantly increased risk for the development of PAH with
      exposure to over-the-counter antiobesity agents containing phenylpropanolamine.
      The first case is reported of fatal PAH in a child heavily treated with cold
      remedies containing phenylpropanolamine, which, in addition to the results of
      SOPHIA, strengthens the hypothesis that phenylpropanolamine is a risk factor for
      the development of PAH.

PMID- 15201269
TI  - Atypical cause of hibernating myocardium due to complex cardiovascular lesions
      associated with Takayasu's arteritis.
AB  - Myocardial hibernation is recognised as chronic hypoperfusion of the myocardium
      and its functional recovery after surgical revascularisation has been described.
      A case of surgery for complex lesions including severe aortic valve
      regurgitation, coronary ostial stenosis, and aortic calcification (porcelain
      aorta) caused by Takayasu's arteritis is presented. The onset of left ventricular
      functional improvement after aortic valve replacement and coronary
      revascularisation were indicative of preoperative atypical myocardial hibernation
      caused by aortic valve disease and coronary artery disease associated with
      Takayasu's arteritis.

PMID- 15201270
TI  - Reversible dilated cardiomyopathy associated with glucagonoma.
AB  - An association between dilated cardiomyopathy and glucagonoma has not previously
      been described. A case of a 54 year old woman with tachycardia and congestive
      heart failure is described. Initial evaluation included an echocardiogram, which
      showed dilated cardiomyopathy with an ejection fraction of 15%. Coronary
      angiography and endomyocardial biopsy did not identify a secondary cause of her
      cardiomyopathy. She subsequently developed necrolytic migratory erythema, and
      imaging of her pancreas identified a pancreatic mass with a major increase of her
      serum glucagon concentration. Tachycardia persisted despite treatment with beta
      blockers. After resection of her tumour, her heart rate normalised and
      subsequently her heart returned to normal size and function. Glucagon is used to
      treat overdoses of beta blockers and calcium channel blockers, increasing heart
      rate by increasing myocardial cyclic AMP concentrations. Although rare, in the
      appropriate clinical setting, glucagonoma should be considered in the
      differential diagnosis for tachycardia and dilated cardiomyopathy.

PMID- 15201271
TI  - Ataxin-10, the spinocerebellar ataxia type 10 neurodegenerative disorder protein,
      is essential for survival of cerebellar neurons.
AB  - Spinocerebellar ataxia (SCA) type 10, an autosomal dominant disease characterized
      by cerebellar ataxia, is caused by a novel pentanucleotide (ATTCT) repeat
      expansion in the SCA10 gene. Although clinical features of the disease are well
      characterized, nothing is known so far about the affected SCA10 gene product,
      ataxin-10 (Atx-10). We have cloned the rat SCA10 gene and expressed the
      corresponding protein in HEK293 cells. Atx-10 has an apparent molecular mass of
      approximately 55 kDa and belongs to the family of armadillo repeat proteins. In
      solution, it tends to form homotrimeric complexes, which associate via a tip-to
      tip contact with the concave sides of the molecules facing each other. Atx-10
      immunostaining of mouse and human brain sections revealed a predominantly
      cytoplasmic and perinuclear localization with a clear restriction to
      olivocerebellar regions. Knock down of SCA10 in primary neuronal cells by small
      interfering RNAs resulted in an increased apoptosis of cerebellar neurons,
      arguing for a loss-of-function phenotype in SCA10 patients.

PMID- 15201272
TI  - ATP-dependent remodeling by SWI/SNF and ISWI proteins stimulates V(D)J cleavage
      of 5 S arrays.
AB  - Control of V(D)J recombination is critical for the generation of a fully
      developed immune repertoire. The molecular mechanisms underlying the regulation
      of antigen receptor gene assembly are beginning to be revealed. Here we studied
      the influence of chromatin modifications on V(D)J cleavage of a polynucleosomal
      substrate, in which V(D)J cleavage is greatly reduced compared with naked DNA.
      ATP-dependent remodeling by human SWI/SNF (hSWI/SNF) in the presence of HMG1 led
      to a substantial increase of cleavage by the recombination activation gene (RAG)
      proteins. Either BRG1, the ATPase subunit of hSWI/SNF, or SNF2h, the ATPase of
      human ISWI complexes, was capable of stimulating V(D)J cleavage of the array,
      although these remodelers act by different mechanisms. No effect of histone
      hyperacetylation was detectable in this system. As is observed on naked DNA, in
      the presence of core RAG1, the full-length RAG2 protein proved to be more active
      than core RAG2 on these polynucleosomal arrays, reinforcing the importance of the
      RAG2 C-terminal domain for efficient recombination. Comparison of 5 S array
      cleavage by the RAG proteins or by the restriction enzyme HhaI after remodeling
      by hSWI/SNF suggested that RAG proteins and HhaI might have different
      requirements for maximal accessibility of the substrate.

PMID- 15201273
TI  - Structure--activity relationships of hainantoxin-IV and structure determination
      of active and inactive sodium channel blockers.
AB  - Hainantoxin-IV (HNTX-IV) can specifically inhibit the neuronal tetrodotoxin
      sensitive sodium channels and defines a new class of depressant spider toxin. The
      sequence of native HNTX-IV is ECLGFGKGCNPSNDQCCKSSNLVCSRKHRWCKYEI-NH(2). In the
      present study, to obtain further insight into the primary and tertiary structural
      requirements of neuronal sodium channel blockers, we determined the solution
      structure of HNTX-IV as a typical inhibitor cystine knot motif and synthesized
      four mutants designed based on the predicted sites followed by structural
      elucidation of two inactive mutants. Pharmacological studies indicated that the
      S12A and R26A mutants had activities near that of native HNTX-IV, while K27A and
      R29A demonstrated activities reduced by 2 orders of magnitude. (1)H MR analysis
      showed the similar molecular conformations for native HNTX-IV and four synthetic
      mutants. Furthermore, in the determined structures of K27A and R29A, the side
      chains of residues 27 and 29 were located in the identical spatial position to
      those of native HNTX-IV. These results suggested that residues Ser(12), Arg(26),
      Lys(27), and Arg(29) were not responsible for stabilizing the distinct
      conformation of HNTX-IV, but Lys(27) and Arg(29) were critical for the
      bioactivities. The potency reductions produced by Ala substitutions were
      primarily due to the direct interaction of the essential residues Lys(27) and
      Arg(29) with sodium channels rather than to a conformational change. After
      comparison of these structures and activities with correlated toxins, we
      hypothesized that residues Lys(27), Arg(29), His(28), Lys(32), Phe(5), and
      Trp(30) clustered on one face of HNTX-IV were responsible for ligand binding.

PMID- 15201274
TI  - Regulation of the yeast EKI1-encoded ethanolamine kinase by inositol and choline.
AB  - Regulation of the EKI1-encoded ethanolamine kinase by inositol and choline was
      examined in Saccharomyces cerevisiae. Transcription of the EKI1 gene was
      monitored by following the expression of beta-galactosidase activity driven by a
      P(EKI1)-lacZ reporter gene. The addition of inositol to the growth medium
      resulted in a dose-dependent decrease in EKI1 expression. Supplementation of
      choline to inositol-containing growth medium brought about a further decrease in
      expression, whereas choline supplementation alone had no effect. Analysis of EKI1
      expression in ino2Delta, ino4Delta, and opi1Delta mutants indicated that the
      transcription factors Ino2p, Ino4p, and Opi1p played a role in this regulation.
      Moreover, mutational analysis showed that the UAS(INO) element in the EKI1
      promoter was required for the inositol-mediated regulation. The regulation of
      EKI1 expression by inositol and choline was confirmed by corresponding changes in
      ethanolamine kinase mRNA, protein, and activity levels. The repression of
      ethanolamine kinase by inositol supplementation correlated with a decrease in the
      incorporation of ethanolamine into CDP-ethanolamine pathway intermediates and
      into phosphatidylethanolamine and phosphatidylcholine.

PMID- 15201275
TI  - Active solubilization and refolding of stable protein aggregates by cooperative
      unfolding action of individual hsp70 chaperones.
AB  - Hsp70 is a central molecular chaperone that passively prevents protein
      aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and
      mediate the proper refolding of proteins in the cell. Yet, the molecular
      mechanism by which the active Hsp70 chaperone functions are achieved remains
      unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold
      misfolded structures in aggregated polypeptides, leading to gradual
      disaggregation. We found that the specific unfolding and disaggregation
      activities of individual DnaK molecules were optimal for large aggregates but
      dramatically decreased for small aggregates. The active unfolding of the smallest
      aggregates, leading to proper global refolding, required the cooperative action
      of several DnaK molecules per misfolded polypeptide. This finding suggests that
      the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can
      recruit random chaperone motions to locally unfold misfolded structures and
      gradually disentangle stable aggregates into refoldable proteins.

PMID- 15201276
TI  - Desensitization of the permeability transition pore by cyclosporin a prevents
      activation of the mitochondrial apoptotic pathway and liver damage by tumor
      necrosis factor-alpha.
AB  - We studied the effects of cyclosporin A (CsA) administration 1) on the properties
      of the permeability transition pore (PTP) in mitochondria isolated from the liver
      and 2) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of
      Escherichia coli (LPS) plus D-galactosamine (D-GalN) in rats. CsA exerted a
      marked PTP inhibition ex vivo, with an effect that peaked between 2 and 9 h of
      drug treatment and decayed with an apparent half-time of about 13 h.
      Administration of LPS plus D-GalN to naive rats caused the expected increased
      serum levels of tumor necrosis factor (TNF)-alpha, liver inflammation with BID
      cleavage, activation of caspase 3, appearance of terminal
      deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive nuclei, and
      release of alanine aminotransferase and aspartate aminotransferase into the
      bloodstream. Treatment with CsA before or within 5 h of the administration of LPS
      plus D-GalN protected rats from hepatotoxicity despite the normal increase of
      serum TNF-alpha and BID cleavage. These results indicate that CsA prevents the
      hepatotoxic effects of TNF-alpha by blocking the mitochondrial proapoptotic
      pathway through inhibition of the PTP and provides a viable strategy for the
      treatment of liver diseases that depend on increased production and/or liver
      sensitization to TNF-alpha.

PMID- 15201277
TI  - Thrombin and tumor necrosis factor alpha synergistically stimulate tissue factor
      expression in human endothelial cells: regulation through c-Fos and c-Jun.
AB  - Tissue factor is critically important for initiating the activation of
      coagulation zymogens leading to the generation of thrombin. Quiescent endothelial
      cells do not express tissue factor on their surface, but many stimuli including
      cytokines and coagulation proteases can elicit tissue factor synthesis. We
      challenged human endothelial cells simultaneously with tumor necrosis factor
      alpha (TNFalpha) and thrombin because many pathophysiological conditions, such as
      sepsis, diabetes, and coronary artery disease, result in the concurrent presence
      of circulating inflammatory mediators and activated thrombin. We observed a
      remarkable synergy in the expression of tissue factor by thrombin plus TNFalpha.
      This was due to altered regulation of the transcription factors c-Jun and c-Fos.
      The activation of c-Jun was greater and more sustained than that obtained with
      either thrombin or TNFalpha alone. Thrombin-stimulated expression of c-Fos was
      both enhanced and prolonged by the concurrent presence of TNFalpha. These changes
      support the increased availability of c-Jun/c-Fos AP-1 complexes for mediating
      transcription at the tissue factor promoter. Transcription factors downstream of
      the extracellular signal-regulated kinases as well as changes in NFkappaB
      regulation were not involved in the synergistic increase in tissue factor
      expression by thrombin and TNFalpha. Thus, concurrent exposure of vascular
      endothelial cells to cytokines and procoagulant proteases such as thrombin can
      result in greatly enhanced tissue factor expression on the endothelium, thereby
      perpetuating the prothrombotic phenotype of the endothelium.

PMID- 15201278
TI  - Sialylated complex-type N-glycans enhance the signaling activity of soluble
      intercellular adhesion molecule-1 in mouse astrocytes.
AB  - Intercellular adhesion molecule-1 (ICAM-1) occurs as both a membrane and a
      soluble, secreted glycoprotein (sICAM-1). ICAM-1 on endothelial cells mediates
      leukocyte adhesion by binding to leukocyte function associated antigen-1 (LFA-1)
      and macrophage antigen-1 (Mac-1). Recombinant mouse sICAM-1 induces the
      production of macrophage inflammatory protein-2 (MIP-2) in mouse astrocytes by a
      novel LFA-1- and Mac-1-independent mechanism. Here we showed that N-glycan
      structures of sICAM-1 influence its ability to induce MIP-2 production. sICAM-1
      expressed in Chinese hamster ovary (CHO) cells was a more potent inducer of MIP-2
      production than sICAM-1 expressed in HEK 293 cells, suggesting that
      posttranslational modification of sICAM-1 could influence its signaling activity.
      To explore the roles of glycosylation in sICAM-1 activity, we expressed sICAM-1
      in mutant CHO cell lines differing in glycosylation, including Lec2, Lec8, and
      Lec1 as well as in CHO cells cultured in the presence of the alpha-mannosidase-I
      inhibitor kifunensine. Signaling activity of sICAM-1 lacking sialic acid was
      reduced 3-fold compared with sICAM-1 from CHO cells. The activity of sICAM-1
      lacking both sialic acid and galactose was reduced 12-fold, whereas the activity
      of sICAM-1 carrying only high mannose-type N-glycans was reduced 12-26-fold.
      sICAM-1 glycoforms carrying truncated glycans retained full ability to bind to
      LFA-1 on leukocytes. Thus, sialylated and galactosylated complex-type N-glycans
      strongly enhanced the ability of sICAM-1 to induce MIP-2 production in astrocytes
      but did not alter its binding to LFA-1 on leukocytes. Glycosylation could
      therefore serve as a means to regulate specifically the signaling function of
      sICAM-1 in vivo.

PMID- 15201279
TI  - Identification of an antigenic domain near the C terminus of human granulocyte
      macrophage colony-stimulating factor and its spatial localization.
AB  - The goal of this study was to map an epitope on the human granulocyte-macrophage
      colony-stimulating factor (hGM-CSF) at its C terminus, a region whose integrity
      is fundamental in maintaining the normal function of this molecule. Residues
      including the fourth alpha-helix (D, 103-116) were analyzed for their role in the
      interaction with antibodies (Abs) raised against the protein. Five peptides
      homologous to different segments of the C terminus of hGM-CSF were synthesized.
      Peptide-(102-121) included the same residues of the alpha-helix D and the next
      five amino acids toward the C terminus; peptide-[E108A]-(102-121) introduced the
      mutation E108A in order to verify the role of acidic residues; peptide-[C96A](93
      110) encompassed the beta-sheet 2 and half of the alpha-helix D; peptide-[C121A]
      (110-127) included the second half of the alpha-helix D and the C terminus of
      hGMCSF; peptide-(13-31)-Gly-Pro-Gly-(103-116) included both the alpha-helices A
      and D connected by the tripeptide Gly-Pro-Gly, which allows the original
      antiparallel orientation of the two alpha-helices to be maintained. Both anti
      protein and anti-peptide-(102-121) antibodies, capable of neutralizing the
      stimulatory activity of hGMCSF in the bone marrow colony-forming assays,
      recognized a specific epitope in the C terminus of hGM-CSF. Molecular modeling
      estimated the surface accessibility of hGM-CSF and the stability of the synthetic
      peptides in aqueous solution. Altogether, our results showed that the immunogenic
      region includes part of the alpha-helix D and the residues 116-120, which are
      external to this helix and particularly exposed on the protein surface,
      confirming the feasible participation of this region in antibody binding.

PMID- 15201280
TI  - pH Sensing by the calcium-sensing receptor.
AB  - The calcium-sensing receptor (CaR) is activated by small changes in the ionic
      extracellular calcium concentration (Ca(o)) within the physiological range,
      allowing the parathyroid gland to regulate serum Ca(o); however, the CaR is also
      distributed in a number of other tissues where it may sense other endogenous
      agonists and modulators. CaR agonists are polycationic molecules, and our
      previous studies suggest that charged residues in the extracellular domain of the
      CaR are critical for receptor activation through electrostatic interactions.
      Therefore, pH could also potentially modulate CaR activation by its polycationic
      agonists. Changes in the concentration of extracellular H(+) substantially
      altered the activation of the CaR by Ca(o) and other CaR agonists. The effects of
      external pH on the CaR's sensitivity to its agonists were observed for both
      acidic and basic deviations from physiological pH of 7.4, with increases in pH
      rendering the receptor more sensitive to activation by Ca(o) and decreases in pH
      producing the converse effect. At pH values more acidic than 5.5, CaR sensitivity
      to its agonists showed some recovery. Changes in the intracellular pH could not
      account for the effects of external pH on CaR sensitivity to its agonists. Other
      G-protein-coupled receptors, which are endogenously expressed in human embryonic
      kidney 293 cells, showed little change in activity with alterations in external
      pH or effects opposite those found for the CaR. Extracellular pH directly alters
      the CaR in the case of Ca(o) and Mg(o) activation; however, the charges on many
      organic and inorganic agonists are pH-dependent. Activating CaR mutations show
      reduced pH(o) modulation, suggesting a molecular mechanism for increased CaR
      activity at physiological pH(o). Several CaR-expressing tissues, including
      regions of the stomach, the kidney, bone, and the brain, could potentially use
      the CaR as a sensor for pH and acid-base status.

PMID- 15201281
TI  - Modulation of L-type calcium channels in Drosophila via a pituitary adenylyl
      cyclase-activating polypeptide (PACAP)-mediated pathway.
AB  - Modulation of calcium channels plays an important role in many cellular
      processes. Previous studies have shown that the L-type Ca(2+) channels in
      Drosophila larval muscles are modulated via a cAMP-protein kinase A (PKA)
      mediated pathway. This raises questions on the identity of the steps prior to
      cAMP, particularly the endogenous signal that may initiate this modulatory
      cascade. We now present data suggesting the possible role of a neuropeptide,
      pituitary adenylyl cyclase-activating polypeptide (PACAP), in this modulation.
      Mutations in the amnesiac (amn) gene, which encodes a polypeptide homologous to
      human PACAP-38, reduced the L-type current in larval muscles. Conditional
      expression of a wild-type copy of the amn gene rescued the current from this
      reduction. Bath application of human PACAP-38 also rescued the current. PACAP-38
      did not rescue the mutant current in the presence of PACAP-6-38, an antagonist at
      type-I PACAP receptor. 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase,
      prevented PACAP-38 from rescuing the amn current. In addition, 2',5'
      dideoxyadenosine reduced the wild-type current to the level seen in amn, whereas
      it failed to further reduce the current observed in amn muscles. H-89, an
      inhibitor of PKA, suppressed the effect of PACAP-38 on the current. The above
      data suggest that PACAP, the type-I PACAP receptors, and adenylyl cyclase play a
      role in the modulation of L-type Ca(2+) channels via cAMP-PKA pathway. The data
      also provide support for functional homology between human PACAP-38 and the amn
      gene product in Drosophila.

PMID- 15201282
TI  - Mapping subunit location on the Saccharomyces cerevisiae origin recognition
      complex free and bound to DNA using a novel nanoscale biopointer.
AB  - The Saccharomyces cerevisiae origin recognition complex (ORC) is composed of six
      subunits and is an essential component in the assembly of the replication
      apparatus. To probe the organization of this multiprotein complex by electron
      microscopy, each subunit was tagged on either its C or N terminus with biotin and
      assembled into a complex with the five other unmodified subunits. A nanoscale
      biopointer consisting of a short DNA duplex with streptavidin at one end was used
      to map the location of the N and C termini of each subunit. These observations
      were made using ORC free in solution and bound to the ARS1 origin of replication.
      This mapping confirms and extends previous studies mapping the sites of subunit
      interaction with origin DNA. In particular, we provide new information concerning
      the stoichiometry of the ORC-ARS1 complex and the changes in conformation that
      are associated with DNA binding by ORC. This versatile, new approach to mapping
      protein structure has potential for many applications.

PMID- 15201283
TI  - The minimal essential core of a cysteine-based protein-tyrosine phosphatase
      revealed by a novel 16-kDa VH1-like phosphatase, VHZ.
AB  - The smallest active protein-tyrosine phosphatase yet (only 16 kDa) is described
      here and given the name VHZ for VH1-like member Z because it belongs to the group
      of small Vaccinia virus VH1-related dual specific phosphatases exemplified by
      VHR, VHX, and VHY. Human VHZ is remarkably well conserved through evolution as it
      has species orthologs in frogs, fish, fly, and Archaea. The gene for VHZ, which
      we designate as DUSP25, is located on human chromosome 1q23.1 and consists of
      only two coding exons. VHZ is broadly expressed in tissues and cells, including
      resting blood lymphocytes, Jurkat T cells, HL-60, and RAMOS. In transfected
      cells, VHZ was located in the cytosol and in other cells also in the nucleoli.
      Endogenous VHZ showed a similar but more granular distribution. We show that VHZ
      is an active phosphatase and analyze its structure by computer modeling, which
      shows that in comparison with the 185-amino acid residue VHR, the 150-residue VHZ
      is a shortened version of VHR and contains the minimal set of secondary structure
      elements conserved in all known phosphatases from this class. The surface charge
      distribution of VHZ differs from that of VHR and is therefore unlikely to
      dephosphorylate mitogen-activated protein kinases. The remarkably high degree of
      conservation of VHZ through evolution may indicate a role in some ancient and
      fundamental physiological process.

PMID- 15201284
TI  - Molecular basis of the differential sensitivity of nematode and mammalian muscle
      to the anthelmintic agent levamisole.
AB  - Levamisole is an anthelmintic agent that exerts its therapeutic effect by acting
      as a full agonist of the nicotinic receptor (AChR) of nematode muscle. Its action
      at the mammalian muscle AChR has not been elucidated to date despite its wide use
      as an anthelmintic in humans and cattle. By single channel and macroscopic
      current recordings, we investigated the interaction of levamisole with the
      mammalian muscle AChR. Levamisole activates mammalian AChRs. However, single
      channel openings are briefer than those activated by acetylcholine (ACh) and do
      not appear in clusters at high concentrations. The peak current induced by
      levamisole is about 3% that activated by ACh. Thus, the anthelmintic acts as a
      weak agonist of the mammalian AChR. Levamisole also produces open channel
      blockade of the AChR. The apparent affinity for block (190 microm at -70 mV) is
      similar to that of the nematode AChR, suggesting that differences in channel
      activation kinetics govern the different sensitivity of nematode and mammalian
      muscle to anthelmintics. To identify the structural basis of this different
      sensitivity, we performed mutagenesis targeting residues in the alpha subunit
      that differ between vertebrates and nematodes. The replacement of the conserved
      alphaGly-153 with the homologous glutamic acid of nematode AChR significantly
      increases the efficacy of levamisole to activate channels. Channel activity takes
      place in clusters having two different kinetic modes. The kinetics of the high
      open probability mode are almost identical when the agonist is ACh or levamisole.
      It is concluded that alphaGly-153 is involved in the low efficacy of levamisole
      to activate mammalian muscle AChRs.

PMID- 15201285
TI  - Autocatalytic processing of HtrA2/Omi is essential for induction of caspase
      dependent cell death through antagonizing XIAP.
AB  - A mature form of nuclear-encoded mitochondrial serine protease HtrA2/Omi is
      pivotal in regulating apoptotic cell death; however, the underlying mechanism of
      the processing event of HtrA2/Omi and its relevant biological function remain to
      be clarified. Here, we describe that HtrA2/Omi is autocatalytically processed to
      the 36-kDa protein fragment, which is required for the cytochrome c-dependent
      caspase activation along with neutralizing XIAP-mediated inhibition of caspases
      through interaction with XIAP, eventually promoting apoptotic cell death. We have
      shown that the autocatalytic processing of HtrA2/Omi occurs via an intermolecular
      event, demonstrated by incubating an in vitro translated HtrA2/Omi (S306A) mutant
      with the enzymatically active glutathione S-transferase-HtrA2/Omi protein. Using
      N-terminal amino acid sequencing and mutational analysis, we identified that the
      autocatalytic cleavage site is the carboxyl side of alanine 133 of HtrA2/Omi,
      resulting in exposure of an inhibitor of apoptosis protein binding motif in its N
      terminus. Our study provides evidence that the autocatalytic processing of
      HtrA2/Omi is crucial for regulating HtrA2/Omi-mediated apoptotic cell death.

PMID- 15201286
TI  - Altered insulin signaling in retinal tissue in diabetic states.
AB  - Both type 1 and type 2 diabetes can lead to altered retinal microvascular
      function and diabetic retinopathy. Insulin signaling may also play a role in this
      process, and mice lacking insulin receptors in endothelial cells are protected
      from retinal neovascularization. To define the role of diabetes in retinal
      function, we compared insulin signaling in the retinal vasculature of mouse
      models of type 1 (streptozotocin) and type 2 diabetes (ob/ob). In streptozotocin
      mice, in both retina and liver, insulin receptor (IR) and insulin receptor
      substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin,
      while IRS-1 protein and its phosphorylation were maintained. By contrast, in
      ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and
      phosphorylation in liver; these were maintained or increased in retina. In both
      mice, Phosphatidylinositol 3,4,5-trisphosphate generation by acute insulin
      stimulation was enhanced in retinal endothelial cells. On the other hand, protein
      levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice.
      Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1
      were responsive to insulin in retina of both mice but were unresponsive in liver.
      HIF-1alpha and vascular endothelial growth factor were increased and endothelial
      nitric-oxide synthase was decreased in retina. These observations indicate that,
      in both insulin-resistant and insulin-deficient diabetic states, there are
      alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced
      mitogen-activated protein kinases responses that could contribute to the
      retinopathy. Furthermore, insulin signaling in retinal endothelial cells is
      differentially altered in diabetes and is also differentially regulated from
      insulin signaling in classical target tissues such as liver.

PMID- 15201287
TI  - Cardiac plasticity in fishes: environmental influences and intraspecific
      differences.
AB  - Fish cardiac physiology and anatomy show a multiplicity of intraspecific
      modifications when exposed to prolonged changes in environmentally relevant
      parameters such as temperature, hypoxia and food availability, and when meeting
      the increased demands associated with training/increased activity and sexual
      maturation. Further, there is evidence that rearing fish under intensive
      aquaculture conditions significantly alters some, but not all, aspects of cardiac
      anatomy and physiology. This review focuses on the responses of cardiac
      physiology and anatomy to these challenges, highlighting where applicable, the
      importance of hyperplastic (i.e. the production of new cells) vs hypertrophic
      (the enlargement of existing cells) growth to the adaptive response of the heart.
      In addition, we summarize recent studies that have explored the relationship
      between the myocardial protection afforded by preconditioning and myocardial
      hypoxia tolerance. This latter research clearly demonstrates the capacity of the
      fish heart to adjust to short-term perturbations, and shows that it can be
      difficult to predict how short-term and long-term alterations in cardiac
      physiology will interact.

PMID- 15201288
TI  - Innate immunity in the malaria vector Anopheles gambiae: comparative and
      functional genomics.
AB  - The resurgence of malaria is at least partly attributed to the absence of an
      effective vaccine, parasite resistance to antimalarial drugs and resistance to
      insecticides of the anopheline mosquito vectors. Novel strategies are needed to
      combat the disease on three fronts: protection (vaccines), prophylaxis/treatment
      (antimalarial drugs) and transmission blocking. The latter entails either killing
      the mosquitoes (insecticides), preventing mosquito biting (bednets and
      repellents), blocking parasite development in the vector (transmission blocking
      vaccines), genetic manipulation or chemical incapacitation of the vector. During
      the past decade, mosquito research has been energized by several breakthroughs,
      including the successful transformation of anopheline vectors, analysis of gene
      function by RNAi, genome-wide expression profiling using DNA microarrays and,
      most importantly, sequencing of the Anopheles gambiae genome. These breakthroughs
      helped unravel some of the mechanisms underlying the dynamic interactions between
      the parasite and the vector and shed light on the mosquito innate immune system
      as a set of potential targets to block parasite development. In this context,
      putative pattern recognition receptors of the mosquito that act as positive and
      negative regulators of parasite development have been identified recently.
      Characterizing these molecules and others of similar function, and identifying
      their ligands on the parasite surface, will provide clues on the nature of the
      interactions that define an efficient parasite-vector system and open up
      unprecedented opportunities to control the vectorial capacity of anopheline
      mosquitoes.

PMID- 15201289
TI  - Dopaminergic and serotonergic innervation of cockroach salivary glands:
      distribution and morphology of synapses and release sites.
AB  - The paired salivary glands in the cockroach are composed of acini with ion
      transporting peripheral P-cells and protein-secreting central C-cells, and a duct
      system for the modification of the primary saliva. Secretory activity is
      controlled by serotonergic and dopaminergic neurons, whose axons form a dense
      plexus on the glands. The spatial relationship of release sites for serotonin and
      dopamine to the various cell types was determined by anti-synapsin
      immunofluorescence confocal microscopy and electron microscopy. Every C-cell
      apparently has only serotonergic synapses on its surface. Serotonergic and
      dopaminergic fibres on the acini have their release zones at a distance of
      approximately 0.5 microm from the P-cells. Nerves between acinar lobules may
      serve as neurohaemal organs and contain abundant dopaminergic and few
      serotonergic release sites. Some dopaminergic and serotonergic release sites
      reside in the duct epithelium, the former throughout the duct system, the latter
      only in segments next to acini. These findings are consistent with the view that
      C-cells respond exclusively to serotonin, P-cells to serotonin and dopamine, and
      most duct cells only to dopamine. Moreover, the data suggest that C-cells are
      stimulated by serotonin released close to their surface, whereas P-cells and most
      duct cells are exposed to serotonin/dopamine liberated at some distance.

PMID- 15201290
TI  - Ontogenetic patterns of limb loading, in vivo bone strains and growth in the goat
      radius.
AB  - As tetrapods increase in size and weight through ontogeny, the limb skeleton must
      grow to accommodate the increases in body weight and the resulting locomotor
      forces placed upon the limbs. No study to date, however, has examined how
      morphological changes in the limb skeleton during growth reflect ontogenetic
      patterns of limb loading and the resulting stresses and strains produced in the
      limbs. The goal of this study was to relate forelimb loads to in vivo bone
      strains in the radius of the domestic goat (Capra hircus) across a range of gaits
      and speeds through ontogeny while observing how the growth patterns of the bone
      relate to the mechanics of the limb. In vivo bone strains in the radius were
      recorded from two groups of juvenile goats (4 kg, 6 weeks and 9 kg, 15 weeks) and
      compared with previously reported strain data for the radius of adult goats.
      Ontogenetic strain patterns were examined in relation to peak forelimb ground
      reaction forces, ontogenetic scaling patterns of cross-sectional geometry and
      bone curvature, and percentage mineral ash content. Peak principal longitudinal
      tensile strains on the cranial surface and compressive strains on the caudal
      surface of the radius increased during ontogeny but maintained a uniform
      distribution, resulting in the radius being loaded primarily in bending through
      ontogeny. The increase in strain occurred despite uniform loading (relative to
      body weight) of the forelimb through ontogeny. Instead, the increase in bone
      strain resulted from strong negative growth allometry of the cross-sectional area
      (proportional to M(0.53)) and medio-lateral and cranio-caudal second moments of
      area (I(ML) proportional to M(1.03), I(CC) proportional to M(0.84)) of the radius
      and only a small increase (+2.8%) in mineral ash content. Even though bone
      strains increased with growth and age, strains in the younger goats were small
      enough to suggest that they maintain safety factors at least comparable with
      adults when moving at similar absolute speeds. Increased variability of loading
      in juvenile animals may also favor the more robust dimensions of the radius, and
      possibly other limb bones, early in growth.

PMID- 15201291
TI  - Purification of a soluble glycoprotein from the uncalcified ecdysial cuticle of
      the blue crab Callinectes sapidus and its possible role in initial
      mineralization.
AB  - A heavily glycosylated soluble protein was purified using a combination of lectin
      affinity and size exclusion chromatography from a soluble extract of uncalcified
      dorsal cuticle of blue crab Callinectes sapidus removed at ecdysis. Similarities
      in apparent molecular mass and carbohydrate composition suggest that this protein
      is the same species previously shown to disappear from soluble extracts
      coincidentally with the onset of mineral deposition in the newly exposed post
      molt cuticle. The amino acid sequence of the N-terminal portion of the core
      polypeptide was determined and polyclonal antibodies were raised against both the
      purified glycoprotein and the peptide. Immunoblots of unfractionated soluble
      extracts taken at various times post-molt illustrated that the anti-peptide
      antibody recognized several polypeptides with electrophoretic mobilities that
      differ from the purified glycoprotein. These bands may be deglycosylation
      products which would not have been purified due to different lectin affinity or
      size. Immunohistochemical analysis indicated uniform protein distribution in the
      exocuticle at ecdysis, but decreased antibody binding at the interprismatic septa
      by 2 h post-molt. The location of the protein is therefore the negative image of
      the calcification pattern in the exocuticle and provides a spatial pattern to
      correlate with the previously reported temporal events. This strengthens the
      hypothesis that the glycoprotein under investigation is an inhibitor of calcite
      nucleation or of initial amorphous calcium carbonate accumulation.

PMID- 15201292
TI  - Basolateral ion transport mechanisms during fluid secretion by Drosophila
      Malpighian tubules: Na+ recycling, Na+:K+:2Cl- cotransport and Cl- conductance.
AB  - Mechanisms of ion transport during primary urine formation by the Malpighian
      tubule of Drosophila melanogaster were analyzed through measurements of fluid
      secretion rate, transepithelial ion flux, basolateral membrane potential (V(bl))
      and intracellular activities of K(+) (a(K)(i)) and Cl(-) (a(Cl)(i)). Calculation
      of the electrochemical potentials for both ions permitted assessment of the
      possible contributions of K(+) channels, Na(+):K(+):2Cl(-) cotransport, and
      K(+):Cl(-) cotransport, to net transepithelial ion secretion across the
      basolateral membrane. The data show that passive movement of both K(+) and Cl(-)
      from cell to bath is favoured across the basolateral membrane, indicating that
      both ions are actively transported into the cell. Contributions of basolateral
      K(+) channels or K(+):Cl(-) cotransporters to net transepithelial ion secretion
      can be ruled out. After prior exposure of tubules to ouabain, subsequent addition
      of bumetanide reduced fluid secretion rate, K(+) flux and Na(+) flux, indicating
      a role for a Na(+):K(+):2Cl(-) cotransporter in fluid secretion. Addition of the
      K(+) channel blocker Ba(2+) had no effect on a(K)(i) or a(Cl)(i). Addition of
      Ba(2+) unmasked a basolateral Cl(-) conductance and the hyperpolarization of
      V(bl) in response to Ba(2+) was Cl(-)-dependent. A new model for fluid secretion
      proposes that K(+) and Cl(-) cross the basolateral membrane through a Na(+)
      driven Na(+):K(+):2Cl(-) cotransporter and that most of the Na(+) that enters the
      cells is returned to the bath through the Na(+)/K(+)-ATPase.

PMID- 15201293
TI  - Local action of exogenous nitric oxide (NO) on the skin blood flow of rock
      pigeons (Columba livia) is affected by acclimation and skin site.
AB  - We studied the blood flow over dorsal and abdominal, non-brooding patch skin of
      two groups of pigeons: one group was thermally acclimated to cold (winter
      acclimatized, WAC) while the other group was acclimated to a mesic environment
      (thermally non-challenged, NOC). Two bilateral patches at the measurement sites
      were treated simultaneously with a gel containing sodium nitrate and ascorbic
      acid, to generate nitric oxide (NO), and a vehicle gel. Blood flow was measured
      by laser Doppler velocimetry. Changes induced by these treatments were calculated
      against basic blood flow values for the corresponding patch. The results showed
      that the basic blood flow over the abdominal skin patches at room temperature was
      higher than over the dorsal skin in both acclimation states, but comparison
      revealed a sustainably higher level of basic skin blood flow in the WAC pigeons.
      The local response to exogenous NO was non-uniform over the two skin areas
      measured, and a specific vasodilatory action on the abdominal microvessels was
      recorded in the NOC pigeons. Abdominal vasodilatation in the WAC pigeons seemed
      to involve other mechanisms as well as local NO-dependent ones, among which the
      role of cold-induced vasodilatation (CIVD) is discussed here. Interestingly, the
      dorsal skin seemed to be less responsive to the action of NO, irrespective of the
      acclimation state. Our results show that acclimation state and skin site affect
      the action of exogenous NO on local skin blood flow, and we suggest that the
      differences reflect acclimation-induced changes in the vascularity of the skin
      and in its sensitivity to thermal stimuli and that the roles of the abdominal and
      dorsal skin are different with respect to environmental changes.

PMID- 15201294
TI  - Learning and memory in Lymnaea are negatively altered by acute low-level
      concentrations of hydrogen sulphide.
AB  - Hydrogen sulphide (H(2)S) is a common industrial pollutant as well as an
      endogenous neural transmitter/neural modulator. Experiments were performed on the
      pond snail Lymnaea stagnalis to determine the acute effects of low-level exposure
      to H(2)S (50-100 micromol l(-1)) on aerial respiratory behaviour, associative
      learning, and its subsequent consolidation into long-term memory (LTM). A 3
      neuron network whose sufficiency and necessity have been demonstrated drives
      aerial respiratory behaviour in Lymnaea. In the presence of 100 micromol l(-1)
      H(2)S the number of bouts of aerial respiration and the total breathing time were
      significantly increased compared to the control hypoxic situation, but were
      equivalent to those observed in snails that had been subjected to a 'more intense
      hypoxic challenge'. In addition, at a concentration of 100 micromol l(-1) H(2)S
      neither associative learning nor long-term memory (LTM) were observed. However,
      snails subjected to a 'more intense hypoxic challenge' still had the capacity to
      learn and form LTM. These snails, in fact, showed statistically the best learning
      and memory performance of any group. While learning and memory were observed at
      50 and 75 micromol l(-1) H(2)S, respectively, they were statistically poorer than
      the learning and memory exhibited by snails in the standard hypoxia condition.
      Hence the ability to learn and form memory was compromised by H(2)S. Thus an
      invertebrate model system with a well-defined neural network can be used to study
      of the effects of H(2)S on the processes of learning and memory.

PMID- 15201295
TI  - Colourful orb-weaving spiders, Nephila pilipes, through a bee's eyes.
AB  - Many orb-weaving spiders in the tropics forage in open sites during the day and
      some of them have both bright and dark colourations. The conspicuous UV
      reflective colour markings of these spiders have been reported to be attractive
      to visually oriented prey and thus could increase the spiders' foraging success.
      Using a combination of field and laboratory studies, we examine whether or not
      the body colouration of orb-weaving spiders exhibits optical properties that are
      attractive to insect prey from the viewpoint of insect visual physiology. We
      compared the prey interception rates and colour contrasts of the typical and
      melanic morphs of the giant wood spider, Nephila pilipes. Results of the field
      study showed that the typical morph caught significantly more insects than the
      melanic morph. Colour contrasts calculated from spectral reflectances of the
      background and body surface of spiders showed that the brightly coloured body
      parts of the typical morph exhibited rather high values, but those of the dark
      body parts were below the discrimination threshold. The differential colour
      contrasts of body parts generated a visual signal unlike that of a spider but
      rather like certain forms of food resources. On the other hand, the melanic
      morphs did not have bright colouration and the colour contrasts of every part of
      the body were significantly higher than the threshold, making the contour of
      spiders quite clear to bees.

PMID- 15201296
TI  - Cadmium effects on mitochondrial function are enhanced by elevated temperatures
      in a marine poikilotherm, Crassostrea virginica Gmelin (Bivalvia: Ostreidae).
AB  - Marine intertidal mollusks, such as oysters, are exposed to multiple stressors in
      estuaries, including varying environmental temperature and levels of trace
      metals, which may interactively affect their physiology. In order to understand
      the combined effects of cadmium and elevated temperature on mitochondrial
      bioenergetics of marine mollusks, respiration rates and mitochondrial volume
      changes were studied in response to different cadmium levels (0-1000 micromol l(
      1)) and temperatures (15, 25 and 35 degrees C) in isolated mitochondria from the
      eastern oyster Crassostrea virginica acclimated at 15 degrees C. It was found
      that both cadmium and temperature significantly affect mitochondrial function in
      oysters. Elevated temperature had a rate-enhancing effect on state 3 (ADP
      stimulated) and states 4 and 4+ (representative of proton leak) respiration, and
      the rate of temperature-dependent increase was higher for states 4 and 4+ than
      for state 3 respiration. Exposure of oyster mitochondria to 35 degrees C resulted
      in a decreased respiratory control and phosphorylation efficiency (P/O ratio)
      compared to that of the acclimation temperature (15 degrees C), while an
      intermediate temperature (25 degrees C) had no effect. Cadmium exposure did not
      lead to a significant volume change in oyster mitochondria in vitro. Low levels
      of cadmium (1-5 micromol l(-1)) stimulated the rate of proton leak in oyster
      mitochondria, while not affecting ADP-stimulated state 3 respiration. In
      contrast, higher cadmium levels (10-50 micromol l(-1)) had little or no effect on
      proton leak, but significantly inhibited state 3 respiration by 40-80% of the
      control rates. Elevated temperature increased sensitivity of oyster mitochondria
      to cadmium leading to an early inhibition of ADP-stimulated respiration and an
      onset of complete mitochondrial uncoupling at progressively lower cadmium
      concentrations with increasing temperature. Enhancement of cadmium effects by
      elevated temperatures suggests that oyster populations subjected to elevated
      temperatures due to seasonal warming or global climate change may become more
      susceptible to trace metal pollution, and vice versa.

PMID- 15201297
TI  - Antennae on transmitters on penguins: balancing energy budgets on the high wire.
AB  - The effect of externally mounted antennae on the energetics of penguins was
      studied by mounting various antennae on a transducer fixed to a model Magellanic
      penguin Spheniscus magellanicus to determine drag, run at speeds of up to 2 m s(
      1) in a swim canal. For rigid antennae set perpendicular to the water flow,
      measured drag increased with increasing swim speed. Increasing antenna length
      (for lengths between 100 and 200 mm) or diameter (for diameters between 1 and 4
      mm) resulted in accelerating increased drag as a function of both antenna length
      and diameter. Where antennae were positioned at acute angles to the water flow,
      drag was markedly reduced, as was drag at higher speeds in flexible antennae.
      These results were incorporated in a model on the foraging energetics of free
      living Magellanic penguins using data (on swim speeds, intervals between prey
      encounters, amount ingested per patch and dive durations) derived from previously
      published work and from a field study conducted on birds from a colony at Punta
      Norte, Argentina, using data loggers. The field work indicated that free-living
      birds have a foraging efficiency (net energy gain/net energy loss) of about 2.5.
      The model predicted that birds equipped with the largest rigid external antennae
      tested (200 mm x 3 mm diameter), set perpendicular to water flow, increased
      energy expenditure at normal swim speeds of 1.77 m s(-1) by 79% and at prey
      capture speeds of 2.25 m s(-1) by 147%, and ultimately led to a foraging
      efficiency that was about 5 times less than that of unequipped birds. Highly
      flexible antennae were shown to reduce this effect considerably. Deleterious
      antenna-induced effects are predicted to be particularly critical in penguins
      that have to travel fast to capture prey. Possible measures taken by the birds to
      increase foraging efficiency could include reduced travelling speed and selection
      of smaller prey types. Suggestions are made as to how antenna-induced drag might
      be minimized for future studies on marine diving animals.

PMID- 15201298
TI  - Developmental allometry of pulmonary structure and function in the altricial
      Australian pelican Pelecanus conspicillatus.
AB  - Quantitative methods have been used to correlate maximal oxygen uptake with lung
      development in Australian pelicans. These birds produce the largest altricial
      neonates and become some of the largest birds capable of flight. During post
      hatching growth to adults, body mass increases by two orders of magnitude (from
      88 g to 8.8 kg). Oxygen consumption rates were measured at rest and during
      exposure to cold and during exercise. Then the lungs were quantitatively assessed
      using morphometric techniques. Allometric relationships between body mass (M) and
      gas exchange parameters (Y) were determined and evaluated by examining the
      exponents of the equation Y=aM(b). This intraspecific study was compared to
      interspecific studies of adult birds reported in the literature. Total lung
      volume scales similarly in juvenile pelicans (b=1.05) as in adult birds (b=1.02).
      However, surface area of the blood-gas barrier greatly increases (b=1.25), and
      its harmonic mean thickness does not significantly change (b=0.02), in comparison
      to exponents from adult birds (b=0.86 and 0.07, respectively). As a result, the
      diffusing capacity of the blood-gas tissue barrier increases much more during
      development (b=1.23) than it does in adult birds of different sizes (b=0.79). It
      increases in parallel to maximal oxygen consumption rate (b=1.28), suggesting
      that the gas exchange system is either limited by lung development or possibly
      symmorphic. The capacity of the oxygen delivery system is theoretically
      sufficient for powered flight well in advance of the bird's need to use it.

PMID- 15201299
TI  - The evolution of recovery from desiccation stress in laboratory-selected
      populations of Drosophila melanogaster.
AB  - We examined the capacity for physiological recovery from the effects of
      desiccation in five replicate populations of Drosophila melanogaster that have
      been selected for enhanced desiccation resistance (D populations) and in five
      replicate control populations (C populations). The capacity to recover was
      signified by the ability to restore three somatic components, namely whole-body
      water, dry mass and sodium content, all of which are reduced during desiccation.
      Throughout a period of recovery following a bout of desiccation, the flies were
      offered one of three fluids: distilled water, saline solution, or saline+sucrose
      solution. Our findings indicate that, when allowed to recover on saline+sucrose
      solution, D populations have the capacity to restore water at a greater rate than
      C populations and are able to fully restore dry mass and sodium content to the
      levels observed in non-desiccated, hydrated D flies. When provided with this same
      solution during recovery, C flies are unable to restore dry mass and are faced
      with an elevated sodium load. Desiccation resistance of the flies subsequent to
      recovery was also examined. We provide evidence that the greatest desiccation
      resistance in the D populations is associated with the restoration of all three
      somatic components, suggesting that not only water content, but also dry mass and
      sodium, may contribute to the enhanced desiccation resistance that has evolved in
      these populations.

PMID- 15201300
TI  - The genes for the helix-loop-helix proteins Id6a, Id6b, Id1 and Id2 are
      specifically expressed in the ventral and dorsal domains of the fish developing
      somites.
AB  - Muscle differentiation is inhibited by members of the Id family that block the
      transcriptional effect of myogenic bHLH regulators by forming inactive
      heterodimers with them. Also, Id proteins promote cell proliferation by
      interacting with key regulators of the cell cycle. In order to determine the role
      of Id-encoding genes during fish development and especially in early myogenesis,
      we examined the expression patterns of Id1, Id2 and two nonallelic Id6 (Id6a and
      Id6b)-encoding genes in developing trout embryos. These four Id paralogs were
      found to exhibit discrete expression in the developing nervous system and in the
      eye rudiment. During the segmentation process, Id6a, Id6b and Id1 were expressed
      in the tail bud, the paraxial mesoderm and the ventral and dorsal domains of
      neoformed somites. As the somite matured in a rostrocaudal progression, the
      labelling for Id1 transcripts rapidly faded whereas labelling for Id6 transcripts
      was found to persist until at least the completion of segmentation. By contrast,
      Id2 transcripts were visualised transiently only in dorsal domains of neoformed
      somites and strongly accumulated in the pronephros. The preferential localisation
      of Id6a, Id6b, Id1 and Id2 transcripts within ventral and/or dorsal extremes of
      the developing somites, suggests that these areas, which were the last ones to
      express muscle-specific genes, contain dividing cells involved in somite
      expansion.

PMID- 15201302
TI  - Wing hair sensilla underlying aimed hindleg scratching of the locust.
AB  - The anatomy and physiology of exteroceptors on the surfaces of the wings have
      been described in many insects, but their roles in behaviour have been less well
      studied. They have often been assumed to have a role primarily in flight. We show
      that the wings of the locust Schistocerca gregaria possess at least three
      different hair types with characteristic patterns of distribution that determine
      the probability of eliciting targeted hindleg scratching behaviour. The different
      hair types are defined by their morphology and innervation. The shortest hairs
      (14-46 microm) are basiconic receptors containing both chemosensory and
      mechanosensory afferents. They are distributed widely across the dorsal surfaces
      of the forewings; some are located on the ventral surfaces of the hindwings, but
      none are found on the ventral surfaces of the forewings or the dorsal surfaces of
      the hindwings. Medium length hairs (73-159 microm) are found on all wing
      surfaces, but are restricted to the veins, principally the subcosta on the dorsal
      surface of the forewings. The longest hairs (316-511 microm) are found only on
      the postcubitus vein on the dorsal surfaces of the forewings, so that they form a
      pair of dorsal rows when the wings are folded at rest. Touching the dorsal
      surface of a forewing can elicit aimed scratching movements of a hindleg, and we
      show that the probability of eliciting a scratch differs for different stimulus
      sites and for different start positions of the hind leg. The effectiveness of
      different stimulus sites can be correlated with the distribution of tactile hairs
      on the dorsal forewing surface. Touching the long hairs provides the strongest
      drive to elicit a scratch, and ablating them reduces the probability to almost
      zero. We conclude that input from forewing tactile hairs plays an important role
      in eliciting hindleg scratching and encodes the spatial location required for
      targeting.

PMID- 15201301
TI  - Reduced juvenile hormone synthesis in mosquitoes with low teneral reserves
      reduces ovarian previtellogenic development in Aedes aegypti.
AB  - We investigated the relationship among nutritional reserves, previtellogenic
      ovary development and juvenile hormone (JH) synthesis in Aedes aegypti female
      mosquitoes. By raising larvae under different nutritional regimes, two adult
      phenotypes (large and small females) were generated, which differed significantly
      in size at eclosion (measured by wing length). We measured the total amount of
      protein, lipids and glycogen in newly emerged (teneral) large and small females.
      Teneral reserves were significantly lower in small females. Maximum
      previtellogenic ovary development occurred only if enough teneral nutrients were
      present. Maximum previtellogenic ovary development was stimulated in small
      females with low teneral nutrients by topically applying a JH analog. The
      biosynthetic activity of Ae. aegypti corpora allata (CA) was studied in vitro
      using a radiochemical method. JH synthesis was significantly reduced in females
      emerged with low teneral reserves and stimulated by sugar feeding. These results
      establish that the CA synthesizes enough JH to activate ovary maturation only in
      the presence of large nutrient reserves.

PMID- 15201303
TI  - Effects of swimming on metabolic recovery from anoxia in the painted turtle.
AB  - Anoxic submergence in the Western painted turtle results in a severe metabolic
      acidosis characterized by high plasma lactate and depressed arterial pH, a
      response similar to that seen in other vertebrates following exhaustive exercise.
      We tested the hypothesis that 1 or 2 h of aerobic swimming following anoxic
      submergence would enhance the rate of lactate disappearance from the blood just
      as sustained aerobic exercise does in mammals and fishes following strenuous
      exercise. Following 2 h of anoxic submergence at 25 degrees C and 1 h of
      recovery, the pattern of plasma lactate disappearance in turtles previously
      trained to swim in a flume and swum aerobically (2-3x resting V(O(2))) for 1 or 2
      h did not differ significantly from that in trained and untrained non-swimming
      turtles. Turtles were fully recovered by 7-10 h post-anoxia. The response
      patterns also did not differ between treatments for arterial P(O(2)), P(CO(2)),
      pH, and plasma glucose and HCO(3)(-). Blood pH and plasma HCO(3)(-) recovered by
      1 and 4 h, respectively. Despite the large lactate load, painted turtles are able
      to sustain periods of continuous swimming for at least 2 h without compromising
      metabolic recovery. Although this activity did not consistently enhance recovery,
      the rate of lactate disappearance was positively correlated with oxygen
      consumption rate in actively and passively recovering turtles. We suggest that
      active recovery was not a more important enhancer of recovery either because
      swimming may have had an inhibitory effect on hepatic gluconeogenesis or that
      there is variation in fuel utilization during the swimming period.

PMID- 15201304
TI  - Adjustments of gastric pH, motility and temperature during long-term preservation
      of stomach contents in free-ranging incubating king penguins.
AB  - Male king penguins are able to store undigested food in their stomach for up to 3
      weeks during their incubation fast, which evidently implies some modification of
      their digestive process. Using small electronic recorders, we studied the change
      in gastric pH, motility and temperature during the first week of food storage.
      The pH could be maintained at values as high as 6 throughout the incubation fast,
      a pH that is unfavourable for avian gastric proteinase activity. Gastric motility
      was never completely inhibited but could be markedly reduced. Stomach temperature
      was maintained at around 38 degrees C. The fact that stomach temperature of
      incubating birds did not show a daily rhythmic fluctuation as seen in non
      breeding birds could be due to temperature constraints on embryo development.
      Thus the present study demonstrates substantial adjustments of pH and gastric
      motility in incubating king penguins, which may contribute to the inhibition of
      digestive gastric processes.

PMID- 15201305
TI  - Caffeine releasable stores of Ca2+ show depletion prior to the final steps in
      delayed CA1 neuronal death.
AB  - In addition to their role in signaling, Ca2+ ions in the endoplasmic reticulum
      also regulate important steps in protein processing and trafficking that are
      critical for normal cell function. Chronic depletion of Ca2+ in the endoplasmic
      reticulum has been shown to lead to cell degeneration and has been proposed as a
      mechanism underlying delayed neuronal death following ischemic insults to the
      CNS. Experiments here have assessed the relative content of ryanodine receptor
      gated stores in CA1 neurons by measuring cytoplasmic Ca2+ increases induced by
      caffeine. These measurements were performed on CA1 neurons, in slice, from normal
      gerbils, and compared with responses from this same population of neurons 54-60 h
      after animals had undergone a standard ischemic insult: 5-min bilateral occlusion
      of the carotid arteries. The mean amplitude of responses in the postischemic
      population were less than one-third of those in control or sham-operated animals,
      and 35% of the neurons from postischemic animals showed very small responses that
      were approximately 10% of the control population mean. Refilling of these stores
      after caffeine challenges was also impaired in postischemic neurons. These
      observations are consistent with our earlier finding that voltage-gated influx is
      sharply reduced in postischemic in CA1 neurons and the hypothesis that the
      resulting depletion in endosomal Ca2+ is an important cause of delayed neuronal
      death.

PMID- 15201306
TI  - Alternative splicing in the voltage-sensing region of N-Type CaV2.2 channels
      modulates channel kinetics.
AB  - The CaV2.2 gene encodes the functional core of the N-type calcium channel. This
      gene has the potential to generate thousands of CaV2.2 splice isoforms with
      different properties. However, the functional significance of most sites of
      alternative splicing is not established. The IVS3-IVS4 region contains an
      alternative splice site that is conserved evolutionarily among CaValpha1 genes
      from Drosophila to human. In CaV2.2, inclusion of exon 31a in the IVS3-IVS4
      region is restricted to the peripheral nervous system, and its inclusion slows
      the speed of channel activation. To investigate the effects of exon 31a in more
      detail, we generated four tsA201 cell lines stably expressing CaV2.2 splice
      isoforms. Coexpression of auxiliary CaVbeta and CaValpha2delta subunits was
      required to reconstitute currents with the kinetics of N-type channels from
      neurons. Channels including exon 31a activated and deactivated more slowly at all
      voltages. Current densities were high enough in the stable cell lines co
      expressing CaValpha2delta to resolve gating currents. The steady-state voltage
      dependence of charge movement was not consistently different between splice
      isoforms, but on gating currents from the exon 31a-containing CaV2.2 isoform
      decayed with a slower time course, corresponding to slower movement of the charge
      sensor. Exon 31a-containing CaV2.2 is restricted to peripheral ganglia; and the
      slower gating kinetics of CaV2.2 splice isoforms containing exon 31a correlated
      reasonably well with the properties of native N-type currents in sympathetic
      neurons. Our results suggest that alternative splicing in the S3-S4 linker
      influences the kinetics but not the voltage dependence of N-type channel gating.

PMID- 15201307
TI  - Adenosine inhibits GABAergic and glycinergic transmission in adult rat substantia
      gelatinosa neurons.
AB  - The effect of adenosine on inhibitory postsynaptic currents (IPSCs) was examined
      in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using
      the whole cell patch-clamp technique. Adenosine reversibly reduced the amplitude
      of GABAergic and glycinergic electrically evoked IPSCs (eIPSCs) in a dose
      dependent manner (EC50 = 14.5 and 19.1 microM, respectively). The A1 adenosine
      receptor agonist N6-cyclopentyladenosine also reduced the eIPSCs, whereas the A1
      antagonist 8-cyclopentyl-1,3-dimethylxanthine reversed the inhibition produced by
      adenosine. In paired-pulse experiments, the ratio of the second to first
      GABAergic or glycinergic eIPSC amplitude was increased by adenosine, whereas the
      response of SG neurons to exogenous GABA or glycine was unaffected. Adenosine
      reduced the frequency of GABAergic and glycinergic spontaneous IPSCs without
      changing their amplitude. This reduction in frequency disappeared in the presence
      of a K+ -channel blocker (4-aminopyridine) but not in the absence of Ca2+. The
      inhibition by adenosine disappeared in the presence of cyclic-AMP analog (8-Br
      cyclic AMP) and adenylate-cyclase activator (forskolin) but not protein-kinase C
      (PKC) activator (phorbol-12,13-dibutyrate). We conclude that adenosine suppresses
      inhibitory transmission in SG neurons by activating presynaptic A1 receptors and
      that this action is mediated by K+ channels and cyclic AMP but not by Ca2+
      channels and PKC. This inhibitory action of adenosine probably contributes to the
      modulation of pain transmission in the SG.

PMID- 15201309
TI  - Impedance control balances stability with metabolically costly muscle activation.
AB  - Humans are able to stabilize their movements in environments with unstable
      dynamics by selectively modifying arm impedance independently of force and
      torque. We further investigated adaptation to unstable dynamics to determine
      whether the CNS maintains a constant overall level of stability as the
      instability of the environmental dynamics is varied. Subjects performed reaching
      movements in unstable force fields of varying strength, generated by a robotic
      manipulator. Although the force fields disrupted the initial movements, subjects
      were able to adapt to the novel dynamics and learned to produce straight
      trajectories. After adaptation, the endpoint stiffness of the arm was measured at
      the midpoint of the movement. The stiffness had been selectively modified in the
      direction of the instability. The stiffness in the stable direction was
      relatively unchanged from that measured during movements in a null force field
      prior to exposure to the unstable force field. This impedance modification was
      achieved without changes in force and torque. The overall stiffness of the arm
      and environment in the direction of instability was adapted to the force field
      strength such that it remained equivalent to that of the null force field. This
      suggests that the CNS attempts both to maintain a minimum level of stability and
      minimize energy expenditure.

PMID- 15201308
TI  - A developmental switch in acute sensitization of small dorsal root ganglion (DRG)
      neurons to capsaicin or noxious heating by NGF.
AB  - Using dissociated rat dorsal root ganglion (DRG) neurons, we have explored the
      ability of nerve growth factor (NGF) to acutely (within minutes) sensitize
      responses of nociceptors to capsaicin or noxious heat during postnatal
      development. While robust sensitization of noxious heat or capsaicin responses by
      NGF is observed in adult DRG neurons, responses to such stimuli in trkA-positive
      neurons from early postnatal animals are not sensitized by NGF. Neurons acquire
      sensitivity to the hyperalgesic effects of NGF between postnatal days 4 and 10
      (P4-P10). In contrast to NGF, bradykinin sensitizes responses to noxious heat in
      both adult and neonatal DRG neurons. These observations suggest a developmental
      switch in signal transduction cascades linking trkA receptors to hyperalgesia
      during postnatal development and differences in the signaling pathways mediating
      bradykinin- and NGF-induced sensitization.

PMID- 15201310
TI  - Factors governing the form of the relation between muscle force and the EMG: a
      simulation study.
AB  - The dependence of the form of the EMG-force relation on key motoneuron and muscle
      properties was explored using a simulation approach. Surface EMG signals and
      isometric forces were simulated using existing motoneuron pool, muscle force, and
      surface EMG models, based primarily on reported properties of the first dorsal
      interosseous (FDI) muscle in humans. Our simulation results indicate that the
      relation between electrical and mechanical properties of the individual motor
      unit level plays the dominant role in determining the overall EMG amplitude-force
      relation of the muscle, while the underlying motor unit firing rate strategy
      appears to be a less important factor. However, different motor unit firing rate
      strategies result in substantially different relations between counts of the
      numbers of motoneuron discharges and the isometric force. Our simulation results
      also show that EMG amplitude (estimated as the average rectified value) increases
      as a result of synchronous discharges of different motor units within the pool,
      but the magnitude of this increase is determined primarily by the action
      potential duration of the synchronized motor units. Furthermore, when the EMG
      effects are normalized to their maximum levels, motor unit synchrony does not
      exert significant effects on the form of the EMG-force relation, provided that
      the synchrony level is held similar at different excitation levels.

PMID- 15201311
TI  - Differences between stereocilia numbers on type I and type II vestibular hair
      cells.
AB  - A major outstanding goal of vestibular neuroscience is to understand the
      distinctive functional roles of type I and type II hair cells. One important
      question is whether these two hair cell types differ in bundle structure. To
      address this, we have developed methods to characterize stereocilia numbers on
      identified type I and type II hair cells in the utricle of a turtle, Trachemys
      scripta. Our data indicate that type I hair cells, which occur only in the
      striola, average 95.9 +/-16.73 (SD) stereocilia per bundle. In contrast, striolar
      type II hair cells have 59.9 +/- 8.98 stereocilia, and type II hair cells in the
      adjacent extrastriola average 44.8 +/- 10.82 stereocilia. Thus type I hair cells
      have the highest stereocilia counts in the utricle. These results provide the
      first direct evidence that type I hair cells have significantly more stereocilia
      than type II hair cells, and they suggest that the two hair cell types may differ
      in bundle mechanics and peak mechanoelectric transduction currents.

PMID- 15201312
TI  - Persistent electrical coupling and locomotory dysfunction in the zebrafish mutant
      shocked.
AB  - On initial formation of neuromuscular junctions, slow synaptic signals interact
      through an electrically coupled network of muscle cells. After the developmental
      onset of muscle excitability and the transition to fast synaptic responses,
      electrical coupling diminishes. No studies have revealed the functional
      importance of the electrical coupling or its precisely timed loss during
      development. In the mutant zebrafish shocked (sho) electrical coupling between
      fast muscle cells persists beyond the time that it would normally disappear in
      wild-type fish. Recordings from sho indicate that muscle depolarization in
      response to motor neuron stimulation remains slow due to the low-pass filter
      characteristics of the coupled network of muscle cells. Our findings suggest that
      the resultant prolonged muscle depolarizations contribute to the premature
      termination of swimming in sho and the delayed acquisition of the normally rapid
      touch-triggered movements. Thus the benefits of gap junctions during early
      synapse development likely become a liability if not inactivated by the time that
      muscle would normally achieve fast autonomous function.

PMID- 15201313
TI  - Protective effect of ifenprodil against spreading depression in the mouse
      entorhinal cortex.
AB  - In the brain, spreading depression (SD) is characterized by a large extracellular
      DC shift, a massive failure of ion homeostasis and a transient cessation of
      neuronal function. Clinically, SD is believed to be involved in various
      neurological disorders including migraine and cerebrovascular diseases. The
      propagation of cortical SD requires the release of glutamate, and N-methyl-D
      aspartate (NMDA) receptors play a crucial role in this process. Here, we have
      isolated the NMDA receptor-mediated component of extracellularly recorded field
      excitatory postsynaptic potentials (fEPSPs) in layers 2-3 of the entorhinal
      cortex of murine brain slices. In the absence of GABAA and AMPA receptor-mediated
      synaptic transmission, stimulation of layer 6 afferents every 15-90 s elicited
      spontaneous SD on average within 18.5 min after the start of the stimulation. In
      the presence of ifenprodil, an NR2B receptor subunit-selective NMDA receptor
      antagonist, the occurrence of SD was nearly abolished. Our results are consistent
      with an important role of NR2B subunits in triggering SD in the entorhinal
      cortex.

PMID- 15201314
TI  - Visual and saccade-related activity in macaque posterior cingulate cortex.
AB  - Previous neurophysiological studies have reported that neurons in posterior
      cingulate cortex (PCC) respond after eye movements, and that these responses may
      vary with ambient illumination. In monkeys, PCC neurons also respond after the
      illumination of large visual patterns but not after the illumination of small
      visual targets on either reflexive saccade tasks or peripheral attention tasks.
      These observations suggest that neuronal activity in PCC is modulated by
      behavioral context, which varies with the timing and spatial distribution of
      visual and oculomotor events. To test this hypothesis, we measured the spatial
      and temporal response properties of single PCC neurons in monkeys performing
      saccades in which target location and movement timing varied unpredictably.
      Specifically, an unsignaled delay between target onset and movement onset
      permitted us to temporally dissociate changes in PCC activity associated with
      either event. Response fields constructed from these data demonstrated that many
      PCC neurons were activated after the illumination of small contralateral visual
      targets, as well as after the onset of contraversive saccades guided by those
      targets. In addition, the PCC population maintained selectivity for small
      contralateral targets during delays of up to 600 ms. Overall, PCC activation was
      highly variable trial to trial and selective for a broad range of directions and
      amplitudes. Planar functions described response fields nearly as well as broadly
      tuned 2-dimensional Gaussian functions. Additionally, the overall responsiveness
      of PCC neurons decreased during delays when both a fixation stimulus and a
      saccade target were visible, suggesting a modulation by divided attention.
      Finally, the strength of the neuronal response after target onset was correlated
      with saccade accuracy on delayed-saccade trials. Thus PCC neurons may signal
      salient visual and oculomotor events, consistent with a role in visual orienting
      and attention.

PMID- 15201315
TI  - Temporal dynamics of shape analysis in macaque visual area V2.
AB  - The firing rate of visual cortical neurons typically changes substantially during
      a sustained visual stimulus. To assess whether, and to what extent, the
      information about shape conveyed by neurons in visual area V2 changes over the
      course of the response, we recorded the responses of V2 neurons in awake,
      fixating monkeys while presenting a diverse set of static shape stimuli within
      the classical receptive field. We analyzed the time course of various measures of
      responsiveness and stimulus-related response modulation at the level of
      individual cells and of the population. For a majority of V2 cells, the response
      modulation was maximal during the initial transient response (40-80 ms after
      stimulus onset). During the same period, the population response was relatively
      correlated, in that V2 cells tended to respond similarly to specific subsets of
      stimuli. Over the ensuing 80-100 ms, the signal-to-noise ratio of individual
      cells generally declined, but to a lesser degree than the evoked-response rate
      during the corresponding time bins, and the response profiles became decorrelated
      for many individual cells. Concomitantly, the population response became
      substantially decorrelated. Our results indicate that the information about
      stimulus shape evolves dynamically and relatively rapidly in V2 during static
      visual stimulation in ways that may contribute to form discrimination.

PMID- 15201316
TI  - Functional connectivity in layer IV local excitatory circuits of rat
      somatosensory cortex.
AB  - There are two types of excitatory neurons within layer IV of rat somatosensory
      cortex: star pyramidal (SP) and spiny stellate cells (SS). We examined the
      intrinsic properties and connectivity between these neurons to determine
      differences in function. Eighty-four whole cell recordings of pairs of neurons
      were examined in slices of rat barrel cortex at 36 +/- 1 degrees C. Only minimal
      differences in intrinsic properties were found; however, differences in synaptic
      strength could clearly be shown. Connections between homonymous pairs (SS-SS or
      SP-SP) had a higher efficacy than heteronymous connections. This difference was
      mainly a result of quantal content. In 42 pairs, synaptic dynamics were examined.
      Sequences of action potentials (3-20 Hz) in the presynaptic neuron consistently
      caused synaptic depression (E2/E1=0.53+/-0.18). The dominant component of
      depression was release-independent; this depression occurred even when preceding
      action potentials had failed to cause a response. The release-dependence of
      depression was target specific; in addition, release-independence was greater for
      postsynaptic SPs. In a subset of connections formed only between SP and any other
      cell type (43%), synaptic efficacy was dependent on the presynaptic membrane
      potential (Vm); at -55 mV, the connections were almost silent, whereas at -85 mV,
      transmission was very reliable. We suggest that, within layer IV, there is
      stronger efficacy between homonymous than between heteronymous excitatory
      connections. Under dynamic conditions, the functional connectivity is shaped by
      synaptic efficacy at individual connections, by Vm, and by the specificity in the
      types of synaptic depression.

PMID- 15201317
TI  - Choline transporter 1 maintains cholinergic function in choline acetyltransferase
      haploinsufficiency.
AB  - Choline acetyltransferase (ChAT), the enzyme that synthesizes the
      neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess
      in cholinergic neurons. The rate-limiting factor in ACh production is the
      provision of choline to ChAT. Cholinergic neurons are relatively unique in their
      expression of the choline transporter 1 (CHT1), which exhibits high-affinity for
      choline and catalyzes its uptake from the extracellular space to the neuron.
      Multiple lines of evidence indicate that the activity of CHT1 is a key
      determinant of choline supply for ACh synthesis. We examined the interaction of
      ChAT and ChT activity using mice heterozygous for a null mutation in the Chat
      gene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative
      to the wild type, but brain ACh levels as well as ACh content and depolarization
      evoked ACh release in hippocampal slices were normal. However, the amount of
      choline taken up by CHT1 and ACh synthesized de novo from choline transported by
      CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1
      protein in several regions of the CNS, were 50-100% higher in Chat+/- than in
      Chat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression
      of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in
      Chat+/- mice, contributing to the maintenance of apparently normal cholinergic
      function as reflected by normal performance of these mice in several behavioral
      assays.

PMID- 15201318
TI  - Sequences of abstract nonbiological stimuli share ventral premotor cortex with
      action observation and imagery.
AB  - Activation triggered by either observed or imagined actions suggests that the
      ventral premotor cortex (PMv) provides an action vocabulary that allows us to
      detect and anticipate basically invariant perceptual states in observed actions.
      In the present study, we tested the hypothesis that the same PMv region is also
      recruited by nonbiological (abstract) stimulus sequences as long as the temporal
      order of stimuli has to be processed. Using functional magnetic resonance
      imaging, we instructed participants to assess expected outcomes in observed
      actions [external biological cues (EB)], motor imagery [internal biological cues
      (IB)], or geometrical figure sequences [external nonbiological cues (EN)]. As
      hypothesized, we found that each condition elicited significant activation within
      PMv [left hemisphere, Brodman Area (BA) 6], in contrast to a sequential target
      detection control task. In addition, cue-specific activations were identified in
      areas that were only engaged for biologically (action) cued (EB, IB) and
      nonbiologically cued (EN) tasks. Biologically cued tasks elicited activations
      within inferior frontal gyri adjacent to PMv (BA 44/45), in the frontomedian
      wall, the extrastriate body area, posterior superior temporal sulci,
      somatosensory cortices, and the amygdala-hippocampal-area, whereas the
      nonbiologically cued task engaged presupplementary motor area, middle frontal
      gyri, intraparietal sulci, and caudate nuclei of the basal ganglia. In sum,
      findings point to a basic premotor contribution to the representation or
      processing of sequentially structured events, supplemented by different sets of
      areas in the context of either biological or nonbiological cues.

PMID- 15201319
TI  - Acetylcholine receptors direct rapsyn clusters to the neuromuscular synapse in
      zebrafish.
AB  - Clustering of nicotinic muscle acetylcholine receptors (AChRs) requires
      association with intracellular rapsyn, a protein with an intrinsic ability to
      self-cluster. Previous studies on sofa potato (sop), an AChR null line of
      zebrafish, have suggested that AChRs may play an active role in subsynaptic
      localization of rapsyn clusters. To test this proposal directly, we identified
      and cloned the gene responsible for the sop phenotype and then attempted to
      rescue subsynaptic localization of the receptor-rapsyn complex in mutant fish.
      sop contains a leucine to proline mutation at position 28, near the N terminus of
      the zebrafish AChR delta subunit. Transient expression of mutant delta subunit in
      sop fish was unable to restore surface expression of muscle AChRs. In contrast,
      expression of wild-type delta subunit restored the ability of muscle to assemble
      surface receptors along with the ability of fish to swim. Most importantly, the
      ability of rapsyn clusters to localize effectively to subsynaptic sites also was
      rescued in large part. Our results point to direct involvement of the AChR
      molecule in restricting receptor-rapsyn clusters to the synapse.

PMID- 15201320
TI  - Drosophila serpin 4 functions as a neuroserpin-like inhibitor of subtilisin-like
      proprotein convertases.
AB  - The proteolytic processing of neuropeptide precursors is believed to be regulated
      by serine proteinase inhibitors, or serpins. Here we describe the molecular
      cloning and functional expression of a novel member of the serpin family, Serine
      protease inhibitor 4 (Spn4), that we propose is involved in the regulation of
      peptide maturation in Drosophila. The Spn4 gene encodes at least two different
      serpin proteins, generated by alternate splicing of the last coding exon. The
      closest vertebrate homolog to Spn4 is neuroserpin. Like neuroserpin, one of the
      Spn4 proteins (Spn4.1) features a unique C-terminal extension, reminiscent of an
      endoplasmic reticulum (ER) retention signal; however, Spn4.1 and neuroserpin have
      divergent reactive site loops, with Spn4.1 showing a generic recognition site for
      furin/SPC1, the founding member of the intracellularly active family of
      subtilisin-like proprotein convertases (SPCs). In vitro, Spn4.1 forms SDS-stable
      complexes with the SPC furin and directly inhibits it. When Spn4.1 is
      overexpressed in specific peptidergic cells of Drosophila larvae, the animals
      exhibit a phenotype consistent with disrupted neuropeptide processing. This
      observation, together with the unique combination of an ER-retention signal, a
      target sequence for SPCs in the reactive site loop, and the in vitro inhibitory
      activity against furin, strongly suggests that Spn4.1 is an intracellular
      regulator of SPCs.

PMID- 15201321
TI  - Endogenous glucocorticoids are essential for maintaining prefrontal cortical
      cognitive function.
AB  - Glucocorticoid hormones are important in the maintenance of many brain functions.
      Although their receptors are distributed abundantly throughout the brain,
      including the prefrontal cortex (PFC), it is not clear how glucocorticoid
      functions, particularly with regard to cognitive processing in the PFC. There is
      evidence of PFC cognitive deficits such as working memory impairment in several
      stress-related neuropsychiatric disorders, including depression, schizophrenia,
      and Parkinson's disease. Disruption of the hypothalamo-pituitary-adrenal (HPA)
      system, which is characterized by attenuated glucocorticoid negative feedback, is
      also observed. In rats, chronic stress induces working memory impairment as a
      result of decreased dopaminergic transmission in the PFC. These chronically
      stressed rats also show HPA disruption; this is caused in part by a reduced
      glucocorticoid response in the PFC. These findings implicate reduced
      glucocorticoid actions in working memory impairment. In the present study, we
      examined the effects of the suppression of endogenous glucocorticoids by
      adrenalectomy (ADX) on working memory in rats and explored the involvement of PFC
      dopaminergic activities in memory. The ADX impaired working memory, decreased
      dopamine release, and upregulated D1 receptors in the PFC. These dysfunctions
      were prevented by corticosterone replacement that reproduced normal physiological
      plasma levels, indicating that suppression of glucocorticoids causes these
      dysfunctions. Moreover, the ADX-induced working memory impairment was ameliorated
      by intra-PFC infusions of a D1 receptor agonist, SKF 81297. Thus, suppression of
      glucocorticoids impaired working memory through a D1 receptor-mediated
      hypodopaminergic mechanism in the PFC. This finding indicates that endogenous
      glucocorticoids are essential for maintaining PFC cognitive function and suggests
      that HPA disruption contributes to PFC cognitive deficits.

PMID- 15201322
TI  - Brain mechanisms for inferring deceit in the actions of others.
AB  - During social interactions, it is important to judge accurately whether a person
      is honest or deceitful. We often use nonverbal cues to infer whether others are
      trying to deceive us. Using functional magnetic resonance imaging, we studied
      subjects watching videos of actors lifting a box and judged whether or not the
      actors were trying to deceive them concerning the real weight of the box. When
      the subjects judged the actions as reflecting deceptive intention, there was
      activation of the amygdala and rostral anterior cingulate cortex. These areas
      were not activated when subjects made judgements about the beliefs rather than
      the intentions of others. We suggest that these activations reflect the
      observers' judgements of social intentions toward themselves and might reflect an
      emotional response to being deceived.

PMID- 15201323
TI  - The role of the central nucleus of the amygdala in mediating fear and anxiety in
      the primate.
AB  - Numerous studies demonstrate that the rhesus monkey is an excellent species with
      which to investigate mechanisms underlying human emotion and psychopathology. To
      examine the role of the central nucleus of the amygdala (CeA) in mediating the
      behavioral and physiological responses associated with fear and anxiety, we used
      rhesus monkeys to assess the effects of excitotoxic lesions of the CeA.
      Behavioral and physiological responses of nine monkeys with bilateral CeA
      destruction (ranging from 46 to 98%) were compared with five animals with
      asymmetric lesions (42-86.5% destruction on the most affected side) and with 16
      unoperated controls. Results suggest that similar to rodent species, the primate
      CeA plays a role in mediating fear- and anxiety-related behavioral and endocrine
      responses. Compared with controls and the asymmetric-lesion group, bilaterally
      lesioned monkeys displayed significantly less fear-related behavior when exposed
      to a snake and less freezing behavior when confronted by a human intruder. In
      addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin
      releasing factor (CRF), and both lesioned groups had decreased plasma ACTH
      concentrations. In contrast to these findings, patterns of asymmetric frontal
      brain electrical activity, as assessed by regional scalp EEG, did not
      significantly differ between control and lesioned monkeys. These findings suggest
      that in primates, the CeA is involved in mediating fear- and anxiety-related
      behavioral and pituitary-adrenal responses as well as in modulating brain CRF
      activity.

PMID- 15201324
TI  - NADPH oxidase contributes to angiotensin II signaling in the nucleus tractus
      solitarius.
AB  - Angiotensin II (AngII), acting through angiotensin type 1 (AT1) receptors, exerts
      powerful effects on central autonomic networks regulating cardiovascular
      homeostasis and fluid balance; however, the mechanisms of AngII signaling in
      functionally defined central autonomic neurons have not been fully elucidated. In
      vascular cells, reactive oxygen species (ROS) generated by the enzyme NADPH
      oxidase play a major role in AngII signaling. Thus, we sought to determine
      whether NADPH oxidase is present in central autonomic neurons and, if so, whether
      NADPH oxidase-derived ROS are involved in the effects of AngII on these neurons.
      The present studies focused on the intermediate dorsomedial nucleus of the
      solitary tract (dmNTS) because this region receives autonomic afferents via the
      vagus nerve and is an important site of AngII actions. Using double-label
      immunoelectron microscopy, we found that the essential NADPH oxidase subunit
      gp91phox is present in somatodendric and axonal profiles containing AT1
      receptors. The gp91phox-labeled dendrites received inputs from large axon
      terminals resembling vagal afferents. In parallel experiments using patch clamp
      of dissociated NTS neurons anterogradely labeled via the vagus, we found that
      AngII potentiates the L-type Ca2+ currents, an effect mediated by AT1 receptors
      and abolished by the ROS scavenger Mn(III) tetrakis (4-benzoic acid) porphyrin
      chloride. The NADPH oxidase assembly inhibitor apocynin and the peptide inhibitor
      gp91phox docking sequence, but not its scrambled version, also blocked the
      potentiation. The results provide evidence that NADPH oxidase-derived ROS are
      involved in the effects of AngII on Ca2+ influx in NTS neurons receiving vagal
      afferents and support the notion that ROS are important signaling molecules in
      central autonomic networks.

PMID- 15201325
TI  - Synaptic contributions to focal and widespread spatiotemporal dynamics in the
      isolated rat subiculum in vitro.
AB  - The subiculum, which has a strategic position in controlling hippocampal
      activity, is receiving significant attention in epilepsy research. However, the
      functional organization of subicular circuits remains unknown. Here, we combined
      different recording and analytical methods to study focal and widespread
      population activity in the isolated subiculum in zero Mg2+ media. Patch and field
      recordings were combined to examine the contribution of different cell types to
      population activity. The properties of cells leading field activity were
      examined. Predictive factors for a cell to behave as leader included exhibiting
      the bursting phenotype, displaying a low firing threshold, and having more distal
      apical dendrites. A subset of bursting cells constituted the first glutamatergic
      type that led a recruitment process that subsequently activated additional
      excitatory as well as inhibitory cells. This defined a sequence of synaptic
      excitation and inhibition that was studied by measuring the associated
      conductance changes and the evolution of the composite reversal potential. It is
      shown that inhibition was time-locked to excitation, which shunted excitatory
      inputs and suppressed firing during focal activity. This was recorded
      extracellularly as a multi-unit ensemble of active cells, the spatial boundaries
      of which were controlled by inhibition in contrast to widespread epileptiform
      activity. Focal activity was not dependent on the preparation or the
      developmental state because it was also recorded under 5 mm [K+]o and in adult
      tissue. Our data indicate that the subicular networks can be spontaneously
      organized as leader-follower local circuits in which excitation is mainly driven
      by a subset of bursting cells and inhibition controls spatiotemporal firing.

PMID- 15201326
TI  - Uropathic observations in mice expressing a constitutively active point mutation
      in the 5-HT3A receptor subunit.
AB  - Mutant mice with a hypersensitive serotonin (5-HT)3A receptor were generated
      through targeted exon replacement. A valine to serine mutation (V13'S) in the
      channel-lining M2 domain of the 5-HT3A receptor subunit rendered the 5-HT3
      receptor 70-fold more sensitive to serotonin and produced constitutive activity
      when combined with the 5-HT3B subunit. Mice homozygous for the mutant allele (5
      HT3Avs/vs) had decreased levels of 5-HT3A mRNA. Measurements on sympathetic
      ganglion cells in these mice showed that whole-cell serotonin responses were
      reduced, and that the remaining 5-HT3 receptors were hypersensitive. Male 5
      HT3Avs/vs mice died at 2-3 months of age, and heterozygous (5-HT3Avs/+) males and
      homozygous mutant females died at 4-6 months of age from an obstructive uropathy.
      Both male and female 5-HT3A mutant mice had urinary bladder mucosal and smooth
      muscle hyperplasia and hypertrophy, whereas male mutant mice had additional
      prostatic smooth muscle and urethral hyperplasia. 5-HT3A mutant mice had marked
      voiding dysfunction characterized by a loss of micturition contractions with
      overflow incontinence. Detrusor strips from 5-HT3Avs/vs mice failed to contract
      to neurogenic stimulation, despite overall normal responses to a cholinergic
      agonist, suggestive of altered neuronal signaling in mutant mouse bladders.
      Consistent with this hypothesis, decreased nerve fiber immunoreactivity was
      observed in the urinary bladders of 5-HT3Avs/vs compared with 5-HT3A wild-type (5
      HT3A+/+) mice. These data suggest that persistent activation of the
      hypersensitive and constitutively active 5-HT3A receptor in vivo may lead to
      excitotoxic neuronal cell death and functional changes in the urinary bladder,
      resulting in bladder hyperdistension, urinary retention, and overflow
      incontinence.

PMID- 15201327
TI  - Morphine-induced changes in delta opioid receptor trafficking are linked to
      somatosensory processing in the rat spinal cord.
AB  - An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to
      assess the distribution and regulation of pharmacologically available delta
      opioid receptors (deltaORs) in the rat lumbar (L4-5) spinal cord. Under basal
      conditions, intrathecal injection of Fluo-DLT resulted in the labeling of
      numerous deltaOR-internalizing neurons throughout dorsal and ventral horns. The
      distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent
      with that of deltaOR-expressing neurons, as revealed by in situ hybridization and
      immunohistochemistry, suggesting that a large proportion of these cells was
      responsive to intrathecally administered deltaOR agonists. Pretreatment of rats
      with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled
      perikaryal profiles within the dorsal horn. These changes were not accompanied by
      corresponding augmentations in either deltaOR mRNA or (125)I-deltorphin-II
      binding levels, suggesting that they were attributable to higher densities of
      cell surface deltaOR available for internalization rather than to enhanced
      production of the receptor. Unilateral dorsal rhizotomy also resulted in
      increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared
      with the side contralateral to the deafferentation or to non-deafferented
      controls, suggesting that deltaOR trafficking in dorsal horn neurons may be
      regulated by afferent inputs. Furthermore, morphine treatment no longer increased
      Fluo-DLT internalization on either side of the spinal cord after unilateral
      dorsal rhizotomy, indicating that microOR-induced changes in the cell surface
      availability of deltaOR depend on the integrity of primary afferent inputs.
      Together, these results suggest that regulation of deltaOR responsiveness through
      microOR activation in this region is linked to somatosensory information
      processing.

PMID- 15201328
TI  - Improvements in the signal-to-noise ratio of motor cortex cells distinguish early
      versus late phases of motor skill learning.
AB  - There are numerous experience-driven changes in cortical circuitry that correlate
      with improved performance. Improved motor performance on a reach-to-grasp task in
      rodents is associated with changes in long-term potentiation (LTP),
      synaptogenesis, and movement representations in primary motor cortex (M1) by
      training days 3, 7, and 10, respectively. We recorded single-cell activity
      patterns in M1 during reach-to-grasp training to test how neural-spiking
      properties change with respect to LTP, synaptogenesis, and motor map changes. We
      also tested how neural-spiking changes relate directly to improved performance by
      monitoring muscle activity patterns. We found that signal-to-noise ratios (SNRs)
      of M1 spiking were significantly improved with practice but only after 7-12 d.
      Three sources of noise were assessed: signal-dependent noise exemplified by the
      slope of the relationship between mean spike count and count variance per burst,
      signal-independent noise exemplified by the offset of this relationship, and
      background firing rates before and after bursts. Signal-independent noise and pre
      burst firing rates were reduced with practice. Early performance gains (days 1-6)
      were dissociated from SNR improvements, whereas later performance gains (day 7
      12) were related directly to the magnitude of improvement in both muscle
      recruitment reliability and success rates. With training, an increased number of
      cells exhibited firing rates that were correlated with muscle recruitment
      patterns, with lags suggesting a primary direction of influence from M1 to
      muscles. These results suggest a functional linkage from local synaptogenesis in
      M1 to improved spiking reliability of M1 cells to more reliable recruitment of
      muscles and finally to improved behavioral performance.

PMID- 15201329
TI  - The juvenile myoclonic epilepsy GABA(A) receptor alpha1 subunit mutation A322D
      produces asymmetrical, subunit position-dependent reduction of heterozygous
      receptor currents and alpha1 subunit protein expression.
AB  - Individuals with autosomal dominant juvenile myoclonic epilepsy are heterozygous
      for a GABA(A) receptor alpha1 subunit mutation (alpha1A322D). GABA(A) receptor
      alphabetagamma subunits are arranged around the pore in a beta-alpha-beta-alpha
      gamma sequence (counterclockwise from the synaptic cleft). Therefore, each alpha1
      subunit has different adjacent subunits, and heterozygous expression of
      alpha1(A322D), beta, and gamma subunits could produce receptors with four
      different subunit arrangements: beta-alpha1-beta-alpha1-gamma (wild type); beta
      alpha1(A322D)-beta-alpha1-gamma (Het(betaalphabeta)); beta-alpha1-beta
      alpha1(A322D)-gamma (Het(betaalphagamma));beta-alpha1(A322D)-beta-alpha1(A322D)
      gamma (homozygous). Expression of a 1:1 mixture of wild-type andalpha1(A322D)
      subunits with beta2S and gamma2S subunits (heterozygous transfection) produced
      smaller currents than wild type and much larger currents than homozygous mutant
      transfections. Western blot and biotinylation assays demonstrated that the amount
      of total and surface alpha1 subunit from heterozygous transfections was also
      intermediate between those of wild-type and homozygous mutant transfections.
      alpha1(A322D) mutations were then made in covalently tethered triplet (gamma2S
      beta2S-alpha1) and tandem (beta2S-alpha1) concatamers to target selectively
      alpha1(A322D) to each of the asymmetric alpha1 subunits. Coexpression of mutant
      and wild-type concatamers resulted in expression of either Het(betaalphabeta) or
      Het(betaalphagamma) receptors. Het(betaalphabeta) currents were smaller than wild
      type and much larger than Het(betaalphagamma) and homozygous currents.
      Furthermore, Het(betaalphabeta) transfections contained less beta-alpha
      concatamer than wild type but more than both Het(betaalphagamma) and homozygous
      mutant transfections. Thus, whole-cell currents and protein expression of
      heterozygous alpha1(A322D)beta2Sgamma2S receptors depended on the position of the
      mutant alpha1 subunit, and GABA(A) receptor currents in heterozygous individuals
      likely result primarily from wild-type and Het(betaalphabeta) receptors with
      little contribution from Het(betaalphagamma) and homozygous receptors.

PMID- 15201330
TI  - Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic
      basal forebrain neurons.
AB  - Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic
      effects of amyloidbeta protein (Abeta) is one of the major, but still elusive,
      therapeutic goals of current research in Alzheimer's disease (AD). To date, no
      receptor has been unequivocally identified for Abeta. Human amylin, which acts
      via a receptor composed of the calcitonin receptor-like receptor and a receptor
      associated membrane protein, possesses amyloidogenic properties and has a profile
      of neurotoxicity that is strikingly similar to Abeta. In this study, using
      primary cultures of rat cholinergic basal forebrain neurons, we show that acetyl
      [Asn30, Tyr32] sCT(8-37) (AC187), an amylin receptor antagonist, blocks Abeta
      induced neurotoxicity. Treatment of cultures with AC187 before exposure to Abeta
      results in significantly improved neuronal survival as judged by MTT and live
      dead cell assays. Quantitative measures of Abeta-evoked apoptotic cell death,
      using Hoechst and phosphotidylserine staining, confirm neuroprotective effects of
      AC187. We also demonstrate that AC187 attenuates the activation of initiator and
      effector caspases that mediate Abeta-induced apoptotic cell death. These data are
      the first to show that expression of Abeta toxicity may occur through the amylin
      receptor and suggest a novel therapeutic target for the treatment of AD.

PMID- 15201331
TI  - Ligand-dependent activation of Slo family channels is defined by interchangeable
      cytosolic domains.
AB  - Large-conductance Ca2+- and voltage-regulated K+ channels (Slo1 BK-type) are
      controlled by two physiological stimuli, membrane voltage and cytosolic Ca2+.
      Regulation by voltage is similar to that in voltage-dependent K+ channels,
      arising from positively charged amino acids primarily within the S4 transmembrane
      helices. The basis for regulation by Ca2+ remains controversial. One viewpoint
      suggests that the extensive cytosolic C terminus contains the Ca2+ regulatory
      machinery, whereas another suggests that the pore-forming module contains the
      Ca2+-sensing elements. To address this issue, we take advantage of another Slo
      family member, the pH-regulated homolog Slo3. We reason that if the ligand
      sensing apparatus is uniquely associated with a particular domain (either the
      pore or the cytosolic domain), exchange of those domains between Slo1 and Slo3
      should result in exchange of ligand dependence in association with the key
      domain. The results show that the Slo3 cytosolic module confers pH-dependent
      regulation on the Slo1 pore module, whereas the Slo1 cytosolic module confers
      Ca2+-dependent regulation on the Slo3 pore module. Thus, ligand-specific
      regulation is defined by interchangeable cytosolic regulatory modules.

PMID- 15201332
TI  - Paradoxical potentiation of neuronal T-type Ca2+ current by ATP at resting
      membrane potential.
AB  - Despite the marked influence on neuronal physiology of the low-voltage activated
      T-type Ca(2+) currents, little is known about the intracellular pathways and
      neurotransmitters involved in their regulations. Here, we report that in
      thalamocortical neurons a phosphorylation mechanism induces an increase both in
      the current amplitude (1.5 +/- 0.27-fold in the ventrobasal nucleus) and its
      inactivation kinetics. Dialysis of the neuron with an ATP-free solution
      suppresses the T-current potentiation, whereas it becomes irreversible in the
      presence of ATPgammaS. Phosphorylation occurs when the channels are inactivated
      and is slowly removed when they recover from inactivation and remain in closed
      states (time constants of the induction and removal of the potentiation: 579 +/-
      143 msec and 4.9 +/- 1.1 sec, respectively, at 25 degrees C). The resulting
      apparent voltage sensitivity of this regulation follows the voltage dependence of
      the current steady-state inactivation. Thus, the current is paradoxically
      inhibited when the preceding hyperpolarization is lengthened, and maximal
      currents are generated after transient hyperpolarizations with a duration (0.7
      1.5 sec) that is defined by the balance between the kinetics of the
      dephosphorylation and deinactivation. In addition, the phosphorylation will
      facilitate the generation of T current at resting membrane potential. This
      potentiation, which is specific to sensory thalamocortical neurons, would
      markedly influence the electroresponsiveness of these neurons and represent the
      first evidence of a regulation of native Cav3.1 channels.

PMID- 15201333
TI  - Histone modifications at gene promoter regions in rat hippocampus after acute and
      chronic electroconvulsive seizures.
AB  - The mechanism of action of electroconvulsive seizures (ECS), one of the most
      effective treatments of major depression, may involve the regulation of gene
      expression. Chromatin remodeling at gene promoter regions is increasingly
      recognized as a key control point of gene expression and may, therefore, partly
      mediate acute and chronic effects of ECS on gene activity. Here, we assayed how
      posttranslational modifications of histones, a major form of chromatin
      remodeling, are altered at several gene promoters in rat hippocampus at 30 min, 2
      hr, and 24 hr after acute or repeated ECS. We performed chromatin
      immunoprecipitation assays to measure levels of histone H3 and H4 acetylation and
      phosphoacetylation at the promoters of the c-fos, BDNF, and CREB (cAMP response
      element-binding protein) genes, the expression of which is altered by ECS. We
      found that, with few exceptions, levels of H4 acetylation correlated with mRNA
      levels for c-fos, BDNF, and CREB throughout the acute and chronic time course
      study, whereas acetylation and phosphoacetylation of H3 were detected more
      selectively. Our findings suggest that the chronic downregulation of c-fos
      transcription, observed in this study, may be achieved at the level of H4
      acetylation, whereas chronic upregulation of BDNF transcription may be sustained
      via control of H3 acetylation, selectively at the BDNF P3 and P4 promoters. These
      data provide the first in vivo demonstration of the involvement of chromatin
      remodeling in ECS-induced regulation of gene expression in the brain and will
      help in understanding the mechanisms underlying the efficacy of ECS in the
      treatment of depression.

PMID- 15201334
TI  - Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed
      death in hippocampal neurons.
AB  - In neurons, excitotoxic stimulation induces mitochondrial calcium overload and
      the release of pro-apoptotic proteins, which triggers delayed cell death. The
      precise mechanisms of apoptogen release, however, remain controversial. To
      characterize the linkage between mitochondrial calcium load and cell
      vulnerability, and to test the hypothesis that only a subpopulation of
      mitochondria damaged by calcium overload releases apoptogens, we have measured
      directly the concentrations of total Ca (free plus bound) in individual
      mitochondria and monitored in parallel structural changes and the subcellular
      localization of pro-apoptotic cytochrome c after NMDA overstimulation in cultured
      hippocampal neurons. Beyond transient elevation of cytosolic calcium and
      perturbation of Na+/K+ homeostasis, NMDA stimulation induced dramatic, but mainly
      reversible, changes in mitochondria, including strong calcium elevation, membrane
      potential depolarization, and variable swelling. Elevation of matrix Ca in the
      approximately one-third of mitochondria that were strongly swollen, as well as
      the absence of swelling when Ca2+ entry was abolished, indicate an essential role
      for Ca overload. Shortly after NMDA exposure, cytochrome c, normally localized to
      mitochondria, became diffusely distributed in the cytoplasm, coincident with the
      appearance of severely swollen mitochondria with ruptured outer membranes; under
      these conditions, cytochrome c was retained in intact mitochondria, implying that
      it was released mainly from damaged mitochondria. Consistent with the role of
      mitochondrial Ca overload, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone
      decreased Ca accumulation, prevented cytochrome c release, and was
      neuroprotective. These results support a mechanism in which delayed excitotoxic
      death involves apoptogen release from a subpopulation of calcium-overloaded
      mitochondria, whereas other, undamaged mitochondria maintain normal function.

PMID- 15201335
TI  - Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses
      by modulating three types of presynaptic calcium channels.
AB  - At many central synapses, endocannabinoids released by postsynaptic cells inhibit
      neurotransmitter release by activating presynaptic cannabinoid receptors. The
      mechanisms underlying this important means of synaptic regulation are not fully
      understood. It has been shown at several synapses that endocannabinoids inhibit
      neurotransmitter release by reducing calcium influx into presynaptic terminals.
      One hypothesis maintains that endocannabinoids indirectly reduce calcium influx
      by modulating potassium channels and narrowing the presynaptic action potential.
      An alternative hypothesis is that endocannabinoids directly and selectively
      inhibit N-type calcium channels in presynaptic terminals. Here we test these
      hypotheses at the granule cell to Purkinje cell synapse in cerebellar brain
      slices. By monitoring optically the presynaptic calcium influx (Ca(influx)) and
      measuring the EPSC amplitudes, we found that cannabinoid-mediated inhibition
      arises solely from reduced presynaptic Ca(influx). Next we found that cannabinoid
      receptor activation does not affect the time course of presynaptic calcium entry,
      indicating that the reduced Ca(influx) reflects inhibition of presynaptic calcium
      channels. Finally, we assessed the classes of presynaptic calcium channels
      inhibited by cannabinoid receptor activation via peptide calcium channel
      antagonists. Previous studies established that N-type, P/Q-type, and R-type
      calcium channels are all present in granule cell presynaptic boutons. We found
      that cannabinoid activation reduced Ca(influx) through N-type, P/Q-type, and R
      type calcium channels to 29, 60, and 55% of control, respectively. Thus, rather
      than narrowing the presynaptic action potential or exclusively modulating N-type
      calcium channels, CB1 receptor activation inhibits synaptic transmission by
      modulating all classes of calcium channels present in the presynaptic terminal of
      the granule cell to Purkinje cell synapse.

PMID- 15201337
TI  - Lhx6 regulates the migration of cortical interneurons from the ventral
      telencephalon but does not specify their GABA phenotype.
AB  - The LIM homeodomain family of transcription factors is involved in many processes
      in the developing CNS, ranging from cell fate specification to connectivity. A
      member of this family of transcription factors, lhx6, is expressed in the medial
      ganglionic eminence (MGE) of the ventral telencephalon, where the vast majority
      of cortical interneurons are generated. Its expression in the GABA-containing MGE
      cells that migrate to the cortex suggests that this gene uniquely or in
      combination with other transcription factors may play a role in the neurochemical
      identity and migration of these neurons. We performed loss of function studies
      for lhx6 in mouse embryonic day 13.5 brain slices and dissociated MGE neuronal
      cultures using Lhx6-targeted small interfering RNA produced by a U6 promoter
      driven vector. We found that silencing lhx6 impeded the tangential migration of
      interneurons into the cortex, although it did not obstruct their dispersion
      within the ganglionic eminence. Blocking lhx6 expression in dissociated MGE
      cultured neurons did not interfere with the production of GABA or its
      synthesizing enzyme. These results indicate that lhx6, unlike the closely related
      member lhx7, does not regulate neurotransmitter choice in interneurons but plays
      an important role in their migration from the ventral telencephalon to the
      neocortex.

PMID- 15201336
TI  - Cone photoreceptors in bass retina use two connexins to mediate electrical
      coupling.
AB  - Electrical coupling via gap junctions is a common property of CNS neurons. In
      retinal photoreceptors, coupling plays important roles in noise filtering,
      intensity coding, and spatial processing. In many vertebrates, coupling is
      regulated during the course of light adaptation. To understand the mechanisms of
      this regulation, we studied photoreceptor gap junction proteins. We found that
      two connexins were expressed in bass cone photoreceptors. Connexin 35 (Cx35) mRNA
      was present in many cell types, including photoreceptors and amacrine, bipolar,
      and a few ganglion cells. Antibodies to Cx35 labeled abundant gap junctions in
      both the inner and outer plexiform layers. In the outer plexiform layer, numerous
      plaques colocalized with cone telodendria at crossing contacts and tip-to-tip
      contacts. Cx34.7 mRNA was found predominantly in the photoreceptor layer,
      primarily in cones. Cx34.7 immunolabeling was limited to small plaques
      immediately beneath cone pedicles and did not colocalize with Cx35. Cx34.7
      plaques were associated with a dense complex of cone membrane beneath the
      pedicles, including apparent contacts between telodendria and cone pedicles.
      Tracer coupling studies of the connexins expressed in HeLa cells showed that
      coupling through Cx35 gap junctions was reduced by protein kinase A (PKA)
      activation and enhanced by PKA inhibition through a greater than fivefold
      activity range. Cx34.7 was too poorly expressed to study. PKA regulation suggests
      that coupling through Cx35 gap junctions can be controlled dynamically through
      dopamine receptor pathways during light adaptation. If Cx34.7 forms functional
      cell-cell channels between cones, it would provide a physically separate pathway
      for electrical coupling.

PMID- 15201338
TI  - Retraction.

PMID- 15201339
TI  - Nck-dependent activation of extracellular signal-regulated kinase-1 and
      regulation of cell survival during endoplasmic reticulum stress.
AB  - In response to stress, the endoplasmic reticulum (ER) signaling machinery
      triggers the inhibition of protein synthesis and up-regulation of genes whose
      products are involved in protein folding, cell cycle exit, and/or apoptosis. We
      demonstrate that the misfolding agents azetidine-2-carboxylic acid (Azc) and
      tunicamycin initiate signaling from the ER, resulting in the activation of Jun-N
      terminal kinase, p44(MAPK)/extracellular signal-regulated kinase-1 (ERK-1), and
      p38(MAPK) through IRE1alpha-dependent mechanisms. To characterize the ER proximal
      signaling events involved, immuno-isolated ER membranes from rat fibroblasts
      treated with ER stress inducers were used to reconstitute the activation of the
      stress-activated protein kinase/mitogen-activate protein kinase (MAPK) pathways
      in vitro. This allowed us to demonstrate a role for the SH2/SH3 domain containing
      adaptor Nck in ERK-1 activation after Azc treatment. We also show both in vitro
      and in vivo that under basal conditions ER-associated Nck represses ERK-1
      activation and that upon ER stress this pool of Nck dissociates from the ER
      membrane to allow ERK-1 activation. Moreover, under the same conditions, Nck-null
      cells elicit a stronger ERK-1 activation in response to Azc stress, thus,
      correlating with an enhanced survival phenotype. These data delineate a novel
      mechanism for the regulation of ER stress signaling to the MAPK pathway and
      demonstrate a critical role for Nck in ER stress and cell survival.

PMID- 15201340
TI  - Expression of a major surface protein of Trypanosoma brucei insect forms is
      controlled by the activity of mitochondrial enzymes.
AB  - In cycling between the mammalian host and the tsetse fly vector, trypanosomes
      undergo major changes in energy metabolism and surface coat composition. Early
      procyclic (insect) forms in the tsetse fly midgut are coated by glycoproteins
      known as EP and GPEET procyclins. EP expression continues in late procyclic
      forms, whereas GPEET is down-regulated. In culture, expression of GPEET is
      modulated by glycerol or glucose. Here, we demonstrate that a glycerol-responsive
      element of 25 nucleotides within the 3' untranslated region of GPEET mRNA also
      controls expression by glucose and during development in the fly. In
      trypanosomes, mitochondrial ATP is produced mainly by the acetate: succinate-CoA
      transferase/succinyl-CoA synthetase (ASCT) cycle, the citric acid cycle, and the
      cytochromes. Silencing of the pyruvate dehydrogenase or succinyl-CoA synthetase
      from the ASCT cycle by RNA interference induces reexpression of GPEET in late
      procyclic forms, whereas inhibition of the citric acid cycle or the cytochromes
      has no effect. In contrast, inhibition of the alternative oxidase, the second
      branch of the electron transport chain, with salicylhydroxamic acid overrides the
      effect of glucose or glycerol and causes a reduction in the level of GPEET mRNA.
      Our results reveal a new mechanism by which expression of a surface glycoprotein
      is controlled by the activity of mitochondrial enzymes.

PMID- 15201342
TI  - Pentoxifylline prevents spontaneous brain ischemia in stroke-prone rats.
AB  - Anti-inflammatory properties of pentoxifylline (PTX) have recently been
      described. Spontaneously hypertensive stroke-prone rats (SHRSP) constitute an
      animal model that develops an inflammatory condition that precedes the appearance
      of brain abnormalities. The aim of the present investigation was to assess: 1)
      the efficacy of PTX treatment in protecting the neural system in SHRSP, and 2)
      how its anti-inflammatory properties might be involved in this effect. Male SHRSP
      fed with a permissive diet received no drug or PTX (100 or 200 mg/kg/day). Brain
      abnormalities detected by magnetic resonance imaging developed spontaneously in
      control rats after 42 +/- 3 days, whereas in rats treated with 100 mg/kg/day PTX,
      abnormalities developed in only 80% of the animals and only after 70 to 80 days.
      Treatment with a higher dose of PTX (200 mg/kg/day) completely protected the
      brain from abnormal development. The drug treatment prevented the accumulation of
      macrophages or CD4+ positive cells, the activation of glia in brain tissues, and
      the appearance of inflammatory proteins and thiobarbituric acid-reactive
      substances in body fluids. PTX treatment did induce a greater increase of serum
      tumor necrosis factor-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL
      6 induced by in vivo administration of lipopolysaccharide (LPS), which suggests a
      protective role for TNF-alpha. PTX also exerted protective effects when it was
      administered after the first occurrence of proteinuria (>40 mg/day). These data
      indicate that PTX treatment dose-dependently prevents the occurrence of
      spontaneous brain damage by reducing inflammatory events. We also hypothesize
      that the increase of TNF-alpha by PTX treatment represents a protective mechanism
      in SHRSP.

PMID- 15201341
TI  - Links between CD147 function, glycosylation, and caveolin-1.
AB  - Cell surface CD147 shows remarkable variations in size (31-65 kDa) because of
      heterogeneous N-glycosylation, with the most highly glycosylated forms
      functioning to induce matrix metalloproteinase (MMP) production. Here we show
      that all three CD147 N-glycosylation sites make similar contributions to both
      high and low glycoforms (HG- and LG-CD147). l-Phytohemagglutinin lectin binding
      and swainsonine inhibition experiments indicated that HG-CD147 contains N
      acetylglucosaminyltransferase V-catalyzed, beta1,6-branched, polylactosamine-type
      sugars, which account for its excess size. Therefore, CD147, which is itself
      elevated on invasive tumor cells, may make a major contribution to the abundance
      of beta1,6-branched polylactosamine sugars that appear on invasive tumor cells.
      It was shown previously that caveolin-1 associates with CD147, thus inhibiting
      CD147 self-aggregation and MMP induction; now we show that caveolin-1 associates
      with LG-CD147 and restricts the biosynthetic conversion of LG-CD147 to HG-CD147.
      In addition, HG-CD147 (but not LG-CD147) was preferentially captured as a
      multimer after treatment of cells with a homobifunctional cross-linking agent and
      was exclusively recognized by monoclonal antibody AAA6, a reagent that
      selectively recognizes self-associated CD147 and inhibits CD147-mediated MMP
      induction. In conclusion, we have 1) determined the biochemical basis for the
      unusual size variation in CD147, 2) established that CD147 is a major carrier of
      beta1,6-branched polylactosamine sugars on tumor cells, and 3) determined that
      caveolin-1 can inhibit the conversion of LG-CD147 to HG-CD147. Because it is HG
      CD147 that self-aggregates and stimulates MMP induction, we now have a mechanism
      to explain how caveolin-1 inhibits these processes. These results help explain
      the previously established tumor suppressor functions of caveolin-1.

PMID- 15201343
TI  - Fenofibrate, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 close KATP
      channels and induce insulin secretion.
AB  - It is known that peroxisome proliferator-activated receptor-gamma (PPAR-gamma)
      ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into
      pancreatic beta-cells, but the precise mechanisms are not clear. The effects of
      PPAR-alpha ligands on pancreatic beta-cells also remain unclear. We investigated
      the effects of PPAR-alpha ligands (fenofibrate and fenofibric acid), a PPAR-gamma
      ligand (troglitazone), and an endogenous ligand of PPAR-gamma [15-deoxy
      Delta12,14-prostaglandin J2 (15-deoxy-Delta12,14-PGJ2)] on KATP channel activity
      in clonal hamster insulinoma cell line, HIT-T15 cells. As assessed by whole-cell
      patch clamp, fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14
      PGJ2 reduced the KATP channel currents, and inhibition continued after washout of
      these agents. The concentration-response curves of fenofibrate, fenofibric acid,
      troglitazone, and 15-deoxy-Delta12,14-PGJ2 showed half-maximal inhibition of KATP
      channel currents (IC50) at 3.26, 94, 2.1, and 7.3 micromol/l, respectively.
      Fenofibrate (> or = 10(-6) mol/l), 15-deoxy-Delta12,14-PGJ2 (> or = 5 x 10(-5)
      mol/l), and troglitazone (> or = 10(-6) mol/l) inhibited [3H]glibenclamide
      binding, but fenofibric acid did not. In addition, fenofibrate (> or = 10(-6)
      mol/l), fenofibric acid (10(-4) mol/l), troglitazone (10(-4) mol/l), and 15-deoxy
      Delta12,14-PGJ2 (> or = 10(-5) mol/l) increased insulin secretion from HIT-T15
      when applied for 10 min. Our data suggest that PPAR-alpha and -gamma ligands
      interact directly with the beta-cell membrane and stimulate insulin secretion.

PMID- 15201344
TI  - Competitive inhibition of the capsaicin receptor-mediated current by
      dehydroepiandrosterone in rat dorsal root ganglion neurons.
AB  - The effects of dehydroepiandrosterone (5-androsten-3beta-ol-17-one; DHEA) and
      related steroids on the capsaicin receptor-mediated current were studied in
      acutely dissociated rat dorsal root ganglion neurons using the whole-cell voltage
      clamp technique. DHEA rapidly and reversibly inhibited the capsaicin-induced
      current in a concentration-dependent manner, with an EC(50) of 6.7 microM and a
      maximal inhibition of 100%. DHEA increased the capsaicin EC(50) with little
      effect on the capsaicin maximal response, suggesting that the blocking action of
      DHEA is competitive. Neither the capsaicin response nor inhibition of the
      capsaicin response by extracellularly applied DHEA was significantly affected by
      inclusion of a saturating concentration of DHEA in the electrode buffer, arguing
      that DHEA acted at the extracellular surface of the membrane. Moreover, DHEA did
      not act through protein phosphatases to inhibit the capsaicin-induced current.
      Furthermore, the stereoisomer of DHEA, 5-androsten-3alpha-ol-17-one, failed to
      inhibit the capsaicin-induced current, producing instead a potentiating effect on
      the capsaicin response, demonstrating that the interaction of steroids with the
      capsaicin receptor is stereospecific. The inhibitory action of DHEA on the
      capsaicin-induced current may provide a basis for reducing capsaicin receptor
      mediated nociception.

PMID- 15201345
TI  - The cognitive neuroscience of autism.

PMID- 15201346
TI  - Expanding clinical dimensions of essential tremor.

PMID- 15201347
TI  - Optimising multi-task performance: opportunities for motoric neurorehabilitation.

PMID- 15201349
TI  - Personality in essential tremor: further evidence of non-motor manifestations of
      the disease.
AB  - OBJECTIVE: To ascertain whether patients with essential tremor have distinct
      definable personality traits. METHODS: A case-control study of patients with
      essential tremor was carried out to look for differences in personality
      characteristics. The controls were derived from the same source population. Using
      the tridimensional personality questionnaire (TPQ), personality traits were
      assessed in three dimensions: harm avoidance (HA), novelty seeking (NS), and
      reward dependence (RD). Additional analyses were conducted to address the
      possibility of selection bias among the patients with essential tremor. RESULTS:
      There were 55 patients and 61 controls. There was a difference between patients
      and controls in HA subscale scores (p = 0.005) but not in NS or RD scores. The
      difference remained significant in analyses that adjusted for age, sex, race, and
      education (p = 0.005). HA subscale scores did not correlate with subjective or
      objective measures of disability or with indices of severity of tremor.
      CONCLUSIONS: Patients with essential tremor scored higher on the harm avoidance
      subscale scores than control subjects. HA subscale scores did not correlate with
      the severity of tremor or with subjective and objective scales of disability,
      suggesting that the personality profile observed was not entirely related to
      functional disability caused by the tremor. Longitudinal studies of personality
      in essential tremor are needed to characterise the stability and evolution of
      these personality traits within the natural history of the disease process.

PMID- 15201350
TI  - Tau gene and Parkinson's disease: a case-control study and meta-analysis.
AB  - OBJECTIVE: To investigate whether the tau H1 haplotype is a genetic risk factor
      in Parkinson's disease and to report a meta-analysis on all previously published
      data METHODS: and results: In a sample of 580 patients with Parkinson's disease
      and 513 controls there was an increased risk of Parkinson's disease for both the
      tau H1 haplotype (p<or=0.0064; odds ratio (OR) 1.34 (95% confidence interval
      (CI), 1.04 to 1.72)) and the H1H1 genotype (p<or=0.0047; OR 1.42 (1.1 to 1.83)).
      Under a fixed effect model, the summary OR for this showed that individuals
      homozygous for the H1 allele were 1.57 times more likely to develop Parkinson's
      disease than individuals carrying the H2 allele (95% CI 1.33 to 1.85; p<0.00001).
      The population attributable risk for the tau variant, for the main comparison of
      H1H1 against H2 carriers, was 24.8% for all studies combined. CONCLUSIONS:
      Homozygosity for the tau H1 is associated with an increased risk of Parkinson's
      disease. This adds to the growing body of evidence that common genetic variation
      contributes to the pathogenesis of this disorder.

PMID- 15201348
TI  - Botulinum toxin in clinical practice.
AB  - Botulinum toxin, the most potent biological toxin, has become a powerful
      therapeutic tool for a growing number of clinical applications. This review draws
      attention to new findings about the mechanism of action of botulinum toxin and
      briefly reviews some of its most frequent uses, focusing on evidence based data.
      Double blind, placebo controlled studies, as well as open label clinical trials,
      provide evidence that, when appropriate targets and doses are selected, botulinum
      toxin temporarily ameliorates disorders associated with excessive muscle
      contraction or autonomic dysfunction. When injected not more often than every
      three months, the risk of blocking antibodies is slight. Long term experience
      with this agent suggests that it is an effective and safe treatment not only for
      approved indications but also for an increasing number of off-label indications.

PMID- 15201351
TI  - Carotid sinus syndrome is common in dementia with Lewy bodies and correlates with
      deep white matter lesions.
AB  - BACKGROUND: Carotid sinus syndrome (CSS) is a common cause of syncope in older
      persons. There appears to be a high prevalence of carotid sinus hypersensitivity
      (CSH) in patients with dementia with Lewy bodies (DLB) but not in Alzheimer's
      disease. OBJECTIVE: To compare the prevalence of CSH in DLB and Alzheimer's
      disease, and to determine whether there is an association between CSH induced
      hypotension and brain white matter hyperintensities on magnetic resonance imaging
      (MRI). METHODS: Prevalence of CSH was compared in 38 patients with DLB (mean (SD)
      age, 76 (7) years), 52 with Alzheimer's disease (80 (6) years), and 31 case
      controls (73 (5) years) during right sided supine carotid sinus massage (CSM).
      CSH was defined as cardioinhibitory (CICSH; >3 s asystole) or vasodepressor
      (VDCSH; >30 mm Hg fall in systolic blood pressure (SBP)). T2 weighted brain MRI
      was done in 45 patients (23 DLB, 22 Alzheimer). Hyperintensities were rated by
      the Scheltens scale. RESULTS: Overall heart rate response to CSM was slower (RR
      interval = 3370 ms (640 to 9400)) and the proportion of patients with CICSH
      greater (32%) in DLB than in Alzheimer's disease (1570 (720 to 7800); 11.1%) or
      controls (1600 (720 to 3300); 3.2%) (p<0.01)). The strongest predictor of heart
      rate slowing and CSH was a diagnosis of DLB (Wald 8.0, p<0.005). The fall in SBP
      during carotid sinus massage was greater with DLB (40 (22) mm Hg) than with
      Alzheimer's disease (30 (19) mm Hg) or controls (24 (19) mm Hg) (both p<0.02).
      Deep white matter hyperintensities were present in 29 patients (64%). In DLB,
      there was a correlation between magnitude of fall in SBP during CSM and severity
      of deep white matter changes (R = 0.58, p = 0.005). CONCLUSIONS: Heart rate
      responses to CSM are prolonged in patients with DLB, causing hypotension. Deep
      white matter changes from microvascular disease correlated with the fall in SBP.
      Microvascular pathology is a key substrate of cognitive impairment and could be
      reversible in DLB where there are exaggerated heart rate responses to carotid
      sinus stimulation.

PMID- 15201352
TI  - Novelty seeking and harm avoidance in Parkinson's disease: effects of asymmetric
      dopamine deficiency.
AB  - OBJECTIVES: Although changes in novelty seeking and harm avoidance have been
      reported among patients with Parkinson's disease (PD), the findings regarding the
      neurochemical correlates of such changes are inconsistent. This study was
      designed to examine the hypothesis that different patterns of motor and
      neurochemical asymmetry in PD may have contributed to the conflicting results.
      METHODS: Forty PD patients (divided into two groups according to initial
      asymmetry in dopamine deficit: left hemisphere, n = 22; right hemisphere, n = 18)
      and 17 age matched healthy controls completed the Tridimensional Personality
      Questionnaire (Cloninger, 1987). RESULTS: Only patients with greater dopamine
      loss in the left hemisphere showed reduced novelty seeking, whereas only patients
      with reduced dopamine in the right hemisphere reported higher harm avoidance than
      matched healthy controls. Novelty seeking was not associated with disease
      duration, current motor symptoms, or medication, whereas harm avoidance was
      significantly correlated only with the severity of bradykinesia and depression.
      CONCLUSIONS: Approach and avoidance reflect different patterns of dopaminergic
      asymmetry. Whereas reduced novelty seeking reflects deficit in the mesolimbic
      branch of ascending dopamine transmission in the left hemisphere, increased harm
      avoidance is associated with greater dopamine loss in the right striatum.

PMID- 15201353
TI  - The generic 15D instrument is valid and feasible for measuring health related
      quality of life in Parkinson's disease.
AB  - OBJECTIVES: To test the validity and feasibility of the generic 15D health
      related quality of life (HRQoL) instrument in Parkinson's disease (PD) and
      compare parkinsonian patients with the general population. Much effort has gone
      into developing disease specific HRQoL measures for PD, but only generic measures
      allow comparisons with the general population. New HRQoL tools are needed for PD
      because earlier ones have low feasibility in elderly patients. METHODS: The study
      comprised 260 patients with idiopathic PD and age and sex matched controls. HRQoL
      was evaluated using the disease specific questionnaire PDQ-39 and the 15D generic
      instrument. PD severity was assessed by Hoehn and Yahr staging, and the
      activities of daily living (ADL) and motor section of the Unified Parkinson's
      Disease Rating Scale (UPDRS). RESULTS: The mean 15D score (scale 0-1; overall
      HRQoL) was lower in PD (0.77) than in controls (0.86). Patients with PD had
      significantly lower scores than controls in 13 of the 15 dimensions of 15D.
      Scores of the corresponding dimensions of PDQ-39 and 15D correlated
      significantly, confirming the convergent validity of 15D. In multiple stepwise
      regression analysis, the UPDRS ADL score explained 55% of the variation in the
      15D score. CONCLUSIONS: 15D is a valid, feasible, and sensitive tool to assess
      quality of life in PD. PD has a major impact on HRQoL, which is related to
      disease progression. Mobility, eating, speech, and sexual functions are most
      affected. The ADL measure of the UPDRS and the 15D provide an easily assessable
      view of HRQoL in PD.

PMID- 15201354
TI  - Platelet-leukocyte interaction and platelet activation in migraine: a link to
      ischemic stroke?
AB  - OBJECTIVES: Migraine has been identified as an independent risk factor for
      ischemic stroke. Both neurogenic inflammation and platelet activation have been
      linked to the pathophysiology of migraine. Increased platelet activation results
      in up-regulation of specific binding to leukocytes which promotes pro
      inflammatory leukocyte secretion and their tethering to endothelium, a mechanism
      that has been demonstrated in stroke and which could provide a link to migraine.
      We aimed to determine whether platelet-leukocyte aggregation is increased in
      migraine patients outside an acute attack. METHODS: Seventy two patients with
      migraine according to IHS criteria were compared to a control group (n = 72).
      Whole blood flow cytometry was used to quantify the activation dependent P
      selectin on the platelet, and to assess the fraction of platelets bound to the
      different leukocyte subsets. RESULTS: Migraine patients showed significantly more
      platelet-leukocyte aggregates compared to the control subjects (p = 0.003). This
      effect was driven by an increased polymorphonuclear cell-platelet aggregation (p
      = 0.003) whereas platelet aggregation with monocytes and lymphocytes was not.
      Platelet activation was also increased (p = 0.001). CONCLUSIONS: In migraine pro
      inflammatory platelet adhesion to leukocytes occurs during the headache free
      interval similar to that seen in acute coronary and cerebrovascular syndromes.
      This may suggest a link between migraine and stroke on a cellular level.

PMID- 15201355
TI  - Migraine treated by Shakespeare's son-in-law, Dr John Hall.

PMID- 15201356
TI  - Survival and quality of life outcome after mechanical ventilation in elderly
      stroke patients.
AB  - OBJECTIVES: Mortality is high and functional outcome poor in mechanically
      ventilated stroke patients. In addition, age >65 years is an independent
      predictor of death at 2 months among these patients. Our objective was to
      determine survival rates, functional outcome, and quality of life (QoL) in stroke
      patients older than 65 years requiring mechanical ventilation. METHODS: A
      prospective cohort study with an additional cross-sectional survey in 65 patients
      aged 65 years and older (mean age (SD): 75.6 (6.0) years) with ischaemic or
      haemorrhagic stroke who underwent mechanical ventilation. Main outcome measures
      were survival rate at 6 months, and Barthel Index (BI), modified Rankin Scale,
      and QoL at 15.8 (SD 8.0) months. RESULTS: Survival rate at 6 months was 40%.
      Elective intubation (odds ratio (OR) 13.6; p = 0.002) was the only independent
      positive predictor for survival, while age >77.5 years (OR 0.1; p = 0.004) and
      white blood count >10/nl at admission (OR 0.31; p = 0.032) were independent
      negative predictors for survival at 6 months. At the time of the cross-sectional
      survey, BI was >70 in five out of 22 patients, 35-70 in three and <35 in the
      remaining 14 patients. QoL was impaired primarily in the physical domain, whereas
      the psychosocial domain was less affected. CONCLUSIONS: Although only 40% of
      elderly patients intubated in the acute phase of stroke survived at least 6
      months, one in four survivors recovered to a good functional outcome with a
      reasonable QoL. Elderly stroke patients need to be selected carefully for
      intensive care treatment, but elective intubation to allow diagnostic procedures
      should not be withheld primarily based on their age.

PMID- 15201357
TI  - Triple carotid aneurysms in a patient with migraine attacks.

PMID- 15201358
TI  - Stops walking when talking as a predictor of falls in people with stroke living
      in the community.
AB  - OBJECTIVE: To test "Stops walking when talking" (SWWT) as a predictor of falls
      among people with stroke living in the community. METHODS: People with stroke
      were identified through hospital records. Mobility, ADL (activities of daily
      living) ability, mental state, mood, and SWWT were assessed in a single session.
      Participants were followed prospectively for six months, using falls diaries and
      regular telephone calls. RESULTS: Sixty three participants (36 men, 27 women;
      mean (SD) age 68.4 (10.6)) were recruited. Four subjects had a brainstem lesion,
      30 had right hemisphere, and 29 left hemisphere infarctions. Mean time since
      onset of stroke was 20 months (range 2-72). Twenty six subjects stopped walking
      when a conversation was started and 16 of them fell during the six month follow
      up period (11 experienced repeated falls). For all fallers (>or=1) the positive
      predictive value of SWWT was 62% (16/26), the negative predictive value 62%
      (23/37), specificity 70% (23/33) and sensitivity 53% (16/30). For repeat fallers
      (>or=2) the positive predictive value of SWWT was 42% (11/26), the negative
      predictive value 89% (33/37), specificity 69% (33/48) and sensitivity 73%
      (11/15). Those who stopped walking were significantly more disabled (p<0.001)
      that is, they were more dependent in activities of daily living, had worse gross
      function as well as worse upper and lower limb function, and had depression (p =
      0.012). CONCLUSIONS: The specificity of the SWWT test was lower but sensitivity
      was higher than previously reported. Although the SWWT test was easy to use, its
      clinical usefulness as a single indicator of fall risk in identifying those
      community dwelling people with stroke most at risk of falls and in need of
      therapeutic intervention is questionable.

PMID- 15201359
TI  - Evidence for grey matter MTR abnormality in minimally disabled patients with
      early relapsing-remitting multiple sclerosis.
AB  - OBJECTIVES: To establish whether magnetisation transfer ratio (MTR) histograms
      are sensitive to change in normal appearing grey matter (NAGM) in early relapsing
      remitting multiple sclerosis (RRMS) in the absence of significant disability; and
      to assess whether grey or white matter MTR measures are associated with clinical
      measures of impairment in early RRMS METHODS: 38 patients were studied (mean
      disease duration 1.9 years (range 0.5 to 3.7); median expanded disability status
      scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls. MTR was determined
      from proton density weighted images with and without MT presaturation. SPM99 was
      used to generate normal appearing white matter (NAWM) and NAGM segments of the
      MTR map, and partial voxels were minimised with a 10 pu threshold and voxel
      erosions. Mean MTR was calculated from the tissue segments. Atrophy measures were
      determined using a 3D fast spoiled gradient recall sequence from 37 patients and
      17 controls. RESULTS: Mean NAGM and NAWM MTR were both reduced in early RRMS
      (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p<0.001; NAWM MTR: 37.9 v
      38.3 pu, p = 0.001). Brain parenchymal fraction (BPF) correlated with NAGM MTR,
      but when BPF was included as a covariate NAGM MTR was still lower in the patients
      (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005). CONCLUSIONS: In
      early RRMS, grey matter MTR abnormality is apparent. The correlation with mild
      clinical impairment (in this essentially non-disabled cohort) suggests that NAGM
      MTR could be a clinically relevant surrogate marker in therapeutic trials.

PMID- 15201360
TI  - Schizophrenia-like psychosis arising de novo following a temporal lobectomy:
      timing and risk factors.
AB  - OBJECTIVES: To clarify risk factors for the development of schizophrenia-like
      psychotic disorders following temporal lobectomy, and to explore the possibility
      that the early postoperative period is a time of high risk for the onset of such
      chronic psychotic disorders. METHODS: Patients who developed schizophrenia-like
      psychosis were identified from a series of 320 patients who had a temporal
      lobectomy for medically intractable epilepsy. The relationship of their disorders
      to both the operation and subsequent seizure activity was examined. Using a
      retrospective case-control design, risk factors for the development of
      schizophrenia-like psychosis were established. RESULTS: Eleven patients who
      developed schizophrenia-like psychosis postoperatively were identified and
      compared with 33 control subjects who remained free of psychosis postoperatively.
      The onset of de novo psychotic symptoms was typically in the first year following
      the operation. No clear relationship between postoperative seizure activity and
      fluctuations in psychotic symptoms emerged. Compared with the controls, patients
      who become psychotic had more preoperative bilateral electroencephalogram (EEG)
      abnormalities, pathologies other than mesial temporal sclerosis in the excised
      lobe and a smaller amygdala on the unoperated side. CONCLUSIONS: Temporal
      lobectomy for medically intractable epilepsy may precipitate a schizophrenia-like
      psychosis. Patients with bilateral functional and structural abnormalities,
      particularly of the amygdala, may be at particular risk for the development of
      such psychoses.

PMID- 15201361
TI  - Pseudosleep events in patients with psychogenic non-epileptic seizures:
      prevalence and associations.
AB  - OBJECTIVES: To determine the prevalence and clinical associations of a history of
      events during sleep in patients with psychogenic non-epileptic seizures (PNES,
      pseudoseizures), and to compare the prevalence of a history of sleep events with
      that in poorly controlled epilepsy. METHODS: Prospective study by semistructured
      interview of the history of event patterns and their clinical associations in 142
      patients with video EEG confirmed PNES, and 100 patients with poorly controlled
      epilepsy. RESULTS: 84/142 patients with PNES (59%) and 47/100 with epilepsy (47%)
      gave a history of events during sleep (p = 0.062). In patients with PNES,
      significant associations were found between a history of sleep events and:
      convulsive clinical semiology, antiepileptic drug treatment, fatigue, suicide
      attempts, mood disorder, and physical abuse. A particularly strong association
      with social security benefit was also found (odds ratio 4.0, p<0.001).
      CONCLUSIONS: The prevalence of a history of sleep events is similar in PNES and
      epilepsy, and is of no value in discriminating between the two, although a
      history of events occurring exclusively during sleep does suggest epileptic
      seizures. The clinical associations found indicate that a combination of
      psychopathological and external influences may be important in determining
      whether or not a patient with PNES gives a history of events during sleep.

PMID- 15201362
TI  - Is postural tremor size controlled by interstitial potassium concentration in
      muscle?
AB  - OBJECTIVES: To determine whether factors associated with postural tremor operate
      by altering muscle interstitial K(+). METHODS: An experimental approach was used
      to investigate the effects of procedures designed to increase or decrease
      interstitial K(+). Postural physiological tremor was measured by conventional
      means. Brief periods of ischaemic muscle activity were used to increase muscle
      interstitial K(+). Infusion of the beta(2) agonist terbutaline was used to
      decrease plasma (and interstitial) K(+). Blood samples were taken for the
      determination of plasma K(+). RESULTS: Ischaemia rapidly reduced tremor size, but
      only when the muscle was active. The beta(2) agonist produced a slow and
      progressive rise in tremor size that was almost exactly mirrored by a slow and
      progressive decrease in plasma K(+). CONCLUSIONS: Ischaemic reduction of postural
      tremor has been attributed to effects on muscle spindles or an unexplained effect
      on muscle. This study showed that ischaemia did not reduce tremor size unless
      there was accompanying muscular activity. An accumulation of K(+) in the
      interstitium of the ischaemic active muscle may blunt the response of the muscle
      and reduce its fusion frequency, so that the force output becomes less pulsatile
      and tremor size decreases. When a beta(2) agonist is infused, the rise in tremor
      mirrors the resultant decrease in plasma K(+). Decreased plasma K(+) reduces
      interstitial K(+) concentration and may produce greater muscular force
      fluctuation (more tremor). Many other factors that affect postural tremor size
      may exert their effect by altering plasma K(+) concentration, thereby changing
      the concentration of K(+) in the interstitial fluid.

PMID- 15201363
TI  - Stereotactic radiosurgery for primary trigeminal neuralgia: state of the evidence
      and recommendations for future reports.
AB  - OBJECTIVE: To identify systematically all the studies reporting outcomes and
      complications of stereotactic radiosurgery for trigeminal neuralgia and to
      evaluate them against predefined quality criteria. METHODS: Inclusion criteria
      for outcome analysis included thorough demographic documentation, defined
      diagnostic and outcome criteria, a minimum of 30 patients treated with 12 months
      median/mean follow up, not more than 20% lost to follow up, Kaplan-Meier
      actuarial analysis, primary trigeminal neuralgia, not more than 10% of patients
      retreated for failure or early recurrence, and minimum dose of 70 Gy. RESULTS: Of
      38 studies identified, four could be used to evaluate rates of pain relief on a
      yearly basis, and two for actuarial rates of complete pain relief; seven provided
      data on latencies and 18 were used to evaluate complications. Pain relief
      typically occurs within three months. Complete relief is initially achieved by
      three quarters of the patients, but half maintain this outcome at three years.
      One half or less can permanently stop drug treatments. Sensory disturbance,
      including anaesthesia dolorosa, is the most frequent complication of stereotactic
      radiosurgery. CONCLUSIONS: Outcomes after stereotactic radiosurgery appear in
      line with other ablative techniques. Results are better when it is used as
      primary treatment in patients with typical symptoms. Current data are largely
      observational and the quality is generally poor. This technique should be
      evaluated in a randomised, controlled trial with universal outcome measures,
      actuarial methodology, and validated measures of patient satisfaction and quality
      of life.

PMID- 15201364
TI  - Effects of surgery on the sensory deficits of syringomyelia and predictors of
      outcome: a long term prospective study.
AB  - OBJECTIVE: To quantify the effects of surgery on the thermal deficits of
      syringomyelia and assess the predictors for such effects. METHODS: The subjects
      were 16 consecutive patients (12 men, 4 women; mean (SD) duration of sensory
      symptoms, 5.1 (4.5) years) presenting with the typical symptoms of syringomyelia
      related to Chiari I malformation or trauma, and requiring surgical treatment.
      They were evaluated before surgery, then at six months and two years. Sensory
      evaluation included determination of the extent of thermal deficits and
      quantitative assessment of thermal, mechanical, vibration detection, and pain
      thresholds. Neuropathic pain intensity was evaluated on visual analogue scales.
      Magnetic resonance imaging was done before and after surgery to measure syrinx
      dimensions. RESULTS: The magnitude and extent of thermal deficits improved in a
      subgroup of patients and this was best predicted by the duration of sensory
      symptoms: patients operated on less than two years after the onset of their
      symptoms tended to improve, while those operated on later were stabilised or
      deteriorated slightly. The effect of surgery on thermal deficits was correlated
      with the duration of sensory symptoms. Surgery also affected vibration deficits
      in patients with the Chiari malformation, neuropathic pain on effort, and syrinx
      dimensions. CONCLUSIONS: The duration of sensory deficits is the best predictive
      factor of the efficacy of surgery for the thermal symptoms of syringomyelia.
      Early surgery is required if these deficits are to be minimised.

PMID- 15201365
TI  - A cohort study of early neurological consultation by telemedicine on the care of
      neurological inpatients.
AB  - OBJECTIVES: To find out the effect of early neurological consultation using a
      real time video link on the care of patients with neurological symptoms admitted
      to hospitals without neurologists on site. METHODS: A cohort study was performed
      in two small rural hospitals: Tyrone County Hospital (TCH), Omagh, and Erne
      Hospital, Enniskillen. All patients over 12 years of age who had been admitted
      because of neurological symptoms, over a 24 week period, to either hospital were
      studied. Patients admitted to TCH, in addition to receiving usual care, were
      offered a neurological consultation with a neurologist 120 km away at the
      Neurology Department of the Royal Victoria Hospital, Belfast, using a real time
      video link. The main outcome measure was length of hospital stay; change of
      diagnosis, mortality at 3 months, inpatient investigation, and transfer rate and
      use of healthcare resources within 3 months of admission were also studied.
      RESULTS: Hospital stay was significantly shorter for those admitted to TCH
      (hazard ratio 1.13; approximate 95% CI 1.003 to 1.282; p = 0.045). No patients
      diagnosed by the neurologist using the video link subsequently had their
      diagnosis changed at follow up. There was no difference in overall mortality
      between the groups. There were no differences in the use of inpatient hospital
      resources and medical services in the follow up period between TCH and Erne
      patients. CONCLUSIONS: Early neurological assessment reduces hospital stay for
      patients with neurological conditions outside of neurological centres. This can
      be achieved safely at a distance using a real time video link.

PMID- 15201366
TI  - Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with
      dementia severity of sporadic Alzheimer's disease.
AB  - BACKGROUND: Genetic polymorphisms of APO-E, homocysteine, and the IL-1 gene
      cluster (IL-1A, IL-1B, receptor antagonist IL-1RN) are associated with sporadic
      Alzheimer's disease and may involve interdependent pathways of neuronal toxicity.
      OBJECTIVE: To determine whether these polymorphisms and the genetic determinants
      of homocysteine (methylenetetrahydrofolate reductase, MTHFR; methionine synthase,
      MTR; transcobalamin, TC) are associated with an increased risk of severe dementia
      in Alzheimer's disease. METHODS: 152 patients with Alzheimer's disease and 136
      controls were studied. The association of occurrence and dementia severity
      (Reisberg score <6 and >or=6) of Alzheimer's disease with APO-E, IL-1A, IL-1B, IL
      1RN, MTHFR677 C-->T and 1298A-->C, MTR 2756 A-->G, and TC 776 C-->G polymorphisms
      was evaluated by multivariate logistic regression analysis after adjustment for
      age, sex, and age of onset of Alzheimer's disease. RESULTS: IL-1A TT and IL-1B
      CT/TT associated genotypes were at risk of Alzheimer's disease (odds ratio 4.80
      (95% confidence interval, 1.32 to 17.40), p = 0.017); the MTR 2756 AA genotype
      was at risk of severe dementia (OR 2.97 (1.23 to 7.21), p = 0.016); IL-1 RN*2 was
      protective (OR 0.28, (0.11 to 0.69), p = 0.006). Allele epsilon4 of the APO-E and
      IL-1B CC genotypes increased the risk of severe Alzheimer's disease associated
      with the MTR 2756 AA genotype by 3.3-fold and 1.5-fold, respectively.
      CONCLUSIONS: Distinct determinants of the IL-1 gene cluster are related to the
      generation and progression of Alzheimer's disease. MTR only influences
      progression of the disease, which may be enhanced by carriage of allele epsilon4
      of APO-E.

PMID- 15201367
TI  - Novel amyloid precursor protein gene missense mutation (D678N) in probable
      familial Alzheimer's disease.
AB  - OBJECTIVE: To describe a novel missense mutation, Asp678Asn (D678N), in the
      amyloid precursor protein (APP) gene in a Japanese pedigree of probable familial
      Alzheimer's disease (FAD). SUBJECT: The proband was a women of 72. Symptoms of
      dementia that fulfilled the criteria for probable Alzheimer's disease appeared at
      about 60 years of age, and slowly worsened over more than 10 years without
      evident cerebrovascular complications, either clinically or neuroradiologically.
      METHODS: Polymerase chain reaction single strand conformational polymorphism (PCR
      SSCP) analysis followed by sequence analysis was used to examine genomic DNA of
      the proband for mutations in the APP gene exons 16 and 17. RESULTS: Analysis of
      the APP exon 16 in the proband showed a GAC to AAC nucleotide substitution in
      codon 678 of the APP gene, causing an amino acid substitution of Asp to Asn
      (D678N). Heterozygosity of the APP D678N mutation was found in the proband and in
      the demented elder sister. CONCLUSIONS: The production and accumulation of
      mutated Abeta (Asn7-Abeta) or the misfunction of D678N mutant APP may have
      pathogenic properties for the development of Alzheimer's disease in this
      pedigree.

PMID- 15201368
TI  - Non-convulsive status epilepticus: a profile of patients diagnosed within a
      tertiary referral centre.
AB  - Non-convulsive status epilepticus (NCSE) is an under-recognised but treatable
      condition with considerable associated morbidity. The files of adult admissions
      were reviewed over four years, during which time 50 episodes of NCSE were
      diagnosed in 45 patients. These findings suggest a broad age range with various
      states of mental acuity and an association with both learning disabilities and
      acute systemic infection. Approximately half of the patients had a previous
      diagnosis of epilepsy at the time of admission, and half had a history of
      generalised tonic-clonic seizures immediately before the onset of their illness.

PMID- 15201369
TI  - The effect of immunomodulatory treatment on multiple sclerosis fatigue.
AB  - OBJECTIVE: To assess the effects of glatiramer acetate and beta interferon on
      fatigue in multiple sclerosis. METHODS: Fatigue was measured at baseline and six
      months using the fatigue impact scale (FIS). Groups (glatiramer acetate and beta
      interferon) were evaluated for the proportion improved, using Fisher's exact
      test. Logistic regression analysis assessed the relation between treatment group
      and improvement and controlled for confounding variables. RESULTS: Six month
      paired FIS assessments were available for 218 patients (76% female). Ages ranged
      between 19 and 61 years, with 86% having relapsing-remitting disease. Glatiramer
      acetate was used by 61% and beta interferon by 39%. At baseline, total FIS and
      subscale scores were comparable in the two groups. More patients improved on
      glatiramer acetate than on beta interferon on total FIS (24.8% v 12.9%, p =
      0.033; adjusted odds ratio = 2.36, 95% confidence interval 1.03 to 5.42), and on
      physical (28.6% v 14.1%, p = 0.013) and cognitive subscales (21.1% v 10.6%, p =
      0.045). Logistic regression analysis confirmed the association between glatiramer
      acetate use and improved fatigue, after accounting for baseline group
      differences. CONCLUSIONS: The odds of reduced multiple sclerosis fatigue were
      around twice as great with glatiramer acetate treatment as with beta interferon.
      Confirmation of this result is required.

PMID- 15201370
TI  - Clinically evidenced unilateral dissociation of saccades and pursuit eye
      movements.
AB  - A patient affected by an ischaemic lesion of the right medial thalamic nucleus
      presented with a uniocular dissociation of upward vertical saccades and pursuit
      movement, with absent upward vertical saccades in the left eye. Clinical
      observations were confirmed by magnetic field scleral search coils analysis.
      During the vertical eye movement the patient denied any diplopia, thus suggesting
      a transient visual suppression in the left eye.

PMID- 15201371
TI  - Anti-Hu associated paraneoplastic sensory neuronopathy with upper motor neurone
      involvement.
AB  - Paraneoplastic neurological syndrome is characterised by neuronal degeneration
      with lymphocytic infiltration in various regions of the central and peripheral
      nervous systems. Motor neurone symptoms may occur as a remote effect of
      malignancy, and have been considered because of the involvement of lower motor
      neurones. A case is reported of an 80 year old woman suffering from
      paraneoplastic sensory neuronopathy with anti-Hu antibody. Postmortem examination
      showed adenocarcinoma of the gall bladder and small cell carcinoma of the
      duodenum. Neuronal loss with lymphocytic infiltration was found in the dorsal
      root ganglia, brain stem, and cerebellum. Despite the absence of upper motor
      neurone signs, there was severe loss of Betz cells and degeneration of the
      bilateral pyramidal tracts. To our knowledge, this is the first demonstration of
      upper motor neurone involvement in anti-Hu associated paraneoplatic syndrome.

PMID- 15201372
TI  - Randomised control trial of tongue acupuncture versus sham acupuncture in
      improving functional outcome in cerebral palsy.
AB  - BACKGROUND: Traditional Chinese medicine (TCM) has been used historically in the
      treatment of cerebral palsy (CP). We investigated the efficacy of acupuncture in
      improving the motor function of children with CP. METHODS: A randomised control
      trial was conducted to assess the effect of tongue acupuncture (TAC) in 33 CP
      children. The subjects were randomised to treatment (n = 22) with TAC or control
      (n = 11). Clinical outcome was evaluated using the gross motor function measure
      (GMFM) and the pediatric evaluation of disability inventory (PEDI). RESULTS: The
      increase in mean GMFM score was significantly greater in the treatment than in
      the control group (p = 0.042). CONCLUSION: An improvement in motor function of CP
      subjects is seen following a short course of acupuncture.

PMID- 15201374
TI  - Retinal abnormalities in CADASIL: a retrospective study of 18 patients.
AB  - BACKGROUND: CADASIL is an inherited small vessel disease related to Notch3 gene
      mutations. AIM: To report retinal findings in symptomatic CADASIL patients.
      METHODS: Assessment of visual acuity (VA), testing of visual fields (VF),
      funduscopic examination (FE), and fluorescein angiography (FA) were carried out
      in 18 symptomatic patients. RESULTS: No visual symptoms were presented by our
      patients. VA was normal in all. Ophthalmologic abnormalities were found in 8
      patients. VF were normal except for a right hemianopia in one subject due to
      ischemic stroke. FE and FA revealed significant abnormalities in seven other
      subjects (mean age: 55 years; range: 39-74): nerve fibre loss (n = 4), cotton
      wool spots (n = 3), sheathed arteries (n = 1), and tortuous arteries (n = 1).
      Only one patient with both tortuous arteries and nerve fibre loss had multiple
      vascular risk factors, and another patient with cotton wool spots was a current
      smoker. DISCUSSION: FE and FA revealed silent retinal abnormalities in CADASIL
      patients with nerve fibre loss in 22% and cotton wool spots in 17%. The presence
      of these abnormal retinal findings does not seem related to the severity of the
      disorder but may be considered as peripheral markers of this genetic disease.

PMID- 15201375
TI  - Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes
      of Friedreich ataxia patients and carriers.
AB  - The most common causative mutation of Friedreich ataxia (FRDA) is the unstable
      hyperexpansion of an intronic GAA triplet repeat that impairs frataxin
      transcription. Using real time quantitative PCR, we showed that FRDA patients had
      residual levels of frataxin mRNA ranging between 13% and 30% and that FRDA
      carriers had about 40% of that of controls. Asymptomatic carriers also showed
      reduced frataxin mRNA levels. We found an inverse correlation between the number
      of GAA repeats and frataxin mRNA levels. Real-time quantitative PCR may represent
      an alternative assay for FRDA molecular diagnosis.

PMID- 15201376
TI  - Lewis Carroll's Humpty Dumpty: an early report of prosopagnosia?

PMID- 15201377
TI  - Blink reflex in primary lateral sclerosis.
AB  - OBJECTIVE: To investigate the underlying pathophysiology of primary lateral
      sclerosis (PLS) regarding possible changes in blink reflex (BR) circuit. METHODS:
      BR was studied in 10 patients in whom diagnosis of PLS was established by
      comparing them to two control groups: ten patients with amyotrophic lateral
      sclerosis (ALS) and 30 healthy volunteers. All patients were followed up annually
      for a 5 year period. A typical evoked potential study of the BR was employed.
      RESULTS: Significantly lower values of R(2) and R(2)' amplitude were found both
      in the PLS and ALS groups compared with the healthy control group. All these
      differences were highly significant (p<0.001). R(1) amplitude and latency, as
      well as R(2) and R(2)' latencies, were normal in all patients. Annually recorded
      follow up data revealed no significant changes in BR values for PLS patients. In
      contrast, for ALS patients, BR progressively disappeared following clinical
      impairment. CONCLUSIONS: The study suggests that BR is abnormal in PLS. It also
      adds some clues regarding PLS pathophysiology and can be helpful as a marker of
      ALS progression.

PMID- 15201379
TI  - Leucoencephalopathy with neuroaxonal spheroids (LENAS) presenting as the
      cerebellar subtype of multiple system atrophy.
AB  - Leucoencephalopathy with neuroaxonal spheroids (LENAS) is a rare disease of
      cerebral and cerebellar white matter. LENAS usually presents as a disorder of
      cognition and behaviour, or with gait dysfunction and ataxia. This report
      describes a patient who had a 14 year course of progressive neurological decline
      consistent with a clinical diagnosis of probable multiple system atrophy, with
      prominent cerebellar dysfunction and dysautonomia. Formal autonomic laboratory
      testing was consistent with global autonomic dysfunction of central origin.
      However, magnetic resonance imaging showed extensive white matter signal
      abnormalities, in addition to moderate cerebral and cerebellar atrophy. On
      postmortem microscopic examination, there were numerous axonal spheroids
      throughout the white matter of both regions. This case of LENAS presented unique
      clinical characteristics, and typical pathological findings.

PMID- 15201378
TI  - Spectroscopy and serial diffusion MR findings in hGH-Creutzfeldt-Jakob disease.
AB  - This report describes the magnetic resonance imaging (MRI) findings in two
      patients fulfilling the diagnostic criteria for human growth hormone Creutzfeldt
      Jakob disease, who initially had pronounced bilateral DWI/FLAIR (diffusion
      weighted imaging/fluid attenuated inversion recovery) hyperintensities in the
      basal ganglia, with decreased apparent diffusion coefficient (ADC) values (range,
      58-82% of normal). MRI spectroscopy, obtained in one case, showed decreased N
      acetyl aspartate/creatine (NAA/Cr) ratio in the atrophic vermis (0.79; normal:
      mean, 1.20; SD, 0.13), despite the lack of DWI/FLAIR signal changes, whereas
      NAA/Cr was normal in the putamina (1.6; normal: mean, 1.56; SD, 0.17), despite
      striking DWI signal changes and decreased ADC values (60% of normal). Serial DWI,
      obtained in the other case, showed a progressive disappearance of DWI hypersignal
      of the basal ganglia replaced by pronounced atrophy. Data from these two patients
      suggest that restricted diffusion associated with a normal NAA value might
      indicate spongiform changes of still viable cells, and that any subsequent
      regression of the DWI signal changes, atrophy, or decreased NAA values could be
      related to progressive neuronal death.

PMID- 15201381
TI  - Increased arterial carboxyhaemoglobin concentrations in patients with sporadic
      amyotrophic lateral sclerosis.

PMID- 15201380
TI  - Adult onset ornithine transcarbamylase deficiency: an unusual cause of semantic
      disorders.
AB  - Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle
      disorder. This condition usually presents in neonates or children. This report
      describes the clinical case of a 21 year old woman who was diagnosed in adulthood
      during the course of an unexplained coma. After recovery from the coma, she
      presented very unusual neuropsychological disorders involving memory and the
      meaning of certain words, suggesting a semantic deficit. The discovery of OTCD in
      adulthood is rare and the neuropsychological consequences may be unique.

PMID- 15201382
TI  - The red ear syndrome.

PMID- 15201383
TI  - Arteriovenous fistula of the superficial temporal artery: an exceptional
      complication of the pterional approach.

PMID- 15201384
TI  - Local pain during REBIF injection is not due to acidic pH.

PMID- 15201385
TI  - Autoimmune neurological disease after cardiac surgery.

PMID- 15201386
TI  - Development of myasthenia gravis in two patients with multiple sclerosis
      following interferon beta treatment.

PMID- 15201388
TI  - Extensive radiculopathy: another false localising sign in intracranial
      hypertension.

PMID- 15201387
TI  - Evidence for an association between the CSF HVA:5-HIAA ratio and aggressiveness
      in frontotemporal dementia but not in Alzheimer's disease.

PMID- 15201389
TI  - Role of entacapone in later Parkinson's disease not yet established.

PMID- 15201390
TI  - Portal-systemic shunts, manganese, and parkinsonism.

PMID- 15201391
TI  - Intraventricular assessment of preoperative electrographic recordings.

PMID- 15201392
TI  - Parkinsonism and persistent vegetative state after head injury.

PMID- 15201395
TI  - Evolution of the transposable element Pokey in the ribosomal DNA of species in
      the subgenus Daphnia (Crustacea: Cladocera).
AB  - Pokey is a member of the piggyBac (previously called the TTAA-specific) family of
      transposons and inserts into a conserved region of the large subunit ribosomal
      RNA gene. This location is a "hot spot" for insertional activity, as it is known
      to contain other arthropod transposable elements. However, Pokey is unique in
      that it is the first DNA transposon yet known to insert into this region. All
      other insertions are class I non-LTR retrotransposons. This study surveyed
      variation in Pokey elements through phylogenetic analysis of the 3' ends of Pokey
      elements from ribosomal DNA (rDNA) in species from the nominate subgenus of the
      genus Daphnia (Crustacea: Cladocera). The results suggest that Pokey has been
      stably, vertically inherited within rDNA over long periods of evolutionary time.
      No evidence was found to support horizontal transfer, which commonly occurs in
      other DNA transposons, such as P and mariner. Furthermore, Pokey has diverged
      into sublineages that have persisted across speciation events in some groups. In
      addition, a new highly divergent paralogous Pokey element was discovered in the
      rDNA of one species.

PMID- 15201394
TI  - A high-throughput assay for Tn5 Tnp-induced DNA cleavage.
AB  - Transposition causes genomic instability by mobilizing DNA elements. This
      phenomenon is mechanistically related to other DNA rearrangements, such as V(D)J
      recombination and retroviral DNA integration. A conserved active site
      architecture within the transposase/integrase superfamily catalyzes these
      distinct phenomena. The Tn5 transposase (Tnp) falls within this protein class,
      and many intermediates of the Tn5 transposition reaction have been characterized.
      Here, we describe a method for the rapid identification of Tn5 Tnp small molecule
      effectors. This high-throughput screening strategy will aid in the identification
      of compounds that perturb Tnp-induced DNA cleavage. This method is advantageous,
      since it identifies effectors that specifically inhibit catalysis without
      inhibiting Tnp-DNA binding interactions. Effectors identified using this method
      will serve as a valuable aid both in the isolation and characterization of metal
      bound reaction intermediates and in co-crystallization studies involving the
      effector, Tnp and DNA, to identify the structural basis of the interaction.
      Furthermore, since Tn5 Tnp shares a similar active site architecture to other
      transposase/integrase superfamily members, this strategy and any effectors
      identified using this method will be readily applicable to these other systems.

PMID- 15201396
TI  - Evolution of beta satellite DNA sequences: evidence for duplication-mediated
      repeat amplification and spreading.
AB  - In this article, we report studies on the evolutionary history of beta satellite
      repeats (BSR) in primates. In the orangutan genome, the bulk of BSR sequences was
      found organized as very short stretches of approximately 100 to 170 bp, embedded
      in a 60-kb to 80-kb duplicated DNA segment. The estimated copy number of the
      duplicon that carries BSR sequences ranges from 70 to 100 per orangutan haploid
      genome. In both macaque and gibbon, the duplicon mapped to a single chromosomal
      region at the boundary of the rDNA on the marker chromosome (chromosome 13 and
      12, respectively). However, only in the gibbon, the duplicon comprised 100 bp of
      beta satellite. Thus, the ancestral copy of the duplicon appeared in Old World
      monkeys ( approximately 25 to approximately 35 MYA), whereas the prototype of
      beta satellite repeats took place in a gibbon ancestor, after apes/Old World
      monkeys divergence ( approximately 25 MYA). Subsequently, a burst in spreading of
      the duplicon that carries the beta satellite was observed in the orangutan, after
      lesser apes divergence from the great apes-humans lineage ( approximately 18
      MYA). The analysis of the orangutan genome also indicated the existence of two
      variants of the duplication that differ for the length (100 or 170 bp) of beta
      satellite repeats. The latter organization was probably generated by
      nonhomologous recombination between two 100-bp repeated regions, and it likely
      led to the duplication of the single Sau3A site present in the 100-bp variant,
      which generated the prototype of Sau3A 68-bp beta satellite tandem organization.
      The two variants of the duplication, although with a different ratios,
      characterize the hominoid genomes from the orangutan to humans, preferentially
      involving acrocentric chromosomes. At variance to alpha satellite, which appeared
      before the divergence of New World and Old World monkeys, the beta satellite
      evolutionary history began in apes ancestor, where we have first documented a low
      copy, nonduplicated BSR sequence. The first step of BSR amplification and
      spreading occurred, most likely, because the BSR was part of a large duplicon,
      which underwent a burst dispersal in great apes' ancestor after the lesser apes'
      branching. Then, after orangutan divergence, BSR acquired the clustered
      structural organization typical of satellite DNA.

PMID- 15201398
TI  - Genome scans of DNA variability in humans reveal evidence for selective sweeps
      outside of Africa.
AB  - The last 50,000-150,000 years of human history have been characterized by rapid
      demographic expansions and the colonization of novel environments outside of sub
      Saharan Africa. Mass migrations outside the ancestral species range likely
      entailed many new selection pressures, suggesting that genetic adaptation to
      local environmental conditions may have been more prevalent in colonizing
      populations outside of sub-Saharan Africa. Here we report a test of this
      hypothesis using genome-wide patterns of DNA polymorphism. We conducted a
      multilocus scan of microsatellite variability to identify regions of the human
      genome that may have been subject to continent-specific hitchhiking events. Using
      published polymorphism data for a total of 624 autosomal loci in multiple
      populations of humans, we used coalescent simulations to identify candidate loci
      for geographically restricted selective sweeps. We identified a total of 13 loci
      that appeared as outliers in replicated population comparisons involving
      different reference samples for Africa. A disproportionate number of these loci
      exhibited reduced levels of relative variability in non-African populations
      alone, suggesting that recent episodes of positive selection have been more
      prevalent outside of sub-Saharan Africa.

PMID- 15201397
TI  - Effects of gene expression on molecular evolution in Arabidopsis thaliana and
      Arabidopsis lyrata.
AB  - We analyzed the complete genome sequence of Arabidopsis thaliana and sequence
      data from 83 genes in the outcrossing A. lyrata, to better understand the role of
      gene expression on the strength of natural selection on synonymous and
      replacement sites in Arabidopsis. From data on tRNA gene abundance, we find a
      good concordance between codon preferences and the relative abundance of
      isoaccepting tRNAs in the complete A. thaliana genome, consistent with models of
      translational selection. Both EST-based and new quantitative measures of gene
      expression (MPSS) suggest that codon preferences derived from information on tRNA
      abundance are more strongly associated with gene expression than those obtained
      from multivariate analysis, which provides further support for the hypothesis
      that codon bias in Arabidopsis is under selection mediated by tRNA abundance.
      Consistent with previous results, analysis of protein evolution reveals a
      significant correlation between gene expression level and amino acid substitution
      rate. Analysis by MPSS estimates of gene expression suggests that this effect is
      primarily the result of a correlation between the number of tissues in which a
      gene is expressed and the rate of amino acid substitution, which indicates that
      the degree of tissue specialization may be an important determinant of the rate
      of protein evolution in Arabidopsis.

PMID- 15201399
TI  - Average allozyme heterozygosity in vertebrates correlates with Ka/Ks measured in
      the human-mouse lineage.
AB  - It is well established that different allozyme proteins vary in heterozygosity in
      averages made over large numbers of species. For example, the enzyme 6
      phosphogluconate dehydrogenase has a much higher average heterozygosity than
      glutamate dehydrogenase. Allozyme data alone provide insufficient power to
      determine the evolutionary cause of such a difference. Many studies have now been
      carried out on the DNA sequences coding for allozymes. These have identified
      diverse selective and nonselective causes of polymorphisms at individual loci.
      However the studies are mainly in a small number of model species; thus, it is
      difficult to identify from these DNA studies specific causes of global average
      heterozygosity differences among allozyme proteins. Here we demonstrate that
      estimates of average heterozygosity for 37 allozyme proteins in vertebrates
      correlate positively with Ka and Ka/Ks but not with Ks, measured in the human
      mouse lineage. The values of Ka/Ks are less than 0.25, and Ka/Ks is negatively
      correlated with subunit number (quaternary structure), a measure of structural
      constraint. Proteins with lower levels of constraint have higher values of both
      Ka/Ks and heterozygosity. These results better support the hypothesis that
      differences in average allozyme diversity between proteins are more closely
      related to differences in the level of purifying selection than to differences in
      the underlying mutation rate or level of positive selection.

PMID- 15201400
TI  - Comparison of site-specific rate-inference methods for protein sequences:
      empirical Bayesian methods are superior.
AB  - The degree to which an amino acid site is free to vary is strongly dependent on
      its structural and functional importance. An amino acid that plays an essential
      role is unlikely to change over evolutionary time. Hence, the evolutionary rate
      at an amino acid site is indicative of how conserved this site is and, in turn,
      allows evaluation of its importance in maintaining the structure/function of the
      protein. When using probabilistic methods for site-specific rate inference, few
      alternatives are possible. In this study we use simulations to compare the
      maximum-likelihood and Bayesian paradigms. We study the dependence of inference
      accuracy on such parameters as number of sequences, branch lengths, the shape of
      the rate distribution, and sequence length. We also study the possibility of
      simultaneously estimating branch lengths and site-specific rates. Our results
      show that a Bayesian approach is superior to maximum-likelihood under a wide
      range of conditions, indicating that the prior that is incorporated into the
      Bayesian computation significantly improves performance. We show that when branch
      lengths are unknown, it is better first to estimate branch lengths and then to
      estimate site-specific rates. This procedure was found to be superior to
      estimating both the branch lengths and site-specific rates simultaneously.
      Finally, we illustrate the difference between maximum-likelihood and Bayesian
      methods when analyzing site-conservation for the apoptosis regulator protein Bcl
      x(L).

PMID- 15201401
TI  - Brain injury induced by intracerebral injection of interleukin-1beta and tumor
      necrosis factor-alpha in the neonatal rat.
AB  - To examine the possible role of inflammatory cytokines in mediating neonatal
      brain injury, we investigated effects of intracerebral injection of IL-1beta (IL
      1beta) or tumor necrosis factor-alpha (TNFalpha) on brain injury in the neonatal
      rat. A stereotaxic intracerebral injection of IL-1beta or TNFalpha (10 ng per
      pup) was performed in postnatal day 5 (P5) SD rats. Although no necrosis of
      neurons was found, increased astrogliosis, as indicated by GFAP positive staining
      was observed 24 and 72 h following the injection of IL-1beta or TNFalpha. IL
      1beta induced apoptotic cell death in the rat brain 24 h after the injection, as
      indicated by increases in positive TUNEL staining and caspase-3 activity, and
      apoptotic cell death was partially blocked by systemic administration of NBQX, an
      antagonist of the AMPA glutamate receptor. IL-1beta also significantly reduced
      the number of developing oligodendrocytes (OLs) 24 h after the injection and this
      impairment was not prevented by NBQX. On the contrary, TNFalpha induced a much
      smaller increase in the number of TUNEL positive cells and did not reduce the
      number of developing OLs. By P8, myelin basic protein (MBP) was clearly detected
      in the control rat brain, while MBP positive staining was very weak, if any, in
      the IL-1beta treated rat brain. MBP expression in the TNFalpha treated rat brain
      was less affected. The overall results indicate that IL-1beta may directly cause
      injuries to developing OLs and impair myelination in the neonatal rat brain and
      TNFalpha may have different roles in mediating brain injury.

PMID- 15201402
TI  - GLP-2 levels in infants with intestinal dysfunction.
AB  - Glucagon Like Peptide 2 (GLP-2) has been proposed as an important regulatory
      hormone in nutrient absorption. The present study was conducted in human infants
      with intestinal dysfunction undergoing surgery, correlating postprandial GLP-2
      levels with intestinal length, nutrient absorption, and patient outcome. We
      hypothesized that GLP-2 levels would be inversely related to nutrient absorption;
      we further hypothesized that post prandial GLP-2 levels would be predictive of
      the ability to wean patients from total parenteral nutrition (TPN), and tolerance
      of enteral feeding. Infants prospectively identified with nutrient malabsorption
      following intestinal surgery were monitored and after initiation of feeds GLP-2
      levels were measured in the fed state. Intestinal length was recorded
      intraoperatively and nutrient absorption was quantified using both a balance
      study, and carbohydrate probe method. 12 infants had GLP-2 levels successfully
      measured; two patients had repeated studies. Average gestational age was 32.7 +/-
      3.4 wk, age at testing was 1.7 +/- 1.4 mo and average weight was 3.5 +/- 1.1 kg.
      Causes of intestinal loss were necrotizing enterocolitis, atresia and volvulus.
      Five patients had severe short bowel syndrome (<50% of normal small intestinal
      length), 3 died. GLP-2 levels were best correlated with residual small intestinal
      length (r2 = 0.75). Correlations with total intestinal length including colon
      were less significant; residual colon appeared to not contribute to measurable
      GLP-2 production. GLP-2 levels were well correlated with tolerance of enteral
      feeds. Contradicting the initial hypothesis, GLP-2 levels were directly
      correlated with nutrient absorptive capacity (correlation with fat absorption: r2
      = 0.72, carbohydrate = 0.50 and protein = 0.54 respectively). There were no
      apparent changes in GLP-2 levels with gestational or postnatal age. As a
      corollary to the correlation with bowel length, a postprandial level of 15 pmol/L
      appeared to be discriminatory; infants with postprandial GLP-2 levels of > 15
      pmol/L were able to be weaned from total parenteral nutrition, while 3 of 4
      infants who had GLP-2 levels less than 15 could not be weaned by one year. These
      results show that in infants with intestinal dysfunction, GLP-2 levels are
      correlated with residual small bowel length and nutrient absorption, and may be
      predictive of outcome. In contrast to adults with intact colon and SBS, infants
      with SBS and intact colon do not appear able to produce GLP-2 in response to
      feeding stimulation. Further studies are suggested to examine the ontogeny of the
      GLP-2 axis and the possible therapeutic role of GLP-2 supplementation.

PMID- 15201403
TI  - Early intestinal bacterial colonization and necrotizing enterocolitis in
      premature infants: the putative role of Clostridium.
AB  - Necrotizing enterocolitis (NEC) is among the most severe conditions that can
      affect preterm infants. Although the etiology of NEC remains unknown, initial
      bacterial colonization could play a pivotal role in the development of NEC. To
      further explore the putative relationship between pathogen microorganisms and
      NEC, we conducted a prospective case-control study in 12 preterm infants with a
      new approach based on molecular techniques. Over an inclusion period of 24 mo, 12
      neonates of <34 wk gestational age admitted to the neonatal unit were enrolled.
      The group included three cases of NEC, and nine control infants without evidence
      of NEC who were matched for gestational age and birth weight. Stool samples were
      collected at weekly intervals from all infants. PCR and temporal temperature
      gradient gel electrophoresis of 16S ribosomal DNA were used to detect the
      establishment of bacterial communities in the digestive tract. A salient feature
      of the bacteriological pattern was observed only in the three infants who later
      developed NEC: A band corresponding to the Clostridium perfringens subgroup could
      be detected in early samples, before diagnosis. There was no evidence for this
      specific band in any of the nine controls. To our knowledge, the current report
      is the first to demonstrate that the use of molecular techniques based on the
      study of bacterial 16S rRNA genes allowed the recognition of C. perfringens
      species in the first 2 wk of life of three infants who later displayed symptoms
      of NEC. A significant temporal relationship was thus established between early
      colonization by Clostridium and the later development of NEC. Compared with
      conventional bacteriological culturing methods, the use of this new molecular
      approach to analyze the gastrointestinal ecosystem should therefore allow a more
      complete and rapid assessment of intestinal flora. Although the current data do
      not constitute definitive proof that the identified bacterial species was a
      causative agent in the development of NEC, they outline the promise of this new
      technique based on molecular biology, and suggest that large-scale studies on a
      much wider population at high risk for NEC may be warranted.

PMID- 15201404
TI  - Effects of maternal undernutrition during late gestation on the lung surfactant
      system and morphometry in rats.
AB  - Intrauterine growth restriction (IUGR) is associated with reduced lung function
      during infancy and throughout adulthood. We investigated the effects of maternal
      undernutrition (50% rations of the control food intake) during the last week of
      gestation on the pulmonary surfactant system and lung morphometry in postnatal
      rats. IUGR rats exhibited a significantly lower body weight, lower lung weight,
      lower lung/body weight ratio, lower lung volume, and lower lung volume/body
      weight ratio on some postnatal days. IUGR rats had a significantly lower lung
      saturated phosphatidylcholine and lower plasma corticosterone levels on postnatal
      d 1 only, and values were comparable between control and IUGR rats in the ensuing
      weeks. Lung surfactant protein (SP)-A, SP-B, SP-C, and SP-D mRNA expressions were
      similar between control and IUGR rats. Volume fractions of the alveolar airspace
      were significantly lower in IUGR rats on postnatal d 7, 14, and 42. Alveolar
      surface areas were significantly lower in IUGR rats during the study period. The
      alveolar surface area/body weight ratio reached a peak on postnatal d 7, and
      values were significantly lower in IUGR rats on postnatal d 1, 14, 28, and 42. We
      conclude that maternal undernutrition during late gestation decreases lung
      surfactant lipid levels in the immediate postnatal period and alters the
      development of lung structure during the postnatal period. Alteration of lung
      surfactant and structure may be important in the pathogenesis of impaired
      pulmonary function in IUGR infants and children.

PMID- 15201405
TI  - Hepatocyte growth factor protects small airway epithelial cells from apoptosis
      induced by tumor necrosis factor-alpha or oxidative stress.
AB  - Involvement of hepatocyte growth factor (HGF) in lung morphogenesis and
      regeneration has been established by in vitro and in vivo experiments in animals.
      In the present study, the protective activity of HGF against tumor necrosis
      factor (TNF)-alpha or hydrogen peroxide (H2O2)-induced damage of pulmonary
      epithelial cells was examined using the human small airway epithelial cell line
      (SAEC). Western blot analysis revealed that the receptor for HGF (c-Met) was
      highly expressed on the surface of SAEC and its downstream signal transduction
      pathway was functional. The SAEC was induced into apoptosis by the treatment with
      TNF-alpha or H2O2 in a dose-dependant manner, but was significantly rescued from
      apoptosis in the presence of HGF. The HGF effect was evident when added not only
      at the same time but also within several hours after treatment. This protective
      activity of HGF against the TNF-alpha- or H2O2-induced apoptosis was mediated, at
      least in part, by up-regulating the nuclear factor kappaB activity and an
      increase in the ratio of apoptosis-suppressing to apoptosis-inducing proteins.
      These results suggest that administration of HGF might exhibit a potent function
      in vivo for protection and improvement of acute and chronic lung injuries induced
      by inflammation and/or oxidative stress.

PMID- 15201406
TI  - Endothelin-A receptor blockade and inhaled nitric oxide in a porcine model of
      meconium aspiration syndrome.
AB  - Acute neonatal pulmonary hypertension is associated with increased activation of
      the endogenous endothelin pathway. We investigated the role of selective
      endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium
      aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets.
      Six controls received no further intervention. Six piglets received 1 mg/kg BQ
      123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six
      commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min.
      The total study duration was 360 min. Meconium aspiration resulted in acute
      pulmonary hypertension and elevated endothelin-1 levels in all animals. There
      were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min
      in controls. In the group receiving BQ-123 first, this agent alone reduced the
      pulmonary artery pressure and pulmonary vascular resistance, and the subsequent
      addition of inhaled nitric oxide further reduced pulmonary artery pressure. In
      the group first receiving nitric oxide alone, this reduced the pulmonary artery
      pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular
      resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to
      be a highly effective pulmonary vasodilator and augmented the effects of nitric
      oxide in this model of acute pulmonary hypertension.

PMID- 15201407
TI  - The cost of admission--tiered copayments for hospital use.

PMID- 15201408
TI  - Thermodynamics, liposuction, and metabolism.

PMID- 15201409
TI  - Infections transmitted through musculoskeletal-tissue allografts.

PMID- 15201410
TI  - B cells, be gone--B-cell depletion in the treatment of rheumatoid arthritis.

PMID- 15201411
TI  - Absence of an effect of liposuction on insulin action and risk factors for
      coronary heart disease.
AB  - BACKGROUND: Liposuction has been proposed as a potential treatment for the
      metabolic complications of obesity. We evaluated the effect of large-volume
      abdominal liposuction on metabolic risk factors for coronary heart disease in
      women with abdominal obesity. METHODS: We evaluated the insulin sensitivity of
      liver, skeletal muscle, and adipose tissue (with a euglycemic-hyperinsulinemic
      clamp procedure and isotope-tracer infusions) as well as levels of inflammatory
      mediators and other risk factors for coronary heart disease in 15 obese women
      before and 10 to 12 weeks after abdominal liposuction. Eight of the women had
      normal glucose tolerance (mean [+/-SD] body-mass index, 35.1+/-2.4), and seven
      had type 2 diabetes (body-mass index, 39.9+/-5.6). RESULTS: Liposuction decreased
      the volume of subcutaneous abdominal adipose tissue by 44 percent in the subjects
      with normal glucose tolerance and 28 percent in those with diabetes; those with
      normal oral glucose tolerance lost 9.1+/-3.7 kg of fat (18+/-3 percent decrease
      in total fat, P=0.002), and those with type 2 diabetes lost 10.5+/-3.3 kg of fat
      (19+/-2 percent decrease in total fat, P<0.001). Liposuction did not
      significantly alter the insulin sensitivity of muscle, liver, or adipose tissue
      (assessed by the stimulation of glucose disposal, the suppression of glucose
      production, and the suppression of lipolysis, respectively); did not
      significantly alter plasma concentrations of C-reactive protein, interleukin-6,
      tumor necrosis factor alpha, and adiponectin; and did not significantly affect
      other risk factors for coronary heart disease (blood pressure and plasma glucose,
      insulin, and lipid concentrations) in either group. CONCLUSIONS: Abdominal
      liposuction does not significantly improve obesity-associated metabolic
      abnormalities. Decreasing adipose tissue mass alone will not achieve the
      metabolic benefits of weight loss.

PMID- 15201412
TI  - The risk of recurrent venous thromboembolism in men and women.
AB  - BACKGROUND: Whether a patient's sex is associated with the risk of recurrent
      venous thromboembolism is unknown. METHODS: We studied 826 patients for an
      average of 36 months after a first episode of spontaneous venous thromboembolism
      and the withdrawal of oral anticoagulants. We excluded pregnant patients and
      patients with a deficiency of antithrombin, protein C, or protein S; the lupus
      anticoagulant; cancer; or a requirement for potentially long-term antithrombotic
      treatment. The end point was objective evidence of a recurrence of symptomatic
      venous thromboembolism. RESULTS: Venous thromboembolism recurred in 74 of the 373
      men, as compared with 28 of the 453 women (20 percent vs. 6 percent; relative
      risk of recurrence, 3.6; 95 percent confidence interval, 2.3 to 5.5; P<0.001).
      The risk remained unchanged after adjustment for age, the duration of
      anticoagulation, and the presence or absence of a first symptomatic pulmonary
      embolism, factor V Leiden, factor II G20210A, or an elevated level of factor VIII
      or IX. At five years, the likelihood of recurrence was 30.7 percent among men, as
      compared with 8.5 percent among women (P<0.001). The relative risk of recurrence
      was similar among women who had had their first thrombosis during oral
      contraceptive use or hormone-replacement therapy and women in the same age group
      in whom the first event was idiopathic. CONCLUSIONS: The risk of recurrent venous
      thromboembolism is higher among men than women.

PMID- 15201413
TI  - Clostridium infections associated with musculoskeletal-tissue allografts.
AB  - BACKGROUND: Allografts are commonly used in orthopedic reconstructive surgery. In
      2001, approximately 875,000 musculoskeletal allografts were distributed by U.S.
      tissue banks. After the death from Clostridium sordellii sepsis of a 23-year-old
      man who had received a contaminated allograft from a tissue bank (Tissue Bank A),
      the Centers for Disease Control and Prevention initiated an investigation,
      including enhanced case finding, of the methods used for the recovery,
      processing, and testing of tissue. METHODS: A case of allograft-associated
      clostridium infection was defined as a culture-proven infection of a surgical
      site within one year after allograft implantation, from January 1998 to March
      2002. We traced tissues to tissue banks that recovered and processed these
      tissues. We also estimated the rates of and risk ratios for clostridium
      infections for tissues processed by the implicated tissue bank and reviewed
      processing and testing methods used by various tissue banks. RESULTS: Fourteen
      patients were identified, all of whom had received allografts processed by Tissue
      Bank A. The rates of clostridium infection were 0.12 percent among patients who
      received sports-medicine tissues (i.e., tendons, femoral condyles, menisci) from
      Tissue Bank A and 0.36 percent among those who received femoral condyles in
      particular. The risk-ratio estimates for clostridium infections from tissues
      processed by Tissue Bank A, as compared with those from other tissue banks, were
      infinite (P<0.001) for musculoskeletal allografts, sports-medicine tissues, or
      tendons. Because Tissue Bank A cultured tissues only after treating them with a
      nonsporicidal antimicrobial solution, some test results were probably false
      negatives. Tissues from implicated donors were released despite the isolation of
      clostridium or bowel flora from other anatomical sites or reports of infections
      in other recipients. CONCLUSIONS: Clostridium infections were traced to allograft
      implantation. We provide interim recommendations to enhance tissue
      transplantation safety. Tissue banks should validate processes and culture
      methods. Sterilization methods that do not adversely affect the functioning of
      transplanted tissue are needed to prevent allograft-related infections.

PMID- 15201414
TI  - Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid
      arthritis.
AB  - BACKGROUND: An open-label study indicated that selective depletion of B cells
      with the use of rituximab led to sustained clinical improvements for patients
      with rheumatoid arthritis. To confirm these observations, we conducted a
      randomized, double-blind, controlled study. METHODS: We randomly assigned 161
      patients who had active rheumatoid arthritis despite treatment with methotrexate
      to receive one of four treatments: oral methotrexate (> or =10 mg per week)
      (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide
      (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined
      according to the criteria of the American College of Rheumatology (ACR) and the
      European League against Rheumatism (EULAR) were assessed at week 24 (primary
      analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion
      of patients with 50 percent improvement in disease symptoms according to the ACR
      criteria, the primary end point, was significantly greater with the rituximab
      methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide
      combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In
      all groups treated with rituximab, a significantly higher proportion of patients
      had a 20 percent improvement in disease symptoms according to the ACR criteria
      (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85
      percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week
      48 in the rituximab-methotrexate group. The majority of adverse events occurred
      with the first rituximab infusion: at 24 weeks, serious infections occurred in
      one patient (2.5 percent) in the control group and in four patients (3.3 percent)
      in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained
      within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis
      despite methotrexate treatment, a single course of two infusions of rituximab,
      alone or in combination with either cyclophosphamide or continued methotrexate,
      provided significant improvement in disease symptoms at both weeks 24 and 48.

PMID- 15201415
TI  - Clinical practice. Palliative care.

PMID- 15201416
TI  - Therapeutic strategies for rheumatoid arthritis.

PMID- 15201417
TI  - Images in clinical medicine. Gas gangrene.

PMID- 15201418
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 19-2004. A 12-year-old boy with fatigue and eosinophilia.

PMID- 15201419
TI  - Mars or venus--is sex a risk factor for recurrent venous thromboembolism?

PMID- 15201420
TI  - GB virus C and survival in persons with HIV infection.

PMID- 15201421
TI  - Drug-induced prolongation of the QT interval.

PMID- 15201422
TI  - EBV and Burkitt's lymphoma.

PMID- 15201423
TI  - A pain in the neck.

PMID- 15201424
TI  - Polycystic kidney disease.

PMID- 15201425
TI  - Case 7-2004: hereditary melanoma and pancreatic cancer.

PMID- 15201426
TI  - Liver transplantation 27 years after bone marrow transplantation from the same
      living donor.

PMID- 15201427
TI  - Thymic carcinoma with overexpression of mutated KIT and the response to imatinib.

PMID- 15201428
TI  - Images in clinical medicine. Radiation injury from a fluoroscopic procedure.

PMID- 15201429
TI  - Too much of a good thing.

PMID- 15201430
TI  - On trial.
AB  - As researchers uncover basic mechanisms that underlie aging, they hope that
      lessons learned from mice, worms, flies, and other lab denizens will apply to
      people. Making that leap requires a new set of scientific approaches, from
      observational studies to the most rigorous of tests, the double-blind,
      randomized, placebo-controlled clinical trial. Navigating this unique scientific
      terrain presents new obstacles for basic-science researchers but can provide the
      ultimate payoff.

PMID- 15201431
TI  - Obesity over the life course.
AB  - Obesity in middle-aged humans is a risk factor for many age-related diseases and
      decreases life expectancy by about 7 years, which is roughly comparable to the
      combined effect of all cardiovascular disease and cancer on life span. The
      prevalence of obesity increases up until late middle age and decreases
      thereafter. Mechanisms that lead to increased obesity with age are not yet well
      understood, but current evidence implicates impairments in hypothalamic function,
      especially impairments in the ability of hypothalamic pro-opiomelanocortin
      neurons to sense nutritional signals. The rapid increase in the prevalence of
      obesity at all ages in the past decade suggests that, in the next two or three
      decades, diseases associated with obesity, especially diabetes, will begin to
      rise rapidly. Indeed, these trends suggest that for the first time in modern
      history, the life expectancy of people in developed societies will begin to
      decrease, unless the rapid increase in the prevalence of obesity can be reversed.

PMID- 15201432
TI  - Synthesis of antimicrofilament marine macrolides: synthesis and configurational
      assignment of a C5-C16 degradation fragment of reidispongiolide A.
AB  - Reidispongiolide A is a representative member of the sphinxolide/reidispongiolide
      group of cytotoxic 26-membered macrolides of marine origin. By interacting with
      actin in the cell cytoskeleton, the reidispongiolides and sphinxolides are potent
      microfilament destabilizing agents that represent a promising mechanism of action
      for developing novel anticancer drugs. An aldol-based synthesis of a library of
      diastereomers of C(8)-C(16) and C(5)-C(16) fragments and detailed NMR comparison
      with a reported degradation fragment enabled a configurational assignment for a
      major part of the reidispongiolide macrocyclic core, thus setting a solid
      foundation for ongoing synthetic efforts.

PMID- 15201433
TI  - Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic
      reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice.
AB  - Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase
      (SERCA2a) by direct binding and is superinhibitory if it binds through
      phospholamban (PLN). To determine whether overexpression of SLN in the heart
      might impair cardiac function, transgenic (TG) mice were generated with cardiac
      specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG
      epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was
      equivalent to that which induces profound superinhibition when coexpressed with
      PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a
      for Ca(2+) was decreased compared with non-TG littermate control hearts. Invasive
      hemodynamic and echocardiographic analyses revealed impaired cardiac
      contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation
      was reduced. In isolated papillary muscle subjected to isometric tension, peak
      amplitudes of Ca(2+) transients and peak tensions were reduced, whereas decay
      times of Ca(2+) transients and relaxation times of tension were increased in TG
      mice. Isoproterenol largely restored contractility in papillary muscle and
      stimulated PLN phosphorylation to wild-type levels in intact hearts. No
      compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and
      calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that
      overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary
      complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through
      stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation
      and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs
      contractility and calcium cycling, but responsiveness to beta-adrenergic agonists
      may prevent progression to heart failure.

PMID- 15201434
TI  - The alpha, beta, gamma, delta-unsaturated aldehyde 2-trans-4-trans-decadienal
      disturbs DNA replication and mitotic events in early sea urchin embryos.
AB  - The polyunsaturated aldehydes are highly reactive products of fatty acid
      peroxidation and combustion of organic materials, and they have been documented
      to have diverse cyctotoxic and genotoxic effects. The alpha,beta,gamma,delta
      unsaturated aldehyde 2-trans-4-trans-decadienal is produced by marine microalgae,
      and it is known to inhibit cell proliferation and induce apoptosis in several
      different cell types. However, the molecular basis for the cell cycle arrest is
      not fully understood. We used sea urchin embryos to examine how some of the key
      events of the mitotic cell division were influenced by this polyunsaturated
      aldehyde. We found that cell divisions in embryos of Sphaerechinus granularis
      were inhibited by 2-trans-4-trans-decadienal in a dose dependent manner with an
      EC50 of 1.3 microM. Mitotic events in the nondividing eggs were characterized
      using immunofluorescent staining. DNA labelling revealed that pronuclear
      migration was inhibited, and a total absence of incorporation of the DNA-base
      analogue 5-bromo-2-deoxyuridine indicated that no DNA replication had occurred.
      Staining of alpha-tubulin subunits showed that tubulin-polymerization was
      disrupted and aberrations were induced in mitotic spindles. Furthermore, we
      monitored the activity of the G2-M promoting complex cyclin B-Cdk1 in newly
      fertilized sea urchin eggs, and found that this complex was not activated in
      embryos treated with 2-trans-4-trans-decadienal despite the accumulation of
      cyclin B.

PMID- 15201435
TI  - Effect of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) on hepatocyte proliferation
      and apoptosis in mice deficient in the p50 subunit of the transcription factor NF
      kappaB.
AB  - Polychlorinated biphenyls (PCBs) are a group of synthetic chemicals that induce
      and promote liver tumors in rodents. We previously showed hepatic nuclear factor
      kappaB (NF-kappaB) activation and increased hepatocyte proliferation in PCB
      treated rats. In this study, the role of NF-kappaB in hepatocyte proliferation
      and apoptosis after PCB administration was analyzed in wild-type mice and in mice
      deficient in the NF-kappaB p50 subunit (p50-/-). In a 2-day study, mice received
      a single intraperitoneal (ip) injection of corn oil or PCB-153. Hepatic NF-kappaB
      DNA binding activity and cell proliferation were increased by PCB-153 in wild
      type mice but not in p50-/- mice. In a 21-day study, mice received six ip
      injections of corn oil or PCB-153 (twice weekly for 3 weeks) and were euthanized
      4 days after the last injection. In this study, NF-kappaB DNA binding activity
      was not increased after PCB-153 treatment in wild-type or p50-/- mice. Cell
      proliferation was significantly increased in the wild-type mice treated with PCB
      153; in the p50-/- mice treated with PCB-153, cell proliferation was greater than
      in untreated mice but less than in wild-type mice treated with PCB-153. The
      livers of p50-/- mice showed greater apoptosis than those of wild-type mice; PCB
      153 decreased apoptosis in p50-/- mice, with higher inhibition in the 21-day
      study than in the 2-day study. RNase protection assays indicated that PCB-153
      decreased the mRNA level of cyclin A2, B1, B2, and C in the 2-day study, but not
      in the 21-day study; however, it did not affect cyclin D1 and D2 mRNA levels at
      either time point. Cyclin D1 protein levels were not affected by PCB-153. Taken
      together, these data indicate that the absence of the NF-kappaB p50 subunit
      alters the proliferative and apoptotic changes in mouse liver in the response to
      PCB-153.

PMID- 15201436
TI  - Bis(2-chloroethoxy)methane-induced mitochondrial and myofibrillar damage: short
      term time-course study.
AB  - Cardiotoxicity induced by 2-, 3-, 5-, and 12-day dermal administration of 400 and
      600 mg/kg/day of bis(2-chloroethoxy)methane to F344/N male and female rats was
      characterized. The severity and incidence of lesions were similar among males and
      females and in all three regions of the heart examined (atrium, ventricle,
      interventricular septum). Damage induced by bis(2-chloroethoxy)methane consisted
      of time-related development of myofiber vacuolation, necrosis, mononuclear-cell
      infiltration, fibrosis, and atrial thrombosis. Changes were pronounced at day 2,
      increased in severity at day 3, appeared to decrease at day 5, and resolved by
      study-day 16 that corresponded to 12 dosings. Ultrastructural analysis of 2- and
      5-day 600 mg/kg/day-treated females elucidated the primary site of damage, the
      mitochondrion, and two types of vacuolation, one that formed as damaged
      mitochondria became devoid of cristae and their bounding double membranes became
      reduced to singleness, and the other manifested as distention of the sarcoplasmic
      reticulum. After the initial damage induced by bis(2-chloroethoxy)methane, or its
      metabolite, thiodiglycolic acid, protective mechanisms within the heart were
      apparently initiated, enabling it to cope with the continued exposure to the
      toxicant while eliminating some damaged myofibers.

PMID- 15201437
TI  - Enhancement of hepatocarcinogenesis by kojic acid in rat two-stage models after
      initiation with N-bis(2-hydroxypropyl)nitrosamine or N-diethylnitrosamine.
AB  - Kojic acid (KA) has been used as a food additive for preventing enzymatic
      browning of crustaceans and as a cosmetic agent for skin whitening. In the
      present experiments, effects of KA on the induction of hepatic pre-neoplastic
      lesions in N-bis(2-hydroxypropyl)nitrosamine-initiated (experiment 1) and non
      initiated (experiment 2) models, and its promoting influence in a medium-term
      liver bioassay (experiment 3) were investigated at dietary doses of up to 2% in
      male F344 rats. In experiment 1, 2% KA feeding induced significant increases in
      numbers (22.3 +/- 13.0 vs 8.5 +/- 3.4 in the 0%) and areas (0.37 +/- 0.29 vs 0.05
      +/- 0.03 in the 0%) of glutathione-S-transferase P form (GST-P)-positive foci and
      toxic changes such as vacuolation of hepatocytes and microgranulomas. The
      development of GST-P-positive foci was pronounced in the animals with
      hepatocellular toxic changes. In experiment 2, numbers (0.65 +/- 0.57 vs 0.17 +/-
      0.28 in the 0%) and areas (0.005 +/- 0.005 vs 0.0007 +/- 0.0012 in the 0%) of GST
      P-positive foci and hepatocellular proliferating cell nuclear antigen (PCNA)
      expression (3.8 +/- 2.3 vs 2.6 +/- 0.7 in the 0%) were significantly increased by
      the 2% treatment. The PCNA-positive hepatocytes were abundantly localized around
      the vacuolated and granulomatous legions in both experiments 1 and 2. In
      experiment 3, significant increases in numbers (16.9 +/- 3.2 vs 8.4 +/- 2.7 in
      the 0%) and areas (1.62 +/- 0.39 vs 0.77 +/- 0.34 in the 0%) of GST-P-positive
      foci were again observed with 2% KA. These results demonstrate tumor-promoting
      and possible hepatocarcinogenic activity of KA at 2%, but the carcinogenic
      potential is likely to be weak. This study also indicated that enhanced
      replication of hepatocytes related to toxic changes might be involved as an
      underlying mechanism.

PMID- 15201439
TI  - Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN)
      and polychlorinated biphenyl (PCB).
AB  - Pregnenolone-16alpha-carbonitrile (PCN) and Aroclor 1254 (PCB) both reduce serum
      thyroid hormone levels in rats, but only PCN consistently produces an increase in
      serum thyrotropin (TSH). PCN-mediated increases in TSH result in increased
      thyroid follicular cell proliferation and hyperplasia, which may represent early
      events on a morphological continuum leading to neoplasia. The purpose of this
      study was to assess whether PCN, a compound that increases serum TSH, and PCB,
      which does not increase TSH, promote thyroid tumors in a two-stage carcinogenesis
      model. Male SD rats were administered the thyroid tumor initiator
      diisopropanolnitrosamine (2.5 g/kg, sc), and after seven days were fed control
      diet, diet containing 1000 ppm PCN, or diet containing 100 ppm PCB for 19 weeks.
      Body weights were unaffected by PCN treatment, but were reduced 21% after 19
      weeks of PCB treatment compared to control. PCN treatment significantly reduced
      serum T4 through week 3 before returning to control concentrations, whereas T4
      levels following PCB treatment fell below detection limits by week 3 and remained
      drastically reduced through week 19. TSH concentrations in PCN-treated rats
      increased three-fold at week 2, then declined to near control values at week 19.
      After one week of PCB treatment, TSH concentrations reached nearly twice that of
      controls, and were sustained until week 6. The incidence of thyroid follicular
      cell proliferative lesions, including cystic and follicular hyperplasia, cystic
      and follicular adenoma, and follicular carcinoma, was significantly increased
      following PCN treatment, but not following PCB treatment. PCB treatment caused an
      increase in thyroid carcinomas (4 of 22 rats) not associated with the
      proliferative-type lesions produced by PCN, despite an increase in TSH serum
      concentrations. In conclusion, PCN appears to promote thyroid tumors in a manner
      consistent with known effects of excessive TSH stimulation. However, thyroid
      carcinomas stemming from PCB treatment indicate that separate mechanisms exist
      for the production of thyroid cancer in rodents by chemicals classically
      considered microsomal enzyme inducers.

PMID- 15201440
TI  - Uptake of inspired propylene oxide in the upper respiratory tract of the f344
      rat.
AB  - Propylene oxide (1,2-epoxypropane) is a nasal toxicant and weak site-of-contact
      carcinogen in the rodent. The current study was aimed at providing quantitative
      information on upper respiratory tract (URT) dosimetry of this vapor. Since
      depletion of nasal non-protein sulfhydryls (NPSH) may be important in the
      toxicity of this vapor and may serve as a biomarker for delivery of propylene
      oxide to nasal tissues, measurements of respiratory and olfactory NPSH content
      after propylene oxide exposure were also made. Towards these ends, uptake of this
      vapor was measured in the surgically isolated URT of the F344 rat at constant
      velocity inspiratory flow rates of 50 or 200 ml/min throughout a 60-min exposure.
      Immediately after exposure, nasal respiratory and olfactory tissues were removed
      and analyzed for NPSH content. Propylene oxide was scrubbed from the airstream
      with moderate efficiency in the isolated URT. Similar uptake efficiencies were
      observed at inspired concentrations of 25, 50, 100, and 300 ppm, averaging 25 and
      11% at flow rates of 50 and 200 ml/min, respectively. After 1-h exposure to
      concentrations of 100 ppm or more, statistically significant depletion of nasal
      respiratory mucosal NPSH was observed. Nasal respiratory mucosal NPSH levels
      averaged approximately 90, 70, 50, 40, and 15% of control levels after 1-h
      exposure to 25, 50, 100, 300, or 500 ppm propylene oxide. Olfactory mucosal NPSH
      levels also generally decreased at 300 or 500 ppm propylene oxide, but did not
      demonstrate statistically significant, consistent changes after propylene oxide
      exposure.

PMID- 15201441
TI  - Inherent redox properties of diesel exhaust particles: catalysis of the
      generation of reactive oxygen species by biological reductants.
AB  - The toxicity of diesel exhaust particles (DEP) can be due to the particle itself,
      extractable components, or both. Many studies focus on the biological properties
      of DEP-extractable components although it is possible that chemical properties
      inherent to the DEP itself can lead to toxicity. Thus, an examination of the
      chemistry inherent to DEP was carried out. Herein, we report that DEP are capable
      of catalyzing the consumption of O2 (monitored using a Clarke electrode) by
      ascorbate and thiols leading to the generation of reactive oxygen species.
      Consistent with the idea that DEP are capable of catalyzing the generation of
      reactive oxygen species, they were also found to catalyze DNA strand breakage via
      an O2- and reductant-dependent process. Significantly, extraction of DEP with
      either organic solvent (methylene chloride) or acid (aqueous HCl) did little to
      abrogate this chemistry. Finally, using electron paramagnetic spectrometry (EPR),
      DEP were found to have paramagnetic properties. The paramagnetic character of DEP
      may be important to their ability to catalyze the formation of reactive oxygen
      species and at least partially responsible for their toxicity. These findings
      indicate that studies that primarily consider or examine particle extracts as the
      toxic components of DEP may be insufficient in describing the toxicity associated
      with DEP exposure.

PMID- 15201442
TI  - TCDD affects DNA double strand-break repair.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant, elicits a
      spectrum of deleterious biological responses including carcinogenesis. We
      hypothesize that TCDD exposure exerts its carcinogenicity, in part, by affecting
      the repair of DNA double strand breaks (DSBs) through homologous recombination
      (HR), mediated by the AhR signaling pathway. To investigate this hypothesis we
      used a Chinese hamster ovary (CHO) cell line (CHO 33) containing a neo direct
      repeat recombination reporter substrate to determine whether TCDD affects DNA DSB
      repair. The Saccharomyces cerevisiae mitochondrial endonuclease I-SceI was used
      to induce a site specific DSB within the upstream neo recombination substrate in
      the CHO 33 cells. The cells were then exposed to 500 pM of TCDD in the presence
      or absence of the AhR antagonist alpha-naphthoflavone (0.1 microM) for 24 h. Two
      weeks later HR frequencies were determined by counting the number of functional
      neo expressing, G418-resistant colonies per live cells plated. TCDD significantly
      increased HR frequency, demonstrating that it does in fact modulate the repair of
      DNA DSBs. Southern blot analysis of G418-resistant colonies using a cDNA neo
      probe determined that both gene conversion and gene deletion HR events occurred
      as a result of DNA DSB repair and TCDD exposure. Exposure of cells to alpha
      naphthoflavone resulted in a significant decrease in TCDD-induced HR frequency.
      These results demonstrate that TCDD, potentially acting via the AhR, can modulate
      HR repair of DNA DSBs in CHO 33 cells.

PMID- 15201443
TI  - Maternal milk as methylmercury source for suckling mice: neurotoxic effects
      involved with the cerebellar glutamatergic system.
AB  - Methylmercury (MeHg) is a highly neurotoxic compound and several studies have
      reported intoxication signs in children whose mothers were exposed to this
      environmental toxicant. Although it is well established that the in utero
      exposure to MeHg causes neurological deficits in animals and humans, there is no
      evidence of the exclusive contribution of lactational exposure to MeHg as a
      possible cause of neurotoxicity in the offspring. In this study, we investigated
      the exclusive contribution of MeHg exposure through maternal milk on biochemical
      parameters related to the glutamatergic homeostasis (glutamate uptake by slices)
      and to the oxidative stress (total and nonprotein sulfhydryl groups, nonprotein
      hydroperoxides, glutathione peroxidase and catalase activities) in the cerebellum
      of suckling mice (Swiss albino). The same parameters were also evaluated in the
      cerebellum of mothers. Our results showed, for the first time, that lactational
      exposure to MeHg caused a high percent of inhibition (50%) on glutamate uptake by
      cerebellar slices in pups. Contrarily, this effect was not observed in mothers,
      which were submitted to a direct oral exposure to MeHg (15 mg/l in drinking
      water). In addition, behavioral/functional changes were observed in the weaning
      mice exposed to MeHg. It was observed an increase in the levels of nonprotein
      hydroperoxides in cerebellum, and this increase was negatively correlated to the
      glutamate uptake by cerebellar slices. This study indicates that (1) the exposure
      of lactating mice to MeHg causes inhibition of the glutamate uptake by cerebellar
      slices in the offspring; (2) this inhibitory effect seems to be related to
      increased levels of hydroperoxide.

PMID- 15201444
TI  - Developmental toxicity of the dithiocarbamate pesticide sodium metam in
      zebrafish.
AB  - Sodium metam (NaM), a dithiocarbamate, is a general agricultural biocide applied
      prior to planting for the elimination of nematodes, soil pathogens, and weeds.
      There is a remarkable paucity of information about the mechanism of action and
      the risk that dithiocarbamates may pose to developing vertebrates. We have
      characterized NaM toxicity during early life stage exposure in zebrafish.
      Zebrafish embryos are most sensitive to NaM exposure during gastrulation and
      early segmentation (4-14 hours post fertilization, hpf). For mortality, the dose
      response curve is steep with an LC(50) estimate of 1.95 microM (248 ppb) at 48
      hpf. The most notable malformation among surviving embryos was a severely twisted
      notochord, which became evident by 24 hpf. Surprisingly, this notochord defect
      was not immediately lethal and the animals continued to grow despite delays in
      hatching, apparent paralysis, and an inability to feed. We have characterized the
      notochord malformation using histological and in situ hybridization techniques.
      collagen 2a1 mRNA expression is normally localized to the notochord sheath cells
      at 24 hpf, whereas in NaM-exposed embryos it is misexpressed in the notochord
      cells. Histological staining and myoD expression indicate that the myotomes of
      the NaM-exposed embryos are less defined, compacted and block-shaped compared to
      controls. The degradation product of NaM, methyl isothiocyanate (MITC), causes
      similar malformations at similar concentrations as NaM, suggesting that MITC or
      another common product may be the active toxicant. Our results indicate that
      developing zebrafish are sensitive to NaM and MITC and we believe that this model
      is ideal to elucidate the molecular mechanism(s) and etiology of NaM toxicity in
      vertebrates.

PMID- 15201445
TI  - Mouse models of triplet repeat diseases.
AB  - Since their discovery in 1991, triplet repeat mutations have been found to be the
      cause of genomic fragile sites, two of which are linked to mental retardation,
      myotonic dystrophy, and several late-onset neurodegenerative diseases. In all
      cases, these mutations exhibit gametic and/or somatic instability once they have
      expanded into the mutant range. The mutations are located in coding and noncoding
      gene regions and have been found to act by dominant and recessive mechanisms. A
      wide range of mouse models has been generated to understand both of the
      mechanisms that underlie repeat instability and the molecular pathogenesis of the
      diseases. Mouse models have proved extremely useful in these goals and are now
      also being used for the preclinical testing of therapeutic compounds. This
      chapter reviews the successes and limitations of the approaches that have been
      developed.

PMID- 15201446
TI  - Analysis of triplet repeat replication by two-dimensional gel electrophoresis.
AB  - Expansions of triplet repeats are responsible for more than 15 hereditary
      neurological disorders in humans. Triplet repeats are fairly stable when the
      number of elementary units is under approx 30, but become polymorphic in length
      with a clear bias for expansions when this threshold is exceeded. This results in
      the rapid addition of hundreds or even thousands of extra repeats and,
      ultimately, disease. The mechanisms of triplet repeat expansions are not yet
      understood. The role of several genetic processes, including replication,
      recombination, and repair, was suggested. However, given the swift accumulation
      of extra DNA material, DNA replication seems to be an intuitive candidate for
      generating expansions. Numerous data point to the aberrant replication of triplet
      repeats as a cause of triplet repeat expansions. Direct experimental proof of
      aberrant replication through triplet repeats was lacking. This encouraged us to
      study the mode of replication fork progression through triplet repeats in vivo.
      We analyzed the effects of triplet repeats on replication of bacterial or yeast
      plasmids using an approach called two-dimensional neutral/neutral gel
      electrophoresis of replication intermediates. This technique, originally
      developed for mapping replication origins, is also instrumental in defining
      replication pause sites. Using this technique, we were able to unambiguously
      demonstrate that expandable triplet repeats attenuate replication fork
      progression in vivo and get some insights into the mechanisms of repeat
      expansions.

PMID- 15201447
TI  - Genetic assays for triplet repeat instability in yeast.
AB  - The unusual genetic features of trinucleotide repeat (TNR) diseases have
      stimulated a substantial body of research into the underlying molecular
      mechanisms of repeat instability. As one useful tool to study TNR instability,
      selectable genetic assays for expansions and contractions were developed in the
      yeast Saccharomyces cerevisiae. These assays are sensitive, quantitative, easy to
      manipulate, and reproducible. Once colonies are identified through genetic
      selection, follow-up experiments with PCR help detail the precise molecular
      changes that occurred at the TNR tract. This chapter describes these yeast assays
      and provides useful technical insights into creating and testing triplet repeat
      instability in a classic model system.

PMID- 15201448
TI  - Detection and isolation of trinucleotide repeat expansions using the RED method.
AB  - To facilitate identification of disease genes containing an expanded
      trinucleotide repeat, a repeat expansion detection (RED) and gene cloning system
      was established. The RED method was developed to enable detection of expanded
      trinucleotide repeat sequences in any DNA sample from any species without prior
      knowledge of the DNA sequences flanking the repeat. The DNA to be tested is used
      as a template for a repeat oligonucleotide to anneal and ligate in a two-step
      cycling procedure. After hundreds of annealing/ligation cycles, a large amount of
      oligonucleotide multimers is accumulated. The longest multimer represents the
      largest repeat expansion in the genome tested. The gene isolation strategy is
      based on size separation of genomic fragments, followed by subcloning and library
      hybridization with an oligonucleotide probe. The expanded trinucleotide repeat is
      identified throughout the procedure using the RED method. Using this approach,
      two disease genes, the Huntington's disease gene and the MJD/SCA3 gene, were
      cloned. This cloning strategy should be applicable to isolation of any DNA
      fragment containing large trinucleotide repeat expansions in any species.

PMID- 15201449
TI  - Analysis of unstable triplet repeats using small-pool polymerase chain reaction.
AB  - Small-pool polymerase chain reaction (PCR) constitutes the PCR amplification of a
      trinucleotide repeat in multiple small pools of input DNA containing in the order
      of from 0.5 to 200 genome equivalents. Products are resolved by agarose gel
      electrophoresis and detected by Southern blot hybridization under conditions that
      allow the identification of products derived from single-input molecules. The
      method allows the detailed quantification of the degree of repeat-length
      variation in a given sample, including the detection of common variants and those
      alleles present only in a small subset of cells. Detailed analysis of repeat
      dynamics is essential for a complete understanding of the molecular mechanisms
      that generate diversity and lead to disease in the unstable trinucleotide DNA
      repeat disorders.

PMID- 15201450
TI  - Real-time RT-PCR for CTG repeat-containing genes.
AB  - Myotonic dystrophy (DM1) is a neuromuscular disorder caused by a CTGn expansion
      in the 3'-untranslated region (UTR) of myotonic dystrophy protein kinase (DMPK).
      SIX5 is a homeodomain gene located just downstream of the repeat, and myotonic
      dystrophy WD protein (DMWD) is located close upstream of DMPK. It has been
      hypothesized that the expansion might influence the expression of the three
      myotonic dystrophy locus genes (DM1-locus), contributing to the complex and
      varied phenotype in this disorder. Real-time quantitative reverse transcription
      polymerase chain reaction, or TaqMan, is a very sensitive method that enables
      quantification of expression levels of genes from small amounts of tissue and
      lowly expressed genes. Because data are collected during the assay, the
      quantification is possible over a wide range of expression levels. By the use of
      a standard curve and an endogenous control, we have applied the TaqMan system for
      absolute quantification of the expression levels of the three genes (DMPK, DMWD,
      and SIX5) in the same tissue sample.

PMID- 15201451
TI  - Antibodies against huntingtin: production and screening of monoclonals and single
      chain recombinant forms.
AB  - Antibodies can be extremely useful tools for the field of triplet repeat
      diseases. These reagents are important for localizing proteins in tissues, and
      within cells, they can be used in the isolation and characterization of the
      components of protein complexes, they can distinguish proteins with normal or an
      expanded polyglutamine repeat, they may be able to distinguish distinct
      conformations of a protein, and they can be used to perturb the function of
      proteins in living cells. Our group has produced monoclonal and recombinant
      single-chain antibodies that can be used for each of these purposes with
      huntingtin. This is the protein that, when mutated to contain an expanded polyQ
      motif, causes Huntington's disease.

PMID- 15201452
TI  - Using antibodies to analyze polyglutamine stretches.
AB  - Expansion of a homomeric stretch of glutamine residues beyond a critical
      threshold can produce neurodegenerative disease. This observation led to the idea
      that abnormal polyglutamine stretches can alter protein structure in ways that
      contribute to disease. Because they are prone to aggregation, proteins with
      abnormal polyglutamine expansions have been difficult to study with conventional
      biophysical approaches. Some of these proteins are also very large, complicating
      efforts to generate them in vitro or to purify them for biochemical studies. An
      alternative approach has been to use antibodies with known binding specificity as
      probes of protein folding and protein structure. Antibodies can often bind to
      specific protein epitopes in situ and are, therefore, one of the few tools that
      can be used to probe protein structure in a physiological context and in the
      presence of that protein's normal binding partners. However, antibodies are
      complex reagents, and an understanding of their binding properties, methods of
      use, and limitations is needed to interpret results properly. We have developed
      monoclonal antibodies that specifically recognize expanded polyglutamine
      stretches in mutant huntingtin. Here, we describe several methods for using one
      of these antibodies to explore the structure of abnormal polyglutamine expansions
      and the proteins that contain them.

PMID- 15201453
TI  - Solubilization of aggregates formed by expanded polyglutamine tract expression in
      cultured cells.
AB  - The expression of expanded polyglutamine in mammalian cells causes the formation
      of aggregates. For elucidation of the biochemical properties of the aggregates,
      isolation and solubilization of the aggregates are required. This chapter
      provides useful protocols for the solubilization of polyglutamine aggregates and
      further applications of protein analysis.

PMID- 15201454
TI  - Caenorhabditis elegans as a model system for triplet repeat diseases.
AB  - Common features underlie the generation and function of neurons in multicellular
      animals. It is likely that conserved pathways and genes also are involved in
      neuronal degeneration and malfunction. To address the molecular mechanisms of
      complex human neurological disorders, many investigators are choosing to study
      these diseases in simpler organisms. The nematode Caenorhabditis elegans provides
      an excellent model system to address genetically the mechanisms of triplet repeat
      diseases. Advantages of using C. elegans as a model system include the ease of
      genetic manipulation, the sequenced genome, and a short life cycle. Furthermore,
      researchers can precisely identify specific neurons and follow their development
      or survival throughout the animal's lifetime. This chapter describes the tools
      and approaches for modeling triplet repeat diseases in C. elegans with a specific
      emphasis on polyglutamine (polyQ) diseases. Although the bulk of the chapter is
      devoted to generating a polyQ disease model in C. elegans, it also addresses
      potential avenues for assessing the impact of specific candidate genes/pathways
      on the disease process, including cell death and aging.

PMID- 15201455
TI  - Monitoring aggregate formation in organotypic slice cultures from transgenic
      mice.
AB  - Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG
      repeat expansion in the first exon of the HD gene. It encodes a protein known as
      huntingtin, which aggregates in the nuclei of affected neurons. These aggregates
      are an obvious therapeutic target, thus an organotypic slice culture assay has
      been designed to screen potential antiaggregation compounds using the R6/2 mouse
      model of HD. This assay allows the aggregates to be fully quantified using
      fluorescent confocal microscopy and gives additional information perturbing to
      drug solubility, delivery, toxicity, concentration, and efficacy of inhibitors.
      This information is essential to the planning and application of an in vivo drug
      trial in the R6/2 mice.

PMID- 15201456
TI  - The CGG repeat and the FMR1 gene.
AB  - This review intends to provide the different DNA methods for diagnosis of the
      repeat in the FMR1 gene. The two DNA methods to determine the CGG repeat size are
      Southern blot hybridization and the polymerase chain reaction (PCR), including
      bisulfite treatment.

PMID- 15201457
TI  - Analysis of CTG repeats using DM1 model mice.
AB  - This chapter describes how transgenic mice can be made with human genomic DNA
      fragments cloned from DM1 patients' DNA and how the CTG repeat instability is
      assessed over generations and in different tissues. Construction of cosmid
      libraries is fully reported from the extraction of high-molecular-weight DNA from
      patients' lymphoid cell lines, to the screening and mapping of the positive
      clones. After establishment of transgenic lines, we explained the methods used to
      analyze (a) the CTG repeats that are inherited from the transgenic parents, with
      regard to age, sex, and parental CTG repeat sizes, and (b) the CTG repeat-length
      variations that can be observed in somatic tissues and in sperm.

PMID- 15201458
TI  - Lentiviral-mediated gene transfer to model triplet repeat disorders.
AB  - This chapter describes the potential use of viral-mediated gene transfer in the
      central nervous system as a new strategy in developing animal models of
      neurodegenerative diseases. To illustrate the approach, procedures for the
      production of lentiviral vectors encoding polyQ proteins are provided, as well as
      methods for the determination of viral titers, in vitro infection, and basic
      protocols for in vivo studies in rodents.

PMID- 15201459
TI  - Mouse tissue culture models of unstable triplet repeats.
AB  - Once into the expanded disease-associated range, trinucleotide repeat alleles
      become dramatically unstable in the germline and in somatic cells. The molecular
      mechanism(s) that underlie this unique form of dynamic mutation are poorly
      understood. Numerous transgenic mouse models of unstable trinucleotide repeats,
      which reconstitute the dynamic nature of somatic mosaicism observed in humans,
      have been generated. Given their easy accessibility, tissues from these mice can
      be collected to establish homogenous cell culture models of trinucleotide repeat
      dynamics. This chapter describes how such cultures can be established and
      maintained. Such in vitro systems may be useful to study relevant biological
      questions concerning fundamental triplet repeat metabolism. In particular,
      monitoring of repeat stability in cells growing under controlled conditions could
      help to clarify the relationship among the accumulation of repeat length
      variation, cell division rates, and DNA replication.

PMID- 15201460
TI  - Neurotransmitter receptor analysis in transgenic mouse models.
AB  - One of the characteristic findings in human Huntington's disease (HD) is the
      alteration of neurotransmitter receptors. To a remarkable degree, transgenic HD
      mouse models recapitulate neurotransmitter receptor alterations. Neurotransmitter
      receptors can be assessed at the protein level by using receptor-binding
      autoradiography. One can also measure levels of receptor messenger RNA with in
      situ hybridization (ISH), employing either oligonucleotide or ribonucleotide
      probes. Both of these techniques-receptor-binding autoradiography and in situ
      hybridization-yield quantitative and regionally specific information regarding
      neurotransmitter receptors. We describe techniques for performing receptor
      binding autoradiography and two types of in situ hybridization using
      oligonucleotide and ribonucleotide probes. With receptor binding and ISH, one can
      obtain quantitative region-specific assessments of neurotransmitter receptor
      alteration, a key pathologic event in HD pathogenesis.

PMID- 15201461
TI  - Chromatin immunoprecipitation technique for study of transcriptional
      dysregulation in intact mouse brain.
AB  - Transcriptional dysregulation has emerged as an important pathologic mechanism
      underlying the pathogenesis of Huntington's disease (HD). The control of
      transcription depends on appropriate binding of transcription factor proteins to
      specific promoter regions of genes. Chromatin immunoprecipitation (ChIP) is a
      technique that has been used to study the association of transcription factors
      with DNA. To address the hypothesis that there is altered transcription factor
      DNA association in HD, we have recently adapted the ChIP technique to the study
      of transgenic mouse brain. Here, we describe our method of performing ChIP in
      intact mouse brain. We have optimized conditions for formaldehyde crosslinking,
      antibody immunoprecipitation, and quantitative real-time polymerase chain
      reaction detection. Using ChIP, one can measure the association of transcription
      factors with specific genes and determine if this association is altered in
      transgenic HD mouse models. ChIP applied to whole-mouse brain can thus offer a
      window into mechanisms of transcriptional dysregulation.

PMID- 15201462
TI  - Techniques for thick-section Golgi impregnation of formalin-fixed brain tissue.
AB  - The histologic staining technique for central nervous system (CNS) tissue known
      as the Golgi technique was initially developed more than 125 yr ago. It was with
      this technique that, for the first time, whole nerve cells and their processes
      were simultaneously observed microscopically. Although the technique was widely
      used in the early 20th century, its use languished to some extent until the late
      1900s when, used in conjunction with ultrastructural studies, it began to provide
      new insights into microscopic anatomy and pathology of the CNS. Several
      permutations of the technique have evolved since its early stages. The one
      represented in this chapter was developed so that Golgi-impregnated CNS tissues
      could be embedded in polymerized plastic and cut into relatively thick sections
      for light microscopic study. The advantages are that (a) sections of the clear
      and almost colorless plastic allow enhanced visualization of the intricate
      structure and ramification of dendritic elements of CNS neurons, (b) because of
      the relatively thick microscopic sections (25-30 micro m), details of lengths and
      arborization of dendritic "trees" can be studied and photographed to provide
      greater detail than in thinner sections, and (c) numbers and morphologic
      characteristics of synaptic spines can be precisely evaluated.

PMID- 15201463
TI  - Assessment of impaired proteasomal function in a cellular model of polyglutamine
      diseases.
AB  - A protein marked for degradation by the ubiquitin-proteasome pathway (UPP) is
      attached to multiple molecules of ubiquitin, a 76-amino-acid protein that targets
      the protein for rapid hydrolysis by 26S proteasome. Impaired function of UPP
      results in accumulation of misfolded and ubiquitinated proteins and has been
      implicated in the pathogenesis of various neurodegenerative diseases, including
      polyglutamine diseases. Impaired function of UPP can be evaluated either by
      assaying the proteasome's protease activity or the accumulation of ubiquitinated
      proteins.

PMID- 15201464
TI  - Assessment of in vitro and in vivo mitochondrial function in Friedreich's ataxia
      and Huntington's disease.
AB  - Huntington's disease (HD) and Friedreich's ataxia (FRDA) are associated with
      defects of respiratory-chain enzyme activities. In the respective disorders,
      these can be identified in tissue samples from postmortem brain and also during
      life from skeletal or cardiac muscle samples. The mitochondrial abnormalities are
      robust and reproducible. In the case of HD, it is uncertain how these
      mitochondrial defects fit in the pathogenetic cascade. Studies are ongoing to
      identify whether the respiratory-chain defect present in the brain is expressed
      in skeletal muscle at the spectrophotometric level. The presence of a
      bioenergetic defect as identified by 31P magnetic resonance spectroscopy (MRS)
      suggests that in HD expression of the mutant protein can exert an influence on
      mitochondrial function in tissues outside the central nervous system (CNS). It
      would appear that frataxin deficiency has a direct effect on mitochondrial
      function, either through iron-sulfur cluster construction or through the
      generation of free radicals. The identification these bioenergetic abnormalities
      in these neurodegenerative disorders has opened up the prospect for the
      development of disease-modifying therapies directed to the biochemical
      abnormalities demonstrated. 31P-MRS studies have detected a deficit of in vivo
      oxidative phosphorylation in the skeletal muscle of FRDA and HD patients and in
      the myocardium of FRDA patients. In both FRDA and HD patients, a relationship
      between the triplet repeat expansion and the extent of in vivo energy metabolism
      deficit has been shown. The total safety of MRS scans makes them an ideal tool
      for repeated assessments to monitor disease progression as well as the effect of
      new therapies. This chapter describes useful methods for assessment of
      mitochondrial function in vitro and in vivo.

PMID- 15201465
TI  - Triplet repeats and DNA repair: germ cell and somatic cell instability in
      transgenic mice.
AB  - This chapter describes methods for the isolation of specific cell types that
      reveal how and where expansion can occur. For the hereditary component of
      expansion, the male germ cell has proved useful in distinguishing processes that
      can contribute to expansion, as described in our article (Nature Genetics 27,
      407, 2001). Mature spermatazoa (SZs) can be isolated directly from the
      epididymis. Haploid spermatids (STs), diploid spermatagonia (SGs), and tetraploid
      spermatocytes (SCs) can be removed from the testis and sorted by fluorescence
      activity cell sorting (FACS); differences in DNA content and morphology allow
      resolution by fluorescence and light scattering. Repeat-length measurement can
      pinpoint the stage at which expansion occurs. Because the timing of meiosis and
      mitosis with respect to sperm development is known, the analysis can distinguish
      repair and replication processes. Furthermore, the possible contribution of Y- or
      X-specific factors can be evaluated by sorting X- and Y-bearing germ cells. To
      enable analysis of female germ cells, we describe methods for oocyte preparations
      and a method for the isolation of the eight-cell-stage embryo. Therefore, the
      methods described here can help to answer such questions as the timing during
      development of expansion, whether expansion is limited to a single period,
      whether both replication and repair contribute to instability, and the role of
      somatic instability in disease. If further expansion of the inherited allele
      contributes to the phenotype, then intervention in somatic tissue might be
      therapeutic.

PMID- 15201466
TI  - Oxidative damage in Huntington's disease.
AB  - Huntington's disease is a hereditary neurodegenerative disorder, characterized by
      motor, psychiatric, and cognitive symptoms. The genetic defect responsible for
      the onset of the disease, expansion of CAG repeats in exon 1 of the gene that
      codes for huntingtin, has been unambiguously identified. On the other hand, the
      mechanisms by which the mutation causes the disease are not completely understood
      yet. However, defects in the energy metabolism of affected cells may cause
      oxidative damage, which has been proposed as one of the underlying molecular
      mechanism that participates in the etiology of the disease. This chapter
      describes methods to genotype mice transgenic for the disease, characterizing
      their progressive neurological phenotype, and biochemical methods that allow
      determining striatal oxidative damage, and establishing the status of both
      protective cellular systems, and biochemical pathways that induce the generation
      of free radicals. The methods described in this chapter permit one to relate the
      neurological phenotype of the mice with the degree of oxidative damage sustained
      by the brain.

PMID- 15201467
TI  - Subjective well-being among African-Americans with spinal cord injury: an
      exploratory study between men and women.
AB  - OBJECTIVE: The purpose of this study was to identify gender differences in
      subjective well-being among 309 African-American participants with spinal cord
      injury (SCI). DESIGN: Cross-sectional. SETTING: A Southeastern specialty
      hospital. PARTICIPANTS: There were a total of 309 participants, all of whom were
      African-Americans. All participants had traumatic SCI, were at least 18 years or
      older at the time of the study, and a minimum of one year had passed since SCI
      onset. MAIN OUTCOME MEASURES: Measures of subjective well-being included the Life
      Situation Questionnaire--Revised, Purpose in Life scale, and the Older Adult
      Health and Mood Questionnaire. RESULTS: Multiple gender differences were
      observed, with women reporting higher scores on depressive symptoms and negative
      affect, but lower scores on purpose in life. Other significant findings were
      observed related to self-reported problems, with men reporting greater problems
      with pressure ulcers and sexual issues and women reporting greater problems in
      several areas related to coping and affect. The only gender difference in life
      satisfaction indicated greater satisfaction with sex life among women.
      CONCLUSION: It is clear from the findings that differences do exist among male
      and female African-Americans with spinal cord injuries. More research is needed
      to definitively outline differences.

PMID- 15201468
TI  - Community integration in spinal cord injury of long duration.
AB  - OBJECTIVE: to examine longitudinal changes in community reintegration among
      people aging with spinal cord injury, and to determine if these changes are
      related to demographic variables and scores on psychosocial measures of stress,
      life satisfaction, depression, psychological well-being, and perceived quality of
      life. DESIGN: 178 members of a British population-based study of outcomes after
      spinal cord injury were evaluated at three-year intervals from 1990 to 1999.
      Participants responded to a questionnaire that included measures of community
      integration and perceived psychosocial status. Scores and results were analyzed
      to identify changes over time in community reintegration. RESULTS: The findings
      indicate a general decline in community reintegration over time in terms of
      physical independence, mobility, occupation and social integration. However,
      economic self-sufficiency appears to steadily improve as time passes. Life
      satisfaction also declined over time and was related to community reintegration.
      Measures of emotional distress were not important predictors of community
      reintegration. CONCLUSIONS: Community reintegration declined over time in this
      sample of British individuals aging with SCI. Although there were concurrent
      relationships between demographic variables of age and neurologic group, neither
      these factors nor duration of injury appeared to impact change in community
      reintegration. More significant was the relationship between perceived life
      satisfaction and community integration.

PMID- 15201469
TI  - Enhancing community re-integration following spinal cord injury.
AB  - This study assessed the efficacy of a community-based program designed to provide
      Independent Living services (ILS) to people with new, traumatic spinal cord
      injuries (SCI). The program was implemented in six communities throughout the US
      served by Model SCI Care Systems where services are provided by Centers for
      Independent Living. Participants consisted of eighty-one people with new,
      traumatic SCI (38% intervention participants and 62% comparison group members).
      Each group was assessed with regard to ILS received, unmet needs for services,
      satisfaction with services and three outcomes: perceived control, quality of life
      and societal participation. Results show that program participants and comparison
      group subjects differed little in terms of either measures of ILS or the outcome
      measures. There were numerous associations between ILS and outcomes; those who
      felt that they did not need ILS tended to have superior outcomes to both those
      who received these services and those who said that they had unmet needs.
      Advocacy services had the strongest association with study outcomes. The study
      highlights the importance of minimizing the need for ILS. It also indicates that
      there is a need for improved communication among rehabilitation professionals
      working in large medical institutions and those working in community
      organizations.

PMID- 15201470
TI  - The current state of personal assistance services: implications for policy and
      future research.
AB  - Personal assistant services (PAS) are designed to support persons with
      disabilities in their routine performance of activities of daily living (ADLs)
      and to provide individuals with disability the opportunity to go to school,
      volunteer, obtain active employment, and participate in social and recreational
      activities. PAS are primary and essential to the realization of societal
      inclusion and personal freedom among persons with severe, disabling conditions.
      This paper reviews the personal assistance literature for persons with spinal
      cord injury and other disabilities. Evidence-based recommendations are made for
      PAS policy initiatives and future directions in PAS research.

PMID- 15201471
TI  - Participation in recreation and sports for persons with spinal cord injury:
      review and recommendations.
AB  - Recreation and sports following Spinal Cord Injury (SCI) are beneficial, but
      under-studied, aspects of community integration. Previous studies have shown that
      sports and recreation can offer numerous physiological and psychological benefits
      to those who participate. This manuscript critically reviews available literature
      focused upon participation in recreation and sports among persons with SCI.
      Issues of participation, technology and safety are discussed and recommendations
      are provided.

PMID- 15201472
TI  - Return to work for persons with spinal cord injury: designing work supports.
AB  - Recent advances in medical practices have led to increased survival rates among
      persons with spinal cord injuries. Many of these individuals find themselves
      unemployed post injury and face a myriad of challenges, such as lack of
      transportation, limited accessibility, and health problems. This paper describes
      how a Supported Employment approach can be used to assist persons with SCI with
      return to work. A number of issues that may impede employment and how to
      circumvent each are offered, along with a case study that describes one
      individual's return to work.

PMID- 15201473
TI  - Assistive technology and computer adaptations for individuals with spinal cord
      injury.
AB  - Spinal cord injury (SCI) commonly occurs in individuals during important years
      for formation of vocational goals, resulting in low post-injury employment rates
      and higher costs to society. Individuals with SCI who are employed have improved
      quality of life. Assistive technology, often available at modest cost, can help
      individuals with SCI to compensate for functional limitations, overcome barriers
      to employability, enhance technical capacities and computer utilization, and
      improve ability to compete for gainful employment.

PMID- 15201474
TI  - Using telework to enhance return to work outcomes for individuals with spinal
      cord injuries.
AB  - Return-to-work is an area of critical concern for individuals with a spinal cord
      injury (SCI), because of the psychological, psychosocial and economic benefits of
      employment. Although the majority of individuals with SCI are employed pre
      injury, they are impeded from maintaining those jobs due to personal,
      organizational and systems level barriers. Telework, which permits home-based
      work through the use of Information and Communication Technologies (ICT),
      alleviates many of return-to-work barriers for individuals with SCI, including
      job demands, mobility limitations, transportation needs and fatigue imposed by
      medical complications. For telework to fulfill its potential as a return-to-work
      strategy, rehabilitation professionals and employers must assess and enhance the
      readiness of the individual, workgroup and organization within the context of a
      disability management program. Strategies for successfully implementing telework
      as a return-to-work strategy for individuals with SCI are discussed, along with
      implications for future research.

PMID- 15201475
TI  - Preliminary assessment of a prototype advanced mobility device in the work
      environment of veterans with spinal cord injury.
AB  - The INDEPENDENCE 3000 IBOT Transporter (IBOT) is an electronically stabilizing
      device for people with disabilities. The purpose of this study was to collect
      qualitative data on the potential for the IBOT to improve employment satisfaction
      of veterans who use wheelchairs to work. This study was based upon observations
      by trained clinicians, and responses to a survey completed by four men with
      traumatic spinal cord injury, who worked in an office environment. The mean age
      of the subjects was 52 +/- 8.8 years. The subjects used the devices to hold eye
      level discussions with colleagues, climb stairs, ascend steep ramps, and
      negotiate curbs. When subjects were asked to rate the ease of getting around in
      the IBOT compared to their personal wheelchairs, they responded with a mean of
      6.7 +/- 1.8 on a 10-point visual analog scale. The response to rating the overall
      function of the IBOT within their working environment yielded a rating of 6.0 +/-
      2.8. Half of the users felt that the IBOT would help them at work and all thought
      it should be made available to veterans who use wheelchairs. A larger study
      should be conducted to determine if the IBOT affects work performance and the
      ability to return to work.

PMID- 15201476
TI  - Rat transgenic models with a phenotype of intracellular Abeta accumulation in
      hippocampus and cortex.
AB  - In this communication we report the characterization of several transgenic rat
      lines expressing human AbetaPP carrying the Swedish and Indiana mutations (coded
      UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19)
      and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg
      rats, the AbetaPP and PS1 transgene expression was largely restricted to the
      hippocampus and neocortex. The PS1 transgenic rats did not produce visible
      changes in Abeta immunoreactivity. The AbetaPP transgenic rats (both the single
      Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalbeta
      accumulation without plaque formation and with no increased immunoreactivity for
      AbetaPP amino and carboxyl-terminal epitopes. This phenotype was apparent as
      early as 6 months of age in the transgenic rat lines carrying the human AbetaPP
      transgene. No senile plaques of aggregated Abeta were observed in any of the
      transgenic lines generated, up to 24 months of age. The hAbetaPP single
      homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in
      glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the
      hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed
      differences in the protein profile between this transgenic line and controls.

PMID- 15201477
TI  - Oestrogen replacement therapy may improve memory functioning in the absence of
      APOE epsilon4.
AB  - There is currently intense controversy regarding the use of hormone replacement
      therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in
      Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be
      modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for
      AD). Here we report the findings of the first study designed to systematically
      explore the interaction of (a) oestrogen replacement therapy (ERT) and (b)
      possession of an epsilon4 allele of APOE on specific elements of episodic
      learning and memory that are commonly used indices of age-related cognitive
      decline. This data represents a cross-sectional analysis of the interaction of
      ERT and APOE genotype on learning and memory in a cohort of 181 healthy
      postmenopausal women [ERT users (n = 101, mean age 65.40 +/- 6.34); ERT non-users
      (n = 80, mean age 67.03 +/- 6.80)] residing in Perth, Western Australia. The
      highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of
      items recalled; P < 0.05) performance was observed in women taking ERT who were
      not carriers of the APOE epsilon4 allele. APOEepsilon4 carriers receiving ERT
      performed no better on episodic memory testing than APOE epsilon4 carriers who
      were not receiving ERT. These cognitive differences related to genetic profile,
      were noted on both recall and recognition (P = 0.005) tests of memory. The
      findings have significance for evaluating whether and when ERT may be clinically
      indicated. Specifically, ERT may benefit the cognitive functioning of women not
      carrying the APOE epsilon4 allele.

PMID- 15201478
TI  - Alzheimer-associated neuronal thread protein mediated cell death is linked to
      impaired insulin signaling.
AB  - Alzheimer-associated neuronal thread protein, AD7c-NTP, accumulates in cortical
      neurons and co-localizes with phospho-tau-containing cytoskeletal lesions in
      brains with AD. Over-expression of AD7c-NTP results in increased neuronal death
      mediated by apoptosis and mitochondrial dysfunction. Empirical studies
      demonstrating differential growth factor responses to AD7c-NTP led to us to
      further investigate the effects of insulin, insulin-like growth factor, type 1
      (IGF-1), nerve growth factor (NGF), and platelet-derived growth factor (PDGF)
      stimulation on neuronal survival mechanisms in relation to AD7c-NTP expression.
      PNET2 human CNS-derived neuronal cells were stably transfected with a cDNA
      encoding AD7c-NTP or chloramphenicol acetyl transferase (CAT) whereby gene
      expression was regulated by an inducible promoter. In cells that expressed AD7c
      NTP, insulin or IGF-1 stimulation was associated with reduced viability with
      increased levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and reduced
      levels of Bcl-2 and phospho-Erk MAPK. In contrast, AD7c-NTP-transfected cells
      stimulated with NGF or PDGF, and CAT-transfected cells stimulated with any one of
      the four growth factors remained viable and had low levels of p53, p21/Waf-1,
      phospho-JNK, and phospho-tau, and abundant Bcl-2 and phospho-Erk expression. The
      results suggest that reduced survival in neurons that over-express AD7c-NTP may
      be mediated by impaired insulin/IGF-1 signaling, and that CNS neurons with
      abundant insulin or IGF-1 receptors may be particularly vulnerable to the adverse
      effects of AD7c-NTP.

PMID- 15201479
TI  - Incubation of nerve endings with a physiological concentration of Abeta1-42
      activates CaV2.2(N-Type)-voltage operated calcium channels and acutely increases
      glutamate and noradrenaline release.
AB  - We wish to understand the normal function of amyloid-beta peptides (Abeta) and to
      see if they destabilize neuronal calcium homeostasis [Mattson et al., J.
      Neurosci. 12 (1992), 376-389]. We observed that a physiological concentration (10
      nM) of Abeta1-42 increased both glutamate and noradrenaline exocytosis from rat
      cortical nerve endings at least in part by activation of N-type Ca2+ channels.
      Abeta oligomers rather than monomers or fibrils probably are the most active
      form. Three alternatively-proposed effects of Abeta (reactive oxygen species
      formation, membrane perforation, and disruption of Ca2+ stores) also were tested
      by incubating nerve endings with a relatively high (by this study's standards)
      concentration of Abeta1-42(100 nM). None of the three proposed effects were
      detected during these incubations. These results support the hypothesis that
      persistent elevations of Abeta, which normally operates as a modulator of N-type
      voltage gated calcium channels, could increase internal nerve ending Ca2+ and
      excitatory neurotransmitter release to produce the early neurotoxic effects that
      eventually lead to Alzheimer's disease.

PMID- 15201480
TI  - Proteome analysis of brain proteins in Alzheimer's disease: subproteomics
      following sequentially extracted protein preparation.
AB  - Quantitative proteome analysis of Alzheimer's disease (AD) brains was performed
      using two-dimensional (2-D) gels in order to find out the pathological protein
      expression in AD. We sequentially extracted brain proteins using two distinct
      sample solutions, yielding different protein fractions (fraction A and B). These
      fractions showed distinct 2-DE patterns with high resolution and excellent
      reproducibility. In fraction A (solubilized by urea and Nonidet P-40 (NP-40)),
      approximately 1300 protein spots were detected, and the relative volume (%VOL)
      significantly increased in five spots and significantly decreased in 10 spots in
      AD. The proteins identified include enzymes, molecular chaperones and
      cytoskeletal proteins. In fraction B (solubilized by urea, thiourea, N-decyl-N,N
      dimethyl-3-ammonio-1-propane sulfonate (SB3-10) and 3-[(3
      cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS)), over 500 protein
      spots were detected in the 2-DE data analysis. The %VOL of three spots was
      significantly increased in AD. Two of these spots were identified as glial
      fibrillary acidic protein (GFAP) using mass spectrometry. These results suggest
      that subproteomics following sequentially extracted brain proteins is a useful
      method for the analysis of brain extracts containing hydrophobic proteins. Our
      findings will prompt further study on disease-linked proteins for the
      investigation of AD pathogenesis and the quest for disease markers.

PMID- 15201481
TI  - Differential susceptibity of transgenic mice lacking one or both apolipoprotein
      alleles to folate and vitamin E deprivation.
AB  - The E4 allele of apolipoprotein E (ApoE) is associated with neurodegeneration in
      part due to increased oxidative stress. Transgenic mice lacking ApoE (-/-)
      represent a model for the consequences of deficiencies in ApoE function. Dietary
      deficiency in folate and vitamin E has previously been shown to potentiate the
      impact of ApoE deficiency; ApoE-/- mice deprived of folate and vitamin E for 1
      month demonstrated increased oxidative damage in brain tissue and impaired
      cognitive performance as compared to ApoE+/+ mice. Since individuals homozygous
      for E4 can demonstrate more increased risk for neurodegeneration and an earlier
      age of onset than individuals heterozygous for E4, we tested the impact of folate
      and vitamin E deprivation on ApoE+/- mice. Thiobarbituric acid-reactive
      substances in brain tissue of ApoE+/- were significantly increased compared to
      ApoE+/+ mice, but this increase was less than that observed in ApoE-/- mice. By
      contrast, livers of ApoE+/- and -/- mice displayed an identical increase over
      that of +/+ mice. ApoE-/- mice, but not +/- or +/+ mice, exhibited impaired
      cognitive performance in maze trials when deprived of folate and vitamin E. These
      findings support the notion that homozygous deficiency of ApoE function can be
      more severe than heterozygous deficiency. They further suggest that the impact of
      partial deficiency in ApoE function may present a latent risk that may manifest
      only when compounded by other factors such as dietary deficiency.

PMID- 15201482
TI  - Injured brain endothelial cells release neurotoxic thrombin.
AB  - The multifunctional serine protease thrombin has been shown to be neurotoxic in
      vitro and in vivo and is demonstrable in the Alzheimer disease (AD) brain. We
      have documented that in AD the cerebral microvasculature is a source of
      inflammatory and neurotoxic proteins. The objective of this study was to
      determine if injured brain endothelial cells could be a source of neurotoxic
      thrombin. Brain endothelial cells were incubated with either sodium nitroprusside
      (SNP, 10 microM), inflammatory proteins (IL-1beta, IL-6, TNFalpha, LPS, IFNgamma)
      or the PKC inhibitor bisindolymaleimide (1 microM) for 24 h and conditioned media
      collected. Endothelial cell conditioned medium was incubated with purified
      apolipoprotein E4 (apoE4) for 24 h, and then analyzed for neurotoxic activity
      against primary cortical cultures and for apoE4 fragments by western blot.
      Endothelial cell conditioned medium collected after treatment with either SNP,
      inflammatory proteins, or the PKC inhibitor bisindolymaleimide, demonstrated a
      significant (p < 0.005) level of thrombin activity, the presence of apoE4
      fragments, and was capable of evoking neuronal cell death. These data demonstrate
      that endothelial cell injury results in thrombin release and suggest that the
      brain microcirculation could be a source of neurotoxic factors in AD.

PMID- 15201483
TI  - The structure function relationship for the Prion protein.
AB  - Central to Prion diseases is the normal endogenous Prion protein, PrPC. In spite
      of years of research the exact function of this protein remains enigmatic.
      Numerous binding partners have been identified for PrPC and due to the presence
      of a repeated sequence of PHGGGWGQ in the proteins amino-terminus it can bind
      metal ions. The protein is a complex molecule and each portion of PrPC possesses
      different roles for function and/ or trafficking. As understanding the role of
      PrPC is central to these disorders the structure/function relationship will be
      reviewed here.

PMID- 15201484
TI  - Aluminium, iron, zinc and copper influence the in vitro formation of amyloid
      fibrils of Abeta42 in a manner which may have consequences for metal chelation
      therapy in Alzheimer's disease.
AB  - Metals are found associated with beta-pleated sheets of Abeta42 in vivo and may
      be involved in their formation. Metal chelation has been proposed as a therapy
      for Alzheimer's disease on the basis that it may safely dissolve precipitated
      Abeta peptides. We have followed fibrillisation of Abeta42 in the presence of an
      additional metal ion (Al(III), Fe(III), Zn(II), Cu(II)) over a period of 32 weeks
      and we have investigated the dissolution of these aged peptide aggregates in the
      presence of both desferrioxamine (DFO) and ethylenediaminetetraacetic acid
      (EDTA). Abeta42 either alone or in the presence of Al(III) or Fe(III) formed beta
      pleated sheets of plaque-like amyloids which were dissolved upon incubation with
      either chelator. Zn(II) inhibited whilst Cu(II) prevented the formation of beta
      pleated sheets of Abeta42and neither of these influences were affected by
      incubation of the aged peptide aggregates with either DFO or EDTA. Freshly
      prepared solutions of Abeta42 either alone or in the presence of added Al(III) or
      Fe(III) did not form beta-pleated amyloid in the presence of DFO when incubated
      for up to 8 weeks. EDTA did not prevent beta-pleated amyloid formation in the
      same treatments and promoted beta-pleated amyloid formation in the presence of
      either Zn(II) or Cu(II). The presence of significant concentrations of Al(III)
      and Fe(III) as contaminants of 'Abeta42 only' preparations suggested that both of
      these metals were involved in either triggering the formation or stabilising the
      structure of beta-pleated amyloid. If the formation of such amyloid is critical
      to the aetiology of AD then the chelation of Al(III) and Fe(III) may prove to be
      a protective mechanism whilst the chelation of Cu(II) and Zn(II) without also
      chelating Al(III) and Fe(III) might actually exacerbate the condition.

PMID- 15201485
TI  - The Amyloid Hypothesis and the clearance and degradation of Alzheimer's beta
      peptide.
AB  - The second generation of therapeutic strategies for Alzheimer's disease (AD)
      embraces the Amyloid Hypothesis, which asserts that through a series of events
      not completely understood, misfolding of the amyloid-beta (Abeta) peptide is a
      primary event eliciting neurodegeneration and AD pathology. A variety of
      approaches are being tried to interrupt the disease process, including reducing
      the production of the Abeta peptide, inhibiting its aggregation, and promoting
      its removal, for example via immunotherapy. The success of anti-Abeta disease
      modifying approaches in eliminating the postulated etiologic form(s) of the
      peptide will ultimately depend on biological clearance and degradation of the
      various forms of the Abeta peptide from the brain compartment. Little is known
      about exchange of the Abeta peptide between the brain and blood. Increased
      understanding of this process in experimental animal models and humans, and how
      it changes with aging, will likely open new therapeutic avenues. It will also be
      needed to properly design early clinical trials to verify the efficacy of
      potential drug candidates working through the Abeta peptide.

PMID- 15201486
TI  - A behavioral and ultrastructural dissection of the interference of aluminum with
      aging.
AB  - The persistence of neuroscientists in exploring aluminium's (Al) possible
      contribution to the pathogenesis of Alzheimer's disease (AD) has resulted in a
      wealth of researches detailing the biological toxicity of this metal. However, to
      date, there have been few accounts of the interference of Al with aging and its
      relevance to the pathogenesis of AD. We investigated the behavioral and the
      ultrastructural signatures of Al in the hippocampus on young and aging rats which
      were exposed for three months to aluminium gluconate. The aging animals displayed
      decreased scores of activity and emotionality, and the Al-exposed aging males had
      altered emotional reactivity behaviors. The electron-microscopic analysis
      indicated that Al promoted in the aging hippocampus a variety of cellular and
      ultrastructural degenerative signs, such as granulo-vacuolar degenerations,
      deposition of lipofuscin and amyloid in the cytoplasm of neurons and astrocytes,
      and in extracellular compartments, Hirano bodies, demyelination and the atrophy
      of the mitochondria. Moreover, the quantitation of myelin sheath width and the
      diameter of mitochondria measured on randomly selected samples confirmed that
      myelin and mitochondria are primary targets of Al's toxicity. Demyelination and
      mitochondrial atrophy seemed more advanced in the hippocampus of Al-exposed aging
      males, supporting the effect of sex suggested by the behavioral results. These
      findings and other collateral results also reported here are discussed in the
      context of a possible involvement of Al in AD, mediated by aging and catalyzed by
      hepatic morphopathology.

PMID- 15201487
TI  - Homocysteine, Alzheimer genes and proteins, and measures of cognition and
      depression in older men.
AB  - The epsilon4 allele of apolipoprotein E (APOE), and the plasma levels of APOE,
      amyloid beta-protein precursor, amyloid beta1-40 (Abeta40) and homocysteine (Hcy)
      have all been correlated with the presence of dementia. Mutations in the
      methylnetetrahydrofolate reductase enzyme (MTHFR) have been associated with
      elevated levels of Hcy. This study explored the association of these factors with
      cognition and depression in community dwelling older men. Two hundred and ninety
      nine men, mean age 78.9 years (SD 2.8), were studied in this cross-sectional
      survey. Mean plasma Hcy was 13.5 (SD 5.3) micromol/L. The MTHFR genotype had no
      obvious impact on Hcy levels. Ln Hcy and Ln Abeta40 were both inversely
      correlated with calculated glomerular filtration rate (cGFR), r = -0.41 (p <
      0.001) and r = -0.28 (p < 0.001), respectively. There was a positive correlation
      between Ln Hcy and Ln Abeta40, r = 0.19 (p < 0.001), which remained significant
      after adjusting for cGFR, with a doubling of Hcy associated with a 24% increase
      of Abeta40. The e4 allele was associated with increased depressive symptoms as
      measured by the Geriatric Depression Scale-15, Odds ratio (OR) = 2.59 (95%CI 1.06
      6.34) and poorer performance on the Clock Drawing Test, OR = 2.32 (95% CI: 1.25
      4.29). There was a positive association between Abeta40 and Hcy, even after
      adjustment for cGFR in this sample of well, community dwelling older men. This
      association may help elucidate the link between elevated levels of Hcy and
      Alzheimer's disease.

PMID- 15201489
TI  - Seeing without the occipito-parietal cortex: Simultagnosia as a shrinkage of the
      attentional visual field.
AB  - Following bi-parietal lesions patient AT showed a severe inability to relocate
      her attention within a visual field which perimetry proved to be near-normal. An
      experimental approach with tasks testing visuo-spatial attention demonstrated a
      shrinkage of A.T.'s attentional visual field. With her visual attention narrowed
      to a kind of functional tunnel vision, the patient exhibited simultanagnosia
      (Wolpert, 1924), a symptom previously described in 1909 by Balint under the label
      of Psychic paralysis of "Gaze". In striking contrast AT showed an efficient and
      effortless perception of complex natural scenes, which, according to recent work
      in normal subjects, necessitate few if any attentional resources.

PMID- 15201490
TI  - A cognitive neuropsychological and psychophysiological investigation of a patient
      who exhibited an acute exacerbated behavioural response during innocuous
      somatosensory stimulation and movement.
AB  - We report findings from a cognitive neuropsychological and psychophysiological
      investigation of a patient who displayed an exacerbated acute emotional
      expression during movement, innocuous, and aversive somatosensory stimulation.
      The condition developed in the context of non-specific white matter ischaemia
      along with abnormalities in the cortical white matter of the left anterior
      parietal lobe, and subcortical white matter of the left Sylvian cortex. Cognitive
      neuropsychological assessment revealed a pronounced deficiency in executive
      function, relative to IQ, memory, attention, language and visual processing.
      Compared to a normal control group, the patient [EQ] displayed a significantly
      elevated skin conductance level during both innocuous and aversive somatosensory
      stimulation. His pain tolerance was also significantly reduced. Despite this, EQ
      remained able to accurately describe the form of stimulation taking place, and to
      rate the levels of pain intensity and pain affect. These results suggest that
      EQ's exaggerated behavioural response and reduced pain tolerance to somatosensory
      stimulation may be linked to cognitive changes, possibly related to increased
      apprehension and fear, rather than altered pain intensity or pain affect per se.

PMID- 15201491
TI  - Laterality of facial expressions of emotion: Universal and culture-specific
      influences.
AB  - Recent research indicates that (a) the perception and expression of facial
      emotion are lateralized to a great extent in the right hemisphere, and, (b)
      whereas facial expressions of emotion embody universal signals, culture-specific
      learning moderates the expression and interpretation of these emotions. In the
      present article, we review the literature on laterality and universality, and
      propose that, although some components of facial expressions of emotion are
      governed biologically, others are culturally influenced. We suggest that the left
      side of the face is more expressive of emotions, is more uninhibited, and
      displays culture-specific emotional norms. The right side of face, on the other
      hand, is less susceptible to cultural display norms and exhibits more universal
      emotional signals.

PMID- 15201493
TI  - A case of camptocormia (bent spine) secondary to early motor neuron disease.
AB  - Camptocormia is a gait disorder, characterized by hyperflexion of thoracolumbar
      spine which increases on walking, and disappears in the supine position. A 48
      year-old man developed progressive gait deterioration for one year and slight
      weakness and tremor of both hands for five months. It eventually became apparent
      that the patient had motor neuron disease, as well as symptoms of extrapyramidal
      disorder.

PMID- 15201492
TI  - Varieties of alexia from fusiform, posterior inferior temporal and posterior
      occipital gyrus lesions.
AB  - Reading impairments of three alexia patients, two pure alexia and one alexia with
      agraphia, due to different lesions were examined quantitatively, using Kanji
      (Japanese morphogram) words, Kana (Japanese phonetic writing) words and Kana
      nonwords. Kana nonword reading was impaired in all three patients, suggesting
      that widespread areas in the affected occipital and occipitotemporal cortices
      were recruited in reading Kana characters (corresponding to European syllables).
      In addition, the findings in patient 1 (pure alexia for Kanji and Kana from a
      fusiform and lateral occipital gyri lesion) and patient 2 (pure alexia for Kana
      from a posterior occipital gyri lesion) suggested that pure alexia could be
      divided into two types, i.e. ventromedial type in which whole-word reading,
      together with letter identification, is primarily impaired because of a
      disconnection of word-form images from early visual analysis, and posterior type
      in which letter identification is cardinally impaired. Another type of alexia,
      alexia with agraphia for Kanji from a posterior inferior temporal cortex lesion
      (patient 3), results from deficient whole-word images of words per se, and thus
      should be designated "orthographic alexia with agraphia". To account for these
      impairments, a weighted dual-route hypothesis for reading is suggested.

PMID- 15201494
TI  - Effects of HMGB-1 overexpression on cell-cycle progression in MCF-7 cells.
AB  - High mobility group-1 (HMGB-1) enhances the DNA interactions and possesses a
      transcriptional activation potential for several families of sequence-specific
      transcriptional activators. In order to examine the effect of HMGB-1 on the cell
      cycle progression in MCF-7 cells, the HMGB-1 expression vector was transfected
      into synchronized MCF-7 cells, and the effect of HMGB-1 overexpression on the
      cell cycle was examined. The HMGB-1 protein level in the transfected cells
      increased 4.87-fold compared to the non-transfected cells. There were few changes
      in the cell cycle phase distribution after HMGB-1 overexpression in the MCF-7
      cells. Following the estrogen treatment, the cell cycle progressed in both the
      HMGB-1 overexpressed MCF-7 and the mock-treated cells. However, a larger
      proportion of HMGB-1 overexpressing MCF-7 cells progressed to the either S or G2
      phase than the mock-treated cells. The mRNA levels of the cell cycle regulators
      changed after being treated with estrogen in both the HMGB-1 overexpressing MCF-7
      and the mock-treated cells, but the changes in the expression level of the cell
      cycle regulator genes were more prominent in the HMGB-1 overexpressing MCF-7
      cells than in the mock-treated cells. In conclusion, HMGB-1 overexpression itself
      does not alter the MCF-7 cell cycle progression, but the addition of estrogen to
      the HMGB-1 overexpressing MCF-7 cells appears to accelerate the cell cycle
      progression.

PMID- 15201495
TI  - Expression of cell cycle regulators during smooth muscle cell proliferation after
      balloon catheter injury of rat artery.
AB  - Intimal hyperplasia is defined as the abnormal migration and proliferation of
      vascular smooth muscle cells (VSMCs) with deposition of extracellular matrix.
      However, the cell cycle regulatory mechanisms of injury-induced VSMC
      proliferation are largely unknown. To examine the expression kinetics of cell
      cycle regulatory factors which is known to be worked positively or negatively, we
      used rat balloon injury model. Marked induction of proliferating cell nuclear
      antigen (PCNA), G1/S cyclin-dependent kinase (cdk2), and its regulatory subunit
      (cyclin E) occurred between 1 and 3 days after balloon arterial injury, and this
      was sustained for up to 7 days and then declined. However, the induction of the
      negative regulators, p21 and p27, occurred between 3 and 5 days of injury, peaked
      after 7 and 14 days and was then sustained. VSMC proliferation after balloon
      catheter injury of the rat iliac artery is associated with coordinated expression
      of positive (cdk2, cyclin E and PCNA) and negative (p21, p27) regulators. Cell
      cycle regulators such as cdk2, cyclin E, p21, p27 may be suitable targets for the
      control of intimal hyperplasia.

PMID- 15201496
TI  - Bacterial growth in amniotic fluid is dependent on the iron-availability and the
      activity of bacterial iron-uptake system.
AB  - In the present study, the relationship among iron-availability, antibacterial
      activity, role of meconium as an iron source and the activity of bacterial iron
      uptake system (IUS) for bacterial growth in amniotic fluid (AF) were
      investigated. Staphylococcus aureus ATCC 6538 and its streptonigrin-resistant
      (SR) mutant with defective IUS were used as the test strains. The growth of S.
      aureus in AF was stimulated dose-dependently by addition of meconium. Bacterial
      growth stimulated by meconium was re-inhibited dose-dependently by addition of
      iron-chelator, dipyridyl and apotransferrin. Iron concentration was correlated
      with the meconium content in AF (r(2)= 0.989, p=0.001). High-affinity IUS of S.
      aureus was expressed only in AF but not in AF with meconium. The growth of SR
      strain was more retarded than that of the parental strain in the iron-deficient
      brain heart infusion (ID-BHI), clear AF and AF containing apotransferrin. The
      retarded growth of both strains in the ID-BHI and AF was recovered by addition of
      holotransferrin, hemoglobin and FeCl3. Taken together, the antibacterial activity
      of AF is closely related with low iron-availability. Bacterial growth in AF
      considerably depends on the activity of bacterial IUS. Meconium acts as one of
      the exogenous iron-sources and thus can stimulate bacterial growth in AF.

PMID- 15201497
TI  - Rapid prenatal diagnosis of Down Syndrome using quantitative fluorescent PCR in
      uncultured amniocytes.
AB  - Rapid prenatal diagnosis of common chromosome aneuploidies have been successful
      through quantitative fluorescent PCR (QF-PCR) assays and small tandem repeat
      (STR) markers. The purpose of our study was to investigate the clinical
      feasibility for rapid prenatal detection of Down syndrome using the quantitative
      fluorescent PCR in uncultured amniocytes. DNA was extracted from uncultured
      amniotic fluid of normal karyotype (n=200) and of Down syndrome (n=21). It was
      amplified using QF-PCR with four STR markers located on chromosome 21. Among
      normal samples, the ranges of diallelic peaks for at least one STR marker were
      1.0-1.3 for D21S11, 1.0-1.4 for D21S1411 and 1.0-1.5 for D21S1270. Down syndrome
      samples showed trisomic triallelic patterns or trisomic diallelic patterns. The
      sensitivity, specificity, and efficiency of the assay for detecting Down syndrome
      were 95.4%, 100%, and 99.5%, respectively. Rapid prenatal diagnosis of Down
      syndrome using QF-PCR is a reliable technique that aids clinical management of
      pregnancy.

PMID- 15201498
TI  - Loss of heterozygosity on chromosomes 3p,8p,9p and 17p in the progression of
      squamous cell carcinoma of the larynx.
AB  - Previous molecular genetic studies of laryngeal squamous cell carcinoma (SCC)have
      shown certain chromosomal regions with recurring alterations. But studies of
      sequential molecular alterations and genetic progression model of laryngeal SCC
      have not been clearly defined. To identify the chromosomal alterations associated
      with the carcinogenesis of laryngeal SCC, we analyzed genomic DNA from
      microdissected squamous metaplasia, squamous dysplasia, invasive SCC, and
      metastatic carcinoma samples from 22 laryngeal SCC patients for loss of
      heterozygosity (LOH) at microsatellite loci. Ten microsatellite markers on
      chromosome 3p, 8p, 9p, and 17p were used. LOH at 9p21 was observed in the all
      stages including squamous metaplasia, squamous dysplasia, invasive SCC and
      metastatic carcinoma. LOH at 17p13.1, 3p25 and 3p14.2 was observed from the
      squamous dysplasia, invasive SCC and metastatic carcinoma. LOH at 8p21.3-p22 was
      observed mainly from the invasive SCC and metastatic carcinoma. The results
      suggest that 9p21 in the early event, 17p13.1, 3p25 and 3p14.2 in the
      intermediate event and 8p21.3- p22 in the late event may be involved in the
      laryngeal carcinogenesis.

PMID- 15201499
TI  - Sixteen cases of sclerosing hemangioma of the lung including unusual
      presentations.
AB  - Sclerosing hemangiomas (SH) of the lung are uncommon tumors and are thought to be
      benign. However, the biologic behavior of this tumor has not yet been
      characterized adequately. The clinicopathologic features were reviewed and
      analyzed for 16 cases of SH. The age of the patients ranged from 37 to 73 yr
      (mean 50.6 yr). There were fifteen female and one male patient. The SH located at
      the intraparenchyme in 14 cases, the interlobar fissure in one case and the
      visceral pleura in one case. The size of SH ranged from 0.3 cm to 8 cm (mean 2.6
      cm). There were five unusual presentations of SH including a case having two SH
      with multiple nodules of atypical adenomatous hyperplasia in the same lobe, a
      case showing adenocarcinoma-like area within the SH, a case showing one
      peribronchial lymph node metastasis (N1 nodal stage) with location of interlobar
      major fissure, a case showing alveolar adenoma-like area within the SH, and one
      case with a large visceral pleural-based pedunculated mass presenting as
      mediastinal mass. All patients were alive and well without recurrence at the last
      follow up. Here, we reviewed previously published literatures and discussed the
      histogenesis of SH.

PMID- 15201500
TI  - Acute and chronic changes of vascular endothelial growth factor (VEGF) in induced
      sputum of toluene diisocyanate (TDI)-induced asthma patients.
AB  - Vascular endothelial growth factor (VEGF) is a multi-functional cytokine involved
      in inflammation, repair and angiogenesis in asthmatic airway. This study aimed to
      evaluate the role of VEGF in immediate bronchoconstriction induced by TDI
      inhalation, and in chronic TDI-asthma patients. 11 newly diagnosed TDI-asthma
      patients (group I), 12 chronic TDI-asthma patients with persistent asthma
      symptoms followed for >4 yr and 15 unexposed healthy controls were enrolled. In
      group I, induced sputum and serum were collected before and 7 hr after placebo-
      and TDI-bronchoprovocation test (BPT). In group II, induced sputum and serum were
      collected every 2 yr. VEGF levels were measured by ELISA. There were no
      significant differences in sputum and serum VEGF levels between patients and
      controls. Before and after placebo and TDI-BPT, no significant changes were noted
      in sputum and serum VEGF levels of group I. In group II patients, sputum VEGF
      showed variable changes at 1-yr, then decreased significantly at 2-yr (p<0.05),
      while serum VEGF showed variable changes at 2-yr, which decreased significantly
      at 4-yr (p<0.05). These results suggest that VEGF may play a minor role in
      immediate bronchoconstriction after TDI-BPT. In chronic TDI-asthma, VEGF may be
      involved to 2 yr after the diagnosis and the contribution may decrease after
      then.

PMID- 15201501
TI  - Assessing the quality and contents of asthma-related information on the Korean
      internet as an educational material for patients.
AB  - Despite the substantial amount of asthma-related information available on the
      internet, little is known about the quality of such information. We assessed
      asthma-related information on the Korean internet intended as an educational
      material for asthma patients. By entering the key word, 'asthma', into 4 popular
      search engines, 32 web sites were identified and categorized with respect to
      authorship. The core asthma educational concepts and Health On the Net Code of
      Conduct principles were used to evaluate informational value and justifiability
      of unreliable information. Eight of 32 web sites were categorized as western
      physician, seventeen as oriental physician, four as commercial, and three as
      others. The mean number of core asthma educational concepts on the whole web
      sites was 2.7 out of 8. By type of authorship, 1.7 on the commercial sites, 2.1
      on the oriental physician sites, 3.5 on the western physician sites, and 5.0 on
      the others sites in decreasing order. One of the western physician sites, two of
      the commercial sites, and all of the oriental physician and others sites
      contained unreliable information. However all of them except one site failed to
      satisfy our criteria of justifiability. Asthma-related information currently
      available on the Korean internet is highly variable in quality and lacks core
      asthma educational concepts and justifiability.

PMID- 15201502
TI  - Combination chemotherapy with 5-fluorouracil and heptaplatin as first-line
      treatment in patients with advanced gastric cancer.
AB  - Heptaplatin is a recently developed platinum derivative. This agent has been
      reported to have a response rate of 17% as a single agent, and tolerable toxicity
      in the treatment of advanced gastric cancer. The aim of this study was to
      evaluate the efficacy and toxicity of a combination of 5-fluorouracil (5-FU) and
      heptaplatin in patients with advanced gastric cancer. Forty-seven chemotherapy
      naive patients with advanced or recurred gastric cancer were recruited. 5-FU was
      administered over 120 hr by continuous intravenous infusion from day 1 to 5, at a
      daily dose of 1,000 mg/m2 and heptaplatin was administered over 1 hr by
      intravenous infusion on day 1 at 400 mg/m2, and this cycle was repeated every 4
      weeks. The response rate was 21%, median progression-free survival was 1.9 months
      (95% CI, 1.6 to 2.2 months). Median overall survival was 6.2 months (95% CI, 4 to
      8.4 months) and the 1-yr survival rate was 29% for all patients. The most
      frequent toxicity was proteinuria. Toxicities were generally mild and reversible.
      This study demonstrates that the combination of 5-FU/heptaplatin combination is
      less active but tolerated in patients with advance gastric cancer.

PMID- 15201503
TI  - Effect of antisense TGF-beta1 oligodeoxynucleotides in streptozotocin- induced
      diabetic rat kidney.
AB  - Transforming growth factor (TGF)-beta1 is an important fibrogenic factor that is
      involved in the pathogenesis of diabetic nephropathy. We evaluated the effect of
      circular antisense TGF-beta1 oligodeoxynucleotides (ODNs) on the TGF-beta1
      expression in the rat mesangial cell culture and in streptozotocin (STZ)-induced
      diabetic rats. Circular antisense TGF-beta1 ODNs were found to be stable in rat
      serum, significantly decreasing TGF-beta1 mRNA expression compared with linear
      antisense ODNs in the rat mesangial cell culture. Circular antisense TGF-beta1
      ODNs were introduced into the tail vein of normal rats using hemagglutinating
      virus of Japan (HVJ)-liposome-mediated gene transfer method and were confirmed to
      be delivered effectively into the kidney, liver, lungs, and spleen. To inhibit
      the overexpression of TGF-beta1 in diabetic kidneys, we introduced circular
      antisense TGF-beta1 ODNs into the STZ-induced diabetic rats. On day 13 after
      circular antisense TGF-beta1 ODNs injection, TGF-beta1 mRNA and protein
      expression markedly decreased and urinary TGF-beta1 excretion rate also dropped
      in the circular antisense TGF-beta1 ODNs-treated diabetic rats. These results
      suggest that circular antisense TGF-beta1 ODNs may be a useful tool for
      developing new therapeutic application for progressive diabetic nephropathy.

PMID- 15201504
TI  - The effects of antidepressant treatment on serum cytokines and nutritional status
      in hemodialysis patients.
AB  - The aim of this study was to investigate the effects of antidepressant treatment
      on serum cytokines and nutritional status in hemodialysis patients. Twenty-eight
      hemodialysis patients with a depressed mood were given 20 mg of fluoxetine for 8
      weeks. The degree of depressive symptoms, the serum levels of interleukin-1beta,
      interleukin-2, interleukin-6, tumor necrosis factor-alpha, c-reactive protein,
      and markers of nutritional status were assessed at baseline and after treatment.
      The outcome was assessed in terms of response to treatment (>50% reduction in the
      score of the Hamilton depression rating scale). Antidepressant treatment
      decreased the serum level of interleukin-beta1 in both response and nonresponse
      groups, and increased the serum level of interleukin-6 only in the response
      group. At baseline, the level of interleukin-6 in the response group was lower
      than in the nonresponse group. Antidepressant treatment also increased fat
      distribution significantly in the response group which might have slightly
      improved the nutritional status. This study suggests that antidepressant
      treatment improve depressive symptoms and may affect immunological functions and
      nutritional status in chronic hemodialysis patients with depression.

PMID- 15201505
TI  - HER-2/neu oncogene amplification by chromogenic in situ hybridization in 130
      breast cancers using tissue microarray and clinical follow-up studies.
AB  - Determining of HER-2/neu oncogene amplification has become clinically important
      for managing breast cancer. Fluorescent in situ hybridization (FISH) and
      immunohistochemistry (IHC) are currently regarded as the standard methods.
      Chromogenic in situ hybridization (CISH) was investigated as a new modification
      with an accurate, sensitive technique. From 1998 to 2002, using CISH and IHC, the
      amplification and protein expression of the HER-2/neu oncogene were examined
      using paraffin sections in 130 breast carcinomas and to determine the prognostic
      role of HER-2/neu for outcome after a follow-up of 24- 64 months. Amplifications
      by CISH and overexpression by IHC were observed in 28 (22%) and 27 cases (20.8%),
      respectively. Of the 104 patients, 20 patients (19.2%) with amplification had a
      shorter disease-free interval (34.9 months vs. 38.0 months in controls)
      (p=0.372). 15 patients (14.4%) had a disease recurrence, but there is no
      significant difference between 3 patients amplifying the oncogene and 12 patients
      without oncogene (20.6 months vs. 19.6 months) (p=0.862). 6 patients (5.8%) of
      these died. CISH is a useful alternative, particularly for confirming the IHC
      results. There is no relationship between the early recurrence and the HER-2/neu
      positive group, but lymph node status was statistically significant.

PMID- 15201506
TI  - Alternative therapy and abnormal liver function during adjuvant chemotherapy in
      breast cancer patients.
AB  - Although hepatotoxicity has been rarely reported during adjuvant chemotherapy in
      breast cancer patients, we observed a high frequency in our patients who were
      also taking alternative agents. We therefore sought to determine the association
      between hepatotoxicity and alternative agents during adjuvant chemotherapy in
      breast cancer patients. All breast cancer patients were treated with the same
      chemotherapeutic regimen and had normal baseline liver function test (LFT). LFT
      was checked repeatedly during each cycle of chemotherapy. Patients showing LFT
      abnormalities were asked about use of alternative agents, and, after the end of
      chemotherapy, a questionnaire was administered to each patient on their use of
      alternative agents. Of 178 patients, 65 (36.5%) admitted using alternative
      therapy, and significantly more patients in this group developed LFT
      abnormalities (37/65, 56.9%) than those who denied taking alternative therapy
      (25/113, 22.1%, p=0.001). Although LFT abnormalities were mild to moderate and
      normalized in most patients after cessation of alternative agents, it remained a
      serious problem in one patient. In conclusion, alternative therapy may be one of
      the etiologies for abnormal LFT in breast cancer patients receiving adjuvant
      chemotherapy.

PMID- 15201507
TI  - Experience with surgical excision in childhood pheochromocytoma.
AB  - Pheochromocytoma is one of the potentially fatal causes of childhood
      hypertension. The study aims to analyze the results of our experiences in
      pheochromocytomas and the long-term results of its surgical treatment in
      children. The records of 15 children (11 boys, 4 girls) treated for
      pheochromocytoma in our unit during the period of 1984 and 2002 were reviewed
      retrospectively. The average age at surgery was 11.7 yr (range 6 yr 9 months-15
      yr 7 months). Localized disease is defined as the cases without the invasion of
      surrounding tissue, regional disease as the invasion of surrounding tissue and
      metastatic disease as distant metastases. The mean follow-up after
      pheochromocytoma excision was 95 months (range 5 to 221 months). Tumors were
      located in the adrenal gland in 11 (bilaterally in 4) and extra-adrenally in 4.
      Localized disease occurred in 14 patients and regional disease in one. Only one
      patient was associated with von Hippel Lindau syndrome. Adrenalectomy or total
      excision of extra adrenal tumor was performed. Four patients (26.7%) recurred
      after the first operation (at 2 yr 9 months to 14 yr) and regional disease
      recurred in one patient three times. Early diagnosis, surgical excision, and long
      term follow up are most important for the appropriate treatment of childhood
      pheochromocytoma.

PMID- 15201508
TI  - Association between bone mineral density and LDL receptor-related protein 5 gene
      polymorphisms in young Korean men.
AB  - Recently, It has been reported that the LDL receptor-related protein 5 (LRP5)
      regulates bone formation, and that mutations of the gene cause osteoporosis
      pseudoglioma syndrome or high bone mass phenotypes. However, the mutations cannot
      explain a genetic trait for osteoporosis in the general population because of
      their rarity. From 219 Korean men aged 20-34 yr, we looked for six known
      polymorphisms causing amino acid changes in the LRP5 coding region, and
      investigated their association with bone mineral density (BMD) at the following
      anatomical sites: lumbar spine (L2-L4) and the left proximal femur (femoral neck,
      Ward's triangle, trochanter and shaft). We found that the Q89R polymorphism was
      significantly associated with BMD at the femoral neck and Ward's triangle
      (p=0.004 and <0.001, respectively). However, after adjusting for age, weight and
      height, a statistically significant association only occurred at the Ward's
      triangle (p=0.043), and a marginal association was observed at the femoral neck
      (p=0.098). No A400V, V667M, R1036Q and A1525V polymorphisms were found, and no
      statistically significant association was found between the A1330V polymorphism
      and BMD at any sites. Although we failed to demonstrate a clear association
      between the LRP5 polymorphism and peak bone mass in young men, the present study
      suggests that larger-scale studies on the Q89R polymorphism need to be performed.

PMID- 15201509
TI  - Effects of alpha-phenyl-N-tert-butyl nitrone (PBN)on brain cell membrane function
      and energy metabolism during transient global cerebral hypoxia-ischemia and
      reoxygenation-reperfusion in newborn piglets.
AB  - We sought to know whether a free radical spin trap agent, alpha-phenyl-N-tert
      butyl nitrone (PBN) influences brain cell membrane function and energy metabolism
      during and after transient global hypoxia-ischemia (HI) in the newborn piglets.
      Cerebral HI was induced by temporary complete occlusion of bilateral common
      carotid arteries and simultaneous breathing with 8% oxygen for 30 min, followed
      by release of carotid occlusion and normoxic ventilation for 1 hr (reoxygenation
      reperfusion,RR). PBN (100 mg/kg) or vehicle was administered intravenously just
      before the induction of HI or RR. Brain cortex was harvested for the biochemical
      analyses at the end of HI or RR. The level of conjugated dienes significantly
      increased and the activity of Na+, K+ -ATPase significantly decreased during
      HI,and they did not recover during RR. The levels of ATP and phosphocreatine
      (PCr)significantly decreased during HI, and recovered during RR. PBN
      significantly decreased the level of conjugated dienes both during HI and RR, but
      did not influence the activity of Na+, K+ -ATPase and the levels of ATP and PCr.
      We demonstrated that PBN effectively reduced brain cell membrane lipid
      peroxidation, but did not reverse ongoing brain cell membrane dysfunction nor did
      restore brain cellular energy depletion, in our piglet model of global hypoxic
      ischemic brain injury.

PMID- 15201510
TI  - Upregulation of glutamate receptors in rat cerebral cortex with neuronal
      migration disorders.
AB  - Neuronal migration disorders (NMDs) constitute the main pathologic substrate of
      medically intractable epilepsy in human. This study is designed to investigate
      the changes in expression of glutamate receptor subtypes on radiation-induced NMD
      in rats. The lesion was produced by intrauterine irradiation (240 cGy) on E17
      rats, and then 10 weeks old rats were used for the study. The pathologic and
      immuno-histochemical findings for glutamate receptor subunit proteins on NMD
      cortex were correlated with development of behavioral seizures and EEG
      abnormality. Spontaneous seizures uncommonly occurred in NMD rats (5%); however,
      clinical stages of seizures were significantly increased in NMD rats by an
      administration of kainic acid. Brains taken from irradiated rats revealed gross
      and histopathologic features of NMD. Focal cortical dysplasia was identified by
      histopathology and immunohistochemistry with neurofilament protein (NF-M/H).
      Significantly strong NR1 and NR2A/B immunoreactivities were demonstrated in
      cytomegalic and heterotopic neurons of NMD rats. The results of the present study
      indicate that epileptogenesis of NMD might be caused by upregulation of glutamate
      receptor expression in dysplastic neurons of the rat cerebral cortex with NMDs.

PMID- 15201511
TI  - Molecular analysis of HLA class II-associated susceptibility to neuroinflammatory
      diseases in Korean children.
AB  - The work was done to study immunogenetic peculiarities of neuroinflammatory
      diseases among Korean children. A total of 13 children with neuroinflammatory
      diseases (8 males and 5 females; mean age 4.6 +/-2.6 yr) were consecutively
      recruited. Geno-mic typing was performed on their HLA DRB/HLA DQB genes using PCR
      SSOP/SSP techniques with gel immunoelectrophoresis. The frequencies of HLA-DR1
      *15 in children with acute disseminated encephalomyelitis (ADEM) (31%) and DQB1
      *06 in other neuroinflammatory diseases (38%) were significantly increased
      compared with control subjects. The frequencies of HLA-DRB3 * 0202 (100%), HLA
      DRB1 * 1302 (67%), HLA-DRB3 * 0301 (67%), and HLA-DQB1 * 0301 (67%) were
      significantly increased in children with multiple sclerosis and the frequencies
      of HLA-DRB1 * 1501 (40%) and HLA-DRB5 * 0101 (40%) were significantly increased
      in children with ADEM. HLA-DRB1 * 1401, HLA- DRB3 * 0202, and HLA-DQB1 * 0502
      were found in children with acute necrotizing encephalopathy. In conclusion, HLA
      DR1 * 15 and DQB1 * 06 may be involved in susceptibility to inflammation in
      Korean children. The frequencies of HLA-DRB1 * 1501, HLA-DRB5 * 0101, HLA-DRB3 *
      0301, and HLA-DQB1* 0602 were not as high in Korean children with multiple
      sclerosis as in western children. However, HLA-DRB3 * 0202 was seen in all
      children with multiple sclerosis. Our data may provide further evidence that the
      immunogenetic background of neuroinflammatory diseases in Korean is distinctly
      different from the ones in western countries. Further studies are necessary to
      confirm this finding.

PMID- 15201512
TI  - Serum lipid concentrations in Croatian veterans with post-traumatic stress
      disorder,post-traumatic stress disorder comorbid with major depressive
      disorder,or major depressive disorder.
AB  - The aim of this study was to assess eventual differences in serum cholesterol,
      low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol
      (HDL-C), triglycerides, LDL-C/HDL-C ratio between veterans with combat-related
      post-traumatic stress disorder (PTSD) only or comorbid with major depressive
      disorder (MDD), veterans with combat experiences with MDD, and healthy control
      group. PTSD and/ or MDD were diagnose according to structured clinical interview
      based on DSM-IV criteria. Additional criteria to diagnose PTSD were Clinician
      Administered PTSD Scale (CAPS), and to diagnose MDD Montgomery-Asberg Depression
      Rating Scale (MADRAS). Serum lipid concentrations were determined by using the
      enzyme-assay method. Veterans with combat-related PTSD as well as veterans with
      combat-related PTSD comorbid with MDD showed significantly higher concentrations
      of cholesterol (F=9.858, p<0.01), triglycerides (F=10.112, p<0.01), LDL-C
      (F=11.145, p<0.01), and LDL-C/HDL-C ratio (F=8.346, p<0.01) vs. veterans with MDD
      or healthy control group. Contrary healthy control group and veterans with MDD
      showed significantly higher concentrations of HDL-C (F=8.421, p<0.01), vs.
      veterans with PTSD or PTSD comorbid with MDD. In conclusion, there are no
      differences in serum lipid concentrations between veterans with combat-related
      PTSD and PTSD comorbid with MDD, but they have higher lipid concentrations than
      veterans with MDD or healthy control subjects.

PMID- 15201513
TI  - Effect of thermal preconditioning before excimer laser photoablation.
AB  - The purposes of this study were to assess the expression patterns of heat shock
      proteins (Hsps), after eyeball heating or cooling, and to elucidate their
      relationships with corneal wound healing and intraocular complications after
      excimer laser treatment. Experimental mice were grouped into three according to
      local pretreatment type: heating, cooling, and control groups. The
      preconditioning was to apply saline eyedrops onto the cornea prior to
      photoablation. Following photoablation, we evaluated corneal wound healing,
      corneal opacity and lens opacity. Hsp expression patterns were elucidated with
      Western blot and immunohistochemical staining. The heating and cooling groups
      recovered more rapidly, and showed less corneal and lens opacity than the control
      group. In the heating and cooling groups, there were more expressions of Hsps in
      the cornea and lens than in the control group. These results were confirmed in
      the Hsp 70.1 knockout mouse model. Our study showed that Hsps were induced by the
      heating or cooling preconditioning, and appeared to be a major factor in
      protecting the cornea against serious thermal damage. Induced Hsps also seemed to
      play an important role in rapid wound healing, and decreased corneal and lens
      opacity after excimer laser ablation.

PMID- 15201514
TI  - Clinical and pathological characteristics of four Korean patients with limb
      girdle muscular dystrophy type 2B.
AB  - Limb-girdle muscular dystrophy type 2B (LGMD2B), a subtype of autosomal recessive
      limb-girdle muscular dystrophy (ARLGMD), is characterized by a relatively late
      onset and slow progressive course. LGMD2B is known to be caused by the loss of
      the dysferlin protein at sarcolemma in muscle fibers. In this study, the clinical
      and pathological characteristics of Korean LGMD2B patients were investigated.
      Seventeen patients with ARLGMD underwent muscle biopsy and the histochemical
      examination was performed. For the immunocytochemistry, a set of antibodies
      against dystrophin, alpha, beta, gamma, delta-sarcoglycans, dysferlin, caveolin
      3, and beta-dystroglycan was used. Four patients (24%) showed selective loss of
      immunoreactivity against dysferlin at the sarcolemma on the muscle specimens.
      Therefore, they were classified into the LGMD2B category. The age at the onset of
      disease ranged from 9 yr to 33 yr, and none of the patients was wheelchair bound
      at the neurological examination. The serum creatine kinase (CK) was high in all
      the patients (4010-5310 IU/L). The pathologic examination showed mild to moderate
      dystrophic features. These are the first Korean LGMD2B cases with a dysferlin
      deficiency confirmed by immunocytochemistry. The clinical, pathological, and
      immunocytochemical findings of the patients with LGMD2B in this study were in
      accordance with those of other previous reports.

PMID- 15201515
TI  - Severe chronic active EBV infection in an adult patient: case report.
AB  - Severe chronic active Epstein-Barr virus (EBV) infection is a rare and life
      threatening illness. Although the criteria for diagnosis include chronic or
      recurrent infectious mononucleosis-like symptoms lasting more than 6 months and
      high titers of anti-EBV antibodies, clinical and laboratory findings may be
      heterogeneous and flexible application of those criteria is necessary in cases
      showing typical clinical and pathologic findings. We report a case of severe
      chronic active EBV infection in a 62-yr-old female patient who showed classical
      clinical findings with infiltration of EBV-infected T lymphocytes in the bone
      marrow, spleen, and lymph nodes, and died four months after presentation.

PMID- 15201516
TI  - Intrapulmonary cystic lymphangioma in a 2-month-old infant.
AB  - Lymphangioma is an abnormal collection of lymphatics that are developmentally
      isolated from the normal lymphatic system. Lymphangioma rarely presents as a
      solitary pulmonary lesion. We report a rare case of intrapulmonary cystic
      lymphangioma involving the upper lobe of the right lung, which presented with
      dyspnea in a 2-month-old infant. High-resolution computed tomography (HRCT) of
      the chest demonstrated a well-circumscribed, multiseptate, cystic lesion in the
      upper lobe of the right lung, mimicking the feature of type I congenital cystic
      adenomatoid mal-formation. The tumor was removed by bilobectomy of the upper and
      middle lobes of the right lung, and its pathologic examination confirmed the
      diagnosis of an intra-pulmonary cystic lymphangioma.

PMID- 15201517
TI  - A hybrid carcinoma of epithelial-myoepithelial carcinoma and adenoid cystic
      carcinoma in maxillary sinus.
AB  - Hybrid carcinoma of the salivary gland is a very rare entity that has been
      described only in the parotid and palate. The occurrence of a hybrid carcinoma of
      maxillary sinus has not been reported. The diagnosis of hybrid carcinoma is
      important particularly when the components of tumor have different biologic
      behaviors. Diagnosis and treatment require a high index of suspicion, especially
      when the tumor is an epithelial-myoepithelial carcinoma, pathological effort to
      look for a more aggressive accompanying tumor, and proper oncologic treatment. We
      describe a case of 26-yr-old woman with a hybrid carcinoma composed of epithelial
      myoepithelial carcinoma with an adenoid cystic carcinoma component (cribriform
      pattern) in the right maxillary sinus with a brief review of the relevant
      literature.

PMID- 15201518
TI  - Successful treatment of protein-losing enteropathy induced by intestinal
      lymphangiectasia in a liver cirrhosis patient with octreotide: a case report.
AB  - A 47-yr-old man with hepatitis B virus associated liver cirrhosis was admitted to
      our hospital with diarrhea and generalized edema and diagnosed as protein-losing
      enteropathy due to intestinal lymphangiectasia by intestinal biopsy and 99m Tc
      albumin scan. During hospitalization, he received subcutaneous octreotide
      therapy. After 2 weeks of octreotide therapy, follow-up albumin scan showed no
      albumin leakage, and the serum albumin level was sustained. We speculate that
      liver cirrhosis can be a cause of intestinal lymphangiectasia and administration
      of octreotide should be considered for patients with intestinal lymphangiectasia
      whose clinical and bio-chemical abnormalities do not respond to a low-fat diet.

PMID- 15201519
TI  - The first case of intraperitoneal bronchogenic cyst in Korea mimicking a
      gallbladder tumor.
AB  - We present a case of an intraperitoneal bronchogenic cyst located at inferior
      surface of the liver, next to the gallbladder which clinically mimicked a
      gallbladder tumor. This is the first case reported in Korea, and we offer reviews
      of the related literatures. A 48-yr-old woman was admitted to our hospital
      because of intermittent abdominal pain in right upper quadrant. Computed
      tomography showed a large mass along-side the gallbladder. During laparotomy, the
      mass showed an ovoid cystic nature, which was attached to the normal gallbladder
      and liver bed. Cyst excision with cholecystectomy was performed, and
      histopathological examination revealed a broncho-genic cyst. Most bronchogenic
      cysts have a benign nature, but malignant changes have also been reported.
      Therefore, if a cystic tumor in the abdomen is suspected during preoperative
      diagnosis, a bronchogenic cyst should be considered in the differential
      diagnosis.

PMID- 15201520
TI  - Two dermoid cysts developing in an accessory ovary and an eutopic ovary.
AB  - Accessory ovary is a rare gynecologic condition, and tumors arising in accessory
      ovaries are extremely rare. Accessory ovary may result from separation of
      migrating ovaries during embryogenesis and injuries such as inflammation and
      operation on normal ovary. Congenital malformations, most frequently
      malformations of the genitourinary organ, are seen in connection with the
      accessory ovary. We experienced the first case of two dermoid cysts developing in
      an accessory ovary located in the left infundibulopelvic ligament and another in
      the eutopic ovary at the same side concurrently. Here, we present this extremely
      rare case with a review of the literature.

PMID- 15201521
TI  - Giant cell malignant fibrous histiocytoma of the breast: a case report.
AB  - A case of primary malignant fibrous histiocytoma of the breast is reported. The
      patient was a 48-yr-old woman with a huge tumor involving almost the entire left
      breast. The central portion of her left breast was already rotted by extensive
      necrosis and inflammation. She was treated by radical mastectomy and axillary
      lymphadenectomy to level I. Pathologic examination supported by an
      immunohistochemical staining confirmed the tumor as malignant fibrous
      histiocytoma of giant cell type. Axillary lymph nodes were free from tumor
      metastasis. She had not taken any postoperative adjuvant therapy. The metastasis
      to lungs was found 2 months after the operation, and she died within 6 months.

PMID- 15201522
TI  - Widespread scleredema accompanied with a monoclonal gammopathy in a patient with
      advanced ankylosing spondylitis.
AB  - Scleredema is a rare cutaneous mucinosis characterized by chronic diffuse
      induration of the skin, and it is occasionally associated with a monoclonal
      gammopathy (MG). Ankylosing spondylitis (AS) is noted to be another, chronic
      systemic inflammatory disorder of the axial skeleton that may accompany the MG.
      However, patients with scleredema and AS accompanied with a MG have not been
      reported in the literature. We here report a 40-yr-old man with scleredema and
      advanced AS accompanied with a MG of IgA-kappa protein. Widespread, long-standing
      scleredema has been developed over 10 yrs after the initial manifestation of AS.
      It is uncertain whether the coexistence of scleredema and AS is more than
      coincidental.

PMID- 15201523
TI  - A case of hypertrophic osteoarthropathy associated with epithelioid
      hemangioendothelioma.
AB  - Epithelioid hemangioendothelioma is a rare vascular tumor, which occurs in the
      lung, liver, bone, and soft tissue. Hypertrophic osteoarthropathy is a syndrome
      characterized by subperiosteal new bone formation, joint effusion and clubbing,
      and may be associated with cyanotic heart disease, chronic pulmonary disease,
      liver disease, and other miscellaneous diseases. The activation of endothelium
      and platelets has been suggested to be involved in the development of
      hypertrophic osteoarthropathy. We report a rare case of hypertrophic
      osteoarthropathy, which developed in association with hepatic epithelioid
      hemangioendothelioma with pulmonary metastasis. We also discuss the role of
      vascular endothelial growth factor in its pathogenesis.

PMID- 15201524
TI  - The role of the private sector in Canadian healthcare.

PMID- 15201525
TI  - Romanow and Kirby on the public/private divide in healthcare: demystifying the
      debate.
AB  - In this paper, we review recent developments in the debate over the role of the
      private sector in healthcare in Canada, with a particular focus on the two major
      federal reports that were released in the autumn of 2002, the final report of the
      Senate Committee on Social Affairs (the Kirby report ) and the Romanow Commission
      report. It is possible to see these reports as representing two polarized
      positions in the public versus private debate. Kirby has often been portrayed as
      an advocate of privatization whereas Romanow has been given the role of champion
      of the public system. However, both conceptualizations are simplistic and
      inaccurate. We argue that rather than cast these two reports as proxies in an
      ideological dispute, it is more helpful to try to glean from them workable and
      flexible solutions to this immensely complex and divisive debate. More
      specifically, using the similarities and the differences manifest in these
      reports as a key reference point, we clarify the extent to which the terms used
      in the public policy debate have accurately represented the reality of the
      funding and delivery mechanisms that actually characterize the Canadian
      healthcare system. This allows us to draw some provisional conclusions on the
      degree of consensus that prevails in the healthcare debate, and on the sources of
      pressure for change. Given the universal emphasis currently placed on the need to
      base policy conclusions on "evidence," we also look at some recent academic
      contributions to the debate, notably by Raisa Deber and Devereaux et al., in
      order to better understand what the best available evidence indicates about the
      merit of the various forms of healthcare delivery. As well, we examine examples
      of private delivery of health services, including the Morgentaler clinics, that
      point to the importance of retaining the space for experimentation with forms of
      delivery that currently exists within the Canadian healthcare system.

PMID- 15201526
TI  - Value(s) for money? Assessing Romanow and Kirby.
AB  - Many people have grave concerns that Canadian taxpayers have not received value
      for the time, energy and money spent on analysis of our healthcare system over
      the last 20 years. The number of reports and recommendations is enormous.
      Millions of dollars have been spent. While we have been busy studying healthcare
      costs, they have risen. How can Canadians judge if we have received our money's
      worth : Some criteria are: there would be greater clarity regarding the goals of
      healthcare system reform; citizens would understand the issues better; federal
      political "wrangling" would be closer to resolution; agreement on long-overdue
      efficiencies would result in obvious improvement; major disagreements about the
      way forward would also be clearly understood; and finally, accountability to
      Canadians for acting on healthcare recommendations would be a reality.

PMID- 15201527
TI  - Public/private boundaries in Canadian healthcare: some clarification.
AB  - Most Canadians think that "medicare"/our healthcare system (for the
      differentiation is certainly not clear) is "public," meaning universal and pre
      paid by their taxes. Those who have heard of the five conditions of the Canada
      Health Act (CHA), or at least the phrase, "public administration," are doubly
      confirmed in their belief. It comes as a surprise to concerned citizens to learn
      that, to get federal funding, a province has to set up a "single payer" for
      health services to fall under medicare, that is, hospitals and physicians. Then,
      if more information is introduced to distinguish between funding and delivery of
      services, and it is stated how the former is public, while the latter is mainly
      private, the audience starts challenging the speaker. Explaining that the
      delivery of services is private because doctors or nurses are not civil servants,
      for example, comes across as one more great Canadian fiction. "After all, they
      are fully remunerated by public funds--my taxes." All of this to recognize that,
      in Canada, discussions around the public/private divide, from whatever angle, are
      surrounded by preconceived, often common-sense, ideas rejected mainly by students
      of healthcare systems.

PMID- 15201528
TI  - Romanow versus Kirby: resolving the differences.
AB  - In their paper on the Romanow and Kirby reports, Chodos and MacLeod make an
      impassioned attempt to bridge the divide between two landmark reports that are
      often painted as polar opposites on the private/public aspect of healthcare
      delivery. Their attempt to reconcile the differences and achieve "a degree of
      consensus" is well worthwhile, and the resulting discussion informative. But in
      the end, can the differences really be reduced to semantics that can be bridged
      with a little common sense, or do they represent two fundamentally different
      views of how things work?

PMID- 15201529
TI  - Does the private sector have a role in Canadian healthcare?
AB  - The current system of public pay with primarily public management for essential
      healthcare services has largely been successful. The Romanow and Kirby reports
      have made compelling arguments for expanding the definition of essential
      healthcare services to include, among other things, medications. The problem
      facing Canadians is that expanding services is not feasible under the current
      structure, as it is not affordable. The rigid adherence to a 45-year-old
      definition of system structure is hampering our ability to innovate. In an
      increasingly unresponsive system, the introduction of private management, through
      the judicious use of private contracts, can improve efficiency and increase
      accountability, while maintaining the important principle of public funding.

PMID- 15201530
TI  - Cats and categories: public and private in Canadian healthcare.
AB  - Arguments about where private sector healthcare delivery fits within a publicly
      funded system should distinguish among types of private delivery. In Canada, most
      healthcare delivery is already private, albeit not-for-profit (e.g., hospitals)
      or small business (e.g., physicians, dentists). The expectation that corporations
      provide a return on investment to shareholders is more problematic if the dual
      loyalties that professionals have as agents of their patients conflict with the
      profit imperative. Consideration of where such firms can generate their profits,
      and the "production characteristics" of healthcare, suggests that certain sectors
      lack the contestability, measurability and complexity needed to make competitive
      markets function effectively. Neither is it likely that competition can co-exist
      with requirements for a single payer. In that connection, it must be recognized
      that the incentives inherent in a corporate structure, all other things being
      equal, appear inimical to many desired outcomes of a healthcare system. These
      tendencies can be controlled, but only through fairly elaborate measurement and
      monitoring of performance, which carry their own costs, and which smaller
      providers may be unable to meet. Chodos, MacLeod, Romanow and Kirby have done a
      great service of reminding us where we want to go--and where we do not.

PMID- 15201531
TI  - The public/private debate in the funding, administration and delivery of
      healthcare in Canada.
AB  - To help clarify the confusing debate concerning the public-private divide in
      Canada and the respective positions of the Romanow and Kirby reports, a new
      approach is proposed. The funding, administration and delivery of the healthcare
      "system" is split into distinct analytical categories and then applied to three
      major coverage groupings: universal public (Canada Health Act) coverage for
      medically necessary/required services; mixed coverage for drug care, home and
      long-term care; and private health goods and services. While there were no
      fundamental differences between Romanow and Kirby concerning the funding of
      public healthcare in Canada, there were some important differences on issues of
      administration. In particular, the Romanow report recommended that home mental
      healthcare services become universally covered under the Canada Health Act as
      well as fundamental changes to the regulation and administration of prescription
      drug care. The reports also differed in terms of framing the private delivery
      question, with the Romanow report questioning whether the evidence justified
      private-for-profit delivery replacing current private not-for-profit or public
      arm's length delivery modes.

PMID- 15201532
TI  - The big thing we haven't done yet.
AB  - In Healing Medicare, Michael Decter (1994) quotes from a speech made in 1982 by
      Tommy Douglas: "When we began to plan medicare (35 years previously), we pointed
      out that it would be in two phases. The first phase would be to remove the
      financial barrier between those giving the service and those receiving it. The
      second phase would be to reorganize and revamp the delivery system--and of
      course, that's the big item. It's the big thing we haven't done yet."

PMID- 15201533
TI  - Public/private pragmatism.
AB  - Howard Chodos and Jeffrey MacLeod offer a breath of fresh air, with their call
      for a pragmatic approach to decisions about the role of the private sector in the
      Canadian healthcare system. At the current rate of growth, Canadians will spend
      125 billion Canadian dollars on health services this year. We have some decisions
      to make: the healthcare system is too big, too complex and too important for us
      to make those decisions based on preconceived notions or ideology.

PMID- 15201535
TI  - Plasma volume and blood pressure regulation in hypertensive pregnancy.
AB  - BACKGROUND: Pre-eclampsia is a multisystem disorder, peculiar to and frequent in
      human pregnancy. It remains a leading cause of maternal and neonatal morbidity
      and mortality. Hemodynamic disturbances are the most prominent features of the
      syndrome. PURPOSE: To provide an overview of plasma volume regulation and blood
      pressure control mechanisms outside pregnancy, and of the changes in normal
      pregnancies and in pregnancies complicated by hypertensive disorders.
      Furthermore, to discuss the rationale of several hemodynamic interventions.
      RESULTS: In normal pregnancy, large cardiovascular changes take place. A
      generalized fall in vascular tone by systemic vasorelaxation causes increased
      blood volume, heart rate and cardiac output. In the preclinical phase,
      differences have been observed between normal and hypertensive pregnancies in the
      function of the autonomic nervous system, cardiac output and plasma volume, the
      volume remaining at the non-pregnant level. In the clinical phase of pre
      eclampsia the typical case picture is one of a vasoconstrictive state with low
      plasma volume and cardiac output, high blood pressure and systemic vascular
      resistance in combination with signs of organ damage [proteinuria, hemolysis
      elevated liver enzymes low platelets (HELLP) syndrome]. Hemodynamic management is
      necessary in severe disease to prevent maternal complications. Management
      primarily focuses on pharmacological treatment of blood pressure. Clinicians make
      educated choices from a limited array of available drugs: beta-receptor
      antagonists, nifedipine, dihydralazine, methyldopa or ketanserine. Other drugs
      have restricted use in pregnancy. Management of low circulating volume with
      plasma expanders remains a subject of controversy.

PMID- 15201536
TI  - Genetic predisposition to salt-sensitivity: a systematic review.
AB  - PURPOSE: To assess the role of genetic polymorphisms in salt sensitivity of blood
      pressure. DATA IDENTIFICATION: We conducted a systematic review by searching the
      Medline literature from March 1993 to June 2003. Each paper was scrutinized and
      data concerning study population, method of salt sensitivity testing, blood
      pressure measurement, definition of salt sensitivity, and effects were extracted.
      STUDY SELECTION AND DATA EXTRACTION: A total of 23 studies met the inclusion
      criteria. There was considerable heterogeneity in the method of salt sensitivity
      testing among the studies. Due to these differences, it was impossible to perform
      pooled analyses by genetic variants. Detailed investigation was done on the alpha
      adducin Gly460Trp, ACE I/D, angiotensinogen M235T, G protein beta 3 C825T,
      aldosterone synthase gene and 11 beta-hydroxysteroid dehydrogenase type 2 G534A
      polymorphism. RESULTS AND CONCLUSIONS: Our analysis shows that the 460Trp variant
      of the alpha-adducin polymorphism is probably associated with a sodium-sensitive
      form of hypertension, while the polymorphisms of the angiotensin II type 1
      receptor gene and the -344C/T variant of the aldosterone synthase gene are not
      associated with this phenotype. In view of the lack of standardization in salt
      sensitivity testing, we propose uniformity in study design in these type of
      studies.

PMID- 15201537
TI  - Neuropeptide Y T1128C polymorphism: an independent predictor of hypertensive and
      cardiovascular diseases?

PMID- 15201538
TI  - Candidate genes, association studies and haplotype analysis in the search for the
      genetic basis of hypertension.

PMID- 15201539
TI  - Assessing arterial baroreflex control of heart rate: new perspectives.

PMID- 15201540
TI  - Hypertension, transforming growth factor-beta, angiotensin II and kidney disease.

PMID- 15201541
TI  - Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential
      hypertension.
AB  - OBJECTIVES: The objectives of this study were to identify polymorphic variants
      within the gene coding for the sodium/hydrogen exchanger type 3 (NHE3) and to
      examine their relationship with hypertension and biochemical indices of sodium
      balance. DESIGN AND METHODS: Case-control comparisons on a total of 691 subjects
      of which 399 (68% with essential hypertension) were of African or Afro-Caribbean
      origin (blacks) and 292 (50% with essential hypertension) were of Caucasian
      origin (whites). RESULTS: Eight exons of the C terminus of the NHE3 gene were
      screened systematically. A total of six variants were identified: (G1579A,
      G1709A, G1867A, C1945T, A2041G and C2405T). Further analyses in relation to
      essential hypertension and phenotypic characteristics were confined to the more
      frequent A2041G and the C2405T polymorphisms. The genotype frequencies of the
      A2041G polymorphism were significantly different between the whites and blacks,
      with the A allele being more frequent in the white population (0.43 for the
      whites and 0.14 for the blacks, respectively; P < 0.001). In contrast, there was
      no significant difference in the C2405T polymorphism between whites and blacks (C
      allele frequency: 0.86 for the whites and 0.88 for the blacks, respectively). In
      both the white and the black groups, there were no significant associations
      between these variants and essential hypertension (P > 0.05) or with serum
      electrolytes, creatinine or plasma renin activity (PRA) (ANOVA P > 0.05).
      CONCLUSIONS: These results suggest a high degree of structural conservation of
      the NHE3 gene; however, the lack of association between these polymorphisms and
      blood pressure status does not necessarily eliminate the participation of this
      important sodium/hydrogen exchanger in the pathophysiology of essential
      hypertension, as we cannot exclude the existence of functionally important
      genetic variants in other sequences within the NEH3 gene.

PMID- 15201542
TI  - Association analysis of the polymorphism T1128C in the signal peptide of
      neuropeptide Y in a Swedish hypertensive population.
AB  - OBJECTIVE: The neuropeptide Y (NPY) signal peptide polymorphism T1128C has been
      linked to several risk factors for cardiovascular disease. The aim of the present
      study was to evaluate the significance of this polymorphism for cardiovascular
      and cerebrovascular disease outcome. DESIGN: In a prospective study cohort, 1032
      hypertensive patients (174 myocardial infarction and 170 stroke patients and 688
      matched controls) were analysed for the T1128C polymorphism in the NPY gene.
      METHODS: The dynamic allele specific hybridization (DASH) method was used for
      genotyping. Serum from the same participants was analysed for total cholesterol,
      high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides.
      RESULTS: The frequency of the NPY T1128C polymorphism was 8.4% among patients
      with a myocardial infarction or stroke, as compared to 5.1% in the control group
      (P = 0.040). The difference remained significant after adjustment for the
      cardiovascular risk factors age, sex, smoking status, body mass index, systolic
      and diastolic blood pressure, presence of diabetes, total cholesterol, HDL, LDL
      and triglycerides. CONCLUSIONS: The present study indicates that the NPY T1128C
      polymorphism is an independent predictor for myocardial infarction and stroke in
      a Swedish hypertensive population.

PMID- 15201543
TI  - Interactions between peroxisome proliferator-activated receptor-gamma 2 gene
      polymorphisms and size at birth on blood pressure and the use of antihypertensive
      medication.
AB  - OBJECTIVE: The combination of small birth size and the Pro12Pro variant of the
      peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene has been
      shown to be associated with insulin resistance, which is linked to hypertension.
      We examined whether the association between small body size at birth and adult
      blood pressure is modulated by PPAR-gamma 2 gene polymorphism, and whether the
      use of any class of antihypertensive medication is related to birth size. DESIGN
      AND METHODS: A total of 500 subjects from an original epidemiological cohort of
      7086 men and women aged 65-75 years attended a clinical study. Two hundred and
      eight of them (73 men and 135 women) were taking antihypertensive medication and
      are included in this study. The Pro12Ala polymorphism of the PPAR-gamma 2 gene
      was determined using the polymerase chain reaction single-strand conformation
      polymorphism method. RESULTS AND CONCLUSIONS: Hypertensive subjects with low
      birth weight or short length at birth and the Pro12Pro variant had raised
      systolic blood pressure. We suggest that insulin resistance enhances the
      regulatory responses of the renin-angiotensin system, leading to raised blood
      pressure levels. Those hypertensive subjects who had small birth size and the
      Pro12Pro variant tended to use angiotensin-converting enzyme inhibitors or
      angiotensin-receptor blockers (ACEI/ARB). This could be because insulin
      resistance interacts with the renin-angiotensin system in ways that make ACEI/ARB
      an effective therapy. Alternative explanations include more severe and treatment
      resistant hypertension, leading to application of ACEI/ARB, or co-morbid
      conditions, such as myocardial infarction and type 2 diabetes, known to be linked
      to low birth weight.

PMID- 15201544
TI  - Angiotensinogen promoter haplotypes are associated with blood pressure in
      untreated hypertensives.
AB  - BACKGROUND: The polymorphic angiotensinogen (AGT) gene is one of the most
      promising candidates for blood pressure (BP) regulation and essential
      hypertension. OBJECTIVES: To investigate whether AGT haplotype analysis adds
      significant information compared to single polymorphism analysis with respect to
      different BP phenotypes in an untreated hypertensive sample. METHODS: Two hundred
      and twelve untreated hypertensive subjects of Caucasian origin were genotyped for
      the AGT polymorphisms C-532T, A-20C, C-18T, and G-6A. RESULTS: In single variant
      analyses, untreated hypertensives, carrying the AGT -532T or -6A alleles had
      significantly higher systolic blood pressure (SBP) and diastolic blood pressure
      (DBP), as well as ambulatory BP values compared to respective non-carriers. In
      haplotype-based analyses, combining all four AGT promoter variants, we
      demonstrate that AGT haplotypes containing different allele combinations at
      positions -532 and -6 were significantly associated with different BP values: (1)
      -532T and -6A with higher, (2) -532C and -6G with lower, (3) -532C and -6A with
      intermediate BP values. Since the result for the -532C/-20A/-18C/-6G haplotype
      was due to differences between non-carriers and carriers of this haplotype on
      both chromosomes, a recessive inheritance model for BP effects could be assumed.
      CONCLUSIONS: Our results designate the C-532T and G-6A as the best candidates for
      functional studies on the AGT gene. Haplotype-based analyses should greatly aid
      in the dissection of the genetic basis of complex traits, such as BP regulation
      and hypertension.

PMID- 15201545
TI  - Arterial stiffness and angiotensinogen gene in hypertensive patients and mutant
      mice.
AB  - OBJECTIVE: To determine whether carotid artery stiffness was increased in
      patients with untreated essential hypertension who are homozygous for the T
      allele of the M235T polymorphism of the angiotensinogen (AGT) gene and in mutant
      mice carrying three copies of the angiotensinogen (Agt) gene. METHODS: Using
      echotracking systems, we studied carotid mechanical properties in 98 never
      treated hypertensive patients according to their AGT genotype, and in Agt mutant
      mice. RESULTS: Patients homozygous for the T allele had a reduced carotid
      distensibility and an increased stiffness of the carotid wall material (Young's
      elastic modulus), independent of blood pressure, compared with patients
      homozygous for the M allele. In Agt1/2 mice, carotid distensibility was not
      significantly different from that of Agt1/1 (wild-type). Moreover, the stiffness
      of the arterial wall material was lower in Agt1/2 mice than in wild-type mice. In
      Agt1/2 mice, the greater blood pressure was not associated with arterial
      hypertrophy, resulting in a greater circumferential wall stress. The in-vivo and
      in-vitro pressor responses to angiotensin II were reduced in Agt1/2 mice, whereas
      the contractile response to phenylephrine was not significantly different between
      Agt1/1 and Agt1/2 mice, indicating the integrity of the contractile apparatus and
      suggesting a dysfunction of the angiotensin II type 1 receptor signalling
      pathways in Agt1/2 mice. CONCLUSION: These data suggest that the angiotensinogen
      TT genotype at position 235 could be a genetic marker for arterial stiffness in
      patients with never-treated hypertension, whereas in Agt1/2 mice the dysfunction
      of the angiotensin II type 1 receptor signalling pathways could explain the lack
      of arterial wall hypertrophy and stiffness.

PMID- 15201546
TI  - Effects of amlodipine and lisinopril on intima-media thickness in previously
      untreated, elderly hypertensive patients (the ELVERA trial).
AB  - OBJECTIVE: To compare the effects of the calcium channel blocker amlodipine and
      the angiotensin-converting enzyme inhibitor lisinopril on intima-media thickness
      (IMT) in elderly, previously untreated hypertensive individuals. DESIGN: A double
      blind randomized parallel-group trial (the ELVERA trial). PATIENTS: The study
      population comprised 166 newly diagnosed hypertensive individuals (aged 60-75
      years) with diastolic blood pressure between 95 and 115 mmHg or systolic blood
      pressure between 160 and 220 mmHg, or both. INTERVENTION: Patients were allocated
      randomly to groups to receive amlodipine 5-10 mg or lisinopril 10-20 mg for 2
      years. MAIN OUTCOME MEASURES: Before and after 1 and 2 years of treatment, IMT
      was measured in three carotid and two femoral arterial sites by B-mode
      ultrasound. The primary endpoint was the change from baseline of the combined
      mean maximum far wall IMT of carotid and femoral arteries, evaluated by repeated
      measurement analysis of the treatment effect in an intention-to-treat analysis.
      RESULTS: After 2 years of treatment, amlodipine decreased IMT by 0.089 mm [95%
      confidence interval (CI) 0.144 to 0.037]. Lisinopril decreased IMT by 0.065 mm
      (95% CI 0.124 to 0.010). No differences between the two drugs were found (P =
      0.18). Both treatment regimens achieved the greatest reduction of IMT after 1
      year, with a slight increase after the second year, whereas the reduction in
      blood pressure was maintained. Comparing the carotid and femoral arteries, a
      significant treatment difference in the change from baseline in favour of
      amlodipine was observed in the IMT of the elastic common carotid artery (P <
      0.05). The effects of the two drugs on the muscular common femoral artery were
      not different. CONCLUSION: In a long-term study, amlodipine and lisinopril reduce
      IMT to a similar extent in newly diagnosed elderly hypertensive patients. It is
      suggested that the two drugs have different effects on arteries that are not
      prone to atherosclerosis.

PMID- 15201547
TI  - Confounding effects of heart rate on pulse wave velocity in paced patients with a
      low degree of atherosclerosis.
AB  - BACKGROUND: Pulse wave velocity (PWV), an index of arterial wall stiffness, is
      modulated by blood pressure (BP). Whether heart rate (HR) is also a modulator of
      PWV is controversial. Recent research involving mainly patients with high aortic
      PWV have found either no change or a positive correlation between the two. Given
      that PWV is increasingly being measured in cardiovascular studies, the
      relationship between HR and PWV should be known in patients with preserved
      arterial wall elasticity. OBJECTIVE: The aim of this study was to evaluate the
      importance of HR as a determinant of the variability in PWV in patients with a
      low degree of atherosclerosis. DESIGN AND METHODS: Fourteen patients (five
      female, nine male; aged 68 +/- 8 years) were evaluated post pacemaker
      implantation due to sick sinus or carotid hypersensitivity syndromes. Carotid
      femoral PWV was measured at rest and during atrial pacing at 80, 90 and 100 bpm
      (paced HR). Arterial femoral blood flow (AFBF) was measured by echodoppler.
      RESULTS: PWV increased from 6.2 +/- 1.5 m/s (mean +/- SD) during resting sinus
      rhythm (HR 62 +/- 8 bpm; mean +/- SD) to 6.8 +/- 1.0, 7.0 +/- 0.9, and 7.6 +/-
      1.1 m/s at pacing rates of 80, 90 and 100 bpm, respectively (P < 0.0001).
      Systolic (SBP) and mean blood pressure (MBP) remained constant at all HR levels,
      whereas AFBF increased in a linear fashion. CONCLUSIONS: These results
      demonstrate that even in patients with a low degree of atherosclerosis, HR is a
      potential modulator of carotid-femoral PWV.

PMID- 15201548
TI  - The upregulation of ICAM-1 and P-selectin requires high blood pressure but not
      circulating renin-angiotensin system in vivo.
AB  - OBJECTIVE: To investigate the separate contributions of blood pressure and the
      circulating renin-angiotensin system to the upregulation of vascular endothelial
      adhesion molecules in vivo. METHODS: One or 4 weeks after constriction of the
      abdominal aortas of Wistar rats, the expressions of intercellular adhesion
      molecule-1 (ICAM-1), P-selectin, nuclear factor (NF) kappa B p65 subunit and
      monocytes were assessed at sites proximal and distal to the site of constriction,
      by western blot, immunohistochemistry, or both. RESULTS: At 1 week, the mean
      arterial pressure was increased significantly at the cervical artery in the group
      with aortic constriction (160 +/- 4 mmHg, compared with 104 +/- 2 mmHg before
      constriction), but not at the femoral artery (111 +/- 10 mmHg, compared with 100
      +/- 2 mmHg before constriction) (P < 0.05), and circulating angiotensin II was
      increased significantly only in the group with aortic constriction (124 +/- 28
      pg/ml, compared with 14 +/- 2 pg/ml in the sham-operated group; P < 0.05). In the
      aorta-constricted group, the expressions of ICAM-1, P-selectin, and NF-kappa B
      p65 subunit were significantly upregulated (2-3.1-fold) at the aorta proximal to
      the constriction compared with those distal to it, which were the same as those
      in the sham-operated group. Immunolocalization of these molecules was observed to
      be on the endothelial cells. Adhesive monocytes on the endothelium were also
      increased significantly only proximal to the constriction in the aorta
      constricted group. At 4 weeks the findings were the same, except that circulating
      angiotensin II was within the normal range in both the aorta-constricted and the
      sham-operated groups. CONCLUSIONS: Our results indicate that the high blood
      pressure, but not the circulating renin-angiotensin system, upregulates the
      expression of ICAM-1 and P-selectin, suggesting that mechanical forces may be
      more important than humoral factors in the upregulation of adhesion molecules in
      hypertension.

PMID- 15201549
TI  - Renal xanthine oxidoreductase activity during development of hypertension in
      spontaneously hypertensive rats.
AB  - BACKGROUND: Hyperuricaemia and reactive oxygen species have recently been
      associated with essential hypertension. Xanthine oxidoreductase (XOR) produces
      urate and, in its oxidase isoform, reactive oxygen species also. Our previous
      studies indicated that hypertension-prone rat strains have greater renal XOR
      activity than their normotensive counterparts, and that dietary sodium modifies
      renal XOR activity. OBJECTIVE: To clarify whether renal XOR induction precedes or
      follows the development of hypertension. METHODS: Five-week-old spontaneously
      hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were kept for 3-8 weeks on
      low sodium (0.3% salt w/w) or high sodium (6.0% salt w/w) intakes, with or
      without allopurinol, an inhibitor of XOR, to study the possible pathogenetic role
      of XOR in hypertension. Systolic blood pressure (SBP), renal XOR activity and
      mRNA expression were measured. RESULTS: Regardless of sodium intake, renal XOR
      activity increased twofold during growth in SHRs, but not in WKY rats. SBP
      increased from 122 +/- 4 to 241 +/- 13 mmHg in SHRs kept on the high-sodium diet
      and to 204 +/- 11 mmHg in those on the low-sodium diet. At the end of the
      experiment, renal XOR activity correlated with SBP in SHRs. Allopurinol prevented
      hypertension-induced left ventricular and renal hypertrophy in SHRs, but had
      negligible effect on blood pressure. CONCLUSION: Renal XOR induction in SHRs does
      not precede the development of hypertension, but progress concomitantly with an
      increase in SBP. The results indicate a role for locally synthesized XOR in the
      development of hypertension-associated end-organ damage, but no major role in the
      development of hypertension.

PMID- 15201550
TI  - Plasma concentration of urotensin II is raised in hypertension.
AB  - OBJECTIVES: Urotensin II is the most potent vasoconstrictor known. Its role in
      hypertension has not been investigated. Here, we studied the plasma levels in
      hypertensive and normotensive human subjects. DESIGN: A cross-sectional case
      control study. SETTING: Hypertension clinic and research clinic of a university
      teaching hospital. PARTICIPANTS: Sixty-two hypertensive outpatient subjects (52%
      male, aged 57 +/- 13 years) and 62 normotensive controls (45% male, aged 54 +/-
      13 years) recruited from the general population. MAIN OUTCOME MEASURES: Plasma
      urotensin II levels measured by radioimmunoassay, systolic and diastolic blood
      pressure. RESULTS: Plasma urotensin II was 8.8 +/- 0.9 pmol/l in normotensive
      controls and 13.6 +/- 1.4 pmol/l in hypertensive subjects (P = 0.005). In
      multiple regression analysis, systolic blood pressure was related to plasma
      urotensin II (beta = 0.31, P < 0.001) and age (beta = 0.28, P = 0.001),
      accounting for 10 and 8%, respectively, of the variance in systolic blood
      pressure. There was no significant correlation with gender, renal function or
      diabetes. CONCLUSIONS: Plasma urotensin II was raised in hypertensive patients
      compared to normotensive controls, and was directly related to systolic blood
      pressure. Our findings raise the possibility that urotensin II may have an
      aetiological role in hypertension and its complications.

PMID- 15201551
TI  - Activation of the renin-angiotensin system in alpha-calcitonin gene-related
      peptide/calcitonin gene knockout mice.
AB  - OBJECTIVE: To test the hypotheses that circulating or tissue renin-angiotensin
      system (RAS) activity is increased in alpha-calcitonin gene-related peptide
      (alpha CGRP) knockout mice, and that this contributes to the increased blood
      pressure in these mice. DESIGN AND METHODS: Three- to six-month-old male alpha
      CGRP/calcitonin knockout mice and wild-type controls were studied. Mean arterial
      pressure (MAP) and its response to an angiotensin II type 1 (AT1) receptor
      blocker, losartan (3 mg/kg intravenously), were determined in conscious,
      unrestrained knockout mice and wild-type mice. Radioimmunoassay and western blot
      were used, respectively, to determine plasma renin activity (PRA) and AT1
      receptor protein content in tissues. RESULTS: Basal MAP and PRA were
      significantly greater in the knockout mice than in the wild-type mice. In
      contrast, AT1 receptor content in the renal medulla was significantly decreased
      in the knockout mice compared with that in wild-type mice. AT1 receptor content
      in the renal cortex and mesenteric resistance arteries was not different in the
      knockout and wild-type mice. Losartan produced a significant decrease in MAP in
      the knockout mice compared with that in wild-type mice. CONCLUSION: Activity of
      the circulating RAS, but not tissue AT1 receptor expression, is increased in
      alpha CGRP/calcitonin knockout mice, which may contribute to the increase in
      blood pressure in this mouse model. The mechanism(s) responsible for the
      increased activity of the circulating RAS in the absence of alpha CGRP throughout
      the developmental stages of these animals remains to be determined.

PMID- 15201552
TI  - Plasminogen activator inhibitor-1 and transforming growth factor-beta 1 in
      carotid glomus and autonomic ganglia from spontaneously hypertensive rats.
AB  - BACKGROUND: Baroreflex and chemoreflex mechanisms play an important role in the
      dynamic adjustments of circulation and ventilation during daily life. Recently,
      we have observed atrophy and marked fibrosis in carotid glomus (CG) from old
      patients with carotid atherosclerosis who died following stroke. However, a
      possible limitation to interpretation of the results in that study was the
      superposition of arterial hypertension, atherosclerosis and aging in the
      patients. Taking this into account, spontaneously hypertensive rats (SHR) were
      used in order to study the CG in an experimental model with only hemodynamic
      stress. OBJECTIVE: To evaluate whether transforming growth factor-beta 1 (TGF
      beta 1) and plasminogen activator inhibitor-1 (PAI-1) were involved in the
      extracellular matrix expansion in CG and autonomic ganglia (AG) in young, male,
      adult SHR. METHODS: Male SHR (n = 10) and Wistar-Kyoto (WKY) rats (n = 10) were
      used. Systolic blood pressure (SBP) was measured monthly up to 8 months of age,
      when the animals were killed; then, CG and AG were excised and processed for
      light microscopy and immunohistochemistry (TGF-beta 1, PAI-1 and protein S100).
      RESULTS: SBP was highly correlated (P < 0.01) with CG fibrosis (r = 0.90), AG
      fibrosis (r = 0.96) and neuron number (r = -0.97). PAI-1 and TGF-beta 1 in CG and
      AG were significantly increased (P < 0.01) in SHR. CONCLUSION: Severe damage was
      observed in CG and AG in SHR, which was, in addition, correlated with SBP. These
      results suggest that permanent high blood pressure produces remarkable lesions in
      these structures, even when the animals are not old. In view of the fact that CG
      and AG are of utmost importance in the genesis of cardiocirculatory reflexes,
      they might be considered as 'target organs' in arterial hypertension.

PMID- 15201553
TI  - Effects of slow, controlled breathing on baroreceptor control of heart rate and
      blood pressure in healthy men.
AB  - BACKGROUND: Slow, controlled breathing has been shown by cross-spectral
      techniques to potentiate arterial baroreflex control of heart rate. However,
      crucial aspects of the effects of slow breathing on the arterial baroreflex
      remain unsettled, namely whether the major function of the arterial baroreflex
      (i.e. the control of blood pressure) is also potentiated and whether baroreflex
      function is differentially modulated according to the age of the individual.
      OBJECTIVE: To examine the bradycardic and depressor responses to selective
      carotid baroreceptor stimulation by the neck chamber technique (-15 and -30 mmHg
      neck suction) and the cross-spectral R-R interval/systolic blood pressure
      relationship (alpha index). METHODS: In 24 resting, supine healthy male
      volunteers (aged 19-66 years, mean +/-SEM 37.5 +/- 3.19 years), blood pressure
      (Finapres), R-R interval (electrocardiogram) and ventilation (impedance) were
      recorded continuously. Both assessments were performed during spontaneous
      breathing and during 6 cycles/min controlled ventilation in random order.
      RESULTS: The depressor and bradycardic responses to neck suction were
      significantly larger during slow breathing than in spontaneous breathing (+32 and
      +85%, respectively; both P < 0.01). The alpha index was also significantly larger
      during slow breathing (+62%; P < 0.01). Even after the volunteers were divided
      into older (> 50 years, n = 9) and younger (< 30 years, n = 9) groups, the
      baroreflex potentiation related to slow breathing was clearcut and significant
      for both the depressor (+46 and +24% older and younger volunteers; both P < 0.01)
      and the bradycardic (+130 and +73% older and younger volunteers; both P < 0.01)
      responses. When the assessment was made by computing the cross-spectral alpha
      index, a marked potentiation related to slow breathing was observed in younger
      volunteers (+99%; P < 0.01), whereas in older volunteers only a trend to an
      enhancement (by 32%; P < 0.055) was observed. CONCLUSIONS: Slow controlled
      breathing is associated with potentiation of both the depressor and the cardio
      inhibitory components of the arterial baroreflex, the potentiation being largely
      similar regardless of the age of the individual.

PMID- 15201554
TI  - Time-domain cross-correlation baroreflex sensitivity: performance on the
      EUROBAVAR data set.
AB  - OBJECTIVE: To test a new method (cross-correlation baroreflex sensitivity, xBRS)
      for the computation of time-domain baroreflex sensitivity on spontaneous blood
      pressure and heart interval variability using the EUROBAVAR data set. METHODS: We
      applied xBRS to the 42 records in the EUROBAVAR data set, obtained from 21
      patients in the lying and standing positions. One patient had a recent heart
      transplant and one was diabetic with evident cardiac autonomic neuropathy. xBRS
      computes the correlation between beat-to-beat systolic blood pressure and R-R
      interval, resampled at 1 Hz, in a sliding 10 s window, with delays of 0-5 s for
      interval. The delay with the greatest positive correlation is selected and, when
      significant at P = 0.01, slope and delay are recorded as one xBRS value. Each 1 s
      of the recording is the start of a new computation. Non-parametric tests are
      used. RESULTS: With patients in the lying position, xBRS yielded a value of 12.4
      ms/mmHg compared with the EUROBAVAR sequential 16.2 ms/mmHg, and for the standing
      positions the respective values were 6.2 and 6.7 ms/mmHg, giving lying to
      standing ratios of 1.96 and 2.10, respectively. xBRS yielded results for all
      files, with 20 values per minute on average at a lower within-patient variance.
      Best delays were 0, 1 and 2 s, and the delay increased by 102 ms when the patient
      was in the standing position. The xBRS method was successful in the patients with
      diabetes and the heart transplant. CONCLUSION: The xBRS method should be
      considered for experimental and clinical use, because it yielded values that
      correlated strongly with and were close to the EUROBAVAR averages, yielded more
      values per minute, had lower within-patient variance and measured baroreflex
      delay.

PMID- 15201555
TI  - Dietary phytoestrogens and vascular function in postmenopausal women: a cross
      sectional study.
AB  - OBJECTIVE: To investigate the effects of low levels of intake of phytoestrogens
      in Western habitual diet on vascular function. DESIGN: A cross-sectional study.
      SETTING: A population-based study. PARTICIPANTS: A total of 301 postmenopausal
      women aged 60-75 years living in The Netherlands. DETERMINANT: Dietary
      phytoestrogen intake as assessed using a food frequency questionnaire covering
      the year prior to enrollment. MAIN OUTCOME MEASURES: Blood pressure,
      hypertension, endothelial function and ankle brachial index. RESULTS: The median
      isoflavone intake was 0.2 mg in the lowest tertile and 11.4 mg in the highest
      tertile. Median lignan intake was 0.8 and 2.2 mg, respectively. No associations
      were found for higher intake of isoflavones, systolic and diastolic blood
      pressures, ankle-arm blood pressure index, endothelial function or hypertension.
      For lignans no association was found for ankle-arm blood pressure index or
      endothelial function, but we did observe lower systolic and diastolic blood
      pressures and a lower prevalence of hypertension (systolic blood pressure
      difference T3-T1, -11.2 mmHg, 95% confidence interval = -17.8 to -4.5, P for
      trend = 0.001; diastolic blood pressure difference T3-T1, -3.6 mmHg, 95%
      confidence interval = -7.8 to 0.6, P for trend = 0,08; and prevalence of
      hypertension, odds ratio T3 versus T1 = 0.41, 95% confidence interval = 0.22
      0.76, P for trend over tertiles = 0.004). CONCLUSION: The results of this study
      suggest a protective effect of dietary lignan intake on blood pressure and
      hypertension, even at low levels.

PMID- 15201556
TI  - Imidapril improves L-NAME-exacerbated nephrosclerosis with TGF-beta 1 inhibition
      in spontaneously hypertensive rats.
AB  - OBJECTIVE: This study was designed to investigate whether chronic angiotensin
      converting enzyme (ACE) inhibition prevents hypertensive glomerular injury and
      inhibits increases in the mRNA levels and immunohistological expression of the
      apoptosis inducer caspase-3, and transforming growth factor (TGF)-beta 1 during
      prolonged nitric oxide synthase (NOS) inhibition with N-nitro-L-arginine methyl
      ester (L-NAME) in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: For
      3 weeks, we studied three groups of 20-week-old male SHR: a control group, a l
      NAME group, and a group treated with L-NAME and the ACE inhibitor imidapril. L
      NAME rats developed severe hypertensive nephrosclerosis with significantly
      elevated blood pressure, markedly increased urinary protein excretion and serum
      creatinine levels, and more severe glomerulosclerosis and tubulo-interstitial
      changes. Levels of TGF-beta 1 mRNA in the renal tissue was also significantly
      increased in L-NAME rats compared with control SHR. Addition of imidapril
      significantly lowered blood pressure, inhibited nephrosclerosis and attenuated
      the mRNA level of TGF-beta 1 in comparison with L-NAME/SHR. Histologically, the
      glomerular cell apoptosis labeling index, terminal doxynucleotidil transferase
      mediated dUTP nick-end labeling of fragmented DNA (TUNEL) and active caspase-3,
      and TGF-beta 1 positive areas were also reduced by imidapril. CONCLUSION: These
      data suggest that imidapril prevents glomerular and arteriolar damages and renal
      functions, through inhibiting both TGF-beta 1 production and apoptosis induction.

PMID- 15201557
TI  - Betaxolol stimulates eNOS production associated with LOX-1 and VEGF in Dahl salt
      sensitive rats.
AB  - OBJECTIVE: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and
      vascular endothelial growth factor (VEGF) may play key roles in atherosclerosis,
      and have been shown to regulate nitric oxide (NO) production. However, the
      molecular mechanisms by which betaxolol, a specific beta 1-antagonist, stimulates
      endothelial NO synthase (eNOS) expression associated with LOX-1 and VEGF are
      unclear. We hypothesized that in the left ventricle of Dahl salt-sensitive (DS)
      rats, betaxolol reduces production of LOX-1 by suppressing NAD(P)H oxidase
      p47phox expression; betaxolol stimulates eNOS production associated with
      expression of VEGF and LOX-1; and betaxolol inhibits adhesion molecule and signal
      transduction, which may be involved in cardiovascular remodeling. METHODS: After
      5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e. at 11 weeks of
      age), a distinct stage of concentric left ventricular hypertrophy was noted.
      Betaxolol (0.9 mg/kg per day) was administered to 6-week-old DS rats for 5 weeks
      until the onset of left ventricular hypertrophy stage. RESULTS: Decreased
      expression of eNOS and VEGF in DS rats was increased by betaxolol. Upregulated
      LOX-1, NAD(P)H oxidase p47phox, intercellular and vascular cell adhesion molecule
      1 expression and phosphorylations of p38 mitogen-activated protein kinase and p65
      nuclear factor-kappa B activity were inhibited by betaxolol. Betaxolol
      administration resulted in significant improvement of cardiovascular remodeling
      and suppression of transforming growth factor-beta 1 and type I collagen
      expression. CONCLUSIONS: These results suggest that cardioprotective effects of
      betaxolol may stimulate eNOS production associated with VEGF and LOX-1, and
      inhibit adhesion molecule and signal transduction in DS rats.

PMID- 15201558
TI  - How much echo left ventricular hypertrophy would be missed in diabetics by
      applying the Losartan Intervention For Endpoint Reduction electrocardiogram
      criteria to select patients for angiotensin receptor blockade?
AB  - OBJECTIVE: The Losartan Intervention For Endpoint Reduction (LIFE) study
      demonstrated a clear mortality benefit in treating hypertensive patients with
      electrocardiogram (ECG) evidence of left ventricular hypertrophy (LVH) with
      losartan rather than atenolol. Previous studies have also shown that identifying
      and treating echo LVH is associated with prognostic benefits in hypertensive
      subjects, and is independent of the presence of ECG LVH. We sought to determine
      how many cases of echo LVH would be missed by applying the ECG criteria for LVH
      used in the LIFE study. DESIGN: A prospective study of 219 patients with type 2
      diabetes recruited from the hospital diabetic clinic. METHODS: Fifteen ECG
      criteria were assessed on each subject and compared with the presence or absence
      of LVH on echocardiography. RESULTS: All the proposed ECG criteria are poor at
      identifying echo LVH in people with diabetes. CONCLUSION: Using ECG LVH to select
      patients for angiotensin receptor blockade would lead to many diabetics with echo
      LVH missing out on the benefits of treatment. This assumes that the benefits seen
      in the LIFE study would also occur if the LIFE strategy were extended to echo LVH
      patients as well as to ECG LVH patients.

PMID- 15201559
TI  - Comparison of the effects of a 7-day period of non-compliance on blood pressure
      control using three different antihypertensive agents.
AB  - OBJECTIVES: To compare blood pressure control during 7 days of drug omission in
      patients taking bendroflumethiazide 2.5 mg, nifedipine LA 30 mg or enalapril 20
      mg once daily and, secondarily, to measure patient compliance. METHODS: Twenty
      four patients with hypertension were assigned, in a random crossover fashion, to
      a sequence of bendroflumethiazide, nifedipine LA and enalapril, each for 4 weeks,
      followed by a 1-week period of dose omission. The patients measured their own
      blood pressure daily using an Omron 705CP monitor. Differences in blood pressure
      from baseline (mean blood pressure during week 4 on treatment) and the week of
      dose omission were compared between the three drugs. Patient compliance was
      measured using pill counts and the Medication Event Monitoring System. RESULTS:
      Bendroflumethiazide maintained blood pressure control during drug omission for
      longer than enalapril or nifedipine LA. The magnitudes of the increase in
      systolic blood pressure (SBP) between baseline and day 7 off treatment were 7.0,
      12.2 and 9.7 mmHg for bendroflumethiazide, nifedipine LA and enalapril,
      respectively. For diastolic blood pressure (DBP), the values were 2.9, 5.3 and
      7.3 mmHg for bendroflumethiazide, nifedipine LA and enalapril, respectively.
      Differences in SBP between bendroflumethiazide and the comparator drugs occurred
      at day 2 off treatment. Differences in DBP between bendroflumethiazide and
      nifedipine were apparent on days 2 and 3 off treatment. Differences in DBP
      between bendroflumethiazide and enalapril were apparent on days 2, 3, 4 and 5 off
      treatment. Patient compliance throughout the study was high in terms of both
      taking the medication when required and omitting the medication when required.
      CONCLUSIONS: Bendroflumethiazide maintained blood pressure control during a
      period of drug omission better than nifedipine or enalapril.

PMID- 15201560
TI  - Evidence for carotid and radial artery wall subclinical lesions in renal
      fibromuscular dysplasia.

PMID- 15201561
TI  - Diuretic-induced hyperuricemia does not decrease cardiovascular risk.

PMID- 15201563
TI  - Hypertension in children and adolescents.

PMID- 15201564
TI  - Microalbuminuria in type 1 diabetes mellitus.

PMID- 15201566
TI  - Costs and quality in the treatment of acute depression in primary care: a
      comparison between England, Germany and Switzerland.
AB  - No study has yet compared the costs and quality of depression treatment between
      European countries. The present study aimed to compare the costs and quality of
      treatment for the first manifestation of an acute major depression in England,
      Germany and Switzerland. Seventy-four randomly selected physician practices
      assessed their services for one hypothetical average patient (cost evaluation)
      and 73 practices reported retrospective data on one real patient (quality
      evaluation) for the year 2001. Reimbursement fees served as unit costs for
      Germany and Switzerland. Average reimbursement fees were used to measure resource
      utilization in all countries. Resource utilization was lowest in Switzerland. The
      percentage of patients receiving evidence-based treatment for major depression
      was insignificantly higher in Switzerland and England compared to Germany (56%,
      52% and 35%, respectively; P>0.30). Switzerland was both the most effective and
      the most efficient country (in terms of resource utilization) in providing
      outpatient treatment for depression.

PMID- 15201565
TI  - Efficacy of sildenafil citrate (Viagra) for the treatment of erectile dysfunction
      in men in remission from depression.
AB  - Erectile dysfunction (ED) and depression are highly prevalent and frequently
      comorbid. Sildenafil effectively treats ED in men with depression and in men
      taking antidepressants. We evaluated the efficacy of sildenafil in men with
      depression in remission and ED. Patients with a history of ED when major
      depressive disorder (MDD) was diagnosed, which persisted after MDD was treated to
      remission, were randomized to 12 weeks of treatment with sildenafil (50 mg,
      flexible) or placebo. Efficacy was assessed using intercourse success rates, a
      global efficacy question (Has treatment improved your erections?), the
      International Index of Erectile Function (IIEF) and Life Satisfaction Checklist
      (LSC). By week 12, intercourse success rates were significantly higher among
      sildenafil- (74%) compared to placebo-treated patients (29%; P=0.0001). About 83%
      and 34% of sildenafil- and placebo-treated patients, respectively, reported
      improved erections (odds ratio=9.4, P=0.0001). IIEF scores in the sildenafil
      group (n=83) were significantly improved compared to those in the placebo group
      (n=85; P <0.0001). LSC sexual life item improved significantly among sildenafil-
      versus placebo-treated patients. The most frequently reported adverse events were
      transient and mild-to-moderate. Sildenafil is an effective and well-tolerated
      treatment for ED in patients with a history of ED at the time of MDD diagnosis,
      and which persisted after the MDD was treated to remission.

PMID- 15201567
TI  - Mean Deviation of Inter-rater Scoring (MDIS): a simple tool for introducing
      conformity into groups of clinical investigators.
AB  - In spite of considerable progress over the past decade, training investigators
      for inter-rater reliability for clinical trials remains a major problem. The aim
      of the present study was to promote a new tool to increase data homogeneity by
      introducing conformity into groups of clinical investigators. The investigators
      scoring grid we are proposing-the Mean Deviation of Inter-rater Scoring (MDIS)
      involves the calculation of the score deviation for each investigator relative to
      the median score of an expert group who had evaluated the same videotape-recorded
      clinical case. Whatever the scale, the score deviation is calculated as the
      absolute deviation value from the median score obtained by the experts for each
      item. The MDIS value is then evaluated from all the scores given by an
      investigator by dividing the total sum of the previously defined values by the
      number of items of the scale. Some examples from practice are given using several
      rating scales: (i) Hamilton Anxiety Rating Scale; (ii) Hamilton Depression Rating
      Scale; (iii) Montgomery Asberg Depression Rating Scale; and (iv) Positive And
      Negative Symptoms Scale. Finally, such a method could also be employed by experts
      to evaluate the quality of videotape-recorded clinical cases used in clinical
      trials, as well as by teachers to evaluate initial or continuous medical
      training.

PMID- 15201568
TI  - Implications of using different cut-offs on symptom severity scales to define
      remission from depression.
AB  - A fundamental question in the medical management of disease is how well treatment
      works. Although there are many ways of defining improvement, one endpoint of
      definite interest is the resolution or remission of the disorder. In short-term
      antidepressant treatment trials, remission is usually defined according to post
      treatment scores on symptom severity measures, such as the Hamilton Rating Scale
      for Depression (HRSD) or the Montgomery-Asberg Depression Rating Scale (MADRS).
      However, there is uncertainty as to what cut-offs should be used on these
      measures to define remission. During the past 2 years, as part of the Rhode
      Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, our
      laboratory has examined the question of how to define remission on the HRSD and
      MADRS. In the present report from the MIDAS project, we examined the impact of
      the cut-off score used to define remission on the percentage of depressed
      outpatients in ongoing treatment who are considered to be in remission. In
      addition, we examined the association between remission status and psychosocial
      impairment for different cut-off scores. Three hundred and three depressed
      psychiatric outpatients were rated on the MADRS, 17-item HRSD, and an index of
      DSM-IV remission status. Approximately one-third of patients completed a measure
      of psychosocial impairment. For both the HRSD and the MADRS, we examined four cut
      off scores for remission. For each cut-off, we determined the percentage of
      patients who met the definition of remission, the percentage of patients who
      continued to meet DSM-IV criteria for major depressive disorder (MDD), and the
      percentage of patients without any self-reported impairment from depression. For
      both scales, the range of cut-off scores was associated with more than a two-fold
      difference in prevalence of remission. Based on higher thresholds to define
      remission, a small percentage of patients met criteria for MDD, whereas no
      patients scoring below the low thresholds had MDD. The threshold to define
      remission was associated with psychosocial impairment: higher cut-off scores were
      associated with lower rates of no impairment. The cut-offs used to define
      remission from depression considerably influence the percentage of patients
      considered to be in remission. Lower cut-off scores than those most commonly used
      to define remission appear to be more valid.

PMID- 15201569
TI  - Direct association between orbitofrontal atrophy and the response of psychotic
      symptoms to olanzapine in schizophrenia.
AB  - The study of cerebral variables associated with response to neuroleptics holds
      interest from both theoretical and clinical points of view. To date, no studies
      have aimed to identify predictors of response to olanzapine based on cerebral
      measurements. Here, we used magnetic resonance to assess the relationship between
      volumes of the prefrontal (dorsolateral and orbitofrontal) and temporal (temporal
      lobe and hippocampus) cortical regions and ventricles and, on the other hand, the
      response to olanzapine in 16 schizophrenic patients. Data from 42 healthy
      controls were used to calculate volume residuals in the patients, defined as
      deviations from the expected values, given individual age and intracranial
      volume. Residuals thus represent the effect of illness on regional measurements.
      The association between clinical change and those residuals was calculated
      separately for the positive, negative and total scores from the Positive and
      Negative Syndrome Scale (PANSS). There was a significant direct association
      between the degree of orbitofrontal atrophy and the improvement of positive
      symptoms with olanzapine. No predictors were found for change in the negative
      dimension. A trend was found for patients with larger ventricles to show a
      greater global decrease in total PANSS scores. Neither age nor duration of
      illness explained a significant proportion of the symptom improvement. This
      result, together with others from the literature, supports the idea that atypical
      antipsychotics may offer some benefit to patients with significant regional
      atrophy, and this may have implications for the choice of antipsychotic in
      clinical practice.

PMID- 15201570
TI  - Improvements in stable patients with psychotic disorders switched from oral
      conventional antipsychotics therapy to long-acting risperidone.
AB  - Recent meta-analytic work suggests atypical antipsychotics may be clinically
      superior to conventional antipsychotics, although many stable patients remain on
      conventional antipsychotic treatment. A long-acting atypical agent may benefit
      patients in realms of both advanced medication delivery and mechanism of action.
      In a multicentre, open-label study of 725 patients with schizophrenia or
      schizoaffective disorder, patients received 25-75 mg of long-acting risperidone
      every 2 weeks for up to 50 weeks, with performance of standard safety and
      efficacy assessments. Data are presented on stable patients receiving oral
      conventional antipsychotics at study entry. In the 46 (6.3%) stable patients
      receiving oral conventional antipsychotics (followed between 6 months and 1 year;
      mean 468 days), mean (SD) Positive and Negative Syndrome Scale (PANSS) total
      score improved from 73.1+/-17.2 to 64.5+/-18.2 (P=0.0006). Clinical improvement
      of > or =20%, > or =40% or > or =60% reduction in PANSS total score occurred in
      49%, 29% and 10% of stable patients, respectively. Extrapyramidal Symptom Rating
      Scale subjective ratings and objective physician ratings (parkinsonism) decreased
      significantly (P<0.05). The hypothesis that switching stable patients treated
      with oral conventional antipsychotics to long-acting risperidone may result in
      significant improvements in psychiatric and movement disorder symptomatology
      merits further investigation.

PMID- 15201571
TI  - Prognostic indicators for early discontinuation of risperidone long-acting
      injection.
AB  - Although efficacy trials have been conducted on risperidone long-acting injection
      (RLAI), its most appropriate utilization in clinical practice remains unclear.
      This 6-month, follow-up study investigated prognostic indicators for early
      discontinuation of RLAI. Consecutive sampling was conducted for adult patients
      with a psychotic disorder commenced on RLAI, whose injection was dispensed by one
      of three South London psychiatric hospital pharmacies. Prescription data were
      collected prospectively and clinical data retrospectively. Eightly-one out of 88
      (92.0%) eligible patients were included, of whom 29 (35.8%) had treatment
      refractoriness and 30 (37.0%) discontinued within 6 months. Patients with a
      preceding oral antipsychotic were more likely to discontinue RLAI than those with
      a preceding depot; treatment refractoriness weakly confounded this relationship
      [summary adjusted odds ratio (OR) 2.68, 95% confidence interval (CI) 0.95-7.53,
      P=0.061]. After adjusting for preceding antipsychotic type, patients with
      treatment refractoriness were no more likely to discontinue than those without
      (summary adjusted OR 1.55, 95% CI 0.59-4.11, P=0.376). Sociodemographic factors
      and other clinical factors were non-predictive of discontinuation. For this first
      wave of patients commenced on RLAI, many had treatment refractoriness. RLAI
      discontinuation is high early on but subsequently tapers off. Preceding
      antipsychotic type (depot versus oral) is a stronger prognostic indicator than
      treatment refractoriness for RLAI discontinuation.

PMID- 15201573
TI  - Weight gain during long-term treatment with olanzapine: a case series.
AB  - The aim of this study was to assess the prevalence of weight gain during long
      term treatment with olanzapine under routine conditions. Weight changes in a
      sample of 27 outpatients with schizophrenic or schizoaffective disorder were
      assessed over a mean duration of treatment of 22 months (6-42 months). Treatment
      with olanzapine was started anew or switched from a conventional antipsychotic
      drug. Eighteen (66.7%) patients gained more than 7% of their initial body weight.
      Mean weight gain was 9.2 kg over the study period for the first year 7.7 kg, and
      only 1.7 kg in the second year. Due to some patients losing weight in the second
      year, the latter finding obscures the fact that more than 50% of patients gained
      considerable weight also during the second year (4.8 kg). Weight gain per month
      was significantly higher in patients with lower body mass index, yet the highest
      weight gain was found in the most obese patient. Weight gain under olanzapine is
      a serious concern, and should be monitored closely and countered by active
      measures.

PMID- 15201572
TI  - Long-acting injectable risperidone: safety and efficacy in stable patients
      switched from conventional depot antipsychotics.
AB  - Long-acting injectable risperidone was assessed in schizophrenia patients who
      were symptomatically stable on conventional depot antipsychotics and who were
      then switched to long-acting risperidone. Participants in this open-label,
      multicentre, 12-week trial had received flupenthixol decanoate, fluphenazine
      decanoate, haloperidol decanoate, or zuclopenthixol decanoate for 4 months or
      longer. Each was considered symptomatically stable by investigators. After
      receiving two cycles of their conventional depot antipsychotic during the run-in
      period, patients were switched to receive long-acting risperidone every 2 weeks
      for 12 weeks at an initial dose of 25 mg. This dose could be increased in 12.5-mg
      increments at 4-week intervals. Ninety-two percent of the patients received all
      six injections; 62% received the 25-mg dose throughout the treatment period.
      Adverse events related to movement disorders were reported in 3%. Severity of
      movement disorders decreased during long-acting risperidone treatment. Positive
      and Negative Syndrome Scale (PANSS) total and factor scores and scores on the
      Clinical Global Impressions severity scale were significantly reduced during
      treatment; 48% of these stable patients showed further symptom improvement (> or
      =20% decrease in PANSS score at endpoint). The results indicate that patients
      with schizophrenia who are symptomatically stable during treatment with a
      conventional depot antipsychotic can be safely and effectively switched to long
      acting injectable risperidone without a prior transition to oral risperidone.

PMID- 15201574
TI  - cagA-positive Helicobacter pylori strains and gastro-oesophageal reflux disease:
      still puzzling?
AB  - Gastro-oesophageal reflux disease (GORD) and Helicobacter pylori infection are
      both common in Western countries. A recently published meta-analysis has shown an
      association between an absence of H. pylori infection and GORD symptoms.
      Infection with cagA-positive H. pylori strains is a causative factor for the
      development of duodenal ulcer and is a risk factor for gastric cancer. Data about
      a protective role of cagA-positive H. pylori strains against more severe reflux
      oesophagitis are documented in several studies, but questioned by some other
      studies. There is a need for further studies to clear the definite role of cagA
      positive H. pylori strains in severe reflux oesophagitis and their possible
      effect on the development of Barrett's adenocarcinoma. The role of Helicobacter
      pylori in gastro-oesophageal reflux disease (GORD) is still discussed
      controversially. Different factors might be responsible for the remarkably
      heterogeneous results of previously performed studies (e.g. location,
      environmental factors and different virulence factors of H. pylori strains). A
      very recently published meta-analysis has shown a significant association between
      the absence of H. pylori infection and GORD symptoms, and a positive correlation
      between anti-H. pylori therapy and the occurrence of both de-novo and
      rebound/exacerbated GORD. The results of this meta-analysis are questioned by
      some authors because of single larger trials and geographical variations of the
      studies analysed. Data on the role of the cytotoxic-associated antigen (cagA)
      positive H. pylori strains are contradictory. Several studies have provided
      evidence supporting the protecting role of cagA-positive H. pylori strains
      against GORD, but these results were not confirmed by all studies. A multitude of
      patients suffer from H. pylori infection and GORD, simultaneously. Therefore,
      further studies are needed to clearly answer the question whether infection with
      cagA-positive H. pylori strains, which bear a well-documented risk for gastric
      cancer and gastro-duodenal ulcer, is really helpful against more severe reflux
      oesophagitis and, in consequence, perhaps protective against Barrett's oesophagus
      and Barrett's adenocarcinoma.

PMID- 15201575
TI  - Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory
      bowel disease.
AB  - Infliximab, a chimeric antibody to tumour necrosis factor-alpha (TNF-alpha),
      holds much promise for the treatment of patients with Crohn's disease. On the
      cellular level, infliximab affects survival and, as presented by Agnholt et al.
      in this issue of the journal, inhibits GM-CSF (granulocyte-macrophage colony
      stimulating factor) production by intestinal T lymphocytes. Future studies will
      reveal whether the pro-apoptotic effect of infliximab is linked to its inhibition
      of endogenous GM-CSF expression in T cells. Treatment of Crohn's disease, a
      severe chronic intestinal disorder, may at times be challenging as it can be
      refractory to routine therapy. Among novel therapeutic strategies, agents that
      neutralize tumour necrosis factor-alpha (TNF-alpha) are of particular interest
      because of the crucial role of TNF-alpha in sustaining chronic mucosal
      inflammation. The exact mechanism of the anti-TNF action, apart from direct
      activity that neutralizes cytokines, is not fully understood. Cellular effects of
      TNF-alpha neutralizing treatment include an increased susceptibility to apoptosis
      of intestinal mucosal T cells. A novel pathway of anti-TNF-alpha interaction with
      T cells has been presented in the current issue of this journal. Agnholt et al.
      have found that in-vivo or in-vitro administration of infliximab, a chimeric
      antibody to TNF-alpha, resulted in a decreased production of GM-CSF (granulocyte
      macrophage colony-stimulating factor) by T cells. Infliximab related down
      regulation of TNF-alpha induced GM-CSF expression may be one of the mechanisms by
      which this drug increases the rate of apoptosis in T cells.

PMID- 15201576
TI  - The role of cagA Helicobacter pylori strains in gastro-oesophageal reflux
      disease.
AB  - BACKGROUND AND AIMS: The role of Helicobacter pylori infection in gastro
      oesophageal reflux disease is controversial. The aim of this study was to
      evaluate the prevalence of colonization by cagA-positive and cagA-negative H.
      pylori strains in the spectrum of gastro-oesophageal reflux disease. METHODS: A
      total of 108 patients (50 male/58 female; mean age, 50.3 years) with dyspepsia
      and peptic ulcer or erosive gastritis/duodenitis were categorized into patients
      without reflux and patients with reflux oesophagitis graded from I to IV. All
      patients underwent upper endoscopy with biopsies of the antrum. H. pylori was
      detected by histology, urease test and polymerase chain reaction. The cagA status
      was diagnosed in the gastric biopsy by polymerase chain reaction. RESULTS: The
      overall prevalence of H. pylori colonization in patients with reflux was 68.6%
      and was 70.2% in those without oesophageal disease (P = 0.862). Colonization by
      cagA-positive strains was also not statistically different between the two groups
      (31.4% versus 40.4%, P = 0.332). However, patients with grades II-IV reflux
      oesophagitis were less colonized by the bacterium (36.4%) than patients with
      grade I oesophagitis (77.5%) (P = 0.009). H. pylori cagA-positive strains were
      also less likely to colonize the stomach of patients with grades II-IV
      oesophagitis (0%), than grade I reflux oesophagitis (40%) patients and controls
      (40.4%). CONCLUSIONS: Infection of the stomach by H. pylori and especially by H.
      pylori cagA strains may play a protective role against the development of the
      most severe forms of gastro-oesophageal reflux disease.

PMID- 15201577
TI  - Increased production of granulocyte-macrophage colony-stimulating factor in
      Crohn's disease--a possible target for infliximab treatment.
AB  - BACKGROUND: The presence of neutrophils among epithelial cells is one of the
      major features of the inflammation in Crohn's disease, and has been used to
      indicate disease activity. The survival of neutrophils outside the blood vessels
      is limited and their longevity is influenced by granulocyte-macrophage colony
      stimulating factor (GM-CSF), which probably reduces neutrophil apoptosis.
      OBJECTIVE: To study GM-CSF production in intestinal cell cultures from Crohn's
      disease patients before and after infliximab treatment. PATIENTS: Colonic mucosal
      biopsies were obtained from 29 Crohn's disease patients before and after three
      infliximab infusions (5 mg/ml) and from ten healthy subjects. METHODS: Biopsies
      were cultured in RPMI at high concentrations of interleukin-2 (IL-2) (2000 U/ml)
      and IL-4 (500 U/ml), but without antigen addition. GM-CSF content was analysed
      after 5 days culture and related to the Crohn's disease activity index (CDAI) and
      compared with the GM-CSF production from healthy subjects. Peripheral leucocyte
      count, C-reactive protein and the degree of mucosal inflammation, evaluated
      histologically, were determined. In-vitro T cell GM-CSF production was studied
      with/without addition of infliximab and after stimulation. RESULTS: GM-CSF
      production was increased in Crohn's disease patients compared with healthy
      controls (P = 0.02) and correlated with the CDAI (Spearman rho = 0.65, P =
      0.001). GM-CSF levels and mucosal histology score decreased (P = 0.007 and P =
      0.01 respectively) after three infliximab infusions, as did the peripheral blood
      leucocyte count (P < 0.001). Infliximab inhibited in-vitro T cell GM-CSF
      production. CONCLUSION: In-vitro cell culture production of GM-CSF was increased
      in Crohn's disease and related to inflammation, but decreased after infliximab
      treatment, probably because intestinal T cell GM-CSF production was reduced.

PMID- 15201578
TI  - Crohn's disease in the over-60 age group: a population based study.
AB  - OBJECTIVES: Late-onset Crohn's disease (CD) may show a distinctive pattern of
      expression. The aim of our study was to describe the incidence or presentation of
      CD in the elderly and compare the outcomes in patients < 60 years or > or = 60
      years at diagnosis. METHODS: The study included a population based inception
      cohort of all incident CD cases diagnosed in Brittany (France) between 1994 and
      1997. Sixty-three patients were > or = 60 years and 201 were < 60 years at
      diagnosis. The physicians managing the patients used standardized questionnaires
      to collect the study data. The questionnaires on outcomes and treatments were
      completed in 2002. RESULTS: In patients > or = 60 years, the annual incidence was
      2.5 per 10 persons and clinical features were similar to those in younger
      patients, except for a higher rate of colon involvement. Among older patients,
      those with diverticula (29/63, 46%) were more likely to have granulomas (58% vs
      33% of patients without diverticula, P < 0.04), but the diagnosis of CD was
      confirmed by lesions remote from the diverticula in most cases (23/29). Early
      resection rates were not higher in older patients, who were less likely to
      require immunosuppressants or re-admission for CD flares, as compared to younger
      patients. Five year mortality in older patients was 16% but was unrelated to CD.
      CONCLUSIONS: In Brittany, the age specific incidence, clinical features, and
      prognosis of CD among the elderly are comparable to those in younger individuals.
      Colon involvement is more common. Concomitant diverticular disease is common and
      should prompt a search for CD lesions at other sites to confirm the diagnosis.
      Older patients are less likely to require immunosuppressants or admission for
      flares.

PMID- 15201579
TI  - Coeliac disease is the most common cause of chronic diarrhoea in Iran.
AB  - OBJECTIVE: Coeliac disease (CD) is one of the most important causes of chronic
      diarrhoea. The prevalence of CD in patients with chronic diarrhoea in Iran
      remains unknown. The aim of this study was to evaluate the prevalence of CD among
      100 Iranian patients with chronic non-bloody diarrhoea. METHODS: One hundred
      consecutive patients with chronic non-bloody diarrhoea of more than 6 weeks
      attending an academic centre in Iran were enrolled. Patients with bloody
      diarrhoea and renal failure were excluded. IgA endomysial antibody (IgA EMA), IgA
      antigliadin antibody (IgA AGA), and total serum IgA were tested in all patients.
      Patients with negative IgA EMA were evaluated for other causes of chronic
      diarrhoea. Patients who had positive IgA EMA underwent upper gastrointestinal
      endoscopy and duodenal biopsy. Patients with a positive IgA EMA were advised to
      follow a gluten-free diet (GFD) strictly for 6 months, and then clinical
      symptoms, serological and haematological tests were re-assessed. RESULTS: A total
      of 100 patients (55 men and 45 women) with chronic non-bloody diarrhoea were
      studied. Mean age of the patients was 31 years. Total serum IgA was in the normal
      range in all participants. Twenty patients (12/45 women; 8/55 men) had positive
      IgA EMA. Fourteen of them also had a positive IgA AGA. CD was diagnosed in 19
      patients (19%). Small intestinal Crohn's disease, small intestinal lymphoma and
      idiopathic aetiology were the next. In patients with CD, after 6 months of a GFD,
      15 patients (75%) had a complete clinical response, three patients (15%) had a
      good response, and one patient (5%) had a partial response. One patient did not
      follow a GFD. CONCLUSION: CD is the most common cause of adult chronic non-bloody
      diarrhoea in Tehran.

PMID- 15201580
TI  - Immunoglobulin coating of faecal bacteria in inflammatory bowel disease.
AB  - OBJECTIVE: An inappropriate mucosal immune response to the commensal bacterial
      flora may play a role in the pathogenesis of inflammatory bowel disease (IBD). In
      this study we determined the percentage of immunoglobulin-coated bacteria in the
      stools of patients and controls. METHODS: Faecal samples were obtained from 18
      patients with IBD (one sample during exacerbation and one shortly after remission
      was achieved), 15 healthy volunteers, eight infectious colitis patients, and 13
      IBD patients in long-term remission. Bacterial immunoglobulin coating was
      determined by flow-cytometry analysis. Faecal alpha-1-antitrypsin concentrations
      were determined by radial immune diffusion. RESULTS: IBD patients had 69 +/- 19%
      immunoglobulin A (IgA)-, 56 +/- 32% immunoglobulin G (IgG)- and 56 +/- 29%
      immunoglobulin M (IgM)-coated bacteria in their faeces. Healthy controls had less
      immunoglobulin coating, respectively 36 +/- 12%, 11 +/- 4% and 11 +/- 7%.
      Infectious colitis patients had 57 +/- 14% IgA, 31 +/- 13% IgG, and 42 +/-16%
      IgM; however, they had higher faecal alpha-1-antitrypsin concentrations than IBD
      patients. Shortly after remission, IBD patients had 65 +/- 20% IgA, 32 +/- 18%
      IgG and 40 +/- 21% IgM. Long-term-remission IBD patients had normal IgG and IgM
      but increased IgA (50 +/- 16%) coating. CONCLUSIONS: Compared with healthy
      controls, patients with IBD had an increased percentage of immunoglobulin-coated
      faecal anaerobic bacteria, both in active disease and shortly after remission.
      These results support the concept that there may be a breakdown of mucosal
      tolerance to the commensal gut flora in IBD.

PMID- 15201581
TI  - CLIP score as a prognostic indicator for hepatocellular carcinoma: experience
      with patients in the Middle East.
AB  - OBJECTIVE: To assess the prognostic ability of the Cancer of the Liver Italian
      Programme (CLIP) score and compare it with the Okuda system in patients with
      hepatocellular carcinoma from the Middle East, where the majority (70%) present
      with intermediate or advanced stages of the disease and do not receive any tumour
      specific treatment. METHODS: The medical records of 145 patients (113 males; mean
      age, 58.8 +/- 12.2 years) diagnosed with hepatocellular carcinoma over a 6-year
      period were reviewed and the disease was staged according to the CLIP and Okuda
      systems. The survival was compared by Kaplan-Meier curves and Cox regression
      analysis. RESULTS: The overall median survival of patients with hepatocellular
      carcinoma was 8.3 months (95% confidence interval, 6.6-9.4). The median survivals
      for CLIP score 0, 1, 2, 3 and 4-6 were 35, 29, 9, 6, and 2 months, respectively;
      for Okuda stages I, II and III, they were 24, 9 and 4 months, respectively. The
      CLIP system was judged to be statistically more efficient and consistent than the
      Okuda in predicting survival in the Cox proportional hazard model. CONCLUSIONS:
      These data from patients with hepatocellular carcinoma in the Middle East suggest
      that the CLIP score is more reliable than the Okuda system in predicting survival
      and can be used efficiently to determine prognosis in patients who present with
      intermediate or late stage of the disease.

PMID- 15201582
TI  - Comparison of comorbidity prevalence in oesophageal and gastric carcinoma
      patients: a population-based study.
AB  - OBJECTIVE: We investigated the distribution of serious comorbidity in patients
      with newly diagnosed oesophageal and gastric cancer between 1993 and 2001. Our
      special interest was comparing distal oesophageal and gastric cardia
      adenocarcinoma patients since a common origin of these tumours has been
      suggested. METHODS: Data on comorbidity (previous cancers, chronic obstructive
      pulmonary diseases, cardiovascular and cerebrovascular diseases, hypertension,
      ulcerative digestive tract diseases, liver diseases and diabetes) were derived
      from a population-based database in The Netherlands to compare risk factor
      profiles for 479 oesophageal squamous cell carcinomas, 339 distal oesophageal
      adenocarcinomas, 570 cardia adenocarcinomas and 1965 subcardia cancers. RESULTS:
      A comparable age and gender distribution was shown in distal oesophageal and
      cardia adenocarcinoma patients. After adjustment for age and gender, only the
      prevalence of previous cancers differed between adenocarcinomas of distal
      oesophagus and cardia [more frequent in distal oesophageal adenocarcinoma
      patients, odds ratio (OR) = 1.84, P = 0.01]. Ulcerative and liver diseases were
      more prevalent in oesophageal squamous cell carcinoma patients as compared with
      distal oesophageal adenocarcinoma patients (OR = 1.90, P = 0.02 and OR = 8.82, P
      = 0.04, respectively), whereas diabetes was more prevalent in the latter (OR =
      0.56, P = 0.03). Cardia adenocarcinoma patients significantly more often had
      hypertension as compared with subcardia cancer patients (OR = 1.53, P = 0.001),
      whereas the latter more often suffered from previous cancers and ulcerative
      diseases (OR = 0.54, P = 0.0009 and OR = 0.25, P < 0.0001, respectively).
      CONCLUSIONS: In terms of comorbidity at diagnosis, cardia adenocarcinoma patients
      resemble distal oesophageal adenocarcinoma patients rather than gastric subcardia
      carcinoma patients, with likewise equal age and gender distribution.

PMID- 15201583
TI  - Hepatocellular carcinoma risk in patients with porphyria cutanea tarda.
AB  - AIM: It has been suggested that patients with porphyria cutanea tarda (PCT) are
      at high risk of developing hepatocellular carcinoma (HCC); however, this has not
      been confirmed by other workers. The aim of our study was to evaluate the
      incidence of HCC in patients with PCT, and to assess the possible co-factors
      associated with cancer development. METHODS: Thirty-nine consecutive patients
      with a diagnosis of PCT were included. Hepatitis B virus and hepatitis C virus
      (HCV) infection was investigated, and a percutaneous liver biopsy was performed.
      Patients were treated with phlebotomies, which resulted in a clinical remission
      in all. These patients were included in a surveillance programme for the
      detection of HCC, with ultrasonography and serum alpha-fetoprotein every 6
      months. RESULTS: Thirty-nine patients (92% male; mean age, 55 +/- 16 years) with
      PCT were included. Alcohol abuse was reported in 87% of the cases. The mean
      follow-up time since the initial diagnosis of PCT was 9.7 years (378 patient
      years of follow-up). Serological markers of past infection with hepatitis B virus
      were found in 20% of the patients, while HCV infection was diagnosed in 56%. The
      stage of fibrosis in patients having liver biopsy was: 0 (32%), 1 (32%), 2 (9%),
      3 (18%), and 4 (9%). HCC was diagnosed in 1/39 patients with PCT (cumulative
      incidence, 2.6%), giving a yearly incidence of 0.26% per patient-year. This
      patient was a 69-year-old male, alcohol abuser, with HCV infection, with a 12
      year period between diagnosis of PCT and HCC, and with liver biopsy (3 years
      before) showing fibrosis stage 3. CONCLUSION: The risk of developing HCC in
      patients with PCT in our area is relatively low (a yearly incidence of less than
      1% per patient-year of follow-up), and perhaps attributable, at least in part, to
      concomitant HCV infection. Patients presenting with PCT should undergo both HCV
      infection determination and liver biopsy, and those with concomitant HCV
      infection or advanced fibrosis/cirrhosis should probably be included in a
      standard surveillance programme in order to achieve early diagnosis of HCC.

PMID- 15201584
TI  - The association between tumour necrosis factor-alpha gene polymorphism and the
      susceptibility to rugal hyperplastic gastritis and gastric carcinoma.
AB  - OBJECTIVES: Some subjects infected by Helicobacter pylori have enlarged folds in
      the gastric body, the precise mechanism of which remains obscure. The aim of this
      study was to clarify the association of tumour necrosis factor-alpha (TNFA) gene
      polymorphism with susceptibility to hyper-rugosity. We also examined the
      association of TNFA polymorphism with gastric carcinoma. SUBJECTS AND METHODS:
      Four hundred and seventy-two subjects (male/female = 351/121, aged 26-81 years)
      without gastric carcinoma (control group), and 300 patients (male/female =
      218/82, aged 32-91 years) with gastric carcinoma. Barium meal roentgenograms were
      performed in 396 subjects in the control group and fold width was measured at the
      greater curvature of the middle portion of the gastric body. Fasting plasma anti
      H. pylori IgG titres, pepsinogens (PGs) I and II were analysed, and TNFA -857
      promoter polymorphism was distinguished by the 5' nuclease polymerase chain
      reaction assay and polymerase chain reaction restriction fragment length
      polymorphism using HincII in both groups. RESULTS: Adjusted odds ratios of TNFA 
      857 T/T genotype and H. pylori seropositivity for hyper-rugosity (fold width =
      6.0 mm) were 6.7 (95% confidence interval (CI) 1.5-28, P < 0.01) and 18.2 (95% CI
      4.2-78, P < 0.0001), respectively. There were no significant differences in any
      genotype or allele frequencies between the control and total gastric carcinoma
      group. In a subgroup of gastric carcinoma patients who were negative for the PG
      assay, however, the odds ratio of the T allele was 1.4 (95% CI 1.0-2.0, P <
      0.05). CONCLUSION: The TNFA -857 T/T genotype and H. pylori infection were
      strongly associated with rugal hyperplastic gastritis. The TNFA -857 T allele may
      promote gastric carcinoma without severe atrophy.

PMID- 15201585
TI  - Sustained exacerbation of cryoglobulinaemia-related vasculitis following
      treatment of hepatitis C with peginterferon alfa.
AB  - Peginterferon is now the gold standard of therapy in patients with chronic
      hepatitis C virus infection. Extrahepatic manifestations of HCV are usually
      treated with interferon alfa. Here we report on a patient with HCV-related
      cirrhosis and cryoglobulinaemia who presented with an acute and long-lasting
      exacerbation of vasculitis during treatment with peginterferon. To our knowledge
      this is the first report of an acute exacerbation of cryoglobulinaemia-related
      vasculitis involving skin, peripheral nerve and kidney in a patient treated with
      peginterferon for HCV-related cirrhosis. The long half-life of peginterferon
      might explain the long-lasting symptoms of vasculitis. Clinicians should be aware
      of possible sustained flare of cryoglobulinaemia-associated vasculitis in
      patients receiving peginterferon.

PMID- 15201586
TI  - Some cases demonstrating the clinical usefulness of therapeutic drug monitoring
      in thiopurine-treated inflammatory bowel disease patients.
AB  - The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective drugs in
      steroid-dependent and refractory inflammatory bowel disease patients. Therapeutic
      drug monitoring (TDM) is a new concept to improve drug efficacy and prevent toxic
      adverse events. As thiopurine metabolism is influenced by genetic polymorphisms
      of methylating enzymes, metabolite levels may vary considerably, enabling
      significant adverse effects. In the present paper five patients are described to
      demonstrate the clinical usefulness of TDM when applying thiopurines for
      inflammatory bowel disease. Emphasized are patients with liver function test
      abnormalities and myelosuppression due to inappropriate 6-MP metabolite levels,
      and subsequently the treatment of these events. In addition, sophisticated 6-MP
      metabolite level-guided therapy, including non-compliance, is demonstrated. These
      cases demonstrate that TDM may improve effectivity and safety of thiopurine
      treatment.

PMID- 15201588
TI  - What a clinician should know about coeliac disease autoantibodies.

PMID- 15201587
TI  - Malnutrition, steatorrhoea and pancreatic head tumour.
AB  - A 61-year-old female patient is described who presented with weight loss,
      steatorrhoea and enlargement of the pancreatic head. Surgical exploration for
      suspected pancreatic cancer revealed multiple peritoneal white spots, initially
      suggestive for peritoneal metastases or tuberculosis but finally identified as
      peritoneal sarcoidosis. Pancreatic insufficiency could not be proven in further
      studies. We found pancreas divisum as an additional cause for the pancreatic head
      mass, and steatorrhoea was due to late-onset oligosymptomatic coeliac disease.
      This case demonstrates diagnostic pitfalls when several rare disorders are
      manifest in a single patient. Coeliac disease and sarcoidosis might be sequels of
      similar immune responses to certain antigens.

PMID- 15201589
TI  - Macro-aspartate aminotransferase and pregnancy: any influence?

PMID- 15201590
TI  - Effects of several socio-demographic factors on hepatitis B immunization rates.

PMID- 15201592
TI  - Spondyloarthropathies.

PMID- 15201593
TI  - Psoriasis vulgaris: an interplay of T lymphocytes, dendritic cells, and
      inflammatory cytokines in pathogenesis.
AB  - PURPOSE OF REVIEW: Discuss and update concepts and hypotheses for the
      pathogenesis of psoriasis based on new research reports (primarily from 2003 and
      early 2004). RECENT FINDINGS: Increases in newly defined dendritic cell subsets,
      cytokines, and chemokines have been identified in psoriasis lesions and have
      modified views of T-cell-mediated pathogenesis. In addition, the psoriasis
      transcriptome has been defined by large-scale genomic expression studies, and
      these data suggest distinct molecular mechanisms of type 1 T-cell-mediated
      inflammation. Somewhat surprisingly, therapeutic clinical trials suggest that
      tumor necrosis factor is a major pathogenic cytokine in psoriasis, whereas
      translational studies point to roles of other innate pathways mediated by heat
      shock proteins, glycolipids, natural killer T cells, or dendritic cells in
      disease pathogenesis. SUMMARY: An interactive network of inflammatory cytokines,
      chemokines, dendritic cells, and type 1 T cells or natural killer T cells
      potentially drives pathogenic inflammation in psoriasis vulgaris. Continued
      clinical studies with defined immune antagonists provide a critical means to
      dissect the contribution of different cell subsets and genomic pathways to the
      pathogenesis of psoriasis vulgaris.

PMID- 15201594
TI  - Pathogenesis of psoriatic arthritis.
AB  - PURPOSE OF REVIEW: Psoriatic arthritis is an inflammatory arthritis associated
      with psoriasis that is more common and severe than initially appreciated. The
      success of biologic agents in psoriatic arthritis has sparked great interest in
      this disorder, although the disease pathogenesis is poorly understood. This
      review focuses on recent advances in the genetic factors and immune pathways that
      have been implicated in susceptibility to disease. In addition, recent studies
      examining the mechanisms that underlie angiogenesis, enthesitis, and bone
      resorption in psoriatic arthritis are discussed. RECENT FINDINGS: Studies
      performed on several different populations indicate that the MHC class I allele
      Cw6 is associated with both early-onset psoriasis and psoriatic arthritis.
      Mutations in the caspase-activating recruitment domain 15 locus on chromosome 16
      are also associated with psoriatic arthritis, providing support for a model
      involving innate immune mechanisms. Evidence for a CD8 antigen-driven acquired
      immune response in psoriatic synovium and blood was reported. The finding of
      elevated levels of vascular endothelial growth factor and angiopoietin 2 in
      psoriatic arthritis synovial vasculature may provide insights into events
      responsible for the tortuous vessel morphology, a histologic feature
      characteristic of psoriatic joints. Tumor necrosis factor (TNF)-alpha is a
      critical factor mediating inflammation in the synovium, enthesis, and bone. In
      particular, osteoclasts resorb bone via a receptor activator of nuclear factor
      kappaB-receptor activator of nuclear factor kappaB ligand signaling pathway that
      is potentiated by TNF-alpha. The lessening of bone marrow edema after anti-TNF
      therapy provides further support for the importance of this cytokine in disease
      pathogenesis. SUMMARY: Recent studies provide additional support for distinct
      pathogenetic mechanisms in psoriatic arthritis that arise from a complex
      interplay between genetic and environmental factors. Histopathologic data and
      results from clinical trials highlight the predominance of TNF-mediated
      inflammation in psoriatic joint tissues.

PMID- 15201595
TI  - Relationship of psoriatic arthritis with the other spondyloarthropathies.
AB  - PURPOSE OF REVIEW: The seronegative spondyloarthropathies are a group of
      disorders sharing common clinical features, the hallmark of which is
      sacroiliitis. Despite the 40 years since psoriatic arthritis was recognized,
      controversy still exists about which patients to include within this disease
      group and the relation of psoriatic arthritis with the other
      spondyloarthropathies. RECENT FINDINGS: Early disease can present difficulties
      because it is inappropriate to use criteria developed on established cases in
      early arthritis, in which many cases may be initially undifferentiated. The
      taxonomy of juvenile spondyloarthropathy remains a contentious issue, and further
      modifications of the Durban criteria have been suggested. The predictive value of
      the European Spondyloarthropathy Study Group criteria for spondyloarthropathy
      varies with the prevalence of the disease in the population under consideration,
      as has been demonstrated in ambulatory practice in France and Spain. It appears
      that physicians differ in their interpretation of the individual features,
      particularly of such clinical items as asymmetry and predominantly lower limb
      involvement. The combination of dactylitis of a toe, heel pain, and
      oligoarthritis appears to be strongly suggestive of psoriatic arthritis. However,
      solitary heel pain can be problematic, and ultrasonographic entheseal erosion at
      the calcaneum has been shown equally in rheumatoid arthritis and psoriatic
      arthritis. MRI may be more sensitive and quantitatively discriminative in
      psoriatic arthritis. Spinal involvement in psoriatic arthritis can be
      asymptomatic, as in classical ankylosing spondylitis. Importantly, psoriatic
      spondylitis has been observed in the absence of sacroiliitis. SUMMARY: Clinicians
      generally agree that psoriatic arthritis constitutes a discreet subset within the
      spondyloarthropathy group, but the demarcation continues to be the subject of
      clinical research. The matter is confounded by the lack of agreed classification
      criteria for psoriatic arthritis; although in both adult and juvenile disease
      criteria for spondyloarthropathy exist, the place of psoriatic arthritis within
      this larger group requires further definition.

PMID- 15201596
TI  - Assessment of outcome in psoriatic arthritis.
AB  - PURPOSE OF REVIEW: A number of drugs for psoriatic arthritis have been tested in
      randomized clinical trials, and more agents are likely to be evaluated in the
      future. Such studies have highlighted the relative lack of well-validated or
      agreed-on outcomes that should be assessed. RECENT FINDINGS: Consensus exercises
      have identified core domains for intervention studies in psoriatic arthritis.
      Many of the tools used to measure these domains have been borrowed from
      rheumatoid arthritis or ankylosing spondylitis, but increasing data relate to
      psoriatic arthritis specifically. Nonetheless, there are gaps in the measurement
      toolkit, particularly with respect to assessing dactylitis and axial
      inflammation. Further validation of functional disability instruments, radiologic
      scoring methods, and enthesitis instruments is also required. Currently available
      composite responder criteria are based principally on peripheral joint
      inflammation and may not be inclusive enough to represent fully the spectrum of
      patients with psoriatic arthritis. SUMMARY: There have been significant
      developments in robust tools for assessing outcome in psoriatic arthritis. Since
      October 2002, much of the activity in this area has been developed by the Group
      for Research and Assessment of Psoriasis and Psoriatic Arthritis and will have
      culminated in the Outcomes Measures in Rheumatology Clinical Trials meeting in
      May 2004. Relatively little of this work has been published at the time of this
      review. Nevertheless, this effort will have a significant influence on the design
      and reporting of clinical trials in psoriatic arthritis.

PMID- 15201597
TI  - Recent advances in the treatment of the spondyloarthropathies.
AB  - PURPOSE OF REVIEW: Recently, there has been renewed interest in the
      spondyloarthropathy family of chronic inflammatory rheumatic conditions, which
      has been fueled to a large extent by the biologic era. Over the period of the
      past 2 years in particular, there have been several notable advances. First,
      there have been a number of large, high-quality randomized controlled trials
      evaluating the tumor necrosis factor (TNF) blockers and conservative treatments
      such as physiotherapy and nonsteroidal anti-inflammatory drugs for use in
      spondyloarthropathy. This has paved the way for the development of better tools
      to assess outcome in these patients both in daily practice and in the context of
      clinical trials. This review uses a systematic approach to outline the most
      recent (within the last 2 years) and the most pertinent advances in the
      treatments of the spondyloarthropathies, with particular emphasis on ankylosing
      spondylitis and psoriatic arthritis. RECENT FINDINGS: Supervised group exercise
      programs maintain flexibility and posture in patients with ankylosing
      spondylitis, and spa therapy is a cost-effective treatment option in ankylosing
      spondylitis. Nonsteroidal anti-inflammatory drugs have a role in symptom
      modification and, more importantly, may prevent structural disease progression in
      patients with ankylosing spondylitis when administered continuously at a fixed
      dose. TNF blockers have been evaluated in a number of randomized controlled
      trials in ankylosing spondylitis and psoriatic arthritis and have been
      demonstrated to be safe and effective in the short-term management of these
      diseases. Longer-term trials are awaited with radiographic outcomes to comment on
      their disease-modifying properties and their long-term safety and efficacy
      profiles. SUMMARY: There has been renewed interest in the spondyloarthropathy
      family of disorders, with an explosion in the number of trials evaluating outcome
      with the TNF blockers. To date, no cure has been found for the disease, but these
      agents are emerging as the best therapeutic option available for patients with
      ankylosing spondylitis and psoriatic arthritis to date.

PMID- 15201598
TI  - Recent advances in the management of psoriatic arthritis.
AB  - PURPOSE OF REVIEW: The incidence of psoriatic arthritis is currently estimated at
      7 to 42% of the population with active psoriasis, considered to affect 2 to 3% of
      the general population. Unmanaged psoriatic arthritis may result in progressive
      radiologic erosion, severe physical limitations, and disability. Newer trials in
      psoriatic arthritis therapy demonstrate ongoing ability to control disease
      symptoms and signs and the progression of the disease significantly. RECENT
      FINDINGS: Recognition of the immunopathogenesis of psoriatic arthritis, as with
      rheumatoid arthritis and psoriasis, prompts ongoing examination of the efficacy
      of several disease-modifying antirheumatic drugs. A new crop of biologics and
      pharmaceuticals with increased molecular specificity compared with traditional
      immunosuppressant disease-modifying antirheumatic drugs have been shown to be
      highly effective in inhibiting the symptoms and progression of psoriatic
      arthritis with less severe side effects. SUMMARY: Therapies either recently
      approved or pending approval by the Food and Drug Administration for psoriatic
      arthritis management are safe and effective in the treatment of symptoms,
      significantly improve quality of life, and prevent long-term progression of the
      disease.

PMID- 15201599
TI  - Host-infectious agent interactions in the pathogenesis of rheumatic disease.

PMID- 15201600
TI  - Clinical and pathologic aspects of arthritis due to Ross River virus and other
      alphaviruses.
AB  - PURPOSE OF REVIEW: Arthritogenic alphaviruses are globally distributed mosquito
      borne RNA viruses causing epidemics of polyarthritis/arthralgia, with disease
      emerging or reemerging and increasingly being reported in travelers. This article
      summarizes the current knowledge of these diseases, focusing on recent
      developments in the understanding of Ross River virus disease. RECENT FINDINGS:
      Alphaviral arthritides have often been blamed for protracted chronic illnesses.
      However, validated quality-of-life questionnaires and exhaustive searches for
      differential diagnoses showed that Ross River virus disease, although severe at
      onset, progressively resolved over 3 to 6 months. Many patients did experience
      long-term disease lasting more than 12 months, but in nearly all cases this was
      due to other conditions, primarily unrelated rheumatic conditions or depression.
      There is no indication that alphaviral arthritides predispose to other
      conditions; thus, patients whose Ross River virus disease has actually resolved
      may be underdiagnosed for other conditions. Ross River virus polyarthritis
      probably arises from inflammation associated with productive viral infections in
      synovial macrophages, which persist despite neutralizing antibodies and antiviral
      cytokine responses. Persistence may be facilitated by downregulation of cytokine
      responses by virus-antibody complexes binding to Fc receptors and induction of
      interleukin-10. How virus escapes neutralizing antibodies remains unclear but may
      involve phagocytosis of apoptotic virus-infected cells and infection of the
      phagocyte via the phagosome. SUMMARY: Diagnosis of alphaviral arthritides is
      complicated by nonspecific symptoms and the lack of commercial serodiagnostic
      kits, except for Ross River and Barmah Forest virus infections in Australia.
      Differential diagnoses should be actively pursued, especially if symptoms
      persist. Treatment with nonsteroidal anti-inflammatory drugs appears largely
      effective, with no evidence of long-term sequelae or relapse.

PMID- 15201601
TI  - Chlamydia-induced arthritis.
AB  - PURPOSE OF REVIEW: Chlamydia-induced arthritis is the most frequent form of
      reactive arthritis in Western countries. This article gives an overview of the
      recent findings with respect to diagnosis, pathogenesis, and therapy of the
      disease. RECENT FINDINGS: Recent advances in the modification and standardization
      of polymerase chain reaction techniques give promise to identify Chlamydia more
      frequently from joint samples. Based on the sequenced chlamydial genome,
      considerable progress has been achieved in the understanding of the Chlamydia
      host cell interaction, indicating that persistence is an alternate state of the
      bacteria used by Chlamydia to escape the immune system of the host rather than a
      general stress response. Furthermore, Chlamydia has the ability to reprogram the
      host cell by chlamydial effector proteins, which are transported from the
      inclusion into the host cell cytoplasm. The role of HLA-B27 is discussed in view
      of the pathogenesis of the disease. HLA-B27 should be considered a risk factor
      for chronic and/or axial disease rather than a true susceptibility factor for the
      development of Chlamydia-induced arthritis. No progress has been made in terms of
      causative therapy aiming at eradication of the bacteria. Tumor necrosis factor
      alpha blocking agents may represent a new option in cases that are refractory to
      therapy. SUMMARY: Molecular biology not only has improved the ability to detect
      Chlamydia in the joint for diagnostic purposes but also has extended the current
      understanding of the pathogenesis of the disease. In contrast to this progress,
      causative therapy of Chlamydia-induced arthritis is still an unfulfilled need.

PMID- 15201602
TI  - Infectious complications of treatment with biologic agents.
AB  - PURPOSE OF REVIEW: There are three tumor necrosis factor-alpha inhibitors on the
      US and European markets today, and uncommon but devastating infectious
      complications accompany their use. This review describes the most important
      pathogen-specific infections and their relative frequency. Recent literature is
      summarized that has helped elucidate the pathophysiologic basis for their
      occurrence. Finally, evolving sets of recommendations for prevention, diagnosis,
      and treatment of infectious complications of their use are explored. RECENT
      FINDINGS: Tuberculosis has continued to be the most common pathogen reported in
      association with infliximab, and less so with etanercept and adalimumab.
      Determining treated population case rates depends on having an accurate
      denominator and reflects the local population's latent infection rate. The same
      is true for histoplasmosis. Other pathogens requiring intact cellular immunity
      for control of latent infection have also been reported. Specific recommendations
      for preventive therapy are being made, but prospective clinical trials are needed
      to assess the risk-benefit of any particular approach. SUMMARY: Microorganisms
      responsible for the infectious complications associated with anticytokine therapy
      are generally intracellular pathogens or pathogens that commonly exist in a
      chronic, latent state and are normally held in check by cell-mediated immunity.
      Diagnosis requires a high index of suspicion and prompt acquisition of
      appropriate tissue for microscopic examination and microbiologic culture. Prompt
      empiric therapy that focuses on the most likely infections is necessary to
      prevent mortality.

PMID- 15201603
TI  - Epstein-Barr virus, arthritis, and the development of lymphoma in arthritis
      patients.
AB  - PURPOSE OF REVIEW: Rheumatoid arthritis is a complex multisystem disorder. The
      manifestations of joint disease are usually clinically apparent, but the effects
      of the concomitant abnormalities of immune function are more subtle. It has been
      suggested that patients with rheumatoid arthritis have an impaired capacity to
      control infection with Epstein-Barr virus. Epstein-Barr virus has oncogenic
      potential and is implicated in the development of some lymphomas. This review
      analyses the relation between Epstein-Barr virus, rheumatoid arthritis, and the
      risk of lymphoma and considers the effect of immunosuppression on this triad.
      RECENT FINDINGS: Recent publications provide evidence for an altered Epstein-Barr
      virus-host balance in patients with rheumatoid arthritis, who have a relatively
      high Epstein-Barr virus load. Large epidemiologic studies confirm that lymphoma
      is more likely to develop in patients with rheumatoid arthritis than in the
      general population. The overall risk of development of lymphoma has not risen
      with the increased use of methotrexate or biologic agents. Histologic analysis
      reveals that most lymphomas in rheumatoid arthritis patients are diffuse large B
      cell lymphomas, a form of non-Hodgkin lymphoma. Epstein-Barr virus is detected in
      a proportion of these. SUMMARY: Overall, patients with rheumatoid arthritis have
      approximately a twofold increased risk of experiencing lymphoma. Some, but not
      all, of this increased risk reflects an increase in Epstein-virus-associated
      lymphomas. This in turn may be influenced by the elevated Epstein-Barr virus load
      found in rheumatoid arthritis patients and may reflect subtle impairment of
      antiviral immunity in this group of patients.

PMID- 15201604
TI  - Bacteria and human autoimmunity: the case of primary biliary cirrhosis.
AB  - PURPOSE OF REVIEW: Primary biliary cirrhosis is a chronic inflammatory disease of
      the intrahepatic bile ducts that eventually leads to liver cirrhosis and organ
      failure, in which several observations suggest an autoimmune origin. Similarly to
      other autoimmune diseases, microbial mediated molecular mimicry is the most
      widely studied trigger that may break immunologic tolerance in primary biliary
      cirrhosis. RECENT FINDINGS: The hypothesis of a bacterial role in the cause of
      primary biliary cirrhosis has received recent attention, based on in vitro data
      and the identification of a unique xenobiotic-metabolizing bacterium that
      modulates naturally occurring environmental estrogens, namely, Novosphingobium
      aromaticivorans. SUMMARY: The evidence indicates that bacteria, through different
      mechanisms, may precipitate autoimmunity in primary biliary cirrhosis and other
      autoimmune diseases. These data have several implications.

PMID- 15201605
TI  - Pattern recognition receptors and their involvement in the pathogenesis of
      arthritis.
AB  - PURPOSE OF REVIEW: Pattern recognition receptors are germ-line encoded receptors
      that recognize specific pathogen-associated molecules, thereby allowing the
      innate immune system to distinguish self from nonself structures. Pattern
      recognition receptors mediate activation of different signaling pathways,
      resulting in the production of proinflammatory cytokines and the expression of
      antimicrobial genes. Additionally, pattern recognition receptors play a central
      role in the activation and direction of the adaptive immune response. This review
      summarizes recent advances in research trying to elucidate the link between
      different pattern recognition receptors and inflammatory autoimmune disorders.
      RECENT FINDINGS: The best known pattern recognition receptors, the toll-like
      receptors, are involved in the regulation of inflammation during infectious
      diseases. They affect apoptotic pathways and dendritic cell maturation, and
      interact with B-cell receptors in priming T-cell responses to host-derived DNA.
      This brought toll-like receptors and other pattern recognition receptors into
      focus as potential players in the induction of autoimmune diseases. Indeed,
      several inflammatory autoimmune diseases have been linked during the past few
      years to defects or polymorphisms of genes encoding pattern recognition
      receptors. SUMMARY: The discovery of toll-like receptors and other groups of
      pattern recognition receptors, such as the caspase recruitment domains or the
      triggering receptors expressed by myeloid cells, allowed one to draw an
      increasingly complex picture of immune responses to pathogens. The growing
      evidence for an involvement of pattern recognition receptors in the pathogenesis
      of autoimmune disorders warrants further investigation of the expression and
      function of pattern recognition receptors to develop novel therapeutics for
      diseases such as rheumatoid arthritis.

PMID- 15201606
TI  - Bone loss in inflammatory arthritis: mechanisms and treatment strategies.
AB  - PURPOSE OF REVIEW: Focal bone loss in inflammatory arthritis begins early in the
      disease process and can contribute to patient morbidity. Current treatment
      strategies primarily target suppression of the inflammatory cascade with varying
      success in limiting the progression of focal bone destruction. This review
      outlines the current understanding of the mechanisms mediating inflammation
      induced focal bone loss in rheumatoid arthritis and other inflammatory
      arthritides and highlights recent studies in animal models of arthritis that have
      contributed to our knowledge of this process. RECENT FINDINGS: Bone-resorbing
      osteoclasts have been identified as important effector cells in inflammation
      induced bone loss in both experimental animal models and human rheumatoid
      arthritis and psoriatic arthritis. The RANK/RANKL (receptor activator of nuclear
      factor-kappaB and RANK ligand) pathway has been shown to be essential for
      osteoclast differentiation in inflammatory arthritis. In addition, in vitro and
      in vivo studies have demonstrated that many cytokines and growth factors
      elaborated by inflamed synovial tissues may contribute to osteoclast
      differentiation and activation. SUMMARY: Elucidation of the mechanisms mediating
      osteoclast differentiation and function has identified new pathways for potential
      targeted therapeutic intervention for focal bone loss in inflammatory arthritis.
      Challenges in the application of this approach are that therapies targeting the
      osteoclast would need to be used in combination with effective anti-inflammatory
      agents, and that pathways mediating osteoclast differentiation and function would
      need to remain at least partially functional to allow for continued skeletal
      remodeling.

PMID- 15201607
TI  - Noninvasive techniques for assessing skeletal changes in inflammatory arthritis:
      bone biomarkers.
AB  - PURPOSE OF REVIEW: Inflammatory arthritis diseases including rheumatoid arthritis
      (RA) are characterized by systemic bone loss and increased risk of osteoporosis
      and local joint bone erosion. Clinical and biologic parameters of disease
      activity and inflammation and radiologic findings are poorly sensitive for
      assessing skeletal changes. More specific biologic markers reflecting systemic
      quantitative and dynamic changes of bone turnover represent promising adjunctive
      tools. RECENT FINDINGS: More specific and well-characterized biochemical assays
      especially for type I collagen-based bone resorption markers have been recently
      developed. Prospective studies indicate that increased levels of some biochemical
      markers of bone resorption are associated with a more rapid progression of joint
      destruction in patients with early RA, independently of disease activity and
      inflammation parameters. This increased bone resorption associated with local
      bone erosion is likely to be mediated by changes in the balance of the OPG/RANK-L
      system (receptor activator of nuclear factor kappaB-ligand and osteoprotegerin)
      as suggested by the significant association of this ratio in serum and long-term
      radiologic progression. Besides their well-documented response to bisphosphonate
      treatment used as adjuvant therapy in patients with glucocorticoid-induced
      osteoporosis, bone markers may be useful to assess potential beneficial effects
      of new disease-modifying antirheumatic drugs on systemic bone loss and on
      progression of joint damage. SUMMARY: Recent evidence suggests that biochemical
      markers of bone resorption may be useful to predict progression of joint damage
      in RA. Together with new biochemical markers of cartilage turnover, they are
      likely to play a major role in assessing effects of treatment on joint damage.
      Their value in assessing systemic and local bone abnormalities should be explored
      in other inflammatory arthritis diseases such as ankylosing spondylarthritis.

PMID- 15201608
TI  - Noninvasive techniques for assessing skeletal changes in inflammatory arthritis:
      imaging technique.
AB  - New imaging techniques such as ultrasound and MRI are likely to play increasing
      roles in the future management of patients with inflammatory arthritis,
      particularly those with rheumatoid arthritis and spondyloarthropathies.
      Ultrasound has a number of distinct advantages including its ability to scan
      multiple joints, safety, and immediately availability in clinic. MRI, however, is
      more sensitive and has a greater field of view because of its tomographic nature.
      Both modalities have the added advantage over radiography in that they can image
      soft tissue as well as bone. Dual X-ray absorptiometry already has an established
      role to play in the assessment of osteoporosis, but new techniques such as
      digital radiogrametry, quantitative CT, and ultrasound potentially will have a
      more important role to play in the future.

PMID- 15201609
TI  - Osteonecrosis: etiology, diagnosis, and treatment.
AB  - PURPOSE OF REVIEW: This review provides an update of the recent progress in
      etiology, pathogenesis, diagnosis, and treatment of osteonecrosis. RECENT
      FINDINGS: Concerning pathogenesis, there is evidence that there is a genetic
      predilection for those who are exposed to the two leading etiologic associations
      for osteonecrosis: corticosteroids and alcohol. Studies concerning the treatment
      of osteonecrosis indicate that most preservative (ie, joint-sparing) procedures
      available today have better results in the precollapse stages of the disease and
      in smaller lesions. Therefore, researchers continue to develop and modify
      diagnostic techniques, particularly relating to MRI, for the identification and
      quantification of osteonecrotic lesions. Advances concerning bone grafting and
      arthroplasty procedures have resulted in improved clinical outcomes for this
      patient population. The future treatment of osteonecrosis may involve genetic or
      cell-based therapies. SUMMARY: Although progress has been made, considerably more
      research is needed before we fully understand this disease. Hopefully, such
      research will lead to effective measures for saving the femoral head or, better
      yet, preventing osteonecrosis.

PMID- 15201610
TI  - Genetic determinants of bone mass.
AB  - PURPOSE OF REVIEW: This review examines recent advances in the analysis of
      genetic determinants of bone mass. It addresses both human and animal linkage
      studies as well as genetic manipulations in animals, inbred mouse models, and
      candidate gene analyses. RECENT FINDINGS: Recent studies have implicated novel
      regulatory pathways in bone biology including both the neuroendocrine system and
      metabolic pathways linked to lipid metabolism. Variations in the lipoprotein
      receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were
      independently identified by linkage in high and low bone mass families.
      Subsequently, other high bone mass syndromes have been shown to have mutations in
      this gene. Neural studies have shown the skeletal regulatory activity of leptin
      and neuropeptide Y receptors via the hypothalamus. Subsequently, the beta
      adrenergic pathway has been implicated, with important changes in bone mass. The
      lipoxygenase 12/15 pathway, identified through inbred mouse models and through
      pharmacologic studies with specific inhibitors, has also been shown to have
      important effects on bone mass. These studies exemplify the value of genetic
      models both to identify and then confirm pathways by mutational study and
      pharmacologic interventions. Continuing candidate gene studies often performed
      with multiple loci complement such discoveries. However, these studies have not
      focused on the clinical endpoint of fracture and few have included large enough
      groups to engender confidence in the associations reported, as such studies may
      require thousands of individuals. Interestingly, results often differ by
      ethnicity, age, or gender. A small proportion have examined whether relevant
      genes influence response to treatment. SUMMARY: The combinations of human and
      animal genetic linkage studies have advanced understanding of the regulation of
      bone mass. Studies ranging from linkage to pharmacology provide optimism for new
      targets and treatments for osteoporosis.

PMID- 15201611
TI  - Parathyroid hormone: evolving therapeutic concepts.
AB  - PURPOSE OF REVIEW: Osteoporosis results from a loss of bone mass and structure
      such that bones break with very little trauma. To reduce bone loss and improve
      strength, antiresorptive agents have been instituted. Just more than a year ago,
      a 34-amino acid fragment of parathyroid hormone (recombinant human parathyroid
      hormone 1-34) was approved for the treatment of osteoporosis. The parathyroid
      hormone treatment works by stimulating bone formation on all bone surfaces and is
      referred to as an osteoanabolic agent. The purpose of this article is to review
      initial phase 2 and phase 3 studies that establish the effectiveness of this
      agent to treat osteoporosis. RECENT FINDINGS: In addition, studies that use
      parathyroid hormone in combination with antiresorptive agents and sequentially
      are reviewed. Last, unresolved issues related to the duration of use of
      parathyroid hormone are discussed. SUMMARY: In summary, parathyroid hormone
      compounds are a major advance in the treatment of osteoporosis. Additional
      research will enlighten clinicians on the most efficacious way to use them.

PMID- 15201613
TI  - Bibliography. Current world literature. Spondyloarthropathies.

PMID- 15201612
TI  - The origins of osteoclasts.
AB  - PURPOSE OF REVIEW: It is now dogma that osteoclasts (OCs) arise from cells of the
      monocyte/macrophage lineage. However, data are accumulating suggesting that a
      relationship exists between B lymphocytes (B cells) and OC differentiation.
      Although the exact nature of this relation is unknown, it takes at least two
      forms. First, molecules that regulate B-cell growth and development have striking
      effects on OC lineage cells particularly at early stages of differentiation.
      Second, the possibility exists that pro-B cells can give rise to osteoclast-like
      cells (OCLs) in vitro and in vivo. Recent data indicate, at the least, that a
      regulatory relation exists between B lymphopoiesis and osteoclastogenesis. RECENT
      FINDINGS: Pax5 is a member of the multigene family that encodes the paired box
      transcription factors. Pax5 is expressed exclusively in B-lymphocyte lineage
      cells extending from early B220 pro-B cells to mature B cells. Mice made
      deficient in Pax5 have a developmental arrest of the B-cell lineage at the pro-B
      cell stage. Pax5-/- pro-B cells could be induced to form OCLs by treatment with
      macrophage colony-stimulating factor and receptor activator of nuclear factor
      kappaB ligand (RANKL). Importantly, Pax5-/- mice are severely osteopenic, missing
      more than 60% of their bone mass. This is the result of a three- to fivefold
      increase in the number of OCs in bone, whereas the number of osteoblasts is
      indistinguishable from controls. SUMMARY: The analysis of a variety of mutations
      in mice supports the hypothesis that B cells and OCs develop in parallel; that
      their development is regulated in a reciprocal manner; and that in the Pax5
      deficient state, OCs arise from pro-B cells.

PMID- 15201614
TI  - Association between cardiac valvular calcification and coronary artery disease in
      a low-risk population.
AB  - BACKGROUND: Mitral annulus calcification (MAC) or aortic valve
      sclerocalcification (AVSC) is common with aging and associated with coronary
      artery disease (CAD) in Caucasians. This study was performed to determine whether
      MAC or AVSC is also associated with, and has a power to predict, CAD in Koreans
      as in Caucasians. METHODS: Three hundred and eight patients with chest pain, who
      had undergone coronary angiography and transthoracic echocardiography, were
      enrolled (189 males; mean 60.5 +/- 9.8 years). RESULTS: The prevalence of MAC and
      AVSC was significantly more common in CAD (+) compared with CAD (-) group
      (83.9%:55.2%, 87.9%:57.5%, respectively, both p < 0.001). On multivariate
      analysis with MAC and AVSC along with conventional coronary risk factors (cRF),
      MAC, male gender, AVSC, and diabetes mellitus were significantly associated with
      CAD (p < 0.001, < 0.001, 0.010 and 0.014 respectively). Additionally, a positive
      linear relationship was found between the prevalence of both MAC and AVSC and the
      extent of CAD defined by the number of stenotic coronary arteries (both p <
      0.001). Furthermore, the odds ratio for CAD in the group with both multiple
      valvular sclerocalcification (MVSC) and > or = 2 cRF was 12.3 compared to the <
      or = 1 cRF group without MVSC. CONCLUSIONS: MAC and AVSC were independently
      associated with CAD in a low-risk Korean population. Also, combination of MVSC
      with > or = 2 cRF increased the predictability of the presence of CAD. Therefore,
      the possibilities of CAD must be considered when MVSC is detected in
      transthoracic echocardiography in patients with > or = 2 cRF.

PMID- 15201615
TI  - A novel minimal-invasive model of chronic myocardial infarction in swine.
AB  - BACKGROUND: Most animal studies on myocardial infarction (MI) have used open
      chest models with direct surgical coronary artery ligation, which imply local as
      well as generalized side effects of major surgery. Some closed-chest models of MI
      have been established, mainly using catheterization techniques with coronary
      artery embolization, balloon occlusion, and intracoronary injection of
      thrombogenic agents. The aim of this study was to develop a closed-chest
      technique of chronic coronary artery occlusion at a selected location with
      subsequent thrombus formation without use of balloon inflation or thrombotic
      chemical agents. METHODS AND RESULTS: A coronary angiography via the carotid
      artery was performed using a 7 F guiding catheter in 21 pigs. After insertion of
      a percutaneous transluminal coronary angioplasty (PTCA) guide wire into the
      distal coronary artery, a vessel-size adapted flexible foreign body comprising an
      open-cell sponge was advanced into the coronary artery via the guide wire by a
      non-inflated PTCA balloon. Five min after removal of the guide wire and the
      balloon catheter, total coronary artery occlusion was documented by angiography.
      Retrograde thrombosis of the coronary artery occurred in three animals. After one
      week, total vessel occlusion at the previously selected location was visualized
      by coronary angiography in animals that had survived. Macroscopic analysis
      demonstrated the foreign body with subsequent thrombus formation in the coronary
      artery and distal MI. Post-mortem histological analysis revealed myocardial
      necrosis and granulocyte infiltration at the margin of the infarction, without
      damage to remote myocardium. CONCLUSIONS: This new easy-to-perform closed-chest
      technique provides reproducible chronic coronary artery occlusion at a selected
      location with subsequent MI. It avoids major surgery and thoracotomy and does not
      require balloon inflation or intracoronary injection of thrombotic or chemical
      agents.

PMID- 15201616
TI  - Biomechanical interaction between cap thickness, lipid core composition and blood
      pressure in vulnerable coronary plaque: impact on stability or instability.
AB  - BACKGROUND: A 'thin' fibrous cap atheroma is the typical morphological
      characteristic of vulnerable plaque. Yet the very pathological studies that have
      provided these descriptions have also shown the actual prediction of plaque
      rupture to be rather less exact. Other relevant characteristics must be involved
      in the mechanisms of plaque rupture--blood pressure loading (P) and the material
      properties of the soft atheromatous core--as predictors of the distribution of
      the peak circumferential stress (PCS) locations. METHODS AND RESULTS: We used a
      computational structural analysis based on three typical in-vivo intravascular
      ultrasound images of fibrous cap atheroma in which we decreased the cap thickness
      (CTh). With different soft atheromatous core Young's moduli (Ecore), 414
      simulations were performed under eight different physiological loading blood
      pressures. The transition from plaque stability to plaque instability was defined
      by a threshold of 300 kPa and is a feature of vulnerability. It was found that
      (1) irrespective of plaque geometry and composition, CTh < 60 microm exposed the
      plaque to PCSs in excess of 300 kPa; (2) the exponential variations in PCS with
      change in CTh and Ecore values show that very slight structural changes are
      enough to tilt a vulnerable plaque from stability to instability or vice versa;
      and (3) the relationship between P and PCS is proportional with P acting as
      trigger or as protector. CONCLUSION: The present study shows why, in clinical
      practice, mere morphological detection by imaging techniques of thin-cap fibro
      atheroma is not in itself enough for the prediction of future rupture.

PMID- 15201617
TI  - Effects of antioxidants on coronary microvascular spasm induced by epicardial
      coronary artery endothelial injury in pigs.
AB  - OBJECTIVES: The effect of oxidative stress on coronary microvascular disease is
      unknown. We investigated whether chronic administration of ascorbic acid (ASC) or
      glutathione (GSH) prevents microvascular dysfunction and remodeling induced by
      upstream repeated coronary artery endothelial injury. METHODS: Balloon
      endothelial injury was repeated at the left anterior descending coronary artery
      (LAD), just distal to an implanted flow meter, every 2 weeks for 6 weeks in pigs.
      Changes in LAD blood flow induced by acetylcholine (ACh) and 5-hydroxytryptamine
      were assessed before each endothelial injury and at 8 weeks after the first
      endothelial injury in pigs without treatment (endothelial injury group, n = 12)
      and in pigs treated with oral ASC (3 g/day) (ASC group, n = 12) and ASC (3 g/day)
      plus GSH (1 g/day) (ASC + GSH group, n = 12). RESULTS: In the endothelial injury
      group, reduced blood flow in response to ACh was augmented from a decrease of 18
      +/- 17% to a decrease of 100% (that is, zero flow, 8 weeks, P < 0.01),
      accompanied by an increase of ascorbyl free radicals (AFRs) in coronary sinus
      blood. In contrast, in the ASC + GSH group, blood flow response to ACh was
      altered to a decrease of 45 +/- 17% (8 weeks, P < 0.01 compared with the
      endothelial injury group), coronary sinus blood AFRs did not change (8 weeks,
      21.4 +/- 12.5 signal intensities, P < 0.01 compared with the endothelial injury
      group) and the rate of platelet aggregation induced by adenosine diphosphate was
      small (8 weeks, 56 +/- 17%, P < 0.01 compared with the endothelial injury group).
      CONCLUSIONS: Chronic administration of antioxidants suppressed microvascular
      hypercontraction, suggesting that it may be a promising therapeutic strategy for
      treating coronary microvessel disorders, including microvascular angina.

PMID- 15201618
TI  - Spinal cord stimulation for refractory angina pectoris: a retrospective analysis
      of efficacy and cost-benefit.
AB  - BACKGROUND: Patients with refractory angina pectoris have severe symptoms despite
      optimal medication, but are not suitable for revascularisation. Spinal cord
      stimulation (SCS) has been used for treating refractory angina pectoris since
      1985. The efficacy of SCS has been proven by randomised controlled trials and
      follow-up studies have shown that SCS is a safe treatment. The objective of the
      current study was to retrospectively analyse the clinical outcomes and cost
      benefit of SCS in patients with refractory angina pectoris. METHODS: Eighteen
      months after SCS implantation, the effects on Canadian Cardiovascular Society
      (CCS) functional level and acute symptom relief of 24 patients with permanent SCS
      were analysed by review of medical records. Nineteen of these 24 patients were
      able to report their anginal frequency, nitroglycerin consumption and subjective
      perception on physical activity and quality of life. RESULTS: Angina frequency
      decreased from a median of 14.0 to 2.3 attacks/week (p < 0.01). Nitroglycerin
      intake decreased from a median of 27.5 to 1.5 doses/week (p < 0.01). Canadian
      Cardiovascular Society angina class improved from a median of three to two (p <
      0.001). During a three-year period before SCS implantation, the hospitalisation
      rate and duration related to coronary artery disease increased progressively. The
      duration of hospitalisation increased from a median of three to 10
      days/patient/year. In the year after SCS implantation the duration of
      hospitalisation decreased to a median of 0 day/patient/year (p < 0.001). The cost
      of hospital care due to coronary artery disease decreased significantly
      thereafter. The total cost of SCS procedure was recovered within 16 months after
      implantation, which is less than 40% of the device life span. CONCLUSIONS: This
      retrospective study indicates that SCS treatment alleviates angina symptoms and
      improves quality of life. The treatment is also effective in preventing
      hospitalisations and saving costs in hospital care. A prospective study is
      warranted to confirm the current observations.

PMID- 15201619
TI  - Chronic stent recoil plays an important role in restenosis of the right coronary
      ostium.
AB  - OBJECTIVE: The efficacy of coronary stenting of aorto-ostial atherosclerotic
      lesions is still unclear. We investigated the frequency and mechanism of stent
      restenosis at this particular lesion. METHODS: Fifty-five consecutive patients
      with 64 native aorto-ostial lesions in the right coronary artery (RCA, n = 38)
      and the left main trunk (LM, n = 26) were treated by conventional stenting.
      Determinants of angiographic restenosis were established. The mechanism of stent
      restenosis was evaluated using post-stenting and follow-up intravascular
      ultrasound (IVUS) findings. RESULTS: Restenosis was more frequent in the RCA than
      in the LM (50% compared with 19%, P < 0.03) and determinants included diabetes
      mellitus (63% compared with 21%, P < 0.03), calcium deposition (58% compared with
      5%, P < 0.003), smaller stent cross-sectional area (SA) (as demonstrated by post
      stenting IVUS studies, 8.1 +/- 1.4 mm compared with 10.2 +/- 2.2 mm, P < 0.01),
      larger plaque burden (64 +/- 6% compared with 57 +/- 8%, P < 0.03) and less
      circular expansion at the aorto-coronary junction. Serial IVUS examination was
      performed in 11 patients with restenosis of the right coronary ostium. The mean
      reduction in the SA was 21% at the aorto-coronary junction (6.4 +/- 1.9 mm, P <
      0.003), whereas the SA at the distal edge was unchanged. Thirty-three per cent of
      late luminal loss was due to chronic stent recoil. CONCLUSION: These findings
      suggest that stenosis of the right coronary ostium is a high-risk lesion for
      stent restenosis. In addition to excessive intimal growth, chronic stent recoil
      might be an important etiologic factor at this particular location.

PMID- 15201620
TI  - Effects of lipid-lowering therapy on coronary artery remodeling.
AB  - BACKGROUND: Although lipid-lowering therapy affects the luminal size of
      atherosclerotic coronary arteries the role of vascular remodeling has not been
      systematically studied. DESIGN/METHODS: Serial three-dimensional volumetric
      intravascular ultrasound (IVUS) was used to study remodeling, which was defined
      as changes in arterial size independent of or dependent on changes in plaque
      size. Using an automated contour detection algorithm, a 1 mm segment of a
      moderate atherosclerotic lesion at the site of the maximal plaque volume at
      baseline was analysed. After 12 months the relationship between the absolute
      change in vessel volume and plaque volume was calculated in 99 patients. There
      was a significant relationship between changes in plaque and vessel volume,
      independent of plaque progression or plaque regression (decrease in plaque size,
      r = 0.60, P < 0.0001 and increase in plaque size, r = 0.49, P < 0.0008,
      respectively; the slopes of the regression equation were 1.03 and 0.80). By means
      of an analysis of covariance we tested whether the regression slopes were equal
      between groups of patients as defined by the low-density lipoprotein-cholesterol
      (LDL-c) level achieved with lipid-lowering therapy. RESULTS: Only patients with
      plaque progression and a LDL-c level < 100 mg/dl had a significantly smaller
      slope than patients with a LDL-c level > 100 mg/dl (-0.14 compared with 1.14, P =
      0.003 ), indicating diminished coronary remodeling. CONCLUSIONS: Serial
      volumetric IVUS confirms the existence of both positive and negative remodeling
      in relation to an increase and decrease in plaque volume. It has been shown that
      the outward remodeling process is diminished in patients with plaque progression
      and intensive lipid-lowering therapy.

PMID- 15201621
TI  - Simvastatin-induced myocardial protection against ischemia-reperfusion injury is
      mediated by activation of ATP-sensitive K+ channels.
AB  - OBJECTIVES: Previous studies have suggested that the 3-hydroxy-3-methylglutaryl
      coenzyme A reductase inhibitors attenuate ischemia-reperfusion injury. We
      investigated whether pretreatment with simvastatin reduces myocardial infarct
      size and whether glyburide, a non-selective inhibitor of the ATP-sensitive K
      channels, abrogates this infarct size-limiting effect. METHODS: Sprague-Dawley
      rats were treated with either simvastatin (20 mg/kg per day) or saline alone for
      3 days. Additional groups of rats were treated as above and on the fourth day
      they received intravenous glyburide (0.3 mg/kg). All rats underwent 30 min of
      coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium
      at risk was assessed with blue dye and infarct size with triphenyltetrazolium
      chloride. RESULTS: Infarct size, expressed as a percentage of the myocardium at
      risk, was significantly smaller in the simvastatin group (n = 8, 20.8 +/- 3.4%)
      than in the placebo group (n = 6, 40.1 +/- 2.7%) (P = 0.001). Glyburide abolished
      the protective effect of simvastatin with infarct size being 34.2 +/- 6.9% and
      29.7 +/- 3.9% of the area at risk in the simvastatin group (n = 7) and placebo (n
      = 7) group, respectively (P = 0.58). CONCLUSIONS: Simvastatin significantly
      reduced myocardial infarct size. The protective effect was completely abrogated
      by glyburide, strongly suggesting that this protective effect is mediated via
      activation of the ATP-sensitive K channels.

PMID- 15201622
TI  - Platelet-derived growth factor improves cardiac function in a rodent myocardial
      infarction model.
AB  - OBJECTIVES: The translation of cardioprotective therapies for myocardial
      infarction requires a preclinical demonstration of improved cardiovascular
      function following acute coronary occlusion. We previously showed that
      pretreatment of rodent hearts with platelet-derived growth factor (PDGF) promotes
      angiogenesis and decreases the extent of myocardial injury measured by histology.
      The present study aimed to determine the correlation of these histological
      findings with noninvasive measures of improvement in cardiac function. METHODS:
      Rats were treated with intramyocardial injections of PDGF (100 ng) or phosphate
      buffer solution (PBS) (n = 6 per group) 24 h prior to acute, permanent ligation
      of the left anterior descending artery and the extent of myocardial injury was
      assessed by Masson's trichrome staining 14 days later. To assess the
      physiological effects of PDGF pretreatment after coronary occlusion, cardiac
      function was assessed noninvasively by electrocardiography, exercise testing and
      echocardiography and correlated with direct histological measures. RESULTS:
      Physiological studies demonstrated that PDGF resulted in lower ST-segment
      elevation at the time of coronary occlusion (0.12 +/- 0.02 mV above baseline)
      than in PBS control rats (0.35 +/- 0.05 mV; P < 0.05). Exercise testing 14 days
      after coronary occlusion revealed that PDGF pretreatment resulted in faster
      maximal exercise speeds (28.54 +/- 3.98 m/min) than in control rats (24.98 +/-
      3.13 m/min; P < 0.05). Echocardiography also revealed that the left ventricular
      factional shortening in the PDGF-pretreated rats was significantly greater (18.47
      +/- 12.21%) than in control animals (4.91 +/- 7.21%; P<0.05). CONCLUSIONS: These
      studies demonstrate that PDGF pretreatment improves cardiac function following
      acute coronary occlusion. Strategies based on the cardioprotective actions of
      PDGF may provide a significant advance in the treatment of myocardial infarction.

PMID- 15201623
TI  - Improvement of cardiac function and beta-adrenergic signal transduction by
      propionyl L-carnitine in congestive heart failure due to myocardial infarction.
AB  - OBJECTIVES: Earlier studies have revealed beneficial effects of metabolic therapy
      in animals with congestive heart failure (CHF) due to myocardial infarction.
      Because heart failure is also associated with attenuated response to
      catecholamines, we examined the effects of propionyl L-carnitine (PLC) (a
      carnitine derivative) therapy on the beta-adrenoceptor (beta-AR) signal
      transduction in the failing heart. METHODS: Heart failure in rats was induced by
      occluding the coronary artery and 3 weeks later the animals were treated with or
      without 100 mg/kg (intraperitoneally, daily) PLC for 5 weeks. The animals were
      assessed for their left ventricular function and inotropic responses to
      isoproterenol. Crude membranes were isolated from the remote, nonischemic
      (viable) left ventricle and examined for changes in beta-AR and adenylyl cyclase
      (AC) activity. RESULTS: Animals with heart failure exhibited depressions in
      ventricular function, positive inotropic response to isoproterenol, beta-AR
      receptor density and basal AC activity; these changes were also attenuated by PLC
      treatment. The stimulation of AC activities with isoproterenol, 5'-guanyl
      imidodiphosphate, forskolin and sodium fluoride was decreased in the failing
      hearts and these changes were also prevented by PLC treatment. CONCLUSION: The
      results indicate that metabolic therapy with PLC not only attenuates the defects
      in heart function but also prevents changes in the beta-AR signal transduction in
      CHF due to myocardial infarction.

PMID- 15201624
TI  - Bibliography. Current world literature.

PMID- 15201626
TI  - National Institute on Alcohol Abuse and Alcoholism report on moderate drinking.
AB  - In support of the 2005 update of the U.S. Department of Agriculture/U.S.
      Department of Health and Human Services Dietary Guidelines, the National
      Institute on Alcohol Abuse and Alcoholism was asked to assess the strength of the
      evidence related to health risks and potential benefits of moderate alcohol
      consumption, with particular focus on the areas of cardiovascular disease, breast
      cancer, obesity, birth defects, breastfeeding, and aging. The findings were
      reviewed by external researchers with extensive research backgrounds on the
      consequences and benefits of alcohol consumption. This report now serves as the
      National Institutes of Health's formal position paper on the health risks and
      potential benefits of moderate alcohol use.

PMID- 15201627
TI  - Prolonged exposure to intermittent alcohol vapors decreases the ACTH as well as
      hypothalamic nitric oxide and cytokine responses to endotoxemia.
AB  - BACKGROUND: Prolonged exposure to alcohol blunts the response of the hypothalamic
      pituitary-adrenal (HPA) axis to various stressors, including the systemic
      injection of a lipopolysaccharide (LPS). We previously showed that decreased
      synthesis of the hypothalamic peptides corticotropin-releasing factor (CRF) and
      vasopressin (VP) played a central role in this phenomenon. However, the
      mechanisms that lead to decreased hypothalamic neuronal activity have not been
      identified. In the present work, we tested the hypothesis that alcohol decreased
      signals that are elicited by LPS and that stimulate hypothalamic CRF and VP
      synthesis, namely nitric oxide (NO) and the proinflammatory cytokines tumor
      necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). METHODS: Adult male
      rats were exposed to intermittent (5 hr/day) alcohol vapors for 5 days. Control
      animals were kept in comparable chambers but not exposed to the vapors. On day 6,
      the animals received an injection of LPS through permanent indwelling intravenous
      cannulae. The dependent variables were plasma ACTH levels measured by IRMA
      (immunoradiometric assay); pituitary and hypothalamic TNF-alpha and IL-6 mRNA
      levels measured by RNase protection assay; basal activity of neuronal NO synthase
      measured by conversion of [14C]arginine to [14C]citrulline, the constitutive
      enzyme that synthesizes NO and modulates the influence of this gas on LPS-induced
      HPA axis activity; and basal and LPS-induced levels of citrulline (an index of NO
      formation) in the hypothalamus, measured by immunocytochemistry. RESULTS: After
      injection with LPS, rats that were pretreated with alcohol exhibited a
      significantly (p < 0.01) decreased release of ACTH, compared with controls. There
      was no difference in basal NO synthase activity or hypothalamic citrulline
      levels. In contrast, LPS-induced hypothalamic citrulline levels were
      significantly (p < 0.01) lower in alcohol-exposed rats, as were pituitary TNF
      alpha and IL-6 transcripts. In the hypothalamus, the TNF-alpha but not IL-6
      response to LPS was also reduced. CONCLUSIONS: These results indicate that
      prolonged exposure to alcohol decreases the ACTH, hypothalamic NO and TNF-alpha,
      and pituitary TNF-alpha and IL-6 responses to LPS. This suggests that altered NO
      and proinflammatory cytokine levels in the brain may modulate the inhibitory
      influence exerted by alcohol on the HPA axis response to endotoxemia.

PMID- 15201628
TI  - A further examination of the relation between trait anger and alcohol-related
      aggression: the role of anger control.
AB  - BACKGROUND: Trait anger has been identified as a risk factor for alcohol-related
      aggression. However, to develop a more accurate risk profile, it is necessary to
      examine the interactive relations between trait anger and other key personality
      variables. The present study examined the influence of anger control on alcohol
      related aggression. METHODS: Participants were 164 social drinking men age 21-35
      years old. Trait anger and anger control were assessed with the State-Trait Anger
      Expression Inventory (Spielberger, 1996). Following consumption of an alcoholic
      or placebo beverage, participants competed in an aggression paradigm in which
      electric shocks were received from and administered to a fictitious opponent
      during a competitive reaction time task. Aggression was operationalized as shock
      intensities administered to the opponent under conditions of low and high
      provocation. RESULTS: Analyses indicated that trait anger significantly predicted
      aggression, but only among men who were intoxicated and reported low levels of
      anger control. CONCLUSIONS: The present findings suggest that anger control may
      be a crucial risk factor in determining whether one's anger proneness will lead
      to intoxicated aggression following provocation.

PMID- 15201629
TI  - Increased anxiety-like behavior and ethanol self-administration in dependent
      rats: reversal via corticotropin-releasing factor-2 receptor activation.
AB  - BACKGROUND: Corticotropin-releasing factor (CRF) has been hypothesized to be one
      of the main regulators of the stress response observed during alcohol withdrawal.
      The CRF receptor subtypes seem to have a differential role in the regulation of
      stress-related behavior. Given the behavioral characterization of these
      receptors, the objective of the following experiments was to characterize the
      role of CRF2 receptors in the interaction between alcohol and stress by examining
      the effects of CRF2 receptor activation in the behavioral stress response and
      ethanol self-administration during early ethanol withdrawal in dependent rats.
      METHODS: Male Wistar rats were made dependent on ethanol via chronic exposure to
      an ethanol containing liquid diet. Behavior in the elevated plus maze and ethanol
      self-administration were measured at 2 hr after removal of the diet. The role of
      the CRF2 receptor in the regulation of these behaviors during the early stages of
      withdrawal was examined via central injection of the highly selective CRF2
      receptor agonist urocortin 3. RESULTS: Rats showed decreased exploration of the
      open arms of the elevated plus maze, an indication of a heightened behavioral
      stress response, after chronic ethanol exposure. This effect was attenuated by
      central injection of urocortin 3. In addition, urocortin 3 injections reversed
      the increase in ethanol self-administration observed during early withdrawal in
      dependent rats. CONCLUSIONS: Reversal of the increased stress-related behavior in
      the elevated plus maze observed after injections of urocortin 3 indicates that
      the decreased responding for ethanol also seen after urocortin 3 administration
      is likely due to a diminished anxiety-like state. These data suggest that
      activation of the CRF2 receptor may provide a novel target in the attenuation of
      the stress response characteristic of the early stages of ethanol withdrawal.

PMID- 15201630
TI  - Controlled and behaviorally relevant levels of oral ethanol intake in rhesus
      macaques using a flavorant-fade procedure.
AB  - BACKGROUND: Flavorant-fading procedures can initiate and maintain oral ethanol
      intake in rodents. The present study developed a similar procedure to achieve
      controlled and behaviorally relevant levels of ethanol intake in monkeys.
      METHODS: Male rhesus macaques (N = 13) were initially given the opportunity to
      consume 0.5 g/kg of a 1% (w/v) ethanol plus 4% (w/v) Tang solution in 1-hr
      limited-access sessions without the requirement of an operant response. Once
      consumption was stable at a particular concentration (%) and/or amount (g/kg),
      animals were given access to higher concentrations and/or amounts of ethanol.
      Animals were tested on a bimanual motor skill (BMS) task 20 and 90 min after
      consumption to assess behavioral impairment. Blood alcohol levels (BALs) were
      assessed after a session in which animals had the opportunity to consume up to
      3.0 g/kg of 6% (w/v) ethanol. RESULTS: The gradual fading up of higher
      concentrations and amounts of ethanol resulted in controlled and robust levels
      (>2.0 g/kg) of ethanol intake in half of the subjects. Increasing the
      concentration of the sweetener from 4 to 6% (w/v) was effective in initiating
      consumption in three animals. Two monkeys required the additional step of
      presenting the increased-sweetener solutions after a meal (postprandial
      consumption) to initiate significant ethanol intake. Animals were significantly
      impaired on the BMS task after consumption of 2.0, 2.5, and 3.0 g/kg of ethanol.
      Individual consumption ranging from 0.8 to 3.0 g/kg of ethanol produced BALs of
      18 to 269 mg/dl. CONCLUSIONS: The flavorant-fading procedure was effective in
      producing behaviorally relevant levels of ethanol consumption in rhesus macaques.
      This model facilitated a randomized-dose procedure to determine the behavioral
      effects of 0.5 to 3.0 g/kg of ethanol. This procedure therefore is of significant
      utility in determining behavioral or physiologic effects of specific doses of
      consumed ethanol in monkeys.

PMID- 15201631
TI  - The effects of NMDA and GABAA pharmacological manipulations on acute and rapid
      tolerance to ethanol during ontogeny.
AB  - BACKGROUND: Sensitivity to several ethanol effects increases during ontogeny,
      perhaps in part because of a notable decline in acute tolerance. In contrast,
      rapid tolerance to ethanol-induced sedation emerges slowly during ontogeny. This
      study tested the hypothesis that ontogenetic differences in glutamate and/or
      gamma-aminobutyric acid systems influence tolerance expression. METHODS: Sprague
      Dawley rats at postnatal day (P)26 or P70 received (+)MK-801, muscimol, or saline
      before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2.
      Loss of and time to regain the righting reflex and blood alcohol levels at
      recovery were recorded. The presence of acute tolerance was indicated as a
      positive slope of the linear regression of blood alcohol levels at recovery
      versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals
      given ethanol only on day 2 with those given ethanol on both days. RESULTS: Acute
      tolerance on day 1 only was observed at P26; this was disrupted by (+)MK-801 but
      not muscimol. Evidence for acute tolerance also emerged in adults on day 2.
      Whereas both drugs increased ethanol sedation at both ages, they did not
      facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not
      evident at P26 regardless of pretreatment when indexed in terms of recovery time.
      CONCLUSIONS: These data provide further evidence for an ontogenetic dissociation
      in the expression of acute and rapid tolerance to ethanol-induced sedation.
      Pharmacological attenuation of the expression of acute tolerance was sufficient
      but not necessary to delay recovery of righting after ethanol. The greater
      propensity of young animals to develop acute tolerance, seemingly modulated in
      part by NMDA receptors, may contribute to their relative resistance to ethanol,
      although other factors, including pharmacokinetic factors, also contribute to
      their more rapid recovery from ethanol sedation.

PMID- 15201632
TI  - Heightened ethanol intake in infant and adolescent rats after nursing experiences
      with an ethanol-intoxicated dam.
AB  - BACKGROUND: Preweanling rats detect ethanol (175 mg/100 ml) in maternal milk when
      the dam is moderately intoxicated. Repeated experiences with the intoxicated dam
      facilitate subsequent recognition of ethanol's chemosensory attributes and
      promote ethanol-related memories with a negative hedonic content. This memory has
      been attributed to the infant's acquired association between ethanol's
      chemosensory attributes and its disruptive effects on maternal care. In this
      study, infant and adolescent ethanol intake patterns were analyzed as a function
      of prior interactions, during early infancy, with their intoxicated dams.
      METHODS: During postpartum days 3, 5, 7, 9, 11, and 13, breast-feeding dams
      received an intragastric administration of either 2.5 g/kg of ethanol or water.
      Pups whose dams had been given one of these two maternal treatments were tested
      on postnatal day 15 for ingestion of 0% (water), 2.5, 5.0, or 10% v/v ethanol
      solution. During adolescence, remaining animals from these litters were first
      adapted to ingest water from drinking tubes and then were given simultaneous
      access to tap water and a given ethanol solution. The first day, a 3% v/v ethanol
      solution was used. This solution was increased by 1% ethanol each following day
      until the solution was 6% v/v ethanol. RESULTS: Maternal drug treatment did not
      affect the body weights of dams, infants, or adolescents. Water intake during
      infancy and adolescence also was unaffected by prior maternal treatment. However,
      infants that had previously interacted with ethanol-intoxicated dams exhibited
      heightened ethanol intake scores (grams per kilogram and percentage body weight
      gains), especially when tested with 5 or 10% v/v ethanol solutions. Similarly,
      adolescent males (but not females) that had interacted with an intoxicated dam
      during infancy also had higher ethanol consumption levels than those that had
      interacted with a nonintoxicated dam. CONCLUSIONS: Contrary to what might be
      expected in animals that acquire an aversive memory for ethanol's chemosensory
      cues as a function of prior interactions with an intoxicated mother, these
      results indicate that such interactions promote a long-lasting increase in
      ethanol intake. These results suggest that rats reared by intoxicated dams become
      sensitive to the negative reinforcing properties of ethanol.

PMID- 15201633
TI  - Discriminative stimulus effects of ethanol in mice lacking the gamma-aminobutyric
      acid type A receptor delta subunit.
AB  - BACKGROUND: Genetically altered mice have been used to examine gene contributions
      to ethanol phenotypes. Recently, mice with a targeted deletion of the delta
      subunit of the gamma-aminobutyric acid (GABA)A receptor have been generated.
      These mice display decreased sensitivity to neuroactive steroids and altered
      responses to some behavioral effects of ethanol. Given the application of drug
      discrimination to characterize receptor-mediated stimulus effects of ethanol and
      given the data showing altered ethanol responses in mice lacking the delta
      subunit of the GABAA receptor, these mice were characterized in an ethanol
      discrimination procedure. It has been shown that neurosteroids will substitute
      for the discriminative stimulus effects of ethanol, and this study aimed to
      determine whether the substitution patterns of neuroactive steroids or other
      GABAA-positive modulators would be altered in these mice. METHODS: Twelve adult
      delta +/+ and delta-/- mice were trained to discriminate between ethanol 1.5 g/kg
      and saline in daily 15-min food-reinforced operant sessions. Once the
      discrimination was trained, substitution tests with ethanol, pentobarbital,
      midazolam, androsterone, alphaxalone, pregnanolone, morphine, zolpidem, and MK
      801 were conducted. RESULTS: Both delta+/+ and delta-/- mice acquired ethanol
      discrimination in a similar number of days. Ethanol, midazolam, alphaxalone,
      pregnanolone, and MK-801 fully substituted (>80%) for ethanol in both delta+/+
      and delta-/- mice. Pentobarbital fully substituted for ethanol in delta-/- mice
      but only partially substituted (74%) for ethanol in delta+/+ mice. Androsterone,
      zolpidem, and morphine did not substitute for ethanol in either delta+/+ or delta
      /- mice. There were no significant differences in the response rate-suppressing
      effects of any of the compounds between delta+/+ and delta-/- mice. CONCLUSIONS:
      The training dose of ethanol resulted in substitution of five GABAA receptor
      ligands, indicating a robust GABAA mediation of ethanol's discriminative stimulus
      effects. Deletion of the delta subunit of the GABAA receptor does not alter the
      acquisition of an ethanol/saline discrimination or the substitution patterns of
      GABAA-positive modulators. Therefore, the delta subunit is not necessary in the
      mediation of ethanol-like effects of any of the GABAA ligands tested, including
      sensitivity to ethanol, barbiturate, benzodiazepine, and neurosteroid
      discriminative stimulus effects.

PMID- 15201634
TI  - Validity of the alcohol use disorders identification test in college students.
AB  - BACKGROUND: High-risk alcohol use among college students is associated with
      accidents, partner violence, unwanted sexual encounters, tobacco use, and
      performance issues. The identification and treatment of high-risk drinking
      students is a priority for many college campuses and college health centers. The
      goal of this study was to test the psychometric properties of the Alcohol Use
      Disorders Identification Test (AUDIT) in college students. METHODS: A convenience
      sample of students coming into a college health clinic was asked to complete the
      10-question AUDIT and then participate in a research interview. The interview
      focused on assessing students for alcohol abuse and dependence by using the
      Composite International Diagnostic Interview Substance Abuse Module and timeline
      follow-back procedures to assess a 28-day drinking history. RESULTS: A total of
      302 students met the eligibility criteria and agreed to participate in the study.
      The sample consisted of 185 females (61%) and 117 males (39%), with a mean age of
      20.3 years. Forty students were abstinent, 88 were high-risk drinkers, and 103
      met criteria for a 12-month history of dependence. Receiver operator curves
      demonstrated that the AUDIT had the highest area under the cure for detecting
      high-risk alcohol use (0.872) and the lowest for identifying persons with a
      lifetime history of alcohol abuse or dependence (0.775). An AUDIT cutoff score of
      6 or greater demonstrated a sensitivity of 91.0% and a specificity of 60.0% in
      the detection of high-risk drinkers. CONCLUSIONS: The AUDIT has reasonable
      psychometric properties in sample of college students using student health
      services. This study supports the use of the AUDIT in this population.

PMID- 15201635
TI  - Alcohol consumption and problems: the relevance of drinking patterns.
AB  - BACKGROUND: Data on risks and benefits associated with drinking patterns provide
      the scientific basis for moderate, low-risk drinking guidelines. Illustrated are
      methods to investigate and adjust for heterogeneity in relations between three
      dimensional drinking patterns and 41 alcohol problems assessed among current
      regular drinkers in the 1988 National Health Interview Survey. METHODS: Three
      dimensions of mean drinking patterns, (i.e., usual quantities, heavy drinking
      rates (days of 5+ drinks/drinking days x 100), and drinking frequencies) were
      estimated in overlapping subsets of the population reporting each of the 41
      problems, and mean usual quantities and heavy drinking rates were plotted against
      frequencies. Respondents were categorized into drinking problem groups associated
      with comparable mean drinking patterns; and main and interactive effects of age
      and sex on drinking patterns were examined by conducting three regression
      analyses within each group, with quantity, frequency, and heavy drinking rates as
      dependent variables, respectively. RESULTS: Analyses revealed substantial
      heterogeneity in relations between drinking patterns and alcohol problems.
      Respondents having only minor problems drank on average two days a week, usually
      had 2.6 drinks, and drank heavily 12-13 days a year. Whereas, those having minor
      and severe problems drank an average of 3.5 days a week, usually had 4.7 drinks,
      and drank heavily 58 days a year. Within each problem group, usual quantity and
      frequency were higher among males than females, but the greatest gender
      differences were seen in heavy-drinking rates. Age-related differences in
      drinking patterns were striking. Usual quantity and heavy-drinking rates
      associated with problems decreased with age, whereas drinking frequency
      increased. CONCLUSIONS: Findings demonstrated the importance of assessing and
      adjusting for heterogeneity in relations between drinking patterns and alcohol
      problems when aggregating and interpreting such data, (e.g., when assessing
      alcohol dependence criteria or evaluating guidelines for moderate drinking), and
      illustrated new methods for doing so.

PMID- 15201636
TI  - Laboratory markers carbohydrate-deficient transferrin, gamma-glutamyltransferase,
      and mean corpuscular volume are not useful as screening tools for high-risk
      drinking in the general population: results from the Study of Health in Pomerania
      (SHIP).
AB  - BACKGROUND: Assessment of high-risk drinking in the general population can be
      problematic: questionnaire-based instruments may carry the problem of random or
      systematic recall bias, and the effectiveness of screening of single biomarkers
      has been shown to be insufficient. In this article, we analyze the alcohol
      intake/biomarker relationship of carbohydrate-deficient transferrin (CDT), gamma
      glutamyltransferase (GGT), and erythrocyte mean corpuscular volume (MCV).
      Specific aims were (1) screening effectiveness comparison of GGT, CDT, and MCV in
      terms of sensitivity, specificity, and positive (PPVs) and negative predictive
      values (NPVs) and the effect of covariates on these measures; (2) the comparison
      of summary measures for the effectiveness of screening: the receiver
      characteristic curve (ROC) and the area under the ROC; and (3) to answer the
      question of which covariates effect which biomarkers and whether accounting for
      relevant covariates increases the prognostic value of biomarkers to levels that
      allow for application in the general population. METHODS: In a representative
      cross-sectional health survey in northeast Germany with data collection from 1997
      to 2001, 4310 men and women were asked for their recent alcohol consumption and
      smoking. Biomarkers were analyzed from blood samples. The effectiveness of
      screening of CDT, GGT, and MCV for high-risk drinking (men: >60 g/day, women: >40
      g/day) was analyzed with PPV and ROC curve analysis. RESULTS: For all three
      biomarkers, PPVs for high-risk drinking are very low (< 50%). There are some
      effects of covariates on screening effectiveness and on PPV, and knowledge of
      these covariates increases screening effectiveness, but no subgroup that had a
      combination of covariate levels and prevalence of high-risk drinking that led to
      a PPV > 50% could be found. CONCLUSIONS: : Accounting for covariates in the
      screening procedure does not lead to a sufficient increase in PPV. Screening
      effectiveness of laboratory markers CDT, GGT, and MCV is insufficient for their
      application as screening tools for high-risk alcohol drinking in the general
      population. This was found using self-reported alcohol consumption as an
      imperfect gold standard, which is a limitation of the study, although self
      reports are the standard instrument in comparable epidemiologic studies.

PMID- 15201637
TI  - Prenatal alcohol exposure causes long-term serotonin neuron deficit in mice.
AB  - BACKGROUND: Previous work from this laboratory showed that prenatal alcohol
      exposure at approximately 100 mg/dl from embryonic day (E)7 to early midgestation
      reduced the number and retarded the migration of serotonin (5-HT) neurons in the
      raphe nuclei in C57BL/6 mice. In this study, we report that the deficit of 5-HT
      neurons found in midgestation persisted on E18 and into young adulthood. METHODS:
      Pregnant dams were treated from E7 to E18 in three groups--(1) the alcohol group,
      fed with liquid diet with 25% ethanol-derived calories; (2) the isocaloric pair
      fed group; and (3) the chow group for analysis of concentrations of active
      caspase-3--to study apoptosis at E18 in the brainstem and the number of 5-HT
      neurons at E18 and postnatal day 45. The concentrations of active caspase-3 were
      determined by using a colorimetric assay, and the 5-HT neurons were determined by
      immunocytochemistry. RESULTS: Prenatal alcohol exposure increased the
      concentration of active caspase-3 in the brainstem and caused reductions in brain
      weight by 20% and in the total number of 5-HT-immunostaining neurons in the
      dorsal and median raphe nuclei by 20% at E18 as compared with those of the pair
      fed and chow controls. Continuous observation from prenatal to postnatal stages
      showed that the reduction of 5-HT-immunostaining neurons in the dorsal and median
      raphe nuclei persisted in the young adult stage. CONCLUSIONS: Upon prenatal
      alcohol exposure, an increased concentration of active caspase-3 and a decreased
      number of 5-HT-immunostaining neurons in the brainstem were observed at E18. The
      decreased number of 5-HT neurons persisted to the young adult stage of postnatal
      day 45. This suggests that ethanol has a long-lasting effect on 5-HT deficit. A
      fetal alcohol exposure-rendered lasting deficit of 5-HT and other transmitter
      systems may underlie the neuropsychiatric deficits in fetal alcohol spectrum
      disorder.

PMID- 15201638
TI  - Differential effects of alcohol drinking pattern on liver enzymes in men and
      women.
AB  - BACKGROUND: Increasing evidence suggests that drinking pattern may have powerful
      implications for health; however, very few studies have focused on the
      association between drinking pattern and risk of alcoholic liver damage. This
      study was aimed at examining the association of gamma-glutamyltransferase (GGT),
      aspartate aminotransferase, and alanine aminotransferase with current alcohol
      consumption and with some aspects of drinking pattern (e.g., drinking frequency
      during the week and in relation to food consumption). METHODS: A cross-sectional
      analysis was conducted of a random sample of 2943 white residents of Erie and
      Niagara Counties in New York State who were 35 to 80 years of age and free from
      known hepatic disease. RESULTS: The most significant associations were found for
      GGT; in both sexes, average levels were significantly higher in current and
      former drinkers compared with lifetime abstainers. In analyses based on quartiles
      of alcohol consumption, only participants in the two top quartiles showed
      significantly elevated enzymes compared with both lifetime abstainers and
      participants in other quartiles. For drinking pattern, there was evidence of sex
      specific associations. In men, daily drinkers showed the highest levels of GGT,
      whereas in women, the highest level of GGT was observed in weekend drinkers.
      Women (but not men) who consumed alcohol without food exhibited higher levels of
      GGT compared with women who consumed alcoholic beverages in relation to food.
      CONCLUSIONS: These findings support the hypothesis that, in addition to amount,
      drinking pattern may affect liver function and that differences exist between
      sexes with regard to the effect of drinking pattern on liver function and
      potential liver damage.

PMID- 15201639
TI  - Differential effects of chronic ethanol administration and withdrawal on gamma
      aminobutyric acid type A and NMDA receptor subunit proteins in male and female
      rat brain.
AB  - BACKGROUND: Investigations have shown that chronic ethanol exposure results in
      selective alterations in levels of gamma-aminobutyric acid (GABA)A and NMDA
      receptor subunits. We previously reported significant sex differences in these
      chronic ethanol-induced adaptations. Because we have more recently found
      important sex differences in timing for the development of and recovery from
      ethanol dependence, we wanted to ascertain whether there were associations
      between overt expression of withdrawal and neuroadaptations at the level of GABAA
      and NMDA receptors. METHODS: Western blot analysis was used to assay protein
      levels for several GABAA and NMDA receptor subunits in rat cerebral cortex and
      hippocampus by using subunit-selective antibodies. Rats were fed 6% ethanol in a
      liquid diet with pair-fed controls. Feeding, harvesting of tissue, and Western
      blot experiments were all conducted while maintaining the paired design. Tissue
      was harvested after 3 days of ethanol exposure, 9 days of ethanol exposure, or 3
      days of ethanol withdrawal after 14 days of liquid diet administration. RESULTS:
      We again found sex-, subunit-, and brain region-selective effects of ethanol
      administration and withdrawal for GABAA and NMDA receptors. There was a strong
      association between increased GABAA receptor alpha4 subunit levels and previously
      determined withdrawal-induced changes in seizure susceptibility, highlighted by
      the sex differences in ethanol exposure length required to cause withdrawal
      signs. In addition, results obtained after 9 days of ethanol administration were
      in general agreement with previous findings after 14 days of ethanol
      administration. CONCLUSIONS: These data further support the suggestion that
      alterations in subunit assembly of GABAA and NMDA receptors may have some
      mechanistic role in neuroadaptations underlying ethanol dependence and
      withdrawal. Furthermore, significant sex differences in these adaptations suggest
      that multiple types of adaptations may be elicited, depending on innate
      differences in the actions/effects of ethanol.

PMID- 15201641
TI  - Gender influences endothelial-dependent arterial dilatation via arterial size in
      youth.
AB  - BACKGROUND: Reduced endothelial-dependent arterial dilatation (EDAD) has been
      suggested as an early marker of arteriosclerosis, since it has been reported to
      correlate with known cardiovascular disease (CVD) risk factors. It is unclear,
      however, whether gender plays a mediating or a moderating role in these
      relationships. The aim of this study was to evaluate the influence of gender on
      EDAD in youth at risk for CVD. METHODS: The sample population of 261 individuals
      (mean age, 20 yr; SD, 3 yr) consisted of 148 African Americans, 113 European
      Americans, 133 males, and 128 females, all with a verified family history of CVD
      (ie, hypertension, myocardial infarction). Anthropometrics, sociometrics,
      hemodynamics, brachial artery diameter, left ventricular mass, and relative wall
      thickness were measured and used as independent variables. EDAD (dependent
      variable) was expressed as percent (%) change of brachial artery diameter to
      reactive hyperemia induced by pressure cuff occlusion and release. Artery
      diameters were calculated via an automated border detection system. RESULTS:
      Percent EDAD change was inversely related to initial diameter of the brachial
      artery. Mean percent EDAD change was 14.37% for female subjects compared with
      10.48% for male subjects. The gender difference was a function of smaller initial
      artery size in the female subjects. When initial diameter and gender were
      considered simultaneously within a multivariate model, the gender effect was
      eliminated. Although a large prediameter effect remained, the relationship
      between prediameter and EDAD was greater in female than in male subjects (ie,
      interaction/moderating effect). CONCLUSION: The data suggest that the smaller the
      artery is, the more it will dilate. Further EDAD investigations are needed to
      predict arteriosclerosis, taking into account of the gender difference in vessel
      size.

PMID- 15201642
TI  - Association between antihypertensive agent use and hospital admissions in a
      managed care population.
AB  - BACKGROUND: Utilization of medical care services has been used as a surrogate for
      outcome of patient compliance with treatment regimens. Antihypertensive treatment
      status and selection of drug agents may influence medical utilization. The
      purpose of this study was to determine the association between medically
      untreated hypertension and treated hypertension according to class of
      antihypertensive agent with the rate of hospitalization. METHODS: This is a
      retrospective, observational study on adult hypertensive patients based on claim
      data from a network-model HMO. The 12,548 patients were identified by ICD-9-CM
      hypertensive codes over a 3-year period. The hospital admission rate was the
      outcome measurement. The exploratory variables included antihypertensive
      treatment status and drug class. Patients' age, gender, and coexisting medical
      conditions were treated as confounding factors. Descriptive analyses and
      multivariate regression analyses were performed. RESULTS: Coexisting medical
      conditions were significant factors in hospital admission rates. Compared with
      diuretic treatment, there were no differences in hospital admission rates among
      hypertensive patients treated with an angiotensin II antagonist or angiotensin
      converting enzyme inhibitor. Untreated patients or those treated with beta
      blockers or calcium channel blockers experienced higher hospitalization rates
      (95% CI, 1.25-1.90, 1.03-1.44, and 1.08-1.46, respectively). CONCLUSIONS:
      Compared with the major antihypertensive agents or no therapy for hypertension,
      diuretic or angiotensin-converting enzyme inhibitor therapy may result in a
      reduced rate of hospital utilization.

PMID- 15201643
TI  - Fenofibrate is effective in treating hypertriglyceridemia associated with HIV
      lipodystrophy.
AB  - OBJECTIVE: To determine the effectiveness of fenofibrate in treating
      hypertriglyceridemia associated with highly active antiretroviral therapy
      associated HIV lipodystrophy syndrome (HLS). METHODS: The authors recruited from
      their HIV metabolic clinic 55 adult patients with anthropomorphic changes
      consistent with HLS together with hypertriglyceridemia. The patients had no prior
      history of taking lipid-lowering medications and were free of liver and renal
      disease. They were on various highly active antiretroviral therapy regimens, and
      these regimens were not altered during the course of the study. Fenofibrate was
      started at 54 mg a day and the dose increased every 2 weeks to a maximum of 162
      mg/day. Fasting lipid concentrations were measured at baseline and 6 months after
      the intervention. RESULTS: At baseline, the fasting plasma concentrations of
      total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol
      were 259 +/- 11, 886 +/- 172, and 35.7 +/- 2.3 (mean +/- SEM) mg/dL,
      respectively. After 6 months of fenofibrate treatment, the fasting plasma
      concentrations were as follows: total cholesterol, 243 +/- 13; triglycerides, 552
      +/- 104, and HDL cholesterol, 35.7 +/- 1.8 mg/dL. The decrease in fasting plasma
      triglyceride concentration was statistically significant (P < 0.05). Fenofibrate
      was well tolerated, and no subjects dropped out of the study. CONCLUSION:
      Fenofibrate is an effective, well-tolerated treatment for hypertriglyceridemia
      associated with HLS.

PMID- 15201644
TI  - Contributions of weekly mean blood glucose values to hemoglobin A1c in insulin
      treated type 2 diabetes: the Diabetes Outcomes in Veterans Study (DOVES).
AB  - BACKGROUND: Daily self-monitored blood glucose testing is recommended for
      patients with insulin-treated type 2 diabetes. However, most patients do not test
      frequently enough for optimal glycemic control. Less frequent testing may be
      sufficient for assessing glycemic control among stable patients as well as
      improving patient compliance. The study objective was to evaluate the weekly
      contribution of glucose readings to hemoglobin (Hb)A1c during an 8-week period of
      intensified self-monitored blood glucose testing. METHODS: The authors randomly
      selected stable, insulin-treated subjects with type 2 diabetes. Subjects
      monitored their blood glucose four times daily for 8 weeks; the authors then
      downloaded glucose meters and measured an HbA1c. Mean blood glucose values were
      calculated for each of the 8 weeks. Multiple linear regression analyses examined
      the contribution of these mean values to the HbA1c. RESULTS: A total of 182
      subjects completed the monitoring protocol; mean HbA1c was 7.63 +/- 1.42%, mean
      glucose was 9.78 +/- 2.27 mmol/L, the regression correlation was 0.77, P < 0.001.
      A fitted multiple linear model using all 8 weekly mean blood glucose values
      showed large variation in their independent contributions to the HbA1c. Mean
      blood glucose values from consecutive weeks were highly correlated and did not
      provide independent information about glycemic control. Stepwise regression
      showed that the mean blood glucose values from weeks 4, 6, and 8 significantly
      and equally influenced HbA1c. CONCLUSIONS: Glycemic control can be efficiently
      assessed by reviewing at least 5 weeks' worth of monitoring results, focusing on
      alternate weeks and giving less weight to more remote readings.

PMID- 15201645
TI  - The clinical and epidemiologic features in 140 patients with lupus nephritis in a
      predominantly black population from one center in Kingston, Jamaica.
AB  - BACKGROUND: Lupus nephritis has emerged as a major factor in the overall survival
      of patients and may help to explain the poor prognosis associated with systemic
      lupus erythematosus (SLE) in black patients. METHODS: The authors reviewed the
      clinical and epidemiologic features of lupus nephritis in 130 women and 10 men
      who were mainly of African descent. RESULTS: The mean (standard deviation) age at
      diagnosis of SLE was 27.9 (10.3) years. The majority of patients (75%) developed
      renal involvement within 1 year of presentation with SLE. The most frequent
      extrarenal manifestations were arthritis (67%), malar rash (44%), serositis
      (41%), and neurologic disorders (30%). Class IV nephritis was the most common
      glomerular lesion, accounting for 49% of the biopsies, with class II accounting
      for a further 23%. Proteinuria was a common feature at presentation in all
      classes. Nephrotic range proteinuria was most common in classes III and IV.
      Prevalence of nephrotic range proteinuria was similar in classes II (23%) and V
      (19%). Hematuria occurred in more than one half of the patients with classes II,
      IV, and V disease. Fifty-nine percent of the patients had renal impairment at the
      time of renal biopsy. The prevalence of hypertension, the nephritic syndrome, and
      renal impairment was significantly higher in class IV patients compared with all
      the other groups. Factors that were significantly associated with classes III and
      IV disease compared with the other classes on univariate analysis were renal
      impairment, proteinuria (but not in nephrotic range), low C3 levels, and anemia.
      CONCLUSIONS: The clinical features of the study patients were similar to those of
      patients belonging to other ethnic groups, but a high proportion of the study
      patients had renal impairment at the time of renal biopsy.

PMID- 15201646
TI  - Differentiating pyopneumothorax and peripheral lung abscess: chest
      ultrasonography.
AB  - BACKGROUND: Differentiation between pyopneumothorax and lung abscess can be
      difficult but has important therapeutic consequences. The role of chest
      ultrasonography in this issue remains undetermined. Sonographic features of
      hydropneumothorax and/or pyopneumothorax are characteristic and not difficult to
      recognize. In this study, the authors evaluate the usefulness of a panel of
      sonographic findings characteristic of hydropneumothorax in distinguishing
      pyopneumothorax from lung abscess. METHODS: This series included 16 patients with
      lung abscess and 19 with pyopneumothorax. A diagnosis of lung abscess or
      pyopneumothorax was based on the following criteria: pus aspiration from the
      lesion, appropriate clinical setting, thoracic computed tomographic findings,
      serial follow-up of chest radiograms, and consistent clinical course. The panel
      of sonographic features suggestive of hydropneumothorax, including the presence
      of air-fluid level, the curtain sign, loss of gliding sign above the air-fluid
      level, and the suspended microbubble sign, were recorded and analyzed by a
      consensus of blinded readers. In addition, sonographic features used to
      differentiate empyema and lung abscess were also evaluated. RESULTS: The results
      indicated that the presence of air-fluid level, the curtain sign, loss of gliding
      sign above the air-fluid level, and the suspended microbubble sign were valuable
      in distinguishing pyopneumothorax from lung abscess. All four sonographic
      findings were observed in 17 of 19 patients with pyopneumothorax. In contrast,
      two or fewer sonographic findings were seen in 16 patients with lung abscess. Our
      results confirmed that the wall characteristics, shape of the lesion, chest wall
      angle, and pleural separation were also useful. CONCLUSIONS: The panel of
      sonographic findings is of considerable value in differentiating pyopneumothorax
      and lung abscess.

PMID- 15201647
TI  - Predictive factors and long-term outcome of respiratory failure after Guillain
      Barre syndrome.
AB  - OBJECTIVE: To analyze predictive factors and long-term recovery in patients with
      Guillain-Barre syndrome (GBS) who are in need of mechanical ventilation. METHODS:
      In this 15-year retrospective study, 77 adult patients were identified with GBS.
      A comparison was made between the clinical data from patients who required
      mechanical ventilation and those who did not. Furthermore, the therapeutic
      outcomes of those 25 patients in need of mechanical ventilation during
      hospitalization at 1 year were determined using a modified Barthel index. A score
      below 12 was defined as a poor outcome, whereas a score of 12 or more was good.
      RESULTS: The study revealed 32% of patients (25/77) in need of respiratory
      support during hospitalization. At a follow-up of 1 year among the 25 ventilated
      patients, 7 patients (28%) had normal or minor signs and symptoms, 6 had
      unassisted gait, 3 had assisted gait, 6 were wheelchair- or bed-bound, and 3
      died. The cause of death was septicemia with septic shock in all 3 cases. Factors
      that predict respiratory failure in the study GBS patients were disability grade
      on admission and areflexia. Those ventilated patients who had low maximal
      inspiratory pressure (PImax) (<14.5 cmH2O) and maximal expiratory pressure
      (PEmax) (<13.5 cmH2O) values at the time of intubation and the presence of
      complications after mechanical ventilation inevitably had worse outcomes than
      those who had not. CONCLUSION: If low values of PImax and PEmax at intubation
      were detected, aggressive respiratory management, which might include
      tracheostomy to allow more efficient bronchial clearing, and prevention of
      complications caused by prolonged course of mechanical ventilation are essential
      to maximize the potential for survival.

PMID- 15201648
TI  - A review of chronic lead intoxication: an unrecognized cause of chronic kidney
      disease.
AB  - Chronic lead nephropathy occurs as a result of years of lead exposure. This
      disease has been prevalent throughout human history. It is important that primary
      care providers and internists recognize this disorder because it can contribute
      to progressive loss of kidney function. Diagnosis is made by a thorough history
      in combination with physical examination. A history of lead intoxication often
      requires knowledge of the various sources of lead exposure. Laboratory tests,
      many previously known and some newly described, are available to further support
      this diagnosis. Therapy to reduce lead burden may be useful when employed early
      in the disease; new data sheds more light on which patients should be treated and
      when such patients should undergo chelation therapy. In particular, treatment
      with calcium EDTA chelation may benefit certain patients with chronic kidney
      disease by slowing the progression to end-stage renal disease.

PMID- 15201649
TI  - Timing of aortic valve surgery in chronic aortic stenosis and regurgitation.
AB  - The correct timing of aortic valve replacement in chronic aortic stenosis or
      regurgitation is a very important and sometimes difficult task for physicians
      caring for patients with aortic valve disease. In this review, we will present
      the current available literature regarding the appropriate management of these
      patients.

PMID- 15201650
TI  - Extensive fibromuscular dysplasia in a patient with Parkinson disease.
AB  - The cause of fibromuscular dysplasia is not known. Ergot derivatives have been
      reported as a potential causative agent. The anti-Parkinson medication pergolide
      is an ergot derivative, but an association between fibromuscular dysplasia and
      this drug has not been previously reported.

PMID- 15201651
TI  - Rhabdomyolysis in response to weight-loss herbal medicine.
AB  - The authors report rhabdomyolysis following the ingestion of weight-loss herbal
      medicine in an otherwise healthy 54-year-old woman. Three hours after ingestion
      of the herbal medicine, the patient suffered chest pain that continued for 2
      hours and resolved gradually. Laboratory investigation showed the presence of
      rhabdomyolysis with peak serum creatine kinase (CK) of 1028 IU/L, which gradually
      decreased and normalized after the herbal medicine was discontinued. The
      pharmacological effects of the active ingredients of the herbal medicine, ma
      huang (ephedrine), guarana (active alkaloid caffeine), chitosan, Gymnena
      sylvestre, Garcinia cambogia (50% hydroxycitric acid), and chromium, are
      discussed, and similar case reports are reviewed. The elevation of CK in this
      case is of concern, as it may denote that muscle breakdown may be one of the
      mechanisms of weight loss in these herbal remedies. Further studies are needed to
      investigate their effects on muscle bulk or CK. Physicians should be aware of the
      potential side effects of many herbal medicines. It may be advisable to measure
      serum CK enzyme for patients who admit using weight-loss herbs.

PMID- 15201652
TI  - Arterial thrombosis due to minimal change glomerulopathy secondary to
      nonsteroidal anti-inflammatory drugs.
AB  - The authors report a 49-year-old woman who had been treated with diclofenac for
      her back pain. Nephrotic syndrome followed by occlusion of the right profound
      femoral and popliteal arteries occurred. Successful thrombectomy was performed.
      Another nonsteroidal anti-inflammatory drug (NSAID) was administered by injection
      during hospitalization. Renal biopsy showed minimal change glomerulopathy (MCG).
      Remission was delayed despite large-dose steroid administration. The delayed
      remission in this patient may be caused by impaired renal function and the
      possible effect of a second period of NSAID administration. The authors present
      the first case of femoral arterial thrombosis associated with nephrotic syndrome
      secondary to NSAID-associated MCG. Careful history-taking and physical
      examination may detect early causes and complications of nephrotic syndrome. Any
      rechallenge of NSAID should be avoided.

PMID- 15201653
TI  - Unilateral pulmonary edema: a rare presentation of congestive heart failure.
AB  - The authors present a case of an 85-year-old woman known to suffer from severe
      congestive heart failure who presented with dyspnea and a unilateral infiltrate
      in the right lung on chest x-ray. Following clinical judgment, she was diagnosed
      with unilateral pulmonary edema and was treated accordingly, with rapid
      improvement of symptoms and disappearance of the infiltrate within 12 hours. The
      patient had been hospitalized many times during the previous years with pulmonary
      edema affecting both lung fields. Unilateral pulmonary edema is an unusual
      clinical condition that has been reported as a manifestation of left heart
      failure, mostly affecting the right lung. The authors emphasize the possible
      presentation of unilateral pulmonary edema in a patient with heart failure and
      recurrent bilateral pulmonary edema.

PMID- 15201654
TI  - Thromboangiitis obliterans (Buerger disease) in a female mild smoker treated with
      spinal cord stimulation.
AB  - The authors report the case of a 42-year-old female mild smoker admitted to the
      Hospital of Ferrara for the onset of asymptomatic necrotic ulcerations localized
      to the second, third, and fourth toes of left foot. Physical examination showed
      asphygmia of inferior limb distal peripheral pulses, with localized extremity
      marbleized and cyanotic skin at the level of the left foot, where necrotic ulcers
      were present at the second, third, and fourth toes. Doppler ultrasonography and
      angiography revealed a severe obliterating arteriopathy of bilateral distal
      arterial circulation. Both blood chemistry panel (including autoimmune and
      hypercoagulable profile) and diagnostic examination findings were normal. Thus,
      the patient met several criteria to be diagnosed with Buerger disease. After an
      attempt at medical therapy with the intravenous administration of the
      prostaglandin-analogue iloprost, given the young age and the lack of viable
      distal target vessels for bypass grafting, a spinal cord stimulator was
      implanted. More than 2 years later, the patient has a normal life.

PMID- 15201655
TI  - Capnocytophaga canimorsus sepsis with purpura fulminans and symmetrical gangrene
      following a dog bite in a shelter employee.
AB  - The authors describe a fatal case of purpura fulminans with symmetrical
      peripheral gangrene and sepsis caused by Capnocytophaga canimorsus in a 45-year
      old, previously healthy woman who was bitten by a dog at an animal shelter where
      she was employed. Absent in this patient were the usual risk factors, including
      immunosuppression, alcohol abuse, corticosteroid therapy, and splenectomy. The
      patient's presentation to the emergency room late in the course of the infection
      probably effected her death. C canimorsus should be strongly suspected in any
      case of septicemia following a dog bite. Prompt therapy may influence the
      potentially fatal course of systemic infection. Employees and/or volunteers who
      work in animal shelters should be cognizant of the potential risks of a dog or
      cat bite and follow recommended procedures when such an incident occurs.

PMID- 15201656
TI  - Meningococcal purpura fulminans in a patient with systemic lupus erythematosus: a
      mimic for catastrophic antiphospholipid antibody syndrome?
AB  - Purpura fulminans (PF) is a life-threatening disorder characterized by acute
      onset of progressive cutaneous hemorrhage, necrosis, and disseminated
      intravascular coagulation. Acute infectious PF occurs most commonly in the
      setting of meningococcal sepsis. When PF occurs in the setting of systemic lupus
      erythematosus (SLE), the catastrophic antiphospholipid antibody syndrome (CAPS)
      must be ruled out because urgent therapy is required. Plasmapheresis is effective
      in both cases, but immunosuppression (high-dose corticosteroids plus
      cyclophosphamide), although beneficial in patients with CAPS, could be harmful in
      patients with meningococcal PF. The authors report here a patient with SLE who
      presented to the intensive care unit with meningococcal PF, acute renal failure,
      and acute respiratory distress syndrome and discuss clinical similarities and
      laboratory differences from CAPS.

PMID- 15201657
TI  - Delivery of proteins and peptides into live cells by means of protein
      transduction domains: potential application to organ and cell transplantation.

PMID- 15201658
TI  - Results of lis2t, a multicenter, randomized study comparing cyclosporine
      microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo
      liver transplantation.
AB  - This is the first multicenter, randomized, open-label study to compare the
      efficacy and safety of cyclosporine A microemulsion (CsA-ME) (Neoral, Novartis,
      Basel, Switzerland ) with C2 monitoring versus tacrolimus in de novo liver
      transplant recipients. Patients were stratified according to hepatitis C virus
      status and randomized to receive CsA-ME (n= 250) or tacrolimus (n= 245) with
      steroids, with or without azathioprine. The primary endpoint was the incidence of
      biopsy-proven acute rejection (BPAR) at 3 months. Secondary endpoints included
      death or graft loss and safety evaluations at 6 months. The incidence of BPAR at
      3 months was 26% in the CsA-ME group and 24% in the tacrolimus group (not
      significant). At 6 months, 89% of patients receiving CsA-ME and 88% of patients
      receiving tacrolimus were alive with a functioning graft. Among the hepatitis C
      virus-positive patients, there was no difference in BPAR, but death or graft loss
      was more frequent in those receiving tacrolimus (15% vs. 6%, P <0.05). Diabetes
      mellitus (14% vs. 7%, P <0.02) and diarrhea (29% vs. 14%, P <0.001) were
      significantly more often reported in patients receiving tacrolimus. The incidence
      of hypertension was similar in both groups. At 6 months, the median total
      cholesterol was 4.7 mmol/L (2.9-7.4 mmol/L) in the CsA-ME arm versus 4.3 mmol/L
      (2.5-6.4 mmol/L) in the tacrolimus arm; the median serum creatinine was 106
      micromol/L (52-238 micromol/L) in the CsA-ME arm versus 103 micromol/L (44-477
      micromol/L) in the tacrolimus arm. Efficacy is equivalent with CsA-ME using C2
      monitoring or tacrolimus in liver transplant recipients. The incidence of adverse
      events is comparable except for a significantly higher incidence of diabetes
      mellitus and diarrhea in the tacrolimus group. Both agents are effective primary
      immunosuppressants in liver transplant recipients.

PMID- 15201659
TI  - C(2) monitoring: out of the blocks but with some way to go!

PMID- 15201660
TI  - Problems of cytomegalovirus: how to measure and how to treat.

PMID- 15201661
TI  - Macrophages play a role in the early phase of corneal allograft rejection in
      rats.
AB  - BACKGROUND: Rat corneal allograft rejection is delayed by repeated local
      injection of liposomes filled with clodronate (dichloromethylene diphosphonate),
      which selectively deplete macrophages. Various administration schedules of
      liposomes were tested to determine the optimum schedule for prevention of graft
      rejection. Cell subpopulations in the anterior segment of the eye were studied at
      different time points after transplantation to assess the kinetics of the immune
      response. METHODS: AO rats were grafted orthotopically with corneal buttons from
      PVG rats. Postoperatively, rats remained untreated or received clodronate
      liposomes subconjunctivally. Clodronate liposomes were injected five times on
      postoperative days (PODs) 0, 2, 4, 6, and 8; or once, on POD 0 or 6; or twice on
      PODs 0 and 2 or PODs 0 and 6. Grafts were examined for signs of rejection
      clinically and immunohistologically. RESULTS: All untreated rats rejected their
      grafts as did all five rats that received clodronate liposomes once on POD 6. In
      all the other administration schedules tested, graft survival was prolonged
      compared with the untreated control group (P <0.01). Injections of clodronate
      liposomes on PODs 0 and 2 proved to be the most effective treatment.
      Histologically reduced influx of virtually all cell types tested was found in
      this group. CONCLUSIONS: To prevent or delay graft rejection, it is necessary to
      administer clodronate liposomes in the early phase after corneal transplantation.
      These results suggest a role for macrophages in the afferent phase of corneal
      graft rejection.

PMID- 15201662
TI  - Assessment of serum matrix metalloproteinases MMP-2 and MMP-9 after human liver
      transplantation: increased serum MMP-9 level in acute rejection.
AB  - BACKGROUND: Alterations in synthesis and breakdown of extracellular matrix
      components play a role in acute rejection after orthotopic liver transplantation
      (OLT). Matrix metalloproteinases (MMPs) are capable of degrading basement
      membranes and are involved in the process of tissue remodelling in inflammation
      and liver fibrosis. METHODS: We examined MMP-2 and MMP-9 in serum of 33 patients
      before and during 1 year after OLT, in 60 controls as well as in some specimens
      of cirrhotic liver and control liver tissue. RESULTS: Serum MMP-2 levels before
      OLT were significantly higher compared with controls and decreased approximately
      50% after OLT. Also, the MMP-2 content of cirrhotic liver specimens was
      significantly higher compared with normal liver. MMP-9 in serum and liver tissue
      of patients were similar to controls, but serum levels showed a peak at 1 week
      after OLT. At this time-point, total and active/inhibitor-complexed MMP-9 was
      significantly higher in patients with rejection (n=13) compared with those
      without rejection (n=20). The relative amount of MMP-9 in the active/inhibitor
      complexed form did not differ between each group over time. Immunohistochemical
      staining at 1 week after OLT showed increased numbers of MMP-9-positive
      inflammatory cells in the portal triads of patients with rejection. CONCLUSIONS:
      Patients with acute allograft rejection have elevated serum levels of MMP-9 1
      week after OLT, which was most likely derived from inflammatory cells. An
      increased MMP-2 serum level and liver tissue content was found in patients with
      cirrhosis, which decreased after OLT. These observations indicate active
      involvement of MMP-2 and -9 in end-stage liver disease and OLT.

PMID- 15201663
TI  - Viral chemokine-binding proteins inhibit inflammatory responses and aortic
      allograft transplant vasculopathy in rat models.
AB  - BACKGROUND: Both CC and CXC chemokines direct monocyte and T-cell migration and
      activation at sites of vascular injury, but the relative contributions of each
      chemokine class to transplant vasculopathy development have not been defined. The
      nonselective C, CC, and CXC chemokine binding protein, M-T7, inhibits
      vasculopathy development after angioplasty and after renal transplant. We have
      assessed the effects of three viral chemokine-binding proteins with differing
      ranges of chemokine inhibition on plaque growth in rats after aortic allograft
      transplant. METHODS: One of two myxomaviral chemokine binding proteins, (1). M
      T1, a selective CC chemokine inhibitor, or (2). M-T7, a nonselective chemokine
      binding protein, was given immediately after transplant. A separate group was
      treated with the gamma68-herpesvirus protein, M3, a C, CC, CXC, and CX3C binding
      protein, with preferential CC binding. RESULTS: Intimal hyperplasia was
      significantly reduced at late times posttransplant after infusion of each
      chemokine-binding protein (P <0.05). Early inhibition of macrophage and T-cell
      invasion was associated with a late decrease in vasculopathy development.
      Infusion of an inactive myxomavirus protein did not inhibit plaque growth.
      Combined high-dose M-T1 and M-T7 did not reduce plaque growth or early cell
      invasion to a greater extent than either protein alone. Coinfusion of the CC
      chemokines macrophage chemoattractant protein-1 and macrophage inflammatory
      protein-1alpha neutralized M-T1 and M-T7 inhibition of monocyte invasion,
      respectively, suggesting a key role for CC chemokine-mediated cellular influx.
      CONCLUSION: Viral chemokine-modulating proteins effectively reduce aortic
      allograft vasculopathy, acting predominantly through inhibition of a CC chemokine
      mediated response.

PMID- 15201664
TI  - Mycophenolate mofetil prevents transplant arteriosclerosis by direct inhibition
      of vascular smooth muscle cell proliferation.
AB  - BACKGROUND.: Transplant arteriosclerosis is one of the main features of chronic
      graft failure in organ transplantation. In this article, the authors investigate
      mechanisms of mycophenolate mofetil (MMF) on prevention of transplant
      arteriosclerosis in a rat aortic allograft model. METHODS: Orthotopic rat
      abdominal aortic transplantation was performed from Brown Norway (RT1) to Lewis
      (RT1) rats. The recipients were divided into three oral treatment groups: (1).
      vehicle; (2). MMF40 (40 mg/kg); and (3). MMF20 (20 mg/kg). The authors
      histologically and immunohistochemically evaluated neointima formation;
      infiltration of macrophages and T cells; and expression of endothelin (ET)-1,
      platelet-derived growth factor (PDGF)-B, PDGF receptor-beta (Rbeta), transforming
      growth factor (TGF) beta 1, and osteopontin (OPN). Using cultured rat vascular
      smooth muscle cells (VSMC), effects of mycophenolic acid (MPA) on ET-1-induced
      proliferation and ERK1/2 activation were also examined in vitro. RESULTS: In the
      vehicle group, marked neointima formation was observed, with massive macrophages
      and T-cell infiltration in neointima, media, and adventitia. Marked expression of
      ET-1, PDGF-B, PDGFR-beta, TGFbeta1, and OPN were also observed in neointima. In
      the MMF40 and MMF20 groups, neointima formation was halted, but macrophages and T
      cells were infiltrated in the adventitia and adhered to the endothelium. In the
      MMF40 group, medial infiltration by macrophages and T cells and intimal
      expression of ET-1, PDGF-B, PDGFR-beta, TGFbeta1, and OPN was inhibited compared
      with the vehicle and MMF20 groups. Furthermore, MPA inhibited ET-1-induced VSMC
      proliferation but failed to inhibit its ERK1/2 activation. CONCLUSIONS: MMF
      treatment might have preventive potential in transplant patients with chronic
      vasculopathy through inhibition of VSMC proliferation.

PMID- 15201665
TI  - Tissue transglutaminase: a mediator and predictor of chronic allograft
      nephropathy?
AB  - BACKGROUND: The precise mechanisms underlying the development of chronic
      allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain.
      The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been
      implicated in renal fibrosis. METHODS.: We investigated the involvement of tTg
      and its crosslink product, epsilon-(gamma-glutamyl) lysine, in 23 human kidney
      allografts during the early posttransplantation period and related these to
      changes of CAN that developed in 8 of them. Sequential biopsies were investigated
      using immunohistochemical, immunofluorescence, and in situ enzyme activity
      techniques. RESULTS: From implantation, tTg (+266%) and epsilon-(gamma-glutamyl)
      lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first
      renal biopsy performed within 3 months from transplantation. This was paralleled
      by elevated tTg in situ activity. The eight patients who developed CAN had
      further increases in immunostainable tTg (+197.2%, P <0.001) and epsilon-(gamma
      glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial
      fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for
      both was predominantly located within the mesangium and the renal interstitium.
      Both implantation and first biopsies showed tTg and epsilon-(gamma-glutamyl)
      lysine crosslinking levels in patients who developed CAN to be twice the levels
      of those with stable renal function. Cox regression analysis suggested the
      intensity of the early tTg staining was a better predictor of inferior allograft
      survival that other histologic markers (hazard ratio=4.48, P =0.04). CONCLUSIONS:
      tTg and epsilon-(gamma-glutamyl) lysine crosslink correlated with the initiation
      and progression of scarring on sequential biopsies from renal-allograft
      recipients who experienced CAN. Elevated tTg may offer an early predictor of the
      development of CAN, whereas tTg manipulation may be an attractive therapeutic
      target.

PMID- 15201666
TI  - Pronlonged hypothermic machine perfusion preserves hepatocellular function but
      potentiates endothelial cell dysfunction in rat livers.
AB  - BACKGROUND: Although hypothermic machine perfusion (HMP) preservation has been
      shown to improve organ function and to expand the organ donor pool, problems
      still exist with the current HMP technology for liver preservation. The present
      study was conducted to investigate endothelial and hepatocellular functions
      following extended HMP (> r =24 hr) in rat liver model. METHODS: Following 24
      hour hypothermic HMP with University of Wisconsin (UW) solution or 24-hour simple
      cold storage (SCS), livers were reperfused with Krebs-Henseleit buffer solution
      at 37 degree C for 30 minutes. Hepatocyte damage and function were assessed by
      measuring lactate dehydrogenase (LDH) activity, bile production, and indocyanine
      green (ICG) extraction. Sinusoidal endothelial cell (SEC) function and
      permeability were determined by hyaluronic acid (HA) uptake and multiple
      indicator dilution (MID) method, respectively. RESULTS: After 24-hour hypothermic
      preservation, HMP livers showed lower released LDH levels, higher bile flow rate,
      and greater hepatic ICG uptake compared with SCS livers. However, LDH levels
      became significantly higher in HMP than in SCS after 30 minutes of warm
      perfusion. The increased enzyme levels were accompanied by a significant increase
      in endothelial permeability to albumin and a decrease in hyaluronic acid uptake
      in HMP compared to SCS. Liver wet/dry weight ratio confirmed a greater edema in
      HMP livers than SCS livers. CONCLUSION: These results suggest that 24-hour
      hypothermic HMP may help preservation of hepatocyte function, but endothelial
      cell dysfunction during the cold preservation may play a key role in hepatocyte
      dysfunction and parenchymal cell death upon reperfusion.

PMID- 15201667
TI  - Role of xanthine oxidoreductase in experimental acute renal-allograft rejection.
AB  - BACKGROUND: Increased oxygen radical production may not only contribute to
      posttransplant ischemia-reperfusion injury but also to acute rejection of renal
      allografts. Xanthine oxidoreductase (XOR) may constitute a relevant reactive
      oxygen species (ROS) source. The study was conducted (1). to determine ROS
      production as well as oxidant and antioxidant enzyme activities in renal grafts
      and (2). to modulate acute rejection by tungsten administration, a specific
      inhibitor of XOR. METHODS: Syngraft (Lewis to Lewis, Fisher344 to Fisher344) and
      allograft (Fisher344 to Lewis) kidney transplantations were performed with or
      without tungsten administration. Analysis was performed at day 1, 3, or 9
      posttransplantation. RESULTS: Generation of ROS was enhanced, being 10-fold
      higher in renal allografts versus control kidneys at day 9 (P <0.01); this was
      associated with histologic signs of acute rejection. Oxygen radicals were
      generated to a significant degree by enhanced XOR activity, which increased more
      than 10-fold in renal allografts at day 9 posttransplantation; XOR protein in
      glomeruli and tubulointerstitium was also elevated in allo-grafts. In addition,
      NADPH oxidase activity increased significantly in allografts. The activity of
      antioxidant enzymes tended to decrease. Tungsten treatment resulted in a
      pronounced reduction of XOR activity and ROS production, without any effect on
      NADPH-oxidase activity; mononuclear cell infiltration and rejection signs were
      significantly ameliorated at day 9 post-transplantation by selective inhibition
      of XOR. CONCLUSIONS: A major part of ROS generation in acute rejection was
      contributed by XOR. ROS are not only associated with but also contribute to acute
      allograft rejection because inhibition of XOR alleviated rejection phenomena.

PMID- 15201668
TI  - Cytomegalovirus infection in organ-transplant recipients: diagnostic value of
      pp65 antigen test, qualitative polymerase chain reaction (PCR) and quantitative
      Taqman PCR.
AB  - BACKGROUND: The human cytomegalovirus (CMV) is a major cause of morbidity and
      mortality in transplant patients. In this study, we compared the diagnostic value
      of pp65 antigen test, qualitative nested polymerase chain reaction (PCR), and
      quantitative Taqman PCR in predicting the clinical outcome of CMV infection.
      METHODS: A total of 169 samples derived from 59 organ-transplant recipients
      (kidney n= 46, liver n= 11, kidney and pancreas n= 2) were analyzed. Peripheral
      blood leukocytes (PBL) were isolated using dextran gradient centrifugation, and 2
      x 10 cells were analyzed for pp65 antigen by immunofluorescence. A crude DNA
      extract obtained from the same number of cells was used for qualitative nested
      PCR and quantitative Taqman PCR analysis. RESULTS.: The correlation coefficient
      of pp65 antigen test and Taqman PCR was R= 0.699 (P = 0.001). With cut-off values
      for pp65 antigen test set at greater than 10 positive nuclei per 2 x 10 PBL,
      sensitivity was 91%, and positive predictive value (PPV) was 70%. When the
      corresponding cut-off value for Taqman PCR was applied (>125000 genome copies per
      2 x 10 PBL), a sensitivity of 83% and a PPV of 68% were found. Both assays
      allowed for the monitoring of successful antiviral therapy. Although qualitative
      nested PCR was highly sensitive (95%), it was less useful in predicting CMV
      disease (PPV 47%) and in therapy control. CONCLUSION: Our data show that pp65
      antigen test and Taqman PCR are almost equivalent in the monitoring of CMV
      infection and disease when identical cell numbers are used for both assays.

PMID- 15201669
TI  - P-glycoprotein activity is decreased in CD4+ but not CD8+ lung allograft
      infiltrating T cells during acute cellular rejection.
AB  - BACKGROUND: Modulation of P-glycoprotein (P-gp) activity in graft-infiltrating T
      cells may alter their susceptibility to immunosuppression. METHODS: P-gp activity
      was measured by rhodamine efflux in T-cell subsets from bronchoalveolar lavage
      (BAL) of five healthy volunteers and 27 lung allograft recipients. The effect of
      T-cell activation on P-gp activity was modeled by stimulation of peripheral blood
      mononuclear cells with staphylococcal enterotoxin B. RESULTS: Most BAL T cells
      expressed memory-effector markers. Patients had a lower proportion of CD4 T cells
      (P = 0.005), whereas control subjects had CD4-to-CD8 ratios similar to peripheral
      blood. In controls, basal P-gp activity was greatly increased in both CD4 (35% P
      gp active) and CD8 (63%) lung T cells compared with peripheral T cells. Basal P
      gp activity was elevated in patient BAL T cells but was lower than control BAL
      activity (CD4, P = 0.07; CD8, P = 0.03). Lung T cells from transplant patients
      had modest (CD4) or marked (CD8) increases in substrate-induced P-gp activity
      compared with normal lung, indicating that P-gp was not irreversibly inhibited.
      Patients with acute cellular rejection (ACR) had reduced P-gp activity in CD4,
      but not CD8, BAL T cells compared with patients without ACR (P = 0.004). To
      determine the relationship between T-cell activation on P-gp modulation, P-gp
      activity was measured in staphylococcal enterotoxin B-stimulated peripheral blood
      mononuclear cells. P-gp activity was abrogated in CD71 cycling cells but remained
      high in a persistent but minor population of resting naive T cells. CONCLUSIONS:
      Lung T cells have increased in vivo P-gp activity and therefore may eliminate
      substrate drugs, resulting in local resistance to immunosuppressive therapy.
      However, P-gp function is reduced during T-cell activation, providing a window of
      susceptibility to treatment during ACR.

PMID- 15201670
TI  - Relationship between CD8+ T-cell phenotype and function, Epstein-Barr virus load,
      and clinical outcome in pediatric renal transplant recipients: a prospective
      study.
AB  - BACKGROUND: The authors studied the relationship between the dynamics of Epstein
      Barr virus (EBV) load, CD8 T-cell activation and differentiation, and EBV
      associated symptoms in 25 children after kidney transplantation (Tx). METHODS:
      Twenty-two patients were enrolled at the time of Tx and three at diagnosis of EBV
      induced post-transplant lymphoproliferative disease (PTLD). EBV load was serially
      measured by a semiquantitative method of DNA amplification in blood cells. The
      percentages of activated (human leukocyte antigen-DR) and of effector-memory
      (CD28) CD8 circulating cytolytic T lymphocytes (CTL) were serially evaluated by
      flow cytometry. The cytotoxic potential of CTL was assessed by a CD3-redirected
      cytotoxic assay. RESULTS: For three children with post-Tx uncomplicated primary
      EBV infection, EBV load peaked by months 1 to 2 after Tx and declined
      spontaneously by months 3 to 6, whereas expansion of activated and effector
      memory CTL was absent (one case) or transient and moderate (two cases). In 15
      patients who were EBV-seropositive before Tx and who did not develop EBV-PTLD,
      transient elevation of EBV load but no noticeable changes in CTL phenotype were
      observed. In contrast, in one child who was also EBV-seropositive before Tx but
      who developed EBV-PTLD, a major and sustained elevation of EBV load and of
      activated and effector-memory CTL was observed. In three patients retrospectively
      enrolled at diagnosis of EBV-PTLD, sustained elevation of both viral load and
      activated T cells was also noticed. Finally, increased cytotoxic activity
      correlated with increased level of activated CTL. CONCLUSIONS: An association
      between high and sustained T-cell activation, EBV load, and the occurrence of EBV
      PTLD was observed. Furthermore, intense cytotoxic activity was observed in EBV
      PTLD, with favorable outcome.

PMID- 15201671
TI  - Knowledge and attitude regarding organ donation among medical students and
      physicians.
AB  - BACKGROUND: There is a discrepancy between demand and supply of donor organs for
      kidney transplantation. Health care providers can influence the willingness to
      donate or hold an organ donor card. It is unclear how educated current and future
      health care professionals are about organ donation and what constitutes their
      attitude toward this topic. METHODS: The authors conducted a cross-sectional
      survey among 1136 medical students and physicians to evaluate the knowledge about
      and attitude toward organ donation and transplantation at a large academic
      medical center in Germany. The authors used a 28-item questionnaire that included
      items on knowledge, attitude, and demographics. RESULTS: Only 8% of the
      respondents felt sufficiently prepared for approaching relatives of potential
      organ donors. Knowledge about and attitude toward organ donation were highly
      associated with increasing level of medical education. In multivariate analyses,
      knowledge (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.08-1.25),
      attitude (OR, 1.03; 95% CI, 1.02-1.04), and level of education (OR for
      preclinical students, 0.39; 95% CI, 0.20-0.76 compared with physicians) were
      significantly associated with the likelihood of holding an organ donor card,
      whereas age, gender, and personal experience with renal replacement therapy were
      not. CONCLUSIONS: Higher medical education is associated with greater knowledge
      about and a more positive attitude toward organ donation. Health care
      professionals with a higher education level are more likely to hold an organ
      donor card and also feel more comfortable in approaching relatives of potential
      organ donors. Educating health care professionals about the organ donation
      process appears to be an important factor in maximizing the benefits from the
      limited organ donor pool.

PMID- 15201672
TI  - De novo malignancies after intestinal and multivisceral transplantation.
AB  - BACKGROUND: Maintenance immunosuppression required after organ transplantation
      creates a permissive environment in which cancer cells can proliferate because of
      lack of natural immunologic surveillance. With more than a decade of clinical
      experience, this report is the first to address the risk of de novo cancer after
      intestinal transplantation. METHODS: A total of 168 consecutive intestinal
      transplant recipients (86 children and 82 adults) were studied, of whom 52% were
      male and 91% were white. Surveillance, Epidemiology, and End Results data was
      used to count expected rates of de novo cancers in the general population matched
      for age, sex, and length of follow-up. RESULTS: With a mean follow-up of 47+/-41
      months, 7 (4.2%) patients developed nonlymphoid de novo cancer, with a cumulative
      risk of 3% at 5 years and 28% at 10 years. Of these malignancies, one was donor
      driven adenocarcinoma. With 0.58 being the expected rate of malignancy for the
      general population, the risk among intestinal recipients was 8.7 times higher (P
      =0.01). Such morbidity was significantly higher (50 times) among younger patients
      (<25 years), with a slight male preponderance. Induction immunosuppression was
      associated with early onset of de novo cancer. Patient survival after diagnosis
      of de novo cancer was 72% at 1 year, 57% at 2 years, and 29% at 5 years.
      CONCLUSION: With conventional immunosuppression, intestinal recipients are at a
      significantly higher risk of developing de novo cancer when compared with the
      general population. Thus, a novel tolerogenic immunosuppressive strategy has been
      recently implemented to reduce the lifelong need for immunosuppression.

PMID- 15201673
TI  - Favorable outcomes among recipients of living-donor nephrectomy using video
      assisted minilaparotomy.
AB  - BACKGROUND: Minimally invasive, living-donor nephrectomy (LDN) is an attractive
      procedure for the donor in kidney transplantation (KTx). Its advantages include
      better cosmesis, shorter hospital stay, and rapid recovery. The most commonly
      performed, minimally invasive nephrectomy is done laparoscopically. However, the
      technical challenges, a steep learning curve for the surgeon, the risk of
      impaired early graft function, and the high cost of the procedure, have prevented
      minimally invasive LDN from gaining wide acceptance. To overcome these problems,
      we have developed a new surgical procedure named video-assisted minilaparotomy
      (VAM) for LDN. VAM-LDN is performed entirely with a small retrieval incision.
      Moreover, it does not require the induction of pneumoperitoneum, thereby avoiding
      potential vascular and renal complications. METHODS: We evaluated the outcome of
      transplant recipients receiving kidneys with the VAM-LDN procedure by
      retrospectively comparing the surgical outcomes of patients who underwent KTx
      with the conventional open nephrectomy (group I, n=82) and VAM-LDN (group II,
      n=70) procedures from March 1, 1997, to June 30, 2002, at our institution. We
      compared postoperative complications, patient and graft survival, and graft
      functions between these two groups during a 12-month follow-up period. RESULTS:
      There were no differences in demographic data, ABO compatibility, degree of human
      leukocyte antigen matching, or method of immunosuppression between the two groups
      (P >0.05). No significant difference was observed in complications such as
      delayed graft function, acute rejection, ureter complication, graft failure, or
      patient's mortality. There was no difference in graft function between the two
      groups, as determined by serum creatinine level measured during the 12-month
      follow-up. CONCLUSION: The short-term recipient outcome was favorable in patients
      who underwent KTx with the VAM-LDN procedure.

PMID- 15201674
TI  - Reconstruction of the ocular surface by transplantation of a serum-free derived
      cultivated conjunctival epithelial equivalent.
AB  - PURPOSE: The purpose of this study was to investigate the use of a serum-free
      derived cultivated conjunctival epithelial sheet for ocular surface
      transplantation and reconstruction. METHODS: Seven subjects with various ocular
      surface disorders were selected for the procedure: one patient had an extensive
      conjunctival nevus, three patients had pterygium, two patients had persistent
      leaking trabeculectomy blebs, and one patient had bilateral superior limbic
      keratoconjunctivitis. Conjunctival epithelial cells were harvested from the
      forniceal conjunctiva of patients 2 weeks before the definitive surgery.
      Cultivation of conjunctival epithelial cells on human amniotic membrane (HAM) was
      carried out under serum-free conditions. At the time of transplantation, the area
      of diseased conjunctiva was excised and the cultured conjunctival epithelium-HAM
      composite was transplanted onto the surgical defect. Patients were followed up
      with serial slit-lamp examinations, fluorescein staining, and photographic
      documentation. RESULTS: A confluent stratified conjunctival epithelial sheet was
      formed on the HAM within 12 to 14 days. Transplanted grafts remained well
      epithelialized after surgery. A successful outcome, defined as resolution of the
      disease, maintenance of conjunctival epithelialization, maintenance of graft
      integrity, and absence of significant complications, was obtained in all seven
      patients. A good functional and cosmetic result was achieved in all eyes. The
      mean follow-up period was 11.6 months (range, 6-18 months). CONCLUSIONS:
      Transplantation of a serum-free derived autologous cultivated conjunctival
      epithelial sheet on HAM was successfully performed in seven patients with ocular
      surface disorders. This may provide a novel method for conjunctival replacement
      in conditions where the normal conjunctiva is damaged or deficient.

PMID- 15201675
TI  - Acute vascular rejection of xenografts: roles of natural and elicited
      xenoreactive antibodies in activation of vascular endothelial cells and induction
      of procoagulant activity.
AB  - BACKGROUND: Hyperacute rejection of vascularized discordant xenografts can now be
      effectively managed. However, acute vascular rejection (AVR) then ensues,
      resulting in graft destruction, coagulopathy, or both within weeks. The aim of
      this study was to determine associations between humoral responses to the
      xenograft and the induction of AVR, coagulopathy, or both. METHODS: In vitro,
      heat-inactivated, naive or sensitized baboon sera containing xenoreactive natural
      or elicited antibodies were used to activate porcine aortic endothelial cells
      (PAEC) in vitro. Tissue factor expression on PAEC was determined as an index of
      heightened procoagulant activity. In vivo, porcine renal xenografts were
      transplanted into immunosuppressed baboons, and at the time of rejection or the
      development of a consumptive coagulopathy, biopsy specimens were obtained for
      studies of xenoreactive antibody binding and tissue factor expression. RESULTS:
      In vitro, incubation of PAEC with naive baboon sera containing natural anti
      Galalpha1,3Gal (Gal) antibodies resulted in minimal tissue factor induction; the
      addition of complement boosted procoagulant responses. Elicited xenoreactive
      antibodies, and to non-Gal epitopes alone, induced high amounts of procoagulant
      activity on PAEC; the addition of complement resulted in overt cytotoxicity. In
      vivo, AVR was associated with xenoreactive antibody deposition in the graft. When
      vascular endothelial binding of xenoreactive antibody was combined with the
      expression of tissue factor, consumptive coagulopathy developed irrespective of
      histopathologic features of AVR. CONCLUSIONS: Our in vitro results indicate that
      elicited antibodies, potentially to non-Gal epitopes, induce endothelial cell
      activation and tissue factor expression; in vivo, a consumptive coagulopathy
      occurred when there was xenoreactive antibody deposition and increase of tissue
      factor.

PMID- 15201676
TI  - Growth factors improve the in vivo migration of human skeletal myoblasts by
      modulating their endogenous proteolytic activity.
AB  - BACKGROUND: A main technological problem related to the clinical application of
      myoblast transplantation is the poor migration of transplanted cells. In this
      study, we investigated a new physiologic approach that consists of coinjecting
      motogenic factors insulin growth factor (IGF)-1 or basic fibroblast growth factor
      (bFGF) to enhance the migration of human skeletal myoblasts. Among the different
      ways by which those factors can induce the cell migration processes, we
      investigated their capacity to enhance cell endogenous proteolytic activity that
      will help transplanted cells to migrate through the extracellular matrix.
      METHODS: In vitro, myoblasts were coincubated with bFGF or IGF-1. Growth factors
      effects on cell migration were evaluated using invasion chambers, and their
      effects on proteolytic systems were evaluated by zymography, Western blot, and
      reverse transcription polymerase chain reaction. In vivo, myoblasts were
      coinjected with growth factors and the intramuscular migration capacity was
      assessed using the microtube technique. RESULTS: In vitro, the presence of IGF-1
      or bFGF significantly enhanced the expression of the gelatinase matrix
      metalloproteinase-9 and focalized the fibrinolytic system activity at the cell
      membrane. In vitro and in vivo, both bFGF and IGF-1 showed strong chemokinetic
      potentials and improved the migration of human myoblasts. Moreover, the
      implication some proteinases in the in vivo enhanced migration was confirmed
      using specific inhibitors (BB94 or amiloride). CONCLUSIONS: These results suggest
      that IGF-1 or bFGF coinjection with human myoblasts increased their proteolytic
      activities and consequently their migratory capacity. This study may help to
      develop approaches that will reduce the number of injection sites for the
      treatment of Duchenne muscular dystrophy patients.

PMID- 15201677
TI  - Use of lentiviral vectors to induce long-term tolerance to gal(+) heart grafts.
AB  - BACKGROUND: Tolerance to organ grafts has been achieved by establishing a state
      of stable mixed-cell chimerism after bone marrow transplantation. Gene therapy
      has been applied to establish chimerism for cells expressing galactose alpha 1,3
      galactose in alpha 1,3 galactosyltransferase deficient (gal knockout) mice using
      retroviral vectors. Limitations to the success of this methodology include short
      term expression of the introduced gene and rejection of gal hearts transplanted
      into these animals within a month. METHODS: Autologous bone marrow from gal
      knockout mice was transduced with a lentiviral vector expressing porcine alpha
      1,3 galactosyltransferase and transplanted into lethally irradiated gal knockout
      mice. Chimerism was monitored by flow cytometry. Hearts from wild type mice
      (gal/) were transplanted into these animals and palpated daily. Xenoantibodies
      directed at the gal carbohydrate or porcine xenoantigens were detected by enzyme
      linked immunosorbent assay. RESULTS: Hearts from wild-type gal/ donors were
      permanently accepted in all mice receiving autologous, transduced bone marrow
      before heart transplantation. Control mice rejected gal hearts within 12 to 14
      days. Histologic analysis demonstrated classical signs of rejection in controls
      and normal myocardium with no evidence of rejection in mice chimeric for the gal
      carbohydrate. Anti-gal xenoantibodies were not produced in gal chimeras, but
      normal antibody responses to other xenoantigens were detected. Specific tolerance
      for the gal carbohydrate was achieved by this procedure. CONCLUSIONS: These
      experiments report the first demonstration of permanent survival of gal hearts
      after transplantation with autologous, transduced bone marrow. Transduction with
      lentiviral vectors results in long-term, stable chimerism at levels sufficient to
      induce long-term tolerance to heart grafts in mice.

PMID- 15201678
TI  - Role of replicative senescence in the progression of fibrosis in hepatitis C
      virus (HCV) recurrence after liver transplantation.
AB  - BACKGROUND: Although hepatitis C virus (HCV) recurrence is almost universal after
      orthotopic liver transplantation (OLT), the impact of viral infection on liver
      graft is highly variable and difficult to predict. Because of the possible
      relationship between replicative senescence (RS) and the accelerated development
      of liver fibrosis, we aimed to assess the potential role of RS in the severity of
      HCV-related chronic hepatitis recurrence after OLT. METHODS: One hundred three
      liver biopsies from 56 patients receiving transplants for HCV-related cirrhosis
      were studied, including 30 revascularization biopsies and 52 and 21 biopsies
      performed during and beyond the first year of OLT, respectively. The presence of
      senescent cells in liver grafts was assessed by the senescence-associated beta
      galactosidase (SA-beta-Gal) staining method. Chronic hepatitis was defined by
      fibrosis stage and necrotico-inflammatory activity grade using the METAVIR score.
      RESULTS: A total of 34 of the 103 (33%) frozen liver biopsies displayed SA-beta
      Gal-positive cells, including 6 (20%) of the revascularization biopsies, 14 (34%)
      of the biopsies performed within the first year, and 10 (46%) of the biopsies
      performed beyond 1 year of follow-up. The presence of senescent cells in
      revascularization biopsies was significantly associated with the degree of
      ischemic necrosis at time of OLT (P = 0.01) and hepatitis C recurrence in the
      first year after OLT (P = 0.05). Furthermore, the presence of RS in the biopsy
      performed within the first year was associated with further development of
      fibrosis (P = 0.05). CONCLUSIONS: These data show that RS has a significant
      impact upon the course of liver transplantation, especially in the long-term
      progression of fibrosis observed in HCV-infected patients.

PMID- 15201679
TI  - Generation of tolerogenic dendritic cells by treatment with mitomycin C:
      inhibition of allogeneic T-cell response is mediated by downregulation of ICAM-1,
      CD80, and CD86.
AB  - BACKGROUND: Deliberately generated tolerogenic dendritic cells (DC) might be a
      useful tool for induction of donor-specific tolerance in transplantation. In this
      article, the authors study the effect of mitomycin C (MMC)-treated DC on rat T
      cells and delineate the mechanism of their conversion into tolerogenic cells.
      METHODS: The influence of MMC treatment on the capacity of DC to activate
      allogeneic T cells was tested in vitro, and the expression of cell surface
      molecules was studied by flow cytometry. RESULTS: MMC-treated DC lose their
      allostimulatory capacity, and this cannot be attributed to cell death or release
      of MMC. Interestingly, suppressed T cells cannot be restimulated, indicating that
      MMC-treated DC induce tolerance. MMC treatment selectively decreases adhesion
      (intercellular adhesion molecule [ICAM]-1) and co-stimulatory (CD80, CD86)
      molecules. Functional blocking of these molecules with specific antibodies
      confers to DC the same T-cell-suppressive properties as treatment with MMC.
      CONCLUSIONS: MMC treatment converts rat DC into tolerogenic cells. This mechanism
      is mediated by decrease of ICAM-1, CD80, and CD86.

PMID- 15201680
TI  - Comparative analysis of live liver donation risk using a comprehensive grading
      system for severity.
AB  - We investigated whether right lobe (RL) liver donation is associated with a
      higher incidence or severity of donor complications than left lobe (LL) liver and
      left lateral segment (LLS) liver donations. We studied 80 living donors: 35 RL
      liver donors and 45 LL/LLS liver donors. A modification of the Clavien
      classification was used to grade the severity of complications. RL and LL/LLS
      liver donations had equivalent blood loss, readmission and reoperation rates, use
      of blood products, and lengths of stay in the intensive care unit and hospital.
      RL liver donors underwent longer surgeries and experienced more postoperative
      pain than LL/LLS liver donors. The overall rate of complications was 33%. There
      was a higher rate of complications in RL liver donors (51%) than LL/LLS liver
      donors (20%). When graded by severity, there were more grade 2 complications in
      RL liver donors than in LL/LLS liver donors. Our report confirms that RL liver
      donation is associated with higher morbidity than LL/LLS liver donation. When the
      complications are systematically graded by severity, there is a significant
      difference in Clavien grade 2 complications in RL liver donors.

PMID- 15201681
TI  - Surgical repair for late-onset hepatic venous outflow block after living-donor
      liver transplantation.
AB  - The incidence of hepatic venous complications in partial liver transplantation is
      more frequent than that in whole liver transplantation. There are no reports of a
      surgical strategy for hepatic venous outflow block (HVOB) after living-donor
      liver transplantation. HVOB was diagnosed when the pull-through pressure gradient
      across the anastomotic site was over 5 mm Hg. Reoperation for venous anastomosis
      was performed if the angioplasty was unsuccessful. After dissection around the
      hepatic venous anastomotic site, a patch venoplasty of the anastomosis was
      performed. When the inferior vena cava was constricted, venoatrial anastomosis
      was performed. In 6 years, 5 of 223 patients experienced HVOB. Balloon
      angioplasty was successfully performed in two patients, a patch venoplasty of the
      anastomosis in two, and venoatrial anastomosis in one. In all patients, the
      ascites stopped. HVOB must be diagnosed as soon as possible with Doppler
      ultrasound and venography. Prompt surgical revision can salvage the grafts.

PMID- 15201682
TI  - Skewing of pretransplant anti-HLA class I antibodies of immunoglobulin G isotype
      solely toward immunoglobulin G1 subclass is associated with poorer renal
      allograft survival.
AB  - Sensitized patients with lymphocytotoxic immunoglobulin (Ig)G anti-human
      leukocyte antigen (HLA) antibodies have an increased risk of rejection and poorer
      graft survival. Little is known, however, about the correlation between IgG
      antibody subclass and clinical outcomes. We identified 20 sensitized renal
      transplant recipients (panel reactive antibody >15%), all of whom had anti-HLA
      class I antibodies of an IgG isotype with known specificity before
      transplantation but who received a crossmatch negative graft. We analyzed the
      degree of skewing solely toward IgG1 (n=11) or to other IgG subclasses with or
      without IgG1 (n=9) and correlated these findings with graft survival. At last
      follow-up (median follow-up 28 months), 6 of 11 patients (55%) with anti-HLA
      antibodies skewed toward IgG1 had lost their grafts compared with 0 of 9 patients
      (0%) with anti-HLA antibodies not skewed toward IgG1 (P =0.01 log-rank test).
      Anti-HLA antibodies of an IgG1 subclass may be a novel marker predicting poor
      graft outcome.

PMID- 15201683
TI  - Successful treatment of severe portopulmonary hypertension after liver
      transplantation by bosentan.

PMID- 15201684
TI  - Use of oral endothelin-receptor antagonist bosentan in the treatment of
      portopulmonary hypertension.

PMID- 15201685
TI  - Tacrolimus and transplantation: a decade in review.
AB  - The concept of replacing failing organs or tissues with healthy ones is as old as
      civilization itself, but it was not until 1954 that the first successful human
      kidney transplant was performed. Since then, improved surgical techniques and
      organ preservation, greater understanding of immunologic barriers, and the
      development of newer and more potent immunosuppressives have combined to make
      human organ transplantation relatively routine. Key to the success of
      transplantation is tacrolimus, originally known as FR000506. The compound, which
      suppresses interleukin-2 production associated with T-cell activation, inhibits
      differentiation and proliferation of cytotoxic T cells. Today, it is recognized
      worldwide as the cornerstone of immunosuppressant therapy.

PMID- 15201686
TI  - Role of tacrolimus in the evolution of liver transplantation.
AB  - Once regarded as a last-resort therapy for patients with end-stage liver disease,
      liver transplantation has become a viable therapeutic option because of sweeping
      improvements in surgical techniques and the development of more powerful
      immunosuppressive agents. The addition of tacrolimus to the immunosuppression
      regimen represents a highly potent therapy and a powerful defense against acute
      rejection. In the decade since tacrolimus was approved for use in the United
      States, it has become a widely used immunosuppressant in the field of liver
      transplantation.

PMID- 15201687
TI  - A decade of progress in kidney transplantation.
AB  - Kidney transplantation has become the treatment of choice for patients with end
      stage renal disease because of better surgical techniques and the availability of
      more powerful immunosuppressive drugs. Regimens of immunosuppression should
      combine both short-term outcomes and predictors of long-term safety and survival.
      The value of tacrolimus for immunosuppression protocols lies in its ability to
      reduce the immunologic risk to the allograft and its excellent safety profile.
      Outcomes for kidney-transplant recipients can be further optimized by
      individualizing therapy to address each patient's risk profile.

PMID- 15201688
TI  - Advances in pancreas transplantation.
AB  - Despite early obstacles impacting the success of pancreatic transplantation, the
      introduction of new procedures and new immunosuppressive therapies during the
      past 2 decades has improved outcomes for pancreatic transplant recipients. For
      example, the use of bladder drainage and better human leukocyte antigen matching
      has helped overcome some of the early obstacles of pancreatic transplantation. In
      addition, the introduction of tacrolimus in 1994 and mycophenolate mofetil in
      1996 has helped lower rates of acute rejection and increase graft survival, with
      less nephrotoxicity than treatment with cyclosporine. Regimens allowing the
      tapering of corticosteroids have also helped reduce the rates of acute pancreas
      rejection. To further improve therapeutic options for patients with type 1
      diabetes or end-stage renal disease, pancreatic islet transplantation and organ
      and islet xenotransplantation should be further explored.

PMID- 15201689
TI  - An update on clinical outcomes in heart and lung transplantation.
AB  - Much progress has been made in heart and lung transplantation over recent
      decades. The immune mechanisms that result in allograft rejection are now better
      understood, and the development of immunosuppressant therapies has decreased
      recipient mortality among transplant recipients. During the 1980s,
      immunosuppressant therapy primarily involved the use of corticosteroids and
      cyclosporine. However, while survival rates increased among transplant
      recipients, many patients experienced primary graft failures, acute and chronic
      rejection, as well as death. Until the introduction of tacrolimus in the early
      1990s, all patients received the same immunosuppressant regimen, regardless of
      its effectiveness. Tacrolimus therapy has contributed much to the success rates
      of both heart and lung transplantation, and by 2001, it had become the preeminent
      immunosuppressant agent used in lung transplantation.

PMID- 15201690
TI  - Advances in small-intestine transplantation.
AB  - Intestinal transplantation has become the treatment of choice for patients who
      are experiencing life-threatening complications of intestinal failure. Early
      attempts with intestinal transplantation were unsuccessful as a consequence of
      both technical and immunologic failures. The introduction of tacrolimus provided
      the immunologic foundation needed for the field to advance. Guidelines for
      patient selection combined with standardization of operative procedures and
      postoperative management has allowed for improved patient and graft survival.
      There has been a gradual improvement in patient survival over the past 10 years,
      most notably in the past 3 years. Nutritional autonomy has been achieved in
      hundreds of patients worldwide. Further advancements in the understanding of the
      immune response to the transplanted intestine are still needed and will allow the
      use of new antirejection medications, resulting in improved outcomes.

PMID- 15201691
TI  - Advances in the prevention of graft-versus-host disease after hematopoietic cell
      transplantation.
AB  - A brief historic review of bone-marrow transplantation, human leukocyte antigen
      matching, pretransplant conditioning, and the use of peripheral blood stem cells
      in hematopoietic cell transplantation (HCT) is presented. Graft-versus-host
      disease (GVHD) is one of the primary challenges to successful HCT. GVHD, its
      clinical impact and traditional prophylactic therapies, as well as recent
      advances in GVHD prevention, are discussed.

PMID- 15201692
TI  - Long-term effects of transplantation on quality of life.
AB  - Identifying predictors of noncompliance and initiating preventive strategies,
      including education and support services, can lessen the occurrence of
      noncompliance. Selection of immunosuppression protocols that involve fewer
      adverse effects and fewer medications can help increase patient satisfaction,
      improve compliance, maintain graft function, and enrich the long-term quality of
      life for transplant recipients.

PMID- 15201693
TI  - New drugs to improve transplant outcomes.
AB  - Fujisawa is committed to improving the outcomes of transplant patients worldwide.
      Research and development programs are underway for a new modified release dosage
      form of tacrolimus (MR-4), a new analog of leflunomide (FK 778), and several
      novel compounds (PG 490-88, AGI 1096) in collaboration with other companies.
      These programs are targeted to address many of the unmet medical needs in
      transplantation including (1) improving compliance, (2) reducing chronic
      rejection, and (3) improving long-term safety by reducing infectious and
      cardiovascular risk.

PMID- 15201694
TI  - Evaluating myocardial depression in sepsis.

PMID- 15201695
TI  - Early activation of gammadelta T lymphocytes in patients with severe systemic
      inflammatory response syndrome.
AB  - Innate immunity plays an important role in host defense after severe insult.
      gammadelta T lymphocytes are recognized as the first line of defense against
      microbial invasion. In this study, we evaluated gammadelta T lymphocytes in the
      peripheral blood of patients with severe systemic inflammatory response syndrome
      (SIRS), and examined on role of these cells. Thirty-seven patients with severe
      SIRS (SIRS criteria and serum C-reactive protein > or = 10 mg/dL) and 27 healthy
      volunteers were studied. Severe SIRS was caused by trauma in 14 patients (Injury
      Severity Score of 30.1 +/- 10.8) and by sepsis in 23 patients. The counts of
      gammadelta and alphabeta T lymphocytes were determined by flow cytometry of cells
      stained with monoclonal antibodies to gammadelta and alphabeta T lymphocyte
      receptors. The activation of these cells was evaluated by flow cytometry of cells
      stained with monoclonal antibodies to CD69 and HLA-DR. Serial counts and
      activation of gammadelta and alphabeta T lymphocytes were also determined in
      eight trauma patients (Injury Severity Score of 31.0 +/- 13.5) during a 2-week
      observation period. The count of gammadelta T lymphocytes in the peripheral blood
      of SIRS patients (30.1 +/- 6.0/microL) was significantly lower (P < 0.05) than
      that of the healthy volunteers (104.3 +/- 10.9/microL). The expression of CD69,
      an index of early activation of T lymphocytes, was significantly greater on
      gammadelta T lymphocytes from SIRS patients (patients 23.9% +/- 3.4%, healthy
      controls 4.8% +/- 0.6%, P < 0.05). In trauma patients, the expression of CD69 on
      gammadelta T lymphocytes increased rapidly within 48 h after injuries. In
      conclusion, gammadelta T lymphocytes are activated and decreased in the
      peripheral blood of severe SIRS patients. In trauma patients, the activation of
      gammadelta T lymphocytes occurs in the fairly acute phase after injuries. These
      results suggest a significant role for gammadelta T lymphocytes as early
      responders after severe insult.

PMID- 15201696
TI  - The capacity of alpha2-macroglobulin to inhibit an exogenous protease is
      significantly increased in critically ill and septic patients.
AB  - The image of alpha2-macroglobulin is based on a paradigm evolved in the 1970s.
      During this decade alpha2-macroglobulin was shown to irreversibly entrap and
      thereby inhibit a maximum of two proteases. Additional binding of nonproteolytic
      proteins, i.e., inflammatory mediators and growth factors, is dependent on the
      conformational status of alpha2-macroglobulin. It was our aim to clarify whether
      the interaction of nonproteolytic proteins with alpha2-macroglobulin during
      inflammatory conditions might also modulate the capacity of alpha2-macroglobulin
      to inhibit proteases. To explore this possibility, bromelain, an exogenous
      protease, was titrated against plasma of critically ill or septic patients, whose
      pathophysiological conditions are defined by a massive release of inflammatory
      mediators. The stoichiometry of bromelain inhibition by alpha2-macroglobulin was
      quantified by caseolytic activity assays. The maximal alpha2
      macroglobulin/bromelain inhibition ratios were significantly increased (1:6 and
      1:8 in the two patient groups, P < 0.01) as compared with control groups (1:2
      with purified alpha2-macroglobulin and 1:4 in healthy volunteers). The increase
      of alpha2-macroglobulin inhibition capacity in patients was paralleled by the
      appearance of a large signal on Western blots, suggesting the formation of
      additional complexes. Our results demonstrate alpha2-macroglobulin to have more
      flexibility than had been thought, and it may thereby contribute to a shift in a
      30-year-old paradigm.

PMID- 15201697
TI  - The anti-inflammatory effect of diazoxide in coronary artery bypass grafting.
AB  - Many therapeutic strategies have been designed to suppress the inflammatory
      response in patients undergoing coronary artery bypass grafting (CABG).
      Pharmacological preconditioning with diazoxide is an alternative in effective
      cardioprotective strategies, but more evidence is required to show its effect on
      the inflammatory response. Forty patients with stable angina who were scheduled
      for isolated elective CABG operations were randomized into control and diazoxide
      (DZX) groups. In the DZX group, 1.5 mg/kg diazoxide was infused intravenously in
      5 min followed by a 5-min washout before commencing the cardiopulmonary bypass.
      In the control group, placebo infusion was given similarly. Blood samples for
      cytokine measurement were collected from the radial artery and coronary sinus
      perioperatively, and hemodynamic data were recorded. Thirty-six patients
      fulfilled the data collection. Cardiac index (CI) increased in both groups over
      time as compared with baseline. In the DZX group, the increase of CI was greater
      than that in the control group (P = 0.002). Systemic and coronary sinus plasma
      levels of IL-6, IL-8, and IL-10 increased significantly after reperfusion in both
      groups as compared with baseline (P < 0.05). IL-6 and IL-8 both reached the peak
      value at 6 h after cardiopulmonary bypass. IL-10 reached peak level at 20 min
      after reperfusion in both groups. There was significantly higher IL-10 in DZX
      groups (P = 0.015). The ratios of IL-6 to IL-10 and IL-8 to IL-10 were
      significantly lower in DZX groups than in controls (P = 0.025 and P = 0.041 for
      each, respectively). Pharmacological preconditioning with DZX in CABG patients
      shifts the circulating inflammatory cytokine balance toward the anti-inflammatory
      direction.

PMID- 15201698
TI  - Expression profiling: toward an application in sepsis diagnostics.
AB  - Sepsis is a common and serious health problem whereby improvements in diagnosis
      are crucial in increasing survival rates. To test whether profiling transcription
      is applicable to sepsis diagnosis, we analyzed whole blood using a microarray
      containing probes for 340 genes relevant to inflammation. The patient's gene
      expression pattern was highly homogenous, resulting in 69% of differentially
      expressed genes. With a positive predictive value of 98%, a list of 50
      differentially expressed genes was compiled, and randomly chosen transcripts were
      confirmed by PCR. Here, we present the first evidence that microarrays can
      identify typical gene expression profiles in the blood of patients with severe
      sepsis. Regardless of the heterogeneity of the patients, we observed a striking
      correlation between the conventional diagnostic classification and our approach.
      The unity of responses suggests that the principle of this multiparameter
      approach can be adapted to early stage sepsis diagnosis.

PMID- 15201699
TI  - Superoxide anion overproduction in sepsis: effects of vitamin e and simvastatin.
AB  - Oxidative stress during sepsis induces tissue damage, leading to organ
      dysfunction and high mortality. The antioxidant effects of vitamin E have been
      reported in several diseases, but not in sepsis. Statins have cholesterol
      independent anti-inflammatory effects that are related to a decrease of
      isoprenoid proteins and oxidative stress. Therefore, we evaluated superoxide
      anion (O2- degree) production and ex vivo effects of vitamin E and simvastatin in
      sepsis. Fourteen healthy volunteers, 14 intensive care unit (ICU) nonseptic, and
      14 ICU patients with sepsis were included in this prospective study. Plasma
      cholesterol, triglyceride, and vitamin E levels were determined by routine
      laboratory tests. Superoxide anion production was measured in the venous blood by
      chemiluminescence technique after phorbol myristate acetate stimulation. Effects
      of vitamin E and simvastatin on O2- degree production was investigated ex vivo.
      Luminescence was indexed to the leukocyte count. We also investigated the in
      vitro effect of simvastatin on translocation of NADPH oxidase p21 Rac2 subunit in
      THP-1 monocytic cell line. The ratio of vitamin E/cholesterol + triglycerides was
      significantly decreased in septic as compared with nonseptic patients and
      volunteers. The O2- degree production was significantly higher in the group of
      septic patients than in the others, regardless of the polymorphonuclear leukocyte
      count. Vitamin E and simvastatin induced ex vivo an inhibition of O2- degree
      production of 20% and 40% respectively. In vitro, simvastatin inhibited phorbol
      myristate acetate-induced- O2- degree production by monocytes through NADPH
      oxidase inactivation. We conclude that sepsis is associated with a significant
      decrease in vitamin E and an overproduction of O2- degree. Vitamin E and
      simvastatin lessen this phenomenon through NADPH oxidase inactivation.

PMID- 15201700
TI  - Response of lung NK1.1-positive natural killer cells to experimental sepsis in
      mice.
AB  - Natural killer cells (NKC) participate in the initiation of the immune response
      and coordination between innate and adaptive immune mechanisms. Their role in
      systemic inflammation induced by trauma or infection (sepsis) is still
      controversial. In the present study, lung NKC and their response to experimental
      sepsis were investigated. Mice were subjected to cecal ligation and puncture
      (CLP) to induce sepsis and acute lung injury (ALI). Animals were sacrificed 1, 4,
      and 7 days postoperatively, and lung histopathology, pulmonary vascular
      permeability, and inflammatory cells accumulation were assessed. On day 4,
      parameters of ALI were most prominent, and lung NK1.1+CD3- cells were isolated
      and studied by flow cytometry. Although CLP did not change the absolute number of
      lung NKC (2.47 +/- 0.52 x 10(5)/lung compared with 2.97 +/- 0.27 x 10(5)/lung in
      the sham group), the peak of the CLP-induced ALI was associated with severe
      dysfunction of lung NKC. Cell cytotoxicity decreased to 25.1 +/- 2.4% (P =
      0.002), and percentage of perforin-positive NKC to 2.7 +/- 0.5% (P = 0.03).
      Cytokine profile of lung NK1.1+CD3- cells was prominently changed. The percentage
      of IFN-gamma-positive cells decreased to 19.7 +/- 5.7% (P = 0.047), but TNF-alpha
      positive cells grew to 26.7 +/- 3.3% (P = 0.02). In summary, severe CLP-induced
      dysfunction of lung NK1.1+CD-3 cells was demonstrated. This may influence the
      outcome of the animals during sepsis and acute lung damage.

PMID- 15201701
TI  - Transcriptional regulation of cardiac sarcoplasmic reticulum calcium-ATPase gene
      during the progression of sepsis.
AB  - Changes in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene expression in the
      rat heart during different phases of sepsis were studied. Sepsis was induced by
      cecal ligation and puncture (CLP). Septic rats were divided into two groups: the
      early hyperdynamic (9 h after CLP, early sepsis) and the late hypodynamic (18 h
      after CLP; late sepsis) groups. Western blot analyses reveal that SERCA2a protein
      level remained unaltered during early sepsis but was decreased by 59% during late
      sepsis. Northern blot analyses show that the steady-state level of SERCA2a mRNA
      stayed unchanged during the early phase but was decreased by 43% during the late
      phase of sepsis. Nuclear runoff assays show that the transcription rate of
      SERCA2a gene transcript remained unaffected during early sepsis but was decreased
      by 34% during late sepsis. The actinomycin D pulse-chase studies indicate that
      the half-life of SERCA2a mRNA was unaffected during the early and the late phases
      of sepsis. These findings demonstrate that during the early phase of sepsis, the
      protein level, the mRNA abundance, and the transcription rate of SERCA2a remained
      unaltered, whereas during the late phase of sepsis, the rate of transcription of
      SERCA2a was decreased, and the decreased transcription rate was associated with
      decreases in SERCA2a mRNA abundance and SERCA2a protein level in the rat heart.
      Based on these data, it is concluded that SERCA2a gene expression decreased
      during the late phase of sepsis in the rat heart and that the decreased
      expression was regulated at the transcriptional level.

PMID- 15201702
TI  - Blunt chest trauma induces delayed splenic immunosuppression.
AB  - Severe blunt chest trauma is frequently associated with multiple organ failure
      and sepsis. Posttraumatic immunosuppression seems to play a major role in their
      development. However, the immunologic alterations following pulmonary contusion
      are insufficiently elucidated. Specifically, it remains unknown whether
      immunocompetent cells located distant from the site of the impact are affected.
      We therefore aimed to characterize the influence of pulmonary contusion on
      lymphocytes and splenic macrophages. Male C3H/HeN mice (n = 8-10/group) were
      anesthetized and subjected to trauma or sham procedure. Blunt chest trauma was
      induced by a blast wave focused on the thorax. Two or 24 h later, splenocytes and
      splenic macrophages were isolated and stimulated for 48 h. The cytokine release
      (IFN-gamma, IL-2, IL-3, IL-10, IL-12, IL-18) from splenocytes as well as from
      splenic macrophages (TNF-alpha, IL-10, IL-12, IL-18) and plasma levels of TNF
      alpha and IL-6 were quantified by ELISA. The results indicate that at 2 h after
      blunt chest trauma, plasma TNF-alpha and IL-6 were markedly increased. At the
      same time, no differences in splenocyte cytokine production were detectable.
      However, at 24 h a significantly depressed cytokine release was observed in
      trauma animals. Furthermore, splenic macrophages showed a significantly decreased
      production of TNF-alpha, IL-10, and IL-12 at 24 h and markedly increased release
      of IL-18 at 2 h after trauma. These results indicate that blunt chest trauma
      causes severe immunodysfunction of lymphocytes and splenic macrophages. Thus,
      lung contusion as a localized type of trauma causes dysfunction of
      immunocompetent cell populations, which are located distant from the site of
      injury.

PMID- 15201704
TI  - Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and
      myocardial ischemia.
AB  - Here we investigate the effects of erythropoietin (EPO) on the tissue/organ
      injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial
      ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized
      with thiopental sodium (85 mg/kg i.p.) and subjected to hemorrhagic shock (HS;
      i.e., mean arterial blood pressure reduced to 45 mmHg for 90 min, followed by
      resuscitation with shed blood for 4 h), endotoxemia (for 6 h), or left anterior
      descending coronary artery occlusion (25 min) and reperfusion (2 h). HS and
      endotoxemia resulted in renal dysfunction and liver injury. Administration of EPO
      (300 IU/kg i.v., n = 10) before resuscitation abolished the renal dysfunction and
      liver injury in hemorrhagic, but not endotoxic, shock. HS also resulted in
      significant increases in the kidney of the activities of caspases 3, 8, and 9.
      This increase in caspase activity was not seen in HS rats treated with EPO. In
      cultured human proximal tubule cells, EPO concentration-dependently reduced the
      cell death and increase in caspase-3 activity caused by either ATP depletion
      (simulated ischemia) or hydrogen peroxide (oxidative stress). In the heart,
      administration of EPO (300 IU/kg i.v., n = 10) before reperfusion also caused a
      significant reduction in infarct size. In cultured rat cardiac myoblasts (H9C2
      cells), EPO also reduced the increase in DNA fragmentation caused by either serum
      deprivation (simulated ischemia) or hydrogen peroxide (oxidative stress). We
      propose that the acute administration of EPO on reperfusion and/or resuscitation
      will reduce the tissue injury caused by ischemia-reperfusion of the heart (and
      other organs) and hemorrhagic shock.

PMID- 15201703
TI  - Toll-like receptor 4 coupled GI protein signaling pathways regulate extracellular
      signal-regulated kinase phosphorylation and AP-1 activation independent of
      NFkappaB activation.
AB  - Previous studies have implicated heterotrimeric Gi proteins in signaling leading
      to inflammatory mediator production induced by lipopolysaccharide (LPS). TLR4 has
      recently been shown to play a central role in response to LPS activation. We
      hypothesized that Gi proteins are coupled to TLR4 activation of signaling
      pathways. To inhibit Gi protein function, human embryonic kidney (HEK) 293 cells
      or RAW 264.7 cells were pretreated with pertussis toxin (PTx), an inhibitor of
      receptor-Galphai interaction, or transfected with dominant negative Galphai3
      (Galphai3dn) or Galphai2 minigene (an inhibitory carboxyl terminus of Galphai2)
      plasmid. The cells were subsequently transfected with constitutively active TLR4
      (TLR4ca) plasmid or TLR4ca together with an NFkappaB or AP-1 reporter construct.
      TLR4ca transfection induced ERK 1/2 activation (157 +/- 14%, P < 0.01), AP-1
      activation (4.0 +/- 0.2-fold, P < 0.01), and NFkappaB activation (8.1 +/- 0.4
      fold, P < 0.01) compared with empty vector controls. Pretreatment with PTx
      inhibited TLR4ca-induced ERK 1/2 phosphorylation (30 +/- 7%, P < 0.05) and AP-1
      activation (36 +/- 3%, P < 0.05) but did not inhibit NFkappaB activation.
      Cotransfection of TLR4ca with Galphai3dn or Galphai2 minigene also reduced TLR4ca
      induced ERK 1/2 phosphorylation (34 +/- 10% and 33 +/- 5%, respectively, P <
      0.05). Constitutively active Galphai2 and Galphai3 plasmids potentiated TLR4ca
      induced ERK 1/2 phosphorylation (27 +/- 3% and 41 +/- 6%, respectively, P <
      0.05). betaARK-ct plasmid, which inhibits the function of betagamma subunit of G
      protein, has no effect on TLR4ca-induced ERK 1/2 phosphorylation. These data
      support our hypothesis and provide the first evidence that Galphai-coupled
      signaling pathways are activated by TLR4. The TLR4-activated Galphai signaling
      pathway activates ERK 1/2 phosphorylation and AP-1 activation independently of
      TLR4-mediated signaling to NFkappaB activation.

PMID- 15201705
TI  - Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep
      with burn and smoke inhalation.
AB  - Acute respiratory distress syndrome is a major complication in patients with
      thermal injury. The obstruction of the airway by cast material, composed in part
      of fibrin, contributes to deterioration of pulmonary gas exchange. We tested the
      effect of aerosol administration of tissue plasminogen activator, which lyses
      fibrin clots, on acute lung injury in sheep that had undergone combined
      burn/smoke inhalation injury. Anesthetized sheep were given a 40% total body
      surface, third degree burn and were insufflated with cotton smoke. Tissue
      plasminogen activator (TPA) was nebulized every 4 h at 1 or 2 mg for each
      nebulization, beginning 4 h after injury. Injured but untreated control sheep
      developed multiple symptoms of acute respiratory distress syndrome: decreased
      pulmonary gas exchange, increased pulmonary edema, and extensive airway
      obstruction. These control animals also showed increased pulmonary transvascular
      fluid flux and increased airway pressures. These variables were all stable in
      sham animals. Nebulization of saline or 1 mg of TPA only slightly improved
      measures of pulmonary function. Treatment of injured sheep with 2 mg of TPA
      attenuated all the pulmonary abnormalities noted above. The results provide
      evidence that clearance of airway obstructive cast material is crucial in
      managing acute respiratory distress syndrome resulting from combined burn and
      smoke inhalation injury.

PMID- 15201706
TI  - A prostaglandin E2 receptor subtype EP4 agonist attenuates cardiovascular
      depression in endotoxin shock by inhibiting inflammatory cytokines and nitric
      oxide production.
AB  - The prostaglandin (PG) E2 receptor subtype EP4 has been found to mediate
      regulation of inflammatory cytokines in macrophages and neutrophils in vitro by
      PGE2. Yet the role of EP4 receptors in endotoxin shock in vivo and whether EP4
      activation is a beneficial treatment are not clear. We tested the effect of an
      EP4 agonist on hemodynamic changes and production of inflammatory cytokines in a
      rat endotoxin-induced shock model. In rats under pentobarbital anesthesia,
      lipopolysaccharide (LPS) was injected, and an EP4 agonist (ONO-AE1-329) was
      administered at one of three concentrations (1, 3, or 10 microg/kg bolus i.v.
      hourly). Mean arterial pressure (MAP) was monitored throughout the experiment,
      and pressor responses to norepinephrine were determined 6 h after LPS injection.
      Serum tumor necrosis factor (TNF)-alpha and serum interleukin (IL)-6 were
      measured 1 h and 6 h after LPS injection. Venous nitrosyl hemoglobin (NO-Hb)
      concentration was measured by electron spin resonance. Expression of mRNAs
      encoding TNF-alpha and inducible nitric oxide synthase (iNOS) in the left
      ventricle and descending aorta was determined with a real-time reverse
      transcription polymerase chain reaction. As time progressed, LPS significantly
      depressed MAP and decreased reactivity to norepinephrine. Infusion of higher
      doses of the EP4 agonist at 3 and 10 microg/kg/h attenuated LPS-induced
      hypotension and hyporeactivity to norepinephrine. LPS significantly increased
      serum concentrations of TNF-alpha and IL-6, and higher doses of EP4 agonist
      significantly attenuated these increases. Left ventricular and aortic expression
      of mRNAs encoding TNF-alpha and iNOS was increased by LPS; again, EP4 agonist at
      higher doses attenuated the increases. LPS-induced production of inflammatory
      mediators and cardiovascular depression were attenuated by EP4 agonist
      administration in an in vivo endotoxin shock model. Anti-inflammatory effects
      thus would be involved in protection by EP4 agonist against cardiovascular
      depression in endotoxin shock.

PMID- 15201707
TI  - Glucagon increases gap junctional intercellular communication via cAMP in the
      isolated perfused rat liver.
AB  - The effects of glucagon on the subacinar distribution of hepatic transmembrane
      potentials were studied in the perfused fasted rat liver. The livers were
      perfused with a Krebs-Henseleit buffer, and membrane potentials of matched
      periportal and pericentral hepatocytes were determined using glass
      microelectrodes. Lactate- and pyruvate-induced glucose production and O2 uptake
      were potentiated by 10(-8) M glucagon. Twenty-five micromoles 8-bromoadenosine
      3',5'cyclic monophosphate (8-BrcAMP) exhibited stimulatory effects similar, in
      terms of glucose production and O2 uptake to those of glucagon. Octanol (0.1 and
      0.5 mM) had no effect on glucose production but reversibly increased O2 uptake by
      16% to 30% over all experiments. Under basal conditions (no exogenous substrate)
      hepatocyte membrane potentials averaged approximately -27 mV, and no gradients
      were found between periportal and pericentral hepatocytes. Addition of lactate
      and pyruvate produced hyperpolarization in all hepatocytes. However, there was a
      small but statistically significant gradient produced across the hepatic acinus
      in membrane potential, i.e., the hyperpolarization was higher in the periportal
      region compared with the pericentral region. Glucagon and 8-BrcAMP induced marked
      hyperpolarization in periportal and pericentral hepatocytes with no gradients
      across the acinus. Although no changes were found under basal and lactate plus
      pyruvate, 0.5 mM octanol induced heterogeneity of membrane potential during
      glucagon and 8-BrcAMP stimulation. Our findings suggest that glucagon-induced
      homogeneity of membrane potential may be mediated by increased gap junctional
      coupling. In addition, cAMP may be responsible for the increase in the
      intercellular communication during glucagon stimulation.

PMID- 15201708
TI  - Neuron-specific-enolase is increased in plasma after hemorrhagic shock and after
      bilateral femur fracture without traumatic brain injury in the rat.
AB  - Neuron-specific enolase (NSE) is an acknowledged marker of traumatic brain
      injury. Several markers originally considered reliable in the setting of
      traumatic brain injury have been challenged after having been studied more
      extensively. The aim of our experimental study was to determine whether NSE is a
      reliable marker of traumatic brain injury early after trauma. Hemorrhagic shock
      was achieved by bleeding anesthetized rats to a mean arterial pressure (MAP) of
      30-35 mmHg through a femoral catheter until incipient decompensation. MAP was
      maintained at 30-35 mmHg until 40% of shed blood had been administered as
      Ringer's solution and was then increased and maintained at 40-45 mmHg for 40 min
      by further administration of Ringer's solution, mimicking the phase of inadequate
      preclinical resuscitation. Blood samples were drawn at the end of the 40-min
      period of inadequate resuscitation. Femur fracture was achieved in anesthetized
      rats by bilateral application of forceps. Blood samples were drawn 30 and 60 min
      after fracture. Hemorrhagic shock caused NSE increase versus laboratory controls
      at the end of inadequate resuscitation (P < 0.01). Bilateral femur fracture
      caused NSE increase versus laboratory controls 30 min after fracture, which was
      significant 60 min after fracture (P < 0.01). During femur fracture, MAP remained
      at a level that is not associated with shock in rats. Our findings show for the
      first time that NSE increases after hemorrhagic shock as well as after femur
      fracture without hemorrhagic shock in rats. From a clinical point of view, these
      findings indicate that NSE cannot be considered a reliable marker of traumatic
      brain injury early after trauma in cases associated with hemorrhagic shock and/or
      femur fracture.

PMID- 15201712
TI  - Comparison of the performance of 6- or 30-night extended wear schedules with
      silicone hydrogel lenses over 3 years.
AB  - AIM: To compare the clinical performance of silicone hydrogel lenses worn for 6-
      or 30-nights, with monthly replacement, for 3 years. METHODS: In this 3-year
      prospective clinical trial, 161 subjects were enrolled and 154 commenced extended
      wear. Clinical performance was assessed by comparing discontinuations and lens
      surface characteristics (front surface deposits, lens wettability, number of
      mucin balls), lens fitting performance (primary gaze movement, lens tightness),
      and physiologic parameters (limbal and bulbar redness, corneal and conjunctival
      staining, microcysts) and subjective parameters (ratings of comfort and vision)
      between groups. RESULTS: Eighty-eight subjects remained in the study after 36
      months. There were no differences in the probability of subjects surviving in
      either group, and the major cause of lens-related discontinuation in both groups
      was contact lens-induced papillary conjunctivitis. There were no clinically
      important differences in performance between wear schedules. CONCLUSION: The long
      term clinical performance of silicone hydrogels worn for 6- or 30-nights
      continuously was similar. Clinical markers of hypoxia were low in both groups,
      and the 6-night wear schedule was not superior to the 30-night wear schedule with
      regard to preventing lens spoilage, improving corneal physiology, or subjective
      symptoms of comfort and vision.

PMID- 15201713
TI  - The Children's Overnight Orthokeratology Investigation (COOKI) pilot study.
AB  - PURPOSE: Innovations in contact lens materials and designs allow patients to wear
      contact lenses during sleep to flatten the cornea and temporarily to reduce
      myopic refractive error and improve unaided visual acuity. We conducted the
      Children's Overnight Orthokeratology Investigation (COOKI) pilot study, a case
      series, to describe the refractive error and visual changes, as well as the
      slitlamp observations associated with overnight orthokeratology in children, over
      a period of 6 months. METHODS: Twenty-nine 8- to 11-year-old children with myopia
      between -0.75 and -5.00 D and <-1.50 D corneal toricity were fitted with corneal
      refractive therapy contact lenses (Paragon Vision Sciences, Mesa, AZ). They were
      examined within 1 hour of awakening and about 6 hours later at 1 day, 1 week, 2
      weeks, 1 month, 3 months, and 6 months after the first night of contact lens
      wear. At each visit, the logarithm of the minimum angle of resolution (logMAR)
      visual acuity, manifest refraction, slitlamp examination, and corneal topography
      were performed. RESULTS: Twenty-three subjects completed the 6-month study. Three
      subjects decided not to wear contact lenses, two did not achieve acceptable fits,
      and one moved from the area. At the 6-month afternoon visit, the mean +/- SD
      uncorrected high-contrast visual acuity was +0.08 +/- 0.15 logMAR (Snellen
      equivalent, 20/24), and the mean +/- SD spherical equivalent refraction was -0.16
      +/- 0.66 D. The corneas of three-fifths of the subjects showed mild staining at
      the morning visit, and one-third of the patients showed mild corneal staining at
      the afternoon visit. The most common type of stain was central punctate staining.
      No subjects experienced lasting adverse visual effects from cornea-reshaping
      contact lens wear during the study period. CONCLUSIONS: Overnight cornea
      reshaping contact lenses are efficacious for young myopic patients, and no
      children experienced a serious adverse event during the study.

PMID- 15201714
TI  - Effect of one overnight wear of orthokeratology lenses on tear composition.
AB  - PURPOSE: To evaluate the effect of one night of orthokeratology lens wear on
      ocular surface health based on the changes in tear components, including
      ascorbate, urate, lactate dehydrogenase (LD), lactoferrin, lipocalin, lysozyme,
      secretory immunoglobulin A (sIgA), and serum albumin. METHODS: Changes in tear
      components in eight healthy young men before and after 7-h overnight ortho-k lens
      wear were studied. Subjects attended on two separate occasions during a 1-week
      period, on one occasion wearing lens overnight and on the other wearing no lens.
      Tears (yawn-induced) were collected by capillary tube before lens fitting and on
      awakening. Tear ascorbate and urate were measured by high-performance liquid
      chromatography; LD was measured by a commercial kit method; tear proteins were
      measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. RESULTS:
      Ascorbate, sIgA, albumin, and LD increased significantly overnight with and
      without overnight lens wear (p < 0.05); however, no significant increases were
      found in tear urate, lactoferrin, lipocalin, or lysozyme (p > 0.05). Without lens
      wear, tear ascorbate, sIgA, albumin, and LD increased by 21%, 34%, 9-fold, and 13
      fold, respectively (p < 0.05). With ortho-k lens wear, significant flattening of
      the apical curvature was observed as expected, and the increases in tear
      ascorbate, sIgA, albumin, and LD (increases were 56%, 76%, 13-fold, and 14-fold,
      respectively) were significantly (p < 0.05) greater than with no lens. There was
      significant correlation seen between changes in albumin and LD with (r = 0.762; p
      = 0.037) and without (r = 0.738; p = 0.046) ortho-k lens wear. CONCLUSIONS: The
      result of tear ascorbate suggests that corneal cell disturbance is small after
      one night of ortho-k lens wear. The marked increases in albumin and LD suggest
      that the ocular surface is under additional hypoxic stress during overnight ortho
      k lens wear.

PMID- 15201715
TI  - Posterior corneal changes with orthokeratology.
AB  - PURPOSE: To investigate changes in corneal thickness and the radius of curvature
      of the posterior corneal surface after orthokeratology (OK) rigid lens wear.
      METHODS: Nineteen young myopic subjects wore reverse-geometry OK lenses (BE/ABE,
      Ultravision Contact Lenses, Brisbane, Australia) every night for 1 month. Central
      and midperipheral corneal thickness (Allergan Humphrey ultrasound, Carl Zeiss
      Meditec, Dublin, CA), topography (EyeSys v.3.1, Houston, TX), subjective
      refraction, and posterior corneal radii (video photography of Purkinje images)
      were evaluated within 2 h of waking, prelens wear, and on four occasions postlens
      wear during a 1-month period. A mixed-models approach was used to analyze the
      data. We modeled the changes in posterior corneal radius of curvature and corneal
      thickness in terms of the sagittal height of the anterior and posterior cornea
      using an ellipsoidal model for the corneal surfaces. RESULTS: Refractive error
      reduced from -2.28 to -0.01 DS within 1 month. A significant thinning of the
      cornea was evident between 1 (p = 0.03) and 2 weeks (p = 0.0048) postlens wear. A
      significant increase in the anterior corneal radius of curvature was present at
      all time periods beyond 1 night (p < 0.001), and a significant posterior corneal
      flattening occurred centrally and midperipherally after 1 week (p = 0.04 and p =
      0.013, respectively). CONCLUSIONS: These findings suggest that in addition to the
      significant topographic flattening of the anterior corneal surfaces, there is
      also a significant flattening of the posterior surface during the early adaptive
      stages of OK lens wear.

PMID- 15201716
TI  - Apical clearance rigid contact lenses induce corneal steepening.
AB  - PURPOSE: Anecdotal reports suggest that steeply fitted rigid contact lenses can
      induce corneal steepening and myopic shifts in refraction. This study
      investigated changes in corneal topography, corneal thickness, and refraction
      after short-term wear of apical clearance lenses. METHODS: : Ten young adults
      participated in the study in which apical clearance lenses (Conoid, Hydron Pty.
      Ltd., Frenchs Forest, NSW, Australia), fitted approximately 0.3 mm steeper than
      the flattest keratometric reading, were worn for 4 h. A polymethyl methacrylate
      (PMMA) lens was worn in one eye, and a Boston XO lens (Bausch & Lomb, Rochester,
      NY) was worn in the other. Lenses were nonfenestrated in the first trial, and a
      single midperipheral fenestration was incorporated for a second trial. Corneal
      topography was monitored using the EyeSys topographic analysis system (EyeSys
      Vision, Inc., Houston, TX); central corneal thickness was quantified using
      ultrasonic pachometry; and refraction and anterior ocular response were also
      monitored. RESULTS: Significant central corneal edema (8.2 +/- 2.2%) was
      demonstrated in the PMMA lens-wearing eye only. Fenestration did not reduce the
      edema response. We found significant corneal steepening over a 5- to 6-mm central
      zone, which was more pronounced in the PMMA lens-wearing eye and was modified by
      lens fenestration. The curvature changes altered central corneal shape from
      prolate (Q = -0.06 +/- 0.10) to oblate (Q = -0.26 +/- 0.31). A slight myopic
      shift in refraction (-0.38 +/- 0.60 D) was found with the PMMA lenses only.
      CONCLUSIONS: : Apical clearance lenses induce corneal steepening after short-term
      wear. Although corneal molding is implicated as the primary factor driving the
      shape change, corneal edema and postlens tear film pressures can modify this
      response.

PMID- 15201717
TI  - Comparison of noninvasive tear break-up time measurements from black and white
      background instruments.
AB  - PURPOSE: To compare noninvasive tear break-up time (NITBUT) measured using a
      black background instrument (NITBUTb) and that measured using a white background
      instrument (NITBUTw). METHODS: The NITBUTb and NITBUTw of the right eye of 58
      asymptomatic subjects aged 16 to 23 years were measured by the same examiner on
      the same day and compared. NITBUT measurement was terminated at 45 s to minimize
      ocular discomfort and reflex tearing. RESULTS: Three subjects had reflex tearing
      during the NITBUT measurement, and nine subjects had either NITBUTb or NITBUTw
      values > 45 s, so their data were excluded. For the 46 subjects with NITBUT < or
      = 45 s, no significant difference between NITBUTb and NITBUTw was found (Wilcoxon
      test p = 0.156). No statistically significant relationship was found between
      NITBUTb and NITBUTw (Spearman r = 0.217, p = 0.147). The agreement between
      NITBUTb and NITBUTw was poor, with a mean difference of 1.3 s and 95% limits of
      agreement of -20.0 to +22.6 s. CONCLUSIONS: There was no significant difference
      in NITBUT made from instruments of different backgrounds if the procedures and
      endpoint criterion were the same. The poor agreement between NITBUTb and NITBUTw
      was due to the large variations in NITBUT rather than the difference in the
      background color of the instrument used. However, use of the black background
      instrument for subjects with dark irides is recommended, as it is relatively
      easier to see the grid image on the eye and > 50% of our subjects complained of
      discomfort from glare with the white background instrument.

PMID- 15201719
TI  - Characterization of the surface of conventional hydrogel and silicone hydrogel
      contact lenses by time-of-flight secondary ion mass spectrometry.
AB  - PURPOSE: To characterize the surfaces of unworn conventional hydrogel and
      silicone hydrogel contact lenses. METHODS: Near-identical formulations of
      poly(hydroxyethyl methacrylate) (pHEMA) were used to manufacture lathe-cut, spun
      cast, and cast-molded contact lenses. The surfaces of two of each of these lens
      types and two of each of two commercially available silicone hydrogel lenses
      balafilcon A (PureVision) and lotrafilcon A (Focus Night and Day)-were analyzed
      using time-of-flight secondary ion mass spectrometry (ToF-SIMS). RESULTS: The ToF
      SIMS spectra revealed the presence of the bulk polymer pHEMA at the surface of
      all three hydrogel lenses, along with other contaminants, such as poly(dimethyl
      siloxane), alkyl sulfates, alkyl-aryl sulfonates, dioctyl phthalate, Irgafos 168,
      sodium, chlorine, aluminum, potassium, calcium, copper, and fluorine, which are
      primarily derived from the various processing steps undertaken in lens
      manufacture, handling, and storage. The amount of bulk polymer detected at the
      surface of the PureVision lens was greater than that detected at the surface of
      the Night and Day lens. In addition, contaminants similar to those found on the
      surfaces of the conventional hydrogel lenses were detected. The Focus Night and
      Day lens appears to be coated with an organo-nitrogen material, which results
      from the plasma deposition of reactive precursors on the surface. CONCLUSIONS: We
      confirm that ToF-SIMS has the capacity to characterize the surface chemistry of
      contact lenses. The ongoing application of this technique can assist researchers
      and clinicians to understand the clinical performance of contact lenses.

PMID- 15201718
TI  - Impact of manufacturing technology and material composition on the clinical
      performance of hydrogel lenses.
AB  - PURPOSE: To establish the clinical impact of three different methods of
      manufacture used to produce soft contact lenses. METHODS: Clinical performance of
      five lens types was investigated by undertaking a prospective, double-masked,
      randomized, crossover study. Three of the lenses were made from poly(hydroxyethyl
      methacrylate) (pHEMA) by three different manufacturing processes (lathing, spin
      casting, and cast molding), and the remaining two lenses were cast molded from
      different materials-hydroxyethyl methacrylate/methacrylic acid and hydroxyethyl
      methacrylate/glycerol methacrylate (HEMA/GMA). All lenses were specially
      fabricated for this work at the same manufacturing plant. Thirty-four soft
      contact lens wearers wore each lens for 1 month on a daily-wear basis. Several
      clinical variables, such as ocular response, visual acuity, lens fitting, prelens
      tear film, lens surface dehydration, subjective response, and protein deposition,
      were measured. RESULTS: In general, the spun-cast pHEMA lens performed inferiorly
      compared with the other pHEMA lenses. This lens induced significantly more limbal
      and conjunctival hyperemia than the cast-molded lens and provided poorer low
      contrast visual acuity (LCVA) than the other two lenses. It dehydrated more and
      had the least on-eye movement. However, the spun-cast lens deposited the least
      protein of the pHEMA lenses. In general, the HEMA/GMA lens performed inferiorly
      compared with the other cast-molded lenses. LCVA was worse with this lens, and
      subjective responses showed that this lens was thought to give the worst visual
      performance of the cast-molded lenses. It was also thought to be the most
      difficult lens to handle. Significantly more breakages occurred with this lens
      than any other. CONCLUSIONS: Overall, this work has shown that manufacturing
      method and material composition have a fundamental effect on many clinical
      properties of a lens. Therefore, method of manufacture is also an important
      consideration in the overall production of a soft lens.

PMID- 15201720
TI  - Effect of two different cleaning methods on the back optic zone radii and surface
      smoothness of menicon rigid gas-permeable lenses.
AB  - PURPOSE: To evaluate and compare changes to the back optic zone radii (BOZR) and
      the level of surface scratches of Menicon rigid gas-permeable (RGP) lenses in and
      between palm and digital cleaning methods and to determine whether these changes
      are affected by different examiners, lens materials, and initial BOZR. METHODS:
      Ninety-six Menicon RGP lenses of two different lens materials (Menicon Z and
      Menicon EX) and of initial BOZR 7.6 and 8.1 mm were cleaned by two independent
      examiners using either palm or digital cleaning methods for a total of 270 times
      (simulating 9 months' use). The study was conducted with the examiners masked as
      to the initial BOZR and the lens material of each lens. The two examiners who
      investigated the BOZR and the lens surfaces were also unaware of the method of
      cleaning used on each lens. The BOZR and the level of scratches on lens surfaces
      were determined before initiating lens rubbing and after every 2 simulated months
      (60 cleanings) for 8 simulated months and again at the ninth simulated cleaning
      month. RESULTS: No lens warpage was observed in any of the lenses cleaned with
      either method. We found no clinically significant changes in the BOZR with the
      number of cleanings between palm and digital cleaning methods for both the steep
      and the flat lenses. Changes to the BOZR were also unaffected by the examiners
      and the lens types. The overall mean +/- SD changes in BOZR (from baseline) after
      9 simulated months were -0.014 +/- 0.025 mm for lenses using palm cleaning and 
      0.010 +/- 0.022 mm for lenses using digital cleaning. The level of scratches on
      the lenses was dependent on the examiners and the number of cleanings but was
      unaffected by the method of cleaning, the lens type, and the initial BOZR of the
      lenses. The level of scratches increased with the number of cleanings, and the
      median level of scratches (range) observed after 9 simulated cleaning months was
      grade 1.0 (0.50 to 1.50) for examiner 1 and grade 1.50 (0.50 to 2.00) for
      examiner 2. These values were, however, not clinically significant. CONCLUSIONS:
      Palm or digital cleaning of Menicon RGP lenses for 9 simulated months of cleaning
      did not lead to any lens warpage. Changes to the BOZR with the number of cleaning
      were not clinically significant with either method of cleaning. Methods of
      cleaning, different examiners following the same procedures, lens types, and
      initial BOZR did not affect BOZR changes. The level of surface scratches was only
      dependent on the examiners and the number of cleanings. However, the changes
      observed were not clinically significant. Because the levels of change to the
      BOZR and surface scratches were comparable for both palm and digital methods of
      cleaning, these lenses may be cleaned using either cleaning method.

PMID- 15201721
TI  - Effectiveness of no-rub contact lens cleaning on protein removal: a pilot study.
AB  - PURPOSE: To compare the amount of protein deposits adhering to human-worn soft
      contact lenses, using the untreated contact lens from the contralateral eye as
      controls, to investigate the capabilities of the No Rub contact lens cleaning
      systems in protein removal from soft contact lenses. METHODS: New 1 Day Acuvue
      soft contact lenses were worn on a daily-wear basis by 16 Hong Kong Chinese
      volunteers on 5 separate days. Four right lenses of each subject were treated
      with No Rub contact lens cleaning systems (Alcon Opti-Free Express, Alcon Opti
      Free Express No Rub Lasting Comfort Formula, B and L ReNu MultiPlus, and Ciba
      Vision SOLO Care Plus). The total amount of protein was extracted from all
      contact lenses and analyzed by the Bradford assay. RESULTS: Among the
      contralateral contact lenses, there was no significant difference in the total
      protein extracted (TPE; 11.2 +/- 3.8 vs. 12.6 +/- 5.2 mg/ml, p = 0.20). There was
      a significant positive correlation in TPE between two lenses worn by the same
      volunteer (R(2) = 0.84, y = 0.79 x + 1.3, p < 0.001). Lenses treated with Opti
      Free Express and Opti-Free Express No Rub Lasting Comfort Formula solutions had
      significantly less TPE (7.3 +/- 5.2 and 6.7 +/- 4.1 mg/ml, respectively, p <
      0.001) than the untreated contralateral lenses (12.7 +/- 6.8 and 13.2 +/- 5.3
      mg/ml, respectively). No statistical difference in TPE was detected in the lenses
      treated with ReNu MultiPlus (13.0 +/- 7.8 mg/ml, p = 0.49) and Solo Care Plus
      (12.1 +/- 8.7 mg/ml, p = 0.99) solutions when compared with their untreated
      contralateral lenses (13.0 +/- 7.8 and 12.1 +/- 8.7 mg/ml, respectively).
      CONCLUSIONS: Not all no-rub contact lens solutions were shown capable of removing
      the protein deposit from soft contact lenses.

PMID- 15201722
TI  - Testing of a dual-mode microwave care regimen for hydrogel lenses.
AB  - PURPOSE: To test the design of a patient care regimen for soft lenses that aims
      to provide the highest standards of disinfecting through use of domestic
      microwave cookers, while also providing storage equipment and solution that
      enable patients to follow a conventional cold disinfecting regimen when
      traveling. The cleaning efficacy of surfactant agents during microwave treatment
      was also considered. METHODS: The microbiologic performance of the regimen and
      its disinfecting apparatus was tested according to the Food and Drug
      Administration (FDA) protocols for contact lens heat disinfectors. Subsequently,
      a prospective pilot clinical trial of the regimen involving 15 subjects was
      carried out to the protocols of the FDA and International Standards Organization
      11,980:1997. RESULTS: Lenses inoculated with 10(7) colony-forming units (cfu) of
      Enterococcus faecalis were disinfected to 0 cfu by a 12-s irradiation of a
      compact disinfecting case that held the lenses suspended in 12 ml saline. A proof
      of operation indicator performed correctly for all 10 cases tested. No adverse
      reactions were found in the pilot patient trial, using Renu multipurpose (Bausch
      and Lomb, Rochester, NY) as the test solution, and no statistically significant
      difference was found between test and control groups in respect of any sign.
      However, the greater incidence of edema, palpebral hyperemia, and lens front
      surface deposition in the microwave test group may be clinically significant.
      CONCLUSIONS: The design of the test care regimen proved easy for patients to
      follow in either hot or cold disinfecting mode. The greater incidence of certain
      signs in the microwave test group suggests the need to continue using a rub and
      rinse step for the microwave mode and for additional investigation into the
      choice of an appropriate multipurpose solution formulation for this proposed
      regimen, preferably one that does not use a block copolymer-type surfactant
      agent.

PMID- 15201726
TI  - Laparoscopic partial nephrectomy and prostatectomy: weighing the costs and the
      benefits.

PMID- 15201727
TI  - Interventions and outcomes. What is important (and what is not)?

PMID- 15201728
TI  - Is a nerve (graft) still a nerve by any other name?

PMID- 15201729
TI  - Genetically modified mice and their use in developing therapeutic strategies for
      prostate cancer.
AB  - PURPOSE: At the National Cancer Institute a comprehensive program has been
      developed for accelerating prostate cancer research, especially in the area of
      mouse models for human cancers. This review focuses on transgenic mouse models
      for elucidating the molecular and cellular processes that lead to prostate cancer
      initiation, progression and metastasis, and on their suitability for therapeutic
      and chemopreventive trials. MATERIALS AND METHODS: Published data from MEDLINE,
      http://emice.nci.nih.gov/, our laboratory and other investigators are reviewed.
      RESULTS: Currently no 1 mouse model displays the entire continuum of human
      prostate cancer initiation, development and metastasis. The loss or over
      expression of a single gene results primarily in epithelial hyperplasia,
      prostatic intraepithelial neoplasia or more aggressive localized adenocarcinoma.
      To date the only models that develop lung, liver and occasionally bone metastasis
      are those that express SV40 large T antigen. A number of models have been used to
      investigate the efficacy of androgen deprivation, lovastatin, vitamin D, the anti
      inflammatory drug E-7869, genistein and (-)-epigallocatechin-3-gallate as
      therapeutic or chemopreventive agents. Noninvasive optical imaging technologies
      facilitate the detection of metastatic lesions and the effects of therapeutic
      agents on tumor regression. CONCLUSIONS: Integrating mouse studies with human
      clinical trials would ensure that mechanisms that promote prostate cancer are
      identified and potential therapeutic targets are validated.

PMID- 15201730
TI  - Prostatic tissue ablation by injection: a literature review.
AB  - PURPOSE: Most men 50 to 80 years old will have development of some degree of
      benign prostatic hyperplasia (BPH). Many who experience lower urinary tract
      symptoms (LUTS) will be treated medically. However, significant numbers will have
      more severe and progressive disease requiring surgery. Transurethral resection of
      the prostate is the current gold standard of treatment for BPH. Minimally
      invasive therapies for symptomatic BPH emerge and fade continuously. However,
      intraprostatic injection for BPH has been used for more than 100 years and may be
      on the verge of a rebirth. The goal of this review is to familiarize the reader
      with the origins and history of intraprostatic injection, and its evolution using
      transperineal, transrectal and transurethral routes with multiple injectants.
      Initially used to treat urinary retention in men with BPH, its primary indication
      is now for LUTS. MATERIALS AND METHODS: We performed a structured MEDLINE review
      of the literature on intraprostatic injections from 1966 to 2003, augmented with
      relevant articles from select journals and documents dating to 1832. RESULTS: In
      patients with BPH transperineal and transurethral injections have the most
      systematic evaluation. Most injectants will cause localized prostatic necrosis
      and gland volume reduction with varying degrees of LUTS relief. Anhydrous ethanol
      is the most widely studied injectable to date. There are advantages and
      disadvantages associated with each route of injection. CONCLUSIONS: Examined for
      more than a century, the potential for using injectables for prostatic tissue
      ablation remains significant. More systematic laboratory research and clinical
      trials, currently ongoing, need to be completed.

PMID- 15201731
TI  - Central nervous system control of the lower urinary tract: new pharmacological
      approaches to stress urinary incontinence in women.
AB  - PURPOSE: Despite the prevalence of stress urinary incontinence in women there are
      no approved drugs for the disease. MATERIALS AND METHODS: Designing medical
      therapies requires a comprehensive understanding of how the internal and external
      sphincters are neurologically controlled. In this review recent advances in
      mapping storage and micturition reflexes, and the association of serotonergic and
      noradrenergic systems with these reflexes are discussed. RESULTS: Urine storage
      and micturition are controlled by a series of hard wired reflexes that are under
      the modulatory influence of serotonin and norepinephrine. Augmentation of the
      serotonergic and noradrenergic systems with duloxetine increases bladder capacity
      and urethral rhabdosphincter activity. The increase in sphincter activity is
      mediated by alpha1 adrenergic receptors and 5-hydroxytryptamine receptors.
      CONCLUSIONS: Increasing rhabdosphincter activity with duloxetine may offer a
      therapeutic benefit in women with stress urinary incontinence.

PMID- 15201732
TI  - An historical review of graduate medical education and a protocol of
      Accreditation Council for Graduate Medical Education compliance.
AB  - PURPOSE: A brief history of American graduate medical education is discussed to
      provide a context for understanding the new standards set forth by the
      Accreditation Council on Graduate Medical Education (ACGME). The evaluation
      protocol of the University of Washington, which is structured around the 6 core
      competencies, is described. MATERIALS AND METHODS: Historical events regarding
      American graduate medical education, national conference information and recent
      ACGME recommendations according to the Outcomes Project are reviewed and
      summarized. These materials were used to design a reasonable program that would
      comply with ACGME recommendations. RESULTS: ACGME tools that represent the 6 core
      competencies have been incorporated into our program and should provide metrics
      that will demonstrate improvement in residency training and education.
      CONCLUSIONS: A key factor to the success of residency training and ACGME
      accreditation will be the education of residents and faculty about the new ACGME
      regulations. The University of Washington Department of Urology is poised to
      engage the new model by creating new call coverage strategies, applying new
      metrics to old teaching models and using electronic database systems.

PMID- 15201733
TI  - Willard E. Goodwin: educator, innovator and pioneer.

PMID- 15201734
TI  - The radiographic evolution of radio frequency ablated renal tumors.
AB  - PURPOSE: Radio frequency ablation (RFA) of renal tumors is a relatively new
      technology. Few groups are familiar with the posttreatment appearance of these
      lesions and how they differ from cryoablated renal masses. We describe the
      evolution of the appearance of these lesions on followup contrast enhanced (CE)
      computerized tomography (CT). METHODS AND MATERIALS: A total of 64 consecutive
      renal tumors treated with RFA from April 2000 to September 2003 for which
      posttreatment CE-CT was done were included in this study. CE-CT was reviewed at 6
      weeks, 3 months, 6 months and every 6 months thereafter to determine the
      characteristic features and evolution of these lesions. RESULTS: Renal tumors
      were treated with CT guided percutaneous (34), laparoscopic (28) or open (2) RFA.
      At a median followup of 13.7 months (range 6 weeks to 29 months) 62 RFA lesions
      demonstrated an absence of contrast enhancement on CE-CT. Treated endophytic
      tumors developed a low density, nonenhancing, wedge-shaped defect with fat
      infiltration seen between the ablated tissue and normal parenchyma. Treated
      exophytic tumors retained a configuration similar to that of the original with a
      lack of contrast enhancement and minimal shrinkage. Percutaneous treated lesions
      developed a peritumor scar or halo that demarcated ablated and nonablated tissue
      (perirenal fat). Persistent tumor was marked by contrast enhancement within the
      ablation borders of the original mass in 1 case, whereas tumor recurred after
      initial successful ablation with an enhancing nodule in 1. CONCLUSIONS: The
      radiographic features and evolution of radio frequency ablated renal tumors are
      unique. Successfully treated tumors demonstrated no contrast enhancement, minimal
      shrinkage and occasional retraction from normal parenchyma by fat infiltration.

PMID- 15201735
TI  - Parenchymal sparing surgery for central renal tumors in patients with hereditary
      renal cancers.
AB  - PURPOSE: Nephron sparing surgery has become accepted surgical practice for
      removing of renal tumors. The resection of central lesions has been thought to be
      more surgically challenging than that of peripheral tumors. We analyzed our
      experience with renal preservation surgery in patients with small hereditary
      central renal tumors. MATERIALS AND METHODS: From 1992 to 2000 we performed 116
      partial nephrectomies with 44 kidneys (38%) demonstrating central renal masses.
      Central renal tumors were defined radiologically as those completely encircled by
      parenchyma or transgressing the interpapillary line on computerized tomography.
      We compared this group to a similar series of 67 patients with hereditary renal
      cancer with only peripheral based tumors. RESULTS: Mean tumor size was 3.2 cm
      (range 1.5 to 7.5). Mean operative time was 352 minutes (range 70 to 830). Renal
      hypothermia and vascular clamping were used in 19 of 44 procedures (41%). Mean
      ischemic time was 55 minutes (range 16 to 143). Mean blood loss was 4.6 l (range
      0.1 to 23). The complication rate was 23% (10 of 44 cases) and with 18% (8 of 44)
      directly related to surgical technique. The mean transfusion requirement was 6.7
      U (range 0 to 32) and 12 of 44 procedures (27%) required no blood products. Mean
      preoperative and postoperative serum creatinine was 1.05 (range 0.6 to 1.8) and
      1.08 mg/dl (range 0.6 to 2.1), respectively. Mean followup was 33.7 months. No
      metastasis developed during followup. CONCLUSIONS: Central renal tumors are a
      common manifestation of hereditary renal cell carcinoma. There was no statistical
      difference found between common operative parameters when central and peripheral
      nephron sparing surgeries were compared. However, mean operative blood loss and
      transfusion requirements were increased in the central tumor group.

PMID- 15201736
TI  - Impact of temporary hilar clamping during laparoscopic partial nephrectomy on
      postoperative renal function: a prospective study.
AB  - PURPOSE: Laparoscopic partial nephrectomy for small renal tumors has been
      increasingly performed in the last few years. We prospectively evaluated
      preoperative and postoperative differential renal function by renal scan in
      patients with contralaterally functioning kidneys who underwent laparoscopic
      partial nephrectomy with hilar clamping. MATERIALS AND METHODS: From July 2002 to
      June 2003, 17 consecutive patients were included in this prospective protocol and
      underwent laparoscopic partial nephrectomy for exophytic tumors using en bloc
      hilar clamping. Preoperative renal scan with differential function was performed
      1 month before and 3 months after surgery in all patients. technetium labeled
      diethylenetetraminepentaacetic acid scan was performed in all patients. RESULTS:
      Mean warm ischemia time was 22.50 +/- 9.78 minutes (range 10 to 44). Preoperative
      differential renal function and glomerular filtration rate (GFR) in the affected
      kidneys were 50.20% +/- 4.90% (range 43 to 58) and 75.56 +/- 16.45 ml per minutes
      (range 39.4 to 105). At postoperative month 3 differential renal function and GFR
      in the affected kidney were 48.07% +/- 7.16% (range 39% to 63%) and 72.03 +/-
      18.17 ml per minutes (range 31 to 101). There was a nonsignificant negative
      association between hilar clamp time and change in renal function (postoperative 
      preoperative) of the affected kidney (r = -0.26, p = 0.31), and a positive
      correlation between clamp time and change in GFR (r = 0.39, p = 0.12) that did
      not reach statistical significance. CONCLUSIONS: In patients with contralaterally
      functioning kidney, temporary hilar clamping with a mean warm ischemia time of
      22.5 minutes results in preservation of renal function in the affected kidney.
      Larger studies with longer followup are necessary to study the impact of warm
      ischemia further.

PMID- 15201737
TI  - Guidelines for the surveillance of localized renal cell carcinoma based on the
      patterns of relapse after nephrectomy.
AB  - PURPOSE: We characterized relapse patterns in patients with sporadic renal cell
      carcinoma (RCC) following radical and partial nephrectomy, and developed
      surveillance guidelines. MATERIALS AND METHODS: Between 1989 and 2000, 495
      patients underwent nephrectomy for RCC at 1 of 5 Canadian referral centers.
      Median followup was 42 months. RESULTS: The rate of relapse, time to relapse and
      site of relapse were associated with pathological stage. Five-year progression
      free probability was 93% for pT1, 81% for pT2, 67% for pT3A and 57% for pT3B (p
      <0.001). Compared to patients with pT1-2 those with pT3A-B lesions had earlier
      relapse after nephrectomy (median 12 vs 26 months, p = 0.001) and were at higher
      risk for relapse at abdominal sites (14% vs 1.8%, p < 0.001). Abdominal relapse
      was detected in the absence of symptoms, abnormal biochemical profile or thoracic
      metastases detectable by chest x-ray in 7 patients (1.4%) overall, including 3
      (0.9%) with pT1, 3 (4%) with pT3A and 1 (3%) with pT3B. CONCLUSIONS: The risk and
      the pattern of relapse of RCC after nephrectomy are associated with pathological
      stage. For the surveillance of recurrent disease after nephrectomy we recommend
      annual clinical assessment and chest x-ray in pT1-2 cases. Patients with pT3A-B
      should be followed every 6 months for the first 3 years with clinical assessment
      and chest x-ray, and annual followup thereafter. The higher risk of abdominal
      relapse in patients with pT3A-B indicates that they should receive surveillance
      abdominal imaging. We recommend abdominal computerized tomography 6, 12, 24 and
      36 months postoperatively.

PMID- 15201738
TI  - The relationship between renal tumor size and metastases in patients with von
      Hippel-Lindau disease.
AB  - PURPOSE: Patients with von Hippel-Lindau disease are at risk for multiple,
      bilateral, recurrent renal tumors and metastases. We previously evaluated the
      relationship between tumor size and metastases in families with hereditary renal
      cancer. We update our findings with about twice the number of patients with von
      Hippel-Lindau disease. MATERIALS AND METHODS: Screening affected kindred or
      retrospective review of medical records identified 181 patients with von Hippel
      Lindau disease and renal cell carcinoma. Patients with small tumors were followed
      with serial imaging until the largest tumor reached 3 cm, at which point surgery
      was recommended. Surgical resection was recommended to patients with tumors
      larger than 3 cm. Patients not undergoing screening often had large renal tumors.
      RESULTS: A total of 108 patients with von Hippel-Lindau disease and solid renal
      tumors on computerized tomography imaging smaller than 3 cm (group 1) were
      followed a mean of 58 months (range 0 to 244). Metastatic disease did not develop
      in any of these patients. Renal tumors larger than 3 cm developed in 73 patients
      with von Hippel-Lindau disease (group 2). Mean followup of group 2 was 72.9
      months (range 0 to 321). The proportion of procedures that were nephron sparing
      was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125
      [69%], Fisher's exact test p <0.0001). Metastases developed in 20 of 73 (27.4%)
      patients in group 2. The frequency of renal tumor metastases increased with
      increasing tumor size. CONCLUSIONS: No renal tumor metastases were found in
      patients with renal tumors less than 3 cm in diameter. We advocate a 3 cm
      threshold for parenchymal sparing surgery in patients with von Hippel-Lindau
      disease to decrease the risk of metastatic disease while preserving renal
      function, avoiding or delaying the need for dialysis and/or renal transplant, and
      decreasing the number of operations which a patient may undergo. We stress the
      importance of early screening in the kindred of patients with von Hippel-Lindau
      disease and vigilant followup thereafter.

PMID- 15201739
TI  - Percutaneous nephroscopic management of upper urinary tract transitional cell
      carcinoma: recurrence and long-term followup.
AB  - PURPOSE: We present long-term results of the percutaneous approach and resection
      of upper urinary tract transitional cell carcinoma, and we evaluate the
      prognostic factors related to recurrence. MATERIALS AND METHODS: A total of 34
      patients underwent primary percutaneous resection of an upper urothelial tumor.
      We treated the patients with a superficial tumor that was completely resected
      macroscopically. Adjuvant topical chemotherapy or immunotherapy was administered.
      Patients were followed with excretory urography. Ureteroscopy and computerized
      tomography were obtained when clinically indicated. RESULTS: With a mean followup
      of 51 months ipsilateral recurrence developed in 41.2%. Median time to recurrence
      was 24 months. The rate of kidney preservation was 73.5%. Two patients died of
      the disease. There was a trend of recurrence in patients with multifocal tumors
      (OR 2.66, 95% CI 0.07-1.92), history of bladder carcinoma in situ (OR 2.4, 95% CI
      1.61-3.74), tumor in renal pelvis (OR 6.45, 95% CI 0.01-1.46) and multiple tumor
      locations (OR 6.53, 95% CI 0.01-1.54). CONCLUSIONS: The percutaneous approach to
      renal urothelial tumor should be considered a valid option with a good long-term
      outcome. Recurrence is not uncommon and, as transitional cell carcinoma
      superficial bladder cancer it may be treated with endourological maneuvers or
      radical surgery, but with the obligation to a long lasting, strict surveillance.

PMID- 15201741
TI  - Seminal sparing cystectomy and ileocapsuloplasty: long-term followup results.
AB  - PURPOSE: The efficacy of nerve sparing techniques to save potency in
      cystoprostatectomy is about 50%. This radical surgery may be proposed to young
      men with normal sexual function. We report the results of a 13-year experience
      with our innovative seminal sparing cystectomy and bladder replacement to
      maintain sexual function in such patients. MATERIALS AND METHODS: Seminal sparing
      cystectomy is a modification of standard radical cystectomy in which the
      posterior bladder dissection is anterior to the seminal vesicle plane to preserve
      the vasa deferens, seminal vesicles, prostatic capsule and neurovascular bundles.
      Ablation of the whole bladder and the prostatic urothelium with surrounding
      hypertrophic tissue is guaranteed, and injury to the pelvic nerve plexus that
      provides autonomic innervation to the corpora cavernosa is avoided. From April
      1990 to December 2002 we performed 68 procedures in 63 patients (7 of whom were
      lost to followup) with superficial bladder cancer resistant to conservative
      therapies (18 patients with stage T1G2 disease, 13 TaG2, 11 T1G3 and 14 TaG3) and
      in 5 patients with invasive bladder cancer (T2G3) which was monofocal and away
      from the bladder neck. All patients had normal sexual function. A complete
      clinical evaluation (with prostate specific antigen [PSA], digital rectal
      examination and transrectal ultrasound) to exclude concomitant prostate cancer
      was performed. Average patient age was 49 years and mean followup was 68 months.
      RESULTS: Normal erectile function was preserved in 58 patients (95%). Complete
      daytime continence was reached in 58 patients (95%) and nighttime continence was
      reached in 19 patients (31%). The early postoperative complication rate was 18%
      and the delayed complication rate was 26.2%. A total of 55 patients (90.2%) are
      alive and 6 patients (9.8%) died, 5 of cancer progression. High grade prostatic
      intraepithelial neoplasia was noticed in prostatic specimens in 3 patients and
      prostatic cancer was noted in 1 patient. These patients had a normal PSA before
      operation and a serum PSA less than 0.2 ng/ml at a mean followup of 19 months. No
      positive margins were identified on permanent histological analysis of the
      specimens, nor were local pelvic recurrences observed. CONCLUSIONS: Our
      innovative technique is safe, effective and easy to perform. The oncological and
      functional results obtained with a long followup justify seminal sparing
      cystectomy as an excellent surgical procedure which can be proposed to some
      oncological and nononcological cases.

PMID- 15201740
TI  - Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy?
AB  - PURPOSE: In this retrospective nonrandomized study we compared the long-term
      outcome in patients with newly diagnosed stage T1G3 bladder cancer treated with
      transurethral resection and bacillus Calmette-Guerin or immediate cystectomy.
      MATERIALS AND METHODS: Of 121 patients with a median age of 67 years (range 36 to
      88) diagnosed with primary T1G3 bladder cancer between 1976 and 1999, 92 were
      treated by transureteral resection with additional intravesical bacillus Calmette
      Guerin and 29 were treated with immediate cystectomy. RESULTS: Of the 92 patients
      treated with an organ preserving approach 29 remained disease-free, local
      recurrence developed in 33 (36%) and progression developed in 30 (33%) at a
      median followup of 6.9 years (range 0.6 to 16.5). Of these 92 patients 27 (29%)
      underwent deferred cystectomy at a median of 12.9 months (range 4.8 to 136), of
      whom 10 (37%) with a median postoperative followup of 19 months (range 2 to 173)
      died of progressive disease with a median survival of 13 months (range 3 to 34)
      after cystectomy. The majority of patients who died of progressive disease
      refused cystectomy, were referred too late for cystectomy, were inoperable or had
      upper urinary tract disease. Six of the 29 patients (21%) undergoing immediate
      cystectomy had progression at a median of 13.2 months (range 5.5 to 37). Overall
      and tumor specific survival at 5 years in patients treated with an organ
      preserving approach was 69% and 80%, and in those treated with immediate
      cystectomy it was 54% and 69%, respectively. CONCLUSIONS: The results of this
      analysis demonstrate that the concept of an organ preserving approach is
      acceptable and spares the bladder in approximately half of the patients with
      primary T1G3 bladder cancer. Of the patients 30% require deferred cystectomy,
      making meticulous, close followup mandatory.

PMID- 15201742
TI  - Prognosis of seminal vesicle involvement by transitional cell carcinoma of the
      bladder.
AB  - PURPOSE: Transitional cell carcinoma (TCC) of the bladder that extends directly
      into contiguous organs (pT4) portends a poor prognosis. The 2002 American Joint
      Committee on Cancer staging system does not include seminal vesicle involvement
      by primary TCC of the bladder. In this analysis we evaluated the clinical
      outcomes and prognostic significance of seminal vesicle involvement with TCC of
      the bladder after radical cystectomy. MATERIALS AND METHODS: From 1971 to 2001,
      1,682 patients underwent radical cystectomy and pelvic lymphadenectomy for
      bladder cancer. Only those tumors that involved adjacent organs through the
      bladder wall (pT4) were included. Overall 132 male patients with a median age of
      68 years (range 36 to 98) qualified for analysis. Patients were stratified into 4
      subgroups of 1) direct extravesical prostatic stromal involvement only in 37
      patients (28%), 2) prostatic stroma and seminal vesicle involvement in 37
      patients (28%), 3) seminal vesicle involvement only in 10 patients (8%) and 4)
      other contiguous pelvic organ involvement (stage pT4b) in 48 patients (36%).
      Overall 88 patients (67%) received some form of adjuvant therapy. At a median
      followup of 12.5 years (range 0 to 15.2) clinical outcomes were analyzed
      including overall and recurrence-free survival using Kaplan-Meier plots. RESULTS:
      There was no significant difference in clinical outcomes or prognosis for groups
      2 and 3, thus they were combined for analysis. Five-year overall survival for any
      seminal vesicle involvement (10%) was significantly worse than prostatic stromal
      involvement only (38%) but was similar to pT4b tumors (7%, p <0.0001). The 5-year
      recurrence-free survival for seminal vesicle involvement (14%) was also
      significantly worse than prostatic stromal involvement alone (68%) but similar to
      that pT4b disease (25%, p = 0.01). Results were controlled for lymph node status.
      CONCLUSIONS: Patients with extravesical tumor extension into seminal vesicles and
      contiguous pelvic organs are at high risk for recurrence and progression.
      Involvement of the seminal vesicles by direct extension of bladder TCC portends a
      prognosis similar to that of pT4b disease and should, therefore, be classified as
      such.

PMID- 15201743
TI  - Nodal involvement in bladder cancer cases treated with radical cystectomy:
      incidence and prognosis.
AB  - PURPOSE: We studied the factors that promote the incidence of nodal metastasis
      and characterized survival predictions in cases treated with radical cystectomy.
      MATERIALS AND METHODS: We retrospectively studied 418 bladder cancer cases
      treated with radical cystectomy and bilateral endopelvic lymphadenectomy. The
      incidence of nodal involvement was correlated with several patient and tumor
      characteristics. The number of involved nodes was also correlated with the number
      of retrieved nodes. Finally, survival in node positive cases was correlated with
      some select pathological features. RESULTS: Of the 418 cases nodal involvement
      was reported in 110 (26.3%). The mean number of harvested nodes per patient +/-
      SE was 17.9 +/- 6.7. The mean number of positive nodes per involved case was 4.1
      +/- 5.4. A weak correlation between the number of retrieved nodes and number of
      positive nodes was noted (r = 0.4). Tumor pT stage and grade, and lymphovascular
      invasion were independent factors promoting the incidence of nodal involvement.
      Three-year disease-free survival in node positive cases was 37.8% +/- 4.8%. Two
      factors had an independent impact on survival in node positive cases, namely pT
      stage and the number of positive nodes. CONCLUSIONS: Tumor pT stage and grade,
      and lymphovascular invasion independently influence the incidence of lymph node
      involvement. There was a weak correlation between the number of retrieved nodes
      and number of positive nodes. The survival probability in pT N+ cases depended on
      pT stage and the number of involved nodes. A prospective study with anatomical
      mapping of retrieved nodes is necessary to define the optimal extent of
      lymphadenectomy with cystectomy.

PMID- 15201744
TI  - Relationship between initial prostate specific antigen level and subsequent
      prostate cancer detection in a longitudinal screening study.
AB  - PURPOSE: Previous studies of archived blood samples from nonscreened populations
      have shown an association between the prostate specific antigen (PSA) and the
      subsequent detection of prostate cancer. In the current study we evaluated the
      relationship between the initial screening PSA and the subsequent risk of
      prostate cancer detected in a prospective, longitudinal screening study. We also
      examined the relationship between initial PSA and the clinicopathological
      features of the cancers detected. MATERIALS AND METHODS: Between May 1991 and
      November 2001 we enrolled 26,111 volunteers in our PSA and digital rectal
      examination based prostate cancer screening study. The men were followed
      biannually or annually depending on the results of previous screening tests. The
      chi-square and Kruskal-Wallis tests were used to compare the clinical stage,
      pathological stage and Gleason score of subsequently detected prostate cancers as
      well as the time to cancer detection in different initial screening PSA strata.
      RESULTS: The initial screening PSA stratum was strongly associated with the
      subsequent detection of prostate cancer as well as the clinicopathological stage
      and grade of the cancers detected. CONCLUSIONS: Even in the lower PSA ranges
      initial screening serum PSA can help identify men at increased risk for
      subsequent prostate cancer detected in a longitudinal screening study.

PMID- 15201745
TI  - Prostate cancer detection with office based saturation biopsy in a repeat biopsy
      population.
AB  - PURPOSE: Patients at increased risk for prostate cancer with previously negative
      biopsies pose a diagnostic challenge. We have previously demonstrated that
      extensive saturation biopsy can be performed in an office setting. We now report
      the diagnostic yield of office saturation biopsy in patients at increased risk
      for prostate cancer and at least 1 negative prior biopsy. MATERIALS AND METHODS:
      We performed saturation prostate biopsy with local anesthesia in the office in
      116 patients with at least 1 prior negative biopsy and with certain risk factors,
      namely persistently elevated prostate specific antigen, abnormal digital rectal
      examination, or prior atypia or PIN on prior biopsy. RESULTS: A total of 34
      cancers were detected for an overall diagnostic yield of 29%. A 64% detection
      rate was noted when a patient had undergone a single prior sextant biopsy.
      Subgroup analysis revealed a cancer detection rate of 41% when only prior sextant
      biopsies were performed, and a 24% detection rate when 10 or more cores were
      taken on prior biopsy. The detection rate was 33% when only 1 prior biopsy was
      taken and it was 24% when 2 or more prior biopsies were performed. CONCLUSIONS:
      Saturation biopsy can be performed safely and effectively in the office with a
      significant diagnostic yield even in patients with previous extended biopsy
      schemes. We believe that it should be the next diagnostic step after an initial
      negative biopsy in patients in whom the diagnosis of prostate cancer is strongly
      suspected.

PMID- 15201746
TI  - Limitations of biopsy Gleason grade: implications for counseling patients with
      biopsy Gleason score 6 prostate cancer.
AB  - PURPOSE: We examined the implications of underestimating Gleason score by
      prostate biopsy in patients with biopsy Gleason 6 prostate cancer with respect to
      adverse pathological findings and biochemical recurrence after radical
      prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed clinical and
      pathological data on a cohort of 531 patients with Gleason score 6 on prostate
      biopsy who underwent radical retropubic prostatectomy between June 1992 and
      January 2002. Patients were excluded if they received neoadjuvant androgen
      deprivation. Concordance between biopsy and radical prostatectomy Gleason score
      was examined. A comparison was made with respect to final radical prostatectomy
      specimen pathology and the risk of biochemical recurrence between cases that
      remained Gleason 6 and those with a final grade of 7 or greater. RESULTS: A total
      of 451 patients were included in the analysis. Mean followup was 55.1 months
      (range 12 to 123.4). Of the patients 184 (41%) had a Gleason score of 7 or
      greater after a review of the entire prostate, while 37 (8%) had a score of less
      than 6 and 230 remained with Gleason 6. Patients who were under graded were more
      likely to have extraprostatic extension (22% vs 4%, p <0.01), seminal vesicle
      invasion (9% vs 2%, p <0.01) and biochemical recurrence (10% vs 3%, p <0.01)
      compared to those who remained with Gleason score 6. CONCLUSIONS: Gleason grade
      on needle biopsy is an inexact predictor of the final grade following radical
      prostatectomy. Patients with biopsy Gleason score 6 who are under graded are at
      significantly higher risk for adverse pathological features and biochemical
      recurrence than patients who remain with Gleason score 6 or less on final
      pathology findings.

PMID- 15201747
TI  - Lymph and blood vessel architecture in benign and malignant prostatic tissue:
      lack of lymphangiogenesis in prostate carcinoma assessed with novel lymphatic
      marker lymphatic vessel endothelial hyaluronan receptor (LYVE-1).
AB  - PURPOSE: Due to the lack of specific markers the analysis of lymphatic vessel
      density (LVD) has been almost impossible in the past. We report the novel
      specific marker for lymphatic endothelium, lymphatic vessel endothelial
      hyaluronan receptor (LYVE-1), in prostatic, benign prostatic hyperplasia (BPH)
      and prostate cancer (PCa) tissue. Normal blood vessels were additionally
      quantified in BPH and PCa. MATERIALS AND METHODS: LYVE-1 lymphatics (LVD) and
      CD34 blood vessels were assessed in 20 paraffin sections of BPH and 50 of PCa
      tissue by immunohistochemistry in a standardized experimental setting. The
      regions of PCa, periphery of the tumor and nontumorous regions of the PCa
      specimens, and BPH tissue were evaluated. Double staining was done (LYVE-1/CD34).
      Acquired data were interrelated and compared to the pathological parameters of
      the specimens. RESULTS: Double staining revealed numerous CD34 blood vessels but
      only a few LYVE-1 lymphatic vessels in BPH and PCa sections. Mean LVD +/- SD was
      distinctly lower (0.55 +/- 0.93) in PCa tissue than in tumor periphery (2.45 +/-
      1.93) and nontumorous (3.16 +/- 2.23) tissue (p <0.0001). Maximum LVD was
      observed in BPH (7.17 +/- 3.61), which differed markedly from nontumorous areas
      of PCa specimens (p <0.001). In contrast to LVD, significantly more blood vessels
      were found in PCa (116.00 +/- 39.25) than in BPH (60.30 +/- 19.34) tissue (p
      <0.001). CONCLUSIONS: LYVE-1 is a specific lymphatic endothelial marker in benign
      and malignant prostate tissues. It is a useful new marker for the investigation
      of lymphatics. To our knowledge we report the immunohistochemical visualization
      and quantification of lymphatic vessels in prostatic tissue for the first time.
      In contrast to the stimulated angiogenesis of blood vessels in PCa, the
      destruction of lymphatic vessels occurs rather than lymphangiogenesis.

PMID- 15201748
TI  - Post-brachytherapy transurethral resection of the prostate in patients with
      localized prostate cancer.
AB  - PURPOSE: We assessed the rate and results of transurethral resection of the
      prostate (TURP) in patients previously treated with brachytherapy as monotherapy
      for localized prostate cancer. MATERIALS AND METHODS: From May 1998 to May 2003,
      600 patients with localized prostate cancer were treated with brachytherapy at
      our institution. Brachytherapy was performed as monotherapy with curative intent
      for clinically localized prostate cancer without adjuvant treatment in patients
      with clinical stages T1c (68.4%) or T2a (31.6%) disease. -Iodine and palladium
      implants were used in 583 and 7 patients, respectively. A real-time interactive
      implantation technique was used in all but the first 17 patients, who were
      treated using a preplanned technique. RESULTS: Of the 600 patients 19 (3.1%)
      underwent TURP after brachytherapy. Among the patients with acute urinary
      retention the median interval between prostate brachytherapy and urinary
      retention was 2 months (range 0.5 to 32). No TURP was done within 6 months after
      implant. The median interval between prostate brachytherapy and TURP was 7 months
      (range 6 to 41) and median prostate specific antigen (PSA) before TURP was 0.5
      ng/ml (range 0.04 to 3.4). In the 19 patients the median weight of resected
      prostatic tissue was 8 gm (range 2 to 19) and 1 to 11 seeds were removed (median
      5). The perioperative and postoperative courses were uneventful. There was no
      TURP related incontinence. With a median followup of 28 months after
      brachytherapy (range 7 to 48) no patient had clinical or biochemical evidence of
      disease progression, and for the group of 19 patients who underwent TURP median
      serum PSA at the end of followup was 0.38 ng/ml (range 0.03 to 3.4). CONCLUSIONS:
      After brachytherapy as monotherapy, TURP can be done safely if indicated. In our
      experience the resection of prostatic tissue along with a limited number of seeds
      at least 6 months after implantation did not impair PSA based biological and
      clinical results of brachy-therapy.

PMID- 15201749
TI  - Real-time transrectal ultrasonography during laparoscopic radical prostatectomy.
AB  - PURPOSE: We describe the technical aspects of real-time transrectal ultrasound
      (TRUS) monitoring and guidance during laparoscopic radical prostatectomy (LRP).
      Furthermore, we describe the TRUS visualized anatomy of periprostatic structures
      during LRP. MATERIALS AND METHODS: In 25 consecutive patients undergoing
      transperitoneal LRP, baseline preoperative, real-time intraoperative and
      immediate postoperative TRUS evaluations were performed. To define periprostatic
      anatomy precisely TRUS measurements were obtained with specific reference to the
      neurovascular bundle (NVB), prostate apex, membranous urethra, bladder neck,
      rectal wall and any cancer nodule. Conventional gray scale, power Doppler,
      harmonic imaging and 3-dimensional ultrasound functions were used. RESULTS: Real
      time TRUS navigation facilitated 3 technical aspects of LRP. 1) It identified the
      correct plane between the posterior bladder neck and prostate base, allowing
      quick laparoscopic identification of the vasa and seminal vesicles. 2) It
      identified the occasional, difficult to see distal protrusion of the prostate
      apex posterior to the membranous urethra, thus enhancing apical dissection with
      negative margins. 3) It provided visualization of any hypoechoic nodule abutting
      the prostate capsule, alerting the laparoscopic surgeon to perform wide
      dissection at that location. TRUS measured various anatomical parameters
      including i) the mean distance +/-SD between the NVB and the lateral edge of the
      prostate a) at apex (1.9 +/- 0.9 mm), b) base (2.5 +/- 0.8 mm) and c) tip of
      seminal vesicle (4.0 +/- 1.6 mm), ii) the dimensions of the NVB a) before (4.5 x
      3.9 mm), b) after (4.2 x 3.6 mm) nerve sparing LRP and c) after nonnerve sparing
      LRP (0.9 x 0.9 mm), iii) arterial blood flow resistive index within NVB a) before
      (0.83 +/- 0.04), b) after (0.84 +/- 0.03) nerve sparing LRP and c) after nonnerve
      sparing LRP (0), iv) and the length of membranous urethra a) before (12.2 +/- 1.1
      mm) and b) after (11.7 +/- 1.0 mm) surgery. Focal distortion of the prostate
      surface by an exophytic nodule was visualized on TRUS in 3 patients,
      necessitating ipsilateral nerve resection at LRP and contributing to negative
      surgical margins. CONCLUSIONS: This initial experience suggests that real-time
      intraoperative TRUS guidance may enhance anatomical performance of LRP. This
      improved understanding of periprostatic anatomy has the potential to improve
      functional and oncological outcomes. Such corroboration is awaited.

PMID- 15201750
TI  - Adverse prognostic significance of capsular incision with radical retropubic
      prostatectomy.
AB  - PURPOSE: The prognostic significance of capsular incision (CPI) at radical
      retropubic prostatectomy remains to be defined. To evaluate this we compared
      prostate specific antigen recurrence for with CPI to that with established
      pathological groups. MATERIALS AND METHODS: From January 1998 to December 2000,
      409 men underwent radical retropubic prostatectomy at our medical center. CPI was
      defined as a positive posterior, lateral or posterolateral surgical margin
      without documented extraprostatic extension (EPE). Excluding patients with
      preoperative androgen ablation, positive lymph nodes or seminal vesicle
      involvement there were 129 with organ confined disease and negative surgical
      margins (pT2/-M), 18 with CPI, 29 with EPE and negative surgical margins (pT3a/
      M), and 24 with EPE and positive surgical margins (pT3a/+M). We compared time to
      biochemical recurrence among these 4 groups using Kaplan-Meier estimates. Cox
      proportional hazard regression was performed to determine the HR of CPI vs the
      other groups, while controlling for age, prostate specific antigen, tumor volume
      and Gleason score. RESULTS: The 3-year likelihood of freedom from biochemical
      recurrence in the CPI group was 65%, for pT2/-M it was 96%, for pT3a/-M it was
      91% and for pT3a/+M it was 58%. The adjusted HR with the 95% CI showed that the
      risk of biochemical recurrence with CPI was 8.4 times higher than that with pT2/
      M (p = 0.002), 5.9 times higher than that with pT3a/-M (p = 0.046) and the same
      as that with pT3a/+M (p = 0.840). CONCLUSIONS: Isolated posterior, lateral and
      posterolateral CPI by our definition occurs not uncommonly and it may represent
      true incision of the capsule and/or difficulty in diagnosing EPE due to a lack of
      extraprostatic tissue in the surgical specimen. However, the prognostic
      significance of CPI as defined appears similar to that of pT3a with positive
      margins.

PMID- 15201751
TI  - Specific complications of radical perineal prostatectomy: a single institution
      study of more than 600 cases.
AB  - PURPOSE: Although groups at several institutions have long experience with
      radical perineal prostatectomy (RPP), only few reports of larger series describe
      associated complications, mostly without reporting management options in detail.
      We analyzed specific perioperative and postoperative complications of the
      perineal approach and management strategies thereof. MATERIALS AND METHODS: The
      medical records of 630 patients who underwent RPP between January 1997 and May
      2003 were retrospectively reviewed in regard to complications and their
      management. Median followup was 8 months (range 1 to 68). RESULTS: Major
      complications requiring open surgical intervention were noted in 11 patients
      (1.7%) for a total surgical revision rate of 2.4% (15 of 630). Two patients with
      persistent urinary fistula required fistula excision and closure. Two patients
      with a rectocutaneous fistula needed temporary diverting colostomy. Three
      patients with a combined urinary and fecal fistula were treated with protective
      colostomy, fistula excision and the interposition of a tunica vaginalis graft. No
      further morbidity was observed in these patients. In 7 patients a subvesical
      hematoma was drained surgically, including 3 mentioned in whom a hematoma
      expanded into the urethral anastomosis. Minor complications, which could be
      successfully managed conservatively or with endoscopic interventions only,
      developed in 124 patients for a total rate of 19.7%. In the long term 9% of the
      patients experienced postoperative de novo changes in stool habits after RPP but
      only 2.7% reported distressing anal sphincter incompetence. CONCLUSIONS: RPP is a
      safe and reproducible procedure with low major complication and reintervention
      rates even in a training center setting with many involved surgeons. A subvesical
      hematoma should be revised early since it can be the origin of subsequent major
      complications.

PMID- 15201752
TI  - Biochemical failure in men following radical retropubic prostatectomy: impact of
      surgical margin status and location.
AB  - PURPOSE: The significance of isolated positive apical surgical margins in radical
      retropubic prostatectomy (RRP) specimens remains controversial. We examine the
      effects of margin status and location on biochemical recurrence rates in patients
      undergoing RRP. MATERIALS AND METHODS: Of 800 patients with RRP we identified 498
      without pathological evidence of lymph node, seminal vesicle or adjacent organ
      involvement and with at least 6 months of followup. Patients were subdivided into
      apex only positive (AM+), nonapical isolated positive (OM+), multiple positive
      (MM+) and negative (SM-) surgical margins. The rate and interval to biochemical
      disease recurrence were determined in each group. Univariate and multivariate
      analysis as well as Kaplan-Meier curves were used to test differences among these
      groups. RESULTS: Of the 498 men who met our inclusion criteria 400 were SM-, 28
      were AM+, 57 were OM+ and 13 were MM+ at a median followup of 49, 59, 64 and 83
      months, respectively. Biochemical recurrence rates for SM-, AM+, OM+ and MM+ were
      9.3%, 21.4%, 26.3% and 30.8%, respectively. Median time to biochemical failure in
      the SM-, AM+, OM+ and MM+ groups was 34, 19.5, 46.0 and 6.8 months, respectively.
      Biochemical recurrence was not statistically different among the AM+, OM+ and MM+
      groups. On univariate analysis AM+, OM+ and MM+ were significant predictors of
      recurrence (p < 0.05, < 0.005, and <0.05, respectively). On multivariate models
      only pretreatment prostate specific antigen and OM+ were independent predictors
      of biochemical recurrence. CONCLUSIONS: A positive surgical margin conveys
      increased risk for biochemical recurrence. Patients with AM+ experienced
      biochemical recurrence more frequently and rapidly than those with SM-. AM+
      conveys a similar risk of recurrence compared with OM+ and MM+. Apical margin
      status did not independently predict biochemical recurrence.

PMID- 15201753
TI  - The role of 111indium-capromab pendetide imaging for assessing biochemical
      failure after radical prostatectomy.
AB  - PURPOSE: Conventional imaging modalities, such as computerized tomography and
      magnetic resonance imaging, lack sensitivity and specificity for detecting
      recurrent prostate cancer after radical surgery. We evaluated the role of the
      indium-capromab pendetide scan, otherwise known as the ProstaScint (Cytogen
      Corp., Princeton, New Jersey) scan, in this setting. MATERIALS AND METHODS: A
      retrospective review was performed of 42 patients undergoing ProstaScint imaging
      for biochemical progression after radical prostatectomy. Of these patients 16
      (38.1%) subsequently completed a course of salvage radiation therapy. RESULTS:
      Median prostate specific antigen (PSA) immediately prior to ProstaScint imaging
      was 1.2 ng/ml (range 0.2 to 4.8). Abnormal accumulation on the ProstaScint scan
      was detected in 36 patients (85.7%). Of the 16 patients undergoing salvage
      radiation therapy 15 had uptake isolated to the prostatic fossa on ProstaScint
      imaging. Ten of these 15 patients (66.7%) achieved undetectable PSA after
      radiation therapy, while 5 (33.3%) had little or no response. Using American
      Society for Therapeutic Radiology and Oncology criteria 3 of 10 responders had
      relapse after an average of 9 months. The remaining 7 patients remained
      biochemically free of disease at last followup. CONCLUSIONS: ProstaScint imaging
      is capable of detecting recurrent prostate cancer at low PSA levels. However,
      only 7 of 15 men (46.7%) with ProstaScint uptake isolated to the prostatic fossa
      showed a durable response to salvage radiation therapy. Based on these findings
      patients might be better treated based on the rate of increase in PSA rather than
      on routine scanning with this test.

PMID- 15201754
TI  - Percent carcinoma in prostatectomy specimen is associated with risk of recurrence
      after radical prostatectomy in patients with pathologically organ confined
      prostate cancer.
AB  - PURPOSE: We evaluated tumor size, measured as the percent of the prostate
      involved by cancer, as a predictor of tumor recurrence after radical
      prostatectomy in patients with pathologically organ confined prostate cancer.
      MATERIALS AND METHODS: One of us (WJC) performed radical retropubic prostatectomy
      in 1,850 men who had pathologically organ confined prostate cancer with tumor
      size recorded between January 1988 and February 2003. The percent of prostate
      tissue involved by carcinoma in the radical prostatectomy specimen was estimated
      by visual inspection. We compared clinicopathological characteristics in patients
      who did and did not have tumor recurrence and stratified them by percent of tumor
      in the prostatectomy specimen. We also evaluated the relationship between percent
      of cancer and biochemical evidence of cancer recurrence. RESULTS: Patients who
      had recurrence were slightly older (mean age 62 vs 60 years, p = 0.004), and had
      higher mean preoperative prostate specific antigen (8.6 vs 6.3 ng/ml, p <0.0001)
      and a higher proportion of poorly differentiated tumors (Gleason grades 8 to 10)
      (7% vs 1%, p = 0.001). The mean percent of cancer was higher in men with
      recurrence (11% vs 7%, p <0.0001). Men with 10% or greater of the gland involved
      by cancer had a 10% recurrence rate compared with a 5% rate in men in whom cancer
      involved less than 10% of the gland (p = 0.001). The 5-year recurrence-free
      survival rate was 94%, 91% and 82% in patients with less than 10%, 10% to 20% and
      greater than 20% of the gland involved. The multivariate Cox model indicated that
      the percent of cancer involvement of the prostate provides unique predictive
      information about the risk of cancer recurrence (p = 0.0001). The estimated 5
      year recurrence-free survival rate based on the Cox model indicated that patients
      with greater than 20% of the gland involved by tumor, clinical stage T2/T3 and
      Gleason sum >/=7 were at substantial risk of cancer recurrence. CONCLUSIONS:
      Tumor size measured as the percent of cancer is an independent predictor of
      cancer recurrence after radical prostatectomy in patients with pathologically
      organ confined prostate cancer.

PMID- 15201755
TI  - The natural history of androgen independent prostate cancer.
AB  - PURPOSE: We describe the natural history of androgen independent prostate cancer
      (AIPC) in the modern prostate specific antigen (PSA) era. MATERIALS AND METHODS:
      Data from 160 patients diagnosed with AIPC between 1989 and 2002 were reviewed.
      No patient had received cytotoxic chemotherapy. Univariate and multivariate
      proportional hazards models were constructed to identify significant risk factors
      for cancer specific survival. Recursive partitioning analysis stratified patients
      into prognostic risk groupings. The types and frequencies of cancer specific
      complications per risk grouping were compared. RESULTS: The final prognostic risk
      model included nadir PSA on androgen deprivation therapy (p = 0.023), time to PSA
      recurrence (p = 0.006) and prostate specific antigen doubling time (p <0.01).
      Three highly independent risk groupings were identified. The observed median
      cancer specific survivals were 14.0 months (95% CI, 8.3-19.8), 38.4 months (95%
      CI, 26.9-49.9) and 89.1 months (95% CI, 69.0-109.2) for low, intermediate and
      high risk groupings, respectively (p <0.001). Patients in the low risk grouping
      experienced significantly fewer cancer specific complications (p = 0.003).
      CONCLUSIONS: This prognostic model stratified patients into 3 highly significant
      and independent risk groupings. A detailed PSA history alone is sufficient to
      risk stratify patients with AIPC.

PMID- 15201756
TI  - Mucinous cystadenoma of the testis.

PMID- 15201757
TI  - Renal and perirenal abscesses in patients with otherwise anatomically normal
      urinary tracts.
AB  - PURPOSE: We characterized evaluation, management and outcomes in a group of
      patients diagnosed with renal and perirenal abscesses who had otherwise
      anatomically normal urinary tracts. MATERIALS AND METHODS: We reviewed our
      experience with renal/perirenal abscesses at University of Texas Medical Branch
      from 1991 to 2002. Treatment was determined by physician preference in each
      individual. RESULTS: Of 70 patients with renal/perirenal abscesses 26 had
      otherwise anatomically normal urinary tracts, 24 (92%) had at least 1 possible
      contributory factor, such as diabetes mellitus, and only 38% had the correct
      diagnosis at initial presentation. The abscess was intranephric in 39% of cases,
      intranephric and perinephric in 19%, and perinephric only in 42%. Of the 26
      patients 18 were treated with percutaneous drainage or aspiration of the abscess
      and 12 (66.7%) had positive cultures. Eight of the 12 patients (67%) with
      positive abscess cultures had the same organism in urine and/or blood. All 26
      patients were treated with broad-spectrum intravenous antibiotics. In most
      patients abscess size influenced additional treatments, such as percutaneous
      needle aspiration or catheter drainage. None of the patients required open
      surgical drainage, nephrectomy or nephrostomy tube placement. At a mean followup
      of 10 months all patients had complete radiographic resolution of the abscess
      without further complications except 1 who had pyelonephritis and another who was
      found to have a poorly perfused kidney. CONCLUSIONS: With accurate diagnosis and
      minimally invasive therapy patients with renal and/or perirenal abscesses and
      otherwise anatomically normal urinary tracts have excellent functional and
      anatomical outcomes.

PMID- 15201758
TI  - Group B streptococcal septicemia following intracavernous injection therapy for
      erectile dysfunction in diabetes.

PMID- 15201759
TI  - Penile prosthesis cultures during revision surgery: a multicenter study.
AB  - PURPOSE: Initial implantation of inflatable penile prosthesis has a 3% risk of
      infection. Reoperation of penile implants has a higher rate of infection,
      estimated between 10% and 18%. To explain the higher risk in revision surgery in
      this prospective study we cultured clinically uninfected prostheses requiring
      revision. Prosthesis pain was also investigated as a predictor of positive
      culture. MATERIALS AND METHODS: At 3 institutions cultures were prospectively
      obtained from 77 clinically uninfected penile prostheses at revision surgery.
      Immediately upon surgical exposure of the pump cultures were obtained. If a
      bacterial biofilm was noted on any component it was additionally cultured. All
      culture isolates positive for a staphylococcus species were tested for
      sensitivity to rifampin and tetracycline (minocycline). An implant is now
      available that is coated with these antibiotics. Patient history of chronic
      prosthesis pain was ascertained. RESULTS: Culture positive bacteria were found in
      54 of 77 (70%) patients with clinically uninfected penile prostheses. In some
      patients more than 1 organism grew and, occasionally, the pump culture was
      negative but the biofilm was positive. Of 54 patients 49 had positive (90%)
      culture for staphylococcus genus with 10 different species. All staphylococcal
      species were sensitive to rifampin and/or tetracycline. We did not find a
      significant association between prosthesis related pain and culture laboratory
      results. CONCLUSIONS: The majority of clinically uninfected penile prostheses
      have organisms growing in the implant spaces at reoperation. Most of these
      organisms are staphylococcal species that are sensitive to rifampin/minocycline.

PMID- 15201760
TI  - Manual lymphatic drainage for the treatment of acute genital lymphedema.

PMID- 15201761
TI  - Metabolic risk factors and the impact of medical therapy on the management of
      nephrolithiasis in obese patients.
AB  - PURPOSE: Previous studies have demonstrated that obesity can increase the risk of
      stone formation as well as recurrence rates of stone disease. Yet appropriate
      medical management can significantly decrease the risk of recurrent stone
      disease. Therefore, we analyzed our obese patient population, assessing the risk
      factors for stone formation and the impact of selective medical therapy on
      recurrent stone formation. MATERIALS AND METHODS: A retrospective chart review
      was performed to identify obese patients with stone disease from our Stone
      Center. Metabolic risk factors for stones were identified as well as patient
      response to medical therapy. A similar analysis was performed on a group of age
      and sex matched nonobese stone formers. RESULTS: Of 1,021 patients 140 (14%) were
      identified as obese (body mass index greater than 30). Of these patients complete
      metabolic evaluations were available in 83 with an average followup of 2.3 years.
      The most common presenting metabolic abnormalities among these obese patients
      included gouty diathesis (54%), hypocitraturia (54%) and hyperuricosuria (43%),
      which presented at levels that were significantly higher than those of the
      nonobese stone formers (p <0.05). Stone analysis was available in 32 obese
      patients with 63% having uric acid calculi. After initiating treatment with
      selective medical therapy obese and nonobese patients demonstrated normalization
      of metabolic abnormalities, resulting in an average decrease in new stone
      formation from 1.75 to 0.15 new stones formed per patient per year in both
      groups. CONCLUSIONS: Obesity, as a result of dietary indiscretion, probable
      purine gluttony and possible type II diabetes, appears to have a significant role
      in recurrent stone formation. Appropriate metabolic evaluation, institution of
      medical therapy and dietary recommendations to decrease animal protein intake can
      significantly improve the risk of recurrent stone formation in these often
      difficult to treat patients.

PMID- 15201762
TI  - Multiple calcium phosphate stones occupying a caliceal diverticulum.

PMID- 15201763
TI  - Fibrin sealant enables tubeless percutaneous stone surgery.
AB  - PURPOSE: Fibrin sealant has been demonstrated to be safe and effective as a
      hemostatic agent and urinary tract sealant. We assessed the ability of fibrin
      sealant to facilitate tubeless management after uncomplicated percutaneous
      nephrolithotomy (PCNL). MATERIALS AND METHODS: Eight consecutive patients
      underwent single access tubeless PCNL for renal calculi in a total of 9 renal
      units in a 2-month period. An additional patient with distal ureteral obstruction
      underwent antegrade ureteroscopy for an 8 x 8 mm distal ureteral stone. Average
      patient age was 47 years and mean stone size was 3.37 cm (range 0.64 to 9.90).
      Following complete stone clearance a Double-J (Medical Engineering Corp., New
      York, New York) ureteral stent was placed antegrade and 2 cc HEMASEEL APR
      (Haemacure Corp., Sarasota, Florida) fibrin sealant was injected under
      nephroscopic or fluoroscopic visualization into the parenchymal defect just
      within the renal capsule. Preoperative and postoperative hematocrit (HCT) was
      determined. Computerized tomography was performed on postoperative day 1 or 2 to
      evaluate retained stone fragments, perinephric fluid and urinary extravasation.
      RESULTS: In the 10 renal units treated via this tubeless technique no
      intraoperative or postoperative complications were noted. Average hospital stay
      was 1.1 days. All patients were discharged home on postoperative day 1 except 1
      undergoing asynchronous bilateral PCNL on consecutive days. The mean
      intraoperative change in HCT was 2.8%. There was no significant change in HCT on
      postoperative day 1. No patient required transfusion. Seven renal units and 1
      ureteral unit had no residual stone fragments for a complete stone-free rate of
      80%. No gross leakage was observed on dressings and postoperative computerized
      tomography failed to demonstrate urinary extravasation. CONCLUSIONS: Tubeless
      PCNL using fibrin sealant at the renal parenchymal defect appears to be safe and
      feasible. Further experience is necessary to determine the role of fibrin sealant
      in percutaneous renal surgery.

PMID- 15201764
TI  - Combined electrohydraulic and holmium:yag laser ureteroscopic nephrolithotripsy
      for 20 to 40 mm renal calculi.
AB  - PURPOSE: Percutaneous nephrolithotripsy is standard treatment for renal calculi
      greater than 2 cm. Modern flexible ureteroscopes using the complementary effects
      of electrohydraulic (EHL) and Ho:YAG laser lithotrites can treat 2 to 4 cm renal
      calculi in minimally invasive fashion with similar or superior results. We
      evaluated the safety and efficacy of ureteroscopic nephrolithotripsy for the
      management of 2 to 4 cm renal calculi in a community setting. MATERIALS AND
      METHODS: Between January 2001 and November 2002 all 15 patients presenting with
      renal calculi 22 to 42 mm long (mean 33) and 275 to 650 mm in area (mean 396), of
      whom 40% had infection, underwent flexible ureteroscopic nephrolithotripsy. A
      total of 13 patients had 3-month followup data. Hard stone components, namely
      calcium oxalate monohydrate and/or apatite, were present in 13 cases (87%).
      Treatment principles were the aggressive treatment of infection, EHL stone
      debulking, Ho:YAG laser lithotripsy to weaken hard stones structurally, manual
      piston irrigation to maintain visibility, bladder drainage to maintain low
      intrarenal pressures, minimum 6-hour postoperative observation and physiological
      passage of stone fragments. RESULTS: In the 13 patients with 3-month followup
      data the stone clearance rate was 92% for complete stone free status and 100% for
      fragments less than 4 mm. This result was achieved at 1 stage in 10 cases 13
      (77%) and at 2 to 4 stages in 1 each. Mean procedure time per stage was 47
      minutes (range 25 to 90) and total procedure time per patient was 66 minutes
      (range 25 to 240). There was no significant change in mean preoperative and
      postoperative hemoglobin (p = 0.87) and creatinine (p = 0.85) in the 16 of 21
      procedures for which data were available. Procedures were done on an outpatient
      basis except in 1 patient, who was hospitalized overnight for the management of
      preexisting pulmonary problems. One rehospitalization for colic management but no
      other unplanned emergency department or clinic visits occurred. All patients were
      rendered infection-free and symptom-free. CONCLUSIONS: Combined EHL and Ho:YAG
      laser flexible ureteroscopic lithotripsy can be an effective treatment with low
      morbidity. As such, it provides an attractive, minimally invasive alternative to
      percutaneous nephrolithotripsy or open surgery in patients with 2 to 4 cm renal
      calculi.

PMID- 15201765
TI  - Can we improve the prediction of stone-free status after extracorporeal shock
      wave lithotripsy for ureteral stones? A neural network or a statistical model?
AB  - PURPOSE: We evaluated whether an artificial neural network (ANN) can improve the
      prediction of stone-free status after extracorporeal shock wave lithotripsy
      (ESWL) (Dornier Medical Systems, Inc., Marietta, Georgia) for ureteral stones
      compared to a logistic regression (LR) model. MATERIALS AND METHODS: Between
      February 1989 and December 1998, 984 patients with ureteral stones, including 780
      males and 204 females with a mean age +/- SD of 40.85 +/- 10.33 years, were
      treated with ESWL. Stone-free status at 3 months was determined by urinary tract
      plain x-ray and excretory urography. Of all patients 919 (93.3%) were free of
      stones. The impact of 10 factors on stone-free status was studied using an LR
      model and ANN. These factors were patient age and sex, renal anatomy, stone
      location, side, number, length and width, whether stones were de novo or
      recurrent, and stent use. An LR model was constructed and ANN was trained on 688
      randomly selected patients (70%) to predict stone-free status at 3 months. The 10
      factors were used as covariates in the LR model and as input parameters to ANN.
      Performance of the trained net and developed logistic model was evaluated in the
      remaining 296 patients (30%), who served as the test set. The sensitivity
      (percent of correctly predicted stone-free cases), specificity (percent of
      correctly predicted nonstonefree cases), positive predictive value, overall
      accuracy and average classification rate of the 2 techniques were compared.
      Relevant variables influencing the construction of the 2 models were compared.
      RESULTS: Evaluating the performance of the LR and ANN models on the test set
      revealed a sensitivity of 100% and 77.9%, a specificity of 0.0% and 75%, a
      positive predictive value of 93.2% and 97.2%, an overall accuracy of 93.2% and
      77.7%, and an average classification rate of 50% and 76.5%, respectively. LR
      failed to predict any nonstone free cases. LR and ANN identified stone location
      and stent use as important factors in determining the outcome, while ANN also
      identified stone length and width as influential factors. CONCLUSIONS: ANN and LR
      could predict adequately those who would be stone-free after ESWL for ureteral
      stones. The neural network has a higher ability to predict those who fail to
      respond to ESWL.

PMID- 15201766
TI  - Management of secondary ureteropelvic junction obstruction after failed primary
      laparoscopic pyeloplasty.
AB  - PURPOSE: Laparoscopic pyeloplasty has been established as a minimally invasive
      alternative to open pyeloplasty. However, little is known about the treatment of
      patients in whom this technique fails. We present our experience with treating
      ureteropelvic junction obstruction after failed primary laparoscopic pyeloplasty.
      MATERIALS AND METHODS: From August 1993 to September of 2003, 227 patients
      underwent laparoscopic pyeloplasty for primary ureteropelvic junction
      obstruction. Of these patients 10 (4.4%), including 6 females and 4 males 24 to
      62 years old (mean age 42.1), underwent secondary treatment after laparoscopic
      pyeloplasty failed. The type of secondary intervention varied by anatomical
      factors, and patient and surgeon preference. Success was defined as symptomatic
      relief and improved radiographic imaging at latest followup. RESULTS: Secondary
      interventions were repeat laparoscopic pyeloplasty in 1 patient, retrograde
      endoscopic balloon dilation in 2 and endopyelotomy in 7 (laser, cold knife and
      cutting balloon endopyelotomy in 3, 2, and 2, respectively). No postoperative
      complications were seen. Patients were followed for a mean of 25.5 months (range
      3 to 96) after the second procedure. Seven of 10 secondary interventions (70%)
      were successful with no obstruction on followup imaging. Three of 10
      interventions (30%) failed, namely 1 laparoscopic pyeloplasty, 1 endoscopic
      balloon dilation and 1 laser endopyelotomy. Failure of the second procedure
      occurred at a mean of 9.3 months. CONCLUSIONS: When given the choice, most
      patients select endoscopic management after failed primary laparoscopic
      pyeloplasty due to its minimally invasive nature and low complication rate.
      Success rates are 70% with repeat intervention. Some patients require a third
      intervention.

PMID- 15201767
TI  - Vena caval transection during retroperitoneoscopic nephrectomy: report of the
      complication and review of the literature.
AB  - PURPOSE: Major vascular injuries are uncommon but serious complications of
      laparoscopic surgery. Early recognition and conversion to an open procedure may
      be required to avoid further complications. We report 2 cases in which the vena
      cava was transected during retroperitoneoscopic nephrectomy, and review the
      literature. MATERIALS AND METHODS: All urological laparoscopic cases from 1993 to
      2002 at 2 institutions were reviewed to identify major vessel transection. Two
      cases of inadvertent transection of the vena cava were identified. Medical
      records were reviewed for clinical and pathological information to identify
      factors leading to this complication. A MEDLINE search was performed to identify
      similar reports in the literature. RESULTS: Two patients at 2 institutions were
      identified with vena caval transection during retroperitoneoscopic nephrectomy.
      In both cases the vena cava was misidentified as a renal vein. The injury was
      recognized immediately in both cases and an open repair was performed by vascular
      surgery. Both patients recovered with no sequelae. In both cases a rotated camera
      on an angled laparoscope in addition to the relative lack of retroperitoneal
      landmarks may have contributed to a loss of orientation within the operative
      field. A similar report of an aortic transection was also found in the
      literature. CONCLUSIONS: Disorientation of the operating surgeon within the
      surgical field secondary to rotation of the camera lens and lack of
      retroperitoneal landmarks may contribute to vena caval transection during
      retroperitoneoscopic nephrectomy. This injury has not been found in
      transperitoneal nephrectomy, likely because more intra-abdominal landmarks exist,
      aiding in maintenance of orientation. Prompt intraoperative recognition and
      repair of the transection results in a favorable outcome.

PMID- 15201768
TI  - Trauma as the cause of Peyronie's disease: penile fracture as a model of trauma.
AB  - PURPOSE: This study was performed to determine whether patients with penile
      fracture or a long history of forcefully bending the erect penis (taqaandan), as
      models of acute and chronic penile trauma, had an increased rate of Peyronie's
      disease (PD). MATERIALS AND METHODS: The study included 193 surgical cases of
      penile fracture (average followup 85 months), 150 cases of long history of
      taqaandan, and 50 cases of PD. All 3 groups of patients were interviewed and
      physically examined. RESULTS: Signs of PD were found in only 1 case of long-term
      taqaandan and in no case of penile fracture. None of the 50 cases of PD had a
      history of penile fracture. CONCLUSIONS: Severe, acute trauma of penile fracture
      and moderate, chronic buckling injury of taqaandan are not associated with later
      development of PD. These findings question whether the hypothesis that trauma,
      trauma-induced smoldering inflammatory cascade and aberrant wound healing are the
      main causes of PD. Alternative, plausible, evidence based explanations should be
      sought for the etiology of PD. Any theory on the etiology of PD should provide an
      explanation for total lack of occurrence of PD following the trauma of penile
      fracture.

PMID- 15201769
TI  - Missed bilateral bladder perforation during pubovaginal sling procedure.

PMID- 15201770
TI  - Neuroanatomy of the human female lower urogenital tract.
AB  - PURPOSE: The neuroanatomy of the female lower urogenital tract remains
      controversial. We defined the topographical anatomy and differential
      immunohistochemical characteristics of the dorsal nerve of the clitoris, the
      cavernous nerve and the nerves innervating the female urethral sphincter complex.
      MATERIALS AND METHODS: A total of 16 normal female human pelvic specimens at 14
      to 34 weeks of gestation were studied by immunohistochemical techniques. Serial
      sections were stained with antibodies raised against the neuronal markers S-100
      and neuronal nitric oxide synthase (nNOS), vesicular acetylcholine transporter,
      calcitonin gene-related peptide and substance P. The serial sections were
      computer reconstructed into 3-dimensional images. RESULTS: Under the pubic arch
      at the hilum of the clitoral bodies the branches of the cavernous nerves joined
      the clitoral dorsal nerve to transform its immunoreactivity to nNOS positive. The
      cavernous nerves originated from the vaginal nervous plexus occupying the 2 and
      10 o'clock positions on the anterolateral vagina and they traveled at the 5 and 7
      o'clock positions along the urethra. The urethral sphincter complex was
      innervated by nNOS immunoreactive and nonimmunoreactive nerve fibers arising from
      the vaginal nervous plexus and pudendal nerve, respectively. CONCLUSIONS: The
      dorsal nerve of the clitoris receives nNOS positive branches from the cavernous
      nerve as a possible redundant mechanism for clitoral erectile function. The
      urethral sphincter complex has dual innervation, which pierces into the urethral
      sphincter complex at different locations. The study of the neuroanatomy of the
      female lower urogenital tract is germane to the strategic design of female
      reconstructive surgery.

PMID- 15201771
TI  - Urological injuries during cesarean section: intraoperative diagnosis and
      management.
AB  - PURPOSE: We report a single center experience with emergency urological
      consultations and interventions during cesarean sections, and provide several
      guidelines for the intraoperative diagnosis and management of urological trauma
      in this specific clinical setting. MATERIALS AND METHODS: From 1996 to 2003
      urological consultations were required in 29 of 10,439 abdominal deliveries
      (0.3%). Patient files were reviewed for obstetric, surgical and followup data.
      RESULTS: In 20 patients (69%) cesarean section was done on an emergency basis for
      fetal distress or placental abruption. Of the 29 urological consults 12 (42%)
      were for inadvertent cystotomy and 17 (58%) were for suspected injuries to the
      ureter. Patients with inadvertent cystotomy underwent concomitant assessment of
      ureteral patency by direct insertion of ureteral catheters through the ureteral
      orifice. Ureteral obstruction was identified in 1 case and promptly repaired by
      dissecting the ureter and releasing offending sutures that were angulating the
      ureter and occluding the lumen. Patients with suspected ureteral damage and an
      intact bladder were studied by endoscopic means (14) or direct surgical
      dissection and exposure of the ureter (3). Endoscopic assessment was performed by
      cystoscopic inspection of stained urine flow from the orifices following the
      administration of intravenous dye (indigo carmine) or by retrograde ureteral
      catheterization. One patient was found to have incomplete ureteral transection,
      which was repaired primarily over a self-retaining ureteral stent. CONCLUSIONS:
      Key factors to obtain optimal results in the management of urological injuries
      during cesarean sections are the early recognition and immediate repair of
      damage. Ureteral catheterization via a cystoscope or directly through the
      orifices should be considered the modality of choice to assess ureteral
      intactness. Algorithms for urological assessment in this clinical setting are
      provided.

PMID- 15201772
TI  - Pregnancy in a patient with an Indiana pouch.

PMID- 15201773
TI  - Urethroplasty in patients older than 65 years: indications, results, outcomes and
      suggested treatment modifications.
AB  - PURPOSE: Despite an aging population, the results of urethroplasty in elderly
      patients have not been extensively reported. We performed a multi-institutional
      review of urethroplasty results in 70 elderly males to determine outcomes.
      MATERIALS AND METHODS: We reviewed all urethroplasties performed on males older
      than 64 years with at least 6 months of followup at 4 medical centers. Stricture
      type varied and included anastomotic urethroplasty (44%), penile fasciocutaneous
      onlay flap (31%), Johanson urethroplasty (stage 1, 6%, stages 1 and 2, 4%),
      buccal mucosa grafts (7%), foreskin grafts (6%) and meatoplasty (1%). RESULTS:
      Stricture recurred in 11 (16%) patients, but was managed with a single direct
      visual internal urethrotomy or dilation in 5 of 11 patients, yielding a final
      success rate of 91%. Recurrent strictures were more common after fasciocutaneous
      flaps (7 of 22 cases, 32%) than end-to-end urethroplasty (2 of 31 cases, 6%, p
      <0.05). Compared to patients younger than 65 years there were more treatment
      failures, but this was not statistically significant. Perioperative complications
      were uncommon. Moderate bladder outlet obstructive symptoms developed in 3
      patients due to benign prostatic hyperplasia. Notably 6 patients treated
      previously for post-radiation strictures did well without complications.
      CONCLUSIONS: Older men tolerate urethroplasty and these data indicate that
      therapy should not be withheld solely on the basis of age. The potential for
      impaired flap blood supply in this population is suggested but has not been
      proven. Benign prostatic hyperplasia must be considered in those patients who
      have decreased stream after stricture repair.

PMID- 15201774
TI  - The male sling for stress urinary incontinence: urodynamic and subjective
      assessment.
AB  - PURPOSE: We prospectively examined whether the fixed urethral resistance of the
      perineal male sling for the treatment of stress incontinence causes significant
      bladder outlet obstruction or de novo voiding dysfunction. MATERIALS AND METHODS:
      A total of 22 patients (average age 67 years old) were evaluated before and after
      surgery with videourodynamics, the self-administered UCLA Prostate Cancer Index
      incontinence section and pad score. RESULTS: Mean followup was 25 months (range 6
      to 42). All patients complained of a moderate to severe problem before surgery.
      After surgery 16 (73%) reported a very small problem/no problem, 3 (14%) a
      moderate problem and 3 (14%) reported a big problem. Average pad use +/- SD
      decreased from 4.6 +/- 2.5 to 0.74 +/- 1.0 pads (p <0.01). Median UCLA Prostate
      Cancer Index incontinence score increased from 82 to 313, p <0.001. Mean
      retrograde leak point pressure (RLPP) increased from 30.4 +/- 15.9 to 59.9 +/-
      9.7 cm water. Bladder outlet obstruction did not develop in any patients after
      surgery. Average maximum flow rate did not change significantly (17.7 +/- 6.5 vs
      19.2 +/- 9.7 ml per second, p = 0.6). Nor was there a significant change in
      detrusor pressure at maximum flow rate (40.3 +/- 9.2 vs 45.8 +/- 14.7 cm water, p
      = 0.3). While de novo urgency or urge incontinence did not develop in any
      patients, 2 of 5 patients with a moderate/big leakage problem demonstrated
      postoperative detrusor overactivity on cystometry. Both individuals requiring
      more than 3 pads daily had a postoperative RLPP of less than 50 cm water.
      CONCLUSIONS: Pad use, leak point pressure and urinary incontinence scores are
      significantly improved after sling surgery. Fixed resistance does not lead to
      bladder outlet obstruction. Postoperative RLPP less than 50 cm water and
      urodynamic detrusor overactivity are associated with increased pad use and
      bother.

PMID- 15201775
TI  - The male sling for stress urinary incontinence: 24-month followup with
      questionnaire based assessment.
AB  - PURPOSE: Stress urinary incontinence after prostate surgery can be a bothersome
      problem, adversely affecting quality of life. We performed a prospective study of
      the male perineal sling for the treatment of stress urinary incontinence with a
      minimum 1-year followup. MATERIALS AND METHODS: A total of 36 patients (average
      age 67 years old) underwent male sling surgery. Patients underwent preoperative
      and postoperative evaluation for bother due to urinary incontinence using the
      UCLA Prostate Cancer Index urinary function section as well as pad score.
      RESULTS: Median followup was 25 months (range 12 to 42). After surgery 24 (67%)
      patients were pad-free, 5 (14%) used 1 pad, 4 (11%) used 2 pads and 3 (8%)
      continued to use 3 or more pads daily. Overall, mean pad use +/- SD decreased
      from 4.6 +/- 2.5 to 0.64 +/- 1.0 pads daily (p <0.001). A total of 30 (83%)
      patients reported a small to no bother from urine leakage after surgery, 3 (8%)
      considered leakage a moderate problem, while 3 (8%) continued to consider it a
      big problem. The median UCLA Prostate Cancer Index urinary function score was
      improved from 33 before surgery to 330 after surgery (p <0.001). There were no
      instances of erosion, infection or prolonged retention. CONCLUSIONS: Medium term
      results for the male sling demonstrate a success rate comparable to that of the
      artificial urinary sphincter (67% pad-free rate and 92% improvement). This
      technique has established a low morbidity and has not been associated with any
      significant complications. Longer followup will ultimately establish whether this
      technique represents a viable long-term alternative to artificial urinary
      sphincter for the treatment of bothersome stress urinary incontinence in men.

PMID- 15201776
TI  - Does Valsalva leak point pressure predict outcome after the distal urethral
      polypropylene sling? Role of urodynamics in the sling era.
AB  - PURPOSE: Recently sling procedures have been shown to be effective in the
      treatment of all types of incontinence. In this study we evaluated the role of
      preoperative Valsalva leak point pressure (VLPP) in predicting the outcome of
      sling surgery. MATERIALS AND METHODS: We prospectively evaluated 174 consecutive
      patients who underwent a distal polypropylene sling procedure for the treatment
      of stress urinary incontinence (SUI). Using SEAPI scores patients were divided by
      VLPP into group 1-60 patients who did not leak on urodynamics, group 2-27
      patients with VLPP greater than 80 cm H2O, group 3-71 patients with VLPP 30 to 80
      cm H2O and group 4-16 patients with VLPP less than 30 cm H2O. Surgical outcomes
      were determined by symptom, bother and quality of life questionnaires filled out
      by patients. The physicians were blinded to patient response. RESULTS: Mean
      followup was 14.7 months (range 12 to 30) and mean patient age was 62 years
      (range 32 to 88). The groups were well matched before surgery with respect to
      age, number of previous surgeries, and severity of SUI symptoms and urge
      incontinence. The percentage of patients who were cured or improved was similar
      among groups. After surgery there was no statistical difference among patient
      mean self-reported symptoms of or bother from SUI or urge incontinence.
      CONCLUSIONS: The distal urethral polypropylene sling provides similar symptom
      improvement in all patients regardless of preoperative VLPP. VLPP is helpful in
      the diagnosis of SUI but appears to be of minimal benefit in predicting the
      outcome of the distal urethral polypropylene sling procedure.

PMID- 15201777
TI  - Small intestinal submucosa for pubourethral sling suspension for the treatment of
      stress incontinence: first histopathological results in humans.
AB  - PURPOSE: Small intestinal submucosa (SIS), a biomatrix of porcine origin, is used
      in pubourethral sling operations for female urinary stress incontinence, among
      other urological and surgical indications. To our knowledge we report the first
      histopathological examination of this biomatrix in human subjects. MATERIALS AND
      METHODS: In a series of 15 patients with pubourethral sling procedures using SIS
      3 reoperations were necessary because of recurrent urinary stress incontinence at
      a mean of 12.7 months. Biopsies were taken from the implantation site of the SIS
      band under the vaginal mucosa. Several immunohistochemical reactions were used to
      identify any inflammatory reaction. RESULTS: The biopsies under investigation
      showed nothing more than focal residues of the SIS implant without any evidence
      of a specific tissue reaction. There were no changes that might point to a
      foreign body reaction. There was likewise no evidence of any significant
      immunological reaction and in particular no evidence of any chronic inflammatory
      reaction. CONCLUSIONS: The morphological findings point to outstandingly good
      biocompatibility of SIS. During healing the material is incorporated into the
      body without any foreign body or inflammatory reaction. The results of the first
      histological investigation of SIS in human subjects emphasize the special status
      of SIS among implant materials.

PMID- 15201778
TI  - Pubovaginal slings for stress urinary incontinence following radical cystectomy
      and orthotopic neobladder reconstruction in women.
AB  - PURPOSE: We evaluated the clinical efficacy of pubovaginal slings for new onset
      stress urinary incontinence following radical cystectomy and orthotopic lower
      urinary tract reconstruction in women. MATERIALS AND METHODS: Between June 1990
      and July 2002, 101 female patients with primary transitional cell carcinoma of
      the bladder were treated with radical cystectomy and orthotopic ileal neobladder
      reconstruction. Four patients 61 to 73 years old underwent pubovaginal slings
      (autologous rectus fascia in 2 and dermal graft in 2) for stress urinary
      incontinence persisting 9 to 20 months following reconstruction with a Studer (2)
      or T pouch (2) ileal neobladder. Pre-cystectomy continence was excellent in 3
      patients, while 1 had mild stress incontinence. All patients had high grade,
      muscle invasive transitional cell carcinoma and/or carcinoma in situ with
      negative urethral margins and 3 of the 4 had lymph node negative disease on
      pathological examination. Two patients were treated with transurethral bulking
      material 4 to 5 months prior to the sling procedure without noticeable
      improvement. RESULTS: Two patients who underwent autologous pubovaginal slings
      had significant complications arising from dissection in the retropubic space,
      including 1 entero-pouch fistula and 1 enterotomy resulting in an enterocutaneous
      fistula, sepsis and subsequent death. These 2 patients had persistent stress
      incontinence despite the sling procedures and they ultimately underwent
      conversion to continent cutaneous urinary diversions. Two patients were treated
      with a dermal graft sling using infrapubic bone anchors through a transvaginal
      approach, obviating the need to enter the pelvis. These patients had uneventful
      postoperative courses and they are currently hypercontinent, performing
      intermittent catheterization with complete daytime continence and only occasional
      nighttime leakage 3 and 9 months following sling surgery. CONCLUSIONS:
      Pubovaginal sling procedures for incontinence following orthotopic neobladder
      reconstruction in women may be complicated due to extensive pelvic surgery.
      Dissection in the retropubic space should be avoided because potentially fatal
      complications may occur. Slings using infrapubic bone anchors may provide the
      best option in such patients in whom conservative management has failed because
      the pelvis need not be violated.

PMID- 15201779
TI  - Concomitant vaginal surgery did not affect outcome of the tension-free vaginal
      tape operation during a prospective 3-year followup study.
AB  - PURPOSE: We compare outcomes when vaginal surgery and a tension-free vaginal tape
      (TVT) operation were done concomitantly and when only a TVT operation was done in
      patients with stress or mixed urinary incontinence. MATERIALS AND METHODS:
      Outcomes in 75 consecutive patients who underwent a TVT operation concomitantly
      with vaginal surgery (group 1) were compared with outcomes in 75 who underwent
      only a TVT operation (group 2) between August 1998 and June 2000. Group 2
      patients were matched for age and incontinence type with group 1 patients. All
      study subjects had a followup visit to the study hospital 2 months after the
      operation. Questionnaire based assessments were done 2 and 3 years after the
      operation. RESULTS: Ten group 1 (13%) and 6 group 2 (8%) patients had a lower
      urinary tract infection. Other infections occurred after operation in 10 group 1
      (13%) and 1 group 2 (1.3%) patients. Four cases (5.3%) of intraoperative bladder
      perforation occurred in group 1. A total of 15 group 1 (20%) and 7 group 2 (9.3%)
      patients were treated for transient urinary retention. Two months after the
      operation 93% of group 1 and 97% of group 2 were free of stress urinary
      incontinence. The corresponding percents 2 years after operation were 88% and
      93%, and at 3 years they were 87% and 92%, respectively. CONCLUSIONS:
      Complications and transient urinary retention occurred more often after TVT
      operations and concomitant vaginal surgery than after the TVT operation alone.
      There were no statistically significant differences in regard to the cure of
      stress urinary incontinence and incidence of urge symptoms during the 3-year
      followup.

PMID- 15201780
TI  - Autonomic response to stress in interstitial cystitis.
AB  - PURPOSE: Previous studies have documented elevations in indices of sympathetic
      activity in cats and humans with interstitial cystitis (IC). To examine potential
      autonomic dysregulation in IC we examined the effects of a laboratory mental
      stress challenge on blood pressure and heart rate (HR) in patients with IC and
      healthy controls. MATERIALS AND METHODS: A total of 14 female patients with IC
      and 14 age matched controls participated in a laboratory session, including a 25
      minute mental stress challenge. Systolic blood pressure (SBP), diastolic blood
      pressure (DBP) and HR were measured at intervals before, during and following the
      stressor. The level of chronic stress, symptom severity and pain at voiding were
      assessed. RESULTS: Mean age was 49 years (range 32 to 66). The resting HR of
      patients with IC (82.02 bpm) was significantly higher than that of controls
      (63.31 bpm, p = 0.0001). There was also suggested evidence of elevated resting
      DBP in patients with IC (p = 0.07) but no significant difference in mean resting
      SBP. Autonomic arousal elicited by the laboratory stressor did not differ between
      the groups and subjects in each group perceived the task as equally stressful.
      Patients with IC had significantly elevated HR at each time point compared with
      controls (p <0.0001) with an average mean difference +/- SD between the groups of
      19.5 +/- 4.0 (main effect for group p <0.0001). Although consistent increases in
      SBP and DBP were observed in patients after baseline, these differences were not
      significant. CONCLUSIONS: Patients with IC had an increased HR at baseline and
      throughout a laboratory mental stress challenge compared to healthy age matched
      women. No differences in HR or blood pressure reactivity were observed between
      the 2 groups.

PMID- 15201781
TI  - Urinary urgency and frequency, and chronic urethral and/or pelvic pain in
      females. Can doxycycline help?
AB  - PURPOSE: Persistent urinary urgency and frequency, and chronic urethral and/or
      pelvic pain in women are often a diagnostic and therapeutic challenge. This can
      be frustrating for patients and physicians. The search for an infectious agent
      often proves futile and after multiple ineffective treatment regimens patients
      may be classified as having interstitial cystitis or referred to a psychiatrist
      as the last option. We evaluated whether treatment with doxycycline of the
      patient and her sexual partner would be beneficial. MATERIALS AND METHODS: Women
      presenting with a history of urinary urgency and frequency, and chronic urethral
      and/or pelvic pain often associated with dyspareunia and/or a history of
      recurrent urinary tract infection were evaluated. Initial examinations included
      urethral and cervical/vaginal swabs, serum analysis, urine examination and
      culture, and bladder barbitage. A total of 103 women with a median age of 46
      years (range 21 to 84) and with a median symptoms history of 60 months (range 3
      to 480) were included. All patients had trigonal leukoplakia at cystoscopy, in
      15% an infectious organism was identified and 30% had leukocyturia. All were
      treated with doxycyclines, and a vaginal antimicrobic and/or antimycotic agent
      following the same regimen, including treatment of the sexual partner. RESULTS:
      After treatment with doxycycline 71% of the women were symptom-free or had a
      subjective decrease in symptoms. CONCLUSIONS: Treatment with doxycycline is
      effective in more than two-thirds of patients complaining of persistent frequency
      and urgency, chronic urethral and/or pelvic pain, and dyspareunia as well as a
      history of recurrent urinary tract infections. In women with negative urinary
      cultures but a history of urgency/frequency probative treatment with doxycycline
      is justified and endoscopic findings may support the hypothesis of chronic
      infection. This should be done especially before contemplating psychiatric
      treatment or diagnosing the patient with interstitial cystitis. We attribute this
      high success rate to simultaneous treatment of the sexual partner, who may be an
      asymptomatic carrier, although this remains to be proved.

PMID- 15201782
TI  - Sacral neuromodulation for refractory detrusor overactivity in women with an
      artificial urinary sphincter.
AB  - PURPOSE: We assessed the efficacy of sacral neuromodulation as an alternative
      therapeutic option in women with an artificial urinary sphincter (AUS) who had de
      novo irritative urinary symptoms (urgency/frequency) refractory to conventional
      treatment. MATERIALS AND METHODS: Between 1984 and 2002 we implanted an AUS in
      350 women and detrusor overactivity developed in 14. Six of the 14 patients
      responding positively to a percutaneous nerve evaluation test (greater than 50%
      subjective/objective improvement) were implanted with an S3 neuromodulator within
      42.8 weeks (range 21 to 106) of AUS implantation. Followup included analysis of
      the voiding diary, a pad test and urodynamic assessment. RESULTS: After 30.5
      months followup (range 14 to 40) 1 patient was dry, 4 were improved and treatment
      failed in 1. At 12 months mean voiding frequency daily had decreased from 17
      (range 12 to 23) to 8 (range 4 to 12) and the mean number of leakages episodes
      daily had decreased from 14.7 (range 8.5 to 17) to 6 (range 4 to 10). Mean voided
      volume had increased from 121.7 (range 90 to 170) to 180 ml (range 120 to 225),
      mean first desire to void volume had increased from 117 (range 88 to 190) to 183
      ml (range 130 to 275) and mean functional bladder capacity had increased from 325
      (range 200 to 530) to 372 ml (range 250 to 580). Uninhibited bladder contractions
      had resolved in 4 of 5 patients. CONCLUSIONS: In women who already have an AUS
      with urge incontinence sacral neuromodulation can help resolve symptoms. Because
      this therapy does not compromise the potential for future treatment, it appears
      to be an alternative option in these patients. It can postpone or avoid more
      mutilating surgery and self-catheterization.

PMID- 15201783
TI  - Intravesical resiniferatoxin versus botulinum-A toxin injections for neurogenic
      detrusor overactivity: a prospective randomized study.
AB  - PURPOSE: We investigated the effectiveness and safety of intravesical
      resiniferatoxin (Sigma Chemical Co., St. Louis, Missouri) and botulinum-A toxin
      injections into the detrusor muscle in a group of spinal cord injured patients
      with neurogenic detrusor overactivity unresponsive to conventional
      anticholinergic therapy. MATERIALS AND METHODS: A total of 25 patients were
      randomly assigned to receive intravesically 0.6 microM resiniferatoxin in 50 ml
      of 0.9% NaCl or injections into the detrusor muscle of 300 units botulinum A
      toxin diluted in 30 ml 0.9% NaCl. Clinical evaluation and urodynamics were
      performed at baseline, and at 6, 12 and 18 months after treatment. RESULTS: In
      both arms there was a significant decrease in catheterization and incontinent
      episodes, and a significant increase in first detrusor contraction and maximum
      bladder capacity at 6, 12 and 18-month followup. There were no local side effects
      with either treatment. Botulinum-A toxin induced a significant decrease in the
      frequency of daily incontinence episodes (p <0.05), a significant increase in
      first uninhibited detrusor contraction (p <0.01) in maximum bladder capacity (p
      <0.01), and a significant decrease in maximum pressure of uninhibited detrusor
      contractions (p <0.01) compared to resiniferatoxin at 6, 12 and 18-month
      followup. CONCLUSIONS: In spinal cord injured patients with refractory neurogenic
      detrusor overactivity, intravesical resiniferatoxin and botulinum-A toxin
      injections into the detrusor muscle provided beneficial clinical and urodynamic
      results with decreases in detrusor overactivity and restoration of urinary
      continence in a large proportion of patients. Botulinum-A toxin injections
      provided superior clinical and urodynamic benefits compared to those of
      intravesical resiniferatoxin.

PMID- 15201784
TI  - Transurethral injection of bulking agents for stress urinary incontinence
      following orthotopic neobladder reconstruction in women.
AB  - PURPOSE: The clinical efficacy of transurethral bulking agents for the treatment
      of new onset urinary incontinence following radical cystectomy and orthotopic
      lower urinary tract reconstruction in women was evaluated. MATERIALS AND METHODS:
      Between 1990 and 2002, 101 female patients with primary transitional cell
      carcinoma of the bladder were treated with radical cystectomy and orthotopic
      ileal neobladder reconstruction. Of the 101 patients 12 (12%) underwent treatment
      for new onset urinary incontinence following exenterative surgery with
      transurethral injection of bulking agents, including collagen in 11 and
      nonabsorbable pyrolytic carbon coated beads in 1. RESULTS: A total of 25
      injections were administered to 12 female patients with a mean age of 75.4 years
      following orthotopic neobladder reconstruction. Mean followup was 22.5 months
      (range 2 to 51). Two of the 12 patients (16.7%) reported complete continence and
      were considered cured, although subjective complaints of urinary frequency
      persisted. Four patients (33%) had decreased objective average daily pad use
      (6.75 to 2.25) and 6 (50%) showed no subjective or objective improvement in
      symptomatology. CONCLUSIONS: Although injection of urethral bulking agents is a
      minimally invasive treatment for stress urinary incontinence following orthotopic
      neobladder reconstruction, long-term results in patients with severe disease show
      a less than optimal durable response.

PMID- 15201785
TI  - Long-term complication due to dextranomer based implant: granuloma causing
      urinary obstruction.

PMID- 15201786
TI  - Bladder neck leiomyoma presenting as voiding dysfunction.

PMID- 15201787
TI  - Coronary artery risk factors in patients with erectile dysfunction.
AB  - PURPOSE: We evaluated the risk factors of coronary artery disease in patients
      with erectile dysfunction (ED). MATERIALS AND METHODS: A total of 417 male
      patients with ED were enrolled in this study. Patients were interviewed for ED
      using the International Index of Erectile Function. All patients were also
      screened for sociodemographic data and risk factors for ischemic heart disease
      (IHD), including age, smoking, diabetes, hypertension, dyslipidemia and
      psychological disorders. Patients underwent routine laboratory investigation plus
      testosterone and prolactin assessment. All patients were referred to a
      cardiologist for IHD evaluation. RESULTS: Mean age +/- SD was 59.1 +/- 10.3
      years. Of the patients 27.3% were younger than 50 years, 37.2% were current or
      former smokers, and 27.6% had mild, 30% had moderate and 42.4% had severe ED. Of
      the patients 26.9% had different degrees of IHD, of whom 84.8% were older than 50
      years. There was a significant association between age and IHD (p <0.05). There
      were significant associations between IHD, and the increased severity and
      progressive course of ED (each p <0.05). Furthermore, higher degrees of IHD were
      significantly associated with severe ED. Diabetes, hypertension, dyslipidemia and
      psychological disorders were present in 75.1%, 39.3%, 45.6% and 8.2% of the
      patients, respectively. Overall 92.1% of the patients with ED had 1 or more
      coronary artery risk factors. The presence of at least 1 risk factor is
      significantly associated with ED in patients with IHD (p <0.05). CONCLUSIONS:
      Coronary artery risk factors are significantly associated with erectile
      dysfunction. A significant association between higher degrees of IHD and the
      increased severity of ED was detected.

PMID- 15201788
TI  - Improvement in erectile function in men with organic erectile dysfunction by
      correction of elevated cholesterol levels: a clinical observation.
AB  - PURPOSE: We determined that use of a statin drug to lower cholesterol would
      improve erectile function in men who have hypercholesterolemia as the only risk
      factor for erectile dysfunction (ED). MATERIALS AND METHODS: A total of 18 men
      were determined to have increased cholesterol as the only risk factor for ED by
      history, system review, physical examination and laboratory analysis. Nine of
      these men agreed to participate in the study. Organic ED was verified by abnormal
      nocturnal penile tumescence and rigidity testing with the RigiScan (UroHealth
      Systems, Inc., Laguna Niguel, California) and Sexual Health Inventory in Men
      questionnaire. Subjects were given atorvastatin with a goal decrease of total
      cholesterol to less than 200 mg/dl and low-density lipoprotein cholesterol to
      less than 120 mg/dl. RigiScan measurements were compared before and after
      treatment with atrovastatin. RESULTS: Mean age +/- SD was 49.7 +/- 7.4 years.
      Mean length of treatment with atrorvastatin was 3.7 +/- 2.1 months. Clinically 8
      of the 9 men had improved erection adequate for penetration during sexual
      intercourse. Mean questionnaire scores improved from 14.2 to 20.7 (p <0.001).
      Mean total and low-density lipoprotein cholesterol decreased significantly after
      treatment (p <0.001). RigiScan measurements showed an increased average penile
      rigidity at the base (p <0.001) and tip (p <0.005) after treatment with
      atorvastatin. CONCLUSIONS: Erectile function improves in men with
      hypercholesterolemia as the only risk factor for ED when treated with
      atorvastatin. Treating hypercholesterolemia may improve ED, while promoting
      primary cardiac prevention.

PMID- 15201789
TI  - Stratification of penile vascular pathologies in patients with Peyronie's disease
      and in men with erectile dysfunction according to age: a comparative study.
AB  - PURPOSE: Erectile dysfunction (ED) occurs in 20% to 54% of men with Peyronie's
      disease (PD). We investigated the role of vascular status in the pathophysiology
      of ED in patients with PD. MATERIALS AND METHODS: A total of 509 consecutive men
      with PD (group 1--impotent 259, 1a, and potent 250, 1b, mean age +/- SD 54.6 +/-
      4.4 years) and 507 consecutive men with ED only (group 2--mean age 49.4 +/- 12.4
      years) underwent penile duplex ultrasonography (PDU). Detailed sexual and medical
      history, and focused physical examination were performed in all patients.
      Patients in the 2, groups were stratified according to age (18 to 80 years) and
      classified according to PDU results (normal vascular status, arterial
      insufficiency, veno-occlusive dysfunction [VOD] and mixed vascular pathology).
      RESULTS: VOD was observed in 23.1% and 42.8% of patients in groups 1 and 2,
      respectively (p <0.05). Although VOD was significantly more common in group 2 (ED
      alone) than in group 1a (PD plus ED) in the third decade (p <0.05), overall PDU
      results showed no statistical difference for VOD between these 2 groups (p
      >0.05). Of note, mixed vascular pathologies were significantly higher in group 1a
      than in group 2 in the third through fifth decades (p <0.05), while arterial
      insufficiency was more common in the seventh decade (p <0.05). CONCLUSIONS: While
      many groups have investigated the vascular causes of ED, the exact etiology of ED
      in men with PD remains controversial. A possible relationship between ED and VOD
      in patients with PD has been previously reported. The current PDU study
      demonstrates that for all ages except 30 to 39 years the prevalence of VOD in
      patients with PD plus ED is similar to that of patients with ED alone.

PMID- 15201790
TI  - Low molecular weight heparin induced priapism.

PMID- 15201791
TI  - Prospective and longitudinal patient self-assessment of health-related quality of
      life following radical perineal prostatectomy.
AB  - PURPOSE: We provide a comprehensive, longitudinal assessment of health related
      quality of life (HRQOL) following radical perineal prostatectomy (RPP). MATERIALS
      AND METHODS: We report the results of a prospective cohort study of 109 patients
      with at least 3 months of followup who underwent RPP between January 2001 and
      July 2003. A validated patient self-assessment questionnaire, the Expanded
      Prostate Cancer Index Composite, was administered preoperatively, and 1, 3, 6, 9,
      12 and 18 months postoperatively. Mean domain specific HRQOL scores were
      calculated as well as the proportion of patients achieving an individual baseline
      by each interval. The Cox proportional hazards model was used to identify
      predictors of a successful return to baseline of disease specific HRQOL scores.
      RESULTS: HRQOL scores were lowest 1 month postoperatively and they increased with
      time. By 6 months a majority of patients had recovered baseline summary scores in
      urinary (65.1%), bowel (93.6%) and hormonal (91.7%) domains at a median of 5.8
      (95% CI 3.6 to 6.2), 1.3 (95% CI 1.1 to 1.5) and 1.3 (95% CI 1.2 to 1.8) months,
      respectively. One in 4 patients recovered the sexual summary score by 18 months.
      Significant independent predictors for the recovery of domain summary scores were
      younger age in urinary (p = 0.001), individual surgeon in bowel (p = 0.022), and
      older age (p = 0.017) and absent medical comorbidities (p = 0.012) in hormonal
      domains. CONCLUSIONS: A majority of patients undergoing RRP experience an early
      recovery of individual urinary, bowel and hormonal HRQOL. Future studies should
      establish the benefit of bilateral nerve sparing RPP on the recovery of sexual
      domain HRQOL.

PMID- 15201792
TI  - Making ends meet: a cost comparison of laparoscopic and open radical retropubic
      prostatectomy.
AB  - PURPOSE: We compared the perioperative costs of laparoscopic radical
      prostatectomy (LRP) and open radical retropubic prostatectomy (RRP) at a
      metropolitan hospital by developing a detailed computer model. MATERIALS AND
      METHODS: Our predictive model incorporates institutional cost centers for
      operative time, operating room consumables, professional fees, hospital room and
      board, oral analgesics, autologous blood banking, blood transfusion and
      cystography. Versions with and without pelvic lymphadenectomy (PLND) were
      evaluated using 1 and 2-way sensitivity analyses. Operative times, lengths of
      stay and transfusion rates were derived from published series. We also reviewed
      individual hospital charges for 172 consecutive prostatectomy cases for
      comparison and validation of model predictions. RESULTS: The model predicted cost
      premiums for LRP of 14.4% (without PLND) and 17.5% (with PLND). The actual
      hospital charge premium for LRP and PLND was 18.4%, which differed from the
      predicted cost premium by less than 1%. The most significant cost centers in
      order of importance were operative time, length of stay and consumables. To
      achieve cost equivalence with RRP, operative times would need to average 159
      minutes (LRP and PLND) and 174 minutes (LRP alone) holding other factors
      constant. Cost equivalence could not be achieved by shortening hospital stay
      alone unless LRP were performed as an outpatient procedure. CONCLUSIONS: Our
      model predicts the perioperative costs of LRP to be greater than RRP by a factor
      of less than 1.2x. If disposable instruments and trocars are eliminated, and
      patients undergoing LRP and PLND are discharged on postoperative day 2, cost
      equivalence with RRP and PLND can be achieved with operative times of 3.4 hours.

PMID- 15201793
TI  - Repeat urethrotomy and dilation for the treatment of urethral stricture are
      neither clinically effective nor cost-effective.
AB  - PURPOSE: We developed an algorithm for the management of urethral stricture based
      on cost-effectiveness. MATERIALS AND METHODS: United Kingdom medical and hospital
      costs associated with the current management of urethral stricture were
      calculated using private medical insurance schedules of reimbursement and clean
      intermittent self-catheterization supply costs. These costs were applied to 126
      new patients treated endoscopically for urethral stricture in a general
      urological setting between January 1, 1991 and December 31, 1999. Treatment
      failure was defined as recurrent symptomatic stricture requiring further
      operative intervention following initial intervention. Mean followup available
      was 25 months (range 1 to 132). RESULTS: The costs were urethrotomy/urethral
      dilation 2,250.00 pounds sterling (3,375.00 dollars, ratio 1.00), simple 1-stage
      urethroplasty 5,015.00 pounds sterling (7,522.50 dollars, ratio 2.23), complex 1
      stage urethroplasty 5,335.00 pounds sterling (8,002.50 dollars, ratio 2.37) and 2
      stage urethroplasty 10,370 pounds sterling (15,555.00 dollars, ratio 4.61). Of
      the 126 patients assessed 60 (47.6%) required more than 1 endoscopic retreatments
      (mean 3.13 each), 50 performed biweekly clean intermittent self-catheterization
      and 7 underwent urethroplasty during followup. The total cost per patient for all
      126 patients for stricture treatment during followup was 6,113 pounds sterling
      (9,170 dollars). This cost was calculated by multiplying procedure cost by the
      number of procedures performed. A strategy of urethrotomy or urethral dilation as
      first line treatment, followed by urethroplasty for recurrence yielded a total
      cost per patient of 5,866 pounds sterling (8,799 dollars). CONCLUSIONS: A
      strategy of initial urethrotomy or urethral dilation followed by urethroplasty in
      patients with recurrent stricture proves to be the most cost-effective strategy.
      This financially based strategy concurs with evidence based best practice for
      urethral stricture management.

PMID- 15201794
TI  - Development and initial evaluation of a novel urology curriculum for medical
      students.
AB  - PURPOSE: After the development and implementation of a novel urology curriculum
      for medical students we evaluated urological learning by medical students using a
      validated measure of learning in the 4 clinical areas of benign prostatic
      hyperplasia, erectile dysfunction, prostate cancer and prostate specific antigen
      screening. MATERIALS AND METHODS: Third year medical students completed an online
      validated pre-test and post-test immediately before and after the mandatory 1
      week clinical rotation in urology. Online pre-surveys and post-surveys were also
      administered. Overall student participation was 90% (37 of 41) with 63% of
      students (26 of 41) completing all 4 tests and surveys. RESULTS: Student overall
      test scores improved significantly upon completion of the 1-week clinical
      rotation in urology (p <0.001). A trend toward increased learning by male
      students was identified (p = 0.07). Significant variation in exposure to
      outpatient clinics and in the performance of physical examination skills was
      observed among the different teaching sites. CONCLUSIONS: This study demonstrates
      significant learning by medical students during their 1-week clinical rotation in
      urology. Further data are needed to confirm the trend toward increased learning
      by males and elucidate its etiology. Scheduling changes have been implemented to
      address the inconsistencies across clinical sites.

PMID- 15201795
TI  - Development of validated instrument to measure medical student learning in
      clinical urology: a step toward evidence based education.
AB  - PURPOSE: To date published efforts to assess and improve medical student learning
      in urology have been limited due to the lack of an assessment tool with which to
      measure student learning. We report the development of a validated measure of
      medical student learning in urology. MATERIALS AND METHODS: Four core topics in
      clinical urology were selected as the focus of the test development, namely
      prostate cancer, screening with prostate specific antigen, benign prostatic
      hyperplasia and erectile dysfunction. Detailed curricula and multiple choice
      questions were created for each topic. Content validity of the curriculum and 28
      item examination was established by a panel of 2 urologists and 2 medical
      physicians. Instrument reliability was determined by administering the test on
      line to third-year surgery students. Test construct validity was established
      through its administration to 19 urology residents and attending physicians.
      RESULTS: Reliability of the 28-item test instrument was measured by Cronbach's
      alpha at 0.76 and its 1-week test-retest reliability was 0.72. All urology
      experts performed well on the test. Mean urological expert scores were
      significantly higher than mean student post-test scores (24.9 +/- 2.1 vs 17.8 +/-
      3.8, 2-tailed t test p <0.001). Urological experts with greater urological
      training had higher scores than those with less residency training. CONCLUSIONS:
      This study documents the development of a validated measure of medical student
      learning in urology. This validated instrument has the potential to improve
      educational quality control at medical schools and facilitate the development of
      effective, evidence based teaching methods.

PMID- 15201796
TI  - Hand assisted laparoscopic training for postgraduate urologists: the role of
      mentoring.
AB  - PURPOSE: Hand assisted laparoscopy (HAL) has recently been accepted as a safe
      alternative for nephrectomy. HAL courses have been offered at several
      institutions to train novice laparoscopic surgeons in this minimally invasive
      surgical procedure. Mentoring by a course instructor or an experienced
      laparoscopist provides assistance to surgeons with their initial operation.
      However, to our knowledge the impact of mentoring on the clinical practice of HAL
      is not known. Therefore, we evaluated the clinical practice patterns of
      urologists following a postgraduate HAL course, comparing course graduates who
      underwent subsequent mentoring with those who were not mentored. MATERIALS AND
      METHODS: A total of 71 urologists attended a postgraduate training course in HAL
      at our institution between March 2002 and October 2002. Graduates were given the
      opportunity for one of the instructors to travel to their home institution and
      mentor them during their initial case(s). Followup surveys were mailed to the
      graduates in March 2003 to evaluate their practice patterns. Responses from
      returned surveys were entered into a dedicated database and data analysis was
      performed. RESULTS: Of the 71 surveys mailed 56 were returned (79%). The majority
      of respondents (91%) described themselves as community based general urologists.
      Respondents were categorized into 1 of 2 groups, namely group 1-those who had
      mentoring by a course instructor (23.2%) or another experienced laparoscopist
      (30.4%) and group 2-those who were not mentored (46.4%). The majority of group 1
      respondents (93%) reported that they were still performing laparoscopic
      procedures at 6 months of followup. However, only 44% of the surgeons in group 2
      were performing laparoscopy at 6 months. The majority of surgeons in group 1
      (72%) reported that their laparoscopic experience had been sufficient to maintain
      their expertise compared to only 42% in group 2. CONCLUSIONS: Mentoring provides
      a useful adjunct to postgraduate urological training and the integration of
      laparoscopic techniques into the community based practice of urology.

PMID- 15201797
TI  - AUA guideline on the pharmacologic management of premature ejaculation.

PMID- 15201798
TI  - Pediatric epithelioid sarcoma of the penis.

PMID- 15201799
TI  - Rigid ureteroscopy for the treatment of ureteral calculi in children.
AB  - PURPOSE: We assess the safety and efficacy of rigid ureteroscopy for the
      treatment of pediatric ureterolithiasis. MATERIALS AND METHODS: The records of 33
      children with an average age of 7.4 years (range 9 months to 15 years) treated
      with rigid ureteroscopy between May 1995 and July 2003 were reviewed. In 35
      ureteral units use of a rigid 6.9 to 10Fr ureteroscope was planned for treating
      stones at various levels of the ureter. Stones were located in the upper ureter
      in 6 cases, middle ureter in 3 and lower ureter in 26. Dilatation of the ureteral
      orifice was necessary in 11 cases. RESULTS: Stone size varied from 3 to 10 mm
      (mean 5.3). In 33 patients (94%) all stone fragments were removed successfully.
      Stones were fragmented with pneumatic lithotripsy in 20 cases and removed by
      forceps without fragmentation in 13. In 1 child an upper ureteral stone migrated
      up to the kidney during ureteroscopy but following extracorporeal shock
      lithotripsy therapy she was rendered stone-free. In another child it was not
      possible to remove the stone. In a 9-month-old female patient with bilateral
      stones it was not possible to enter the left ureter because of a tight orifice
      resistant to balloon dilation. At the end of the procedure a 3 or 4Fr ureteral or
      a 4.8Fr Double-J (Medical Engineering Corp., New York, New York) stent was left
      in place for 3 days to 3 weeks in 12 cases. There were no cases of ureteral
      perforation. Of the patients 31 were followed for 1 to 36 months. No incidence of
      vesicoureteral reflux was detected in 9 who underwent postoperative cystography.
      CONCLUSIONS: After becoming experienced and meticulously working with finer
      instruments in adults, rigid ureteroscopy can be a safe and efficient treatment
      for ureteral stones in every location in children.

PMID- 15201800
TI  - Classification of prepuce in hypospadias according to morphological abnormalities
      and their impact on hypospadias repair.
AB  - PURPOSE: We investigated the morphology of the hypospadiac prepuce to develop a
      classification of different prepuce types in hypospadias. We also assessed the
      correlation between morphology and vascularization of the prepuce and their
      impact on results of hypospadias repair. MATERIALS AND METHODS: From September
      1997 to December 2001, 174 patients 18 months to 24 years old (mean age 49
      months) underwent hypospadias surgery. The prepuce morphology was analyzed by
      evaluation of the prepuce skin distribution, development and deformities. The
      development and course of blood vessels were analyzed using preputial
      illumination. According to morphology and blood supply, different types were
      compared. Of 174 analyzed cases 163 prepuces were used for urethroplasty.
      RESULTS: Based on the predominant morphology characteristics and abnormalities,
      we classified the analyzed prepuces into 6 groups of A-"monk's hood" or "1
      humped" (43 cases, 24.7%), B-"cobra eyes" (80, 45.9%), C-"normal" (intact) (4,
      2.3%), D-"flat" (24, 13.8%), E-"v"-shaped (16, 9.2%), and F-"collar-scarf" (7,
      4.0%). Cobra eyes and monk's hood prepuces had the most favorable vascular
      pattern for the creation of flaps, the prepuces while the "flat" and "v"-shaped
      prepuces had the most unfavorable vascular pattern. Mean followup after
      hypospadias repair was 34 months (range 24 to 48). Complications (stenosis,
      fistula diverticulum) developed in 8.9% of the patients after "cobra eyes" and
      "monk's hood" prepuces were used for urethroplasty and in 25% when "v"-shaped and
      "flat" prepuces were used. CONCLUSIONS: Morphological characteristics correlated
      with vascularization of the hypospadiac prepuce. Underdeveloped prepuces and
      those with unfavorable vascular pattern used for urethroplasty had a higher
      percentage of complications. In severe hypospadias the anatomical features of the
      prepuce have greater influence on the proper choice of 1 or 2-stage repair.

PMID- 15201801
TI  - Long-term outcome of vesicoureteral reflux associated chronic renal failure in
      children. Data from the ItalKid Project.
AB  - PURPOSE: The nephropathy associated with vesicoureteral reflux (VUR) is one of
      the leading causes of chronic renal failure (CRF) in children. We describe the
      clinical course of the disease based on information available in the ItalKid
      Project database, and analyze the predictive value of baseline renal function,
      age at VUR diagnosis and urinary protein excretion in relation to the risk of
      progressive renal failure. MATERIALS AND METHODS: As of December 31, 2001 the
      registry included a total of 343 patients (261 males) with a diagnosis of primary
      VUR, which was the leading single cause of CRF, accounting for 25.4% of all
      patients with CRF. RESULTS: The estimated risk of end stage renal disease (ESRD)
      by age 20 years was 56%. The patients with a creatinine clearance (Ccr) of less
      than 40 ml per minute at baseline had an estimated 4-fold greater risk of ESRD
      developing in comparison with those whose Ccr was 40 to 75 ml per minute. No
      significant difference in probability of disease progression to ESRD was found
      between subjects diagnosed with VUR at age 6 months or less and those diagnosed
      later (older than 6 months). Furthermore, children with normal urinary protein
      excretion (a urinary protein [uPr]/urinary creatinine [uCr] ratio of less than
      0.2 in 36 patients) and low grade proteinuria (uPr/uCr 0.2 to 0.8 in 34 patients)
      at baseline showed a significantly slower decrease in mean Ccr than those with
      moderate proteinuria (uPr/uCr greater than 0.8 in 34 patients). Hypertension
      and/or antihypertensive treatment (including antiprogressive drugs) were reported
      in 29.1% of patients. CONCLUSIONS: The results of the present study define the
      long-term risk of ESRD in a large population of children with CRF and VUR, and
      provide some critical information for identifying the prognosis.

PMID- 15201802
TI  - Prevalence of diurnal voiding symptoms and difficult arousal from sleep in
      children with nocturnal enuresis.
AB  - PURPOSE: We analyzed the relative contribution of detrusor instability and
      difficult arousal from sleep in the genesis of nocturnal enuresis (NE), and
      evaluate a clinical feature that may prospectively help differentiate patients
      with monosymptomatic NE (mono NE) from those with diurnal voiding symptoms (DVSs)
      of urgency and urge incontinence associated with NE (NE + DVSs). MATERIALS AND
      METHODS: Patients referred for voiding problems and 627 controls were evaluated
      for NE, DVSs, nocturia and arousal from sleep on a scale of 1 to 8. Patients were
      categorized into 3 groups-mono NE of primary or secondary onset (200, boys 71%,
      girls 29%), primary or secondary NE + DVSs (329, boys 43%, girls 57%) and
      isolated DVSs (146, boys 21%, girls 79%). RESULTS: DVSs were noted in 49% of boys
      and 76% of girls with NE, although 40% of patients or parents did not complain of
      DVSs. The DVSs were elicited on detailed interrogation or on finding evidence of
      urinary incontinence on perineal examination. While one-third of controls and
      patients with isolated DVSs manifested nocturia at least twice a month, only 6%
      of bedwetters did so. Difficult arousal from sleep (scores 6 to 8) was more
      prevalent in patients with NE (59%) than controls (20%) or patients with isolated
      DVSs (5%), and in patients with mono NE and primary NE than in NE + DVSs or
      secondary NE, with reverse prevalence for nocturia. Easy sleep arousal (scores 1
      to 3) was noted in 65% of patients with secondary NE + DVSs vs up to 6% of other
      NE subgroups. Compared to patients with mono NE, those with NE + DVSs had a
      higher prevalence of urinary tract infection (UTI), encopresis,
      psychosocial/learning problems, and family history of UTI and DVSs, ie problems
      associated with detrusor instability. CONCLUSIONS: DVSs accompany NE in two
      thirds of patients but can be missed during a cursory history. Difficult sleep
      arousal seems to have a major role in primary mono NE, and detrusor instability
      in secondary NE + DVSs. In patients with NE a history of frequent nocturia, easy
      sleep arousal, UTI, encopresis, psychosocial learning problems or family history
      of UTI and DVSs should raise the suspicion for associated undisclosed DVSs.

PMID- 15201803
TI  - The neonatal vanishing kidney: congenital and vascular etiologies.

PMID- 15201804
TI  - Testosterone enanthate therapy is effective and independent of SRD5A2 and AR gene
      polymorphisms in boys with micropenis.
AB  - PURPOSE: We report penile length (PL) responses to testosterone enanthate (TE)
      therapy for micropenis, and the relevance of the V89L polymorphism of SRD5A2
      encoding the 5alpha-reductase type 2 and CAG repeat length polymorphism of AR
      encoding the androgen receptor. MATERIALS AND METHODS: A total of 53 Japanese
      boys with micropenis (less than -2.0 SD) 0 to 13 years old who had no SRD5A2 or
      AR mutation were examined. TE was given at a dosage of 25 mg intramuscularly, and
      PL was measured at least 4 weeks after the injection. The 2 polymorphisms were
      determined by direct sequencing. RESULTS: PLs became -2.0 SD or greater in all
      the boys after TE therapy (1 injection in 4 boys, 2 in 28, 3 in 19 and 4 in 2),
      with a significant increase in the medians of PLs (from 2.5 to 3.5 cm, p <0.0001)
      and SD score, (from -2.6 to -0.7, p <0.0001). The increment in actual PL at the
      first injection ranged from 0.2 to 1.5 cm (median 0.6) and was independent of age
      (r = 0.22, p = 0.12) and body surface area (r = 0.11, p = 0.43), while that in PL
      SD score at the first injection ranged from 0.3 to 2.5 (1.0) and was inversely
      correlated with age (r = -0.33, p = 0.02) and body surface area (r = -0.37, p =
      0.008). The actual PL increment at the first injection was also unrelated to
      initial PL (r = -0.03, p = 0.81). The median of actual PL increments at the first
      injection was similar among boys with V/V, V/L and L/L genotypes of SRD5A2 (0.6
      cm in 18, 0.7 cm in 30 and 0.5 cm in 5, respectively, p = 0.77), and between boys
      with and without long CAG repeats (26 or greater) of AR (0.65 cm in 6 and 0.6 cm
      in 47, respectively, p = 0.77). In addition, there was no significant correlation
      between actual PL increment at the first injection and CAG repeat length (r =
      0.06, p = 0.67). CONCLUSIONS: Our results suggest that administration of 25 mg TE
      is effective for micropenis in prepubertal boys with no SRD5A2 or AR mutation,
      with variable but significant PL increments, and that the penile responsiveness
      to TE therapy is independent of the V89L and the CAG repeat length polymorphisms.

PMID- 15201805
TI  - Partial nephrectomy with fibrin glue repair: measurement of vascular and
      pelvicaliceal hydrodynamic bond integrity in a live and abbatoir porcine model.
AB  - PURPOSE: Some of the challenges during partial nephrectomy include control of
      bleeding and repair of the pelvicaliceal system. Fibrin tissue sealants have
      recently been used to achieve hemostasis and collecting system closure in open
      and laparoscopic partial nephrectomy. However, there exist little data regarding
      the intrinsic strength of the bond, especially when applied to the vasculature
      and the urinary collecting system of the transected kidney. We examined the
      hydrodynamic bond integrity of a commercially available fibrin tissue sealant in
      a live porcine animal model undergoing partial nephrectomy. MATERIALS AND
      METHODS: Open partial nephrectomy was performed in 19 porcine renal units.
      Collecting system entry was confirmed by methylene blue instillation into the
      proximal ureter. Fibrin tissue sealant was used to repair 16 renal units, that is
      8 kidneys hardened in vivo for 10 minutes and 8 hardened in vivo for 60 minutes.
      In an additional 3 renal units monopolar electrocautery was used to achieve
      hemostasis (no fibrin glue used). The strength of vasculature repair was
      performed by infusing saline into the renal artery (renal vein ligated) and
      measuring pressure at bond rupture. Similarly the integrity of pelvicaliceal
      repair was evaluated by retrograde infusion of saline into the collecting system
      via the proximal ureter and measurement of pressure at bond rupture. RESULTS:
      Fibrin tissue sealant was successful in achieving prompt hemostasis and it was
      subjectively superior to cautery alone with regard to bleeding control. Mean
      renal vascular and pelvicaliceal burst pressure for fibrin sealant treated
      kidneys was 378 (median 420) and 166 mm Hg (median 170), respectively. There was
      no significant difference in 10 vs 60-minute hardening times in treated kidneys.
      In comparison, vascular and pelvicaliceal burst pressure for nontreated (cautery
      alone) kidneys was 230 (median 220) and 87 mm Hg (median 90), respectively.
      CONCLUSIONS: Commercially available fibrin tissue sealants can provide
      supraphysiological renal parenchyma and collecting system sealing pressures after
      partial nephrectomy. This information supports the potential use of fibrin
      sealants during open and laparoscopic partial nephrectomy.

PMID- 15201806
TI  - Monitoring the serological proteome: the latest modality in prostate cancer
      detection.
AB  - PURPOSE: Various strategies have recently emerged to improve the diagnostic
      prediction of prostate cancer (CaP). One such strategy includes the mass
      profiling of serum protein fractions selectively adsorbed onto chemically
      modified probes. In the current study we further validated this approach, while
      offering a more versatile, less expensive and yet equally predictive alternative
      to existing technologies. MATERIALS AND METHODS: A solid core lipophilic C-18
      resin was used to extract and enrich the low molecular weight protein fraction
      from patient serum for further analysis by mass spectrometry. Mass spectra
      generated from a 48 patient training set were data mined using multivariate
      analysis to identify diagnostically significant protein peaks. These peaks were
      then used to test a blinded study set comprising 168 patients with common
      statistical algorithms and commercially available software packages. RESULTS: A
      total of 36 peaks generated from the training set were used to test the combined
      set of 168 serum samples obtained from 98 healthy individuals and 70 patients
      with CaP. We report a sensitivity of 94.1% and a specificity of 99.0% with 1
      false-positive, 4 false-negative and 5 nondiagnosed cases. CONCLUSIONS: Our
      results further indicate that mass profiling of serological proteins provides a
      means for the accurate detection of CaP. In addition, our approach was found to
      be superior to chip based protocols, generating rich, sharp, highly reproducible
      spectra attainable in a high throughput manner and at minimal cost. This
      technique is also scaleable for subsequent protein characterization using
      multidimensional protein identification technologies. Finally, analyses of mass
      spectra with commercially available statistical applications was found to be
      highly effective in generating highly discriminatory m/z values for CaP
      diagnosis.

PMID- 15201807
TI  - Nitric oxide donating nonsteroidal anti-inflammatory drugs induce apoptosis in
      human prostate cancer cell systems and human prostatic stroma via caspase-3.
AB  - PURPOSE: New nitric oxide (NO) donating nonsteroidal anti-inflammatory drugs
      (NSAIDs) have been synthesized to counteract the side effects of conventional
      NSAIDs. Mounting evidence suggests that NSAIDs may have a possible
      chemopreventative/therapeutic role in prostate cancer. NO is a powerful
      biological messenger with multiple cellular effects. We established the effects
      of 2 of these new drugs in prostate cell systems. MATERIALS AND METHODS: We
      studied the effects of NO-ibuprofen (NCX 2111) and NO-aspirin (NCX 4060) on
      hormone sensitive (LNCap) and insensitive (PC3) prostate cancer epithelial cell
      lines as well as primary cultures of prostatic stroma. Proliferation was measured
      using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazalium bromide)
      assay to examine proliferation. Subsequently flow cytometry, cell cycle analysis
      and TUNEL staining were used to look for apoptosis. Caspase-3 expression was also
      examined in treated cell types. RESULTS: NCX 2111 and NCX 4060 were found to be
      potent inhibitors of proliferation in a dose dependent fashion. The 2 drugs
      induced apoptosis, as seen by flow cytometry, cell cycle analysis and TUNEL
      staining, at doses between 10 and 100 microM. These NO-NSAIDs increased caspase-3
      expression. NCX 4060 was more effective at lower concentrations (10 microM) but
      each compound was much more potent than conventional ibuprofen and aspirin at
      inducing apoptosis and inhibiting proliferation. CONCLUSIONS: NO-NSAIDs are
      potent antiproliferative pro-apoptotic compounds in prostate cell systems. This
      pro-apoptotic effect is mediated via caspase-3 and it is independent of the type
      of prostate cell used. These findings have ramifications for the use of these new
      drugs in prostate cancer chemoprevention or treatment.

PMID- 15201808
TI  - The speed of ice growth as an important indicator in cryosurgery.
AB  - PURPOSE: We consider the speed of ice growth as an indicator of the speed of
      cooling and investigated its impact on the factors at the cell death boundary in
      an in vitro simulated cryosurgical system. MATERIALS AND METHODS: PC-3 cells were
      cultured in culture plates and simulated cryosurgery was performed under
      different speeds of ice growth using an in vitro simulated cryosurgical system.
      The freezing front was closely monitored. Cells were fixed and stained 24 hours
      after cryosurgery. The distance from the cell death boundary to the ice front was
      measured and defined as the distance gap. It was correlated with the speed of ice
      growth. Temperature history at the cell death boundary was retrieved and also
      correlated with the speed of ice growth. RESULTS: A high correlation between the
      speed of ice growth and the temperature gradient plus an inverse correlation
      between the speed of ice growth and the distance gap were found. The distance gap
      narrowed when the speed of ice growth was around 3 mm per minute but widened when
      the speed of ice growth was slower than 1.5 mm per minute. CONCLUSIONS: Changes
      in ice growth speed indicate changes in the temperature gradient, and the
      distance between the ice front and the cell death boundary. Different treatment
      end points should be chosen according to the speed of ice growth to increase
      accurate cell killing.

PMID- 15201809
TI  - The effect of treatment strategy on stone comminution efficiency in shock wave
      lithotripsy.
AB  - PURPOSE: The comminution of kidney stones in shock wave lithotripsy (SWL) is a
      dose dependent process caused primarily by the combination of 2 fundamental
      mechanisms, namely stress waves and cavitation. The effect of treatment strategy
      with emphasis on enhancing the effect of stress waves or cavitation on stone
      comminution in SWL was investigated. Because vascular injury in SWL is also dose
      dependent, optimization of the treatment strategy may produce improved stone
      comminution with decreased tissue injury in SWL. MATERIALS AND METHODS: Using an
      in vitro experiment system that mimics stone fragmentation in the renal pelvis
      spherical BegoStone (Bego USA, Smithfield, Rhode Island) phantoms (diameter 10
      mm) were exposed to 1,500 shocks at a pulse repetition rate of 1 Hz in an
      unmodified HM-3 lithotripter (Dornier Medical Systems, Kennesaw, Georgia). The 3
      treatment strategies used were increasing output voltage from 18 to 20 and then
      to 22 kV every 500 shocks with emphasis on enhancing the effect of cavitation on
      medium fragments (2 to 4 mm) at the final treatment stage, decreasing output
      voltage from 22 to 20 and then to 18 kV every 500 shocks with emphasis on
      enhancing the effect of stress waves on large fragments (greater than 4 mm) at
      the initial treatment stage and maintaining a constant output voltage at 20 kV,
      as typically used in SWL procedures. Following shock wave exposure the size
      distribution of fragments was determined by the sequential sieving method. In
      addition, pressure waveforms at lithotripter focus (F2) produced at different
      output settings were measured using a fiber optic probe hydrophone. RESULTS: The
      rate of stone comminution in SWL varied significantly in a dose dependent manner
      depending on the treatment strategies used. Specifically the comminution
      efficiencies produced by the 3 strategies after the initial 500 shocks were
      30.7%, 59% and 41.9%, respectively. After 1,000 shocks the corresponding
      comminution efficiencies became similar (60.2%, 68.1% and 66.4%, respectively)
      with no statistically significant differences (p = 0.08). After 1,500 shocks the
      final comminution efficiency produced by the first strategy was 88.7%, which was
      better than the corresponding values of 81.2% and 83.5%, respectively, for the
      other 2 strategies. The difference between the final comminution efficiency of
      the first and second strategies was statistically significant (p = 0.005).
      CONCLUSIONS: Progressive increase in lithotripter output voltage can produce the
      best overall stone comminution in vitro.

PMID- 15201810
TI  - Determination of the calcium oxalate crystallization risk from urine samples: the
      BONN Risk Index in comparison to other risk formulas.
AB  - PURPOSE: Regular risk evaluation and risk monitoring during stone therapy are
      recommended measures to ensure reduction of recurrence of crystal formation. This
      strategy optimizes the patient treatment by a more individual approach and
      decreases expensive over treatment. We evaluated the BONN Risk Index (BRI)
      through data actualization and evaluation refinement. The BRI was compared with
      the most common methods of risk evaluation, namely calculation of relative
      urinary calcium oxalate (CaOx) supersaturation (RS) and of the urine activity
      product (AP)CaOx index to estimate the urine AP with respect to CaOx. MATERIALS
      AND METHODS: A total of 201, 12 and 24-hour urine samples were collected from 95
      healthy volunteers and from 106 CaOx stone formers. Crystallization experiments
      following the BRI method were performed. RS and APCaOx were calculated from
      urinalysis. Data were indexed and individually grouped into 8 classes, and
      frequency distributions were plotted. A calculation scheme for the BRI based
      estimation of the statistical probability of a clinically healthy person being a
      (still nondetected) CaOx stone former is provided. RESULTS: Logarithmically
      arranged BRI groups from healthy subject and patient data showed Gaussian
      frequency distributions. Compared with RS and APCaOx BRI allowed optimum
      distinction between healthy subjects and stone formers. The healthy subject
      probability of already being a CaOx stone former strongly increased with
      increasing BRI. CONCLUSIONS: The BRI for evaluating CaOx crystallization risk
      allows reliable distinction between healthy subjects and CaOx stone formers.
      Although RS and APCaOx require much more analytical efforts for determination,
      their results do not show higher reliability.

PMID- 15201811
TI  - Accumulated endogenous nitric oxide synthase inhibitors in inhibiting urethral
      relaxation following estrogen supplementation in ovariectomized rabbits.
AB  - PURPOSE: We investigated the possible role of the endogenous nitric oxide (NO)
      synthase (NOS) inhibitors N-monomethyl-L-arginine (L-NMMA) and asymmetrical N, N
      dimethyl-L-arginine (ADMA) in inhibiting urethral relaxation following estrogen
      supplementation in ovariectomized rabbits. MATERIALS AND METHODS: A total of 16
      mature Japanese White female rabbits were divided into 2 groups. In the control
      group rabbits were sacrificed 2 weeks after bilateral ovariectomy. In the
      estrogen group estradiol was administered subcutaneously for 2 weeks with the aid
      of sustained release pellet from 2 weeks after ovariectomy until sacrifice.
      Isolated urethra was cut into transverse strips for functional study and
      processed to determine endogenous NOS inhibitors, NOS activity, dimethylarginine
      dimethylaminohydrolase (DDAH) activity as a metabolizing enzyme of endogenous NOS
      inhibitors and cyclic guanosine monophosphate production. RESULTS: Electrical
      field stimulation produced NO mediated and neurogenic relaxation of the urethral
      strip in the presence of guanethidine and atropine under contraction with
      phenylephrine. Relaxation was significantly decreased in the estrogen group and
      accompanied by decreased cyclic guanosine monophosphate production. Sodium
      nitroprusside induced relaxation was not different between the 2 groups. The
      content of L-NMMA plus ADMA in the urethra was significantly increased in the
      estrogen group. Ca dependent NOS activity in the urethra remained unaffected.
      DDAH activity was significantly lower in the estrogen group. CONCLUSIONS:
      Estrogen supplementation leads to decreased NO mediated and neurogenic urethral
      relaxation through the accumulation of L-NMMA and ADMA in the urethra. The
      accumulation of NOS inhibitors is possibly brought about by impaired DDAH
      activity.

PMID- 15201812
TI  - 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits prostatic epithelial bud formation
      by acting directly on the urogenital sinus.
AB  - PURPOSE: In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
      exposure causes lobe specific inhibition of prostate development in C57BL/6 mice
      due primarily to region specific inhibition of prostatic epithelial bud formation
      by the urogenital sinus (UGS). This inhibition requires that the receptor for
      TCDD, the aryl hydrocarbon receptor (AhR), must be present. We tested the
      hypothesis that TCDD inhibits prostatic epithelial bud formation by acting
      directly on the UGS. MATERIALS AND METHODS: UGSs were removed from WT and AhR
      null mutant (AhRKO) male C57BL/6 mice on gestation day 14 and incubated in vitro
      with vehicle, 10-8 M testosterone or 10-8 M testosterone plus 10-9 M TCDD for 5
      days. Budding was evaluated by a newly developed technique, namely scanning
      electron microscopy of UGS epithelium after removal of UGS mesenchyme. RESULTS:
      Few buds were present in UGSs of either genotype in the absence of testosterone,
      while many were observed when testosterone was present. TCDD prevented prostatic
      epithelial buds from forming in UGSs from WT mice but it had no effect on UGSs
      from AhRKO mice. CONCLUSIONS: TCDD can act directly on the UGS to cause AhR
      dependent inhibition of prostatic epithelial bud formation. Because this
      inhibition occurred at a TCDD concentration similar to the estimated
      concentration at which TCDD inhibits bud formation in vivo, it appears that TCDD
      inhibits prostatic budding primarily via direct effects on the UGS rather than
      indirectly through effects on other organs.

PMID- 15201813
TI  - Involvement of increased arginase activity in impaired cavernous relaxation with
      aging in the rabbit.
AB  - PURPOSE: Arginase shares L-arginine as a common substrate with nitric oxide (NO)
      synthase (NOS). We examined whether increased arginase activity is involved in
      impaired cavernous relaxation with aging in the rabbit. MATERIALS AND METHODS:
      Young adult (3 to 5 months old) and aged (36 to 48 months old) rabbits were used
      for the current experiments. Cavernous tissues obtained from the 2 groups were
      processed for isometric tension experiments, cyclic guanosine monophosphate
      determination, measurements of NOS and arginase activities, endogenous
      methylarginines and L-arginine. RESULTS: Carbachol (CCh) produced an endothelium
      dependent and NO mediated relaxation that was significantly impaired in aged
      cavernous specimens without change in sodium nitroprusside induced relaxation.
      Stimulated cyclic guanosine monophosphate production with CCh was significantly
      decreased in aged cavernous specimens. Ca dependent NOS was predominant in rabbit
      cavernous specimens. Ca dependent and independent NOS activities remained
      unchanged in the 2 groups. The tissue contents of N-monomethyl-L-arginine and
      asymmetric N,N-dimethyl-L-arginine as endogenous NOS inhibitors, symmetrical N,N'
      dimethyl-L-arginine and L-arginine as a substrate of NOS were decreased in aged
      cavernous specimens. Arginase activity was significantly higher in aged cavernous
      specimens. Impaired CCh induced relaxation in aged cavernous specimens was
      normalized in the presence of N-hydroxy-L-arginine as an arginase inhibitor or by
      the supplementation of excess L-arginine. CONCLUSIONS: These results strongly
      suggest that impaired endothelium dependent and NO mediated cavernous relaxation
      with aging is due to decreased NO production, which would result from increased
      arginase activity and probably from decreased L-arginine content.

PMID- 15201814
TI  - Schwann cell seeded guidance tubes restore erectile function after ablation of
      cavernous nerves in rats.
AB  - PURPOSE: Dissection of the cavernous nerves eliminates spontaneous erections. We
      evaluated the ability of Schwann cell seeded nerve guidance tubes to restore
      erections after bilateral cavernous nerve resection in rats. MATERIALS AND
      METHODS: Sections (5 mm) of the cavernous nerve were excised bilaterally,
      followed by immediate bilateral microsurgical reconstruction. In 10 animals per
      group (20 study nerves) reconstruction was performed by genitofemoral nerve
      interposition, interposition of silicone tubes or interposition of silicone tubes
      seeded with homologous Schwann cells. As the control 10 animals (20 study nerves)
      underwent sham operation (positive control) and bilateral nerve ablation (without
      reconstruction) was performed in a further 10 (negative control). Erectile
      function was evaluated 3 months postoperatively by relaparotomy, electrical nerve
      stimulation and intracavernous pressure recording. RESULTS: After 3 months
      neurostimulation resulted in an intact erectile response in 90% (18 of 20) of
      Schwann cell grafts, while treatment with autologous nerves (30% or 6 of 20) or
      tubes only (50% or 10 of 20) was less successful (p <0.01). Whereas untreated
      ablated rats showed no inducible erections (0% or 0 of 20), all sham operated
      animals had an intact erectile response (100% or 20 of 20). Maximum
      intracavernous pressure upon electrostimulation was significantly elevated using
      Schwann cell grafts compared to results in the other treatment groups (p <0.001).
      Morphological evaluation revealed advanced regeneration within Schwann cell
      grafts. CONCLUSIONS: Schwann cell seeded guidance tubes restore erectile function
      after the ablation of cavernous nerves in rats and they are superior to
      autologous nerve grafts.

PMID- 15201815
TI  - Laboratory based training in urological microsurgery with bench model simulators:
      a randomized controlled trial evaluating the durability of technical skill.
AB  - PURPOSE: We evaluated the durability of laboratory based technical skills
      training in urological microsurgery using bench model simulators. METHODS AND
      MATERIALS: A total of 50 junior surgery residents (post-graduate years 1 to 3)
      were recruited to participate in a focused training program in urological
      microsurgery. Prior to training subjects were randomized to receive hands-on
      training with bench model simulators (silicone tubing or live rat vas deferens,
      40) or didactic training alone (10). Four months following the original training
      program the technical performance of 18 returning subjects (13 from the bench
      model and 5 from the didactic training group) was reevaluated using a high
      fidelity, live animal model (vasovasostomy and rat vas deferens). Outcome
      measures included blinded, expert assessment of videotaped performance using
      checklists and global rating scores, and evaluation of anastomotic patency.
      RESULTS: The retention test checklist (p <0.001), global rating scores (p <0.001)
      and anastomotic patency rates (p = 0.05) in the live animal model remained
      significantly higher for subjects who originally received hands-on bench model
      training compared with those who received didactic training alone. The number of
      interim practice opportunities with microsurgery correlated significantly with
      expert global ratings of surgical performance irrespective of the nature of
      training (r = 0.54, p = 0.02). CONCLUSIONS: Laboratory based technical skills
      training with bench models can lead to a significant retention of technical skill
      by novice surgeons. Measured performance improvements appear to be durable with
      time. However, the opportunity for repeat hands-on practice appears to maximize
      the retention of technical skill.

PMID- 15201816
TI  - Development of a renal tumor mimic model for learning minimally invasive nephron
      sparing surgical techniques.
AB  - PURPOSE: New laparoscopic partial nephrectomy and tumor ablation techniques are
      continuously being developed and evaluated in large animal models. However, to
      our knowledge no reliable renal tumor model exists to evaluate procedure
      efficacy. We developed and assessed the reliability of a tumor mimic model to
      serve as a training tool for minimally invasive kidney surgery. MATERIALS AND
      METHODS: An agarose based model was created using a mixture of 3% agarose, 3%
      cellulose, 7% glycerol and 0.05% methylene blue. It is liquid when heated, but
      solidifies after cooling to physiological temperatures. The agar was injected
      (0.7 cc) into porcine renal parenchyma to make endophytic or completely
      intraparenchymal lesions. Three-dimensional ultrasound images of the lesions were
      obtained during initial development to ensure spherical lesions. A group of 20
      lesions was initially placed in an ex vivo setting to assess size consistency and
      define baseline impedance characteristics. An additional 20 tumor mimics each
      were established in a laparoscopic model in a laparoscopic box trainer and an in
      vivo laparoscopic model. They were ablated with a temperature based radio
      frequency generator to assess impedance characteristics but the efficacy of
      ablation was not assessed. The in vivo model consisted of placing the agar lesion
      percutaneously under direct laparoscopic vision. RESULTS: The agarose mixture was
      easily injected and readily visible on ultrasound as hyperechoic distinct
      lesions. Lesions had a mean size of 10.8 +/- SD 1.3 mm on ultrasound and 10.9 +/-
      1.2 mm grossly. The impedance of normal renal parenchyma and unablated lesions
      was similar. Mean lesion size in the ex vivo model after radio frequency ablation
      was 9.8 +/- 2.0 mm on ultrasound, which was similar to the gross mean lesion size
      of 9.7 +/- 1.0 mm. Similar results were obtained for the in vivo model with a
      mean size of 10.1 +/- 2.1 and 10.4 +/- 1.5 mm, respectively. The lesions were
      easily identified grossly as blue solid lesions that replaced renal parenchyma.
      CONCLUSIONS: The described renal tumor mimic model reproducibly creates ex vivo
      and in vivo porcine kidney lesions. Lesion size and impedance do not change with
      the application of radio frequency energy. This model should be a valuable
      adjunct in the development, assessment and teaching of novel, nephron sparing,
      minimally invasive surgical techniques.

PMID- 15201817
TI  - Re: extended radical lymphadenectomy in patients with urothelial bladder cancer:
      results of a prospective multicenter study.

PMID- 15201819
TI  - Re: no increased prostate cancer incidence after negative transrectal ultrasound
      guided multiple biopsies in men with increased prostate specific antigen and/or
      abnormal digital rectal examination.

PMID- 15201820
TI  - Re: total pelvic exenteration: effective palliation of perineal pain in patients
      with locally recurrent prostate cancer.

PMID- 15201822
TI  - Re: a catheter based method to activate urethral sensory nerve fibers.

PMID- 15201823
TI  - Re: a survey of voiding dysfunction in children with attention deficit
      hyperactivity disorder.

PMID- 15201825
TI  - Re: urologists on a tightrope-do we have a net?

PMID- 15201829
TI  - Teaching symptom management in end-of-life care: the didactic content and
      teaching strategies based on the end-of-life nursing education curriculum.
AB  - Relief of symptoms for patients and families throughout the illness trajectory
      requires that palliative care practitioners have knowledge and skill, both in
      assessment and use of pharmacologic and complementary therapies. This article
      presents the didactic content of symptom assessment and management, and the
      experiential experiences used in a nondrug laboratory within the End-of-Life
      Nursing Education Consortium (ELNEC) curriculum.

PMID- 15201833
TI  - Preceptor preparation: an investment in the future.
AB  - Preceptor preparation is critical to the success of all orientation programs.
      This article focuses on the purposes of preceptor preparation and a series of
      programs developed for the staff of Surgical Services. The programs are leveled
      and focus on basic and advanced concepts. The advanced program is a means of
      reward and recognition for preceptors in the various surgical services areas. The
      programs are designed for nurses and other staff involved in precepting new
      employees.

PMID- 15201831
TI  - Structured orientation for new graduates: a retention strategy.
AB  - This program sought to increase retention rates through the use of a structured,
      progressive orientation program. Twenty new graduate nurses participated in the
      13-week program. Tools used to evaluate success were Performance Based
      Development System, American Society for Training and Development Evaluation
      Tool, the Professional Judgment Rating Form-Novice/Internship Level, and
      Retention Rates. Results of the program suggest that an orientation program
      focused on development of critical thinking skills, patient care management, and
      enhancement of self-esteem directly influenced retention.

PMID- 15201834
TI  - Clinical objectives: a method to evaluate clinical performance in critical care
      orientation.
AB  - Evaluation of clinical performance can often be difficult because of the
      subjectivity and lack of clinical objectives to guide the evaluation process.
      Although the use of clinical objectives is not a new concept, many orientation
      programs do not offer clinical objectives to assess the progress of the
      orientee's clinical learning. Effective evaluation of clinical performance has
      been a recurrent problem for nurse educators. This may be because of difficulty
      in clearly defining objective measurement criteria. This article details the use
      of clinical objectives in evaluation of clinical performance in nurses orienting
      to the critical care environment.

PMID- 15201835
TI  - Creating a successful clinical extern program using a program planning logic
      model.
AB  - Creative programs, such as a clinical externship for employment of nursing
      students, can be successfully created using a program planning logic model. The
      planning, implementation, and evaluation components of a clinical extern program
      will be demonstrated using logic model. The use of the logic model was
      instrumental to the success of the program.

PMID- 15201836
TI  - Genomics education for nurses in practice.
AB  - Genomics information will make it possible to identify individuals who have, or
      are at risk to develop, health problems and to diagnose and treat them in ways
      that until recently were not possible. The majority of nurses in practice today
      do not have adequate knowledge about genomics. This article describes a diverse
      and extensive education program initiated to provide information to nurses.
      Important aspects to consider for all nursing genomics education programs are
      that they need to be relevant to practice, multifaceted, and ongoing as
      information continues to unfold about the human genome and application to
      healthcare.

PMID- 15201837
TI  - The shortage of full-time nurses working at the bedside is becoming a national
      concern.

PMID- 15201838
TI  - Staff development story.

PMID- 15201841
TI  - Cigarette use among high school students--United States, 1991-2003.
AB  - Cigarette use is the leading preventable cause of death in the United States. One
      of the national health objectives for 2010 is to reduce the prevalence of current
      cigarette use among high school students to < or =16%. To examine changes in
      cigarette use among high school students in the United States during 199-2003,
      CDC analyzed data from the national Youth Risk Behavior Survey (YRBS). This
      report summarizes the results of that analysis, which indicated that although 1)
      the prevalence of lifetime cigarette use was stable among high school students
      during the 1990s and 2) the prevalence of both current and current frequent
      cigarette use increased into the late 1990s, all three behaviors had declined
      significantly by 2003. Prevention efforts must be sustained to ensure this
      pattern continues and the 2010 objective is achieved.

PMID- 15201842
TI  - Diminishing racial disparities in early-onset neonatal group B streptococcal
      disease--United States, 2000-2003.
AB  - Increased use of intrapartum antibiotics to prevent perinatal group B
      streptococcal (GBS) disease during the 1990s led to substantial declines in the
      incidence of GBS disease in newborns. Despite this success, at the end of the
      1990s, early-onset GBS disease (in infants aged <7 days) continued to be a
      leading infectious cause of neonatal mortality in the United States, and black
      infants remained at higher risk than white infants. In 2002, CDC and the American
      College of Obstetricians and Gynecologists (ACOG) revised guidelines for
      prevention of early-onset GBS disease to recommend late prenatal screening of all
      pregnant women and intrapartum antibiotic prophylaxis (IAP) for GBS carriers.
      These guidelines were expected to result in further declines in early-onset
      disease. This report updates early-onset incidence trends since 1999 analyzed by
      using population-based, multistate data from the Active Bacterial Core
      surveillance (ABCs)/Emerging Infections Program Network. The results of the
      analysis indicated that 1) after a plateau in early-onset disease incidence
      during 1999-2002, rates declined 34% in 2003 and 2) although racial disparities
      in incidence persist, rates for blacks now approach the 2010 national health
      objective of 0.5 cases per 1,000 live births. Continued implementation of
      screening and prophylaxis guidelines by clinicians and public health
      practitioners should lead to further declines in racial disparities.

PMID- 15201843
TI  - Laboratory practices for prenatal group B streptococcal screening--seven states,
      2003.
AB  - In the United States, group B streptococcus (GBS) is the leading cause of serious
      bacterial infections in newborns. In 1996, consensus guidelines for use of
      intrapartum antibiotic prophylaxis (IAP) to prevent perinatal GBS disease
      recommended either of two methods for identifying candidates for
      chemoprophylaxis: 1) late prenatal culture-based screening for GBS colonization
      or 2) monitoring of women intrapartum for particular risk factors associated with
      early-onset GBS disease. Evidence that culture-based screening was substantially
      more effective than the risk-based approach led to revised guidelines in 2002
      recommending late prenatal GBS screening for all pregnant women. Although methods
      for isolation and identification of GBS from prenatal specimens remained the same
      as those recommended in 1996, the 2002 guidelines recommended that laboratories
      perform antimicrobial susceptibility testing on prenatal GBS isolates from women
      at high risk for penicillin anaphylaxis and clarified that laboratories should
      report the presence of any GBS in urine specimens from pregnant women. To assess
      laboratory adherence to recommendations in the 2002 guidelines, CDC's Active
      Bacterial Core surveillance (ABCs)/Emerging Infections Program Network surveyed
      clinical laboratories about prenatal culture-processing practices in 2003. This
      report summarizes the results of that survey, which indicated that, although
      adherence to GBS isolation procedures was high, opportunities exist to improve
      implementation of recommendations related to antimicrobial susceptibility testing
      and GBS bacteriuria.

PMID- 15201844
TI  - Nontuberculous mycobacterial infections after cosmetic surgery--Santo Domingo,
      Dominican Republic, 2003-2004.
AB  - Rapidly growing mycobacteria have been associated with postoperative infections
      in patients undergoing cosmetic surgery procedures. In April 2004, CDC received
      reports of infections caused by rapidly growing mycobacteria in patients who had
      undergone cosmetic surgery procedures in Santo Domingo, Dominican Republic (DR).
      CDC, along with state and local health departments, is investigating additional
      cases identified by passive surveillance (i.e., solicitation of reports from
      clinicians by using electronic networks) and, in some areas, active surveillance
      (i.e., review of laboratory reports).

PMID- 15201845
TI  - Lead poisoning from ingestion of a toy necklace--Oregon, 2003.
AB  - Although ingestion of dust from lead-based paint is the most common source of
      lead exposure among children in the United States, lead also can be present in
      unsuspected objects. Ingestion of these objects can result in elevated blood lead
      levels (BLLs). This report describes an investigation by the Deschutes County
      Health Department and the Oregon Department of Human Services of lead poisoning
      in a boy who swallowed a medallion pendant from a necklace sold in a toy vending
      machine. The investigation resulted in a nationwide recall in September 2003 of
      the implicated toy necklace. Clinicians and caregivers should consider lead
      poisoning in any child who ingests, or puts in his mouth, a metal object. Cases
      of lead poisoning should be reported immediately to public health authorities to
      prevent other children from being exposed to the same sources of lead.

PMID- 15201846
TI  - West Nile virus activity--United States, June 9-15, 2004.
AB  - As of June 15, a total of 14 human cases of West Nile virus (WNV) illness had
      been reported to CDC through ArboNET from five states. Ten cases were reported
      from Arizona, and one case each from California, New Mexico, South Dakota, and
      Wyoming (Figure). Ten (71%) of the cases occurred in males; the median age of
      patients was 53 years (range: 9-69 years), and dates of illness onset ranged from
      May 8 to June 1.

PMID- 15201847
TI  - Coral communities are regionally enriched along an oceanic biodiversity gradient.
AB  - Ecological communities are influenced by processes operating at multiple scales.
      Thus, a better understanding of how broad- as well as local-scale processes
      affect species diversity and richness is increasingly becoming a central focus in
      modern community ecology. Here, in a study of unprecedented geographical scope,
      we show significant regional and local variation in the species richness of coral
      assemblages across an oceanic biodiversity gradient. The gradient that we sampled
      extends 10,000 km eastwards from the world's richest coral biodiversity hotspot
      in the central Indo-Pacific. Local richness and the size of regional species
      pools decline significantly across 15 islands spanning the gradient. In addition,
      richness declines across three adjacent habitats (reef slopes, crests and flats).
      In each habitat, a highly consistent linear relationship between local and
      regional species richness indicates strong regional enrichment. Thus, even on the
      most diverse coral reefs in the world, local coral assemblages are profoundly
      affected by regional-scale processes. Understanding these historical and
      biogeographical influences is essential for the effective management and
      preservation of these endangered communities.

PMID- 15201848
TI  - MRD parameters using immunophenotypic detection methods are highly reliable in
      predicting survival in acute myeloid leukaemia.
AB  - Outgrowth of minimal residual disease (MRD) in acute myeloid leukaemia (AML) is
      responsible for the occurrence of relapses. MRD can be quantified by
      immunophenotyping on a flow cytometer using the expression of leukaemia
      associated phenotypes. MRD was monitored in follow-up samples taken from bone
      marrow (BM) of 72 patients after three different cycles of chemotherapy and from
      autologous peripheral blood stem cell (PBSC) products. The MRD% in BM after the
      first cycle (n=51), second cycle (n=52) and third cycle (n=30), as well as in
      PBSC products (n=39) strongly correlated with relapse-free survival. At a cutoff
      level of 1% after the first cycle and median cutoff levels of 0.14% after the
      second, 0.11% after the third cycle and 0.13% for PBSC products, the relative
      risk of relapse was a factor 6.1, 3.4, 7.2 and 5.7, respectively, higher for
      patients in the high MRD group. Also, absolute MRD cell number/ml was highly
      predictive of the clinical outcome. After the treatment has ended, an increase of
      MRD% predicted forthcoming relapses, with MRD assessment intervals of < or =3
      months. In conclusion, MRD parameter assessment at different stages of disease is
      highly reliable in predicting survival and forthcoming relapses in AML.

PMID- 15201849
TI  - Betulinic acid-induced apoptosis in leukemia cells.
AB  - Betulinic acid (BA), a natural component isolated from Birch trees, effectively
      induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little
      toxicity in animal trials. Here, we show that BA-induced marked apoptosis in 65%
      of primary pediatric acute leukemia cells and all leukemia cell lines tested.
      When compared for in vitro efficiency with conventionally used cytotoxic drugs,
      BA was more potent than nine out of 10 standard therapeutics and especially
      efficient in tumor relapse. No crossresistances were found between BA and any
      cytotoxic drug. Intracellular apoptosis signaling in leukemia tumor cells
      paralleled the pathway found in neuroectodermal cells involving caspases, but not
      death receptors. In isolated mitochondria, BA induced release of both cytochrome
      c and Smac. Taken together, BA potently induces apoptosis in leukemia cells and
      should be further evaluated as a future drug to treat leukemia.

PMID- 15201850
TI  - Waldenstrom's macroglobulinemia evolving into acute lymphoblastic leukemia: a
      case report and a review of the literature.

PMID- 15201851
TI  - Development of a quantitative-PCR method for specific FLT3/ITD monitoring in
      acute myeloid leukemia.

PMID- 15201853
TI  - The first evidence of the tumor-induced angiogenesis in vivo by using the
      chorioallantoic membrane assay dated 1913.

PMID- 15201852
TI  - Clinical features of childhood acute myeloid leukaemia with specific gene
      rearrangements.

PMID- 15201854
TI  - Low-dose ARAC, donor cells, and GM-CSF for treatment of recurrent acute myeloid
      leukemia after allogeneic stem cell transplantation.

PMID- 15201855
TI  - Topoisomerase IIalpha as a prognostic factor in mantle cell lymphoma.

PMID- 15201856
TI  - Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells
      sensitive and resistant to imatinib mesylate.
AB  - Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been
      cast into shadow by the evolution of clinical resistance during therapy.
      Resistance to imatinib can arise by multiple mechanisms including amplification
      or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor
      option for either of these patient groups. Recently, however, a structurally
      distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described,
      and these compounds are predicted to make different molecular contacts in the Abl
      kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase
      activities, both of which are thought to be relevant to survival of the leukemic
      cell. We asked whether these drugs could selectively induce cell death in murine
      cell line models of CML cells sensitive and resistant to imatinib by different
      mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly
      potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant
      cells, they are almost completely ineffective against cells expressing the T315I
      mutant. This implies that despite structural differences from imatinib, these
      drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl
      protein, but may be effective in cases where selection of cells overexpressing
      the oncoprotein leads to refractoriness to imatinib.

PMID- 15201857
TI  - Immediate changes in lung compliance following natural surfactant administration
      in premature infants with respiratory distress syndrome: a controlled trial.
AB  - OBJECTIVE: To compare immediate changes in lung compliance following the
      administration of two commercially available natural surfactants. METHOD: We
      conducted a prospective, randomized study of 40 preterm infants with respiratory
      distress syndrome requiring surfactant. Infants received either Infasurf or
      Survanta. The primary outcome measure was the change in compliance assessed by
      bedside pulmonary monitoring. RESULTS: There were no significant changes in
      dynamic lung compliance within or between the two groups 1 hour after surfactant
      administration. However, infants given Survanta required more doses per patient
      (4 vs 2, p=0.05) and were more likely to require >2 doses (57 vs 26%, p=0.05).
      Infants requiring >1 dose of surfactant had a greater change in airway pressure
      and improved oxygenation just before the second dose when treated with Infasurf.
      CONCLUSIONS: We found no significant difference in acute changes in lung
      compliance. However, treatment with Infasurf seems to be more long lasting than
      Survanta.

PMID- 15201858
TI  - The importance of iatrogenesis in the founding of modern neonatology.

PMID- 15201859
TI  - Exercise blood pressure in young adults as a predictor of future blood pressure:
      a 12-year follow-up of medical school graduates.
AB  - It has not been fully clarified whether exercise blood pressure (BP) in young
      adult men and women is useful to predict future BP, especially in Asian people. A
      long-term prospective study was conducted in graduates of a medical school in
      Japan; 138 men and 76 women whose mean age was 19.8 and 19.2, respectively, at
      baseline. A 5-min exercise tolerance test was performed at baseline, and BP
      immediately after exercise was measured. BP at 50% intensity exercise was also
      calculated. Multiple regression analysis was carried out to clarify the
      relationship of exercise BP at baseline to follow-up BP after an average of 12
      years. In multivariate-adjusted models, the relationship of systolic blood
      pressure (SBP) at follow-up was stronger to SBP immediately after exercise
      (F=7.7, P=0.006) than to resting SBP (F=3.7, P=0.055) in men. The models in men
      showed that SBP immediately after exercise was a stronger predictor of follow-up
      SBP than SBP at 50% intensity exercise, and the results were similar for
      diastolic blood pressure (DBP) in men. For SBP in women, resting SBP was the
      strongest predictor of follow-up SBP (F=14.3, P<0.001), and exercise SBP was not
      significant predictor. For DBP in women, any DBP at rest or after exercise was
      not significantly related to DBP at follow-up. In young adult men, SBP and DBP
      immediately after exercise would be a stronger predictor of future SBP and DBP
      rather than BP at rest. However, in young adult women, resting SBP rather than
      exercise SBP would be better to predict future SBP.

PMID- 15201860
TI  - Why do patients with erectile dysfunction abandon effective therapy with
      sildenafil (Viagra)?
AB  - This prospective study determined the rate of abandonment of sildenafil therapy
      and assessed the reasons for abandonment. Between January 2001 and December 2002,
      234 patients with erectile dysfunction (ED) at three independent centers
      successfully began therapy with sildenafil 50 or 100 mg. The rate of
      noncompliance was 31%. A telephone survey of these patients was conducted to
      determine the reasons for abandonment. The majority reported that they had had no
      opportunity or desire for sexual intercourse or that their partners had shown no
      sexual interest. Few patients stated that the high cost of the medication or that
      adverse events were the cause.

PMID- 15201861
TI  - Role of penile electrodermal activity in the evaluation of autonomic innervation
      of corpus cavernosum.
AB  - Electrodiagnostic tests measuring the activities of cavernous smooth muscle and
      sudomotor structures of penile skin are used in order to evaluate autonomic
      innervation of the penis. Owing to closeness of these tissues, the interference
      of sympathetic activity during recording is a possibility. In this study, we
      investigated this possibility in 10 patients whose cavernosal tissues were
      destroyed during penile prosthesis implantation by comparing the pre- and
      postoperative penile skin electrodermal activities. Penile electrodermal
      activities were recorded with surface electrodes before and after the operation.
      All of the patients had spontaneous and evoked penile electrodermal activity
      (EDA). The mean amplitude of evoked EDA decreased from 2159+/-700 to 1413+/-515
      microV following penile prosthesis surgery (P=0.017). The decrease in the
      amplitude of penile-evoked EDA following penile prosthesis implantation suggests
      the contribution of cavernous smooth muscle activity to the sudomotor responses
      prior to operation. Although corpus cavernosum sympathetic activity contributes
      to the penile skin recordings, these recordings are mostly the result of penile
      skin sudomotor sympathetic activity. Therefore, surface potentials recorded from
      penile skin should not be used for the evaluation of autonomic innervation of
      corpus cavernosum.

PMID- 15201862
TI  - Cloning of murine IL-22 receptor alpha 2 and comparison with its human
      counterpart.
AB  - We have identified the mouse and rat homologs of human interleukin-22 receptor
      alpha 2 (IL-22R alpha 2) and compared the localization, structure, and expression
      of the encoding murine and human genes. The mouse IL-22R alpha 2-encoding gene is
      located on chromosome 10A3 between, like in human, the genes for interferon-gamma
      R1 and IL-20R1. It spans a region of approximately 10 kb therefore being three
      times shorter than the human gene. Although the overall gene structure in both
      species is similar, the mouse gene lacks a counterpart to the third coding exon
      of the human gene known to be alternatively spliced. Like in human, mouse and rat
      IL-22R alpha 2 exist only as soluble receptors as deduced from the lack of
      transmembrane and intracellular domains encoding sequences. Quantitative
      expression analyses showed, analogically to the human system, a limited tissue
      distribution of mouse IL-22R alpha 2 mRNA. Differential modulation of IL-22R
      alpha 2 mRNA expression was observed upon systemic inflammation in mice in
      spleen, thymus, and lymph node.

PMID- 15201863
TI  - Genetic control of autoantibody expression in autoimmune myasthenia gravis: role
      of the self-antigen and of HLA-linked loci.
AB  - Autoantibodies against the muscle acetylcholine receptor (AChR) play an essential
      role in the pathophysiology of autoimmune myasthenia gravis (MG). Their serum
      titers, however, vary considerably among patients. Our aim was to investigate
      whether their variation might be explained by genetic factors. Using different
      methods, we have obtained strong evidence for a three-locus association
      influencing autoantibody titers in MG patients with thymus hyperplasia or with a
      normal thymus. Two of the loci, one encoding the AChR alpha-subunit, the other
      encoding the alpha-chain of the class II antigen-presentation molecule, HLA-DQ,
      demonstrated interaction to determine high autoantibody titers. The third locus
      was associated with the 8.1 ancestral HLA haplotype. It exerted an additive
      effect and it is postulated to have a nonantigen specific immunoregulatory
      function. Our study demonstrates for the first time that polymorphism of an
      autoantigen gene may quantitatively modify the immune response against it.
      Altogether, the data lend support to a three-gene model to explain autoantibody
      expression in a subset of MG patients.

PMID- 15201864
TI  - Structural basis of dynamic glycine receptor clustering by gephyrin.
AB  - Gephyrin is a bi-functional modular protein involved in molybdenum cofactor
      biosynthesis and in postsynaptic clustering of inhibitory glycine receptors
      (GlyRs). Here, we show that full-length gephyrin is a trimer and that its
      proteolysis in vitro causes the spontaneous dimerization of its C-terminal region
      (gephyrin-E), which binds a GlyR beta-subunit-derived peptide with high and low
      affinity. The crystal structure of the tetra-domain gephyrin-E in complex with
      the beta-peptide bound to domain IV indicates how membrane-embedded GlyRs may
      interact with subsynaptic gephyrin. In vitro, trimeric full-length gephyrin forms
      a network upon lowering the pH, and this process can be reversed to produce
      stable full-length dimeric gephyrin. Our data suggest a mechanism by which
      induced conformational transitions of trimeric gephyrin may generate a reversible
      postsynaptic scaffold for GlyR recruitment, which allows for dynamic receptor
      movement in and out of postsynaptic GlyR clusters, and thus for synaptic
      plasticity.

PMID- 15201865
TI  - Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent
      chromatin retention.
AB  - Mdc1/NFBD1 controls cellular responses to DNA damage, in part via interacting
      with the Mre11-Rad50-Nbs1 complex that is involved in the recognition,
      signalling, and repair of DNA double-strand breaks (DSBs). Here, we show that in
      live human cells, the transient interaction of Nbs1 with DSBs and its
      phosphorylation by ATM are Mdc1-independent. However, ablation of Mdc1 by siRNA
      or mutation of the Nbs1's FHA domain required for Mdc1 binding reduced the
      affinity of Nbs1 for DSB-flanking chromatin and caused aberrant pan-nuclear
      dispersal of Nbs1. This occurred despite normal phosphorylation of H2AX,
      indicating that lack of Mdc1 does not impair this DSB-induced chromatin change,
      but rather precludes the sustained engagement of Nbs1 with these regions. Mdc1
      (but not Nbs1) became partially immobilized to chromatin after DSB generation,
      and siRNA-mediated depletion of H2AX prevented such relocalization of Mdc1 and
      uncoupled Nbs1 from DSB-flanking chromatin. Our data suggest that Mdc1 functions
      as an H2AX-dependent interaction platform enabling a switch from transient, Mdc1
      independent recruitment of Nbs1 to DSBs towards sustained, Mdc1-dependent
      interactions with the surrounding chromosomal microenvironment.

PMID- 15201866
TI  - Retroviral mRNA nuclear export elements regulate protein function and virion
      assembly.
AB  - Rodent cells are notable for their inability to support normal assembly of HIV
      particles. In this report, we address possible causes for this defect by
      considering the hypothesis that mRNA-associated events occurring in the nucleus
      can regulate the activity of their encoded proteins in the cytoplasm. We show
      that altering the RNA nuclear export element used by HIV gag-pol mRNA from the
      Rev response element to the constitutive transport element restores both the
      trafficking of Gag to cellular membranes and efficient HIV assembly in murine
      cells. These results suggest that two phases of the HIV life cycle, RNA export
      and capsid assembly, that have hitherto been regarded as distinct are, in fact,
      linked. Thus, protein function and fate may depend upon the full and precise
      history of its encoding mRNA.

PMID- 15201867
TI  - Mmr1p is a mitochondrial factor for Myo2p-dependent inheritance of mitochondria
      in the budding yeast.
AB  - Class V myosins play a pivotal role in organelle distribution. In the budding
      yeast, Myo2p, a class V myosin, is essential for mitochondrial distribution. We
      identified MMR1 as a high-dose suppressor of the myo2 mitochondrial defect and
      that Mmr1p resides restrictively on the bud-localizing mitochondria and forms a
      complex with Myo2p tail. Mmr1p loss delayed mitochondrial transfer to buds and
      completely abolished mitochondrial distribution in the absence of Ypt11p, which
      promotes mitochondrial distribution by complex formation with Myo2p tail. The
      myo2-573 mutation, which causes a mitochondrial distribution defect and
      inactivates the Mmr1p function, reduced association between Myo2p and Mmr1p and
      depolarized Mmr1p localization on mitochondria. These strongly suggest that Mmr1p
      is a key mitochondrial component of the link between Myo2p and mitochondria for
      Myo2p-dependent mitochondrial distribution. Genetical analysis revealed that the
      Mmr1p-Myo2p pathway is independent of the Ypt11p-Myo2p pathway, suggesting that
      an essential system for mitochondrial distribution is composed of two independent
      Myo2p pathways.

PMID- 15201870
TI  - Schools at 10(20) eV and beyond.

PMID- 15201871
TI  - On with the show.

PMID- 15201868
TI  - The newly discovered Q motif of DEAD-box RNA helicases regulates RNA-binding and
      helicase activity.
AB  - DEAD-box proteins are the most common RNA helicases, and they are associated with
      virtually all processes involving RNA. They have nine conserved motifs that are
      required for ATP and RNA binding, and for linking phosphoanhydride cleavage of
      ATP with helicase activity. The Q motif is the most recently identified conserved
      element, and it occurs approximately 17 amino acids upstream of motif I. There is
      a highly conserved, but isolated, aromatic group approximately 17 amino acids
      upstream of the Q motif. These two elements are involved in adenine recognition
      and in ATPase activity of DEAD-box proteins. We made extensive analyses of the Q
      motif and upstream aromatic residue in the yeast translation-initiation factor
      Ded1. We made site-specific mutations and tested them for viability in yeast.
      Moreover, we purified various mutant proteins and obtained the Michaelis-Menten
      parameters for the ATPase activities. We also measured RNA affinities and strand
      displacement activities. We find that the Q motif not only regulates ATP binding
      and hydrolysis but also regulates the affinity of the protein for RNA substrates
      and ultimately the helicase activity.

PMID- 15201869
TI  - Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T)
      inhibitor.
AB  - The positive transcription elongation factor b (P-TEFb) plays a pivotal role in
      productive elongation of nascent RNA molecules by RNA polymerase II. Core active
      P-TEFb is composed of CDK9 and cyclin T. In addition, mammalian cell extracts
      contain an inactive P-TEFb complex composed of four components, CDK9, cyclin T,
      the 7SK snRNA and the MAQ1/HEXIM1 protein. We now report an in vitro
      reconstitution of 7SK-dependent HEXIM1 association to purified P-TEFb and
      subsequent CDK9 inhibition. Yeast three-hybrid tests and gel-shift assays
      indicated that HEXIM1 binds 7SK snRNA directly and a 7SK snRNA-recognition motif
      was identified in the central part of HEXIM1 (amino acids (aa) 152-155). Data
      from yeast two-hybrid and pull-down assay on GST fusion proteins converge to a
      direct binding of P-TEFb to the HEXIM1 C-terminal domain (aa 181-359).
      Consistently, point mutations in an evolutionarily conserved motif (aa 202-205)
      were found to suppress P-TEFb binding and inhibition without affecting 7SK
      recognition. We propose that the RNA-binding domain of HEXIM1 mediates its
      association with 7SK and that P-TEFb then enters the complex through association
      with HEXIM1.

PMID- 15201872
TI  - Scientists cry foul as Elsevier axes paper on cancer mortality.

PMID- 15201873
TI  - Funding review set to buck up basic research.

PMID- 15201874
TI  - Fresh study questions oldest traces of life in Akilia rock.

PMID- 15201875
TI  - Dutch set the pace in bid to clean up diet supplements.

PMID- 15201877
TI  - Future brightens for Eddington project to hunt distant planets.

PMID- 15201876
TI  - Genomics institute rejects Venter's streamlining plan.

PMID- 15201878
TI  - Bacteria raid may lead to trial for artist tackling biodefence.

PMID- 15201879
TI  - Stem-cell library boosts the case for change.

PMID- 15201880
TI  - Alcohol report directs drinkers to their doctors.

PMID- 15201882
TI  - Oil exploration: every last drop.

PMID- 15201883
TI  - Mental health: Asia's tigers get the blues.

PMID- 15201884
TI  - European science must embrace modernization.

PMID- 15201885
TI  - Reliable regional climate model not yet on horizon.

PMID- 15201886
TI  - Fame and popularity are no bar to Royal Society.

PMID- 15201891
TI  - The ties that bind.

PMID- 15201892
TI  - Planetary science: on Earth, as it is on Mars?

PMID- 15201893
TI  - Molecular biology: the loader of the rings.

PMID- 15201894
TI  - Laser physics: fantastic plastic.

PMID- 15201896
TI  - Neurobiology: why voles stick together.

PMID- 15201897
TI  - Quantum physics: push-button teleportation.

PMID- 15201898
TI  - Atmospheric chemistry: fire and ice.

PMID- 15201899
TI  - Obituary: Carl-Ivar Branden (1934-2004).

PMID- 15201902
TI  - A possible terrestrial analogue for haematite concretions on Mars.
AB  - Recent exploration has revealed extensive geological evidence for a water-rich
      past in the shallow subsurface of Mars. Images of in situ and loose accumulations
      of abundant, haematite-rich spherical balls from the Mars Exploration Rover
      'Opportunity' landing site at Meridiani Planum bear a striking resemblance to
      diagenetic (post-depositional), haematite-cemented concretions found in the
      Jurassic Navajo Sandstone of southern Utah. Here we compare the spherical
      concretions imaged on Mars to these terrestrial concretions, and investigate the
      implications for analogous groundwater-related formation mechanisms. The
      morphology, character and distribution of Navajo haematite concretions allow us
      to infer host-rock properties and fluid processes necessary for similar features
      to develop on Mars. We conclude that the formation of such spherical haematite
      concretions requires the presence of a permeable host rock, groundwater flow and
      a chemical reaction front.

PMID- 15201901
TI  - Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex.
AB  - Sliding clamps are ring-shaped proteins that encircle DNA and confer high
      processivity on DNA polymerases. Here we report the crystal structure of the five
      protein clamp loader complex (replication factor-C, RFC) of the yeast
      Saccharomyces cerevisiae, bound to the sliding clamp (proliferating cell nuclear
      antigen, PCNA). Tight interfacial coordination of the ATP analogue ATP-gammaS by
      RFC results in a spiral arrangement of the ATPase domains of the clamp loader
      above the PCNA ring. Placement of a model for primed DNA within the central hole
      of PCNA reveals a striking correspondence between the RFC spiral and the grooves
      of the DNA double helix. This model, in which the clamp loader complex locks onto
      primed DNA in a screw-cap-like arrangement, provides a simple explanation for the
      process by which the engagement of primer-template junctions by the RFC:PCNA
      complex results in ATP hydrolysis and release of the sliding clamp on DNA.

PMID- 15201903
TI  - Deterministic quantum teleportation with atoms.
AB  - Teleportation of a quantum state encompasses the complete transfer of information
      from one particle to another. The complete specification of the quantum state of
      a system generally requires an infinite amount of information, even for simple
      two-level systems (qubits). Moreover, the principles of quantum mechanics dictate
      that any measurement on a system immediately alters its state, while yielding at
      most one bit of information. The transfer of a state from one system to another
      (by performing measurements on the first and operations on the second) might
      therefore appear impossible. However, it has been shown that the entangling
      properties of quantum mechanics, in combination with classical communication,
      allow quantum-state teleportation to be performed. Teleportation using pairs of
      entangled photons has been demonstrated, but such techniques are probabilistic,
      requiring post-selection of measured photons. Here, we report deterministic
      quantum-state teleportation between a pair of trapped calcium ions. Following
      closely the original proposal, we create a highly entangled pair of ions and
      perform a complete Bell-state measurement involving one ion from this pair and a
      third source ion. State reconstruction conditioned on this measurement is then
      performed on the other half of the entangled pair. The measured fidelity is 75%,
      demonstrating unequivocally the quantum nature of the process.

PMID- 15201905
TI  - In situ observation of colloidal monolayer nucleation driven by an alternating
      electric field.
AB  - The nucleation of crystalline materials is a hotly debated subject in the
      physical sciences. Despite the emergence of several theories in recent decades,
      much confusion still surrounds the dynamic processes of nucleation. This has been
      due in part to the limitations of existing experimental evidence. Charged
      colloidal suspensions have been used as experimental model systems for the study
      of crystal nucleation and structural phase transitions, as their crystallization
      phase diagram is analogous to that of atomic and molecular systems, but they can
      be visualized using microscopy. Previously, three-dimensional imaging of
      colloidal nucleation dynamics was achieved using confocal microscopy. However,
      the limited temporal resolution of the confocal microscope is of concern when
      trying to capture real-time colloidal crystal nucleation events. Moreover, as the
      thermodynamic driving force has remained undefined, data on key factors such as
      the critical nuclei size are at best semiquantitative. Here we present real-time
      direct imaging and quantitative measurements of the pre- and post-nucleation
      processes of colloidal spheres, and the kinetics of nucleation driven by an
      alternating electric field, under well-defined thermodynamic driving forces. Our
      imaging approach could facilitate the observation of other rarely observed
      phenomena, such as defect and grain-boundary formation and the effects of foreign
      particles during crystallization. Furthermore, it may prove useful in identifying
      optical and biological technologies based on colloids.

PMID- 15201904
TI  - Deterministic quantum teleportation of atomic qubits.
AB  - Quantum teleportation provides a means to transport quantum information
      efficiently from one location to another, without the physical transfer of the
      associated quantum-information carrier. This is achieved by using the non-local
      correlations of previously distributed, entangled quantum bits (qubits).
      Teleportation is expected to play an integral role in quantum communication and
      quantum computation. Previous experimental demonstrations have been implemented
      with optical systems that used both discrete and continuous variables, and with
      liquid-state nuclear magnetic resonance. Here we report unconditional
      teleportation of massive particle qubits using atomic (9Be+) ions confined in a
      segmented ion trap, which aids individual qubit addressing. We achieve an average
      fidelity of 78 per cent, which exceeds the fidelity of any protocol that does not
      use entanglement. This demonstration is also important because it incorporates
      most of the techniques necessary for scalable quantum information processing in
      an ion-trap system.

PMID- 15201906
TI  - The influence of ridge migration on the magmatic segmentation of mid-ocean
      ridges.
AB  - The Earth's mid-ocean ridges display systematic changes in depth and shape, which
      subdivide the ridges into discrete spreading segments bounded by transform faults
      and smaller non-transform offsets of the axis. These morphological changes have
      been attributed to spatial variations in the supply of magma from the mantle,
      although the origin of the variations is poorly understood. Here we show that
      magmatic segmentation of ridges with fast and intermediate spreading rates is
      directly related to the migration velocity of the spreading axis over the mantle.
      For over 9,500 km of mid-ocean ridge examined, leading ridge segments in the
      'hotspot' reference frame coincide with the shallow magmatically robust segments
      across 86 per cent of all transform faults and 73 per cent of all second-order
      discontinuities. We attribute this relationship to asymmetric mantle upwelling
      and melt production due to ridge migration, with focusing of melt towards ridge
      segments across discontinuities. The model is consistent with variations in
      crustal structure across discontinuities of the East Pacific Rise, and may
      explain variations in depth of melting and the distribution of enriched lavas.

PMID- 15201907
TI  - Radiocarbon evidence of mid-Holocene mammoths stranded on an Alaskan Bering Sea
      island.
AB  - Island colonization and subsequent dwarfing of Pleistocene proboscideans is one
      of the more dramatic evolutionary and ecological occurrences, especially in
      situations where island populations survived end-Pleistocene extinctions whereas
      those on the nearby mainland did not. For example, Holocene mammoths have been
      dated from Wrangel Island in northern Russia. In most of these cases, few details
      are available about the dynamics of how island colonization and extinction
      occurred. As part of a large radiocarbon dating project of Alaskan mammoth
      fossils, I addressed this question by including mammoth specimens from Bering Sea
      islands known to have formed during the end-Pleistocene sea transgression. One
      date of 7,908 +/- 100 yr bp (radiocarbon years before present) established the
      presence of Holocene mammoths on St Paul Island, a first Holocene island record
      for the Americas. Four lines of evidence--265 accelerator mass spectrometer (AMS)
      radiocarbon dates from Alaskan mainland mammoths, 13 new dates from Alaskan
      island mammoths, recent reconstructions of bathymetric plots and sea
      transgression rates from the Bering Sea--made it possible to reconstruct how
      mammoths became stranded in the Pribilofs and why this apparently did not happen
      on other Alaskan Bering Sea islands.

PMID- 15201908
TI  - Upwelling-driven nearshore hypoxia signals ecosystem and oceanographic changes in
      the northeast Pacific.
AB  - Seasonal development of dissolved-oxygen deficits (hypoxia) represents an acute
      system-level perturbation to ecological dynamics and fishery sustainability in
      coastal ecosystems around the globe. Whereas anthropogenic nutrient loading has
      increased the frequency and severity of hypoxia in estuaries and semi-enclosed
      seas, the occurrence of hypoxia in open-coast upwelling systems reflects ocean
      conditions that control the delivery of oxygen-poor and nutrient-rich deep water
      onto continental shelves. Upwelling systems support a large proportion of the
      world's fisheries, therefore understanding the links between changes in ocean
      climate, upwelling-driven hypoxia and ecological perturbations is critical. Here
      we report on the unprecedented development of severe inner-shelf (<70 m) hypoxia
      and resultant mass die-offs of fish and invertebrates within the California
      Current System. In 2002, cross-shelf transects revealed the development of
      abnormally low dissolved-oxygen levels as a response to anomalously strong flow
      of subarctic water into the California Current System. Our findings highlight the
      sensitivity of inner-shelf ecosystems to variation in ocean conditions, and the
      potential impacts of climate change on marine communities.

PMID- 15201910
TI  - Local-feature assembling in visual pattern recognition and generalization in
      honeybees.
AB  - Generalization is a cognitive ability that allows similar stimuli along a given
      dimension to be treated as equivalents. Insects exhibit high levels of visual
      generalization. Honeybees trained to recognize complex visual stimuli on the
      basis of a single feature generalize their choice to novel stimuli sharing that
      common feature with the trained stimuli. The demonstration of this kind of
      performance has been limited to the use of a single visual feature, and the
      possibility that bees link different features in learning a visual pattern has
      been denied. Here we show that honeybees trained with a series of complex
      patterns sharing a common layout comprising four edge orientations remember these
      orientations simultaneously in their appropriate positions, and generalize their
      response to novel stimuli that preserve the trained layout. Honeybees also
      generalize their response to patterns with fewer correct orientations, depending
      on their match with the trained layout. Stimulation of the achromatic L
      photoreceptor input is necessary for this task. The mini-brain of the honeybee
      can thus extract regularities in its environment and establish correspondences
      among correlated features. It can thus generate a large set of object
      descriptions from a finite set of elements.

PMID- 15201909
TI  - Enhanced partner preference in a promiscuous species by manipulating the
      expression of a single gene.
AB  - The molecular mechanisms underlying the evolution of complex behaviour are poorly
      understood. The mammalian genus Microtus provides an excellent model for
      investigating the evolution of social behaviour. Prairie voles (Microtus
      ochrogaster) exhibit a monogamous social structure in nature, whereas closely
      related meadow voles (Microtus pennsylvanicus) are solitary and polygamous. In
      male prairie voles, both vasopressin and dopamine act in the ventral forebrain to
      regulate selective affiliation between adult mates, known as pair bond formation,
      as assessed by partner preference in the laboratory. The vasopressin V1a receptor
      (V1aR) is expressed at higher levels in the ventral forebrain of monogamous than
      in promiscuous vole species, whereas dopamine receptor distribution is relatively
      conserved between species. Here we substantially increase partner preference
      formation in the socially promiscuous meadow vole by using viral vector V1aR gene
      transfer into the ventral forebrain. We show that a change in the expression of a
      single gene in the larger context of pre-existing genetic and neural circuits can
      profoundly alter social behaviour, providing a potential molecular mechanism for
      the rapid evolution of complex social behaviour.

PMID- 15201911
TI  - Mechanoelectrical transduction of adult outer hair cells studied in a gerbil
      hemicochlea.
AB  - Sensory receptor cells of the mammalian cochlea are morphologically and
      functionally dichotomized. Inner hair cells transmit auditory information to the
      brain, whereas outer hair cells (OHC) amplify the mechanical signal, which is
      then transduced by inner hair cells. Amplification by OHCs is probably mediated
      by their somatic motility in a mechanical feedback process. OHC motility in vivo
      is thought to be driven by the cell's receptor potential. The first steps towards
      the generation of the receptor potential are the deflection of the stereociliary
      bundle, and the subsequent flow of transducer current through the
      mechanosensitive transducer channels located at their tips. Quantitative
      relations between transducer currents and basilar membrane displacements are
      lacking, as well as their variation along the cochlear length. To address this,
      we simultaneously recorded OHC transducer currents (or receptor potentials) and
      basilar membrane motion in an excised and bisected cochlea, the hemicochlea. This
      preparation permits recordings from adult OHCs at various cochlear locations
      while the basilar membrane is mechanically stimulated. Furthermore, the
      stereocilia are deflected by the same means of stimulation as in vivo. Here we
      show that asymmetrical transducer currents and receptor potentials are
      significantly larger than previously thought, they possess a highly restricted
      dynamic range and strongly depend on cochlear location.

PMID- 15201912
TI  - Plant retinoblastoma homologues control nuclear proliferation in the female
      gametophyte.
AB  - Haploid spores of plants divide mitotically to form multicellular gametophytes.
      The female spore (megaspore) of most flowering plants develops by means of a well
      defined programme into the mature megagametophyte consisting of the egg apparatus
      and a central cell. We investigated the role of the Arabidopsis retinoblastoma
      protein homologue and its function as a negative regulator of cell proliferation
      during megagametophyte development. Here we show that three mutant alleles of the
      gene for the Arabidopsis retinoblastoma-related protein, RBR1 (ref. 4), are
      gametophytic lethal. In heterozygous plants 50% of the ovules are aborted when
      the mutant allele is maternally inherited. The mature unfertilized mutant
      megagametophyte fails to arrest mitosis and undergoes excessive nuclear
      proliferation in the embryo sac. Supernumerary nuclei are present at the
      micropylar end of the megagametophyte, which develops into the egg apparatus and
      central cell. The central cell nucleus, which gives rise to the endosperm after
      fertilization, initiates autonomous endosperm development reminiscent of
      fertilization-independent seed (fis) mutants. Thus, RBR1 has a novel and
      previously unrecognized function in cell cycle control during gametogenesis and
      in the repression of autonomous endosperm development.

PMID- 15201913
TI  - Mental barriers.

PMID- 15201914
TI  - Stars in the making.

PMID- 15201918
TI  - [Cost of infection in COPD].

PMID- 15201916
TI  - Scientists and societies. Two-body problem.

PMID- 15201919
TI  - [Telithromycin].

PMID- 15201920
TI  - [Biofilm: model of bacterial communication and resistance to antimicrobial
      agents].

PMID- 15201921
TI  - [Antimicrobial drug resistance in non-typhi Salmonellae in Castilla y Leon].
AB  - We studied the antibiotic susceptibility of 309 Salmonella isolates obtained from
      three hospitals serving the provinces of Salamanca, Avila and Zamora in the
      region of Castilla y Leon (mid-west Spain). The susceptibility to 18 antibiotics
      was studied using the agar dilution method, according to NCCLS guidelines, and
      the most common multiresistance phenotypes were determined for each province. We
      observed clear susceptibility differences between the two main serotypes found,
      S. enteritidis and S. typhimurium. Seventy percent of S. typhimurium were
      resistant to amoxicillin. In 44% of these isolates, amoxicillin resistance was
      associated with resistance to streptomycin, sulfonamides, tetracyclines and
      chloramphenicol. S. enteritidis was susceptible to most antibiotics tested;
      amoxicillin resistance was observed in 23.3%, and nalidixic acid resistance in
      49.6%. Resistance to nalidixic acid was higher in S. enteritidis than in any
      other serotypes. According to NCCLS breakpoints, no strain was resistant to
      fluoroquinolones. However, according to MENSURA criteria, 9% of S. typhimurium
      isolates were resistant to ciprofloxacin. Resistance to cotrimazole and
      gentamicin was less than 10% for all the serotypes tested. The results indicate
      that S. typhimurium showed greater resistance and a high multidrug resistance
      rate. Conversely, S. enteritidis showed high resistance only to amoxicillin and
      nalidixic acid, though in most cases there was no correlation between this
      resistance and reduced susceptibility to fluoroquinolones.

PMID- 15201922
TI  - [Change in resistance to quinolones and betalactams in different serogroups of
      Salmonella during the last decade in a Madrid hospital].
AB  - The prevalence of antibiotic resistance was studied in 3230 strains of Salmonella
      enterica isolated in the Hospital Universitario La Paz in Madrid, Spain, from
      1991 to 2001. Betalactam antibiotic resistance has been notorious in serogroup
      B4; the highest prevalence of ampicillin resistance (84%) was reached in 2000 and
      that of amoxicillin-clavulanic acid (45%) in 1996. Resistance to cephalosporins
      has been controlled, although in 2000 cefazolin resistance reached 37% in
      serogroup C2-8. An increase in first generation quinolone resistance was detected
      in every serogroup, especially in D9 and C2-8, which showed an increase from 6%
      and 15% in 1991, respectively, to 40% and 85% in 2001. Although important
      resistance to ciprofloxacin has not yet been detected, the activity of
      fluoroquinolones against Salmonella must be closely monitored.

PMID- 15201923
TI  - [Antifungal susceptibility of Acremonium species using E-test and Sensititre].
AB  - Filamentous fungi have become a common cause of severe infections, especially in
      immunocompromised patients. In recent years, the number and diversity of the
      infections caused by Acremonium species have increased and numerous species have
      been implicated. As is the case for most emerging pathogens, the optimal
      therapeutic approach to Acremonium species remains to be determined. We used two
      methods to determine the in vitro susceptibility to amphotericin B, itraconazole
      and fluconazole for 15 clinical isolates of eight different species of
      Acremonium. The MICs were determined according to protocol M38-A of the National
      Committee for Clinical Laboratory Standards (NCCLS) document, using the
      Sensititre and E-test microdilution methods. Amphotericin B was effective in
      vitro for few species using the Sensititre method. However, high MICs were
      obtained with E-test. Fluconazole and itraconazole were ineffective according to
      both methods. Acremonium species are generally resistant to the most commonly
      used antifungal agents. Consequently, Acremonium susceptibility testing is
      recommended to assist in choosing adequate treatment of infections caused by this
      filamentous fungus.

PMID- 15201924
TI  - [Usefulness of the E-test and its assay conditions in the study of the
      interaction of antifungal agents. A pilot study].
AB  - Preliminary data from a pilot study to assess the usefulness of the E-test in the
      study of antimycoctics are presented, evaluating assay and reproduction
      conditions. Results are compared with those obtained using the checkerboard
      method and mortality-time curves. Trials were carried out with a strain of
      Candida albicans (ATCC 90028). The E-test strips were combined in direct
      proportion, MIC-MIC, and in inverse proportion. The results showed that the
      method can be reproduced, is easy to carry out and may be suitable for the study
      of the in vitro interaction of antimycotics on yeast. The directly and inversely
      proportionate strip combination appeared to be the most suitable. At the
      prediffusion stage, the most highly water-soluble antimycotic should be used. The
      recommended time for prediffusion is one hour for water-soluble antimycotics, and
      two hours for non-water-soluble ones. The E-test showed good correlation with
      mortality-time curves. Nonetheless, in vivo correlation studies are required to
      determine the usefulness of the results in vitro and the most suitable method of
      measurement

PMID- 15201925
TI  - [Levofloxacin in patients in the ICU. Factors influencing the choice of dose and
      its use in combined therapy].
AB  - This study aimed to identify factors that influence the selection of different
      approaches to prescribing levofloxacin (e.g., monotherapy vs. combined therapy,
      12-h vs. 24-h interval) and the effect on mortality in the ICU. An observational,
      prospective, multicenter study was conducted. A logistic regression analysis was
      performed to identify factors associated with the prescription of levofloxacin in
      combined therapy and at a dose of 500 mg every 12 hours. In addition, a logistic
      regression analysis was conducted to determine the impact of the different
      prescribing methods on mortality in the ICU. The most frequently administered
      initial dose was 500 mg/24 h (48.5%) and 500 mg/12 h (48.3%). No factors were
      found to influence the choice of daily dose. A total of 49.7% of levofloxacin
      prescriptions were in combined therapy. Factors influencing the decision to
      prescribe a combined regimen included diagnosis of extra-ICU nosocomial infection
      (OR: 1.97; 95% CI: 1.13-3.42); severe sepsis (OR: 2.56; 95% CI: 1.66-3.94);
      septic shock (OR: 6.22; 95% CI: 3.54-10.9); and identification of the causative
      pathogen (OR: 1.99: 95% CI: 1.34-2.95). The mortality rate was 21.4% and the
      related factors were septic shock (OR: 3.09; 95% CI: 1.38-6.91); treatment
      failure (OR: 23.4; 95% CI: 12.3-44.6); and combined therapy (OR: 2.36; 95% CI:
      1.21-4.59). The selection of the initial dose of levofloxacin was not influenced
      by any factor, as long as the antibiotic was given in combined therapy in
      patients in whom the cause of the infection had been identified, in patients with
      greater systemic response, and in nosocomial infection outside the ICU. The
      selection of combined therapy was associated with a worse prognosis.

PMID- 15201926
TI  - [Grounds for and new perspectives on the rational use of antifungal agents].

PMID- 15201927
TI  - [Relationship between structure and function in the azoles].

PMID- 15201929
TI  - [Criteria for sensitivity to azoles].

PMID- 15201928
TI  - [Diagnosis of invasive mycosis. Detection of galactomannan].

PMID- 15201930
TI  - [Clinical-microbiological correlation in patients treated with azoles].

PMID- 15201931
TI  - [Azoles: Prophylactic or therapeutic?].

PMID- 15201932
TI  - [Clinical importance of azoles in antifungal therapy: treatment or prophylaxis
      with new azoles in hematology].

PMID- 15201933
TI  - [Prevention of fungal infections of endogenic origin].

PMID- 15201934
TI  - [Contribution of second-generation azoles in Candida spp. infections].

PMID- 15201935
TI  - [Biological modulation of IL-1 activity: role and development of its natural
      inhibitor IL-1Ra].
AB  - IL-1 and TNF-alpha are potent inducers of matrix metalloproteinases (MMP),
      eicosanoids, nitric oxide oxydase (iNOS), receptor activator of NF-kB ligand
      (RANKL), products involved in the destruction of the extracellular matrix, the
      cartilage and in bone resorption. IL-1, particularly important at the local
      level, is more potent than TNF-alpha in stimulating MMP and specifically in
      impeding cartilage repair. However, IL-1 and TNF-alpha strongly synergize in
      multiple biological functions. Blockade of IL-1 by IL-1 receptor antagonist (IL
      1Ra, sIL-1RII) in combination with the soluble IL-1 accessory protein (IL-1R AcP)
      result in a long-term beneficial effect in chronic inflammatory diseases. The
      association with anti-TNF-alpha therapy may also represent a logical approach,
      considering the number of patients that do not respond to either compound alone.

PMID- 15201936
TI  - [Advances in immunology and rheumatoid arthritis pathogenesis].
AB  - The pathogenesis of Rheumatoid Arthritis (RA) is still largely unknown. From the
      seminal experimental studies, suggesting a multifactorial mechanism leaded by an
      antigen specific activation, the direct role of innate immunity in the disease
      progression has been recently emphasized. In the natural history of RA,
      characterized by the three phases of the induction, maintenance and tissue
      destruction, innate immunity seems to be the central player. On the other hands
      the recent advances about the molecules involved in the T lymphocyte activation,
      the T cell role in the mechanism of erosion, and the studies about chemokines in
      the homing and angiogenesis processes support the theory of an antigen specific
      activation of the adaptive immune system. Therefore, during RA, the pathogenesis
      of sinovitis and erosions comes from independent pathways involving either innate
      and adaptive immunity resulting in the final induction of the articular damage.

PMID- 15201937
TI  - [Outcome predictors in rheumatoid arthritis].
AB  - Predicting which patients will develop severe rheumatoid arthritis is essential
      for selection of the most appropriate treatment regimen in early arthritis. The
      key outcomes in rheumatoid arthritis are persistence of the disease, joint damage
      (evaluated by X-ray progression), functional disability, and mortality rate.
      Rheumatoid factor positivity and number of swollen joints appear to be related to
      all of these outcomes, while radiologic scores are mostly related to joint damage
      and health assessment questionnaire (HAQ) to functional disability. Other
      relevant prognostic parameters are erythrocyte sedimentation rate or serum C
      reactive protein levels, and antibodies to citrullinated peptides.

PMID- 15201938
TI  - [Correlation between radiographic, echographic and MRI changes and rheumatoid
      arthritis progression].
AB  - OBJECTIVES: To review the imaging methods used for the evaluation of disease
      progression in rheumatoid arthritis (RA) and to evaluate the results of their
      application in pharmacological trials. METHODS: Literature articles dealing with
      radiology, echography, and magnetic resonance imaging (MRI) of patients with RA
      were evaluated in a non-systematic fashion. RESULTS: Conventional radiology is
      the gold standard for the evaluation of disease progression in RA because of its
      diffusion, economy, and standardization. Different techniques have been proposed
      to evaluate radiological damage of the joints, with the Larsen's and Sharp's
      methods being most widely used. These methods are commonly used for the
      evaluation of the ability of DMARDs to slow RA progression. Among traditional
      DMARDs, gold salts, sulphasalazine, methotrexate, cyclosporin, and leflunomide
      have shown efficacy in slowing the appearance of new erosions. The same effect
      has been recently demonstrated for infliximab plus methotrexate, anakinra and
      etanercept. However, conventional radiology has several disadvantages, because it
      is monoplanar and has a low sensitivity to change. Newer imaging techniques, such
      as echography and MRI are extensively studied and have been used occasionally in
      the mediumterm evaluation of DMARDs, with promising results. CONCLUSIONS:
      Although conventional radiology is still the gold standard for the evaluation of
      disease progression in RA, newer techniques are increasingly studied. In
      particular, standardization of echographic and MRI imaging of the joints is in
      progress.

PMID- 15201939
TI  - [IL-1Ra: its role in rheumatoid arthritis].
AB  - Interleukin-1 (IL-1) is one of the pivotal cytokines in initiating and driving
      the processes of rheumatoid arthritis (RA), and the body's natural response, IL-1
      receptor antagonist (IL-1Ra), has been shown conclusively to block its effects.
      IL-1 mediate several clinical symptoms of the inflammatory reaction (i.e. fever,
      pain, sleep disturbances). IL-1 is considered a key mediator in RA joint damage
      because of its greater capacity (greater than TNF) of increasing matrix
      degradation by inducing the production of MMPs and PGE2 in synovial cells, as
      well by its role as mediator of bone and cartilage destruction. In addition, IL-1
      decreases the repair process by suppressing matrix synthesis and shows a strong
      synergism with TNF in inducing many inflammatory genes at both local and systemic
      level. The induced endogenous production of IL-1Ra, in presence of the RA
      synovitis, is too low to contrast the high affinity of IL-1 for the cell
      receptors. Therefore, IL-1Ra presence should result in very effective prevention
      of IL-1 signal transduction particularly in the inflammatory site. In laboratory
      and animal studies inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra
      proved beneficial to the outcome. IL-1Ra is a member of the IL-1 superfamily. The
      effects of different DMARDs on IL-1Ra levels in RA patients support the important
      role that selected anticytokine treatments might exert in the pathophysiology of
      the disease. However, since anti TNF-alpha therapy it is not effective in all RA
      patients, nor does it fully control the arthritic process in affected joints of
      good responders and complete TNF suppression should be avoided, the combined
      treatment with intermediate doses of TNF and IL-1 blockers, reaching synergistic
      suppression of arthritis, seems warranted in RA.

PMID- 15201940
TI  - [Reconstructing the pyramid as a therapeutic approach to rheumatoid arthritis].
AB  - Several recent clinical studies have clearly established that rheumatoid
      arthritis (RA) is a disease identifiable since its early phases, a disease that
      can be adequately and efficaciously treated provided the therapeutic program can
      be started early on. To reach the aim of controlling effectively the disease and
      of leading the patients to live a normal life, several points must be fulfilled.
      The first is an early diagnosis obtained through a careful clinical examination
      along with an appropriate laboratory immunological work-up, followed by an
      adequate monotherapy within the first 4 months from symptoms onset. The second is
      the therapeutic re-assessment that needs to be done every three months, to start
      a possible combination therapy (COMBO), in order to rescue monotherapy failures.
      The third is the initiation of biological response modifiers (BRMs) within 6
      months from monotherapy onset, within 3 months from COMBO in the most resistant
      cases. Having at hand several molecules with BRMs characteristics, we believe
      that the future appears much more favourable in most cases even in those with the
      severe disease.

PMID- 15201941
TI  - Therapeutic gene transfer for rheumatoid arthritis.
AB  - Rheumatoid arthritis (RA) is a severe autoimmune systemic disease. Chronic
      synovial inflammation results in destruction of the joints. No conventional
      treatment is efficient in RA. Gene therapy of RA targets mainly the players of
      inflammation or articular destruction: TNF-alpha or IL-1 blocking agents (such as
      anti-TNF-alpha monoclonal antibodies, soluble TNF-alpha receptor, type II soluble
      receptor of IL-1, IL-1 receptor antagonist), anti-inflammatory cytokines (such as
      IL-4, IL-10, IL-1), growth factors. In this polyarticular disease, the vector
      expressing the therapeutic protein can be administered as a local (intra
      articular injection) or a systemic treatment (extra articular injection). All the
      main vectors has been used in experimental models, including the more recent
      lentivirus and adeno-associated virus. Ex vivo gene transfer was done with
      synovial cells, fibroblasts, T cells, dendritic cells, and different cells from
      xenogenic origin. In vivo gene therapy is simpler, although less controlled
      method. Clinical trials in human RA has started with ex vivo retrovirus
      expressing IL-1 receptor antagonist and have demonstrated the feasibility of the
      strategy of gene therapy. The best target remains to be determined and extensive
      researches have to be conducted in pre-clinical studies.

PMID- 15201942
TI  - [IL-1Ra (recombinant human IL-1 receptor antagonist) in the treatment of
      rheumatoid arthritis: the efficacy].
AB  - Interleukin 1 receptor antagonist (IL-1Ra) is a naturally occurring IL-1
      inhibitor, acting as a "receptor antagonist", which blocks IL-1 mediated signal
      transduction. In 1990 IL-1Ra was cloned and later on, a large numbers of studies
      led to disclosure of the crucial importance of the imbalance between IL-1 and IL
      1Ra in the pathogenesis of rheumatoid arthritis (RA). In 1991, almost 8 years
      after the initial isolation of IL-1, recombinant IL-1Ra (IL-1ra, Kineret) was
      introduced in clinical trials involving patients with RA. Between 2001 and 2002
      IL-1ra was approved by the US Food and Drug Administration and by the European
      Agency for the Evaluation of the Medicinal Products and in 2003 it was registered
      in Italy, too. In RA recombinant IL-1ra has been evaluated in 5 randomized,
      placebo-controlled clinical trials involving more than 2900 patients. Two of the
      trials involved the use of IL-1ra as monotherapy versus placebo and two trials in
      combination with methotrexate (MTX); the last trial explored the use of a fixed
      100 mg/day IL-1ra dosage in a RA patient population including a wide array of co
      morbid conditions as well as concomitant medications. The studies confirmed both
      the efficacy and the safety of IL-1ra in patients with active and severe RA. 43%
      of patients receiving 150 mg/day IL-1ra achieved a 20% response according to the
      American College of Rheumatology criteria (ACR20), compared to 27% in the placebo
      group. In the MTX combination therapy study, 42% of the patients receiving 1
      mg/Kg/day of IL-1ra achieved an ACR20, 24% an ACR50 and 10% an ACR70. In each
      study, significant improvements in the Health Assessment Questionnaire scores
      (HAQ) were observed. There were rapid gains in the number of days at work or
      domestic activity in the treated patients, and the increases in productivity were
      dose related. At early 24 weeks, there was significant reduction of both the
      score for progression of joint space narrowing (JSN) and the Total modified Sharp
      Genant score (a combination of erosion and JSN) in all treatment groups (30,75
      and 150mg/day). The clinical benefits of treatment with daily subcutaneous
      injections of IL-1ra in active RA patients were maintained for up to 48 weeks. IL
      1ra, a selective inhibitor of the IL-1 pathway, represents an important new
      biologic approach to treating patients with RA, that significantly reduces
      clinical signs and symptoms of the disease and joint destruction and has proved
      safe and well tolerated also in combination with other DMARDs and concomitant
      medications.

PMID- 15201943
TI  - [The safety of interleukin-1 receptor antagonist (anakinra) in the treatment of
      rheumatoid arthritis].
AB  - The safety profile of interleukin-1 receptor antagonist (anakinra) has been
      studied with randomised, placebo-controlled trials involving 2932 patients
      affected by rheumatoid arthritis. The most frequently reported adverse events
      were represented by injection site reactions (71%) and headache (13.6%). No
      statistically significant difference in the incidence of infections was observed
      among the patients treated with the interleukin-1 receptor antagonist and the
      patients receiving placebo. In particular, the incidence of serious infections
      was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in
      patients on placebo. The reported serious infections consisted of pneumonia,
      cellulitis, bone and joint infections, bursitis. No case of opportunistic
      infections or tubercolosis was observed. The results of clinical studies suggest
      that anakinra is a new well-tolerated drug for the treatment of patients affected
      by rheumatoid arthritis.

PMID- 15201944
TI  - [Farmacoeconomic impact of anti-TNF-alpha].
AB  - The anti-TNF-alpha are undoubtedly an efficacious cure in the treatment of
      rheumatoid arthritis, but their costs are so high that a thorough
      pharmacoeconomical evaluation is needed in order to identify the specific
      conditions in which their use is to be considered convenient. For this reason
      there are related the most important experiences that have studied the cost
      efficacy and cost-utility relationships of anti-TNF-alpha drugs, which have been
      made marketable in Italy. The data available, unfortunately, are too various to
      allow a final settlement of the chart of convenience between the different
      therapeutic alternatives. Moreover the socio-medical reality in Italy is so much
      different from the ones in other countries that it is impossible to try and use
      the foreign experiences. In a country of high social commitment like Italy, a
      fair judgment can thereafter be made only when the issue is considered related to
      our society, taking in account the summation of the medical costs endured by the
      National Health System, the patient's expenses and the ones that are a
      consequence of the loss of productivity.

PMID- 15201945
TI  - [Disability and quality of life of patients with rheumatoid arthritis: assessment
      and perspectives].
AB  - Functional disability and quality of life in rheumatoid arthritis (RA) are key
      outcomes that determine patient's demand for care, and influence their compliance
      and satisfaction with treatment. In the recent years the demand to collect
      outcome data is ever increasing as a means for the validation of quality care,
      and the development of effective outcome measures has become a major thrust of
      health research and has contributed to better understanding the relationship
      between outcomes and specific elements of health care. There are several disease
      generic and specific instruments available that have proven valuable in outcome
      testing in RA. The first instruments provide a broad picture of health status
      across a range of conditions, whereas the latter are more sensitive to the
      disorder under consideration and are therefore more likely to reflect clinically
      important changes. When necessary, this kind of scales can be supplemented with
      specialised domain-specific scales (for the assessment of psychological well
      being, social role functioning, or other). As in other fields, these measurement
      instruments mainly focus on: a) clinical signs and symptoms (physiologic and
      biologic); b) physical and/or cognitive functioning; c) well-being and emotional
      functioning; d) social functioning; e) satisfaction with care and other personal
      constructs (life satisfaction, spirituality, etc.); f) health-related quality of
      life (HRQOL). Over the past 20 years, there has been a better recognition of the
      patient's point of view as an important component in the assessment of health
      care outcomes, and an increasing interest in HRQOL as an important area of
      research, due to the rising burden of chronic diseases, longer expectation of
      life, the growing number of health intervention alternatives, and greater
      emphasis on humanising health care. In addition, decision-making on issues of
      cost-effectiveness across health inputs and resource allocation across health
      programs is likely to be more sound if informed by HRQOL evidence. This paper
      reviews the literature and discusses the major issues regarding mainly measures
      of physical function (e.g., mobility or daily activities) and health status,
      including some so called HRQOL instruments.

PMID- 15201946
TI  - [Subclinical thyroid disease].

PMID- 15201947
TI  - [High resolution reconstruction of PET images using the iterative OSEM
      algorithm].
AB  - AIM: Improvement of the spatial resolution in positron emission tomography (PET)
      by incorporation of the image-forming characteristics of the scanner into the
      process of iterative image reconstruction. METHODS: All measurements were
      performed at the whole-body PET system ECAT EXACT HR(+) in 3D mode. The acquired
      3D sinograms were sorted into 2D sinograms by means of the Fourier rebinning
      (FORE) algorithm, which allows the usage of 2D algorithms for image
      reconstruction. The scanner characteristics were described by a spatially variant
      line-spread function (LSF), which was determined from activated copper-64 line
      sources. This information was used to model the physical degradation processes in
      PET measurements during the course of 2D image reconstruction with the iterative
      OSEM algorithm. To assess the performance of the high-resolution OSEM algorithm,
      phantom measurements performed at a cylinder phantom, the hotspot Jaszczack
      phantom, and the 3D Hoffmann brain phantom as well as different patient
      examinations were analyzed. RESULTS: Scanner characteristics could be described
      by a Gaussian-shaped LSF with a full-width at half-maximum increasing from 4.8 mm
      at the center to 5.5 mm at a radial distance of 10.5 cm. Incorporation of the LSF
      into the iteration formula resulted in a markedly improved resolution of 3.0 and
      3.5 mm, respectively. The evaluation of phantom and patient studies showed that
      the high-resolution OSEM algorithm not only lead to a better contrast resolution
      in the reconstructed activity distributions but also to an improved accuracy in
      the quantification of activity concentrations in small structures without leading
      to an amplification of image noise or even the occurrence of image artifacts.
      CONCLUSION: The spatial and contrast resolution of PET scans can markedly be
      improved by the presented image restauration algorithm, which is of special
      interest for the examination of both patients with brain disorders and small
      animals.

PMID- 15201948
TI  - [Establishment and application of diagnostic reference levels for nuclear
      medicine procedures in Germany].
AB  - Diagnostic reference levels (DRL) were introduced in Germany by a publication in
      the Bundesanzeiger Nr. 143 from August 5, 2003. Thereby a recommendation of the
      International Commission on Radiological Protection (ICRP) from 1996 and a demand
      by the EU Guideline 97/43/EURATOM from 1997 is converted into national law. AIM
      of this paper is to acquaint with and to justify the determined DRL as well as to
      provide information on the practical use of the concept of the DRL. MATERIAL AND
      METHOD: DRL were established by experts on the basis of a national survey
      conducted in hospitals and private practices as well as of national and
      international recommendations and published by the Federal Office for Radiation
      Protection. Besides the data basis the dosimetric principles are described for
      the estimation of the effective doses of the various examinations. RESULTS: DRL
      were established for 10 frequent and dose-relevant examinations constituting more
      than 80% of all nuclear medicine examinations currently performed in Germany. For
      some examinations two different DRL were given to take into account clinical
      conditions. For paediatric examinations fractions of the activities to be
      administered to adults are given dependent on the body weight. DISCUSSION: The
      published DRL are in agreement with the majority of national and international
      recommendations and with the present practice of nuclear medicine examinations in
      Germany. They are related to average activities for groups of patients with
      standard sizes and, moreover, to typical examinations with current standard
      equipment. It is planned to check and to reconsider the DRL about every 2-3
      years.

PMID- 15201949
TI  - Preoperative localization of parathyroid glands. Use of MRI, scintigraphy, and
      image fusion.
AB  - AIM: Minimally invasive resection of hyperfunctional parathyroid glands is an
      alternative to open surgery. However, it requires a precise preoperative
      localization. This study evaluated the diagnostic use of magnetic resonance (MR)
      imaging, parathyroid scintigraphy, and consecutive image fusion. PATIENTS,
      METHODS: 17 patients (9 women, 8 men; age: 29-72 years; mean: 51.2 years) with
      primary hyperparathyroidism were included. Examination by MRI used unenhanced T1-
      and T2-weighted sequences as well as contrast-enhanced T1-weighted sequences.
      (99m)Tc-MIBI scintigraphy consisted of planar and SPECT (single photon emission
      tomography) imaging techniques. In order to improve the anatomical localization
      of a scintigraphic focus, SPECT-data were fused with the corresponding MR-data
      using a modified version of the Express 5.0 software (Advanced Visual Systems,
      Waltham, MA). Results of image fusion were then compared to histopathology.
      RESULTS: In 14/17 patients, a single parathyroid adenoma was found. There were 3
      cases with hyperplastic glands. MRI detected 10 (71%), scintigraphy 12 (86%)
      adenomas. Both modalities detected 1/3 patients with hyperplasia. Image fusion
      improved the anatomical assignment of the 13 scintigraphic foci in five patients
      and was helpful in the interpretation of inconclusive MR-findings in two
      patients. CONCLUSIONS: Both MRI and (99m)Tc-MIBI scintigraphy sensitively detect
      parathyroid adenomas but are less reliable in case of hyperplastic glands. In
      case of a scintigraphic focus, image fusion considerably improves its topographic
      assignment. Furthermore, it facilitates the evaluation of inconclusive MRI
      findings.

PMID- 15201950
TI  - 18F-FDG PET for detecting recurrent head and neck cancer, local lymph node
      involvement and distant metastases. Comparison of qualitative visual and
      semiquantitative analysis.
AB  - AIM: Assessment of the clinical value of (18)F-FDG-PET for detection of recurrent
      head and neck cancer, local lymph node involvement and distant metastases
      comparing a qualitative visual with a semiquantitative analysis (SUV values).
      PATIENTS, METHODS: Retrospective evaluation of 73 (18)F-FDG PET studies in 55
      patients by use of a four-step qualitative visual grading system and calculation
      of standard uptake values in pathological lesions. Calculation of SUV values in
      normal regions for generating a map of physiological (18)F-FDG distribution.
      Correlation to histopathological findings and clinical follow-up. RESULTS: 1.
      Qualitative visual analysis of (18)F-FDG PET studies: a) local recurrence
      sensitivity 79%, specificity 97%, positive predictive value 95%, negative
      predictive value 85%, and diagnostic accuracy 89%; b) local metastatic lymph
      nodes 100%, 95%, 85%, 100%, 96%; c) distant metastases 100%, 98%, 86%, 100%, 98%,
      respectively. 2. Semiquantitative analysis had only little incremental, non
      significant value in comparison to qualitative visual analysis for the detection
      of a local recurrence in two patients: a) local recurrence: sensitivity 83%,
      specificity 100%, positive predictive value 100%, negative predictive value 88%,
      and diagnostic accuracy 93%; b) local metastatic lymph nodes or c) distant
      metastases did not change in comparison to qualitative visual analysis.
      CONCLUSION: (18)F-FDG PET is an effective tool for re-staging of patients with
      suspected recurrence after therapy for head and neck cancer.

PMID- 15201951
TI  - Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin)
      in mouse xenografts.
AB  - Cisplatin has been one of the most widely used and most effective cytotoxic
      agents in the treatment of malignancies but causes severe adverse reactions
      including nausea/vomiting, renal toxicity, gastrointestinal toxicity, peripheral
      neuropathy, asthenia, and ototoxicity. A liposomal formulation of cisplatin,
      Lipoplatin, was developed in order to reduce the systemic toxicity of cisplatin.
      A single treatment of rats with 30 mg/kg Lipoplatin resulted in no toxicity
      whereas 2 or 3 weekly administrations at 30 mg/kg to rats gave neutropenia but no
      nephrotoxicity. On the contrary, a single injection to rats of 5 mg/kg cisplatin
      resulted in severe nephrotoxicity. Thus, Lipoplatin is less toxic than cisplatin
      in rats. Intraperitoneal or intravenous injection of Lipoplatin to SCID (severe
      combined immunodeficient) mice with subcutaneous breast MCF-7 or prostate LNCaP
      human tumors resulted in size reduction of the tumors; histological examination
      of the treated tumors in xenografts was consistent with apoptosis in tumor cells;
      thus, Lipoplatin appears to exert its cytotoxic effects to tumors in a mechanism
      similar to that of cisplatin. The preclinical studies reported here set the
      foundation for the clinical use of Lipoplatin as an exciting new drug with lower
      toxicity than cisplatin, endowed with proapoptotic properties.

PMID- 15201952
TI  - The influence of matrix metalloproteinase-7 on early mammary tumorigenesis in the
      multiple intestinal neoplasia mouse.
AB  - The multiple intestinal neoplasia (Min/+) mouse, which carries a mutant
      adenomatous polyposis coli (Apc) allele, is a model for human familial colon
      cancer. Like the human syndrome caused by mutant APC, the Min/+ mouse syndrome
      shows susceptibility to tumors of other tissues, including the mammary gland. The
      matrix metalloproteinase (MMP) MMP-7 (matrilysin) gene is transcriptionally
      induced by signal transduction pathways resulting from loss of APC function, and
      contributes to the progression of benign and malignant intestinal epithelial
      cells. Mammary tumors that develop in Min/+ mice express MMP-7. To investigate
      whether mutant APC and MMP-7 can cooperate in mammary tumorigenesis, we compared
      N-ethyl-N-nitrosourea (ENU)-enhanced mammary tumor formation in Min/+ mice that
      were either wild-type or deficient in MMP-7. Min/+ mice lacking MMP-7 demonstrate
      a 60% reduction in the number of early focal lesions in the mammary gland at
      early, but not later, timepoints. We conclude that MMP-7 transiently influences
      early stage mammary tumorigenesis.

PMID- 15201953
TI  - Prediction of 5'-deoxy-5-fluorouridine sensitivity in colorectal cancer cases by
      thymidine phosphorylase activity and preliminary identification of susceptibility
      related genes.
AB  - We confirmed that the enzyme activity of thymidine phosphorylase (TP) can
      substitute for 5'-deoxy-5-fluorouridine (5'-dFUR) sensitivity in clinical
      colorectal cancer (CRC) tissues. Moreover, the idenfication of susceptible genes
      other than TP will be desired for prediction or treatment of 5'-dFUR. We
      initially established conditions for the MTT assay system in vivo to compare the
      growth inhibition rate and TP activity in 18 cases of CRC. TP activity levels
      were concordant with 5'-dFUR sensitivity in the CRCs (p<0.05). In 18 CRC cases, 4
      cases of high sensitivity and 3 cases of low sensitivity to 5'-dFUR were compared
      to analyze expression profiles of 9437 genes on cDNA microarray chips. As a
      result, a cluster of genes related to the sensitivity were identified and another
      cluster of genes related to the insensitivity of 5'-DFUR were also listed. We
      determined that TP expression can precisely predict 5'-dFUR sensitivity in CRCs
      and found susceptibility related genes.

PMID- 15201954
TI  - Disruption of p53-p21/WAF1 cell cycle pathway contributes to progression and
      worse clinical outcome of hepatocellular carcinoma.
AB  - p53-p21/WAF1 cell cycle pathway plays an important role in growth control, and
      the inappropriate deregulation of this pathway has been implicated in
      carcinogenesis. Although the role of p53 in hepatocellular carcinoma (HCC) has
      been suggested, its exact molecular mechanism in relation to its down-stream gene
      p21/WAF1 remains unclear. To investigate the relationship between the expression
      of p53 and p21/WAF1 and the possible roles of the 2 proteins in HCC, we examined
      the intracellular expression of p53, p21/WAF1 and PCNA immunohistochemically,
      together with apoptosis by terminal deoxynucleotidyl transferase-mediated
      deoxyuridine triphosphate nick-end labeling assay in 35 clinical tissue
      specimens. The correlation between the clinicopathologic parameters and the
      intracellular gene expression were analyzed. The results showed that p53 over
      expression is a reliable marker for mutational modulation of p53 function. p53
      was negatively correlated with p21/WAF1 in hepatitis B virus-related HCC
      (p=0.024, r=-0.432). Patients with a high p53 expression had a significantly
      higher Edmondson grading (12/21 vs 13/14, p=0.024) and larger tumor size (10 vs 6
      cm, p=0.029). Patients with higher p53 expression had shorter disease-free
      survival (4 vs 19 months, p=0.0131) and overall survival (11 vs 42 months,
      p=0.0031). Intracellular expression of p21/WAF1 was positively correlated to
      proliferating cell nuclear antigen (p=0.001, r=0.776) and apoptosis (p=0.003,
      r=0.639). Our findings suggest that disruption of p53-p21/WAF1 cell cycle
      pathways contributes to tumor progression and worse clinical outcome of HCC.

PMID- 15201955
TI  - Differences in genetic expression profiles between young-age and old-age gastric
      adenocarcinoma using cDNA microarray for endocrine disruptor study.
AB  - In the current study, we compared the differential expression profiles of genes
      affected by endocrine disruptor in gastric carcinomas of the young and old using
      cDNA microarray. Five gastric carcinoma tissues of young patients (< or =35
      years) were compared with 5 disease-free gastric tissues of age-matched healthy
      young people (experiment 1) and 5 gastric carcinoma tissues of old patients (> or
      =65 years) (experiment 2), respectively. We hybridized the tissues with
      IntelliGene Human DNA Chip for endocrine disruption study, and identified finally
      the results common to the two experiments. Of the 220 genes represented on the
      array, 6 genes were up-regulated and 3 genes were down-regulated in the gastric
      carcinomas of young patients compared with those of old patients and those of the
      young volunteers. In conclusion, the genes affected by endocrine disruptors were
      differently expressed in young-age gastric carcinoma versus the old-age gastric
      carcinoma. So, we suggest that the gastric carcinoma in the young is the result
      of a genetic background that differs from that of the old and endocrine
      disruptors may play an important role in the carcinogenesis of gastric carcinoma
      in the young.

PMID- 15201956
TI  - Protection against methotrexate toxicity by a soybean protein- and omega-3 fatty
      acid-containing diet: comparative study with a casein-containing diet.
AB  - Effects of two clinically used liquid diets on toxicity and antitumor activity of
      methotrexate (MTX) were investigated in Sprague-Dawley (SD) rats and tumor
      bearing mice, respectively. Diets tested were commercially available formulas
      enriched either with soybean and omega-3 fatty acids or with casein. The soybean
      containing diet offered significant protection against MTX toxicity in rats
      compared with the casein-containing diet, completely alleviating MTX-induced
      anorexia, diarrhea, and weight loss, when ingested as the sole diet and fed 7
      days prior to and 7 days following intraperitoneal MTX injection. As a result,
      90% of rats were alive on soybean-containing diet while all rats were dead on
      casein-containing diet. Histologic examination of the small intestine of MTX
      treated rats revealed that the soybean-containing diet significantly prevented
      loss of mucosal villus tips compared to the casein-containing diet.
      Pharmocokinetic examination indicated that plasma MTX concentrations were similar
      for rats in the two diet-defined groups. No significant differences were observed
      between diets in survival of mice injected with L1210 mouse leukemia cells and
      subsequently with MTX. Thus the soybean-containing diet appeared to be superior
      to the casein-containing diet in preventing gastrointestinal toxicity while
      preserving antitumor activity. A soybean diet enriched in omega-3 fatty acids may
      be a useful adjunct to MTX treatment of human cancers.

PMID- 15201957
TI  - Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the
      soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3.
AB  - Malignant gliomas, most of which show an elevated level of vascular endothelial
      cell growth factor (VEGF) expression, are well known for their hyper-vascularity.
      One of the possible inducers of VEGF in tumor cells is nitric oxide (NO), which
      is synthesized by NO synthase and stimulates soluble guanylate cyclase (GC) in
      tumor cells. Here, we report that 2 of 9 human glioma cell lines, CCF-STTG1 and U
      87MG, overproduced cyclic GMP (cGMP) and showed increased expression of both or
      either subunits of soluble GC1, GUCY1A3 and GUCY1B3. Transfection of antisense
      GUCY1A3 or GUCY1B3 into these two glioma cell lines markedly reduced the content
      of cGMP and expression of VEGF. The angiogenic activity in vitro was subsequently
      inhibited, which was determined by induction of HUVEC cell growth. Furthermore,
      subcutaneous tumor formation by U-87MG cells in nude mice was dramatically
      suppressed to less than 0.05% in volume by transfection of either antisense
      GUCY1A3 or antisense GUCY1B3, which was accompanied by the significant decrease
      in vascular index to about 10%. These findings demonstrate that cGMP is an
      upstream mediator of VEGF expression in glioma cells and that soluble guanylate
      cyclases could be the target molecules for controlling neo-vascularization in a
      subset of human malignant gliomas.

PMID- 15201958
TI  - Suppression of peritoneal metastasis in human gastric carcinoma by enhanced
      immunogenicity of B7-1 transfection.
AB  - B7-1, a co-stimulatory factor, has been reported to induce cytotoxic T
      lymphocytes (CTL). In the present study, we transfected B7-1 genes into a gastric
      cancer cell line (2MD3) and analyzed the effects of B7-1 transduction on
      peritoneal metastasis in vitro and in vivo. We revealed that mononuclear
      lymphocytes show significantly stronger adherence and cytotoxicity to B7-1
      transfected cells (2MD3/B7) than to their parent 2MD3 cells. We also demonstrated
      that mice inoculated with 2MD3/B7 cells in the peritoneal cavity have a
      significantly better survival rate than those inoculated with 2MD3 cells (log
      rank test, p<0.01). Histologic findings showed that leukocytes intensively
      infiltrate the 2MD3/B7 metastatic nodules, but can scarcely be observed in the
      nodules associated with 2MD3 cells. These findings indicate that the B7-1 may
      play an important role in suppressing peritoneal metastasis by the mechanism of
      enhanced immunogenicity, and that B7-1 gene transduction might be effective
      against peritoneal metastases of gastric cancer.

PMID- 15201959
TI  - Criteria for predicting the recurrence and metastasis of stage I and II gastric
      cancer without lymph node metastasis.
AB  - This study examined whether detection of occult neoplastic cells (ONCs) in lymph
      nodes or the high-risk criteria for recurrence/metastasis of colorectal cancer
      were useful for predicting the recurrence of primary gastric cancer. The subjects
      were 122 patients with node-negative stage I or stage II primary gastric cancer.
      Prediction of recurrence using ONCs showed a sensitivity of 25.0% (2/8),
      specificity of 97.1% (100/103), and accuracy of 61.1% in stage I patients, while
      the respective values were 75.0% (3/4), 100.0% (7/7), and 87.5% in stage II
      patients. Prediction of recurrence in patients who fulfilled 2 or more of the
      high-risk criteria showed a sensitivity of 37.5% (3/8), specificity of 94.2%
      (97/103), and accuracy of 65.9% for stage I patients, while the respective values
      were 100.0% (4/4), 85.7% (6/7), and 92.9% for stage II patients. These results
      suggest that the prediction of recurrence based on the high-risk criteria shows a
      high sensitivity, specificity, and accuracy in patients of stage II gastric
      cancer without lymph node metastasis.

PMID- 15201960
TI  - Accuracy of criteria for predicting recurrence and metastasis in stage II and III
      gastric cancer patients with lymph node metastasis.
AB  - This study assessed the prediction of gastric cancer recurrence based on
      detection of occult neoplastic cells (ONCs) in lymph nodes, and by using criteria
      that were developed to identify patients with a high risk of
      recurrence/metastasis. The subjects were 60 patients of stage II or III gastric
      cancer with lymph node metastasis. Prediction of recurrence based on the
      detection of ONCs showed a sensitivity of 33.3% (2/6), specificity of 70.0%
      (7/10), and accuracy of 51.7% in stage II patients, while the sensitivity was
      73.5% (25/34), specificity was 100.0% (10/10), and accuracy was 86.8% in stage
      III patients. Prediction of recurrence based on the presence of at least 2 high
      risk criteria had a sensitivity of 33.3% (2/6), specificity of 100.0% (10/10),
      and accuracy of 66.7% in stage II patients, while the sensitivity was 82.4%
      (28/34), specificity was 80.0% (8/10), and accuracy was 81.2% in stage III
      patients. These results suggest that prediction of recurrence/metastasis soon
      after surgery using ONCs plus the high-risk criteria can increase the specificity
      in stage II cancer, and can achieve a sensitivity of 80% or more with a high
      specificity and accuracy in stage III cancer.

PMID- 15201961
TI  - The use of self-expandable metal stents in the palliation of malignant bowel
      obstruction.
AB  - Palliation of malignant gastrointestinal obstruction is a major aspect of
      oncology. We assessed the efficacy of stents in the palliation of gastric outlet,
      duodenal and colonic obstruction. We undertook a retrospective study of 35
      consecutive patients who were referred for stent insertion with palliative intent
      from June, 1999 to March, 2003. Thirty-two stents were successfully placed in 30
      patients. Technical success rate was 86% (30/35 patients). Of the patients who
      had successful insertion, 83% had complete relief of symptoms. In 1 patient the
      stent failed to expand. There was no procedure related mortality. Median survival
      was 1.6 months (range, 0-14.8). The conclusion was that self-expandable metal
      stents provide an effective method of palliation in malignant gastrointestinal
      obstruction, with high clinical and technical success rates and low complication
      rates.

PMID- 15201962
TI  - Midkine promoter-based conditionally replicative adenovirus for malignant glioma
      therapy.
AB  - Little is known concerning promoters or gene therapy specific for malignant
      glioma. To explore the potential use of midkine promoter in gene therapy for
      malignant glioma, we constructed a midkine promoter-based conditionally
      replicating adenovirus (Ad-MK). Midkine was overexpressed in malignant glioma
      tissues but cyclooxygenase-2 was not. The midkine promoter activity of the 600-bp
      fragment was 2 orders of magnitude higher in midkine-positive glioma cells than
      in midkine-negative primary normal brain cells. Ad-MK showed strong oncolytic
      effects in midkine-positive glioma cells but did not exhibit cytotoxicity in
      midkine-negative primary normal brain cells. The cell-killing effect was evident
      in E3-intact Ad-MK more than in E3-deleted Ad-MK. In an animal experiment, Ad-MK
      completely eradicated midkine-positive glioma xenografts. These findings indicate
      that midkine promoter-based conditionally replicative adenovirus might be a
      promising new modality of gene therapy for malignant glioma.

PMID- 15201963
TI  - New approaches in the diagnostic procedure of malignant pleural effusions.
AB  - The content of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (Ca 19
      9), carbohydrate antigen 15-3 (Ca 15-3) and the expression of LewisY related
      carbohydrate antigens in benign and malignant pleural effusion were determined.
      These included 35 malignant pleural effusions: 13 breast cancers, 12 lung cancers
      (6 squamous cell carcinomas, 5 adenocarcinomas and 1 microcytoma), 2
      mesotheliomas, 1 epithelioma, 1 kidney cancer, 1 hepatocarcinoma, 1 colon
      carcinoma, 3 lymphomas, 1 osteosarcoma and 9 benign pleural effusions. We showed
      that pleural fluid content of CEA, Ca 19-9 and Ca 15-3 were higher in malignant
      than in benign effusions. However CEA levels in squamous lung cancers were very
      high in both serum and pleural fluids whereas its levels were only slightly above
      the cut-off in breast cancers and in lung adenocarcinomas. Serum and pleural
      fluid Ca 15-3 values were higher in breast and in lung cancers with the highest
      values in the patients with breast cancer. Furthermore, the LewisY related
      carbohydrate antigens, evaluated by the reactivity of the cell extracts to MAb
      B3, were expressed only in breast cancers. These data suggest that pleural fluid
      content of CEA, and Ca 15-3 associated with the immunoblotting of cell extracts
      with MAb B3 appear to be very useful to improve the diagnosis of malignant
      pleural effusions.

PMID- 15201964
TI  - Sensitivity of scirrhous gastric cancer to 5-fluorouracil and the role of cancer
      cell-stromal fibroblast interaction.
AB  - Scirrhous gastric cancer is resistant to chemotherapy in comparison to other
      types of gastric cancers, and cancer cell-stromal fibroblast interactions play an
      important role in progression of scirrhous gastric cancer. We examined the effect
      of cancer cell-stromal fibroblast interactions on the sensitivity of an in vitro
      scirrhous gastric cancer model to the chemotherapeutic agent 5-FU. The model
      consisted of a human scirrhous gastric cancer cell line, KATO-III, and a human
      fibroblast cell line, KMST-6, maintained in collagen gel droplet cultures. KATO
      III cell sensitivity to 5-FU was significantly decreased in co-cultures with KMST
      6. KMST-6 cell sensitivity to 5-FU was also decreased in co-cultures with KATO
      III. The addition of tranilast alone inhibited KMST-6, but not KATO-III, cell
      proliferation. In combination with 5-FU, tranilast significantly enhanced KATO
      III cell sensitivity to 5-FU. These results suggest that (i), scirrhous gastric
      cancer cell sensitivity to 5-FU is decreased by the interactions between the
      cancer cells and stromal fibroblasts and (ii), tranilast enhances the sensitivity
      of scirrhous gastric cancer cell to 5-FU by inhibiting stromal fibroblast
      proliferation.

PMID- 15201965
TI  - 1,4-Bis(1-naphthyl)-2,3-dinitro-1,3-butadiene a novel anticancer compound
      effective against tumor cell lines characterized by different mechanisms of
      resistance.
AB  - The inhibition of cell proliferation by 1,4-bis (1-naphthyl)-2,3-dinitro-1,3
      butadiene (Naph-DNB) was evaluated in vitro against 4 cell lines (L1210/DDP,
      A2780/DX3, HCT-8/FU7dR, A549-T12) selected for their resistance to cisplatin,
      doxorubicin, 5-fluorouracil and taxol, and their wild-type counterparts. Naph-DNB
      is a novel anti-cancer compound obtained years ago within a research project of
      Organic Chemistry aimed at synthesizing 2,3-dinitrobutadiene derivatives. Because
      of its chemical structure, Naph-DNB was suggested to interact with nucleic acids,
      in particular DNA, and the other cellular macromolecules. This hypothesis made us
      consider Naph-DNB as a candidate for studies concerning its antitumour activity.
      We used the MTT assay to test the inhibition of cell proliferation after
      incubation of the cell lines with Naph-DNB for 72 h. For comparison, resistant
      and wild-type cell lines were also tested against those anticancer drugs used in
      vitro for their selection. In these culture conditions Naph-DNB retained its
      inhibiting activity against all resistant cells with IC50 values similar to those
      obtained in corresponding wild-type cell lines. Moreover, Naph-DNB was twice as
      effective as 5-fluorouracil against wild-type HCT-8 cells. Our previous findings
      about the interaction of Naph-DNB with DNA through the formation of interstrand
      cross-links suggested a mechanism of action similar to that of
      platinum/alkylating agents or topoisomerase inhibitors (intercalating agents).
      Our present data obtained by the K-SDS precipitation assay in A2780 and A549
      cells showed that Naph-DNB is not able to form a stable topoisomerase-DNA complex
      as is the case for topoisomerase inhibitors. In conclusion, our results indicate
      that Naph-DNB is able to overcome some of the classical mechanisms of resistance
      selected by some anticancer drugs mainly used in clinical setting.

PMID- 15201966
TI  - Aberrant methylation in promoter-associated CpG islands of multiple genes in
      relapsed childhood acute lymphoblastic leukemia.
AB  - Methylation profile was analyzed in nine cases of relapsed childhood acute
      lymphoblastic leukemia (ALL) for p14, p15, p16, Rb, MGMT, APC, hMLH1, RARbeta,
      RIZ, DAPK, and FHIT genes by using methylation specific polymerase chain reaction
      (MSP) analysis. Frequency of methylation in each gene was: MGMT, 56%; RARbeta,
      44%; and p16, 22%, respectively. None of the p14, p15, Rb, APC, hMLH1, RIZ, DAPK,
      and FHIT genes were hypermethylated. Five (56%) of 9 cases showed methylation of
      at least one gene. All of the samples with hypermethylation in p16 and MGMT gene
      at relapse, had already acquired the change at the time of initial diagnosis.
      Interestingly, three of 4 cases with RARbeta gene methylation at relapse did not
      have methylation of this gene at the time of initial presentation. These results
      suggest that hypermethylation might be involved in the relapse of childhood ALL.

PMID- 15201967
TI  - High frequency methylation of p16INK4A gene during 4-nitroquinoline 1-oxide
      induced rat tongue carcinogenesis.
AB  - The p16INK4A tumor suppressor gene can be inactivated by hypermethylation of the
      promoter region in many type of tumors including oral cancer. We recently studied
      the relationship of inactivation of p16INK4A and tumorigenesis in oral cancer.
      The aim of the present study was to describe the relationship between macroscopic
      changes of rat oral mucosa treated with 4-nitroquinoline 1-oxide (4NQO) and an
      inactivation of p16INK4A. We analyzed the relation of p16INK4A inactivation by
      hypermethylation of the promoter region of p16INK4A gene using polymerase chain
      reaction (PCR), PCR-single-strand confirmation polymorphism (PCR-SSCP), and
      methylation-specific-PCR (MSP). We observed that methylation of p16INK4A genes
      were rare in mild and moderate dysplasia, but inactivation was observed at high
      frequency even in severe dysplasia and SCCs in rat carcinogenesis. The expression
      pattern of p16INK4A protein, detected by western blotting and
      immunohistochemistry, were similar to the hypermethylation status of the p16INK4A
      promoter region. Inactivation by hypermethylation of the promoter region of
      p16INK4A gene was related to carcinogenesis of oral cancer.

PMID- 15201968
TI  - Expression of DOL54 is not restricted to myxoid liposarcomas with the FUS-DDIT3
      chimera but is found in various sarcomas.
AB  - The DOL54 gene [also known as megakaryocyte stimulating factor, articular
      superficial zone protein (SZP) or proteoglycan 4 (PRG4)], was cloned as a
      downstream target gene of the FUS-DDIT3 chimera, which is the fusion gene that
      characterizes myxoid liposarcoma (MLS). Activation of DOL54 was found to require
      an intact DNA binding domain of the DDIT3 protein and to be dependent on the
      presence of the N-terminal part of the FUS protein. Although originally suggested
      to be of oncogenic significance, expression analysis of DOL54 in tumors has so
      far been limited to a few cases of liposarcoma and malignant fibrous histiocytoma
      (MFH). In the present study we were interested to evaluate whether DOL54
      expression can be associated with other fusion genes in which FUS is the 5'
      partner. Thus, we investigated the expression of DOL54 in low grade fibromyxoid
      sarcoma (LGFMS) carrying the FUS-BBF2H7 chimeric transcript. We also included
      synovial sarcomas (SS), Ewing tumors (ET), extraskeletal myxoid chondrosarcomas
      (EMC) and MFH. The first 3 of these tumor types are characterized by chromosomal
      translocations that give rise to fusion genes not involving FUS, while no
      specific chimeric genes have been reported in MFH. DOL54 expression was found in
      8/12 LGFMS carrying the FUS-BBF2H7 chimera but also in 8/10 of the examined MFH,
      5/7 SS, 2/5 ET and 7/7 examined EMC. The results of our study clearly show that
      expression of DOL54 is not only a characteristic feature of MLS with the FUS
      DDIT3 chimera but that this is a frequent finding also in various other sarcomas.

PMID- 15201969
TI  - Updating trends in cutaneous cancers in south-east Belgium.
AB  - From data collected in a dermatopathology laboratory, the ratios between the
      numbers of specific cancers represent good markers for identifying any
      epidemiological shift in their prevalence and incidence among the reference
      population. The objective of the present study was to assess the ratios of the
      annual incidence of skin cancers in the Mosan region and Ardennes of Belgium over
      the past 6 years, and to compare the data with previous similar evaluations. A
      total of 7,640 skin cancers were collected and compared with regard to age and
      gender. Changes in time show that the trend of the increase in incidence of
      malignant melanoma (MM) is more impressive than that of squamous cell carcinoma
      (SCC) and basal cell carcinoma (BCC). The age distribution of BCC and SCC
      confirms the increasing risk with ageing. By contrast, there is a steady decrease
      over the past decade in the mean age for MM, teenagers and young adults now form
      an expanding proportion of MM patients. There is an ongoing trend in diagnosing
      an increased number of skin cancers in our laboratory. This trend is particularly
      obvious for MM affecting young adults.

PMID- 15201970
TI  - A convenient murine model for the study of intra-abdominal lymph node metastasis.
AB  - Lymph node metastasis is one of the most important prognostic factors for cancer
      patients. There are few animal models of lymph node metastasis. The purpose of
      this study was to develop a simple animal model without surgical trauma. B16F10
      melanoma (1 x 10(6) cells in 0.1 ml phosphate-buffered saline) were slowly
      injected into the retroperitoneal space followed by direct puncture at the
      position between the anus and tail of 50 female C57BL6 mice. At 1-week intervals
      for 4 weeks after the procedure, we examined the retroperitoneal tumor and intra
      abdominal lymph nodes. There was no morbidity and no mortality. At 2 weeks after
      inoculation, the retroperitoneal tumor was visible macroscopically at the
      position between the rectum and the sacrum, and histological examination showed
      the occurrence of intra-abdominal lymph node metastasis in all mice. The number
      of positive nodules was increased and was affected by the amount of cancer cells
      inoculated and the interval from inoculation to lymph node metastasis. A
      convenient murine model for the study of lymph node metastasis has been
      developed. Our animal model does not involve surgical trauma and may be useful in
      the analysis of the association between surgical stress and lymph node metastasis
      and in the elucidation of the mechanism and prevention of lymph node metastasis.

PMID- 15201971
TI  - Ceramide triggers caspase activation during gamma-radiation-induced apoptosis of
      human glioma cells lacking functional p53.
AB  - We have previously shown that treatment of human glioma U87-MG cells expressing
      wild-type p53 with a DNA topoisomerase II inhibitor, etoposide resulted in
      ceramide-dependent apoptotic cell death. However, U87-W E6 cells lacking
      functional p53 due to the expression of human papilloma virus type 16 (HPV-16) E6
      oncoprotein were resistant to etoposide. In order to gain insight into the roles
      of p53 and ceramide in gamma-radiation-induced glioma cell death, we used U87-W
      E6 and vector-infected U87-LXSN cells. U87-LXSN glioma cells expressing wild-type
      p53 were relatively resistant to gamma-radiation. U87-W E6 cells, which lost
      functional p53, became susceptible to radiation-induced apoptosis. Activation of
      caspase-3, and formation of ceramide by acid sphingomyelinase, but not by neutral
      sphingomyelinase, were associated with p53-independent apoptosis. Radiation
      induced caspase activation and apoptotic death in U87-W E6 cells were modified by
      the agents which affected ceramide metabolism. SR33557, an inhibitor of acid
      sphingomyelinase, suppressed radiation-induced caspase activation and then
      apoptotic cell death. In contrast, N-oleoylethanolamine (OE) and D-threo-1-phenyl
      2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibit ceramidase and UDP
      glucose:ceramide glucosyltransferase-1, respectively, and then augment ceramide
      formation, enhanced radiation-induced caspase activation. These results indicate
      that glioma cells with functional p53 were relatively resistant to gamma
      radiation, and that ceramide may play an important role in caspase activation
      during gamma-radiation-induced apoptosis of glioma cells lacking functional p53.

PMID- 15201972
TI  - Quantitative assessment of HER2/neu expression by real-time PCR and fluorescent
      in situ hybridization analysis in low-grade osteosarcoma.
AB  - Low-grade osteosarcoma is a rare variant of osteosarcoma. Although malignant, it
      must be distinguished from conventional osteosarcomas because of its excellent
      prognosis. Numerous published papers have described the expression of HER2/neu
      oncogene in osteosarcoma as a poor prognostic factor; however their results are
      discordant. To address the expression of HER2/neu and to validate the assessment
      methods of amplification of the HER2/neu oncogene, the authors have employed
      quantitative real-time PCR and fluorencent in situ hybridization analysis (FISH)
      in 21 low-grade osteosarcomas. We calculated the quantification of HER2/neu
      oncogene amplification as the ratio of measured HER2/neu gene/beta-globin
      reference gene in real-time PCR. All 21 cases had amplified signals in the
      quantitative real-time PCR. However, in the FISH analysis, HER2/neu oncogene
      amplification was only identified in 26% (5/19). The exact reasons for the
      discordance between these two methods are unknown; however, variable histological
      features might play a potential role. In conclusion, as our study showed
      amplification of HER2/neu oncogene in low-grade osteosarcoma, we assume that
      expression of HER2/neu is not a poor prognostic factor in low-grade osteosarcoma.

PMID- 15201973
TI  - Promoter hypermethylation and silencing of CHFR mitotic stress checkpoint gene in
      human gastric cancers.
AB  - CHFR is a recently identified mitotic stress check-point gene. CHFR is
      ubiquitously expressed in normal human tissues, whereas loss of CHFR expression
      has been observed in human tumors. Silencing of CHFR has been associated with
      aberrant promoter methylation and histone deacetylation in several cancer types.
      In this study, we investigated epigenetic CHFR inactivation in human gastric
      cancers by examining CHFR expression and methylation status in gastric cancer
      cell lines with RT-PCR analysis, bisulfite PCR and sequencing. A series of
      primary gastric tumors were also analyzed for CHFR methylation. Eight of 12
      (66.7%) gastric cancer cell lines and 19/43 (44.2%) primary gastric tumors showed
      CHFR methylation. In addition, CpG methylation status correlated well with CHFR
      expression in the human gastric cancer cell lines, in which treatment with 5-aza
      dC resulted in de novo or enhanced expression of CHFR. Combination treatment of 5
      aza-dC with trichostatin A showed a synergistic effect on CHFR expression in some
      cases. Our results indicate that aberrant promoter methylation of the CHFR gene
      was observed in a significant proportion of human gastric cancers and was
      responsible for the inactivation of the CHFR gene in gastric cancers.

PMID- 15201974
TI  - Oxaliplatin/rituximab combination in the treatment of intermediate-low grade non
      Hodgkin's lymphoma of elderly patients.
AB  - High and intermediate grade non-Hodgkin's lymphomas (NHL) require treatments with
      aggressive chemotherapy schedules. However, low grade NHLs display a low
      chemoresponsiveness and patients aged >65 years often do not tolerate
      anthracycline and corticosteroid-containing chemotherapy regimens. Therapeutic
      options in this subset of patients are watchful waiting, oral alkylating agents,
      purine nucleoside analogues, combination chemotherapy, interferon and monoclonal
      antibodies. The approval of rituximab, an unconjugated chimeric antibody against
      the CD20 antigen for the treatment of B-cell NHL marked a milestone in the
      development of antibody treatment. Moreover, promising results have also been
      found with oxaliplatin in patients with NHL and reversible, cumulative,
      peripheral sensory neuropathy is the principle dose-limiting factor of
      oxaliplatin therapy. On the basis of these considerations we have performed a
      feasibility study in NHL in patients aged >65 years using as schedule: 130 mg/m2
      oxaliplatin every 21 days and 375 mg/m2 rituximab weekly. We have enrolled 8
      patients, 2 males and 6 females (mean age 69.2+/-3.1 years; median, 67 years)
      affected by intermediate or high grade stage III/IV NHL. Six patients have
      cardiac abnormalities (myocardial function between 45 and 50%) and 1 increase of
      transaminasemia due to active chronic hepatitis. All the patients included in the
      study were treated for at least 3 cycles and 31 cycles were completed. We have
      recorded grade I/II (CTC) neurotoxicity in 30%, grade I anemia in 25% and grade I
      neutropenia in 20% of the patients. No infusional reactions, liver or renal
      toxicity neither nausea and/or vomiting were recorded. One complete response, 3
      partial response and 3 minimal response were obtained at 11 months of median time
      follow-up. These results demonstrate the feasibility of this schedule which
      offers a suitable alternative regimen to treat elderly patients with NHL and
      shows a good efficacy and an acceptable toxicity profile.

PMID- 15201975
TI  - Less frequent promoter hypermethylation of DLC-1 gene in primary breast cancers.
AB  - Absence or low expression of DLC-1, a tumor suppressor gene, in breast cancers
      has been shown recently. LOH of 8p12-p22, on which DLC-1 is located, is frequent
      in breast cancers, but the correlation between low expression of DLC-1 and LOH
      has not been confirmed. To determine the implication of aberrant methylation, one
      of the most frequent mechanisms of silencing the tumor suppressor or cancer
      related genes, we examined the methylation status of DLC-1 promoter region in
      breast cancer cell lines and primary breast tumors. The hypermethylation status
      was examined by MSP and 25% of cell lines harbored a methylated allele. The gene
      silencing by methylation was also confirmed by the re-expression of DLC-1 by the
      5-aza-2'-deoxycytidine treatment in DLC-1 hypermethylated cell line. But the
      methylation of DLC-1 gene was less frequently shown in primary breast cancers
      (10%). These data suggest that hypermethylation is responsible for silencing of
      DLC-1 gene in a limited portion of breast cancers.

PMID- 15201976
TI  - Prognostic significance of cancer-testis gene expression in resected non-small
      cell lung cancer patients.
AB  - MAGE, BAGE and GAGE genes encode T cell-defined tumor-associated antigens (TAA),
      which are expressed by various human tumors and are silent in normal tissues.
      Because of their expression pattern these TAA have received attention as
      potential targets for active immunotherapy and as molecular tumor markers. Both
      of these features are potentially useful in improving treatment of non-small cell
      lung cancer (NSCLC). We analyzed the expression of some members of the MAGE, BAGE
      and GAGE gene families by reverse transcription polymerase chain reaction (RT
      PCR) in a cohort of 46 NSCLC patients who underwent complete resection and were
      followed-up for a median period of 41 months. A substantial proportion (range, 25
      41%) of NSCLC expressed MAGE-A1, -A2, -A3, GAGE-1, -2, -8 and MAGE-B2 genes. On
      the contrary, BAGE and MAGE-B1 were expressed less frequently (17% and 11%,
      respectively). Overall, 59% of NSCLC patients expressed at least one gene and
      therefore could be eligible for tumor-specific immunotherapy protocols. Moreover,
      while MAGE-A, BAGE and MAGE-B genes did not provide any prognostic information,
      GAGE expression was associated with a worse survival (p=0.05). Multivariate
      analysis confirmed this association, which is independent of TNM stage and other
      clinicopathologic variables. In conclusion, the detection of GAGE gene expression
      by RT-PCR appears to be an independent survival predictor in completely resected
      NSCLC patients.

PMID- 15201977
TI  - Non-random distribution of chromatid breaks in lymphocytes of laryngeal squamous
      cell carcinoma patients.
AB  - The frequency and localization of mutagen-induced chromatid breaks in peripheral
      blood lymphocytes (PBLs) were investigated for association with squamous cell
      carcinoma (SCC) of the larynx. The case-control study was performed in 52
      patients with laryngeal SCC and in 47 cancer-free controls. The analyses were
      based on the bleomycin sensitivity assay. The differences between cases and
      controls were estimated using Mann-Whitney U test and unconditional logistic
      regression. The total number of chromatid breaks in PBLs of patients was
      significantly higher compared with healthy controls (p<0.0001); the increase was
      observed in almost all chromosomal arms. In a number of chromosomal regions, the
      relative frequency of breaks was higher in patients; this increase was
      statistically significant for 1p22, 5q31, 6q23 and 10q24. The majority of sites
      with the increased proportion of breaks in patients were identified as regions
      containing loci involved in DNA repair, cell cycle regulation, suppressor genes
      and oncogenes. Revealing non-random distribution of chromatid breaks specifically
      associated with laryngeal SSC may be instrumental for defining regions involved
      in the etiology of this disease.

PMID- 15201978
TI  - Study of the combined effect of X-irradiation and epigallocatechin-gallate (a tea
      component) on the growth inhibition and induction of apoptosis in human cancer
      cell lines.
AB  - Over the past 15 years, some potential anticarcinogenic and anti-inflammatory
      effects of antioxidants have been defined. Antioxidants are known to act as
      powerful free-radical scavengers. Free radicals are able to induce DNA strand
      breaks and oxidative modifications of DNA bases and are not only produced
      naturally in the cell following a stress or respiration but also following
      ionizing radiation. The present study was undertaken in order to explore whether
      some antioxidants naturally present in the food or in the beverages could enhance
      apoptosis in cancerous cells submitted to X-irradiation. Epigallocatechin gallate
      (EGCG), a potent antioxidant present in tea was tested on three human cancerous
      cell lines: HeLa (derived from cervix carcinoma), K-562 (derived from chronic
      myelogenous leukaemia) and IM-9 (derived from multiple myeloma). The parameters
      investigated were cell proliferation, morphological changes, cell cycle effects
      and apoptosis. When given alone, irradiation induced a decrease of cell
      proliferation and an increase of apoptosis as well as the appearance of polyploid
      cells in the three cell lines. All these effects were dose-dependent. Taking into
      account the various parameters, IM-9 cells appeared as the most radiation
      sensitive and HeLa cells as the least radiation sensitive, while K-562 cells
      exhibited an intermediary radiation sensitivity. EGCG had no effect on cell
      proliferation, while it induced a dose-dependent increase of apoptosis in the
      three cell lines. IM-9 cells were again most sensitive to this effect, while HeLa
      and K-562 cells were slightly less sensitive. A combined treatment by X
      irradiation and EGCG resulted in a significant enhancement of apoptosis
      correlated with a decrease of proliferation in IM-9 and K-562 cells and at a
      lesser extent, in HeLa cells, compared to treatments by either EGCG or ionising
      radiation alone. In conclusion, these preliminary results show that depending on
      the concentration and on the cell line, EGCG could act as a radiation enhancer on
      cancerous cell lines.

PMID- 15201979
TI  - Relation between HPV-DNA and expression of p53, bcl-2, p21WAF-1, MIB-1, HER-2/neu
      and DNA ploidy in early cervical carcinoma: correlation with clinical outcome.
AB  - The purpose of the present study was to analyze the relation between the
      expression of p53, bcl-2, p21WAF1, MIB-1, HER-2/neu, DNA ploidy and HPV16 or 18
      infections with clinical parameters. HPV-DNA was evaluated in 171 early cervical
      carcinomas treated from 1965 to 1990 and detected by PCR (polymerase chain
      reaction) on paraffin specimens obtained before therapy was started. HPV-DNA of
      any type was detected in 78% (86/110) of all tumors, HPV16 was the predominant
      type and was seen in 56% (62/110), HPV18 in 8% (9/110) and HPV35 in 21% (23/110).
      Patients with HPV16 or 18 were significantly (P=0.011) younger than patients with
      tumors not containing these two HPV subtypes. Lymph node metastases were seen
      more frequently (P=0.047) in tumors expressing HPV16 or 18. Tumor size was
      associated with the HPV-type. The frequency of DNA aneuploidy was lower in high
      risk HPV tumors than in tumors with other HPV subtypes (P=0.014). MIB-1
      expression was highly significantly (P=0.00007) associated with presence of HPV16
      or 18. The cancer-specific survival rate was lower for patients with HPV16 and 18
      positive tumors, but the difference was not statistically significant. The
      overall 5-year survival rate of the complete series was 91%. In conclusion, the
      HPV DNA subtype was a prognostic factor in early stage cervical cancer and it was
      associated with age, positive lymph nodes, tumor size, DNA ploidy and the
      proliferation marker MIB-1.

PMID- 15201981
TI  - Response of T- and B-lymphocytes in the spleen of mammary tumor-bearing rats to
      treatment with tamoxifen and soluble tumor-associated antigens.
AB  - We analyzed the role of T- and B-lymphocytes in the antitumor effects of the
      anticancer drug tamoxifen and soluble tumor-associated antigens (sTAA) on rat
      mammary carcinogenesis. Studies were performed on the spleen from the following
      groups of mammary tumor-bearing rats. i) Rats in group 1 were not exposed to DMBA
      and served as age-related controls. Rats in other groups were exposed to DMBA and
      received different types of treatment; ii) rats in group 2, received no
      additional treatment, and served as carcinogen-related controls; iii) rats in
      group 3 were treated with the commercial hormone-dependent anticancer drug
      tamoxifen by weekly subcutaneous (s.c.) injections of 10 mg dissolved in 0.5 ml
      distilled water per rat; iv) rats in group 4 were vaccinated s.c. weekly with a
      preparation of sTAA (50 micro l/rat) dissolved in 0.5 ml of phosphate-buffered
      saline; v) rats in group 5 were treated with tamoxifen and were also vaccinated
      with a preparation of sTAA. Different zones of the spleen were measured and their
      T- and B-cell contents were analyzed immunohistochemically. The treatment with
      tamoxifen significantly increased the total number of lymphocytes in the
      follicles, PALS (periarterial lymph sheath) and red pulp relative to all other
      groups. The combined treatment with tamoxifen and sTAA increased the areas of
      white pulp, the PALS, and marginal zone. The number of B-cells was higher in the
      marginal zone of spleens from age-related controls, as well as from rats treated
      with sTAA and those treated with tamoxifen and sTAA. The number of CD4+
      lymphocytes in the PALS was higher in rats treated with sTAA and tamoxifen, and
      notably so in those treated with sTAA alone. The number of CD8+ lymphocytes was
      significantly lower in the PALS of spleens from all tumor-bearing rat groups
      compared to the unexposed age-related control rats. We suggest that the tumor
      suppressive effect of sTAA and tamoxifen is accompanied by the activation of B-
      and T-lymphocyte production.

PMID- 15201980
TI  - DNA methylation of multiple genes and clinicopathological relationship of non
      small cell lung cancers.
AB  - Aberrant methylation of 5' CpG islands is thought to play an important role in
      the inactivation of tumor suppressor genes in several types of cancers. In non
      small cell lung cancer (NSCLC), several genes are known to be frequently
      methylated and the correlation of their methylation with clinical features has
      been studied. We determined the methylation of p16, CDH13 and RAR-beta which were
      reported to be methylated frequently in NSCLCs and HPP-1 which was known to be
      methylated in other types of cancers. The correlation between methylation and
      clinicopathological features were examined. The frequencies of methylation in
      NSCLCs were 20% for p16, 37% for CDH13, 34% for RAR-beta, and 13% for HPP1. The
      methylation of p16 is correlated with smoking history and methylation of HPP1 was
      significantly more frequent in adenocarcinomas than in squamous cell carcinomas.
      This is the first description of aberrant methylation of the HPP1 gene in lung
      cancers and our data support the previous reports on methylation in NSCLCs and
      association with smoking.

PMID- 15201982
TI  - Cellular response of X-ray sensitive hamster mutant cell lines to gemcitabine,
      cisplatin and 5-fluorouracil.
AB  - Five mutant Chinese hamster cell lines deficient in DNA repair with the
      corresponding parental cell lines were used to determine their sensitivity to
      cisplatin, 5-fluorouracil and gemcitabine. The mutations in the cell lines led to
      defective single strand break repair (EM-C11), defective recombination mediated
      repair (irs1SF), defective double strand break repair (XR-V15B, a Ku-80 mutant
      and CR-C1, a DNA-PKcs mutant) and an AT-like mutation (VC-4). All mutant cell
      lines had an impaired doubling time during exponential growth and an increased
      sensitivity to X-irradiation. We may conclude that for cisplatin-induced
      cytotoxicity the homologous recombination-associated DNA repair plays an
      important role in the repair of the cisplatin induced lesions, confirming
      previous results. In 5-FU and gemcitabine induced toxicity to cells, repair
      processes involved with radiation-induced damage were not implicated. This is in
      striking contrast to the role of cisplatin in radiosensitization where inhibition
      of the NHEJ pathway is implicated, and to the role of gemcitabine in
      sensitization where specific interference with the HR pathway is implicated.

PMID- 15201983
TI  - 8-Chloro-adenosine sensitizes a human hepatoma cell line to TRAIL-induced
      apoptosis by caspase-dependent and -independent pathways.
AB  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the
      tumor necrosis factor (TNF) super-family, induces apoptosis in various cancer
      cells with little or no effect on normal cells. 8-Chloro-adenosine (8-Cl-Ado) is
      a potential anti-cancer chemical agent now in clinical trail phase II, though its
      molecular mechanism remains poorly understood. In the present study, we report
      that 8-Cl-Ado can promote TRAIL killing activity in the hepatoma cell line BEL
      7402 in dose- and time-dependent manner when jointly used in vitro. We showed
      that the expression of death receptor DR5, but not DR4 was up-regulated and the
      decoy receptor DcR1 was down-regulated in the cells treated with 8-Cl-Ado and the
      recombinant soluble TRAIL (rsTRAIL, 95-281 a.a.). Further experiments
      demonstrated that caspase-family inhibitor z-VAD-fmk prevented the cells from
      apoptosis induced by co-treatment with 8-Cl-Ado and rsTRAIL for 6 h, however,
      apoptosis occurred in the cells cultured for 24 h, suggesting that co-treatment
      induce a caspase-dependent and -independent signaling pathway in the BEL-7402
      cells. This phenomenon was confirmed by cleavage analysis of caspase-3 and
      poly(ADP-ribose) polymerase (PARP), and ROS (reactive oxygen species) assay,
      respectively. Moreover, transcriptional activity test showed that NF-kappaB was
      inhibited in the BEL-7402 cells during co-treatment. Our results provided
      evidence for the first time that 8-Cl-Ado sensitizes the human hepatoma cells BEL
      7402 to rsTRAIL-induced apoptosis by up-regulating DR5 expression, inactivating
      the NF-kappaB activity, and signaling by the caspase-dependent and -independent
      pathway.

PMID- 15201984
TI  - A short region of the promoter of the breast cancer associated PLU-1 gene can
      regulate transcription in vitro and in vivo.
AB  - The recently cloned gene PLU-1 shows restricted expression in adult tissues, with
      high expression being found in testis, and transiently in the pregnant mammary
      gland. However, both the gene and the protein product are specifically up
      regulated in breast cancer. To investigate the control of expression of the PLU-1
      gene, we have cloned and functionally characterised the 5' flanking region of the
      gene, which was found to contain another putative gene. Two transcription start
      sites of the PLU-1 gene were mapped by 5' RACE. A short proximal 249 bp region
      was defined using reporter gene assays, which encompasses the major transcription
      start site and exhibits a strong constitutive promoter activity in all cell lines
      tested. However, regions upstream of this sequence repress transcription more
      effectively in a non-malignant breast cell line as compared to breast cancer cell
      lines. The 249 bp region is GC-rich and includes consensus Sp1 sites, GC boxes,
      cAMP-responsive element (CRE) and other putative cis-elements. Mutational
      analysis showed that two intact conserved Sp1 binding sites (shown here to bind
      Sp1 and/or Sp3) are critical for constitutive promoter activity, while a negative
      role for a neighbouring GC box is indicated. The sequence of the core promoter is
      highly conserved in the mouse and Plu-1 expression in the mouse embryo has been
      documented. Using transgenesis, we therefore examined the ability of the 249 bp
      fragment to control expression of a reporter gene during embryogenesis. We found
      that not only is the core promoter sufficient to activate transcription in vivo,
      but that the expression of the reporter gene coincides both temporally and
      spatially with regions where endogenous Plu-1 is highly expressed. This suggests
      that tissue specific controlling elements are found within the short fragment and
      are functional in the embryonic environment.

PMID- 15201985
TI  - Molecular analysis of an immature ovarian teratoma with gliomatosis peritonei and
      recurrence suggests genetic independence of multiple tumors.
AB  - Immature ovarian teratoma is a common germ cell tumor of young women. Patients
      with immature teratoma often exhibit multiple neoplasms, including tumors outside
      the ovaries, and occasionally a rare benign condition termed gliomatosis
      peritonei (GP). These multiple neoplasms are generally believed genetically
      linked progeny of the ovarian tumor resulting from local recurrence/spread. In
      this study, we performed a molecular analysis of a single patient clinically
      diagnosed with immature ovarian teratoma, GP, and recurrent pelvic mucinous
      teratoma. Microsatellite PCR and amplicon analysis was performed to genetically
      characterize tissue samples from omental glial implants and multiple peritoneal
      tumors. PCR-based amplification of microsatellite markers identifies unique
      genetic differences (allelic variation) between tumors resulting from divergent
      natural histories among multiple tumor nodules in a single patient. A total of 21
      different microsatellite markers were employed, and seven provided informative
      results (D3S1744, D6S1056, D7S2846, D14S306, D16S764, D18S858, D22S420). These
      markers demonstrated mutually exclusive genetic differences among the tumors from
      this patient, establishing the neoplasms as genetically distinct from each other
      (non-identical), and that no lineage relationship exists among them. This
      observation suggests that the multiple tumors arising in this patient with
      immature ovarian teratoma, GP, and recurrent pelvic mucinous neoplasm represent
      multiple independent tumors rather than true tumor recurrence/spread. The results
      of this study suggest strongly that patients with recurrent teratoma may be
      afflicted with a tumor-prone syndrome where one or more peritoneal cell types or
      populations are predisposed to neoplastic conversion and formation of tumors as a
      result of an endogenous or exogenous neoplastic stimuli.

PMID- 15201986
TI  - Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the
      head and neck.
AB  - The human p63 gene encodes a series of protein isoforms that differ in their N-
      and/or C-terminal sequences and possess widely varying activities in promoting or
      repressing p53-related functions and in regulating the proliferation and
      differentiation of epithelial cells. To gain further information on the role of
      p63 expression in human tumours, we used quantitative real-time RT-PCR to study
      individual p63 isoforms in squamous cell carcinomas of the head and neck (SCCHN).
      In keeping with previous reports, expression of the deltaN- and p63alpha-isoforms
      predominated and deltaNp63 mRNA was expressed at significantly higher levels in
      tumours compared to matched normal tissues. Some tumours also expressed the
      highly efficient transactivator TA- and p63beta-isoforms, and p63beta was
      significantly increased in tumours compared to matched normal tissue. We could
      not identify any correlations between different p63-isoform expression patterns
      and proliferation, p53 status, or telomerase expression. All p63 isoforms could
      be identified in normal surface epithelium, and micro-dissection showed that the
      high levels present in basal layers were similar to those seen in tumour tissues.
      Thus, high-level expression of deltaNp63 in tumour cells may represent maintained
      expression by the basal cells from which the tumour arose, rather than
      representing a true over-expression of p63 during tumourigenesis. Tobacco usage,
      a genotoxic predisposing factor for SCCHN, had no effect on p63 expression in
      oral epithelium. Taken together, our data indicate that SCCHN maintain expression
      of high levels of deltaNp63alpha in combination with varying levels of other p63
      isoforms, some of which are highly efficient transcriptional activators. The
      complexity of these p63 expression patterns seen in primary SCCHN indicates that
      p63 has multifaceted roles in tumour biology.

PMID- 15201987
TI  - Mapping ALA-induced PPIX fluorescence in normal brain and brain tumour using
      confocal fluorescence microscopy.
AB  - We have mapped the microscopic distribution of aminolevulinic acid (ALA) induced
      protoporphyrin IX (PPIX) in normal rabbit brain and in brain tumour at various
      time intervals after i.v. injection of ALA. In normal brain, regions without a
      blood-brain barrier (BBB) such as the choroid plexus and meninges and also
      structures associated with the CSF synthesized the highest amounts of PPIX. We
      also detected ALA in the CSF within 2 h after ALA administration when the serum
      concentration was high. Our fluorescence studies have shown that ALA is able to
      cross an intact BBB and be metabolized in regions with a BBB. This is evident in
      regions of the brain such as the hippocampus, thalamus, cerebellar folia and
      brain stem that are remote from the meninges or choroid plexus. However, the
      relative peak PPIX fluorescence in these regions are much lower than in regions
      without a BBB. Our imaging studies have shown that neurons in different regions
      of normal brain with an intact BBB exhibit varying capacities to metabolize ALA.
      The grey matter regions of the cerebrum and cerebellum also showed higher PPIX
      fluorescence compared to white matter regions in these same structures. Our study
      showed that tumour tissue had the highest PPIX fluorescence compared to normal
      contralateral cerebral cortex. Maximum selectivity was achieved between tumour
      and normal tissue at 24 h. PPIX fluorescence in normal blood vessels appear to be
      mainly due to metabolism of internalized ALA from serum and not due to high PPIX
      levels. In conclusion, ALA does cross the BBB and all regions of the brain with
      the exception of the hypothalamus, exhibit a dynamic synthesis of PPIX from ALA.
      Increased PPIX accumulation in tumour and inflamed brain tissue in comparison to
      normal brain tissue suggest the feasibility of selective photosensitization of
      such tissue.

PMID- 15201988
TI  - Cepharanthin enhances adriamycin sensitivity by synergistically accelerating
      apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F
      AR.
AB  - Cepharanthin (CEP) is a biscoclaurine alkaloid extracted from Stephania
      cepharantha Hayata. CEP is reported to inhibit drug resistance by inhibiting P
      glycoprotein, a drug efflux pump, and recently to induce apoptosis. In the
      present study, we examined the effects of CEP as an inhibitor of adriamycin (ADR)
      resistance on ADR-induced apoptosis and necrosis. First, we established p53
      deficient ADR-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR.
      Resistant cells showed a higher level of intracellular glutathione peroxidase
      activity than parent cells. P-glycoprotein was overexpressed in resistant cells.
      The intracellular ADR level of resistant cells was lower than that of parent
      cells. One micro g/ml CEP eliminated the degradation of intracellular ADR of
      resistant cells; that is, to a level equivalent to that of the parent cells. CEP
      of 0.5 micro g/ml, which was not cytotoxic when used alone, significantly
      increased the ADR sensitivity of resistant cells, to a level similar to the
      parent cell level. Isosorbide 5-mononitrate, a potential nitric oxide-generation
      agent, combined with CEP further increased the ADR sensitivity of resistant
      cells, indicating a synergistic effect of CEP and isosorbide 5-mononitrate on ADR
      cytotoxicity. Time-lapse microscopic observation revealed that ADR dominantly
      induced apoptosis much more than necrosis for both parent and resistant cells,
      and that the use of 0.5 micro g/ml CEP with ADR synergistically accelerated
      apoptosis in resistant cells. Finally, we clarified the property by which CEP
      synergistically accelerates ADR-induced apoptosis. This property might be a new
      mechanism that explains how CEP overcomes ADR resistance.

PMID- 15201990
TI  - The clinicopathological significance of the expression of CXCR4 protein in oral
      squamous cell carcinoma.
AB  - We have demonstrated the possibility that the stromal cell-derived factor-1 (SDF
      1; CXCL12)/CXCR4 system might be involved in the establishment of lymph node
      metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the
      role of the SDF-1/CXCR4 system in oral SCC, we examined the expression of CXCR4
      and SDF-1 in biopsy specimens from 61 patients with oral SCC by means of
      immunohistochemistry, and investigated several clinicopathological factors,
      including age, sex, lymph node metastasis, invasion, recurrence and prognosis.
      The expression of CXCR4 and SDF-1 was observed in 57.3 and 11.4% of our subjects,
      respectively. Although we were unable to find a statistically significant
      association between the expression of SDF-1 and any clinicopathological factors,
      we did find a significant association between the expression of CXCR4 and lymph
      node metastasis (P=0.0417). Moreover, the mode of invasion (P=0.0002) and
      recurrence of the tumors (P=0.0185) were strongly associated with CXCR4
      expression, and the CXCR4-positive group showed a significantly poorer prognosis
      than the CXCR4-negative group (P=0.0401). Recombinant SDF-1alpha stimulated in
      vitro invasiveness and scattering in CXCR4-expressing oral SCC cells, but the
      treatment did not affect the expression of matrix metalloproteinases or urokinase
      type plasminogen activator. These results indicate that SDF-1/CXCR4 signaling in
      oral SCC cells might be involved in the diverse action of oral SCC, including
      invasion or micrometastasis at the primary site and lymph node metastasis.

PMID- 15201989
TI  - Combination of caspase transfer using the human telomerase reverse transcriptase
      promoter and conventional therapies for malignant glioma cells.
AB  - Recently, we have reported the therapeutic efficacy of delivering initiator
      caspase (caspase-8) or executioner active caspase (rev-caspase-6) to telomerase
      positive malignant glioma cells using the human telomerase reverse transcriptase
      (hTERT) gene promoter system (hTERT/caspase-8 or hTERT/rev-caspase-6). In the
      present study, we investigated if conventional treatments for malignant gliomas
      augment the efficacy of the hTERT/caspase therapy. First, we demonstrated that
      hTERT/rev-caspase-6 exhibited a greater ability to induce apoptosis in malignant
      glioma U87-MG and U373-MG cells than hTERT/caspase-8. Next, as conventional
      treatments to combine with hTERT/rev-caspase-6, apoptosis-inducing agents
      [cisplatin (CDDP), paclitaxel (PTX), and BCNU] and non-apoptosis-inducing
      therapies [temozolomide (TMZ) and gamma-irradiation (IR)] were used. Combination
      of hTERT/rev-caspase-6 gene therapy with PTX yielded a dose-dependent additive
      effect, while CDDP and BCNU had additive effect only when tumor cells were
      treated at IC75 of each agent. A decline in the combination effect of CDDP and
      BCNU at IC50 was due to decreased activity of telomerase in treated tumor cells
      prior to the hTERT/rev-caspase-6 transfer. On the other hand, TMZ or IR had no
      significant additive effect on induction of apoptosis. These results suggest that
      agents, which induce apoptosis without inhibiting telomerase activity are a
      promising counterpart to combine with hTERT/rev-caspase-6 therapy for the
      management of malignant gliomas.

PMID- 15201991
TI  - Mutations of the ING1 tumor suppressor gene detected in human melanoma abrogate
      nucleotide excision repair.
AB  - Epidemiological evidence indicates that ultraviolet radiation (UVR) is the
      primary environmental cause of the rapid increase in the incidence of human
      cutaneous melanoma observed in the past decades. However, the genetic changes
      caused by UVR that lead to melanoma formation remain unclear. The ING1 (inhibitor
      of growth 1) tumor suppressor plays an important role in cellular stress response
      to UVR. To further investigate whether ING1 is involved in melanoma development,
      we examined the mutational status of the ING1 gene in 46 human cutaneous melanoma
      biopsies and characterized the biological importance of ING1 mutations in
      nucleotide excision repair. Single-strand conformation polymorphism and DNA
      sequencing were used to detect the mutational status of the ING1 gene. The host
      cell-reactivation assay and radioimmunoassay were used to determine the role of
      ING1 mutations in nucleotide excision repair. We show that 20% of the melanoma
      primaries contained missense mutations in the SAP30-interacting domain and PHD
      finger motif of the ING1 gene with the R102L and N260S alterations observed more
      than once. Furthermore, our data indicate that patients that harbor ING1
      mutations in the tumors have a higher risk to die from the disease within 5 years
      (50%) compared to patients with no ING1 mutation (18%). Moreover, we demonstrated
      that mutations at codon 102 or 260 as well as deletion of the PHD finger motif
      are detrimental to p33ING1-mediated enhancement of DNA repair. Taken together,
      our data indicate that ING1 mutations abrogate its enhancement in nucleotide
      excision repair.

PMID- 15201992
TI  - Psoriasin is aberrantly expressed in human breast cancer and is related to
      clinical outcomes.
AB  - Psoriasin (S100A7) is a member of the S100 gene family that is involved in
      psoriasis, which can be induced in cultured squamous epithelial cells.
      Previously, this molecule has been shown to be over-expressed in human ductal
      carcinoma in situ and invasive breast cancers. This current study examine the
      levels of expression of this molecule in a group of human breast tumours, with
      particular emphasis on the relationship with the clinical outcomes using
      quantitative PCR and the distribution in tumours using immunohistochemistry.
      Psoriasin is primarily expressed in breast cancer cells, and at very low level in
      normal breast epithelial cells. Quantitative analysis of psoriasin mRNA has shown
      that breast tumour tissues exhibited a significantly high level of psoriasin
      compared with normal tissues (p=0.0026). The levels do not correlate with nodal
      status of breast tumours, however levels in grade 2 and grade 3 tumours were
      significantly higher compared with that in grade 1 tumours (p=0.07 and p=0.0015,
      vs grade 1 respectively). Lobular carcinoma also had higher levels of psoriasin
      compared with ductal tumours. The most interesting observation is that levels of
      psoriasin were significantly higher in patients who developed metastatic disease
      and in patients who died of breast cancer (p=0.02 and p<0.001, vs disease-free,
      respectively). It is concluded that aberrant expression of psoriasin is commonly
      seen in human breast cancer and that excessively high levels are correlated with
      the clinical outcomes.

PMID- 15201994
TI  - Long-term presence of androgens and anti-androgens modulate EGF-receptor
      expression and MAP-kinase phosphorylation in androgen receptor-prostate positive
      cancer cells.
AB  - Prostate cancer (Pca) progression from an androgen-dependent to an androgen
      independent state occurs in patients who undergo hormonal therapy. There is
      evidence indicating that deregulation of the epidermal growth factor receptor
      (EGFR) pathway plays a critical role in this phenomenon. In this study we
      addressed the question by stably transfecting the androgen receptor (AR) cDNA
      into the AR-negative Pca cell line DU145 that expresses high levels of EGFR. The
      resulting cell line has been named DU145-AR. We showed that the introduction of
      the AR restored positive androgen regulation of tumour cell growth and gene
      expression in vitro. The DU145-AR cells grown in culture medium containing
      androgens exhibited a transient up-regulation of EGFR levels with a subsequent
      down-regulation. This phenomenon was reversible, upon addition of
      hydroxiflutamide (HF) to the culture medium, but after prolonged treatment. When
      the EGFR repression is relieved in the presence of HF, the cells become more
      responsive either to EGF mediated growth or to anti-proliferative effect of
      PKI166, an inhibitor of EGFR phosphorylation. Moreover, we found a significant
      increase of the activated form of mitogen-activated-protein kinase (MAPK) in
      cells treated with HF. PKI166 blocked this HF mediated-MAPK activation,
      suggesting that the activation of MAPK is an event dependent on EGFR function.
      Our data demonstrate that hormone sensitive Pca cells possess a mechanism able to
      limit EGFR expression. Up-regulation of EGFR in response to long-term HF
      treatment could represent an attempt to rescue cell growth through a compensatory
      survival pathway.

PMID- 15201993
TI  - Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in
      colorectal tumors.
AB  - In colorectal tumors, S-phase kinase-associated protein 2 (Skp2) still has
      numerous important questions unanswered: its expression in adenomas, its
      correlation with key clinicopathological indices, its association with patient
      prognosis, its variation in lymph node metastases, and its association with many
      cell-cycle regulators. To answer these questions in colorectal tumors, Skp2,
      cyclin A, cyclin B1, cyclin E, CDK2, and Ki67 were immunohistochemically stained
      in 12 normal mucosa, 36 adenomas, 11 carcinomas in adenomas, 102 primary
      carcinomas, and 12 paired lymph node metastases; and Skp2 was examined by Western
      blot in 8 pairs of normal mucosa and carcinomas. Situated in nuclei, Skp2
      expression significantly increased from normal mucosa through adenoma to primary
      carcinoma (p<0.0001), from mild through moderate to severe dysplasia in adenomas
      (p=0.038), from peripheral adenoma to paired central carcinoma (p=0.0033), and
      from primary carcinoma to lymph node metastasis (p=0.015), and these increases
      were confirmed by Western blot. Expression, however, relatively declined
      significantly in the primary carcinomas showing deep invasion (p=0.0113), lymph
      nodal metastases (p=0.0268), and poor prognosis for all (p=0.0104) or stage III
      patients (p=0.0119). High Skp2 was also significantly linked with elevated cyclin
      A, cyclin B1, cyclin E, CDK2 (in primary carcinomas only), and Ki67 in both
      adenomas and primary carcinomas. Thus, overexpression of Skp2 is associated with
      colorectal carcinogenesis and late metastasis to lymph nodes, whereas relative
      reduction of Skp2 is correlated with local invasion of primary carcinoma.

PMID- 15201995
TI  - Ultraviolet radiation induces release of MIA: a new mechanism for UVR-induced
      progression of melanoma.
AB  - MIA is a potent melanoma detachment factor that interferes with cellular
      adherence by binding to fibronectin and laminin, blocking their interaction with
      alpha4beta1 and alpha5beta1 integrins. The direct correlation between serum MIA
      levels of patients with progressing melanomas and tumor load supports a role for
      MIA as a melanoma progression factor. The goal of this study was to determine the
      effect of ultraviolet radiation (UVR), activating ras mutation, or loss of p53
      function on MIA expression and release from melanoma cells. We previously showed
      that transfection of a mutant constitutively active ras into the melanoma cell
      line, WM35, induces a phenotypic change from radial to vertical growth,
      exhibiting increased proliferation and migration. Here, we report that MIA
      release was elevated in a ras-transfected cell line. In addition, loss of
      functional p53, using a dominant negative construct, substantially lowered the
      level of MIA release compared to control. UVR stimulated release of MIA into the
      extracellular compartment in both the control and ras-transfected cell lines. In
      addition, MIA mRNA was increased following UVR in all cell lines tested. By
      inducing either apoptosis or necrosis, we were able to confirm that MIA protein
      is not released from cells due to cell death alone. We have identified a
      transcriptional effect of UVR on MIA expression and have shown that release of
      MIA protein is dependent upon functional p53. We propose that UVR-induced
      production and release of MIA may promote the detachment of radial and vertical
      growth phase melanomas from basement membrane or matrix proteins, serving as a
      unique progression mechanism for melanoma.

PMID- 15201996
TI  - Transcriptional up-regulation of Gadd45a in Patched-associated medulloblastoma.
AB  - Medulloblastoma (MB) is a highly malignant embryonal tumor of the cerebellum with
      a preferential manifestation in children. Although the majority of MBs occur
      sporadically, this tumor is also associated with familial cancer syndromes
      including the nevoid basal cell carcinoma or Gorlin syndrome. Mutations in the
      tumor suppressor gene PATCHED 1 (PTCH1) have been described in both familial and
      sporadic cases and inactivation of one Patched 1 (Ptch1) allele in mice promotes
      development of MB. In order to determine candidate genes involved in
      tumorigenesis of MB, we have screened tumors of heterozygous Ptch1 mice for
      differentially expressed genes by means of cDNA microarray technology. Our data
      show that genes involved in cell cycle, signal transduction and metastasis are
      transcriptionally up-regulated in MB compared to normal cerebellum. Gene ontology
      analysis reveals cell cycle regulators to be the predominant functional gene
      class altered in MB of Ptch1 mutants, including D-type cyclins and cyclin
      dependent kinase 4. We furthermore describe that overexpression of the growth
      arrest and DNA-damage-inducible gene Gadd45a is common in Ptch1-associated tumors
      and Ptch1 null embryos. These results suggest that cDNA microarray technology is
      a useful tool to discover genes involved in the development of MB that arise in
      response to a persistent activation of sonic hedgehog (Shh) signaling. This
      approach may provide novel data for diagnosis, treatment and prevention of human
      PTCH1-related malignancies.

PMID- 15201997
TI  - Immunological evaluation of vaccination with pre-designated peptides frequently
      selected as vaccine candidates in an individualized peptide vaccination regimen.
AB  - We previously conducted a trial of an 'individualized' regimen, in which cancer
      patients were vaccinated with peptides after the confirmation of pre-existing
      peptide-specific cytotoxic T lymphocyte (CTL) precursors. In this study, we
      performed a new trial of 'pre-designated' regimen, in which cancer patients were
      vaccinated with peptides that were frequently selected as vaccine candidates in
      the preceding individualized regimen. Eighteen cancer patients (10 with uterine
      cervical cancer and 8 with gastric cancer) were enrolled in the new regimen. The
      pre-designated regimen was well tolerated by all patients. Although peptide
      specific CTL precursors and humoral responses increased in the majority of
      patients with the pre-designated regimen, neither of the responses correlated
      with clinical outcome. Three patients had long stable disease, and their pre
      vaccination peripheral blood mononuclear cells contained peptide-specific CTL
      precursors reactive to more than 2 of 4 peptides. With the pre-designated
      regimen, the levels of pre-existing immunoglobulin G reactive to non-vaccinated
      peptides decreased in 5 of 15 patients with progressive disease, and their time
      to progression was very short, whereas such a decrease was rarely observed in the
      preceding individualized regimen. These results suggest that the pre-designated
      regimen can elicit a primary immune response, but may incidentally suppress pre
      existing immune responses.

PMID- 15201998
TI  - Evidence for existence of oligoclonal tumor-infiltrating lymphocytes and
      predominant production of T helper 1/T cytotoxic 1 type cytokines in gastric and
      colorectal tumors.
AB  - Tumor-infiltrating lymphocytes (TIL) play a central role in cellular immunity
      against tumor. We have revealed the characteristics of TILs in terms of T-cell
      receptor (TCR) repertoire, T-cell clonality, and cytokine production. TCR
      repertoire analyses and CDR3 size spectratyping were performed using peripheral
      blood mononuclear cells (PBMCs) and tissue specimens of gastric or colorectal
      cancers surgically resected from 11 patients. The cytokine expression was
      measured by real-time quantitative polymerase chain reaction. TCR repertoires
      were similar among multiple tissue specimens from different sites of the same
      tumor. Similar peak patterns of CDR3 size spectratyping were observed among these
      tumor specimens, but not in normal tissues or PBMCs. In addition, identical peaks
      were detected in multiple specimens of the same tumor. The ratio of the levels of
      IFN-gamma to that of IL-4 is significantly higher for tumor lesions compared with
      PBMCs. These results suggested that a limited number of TILs locally expand in
      response to tumor antigens exiting within gastric or colorectal cancers and local
      predominant production of the T helper 1/T cytotoxic 1 type cytokine may affect
      the anti-tumor immune response of TILs.

PMID- 15201999
TI  - Prognostic significance of additional cytogenetic abnormalities in newly
      diagnosed patients with Philadelphia chromosome-positive chronic myelogenous
      leukemia treated with interferon-alpha: a Cancer and Leukemia Group B study.
AB  - Secondary cytogenetic abnormalities at diagnosis of Philadelphia chromosome
      positive (Ph+) chronic myelogenous leukemia (CML) have been associated with an
      inferior outcome in reported series of largely chemotherapy-treated patients. To
      date, no study has specifically focused on the prognostic significance of
      secondary karyotypic abnormalities, detected at the time of diagnosis, in
      interferon (IFN)-alpha treated patients. We compared the outcome of 29 newly
      diagnosed Ph+ CML patients with additional abnormalities to that of 234 sole Ph+
      patients, treated on CALGB protocols with IFN-alpha alone or together with IFN
      gamma or low-dose cytarabine. Complete and partial cytogenetic responses were
      achieved in 20 and 19% of sole Ph+ patients, compared to 23 and 18%,
      respectively, of patients with additional abnormalities (P=1.00). None of 4
      patients with 'high-risk' secondary abnormalities [+8, +Ph and i(17)(q10)], for
      whom follow-up cytogenetic samples were available, achieved a cytogenetic
      response. With a median follow-up of 11.3 years, the median overall survival (OS)
      was 6.0 years for sole Ph+ patients compared to 7.5 years for patients with
      additional abnormalities (P=0.70), with corresponding 8-year OS of 36 and 38%,
      respectively. On multivariable analysis, only age (P<0.001) and white blood cell
      count (P=0.02) were associated with outcome. We conclude that, with the possible
      exception of +8, +Ph and i(17)(q10), additional chromosomal abnormalities at
      diagnosis are not associated with inferior outcome in Ph+ CML patients treated
      with IFN-alpha-based therapy.

PMID- 15202000
TI  - Selective expression of HERG and Kv2 channels influences proliferation of uterine
      cancer cells.
AB  - Voltage-gated potassium (Kv) channels play important roles in differentiation and
      growth of non-excitable cells. Inhibition of these channels is also known to
      suppress proliferation of various cancer cells. Here we examine expression of K+
      channel subunit genes in various uterine cancer cells and their roles in cell
      proliferation. RT-PCR analysis reveals that cervical squamous cell carcinoma (C
      33A, MS-751 and QG-U), and endometrial adenocarcinoma (AN3-CA, KLE and Ishikawa),
      but not cervical adenocarcinoma (CAC-1 and OMC-4), expresses both or either one
      of the two human eag-related genes (HERG2 and 3, or KCNH6 and 7). In addition,
      mRNAs for one-transmembrane auxiliary subunits (KCNE1-3) are significant in these
      cells. Moreover, the two cervical adenocarcinoma cell lines, as well as some of
      the squamous and endometrial cancer cell lines, express mRNAs for Kv2.1 and the
      silent regulatory subunit for Kv2.1 channels, Kv9.3. Thus, squamous/endometrial
      cancer cells contain HERG-KCNE channel complexes, whereas Kv2.1-Kv9.3 channels
      may be major components of Kv channels in cervical adenocarcinoma cells. To
      evaluate the involvement of these channels in cell proliferation, we used the
      specific blockers for HERG and Kv2.1-containing channels, E-4031 and hanatoxin-1.
      E-4031 significantly reduced proliferation of C-33A, MS-751 and QG-U by 15-30%.
      Similarly, hanatoxin-1 suppressed growth of Kv2.x-expressing cells (25-40%).
      Finally, FACS analysis indicates that inhibition of HERG channels reduces a
      population of cells in the G2/M phase. These results suggest that HERG-KCNE and
      Kv2.1-Kv9.3 channels are selectively involved in proliferation of distinct
      uterine cancer cells.

PMID- 15202001
TI  - Elevated expression of DNA polymerase kappa in human lung cancer is associated
      with p53 inactivation: Negative regulation of POLK promoter activity by p53.
AB  - DNA polymerase kappa (POLkappa) is a low fidelity translesional DNA polymerase
      implicated in spontaneous and DNA damage-induced mutagenesis. We have previously
      shown that POLkappa was frequently overexpressed in human lung cancer tissues as
      compared with their matched non-tumorous tissue counterpart. In the present
      study, we found a close correlation between elevated POLkappa expression and p53
      inactivation in lung cancer tissues. To investigate whether POLK expression might
      be regulated by p53, we have determined the transcriptional initiation site of
      POLK gene and examined its promoter activity in A549, H358-129, and PC-3 human
      lung cancer cell lines. Wild-type p53, but not a mutant p53 (R273H) devoid of the
      DNA-binding activity, strongly inhibited POLK promoter activity in these cells.
      In addition, POLK promoter exhibited a significantly higher activity in p53-/-
      murine embryo fibroblasts (MEF) than in p53+/- and p53+/+ MEF. These results link
      p53 status with POLkappa expression and suggest that loss of p53 function may in
      part contribute to the observed POLkappa upregulation in human lung cancers.

PMID- 15202002
TI  - Tissue microarrays--big potential from small samples (review).
AB  - For well over a century, pathologists have used formalin-fixed paraffin-embedded
      tissues for microscopic examination and subsequent diagnosis of human disease.
      However, this type of approach is usually limited to the analysis and/or
      detection of one or two specific features on a single slide from an individual
      section. This area of histological study has been revolutionised by the
      development of tissue microarrays (TMAs). This review describes the development
      and use of TMAs and discusses their possible applications to clinical oncological
      practice.

PMID- 15202003
TI  - Interleukin-1beta and tumour necrosis factor-alpha promote the transformation of
      human immortalised mesothelial cells by erionite.
AB  - Asbestos fails to induce the transformation of human mesothelial cells in vitro
      although it has been known as a potential carcinogen to human mesothelial cells.
      Interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) are
      major cytokines released by macrophages after inhalation of asbestos. These
      cytokines can regulate mesothelial cell proliferation both in vitro and in vivo.
      In the present study, we used the growth in soft agar as an index of
      transformation and investigated the role of IL-1beta and TNF-alpha during the
      process of human mesothelial cell carcinogenesis. Both IL-1beta and TNF-alpha
      were demonstrated to enhance erionite-induced transformation of the immortalised,
      non-tumorigenic human mesothelial cell line (MeT-5A) in vitro. The MeT-5A cells
      could only be transformed when the cells were exposed to a combination of
      cytokines and erionite, or at least two cytokines together without erionite, for
      at least 4 months in vitro. The findings presented here suggest that IL-1beta and
      TNF-alpha play a significant role in the pathogenesis of mesothelioma, and that
      it might be desirable to block or inhibit cytokine secretion in high risk
      populations to prevent mesothelioma.

PMID- 15202004
TI  - Loss of 14q31-q32.2 in renal cell carcinoma is associated with high malignancy
      grade and poor survival.
AB  - The present study was undertaken to further approach the importance of 14q
      deletions in renal cell carcinoma (RCC) development. The initial screening using
      2 RFLP markers from distal 14q identified loss of heterozygosity (LOH) in 17 of
      45 informative cases (38%). In addition, in 37 patients with primary RCCs, it was
      shown that cases with LOH at D14S1 had significantly shorter survival as compared
      to cases with-out LOH (p<0.005). Subsequently, 19 primary tumors and 6 metastases
      were genotyped for 20 polymorphic markers and the findings were evaluated in
      relation to the clinical characteristics of the primary tumor and the survival
      during follow-up. Overall LOH was identified in 11 of the primary tumors (58%)
      and 4 of the metastases (66%). In metastases as well as in primary tumors the
      highest frequency of LOH was detected with markers from the distal part of the
      chromosome i.e., 14q32. Five minimal regions of overlapping deletions were
      identified, three of which (II, IV and V) were defined from the primary RCCs.
      From centromere to telomere these include region I proximal of D14S259, region II
      between D14S255 and D14S588, region III in the D14S61-D14S617 interval, region IV
      between D14S617 and D14S260, and region V telomeric of D14S1007. For the primary
      tumors, losses in regions IV and V were each significantly associated with high
      tumor grade (i.e., grade 3; p<0.05). Furthermore, LOH within region IV was also
      associated with a significantly shorter survival (p=0.02). In conclusion, the
      high frequency of distal 14q LOH supports the relevance of this alteration for
      the development of RCC.

PMID- 15202005
TI  - Modulation of the HSV-TK/ganciclovir bystander effect by n-butyrate in
      glioblastoma: correlation with gap-junction intercellular communication.
AB  - The efficacy of HSV-TK/ganciclovir gene therapy largely relies on the bystander
      effect, i.e. the ability of transfected cells to kill the adjacent, untrasfected
      cells. This mechanism itself depends chiefly on the transfer via gap junctions of
      phosphorylated ganciclovir between cells, and is often deficient in
      glioblastomas. In this report, we demonstrate that n-butyrate markedly enhances
      the gap junction intercellular communication of GJIC-deficient glioma cells, and
      significantly increases the bystander effect in such cells. This effect of n
      butyrate appears to be independent from its HDAC inhibitory effect, since
      trichostatin A does not reproduce it.

PMID- 15202007
TI  - Gefitinib ('Iressa', ZD1839), a selective epidermal growth factor receptor
      tyrosine kinase inhibitor, inhibits pancreatic cancer cell growth, invasion, and
      colony formation.
AB  - Pancreatic cancer is a devastating malignancy, characterized by low
      responsiveness to conventional chemotherapies. Gefitinib, an epidermal growth
      factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has shown clinical activity
      against EGFR-expressing tumors. Since pancreatic cancers frequently overexpress
      EGFR (ErbB-1) and its ligands, our aim was to investigate the potential role of
      gefitinib in this disease. The GI50 of gefitinib as well as the effects of
      gefitinib on growth factor actions in pancreatic cancer cell lines were analyzed
      using MTT assays. FACS analysis using Annexin and propidium iodide (PI) staining
      were performed to study cell cycle, apoptosis and cell death. Western blot
      analysis was carried out to investigate expression levels of the 4 members of the
      ErbB family of receptors in pancreatic cancer cell lines, as well as MAP kinase
      and EGFR phosphorylation. Soft agar assays were used to measure colony
      formations. Invasiveness of cancer cells was analyzed using Matrigel-coated
      filters. gefitinib inhibited cell proliferation of pancreatic cancer cell lines
      with GI50 concentrations ranging from 2.5 to over 10 micro M. Gefitinib
      completely inhibited EGF-induced cell proliferation, but did not significantly
      influence insulin-like growth factor (IGF)-induced mitogenesis. Gefitinib also
      completely abolished EGF-induced phosphorylation of EGFR and MAP kinase.
      Furthermore, gefitinib inhibited basal and EGF-induced anchorage-independent cell
      growth and invasion. Our data demonstrate that gefitinib inhibits pancreatic
      cancer cell growth through EGFR-dependent pathways. Gefitinib also inhibits
      anchorage-independent growth and invasiveness, suggesting that gefitinib may
      offer a new approach for the treatment of pancreatic cancer.

PMID- 15202006
TI  - cDNA microarray analysis of endothelial cells in response to green tea reveals a
      suppressive phenotype.
AB  - Green tea may prevent cancer, partially by inhibiting tumor angiogenesis. Our
      previous studies showed that green tea extract was effective in inhibiting breast
      cancer and endothelial cell proliferation in vitro, and suppressed xenograft size
      and decreased the tumor vessel density in vivo. Here, we set out to further
      investigate the molecular mechanisms of this observed angiogenesis suppression.
      We utilized cDNA microarray technology to profile the global changes in
      endothelial cellular gene expression in response to green tea. HUVEC (human
      umbilical vein endothelial cells) were exposed in vitro to green tea for either 6
      or 48 h. Only statistically significantly differentially expressed genes were
      analyzed. Gene profiling demonstrated a global down-regulation of multiple genes
      involved in endothelial cell growth, signal transduction and oxidation,
      accompanied by up-regulation of several apoptotic genes. We validated these
      observations by showing positive correlations with biological assays of cellular
      proliferation, cell cycle, and apoptosis. The anti-oxidant characteristics of
      green tea and its metabolites were confirmed in the ORAC (oxygen radical
      absorbance capacity) assay. cDNA microarray revealed that green tea has an
      overall suppressive effect on multiple pathways in endothelial cells. This study
      contributes to the comprehensive analysis of the molecular effects of green tea
      on endothelial cells, and provides insight into genes that may be important in
      chemoprevention.

PMID- 15202008
TI  - In vitro quantification of the cytotoxic T lymphocyte response against human
      telomerase reverse transcriptase in breast cancer.
AB  - Telomerase is expressed in approximately 90% of breast cancers but not in normal
      somatic cells. The catalytic subunit of telomerase, human telomerase reverse
      transcriptase (hTERT), is a widely expressed tumour-associated antigen against
      which specific cytotoxic T lymphocyte (CTL) responses have been identified. Human
      CD8+ CTL have been shown to recognise hTERT synthetic peptides in an HLA
      restricted manner and to lyse hTERT+ tumour cells. This study has investigated
      the specific CD8+ CTL response in a defined cohort of primary breast cancer
      patients against 3 hTERT peptides using an IFNgamma ELISpot assay. A specific
      CD8+ CTL response against at least one of the hTERT peptides was observed in 75%
      of cancer patients, with 8/17 patients responding to both HLA-A2 restricted
      peptides. In contrast, 38% of normal healthy female controls responded against a
      single peptide only. This suggests that a specific immune response exists against
      hTERT in breast cancer patients and that hTERT is a suitable target for tumour
      based immunotherapy.

PMID- 15202009
TI  - Identification and characterization of human FOXN6, mouse Foxn6, and rat Foxn6
      genes in silico.
AB  - Forkhead-box (FOX) transcription factors are implicated in carcinogenesis through
      gene amplification, retroviral integration, or chromosomal translocation. FOXN1,
      FOXN2 (HTLF), FOXN3 (CHES1), FOXN4 and FOXN5 (FOXR1) constitute the FOXN family.
      Here, we identified and characterized human FOXN6 (FOXR2) and rodent Foxn6
      (Foxr2) orthologs by using bioinformatics. Human FOXN6 gene was identified within
      human genome sequence RP11-167P23 (AL159987.19), mouse Foxn6 gene within mouse
      genome sequence RP23-180D16 (AL672293.14), and rat Foxn6 gene within rat genome
      sequence CH230-264B14 (AC106980.5). FOXN6, RRAGB (RAGB), and KLF8 genes were
      clustered at human chromosome Xp11.21. Foxn6, Rragb, and Klf8 genes were also
      clustered at mouse chromosome XF3 as well as at rat chromosome Xq14. Human FOXN6
      mRNA was expressed in breast cancer cell line and primary breast cancer. Mouse
      Foxn6 mRNA was expressed in E9.5 embryo. Human FOXN6 (286 aa) showed 57.7% total
      amino-acid identity with human FOXN5, 53.8% total-amino-acid identity with mouse
      Foxn6 (277 aa), and 52.4% total-amino-acid identity with rat Foxn6 (277 aa).
      Codon 167-248 of human FOXN6 was the Forkhead domain. FN56 domain (codon 1-69 of
      FOXN6) was identified as a novel domain conserved among FOXN6 and FOXN5
      orthologs. Mammalian FOXN6 orthologs were found consisting of FN56 and FOX
      domains. Phylogenetic analyses revealed that FOXN family proteins are classified
      into three subfamilies: i) FOXN6 and FOXN5 orthologs; ii) FOXN1 and FOXN4
      orthologs; iii) FOXN2 and FOXN3 orthologs. This is the first report on human
      FOXN6, mouse Foxn6, and rat Foxn6 genes.

PMID- 15202010
TI  - Identification and characterization of human TP53I5 and mouse Tp53i5 genes in
      silico.
AB  - TP53 gene, encoding tumor protein P53, is frequently inactivated in various types
      of human cancer, including colorectal, lung, and gastric cancer. Cancer cells
      with TP53 mutation acquire malignant potentials, such as selective growth
      advantage, genomic instability, resistance to apoptosis, and promotion of
      angiogenesis. U33271 partial cDNA isolated from HPV-18 E6/E7 immortalized
      keratinocytes is derived from one of P53-traget genes. Here, we identified and
      characterized the TP53I5 (tumor protein P53 inducible protein 5) gene
      corresponding to U33271 partial cDNA by using bioinformatics. FLJ23270
      (AK026923.1) was the representative human TP53I5 cDNA. TP53I5 gene, consisting of
      23 exons, was located at human chromosome 11p15.5. TP53I5 mRNA was expressed in
      human colorectal, lung, and breast cancer. IMAGE5352905 (BC025477.1) and
      IMAGE6508837 (NM_178381.2) were aberrant mouse Tp53i5 cDNAs with multiple
      frameshifts due to retention of intronic sequences. Complete coding sequence of
      mouse Tp53i5 cDNA was determined by assembling nucleotide positions 1-1213, 1293
      1740, 1745-2045, and 2071-3088 of BC025477.1. Tp53i5 gene was located at mouse
      chromosome 7F5. Human TP53I5 (782 aa) and mouse Tp53i5 (747 aa), showing 71.1%
      total-amino-acid identity, were eight-transmembrane proteins with N- and C
      terminal tails facing the cytoplasm. TP53I5 orthologs were homologous to TMEM16A
      (FLJ10261 or ORAOV2), TMEM16B, TMEM16C, TMEM16D, TMEM16E and TMEM16F with the
      TM16H1, TM16H2, and TM16H3 domains. TP53I5 was identified as a novel member of
      the TMEM16 family based on membrane topology and TM16H1-3 domains. This is the
      first report on the human TP53I5 and mouse Tp53i5 genes.

PMID- 15202011
TI  - Synthetic bile acid derivatives inhibit cell proliferation and induce apoptosis
      in HT-29 human colon cancer cells.
AB  - As previously demonstrated, the synthetic bile acid derivatives mediate anti
      proliferative properties in a variety of human cancer cells. In the present
      study, the effects of the synthetic derivatives of ursodeoxycholic acid (UDCA),
      HS-1030 and HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on
      the proliferation of HT-29 human colon cancer cells were investigated. Whereas
      UDCA and CDCA had no effect on the growth of cells in the concentration ranges we
      have tested, HS-1199 and HS-1200 completely inhibited cell proliferation, while
      HS-1030 and HS-1183 showed weak inhibitory activities. Simultaneous estimation of
      cell cycle parameters and apoptosis by flow cytometry showed that the synthetic
      bile acid derivatives produced the arrest of cell cycle progression at the G1
      phase and ensuing increase of sub-G1 fraction, which resulted in the induction of
      apoptosis. The induction of apoptosis was confirmed by observation of cleavages
      of poly(ADP-ribose) polymerase and DNA fragmentation. Furthermore, Western blot
      analysis showed decreased expression levels of cyclin D1, cyclin E, cyclin A,
      Cdk2, Cdk4, and Cdk6 proteins. In addition, the synthetic bile acid derivatives
      markedly induced the level of Cdk inhibitor, p21WAF1/CIP1, in a p53-independent
      manner. Furthermore, the exposure of cells to the synthetic bile acid derivatives
      resulted in a decrease in the level of pRb and enhanced binding between pRb and
      E2F-1. Based on these data, these synthetic bile acid derivatives may serve as
      potential lead compounds in the treatment of colon cancer.

PMID- 15202012
TI  - Molecular therapy versus standard treatment in allergy (Review).
AB  - The increasing knowledge concerning pathomechanism of allergy creates new
      perspectives for treatment. Standard methods currently applied in allergy act
      multidirectional, usually being crude and unselective. Moreover, such therapy
      does not eliminate the cause of hyperresponse reaction and often fails to restore
      the immunological balance. It is also noteworthy that the conventional therapy
      frequently affects different tissues not directly involved in allergic reaction
      and thus it may exert numerous side effects. The hypersensitivity was found to be
      related to some cytokines network abnormalities. Among cytokines, there are a
      few, well-recognized factors e.g., interleukin-4 (IL-4), IL-5 and IL-13, which
      play a pivotal role in allergy. Thus, the major goal for causal allergy treatment
      should be restoration of the balance in cytokine-mediated regulation of allergen
      driven immunological response. It could be achieved by administration of missing
      cytokines, e.g., interferon-gamma (IFN-gamma) and/or down regulation of excessive
      one, e.g., IL-4, IL-13. Such a therapy, directed towards only specific, allergy
      involved molecules, should not affect the other by-standing particles or
      reactions. Obviously, a good target for this kind of treatment could be
      immunoglobulin E (IgE) that is causally related to anaphylactic response.
      Furthermore, especially promising objectives for molecular therapy seem to be
      some cytokine receptors and signal transduction pathways and some adhesion
      molecules. The most recent therapeutical strategies attempting to restore
      immunological balance in allergy are presented. They include, among others, anti
      cytokine antibodies, their soluble receptors, antisense oligonucleotides and
      small interfering RNA. Although many of these topical methods are still in the
      trial phase, we suppose they will become a clinical reality in the near future.

PMID- 15202013
TI  - Apoptosis in prostate cancer: progressive and therapeutic implications (Review).
AB  - Prostate cancer is the most common non-cutaneous malignancy in American men and
      the second greatest cause of cancer-related death. Development of effective
      therapeutic modalities for the treatment of this cancer relies heavily on
      understanding the molecular alterations that result in the initiation and
      progression of the tumorigenic process. Increasing evidence indicates that
      impaired ability to undergo apoptosis plays an important role in the evolution
      from androgen-dependent to androgen-independent prostate cancer. In this review,
      we address recent progress toward the central objectives of understanding the
      molecular events that contribute to prostate cancer progression. We focus on some
      key regulatory molecules, including the pro-apoptotic regulators p53, PTEN,
      caspases and Par-4, and the anti-apoptotic molecules Bcl-2, NF-kappaB and Akt, to
      discuss their roles in prostate cancer progression and their therapeutic
      implications in human prostate carcinoma.

PMID- 15202014
TI  - Secretory immune system in human embryonic and fetal development: joining chain
      and immunoglobulin transport (Review).
AB  - The role of joining (J) chain, one of the protein components of the secretory
      immune system (SIS), in the immune reactions of the human embryo and fetus was
      analyzed on the basis of data from the literature and our previous studies. All
      organs and structures, including extra-corporeal ones, of 18 embryos (4-8 weeks
      of development) and 45 fetuses (9-38 weeks) were studied using methods of
      pathomorphology, immunohistochemistry and morphometry. This approach enabled us
      to analyze the problem in the whole organism throughout its embryonic and fetal
      development. J chain, as well as polymeric immunoglobulin (Ig) receptor-secretory
      component (pIgR/SC) and Igs, are already widely distributed in 4-week-old embryos
      before the appearance of the common immune system. The whole complex of protein
      components of the SIS was seen in mucous layers, and in blood-tissue and tissue
      tissue barrier structures. Therefore, we can consider two parts of the SIS:
      mucosal and barrier. Already in embryos, an increase in the functional activity
      of the SIS following massive antigenic attack in cases of acute chorioamnionitis
      reflects the increased exocrine secretion of Igs. The J chain appears to
      participate in the endocytosis but not exocytosis of Igs. J chain and Igs, but
      not pIgR/SC, were present in cells of the heart, endocrine glands, gonads and
      some other organs. The exocrine secretion of Igs, the main function of the SIS,
      is absent in these organs, and, they are therefore, not considered part of the
      SIS.

PMID- 15202015
TI  - Identification of differentially expressed genes in clinically distinct groups of
      serous ovarian carcinomas using cDNA microarray.
AB  - To identify changes in gene expression in serous epithelial ovarian cancers
      (SEOC), we utilized cDNA microarrays consisting of 2382 genes with cancer related
      properties to analyze tumors from 20 patients with defined clinical out-comes.
      The significance analysis of microarrays method was used to determine
      differentially expressed genes, leading to the identification of 134 up-regulated
      and 231 down-regulated genes overall. By increasing the stringency of the
      statistical selection criteria, 41 over-expressed and 51 under-expressed genes
      were identified. The median duration of follow-up of the 20 patients was 16.8
      months with a median progression free survival of 7.0 months. We found 11 genes
      that were differentially over-expressed in patients with recurrent disease, and 3
      genes (homo sapiens mRNA for Ins P3 5-phophatase, lipoma HMGIC fusion partner
      like 2 and CD63 melanoma 1 antigen) in patients who were dead of disease.
      Subsequently, we examined the distribution of the differentially expressed genes
      in the cDNA library database from adult human tumor and normal tissues using the
      DigiNorthern method to identify a subset of genes with relatively restricted
      tissue distribution. Finally, protein expression of 5 selected genes were further
      examined using immunohistochemistry applied on a tissue microarray prepared from
      an independent panel of 93 SEOC tissues. The results provided validation for 2
      under-expressed genes (E2F transcription factor 5 and CK14) and 3 over-expressed
      genes (Bcl2-like 1, COX-2, CD63). Our study demonstrates differential gene
      expression in clinically distinct groups of SEOC using cDNA microarray. These
      genes may potentially be useful as biomarkers and/or targets for therapeutic
      intervention.

PMID- 15202017
TI  - Expression of CXCL16 in human rectal cancer.
AB  - Local immunoregulation mediated by infiltration of inflammatory cells into
      colorectal adenocarcinomas is important for tumour progression. Tumour-associated
      macrophages and T cells are predominant components of chemokine-guided infiltrate
      of most colorectal tumours. CXCL16 is a newly discovered CXC chemokine expressed
      by antigen presenting cells attracting Th1, Tc and NK T cells. In this study,
      which is the first report on expression of the chemokine CXCL16 in human rectal
      cancer, CXCL16 gene and protein expression were analysed in cancer and normal
      adjacent tissue. Immunohistochemistry revealed CXCL16 expression in macrophages
      in normal tissue. The CXCL16 was found to a very limited extent in tumour
      associated macrophages. Western blot analysis showed a suppression of CXCL16
      protein in rectal cancer compared to non-cancer tissue in 83% of the patients
      (n=23, P=0.003). However, with real-time PCR mRNA was not down-regulated in the
      cancer compared to normal tissue, which may depend on regulated factor(s) at the
      level of translation and/or post-translation. The results may reflect one of the
      immunological mechanisms underlying carcinogenesis.

PMID- 15202016
TI  - Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced
      retinal vascular endothelial growth factor overexpression.
AB  - We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important
      mechanism in the oxidative stress-related development of diabetic retinopathy. In
      the experiments reported here, we evaluated if: a) PARP activation is present in
      the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and
      1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF
      formation. In vivo studies were performed in control and streptozotocin-diabetic
      rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3
      mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In
      vitro studies were performed in human retinal pigment epithelial cells exposed to
      normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200
      and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD
      concentration reduced in diabetic rats, and both variables were corrected by PARP
      inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA
      (ribonuclease protection assay) abundance, was increased in diabetic rats, and
      this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol.
      PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or
      lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in
      both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA
      overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein
      was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced
      VEGF production at post-transcriptional level, downstream from the sorbitol
      pathway activation and oxidative stress. The results justify studies of PARP
      inhibitors in models of retinopathy of prematurity and diabetic retinopathy.

PMID- 15202018
TI  - Acute effect of ischemia on adrenomedullin immunoreactivity in the rat heart: an
      immunocytochemical study.
AB  - We investigated by immunocytochemistry (ICC) the acute effects of ischemia on the
      distribution in the rat heart of adrenomedullin (AM), a potent hypotensive
      peptide which is expressed in the cardiovascular system, where it is known to
      play a major regulatory and protective role. Hearts, collected from adult male
      Sprague-Dawley rats, were perfused with the Langendorff technique, and "global"
      ischemia was obtained by stopping perfusion for 20 min. Hearts were frozen, and
      ICC was performed using a specific anti-rat AM1-50 antibody and secondary
      peroxidase-conjugated antibodies. ICC demonstrated AM-immunoreactivity (IR) in
      cardiomyocytes and especially in the wall of coronary vessels. Quantitative
      densitometry showed that acute ischemia significantly decreased AM-IR in coronary
      arterioles, thereby suggesting that it markedly stimulates AM release. The
      conclusion is drawn that acute ischemia and ensuing hypoxia activate in the rat
      heart the release of AM, which by its coronarodilatory action may enhance heart
      blood flow.

PMID- 15202019
TI  - Upregulation of tumour endothelial marker-8 by interleukin-1beta and its impact
      in IL-1beta induced angiogenesis.
AB  - Tumour endothelial marker-8 (TEM-8) has been found to be selectively upregulated
      in tumour-associated endothelial cells and is implicated in tumour specific
      angiogenesis. Specific factors, indigenous to tissues and tumours that regulate
      the TEM-8 mechanism in angiogenesis are not defined. We report for the first time
      that interleukin-1beta induces the expression of TEM-8 in endothelial cells.
      Human vascular endothelial cells (HECV), which strongly express IL-1beta receptor
      (as revealed by RT-PCR, Western blotting), increased the level of TEM-8
      expression following stimulation with IL-1beta (as revealed by conventional and
      quantitative RT-PCR). Using a newly developed antibody to human TEM-8, we have
      further demonstrated that IL-1beta significantly raised the level of TEM-8 at the
      protein level, as revealed by Western blotting. In vitro tubule forming assay,
      revealed that IL-1beta significantly induced the formation of capillary-like
      tubules from the HECV cells, accompanied by an increase in TEM-8 expression. It
      is concluded that IL-1beta is a powerful regulator of the expression of TEM-8 in
      vascular endothelial cells. Our results suggest an important pathway through
      which IL-1beta regulates tumour-associated angiogenesis.

PMID- 15202020
TI  - Receptor activator of NF-kappaB ligand-stimulated osteoclastogenesis in mouse
      marrow culture is suppressed by zinc in vitro.
AB  - Zinc has been shown to have an inhibitory effect on osteoclastic bone resorption
      in vitro. This study was undertaken to determine whether the inhibitory action of
      zinc on osteoclastogenesis is related to receptor activator of NF-kappaB ligand
      (RANKL), which plays a pivotal role in differentiation from pre-osteoclasts to
      osteoclasts. Mouse marrow cells were cultured for 3 days in alpha-minimal
      essential medium containing lipopolysaccharide (LPS), tumor necrosis factor-alpha
      (TNFalpha), or RANKL, which stimulates osteoclastogenesis; then zinc sulfate was
      added to the culture medium containing each osteoclastogenesis-stimulating
      factor, and the cells were further incubated for 4 days. Osteoclast-like cell
      formation was estimated by staining for tartrate-resistant acid phosphatase
      (TRACP), a marker enzyme of osteoclasts. The presence of LPS (10 micro g/ml),
      TNFalpha (10 ng/ml), or RANKL (10 or 20 ng/ml) with M-CSF (10 or 20 ng/ml)
      induced a remarkable increase in osteoclast-like multinucleated cells (MNCs). The
      stimulatory effect of LPS was not significantly altered by the addition of zinc
      sulfate (10(-6)-10(-4) M). Meanwhile, TNFalpha- or RANKL-induced osteoclast-like
      cell formation was significantly inhibited in the presence of zinc sulfate (10(
      6)-10(-4) M). The effect of zinc sulfate (10(-4) M) in inhibiting RANKL-induced
      osteoclast-like cell formation was completely abolished in the presence of
      cycloheximide (10(-7) M), an inhibitor of translation in protein synthesis, or
      5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB; 10(-6) M), an inhibitor
      of transcription. These results suggest that the inhibitory action of zinc on
      osteoclastogenesis is partly due to suppressing signaling pathway which is
      related to RANKL stimulation in osteoclast development.

PMID- 15202021
TI  - Response of antioxidant enzymes and redox metabolites to cadmium-induced
      oxidative stress in CRL-1439 normal rat liver cells.
AB  - Cadmium is a non-physiological heavy metal released into the environment and
      workplace as a result of industrial, municipal, and agricultural activities. The
      association of Cd with pulmonary, prostatic and testicular cancer may be related
      to the ability of Cd to induce oxidative stress, which could in turn cause
      oxidative damage to DNA. This study examines the response of antioxidant enzymes
      and metabolites to Cd-induced oxidative stress in normal liver cells. We found a
      definite concentration-dependent increase in ROS when CRL-1439 normal liver cells
      were exposed to various concentrations of Cd2+ (100-300 microM). An increase in
      ROS production is an indication of oxidative stress, which is known to impact on
      the performance of antioxidant enzymes and metabolites in the cell. In fact, we
      found that superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR)
      and glutathione peroxidase (GPx) lost activities upon a 4-h exposure of liver
      cells to levels of Cd2+ ranging from 100 to 300 microM. After exposure of cells
      for 8 h, the activity of SOD and GPx increased while those of CAT and GR
      decreased substantially. The metabolites glutathione (GSH), oxidized glutathione
      (GSSG) and total thiols showed a decrease in concentration after 4 or 8 h of
      incubation of liver cells with Cd (100-300 microM). Malondialdehyde (MDA) on the
      other hand, showed an increase in concentration after 4-8 h of incubation of
      liver cells with Cd due to lipid peroxidation. The relationships of these fluxes
      to oxidative stress as well as intracellular redox homeostasis are discussed.

PMID- 15202022
TI  - Magnetic resonance spectroscopy and chromatographic methods identify altered
      lipid composition in human renal neoplasms.
AB  - We report on the characterization of the lipid obtained from cortical and
      medullary normal human kidney tissue, benign renal neoplasms (oncocytoma) and 2
      different types of malignant renal neoplasms (chromophobic cell carcinoma and
      clear cell carcinoma). The total lipid fractions were analyzed by 13C magnetic
      resonance spectroscopy and thin-layer chromatography, whereas the composition of
      the total fatty acids and the content of total cholesterol were determined by gas
      chromatography. alpha-Tocopherol was detected and quantified by high-performance
      liquid chromatography. The spectroscopic and chromatographic analysis revealed
      significant differences in the renal tissues examined. It was confirmed that
      cholesteryl esters (mainly oleate) are typical of clear cell renal carcinomas.
      Their potential role as prognostic and diagnostic factors is discussed, with
      particular emphasis on its capability to indicate the tumor diffusion in healthy
      renal parenchyma. alpha-Tocopherol is prevalent in clear cell carcinoma and it is
      present in nearly the same low amounts in cortex, medulla and chromophobic cell
      renal carcinoma. Q10 coenzyme and dolichols were detected by thin-layer
      chromatography and they are present in significant amounts in the cortex and the
      benign oncocytoma. Great variations were found in the distribution of saturated
      and unsaturated fatty acids, especially in the docosapentaenoic, docosahexaenoic
      and arachidonic acids and the corresponding omega-6/omega-3 fatty acids ratio.

PMID- 15202023
TI  - Association of HPV infection with prognosis after neoadjuvant chemotherapy in
      advanced uterine cervical cancer.
AB  - Whether the human papillomavirus (HPV) status of the tumor affects the
      sensitivity to neoadjuvant chemotherapy, and the prognosis in advanced uterine
      cervical cancer (FIGO stage III or higher) remains unknown. We examined the HPV
      status of 43 patients who had received CDDP therapy by balloon-occluded arterial
      infusion (BOAI), as neoadjuvant chemotherapy for advanced uterine cervical cancer
      (squamous cell carcinoma) stage III or higher. DNA was extracted from formalin
      fixed, paraffin-embedded tumor samples obtained by punch biopsy before the
      neoadjuvant chemotherapy. The detection of HPV and its typing were analyzed by a
      polymerase chain reaction (PCR)-based assay using consensus primers for the L1
      consensus regions. HPV DNA was detected in all 43 patients (100%): 29 cases with
      HPV 16 (67.4%), 5 cases with HPV 33 (11.6%), 4 cases with HPV 31 (9.3%), 3 cases
      with HPV 35 (7.0%), 1 case with HPV 18 (2.3%) and 1 case with HPV 58 (2.3%). The
      HPV types were divided into 3 groups, HPV 16, HPV 33 and other HPV types (HPV 18,
      31, 35, 58), and comparisons and examinations were performed among the 3 groups.
      Although the rates of tumor reduction and operation accomplishment after 3
      courses of BOAI showed no significant differences among the 3 groups, there were
      significant differences in the survival rates. The survival rate of advanced
      uterine cervical cancer patients with HPV 33 infection was the highest, followed
      by that of patients with HPV 16 infection. The survival rates of patients with
      the other types of HPV infection were the worst among the 3 groups and
      significantly lower than those of patients with HPV 16 or HPV 33 infection. The
      differences in the curative effect after BOAI may depend on the different
      characters of the HPV types.

PMID- 15202024
TI  - Dissimilar effects of D-mannoheptulose on the phosphorylation of alpha- versus
      beta-D-glucose by either hexokinase or glucokinase.
AB  - D-mannoheptulose inhibits D-glucose phosphorylation by hexokinase isoenzymes. The
      present study aims at investigating whether the pattern of such an inhibition
      differs in the case of alpha- versus beta-D-glucose. The phosphorylation of alpha
      and beta-D-[U-14C]glucose was measured over 60-min incubation at 4 degrees C in
      the presence of bovine heart hexokinase and over 10 min at 24 degrees C in the
      presence of human liver glucokinase. The relative extent of the inhibitory action
      of D-mannoheptulose (0.02-10.0 mM) was always less marked with alpha- than beta-D
      glucose. In the case of hexokinase, the experiments conducted at the high
      concentration of the D-glucose anomers (1.0 mM) revealed that D-mannoheptulose,
      at low concentrations (0.2-0.5 mM), may unexpectedly increase the phosphorylation
      of alpha-D-glucose. These findings thus document anomeric specificity in terms of
      the inhibitory action of D-mannoheptulose upon alpha- versus beta-D-glucose
      phosphorylation by either hexokinase or glucokinase.

PMID- 15202025
TI  - Factors affecting bryostatin 1-enhanced 2-CdA cytotoxicity in resistant B-cell
      chronic lymphocytic leukemia.
AB  - Pre-treatment with bryostatin 1 (bryo) has been shown to potentiate the efficacy
      of (2-chloro-2-deoxyadenosine, cladribine, 2-CdA) in B-cell chronic lymphocytic
      leukemia (B-CLL) by increasing the ratio of deoxycytidine kinase (dCK) to 5'
      nucleotidase (5'-NT) activity. The bryo-induced increase in dCK/5'-NT activity
      alone has not been a conclusive indication of final clinical outcome. Therefore,
      we used an ex vivo assay to investigate factors which may affect the bryo-induced
      enhancement of 2-CdA efficacy in B-CLL patient-derived samples. Bryo-induced
      increase in dCK/5'-NT was inversely associated with Rai stage CLL (r=-0.86).
      Increased dCK/5'-NT activity was not correlated with increased efficacy (cell
      death) or percentage of cellular [8-3H]-2-CdA converted to [8-3H]-2-CdATP ex
      vivo. Bryo pre-treatment increased the cellular uptake of [8-3H]-2-CdA and
      incorporation of [8-3H]-2-CdA metabolites into the DNA fraction. Cell death from
      2-CdA was inversely correlated with bryo-induced activity of the DNA repair
      enzyme, DNA-PKcs, (r=-0.77). Thus, the ability of B-CLL to repair damaged DNA may
      be a more important predictor of the response to bryo/2-CdA and eventual clinical
      outcome than dCK/5'-NT activity. Additional CLL patients under bryo-2-CdA therapy
      are needed to verify these important observations.

PMID- 15202026
TI  - Identification and characterization of the human FMN1 gene in silico.
AB  - Mouse Formin (Fmn1) protein plays a key role in limb morphogenesis. Fmn1 is one
      of the actin regulators with scaffold function, interacting with Profilin, SRC,
      EMS1, FNBP1, FNBP2, FNBP3, FNBP4, WBP4 and alpha-catenin. Fmn1, Fmn2, FHOD1,
      FHOD3, GRID2IP and FHDC1 are non-FDD-type Formin homology proteins, while FMNL1,
      FMNL2, FMNL3, DIAPH1, DIAPH2, DIAPH3, DAAM1 and DAAM2 are FDD-type Formin
      homology proteins. Here, we identified the human FMN1 gene by using
      bioinformatics. The complete coding sequence of human FMN1 cDNA was determined by
      assembling AC055874.8 genome sequence (nucleotide position 178207-180073),
      AI040235 EST (complementary sequence for nucleotide position 331-156) and
      FLJ45135 cDNA (nucleotide position 319-3310). FMN1 isoform 1 (exons 1-18) and FMN
      isoform 2 (exons 1b and 3-18) were transcribed due to alternative splicing of the
      alternative promoter type. The FMN1 gene at human chromosome 15q13.3 was located
      between CKTSF1B1 (Gremlin) and RYR3 genes. The Xenopus fmn1 gene was identified
      within the Xenopus genome sequence CH216-24N20 (AC147835.1). The FMH1 domain
      (codon 1-120 of FMN1) and FMH2 domain (codon 683-835 of FMN1) were identified as
      novel regions conserved among human FMN1, mouse Fmn1, and Xenopus fmn1. The FMH2
      domain was almost identical to the alpha-catenin binding domain of mouse Fmn1.
      Human FMN1 (1419 aa), showing 77.1% total amino-acid identity with mouse Fmn1,
      was found consisting of FMH1, FMH2, FH1 and FH2 domains. This is the first report
      on the identification and characterization of the human FMN1 gene as well as the
      FMH1 and FMH2 domains.

PMID- 15202027
TI  - Identification and characterization of human FOXK1 gene in silico.
AB  - Forkhead-box (FOX) family transcription factors are implicated in carcinogenesis
      and embryogenesis. Here, we identified and characterized the human FOXK1 gene by
      using bioinformatics. Complete coding sequence of human FOXK1 cDNA was determined
      by assembling CB959941 EST, AW206906 EST, and 5'-truncated FLJ16099 (AK122663.1)
      cDNA. FOXK1 gene, consisting of nine exons, was mapped to human chromosome
      7p22.1. Mouse Foxk1 (NM_199068.1) was an aberrant cDNA with frame shifts due to
      multiple insertions and deletions, while mouse IMAGE6853263 (BC060238.1) was a
      Foxk1 cDNA with a frame shift due to two base deletions. Complete coding sequence
      of mouse Foxk1 cDNA was determined by inserting CA nucleotides between nucleotide
      position 1628 and 1629 of BC060238.1. Foxk1 gene, consisting of nine exons, was
      mapped to mouse chromosome 5G2. Because interleukin enhancer-binding factor 1
      (ILF1) gene at human chromosome 17q25.3 was the paralog of FOXK1 gene, ILF1 gene
      was designated the FOXK2 gene. Xenopus BC046369.1 cDNA was Foxk2 ortholog rather
      than Foxk1 ortholog. Human FOXK1 (733 aa) showed 88.7% total amino-acid identity
      with mouse Foxk1 (719 aa), 48.7% total amino-acid identity with human FOXK2, and
      47.5% total amino-acid identity with Xenopus Foxk2. Forkhead associated (FHA)
      domain and FOX domain were conserved among human FOXK1, FOXK2, mouse FoxK1, and
      Xenopus Foxk2. At least 42 FOX family genes, including FOXK1, FOXN5 (FOXR1) and
      FOXN6 (FOXR2), have been identified within the human genome.

PMID- 15202028
TI  - Changes in circulating levels of vascular endothelial growth factor and vascular
      endothelial growth factor receptor-2 after carotid endarterectomy.
AB  - It has been shown that vascular endothelial growth factor (VEGF) and vascular
      endothelial growth factor receptor-2 (VEGFR-2) are upregulated in severe carotid
      stenosis. However, it is unknown whether carotid endarterectomy (CEA) affects
      serum level of these molecules. We investigated changes in concentration of VEGF
      and VEGFR-2 in patients undergoing carotid endarterectomy. Forty-three patients
      with extracranial carotid stenosis (>70%), were studied. Patients with severe
      vertebrobasilar stenosis, recent (<1 month) vascular event (stroke, coronary
      infarction, arterial thromboembolism), critical ischemia of lower extremity,
      recent infection, autoimmune disease or malignancy were excluded from the study.
      Blood samples were taken before CEA and on the second post-operative day. Thirty
      healthy blood donors served as a control group. We used enzyme linked immuno
      absorbent assay as a method for the determination of VEGF and VEGFR-2. Pre
      operative levels of VEGF (371+/-42 pg/ml) and VEGFR-2 (8424+/-356 pg/ml) were
      significantly elevated. There was significant decrease in both VEGF (152 pg/ml)
      and VEGFR-2 (1297 pg/ml) after CEA, without however reaching normal values. In
      asymptomatic patients and in patients with a contralateral carotid stenosis of
      >50%, however, the observed reduction of VEGF did not reach statistical
      significance. On the other hand, in the same subgroups, a major decrease of VEGFR
      2 values was observed. VEGF and VEGFR-2 showed a very significant increase in
      serum of patients with severe carotid stenosis. These pre-operative levels
      decreased significantly after endarterectomy, and the changes emphasize the
      importance of these molecules in carotid disease progression.

PMID- 15202030
TI  - [Influenza vaccination: coverage of Portuguese population from 1998/1999 a
      2002/2003].
AB  - Between 1999 and 2003 the Portuguese National Health Observatory, has conducted
      four telephone surveys (1998/99, 1999/00, 2001/02 and 2002/03) using the ECOS -
      Em Casa Observamos Saude - panel of Portuguese families, with telephone aiming at
      studying the influenza vaccination coverage of the mainland Portuguese
      population. From the results it can be highlighted: The percentage of individuals
      that declared to have taken the influenza vaccine, showed a consistent increase
      between 1998/99 (14.2%) and 2001/02 (17.0%), and a decrease in 2002/03 (15.0%),
      without statistical significance. In 2002/03, the age group 65 years and older
      had the highest coverage of influenza vaccination (36.9%). The lowest percentage
      occurred in the 15 - 44 age group (7.0%). The individuals that declared to suffer
      from chronic diseases (asthma, rheumatic disease, hypertension and diabetes),
      showed higher coverage when compared with the general population. The highest
      values were verified in individuals that declared to suffer from diabetes (34.5%)
      and asthma (34.3%). Based on these results, it figures out important to promote a
      larger coverage of the influenza vaccination in the individuals with 65 years or
      more, once this coverage is not sufficiently high, if compared with the estimates
      from other European countries. Although there are no European estimates to
      compare with, it seems equally necessary to take measures to improve the
      coverage, in the risk groups studied, as well as in others risk groups that were
      not included the present study.

PMID- 15202031
TI  - [Lung function tests: the pneumologist and ambulatory care].
AB  - Lung function testing (LFT) has been standardized and greatly improved in the
      last three decades, but its relative complexity has driven to recent
      sistematization and standardization of its applicability in the office and in
      primary care. In memorian of Prof Antonio Couto, and of his outstanding role in
      the promotion of LFT in Potyugal, this conference deals with the definition of
      office spirometry, its application range, and the essential steps for the
      performance, in acceptable quality and reproducibility conditioms. The role of
      the specialist in promoting this method, and his support to possible spirometry
      performers, is aimed as an important request in the success of the practical and
      used technique in family practice and primary health care.

PMID- 15202032
TI  - [Tuberculosis. Future perspectives].
AB  - Tuberculosis remains a major health problem around the world and its incidence is
      growing 0.4% each year. There are 2 billions of infected, 8.4 millions new cases
      every year and 16 million patients. The association of VIH and tuberculosis, the
      increasing number of multidrug resistance, failure of health systems, greater
      mobility of people, poverty, wars and social exclusion, are the major causes of
      the epidemiological situation. Faster, more specific and sensible diagnostic
      methods are being investigated. Some of them use molecular biology techniques,
      some uses radioisotopes and some others are based on colour and fluorescence
      modifications of dyes. New drugs, new routes of administration and ways for
      increasing compliance are under investigation. More potent drugs, with greater
      biodisponibility and adequate pharmacokinetics for shorter treatments for
      multidrug and latent forms of bacilli are needed. New vaccines are under
      investigations, namely Adjuvant Subunits Vaccines, DNA Vaccines DNA, no
      micobacterianos vectors, and attenuated living vaccines are being tested. Finally
      some considerations are made concerning the need of global committement to win
      the fight against tuberculosis in the near future.

PMID- 15202033
TI  - [Pulmonary aspects in alpha-1-antitrypsin deficiency].
AB  - Alpha-1-antitrypsin deficiency is an autosomal hereditary disorder and the large
      majority of individuals with severe deficiency are protease inhibitor type ZZ.
      The disease occurs predominantly in white persons of European origin and its
      frequency in Europe and North America is comparable to that of cystic fibrosis (1
      in 2000 to 1 in 7000). Persons with this deficiency may have no clinical
      manifestations, but the most prevalent clinical disorder associated, also pointed
      as the most frequent cause of disability and death, is chronic obstructive
      pulmonary disease. In those individuals, tobacco smoking is the major risk. The
      condition appears to be widely underdiagnosed, based on studies. Several
      strategies have been explored in the treatment of this deficiency.

PMID- 15202034
TI  - [Emphysema and lung volume reduction surgery--a case report].
AB  - Lung volume reduction surgery (LVRS) has been proposed as a palliative therapy in
      severe emphysema, with good results in lung function improvement, exercise
      capacity and quality of life. The authors present a case report of a 34 years old
      man with severe, heterogeneous lung emphysema submit to bilateral LVRS in 2000
      January. Pre-surgical conditions, clinical and radiological evolution after
      surgery and for a 30 months follow up were analysed. Based on a literature
      revision, some technical aspects of LVRS, selection criteria and comparative
      study of medical and surgical therapy were discussed.

PMID- 15202035
TI  - [Recurrent pleural effusion with macroglobulinemia--case report with revision of
      the literature].
AB  - We describe a case of chronic relapsing pleural effusion in a 73 year old male
      with lympho-palsmocytic pleural infiltration and monoclonal gamopathy (IgMk), and
      no other manifestation of Waldenstromacute;s Disease (W.D.). The patient was
      treated symptomatically and remained in good general condition up to his death
      from unrelated causes after 3 years of evolution. We reviewed the literature
      trying to define the different presentations of W.D.

PMID- 15202036
TI  - [Analysis of FIM-values during the hospital treatment of patients with acute
      spinal cord injury].
AB  - The cost pressures in the German health care system continue to rise. In the
      context of the introduction of the DRG system, adequate treatment of paraplegic
      and tetraplegic patients within the financial limits will become even more
      difficult. In dispute with health care insurance companies, scientifically sound
      studies have been lacking to justify a treatment lasting up to six months as an
      in-patient of individuals with acute spinal cord injury or disease. The FIM
      (Functional Independence Measurement), established as a reliable tool in the
      evaluation of the functional development of patients presenting with acute spinal
      cord lesions, has been used as the basic tool in our study. Under the conditions
      of a specialized spinal cord injury centre the FIM showed a statistically highly
      significant increase of functional independence during the entire course of
      treatment. No therapeutic standstill could be detected in order to determine a
      point of discharge. Even in the last six weeks of treatment significant progress
      in functional independence can be observed.

PMID- 15202037
TI  - [Treadmill therapy in patients after ischaemic stroke].
AB  - Treadmill training with body weight support was applied in 30 patients who had
      suffered an ischaemic stroke, with the goal of improving their independence in
      the activities of daily living (ADL). The following inclusion criteria were used:
      inability to walk (FAC-score 0 - 2); motor abilities (the ability to sit without
      support, a palpable muscle function of the hip extensors, abductors and the knee
      extensors in the affected leg); adequate cooperation, motivation and vigility;
      absence of muscle contractures which would affect gait; onset of therapy no later
      than one year after the incident. The average duration of treadmill training was
      6,6 weeks. The patients' age was an average 68 years (48 - 82). 87 % of the
      patients were able to improve their gait within the Functional Ambulation
      Categories (FAC) scale. 60 % of the patients achieved the ability to walk
      independently without technical aid. Apart from improving their gait, the
      patients also attained significantly increased scores in the motor scale of the
      Rivermead Motor Assessment (gross function) and the motor part of the ADL scale
      of the Barthel Index (items 2 - 4) and the Functional Independence Measure (items
      3 and 4). Treadmill training is establishing itself as an important therapeutic
      approach in gait rehabilitation with patients with acquired brain damage.

PMID- 15202038
TI  - [Treatment specificity in chronic-back pain: is optimized rehabilitation
      allocation enough?].
AB  - The multidimensional and heterogeneous etiogenesis of chronic low back pain
      requires multimodal as well as specific treatment programmes. Aim of the present
      study was to increase the specificity of treatment already at the interface
      "family health care - assigning institution - rehabilitation clinic" by
      supporting the assignment to orthopaedic or psychosomatic rehabilitation through
      extensive diagnostics and deriving a patient's profile of risk factors in the
      forefield of rehabilitation. In a prospective randomized control group design the
      rehabilitation success in 309 persons (age 22 - 58) suffering from chronic low
      back pain was compared on risk factor specific vs. conventional assignment.
      Between 22 % and 27 % of the assignments following conventional criteria have to
      be considered as false. On the other hand, rehabilitation success did not turn
      out to have been increased by specific assignment. In conclusion, implications
      for more far-reaching change in treatment programmes within and subsequent to
      stationary rehabilitation are discussed.

PMID- 15202039
TI  - [Stepwise occupational reintegration after orthopedic rehabilitation-
      participants, realization, effectiveness, and optimization requirements].
AB  - This paper presents research results on stepwise occupational reintegration in
      patients with orthopaedic diseases, predominantly back pain. A retrospective
      questionnaire study was performed from January to May 2003. We questioned 534
      insurants of the LVA (statutory pension insurance institute) in Schleswig
      Holstein who had completed orthopaedic rehabilitation between 1999 and 2001 and
      had been recommended for stepwise occupational reintegration. The participant
      rate was 47% (n = 250 completed questionnaires). The standardized survey included
      demographic as well as illness-, rehabilitation- and job-related information.
      Particularly, information about the beginning and implementation of the stepwise
      occupational reintegration programme, its evaluation by the insurants, and their
      reintegration into working life was gathered. Stepwise occupational reintegration
      was recommended for 4.5% of the rehabilitation patients; 57% of them acted on
      this suggestion. The results show a positive appraisal of the stepwise
      occupational reintegration programme in general and high rates of reintegration
      (more than 80%) at mid-term. However, the dropout rate of 15% is quite high. The
      results suggest a necessity for optimization especially regarding initiation of
      the stepwise occupational reintegration programme, patient motivation, and better
      support for patients during the programme. Thus, a close linkage of stepwise
      occupational reintegration with accompanying rehabilitation programmes offers
      promising perspectives for purposive occupation-orientated rehabilitation
      programmes.

PMID- 15202040
TI  - [Further development of peer-review-procedures in medical rehabilitation].
AB  - In 2002, the peer review for the somatic indications of medical rehabilitation
      was further developed. This process was aimed at adjusting the peer review
      checklist to the "Guide for the Uniform Medical Report of the Statutory German
      Pension Insurance Scheme" ("Leitfaden zum einheitlichen Entlassungsbericht der
      Rentenversicherung"), at harmonising the peer review with the version used in the
      quality assurance programme of the German health insurance and at reducing
      requirements by focusing on criteria relevant in the individual case. This paper
      reports on the consensus process carried out and outlines the modifications of
      the peer review procedure.

PMID- 15202041
TI  - [Quality management in a combined clinic - the quality management system
      according to DIN EN ISO 9001 of the The German Association of Spa Accommodation
      Resorts e. V. (VdKB)].
AB  - The implementation of a quality system in health care organizations offers huge
      potentials for improvement and development. But the realization of such systems
      necessitates high investments, which small companies and family businesses often
      are unable to raise. The German Association of Spa Accommodation Resorts (VdKB)
      commissioned two consultants to develop a reasonably priced implementation
      concept of a DIN EN ISO 9001 quality system specially adjusted to small companies
      and family businesses in medical spa and rehabilitation services, which was
      successfully accredited in May 2003. This paper describes fundamental
      requirements in combine management systems, considers the pros and cons of
      management combines and demonstrates the practical realization of combine
      requirements on the example of the VdKB-combine system.

PMID- 15202042
TI  - [Significance, effect size, and confidence interval].
AB  - The term "statistical significance" is often misunderstood. The result of a study
      may be labelled to be "highly significant" as if implying "highly important".
      Statistically significant, however, does only mean that a study result might have
      been found with a predefined probability (conventionally set at 5 %) even when
      the null hypothesis is true in the population, i. e. the effect found in the
      study sample does not exist in reality. Whether a result proves to be significant
      or not largely depends on sample size. Thus, in a large sample minimal effects of
      no practical relevance may turn out significant whereas in a small sample even
      large, important effects may fail to reach the significance level. As a
      consequence, when presenting the results of a study the effect size should be
      reported together with a confidence interval indicating the probable range that
      contains the population effect.

PMID- 15202043
TI  - [Participation in working life through prevention and medical rehabilitation-
      report of the Conference of the Rehabilitation Sciences Research Network Saxonia
      Anhalt/Mecklenburg-Western Pomerania held March 25/26, 2004].

PMID- 15202044
TI  - An evaluation of colorectal endoscopic mucosal resection using high-magnification
      chromoscopic colonoscopy: a prospective study of 1000 colonoscopies.
AB  - BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection provides an alternative
      to surgery for resection of sessile and flat colorectal lesions. High
      magnification chromoscopic colonoscopy may allow early detection and anticipate
      histological diagnosis by identifying colonic crypt patterns. The aim of the
      present study was to assess the efficacy and safety of en-bloc endoscopic mucosal
      resection with high-magnification chromoendoscopy in the management of sessile
      and flat colorectal lesions </= 20 mm. PATIENTS AND METHODS: A single endoscopist
      using high-magnification chromoendoscopy prospectively examined 1000 patients
      attending for routine colonoscopy. Patients were selected for inclusion in the
      study if they were considered to be at high risk for underlying colorectal
      neoplasia or polyps. Within the study period, 1000 patients (29 %) qualified for
      entry from a total of 3480 colonoscopies conducted in our institution. Endoscopic
      mucosal resection was carried out in appropriate flat and sessile lesions.
      RESULTS: Endoscopic mucosal resection was carried out in 599 lesions. Complete
      histological resection was confirmed in 576 (96 %). Perforation occurred in one
      patient (0.2 %) and bleeding in 12 (2 %). A total of 254 lesions (40 %; excluding
      hyperplasia/metaplasia) were flat or depressed, and 374 (60 %) were sessile.
      Fifty-eight flat lesions (23 %) contained high-grade dysplasia or beyond,
      compared to 33 sessile lesions (9.0 %; P = 0.001). After resection, 21 lesions
      were upgraded histologically, with 17 being defined as adenoma with high-grade
      dysplasia or beyond. CONCLUSIONS: This study confirms that flat adenomas and
      carcinomas occur in the West and demonstrates the malignant potential of such
      lesions, which can be managed successfully using endoscopic techniques.
      Endoscopic mucosal resection with high-magnification chromoscopy is a safe and
      effective form of treatment for sessile or flat colorectal lesions. Complete
      resection can improve the accuracy of histopathological diagnosis. However,
      colonoscopists require training in these procedures in order to improve the rate
      of colorectal cancer detection.

PMID- 15202045
TI  - Reasons for failure to diagnose colorectal carcinoma at colonoscopy.
AB  - BACKGROUND AND STUDY AIMS: Colonoscopy can produce false-negative results, and
      the reasons for this remain obscure. The aim of this study was to examine why
      cancers are missed at colonoscopy. PATIENTS AND METHODS: All colonoscopies
      carried out at Christchurch Hospital, New Zealand, over a 43-month period (1
      October 1997 - 30 April 2001) were retrospectively analyzed (the data having been
      prospectively collected). All cases of colorectal carcinoma during the period 1
      October 1997 - 30 July 2001 (3 months longer, to capture delayed diagnoses) were
      also identified. The two databases were then compared, and all cases in which a
      colonoscopy had been performed more than 6 weeks before a colorectal carcinoma
      specimen being received by the pathology department were identified and analyzed.
      RESULTS: A total of 5055 colonoscopies were undertaken in 4598 patients. Over
      this period, 630 colorectal carcinomas were identified in the pathology database;
      286 of the patients affected were in the colonoscopy and pathology database.
      Sixty-six patients had had a colonoscopy performed more than 6 weeks before the
      diagnosis of colorectal carcinoma. Carcinoma was identified in 48 of these 66
      patients, and management was being provided. Seventeen cancers (5.9 %) were
      missed at colonoscopy, and the patients had had an incomplete colonoscopy in nine
      of these cases. In seven of the 17, an alternative benign cause was recorded. In
      four patients, a lesion was seen and thought to be benign, although subsequently
      proven not to be. In another four cases, the cancer was not diagnosed despite
      adequate bowel preparation and what was thought by the colonoscopist to be an
      adequate colonoscopy. CONCLUSIONS: Colonoscopy missed 17 of 286 cancers (5.9 %).
      The reasons why cancers were missed relate to incomplete colonoscopy, poor bowel
      preparation, misinterpretation of what was seen, failure to carry out adequate
      biopsy (and follow-up) of lesions seen, and systems failures related to follow-up
      investigations in patients who had an incomplete colonoscopy. The fact that
      colonoscopy and barium enema investigations may fail to diagnose cancers has
      important medicolegal implications. The recognition that colonoscopy may miss a
      cancer should encourage doctors to reinvestigate patients when there is a lack of
      correlation between the clinical and investigative findings.

PMID- 15202046
TI  - Early colonoscopy in patients with acute diverticulitis: results of a prospective
      pilot study.
AB  - BACKGROUND AND STUDY AIMS: Outcomes following early colonoscopy in patients with
      acute diverticulitis have not previously been studied. The present study
      describes the effects of early colonoscopy in patients with acute diverticulitis.
      PATIENTS AND METHODS: Consecutive patients hospitalized for acute diverticulitis
      were included in the study. In the first phase, patients with adjacent
      peridiverticular air or fluid on computed tomography (CT) were excluded. In the
      second phase of the study, only patients with free intraperitoneal air were
      excluded. RESULTS: The study population consisted of 107 patients. During the
      first phase of the study, 49 patients were included; 10 were excluded because of
      peridiverticular air or fluid. The remaining 39 patients underwent uneventful
      colonoscopy. During the second phase of the study, 58 patients were included;
      four were excluded because of free air in the peritoneum. The remaining 54
      patients underwent colonoscopy, and perforation of the sigmoid colon occurred in
      one patient with peridiverticular air. Complete colonoscopy to the cecum or to
      the obstructing tumor was achieved in 76 patients (81.7 %). A second colonoscopy
      performed 6 weeks later in 16 of the remaining 17 patients was successfully
      completed. Findings during the first colonoscopy were polyps in nine cases, polyp
      with infiltrating adenocarcinoma in one, obstructing adenocarcinoma in one, and a
      bone trapped in a diverticulum in another one. The latter two patients had a more
      protracted course and were clearly the ones who benefited most from the
      colonoscopy. CONCLUSIONS: Early colonoscopy in patients with acute diverticulitis
      may alter the working diagnosis and be of therapeutic value. The rate of cecal
      intubation is lower and the perforation rate appears to be higher. A clear-cut
      indication therefore has to be evident clinically.

PMID- 15202047
TI  - Sympathovagal balance fluctuates during colonoscopy.
AB  - BACKGROUND AND STUDY AIM: Colonoscopy is a common gastroenterological procedure
      for investigation of the bowel. The main side effects of colonoscopy are pain
      during investigation, cardiovascular complications and very rarely even death.
      The aim of this study was to compare the continuous fluctuation of heart rate
      variability (HRV) components during colonoscopy under normal conditions,
      analgesia/sedation, and total intravenous anesthesia. PATIENTS AND METHODS: 37
      consecutive patients (aged 35 - 65), were randomly allocated to three groups: no
      sedation (control group 1); analgesia/sedation (group 2); and total intravenous
      anesthesia (group 3). Holter electrocardiography and subsequent frequency domain
      analysis were undertaken. The low-frequency (LF, 0.04 - 0.15 Hz) and the high
      frequency (HF, 0.15 - 0.40 Hz) components were estimated using spectral analysis
      in the usual way. Normalized units (nu) were calculated from the following
      equations: LFnu = LF/(LF + HF), and HFnu = HF/(LF + HF). RESULTS: Groups 2 and 3
      were found to have a significantly lower HFnu and higher LFnu than group 1
      essentially throughout the procedure. A one-way analysis of variance and t-test
      confirmed that the differences were significant when the colonoscope reached the
      splenic flexure as were the LF/HF balances at the splenic and hepatic flexures
      and the cecum. The percentage change in LF/HF was also analyzed, and it was found
      that in group 3 the mean change was over 136 % when the colonoscope reached the
      sigmoid flexure, which was significantly higher than in the other two groups.
      CONCLUSION: Most changes in HRV components occurred during colonoscopy of the
      left side of the bowel. Analgesia/sedation and total intravenous anesthesia
      increased HRV by increasing the LF component.

PMID- 15202048
TI  - Diagnostic performance of light-induced fluorescence endoscopy for gastric
      neoplasms.
AB  - BACKGROUND AND STUDY AIM: Malignant tumors generate autofluorescent patterns that
      differ from those of normal tissue. However, whether autofluorescent diagnosis
      could be genuinely useful in screening for gastric neoplasms has not been well
      investigated in clinical practice. Accordingly, we retrospectively studied our
      experience with this diagnostic technique for various gastric lesions and
      assessed its diagnostic utility. PATIENTS AND METHODS: Autofluorescence diagnosis
      of 109 gastric lesions in 79 patients was done, without knowledge of the
      diagnosis by conventional white light endoscopy, retrospectively and
      independently by three endoscopists with 6 years', two years' and no experience
      of the technique. After examination of the interobserver bias in the assessment
      of autofluorescent pseudocolor in light-induced fluorescence endoscopy (LIFE),
      the relationship between pseudocolor and characteristics of gastric lesions
      (including histology, macroscopic type, and depth of invasion) were investigated.
      RESULTS: The kappa statistic for agreement in pseudocolor diagnosis between the
      three endoscopists was 0.71. The assessment of pseudocolor by all of the
      observers was in agreement in 67 of the total of 109 lesions (61.5 %). Experience
      with the LIFE technique did not improve the accuracy of pseudocolor
      determination. All of the cancers, 87.5 % of the adenomas, and 50.9 % of the
      benign lesions were recognized as having an abnormal autofluorescent image. None
      of the gastric cancers and 49.1 % of the benign lesions were evaluated as having
      a normal autofluorescence image. The histopathological and macroscopic types of
      tumors and their depths of invasion were not reflected in the autofluorescence
      diagnosis. CONCLUSIONS: LIFE provided a sensitivity of 96.4 % and specificity of
      49.1 %, suggesting that this technique has limited clinical utility, regardless
      of the merits of acceptable interobserver bias and lack of necessity for
      experience with this technique.

PMID- 15202049
TI  - Risk factors for mortality in patients undergoing percutaneous endoscopic
      gastrostomy.
AB  - BACKGROUND AND STUDY AIMS: Percutaneous endoscopic gastrostomy (PEG) is a method
      used for feeding patients who are unable to eat. High early mortality rates among
      hospitalized patients have been reported. The aim of this study was to shed light
      on the risk factors for early mortality after PEG tube insertion. PATIENTS AND
      METHODS: Outpatients from nursing homes and hospitalized patients who underwent
      PEG between July 1995 and July 2001 were compared. Survival analysis was used to
      assess mortality after PEG. In a logistic regression analysis, mortality within
      30 days among hospitalized patients was chosen as the outcome variable and the
      predictor variables were demographic characteristics, co-morbid conditions, and
      indication for PEG. RESULTS: A total of 502 PEG tubes were inserted in 419
      hospitalized and 83 nursing-home patients. The prevalence of co-morbid conditions
      was similar in the two groups. Both the 30- and 60-day mortality rates were
      around six times higher in the hospitalized patient group than in the nursing
      home patient group (30-day mortality rate 8 % vs. 1.2 %, P = 0.034; 60-day
      mortality rate 12 % vs. 2.4 %, P = 0.016). Risk factors for 30-day mortality
      among hospitalized patients were: serum albumin < 3 g/dl (odds ratio 2.82, 95 %
      CI 1.34 - 5.96), chronic obstructive pulmonary disease (odds ratio 2.79, 95 % CI
      1.26 - 6.14), and diabetes mellitus (odds ratio 2.44, 95 % CI 1.20 - 4.97).
      CONCLUSIONS: Compared with nursing-home patients, hospitalized patients are at
      higher risk for early mortality after PEG. The presence of diabetes, chronic
      obstructive pulmonary disease, and a low serum albumin level each increase the 30
      day mortality risk among hospitalized patients threefold.

PMID- 15202050
TI  - Prediction of therapy in primary endoscopic retrograde cholangiopancreatography.
AB  - BACKGROUND AND STUDY AIMS: It seems rational to perform endoscopic retrograde
      cholangiopancreatography (ERCP) if the probability of endoscopic therapy is high,
      but to carry out magnetic resonance cholangiopancreatography (MRCP) or endoscopic
      ultrasound (EUS) first if this probability is moderate or low. The aim of the
      present study was to develop a model describing the probability of endoscopic
      therapy in patients without previous biliary imaging. PATIENTS AND METHODS: The
      development of the model was based on stepwise multiple logistic regression
      applied to 2470 prospectively registered first-time ERCP procedures. The model
      was evaluated by application to 442 prospectively registered first-time ERCP
      procedures entered in the database in the following 2 years. RESULTS: Predictors
      selected were: age, gender, p-amylase >/= 400 U/l, ln(s-bilirubin), ln(s-alkaline
      phosphatase), common bile duct (CBD) stone seen on transabdominal
      ultrasonography, gallbladder stone seen on transabdominal ultrasonography,
      interaction of dilated bile ducts seen on transabdominal ultrasonography with
      ln(s-bilirubin), and interaction between age and male gender. The area under the
      receiver operating characteristic (ROC) curve was 0.875 and there was good fit of
      the model. A test with a probability cutoff value of 80 % had a positive
      predictive value (PPV) of 92.8 %. Specificity was 87.1 % and, using this test,
      52.4 % of patients would have been selected for primary ERCP. In the application
      cohort, the frequency of therapy was higher than in the development cohort. The
      area under the ROC curve was 78.7 %. When used in the evaluation cohort, with a
      cutoff probability of 80 %, the test had sensitivity 84.0 %, specificity 49.5 %,
      negative predictive value (NPV) 46.6 % and PPV 85.6 %. Of the patients, 76.7 %
      would have been selected for ERCP. This would have identified 85.5 % of
      individuals needing therapeutic ERCP without use first of MRCP or EUS. Test
      positive cases constituted 90.3 % of stent insertions and 86.3 % of stone
      extractions. CONCLUSIONS: The model is useful for selection of patients for ERCP
      at our center.

PMID- 15202051
TI  - Predictive factors for pancreatic cancer in patients with chronic pancreatitis in
      association with K-ras gene mutation.
AB  - BACKGROUND AND STUDY AIMS: Chronic pancreatitis is considered to be a
      predisposing factor for pancreatic ductal adenocarcinoma (PAC). The purpose of
      this study was to examine the prognostic value of a finding of mutated (K- ras)
      gene in predicting the development of PAC in patients with chronic pancreatitis.
      PATIENTS AND METHODS: The pancreatic duct brushings of 146 patients with chronic
      pancreatitis were examined in order to identify K- ras gene mutations. A total of
      112 patients were followed up (median duration 42 months) using clinical
      evaluation, serum CA19 - 9 levels, and imaging studies. RESULTS: One or more K-
      ras mutations were found in 57 of the 146 patients with chronic pancreatitis (39
      %). Patients harboring K- ras mutations had a higher incidence of persistent
      alcohol consumption ( P = 0.041) and of prior rupture of the main pancreatic duct
      ( P = 0.040). A finding of nuclear atypia in brushing cytology was also more
      common in patients with K- ras mutation ( P = 0.048). Out of the 112 patients who
      were followed up, PAC occurred in four of the 44 patients who had a K- ras
      mutation, but in none of the 68 patients with the wild genotype ( P = 0.022). PAC
      occurred in three of the 25 patients who did not have pancreatic calcifications (
      P = 0.034) and in four of the 54 patients who had demonstrated exocrine
      insufficiency, but in none of the 58 patients with preserved exocrine function (
      P = 0.051). Using stepwise logistic regression, the absence of calcifications,
      the presence of exocrine insufficiency, and the presence of K- ras mutation were
      identified as independent predictive factors for cancer development in all
      patients with chronic pancreatitis. CONCLUSIONS: K- ras gene mutations occur in
      chronic pancreatitis and are associated with evolution towards PAC. The absence
      of pancreatic calcifications and the presence of exocrine insufficiency were
      identified as additional predictive factors for the development of PAC.

PMID- 15202052
TI  - Self-expanding metal stents for gastroduodenal malignancies: systematic review of
      their clinical effectiveness.
AB  - BACKGROUND AND STUDY AIMS: The current standard approach to the management of
      malignant gastric outlet obstruction mainly involves bypass surgery, which is
      associated with significant rates of mortality and morbidity. Recently, metal
      stents have emerged as a new therapeutic option. The aim of the present study was
      to review the currently published evidence on the effectiveness and safety of
      this form of endoscopic treatment. MATERIALS AND METHODS: A systematic review of
      the published data was carried out by searching medline, embase, and abstracts
      from the major gastroenterological conferences from January 1992 to September
      2003. A total of 136 relevant publications were identified (case series, single
      case reports, letters and editorials, or reviews). The systematic review included
      32 case series from a total of 46 publications identified as reporting primary
      clinical data. Abstracts and single case reports were not taken into account.
      Analysis of these 32 case series included data on technical success (successful
      stent placement and deployment), clinical success (relief of symptoms such as
      nausea and vomiting, and/or improvement of food intake), and complications.
      Pooled results were calculated from the 32 studies (10 of which were
      prospective). RESULTS: Stent insertion was attempted in 606 patients with
      malignant symptomatic gastroduodenal obstruction; 94 % of the patients were
      unable to take food orally or were mainly ingesting liquids. Stent placement and
      deployment were successful in 589 of the patients (97 %). Clinical success was
      achieved in 526 patients in the group in which technical success was reported (89
      %; 87 % of the entire group undergoing stenting). Disease-related factors
      accounted for the majority of clinical failures. Oral intake became possible in
      all of the patients in whom a successful procedure was carried out, with 87 %
      taking soft solids or a full diet, with final resolution of symptoms occurring
      after a mean of 4 days. There was no procedure-related mortality. Severe
      complications (bleeding and perforation) were observed in seven patients (1.2 %).
      Stent migration was reported in 31 patients (5 %). Stent obstruction occurred in
      104 cases (18 %), mainly due to tumor infiltration. The mean survival period was
      12.1 weeks. CONCLUSIONS: Published evidence from case series suggests that
      gastroduodenal stenting offers good palliation and is a safe and effective
      treatment option in patients with a short remaining lifespan. However, patient
      selection for this intervention continues to be an issue requiring thorough
      consideration, and studies comparing the method with surgery are needed.

PMID- 15202053
TI  - Missing colorectal cancer.

PMID- 15202054
TI  - Management of malignant strictures of the cervical esophagus with a newly
      designed self-expanding metal stent.
AB  - Recently, the use of self-expanding metal stents has become a well-established
      method of palliative treatment for stenotic malignant diseases in the middle and
      distal esophagus. However, published results on the use of self-expanding metal
      stents in cervical esophageal cancer are somewhat limited by a paucity of
      clinical details and experience. A new self-expanding esophageal metal stent with
      a short upper flange 0.7 cm in length was studied prospectively in order to
      assess its efficacy for palliative treatment. This report presents experience in
      three patients in whom this new stent was used in the treatment of cervical
      esophageal cancers. Stent placement was successful in all three patients, with no
      serious complications such as esophageal perforation, hemorrhage, or foreign-body
      sensation. All of the patients experienced rapid improvement in dysphagia and
      clinical symptoms. The newly designed self-expanding stent can be of value in the
      treatment of stenotic cervical esophageal cancer.

PMID- 15202055
TI  - Ultrasound-guided radiofrequency ablation: a new treatment option after failure
      to stop severe acute upper gastrointestinal tumor bleeding using endoscopic
      techniques.
AB  - Endoscopy is well established as the primary approach in cases of severe acute
      upper gastrointestinal bleeding. Although endoscopic techniques can achieve
      hemostasis in up to 95% of instances, not all sources of bleeding seen at
      endoscopy can be managed endoscopically. Massive and diffuse bleeding from
      locally advanced gastric adenocarcinoma is not usually self-limit-ing and is
      often refractory to endoscopic treatment. If surgery or endovascular tumor
      embolization are not possible after failure of endoscopic hemostasis, the
      situation may become life-threaten-ing. We present a new option for the treatment
      of patients in this rare but potentially fatal situation, which involves
      radiofrequency ablation using a needle electrode placed percutaneously un-der
      ultrasound guidance.

PMID- 15202056
TI  - Endoscopically assisted video capsule endoscopy.

PMID- 15202058
TI  - Intramucosal adenocarcinoma of the appendix.

PMID- 15202060
TI  - Severe cardiogenic pulmonary edema precipitated by a therapeutic ERCP.

PMID- 15202063
TI  - Quality assurance in endoscopy should include data on sedation.

PMID- 15202065
TI  - Capsule endoscopy and Crohn's disease.

PMID- 15202066
TI  - Multiple stercoral ulcers caused by habitual excessive daily intake of natto
      (fermented soybeans).

PMID- 15202068
TI  - Don't always trust the guide!

PMID- 15202067
TI  - Colonic perforations after gas explosion induced by argon plasma coagulation.

PMID- 15202069
TI  - Lasso technique for retrieval of a dislocated and impacted esophageal stent.

PMID- 15202070
TI  - Gastric penetration of gastric bands.

PMID- 15202071
TI  - A predominantly neolithic origin for Y-chromosomal DNA variation in North Africa.
AB  - We have typed 275 men from five populations in Algeria, Tunisia, and Egypt with a
      set of 119 binary markers and 15 microsatellites from the Y chromosome, and we
      have analyzed the results together with published data from Moroccan populations.
      North African Y-chromosomal diversity is geographically structured and fits the
      pattern expected under an isolation-by-distance model. Autocorrelation analyses
      reveal an east-west cline of genetic variation that extends into the Middle East
      and is compatible with a hypothesis of demic expansion. This expansion must have
      involved relatively small numbers of Y chromosomes to account for the reduction
      in gene diversity towards the West that accompanied the frequency increase of Y
      haplogroup E3b2, but gene flow must have been maintained to explain the observed
      pattern of isolation-by-distance. Since the estimates of the times to the most
      recent common ancestor (TMRCAs) of the most common haplogroups are quite recent,
      we suggest that the North African pattern of Y-chromosomal variation is largely
      of Neolithic origin. Thus, we propose that the Neolithic transition in this part
      of the world was accompanied by demic diffusion of Afro-Asiatic-speaking
      pastoralists from the Middle East.

PMID- 15202072
TI  - Large-scale single-nucleotide polymorphism (SNP) and haplotype analyses, using
      dense SNP Maps, of 199 drug-related genes in 752 subjects: the analysis of the
      association between uncommon SNPs within haplotype blocks and the haplotypes
      constructed with haplotype-tagging SNPs.
AB  - To optimize the strategies for population-based pharmacogenetic studies, we
      extensively analyzed single-nucleotide polymorphisms (SNPs) and haplotypes in 199
      drug-related genes, through use of 4,190 SNPs in 752 control subjects. Drug
      related genes, like other genes, have a haplotype-block structure, and a few
      haplotype-tagging SNPs (htSNPs) could represent most of the major haplotypes
      constructed with common SNPs in a block. Because our data included 860 uncommon
      (frequency <0.1) SNPs with frequencies that were accurately estimated, we
      analyzed the relationship between haplotypes and uncommon SNPs within the blocks
      (549 SNPs). We inferred haplotype frequencies through use of the data from all
      htSNPs and one of the uncommon SNPs within a block and calculated four joint
      probabilities for the haplotypes. We show that, irrespective of the minor-allele
      frequency of an uncommon SNP, the majority (mean +/- SD frequency 0.943+/-0.117)
      of the minor alleles were assigned to a single haplotype tagged by htSNPs if the
      uncommon SNP was within the block. These results support the hypothesis that
      recombinations occur only infrequently within blocks. The proportion of a single
      haplotype tagged by htSNPs to which the minor alleles of an uncommon SNP were
      assigned was positively correlated with the minor-allele frequency when the
      frequency was <0.03 (P<.000001; n=233 [Spearman's rank correlation coefficient]).
      The results of simulation studies suggested that haplotype analysis using htSNPs
      may be useful in the detection of uncommon SNPs associated with phenotypes if the
      frequencies of the SNPs are higher in affected than in control populations, the
      SNPs are within the blocks, and the frequencies of the SNPs are >0.03.

PMID- 15202073
TI  - [Attention deficit hyperactivity syndrome and the capacity to practice sports].
AB  - OBJECTIVE: To know the sportive activities of children and adolescents, males,
      with attention deficit-hyperactivity disorder (ADHD). PATIENTS AND METHODS: There
      were studied 100 patients, all males, with ages ranging 6 to 16 years (average:
      9.28 years), 50 of the hospital and 50 of the private consultation. The subgroup
      of ADHD was identified in all patients. The patients were asked on the sports
      most usually made, although the response had to be confirmed by the parents.
      RESULTS: Twenty-five cases showed attention deficit, 16 hyperactivity, and 59
      combined form. If only one sport is to have had in consideration, football was
      the most practiced sport, with 20 cases. If a second sportive activity was also
      considered, cycling was the most practiced sport, with 29 cases, while only 23
      patients played football (more than a 50% as goalkeeper) if we wanted the two
      first options. A less number of cases made basketball, swimming, judo or
      taekwondo, vasque ball and several others. Thirty three patients did not make any
      sport and most of them showed an unsporting attitude. Less than a half of the
      cases showed motivation to practice sport and less than a third was disciplined
      obeying the orders of the coach and/or the leader. CONCLUSION: The patients with
      ADHD mostly show little motivation for the sport activities, being cycling and
      football (preferable as goalkeeper) the two most frequently practiced. The
      patients usually show little motivation and discipline.

PMID- 15202074
TI  - [Transcranial Doppler velocimeter in pregnant and later normotensive puerperal
      women].
AB  - INTRODUCTION: The physiological changes that take place in blood flow in the
      brain during pregnancy and the puerperium are still only poorly understood. The
      harmlessness of transcranial Doppler (TCD) makes it a suitable method of study.
      AIMS: The purpose of this study was to determine the TCD velocimeter reading at
      the end of pregnancy and in the early puerperium of healthy expectant mothers.
      SUBJECTS AND METHODS: TCD was used to perform a bilateral study of the anterior
      (ACA), middle (MCA) and posterior cerebral arteries (PCA). Arterial blood
      pressure and haematocrit were also measured. Mean velocity (MV), the pulsatility
      index (PI), mean arterial blood pressure and haematocrit were employed as
      variables in the statistical analysis. Results from 44 normotensive pregnant
      women in the latter stages of gestation (week 33 to term) were compared with
      those of a control group made up of 58 women of a similar age, who were
      normotensive and not pregnant. The study was repeated in the group of pregnant
      women during the early puerperium (the first five days after labour) and the two
      different results were compared. RESULTS: Age and MAP were similar in the
      gestating and non-gestating groups. Haematocrit was significantly lower in the
      former (p < 0.001) and MV were significantly lower in the pregnant women in all
      the arteries (p < 0.001), whereas the PI were also significantly lower in four of
      the six territories that were studied (p < 0.005). During the puerperium, a
      significant rise in MV was observed in all the arteries (p < 0.001) and the PI
      increased in three of them (p < 0.05). In this phase, the mean arterial pressure
      rose (p < 0.05), although haematocrit levels dropped (p < 0.001). CONCLUSIONS:
      The low MV and PI seen at the end of pregnancy are compatible with cerebral
      vasodilatation. MV increase during the early puerperium and is probably linked to
      a relative hyperperfusion.

PMID- 15202075
TI  - [Growth charts for the Spanish population with neurofibromatosis type 1].
AB  - OBJECTIVE: To make the charts of stature and head circumference of Spanish
      pediatric patients affected with neurofibromatosis type 1 (NF1), to compare them
      with the ones from a healthy population and to review the possible causes of its
      alterations. PATIENTS AND METHODS: We obtained the data from 251 Spanish patients
      (122 women and 129 men) with NF1 seen in seven hospitals between the years 2000
      and 2002, with ages between 1 month and 18 years old. The calculation of the 50th
      centile or median was done using the method of mobile variables, and the 3rd and
      97th centiles where calculated from this median. RESULTS: Girls with NF1 have a
      shorter stature than the healthy ones, which becomes evident after 10 years of
      age. We have not found differences in the stature between boys with the disease
      and those without it. In regards to head circumference, in boys and girls we have
      observed that it is bigger throughout life in patients affected with NF1, and
      that the 50th centile of healthy people correlates with the 3rd centile of those
      affected, the 97th centile of the healthy ones with the 50th centile of those
      affected, being the 3rd centile of the healthy people well below the 3rd centile
      of the affected ones, and the 97th centile of the affected ones well above the
      97th of the healthy people. CONCLUSIONS: The short stature in postpuberal girls
      and the macrocephaly in both sexes at all ages, are primary characteristics in
      the NF1 and they are not usually related with other alterations, although they
      are not specific for this illness.

PMID- 15202076
TI  - [Ischemic brain lesions following carotid revascularisation procedures: a
      comparative study using diffusion-weighted magnetic resonance imaging].
AB  - INTRODUCTION: The risk of cerebral embolism following angioplasty-stent placement
      (AGP) is higher than that observed after a carotid endarterectomy (CE) using
      transcranial Doppler ultrasonography. Nevertheless, no studies have been
      conducted to compare the two revascularisation procedures with the latest
      neuroimaging techniques. AIMS: To analyse the presence and repercussion of acute
      cerebral ischemia detected by diffusion-weighted magnetic resonance imaging (DMR)
      following carotid revascularisation procedures. PATIENTS AND METHODS: Our
      prospective study included a sample of 20 consecutive patients with
      atherosclerotic stroke and symptomatic carotid stenosis > 70% according to NASCET
      criteria and treated by CE (n = 10) or AGP (n = 10). Patients were submitted to a
      DMR during the 48 hours prior to revascularisation and another within the 72
      hours following the intervention in order to evaluate the existence of new acute
      cerebral ischemic lesions. Patients were explored by a neurologist before and
      after the intervention. RESULTS: DMR allowed new areas of cerebral ischemia to be
      detected in 10% of the CE and in 40% of the AGP patients. 50% of the post-AGP
      ischemic lesions were multiple and 10% of the lesions in each therapeutic group
      presented some clinical correlation in the form of transient neurological focal
      signs. No significant differences were observed with respect to the pattern of
      risk of complications between the two therapeutic groups and no factors
      associated to a higher risk of new ischemic lesions were detected by DMR in
      patients submitted to AGP. CONCLUSIONS: Carotid AGP is linked to a higher
      frequency of new ischemic lesions in the brain than in the case of CE.
      Nevertheless, these ischemic lesions detected by DMR are usually silent.
      Symptomatic complications were similar in the two procedures.

PMID- 15202077
TI  - [Paediatric neurology health care activity in a tertiary hospital. A study
      comparing it with adult neurology and non-neurological paediatrics].
AB  - INTRODUCTION: Paediatric neurology (PN) remains 'hidden' somewhere between
      paediatrics and neurology in almost all health care centres and this makes it
      difficult to allocate resources in a proper manner. AIMS: Our objective in this
      study was to analyse PN health care activity and compare it with adult neurology
      (AN) and with non-neurological paediatrics (NNP). MATERIAL AND METHODS: PN health
      care activity registry for the year 2002. AN and NNP data were collected from the
      hospital's Computer Service. RESULTS: In all, 1300 PN visits were made, 428 of
      which were new and 872 successive, which represent 16.2% of paediatric visits
      (30% new, 13.3% successive) and 10.3% of neurological visits (12.4% new, 10.2%
      successive). The rates of new and successive visits in PN are: 32.6, 10.7 and
      21.9 per 1000 children, and in AN: 44.2, 12.5 and 31.7 per 1000 adults. A total
      number of 94 hospitalised children were attended, 3.3% of all paediatric
      admissions and 9.2% of the total neurological attention in inpatients. The rates
      are 2.36 per 1000 children in PN and 3.9 per 1000 adults in AN. There is greater
      demand among smaller children. The most frequent pathologies are headaches in
      clinical visits and epilepsy in hospitalised patients. CONCLUSIONS: PN is
      essentially a service used by outpatients. It accounts for a high percentage of
      hospital paediatric visits. The activity rates per 1000 children and per 1000
      adults are similar. The increased birth rate raises PN activity to a level that
      is higher than would normally be desirable, due to the growth in the population.

PMID- 15202079
TI  - [Neonatal Cornelia de Lange syndrome].
AB  - INTRODUCTION: Cornelia de Lange syndrome is a rare polimalformative association
      that shows an expresivity of unknown etiology being most cases sporadic. The
      diagnosis is clinical. CASE REPORTS: Two female newborns without remarkable
      antecedents affected of intrauterine growth retardation were born by cesarean
      section due to risk of perinatal asphyxia. Both cases had a harmonic hypotrophy
      and a very similar clinical phenotype, especially the craniofacial anomalies,
      with typical facial features and limb alterations. Besides, the evolution
      confirms the diagnosis because in both cases the delay of somatic development and
      microcephaly, as well as moderate-severe psychomotor delay and behavior
      alterations were present. Likewise, both cases have developed typical medical
      complications of the condition. The complementary study showed in both patients
      an important dysfunction of the auditory ways and a atrial septal defect. They
      were soon included in sensory and motor program of rehabilitation. CONCLUSION: We
      present two cases of Cornelia de Lange syndrome of neonatal diagnosis that we
      consider of interest due to the importance of an early recognition of the
      clinical condition for the family advice and the medical aid and for an
      appropriate development.

PMID- 15202078
TI  - [Familiar chronic progressive external ophthalmoplegia of mitochondrial origin].
AB  - INTRODUCTION: The syndrome of chronic progressive external ophthalmoplegia (CPEO)
      is a mitochondrial disease characterized by ptosis and ophthalmoplegia has that
      has been associated to the presence of large deletion, single or multiple, in the
      mitochondrial DNA of skeletal muscle. CASE REPORT: We report a familiar case of
      chronic progressive external ophthalmoplegia of maternal inheritance that began
      at birth, and developed with slow progression but with no multisystemic
      involvement. Non of the affected individuals had ragged-red fibers in skeletal
      muscle. Genetic analysis of mitochondrial DNA revealed the presence of a single
      deletion of 4,977 bp that encompasses the nucleotide positions 8,482 to 13,460,
      flanked by a direct repeat sequence. CONCLUSIONS: The amount of deleted
      mitochondrial DNA (15%) in this patient's muscle suggests, even if the percentage
      of the mutation is low, that this deletion is the molecular cause of the
      phenotypic presentation of this patient. This is one of the few cases described
      in the literature of CPEO maternally inherited.

PMID- 15202080
TI  - [Ischemic stroke as a presentation of essential thrombocythemia. Four case
      reports].
AB  - INTRODUCTION: Essential thrombocythemia (ET) is a myelodysplastic syndrome that
      constitutes an infrequent cause of ischemic stroke. Few clinical reports have
      been published describing the clinical onset of ET in the form of a vascular
      accident. CASE REPORT: We describe four cases of patients with no known
      haematological pathology who began with an ischemic stroke and were later
      diagnosed as suffering from ET, following an aetiological investigation. The
      patients were all young, under 45 years of age, with no significant vascular risk
      factors, who presented a clinical picture of ischemic stroke and platelet counts
      above normal values, although in two cases they were below 600 x 10(9)/L. As they
      progressed, their platelet counts were constantly above this threshold and a
      diagnosis of ET was reached. CONCLUSIONS: Although ET is an infrequent cause of
      ischemic stroke, it must be taken into account even in young patients and when
      platelet counts do not exceed 600 x 10(9)/L. Antiplatelet drug therapy must be
      indicated in all cases and the clinician must evaluate the suitability of
      cytoreductive therapy in patients with a high risk of thrombotic event
      recurrence, especially if platelet counts are above 600 x 10(9)/L.

PMID- 15202081
TI  - [Headache and fainting as initial symptoms of syringomyelia associated to Arnold
      Chiari and facial angiomatous nevus].
AB  - INTRODUCTION: Syringomyelia and Arnold-Chiari malformation are two dysraphism
      that often appear together. Clinical manifestations are diverse although some
      patients remain asymptomatic for years. Syncope, supposedly due to a dysfunction
      of medulla baroceptors and spinal cord intermediolateral horn, is uncommon,
      particularly as the initial symptom. CASE REPORT: 34 year old woman, with a
      facial angiomatous nevus, presented with two episodes of headache followed by
      syncope; neurological examination was apparently normal. MRI showed mild
      supratentorial hydrocephalus, Arnold-Chiari malformation and cervical
      syringomyelia, with no vascular anomalies. CONCLUSION: This case, which shares
      some features with Sturge-Weber syndrome and PHACE syndrome, enhances the
      importance of the search for anomalies in patients with paroxistical symptoms and
      cutaneous lesions.

PMID- 15202082
TI  - [Smith-Magenis syndrome: a report of two new cases and an approximation to their
      characteristic behavioural phenotype].
AB  - INTRODUCTION: Smith-Magenis syndrome (SMS) is a well defined contiguous gene
      syndrome that is caused by an interstitial deletion in the 17p11.2 region. It is
      characterised by the presentation of characteristic facial features,
      brachydactylia, short stature, varying degrees of mental retardation, occasional
      neuropathy and a specific behavioural phenotype that points to this entity. AIMS:
      Our aim was to report the cases of two children with SMS and carry out an
      approximation towards their characteristic behavioural phenotype. CASE REPORTS:
      We studied the cases of two 12-year-old children who were suspected of suffering
      from SMS following the findings of a physical exploration and the presence of a
      specific behavioural phenotype. This was confirmed by the genetic-molecular study
      which proved the existence of the 17p11.2 deletion. CONCLUSIONS: Although SMS is
      a relatively infrequent syndrome, a patient with mental retardation and
      characteristic dysmorphic features who presents an especially relevant
      behavioural disorder including different stereotypic movements, aggression
      phenomena and sleep disorders is suggestive of this diagnostic possibility.

PMID- 15202083
TI  - [Neuronal survival following axotomy: a model for the experimental section of the
      optic nerve].
AB  - INTRODUCTION AND OBJECTIVES: Retina is a privileged tissue to study the central
      nervous system (CNS) due to the disposition of different cell types and synaptic
      plexus. Moreover, the retina and the optic nerve are accessible for manipulation
      and surgery. Neuronal consequences of axotomy have been widely studied in this
      portion of the CNS. This paper offers a brief review of the morphological changes
      experienced by axotomized cells. We show these consequences in retinal ganglion
      cells (RGCs) injured by optic nerve section. DEVELOPMENT: Neurons transmit
      information to other cells through their axons; by cutting the axon not only the
      synaptic transmission is interrupted, but cell death is induced in axotomized
      neurons. In many cases degeneration of pre and postsynaptic neurons is also
      triggered. However, in the retinal model, some RGCs are able to survive to
      axotomy; they experience profound changes trying to adapt to a new situation.
      Such changes have been observed in labeled axotomized cells. CONCLUSION:
      Knowledge of the qualitative and quantitative changes after injury, as well as
      the determination of no return point in the evolution of the lesion are aspects
      that must be known before to start a repairing therapy of the function.

PMID- 15202084
TI  - [Relationship between body temperature and prognosis, and neuroprotective effect
      of hypothermia in acute stroke patients].
AB  - AIMS: We review the relationship between body temperature and severity of acute
      stroke, and evaluate published evidence about the possible neuroprotective effect
      of hypothermia in these patients. METHODS: In acute stroke patients, hypothermia
      increases oxygen consumption and metabolic demands of cerebral cells, favors
      liberation of oxygen radicals, glutamate, and other neurotransmisors involved in
      brain injury, and enhances biochemical processes leading to apoptosis.
      Preliminary data suggest that induced hypothermia is feasible and relatively safe
      in acute stroke patients; this may lead to a better outcome in terms of reduced
      mortality and less disabling sequelae in survivors. To enhance its possible
      efficacy, hypothermia should be started in the first 6 to 12 hours after the
      event, should be prolonged for at least 24 to 48 hours, and should be done with
      cooling blankets or ice pads, as antipyretics are not effective to induce
      hypothermia in normothermic subjects. CONCLUSIONS: Hyperthermia is deleterious in
      acute stroke patients and must be treated. Hypothermia should not be considered a
      routine procedure in these patients until its safety and efficacy has been
      demonstrated in large trials. Patients with induced hypothermia should be closely
      monitorized to reduce the risk of adverse effects related to the procedure.

PMID- 15202085
TI  - [Stevens-Johnson syndrome, toxic epidermal necrolysis and phenytoin. Factors
      linked to a higher risk].
AB  - INTRODUCTION: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
      are severe, although not very common, clinical skin pictures that are usually
      related to the use of medication. Several antiepileptic drugs, including
      phenytoin, have been linked to SJS/TEN. Some authors have described an increased
      risk for SJS/TEN when phenytoin is associated to radiotherapy, while others
      report the possibility of an increased risk when it is associated to corticoids.
      DEVELOPMENT: This work includes a review of the spontaneous reports of suspected
      cases of phenytoin-linked SJS/TEN recorded in the database of the
      Pharmacovigilance Department at Pfizer-Espana between October 2000 and December
      2003. Nine cases compatible with SJS/TEN were found; four occurred in cancer
      patients that had received radiotherapy, three of whom were also treated with
      corticoids. DISCUSSION AND CONCLUSIONS: After reviewing the spontaneously
      reported cases in the database of the Pharmacovigilance Department at Pfizer
      Espana as well as the cases in the literature, it can be concluded that when it
      comes to indicating a prophylactic antiepileptic treatment for cancer patients
      with cerebral metastasis, the clinician must take into account the existence of a
      greater risk of SJS/TEN if the patient is going to receive radiotherapy. If the
      patient already presents a history of skin rashes following administration of an
      antiepileptic drug, care must be taken in choosing another because phenytoin
      together with carbamazepine, phenobarbital and lamotrigine have all been linked
      to SJS/TEN. Cross-sensitivity of carbamazepine and barbiturates with phenytoin
      has been observed. Gabapentin and valproic acid could be considered as
      therapeutic options in such cases.

PMID- 15202086
TI  - [Neck vibration: usefulness in neurotology].
AB  - INTRODUCTION: Recently, mechanical vibration on the neck has begun to be used to
      improve diagnostic sensitivity in patients who have vestibular disorders. METHOD:
      We review results of studies of this stimulus in normal subjects and patients
      with vestibular lesions: the ocular responses, changes in the subjective straight
      ahead, and postural changes generated by the neck vibration. CONCLUSION: Although
      the underlying mechanism for the responses to neck vibration remains uncertain,
      it is an excellent addition to the neurotologic exam since it allows us
      demonstrate vestibular deficit with greater sensitivity than other maneuvers. As
      vibration is easy to apply it can be useful for screening in patients who
      complain of dizziness.

PMID- 15202087
TI  - [The neuronal foundations of human violence].
AB  - AIMS: The purpose of this work was to collect and integrate the information
      available from different studies on the neuronal foundations of human violence
      and to highlight the most recent fundamental contributions made by neuroimaging
      techniques. DEVELOPMENT: First, we offer a general view of the studies carried
      out in animals and then a description of the first approximations to the study of
      this subject. Following that, some of the most recent neuroimaging studies are
      outlined and the relationship between cerebral lateralisation and aggression is
      analysed. Finally, we consider the role played by the autonomous nervous system
      and several explanatory theoretical models are put forward. CONCLUSIONS: Broadly
      speaking, research conducted in animals and in humans coincides to a large
      extent. Although the first approximations to the study of aggression and violence
      offered a large amount of information about the neuronal foundations of these
      kinds of conduct, the most recent studies using neuroimaging have meant an
      important step forward in this field. These studies have shown that different
      samples of violent subjects present a number of structural and functional
      anomalies in the temporal and frontal lobes, which differ according to the type
      of aggression. It has also been suggested that there could be a higher rate of
      antisocial conduct among left-handed individuals. In addition, for several
      different psychophysiological variables, such as electrodermal activity and heart
      rate, there is a lower level and a lower response to stimulation, and a number of
      different integrating theoretical models have been proposed in an attempt to
      account for aggression and violence in humans.

PMID- 15202088
TI  - [Angiogenesis in human cerebral ischemia].
AB  - OBJECTIVE: We aimed to review current knowledge about angiogenesis processes
      following stroke and possible benefit of future therapeutic angiogenic-related
      treatments. DEVELOPMENT: Angiogenesis is a physiopathologic process where new
      vessels arise from pre-existing ones within different phases: sprouting and
      maturation. To modulate angiogenesis there is a balance between several promoters
      like VEGF, bFGF, MMPs, etc. but also with inhibitors or angiostatic molecules
      such as angiostatin, endostatin, etc. In human pathologies angiogenesis has a
      dual effect: useful in wound healing, tissue remodelling or ischemic heart
      disease but harmful in cancer, rheumatoid arthritis or atheroma plaque
      instability and rupture. Angiogenesis is involved in some cerebrovascular
      diseases. Following ischemic stroke there is an overexpression of several
      molecules related with this process, although its finality remains largely
      unknown. CONCLUSION: Angiogenesis is activated after stroke modifying capillary
      network. To obtain advantages from angiogenesis, it will be essential to achieve
      the temporal profile of these molecules in humans, and to investigate if its
      effects are different in acute or chronic stroke phases. In the future,
      angiogenesis modulation could take part of a combined stroke therapy.

PMID- 15202089
TI  - [Toxic encephalopathies].
AB  - INTRODUCTION AND DEVELOPMENT: Due to an increase in the use of industrial
      products (gases, solvents, pesticides, heavy metals, pharmaceuticals, and so on)
      living beings are exposed to the effects of many new substances, many of whose
      possibly toxic effects were not researched sufficiently before being put to use
      on a massive scale. Owing to their particular physiology, habitat and behaviour,
      children and teenagers are often a target for these substances. Most of the
      intoxications present with symptoms and signs of nervous system involvement that
      are similar to those caused by other diseases. In certain cases, a diagnosis is
      provided by the setting or witnesses. In other cases, however, first a high
      degree of suspicion is required and then this is sometimes confirmed by
      toxicology laboratory studies. CONCLUSIONS: When intoxication is suspected in a
      child or they need treatment, such patients must visit a toxicological care
      centre. In spite of the campaigns aimed at preventing intoxications, they are
      still a common cause of high morbidity and mortality rates among children and
      teenagers.

PMID- 15202090
TI  - [Analysis of 18 cases of Becker muscular dystrophy].

PMID- 15202091
TI  - [CRST syndrome and polyneuropathy].

PMID- 15202092
TI  - [Chorea following withdrawal of quetiapine].

PMID- 15202093
TI  - [Worsening for using statin in carnitine palmityol transferase deficiency
      myopathy].

PMID- 15202094
TI  - [Reply. Blink reflex (r3) and facial palsy].

PMID- 15202095
TI  - [Reply. Dejerine and Roussy: their publications and work].

PMID- 15202099
TI  - Positron emission tomography in the evaluation of lymphoma.
AB  - Positron emission tomography (PET) using (18)F-fluoro-deoxyglucose (FDG) has
      emerged in recent years as an important tool for the evaluation of lymphoma
      patients during their course of disease. At diagnosis, FDG imaging is capable of
      detecting nodal and extra nodal sites of disease and provides accurate staging.
      FDG-PET is superior to computed tomography, during and at the end of first-line
      treatment or salvage therapeutic regimens, as a tool for monitoring therapeutic
      response. PET enables the differential diagnosis of residual viable tumor versus
      a remnant fibrotic or necrotic mass. PET also provides prognostic data of high
      clinical significance for both Hodgkin's disease and non-Hodgkin's lymphoma.
      Results of this metabolic imaging modality, interpreted in view of the pretherapy
      risk profile of the individual patient, are predictive of the immediate success
      of a certain therapeutic strategy, as well as of overall and disease-free
      survival. PET appears to play also an important role in the detection of lymphoma
      relapse. Data comparing (67)Gallium scintigraphy and FDG-PET indicate the latter
      as the functional imaging modality of choice for assessment of lymphoma patients.
      Preliminary studies show an additional value of fused PET/computed tomography
      imaging for further improved diagnosis, staging and definition of status of
      lymphoma.

PMID- 15202100
TI  - Positron emission imaging of head and neck cancer, including thyroid carcinoma.
AB  - Most positron emission tomography (PET) imaging studies in head and neck cancer
      are performed using the radiotracer 18-fluorodeoxyglucose ((18)FDG). PET with FDG
      has become a standard clinical imaging modality in patients with head and neck
      cancer. It contributes valuable information in localizing a primary tumor in
      patients with neck nodal metastases from an unknown primary, in the staging of
      primary head and neck cancer, and in the detection of recurrent disease. In
      addition, FDG-PET provides independent prognostic information in patients with
      newly diagnosed and recurrent head and neck cancer. PET/CT improves lesion
      localization and accuracy of FDG-PET and is strongly recommended in patients with
      head and neck cancer. After thyroidectomy, FDG-PET has proven useful in patients
      with clinical or serological evidence of recurrent or metastatic thyroid
      carcinoma but negative whole body iodine scan. PET shows metastatic disease in up
      to 90% of these patients, thereby providing a rational basis for further studies
      and therapy. In patients with medullary thyroid cancer with elevated calcitonin
      levels following thyroidectomy, FDG-PET has a sensitivity of 70-75% for
      localizing metastatic disease. Occasionally incidental intense FDG uptake is
      observed in the thyroid gland on whole body PET studies performed for other
      indications. Although diffuse FDG uptake usually indicates thyroiditis, focal
      uptake has been related to thyroid cancer in 25-50% of cases and should therefore
      be evaluated further if a proven malignancy would cause a change in patient
      management.

PMID- 15202101
TI  - Neoplasms of the esophagus and stomach.
AB  - Esophageal cancer is one of the most lethal of all neoplasms. During the last two
      decades, there have been significant changes in the epidemiology and treatment of
      esophageal cancer. The incidence of adenocarcinoma is increasing whereas that of
      squamous cancer is decreasing. Surgery, the mainstay of treatment of esophageal
      cancer, has been used with neoadjuvant chemoradiotherapy to improve prognosis in
      patients with localized disease. Accurate staging is essential for selection of
      the best mode of therapy and to predict prognosis. In addition, with widespread
      use of neoadjuvant therapy, accurate assessment of response to therapy has become
      very important because responders have better a prognosis than nonresponders.
      Anatomical imaging methods, such as computed tomography and endoscopic
      ultrasonography, that are commonly used to evaluate esophageal cancer have
      shortcomings in demonstrating the true extent of disease and in assessing or
      predicting response to therapy. Positron emission tomography (PET) with 2
      [(18)F]fluoro-2-deoxy-d-glucose (FDG) has been shown to be a useful adjunct to
      anatomical imaging methods. For initial staging of esophageal cancer, the
      combination of PET and endoscopic ultrasonography with fine-needle aspiration
      biopsy has been suggested to be the most effective strategy. For restaging and
      monitoring response to therapy, FDG-PET has been shown to be superior to
      conventional imaging. The incidence of gastric cancer is decreasing worldwide,
      but it is also a highly lethal cancer. Similar to esophageal cancer, noninvasive
      staging of this cancer is unsatisfactory. Approximately one-third of the patients
      thought to have limited disease and to be candidates for surgery by conventional
      staging methods, are found to have advanced disease at surgery. Only a few
      published studies have evaluated gastric cancer with FDG-PET. These studies
      suggest that FDG-PET may be useful in evaluating gastric cancers of intestinal
      type and nonmucinous tumors.

PMID- 15202102
TI  - PET and PET-CT for evaluation of colorectal carcinoma.
AB  - The evaluation of patients with known or suspected recurrent colorectal carcinoma
      is now an accepted indication for positron emission tomography using (18)F
      fluorodeoxyglucose (FDG-PET) imaging. FDG-PET does not replace imaging modalities
      such as computed tomography (CT) for preoperative anatomic evaluation but is
      indicated as the initial test for diagnosis and staging of recurrence and for
      preoperative staging (N and M) of known recurrence that is considered to be
      resectable. FDG-PET imaging is valuable for the differentiation of posttreatment
      changes from recurrent tumor, differentiation of benign from malignant lesions
      (indeterminate lymph nodes, hepatic and pulmonary lesions), and the evaluation of
      patients with rising tumor markers in the absence of a known source. The addition
      of FDG-PET to the evaluation of these patients reduces overall treatment costs by
      accurately identifying patients who will and will not benefit from surgical
      procedures. Although initial staging at the time of diagnosis is often performed
      during colectomy, FDG-PET imaging is recommended for a subgroup of patients at
      high risk (with elevated CEA levels) and normal CT and for whom surgery can be
      avoided if FDG-PET shows metastases. Screening for recurrence in patients at high
      risk has also been advocated. FDG-PET imaging seems promising for monitoring
      patient response to therapy but larger studies are necessary. The diagnostic
      implications of integrated PET-CT imaging include improved detection of lesions
      on both the CT and FDG-PET images, better differentiation of physiologic from
      pathologic foci of metabolism, and better localization of the pathologic foci.
      This new powerful technology provides more accurate interpretation of both CT and
      FDG-PET images and therefore more optimal patient care. PET-CT fusion images
      affect the clinical management by guiding further procedures (biopsy, surgery,
      radiation therapy), excluding the need for additional procedures, and changing
      both inter- and intramodality therapy.

PMID- 15202103
TI  - Current and future uses of positron emission tomography in breast cancer imaging.
AB  - Positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) has been
      used for the detection, staging, and response monitoring in breast cancer
      patients. Although studies have proven its accuracy in detection of the primary
      tumor and axillary staging, its most important current clinical application is in
      detection and defining the extent of recurrent or metastatic breast cancer and
      for monitoring response to therapy. PET is complementary to conventional methods
      of staging in that it provides better sensitivity in detecting nodal and lytic
      bone metastases; however, it should not be considered a substitute for
      conventional staging studies, including computed tomography and bone
      scintigraphy. FDG uptake in the primary tumor carries prognostic information, but
      the underlying biochemical mechanisms that are responsible for enhanced glucose
      metabolism have not been completely elucidated. Future work using other PET
      tracers besides FDG will undoubtedly help our understanding of tumor biology,
      improve our ability to measure and predict response and help tailor therapy to
      individual patients.

PMID- 15202104
TI  - "Aha!" effects in a guessing riddle task: an event-related potential study.
AB  - Insight problem solving has been the topic of much investigation. It is believed
      widely that insight critically contains the process of breaking one's mental set.
      Recent functional magnetic resonance imaging (fMRI) research on puzzle solving
      showed that insight was associated with activities in anterior cingulate cortex
      (ACC) and other areas (Luo and Niki [2003]: Hippocampus 13:274-281). We proposed
      ACC might mediate processes of breaking one's mental set, given its well-known
      role in cognitive conflict. In the present research, high-density event-related
      potentials (ERPs) were recorded to examine the electrophysiologic correlates of
      insight problem solving. One hundred twenty interesting Chinese riddles (half
      difficult and half easy) were adopted as materials. For each trial, subjects were
      either given an easy puzzle followed by a keyword that was consistent with the
      subject's initial thinking ("No-aha answer"), or a difficult puzzle followed by a
      keyword that was consistent with an unusual interpretation, so that it broke the
      subject's initial mental set ("Aha answer"). Results from 14 subjects showed that
      Aha answers elicited a more negative ERP deflection than did No-aha answers in
      the time window from 250-500 msec after onset of the answer. The ERP difference
      wave (Aha minus No-aha answer) showed the maximum amplitude over the central site
      (Cz) with a peak latency of 380 msec (N380). Voltage and current density maps of
      the difference wave showed strong activity and current density in the
      frontocentral region. Dipole analysis localized the generator of the N380 in the
      ACC. N380 therefore probably reflects an "Aha!" effect, and the ACC generator may
      be involved in the breaking of mental set.

PMID- 15202105
TI  - A split-merge-based region-growing method for fMRI activation detection.
AB  - We introduce a hybrid method for functional magnetic resonance imaging (fMRI)
      activation detection based on the well-developed split-merge and region-growing
      techniques. The proposed method includes conjoining both of the spatio-temporal
      priors inherent in split-merge and the prior information afforded by the
      hypothesis-led component of region selection. Compared to the fuzzy c-means
      clustering analysis, this method avoids making assumptions about the number of
      clusters and the computation complexity is reduced markedly. We evaluated the
      effectiveness of the proposed method in comparison with the general linear model
      and the fuzzy c-means clustering method conducted on simulated and in vivo
      datasets. Experimental results show that our method successfully detected
      expected activated regions and has advantages over the other two methods.

PMID- 15202106
TI  - Cross-modal temporal order memory for auditory digits and visual locations: an
      fMRI study.
AB  - A function of working memory is to remember the temporal sequence of events,
      often occurring across different sensory modalities. To study the neural
      correlates of this function, we conducted an event-related functional magnetic
      resonance imaging (fMRI) experiment with a cross-modal memory task. Subjects were
      required to recall auditory digits and visual locations either in mixed order
      (cross-modality) or in separate order (within-modality). To identify the brain
      regions involved in the memory of cross-modal temporal order, we compared the
      blood oxygenation level-dependent (BOLD) response between the mixed and the
      separate order tasks. As a control, cortical areas sensitive to the memory load
      were mapped by comparing the 10-item condition with the 6-item condition in the
      separate order task. Results show that the bilateral prefrontal, right premotor,
      temporo-parietal junction (TPJ) and left superior parietal cortices had
      significantly more activation in the mixed task than in the separate task. Some
      of these areas were also sensitive to the memory load, whereas the right
      prefrontal cortex and TPJ were relatively more sensitive to the cross-modal order
      but not the memory load. Our study provides potential neural correlates for the
      episodic buffer, a key component of working memory as proposed previously
      [Baddeley. Trends Cogn Sci 2000;4:417-423].

PMID- 15202107
TI  - Automatic attention to emotional stimuli: neural correlates.
AB  - We investigated the capability of emotional and nonemotional visual stimulation
      to capture automatic attention, an aspect of the interaction between cognitive
      and emotional processes that has received scant attention from researchers. Event
      related potentials were recorded from 37 subjects using a 60-electrode array, and
      were submitted to temporal and spatial principal component analyses to detect and
      quantify the main components, and to source localization software (LORETA) to
      determine their spatial origin. Stimuli capturing automatic attention were of
      three types: emotionally positive, emotionally negative, and nonemotional
      pictures. Results suggest that initially (P1: 105 msec after stimulus), automatic
      attention is captured by negative pictures, and not by positive or nonemotional
      ones. Later (P2: 180 msec), automatic attention remains captured by negative
      pictures, but also by positive ones. Finally (N2: 240 msec), attention is
      captured only by positive and nonemotional stimuli. Anatomically, this sequence
      is characterized by decreasing activation of the visual association cortex (VAC)
      and by the growing involvement, from dorsal to ventral areas, of the anterior
      cingulate cortex (ACC). Analyses suggest that the ACC and not the VAC is
      responsible for experimental effects described above. Intensity, latency, and
      location of neural activity related to automatic attention thus depend clearly on
      the stimulus emotional content and on its associated biological importance.

PMID- 15202108
TI  - Visual recognition of faces, objects, and words using degraded stimuli: where and
      when it occurs.
AB  - We studied time course and cerebral localisation of word, object, and face
      recognition using event-related potentials (ERPs) and source localisation
      techniques. To compare activation rates of these three categories, we used
      degraded images that easily pop out without any change in the physical features
      of the stimuli, once the meaning is revealed. Comparisons before and after
      identification show additional periods of activation beginning at 100 msec for
      faces and at around 200 msec for objects and words. For faces, this activation
      occurs predominantly in right temporal areas, whereas for objects, the specific
      time period gives rise to bilateral posterior but right dominant foci. Finally,
      words show a maximum area of activation in the left temporooccipital area at
      their specific time period. These results provide unequivocal evidence that when
      effects of low-level visual features are circumvented, faces, objects, and words
      are not only distinct in terms of their anatomic routes, but also in terms of
      their times of processing.

PMID- 15202109
TI  - Reliability of brain volumes from multicenter MRI acquisition: a calibration
      study.
AB  - Multicenter studies can provide additional information over single center studies
      because of their increased statistical power. Because similar acquisition
      protocols are being used internationally for structural magnetic resonance
      imaging (MRI) studies of the human brain, volumetric MRI data studies seem
      suitable for this purpose. Possible systematic differences between sites should
      be avoided, however, particularly when subtle differences in tissue volume are
      being searched for, such as in neuropsychiatric diseases. In this calibration
      study, the brains of six healthy volunteers were (re)scanned with MR scanners
      from four different manufacturers at five different sites, using the local
      acquisition protocols. The images were segmented at a central reference site. The
      intraclass correlation coefficient (ICC) was determined for the whole brain, gray
      and white matter, cerebellum, and lateral and third ventricle volumes. When
      required, the processing algorithms were calibrated for each site. Calibration of
      the histogram analysis was needed for segmentation of total brain volume at one
      site and for gray and white matter volume at all sites. No (additional)
      calibration was needed for cerebellum and ventricle volumes. The ICCs were > or =
      0.96 for total brain, > or = 0.92 for cerebellum, > or = 0.96 for lateral
      ventricle, > or = 0.21 for third ventricle, > or = 0.84 for gray matter, and > or
      = 0.78 for white matter volume. Calibration of segmentation procedures allows
      morphologic MRI data acquired at different research sites to be combined reliably
      in multicenter studies.

PMID- 15202110
TI  - Neural substrates differentiating global/local processing of bilateral visual
      inputs.
AB  - We investigated neural substrates of global/local processing of bilateral
      hierarchical stimuli using functional magnetic resonance imaging (fMRI). Subjects
      were presented with two compound letters that were displayed simultaneously in
      the left and right visual fields, respectively. In a steady-state, block-design
      paradigm, hemodynamic responses were recorded while subjects detected infrequent
      global or local targets presented in one hemifield in separate epochs of trials.
      While behavioural responses were more accurate and faster to global than local
      targets, attention to the global level of bilateral visual inputs induced
      stronger activations in the left and right temporal cortex relative to attention
      to the local level. However, attention to the local level generated stronger
      activations in bilateral superior parietal cortex compared with attention to the
      global level. The results suggest that distinct neural substrates in the temporal
      and parietal cortices are preferentially engaged in the global and local
      processing of bilateral visual inputs, respectively.

PMID- 15202111
TI  - Evaluation of an image-guided, robotically positioned transcranial magnetic
      stimulation system.
AB  - The emergence of transcranial magnetic stimulation (TMS) as a tool for
      investigating the brain has been remarkable over the past decade. While many
      centers are now using TMS, little has been done to automate the delivery of
      planned TMS stimulation for research and/or clinical use. We report on an image
      guided robotically positioned TMS system (irTMS) developed for this purpose.
      Stimulation sites are selected from functional images overlaid onto anatomical MR
      images, and the system calculates a treatment plan and robotically positions the
      TMS coil following that plan. A new theory, stating that cortical response to TMS
      is highest when the induced E-field is oriented parallel to cortical columns, is
      used by the irTMS system for planning the position and orientation of the TMS
      coil. This automated approach to TMS planning and delivery provides a consistent
      and optimized method for TMS stimulation of cortical regions of the brain. We
      evaluated the positional accuracy and utility of the irTMS system with a B-shaped
      TMS coil. Treatment plans were evaluated for sites widely distributed about a
      head phantom with well-defined landmarks. The overall accuracy in positioning the
      planned site of the TMS coil was approximately 2 mm, similar to that reported for
      the robot alone. The estimated maximum range of error in planned vs. delivered E
      field strength was +4%, suggesting a high degree of accuracy and reproducibility
      in the planned use of the irTMS system.

PMID- 15202112
TI  - The effect of MR scanner noise on auditory cortex activity using fMRI.
AB  - Auditory functional magnetic resonance imaging (fMRI) studies are limited by the
      presence of noise produced by echo planar imaging (EPI). The current study
      quantifies the effect of MR scanner noise on psychophysical measures of the
      perception of loudness and on measures of tonotopy, the representation of
      auditory frequencies within the auditory cortex. Seven normal hearing adults were
      examined using tones of 5 different auditory frequencies (250, 500, 1,000, 2,000,
      4,000 Hz) of equal loudness. Using an imaging protocol with peak MR scanner noise
      at 1,460 Hz, the perception of loudness and detectable fMRI activity in response
      to a 1-kHz tone was less compared to other frequencies. When the imaging protocol
      was changed such that peak MR scanner noise occurred at 2,080 Hz, the perception
      of loudness and detectable fMRI activity in response to a 2-kHz tone was less
      compared to other frequencies. The reduction in the measured fMRI activity for
      tones near scanner frequencies may be due to an inflated scanner-induced baseline
      at those frequencies. In addition, fMRI activity decreased with increasing
      frequency, possibly due to the upward spread of masking of low-frequency, high
      intensity tonal stimuli or the proximity of low-frequency core and belt areas of
      the auditory cortex. These results demonstrate the direct effect of scanner noise
      and high-intensity tonal stimuli on measurements of auditory cortex tonotopy.

PMID- 15202113
TI  - Technical and clinical evaluation of anti-ribosomal P protein immunoassays.
AB  - Autoantibodies to the three ribosomal phospho (-P) proteins P0, P1, P2, referred
      to as Rib-P, are specifically found in 10-40% of patients with systemic lupus
      erythematosus. The variations in the observed frequency of these autoantibodies
      is related to a number of factors such as the test system used to detect the
      antibodies. Several immunoassays that were designed for research and diagnostic
      laboratory use have been developed. The autoantigens employed in these tests
      include native proteins, recombinant polypeptides, and synthetic peptides. In
      this study, we compared the technical and clinical accuracy of anti-Rib-P
      antibody assays from different commercial suppliers including ELISA systems and a
      novel addressable laser bead assay (from Euroimmun, MBL, Pharmacia Diagnostics,
      INOVA). Although the assays from all suppliers used in this study performed well
      in the technical part of the study, relatively poor correlations and significant
      differences in the clinical accuracy were found. Based on the results, we
      conclude that the detection of anti-Rib-P antibodies strongly depends on both the
      nature of the antigen and the detection system. We recommend that anti-Rib-P
      assays should be standardized on an international level. The Varelisa Rib-P
      profile and the addressable laser bead Rib-P assays represent promising tools and
      platforms for the detection of anti-Rib-P antibodies in the future.

PMID- 15202114
TI  - Rapid, simple, and reliable method for the diagnosis of CAPD peritonitis using
      the new MMP-9 test kit.
AB  - The objective of the present study was to evaluate the sensitivity and efficiency
      of the matrix metalloproteinase-9 (MMP-9) test kit for the diagnosis of bacterial
      peritonitis in patients undergoing peritoneal dialysis (PD). Peritoneal effluents
      were collected from seven continuous ambulatory PD (CAPD) patients with
      peritonitis, four patients with suspected peritonitis, 30 maintenance PD patients
      without infection, and seven patients at initiation of PD. The MMP-9 test kit was
      used to analyze 112 peritoneal effluent samples. These peritoneal effluents were
      also used to count leukocytes and examine microorganisms. MMP expression was
      measured by gelatin zymography, and activities were measured by an enzyme-linked
      immunosorbent assay (ELISA). The relationship between the reactivity of the test
      kit and the number of leukocytes in the samples was examined. There was a
      significant difference in the number of leukocytes in peritoneal effluents
      between the negative and positive groups detected by the MMP-9 test kit (P <
      0.0001). The results obtained with the MMP-9 test kit were negative for
      peritoneal effluent samples that did not show increased cell counts. The
      reactivity of the MMP-9 test kit showed no significant differences among various
      microorganisms, and remained stable. The MMP-9 test kit appears to be a simple
      and reliable method for early diagnosis of CAPD peritonitis, and reflects the
      leukocyte count in peritoneal effluents.

PMID- 15202115
TI  - Urinary protein fraction in healthy subjects using cellulose acetate membrane
      electrophoresis followed by colloidal silver staining.
AB  - We previously reported a rapid and highly sensitive colloidal silver staining
      solution suitable for the cellulose acetate membrane. This method was useful for
      detecting even very small amounts of urinary protein. In the present study, we
      examined urinary protein fractions in healthy subjects, using cellulose acetate
      membrane electrophoresis (CAE) with a highly sensitive colloidal silver staining,
      in an attempt to determine the clinical relevance of urinary protein fractions.
      Sixty unconcentrated spot urine specimens were analyzed by CAE and calculated by
      densitometry. All of the samples were separated into five fractions by CAE. The
      mean +/- 1 SD of the percentage of five fractions was 28.37 +/- 8.51 in albumin,
      4.30 +/- 4.19 in alpha1-globulin, 14.41 +/- 6.14 in alpha2-globulin, 19.45 +/-
      7.10 in beta-globulin, and 33.46 +/- 8.24 in gamma-globulin. The albumin/globulin
      (A/G) ratio was 0.41 +/- 0.17. These six items and the concentrations of total
      protein, albumin, and beta-N-acetyl-D-glucosaminidase (NAG) did not significantly
      differ between males and females. NAG is the marker of tubulointerstitial
      nephropathy. The results suggest that there are no gender-dependent differences
      in the urinary protein fractions of healthy subjects.

PMID- 15202116
TI  - Beta-trace protein, a new marker of GFR, may predict the early prognostic stages
      of patients with type 2 diabetic nephropathy.
AB  - The relationship between serum levels of beta-trace protein (BTP) or serum
      creatinine (s-Cr) and the prognostic stages of type 2 diabetic nephropathy was
      determined. Serum samples from 174 patients with type 2 diabetes were obtained
      from Juntendo University Hospital, Tokyo, and Juntendo Urayasu Hospital, Chiba,
      Japan. They were classified into four groups according to the Report of the
      Ministry of Health and Welfare of Japan (1991, p 251-256) as follows: Stage I
      (normoalbuminuric stage), Stage II (microalbuminuric stage), Stage IIIA
      (macroalbuminuric stage without renal dysfunction), Stage IIIB (macroalbuminuric
      stage with renal dysfunction), and Stage IV (renal failure stage). Among these
      patients, 68 were Stage I, 29 Stage II, 32 Stage IIIA, 17 Stage IIIB, and 28
      Stage IV. Levels of serum BTP were measured using the nephelometric assay on a
      BNA II analyzer (Dade Behring Diagnostics, Marburg, Germany). The mean levels of
      serum BTP in Stage IIIA were significantly higher than those in Stage I or II (P
      < 0.00001, P < 0.002, respectively). However, the mean levels of s-Cr in Stage
      IIIA were not significantly higher than that in Stage I or II. In conclusion,
      serum BTP was a good marker for the identification of early renal impairment in
      type 2 diabetes.

PMID- 15202117
TI  - Stability of fat-soluble and water-soluble vitamins in artificially prepared,
      vitamin-enriched, lyophilized serum.
AB  - Vitamin-enriched, lyophilized serum (VES) was prepared for an inter-laboratory
      study to compare vitamin assays. The VES contained water-soluble vitamins
      (vitamin B1, vitamin B12, vitamin C, and folate), fat-soluble vitamins (vitamin A
      and vitamin E), and cholesterol. We performed stability studies and determined
      vitamin concentrations and total cholesterol in VES stored at -20 degrees C for
      12 months. Our recovery of the water-soluble vitamins in reconstituted VES was 70
      142%, but we recovered only 33-45% of the fat-soluble vitamins. Physicochemical
      properties, such as specific gravity and viscosity of the reconstituted VES did
      not affect manual or automated measurements of these vitamins. Vial-to-vial
      differences found for the VES were the same as the within-day analytical
      variations. There was no evidence of degradation of vitamin A, vitamin B1,
      vitamin B12, vitamin C, folate, and cholesterol over 12 months in VES stored at 
      20 degrees C. Following deproteinization, vitamin C concentration was found to be
      lower than when not deproteinated. Vitamin E was less stable in VES, however, and
      the degradation during 12 months was lower than the between-day analytical
      variation of the assay. Our VES is the first preparation of lyophilized control
      serum that contains water-soluble and fat-soluble vitamins.

PMID- 15202118
TI  - Immunoglobulin (Ig) M antibody against myelin associated glycoprotein (MAG): A
      comparison of methods.
AB  - The presence of immunoglobulin (Ig)M antibody against myelin associated
      glycoprotein (MAG) has been associated with autoimmune demyelinating,
      sensorimotor neuropathies. Approximately 50% of patients with IgM paraproteinemia
      and associated peripheral neuropathy possess antibodies against MAG. These
      autoantibodies are thought to interfere with the process of myelination, myelin
      maintenance, or axon-Schwann cell interaction. The detection of these
      autoantibodies is useful to the clinician and is suggestive of active
      demyelination in a peripheral neuropathy. Our objective in this study was to
      compare the results obtained using three different methods (dual enzyme
      immunoassay [EIA], immunofluorescent antibody [IFA] and Western blot [WB]) for
      detecting IgM antibody against MAG in patients suspected of having autoimmune
      demyelinating neuropathies. Since the dual EIA utilized two different antigens,
      results from this assay were separated into two groups: MAG and sulfate-3
      glucuronyl paragloboside (SGPG). When compared to WB (gold standard), percent
      agreement, sensitivity, and specificity for EIA and IFA are as follows: MAG EIA
      (68.3, 100.0, and 60.6); SGPG EIA (95.1, 100.0, and 93.9); and myelin IFA (97.6,
      100.0, and 97.0). The authors conclude that the SGPG EIA and myelin IFA compared
      well with the standard WB method when detecting IgM antibody against MAG (100
      kD). Many sera demonstrated reactivity on the MAG EIA that were negative by WB
      (100 kD glycoprotein). The authors recommend screening for MAG IgM in suspected
      patient sera by SGPG EIA or myelin IFA and utilizing these same methods to titer
      sera confirmed positive by WB.

PMID- 15202119
TI  - Spectrophotometric determination of leukocytes in urine.
AB  - A spectrophotometric method based on myeloperoxidase activity for the
      determination of leukocytes in urine is described. Red cells that may be found in
      urine samples were lysed by an ammonium chloride method. Leukocytes were then
      sedimented by centrifugation and lysed using Triton X-100 (Sigma Chemicals Co.,
      St. Louis, MO). Myeloperoxidase-catalyzed oxidation of o-dianisidine was carried
      out at 37 degrees C, pH 7. The reaction was stopped with the addition of 2 M
      H2SO4, and a stable form of oxidized o-dianisidine in acidic solution was
      obtained. Solid particles that may be found in urine samples were removed by
      centrifugation to avoid turbidity, and absorbance values of the supernatants were
      recorded at 400 nm. An Average number of leukocytes were noted per number of
      fields by microscopic examination and were related with the absorbance values of
      the supernatants at 400 nm. Pearson correlation (r) between our presented
      spectrophotometric analysis results and visual microscopic analysis was 0.877.
      Roche Combur 10-test M strips (Roche, Mannheim, Germany) and Multistix 10 SG
      Bayer test strips (Bayer Diagnostics, UK) were 0.645 and 0.648, respectively (P <
      0.0001).

PMID- 15202120
TI  - Modeling of methyl isothiocyanate air concentrations associated with community
      illnesses following a metam-sodium sprinkler application.
AB  - BACKGROUND: A series of illnesses occurred in Earlimart, CA on November 13, 1999
      following a metam-sodium sprinkler application to a potato field on the southern
      edge of the town. METHODS: Case information was obtained from direct interviews,
      from illness complaints filed with state or county agencies, or from illness
      reports filed by community physicians for 173 subjects. Air concentrations of the
      by-product methyl isothiocyanate (MITC) during the episode were estimated based
      upon the Industrial Source Complex Short-Term (ISC3) air dispersion model,
      estimates from prior metam-sodium monitoring studies, and data from weather
      stations in two adjoining communities. RESULTS: Weather station data indicated
      that the November 13th incident corresponded with a temperature inversion at
      approximately 5:00 p.m. and a shift in the direction of prevailing wind from
      northwest to southeast. On the edge of Earlimart, 1-hr time weighted average
      (TWA) MITC concentration estimates ranged from 0.5 to 1 ppm. Of the 173 subjects,
      170 had MITC-compatible symptoms, including eye or upper respiratory irritation
      (77.6%), non-specific systemic symptoms (64.7%), and lower respiratory symptoms
      (20.0%). 78.2% were exposed within 0.5 miles of the northern edge of the treated
      field where average 1 hr MITC concentrations exceeded the 800 ppb ocular
      irritation threshold. CONCLUSIONS: ISC3 modeling is a useful means of evaluating
      MITC concentrations for illness episodes when industrial hygiene assessment is
      not possible.

PMID- 15202121
TI  - Ischemic heart disease mortality among heavy equipment operators.
AB  - BACKGROUND: Inhalation of fine particulate is hypothesized to increase risk of
      heart disease events. METHODS: Seven Ontario construction unions participated in
      a retrospective cohort mortality study. Proportional mortality ratios (PMRs) were
      computed and a mortality odds ratio (MOR) analysis was performed to compare the
      risk of ischemic heart disease (IHD) mortality among heavy equipment operators
      (HEO) to that of members of other unions. Deaths attributed to lung cancer,
      mesothelioma, and accidental causes were excluded from the comparison. RESULTS:
      Two hundred fifty nine of 1,009 deaths among the HEO were attributed to IHD. The
      PMR was 1.09 (0.96-1.2). None of the IHD PMRs among the other six unions exceeded
      0.89. The MOR for IHD mortality, comparing the HEO to all other workers combined
      was 1.47 (1.17-1.84) for ages 25-64, was 1.20 (0.96-1.50) for ages 65 or more,
      and was 1.32 (1.13-1.55) for all ages combined. CONCLUSIONS: Increased risk of
      IHD mortality among HEO is consistent with the hypothesis that exposure to diesel
      fume has adverse effects upon the heart and circulatory system.

PMID- 15202122
TI  - Use of qualitative methods to map job tasks and exposures to occupational hazards
      for commercial fishermen.
AB  - BACKGROUND: Understanding job tasks and estimating occupational exposures is
      difficult for self-employed or autonomous workers, who tend to be dispersed, with
      no fixed workplace, employment records, or historical exposure measurements.
      METHODS: We used ethnographic methods to collect work information for southern
      commercial fishermen. Major activities were mapped using the seasonal round, an
      anthropological tool that records activities of groups whose lifeways depend on
      natural cycles. RESULTS: Fishermen's work schedules depended on boat size, gear,
      market fluctuations, and regulations, as well as season. The seasonal round
      guided the analysis of qualitative data on annual cycles of activities increasing
      understanding of exposures and their variation. CONCLUSIONS: Combined with
      detailed exposure information this framework for organizing and categorizing
      seasonal activities could improve accuracy of exposure information and guide
      quantitative analysis in work settings that challenge standard exposure
      assessment methods.

PMID- 15202123
TI  - Nonfatal occupational injuries from slips, trips, and falls among older workers
      treated in hospital emergency departments, United States 1998.
AB  - BACKGROUND: Falls are a leading cause of injury among older adults. As the
      workforce demographics shift to an older population, the dearth of information on
      occupational falls among older adults must be addressed. METHODS: A national
      probability sample of hospital emergency departments (EDs) (National Electronic
      Injury Surveillance System) was utilized to characterize falls at work. RESULTS:
      Older workers were found not to be at increased risk of a fall injury, but were
      more likely than younger workers to be hospitalized post-injury. Same-level falls
      were the most common type of incident among older workers. Falls from height were
      more prevalent among men than women. The narrative case descriptions for same
      level falls to the floor primarily implicated floor contamination and tripping
      hazards. CONCLUSIONS: Fall prevention programs targeted to older workers must
      examine extrinsic sources of falls, particularly surface traction, contaminant
      control, and footwear.

PMID- 15202124
TI  - Prevalence and predictors of respiratory symptoms among New York farmers and farm
      residents.
AB  - BACKGROUND: Data from telephone interviews with New York farmers and farm
      residents were used to study the prevalence and risk factors of symptoms that
      could be related to asthma and allergies. METHODS: Participants were asked if
      they had wheezing or whistling in the chest in the past year and about the
      occurrence of stuffy, itchy, runny nose or watery, itchy eyes in the past year.
      RESULTS: The prevalence of wheeze was 18.2% and of stuffy nose/watery eyes was
      57.4% (N = 1,620). Significant risk factors for wheeze were cigarette smoking, a
      systemic reaction to allergy skin testing, immunotherapy, or insect sting,
      reactivity to a pet, having goats, and more acreage in corn for silage.
      Significant risk factors of stuffy nose/watery eyes were younger age, having more
      than a high school education, being a worker on the farm, and having done
      spraying. CONCLUSIONS: Wheeze may be indicative of existing or latent asthma, a
      potentially limiting respiratory illness. Stuffy, itchy, runny nose or watery,
      itchy eyes, which may cause irritation and discomfort, may also indicate an
      increased sensitivity to respirable dusts and chemicals. This cohort of New York
      farmers had significant farm-related risk factors for wheeze and stuffy
      nose/watery eyes.

PMID- 15202126
TI  - Impacts of health and safety education: comparison of worker activities before
      and after training.
AB  - BACKGROUND: The International Chemical Workers Union Council (ICWUC) Center for
      Worker Health and Safety Education in Cincinnati, Ohio, trains workers to protect
      themselves from hazards due to chemical spills and other chemical exposures. We
      evaluated whether the ICWUC Hazardous Waste Worker Training Program affects the
      attitudes and post-training activities, of trained union workers. METHODS:
      Detailed survey questionnaires were administered to 55 workers prior to and 14-18
      months following training. Surveys queried trainees' interest and involvement in
      safety and health, use of information resources, training activities at their
      worksite, and their attempts and successes at making worksite improvements.
      RESULTS: Post-training, the study population showed an increase in training of
      other workers, use of resources, attempts at improvements, success rates for
      those attempting change, and overall success at making improvements. Self
      reported interest decreased, and self reported involvement in health and safety
      did not significantly change. CONCLUSION: The study demonstrates that workers are
      more willing to attempt to change worksite conditions following training, and
      that their efficacy at making changes is substantially greater than before they
      were trained. The study confirms earlier work and strengthens these conclusions
      by using statistically tested comparisons of impact measures pre- and post
      training.

PMID- 15202125
TI  - Working conditions and health among female and male employees at a call center in
      Sweden.
AB  - BACKGROUND: The call center industry is one of the most expansive labor market
      sectors in Sweden today. The purpose of this study was to investigate the working
      conditions and symptoms among employees at a call center in Sweden. METHODS: This
      study represents the cross-sectional baseline survey, which was part of a
      prospective cohort study. Fifty-seven call center workers were compared with a
      reference group of 1,459 professional computer users from other occupations. A
      questionnaire covered physical and psychosocial working conditions and symptoms
      during the last month. Structured observations in accordance with an ergonomic
      checklist were used to assess workstation design during the subject's ordinary
      work. RESULTS: The call center group had worked for a shorter time in their
      present tasks and spent longer continuous time in front of the computer than the
      reference group. There were deficiencies in workspace, keyboard- and input device
      placement. The subjects reported poor support from their immediate supervisor,
      low control and limited opportunities to influence their work. A higher
      proportion of the call center group reported musculoskeletal symptoms.
      CONCLUSION: The call center operators were exposed to working conditions that in
      other studies have indicated an increased risk of developing musculoskeletal
      disorders. The study also shows that young computer operators in the call center
      group with a short working career had a higher prevalence of neck- and upper
      extremity symptoms than older computer workers in other labor market sectors.

PMID- 15202127
TI  - Good practices in managing work-related indoor air problems: a psychosocial
      perspective.
AB  - BACKGROUND: Indoor air problems at workplaces are often exceedingly complex.
      Technical questions are interrelated with the dynamics of the work community, and
      the cooperation and interaction skills of the parties involved in the problem
      solving process are also put to the test. The objective of our study was to
      analyze the process of managing and solving indoor air problems from a
      psychosocial perspective. METHODS: This collective case study was based on data
      from questionnaires, interviews and various documentary materials. Technical
      inspections of the buildings and indoor air measurements were also carried out.
      RESULTS: The following four factors best differentiated successful cases from
      impeded cases: extensive multiprofessional collaboration and participative
      action, systematic action and perseverance, investment in information and
      communication, and process thinking and learning. The study also proposed a
      theoretical model for the role of the psychosocial work environment in indoor air
      problems. CONCLUSIONS: The expertise related to social and human aspects of
      problem solving plays a significant role in solving indoor air problems. Failures
      to properly handle these aspects may lead to resources being wasted and result in
      a problematic situation becoming stagnant or worse.

PMID- 15202128
TI  - A cluster of male breast cancer in office workers.
AB  - Three cases of male breast cancer were diagnosed among a small group of men who
      worked in a basement office of a multi-story office building. This office was
      adjacent to an electrical switchgear room which generated high magnetic fields in
      their work space. The risk of male breast cancer in this group was increased
      about 100-fold (observe three cases, expect 0.03 cases; P < 0.00001). Since 1991,
      15 epidemiologic studies have associated male breast cancer with exposure to
      electromagnetic field.

PMID- 15202129
TI  - Statement of the Collegium Ramazzini.

PMID- 15202130
TI  - Re: Attfield M, Costello J. Quantitative exposure-response for silica dust and
      lung cancer in Vermont granite workers. Am J Ind Med 45:129-138, 2004.

PMID- 15202143
TI  - Diagnosis and management of hyperthyroidism and hypothyroidism.

PMID- 15202144
TI  - Fact and fantasy.

PMID- 15202145
TI  - Fact and fantasy.

PMID- 15202146
TI  - Nurses' addictions.

PMID- 15202147
TI  - Silica and noise exposure during installation of fibercement siding.

PMID- 15202148
TI  - Standards activities of the ASTM International Committee on Atmospheric Sampling
      and Analysis.

PMID- 15202149
TI  - The development of an ergonomics training program to identify, evaluate, and
      control musculoskeletal disorders among nursing assistants at a state-run
      veterans' home.
AB  - Nursing assistants (NAs) who work in nursing and personal care facilities are
      twice and five times more likely, respectively, to suffer a musculoskeletal
      disorder compared to service industries and other health care facilities,
      respectively. The purpose of this study was to develop an ergonomics training
      program for selected NAs at a state-run veterans' home to decrease
      musculoskeletal disorders by 1) developing questionnaires to assess
      musculoskeletal stress, 2) evaluating the work environment, 3) developing and
      using a training package, and 4) determining the application of the information
      from the training package by NAs on the floor. Results show two new risk factors
      not previously identified for nursing personnel in the peer-reviewed literature.
      Quizzes given to the nursing personnel before and after training indicated a
      significant improvement in understanding the principles of ergonomics and patient
      handling techniques. Statistical analysis comparing the pre-training and post
      training questionnaires indicated no significant decrease in musculoskeletal risk
      factors and no significant reduction in pain or discomfort or overall mental or
      physical health.

PMID- 15202150
TI  - Potentially pathogenic, slow-growing mycobacteria released into workplace air
      during the remediation of buildings.
AB  - Construction workers' exposure to airborne viable mycobacteria was studied during
      the remediation of three moldy and two nonmoldy buildings. Furthermore, the
      concentrations of airborne fungal and actinobacterial spores were determined. The
      samples for the microbial analyses were collected using a six-stage impactor and
      an all-glass impinger sampler, and by filter sampling. Specific mycobacteria
      media and nonselective media were used for the cultures. The samples were
      cultured for the total numbers of rapidly growing and slow-growing mycobacteria,
      and the isolates obtained were identified to the genus or species level.
      Mycobacteria were recovered from the air during the remediation of two of the
      moldy buildings and one nondamaged building. Concentrations of mycobacteria up to
      160 cfu/m3 were detected. A total of 43 mycobacterial isolates was recovered.
      Most of the isolates were slow-growers, only two rapid-growing strains being
      detected. The 38 identified isolates belonged to potentially pathogenic species,
      including Mycobacterium avium complex, M. scrofulaceum, and M. fortuitum, and to
      saprophytic species, including M. nonchromogenicum and M. terrae. Mycobacteria
      were the most often detected in samples taken with a six-stage impactor. They
      were found in buildings with both high and low concentrations of fungi. In
      conclusion, mycobacteria, both potentially pathogenic and saprophytic species,
      may be released into the indoor air during the remediation of buildings.

PMID- 15202151
TI  - Release of simulated anthrax particles from disposable respirators.
AB  - A preliminary study was undertaken to evaluate the potential for a disposable
      respirator that has been contaminated with anthrax spores to release spores in
      handling after use. The release of inert particles from disposable respirators
      was measured for masks dropped 3 feet onto a hard surface. Ten experimental runs
      were conducted for each of two N95 mask types, the Moldex 2200N95 and the 3M
      8210. Anthrax spores were simulated with a test aerosol of single and double 1
      micron polystyrene spheres. For the Moldex mask loaded with approximately 20
      million spheres on it, an average of 0.16% was released; for the 3M mask an
      average of 0.29% was released.

PMID- 15202152
TI  - Risk factors for work-related low back pain in registered nurses, and potential
      obstacles in using mechanical lifting devices.
AB  - Back pain disability is a serious and costly problem affecting the nursing
      profession. The purposes of this study were to determine risk factors for work
      related low back pain (WRLBP) in registered nurses and to record the reported use
      or reasons for nonuse of mechanical lifts. Our hypothesis was that workers who
      attributed the cause of WRLBP to their own actions would be knowledgeable about
      back safety, would be more likely to use lifts, and would report less WRLBP. A
      random sample of 270 registered nurses was selected from two acute care hospitals
      in central Illinois to identify WRLBP risk factors. This cross-sectional study
      gathered information on individual, physical workload, psychological, and
      organizational factors that may present a risk for WRLBP. Information was also
      collected on the use of safety devices and back pain symptoms. The response rate
      was 50.4%. Nearly 84% of respondents had WRLBP in the past, and 36.2% had WRLBP
      in the past year that limited movement or interfered with routine activities.
      Among the risk factors significantly associated with WRLBP were more years worked
      in nursing, frequent lifting, and low social support. Only 11% reported that they
      routinely used mechanical lifting devices, and the primary reason given for
      failure to use lifting equipment was unavailability of equipment. The reasons for
      the lack of use of mechanical lifts should be investigated and addressed.

PMID- 15202153
TI  - Respiratory protection against Mycobacterium tuberculosis: quantitative fit test
      outcomes for five type N95 filtering-facepiece respirators.
AB  - In preparing to fit test a large workforce, a respirator program manager needs to
      initially choose respirators that will fit the greatest proportion of employees
      and achieve the best fits. This article discusses our strategy in selecting
      respirators from an initial array of seven NIOSH-certified Type N95 filtering
      facepiece devices for a respiratory protection program against Mycobacterium
      tuberculosis (M. tb) aerosol. The seven respirators were screened based on
      manufacturer-provided fit test data, comfort, and cost. From these 7 devices, 5
      were chosen for quantitative fit testing on 40 subjects who were a convenience
      sample from a cohort of approximately 30,000 workers scheduled to undergo fit
      testing. Across the five brands, medium/regular-size respirators fit from 8% to
      95% of the subjects; providing another size of the same brand improved the pass
      rates slightly. Gender was not found to significantly affect fit test pass rates
      for any respirator brand. Among test panel members, an Aearo Corporation
      respirator (TC 84A-2630) and a 3M Company respirator (TC 84A-0006) provided the
      highest overall pass rates of 98% and 90%, respectively. We selected these two
      brands for fit testing in the larger worker cohort. To date, these two
      respirators have provided overall pass rates of 98% (1793/1830) and 88% (50/57),
      respectively, which are similar to the test panel results. Among 1850 individuals
      who have been fit tested, 1843 (99.6%) have been successfully fitted with one or
      the other brand. In a separate analysis, we used the test panel pass rates to
      estimate the reduction in M. tb infection risk afforded by the medium/regular
      size of five filtering-facepiece respirators. We posed a low-exposure versus a
      high-exposure scenario for health care workers and assumed that respirators could
      be assigned without conducting fit testing, as proposed by many hospital
      infection control practitioners. Among those who would pass versus fail the fit
      test, we assumed an average respirator penetration (primarily due to faceseal
      leakage) of .04 and 0.3, respectively. The respirator with the highest overall
      pass rate (95%) reduced M. tb infection risk by 95%, while the respirator with
      the lowest pass rate (8%) reduced M. tb infection risk by only 70%. To promote
      the marketing of respirators that will successfully fit the highest proportion of
      wearers, and to increase protection for workers who might use respirators without
      the benefit of being fit tested, we recommend that fit testing be part of the
      NIOSH certification process for negative-pressure air-purifying respirators with
      tightly fitting facepieces. At a minimum, we recommend that respirator
      manufacturers generate and provide pass rate data to assist in selecting
      candidate respirators. In any event, program managers can initially select
      candidate respirators by comparing quantitative fit tests for a representative
      sample of their employee population.

PMID- 15202154
TI  - Comparison of simulated respirator fit factors using aerosol and vapor
      challenges.
AB  - Although not well established, mask leakage measured using submicron aerosol
      challenges is generally accepted as being representative of vapor challenges. The
      purpose of this study was to compare simulated respirator fit factors (FFs)
      measured using vapor challenges to those measured using an aerosol challenge. A
      full-facepiece respirator was mounted on a headform inside a small enclosure and
      modified with controlled leaks (laser-drilled orifices) to produce FFs ranging
      from about 300 to 30,000. A breathing machine was used to simulate breathing
      conditions of 1.0 L tidal volume and 25 breaths/min. A monodisperse aerosol
      consisting of 0.72 micron polystyrene latex spheres (PSL) was used for the
      reference test aerosol, and FFs were measured using a laser aerosol spectrometer.
      An inert gas, sulfur hexafluoride (SF6), and an organic vapor, isoamyl acetate
      (IAA), were used as the vapor challenges. The in-mask concentration of SF6 was
      measured using a gas chromatograph (GC). A GC was also used to quantify in-mask
      IAA concentration samples actively collected with sorbent tubes. FF measurements
      made with the PSL aerosol challenge were conducted in sequence with the SF6 and
      IAA challenges, without disturbing the mask, to yield matched data pairs for
      regression analysis. FFs measured using the PSL reference aerosol were found to
      correlate well with those measured with the SF6 (r2 = 0.99) and IAA (r2 = 0.98)
      vapor challenges. FFs measured using IAA tended to be higher at values below
      10,000. The best agreement was observed with the inert gas, SF6. The results of
      this study suggest that submicron aerosols are suitable as quantitative fit test
      challenges for assessing the performance of respirators against inert vapors.

PMID- 15202155
TI  - Cadmium exposures at three nonferrous foundries: an unexpected trace source.
AB  - Trace substances are often ignored as a potential source of significant
      occupational exposures. Trace substances include intermediates, byproducts,
      natural components, or a minor additive. An unexpected finding from a lead
      exposure assessment at a brass foundry was the identification of cadmium in one
      of the samples. Cadmium exposure was unexpected since it was not listed on the
      available documents (e.g., MSDS) and its presence was unknown to foundry
      representatives. Cadmium was found to be a trace component (maximum of 0.003%) in
      special high-grade (SHG) zinc added to molten brass or bronze alloys. Employees
      using as little as four pounds of SHG zinc containing 0.0004% cadmium had
      exposures that exceeded the Occupational Safety and Health Administration's 2.5
      micrograms/m3 action level and 5 micrograms/m3 permissible exposure limit.
      Cadmium exposures at the three nonferrous foundries in this study were variable
      but, in general, metal pourers had the highest exposures (up to 7.2
      micrograms/m3), followed by finishing workers (up to 1.9 micrograms/m3), and then
      furnace operators (up to 1.6 micrograms/m3). A pourer's exposure during a 3-min
      metal pouring cycle was 34.4 micrograms/m3. Air samples taken in the plume
      emitted after adding one pound (454 g) of zinc to the molten metal contained high
      cadmium levels (up to 3070 micrograms/m3) demonstrating zinc was the cadmium
      source. This study shows that the trace cadmium in SHG zinc can result in
      overexposures when used for brass and bronze alloying and trace components must
      be considered when evaluating potential employee exposures.

PMID- 15202156
TI  - Association between lung function and exposure to smoke among firefighters at
      prescribed burns.
AB  - We investigated the short-term effects of exposures to PM3.5, acrolein,
      formaldehyde, and carbon monoxide on lung function in a group of firefighters
      performing prescribed burns. Spirometric measurements were made on 65
      firefighters at the beginning, midpoint, and end of their work shift, while
      exposure was measured over the entire day. The interquartile range (IQR) of daily
      personal PM3.5 exposures was 235 micrograms/m3 to 1317 micrograms/m3, with an
      average daily exposure of 882 micrograms/m3. Concentrations of acrolein (IQR:
      [0.002, 0.018] ppm), formaldehyde (IQR: [0.008, 0.085] ppm), and carbon monoxide
      (IQR: [2.10, 10.48] ppm) were similarly elevated. In this group of firefighters,
      FEV1 changed by -0.125 L from preshift to postshift (p < .001). We examined the
      association between this cross-shift lung function decrement and smoke exposure.
      A 1000 micrograms/m3 increase in PM3.5 was associated with a -0.030 L change in
      the cross-shift FEV1 (95% CI [-0.087, 0.026]). Acrolein, formaldehyde, and carbon
      monoxide exposure were also not significantly associated with changes in FEV1,
      FVC, or FEF25-75. We concluded that while firefighters' lung function
      significantly decreased from preshift to postshift, firefighters exposed to
      greater concentrations of respiratory irritants did not experience greater lung
      function decrements. We could not establish a significant link to any of the
      individual toxic components of smoke we measured.

PMID- 15202157
TI  - Sampling and analysis of butyltin compounds in air using gas chromatography and
      flame photometric detection.
AB  - Organotin compounds are used in a variety of applications including stabilizers,
      catalysts, antifouling agents, and biocides. Because of the widespread use of
      organotin compounds in industry and their wide range of toxic effects, it is
      important to measure worker exposure to specific organotin compounds. Three
      butyltin compounds were selected for this study--butyltin trichloride, dibutyltin
      dichloride, and tributyltin chloride. These three compounds are typically present
      in the same work environment; therefore, developing a sampling and analytical
      method that would allow all three butyltin compounds to be sampled and analyzed
      simultaneously was desired. A derivatization procedure using sodium
      tetraethylborate (STEB) was selected for study and validation. The validation
      study demonstrated that sampling using the Occupational Safety and Health
      Administration (OSHA) Versatile Sampler (OVS) with XAD-2 resin sorbent and
      analysis using gas chromatography/flame photometric detection (GC/FPD) can be
      used to evaluate worker exposures to specific butyltin chlorides over the range
      of 5 to 270 micrograms/m3 collected at a flowrate of 0.25 L/min over a 3-hour
      period for a 45-L air sample. Breakthrough studies at 1.5 times the occupational
      exposure guideline (OEG) of 0.05 mg/m3 showed that samples could be collected at
      flowrates up to 0.5 L/min for 12 hours without breakthrough. The 14-day storage
      stability study showed apparent degradation of tributyltin and monobutyltin
      within a 3-day storage period at both ambient and refrigerated temperatures.
      There was no further degradation from 3 to 14 days. The stability of dibutyltin
      was unaffected by storage condition over the 14-day storage study. Subsequent
      stability studies incorporating a spiking solution control sample were conducted
      extending the stability study out to 27 days. These data show that all three
      butyltins were stable at either ambient or refrigerated conditions.

PMID- 15202159
TI  - Castleman disease: a case with atypical presentation.
AB  - Castleman disease is a benign lymphoproliferative disorder characterized by
      enlarged lymph nodes. In children the disease is rare, usually localized, and
      asymptomatic. Resection of the node is almost always curative. A case is reported
      that was diagnosed as hyaline vascular-type Castleman disease at 1 year of age.
      The disease recurred from infraclavicular region in addition to primary site,
      even though total excision was performed. Although the disease is mullticentric
      after recurrence, the patient has no systemic symptoms.

PMID- 15202158
TI  - The psuedo-Chediak-Higashi anomaly: an unusual staining pattern in an Indian
      child with acute myeloid leukemia.
AB  - The authors describe the psuedo-Chediak-Higashi anomaly in a 12-year-old boy with
      acute myeloid leukemia (AML-M2). There were large purple granules in the blasts,
      promyelocytes, and myelocytes. Instead of the previously described patterns, the
      authors observed a unique rim pattern staining of the granules in both the May
      Grunwald-Giemsa and the myeloperoxidase stains. Moreover, many of the granules
      had central vacuoles with strong myeloperoxidase positivity at the periphery. The
      bone marrow had a much higher positivity for these mega-granules as compared to
      the peripheral blood. On remission, these granules were no longer seen. To the
      best of the authors' knowledge, this pattern of staining has not been previously
      reported in the literature.

PMID- 15202160
TI  - Characterization of bone marrow stromal abnormalities in a patient with
      constitutional trisomy 8 mosaicism and myelodysplastic syndrome.
AB  - The development of myeloid leukemias and myelodysplastic syndrome (MDS) is common
      in children with trisomy 8 mosaicism. However, the mechanisms by which the
      presence of an additional chromosome 8 translates to an increased risk of
      leukemias and MDS is currently unknown. The authors describe the analysis of
      stromal cells from a pediatric MDS patient with constitutional trisomy 8. Patient
      and control marrow stromal cells were analyzed for alterations in cytokine
      production. Clonogenic assays were used to examine stromal support for
      hematopoiesis. The interplay between leukemia cells and stroma was studied by co
      culture experiments. The results indicate that stromal cell function in this
      patient was seriously altered in favor of progenitor cell proliferation and
      expansion. This indicates that constitutional trisomy 8 in stromal cells plays a
      critical role in the pathogenesis of MDS.

PMID- 15202161
TI  - Parvovirus B19 infection associated with severe aplastic anemia in an
      immunocompetent patient.
AB  - Human parvovirus B19 (PVB19) infection may cause mild pancytopenia characterized
      by transient and spontaneous recovery in healthy subjects. Severe aplastic anemia
      associated with PVB19 infection in patients without an underlying disease has
      been described in a number of reports. Here, a previous healthy, 10-year-old girl
      with severe aplastic anemia associated with PVB19 infection is described. The
      patient underwent bone marrow transplantation from her HLA-identical sibling
      resulting in complete recovery. PVB19 infection should be considered as one of
      the causes of aplastic anemia in patients without an underlying disease.

PMID- 15202162
TI  - Single-dose oral granisetron versus multidose intravenous ondansetron for
      moderately emetogenic cyclophosphamide-based chemotherapy in pediatric
      outpatients with acute lymphoblastic leukemia.
AB  - This prospective study was designed to compare the efficacy of ondansetron with
      granisetron in terms of complete emesis control and time spent in an ambulatory
      care setting in children with acute lymphoblastic leukemia (ALL) undergoing
      moderately emetogenic cyclophosphamide-based chemotherapy. The costs for both
      treatments are also examined. A total of 33 children (mean age: 7.8 +/- 4.9 year)
      were studied during 66 chemotherapy cycles. Analysis was based on 33 courses of a
      single oral dose of granisetron and 33 courses of ondansetron incorporating 2
      intravenous doses of ondansetron 0.15 mg/kg followed by 1 dose of the same dosage
      orally. There was no significant difference between the 2 treatments in terms of
      overall efficacy (McNemar's chi-square test). Twenty of 33 patients (60.6%)
      receiving granisetron and 15 of 33 patients (45.5%) receiving ondansetron
      experienced no emesis 24 h after chemotherapy (p = .227). Boys experienced
      greater rates of vomiting than did girls despite antiemetic treatment; however,
      no apparent reason for the gender discrepancy was noted. Both antiemetic regimens
      have similar antiemetic efficacy for treating the moderately emetogenic effects
      associated with cyclophosphamide-based chemotherapy. It is possible that the
      granisetron regimen may be preferable because it is simpler to administer and
      more cost-effective.

PMID- 15202163
TI  - Childhood cancer in developing countries.
AB  - The problem of childhood cancer cannot be evaluated separately from developmental
      levels and states of health of the countries. Rapid increase in population,
      poverty, poor hygiene, lack of education, and multitude health problems impede
      the development of pediatric oncology and success of the management of childhood
      cancer in developing countries. More than 85% pediatric cancer cases occur in
      developing countries that use less than 5% of world resources. The rate will
      exceed 90% in the next two decades, due to the increase of youth population in
      favor of developing countries. Incidence rates, pathology, and clinical
      characteristics of various cancers seem different in developing and developed
      countries. Different environments, life styles, dietary habits, and hygienic
      conditions are the main reasons for those differences. Unprecedented changes in
      diagnostic techniques, treatment methods and supportive care have occurred during
      the last decades. Consequently, management has improved and the mortality rates
      have decreased. Most of the children with cancer living in developing countries
      could not profit from those advances in pediatric oncology because of the cost.

PMID- 15202164
TI  - Effect of factor VIIIc levels in pediatric stroke patients.
AB  - Twenty consecutive patients with ischemic stroke confirmed by magnetic resonance
      imaging and 40 healthy age-matched controls were enrolled in the study. Thirteen
      of the patients had an underlying disease and/or risk factors. Infection was the
      most common underlying factor (4 patients). Four patients had heterozygote FVL
      and 3 patients showed heterozygosity for PT 20210A. A weak positive association
      between FV1691A and high FVIIIc levels (r = -.110) was determined. Comparison of
      the prevalence of high FVIIIc levels in patients and healthy subjects with and
      without FVL/PT 20210 indicated that high FVIII levels are an independent risk
      factor.

PMID- 15202165
TI  - Double allogeneic peripheral blood stem cell transplantation in a 9-year-old
      patient with relapsed acute lymphoblastic leukemia: case report.
AB  - A 9-year-old female patient with relapsed leukemia that was refractory to
      conventional reinduction chemotherapy was successfully treated with double
      allogeneic peripheral blood stem cell transplantation. The conditioning regimen
      for the first transplantation consisted of busulfan, etoposide, and melphalan,
      and that for the second transplantation was total body irradiation and thiotepa.
      Neither severe regimen-related toxicity nor graft-versus-host disease was
      observed. The patient is in complete remission without major complications for 5
      years. Double transplantation should be considered as one of the possible
      treatments for refractory acute lymphoblastic leukemia.

PMID- 15202166
TI  - Secondary hemophagocytic lymphohistiocytosis induced by malaria infection in a
      child with Langerhans cell histiocytosis.
AB  - Since the first description of infection-associated hemophagocytosis (IAHS), the
      list of precipitating infectious agents causing hemophagocytic syndrome has
      grown. A lymphohistiocytic proliferation with hemophagocytosis may develop as a
      result of macrophage activation, viral or bacterial infection, parasitic
      infestations, or malignancy. The authors report on a 3-year-old boy with
      Langerhans cell histiocytosis (LCH), who developed IAHS during malaria infection.
      Hemophagocytic syndromes may complicate the course of LCH and cause diagnostics
      problems. Malaria is one of many infections that can precipitate secondary
      hemophagocytic lymphohistiocytosis.

PMID- 15202167
TI  - A fetal case of transient abnormal myelopoiesis with severe liver failure in Down
      syndrome: prognostic value of serum markers.
AB  - The authors recently encountered a lethal case of Down syndrome with transient
      abnormal myelopoiesis (TAM). Although the peripheral white blood cell count and
      blast cells had improved without specific treatment, the patient died of severe
      coagulopathy due to liver fibrosis when he was 5 years old. The prognosis of TAM
      with liver fibrosis was poor. The patient had high levels of N-terminal peptide
      of III procollagen, type IV collagen, and hyaluronic acid. These serum makers are
      noninvasive indicators of liver fibrosis and may be useful as prognostic
      indicators of TAM in Down syndrome.

PMID- 15202169
TI  - Executive pay hide-and-seek. With the IRS poised to inspect compensation at tax
      exempt not-for-profits, perks and benefits for hospital executives likely to get
      much closer attention.
AB  - Not-for-profits will have someone else looking over their shoulder soon--the IRS.
      The new IRS commissioner overseeing tax-exempt organizations says his unit will
      look at executive compensation, and execs making more than $1 million are sure to
      get scrutiny. Healthcare tax lawyer Todd Greenwalt, left, says it's likely the
      IRS will use the data it gleans to create best-practices guidance.

PMID- 15202168
TI  - The prognosis and survival of childhood acute lymphoblastic leukemia with central
      nervous system relapse.
AB  - Central nervous system (CNS) relapse in childhood acute lymphoblastic leukemia
      (ALL) has been overcome by sensitive therapeutic approachs. This study was
      planned to present the development of CNS relapse and survival in newly diagnosed
      190 ALL patients whose cases were followed in the authors' unit between March
      1991 and May 2002. St. Jude Study XI protocol was given to the patients who
      applied between March 1991 and March 1997 (group A) (n = 122), and St. Jude Study
      XIII protocol was given to the patients who applied between March 1997 and May
      2002 (group B) (n = 68). The patients having isolated CNS relapse in group A
      received craniospinal irradiation (CSI) median 3.5 months after CNS relapse
      (range 2-6 months), a short time after reinduction, and 2 cures of consolidation.
      In group B, patients having isolated CNS relapse received IT once a month and a
      high-dose methotrexate treatment once every 8 weeks and 3 or 4, cures later
      therapy CSI median 7 months after CNS relapse (range 6-8 months) was given. When
      the overall survival rates of the 2 groups are compared, a statistically
      significant higher survival rate at 5 years was determined in group B than in
      group A (respectively, 82.3%, 58.4%) (p < .05). When subgroups of the patients
      (that is, those with no relapse, isolated CNS or BM relapse, or CNS + BM relapse)
      were compared in both groups, it was found that survival was much higher for the
      ones with no relapse and with isolated CNS relapse (respectively, 87.9%, 72.7%)
      compared to isolated BM or CNS + BM relapse groups (respectively, 10%, 13.3%) (p
      < .05). In a conclusion, for children with acute lymphoblastic leukemia and an
      isolated CNS relapse, with delayed definitive craniospinal irradiation allowing
      more intensive systemic and intrathecal chemotherapy results in better overall
      survival than has been previously reported.

PMID- 15202170
TI  - Slipping through the cracks. Outsourcing staff doesn't mean hospitals are off the
      hook on background checks.

PMID- 15202171
TI  - Stapling standards. Group issues bariatric best-practice guidelines.

PMID- 15202172
TI  - Shifting funds to cities. Plan to redirect bioterror funds upsets states.

PMID- 15202173
TI  - Stating their case. Debate shows details of candidates' health agendas.

PMID- 15202174
TI  - Shedding some light. CMS clarifies aspects of EMTALA.

PMID- 15202175
TI  - A costly conflict. Hospitals should take a stand against dirty deals with drug,
      device firms.

PMID- 15202176
TI  - Core leadership concerns. We must change the way we train the next generation of
      healthcare managers.

PMID- 15202177
TI  - The chairman's now in charge. Some hospital boards decide that their chairman is
      the best choice to become CEO. But governance experts warn of pitfalls.

PMID- 15202178
TI  - Patient tower. After a nearly 20-year struggle--involving financial, political,
      technical and legal obstacles, to name a few--a New Jersey medical center finally
      opens.

PMID- 15202179
TI  - Harmony in healthcare. HFMA's Annual National Institute tunes into members'
      capital needs.

PMID- 15202180
TI  - Talking points.

PMID- 15202181
TI  - TBI patients benefit from vocational rehab.

PMID- 15202182
TI  - The secret garden.

PMID- 15202183
TI  - The hot and the cold of it.

PMID- 15202184
TI  - Beyond musculoskeletal injury: two dimensional modalities.

PMID- 15202185
TI  - State of the art.
AB  - Many falls and injuries related to falls can be prevented with existing knowledge
      and technology. But effective fall prevention will require the collaborative
      efforts of many organizations as well as changes in the behavior of older adults
      and providers, and systematic changes in organizations. Many effective
      interventions currently exist, but improved access, additional resources, and
      coordination and commitment across systems are needed. In summary, we know how to
      prevent falls and reduce injuries, using proven intervention strategies aimed at
      both low-risk and high-risk older adults. There is a wide spectrum of screening
      and assessment tools available and effective intervention practices. The
      challenge now is to put into practice throughout California the state-of-the art
      knowledge that has already been compiled through innovative programs and rigorous
      research.

PMID- 15202186
TI  - Taking the load off.

PMID- 15202187
TI  - Eye of the beholder.

PMID- 15202188
TI  - Pushing for results.

PMID- 15202189
TI  - Stopping the repetition.

PMID- 15202190
TI  - Ortho opportunities. There are multiple venue options for orthopedic services.

PMID- 15202191
TI  - Voluntary innovation. CCI is a big step in fee-for-service Medicare.

PMID- 15202192
TI  - Health care must be transformed.

PMID- 15202193
TI  - The changing landscape of Medicare secondary payer rules.

PMID- 15202194
TI  - Quo vadis? Practice management--are you going where you want?

PMID- 15202195
TI  - Open-source software. What it means for the medical community.

PMID- 15202196
TI  - The Zen of coaching free throws and physician documentation.

PMID- 15202197
TI  - Governance forms the framework for a group's decisions.

PMID- 15202198
TI  - The employee handbook. A 'go-to' guide for your practice.

PMID- 15202199
TI  - By the book. Lessons learned from developing a physician-owners' manual.

PMID- 15202200
TI  - Stark II, phase II. What it means for physician compensation.
AB  - The author reviews some of the new physician self-referral (Stark) rule's key
      implications for medical group compensation plans. In Phase II of the Stark law,
      the Centers for Medicare & Medicaid Services clarified certain provisions and
      addressed others not dealt with in Phase I. The changes have important, generally
      positive implications for physician compensation in medical groups and elsewhere.
      The rules codify common-sense ideas that physicians can receive direct
      compensation for their labor and for the financial success of their group
      practices.

PMID- 15202201
TI  - Meeting management. Get the most from your gatherings.

PMID- 15202203
TI  - The ol' switcheroo. Using knowledge from other industries.
AB  - As in any industry, the supply chan is vital to the success of overall business
      operations. Because the cost of supplies in health care is second only to labor,
      hospitals are naturally concerned with running operations efficiently. However,
      disparities in funding, locale, staffing and a variety of other factors prevent
      every hospital and system from using the same methods. The common thread is that
      hospitals are always seeking better ways to improve business, or--as one
      materials manager recently said--at least they should be. And although not every
      tactic is right for every business, an idea needs to be examined before it can be
      dismissed. In a three-part series, MMHC takes a look at supply chain practices
      that are not necessarily industrywide trends, but are pieces of overall
      strategies that have worked for some hospitals. In the first installment, the
      supply chain is examined from the an outsider's point of view as individuals
      who've had successful careers elsewhere move into health care to provide a fresh
      perspective and solutions to common problems.

PMID- 15202202
TI  - The ABCs of DIMS.
AB  - Document imaging and management The authors urge practices that haven't fully
      implemented a complete electronic medical record or computerized patient record
      system to consider some sort of document imaging and management system (DIMS).

PMID- 15202204
TI  - Waste management watch.

PMID- 15202205
TI  - Room for tracking. RFID technology finds the way.

PMID- 15202206
TI  - Stats. Reprocessing growth.

PMID- 15202207
TI  - Are you aggressively addressing ED crowding? JCAHO says you must.

PMID- 15202208
TI  - Prevent infant abductions with FMEA processes.

PMID- 15202209
TI  - Complying with JCAHO's read-back requirement.

PMID- 15202210
TI  - Key words, eye contact boost satisfaction scores.

PMID- 15202211
TI  - Program targets patient, physician satisfaction.

PMID- 15202212
TI  - Telling the patient satisfaction story.

PMID- 15202213
TI  - The science of compliance. CMS is enlisting hospitals for pilot program to help
      determine why some billing-compliance programs work while others don't.
AB  - If you've ever wondered if compliance programs really work, you're not alone; the
      CMS is trying to come up with an answer. A pilot program will study up to a dozen
      programs to assess their effectiveness and gather best-practices data. The plan
      is already winning praise. "The burning question is which components of
      compliance programs are the most effective," says Roy Snell, left, of the Health
      Care Compliance Association.

PMID- 15202214
TI  - Safe zone. Medicaid will escape cuts for now, observers say.

PMID- 15202215
TI  - Now delivering. Cardinal flies into new territory with Alaris deal.

PMID- 15202216
TI  - Final four. Two schools picked for pilot have ties to NCHL board.

PMID- 15202217
TI  - Doc: law is unCONstitutional Lawsuit says Georgia statute promotes monopolies.

PMID- 15202218
TI  - Systematic healing. Report says Caritas Christi 'on the threshold of crisis'.

PMID- 15202219
TI  - Med malaise. Backers of strict malpractice liability limits ignore real solutions
      to insurance crisis.

PMID- 15202220
TI  - A rural success story. Medicare 'Flex' program helps ensure healthcare for
      communities in need.

PMID- 15202221
TI  - Critically acclaimed. Critical-access designation, other federal programs are
      helping rural hospitals improve and expand their services, not just survive.

PMID- 15202222
TI  - How hospitals measure up. Annual 100 top hospitals list from Solucient highlights
      facilities that know how to improve their quality, profitability and service.

PMID- 15202223
TI  - Questions of leadership. Survey of CIOs places lack of high-level planning,
      support among the primary reasons behind failure of IT projects.

PMID- 15202224
TI  - [Simulation of effects to tropospheric ozone over South East Asia and south China
      from biomass burning].
AB  - The ozone variation led by biomass burning in Spring 2000 over South East Asia
      and South of China region was simulated with a combined regional climate model
      and atomospheric chemical model. It was found that ozone was added by the
      pollutant of biomass burning both over source area and down wind area. The ozone
      of lower troposphere was affected by the pollutant over source area, so did the
      ozone in middle troposphere over down wind area. An ozone increase of 9.0-12.0 x
      10(-2) g/m2 over South of China was found. The range of ozone increase between
      1000-900 hPa over source area was more than 36 x 10(-9) m3/m3.

PMID- 15202225
TI  - [Analyses of the correlation between the fluxes of CO2 and the distribution of C
      & N in grassland soils].
AB  - Using static dark enclosed chamber technique, the emissions of CO2 from typical
      temperate grasslands such as Stipa baicalensis, Leymus chinensis, Stipa grandis
      and Stipa krylovii in Xilin River Basin of Inner Mongolia were measured. And the
      contents of organic carbon and total nitrogen in different soil layers were also
      studied to analyze the correlation between the emissions of CO2 and the contents
      of C & N. The results showed that the emissions of CO2 from the 4 grassland
      communities were significantly positively correlated with soil organic carbon and
      total nitrogen in different layers of grassland soils, and the correlation
      coefficients were almost all above 0.8. That meant the flux of CO2 is severely
      influenced by the contents of soil organic carbon and total nitrogen when
      environmental factors were similar. The decreases of soil organic carbon and
      total nitrogen with the depth into soils (more than 70% of the contents
      centralizes above 0-30 cm layer) showed that most of them came from the
      decomposition of organic matter on the earth's surface. In the 0-100 cm layer of
      grassland soils, the decreases of amount of soil organic carbon and total
      nitrogen from Stipa baicalensis, Stipa grandis and Leymus chinensis grasslands to
      Stipa krylovii grassland orderly showed that the impacts of precipitation,
      evaporation and dryness index on the distribution of soil organic carbon and
      total nitrogen were important.

PMID- 15202226
TI  - [The research on the law of greenhouse gases emission from warm temperate forest
      soils in Beijing region].
AB  - In situ measurements by closed chamber technique were done to investigate the law
      of greenhouse gases (Methane, carbon dioxide and Nitrous Oxide) fluxes emission
      from different warm temperate forest soils (Broad-leaved forest, Form. Quercus
      liaotungensis and Form. Pinus tabulae) of Dongling mountain in Beijing region.
      Results show that the all representative types forest soils were sink of CH4 and
      source of CO2 and N2O. Different type of vegetables and soils result of different
      fluxes range of the main greenhouse gases. The fluxes range of CH4, CO2 and N2O
      emission from the three types forest soils were: 42-103 micrograms/(m2.h), 15-344
      mg/(m2.h) and -61-101 micrograms/(m2.h); 13-182 micrograms CH4/m2.h, 23-380
      mg/(m2.h) and -15-183 micrograms/(m2.h); 12-128 ug CH4/m2.h, 15-292 mg/(m2.h) and
      -94-153 micrograms/(m2.h); respectively. The mean fluxes of CH4, CO2 and N2O
      emission from the three types forest soils during the observation period were: 
      66 micrograms/(m2.h), 145 mg/(m2.h) and 22 micrograms/(m2.h); -67
      micrograms/(m2.h), 146 mg/(m2.h) and 45 micrograms/(m2.h); -79 micrograms/(m2.h),
      150 mg/(m2.h) and 31 micrograms/(m2.h), respectively. The total amounts of CH4
      CO2 and N2O emission from the three types forest soils were -5.34 kg/(hm2.a),
      13.9 Mg/(hm2.a) and 2.58 kg/(hm2.a); -6.20 kg/(hm2.a), 14.07 Mg/(hm2.a) and 4.19
      kg/(hm2.a); -6.85 kg/(hm2.a), 15.71 Mg/(hm2.a) and 4.30 kg/(hm2.a), respectively.

PMID- 15202227
TI  - [Experimental study of catalytic reduction of SO2 on CeO2-La2O3/gamma-Al2O3 rare
      earth mixed compounds].
AB  - Addition of rare earth oxide CeO2 with variable valences to La2O3 formed a
      mixture of rare earth oxides. This mixture can be used as the catalyst for the
      reduction of SO2 by CO. In a fixed-bed flow reactor, experimental were
      investigated for studying the activation process of this catalyst and effect
      factors such as temperature and concentration ratio of reactant on the activation
      reaction under the following conditions: composition of the gas mixture SO2:CO =
      1:3, balancing with N2 and feed flow rate 1000 mL/min. The phase structure
      changes of this catalyst were expressed with XRD and XPS. The results
      demonstrated that the activation temperature of CeO2-La2O3/gamma-Al2O3 is 50-100
      degrees C lower than that of a single component La2O3/gamma-Al2O3 or CeO2/gamma
      Al2O3, and the mixture of rare earth oxides has higher activity on catalytic
      reduction of SO2 by CO. It's most likely that the result reveals on the synergism
      between CeO2 and La2O3.

PMID- 15202228
TI  - [Study on odors treatment by the combination of bacteria and fungi].
AB  - The aim of this study was to establish a novel combined-bioreactor for the
      treatment of odors. The combined-bioreactor consists of two zones, one bacteria
      zone and one fungi zone. An experiment for the odor treatment was carried out,
      and the removal efficiency of acetic acid, ammonia, styrene, hydrogen sulfide,
      ethyl mercaptan and diethylsulfide which were main material in this experimental
      odor were 97.1%, 96.7%, 96.6%, 92.1%, 78% and 83%, respectively. The experimental
      results clearly showed that bacteria and fungi in the combined-bioreactor had a
      synergistic reaction, therefore, the hydrophilic and hydrophobic compounds can be
      efficiently removed in this combined-bioreactor. The monitor results indicated
      that the removals of the compounds with varying water solubility were different
      in the two zones of the bioreactor.

PMID- 15202229
TI  - [The material character of sand dust and analysis on the cause of formation of
      the sand-dust storm in northeast district in spring of 2002].
AB  - The paper analyzed the particle distribution, pollen combination of sand dust
      storm in northeast district in spring, 2002. It was found that there is abundant
      pollen, based on pollen combination sand source at new angle can be analyzed, and
      the distribution laws of the bowling sand and sand dust storm in season, in
      yearly, in geological periods and mankind historic periods can be explained. The
      blowing sand and sand dust storm often appeared in geological period and mankind
      historic period in northeast district, and mainly appeared in winter and in
      spring and they dropped fluctuationally in fifty years. The frequency of the sand
      dust storm increased since 2000. The frequency of blowing sand and sand dust
      storm was controlled by the strength of the monsoon wind in winter. Which the
      Enino and anti-Enino alternately occurs was influenced by the periodic change of
      the strength of monsoon wind in winter in Eastern Asia. The cold and dry climate
      combination in winter and spring was favorable of the occurrence of sand dust
      weather. The frequency of the sand dust weather will not obviously increase in
      several years.

PMID- 15202230
TI  - [A virtual water analysis for agricultural production and food security].
AB  - Water resource demand is increasing with the population growth and economic
      development. Water resource problem for agriculture and food security have become
      one of the global focal points because of water resource scarcity. The concept of
      virtual water is useful to analyze and impair this problem. In this paper,
      virtual water implication was described, and international study progress about
      it was briefly reviewed. Furthermore, China's agricultural water scarcity and
      food security were analyzed. According to the grain import prediction and
      agricultural production conditions of China, the virtual water equivalents of
      China in 2010 and 2020 were evaluated, which were 88 x 10(9) m3 in 2010 and 95 x
      10(9) m3 in 2020. With the function of virtual water to agricultural water
      stress, virtual water strategy was suggested to relieve agricultural production
      pressure from water resource and meet growing food demand as well as to promote
      water resource sustainability in China.

PMID- 15202231
TI  - [Research on the relationship between water and eco-environment construction in
      Loess Hilly and Gully regions].
AB  - Water is an important factor for eco-environmental construction. Eco
      environmental construction has a great impact on water. There is a circular
      correlation between eco-environmental construction and water. Water resource is
      lack and loss of soil and water is serious in the loess hilly and gully regions.
      The regions are the main regions of eco-environmental construction, especially of
      vegetation restoration and rehabilitation. It is important studying the
      relationship between water and eco-environmental construction in the regions.
      According to the data in Yanhe River watershed, some conclusion are demonstrated:
      1. More water resource was demanded when population was increasing rapidly and
      economy was developing fleetly. Water for eco-environmental construction was
      threatened directly. 2. Eco-environmental construction, especially the built
      vegetation decreased the runoff. The dried soil layers have appeared in some
      places. 3. Shortage of water resource limited the farther tree and grass planting
      and brought on some negative impacts. Small aged trees have appeared in some
      places. The eco-environmental benefits of the built vegetation have been
      influenced. On the basis of relationship between water and eco-environmental
      construction, some advice for sustainable use of water resource, sustainable
      construction of eco-environment and sustainable development of society and
      economy was given.

PMID- 15202232
TI  - [Degradation mechanism of ozonation of endocrine disruptor (alachlor) in drinking
      water].
AB  - In this study, the degradation mechanism of an endocrine disruptor, alachlor, by
      ozonation was investigated. HPLC, GC, IC and UV were used to follow the
      intermediate and ultimate oxidation products produced in the ozonation of
      alachlor. The results showed that 94% alachlor was degraded after being directly
      ozonated for 30 min at acidic condition. But alachlor could not be completely
      degraded to CO2 and H2O, which was 35 percentage of TOC removal after being
      ozonated for 180 min. Several intermediate oxidation products were observed by UV
      and HPLC. Organic acids of small molecular were produced in the ozonation,
      resulting in the decreasing of pH from 5.96 to 3.94. The broken of alachlor
      structure was verified by the creation of inorganic ions in the ozonation.

PMID- 15202233
TI  - [Preliminary health risk assessment of heavy metals in drinking waters in
      Beijing].
AB  - Concentrations distribution of the Cu, Hg, Cd, As in drinking water in the 8 city
      districts and 10 counties in Beijing was studied based on a total of 120 random
      samples. Health risks associated with 4 metals in drinking water were assessed
      using USEPA health risk assessment model. The results showed that the
      concentrations of the heavy metals in drinking water in Beijing ranged from 0.81
      to 6.96 micrograms.L-1 for Cu, 0.34-0.82 microgram.L-1 for Cd, 0.10-0.74
      microgram.L-1 for Hg and 0.19-3.02 micrograms.L-1 for As. Among the health risks
      caused by the carcinogens in drinking water, the largest risk associated with As
      should be in Tongzhou County (2.0 x 10(-5).a-1) and that with Cd should be in
      Changping County (2.3 x 10(-6).a-1), while both were significantly lower than the
      maximum allowance levels recommended by ICRP(5 x 10(-5).a-1). Among the non
      carcinogenic risks in drinking water, the largest risk was the risk associated
      with Hg, followed by Cu. The non-carcinogenic risks levels ranged from 10(-8) to
      10(-9), much lower than the maximum allowance levels recommended by ICRP.

PMID- 15202234
TI  - [Investigation of bromate, haloacetic acids and perchlorate in Beijing's drinking
      water].
AB  - Disinfection by-products and perchlorate in the raw water and finished water of
      Beijing's a drinking water plants were investigated. The results indicated that
      there was little bromate in the drinking water. Five haloacetic acids (HAAs) were
      found in the water. The concentrations of the sum of the five HAAs were ranged
      from 42.1 micrograms/L to 149.5 micrograms/L. In the HAAs, the chlorine
      containing HAAs accounted for more than 90% of the total HAAs. In the five HAAs,
      the concentration order of the HAAs were trichloroacetic acid > dichloroacetic
      acid > bromochloroacetic acid > dibromoacetic acid > bromodichloroacetic acid.
      The HAAs in Beijing's drinking water were much influenced by the variation of
      season. They had the highest concentrations in September and lowest concentration
      in April, respectively. For perchlorate in Beijing's drinking water, it was
      greatly influenced by the groundwater. Its concentrations were between 0.1-6.8
      micrograms/L in the finished drinking water. It had peak value in November and
      minimum value in July, respectively.

PMID- 15202235
TI  - [Influence of terrestrial nutrient input on biogenic production of
      dimethylsulfide in Quingdao coastal water].
AB  - Nearshore water is one of the most important emission area of
      dimethylsulfide(DMS), at the same time, nearshore water is highly disturbed by
      human activities. The objectives of this study were to investigate the DMS
      concentration of coastal water and try to analyze the factors governing its
      distribution. Four situ investigations were made in the coastal water of Qingdao,
      which is located at west coast of Yellow Sea. DMS concentrations of surface water
      showed a clear seasonal variation with peak values during the summer. Spatial and
      temporal distributions of DMS in three studied areas(havey polluted area, light
      polluted area, and clean area) were irregular, but when the concentrations of DMS
      were moralized to chlorophyll a as a measure of phytoplankton biomass, there was
      significant difference of DMS/Chl a among the three areas, with the nutrient
      concentration improved, the DMS/Chl a decreased. And there was the positive
      relation between transparency and DMS/Chl a, especially in summer.

PMID- 15202236
TI  - [Speciation and distribution characters of rare earth elements in the Baotou
      Section of the Yellow River].
AB  - As a whole of water column, suspended matter and surface sediment in the
      mainstream and the branch taking up industry wastewater, speciation and
      distribution characters of rare earth elements (REEs) were investigated
      systemically in the Baotou section of the Yellow River. This study shows that
      rare earth elements in the mainstream of the Baotou section of the Yellow River
      mainly exist in suspended particles, and the dissolved contents are in extremely
      minute quantities. REEs mainly exist in dissolved particles in the branch taking
      up industry wastewater, and suspended sigma REE and dissolved sigma REE are
      obviously higher than those in the mainstream. The change of sigma REE of
      dissolved particles in water phase along the Baotou section of the Yellow River
      is very similar to that of sigma REE of suspended particles, and consistent along
      the main river, it is that sigma REE increase appreciably from the control
      profile to the keystone discharged section, come to a head in the D site and
      reduce in the E site. This distribution pattern indicates pile industry
      wastewater of Baotou to rare earth elements in the mainstream of the Yellow
      River, particularly LREE. The REE distribution in the mainstream of the Baotou
      section of the Yellow River is the same, with LREE enrichment and Eu depletion.
      But LREE origin of D site is different from the other sites by excursion of LREE
      distribution curve and other geochemical parameters, they are origin of industry
      wastewater piled, otherwise the other four sites are origin of loess altiplano.
      And HREE are origin of loess altiplano in all the sites. The speciation
      characteristics of REE in the sediments and suspended matter are quite similar
      with the amount in as follows: residual >> bound to carbonates, bound to Fe-Mn
      oxides > bound to organic matter >> exchangeable. REEs exchangeable in surface
      sediment and suspended matter in the branch taking up industry wastewater are
      higher than those in the mainstream, it confirms that REEs in the mainstream
      mainly exist in suspended particles, and mainly exist in dissolved particles in
      the branch.

PMID- 15202237
TI  - [Preparation of polyaluminum silicate chloride (PASC) from
      tetraethylorthosilicate (TEOS) and its physicochemical characteristics].
AB  - A new type of polyaluminum silicate chloride [PASC(A)] was prepared by employing
      tetraethylorthosilicate (TEOS) as silicon source. By comparing PASC(A) with the
      conventional product [PASC(B)], the effects of B value and Si/Al molar ratio on
      the pH value and the Zeta potential of PASC(A) were investigated. The influence
      of the incorporation of silicon into PASC on the molecular structure and
      aluminium species was also studied by acidification method and 27Al NMR
      spectroscopy. The results show that the PASC(A) has higher polymerization degree,
      narrow distribution of molecular weight and symmetrical distribution of aluminium
      and silicon in PASC molecule. It is more difficult to be acidified, and moreover,
      it can reduce the loss of Al13 species. All the above advantages of PASC(A) are
      due to its special synthesis method.

PMID- 15202238
TI  - [Formation of an acetic-acid type microbial metabolism pathway and its stability
      during the course of sulfate-reduction].
AB  - Continuous-flow experiment was conducted in an acidogenic sulfate-reducing
      reactor supplied with molasses as sole carbon resource and sulfate sodium as
      electron acceptor. The composition of Volatile fat acid(VFA) in terminal liquid
      products, the distribution of acetic acid, the existence of microbial populations
      and the interspecific relationship between sulfate-reducing bacteria (SRB) and
      acidogenic bacteria (AB) were investigated in different experimental stages when
      sulfate removal rate and gas production maintained at a relatively stable status.
      The experimental results showed that an acetic-acid type microbial metabolism
      pathway was formed based on the fact that the proportion of acetic acid in
      terminal liquid products was as high as 50% to 82%. It was also explained the
      formation of acetic-acid type microbial metabolism pathway was resulted from
      acetic acid accumulation in the terminal liquid products, which was subjected to
      the bio-chain cooperation relationship between populations of SRB and AB, and the
      incomplete-oxidation of organic substance in acidogenic-phase reactor of two
      phase anaerobic treatment process. It was also presented that the formation of
      acetic-acid type microbial metabolism pathway depended on the capability of
      acetic-acid utilized-SRB (ASRB) population competing against other populations
      and its ability of acetic acid consumption. Furthermore, this kind of metabolism
      pathway could offer suitable carbon resource for methane producing reactor in the
      two-phase anaerobic treatment process, and has significant effect on the sulfate
      removal rate of the whole treatment system and its running stability.

PMID- 15202239
TI  - [Research on desulfurization using coke-oven wastewater with pulsed corona
      discharge].
AB  - A recent investigation into the application of pulsed corona discharge process,
      in which simultaneous SO2 removal from simulated flue gas and coke-oven
      wastewater degradation, was conducted at Wuhan Integrated Steel Plant. The
      outcome indicates that coke-oven wastewater had good desulfurization ability, and
      SO2 removal efficiency increased gradually as the simulated flue gas temperature
      increasing in the temperature range used during the experiment. When the flow of
      simulated flue gas was 428 m3/h, the temperature of simulated flue gas was 65
      degrees C and coke-oven wastewater flow was 107 L/h, the desulfurization rate was
      85%. Introducing pulsed corona discharge to the reactor enhanced the removal
      efficiencies of SO2, the desulfurization rate increased to 90% when high voltage
      was 52kV. When SO2 was removed from simulated flue gas by pulsed corona
      discharge, oil and phenols content in coke-oven wastewater decreased 39.26% and
      68.75% respectively, and 99.98% content of cyanide was degraded, which is of
      important value in solving the inactivation problem of aerobic bacteria in
      biological treatment of coke-oven wastewater.

PMID- 15202240
TI  - [Decolorization conditions for reactive brilliant blue KN-R by three fungi].
AB  - Seventeen strains with wideranging decolorization ability were screened from
      contaminated soil and were applied on the decoloring of dye wastewater. Three
      strains were selected due to their high decolorization capacity on azo dyes,
      anthraquinone dyes and triphenylmethane dyes. The three strains were named as
      Strain I, Strain II, Strain III. This three superior strains were identified as
      penicillium link (Strain I & strain II) and Cephalosporium corda (strain III).
      Using aqueous samples, the influences of several factors on decolorization were
      reported, such as pH, carbon source, temperature and so on. And then applying of
      these strains for treatment of actual wastewater have also been done. The results
      showed that the optimal pH, temperature and carbon source were 5-9, 18-37 degrees
      C and 0.5% respectively, under those conditions the decolorization removal rate
      was 70%. And these fungi have a good prospect for the treatment of dye
      wastewater.

PMID- 15202241
TI  - [Influence of effluent discharging modes on membrane fouling in a submerged
      membrane bioreactor].
AB  - The influence of effluent discharging modes on membrane fouling in a submerged
      membrane bioreactor was evaluated, and the feasibility of the characterization of
      membrane fouling using Flundlich isothermal adsorption equation was also explored
      in this paper. Under the same operation conditions, the adsorption equations of
      three discharging modes of vacuum pump drawing combined with air back-blowing,
      vacuum pump drawing and suck pump drawing were 2.59ce1/0.957, 7.415ce1/1.369 and
      7.10ce1/1.015. Experiment results showed that the effluent-discharging mode had a
      significant influence on membrane fouling in the submerged membrane bioreactor.
      Among three discharging modes, the membrane fouling degree in the mode of vacuum
      pump drawing combined with air back-blowing was the lightest. The experimental
      results also indicated that Flundlich isothermal adsorption equation is
      applicable in the characterization of membrane fouling.

PMID- 15202242
TI  - [Treatment of wastewater containing Cr(VI) by LDH synthesizing in situ].
AB  - The objective of this work was to investigate the efficiency and factors
      impacting of removal Cr(VI) from wastewater by layer double hydroxide
      synthesizing in situ. Principle of the method may be described as follow: Mg2+
      and Al3+ hydrolysis and forms Mg/Al-LDH by adding Mg2+, Al3+ and NaOH into
      wastewater containing Cr(VI), Cr(VI) anions are selectively intercalated into
      interlayer of LDH to balance positive structural charge. While Mg2+ and Al3+ co
      precipitates and forms LDH, the Cr(VI) in wastewater is removal by settle of LDH
      synthesizing in situ, which are confirmed by analysis of X-ray diffraction on
      settle and chemical analysis on aqueous. The results indicate that factors of
      impacting on efficiency of removal Cr(VI) include in amount of adding Mg2+ and
      Al3+, Mg/Al ratio, pH and concentration of Cr(VI) in wastewater. The maximal
      removal efficiency of Cr(VI) can be reached when pH values are between 8.5 and 9,
      and Mg/Al ratios are between 1:1 and 2:1, meanwhile, Mg and Al added can be taken
      good use of. This technology has present extraordinary efficiency of wastewater
      treatment.

PMID- 15202243
TI  - [Inhibition of aromatics on ammonia-oxidizing activity of sediment].
AB  - The inhibition of 24 aromatics on ammonia-oxidizing activity of nitrifying
      bacteria in sediment was measured. The effects of the kind, number and position
      of substituted groups on ammonia-oxidizing activity of nitrifying bacteria were
      discussed. The inhibition of mono-substituted benzenes on ammonia-oxidizing
      activity of nitrifying bacteria were in order of -OH > -NO2 > -NH2 > -Cl > -CH3 >
      -H. The position of substituted groups of di-substituted benzenes also affected
      the inhibition, and the inhibitions of dimethylbenzenes(xylene) were in order of
      meta-> ortho-> para-. The increase in number of substituted group on benzene-ring
      enhanced the inhibition of aromatics studied in this study on nitrifying
      bacteria. There was a linear relationship between inhibition (IC50, mumol.L-1) of
      aromatics on ammonia-oxidizing activity and total electronegativity (sigma E) of
      aromatics: lgIC50 = 14.72 - 0.91 sigma E.

PMID- 15202244
TI  - [Movement and transformation of nitrate in soil by non-uniform electrokinetics].
AB  - Movement and accumulation of nitrate in soil and groundwater has become a serious
      threat in many cities and agricultural areas. At the same time, application of
      nitrate as bacterial nitrogenous nutrient in the in-situ bioremediation of some
      organics-polluted sites is often required. Laboratory experiments were conducted
      to examine the feasibility of using non-uniform electrokinetics (NUEK) to control
      the movement of nitrate in unsaturated soil-water system. A natural soil taken
      from woodland was used as experimental soil. Three electrokinetic processes were
      tested in bench-scale cells at a constant potential gradient of 1.0 V/cm:
      unidirectional NUEK, NUEK with periodic polarity-reversal, and conventional
      uniform electrokinetic (UEK). The tests showed that NUEK drove NO3- through the
      experimental soil at a rate of 13.5-20 cm/d depending upon the concentration of
      NO3- and the distribution of electric field density. Compared with UEK, NUEK
      process more effectively concentrated and retained NO3- close to the anode.
      Moreover, NUEK process maintained soil characteristics and consumed much less
      electric energy. Reversal the polarity of NUEK weakened the concentration of NO3-
      to electrodes, but it stimulated the transformation of NO3- to NO2- and further
      lowered the electric energy consumption.

PMID- 15202245
TI  - [Bio-environmental effects and index of remediation of multi-heavy metals
      polluted red soils].
AB  - A pot experiment was conducted to study the bio-environmental effects of lime and
      organic manure application on red soil and paddy soil derived from red sandstone
      and polluted by multi-heavy metals. The results indicated that liming decreased
      the content of soil bioavailable Cu and Pb extracted with 0.05 mol/L HCl, while
      applying hog manure increased that of Cd. Soil bioavailable heavy metals (HMs)
      showed an apparent relationship with soil dissolved carbon. Applying lime and
      organic manure has a positive physiological effect on soil microorganisms and
      sweet potato. Many indexes, i.e. the number of soil actinomycetes, the content of
      HMs in the root of sweet potato, showed the remarkable relationship with soil
      bioavailable Cu, Cd and Pb. However, some indexes of soil and plant only relative
      to one or two soil bioavailable HMs. For example, soil microbial biomass carbon
      correspondent with soil bioavailable Cd. Only the content of Cu in the stem and
      leaf showed a notable relationship with soil effective Cu. Soil effect Cu and Pb
      rather Cd showed remarkable relation with mean transpiration rate, total biomass
      and leaf area index of sweet potato. The daily mean value in the seedling stage
      showed a stronger relationship with soil bioavailable Cu and Pb. Therefore these
      two physiological indexes can reflect the change of soil metallic contamination.

PMID- 15202246
TI  - [Mercury pollution and its ecosystem effects in Wanshan mercury miner area,
      Guizhou].
AB  - Samples of water, soil, plants, crops and animals collected from Wanshan mercury
      miner area, Guzhou Province, were analyzed with an AMA-254 liquid/solid mercury
      analyzer. It was shown that mercury pollution is mainly in soil and air; except
      water from a pool, no anomaly mercury is found in waters. Mercury content in soil
      is 24.31-347.52 mg.kg-1, two or three magnitude higher than the average value of
      Chinese soils; mercury content in plants is 0.47-331.4 mg.kg-1, and moss can
      enrich much mercury. Due to the long time of exploration and smelting, abundant
      mercury are accumulated in the local ecosystem, and healthy of local people are
      threatened seriously.

PMID- 15202247
TI  - [Risk analysis of naphthalene pollution in soils of Tianjin].
AB  - Three approaches were applied and evaluated for probabilistic risk assessment of
      naphthalene in soils of Tianjin, China, based on the observed naphthalene
      concentration of 188 top soil samples from the area and LC50 of naphthalene to
      ten typical soil fauna species from the literature. It was found that the
      overlapping area of the two probability density functions of concentration and
      LC50 was 6.4%, the joint probability curve bend towards and very close to the
      bottom and left axis, and the calculated probability that exposure concentration
      exceeds LC50 of various species was as low as 1.67%, all indicating a very much
      acceptable risk of naphthalene to the soil fauna ecosystem and only some of very
      sensitive species or individual animals are threaten by localized extremely high
      concentration. The three approaches revealed similar results from different
      viewpoints.

PMID- 15202248
TI  - [Field investigation on ecological effect of windbreak and soil erosion reduction
      from sandy grasslands].
AB  - Through field observation of the variation of vegetational characteristics and
      sand transported rate in sandy grasslands at different levels of desertification
      during the spring erosive period, the ecological effects of windbreak and soil
      erosion reduction from sandy grasslands of the Horqin Sandy Land were studied.
      The results showed that vegetational coverage varied obviously from 0.3% in the
      shifting sand land of the severe desertification to 16% in the fixed sand land of
      the least desertification in mid May. Increases in vegetational coverage led to a
      corresponding increase in surface roughness length from 0.013 cm in the shifting
      sand land to 0.111 cm in the fixed sand land, thus resulting in an increase in
      friction velocity from 0.272 m.s-1 in the shifting sand land to 0.823 m.s-1 in
      the fixed sand land and a decrease in mean wind speed near the surfaces from 7.0
      m.s-1 in the shifting sand land to 3.8 m.s-1 in the fixed sand land. This in turn
      led to a reduction in the total sand transported rate within the height of 0-20
      cm from 88.8 g.(h.cm2)-1 in the shifting sand land to 1.6 g.(h.cm2)-1 in the
      fixed sand land. When the experimental data were analyzed by regressing the total
      sand transported rate (Q) against vegetational coverage (VC), a model of
      predictive regression was developed: Q = 3.93 + 93.66e-0.60VC(R2 = 0.893, p <
      0.0001, n = 40).

PMID- 15202249
TI  - [Purification capacity of ditch wetland to agricultural non-point pollutants].
AB  - Ditch wetlands have the capacity to remove and purify non-point pollutants from
      agricultural drainage by sediment retention, plant absorption and microorganism
      decomposition. Phragmites communis and Zizania latifolia are two main kinds of
      plants growing naturally in ditch wetlands in the lower reaches of the Yangtze
      River. They can absorb N and P efficiently, which is the main mechanism of non
      point source pollutants purification by wetlands. The harvest of Phragmites
      communis and Zizania latifolia will take away 463-515 kg/hm2 of N and 127-149
      kg/hm2 of P each year, it equal to N and P discharged from 2.3-3.2 hm2 and 1.3
      3.0 hm2 of fields respectively in this area. The absorption and decomposition
      capacity of Zizania latifolia wetland is higher than Phragmites communis wetland.
      After harvest of plants, wetlands are uncovered to sunlight and oxygen that
      speeds the transportation and decomposition of nutrients. The amount of organic
      matters, TN and TP are higher in sediment of harvested area than in that of
      control. Therefore, seasonal harvest of plants is an efficient measure for
      wetlands to purify nutrients and alleviate eutrophication of lakes.

PMID- 15202250
TI  - [Issues concerned with the bioremediation of contaminated soils].
AB  - Several issues faced in the process of bioremediation were discussed in this
      paper, which are included as below: The principal and condition for the
      introducing of foreigner microbial; Mechanisms of suitability for microorganisms
      in the bioremediation process and the factors that influenced the degradation of
      pollutants; The correlations between the concentration of pollutants and their
      bioremediation; The secondary pollutants in the process of degradation of organic
      chemicals; The technology amplification of bioremediation technique on situ
      or/and in situ; the leaching process of contaminants; The Eco-toxicological
      diagnosis and evaluation for bioremediation technology and so on in order to
      enhance the realization for problems existed in the process of bioremediation and
      make it possible for more effective application of the bioremediation technology.

PMID- 15202251
TI  - [Characteristics of vertical distribution of oxygen concentration and consumption
      rate in aerobic static composting].
AB  - It is of important to improve the composting techniques and the structure of the
      pile to know the vertical distribution of oxygen concentration and oxygen
      consumption rate. The characteristics of oxygen supplement and consumption were
      analyzed in aerobic static composting. The oxygen concentration at different
      parts of the pile could increase from 17% to 20.6% after ventilation during
      different stages of composting. The decrease rate of oxygen concentration at the
      upper part was faster than that of the middle and bottom of the pile, and the
      oxygen concentration at the upper part was lower, which could be 3%. After same
      time of stopping ventilation, the oxygen concentration before ventilation
      increased along with the proceeding of composting. The oxygen concentration
      before ventilation could be upper 10% at the middle and bottom of the pile after
      the middle stage of high temperature, and the decrease rate of oxygen
      concentration declined too.

PMID- 15202252
TI  - [The stratification of moisture content and its dynamics in co-composting of
      sewage sludge and pig manure].
AB  - The experiment of co-composting of sewage sludge and pig manure was studied. The
      moisture contents were 50.82%-60.87% at the stage of temperature rising and 38.7%
      52.17% at the stage of thermophilic fermentation, and the stratification of
      moisture content were not obvious for both stages because the door, the internal
      wall and the depth of the composting bay had little effect on the stratification.
      At the stage of cooling, the moisture content was 24.54%-49.39%, and the
      stratification of moisture content was remarkable as the door, the internal wall
      and the depth of the composting bay had great influence on it. At the stage of
      maturity, the moisture content was 19.18%-49.34%, and the stratification of
      moisture weakened, for which the door and the internal wall were mainly
      responsible. At the different composting stage, the degree of difference of
      moisture content on the profiles of the pile was of the order: maturity stage >
      cooling stage > thermophilic stage = temperature rising stage, and the moisture
      content in the pile was as follows: the lower > the middle > the upper. The
      relation between moisture content and composting time meeted with two-order
      kinetics equation.

PMID- 15202253
TI  - [Application of high-efficient cellulose utilization microorganisms in co
      composting of vegetable wastes and flower stalk].
AB  - An inoculation composing 17 species of cellulose utilization microorganisms was
      used in co-composting of vegetable wastes and flower stalk, and the efficiency of
      the inoculation on lignocellulose degradation was studied. The experiments result
      show that at the beginning of the first stage of composting, inoculating
      cellulose utilization microorganism in the substrates with 0.5% (V/V) can improve
      the biomass of the microorganisms into the substrates greatly and make them
      dominant ones. When the temperature was controlled as 55 degrees C, the biomass
      of cellulose utilization microorganisms can keep between [symbol: see text] 3.84
      x 10(9)-1.80 x 10(10) CFU/g. At the beginning of the second stage, inoculating
      with 1% (V/V) can improve the temperature during this period effectively.
      Monitoring of the content of lignocelluloses in the substrate shows that the
      inoculation of cellulose utilization microorganism can accelerate the degradation
      of cellulose. The degradation efficiency of cellulose under inoculation condition
      is 23.64% higher than those without inoculation. This shows that inoculating with
      cellulose utilization microorganisms in each stage of the composting can greatly
      decompose the lignocellulose in the substrates, accelerate the co-composting
      process and improve the quality of composting production.

PMID- 15202254
TI  - [Spatial and temporal distribution of organochlorine pesticides (OCPs) in surface
      water from the Pearl River Artery estuary].
AB  - Six water samples were collected, and twenty-one compounds of organochlorine
      pesticides (OCPs) in surface water from the Pearl River Artery estuary were
      analyzed quantitatively, based on USEPA 8000 series methods and under quality
      assurance and quality control (QA/QC). The total (particulate plus dissolved
      phase) concentration of OCPs in surface water from the Pearl River Artery estuary
      in both high flow season and low flow season were 9.7 ng/L-26.3 ng/L and 41.7
      ng/L-122.5 ng/L respectively. The concentration of total HCHs and total other
      OCPs was much higher than that of DDTs. The seasonality of the concentration of
      OCPs was significantly, and the level of OCPs in low flow season was higher than
      that of OCPs in high flow season. The spatial and temporal distribution of OCPs
      suggested that there were significant differences of OCPs between the East River
      (Dongjiang) network and Guangzhou channel and the nonpoint-source pollution of
      OCPs was found in the Pearl River Artery estuary, particularly in high flow
      season.

PMID- 15202255
TI  - [Polychlorinated biphenyls residues in eggs of different ages night heron
      breeding in Yuantouzhu, China].
AB  - 61 eggs of night heron (Nycticorax nycticorax) were collected in 2000 in
      Yuantouzhu of Tai lake, China. The breeding birds were divided into three groups
      by age, namely two, three, four years. The residues of 15 polychlorinated
      biphenyl congeners in eggs were studied. 15 congeners were found in all egg
      samples, and PCB118 at the highest level, PCB87, PCB101 and PCB153 at second
      levels. Total residues of the 4 congeners occupied about 75%-85% of sum 15
      congeners residues found in eggs. It was obviously that residues of congeners
      containing 5-6 chlorine atoms were more than others in eggs. Residues of PCBs in
      eggs increased with age of breeding birds. The total PCBs concentration in eggs
      of four years group were higher than that of three years group, two years group
      by 47.5% and 60.9% respectively. Different from the result of the similar studies
      in European countries, USA and Japan: the residue of PCB153 is the highest, it
      was found that in this study the residue of PCB118 is the highest in eggs, which
      is about 30% of the total PCBs residues, while the PCB153 17% only.

PMID- 15202256
TI  - [PAHs in foliar dust from Beijing urban area].
AB  - A five-step sequential elution procedure with or without supersonic effect was
      tested for extraction of foliar dust from leaves of Euonymus japonicus collected
      at two locations of Beijing urban area. The samples were collected from either
      roadside or campus far away from any motor traffic. The foliar dust was
      characterized for size distribution, organic carbon content, and PAHs content. It
      was found that majority of the foliar dust can be eluted in 4 min by distill
      water under supersonic effect at room temperature without shaking. The amount of
      foliar dust on the sample from roadside was almost twice as much as those from
      campus, while the particle size of the former was relatively large. Large amount
      of coarse particles came from disturbance of motor vehicles. Slightly high
      concentrations of PAH species were detected in the sample from campus compared to
      those in the samples collected from roadside.

PMID- 15202257
TI  - [Biosorption of Pb2+ by Bacillus cereus biomass].
AB  - In this paper, the potentiometric titration and the sorption experiments were
      applied to investigate the biosorption behavior of Pb2+ on Bacillus cereus
      biomass. It was shown that the biosorption capacities increased with increasing
      pH from 3 to 7, and the higher concentration of the biomass in solution was
      favorable to the sorption of Pb2+. Langmuir model simulated the adsorption data
      of Pb2+ ion very well, and the saturated sorption capacity for Pb2+ ion achieved
      36.7 mg.g-1 dry biomass. According to the result of the potentiometric titration,
      the Gran plots for the hydroxide back-titration of biomass suspension systems
      were utilized to derive the specific volume of titrant at the equivalence point
      (Ve), furthermore, the total surface site concentration was calculated.

PMID- 15202258
TI  - [Characteristic analysis of heavy metals' evaporation of MSWI fly ash].
AB  - In order to reduce the secondary pollution caused by municipal solid waste
      incineration (MSWI) fly ash, it must be treated soundly before final disposal,
      because the content of heavy metals in MSWI fly is high. In this paper, the
      evaporation of heavy metals (Pb, Cd, Cu, Zn) were studied between 600 degrees C
      1100 degrees C, meanwhile the influence of CaCl2 on heavy metals' evaporation was
      studied. The result shown that without chlorination agent, the evaporation for Pb
      and Cd were as high as above 90%, about 80% for Cu, less than 40% for Zn. It was
      also found the evaporation of the heavy metals was enhanced when chlorination
      agent was added, and for Zn the evaporation increase was the most.

PMID- 15202259
TI  - [Study on the calcium-based sorbent for removal fluorine during coal combustion].
AB  - In the paper, the reaction of CaO-HF and fluorine removal mechanics at high
      temperature by blending calcium-based sorbents with coal during coal combustion
      were discussed, and test results about fluorine retention during coal combustion
      in fluidized bed and chain-grate furnace were reported. The results identified
      that lime and calcium-based sorbets developed can restratin the emission of
      fluorine during coal combustion. The efficiency of fluorine removal can reach
      66.7%-70.0% at Ca/F 60-70 by blending lime with coal in fluidized bed combustion,
      and the efficiency of fluorine removal are between 57.32% and 75.19% by blending
      calcium-based sorbets with coal in chain-grate furnace combustion. Blending CaO
      or lime with coal during coal combustion can remove SO2 and HF simultaneously.

PMID- 15202260
TI  - [Skeletonized right gastroepiploic artery for coronary artery bypass grafting;
      evaluation of intraoperative graft flow and postoperative angiographic result].
AB  - We evaluated the efficacy of using the skeletonized right gastroepiploic artery
      (RGEA) in coronary artery bypass grafting (CABG). The RGEA was harvested either
      as a pedicle (group P, n = 14) or in a skeletonized fashion using a Harmonic
      Scalpel (group S, n = 14). The free flow of the RGEA was too small to be measured
      in some cases in group P. On the other hand, the free flow of the RGEA could be
      measured in all cases in group S, and that value obtained was comparable to the
      free flow of the left internal thoracic artery. The skeletonization of the RGEA
      also allowed us to directly visualize this vessel, and thus helped us to evaluate
      the quality of this artery. Postoperatively, all RGEAs were patent in both
      groups. The RGEA diameters on the postoperative angiography showed the RGEAs in
      group S to have a wider caliber, however, the differences in the values for each
      group did not reach statistic significance. Neither the operation time nor the
      postoperative hospital stay were substantially lengthened due to the
      skeletonization of the RGEA. In conclusion, the skeletonization of the RGEA using
      a Harmonic Scalpel is safe and effective modality which enables surgeons to
      directly visualize arteries in order to determine their quality and thereby
      making it easier to perform sequential bypass grafting. The method also
      demonstrated an excellent quality of the patent graft on postoperative
      angiography. We therefore consider the skeletonization of the RGEA to be a very
      useful method for harvesting the RGEA in CABG.

PMID- 15202261
TI  - [Prognosis of resected stage I bronchioloalveolar carcinoma of the lung].
AB  - In this retrospective study, we investigated the prognosis of 25 patients with
      resected bronchioloalveolar carcinoma (BAC) of 3.0 cm or less in diameter. We
      assigned a diagnosis of BAC for non-invasive tumors as defined by the World
      Health Organization (WHO) classification. The patients ranged in age from 47 to
      78 years with an average of 64.0 years. Eighteen patients (72%) were male and 7
      patients (28%) were female. All the patients underwent complete resection. As the
      mode of surgical resection, at least lobectomy was performed in 84%. Sections of
      the resected tumor were stained by HE and Elastica, and then examined by light
      microscopy. The tumors ranged in size from 0.5 to 3.0 cm with an average of 1.9
      cm. Neither pleural involvement nor vascular permeation was seen in BACs. There
      was also no lymph node involvement for BACs. The 5-year disease-free survival
      rate of all 25 patients with BAC was 100%. The unequivocally recognizing invasive
      features by morphology is important for a prospect of the prognosis of resected
      BACs.

PMID- 15202262
TI  - [On-pump beating aortic valve replacement for severe aortic regurgitation due to
      infective endocarditis].
AB  - A 37-year-old man was suffering from pneumonia and severe aortic regurgitation
      due to acute aortic valve endocarditis with the annular abscess with
      Staphylococcus aureus. Preoperative serum brain natriuretic peptide was over
      2,000 pg/ml. Preoperative arterial oxygen saturation was 82% on mechanical
      ventilation (Fio2: 1.0) with nitric oxide inhalation. Under a full median
      sternotomy, total normothermic cardiopulmonary bypass was established. Using the
      normothermic retrograde continuous coronary sinus perfusion of oxygenated blood,
      on-pump beating aortic valve replacement (AVR) was performed. Veno arterial
      bypass was required for 72 hours postoperatively. Postoperative course was
      otherwise uneventful. On-pump beating AVR seemed to be one of the useful
      procedures for a high-risk patient.

PMID- 15202263
TI  - [Thoracoscopic pericardial resections for malignant pericardial effusions].
AB  - We have performed 5 thoracoscopic pericardial resections for malignant
      pericardial effusions. An initial trocar was placed in the seventh or eighth
      intercostal space posterior to the midaxillary line. Two additional trocars were
      placed, usually in the sixth intercostals spaces in the anterior axillary and
      posterior axillary lines. Using an endoscopic grasping instrument and scissors
      through the working ports, a pericardial resection was performed. All patients
      were successfully managed by thoracoscopic pericardial resections. Two of the 5
      patients had associated malignant pleural effusions that were able to be managed
      at the same time by thoracoscopy. The average chest tube duration was 1.8 days.
      There has been no reaccumulation of pericardial effusions in all patients at an
      average follow-up of 5 months. The thoracoscopic approach could be minimally
      invasive and the procedure of choice in performing pericardial resections in
      selected patients with malignant pericardial effusions who are expected to have a
      reasonable life expectancy.

PMID- 15202264
TI  - [Prospective study of systemic inflammatory response syndrome after cardiac
      surgery as a effective indicator].
AB  - This prospective study was designed to elucidate the meaning of systemic
      inflammatory response syndrome (SIRS), the mechanisms that lead to the
      protraction of SIRS, and whether SIRS is potentially a simple and effective
      postoperative indicator or not in patients who are operated on with
      cardiopulmonary bypass (CPB). We studied the duration of SIRS in 90 patients. Our
      data showed that 83 (92%) of the 90 patients met 2 or more criteria for SIRS and
      that significant relationship between the protraction of SIRS and the duration of
      aortic clamping time, CPB time, operation time, and the risk of postoperative
      organ damage and complication. Those results suggest that SIRS after cardiac
      surgery with CPB can be regarded as right criteria and highly valuable indexes of
      preparatory state of organ dysfunction.

PMID- 15202265
TI  - [Anterior cervical approach for resection of brachial plexus schwannoma expanding
      into the thoracic apex].
AB  - Primary tumors of the brachial plexus are unusual. We describe 2 patients with
      schwannomas of the brachial plexus that had the radiologic appearance of apical
      lung masses. We used anterior cervical approach for both of the patients. Our
      technique permitted safe and complete resection of the tumors of this complex
      area. Both tumors were arising from the Th1 component of brachial plexus.
      Histopathological findings revealed that both of the tumors were benign
      schwannomas. This approach is quick and safe, allowing much better control of the
      important vascular and neural structures of the thoracic apex. Tumors at the area
      are inaccessible by using posterolateral thoracotomy or video-assisted thoracic
      surgery. We suggest that the anterior cervical approach would be applied for the
      resection of other kind of tumors in the thoracic apex.

PMID- 15202266
TI  - [The effect and role of the intraaortic balloon pumping in off-pump coronary
      artery bypass].
AB  - Eighty consecutive patients who underwent off-pump coronary artery bypass (OPCAB)
      were studied. They were divided into group I (n = 10) which received preoperative
      intraaortic balloon pumping (IABP), and group II (n = 70) which did not receive
      IABP. The indications for preoperative IABP were severe left main coronary artery
      disease in 7 patients, severe 3 vessel disease in 3 patients, unstable angina in
      5 patients, acute myocardial infarction in 3 patients. There was no operative
      mortality in both groups. The average number of distal anastomosis 2.7/patients
      in group I and 3.3/patients in group II. There was no differences in ventilator
      support time, length of stay in the intensive care unit and morbidity between 2
      groups. The average postoperative IABP support time was 5.4 hours. There was no
      IABP-related complication in group I. IABP was very effective to perform OPCAB
      surgery safety. Preoperative IABP may be effective modality to support OPCAB
      surgery not only in emergent case but also in elective case.

PMID- 15202267
TI  - [Postoperative temporal elevation of tumor marker in primary lung cancer
      patients].
AB  - Serum tumor marker measurement in addition to radiological examination is useful
      to detect postoperative recurrence and metastasis. Surgically treated 8 primary
      non-small cell lung cancer patients who showed negative serum tumor marker
      postoperatively elevated their markers temporally. Five of the 8 patients did not
      show recurrence or metastasis in their last confirmation days. These 5 patients
      had inflammatory disease when the postoperative marker became positive
      temporally. Remaining 3 patients did not have inflammatory disease when the
      marker elevated temporally. The marker of the 3 patients became negative again,
      however, the 3 patients showed recurrence or metastasis during 1 year after
      temporally elevated day. In conclusion, if there is no inflammatory disease when
      the negative marker becomes positive temporally, the recurrence or metastasis may
      be observed during 1 year after temporally elevated day. And when the recurrence
      or metastasis is observed radiologically, the marker may become negative.

PMID- 15202268
TI  - [Cholesterol crystal embolization exacerbated after the off-pump coronary artery
      bypass; report of a case].
AB  - A 66-year-old man with left main trunk disease was treated under a diagnosis of
      acute myocardial infarction based on coronary angiography by off-pump coronary
      artery bypass (OPCAB). About 1 month after operation, his renal function
      deteriorated and purpura appeared on both feet, especially at the toe tips. In
      this case, steroid therapy was performed and the patient survived. Cholesterol
      embolism rarely occurs after angiographic procedure or cardiovascular surgery. In
      general, it is associated with high morbidity and mortality, but no optimal
      treatment has yet been developed. This underlines the importance of careful
      observation and skin biopsy for early diagnosis.

PMID- 15202269
TI  - [Surgical osteoplasty of the left main coronary artery using the right internal
      thoracic artery].
AB  - A 39-year-old female with a history of progressive refractory angina required
      medical treatment. A coronary angiography showed 75% left coronary ostial
      stenosis without any other atherosclerotic lesions. The isolated ostial stenosis
      of the left main coronary artery was reconstructed by patch angioplasty, using a
      proximal segment of the right internal thoracic artery. The transaortic patch
      angioplasty was performed using a superior approach, which allowed a good
      exposure of the left coronary artery to the aorta without difficulty. A
      postoperative coronary angiography showed satisfactory patency, and a small
      biopsy of the ostial tissue demonstrated findings compatible with fibromuscular
      dysplasia. Based on this outcome, a proximal segment of the internal thoracic
      artery appears to provide a suitable patch material for enlarging the left
      coronary ostium.

PMID- 15202270
TI  - [Partial anomalous pulmonary venous drainage to the high superior vena cava;
      repair by direct anastomosis between the superior vena cava and the right atrial
      appendage; report of a case].
AB  - A 10-year-old boy with partial anomalous pulmonary venous connection to the high
      superior vena cava (SVC) underwent surgical repair by Williams method. The SVC
      was divided above the orifice of the anomalous pulmonary vein. The proximal end
      of the SVC was closed and the distal end of the SVC was anastomosed to the right
      atrial appendage (RAA). The anomalous pulmonary vein was rerouted to the left
      atrium via the SVC and the surgically enlarged central type atrial septal defect
      (ASD). The postoperative course was uneventful except transient sinus bradycardia
      and catheter study showed no stenosis of the SVC and the RAA.

PMID- 15202271
TI  - [Multi-vessel dissection; report of a case].
AB  - We report an extremely rare case of multi-vessel dissection including left
      carotid artery, ascending aorta and thoracoabdominal aorta independently. A 65
      year-old man suffered from cerebral infarction due to left carotid artery
      dissection. Five days later, he complained of severe back pain and was diagnosed
      as acute DeBakey type IIIb aortic dissection. He had been treated medically. One
      month later, computed tomography (CT) scan demonstrated DeBakey type II as well
      as type IIIb aortic dissections. The ascending aorta was replaced on August 8,
      2001. Then replacement of the descending thoracic aorta with reconstruction of
      the eighth and tenth intercostal arteries was performed on September 26, 2001.
      The left carotid artery dissection has been treated medically.

PMID- 15202272
TI  - [Scimitar syndrome; report of a case].
AB  - A 17-year-old woman with scimitar syndrome without an atrial septal defect was
      operated by intra-cardiac conduit repair. Computed tomography (CT) and magnetic
      resonance imaging (MRI) showed resolution images of anatomical findings of
      scimitar vein. Surgical procedures for the scimitar syndrome have varied
      according to the anatomic features presented in each case. The detection of
      precise anatomy of scimitar syndrome is important for determining the appropriate
      surgical procedure. Images of 3-dimensional (3-D) CT and MRI of scimitar syndrome
      were demonstrated.

PMID- 15202273
TI  - [Thoracoscopically resected cystic mediastinal hemangioma; report of a case].
AB  - An asymptomatic 66-year-old female was admitted because of an abnormal shadow on
      chest X-ray. Computed tomography (CT) revealed that a well-marginated round mass
      with low density, about 3 cm in diameter, was located in the right anterior
      superior mediastinum. The border was partially enhanced at contrast material
      enhanced CT. Magnetic resonance imaging (MRI) [T 2-weighted] showed the lesion as
      a high intensity tumor. We performed thoracoscopic surgery and resected the easy
      bleeding tumor completely. The tumor was dark red in color and contained old
      blood. The histopathological diagnosis was hemangioma. There was no recurrence
      for 3 years. Hemangiomas should be considered in the differential diagnosis of
      well-marginated masses. Thoracoscopic surgery is the very useful methods to
      resect the mediastinal hemangioma.

PMID- 15202274
TI  - [Diplopia and blepharoptosis associated with orbital emphysema following
      thoracotomy with lung cancer; report of a case].
AB  - BACKGROUND: Orbital emphysema is a common complication of trauma and fracture of
      orbital bones. However, subcutaneous emphysema also can rarely lead to orbital
      emphysema. We reported the clinical and radiological findings in a patient with
      diplopia and blepharoptosis following thoracotomy for lung cancer. CASE: A 76
      year-old man had undergone left inferior lobectomy and ND 2 a in October 2002,
      based on the clinical diagnosis of stage IB lung squamous cell carcinoma. He
      presented with diplopia and blepharoptosis several days following thoracotomy.
      Chest X-ray demonstrated extensive subcutaneous emphysema, and physical
      examination also revealed diffuse subcutaneous emphysema including face and
      palpebrae. Head computed tomography (CT) revealed subcutaneous emphysema in the
      infratemporal fossa bilaterally. His diplopia and blepharoptosis gradually
      resolved, and he was discharged with no visual complaints on the fourteenth
      postoperative day. CONCLUSIONS: Subcutaneous emphysema can lead to diplopia and
      orbital emphysema in the absence of orbital trauma. Early surgical intervention
      for air leakage is highly recommended to avoid both the orbital emphysema and the
      visual complications in the event that subcutaneous emphysema should get to
      including face or palpebrae.

PMID- 15202275
TI  - [Probable toxic shock syndrome following pleural drainage].
AB  - Toxic shock syndrome (TSS) is rare complication after minor surgical procedure. A
      22-year-old man was admitted our hospital with spontaneous pneumothorax on the
      right side. Few days after pleural drainage, he developed a high fever often over
      40 degrees C and a rash, most demonstrating a truncal, "sunburn" pattern.
      Initially, he was diagnosed as right pylothorax, but the clinical course was not
      typical and antibiotic treatment was not effective. Two weeks later, desquamation
      of the hands and feet were noted, and methicillin-resistant Staphylococcus aureus
      (MRSA) isolated from the pleural effusion were identified as TSS toxin (TSST)-1
      and enterotoxin-C producing. He was diagnosed as probable TSS, and recovered by
      steroid therapy. Early awareness and recognition of this disease is necessary for
      surgeons.

PMID- 15202276
TI  - [Pulmonary metastasis of uterine leiomyosarcoma 8 years after hysterectomy;
      report of a case].
AB  - A 57-year-old woman, who had undergone hysterectomy for uterine leiomyosarcoma 8
      years ago, was admitted to our hospital for pulmonary tumors on chest X-ray. Two
      tumors were recognized on each side at left and right lung field by computed
      tomography (CT). Two-staged tumor resection was performed by left thoracotomy and
      by video-assisted thoracoscopic surgery (VATS) in the right. The histologic
      findings showed that those tumors were metastases of uterine leiomyosarcoma. This
      case suggests that the long term follow-up is necessary in the case of uterine
      leiomyosarcoma after operation.

PMID- 15202277
TI  - [Anterior mediastinal mass with hyperthyroidism; report of a case].
AB  - The patient was a 27-year-old man who had been diagnosed as having
      hyperthyroidism and with an anterior mediastinal mass which was reduced in size
      after anti-thyroid therapy. This mass was thought to be thymic hyperplasia
      associated with hyperthyroidism. An anterior mediastinal mass accompanying
      hyperthyroidism should be surgically treated when it dose not regress after an
      appropriate antithyroid therapy or there is a clinical suspicion of malignancy.

PMID- 15202278
TI  - [Analysis of genomic structure and regulation of virulence genes of Clostridium
      perfringens].

PMID- 15202279
TI  - [Establishment of detection and quantification system of periodontopathic
      bacteria by molecular biology-technique and molecular analysis of human oral
      microbiota].

PMID- 15202280
TI  - [Interactions of botulinum and cholera toxin with host intestinal epithelial
      cells].

PMID- 15202281
TI  - [Motility- and chemotaxis-related genes of Vibrio spp. and their involvement in
      virulence].

PMID- 15202282
TI  - [Helicobacter pylori infection and epithelial cell signaling in gastric
      pathogenesis].

PMID- 15202283
TI  - HIPAA Privacy Rules: protecting patient information requested through discovery,
      subpoenas and court orders.
AB  - Health plans routinely receive requests for patient health care information in
      lawsuits and administrative proceedings, whether through court order, subpoena,
      discovery requests or otherwise. The HIPAA Privacy Rules describe what
      protections a health plan must obtain before disclosing patient health
      information without prior authorization. This article focuses on the regulatory
      framework governing health plans, a review of recent case law applying these
      HIPAA regulations and a practical guide for how a health plan may proceed upon
      receiving requests for disclosure.

PMID- 15202284
TI  - Are your employees minding their behavior?
AB  - Self-managed, "tailored" behavioral change programs cross both wellness and
      disease management issues and can impact the bottom line on health care costs of
      both employer and employee. For example, a back pain program can help change
      employee behavior to prevent the incidence and upflow of a condition to more
      severe and debilitating situations.

PMID- 15202285
TI  - Succession and failure.
AB  - Norman Windom, the chairman of Tiverton Media, may not know much about the world
      of popular music, but he does fancy himself a careful planner and a superb judge
      of managerial talent. That's why he's been grooming COO Sean Kinnane, a Wharton
      minted numbers man, to take over an important division, Aleph Records, and one
      day Tiverton itself. But Derek Solomon, Aleph's 68-year-old CEO and founder,
      remains a creative force and a father figure to the label's artists. What's more,
      he's touchy about anything that might slow down Aleph's responses to the market's
      ever-shifting preferences--or that might call into question his indispensability.
      Though Sean dutifully participates in Tiverton's broad-based and elaborate
      executive development plan, he senses that Aleph's future leadership structure is
      uncertain. As impatient as he is ambitious, he announces that he's leaving
      Tiverton for more suitable pastures. Several of his associates, also unsure about
      their fate within Aleph, are following him out the door. In one fell swoop,
      they've torn Norman's proud succession plan apart. What kind of plan should the
      board adopt going forward? Commenting on this fictional case study are Francis N.
      Bonsignore, a senior vice president at Marsh & McLennan; Michelle L. Buck, a
      clinical associate professor of management and organizations at Northwestern's
      Kellogg School of Management; Jon Younger, who heads leadership development at
      National City Corporation, a financial holding company in Cleveland; and Thomas
      Leppert, the chairman and CEO of the Turner Corporation, a large construction
      company in Dallas.

PMID- 15202286
TI  - The perils of the imitation age.
AB  - Imitation exerts enormous influence over society, and business and finance in
      particular. And its influence has grown as the avenues by which people imitate-
      and are imitated--have multiplied and the process has gotten faster. Thousands of
      communications channels make it possible for virtually anyone in the developed
      world to know, almost instantaneously, what others do, think, believe, claim, or
      predict. More significantly, we can and do act upon such knowledge. The resulting
      fads and fashions, bubbles and crashes are ever more frequent, severe, and
      complex. The information age has cast up more than its share of paradoxes,
      including this one: When information is plentiful, we often use it not to make
      better decisions but to imitate others--and their mistakes. In consumer
      purchases, financial markets, and corporate strategy, what others do matters more
      to us than the facts. When there's too much information, imitation becomes a
      convenient heuristic. This is the basis for a self-referential society. Imitation
      has its virtues, but it also promotes instability and unpredictability. That's
      because, by definition a multiplier, it can swell a single opinion into a mass
      movement or catapult the smallest player to the forefront of a market. Mastering
      the dynamics of self-reference won't ensure mastery of its consequences. But
      businesses that understand how imitation works can at least attempt to gird
      themselves against its worst effects--by accounting for it in their forecasts and
      risk-management plans, by becoming more sensitive to unexpectedly changing
      circumstances, and by avoiding mindless imitation of other companies' moves. In
      some instances, they may even be able to build strategies around self-reference
      and use the tools of imitation to capture new business. That won't make the world
      any less confusing. But it may make it more profitable.

PMID- 15202287
TI  - What makes an effective executive.
AB  - An effective executive does not need to be a leader in the typical sense of the
      word. Peter Drucker, the author of more than two dozen HBR articles, says some of
      the best business and nonprofit CEOs he has worked with over his 65-year
      consulting career were not stereotypical leaders. They ranged from extroverted to
      nearly reclusive, from easygoing to controlling, from generous to parsimonious.
      What made them all effective is that they followed the same eight practices: They
      asked, "What needs to be done?" They also asked, "What is right for the
      enterprise?" They developed action plans. They took responsibility for decisions.
      They took responsibility for communicating. They were focused on opportunities
      rather than problems. They ran productive meetings. And they thought and said
      "we" rather than "I." The first two practices provided them with the knowledge
      they needed. The next four helped them convert this knowledge into effective
      action, for knowledge is useless to executives until it has been translated into
      deeds. The last two ensured that the whole organization felt responsible and
      accountable. Effective executives know that they have authority only because they
      have the trust of the organization. This means they must think of the needs and
      opportunities of the organization before they think of their own needs and
      opportunities. The author also suggests a ninth practice that's so important, he
      elevates it to the level of a rule: Listen first, speak last. The demand for
      effective executives is much too great to be satisfied by those few people who
      are simply born to lead. Effectiveness is a discipline. And, like every
      discipline, it can be learned and must be earned.

PMID- 15202288
TI  - Redefining competition in health care.
AB  - The U.S. health care system is in bad shape. Medical services are restricted or
      rationed, many patients receive poor care, and high rates of preventable medical
      error persist. There are wide and inexplicable differences in costs and quality
      among providers and across geographic areas. In well-functioning competitive
      markets--think computers, mobile communications, and banking--these outcomes
      would be inconceivable. In health care, these results are intolerable, with life
      and quality of life at stake. Competition in health care needs to change, say the
      authors. It currently operates at the wrong level. Payers, health plans,
      providers, physicians, and others in the system wrangle over the wrong things, in
      the wrong locations, and at the wrong times. System participants divide value
      instead of creating it. (And in some instances, they destroy it.) They shift
      costs onto one another, restrict access to care, stifle innovation, and hoard
      information--all without truly benefiting patients. This form of zero-sum
      competition must end, the authors argue, and must be replaced by competition at
      the level of preventing, diagnosing, and treating individual conditions and
      diseases. Among the authors' well-researched recommendations for reform:
      Standardized information about individual diseases and treatments should be
      collected and disseminated widely so patients can make informed choices about
      their care. Payers, providers, and health plans should establish transparent
      billing and pricing mechanisms to reduce cost shifting, confusion, pricing
      discrimination, and other inefficiencies in the system. And health care providers
      should be experts in certain conditions and treatments rather than try to be all
      things to all people. U.S. employers can also play a big role in reform by
      changing how they manage their health benefits.

PMID- 15202289
TI  - Understanding "people" people.
AB  - Nearly all areas of business--not just sales and human resources--call for
      interpersonal savvy. Relational know-how comprises a greater variety of aptitudes
      than many executives think. Some people can "talk a dog off a meat truck," as the
      saying goes. Others are great at resolving interpersonal conflicts. Some have a
      knack for translating high-level concepts for the masses. And others thrive when
      they're managing a team. Since people do their best work when it most closely
      matches their interests, the authors contend, managers can increase productivity
      by taking into account employees' relational interests and skills when making
      personnel choices and project assignments. After analyzing psychological tests of
      more than 7,000 business professionals, the authors have identified four
      dimensions of relational work: influence, interpersonal facilitation, relational
      creativity, and team leadership. This article explains each one and offers
      practical advice to managers--how to build a well-balanced team, for instance,
      and how to gauge the relational skills of potential employees during interviews.
      To determine whether a job candidate excels in, say, relational creativity, ask
      her to describe her favorite advertising campaign, slogan, or image and tell you
      why she finds it to be so effective. Understanding these four dimensions will
      help you get optimal performance from your employees, appropriately reward their
      work, and assist them in setting career goals. It will also help you make better
      choices when it comes to your own career development. To get started, try the
      authors' free online assessment tool, which will measure both your orientation
      toward relational work in general and your interest level in each of its four
      dimensions.

PMID- 15202290
TI  - Chronic time abuse.
AB  - Anyone who has ever managed people who abuse time--whether they are chronic
      procrastinators or individuals who work obsessively to meet deadlines weeks in
      advance--knows how disruptive they can be to a business's morale and operating
      efficiency. But lessons in time management will have no impact on these
      employees. That's because real time abuse results from psychological conflict
      that neither a workshop nor a manager's cajoling can cure. Indeed, the time
      abuser's quarrel isn't even with time but rather with a brittle self-esteem and
      an unconscious fear of being evaluated and found wanting. This article describes
      four types of time abusers typically encountered in the workplace: Perfectionists
      are almost physically afraid of receiving feedback. Their work has to be
      "perfect," so they can increase their likelihood of earning a positive evaluation
      or at least avoid getting a negative one. Preemptives try to be in control by
      handing in work far earlier than they need to, making themselves unpopular and
      unavailable in the process. People pleasers commit to far too much work because
      they find it impossible to say no. Procrastinators make constant (and often
      reasonable-sounding) excuses to mask a fear of being found inadequate in their
      jobs. Managing these four types of people can be challenging, since time abusers
      respond differently from most other employees to criticism and approval. Praising
      a procrastinator when he is on time, for instance, will only exacerbate the
      problem, because he will fear that your expectations are even higher than before.
      In fact, some time abusers, like the perfectionist, may need professional
      treatment. This article will give you insight into why they are the way they are-
      and what can be done to help them manage their problems.

PMID- 15202291
TI  - Will you survive the services revolution?
AB  - Of late, offshoring and outsourcing have become political hot buttons. These o
      words have been conflated to mean that high-paying, white-collar jobs have been
      handed to well-trained but less expensive workers in India and other locales. The
      brouhaha over the loss of service jobs, which currently account for over 80% of
      private-sector employment in the United States, is not merely an American
      phenomenon. The fact is that service-sector jobs in all developed countries are
      at risk. Regardless of what the politicians now say, worry focused on offshoring
      and outsourcing misses the point, the author argues. We are in the middle of a
      fundamental change, which is that services are being industrialized. Three
      factors in particular are combining with outsourcing and offshoring to drive that
      transformation: The first is increasing global competition, where just as with
      manufactured goods in the recent past, foreign companies are offering more
      services in the United States, taking market share from U.S. companies. The
      second is automation: New hardware and software systems that take care of back
      room and front-office tasks such as counter operations, security, billing, and
      order taking are allowing firms to dispense with clerical, accounting, and other
      staff positions. The third is self-service. Why use a travel agent when you can
      book your own flight, hotel, and rental car online? As these forces combine to
      sweep across the service sector, executives of all stripes must start thinking
      about arming and defending themselves, just as their manufacturing cousins did a
      generation ago. This will demand proactive and far-reaching changes, including
      focusing specifically on customer preference, quality, and technological
      interfaces; rewiring strategy to find new value from existing and unfamiliar
      sources; de-integrating and radically reassembling operational processes; and
      restructuring the organization to accommodate new kinds of work and skills.

PMID- 15202292
TI  - Sharpening the intangibles edge.
AB  - Intangible assets--patents and know-how, brands, a skilled workforce, strong
      customer relationships, software, unique processes and organizational designs,
      and the like--generate most of a company's growth and shareholder value. Yet
      extensive research indicates that investors systematically misprice the shares of
      intangibles-intensive enterprises. Clearly, overpricing wastes capital. But
      underpricing raises the cost of capital, hamstringing executives in their efforts
      to take advantage of further growth opportunities. How do you break this vicious
      cycle? By generating better information about your investments in intangibles,
      and by disclosing at least some of that data to the capital markets. Getting at
      that information is easier said than done, however. There are no markets
      generating visible prices for intellectual capital, brands, or human capital to
      assist investors in correctly valuing intangibles-intensive companies. And
      current accounting practices lump funds spent on intangibles with general
      expenses, so that investors and executives don't even know how much is being
      invested in them, let alone what a return on those investments might be. At the
      very least, companies should break out the amounts spent on intangibles and
      disclose them to the markets. More fundamentally, executives should start
      thinking of intangibles not as costs but as assets, so that they are recognized
      as investments whose returns are identified and monitored. The proposals laid
      down in this article are only a beginning, the author stresses. Corporations and
      accounting bodies should make systematic efforts to develop information that can
      reliably reflect the unique attributes of intangible assets. The current serious
      misallocations of resources should be incentive enough for businesses to join-
      and even lead--such developments.

PMID- 15202293
TI  - Capitalizing on capabilities.
AB  - By making the most of organizational capabilities--employees' collective skills
      and fields of expertise--you can dramatically improve your company's market
      value. Although there is no magic list of proficiencies that every organization
      needs in order to succeed, the authors identify 11 intangible assets that well
      managed companies tend to have: talent, speed, shared mind-set and coherent brand
      identity, accountability, collaboration, learning, leadership, customer
      connectivity, strategic unity, innovation, and efficiency. Such companies
      typically excel in only three of these capabilities while maintaining industry
      parity in the other areas. Organizations that fall below the norm in any of the
      11 are likely candidates for dysfunction and competitive disadvantage. So you can
      determine how your company fares in these categories (or others, if the generic
      list doesn't suit your needs), the authors explain how to conduct a "capabilities
      audit," describing in particular the experiences and findings of two companies
      that recently performed such audits. In addition to highlighting which intangible
      assets are most important given the organization's history and strategy, this
      exercise will gauge how well your company delivers on its capabilities and will
      guide you in developing an action plan for improvement. A capabilities audit can
      work for an entire organization, a business unit, or a region--indeed, for any
      part of a company that has a strategy to generate financial or customer-related
      results. It enables executives to assess overall company strengths and
      weaknesses, senior leaders to define strategy, midlevel managers to execute
      strategy, and frontline leaders to achieve tactical results. In short, it helps
      turn intangible assets into concrete strengths.

PMID- 15202294
TI  - Fixing kids' sports.

PMID- 15202295
TI  - Coffee, tea, or exercise?

PMID- 15202297
TI  - [Arrhythmia and left ventricle remodeling in acute myocardial infarct:
      recommendations for drug therapy].
AB  - Occurrences of arrhythmias during the acute myocardial infarction is explained
      with local ischaemia, but mechanism of later occurrences is unclear. Our study
      had for the aim to examine relationship between postinfarction left ventricle
      dilatation and appearance of arrhythhmias, and to show drug effects on
      remodelling. Patients who developed progressive left ventricle dilatation had
      higher mortality then patients without changes of left ventricle volume, and
      mortality is due of sudden cardiac death. Drugs who had preventive effects or
      reverse remodelling can help in prevention of malignant arrhythhmias and sudden
      cardiac death. It is showed that ACE inhibitors, beta-blockers and aldosterone
      antagonists had preventive effects on left ventricle remodelling. The combined
      therapy with ACE inhibitors, beta-blockers and aldosterone antagonists is showed
      as the most-effective in prevention of remodelling, appearaance of arrhythhmias
      and sudden cardiac death.

PMID- 15202298
TI  - [Multivascular atherosclerosis, the Sarajevo Vascular Study].
AB  - INTRODUCTION: We started with Sarajevo Vascular Study (SVS) in 1994 with basic
      aim to evaluate arterial occlusive disease (AOD) of lower extremities and
      investigate possible effect of amelioration of risk factors to atherosclerosis
      regression. In 1996 we expanded SVS to polyvascular atherosclerotic disease,
      asymptomatic or symptomatic atherosclerotic disease on various vascular beds i.e.
      lower extremity arterial occlusive disease (AOD), cerebrovascular disease (CVD),
      coronary artery disease (CAD). We enrolled a total of 1680 pts. in the study but
      this number has changed depending on war migrations, comorbidity, or paramedical
      reasons. Follow-up of 10 yrs. had 645 pts, and follow-up of 8 yrs. had 1035 pts.
      METHOD: We enrolled a total of 1680 pts, 954 pts with symptomatic disease, and
      246 pts without atherosclerotic disease but with at least 3/8 multiple risk
      factors (MRF), and as controls 400 pts without vascular disease and less than 3
      MRF. STUDY DESIGN: one center, prospective, consecutive, with evaluation of
      epidemiological data--gender, age, comorbidity, antropometrical data, hemodynamic
      data--systolic and dystolic velocities, pulsatility and resistive indices, and
      morphologic data. Clinical variables--gender, age, hypertension, smoking,
      hyperlipoproteinemia, diabetes mellitus, obesity and fibrinogen. Score of MRF was
      calculated as x/8. RESULTS: Out of total of 645 pts (10 yrs. follow-up) 399 pts
      (62%) had AOD, out of them single AOD had 295 pts (74%), and polyvascular disease
      104 pts (26%). 63 (61%) pts of symptomatic group had combination of AOD + CAD,
      and 41 pts (39%) had AOD + CVD + CAD. In the pts with 8 yrs. follow-up (n-1035)
      AOD had 548 pts. (53%), single AOD had 334 pts (57%) and polyvascular had 122 pts
      (39%). Out of symptomatic pts. 71 (58.2%) had AOD + CAD, and 51 (41.8%) had AOD +
      CAD + CVD. Asymptomatic disease on the very entry period of the study was
      significant for both groups, p < 0.01. CONCLUSIONS: (i) we found a significant
      number of asymptomatic atherosclerotic changes on other vascular beds, (ii) score
      of MRF has correlated with polyvascular disease and with overall outcome (iii)
      antropomethric, haemodynamic, and morphological parameters of human blood vessels
      have been measured and systematically documented in Bosnia and Herzegovina.

PMID- 15202299
TI  - [Pericarditis and exudative pleuritis in patients with systemic lupus
      erythematosus before and after therapy].
AB  - AIM OF THE STUDY: To establish the presence of pericarditis and exudative
      pleuritis in patients with systemic lupus erythematosus (SLE) prior to and after
      glicocorticoid and cytotoxic therapy. PATIENTS AND METHODS: In 43 patients, 39
      women and 4 men, with SLE (disease was diagnosed according to revised American
      College of Rheumatology ACR criterias, 1997), aged between 20 and 61 and averaged
      disease duration of 5.54 +/- 5.74 years, heart/lung radiology and heart
      echosonography were performed in order to discover possible serositis
      (pericarditis and exudative pleuritis) prior to and after cytotoxic and
      glucocorticoid therapy. RESULTS: The presence of pericarditis and exudative
      pleuritis was established in 20 patients (47%) before the therapy. After the
      therapy pericarditis was present in 2 patients, average volume of 150 ml, and
      exudative pleuritis was also present in phrenicocostal sinus, but its volume was
      minimal. This table is showing the results of our study on patients with SLE and
      serositis. The results were compared with the results of European and Belgrade
      group in year 2000. [table: see text] CONCLUSION: Higher frequency of serositis
      (pericarditis and exudative pleuritis) in our study is probably a result of more
      active disease, and the effects of cytotoxic and glucocorticoid therapy were
      satisfing exept in two patients who were resistant on therapy. That is the reason
      why we had to consider plasmapheresis.

PMID- 15202300
TI  - [The U-wave in ischemia and left ventricular dysfunction after myocardial
      infarct].
AB  - INTRODUCTION: The occurrence of U-wave in electrocardiogram appears after T-wave.
      It is period of the greatest excitability of the myocardium in heart electrical
      activity usually of the some direction as its own T-wave. AIM OF THE WORK
      ANALYSE: U-wave with ischaemia and dysfunction of the myocardium in exercise
      test. MATERIAL AND METHODS: The prospective study has been done for 51 patients.
      Electrocardiogram, exercise test vas made for all patients and immediately after
      test, echocardiography with Doppler and colour-Doppler. In the analysis of
      dysfunction of the left chamber these important parameters were followed: METS;
      decrease of blood pressure, devaluation of ST-segment, U-wave, heart rate,
      dyspnea, sweating and paleness. RESULTS: Positive U-wave was noticed in 51%,
      negative in 24% examinees. Sensitivity of U-wave on the base of the breakdown of
      segmental vall motion in echocardiography (ischaemia) is 66.67% with false
      negative resists of 33.33%. Systolic dysfunction with influential parameters
      correlates in the best way with decrease of blood pressure and regressive
      coefficient is 66.93, but the weabest correlation is with U-wave (0.53).
      Correlative coefficient for U-wave in systolic function is 0.263. Regressive
      coefficient with influential parameters in diastolic dysfunction is 3.34,
      correlative coefficient is 0.108. CONCLUSIONS: U-wave in registered at rest after
      exercise test when heart rate is equal or below 95 in a minute. Registration of U
      wave is an additional parameter in diagnostics of ischaemia and dysfunction of
      the myocardium of the left chamber (small influence).

PMID- 15202301
TI  - [Statins in dyslipidemia associated with acute myocardial infarct].
AB  - Long time ago lipids increased in blood have been known as risk factor for
      atherosclerosis that causes coronary heart disease among which myocardial
      infarction is the most complicated. Aim were to present the lipids status
      structure in patients with acute myocardial infarction and on the basis of that
      to suggest corresponding statin in treatment. Our research involved 202 patients
      with acute myocardial infarction, patients were both gender and from 37 to 89
      year. Out of total number of patients, 100 of them were with anterior myocardial
      infarction (group I) and 102 with inferior myocardial infarction (group II).
      Whole cholesterol, low density lipoproteins, high density lipoproteins and
      triglycerides were followed. Hi square test and variance analysis were used to
      prove statistically significant difference. In the sample of group I increased
      LDL was found in 92 patients and increased TGL in 46 patients while decreased HDL
      was found in 61 patients. In the sample of group II increased LDL was found in 64
      patients, increased TGL in 44 patients, while decreased HDL was found in 51
      patients. We analysed the next combinations in both groups: LDL > with HDL <; LDL
      > with TGL >; HDL < with TGL >; LDL >, TGL > with HDL <. Combination decreased
      HDL with increased TGL was found in group I in 5 patients, and in group II in 12
      patients. Other combinations in both groups were similarly values. On the basis
      of the obtained results we found statistically significant difference between the
      two groups of patients. Patients in group I have more frequently increased values
      of LDL in comparison to patients in group II (p < 0.00005). In patients in group
      II who had decreased HDL and increased TGL statistically significant difference
      was found in comparison to the patients in group I (p < 0.02). On the basis of
      the obtained results and up to now studies on statins effects we suggest
      Atorvastatin for treatment the patients with anterior myocardial infarction,
      increased LDL with normal values of HDL and Simvastatin for treatment the
      patients with inferior myocardial infarction, decreased HDL.

PMID- 15202302
TI  - [Beating heart surgery in the treatment of stenoses of the main branch of the
      left coronary artery].
AB  - This study reviewed the early experience with off-pump coronary artery bypass
      surgery in treatment of patients with severe left main coronary artery stenosis.
      From May 2002-December 2003, 75 patients with significant left main coronary
      artery stenosis (> or = 50%) underwent coronary artery bypass grafting. 35
      patients were operated without the use of cardiopulmonary bypass (OPCAB) and
      compared with 40 patients operated with the use of cardiopulmonary bypass
      (ONCAB). Mean age, ejection fraction and EUROSCORE were similar in both groups.
      Average grafts per patients was also similar (OPCAB 3.0 vs. ONCAB 3.2). The
      incubation time (3.1 vs. 5.8 hours), blood loss (445 vs. 610 ml) and hospital
      stay (6.8 vs. 8.1 days) were less in OPCAB group. There was no mortality in OPCAB
      group whereas 2 patients (5.0%) died in ONCAB group. Our early experience
      suggests that off-pump coronary artery bypass surgery is effective in treatment
      of patient with severe left main coronary artery stenosis and has advantages
      compare to operations with the use of cardiopulmonary bypass.

PMID- 15202303
TI  - [Atherosclerosis in patients hospitalized at the Internal Medicine Clinic in
      Mostar in the past three years].
AB  - Atherosclerosis, polygenetic, multifactorial and chronic progressive disease of
      arteries leaves significant consequences on organs and their systems and cause
      frequent hospitalisations of patients. Aim found out frequency of atherosclerosis
      process and its consequences (acute myocardial infarction, cardiomyopathy,
      cerebrovascular insult, renal diseases and diseases of peripheral blood vessels)
      together with risc factors (artery hypertension, diabetes mellitus,
      hyperlipidemia, smoking, obesitas, stress an so on.) at patients of Internal
      Clinic in Mostar in the last three years (2001; 2002; 2003). RESULTS AND METHODS:
      During last three years we hospitalised 7278 patients which consequences and
      manifestations of arterosclerosis process had 4825 patients or 66.29% (male 2595
      or 53.7% and female 2230 or 46.22%. Most frequent were CM (1496 or 31%) CAD (1036
      or 21.47%) peripheral vessel diseases (169 or 3.5%) and the most significant CVI
      (104 or 2.15%) which were at our clinic as complication for other internal
      diseases.

PMID- 15202304
TI  - [Sudden cardiac death (SCD) in Mostar in 2003].
AB  - Sudden Cardiac Death (SCD), although all the technical medical developments in
      diagnostics and therapy is one of the biggest health problems in BH and the
      world. Incidence rates of SCD ranging between 0.36 to 1.28 per 1000 inhabitants
      in the general population in Western countries and 1/1000/year in the world. AIM:
      Considering of the incidence SCD in Mostar in 2003 and causes here events.
      METHODS AND RESULTS: With the standard methods of statistics and data regarding
      of Federal statistical office, the hospitals protocols and Emergency medical
      services of Mostar, and results of studies in the preventive actions SCD in BH of
      Association of Cardiologist of Bosnia and Herzegovina and Public Health office of
      BH made correlation and considered that the incidence SCD in Mostar is 0.42% in
      the general population or 50.8% all the natural death. The biggest is at people
      aged after 60 in 82.74%, more in men to women (53.36%). In the 30 deaths of the
      infarct myocardiac in Clinical Hospital of Mostar in 2003, 16 is sudden death,
      with 53.33%. Hospital sudden death is most in the women 62.5%. CONCLUSION: High
      incidence of sudden death in Mostar in 4.2/1000/year is results the
      multifactorial risc factors of coronary artery disease and beggest stress in
      Mostar in the postwar period especially with administrative regulation of the
      city.

PMID- 15202305
TI  - [Trends in cardiovascular diseases in Bosnia-Herzegovina and some European
      countries].
AB  - In the last twenty years, the European office of WHO with its expert groups
      designated CVD as a problem of top priority in European health policy. The
      documents of WHO related to CVD, and their directives to member countries, are
      illustrated in this paper. The authors emphasize that according to available
      data, CVDs are cause of 40% of total mortality among the European population
      above the age of 75. In Bosnia and Herzegovina, CVDs are the leading cause of
      mortality in the last few years. The difference in incidence and prevalence of
      CVD among European countries is emphasized in the paper. According to the
      available data of WHO, the greatest incidence and prevalence of these diseases is
      in East European and Central European countries and the lowest in Mediterranean
      countries, with the exception of Bosnia and Herzegovina. The evaluation of the
      present state of frequency of CVD in Europe and the projection of their trends in
      some countries until 2020 is given in the paper. An alternative projection of the
      trends of CVD in Bosnia and Herzegovina, including a variant of application of
      organized preventive programs, is presented in the paper. Illustrative examples
      of the effects of preventive programs in some European countries, and
      possibilities of their application in Bosnia and Herzegovina are presented in
      this paper. Cost analysis of the application of preventive programs and their
      effects on the reduction of number of people affected by CVD in the short period
      until 2010 and 2020 is also elaborated in this paper.

PMID- 15202306
TI  - [Therapy of hypertension 2004--quo vadis?].
AB  - Management of hypertension, at the beginning of the new millennium, persists in
      being a difficult, demanding and responsible task. Beta blockers and diuretics
      reduce mortality, stroke and coronary disease in patients suffering from arterial
      hypertension. Newer antihypertensive drugs which block the renin angiotensin
      system, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin
      receptor blockers (ARBs), may have additional benefits in high-risk individuals
      with normal blood pressure. The additional benefit has been confirmed in LIFE and
      ANBP2 studies. In HOPE study, application of the ACE inhibitors in high-risk
      patients with "normal" BP values resulted in reduction of major cardiovascular
      events. Problem of adherence to therapy also continues to be one of the most
      important problems in management of hypertension. The success of antihypertensive
      management is directly proportional to the adherence to therapy. The new European
      guidelines for the management of arterial hypertension and JNC 7 recommendations
      offer a rational and effective approach to management of hypertension. These two
      documents contain a series of new attitudes, and reminded of some old and opened
      some new questions.

PMID- 15202307
TI  - [New approach in the diagnosis of acute coronary syndrome].
AB  - CVD are on the first place among death causes in the world. The half of all death
      at middle age persons is CVD causality, the most often because of ischaemic heart
      diseases, and there are a few clinic forms: acute coronary syndrome, stabile
      pectoral angina, variant pectoral angina, syndrome x, and silent myocardial
      ischemia. Toward definition ACS include clinical manifestation causality of
      myocardial ischemia due of atherosclerotic plague rupture. ACS include: non
      stable pectoral angina non-Q infarction, Q myocardial infarction and sudden
      cardiac death. Consequence of plague rupture is occlusive thrombus which produces
      typical ST elevation on ECG after that appearance Q-in ECG with blood markers
      elevation (Troponin I, T, CK and CK-MB). There are sometimes non-typical ST
      elevation on ECG with blood markers elevation and chest pain. On that way becomes
      non-Q infarction. Smaller thrombus make non stable pectoral angina and appearance
      of ST depression on ECG without blood markers elevation. Sometimes sudden cardiac
      death is the first sign of coronary disease in the diagnostic management coronary
      disease due of: clinical symptom of chest pain, ECG (with or without ST
      elevation) and appearance appsence biochemical blood markers (at myocardial
      necrosis troponins are present in blood during 14 days, CK-MB is present 3 days).
      Sometimes echocardiography examination is helpful in estimate of regional kinetic
      disorders. European society of cardiologists made guidelines for management od
      ACS without ST elevation and guidelines management of acute myocardial infarction
      with ST elevation.

PMID- 15202308
TI  - [New aspects in the diagnosis of pulmonary embolism].
AB  - Pulmonary embolism (PE) and deep venous thrombosis (DVT), venous thromboembolism
      (VTE) respectively, are relatively frequent diseases. Despite progress in early
      detection and treatment, the rates of mortality and recurrent PE, remain high.
      Clinical findings include oligosymptomatic conditions with unexplained chest
      discomfort or shortness of breath that cannot be recognized as PE, but also and
      massive embolism with hemodynamic colapse and sudden cardiac death (SCD). The
      time from the first symptoms, till PE diagnosis is the most important for
      prognosis. Diagnostic methods include non imaging methods as plasma d-dimer
      Elisa, electrocardiogram, and many imaging methods from roentgenography,
      echocardiography, lung scanning, spiral chest computed tomography, magnetic
      resonance imaging to pulmonary angiography as "the gold standard" for PE
      diagnosis. It is recommended integrated diagnostic approach and various
      algorithms according to medical equipment and staff skill of a hospital.

PMID- 15202309
TI  - [Anatomic variations of the cystic duct and its junction with the common hepatic
      duct].
AB  - The ductus cysticus is variable in the length, position and the site where it
      enters the ductus hepaticus communis--the cystohepatic junction. The
      investigations were carried out on 100 livers (50 anatomical preparations and 50
      patients) adults of both sexes, randomized trial. Main methods of the research
      were: anatomical macrodissection and analysis of the clinical radiograms. The
      ductus cysticus were present as: flat--down course in 70%, flat--horizontal
      course in 2%, flat--ascendant course in 4%, curved in the shape "J" in 10%,
      curved in the shape "S" in 12% and curved in the shape "U" in 2%. The
      cystohepatic junction shows variations in topographic zones.

PMID- 15202310
TI  - [Stereologic analysis of renal cortical structures during compensatory
      hypertrophy in rats].
AB  - The qualitative and quantitative study of renal cortical structures was performed
      seven days after unilateral nephrectomy. Adult Wistar rats (10 male and 10
      female) were ether-anaesthetized and the kidneys were removed by dorsolateral
      approach. Renal hypertrophy was determined by measurement of kidney dry mass. The
      samples of renal tissue were embedded in paraffin, sectioned at 6 microns and
      stained by azan and haematoxylineosin methods. The volume densities of renal
      corpuscles, the epithelium of tubules, luminal space of tubules and cortical
      interstitial structures were calculated using Weibel's multipurpose test system M
      42. The qualitative analysis was performed to determine possible structural sex
      differences of cortical parenchyma during compensatory hypertrophy. There was no
      significant difference in volume densities of renal corpuscles and distal tubules
      between control and hypertrophic kidney. The volume density of the epithelium of
      proximal tubules and interstitial blood vessels were statistically significant
      increased in hypertrophic kidney compared to the values determined in control
      kidney. The volume density of luminal space of proximal tubules and interstitial
      tissues were statistically significant decreased in hypertrophy compared to
      control kidney. The data from present studies shows that the increase in
      epithelial volume of proximal tubules and interstitial blood vessels volume have
      the primary role in compensatory kidney enlargement after unilateral nephrectomy,
      while renal corpuscles do not participate significantly.

PMID- 15202311
TI  - [Importance of immunoglobulins and nutrition in infections in neonates].
AB  - The purpose of the study was an estimation of the immunoglobulin serum and the
      way of nutrition of a new-born child at the beginning of bacterial infections
      during the first month of life. 120 new-born children (infantiles) of both sexes
      was prospectively studied, who were born in the Gynecology-obstetrician clinic in
      Tuzla, in the period from March-May 2000 year. On the base of mothers SES during
      the pregnancy, new-born children were separated in two groups. Group A was formed
      of 60 new-born children (32 female and 28 male), mothers had good SES during the
      pregnancy, and concentration of serum immunoglobulin G (IgG) examined from cords
      blood, from 10.02 to 17.58 g/L (X 14.48 g/L +/- 1.87). Group B was formed of 60
      new-born children (27 female and 33 male), with bad mothers SES and with
      concentration of IgG from 6.80 to 13.01 g/L (X 10.62 g/L +/- 1.49).
      Immunoglobulins M and immunoglobulins A were negative in both groups of children.
      During the first month of life it was studied the way of nutrition and health
      condition of each new-born child. New-born children with bad mothers SES during
      the pregnancy, with low values of IgG and who were on the artificial food
      (nutrition), were showing with the significant difference (p < 0.001) in
      bacterial infections, comparing with the group who had good IgG. The new-born
      children with natural nutrition, despite the lower concentration of IgG, were
      protected from severe bacterial infections.

PMID- 15202312
TI  - [Urgent neurologic states: experience at the Neurology Clinic in Sarajevo].
AB  - There is a quite good definition of medical care for patients suffering from
      chronicle neurological diseases. However the neurologist role in taking care of
      urgent cases is substantially less determined. This paper is analyzing one year
      efforts of the on duty neurological team in the Out Patient Department and
      Emergency Division of the Neurology Department in Sarajevo. During this period
      the on duty neurological team examined the total of 3939 patients, out of which
      1022 patients where kept for treatment. The patients where most frequently
      assigned to the Emergency unit for following reasons: vascular incident of the
      Central Nervous System(1955 patients or 50%), cerebrovascular accident
      represented with 1290 or 33%, and TIA of the carotid and vertebrobasilar area 544
      or 14% along with hypertensive encephalopathia, 118 or 3%. This is followed by
      the group of the short-term disturbance of consciousness (472 or 125), out of
      which the consciousness crises represented 257 or 7%, and epileptic crises 215 or
      5%. Following are the lower percentages of the headaches (287 or 7%), radicular
      painful syndrome of cervical and lumbal area (209 or 5%), vertigo (183 or 5%),
      neurophatia (167 or 4%), etc. The more extensive number of patients admitted at
      the Emergency Division where suffering from brain stroke (800 or 78%), TIA was
      represented by a lower number (172 or 17%). Only 50 patients had other diagnosis.
      The ischemic stroke represented 674 or 81% with patients suffering from the brain
      stroke and the hemorrhagic stroke 153 or 19%. Today, the urgent neurological
      conditions represent a particular area of Neurology, not only neurologists need
      to know but also other medical doctors, to enable the patients to be forwarded on
      time to the appropriate care institution.

PMID- 15202313
TI  - [Anxiety and depression in deaf and hard-of-hearing adults].
AB  - The main purpose of this study was to determine the differences between the
      anxiety and depression degree in individuals with severe hearing impairments and
      deaf people in relation to sex and marital status. The sample consisted of 54
      subjects, 35 males and 19 females, aged from 18-61 years, with hearing loss
      greater than 60 dB. We used "SCL-90-R" (Symptom Checklist-90-Revised), to assess
      the level of anxiety and depression. For the examination of marital stress we
      used "Stockholm Marital Stress Scale". The results showed that deaf and hard-of
      hearing individuals demonstrated certain anxiety and depression levels which
      correlated significantly with marital status, marital stress, and communication
      problems. The married deaf subjects showed higher anxiety degree than single one.
      We determined the statistically significant differences for the anxiety level (p
      < .03861), age (p < .0006), and communication problems (p < .033) between the
      married and single deaf people. The females exhibited higher anxiety and
      depression levels than males, but these differences were not statistically
      significant. For the prevention of psychological problems in deaf and hard-of
      hearing individuals it is necessary to pay attention to their communication
      problems which are a condition for adequate society integration.

PMID- 15202314
TI  - Comparing youth health in Sweden and Bosnia.
AB  - The Adolescence Medical Group in Sweden has performed a questionnaire every
      second year since 1990. The questionnaire is performed during school hours in
      seventh and ninth grade and also in the second grade in the upper secondary
      school (gymnasium). The questionnaire is completed anonymously. The schools are
      not chosen by statistical methods, but more depending on youth-health-iterested
      school doctors and nurses who have interest in these studies. The result of these
      studies has been used locally in each community, but also been reported for
      example i Acta Pediatrica. After the war in Bosnia there has been different
      projects to help to build up the countries health system, for example in
      psychiatry. The question was laso raised how the youth health was in Bosnia.
      Representatives from the Adolescence section in Sweden were invited to Bosnia to
      introduce the questionnaire and also to help in analysing the results. We were
      also in Bosnia to present results to local authorities and those who performed
      the study locally.

PMID- 15202315
TI  - [Sensitivity, specificity and predictive value of the treadmill stress test in
      comparison with coronary angiography findings].
AB  - Precondition to prevention and control of morbidity and mortality of myocardial
      ischemia--coronary disease, is its good diagnostic. Goal of this study is to
      asses diagnostic significance of positive trademill stress test in diagnosis of
      coronary disease. MATERIAL AND METHODS: we analyzed 120 patients with markedly
      positive classic trademill stress test using Bruce protocol in the year 2003. In
      all cases, positive stress test was followed by selective angiography, using
      standard technique with multiple sections. Blood vessel narrowing of more than
      50% was chosen as the criteria for positive angiographie finding. With the help
      of coronary angiography, it was found that 62 (51.7%) of patients has stenosis of
      less than 50% or normal angiographic finding. 58 (48.3%) of patients had stenosis
      of more than 50%. Of that number, 24 (41.4%) had one-vessel coronary disease, 12
      (20.7%) two-vessel coronary disease, and 10 (34.5%) three-vessel coronary
      disease. 2 patients (3.4%) had stenosis of the trunk of left coronary artery.
      Results of this study show that the sensitivity of trademill stress-test is less
      than optimal, and should be supplemented by other non-invasive techniques (such
      as myocardial perfusion scintigraphy, radionuclide ventriculography and stress
      echocardiography) in diagnostics of coronary disease.

PMID- 15202316
TI  - [Analysis of the quality of life in patients with spinal lesions in the Canton of
      Sarajevo].
AB  - The author present in the retrospective analysis 10 patients (52 females, 48
      males) with the condition of paraplegy in Canton Sarajevo in the period 01.01.
      31.12.2002. year. In all the patients were followed the total life and working
      activities as are proclaim by UN 1994. The standard rules for the equal
      possibilities of the persons with unableness what predicts the insurance of their
      rights from the medical care and additional services. The results of the
      examination show that there does not exist one program for the professional
      direction and that only 8 (16%) males and 2 (4%) females employed while the rest
      unemployed, prematurely retired people or it is about the children it schooling.
      Although the persons with paraplegia get qualified as the persons with unableness
      of the adaptation and the life--housing adaptation only portionally performed
      (entrance in the flat--house 30%, bathroom/WC 26%, the thresholds 60%). They are
      identical the situations and with use of the utilities: wheel chair--stand--beds
      (92%:2%:29%). The particular caution is by the parents, marital partner 32% and
      27% by brother, sister or another family member. The results which concern life
      of the examinees in the community show that 16% of examinees live along. The
      identical is the situation when ace in question also the members in the
      association and attending of the tuition at schools or faculties.

PMID- 15202317
TI  - [Analysis of abortion trends in the Zenica-Doboj Canton].
AB  - Authors present results of statistical analysis of data of abortions, in period
      since 1980 up to date. The frequency and trend of the abortions in the entitled
      canton of Federation of Bosnia and Herzegovina, in the period 1980-1989 and 1996
      2001. It was found that the percentage of abortions had been yearly growing, from
      66 cases per 100 deliveries in the year 1980, 88 cases in the year 1985, to 97
      cases in the year 1989. Comparing to Zenica-Doboj Canton, in the regions of
      Doboj, Tuzla, Sarajevo, the number of abortions in the mentioned period was
      remarkably higher varying from 127 to 178 cases per 100 deliveries. It is worthy
      to notify that in the period 1996-2001 the participation of young women in the
      abortions with the percentage of 2.5% in the year 1996, had been rather
      indicative showing the tendency of growing during the rest years of the
      investigated period. The women of the age group between 25 and 39 were the main
      candidates for artificial abortions, the ladies within 30-34 years of age being
      most predominant. It is also remarkable that in the last four years the elderly
      ladies (elder than 49 years of age) showed the tendency of artificial abortions,
      up to 0.49 cases per hundred deliveries.

PMID- 15202318
TI  - [Viruses in drinking water: HAV and enteroviruses].
AB  - The presence of waterborne enteric pathogens (bacteria, viruses and protozoa) in
      potable water represents a potential danger for people's health. While doing a
      microbiological examination of potable water on a regular basis, we obtain a
      constant control of presence of the bacteria that contaminate water. However, the
      water examination of the enteric viruses is done only when we have some large
      scale hydrous epidemics. Finding the bacteria wich point to fecal contamination
      of drinking water is not a safe indicator of presence of the enteric viruses.
      After a two step RT/PCR examination on viruses in 84 samples of potable water,
      the enteroviruses were found in 53 out of 84 samples (63.09%), while the
      hepatitis A virus was not found after one step RT/PCR examination. In conclusion,
      we emphasize the need of standardizing the method of potable water viruses
      detection, in order to legalize the need of its regular application.

PMID- 15202319
TI  - [Nitric oxide--a potential modulator of left ventricular diastolic function in
      hemodialysis patients treated with erythropoietin].
AB  - Left ventricular hypertrophy (LVH) is commonly present in hemodialysis patients
      (HD pts) and is considered as an independent risk factor for high mortality. Many
      studies have confirmed sound connection between anemia and LVH in this patients.
      OBJECTIVE: To analyse dystolic function of LVH in uraemic pts during the 6 months
      human recombinant erythropoectin (rHu-Epo) treatment of anemia, with emphasis on
      the role of nitric oxide (NO), whose role in regulation of LV diastolic
      distensibility has been hinted in some recent studies. PATIENTS AND METHODS: The
      study included 20 HD pts, aged 39.6 +/- 5.3 yrs, with the same condition of HD
      treatment, signs of anemia and echocardiographically verified LVH. Pulse Doppler
      echocardiography confirmed LV diastolic function as a ratio of early to late
      diastolic mitral flow velocity (E/A). Nitrate concentration was determined by
      colorimetric method using Greiss reagent. Renal anemia was treated with rHuEpo.
      RESULTS: Six months rHuEpo treatment of anemia in HD pts with LVH caused
      significant reduction of LV mass index (p = 0.008). However, we observed
      unfavourable fall in LV diastolic function (E/A = 0.83, p = 0.007). In the same
      time, it was found that the serum NO level was higher for 11.8% in HD pts with
      LVH as compared with the pts with normal LV mass. Also, the significant positive
      correlation was found between the level of NO and LV mass index before (p =
      0.004) and after rHuEpo therapy (p = 0.03), as well as a significant positive
      correlation between NO and E/A in the same conditions (p = 0.002) and p = 0.049).
      Level of NO negatively correlates with blood hemoglobin level, but without
      statistical significance. CONCLUSIONS: Correction of anemia with rHuEpo leads to
      the significant partial regression of LVH. Reduction of diastolic function of LV,
      observed after diminished LV mass index, could be related to the significant fall
      of NO level and damaged response of LV to NO. The results of the study strongy
      suggest that NO can present an important determinant of LV diastolic function in
      uraemic pts.

PMID- 15202320
TI  - [Effect of erythropoietin on gonadotropic hormones and sexual function in
      patients on hemodialysis].
AB  - INTRODUCTION: Correction of anemia in haemodialysed patients by recombinant human
      erythropoetin (R-Hu Epo) has been reported to improve sexual functions and
      hormonal disturbances. The purpose of this study was to evaluate how levels of
      sexual hormones and sexual function differ before and during a 12 month R-Hu Epo
      therapy. MATERIALS AND METHODS: Thirty six male patients, mean age 47.5 +/- 12.78
      and thirty six female patients, mean age 53.0 +/- 10.14, were included in this
      study. All patients were dialyzed 3 times per week with haemodialysis mean
      duration of 4.56 +/- 3.84 years. In order to evaluate sexual activities, the
      questionnaire was presented to all patients. The levels of prolactin,
      testosterone, FSH, LH were measured at the beginning of the study and every forth
      month during the study. RESULTS: During twelve month therapy with Epo, serum
      hemoglobin significantly increased from 96.0 +/- 13.3 g/dl to 104.0 +/- 17.2 g/dl
      (p < 0.005), and hematocrit value rose from 0.284 +/- 0.046% to 0.308 +/- 0.052%
      (p < 0.05). Prolactin was not significantly decreased: at the beginning of the
      study was 540.3 +/- 302.2 and at the end 537.4 +/- 297.1 microIU/ml. Testosterone
      concentrations were in normal range in male patients (18.26 +/- 8.61 microIU/ml).
      There was significant difference in value of LH in female patients which
      increased from 57.68 +/- 62.58 to 73.79 +/- 68.52 IU/L. Improvement of sexual
      function was remarkable in female patients. In male patients sexual desire,
      frequency of sexual intercourse was strengthen after R-Hu epo therapy.
      CONCLUSION: Better sexual functions in our patients after treatment with R-Hu Epo
      did not correlate with hormonal disturbances except changes of LH that increased
      at the end of the therapy.

PMID- 15202321
TI  - [Reliability of screening methods in the diagnosis of dysplasia and cervical
      carcinoma in asymptomatic women].
AB  - The aim of this study was to estimate the reliability and accuracy of the chosen
      methods: cytological results (PAP smear) and colposcopic findings in the
      detection of cervical dysplasia and cervical cancer. MATERIAL AND METHODS: We
      have analyzed post conization pathohistological results and compared them with
      cytology results and colposcopic findings in 51 patients. Surgical procedure
      (conization) was performed for diagnostic and therapeutic reasons. RESULTS:
      Results have shown that there is a positive correlation between cytological and
      colposcopic results on one side and post conization pathohistological results, on
      the other side (p < 0.02). CONCLUSION: According to our experience, both
      screening methods (cytology and colposcopy) are reliable methods if performed by
      properly educated staff, and they both influence (reduce) morbidity and mortality
      among women.

PMID- 15202322
TI  - [Trial of labor after previous cesarean section].
AB  - Elective repeat cesarean section continues to remain the standard to care at GYK
      and OBST. Department in Sarajevo. This paper is a study of 216 patients with
      previous cesarean section who requested and were allowed a trial of labor. One
      hundred fifty-six (72%) achieved successful vaginal delivery with no maternal or
      fetal mortality or significant morbidity. Review of the USA literature indicates
      similar results in other independent studies. Continued accumulation of cases
      showing the efficacy of post-cesarean section trial of labor should encourage a
      reassessment of the continuing practice of elective repeat cesarean section.

PMID- 15202323
TI  - [Pseudoaneurysm in the posterior wall of the left ventricle with perforation of
      the left ventricle due to a firearm injury].
AB  - In a moment of injury Sarajevo was a war zone. Patient was shot with a bullet on
      a left side thorax and a heart. Immediately after injury patient only received a
      first aid in Sarajevo and than later cardiosurgery treatment abroad precisely in
      Italy. For a last couple of years patient because of subjective changes and
      objective symptoms was treated conservative. After the right diagnosis was
      established (pseudoaneurysm of left ventricle) patient received an open heart
      surgery.

PMID- 15202324
TI  - [Establishment of the Regional Hospital in Sarajevo].
AB  - The authors presented work of Muslim Charitable Hospital in Sarajevo, which was
      established in the year of 1866 and the reason why Lands Hospital was also
      established in the same city. They presented the latter and the first five years
      of its functioning too. They also presented six figures, which undoubtfully
      argued that Land Hospital was not builder for domestic inhabitants already for
      medical purposes of occupational troops and all those, which was coming with
      them. But domestic inhabitants very soon occupied almost all beds in new
      hospital, because hospital was established allotted and sanitary occasions in
      Bosnia and Herzegovina irrespective of many community hospitals were not finished
      and ended with the Muslim Charitable Hospital, because of its small capacity and
      arising of necessities of inhabitants.

PMID- 15202325
TI  - [Secondary prevention and conservative therapy of obliterative arteriosclerosis].
AB  - The author gives an overview of the main ways of medical therapy for patients
      with peripheral arterial obliterative disease. The importance of possible
      modification of the risk factors is emphasized especially beneficial effects of
      supervised walking-based exercise program. It is considered proven that the
      antiplatelet therapy and antilipidemic treatment reduce the risk of progressive
      atherosclerotic processes. The author summarizes the mechanisms and clinical
      effects of drugs influencing haemostation and haemorheology as well as
      vasodynamic agents. The results of clinical trials show a marked improvement of
      intermittent claudication by combination of preventive and therapeutic ways in
      majority of patients with peripheral arterial obliterative disease.

PMID- 15202327
TI  - [New results in allotransplantation of pancreatic islet cells].
AB  - An up-to-date synthesis of pancreatic islet allotransplantation is included in
      this summary, with emphasis on new developments and clinical results of the
      field. Rationale for islet transplantation in type 1 diabetes mellitus, current
      patient selection criteria, clinical data, technical aspects of organ
      procurement, islet isolation and transplantation are highlighted. The current
      challenges are also presented and analysed. Significant advances in clinical
      islet transplantation have been achieved recently. New immunosuppressive
      strategies were introduced, there were considerable changes in the patient
      selection criteria. International collaborations were established in order to
      standardize islet isolation and transplantation procedures. The spectacular
      results, recently reported by the Edmonton-group, represent a major breakthrough
      of the field and the outcomes are comparable with the results of whole pancreas
      transplantation. Islet transplantation became one of the most promising fields of
      tolerance induction research. Although still considered experimental, within the
      frameworks of expanding international collaborations, pancreatic islet
      allotransplantation gains more and more recognition in the clinical practice.
      These elements give hope that diabetes might be in the near future treated by
      islet cell transplantation.

PMID- 15202326
TI  - [Osteoporosis associated with inflammatory bowel diseases].
AB  - Inflammatory bowel diseases, most frequently Crohn's disease, are frequently
      accompanied by decreased bone mineral content (30-70%). The osteopenia is not
      explained by the side effects of treatment or the secondary malabsorption. There
      must be a common pathological pathway in the background. The mineral content of
      bones is most easily measured by dual-ray absorptiometry. The measurement should
      be performed at the time of the diagnosis of bowel disease. It is useful to
      perform some routine laboratory examinations (serum calcium and phosphate,
      urinary calcium excretion level, etc.) and some special tests (serum osteocalcin
      and crosslaps) to exclude some other pathological pathways as well as to plan the
      anti-osteoporotic therapy. Appropriate calcium and vitamin-D supplementation is
      essential in prevention and therapy as well. Several drug-classes have proven
      useful in the therapy of severe osteoporosis associated with inflammatory bowel
      diseases such as bisphosphonates, hormone replacement therapy, selective estrogen
      receptor modulators and calcitonin. The authors provide an algorithm for the
      therapy of metabolic bone disease in inflammatory bowel disease.

PMID- 15202328
TI  - [Laparoscopic treatment of bile leakage from the Luschka duct after laparoscopic
      cholecystectomy].
AB  - The possible reasons for bile leakage following laparoscopic cholecystectomy are
      the injury of the common bile duct, the insufficient treatment of cystic duct
      (non competent or non closing, or spontaneously removing clip, stumpnecrosis due
      to electrocoagulation near to clipp, rupture adjacent to the clipp) or the
      opening of an aberrant bile duct. The latter often may occur in case of the
      anatomic variation described by Hubert von Luschka (1820-1875) a German anatomist
      as the duct named after Luschka. In a favorable case the accessory bile duct
      closes by itself, but occasionally developing biloma and/or biliary peritonitis
      need to be operated on. The authors write about the case of a 52 years old female
      patient, who underwent laparoscopic cholecystectomy, and 3 days later the
      complication was averted through the application of relaparoscopy with
      intracorporal suture. In connection with this case the authors acquaint the
      readers with the biography, the academic carrier of Hubert von Luschka, and the
      literature related to Luschka duct is surveyed.

PMID- 15202330
TI  - [Dr. Balazs Szendi, Hungarian pioneer of the ethology of the human fetus].

PMID- 15202329
TI  - [Treatment of chronic hepatitis C].

PMID- 15202331
TI  - [Dr. Gyula Kerkovits, cardiologist, honorary citizen of his native village].

PMID- 15202332
TI  - Makeover nation. Americans are opting for cosmetic surgery in record numbers. But
      do they know the risks?

PMID- 15202333
TI  - Our biotech bodies, ourselves.

PMID- 15202334
TI  - Medications. Rx: split decisions.

PMID- 15202335
TI  - Bed-exit alarms. A component (but only a component) of fall prevention.
AB  - Patient falls are a common cause of morbidity, nonfatal injuries, and trauma
      related hospitalizations in the United States. Sometimes, they're even fatal.
      Falls typically occur either while the patient is getting into or out of bed or
      shortly after the patient has exited the bed. One means of helping to reduce the
      number of patient falls is the bed-exit alarm. Such alarms can be either built-in
      devices incorporated into the beds themselves or stand-alone units consisting of
      a portable control unit and a pressure- or position-sensitive sensor. They can
      serve as an "early warning system" alerting nursing staff when patients attempt
      to leave their beds unassisted. However, bed-exit alarms do not themselves
      prevent falls--a fact that is not always clearly understood. To be effective,
      they need to be implemented with care and with a clear understanding of their
      limitations. In this article, we describe the types of stand-alone bed-exit
      alarms currently available on the market and provide guidance to facilities on
      how to implement them effectively. We also review the elements of an effective
      fall-prevention program and recount one hospital's success in reducing patient
      falls. We are in the process of conducting a comparative evaluation of a number
      of bed-exit alarms, which will be published in an upcoming issue of Health
      Devices.

PMID- 15202336
TI  - Lower-protein latex gloves. A way to reduce allergic reactions in hospital staff.
AB  - It has long been accepted that the proteins in natural rubber latex (NRL) medical
      gloves can cause sensitivity reactions in some healthcare workers. What hasn't
      been clear is whether the amount of protein in the gloves relates to the number
      of people who react to NRL gloves. Recent studies, however, clearly demonstrate
      that it does. By using lower-protein gloves, hospitals can help address NRL
      allergy issues among glove users. Recent standards from the American Society for
      Testing and Materials (ASTM) have recommended using gloves with aqueous soluble
      protein content no higher than 200 micrograms per square decimeter
      (microgram/dm2) of glove material. But some gloves are available with protein
      levels as low as 50 micrograms/dm2. ECRI believes that hospitals should use NRL
      gloves with the lowest possible protein levels. Hospitals wishing to buy low
      protein gloves should look for labeling that lists the protein content of the
      gloves, that identifies them as conforming with the latest ASTM standards, or
      that lists a new type of certification--the Standard Malaysian Glove (SMG)
      certification. The SMG program sets glove requirements that include barrier
      strength and protein content. Gloves bearing the SMG label conform to published
      standards and are routinely inspected for quality.

PMID- 15202337
TI  - Datex-Ohmeda S/5 Compact monitors can experience power supply failures at start
      up and during operation.

PMID- 15202338
TI  - Erroneous voxel sizes on 3-D reconstructions using GE advantage CT workstation.

PMID- 15202339
TI  - Compressor shutdown on Cincinnati Sub-Zero Hemotherm Dual Reservoir
      Cooler/Heater.

PMID- 15202340
TI  - Purchasing MR-safe or MR-compatible equipment.

PMID- 15202341
TI  - Teaching methods in the affective domain.

PMID- 15202342
TI  - Biological effects of diagnostic imaging.

PMID- 15202343
TI  - PACS integration and work flow.

PMID- 15202344
TI  - Educational philosophies.

PMID- 15202345
TI  - RA certification update.

PMID- 15202346
TI  - Giant cell tumor.

PMID- 15202347
TI  - First you see it, now you don't.

PMID- 15202348
TI  - All the world's a schoolroom.

PMID- 15202349
TI  - Patient page. Chest radiography.

PMID- 15202350
TI  - What research practices in China may teach the U.S.

PMID- 15202351
TI  - Tests involving humans subjects: old and new in China.

PMID- 15202352
TI  - Ethical principles for the conduct of research involving human subjects:
      historical considerations.

PMID- 15202353
TI  - When experiments go wrong: the U.S. perspective.
AB  - The view that once prevailed in the U.S.--that research is no more dangerous than
      the activities of daily life--no longer holds in light of recent experience.
      Within the past few years, a number of subjects (including normal volunteers)
      have been seriously injured or killed in research conducted at prestigious
      institutions. Plainly, when we are talking about research going wrong, we're
      talking about something very important. We have seen that experiments can go
      wrong in several ways. Subjects can be injured--physically, mentally, or by
      having other interests violated. Investigators can commit fraud in data
      collection or can abuse subjects. And review mechanisms--such as IRBs--don't
      always work. The two major issues when research goes wrong in any of these ways
      are, first: What will be done for subjects who have suffered an injury or other
      wrong? and second: How will future problems be prevented? The present system in
      the U.S. is better at the second task than the first one. Part of the difficulty
      in addressing the first lies in knowing what "caused" an apparent injury.
      Moreover, since until recently the problem of research-related injuries was
      thought to be a small one, there was considerable resistance to setting up a non
      fault compensation system, for fear that it would lead to payment in many cases
      where such compensation was not deserved. Now, with a further nudge from the NBAC
      there is renewed interest in developing a formal system to compensate for
      research injuries. Finally, I have tried to show that our system of local
      oversight is only partially effective in improving the design of experiments and
      the consent process in light of "unexpected (adverse) results." As many
      observers, including the federal General Accounting Office (GAO), have reported,
      the requirement for "continuing review" of approved research projects is the weak
      point in the IRB system. The probable solution would be to more strictly apply
      the requirement that investigators report back any adverse results, de
      emphasizing the "screen" introduced by the present language about "unexpected"
      findings. Yet, despite its weaknesses, there are good aspects to the local basis
      of our oversight system, and when problems become severe enough, OHRP is likely
      to evaluate a system and insist on local improvements. Thus, while the U.S.
      system is far from perfect in responding when research goes wrong, our experience
      may be useful to others in crafting a system appropriate to their own
      circumstances. One of the major tasks will be to adequately define what triggers
      oversight--that is, who reports what to whom and when? The setting of this
      trigger needs to balance appropriate incentives and penalties. Any system,
      including our own, will, in my opinion, work much better once an accreditation
      process is in place, which will offer much more current and detailed information
      on how each IRB is functioning and what steps are needed to help avoid
      "experiments going wrong."

PMID- 15202354
TI  - Clinical trials in China: protection of subjects' rights and interests.

PMID- 15202355
TI  - Informed consent in research involving human subjects.

PMID- 15202356
TI  - Special challenges to the informed consent doctrine in the United States.

PMID- 15202357
TI  - Conflict of interests in research ethics: a Chinese perspective.

PMID- 15202358
TI  - Clinical trials in traditional Chinese medicine.

PMID- 15202359
TI  - Research with vulnerable participants.

PMID- 15202361
TI  - The individual and the community in international genetic research.

PMID- 15202360
TI  - Evaluation of the informed consent process in a randomized controlled trial in
      China: the Sino-U.S. NTD project.

PMID- 15202362
TI  - Future challenges from the U.S. perspective: trust as the key to clinical
      research.

PMID- 15202363
TI  - The use of human subjects in research conference.

PMID- 15202364
TI  - Senate again stymies MedMal reform.

PMID- 15202365
TI  - CMS clarifies exceptions to specialty hospital moratorium.

PMID- 15202366
TI  - Medicare: actuarial assumptions probed, trustees report released.

PMID- 15202367
TI  - Medicare's new drug discount card.

PMID- 15202368
TI  - McDonald's CEO health: don't ask, do tell.

PMID- 15202369
TI  - Blood feud.

PMID- 15202370
TI  - Hospitals' terminal disease. Health-care spending continues to rise--so why is
      this industry struggling to grow?

PMID- 15202372
TI  - [Capsule endoscopy visions].

PMID- 15202371
TI  - This man would have you live a really, really, really, really long time.

PMID- 15202373
TI  - [A new epoch of arrhythmia treatment?].

PMID- 15202374
TI  - [Invasive treatment of cardiac arrhythmias. A survey of activities and
      expectations concerning the development in the coming decades].

PMID- 15202375
TI  - [Gene mutations connected to Crohn disease].

PMID- 15202376
TI  - [Capsule endoscopy--a new imaging method in gastroenterology].

PMID- 15202377
TI  - [Relation between postmenopausal hormone replacement therapy and ischemic heart
      based on a Danish prospective cohort study].

PMID- 15202378
TI  - [The Danish Hernia Database--four years' results].

PMID- 15202379
TI  - [The effect of soluble dietary fibers on glycemic regulation and lipid status in
      patients with type 2 diabetes mellitus].

PMID- 15202380
TI  - [Oxidative DNA damage in human leukocytes in antioxidant intervention studies].

PMID- 15202381
TI  - [Rising prevalence and decreasing mortality of diabetes in the county of Funen].

PMID- 15202382
TI  - [Termination of ventilator therapy in a patient with amyotrophic lateral
      sclerosis].

PMID- 15202383
TI  - [Hemobilia, a rare complication of liver biopsy].

PMID- 15202384
TI  - [Picture of the month: purulent pericarditis and lobar pneumonia].

PMID- 15202385
TI  - [The diagnostic value of the histopathological examination in the investigation
      of liver tumors].

PMID- 15202386
TI  - [A dangerous book?].

PMID- 15202387
TI  - [Vitamin D--quo vadis?].

PMID- 15202388
TI  - [Wrong solution of a serious problem].

PMID- 15202389
TI  - [Hypothermia].

PMID- 15202390
TI  - [130 km/hour is probably unethical for physicians].

PMID- 15202391
TI  - A shot or a pill: exploring biomedical approaches to HIV prevention.

PMID- 15202392
TI  - Informed consent in HIV research.

PMID- 15202393
TI  - Disease management. CDC reorganizes.

PMID- 15202394
TI  - Cirque du Soleil to pay $600,000 settlement in discrimination suit.

PMID- 15202395
TI  - Positive HIV tests causes changes in porn filming industry.

PMID- 15202396
TI  - Case consolidation approved in blood contamination suits.

PMID- 15202397
TI  - Testing. Court will hear case of woman wrongly told she had HIV.

PMID- 15202398
TI  - Prevention. San Francisco mayor proposes intensive outreach program.

PMID- 15202399
TI  - Advocates stroke out at NIMBY.

PMID- 15202400
TI  - Exposure. Order for HIV-positive man to wear spit hood in court upheld.

PMID- 15202401
TI  - ADA. Accommodation claim fails for man replaced due to AIDS.

PMID- 15202402
TI  - HIV-related depression unable to overturn tough sentence.

PMID- 15202403
TI  - Prisons. HIV-positive inmate's deliberate indifference claim fails.

PMID- 15202404
TI  - Prisons. Segregation of HIV-positive inmates in Miss. upheld.

PMID- 15202405
TI  - Parole supervision reinstated for HIV-positive offender.

PMID- 15202406
TI  - Drug pricing. HIV/AIDS patients file federal antitrust suit against Abbott.

PMID- 15202407
TI  - Genes, ethnicity, and efavirenz response: clinical pharmacology update from the
      11th CROI.

PMID- 15202408
TI  - Syphilis rates climb again.

PMID- 15202409
TI  - Travel advice for HIV-infected individuals.

PMID- 15202410
TI  - Aid programs. Panel: combine HIV care with entitlement programs.

PMID- 15202411
TI  - States implement emergency measures to keep ADAPs alive.

PMID- 15202412
TI  - FDA guidelines revised for combination HIV therapies.

PMID- 15202413
TI  - ADA. Company lawfully terminated employee with AIDS.

PMID- 15202414
TI  - HIV testing upheld for man convicted of child sexual abuse.

PMID- 15202415
TI  - ADAP. Rationing of AIDS drugs feared.

PMID- 15202416
TI  - ADAP. Virginia to address gap in HIV health services.

PMID- 15202417
TI  - Author describes role of U.S. apathy in growing pandemic.

PMID- 15202418
TI  - Author addresses U.S. response to AIDS pandemic.

PMID- 15202419
TI  - Medical marijuana. AIDS patients get injunction against DEA agents.

PMID- 15202420
TI  - Treatment and care of patients with chronic severe brain damage. Medical-ethical
      guidelines of the Swiss Academy of Medical Science.

PMID- 15202421
TI  - [Are newspapers a reliable source of information about doping in sports?].
AB  - To study the coverage by French newspapers of doping in sports, we performed a
      systematic review of articles appearing between January and March 2003 on the
      following French websites: L'Equipe, Le Monde, Le Figaro, Liberation, La Depeche
      du Midi and Agence France-Presse (AFP). We recorded a total of 58 articles about
      doping. Among them, 48 (83%) were collected from the AFP news. L'Equipe, a French
      sports newspaper, published seven articles (12%). Most of the recorded data
      reported results of worldwide antidoping control (71%). No information about new
      drugs was found. The analysis of the selected articles pointed out the following:
      (i) the seriousness of observations related to doping since, during this 3-month
      period, we noted two deaths of athletes; (ii) the risks associated with the use
      of dietary supplements, particularly products including amphetamine derivatives;
      (iii) the interest in judicial investigation as an information source about
      doping in sports (investigation of suspicious deaths of Italian football
      players); and (iv) identification of the sports involved in doping (cycling, but
      also athletics, football, rugby). Systematic analysis of newspaper reports can be
      considered as a relevant method for monitoring the pharmacovigilance and
      pharmacoepidemiology of doping in sports.

PMID- 15202422
TI  - [Drug-induced tremor and acute movement disorders].
AB  - The main clinical characteristics and aetiology of drug-induced tremor and acute
      movement disorders (myoclonus, chorea, athetosis, dyskinesia, dystonia, tics) are
      reviewed and discussed in this article. Tremor is the most frequent drug-induced
      acute movement disorder. Drug intake (and, initially, true or 'hidden'
      neuroleptic or psychoactive drugs) should be suspected as the cause of every
      abnormal movement. Drug-induced acute movement disorders usually disappear
      spontaneously after withdrawal of the suspected drug without any drug treatment.
      Drug-induced tremor and movement disorders are often poorly described in the
      Summary of Products Characteristics (SPC).

PMID- 15202424
TI  - Symposium: when people attack people: ethics, law, and policy of violence.
      Proceedings of the Tenth Annual Thomas A. Pitts Memorial Lectureship. Charleston,
      South Carolina, USA.

PMID- 15202423
TI  - [REBEn: space of diffusion of hospital nursing knowledge --from 1951 to 2001].
AB  - Research on the scientific production on Hospital Nursing published by REBEn.
      OBJECTIVES: Classify the articles published from 1951 to 2001 and analyze this
      Review as a space for the diffusion of knowledge in that area. REFERENCES:
      Concept of cultural diffusion and its constituent historical processes.
      INSTRUMENT: Form applied in 254 articles. Data were submitted to descriptive
      statistics and led to the following categories: "production of articles in the
      concerning areas", "articles' scope", "types of articles", and "articles'
      origin". Our findings showed significant scientific production in those areas
      within the focused scopes and types of articles. Our conclusions indicate REBEn
      as a representative space of national diffusion of knowledge on hospital nursing
      and professional culture, contributing to the development of Nursing as a
      science.

PMID- 15202425
TI  - Abstracts of the 45th International Conference on the Bioscience of Lipids. May
      25-29, 2004, Ioannina, Greece.

PMID- 15202426
TI  - [Purulent mediastinitis].

PMID- 15202427
TI  - Proceedings of the 41st Annual Rocky Mountain Bioengineering Symposium and the
      41st International ISA Biomedical Sciences Instrumentation Symposium.  April 23
      25, 2004. Fort Collins, Colorado, USA.

PMID- 15202428
TI  - Cariology in the 21st Century. State of the art and future perspectives.
      Proceedings of a symposium held at the 50th Anniversary European Organisation for
      Caries Research Congress. July 2-6, 2003. Konstanz, Germany.

PMID- 15202429
TI  - International Federation of Dental Anaesthesiology Societies 10th International
      Dental Congress on Modern Pain Control. Edinburgh, June 2003. Abstracts.

PMID- 15202430
TI  - The re-appearing shadow of 1918: trends in the historiography of the 1918-19
      influenza pandemic.
AB  - This article traces the ways in which the subject of the "Spanish" Influenza
      pandemic of 1918-19, the worst short-term pandemic of modern times, has been
      treated (or ignored) by historians over the last 86 years. In doing so , it
      identifies four distinct surges of interest in the topic, each producing a
      different conception of this pandemic as history: as epidemiology, as high drama,
      as social science and ecology, and as scientific saga. It seeks to explain these
      differing conceptions as part of a wider phenomenon, viz., how an event can be
      neglected, discovered, made, and re-made as history.

PMID- 15202431
TI  - Bibliography. Current world literature. Diseases of the aorta, pulmonary, and
      peripheral vessels.

PMID- 15202432
TI  - Abstracts of the 4th International Symposium on Inherited Diseases of the
      Pancreas. November 7-9, 2003. Chicago, Illinois, USA.

PMID- 15202433
TI  - Oswald Avery: the professor, DNA, and the Nobel Prize that eluded him.
AB  - In 1944, two Canadians, Oswald Avery and Colin MacLeod, and an American, MacLyn
      McCarty, published a paper in The Journal of Experimental Medicine that
      demonstrated genes to be the chemical, deoxyribonucleic acid (DNA). Even though
      this paper is now regarded as the single mos important publication in biology of
      the 20th century, Avery was not awarded the Nobel Prize. This raises the question
      as to why his work did not earn him the Prize. These are several possible
      reasons: the discovery may have been ahead of tis time; all three authors were
      physician-scientists ans not recognized chemists or geneticists; and Avery, the
      principal author, had reached an advanced age and characteristically took an
      extremely cautious and low-key approach to his work. Discussion of these reasons
      in turn raises other issues surrounding the recognition of the work of celebrated
      scientist, from Galileo and Copernicus onwards.

PMID- 15202434
TI  - Think STOP before going "off-label".

PMID- 15202435
TI  - Abstracts of the 4th World Congress on the Aging Male. Prague, Czech Republic,
      February 26-29, 2004.

PMID- 15202436
TI  - Almonte's great train disaster: Shaping nurses' roles and the civilian use of
      blood transfusion.
AB  - Blood transfusion was initially a small-scale, labour-intensive therapy
      administered by physicians. Through the first decades of the 20th century,
      transfusion comprised a "last resort" measure used and tested primarily in the
      context of war. Media accounts of the Almonte train disaster on the night of 27
      December 1942 linked survival to the newly established blood bank located 42 km
      east in Ottawa, Ontario. This event did not constitute a "first time" occurrence
      or a "great discovery" in the history of blood. But it did illustrate in a very
      visible and public manner that blood transfusion technology was now readily
      available for use in general hospitals and civilian populations. Canada had an
      infrastructure for the collection, processing, storage, and transportation of
      blood products, and for the recruitment of blood donors by the mid-1940s. As the
      need for blood declined toward the end of World War II, transfusion became a
      technology in need of application. The extension of transfusion to civilian
      populations, however, would require a ready source of labour-increased numbers of
      health care workers who were available continuously with the necessary knowledge
      and skills to assume the responsibility. Nurses were well situated for this
      technological role by a convergence of scientific, economic, labour, gender,
      professional, and educational influences that both facilitated and constrained
      blood transfusion as a nursing competency. This paper examines how the expanded
      use of one medical technology shaped related roles for nurses. Transfusion
      ultimately influenced nurses' work and the composition of the workforce as the
      first medical act "delegated" to nurses in Ontario (1947), setting a precedent
      for the delegation of further technologies over the next four decades.

PMID- 15202437
TI  - Helicobacter pylori eradication in nonulcer dyspepsia: clearing up the
      controversy.

PMID- 15202438
TI  - 2004 Annual Spring Meeting of the Austrian Society of Hematology and Oncology. 15
      17 April 2004, Vienna, Austria. Abstracts.

PMID- 15202440
TI  - Abstracts of the 39th Meeting of the Canadian Congress of Neurological Sciences.
      Calgary, Alberta, Canada, June 8-12, 2004.

PMID- 15202441
TI  - Proceedings of the 31st Annual Meeting of the European Society of Muscle
      Research. September 2003. Lunteren, The Netherlands.

PMID- 15202442
TI  - Abstracts of the 37th Malaysia-Singapore Congress of Medicine. 4-7 September
      2003.

PMID- 15202444
TI  - Abstracts of the 6th Asia Pacific Congress of Endoscopic Surgery. 10-13 September
      2003.

PMID- 15202443
TI  - The turning point from an archaic Arab medical system to an early modern European
      system in Jerusalem according to the Swiss physician Titus Tobler (1806-77).
AB  - Until the end of the Ottoman period the Hippocratic-Galenic doctrine, which had
      been improved by medieval Muslim medicine, was the pre-dominant medicine in the
      Holy Land. The penetration of modern medicine into the region was a slow process,
      advancing step by step over the years until it was established around the end of
      the 19th century.Dr. Titus Tobler, a Swiss physician of many talents, first
      visited Jerusalem in 1835, then again in 1845, 1857, and 1865. He reported his
      experiences and impressions in several books and articles. His publications
      portray the condition of medicine in the city before the advent of European
      physicians, their arrival, and the establishment of the first hospitals in the
      city. Thanks to his endeavours, a professional description of the medical
      conditions prevailing in Jerusalem in the mid-19th century is available to the
      public. Tobler's writings include descriptions of the healers, blood-letters,
      quacks, medicinal substances and their market, and the diseases and illnesses
      from which the inhabitants suffered. In addition, Tobler produced a detailed
      report of the different hospitals, pharmacies, European physicians, and their
      experiences. A digest of Tobler's information, its fresh systematic arrangement,
      and its comparison with other historical sources, early as well as recent,
      produces a better picture than ever previously available of the medical
      conditions of the city in the final years of the ascendancy of Arab medical
      systems and in the early stages of early modern European medicine in Jerusalem
      and the Holy Land.

PMID- 15202445
TI  - Cutting balloon angioplasty to treat carotid in-stent restenosis.

PMID- 15202446
TI  - Bibliography. Current world literature. Kidney, testis and penile cancer.

PMID- 15202447
TI  - Bibliography. Current world literature. Reconstructive surgery.

PMID- 15202448
TI  - [Recommendations for quality control of cervico-vaginal cytology].

PMID- 15202449
TI  - FemoStop system for arterial puncture site closure.

PMID- 15202450
TI  - Abstracts of the 8th Danube Symposium of Paediatric Surgery. Bratislava,
      Slovakia, October 2-4, 2003.

PMID- 15202451
TI  - Use of FemoStop system for arterial puncture site closure after coronary
      angioplasty.

PMID- 15202452
TI  - A Festschrift in Honor of Bryan D. Hall. March 12, 2003. Lake Arrowhead,
      California, USA.

PMID- 15202453
TI  - Health care fraud and abuse data collection program: technical revisions to
      healthcare integrity and protection data bank data collection activities. Interim
      final rule with comment period.
AB  - The rule makes technical changes to the Healthcare Integrity and Protection Data
      Bank (HIPDB) data collection reporting requirements set forth in 45 CFR part 61
      by clarifying the types of personal numeric identifiers that may be reported to
      the data bank in connection with adverse actions. Specifically, the rule
      clarifies that in lieu of a Social Security Number (SSN), an individual taxpayer
      identification number (ITIN) may be reported to the data bank when, in those
      limited situations, an individual does not have an SSN.

PMID- 15202454
TI  - [Interaction between mathematics and melancholy].
AB  - The copperplate Melencolia I engraved by Durer in 1514 illustrates various
      interdependencies between mathematics and melancholy. Durer's engraving is one of
      the best known works of art in our western history. Up to our own times it has
      been interpreted repeatedly. The significance of Durer's Melencolia I for our
      cultural history is subject of this essay. On the one hand the various changes of
      the conception of melancholy from antiquity up to Durer' s times will be called
      in mind. In addition to it some examples will assert that during the last five
      centuries the correlation between mathematics and melancholy has been
      contemplated and shaped as well.

PMID- 15202455
TI  - Special supplement: creative / artistic narratives of illness.

PMID- 15202457
TI  - Dr Witty and a Nun Appleton poisoning.

PMID- 15202459
TI  - Children in the focus of the attention of pediatricians and pediatric surgeons.
AB  - Children represent the future of humankind. They are the bridge to our
      immortality. They get the attention of everybody who wants to help and do
      something for them. It is a common interest of pediatricians and pediatric
      surgeons to provide ill children with almost care. In the context of historic
      development of medicine, the author focuses her attention on the development of
      pediatric and surgical care of children with the emphasis given to the care of
      critically ill children suffering from inborn heart defects. The author uses the
      example of co-operation of pediatric cardiologists and cardiosurgeons as the base
      for her reflections of ethical principles, norms and attitudes to the
      implementation of modern surgical techniques in the treatment of newborn babies
      suffering from the syndrome of left-heart hypoplasia. The history of child-care
      in general and especially that dedicated to newborn babies suffering from inborn
      heart defects in Slovakia is associated with the personality of Professor Siman,
      a significant Slovak cardiosurgeon.

PMID- 15202460
TI  - James David Ebert.

PMID- 15202462
TI  - [The development of rural medicine: medical activities of Saku Hospital].
AB  - Saku Hospital in Usuda-machi of Nagano Prefecture is famous for its medical
      activities for rural people. The activities of Saku Hospital were practiced not
      only in the hospital but also in the local community. Immediately after the
      establishment of the hospital, in 1945, doctors and nurses visited patients in
      their homes. In the medical activities, at the village, the hospital staff
      discovered a lot of latent diseases among the rural people. To clarify these
      diseases, the staff surveyed the life of the villagers based on medical ecology,
      as well as the medical treatment. Latent diseases were analyzed from a medical
      and social viewpoint. As a result, the staff came to recognize the importance of
      the prevention of disease, as well as medical treatment. To prevent diseases, the
      hospital started health promotion activities in the 1950s, cooperating with the
      administration of the villages. Medical examination were carried out periodically
      and health education was promoted to improve the consciousness of the people
      regarding health. Medical activities of Saku Hospital, which were not limited to
      clinical medicine, proved "prevention is superior to treatment." This conclusion
      teaches us the importance of social medicine as well as that of biomedicine and
      indicates the way of future medical activities.

PMID- 15202463
TI  - Abstracts of SCANNING 2004. Washington, DC, USA, April 27-29, 2004.

PMID- 15202464
TI  - Abstracts of the 147th Meeting of the Acoustical Society of America, 75th
      anniversary celebration. New York, New York, USA. 24-28 May 2004.

PMID- 15202466
TI  - Associated Professional Sleep Societies, LLC 18th annual meeting. June 5-10,
      2004, Philadelphia, Pennsylvania, USA. Abstracts.

PMID- 15202465
TI  - Abstracts of the 27th Annual Conference on Shock. Halifax, Nova Scotia, Canada.
      June 5-8, 2004.

PMID- 15202467
TI  - ["A view of euthanasie" by Ohgai Mori: A viewpoint on the quality of life].
AB  - Ohgai's "A view of Euthanasie" opens, as is well-known, with the defining line,
      "Euthanasie" means peaceful repose. The true meaning of this noteworthy medical
      essay, as we are now convinced, is not merely a guiding principle in "Euthanasie"
      - that is, the aspiration for a painless, peaceful death, as it was used in the
      clinical medical science of Japan in the earliest stage of modern times. Rather,
      we should understand that Ohgai wished to argue in detail and enlighten us upon
      the Quality of Life in its true meaning and how it could be realized and
      maintained in the practical nursing of patients in the terminal stage of
      life.This interpretation of Ohgai's view allows us to understand that such
      affirmative and creditable medical decorum regarding the "solemn and ceremonial
      function of man's last moments" makes it possible to stabilize our viewpoint of
      the true meaning of the "Quality of Life".

PMID- 15202468
TI  - [Activities of medical treatment and culture carried out by modern Japan in
      China: A study on the Dojin Association].

PMID- 15202469
TI  - Michael Heidelberger.

PMID- 15202470
TI  - Alfred Day Hershey.

PMID- 15202471
TI  - David Rittenberg.

PMID- 15202472
TI  - Ruth Sager.

PMID- 15202473
TI  - Ray Fred Smith.

PMID- 15202474
TI  - South Koreans create human stem cell line using nuclear transfer.

PMID- 15202475
TI  - Bioethics needs to rethink its agenda.

PMID- 15202476
TI  - Caring for OCD patients in the emergency department.

PMID- 15202477
TI  - Bibliography. Current world literature. Coronary artery surgery.

PMID- 15202478
TI  - Bibliography. Current world literature. Food allergy.

PMID- 15202479
TI  - Bibliography. Current world literature. Ischemic heart disease.

PMID- 15202480
TI  - Bibliography. Current world literature. Clinical trials.

PMID- 15202481
TI  - The need for specialized vascular units: the ADAPT approach.

PMID- 15202482
TI  - Vascular medicine--a scientific profile.

PMID- 15202483
TI  - Historical diagnosis & treatment. Psoriasis.

PMID- 15202485
TI  - Nocturia.

PMID- 15202486
TI  - Clayton Samuel White.

PMID- 15202487
TI  - Cytotoxic and topographical properties of 6-arylidene-2
      dimethylaminomethylcyclohexanone hydrochlorides and related compounds.
AB  - A number of 2-arylidenecyclohexanones (1a-h) were converted into the
      corresponding Mannich bases (2a-h) and (3a,f). Evaluation against murine L1210
      cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed the marked
      cytotoxicity of the Mannich bases and also the fact that almost invariably these
      compounds were more potent than the precursor enones (1a-h). Further evaluation
      of most of the Mannich bases towards a panel of nearly 60 human tumour cell lines
      confirmed their utility as potent cytotoxins. In this assay, the compounds showed
      growth-inhibiting properties greater than the anticancer alkylator melphalan.
      QSAR studies revealed that in some cell lines compounds possessing small electron
      attracting aryl substituents showed the greatest potencies. Molecular modeling
      and X-ray crystallography demonstrated that various interatomic distances and
      torsion angles correlated with cytotoxicity. A representative compound (2a)
      demonstrated weak inhibiting properties towards human N-myristoyltransferase and
      stimulated a tyrosine protein kinase. A single dose of 100 mg/kg of most of the
      compounds did not prove to be lethal in mice.

PMID- 15202488
TI  - Xanthine oxidase inhibition by 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), an
      antagonist of adenosine receptors.
AB  - Xanthine oxidase (XO), an enzyme involved in purine metabolism, is a source of
      either oxidants (superoxide radical) or antioxidants (uric acid). Interference
      with XO activity can lead to oxidative stress, thus contributing to the
      pathogenesis of cardiovascular diseases. The adenosine receptors antagonist, 1,3
      dipropyl-8-sulfophenylxanthine (DPSPX), induces hypertension and cardiovascular
      injury in rats. Since DPSPX is a xanthine, we aimed at evaluating DPSPX's
      influence on XO activity to ascertain its contribution to DPSPX-induced
      hypertension. The activity of isolated XO in the presence of DPSPX was evaluated
      spectrophotometrically. Serum and urinary uric acid levels of DPSPX-treated rats
      were measured using a commercial kit. DPSPX inhibited XO activity in a
      concentration-dependent manner and reduced rat serum and urinary uric acid
      levels. It can be concluded that: DPSPX is an inhibitor of XO; decreased
      generation of uric acid may lead to oxidative stress, thus contributing to
      endothelial dysfunction and vascular morphological changes in DPSPX-treated rats.

PMID- 15202489
TI  - Synthesis of hydroxy derivatives of highly potent non-steroidal CYP 17 inhibitors
      as potential metabolites and evaluation of their activity by a non cellular assay
      using recombinant human enzyme.
AB  - Inhibition of CYP 17 is a promising strategy for the treatment of prostate
      cancer. Recently two non-steroidal compounds with high in vitro activity were
      synthesized in our group (BW19 and BW95). However, after a few hours they showed
      in vivo a strong decrease in their activity. This might be due to a fast
      biodegradation. Potential hydroxy and epoxy metabolites were synthesized and
      their inhibitory activities were tested by a new non-cellular assay using
      recombinant enzyme. As source, membrane fractions of E. coli pJL17/OR
      coexpressing human CYP 17 and rat NADPH-P450-reductase were, used. Showing a high
      and constant CYP 17 activity and a fast and easy isolation procedure the new
      method was advantageous compared with the microsomal assay. Interestingly, all
      the new synthesized hydroxy and epoxy compounds except one showed a lower
      inhibition of CYP 17 than the parent compounds. Thus, the loss of in vivo
      activity may be partly explained.

PMID- 15202490
TI  - Synthesis of aldehydo-sugar derivatives of pyrazoloquinoline as inhibitors of
      herpes simplex virus type 1 replication.
AB  - Synthesis of a novel series of structurally related pyrazoloquinoline nucleosides
      is described. All the newly synthesized compounds were examined for their in
      vitro antiviral activity against herpes simplex type-1 as shown by two different
      bioassays, namely; crystal violet staining or the MTS tetrazolium dye
      measurement. The acute toxicity (LD50) values of the biologically active
      compounds were determined.

PMID- 15202492
TI  - Investigation of glucose 6-phosphate dehydrogenase (G6PD) kinetics for normal and
      G6PD-deficient persons and the effects of some drugs.
AB  - In the present study, blood samples from 1183 children aged 0.5-6 years were
      taken. Three children were found with G6PD deficiency by examining the enzyme
      activity and hemoglobin ratio. Some kinetic properties of glucose 6-phosphate
      dehydrogenase enzyme (G6PD) were studied after the purification of the enzyme
      with ammonium fractionation, dialysis and 2',5' ADP-Sepharose 4B affinity
      chromatography from a healthy person and from three G6PD-deficient people. The
      purity of the enzymes was confirmed by SDS-PAGE electrophoresis. The effects of
      some drugs which are known inhibitors of G6PD activity were studied. Some of the
      drugs stimulated the activity of the enzyme in two of the three cases with G6PD
      deficiency. KM values, Vmax values for G6P and NADP+, optimum pH and optimum
      temperature for the enzyme from the healthy person and the three G6PD-defficient
      people are reported.

PMID- 15202491
TI  - Reactivation of cyclosarin-inhibited rat brain acetylcholinesterase by pyridinium
      -oximes.
AB  - Cyclohexyl methylphosphonofluoridate (cyclosarin, cyclosin, GF) is a highly toxic
      organophosphate, which is resistant to conventional oxime therapy. To gain
      insight into the reactivation kinetics, rat brain acetylcholinesterase (AChE) was
      inhibited in vitro by cyclosarin (pH 8.0, 25 degrees C) and reactivated with 22
      different pyridiniumoximes. Three compounds were shown to be superior to the
      other oximes: 4-carbamoyl-4'-[(hydroxyimino)methyl]-1,1'
      (oxydimethylene)dipyridin-1-ium dichloride (HS-6), 4'-carbamoyl-2
      [(hydroxyimino)methyl]-1,1'-(oxydimethylene)dipyridin-1-ium dichloride (HI-6),
      and 4'-carbamoyl-2-[(hydroxyimino)-methyl]-1,1'-(but-2-ene-1,4-diyl)dipyridin-1
      ium dichloride (BI-6).

PMID- 15202493
TI  - Binding of transition metal ions [cobalt, copper, nickel and zinc] with furanyl-,
      thiophenyl-, pyrrolyl-, salicylyl- and pyridyl-derived cephalexins as potent
      antibacterial agents.
AB  - A method is described for the preparation of novel cephalexin-derived furanyl-,
      thiophenyl-, pyrrolyl-, salicylyl- and pyridyl-containing compounds showing
      potent antibacterial activity. The binding of these newly synthesized
      antibacterial agents with metal ions such as cobalt(II), copper(II), nickel(II)
      and zinc(II) has been studied and their inhibitory properties against various
      bacterial species such as Escherichia coli, Staphylococcus aureus, Pseudomonas
      aeruginosa, and Klebsiella pneumoniae are also reported. These results suggest
      that metal ions to possess an important role in the designing of metal-based
      antibacterials and that such complexes are more effective against infectious
      diseases compared to the uncomplexed drugs.

PMID- 15202494
TI  - Trypanothione reductase activity is prominent in metacyclic promastigotes and
      axenic amastigotes of Leishmania amazonesis. Evaluation of its potential as a
      therapeutic target.
AB  - The activity of trypanothione reductase in Leishmania amazonensis was evaluated
      and it was demonstrated that TR is expressed in the soluble fractions of
      infective promastigotes and amastigotes, while non-infective promastigotes
      expressed the enzyme at basal levels. This data allows an association of enzyme
      activity and the infective capacity of the parasite. We have also previously
      demonstrated that amidine compounds (N, N'-diphenyl-4-methoxy-benzamidine and
      pentamidine) were active against this parasite. Here, experiments concerning the
      effect of these compounds on TR activity, showed that both compounds
      significantly inhibited the enzyme. However, against glutathione reductase, only
      pentamidine showed a significant inhibitory action, suggesting an association
      with the toxic effects of this drug used in the clinic for the treatment of
      leishmaniasis.

PMID- 15202495
TI  - Heavy metal ions inhibition of jack bean urease: potential for rapid contaminant
      probing.
AB  - The kinetics of heavy metal ions inhibition of jack bean urease was studied by
      progress curve analysis in a reaction system without enzyme-inhibitor
      preincubation. The inhibition was found to be biphasic with an initial, small
      inhibitory phase changing over the time course of 5-10 min into a final linear
      steady state with a lower velocity. This time-dependent pattern was best
      described by mechanism B of slow-binding inhibition, involving the rapid
      formation of an EI complex that subsequently undergoes slow conversion to a more
      stable EI* complex. The kinetic parameters of the process, the inhibition
      constants Ki and Ki* and the forward k5 and reverse k6 rate constants for the
      conversion, were evaluated from the reaction progress curves by nonlinear
      regression treatment. Based on the values of the overall inhibition constant Ki*,
      the heavy metal ions were found to inhibit urease in the following decreasing
      order: Hg2+ > Cu2+ > Zn2+ > Cd2+ > Ni2+ > Pb2+ > Co2+ > Fe3+ > As3+. With the Ki*
      values as low as 1.9 nM for Hg2+ and 7.1 nM for Cu2+, 100-1000 times lower than
      those of the other ions, urease may be utilized as a bioindicator of the trace
      levels of these ions in environmental monitoring, bioprocess control or
      pharmaceutical analysis.

PMID- 15202496
TI  - Kinetic and structural analysis of the inhibition of adenosine deaminase by
      acetaminophen.
AB  - Kinetic and thermodynamic studies have been made on the effect of acetaminophen
      on the activity and structure of adenosine deaminase in 50 mM sodium phosphate
      buffer pH 7.5, at two temperatures of 27 and 37 degrees C using UV
      spectrophotometry, circular dichroism (CD) and fluorescence spectroscopy.
      Acetaminophen acts as a competitive inhibitor at 27 degrees C (Ki = 126 microM)
      and an uncompetitive inhibitor at 37 degrees C (Ki = 214 microM). Circular
      dichroism studies do not show any considerable effect on the secondary structure
      of adenosine deaminase by increasing the temperature from 27 to 37 degrees C.
      However, the secondary structure of the protein becomes more compact at 37
      degrees C in the presence of acetaminophen. Fluorescence spectroscopy studies
      show considerable change in the tertiary structure of the protein by increasing
      the temperature from 27 to 37 degrees C. Also, the fluorescence spectrum of the
      protein incubated with different concentrations of acetaminophen show different
      inhibition behaviors by the effector at the two temperatures.

PMID- 15202497
TI  - Metalloantibiotics: synthesis and antibacterial activity of cobalt(II),
      copper(II), nickel(II) and zinc(II) complexes of kefzol.
AB  - Kefzol (kzl), a beta-lactam antibiotic, possesses various donor sites for
      interaction with transition metal(II) ions [Co(II), Cu(II), Ni(II) and Zn(II)] to
      form complexes of the type [M(kzl)2]Cl2 and [M(kzl)Cl], with molar ratio of
      metal: ligand (M:L) of 1:2 and 1:1 respectively. These complexes were prepared
      and characterized by physicochemical and spectroscopic methods. Their IR and NMR
      spectra suggest that kefzol potentially acts as a bidentate, tridentate as well
      as monoanionic tetradentate ligand. The complexes have been screened for
      antibacterial activity and results were compared with the activity of the
      uncomplexed antibiotic against Staphylococcus aureus, Klebsiella pneumoniae,
      Pseudomonas aeruginosa, Escherichia coli and Proteus mirabilis. The metal
      complexes were found to be more potent against one or more bacterial species than
      the uncomplexed kefzol.

PMID- 15202498
TI  - Antifungal cobalt(II), copper(II), nickel(II) and zinc(II) complexes of furanyl
      ,thiophenyl-, pyrrolyl-, salicylyl- and pyridyl-derived cephalexins.
AB  - Some novel cephalexin-derived furanyl, thiophenyl, pyrrolyl, salicylyl and
      pyridyl Schiff's bases and their cobalt (II), copper (II), nickel (II) and zinc
      (II) complexes have been synthesized and studied for their antifungal properties
      against Trichophyton longifusus, Candida albicans, Aspergillus flavus,
      Microsporum canis, Fusarium solani and Candida glaberata. The presence of metal
      ions in the investigated Schiff's base complexes reported here lead to
      significant antifungal activity, whereas the parent ligands were generally less
      active.

PMID- 15202499
TI  - Aldolase and actin protect rabbit muscle lactate dehydrogenase from ascorbate
      inhibition.
AB  - Muscle-type LDH (LDH-m4) activity is critical for efficient anaerobic glycolysis.
      The results here show that rabbit LDH-M4 is inhibited by concentrations of
      ascorbate normally found in tissues. Aldolase and muscle G-actin were found to
      protect and to reverse inhibitions of LDH-m4 by ascorbate. G-actins showed some
      species specificity. Myosin, tropomyosin and troponin from rabbit muscle and
      muscle proteins from other animal sources had no affect on the inhibitions by
      ascorbate. The substrate inhibition of LDH-m4 by pyruvate is partially relieved
      by the presence of aldolase and lowers the Km without affecting the Vm. G-actin
      under similar conditions has no affect. It is believed that these studies reflect
      some of the resting properties of glycolytic enzymes that bind and unbind to
      contractile elements. It is proposed that ascorbate facilitates the storage of
      glycogen in muscle at rest by inhibiting glycolysis.

PMID- 15202500
TI  - Cinnamomin--a versatile type II ribosome-inactivating protein.
AB  - Ribosome-inactivating proteins (RIPs) are a group of toxic proteins that can
      specifically act on the universally conserved sarcin/ricin domain (S/R domain) of
      the largest RNA in ribosome and thus irreversibly inactivate ribosome for protein
      synthesis. Cinnamomin is a multifunctional type II RIP isolated in our laboratory
      from the mature seeds of the camphor tree. This protein has been extensively
      studied with regard to its purification, characteristics, structure and function,
      genetic expression, enzymatic mechanism, physiological role in seed cell and
      toxicity to cancer cells and insect larvae. The research results of cinnamomin
      obtained in our laboratory are summarized in this review. Understanding of
      cinnamomin and the relative new proteins will help expand our knowledge of RIPs
      and may accelerate theoretical study and the development of their potential
      applications.

PMID- 15202501
TI  - Multiple functions of nuclear DNA helicase II (RNA helicase A) in nucleic acid
      metabolism.
AB  - Nuclear DNA helicase II (NDH II), or RNA helicase A (RHA), was initially
      discovered in mammals by conventional protein purification methods. Molecular
      cloning identified apparent sequence homologies between NDH II and a Drosophila
      protein named maleless (MLE), the latter being essential for the Drosophila X
      chromosome dosage compensation. Increasing amounts of evidence suggest that NDH
      II is involved in multiple aspects of cellular and viral DNA and RNA metabolism.
      Moreover the functions of NDH II may have potential clinical implications related
      to viral infection, autoimmune diseases, or even tumorigenesis.

PMID- 15202502
TI  - Construction, expression, and characterization of a recombinant annexin B1-low
      molecular weight urokinase chimera in Escherichia coli.
AB  - To produce a thrombi-targeting plasminogen activator, low molecular weight single
      chain urokinase gene (scuPA32k) was spliced with the full-length cDNA of annexin
      B1 gene (anxB1) by overlap extension method. The fused gene anxB1scuPA was
      ligated into pET28a vector, transformed into E. coli BL21-RIL, and then induced
      to express under the control of T7 promoter. The AnxB1ScuPA protein expressed
      amounted to 22% of the total bacterial proteins. The product was refolded, and
      then purified by using DEAE Sepharose fast flow ion-exchange column and Superdex
      S-200 gel-filtration column. HPLC analysis revealed that the final purity is
      about 95%. The specific activity of AnxB1ScuPA, measured as amidolytic activity,
      reached 100,000 IU/mg. It had a similar S2444 catalytic efficiency (kcat/Km) to
      ScuPA32k, and also showed high activated-platelet membrane-binding activity and
      anticoagulant activity, indicating that the chimera fully retained the components
      of enzymatic and membrane-binding activities of the parent molecules. In vivo
      test revealed that, the dogs administered with AnxB1ScuPA had less reperfusion
      time, higher reperfusion ratio, and less bleeding effects than those with
      urokinase. These findings indicated that AnxB1ScuPA might have advantages over
      current available thrombolytic agents.

PMID- 15202503
TI  - Structural analysis and identification of cis-elements of rice osRACD gene.
AB  - The osRACD gene correlated with fertility transformation in the photoperiod
      sensitive genic male sterile rice (PGMR), Nongken 58S, encoded a rice (Oryza
      sativa L. ssp. japonica) small GTPase belonging to the Rac/Rho family. Inverse
      PCR was performed to amplify a fragment about 1.4 kb in 5' upstream region of the
      osRACD promoter. Deletion mutation and gel mobility shift assay characterized two
      fragments (-799 to -686 nt, and -686 to -431 nt) in the osRACD promoter that
      could be involved in its transcriptional regulation. When these two deletion
      fragments were used as probe respectively, a retarded band appeared in the
      nuclear extracts of fertile 58S rice under short day (58S-SD). Whereas no
      retarded band was shown in the nuclear extracts of sterile 58S rice under long
      day (58S-LD). Competition assay indicated that the factors in the retarded bands
      binding to these two fragments were the same trans-acting factor (termed rice
      factor, RF). The binding affinity of RF was affected by phosphorylation and was
      higher in SD-growth rice than that of LD-growth rice.

PMID- 15202504
TI  - Inhibition of Fas-mediated apoptosis in Yac-1 cell via Anti-Fas ribozyme.
AB  - To detect a new and more effective way against apoptosis mouse lymphomatic cell
      line Yac-1 in which fas gene was expressed highly was used as a model for
      studying the effects of anti-Fas ribozyme on Fas-mediated apoptosis. A hammerhead
      ribozyme gene targeting the fas mRNA was synthesized and its in vitro
      transcription vector was constructed, which was transfected into Yac-1 cells
      using electroporation. Rz596 expression was detected using RT-PCR, and Fas
      expression in Yac-1 cells was detected using RT-PCR, Western blot and flow
      cytometry. After treated with anti-Fas antibody (JO2), Yac-1 cell viability was
      measured with MTT assay, caspase-3 proteolytic activity was detected, and cell
      apoptosis was measured according to annexin V apoptosis detecting kit. Anti-Fas
      ribozyme could cleave fas mRNA efficiently in vivo and in vitro. Fas expression
      in Yac-1 cells transfected with anti-Fas ribozyme was decreased remarkably and
      correlated with resistance to Fas-mediated apoptosis as determined by flow
      cytometry and caspase-3 proteolytic activity. Anti-Fas ribozyme was detected in
      cells transfected with pU6-RZ596 and pU6-dRZ596 and could remarkably decrease the
      Fas expression in Yac-1 cells, which made Yac-1 cells get rid of Fas-mediated
      apoptosis. Because of wide expression of fas in organs and tissues, our research
      was very useful for studying the inhibition of apoptosis of many organs and
      tissues in the future.

PMID- 15202505
TI  - Schistosoma japonicum: isolation and identification of peptides mimicking
      ferritin epitopes from phage display library.
AB  - In an attempt to isolate and identify the antigenic epitopes on ferritin of
      Schistosoma japonicum (SjFer) and to test their protective potentiality against
      Schistosoma japonicum (S.j), polyclonal antisera against SjFer was prepared to
      screen a 12-mer random peptide library. Three rounds of biopanning were performed
      and resulted in an enrichment. Six peptides selected randomly from the third
      elute were all found to be positive by evaluating the binding to anti-SjFer sera
      by ELISA and Western blotting. Three amino acid sequences were deduced from the
      six phage clones by sequencing. When they were used to vaccinate mice, the three
      peptides could induce significant reduction in adult worms (26.7%, 20.4%, and
      25.9%) as well as in liver eggs per gram (LEPG) (40.0%, 38.2%, and 40.8%). This
      result showed that three mimotopes on SjFer were obtained and they could induce
      significant protective efficacy against S.j.

PMID- 15202506
TI  - Effects of Huangqi (Hex) on inducing cell differentiation and cell death in K562
      and HEL cells.
AB  - Huangqi (Astragalus membranaceus), a traditional Chinese medicine, has been used
      to ameliorate side effects of cancer chemotherapy in China. However, little is
      known about its molecular mechanisms. Here we show that induction of K562 or HEL
      cells with 1.5 mg/ml of Huangqi (Hex) (Components extracted from Huangqi) for 3-5
      d results in the expression of beta-globin gene in both cell lines and leads to
      terminal differentiation. Moreover, the apoptosis in HEL cells can be induced by
      increasing concentration of Huangqi (Hex) to 4.5 mg/ml for 3-5 d. Upregulation of
      Apaf-1, caspase-3 and acetylcholinesterase (AChE) in HEL cells may play a crucial
      role in the process of apoptosis. The prospect of inducing expression of adult
      (beta) globin gene and apoptosis selectively in cancer cells is obviously
      attractive from a therapeutic point of view.

PMID- 15202507
TI  - Effect of apolipoprotein A-I on ATP binding cassette transporter A1 degradation
      and cholesterol efflux in THP-1 macrophage-derived foam cells.
AB  - Cholesterol-loaded macrophage foam cells are a central component of
      atherosclerotic lesions. ATP binding cassette transporter A1 (ABCA1), the
      defective molecule in Tangier disease, mediates the efflux of phospholipid and
      cholesterol from cells to apolipoprotein A-I (apoA-I), reversing foam cell
      formation. This study investigated the effect of apoA-I on ABCA1 degradation and
      cholesterol efflux in THP-1 macrophage-derived foam cells. After exposure of the
      cultured THP-1 macrophage-derived foam cells to apoA-I for different time,
      cholesterol efflux, ABCA1 mRNA and protein levels were determined by FJ-2107P
      type liquid scintillator, RT-PCR and Western blot, respectively. The mean ABCA1
      fluorescence intensity on THP-1 macrophage-derived foam cells was detected by
      flow cytometry. Results showed that apoA-I markedly increased ABCA1-mediated
      cholesterol efflux from THP-1 macrophage-derived foam cells. This was accompanied
      by an increase in the content of ABCA1. ApoA-I did not alter ABCA1 mRNA
      abundance. Significantly, thiol protease inhibitors increased the level of ABCA1
      protein and slowed its decay in THP-1 macrophage-derived foam cells, whereas none
      of the proteosome-specific inhibitor lactacystin, other protease inhibitors, or
      the lysosomal inhibitor NH4Cl showed such effects. The apoA-I-mediated cellular
      cholesterol efflux was enhanced by thiol protease inhibitors. Our results
      suggested that thiol protease inhibitors might provide an alternative way to
      upregulate ABCA1 protein. This strategy is especially appealing since it may
      mimic the stabilizing effect of the natural ligands apoA-I.

PMID- 15202508
TI  - Identification and characteristics of a novel E1 like gene nUBE1L in human
      testis.
AB  - A gene, presumably involved in spermatogenesis, was identified and characterized
      by using cDNA microarray. Hybridization intensity was 2.13 fold higher in adult
      testis than that in fetal testis. The full length of this gene was 4288 bp and it
      encoded a 578 amino acid protein. Conserved structure and amino acid sequence
      analysis revealed that the protein contained 1 Thif-domain, 2 UBACT-domains, and
      a functional active site cysteine lay upstream of UBACT domain, all of them also
      existed in ubiquitin-activating enzyme E1 and E1 like proteins. So we named this
      gene as a novel ubiquitin-activating enzyme E1 like gene (nUBE1L). Expression
      profile showed that nUBE1L was predominantly expressed in testis. Comparison of
      the expression of nUBE1L in different developmental stages of testis indicated
      that it was highly expressed in adult testis. In conclusion, nUBE1L is a novel
      human E1 like gene highly expressed in adult testis, which plays key role in
      ubiquitin system, and accordingly influences spermatogenesis and male fertility.

PMID- 15202509
TI  - Dicoumarol alters cellular redox state and inhibits nuclear factor kappa B to
      enhance arsenic trioxide-induced apoptosis.
AB  - The effects of a number of cytotoxic drugs are influenced by cellular
      reduction/oxidation (redox) state. In the present study, we attempt to explore if
      dicoumarol, an inhibitor of NADPH: quinone oxidoreductase (NQO1), alters the
      cellular redox state and how this alteration affects the redox-related apoptosis.
      Flow cytometry was used to assess the reactive oxygen species (ROS) level and
      apoptotic rates of HeLa cells treated with arsenic trioxide (As2O3) alone or in
      combination with natural anthraquinone emodin and dicoumarol or plus N-acetyl
      cysteine. Western blot, immunofluorescence, electrophoretic mobility shift assay
      and luciferase assay were used to detect Nuclear Factor kappa B (NF-kappaB)
      activation. The results showed that dicoumarol synergized with emodin to
      sensitize HeLa cells to As2O3-induced apoptosis through raising the ROS level.
      More notably, this enhanced susceptibility was associated with a ROS-mediated
      inhibition of NF-kappaB activation in which the combinative treatment with
      dicoumarol prevented NF-kappaB from binding to target DNA. It was suggested that
      dicoumarol in combination with anthraquinones might be a novel strategy to expand
      the chemotherapeutic spectrum of As2O3 by means of interfering the cellular redox
      state.

PMID- 15202510
TI  - DNA microarrays and pharmacogenomics.
AB  - The DNA microarrays have proven to be a state of the art technique for high
      throughput comprehensive analysis of thousand of genes in parallel. The
      application of a DNA microarray to compare normal and pathological cells, tissues
      or organs may allow, along with classical positional cloning techniques, to speed
      up the discovery of genes and gene pathways implicated in several diseases. This
      in turn will result in further application of the DNA microarray technique in the
      field of pharmacogenomics in order to characterize and validate new therapeutic
      targets, their mechanism of action, metabolic pathways and unwanted secondary
      effects. However, the lack of standardized criteria for the analysis and
      interpretation of the huge amount of data generated by DNA microarrays may hamper
      its utilization on a routine basis in the human health domain.

PMID- 15202511
TI  - Pharmacogenetics of antipsychotic-induced weight gain.
AB  - Weight gain appears to be a serious side effect encountered during treatment with
      many antipsychotic drugs. Although the propensities of inducing weight gain vary
      considerably between antipsychotics, weight gain is mostly observed in atypical
      antipsychotics, increasingly prescribed for a variety of psychiatric disorders.
      Beside the psychological consequences weight gain may influence patients'
      compliance and secondary medical comorbidities related to being overweight may
      arise, including diabetes, hypertonia, respiratory problems, and some types of
      cancer. Obesity research generally suggests that a complex system of
      neurotransmitters, neuropeptides, hormones and immune related factors interact in
      neural circuits involving at least the hypothalamus, the solitary tract and
      cortical structures to regulate energy homeostasis and body weight.
      Antipsychotics that have weight gain inducing properties may disrupt associated
      pathways at any of these levels, although it remains unclear what the mechanisms
      of action might be. Given the potential deleterious effects of weight gain,
      individual predictors of weight gain would be extremely helpful at the beginning
      of pharmacological treatment with atypical antipsychotics, allowing obesity to be
      avoided or for counteractive steps such as dietary restrictions to be taken in
      predisposed individuals. So far, only a few predictors to detect individuals at
      high risk have been reported and these have limited power. It is likely that
      genetic factors play a major role in determining individual response to
      antipsychotics as well as their side effect profile. In this article, we have
      reviewed literature related to antipsychotic-induced weight gain and have
      discussed the major issues, before updating the reader on current obesity
      research findings. Finally, we emphasize previous studies relating to the
      pharmacogenetics of antipsychotic-induced weight gain.

PMID- 15202512
TI  - Pharmacogenetics of neoplastic diseases: new trends.
AB  - The study of the influence of genotype on drug activity and efficacy
      (pharmacogenetics) and the genome-wide approach to drug discovery and
      interpretation of complex pharmacological responses (pharmacogenomics) are
      gaining momentum in current molecular medicine. The reasons of the variable
      activity and tolerability of cancer chemotherapy are being unraveled by the
      discovery of genotypic alterations affecting pharmacokinetics and
      pharmacodynamics of drugs. Indeed, genetic variability may alter drug catabolism
      (i.e. dihydropyrimidine dehydrogenase for 5-fluorouracil, thiopurine-S-methyl
      transferase for thiopurines, aldehyde dehydrogenase for cyclophosphamide) and
      anabolism (i.e. thymidine phosphorylase for capecitabine, deoxycitidine kinase
      for gemcitabine). Moreover, increased expression of transporter systems (i.e. the
      ATP binding cassette (ABC) superfamily) is associated with reduction of the
      cytoplasmic levels of drugs which may be unable to exert a cytotoxic effect.
      Additional systems could protect tumor cells from drug cytotoxicity, including
      the DNA repair machinery (nucleotide excision repair (NER) and DNA
      alkyltransferases) and antiapoptotic systems (i.e. bcl-2). Finally, alterations
      of drug targets may be associated with a decrease in the effectiveness of
      chemotherapy (i.e. mutations affecting tubulin and topoisomerase I for taxanes
      and irinotecan, respectively, and increased expression of thymidilate synthase
      for 5-fluorouracil). Therefore, genetic analysis has the potential to predict
      treatment efficacy and tolerability. However, major problems encountered in
      pharmacogenetic and pharmacogenomic studies are the need of extensive validation
      of available technology, the difficulties in obtaining a suitable amount of
      tissue from patients during the course of their disease and the extremely complex
      regulation of gene function. From this perspective, the evaluation of the
      cellular effect of drugs in relation to protein expression and function
      (pharmacoproteomics) may be able to overcome these obstacles, and allow the
      optimisation of cancer chemotherapy in association with a pharmacogenetic
      approach.

PMID- 15202513
TI  - Trends in pharmacogenomics of drugs used in the treatment of asthma.
AB  - Pharmacogenetic studies of drugs used in the treatment of asthma have produced a
      few examples of reduced response in patients carrying specific genotypes in genes
      involved in the action of beta-2 agonists or leukotriene modifiers. Other
      candidate genes related to these drugs, as well as glucocorticoids, theophilline,
      anticholinergics, antihistaminics, and drug-metabolizing enzymes, may be
      proposed. Statistical power and population stratification may be issues of
      importance in case-control association studies. Future developments include
      expanded gene knowledge from asthma genetic and genomic studies, the development
      of new preventive and curative treatments, multiple contemporary genotyping
      methods for pharmacogenetically important genes in a given individual, and the
      construction of asthma functional pharmacogenomic profiles. In conclusion, it
      seems that asthma pharmacogenetic studies need to be replicated in prospective
      clinical trials in different populations with a large number of subjects being
      genotyped. It is suggested that large clinical trials which are proposed for
      asthma drugs experimentation should include a pharmacogenetic study as well.

PMID- 15202514
TI  - Trends in pharmacogenomics of drugs acting on hypertension.
AB  - With the recent rapid increase in scientific understanding of the human genome it
      is becoming possible to identify the extent to which genetic variations influence
      drug response. The emergence of pharmacogenetics heralds a new era in which drug
      therapies will be selected on the basis of differences in individuals' genotypes,
      enhancing drug safety and efficacy. The major focus of this review is
      pharmacogenetics of antihypertensive drugs. Genetics can influence the
      pharmacokinetics and pharmacodynamics of such drugs at different levels. The
      presently available applications of genetic concepts to some drugs commonly used
      in the treatment of hypertension (ACE-inhibitors, diuretics, beta-blockers...)
      will be summarized. Also sensitivity to salt intake will be considered as an
      example of pharmacogenetics. The identification of genetic markers of drug
      response will help to achieve a better control of blood pressure in the
      population, by allowing a better tailor of antihypertensive therapy to individual
      patients.

PMID- 15202515
TI  - Pharmacogenetics and pharmacogenomics: are they still promising?
AB  - In the last several years pharmacogenetics and pharmacogenomics have attracted
      the interest of the scientific community and of important pharmaceutical groups.
      What is the consequence for medicine and for the pharmaceutical industry? What
      has emerged from this investment, and what can we expect for the future? As with
      many new technologies, pharmacogenetics and pharmacogenomics were first adapted
      with much enthusiasm, and then found to require time and experience, together
      with sustained investment, before they could take their full place in drug
      discovery and development. The benefits of these technologies are now emerging,
      however, and they have become essential tools for the pharmaceutical industry.

PMID- 15202516
TI  - Adverse drug reactions: role of pharmacogenomics.
AB  - Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality.
      The majority of ADRs can be considered common disorders with considerable
      clinical variability (clinical phenotype) in which many different genes are
      involved together with environmental variables. Pharmacogenomics is the study of
      how genes affect the individual response to drugs. There is some evidence that in
      the future the use of pharmacogenomics could help to reduce ADRs, as it aims to
      predict which patients are likely to respond to a particular drug and which
      patients are likely to have significant ADRs. In this article some examples of
      genetic polymorphisms affecting drug kinetics, drug toxicity and hypersensitivity
      related to ADRs are illustrated.

PMID- 15202517
TI  - Ethical considerations on pharmacogenomics.
AB  - Pharmacogenetics offers the prospect of an era of safer and more effective drugs,
      as well as more individualized use of drug therapies. The effect of human genetic
      variance on responses to therapy will influence drug-development clinical trials
      and the use of products in clinical practice. It also promises to raise new
      ethical challenges, in particular in the fields of research and therapy. Last but
      not least, pharmacogenetics is likely to fulfil the old dream of an
      individualised medicine, but in a totally unexpected way.

PMID- 15202518
TI  - The first International Workshop on Non-Hodgkin's Lymphoma: taking a close look
      at current issues and future developments.

PMID- 15202519
TI  - Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6.
AB  - Non-Hodgkin's lymphomas (NHL) form a heterogeneous group of diseases, with
      diffuse large B-cell lymphoma (DLBCL) comprising the largest subgroup. The
      commonest chromosomal translocations found in DLBCL are those affecting band
      3q27. In 35% of DLBCL cases, as well as in a small fraction of follicular
      lymphomas, the normal transcriptional regulation of Bcl-6 is disrupted by these
      chromosomal translocations. In addition, about three-quarters of cases of DLBCL
      display multiple somatic mutations in the 5' non-coding region of Bcl-6, which
      occur independently of chromosomal translocations and appear to be due to the IgV
      associated somatic hypermutation process. Bcl-6 is a 95-kD nuclear phosphoprotein
      belonging to the BTB/POZ (bric-a-brac, tramtrack, broad complex/Pox virus zinc
      finger) zinc finger family of transcription factors. It has been suggested that
      Bcl-6 is important in the repression of genes involved in the control of
      lymphocyte activation, differentiation, and apoptosis within the germinal center,
      and that its down-regulation is necessary for normal B-cells to exit the germinal
      center. Bcl-6 remains constitutively expressed in a substantial proportion of B
      cell lymphomas. Recently, acetylation has been identified as a mode for down
      regulating Bcl-6 activity by inhibition of the ability of Bcl-6 to recruit
      complexes containing histone deacetylases (HDAC). The pharmacologic inhibition of
      two recently identified deacetylation pathways, HDAC- and silent information
      regulator (SIR)-2-dependent deacetylation, results in the accumulation of
      inactive acetylated Bcl-6 and thus in cell cycle arrest and apoptosis in B-cell
      lymphoma cells. These results reveal a new method of regulating Bcl-6, with the
      potential for therapeutic exploitation. These studies also indicate a novel
      mechanism by which acetylation promotes transcription, not only by modifying
      histones and activating transcriptional activators, but also by inhibiting
      transcriptional repressors.

PMID- 15202520
TI  - Molecular pathogenesis of mucosal-associated lymphoid tissue (MALT) lymphoma.
AB  - Extranodal marginal zone B-cell lymphomas of mucosal-associated lymphoid tissue
      (MALT)-type occur in a number of anatomic sites, but share overlapping
      morphological and immunophenotypic features. Helicobacter pylori infection has
      been identified as an etiological factor in gastric MALT lymphoma, but the cause
      of MALT lymphomas at other sites remains a matter of speculation. Despite these
      limitations in understanding the etiology of MALT lymphoma, standard cytogenetic
      analysis has proved useful by demonstrating similar alterations in MALT lymphomas
      from different anatomic sites. The common cytogenetic alterations that
      characterize MALT lymphomas include t(11:18)(q21:q21), t(1;14)(p22;q32) and, more
      recently, t(14;18)(q32;q21). The apparent complexity of the cytogenetic
      alterations that have now been implicated in the pathogenesis of extranodal MALT
      lymphoma serves as a paradigm for molecular cross talk in neoplastic disease.
      Recent data have shown that these very disparate translocations affect a common
      signaling mechanism, and thus unify all three under a common pathogenesis,
      resulting in the constitutive activation of the NF-kappaB pathway.

PMID- 15202521
TI  - Pathobiology of primary mediastinal B-cell lymphoma.
AB  - Controversy still exists over the response to therapy and prognosis of patients
      with primary mediastinal B-cell lymphoma (PMBL). Recent data from the
      International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B
      (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin)
      chemotherapy regimen followed by radiotherapy may be a better induction strategy
      than other previously used treatments. Although the pathobiology of PMBL has been
      widely studied, its precise histology, phenotype, and molecular characteristics
      are still not clear. To date, phenotypic analysis has revealed the following
      phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21,
      Class I/II major histocompatibility antigens, and a variety of other
      immunohistochemical markers. CD79a is generally detected, despite an absence of
      surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is
      weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic
      large cell lymphoma. BCL-2 protein is usually expressed but there are few data
      describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell
      transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in
      segments of chromosome 9p, including amplification of the REL proto-oncogene and
      the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations
      or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over
      expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent,
      suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent
      reports show isotype-switched Ig genes with a high frequency of somatic
      hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene.
      The IELSG collected 137 PMBL cases for extensive pathologic review.
      Histologically, the lymphomatous growth was predominantly diffuse with sclerosis
      that induced compartmentalized cell aggregation. It consisted of large cells with
      varying degrees of nuclear polymorphism and clear to basophilic cytoplasm.
      Molecular analysis was performed on 40 cases and showed novel findings. More than
      half of the cases displayed bcl-6 gene mutations, which usually occurred together
      with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4
      expression. The present study supports the concept that PBML is derived from
      activated GC or post-germinal center cells. However, it differs from other
      aggressive B-cell lymphomas in that it shows defective Ig production despite the
      expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H)
      gene crippling mutations.

PMID- 15202522
TI  - Risk factors for Hodgkin's lymphoma by EBV status and significance of detection
      of EBV genomes in serum of patients with EBV-associated Hodgkin's lymphoma.
AB  - Epstein Barr virus (EBV) is associated with around one-third of Hodgkin's
      lymphoma (HL) cases and this association is believed to be causal. In these EBV
      associated cases, there is a clonal EBV infection within tumors, and EBV genomes
      and gene products are detectable in Hodgkin and Reed-Sternberg (HRS) cells. The
      proportion of EBV-associated HL in any population varies with age, sex, ethnicity
      and histologic subtype. Two population-based epidemiologic studies have examined
      risk factor profiles in HL with cases stratified according to EBV status. For EBV
      associated HL cases, there is a small peak in incidence in young adults (15-24
      years) and a second larger peak in older adults. By contrast, HL that is not
      associated with EBV (EBV-negative HL) accounts for the major part of the young
      adult incidence peak after which the incidence of this disease entity then
      declines. Prior infectious mononucleosis (IM) is associated with an increased
      risk of developing HL, and there is a specific, probably causal, association
      between previous IM and young adult EBV-associated HL. We therefore believe that
      the small peak in the incidence of EBV-associated HL in young adults is real and
      related to late infection by EBV. EBV-associated HL in childhood and young
      adults, therefore, appears to follow primary infection by the virus. At the time
      of diagnosis, EBV-associated HL patients have an increased frequency of
      circulating EBV-infected cells compared to patients with EBV-negative HL and
      normal controls. The EBV is present in memory B cells and most probably reflects
      increased viral replication at another site, such as the oropharynx. EBV genomes
      are detectable in the serum and plasma of EBV-associated HL cases. The origin of
      EBV genomes in serum/plasma differs in different disease states; in HL viral
      genomes are present as naked DNA and are probably shed from tumors. EBV genome
      copy number in serum/plasma may provide an indication of tumor burden and may
      prove to be a useful marker for monitoring HL patients. The etiology of EBV
      negative HL remains unknown and, while the involvement of an infectious agent may
      be suspected, none has yet been identified. Overall, epidemiologic studies
      support the idea that HL can be divided into two etiologic subgroups on the basis
      of EBV status and suggest that EBV-associated cases can be further divided into
      three groups related to age at diagnosis.

PMID- 15202523
TI  - Association between SV40 and non-Hodgkin's lymphoma.
AB  - Millions of people worldwide were inadvertently exposed to live simian virus 40
      (SV40) between 1955 and 1963 through immunization with SV40-contaminated polio
      vaccines. Although the prevalence of SV40 infections in humans is not known,
      numerous studies suggest that SV40 is a pathogen resident in the human population
      today. SV40 is a potent DNA tumor virus that is known to induce primary brain
      cancers, bone cancers, mesotheliomas, and lymphomas in laboratory animals. SV40
      oncogenesis is mediated by the viral large tumor antigen (T-ag), which
      inactivates the tumor suppressor proteins p53 and pRb. During the last decade,
      independent studies using different molecular biology techniques have shown the
      presence of SV40 DNA, T-ag, or other viral markers in primary human brain and
      bone cancers and malignant mesotheliomas. Evidence suggests that there may be
      geographic differences in the frequency of these virus-positive tumors. Recent
      large independent controlled studies have shown that SV40 T-ag DNA is
      significantly associated with human non-Hodgkin's lymphoma (NHL). In our study,
      we analyzed systemic NHL from 76 HIV-1-positive and 78 HIV-1-negative patients,
      and nonmalignant lymphoid samples from 79 HIV-1-positive and 107 HIV-1-negative
      patients without tumors; 54 colon and breast carcinoma samples served as cancer
      controls. We used polymerase chain reaction (PCR) followed by Southern blot
      hybridization and DNA sequence analysis to detect DNAs of polyomaviruses and
      herpesviruses. SV40-specific DNA sequences were detected in 64 (42%) of 154 NHL,
      none of 186 nonmalignant lymphoid samples, and none of 54 control cancers. For
      NHL from HIV-1-positive patients, 33% contained SV40 DNA and 39% Epstein Barr
      virus (EBV) DNA, whereas NHLs from HIV-1-negative patients were 50% positive for
      SV40 and 15% positive for EBV. Few tumors were positive for both SV40 and EBV.
      Human herpesvirus type 8 was not detected. SV40 sequences were found most
      frequently in diffuse large B cell and follicular-type lymphomas. We conclude
      that SV40 is significantly associated with some types of NHL and that lymphomas
      should be added to the types of human cancers associated with SV40.

PMID- 15202524
TI  - Gene expression profiling of diffuse large B-cell lymphoma.
AB  - Initial gene expression profiling studies of diffuse large B-cell lymphoma
      (DLBCL) revealed that this single diagnosis actually encompasses two distinct
      diseases that differ in the expression of hundreds of genes. One subtype,
      germinal center B-cell-like (GCB) DLBCL, strongly resembles normal germinal
      center B-cells and has a good prognosis following chemotherapy, whereas activated
      B-cell-like (ABC) DLBCL resembles mitogenically activated blood B cells and has a
      poor outcome. An expanded analysis of 274 DLBCL cases confirmed the existence of
      the GCB and ABC subgroups, but demonstrated that additional subgroups exist.
      Furthermore, two recurrent oncogenic events in DLBCL, t(14;18) and amplification
      of the c-rel locus on chromosome 2p, were only observed in GCB DLBCL, whereas
      constitutive activation of NF-kappaB was seen in ABC DLBCL, showing that the gene
      expression subgroups represent pathogenetically distinct diseases. Gene
      expression profiling has also been used to identify individual genes that predict
      overall survival in DLBCL, the majority coming from gene expression signatures
      that reflect the cell of origin, proliferation rate, and host immune response to
      the tumor. A multivariate model including 17 genes representing these biological
      features divided patients with DLBCL into quartiles with strikingly distinct 5
      year survival rates, ranging from 73% to 15%. The use of gene expression
      profiling should eventually lead to an integration of molecular diagnosis and
      consequent selection of the most appropriate treatment.

PMID- 15202525
TI  - Cutaneous T-cell lymphoma: epidemiology, etiology, and classification.
AB  - The term cutaneous T-cell lymphoma (CTCL) describes a heterogeneous group of
      neoplasms of skin-homing T-cells that vary considerably in clinical presentation,
      histologic appearance, immunophenotype, and prognosis. CTCL represent
      approximately 75-80% of all primary cutaneous lymphomas, whereas primary
      cutaneous B cell lymphomas account for approximately 20-25%. For many years
      mycosis fungoides and Sezary's syndrome were the only known types of CTCL. In the
      last decade, based on a combination of clinical, histological, and
      immunophenotypical criteria, new types of CTCL have been defined and new
      classifications for this group of primary cutaneous lymphomas have been
      formulated. In this overview, characteristic features of the different types of
      CTCL recognized in the European Organization for Research and Treatment of Cancer
      (EORTC) classification for primary cutaneous lymphomas and the World Health
      Organization (WHO) classification will be reviewed. Key conclusions from this
      brief overview are: (1) that the term CTCL does not refer to a single disease
      entity, but to a group of diseases with different clinical behaviors, therapeutic
      requirements, and prognoses; (2) that diagnosis and classification should always
      be based on a combination of clinical, histologic, and immunologic criteria; and
      (3) that the WHO and EORTC classification schemes are broadly equivalent for
      almost 90% of CTCL patients. Key research priorities are to develop effective
      therapies for peripheral T-cell lymphoma, extranodal NK (natural killer) T-cell
      lymphoma and so-called blastic NK cell lymphoma, and to determine molecular
      profiles for all forms of CTCL.

PMID- 15202526
TI  - Overview of cutaneous T-cell lymphoma: prognostic factors and novel therapeutic
      approaches.
AB  - The cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of entities.
      The WHO classification distinguishes indolent low-risk entities, including
      mycosis fungoides/Sezary syndrome (MF/SS), from aggressive entities, including
      peripheral T-cell lymphoma and its variants and HTLV-1 associated acute T-cell
      leukemia/lymphoma. Mycosis fungoides represents the most benign of the cutaneous
      T-cell lymphomas, with 10-year relative survival ranging from 100% to 41%,
      depending on the degree of skin involvement. Probability of progression to
      extracutaneous disease within 20 years of diagnosis can be up to 40%, depending
      on stage. Treatment strategies for early stage CTCL include topical therapies
      with or without interferon-alpha or oral agents, while advanced stage patients
      often progress and are treated with chemotherapy and novel agents. Multiagent
      cytotoxic regimens are palliative with no demonstrated survival benefit. Among
      the novel therapies for CTCL is bexarotene, a retinoid X-receptor (RXR)-selective
      agonist, which has demonstrated efficacy in advanced refractory CTCL. Other novel
      agents include the interleukin (IL)-2 fusion toxin (ONTAK), pentostatin (a potent
      adenosine deaminase inhibitor), histone deacetylase inhibitors such as
      depsipeptide, NF-kappaB inhibitors, cytokine receptor antagonists,
      immunomodulatory therapies and allogeneic stem cell therapy. The value of new
      therapeutic approaches to CTCL urgently needs to be assessed.

PMID- 15202527
TI  - AIDS-related non-Hodgkin's lymphoma: etiology, epidemiology, and impact of highly
      active antiretroviral therapy.
AB  - Lymphoproliferative disorders (LPD) occur more frequently in the immunosuppressed
      host compared to those who are immunocompetent. The biological and clinical
      characteristics of a particular LPD are specific to the underlying immune defect,
      though there are clear similarities in the various tumor types that occur.
      Immunosuppression-related LPD are more frequently associated with gamma
      herpesviruses suggesting that the immunologic environment influences
      tumorigenesis. Clinical outcomes may be optimized when appropriate treatment
      strategies are based on consideration of the underlying immunodeficiency and on
      the tumor biology. Consistent with this observation, in AIDS-related lymphomas
      (ARL), tumor biology, clinical presentations, and treatment outcomes are
      correlated with the CD4 cell count. This review will consider the role of immune
      deficiency in HIV disease on ARL pathogenesis and epidemiology, and the impact
      that highly active antiretroviral therapy has had in this disease.

PMID- 15202528
TI  - Mantle cell lymphoma: non-myeloablative versus dose-intensive therapy.
AB  - Mantle cell lymphoma (MCL) is now recognized as an aggressive lymphoma, in which
      there is frequent development of resistance to chemotherapy and a median survival
      period of 3-4 years. In recent years, the use of the chimeric monoclonal antibody
      rituximab, which is directed against the CD20 antigen, has provided new
      possibilities for the treatment of MCL. Rituximab alone produces overall response
      rates of 30-33% in patients with MCL, and is also effective at inducing complete
      responses in combination with CHOP (cyclophosphamide, doxorubicin, vincristine,
      prednisone). Furthermore, the addition of rituximab to the regimen of
      fractionated Hyper-CVAD/MTX-AraC
      (cyclophosphamide/doxorubicin:vincristine/dexamethasone alternated with
      methotrexate/cytarabine) has been found to produce responses and relapse-free and
      overall survival in younger patients that are comparable to those seen with Hyper
      CVAD/MTX-AraC plus stem cell transplantation. Despite these promising results,
      patients aged > 65 years have a poor prognosis, and further studies are required
      to improve outcomes in this population.

PMID- 15202529
TI  - Indolent B-cell malignancies: immune recognition and antiself.
AB  - B-cell malignancies appear to be ideal candidates for treatment with
      immunotherapeutic approaches. Monoclonal antibodies that target cell-surface
      determinants have been used as single agents in B-cell malignancies, in
      combination with chemotherapy, and coupled to other agents to create
      radioimmunoconjugates and immunotoxins. Another approach is to take advantage of
      the graft-vs.-lymphoma effect seen following allogeneic bone marrow
      transplantation. To exploit this effect without inducing the complication of
      graft-vs.-host disease, it is necessary to understand the mechanisms whereby
      lymphoma cells escape T-cell-mediated responses. CD40 activation may offer a
      means of increasing the immunogenicity of lymphoma cells and of stimulating
      allogeneic T-cell proliferation and cytokine production. Vaccination using tumor
      specific antigens shows promise as a therapeutic strategy. Pre-clinical studies
      with immunoglobulin idiotype peptides have shown that humoral and cellular immune
      responses can be stimulated by antibodies to these peptides, but better tumor
      antigens need to be identified that can reliably generate cytotoxic T-cell
      responses. Candidate antigens include heteroclitic peptides from the
      immunoglobulin V region and newly identified antigens including the cytochrome
      P450 1B1. Clinical trials are ongoing in all these fields.

PMID- 15202530
TI  - Vaccine therapy in NHL: future promises and current limitations.
AB  - Recent advances in genomics are revealing new molecular targets for vaccination
      strategies in cancer, and unraveling the immune pathways that must be activated.
      Initially, work focused on idiotypic antigen expressed by the clonal
      immunoglobulin (Ig) of B-cell tumors. This involved assembling the encoding V(H)
      and V(L) genes as single-chain Fv (scFv), which has been fused to Fragment C
      (FrC) of tetanus toxin to enhance recognition and response. The fusion gene
      induces strong anti-idiotypic protection against lymphoma in experimental models,
      and is now in clinical trials with encouraging results emerging. This principle
      of fusing a pathogen-derived sequence is widely applicable. A coat protein from a
      potato virus substituted for the FrC sequence has also been found to be capable
      of promoting anti-tumor immunity. The current design is effective in inducing
      anti-idiotypic (Id) antibody and CD4+ T-cell attack. For intracellular tumor
      antigens expressed as MHC Class I-associated peptides, a design consisting of a
      gene encoding a single domain of FrC linked to a candidate peptide sequence has
      been developed. This induces fast cytotoxic T-cell attack on peptide-expressing
      tumor cells. Injection of DNA appears safe and clinical trials will test the
      efficacy of this approach, and probably lead to improvements in these flexible
      vaccines.

PMID- 15202531
TI  - The allogeneic effect in non-Hodgkin's lymphoma.
AB  - Allogeneic hematopoietic stem cell transplantation (HSCT) has been restricted to
      medically fit patients under the age of 55 years due to adverse effects of the
      intensive conditioning regimens. Autologous HSCT has not proven to be a
      particularly effective treatment for patients with low-grade non-Hodgkin's
      lymphoma (NHL). Much of the benefit of allogeneic HSCT appears to be mediated by
      a graft-vs.-tumor (GVT) effect. Reduced-intensity regimens in allogeneic HSCT
      have been developed to minimize conditioning regimen-related toxicities and to
      control the malignancy until a GVT effect is established. A number of studies
      investigating reduced-intensity allogeneic HSCT are discussed. Results from these
      studies suggest that indications for allogeneic transplant include patients with
      low-grade NHL with a sibling or matched donor who are under 60 years of age;
      young patients with mantle cell lymphoma who are in first remission and have a
      sibling or matched donor; patients with high-grade NHL who have already failed an
      autograft but have chemosensitive disease, and those under 30 years of age who
      have poor-risk disease and are in first remission. It is concluded that reduction
      in treatment-related mortality with reduced-intensity HSCT and the presence of
      GVT effects increases the applicability of allogeneic transplantation for NHL.
      However, treatment will be improved by optimizating conditioning regimens and a
      better understanding of patient selection criteria and the immune processes
      involved in graft-vs.-host disease and GVT.

PMID- 15202532
TI  - Graft-vs.-lymphoma effect in various histologies of non-Hodgkin's lymphoma.
AB  - Generally, there is a significantly lower risk of lymphoma relapse following
      allogeneic than after autologous stem cell transplant. Factors contributing to
      this lower risk of relapse include an absence of the use of ablative
      conditioning, with a tumor-free graft, and the generation of a graft-vs.-tumor
      (GVT) immune response. Allogeneic transplantation, however, has the possibility
      of graft-vs.-host disease (GVHD). The use of autologous and conventional
      allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma,
      diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma is
      discussed. Due to a 1-year transplant-related mortality of 30-40% and
      complications caused by GVHD, conventional, myeloablative, allogeneic
      transplantation is a high-risk option for low-grade lymphoproliferative
      disorders. Novel applications of allogeneic HSCT are described that take
      advantage of a GVT effect while reducing the risk of GVHD. Minimally myelotoxic
      pretransplant conditioning regimens allow host antigen-presenting cells to
      persist, enabling presentation of host minor histocompatibility antigens to donor
      T cells, causing a GVT response. Although complications may arise due to GVHD,
      non-myeloablative HSCT can be offered to patients previously ineligible for
      conventional high-dose treatment. A protocol developed in Seattle using a low
      dose total body irradiation (TBI)-based conditioning regimen with
      immunosuppression using mycophenolate mofetil in combination with cyclosporin has
      been used in a multicenter trial. To overcome the problem of graft rejection
      fludarabine was later added to the protocol. A second protocol from a smaller
      trial used a preparative, conventional-dose regimen of fludarabine, given with
      cyclophosphamide. Rituximab was also given to provide synergistic action with the
      chemotherapy to enhance tumor control in the early post-transplant period to
      allow time for the establishment of the GVT effect. Following transplantation,
      GVHD prophylaxis was given using tacrolimus with methotrexate. A trial of a
      further variation of allogeneic HSCT, tandem auto/allo transplants, is described.
      First, high-dose therapy with autologous PBSC rescue was used to cytoreduce the
      disease. This was followed by a reduced-intensity or non-myeloablative allogeneic
      graft. This procedure was devised to take advantage of high-dose therapy and
      allogeneic HSCT. Results for non-myeloablative allogeneic HSCT are particularly
      promising in low-grade NHL and the GVT effect may augment response and delay or
      prevent relapse. However, for aggressive disease, non-myeloablative regimens are
      only indicated for patients with minimal disease, as the non-myeloablative
      regimens are unable to control the tumor before the generation of a GVT effect,
      and/or lack the ability to control rapidly proliferating disease. Patients with
      relapsed disease may require a higher-dose regimen or tandem transplant approach.

PMID- 15202533
TI  - ABCs of radioisotopes used for radioimmunotherapy: alpha- and beta-emitters.
AB  - Although the introduction of the monoclonal antibody rituximab 5 years ago led to
      a marked improvement in the treatment of non-Hodgkin's lymphoma (NHL), most
      patients do not experience a complete response to therapy, and many who do
      respond relapse. One way of improving the efficacy of monoclonal antibodies is to
      use them to deliver cytotoxic agents, such as radionuclides, to the tumor.
      Monoclonal antibodies armed with radionuclides provide a means of targeting
      radiation therapy specifically to tumor cells that express the antigen to which
      the antibody was originally raised. Subsequently, in 2002, the first radiolabeled
      monoclonal antibody, 90Y-ibritumomab tiuxetan was approved for the treatment of
      patients with relapsed or refractory low-grade follicular or transformed B-cell
      NHL, including patients with follicular lymphoma refractory to rituximab.
      Attempts to optimize the efficacy of radioimmunotherapy are ongoing, however, and
      there are three factors that need to be considered: choice of antibody/antigen,
      choice of delivery of system to be used, and choice of radionuclide. CD25 (IL-2R
      alpha) is an ideal choice for a target antigen as it is over-expressed by a
      number of tumor cells, including adult T-cell leukemia (ATL); 9 of 16 patients
      with ATL responded to treatment with anti-Tac (which targets the interleukin-2
      receptor-alpha [IL-2R alpha]), conjugated to 90Y. The dose of radionuclide that
      can be delivered to a tumor can be increased dramatically by using a three-step
      process in which the antibody and radioactivity are delivered separately to the
      antigen in order to improve tumor-to-normal tissue ratios. The most commonly used
      radionuclides in radioimmunotherapy to date are beta-emitters. However, the
      pretargeting process makes the use of short-lived alpha-emitters more feasible.
      The results of experiments involving this pretargeting process and alpha- and
      beta-emitting radionuclides in leukemia and lymphoma models suggest that alpha
      emitters may be more effective in the treatment of small tumors, micrometastases
      and isolated cells, and that beta-emitters may be more suitable for use in large
      tumor masses, such as lymphomas.

PMID- 15202534
TI  - Pharmacogenetics and proteomics of anticancer drugs in non-Hodgkin's lymphoma.
AB  - The variability of tumor responses to chemotherapeutic agents is a topic of major
      interest in current cancer research. Advances in the knowledge of dysregulation
      of key molecular pathways in cancer cells have enabled techniques to be developed
      that can profile tumor cells for their genetic background, allowing selection of
      anticancer agents on an individual basis. The next generation of anticancer
      treatments might therefore be tailored according to the molecular alterations
      identified in tumor cells of individual patients. However, before these
      alterations can be exploited from a therapeutic point of view, it is necessary to
      understand how such alterations influence the cellular pathways that control
      sensitivity to chemotherapeutic agents. Pharmacogenetics and pharmacoproteomics,
      novel disciplines that investigate the relationship between gene and protein
      expression in tumor cells and the response to anticancer agents, will be
      instrumental in developing optimal chemotherapeutic regimens for patients with
      non-Hodgkin's lymphoma.

PMID- 15202535
TI  - Working memory performance in poor outcome schizophrenia: relationship to age and
      executive functioning.
AB  - Performance on the Letter-Number Sequencing (LNS) and Wisconsin Card Sorting
      Tests (WCST) have been shown to be significantly correlated in patients with
      schizophrenia, a relationship postulated to be due to working memory demands of
      the two tests (Gold, Carpenter, Randolph, Goldberg, & Weinberger, 1997). An
      alternative explanation for the association between these two tests is their
      sorting demands, in that both require sorting of information albeit in slightly
      different ways. If the latter explanation is valid, then working memory tasks
      that do not require sorting or other conceptualization demands should be less
      predictive of WCST performance than LNS. These hypotheses were examined in 34
      poor outcome patients with schizophrenia, one-half of whom were over the age of
      65. Patients were evaluated on Digit Span Forward, spatial working memory, LNS,
      and the WCST. It was found that WCST performance was significantly associated
      with performance on the LNS but no other working memory task. Age related
      performance differences were greatest on the WCST Categories and floor effects
      were noted on this test in one-half of the subjects. Analyses predicting WCST
      Categories in subjects whose scores were greater than zero (n = 16) also
      demonstrated that LNS, but not Digit Span or spatial working memory (any delay)
      predicted WCST performance. These findings indicate that LNS may be an index of
      executive functioning, particularly in patients who cannot perform the WCST.

PMID- 15202536
TI  - Say it with me: stuttering inhibited.
AB  - This study examined fluency enhancement in people who stutter via the concomitant
      presentation of silently mouthed visual speech. Ten adults who stutter recited
      memorized text while watching another speaker silently mouth linguistically
      equivalent and linguistically different material. Relative to a control
      condition, in which no concomitant stimulus was provided, stuttering was reduced
      by 71% in the linguistically equivalent condition versus only 35% in the
      linguistically different condition. Despite being an 'incomplete' second speech
      signal, visual speech possesses the capacity to immediately and substantially
      enhance fluency when it is linguistically equivalent to the intended utterance.
      It is suggested that fluency enhancement via concomitantly presented external
      speech is achieved through the extraction of relevant speech gestures from the
      external speech signal that compliment the intended production, thereby
      compensating for possible internal inconsistencies in the matching of speech
      codes in people who stutter. As visual speech perception relies on fewer
      redundant cues to demarcate the intended gestures, when used as an external
      stuttering inhibitor, higher degrees of linguistic equivalence seem to be
      necessary for optimal stuttering inhibition.

PMID- 15202537
TI  - Response selection deficits in melancholic but not nonmelancholic unipolar major
      depression.
AB  - One consistent functional imaging finding from patients with major depression has
      been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been
      most commonly reported, but some studies suggest relative hyperperfusion is
      associated with response to somatic treatments. Despite these indications of the
      possible importance of the ACC in depression there have been relatively few
      cognitive studies ACC function in patients with major depression. The present
      study employed a series of reaction time (RT) tasks involving selection with
      melancholic and nonmelancholic depressed patients, as well as age-matched
      controls. Fifteen patients with unipolar major depression (7 melancholic, 8
      nonmelancholic) and 8 healthy age-matched controls performed a series of response
      selection tasks (choice RT, spatial Stroop, spatial stimulus-response
      compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and
      error data were collected. Melancholic patients were significantly slower than
      controls on all tasks but were slower than nonmelancholic patients only on the
      Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from
      the control group on any task. The Stroop task seems crucial in differentiating
      the two depressive groups, they did not differ on the choice RT or SRC tasks.
      This may reflect differential task demands, the SRC involved symbolic
      manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex
      (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may
      engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the
      melancholic group showed a greater ventral ACC-OFC deficit than the
      nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.

PMID- 15202538
TI  - Failure to inhibit the reading response on the Stroop Test: a pathognomonic
      indicator of suspect effort.
AB  - We present 6 patients who displayed noncredible effort on neuropsychological
      testing (verified by failures on specialized measures designed to discreetly
      assess effort status and multiple behavioral inconsistencies) and complained of
      complete illiteracy secondary to impoverished educational history, learning
      disability, or acquired brain injury. The Stroop Test, a measure of a specific
      aspect of executive function requiring inhibition of an automatized oral reading
      response in favor of a less habitual, competing color-naming response, was
      administered to these patients. All six subjects claimed that they were unable to
      perform the Word-Reading trial as a consequence of total reading disability, but
      on the Color-Word Interference trial, they all committed "errors" by reading the
      written words. Five of the six subjects also performed substantially slower on
      the Interference condition relative to the Color-Naming trial, indicating that
      they were in fact inhibiting a reading response. However, in cases involving
      complaints of complete reading illiteracy, the observation of these individuals
      performing an act that they claimed to be unable to do was the most powerful and
      pathognomonic indicator of deliberate feigning or exaggeration of impairment in
      these cases.

PMID- 15202539
TI  - Conditional-associative learning in eating disorders: a comparison with OCD.
AB  - The acquisition of conditional associations using neutral and individually
      threatening verbal stimuli was assessed in 16 females with anorexia nervosa (AN),
      obsessive-compulsive disorder (OCD), bulimia nervosa and normal controls,
      respectively. Groups did not differ in terms of age, sex, intelligence,
      depression, verbal memory and verbal fluency measures. Patients and controls were
      widely comparable on tests assessing neuropsychological functioning. In the
      conditional-associative learning (CAL)-task only anorectic and OCD-patients
      displayed an impaired performance with neutral material but not with individually
      threatening material. Such a deficit was not evident in bulimics or in normal
      controls. These findings support the assumptions from functional neuroimaging
      investigations in AN and OCD and provide evidence that obsessive and compulsive
      behavior could have its origin within common neurobiological dysfunctions. The
      CAL possibly serves as a functional correlate of a neurophysiological dysfunction
      in obsessive-compulsive spectrum disorders.

PMID- 15202540
TI  - Self-reported everyday memory and depression in patients with multiple sclerosis.
AB  - Depression and memory difficulties are among the most common complaints voiced by
      patients with multiple sclerosis (MS). Nevertheless, little is known about how
      depression might affect patients' perceptions of their memory difficulties. The
      present investigation was designed to explore this issue. Results supported a
      model that integrates aspects of Beck's theory of depression and the concept of
      depressive realism. Consistent with the depressive realism literature,
      nondepressed MS patients significantly overestimated their everyday memory
      compared with their actual performance on verbal memory and
      attention/concentration indices, whereas moderately depressed patients' everyday
      memory ratings mirrored their actual neuropsychological performance. Supporting
      Beck's negative cognitive schema notion, mildly depressed patients significantly
      overestimated their memory difficulties. Implications for the treatment of memory
      problems among MS patients are discussed.

PMID- 15202541
TI  - Awareness in early-stage Alzheimer's disease: relationship to outcome of
      cognitive rehabilitation.
AB  - Awareness of difficulties may have an important impact on functioning and
      response to intervention in early-stage Alzheimer's disease (AD). Clinical
      reports and retrospective studies suggest an association, but this has not
      previously been tested in a prospective study. Using a new measure of awareness,
      the Memory Awareness Rating Scale (MARS), which was designed to take account of
      methodological limitations identified in a review of previous studies, the
      present study explored the relationship between awareness of difficulties and
      outcome of a cognitive rehabilitation (CR) intervention in 12 participants with a
      diagnosis of early-stage Alzheimer's disease. The relationship between awareness
      and mood, behaviour and executive function was also assessed. The results provide
      the first demonstration in a prospective study that higher levels of awareness
      are related to better CR outcomes. Awareness was associated with depression and
      reported behaviour problems, but not with performance on tests of executive
      function. These results suggest that variations in level of awareness in early
      stage AD are influenced by psychological factors, and that explanatory models
      need to take these factors into account. Awareness of difficulties may serve as a
      useful predictor of the likely effectiveness of CR, andthis may assist clinicians
      in selecting appropriate interventions for individuals with early-stage AD.

PMID- 15202542
TI  - The contributions of attention and working memory to age differences in concept
      identification.
AB  - The contributions of attention and working memory to adult age differences in
      concept identification were examined in two experiments using the standard
      version of the California Card Sorting Test plus two modified versions. Older
      adults demonstrated global reductions in their ability to identify concepts
      whether sorting stimuli, identifying concepts used by the examiner, or generating
      concepts from abstract cues. Although age differences in selective attention and
      interference control did not contribute to these deficits, reduced working memory
      accounted for the age-related increase in perseverative errors. Our conclusions
      focus on whether impairments in working memory might fully account for age
      differences in concept identification.

PMID- 15202543
TI  - Modified Card Sorting Test: normative data.
AB  - The Modified Card Sorting Test (MCST), a shortened version of the Wisconsin Card
      Sorting Test, proposed by Nelson in 1976 is a neuropsychological test that is
      widely used in clinical settings for the evaluation of executive functions in
      patients with focal, traumatic and degenerative brain diseases. Despite its
      frequent use, normative data for the MCST are scant. The aim of this study was to
      collect normative data for the MCST on a sample including 248 healthy individuals
      ranging from 20 to 90 years of age and equally distributed for education level
      and sex (124 males and 124 females). Performance on the MCST was scored by
      computing the number of categories achieved by a participant, and the number of
      perseverative errors. Multiple regression analyses revealed a significant effect
      of age and education on the number of categories and perseverative errors but no
      effect of sex. Cut-off scores were then determined and equivalent scores computed
      for both the number of categories and the perseverative errors. The availability
      of normative data for the MCST will be very valuable in clinical settings for
      testing patients with focal, traumatic and degenerative brain diseases. The use
      of reference norms will permit a better characterisation of a patient's impaired
      and spared abilities.

PMID- 15202544
TI  - How efficient is a simple copying task to diagnose spatial neglect in its chronic
      phase?
AB  - Twenty-five patients with spatial neglect were tested in the acute phase and
      about 1.3 years after a right-hemisphere stroke. Ten patients had developed
      chronic spatial neglect. We investigated how sensitive a simple copying task is
      in detecting spatial neglect in the chronic phase. When the stroke was acute, all
      10 patients omitted a considerable number of contralesionally located items in
      the copying task. In the chronic phase, 60% of the chronic neglect patients still
      demonstrated noticeable neglect in the copying task. The data indicate that a
      simple task such as the copying of a multi-object scene is a helpful tool to
      detect residual symptoms of spatial neglect even more than 1 year after the
      stroke.

PMID- 15202545
TI  - The effects of list difficulty and modality of presentation on a computerized
      version of the Paced Serial Addition Test (PSAT).
AB  - The Paced Serial Addition Test (PSAT) presents a series of digits at different
      speeds with the requirement that the two most recent numbers be added together.
      Although the PSAT is a relatively difficult test, its level of difficulty may be
      decreased by changing the number list to make the answers simpler and by
      presenting the digits visually rather than aurally. In view of this, the present
      experiment varied both task difficulty (easy vs. hard) and mode of presentation
      (visual vs. auditory). Task difficulty was manipulated by using two different
      lists composed of single digits whose answers ranged between 2 and 10 (easy) or 2
      and 18 (hard). All stimuli were presented by computer which permitted measurement
      of response latencies, as well as correctness of responding. The results showed
      that mode of presentation, but not task difficulty, produced highly significant
      effects. Additional evidence showed that the ability to compute answers to simple
      addition problems must be considered as a modulator variable. However, an
      individual's basic arithmetic ability is not as critical as the modality in which
      a stimulus is presented. The lower performance associated with the auditory
      version (i.e., PASAT) was interpreted as an interference effect caused by both
      the stimulus and the response occurring in a single auditory information
      processing channel. This interpretation suggests that the PASAT's well documented
      sensitivity to traumatic brain injury (TBI) may be due, at least in part, to an
      increased susceptibility to interference effects rather than attributable solely
      to a decreased rate of information processing.

PMID- 15202546
TI  - The effects of literacy and education on the quantitative and qualitative aspects
      of semantic verbal fluency.
AB  - Semantic verbal fluency tasks are commonly used in neuropsychological assessment.
      Investigations of the influence of level of literacy have not yielded consistent
      results in the literature. This prompted us to investigate the ecological
      relevance of task specifics, in particular, the choice of semantic criteria used.
      Two groups of literate and illiterate subjects were compared on two verbal
      fluency tasks using different semantic criteria. The performance on a food
      criterion (supermarket fluency task), considered more ecologically relevant for
      the two literacy groups, and an animal criterion (animal fluency task) were
      compared. The data were analysed using both quantitative and qualitative
      measures. The quantitative analysis indicated that the two literacy groups
      performed equally well on the supermarket fluency task. In contrast, results
      differed significantly during the animal fluency task. The qualitative analyses
      indicated differences between groups related to the strategies used, especially
      with respect to the animal fluency task. The overall results suggest that there
      is not a substantial difference between literate and illiterate subjects related
      to the fundamental workings of semantic memory. However, there is indication that
      the content of semantic memory reflects differences in shared cultural background
      -in other words, formal education--, as indicated by the significant interaction
      between level of literacy and semantic criterion.

PMID- 15202547
TI  - Unawareness of cognitive deficits and daily functioning among persons with
      traumatic brain injuries.
AB  - This study examines levels of unawareness of cognitive deficits and their
      relationship to functional outcome among persons with traumatic brain injury
      (TBI). Data from 61 persons with TBI and 34 family members consisting of various
      measures were used. The results suggest that awareness of cognitive deficits is
      not differentially distributed along a concrete-abstract continuum of cognitive
      domains. Awareness in this sample was significantly related to psychiatric
      symptomatology and partially associated with behavior disturbances and daily
      functioning, but not with vocational outcomes. Persons with TBI who over
      estimated their cognitive abilities were found to function worse on most outcome
      measures, except vocation, than persons who did not overestimate their abilities.

PMID- 15202548
TI  - Essential books and journals in clinical neuropsychology: an Australian
      perspective.
AB  - To assist in the identification of key professional resources for
      neuropsychologists, 214 Australian clinical neuropsychologists were asked to
      identify "essential" reference materials. Fifty members of the Australian College
      of Clinical Neuropsychologists returned useable surveys. Forty-three respondents
      provided information about which clinical neuropsychology books and journals they
      considered essential and why. Results showed 15 books, including 3 Australian
      books, and 31 journals were included in the essential reading list of at least
      10% of this sample. Compared to similar previous surveys (predominantly conducted
      overseas and mostly over 10 years ago), the results of this survey suggest that,
      Australian neuropsychologists have similar views about the top ranking books and
      journals in clinical neuropsychology as their overseas counterparts. An exception
      to this general trend may be the status of reference books containing norms,
      which appear to be growing in perceived importance. Importantly, the results of
      this survey may be used to help practitioners identify key professional resources
      in the area of clinical neuropsychology.

PMID- 15202549
TI  - CoMFA and CoMSIA 3D QSAR studies on pimarane cyclooxygenase-2 (COX-2) inhibitors.
AB  - Comparative molecular field analysis and comparative molecular similarity indices
      analysis were performed on twenty five analogues of pimarane COX-2 inhibitor to
      optimize their cyclooxygenase-2 (COX-2) selective anti-inflammatory activities.

PMID- 15202550
TI  - Synthesis and biological evaluation of new thiazolopyrimidines.
AB  - In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2
      thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such
      as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin
      2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4
      b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and
      antitumor agents. Some of the tested compounds showed promising antimicrobial
      activity and non of them showed any appreciable antitumor activity.

PMID- 15202551
TI  - Synthesis and cytotoxic activity of 1-(1-benzoylindoline-5-sulfonyl)-4
      phenylimidazolidinones.
AB  - The novel 1-(1-benzoylindoline-5-sulfonyl)-4-phenyl-4,5-dihydroimidazolones 2
      shows highly potent and broad cytotoxicities. Their cytotoxicities against human
      lung carcinoma A549, human chronic myelogenous leukemia K562, and human ovarian
      adenocarcinoma SK-OV-3 are compatible with doxorubicin. Compound 2p (1-[(4
      aminobenzoyl)indoline-5-sulfonyl])-4-phenyl-4,5-dihydroimidazolone) exhibits a
      cytotoxicity that is far more potent than doxorubicin and also exhibits highly
      effective antitumour activities against murine (3LL, Colon 26) and human
      xenograft (NCI-H23, SW620) tumor models.

PMID- 15202552
TI  - 5-Arylidene-2(5H)-furanone derivatives: synthesis and structure-activity
      relationship for cytotoxicity.
AB  - Thirty-eight 5-arylidene-2(5H)-furanone derivatives possessing halo-, methoxy-,
      oxo-, dioxo-, and thiophenyl groups as well as anthraquinone and naphthquinone
      moieties were synthesized, and their cytotoxicity was evaluated against various
      cancer cell lines. The introduction of halogen atoms or nitro group at aromatic
      ring of 5-arylidene-2(5H)-furanone was shown to increase the cytotoxicity with 5
      (3-nitrobenzylidene)-2(5H)-furanone (21) being the most potent. Among anthracenyl
      or naphthalenyl derivatives, (E)-5-[2-(1,4-dimethoxy-9,10-dioxo) anthracenyl]
      2(5H)-furanone (34) showed the most potent cytotoxic activity.

PMID- 15202553
TI  - Synthesis and anticonvulsant evaluation of N-substituted-isoindolinedione
      derivatives.
AB  - A series of N-substituted-1,3-isoindolinedione derivatives (2-16) were
      synthesized for the purpose of defining the effect of N-substitution on the
      anticonvulsant activity of these derivatives. The target compounds (2-16) were
      obtained by condensation of phthalic anhydride with the corresponding amine
      derivative. The structures of the synthesized derivatives (2-16) were confirmed
      by means of IR, 1H-NMR, 13C-NMR, MS and elemental analyses. The anticonvulsant
      activity of all compounds (2-16) were evaluated by subcutaneous
      pentylenetetrazole seizure threshold test at doses of 0.2, 0.4 and 0.8 mmol/kg
      compared with sodium valproate as a positive control. Their neurotoxicity were
      determined by the rotorod test. Many of the present series of compounds showed
      good anticonvulsant activity at the tested doses, as compared to sodium
      valproate. Three of them (4, 6 and 11) exhibited 100% protection against
      convulsions, neurotoxicity and death at all tested doses. Out of the series, two
      compounds (12 and 13) were completely inactive with 100% mortality. 3-(p
      chlorophenyl)-4-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)butanoic acid derivative
      (11) has emerged as the most active compound which is 20 times more active than
      valproate with ED50 8.7, 169 mg/kg; TD50 413, 406 mg/kg and PI 47.5, 2.4. The
      results revealed the importance of the combination of baclofenic and phthalimide
      moieties (compound 11) as a promising anticonvulsant candidate.

PMID- 15202554
TI  - Antituberculosis agents X. Synthesis and evaluation of in vitro antituberculosis
      activity of 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,3,4
      thiadiazole derivatives.
AB  - Two series of 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5
      propyl, allyl and propargyl)thio-1,3,4-thiadiazoles (6a-f) and 2-(5-nitro-2
      furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-(nitrobenzyl)thio-1,3,4
      thiadiazole derivatives (8a-f) have been synthesized and evaluated against
      Mycobacterium tuberculosis, as part of the TAACF TB screening program under
      direction of the US National Institute of Health, the NIAID division. Primary
      screening was conducted at a single concentration, 6.25 microg mL(-1), against M.
      tuberculosis H37Rv in BACTEC 12B medium, using the Microplate Alamar Blue Assay
      (MABA). The minimum inhibitory concentration (MIC) was determined for the
      compounds that demonstrated > or = 90% growth inhibition in the primary
      screening. A varying degree of antituberculosis activity (from 0-97% of growth
      inhibition) was observed with the alkylthio series (6a-f), and the nitroimidazole
      derivative with a propylthio group (6b) and the nitrofuran derivative with a
      propargylthio group (6e), were the most active compounds (MIC=3.13 and 1.56
      microg mL(-1), respectively). Among the nitrobenzylthio derivatives (8a-f), all
      the ortho, meta and para nitrobenzyl isomers in the nitrofuran series exhibited
      good antituberculosis activity (MIC=3.13 microg mL(-1)), while the corresponding
      nitroimidazole analogues were completely inactive (Inhibition=0%).

PMID- 15202555
TI  - Antimycobacterial activity and cytotoxicity of flavonoids from the flowers of
      Chromolaena odorata.
AB  - From the flowers of Chromolaena odorata (Eupatorium odoratum) four flavanones,
      isosakuranetin (5,7-dihydroxy-4'-methoxyflavanone) (1), persicogenin (5,3'
      dihydroxy-7,4'-dimethoxyflavanone) (2), 5,6,7,4'-tetramethoxyflavanone (3) and 4'
      hydroxy-5,6,7-trimethoxyflavanone (4), two chalcones, 2'-hydroxy-4,4',5',6'
      tetramethoxychalcone (5) and 4,2'-dihydroxy-4',5',6'-trimethoxychalcone (6), and
      two flavones, acacetin (5,7-dihydroxy-4'-methoxyflavone) (7) and luteolin
      (5,7,3',4'-tetrahydroxyflavone) (8) were isolated and identified. Compound 1
      exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis
      with the MIC value of 174.8 microM, whereas compounds 4, 7, and 8 exhibited weak
      activity with the MIC values of 606.0, 704.2 and 699.3 microM respectively.
      Compound 7 showed moderate cytotoxicity against human small cell lung cancer (NCI
      H187) cells with the MIC value of 24.6 microM, whereas compound 8 exhibited
      moderate toxicity against NCI-H187 cells and week toxicity against human breast
      cancer (BC) cells with the MIC values of 19.2 and 38.4 microM respectively.

PMID- 15202556
TI  - Structure-related cytotoxicity and anti-hepatofibric effect of asiatic acid
      derivatives in rat hepatic stellate cell-line, HSC-T6.
AB  - The structural relationship of 16 asiatic acid (AA) derivatives, including AA and
      asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6
      cells, were investigated. Cytotoxicities of AA derivatives varied from 5.5 microM
      to over 2000 microM of IC50 depending on AA functional group modifications.
      Substituting the hydroxyl group at the C(2) to N[triple bond]C and substituting
      bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the
      cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly
      reduced it. Modification of the carboxylic acid group at C28 also reduced the
      cytotoxicity. The collagen synthesis determined by hydroxyproline content in the
      cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA
      derivatives. The anti-hepatofibrotic effect of these compounds might be due to
      the reduced expression of prolyl 4-hydroxylase alpha and beta subunits and TIMP2.
      However, the inhibition of collagen by asiaticoside derivatives did not show any
      structural-activity relationship.

PMID- 15202557
TI  - Excavation of lead compounds that inhibit mast cell degranulation by
      combinatorial chemistry and activity-guided.
AB  - An allergic reaction ensues after antigen binds to mast cell or basophil high
      affinity IgE receptor, Fc epsilonRI, resulting in degranulation of various
      inflammatory mediators that produce various allergic symptoms. In this study, i)
      we isolated the active component for the inhibition of mast cell degranulation
      from the extract of leaves of Castanea crenata and identified it as quercetin;
      ii) we established the total synthesis procedure of quercetin; iii) using
      quercetin as positive control, we excavated some lead compounds that possess
      inhibitory activities for mast cell degranulation by screening the chemical
      libraries of 1,3-oxazolidine derivatives prepared by solid phase combinatorial
      chemistry. Some of 1,3-oxazolidine compounds possessing acetyl and 3',4'
      dichlorophenyl group displayed strong inhibitory activities on Fc epsilonRI
      mediated mast cell degranulation, suggesting that they can be used as lead
      compounds for the development of anti-allergic agents.

PMID- 15202558
TI  - Ginsenosides inhibit NMDA receptor-mediated epileptic discharges in cultured
      hippocampal neurons.
AB  - Epilepsy or the occurrence of spontaneous recurrent epileptiform discharges
      (SREDs, seizures) is one of the most common neurological disorders. Shift in the
      balance of brain between excitatory and inhibitory functions due to different
      types of structural or functional alterations may cause epileptiform discharges.
      N-Methyl-D-aspartate (NMDA) receptor dysfunctions have been implicated in
      modulating seizure activities. Seizures and epilepsy are clearly dependent on
      elevated intracellular calcium concentration ([Ca2+]i) by NMDA receptor
      activation and can be prevented by NMDA antagonists. This perturbed [Ca2+]i
      levels is forerunner of neuronal death. However, therapeutic tools of elevated
      [Ca2+]i level during status epilepticus (SE) and SREDs have not been discovered
      yet. Our previous study showed fast inhibition of ginseng total saponins and
      ginsenoside Rg3 on NMDA receptor-mediated [Ca2+]i in cultured hippocampal
      neurons. We, therefore, examined the direct modulation of ginseng on hippocampal
      neuronal culture model of epilepsy using fura-2-based digital Ca2+ imaging and
      neuronal viability assays. We found that ginseng total saponins and ginsenoside
      Rg3 inhibited Mg2+ free-induced increase of [Ca2+]i and spontaneous [Ca2+]i
      oscillations in cultured rat hippocampal neurons. These results suggest that
      ginseng may play a neuroprotective role in perturbed homeostasis of [Ca2+]i and
      neuronal cell death via the inhibition of NMDA receptor-induced SE or SREDs.

PMID- 15202559
TI  - Effects of polysaccharide ginsan from Panax ginseng on liver function.
AB  - Ginsan, a polysaccharide isolated from Panax ginseng, has been shown to be a
      potent immunomodulator, producing a variety of cytokines such as TNF-alpha, IL-1,
      IL-2, IL-6, IL-12, IFN-gamma and GM-CSF, and stimulating lymphoid cells to
      proliferate. In the present study, we analyzed some immune functions 1st-5th days
      after ginsan i.p. injection, including the level of non-protein thiols (NPSH) as
      antioxidants, heme oxygenase (HO) activity as a marker of oxidative stress,
      zoxazolamine-induced paralysis time and level of hepatic cytochrome P-450
      (CYP450) as indices of drug metabolism system, and activities of serum aspartate
      aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase
      (ALP), total bilirubin, and albumin level as indicators of hepatotoxicity. Ginsan
      in the dose of 100 mg/kg caused marked elevation (1.7 to approximately 2 fold) of
      HO activity, decrease of total CYP450 level (by 20-34%), and prolongation of
      zoxazolamine-induced paralysis time (by 65-70%), and showed some differences
      between male and female mice. Ginsan treatment did not seem to cause hepatic
      injury, since serum AST, ALT, and ALP activities and levels of total bilirubin
      and albumin were not changed.

PMID- 15202560
TI  - Solid-phase extraction of L-muscone from aqueous samples with Amberlite XAD-4 for
      gas chromatographic assay.
AB  - An efficient analytical method was devised for the accurate L-muscone assay in
      aqueous samples. It involves solid-phase extraction of L-muscone in adsorption
      mode using XAD-4 as the sorbent and dichloromethane modified with 10% (v/v)
      methanol as the eluting solvent. The gas chromatographic analysis of the eluate
      residue dissolved in toluene on a DB-5MS capillary column provided complete
      resolution of L-muscone from the co-extracted interferences. The overall method
      showed excellent linearity (r2 > or = 0.9994) in the range of 0.1 to 2.0
      microg/mL with good intra- and inter-day precisions (% RSD = 2.5 to approximately
      7.3) and with high extraction recovery rates (> or = 98.1%). When the present
      method was applied to a L-muscone herbal drink product, the within-batch RE (%)
      in the labeled concentration (1.5 microg/mL) for the three randomly chosen
      bottles were -2.4, -1.3 and -3.3 with high precision (% RSD < or = 3.1). The
      present method is considered to be suitable for quality control evaluation on
      liquid drinks and other complex formulations fortified with L-muscone.

PMID- 15202561
TI  - Flavonoids of Crotalaria sessiliflora.
AB  - Phytochemical investigation of the whole plants of Crotalaria sessiliflora L. led
      to the isolation of four flavonoids. The structures of these compounds were
      identified as 2',4',5,7-tetrahydroxyisoflavone (1), 2',4',7-trihydroxyisoflavone
      (2), 4',7-dihydroxyflavone (3), and isovitexin (4) using spectroscopic analysis.
      Among these, compounds 2, and 3 have not been reported from Crotalaria species,
      whereas compounds 1, and 4 were reported from this plant for the first time.

PMID- 15202562
TI  - Differential metabolism of the pyrrolizidine alkaloid, senecionine, in Fischer
      344 and Sprague-Dawley rats.
AB  - The pyrrolizidine alkaloids (PAs), contained in a number of traditional remedies
      in Africa and Asia, show wide variations in metabolism between animal species but
      little work has been done to investigate differences between animal strains. The
      metabolism of the PA senecionine (SN) in Fischer 344 (F344) rats has been studied
      in order to compare to that found in the previously investigated Sprague-Dawley
      (SD) rats (Drug Metab. Dispos. 17: 387, 1989). There was no difference in the
      formation of (+/-) 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP,
      bioactivation) by hepatic microsomes from either sex of SD and F344 rats.
      However, hepatic microsomes from male and female F344 rats had greater activity
      in the N-oxidation (detoxication) of SN by 88% and 180%, respectively, when
      compared to that of male and female SD rats. Experiments conducted at various pH
      showed an optimum pH of 8.5, the optimal pH for flavin-containing monooxygenase
      (FMO), for SN N-oxidation by hepatic microsomes from F344 females. In F344 males,
      however, a bimodal pattern was obtained with activity peaks at pH 7.6 and 8.5
      reflecting the possible involvement of both cytochrome P450 (CYP) and FMO. Use of
      specific inhibitors (SKF525A, 1-benzylimidazole and methimazole) showed that the
      N-oxide of SN was primarily produced by FMO in both sexes of F344 rats. In
      contrast, SN N-oxide formation is known to be catalyzed mainly by CYP2C11 rather
      than FMO in SD rats. This study, therefore, demonstrated that there were
      substantial differences in the formation of SN N-oxide by hepatic microsomes from
      F344 and SD rats and that this detoxification is catalyzed primarily by two
      different enzymes in the two rat strains. These findings suggest that significant
      variations in PA biotransformation can exist between different animal strains.

PMID- 15202563
TI  - Estrogen receptor enhances the antiproliferative effects of trichostatin A and HC
      toxin in human breast cancer cells.
AB  - Trichostatin A, an antifungal antibiotics, and HC-toxin are potent and specific
      inhibitors of histone deacetylase activity. Histone deacetylase inhibitors are
      new class of chemotherapeutic drugs able to induce tumor cell apoptosis and/or
      cell cycle arrest. In this study, the antiproliferative activities of
      trichostatin A and HC-toxin were compared between estrogen receptor positive
      human breast cancer cell MCF-7 and estrogen receptor negative human breast cancer
      cell MDA-MB-468. Trichostatin A and HC-toxin showed potent antiproliferative
      activity in both MCF-7 and MDA-MB-468 cells. In MCF-7 cells that contain high
      level estrogen receptor, trichostatin A and HC-toxin brought about three-times
      more potent cell growth inhibitory effect than estrogen receptor negative MDA-MB
      468 cells. Both trichostatin A and HC-toxin showed cell cycle arrest at G2/M
      phases of MCF-7 and MDA-MB-468 cells in a dose- and time-dependent manner.
      Trichostatin A and HC-toxin also induced apoptosis from MCF-7 and MDA-MB-468
      cells in a dose- and time-dependent manner. Results of this study suggested that
      antiproliferative effects of trichostatin A and HC-toxin might be involved in
      estrogen receptor signaling pathway, but cell cycle arrest and apoptosis of
      trichostatin A and HC-toxin might not be involved in estrogen receptor system of
      human breast cancer cells.

PMID- 15202564
TI  - Self-assembled polymeric nanoparticles of poly(ethylene glycol) grafted pullulan
      acetate as a novel drug carrier.
AB  - Self-assembling nanospheres of hydrophobized pullulan have been developed.
      Pullulan acetate (PA), as hydrophobized pullulan, was synthesized by acetylation.
      Carboxymethylated poly(ethylene-glycol) (CMPEG) was introduced into pullulan
      acetate (PA) through a coupling reaction using N,N'-dicyclohexyl carbodiimide
      (DCC). A synthesized PA-PEG-PA (abbreviated as PEP) conjugate was confirmed by
      Fourier transform-infrared (FT-IR) spectroscopy. Since PEP conjugates have
      amphiphilic characteristics in aqueous solution, polymeric nanoparticles of PEP
      conjugates were prepared using a simple dialysis method in water. From the
      analysis of fluorescence excitation spectra primarily, the critical association
      concentration (CAC) of this conjugate was found to be 0.0063 g/L. Observations by
      scanning electron microscopy (SEM) showed the spherical morphologies of the PEP
      nanoparticles. The particle size distribution of the PEP conjugates was
      determined using photon correlation spectroscopy (PCS) and the intensity-average
      particle size was 193.3 +/- 13.53 nm with a unimodal distribution. Clonazepam
      (CNZ), as a model drug, was easy to entrap into polymeric nanoparticles of the
      PEP conjugates. The drug release behavior was mainly diffusion controlled from
      the core portion.

PMID- 15202565
TI  - Kinetic property and phylogenic relationship of 2-hydroxymuconic semialdehyde
      dehydrogenase encoded in tomC gene of Burkholderia cepacia G4.
AB  - 2-Hydroxymuconic semialdehyde (2-HMS) dehydrogenase catalyzes the conversion of 2
      HMS to 4-oxalocrotonate, which is a step in the meta cleavage pathway of aromatic
      hydrocarbons in bacteria. A tomC gene that encodes 2-HMS dehydrogenase of
      Burkholderia cepacia G4, a soil bacterium that can grow on toluene, cresol,
      phenol, or benzene, was overexpressed into E. coli HB101, and its gene product
      was characterized in this study. 2-HMS dehydrogenase from B. cepacia G4 has a
      high catalytic efficiency in terms of Vmax/Km towards 2-hydroxy-5-methylmuconic
      semialdehyde followed by 2-HMS but has a very low efficiency for 5-chloro-2
      hydroxymuconic semialdehyde. However, the enzyme did not utilize 2-hydroxy-6-oxo
      hepta-2,4-dienoic acid and 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid as
      substrates. The molecular weight of 2-HMS dehydrogenase from B. cepacia G4 was
      predicted to be 52 kDa containing 485 amino acid residues from the nucleotide
      sequence of the tomC gene, and it exhibited the highest identity of 78% with the
      amino acid sequence of 2-HMS dehydrogenase that is encoded in the aphC gene of
      Comamonas testosteroni TA441. 2-HMS dehydrogenase from B. cepacia G4 showed a
      significant phylogenetic relationship not only with other 2-HMS dehydrogenases,
      but also with different dehydrogenases from evolutionarily distant organisms.

PMID- 15202566
TI  - Pharmacokinetics of primaquine and carboxyprimaquine in Korean patients with
      vivax malaria.
AB  - Primaquine is used for relapses caused by vivax malaria hypnozoites. No studies
      on the pharmacokinetics of primaquine (PMQ) has been reported in Korean patients.
      In our study, thirty vivax malaria patients were given 15 mg primaquine daily for
      14 days after 3 days of chloroquine treatment. Plasma samples were taken at
      intervals after each daily dose of PMQ for 3 days. Plasma concentrations of PMQ
      and carboxyprimaquine (CPMQ), the major metabolite of primaquine, were measured
      by HPLC. The PMQ concentrations reached a maximum of 0.28+/-0.18 microg/mL at 1.5
      h after the first dose. The maximum concentration of CPMQ was 0.32+/-0.13
      microg/mL at 4 h. Higher drug concentrations with repeated dosing were observed
      for CPMQ, but not for the parent drug, PMQ. The elimination half-life was 3.76+/
      1.8 h and 15.7+/-12.2 h, for PMQ and CPMQ, respectively. Large variation in the
      plasma concentrations of both drugs was observed. Overall, PMQ is absorbed and
      metabolized rapidly after oral administration. It was noted that the mean peak
      plasma concentration of PMQ was significantly higher and that of CPMQ was lower
      in our patients compared to other studies. This suggests a potential difference
      of inter-ethnic groups, which warrants further investigations.

PMID- 15202567
TI  - Reviewing in science requires quality criteria and professional reviewers.

PMID- 15202568
TI  - PEGylation significantly affects cellular uptake and intracellular trafficking of
      non-viral gene delivery particles.
AB  - In vitro studies of non-viral gene delivery vectors are typically not performed
      at physiological conditions, and thus may not provide meaningful results for in
      vivo investigations. We determine if polycation-plasmid DNA complexes
      (polyplexes) exploited for in vitro studies behave similarly to variants more
      applicable to in vivo use by examining their cellular uptake and trafficking.
      Branched polyethylenimine (25 kDa) or a linear beta-cyclodextrin-containing
      polymer are each used to formulate polyplexes, which can be PEGylated (PEG:
      poly(ethylene glycol)) to create particles stable in physiological salt
      concentrations. Particle size, cellular uptake, intracellular trafficking, and
      reporter gene expression are reported for polyplexes and for their PEGylated
      variants. PEGylation confers salt stability to particles but produced a reduction
      in luciferase expression. Examination of in vitro particle internalization by
      transmission electron microscopy shows unmodified polyplexes entering cells as
      large aggregates while PEGylated particles remain small and discrete, both
      outside and within cells. Unmodified and PEGylated particles enter cells through
      the endocytic pathway and accumulate in a perinuclear region. Immunolabeling
      reveals unpackaged exogenous DNA in the cytoplasm and nuclei. It appears all
      particle types traffic towards the nucleus within vesicles and undergo
      degradation in vesicles and/or cytoplasm, and eventually some exogenous DNA
      enters the nucleus, where it is transcribed. In comparing polyplexes and their
      PEGylated variants, significant differences in particle morphology, cellular
      uptake, and resultant expression suggest that in vitro studies should be
      conducted with particles prepared for physiological conditions if the results are
      to be relevant to in vivo performance.

PMID- 15202569
TI  - Differential RNA interference: replacement of endogenous with recombinant low
      density lipoprotein receptor-related protein (LRP).
AB  - The interpretation of experiments involving the overexpression of a recombinant
      cDNA is often hampered by the interference of mRNA expression from the endogenous
      gene locus. Unless cell lines from naturally occurring mutations or knockout mice
      are available, difficult and time-consuming gene targeting techniques are
      required to inhibit endogenous gene expression. Using a method we refer to as
      "differential RNA interference" we demonstrate that RNA interference can be used
      to selectively suppress endogenous gene expression without affecting the
      expression of a co-transfected recombinant version of the same protein.
      Functional analyses of recombinant low density lipoprotein receptor-related
      protein (LRP) to study its involvement in lipid metabolism have been shown to be
      extremely difficult due to its large cDNA and the unavailability of suitable LRP
      deficient cell lines. We constructed an expression vector containing the full
      length coding sequence of human LRP fused to EGFP and a vector expressing small
      hairpin RNA directed against the 3'-untranslated region of the wild-type human
      LRP mRNA (LRP-shRNA). When overexpressed, EGFP-tagged LRP colocalizes with
      endogenous LRP and stimulates the uptake of LRP ligands. Overexpression of LRP
      shRNA vectors significantly inhibits LRP expression, as judged by quantitative RT
      PCR, Western blot and immunofluorescence analysis, and it dramatically decreases
      receptor-associated protein (RAP) uptake. Finally, co-transfection of EGFP-LRP
      and LRP-shRNA vectors demonstrates selective inhibition of endogenous LRP
      expression without affecting simultaneous expression of recombinant LRP protein.
      Thus, utilization of "differential RNA interference" provides a new experimental
      approach to selectively study the function of any recombinant protein in any
      given cell line without interference of endogenous protein expression.

PMID- 15202570
TI  - Characterization of the TGN exit routes in AtT20 cells using pancreatic amylase
      and serum albumin.
AB  - The AtT20 pituitary cell is the one that was originally used to define the
      pathways taken by secretory proteins in mammalian cells. It possesses two
      secretory pathways, the constitutive for immediate secretion and the regulated
      for accumulation and release under hormonal stimulation. It is in the regulated
      pathway, most precisely in the immature granule of the regulated pathway, that
      proteolytic maturation takes place. A pathway that stems from the regulated one,
      namely the constitutive-like pathway releases proteins present in immature
      granules that are not destined for accumulation in mature granules. In AtT20
      cells proopiomelanocortin the endogenous precursor of the accumulated
      adrenocorticotropic hormone, is predominantly secreted in a constitutive manner
      without proteolytic maturation. In order to better understand by which secretory
      pathway intact proopiomelanocortin is secreted by a cell line possessing a
      regulated secretory pathway, it was transfected with rat serum albumin (a marker
      of constitutive secretory proteins), and pancreatic amylase (a marker of
      regulated proteins). COS cells were also transfected in order to serve as control
      of release by the constitutive pathway. It was observed that both the basal and
      stimulated secretions of albumin and proopiomelanocortin from AtT20 cells are
      identical. In addition, secretagogue stimulation when POMC is in transit in the
      trans-Golgi network decreases its constitutive secretion by 50%. It was also
      observed using cell fractionation and 20 degrees C secretion blocks that albumin
      and proopiomelanocortin are present in the regulated pathway, presumably in the
      immature granules, and are secreted by the constitutive-like secretory pathway.
      These observations show that stimulation can increase sorting into the regulated
      pathway, and confirm the importance of the constitutive-like secretory pathway in
      the model AtT20 cell line.

PMID- 15202571
TI  - Texture optimization of water-in-oil emulsions.
AB  - The aim of this research is to demonstrate the effect of variations in certain
      parameters of the oily phase (OP) in water-in-oil (W/O) emulsions on rheological
      and texture properties of finished products. The formulated emulsions were
      selected according to an optimal experimental procedure. The applied variations
      were nature of the OP, its volume fraction, the hydrophilic-lipophilic balance
      (HLB) value, and the surfactant proportion. Results are presented for the
      followed tests carried out on the emulsions: texture analysis, rheology, and
      particle size analysis. The oils used in the study were sweet almond oil, liquid
      paraffin, maize oil, cyclomethicone, dimethicone, and wheat germ oil. The
      resulting data demonstrate a notable influence of the volume fraction oil on
      hardness, viscosity, adhesiveness, and cohesiveness of W/O emulsions. Emulsion
      hardness and viscosity increased as the OP percentage increased; this effect
      being even more pronounced for the vegetable oils. In contrast, emulsion
      adhesiveness and cohesiveness decreased as the volume fraction oil increased. The
      HLB value of the surfactant mixture of the emulsion also influenced hardness,
      adhesiveness, and elasticity, increasing or decreasing as HLB value did.

PMID- 15202572
TI  - Roller compaction of crude plant material: influence of process variables,
      polyvinylpyrrolidone, and co-milling.
AB  - Roller compaction of a milled botanical (Baphicacanthus cusia) with and without a
      binder, polyvinylpyrrolidone (PVP) was conducted. Effects of co-milling on binder
      function and flowability of the powder blend was also investigated. Flakes were
      comminuted, and the size and size distribution, friability, Hausner ratio, and
      Carr index of the granulations were determined. Crude herb should be reduced to a
      suitable size for it to be successfully roller compacted. Larger-sized and less
      friable granules were obtained with decreasing roller speed. Addition of PVP
      affected the flowability and binding capacity of the herbal powder blend, which
      influenced size and friability of the granules. Co-milling of PVP with the herbal
      powder enhanced the flow of the blends and the effectiveness of the binder, which
      contributed favorably to the roller-compacted product. Roller compaction is a
      convenient and cost-effective granulating technique suitable for milled
      botanicals. Co-milling can be used to improve the properties of roller-compacted
      products.

PMID- 15202573
TI  - Influence of enteric-coated lactose on the release profile of 4-aminopyridine
      from HPMC matrix tablets.
AB  - A weakly basic experimental drug, 4-aminopyridine, was taken as a model to study
      the influence of enteric-coated lactose (EL) on the release profile from
      hydroxypropyl methylcellulose matrices. Powder mixtures were wet-granulated with
      water. The dried granulation was compressed with a hydraulic press at 85 MPa.
      Dissolution studies were made using HCl 0.1 N and then phosphate buffer pH 7.4.
      Dissolution curves were described by M(t)/M(inf) = k*t(N). A trend toward
      increasing exponent (n) and decreasing release constant (k) values is observed
      with increasing EL concentrations up to 9%; this is attributed to an increasing
      obstruction of the diffusion path by isolated EL particles that are insoluble in
      HCl and are surrounded by a water-filled space. After a critical EL
      concentration, the water-filled spaces surrounding EL particles percolate,
      producing the opposite effect, increasing the release constant and decreasing the
      exponent (n) values as the EL proportion increases from 10% to 50%. EL particles
      (2% to 9%) decrease the drug and water transport in matrices dissolving in HCl.
      Thereafter, at pH 7.4, the pores formed by dissolution of EL particles produce
      the opposite. Both processes contribute to flattening the release profile.
      Release profiles with decreasing release constant values show a logarithmic trend
      toward increasing values of the exponent (n), changing from diffusion toward
      relaxation-erosion-controlled processes.

PMID- 15202574
TI  - Development of oral controlled-release tablet formulations based on diltiazem
      carrageenan complex.
AB  - Diltiazem HCl and lambda carrageenan react in distilled water to give a slightly
      soluble interaction product. The aim of this work was to verify the possible
      employment of lambda carrageenan-diltiazem (DTZ) complex in controlled-release
      formulations. The influence of complex particle size, compression force, pH of
      the dissolution medium, and tablet dimensions on drug release has been evaluated.
      The results confirm the suitability of the DTZ-carrageenan interaction product
      for controlled-release formulations. Good compaction properties allow tablets to
      slowly erode, with only the addition of the amount of hydroxypropyl
      methylcellulose (HPMC) necessary as a binding agent. The use of the finest sieve
      fraction results in the highest crushing strength values and in the slowest
      release rate, both in pH 1.2 and in pH 6.8. The force of compression does not
      affect the drug release for values over 16 kN. The release rate increases when
      the geometry of the tablet is varied so the surface/ volume ratio of the tablet
      is increased, suggesting a release mechanism involving surface
      dissolution/erosion.

PMID- 15202575
TI  - Influences of layering on theophylline pellet characteristics.
AB  - This study evaluated and compared theophylline pellets prepared by both
      suspension and powder layering processes using the bottom spray coater and the
      tangential rotary granulator, respectively. Hydroxypropyl methylcellulose (HPMC)
      and hydroxypropyl cellulose (HPC) were employed as binders at various
      concentrations. The pellets were coated with Eudragit RS and RL to various
      levels. It was found that pellet sizes, true densities, and drug contents were
      comparable and independent of processes and binder levels. However, the increase
      in binder resulted in lower porosity and pore size, as well as smoother pellet
      surface. The powder layered pellets possessed higher pellet density and smoother
      surface than did the suspension layered pellets due to the greater consolidation
      resulted from tumbling and colliding of pellets. Powder x-ray diffraction pattern
      revealed that theophylline present in the suspension layered pellets was a
      mixture of anhydrous form II and hydrate, indicating that transformation could
      occur in aqueous medium. Drug release from uncoated pellets was found to be
      complete within 20 min. For coated pellets, the release was markedly decreased
      with the increase in Eudragit level. Both film thickness and anhydrous/hydrate
      form influenced the release of drug from the pellets. In general, two methods of
      layering produced the pellets of slightly differences in pellet properties;
      however, changes of drug characteristics could occur in suspension.

PMID- 15202576
TI  - Antioxidant-accelerated oxidative degradation: a case study of transition metal
      ion catalyzed oxidation in formulation.
AB  - Oxidation presents a constant challenge for formulation scientists trying to
      develop stable dosage forms. Antioxidants are commonly used in formulation to
      alleviate the oxidation problem but they do not always achieve the desired
      results. In this study, a case of antioxidant-accelerated oxidation degradation
      in formulation is reported. The oxidation mechanism of a development drug
      candidate (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol
      (1) in solution was investigated under various oxidative conditions, which
      include at different oxygen level, with transition metal ion spiking, and under
      light exposure with presence of photosensitizer. Oxidative degradation products
      and kinetics were monitored by high-performance liquid chromatography (HPLC).
      Kinetic solvent isotope effects of I oxidation in formulation, under metal ion
      catalysis, and upon photocatalysis were obtained. Metal ion spiking, exposure to
      stainless steel, as well as introduction of antioxidants such as ascorbic acid,
      thioglycerol, and sodium bisulfate, accelerated the oxidative degradation.
      Treatment of the solution with metal chelating resin inhibited oxidation. Kinetic
      solvent isotope effects are in agreement with a metal-catalyzed oxidation
      mechanism and inconsistent with a singlet oxygen pathway. On the basis of kinetic
      data, an oxidative fragmentation mechanism initiated by a metal ion catalyzed
      active oxygen species is suggested as the primary pathway for the oxidative
      degradation of I. Other oxidative species may be implied in the long-term
      oxidative degradation. Because many antioxidants act as pro-oxidants in metal
      catalyzed oxidation, controlling metal ion contamination level in the excipients
      and limiting available molecular oxygen are recommended for formulation
      development.

PMID- 15202577
TI  - Novel chewable sustained-release tablet containing verapamil hydrochloride.
AB  - The aim of this research is to produce a compactable self-sealing chewable tablet
      of verapamil hydrochloride. Tablets were prepared by compressing beads coated
      with multiple layers including drug, hydroxypropyl methylcellulose, polyethylene
      oxide, ethylcellulose, lactose, and sodium starch glycolate. Dissolution studies
      were carried out according to the USP XXII paddle method for 14 h. A new tablet
      formulation was evaluated in three different forms: 1) whole tablet, 2) crushed
      tablet using a commercial tablet crusher, and 3) tablet chewed in the mouth and
      then expelled into dissolution fluid. Sustained release from the new formulation
      was maintained and was similar in all three different treatments, and similar to
      drug release from intact commercially available Isoptin SR, but crushing or
      chewing destroyed the sustained release property of Isoptin SR (as expected).
      This new formulation can be administered either by swallowing the whole tablet or
      by first crushing or chewing the tablet. Controlled release properties of this
      new formulation do not change by chewing or crushing the tablet first. Such a
      tablet could be valuable for all patients including those who have difficulty
      swallowing, such as pediatrics and geriatrics.

PMID- 15202578
TI  - Influence of formaldehyde impurity in polysorbate 80 and PEG-300 on the stability
      of a parenteral formulation of BMS-204352: identification and control of the
      degradation product.
AB  - The purpose of this study was to identify a degradation product formed in the
      clinical parenteral formulation of BMS-204352, investigate the role of excipients
      in its formation, and develop a strategy to minimize/control its formation. The
      degradant was identified as the hydroxy methyl derivative (formaldehyde adduct,
      BMS-215842) of the drug substance based upon liquid chromatography/mass
      spectroscopy (LC/MS), liquid chromatography/mass spectroscopy/mass spectroscopy
      (LC/MS/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to
      an authentic sample of hydroxymethyl degradation product, BMS-215842. An assay
      method for the detection of formaldehyde based on HPLC quantitation of
      formaldehyde dinitrophenylhydrazone was developed to quantitate its levels in
      various Polysorbate 80 and PEG 300 excipient lots. A direct relationship between
      the levels of formaldehyde in the excipients and the formation of the
      hydroxymethyl degradant was found. To confirm the hypothesis that the
      formaldehyde impurity in these two excipients contributed to the formation of the
      hydroxymethyl degradant, several clinical formulation lots were spiked with
      formaldehyde equivalent to 1, 10, and 100 mg/g of BMS-204352. A correlation was
      found between the formaldehyde level and the quantity of the hydroxymethyl
      degradant formed upon storage at 5 and 25 degrees C. From these experiments, a
      limit test on the formaldehyde content in polysorbate 80 and PEG 300 can be set
      as part of a strategy to limit the formation of the degradation product.

PMID- 15202579
TI  - Extruded and spheronized beads containing no microcrystalline cellulose:
      influence of formulation and process variables.
AB  - The purposes of this study were to investigate the use of chitosan in the
      manufacture of beads by extrusion-spheronization without inclusion of
      microcrystalline cellulose, and to study the effect of formulation and process
      variables on the characteristics of the beads. Beads containing chitosan, fine
      particle ethylcellulose, hydroxypropyl methylcellulose (HPMC), and caffeine as
      the model drug were manufactured. Bead size, yield, shape, friability, density,
      porosity, and release studies were determined. Spherical beads with good
      mechanical properties could be manufactured without microcrystalline cellulose.
      Release studies showed that there was immediate release of drug from the beads. A
      five factor, half fraction screening design was employed to study the effect of
      formulation variables and process variables on the properties of the beads.
      Statistical analysis indicated that formulation variables such as the chitosan
      content, HPMC content, and water content, and process variables such as the
      spheronizer speed and extruder speed significantly affected the physical
      properties of the beads. The bead size decreased with an increase in chitosan
      content. Significant two-factor interactions exist between the variables for
      several of the measured responses. Beads with high percentage yield and high
      sphericity can be obtained at high chitosan content, and low HPMC content, water
      content, spheronizer speed, and extruder speed. Less friable beads can be
      obtained at high levels of studied formulation variables and low levels of
      studied process variables. Beads of high density and low porosity can be
      manufactured at high levels of the studied formulation and process variables.
      Regression equations were generated using Statgraphics Plus software that can be
      used to develop formulations with desired bead properties. Chitosan was useful to
      provide beads of acceptable physical properties using water as a granulating
      fluid in the extrusion-spheronization process.

PMID- 15202580
TI  - Correlation of the thermal stability of phospholipid-based emulsions and the
      microviscosity measurements using fluorescence polarization.
AB  - The fluorescence polarization technique was used to measure the microviscosity of
      a series of phospholipid-based emulsions. Fourteen different oil-in-water
      emulsions containing 20% medium chain length triglycerides, various
      concentrations and types of phospholipids, and 2.2% glycerin were prepared by
      microfluidization and pH-adjusted to 4.0 or 7.4. Microviscosity was measured by
      determining the anisotropy of a fluorophore probe (1,6-phenyl 1,3,5-hexatriene)
      which was found to obey Perrin's equation as has been previously reported for
      liposomes and membrane bilayers. Moreover the method was validated by comparing
      viscosities of phospholipid-oil mixtures measured by rheometry and fluorescence
      polarization. The viscosities determined by fluorescence polarization were within
      6% of the values obtained by classic rheometry. Emulsions were also subjected to
      thermal stress at 121 degrees C. The droplet growth rate was estimated by
      measuring the time-dependent mean droplet diameter using photon correlation
      spectroscopy. The logarithm of the droplet growth rate was found to be directly
      proportional to the interfacial rigidity (i.e., the inverse microviscosity) which
      suggested that coalescence rather than molecular diffusion is the primary
      mechanism of droplet growth under these conditions of thermal stress.

PMID- 15202581
TI  - The evolving role of bisphosphonates: cancer treatment-induced bone loss.

PMID- 15202582
TI  - Pathophysiology and implications of cancer treatment-induced bone loss.
AB  - Many prostate and breast cancer patients will experience bone complications,
      including but not limited to skeletal fracture and spinal cord compression. Bone
      loss resulting from the treatment of cancer is increasingly recognized as a
      complication of the hypogonadal state induced by cancer therapies. Early
      diagnosis and treatment of bone loss are important interventions for the
      maintenance of bone health in cancer patients on hormone-depletion therapy.
      Identification of patients at risk for skeletal fracture is important for
      interventions that may reduce the incidence of disability and future fractures.
      Basic treatment for bone loss in general includes calcium and vitamin D
      supplementation, but the most effective option is treatment with various types of
      bisphosphonates. This paper will explore treatment-induced bone loss in detail,
      with a concentration on bisphosphonate therapy.

PMID- 15202583
TI  - Hormone- and chemotherapy-induced bone loss in breast cancer.
AB  - Hormonal and chemotherapies have been shown to have a profound, positive impact
      on survival in cancer patients but are associated with adverse effects on bone.
      The abrupt decrease in bone mineral density caused by these therapies is an
      emerging treatment challenge. In particular, as the aromatase inhibitors are more
      widely used, studies indicate that there will be an increased fracture risk.
      Adjuvant therapy with selective estrogen receptor modifiers spares bone loss in
      postmenopausal women but not in premenopausal women. Thus other strategies to
      protect bone are needed. This article discusses various treatments that attempt
      to offset this bone loss--mainly the protective effects of several
      bisphosphonates.

PMID- 15202584
TI  - The role of bisphosphonates in men with prostate cancer receiving androgen
      deprivation therapy.
AB  - Primary and secondary osteoporosis are prevalent in more than 2 million American
      men. One of the main causes of this is hypogonadism, in turn brought upon by
      early androgen deprivation therapy used in prostate cancer treatment. Androgen
      deprivation therapy produces a host of adverse effects on the skeleton, including
      an increase in bone turnover, a decrease in bone mineral density, and an increase
      in fracture risk. In addition, based on observations in preclinical models, these
      adverse effects on the skeletal integrity may promote the development of or
      progression of metastasis to bone. Loss of bone due to androgen deprivation
      therapy is an important clinical issue for many men with prostate cancer, but
      osteoporosis is not an inevitable consequence of androgen deprivation therapy.
      Because of interpatient variations in peak bone mass as well as differences in
      rates of treatment-related bone loss, not all men with prostate cancer require
      treatment for osteoporosis. All men on androgen deprivation therapy should
      receive calcium and multivitamin supplements and should be considered for
      bisphosphonate therapy; this is particularly so for men with either a low
      baseline BMD or observed high rates of bone loss during androgen deprivation
      therapy.

PMID- 15202585
TI  - New generation of bisphosphonates: broad clinical utility in breast and prostate
      cancer.
AB  - Cancer treatment-induced bone loss is an emerging problem for patients with
      breast and prostate cancer, who are often treated with cancer therapies earlier
      in the disease process. Bone loss associated with cancer therapy can also
      progress rapidly and may cause significant morbidity in these patients. Many
      patients with metastatic prostate or breast cancer develop bone metastases and
      subsequent skeletal-related events. Studies suggest that bisphosphonates can
      maintain bone health when introduced early in the continuum of cancer care. They
      have shown efficacy in the prevention of bone loss and the more potent i.v.
      bisphosphonate, zoledronic acid, has prevented bone loss in addition to
      increasing BMD in prostate cancer patients with cancer treatment-induced bone
      loss. Intravenous zoledronic acid or pamidronate can be considered the standard
      of care for the treatment of osteolytic bone metastases in breast cancer.
      Clinical trials addressing the treatment of bone metastases related to prostate
      cancer have shown zoledronic acid to be the only bisphosphonate to have a
      significant positive effect on skeletal-related events.

PMID- 15202586
TI  - Toward the center.

PMID- 15202587
TI  - Forced eruption of maxillary incisor teeth from the lingual side.
AB  - A major disadvantage in using the forced eruption technique is the necessity for
      the placement of an unesthetic orthodontic appliance, especially when the tooth
      involved is a maxillary incisor. The aim of this article is to present two
      alternative simple, specific task-oriented devices that may be placed on the
      lingual side of the teeth and may be used in the anterior of the mouth without
      compromising appearance.

PMID- 15202588
TI  - Cantilever fixed prostheses utilizing dental implants: a 10-year retrospective
      analysis.
AB  - OBJECTIVE: The dental literature has been unclear about long-term success of
      fixed cantilever prostheses supported by dental implants. The disappointing
      results reported when cantilever fixed partial dentures (FPDs) are supported with
      natural teeth are not directly applicable to implant cantilever FPDs. This
      article reports on 10 years of implant-retained fixed prostheses primarily in the
      maxillary arch using the ITI dental implant system. METHOD AND MATERIALS: Sixty
      cantilever prostheses using 115 ITI dental implants on 36 patients were placed
      and monitored over a 10-year period. RESULTS: No implant fractures, abutment
      fractures, porcelain fractures, prosthesis fractures, soft tissue recession, or
      radiographic bone loss were recorded. All 60 cantilevered prostheses remain in
      satisfactory function. CONCLUSION: Positive, long-term results, using implant
      retained cantilever FPDs can be achieved by: (1) using a rough surface implant of
      4.1 mm or greater; (2) using an implant/abutment design that reduces stacked
      moving parts and reduces the implant-to-crowns ratio; and (3) using a cementable
      prosthesis design that eliminates the need for occlusal screw retention.

PMID- 15202589
TI  - Comparative study of retentive anchor systems for overdentures.
AB  - OBJECTIVES: This study aimed to evaluate the retention on two or four implants of
      eight resilient and nonresilient retentive anchors used in overdentures. METHOD
      AND MATERIALS: Eight groups of retentive anchors were used: Dyna and Shiner
      (magnets); Dalla Bona and O-Ring (balls); Ceka Revax and Zaag attachments
      (studs); the cast bar (Dolder type) system with plastic clips; and the milled
      bars system. These specimens with their respective overdentures were prepared on
      two similar acrylic resin models with four implants (3.75 x 13 mm). Ten tensile
      strength tests (Instron) were performed on each group at a speed of 3 mm per
      minute. The statistical analysis (one-way analysis of variance, Tukey's HSD test)
      was considered significant. RESULTS: The pull force values ranged between 0.400
      and 3.800 daN (International System of Units). There was a significant difference
      in retention in favor of the milled bars in comparison with the Ceka Revax, Hader
      bars, Zaag attachments, O-Ring, and Dyna groups, and a marginally significant
      difference compared with the Dalla Bona group. There was a highly significant
      difference with the Shiner magnets. CONCLUSION: The milled bar system was the
      most retentive anchor, with the Dalla Bona, Ceka Revax, Hader Bar, Zaag
      attachment, and O-Ring groups being the second most retentive. The least
      retentive groups were the Shiner and Dyna magnets. Proper abutment placement in
      the mandible and the correct selection of the retentive anchor will improve
      overdenture retention.

PMID- 15202590
TI  - Simulating periodontal effects in dental osseointegrated implants: effect of an
      intramobile damping element on the fatigue strength of dental implants--an in
      vitro test method.
AB  - OBJECTIVE: The purpose of this study was to develop and adapt a new method for
      testing dental implant systems and to apply it to existing systems with and
      without dampers. The parameters examined were the fatigue strength of the
      superstructure-retaining titanium screw, the deformation of the damper, and the
      effect on the supporting, bone-stimulating, and embedding material. METHOD AND
      MATERIALS: Ten pairs of implant specimens were prepared according to standard
      laboratory procedure and embedded in transparent polymethylmethacrylate (PMMA).
      Five pairs were provided with polyoxymethylene dampers and five with nondamping
      titanium connectors. Each pair was connected with a metal beam, and cyclic loads
      were applied with a pneumatic-driven machine at a frequency of 2 Hz. Chewing
      forces of 150 to 450 N were transmitted by springs individual to each specimen.
      For each of the 2 x 10(5) cycles, there was a control of the retaining screw and
      bonding between the fixture and embedding material by registration of gap
      propagation in the implant-PMMA interface. RESULTS: A significant damping effect
      was noticed on the implant--embedding material interface. Damping did affect the
      superstructure, since the retaining screws were plastically deformed. The screws
      were unscrewed when the applied load exceeded 300 N, while the undamped system
      was seemingly unaffected. CONCLUSION: The study method made it possible to
      evaluate damping effects on different levels of implant systems, while satisfying
      the requirements for testing in a "clinical-like" way. PMMA was comparable to
      bone in supporting implants during fatigue testing.

PMID- 15202591
TI  - Ethics of esthetic dentistry.
AB  - Patient demand for esthetics has increased globally, and often for reasons of
      patient self-esteem. However, important ethical issues encompass treatment for
      purely esthetic reasons. Also, perceptions of what is esthetic differ among
      patients and clinicians. Therefore, the aim of this article is to make
      suggestions regarding some of the issues surrounding the ethical, esthetic
      treatment of patients, as well as present three cases illustrating the different
      meanings of esthetic health to different people.

PMID- 15202592
TI  - Effect of cavity disinfectants on the sealing ability of nonrinsing dentin
      bonding resins.
AB  - OBJECTIVES: The purpose of this study was to determine the effect of three cavity
      disinfectants (chlorhexidine gluconate-based, Consepsis; benzalkonium chlorite
      based, Tubulicid red; iodine-potassium iodide/copper sulphate-based, Ora-5) on
      the microleakage of nonrinsing dentin-bonding systems, Clearfil SE Bond and
      Prompt L-Pop. METHOD AND MATERIALS: Class V cavity preparations were placed on
      the buccal and lingual surfaces of extracted molars with occlusal margins at the
      enamel and gingival margins in cementum. In the experimental groups, cavities
      were treated with combinations of one of the three cavity disinfectants with
      either Clearfil SE Bond or Prompt L-Pop. The preparations without disinfectant
      application were used as the negative controls for each adhesive system, and the
      cavities in which neither disinfectant nor dentin-bonding resin were applied,
      served as the positive controls. After the cavity preparations were restored with
      resin composite, specimens were thermocycled, stained, and sectioned to evaluate
      dye penetration. The tooth-resin composite interface of the sectioned specimens
      was examined under scanning electron microscopy. RESULTS: Consepsis and Tubulicid
      red did not significantly affect the sealing ability of Clearfil SE Bond and
      Prompt L-Pop. Ora-5 exhibited gap formations at the tooth-resin composite
      interface and produced significantly higher microleakage when used with these
      bonding systems. CONCLUSION: Consepsis and Tubulicid red can be used as cavity
      disinfectants with Clearfil SE Bond and Prompt L-Pop without affecting their
      sealing abilities. However, Ora-5 is not an appropriate disinfectant to use with
      these bonding systems.

PMID- 15202593
TI  - Maxillary nerve block--a new approach using a computer-controlled anesthetic
      delivery system for maxillary sinus elevation procedure. A prospective study.
AB  - OBJECTIVE: The maxillary (or second division) nerve block is an effective method
      of achieving profound anesthesia of a hemimaxilla. This block can be used for
      procedures involving the maxillary sinus, including the maxillary sinus elevation
      procedure. The purpose of this study was to evaluate a computer-controlled
      anesthetic delivery system (Wand) for maxillary nerve block injection to attain
      maxillary sinus anesthesia for sinus floor elevation procedure. METHOD AND
      MATERIALS: The study population consisted of 61 healthy adult patients, ranging
      in age from 40 to 72 years (mean 45 years), who received 76 maxillary nerve
      blocks (17 having both right and left maxillary blocks) by means of the Wand
      system via the greater palatine nerve approach, for sinus floor elevation
      procedure. Two patients (3%) were excluded from the study due to the inability to
      negotiate the greater palatine foramen. For each block, two cartridges of 2%
      lidocaine hydrochloride with adrenaline (1:100,000) were administered, using a 27
      gauge--long needle. After ensuring the anesthetized areas (waiting time 2.5
      minutes), the sinus elevation procedure was performed. Parameters recorded were
      the success or failure of anesthesia, positive (blood) aspiration, bony
      obstructions in the greater palatine canal, and complications. RESULTS: The use
      of this technique increased the ability to more easily locate the greater
      palatine foramen. A local infiltration (at the incisor region) was needed in 13
      (17%) of the blocks, and seven (9.2%) sites required an extra infraorbital block
      injection in addition to the maxillary nerve block. One block had a positive
      aspiration. There were no bony obstructions demonstrated in the canal interfering
      with the injection, and no complications were recorded. CONCLUSION: The Wand
      appears to offer a number of advantages over the hand-held syringe when the
      greater palatine block technique for the maxillary nerve block is used. It is
      suggested that, when indicated, and with the required knowledge and respect for
      the associated anatomy, this technique should be considered with greater ease and
      more confidence.

PMID- 15202594
TI  - The patient with an odontogenic infection.
AB  - The routine use of antibacterial agents for the management of odontogenic
      infections has not been shown to be effective and is inappropriate. Most of these
      bacterial infections can be resolved satisfactorily through an approach that
      incorporates debridement (primary dental care) in conjunction with local
      anesthesia. Odontogenic infections are polymicrobial. Facultative anaerobes,
      particularly viridans streptococci, accompanied by strict anaerobes, appear to
      predominate in all types of odontogenic infections. When antibacterial
      chemotherapy is indicated, the drug of choice should be either the most effective
      drug against the infective pathogens or the least toxic alternative among several
      available agents. It should also be emphasized that drugs seldom exert their
      beneficial effects without also causing adverse side effects. Dealing with this
      certainty, the clinician familiar with the mechanisms of action, principles of
      disposition, and therapeutic and adverse effects of antibacterial agents, has the
      advantage.

PMID- 15202595
TI  - Bell's palsy.

PMID- 15202596
TI  - A rapid densitometric method for the analysis of hyoscyamine and scopolamine in
      solanaceous plants and their transformed root cultures.
AB  - A rapid and convenient method for sample preparation and simultaneous
      densitometric quantification of hyoscyamine (1) and scopolamine (2) has been
      developed. The alkaloid profiles of plant samples, as well as the content of 1
      and 2, determined by TLC-densitometry corresponded well with those obtained using
      a GC method. The proposed method is simple and sensitive and can be used for the
      routine assay of 1 and 2, and for screening for alkaloid-rich and biochemically
      interesting transformed root cultures and intact solanaceous plants.

PMID- 15202597
TI  - Variation of the essential oil content and composition in leaves from cultivated
      plants of Hypericum androsaemum L.
AB  - The amount and composition of the essential oil from leaves of Hypericum
      androsaemum L. cultivated in Arouca (Portugal) were determined in six samples
      harvested during 1 year at intervals of 2 months. The seasonally dependent
      essential oil content ranged from 0.7 mg/g biomass dry weight in September to 3.4
      mg/g in February. The oil contained more than 80 compounds, 70 of which
      (constituting 88-93% of the total oil) were identified by GC and GC-MS. An
      approximation of the absolute quantification of each compound and compound class
      was performed using a GC method with an internal standard. The relative and the
      absolute content of each compound and compound class changed during the year. At
      the end of the winter and in the spring, the essential oil was dominated by
      sesquiterpene hydrocarbons and accumulated a high number of intermediate to long
      chain n-alkanes and 1-alkenes. In September, the essential oil contained the
      lowest levels of sesquiterpene hydrocarbons (43%) and the highest levels of 1
      octene and 2-hexenal (38%). In February, the essential oil had the highest level
      of sesquiterpene hydrocarbons (73%) and the highest diversity of intermediate to
      long chain n-alkanes and 1-alkenes.

PMID- 15202598
TI  - Quantitative determination of curcuminoids in Curcuma rhizomes and rapid
      differentiation of Curcuma domestica Val. and Curcuma xanthorrhiza Roxb. by
      capillary electrophoresis.
AB  - The three major curcuminoids, curcumin, demethoxycurcumin and bis
      demethoxycurcumin, from Curcuma domestica Val. (Curcuma longa L.) and Curcuma
      xanthorrhiza Roxb. (Zingiberaceae) were fully separated and quantified in less
      than 5 min using a capillary zone electrophoresis method with standard fused
      silica capillaries and photodiode array detection. An electrolyte solution of 20
      mM phosphate, 50 mM sodium hydroxide and 14 mM beta-cyclodextrin was found to be
      appropriate. Quantification was performed with 3,4-dimethoxy-trans-cinnamic acid
      as internal standard, and the limit of detection was 0.01 mg/mL. Extraction,
      stabilisation during sample storage and quantification procedures were optimised
      and carried out with drugs and commercial curry powder from different
      provenances. The results were compared with the photometric method of the
      monograph Curcumae xanthorrhizae rhizoma of the European Pharmacopoeia.

PMID- 15202599
TI  - A modified method for determining protein binding capacity of plant polyphenolics
      using radiolabelled protein.
AB  - A modified radiochemical protein binding method for determining the protein
      binding capacity of plant polyphenolics (tannins) is described. Purified tannin
      or unfractionated plant extracts were immobilised on filter paper discs and
      incubated with the 125I-labelled bovine serum albumin. Protein bound to the disc
      was proportional to the amount of tannin applied to the disc, although at high
      concentrations of polyphenolics the discs became saturated and the relationship
      was no longer applicable. The method was validated using purified procyanidin
      from Sorghum grain and has been applied to crude polyphenolic extracts from
      maple, white oak, black oak, walnut and tulip poplar leaves. Specific chemical
      assays for the determination of proanthocyanidins (acid butanol method) and
      hydrolysable tannins (modified potassium iodate method) were employed to validate
      the new protein binding method with the complex plant extracts.

PMID- 15202600
TI  - Standardisation of Gymnema sylvestre r. Br. with reference to gymnemagenin by
      high-performance thin-layer chromatography.
AB  - A simple and reproducible HPTLC method for the determination of gymnemagenin (1)
      in Gymnema sylvestre has been developed. Components were separated on pre-coated
      silica gel 60 F254 plates with chloroform:methanol (9:1) and scanned using a
      densitometric scanner in the UV reflectance mode at 290 nm. Linearity of
      determination of 1 was observed in the range 4-10 microg. The average percentage
      recovery of 1 from an extract was 99.09 +/- 0.29, and the content of 1 in leaves
      of the title plant was 1.61% (dry weight).

PMID- 15202601
TI  - Computer-assisted, high-performance liquid chromatography with mass spectrometric
      detection for the analysis of coumarins in Peucedanum palustre and Angelica
      archangelica.
AB  - A reversed-phase HPLC method with atmospheric pressure chemical ionisation MS
      detection has been developed for the separation and identification of coumarins
      in plants of Peucedanum palustre L. (Moench) and Angelica archangelica (L.) var.
      archangelica. The Turbo Method Development program was utilised to optimise the
      mobile phase with two organic solvents (acetonitrile and methanol) and two
      aqueous solutions (1.0% formic acid and 10 mM ammonium acetate). Optimisation of
      the solvent gradients for the method was performed with the aid of the DryLab
      program. Analyses were carried out using a Phenomenex Prodigy RP C18 column.
      Fifty-two peaks (14 of which were associated with coumarins) were separated in 30
      min from extracts of P. palustre, and 48 peaks (15 associated with coumarins)
      from extracts of A. archangelica. A total of 21 different coumarin-type compounds
      were identified in the aerial and the underground parts of the title plants.
      Isopimpinellin and pimpinellin were found for the first time in P. palustre and
      were identified by comparison of retention times and MS data obtained following
      the analysis of pure standards. This is the first report of the coumarin
      composition of the umbels of P. palustre.

PMID- 15202602
TI  - An electrophoretic profiling method for thiol-rich phytochelatins and
      metallothioneins.
AB  - Thiol-rich peptides such as phytochelatins (PCs) and metallothioneins (MTs) are
      important cellular chelating agents which function in metal detoxification and/or
      homeostasis. The variations in molecular sizes and lack of chromophores of these
      peptides make their analysis difficult. This paper reports an electrophoresis
      based method for a broad screen of thiol-rich peptides and proteins. The method
      uses the thiol-selective fluorescent tag, monobromobimane, coupled with Tricine-
      sodium dodecyl sulphate--urea polyacrylamide gel electrophoresis for a sensitive
      determination of both PCs and MTs. Results for PCs were confirmed by two
      dimensional NMR and HPLC-tandem MS analyses. Sample throughput is substantially
      improved over chromatography-based methods through parallel sample analysis in 1
      h of electrophoretic separation. The method is versatile in that peptides ranging
      from glutathione to large proteins can be analysed by simple modification(s) of
      the extraction and electrophoretic conditions, and the nature of the method
      supports serendipitous detection of unexpected or novel thiol metabolites.

PMID- 15202603
TI  - Low-molecular-weight components of olive oil mill waste-waters.
AB  - A new lignan 1-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-6-(3-acetyl-4-hydroxy-5
      methoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, the secoiridoid 2H-pyran-4-acetic
      acid,3-hydroxymethyl-2,3-dihydro-5-(methoxycarbonyl)-2-methyl-, methyl ester, the
      phenylglycoside 4-[beta-D-xylopyranosyl-(1-->6)]-beta-D-glucopyranosyl-1,4
      dihydroxy-2-methoxybenzene and the lactone 3-[1-(hydroxymethyl)-1-propenyl] delta
      glutarolactone were isolated and identified on the basis of spectroscopic data
      including two-dimensional NMR, as components of olive oil mill waste-waters. The
      known aromatic compounds catechol, 4-hydroxybenzoic acid, protocatechuic acid,
      vanillic acid, 4-hydroxy-3,5-dimethoxybenzoic acid, 4-hydroxyphenylacetic acid,
      3,4-dihydroxyphenylacetic acid, tyrosol, hydroxytyrosol, 2-(4-hydroxy-3
      methoxy)phenylethanol, 2-(3,4-dihydroxy)phenyl-1,2-ethandiol, p-coumaric acid,
      caffeic acid, ferulic acid, sinapic acid, 1-O-[2-(3,4-dihydroxy)phenylethyl]-(3,4
      dihydroxy)phenyl-1,2-ethandiol, 1-O-[2-(4-hydroxy)phenylethyl]-(3,4
      dihydroxy)phenyl-1,2-ethandiol, D(+)-erythro-1-(4-hydroxy-3-methoxy)-phenyl-1,2,3
      propantriol, p-hydroxyphenethyl-beta-D-glucopyranoside,2(3,4
      dihydroxyphenyl)ethanol 3beta-D-glucopyranoside, and 2(3,4
      dihydroxyphenyl)ethanol 4beta-D-glucopyranoside were also confirmed as
      constituents of the waste-waters.

PMID- 15202604
TI  - Polyoxypregnane glycosides from Caralluma retrospiciens.
AB  - Six related polyoxypregnane glycosides were isolated and characterised from
      Caralluma retrospiciens leaves. The compounds were identified as 12beta
      benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[3-O-methyl-6-deoxy-beta-D
      allopyranosyl-(1 --> 4)-beta-D-cymaropyranosyl-(1 --> 4)-]-beta-D
      cymaropyranoside], 12beta-benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O-[beta
      D-glucopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1 --> 4)-beta
      D-cymaropyranosyl-(1 --> 4)-beta-D-cymaropyranoside], 12beta-benzoyloxy
      8beta,14beta-dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl-(1 --> 4)-3-O
      methyl-6-deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D
      galactopyranoside], 12beta-benzoyloxy-8beta,14beta-dihydroxypregn-20-one-3-O
      [beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranosyl-(1 --> 4)-3-O-methyl-6
      deoxy-beta-D-galactopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D
      galactopyranoside], 12beta-benzoyloxy-11alpha-isovaleroyloxy-8beta,14beta
      dihydroxypregn-20-one-3-O-[beta-D-glucopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy
      beta-D-galactopyranosyl-(1 --> 4)-3-O-methyl-6-deoxy-beta-D-galactopyranoside],
      and 12beta-benzoyloxy-11alpha-isovaleroyloxy-8beta,14beta-dihydroxypregn-20-one-3
      O-[beta-D-glucopyranosyl (1 --> 4)-3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1 -->
      4)-beta-D-cymaropyranosyl-(1 --> 4)-beta-D-cymaropyranoside]. The structures were
      determined by detailed analysis of one- and two-dimensional NMR spectra as well
      as by chemical means. The compounds showed cytotoxic activities towards brine
      shrimp having IC50 values of 1.19 x 10(-4), 8.83 x 10(-5), 2.64 x 10(-4), 2.26 x
      10(-4), 2.39 x 10(-4) and 1.70 x 10(-4) M, respectively. This is the first report
      of the isolation of these compounds from a natural source.

PMID- 15202605
TI  - Assay of quadranguloside, the major saponin of leaves of Passiflora alata, by
      HPLC-UV.
AB  - An HPLC method with UV detection has been developed and validated in order to
      quantify quadranguloside, the main saponin of the leaves of Passiflora alata. The
      analysis was achieved by simple isocratic elution (with acetonitrile:aqueous
      phosphoric acid) using a Nova-Pak phenyl column. The amount of quadranguloside
      present in aqueous extracts from leaves of P. alata was estimated to be 22.2%
      (w/w), corresponding to 0.8% (w/w) in relation to dried leaves. The assay method
      described is simple, rapid, accurate and sensitive, and may form part of future
      drug authentication protocols.

PMID- 15202606
TI  - A direct liquid, non-equilibrium solid-phase micro-extraction application for
      analysing chemical variation of single peltate trichomes on leaves of Salvia
      officinalis.
AB  - A non-equilibrium solid phase micro-extraction application was tested for the
      rapid extraction of essential oil from single oil glands of sage and the oil
      components compared with those determined by solvent extract and distillation.
      Oil glands were directly ruptured with a polydimethylsiloxane-coated fused silica
      fibre and the essential oil was sorbed. Three insertion levels of an individual
      plant of Salvia officinalis involving an immature apical young leaf, an expanding
      and a fully developed leaf, respectively, were used to determine the
      applicability of this method. Thirty-eight components in the oil could be
      identified by GC-MS. The method only showed small semi-quantitative differences
      compared with conventional methods. Chemical variation of single oil glands
      within the immature and premature leaf was higher than within the homogeneous
      mature leaf. The intermediary, still-expanding leaf was used to carry out a
      detailed study of the glands. The basal region of the intermediary leaf contained
      compounds in high conformity with the young leaf trichomes. The remaining oil
      glands of this leaf showed inconsistent accumulation patterns.

PMID- 15202607
TI  - Current awareness in phytochemical analysis.

PMID- 15202608
TI  - Hypertensive nephrosclerosis: update.
AB  - PURPOSE OF VIEW: A major clinical trial and a meta-analysis completed within the
      past year addressed the issue of renal disease progression after blood pressure
      lowering treatment in patients with hypertension and diminished renal function.
      Important human and animal studies have addressed mechanistic issues regarding
      renal disease progression. These advances warrant detailed discussion. RECENT
      FINDINGS: The African American Study of Kidney Disease and Hypertension Study
      Group trial found that an angiotensin-converting enzyme inhibitor was superior to
      a calcium antagonist or beta-blocker in ameliorating renal disease progression in
      African-Americans. An attempt to show an advantage of lowering blood pressure to
      less than 130/80 compared with 140/90 mmHg showed no additional benefit. However,
      a meta-analysis of 2000 non-diabetic hypertensive patients suggested that lower
      blood pressures are beneficial, particularly in individuals with proteinuria. An
      autopsy study of hypertensive and normotensive individuals dying in motor vehicle
      accidents supported the theory that hypertensive individuals have fewer, albeit
      larger, glomeruli than normotensive individuals. An animal study in sheep showed
      similar findings in sheep born to dams given dexamethasone compared with placebo.
      Animal studies involving stress, immunity, and cytokines shed further light on
      the mechanisms. The transfer of Smad7 ameliorated renal damage in rats with
      ureteral obstruction and fibrosis. SUMMARY: Guidelines suggest prescribing
      angiotensin-converting enzyme inhibitor or angiotensin 1 receptor blocker therapy
      to all patients with decreased renal function and hypertension with or without
      diabetes. The possibility that essential hypertension involves reduced glomerular
      numbers received support, as well as the theory of prenatal imprinting. Progress
      is being made regarding basic mechanisms and novel therapies.

PMID- 15202609
TI  - The role of calcium antagonists in chronic kidney disease.
AB  - PURPOSE OF REVIEW: To review goals of antihypertensive treatment in chronic
      kidney disease in the context of what role calcium antagonists play toward
      reducing progression of kidney disease. RECENT FINDINGS: All recently published
      guidelines recommend a blood pressure goal of less than 130/80 mmHg in patients
      with chronic kidney disease. Use of calcium antagonists is not recommended as
      part of the initial armamentarium. Angiotensin-converting enzyme inhibitors and
      angiotensin II receptor blockers, when used in concert with diuretics reduce
      blood pressure as well as both proteinuria and the rate of decline in the
      glomerular filtration rate. The evidence for calcium antagonists in this regard
      is more divergent. Dihydropyridine calcium antagonists, e.g. amlodipine,
      felodipine, help achieve blood pressure goals and reduce stroke risk. When used
      with a renin-angiotensin system blocker they do not detract from the benefits of
      this blockade on slowing progression of kidney disease. Non-dihydropyridine
      calcium antagonists, e.g. verpamil or diltiazem, decrease proteinuria and in
      studies with 5 to 6 years follow-up preserve kidney function similarly to
      angiotensin-converting enzyme inhibitors. The reason for this outcome difference
      between calcium antagonists is partial preservation of renal autoregulation
      compared to its obliteration by the dihydropyridine subclass. SUMMARY: Use of
      calcium antagonists is safe and necessary to achieve blood pressure goals in
      people with chronic kidney disease. While both subclasses are safe and necessary
      to achieve blood pressure goals, dihydropyridine calcium antagonists fail to
      significantly slow the progression of kidney disease among patients with
      established nephropathy and macroalbuminuria when compared to agents that block
      the renin-angiotensin system.

PMID- 15202610
TI  - The association between congestive heart failure and chronic renal disease.
AB  - PURPOSE OF REVIEW: Recent findings on the relationship between congestive heart
      failure and renal failure are summarized in this review. RECENT FINDINGS:
      Congestive heart failure is found in about one-quarter of cases of chronic kidney
      disease. The most common cause of congestive heart failure is ischemic heart
      disease. The prevalence of congestive heart failure increases greatly as the
      patient's renal function deteriorates, and, at end-stage renal disease, can reach
      65-70%. There is mounting evidence that chronic kidney disease itself is a major
      contributor to severe cardiac damage and, conversely, that congestive heart
      failure is a major cause of progressive chronic kidney disease. Uncontrolled
      congestive heart failure is often associated with a rapid fall in renal function
      and adequate control of congestive heart failure can prevent this. The opposite
      is also true: treatment of chronic kidney disease can prevent congestive heart
      failure. There is new evidence showing the cardioprotective effect of carvedilol
      in patients on dialysis, and of simvastatin and eplerenone in patients with
      congestive heart failure. Use of non-steroidal anti-inflammatory drugs doubles
      the rate of hospitalization in patients with congestive heart failure. Anemia has
      been found in one-third to half the cases of congestive heart failure, and may be
      caused not only by chronic kidney disease but by the congestive heart failure
      itself. The anemia is associated with worsening cardiac and renal status and
      often with signs of malnutrition. Control of the anemia and aggressive use of the
      recommended medication for congestive heart failure may improve the cardiac
      function, patient function and exercise capacity, stabilize the renal function,
      reduce hospitalization and improve quality of life. Congestive heart failure,
      chronic kidney disease and anemia therefore appear to act together in a vicious
      circle in which each condition causes or exacerbates the other. Both congestive
      heart failure and anemia are often undertreated. Cooperation between
      nephrologists and other physicians in the treatment of patients with anemic
      congestive heart failure may improve the quality of care and the subsequent
      prognosis for both congestive heart failure and chronic kidney disease. SUMMARY:
      Adequate and early detection and aggressive treatment of congestive heart failure
      and chronic kidney disease and the associated anemia may markedly slow the
      progression of both diseases.

PMID- 15202611
TI  - IgA nephropathy: an update.
AB  - PURPOSE OF REVIEW: The elution of nephrectomy specimens from patients with IgA
      nephropathy yields IgA1 with galactose-deficient glycans in the hinge region. In
      this review, we summarize recent advances in our understanding of the role of the
      aberrant immunoglobulin in the pathogenesis of this form of glomerulonephritis.
      In the absence of a disease-specific therapy, we discuss current therapeutic
      approaches. RECENT FINDINGS: Galactose-deficient IgA1 forms macromolecular
      complexes that bind to mesangial cells and stimulate them to proliferate,
      synthesize various cytokines and chemokines, and secrete extracellular matrix
      proteins. Whereas progress has been made in understanding the glycosylation
      pathways of IgA1 O-linked glycans and binding galactose-deficient IgA1-complexes
      to mesangial cells, there is still no IgA nephropathy-specific therapy. The
      current approach to suppress the effects of angiotensin II, by angiotensin
      converting enzyme inhibitors, angiotensin II receptor type 1 blockers, or both,
      as a cornerstone of the therapy of IgA nephropathy has been strengthened by
      recent studies. Treatment with glucocorticoids, cyclophosphamide, or both, may be
      appropriate for a subset of IgA nephropathy patients. SUMMARY: A better
      understanding of the mechanisms underlying the synthesis of galactose-deficient
      IgA1, the formation of circulating immune complexes, and interactions with
      mesangial cells will provide further insights into the pathogenetic mechanisms
      that culminate in the glomerular and interstitial damage of IgA nephropathy, and
      could identify novel therapeutic targets in the prevention and management of this
      renal disease.

PMID- 15202612
TI  - Novel insights into the pathogenesis of uric acid nephrolithiasis.
AB  - PURPOSE OF REVIEW: The factors involved in the pathogenesis of uric acid
      nephrolithiasis are well known. A low urinary pH is the most significant element
      in the generation of stones, with hyperuricosuria being a less common finding.
      The underlying mechanism(s) responsible for these disturbances remain poorly
      characterized. This review summarizes previous knowledge and highlights some
      recent developments in the pathophysiology of low urine pH and hyperuricosuria.
      RECENT FINDINGS: Epidemiological and metabolic studies have indicated an
      association between uric acid nephrolithiasis and insulin resistance. Some
      potential mechanisms include impaired ammoniagenesis caused by resistance to
      insulin action in the renal proximal tubule, or substrate competition by free
      fatty acids. The evaluation of a large Sicilian kindred recently revealed a
      putative genetic locus linked to uric acid stone disease. The identification of
      novel complementary DNA has provided an interesting insight into the renal
      handling of uric acid, including one genetic cause of renal uric acid wasting.
      SUMMARY: The recognition of metabolic, molecular, and genetic factors that
      influence urinary pH, and uric acid metabolism and excretion, will provide novel
      insights into the pathogenesis of uric acid stones, and open the way for new
      therapeutic strategies.

PMID- 15202613
TI  - Brain mineralocorticoid receptors: orchestrators of hypertension and end-organ
      disease.
AB  - PURPOSE OF REVIEW: 'New' tasks have been discovered for aldosterone and its
      receptor, the mineralocorticoid receptor, within both epithelial tissues of
      vectorial ion and water transport, such as the kidney, and non-epithelial organs,
      including the brain, heart and vessels. Promising results of clinical trials
      using low doses of mineralocorticoid receptor antagonists to forestall end-organ
      disease is resulting in an increase in their use, yet the biology of the
      mineralocorticoid receptor is far from clear. RECENT FINDINGS: Mineralocorticoid
      receptors within the kidney, heart and blood vessels mediate direct effects of
      aldosterone, including tissue inflammation, hypertrophy and fibrosis, that are
      independent of blood pressure. Activation, by aldosterone, of mineralocorticoid
      receptors in the brain increases central sympathetic nervous system drive to the
      periphery, thereby producing hypertension through multiple mechanisms, and
      increases levels of proinflammatory cytokines in both the circulation and
      peripheral tissues. Blocking of the mineralocorticoid receptor of the forebrain
      lowers the levels of peripheral tissue cytokines, including those induced by
      ischemic injury in the heart. Aldosterone is produced within the heart, blood
      vessels and brain, potentially liberating regulation of local concentrations of
      the steroid from peripheral mechanisms of control. A conundrum yet to be
      explained is the ligand-dependent functional specificity of the mineralocorticoid
      receptor in some non-epithelial tissues, which may be crucial to our
      understanding the end-organ pathophysiology of hypertension. SUMMARY: New
      technology is rapidly adding layers of complexity to, rather than simplifying,
      our understanding of the facile terms 'hemodynamic homeostasis' and 'end-organ'
      disease, but within this new knowledge lies the promise of better, more precise
      treatment of hypertension and its sequelae.

PMID- 15202614
TI  - Role of matrix metalloproteinases in hypertension-associated cardiac fibrosis.
AB  - PURPOSE OF REVIEW: The potential contribution of alterations in matrix
      metalloproteinase activity to the development of myocardial fibrosis in
      hypertensive heart disease is reviewed. RECENT FINDINGS: A number of experimental
      and clinical studies provide information on alterations in the balance between
      matrix metalloproteinase-1 or collagenase and tissue inhibitor of matrix
      metalloproteinases-1, which result in depressed proteolytic activity of the
      enzyme in animals and humans with hypertensive heart disease. While some recent
      data point to a genetic origin of such an imbalance, other findings suggest that
      depressed collagenase activity may contribute to disturbances of cardiac function
      via facilitation of myocardial fibrosis. On the other hand, emerging information
      is providing the basis for the notion that other matrix metalloproteinases,
      namely gelatinases, may participate in the process of myocardial fibrosis through
      stimulation of fibrillar collagen synthesis. Some fragmented matrix peptides or
      matrikines may be the mediators of the profibrotic action of these matrix
      metalloproteinases. SUMMARY: The matrix metalloproteinases represent an important
      biological system within the myocardium designed to maintain the complex and
      dynamic microenvironment of the extracellular matrix. Improved understanding of
      how this system is dysregulated in hypertensive heart disease will probably
      provide new insights into, and strategies for, heart failure.

PMID- 15202615
TI  - Role of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in
      hypertension.
AB  - PURPOSE OF REVIEW: Cytochrome P-450 metabolites of arachidonic acid have been
      reported to play an important role in the control of renal function and vascular
      tone, and in the long-term control of arterial pressure. In this regard, 20
      hydroxyeicosatetraenoic acid is a potent vasoconstrictor that inhibits sodium
      reabsorption in the kidney. Epoxyeicosatrienoic acids are endothelium-derived
      relaxing factors that hyperpolarize vascular smooth muscle cells and also promote
      sodium excretion in the kidney. RECENT FINDINGS: Studies have demonstrated that
      the expression of cytochrome P-450 enzymes and the synthesis of 20
      hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in the kidney and
      peripheral vasculature are altered in many genetic and experimental models of
      hypertension. The production of these compounds is altered following exposure to
      high-salt or high-fat diets, in hepatorenal syndrome, in diabetes and in patients
      with toxemia of pregnancy. However, the functional significance of changes in the
      formation of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in the
      pathogenesis of hypertension are just being uncovered. SUMMARY: This review
      summarizes recent findings that address the issue of whether cytochrome P-450
      metabolites of arachidonic acid play an important role in the regulation of renal
      tubular and peripheral vascular function and contribute to the pathogenesis of
      hypertension.

PMID- 15202616
TI  - Leptin, obesity and cardiovascular disease.
AB  - PURPOSE OF REVIEW: Obesity is a risk factor for cardiovascular diseases. Leptin
      levels are increased in obesity and leptin exhibits cardiovascular actions that
      may contribute to increased cardiovascular risk. We review the sympathetic, renal
      and vascular actions of leptin and their relevance to cardiovascular disease.
      RECENT FINDINGS: Leptin possesses cardio-renal actions potentially contributing
      to obesity-related hypertension including generalized sympathoactivation.
      However, given that leptin resistance occurs in obesity, it has been difficult to
      link hyperleptinemia with hypertension. One possibility is that leptin resistance
      is confined to the metabolic effects of leptin, with preservation of its
      sympathoexcitatory actions. Other mechanisms may contribute to the pressor
      effects of leptin. For instance, angiotensin II induces leptin generation. Leptin
      also potentiates the pressor effect of insulin. Therefore, interactions between
      angiotensin II and insulin with leptin could have deleterious cardiovascular
      effects in obesity. Additionally, leptin appears to stimulate vascular
      inflammation, oxidative stress and hypertophy. These actions may contribute to
      the pathogenesis of hypertension, atherosclerosis, and left ventricular
      hypertrophy. SUMMARY: The potential actions of leptin in the pathophysiology of
      cardiovascular complications of obesity are diverse, despite evidence of leptin
      resistance to its metabolic actions. However, most information about
      cardiovascular actions of leptin derives from in-vitro and animal studies. Future
      research in humans is widely awaited.

PMID- 15202617
TI  - Dementia and antihypertensive treatment.
AB  - PURPOSE OF REVIEW: We present an updated overview on the long-term effects of
      hypertension on the occurrence of cognitive dysfunction and overt degenerative or
      vascular dementia later in life. The preventative effects of antihypertensive
      treatment in this regard are examined, with a focus on placebo-controlled, double
      blind, randomized prospective trials. RECENT FINDINGS: The stereotypical
      straightforward linear relationship between mid-life hypertension and dementia
      later in life can no longer be considered strictly invariable. Successfully
      treated hypertensive patients who are still at risk for clinical dementia late in
      life may ultimately fare better in the presence of a slightly elevated rather
      than low systolic blood pressure. The mechanisms underlying this 'J-curve'
      phenomenon are currently being explored. Recently completed prospective
      randomized antihypertensive trials (Syst-Eur 2, PROGRESS and SCOPE) have yielded
      variable results, and merit cautious interpretation. SUMMARY: The incidence and
      prevalence of dementia are increasing exponentially worldwide, particularly in
      those older than 70 years. Because hypertension predisposes to dementia,
      therapeutic blood pressure titration should be maintained over the years, and
      intensified beyond 70 years in order to avoid over-treatment in the latter
      period.

PMID- 15202618
TI  - Renoprotection by enzyme replacement therapy.

PMID- 15202619
TI  - Bibliography. Current world literature. Clinical nephrology.

PMID- 15202620
TI  - Bibliography. Current world literature. Pathophysiology of hypertension.

PMID- 15202621
TI  - Personal professional journeys.

PMID- 15202622
TI  - The heart, mind, and soul of professionalism in occupational therapy.

PMID- 15202623
TI  - A training apartment with electronic aids to daily living: lived experiences of
      persons with brain damage.
AB  - OBJECTIVE: The objective of this study was to investigate how persons with
      acquired brain damage experienced their 1-week stay in an apartment fitted with
      electronic aids to daily living (EADL). The study focused on how the individuals
      adapted to this artificial environment in their performance of daily activities
      and how their occupational experiences influenced their view of the future.
      METHODS: The 11 participants were interviewed on the last day of their
      rehabilitation period in an EADL-equipped training apartment. The data were
      collected and analyzed using the Empirical Phenomenological Psychological (EPP)
      method. FINDINGS: The findings revealed four main characteristics that described
      an adaptation process that occurred during the week in the EADL-equipped training
      apartment: plunging into an EADL-equipped environment, "landing" and feeling
      comfortable with the new environment, incorporating the "new" in daily
      activities, and "taking-off" for the future. CONCLUSION: In a short time, the
      combination of the EADL and the aesthetically attractive environment gave the
      participants experiences that contributed to a "taking off" for their future
      life. Findings from this study suggest that, in clinical practice, clients may
      need initial guidance from the therapists to "land" and feel comfortable in a new
      environment, like a training apartment, before they can learn how to incorporate
      new electronic aids in their every day activities.

PMID- 15202624
TI  - Comparing learning of cooking in home and clinic for people with schizophrenia.
AB  - OBJECTIVE: The purpose of this study was to compare learning of a functional
      living skill in two contexts for individuals with long-term schizophrenia.
      METHOD: Forty-four people with schizophrenia were matched on cognitive level. One
      of each pair was randomly designated to either a clinic or home cooking group,
      with the other assigned to the remaining group. Cooking skill was assessed using
      the Kitchen Task Assessment-Modified (KTA-M) both before and after the
      intervention. Learning for each group was analyzed using t tests. A multiple
      regression analysis to control for baseline differences was used to compare the
      learning of the two groups. RESULTS: Participants in both groups scored
      significantly higher on the KTA-M after cooking lessons (t = 5.57, df = 21, p <
      .0001--clinic; t = 7.81. df = 21, p < .0002--home) reflecting learning of cooking
      skill; there was no statistically significant difference in scores on the KTA-M
      between the two groups based on where the learning took place (beta = -1.8, df =
      42, p < 0.23). Qualitative differences between the learning environments provide
      suggestions for teaching functional living skills to this population.
      CONCLUSIONS: Learning new skills in the home was not better than learning in the
      clinic for people with schizophrenia in this study. Further research on the
      effect of context on learning for people with cognitive dysfunction and
      schizophrenia is recommended.

PMID- 15202625
TI  - Occupational therapy assessment of open-road driving performance: validity of
      directed and self-directed navigational instructional components.
AB  - OBJECTIVE: The purpose of this study was to validate an assessment tool used by
      occupational therapists to evaluate on-road driving performance. METHODS: The
      driving assessment was conducted over a 15-km route that consisted of a range of
      traffic situations and contained both directed and self-directed navigational
      instruction. The driving performance of four groups of drivers of different ages
      and visual characteristics was assessed independently by an occupational
      therapist and driving instructor using a range of scoring criteria. RESULTS: The
      occupational therapist scores were significantly affected by the drivers' age and
      visual characteristics (directed navigation, F(3,133) = 6.05, p = 0.001; self
      directed navigation, F(3,133) = 5.04, p < 0.002), and these group differences
      were greater for self-directed navigational instruction. The occupational
      therapist scores were highly correlated with the driving instructor's global
      driver safety rating (r = 0.76, p < 0.001). DISCUSSION: The driving assessment
      instrument was a valid measure of on-road driving performance relative to an
      independent global driving safety evaluation. The instrument provided detailed
      information regarding driving performance and highlighted areas of difficulty,
      particularly when drivers followed self-navigational instruction.

PMID- 15202626
TI  - Prevalence of parents' perceptions of sensory processing disorders among
      kindergarten children.
AB  - This study is the first to systematically examine estimated rates of sensory
      processing disorders using survey data. Parents of incoming kindergartners from
      one suburban U.S. public school district were surveyed using the Short Sensory
      Profile, a parent-report screening tool that evaluates parents' perceptions of
      functional correlates of sensory processing disorders (McIntosh, Miller, Shyu, &
      Dunn, 1999a). A total of 703 completed surveys were returned, which represents
      39% of the kindergarten enrollment (n = 1,796) in the district for the 1999-2000
      school year. Of the 703 children represented by the surveys, 96 children (13.7%
      of 703) met criteria for sensory processing disorders based upon parental
      perceptions. A more conservative prevalence estimate of children having sensory
      processing disorders based on parental perceptions was calculated by assuming
      that all non-respondents failed to meet screening criteria. This cautious
      estimate suggests that based on parents' perceptions, 5.3% (96 of 1796) of the
      kindergarten enrollment met screening criteria for sensory processing disorders.
      These percentages are consistent with hypothesized estimates published in the
      literature. Findings suggest a need for rigorous epidemiological studies of
      sensory processing disorders.

PMID- 15202627
TI  - Responses of preschool children with and without ADHD to sensory events in daily
      life.
AB  - OBJECTIVE: The purpose of this study was to compare parents' perceptions of the
      responses of their preschool children, with and without attention deficit
      hyperactivity disorder (ADHD), to sensory events in daily life in Israel. In
      addition, the relationship between levels of hyperactivity and sensory deficits
      was examined. METHOD: The Sensory Profile Questionnaire (SP) was completed by
      mothers of forty-eight 4- to 6-year-old children with ADHD, and mothers of 46
      children without disabilities. A matched group comparison design was used to
      identify possible differences in sensory processing. RESULTS: Based on the
      measure of mothers' perceptions, children with ADHD demonstrated statistically
      significant differences from children without ADHD in their sensory
      responsiveness as reflected in 6 out of 9 factor scores (p < .001-.05), and on
      their sensory processing, modulation, and behavioral and emotional responses, as
      reflected in 11 out of 14 section scores (p < .001-.05). Scores on the SP yielded
      statistically significant low to moderate correlations with scores on the
      hyperactive scale of the Preschool Behavior Questionnaire (r = .28-.66).
      CONCLUSION: The findings of the present study suggest that young children with
      ADHD may be at increased risk of deficits in various sensory processing
      abilities, over and above the core symptoms of ADHD. Early identification and
      treatment of sensory processing deficits from a young age may extend our ability
      to support the successful performance of children with ADHD in meaningful and
      productive occupations.

PMID- 15202628
TI  - Using Deweyan philosophy to rename and reframe adaptation-to-environment.
AB  - John Dewey's philosophy has been suggested as having been formative in the
      philosophy of occupational therapy, but the occupational therapy literature
      offers few analyses of Dewey's work and its implications for the discipline. I
      offer an abbreviated analysis of Deweyan philosophy and then assess how
      adequately that philosophical corpus has been interpreted in the occupational
      therapy literature. My conclusion is that significant inconsistencies exist
      between a Deweyan perspective and selected concepts in occupational therapy. I
      take particular issue with the concept of adaptation-to-environment and
      specifically with aspects of that conceptualization that I term "environment as
      container," "subjective-internalized focus," and "mechanization of processes." I
      offer an alternative concept, "place integration," that is more consistent with
      Dewey's philosophy. The advantages of the conceptual renaming and reframing are
      discussed.

PMID- 15202629
TI  - Trowels labeled ergonomic versus standard design: preferences and effects on
      wrist range of motion during a gardening occupation.
AB  - OBJECTIVE: The purposes of this study were to determine whether a garden trowel
      labeled ergonomic provided better wrist positioning when planting than a standard
      designed trowel and whether participants perceived the ergonomic labeled trowel
      as more comfortable and easier to use than the standard-designed trowel. METHOD:
      Participants included 64 females, ages 20-50 years, with no self-reported disease
      or disability impairing their preferred upper extremity. Participants used both
      trowels to fill flowerpots with soil in a randomized, repeated measures,
      counterbalanced design. The wrist movements of ulnar and radial deviation, and
      palmar and dorsiflexion were measured with an electrogoniometer (Penny and Giles
      Biometrics Limited Goniometer XM65). Participants answered questions regarding
      their interest in gardening, ease of use and comfort of each trowel, and trowel
      preference. RESULTS: A one-tailed paired ttest showed that the trowels did not
      differ in the extremes of dorsiflexion elicited and the extremes of the other
      wrist movements were not in the predicted direction. Participants rated the
      trowels similarly for comfort and ease of use. Participants were evenly divided
      on personal preference for the two trowels. CONCLUSION: Occupational therapists
      should be cautious when recommending a gardening trowel based on it being labeled
      ergonomic, as it may not produce better wrist positioning than a non
      ergonomically labeled trowel. Fitting a person with the right trowel involves an
      assessment of tool-influenced wrist positioning as well as individual perceptions
      of comfort and ease of tool use.

PMID- 15202630
TI  - Psychometric properties of the scorable self-care evaluation.
AB  - OBJECTIVE: The purpose of this study was to examine evidence for the reliability
      and validity of the Scorable Self-Care Evaluation (SSCE), an 18-item assessment
      of observed and perceived self-care performance commonly used with persons with
      psychiatric disabilities. METHOD: As part of a longitudinal study, 70 adults with
      psychiatric disabilities were administered two cognitive measures, the Wisconsin
      Card Sorting Test and the Logical Memory subscales of the Weschler Memory Scale,
      at baseline, and the SSCE at follow-up. After transforming the weighted item
      scores, intraclass correlation coefficients were used to examine inter-rater
      reliability and Rasch analysis was used to examine internal consistency of the
      SSCE. Spearman rank-order correlations were used to examine construct validity.
      RESULTS: High interrater reliabilities were found for the four subscale scores
      (ICCs ranging from .96 to 1.00, p < .001) and the total scores (ICC = .98, p <
      .001) of the SSCE. Rasch analysis indicated that no items misfit; however, some
      items showed a weak distribution across all possible scores. The SSCE subscale
      and total scores correlated to varying degrees with the cognitive measures.
      CONCLUSION: The SSCE has the potential to be a reliable and valid clinical
      measure, as demonstrated by the results of the current study. However, these
      results were only achieved using a transformation of the current scoring system
      for the SSCE, pointing to the need for further revision of the test items and
      scoring system.

PMID- 15202631
TI  - Effects of problem-based learning on clinical reasoning in occupational therapy.
AB  - OBJECTIVE: Problem-based learning (PBL) has been described as an educational
      method that enhances clinical reasoning skills. The purpose of this study was to
      determine the effects of an intensive, problem-based course on the development of
      clinical reasoning skills of undergraduate occupational therapy students. METHOD:
      A quasi-experimental pretest-posttest design was used with a convenience sample
      of 48 undergraduate seniors. All students participated in an intensive 5-week, 30
      hour, PBL course scheduled just prior to Level II fieldwork. The Self-Assessment
      of Clinical Reflection and Reasoning (SACRR) developed by Royeen, Mu, Barrett,
      and Luebben (2001) was administered on the first and last days of the course.
      RESULTS: The Wilcoxon Signed Ranks Test revealed statistically significant
      differences in pre- and posttest scores for 11 of 26 items on the SACRR. In
      addition, the overall total score increased from 96.88 to 102.55 (p < .01).
      CONCLUSION: The results suggest that a short, but intensive PBL course in the
      senior year of an occupational therapy curriculum can significantly facilitate
      the development of students' clinical reasoning skills.

PMID- 15202632
TI  - Occupational performance needs of adolescents in alternative education programs.
AB  - OBJECTIVE: Alternative education programs are schools that accept students who
      have not been successful in the general education setting. This study focuses on
      developing a better understanding of the needs of students in three area
      alternative education schools. METHODS: A needs assessment was created and
      distributed to the staff of each school regarding the problem areas of
      alternative education students. Data were analyzed descriptively. RESULTS: Thirty
      nine of 47 surveys were returned resulting in an overall return rate of 83%. The
      staff identified several potential deficit areas faced by the students in these
      alternative education programs. The most frequently identified deficits included
      poor time management skills, decreased healthy participation in hobbies and
      leisure activities, and a lack of healthy lifestyle behaviors. In addition, the
      staff reported that many students had cognitive deficits including reduced
      ability to follow multistep directions, impaired higher-level thinking skills,
      reduced attention span, and limited memory. CONCLUSION: The results of this study
      are consistent with literature that suggests the students in alternative
      education settings may have underlying deficits that interfere with learning and
      produce misbehaviors. The alternative education programs should be further
      explored as a potential practice area for occupational therapists.

PMID- 15202633
TI  - Parent-child interactions and everyday routines in young children with failure to
      thrive.
AB  - OBJECTIVE: This pilot study explored the use of a parent-child interaction scale
      during a nonfeeding event and a systematic method for recording children's sleep
      and feeding routines at home to determine if these two measures could be useful
      additions to the occupational therapy assessment of young children with failure
      to thrive. METHOD: Five mother-child dyads were administered the Nursing Child
      Assessment Teaching Scale (NCATS) and the mothers completed a 24-hour, 7-day
      Sleep Activity Record (SAR). RESULTS: Two of the five dyads scored below the 10th
      percentile cutoff on the NCATS indicating low levels of mutually adaptive
      interactions. The NCATS subscale scores revealed low performance in three of the
      mothers, but none of the children. The SAR documented concerns in the sleep and
      feeding patterns in 4 of the 5 children, including irregular bedtimes, frequent
      nighttime wakening, and irregular feeding times. DISCUSSION: The NCATS and SAR
      revealed a wide range of strengths and concerns in this sample. Findings suggest
      that occupational therapists evaluating the complex nature of failure to thrive
      in young children should consider including measures to assess parent-child
      interactions during nonfeeding situations, as well as obtain information on the
      children's sleep and feeding routines.

PMID- 15202634
TI  - Challenges and strategic solutions for a research emergent profession.
AB  - This paper explores some of the truisms associated with evidence-based practice.
      The intention is to remind the reader that evidence-based practice is a decision
      making tool and not a rule; and to propose a strategic approach to overcoming the
      challenges we face as a research emergent profession.

PMID- 15202635
TI  - Embracing diversity in our profession.

PMID- 15202636
TI  - Effects of somatic cell count and stage of lactation on the plasmin activity and
      cheese-making properties of ewe milk.
AB  - The experiment was conducted from March to July 2002 using 5 intensively managed
      flocks of Southern Italy. In each flock, 2 groups of 50 ewes were created. The
      groups were designated LSCC (low somatic cell count [SCC]) when their milk SCC
      was lower than 500,000/mL and HSCC (high SCC) when their milk SCC was higher than
      1,000,000/mL. Bulk milk and whey samples were analyzed for fat, total protein,
      lactose, casein, and whey protein contents. Renneting properties of milk were
      also determined. Moisture, NaCl, and nitrogen fractions were determined in fresh
      cheese curds. In addition, plasmin (PL) and plasminogen (PG) activities in milk
      and cheese were monitored. The proteolytic activity of plasmin by urea
      polyacrylamide gel electrophoresis and the white blood cell (WBC) differentials
      were determined. The HSCC resulted in higher pH values in milk and in higher
      moisture and lower fat contents in fresh cheese curds. Moreover, a lower recovery
      of fat and whey proteins was obtained from the HSCC than from the LSCC raw milk.
      The crude protein and casein contents were higher in the HSCC than in the LSCC
      curds during early and midlactation; an opposite trend was observed in late
      lactation. Plasmin and PG activities underwent more marked fluctuations in the
      LSCC than in the HSCC curds through lactation. The results of this experiment
      demonstrate that the PL activity in ewe milk is markedly influenced by the SCC,
      although SCC is not the only parameter for predicting PL and PG evolution in ewe
      milk. The LSCC milk resulted in a higher proteolytic potential of Canestrato
      pugliese cheese curds.

PMID- 15202637
TI  - Measurement of bovine IgG by indirect competitive ELISA as a means of detecting
      milk adulteration.
AB  - The aim of this work was to develop an assay capable of detecting adulteration of
      high premium milk with milk from cheaper sources. An indirect, competitive ELISA
      was developed for the rapid detection of cows' milk in the milk of goat, sheep,
      and buffalo. The assay uses a monoclonal antibody produced against bovine IgG.
      This antibody recognizes a species-specific epitope on the heavy chain of both
      bovine IgG1 and IgG2. A peroxidase-conjugated anti-mouse IgG antibody was used to
      detect bound monoclonal antibody and subsequent enzymatic conversion of substrate
      resulted in clear differences in absorbance when assaying different mixtures of
      milks adulterated with cows' milk. Once optimized, the ELISA was found to be
      highly specific. Detection limits of the assay are 1.0 microg/mL of bovine IgG,
      or 0.1% (vol/vol) adulteration with cows' milk. The assay was highly reproducible
      (CV < 10%) and performed equally well when used to detect bovine IgG in mixtures
      with the 3 types of milk tested. The ELISA performance makes it suitable for
      development as a kit, for use in the field as a high throughput screening ELISA.

PMID- 15202638
TI  - Effect of the metabolism of urea on the acidifying activity of Streptococcus
      thermophilus.
AB  - One of the main functions of Streptococcus thermophilus strains used in the dairy
      industry is the production of lactic acid. In cheese and fermented milk
      manufacturing processes, the pH evolution kinetics must be reproducible in order
      to ensure the good quality of the final products. The objective of the present
      study was to investigate the effect of the metabolism of urea on the acidifying
      activity of fast- and slow-acidifying strains of S. thermophilus. Milk treatment
      with a purified urease and utilization of the urease inhibitor flurofamide
      revealed that urea metabolism by S. thermophilus influences the pH evolution
      kinetics through 2 distinct means. First, ammonia production from urea tends to
      increase the pH. This effect is greater when lactic acid concentration is low due
      to a lower buffering capacity of milk. Second, urea metabolism also modifies
      growth and lactic acid production by S. thermophilus. Depending on the strains
      and the growth stage of the cultures, consumption of urea induces either a faster
      or a slower pH decrease. For the slow-acidifying strain RD678, suppression of
      urea metabolism by adding flurofamide decreased the time necessary to reach pH 6
      by 195 min. This effect was less pronounced for the 2 fast-acidifying strains
      RD674 and RD677. These results show that urea metabolism may have a considerable
      influence on the acidifying properties of S. thermophilus strains.

PMID- 15202639
TI  - Occurrence of polycyclic aromatic hydrocarbons in smoked cheese.
AB  - The presence of polycyclic aromatic hydrocarbons (PAH) in smoked cheeses of
      different origin was studied. The samples were subjected to an initial extraction
      of fat and an alkaline treatment, extracted with cyclohexane, cleaned up by means
      of solid-phase extraction tubes, and analyzed by gas chromatography/mass
      spectrometry (GC/MS) operating in selective ion-monitoring mode (SIM). The
      results revealed the presence of numerous polycyclic aromatic hydrocarbons in the
      exterior zone of the samples, some of them with methyl groups. In all cases, the
      concentrations of compounds of low molecular weight were much higher than those
      of high molecular weight. Polycyclic aromatic hydrocarbons with varying degrees
      of carcinogenicity were identified, including benzo(a)pyrene in concentrations,
      which, although they did not exceed the limit established for this compound in
      the rind of ripened cheeses, do exceed the limit of 0.03 microg/kg fixed for
      other foods smoked with smoke flavorings. Significant differences in the number
      and concentration of PAH in smoked cheese also were observed from rind to
      interior, the rind being the most contaminated zone.

PMID- 15202640
TI  - Influence of residual milk-clotting enzyme on alpha(s1) casein hydrolysis during
      ripening of Reggianito Argentino cheese.
AB  - Milk-clotting enzyme is considered largely denatured after the cooking step in
      hard cheeses. Nevertheless, typical hydrolysis products derived from rennet
      action on alpha(s1)-casein have been detected during the ripening of hard
      cheeses. The aim of the present work was to investigate the influence of residual
      milk-clotting enzyme on alpha(s1)-casein hydrolysis in Reggianito cheeses. For
      that purpose, we studied the influence of cooking temperature (45, 52, and 60
      degrees C) on milk-clotting enzyme residual activity and alpha(s1)-casein
      hydrolysis during ripening. Milk-clotting enzyme residual activity in cheeses was
      assessed using a chromatographic method, and the hydrolysis of alpha(s1)-casein
      was determined by electrophoresis and high performance liquid chromatography.
      Milk-clotting enzyme activity was very low or undetectable in 60 degrees C- and
      52 degrees C-cooked cheeses at the beginning of the ripening, but it increased
      afterwards, particularly in 52 degrees C-cooked cheeses. Cheese curds that were
      cooked at 45 degrees C had higher initial milk clotting activity, but also in
      this case, there was a later increase. Hydrolysis of alpha(s1)-casein was
      detected early in cheeses made at 45 degrees C, and later in those made at higher
      temperatures. The peptide alpha(s1)-I was not detected in 60 degrees C-cooked
      cheeses. The results suggest that residual milk-clotting enzyme can contribute to
      proteolysis during ripening of hard cheeses, because it probably renatures
      partially after the cooking step. Consequently, the production of peptides
      derived from alpha(s1)-casein in hard cheeses may be at least, partially due to
      this proteolytic agent.

PMID- 15202641
TI  - Factors affecting calcium lactate and liquid expulsion defects in Cheddar cheese.
AB  - This paper summarizes the results of 2 studies designed to investigate the
      influence of several manufacturing and curing treatments on the appearance of
      Cheddar cheese defects. Specifically, 2 defects, calcium lactate crystal
      formation and the expulsion of free liquid (weeping) were monitored in Cheddar
      cheese. Both studies were conducted at a commercial cheese manufacturing facility
      that produces Cheddar in 18.14-kg (40-lb) blocks. In the first study we monitored
      cheese calcium, both total and soluble during manufacture and early curing. In
      the second study we measured cheese pH from 3 d through 8 mo, as well as some
      factors that are influenced by cheese pH. Early cheese pH (3 d to 7 d) patterns
      were used to select vats of cheese for retail packaging. Mild Cheddar packaged at
      30 d postmanufacture and sharp Cheddar packaged at 8 mo postmanufacture from the
      same vats were monitored for the incidence and severity of the defects. Our
      results indicated that factors measured in early stages of manufacture and curing
      (less than 7 d) such as cheese pH at mill, lactic acid concentration, nonprotein
      nitrogen, and calcium (total and soluble) in cheese did not correlate with the
      appearance of either calcium lactate or expulsion of free liquid in packaged
      cheeses. Factors including pH, lactic acid concentrations, and soluble calcium
      measured during curing (greater than 7 d) of cheese were found to be
      statistically significant in the development of defects and appeared to be
      associated with use of specific starter culture groups. In the study, 5 different
      starter culture groups, each consisting of a 4-strain blend of Lactococcus lactis
      ssp. cremoris and Lactococcus lactis ssp. lactis, were used to manufacture the
      cheeses. Cheese manufactured with one particular culture group showed no
      incidence of calcium lactate crystal formation or weeping during curing and shelf
      life of cheeses in this study. This starter group also generated the least amount
      of pH change in cheese during the first month of curing. From these results we
      conclude that starter culture group, more than any other factor measured, played
      an important role in the development of calcium lactate and liquid expulsion
      defects in Cheddar cheese. Starter culture group appeared to strongly influence
      cheese pH, lactic acid, and soluble calcium concentrations during curing and
      storage.

PMID- 15202642
TI  - Mild to moderate clinical mastitis: efficacy of intramammary amoxicillin,
      frequent milk-out, a combined intramammary amoxicillin, and frequent milk-out
      treatment versus no treatment.
AB  - Study objectives were to determine the efficacy of 4 methods (intramammary
      amoxicillin, frequent milk-out, a combined intramammary amoxicillin and frequent
      milk-out, and no treatment) of managing mild to moderate clinical mastitis in a
      university dairy herd. Clinical and microbiological cures, milk production,
      disease progression, and California Mastitis Tests scores were evaluated. Cows
      meeting the study criteria were assigned to one of four treatment options based
      on a systematic randomization scheme (blocked by stage of lactation). Treatments
      were initiated prior to knowledge of culture results. Cows were observed and
      evaluated on d 1 to 8, 15, 22, 29, and 36. Overall, treatments were not
      significantly different than controls. However, when efficacy was evaluated by
      pathogen group, differences were observed. Intramammary amoxicillin appeared to
      be the most efficacious treatment for environmental streptococci. Frequent milk
      out appeared to be detrimental for environmental streptococci. Treatment method
      appeared to have little effect on Escherichia coli mastitis, as nearly all cases
      recovered within a short time frame. None of the treatments were satisfactory for
      cases of Klebsiella mastitis. When obtained in a timely manner, treatment
      selection for clinical mastitis should be based on culture results.

PMID- 15202643
TI  - The use of test day information to predict energy intake of dairy cows in early
      lactation.
AB  - This study aimed to validate a previously developed model for the estimation of
      energy balance in high producing dairy cows from test day information during the
      first 12 wk of lactation. Monensin (an ionophor) increases the energy status of
      dairy cows. Gold standard for the validation was a higher energy status,
      indicated by lower blood ketone body concentrations, lower percent milk fat, and
      higher milk-yield of monensin-supplemented than control cows in 8 randomized
      block design feeding trials. Estimated energy intake (eE(intake)) was calculated
      as estimated energy balance (eEB) plus energy in actual milk produced (in units
      of MJ(nel)) plus a constant or variable amount of energy required for
      maintenance. The variable amount was based on BW, while the constant was the
      average BW in each parity group (1, 2, 3, 4+). Both eEB and eE(intake) were
      compared between groups of cows with and without monensin supplementation (n =
      600 lactations). The trials started with a presupplement period during lactation
      wk 2 to 5 followed by a supplementation period during lactation wk 6 to 12.
      During the presupplement period, both eEB and eE(intake) were similar for all
      cows. At 2, 3, and 8 wk after starting the monensin supplementation, the eEB of
      the supplemented cows was significantly higher, while eE(intake) was
      significantly higher throughout the supplementation period. The results were
      similar for the 2 methods of calculating energy for maintenance, variable or
      constant. The feed conversion efficiency, calculated as kg of fat-protein
      corrected milk per MJ(nel) of eE(intake), was highest in first calving cows
      compared with cows having more lactations, and correlated with standard milk
      production at trial group level. It was concluded that eE(intake) was a valid
      measure of net energy absorption.

PMID- 15202644
TI  - Persistency of adenoviral-mediated lysostaphin expression in goat mammary glands.
AB  - Gene therapy has great potential to enable synthesis of protein molecules in
      targeted cells of an animal. One application may be the production of
      antibacterial enzymes by the mammary gland as a means of preventing or treating
      mastitis. We have previously demonstrated that goat mammary cells are capable of
      producing lysostaphin, an antistaphylococcal enzyme, after being transduced in
      vivo with a recombinant adenoviral vector containing a modified lysostaphin gene
      (Ad-lys). The current study examined duration of expression, and antibody
      response to lysostaphin and the adenoviral vector. Following intramammary
      infusion into nonlactating goats (n = 4), recovery of transducible adenoviral
      vector in mammary secretions persisted for 11 d. Transducible vector was not
      detected in serum, saliva, urine, or feces. Peak lysostaphin concentrations (< 20
      microg/mL) in mammary secretions of infused udders were detected approximately 1
      wk postinfusion, and generally returned to undetectable levels after an
      additional 1 to 2 wk. The poor persistency of expression was likely due to the
      very potent immune response to both the adenovirus and the expressed lysostaphin.
      Serum IgG antibodies recognizing the adenoviral vector developed within 7 d of
      the infusion, and titers rose dramatically to greater than 1:1 x 10(5). Similar
      titers of serum IgG antibodies to lysostaphin developed in 3 goats, with more
      moderate titers in the fourth goat. The antibody response to lysostaphin was
      delayed by approximately 4 d in comparison to the response to the adenovirus.
      Serum IgG antibody profiles were reflected in mammary secretions. No IgA
      antibodies to adenovirus or lysostaphin were detected in sera or mammary
      secretion. We demonstrate that while the lysostaphin gene can be introduced to
      the mammary gland using an adenoviral-mediated gene transfer technique, the
      strong immune response that it provokes makes the approach unsuitable for
      combating mastitis.

PMID- 15202645
TI  - Peripartum serum vitamin E, retinol, and beta-carotene in dairy cattle and their
      associations with disease.
AB  - Peripartum decreases in serum concentrations of vitamins A and E may contribute
      to impaired immune function in dairy cows. The objectives of this study were to
      describe peripartum serum concentrations of alpha-tocopherol, beta-carotene, and
      retinol and their associations with disease risk. On 20 farms over 1 yr, blood
      samples were collected weekly from 1057 cows from 1 wk before expected calving
      until 1 wk postpartum. Serum concentrations of alpha-tocopherol, beta-carotene,
      and retinol, as well as several biochemical variables were measured. Their
      associations with the risk of retained placenta or clinical mastitis were modeled
      separately with logistic regression, and the factors associated with the
      concentration of each vitamin were modelled with mixed linear regression.
      Differences in vitamin concentrations between 2 batches of sera analyzed 6 mo
      apart required stratification of statistical analyses. Accounting for the effects
      of parity, season, and twins, an increase in alpha-tocopherol of 1 microg/mL in
      the last week prepartum reduced the risk of retained placenta by 20%, whereas
      serum nonesterified fatty acid concentration > or = 0.5 mEq/L tended to increase
      risk of retained placenta by 80%. In the last week prepartum, a 100 ng/mL
      increase in serum retinol was associated with a 60% decrease in the risk of early
      lactation clinical mastitis. There were significant positive associations of
      peripartum serum concentrations among each of alpha-tocopherol, beta-carotene,
      and retinol.

PMID- 15202646
TI  - The effect of protein intake on performance of cows in hot environmental
      temperatures.
AB  - Two trials were conducted with cows in commercial herds during midlactation to
      evaluate the effect of dietary crude protein (CP) concentration on the
      production, composition, and efficiency of milk production under hot ambient
      conditions. Cows were group-fed in trial 1, which was conducted in two herds, and
      were fed individually in trial 2. The respective average ambient temperature,
      relative humidity, and temperature-humidity index (THI) were 31 degrees C, 45%,
      and 78 in trial 1 and 27 degrees C, 70%, and 76 in trial 2. Cows were cooled by
      forced evaporative means six times daily in trial 1 and three times daily in
      trial 2. Dietary CP was 15.3 or 17.3% of dry matter (DM) in trial 1 and 15.1 or
      16.7% of DM in trial 2. The respective ratios of rumen-degradable organic matter
      (RDOM) to rumen-degradable protein were 5.3 and 4.8 for the low CP (LP) and high
      CP (HP) diets. Average DM intake, milk yield, and milk fat and protein
      concentrations were 22 and 23 kg/d, 34 and 35 kg/d, 3.1 and 3.4%, and 3.2 and
      3.1% in trials 1 and 2, respectively, and were similar among diets in both
      trials. The resultant calculated milk protein efficiency ratio and overall CP
      efficiency were 0.31 and 0.32 for the LP diets and 0.28 and 0.29 for the HP
      diets. In cows fed the LP diet, diet rumen ammonia was lower in trial 1, and milk
      urea N was lower in trial 2. The BW change was higher in trial 1, and tended to
      be higher in trial 2, with the LP diets. Changes in body condition score in
      trials 1 and 2 tended to be higher with the LP diets. It was concluded that a
      dietary CP content of 15.3% is adequate to maintain production in heat-exposed
      dairy cows producing 35 kg of milk/d, provided that the forced evaporative
      cooling and the ratio of RDOM to rumen-degradable protein is appropriate

PMID- 15202647
TI  - Fermentation acids, aerobic fungal growth, and intake of napiergrass ensiled with
      nonfiber carbohydrates.
AB  - This study evaluated fermentation characteristics and fungal numbers of
      napiergrass silages prepared with and without added raw or heated corn meal (10%,
      fresh-weight basis) at ensiling. Corn was added to napiergrass so that the silage
      would contain concentrate similar to that of corn silage with minimum grain
      content. The silages treated with raw or heated corn were fed to dairy does to
      compare voluntary silage consumption. After 8 wk of fermentation, pH for silage
      treated with heated corn was lowest, and that for napiergrass ensiled alone was
      highest among the treatments. The addition of corn increased lactic acid, but
      propionic and butyric acids were also elevated. Acetic acid decreased in response
      to the supplementation of corn but remained the dominant acid for all silages.
      Numbers of fungi (yeasts plus molds) in silages did not differ significantly at
      silo opening or after 24 h of exposure to air. However, the numbers of fungi at
      48 h in aerated silages containing corn were lower than were the fungi counts in
      the control silage. When the silages were offered free choice along with
      concentrate at a fixed rate, dairy does tended to consume more silage treated
      with heated corn than raw corn. Whole-tract nutrient digestibility and serum
      glucose and urea N were not altered. These results indicate that the addition of
      either raw or heated corn meal to napiergrass at ensiling was beneficial to
      silage fermentation quality because it decreased pH, increased lactic acid, and
      apparently suppressed fungal populations via elevated antifungal acids. A further
      advantage of heated corn vs. raw corn was increased silage intake.

PMID- 15202648
TI  - Comparison of brown midrib-6 and -18 forage sorghum with conventional sorghum and
      corn silage in diets of lactating dairy cows.
AB  - Total mixed rations containing conventional forage sorghum, brown midrib (bmr)-6
      forage sorghum, bmr-18 forage sorghum, or corn silage were fed to Holstein dairy
      cows to determine the effect on lactation, ruminal fermentation, and total tract
      nutrient digestion. Sixteen multiparous cows (4 ruminally fistulated; 124 d in
      milk) were assigned to 1 of 4 diets in a replicated Latin square design with 4-wk
      periods (21-d adaptation and 7 d of collection). Diets consisted of 40% test
      silage, 10% alfalfa silage, and 50% concentrate mix (dry basis). Acid detergent
      lignin concentration was reduced by 21 and 13%, respectively, for the bmr-6 and
      bmr-18 sorghum silages when compared with the conventional sorghum. Dry matter
      intake was not affected by diet. Production of 4% fat-corrected milk was greatest
      for cows fed bmr-6 (33.7 kg/d) and corn silage (33.3 kg/d), was least for cows
      fed the conventional sorghum (29.1 kg/d), and was intermediate for cows fed the
      bmr-18 sorghum (31.2 kg/d), which did not differ from any other diet. Total tract
      neutral detergent fiber (NDF) digestibility was greatest for the bmr-6 sorghum
      (54.4%) and corn silage (54.1%) diets and was lower for the conventional (40.8%)
      and bmr-18 sorghum (47.9%) diets. In situ extent of NDF digestion was greatest
      for the bmr-6 sorghum (76.4%) and corn silage (79.0%) diets, least for the
      conventional sorghum diet (70.4%), and intermediate for the bmr-18 sorghum silage
      diet (73.1%), which was not different from the other diets. Results of this study
      indicate that the bmr-6 sorghum hybrid outperformed the conventional sorghum
      hybrid; the bmr-18 sorghum was intermediate between conventional and bmr-6 in
      most cases. Additionally, the bmr-6 hybrid resulted in lactational performance
      equivalent to the corn hybrid used in this study. There are important
      compositional differences among bmr forage sorghum hybrids that need to be
      characterized to predict animal response accurately.

PMID- 15202649
TI  - Disappearance of docosahexaenoic and eicosapentaenoic acids from cultures of
      mixed ruminal microorganisms.
AB  - Previous studies showed conflicting results regarding the ability of ruminal
      microorganisms to hydrogenate docosahexaenoic acid (C22:6, DHA) and
      eicosapentaenoic acid (C20:5, EPA). To determine the disappearance of DHA and EPA
      from mixed ruminal cultures, 2 ruminal in vitro experiments were conducted using
      graded levels of DHA and EPA. The first experiment examined DHA added at 0, 5,
      10, 15, and 20 mg per culture flask. In the second experiment, EPA was added at
      0, 5, 10, and 15 mg per culture flask. Docosahexaenoic acid and EPA were
      incubated in triplicate in 125-mL flasks, and 5 mL of culture contents was taken
      at 0, 12, and 24 h for fatty acid analysis by gas liquid chromatography. After 24
      h of incubation, 4.1, 4.1, 4.0, and 3.3 mg of DHA disappeared from the 5, 10, 15,
      and 20 mg of DHA cultures, respectively. In the second experiment, 5, 8.3, and
      7.1 mg of EPA disappeared after 24 h of incubation for the 5-, 10-, and 15-mg EPA
      cultures, respectively. Addition of DHA to cultures increased trans-C18:1 fatty
      acid accumulation by 105, 91, 82, and 74% for the 5, 10-, 15-, and 20-mg
      cultures, respectively, compared with control. The addition of EPA increased
      trans-C18:1 fatty acid accumulation by 56, 64, and 55% for the 5-, 10-, and 15-mg
      EPA cultures, respectively, compared with control. Addition of DHA and EPA to
      cultures caused a reduction in C18:1 n-9 and C18:2 n-6 biohydrogenation compared
      with control. Results from these experiments clearly demonstrate the ability of
      ruminal microorganism to transform DHA and EPA to other fatty acids causing their
      disappearance from cultures.

PMID- 15202650
TI  - Effect of alfalfa forage preservation method and particle length on performance
      of dairy cows fed corn silage-based diets and tallow.
AB  - A study was conducted to evaluate the effect of including alfalfa preserved
      either as silage or long-stem or chopped hay on DMI and milk fat production of
      dairy cows fed corn silage-based diets with supplemental tallow (T). Fifteen
      Holstein cows that averaged 117 DIM were used in a replicated 5 x 5 Latin square
      design with 21-d periods. Treatments (DM basis) were: 1) 50% corn silage:50%
      concentrate without T (CS); 2) 50% corn silage:50% concentrate with 2% T (CST);
      3) 25% corn silage:25% short-cut alfalfa hay:50% concentrate with 2% T (SAHT); 4)
      25% corn silage:25% long-cut alfalfa hay:50% concentrate with 2% T (LAHT); and 5)
      25% corn silage:25% alfalfa silage:50% concentrate with 2% T (AST). Cows were
      allowed ad libitum consumption of a TMR fed 4 times daily. Diets averaged 16.4%
      CP and 30.3% NDF. Including 2% T in diets with corn silage as the sole forage
      source decreased DMI and milk fat percentage and yield. Replacing part of corn
      silage with alfalfa in diets with 2% T increased milk fat percentage and yield.
      The milk fat of cows fed CST was higher in trans-10 C18:1 than that of cows fed
      diets with alfalfa. No effect of alfalfa preservation method or hay particle
      length was observed on DMI and milk production. The milk fat percentage and yield
      were lower, and the proportion of trans-10 C18:1 in milk fat was higher for cows
      fed LAHT than for cows fed SAHT. Alfalfa preservation method had no effect on
      milk fat yield. Ruminal pH was higher for cows fed alfalfa in the diets, and it
      was higher for cows fed LAHT than SAHT. Feeding alfalfa silage or chopped hay
      appears to be more beneficial than long hay in sustaining milk fat production
      when 2% T is fed with diets high in corn silage. These results support the role
      of trans fatty acids in milk fat depression.

PMID- 15202651
TI  - Performance of lactating dairy cows fed whole cottonseed with elevated
      concentrations of free fatty acids in the oil.
AB  - Twenty-four multiparous cows were used in a 10-wk randomized block design trial
      to evaluate the effects of feeding whole cottonseed (WCS) containing increasing
      concentrations of free fatty acids (FFA) in the oil on nutrient intake and
      digestibility, milk yield and composition, and select plasma metabolites. Two
      lots of WCS containing either 3 or 12% FFA were blended to provide WCS with 3, 6,
      9, and 12% FFA. Cottonseeds were included in the wheat silage-based total mixed
      ration at 12.5% of dry matter (DM). There was no difference in intakes of DM,
      crude protein (CP), or neutral detergent fiber; yield of milk; or percentages of
      milk protein, lactose, or SNF. Milk fat percentage was lowest for the diet
      containing WCS with 6% FFA. Concentrations of individual milk fatty acids C6:0
      decreased and C16:1 increased linearly as FFA in WCS increased. A cubic response
      was observed for concentrations of C8:0, C10:0, and C12:0 because of higher
      concentrations when diets contained WCS with 6% FFA than 3 and 12% FFA, which
      were higher than 9% FFA. Intake and apparent total tract digestibility of acid
      detergent fiber increased linearly as FFA concentration in WCS increased.
      Apparent NDF digestibility was highest for diets containing WCS with 3 and 6%
      FFA; CP digestibility was highest with WCS containing 3 and 9% FFA. Differences
      in milk fatty acid concentration and nutrient digestibility suggest minor changes
      in rumen fermentation; however, feeding WCS with up to 12% FFA did not negatively
      impact nutrient intake and digestibility or milk yield or composition.

PMID- 15202652
TI  - Unrestricted feed intake during the dry period impairs the postpartum oxidation
      and synthesis of fatty acids in the liver of dairy cows.
AB  - The purpose of this study was to determine the activities of key hepatic enzymes
      of fatty acid synthesis and oxidation in cows that had excessive body fat at
      parturition. Dairy cows were allocated to either an experimental group or a
      control group. All cows were offered a total mixed ration with an energy content
      of 6.6 MJ of net energy for lactation per kilogram of dry matter and consisting
      of corn silage, beet pulp, rapeseed meal, and soybean meal. Control cows were
      restricted to 6.8 kg/dry matter of the mixed ration in the dry period.
      Experimental cows had unrestricted access to the mixed ration during the dry
      period to increase body fat and induce fatty liver postpartum. Blood and liver
      samples were collected 1 wk before and 1, 2, and 4 wk after parturition. Before
      parturition, neither the serum nonesterifled fatty acids nor the hepatic
      triacylglycerol concentrations differed between experimental and control cows.
      After parturition, the values for these variables were greater in experimental
      cows than in control cows. Plasma 3-hydroxybutyrate increased sharply after
      parturition in the experimental group. In liver, the activity of acetyl-CoA
      carboxylase was already significantly lower in the experimental group before
      parturition. After parturition, the activities of acetyl-CoA carboxylase and
      fatty acid synthase dropped in the experimental group. The activity of 3-hydroxy
      acyl-CoA dehydrogenase in liver was less in experimental cows following
      parturition. Hepatic citrate synthase activity increased only in the control
      group after parturition. Unrestricted feed intake before parturition reduces de
      novo fatty acid synthesis as well as fatty acid oxidation after parturition. The
      reduction in fatty acid oxidation following parturition may contribute to
      postpartum accumulation of triacylglycerol in the livers of cows with
      unrestricted access to feed during the dry period.

PMID- 15202653
TI  - Production and blood parameters of Holstein cows treated prepartum with sodium
      monensin or propylene glycol.
AB  - Forty-five multiparous Holstein cows were assigned to one of 3 treatments in a
      randomized complete block design. The objective was to evaluate the effects of
      sodium monensin (M) and propylene glycol (PPG) during the prepartum period on
      performance and metabolic parameters during the late dry and first 9 wk
      postpartum for cows receiving M postpartum. Treatments were: control (C), M in a
      controlled-release capsule to deliver 335 +/- 33 mg/d for approximately 100 d,
      and 300 mL/d of PPG drenched orally. Treatments started at 35 and 21 d prior to
      the expected date of calving for cows receiving M and PPG, respectively. To
      ensure that all treatments would be restricted to the prepartum period, C and PPG
      cows received a M controlled-release capsule in the first 24 h after calving.
      Prepartum propylene glycol administration increased concentrations of glucose and
      insulin, and decreased beta-hydroxybutyrate and nonesterified fatty acids in
      plasma prepartum. Milk production was similarly affected by treatments. However,
      prepartum M treated cows tended to produce more 3.5% fat-corrected milk compared
      with control, but similar to PPG. Milk fat content and yield tended to be greater
      for cows that received M prepartum than for C cows, while PPG cows were similar
      to M and C. Prepartum administration of M decreased milk protein content, but no
      effect was observed on protein yield.

PMID- 15202655
TI  - Random regression test-day models with residuals following a Student's-t
      distribution.
AB  - First-lactation milk yield test-day records of Canadian Holsteins were analyzed
      by single-trait random regression test-day models that assumed normal or
      Student's-t distribution for residuals. Objectives were to test the performance
      of the robust statistical models that use heavy-tailed distributions for the
      residual effect. Models fitted were: Gaussian, Student's-t, and Student's-t with
      fixed number of degrees of freedom (equal to 5, 15, 30, 100 or 1000) for the t
      distribution. Bayesian methods with Gibbs sampling were used to make inferences
      about overall model plausibility through Bayes factors, posterior means for
      covariance components, estimated breeding values for regression coefficients,
      solutions for permanent environmental regressions, and residuals of the models.
      Bayes factors favored Student's-t model with the posterior mean of degrees of
      freedom equal to 2.4 over all other models, indicating very strong departure from
      normality. Number of outliers in Student's-t model was reduced by 35% in
      comparison with the Gaussian model. Differences in covariance components for
      regression coefficients between models were small, and rankings of animals based
      on additive genetic merit for the first two regression coefficients (total yield
      and persistency) were similar. Results from the Gaussian and Student's-t models
      with fixed degrees of freedom become more alike (smaller departures from
      normality for Student's-t models) with increasing number of degrees of freedom
      for the t-distributions. For any pair of Student's-t models, the one with the
      smaller number of degrees of freedom for the t-distribution was shown to be
      superior. Similarly, number of outliers increased with increasing degrees of
      freedom for the t distribution.

PMID- 15202654
TI  - Fine mapping of milk production QTL on BTA6 by combined linkage and linkage
      disequilibrium analysis.
AB  - Combined linkage and linkage disequilibrium analysis were used to refine the
      position of a previously detected QTL affecting milk production traits on bovine
      chromosome 6. Through a series of single- and multitrait and single- and
      multipoint QTL analyses, the QTL could be positioned to a 7.5-cM interval
      surrounded by the markers BMS2508 and FBN12. The most significant results were
      found for fat percentage and protein percentage. This effect seemed to be caused
      by a QTL allele embedded in one specific marker haplotype that caused a reduction
      in fat and protein yields and a concomitant increase of milk yield, thus
      resulting in a marked reduction of fat and protein percentages.

PMID- 15202656
TI  - Genetic parameters for stillbirth in Danish Holstein cows using a Bayesian
      threshold model.
AB  - The objective of this study was to make an inference about the direct and
      maternal genetic variation of stillbirth for first-calving Holstein cows and to
      estimate the effect of breed and heterosis for original Danish black and white
      and Holstein-Friesian. A Bayesian threshold model, which included correlated
      genetic effects of sires and maternal grandsires was used. Marginal posterior
      distributions of effects were obtained using Gibbs sampling. Point estimates were
      compared with results from a linear model using REML. Data with and without twins
      were analyzed and models with and without effects of breed and heterosis were
      fitted, but estimates of genetic parameters were almost identical. In all the
      analyses with threshold models, the marginal posterior mean (and standard
      deviation) was 0.10 (0.014) for the direct heritability, 0.13 (0.015) for the
      maternal heritability, and 0.05 (0.10) for the genetic correlation between direct
      and maternal effects. The stillbirth rate tended to increase with a higher
      proportion of Holstein-Friesian in the calf and in the dam, but no effects of
      breed and heterosis were significant. Joint sampling of all location parameters
      was found superior to univariate sampling in terms of much better mixing
      properties of the fixed effects. Based on the results showing genetic variation
      for stillbirth at first calving, both the direct and the maternal effect could be
      included in the breeding program.

PMID- 15202657
TI  - Heritability and correlations for body condition score and dairy form within and
      across lactation and age.
AB  - The objectives of the current study were to investigate the relationship between
      body condition score (BCS) and dairy form and changes in genetic parameters for
      BCS and dairy form within and across lactations and age. Body condition score and
      dairy form were obtained from the Holstein Association USA, Inc. Records were
      edited to include those cows classified between 24 and 60 mo of age and between 0
      and 335 d in milk (DIM). A minimum of 20 daughters per sire and 15 cows per herd
      classification visit were required. The dataset consisted of 135,178 records from
      119,215 cows. Repeatability, multiple trait, and random regression models were
      used to analyze the data. All models included fixed effects for herd
      classification visit, age within lactations 1, 2, and 3 or higher, and 5th-order
      polynomials for DIM. Random effects included sire and permanent environment for
      all models. Random regression models included age at classification nested within
      sire or DIM and lactation number nested within sire. Genetic variance for both
      BCS and dairy form was lowest in early lactation and highest in midlactation.
      Genetic correlations within and across lactations were high. The genetic
      correlation between DIM 0 in lactation 1 and DIM 305 in lactation 3 was estimated
      to be 0.77 for BCS and 0.60 for dairy form. The genetic correlation estimate
      between 30 mo of age at classification and 50 mo of age at classification was
      0.94 for both dairy form and BCS. The repeatability models appeared to generate
      accurate evaluations for BCS or dairy form at all ages and stages of lactation.

PMID- 15202658
TI  - Performance of Holstein clones in the United States.
AB  - Phenotypic and genetic performance of US Holstein clones from embryo splitting
      (ETS) and nuclear transfer (ETN) was documented for yield and fitness traits.
      Holstein Association USA has registered 2319 ETS and 215 ETN clones. The number
      of male clones has decreased. Animals selected for cloning were slightly superior
      genetically to population mean for yield traits. For females, mean superiority of
      pedigree merit of ETS clones was 186 kg for milk, 9 kg for fat, and 7 kg for
      protein compared with the population for the same birth year; for ETN clones,
      superiority to the population was 165, 10, and 8 kg. Advantage in pedigree merit
      for male clones generally was slightly greater. The small pedigree advantage for
      female clones of <1 standard deviation above breed mean indicates that selection
      of animals to clone was not based primarily on yield. Yield deviations were lower
      for ETS clones than for their full siblings, which indicates a possible impact of
      the technology on performance. Yields were lower for ETN clones than for their
      noncloned full siblings, but differences were small and based on small numbers of
      clones. Milk composition for cloned cows was not different from that for the
      population. Estimated genetic merit based on daughter yield was more similar for
      male clone pairs with apparent identical genotype than for clone pairs from the
      same biotechnology but nonidentical as confirmed by blood typing. For ETS clones
      with confirmed identical genotypes, identical genetic merit should be assigned.

PMID- 15202659
TI  - Measurement of gas holes and mechanical openness in cheese by image analysis.
AB  - A method to measure the amount of the surface area of cheese slices occupied by
      gas holes was developed to reflect the relative gas production among different
      cheeses. A digital camera mounted on a copy stand with lighting was used to make
      digital images of each slice of cheese. A commercial digital image analysis
      software program was used and an algorithm was written to measure the area of the
      image of the cheese slice occupied by holes. The image was cropped and scanned to
      determine which color channel produced the best image contrast. The MATLAB
      program allowed the user to eliminate mechanical openness or false holes and then
      to scan the image to produce a percent distribution of pixels in the image as a
      function of pixel intensity. The user then determined a threshold value to
      differentiate pixels that were in holes from those representing areas with no
      holes. The percentage of the total surface area occupied by holes was calculated.
      The coefficient of variation of the method ranged from 2.43% with gas holes of
      about 1% of the surface of the cheese slice to a coefficient of variation of
      0.92% with gas holes of about 6.8% of the surface area of the cheese slice.
      Examples of applications of this method are given for Emmental, Ragusano, and
      Cheddar cheeses. The method can be used as a tool in research studies to
      correlate the amount of gas production with manufacturing conditions or as a
      quality control tool in cheese manufacturing.

PMID- 15202660
TI  - Minimizing variations in functionality of whey protein concentrates from
      different sources.
AB  - Enhancement in processing technology has improved the nutritional and functional
      properties of whey protein concentrates by increasing the content and quality of
      the protein, leading to their increased use in different food products. The
      extent of heat treatment affects the quality of the whey protein concentrate, and
      wide variation in product quality exists due to the various means of manufacture
      and from the whey product history from farm to factory. The study was carried out
      with 6 commercial whey protein concentrates with 80% protein (WPC80) to determine
      variations in physical properties, particle size and density, and functional
      properties--solubility, gel strength, foam volume, and stability. Significant
      differences were observed among all the products for every property compared.
      Particulate size was the most important determinant of functional
      characteristics. Larger particulate WPC80 had significantly higher fat content
      and were less soluble with poor foam stability; but narrowing the particle size
      distribution through sieving, minimized variations. We determined that sieving
      all products within the particle size distribution range of 100 to 150 microns
      minimized variation in physical composition, making functionality uniform. WPC80
      from different manufacturers can be made to perform uniformly within a narrow
      functionality range by reducing the particle size distribution through sieving.

PMID- 15202661
TI  - Moisture content, thickness, and lesions of sole horn associated with thin soles
      in dairy cattle.
AB  - Thin soles and resulting lameness are often associated with increased culling
      rates in large dairy operations. The moisture content of the sole horn may cause
      the horn to be softer, thus predisposing it to an increased rate of wear. For
      that reason, the first objective of this study was to determine the moisture
      content of the sole horn of thin-soled cows. The second objective was to document
      physical changes of the claw associated with thin soles. Twenty-six adult
      Holstein cows showing signs of thin soles, and 16 normal cows were used in the
      study. Selection criteria for thin-soled cows included a dorsal wall length of
      less than 7.5 cm and the following clinical signs: painful gait, arched back, and
      specific leg lameness. Sixteen normal adult cows with dorsal wall length in
      excess of 7.5 cm were randomly selected. For thin-soled cows, the moisture
      contents of sole horn were 37.1 +/- 0.7% for front claws and 40.5 +/- 0.7% for
      rear claws. These values were significantly different from each other. Moisture
      contents of sole horn from normal cows were 31.08 +/- 0.93% for front claws and
      33.1 +/- 0.9% for rear claws, which were significantly different from each other
      and different from thin-soled cows. Rear claws had higher moisture contents than
      front claws. Mean sole horn thickness was 4.23 +/- 0.18 mm for the rear lateral
      claws and 5.15 +/- 0.18 mm for the rear medial claws. The average dorsal wall
      lengths were 66.8 +/- 3.94 mm for rear lateral claws and 69.1 +/- 7.25 mm for
      rear medial claws. Thirty percent of rear feet with thin soles had pathological
      claw horn lesions including sole/white line separation (72%) and sole ulcers
      (28%). Of the affected claws, 13% had more than one lesion. Seventy-seven percent
      of claw lesions occurred in the lateral claw.

PMID- 15202662
TI  - Designing the automatic milking farm in a hot climate.
AB  - A mathematical simulation model was used to assist 5 farmers in developing design
      criteria for inclusion of robotic milking systems in each farm situation. The
      barn layout influences arrivals of cows to the milking robot as well as other cow
      traffic and must be carefully planned. Each farmer had individual objectives and
      consequently unique design criteria that determined the optimal solution.
      Planning factors addressed by simulations on these farms included: 1) optimal cow
      cooling locations; 2) optimal facility allocation in expanding dairies; 3)
      concentrate feeder locations and feeding management; 4) number of feeders--based
      on expected rations; 5) use of a robot in an open cowshed without free stalls; 6)
      number of robots needed, currently and in the future; 7) eight robots working in
      harmony; 8) robot locations that allow for expansion; 9) floor space needed in
      each barn section including maternity and veterinary treatment areas; 10)
      location of bottlenecks that limit efficiency or expansion; and 11) cow traffic
      routine as affected by management practices, feed allocation, and farm layout.
      The simulation allowed farmers to receive a course in managing a "virtual robotic
      milking farm" before installation of the barn. Therefore, each could be more
      confident that his future barn would work properly under his unique local
      conditions and management practices. One farm checked 2 yr after construction
      achieved an average daily robot utilization of 84%, nearly matching the 85%
      projected before the barn was built. Important variables considered in the
      simulations were facility allocation, cow space needed in each farm area, robot
      utilization, number of cows, milk yield, milk flow rate, feeding method and
      timing, robot location and orientation, and farm physical layout.

PMID- 15202663
TI  - Effect of topical angiotensin II on prelaminated flaps in rats and evaluation of
      angiogenesis with an immunohistochemical marker.
AB  - The effects of a single topical dose of angiotensin II (AII) on prelamination of
      flaps were investigated in rats using an immunohistochemical marker. Ninety rats
      were randomly divided into three groups (n = 30 in each). The control group were
      given nothing; the vehicle group were given only carboxymethyl cellulose, and the
      treatment group were given topical AII with carboxymethyl cellulose between the
      flap and the skin graft. According to the day of evaluation of vascularisation,
      each group was randomly divided into three sub-groups on days 4, 7, and 14 (n =
      10 in each). Paraffin sections of the tissues were cut at the flap-graft
      interface and stained immunohistochemically with factor VIII-related antigen
      (FVIIIRAg). Capillaries and venules that stained were counted. The number of
      vessels in the groups on day 4 were similar, but by day 7 the number of vessels
      was significantly greater in the treatment group than the other two. The number
      of vessels in the treatment group on day 14 was greater than in the other two
      groups, but not significantly so. We conclude that a single topical dose of AII
      increases the vascularisation at the flap and skin graft interface by
      angiogenesis.

PMID- 15202664
TI  - Zygoma fixture in the management of advanced atrophy of the maxilla: technique
      and long-term results.
AB  - Despite refinements in surgical technique, including bone grafting and
      sophisticated prosthetic reconstructions, there are limitations to what can be
      achieved with bone-anchored fixed prostheses in patients with advanced atrophy of
      the maxillae. A new approach was suggested by a long-term study on onlay bone
      grafting and simultaneous placement of a fixture based on a new design: the
      zygoma fixture, and the aim of this study was to assess its potential. Twenty
      eight consecutive patients with severely resorbed edentulous maxillae were
      included, 13 of whom had previously had multiple fixture surgery in the jawbone
      that had failed. A total of 52 zygoma fixtures and 106 conventional fixtures were
      installed. Bone grafting was deemed necessary in 17 patients. All patients have
      been followed for at least five years, and nine for up to 10 years. All patients
      were followed up with clinical and radiographic examinations, and in some cases
      rhinoscopy and sinoscopy as well. Three zygoma fixtures failed; two at the time
      of connection of the abutment and the third after six years. Of the conventional
      fixtures placed at the time of the zygoma fixture, 29 (27%) were lost. The
      overall prosthetic rehabilitation rate was 96% after at least five years of
      function. There were no signs of inflammatory reaction in the surrounding antral
      mucosa. Four patients with recurrent sinusitis recovered after inferior meatal
      antrostomy. To conclude, the zygoma fixture seems to be a valuable addition to
      our repertoire in the management of the compromised maxilla.

PMID- 15202665
TI  - Sinuscopy in patients with titanium implants in the nose and sinuses.
AB  - Foreign bodies in the nose and sinuses can cause chronic infections. Long
      titanium fixtures through the maxilla to the zygomatic bone were followed up with
      a sinuscope in 14 patients after more than one year. There were no signs of
      infection or inflammation in the mucosa around the fixtures.

PMID- 15202666
TI  - Partially de-epithelialised and buried V-Y advancement flap for reconstruction of
      sacrococcygeal and ischial defects.
AB  - Defects in the sacrococcygeal and ischial soft tissues can be treated with
      gluteus maximus and posterior thigh V-Y advancement flaps. However, late
      complications include recurrence and dehiscence of the suture line. Increasing
      the amount of the soft tissues over the bony prominences and multilayered closure
      may have an advantage for long-term durability. We modified the V-Y advancement
      technique by de-epithelialising the medial parts of the flap and burying them
      under the opposing edge of the wound or the flap. Sixteen patients with various
      defects of the sacrococcygeal and ischial soft tissues were operated on using
      this technique. All the flaps healed well with no partial or complete loss of the
      flap. Three patients developed complications. The main advantage of our technique
      is the use of healthy tissues to obliterate the dead spaces under the edges of
      the wound or the opposing flap. In this way, not only the defect in the skin but
      the defect in the subcutaneous tissue, with its iceberg tip at the surface, is
      treated effectively. To have an additional layer of tissue between the bone and
      the superficial tissues provides an extra cushion of soft tissue and avoids
      putting the suture line directly over the bony prominences. We used this
      modification safely for both unilateral and bilateral flaps. It could also be
      used successfully in other parts of the body.

PMID- 15202667
TI  - Advancement of the frontalis muscle for ptosis of the brow associated with
      essential blepharospasm.
AB  - We evaluated our results of advancement of the frontalis muscle to correct brow
      ptosis associated with blepharospasm in five patients who had difficulty opening
      their eyelids as a result of ptosis even after injections of botulinum toxin. The
      frontalis muscle was retracted inferiorly and connected directly to the skin of
      the eyebrow. Postoperatively the level of the eyebrow was raised above the
      superior orbital rim in all cases during the observation period (4 to 15 months).
      Although the operation did not improve muscle spasms, it successfully shortened
      the duration of involuntary closure of the eyelid. The only postoperative
      complication was lymphoedema of the eyelids. Results of postoperative injection
      of botulinum toxin were satisfactory. Advancement of the frontalis muscle
      corrects brow ptosis without major complications, and is complementary to
      injection of botulinum toxin.

PMID- 15202668
TI  - Early use of artificial sensibility in hand transplantation.
AB  - Hands were transplanted from brain-dead donors for the treatment of two male
      unilateral amputees, aged 35 years and 32 years, involved in the Italian Hand
      Transplantation Programme. Each had lost his right dominant hand, in a farming
      accident and an explosion, respectively. In one case artificial sensibility was
      applied postoperatively using a Sensor Glove that transformed vibrotactile
      stimuli induced by touch, to stereophonic vibroacoustic stimuli perceived through
      earphones. The principle is based on the brain's capacity for multimodal
      plasticity, implying that deprivation of one sense (somatosensory) can be
      compensated for by another sense (auditory). Functional magnetic resonance images
      (fMRI) taken at regular intervals showed that cortical remodelling of the
      transplanted hand within the sensory-motor maps occurred early in the patient who
      used the artificial sensibility regimen compared with the one who did not. We
      conclude that postoperative use of a device using hearing as a substitution for
      sensation in hand transplantation may have considerable potential value for
      speeding up cortical integration of a transplanted hand.

PMID- 15202669
TI  - Radial forearm flaps for reconstruction in hand surgery.
AB  - Thirty-seven patients were treated using distally-based island radial forearm
      flaps. There were 31 men and six women. Reconstructed sites involved the dorsum
      of the hand (n = 17), the thumb (n = 11), the fingers (n = 5), the first web (n =
      3), and the palm (n = 1). Sensory flaps were transferred in 15 cases,
      osteocutaneous flaps in six, and tendocutaneous flaps in eight. All the flaps
      survived. There were five donor-site complications, but no functional
      disturbances. Three patients had symptoms of cold intolerance. There were no
      radial fractures. In the six cases with osteocutaneous flaps, a mean of 2.6
      months (range 2-3) was needed to obtain bony union. Among the eight cases with
      tendocutaneous flaps, postoperative tenolysis was required in two cases, and
      finally seven achieved a satisfactory outcome. The mean moving 2-point
      discrimination of the sensory flaps was 13 mm.

PMID- 15202670
TI  - Restoration of opposition of the fifth finger of the hand.
AB  - I describe a technique for surgical restoration of opposition of the fifth
      finger, which includes transfer of the extensor digiti quinti tendon between the
      fifth and fourth metacarpals towards the dorsoulnar aspect of the neck of the
      fifth metacarpal, where the transferred tendon is fixed to the opponens digiti
      quinti tendon. I have operated on 11 patients with paralysis of all the
      hypothenar muscles, all of whom were followed up from one to three years
      postoperatively. Ten were successful.

PMID- 15202671
TI  - Simple repair of complex rectovaginal fistulas.
AB  - We describe a successful anterior rectal wall advancement flap in two patients
      with complex rectovaginal fistulas. Our technique used a wide transversely
      incised flap, which ensures adequate blood supply, facilitates wide dissection,
      allows approximation of the anterior rectal wall without tension, and secures
      closure of the orifice of the fistula.

PMID- 15202672
TI  - Bilateral congenital hypoplastic pulps of the little finger: reconstruction with
      a neurovascular step-advancement flap.
AB  - We describe a case of bilateral congenital hypoplastic finger pulps of the little
      finger in a 6-year-old girl in whom reconstruction with a neurovascular step
      advancement flap was used to restore soft tissue padding of the pulps.

PMID- 15202673
TI  - [Gastric preneoplastic changes].
AB  - Gastric cancer (GC) is the second most common cause of cancer related death
      worldwide. The 5-year relative survival rate ranges from 10 to 20% of cases.
      Therefore, it is necessary to diagnose gastric non invasive neoplasia (formerly
      dysplasia). Correa suggested more than 20 years ago that there was a histological
      cascade leading to GC: chronic active gastritis --> atrophy (AG) --> achlorydria
      with nitrocompounds increase --> intestinal metaplasia (IM) type I --> IM type
      III --> low grade dysplasia (LGD) --> high grade dysplasia (HGD) --> GC. The
      discovery of Helicobacter pylori infection has imposed a revision of the various
      pathogenetic stages: 1) GC may arise in the same context as IM and dysplasia, but
      without any documentable precursor. GC can develop in a context of
      normochloridria; 2) there are not sufficient data to support endoscopic
      surveillance for patients with AG; 3) there are doubts about the real necessity
      to operate histologically a subdivision of IM in subtypes: probably it is more
      important the extent of IM; 4) dysplasia is the only true histological marker of
      CG. In fact, LGD is associate or progressed to GC in the 9% of cases, HGD is
      associated or progressed to GC in the 74% of cases. It emerges the real oncologic
      risk of dysplasia. Such data are confirmed by immunohistochemical study of the
      dysplastic lesions. Therefore, an appropriate follow-up of non invasive neoplasia
      increases the likelihood of CG being detected in its potentially curable stage.

PMID- 15202674
TI  - [Job satisfaction, depressive and anxiety disorders among hospital personnel at
      IDI Sanita, Rome].
AB  - Job satisfaction and psychological well-being of healthcare personnel and staff
      represent relevant issues for continuous quality improvement in health care
      organisations. The aim of this study was to evaluate job satisfaction, as well as
      the frequency of psychiatric minor disorders, among the personnel working at IDI
      Sanita, Rome (IDI-IRCCS and S. Carlo Hospital). An anonymous questionnaire was
      distributed, with the following sections:1) a validated set of items regarding
      various aspects of job satisfaction; 2) a 0 to 10 analogue scale to express a
      total satisfaction score; 3) the GHQ-12 to evaluate psychiatric symptoms.
      Relationships with hierarchical authorities, development possibilities, and role
      recognition were identified as the main determinants of being satisfied. It was
      observed a 6.2 mean satisfaction score. About 1/3 of respondents showed a high
      likelihood to develop symptoms of depression and anxiety. A high level of job
      satisfaction appeared as a protective factor for that kind of symptoms. Analysing
      job satisfaction levels and psychological symptoms among hospital personnel
      allows to identify the most important problems to solve. These will be the main
      targets of intervention.

PMID- 15202675
TI  - [Allergic rhinitis frequently impairs bronchial function].
AB  - There is a clear connection between upper and lower airways. Allergic rhinitis
      may affect asthma by worsening natural history. Airways share similarities and
      differences such as: epidemiology, anatomy, physiology, immunopathology, and
      treatment. In asthmatic patients non-responder to conventional treatment,
      therapeutic success may be achieved only by recognizing and treating co-existent
      upper airways disorders. New therapeutical strategies should be based on a
      rational (i.e. considering the pathophysiology of the single patient) use of:
      antihistamines, antileukotrienes, and corticosteroids.

PMID- 15202676
TI  - [Transabdominal US-guided FNAB in the diagnosis of gastric GIST].
AB  - Immunohistochemical staining for CD 117 and morphologic features like mitotic
      activity are crucial respectively in diagnosing GI stromal tumours and in
      defining the risk of malignant behaviour in GISTs. In the case reported both
      requirements have been fulfilled through specimens obtained by transabdominal US
      guided FNAB of a gastric submucosal tumour.

PMID- 15202677
TI  - [Description of a clonal T cell population in peripheral blood and bone marrow
      from a patient with B lymphocytic lymphoma].
AB  - A clonal T cell population in peripheral blood of patients with multiple myeloma
      and chronic lymphocytic leukemia has recently been observed. We describe a 73
      years old woman with B cell lymphoma who presented a clonal T cell population in
      peripheral blood and bone marrow.

PMID- 15202678
TI  - [Polyneuritis cranialis HHV-6 infection associated].
AB  - Human herpesvirus 6 (HHV-6) has been shown to be a common cause of acute febrile
      disease in young children, including exanthema subitum. HHV-6 has also been
      associated with a number of neurologic disorders including encephalitis and the
      virus has been postulated to play a role in acquired immunodeficiency syndrome,
      multiple sclerosis and chronic fatigue syndrome. The disorder of multiple cranial
      nerve palsies without spinal cord involvement is referred to as polyneuritis
      cranialis and is rare. The Authors describe a case of polyneuritis cranialis in a
      52-year old woman treated with ganciclovir and only complete eradication of the
      virus.

PMID- 15202679
TI  - [Hemophilic arthropathy].
AB  - Hemarthrosis is the most frequent clinical manifestation of severe hemophilia.
      Recurrent hemarthroses in a joint lead to the development of anatomical changes
      which result, through an intermediate stage called chronic synovitis, in
      degenerative arthritis, an extremely disabling disease. In this review, we
      briefly report the main physio-pathologic, clinic and therapeutic characteristics
      of the hemophilic arthropathy.

PMID- 15202680
TI  - [Lipodystrophy and lipid metabolism alterations in HIV-infected patients
      receiving highly active antiretroviral therapy (HAART)].
AB  - A wide range of morphologic alterations and lipid metabolism abnormalities have
      been recently described in HIV-infected patients receiving a protease inhibitor
      based highly active antiretroviral therapy. The hyperlipidaemia may involve up to
      70-80% of HIV-positive subjects treated with a protease inhibitor-containing
      regimen, and it is frequently (but not always) associated with the fat
      redistribution syndrome or lipodystrophy. The potential clinico-pathological
      consequences of HIV-associated hyperlipidaemia are not completely known, but
      several anecdotal observations reported an increased risk of prematury coronary
      artery diseases in young HIV-positive individuals receiving protease inhibitors,
      besides peripheral atherosclerosis and acute pancreatitis. A hypolipidaemic diet
      and regular physical exercise may act favourably on dyslipidaemia, but
      pharmacological therapy becomes necessary when hyperlipidaemia is severe or
      pesists for a long time. The choice of hypolipidaemic drugs is problematic
      because of potential pharmacological interactions with antiretroviral compounds
      and other antimicrobial agents, associated with an increased risk of toxicity and
      intolerance.

PMID- 15202681
TI  - [Noninvasive mechanical ventilation in acute respiratory failure].
AB  - Mechanical ventilation is the essential treatment for acute respiratory failure.
      The methods used differ greatly depending on whether one chooses invasive or
      noninvasive. Noninvasive ventilation avoids orotracheal intubation, facilitates
      weaning and, if negative pressure ventilation is integrated with positive
      pressure ventilation, the majority of patients will not need intubated. The ideal
      setting for mechanical ventilation, where possible, is the Respiratory Intensive
      Care Unit.

PMID- 15202682
TI  - Spatial navigation and hippocampal place cell firing: the problem of goal
      encoding.
AB  - Place cells are hippocampal neurons whose discharge is strongly related to a
      rat's location in the environment. The existence of such cells, combined with the
      reliable impairments seen in spatial tasks after hippocampal damage, has led to
      the proposal that place cells form part of an integrated neural system dedicated
      to spatial navigation. This hypothesis is supported by the strong relationships
      between place cell activity and spatial problem solving, which indicate that the
      place cell representation must be both functional and in register with the
      surroundings for the animal to perform correctly in spatial tasks. The place cell
      system nevertheless requires other essential elements to be competent, such as a
      component that specifies the overall goal of the animal and computes the path
      required to take the rat from its current location to the goal. Here, we propose
      a model of the neural network responsible for spatial navigation that includes
      goal coding and path selection. In this model, the hippocampal formation allows
      for place recognition, and stores the set of places that can be accessed from
      each position in the environment. The prefrontal cortex is responsible for
      encoding goal location and for route planning. The nucleus accumbens translates
      paths in neural space into appropriate locomotor activity that moves the animal
      towards the goal in real space. The complete model assumes that the hippocampal
      output to nucleus accumbens and prefrontal cortex provides information for
      generating solutions to spatial problems. In support of this model, we finally
      present preliminary evidence that the goal representation necessary for path
      planning might be encoded in the prelimbic/infralimbic region of the medial
      prefrontal cortex.

PMID- 15202683
TI  - Corticosteroids, depression and the role of serotonin.
AB  - Patients frequently use medications simultaneously for different complaints,
      without being aware of the interactions these products may have. An example of
      this is the simultaneous use of corticosteroids and medications for depression,
      defiant or aggressive behaviour. Research has also indicated that corticosteroids
      lower serotonin levels. However, lowered serotonin levels may result in
      depression, aggression and other psychological conditions. These secondary
      complaints, caused by the corticosteroids and other products that lower serotonin
      levels, may then be treated with selective serotonin reuptake inhibitors (SSRIs)
      or psycho-stimulants (that are known to indirectly increase serotonin levels).
      The current research takes a look at lowered serotonin levels when using
      corticosteroids, as well as the interactions with SSRIs and psycho-stimulants.
      Furthermore, evidence is presented to prove the hypothesis that some individuals
      with asthma (e.g. children using systemic corticosteroids that lower serotonin
      levels) might present with symptoms of depression, attention deficit
      hyperactivity disorder (ADHD), oppositional defiant disorder and even conduct
      disorder; and that treating these secondary complaints with SSRIs and psycho
      stimulants will result in the upregulating of serotonin levels, and that, in
      turn, will trigger asthma.

PMID- 15202684
TI  - Local effects of BDNF on dendritic growth.
AB  - The development of dendrites is a crucial step in the formation of cortical
      circuitry. The morphogen brain-derived neurotrophic factor (BDNF) may mediate the
      effects of activity on dendritic morphology since its expression and release are
      thought to be activity-dependent. Using two-photon microscopy, the autocrine and
      paracrine effects of BDNF on dendritic morphology were assessed. Overexpression
      of BDNF profoundly altered the form and stability of basal dendritic arbors via
      an autocrine mechanism. Paracrine BDNF also altered dendritic branching, though
      in a highly local fashion. BDNF is capable of acting as an intercellular
      morphogen, and could hypothetically shape dendritic arbors to best fit the
      developing structure and function of the pre-synaptic circuit.

PMID- 15202686
TI  - Subungual slivers may be treated conservatively.

PMID- 15202685
TI  - The contribution of small animal positron emission tomography to the
      neurosciences--a critical evaluation.
AB  - This article presents an overview of those animal studies which so far have been
      performed with dedicated small animal positron emission tomographs in the field
      of the neurosciences. In vivo investigations focus on energy metabolism,
      perfusion and receptor/transporter binding in rat models of reinforcement,
      learning and memory, traumatic brain injury, epilepsy, depression, cardiovascular
      diseases--such as ischemia and focal stroke--and neurodegenerative disorders such
      as Alzheimer's, Parkinson's and Huntington's disease. In the majority of studies,
      important novel aspects arise from the fact that the investigators made use of an
      option inherent to in vivo studies, namely to conduct longitudinal investigations
      on the same animals. Relevant findings pertain to the relationship of brain
      metabolism/perfusion and the cholinergic system, the regulation state of dopamine
      receptors upon cocaine administration and withdrawal, the regulation state of
      dopamine receptors and transporters in animal models of Parkinson's and
      Huntington's disease, and potential treatments of progressive dopaminergic
      depletion with adenoviral vectors, embryonic grafts, stem cells and nerve growth
      factors.

PMID- 15202687
TI  - Removing splinters should be a very simple procedure.

PMID- 15202688
TI  - Bupropion should be included in article on antidepressants.

PMID- 15202689
TI  - A joint clinical practice guideline for acute otitis media.

PMID- 15202690
TI  - The persistent value of the autopsy.

PMID- 15202691
TI  - Chiropractors are not a usual source of primary health care.
AB  - Chiropractors are the largest source of office-based care in the United States
      that does not involve a physician, but people do not view chiropractors as
      primary providers of health care or advice. Unlike the care given by primary care
      providers, the majority of care provided by chiropractors is limited to
      musculoskeletal problems.

PMID- 15202692
TI  - Counseling patients on mass media and health.

PMID- 15202693
TI  - Prevention and treatment of overweight in children and adolescents.
AB  - Overweight in childhood and adolescence is an important public health issue
      because of its rapidly increasing prevalence and associated adverse medical and
      social consequences. Recent studies have estimated that 15 percent of children in
      the United States are at risk for overweight, and an additional 15 percent are
      overweight. Important predictors of overweight include age, sex, race/ethnicity,
      and parental weight status. Generally, school-based prevention programs are not
      successful in reducing the prevalence of obesity. Treatment interventions include
      behavioral therapy, reduction in sedentary behavior, and nutrition and physical
      activity education. These interventions are moderately successful but may not be
      generalized to the primary care setting. Family physicians should focus on
      identifying at-risk and overweight children and adolescents at an early stage and
      educating families about the health consequences of being overweight.
      Interventions should be tailored to the patient and involve the entire family.

PMID- 15202694
TI  - Hemolytic anemia.
AB  - Hemolysis presents as acute or chronic anemia, reticulocytosis, or jaundice. The
      diagnosis is established by reticulocytosis, increased unconjugated bilirubin and
      lactate dehydrogenase, decreased haptoglobin, and peripheral blood smear
      findings. Premature destruction of erythrocytes occurs intravascularly or
      extravascularly. The etiologies of hemolysis often are categorized as acquired or
      hereditary. Common acquired causes of hemolytic anemia are autoimmunity,
      microangiopathy, and infection. Immune-mediated hemolysis, caused by
      antierythrocyte antibodies, can be secondary to malignancies, autoimmune
      disorders, drugs, and transfusion reactions. Microangiopathic hemolytic anemia
      occurs when the red cell membrane is damaged in circulation, leading to
      intravascular hemolysis and the appearance of schistocytes. Infectious agents
      such as malaria and babesiosis invade red blood cells. Disorders of red blood
      cell enzymes, membranes, and hemoglobin cause hereditary hemolytic anemias.
      Glucose-6-phosphate dehydrogenase deficiency leads to hemolysis in the presence
      of oxidative stress. Hereditary spherocytosis is characterized by spherocytes, a
      family history, and a negative direct antiglobulin test. Sickle cell anemia and
      thalassemia are hemoglobinopathies characterized by chronic hemolysis.

PMID- 15202695
TI  - Diastolic heart failure: challenges of diagnosis and treatment.
AB  - Diastolic heart failure, a major cause of morbidity and mortality, is defined as
      symptoms of heart failure in a patient with preserved left ventricular function.
      It is characterized by a stiff left ventricle with decreased compliance and
      impaired relaxation, which leads to increased end diastolic pressure. Signs and
      symptoms are similar to those of heart failure with systolic dysfunction. The
      diagnosis of diastolic heart failure is best made with Doppler echocardiography.
      Based on current knowledge, pharmacologic treatment of diastolic heart failure
      should focus on normalizing blood pressure, promoting regression of left
      ventricular hypertrophy, avoiding tachycardia, treating symptoms of congestion,
      and maintaining normal atrial contraction when possible. Diuretic therapy is the
      mainstay of treatment for preventing pulmonary congestion, while beta blockers
      appear to be useful in preventing tachycardia and thereby prolonging left
      ventricular diastolic filling time. Angiotensin-converting enzyme inhibitors and
      angiotensin-receptor blockers may be beneficial in patients with diastolic
      dysfunction, especially those with hypertension. Evidence from adequately powered
      randomized controlled trials, however, is not available yet. The outcomes of
      ongoing clinical trials may provide much-needed information to move from
      intuitive treatment to therapy based on evidence that matters: decreased
      morbidity and mortality and improved quality of life.

PMID- 15202696
TI  - Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine.
AB  - Club drugs are substances commonly used at nightclubs, music festivals, raves,
      and dance parties to enhance social intimacy and sensory stimulation. The most
      widely used club drugs are 3,4-methylenedioxymethamphetamine (MDMA), also known
      as ecstasy; gamma-hydroxybutyrate (GHB); flunitrazepam (Rohypnol); and ketamine
      (Ketalar). These drugs are popular because of their low cost and convenient
      distribution as small pills, powders, or liquids. Club drugs usually are taken
      orally and may be taken in combination with each other, with alcohol, or with
      other drugs. Club drugs often are adulterated or misrepresented. Any club drug
      overdose should therefore be suspected as polydrug use with the actual substance
      and dose unknown. Persons who have adverse reactions to these club drugs are
      likely to consult a family physician. Toxicologic screening generally is not
      available for club drugs. The primary management is supportive care, with
      symptomatic control of excess central nervous system stimulation or depression.
      There are no specific antidotes except for flunitrazepam, a benzodiazepine that
      responds to flumazenil. Special care must be taken for immediate control of
      hyperthermia, hypertension, rhabdomyolysis, and serotonin syndrome. Severe drug
      reactions can occur even with a small dose and may require critical care. Club
      drug over-dose usually resolves with full recovery within seven hours. Education
      of the patient and family is essential.

PMID- 15202697
TI  - Information from your family doctor. Club drugs--myths and risks.

PMID- 15202698
TI  - Sialorrhea: a management challenge.
AB  - Sialorrhea (drooling or excessive salivation) is a common problem in
      neurologically impaired children (i.e., those with mental retardation or cerebral
      palsy) and in adults who have Parkinson's disease or have had a stroke. It is
      most commonly caused by poor oral and facial muscle control. Contributing factors
      may include hypersecretion of saliva, dental malocclusion, postural problems, and
      an inability to recognize salivary spill. Sialorrhea causes a range of physical
      and psychosocial complications, including perioral chapping, dehydration, odor,
      and social stigmatization, that can be devastating for patients and their
      families. Treatment of sialorrhea is best managed by a clinical team that
      includes primary health care providers, speech pathologists, occupational
      therapists, dentists, orthodontists, neurologists, and otolaryngologists.
      Treatment options range from conservative (i.e., observation, postural changes,
      biofeedback) to more aggressive measures such as medication, radiation, and
      surgical therapy. Anticholinergic medications, such as glycopyrrolate and
      scopolamine, are effective in reducing drooling, but their use may be limited by
      side effects. The injection of botulinum toxin type A into the parotid and
      submandibular glands is safe and effective in controlling drooling, but the
      effects fade in several months, and repeat injections are necessary. Surgical
      intervention, including salivary gland excision, salivary duct ligation, and duct
      rerouting, provides the most effective and permanent treatment of significant
      sialorrhea and can greatly improve the quality of life of patients and their
      families or caregivers.

PMID- 15202699
TI  - Persistent pruritic papules.

PMID- 15202700
TI  - Information from your family doctor. Cuts, scrapes, and stitches.

PMID- 15202701
TI  - Information from your family doctor. Bike safety tips.

PMID- 15202702
TI  - Information from your family doctor. Dog bites: teaching your child to be safe.

PMID- 15202703
TI  - Information from your family doctor. Sunshine rules for children.

PMID- 15202704
TI  - AAP, AAFP release guideline on diagnosis and management of acute otitis media.

PMID- 15202705
TI  - Using medical interpreters.

PMID- 15202706
TI  - Chlorophyll and carotenoid degradation mediated by thylakoid-associated
      peroxidative activity in olives (Olea europaea) cv. hojiblanca.
AB  - A peroxidative activity was found in solubilized thylakoid membranes of olives
      (Olea europaea) cv. hojiblanca that catalyses degradation of chloroplast pigments
      in the presence of H2O2 and 2,4-dichlorophenol (DCP). The intermediate products
      of this degradation were analyzed using HPLC with diode array detection and the
      results indicated that 13(2)-OH-chlorophyll a and 13(2)-OH-chlorophyll b were the
      primary catabolites. The peroxidative activity assosiated with the thylakoid
      membranes affected, not only chlorophyll a and chlorophyll b, but also other
      accessory pigments in the photosynthetic process, such as the carotenoids.
      Quantitatively, the progressive decrease of the ratios Chl a/b and total Chls
      a+b/carotenoids indicated a more rapid disappearance of Chl a than of Chl b and a
      faster degradation of Chls a+b than of carotenoids.

PMID- 15202707
TI  - Manipulation of the onset of ectomycorrhiza formation by indole-3-acetic acid,
      activated charcoal or relative humidity in the association between oak
      microcuttings and Piloderma croceum: influence on plant development and
      photosynthesis.
AB  - A Petri dish system in which development of oak (Quercus robur L.) microcuttings
      is stimulated by the late stage ectomycorrhizal (EM) fungus Piloderma croceum J.
      Erikss. & Hjortst. in a long pre-symbiotic stage was optimised to allow
      synchronous, rhythmic plant growth. Addition of indole-3-acetic acid or activated
      charcoal to the medium caused an early and more intensive EM formation coupled
      with suppression of most developmental effects of P. croceum. Leaf area,
      chlorophyll fluorescence, and content were compared in inoculated and
      uninoculated plants grown at two relative humidity levels (45 and 95%) and under
      consideration of three possible answers to inoculation, that is, no or EM
      formation after the 1st or the 2nd shoot flush. The culture conditions for
      uninoculated plants were suboptimal, leading toward photochemical stress
      reflected by a non photochemical quenching (qE) increase and a reduced Chl
      content at the end of the assay. Prior to EM formation, inoculation itself
      enhanced the optimal (Fv/Fm) and effective (phiPSII) quantum yield in leaves of
      the 1st shoot flush under reduced relative humidity. It also fully protected the
      plants against stress during the complete assays. The results indicate that
      inoculated plants only form EM once they have acquired a sufficient development
      level and C-providing capacity. However, the fungus actively improves the
      development and photosynthesis of plants up to the pre-mycorrhizal stage, helping
      them to reach this capacity.

PMID- 15202708
TI  - Different classes of proteases are involved in the response to drought of
      Phaseolus vulgaris L. cultivars differing in sensitivity.
AB  - Protein breakdown and recycling, which depend on the levels of proteolytic
      enzymes, are an essential part of the plant response to environmental stress. In
      order to study changes in the activity of proteases in Phaseolus vulgaris L.
      subjected to water deficit, three cultivars of European origin that exhibit
      different degrees of sensitivity to drought were chosen on the basis of changes
      in water potential, psiw, water and protein contents of leaves during progressive
      water deficit, and loss of membrane integrity after osmotic stress. Twenty-day
      old plants were subjected to water deficit by withholding irrigation. Specific
      enzyme activities in leaf extracts were determined for plants under different
      degrees of drought stress using different substrates and protease inhibitors.
      Proteolytic activities were partially characterized by gel exclusion
      chromatography. Activities of two of the three identified serine proteinases
      changed under water deficit. The activity of the one with apparent molecular mass
      of approximately 65 kDa was observed to increase progressively with increasing
      withdrawal of water in the more sensitive cultivars, but to decrease in the more
      resistant cultivar. The same activity was elevated in senescent leaves. Under
      conditions of severe water deficit, the most sensitive cultivar exhibited a
      marked increase in the activity of two different aminopeptidases, while the more
      resistant cultivar showed a significant decrease in the activity of these
      aminopeptidases. These results point to complex and probably specific roles for
      different proteases in the plant response to drought.

PMID- 15202709
TI  - Defense potentials to NaCl in a mangrove, Bruguiera parviflora: differential
      changes of isoforms of some antioxidative enzymes.
AB  - In order to assess the role of the antioxidative defense system against salt
      treatment, the activities of some antioxidative enzymes and levels of
      antioxidants were monitored in a true mangrove, Bruguiera parviflora, subjected
      to varying levels of NaCl under hydroponic culture. In the leaves of B.
      parviflora, salt treatment preferentially enhanced the content of H2O2 as well as
      the activity of ascorbate peroxidase (APX), guaiacol peroxidase (GPX),
      glutathione reductase (GR), and superoxide dismutase (SOD), whereas it induced
      the decrease of total ascorbate and glutathione (GSH+GSSG) content as well as
      catalase (CAT) activity. Analysis of isoforms of antioxidative enzymes by native
      PAGE and activity staining revealed that leaves of B. parviflora had one isoform
      each of Mn-SOD and Cu/Zn-SOD and three isoforms of Fe-SOD. Expression of Mn-SOD
      and Fe-SOD-2 was preferentially elevated by NaCl. Similarly, out of the six
      isoforms of GPX, the GPX-1, 2, 3 and 6 were enhanced by salt treatment but the
      levels of GPX-4 and -5 changed minimally as compared to those of a control.
      Activity staining gel revealed only one prominent isoform of APX and two isoforms
      of GR (GR-1 and GR-2), all of these isoforms increased upon salt exposure. Four
      CAT-isoforms were identified, among which the prominent CAT-2 isoform level was
      maximally reduced, suggesting differential down regulation of CAT isoforms by
      NaCl. The concentrations of malondialdehyde (MDA), a product of lipid
      peroxidation, remained unchanged in leaves of the plant treated with different
      concentrations of NaCl. This suggests that plants are protected against activated
      oxygen species by the elevated levels of certain antioxidative enzymes, thus
      avoiding lipid peroxidation during salt exposure. The differential changes in the
      levels of the isoforms due to NaCl treatment may be useful as markers for
      recognizing salt tolerance in mangroves.

PMID- 15202710
TI  - Recovery of uptake and assimilation of nitrate in Scenedesmus sp. previously
      exposed to elevated levels of Cu2+ and Zn2+.
AB  - A study of the effects of elevated levels of Cu2+ and Zn2+ on NO3- uptake and
      nitrate reductase (NR) activity in Scenedesmus sp. was carried out. The two
      metals inhibited NR and NO3- uptake in a concentration-dependent manner, with the
      latter process being inhibited more strongly than the former. After withdrawal of
      metal stress, NR activity and NO3- uptake recovered in a metal ion concentration
      dependent manner. Dark pretreatment of the alga enhanced the toxic effects of the
      metal ions on NR activity and NO3- uptake. The recovery from metal stress was
      slower in the dark-pretreated cells in comparison to the light-pretreated cells.
      No recovery of NR and NO3- uptake occurred in the presence of the photosynthetic
      inhibitor, 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), suggesting that
      photosynthesis was required for the recovery from metal stress. Cycloheximide
      blocked the recovery of NR activity in metal-treated alga, suggesting that new
      enzyme synthesis was required for the recovery from metal stress.

PMID- 15202711
TI  - Contributions of soluble carbohydrates to the osmotic adjustment in the C4 grass
      Setaria sphacelata: a comparison between rapidly and slowly imposed water stress.
AB  - Photosynthetic carbohydrate content in Setaria sphacelata var. splendida under
      rapidly and slowly induced water deficit and its contribution to osmotic
      adjustment were studied. In short-term stress experiments, a decrease in the
      total content of sucrose (Su) and starch (St) was observed in leaf discs
      submitted to stress. An increase in the ratio between free hexoses and sucrose
      was found in stressed leaves, but no significant differences were found in the
      amount of free hexoses nor in the ratio between soluble and insoluble sugars. In
      long-term stress experiments, a higher amount of soluble sugars and a lower
      amount of starch were found in stressed leaves, when compared to the control. The
      ratios of free hexoses to sucrose and of soluble to insoluble sugars were also
      higher in stressed leaves. The contribution of the accumulation of soluble sugars
      to osmotic adjustment was absent in rapidly stressed leaves and was of minor
      importance in slowly stressed leaves.

PMID- 15202712
TI  - Marked changes in volume of mesophyll protoplasts of pea (Pisum sativum) on
      exposure to growth hormones.
AB  - The present study reports quick and significant changes induced by plant hormones
      in the volume of mesophyll protoplasts of pea (Pisum sativum). Four plant
      hormones: gibberellic acid (GA3), indole 3-acetic acid (IAA), abscisic acid
      (ABA)(+/-) and methyl jasmonate (MJ), caused marked changes in the volume of
      mesophyll protoplasts. GA3 and IAA increased the volume of the protoplasts (up to
      90%) whereas the ABA and MJ decreased (by about 40%) the volume. Aquaporins or
      water channels appear to play an important role in swelling/shrinkage of the
      protoplasts as indicated by the suppression of volume changes by HgCl2 and
      reversal by mercaptoethanol. The possible role of secondary messengers in volume
      changes induced by GA3 was investigated by using selected pharmacological
      reagents. The GA3 induced swelling was restricted by GDP-beta-S (G-protein
      antagonist), U73122 (phospholipase C inhibitor), and TFP (calmodulin antagonist),
      but was not affected by 1-butanol (phospholipase D inhibitor), GTP-gamma-S (G
      protein agonist), or verapamil (calcium channel blocker). The results suggest
      that the mesophyll protoplasts can be a simple and useful system for further
      studies on volume changes in plant tissues.

PMID- 15202713
TI  - Correlation of endogenous free polyamine levels with root nodule senescence in
      different genotypes in Vigna mungo L.
AB  - Endogenous free polyamines, nitrogenase (EC 1.1.8.6.1, acetylene reduction), and
      leghaemoglobin (pyridine-hemochrome assay) levels were compared among five
      genotypes of developing Vigna root nodules grown under field conditions.
      Nitrogenase activity and leghaemoglobin level attained a peak at the flowering
      stage and gradually declined thereafter. Individual and total polyamine also
      followed the same pattern. Ranking on the basis of legume yield and other
      morphometric attributes was PDU-2 > UH-28 > UH-82 > T-9 > Sardhomash. Except
      spermine, the levels of putrescine, spermidine, and total polyamine showed
      significant differences (p<0.05) amongst the genotypes, particularly from
      flowering to mid-pod development stage. Genotype, development stage, and their
      interaction between the two had significant (p<0.01) effects on individual as
      well as total polyamines. Moreover, significant high linear correlations were
      found between total free polyamine and putrescine with conventional nodule
      senescence marker like nitrogenase (R2 = 0.94 and R2 = 0.92, respectively).
      Putrescine had an overall positive correlation with high legume yield. The
      results strongly suggest a relationship between polyamine and nodule senescence.
      Endogenous free polyamine and putrescine may be considered as genotypic markers
      for nodule senescence in field grown V. mungo. It is suggested that the flowering
      stage is more suitable for selection.

PMID- 15202714
TI  - Respiratory acclimation in Arabidopsis thaliana leaves at low temperature.
AB  - Acclimation of 25 degrees C-grown Arabidopsis thaliana at 5 degrees C resulted in
      a marked increase of leaf respiration in darkness (Rd) measured at 5 degrees C.
      Rd was particularly high in leaves developed at 5 degrees C. Leaf respiration
      (non-photorespiratory intracellular decarboxylation) in the light (Rl) also
      increased during cold acclimation, but less so than did Rd. The ratio Rd/Pt (Pt -
      true photosynthesis) was higher in more acclimated or cold-developed leaves,
      while the ratio Rl/Pt remained unchanged. In cold-acclimated leaves, Rl did not
      correlate with 3-phosphoglycerate and pyruvate nor with hexose phosphate pools in
      the cytosol. Rl in A. thaliana leaves was probably not limited by the substrate
      during cold acclimation. Under the conditions tested, Rd was more sensitive to
      low temperature stress than Rl.

PMID- 15202715
TI  - Leaf and canopy photosynthetic characteristics of cotton (Gossypium hirsutum)
      under elevated CO2 concentration and UV-B radiation.
AB  - Increases in both atmospheric CO2 concentration ([CO2]) and ultraviolet-B (UV-B)
      radiation on the Earth's surface are features of current climate change patterns.
      An experiment was conducted in sunlit, controlled environment chambers known as
      Soil-Plant-Atmosphere-Research (SPAR) units to determine interactive effects of
      elevated [CO2] and UV-B radiation on leaf and canopy photosynthetic
      characteristics of cotton. Six treatments were comprised of two CO2 levels of 360
      (ambient) and 720 (elevated) microL L(-1) and three levels of 0 (control), 8, and
      16 kJ m(-2) d(-1) biologically effective UV-B radiation. Treatments were imposed
      for 66 days from crop emergence through three weeks after the first flower stage.
      Plants grown in elevated [CO2] had significantly greater leaf area, higher leaf
      and canopy net photosynthetic rates (PN), lower dark respiration rate (Rd), and
      lower light compensation point (LCP) than plants grown in ambient [CO2]. There
      was no difference in CO2 compensation point (gamma), maximum rate of Rubisco
      activity (Vcmax), or light-saturated rate of electron transport (Jmax) between
      ambient and elevated CO2 treatments. When plants were grown in 8 kJ m(-2) d(-1)
      UV-B radiation, most of the measured photosynthetic parameters did not differ
      from control plants. High UV-B (16 kJ) radiation, however, caused 47-50% smaller
      leaf area, 38-44% lower leaf PN, 72-74% lower Vcmax, and 61-66% lower Jmax
      compared to the control. There were no interactive effects of [CO2] and UV-B
      radiation on most of the photosynthetic parameters measured. From the results, it
      is concluded that decreased canopy photosynthesis due to enhanced UV-B radiation
      in cotton is associated with both smaller leaf area and lower leaf PN, and loss
      of Rubisco activity and electron transport are two major factors in UV-B
      inhibition of leaf PN.

PMID- 15202716
TI  - Copper-induced oxidative stress in the chlorophycean microalga Chlorella
      vulgaris: response of the antioxidant system.
AB  - A concentration dependent increase in lipid peroxidation, carotenoid content and
      activity of superoxide dismutase was observed in the green microalga Chlorella
      vulgaris following copper exposure. In contrast, activities of catalase,
      ascorbate peroxidase and glutathione reductase, and the cellular GSH, ascorbate
      and K+ pool depicted a reverse trend. However, a significant rise in
      intracellular proline content was also evident in copper supplemented cultures.
      Though this study depicted the malfunction of the major antioxidant system of C.
      vulgaris under copper stress the test organism was found to survive and grow even
      at 3.0 microg mL(-1) of Cu treatment (32% growth). Further study is needed to
      establish the role of proline in metal toxicity regulation.

PMID- 15202717
TI  - Dark chilling inhibition of photosynthesis and symbiotic nitrogen fixation in
      soybean during pod filling.
AB  - The growth stage of a soybean [Glycine max (L.) Merrill] plant may influence its
      physiological response to dark chilling. Opposed to vegetative development, the
      intense nutrient and energy requirements of the developing seeds during pod
      filling could cause additional chilling damage and decreased recovery capacity.
      Previously, we investigated dark chilling tolerance during vegetative development
      in two soybean genotypes, 'Maple Arrow' and 'Fiskeby V' and consistently found
      that photosynthesis and symbiotic nitrogen fixation (SNF) was less affected by
      dark chilling in 'Maple Arrow'. In this study we describe the dark chilling
      response of the same genotypes during pod filling. Our aim was to establish
      whether the potential selection criteria for dark chilling tolerance, identified
      during vegetative development, was equally sensitive during pod filling. The
      results indicate that photosynthesis is less affected by dark chilling in 'Maple
      Arrow' than in 'Fiskeby V', not only during vegetative development, but also
      during the critical reproductive stage of pod filling. 'Fiskeby V' also lacks the
      ability to restore normal photosynthetic capacity during an extended recovery
      treatment. The decrease of nodule ureide content indicates that SNF was inhibited
      to a similar extent in both genotypes. Nodule ureide content was reduced more
      than stem ureide content, suggesting that the former is a more sensitive
      indicator of chilling stress effects on SNF. The results indicate that certain
      photosynthetic and fluorescence parameters are sensitive indicators of dark
      chilling tolerance throughout plant development and should prove valuable in
      future breeding programmes aimed at increasing the chilling tolerance of soybean.

PMID- 15202718
TI  - Expression of streptavidin in tomato resulted in abnormal plant development that
      could be restored by biotin application.
AB  - Biotin is an essential cofactor for a variety of carboxylase and decarboxylase
      reactions and is involved in diverse metabolic pathways of all organisms. In the
      present study we tested the hypothesis that controlling biotin availability by
      the expression of Streptomyces avidinii streptavidin, would impede plant
      development. Transient expression of streptavidin fused to plant signal peptide,
      bacterial signal peptide or both, in tomato (Lycopersicon esculentum cv. VF36)
      plants resulted in various levels of tissue impairment, exhibited as lesion
      development on 1-week-old tomato seedlings. The least toxic construct was
      introduced to tomato (stable transformation) under the constitutive CaMV 35S
      promoter, and lesions appeared on stems, flower morphologies were modified and
      numbers and sizes of fruits were altered. Furthermore, tissue-specific expression
      of the streptavidin, by means of the beta-phaseolin or TobRB7 promoters, resulted
      in localised effects, i.e., impaired seed formation or seedless fruits,
      respectively, with no alteration in the morphology of the other plant organs.
      External application of biotin on streptavidin-expressing tomato plants prevented
      the degeneration symptoms and facilitated normal plant development. It can be
      concluded that expression of streptavidin in the plant cell can lead to local and
      temporal deficiencies in biotin availability, impairing developmental processes
      while biotin application restores plant growth cycle.

PMID- 15202719
TI  - Tobacco PR-2d promoter is induced in transgenic cucumber in response to biotic
      and abiotic stimuli.
AB  - The PR-2d promoter/uidA (GUS) gene construct was introduced into the cucumber
      (Cucumis sativus L.) genome and several transgenic lines were produced.
      Activation of the PR-2d promoter was investigated in these plants in response to
      inoculation with fungal pathogens and after salicylic acid (SA) or cold
      treatments. Treatment with exogenous SA increased GUS activity 2 to 11 fold over
      that of the control. Endogenous SA and its conjugate salicylic acid glucoside
      (SAG) rose in parallel after inoculation with the fungal pathogen
      Pseudoperonospora cubensis, with SAG becoming the predominant form. The free SA
      levels increased 15 fold above the basal level at 5 dpi and preceded the
      induction of the PR-2d promoter by five days, which occurred at 10 dpi with a 12
      fold increase over the control. Inoculation with another fungal pathogen,
      Erysiphe polyphage, increased GUS activity 4 to 44 fold over that of the control.
      During normal development of flowers in the cucumber, the PR-2d/uidA gene
      expressed in the floral organs was similar to that of the primary host. In
      addition, we present the first evidence that the PR-2d promoter was induced (624
      fold) under cold stress. We demonstrate that in the heterologous state the gene
      construct was expressed according to the signalling pattern of the native species
      and was stably transmitted to progeny over four generations.

PMID- 15202720
TI  - The T-helper1/T-helper2 paradigm: still valid for drug discovery but with some
      essential refinement.

PMID- 15202721
TI  - New strategies for the treatment of chronic rejection.
AB  - Chronic allograft rejection is a slow, progressive process characterized by
      interstitial fibrosis, luminal obliteration and declining organ function,
      eventually resulting in graft loss. While optimizing the immunosuppressive
      regimen has improved short-term allograft survival, chronic rejection remains a
      major cause of late graft loss. Although non-immunological mechanisms can
      contribute to chronic rejection, there is compelling evidence that major
      histocompatibility complex-driven processes play a dominant role in the
      development of the disease. While some immunosuppressive drugs currently in
      clinical use, such as mycophenolate mofetil and rapamycin, have favorable effects
      on the incidence of chronic graft failure, the most effective way to overcome
      chronic rejection may be to induce immunological tolerance.

PMID- 15202722
TI  - CCR1 antagonists for the treatment of autoimmune diseases.
AB  - Chemokines are 8- to 10-kDa proteins that regulate leukocyte infiltration into
      inflammatory sites. The therapeutic potential of inhibiting these proteins is
      supported by their increased expression in human diseases, numerous studies in
      animal models of disease and, in some cases, by human genetic association
      studies. These findings, combined with the ability of chemokines to interact with
      7-transmembrane G protein-coupled receptors, render them attractive drug
      discovery targets. This article reviews the evidence that supports a role for the
      chemokine receptor CCR1 in the pathogenesis of autoimmune diseases, progress made
      in identifying low molecular-weight antagonists and the current status of agents
      undergoing clinical evaluation.

PMID- 15202723
TI  - C5a receptor antagonists for the treatment of inflammation.
AB  - The anaphylatoxin C5a is a classic, potent inflammatory mediator, with biological
      activities that have been implicated in a variety of diseases. As a result of two
      decades of study, C5a receptor antagonists that prevent high-affinity binding of
      C5a to its receptor have been discovered, which show therapeutic effects in
      various inflammatory disease models. Moreover, the involvement of C5a in disease
      models has been demonstrated in various experiments using C5/C5a receptor
      deficient mice and anti-C5/C5a antibodies. It is therefore anticipated that these
      antagonists will have potential as novel anti-inflammatory therapeutics.

PMID- 15202724
TI  - Metalloprotease inhibitors as anti-inflammatory agents: an evolving target?
AB  - The metalloproteases (MMPs) are a family of enzymes that are important for tissue
      remodeling. These enzymes have been implicated in a number of pathologies,
      including cancer, arthritis, atherosclerosis and chronic obstructive pulmonary
      disease. Thus, inhibitors of MMPs may have utility in the therapy of inflammatory
      diseases, particularly in arthritis where current therapies do not halt the
      progression of the disease. Many compounds have been identified as inhibitors of
      MMPs, and some have progressed to the clinic. However, no compound developed as
      an MMP inhibitor has been licensed for clinical use thus far. This review
      discusses this therapeutic area and compares inhibitors of MMPs with other novel
      therapeutic approaches in the treatment of inflammatory disease. Inhibitors of
      MMPs may find utility in disorders not currently targeted, but where MMPs are
      involved in the pathology.

PMID- 15202725
TI  - Lupus-like autoimmunity caused by defects in T-cell signal transduction.
AB  - Systemic lupus erythematosus (SLE) is a prevalent, non-organ-specific autoimmune
      disease that is partially caused by genetic factors. Types of genetic factors
      that can contribute to lupus have been revealed by studies of naturally occurring
      and genetically engineered mutant mice which are susceptible to this disease.
      Notably, a number of mutant mice have been reported that point to defective T
      lymphocyte signal transduction as one potential cause of lupus. Deficient
      expression of adapter proteins, cell cycle control proteins, ubiquitin ligases
      and transcription factors, and impaired phosphatidylinositol 3-kinase (PI3
      kinase) and Ras signaling in T-cells, all promote lupus in mice. These findings
      have important implications for the causes and treatment of human SLE.

PMID- 15202726
TI  - Dissociated glucocorticoid receptor ligands.
AB  - Since their introduction, the extraordinary importance of glucocorticoids in the
      treatment of inflammatory and autoimmune disorders is undisputed, despite their
      known undesirable side effects. In the 1990s, major scientific progress was made,
      with the discovery that positive and negative regulation of gene expression via
      the glucocorticoid receptor are mediated by different mechanisms. This discovery
      led to the assumption that it may be possible to dissociate the therapeutic
      effects of glucocorticoids from their side effects by using ligands which
      specifically or preferentially address one of the two pathways. Several
      pharmaceutical companies are currently pursuing this goal.

PMID- 15202727
TI  - Targeting nitric oxide in the gastrointestinal tract.
AB  - This review discusses the contributions of the three nitric oxide (NO) synthase
      (NOS) isozymes neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS
      (iNOS) to the function and diseases of the gastrointestinal tract. Small
      (nanomolar) quantities of NO produced by calcium-dependent nNOS play a
      physiological role in peristalsis and sphincter function of the intestine.
      Decreased nNOS function can result in aperistalsis and obstructive sphincters. NO
      produced by eNOS dilates mucosal blood vessels and prevents leukocyte
      aggregation, and is therefore essential for the maintenance of mucosal blood
      flow. Absence of eNOS-derived NO results in an increased susceptibility of the
      gastrointestinal tract to injury. Selective NO delivery by gene therapy or NO
      donating compounds may offer new therapeutic options in motility disorders of the
      gut and the prevention of mucosal injury. The effects of large (micromolar)
      amounts of NO as produced by iNOS are less well understood. Large amounts of NO
      can increase gut permeability, induce apoptosis and stimulate intestinal
      secretion, while NO can also kill bacteria, block apoptosis and reduce
      inflammation by inhibiting activation of nuclear factor-kappaB (NFkappaB).
      Lumenal donation of NO could therefore block NFkappaB activation and be a
      treatment option in inflammatory conditions of the bowel.

PMID- 15202728
TI  - New nitric oxide-donating drugs for the treatment of airway diseases.
AB  - Nitric oxide (NO) is involved in many pathological and physiological processes in
      mammals, providing a possible biological basis for the use of NO replacement
      therapy in many conditions. A series of compounds have been synthesized in which
      an NO-releasing group has been linked to well-established parent molecules. This
      strategy has resulted in novel molecules with an improved profile of
      pharmacological activity, either in terms of enhanced therapeutic efficacy or
      reduced side effects. This review examines the biological significance,
      mechanism(s) of action and therapeutic potential of such compounds in respiratory
      disease.

PMID- 15202729
TI  - ISAtx-247 (Isotechnika/Roche).
AB  - ISAtx-247 is a ciclosporin A analog under development by Isotechnika and Roche as
      an immunosuppressant for the potential prevention of organ rejection after
      transplantation, and for the potential treatment of autoimmune diseases such as
      rheumatoid arthritis, psoriasis and type 1 diabetes. A phase II renal
      transplantation study had been completed by June 2003.

PMID- 15202730
TI  - Nitroflurbiprofen (NicOx).
AB  - Nitroflurbiprofen is a nitrosylated flurbiprofen analog under development by
      NicOx for the potential treatment of urinary incontinence, Alzheimer's disease
      (AD) and the prevention and treatment of accelerated bone resorption associated
      with disorders such as osteoporosis, inflammatory joint disease and Paget's
      disease. In addition, a topical formulation of nitroflurbiprofen is under
      development for the potential treatment of dermatological disorders, including
      contact urticaria. By 1999, nitroflurbiprofen was in phase IIa trials for urinary
      incontinence, Paget's disease and osteoporosis, and phase II trials of the
      topical formulation were underway in contact urticaria by March 2002. Phase I
      trials for AD had commenced by May 2003, and in September 2003, NicOx was
      intending to conduct further phase II trials for micturition disorders in 2003.

PMID- 15202731
TI  - Talniflumate (Genaera).
AB  - Talniflumate, an anti-inflammatory molecule that was originally developed by
      Laboratorios Bago, is currently being developed by Genaera as a mucoregulator for
      the treatment of cystic fibrosis, chronic obstructive pulmonary disease and
      asthma. Phase I trials with talniflumate had been completed by August 2001, and
      phase II trials were underway in Ireland for the treatment of cystic fibrosis.

PMID- 15202732
TI  - Cleaning protocols in the IVF laboratory.

PMID- 15202733
TI  - Use of stimulated serum estradiol measurements for the prediction of
      hyperresponse to ovarian stimulation in in vitro fertilization (IVF).
AB  - PURPOSE: In ovarian stimulation an exaggerated ovarian response is often seen and
      is related to medical complications, such as ovarian hyperstimulation syndrome
      (OHSS), and increased patient discomfort. If it were possible to identify
      hyperresponders at an early stage of the stimulation phase, adaptation of the
      stimulation protocol would become feasible to minimize potential complications.
      Therefore, we studied the usefulness of measuring stimulated serum estradiol (E2)
      levels in predicting ovarian hyperresponse. METHODS: A total of 109 patients
      undergoing their first IVF treatment cycle using a long protocol with GnRH
      agonist was prospectively included. The E2 level was evaluated on day 3 and 5 of
      the stimulation phase. Two outcome measures were defined. The first was ovarian
      hyperresponse (collection of > or = 15 oocytes at retrieval and/or peak E2 >
      10000 pmol/L, or cancellation due to > or = 30 follicles growing and/or peak E2 >
      15000 pmol/L, or OHSS developed). The second outcome measure comprised a subgroup
      representing the more severe hyperresponders. named extreme-response
      (cancellation or OHSS developed). RESULTS: The data of 108 patients were
      analyzed. The predictive accuracy of E2 measured on stimulation day 3 towards
      ovarian hyperresponse was clearly lower than that of E2 measured on stimulation
      day 5 (area under the receiver operating characteristic curve (ROCAUC) 0.75 and
      0.81, respectively). For extreme-response the predictive accuracy of E2 measured
      on stimulation day 3 or 5 was comparable (ROCAUC 0.81 and 0.82, respectively).
      For both outcome measures the stimulated E2 tests yielded only acceptable
      specificity with moderate sensitivity at higher cutoff levels. Prediction of
      extreme-response seemed slightly more effective due to a lower error rate.
      CONCLUSIONS: There is a significant predictive association between E2 levels
      measured on stimulation day 3 and 5 and both ovarian hyperresponse and extreme
      response in IVF. However, the clinical value of stimulated E2 levels for the
      prediction of hyperresponse is low because of the modest sensitivity and the high
      false positive rate. For the prediction of extreme-response the clinical value of
      stimulated E2 levels is moderate.

PMID- 15202734
TI  - Mean ovarian diameter (MOD) as a predictor of poor ovarian response.
AB  - PURPOSE: To determine the predictive value of mean ovarian diameter of ovarian
      response in controlled ovarian hyperstimulation (COH), in outcome with normal FSH
      level in early follicular phase of menstrual cycle. METHODS: A prospective study
      established the prognostic value of the mean ovarian diameter of total 57 cases,
      including 17 patients undergoing IVF treatment with poor ovarian response and 40
      patients (control group) with adequate ovarian response. RESULTS: The mean
      ovarian diameter (MOD) of patients in the cancelled group was significantly lower
      (19.23 +/- 2.78) than in a comparable control group (24.67 +/- 3.38) [p < 0.001].
      The mean ovarian diameter was a good predictor of poor ovarian response-area
      under receiver operating characteristic curve-ROCAUC = 0.88. The best criterion
      value discriminating between cancelled cycle and punctured was < or = 20.6 mm.
      CONCLUSIONS: Our data demonstrate that the mean ovarian diameter provides good
      prognostic information in outcomes with poor ovarian response during controlled
      ovarian hyperstimulation in IVF. The test is easy to perform and it is a good
      informative resource.

PMID- 15202735
TI  - Why do older women have poor implantation rates? A possible role of the
      mitochondria.
AB  - Mitochondria are organelles responsible for oxidative phosphorylation, the main
      energy source for all eukaryotic cells. In oocytes and embryos, it seems that
      mitochondria provide sufficient energy for fecundation by supporting spindle
      formation during meiosis II, and for implantation. Since mitochondria are
      inherited from mother to child, it is important that oocyte mitochondria should
      be intact. Older women seem to have more mitochondrial DNA mutations, which can
      be responsible for poor implantation and aneuploidy, two conditions that occur
      more often in this group. In the present report we propose a new model to explain
      why older women have poor implantation rates.

PMID- 15202736
TI  - Birth weight discordance in spontaneous versus induced twins: impact on perinatal
      outcome.
AB  - PURPOSE: To compare the rate of birth weight discordance and perinatal outcome of
      twin pregnancies after assisted reproduction with that of spontaneous twins.
      METHOD: A total of 12,920 deliveries were analyzed retrospectively. Seventy-five
      twin pregnancies after ART were compared to the 94 spontaneous counterparts.
      Birth weight discordance was defined as a difference of 20% or more. RESULTS:
      Discordance rate was elevated (25.3% vs. 17.0%) among ART twins. SGA was
      increased and NICU admission was more frequent in discordant group. Unlike-sexed
      twins were more prevalent (73.7% vs. 37.5%) among discordants after ART.
      CONCLUSIONS: ART can increase discordance rate which can elevate perinatal risk.

PMID- 15202737
TI  - Pregnancy and delivery after stimulation with rFSH of a galatosemia patient
      suffering hypergonadotropic hypogonadism: case report.
AB  - PURPOSE: To determine if hypergonadotropic hypogonadism related to galactosemia
      could be linked to anomaly of the circulating FSH. A 26-year-old woman, suffering
      GALT (Galactoso-1-phosphate uridyltransferase) had a premature ovarian failure
      with amenorrhea since the age of 19. The circulating level for FSH was 83 and 34
      mU/mL for LH. METHODS: After treatment with a hormonal substitution cycle
      including estradiol and progesterone, the patient underwent stimulations with
      recombinant FSH. The first cycle, one 16-mm diameter follicle and the second
      cycle one follicle of 17.5 mm of diameter were obtained at the time of ovulation
      induction. RESULTS: The patient conceived and delivered a female baby weighting
      3.38 kg after the second stimulation protocol. CONCLUSIONS: The impact of
      galactosemia on the ovary seems rather related to the absence of recognition of
      circulating FSH by its receptor and not to a toxic alteration of the ovary by
      itself as it is currently reported. The rFSH treatment following hormonal
      substitution cycles allows to overcome infertility problems.

PMID- 15202738
TI  - Testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) in
      hypogonadotropic hypogonadism with persistent azoospermia after hormonal therapy.
AB  - PURPOSE: We aimed to retrieve testicular sperm to be employed on intracytoplasmic
      sperm injection (ICSI) cycles on a male affected of hypogonadotropic hypogonadism
      (HH) that remained azoospermic after long-time hormonal treatment. METHODS:
      Design. We initially performed hormonal therapy using gonadotropins to achieve
      spermatogenesis. After several semen analyses, we weighed the possibility of
      looking for testicular spermatozoa for ICSI. Setting. A private university
      affiliated setting. Patient. A 30-years-old man diagnosed 10 years ago to suffer
      from idiopathic, prepubertal HH. Interventions. Gonadotrophin treatment was
      initiated with hCG and follicle stimulating hormone (FSH). Testicular sperm
      extraction was carried out when repeated spermiograms were negative. Motile
      testicular spermatozoa were cryopreserved and were subsequently employed for
      ICSI. Multiple follicular development was stimulated with gonadotropins after a
      downregulation with gonadotropin-releasing hormone (GnRH) antagonists in the
      woman. Main Outcome Measures. Seminal analyses were performed after 3, 6, and 12
      months of treatment and serum FSH, luteinizing hormone (LH) and testosterone
      levels were also measured. RESULTS: Seminal analysis showed always azoospermia.
      Serum FSH was 2.9 mIU/mL, serum LH >1 mIU/mL and serum testosterone 7.9 ng/mL (12
      months after treatment). Nine oocytes were collected by ultrasound-guided
      transvaginal route and eight of them were microinjected with motile, frozen
      thawed testicular spermatozoa. Four oocytes were fertilized. Three embryos were
      transferred without pregnancy. CONCLUSIONS: The case report here presented shows
      that the currently available assisted reproduction techniques may be of value in
      patients with HH not responding to conventional hormonal treatments.

PMID- 15202739
TI  - Eye of newt, toe of frog: drug compounding: proceed with caution.

PMID- 15202740
TI  - Sleep apnea.

PMID- 15202741
TI  - Early versus late.

PMID- 15202742
TI  - Infection control and prions.

PMID- 15202743
TI  - Bleaching agents.

PMID- 15202744
TI  - The EBD approach.

PMID- 15202745
TI  - Implants and arteries.

PMID- 15202746
TI  - Funding research.

PMID- 15202747
TI  - Case closed.

PMID- 15202748
TI  - New national guidelines on hypertension: a summary for dentistry.
AB  - BACKGROUND: Periodically, the National Heart, Lung, and Blood Institute publishes
      recommendations on the prevention, detection, evaluation and treatment of high
      blood pressure. The Seventh Report of the Joint National Committee on Prevention,
      Detection, Evaluation, and Treatment of High Blood Pressure--known as "JNC 7"-
      substantially revises previous recommendations. METHODS: This report represents
      the consensus opinion of a coalition of 39 major professional, public and
      voluntary organizations and seven federal agencies. All currently available
      literature on hypertension was reviewed by a select committee of experts on
      hypertension (including one of the authors [L.M.P.]) and was used to formulate
      this new report. RESULTS: The authors present highlights of the JNC 7 report. In
      addition, they offer the findings of their review of dental literature dealing
      with patients who have hypertension, into which they integrate information from
      the JNC 7, and update dental management recommendations. These new guidelines
      provide key messages to all health care professionals and are designed to improve
      the diagnosis and treatment of people with hypertension. CONCLUSIONS: Because
      hypertension affects nearly 50 million people in the United States and underlies
      most cardiovascular disease, its diagnosis and control should be of concern to
      all health care providers. Many people have undetected hypertension, and current
      levels of detection and control need to be improved. CLINICAL IMPLICATIONS: All
      health care providers, including dentists and members of the dental team, need to
      be involved in detection and management of this important public health problem.
      The dentist can play an important role in the detection and management of
      hypertension.

PMID- 15202749
TI  - The new blood pressure guidelines: a digest.
AB  - BACKGROUND: In December 2003, the National High Blood Pressure Education Program
      of the National Heart, Lung, and Blood Institute finalized the Seventh Report of
      the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
      of High Blood Pressure, called JNC 7. OVERVIEW AND CONCLUSIONS: On the basis of
      new trials and observational studies, and the need for clear and concise
      guidelines, the JNC implemented changes in blood pressure classification,
      nomenclature, treatment and prevention in the JNC 7 report. One of the key
      messages of the report is that systolic blood pressure higher than 140
      millimeters of mercury in people older than 50 years of age is a more important
      risk factor than diastolic blood pressure. Another finding is that people with
      normal blood pressure at the age of 55 to 65 years have an 80 to 90 percent risk
      of developing hypertension by the age of 80 to 85 years. CLINICAL IMPLICATIONS:
      JNC 7 emphasizes that health care professionals besides physicians, including
      dentists, need to help patients by reinforcing hypertension-related lifestyle
      modifications, pharmacological therapies and adherence to treatment.

PMID- 15202751
TI  - Perceptions of desirable tooth color among parents, dentists and children.
AB  - BACKGROUND: As part of a large-scale fluoridation cessation study, standardized
      examiners assessed 8,281 school-aged children for dental fluorosis using the
      Thylstrup Fejerskov index, or TFI, in which scores range from 0 (no fluorosis) to
      9 (severe loss of enamel with change of anatomical appearance). METHODS:
      Dentists, parents and children were asked to respond to a statement, "The color
      of these teeth (mine or my child's) is pleasing and looks nice." Agreement or
      disagreement with the statement was indicated on a five-level scale, with a
      rating of 1 representing total agreement with the reference statement. The
      authors used repeated-measures analysis of variance to ascertain differences in
      satisfaction with the esthetic appearance of the subject's tooth color across
      dentists', parents' and subjects' perceptions. RESULTS: Girls were more critical
      of their tooth color than were boys; however, parents and dentists were more
      critical of boys' tooth color than of girls'. While younger subjects were more
      critical than older subjects, parents of younger subjects were less critical than
      those of older subjects. Dentists' ratings were not significantly associated with
      subjects' age group. Subjects with a TFI score of 1 or 2 were not significantly
      more critical than subjects with a TFI score of 0, while those with a TFI score
      of 3 of higher were. Similarly, only parents of subjects with a TFI score of 3 of
      higher had significantly different ratings. CONCLUSIONS: The three stakeholders
      in the esthetic treatment of children-parents, dentists and patients-appear to
      see the potential outcome of such treatment differently. CLINICAL IMPLICATIONS:
      Dentists should ensure that parents and children agree about the course of
      treatment, the rationale for undertaking it and the results that could reasonably
      be expected.

PMID- 15202750
TI  - The effect of surface finishing and storage solutions on the color stability of
      resin-based composites.
AB  - BACKGROUND: The authors tested the hypothesis that surface-finishing treatments
      and the type of storage solutions significantly affected the staining of resin
      based composites, or RBCs, and unfilled resins, or URs. METHODS: Fifty-four RBC
      and 54 UR disks were polymerized through a polyester film strip (Mylar, DuPont,
      Wilmington, Del.) and polished in one of three groups: 1-micrometer aluminum
      oxide, 15-microm diamond plate and no treatment (polyester film). All specimens
      were immersed in water for two days and then in coffee, cola or red wine for
      seven more days at 37 C. The authors recorded tristimulus color measurements
      before the immersions; after one and two days in water; and after one, two, three
      and seven days in the storage solutions. RESULTS: Most of the color changes
      occurred between day 2 in water and day 7 in the staining solution. Analysis of
      variance showed that the finishing treatment and storage solution significantly
      influenced the overall color change (deltaE), and interactions occurred between
      the finishing treatment and the storage solution (P < .0001) for both materials.
      RBC specimens generally exhibited greater color changes than did UR specimens.
      The polyester film finishing exhibited the greatest amount of color change, while
      the diamond finishing exhibited the least amount of color change. Immersion in
      wine caused the greatest color change for both materials; cola and coffee
      resulted in the smallest color change for RBC and UR specimens, respectively.
      CONCLUSIONS: Finishing treatments and storage solutions significantly affect the
      surface staining of RBC materials. Polyester film finishing and red wine produced
      the greatest color change after seven days for RBC specimens. CLINICAL
      IMPLICATIONS: Clinicians should remove the polyester film-finished surface and
      advise patients that drinking wine could intensify surface staining on RBC
      restorations.

PMID- 15202752
TI  - Clinical performance of large, all-ceramic CAD/CAM-generated restorations after
      three years: a pilot study.
AB  - BACKGROUND: Adhesively luted all-ceramic restorations preserve and stabilize
      weakened tooth structure, but there is little published information about the
      clinical performance of large, all-ceramic restorations. METHODS: In this pilot
      study, the authors placed 58 large, single-tooth, all-ceramic restorations in 26
      patients using a computer-aided design/computer-aided manufacturing, or CAD/CAM,
      system (CEREC 2, Sirona Dental Systems GmbH, Bensheim, Germany). They documented
      the maximum height of the restoration and remaining cementoenamel junction, or
      CEJ. In 21 cases, rubber dam isolation was not possible during adhesive luting.
      They re-evaluated the restorations after three years according to the U.S. Public
      Health Service criteria. RESULTS: After three years, the authors rated 56 (97
      percent) of the 58 restorations as Bravo or better in regard to marginal
      integrity, secondary caries (four could not be rated), discoloration and
      anatomical form. One restoration was rated as Charlie because of poor marginal
      integrity, and one restoration had to be replaced owing to a bulk fracture. The
      authors rated the adequacy of proximal contact and occlusal relationships as
      acceptable-to-good for all restorations. Neither the extent of the remaining
      enamel at the cavity margin nor application of a rubber dam had any statistically
      significant influence (chi2 test, P > .05) on the clinical performance of the
      restorations after three years. CONCLUSIONS: At the three-year recall
      appointment, the authors found that the adhesively luted all-ceramic restorations
      had successfully repaired large coronal defects, irrespective of the cavity
      margin location (that is, coronal or apical to the CEJ). CLINICAL IMPLICATIONS:
      Tooth-colored, all-ceramic CAD/CAM-generated restorations are an alternative to
      conventional restorations if large coronal defects need to be treated.

PMID- 15202753
TI  - Diagnosing bulimia nervosa with parotid gland swelling.
AB  - BACKGROUND: The authors describe bulimia nervosa, or BN, and its effect on the
      parotid gland. The associated asymptomatic bilaterally enlarged parotid glands
      often present a diagnostic dilemma. CASE DESCRIPTION: The authors present a case
      of a 22-year-old woman with BN who had bilateral parotid gland swelling, serum
      electrolyte alteration and no dental stigmata. Her principal concern was the
      associated cosmetic deformity. CLINICAL IMPLICATIONS: Because patients with BN
      who have parotid gland swelling usually are secretive about their purging, the
      diagnosis may be confirmed by conducting a clinical examination and a serum
      electrolyte study. Prompt diagnosis can avoid serious medical complications.

PMID- 15202754
TI  - Systemic amyloidosis manifesting as localized, severe periodontitis.
AB  - BACKGROUND: Amyloidosis comprises a heterogenous group of disorders characterized
      by amyloid deposition in various organs. The authors document a case in which
      amyloidosis manifested as a localized, severe, periodontal disease. CASE
      DESCRIPTION: A 73-year-old woman visited her dentist because of pain and
      increased mobility of her mandibular bridge. Radiographic examination revealed
      severe vertical bone loss associated with tooth no. 27. One of the authors
      extracted the tooth, removed tissue with a curet from this site and submitted it
      for pathological examination. He made a diagnosis of amyloidosis on the basis of
      histological and immunohistochemical findings. CLINICAL IMPLICATIONS: Clinicians
      should consider periodontal involvement in amyloidosis as a possible cause of
      severe, localized, periodontal disease, particularly in patients with chronic
      inflammatory disorders or a history of amyloidosis.

PMID- 15202755
TI  - Making provisional restorations easy, predictable and economical.

PMID- 15202757
TI  - Employee incentive programs.
AB  - One great benefit of employee incentive programs is that they connect team
      compensation with practice performance. Options are always available to keep the
      incentive programs exciting and motivating. The key is to understand the goal and
      to put in place the employee incentive program that works for your practice.

PMID- 15202756
TI  - Clinical evaluation of a combined in-office and take-home bleaching system.
AB  - BACKGROUND: Tooth whitening is one of the fastest growing areas in cosmetic and
      restorative dentistry. An increasing number of patients are demanding faster ways
      to bleach their teeth. Therefore, clinicians are being pushed to seek quicker and
      easier means to bleach their patients' teeth, while maintaining safety in
      bleaching procedures. METHODS: The authors included in the clinical trial 10
      subjects 18 years of age or older, each of whom had six caries-free maxillary
      anterior teeth without restorations on the labial surfaces and no tooth
      sensitivity. For each subject, one-half of the maxillary arch received a 35
      percent hydrogen peroxide (Group 1) gel application for 30 minutes, and the other
      one-half of the maxillary arch received a 38 percent hydrogen peroxide (Group 2)
      gel application for 30 minutes. The in-office bleaching treatment was maintained
      and reinforced using a 10 percent carbamide peroxide at-home bleaching agent for
      60 minutes. Subjects repeated both the in-office and take-home bleaching
      treatments for three consecutive days. RESULTS: The shade change was 8.5 for
      Group 1 and 9 for Group 2. There was no statistically significant difference
      between the two groups (P = .3434). An average shade rebound of two shades was
      recorded at seven days for both treatment systems. No sensitivity was reported
      during or after the bleaching treatment. CONCLUSIONS: When combined with 10
      percent carbamide peroxide at-home applications, use of the Group 1 and Group 2
      bleaching materials resulted in significant tooth lightening. CLINICAL
      IMPLICATIONS: By using the clinical technique presented, clinicians can reduce
      the time required to complete tooth-whitening treatment. Using the correct tray
      design and improved chemical formulations of tooth whiteners may reduce gingival
      and tooth sensitivity, thus increasing safety.

PMID- 15202758
TI  - Assessing differences in hours worked between male and female dentists: an
      analysis of cross-sectional national survey data from 1979 through 1999.
AB  - BACKGROUND: Women are increasingly entering the dental work force. This study
      examines the impact of sex, age and other demographic characteristics on
      dentists' work force participation and on hours worked from 1979 through 1999.
      METHODS: The study drew on cross-sectional data on dentists (4,209 men and 354
      women) from national population surveys conducted by the U.S. Bureau of Labor
      Statistics from 1979 through 1999. The authors used descriptive statistics and
      regression analyses to examine sex differences in work force participation and in
      hours worked across age, as well as other factors. RESULTS: Work force
      participation was high for both men and women. Men worked more hours and worked
      part time less frequently; they worked more than 42 hours per week more
      frequently. Older dentists worked fewer hours, with a larger impact of age seen
      among men. Having children had a significantly greater effect on the number of
      hours worked per week among female dentists than among male dentists.
      CONCLUSIONS: There were significant differences in dentists' hours worked by sex
      and by age. The consistency of the results with past studies suggests these
      differences will hold in the near future. PRACTICE IMPLICATIONS: Women's entry
      into the dental work force has been significant and has helped maintain the
      supply of dentists. Sex differences in the work force should be considered in
      evaluating the supply of dentists and related work force policy.

PMID- 15202759
TI  - Fracture resistance of roots endodontically treated with a new resin filling
      material.
AB  - BACKGROUND: The authors evaluated the fracture resistance of endodontically
      treated teeth filled with either gutta-percha or a new resin-based obturation
      material. METHODS: The authors prepared and randomly divided 80 single-canal
      extracted teeth into five groups: lateral and vertical condensation with gutta
      percha, lateral and vertical condensation with the new resin-based obturation
      material, and a control group with no filling material. The specimens were stored
      in 100 percent humidity for two weeks, mounted in polyester resin and loaded to
      failure. RESULTS: The authors found statistically significant differences among
      the experimental groups (P < .05). The groups with the new material displayed
      higher mean fracture loads and the gutta-percha groups lower mean fracture load
      values than the control unfilled group. However, the differences were not
      significant. The groups with the new material displayed significantly higher mean
      fracture loads than gutta-percha groups independent of the filling technique
      used. CONCLUSIONS: Filling the canals with the new resin-based obturation
      material increased the in vitro resistance to fracture of endodontically treated
      single-canal extracted teeth when compared with standard gutta-percha techniques.
      CLINICAL IMPLICATIONS; If other properties of the new resin-based obturation
      material compare favorably with those of gutta-percha for filling the root canal,
      it should be considered as a replacement for gutta-percha, as the results of this
      study indicate that it could provide enhanced resistance to tooth fracture.

PMID- 15202760
TI  - Who's liable when an employee quits because of sexual harassment? Supreme Court
      to rule on employers' liability for supervisors' conduct.

PMID- 15202761
TI  - For the dental patient. Here comes the bride ... and her teeth are nice and
      bright.

PMID- 15202762
TI  - Inhibitory effects of lysophosphatidylcholine on the dopaminergic system.
AB  - Lysophosphatidylcholine (lyso-PTC) is formed by phospholipase A2 (PLA2) from
      phosphatidylcholine (PTC), that is produced through phosphatidylethanolamine
      (PTE) methylation. 1-Methyl-4-phenyl-pyridinium (MPP+), a Parkinson's disease
      (PD) inducing agent, and S-adenosylmethionine (SAM), a biological methyl donor,
      increase lyso-PTC formation and both induce PD-like changes in animal models. In
      the current study, we investigated the effect of lyso-PTC on the dopaminergic
      system to determine the modulating role of lyso-PTC in dopaminergic
      neurotransmission. The results of these experiments show that lyso-PTC has a
      remarkable inhibitory effect on dopamine D1 and D2 receptor binding activities in
      the striatal membrane prepared from Sprague-Dawley rats. Lyso-PTC decreased the
      Bmax values of both D1 and D2 receptor binding activities. The Kd values for D1
      and D2 receptors were not changed, but lyso-PTC also inhibited dopamine
      transporter and decreased striatal dopamine turnover rate. MPP+ showed similar,
      but less potent effects. The current studies suggest that lyso-PTC significantly
      impair the dopaminergic system and might play a role in MPP+ and SAM induced PD
      like changes through its inhibitory effects on dopaminergic neurotransmission.

PMID- 15202763
TI  - In vitro activation of protein kinase C by beta-N-oxalyl-L-alpha,beta
      diaminopropionic acid, the Lathyrus sativus neurotoxin.
AB  - Beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (L-ODAP) toxicity has been
      associated with lathyrism; a spastic paraparesis caused by excessive dietary
      intake of the pulse Lathyrus sativus. We investigated the effect of Lathyrus
      neurotoxin L-ODAP on protein kinase C (PKC) activity under in vitro conditions. L
      ODAP activated phosphorylation activity of purified chick brain PKC. Both lysine
      rich (histone III-S) and arginine-rich (protamine sulfate) substrate
      phosphorylation was enhanced in the presence of L-ODAP. The activation is
      concentration dependent, and maximal activation is observed at 100 microM
      concentration. Protamine sulfate phosphorylation was enhanced by 47%, whereas
      histone III-S phosphorylation was enhanced by 50% over PS/PDBu/Ca2+ dependent
      activity. The nontoxic D-isomer (D-ODAP) did not affect both histone III-S and
      protamine sulfate phosphorylation activity. These results indicate that L-ODAP
      taken up by neuronal cells could also contribute to PKC activation and so be
      associated with toxicity.

PMID- 15202764
TI  - Hypothalamic proline-rich polypeptide protects brain neurons in aluminum
      neurotoxicosis.
AB  - The damaging effect of aluminum ions (Al3+) on the organism is widely
      investigated in clinics and experiments that indicate its role as a participant
      in the synthesis of precursors for amyloid proteins and as a potential agent in
      the ethiology of Alzheimer's disease. It has been shown that Al produces
      neurotoxic effects. We established that AlCl3 produces degenerative changes in
      the ultrastructure of Hasserian neurinoma cells in vitro and in L929 fibroblast
      cells. Proline-rich peptide-1 (PRP-1) isolated from neurosecretory granules of
      bovine neurohypophysis is a potent antineurodegenerative agent against spinal
      cord hemisection and crush syndrome-induced neurodegeneration of brain and spinal
      cord neurons. PRP-1 is one of the neurotrophic brain factors. By electron
      microscopic study of the rat hippocampus and other tissues, we succeeded in
      visualizing the epithelioprotectory effect of PRP-1, contributing as a powerful
      agent in removal of aluminum accumulation in different tissues in experimental
      aluminum neurotoxicosis.

PMID- 15202765
TI  - Cytoprotective effect of estrogen on ammonium chloride-treated C6-glioma cells.
AB  - The potential cytoprotective effects of estrogen in the brain are of special
      interest in aging, neurodegenerative diseases, exposure to toxins, and trauma.
      Estrogen effects on neurons have been widely explored, but less is known about
      estrogen effects on glia. Glial cells are primary targets of ammonia toxicity,
      which arises from liver disease or failure (such as from cirrhosis in
      alcoholics), urea cycle disorders, or inborn errors of metabolism. We examined
      the ability of estrogen to protect glial cells from ammonium chloride toxicity
      using an in vitro model system. C6-glioma cells in later passage have many
      astrocytic characteristics and provided a convenient and well established model
      system for this work. When C6-glioma cells were exposed to 15 mM ammonium
      chloride, we observed major cell death (only 32% cell survival relative to
      control) within 72 h. Pretreatment with 17beta-estradiol (10 microM)
      significantly protected C6-glioma cells from ammonia toxicity (99% cell survival
      relative to control). In addition to enhancing the viability of C6-glioma cells
      against ammonia challenge, estrogen pretreatment was also found to protect
      mitochondrial function as assayed using the MTT reduction assay. Mitochondrial
      function was reduced to 39% of control levels in ammonia-challenged cultures and
      was mostly protected by estrogen (72% of control levels). The findings are
      potentially relevant for the development of therapeutic strategies to protect
      glial cells against ammonia toxicity resulting from hepatic failure or other
      causes.

PMID- 15202766
TI  - Nigrostriatal modifications after vanadium inhalation: an immunocytochemical and
      cytological approach.
AB  - Vanadium (V) has increased in the air as a component of suspended particles
      originated from fuel combustion. In this report, a model of inhaled V in mice was
      implemented to identify the effect that V has in the corpus striatum and
      substantia nigra, structures with high concentrations of dopamine and scarce
      antioxidants burden. Mice inhaled 0.02 M V2O5 1 h twice a week and were
      sacrificed at points from 1 to 8 weeks after inhalation, perfused, and processed
      for Golgi method and for tyroxine hidroxylase (TH) inmunocytochemistry.
      Cytological analysis consisted in counting the number of dendritic spines in 20
      medium-size spiny neurons and the number of TH immunoreactive neurons in the
      substatia nigra pars compacta. Dendritic spine density decreased drastically
      after V exposure; the same was observed with the TH-positive neurons, which
      decreased in a time-dependent mode. No previous morphological studies about V and
      nervous system have been reported. The decrease in spine density and in TH
      positive neurons might have functional repercussions that should be studied
      because the trend of this element in the atmosphere is to increase.

PMID- 15202767
TI  - Inhibition of SIN-1-induced change in mitochondrial membrane permeability in PC12
      cells by dopamine.
AB  - Dopamine (50 or 100 microM) attenuated the nuclear damage and cell death due to
      500 microM SIN-1, a donor of superoxide and nitric oxide, in differentiated PC12
      cells whereas 200 microM dopamine did not depress cell death. Dopamine at 50-100
      microM for a 4-h treatment did not show a significant cytotoxic effect on PC12
      cells. Dopamine (100 microM) inhibited the decrease in mitochondrial
      transmembrane potential, cytochrome c release, activation of caspase-3, formation
      of reactive oxygen species, and depletion of glutathione (GSH) due to 500 microM
      SIN-1 in PC12 cells. The reaction of dopamine with peroxynitrite reduced an
      amount of peroxynitrite. The results suggest that dopamine exhibits a biphasic
      effect against the cytotoxicity of SIN-1 depending on concentrations. Dopamine at
      50-100 microM may attenuate the reactive nitrogen species-induced viability loss
      in PC12 cells by suppressing the mitochondrial membrane permeability change
      through inhibition of the formation of reactive species, including peroxynitrite.

PMID- 15202768
TI  - NTPDase and 5'-nucleotidase activities in synaptosomes of hippocampus and serum
      of rats subjected to homocysteine administration.
AB  - Patients with homocystinuria, an inborn error of metabolism, present neurological
      dysfunction and commonly experience frequent thromboembolic complications. The
      nucleoside triphosphate diphosphohydrolase (NTPDase) and 5'-nucleotidase enzymes
      regulate the nucleotide/nucleoside ratio in the central nervous system and in the
      circulation and are thought to be involved in these events. Thus, the current
      study investigated the effect of homocysteine administration on NTPDase and 5'
      nucleotidase activities, in the synaptosomal fraction of rat hippocampus, and on
      nucleotidase activities in rat serum. Twenty-nine-day-old Wistar rats were
      divided in two groups: group I (control), animals received 0.9% saline; group II
      (homocysteine-treated), animals received one single subcutaneous injection of
      homocysteine (0.6 micromol/g). Rats were killed 1 h after the injection. NTPDase
      and 5'-nucleotidase activities from brain and serum were significantly increased
      in the homocysteine-treated group. Results show that, in hippocampus, ATP and ADP
      hydrolysis increased by 20.5% and 20%, respectively, and AMP hydrolysis increased
      by 48%, when compared to controls. In serum, ATP and ADP hydrolysis increased
      136% and 107%, respectively, and AMP hydrolysis increased 95%, in comparison to
      controls. The current data strongly indicate that in vivo homocysteine
      administration alters the activities of the enzymes involved in nucleotide
      hydrolysis, both in the central nervous system and in the serum of adult rats.

PMID- 15202769
TI  - Subcellular distribution of alpha1 and beta2/3 GABA(A) receptor subunits in
      sensory neurons of the bovine trigeminal mesencephalic nucleus: evidence
      suggesting their axoplasmic transport.
AB  - Neurons were free-hand isolated under the stereomicroscope from the bovine
      trigeminal mesencephalic nucleus. These neurons were challenged with monoclonal
      antibodies against the alpha1 and the beta2/3 subunits of the GABA(A) receptor.
      The neurons showed a strong reaction to both antibodies. The reaction was mainly
      intracellular in the round cell bodies and in the axoplasm of the axon emerging
      from these pseudounipolar cells. This suggests the synthesis of these subunits in
      the cell body and their transport along the axon.

PMID- 15202770
TI  - Effects of acute lorazepam administration on aminergic activity in normal elderly
      subjects: relationship to performance effects and apolipoprotein genotype.
AB  - The effects of acute lorazepam challenges on plasma (p) HVA, MHPG, and 5-HIAA,
      and their relationship to drug-induced cognitive and motor deficits and the
      apolipoprotein (APOE)-epsilon4 allele were examined. Eighteen healthy elderly (8
      epsilon4 carriers) received placebo or acute oral lorazepam doses (0.5 mg or 1
      mg) in random sequence, 1-week apart. Cognitive assessment and plasma levels of
      pHVA, pMHPG, and p5-HIAA were determined at baseline and at 1, 2.5, and 5 h
      postchallenge. There was no drug-to-placebo difference in monoamine levels and no
      consistent relationship between changes in monoamine levels and cognitive
      performance, regardless of epsilon4 status. However, the 1.0 mg dose increased p5
      HIAA in epsilon4 carriers, whereas it caused a reduction in noncarriers. Higher
      baseline pMHPG and p5-HIAA levels were associated with better baseline memory.
      The epsilon4 allele may modulate the effect of lorazepam on p5-HIAA, but further
      studies are needed to confirm this finding and elucidate its possible
      significance.

PMID- 15202771
TI  - Macrophage migration inhibitory factor: identification of the 30-kDa MIF-related
      protein in bovine brain.
AB  - Macrophage migration inhibitory factor (MIF) is a ubiquitous protein playing
      various immunologic, enzymatic, and hormonal roles. MIF was originally identified
      for its capacity to inhibit the random movement of macrophages in vitro. MIF is
      widely expressed in many tissues with particularly high levels in the nervous
      system. Using the reversed-phase HPLC, N-terminal microsequence analysis, and
      database searching, we have identified in bovine brain several MIF-like proteins.
      According to mass spectral analysis, the molecular masses for three of them were
      determined as 12,369.2, 12,299.7, and 9,496.2 Da. In addition, we have identified
      another MIF-related protein (29,568.9 Da) by Western blotting using anti-MIF
      antibody raised to MIF (having an apparent molecular weight of 12 kDa) isolated
      to homogeneity from bovine brain cytosol. The modified purification procedure was
      mainly based on exclusion- and ion-exchange chromatography. Using p
      hydroxyphenylpyruvic acid as a substrate, we have demonstrated tautomerase
      activity of the isolated MIF. The N-terminal sequences for all MIF-like proteins
      were found to be identical. Several other higher molecular weight putative MIF
      related proteins were also revealed in the bovine brain cytosol extract. A
      multifunctional nature of MIF is suggested to be a result of its occurrence in
      different oligomerization states in a wide variety of tissues and cells.

PMID- 15202772
TI  - Syntaxin 1A and receptor for activated C kinase interact with the N-terminal
      region of human dopamine transporter.
AB  - The dopamine transporter (DAT) regulates the extent and duration of dopamine
      receptor activation through sodium-dependant reuptake of dopamine into
      presynaptic neurons, resulting in termination of dopaminergic neurotransmission.
      Using the yeast two-hybrid system, we have identified novel interactions between
      DAT, the SNARE protein syntaxin 1A, and the receptor for activated C kinases
      (RACK1). This association involves the intracellular N-terminal domain of human
      DAT (hDAT). Our data suggest that hDAT may exist as dimers or oligomers and that
      its protein-protein interactions with syntaxin 1A and RACK1 form functional
      regulatory complexes that may mediate DAT trafficking through modulation of hDAT
      phosphorylation by PKC.

PMID- 15202773
TI  - Biochemical characterization of the coating mechanism of the endosomal donor
      compartment of synaptic vesicles.
AB  - The heterotetrameric adaptor protein complex, AP-3, sorts proteins to both the
      endosome/lysosome and the synaptic vesicles. We have characterized the
      recruitment of pure AP-3 complex and ADP-ribosylation factor (ARF) onto the
      endosomal donor compartments that give rise to synaptic vesicles. We demonstrated
      that endosomes become heavier in a sucrose gradient after incubation with rat
      brain cytosol and a nonhydrolyzable GTP analog, GTPgammaS. This process requires
      a small GTPase, ARF-1. Furthermore, the endosomal coating is specific for AP-3
      but not the AP-2 complex. This process requires only two soluble proteins AP-3
      and ARF, with the recruitment of AP-3 being saturable at about 30 nM. These
      results establish that the synaptic vesicle's donor membrane is coated with AP-3
      before vesiculation, in a coat-protein-specific and dose-dependent fashion.

PMID- 15202774
TI  - EGb761 pretreatment reduces monoamine oxidase activity in mouse corpus striatum
      during 1-methyl-4-phenylpyridinium neurotoxicity.
AB  - EGb761 produces reversible inhibition of both monoamine oxidase (MAO) isoforms in
      the central nervous system. 1-Methyl-4-phenylpyridinium (MPP+) neurotoxicity is
      prevented by treatment with the MAO inhibitor pargyline. We investigated EGb761's
      effect on striatal MAO activity during MPP+ neurotoxicity. C-57 black mice were
      pretreated with EGb761 (10 mg/kg) daily for 17 days followed by administration of
      MPP+ (0.72 mg/kg). MPP+ enhanced striatal MAO (30%) activity at 6 h, and EGb761
      prevented this effect. MAO-B activity in striatum was enhanced (70%) 6 h after
      MPP+ administration and was reduced to almost normal levels in EGb761 + MPP+
      group compared to MPP+ group. Pretreatment with EGb761 partially prevented (32%)
      the striatal dopamine-depleting effect of MPP+ and prevented the reduction in
      striatal tyrosine hydroxylase activity (100%). Results suggest that EGb761
      supplements may be effective in reducing MAO activity as well as enhancement in
      dopamine metabolism, thereby preventing MPP+-neurotoxicity.

PMID- 15202775
TI  - Down-regulation of AMPA glutamate receptors reduces cerebrocortical metabolic
      response to stimulation.
AB  - We tested the hypothesis that chronic stimulation of AMPA (alpha-amino-3-hydroxy
      5-methyl-4-isoxazolepropionate) glutamate receptors with an agonist causes down
      regulation of the receptor protein and a decrement in basal and/or stimulated
      cerebral O2 consumption. Male Wistar rats were intradurally infused with 10
      microM AMPA by an osmotic pump at a rate of 1 microl/h for 6 days. As a result,
      the specific binding of (S)-[3H]-5-fluorowillardiine to AMPA receptors in the
      cerebral cortex decreased 46% from 2.7 +/- 0.3 to 1.5 +/- 0.6 (density units).
      Under isoflurane anesthesia and after topical stimulation to the right cerebral
      cortex with 10(-3) M AMPA, cerebral blood flow (14C-iodoantipyrine method) and O2
      consumption (cryomicrospectrophotometrically determined) were determined in
      control and down-regulated rats. Down-regulation of AMPA receptors did not alter
      basal O2 consumption. In control, after agonist stimulation, the O2 consumption
      in the ipsilateral cortex increased by 34%, (4.7 +/- 0.5 ml O2 x min(-1) x 100 g(
      1) compared to 3.5 +/- 0.4 in the contralateral cortex). In the down-regulated
      rats, the O2 consumption did not significantly increase (4.0 +/- 1.5 ml O2 x min(
      1) x 100 g(-1) compared to 3.3 +/- 1.7 in the contralateral cortex) after AMPA.
      In conclusion, following chronic simulation, AMPA receptors underwent down
      regulation, but such down-regulation did not alter basal cerebrocortical blood
      flow or O2 consumption. AMPA down-regulation reduced the agonist stimulated
      increase in cortical O2 consumption.

PMID- 15202776
TI  - Decreased histamine-stimulated phosphoinositide hydrolysis in the cerebral cortex
      of a rat line selectively bred for high alcohol preference.
AB  - This study sheds light on the comparative analysis of agonist-stimulated
      phosphoinositide (PI) hydrolysis in the cerebral cortex of alcohol-naive rats
      from established lines selectively bred for low alcohol preference (LAP) and high
      alcohol preference (HAP). The effect of histamine (1.0 mM), but neither
      norepinephrine (0.1 mM) nor carbachol (0.5 mM), on PI hydrolysis was
      significantly reduced in HAP rats (0.4 +/- 5.0 fmol/mg protein [3H]inositol
      phosphates formed over basal) compared with LAP rats (25.5 +/- 10.0 fmol/mg
      protein). The contents of monoamines (dopamine, norepinephrine, and serotonin)
      and histamine in the cerebral cortex did not significantly differ between LAP and
      HAP rats, nor did the contents of their metabolites, except 3-methoxy-4
      hydroxyphenylglycol (one of the metabolites of norepinephrine) and N(tau)
      methylhistamine, which was not detected in our system. The histamine stimulatory
      effect was unchanged in the cerebral cortex of an intact Wistar rat that was
      treated with intraperitoneal injection of alcohol (1.0 g/kg once per day for 14
      days). The results of the current study indicate that the decrease in the
      histamine effect on PI hydrolysis in HAP rats might be attributed to that
      particular rat line.

PMID- 15202777
TI  - Differential interactions of desipramine with amphetamine and methamphetamine:
      evidence that amphetamine releases dopamine from noradrenergic neurons in the
      medial prefrontal cortex.
AB  - Amphetamine is more effective than methamphetamine at raising dopamine levels in
      the prefrontal cortex. The current study tested the hypothesis that
      norepinephrine transporters are involved in this difference. Using microdialysis,
      dopamine, norepinephrine, and serotonin were measured in the rat prefrontal
      cortex after administration of methamphetamine or amphetamine, with and without
      perfusion of desipramine. Amphetamine raised norepinephrine levels more than
      methamphetamine did. Desipramine raised dopamine and serotonin levels but did not
      alter metabolite levels. Desipramine attenuated the increase in dopamine by
      amphetamine while increasing the dopamine released by methamphetamine. These data
      suggest that methamphetamine and amphetamine differ in altering prefrontal
      cortical dopamine levels and in interacting with norepinephrine transporters. It
      is proposed that amphetamine releases dopamine in the prefrontal cortex primarily
      through norepinephrine transporters, whereas methamphetamine interacts minimally
      with norepinephrine transporters.

PMID- 15202778
TI  - The effects of calpain inhibition on IkB alpha degradation after activation of
      PBMCs: identification of the calpain cleavage sites.
AB  - Human peripheral blood mononuclear cells (PBMCs) were activated using anti
      CD3/CD28 (HIT3A/CD28.2) resulting in degradation of IkB alpha, an inhibitor of
      NFkB, relative to unactivated cells. Degradation of IkB alpha began by 30 min and
      proceeded for at least 5 h. Calpeptin, a calpain inhibitor, inhibited IkB alpha
      degradation in a time- and dose-dependent manner. Furthermore, calpain inhibition
      increased IkB alpha levels compared to nonactivated controls. Recombinant IkB
      alpha was incubated with purified porcine m-calpain in the presence of 0.1%
      Triton X-100, and the degradation products were monitored by SDS-PAGE and
      sequenced. Most of the degradation products were peptides derived from calpain,
      but one was derived from IkB alpha cleaved between amino acids 50 and 51
      (glutamine and glutamic acid). The liberated fragment included the entire signal
      response domain (SRD), a region containing key serine and threonine residues
      necessary for phosphorylation by the IKKinase complex and sites required for
      ubiquitination. The results suggest that calpain plays an important role in IkB
      alpha degradation, a crucial event in T cell activation.

PMID- 15202779
TI  - Decrease in Ca2+-activated K+ conductance in differentiated C6-glioma cells.
AB  - Ca2+-activated K+ channels were studied in C6-glioma cells in an attempt to
      correlate changes in expression with cell proliferation and differentiation. In
      this study, we treated C6-glioma cells with thapsigargin for 48 h. Cell
      proliferation was markedly inhibited, and cell morphology changed from round to a
      spindle differentiated shape. Furthermore, intracellular calcium concentration
      was initially increased during acute treatment with thapsigargin. The internal
      [Ca2+]i pool was eventually depleted after a 48-h thapsigargin treatment. We have
      characterized Ca2+-activated K+ currents in less differentiated C6 cells. After
      differentiation of C6 cells induced by thapsigargin, Ca2+-activated K+ currents
      were selectively suppressed. These data lend further support to the notion that
      the expression of Ca2+-activated K+ channels is intimately associated with the
      proliferation of C6-glioma cells, and the suppression of Ca2+-activated K+
      channels coincides with the inhibition of proliferation and subsequent induction
      of cell differentiation.

PMID- 15202780
TI  - Differential postmortem delay effect on agonist-mediated phospholipase Cbeta
      activity in human cortical crude and synaptosomal brain membranes.
AB  - The phosphoinositide signal transduction system, and particularly, phospholipase
      Cbeta isozymes, are relevant in the etiopathogeny of human neuropsychiatric
      pathologies such as depression. Stimulation of phospholipase Cbeta activity by
      muscarinic receptors and G proteins was determined in crude and synaptosomal
      membrane preparations from nine postmortem human frontal cortices (postmortem
      delay range 8 to 50 h). Thus, the phospholipase Cbeta activity was determined by
      measuring the hydrolysis of exogenous [3H]-phosphatidylinositol 4,5-bisphosphate.
      There was a postmortem delay-mediated decrease in the PIP2 hydrolysis
      irrespective of the membrane preparation used (P < 0.05). Moreover, there were
      statistically significant differences for exponential decay curve parameters (K
      factor and Span) of PLCbeta activity induced by agonist-mediated activation
      between crude and synaptosomal membrane preparations. These results show that the
      postsynaptic component of the PLCbeta activity is more sensible to the postmortem
      delay effect.

PMID- 15202781
TI  - Beyond cholesterol--inflammatory cytokines, the key mediators in atherosclerosis.
AB  - The development of atherosclerotic lesions encompasses a cascade of cellular and
      molecular responses that can at best be characterized as an inflammatory process,
      and exhibits striking similarities to autoimmune diseases, such as rheumatoid
      arthritis. Chemokines, cytokines and their receptors are critically involved in
      initiation and perpetuation of atherosclerosis, and they play important roles at
      all levels in the pathogenesis of this disease. In the present article, the
      currently available information on cytokines and chemokines as key mediators in
      atherosclerosis is reviewed. Furthermore, based on recent experiences of our own
      with very early stages of atherosclerosis, possible new ways to make use of these
      parameters toward improved early detection, prevention and treatment of this
      disease are indicated.

PMID- 15202782
TI  - The emerging value of P-selectin as a disease marker.
AB  - Activated platelets are key components in many arterial disorders. P-selectin is
      an activation-dependent platelet receptor, which is also identified in
      endothelial cells. Together with E- and L-selectin it constitutes the selectin
      family. These transmembrane proteins have continued to attract great interest as
      they support rapid and reversible cell adhesion in flow systems and thus play an
      essential role in multicellular interactions during thrombosis and inflammation.
      Similarly to other lectins, selectins bind to different glycoconjugates with
      varying affinities. Protein ligands, equipped with the appropriate carbohydrate
      and sulfate moieties for P-selectin binding, have been identified in normal
      peripheral blood leukocytes and several non-hematopoietic organs, as well as on
      cancer cells. For diagnostic purposes, P-selectin can readily be detected on the
      platelet surface by flow cytometry and by ELISA as a soluble ligand in the
      plasma. Along with other markers, these data can be used in the assessment of
      platelet activation status. Such results bear clinical significance since P
      selectin has been implicated in the pathogenesis of wide-spread disorders
      including coronary artery disease, stroke, diabetes and malignancy.

PMID- 15202784
TI  - Detection of the Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms of the
      NOD2/CARD15 gene by real-time PCR with melting curve analysis.
AB  - Crohn's disease is a complex disorder, with multiple genetic traits. A frameshift
      mutation (Leu1007fsinsC) and two missense mutations (Gly908Arg and Arg702Trp) in
      the NOD2/CARD15 gene are strongly associated with susceptibility to Crohn's
      disease. The presence of one of these risk alleles confers a 2- to 4-fold
      increase in the risk of developing Crohn's disease, and the presence of two
      mutant alleles increases the risk over 20-fold. To facilitate the analysis of
      these polymorphisms, we developed three LightCycler assays to detect the missense
      mutations Arg702Trp and Gly908Arg and the frameshift mutation Leu100fsinsC in the
      NOD2/ CARD15 gene. All three assays can be run simultaneously on one LightCycler
      using identical cycling parameters. Analysis of 53 DNAs from Crohn's patients
      helped to identify carriers at allele frequencies similar to other Caucasian
      populations. The sequencing of such DNAs confirmed the accuracy of the assays. In
      conclusion, we present three rapid and robust assays to detect the Arg702Trp, the
      Gly908Arg and the Leu1007fsinsC ins mutations in the NOD2/CARD15 gene [corrected]

PMID- 15202783
TI  - Analysis of candidate genes in Polish families with obesity.
AB  - This study analyzes the relationship between risk factors related to
      overweight/obesity, insulin resistance, lipid tolerance, hypertension,
      endothelial function and genetic polymorphisms associated with: i) appetite
      regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R));
      ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator
      activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF
      alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism
      (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3
      adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1)
      and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40
      obese Caucasian families from southern Poland participated in the study. The
      genotypes were analyzed by restriction fragment length polymorphism-polymerase
      chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity
      (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio
      (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during
      oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral
      lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin
      sensitivity indexes: homeostasis model assessment of insulin resistance, whole
      body insulin sensitivity index, hepatic insulin sensitivity and early secretory
      response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were
      calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR
      gamma2 linked to morbid obesity were not detected in our group. A weak
      correlation between obesity and certain gene polymorphisms was observed. Being
      overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA
      tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin
      resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G)
      allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was
      characterized by high leptin output during OLTT. We conclude that the
      polymorphisms we investigated were weakly correlated with obesity but
      significantly modified the risk factors of the metabolic syndrome.

PMID- 15202785
TI  - Up-regulation of reactive oxygen species (ROS) and resistance to Fas-mediated
      apoptosis in the C33A cervical cancer cell line transfected with IL-18 receptor.
AB  - Cervical cancer cells were transfected with a newly discovered interleukin (IL)
      18 receptor to investigate the effect of endogenous IL-18 on the regulation of
      immune-related factors such as Fas (CD95/Apo-1)/Fas ligand and intercellular
      adhesion molecules. Transfection of the IL-18 receptor selectively induced a
      slight enhancement of the Fas via the up-regulation of intracellular reactive
      oxygen species and IL-18 in cervical carcinoma C33A cells, whereas there were no
      effects on the expression of p53, intercellular adhesion molecules-1 and Fas
      ligand. Neither IL-18 receptor transfection nor recombinant IL-18 enhanced
      interferon-gamma production in C33A cells. Thus, IL-18 receptor transfection
      induced IL-18 expression and enhanced intracellular reactive oxygen species and
      Fas expression in C33A cells in an interferon-gamma-independent pathway. However,
      treatment with agonistic anti-Fas antibody did not induce the apoptosis of
      C33A/IL-18 receptor transfectants, suggesting that either reactive oxygen species
      play a key role in resisting the Fas-induced apoptosis of C33A cells, or Fas was
      not functional. These results show that C33A/IL-18 receptor cells are resistant
      to the apoptosis and thus can survive against the immune surveillance and
      activated immune cells. Our results thus suggest that IL-18 and IL-18 receptor,
      together, may play a role in immunoregulation or in inflammation by augmenting
      the levels of IL-18 and reactive oxygen species in C33A cells.

PMID- 15202786
TI  - Rapid detection of mutations in Wilson disease gene ATP7B by DNA strip
      technology.
AB  - Wilson disease leads to severe hepatic and neurological pathology resulting from
      cellular copper overload in the respective tissue. Although the affected gene,
      ATP7B, has been identified, genetic testing is challenging, time-consuming and
      expensive. Here we describe the development and use of a novel diagnostic test
      for four frequent mutations (M769V, W779X, H1069Q and P1134P-fs) found in Germany
      and many other countries in Europe. The test is based on multiplex polymerase
      chain reaction and DNA strip technology and was found to be highly sensitive and
      specific, as well as timely and cost-effective. We conclude that this test is a
      useful and reliable tool to screen Wilson disease patients and their family
      members for these mutations and may facilitate diagnosis in this complex disease.

PMID- 15202787
TI  - Moderate exercise with a dietary vitamin C and E combination protects against
      streptozotocin-induced oxidative damage to the blood and improves fetal outcomes
      in pregnant rats.
AB  - A considerable amount of clinical and experimental evidence now exists suggesting
      that many biochemical pathways strictly associated with diabetes increase the
      production of reactive oxygen species (ROS). However, daily moderate exercise and
      vitamins C and E (VCE) supplementation can be beneficial to diabetes due to
      reducing blood glucose and free radical production. In the present study, we
      investigated the effect of VCE and moderate exercise on lipid peroxidation (MDA)
      and scavenging enzyme activity in the blood of STZ-induced diabetic pregnant
      rats. Fifty female Wistar rats were used and were randomly divided into five
      groups. The first and second were used as the control and pregnant control
      groups, respectively. The third group was the pregnant diabetic group. The fourth
      group was the diabetic-pregnant-exercise group. VCE-supplemented feed was given
      to pregnant-diabetic-exercise rats constituting the fifth group. Animals in the
      exercised groups were moderately exercised daily on a treadmill (16.1 m/min, 45
      min/d) for three weeks (five days a week). Diabetes was induced on day zero of
      the study. Body weights in the five groups were recorded weekly. Plasma and red
      blood cell (RBC) samples were taken from all animals on day 20. Glutathione
      peroxidase (GSH-Px), catalase and reduced glutathione (GSH) levels in plasma and
      RBCs, glucose, vitamins A, E and beta-carotene in plasma, the number of fetuses,
      and body weight were lower in pregnant diabetic rats than in control animals,
      whereas there was a significant increase in platelet counts and plasma and RBC
      MDA levels. The decreased antioxidant enzymes did not improve through exercise
      only. However, the decreased vitamins, and increased MDA, glucose levels and
      white blood cell (WBC) counts were improved either by exercise or exercise plus
      VCE supplementation. There were no significant changes in the RBC counts and
      hemoglobin values in the five groups. In conclusion, these data demonstrate that
      there is an increase in MDA in the blood of diabetic pregnant animals, whereas
      there is a decrease in the number of fetuses, antioxidant vitamins and enzymes.
      However, dietary VCE with moderate exercise may strengthen the antioxidant
      defense system due to reducing ROS. They may play a role in preventing diabetes
      related diseases of pregnant subjects.

PMID- 15202788
TI  - Plasma levels of 7-hydroxylated dehydroepiandrosterone (DHEA) metabolites and
      selected amino-thiols as discriminatory tools of Alzheimer's disease and vascular
      dementia.
AB  - OBJECTIVE: The early differential diagnosis of Alzheimer's disease (AD) remains
      still problematic. We developed a laboratory test enabling us to distinguish
      patients with AD from those with vascular dementia (VD) and healthy subjects.
      METHODS: The AD group consisted of 22 women and 18 men. The VD group consisted of
      16 women and 8 men. Age-matched controls consisted of 12 women and 9 men. Plasma
      pregnenolone sulfate (PregS), dehydroepiandrosterone (DHEA) and its sulfate
      (DHEAS) were determined by radioimmunoassay. 17-Hydroxypregnenolone (17Preg) and
      7-hydroxylated metabolites of DHEA (7alphaDHEA, 7betaDHEA) were determined by
      radioimmunoassay after separation by high performance liquid chromatography
      (HPLC). Homocysteine (Hcy), cysteine (Cys), cysteinylglycine (Cysgly) and
      glutathione (GSH) were measured by HPLC. RESULTS: The ANOVA results of
      significant between-group differences were as follows: The PregS and the 17-Preg
      and DHEAS levels were independent from the diagnosis. The 7alphaDHEA levels
      significantly depended on the sex (p < 0.05) and diagnosis (p < 0.01). Amino
      thiols were influenced by the diagnosis (p < 0.01, p = 0.0541, p < 0.01 and p =
      0.0536 for Cys, Hcy, Cysgly and GSH, respectively). Using a stepwise backward
      regression analysis, the following parameters were obtained: X = 11.5 + 4.03 x
      sex +1.09 x Hcy + 0.190 x PregS - 4.76 x DHEAS + 3.00 x DHEA - 34.3 x 77alphaDHEA
      - 0.885 x Cysgly from which P-value as a discriminator was calculated according
      to the formula: P = 1/(1 + e(-x)). Then, for P > 0.5, a subject was considered as
      AD-positive (with 89% correct prediction). DISCUSSION: The opportunity of early
      differential diagnosis of AD should help physicians to use suitable treatment for
      retardation of pathological processes.

PMID- 15202789
TI  - Abnormalities in apolipoprotein and lipid levels in an HIV-infected Brazilian
      population under different treatment profiles: the relevance of apolipoprotein E
      genotypes and immunological status.
AB  - HIV infection is associated with disturbances in lipid metabolism due to a host's
      response mechanism and the current antiretroviral therapy. The pathological
      appearance and progression of atherosclerosis is dependent on the presence of
      injurious agents in the vascular endothelium and variations in different subsets
      of candidate genes. Therefore, the Hha I polymorphism in the apolipoprotein E
      gene was evaluated in addition to triglycerides, total cholesterol, very low
      density lipoprotein (VLDL), LDL, high-density lipoprotein (HDL), and
      apolipoprotein (apo) Al, B and E levels in 86 Brazilian HIV-infected patients and
      29 healthy controls. The allele frequency for apoE in the HIV-infected group and
      controls was in agreement with data on the Brazilian population. Dyslipidemia was
      observed in the HIV group and verified by increased levels of triglycerides, VLDL
      and apoE, and decreased levels of HDL and apoAl. The greatest abnormalities in
      these biochemical variables were shown in the HIV-infected individuals whose
      immune function was more compromised. The effect of the genetic variation at the
      APOE gene on biochemical variables was more pronounced in the HIV-infected
      individuals who carried the apoE2/3 genotype. The highly active anti-retroviral
      therapy (HAART)-receiving group presented increased levels of total cholesterol
      and apoE. Dyslipidemia was a predictable consequence of HIV infection and the
      protease inhibitors intensified the increase in apoE values.

PMID- 15202790
TI  - An International Standard for whole blood folate: evaluation of a lyophilised
      haemolysate in an international collaborative study.
AB  - Folate measurements, particularly for whole blood, show wide inter-laboratory and
      inter-methodology variability. This variability appears to be due in part to the
      lack of internationally accepted reference materials. A whole blood haemolysate,
      lyophilised in ampoules and designated 95/528, was therefore evaluated by 15
      laboratories in five countries for its suitability as an International Standard
      (IS) for whole blood folate. The preparation was assayed using a variety of
      microbiological and protein-binding methodologies against local standards and
      calibrators. A consensus folate content was assigned to 95/528. The inclusion of
      three whole blood samples in the study with widely differing folate levels
      demonstrated a considerable reduction in inter-laboratory variability when the
      folate content of the samples was determined relative to the proposed IS 95/528
      rather than to laboratories' local standards and calibrators. Accelerated
      degradation studies indicated that the folate content of 95/528 is stable when
      stored at -20 degrees C. On the basis of the results presented here, the World
      Health Organization Expert Committee on Biological Standardization established
      95/528 as an IS for whole blood folate.

PMID- 15202791
TI  - Population-specific reference values for thyroid hormones on the Abbott ARCHITECT
      i2000 analyzer.
AB  - Reliable reference ranges are important in the interpretation of laboratory data,
      and it is incumbent on each laboratory to verify that the ranges they use are
      appropriate for the patient population they serve. The objective of this study
      was to determine population-specific reference ranges for thyroid stimulating
      hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and total
      triiodothyronine (TT3) on the Abbott ARCHITECT 12000 analyzer. For this study, we
      used human serum samples collected from a population in Castilla y Leon, Spain.
      Serum samples were collected from 304 individuals (male, n = 151; female, n =
      153; age 12-94 years) representing outpatients (n=100), hospitalized patients (n
      = 104) and apparently healthy subjects (n = 100). Individuals taking any
      medications, with a history of thyroid disorder, or severe non-thyroidal illness
      were excluded from the study. For healthy subjects, the following reference
      intervals were determined: TSH, 0.51-5.95 mlU/l; fT4, 0.84-1.42 ng/dl (10.77-
      18.21 pmol/l); fT3, 1.48-3.37 pg/ml (2.27-5.18 pmol/l); and TT3, 0.65-1.46 ng/ml
      (1.00-2.24 nmol/l). In this group, TSH and fT4 showed significant differences
      between men and women, but fT3 and TT3 did not. Conversely, fT3 and TT3 showed
      significant age-related differences, but TSH and fT4 did not. Within the
      outpatient group, no significant differences were seen between men and women for
      any of the hormones, but age-related differences were significant for fT3 and
      TT3. Within the hospitalized patient group, significant differences between men
      and women were found for TSH only, and age-related differences were significant
      for TSH, fT3 and TT3. Our findings are basically in accordance with previously
      published results for fT3, TT3 and TSH, but for fT4 our results differ from other
      data in the literature. This highlights the need for laboratories to confirm that
      the reference ranges they use are appropriate for the population they serve.

PMID- 15202792
TI  - Amphetamines and 3,4-methylendioxymetamphetamine (MDMA): evaluation of KIMS
      (kinetic interaction of microparticles in solution) assay at two cut-off levels.
AB  - Two screening methods for the assay of amphetamines and their derivatives have
      been applied to the same analytical instrument for their evaluation. In addition
      to an assay at a cut-off of 1000 microg/l, a new specific reagent was evaluated
      for an ultra-sensitive assay of amphetamines and 3,4-methylendioxymetamphetamine
      with a cut-off of 300 microg/l. The assay confirmation was performed using high
      performance liquid chromatography and gas chromatography/ mass spectrometry
      techniques. The results were positive for both screening methods, confirming the
      efficacy of two simultaneous methods with different cut-off levels.

PMID- 15202793
TI  - Comparison of sensitivity and specificity of serum poly-C avid ribonuclease
      activity and C-reactive protein concentration in detection of mild and severe
      acute pancreatitis.
AB  - The aim of this study was to compare diagnostic performance of C-reactive protein
      (CRP) and poly-C avid ribonuclease (P-RNase) levels in the prediction of a severe
      clinical course of acute pancreatitis (AP). The study included 36 patients with
      mild and 20 with severe AP. CRP concentration was measured by an
      immunonephelometric method and P-RNase activity by the rate of polycytidylate
      hydrolysis at pH 7.8. At the time of admission, both P-RNase and CRP levels were
      significantly increased in all patients when compared to healthy subjects (29.2
      vs. 18.7 U/l and 91.1 vs. 2.89 mg/l; p < 0.001). Up to days 3 and 4 a further
      increase in P-RNase was observed. On the other hand, the increase in CRP
      continued only through days 2 and 3 (p < 0.001). Severe acute pancreatitis (SAP)
      and mild acute pancreatitis (MAP) differed significantly with respect to P-RNase
      levels on all days studied; whereas CRP levels differed significantly on days 2-5
      but did not differ at admission. Receiver operating characteristic (ROC) curve
      function analysis yielded the best sensitivity of SAP detection for P-RNase,
      equaling 72.2%, at the cut-off point value 65.3 U/l on day 3 after admission. The
      sensitivity of CRP for detection of SAP was 85.0% at 125.7 mg/l on the 2nd day
      after admission. Both parameters studied were significantly associated with the
      severity of the AP clinical course; however, on days 1 and 2 post-admission, P
      RNase was more specific for detection of SAP than CRP (94.4% vs. 77.1% on the 1st
      day and 94.4% vs. 55.5% on the 2nd day). In conclusion, P-RNase has shown an
      excellent performance for early differentiation of acute necrotizing
      pancreatitis.

PMID- 15202794
TI  - Emergency department triage of patients with acute chest pain: definition of
      cardiac troponin I decisional value to manage patients without
      electrocardiographic evidence of ischemia.
AB  - The aim of this study was to define the use of a new cardiac troponin I (cTnI)
      assay for emergency patients with chest pain and no specific electrocardiographic
      changes consistent with the presence of ischemia. Patients (n = 106) admitted in
      Emergency/Cardiology Departments for chest pain and suspicion of acute coronary
      syndrome (ACS) were randomized into two diagnosis groups (ACS or non-ACS) by two
      independent cardiologists. cTnI measurements were performed at admission, and 6
      hours and 12 hours later with a new generation assay (Access AccuTnI, Beckman
      Coulter). Using an upper reference limit of 0.04 microg/l, 27 patients had a cTnI
      elevation not related to the final diagnosis of ischemia; the positive predictive
      value (PPV) was 67% with specificity 48%. The decisional value was re-defined and
      set at 0.16 microg/l, a concentration corresponding to the 99th percentile of the
      non-ACS patient group. Precision (coefficient of variation) was 8% at this level,
      PPV 97% and specificity 98%. This new decisional value is now used in our
      institution and could be included in standard care guidelines to improve the
      management of patients presenting chest pain in emergency departments.

PMID- 15202795
TI  - Genetic analysis of glutathione S-transferase A1 and T1 polymorphisms in a
      Japanese population.
AB  - Novel allelic variants have been found in the glutathione S-transferase (GST) A1
      and T1 genes. The former GSTA1*B allele is associated with low expression and the
      latter GSTT1*B allele lacks GSTT1 activity. The information on frequencies of
      both variants is poorly documented in the Japanese population. In this study we
      determined the frequencies of allelic variants of GSTA1 and GSTT1 in a Japanese
      population using PCR-restriction fragment length polymorphism and allele-specific
      PCR. The frequencies of GSTA1*B, GSTT1*0 and GSTT1*B alleles in the subjects were
      16.0%, 71.1% and 0%, respectively. This is the first report on the frequencies of
      allelic variants of GSTA1 and GST-1 in a Japanese population.

PMID- 15202796
TI  - The European Register for Specialists in Clinical Chemistry and Laboratory
      Medicine: Code of Conduct.
AB  - The European Communities Confederation of Clinical Chemistry and Laboratory
      Medicine (EC4) opened a Register for European Specialists in Clinical Chemistry
      and Laboratory Medicine in 1997. The operation of the Register is undertaken by a
      Register Committee (EC4RC). During the last 6 years more than 1500 specialists in
      clinical chemistry and laboratory medicine have joined the Register. In this
      article a Code of Conduct for Registrants which was approved at the EC4 Register
      Committee meeting in Amsterdam, 8 November 2003 is presented.

PMID- 15202797
TI  - Decision cut-off of the polyethylene glycol precipitation technique in screening
      for macroprolactinemia on Immulite 2000.

PMID- 15202798
TI  - No bias between the first and the new version of radioimmunoassay for serum holo
      transcobalamin by Axis-Shield.

PMID- 15202799
TI  - Implemented as intended? Recording family worker activities in a Families First
      program.
AB  - In evaluating family preservation services, it is important not only to study the
      service outcomes and the family characteristics, but also what actually happens
      during the treatment. This requires a program model. This article describes how a
      program model works, prescribes how workers should carry it out, and describes
      how researchers should measure the program's characteristics. The authors use
      data from Families First in The Netherlands to test the model. Results show that
      the method of the program meets the specified characteristics. The results are
      important for treatment, policy, education, and evaluation research.

PMID- 15202800
TI  - Improving access to health care for foster children: the Illinois model.
AB  - Children in foster care have lower health status than do their peers and limited
      access to health care. The Illinois Department of Children and Family Services
      developed HealthWorks, a separate primary care preferred provider system for
      children in foster care. This study compared claims data for children in
      HealthWorks with children not enrolled in HealthWorks and with children in Aid to
      Families with Dependent Children (AFDC) who had never entered foster care.
      Children enrolled in HealthWorks were more likely than were other children to
      receive all of the services except general inpatient hospitalizations. They had
      greater odds of receiving general exams and physicians' services and were more
      likely to visit the emergency room than children who were not enrolled. They were
      more likely to receive all of the measured services when compared with children
      receiving Medicaid through AFDC.

PMID- 15202801
TI  - Extending transitional services to former foster children.
AB  - This article describes what a private agency expended while addressing the
      transitional needs of former long-term foster youth and examines the association
      between expenditures and adult outcomes. Not all young adults accepted supports
      extended to them. In the sample, 41% of the young adults incurred expenses after
      age 19. Of those using supports, about two-thirds incurred expenses for higher
      education, and slightly fewer for continued housing support. Median expenses were
      generally stable or declining between ages 19 and 21, although almost all
      declined after age 22. Young adults who received extended supports tended to be
      better off at follow-up, although some troubled young adults used extensive,
      expensive services.

PMID- 15202802
TI  - The Parent Satisfaction with Foster Care Services Scale.
AB  - Client satisfaction measures are an essential component of program evaluation.
      This article describes the development of a scale for measuring the satisfaction
      levels of parents whose children have received foster care services. Subjected to
      various statistical measures, the Parent Satisfaction with Foster Care Services
      Scale appears to be a reliable instrument with the promise of utility for social
      work researchers, practitioners, and administrators.

PMID- 15202803
TI  - Introduction to the special issue on resilience.
AB  - This article introduces this special issue on resilience by briefly reviewing its
      history and how contemporary researchers and theorists deliberate it today.
      Resilience, as a concept, emerged primarily from the work of Norman Garmezy, Emmy
      Werner, and Ruth Smith. It has transformed the field and shifted research,
      theory, and practice paradigms to a focus on strengths rather than deficits.

PMID- 15202804
TI  - Parent/child transactional processes predictive of resilience or vulnerability to
      "substance abuse disorders".
AB  - This article discusses implications of a theoretical model of resilience--the
      Resilience Framework, including the impact of parent/child transactional
      processes in moderating or mediating a child's biological or environmental risks
      and later substance misuse. Research is presented on behavioral and emotional
      precursors of substance abuse disorders in children of substance users.
      Detrimental processes within dysfunctional family environments are presented
      followed by a listing of strategies for increasing resilience in youth by
      improving family dynamics. The value in elucidating these interactive processes
      is to increase our understanding of ways to reduce the impact of risk factors.
      Prevention providers should use these strategies as benchmarks for selecting or
      developing effective family-focused prevention programs. Resources are presented
      for finding effective family interventions as well as an example of a family
      intervention based on resilience principles, namely the Strengthening Families
      Program. Recommendations are made for future research and better dissemination of
      evidence-based family interventions.

PMID- 15202805
TI  - The role of caring adults in the lives of children of alcoholics.
AB  - Longitudinal studies of children of alcoholics in a community context are rare,
      but are of special interest because they provide the opportunity to study
      families with alcoholic parents who do not reach clinical settings and with
      offspring who do not receive professional help. The current study reports on the
      65 offspring of alcoholics who participated in the Kauai Longitudinal Study. The
      extensive data on these analyses included questionnaires and interviews of both
      children and adults that were collected over a 30-year period. The data showed
      that individuals who coped effectively with the trauma of growing up in an
      alcoholic family and who became competent adults relied on a significantly larger
      number of sources of support in their childhood and youth than did the offspring
      of alcoholics with coping problems by age 32.

PMID- 15202806
TI  - Alcohol, tobacco, other drug use, and violent behavior among Native Hawaiians:
      ethnic pride and resilience.
AB  - The present study includes data from a sample of 88 Native Hawaiians living in a
      rural community on an outer island. Alcohol, tobacco, and other drug (ATOD) use,
      and violent behavior were examined, including age at first experience, lifetime
      and 30-day frequency of experience, and interference related to substance use,
      along with other resilience indicators such as self-reported health, happiness,
      and ethnic identity. The data suggested that age at first use of alcohol,
      tobacco, and other drugs appeared to occur within the same period of time, at
      approximately age 16. With respect to violent behavior, educational attainment
      was higher for individuals whose age at first victimization was later. Two
      relationships were found between ATOD use and violent behavior. First, the data
      suggest that the age at first use of alcohol was significantly correlated with
      lifetime frequency of violence exposure including witnessing, perpetrating, and
      being a victim of violence. Second, age at first victimization was correlated
      with current marijuana use, while age at first perpetration of violence was
      correlated with current crystal methamphetamine use. Lastly, individuals
      reporting very strong ethnic pride had significantly fewer lifetime instances of
      witnessing, perpetrating, and being the victim of violence. Thirty-day
      frequencies of perpetrating and being the victim of violence were also
      significantly different between respondents who reported very strong ethnic pride
      and those who reported being less proud, suggesting that ethnic pride is an
      important protective factor against experiencing violent behavior and may
      encourage resilience in this group.

PMID- 15202807
TI  - Educational resilience among youth at risk.
AB  - Educational experts and others recognize the importance of early school
      experiences on later educational outcomes. Following a sample of youth based on
      692 files from low-income, single parent families over time, from one urban
      school district in the Southeastern United States, 1989-1990 to 1996-1997, we
      apply event history analytic techniques to examine the relationship between first
      grade retention and completing high school. The findings indicate that being
      retained in the first grade increases the risk of dropping out of high school
      years later. The results also show a link between retention, extracurricular
      activity participation, and high school completion. The risk of dropping out is
      lower for those youth who were retained and were involved in activities during
      high school. The implication is that educational trajectories can be redirected
      such that positive educational outcomes can occur.

PMID- 15202808
TI  - Cognitive transformation as a marker of resilience.
AB  - Individuals often report positive, transformative changes in response to
      adversity. Cognitive transformation involves a turning point in a person's life
      characterized by: (1) the recognition that coping with adversity resulted in new
      opportunities; and, (2) the reevaluation of the experience from one that was
      primarily traumatic or threatening to one that is growth-promoting. Cognitive
      transformation often signifies enhanced adaptation to adverse circumstances, and
      thus, is a marker of resilience. The present study examined the relationship of
      cognitive transformation to indicators of resilience among 35 acutely bereaved
      young adults and a nonbereaved comparison group. Findings strongly supported the
      hypothesis that transformation predicts resilience, and may reduce one's risk
      trajectory to enhance adaptation. Results are discussed in terms of their
      implications for research on resilience, and on recovery from acute or chronic
      adverse circumstances, including addiction.

PMID- 15202809
TI  - Why some kids do well in bad situations: relation of parental alcohol misuse and
      parentification to children's self-concept.
AB  - Between 1991 and 1994 a sample of high- and low-functioning 10-18-year-old
      children of alcohol misusing and nonalcohol misusing parents were assessed on
      degree of problematic parental role functioning (parentification) and global self
      concept. The high functioning children had been chosen by their teachers to
      receive training as peer counselors, whereas the low functioning children were in
      either psychiatric facilities or the custody of family and children services. The
      parentification scores of the latter significantly exceeded those of the former.
      Children of alcoholic parents also scored higher on the parentification measure
      than did those with nonalcoholic parents. Within the high functioning group
      hierarchical regression analysis revealed that while parental alcohol misuse
      status accounted for a small but significant amount of the variance in self
      concept, the effect of this variable was substantially reduced after entering
      level of parentification into the equation. By contrast, within the low
      functioning group parental alcohol misuse status was not significantly related to
      self-concept whereas level of parentification was. The results are discussed
      within a family systems framework.

PMID- 15202810
TI  - Selected references on resilience.

PMID- 15202811
TI  - Critical care nephrology: the journey has begun.

PMID- 15202812
TI  - Incidence and definition of sepsis and associated organ dysfunction.
AB  - AIMS: To discuss the incidence, outcome and predisposing factors to systemic
      inflammatory response syndrome (SIRS), sepsis, and multiple organ failure.
      METHODS: A qualitative review of the literature. RESULTS: Case definitions of
      sepsis and severe sepsis, though clarified recently, are still arbitrary. It
      seems, however, that SIRS is not useful in identifying severe sepsis while organ
      failure has become a cornerstone for this definition. Incidence of severe sepsis
      appears to be approximately 10% of all ICU admissions, totaling nearly one
      million cases annually in the U.S. alone, and rising. Mortality associated with
      these events is still high, especially among ICU patients. Recent studies have
      been demonstrating an association between a variety of genetic polymorphisms and
      progression to and dying from sepsis. CONCLUSION: Recently there has been an
      increasing amount of information enabling characterization of the epidemiology of
      sepsis, which may help to direct appropriate care in the coming years.

PMID- 15202813
TI  - The development of drotrecogin alfa (activated) for the treatment of severe
      sepsis.

PMID- 15202814
TI  - Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute
      renal failure: a two-year single center report.
AB  - Extended daily dialysis (EDD) is an easily implemented alternative to continuous
      renal replacement therapy (CRRT) in the intensive care unit (ICU). Since EDD
      offers most of the advantages of CRRT, we sought to compare the effectiveness of
      these two modalities. In this 2-year study, 54 ICU patients with ARF were treated
      with either continuous hemodialysis (CHD) or EDD. Oliguria was present in 64% of
      patients who received CHD vs. 73% of EDD patients (p=NS) while 93% of CHD and 81%
      of EDD patients required mechanical ventilation (p=NS). Patients treated with EDD
      were younger than those who received CHD (47.0 +/- 12.6 vs. 56.7 +/- 13.7,
      p=0.009), but there were no significant differences in gender or mean APACHE II
      scores at the time of randomization. Mean arterial blood pressures measured
      during treatment were maintained between 70 and 80 mmHg for both EDD and CHD and
      average daily serum electrolyte levels fell within normal ranges for EDD and CHD.
      Average daily fluid input and output were 5.8 +/- 3.3 L and 6.0 +/- 3.2 L for CHD
      vs. 3.3 +/- 2.6 and 3.0 +/- 1.7 L for EDD after exclusion of data from 2 burn
      patients. Hourly heparin anticoagulation rates were 1080 U/hour for CHD and 643
      U/hour for EDD, p=0.02. Anticoagulation-free treatments were performed during 43%
      of all EDD treatments vs. 21% of all CHD treatments, p<0.001. Clotting of the
      dialyzer or circuit occurred at least once during 51% of all CHD treatment days
      vs. 22% of EDD treatments (p<0.001). We conclude that EDD is a safe, effective
      alternative to CRRT that offers comparable hemodynamic stability and excellent
      small solute control.

PMID- 15202815
TI  - Prolonged daily intermittent renal replacement therapy in ICU patients by ICU
      nurses and ICU physicians.
AB  - OBJECTIVES: Prolonged daily intermittent renal replacement therapy (PDIRRT) has
      been proposed as a new form of treatment for severe acute renal failure (ARF).
      However, this treatment has so far implied a) full dependence on nephrological
      input, b) lack of any convective clearance and c) limited purification of
      dialysate water. The aim of this study was to establish the feasibility and
      safety of performing PDIRRT in the ICU with a) no nephrological input, b) the
      addition of some convective clearance with on-line fluid replacement and c) a new
      advanced water purification system. DESIGN: Prospective observational study.
      PATIENTS: Fourteen patients treated with PDIRRT. SETTING: ICU of tertiary
      institution. INTERVENTIONS: Treatment of patients with severe ARF and critical
      illness with PDIRRT. Prescription of treatment by ICU physicians. Conduct of
      treatment by ICU nurses. Use of combined convective and diffusive therapy with on
      line generation of fluid replacement, application of a double-filtration water
      purification system. MEASUREMENTS AND MAIN RESULTS: We prospectively collected
      demographic, biochemical, hemodynamic and clinical data in 14 patients, who
      received 30 PDIRRT treatments for a cumulative treatment time of 205.4 hours. The
      mean age was 57.9 +/- 16.0. Eight patients were male and 6 female. Their mean
      APACHE II score was 24.6 +/- 5.9 and their SAPS II score was 41.7 +/- 18.8.
      PDIRRT was used after at least 24 hours of initial stabilization with continuous
      veno-venous hemofiltration (CVVH). Blood flow was kept at 100 ml/min dialysate
      flow at 200 ml/min and convective clearance varied from 21 ml/min to 33 ml/min.
      All patients were either anuric or oliguric (UO < 400 ml/day). Ten patients were
      on mechanical ventilation and 11 patients on vasopressor support. Mean treatment
      session time was 6.9 +/- 1.8 hours. The mean pre-PDIRRT urea was 19.2 +/- 6.9
      mmol/L and the creatinine was 274 +/- 116 micromol/L. The mean pre-PDIRRT lactate
      was 2.95 +/- 2.24 mmol/L. Following treatment, all had significantly decreased to
      13.2 +/- 6.3 mmol/L, 215 +/- 95 micromol/L and 2.25 +/- 1.61 mmol/L, respectively
      (p=<0.0001, <0.0001, <0.05). Bicarbonate levels remained stable during treatment
      (23.0 +/- 3.8 mmol/L to 23.1 +/- 2.5 mmol/L). Mean norepinephrine dose changed
      from 8.8 +/- 11.9 microg/min to 12.9 +/- 27.0 microg/min after treatment (NS).
      There were no complications of therapy. Patient ICU survival was 71.4%.
      CONCLUSIONS: PDIRRT with combined diffusive and convective clearance is an
      efficacious form of renal replacement, which can be safely and effectively
      conducted by ICU nurses following prescription by ICU physicians without any
      nephrological involvement and with adequate double filtration water purification.

PMID- 15202816
TI  - Cytokine removal during continuous renal replacement therapy: an ex vivo
      comparison of convection and diffusion.
AB  - BACKGROUND AND OBJECTIVES: It is unknown whether cytokine adsorption to the
      membrane during continuous renal replacement therapy is affected by the
      technique. Such knowledge might affect the choice of technique in vivo.
      Accordingly, we conducted an ex vivo study to test whether continuous veno-venous
      hemofiltration (CVVH) or continuous veno-venous hemodialysis (CVVHD) affect
      cytokine adsorption differently. SETTING: Laboratory attached to the Intensive
      Care Unit of a tertiary hospital. DESIGN: Six healthy human volunteers donated
      blood, which was incubated with endotoxin. Control blood was left at room
      temperature, and treatment blood was recirculated for eight hours through closed
      circuits using polyacrylonitrile membranes (AN69). The effect of CVVH and CVVHD
      on cytokine removal from the circuits was compared. MEASUREMENTS: The
      concentrations of interleukins (IL)-1beta, 6, 8, 10 and TNF were measured in the
      control samples, pre-and post-filter and in the effluent at baseline and hourly
      thereafter. The clearances by adsorption, and filtration were calculated.
      RESULTS: Control cytokine concentrations remained the same or increased slightly.
      Adsorption was the major mechanism of removal for all cytokines with the
      exception of IL-1beta, but the effect was short-lived. Peak adsorption generally
      occurred at baseline before the start of CVVH and CVVHD, with clearances ranging
      from 43.7 ml/min (for IL-8) to 7.6 ml/min (for IL-10). The time-weighted average
      total clearances during CVVH were 23.3, 4.3, 3.8, -2.0, and 15 ml/min for IL-8,
      IL-1beta, TNF, IL-6, and IL-10 respectively. The corresponding clearances during
      CVVHD were 19.0, 10.7, 2.7, 2.4, and 0.3 ml/min. IL-10 clearances were greater
      during CVVH than CVVHD (p=0.03). Non adsorptive CVVH clearance of IL-1beta was
      greater than CVVHD clearance, but this advantage was outweighed by an increased
      tendency of the membrane to release IL-1beta into the circuit during HF.
      CONCLUSIONS: The technique of solute removal had only a minor effect on the
      magnitude of cytokine adsorption, and neither technique had the advantage for all
      the measured cytokines.

PMID- 15202817
TI  - Pulse high volume hemofiltration.
AB  - The sepsis syndrome is the most common cause of acute renal failure and multiple
      organ dysfunction in critically ill subjects and continues to have an alarmingly
      high mortality. Normal immune homeostasis is interrupted by a complex storm of
      inflammatory mediators responsible for the deleterious effects. Extracorporeal
      blood purification techniques can confer benefits in sepsis by proven non
      specific removal of these mediators (pro- or anti-inflammatory), and provide a
      logical and adequate approach to treat this syndrome. High volume hemofiltration
      (HVHF) has had the most dramatic effect conferring benefits in hemodynamics,
      reduction in vasopressor doses and improvement in survival. "Pulse HVHF" is the
      latest approach which may offer the most efficient results: a daily schedule of 6
      8 hours followed by standard CVVH. This paper describes the rationale and
      potential of this technique. Reliability and tolerance of this technique and
      biological effects are described.

PMID- 15202818
TI  - First clinical trial for a new CRRT machine: the Prismaflex.
AB  - A new CRRT machine has been designed to fulfill the expectations of nephrologists
      and intensivists operating in the common ground of critical care nephrology. The
      new equipment is called "Prismaflex" (Gambro-Dasco, Mirandola, Modena) and it is
      the natural evolution of the Prisma machine that has been utilized worldwide for
      CRRT in the last decade. We performed a preliminary "alfa trial" to establish
      usability, flexibility and realiability of the new device. Accuracy was also
      tested by recording various operational parameters during different intermittent
      and continuous renal replacement modalities. Forty-one runs were conducted on 13
      patients and the difference between delivered and prescribed parameters was
      always lower than 2%. We concluded that the new Prismaflex is a well designed new
      machine for CRRT and can be safely and effectively utilized in the critical care
      nephrology setting.

PMID- 15202819
TI  - Percutaneous bridge to heart transplantation by venoarterial ECMO and transaortic
      left ventricular venting.
AB  - We report a case in which life support for cardiogenic shock was achieved by a
      nonpulsatile venoarterial bypass, and left ventricular decompression was obtained
      by a catheter placed percutaneously through the aortic valve into the left
      ventricle. The blood drained from the left ventricle was pumped into the femoral
      artery. The normalization of left heart filling pressures allowed the resolution
      of pulmonary edema, and the patient underwent a successful heart transplantation
      following 7 days of mechanical cardiocirculatory support.

PMID- 15202820
TI  - Clinical evaluation of internal hemodiafiltration (iHDF): a diffusive-convective
      technique performed with internal filtration enhanced high-flux dialyzers.
AB  - AIM: Efficiency in removing middle molecules such as beta2-microglobulin (beta2
      MG) is one of the main purposes of modern dialytic therapy. In order to achieve
      this, techniques requiring complex machines and substitution fluid have been
      developed over recent years. Alternatively, the internal filtration/back
      filtration phenomenon can be used. The recent development of a so-called
      "internal filtration enhanced dialyser" prompted us to compare the removal of
      beta2-MG together with other small molecules when the dialyser was used either in
      standard hemodiafiltration (HDF) or internal hemodiafiltration (iHDF). METHODS:
      Ten stable, anuric, hemodialysis (HD) patients treated by thrice weekly standard
      bicarbonate HD using low-flux synthetic membrane entered the study. A new high
      flux polysulfone dialyser designed with the specific aim of enhancing internal
      filtration (BS-1.6 UL, 1.6 m2, Toray Industries) was used. Post dilution HDF (2.5
      l/hour of substitution fluid, dialysate flow 500 ml/min) was compared with iHDF
      (dialysate flow 750 ml/min), with blood flow at 300 ml/min. Samples were obtained
      at the start and at the end of the session in order to measure the % removal of
      urea, creatinine, uric acid, phosphate and beta2-MG (corrected for total protein
      concentration). In addition, after 20 min of dialysis the clearances of the same
      molecules were measured. A mathematical model has been developed for the
      description of the hydrodynamic phenomena taking place within the dialyser and of
      fluid filtration across the membrane. RESULTS: No significant differences have
      been observed in removal rate switching from HDF to iHDF except for beta2-MG
      removal, which was slightly higher in HDF than in iHDF Phosphate clearance is
      significantly higher than those obtained with creatinine in both HDF (p<0.005)
      and iHDF (p<0.01) modalities. The total convection calculated with the model is
      reduced with respect to HDF only by 24% (4100 ml/h vs. 5400 ml/h on the average).
      CONCLUSIONS: iHDF is a high flux dialysis method, which, if performed with a
      dialyser designed to enhance internal filtration, obtains a much higher removal
      rate in comparison with dialysers in traditional high flux dialysis, as
      previously reported in the literature. Provided that the dialyser is used on a
      dialysis machine working with ultra pure dialysate and UF control, this dialyser
      line can perform reliable internal HDF without the need for replacement solution.
      Considering the narrow difference in performance observed between iHDF and HDF,
      and the increasing number (and age) of patients leading to higher dialysis costs,
      iHDF represents a cost-effective alternative to other diffusive-convective
      techniques.

PMID- 15202821
TI  - Internal hemodiafiltration (iHDF): a possible option to expand hemodiafiltration
      therapy.

PMID- 15202822
TI  - An easy technique to digest and isolate UHMWPE wear particles from a hip joint
      simulator.
AB  - The size and morphology of polyethylene wear particles isolated from in vitro
      tests were analysed in this study. There are some major controversies emerging in
      the literature that will only be resolved by careful particles analysis. Since it
      is difficult to identify the factors that affect size and morphology of the wear
      particles, the goal of this study was to compare four different polymer wear
      debris isolation techniques (base method and acid treatment) under identical
      conditions in a hip joint simulator to obtain polyethylene wear particles. We
      investigated achieving particulate isolation by using a different approach to the
      one reported in the literature that involved an easier and streamline method of
      particle debris isolation. The new method, compared to the previous one, used a
      strong base, normal centrifugation, and filtration to digest the serum
      constituents thus isolating the polyethylene particle debris from lubricant. In
      all four methods the isolation involved some or all of the following steps:
      density gradient separation, centrifugation or ultracentrifugation, and washing.
      However, a requirement for all these techniques was that the lubricant had to be
      devoid of organic compounds in order to effectively image and count the particle
      debris. The results from these studies clearly show that this new method of
      particle isolation is easier and more streamlined than the three methods analysed
      and reported in literature because it did not involve ultracentrifugation and is
      quicker.

PMID- 15202824
TI  - Impact factor 2002--too much "impact"?

PMID- 15202825
TI  - Institute for Nutrition, Metabolism and Diabetes.

PMID- 15202823
TI  - Pulsatile roller pump perfusion is safe in high risk patients.
AB  - In this study, controllability, safety, blood cell depletion, and hemolysis of a
      pulsatile roller pump in high-risk patients was evaluated. Sarns 8000 roller pump
      (Sams, Terumo CVS, Ann Arbor, MI, USA) with a pulsatile control module was used
      as arterial pump in a clinical setting. Forty patients undergoing elective open
      heart surgery with high-risk either having chronically obstructive pulmonary
      disease or chronic renal failure were randomly included in the study to be
      operated on using pulsatile perfusion or non-pulsatile perfusion. Blood samples
      were withdrawn at induction of anesthesia, at the time of aortic clamping and de
      clamping and at 1 hour and 24 hours following cessation of the bypass. Hematocrit
      and plasma free hemoglobin values were measured. We observed that the pulsatile
      roller pump perfusion and the extracorporeal circuit used in the clinical study
      is safe in high-risk patients undergoing cardiopulmonary bypass. We did not face
      any emboli, hemolysis, or technical problems. Pulsatile roller pump perfusion
      with Sarns 8000 heart-lung machine is a simple and reliable technique and can be
      easily applied during open heart surgery.

PMID- 15202826
TI  - Dissecting technology-enabled knowledge translation: essential challenges,
      unprecedented opportunities.

PMID- 15202827
TI  - Soluble adhesion molecules in acute ischemic stroke.
AB  - BACKGROUND: Inflammatory adhesion molecules play a key role in the development of
      ischemic lesions. Elevated plasma concentrations of soluble adhesion molecules
      are reported in stroke patients, but data are still controversial. Our aim was to
      explore the potential association of plasma levels of soluble (s) intercellular
      and vascular cellular adhesion molecules-1 (sICAM-1 and sVCAM-1), sE-selectin and
      sL-selectin with acute ischemic stroke. METHODS: At our university hospital in
      Zagreb, Croatia, we prospectively enrolled 67 subjects with acute ischemic
      stroke, as well as 76 consecutive healthy individuals as controls who were
      visiting the centre for reasons unrelated to stroke. Serum concentrations of the
      molecules of interest were determined by means of quantitative sandwich enzyme
      immunoassay. RESULTS: Mean levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.034) and
      sE-selectin (p < 0.002) were higher in patients than in controls, whereas sL
      selectin was lower in patients (p = 0.043). In patients, levels of soluble
      adhesion molecules were independent of age and sex except for sL-selectin, which
      was inversely correlated with age (r = -0.260, p = 0.034) and higher in women (p
      = 0.006) and diabetics (n = 14; p = 0.004). Serum levels did not differ
      significantly with respect to carotid atherosclerotic disease, smoking status,
      hypertension or hypercholesterolemia. As well as correlating with each other,
      concentrations of soluble adhesion molecules in patients correlated with
      traditional biochemical markers of inflammation: total leukocyte count,
      erythrocyte sedimentation rate (ESR) and C-reactive protein level. Concentrations
      of sICAM-1 and high-density lipoprotein-cholesterol and ESR were identified as
      significant independent predictors/indicators of acute ischemic stroke.
      CONCLUSIONS: Acute ischemic stroke is associated with elevated plasma levels of
      sICAM-1, sVCAM-1 and sE-selectin, independent of age, sex and other recognized
      risk factors for stroke. Decreased levels of sL-selectin are associated with
      acute stroke. The observed changes in serum concentrations of adhesion molecules
      indicate inflammatory process occurring during acute cerebral ischemia.

PMID- 15202828
TI  - Cardiac matrix remodelling in congestive heart failure: the role of matrix
      metalloproteinases.
AB  - BACKGROUND: Congestive heart failure (CHF), the most frequent reason for hospital
      admission of elderly patients, is an important and rapidly increasing cause of
      morbidity and mortality worldwide. Its development is accompanied by left
      ventricle (LV) dilatation and pump dysfunction. The extracellular space in the
      heart is now recognized as an essential element of myocardial structure and
      function, and a dynamic participant in remodelling. The matrix metalloproteinases
      (MMPs) are an endogenous enzyme system responsible for extracellular collagen
      degradation and remodelling. OBJECTIVES: To evaluate the potential role of
      several MMPs (MMP-1, MMP-3 and MMP-9) in CHF. PATIENTS AND METHODS: We recruited
      30 consecutive patients with moderate to severe CHF who presented for heart
      failure management, along with 15 age- and sex-matched control participants. Two
      dimensional and M-mode echocardiographic studies were used to assess LV size and
      function and hence assess LV remodelling. MMP-1, -3 and -9 concentrations in
      serum were measured by ELISA at the time of admission and diagnosis. RESULTS:
      Serum levels of all 3 metalloproteinases were higher in patients with CHF than in
      controls; those of MMP-3 were markedly increased in patients with severe CHF.
      CONCLUSIONS: The association found between LV performance and MMP levels suggests
      that MMPs are implicated in CHF, that serum concentrations of MMPs may serve as
      markers for CHF, and that MMPs are a potential novel therapeutic target.

PMID- 15202829
TI  - Permanent global amnesia: case report.
AB  - PURPOSE: To present a case of permanent global amnesia related to hippocampal
      damage. Permanent global amnesia is a very rare condition of unknown etiology;
      lesions restricted to the hippocampus are uncommon, which hinders investigations
      of this pattern of memory loss. This case is unusually well documented, as the
      patient underwent extensive neuropsychological evaluations. CLINICAL FEATURES: A
      cheerful right-handed, 83-year-old retired electrician was first evaluated in
      1990 for progressive difficulty in learning new information and in recalling
      events over the preceding 3-4 years. Tests over the next 5 years showed that the
      impairment was confined to episodic declarative memory. New verbal information
      could be stored only in episodic memory in a restricted manner, limited by short
      term memory capacity. A relatively mild retrograde amnesia was detected. Semantic
      and implicit memory was spared, as were other functions evaluated. The patient's
      language and executive function were strikingly efficient. Magnetic resonance
      imaging of the brain showed bilateral atrophy of the hippocampi and amygdalae,
      ruling out conditions such as tumour growth. A diagnosis of permanent global
      amnesia was made. In the ensuing years, the retrograde amnesia worsened, but no
      new deficits were identified. CONCLUSION: This case, the first with a detailed
      cognitive examination, is evidence of a relatively pure hippocampal pattern for
      memory loss in permanent global amnesia.

PMID- 15202830
TI  - Long-term warfarin treatment may induce arterial calcification in humans: case
      report.
AB  - PURPOSE: To report a case of arterial calcification in a person who has had long
      term treatment with warfarin. Although the anticoagulant has been shown to induce
      arterial calcification in laboratory animals, there have been no previous reports
      implicating warfarin as a clinical factor. CLINICAL FEATURES: On routine annual
      examination, the coronary arteries of a healthy man with no symptoms who has had
      long-term warfarin treatment were found to be highly calcified. CONCLUSION: It
      would be prudent to further evaluate experimentally the relationship of warfarin
      and arterial calcification. We suggest that physicians prescribing long-term
      warfarin treatment consider arterial calcification as one of its potential
      consequences.

PMID- 15202831
TI  - Serum antibody reactivity to human intracisternal A-type particle retrovirus
      proteins in systemic sclerosis patients.
AB  - Serum antibodies against human intracisternal A-type particle (HIAP) endogenous
      retrovirus have been found to be associated with various autoimmune pathologies.
      To evaluate the presence of serum antibody reactivity to HIAP proteins in
      systemic sclerosis, a Western blot analysis was performed on sera from 42
      patients with systemic sclerosis, in comparison with 18 sera from patients with
      primary biliary cirrhosis and 52 healthy subjects. A positive Western blot was
      found in 55.5% of serum samples from patients with primary biliary cirrhosis and
      in 66.0% of patients with systemic sclerosis. None of the 52 healthy subjects
      showed positive results. Although this difference may be attributable either to
      an autoimmune response to antigenically related cellular proteins or to a
      specific antibody response to HIAP proteins expressed as an incidental
      consequence of attendant pathological processes, the high prevalence of
      antibodies against HIAP proteins demonstrated in patients with systemic sclerosis
      may be considered a hallmark of this disease.

PMID- 15202832
TI  - Methicillin-resistant Staphylococcus aureus colonization in inflammatory versus
      non-inflammatory skin diseases: who should be screened?
AB  - The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) was
      prospectively investigated in a dermatology outpatient setting. Swabs were taken
      from anterior nares, perineum and lesional skin in 229 patients with erosive
      inflammatory skin diseases (n=88), venous leg ulcers (n=58) or basal cell
      carcinoma (n=83) and processed by standard methods. The isolated MRSA strains
      were characterized by pulsed-field gel electrophoresis after digestion with the
      restriction enzyme SmaI. MRSA carriage was detected in 10/88 patients with
      inflammatory skin diseases, 5/58 with venous leg ulcers and 0/83 with basal cell
      carcinoma. Most of the MRSA isolates could be identified as either the Rhine
      Hessen epidemic strain or local epidemic strains. None of the isolated strains
      was resistant to vancomycin, gentamicin or mupirocin. MRSA is uncommon in
      outpatients in our dermatology clinic; however, the presence of chronic ulcers
      and erosions was significantly associated with MRSA positivity. Therefore,
      patients with chronic ulcers and erosions should be screened for MRSA
      colonization to implement infection control measures.

PMID- 15202833
TI  - Lack of association of CCR4 single nucleotide polymorphism with atopic dermatitis
      in Japanese patients.
AB  - CCR4, a member of the CC chemokine receptor family, is believed to play an
      important role in the pathogenesis of atopic dermatitis. To examine whether CCR4
      single nucleotide polymorphism (SNP) is associated with susceptibility to atopic
      dermatitis, we investigated the allele and genotype frequencies of C1014T SNP of
      CCR4 in 198 Japanese patients with atopic dermatitis and controls by a PCR
      restriction fragment length polymorphism method. There was no significant
      difference in allele or genotype frequencies between patients with atopic
      dermatitis and controls. Serum IgE levels and peripheral blood eosinophil counts
      were not significantly different among genotypes. There was also no significant
      difference in allele or genotype frequencies between the patient subgroup with
      and without asthma, with mild or moderate disease, with and without family
      history of atopic dermatitis, or with and without family history of atopic
      disorders. C1014T SNP of CCR4 does not appear to be associated with
      susceptibility to atopic dermatitis in Japanese patients.

PMID- 15202834
TI  - Stimulatory effect of boron and manganese salts on keratinocyte migration.
AB  - Keratinocyte proliferation and migration are essential for the reconstruction of
      the cutaneous barrier after skin injury. Interestingly, thermal waters which are
      rich in trace elements (e.g. boron and manganese), are known to be able to
      improve wound healing. In order to understand the mechanism of action of this
      effect, our study investigated the in vitro modulation of keratinocyte migration
      and proliferation by boron and manganese salts, which are present in high
      concentrations in a thermal water (Saint Gervais). Our in vitro study
      demonstrated that incubating keratinocytes for 24 h with boron salts at
      concentrations between 0.5 and 10 microg/ml or manganese salts at concentrations
      between 0.1 and 1.5 microg/ml accelerated wound closure compared with control
      medium (+20%). As this acceleration was not related to an increase in
      keratinocyte proliferation we suggest that boron and manganese act on wound
      healing mainly by increasing the migration of keratinocytes.

PMID- 15202835
TI  - A left/right comparison of twice-daily calcipotriol ointment and calcitriol
      ointment in patients with psoriasis: the effect on keratinocyte subpopulations.
AB  - Vitamin D3 analogues are a first-line treatment of chronic plaque psoriasis, but
      so far, comparative clinical studies on calcipotriol and calcitriol ointment are
      sparse, and in particular no comparative studies are available on cell biological
      effects of these compounds in vivo. Using flow cytometric assessment, we
      investigated whether these compounds had different effects on the composition and
      DNA synthesis of epidermal cell populations responsible for the psoriatic
      phenotype. For 8 weeks, 20 patients with psoriasis vulgaris were treated twice
      daily with calcipotriol and calcitriol ointment in a left/right comparative
      study. Before and after treatment, clinical assessment of target lesions was
      performed, together with flow cytometric analysis of epidermal subpopulations
      with respect to keratin (K) 10, K6, vimentin and DNA distribution. Treatment with
      each compound resulted in a substantial clinical improvement, a reduction of the
      K10-K6- population and an increase of the K10+K6- population. A correlation was
      found between the clinical response of calcipotriol and the K10+K6- population,
      and the clinical response of calcitriol and the K10+K6- population, as well as
      the percentage of cells in the S, G2 and M phase of the cell cycle within the K10
      K6- population, suggesting that the analogues have a different preference for
      affecting the K10+K6- pool (committed differentiated cells) or affecting the K10
      K6- pool (basal cells).

PMID- 15202836
TI  - Correlation between endocrinological parameters and acne severity in adult women.
AB  - Many studies demonstrate increased androgen levels and high prevalence of
      polycystic ovaries in women affected by acne. We evaluated the relationship
      between clinical features, ultrasonographic data on polycystic ovaries and
      hormonal parameters in 129 women >17 years of age with acne. Serum levels of
      androgens of ovarian and adrenal origin were measured. Menstrual cycle
      regularity, hirsutism, body mass index and ultrasonographic evaluation of ovaries
      were recorded. Raised levels of at least one androgen were evident in a majority
      of our patients. Only 19% of them had polycystic ovary syndrome. Hirsutism and
      acne severity correlated negatively with serum sex hormone-binding globulin
      (SHBG) levels (p<0.05). No correlation between acne severity and hirsutism was
      found. In post-pubertal women, severity of acne seems to depend on peripheral
      hyperandrogenism, with a negative relationship between the acne severity and
      serum SHBG levels. We strongly recommend the evaluation of serum SHBG levels in
      women with acne in order to select patients who can have a better response to
      appropriate hormonal regimes.

PMID- 15202837
TI  - Psychological symptoms and quality of life of dermatology outpatients and
      hospitalized dermatology patients.
AB  - The aim of the investigation was to compare psychological symptoms and health
      related quality of life of dermatology patients and healthy controls. The sample
      consisted of 333 consecutively recruited patients from four dermatology
      outpatient clinics, 172 hospitalized dermatological patients from two university
      hospitals and 293 matched healthy controls. All patients and controls completed
      Beck's Depression Inventory, the Brief Symptom Inventory and the Dermatology Life
      Quality Index. Hospitalized patients were more distressed than outpatients and
      healthy controls and reported greater impairment of disease-related quality of
      life than outpatients. More hospitalized patients had suicidal thoughts and were
      characterized as having severe to moderate depression compared with outpatients
      and controls. Female patients and younger patients were generally more distressed
      than male patients and older patients, and patients with atopic dermatitis and
      psoriasis were more distressed than patients with urticaria and eczemas. Disease
      related impairment of quality of life was the main predictor of psychological
      symptoms, when controlling for diagnosis, age, gender, disease duration and
      disease severity. Although older age was associated with fewer psychological
      symptoms, our data suggest that skin disease affects quality of life equally in
      young and older patients. The findings highlight the importance of recognizing
      disease-related psychological problems and possible psychiatric comorbidity of
      dermatology patients, especially among patients with atopic dermatitis and
      psoriasis.

PMID- 15202838
TI  - Recognition of depressive and anxiety disorders in dermatological outpatients.
AB  - Although mental disorders are frequent among dermatological patients, little is
      known about their recognition by dermatologists. This study aimed to assess
      dermatologists' ability to recognize depressive and anxiety disorders. All adult
      outpatients who visited four dermatologists on predetermined days (n=317)
      completed the 12-item General Health Questionnaire (GHQ-12) and the section on
      depressive and anxiety disorders of the Patient Health Questionnaire (PHQ).
      Dermatologists, masked to GHQ-12 and PHQ scores, rated patients' mental health
      status. The analysis was performed on 277 patients (87%) with complete data. With
      the PHQ as criterion standard, the dermatologists' assessment sensitivity was
      33%, while specificity was 76%. In most cases of disagreement between the
      dermatologists and the PHQ, the GHQ-12 corroborated the PHQ classification.
      Anxiety disorders tended to be recognized better than depressive disorders. Among
      patients with a PHQ diagnosis, male gender tended to be associated with
      misclassification by dermatologists. Although limitations inherent in self-report
      psychiatric assessment should be considered, this study suggests that mental
      disorders often go unrecognized in dermatological patients. This issue might be
      addressed by implementing specific training programmes, using validated screening
      questionnaires for depression and anxiety, and developing rational consultation
      liaison services.

PMID- 15202839
TI  - Munich method of micrographic surgery for basal cell carcinomas: 5-year
      recurrence rates with life-table analysis.
AB  - The aim of this study was to find the recurrence rates of basal cell carcinomas
      treated with micrographic surgery in the Department of Dermatology, University of
      Regensburg. From 1992 to 1997, 261 basal cell carcinomas (178 primary and 83
      recurrent) have been treated. The mean duration of follow-up was 5 years (range 1
      9). Data were analysed by life-table analysis. Eleven basal cell carcinomas (6
      primary and 5 recurrent) recurred. The 5-year recurrence rates were 3.3% for
      primary and 7.3% for recurrent basal cell carcinomas. Our results are comparable
      with previously published data from Europe but seem higher than those reported in
      the USA. Use of different statistical methods to report the recurrence rates
      mainly accounts for the discrepancy among studies. For a better comparison among
      studies on recurrence rates, a standard statistical method should be used, and we
      support the idea that life-table analysis provides the best approximation of the
      true recurrence rates.

PMID- 15202840
TI  - Systemic contact dermatitis from herbal and homeopathic preparations used for
      herpes virus treatment.
AB  - Systemic contact dermatitis may occur in contact-sensitized individuals when they
      are exposed to haptens orally, transcutaneously, intravenously or by inhalation.
      We report the case of a woman developing a diffuse skin eruption after the
      topical use of Rhus toxicodendron alcoholic extract and the oral introduction of
      a homeopathic preparation of the same substance for herpes treatment. An open
      test, performed with the Rhus toxicodendron tincture, showed an erythemato
      oedematous response at 48 h and vesicular reaction at 96 h that was still present
      after 7 days. Patch test with 65% ethyl alcohol gave negative results. The open
      test performed, as control, in eight healthy informed subjects revealed negative
      responses to Rhus tincture application. The result is interesting because in
      Italy, allergic contact dermatitis to Rhus is uncommon and this case increases
      the understanding of the pathogenetic mechanism leading to systemic contact
      dermatitis development.

PMID- 15202841
TI  - Invasive squamous cell carcinoma treated with imiquimod 5% cream.

PMID- 15202842
TI  - Lichenoid drug eruption with HMG-CoA reductase inhibitors (fluvastatin and
      lovastatin).

PMID- 15202843
TI  - Multiple fibrous papulosis: a variant of white fibrous papulosis of the neck?

PMID- 15202844
TI  - Localized transient acantholytic dermatosis in a patient with left hemiparesis.

PMID- 15202845
TI  - Treatment of chronic discoid lupus erythematosus with topical tacrolimus.

PMID- 15202846
TI  - A case of nevoid acanthosis nigricans.

PMID- 15202847
TI  - Rheumatoid neutrophilic dermatitis as presenting sign of seronegative arthritis.

PMID- 15202848
TI  - Black lunula caused by Tegafur.

PMID- 15202849
TI  - Facial erythema alone as a manifestation of chronic graft-versus-host disease.

PMID- 15202850
TI  - Eruptive pseudoangiomatosis: three cases in Korean middle-aged women.

PMID- 15202851
TI  - Painful nodule on the scalp: a case of primary cutaneous adenoid cystic
      carcinoma.

PMID- 15202852
TI  - Nerve involvement in Indian post kala-azar dermal leishmaniasis.

PMID- 15202853
TI  - Infliximab (Remicade) for acute, severe pustular and erythrodermic psoriasis.

PMID- 15202854
TI  - Enlarged hair follicles in patients with Ehlers-Danlos syndrome.

PMID- 15202855
TI  - Diffuse dermal angiomatosis due to an iatrogenic arteriovenous fistula.

PMID- 15202856
TI  - Dyshidrosiform bullous pemphigoid.

PMID- 15202857
TI  - No significant association between CYP1A2 polymorphism and porphyria cutanea
      tarda.

PMID- 15202858
TI  - Differentiation of rat neural stem cells and its relationship with environment.
AB  - OBJECTIVE: To explore the differentiation fates of rat neural stem cells (NSCs)
      in different environmental conditions. METHODS: NSCs derived from 16-day-old rat
      embryo were proliferated in vitro and implanted into the brain of rats with intra
      cerebral hemorrhage. At the same time some NSCs were co-cultured in vitro with
      Schwann cells derived from newborn rats. MAP-2, GFAP and GalC (which are the
      specific markers of neural cells, astrocytes and oligodendrocytes respectively),
      BrdU and beta-tubulin were detected by immunohistochemical and immunofluorescent
      methods. RESULTS: BrdU positive cells that were implanted into the brain
      distributed around the hemorrhagic area. The majority of them were GFAP positive
      astrocytes while a few of them were beta-tubulin positive neural cells or GalC
      positive oligodendrocytes. After being co-cultured with Schwann cells in vitro,
      NSCs are predominately shown beta-tubulin and MAP-2 positive, and only a minority
      of them were GFAP or GalC positive. CONCLUSIONS: The hemorrhagic environment in
      vivo induces NSCs to differentiate mainly into astrocytes while co-culture with
      Schwann cells in vitro induce the majority of NSCs to differentiate into neural
      cells.

PMID- 15202859
TI  - Dynamic analyses of PrP and PrP(Sc) in brain tissues of golden hamsters infected
      with scrapie strain 263K revealed various PrP forms.
AB  - OBJECTIVE: To expatiate dynamic changes in hamsters infected with scrapie strain
      263K, to observe the presence and aggravation of various forms of PrP and PrP(Sc)
      during incubation period, and to probe primarily the relationship between the
      onset of clinic manifestations and the presence of different PrP(Sc) forms.
      METHODS: Hamster-adapted scrapie strain 263K was intracerebrally inoculated into
      hamsters. Different forms of PrP and PrP(Sc) were monitored dynamically by
      Western blot and immuno-histochemical assays. The presence of scrapie-associated
      fibril (SAF) was assayed by electron microscopy analysis (EM) and immuno-golden
      EM. RESULTS: PrP(Sc) was initially detected in the brain tissues of the animals
      in 20 days post-inoculation by immunohistochemistry and 40 days with Western
      blot. Quantitative evaluations revealed that the amounts of PrP and PrP(Sc) in
      brain tissues increased along with the incubation. Several high and low molecular
      masses of PrP were seen in the brains of the long-life span infected animals.
      Deglycosylation assays identified that the truncated PrP in the infected brains
      showed similar glycosylation patterns as the full-length PrP. The presence of
      short fragments was seemed to relate with the onset of clinical conditions.
      CONCLUSION: These results indicate that infectious agents exist and accumulate in
      central nerve system prior to the onset of the illness. Various molecular
      patterns of PrP(Sc) may indwell in brain tissues during the infection.

PMID- 15202860
TI  - Microbial degradation of quinoline: kinetics study with Burkholderia picekttii.
AB  - OBJECTIVE: To investigate the kinetics of quinoline biodegradation by
      Burkholderia pickttii, a gram negative rod-shaped aerobe, isolated in our
      laboratory. METHODS: HPLC (Hewlett-Packard model 5050 with an UV detector) was
      used for the analysis of quinoline concentration. GC/MS method was used to
      identify the intermediate metabolites of quinoline degradation. RESULTS: The
      biodegradation of quinoline was inhibited by quinoline at a high concentration,
      and the degradation process could be described by the Haldane model. The kinetic
      parameters based on Haldane substrate inhibition were evaluated. The values were
      vmax = 0.44 h(-1), K(S) = 166.7 mg/L, Ki = 650 mg/L, respectively. The quinoline
      concentration to avoid substrate inhibition was inferred theoretically and
      determined to be 329 mg/L. CONCLUSION: The biodegradation of quinoline conforms
      to the Haldane inhibition model and the main intermediate metabolite of quinoline
      biodegradation is 2-hydroxy-quinoline.

PMID- 15202861
TI  - Chelation in metal intoxication XLVI: synthesis of some alpha-mercapto-beta
      substituted aryl acrylic acids and their in vitro cadmium chelating ability.
AB  - OBJECTIVE: To synthesize some new alpha-mercapto-beta-substituted aryl acrylic
      acids, characterize them and investigate their in vitro cadmium chelating
      ability. METHODS: Six alpha-mercapto-beta-substituted aryl acrylic acids were
      prepared by the alkaline hydrolysis of 5- (aryl methylene) rhodanines, obtained
      from the condensation of substituted aldehydes and rhodanine following the
      reported procedure. The new compounds were characterized by elemental analysis,
      infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. The liver and
      kidney from cadmium chloride pre-administered rats were homogenized and their
      nuclear mitochondrial fraction (NMF) and supernatant cytosol fraction (SCF) were
      separated. A measured volume of each fraction was dialyzed separately using
      "dialysis sack" against buffered-KCl medium containing a compound in the final
      concentration of 1 x 10(-3) mol/L for 3 h at 37 degrees C. The whole content of
      "sack" was subjected to cadmium estimation following digestion with conc. Nitric
      acid was detected using flame atomic absorption spectrometer. RESULTS: The in
      vitro screening showed that alpha-mercapto-beta-(p-methoxyphenyl) acrylic acid
      (compound 2) and alpha-mercapto-beta-(m-methoxy, p-hydroxyphenyl) acrylic acid
      (compound 4) were more effective than alpha-mercapto-beta-thienyl acrylic acid
      (compound 1) and alpha-mercapto-beta-(p-dimethylaminophenyl) acrylic acid
      (compound 3) in mobilizing cadmium as their dialyzable chelates. The presence of
      a methoxy group on the phenyl moiety (compounds 2 and 4) increases the metal
      chelating ability of mercapto acrylic acids. CONCLUSIONS: Compounds 2 and 4 seem
      to have accessibility to the cellular system and capability of chelating-out the
      intracellularly bound cadmium.

PMID- 15202862
TI  - ROS-related enzyme expressions in endothelial cells regulated by tea polyphenols.
AB  - OBJECTIVE: Elevation of reactive oxygen species (ROS), especially the level of
      superoxide is a key event in many forms of cardiovascular diseases. To study the
      mechanism of tea polyphenols against cardiovascular diseases, we observed the
      expressions of ROS-related enzymes in endothelial cells. METHODS: Tea polyphenols
      were co-incubated with bovine carotid artery endothelial cells (BCAECs) in vitro
      and intracellular NADPH oxidase subunits p22phox and p67phox, SOD-1, and catalase
      protein were detected using Western blot method. RESULTS: Tea polyphenols of 0.4
      microg/mL and 4.0 microg/mL (from either green tea or black tea) down-regulated
      NADPH oxidase p22phox and p67phox expressions in a dose-negative manner (P <
      0.05), and up-regulated the expressions of catalase (P < 0.05). CONCLUSIONS: Tea
      polyphenols regulate the enzymes involved in ROS production and elimination in
      endothelial cells, and may be beneficial to the prevention of endothelial cell
      dysfunction and the development of cardiovascular diseases.

PMID- 15202863
TI  - Radiation-induced bystander effect in immune response.
AB  - OBJECTIVE: Since most reports on bystander effect have been only concerned with
      radiation-induced damage, the present paper aimed at disclosing whether low dose
      radiation could induce a stimulatory or beneficial bystander effect. METHODS: A
      co-culture system containing irradiated antigen presenting cells (J774A.1) and
      unirradiated T lymphocytes (EL-4) was established to observe the effect of
      J774A.1 cells exposed to both low and high doses of X-rays on the unirradiated EL
      4 cells. Incorporation of 3H-TdR was used to assess the proliferation of the EL-4
      cells, expression of CD80/86 and CD48 on J774A.1 cells was measured with
      immunohistochemistry and flow cytometry, respectively. NO release from J774A.1
      cells was estimated with nitrate reduction method. RESULTS: Low dose-irradiated
      J774A.1 cells could stimulate the proliferation of the unirradiated EL-4 cells
      while the high dose-irradiated J774A.1 cells exerted an inhibitory effect on the
      proliferation of the unirradiated EL-4 cells. Preliminary mechanistic studies
      illustrated that the differential changes in CD48 expression and NO production by
      the irradiated J774A.1 cells after high and low dose radiation might be important
      factors underlying the differential bystander effect elicited by different doses
      of radiation. CONCLUSION: Stimulatory bystander effect can be induced in immune
      cells by low dose radiation.

PMID- 15202864
TI  - Endosulfan-mediated biochemical changes in the freshwater fish Clarias batrachus.
AB  - OBJECTIVE: Endosulfan is an extremely toxic organochlorine pesticide to aquatic
      organisms which might be hampering fish health through impairment of metabolism
      sometimes leading to death. So an experimental protocol was designed to look at
      endosulfan effects on a number of selected biochemical endpoints as well as to
      develop a mechanistic understanding of biochemical effects of endosulfan in
      freshwater fish. METHODS: The adult freshwater catfish Clarias batrachus were
      collected and acclimatized to laboratory condition for two weeks prior to
      experimentation. The toxicity bioassay test of commercial grade endosulfan (35%
      EC) was conducted for 21 days to determine its initial lethal concentration. The
      fish were exposed to sublethal concentration of endosulfan (0.06 mg/L) for 21
      days. Pesticide-withdrawal experiments were also performed to study recovery.
      Protein synthesis inhibitors were injected to know the possible mechanism of
      recovery. The specimens of C. batrachus were sacrificed and brain, liver and
      caudal white skeletal muscle were removed. Tissues were homogenized and fractions
      were obtained by differential centrifugation. The activities of citrate synthase
      (CS), glucose 6-phosphate dehydrogenase (G6-PDH) and lactate dehydrogease (LDH)
      were assayed spectrophotometrically. Similarly, DNA, RNA and protein content were
      measured as per standard procedure. RESULTS: The exposure of sublethal
      concentration of endosulfan decreased the activity of citrate synthase (CS) and
      glucose 6-phosphate dehydrogenase (G6-PDH) in the brain, liver and skeletal
      muscle of the freshwater catfish, C. batrachus. The brain lactate dehydrogenase
      (LDH) activity was also reduced in response to endosulfan toxicity. The maximum
      reduction in activities of these enzyme was 34%-43%. Withdrawal of endosulfan
      restored the enzyme activity to control level in all the three tissues. The
      recovery in enzyme activity appears to be due to dissociation of endosulfan or
      its metabolite(s) from the enzyme molecules and/or fresh synthesis of enzymes.
      The treatment of actinomycin D or cycloheximide partially inhibited the
      withdrawal-dependent increase in enzyme activity. This substantiates de novo
      synthesis of enzyme during recovery period. Since the reduction in enzyme
      activity was more pronounced in response to actinomycin D, endosulfan might be
      inhibiting the transcription process. But endosulfan did not produce any
      significant effect on DNA content and RNA/DNA. However, the RNA and protein
      contents of brain, liver and skeletal muscle decreased significantly in tissues.
      The maximum decrease in RNA and protein was approximately 30%-37%. Withdrawal of
      endosulfan from the medium for 21 days restored the RNA, and protein contents
      nearly to their control levels. The treatment of actinomycin D or cycloheximide
      partially inhibited the withdrawal-dependent increase in these macromolecular
      contents. This effect was more pronounced in case of actinomycin D which again
      supports the possibility of endosulfan-induced inhibition at transcription level.
      CONCLUSION: The present study suggests endosulfan-induced impairment of
      metabolism in fish, which appeared to be due to inhibition of transcription at
      some unknown points.

PMID- 15202865
TI  - Polymorphism of methionine synthase gene in nuclear families of congenital heart
      disease.
AB  - OBJECTIVE: To investigate the relation of methionine synthase (MS) gene variation
      with congenital heart disease (CHD) phenotype. METHODS: One hundred and ninety
      three CHD patients (94 males and 99 females) and their biological parents
      (nuclear families) in Liaoning Province were selected as the case group, and
      another 104 normal persons (60 males and 44 females) and their parents without
      family history of birth defects as the control group. For all subjects the
      polymorphism of MS gene A2756G locus was examined by PCR-RFLP method. RESULTS: In
      offspring of the control group the frequencies of MS genotype (+/-) and allele
      (+) were 10.7% and 5.3%, without existence of homozygote. The MS genotype
      distribution and allele frequencies of CHD patients and their mothers were not
      significantly different from the control (P > 0.05). The frequency of allele (+)
      in case fathers (5.0%) was apparently lower than that in the control (9.1%, P =
      0.060), and the odds ratio (OR) was 0.53 (95% CI: 0.25-1.09). There was no
      difference in parents' genotype combination between the two groups, and in
      genotype distribution among different types of CHD. Analysis of genetic
      transmission indicated that mutation allele (+) existed transmission
      disequilibrium in CHD nuclear families. The percentage of allele (+) transmitted
      from parents was lower than that allele (-) with OR 0.26 (95% CI: 0.11-0.60).
      CONCLUSION: MS gene variation in parents is associated with occurrence of CHD in
      offspring, and mutation allele (+) in parents may be related with the decrease of
      CHD risk in offspring.

PMID- 15202866
TI  - Comparison study on clinical and neuropathological characteristics of hamsters
      inoculated with scrapie strain 263K in different challenging pathways.
AB  - OBJECTIVE: To understand the infectious characteristics of a hamster-adapted
      scrapie strain 263K with five different routes of infection including
      intracerebral (i.c.), intraperitoneal (i.p.), intragastrical (i.g.), intracardiac
      and intramuscular (i.m.) approaches. METHODS: Hamsters were infected with crude-
      or fine-prepared brain extracts. The neuropathological changes, PrP(Sc) deposits,
      and patterns of PK-resistant PrP were analyzed by HE stain, immnunohistochemistry
      (IHC) assay and Western blot. Reactive gliosis and neuron loss were evaluated by
      glial fibrillary acidic protein (GFAP) and neuron specific enolase (NSE) specific
      IHC. RESULTS: The animals inoculated in i.m. and i.p. ways with crude PrP(Sc)
      extracts showed clinical signs at the average incubation of 69.2 +/- 2.8 and 65.5
      +/- 3.9 days. Inoculation in i.c. and intracardiac ways with fine PrP(Sc)
      extracts (0.00035 g) caused similar, but relative long incubation of around 90
      days. Only one out of eight hamsters challenged in i.g. way with low dosage (0.01
      g) became ill after a much longer incubation (185 d), while all animals (4/4)
      with high dosage (0.04 g) developed clinical signs 105 days postinfection. The
      most remarkable spongiform degeneration and PrP(Sc) deposits were found in brain
      stem among the five challenge groups generally. The number of GFAP-positive
      astrocytes increased distinctly in brain stems in all infection groups, while the
      number of NSE-positive cells decreased significantly in cerebrum, except i.c.
      group. The patterns of PK-resistant PrP in brains were basically identical among
      the five infection routes. CONCLUSION: Typical TSE could be induced in hamsters
      by inoculating strain 263K in the five infection ways. The incubation periods in
      bioassays depend on infective dosage, administrating pathway and preparation of
      PrP(Sc). The neuropathological changes and PrP(Sc) deposits seem to be related
      with regions and inoculating pathways.

PMID- 15202867
TI  - Effects of AGEs on oxidation stress and antioxidation abilities in cultured
      astrocytes.
AB  - OBJECTIVE: To investigate whether two kinds of in vitro prepared advanced
      glycation end products (AGEs), Glu-BSA and Gal-BSA, could change oxidation stress
      and anti-oxidation abilities in astrocytes, and thus might contribute to brain
      injury. METHODS: Changes of GSH, MDA, SOD, MAO-B, nitric oxide were measured
      after AGEs treatment. RESULTS: Both 0.1 g/L Glu-BSA and Gal-BSA could slightly
      decrease GSH level, while 1 g/L of them significantly decreased GSH level by 35%
      and 43% respectively. The MDA levels of both 1 g/L AGEs treated groups (306 +/-
      13 and 346 +/- 22) were higher than that of the normal group (189 +/- 18), which
      could be inhibited by free radical scavenger NAC. The SOD activities of both 1
      g/L AGEs treated groups (67.0 +/- 5.2 and 74.0 +/- 11.0) were lower than that of
      the normal group (85.2 +/- 8.0). Both 0.1 g/L AGEs could slightly increase the
      activity of MAO-B, while 1 g/L of them could increase MAO-B activity by 1.5 and
      1.7 folds respectively. Both AGEs stimulation could produce NO level by 1.7 and 2
      folds respectively. CONCLUSION: Enhanced levels of astrocytic oxidation stress
      and decrease of antioxidation abilities may contribute to, at least partially,
      the detrimental effects of AGEs in neuronal disorders and aging brain.

PMID- 15202868
TI  - Water quality assessment of the River Nile system: an overview.
AB  - OBJECTIVES: The main objective of the present article is to assess and evaluate
      the characteristics of the Nile water system, and identify the major sources of
      pollution and its environmental and health consequences. The article is also
      aimed to highlight the importance of water management via re-use and recycle of
      treated effluents for industrial purpose and for cultivation of desert land.
      METHOD: An intensive effort was made by the authors to collect, assess and
      compile the available data about the River Nile. Physico-chemical analyses were
      conducted to check the validity of the collected data. For the determination of
      micro-pollutants, Gas Chromatography (GC) and High Performance Liquid
      Chromatography (HPLC) were used. Heavy metals were also determined to investigate
      the level of industrial pollution in the river system. RESULTS: The available
      data revealed that the river receives a large quantity of industrial, agriculture
      and domestic wastewater. It is worth mentioning that the river is still able to
      recover in virtually all the locations, with very little exception. This is due
      to the high dilution ratio. The collected data confirmed the presence of high
      concentrations of chromium and manganese in all sediment samples. The residues of
      organo-chlorine insecticides were detected in virtually all locations. However,
      the levels of such residues are usually below the limit set by the WHO for use as
      drinking water. The most polluted lakes are Lake Maryut and Lake Manzala.
      Groundwater pollution is closely related to adjacent (polluted) surface waters.
      High concentrations of nutrients, E. coli, sulfur, heavy metals, etc. have been
      observed in the shallow groundwater, largely surpassing WHO standards for
      drinking water use. CONCLUSION: A regular and continuous monitoring scheme shall
      be developed for the River Nile system. The environmental law shall be enforced
      to prohibit the discharge of wastewater (agricultural, domestic or industrial) to
      River Nile system.

PMID- 15202869
TI  - Arsenic induced inhibition of delta-aminolevulinate dehydratase activity in rat
      blood and its response to meso 2,3-dimercaptosuccinic acid and monoisoamyl DMSA.
AB  - OBJECTIVE: The objective of this study was to investigate arsenic induced changes
      in blood delta-aminolevulinic acid dehydratase (ALAD) after in vitro and in vivo
      exposure to this element and its response to co-administration of meso 2,3
      dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) either individually
      or in combination. METHODS: Rat whole blood was exposed to varying concentrations
      (0.1, 0.2 and 0.5 mmol/L) of arsenic (III) or arsenic (V), to assess their
      effects on blood ALAD activity. Varying concentrations of MiADMSA and DMSA (0.1,
      0.5 and 1.0 mmol/L) were also tried in combination to determine its ability to
      mask the effect of arsenic induced (0.5 mmol/L) inhibition of blood ALAD in
      vitro. In vitro and in vivo experiments were also conducted to determine the
      effects of DMSA and MiADMSA either individually or in combination with arsenic,
      on blood ALAD activity and blood arsenic concentration. RESULTS: In vitro
      experiments showed significant inhibition of the enzyme activity when 0.1-0.5
      mmol/L of arsenic (III and V) was used. Treatment with MiADMSA increased ALAD
      activity when blood was incubated at the concentration of 0.1 mmol/L arsenic
      (III) and 0.1 mmol/L MiADMSA. No effect of 0.1 mmol/L MiADMSA on ALAD activity
      was noticed when the arsenic concentration was increased to 0.2 and 0.5 mmol/L.
      Similarly, MiADMSA at a lower concentration (0.1 mmol/L) was partially effective
      in the turnover of ALAD activity against 0.5 mmol/L arsenic (III), but at two
      higher concentrations (0.5 and 1.0 mmol/L) a complete restoration of ALAD
      activity was observed. DMSA at all the three concentrations (0.1, 0.5 and 1.0
      mmol/L) was effective in restoring ALAD activity to the normal value.
      CONCLUSIONS: The results thus suggest that arsenic has a distinct effect on ALAD
      activity. Another important toxicological finding of the present study, based on
      in vivo experiments further suggests that combined administration of DMSA and
      MiADMSA could be more beneficial for reducing blood ALAD inhibition and blood
      arsenic concentration than the individual treatment.

PMID- 15202870
TI  - A study on detecting and identifying enteric pathogens with PCR.
AB  - OBJECTIVE: To develop a rapid and definite diagnostic test of bacterial enteritis
      caused by pathogenic enterobacteria, the most frequent etiologic agent of
      infectious enteritis in the world. METHODS: A set of conventional PCR assays were
      applied to detect and identify salmonella, shigella, and E. coli O157:H7 directly
      from pure culture and fecal samples. The general primers of pathogenic
      enterobacteria were located on the uidA gene, which were found not only in E.
      coli nuclear acid, but also in shigella and salmonella genes. Shigella primer was
      from ipaH gene whose coded invasive plasmid relative antigen existed both in
      plasmid and in genome. The primers of salmonella were designed from the 16SrRNA
      sequence. The primer of E. coli O157:H7 was taken from eaeA gene. Five random
      primers were selected for RAPD. The detection system included common PCR, semi
      nested PCR and RAPD. RESULTS: This method was more sensitive, specific and
      efficient and its processing was rapid and simple. For example, the method could
      be used to specifically detect and identify salmonella, shigella, and E. coli
      O157:H7, and its sensitivity ranged from 3 to 50 CFU, and its detection time was
      4 hours. CONCLUSION: This PCR method, therefore, can serve as a routine and
      practical protocol for detecting and identifying pathogenic microorganisms from
      clinical samples.

PMID- 15202871
TI  - Spinal epidural hematoma causing acute cauda equina syndrome.
AB  - Spinal epidural hematoma (SEH) is an uncommon cause of acute cauda equina
      syndrome. Most of these hematomas are caused by trauma, anticoagulation therapy,
      and vascular anomalies or occur following spinal epidural procedures and, rarely,
      spinal surgery. Spontaneous SEH is an extremely rare occurrence. The incidence of
      symptomatic postoperative SEH is 0.1 to 3%. Clinical evaluation is the most
      important tool in the early diagnosis of SEH. Once the disease is suspected
      clinically and confirmed on diagnostic imaging, emergency evacuation of the
      lesion should be performed. Prognosis depends on the rate of development of
      symptoms, interval to surgery, level of spinal involvement, and degree of
      neurological deficit.

PMID- 15202872
TI  - Infectious origins of cauda equina syndrome.
AB  - Infections in the spine can lead to a wide range of problems for both the patient
      and physician. There is perhaps no more devastating complication than the
      neurological consequences of a cauda equina syndrome due to spinal infection. A
      variety of organisms and origins can make diagnosis and treatment of spinal
      infection a difficult task. Both pyogenic and nonpyogenic organisms can cause
      vertebral involvement and can result in an epidural abscess with neurological
      compromise. Nonetheless, these two types of infections vary greatly in terms of
      associated patient demographics, clinical course, and treatments. The purpose of
      this paper was to review these types of infections and summarize treatment
      recommendations for this difficult condition.

PMID- 15202873
TI  - Cauda equina syndrome caused by primary and metastatic neoplasms.
AB  - Cauda equina syndrome (CES) is defined as the constellation of symptoms that
      includes low-back pain, sciatica, saddle anesthesia, decreased rectal tone and
      perineal reflexes, bowel and bladder dysfunction, and variable amounts of lower
      extremity weakness. There are several causes of this syndrome including trauma,
      central disc protrusion, hemorrhage, and neoplastic invasion. In this manuscript
      the authors reviewed CES in the setting of both primary and secondary neoplasms.
      They examined the various primary tumor types in this region as well as those
      representative of metastatic spread. Both surgical and nonsurgical management in
      this setting were studied.

PMID- 15202874
TI  - Conus medullaris and cauda equina syndrome as a result of traumatic injuries:
      management principles.
AB  - Conus medullaris syndrome (CMS) and cauda equina syndrome (CES) are complex
      neurological disorders that can be manifested through a variety of symptoms.
      Patients may present with back pain, unilateral or bilateral leg pain,
      paresthesias and weakness, perineum or saddle anesthesia, and rectal and/or
      urinary incontinence or dysfunction. Although patients typically present with
      acute disc herniations, traumatic injuries at the thoracolumbar junction at the
      terminal portion of the spinal cord and cauda equina are also common.
      Unfortunately, a precise understanding of the pathophysiology and optimal
      treatments, including the best timing of surgery, has yet to be elucidated for
      either traumatic CES or CMS. In this paper the authors review the current
      literature on traumatic conus medullaris and cauda equina injuries and available
      treatment options.

PMID- 15202875
TI  - Cauda equina syndrome after induction of spinal anesthesia.
AB  - In this report the authors present a case of cauda equina syndrome that developed
      following induction of spinal anesthesia in a patient who had no apparent
      preexisting bleeding abnormality. An acute subdural hematoma caused the syndrome
      and was believed to have resulted from direct vascular trauma during
      administration of spinal anesthesia or from vascular trauma combined with
      thrombocytopenia in the postoperative period.

PMID- 15202876
TI  - Cauda equina syndrome in patients with low lumbar fractures.
AB  - OBJECT: Symptoms of cauda equina syndrome (CES) can include low-back pain,
      sciatica, lower-extremity weakness, sensory deficit, perineal hypesthesia or
      anesthesia, and loss of bowel or bladder function. Several causes of the syndrome
      are recognized, but its optimal treatment remains controversial and has been
      broadly based on data gathered from series involving herniated discs. Information
      on the treatment of CES caused by low lumbar traumatic injuries has not been well
      documented. METHODS: Between January 2000 and December 2003, 17 consecutive cases
      of CES caused by low lumbar traumatic injuries at L2-5 were identified. The
      traumatic injuries consisted of gun shot wound in two cases, motor vehicle
      accident in 11, and a fall from height in four. Conus medullaris injuries causing
      CES were excluded from this review. Presenting symptoms, mechanisms of injury,
      radiographic images, timing of surgery, surgical approaches, and neurological
      status at the final follow up were documented. All patients underwent follow up
      of at least 12 months. Fourteen of 17 patients had satisfactory outcomes. Despite
      undergoing surgery within the first 24 hours postinjury, three patients had what
      was classified as a poor outcome given their residual deficits and included two
      cases with gunshot injuries. Recovery of leg weakness occurred within 4 months,
      whereas bladder and bowel function recovered within 3 months. All patients in
      this series underwent decompression within less than 48 hours after syndrome
      onset. Overall, the authors found no difference regarding timing of surgery
      between patients in the satisfactory outcome group and those in the poor outcome
      group. CONCLUSIONS: Based on the evidence in this study, the severity of a
      patient's condition on initial presentation is the most crucial factor in
      predicting outcome following CES due to low lumbar injuries. Although the matter
      of the timing of surgery remains controversial, the authors of this study
      recommend that surgery be performed within 48 hours of syndrome onset.

PMID- 15202877
TI  - Cauda equina syndrome as a postoperative complication of lumbar spine surgery.
AB  - OBJECT: The term "cauda equina syndrome" (CES) has been used to describe the
      signs and symptoms in patients with compressive neuropathy of multiple lumbar and
      sacral roots. This syndrome is well known as an indication for surgical
      intervention in treating lumbar spine disease, but relatively unknown as a
      postoperative complication following surgery for disease. In this study the
      author describes two cases of CES that occurred following uneventful lumbar spine
      procedures--one microdiscectomy and one decompressive laminectomy. METHODS:
      Preoperative, operative, and postoperative management is discussed and the
      relevant literature reviewed. One patient suffered perineal numbness and bowel
      and bladder difficulty following a decompressive laminectomy. Postoperative
      imaging studies were negative for residual lesion and the treatment goal pursued
      was partial long-term resolution of symptoms. The second patient had progressive
      numbness and weakness in the lower extremities. Results of urgent postoperative
      magnetic resonance imaging studies were inconclusive and repeated exploration was
      performed within hours of the initial procedure. The patient made a full
      recovery, although the intraoperative findings did not reveal a clear cause of
      the patient's symptoms. CONCLUSIONS: Postoperative symptoms of partial or
      complete CES represent a medical emergency, especially if they are progressive.
      It is necessary to perform urgent postoperative imaging in patients, but the
      results are not always helpful. Surgical exploration is warranted if a mass
      lesion is demonstrated on imaging studies or if symptoms progress and the disease
      origin is not clear based on available information.

PMID- 15202878
TI  - Medicolegal consequences of cauda equina syndrome: an overview.

PMID- 15202879
TI  - Neuroendoscope-assisted evacuation of large intracerebral hematomas: introduction
      of a new, minimally invasive technique. Preliminary report.
AB  - OBJECT: The aim of this study was to describe a new, minimally invasive technique
      for the endoscopic evacuation of intracerebral hematomas (ICHs) and the clinical
      and radiological outcomes in patients who underwent the procedure. The authors
      used a multifunctional three-in-one endoscopic instrument that combines a 0
      degrees, 4-mm rigid telescope, an irrigation cannula, and a cautery electrode.
      METHODS: In 13 patients a small keyhole craniotomy was made through noneloquent
      cortex to gain access to the hematoma. After opening the dura mater, a small
      cortical tunnel (approximately 6 mm in diameter) was created using bipolar
      forceps and suction to enter into the clot. The three-in-one endoscope was then
      introduced to provide illumination and irrigation inside the cavity. The clot was
      safely aspirated under endoscopic vision and constant irrigation by performing
      microsurgical suction with the other hand. Hemostasis could be achieved using
      electrocautery and Surgicel. This technique eliminates the use of an endoscopic
      sheath, thus providing more maneuverability to the neurosurgeon. The brilliant
      illumination provided by the endoscope and the possibility of using
      electrocautery in the depths of the brain combined with the increased
      maneuverability make this technique valuable. Near-complete hematoma evacuation
      was achieved in 11 (85%) of 13 patients. There were four deaths (30%).
      CONCLUSIONS: Safe and effective evacuation of large ICHs is possible by using the
      three-in-one endoscopic device. Appropriate indications for surgery in patients
      with large intracerebral hemorrhage must be developed.

PMID- 15202880
TI  - Iatrogenic spondylodiscitis. Case report and review of literature.
AB  - Iatrogenic intervertebral disc space infection is encountered following
      microsurgical discectomy, percutaneous laser disc decompression, automated
      percutaneous lumbar nucleotomy operations, and discography. The purpose of this
      paper is to present a case report and review the literature on the uncommon
      origins of pyogenic spondylodiscitis and to emphasize the significance of
      prophylactic antibiotic therapy following transrectal ultrasonography-guided
      needle biopsy of the prostate (TUGNBP). According to the authors, this is the
      first reported case of pyogenic spondylodiscitis as a complication of TUGNBP in
      the English language literature.

PMID- 15202881
TI  - Clar valence bond representation of pi-bonding in carbon nanotubes.
AB  - The application of the Clar aromatic sextet valence bond (VB) model to extended,
      defect-free single-walled carbon nanotubes (CNTs) with roll-up vectors (m, n)
      provides a real space model of their electronic structure. If m - n = 3k, where k
      is an integer, then all pi-electrons can be represented by aromatic sextets, and
      the CNT is fully benzenoid; the converse is also true. Since m - n = 3k is known
      to be a necessary criterion for conductivity in CNTs, only fully benzenoid CNTs
      are metallic, and only potentially metallic CNTs are fully benzenoid. This
      behavior contrasts with that of planar polycyclic aromatic hydrocarbons, in which
      the fully benzenoid structures are known to have large HOMO-LUMO gaps. For CNTs
      that are not fully benzenoid, e.g., m - n = 3k + l, where l = 1 or 2 and k is an
      integer, a seam of double bonds wraps about an otherwise benzenoid CNT at the
      chiral angle - 60 degrees or the chiral angle, respectively. Nucleus-independent
      chemical shift calculations on hydrogen-terminated CNT segments support this, and
      show that the magnetic manifestation of aromatic sextets is not due to electron
      correlation. The resonance hybrid of the Clar VB structures corresponds to
      patterns occasionally observed in scanning tunneling microscopy images of CNTs.

PMID- 15202883
TI  - Mechanisms of Staudinger reactions within density functional theory.
AB  - The Staudinger reactions of substituted phosphanes and azides have been
      investigated by using density functional theory. Four different initial reaction
      mechanisms have been found. All systems studied go through a cis-transition state
      rather than a trans-transition state or a one-step transition state. The one-step
      pathway of the phosphorus atom attacking the substituted nitrogen atom is always
      unfavorable energetically. Depending on the substituents on the azide and the
      phosphane, the reaction mechanism with the lowest initial reaction barrier can be
      classified into three categories: (1). like the parent reaction, PH(3) + N(3)H,
      the reaction goes through a cis-transition state, approaches a cis-intermediate,
      overcomes a PN-bond-shifting transition state, reaches a four-membered ring
      intermediate, dissociates N(2) by overcoming a small barrier, and results in the
      final products: N(2) and a phosphazene; (2). once reaching the cis-intermediate,
      the reaction goes through the N(2)-eliminating transition state and produces the
      final products; (3). the reaction has a concerted initial cis-transition state,
      in which the phosphorus atom attacks the first and the third nitrogen atoms of
      the azide simultaneously and reaches an intermediate, and then the reaction goes
      through similar steps of the first reaction mechanism. In contrast to the
      previous predictions on the relative stability of the unsubstituted cis
      configured phosphazide intermediate and the unsubstituted trans-configured
      phosphazide intermediate, the total energy of the substituted trans-configured
      phosphazide intermediate is close to that of the substituted cis-configured
      phosphazide intermediate. The preference of the initial cis-transition state
      reaction pathway is thoroughly discussed. The relative stability of the cis- and
      the trans-intermediates is explored and analyzed with the aid of molecular
      orbitals. The effects of substituents and solvent effects on the reaction
      mechanisms of the Staudinger reactions are discussed in detail.

PMID- 15202882
TI  - Design and synthesis of photochemically controllable restriction endonuclease
      BamHI by manipulating the salt-bridge network in the dimer interface.
AB  - The strategy for the design of photochemically controllable enzymes by
      manipulating the dimer interface is described. Employing a restriction
      endonuclease BamHI, the selective incorporation of amino acids having a
      photoremovable 6-nitroveratryl group into the specific position (Lys132) in the
      dimer interface of the BamHI mutant (H133A) was performed. The activity of the
      photofunctionalized BamHI mutant was significantly suppressed, and the following
      photoirradiation induced the recovery of the activity. In addition, uncaging of
      the 6-nitroveratryl group introduced to Lys132 did not seriously reduce the
      catalytic activity and affinity for the substrate. These results indicate that
      the activity of the enzyme can be effectively regulated by caging and uncaging of
      the specific amino acid in the dimer interface using the photoremovable group.

PMID- 15202884
TI  - Rationale for the acidity of Meldrum's acid. Consistent relation of C-H acidities
      to the properties of localized reactive orbital.
AB  - Detailed investigation on the origin of the acidity of the alpha-protons of a set
      of the carbonyl molecules was carried out on the basis of properties of the
      localized molecular orbital. An anomalously high acidity of Meldrum's acid, as
      compared with those of dimedone and dimethyl malonate, is one of the well-known
      but unresolved issues. The well-localized sigma orbitals of the C-H bonds at the
      alpha-position of the carbonyl groups can be obtained with the reactive hybrid
      orbital (RHO) theory. We found that the energy levels of the unoccupied RHOs of
      the C-H moiety of Meldrum's acid and other carbonyl compounds showed a good
      linear correlation with the experimental deprotonation energies. This is probably
      because the deprotonation reaction to form the proposed naked anions in a polar
      solvent is a highly endothermic process, in which the thermodynamic energy
      differences between the neutral molecules and the corresponding anions
      approximately coincide with the activation energies. We also investigated the
      effect of the conformational change upon deprotonation on the electron-accepting
      energy level of the relevant C-H bonds of cyclic/acyclic and
      monocarbonyl/dicarbonyl compounds. A conformational change occurs in the cases of
      cyclic six-membered compounds, but its influence on the reactivity of the C-H
      bond is small. The acidity of dicarbonyl compounds, including Meldrum's acid,
      showed a good correlation with the deviations from the perpendicular position of
      the dihedral angles of the relevant C-H bond with respect to the adjacent
      carbonyl C=O bond. This angle parameter can be related to the magnitude of the in
      phase orbital interaction between the sigma(CH) and pi(C)(=)(O) orbitals, which
      facilitate electron acceptance. These results indicated that the acidity of the
      alpha-proton of carbonyl compounds can be represented in terms of the electron
      accepting orbital levels of the unoccupied RHO of the C-H moiety. All the linear
      relationships found in the present work strongly suggested that the acidity of
      Meldrum's acid, which is conventionally regarded as an anomaly, is consistent
      with those of the other carbonyl compounds.

PMID- 15202885
TI  - Electronic state of push-pull alkenes: an experimental dynamic NMR and
      theoretical ab initio MO study.
AB  - The (1)H and (13)C NMR spectra of a number of push-pull alkenes were recorded and
      the (13)C chemical shifts calculated employing the GIAO perturbation method. Of
      the various levels of theory tried, MP2 calculations with a triple-zeta-valence
      basis set were found to be the most effective for providing reliable results. The
      effect of the solvent was also considered but only by single-point calculations.
      Generally, the agreement between the experimental and theoretically calculated
      (13)C chemical shifts was good with only the carbons of the carbonyl,
      thiocarbonyl, and cyano groups deviating significantly. The substituents on the
      different sides of the central C=C partial double bond were classified
      qualitatively with respect to their donor (S,S < S,N < N,N) and acceptor
      properties (C identical with N < C=O < C=S) and according to the ring size on the
      donor side (6 < 7 < 5). The geometries of both the ground (GS) and transition
      states (TS) of the restricted rotation about the central C=C partial double bond
      were also calculated at the HF and MP2 levels of theory and the free energy
      differences compared with the barriers to rotation determined experimentally by
      dynamic NMR spectroscopy. Structural differences between the various push-pull
      alkenes were reproduced well, but the barriers to rotation were generally
      overestimated theoretically. Nevertheless, by correlating the barriers to
      rotation and the length of the central C=C partial double bonds, the push-pull
      alkenes could be classified with respect to the amount of hydrogen bonding
      present, the extent of donor-acceptor interactions (the push-pull effect), and
      the level of steric hindrance within the molecules. Finally, by means of NBO
      analysis of a set of model push-pull alkenes (acceptors: -C identical with N, 
      CH=O, and -CH=S; donors: S, O, and NH), the occupation numbers of the bonding pi
      orbitals of the central C=C partial double bond were shown to quantitatively
      describe the acceptor powers of the substituents and the corresponding occupation
      numbers of the antibonding pi orbital the donor powers of the substituents. Thus,
      for the first time an estimation of both the acceptor and the donor properties of
      the substituents attached to the push-pull double bond have been separately
      quantified. Furthermore, both the balance between strong donor/weak acceptor
      substituents (and vice versa) and the additional influences on the barriers to
      rotation (hydrogen bonding and steric hindrance in the GSs and TSs) could be
      differentiated.

PMID- 15202886
TI  - Simple amine/Pd(OAc)(2)-catalyzed suzuki coupling reactions of aryl bromides
      under mild aerobic conditions.
AB  - A new palladium catalyst (DAPCy) made from Pd(OAc)(2) and commercially available,
      inexpensive dicyclohexylamine has been developed for the Suzuki coupling reaction
      of aryl bromides with boronic acids to give the coupling products in good to high
      yields. The air-stable catalyst was characterized and well-defined by X-ray
      crystallography. A catalytic system involving DAPCy in dioxane demonstrates a
      temperature-dependent reactivity toward aryl bromides with different electronic
      substituents, and selectively couples electron-deficient aryl bromides with
      boronic acids over electron-rich ones at room temperature. Another catalytic
      system employing DAPCy in EtOH provides a general and convenient method to
      prepare biaryls from aryl bromides and boronic acids with a broad range of
      functional groups at room temperature and under aerobic conditions.

PMID- 15202887
TI  - Crystallographic/experimental electron density characterizations and reactions
      with nucleophiles of beta-enaminonitriles possessing a pyrrolobenzazepine core.
AB  - In connection with a total synthesis of cephalotaxine (1a), we have examined the
      addition of various nucleophilic reagents to [ABC] subunits 2 and 7 possessing a
      pyrrolobenzazepine core. In fact, this reaction implicates invariably the
      carbonyl group of 2. Regarding the reaction of 7 with nucleophiles, the most
      striking aspect is the complete lack of reactivity of the enaminonitrile moiety.
      For instance, the condensation of 7 with methylmagnesium bromide involves
      exclusively the cleavage of the dioxole ring, yielding regioisomers 9 and 10.
      With the aim of understanding the unexpected reactivity of 2 and 7 toward
      nucleophiles, crystallographic studies of 2 and 7 and an experimental electron
      density determination of 7 were carried out. The marked reactivity of the
      carbonyl group of 2 was interpreted by invoking the weakness of the amide
      resonance, due to a pronounced delocalization of the N(9) lone pair over the
      enaminonitrile moiety. The electron density study of 7 reveals this electron
      delocalization along the enaminonitrile fragment, highlighted and quantified
      through the bond geometries, topological indicators, and atomic charges, a
      phenomenon that is responsible for the failure of the addition of nucleophilic
      species.

PMID- 15202888
TI  - Stolonilactone, a novel terpenoid-related compound, isolated from the Okinawan
      soft coral Clavularia koellikeri.
AB  - A novel terpenoid-related compound, stolonilactone (1), was isolated from the
      Okinawan soft coral Clavularia koellikeri. The structure of 1 was elucidated on
      the basis of spectroscopic analysis. A possible biogenesis of 1 through the [4 +
      2]-cycloaddition of a trisnorsesquiterpenoid-type diene and a cembranolide-type
      dienophile is proposed.

PMID- 15202889
TI  - Photoinitiated carbonylation with [(11)C]carbon monoxide using amines and alkyl
      iodides.
AB  - Photoinitiated radical carbonylation with [(11)C]carbon monoxide at low
      concentration was employed in syntheses of carbonyl-(11)C-labeled amides using
      alkyl iodides and amines as precursors. Eleven (11)C-amides were synthesized in
      up to 74% decay-corrected radiochemical yields with reaction times of 400 s and
      with up to 95% conversion of carbon monoxide. Starting with 26.3 GBq of
      [(11)C]carbon monoxide, 10.6 GBq of 1-cyclohexane [(11)C]carbonyl-4-phenyl
      piperazine (15) was obtained within 35 min from the end of bombardment (33
      microA) and with a specific radioactivity of 192 GBq/micromol at the same time
      point. The influence of solvents was investigated. The described procedure
      extends the range of accessible labeling methods. The method may also be useful
      for preparation of (13)C- and (14)C-substituted compounds.

PMID- 15202890
TI  - Stereoselective synthesis of 3-hydroxyproline benzyl esters from N-protected beta
      aminoaldehydes and benzyl diazoacetate.
AB  - The synthesis of a series of 3-hydroxyproline benzyl esters from alpha-alkyl and
      alpha-alkoxy N-protected aminoaldehydes with benzyl diazoacetate is described.
      Aldehydes with alpha-alkyl substituents afforded prolines as a single
      diastereomer with a trans-cis relative configuration in 14-77%. An alpha-tert
      butyldimethylsilyloxy aminoaldehyde afforded a proline as a single diastereomer
      with a trans-trans relative configuration in 37% yield.

PMID- 15202891
TI  - Study on reactions of 2-(dinitromethylene)-4,5-imidazolidinedione.
AB  - Some new reactions of 2-(dinitromethylene)-4,5-imidazolidinedione (1) with water,
      alcohols, carboxylic acids, and alkalis were discovered. By reaction of 1 with
      carboxylic acids, large particle size 1,1-diamino-2,2-dinitroethylene (2) was
      prepared. By reaction of 1 with methanol, the methanol adduct (4) was synthesized
      and characterized. By reaction of 1 with water, the synthetic pathway of 2
      methylimidazole to 2 could be achieved in a continuous process. By reaction of 1
      with KOH, 2 and potassium dinitromethane (6) could be formed at different
      temperature, respectively. Compounds 1 and 4 decomposed into parabanic acid (5),
      losing nitrogen oxides and carbon oxides. Some explosive properties of 1 were
      studied. The mechanisms of synthesis of 1, 2, and 5 are discussed.

PMID- 15202892
TI  - Biotinylated geldanamycin.
AB  - Inhibition of the 90 kDa heat shock proteins (Hsp90) represents a promising new
      chemotherapeutic approach for the treatment of several cancers. Hsp90 is
      essential to the survival of cancer cells and is inhibited by members of the
      ansamycin family of antibiotics. In particular, the quinone-containing
      antibiotics geldanamycin (GDA) and herbimycin A inhibit Hsp90 function in vitro
      at low micromolar concentrations via interaction with an ATP binding domain. Many
      proteins bind ATP, and the discovery of selective Hsp90 inhibitors requires the
      identification of other proteins that bind GDA and may cause undesired effects.
      Biotinylated analogues of GDA with varying tether lengths have been synthesized
      to elucidate other proteins that competitively bind GDA. Analogues containing a
      photolabile tether have also been prepared as a complementary method for the
      removal of GDA-bound proteins from neutravidin-containing resin. Preliminary
      studies indicate several proteins other than Hsp90 are isolated with biotinylated
      GDA.

PMID- 15202893
TI  - Ionic liquids as a convenient new medium for the catalytic asymmetric
      dihydroxylation of olefins using a recoverable and reusable osmium/ligand.
AB  - The use of room-temperature ionic liquids (RTILs) in the Sharpless catalytic
      asymmetric dihydroxylation (AD) as a cosolvent or replacement of the tert-butanol
      was studied in detail by screening 11 different RTILs. The AD reaction is faster
      in 1-n-butyl-3-methylimidazolium hexafluorophosphate [C(4)mim][PF(6)] as a
      cosolvent than in the conventional system of tert-butanol/H(2)O. For the range of
      six substrates tested, comparable or even higher yields and enantiomeric excess
      (ee) were found using [C(4)mim][PF(6)] or 1-n-octyl-3-methylimidazolium
      hexafluorophosphate [C(8)mim][PF(6)] compared to the conventional solvent system.
      Due to high affinity of the catalytic osmium/quiral ligand system to the ionic
      liquid, the use of ionic liquid/water (biphasic) or ionic liquid/water/tert
      butanol (monophasic) solvent systems provides a recoverable, reusable, robust,
      efficient, and simple system for the AD reaction. Using 1-hexene and
      [C(4)mim][PF(6)] as RTIL it was possible to reuse the catalytic system for 9
      cycles with only a 5% of yield reduction from the first cycle, allowing an
      overall yield of 87%, TON = 1566, and with similar ee. Additionally, for each
      cycle, after extraction of the reaction mixture with diethyl ether, the osmium
      content in the organic phase (containing the AD product) and in the aqueous phase
      was in the range of the detection limit (<or=3%, <or=7 ppb) and 3-6% of initial
      amount, respectively. In contrast, the ionic liquid phase retained more than 90%
      of the osmium content of the previous cycle.

PMID- 15202894
TI  - Polyvalent interactions in unnatural recognition processes.
AB  - The synthesis of two cluster compounds, one containing six secondary
      dialkylammonium ion centers and the other possessing six benzo-m
      phenylene[25]crown-8 (BMP25C8) macrocycles, both appended to
      hexakis(thiophenyl)benzene cores, is described. The binding of these clusters
      with complementary mono- and divalent ligands is investigated with NMR
      spectroscopy to probe polyvalency in these unnatural recognition systems. The
      ability of the two different families of clusters to bind complementary
      monovalent ligands is compared with that of the monovalent receptor pair, namely
      the dibenzylammonium ion and BMP25C8. This comparison is made possible by
      determining an average association constant (K(AVE)) for the binding of each
      recognition site on the cluster with the corresponding monovalent ligand. We have
      found that the clustering of recognition sites together in one molecule is
      detrimental to their individual abilities to bind monovalent ligands. In the case
      of the polyvalent interaction between the hexakisBMP25C8 cluster and divalent
      dialkylammonium ions, an association constant, K(POLY), was calculated from the
      value of K(AVE) determined for the complexation of the individual component
      recognition sites. This polyvalent interaction is significantly stronger than
      that associated with the averaged monovalent interactions.

PMID- 15202895
TI  - Synthesis of double-armed lariat ethers with pyrene moieties at each end of two
      sidearms and their fluorescence properties in the presence of alkali metal and
      alkaline earth metal cations.
AB  - Two types of double-armed lariat ether derivatives having pyrene moieties at each
      end of two sidearms, (3x + 1)-crown-x derivatives 1 (x = 5), 2 (x = 6), and 3 (x
      = 4) (type A) and 3y-crown-y derivatives, 6 (y = 5) and 7 (y = 6) (type B), were
      synthesized, and their complexation behavior toward alkali metal and alkaline
      earth metal cations was examined by fluorescence spectroscopy. Pyrene excimer
      emission decreased accompanied by an increase in monomer emission upon metal ion
      complexation. This finding is ascribed to the change of the spatial distance of
      two pyrene rings by movement suppression of both the crown ring and one of the
      two sidearms based on complexation with the metal cation. The selectivity for
      alkaline earth metal cations was highly dependent on the fitness of the host
      cavity and the guest size. Although most of the fluorophores did not respond to
      alkali metal cations, only trans-7a containing an 18-crown-6 ring showed K(+)
      selectivity.

PMID- 15202896
TI  - Lewis acid catalyzed allylboration: discovery, optimization, and application to
      the formation of stereogenic quaternary carbon centers.
AB  - A full account of the development of the first catalytic manifold for the
      additions of allylboronates to aldehydes is described. The thermal additions
      (both diastereospecific and enantioselective) of 2-carboxyester 3,3-disubstituted
      allylboronates 1 to both aromatic and aliphatic aldehydes give biologically and
      synthetically important exo-methylene butyrolactones 2 containing a beta
      quaternary carbon center. Although the thermal reaction requires 14 d at room
      temperature to reach completion, the presence of certain metal salts allows for a
      12-16 h reaction while preserving the diastereospecificity observed in the
      uncatalyzed process. Preliminary mechanistic studies on the origin of the
      catalytic effect are described as well as stereoselective transformations of
      lactones 2 into cyclic and acyclic stereotriads with potential usefulness as
      synthetic intermediates.

PMID- 15202897
TI  - Efficient total syntheses of phytoalexin and (+/-)-paniculidine B and C based on
      the novel methodology for the preparation of 1-methoxyindoles.
AB  - A general route to 2-unsubstituted-1-methoxyindoles, based on our methodology for
      the synthesis of 1-methoxyindoles, is reported. This synthesis renders
      accessibility to a variety of natural products possessing the said skeleton. A
      direct synthesis of phytoalexin (1), (+/-)-paniculidine B (2), and (+/-)
      paniculidine C (3) is disclosed based on the methodology. The synthesis of
      paniculidine B (2) has been achieved from aldehyde 10 in only two steps in 88%
      yield and in five steps from a methoxyindole compound 8 obtained using our
      earlier methodology.

PMID- 15202898
TI  - Ruthenium- and rhodium-catalyzed direct carbonylation of the ortho C-H bond in
      the benzene ring of N-arylpyrazoles.
AB  - The direct carbonylation of C-H bonds in the benzene ring of N-phenylpyrazoles
      via catalysis by ruthenium or rhodium complexes is described. The reaction of N
      phenylpyrazoles with carbon monoxide and ethylene in the presence of
      Ru(3)(CO)(12) or Rh(4)(CO)(12) resulted in the site-selective carbonylation of
      the ortho C-H bonds in the benzene ring to give the corresponding ethyl ketones.
      A variety of functional groups on the benzene ring can be tolerated. N
      Phenylpyrazoles have higher reactivities than would be expected, based on the
      pK(a) values of the conjugate acid of pyrazole. The choice of solvent for this
      reaction is significant, and N, N-dimethylacetamide (DMA) gives the best result.

PMID- 15202899
TI  - Glucuronic acid derivatives as branching units for the synthesis of glycopeptide
      mimetics.
AB  - Natural glycopeptides and glycoproteins exhibit a large structural diversity,
      which can be mimicked by synthetic glycopeptide derivatives to assist the
      investigation of biological functions and structure-activity relationships. Here,
      dendronized saccharides were synthesized to provide glycosyl amino acids,
      equipped with a branching element for the preparation of branched glycopeptide
      mimetics. An optimized Staudinger-type reaction served as key reaction en route
      to the complex glycopeptide 14, in which three mannose moieties were connected to
      the branched glucuronyl scaffold.

PMID- 15202900
TI  - Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l
      lyxopyranosyl]thymine.
AB  - Previously different types of nucleosides with a six-membered carbohydrate moiety
      have been evaluated for their potential antiviral and antibiotic properties and
      as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with
      a 1,4-substitution pattern like 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l
      lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this
      nucleoside would show the (4)C(1) conformation in contrast to anhydrohexitol
      nucleosides (1) whose most stable conformation is (1)C(4). The key to the
      synthesis of 4 involves the stereoselective introduction of the hydroxymethyl
      group onto the C-4 carbon of the pyranose sugar. Attempts to achieve this via
      hydroboration/oxidation of a C-4'-exocyclic vinylic intermediate selectively
      yielded the undesired alpha-directed hydroxymethyl group. Therefore, we envisaged
      another approach in which the C-4 substituent was introduced upon treatment of
      2,3-O-isopropylidene-1-O-methyl-4-O-phenoxythiocarbonyl-alpha-l-lyxopyranose with
      beta-tributylstannyl styrene. This allowed stereoselective beta-directed
      introduction of a 2-phenylethenyl group at C-4, which was converted via
      oxidation/reduction (OsO(4), NaIO(4)/NaBH(4)) into the desired 4-hydroxymethyl
      group (20). The resulting 1-O-methyl-2,3,6-tri-O-acetyl-protected sugar was
      coupled with silylated thymine, using SnCl(2) as Lewis acid (22). After suitable
      protection, Barton deoxygenation of the 2'-hydroxyl function of the obtained ribo
      nucleoside yielded the desired 2'-deoxynucleoside 4, indeed showing the expected
      equatorial orientation of the thymine ring ((4)C(1)).

PMID- 15202901
TI  - Stereoselective addition of alpha-sulfinyl carbanions to N-p
      tolylsulfinylketimines: synthesis of optically pure 1,2,2'-trialkyl-2
      aminoethanols.
AB  - The reactions of lithium carbanions derived from both enantiomers of methyl (1)
      and ethyl p-tolyl sulfoxide (2) with (S)-N-arylsulfinylketimines 3 and 4 took
      place in a highly stereoselective manner and good isolated yields. The
      configuration of the carbon bonded to nitrogen relies exclusively on the N
      sulfinylimine configuration. When ethyl p-tolyl sulfoxide (2) is use as
      nucleophile, two chiral centers are created simultaneously, where the
      configuration of the carbon bonded to the sulfur is mainly controlled by 2. The
      asymmetric induction increases with the temperature, being total at room
      temperature in the case of the matched pair of reactants. A non-oxidative
      Pummerer reaction on the obtained aminosulfoxides allows a straightforward
      synthesis of optically pure 1,2-ethanolamines with one or two chiral centers,
      including amino alcohols with a bulky quaternary carbon bonded to the amine
      group.

PMID- 15202902
TI  - Design of polyaromatic hydrocarbon-supported tin reagents: a new family of tin
      reagents easily removable from reaction mixtures.
AB  - We report in this paper the preparation and use of stannanes 11, 12a, and 12b,
      compounds whose 3-pyrenylpropyl side chain affinity for activated carbon
      simplifies tin removal and product isolation. Our pyrene-supported reagents can
      be used for radical reductions and cyclizations (11), radical and cationic
      allylations (12a), and Stille couplings (12b) in much the same way as tributyltin
      derivatives.

PMID- 15202903
TI  - Phytoalexins from the crucifer rutabaga: structures, syntheses, biosyntheses, and
      antifungal activity.
AB  - Phytoalexins are inducible chemical defenses produced de novo by plants in
      response to diverse forms of stress, including microbial attack. Our search for
      phytoalexins from economically important crucifers lead us to examine rutabaga
      tubers (Brassica napus L. ssp. rapifera). Three new phytoalexins, named isalexin
      (9), brassicanate A (10), and rutalexin (11), were isolated together with five
      known phytoalexins, brassinin (4), 1-methoxybrassinin (5), spirobrassinin (13),
      brassicanal A (14), and brassilexin (15). The chemical structures of the new
      phytoalexins were proven by syntheses, and their biological activity against four
      plant pathogens were determined. Biosynthetic studies using tetra- and
      pentadeuterated precursors established that indolyl-3-acetaldoxime (22) and
      brassinin (4) are precursors of brassicanate A (10) and rutalexin (11) and that
      cyclobrassinin (23) is a biosynthetic precursor of rutalexin (11), whereas
      tryptamine (24) is not a precursor of rutabaga phytoalexins.

PMID- 15202904
TI  - Efficient preparation of a 1,3-diazidocyclitol as a versatile 2-deoxystreptamine
      precursor.
AB  - A synthesis route toward 2-deoxystreptamine, a common structure in many of the
      clinically important aminoglycosides, is presented. Starting from p-benzoquinone
      and cyclopentadiene, 2-deoxystreptamine is synthesized with key steps involving
      Pd(0)-catalyzed rearrangement, a retro-Diels-Alder by flash vacuum thermolysis,
      and Yb(III)-directed regioselective epoxide opening. The obtained diazidocyclitol
      17 is a suitable 2-deoxystreptamine precursor, conveniently protected for
      incorporation in new aminoglycoside entities.

PMID- 15202905
TI  - Facile and selective deallylation of allyl ethers using
      diphosphinidenecyclobutene-coordinated palladium catalysts.
AB  - (pi-Allyl)palladium triflate bearing a 1,2-bis(4-methoxyphenyl)-3,4-bis(2,4,6-tri
      tert-butylphenylphosphinidene)cyclobutene ligand (DPCB-OMe), [Pd(eta(3)
      C(3)H(5))(DPCB-OMe)]OTf, efficiently catalyzes deallylation of a variety of allyl
      ethers in aniline to give corresponding alcohols in high yields under mild
      conditions. The reactions can be performed in air without loss of a variety of
      functionalities including vinyl, alkynyl, hydroxy, acetoxy, silyloxy, and acetal
      groups. Allyl 2-allyloxybenzoate selectively undergoes deallylation of the
      allyloxy group to give allyl salicylate in quantitative yield.

PMID- 15202906
TI  - Synthesis of d- and l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5
      hydroxymethylproline and tripeptides containing them.
AB  - Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert
      butoxycarbonyl)-5,6-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3
      and (+)-3) have been obtained from the Diels-Alder adduct of N-(tert
      butoxycarbonyl)pyrrole and 2-bromo-1-(p-toluenesulfonyl)acetylene, including the
      Alexakis optical resolution of ketone (+/-)-3 via formation of cyclic aminals
      with (1R,2R)-diphenylethylenediamine. Compounds (-)-3 and (+)-3 were converted
      into d- and l-2,3-trans-3,4-cis-4,5-trans-N-(tert-butoxycarbonyl)-5-hydroxymethyl
      3,4-isopropylidenedioxyprolines (-)-4 and (+)-4, respectively. Applying the Boc
      and Fmoc strategies of peptide synthesis, these compounds were used to construct
      two tripeptides containing the d- or l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy
      5-hydroxymethylproline.

PMID- 15202907
TI  - Synthesis and electron-donor ability of the first conjugated pi-extended
      tetrathiafulvalene dimers.
AB  - A series of novel conjugated homo (16a,b) and heterodimers (20) of pi-extended
      tetrathiafulvalenes with p-quinodimethane structures (exTTFs) linked by a
      conjugative vinyl spacer have been prepared by olefination Wittig-Horner reaction
      from the corresponding quinones (14, 19) and phosphonates (15a,b). The redox
      properties, determined by cyclic voltammetry, reveal a strong donor character and
      the presence of only one four-electron oxidation wave to form the tetracation
      species at oxidation potential values quite similar to those found for the
      related monomers. Theoretical calculations (PM3) show a planar central stilbene
      moiety and highly distorted exTTF units. The electronic spectra support as well
      as the electrochemical data and theoretical calculation the lack of significant
      communication between the exTTF units.

PMID- 15202908
TI  - Biradicals/zwitterions from thermolysis of enyne-isocyanates. Application to the
      synthesis of 2(1H)-pyridones, benzofuro[3,2-c]pyridin-1(2H)-ones, 2,5-dihydro-1H
      pyrido[4,3-b]indol-1-ones, and related compounds.
AB  - Thermolysis of benzannulated enyne-isocyanates 13 and enyne-isocyanates 36 and 37
      promoted the cycloaromatization reactions to generate in situ O,4-didehydro-2
      hydroxyquinolines and O,4-didehydro-2-hydroxypyridines, respectively, as reactive
      intermediates. These cycloaromatized intermediates could be captured either as
      biradicals and/or as zwitterions depending on the nature of the substituent at
      the alkynyl terminus. The intermediate derived from cycloaromatization of 13a
      bearing a phenyl substituent could be regarded as biradical 14, which then
      abstracts hydrogen atoms from gamma-terpinene leading to 2(1H)-quinolinone 15.
      Alternatively, the same intermediate could also be regarded as zwitterion 14',
      which then undergoes an initial hydride abstraction from gamma-terpinene followed
      by protonation to produce 15. The presence of a 2-phenylethyl substituent in 13b
      and 37a or a 2-methylphenyl substituent in 37b also allowed the resulting
      intermediates to be captured intramolecularly either as biradicals or as
      zwitterions, producing 2(1H)-quinolinone 19, 2(1H)-pyridone 39, and
      benzopyranopyridine 43, respectively. On the other hand, with a 2-methoxyphenyl,
      a 2-(dimethylamino)phenyl, or a 3-methoxypropyl substituent, the chemical
      behavior of the cycloaromatized adduct could be best accounted for in terms of a
      zwitterionic intermediate leading to benzofuro[3,2-c]quinolin-6(5H)-one (20),
      5,11-dihydro-11-methyl-6H-indolo[3,2-c]quinolin-6-one (25), benzofuro[3,2
      c]pyridin-1(2H)-one 44, 2,5-dihydro-2,5-dimethyl-1H-pyrido[4,3-b]indol-1-one 46,
      and related compounds. Interestingly, thermolysis of 37f bearing a 2
      (methoxymethyl)phenyl substituent at the alkynyl terminus produced the unexpected
      benzopyranopyridine 56 as the major product in a process involving the cleavage
      of the bond between the methoxyl oxygen and the adjacent methylene carbon. The
      efficiency and selectivity of the cycloaromatization reaction could also be
      enhanced by the introduction of 1.1 to 10 equiv of dimethylphenylsilyl chloride
      to the reaction mixture to capture the resulting zwitterion.

PMID- 15202909
TI  - Synthetic studies on macroviracin A: a rapid construction of C(42) macrocyclic
      dilactone corresponding to the core.
AB  - The C(2)-symmetric macrodiolide core 2 of an antiviral agent, macroviracin A (1),
      was constructed in a single step by the intermolecular macrodimerization of C(22)
      hydroxy carboxylic acid 3 with 2-chloro-1,3-dimethylimidazolinium chloride and
      DMAP in the presence of sodium hydride (NaH). The use of potassium hydride
      instead of NaH caused the intramolecular cyclization, predominantly providing the
      corresponding monomer 26. The acid 3 was synthesized through a series of
      reactions such as the coupling reaction of acetylene 5 and oxirane 6,
      stereoselective glycosidation with the trichloroacetimidate method, and Jones
      oxidation.

PMID- 15202910
TI  - concise synthesis of 4-acylamino analogues of 2-aminobicyclo[3.1.0]hexane-2,6
      dicarboxylic acids (LY354740) from an acylnitroso Diels-Alder cycloadduct.
AB  - Concise total syntheses of 4-acylamino analogues of LY354740 were accomplished
      employing an N-Boc acylnitroso Diels-Alder cycloadduct as the starting material.
      The syntheses involved N-O bond cleavage, oxidation, intermolecular
      cyclopropanation, Bucherer-Bergs reaction, hydrolysis, and regioselective
      acylation with a temporary copper chelate. The synthesis of an optically active
      compound was also achieved.

PMID- 15202911
TI  - Efficient reductive selenation of aromatic aldehydes to symmetrical diselenides
      with Se/CO/H(2)O under atmospheric pressure.
AB  - An efficient method for the synthesis of symmetrical diselenides is described.
      Reductive selenation of aromatic and heterocyclic aromatic aldehydes (ArCHO) with
      Se/CO/H(2)O in DMF afforded diselenides (ArCH(2)SeSeCH(2)Ar) in yields up to 94%
      under atmospheric pressure without use of a base.

PMID- 15202912
TI  - Open-cage fullerene derivatives with 15-membered-ring orifices.
AB  - The addition reaction of the N-MEM-ketolactam derivative of [60]fullerene with
      phenyl, p-Br-phenyl, and p-MeO-phenyl hydrazines proceeds regioselectively,
      affording three open-cage fullerene derivatives bearing a 15-membered-ring
      orifice on the fullerene cage. Both experimental data and theoretical
      calculations were utilized for the structure determination of the new
      [60]fullerene adducts.

PMID- 15202913
TI  - A new route to aristocularine alkaloids: total synthesis of aristoyagonine.
AB  - A short and efficient synthesis of aristocularines, involving the sequential
      construction of phosphorylated 4-alkoxyisoindolinones, Horner-type reaction, and
      ultimate cyclization by diaryl ether coupling, is disclosed. The success of this
      new conceptual approach is demonstrated by the total synthesis of the
      aristocularine alkaloid aristoyagonine.

PMID- 15202914
TI  - Development of a new dimeric cyclophane ligand: application to enhanced diastereo
      and enantioselectivity in the catalytic synthesis of beta-lactams.
AB  - We detail the synthesis of a new C(2)-symmetric bis(cyclophane) ligand system
      that can be thought of as electronically analogous to binol, but which possesses
      the added "third dimension" of cyclophane chirality. The ligand synthesis
      involves a spontaneous (but unexpected) atropisomerization to the desired
      product. We have employed this ligand to form a metal complex that is an
      effective cocatalyst for the highly enantio- and diastereoselective catalytic
      asymmetric synthesis of a beta-lactam.

PMID- 15202915
TI  - Concise formal synthesis of the bryostatin southern hemisphere (C17-C27).
AB  - An efficient synthesis of Hale and co-workers' C17-C27 bryostatin southern
      hemisphere intermediate has been accomplished in six steps and 33% overall yield
      from (R)-2-(benzyloxy)propanal. The synthesis features a one-pot DIBALH/HWE ester
      homologation as well as a novel acetonide rearrangement/glycal formation cascade.

PMID- 15202916
TI  - Chemoenzymatic synthesis and synthetic application of enantiopure
      aminocyclopentenols: total synthesis of carbocyclic (+)-uracil polyoxin C and its
      alpha-epimer.
AB  - Carbocyclic uracil polyoxin C (+)-2 and its alpha-epimer (-)-3 were synthesized
      in an efficient fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (+/
      )-7. The synthesis incorporates a concise, inexpensive chemoenzymatic synthesis
      of enantiopure aminocyclopentenols, a Pd(0)-catalyzed substitution reaction, and
      a mild reduction of an alpha-nitro ester by TiCl(3)/sodium borohydride.
      Significantly, this process demonstrates the synthetic utility of the versatile
      enantiopure aminocyclopentenol building block (-)-4.

PMID- 15202917
TI  - Palladium(0)-catalyzed stereoselective cyclization of allenenes: divergent
      synthesis of pyrrolidines and 3-azabicyclo[3.1.0]hexanes from single allenenes.
AB  - Two novel palladium(0)-catalyzed cyclizations of allenenes are described.
      Treatment of allenenes such as N-(1-alkyl-2,3-butadienyl)-N-allylsulfonamide with
      an aryl halide and K(2)CO(3) in the presence of a catalytic amount of
      Pd(PPh(3))(4) in dioxane affords 2,3-cis-pyrrolidines in a stereoselective
      manner. In sharp contrast, cyclization of the same allenenes using catalytic
      Pd(2)(dba)(3) x CHCl(3) in the presence of allyl methyl carbonate in CH(3)CN
      leads to stereoselective formation of a 3-azabicyclo[3.1.0]hexane framework in
      moderate yields.

PMID- 15202918
TI  - Stereoselective one-pot synthesis of substituted (4Z)-2-alkyl-4-benzylidene- 4H
      1,3-benzothiazines.
AB  - Substituted (4Z)-4-benzylidene-2-methyl-4H-1,3-benzothiazines (1). and (4Z)-2
      ethyl-4-benzylidene-4H-1,3-benzothiazines (2). were synthesized by direct
      stereoselective reactions of S-phenyl ethanethioate or S-phenyl propanethioate
      with substituted benzyl nitriles in the presence of triflic anhydride.

PMID- 15202919
TI  - A fast assembly of pentacyclic benz[f]indolo[2,3-a]quinolizidine core by tandem
      intermolecular formal aza-[3 + 3] cycloaddition/Pictet-Spengler cyclization: a
      formal synthesis of (+/-)-tangutorine.
AB  - We have described a concise construction of the pentacyclic benz[f]indolo[2,3
      a]quinolizidine intermediate 3 (with an overall yield of 54% for three steps),
      featuring a tandem intermolecular formal aza-[3 + 3] cycloaddition/Pictet
      Spengler cyclization. The present work can be considered as a formal synthesis of
      beta-carboline alkaloid (+/-)-tangutorine. Our strategy disclosed herein
      constitutes a new effective general synthetic approach toward the
      indoloquinolizidine family of alkaloids.

PMID- 15202920
TI  - Efficient asymmetric synthesis of (S)- and (R)-N-Fmoc-S-trityl-alpha
      methylcysteine using camphorsultam as a chiral auxiliary.
AB  - (1R)-(+)-2,10- and (1S)-(-)-2,10-camphorsultam were acylated with ethyl 2
      phenylthiazoline 4-carboxylate to afford (+)- and (-)-2
      phenylthiazolinylcamphorsultam, which were stereoselectively alkylated with MeI
      in the presence of n-BuLi. Alkylation of these phenylthiazolinylcamphorsultams
      occurred from the beta-face rather than alpha-face, resulting in the formation of
      (S)-alpha-methylcysteine from (1R)-(+)-2,10-camphorsultam and (R)-alpha
      methylcysteine from (1S)-(-)-2,10-camphorsultam after acidic hydrolysis.
      Subsequent protection of the side chain thiol group with trityl alcohol and alpha
      amine function with Fmoc-OSu furnished fully protected (S)- and (R)-N-Fmoc-S
      trityl-alpha-methylcysteine in overall 20% yield.

PMID- 15202921
TI  - Enyne versus diene RCM in the synthesis of cyclopentene derivatives toward the A
      ring of FR182877.
AB  - The A ring of FR182877, exemplified by ent-4-b,c, has been synthesized, involving
      an enyne RCM as the key step. A systematic comparison of enyne vs diene RCM for
      the formation of cyclopentene derivatives showed that the latter metathesis
      proceeds much more easily even for this ring size.

PMID- 15202922
TI  - Novel synthetic route to octasubstituted naphthalenes from four alkynes and one
      olefin unit via zirconacyclopentadienes and 1,2-diiodo-3,4,5,6-tetraalkylbenzene.
AB  - 1,2,3,4-Tetrasubstituted benzene derivatives were prepared by the reaction of
      zirconacyclopentadienes with vinyl bromide in the presence of NiCl(2)(PPh(3))(2).
      1,2-Diiodo-3,4,5,6-tetraalkylbenzenes were formed by treatment of 1,2,3,4
      tetraalkylbenzenes with iodine and periodic acid in the presence of a catalytic
      amount of sulfuric acid. Reaction of the 1,2-diiodo-3,4,5,6-tetraalkylbenzenes
      with zirconacyclopentadienes in the presence of a stoichiometric amount of CuCl
      gave sterically crowded octasubstituted naphthalenes in moderate yields.

PMID- 15202923
TI  - Regioselective quinazolinone-directed ortho lithiation of quinazolinoylquinoline:
      practical synthesis of naturally occurring human DNA topoisomerase I poison
      luotonin a and luotonins B and E.
AB  - A regioselective quinazolinone-directed ortho lithiation on an adjacent quinoline
      moiety has been used as a key step for a short, efficient, and practical
      synthesis of the human DNA topoisomerase I poison luotonin A and luotonins B and
      E. The quinazolinoylquinoline 5 on treatment with in situ-generated
      nonnucleophilic mesityllithium furnished the desired dilithiated intermediate 6,
      which on treatment with formaldehyde followed by Mitsunobu ring closure reaction
      gave luotonin A (1a) in very good yield. The reaction of dilithiated intermediate
      6 with DMF directly furnished luotonin B (1b) in 81% yield. Luotonin B (1b) on
      methylation with p-TSA/methanol gave luotonin E (1c) in 82% yield.

PMID- 15202924
TI  - High levels of salivary lactobacilli in Estonian schoolchildren.
AB  - AIM: This was to assess oral salivary lactobacilli levels compared with oral
      health in a group of 12-year-old schoolchildren in Tartu, Estonia. METHODS: Whole
      saliva samples were collected and transferred to dip-slides (Dentocult LB) and
      incubated at 37 degrees C for 3 days. Dental caries, dental plaque, and data
      concerning the general health, dental habits and eating patterns were recorded.
      RESULTS: Salivary lactobacilli were found in all children, with a quarter of them
      having high or very high lactobacilli counts. Caries prevalence of 75% and 2.6
      DMFT were recorded. A positive correlation was found between the DMFS counts and
      the lactobacilli counts. CONCLUSION: High levels of salivary lactobacilli were
      found in Estonian schoolchildren. Caries indicators of these children were
      slightly higher than in the same age group in Nordic countries.

PMID- 15202925
TI  - Case report: the Lesch-Nyhan syndrome.
AB  - BACKGROUND: The Lesch-Nyhan syndrome (LNS) is a rare x-linked excessive disorder
      of purine metabolism, caused by the congenital absence of hypoxanthine guanine
      phosphoribosyl transferase (HGPRT). CASE REPORT: In January 2000 a 2 year old boy
      was referred to a paediatric dental office in Landshut, Germany, because of
      severe and repeated lip chewing and aggressive tongue biting. A medical history
      revealed a normal pregnancy with no complications but a diagnosis of muscular
      hypotonia was made at four months of age. At 18 months a diagnosis of LNS was
      established through biochemical analysis and molecular examinations. The child
      displayed self-destructive behaviour, typical in children with LNS. Shortly
      thereafter the patient was supplied with arm cuffs for self-protection which were
      not tolerated and the self-mutilation continued. Eventually the extraction of all
      primary teeth was deemed necessary to prevent additional medical problems for
      this child. FOLLOW-UP: One year after the dental extractions the patient
      presented with no bite injuries but was now using his fingers to injure himself.

PMID- 15202926
TI  - Case report: the importance of oral manifestations in diagnosing iron deficiency
      in childhood.
AB  - AIM: The aim of this article is to report a case of iron deficiency diagnosed in
      a child after routine oral examination. CASE REPORT: A 5-year-old male child of
      African descent was brought to the paediatric dental clinic of a public
      university in Rio de Janeiro, Brazil. His mother's main complaint was her child's
      decayed teeth and sensitivity in the tongue every time he ate spicy or hot food.
      Anamnesis revealed chronic respiratory problems due to allergy, two previous
      episodes of anaemia and hospitalization about 15 months before the dental visit
      because of severe primary herpetic gingivostomatitis. Soft tissue examination
      revealed his tongue had various patches of atrophic mucosa characterizing absence
      of papillae in these areas. The child's dietary assessment indicated that he
      never ate meat or vegetables. Haematological investigation showed that the child
      probably had an iron deficiency, although the full blood count was not totally
      compatible with anaemia. A rapid initial recovery was quite noticeable after the
      beginning of oral therapy with ferrous sulphate, as remission of tongue
      sensitivity as well as papillae neoformation were observed.

PMID- 15202927
TI  - Caveolae--an alternative endocytotic pathway for targeted drug delivery.
AB  - Caveolae are bottleshape-like invaginations of the plasma membrane. After
      internalization they are involved in endocytosis, transcytosis, potocytosis, and
      pinocytosis. Our recently expanded knowledge has made clear that various
      molecules and macromolecular complexes enter the cells after docking on caveolar
      receptors, before subsequent internalization of the caveolae. The internalization
      is initiated by the ligand receptor interaction. Folate, cholesterol, serum
      lipoproteins, and liposomes are among the most common examples. It is important
      to point out that, in contrast to the classic clathrin-dependent endocytosis, the
      caveolar internalization pathway seems to avoid the lysosomes. Internalized
      caveolae fuse with caveosomes, and the caveosomes deliver their contents into
      other subcellular (non-lysosomal) compartments. The bypass of the acidic and
      harmful milieu might be a major advantage for drug delivery via the caveolar
      pathway. Not all cell types have caveolae. Cells, where the Caveolin I protein is
      not expressed, do not develop caveolar invaginations. However, these cells have
      caveolar-equivalent plasma membrane domains, so-called "lipid rafts." Lipid rafts
      are assembled from the same lipid constituents and proteins as caveolae, but they
      are flat. Specific ligands may also dock on appropriate receptors of the raft
      domain. As a complication, certain types of ligand-covered raft receptors can
      migrate to clathrin-coated pits and get internalized via clathrin-coated
      vesicles. Nevertheless, suitable ligands or antibodies developed against proteins
      of the caveolar/raft domains may selectively direct the attached drug carrier to
      the less harmful caveolar/raft pathway. Thus, understanding of caveolar transport
      may help in the rational design of more effective drug carriers.

PMID- 15202928
TI  - Penetration enhancement of transdermal delivery--current permutations and
      limitations.
AB  - In order to achieve enhanced topical drug delivery, it is necessary to make
      physical or biomolecular structural alterations to the stratum corneum by
      suitable techniques or by the use of specific chemical agents or drug carriers.
      The role of the chemical penetration enhancer is to reversibly alter the barrier
      properties of the stratum corneum by disruption of the membrane structures or by
      maximizing drug solubility within the skin. Alternatively, permeant delivery to
      the dermal vasculature using one of several physical methods to reduce
      diffusional resistance within the skin may be used to promote drug penetration.
      In the present article, we summarize the major facets of the diverse spectrum of
      penetration enhancement techniques that include modification of the stratum
      corneum, lipid-based delivery systems, drug/vehicle interactions, bypassing the
      stratum corneum, and electrical techniques of enhancement.

PMID- 15202929
TI  - Invasive measurements of pulse wave velocity correlate with the degree of aortic
      valve calcification and severity associated with matrix metalloproteinases in
      elderly patients with aortic valve stenosis.
AB  - The aim of the present study was to assess the association between invasive PWV
      (pulse wave velocity), serum levels of MMPs (matrix metalloproteinases) and the
      echocardiographic severity and calcification score of degenerative AS (aortic
      stenosis). We enrolled 30 patients (16 males; age, 61.3+/-8.2 years) diagnosed
      with degenerative AS and an additional 30 age- and sex-matched control patients.
      Invasive PWV methods with a pigtail catheter and double-channel recording were
      performed in both groups in our catheterization laboratory. We scored the
      severity of calcification at the AV (aortic valve) during two-dimensional
      echocardiography. The association between the trans-valvular pressure gradient,
      the severity of calcification of the AV and the value of PWV were analysed. We
      also analysed the serum levels of MMP-9, MMP-3 and TIMP-1 (tissue inhibitor of
      metalloproteinases-1) in these patients. In the group with degenerative AS, mean
      AV pressure gradients (56.0 compared with 9.5 mmHg; P<0.001) and calcified AV
      scoring (3.3+/-1.2 compared with 2.1+/-0.9; P<0.001) were higher than in the
      control group. In addition, PWV was faster in the group with degenerative AS
      (15.5+/-3.8 compared with 8.0+/-2.7 m/s; P=0.001). After being adjusted for age,
      sex, mean blood pressure and left ventricular function, both the AV pressure
      gradient and the severity of calcification were strongly correlated with PWV
      (R=0.706, P<0.0001, and R=0.561, P=0.03 respectively). In addition, the serum
      levels of MMP-9, MMP-3 and TIMP-1 were all significantly higher and correlated
      with PWV in the group with AS (all P<0.05). With higher serum levels of MMPs and
      their inhibitors, we found that this invasive measurement of PWV was associated
      strongly with the pressure gradient and calcification of AV. More advanced
      degenerative changes in AV was probably associated with more severe aortic
      arteriosclerosis.

PMID- 15202930
TI  - Vasoconstrictor products of cyclo-oxygenase activity limit acetylcholine-induced
      cutaneous vasodilatation in young men.
AB  - In healthy young men (age, 20-22 years), we tested the role of prostanoids
      produced by the COX (cyclo-oxygenase) pathway in cutaneous vasodilatation evoked
      in the finger by ACh (acetylcholine). To this end, changes in cutaneous RCF (red
      cell flux), recorded by the laser Doppler technique, evoked by a series of
      iontophoretic pulses of ACh were tested before and after oral aspirin (600 mg).
      Increases in RCF produced by successive pulses of ACh up to a mean change of
      125.5 +/- 11.8 PU (perfusion units) were potentiated 30 min after aspirin (160.0
      +/- 12.4 PU; P < 0.05). By contrast, aspirin had no effect on increases in RCF
      evoked by iontophoretic application of the NO (nitric oxide) donor and
      endothelium-independent dilator sodium nitroprusside (mean increases in RCF were
      73.8 +/- 9.8 PU before and 79.1 +/- 12.2 PU after aspirin). The ACh-evoked
      increases in RCF were also potentiated 3 h after oral administration of the
      antioxidant vitamin C (1000 mg; 139.1 +/- 15.4 PU before and 170.5 +/- 13.5 PU
      after vitamin C; P < 0.05). We propose that, in healthy young men, cutaneous
      vasodilatation evoked in the finger by the endothelium-dependent dilator ACh is
      limited by constrictor products of the COX pathway, including PGH2 (prostaglandin
      H2), TXA2 (thromboxane A2) and/or superoxide anions. This effect of the COX
      products may be an early marker of the increased risk of cardiovascular disease
      in men compared with women.

PMID- 15202931
TI  - Novel prenyl-linked benzophenone substrate analogues of mycobacterial
      mannosyltransferases.
AB  - PPM (polyprenol monophosphomannose) has been shown to act as a glycosyl donor in
      the biosynthesis of the Man (mannose)-rich mycobacterial lipoglycans LM
      (lipomannan) and LAM (lipoarabinomannan). The Mycobacterium tuberculosis PPM
      synthase (Mt-Ppm1) catalyses the transfer of Man from GDP-Man to polyprenyl
      phosphates. The resulting PPM then serves as a donor of Man residues leading to
      the formation of an alpha(1-->6)LM intermediate through a PPM-dependent alpha(1-
      >6)mannosyltransferase. In the present study, we prepared a series of ten novel
      prenyl-related photoactivatable probes based on benzophenone with lipophilic
      spacers replacing several internal isoprene units. These probes were excellent
      substrates for the recombinant PPM synthase Mt-Ppm1/D2 and, on photoactivation,
      several inhibited its activity in vitro. The protection of the PPM synthase
      activity by a 'natural' C(75) polyprenyl acceptor during phototreatment is
      consistent with probe-mediated photoinhibition occurring via specific covalent
      modification of the enzyme active site. In addition, the unique mannosylated
      derivatives of the photoreactive probes were all donors of Man residues, through
      a PPM-dependent mycobacterial alpha(1-->6)mannosyltransferase, to a synthetic
      Manp(1-->6)-Manp-O-C(10:1) disaccharide acceptor (where Manp stands for
      mannopyranose). Photoactivation of probe 7 led to striking-specific inhibition of
      the M. smegmatis alpha(1-->6)mannosyltransferase. The present study represents
      the first application of photoreactive probes to the study of mycobacterial
      glycosyltransferases involved in LM and LAM biosynthesis. These preliminary
      findings suggest that the probes will prove useful in investigating the
      polyprenyl-dependent steps of the complex biosynthetic pathways to the
      mycobacterial lipoglycans, aiding in the identification of novel
      glycosyltransferases.

PMID- 15202932
TI  - Incomplete glycosylation and defective intracellular targeting of mutant solute
      carrier family 11 member 1 (Slc11a1).
AB  - Solute carrier family 11 member 1 (Slc11a1, formerly Nramp1) is a highly
      glycosylated, 12 transmembrane domain protein expressed in macrophages. It
      resides in the membrane of late endosomes and lysosomes, where it functions as a
      bivalent cation transporter. Mice susceptible to infection by various
      intracellular pathogens including Leishmania donovani and Salmonella typhimurium
      carry a glycine to aspartic acid substitution at position 169 (G169D, Gly(169)-
      >Asp), within transmembrane domain 4 of Slc11a1. To investigate the molecular
      pathogenesis of infectious disease susceptibility, we compared the behaviour of
      heterologously and endogenously expressed wild-type and mutant Slc11a1 by
      immunofluorescence, immunoelectron microscopy and Western-blot analysis. We found
      occasional late endosome/lysosome staining of mutant protein using immunoelectron
      microscopy, but most of the mutant Slc11a1 was retained within the ER
      (endoplasmic reticulum). Using glycosylation as a marker for protein maturation
      in two independent heterologous expression systems, we found that most mutant
      Slc11a1 existed as an ER-dependent, partially glycosylated intermediate species.
      Correct endosomal targeting of wild-type Slc11a1 continued despite disruption of
      N-glycosylation sites, indicating that glycosylation did not influence folding or
      sorting. We propose that the G169D mutation causes localized misfolding of
      Slc11a1, resulting in its retention in the ER and manifestation of the loss of
      function phenotype.

PMID- 15202933
TI  - Insertion of the amyloid precursor protein into lipid monolayers: effects of
      cholesterol and apolipoprotein E.
AB  - APP (amyloid precursor protein), together with Chol (cholesterol) and ApoE
      (apolipoprotein E), has been linked to Alzheimer's disease. We have examined the
      hypothesis that interaction of APP with the lipid membranes is modulated by Chol
      and ApoE. Insertion of APP into lipid monolayers was first evidenced as an
      increase in the surface pressure. APP injected into a subphase induced a
      substantial increase in the surface pressure of monolayers prepared from PC (L
      alpha-phosphatidylcholine), Chol, SPM (sphingomyelin) and PS (L-alpha
      phosphatidylserine), the major lipids present in the plasma membranes of brain
      cells. At a given initial pressure, the insertion of APP into expanded monolayers
      is higher than that in condensed monolayers, in the order Chol>PC>SPM>PS. The
      membrane insertion capacity of APP was also measured from surface pressure versus
      area (pi-A) isotherms of APP-lipid monolayers. The increase in the mean area per
      molecule in protein-lipid monolayers, in the order PC>Chol>PS>SPM, provides
      further evidence for protein-lipid interactions. These interactions occurred at
      optimum salt levels and optimum pH values close to physiological conditions (150
      mM NaCl and pH 7.4). In addition, ApoE4 affected the insertion of APP into lipid
      films. APP-ApoE complexes showed a decreased ability to penetrate lipid
      monolayers at a constant area. APP-ApoE complexes expanded the pi-A isotherm of a
      Chol monolayer to a lesser extent than APP alone. These experiments demonstrate
      the roles of Chol and ApoE in the modulation of membrane insertion of APP.

PMID- 15202935
TI  - Exchange protein directly activated by cAMP (EPAC) interacts with the light chain
      (LC) 2 of MAP1A.
AB  - Using EPAC1 (exchange protein directly activated by cAMP 1) as bait in two-hybrid
      screens of foetal and adult human brain libraries, we identified the LC2 (light
      chain 2) of MAP1A (microtubule-associated protein 1A) as a protein capable of
      interaction with EPAC1. We applied an immunoprecipitation assay to demonstrate
      protein interaction between EPAC1 and LC2 in co-transfected human embryonic
      kidney 293 cells. EPAC2 also co-immunoprecipitated with LC2 from extracts of rat
      cerebellum. Immunolocalization in co-transfected human embryonic kidney 293 cells
      revealed that EPAC1 co-localizes with LC2 throughout the cell body. We found that
      endogenous EPAC2 is also immunolocalized with LC2 in PC12 cells.
      Immunolocalization of EPAC1 in transfected COS1 cells showed that EPAC1 is
      associated with the perinuclear region surrounding the nucleus and filamentous
      structures throughout the cell. Removal of the cAMP-binding domain of EPAC1
      (DeltacAMP-EPAC1) appeared to disrupt targeting of EPAC1 in cells resulting in a
      more dispersed staining pattern. Using two-hybrid assay, we tested the ability of
      LC2 to interact with DeltacAMP-EPAC1 and DeltaDEP-EPAC1, which lacks a DEP domain
      (dishevelled, Egl-10 and pleckstrin homology domain). We found that deletion of
      the cAMP-binding domain inhibited interaction between EPAC1 and LC2 in a two
      hybrid assay, but removal of the DEP domain had little effect. LC2 was found to
      interact with a glutathione-S-transferase-fusion protein of the cAMP-binding
      domain of EPAC1 in a pull-down assay, but not the DEP, REM (Ras exchange motif)
      or CAT (catalytic) domains. Together with our two-hybrid results, this suggests
      that the cAMP-binding domain of EPAC1 mediates interaction with LC2.

PMID- 15202936
TI  - Inhibition of P-glycoprotein and increasing of drug-sensitivity of a human
      carcinoma cell line (KB-A-1) by an antisense oligodeoxynucleotide-doxorubicin
      conjugate in vitro.
AB  - To improve the antisense activity of AS ODN (antisense oligodeoxynucleotide), a
      conjugate covalently linked to DOX (doxorubicin) at its 3'-end was synthesized
      and its antisense activity in human carcinoma DOX-resistant cells (KB-A-1) was
      investigated in vitro. The intracellular DOX concentration in KB-A-1 cells
      treated with the conjugate was detected in vitro by HPLC. Results showed that the
      intracellular DOX concentration was 6.4-fold higher in KB-A-1 cells treated with
      the conjugate when compared with that in the cells treated with DOX alone. In
      contrast, a 1.8-fold increase in the concentration of DOX was observed when the
      cells were treated with AS ODN. Reverse transcriptase PCR and Western-blot
      analysis showed a more significant decrease in the amount of mdr1 (multidrug
      resistance 1 gene) mRNA and P-glycoprotein in KB-A-1 cells. Chemosensitivity of
      KB-A-1 cells to DOX was also investigated in vitro. When the cells were first
      exposed to the conjugate (0.5 microM) for 24 h and then exposed to DOX for 24 h,
      the IC(50) value of DOX decreased from 21.5 to 2.2 microM, whereas the IC(50)
      value of DOX decreased only to 16.8 microM when the cells were treated with the
      mixture of the same concentration of AS ODN. These results suggest that the
      conjugate is effective in reversing multidrug resistance. Further studies will be
      conducted to explore the effect of the conjugate on tumours in vivo.

PMID- 15202934
TI  - The nuclear bile acid receptor FXR is activated by PGC-1alpha in a ligand
      dependent manner.
AB  - The nuclear bile acid receptor FXR (farnesoid X receptor) is one of the key
      factors that suppress bile acid biosynthesis in the liver. PGC-1alpha [PPARgamma
      (peroxisome-proliferator-activated receptor gamma) co-activator-1alpha] is known
      to control energy homoeostasis in adipose tissue, skeletal muscle and liver. We
      performed cell-based reporter assays using the expression system of a GAL4-FXR
      chimaera, the ligand-binding domain of FXR fused to the DNA-binding domain of
      yeast GAL4, to find the co-activators for FXR. We found that the transcriptional
      activation of a reporter plasmid by a GAL4-FXR chimaera was strongly enhanced by
      PGC-1alpha, in a ligand-dependent manner. Transcriptional activation of the SHP
      (small heterodimer partner) gene by the FXR-RXRalpha (retinoid X receptor alpha)
      heterodimer was also enhanced by PGC-1alpha in the presence of CDCA
      (chenodeoxycholic acid). Co-immunoprecipitation and pull-down studies using
      glutathione S-transferase-PGC-1alpha fusion proteins revealed that the ligand
      binding domain of FXR binds PGC-1alpha in a ligand-influenced manner both in vivo
      and in vitro. Furthermore, our studies revealed that SHP represses its own
      transcription, and the addition of excess amounts of PGC-1alpha can overcome the
      inhibitory effect of SHP. These observations indicate that PGC-1alpha mediates
      the ligand-dependent activation of FXR and transcription of SHP gene.

PMID- 15202937
TI  - Effects of buffer properties on cyclodextrin glucanotransferase reactions and
      cyclodextrin production from raw sago (Cycas revoluta) starch.
AB  - Results from the present study have shown that the ionic species of buffers, pH
      values and reaction temperature can affect the enzyme unit activities and product
      specificity of Toruzyme (Novo Nordisk A/S Bagsvaerd, Denmark) CGTase
      (cyclodextrin glucanotransferase). Applying a similar reaction environment
      (acetate buffer, pH 6.0; temperature, 60 degrees C), the CGTase was found to be
      capable of producing pre dominantly beta-cyclodextrin from either raw or
      gelatinized sago (Cycas revoluta) starch. Changing the buffer from acetate to
      phosphate reduced the yield of beta-cyclodextrin from 2.48 to 1.42 mg/ml and also
      affected the product specificity, where production of both alpha- and beta
      cyclodextrins were more pronounced. The decrease in the production of
      cyclodextrins in phosphate buffer was significant at both pH 6.0 and 7.0.
      However, changing the buffer to Tris/HCl (pH 7.0) showed a significant increase
      in beta-cyclodextrin production. Increasing the ionic strength of sodium acetate
      and Tris/HCl buffers at pH 6.0 and 7.0 to equivalent ionic strength of phosphate
      buffers showed no significant effects on cyclodextrin production. Higher yield of
      cyclodextrins at pH 7.0 when Tris/HCl was used might be due to the binding of
      chloride ions at the calcium-binding sites of the CGTase, resulting in the shift
      of the optimum pH close to physiological environment, leading to an increase in
      the activities and specificity.

PMID- 15202938
TI  - ARTs in action in nonhuman primates: symposium summary--advances and remaining
      issues.

PMID- 15202939
TI  - From sequence to structure and back again: approaches for predicting protein-DNA
      binding.
AB  - Gene regulation in higher organisms is achieved by a complex network of
      transcription factors (TFs). Modulating gene expression and exploring gene
      function are major aims in molecular biology. Furthermore, the identification of
      putative target genes for a certain TF serve as powerful tools for specific
      targeting of rational drugs.Detecting the short and variable transcription factor
      binding sites (TFBSs) in genomic DNA is an intriguing challenge for computational
      and structural biologists. Fast and reliable computational methods for predicting
      TFBSs on a whole-genome scale offer several advantages compared to the current
      experimental methods that are rather laborious and slow. Two main approaches are
      being explored, advanced sequence-based algorithms and structure-based
      methods.The aim of this review is to outline the computational and experimental
      methods currently being applied in the field of protein-DNA interactions. With a
      focus on the former, the current state of the art in modeling these interactions
      is discussed. Surveying sequence and structure-based methods for predicting
      TFBSs, we conclude that in order to achieve a sound and specific method
      applicable on genomic sequences it is desirable and important to bring these two
      approaches together.

PMID- 15202940
TI  - Molecular signatures of cell cycle transcripts in the pathogenesis of Glial
      tumors.
AB  - BACKGROUND: Astrocytic brain tumors are among the most lethal and morbid tumors
      of adults, often occurring during the prime of life. These tumors form an
      interesting group of cancer to understand the molecular mechanism of
      pathogenesis. Histological grading of Astrocytoma based on WHO classification
      does not provide complete information on the proliferation potential and
      biological behavior of the tumors. It is known that cancer results from the
      disruption of the orderly regulated cycle of replication and division. In the
      present study, we made an attempt to identify the cell cycle signatures and their
      involvement in the clinical aggressiveness of gliomas. METHODS: The variation in
      expression of various cell cycle genes was studied in different stages of glial
      tumor progression (low and high grades), and the results were compared with their
      corresponding expression levels in the normal brain tissue. Macroarray analysis
      was used for the purpose. RESULTS: Macroarray analysis of 114 cell cycle genes in
      different grades of glioma indicated differential expression pattern in 34% of
      the gene transcripts, when compared to the normal tissue. Majority of the
      transcripts belong to the intracellular kinase networks, cell cycle regulating
      kinases, transcription factors and transcription activators. CONCLUSION: Based on
      the observation in the expression pattern in low grade and high grade gliomas, it
      can be suggested that the upregulation of cell cycle activators are seen as an
      early event in glioma; however, in malignancy it is not the cell cycle activators
      alone, which are involved in tumorigenesis. Understanding the molecular details
      of cell cycle regulation and checkpoint abnormalities in cancer could offer an
      insight into potential therapeutic strategies.

PMID- 15202941
TI  - Socio-economic differences and health seeking behaviour for the diagnosis and
      treatment of malaria: a case study of four local government areas operating the
      Bamako initiative programme in south-east Nigeria.
AB  - BACKGROUND: Malaria is one of the leading causes of mortality and morbidity in
      Nigeria. It is not known how user fees introduced under the Bamako Initiative
      (BI) system affect healthcare seeking among different socio-economic groups in
      Nigeria for diagnosis and treatment of malaria. Reliable information is needed to
      initiate new policy thrusts to protect the poor from the adverse effect of user
      fees. METHODS: Structured questionnaires were used to collect information from
      1594 female household primary care givers or household head on their socio
      economic and demographic status and use of malaria diagnosis and treatment
      services. Principal components analysis was used to create a socio-economic
      status index which was decomposed into quartiles and chi-square for trends was
      used to calculate for any statistical difference. RESULTS: The study showed that
      self diagnosis was the commonest form of diagnosis by the respondents. This was
      followed by diagnosis through laboratory tests, community health workers, family
      members and traditional healers. The initial choice of care for malaria was a
      visit to the patent medicine dealers for most respondents. This was followed by
      visit to the government hospitals, the BI health centres, traditional medicine
      healers, private clinics, community health workers and does nothing at home.
      Furthermore, the private health facilities were the initial choice of treatment
      for the majority with a decline among those choosing them as a second source of
      care and an increase in the utilization of public health facilities as a second
      choice of care. Self diagnosis was practiced more by the poorer households while
      the least poor used the patent medicine dealers and community health workers less
      often for diagnosis of malaria. The least poor groups had a higher probability of
      seeking treatment at the BI health centres (creating equity problem in BI),
      hospitals, and private clinics and in using laboratory procedures. The least poor
      also used the patent medicine dealers and community health workers less often for
      the treatment of malaria. The richer households complained more about poor staff
      attitude and lack of drugs as their reasons for not attending the BI health
      centres. The factors that encourage people to use services in BI health centres
      were availability of good services, proximity of the centres to the homes and
      polite health workers. CONCLUSIONS: Factors deterring people from using BI
      centres should be eliminated. The use of laboratory services for the diagnosis of
      malaria by the poor should be encouraged through appropriate information,
      education and communication which at the long run will be more cost effective and
      cost saving for them while devising means of reducing the equity gap created.
      This could be done by granting a properly worked out and implemented fee
      exemptions to the poor or completely abolishing user fees for the diagnosis and
      treatment of malaria in BI health centres.

PMID- 15202942
TI  - Primary source of income is associated with differences in HIV risk behaviors in
      street-recruited samples.
AB  - BACKGROUND: The relationship between primary source of income and HIV risk
      behaviors and the racial/ethnic differences in risk behavior profiles among
      disadvantaged populations have not been fully explored. This is unusual given
      that the phenomenon of higher risk in more disadvantaged populations is well
      known but the mechanisms remain unclear. We examined the relationship between
      primary source of income and differences in HIV risk behaviors among four
      racial/ethnic groups in the southern United States. METHODS: Self-reported data
      on primary source of income and HIV risk behaviors were collected from 1494
      African American, Hispanic, Asian, and White men and women in places of public
      congregation in Houston, Texas. Data were analyzed using calculation of
      percentages and by chi-square tests with Yates correction for discontinuity where
      appropriate. RESULTS: Data revealed that a higher proportion of whites were
      involved in sex for money exchanges compared to the other racial groups in this
      sample. The data suggest that similar street sampling approaches are likely to
      recruit different proportions of people by primary income source and by
      ethnicity. It may be that the study locations sampled are likely to
      preferentially attract those involved in illegal activities, specifically the
      white population involved in sex for drug or money exchanges. Research evidence
      has shown that people construct highly evolved sexual marketplaces that are
      localized and most unlikely to cross racial, ethnic, and socioeconomic or
      geographical boundaries. Thus, the areas that we sampled may have straddled a
      white sexual marketplace more than that of the other groups, leading to an over
      representation of sex exchange in this group. Drug use was highest among those
      with illegal primary sources of income (sex exchange and drug dealing and theft),
      and they were also those most likely to have injected drugs rather than
      administered them by any other route (p < 0.001). In addition, bisexual or
      homosexual identification was reported by more respondents in the sex exchange as
      primary source of income category. The number of sexual partners in the last
      three months followed a similar pattern, with those whose primary source of
      income was drug dealing or theft reporting relatively high partner numbers.
      CONCLUSIONS: These data suggest that social disadvantage is associated with HIV
      risk in part by its association with drug and sex work for survival, and offers
      one variable that may be associated with the concentration of disease among those
      at greatest disadvantage by having an illegal and unstable primary income source.

PMID- 15202943
TI  - A two-dimensional mathematical model of percutaneous drug absorption.
AB  - BACKGROUND: When a drug is applied on the skin surface, the concentration of the
      drug accumulated in the skin and the amount of the drug eliminated into the blood
      vessel depend on the value of a parameter, r. The values of r depend on the
      amount of diffusion and the normalized skin-capillary clearance. It is defined as
      the ratio of the steady-state drug concentration at the skin-capillary boundary
      to that at the skin-surface in one-dimensional models. The present paper studies
      the effect of the parameter values, when the region of contact of the skin with
      the drug, is a line segment on the skin surface. METHODS: Though a simple one
      dimensional model is often useful to describe percutaneous drug absorption, it
      may be better represented by multi-dimensional models. A two-dimensional
      mathematical model is developed for percutaneous absorption of a drug, which may
      be used when the diffusion of the drug in the direction parallel to the skin
      surface must be examined, as well as in the direction into the skin, examined in
      one-dimensional models. This model consists of a linear second-order parabolic
      equation with appropriate initial conditions and boundary conditions. These
      boundary conditions are of Dirichlet type, Neumann type or Robin type. A finite
      difference method which maintains second-order accuracy in space along the
      boundary, is developed to solve the parabolic equation. Extrapolation in time is
      applied to improve the accuracy in time. Solution of the parabolic equation gives
      the concentration of the drug in the skin at a given time. RESULTS: Simulation of
      the numerical methods described is carried out with various values of the
      parameter r. The illustrations are given in the form of figures. CONCLUSION:
      Based on the values of r, conclusions are drawn about (1) the flow rate of the
      drug, (2) the flux and the cumulative amount of drug eliminated into the receptor
      cell, (3) the steady-state value of the flux, (4) the time to reach the steady
      state value of the flux and (5) the optimal value of r, which gives the maximum
      absorption of the drug. The paper gives valuable information which can be
      obtained by this two-dimensional model, that cannot be obtained with one
      dimensional models. Thus this model improves upon the much simpler one
      dimensional models. Some future directions of the work based on this model and
      the one-dimensional non-linear models that exist in the literature, are also
      discussed.

PMID- 15202944
TI  - Plasmodium falciparum gametocyte carriage in asymptomatic children in western
      Kenya.
AB  - BACKGROUND: Studies on Plasmodium falciparum gametocyte development and dynamics
      have almost exclusively focused on patients treated with antimalarial drugs,
      while the majority of parasite carriers in endemic areas are asymptomatic. This
      study identified factors that influence gametocytaemia in asymptomatic children
      in the absence and presence of pyrimethamine-sulphadoxine (SP) antimalarial
      treatment. METHODS: A cohort of 526 children (6 months-16 years) from western
      Kenya was screened for asexual parasites and gametocytes and followed weekly up
      to four weeks. Children with an estimated parasitaemia of > or =1,000
      parasites/microl were treated with SP according to national guidelines. Factors
      associated with gametocyte development and persistence were determined in
      untreated and SP-treated children with P. falciparum mono-infection. RESULTS:
      Gametocyte prevalence at enrollment was 33.8% in children below five years of age
      and decreased with age. In the absence of treatment 18.6% of the children
      developed gametocytaemia during follow-up; in SP-treated children this proportion
      was 29.8%. Age, high asexual parasite density and gametocyte presence at
      enrollment were predictive factors for gametocytaemia. The estimated mean
      duration of gametocytaemia for children below five, children from five to nine
      and children ten years and above was 9.4, 7.8 and 4.1 days, respectively.
      CONCLUSION: This study shows that a large proportion of asymptomatic untreated
      children develop gametocytaemia. Gametocytaemia was particularly common in
      children below five years who harbor gametocytes for a longer period of time. The
      age-dependent duration of gametocytaemia has not been previously shown and could
      increase the importance of this age group for the infectious reservoir.

PMID- 15202945
TI  - The relationship between the Plasmodium falciparum parasite ratio in childhood
      and climate estimates of malaria transmission in Kenya.
AB  - BACKGROUND: Plasmodium falciparum morbid and fatal risks are considerably higher
      in areas supporting parasite prevalence > or =25%, when compared with low
      transmission areas supporting parasite prevalence below 25%. Recent descriptions
      of the health impacts of malaria in Africa are based upon categorical
      descriptions of a climate-driven fuzzy model of suitability (FCS) for stable
      transmission developed by the Mapping Malaria Risk in Africa collaboration
      (MARA). METHODS: An electronic and national search was undertaken to identify
      community-based parasite prevalence surveys in Kenya. Data from these surveys
      were matched using ArcView 3.2 to extract spatially congruent estimates of the
      FCS values generated by the MARA model. Levels of agreement between three classes
      used during recent continental burden estimations of parasite prevalence (0%, >0
      <25% and > or =25%) and three classes of FCS (0, >0-<0.75 and > or =0.75) were
      tested using the kappa (k) statistic and examined as continuous variables to
      define better levels of agreement. RESULTS: Two hundred and seventeen independent
      parasite prevalence surveys undertaken since 1980 were identified during the
      search. Overall agreement between the three classes of parasite prevalence and
      FCS was weak although significant (k = 0.367, p < 0.0001). The overall
      correlation between the FCS and the parasite ratio when considered as continuous
      variables was also positive (0.364, p < 0.001). The margins of error were in the
      stable, endemic (parasite ratio > or =25%) class with 42% of surveys represented
      by an FCS <0.75. Reducing the FCS value criterion to > or =0.6 improved the
      classification of stable, endemic parasite ratio surveys. Zero values of FCS were
      not adequate discriminators of zero parasite prevalence. CONCLUSION: Using the
      MARA model to categorically distinguish populations at differing intensities of
      malaria transmission in Kenya may under-represent those who are exposed to
      stable, endemic transmission and over-represent those at no risk. The MARA
      approach to defining FCS values of suitability for stable transmission represents
      our only contemporary continental level map of malaria in Africa but there is a
      need to redefine Africa's population at risk in accordance with both climatic and
      non-climatic determinants of P. falciparum transmission intensity to provide a
      more informed approach to estimating the morbid and fatal consequences of
      infection across the continent.

PMID- 15202946
TI  - Type-selective muscular degeneration promotes infiltrative growth of
      intramuscular lipoma.
AB  - BACKGROUND: Intramuscular lipoma is a relatively common benign neoplasm that is
      occasionally described as an infiltrating lipoma. Typical benign tumors show a
      clear margin, however, the infiltrative growth pattern of this lipoma mimics that
      of a malignant tumor. Although its growth has an effect on muscle bundles and it
      is known to never metastasize, the mechanism of infiltrative growth is not well
      understood. Previously, little attention has been paid to pathogenic features of
      muscle fibers around an intramuscular lipoma. METHODS: In the present study, we
      focused on pathologic changes of the surrounding skeletal muscles especially to
      the degenerative features of involving muscular types, and evaluate the role of
      type-selective muscular degeneration for the infiltrative growth of intramuscular
      lipomas. Following a review of the medical records in our institute, 17 lesions
      containing muscle tissues in their specimens (15 infiltrating lipomas, 2 well
      circumscribed lipomas) were analyzed immunohistochemically. The tumor from the
      most recent case was also subjected to ultrastructural analysis. Two cases of the
      traumatic muscle damage were also evaluated as the control experiments. RESULTS:
      These analyses revealed type-selective muscle involution in 11 of 17
      intramuscular lipomas and in 10 of 11 of the infiltrative type, with an involving
      pattern that resembled that of a neurogenic or myogenic disorder.
      Immunoreactivity to cathepsin-D, a lysosomal catabolic enzyme, was increased in
      the involved muscle fibers. Subsarcolemmal vacuoles in the muscle fibers of the
      peripheral areas were also positive for cathepsin-D, while degenerative findings
      were not visually apparent in these areas. Ultrastructural analysis revealed
      degenerative changes in those fibers. Neither positive staining for cathepsin-D
      nor type-selective atrophy was detected in the sections of traumatic muscle
      damage. CONCLUSIONS: Our findings suggest that type-selective muscular
      degeneration and endomysial fatty growth as a result of atrophy may modulate the
      infiltrating growth characteristic of intramuscular lipoma.

PMID- 15202947
TI  - Exploratory spatial data analysis for the identification of risk factors to birth
      defects.
AB  - BACKGROUND: Birth defects, which are the major cause of infant mortality and a
      leading cause of disability, refer to "Any anomaly, functional or structural,
      that presents in infancy or later in life and is caused by events preceding
      birth, whether inherited, or acquired (ICBDMS)". However, the risk factors
      associated with heredity and/or environment are very difficult to filter out
      accurately. This study selected an area with the highest ratio of neural-tube
      birth defect (NTBD) occurrences worldwide to identify the scale of environmental
      risk factors for birth defects using exploratory spatial data analysis methods.
      METHODS: By birth defect registers based on hospital records and investigation in
      villages, the number of birth defects cases within a four-year period was
      acquired and classified by organ system. The neural-tube birth defect ratio was
      calculated according to the number of births planned for each village in the
      study area, as the family planning policy is strictly adhered to in China. The
      Bayesian modeling method was used to estimate the ratio in order to remove the
      dependence of variance caused by different populations in each village. A
      recently developed statistical spatial method for detecting hotspots, Getis's 7,
      was used to detect the high-risk regions for neural-tube birth defects in the
      study area. RESULTS: After the Bayesian modeling method was used to calculate the
      ratio of neural-tube birth defects occurrences, Getis's statistics method was
      used in different distance scales. Two typical clustering phenomena were present
      in the study area. One was related to socioeconomic activities, and the other was
      related to soil type distributions. CONCLUSION: The fact that there were two
      typical hotspot clustering phenomena provides evidence that the risk for neural
      tube birth defect exists on two different scales (a socioeconomic scale at 6.84
      km and a soil type scale at 22.8 km) for the area studied. Although our study has
      limited spatial exploratory data for the analysis of the neural-tube birth defect
      occurrence ratio and for finding clues to risk factors, this result provides
      effective clues for further physical, chemical and even more molecular laboratory
      testing according to these two spatial scales.

PMID- 15202949
TI  - Racial discrepancies in the association between paternal vs. maternal educational
      level and risk of low birthweight in Washington State.
AB  - BACKGROUND: The role of paternal factors in determining the risk of adverse
      pregnancy outcomes has received less attention than maternal factors. Similarly,
      the interaction between the effects of race and socioeconomic status (SES) on
      pregnancy outcomes is not well known. Our objective was to assess the relative
      importance of paternal vs. maternal education in relation to risk of low birth
      weight (LBW) across different racial groups. METHODS: We conducted a
      retrospective population-based cohort study using Washington state birth
      certificate data from 1992 to 1996 (n = 264,789). We assessed the associations
      between maternal or paternal education and LBW, adjusting for demographic
      variables, health services factors, and maternal behavioral and obstetrical
      factors. RESULTS: Paternal educational level was independently associated with
      LBW after adjustment for race, maternal education, demographic characteristics,
      health services factors; and other maternal factors. We found an interaction
      between the race and maternal education on risk of LBW. In whites, maternal
      education was independently associated with LBW. However, in the remainder of the
      sample, maternal education had a minimal effect on LBW. CONCLUSIONS: The degree
      of association between maternal education and LBW delivery was different in
      whites than in members of other racial groups. Paternal education was associated
      with LBW in both whites and non-whites. Further studies are needed to understand
      why maternal education may impact pregnancy outcomes differently depending on
      race and why paternal education may play a more important role than maternal
      education in some racial categories.

PMID- 15202948
TI  - Association of HLA Class I and Class II genes with bcr-abl transcripts in
      leukemia patients with t(9;22) (q34;q11).
AB  - BACKGROUND: Based on the site of breakpoint in t(9;22) (q34;q11), bcr-abl fusion
      in leukemia patients is associated with different types of transcript proteins.
      In this study we have seen the association of HLA genes with different types of
      bcr-abl transcripts. The association could predict the bcr-abl peptide
      presentation by particular HLA molecules. METHODS: The study included a total of
      189 patients of mixed ethnicity with chronic myelogenous leukemia and acute
      lymphocytic leukemia who were being considered for bone marrow transplantation.
      Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA
      typing was performed by molecular methods. The bcr-abl and HLA association was
      studied by calculating the relative risks and chi-square test. RESULTS:
      Significant negative associations (p < 0.05) were observed with HLA-A*02 (b2a2,
      e1a2), -A*68 (b2a2, b3a2, e1a2), -B*14 (b2a2, b3a2, e1a2), -B*15 (b2a2, b3a2), 
      B*40 (b2a2), -DQB1*0303 (b2a2, b3a2), -DQB1*0603 (b2a2), -DRB1*0401 (e1a2), 
      DRB1*0701 (b3a2), and -DRB1*1101 (b2a2). CONCLUSIONS: The negative associations
      of a particular bcr-abl transcript with specific HLA alleles suggests that these
      alleles play a critical role in presenting peptides derived from the chimeric
      proteins and eliciting a successful T-cell cytotoxic response. Knowledge of
      differential associations between HLA phenotypes and bcr-abl fusion transcript
      types would help in developing better strategies for immunization with the bcr
      abl peptides against t(9;22) (q34;q11)-positive leukemia.

PMID- 15202950
TI  - The Platino project: methodology of a multicenter prevalence survey of chronic
      obstructive pulmonary disease in major Latin American cities.
AB  - BACKGROUND: The prevalence of Chronic Obstructive Pulmonary Disease (COPD) in
      many developed countries appears to be increasing. There is some evidence from
      Latin America that COPD is a growing cause of death, but information on
      prevalence is scant. It is possible that, due to the high frequency of smoking in
      these countries, this disease may represent a major public health problem that
      has not yet been recognized as such. The PLATINO study is aimed at measuring COPD
      prevalence in major cities in Latin America. METHODS/DESIGN: A multi-country
      survey is being carried out in major cities in Latin America. In each
      metropolitan area, a population-based sample of approximately 1,000 individuals
      aged 40 years or older is being interviewed using standardized questionnaires.
      Eligible subjects are submitted to pre- and post-bronchodilator spirometry, and
      classified according to several criteria for COPD. Anthropometric examinations
      are also performed. Several risk factors are being studied, including smoking,
      socioeconomic factors, exposure to domestic biomass pollution, occupational
      exposure to dust and hospital admissions due to respiratory conditions during
      childhood. Whether or not subjects affected by COPD are aware of their disease,
      and if so how it is being managed by health services, is also being investigated,
      as are the consequences of this condition on quality of life and work
      performance. RESULTS: At the present time, the study is completed in Sao Paulo,
      Mexico City and Montevideo; Chile has started the study in March 2004 and it will
      be followed by Venezuela; two other metropolitan areas could still join the
      PLATINO project. Similar sampling procedures, with stratification for socio
      economic status, are being used in all sites. Strict coordination, training and
      standardization procedures have been used to ensure comparability of results
      across sites. Overall 92% of the pre-bronchodilator spirometry tests fulfilled
      ATS criteria of quality in the three first sites (97% in Montevideo, 91% in
      Mexico and 89% in Sao Paulo). CONCLUSIONS: The PLATINO project will provide a
      detailed picture of the global distribution of COPD in Latin America. This
      project shows that studies from Latin America can be carried out with adequate
      quality and be of scientific value.

PMID- 15202951
TI  - Predicting N-terminal myristoylation sites in plant proteins.
AB  - BACKGROUND: N-terminal myristoylation plays a vital role in membrane targeting
      and signal transduction in plant responses to environmental stress. Although N
      myristoyltransferase enzymatic function is conserved across plant, animal, and
      fungal kingdoms, exact substrate specificities vary, making it difficult to
      predict protein myristoylation accurately within specific taxonomic groups.
      RESULTS: A new method for predicting N-terminal myristoylation sites specifically
      in plants has been developed and statistically tested for sensitivity,
      specificity, and robustness. Compared to previously available methods, the new
      model is both more sensitive in detecting known positives, and more selective in
      avoiding false positives. Scores of myristoylated and non-myristoylated proteins
      are more widely separated than with other methods, greatly reducing ambiguity and
      the number of sequences giving intermediate, uninformative results. The
      prediction model is available at http://plantsp.sdsc.edu/myrist.html. CONCLUSION:
      Superior performance of the new model is due to the selection of a plant-specific
      training set, covering 266 unique sequence examples from 40 different species,
      the use of a probability-based hidden Markov model to obtain predictive scores,
      and a threshold cutoff value chosen to provide maximum positive-negative
      discrimination. The new model has been used to predict 589 plant proteins likely
      to contain N-terminal myristoylation signals, and to analyze the functional
      families in which these proteins occur.

PMID- 15202952
TI  - Genetic characterization of the Indian cattle breeds, Ongole and Deoni (Bos
      indicus), using microsatellite markers - a preliminary study.
AB  - BACKGROUND: Molecular characterization of cattle breeds is important for the
      prevention of germplasm erosion by cross breeding. The Indian zebu cattle have
      their significant role in evolution of present day cattle breeds and development
      of some of the exotic breeds. Microsatellites are the best available molecular
      tools for characterization of cattle breeds. The present study was carried out to
      characterize two Indian cattle breeds, Ongole and Deoni, using microsatellite
      markers. RESULTS: Using 5 di- and 5 tri-nucleotide repeat loci, 17 Ongole and 13
      Deoni unrelated individuals were studied. Of the ten loci, eight revealed
      polymorphism in both the breeds. The di-nucleotide repeat loci were found to be
      more polymorphic (100%) than tri-nucleotide repeat loci (60%). A total of 39
      polymorphic alleles were obtained at 4.5 alleles per locus in Ongole and 4.1 in
      Deoni. The average expected heterozygosity was 0.46 (+/-0.1) and 0.50 (+/-0.1) in
      Ongole and Deoni breeds, respectively. The PIC values of the polymorphic loci
      ranged from 0.15 to 0.79 in Ongole and 0.13 to 0.80 in Deoni breeds. Six Ongole
      specific and three Deoni specific alleles were identified. The two breeds showed
      a moderate genetic relationship between themselves with a FST value of 0.117 (P =
      0.01). CONCLUSIONS: This preliminary study shows that microsatellite markers are
      useful in distinguishing the two zebu breeds namely, Ongole and Deoni. Further
      studies of other zebu breeds using many microsatellite loci with larger sample
      sizes can reveal the genetic relationships of Indian breeds.

PMID- 15202953
TI  - Comparing transformation methods for DNA microarray data.
AB  - BACKGROUND: When DNA microarray data are used for gene clustering,
      genotype/phenotype correlation studies, or tissue classification the signal
      intensities are usually transformed and normalized in several steps in order to
      improve comparability and signal/noise ratio. These steps may include subtraction
      of an estimated background signal, subtracting the reference signal, smoothing
      (to account for nonlinear measurement effects), and more. Different authors use
      different approaches, and it is generally not clear to users which method they
      should prefer. RESULTS: We used the ratio between biological variance and
      measurement variance (which is an F-like statistic) as a quality measure for
      transformation methods, and we demonstrate a method for maximizing that variance
      ratio on real data. We explore a number of transformations issues, including Box
      Cox transformation, baseline shift, partial subtraction of the log-reference
      signal and smoothing. It appears that the optimal choice of parameters for the
      transformation methods depends on the data. Further, the behavior of the variance
      ratio, under the null hypothesis of zero biological variance, appears to depend
      on the choice of parameters. CONCLUSIONS: The use of replicates in microarray
      experiments is important. Adjustment for the null-hypothesis behavior of the
      variance ratio is critical to the selection of transformation method.

PMID- 15202954
TI  - Refining dog husbandry and care. Eighth report of BVAAWF/FRAME/RSPCA/UFAW Joint
      Working Group on Refinement.

PMID- 15202985
TI  - Consumer information gap on behavioral aspects of dietary change.

PMID- 15202986
TI  - Casting health messages in terms of responsibility for dietary change: increasing
      fruit and vegetable consumption.
AB  - OBJECTIVE: To compare the effectiveness of messages emphasizing the importance of
      either personal or social responsibility for dietary behavior change in
      increasing fruit and vegetable intake. DESIGN/SETTING: Randomly assigned
      individually or socially oriented messages were delivered at baseline, 1 week,
      and 2 and 3 months later. Telephone surveys were conducted at baseline and 1 and
      4 months later. PARTICIPANTS: 528 callers to a cancer information hotline who
      were not meeting the "5 A Day" dietary recommendation. INTERVENTIONS: A brief
      telephone-delivered message and 3 mailings of pamphlets and promotional items
      encouraging fruit and vegetable intake that emphasized either personal or social
      responsibility. MAIN OUTCOME MEASURES: Fruit and vegetable intake 1 and 4 months
      post baseline. ANALYSIS: Chi-square, t tests, and analyses of variance and
      covariance. RESULTS: Both types of messages increased intake substantially (P
      =.01). To some extent, the social responsibility message continued to motivate
      increased intake over time compared with the personal responsibility message.
      CONCLUSIONS AND IMPLICATIONS: These minimal interventions had a substantial
      impact on fruit and vegetable intake. Health messages might be more effective
      over the longer term if they are designed to emphasize the importance of social
      responsibility, although further study is needed to confirm the robustness of
      these findings.

PMID- 15202987
TI  - Pregnant women and listeriosis: preferred educational messages and delivery
      mechanisms.
AB  - OBJECTIVE: To characterize pregnant women's food safety practices, to evaluate
      the impact of existing educational messages on the risks and prevention of
      listeriosis, and to identify preferred delivery methods for educational
      initiatives. DESIGN: Eight focus group discussions conducted with pregnant women
      in 4 locations. SETTING: Focus group discussions led by moderators using a
      prepared moderator guide. PARTICIPANTS: Purposeful sampling was used to select
      the 63 pregnant women who participated in this study. The focus groups were
      segmented by location and education level. PHENOMENON OF INTEREST: Food safety
      knowledge and food-handling practices, food safety practices during pregnancy,
      attitudes toward listeriosis brochure, and preferred delivery methods. ANALYSIS:
      Focus group discussions were videotaped and audiorecorded. Detailed summaries of
      each discussion were prepared and systematically analyzed to identify common
      themes within and across groups. RESULTS: Participants were not aware of the
      risks of listeriosis and recommended practices for listeriosis prevention; thus,
      they were not taking precautions during their pregnancy to prevent listeriosis.
      CONCLUSIONS AND IMPLICATIONS: The study identified the need to develop
      educational materials on listeriosis targeted specifically to pregnant women and
      to partner with obstetricians and other health care providers to deliver these
      materials to pregnant women.

PMID- 15202988
TI  - Influence of the Fight BAC! food safety campaign on an urban Latino population in
      Connecticut.
AB  - OBJECTIVE: To assess the coverage and consumer satisfaction with the Fight BAC!
      campaign and to evaluate the influence of the campaign on food safety knowledge,
      attitudes, and behaviors among a predominantly Latino population living in inner
      city Hartford, Connecticut. DESIGN: A cross-sectional pre- and post-survey was
      administered to 500 Latino consumers in either English or Spanish. It included 30
      food safety-related questions and information on the socioeconomic and
      demographic characteristics of participants. SETTING AND PARTICIPANTS:
      Respondents were selected from Latino households, with at least one child 12
      years old or under, located in 5 predominantly Latino neighborhoods in inner-city
      Hartford. INTERVENTION: Fight BAC! media campaign. RESULTS: Seventy-three percent
      of respondents were exposed to at least one campaign media item and were highly
      satisfied with it. Recognition of the Fight BAC! logo increased from 10% to 42%
      between surveys (P <.001). Individuals exposed to the campaign were more likely
      to have a food safety knowledge score of at least 2 of a possible 4 compared with
      unexposed counterparts (odds ratio = 3.54; 95% CI 1.74-7.18; P <.001). They were
      also more likely to report defrosting meats in the refrigerator (14% vs 7%; P
      =.01). There was a dose-response association between the degree of campaign
      exposure and awareness of the term "cross-contamination." CONCLUSION AND
      IMPLICATIONS: Social marketing campaigns that take advantage of multiple
      culturally relevant media channels are likely to improve food safety awareness
      and bring about changes in food safety knowledge and attitudes among Latino
      consumers.

PMID- 15202989
TI  - Nutrition education intervention for college female athletes.
AB  - OBJECTIVE: To evaluate the efficacy of a nutrition education intervention for
      college female athletes to improve nutrition knowledge, build self-efficacy with
      respect to making healthful dietary choices, and improve dietary intake. DESIGN:
      A pretest-posttest control group design was implemented. PARTICIPANTS: A women's
      soccer team (n =15) and a women's swim team (n = 15) were randomly assigned to
      experimental and control groups, respectively. INTERVENTION: The intervention
      focused on nutrition knowledge, self-efficacy in making healthful dietary
      choices, and dietary practices to demonstrate treatment effect. MAIN OUTCOME
      MEASURES: Dependent variables were nutrition knowledge, self-efficacy, and
      dietary practices. Independent variables were group assignment. ANALYSES: The
      Mann-Whitney U test was used to analyze the results between groups, and the
      Fisher exact probability test was used to detect differences between groups in
      the number of positive dietary changes. RESULTS: Treatment participants
      significantly improved nutrition knowledge, self-efficacy (P <.05), and the
      overall number of positive dietary changes (P <.03). CONCLUSIONS: This study
      reduces the paucity of nutrition education intervention research among athletes
      and demonstrates the ability to increase not only nutrition knowledge, which is
      typically reported, but also self-efficacy and improvement in overall positive
      dietary changes during an 8-week intervention.

PMID- 15202990
TI  - Consumption and perceptions of soy among low-income adults.
AB  - OBJECTIVE: To assess the consumption and perceptions of soy among low-income
      adults. DESIGN: A survey, which included demographic items, Likert scales for
      items on perceived benefits and barriers to soy consumption and factors that may
      increase soy consumption, and a soy food consumption frequency questionnaire.
      SUBJECTS/SETTING: A convenience sample of 353 adults enrolled in either the
      Pennsylvania Expanded Food and Nutrition Education Program or the Pennsylvania
      Food Stamp Nutrition Education Program. STATISTICAL ANALYSES: Descriptive
      statistics. RESULTS: Few participants (13%; n = 44) reported currently consuming
      soy foods. The percentage of respondents recognizing potential health benefits of
      soy ranged from 53% to 57%. The major barriers to soy consumption were a lack of
      knowledge on how to use soy (87%), cost (55%), and unavailability (45%).
      Participants indicated that education on how to use and incorporate soy into the
      diet (88%) and addition of soy into familiar foods (82%) may increase their soy
      consumption. APPLICATIONS/CONCLUSIONS: The findings suggest that this population
      would benefit from exposure to soy foods and instruction on preparing low-cost
      soy foods that can easily be included in their diet, in addition to education on
      the potential health benefits of soy foods. The results may provide direction for
      the development of curricula that educate this population on the potential
      benefits and uses of soy.

PMID- 15202991
TI  - Two models for defining the relationship between theory and practice in nutrition
      education: is the scientific method meeting our needs?
AB  - This article describes two models for linking theory and practice in nutrition
      education and traces how concerns about the validity of different types of
      research drive the choice of models. In the scientific model, theory is defined
      in terms of statements from which one can deduce hypotheses, which can then be
      tested in experimental research designs. In the scientific model, practitioners
      are expected to replicate the methods used by researchers to effect targeted
      changes in the dependent variable of interest, usually health or eating
      behaviors. The ethical and epistemological shortcomings of the scientific model
      are then examined. The report goes on to describe an alternative approach, termed
      the humanistic model. In the humanistic model, theory is defined in terms of
      statements that seek to clarify basic social values. In the humanistic model,
      practitioners use theory as a stimulus for dialogue about the role of eating
      habits in living the kind of life that community members find most valuable.
      Examples of humanistic research relevant to nutrition education are presented,
      and the limitations of establishing the certainty of claims made using humanistic
      criteria are discussed. The article concludes with a discussion of the
      implications of the humanistic model for professional preparation.

PMID- 15202992
TI  - An innovative approach to goal setting for adolescents: guided goal setting.

PMID- 15202993
TI  - From the pyramid to the plate: a curriculum for individuals and groups with type
      2 diabetes.

PMID- 15202995
TI  - The fragile X-related gene affects the crawling behavior of Drosophila larvae by
      regulating the mRNA level of the DEG/ENaC protein pickpocket1.
AB  - BACKGROUND: Fragile X syndrome is caused by loss-of-function mutations in the
      fragile X mental retardation 1 (FMR1) gene. How FMR1 affects the function of the
      central and peripheral nervous systems is still unclear. FMR1 is an RNA binding
      protein that associates with a small percentage of total mRNAs in vivo. It
      remains largely unknown what proteins encoded by mRNAs in the FMR1-messenger
      ribonuclear protein (mRNP) complex are most relevant to the affected
      physiological processes. RESULTS: Loss-of-function mutations in the Drosophila
      fragile X-related (dfmr1) gene, which is highly homologous to the human fmr1
      gene, decrease the duration and percentage of time that crawling larvae spend on
      linear locomotion. Overexpression of DFMR1 in multiple dendritic (MD) sensory
      neurons increases the time percentage and duration of linear locomotion; this
      phenotype is similar to that caused by reduced expression of the MD neuron
      subtype-specific degenerin/epithelial sodium channel (DEG/ENaC) family protein
      Pickpocket1 (PPK1). Genetic analyses indicate that PPK1 is a key component
      downstream of DFMR1 in controlling the crawling behavior of Drosophila larvae.
      DFMR1 and ppk1 mRNA are present in the same mRNP complex in vivo and can directly
      bind to each other in vitro. DFMR1 downregulates the level of ppk1 mRNA in vivo,
      and this regulatory process also involves Argonaute2 (Ago2), a key component in
      the RNA interference pathway. CONCLUSIONS: These studies identify ppk1 mRNA as a
      physiologically relevant in vivo target of DFMR1. Our finding that the level of
      ppk1 mRNA is regulated by DFMR1 and Ago2 reveals a genetic pathway that controls
      sensory input-modulated locomotion behavior.

PMID- 15202996
TI  - MicroRNA regulation of NAC-domain targets is required for proper formation and
      separation of adjacent embryonic, vegetative, and floral organs.
AB  - BACKGROUND: MicroRNAs (miRNAs) are approximately 21 nucleotide (nt) RNAs that
      regulate gene expression in plants and animals. Most known plant miRNAs target
      transcription factors that influence cell fate determination, and biological
      functions of miRNA-directed regulation have been reported for four of 15 known
      microRNA gene families: miR172, miR159, miR165, and miR168. Here, we identify a
      developmental role for miR164-directed regulation of NAC-domain genes, which
      encode a family of transcription factors that includes CUP-SHAPED COTYLEDON1
      (CUC1) and CUC2. RESULTS: Expression of a miR164-resistant version of CUC1 mRNA
      from the CUC1 promoter causes alterations in Arabidopsis embryonic, vegetative,
      and floral development, including cotyledon orientation defects, reduction of
      rosette leaf petioles, dramatically misshapen rosette leaves, one to four extra
      petals, and one or two missing sepals. Reciprocally, constitutive overexpression
      of miR164 recapitulates cuc1 cuc2 double mutant phenotypes, including cotyledon
      and floral organ fusions. miR164 overexpression also leads to phenotypes not
      previously observed in cuc1 cuc2 mutants, including leaf and stem fusions. These
      likely reflect the misregulation of other NAC-domain mRNAs, including NAC1,
      At5g07680, and At5g61430, for which miR164-directed cleavage products were
      detected. CONCLUSIONS: These results demonstrate that miR164-directed regulation
      of CUC1 is necessary for normal embryonic, vegetative, and floral development.
      They also show that proper miR164 dosage or localization is required for
      separation of adjacent embryonic, vegetative, and floral organs, thus implicating
      miR164 as a common regulatory component of the molecular circuitry that controls
      the separation of different developing organs and thereby exposes a
      posttranscriptional layer of NAC-domain gene regulation during plant development.

PMID- 15202997
TI  - Mutual exclusion of sensory bristles and tendons on the notum of dipteran flies.
AB  - BACKGROUND: Genes of the achaete-scute complex encode transcription factors whose
      activity regulates the development of neural cells. The spatially restricted
      expression of achaete-scute on the mesonotum of higher flies governs the
      development and positioning of the large sensory bristles. On the scutum the
      bristles are arranged into conserved patterns, based on an ancestral arrangement
      of four longitudinal rows. This pattern appears to date back to the origin of
      cyclorraphous flies about 100-140 million years ago. The origin of the four-row
      bauplan, which is independent of body size, and the reasons for its conservation,
      are not known. RESULTS: We report that tendons for attachment of the indirect
      flight muscles are invariably located between the bristle rows of the scutum
      throughout the Diptera. Tendon development depends on the activity of a
      transcription factor encoded by the gene stripe. In Drosophila, stripe and
      achaete-scute have separate expression domains, leading to spatial segregation of
      tendon precursors and bristle precursors. Furthermore the products of these genes
      act antagonistically: ectopic sr expression prevents bristle development and
      ectopic sc expression prevents normal muscle attachment. The product of stripe
      acts downstream of Achaete-Scute and interferes with the development of bristle
      precursors. CONCLUSIONS: The pattern of flight muscles has changed little
      throughout the Diptera and we argue that the sites of muscle attachment may have
      constrained the positioning of bristles during the course of evolution. This
      could account for the pattern of four bristle rows on the scutum.

PMID- 15202998
TI  - ARF1 regulates Nef-induced CD4 degradation.
AB  - BACKGROUND: The HIV Nef protein downregulates CD4 through sequential connection
      with clathrin-coated pits and the COP1 coatomer, resulting in accelerated
      endocytosis and lysosomal targeting. RESULTS: Here we report that the small
      GTPase ARF1 controls the Nef-induced, COP-mediated late-endosomal targeting of
      CD4. We find that Nef binds ARF1 directly and can recruit the GTPase onto
      endosomal membranes. Furthermore, a complex comprising Nef, ARF1, and betaCOP can
      be immunoprecipitated from cells expressing the viral protein. Residues in a C
      terminal loop of the viral protein facilitate both these interactions and the
      targeting of Nef and CD4 to acidic late endosomes, whereas other residues
      primarily involved in mediating CD4 endocytosis are dispensable for this process.
      Finally, a dominant-negative ARF1 mutant blocks the migration of the Nef-CD4
      complex to lysosomes. CONCLUSIONS: Our results support a model in which ARF1 is
      the immediate downstream partner of Nef for CD4 lysosomal targeting.

PMID- 15202999
TI  - Taste perception and coding in Drosophila.
AB  - BACKGROUND: Discrimination between edible and contaminated foods is crucial for
      the survival of animals. In Drosophila, a family of gustatory receptors (GRs)
      expressed in taste neurons is thought to mediate the recognition of sugars and
      bitter compounds, thereby controlling feeding behavior. RESULTS: We have
      characterized in detail the expression of eight Gr genes in the labial palps, the
      fly's main taste organ. These genes fall into two distinct groups: seven of them,
      including Gr66a, are expressed in 22 or fewer taste neurons in each labial palp.
      Additional experiments show that many of these genes are coexpressed in partially
      overlapping sets of neurons. In contrast, Gr5a, which encodes a receptor for
      trehalose, is expressed in a distinct and larger set of taste neurons associated
      with most chemosensory sensilla, including taste pegs. Mapping the axonal targets
      of cells expressing Gr66a and Gr5a reveals distinct projection patterns for these
      two groups of neurons in the brain. Moreover, tetanus toxin-mediated inactivation
      of Gr66a- or Gr5a-expressing cells shows that these two sets of neurons mediate
      distinct taste modalities-the perception of bitter (caffeine) and sweet
      (trehalose) taste, respectively. CONCLUSION: Discrimination between two taste
      modalities-sweet and bitter-requires specific sets of gustatory receptor neurons
      that express different Gr genes. Unlike the Drosophila olfactory system, where
      each neuron expresses a single olfactory receptor gene, taste neurons can express
      multiple receptors and do so in a complex Gr gene code that is unique for small
      sets of neurons.

PMID- 15203000
TI  - Cleaner fish use tactile dancing behavior as a preconflict management strategy.
AB  - The most commonly asked question about cooperative interactions is how they are
      maintained when cheating is theoretically more profitable. In cleaning
      interactions, where cleaners remove parasites from apparently cooperating
      clients, the classical question asked is why cleaner fish can clean piscivorous
      client fish without being eaten, a problem Trivers used to explain reciprocal
      altruism. Trivers suggested that predators refrain from eating cleaners only when
      the repeated removal of parasites by a particular cleaner results in a greater
      benefit than eating the cleaner. Although several theoretical models have
      examined cheating behavior in clients, no empirical tests have been done (but see
      Darcy ). It has been observed that cleaners are susceptible to predation. Thus,
      cleaners should have evolved strategies to avoid conflict or being eaten. In
      primates, conflicts are often resolved with conflict or preconflict management
      behavior. Here, I show that cleaner fish tactically stimulate clients while
      swimming in an oscillating "dancing" manner (tactile dancing) more when exposed
      to hungry piscivorous clients than satiated ones, regardless of the client's
      parasite load. Tactile dancing thus may function as a preconflict management
      strategy that enables cleaner fish to avoid conflict with potentially "dangerous"
      clients.

PMID- 15203001
TI  - Incidental processing of biological motion.
AB  - The successful detection of biological motion can have important consequences for
      survival. Previous studies have demonstrated the ease and speed with which
      observers can extract a wide range of information from impoverished dynamic
      displays in which only an actor's joints are visible. Although it has often been
      suggested that such biological motion processing can be accomplished relatively
      automatically, few studies have directly tested this assumption by using
      behavioral methods. Here we used a flanker paradigm to assess how peripheral "to
      be-ignored" walkers affect the processing of a central target walker. Our results
      suggest that task-irrelevant dynamic figures cannot be ignored and are processed
      to a level where they influence behavior. These findings provide the first direct
      evidence that complex dynamic patterns can be processed incidentally, a finding
      that may have important implications for cognitive, neurophysiological, and
      computational models of biological motion processing.

PMID- 15203002
TI  - Motion-sensitive neurones in V5/MT modulate perceived spatial position.
AB  - Until recently, it was widely believed that object position and object motion
      were represented independently in the visual cortex. However, several studies
      have shown that adaptation to motion produces substantial shifts in the perceived
      position of subsequently viewed stationary objects. Two stages of motion
      adaptation have been proposed: an initial stage at the level of V1 and a
      secondary stage thought to be located in V5/MT. Indeed, selective adaptation can
      be demonstrated at each of these levels of motion analysis. What remains unknown
      is which of these cortical sites are involved in modulating the positional
      representation of subsequently viewed objects. To answer this question directly,
      we disrupted cortical activity by using transcranial magnetic stimulation (TMS)
      immediately after motion adaptation. When TMS was delivered to V5/MT after motion
      adaptation, the perceived offset of the test stimulus was greatly reduced. In
      marked contrast, TMS of V1 had no effect on the changes that normally occur in
      perceived position after motion adaptation. This result demonstrates that the
      anatomical locus at which motion and positional information interact is area
      V5/MT rather than V1/V2.

PMID- 15203003
TI  - The role of substrate curvature in actin-based pushing forces.
AB  - The extension of the plasma membrane during cell crawling or spreading is known
      to require actin polymerization; however, the question of how pushing forces
      derive from actin polymerization remains open. A leading theory (herein referred
      to as elastic propulsion) illustrates how elastic stresses in networks growing on
      curved surfaces can result in forces that push particles. To date all examples of
      reconstituted motility have used curved surfaces, raising the possibility that
      such squeezing forces are essential for actin-based pushing. By contrast, other
      theories, such as molecular ratchets, neither require nor consider surface
      curvature to explain pushing forces. Here, we critically test the requirement of
      substrate curvature by reconstituting actin-based motility on polystyrene disks.
      We find that disks move through extracts in a manner that indicates pushing
      forces on their flat surfaces and that disks typically move faster than the
      spheres they are manufactured from. For a subset of actin tails that form on the
      perimeter of disks, we find no correlation between local surface curvature and
      tail position. Collectively the data indicate that curvature-dependent mechanisms
      are not required for actin-based pushing.

PMID- 15203004
TI  - Phosphorylation regulates the dynamic interaction of RCC1 with chromosomes during
      mitosis.
AB  - The small GTPase Ran has multiple roles during the cell division cycle, including
      nuclear transport, mitotic spindle assembly, and nuclear envelope formation.
      However, regulation of Ran during cell division is poorly understood. Ran-GTP is
      generated by the guanine nucleotide exchange factor RCC1, the localization of
      which to chromosomes is necessary for the fidelity of mitosis in human cells.
      Using photobleaching techniques, we show that the chromosomal interaction of
      human RCC1 fused to green fluorescent protein (GFP) changes during progression
      through mitosis by being highly dynamic during metaphase and more stable toward
      the end of mitosis. The interaction of RCC1 with chromosomes involves the
      interface of RCC1 with Ran and requires an N-terminal region containing a nuclear
      localization signal. We show that this region contains sites phosphorylated by
      mitotic protein kinases. One site, serine 11, is targeted by CDK1/cyclin B and is
      phosphorylated in mitotic human cells. Phosphorylation of the N-terminal region
      of RCC1 inhibits its binding to importin alpha/beta and maintains the mobility of
      RCC1 during metaphase. This mechanism may be important for the localized
      generation of Ran-GTP on chromatin after nuclear envelope breakdown and may play
      a role in the coordination of progression through mitosis.

PMID- 15203005
TI  - Soluble guanylate cyclases act in neurons exposed to the body fluid to promote C.
      elegans aggregation behavior.
AB  - The genome of the nematode Caenorhabditis elegans encodes seven soluble guanylate
      cyclases (sGCs). In mammals, sGCs function as alpha/beta heterodimers activated
      by gaseous ligands binding to a haem prosthetic group. The principal activator is
      nitric oxide, which acts through sGCs to regulate diverse cellular events. In C.
      elegans the function of sGCs is mysterious: the worm genome does not appear to
      encode nitric oxide synthase, and all C. elegans sGC subunits are more closely
      related to mammalian beta than alpha subunits. Here, we show that two of the
      seven C. elegans sGCs, GCY-35 and GCY-36, promote aggregation behavior. gcy-35
      and gcy-36 are expressed in a small number of neurons. These include the body
      cavity neurons AQR, PQR, and URX, which are directly exposed to the blood
      equivalent of C. elegans and regulate aggregation behavior. We show that GCY-35
      and GCY-36 act as alpha-like and beta-like sGC subunits and that their function
      in the URX sensory neurons is sufficient for strong nematode aggregation. Neither
      GCY-35 nor GCY-36 is absolutely required for C. elegans to aggregate. Instead,
      these molecules may transduce one of several pathways that induce C. elegans to
      aggregate or may modulate aggregation by responding to cues in C. elegans body
      fluid.

PMID- 15203006
TI  - VP16 and ubiquitin; binding of P-TEFb via its activation domain and ubiquitin
      facilitates elongation of transcription of target genes.
AB  - Acidic or type IIB transcriptional activation domains (AADs) increase rates of
      initiation as well as elongation of transcription. For the former effects, AADs
      bind general transcription factors and larger coactivator complexes, which
      position RNA polymerase II (RNAPII) at sites of initiation of transcription. For
      the latter effects, their ubiquitylation plays an important role. In this study,
      this posttranslational modification increased the binding between a prototypic
      AAD and the positive transcription elongation factor b (P-TEFb), which contains a
      C-type cyclin (CycT1, CycT2, or CycK) and Cdk9. By phosphorylating negative
      elongation factors and the C-terminal domain of RNAPII, P-TEFb modifies the
      transcription complex for efficient elongation and cotranscriptional processing
      of mRNA. Indeed, the activation domain of VP16 and ubiquitin bound the cyclin
      boxes and the C terminus in CycT1, respectively. Moreover, the artificial fusion
      of ubiquitin with VP16 not only increased its activity via DNA and RNA, which was
      reflected in increased ratios of elongated to initiated transcripts, but rescued
      the deleterious substitution of alanine for phenylalanine at position 442 in its
      AAD. Thus, the ubiquitylation of AADs increases their interaction with P-TEFb and
      augments rates of elongation of transcription.

PMID- 15203007
TI  - Requirements of cyclin a for mitosis are independent of its subcellular
      localization.
AB  - Cyclin A (CycA), the only essential mitotic cyclin in Drosophila, is cytoplasmic
      during interphase and accumulates in the nucleus during prophase. We show that
      interphase localization is mediated by Leptomycin B (LMB)-sensitive nuclear
      export. This is a feature shared with human CyclinB1, and it is assumed that
      nuclear accumulation is necessary for mitotic entry. Here, we tested if the
      unique mitotic function of CycA requires nuclear accumulation. We fused
      subcellular localization signals to CycA and tested their mitotic capability.
      Surprisingly, nuclear accumulation was not required, and even a membrane-tethered
      form of CycA was able to induce mitosis. We noted that Cyclin B (CycB) protein
      disappears prematurely in CycA mutants, reminiscent of rca1 mutants. Rca1 is an
      inhibitor of Fizzy-related-APC/C activity, and in rca1 mutants, mitotic cyclins
      are degraded in G2 of the 16(th) embryonic cell cycle. Overexpression of Rca1 can
      restore mitosis in CycA mutants, indicating that the mitotic failure of CycA
      mutants is caused by premature activation of the APC/C. The essential mitotic
      function of CycA is therefore not the activation of numerous mitotic substrates
      by Cdk1-dependent phosphorylation. Rather, CycA-dependent kinase activity is
      required to inhibit one inhibitor of mitosis, the Fzr protein.

PMID- 15203008
TI  - Who's akin to the big bad wolf?

PMID- 15203009
TI  - Changing places. Interview by Graham Tebb.
AB  - Kim Nasmyth is set to move from the Institute of Molecular Pathology in Vienna to
      take up a new post in Oxford. He talks to Graham Tebb about his reasons for
      returning to the UK and plans for the future.

PMID- 15203011
TI  - Parasitoids.

PMID- 15203012
TI  - Towing the line.

PMID- 15203013
TI  - Q & A. David Burr.

PMID- 15203014
TI  - Breaking symmetry in myxobacteria.

PMID- 15203015
TI  - Ancient mitochondrial DNA from hair.

PMID- 15203016
TI  - Individual protochordates have unique immune-type receptor repertoires.

PMID- 15203017
TI  - Actin polymerization: forcing flat faces forward.
AB  - Actin polymerization has been shown to be sufficient to propel curved objects,
      for example beads and vesicles coated with the Listeria monocytogenes protein
      ActA. Recent studies suggest that actin polymerization on flat surfaces can also
      provide the propulsive force to push them forward.

PMID- 15203018
TI  - Behavioural biology: fortune favours bold and shy personalities.
AB  - A new study has shown that in the great tit (Parus major) bold males and shy
      females apparently flourish after rich winter pickings, while shy males and bold
      females profit from meagre winters. This groundbreaking work exemplifies the
      approach required for a biological understanding of an apparently common animal
      trait - personality.

PMID- 15203019
TI  - Genome evolution: the dynamics of static genomes.
AB  - A random survey of a microsporidian genome has revealed some striking features.
      Although the genomes of microsporidians are among the smallest known for
      eukaryotes, their organisation appears to be well conserved.

PMID- 15203020
TI  - Animal navigation: path integration, visual landmarks and cognitive maps.
AB  - Animals typically have several navigational strategies available to them.
      Interactions between these strategies can reduce navigational errors and may lead
      to the emergence of new capacities.

PMID- 15203021
TI  - Psychophysics: catching the old codger's eye.
AB  - Some visual stimuli are bistable, with perception alternating irregularly between
      two alternatives. Recent work suggests that the neural processing of these
      alternations must occur at low levels of the visual system.

PMID- 15203022
TI  - Drosophila gastrulation: identification of a missing link.
AB  - Drosophila gastrulation serves as a model system to elucidate the genetic and
      molecular mechanisms involved in morphogenetic movements. The ligand of the FGF
      receptor Heartless, which is involved in mesoderm movement, has now been isolated
      and shown to be a link between a morphogen gradient and cell behavior.

PMID- 15203023
TI  - Membrane targeting: getting Arl to the Golgi.
AB  - Post-translational modification with myristoyl or prenyl groups is essential for
      membrane association of many small GTPases in the Ras superfamily. Two recent
      papers show that, rather than myristoylation, amino-terminal acetylation of the
      Arf-like protein Arl3p is required for Golgi targeting via an interaction with an
      integral membrane protein called Sys1.

PMID- 15203024
TI  - Bacterial chemosensing: cooperative molecular logic.
AB  - Bacterial chemotaxis is mediated by transmembrane receptors that bind attractant
      and repellent chemicals and control an intracellular protein kinase. Each cell
      contains thousands of receptor subunits that form a tightly packed array at one
      pole. Recent studies of bacterial behavior have begun to reveal the molecular
      logic of this sensory architecture.

PMID- 15203025
TI  - Plant development: YODA the stomatal switch.
AB  - The appearance of stomatal pores during plant evolution is believed to have been
      a crucial step in land colonisation. A recent screen for genes involved in
      stomatal development has identified for the first time a mutant plant with no
      stomata; the results implicate a MAP kinase cascade in stomatal development.

PMID- 15203026
TI  - Method for the determination of five toxicologically relevant arsenic species in
      human urine by liquid chromatography-hydride generation atomic absorption
      spectrometry.
AB  - An analytical method for the simultaneous quantitation of arseneous acid
      (As(III)), arsenic acid (As(V)), monomethylarsonic acid (MMA), dimethylarsinic
      acid (DMA) and trimethylarsine oxide (TMAO) in human urine by coupling of high
      performance liquid chromatography with hydride generation atomic absorption
      spectrometry (HPLC/HG-AAS) via a flow-injection interface is presented. After
      arsenic species separation by anion-exchange displacement chromatography the
      compounds are on-line reduced to their corresponding hydrides and detected by
      atomic absorption spectrometry. Detection limits range from 1.1 (TMAO) to 2.6
      microg/L (As(V)). The method has been applied to determine arsenic species in the
      urine of a volunteer before and after consumption of seafood as well as to
      analyse certified reference urine samples for their arsenic species content.

PMID- 15203027
TI  - Determination of serotonin, noradrenaline, dopamine and their metabolites in rat
      brain extracts and microdialysis samples by column liquid chromatography with
      fluorescence detection following derivatization with benzylamine and 1,2
      diphenylethylenediamine.
AB  - A highly selective and sensitive column liquid chromatographic method for
      fluorescence determination of serotonin (5-HT), dopamine (DA), noradrenaline (NA)
      and their related metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4
      dihydroxyphenylacetic acid (DOPAC) following derivatization with benzylamine and
      1,2-diphenylethylenediamine (DPE) is described. The monoamines and the
      metabolites (20 microl samples) were derivatized in a two-step reaction,
      initiated with 20 microl of 0.3M benzylamine in 0.3M 3
      cyclohexylaminopropanesulfonic acid (CAPS) buffer (pH 10.0), (for 5-HT, 5-HIAA, 2
      min, 24 degrees C) and followed by 20 microl of 0.1M DPE in 0.3M glycine buffer
      (pH 10.0), (for DA, NA, DOPAC, 20 min, 50 degrees C). Both reagents contained
      0.02 M potassium hexacyanoferrate(III) and 50% (v/v) methanol. The resulting
      highly fluorescent and stable benzoxazole derivatives were isocratically
      separated on a reversed-phase column (150 mm x 1.5 mm i.d., packed with C18
      silica, 5 microm) within 45 min. Using fluorescence detection at ex. and em.
      wavelengths of 345 and 480 nm, respectively, the detection limit (signal-to-noise
      ratio of 3) for 5-HT, DA, NA, 5-HIAA, L-DOPA and DOPAC ranged between 0.08 and
      5.65 fmol per 20-microl injection (12-847.5 pM in standard solution). The
      concentrations of monoamines (expressed in microg/g wet weight, mean +/- S.E.M.,
      n=5) in tissue extracts from the rat striatum were: 0.45+/-0.05 (5-HT), 4.27+/
      0.08 (DA), 0.27+/-0.04 (NA), 0.55+/-0.06 (5-HIAA), 1.26+/-0.16 (L-DOPA) and
      1.62+/-0.11 (DOPAC). Microdialysis samples were collected in 20 min intervals
      from the probes implanted in the striatum of awake rats. The basal monoamine
      levels (in fmol/20 microl, mean +/- S.E.M., n=5) in the dialysates were: 4.0+/
      0.7 (5-HT), 78.4+/-9.1 (DA), 6.4+/-0.8 (NA), 785.5+/-64.5 (5-HIAA) and 5504.5+/
      136.5 (DOPAC). It is concluded that the new fluorescence derivatization protocol
      provides an excellent means for simultaneous determination of all three
      monoamines both in the complex samples (e.g. brain homogenates) and also at trace
      levels, such as those found in the microdialysis samples.

PMID- 15203028
TI  - Simultaneous determination of endogenous and 13C-labelled thyroid hormones in
      plasma by stable isotope dilution mass spectrometry.
AB  - This study describes a capillary gas chromatography-mass spectrometry (GC-MS)
      method for the simultaneous determination of endogenous thyroid hormone
      (thyroxine, T4) and its 13C-labelled analogue (13C6-thyroxine) in plasma. 13C9
      thyroxine was used as analytical internal standard. A double derivatization
      (CH3OH/HCl and HFBA) inducing good GC mobility was used for the GC-MS analysis of
      the thyroid hormones. Quantification was carried out by selected ion monitoring
      (SIM) of specific ions of the fragment ions (m/z 970/976/979). The detection
      limit of the present GC-MS-SIM method was found to be 100 pg per injection for
      thyroxine (S/N=3.0). A first implementation in in vivo tests of 13C6-T4 like
      metabolic tracer was carried out under veterinary control on one cat and one
      rabbit. The thyroxine follow-up was done by GC-MS and based on double isotopic
      dilution with two different regio-selective 13C-labelled molecules of the same
      hormone. The present paper discusses the possibilities and limitations of this
      methodology. The in vivo experiment demonstrated that the use of stable isotopes
      and mass spectrometry provide a reliable methodology for hormonal monitoring.

PMID- 15203029
TI  - Potential of biopartitioning micellar chromatography as an in vitro technique for
      predicting drug penetration across the blood-brain barrier.
AB  - The blood-brain barrier (BBB) is considered to be the main barrier to drug
      transport into the central nervous system (CNS). The BBB restricts the passive
      diffusion of many drugs from blood to brain. The ease with which any particular
      drug diffuses across the BBB is determined largely by the molecular features of
      drugs, and it is therefore possible to predict the BBB permeability of a drug
      from its molecular structure. Biopartitioning micellar chromatography (BMC), a
      mode of micellar liquid chromatography that uses micellar mobile phases of Brij35
      in adequate experimental conditions, can be useful in mimicking the drug
      partitioning process into biological systems. Retention in BMC depends on the
      hydrophobicity, electronic and steric properties of drugs. In this paper, the
      usefulness of BMC for predicting the BBB penetration ability of drugs expressed
      as the brain/blood distribution coefficient (BB) is demonstrated. A multiple
      linear regression (MLR) model that relates the BB distribution coefficients data
      with BMC retention data and total molar charge is proposed. The model is obtained
      using 44 heterogeneous drugs including, neutral, anionic, and cationic compounds.
      A comparison with other reported methodologies to predict the BBB permeability is
      also presented.

PMID- 15203030
TI  - Liquid chromatography method for the quantitation of the breast cancer resistance
      protein ABCG2 inhibitor fumitremorgin C and its chemical analogues in mouse
      plasma and tissues.
AB  - Fumitremorgin C (FTC) was recently discovered to be a potent and selective
      inhibitor of the breast cancer resistance protein (BCRP/ABCG2). FTC was shown to
      reverse multidrug resistance mediated by BCRP and to increase the cytotoxicity of
      several anticancer agents in vitro. To support in vivo studies a reverse phase
      HPLC method with ultraviolet detection was developed to quantitate FTC in mouse
      plasma and tissues. Further, assay method validation was performed for the
      determination of FTC in mouse plasma. Plasma standard curves ranged from 0.03 to
      30 microg/ml, while the various tissue assay ranges differed to some extent. The
      sample preparation consisted of acetonitrile precipitation with separation
      accomplished with a C18 Novapak column and a C18 pre-column utilizing an
      isocratic mobile phase of ammonium acetate and acetonitrile. UV detection was set
      at 225 nm for FTC and at 312 nm for roquefortine, the internal standard. The
      retention times were approximately 9.5 min for FTC and 13.0 min for roquefortine.
      The recoveries for FTC and roquefortine from plasma were 90.8+/-5.8% and 111.6+/
      13.6, respectively. The reported assay can be used for future study of BCRP
      resistance in vivo in different biological matrices. Further, we found that a
      more potent analogue of FTC, Ko143, was able to be extracted and detected, with a
      maximal UV absorbance at 320 nm under the conditions reported.

PMID- 15203031
TI  - Improving automatic peptide mass fingerprint protein identification by combining
      many peak sets.
AB  - An automated peak picking strategy is presented where several peak sets with
      different signal-to-noise levels are combined to form a more reliable statement
      on the protein identity. The strategy is compared against both manual peak
      picking and industry standard automated peak picking on a set of mass spectra
      obtained after tryptic in gel digestion of 2D-gel samples from human fetal
      fibroblasts. The set of spectra contain samples ranging from strong to weak
      spectra, and the proposed multiple-scale method is shown to be much better on
      weak spectra than the industry standard method and a human operator, and equal in
      performance to these on strong and medium strong spectra. It is also demonstrated
      that peak sets selected by a human operator display a considerable variability
      and that it is impossible to speak of a single "true" peak set for a given
      spectrum. The described multiple-scale strategy both avoids time-consuming
      parameter tuning and exceeds the human operator in protein identification
      efficiency. The strategy therefore promises reliable automated user-independent
      protein identification using peptide mass fingerprints.

PMID- 15203032
TI  - Determination of rofecoxib in human plasma and breast milk by high-performance
      liquid chromatographic assay.
AB  - A rapid and simple HPLC assay was developed for the determination of rofecoxib in
      human plasma and breast milk. After solid-phase extraction, rofecoxib was
      resolved on a C18 column and detected by UV detection at 272 nm. Standard curves
      were linear over the concentration range 10-2000 microg/L (r2 >0.99). Intra- and
      inter-day coefficients of variation for both matrices were <10% and the limit of
      quantification was around 10 microg/L.

PMID- 15203033
TI  - Improved purification of beta-lactoglobulin from acid whey by means of ceramic
      hydroxyapatite chromatography with sodium fluoride as a displacer.
AB  - The successful separation of beta-lactoglobulin from other bovine whey proteins
      was performed by ceramic hydroxyapatite chromatography with a fluoride ion
      gradient in phosphate buffer as displacement agent. The method was applied to
      acid whey originating from milk of healthy as well as of mastitic cows. beta
      Lactoglobulin was completely eluted in one peak at a fluoride concentration of
      about 0.6 mol/l. The purity of beta-lactoglobulin in this fraction was at least
      96% if whey from healthy milk was processed. Co-eluted contaminants are traces of
      immunoglobulin G, serum albumin and lactoferrin. In case of mastitic whey the
      proportion of beta-lactoglobulin is diminished as the amounts of immunglobulin G,
      serum albumin and lactoferrin are increased within this fraction. Size exclusion
      chromatography on Superdex 75 pg effectively removed contaminants resulting in a
      purity for beta-lactoglobulin from normal whey of approximately 99%. The yield of
      beta-lactoglobulin from physiological whey was 50-55% referring to the fraction
      highly enriched with beta-lactoglobulin by hydroxyapatite chromatography. In case
      of mastitic milk the higher amounts of contaminants were also removed
      successfully by size exclusion chromatography.

PMID- 15203034
TI  - Determination of arginine-vasotocin and isotocin in fish plasma with solid-phase
      extraction and fluorescence derivatization followed by high-performance liquid
      chromatography.
AB  - A new HPLC assay for plasma arginine-vasotocin (AVT) and isotocin (IT)
      determination based on fluorescence detection preceded by combination of solid
      phase extraction (SPE) and fluorescence derivatization is presented. Plasma
      samples retained on solid support were purified and then derivatized by the
      fluorescent compound 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). The peptide
      derivatives were eluted from cartridges, pre-concentrated and analyzed by HPLC
      system with fluorescent detection. The separation was carried out on a reversed
      phase column with solvent gradient system. The assay was linear in the range 15
      220 pmol ml(-1) for AVT r2=0.998 and 10-220 pmol ml(-1) for IT r2=0.996. The
      detection limits for AVT and IT were 0.8 and 0.5 pmol ml(-1) (3:1, signal-to
      noise), respectively. The recoveries of derivatized hormones were in the range 89
      93%. Both of the inter- and intra-day assay precision were below 5.5 and 9% for
      AVT and IT, respectively. The assay should be also applicable to plasma and
      tissue samples from other animals with only minor modification.

PMID- 15203035
TI  - Rapid high-throughput assay for the measurement of amino acids from
      microdialysates and brain tissue using monolithic C18-bonded reversed-phase
      columns.
AB  - A rapid precolumn high-performance liquid chromatography method based on
      fluorescence detection has been developed for the measurement of multiple amino
      acids from both ex vivo and in vivo biological samples using monolithic C18
      columns. A mixture of 18 primary amino acids were derivatised with napthalene-2,3
      dicarboxaldehyde (NDA) in the presence of cyanide. The resulting isoindole
      derivatives were resolved within 10 min using a linear binary gradient elution
      profile with Rs values in the range 1.2-9.0. The limit of detection (LOD) was
      found to be between 6.0 and 60 fmol for 5 microl injection with a signal to noise
      ratio of 3:1. The NDA derivatives were found to be stable for 9 h at 4 degrees C.
      This assay has been employed for the rapid analysis of amino acids from brain
      tissue and microdialysis samples. Examples of application of the method are
      given.

PMID- 15203036
TI  - Determination of a novel substance P inhibitor in human plasma by high
      performance liquid chromatography with atmospheric pressure chemical ionization
      mass spectrometric detection using single and triple quadrupole detectors.
AB  - Methods based on high-performance liquid chromatography (HPLC) with atmospheric
      pressure chemical ionization (APCI) mass spectrometric (MS) detection using
      either single (MS) or triple (MS/MS) quadrupole mass spectrometric detection for
      the determination of (2R)-[1(R)-(3,5-bis-trifluoromethylphenyl)ethoxy]-3(S)-(4
      fluoro-phenyl)morpholin-4-ylmethyl]-5-oxo-4,5-dihydro-[1,2,4]triazol)methyl
      morpholine (Aprepitant, Fig. 1) in human plasma has been developed. Aprepitant
      (I) and internal standard (II, Fig. 1) were isolated from the plasma matrix
      buffered to pH 9.8 using a liquid-liquid extraction with methyl-t-butyl ether
      (MTBE). The analytes were separated on a Keystone Scientific's Javelin BDS C-8 2
      mm x 4.6 mm 3 microm guard column coupled to BDS C-8 50 mm x 4.6 mm 3 microm
      analytical column, utilizing a mobile phase of 50% acetonitrile and 50% water
      containing 0.1% formic acid and 10 mM ammonium acetate delivered at a flow rate
      of 1 ml/min. The single quadrupole instrument was operated in a single ion
      monitoring (SIM) mode analyzing the protonated molecules of Aprepitant and II at
      m/z 535 and 503, respectively. The triple quadrupole mass spectrometer was
      operated in multiple reaction monitoring mode (MRM) monitoring the precursor -->
      ion combinations of m/z 535 --> 277 and 503 --> 259 for Aprepitant and II,
      respectively. The linear calibration range for both single and triple quadrupole
      detectors was from 10 to 5000 ng/ml of plasma with coefficients of variation less
      than 8% at all concentrations. Both single and triple quadrupole instruments
      yielded similar precision and accuracy results. Matrix effect experiments
      performed on both instruments demonstrated the absence of any significant change
      in ionization of the analytes when comparing neat standards to analytes in the
      presence of plasma matrix. Both instruments were used successfully to support
      numerous clinical trials of Aprepitant.

PMID- 15203037
TI  - Liquid chromatography analysis of N-(2-mercaptopropionyl)-glycine in biological
      samples by ThioGlo 3 derivatization.
AB  - N-(2-Mercaptopropionyl)-glycine (MPG) is a synthetic aminothiol antioxidant that
      is used in the treatment of cystinuria, rheumatoid arthritis, liver and skin
      disorders. Recent studies have shown that MPG can function as a chelating,
      cardioprotecting and a radioprotecting agent. Several other studies have shown
      that it may also act as a free radical scavenger because of its thiol group.
      Thiol-containing compounds have been detected in biological samples by various
      analytical methods such as spectrophotometric and colorimetric methods. However,
      these methods require several milliliters of a sample, time-consuming procedures
      and complicated derivatization steps, as well as having high detection limits.
      The present study describes a rapid, sensitive and relatively simple method for
      detecting MPG in biological tissues by using reverse-phase HPLC. With ThioGlo 3
      [3H-Naphto[2,1-b] pyran, 9-acetoxy-2-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)
      phenyl-3-oxo-)] as the reagent, highly fluorescent derivatives of thiols can be
      obtained that are suitable for HPLC. MPG is derivatized with ThioGlo 3 and is
      then detected flourimetrically by reverse phase HPLC using a C18 column as the
      stationary phase. Acetonitrile: Water (75:25) with acetic acid and phosphoric
      acid (1 mL/L) is used as the mobile phase (excitation wavelength, 365 nm;
      emission wavelength, 445 nm). The calibration curve for MPG is linear over a
      range of 10-2500 nM (r=0.999) and the coefficients of the variation of within-run
      and between-run precision were found to be 0.3 and 2.1%, respectively. The
      detection limit was 5.07 nM per 20 microL injection volume. Quantitative relative
      recovery of MPG in the biological samples (plasma, lung, liver, kidney and brain)
      ranged from 90+/-5.3 to 106.7+/-9.3 %. Based on these results, we have concluded
      that this method is suitable for determining MPG in biological samples.

PMID- 15203038
TI  - Purification of antibodies against N-homocysteinylated proteins by affinity
      chromatography on Nomega-homocysteinyl-aminohexyl-Agarose.
AB  - Modification with homocysteine (Hcy)-thiolactone leads to the formation of N-Hcy
      Lys-protein. Although N-Hcy-Lys-proteins are immunogenic, pure antibodies have
      not yet been obtained. Here we describe synthesis and application of Nomega
      homocysteinyl-aminohexyl-Agarose for affinity purification of anti-N-Hcy-Lys
      protein antibodies. Nomega-homocysteinyl-aminohexyl-Agarose was prepared by N
      homocysteinylation of omega-aminohexyl-Agarose with Hcy-thiolactone. Immune serum
      was obtained from rabbits inoculated with N-Hcy-Lys-keyhole limpet hemocyanine
      and IgG fraction prepared by chromatography on protein A-Agarose. Anti-N-Hcy-Lys
      protein IgG was adsorbed on Nomega-homocysteinyl-aminohexyl-Agarose column at pH
      8.6 and eluted with a pH 2.3 buffer. Enzyme-linked immunosorbent assays
      demonstrate that the antibody recognizes specifically N-homocysteinylated
      variants of hemoglobin, albumin, transferrin, and antitrypsin.

PMID- 15203039
TI  - Liquid chromatographic-mass spectrometric method to assess cytochrome P450
      mediated metabolism of testosterone by rat everted gut sacs.
AB  - A rapid, sensitive and specific method was developed for the simultaneous assay
      of testosterone, androstenedione and 6beta-hydroxytestosterone (6beta-OHT) in the
      TC199 tissue culture medium used in intestinal drug metabolism studies with the
      rat everted gut sac model. An electrospray LC-MS method was validated in the
      concentration range of 0.025-9.5 microM (7.2 ng-2.7 microg/mL) for testosterone
      and androstenedione and 0.01-4 microM (3 ng-1.2 microg/mL) for 6beta
      hydroxytestosterone. The limits of quantification (LOQ) with an injection volume
      of 10 microL were 0.0005 microM (4.9 fmol, 1.4 pg injected), 0.004 microM (0.04
      pmol, 11.4 pg injected) and 0.03 microM (0.3 pmol, 91 pg injected), respectively.
      The method also detected the other testosterone metabolites, the 16alpha-, 16beta
      , 2beta- and 2alpha-hydroxytestosterones and was then used to study the
      metabolism of testosterone during its absorption by rat intestine in vitro, using
      everted gut sacs.

PMID- 15203040
TI  - Determination of moclobemide in human plasma by high-performance liquid
      chromatography with spectrophotometric detection.
AB  - A simple and sensitive high-performance liquid chromatographic (HPLC) method with
      spectrophotometric detection was developed for the determination of moclobemide
      in human plasma. Plasma samples were extracted under basic conditions with
      dichloromethane followed by back-extraction into diluted phosphoric acid.
      Isocratic separation was employed on an ODS column (250 mm x 4.6 mm, 5 microm) at
      room temperature. The mobile phase consisted of 5 mM NaH2PO4-acetonitrile
      triethylamine (1000:350:10 (v/v/v), pH 3.4). Analyses were run at a flow-rate of
      1.0 ml/min and ultraviolet (UV) detection was carried out at 240 nm. The method
      was specific and sensitive with a quantification limit of 15.6 ng/ml and a
      detection limit of 5 ng/ml at a signal-to-noise ratio of 3:1. The mean absolute
      recovery was about 98.2%, while the intra- and inter-day coefficient of variation
      and percent error values of the assay method were all at acceptable levels.
      Linearity was assessed in the range of 15.6-2000 ng/ml in plasma with a
      correlation coefficient of greater than 0.999. This method has been used to
      analyze several hundred human plasma samples for bioavailibility studies.

PMID- 15203041
TI  - Interaction of L-glutamate oxidase with triazine dyes: selection of ligands for
      affinity chromatography.
AB  - Glutamate oxidase (GOX, EC 1.4.3.11) from Streptomyces catalyses the oxidation of
      L-glutamate to alpha-ketoglutarate. Its kinetic constants for L-glutamate were
      measured equal to 2 mM for Km and 85.8 s(-1) for kcat. BLAST search and amino
      acid sequence alignments revealed low homology to other L-amino acid oxidases (18
      38%). Threading methodology, homology modeling and CASTp analysis resulted in
      certain conclusions concerning the structure of catalytic alpha-subunit and led
      to the prediction of a binding pocket that provides favorable conditions of
      accommodating negatively charged aromatic ligands, such as sulphonated triazine
      dyes. Eleven commercial textile dyes and four biomimetic dyes or minodyes,
      bearing a ketocarboxylated-structure as their terminal biomimetic moiety,
      immobilized on cross-linked agarose gel. The resulted mini-library of affinity
      adsorbents was screened for binding and eluting L-glutamate oxidase activity. All
      but Cibacron Blue 3GA (CB3GA) affinity adsorbents were able to bind GOX at pH
      5.6. One immobilized minodye-ligand, bearing as its terminal biomimetic moiety p
      aminobenzyloxanylic acid (BM1), displayed the higher affinity for GOX. Kinetic
      inhibition studies showed that BM1 inhibits GOX in a non-competitive manner with
      a Ki of 10.5 microM, indicating that the dye-enzyme interaction does not involve
      the substrate-binding site. Adsorption equilibrium data, obtained from a batch
      system with BM1 adsorbent, corresponded well to the Freundlich isotherm with a
      rate constant k of 2.7 mg(1/2)ml(1/2)/g and Freundlich isotherm exponent n of 1.
      The interaction of GOX with the BM1 adsorbent was further studied with regards to
      adsorption and elution conditions. The results obtained were exploited in the
      development of a facile purification protocol for GOX, which led to 335-fold
      purification in a single step with high enzyme recovery (95%). The present
      purification procedure is the most efficient reported so far for L-glutamate
      oxidase.

PMID- 15203042
TI  - Liquid chromatographic-mass spectrometric determination of endogenous gamma
      hydroxybutyrate concentrations in rat brain regions and plasma.
AB  - A new liquid chromatographic-mass spectrometric (LC-MS) method for determining
      trace concentrations of gamma-hydroxybutyric acid (GHB) in biological samples has
      been developed. This method utilizes solid-phase extraction for separation,
      deuterated GHB as an internal standard (IS) and multiple reaction monitoring
      (MRM) in the negative ion mode to detect the parent and product ions (103 and 57
      for GHB, and 109 and 61 for D6-GHB, respectively). The assay produces excellent
      linearity and reproducibility, with a limit of quantification (LOQ) of about 0.1
      microg/ml. The method has been applied for the determination of endogenous GHB in
      various rat brain regions.

PMID- 15203043
TI  - Experimental design-based development of a rapid capillary electrophoresis method
      for determining impurities in the tetrapeptide H-Tyr-(D)Arg-Phe-Phe-NH2.
AB  - A capillary electrophoresis (CE) method has been developed and validated for
      separating the tetrapeptide H-Tyr-(D)Arg-Phe-Phe-NH2 and nine related substances.
      The method was developed using experimental design in a four-step procedure, in
      which eight variables were investigated in a total of 47 experiments. The
      preferred background electrolyte (BGE) consisted of 0.1M malonic acid at pH 2.5
      with 7 mM heptakis(2,6-di-O-methyl)-beta-cyclodextrin (2,6-DM-beta-CD). The
      separation of H-Tyr-(D)Arg-Phe-Phe-NH2 and the related substances was
      accomplished within 15 min, with a resolution greater than 1.5 between all peaks.
      The method was then investigated with respect to its selectivity, linearity,
      precision, detection limit (LOD) and quantitation limit (LOQ). In addition, a
      system suitability test was performed and response factors were determined,
      essentially following International Conference of Harmonization guidelines for
      the validation of analytical methods. LOD and LOQ for the related substance H-Arg
      Phe-NH2 were found to be 0.3 and 0.8 microg/ml, respectively, at a target H-Tyr
      (D)Arg-Phe-Phe-NH concentration of 1mg/ml. The method performed well with respect
      to all of the validation parameters.

PMID- 15203044
TI  - Determination of trimethoprim in low-volume human plasma by liquid
      chromatography.
AB  - Trimethoprim is an anti-infective agent used in the treatment of urinary and
      respiratory tract infections and mild to moderate pneumocystis carinii pneumonia.
      Trimethoprim is also a selective in vitro inhibitor of cytochrome P450 2C8 and
      may have utility as an in vivo inhibitor of this enzyme. A simplified high
      performance liquid chromatography (HPLC) method was developed to determine
      trimethoprim in human plasma. Samples are processed by protein precipitation with
      perchloric acid and chromatographic separation is achieved on a Synergi Polar-RP
      column (4 micron, 150 mm x 4.6 mm) using a mobile phase consisting of 50 mM
      ammonium formate-acetonitrile-methanol (pH=3.0; 90:6:4 (v/v/v)). Detection is
      monitored at 280 nm. Intra- and inter-day precision ranged from 1.1 to 1.9 and
      0.9 to 4.1%, respectively. The assay is simple, economical, precise, and is
      directly applicable to human studies involving steady state trimethoprim
      pharmacokinetics.

PMID- 15203045
TI  - Analysis of substance P in rat brain by means of immunoaffinity capture and
      matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry.
AB  - Interest in the analysis of low abundance neuropeptides particularly using matrix
      assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF
      MS) is increasing because these neuropeptides are essential to the mechanism of
      transportation and the metabolism. This article describes an immunoprecipitation
      procedure that is suitable for MALDI-MS analysis of substance P (SP), a
      neuropeptide, in rat brain tissues. Substance P was precipitated from brain
      tissue extracts by immunoprecipitation with antibodies directed against SP, and
      are analyzed by MALDI-TOF-MS. Mass spectrometric analysis showed a singly charged
      [M+H]+ ion peak that corresponded to the SP molecular mass and was observed with
      a detection error of 1.6%. The average mass errors between the observed and
      theoretical molecular mass were within the 0.11 Da range. Capillary zone
      electrophoresis analysis was subsequently performed, and the effects of the
      different separation parameters were examined. Beginning with milligram
      quantities of brain tissue, picomole quantities of SP could be detected using
      this method.

PMID- 15203046
TI  - Preparation and characterisation of surfaces properties of
      poly(hydroxyethylmethacrylate-co-methacrylolyamido-histidine) membranes:
      application for purification of human immunoglobulin G.
AB  - In this study, an affinity membrane containing L-histidine as an amino acid
      ligand was used in separation and purification of human immunoglobulin G (HIgG)
      from solution and human serum. The polarities and the surface free energies of
      the affinity membranes were determined by contact angle measurements. HIgG
      adsorption and purification onto the affinity membranes from aqueous solution and
      human serum were investigated in a batch and a continuous system. Effect of
      different system parameters such as ligand density, adsorbent dosage, pH,
      temperature, ionic strength and HIgG initial concentration on HIgG adsorption
      were investigated. The maximum adsorption capacity of p(HEMA-MAAH-4) membranes
      for HIgG was 13.06 mgml(-1). The reversible HIgG adsorption on the affinity
      membrane obeyed both the Langmuir and Freundlich isotherm models. The adsorption
      data was analysed using the first- and second-order kinetic model and the
      experimental data was well described by the first-order equations. In the
      continuous system, the purity of the eluted HIgG, as determined by HPLC, was 93%
      with recovery 58% for p(HEMA-MAAH-4) membrane. The affinity membranes are stable
      when subjected to sanitization with sodium hydroxide after repeated adsorption
      elution cycles.

PMID- 15203047
TI  - Novel methylcellulose-immobilized cation-exchange precolumn for on-line
      enrichment of cationic drugs in plasma.
AB  - We developed a novel methylcellulose-immobilized strong cation-exchange (MC-SCX)
      precolumn for direct analysis of drugs in plasma. MC-SCX consists of silica gel
      with a methylcellulose outer-surface and a 2-(4-sulfophenyl) ethyl phase inner
      surface. The MC-SCX precolumn was evaluated by direct analysis using pyridoxine,
      atenolol and sulpiride spiked in plasma, using a column-switching HPLC system.
      Each drug was retained and enriched on MC-SCX using an acidic mobile phase, which
      resulted in good linearity, sufficient reproducibility, intra- and inter day
      precision, and accuracy in analytical ion-pair LC with trifluoroacetic acid. The
      analytical methods for model drugs were applied to pharmacokinetics of atenolol
      and sulpiride in rats.

PMID- 15203048
TI  - Development and validation of a gas chromatography-mass spectrometry method for
      the simultaneous determination of buprenorphine, flunitrazepam and their
      metabolites in rat plasma: application to the pharmacokinetic study.
AB  - Buprenorphine (BUP), a synthetic opioid analgesic, is frequently abused alone,
      and in association with benzodiazepines. Fatalities involving buprenorphine alone
      seem very unusual while its association with benzodiazepines, such as
      flunitrazepam (FNZ), has been reported to result in severe respiratory depression
      and death. The quantitative relationship between these drugs remain, however,
      uncertain. Our objective was to develop an analytical method that could be used
      as a means to study and explore, in animals, the toxicity and pharmacological
      interaction mechanisms between buprenorphine, flunitrazepam and their active
      metabolites. A procedure based on gas chromatography-mass spectrometry (GC-MS) is
      described for the simultaneous analysis of buprenorphine, norbuprenorphine
      (NBUP), flunitrazepam, N-desmethylflunitrazepam (N-DMFNZ) and 7
      aminoflunitrazepam (7-AFNZ) in rat plasma. The method was set up and adapted for
      the analysis of small plasma samples taken from rats. Plasma samples were
      extracted by liquid-liquid extraction using Toxi-tubes A. Extracted compounds
      were derivatized with N,O-bis-(trimethylsilyl)trifluoroacetamide (BSTFA), using
      trimethylchlorosilane (TMCS) as a catalyst. They were then separated by GC on a
      crosslinked 5% phenyl-methylpolysiloxane analytical column and determined by a
      quadrupole mass spectrometer detector operated under selected ion monitoring
      mode. Excellent linearity was found between 0.125 and 25 ng/microl plasma for
      BUP, 0.125 and 12.5 ng/microl for NBUP and N-DMFNZ, 0.125 and 5 ng/microl for
      FNZ, and between 0.025 and 50 ng/microl for 7-AFNZ. The limit of quantification
      was 0.025 ng/microl plasma for 7-AFNZ and 0.125 ng/microl for the four other
      compounds. A good reproducibility (intra-assay CV=0.32-11.69%; inter-assay
      CV=0.63-9.55%) and accuracy (intra-assay error=2.58-12.73%; inter-assay
      error=0.83-11.07%) were attained. Recoveries were 71, 67 and 81%, for BUP, FNZ
      and N-DMFNZ, respectively, and 51% for NBUP and 7-AFNZ, with CV ranging from 5.4
      to 13.9%, and were concentration-independent. The GC-MS method was successfully
      applied to the pharmacokinetic study of BUP, NBUP, FNZ, DMFNZ and 7-AFNZ in rats,
      after administration of BUP and FNZ.

PMID- 15203049
TI  - Rapid determination of chloramphenicol and its glucuronide in food products by
      liquid chromatography-electrospray negative ionization tandem mass spectrometry.
AB  - Chloramphenicol (CAP) is subjected to monitoring in food products, with a minimum
      required performance level set at 0.3 ng/g. CAP was isolated from chicken meat
      and seafood by very simple solvent extraction procedure. For honey, a fast SPE
      procedure was applied. CAP-D5 was used as internal standard. HPLC separation was
      done on RP18 123 mm x 3 mm column in acetonitrile-ammonium formate 10 mM, pH 3.0
      (40:60) at flow rate of 0.3 ml/min. A TSQ Quantum instrument with ESI source has
      been used in negative ionization mode. A MRM procedure has been applied and
      following transitions were monitored: m/z 321 > 152 (quantifier), 321 > 194, 321
      > 257(qualifiers), 326 > 157 (IS). CAP peak was eluted at around 5 min; the total
      run time was 7 min. LOD was around 0.1 ng/g meat or 0.05 ng/g honey. Matrix
      effects were studied for all materials used, involving injection of blank
      extracts with post-column infusion of CAP, as well as checking the influence of
      the co-injected blank extracts on the signal intensity of CAP. No influence of
      matrix on the results of CAP determination were observed. The method allows
      analyzing up to 30 duplicate samples per day, including all calibration
      standards. Additionally, the method for determination of CAP glucuronide (CAP-G)
      was established, using urine from rats that were given this drug as a source of
      the metabolite. Full validation of the metabolite was not possible, due to the
      unavailability of reference standard.

PMID- 15203050
TI  - EEG dynamics in patients with Alzheimer's disease.
AB  - Alzheimer's disease (AD) is the most common neurodegenerative disorder
      characterized by cognitive and intellectual deficits and behavior disturbance.
      The electroencephalogram (EEG) has been used as a tool for diagnosing AD for
      several decades. The hallmark of EEG abnormalities in AD patients is a shift of
      the power spectrum to lower frequencies and a decrease in coherence of fast
      rhythms. These abnormalities are thought to be associated with functional
      disconnections among cortical areas resulting from death of cortical neurons,
      axonal pathology, cholinergic deficits, etc. This article reviews main findings
      of EEG abnormalities in AD patients obtained from conventional spectral analysis
      and nonlinear dynamical methods. In particular, nonlinear alterations in the EEG
      of AD patients, i.e. a decreased complexity of EEG patterns and reduced
      information transmission among cortical areas, and their clinical implications
      are discussed. For future studies, improvement of the accuracy of differential
      diagnosis and early detection of AD based on multimodal approaches, longitudinal
      studies on nonlinear dynamics of the EEG, drug effects on the EEG dynamics, and
      linear and nonlinear functional connectivity among cortical regions in AD are
      proposed to be investigated. EEG abnormalities of AD patients are characterized
      by slowed mean frequency, less complex activity, and reduced coherences among
      cortical regions. These abnormalities suggest that the EEG has utility as a
      valuable tool for differential and early diagnosis of AD.

PMID- 15203051
TI  - Evaluation of sudomotor function.

PMID- 15203052
TI  - The after effects of motor cortex rTMS depend on the state of contraction when
      rTMS is applied.
AB  - OBJECTIVE: To test whether the after effects of 5 Hz focal rTMS over the primary
      motor cortex are modulated by the state of muscle contraction when the rTMS is
      applied. METHODS: Ten healthy volunteers gave informed consent to the studies.
      Fifty stimuli at active motor threshold intensity were applied at 5 Hz to the
      forearm motor area during 10% MVC isometric wrist flexion, 10% MVC wrist
      extension and at rest. Short interval intracortical inhibition (SICI:
      interstimulus intervals of 2-5 ms) and intracortical facilitation (interstimulus
      intervals of 7 and 10 ms) were recorded at rest before and after rTMS from flexor
      carpi radialis (FCR) and extensor carpi radialis (ECR) muscles with surface
      electrodes. RESULTS: rTMS during wrist flexion decreased SICI in the FCR whereas
      SICI was increased if rTMS was given during wrist extension. The opposite was
      true in ECR: SICI was increased if rTMS was applied during wrist flexion, whereas
      it was reduced if rTMS was given during wrist extension. rTMS applied at rest
      produced a small overall decrease of SICI in FCR and ECR but this was not
      individually significant in the FCR. The 10 s wrist flexion without any rTMS did
      not have any effect on SICI. CONCLUSIONS: The after effects of motor cortex rTMS
      can be selectively modulated by the pattern of muscle contraction.

PMID- 15203053
TI  - Long-lasting increase in corticospinal excitability after 1800 pulses of
      subthreshold 5 Hz repetitive TMS to the primary motor cortex.
AB  - OBJECTIVE: To study the after effects of high-frequency repetitive transcranial
      magnetic stimulation (rTMS) over the primary motor cortex (M1) on corticospinal
      excitability. METHODS: Eight healthy volunteers received either 150 or 1800
      stimuli of 5 Hz rTMS on two separate days in a counterbalanced order. rTMS was
      given over the 'motor hot spot' of the right first dorsal interosseus (FDI)
      muscle using an intensity of 90% of resting motor threshold (referred to as
      subthreshold rTMS). We evaluated the amplitude of the motor-evoked potential
      (MEP), short-latency intracortical inhibition (SICI), short-latency intracortical
      facilitation (SICF), and cortical silent period (CSP) before and for about 30 min
      after rTMS. MEPs were recorded from the right FDI muscle and abductor digiti
      minimi (ADM) muscle. RESULTS: 1800 stimuli induced an increase in MEP amplitude
      in the relaxed FDI muscle, but not in the relaxed ADM muscle. This facilitatory
      after effect was stable for at least 30 min. Prolonged 5 Hz rTMS had no effect on
      the relative magnitude of SICI and SICF. 150 stimuli caused no lasting modulation
      of MEP amplitudes in either muscle. In a subgroup of 5 subjects, 900 conditioning
      stimuli caused only a short-lived MEP facilitation. 5 Hz rTMS did not modify the
      duration of the CSP during tonic contraction. CONCLUSIONS: A single session of
      subthreshold 5 Hz rTMS to the M1 can induce a long-lasting and muscle-specific
      increase in resting corticospinal excitability. However, a sufficient number of
      conditioning stimuli is necessary to produce persistent corticospinal
      facilitation.

PMID- 15203054
TI  - Abnormalities of prepulse inhibition do not depend on blink reflex excitability:
      a study in Parkinson's disease and Huntington's disease.
AB  - OBJECTIVE: Prepulse inhibition of the blink reflex is a robust phenomenon with an
      interesting physiology and a large potential for clinical applicability. In the
      study presented here we investigated whether the blink reflex inhibition by a
      prepulse (BRIP) is influenced by the blink reflex excitability recovery (BRER).
      METHODS: The study was undertaken in 20 patients with Parkinson's disease (PD),
      20 patients with Huntington's disease (HD) and 20 healthy volunteers. BRER was
      determined by measuring the size of the response to a test supraorbital nerve
      stimulus as a percentage of the response to a conditioning stimulus at inter
      stimuli intervals of 100-1000 ms. BRIP was determined as the percentage reduction
      induced in the response to a supraorbital nerve stimulus by either a low
      intensity auditory click or a weak third finger somatosensory stimulus, applied
      with a leading interval of 50-110 ms. RESULTS: There was a negative correlation
      between the percentage BRER and the percentage BRIP (Pearson's correlation
      coefficient of -0.37). BRER was enhanced in 14 PD patients (70%) and 6 HD
      patients (30%), while it was depressed in 10 HD patients (50%). BRIP was
      significantly reduced in 15 PD patients (75%) and 16 HD patients (80%). No
      significant correlation was found between abnormally enhanced BRER and abnormally
      reduced BRIP in all patients as a group (chi(2)=2.4;P=0.11). A weak correlation
      was found in PD patients (P=0.019) and no correlation was observed in HD patients
      (P=0.8). CONCLUSIONS: Our results indicate that an abnormally reduced BRIP was
      not always accompanied by an abnormally enhanced BRER in patients with HD. The
      two tests likely assess specific and distinct brainstem functions, and provide
      different types of information. While BRIP may be the result of a widespread
      integrative processing of sensory stimuli, BRER likely reflects the excitability
      of a chain of brainstem inter-neurons. SIGNIFICANCE: BRER and BRIP provide
      independent information on the state of functionally separate circuits that
      converge on trigemino-facial brainstem inter-neurons.

PMID- 15203055
TI  - Dipole source localization of event-related brain activity indicative of an early
      visual selective attention deficit in ADHD children.
AB  - OBJECTIVE: This study was aimed at investigating whether attention-deficit
      hyperactivity disorder (ADHD) children suffer from specific early selective
      attention deficits in the visual modality with the aid of event-related brain
      potentials (ERPs). Furthermore, brain source localization was applied to identify
      brain areas underlying possible deficits in selective visual processing in ADHD
      children. METHODS: A two-channel visual color selection task was administered to
      18 ADHD and 18 control subjects in the age range of 7-13 years and ERP activity
      was derived from 30 electrodes. RESULTS: ADHD children exhibited lower perceptual
      sensitivity scores resulting in poorer target selection. The ERP data suggested
      an early selective-attention deficit as manifested in smaller frontal positive
      activity (frontal selection positivity; FSP) in ADHD children around 200 ms
      whereas later occipital and fronto-central negative activity (OSN and N2b; 200
      400 ms latency) appeared to be unaffected. Source localization explained the FSP
      by posterior-medial equivalent dipoles in control subjects, which may reflect the
      contribution of numerous surrounding areas. CONCLUSIONS: ADHD children have
      problems with selective visual processing that might be caused by a specific
      early filtering deficit (absent FSP) occurring around 200 ms. The neural sources
      underlying these problems have to be further identified. Source localization also
      suggested abnormalities in the 200-400 ms time range, pertaining to the
      distribution of attention-modulated activity in lateral frontal areas.

PMID- 15203057
TI  - Magnetoencephalographic study of occipitotemporal activity elicited by viewing
      mouth movements.
AB  - OBJECTIVE: We studied the temporal and spatial characteristics of neural
      responses elicited by viewing mouth movements using magnetoencephalography.
      METHODS: We focused on differences in responses to mouth opening and closing
      movements by apparent motion, using an averting eyes condition as a control.
      RESULTS: A large clear MEG component, 1 M (mean peak latency of approximately 160
      ms), was elicited by both mouth movements. We modeled the neural sources using a
      brain electric source analysis (BESA) method and placed the sources around: (1)
      the occipitotemporal border at human MT/V5, (2) the primary visual cortex (V1),
      and (3) fusiform gyrus. The calculated activity of Source (1) was large whereas
      the activity of the others was small or negligible. Source (1), as calculated
      separately for mouth closing and opening movements and eye movement, showed no
      significant different amplitude and locations. We did not find any activity in
      the superior temporal sulcus (STS). CONCLUSIONS: Our results indicate that human
      MT/V5 is active in the perception of both mouth and eye motions. Viewing mouth
      and eye movements elicits no significant differences in MT/V5 activity,
      indicating that the perception of movement of facial parts is probably processed
      in the same manner. SIGNIFICANCE: Characteristic activities in the human MT/V5
      elicited by viewing mouth movement were clarified by MEG.

PMID- 15203056
TI  - The NoGo P300 'anteriorization' effect and response inhibition.
AB  - OBJECTIVE: The P300 event-related potential shows anterior P300 increases on NoGo
      tasks (target stimulus=withhold response) relative to Go tasks (target
      stimulus=commit response). This 'NoGo anteriorization' has been hypothesized to
      reflect response inhibition. However, silent-count tasks show similar P300
      anteriorization. The P300 anteriorization on silent-count tasks relative to Go
      tasks cannot reflect inhibition-related processes, and questions the degree to
      which anteriorization observed on NoGo trials can be ascribed to response
      inhibition. Comparison of anteriorization between the silent-count and NoGo tasks
      is thus essential. P300 topography on NoGo and silent-count tasks has not been
      previously compared. METHODS: P300 on Go, NoGo, and silent-count auditory oddball
      tasks were compared. If the NoGo P300 anteriorization reflects response
      inhibitory processes, the NoGo P300 should be larger anteriorly than the Go P300
      (overt responses) and the silent-count P300s (covert responses). If
      anteriorization primarily reflects negative voltage Go task motor activity that
      reduces the normal frontal P300 amplitude, then the Go task P300 should be
      smaller than both the NoGo and silent-count P300s, which should not differ from
      one another. RESULTS: The Go task elicited a bilaterally reduced frontal P300 and
      asymmetrical frontal P300 relative to both the NoGo and silent-count tasks. The
      NoGo task P300 and silent-count task P300 showed similar amplitude and
      topography. P300 and slow wave on the NoGo task were not asymmetrical.
      CONCLUSIONS: The increased frontal P300 in NoGo tasks cannot be attributed solely
      to a positive-going inhibitory process, but likely reflects negative voltage
      response execution processes on Go trials. However, the alternative explanation
      that memory-related processes increase the silent-count P300 anteriorly to the
      same degree as NoGo inhibitory processes cannot be ruled out.

PMID- 15203058
TI  - Asymmetry in alpha power predicts accuracy of hemispheric lexical decision.
AB  - OBJECTIVE: Previous work has shown that individual differences in resting alpha
      asymmetry are associated with efficacy on a variety of cognitive tasks. Still
      unresolved is how ongoing alpha asymmetry relates to behavioral asymmetry,
      explored here using lateralized lexical decision. METHODS: Alpha power
      immediately preceding lexical decision trials was measured to assess cognitive
      engagement during word recognition. This was compared with behavioral performance
      for the task, measured by accuracy and latency of the lexical decision response.
      RESULTS: Greater relative left hemisphere alpha power (i.e. higher asymmetry)
      immediately before presentation of a word led to reduced likelihood for its
      successful identification. Greater alpha asymmetry was also associated with
      reduced performance for identifying stimuli lateralized to the right visual
      field. CONCLUSIONS: Word recognition is facilitated by decreased asymmetry in
      cognitive engagement in the two cerebral hemispheres, particularly when the
      stimuli are lateralized to the left hemisphere (right visual field).
      SIGNIFICANCE: Results address the role of cognitive engagement in the two
      cerebral hemispheres, and its relationship with lexical access.

PMID- 15203060
TI  - Rapid change of tonotopic maps in the human auditory cortex during pitch
      discrimination.
AB  - OBJECTIVE: To study early cognitive processes and hemispheric differences in the
      primary auditory cortex during selective attention. METHODS: We measured auditory
      evoked magnetic fields (AEFs) to 400 and 4000 Hz tone pips that were randomly
      presented at the right or left ear. Subjects paid attention to target stimuli
      during pitch (high or low) or laterality (left or right) discrimination tasks. In
      the control session, 400 or 4000 Hz tone alone was presented at the left or right
      ear. We calculated the location and strength of N100m dipole for 400 and 4000 Hz
      tones, based on the AEFs obtained from the hemisphere contralateral to the
      stimulated ear. RESULTS: N100m amplitude increased in both hemispheres in pitch
      or laterality discriminating conditions. N100m latency also shortened during
      selective attention. The N100m dipole distance between 400 and 4000 Hz tones was
      enlarged, especially in the right auditory cortex during pitch discrimination
      task, but was unchanged during the laterality discrimination task. CONCLUSIONS:
      We conclude that these dynamic changes in the N100m dipole reflect short-term
      plastic changes in the primary auditory cortex, supporting early selection
      models. SIGNIFICANCE: This work is the first to disclose short-term plastic
      changes during pitch discrimination in the human auditory cortex based on the
      analysis of magnetoencephalography.

PMID- 15203059
TI  - ERP evidence of impaired central nervous system function in virally suppressed
      HIV patients on antiretroviral therapy.
AB  - OBJECTIVE: To examine the effects of human immunodeficiency virus (HIV) on
      central nervous system (CNS) function in patients receiving antiretroviral
      therapy (ART) who have suppressed viral loads. METHODS: Event-related brain
      potentials (ERPs) were recorded from 15 virally suppressed HIV patients and 15
      age-, sex-, and education-matched controls while they performed a 3-stimulus
      auditory oddball task. The amplitude and latency of the P3a, P3b, and early
      auditory components were examined in HIV patients and controls. RESULTS: Virally
      suppressed HIV patients on ART were more depressed than controls, as determined
      by the Beck Depression Inventory (BDI). After controlling for the effects of
      depression, HIV patients had smaller P2, P3a, and P3b amplitudes and longer P3a
      and P3b latency than control subjects. BDI scores correlated positively with N1
      latency in HIV patients and negatively with P3b amplitude in all subjects.
      CONCLUSIONS: These electrophysiological results suggest that, even in the absence
      of detectable levels of HIV in the peripheral blood, viral replication persists
      in the CNS and continues to cause disease in HIV patients on ART.

PMID- 15203061
TI  - Brain-stem auditory impairment during the neonatal period in term infants after
      asphyxia: dynamic changes in brain-stem auditory evoked response to clicks of
      different rates.
AB  - OBJECTIVE: To explore dynamic changes in brain-stem auditory electrophysiology
      during the neonatal period in term infants after perinatal asphyxia. METHODS:
      Sixty-eight term newborn infants who suffered asphyxia were studied on days 1, 3,
      5, 7, 14 and 30 after birth. Brain-stem auditory evoked response (BAER) was
      recorded with clicks, delivered at 21, 51 and 91 s(-1) and > or =40 dB above BAER
      threshold of each subject. RESULTS: During the neonatal period wave I latency in
      the infants after asphyxia increased slightly while later BAER components changed
      more significantly. On the first day after birth wave III and V latencies and I-V
      and III-V intervals increased significantly at all rates of clicks (ANOVA P<0.01
      0.001). On day 3, the latencies and intervals increased further. III-V/I-III
      interval ratio increased at 51 and 91 s(-1), suggesting a relatively more
      significant increase in III-V interval than in I-III interval at higher rates.
      Thereafter, wave III and V latencies and all intervals decreased progressively,
      although these BAER variables were still significantly longer than in normal
      controls on days 5 and 7 (P<0.05-0.001) On day 30, all latencies and intervals
      approached near normal values, with a slight increase in wave V latency and I-V
      and III-V intervals at 51 and 91 s(-1). CONCLUSIONS: Perinatal asphyxia has a
      major effect on central auditory function, resulting in acute impairment. The
      impairment progresses during the first 3 days and then tends towards recovery. By
      1 month the impaired auditory function has largely returned to normal.
      Significant increase in click rates can moderately improve the detection of
      auditory impairment. SIGNIFICANCE: After perinatal asphyxia early detection of
      hypoxic-ischaemic damage to the central auditory system and initialisation of
      neuroprotective and therapeutic measures during the first hours after birth are
      critical to prevent or reduce deterioration of central impairment.

PMID- 15203062
TI  - Short-latency components of evoked potentials to median nerve stimulation
      recorded by intracerebral electrodes in the human pre- and postcentral areas.
AB  - OBJECTIVE: To study whether sensory afferents of the hand projected directly to
      the primary motor cortex (M1) as they have been well electrophysiologically
      described in monkeys but not in humans. METHODS: We recorded intracerebrally in
      the central areas (pre- and/or postcentral gyrus) somatosensory evoked potentials
      (SEPs) to median nerve stimulation in 5 (4 women, 1 man; age 14-37 years)
      epileptic patients during presurgical evaluation. RESULTS: The primary
      somatosensory cortex (S1) showed negative-positive components peaking at about 20
      and 30 ms, respectively. By contrast, M1 disclosed SEPs of two types of waveforms
      depending on the portion of the precentral gyrus explored by the different
      contacts of the electrode. Here, we demonstrated, for the first time, in the
      medial portion of M1, shaped like an omega in the axial plane, corresponding to
      the motor hand area, the occurrence of a primary negative component as in S1, but
      of higher amplitude and peaking at about 4 ms later. In other respects, the
      lateral portion of M1 disclosed positive-negative components peaking at about 21
      and 31 ms, respectively. CONCLUSIONS: These electrophysiological findings, based
      on accurate spatial and temporal resolution of intracerebral recordings,
      suggested that somatosensory inputs from the hand projected directly to M1 in its
      medial portion.

PMID- 15203063
TI  - Disinhibition of the somatosensory cortex in cervical dystonia-decreased
      amplitudes of high-frequency oscillations.
AB  - OBJECTIVE: To determine whether patients with cervical dystonia have
      electrophysiological signs of disinhibition in the somatosensory cortex by
      recording high-frequency oscillations (HFOs) in somatosensory evoked potentials
      (SEPs). METHODS: HFOs were recorded in 13 patients and 10 age-matched control
      subjects, and the data were analyzed statistically by paired comparison and by
      Pearson's correlation. RESULTS: In patients with cervical dystonia, the early
      part of HFOs showed a significant decrease in amplitude, and the amplitude ratios
      of both early and late parts of HFOs/N20 potential were also significantly
      decreased. The amplitudes of HFOs and N20 potential were linearly correlated in
      the control subjects but not in dystonia patients. CONCLUSIONS: Patients with
      cervical dystonia may suffer from a disturbance of inhibition in the sensory
      cortex. This disturbance is reflected by decreased HFO amplitude, representing
      decreased activities of inhibitory interneurons in area 3b.

PMID- 15203064
TI  - A new non-invasive method for recording the electro-olfactogram using external
      electrodes.
AB  - OBJECTIVE: The aim of this investigation was to explore the possibility of
      recording the electro-olfactogram (EOG) using external electrodes placed on the
      root of the nose on either side of the bridge and at the medial termination of
      the eyebrows. The EOG is considered to be the summated generator potential of
      olfactory receptor cells and therefore represents peripheral olfactory events.
      Recording of human EOG is technically difficult due to poor access to the
      olfactory mucosa and the nasal irritation is tolerated by few subjects. METHODS:
      The evoked potentials at these sites in response to two odourants, n-amyl acetate
      and benzaldehyde, were recorded simultaneously with the EOG, recorded
      conventionally with an intranasal electrode, and the olfactory event-related
      potential (OERP) recorded using scalp electrodes. RESULTS: The extranasal
      potential recorded at the root of the nose, 0.5-1 cm below the nasion, 1 cm from
      the ridge and ipsilateral with the stimulus, had the highest degree of
      correlation with the intranasal EOG. We refer to this site as N1 (left side) and
      N2 (right side). Further analysis demonstrated that the latency, the time
      constant of the rising phase and the amplitude of the evoked potential recorded
      at N1 also had a higher correlation coefficient with the EOG than did those
      potentials recorded at other sites. Statistical analysis indicated that the
      latency and time constant of the response recorded externally at N1 were the same
      as those of the EOG recorded intranasally. CONCLUSIONS: We conclude that an
      olfactory evoked potential, with many of the characteristics of the EOG recorded
      from the olfactory mucosa, can be recorded externally at a site close to the
      bridge of the nose. SIGNIFICANCE: This non-invasive method of recording the EOG
      will have benefits for the objective assessment of olfactory function.

PMID- 15203065
TI  - Attention to a painful cutaneous laser stimulus modulates electrocorticographic
      event-related desynchronization in humans.
AB  - OBJECTIVE: To test the hypothesis that attention to painful cutaneous laser
      stimuli enhances event-related desynchronization (ERD) in cortical regions
      receiving nociceptive input. METHODS: We used wavelet time-frequency analysis and
      bandpass filtering to measure ERD quantitatively in subdural
      electrocorticographic recordings while subjects either attended to, or were
      distracted from, a painful cutaneous laser stimulus. RESULTS: ERD were observed
      over primary somatosensory and parasylvian (PS) cortices in all 4 subjects, and
      over medial frontal cortex in 1 subject. Laser-evoked potentials were also
      observed in all 3 regions. In all subjects, ERD was more widespread and intense,
      particularly over PS, during attention to laser stimuli (counting stimuli) than
      during distraction from the stimuli (reading for comprehension). CONCLUSIONS:
      These findings suggest that pain-associated ERD is modulated by attention,
      particularly over PS. SIGNIFICANCE: This study suggests that thalamocortical
      circuits are involved in attentional modulation of pain because of the proposed
      role of these circuits in the mechanisms of ERD.

PMID- 15203066
TI  - Brain-stem auditory and visual evoked potentials in children with Krabbe disease.
AB  - OBJECTIVE: There are few reports in the literature detailing brain-stem auditory
      and visual evoked potentials (BAEP and VEP) in children with Krabbe disease (KD).
      The purpose of this study was to provide a descriptive analysis of the BAEP and
      VEP findings in these children. METHODS: Charts of children with KD were
      reviewed. BAEP and VEP studies performed on these children were reviewed;
      findings in the early infantile and late onset KD (EIKD, LOKD, respectively)
      groups were also examined. Likelihood ratios (LR) for the neurophysiologic tests
      being abnormal in the various groups were also determined. RESULTS: BAEP
      abnormalities were seen in 15/17 (88%) children with EIKD and 2/5 (40%) children
      with LOKD, LR statistically significant. In the EIKD group, all 13 symptomatic
      children had an abnormal BAEP, whereas 2/4 (50%) of the pre-symptomatic children
      had similar findings, LR statistically significant. VEP abnormalities were noted
      in 8/15 (53%) children with EIKD and none of the children with LOKD, LR
      statistically significant. In the EIKD group, the 8/12 (67%) symptomatic children
      had an abnormal VEP, whereas none of the pre-symptomatic children did, LR
      statistically significant. Subgroup analyses of the LOKD subgroups did not yield
      significant findings. CONCLUSIONS: BAEP abnormalities are among the first
      objective indications of central nervous system disease in children with EIKD.
      VEP abnormalities occur later in the course of the illness. Both tests are less
      helpful in children with LOKD. SIGNIFICANCE: BAEP and VEP testing is helpful in
      objective evaluation of children with KD.

PMID- 15203067
TI  - Evaluation of L1 and L2 minimum norm performances on EEG localizations.
AB  - OBJECTIVE: In this work we study the performance of minimum norm methods to
      estimate the localization of brain electrical activity. These methods are based
      on the simplest forms of L(1) and L(2) norm estimates and are applied to
      simulated EEG data. The influence of several factors like the number of
      electrodes, grid density, head model, the number and depth of the sources and
      noise levels was taken into account. The main objective of the study is to give
      information about the dependence, on these factors, of the localization sources,
      to allow for proper interpretation of the data obtained in real EEG records.
      METHODS: For the tests we used simulated dipoles and compared the localizations
      predicted by the L(1) and L(2) norms with the location of these point-like
      sources. We varied each parameter separately and evaluated the results. RESULTS:
      From this work we conclude that, the grid should be constructed with
      approximately 650 points, so that the information about the orientation of the
      sources is preserved, especially for L(2) norm estimates; in favorable noise
      conditions, both L(1) and L(2) norm approaches are able to distinguish between
      more than one point-like sources. CONCLUSIONS: The critical dependence of the
      results on the noise level and source depth indicates that regularized and
      weighted solutions should be used. Finally, all these results are valid both for
      spherical and for realistic head models.

PMID- 15203068
TI  - Factor structure of the human gamma band oscillatory response to visual
      (contrast) stimulation.
AB  - OBJECTIVE: Visual contrast stimulation evokes in man an oscillatory mass response
      at approximately 20.0-35.0 Hz, consistent with stimulus-dependent synchronous
      oscillations in multiunit animal recordings from visual cortex, but shorter in
      duration and phase-locked to stimulus. A factor analysis was applied to
      characterize the signal structure under stimulus conditions inducing an
      oscillatory response and to identify possible subcomponents in normal volunteers.
      METHODS: Contrast stimuli were gratings with a sinusoidal luminance profile (9.0
      degrees; 5.0 cycle/degree; 80% contrast; reversal 1.06 Hz). The amplitude
      spectrum of the signal was computed by Discrete Fourier Transform (DFT) and the
      oscillatory response was separated from the corresponding visually evoked
      potential (VEP) by DFT high-pass filter at 19.0 Hz. Nine consecutive waves were
      identified in all subjects (60 volunteers), with amplitudes/latencies consistent
      with normative studies. A factor analysis was computed 1- in the frequency
      domain, on the amplitude values of the signal components (2 Hz resolution), and 2
      in the time domain, on the latencies/amplitudes of the averaged VEP and
      oscillatory responses. RESULTS: (1) Two non-overlapping factors accounted for the
      approximately 2-20.0 and approximately 20.0-40.0 Hz signal components, with
      separation of the approximately 20.0-35.0 Hz oscillatory response from low
      frequency VEPs. (2) Two factors on latencies and one factor on amplitudes
      (independent of each other and from those of VEPs) accounted for the average
      approximately 20.0-35.0 Hz oscillatory response. CONCLUSIONS: The factor
      structure further indicates an oscillatory structure and some independence from
      conventional VEPs of the human oscillatory response to contrast, with a
      separation between the oscillatory response early and late waves possibly
      reflecting functional differences.

PMID- 15203070
TI  - Usefulness of an increase in size of motor unit potential sample.
AB  - OBJECTIVE: It is known that the sensitivity of quantitative electromyographic
      (EMG) analysis of motor unit potentials (MUPs) improves with an increase in MUP
      sample size to more than 20. However, no normative data and estimate of
      sensitivity have been published. METHODS: In the present study sample sizes of 5,
      10, 15, 20, 30 and 40 MUPs were obtained from the external anal sphincter (EAS)
      muscles of 81 controls and 70 patients with cauda equina lesions. For each sample
      size normative limits and sensitivities for mean values and 'outliers' were
      calculated for 8 MUP parameters. RESULTS: As the size of the MUP samples
      increased, normative limits narrowed and sensitivities increased for both
      statistics of all MUP parameters (sensitivities were 26% at 10, 44% at 20, and
      67% at 40 MUPs with mean values and outliers of MUP area, duration and number of
      turns). CONCLUSIONS: Our results confirmed a substantial increase in the
      sensitivity of MUP analysis by enlargement of the MUP sample size to more than 20
      MUPs. The gain in sensitivity seem to be greater than the increase obtained by
      examination of contralateral EAS muscle. SIGNIFICANCE: Findings might be useful
      to clinical neurophysiologists planning strategies for electrodiagnostic
      evaluation of lower sacral segments.

PMID- 15203069
TI  - Sensory nerve conduction of the plantar nerve compared with other nerve
      conduction tests in rats.
AB  - OBJECTIVE: In rats the available techniques for evaluation of sensory nerve
      conduction are limited. We report a new method of sensory nerve conduction of the
      plantar nerve using needle electrodes as the recording electrodes behind the
      medial malleolus and ring electrodes as the stimulating electrodes around the
      three middle toes. METHODS: We performed this sensory nerve conduction test in 25
      rats during their growth over a 6 weeks' period and compared this method with the
      motor nerve conduction and H-reflex sensory nerve conduction of the tibial nerve
      in 10 rats, and with the motor and mixed nerve conductions of the tail nerve in
      15 rats. RESULTS: There was a highly or moderately significant correlation
      between the body weight and sensory nerve conduction velocity (NCV) of the
      plantar nerve, mixed NCV and motor NCV of the tail nerve, indicating a growth
      related increase in the NCV. The growth-related increase in the NCV was not
      observed in the motor and H-reflex sensory nerve conductions of the tibial
      nerves. CONCLUSIONS: This test is simple and reliable and can be used for the
      sensory nerve conduction test in rats.

PMID- 15203071
TI  - Subclinical cranial nerve involvement in hereditary motor and sensory neuropathy:
      a combined conduction study with electrical and magnetic stimulation.
AB  - OBJECTIVE: To evaluate the electrophysiological findings of clinically unaffected
      cranial nerves (facial, accessory and hypoglossal nerves) in hereditary motor and
      sensory neuropathy (HMSN). METHODS: The conduction times of the facial,
      accessory, and hypoglossal nerves in 10 patients with HMSN type I (HMSN I), 2
      patients with HMSN Type II (HMSN II), and 20 normal controls were determined. The
      extra- and intracranial segments of the cranial nerves were stimulated
      electrically and magnetically, respectively. The relationships between the
      conduction parameters of the cranial nerves and limb nerves were analyzed.
      RESULTS: In patients with HMSN I, the conduction times of the distal and proximal
      segments were significantly prolonged in all 3 cranial nerves. A positive
      correlation was found between the conduction parameters of the cranial nerves and
      the limb nerves. CONCLUSIONS: Electrophysiological involvement of the whole
      segment of the facial, accessory and hypoglossal nerves is common in patients
      with HMSN I without clinical signs of alterations. The degree of conduction
      slowing of the facial, accessory, and hypoglossal nerves paralleled that of limb
      nerves.

PMID- 15203072
TI  - Electric field properties of two commercial figure-8 coils in TMS: calculation of
      focality and efficiency.
AB  - OBJECTIVE: To compare two commonly used TMS coils, namely the Medtronic MC-B70
      double coil and the Magstim 70 mm double coil, with respect to their electric
      field distributions induced on the cortex. METHODS: Electric field properties are
      calculated on a hemisphere representing the cortex using a spherical head model.
      The coil designs are characterised using several parameters, such as focality,
      efficiency and stimulation depth. RESULTS: Medtronic and Magstim coils exhibit
      similar focality values and stimulation depths, despite very different coil
      designs. However, the Medtronic coil is about 1.2 times more efficient compared
      to the Magstim coil. This difference corresponds to different motor and visual
      phosphene thresholds obtained in previous physiological studies, thereby
      validating the chosen coil modelling approach. Focality of the Medtronic coil
      changed less with varying coil-cortex distance compared to the Magstim coil,
      whereas both coils exhibited similar dependencies on changes in cortex radius.
      CONCLUSIONS: The similar values for focality and stimulation depth indicate that
      both coil types should evoke similar physiological effects when adjusting for the
      different efficiencies. The different physiological thresholds of the two coils
      can be traced back to differences in coil design. Ideally, focality should depend
      neither on coil-cortex distance nor on cortex radius in order to allow for an
      inter-subject comparability. In particular, in motor mapping experiments the size
      of the resulting maps is affected by these two parameters. Consequently, they are
      at least partially the cause of the variability across subjects seen in these
      experiments.

PMID- 15203073
TI  - Seizure induced by fast repetitive transcranial magnetic stimulation.

PMID- 15203074
TI  - Triple stimulation technique (TST) in amyotrophic lateral sclerosis.

PMID- 15203075
TI  - Differences in epidemiology, liver disease and treatment response among HCV
      genotypes.

PMID- 15203076
TI  - Safety and efficacy of hepatitis B surface antigen-pulsed dendritic cells in
      human volunteers.
AB  - Hepatitis B surface antigen (HBsAg)-pulsed murine spleen dendritic cells (DCs)
      have shown tremendous therapeutic potentials in chronic hepatitis B virus (HBV)
      carriers however, there has been no study regarding the feasibility of using
      HBsAg-pulsed DCs in human. Five human healthy volunteers with no apparent
      concomitant diseases were enrolled in this study. DCs were enriched from
      peripheral blood of each volunteer in endotoxin-free and sterilized conditions.
      HBsAg-pulsed DCs were prepared by culturing DCs with a commercial-available human
      grade vaccine containing HBsAg. After assessing the expression of HLA DR and CD86
      on HBsAg-pulsed DCs, 5 million HBsAg-pulsed DCs were injected intradermally,
      once, to each volunteer. The volunteers were serially observed for safety and
      efficacy of administration of HBsAg-pulsed DCs. No evidence of physical,
      biochemical, and immunological abnormalities were documented in any volunteer
      during the next 28 days following administration of HBsAg-pulsed DCs. A single
      administration of HBsAg-pulsed DCs resulted in upregulation of anti-HBs in two
      anti-HBs(+) volunteers. Moreover, anti-HBs were detected in two anti-HBs(-)
      volunteer, 2 weeks after administration of HBsAg-pulsed DCs. This study provides
      the scientific and ethical basis for using HBsAg-pulsed DCs for therapeutic and
      prophylactic purposes in patients with chronic hepatitis B and non-responders to
      hepatitis B vaccine, respectively.

PMID- 15203077
TI  - The significance of interferon and ribavirin combination therapy followed by
      interferon monotherapy for patients with chronic hepatitis C in Japan.
AB  - One hundred seventy-one patients with chronic hepatitis C were included in this
      study (genotype1 and high viral loads (1H), [Formula: see text]; non-1H,
      [Formula: see text]; N.D., [Formula: see text] ). The combination therapy of
      interferon and ribavirin for 24 weeks with an additional 24 weeks of interferon
      monotherapy (48-week treatment) was undergone by 42 1H patients and 5 non-1H
      patients. The combination therapy of interferon and ribavirin was administered
      for 24 weeks in 67 1H patients and 22 non-1H patients. Among the 1H patients, the
      HCV relapse rate was significantly higher in those receiving 24-week combination
      treatment than in those receiving 48-week treatment (78% versus 42%, [Formula:
      see text] ). Among the non-1H patients, no significant difference was found
      between them. Sustained virological response (SVR) rates were observed to
      decrease as the timing of HCV RNA disappearance was delayed. In spite of the
      small rate (16%), SVR was obtained from the patients who became negative for HCV
      RNA by week 24 (beyond week 12) only in those receiving 48-week treatment. In 1H
      patients, 24-week combination treatment followed by interferon monotherapy for 24
      weeks was concluded to be the treatment offering the most hope among those that
      the medical insurance can be applied in Japan.

PMID- 15203078
TI  - Expression of human glucocorticoid receptor in lymphocytes of patients with
      autoimmune hepatitis.
AB  - Background and aim: Alternative splicing of human glucocorticoid receptor (hGR)
      premessenger RNA (mRNA) generates two highly homogenous isoforms, termed hGRalpha
      and hGRbeta. hGRalpha is a ligand-activated transcription factor, which, in the
      hormone-bound state, modulates the expression of glucocorticoid-responsive genes
      by binding to specific glucocorticoid response element DNA sequences. In
      contrast, hGRbeta may be an endogenous inhibitor of glucocorticoid action and
      transcriptionally inactive. hGRbeta protein has been known to correlate with the
      development of glucocorticoid resistance. Glucocorticoids can effectively relieve
      autoimmune hepatitis (AIH), but some patients with this disease are refractory
      even when glucocorticoids are administered. The aim of this study was to
      determine the incidence of hGRbeta mRNA in patients with AIH by reverse
      transcription polymerase chain reaction (RT-PCR), and to compare the clinical
      characteristics of hGRbeta-positive and -negative patients with AIH. Materials
      and methods: RNA was obtained from peripheral blood mononuclear cells (PBMCs) of
      62 patients, consisting of 26 with AIH, 10 with primary biliary cirrhosis (PBC),
      seven with chronic viral hepatitis (CVH), 10 with ulcerative colitis (UC), six
      with pemphigus, and three with systemic lupus erythematosus (SLE), and 10 healthy
      volunteers. The total RNA obtained was reverse transcribed, the resulting
      complementary DNA amplified using specific primers for hGRalpha and hGRbeta.
      Results: The hGRalpha mRNA was detected in RNA from PBMCs of all patients and
      healthy volunteers. The hGRbeta mRNA was detected in 15 (57.6%) patients with
      AIH. This incidence was significantly higher than that for patients with PBC (0%)
      or CVH (28.6%) or for healthy volunteers (20.0%) ( [Formula: see text] ). Of the
      hGRbeta-positive and -negative groups, serum ALT and total bilirubin (TB) levels
      were significantly higher in the positive group ( [Formula: see text] ). The
      total dose of glucocorticoid was higher in the positive group, but the difference
      was not statistically significant. However, the average monthly dose was
      significantly higher in the positive group ( [Formula: see text] ). The rate of
      relapse of AIH was significantly higher in the positive group (60.0%) than in the
      negative (10.0%) ( [Formula: see text] ). The rate of usage of immunosuppressive
      drugs was higher in the positive group (33.3%) than in the negative (18.2%), but
      the difference was not statistically significant. Conclusions: These data show
      that hGRbeta expression in PBMCs of patients with AIH assessed by RT-PCR is
      closely associated with resistance to glucocorticoids which affects the outcome
      of therapy with this drug.

PMID- 15203079
TI  - Analysis of 388 cases of primary sclerosing cholangitis in Japan; Presence of a
      subgroup without pancreatic involvement in older patients.
AB  - We analyzed 388 cases of primary sclerosing cholangitis (PSC) in Japan, according
      to a questionnaire sent to gastroenterologists. There was male predominance
      (59%), and interestingly there were two peaks in the age distribution as seen in
      the previous study. Jaundice and itching, major symptoms in PSC patients included
      in the diagnostic criteria, were observed only 28 and 16%, respectively. Alkaline
      phosphatase level was less than twofold of the upper limit of the normal range in
      35%. In this regard, the diagnostic criteria in 2003 from Mayo Clinic, including
      cholestatic symptoms and two to three-fold increases in serum alkaline
      phosphatase, should be modified in Japan. Inflammatory bowel diseases were
      complicated in 37%, and autoimmune pancreatitis (AIP) in 7.2%. PSC cases with
      inflammatory bowel diseases were younger than the average, creating the first
      peak in the age distribution, and have similar characteristics compared to
      patients with PSC in foreign countries. By contrast, those with AIP, who were
      more than 50 years old, responded well to corticosteroid therapy. In addition,
      even after the exclusion of cases of sclerosing cholangitis complicated with AIP,
      the second peak in the age distribution was clearly evident. Therefore, we
      conclude that PSC patients without apparent involvement of the pancreas are
      present in the older patients and seem to be specific in Japan.

PMID- 15203080
TI  - Mutations identified in the human multidrug resistance P-glycoprotein 3 (ABCB4)
      gene in patients with primary hepatolithiasis.
AB  - Primary hepatolithiasis (HL), highly prevalent in the Far East, including Japan,
      is characterized clinically by chronic proliferative cholangitis with frequent
      recurrences. In HL patients, hepatic hyposecretion of phospholipid due to
      decreased multidrug resistance P-glycoprotein 3 (MDR3; now referred to as ABCB4)
      expression levels (Hepatology 2001;33:1194-1205) may contribute to the formation
      of aggressive ductular lesions through a decreased formation of mixed micelles.
      However, specified factors underlying the decreased expression levels of MDR3
      have not been well defined. To determine whether the decreased MDR3 expression
      level is associated with the gene mutations, mutation analysis of cDNA of the
      MDR3 gene with focus on the coding region was performed using liver specimens.
      Heterozygous mutations were detected in only two of 16 HL patients. By sequence
      analysis of the gene, a 77-bp deletion at nucleotides 537-613 in exon 7 in
      transmembrane domain (TM) 3, which results in a frameshift at codon 179 and an
      early stop codon predicting a truncated protein, was found as a heterozygous
      mutation in two of the 16 patients. A 1-bp deletion at nucleotide 1015 in exon 10
      in TM 6 was found as a heterozygous mutation in one of those two patients, and a
      242-bp deletion at nucleotides 2683-2924 in exons 22-23 in TM 11 was found as a
      heterozygous mutation in the same patient. No other mutations were found in the
      other 14 patients. In real-time polymerase chain reaction (PCR), no significant
      difference was found between the mRNA levels of MDR3 in the two HL patients with
      mutations nor in the other 14 patients without mutations. Immunostaining of MDR3
      protein was found in the bile canaliculi of liver sections from the two patients
      with mutations. The results suggest that in primary HL the decreased
      transcription levels of MDR3 in the liver are not due to the mutations detected
      in the coding region of the gene.

PMID- 15203081
TI  - Apoptotic hepatocellular carcinoma HepG2 cells accelerate blood coagulation.
AB  - Backgrounds and Aim: Intrasinusoidal microthrombosis is considered to be a cause
      of massive hepatocyte death in fulminant hepatic failure. Generally, apoptotic
      cells express phosphatidyl serine (PS) outside the plasma membrane, which is also
      expressed on the surface of activated platelets and accelerates fibrin-thrombus
      formation. Therefore, the acceleration of blood coagulation on the surface of
      apoptotic hepatocytes may occur because hepatocytes are in direct contact with
      plasma that passes through fenestrations of the sinusoidal endothelium. To test
      this hypothesis, we investigated the coagulation activity of apoptotic
      hepatocytes. Methods: (1) The apoptosis of Hep G2 cells was induced by
      staurosporin (STS). PS expression was determined by confocal microscopy with FITC
      annexin V, a specific inhibitor of PS activity. (2) One million HepG2 cells
      treated with STS with or without pretreatment with annexin V were exposed to
      activated factor X, CaCl(2) and prothrombin. Thrombin generation was determined
      using a thrombin-specific chromogenic substrate. Results: (1) The percentage of
      apoptotic cells and PS-expressing cells markedly increased following the STS
      treatment. (2) The thrombin generation significantly increased with STS-treatment
      in a dose dependent manner. (3) The increase in thrombin generation by STS
      treatment was abolished following pretreatment with annexin V. Conclusion:
      Apoptotic hepatocytes accelerate blood coagulation through the expression of a PS
      dependent pro-coagulant surface.

PMID- 15203082
TI  - Induction of Bcl-xL is a possible mechanism of anti-apoptotic effect by
      prostaglandin E2 EP4-receptor agonist in human hepatocellular carcinoma HepG2
      cells.
AB  - Because fulminant hepatic failure has a poor prognosis without liver
      transplantation, it is required to develop new therapies directed toward
      hepatocyte protection and regeneration. Previously, we showed the anti-apoptotic
      effects of a prostaglandin E2 EP4-receptor agonist (PGE2R-A) in a rat model of
      acute liver failure. The aim of this study is to determine the anti-apoptotic
      mechanism underlying the hepatocyte protective effect of PGE2R-A in vitro.
      Method: (1) Apoptosis was induced in HepG2 cells using CH11, an agonistic anti
      Fas antibody. The apoptosis index (percentage of apoptotic cells with respect to
      the total number of cells) was sequentially estimated after the administration of
      CH11 alone or CH11 together with indomethacin or PGE2R-A (ONO-AE1-437). (2) The
      expression levels of Bcl-xL and Mcl-1, members of the anti-apoptotic Bcl-2
      family, were sequentially determined by western blot analysis after treatment
      with PGE2R-A. Results: (1) Apoptosis indexes 6h after treatment with CH11 alone,
      CH11 plus indomethacin, and CH11 plus PGE2R-A were 24, 42, and 16%, respectively.
      (2) The expression level of the Bcl-xL protein and mRNA significantly increased
      30-180min after treatment with PGE2R-A, while indomethacin decreased the
      expression levels of Mcl-1 proteins. Conclusion: Direct induction of Bcl-xL plays
      an important role in the hepatocyte protective effects induced by PGE2R-A.

PMID- 15203083
TI  - Spontaneous regression of hepatocellular carcinoma: two case reports and a
      literature review.
AB  - Spontaneous regression of a malignant tumor is extremely rare. Here we report two
      cases of spontaneous regression of hepatocellular carcinoma (HCC), and review the
      associated literature. Case 1 was a 77-year-old male with HCC in the right lobe
      and multiple lung metastases. alpha-fetoprotein (AFP) and protein induced by
      vitamin K deficiency or antagonist II (PIVKA-II) were >50,000ng/ml and
      21,500mAU/ml, respectively. He and his family refused further treatment, and he
      was discharged. Four months after the diagnosis, dramatic diminution of HCC and
      lung metastases was noted, and the HCC had disappeared completely 12 months
      later. Case 2 was a 72-year-old male with multiple nodular regions with enhanced
      circumference in the right lobe, the largest of which was 8cm in diameter,
      referred to the gastroenterology unit of our hospital. Laboratory analyses showed
      positive for hepatitis C virus antibody, and AFP and PIVKA-II were 936.3ng/ml and
      2,380mAU/ml, respectively. However, he and his family refused further treatment,
      and he was followed-up as an outpatient by a local clinic. Two years later,
      radiological investigations revealed remarkable regression of HCC. Laboratory
      analyses showed that PIVKA-II had decreased to the normal range, while AFP had
      increased to double the original value.

PMID- 15203084
TI  - The pharmaceutical industry in the Arab world: challenges, controversies, and
      future outlook.

PMID- 15203087
TI  - Janet Woodcock discusses the FDA and the drug development process. Interview by
      Christopher Watson.
AB  - Currently Acting Deputy Commissioner for Operations at FDA, Janet Woodcock has
      served as Director, Center for Drug Evaluation and Research at FDA since 1994.
      She previously served in other positions in FDA including Director, Office of
      Therapeutics Research and Review and Acting Deputy Director, Center for Biologics
      Evaluation and Research. She received her MD from Northwestern Medical School and
      held faculty appointments at the Pennsylvania State University and the University
      of California in San Francisco. She joined FDA in 1986.

PMID- 15203088
TI  - Automated high-throughput patch-clamp techniques.

PMID- 15203089
TI  - Real options are neither complicated nor unrealistic.

PMID- 15203090
TI  - Neurodegenerative disease research in the 21st century.

PMID- 15203091
TI  - Catalytic antioxidants: a radical approach to new therapeutics.
AB  - In humans, several pathologies involve the overproduction of reactive oxygen
      species. Metal-containing catalytic antioxidants have emerged as a novel class of
      potential therapeutic agents that scavenge a wide range of reactive oxygen
      species. There are three structural classes of manganese-containing catalytic
      antioxidants that have efficacy in several oxidative stress models of human
      disease. The classes are divided based on their in vitro selectivity towards the
      scavenging of superoxide. The selective catalytic antioxidants include the
      macrocyclics, whereas the non-selective catalytic antioxidants include the salens
      and porphyrins. Cardiovascular, neurodegenerative and inflammatory lung disorders
      are all potentially important targets for catalytic antioxidant therapy.

PMID- 15203092
TI  - Translating pharmacogenetics and pharmacogenomics into drug development for
      clinical pediatrics and beyond.
AB  - Pharmacogenetic and pharmacogenomic investigations conducted in children must
      consider that human development from conception through to adolescence is a
      rapidly changing, dynamic process. An improved understanding of the gene networks
      that are involved in growth and development and of the unintended consequences of
      modulating those systems could provide insights into the susceptibility of an
      individual to drug-induced birth defects and to pediatric adverse drug reactions.
      Furthermore, these technologies potentially present the opportunity to develop
      novel, effective treatments for childhood diseases and for adult diseases that
      manifest primarily during childhood. The lack of pharmacogenetic and
      pharmacogenomic investigations in children and the potential to impact on all age
      groups provides a considerable incentive to invest in this area of research.

PMID- 15203093
TI  - The implications of polymorphisms in mammalian flavin-containing monooxygenases
      in drug discovery and development.
AB  - Use of the human flavin-containing monooxygenases (FMOs) in drug design and
      discovery could represent a paradigm shift in drug development and basic
      research. Although FMOs have been previously viewed as minor contributors to drug
      metabolism, the advantages associated with using FMOs to diversify the metabolism
      of a drug are now being recognized. Because FMOs typically oxygenate a wide
      variety of nucleophilic compounds to polar, benign metabolites, and because drugs
      do not induce expression of FMOs or inhibit their activity, potential drug-drug
      interactions are minimized. Interindividual variation for this class of enzyme is
      largely dependent on genetic variation. Examples of FMO allelic variation and
      splicing variants suggest that these genetic mutations could contribute to the
      interindividual and interethnic variability of FMO-mediated metabolism.

PMID- 15203098
TI  - Glial cells.
AB  - The nervous system is built from two broad categories of cells, neurones and
      glial cells. The glial cells outnumber the neurones and the two cell types occupy
      a comparable amount of space in nervous tissue. The main glial cell types are, in
      the central nervous system, astrocytes and oligodendrocytes and, in the
      peripheral nervous system, Schwann cells, enteric glial cells and satellite
      cells. In the embryo, glial cells form a cellular framework that permits the
      development of the rest of the nervous system, and regulate neuronal survival and
      differentiation. The best known function of glia in the adult is the formation of
      myelin sheaths around axons thus allowing the fast conduction of signalling
      essential for nervous system function. Glia also maintain appropriate
      concentrations of ions and neurotransmitters in the neuronal environment.
      Increasing body of evidence indicates that glial cells are essential regulators
      of the formation, maintenance and function of synapses, the key functional unit
      of the nervous system.

PMID- 15203099
TI  - Polycystic kidney disease: new understanding in the pathogenesis.
AB  - Polycystic kidney disease (PKD) is a disease of the nephron, characterized by the
      formation of multiple renal tubular cysts, leading to endstage renal failure. The
      most common form is autosomal dominant PKD (ADPKD) and is caused by mutations in
      the PKD1 gene in 85% of cases or in PKD2 in 10-15%. Rarer forms include autosomal
      recessive PKD (ARPKD) and nephronophthisis with high mortality and morbidity in
      children. Recent advances suggest that the PKD1-encoded protein, polycystin-1, is
      a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in
      the extracellular environment at the basal surface in focal adhesion complexes;
      at the lateral surface in cell adherens junctions; and in the lumen at the apical
      primary cilium. Activation via multiprotein complex formation, intracellular
      signal transduction cascades and regulation of fetal gene transcription leads to
      appropriate renal tubule epithelial cell division and differentiation in normal
      kidneys, but is disrupted in PKD resulting in cyst formation.

PMID- 15203100
TI  - Hepatitis C and treatment with pegylated interferon and ribavirin.
AB  - Hepatitis C is a hepatotropic RNA virus with a propensity to cause chronic
      infection, causing a worldwide burden of chronic hepatitis, cirrhosis and
      hepatocellular carcinoma. Both viral elimination and hepatocellular damage are
      thought to be immune mediated with T-helper and cytotoxic T-lymphocytes central
      to these events. A delay in the onset of adaptive immunity following infection
      indicates that a defect in the innate immune response may lead to viral
      persistence with a combination of other mechanisms subsequently contributing.
      Antiviral therapy based on interferon-alpha leads to resolution of disease in
      approximately 50% of patients. Specific anti-hepatitis C anti-viral drugs are
      being developed.

PMID- 15203101
TI  - C-type natriuretic peptide: new candidate for endothelium-derived hyperpolarising
      factor.
AB  - Endothelium-derived hyperpolarising factor (EDHF) is an important regulator of
      vascular tone; however, its identity is still unclear. Several different
      molecules have been suggested, the most recent of which is the 22-amino acid
      peptide C-type natriuretic peptide (CNP). CNP induces hyperpolarisation and
      relaxation of rat mesenteric resistance artery vascular smooth muscle through
      activation of natriuretic peptide receptor subtype C (NPR-C) and the same
      potassium channels as EDHF. In addition, this peptide is released from
      endothelial cells of the perfused rat mesenteric bed in response to endothelium
      dependent vasodilators. Thus, CNP is likely to play a vital role in regulation of
      vascular tone. In addition, since there is evidence that up-regulation of EDHF
      occurs where normal endothelium function has been compromised, modulation of this
      pathway represents a novel target for therapeutics in the treatment of
      inflammatory cardiovascular pathologies characterised by endothelial dysfunction.

PMID- 15203102
TI  - Macrophage inflammatory protein-1.
AB  - Macrophage inflammatory protein (MIP)-1alpha was identified 15 years ago as the
      first of now four members of the MIP-1 CC chemokine subfamily. These proteins
      termed CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL9/10 (MIP-1delta), and CCL15 (MIP
      1gamma) according to the revised nomenclature for chemokines are produced by many
      cells, particularly macrophages, dendritic cells, and lymphocytes. MIP-1
      proteins, which act via G-protein-coupled cell surface receptors (CCR1, 3, 5),
      e.g. expressed by lymphocytes and monocytes/macrophages (MPhi), are best known
      for their chemotactic and proinflammatory effects but can also promote
      homoeostasis. The encouraging results of preclinical studies in murine models of
      inflammation, i.e. asthma, arthritis, or multiple sclerosis, have led to the
      development of potent CCR3 and 5 antagonists, some of which are currently being
      tested in first clinical trials.

PMID- 15203103
TI  - Mitochondrial ferritin.
AB  - A novel ferritin type specifically targeted to mitochondria has been recently
      found in human and mouse. It is structurally and functionally similar to the
      cytosolic ferritins, well-characterized molecules found in most living systems
      which are designed to store and detoxify cellular iron. Cytosolic ferritins in
      mammals are ubiquitous while mitochondrial ferritin expression is restricted
      mainly to the testis, neuronal cells and islets of Langherans. In addition, it is
      abundant in the iron-loaded mitochondria of erythroblasts of patients with
      sideroblastic anaemia. The characterization of recombinant and transfected
      mitochondrial ferritin indicated that this protein has a role in protecting
      mitochondria from iron-induced damage. These data suggest that it is an
      interesting tool to study the iron metabolism in this organelle. In addition, it
      may be useful for the diagnosis of myelodysplastic syndromes and in protecting
      mitochondria from the toxic effects of excess iron.

PMID- 15203104
TI  - The actin cytoskeleton in normal and pathological cell motility.
AB  - Cell motility is crucial for tissue formation and for development of organisms.
      Later on cell migration remains essential throughout the lifetime of the organism
      for wound healing and immune responses. The actin cytoskeleton is the cellular
      engine that drives cell motility downstream of a complex signal transduction
      cascade. The basic molecular machinery underlying the assembly and disassembly of
      actin filaments consists of a variety of actin binding proteins that regulate the
      dynamic behavior of the cytoskeleton in response to different signals. The
      multitude of proteins and regulatory mechanisms partaking in this system makes it
      vulnerable to mutations and alterations in expression levels that ultimately may
      cause diseases. The most familiar one is cancer that in later stages is
      characterized by active aberrant cell migration. Indeed tumor invasion and
      metastasis are increasingly being associated with deregulation of the actin
      system.

PMID- 15203106
TI  - TRPC3-like protein and vitamin D receptor mediate 1alpha,25(OH)2D3-induced SOC
      influx in muscle cells.
AB  - 1alpha,25-Dihydroxy-Vitamin-D3 (1alpha,25(OH)2-Vitamin D3) stimulates in skeletal
      muscle cells Ca2+ release from inner stores and influx through both voltage
      dependent and store-operated Ca2+ (SOC, CCE) channels. We investigated the
      involvement of TRPC proteins and Vitamin D receptor (VDR) in CCE induced by
      1alpha,25(OH)2D3 in chick muscle cells. Two fragments were amplified by RT-PCR,
      exhibiting approximately 80% sequence homology with mammalian TRPC3/6/7. Northern
      and Western blots employing a TRPC3-probe and anti-TRPC3 antibodies,
      respectively, confirmed endogenous expression of a TRPC3-like protein of 140 kDa.
      Spectrofluorimetric measurements in Fura-2 loaded cells showed reduced CCE and
      Mn2+ entry in response to either thapsigargin or 1alpha,25(OH)2D3 upon
      transfection with anti-TRPC3/6/7 antisense oligodeoxynucleotides (ODNs).
      Transfection with anti-VDR antisense ODNs diminished 1alpha,25(OH)2D3-dependent
      Ca2+ and Mn2+ influx. Co-immunoprecipitation of TRPC3-like protein and VDR under
      non-denaturating conditions was observed. We propose that endogenous TRPC3-like
      proteins and the VDR participate in the modulation of CCE by 1alpha,25(OH)2D3 in
      muscle cells, which could be mediated by an interaction between these proteins.

PMID- 15203107
TI  - Vitamin C or Vitamin B6 supplementation prevent the oxidative stress and decrease
      of prostacyclin generation in homocysteinemic rats.
AB  - We hypothesize that homocysteinemia causes oxidative stress, decreases the aortic
      ability to generate prostacyclin and that antioxidants have a protective role.
      Four groups of eight rats each were fed for 8 weeks the control diet (group A),
      control diet with folic acid omitted and excess methionine (Me) added to drinking
      water (group B), diet B + 500 mg/kg of Vitamin C (group C) or diet B + 60 mg/kg
      Vitamin B6 (group D). The three groups of rats fed folic acid deficient (FD)
      diets (groups B, C and D) were homocysteinemic as indicated by the significant
      increase in their serum homocysteine (HC) concentration. Rats fed diet B had
      oxidative stress as indicated by an increase in serum thiobarbituric acid
      reactive substances (TBARS) and advanced oxidation protein products (AOPP) and
      urinary isoprostanes and had a decreased ability of their aortas to generate
      prostacyclin. Homocysteinemic rats fed a FD diet + Vitamin C (group C) or Vitamin
      B6 (group D) also had high levels of serum homocysteine but the oxidative stress
      markers and the ability of their aortas to generate prostacyclin returned to
      normal. This indicates that the homocysteinemic effect is through an oxidative
      mechanism and that Vitamin C as a free radical scavenger prevents these effects.
      Serum Vitamin C and liver glutathione concentrations significantly increased in
      rats fed excess Vitamin B6 compared to the control or FD rats. This may explain
      why Vitamin B6 has an antioxidative effect.

PMID- 15203108
TI  - Specificity comparison of a serine endopeptidase (SH1) and a serine thiol
      endopeptidase (STH2) purified from human urine.
AB  - In this study, we compared the properties of a serine endopeptidase H1 (SH1) and
      a serine thiol endopeptidase (STH2) purified from human urine by DEAE-cellulose
      followed by a Bio Gel A0.5 m or Sepharose Mercurial chromatographs. These enzymes
      differ in their action upon different hormone peptides. We used fluorogenic
      substrates to further characterize the enzyme. The substrate specificity of
      urinary SH1 was studied using different internally quenched fluorescent peptides,
      and AbzFGQEDDnp was hydrolyzed by SH1. Other enzymes present in urine, such as
      serine endopeptidase H2, prolyl endopeptidase, neutral endopeptidase like and
      angiotensin-I converting enzyme, were not able to hydrolyze this substrate. SH1
      is 100% inhibited by PMSF and resistant to EDTA, OPA, thiorphan, E64, pOHMB and
      phosphoramidon. Endopeptidase STH2 is completely inhibited by PMSF, E64 and
      pOHMB. Enzyme SH1 hydrolyzes the peptide bound F5-S6 at bradykinin (BK:
      RPPGFSPFR) molecule and R-Q at AbzBKQEDDnp. When studying enzyme STH2, the
      cleavage sites determined to the related substrates were F5-S6 using BK as
      substrate and F-R using AbzBKQEDDnp. The kilometers value obtained for
      AbzBKQEDDnp and AbzFGQEDDnp were 1.18 and 0.007 uM, respectively. Kininases from
      kidney and urine can hydrolyze peptide bounds from components of the kallikrein
      kinin system, the angiotensin-renin system and the neuropeptides system, straight
      contributing in kidney homeostasis. SH1 was located at the distal tubule
      [Casarini et al., 1999a, Am. J. Physiol. 277, F66] and can have an important
      function in the control of kinin found in this portion, since is known that all
      components of the kallikrein-kinin system were found in this portion. The
      physiological role of SHT2 could be related to the inter-relation between the
      kallikrein-kinin system and neuropeptides in the control of the water electrolyte
      balance [Braz. J. Med. Biol. Res. 25 (3) (1992) 219].

PMID- 15203109
TI  - Cell cycle arrest and modulation of HO-1 expression induced by acetyl salicylic
      acid in hepatocarcinogenesis.
AB  - BACKGROUND AND AIMS: Control of cell proliferation is important for cancer
      prevention since cell proliferation has an essential role in carcinogenesis. In
      rodent carcinogenesis models, antioxidant agents suppress carcinogen-induced
      cellular hyper proliferation in the target organs. Strict control of cell
      division is an essential process to ensure that DNA synthesis and mitotic
      division are accurately and coordinately executed. We studied the interplay
      between cell cycle and heme oxygenase-1 (HO-1) and the effect of the
      acetylsalicylic acid (ASA) in hepatic carcinogenesis. METHODS: Male CF1 mice pre
      treated with dietary p-dimethylaminoazobenzene (DAB; 0.5%, w/w) were fed with ASA
      (0.16%, w/w). We investigated the hepatic expression of cyclin D1, cyclin E,
      Cdk2, Cdk4, p21, p27, p53; the level of bcl-2, an antiapoptotic protein and of
      heme oxygenase-1 (HO-1), a marker of oxidative stress, by Western blot analysis.
      RESULTS: The treatment with ASA produced an important attenuation in the
      induction of cyclin E and cyclin D1 provoked by DAB. p21 and p27 levels were
      increased when animals received both drugs. The administration of ASA to DAB
      treated animals induced Cdk2 (29%). HO-1 induction (65%) provoked by DAB was
      diminished by ASA administration reaching lower induction levels (23%).
      CONCLUSION: The deregulation of cyclin/CDK expression and the up-regulation of
      p21 and p27 with the administration of ASA, post-treatment of the carcinogen
      administration, would block the pass through out to the G0/G1 check point to
      permit the cells to repair their DNA and HO-1 protected the liver from reactive
      oxygen species produced from DAB.

PMID- 15203110
TI  - Identification of heparin affin regulatory peptide domains with potential role on
      angiogenesis.
AB  - Heparin affin regulatory peptide (HARP) is a growth factor displaying high
      affinity for heparin. It is present in the extracellular matrix of many tissues,
      interacting with heparan sulfate and dermatan/chondroitin sulfate
      glycosaminoglycans. We have previously shown that HARP is implicated in the
      control of angiogenesis and its effects are mimicked, at least in part, by
      synthetic peptides that correspond to its N and C termini. In the present work,
      we show that HARP is cleaved by plasmin, leading to the production of five
      peptides that correspond to distinct domains of the molecule. Heparin, heparan
      sulfate and dermatan sulfate, at various HARP to glycosaminoglycan ratios,
      partially protect HARP from plasmin degradation. The molecules with higher
      affinity to HARP are the more protective, heparin being the most efficient. The
      peptides that are produced from cleavage of HARP by plasmin, affect in vivo and
      in vitro angiogenesis and modulate the angiogenic activity of vascular
      endothelial growth factor on human umbilical vein endothelial cells. Similar
      results were obtained in vitro with recombinant HARP peptides, identical to the
      peptides generated after treatment of HARP with plasmin. These results suggest
      that different regions of HARP may induce or inhibit angiogenesis.

PMID- 15203111
TI  - Curcumin modulates free radical quenching in myocardial ischaemia in rats.
AB  - This study was designed to investigate the protective effect of curcumin (CUR)
      against isoprenaline induced myocardial ischaemia in rat myocardium. The effect
      of single oral dose of curcumin (15 mg kg(-1)), administered 30 min before and/or
      after the onset of ischaemia, was investigated by assessing oxidative stress
      related biochemical parameters in rat myocardium. Curcumin pre and post-treatment
      (PPT) was shown to decrease the levels of xanthine oxidase, superoxide anion,
      lipid peroxides (LPs) and myeloperoxidase while the levels of superoxide
      dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S
      transferase (GST) activities were significantly increased after curcumin PPT.
      Histopathological and transmission electron microscopical studies also confirmed
      the severe myocardial damage occurring as a consequence of isoprenaline induced
      ischaemia and they also showed the significant improvement effected by curcumin
      PPT. These findings provided evidence that curcumin was found to protect rat
      myocardium against ischaemic insult and the protective effect could be attributed
      to its antioxidant properties as well as its inhibitory effects on xanthine
      dehydrogenase/xanthine oxidase (XD/XO) conversion and resultant superoxide anion
      production.

PMID- 15203112
TI  - In vitro modification of betaine-homocysteine S-methyltransferase by tissue-type
      transglutaminase.
AB  - Transglutaminases catalyze the cross-linking and amine incorporation of proteins,
      and are implicated in various biological phenomena. To elucidate the
      physiological roles of transglutaminase at the molecular level, we need to
      identify its physiological protein substrates and clarify the relationship
      between transglutaminase modification of protein substrates and biological
      responses. Here we examined whether betaine-homocysteine S-methyltransferase
      (BHMT: EC 2.1.1.5) can be a substrate of tissue-type transglutaminase by in vitro
      experiments using porcine liver BHMT and guinea pig liver transglutarninase.
      Guinea pig liver transglutaminase incorporated 5-(biotinamido) pentylamine and
      [3H] histamine into BHMT in a time-dependent manner. Putrescine and spermidine
      also seemed to be incorporated into BHMT by transglutaminase. In the absence of
      the primary amines, BHMT subunits were cross-linked intra- and intermolecularly.
      BHMT activity was decreased significantly through the cross-linking by
      transglutaminase. Histamine incorporation slightly reduced the BHMT activity.
      Peptide fragments of BHMT containing the glutamine residues reactive for
      transglutaminase reaction were isolated through biotin labelling, proteinase
      digestion, biotin-avidin a affinity separation, and reverse phase HPLC. The
      results of amino acid sequence analyses of these peptides and sequence homology
      alignment with other mammalian liver BHMT subunits showed that these reactive
      glutamine residues were located in the region near the carboxyl terminal of
      porcine BHMT subunit. These results suggested that the liver BHMT can be modified
      by tissue-type transglutaminase and its activity is regulated repressively by the
      modification, especially by the cross-linking. This regulatory reaction might be
      involved in the regulation of homocysteine metabolism in the liver.

PMID- 15203113
TI  - The mouse liver content of carbonic anhydrase III and glutathione S-tranferases
      A3 and P1 depend on dietary supply of methionine and cysteine.
AB  - The contents of glutathione S-transferase (GST) subunits, carbonic anhydrase III
      (CAIII), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and a 230 kDa protein
      are affected by protein deprivation in mouse liver. In order to know if
      particular amino acids control these contents, the effects of feeding for 5 days
      with diets containing different amino acids were examined. After an exploration
      using SDS-PAGE analysis, the action of selected diets was further examined by
      distinct techniques. The 230 kDa protein was identified as fatty acid synthase
      (FAS) by both mass spectrometry and amino acid sequence analyses. Dietary tests
      showed that: (1) a protein-free diet (PFD) increased the content of glutathione S
      transferases P1 and M1, and glyceraldehyde-3-phosphate dehydrogenase, while the
      content of glutathione S-transferase A3, fatty acid synthase and carbonic
      anhydrase III decreased; (2) a protein-free diet having either methionine or
      cysteine preserved the normal contents of glutathione S-transferases P1, A3, M1
      and carbonic anydrase III; (3) a protein-free diet having threonine preserved
      partially the normal contents of glutathione S-transferases P1, A3, M1 and
      carbonic anhydrase III; (4) a protein-free diet having methionine, threonine and
      cysteine prevented in part the loss of fatty acid synthase; and (5) the
      glyceraldehyde-3-phosphate dehydrogenase content was controlled by increased
      carbohydrate level and/or by lower amino acid content of diets, but not by any
      specific amino acid. These data indicate that methionine and cysteine exert a
      main role on the control of liver glutathione S-transferases A3 and P1, and
      carbonic anhydrase III. Thus, they emerge necessary to prevent unsafe alterations
      of liver metabolism caused by protein deprivation.

PMID- 15203114
TI  - Investigating filopodia sensing using arrays of defined nano-pits down to 35 nm
      diameter in size.
AB  - In order for cells to react to topography, they must be able to sense shape. When
      considering nano-topography, these shapes are much smaller than the cell, but
      still strong responses to nano-topography have been seen. Filopodia, or
      microspikes, presented by cells at their leading edges are thought to be involved
      in gathering of special information. In order to investigate this, and to develop
      an understanding of what size of feature can be sensed by cells, morphological
      observation (electron and fluorescent microscopy) of fibroblasts reacting to nano
      pits with 35, 75 and 120 nm diameters has been used in this study. The nano-pits
      are especially interesting because unlike many of the nanofeatures cited in the
      literature, they have no height for the cells to react to. The results showed
      that cell filopodia, and retraction fibres, interacted with all pit sizes,
      although direct interaction was hard to image on the 35 nm pits. This suggests
      that cells are extremely sensitive to their nanoevironment and that should be
      taken in to consideration when designing next-generation tissue engineering
      materials. We suggest that this may occur through nanocontact guidance as
      filopodia are moved over the pits.

PMID- 15203115
TI  - Human Doppel and prion protein share common membrane microdomains and
      internalization pathways.
AB  - Doppel is the first identified homologue of the prion protein (PrPc) implicated
      in prion disease. Doppel is considered an N-truncated form of PrPc, and shares
      with PrPc several structural and biochemical features. When over expressed in the
      brain of some PrP knockout animals, it provokes cerebellar ataxia. As this
      phenotype is rescued by reintroducing the PrP gene, it has been suggested that
      Doppel and PrPc have antagonistic functions and may compete for a common ligand.
      However, a direct interaction between the two proteins has recently been
      observed. To investigate whether the neuronal environment is suitable for such
      possibility, human Doppel and PrPc were expressed separately, or together, in
      neuroblastoma cells, and then studied by biochemical and immunomicroscopic tools,
      as well as in intact cells expressing fluorescent fusion constructs. The results
      demonstrate that Doppel and PrPc co-patch extensively at the plasma membrane, and
      get internalized together after ganglioside cross-linking by cholera toxin or
      addition of an antibody against only one of the proteins. These processes no
      longer occur if the integrity of rafts is disrupted. We also show that, whereas
      each protein expressed alone occupies Triton X-100-insoluble membrane
      microdomains, co-transfected Doppel and PrPc redistribute together into a less
      ordered lipidic environment. All these features are consistent with interactions
      occurring between Doppel and PrPc in our neuronal cell model.

PMID- 15203116
TI  - Expression of 25 kDa thiamine triphosphatase in rodent tissues using quantitative
      PCR and characterization of its mRNA.
AB  - Thiamine triphosphate (ThTP) is found in most organisms, but its biological role
      remains unclear. In mammalian tissues, cellular ThTP concentrations remain low,
      probably because of hydrolysis by a specific 25 kDa thiamine triphosphatase
      (ThTPase). The aim of the present study was to use quantitative PCR, for
      comparing the 25 kDa ThTPase mRNA expression in various mouse tissues with its
      enzyme activities. ThTPase mRNA was expressed at only a few copies per cell. The
      highest amount of mRNA was found in testis, followed by lung and muscle, while
      the highest enzyme activities were found in liver and kidney. The poor
      correlation between mRNA levels and enzyme activities might result either from
      tissue-specific post-transcriptional regulation of mRNA processing and/or
      translation or from the regulation of enzyme activities by post-translational
      mechanisms. Purified recombinant human ThTPase was phosphorylated by casein
      kinase II, but this phosphorylation did not modify the enzyme activity. However,
      the characterization of the 3'-untranslated mRNA region revealed a unique, highly
      conserved, 200-nucleotide sequence that might be involved in translational
      control. In situ hybridization studies in testis suggest a predominant
      localization of ThTPase mRNA in poorly differentiated spermatogenic cells. This
      is the first study demonstrating a cell-specific 25 kDa ThTPase mRNA expression,
      suggesting that this enzyme might be related to the degree of differentiation or
      the metabolic state of the cell.

PMID- 15203117
TI  - L-FABP is exclusively expressed in alveolar macrophages within the myeloid
      lineage: evidence for a PPARalpha-independent expression.
AB  - Peroxisome proliferator-activated receptors (PPARs) play a role in inflammation
      and, in particular, PPARgamma is involved in monocyte/macrophage differentiation.
      Members of the fatty acid-binding protein (FABP) family have been reported to
      function as transactivators for PPARs. Therefore, the expression of PPARs and
      FABPs in the myeloid lineage was investigated by real-time PCR and
      immunofluorescence analysis. We found adipocyte-, epidermal-, and heart-type FABP
      to be ubiquitously expressed within the myeloid lineage. In contrast, liver-type
      FABP was exclusively detected in murine alveolar macrophages (AM), confirmed on
      protein level by double fluorescence analysis. The PPAR subtypes also showed a
      temporally and spatially regulated expression pattern in myeloid cells: the beta
      subtype was expressed in bone marrow, peritoneal, and alveolar macrophages,
      whereas it was not detected in dendritic cells (DCs). The gamma1-isoform was
      present in all cells, however, at different levels, whereas the gamma2-isoform
      was expressed in alveolar macrophages and dendritic cells. A low level PPARalpha
      mRNA could be detected in peritoneal macrophages and immature dendritic cells but
      not in mature dendritic cells and bone marrow macrophages. Interestingly,
      PPARalpha mRNA was also absent in the alveolar macrophages although liver-type
      FABP was expressed, indicating that gene expression of liver-type FABP was
      independent of PPARalpha. Since liver-type FABP is known as transactivator of
      PPARgamma the simultaneous expression of both proteins may have general
      implications for the activation of PPARgamma in alveolar macrophages.

PMID- 15203118
TI  - A blood plasma inhibitor is responsible for circadian changes in rat renal Na,K
      ATPase activity.
AB  - Rhythmic changes in activity following a circadian schedule have been described
      for several enzymes. The possibility of circadian changes in Na,K-ATPase activity
      was studied in homogenates of rat kidney cortex cells. Male Sprague-Dawley rats
      were kept on a schedule of 12h light (06:00-18:00 h) and 12 h darkness (18:00
      06:00 h) for 2 weeks. At the end of the conditioning period, one rat was killed
      every 2 h, until completion of a 24 h cycle. Outermost kidney cortex slices were
      prepared, homogenized and assayed for Na,K-ATPase activity. The whole procedure
      was repeated six times. Na,K-ATPase activity shows an important oscillation (2
      cycles/24 h). Peak activities were detected at 09:00 and 21:00 h, whereas the
      lowest activities were detected at 15:00 and 01:00-03:00 h. The highest activity
      was 40+/-3 nmoles Pi mg protein(-1)min(-1) (09:00 h), and the lowest was 79+/-3
      nmoles Pi mg protein(-1)min(-1) (15:00 h). The amount of the Na+-stimulated
      phosphorylated intermediate is the same for the 09:00 h and 15:00 h homogenates.
      Preincubation of 09:00 h kidney cortex homogenates with blood plasma drawn from
      rats at either 03:00 h or 15:00 h, significantly inhibited their Na,K-ATPase
      activity. This inhibition was not seen when the preincubation was carried out
      with either 09:00 h or 21:00 h blood plasma. The striking oscillation (2
      cycles/24 h) of the Na,K-ATPase activity of rat kidney cortex cells is ascribed
      to the presence of an endogenous inhibitor in blood plasma.

PMID- 15203119
TI  - Methionine 35 oxidation reduces toxic effects of the amyloid beta-protein
      fragment (31-35) on human red blood cell.
AB  - Amyloid beta-peptide, the central constituent of senile plaques in Alzheimer's
      disease brain, has been shown to be a source of free radical oxidative stress
      that may lead to neurodegeneration. In particular, it is well known that
      oxidation of methionine 35, is strongly related to the pathogenesis of
      Alzheimer's disease, since it represents the residue in the beta-amyloid peptide
      most susceptible to oxidation "in vivo". In this study, the fragment 31-35 of the
      beta-amyloid peptide, which has a single methionine at residue 35, was used to
      investigate the influence of the oxidation state of methionine-35 on the beta
      amyloid peptide (31-35) mediated cytotoxic effects. Because no extensive studies
      have yet addressed whether amyloid beta peptides-mediated toxic effects can occur
      in the absence of mitochondria, human red blood cells were used as cell model.
      Exposure of intact red blood cells to beta-amyloid peptide (31-35) induced a
      marked stimulation (approximately 45%) of the pentose phosphate pathway and a
      significant inhibition of the red cell enzyme catalase, compared with the results
      observed in control red blood cells. In contrast, exposure of red blood cells to
      the beta-amyloid peptide (31-35)-Met35OX i.e. in which the sulfur of methionine
      is oxidised to sulfoxide, induced a slight activation of PPP (approximately 19%),
      and an inhibition of catalase activity lower with respect to the results observed
      in beta-amyloid peptide (31-35)-treated red blood cells. Since the activities of
      red cell phosphofructokinase, glucose-6-phosphate dehydrogenase, glutathione
      peroxidase, glutathione reductase and the functionality of hemoglobin were not
      modified within the red cell following to beta-amyloid peptides exposure, it is
      likely that beta-amyloid (31-35)-catalase interaction may represent a selective
      toxic event. Together, these results support the hypothesis that Abeta peptide
      and the oxidative state of Met-35 may be involved in the mechanisms responsible
      of neurodegeneration in Alzheimer's disease.

PMID- 15203120
TI  - Suramin interaction with human alpha-thrombin: inhibitory effects and binding
      studies.
AB  - Suramin is a hexasulfonated naphthylurea commonly used as antitrypanosomial drug
      and more recently for the treatment of malignant tumors. Here we show that
      suramin binds to human alpha-thrombin inhibiting both the hydrolysis of the
      synthetic substrate S-2238 (IC50 = 40 microM), and the thrombin-induced
      fibrinogen clotting (IC50 = 20 microM). The latter is completely reversed by
      albumin (30 mg mL(-1)) suggesting that, at therapeutic concentrations, suramin is
      unable to affect alpha-thrombin activity in the plasma. Kinetic analysis showed
      that suramin acts as a non-competitive inhibitor decreasing Vmax without changing
      the Km for S-2238 hydrolysis. Calorimetric studies revealed two distinct binding
      sites for suramin in alpha-thrombin. In addition, circular dichroism studies
      showed that suramin causes significant changes in alpha-thrombin tertiary
      structure, without affecting the secondary structure content. Interaction with
      alpha-thrombin resulted in an increased fluorescence emission of the drug.
      Complex formation was strongly affected by high ionic strength suggesting the
      involvement of electrostatic interactions. Altogether our data suggest that part
      of the biological activities of suramin might be related to alpha-thrombin
      inhibition at extra-vascular sites.

PMID- 15203121
TI  - Altered activities of cyclic nucleotide phosphodiesterases and soluble guanylyl
      cyclase in cultured RFL-6 cells.
AB  - We utilized rat fetal lung fibroblasts (RFL-6) to evaluate our PDE5 inhibitors at
      cellular level and observed a decrease in cGMP accumulation induced by sodium
      nitroprusside (SNP) and PDE5 inhibitors with passage. To further investigate this
      observation, we examined cGMP synthesis via soluble guanylyl cyclase (sGC) and
      degradation via phosphodiesterases (PDEs) at different passages. At passage (p)4,
      p9, p14, major cGMP and cAMP degradation activities were contributed by PDE5 and
      PDE4, respectively. The PDE5 activity decreased 50% from p4 to p14, while PDE4
      activity doubled. The cGMP accumulation was evaluated in the presence of sodium
      nitroprusside (SNP) and/or PDE inhibitors in p4 and p14 cells. SNP together with
      sildenafil, a PDE5 inhibitor, induced dose-dependent increase in cGMP levels in
      cells at p4, but showed little effect on cells at p14. The possible down
      regulation of sGC at mRNA level was explored using real-time RT-PCR. The result
      showed the mRNA level of the alpha1 subunit of sGC decreased about 98% by p9,
      while the change on beta1 mRNA was minimal. Consistently, sGC activities in cell
      lysate decreased by 94% at p9. Forskolin stimulated a dramatic increase in cAMP
      levels in cells at all passages examined. Our results show that sGC activity
      decreased significantly and rapidly with passage due to a down regulation of the
      alpha1 subunit mRNA, yet the adenylyl cyclase activity was not compromised. This
      study further emphasized the importance of considering passage number when using
      cell culture as a model system to study NO/cGMP pathway.

PMID- 15203122
TI  - Prolonged survival of mouse skin allografts after transplantation of fetal liver
      cells transduced with hIL-10 gene.
AB  - INTRODUCTION: Interleukin-10 (IL-10) is a cytokine with a moleculary weight of 18
      kDa, that was first identified as being produced by Th2 cells. It appears to have
      anti-inflammatory action by diminishing the production of pro-inflammatory
      cytokines produced by Th1 cells. IL-10 also regulates the differentiation and
      proliferation of several immune cells such as T cells, B cells, natural killer
      cells, antigen-presenting cells, mast cells and granulocytes. Recent data
      suggest, however, that IL-10 also has immunostimulatory properties with important
      consequences on the prognosis of disease. In this study, we demonstrate the
      importance of injection of hematopoietic fetal liver cells transduced with the
      human IL-10 (hIL-10) gene into an allogenic recipient subsequently transplanted
      with allogenic skin grafts. The immaturity of stem cells and precursor cells from
      fetal liver and their transient survival in the host, due to the production of
      hIL-10, may afford 'prope' tolerance. It also explains the lack of graft-vs.-host
      reaction (GvHR) and the delay in rejection of the specific donor skin grafts
      after virtual disappearance of donor hematopoietic cells. OBJECTIVES:
      Transduction of CBA hematopoietic fetal cells with the human IL-10 gene was used
      with the aim of inducing tolerance to donor antigen in recipient BALB/c mice. The
      observed effects were prolonged IL-10 production, donor cell chimerism in the
      host and delayed rejection of skin grafts from the specific donor strain.
      MATERIALS AND METHODS: To prevent or delay rejection of highly incompatible skin
      allografts, we used IL-10 gene transfer to establish chimerism with donor
      hematopoietic cells. Fetal liver cells from CBA mice were transduced with the
      human IL-10 gene and injected into BALB/c mice. RESULTS: Human IL-10, which is
      active in mice but does not cross-react with murine IL-10 in ELISA, was produced
      in vivo for 3 weeks. Donor cells were identified in the recipients during the
      same time period, on the basis of presence of the H-2 k gene and human IL-10
      intracellular protein. Skin allografts from CBA or C57BL/6 mice survived for a
      mean of 9.5 days in recipient mice injected with non-transduced cells. In
      contrast, survival of CBA allograft was extended to 18.9+/-1.8 days in recipients
      injected with hIL-10-transduced fetal liver cells from CBA mice. Human IL-10
      alone, without donor hematopoietic cell engraftment, did not prolong graft
      survival (9.6+/-1.2 days). CONCLUSIONS: IL-10 transduction of donor hematopoietic
      stem cells resulted in production of IL-10, cell engraftment and chimerism.
      Although full tolerance was not obtained at this level of donor cell development
      in the host, a specific and highly significant (P<0.001) prolongation of the
      survival of donor skin allografts was observed.

PMID- 15203123
TI  - Polyclonal antithymocyte globulins reduce the expression of IL-4 in a non-human
      primate model of ischemia-reperfusion injury.
AB  - Ischemia-reperfusion injury (IRI) is a non-specific, antigen independent event,
      which significantly influences the outcome of transplanted organs. Interleukin-4
      (IL-4) is an immunological mediator belonging to the interleukin family that
      mainly regulates the differentiation of T-helper lymphocytes into Th2 phenotype
      as well as enhances cellular activation, both are important features in IRI. The
      influence of polyclonal antithymocyte globulins (ATGs) on expression of IL-4 in
      reperfused tissues of cynomolgus monkeys (n=18) after 60 min of ischemia was
      assessed by immunohistochemical methods. Our results show an inhibition of the
      production and release of IL-4 by activated lymphocytes in the groups treated
      with ATGs in comparison to control, although a causal relationship between IL-4
      and tissue damage was not demonstrated. Implication of IL-4 as an inflammatory
      mediator upon IRI must be further investigated.

PMID- 15203124
TI  - Porcine cell microchimerism but lack of productive porcine endogenous retrovirus
      (PERV) infection in naive and humanized SCID-beige mice treated with porcine
      peripheral blood mononuclear cells.
AB  - Pigs are considered a suitable source of cells and organs for
      xenotransplantation. All known strains of pigs contain porcine endogenous
      retrovirus (PERV) and PERV released by porcine cells may infect human cells in
      vitro and severe-combined immunodeficient (SCID) mice in vivo. Humanized SCID (hu
      SCID) mice develop immune response to porcine antigens. Here we investigated PERV
      transmission in humanized SCID-beige mice using porcine peripheral blood
      mononuclear cells (PBMC) as the donor tissue (and the source of PERV). Mice were
      infused in the peritoneal cavity with 1.5-3.0 x 10(7) unfractionated human PBMC.
      Unfractionated porcine PBMC (1.5-3.0 x 10(7) cell/mouse) were infused to the mice
      simultaneously with human PBMC or 3 weeks after human PBMC infusion. The treated
      mice were monitored for weight and skin changes, donor cell chimerism, anti-pig
      antibodies and PERV transmission. All humanized mice tested 5-12 weeks after
      human PBMC transplantation were macrochimeric (up to 40% of cells in blood) for
      human cells, where 99% of the human cells were T-lymphocytes. Although human B
      lymphocytes were very rare in the blood of humanized mice at that point, the mice
      were positive for human anti-pig natural antibodies. The control SCID-beige mice
      or mice treated with porcine PBMC alone were negative for anti-porcine
      antibodies. Approximately 70% of the humanized mice treated with porcine PBMC
      were also microchimeric for porcine cells. Although some tissue samples of these
      mice were positive for PERV DNA in the absence of porcine DNA indicating PERV
      infection, the infection was non-productive as PERV transcripts were not
      detectable in those tissues. PERV infection of human and mouse cells in vitro by
      co-culturing with porcine PBMC was also non-productive. Humanized SCID-beige mice
      suffered weight loss and occasional minor skin changes due to graft vs. host
      disease caused by human PBMC but none of the mice showed observable effect
      attributable to the apparent PERV infection alone.

PMID- 15203125
TI  - Both T and non-T cells with proliferating potentials are effective in inducing
      suppression of allograft responses by alloantigen-specific intravenous
      presensitization combined with suboptimal doses of 15-deoxyspergualin.
AB  - In an MHC class I-disparate combination of mouse strains, a single intravenous
      injection of donor spleen cells combined with 10 suboptimal doses of 15
      deoxyspergualin (DSG) administration was effective in inducing donor-specific
      suppression of cytotoxic T-lymphocyte (CTL) responses and prolonged survival of
      the relevant skin allograft. Proliferative potentials of the donor spleen cells
      were requirement for the induction of suppressed allospecific responses, but both
      highly purified T cells and non-T cells were equally effective to induce the
      suppression of CTL responses by intravenous injection. These results have shown
      that, although working on different mechanisms, DSG is as effective as FK506 or
      rapamycin in inducing allograft tolerance when used at suboptimal doses along
      with the donor-specific intravenous presensitization, and an immune mechanism
      other than well-characterized veto T cells is working in this model in
      suppressing alloreactive CTL precursors.

PMID- 15203126
TI  - Induction of MIP-1alpha in Kupffer cell by portal venous transfusion.
AB  - INTRODUCTION: Previous studies have shown that portal venous transfusion (PVT)
      induces a state of immunosuppression, and Kupffer cells may be involved in the
      mechanism. OBJECTIVE: This study was aimed to investigate the effect of PVT on
      Kupffer cell gene expression. MATERIALS AND METHODS: Each BALB/C mouse was
      subjected to laparotomy and received one of five treatments: PVT, portal venous
      saline injection (PVS), inferior vena caval transfusion (IVCT), inferior vena
      caval saline injection (IVCS) or sham operation (S). The blood for PVT and IVCT
      was sampled from C57BL/6J mice. Kupffer cells were then isolated 1 or 24 h after
      each of the 5 treatments, for a total of 10 experimental groups (1-h PVT, PVS,
      IVCT, IVCS and S, and 24-h PVT, PVS, IVCT, IVCS and S) from BALB/C mice. To
      examine the effect of PVT on Kupffer cell gene expression, RT-PCR differential
      display was performed. RESULTS: Increase in the expression of MIP-1alpha mRNA
      post PVT and IVCT was identified by differential display. PVT groups revealed
      higher levels of serum MIP-1alpha than any other groups. CONCLUSION: These
      results suggest that MIP-1alpha may be involved in a cascade of signaling events
      associated with the PVT-mediated immunologic modulation in Kupffer cells.

PMID- 15203127
TI  - Effect of simvastatin in the treatment of highly sensitized dialysis patients:
      the pre and post-renal transplantation follow-up outcomes.
AB  - The graft survival rates of sensitized kidney recipients have been shown to be
      lower than non-sensitized patients. Therefore, panel reactive antibody (PRA) and
      cross-match determination is accepted as mandatory screening for renal
      transplantation candidates. Our recent previous study has shown that simvastatin
      had a significant immunosuppressive effect in PRA-positive and/or crossmatch
      positive patients. We present the pre and post-transplantation follow-up outcomes
      of simvastatin treatment in the highly sensitized dialysis patients. Thirty
      patients were followed for a mean period of 26 months. The PRA and flow
      cytometric measurements were performed at monthly intervals. Ten patients
      underwent successful kidney transplantation (eight living-related and two
      cadaveric). None of the patients developed hyperacute or acute rejection, and
      there was no graft loss during 19.8+/-6.2 months of post-transplantation follow
      up. Of the 18 patients who stayed on dialysis throughout the study with PRA
      positivity, six were lost to follow-up and three spontaneously stopped taking the
      simvastatin. In the latter three cases, the PRA levels rose significantly after
      the drug was discontinued. Eight of the remaining nine PRA-positive patients
      showed significant drops in mean PRA level over the study period, and entered the
      range considered acceptable for transplantation. Only one patient showed
      persistently high PRA levels throughout the study. In one patient, the drug had
      to be discontinued due to acute toxic hepatitis. In conclusion, the results
      indicate that continuous simvastatin therapy effective in immunized and highly
      sensitized dialysis patients. Meanwhile, it has beneficial effect on 1-year graft
      survival in sensitized renal transplantation group.

PMID- 15203128
TI  - IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced
      cell death and functional impairment in vitro and in vivo.
AB  - Protection of pancreatic islet beta cells from pro-inflammatory cytokines-induced
      cell death and functional impairment is a key issue in developing therapeutic
      interventions of type 1 diabetes mellitus including islet transplantation. The
      effects of IL-6 on the protection of beta cells in vitro and in vivo were
      examined. Freshly isolated islets or MIN6 beta cells, when pre-incubated with IL
      6, showed significantly higher viabilities measured by MTT assay and FACS
      analysis of PI stained cells against pro-apoptotic signaling delivered by IL
      1beta, TNF-alpha and IFN-gamma. Insulin secretory function was also significantly
      protected in static culture with glucose and KCl stimulation. In vivo assessment
      using marginal mass syngeneic islet transplantation in mouse model revealed IL-6
      conferred significantly better blood glucose control and graft survival rate over
      50 days. Conclusively, IL-6 protects pancreatic islets or beta-cells from
      inflammatory cytokines-induced cell death and functional impairment both in vitro
      and in vivo. This strategy could be exploited in the clinical setting to maintain
      functional islet mass.

PMID- 15203129
TI  - Ex vivo lymphocyte proliferative function is severely inhibited in renal
      transplant patients on mycophenolate mofetil treatment.
AB  - Mycophenolate mofetil (MMF) is a recently introduced immunosuppressive drug. Its
      active form is mycophenolic acid (MPA). MPA specifically inhibits de novo purine
      synthesis, which is vital for T and B lymphocyte proliferation. We measured
      lymphocyte subset numbers and mitogen induced proliferation in kidney transplant
      recipients on different combinations of MMF, cyclosporin A (C), azathioprine (A)
      and prednisolone (P) (C+A n=70; C+A+P n=15; C+MMF n=45; C+MMF+P n=37) and normals
      (n=73). Patients on MMF had severely reduced phytohaemagglutinin A (PHA) induced
      proliferation compared to normals (Nml 2766+/-926 CPM/1000 lymphocytes [mean+/
      S.D.]; C+MMF 282+/-406; C+MMF+P 195+/-496); non-MMF patients did not differ from
      normal. Similar inhibition of Poke Weed Mitogen and Staphylococcal enterotoxin B
      induced proliferation was observed. Cell cycle studies established that MMF
      patients had a significantly higher proportion of lymphocytes in the G0/G1 phase
      following PHA stimulation than the non-MMF patients. All transplant groups had
      significantly lower B cell numbers than the normal controls but no differences in
      CD4 and CD8 T cell numbers. All but the C+MMF group had significantly lower
      CD16+NK cell numbers than normal, while only the non-MMF groups had significantly
      lower CD56+NK cell numbers. The proliferation assay used was an ex vivo diluted
      whole blood technique. Removal of residual MPA by washing the plasma out prior to
      mitogen stimulation led to a significant increase in proliferation in six out of
      seven cases. In summary we have found that MMF treatment has a strikingly
      inhibitory effect on patient ex vivo lymphocyte mitogenic function.

PMID- 15203130
TI  - Anti-HLA antibody analysis and crossmatching in heart and lung transplantation.
AB  - Although the clinical significance of anti-HLA antibodies in heart and lung
      transplantation is less well studied than in renal transplantation, several
      studies have shown that heart and lung recipients transplanted in the presence of
      donor-specific antibodies are at increased risk for early acute rejection and
      have a lower graft survival. In an effort to avoid any increase in organ ischemia
      time, heart and lung candidates with anti-HLA antibodies have to be identified
      prior to transplantation and crossmatches performed with donor materials obtained
      prior to organ recovery. Both class I and II antibodies have been found to be
      associated with chronic rejection, defined in heart transplantation as transplant
      related coronary artery disease (TRCAV) and in lung transplantation as
      obliterative bronchiolitis (OB) or bronchiolitis obliterative syndrome (BOS).
      Post-transplant de novo development of donor antigen-specific class II antibodies
      has been found to be especially deleterious, significantly increasing the risk of
      chronic rejection and poor graft outcome. Based on the review of studies
      regarding the development of anti-HLA antibodies and thoracic organ allograft
      rejection several conclusions can be drawn. The presence of class I and II
      directed anti-HLA antibodies, detected by any method, are associated with acute
      and chronic rejection in heart and lung transplantation. Different therapeutic
      strategies have been used pre-transplantation to decrease the level of anti-HLA
      antibodies and post-transplantation to maintain low antibody levels or treat
      rejection, thereby improving graft outcome. Thus, monitoring the presence and the
      level of anti-HLA antibodies is prognostic of graft outcome and allows for
      measurement of therapeutic efficacy.

PMID- 15203131
TI  - Aggregation and G-quadruplex DNA-binding study of 6a,12a-diazadibenzo
      [a,g]fluorenylium derivative.
AB  - The aggregation and DNA binding behavior of a new G-quadruplex selective ligand,
      6a,12a-diazadibenzo-[a,g]fluorenylium derivative, was studied by UV-vis
      absorption and fluorescence spectroscopy. The formation of ligand aggregates with
      different spectral characteristics was observed at low and high concentration of
      NaCl, respectively. The ligand binds to G-quadruplex with much higher affinity
      than to single- and double-stranded DNA.

PMID- 15203132
TI  - Discovery of small molecule antagonists of TRPV1.
AB  - Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1)
      are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure
      activity relationship with several potent analogues identified. Pharmacological
      studies using electrophysiological and FLIPR Ca(2+) based assays showed compound
      5 was an antagonist versus capsaicin, noxious heat and acid mediated activation
      of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which
      compounds from this series cause inhibition via an extracellularly accessible
      binding site on the TRPV1 receptor.

PMID- 15203133
TI  - Biological evaluation of substituted quinolines.
AB  - Several quinolines were synthesized and evaluated in vitro against several
      parasites (Trypanosoma brucei, T. cruzi, Leishmania infantum, L. amazonensis,
      Plasmodium falciparum). Then, they were evaluated in vitro (at 10 microM),
      against HTLV-1 transformed cells. A few of them displayed interesting activities,
      comparable to the reference drugs.

PMID- 15203134
TI  - Synthesis and pharmacological evaluation of amide conjugates of NSAIDs with L
      cysteine ethyl ester, combining potent antiinflammatory and antioxidant
      properties with significantly reduced gastrointestinal toxicity.
AB  - The synthesis and pharmacological evaluation of a series of amide derivatives of
      NSAIDs with L-cysteine ethyl ester is described. The novel derivatives are potent
      antiinflammatory, antioxidant and hypocholesterolemic-hypolipidemic agents, while
      they demonstrate considerably reduced gastrointestinal toxicity. This molecular
      modification may offer a general route to safer antiinflammatory agents,
      potentially suitable for chronic use in conditions such as neurodegenerative
      disorders.

PMID- 15203135
TI  - Synthesis and evaluation of substrate-mimicking cytosolic phospholipase A2
      inhibitors--reducing the lipophilicity of the arachidonyl chain isostere.
AB  - The high lipophilicity of a series of cytosolic phospholipase A(2) inhibitors has
      been reduced by the modification of a decyloxyphenyl chain designed to mimic the
      arachidonyl group of the natural substrate. These changes have resulted in an
      improvement in the whole cell potency of the inhibitors.

PMID- 15203136
TI  - (+/-)8-Amino-5,6,7,8-tetrahydroisoquinolines as novel antinociceptive agents.
AB  - Several amine-substituted 8-amino-5,6,7,8-tetrahydroisoquinolines were examined
      as conformationally-constrained analogs of the nicotinic cholinergic (nACh) 3
      (aminomethyl)pyridines. Although these ligands failed to bind at nACh receptors,
      the N-ethyl-N-methyl analog 3d was found to be at least equipotent with nicotine
      in rodent tests of antinociception. The mechanism of action of 3d is currently
      unknown.

PMID- 15203137
TI  - Structural variations in keto-glutamines for improved inhibition against
      hepatitis A virus 3C proteinase.
AB  - A series of keto-glutamine tetrapeptide analogs containing a 2-oxo-pyrrolidine
      ring as a glutamine side chain mimic were synthesized with both R and S
      configuration at the beta-carbon. Compounds bearing a phthalhydrazide moiety show
      improved reversible inhibition of HAV 3C proteinase in the low micromolar range.

PMID- 15203138
TI  - Synthesis of nitrated indenoisoquinolines as topoisomerase I inhibitors.
AB  - Indenoisoquinolines and dihydroindenoisoquinolines have been synthesized
      possessing a nitro-substituted isoquinoline ring in an effort to explore the
      effects of electron-withdrawing substituents on biological activity. The in vitro
      anticancer activities of these molecules have been tested in the National Cancer
      Institute's screen of 55 cell lines. The compounds have also been tested for
      topoisomerase I (top1) inhibition. The results indicate that these substances are
      a potent class of top1 inhibitors with sub-micromolar cytotoxicity mean graph
      midpoints (MGM) and top1 inhibition equal to camptothecin.

PMID- 15203139
TI  - Antimitotic activity of glaupalol-related coumarins from Glaucidium palmatum.
AB  - Two new coumarins, glaumacidines A (1) and B (2), and the related coumarins (3-7)
      have been isolated from the rhizomes of Glaucidium palmatum (Glaucidiaceae). The
      absolute configurations of 1 and 2 and trans- and cis-glaupadiols (3 and 4,
      respectively) were elucidated by spectroscopic data, chemical derivatization, and
      exciton chirality method. Glaupalol (5) enhanced the polymerization of tubulin
      and affected synergistically with paclitaxel on inhibition of KB cell
      proliferation.

PMID- 15203140
TI  - Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin
      releasing factor-1 antagonists with adequate lipophilicity and water solubility.
AB  - In our efforts to identify potent CRF(1) antagonists with proper physicochemical
      properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups,
      such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized.
      Several positions of the core structure were identified, where a polar group was
      tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to
      have good binding affinity and potent antagonistic activity at the human CRF(1)
      receptor. Moreover, this compound had proper lipophilicity (log D = 2.78) and
      good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure
      when given orally.

PMID- 15203141
TI  - Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building
      block of piperazine-based CCR5 antagonists.
AB  - 4-Substituted-4-aminopiperidine is an interesting structural motif found in a
      number of bioactive compounds. An efficient and convenient method for the
      synthesis of 4-differently substituted-4-aminopiperidine derivatives was
      described, employing isonipecotate as a starting material and Curtius
      rearrangement as a key step. The alkylation of isonipecotate could introduce
      various substituents at the 4-position of the piperidine ring. With this key
      building block, we are able to efficiently synthesize piperazino-piperidine based
      CCR5 antagonist in a highly convergent manner free of using toxic reagents such
      as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5
      antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent
      yield using N'-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The
      new methodology provides a facile and practical access to the piperazino
      piperidine amide analogs as HIV-1 entry inhibitors.

PMID- 15203142
TI  - Novel delta2-isoxazolines as group II phospholipase A2 inhibitors.
AB  - The synthesized imidazolyl substituted delta2-isoxazolines were subjected to
      Phospholipase A(2) (PLA(2)) enzyme inhibitory activity against snake venom source
      and their structure-activity relationship with respect to different groups
      attached to this moiety is reported for the first time. The crystal structure of
      the compound 2-butyl-5-chloro-3H-imidazolyl-4-carbaldehyde oxime 2, an
      intermediate for the construction of isoxazolines is reported. These compounds
      exerted a significant PLA(2) enzyme inhibitory activity against group II PLA(2).
      The in vivo activity on mice of selected compounds 3bI and 3bIV shows the
      comparable anti-inflammatory activity with the known standard ursolic acid.

PMID- 15203143
TI  - Synthesis and antiangiogenic activity of exo-olefinated deoxoartemisinin
      derivatives.
AB  - 10-exo-Bromoalkylidene and benzylidene deoxoartemisinin derivatives with
      antiangiogenic activity were synthesized from corresponding 10-alkanesulfonyl
      dihydroartemisinin and 10-phenylmethanesulfonyl dihydroartemisinin using a highly
      efficient, mild, and simple Ramberg-Backlund rearrangement.

PMID- 15203144
TI  - Design, synthesis and cytotoxic studies on the simplified oxy analog of
      eleutherobin.
AB  - A straight forward entry into nine membered B ring of eleutherobin as oxy analog
      and its cyctotoxic properties on HBL cell lines is described. Molecular modeling
      studies were carried out to ascertain the binding of the model compound to the
      active site of beta-tubulin.

PMID- 15203145
TI  - Design, synthesis, and biological evaluation of novel T-Type calcium channel
      antagonists.
AB  - This paper describes the synthesis of several novel T-type calcium channel
      antagonists that inhibit calcium influx into the cell, which in turn regulates
      unknown aspects of the cell cycle pathway that are responsible for cellular
      proliferation. A library of compounds was synthesized and a brief structure
      activity relationship will be described. From these studies we have identified a
      compound (1) that displays anti-proliferative activity in the low micromolar
      range across a variety of cancer cell lines.

PMID- 15203147
TI  - QSAR of adenosine receptor antagonists. Part 3: Exploring physicochemical
      requirements for selective binding of 1,2,4-triazolo[5,1-i]purine derivatives
      with human adenosine A3 receptor subtype.
AB  - Considering potential of selective adenosine A3 receptor antagonists in the
      development of prospective therapeutic agents, an attempt has been made to
      explore selectivity requirements of 1,2,4-triazolo[5,1-i]purine derivatives for
      binding with cloned human adenosine A3 receptor subtype. In this study, partition
      coefficient (logP) values of the molecules (calculated by Crippen's fragmentation
      method) and Wang-Ford charges of the common atoms of the triazolopurine nucleus
      (calculated from molecular electrostatic potential surface of energy minimized
      geometry using AM1 technique) were used as independent variables along with
      suitable dummy parameters. The best equation describing A3 binding affinity
      [n=29, Q2=0.796, Ra2=0.853, R2=0.874, R=0.935, s=0.342, F=41.5 (df 4,24),
      SDEP=0.396] showed parabolic relation with logP (optimum value being 4.134).
      Further, it was found that an aromatic substituent conjugated with the triazole
      nucleus should be present at R2 position for A3 binding affinity. Again, high
      negative charges on N2 and N4 are conducive to the binding affinity. While
      exploring selectivity requirements of the compounds for binding with A3 receptor
      over that with A2A receptor, the selectivity relation [n=23, Q2=0.909, Ra2=0.918,
      R2=0.933, R=0.966, s=0.401, F=62.4 (df 4,18), SDEP=0.412] showed that an aromatic
      R2 substituent conjugated with the triazole nucleus contributes significantly to
      the selectivity. Again, presence of a 4-substituted-phenyl ring (except 4-OH
      phenyl and 4-CH3-phenyl) at R2 position also increases selectivity. Further,
      charge difference between N2 and N11 (negative charge on the former should be
      higher and that on the latter should be less) contributes significantly to the
      selectivity. In addition, negative charge on N7 is conducive while presence of
      substituents like propyl, butyl, pentyl or phenyl at R1 position is detrimental
      for the A3 selectivity.

PMID- 15203146
TI  - Inhibition of monoamine oxidases by coumarin-3-acyl derivatives: biological
      activity and computational study.
AB  - A series of coumarin-3-acyl derivatives have been synthesized and investigated
      for the ability to inhibit selectively monoamine oxidases. The coumarin-3
      carboxylic acids, 2a-e, proved to be reversible and selective inhibitors of the
      MAO-B isoform, displaying pIC(50) values of particular interest: 2a shows pIC(50)
      7.76 and a selectivity index (pS.I.) 2.94 and 2b shows pIC(50) 7.72 and a pS.I.
      of 2.80. The coumarin-3-acyl chlorides 3a-e showed high pIC(50) values against
      both MAO-A and MAO-B isoforms, 3d being the highest against MAO-B with a pIC(50)
      value of 8.00. In order to rationalize the activity/selectivity results,
      molecular descriptors were generated. Further insight about enzyme-inhibitor
      interaction was obtained by docking experiments with the MAO-B isoform.

PMID- 15203148
TI  - Molecular modeling on DNA cleavage activity of seryl-histidine and related
      dipeptide.
AB  - Molecular interaction between seryl-histidine (or seryl-histidine related
      dipeptides) and DNA model molecule 5'-TpTpdC-3' was studied by a molecular
      docking procedure. The key structural features of DNA cleaving activity were
      investigated.

PMID- 15203149
TI  - Structure-based design of amidinophenylurea-derivatives for factor VIIa
      inhibition.
AB  - The amidinophenylurea scaffold was earlier shown to provide an excellent template
      for the synthesis of novel and potent inhibitors of the blood coagulation factor
      VIIa. In this contribution we describe the structure-based design of potent
      ligands guided by X-ray crystallography, molecular modeling and docking studies.
      The design and synthetic efforts were directed towards novel modifications to
      explore the protease binding region close to the S4 subsite.

PMID- 15203150
TI  - Synthesis and biological evaluation of imidazole-based small molecule antagonists
      of the melanocortin 4 receptor (MC4-R).
AB  - A novel series of imidazole-based small molecule antagonists of the melanocortin
      4 receptor (MC4-R) is reported. Members of this series have been identified,
      which exhibit sub-micromolar binding affinity for the MC4-R, functional potency
      <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially
      useful in the therapeutic treatment of involuntary weight loss due to advanced
      age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.

PMID- 15203151
TI  - Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor
      through structure-based drug design and parallel synthesis.
AB  - Through structure-based drug design and parallel synthesis, we have discovered a
      novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines
      as guanidine bioisosteres. These compounds have been found to be highly potent,
      highly selective, and orally bioavailable.

PMID- 15203152
TI  - Glyco-optimization of aminoglycosides: new aminoglycosides as novel anti
      infective agents.
AB  - Glyco-optimization (OPopS) of aminoglycosides has been performed by replacing the
      existing sugar moiety with a variety of sugar derivatives. Glycosylation of the 6
      position of nebramine provided a library of novel 4,6-linked aminoglycosides
      (AMGs). Among them, compounds 8b,g,i,l, and 8u with 2"-amino, 2",3"-diamino,
      2",4"-diamino, 3",4"-diamino, 3"-amino groups, respectively, showed significant
      antimicrobial activity against Gram-(+) and -(-) bacteria. Several were
      particularly potent against Pseudomonus aeruginosa with MICs in the 1-2 microg/mL
      range.

PMID- 15203153
TI  - Structure activity studies of ring E analogues of methyllycaconitine. Part 2:
      Synthesis of antagonists to the alpha3beta4* nicotinic acetylcholine receptors
      through modifications to the ester.
AB  - The development of novel agents for the differentiation of neuronal nicotinic
      acetylcholine receptors (nAChRs) is important for the treatment of a variety of
      pathological conditions. We have prepared and evaluated a number of simpler
      analogues of the norditerpeniod alkaloid methyllycaconitine (MLA) in an effort to
      understand molecular determinants of nAChR*small molecule interactions. We have
      previously reported the synthesis and evaluation of a series of ring E analogues
      of MLA. We report here the optimization of the alpha3beta4* functional activity
      of this series of compounds through modification of the ester.

PMID- 15203154
TI  - Synthesis and antibacterial activity of O-substituted nocathiacin I derivatives.
AB  - The synthesis and antibacterial activity of a series of new nocathiacin I
      derivatives (1-12) containing polar water solubilizing groups is described. Most
      of these compounds exhibited potent antibacterial activity and have improved
      water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo
      activity.

PMID- 15203155
TI  - Estrogen receptor ligands. Part 5: The SAR of dihydrobenzoxathiins containing
      modified basic side chains.
AB  - Dihydrobenzoxathiin analogs (1-11) with modifications on the basic side chain
      region were prepared and evaluated for estrogen/anti-estrogen activity in both in
      vitro and in vivo models. The compounds generally maintained a high degree of
      selectivity for ERalpha over ERbeta, similar to the original lead compound I.
      Many of the compounds also maintained high potency in the inhibition of human
      carcinoma MCF-7 cell growth. However, all were less potent in the inhibition of
      estradiol-triggered uterine growth. This work demonstrates the sensitive nature
      of modification to the antagonist basic side chain region.

PMID- 15203156
TI  - Estrogen receptor ligands. Part 6: Synthesis and binding affinity of
      dihydrobenzodithiins.
AB  - Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the
      dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor
      Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high
      degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo
      antagonism/agonism activity exhibited by the lead class in an immature rat
      uterine growth model.

PMID- 15203157
TI  - Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic
      and heterocyclic sulfonamides: a novel target for the drug design.
AB  - The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII
      (CA XIII) has been investigated with a series of aromatic and heterocyclic
      sulfonamides, including some of the clinically used derivatives, such as
      acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib.
      Inhibition data for the physiologically relevant isozymes I and II (cytosolic
      forms) and the tumor associated isozyme IX (transmembrane) were also provided for
      comparison. A very interesting and unusual inhibition profile against CA XIII
      with these sulfonamides has been observed. The clinically used compounds (except
      valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with
      Ki's in the range of 17-23 nM, whereas sulfanilamide, halogenated sulfanilamides,
      homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were
      slightly less effective, with Ki's in the range of 32-56 nM. Several low
      nanomolar (Ki's in the range of 1.3-2.4 nM) CA XIII inhibitors have also been
      detected, all of them belonging to the sulfanilyl-sulfonamide type of inhibitors,
      of which aminobenzolamide is the best known representative. Because CA XIII is an
      active isozyme predominantly expressed in salivary glands, kidney, brain, lung,
      gut, uterus, and testis, where it probably plays an important role in pH
      regulation, its inhibition by sulfonamides may lead to novel therapeutic
      applications for this class of pharmacological agents.

PMID- 15203158
TI  - Halothiophene benzimidazoles as P1 surrogates of inhibitors of blood coagulation
      factor Xa.
AB  - Neutral weak halothiophene benzimidazole inhibitors of the serine protease factor
      Xa were identified via screening of a compound library. The X-ray crystal
      structure of representative 3a bound to human fXa confirmed the S1 binding mode.
      Starting from 3a a series of halothiophene benzimidazoles was synthesized and
      investigated for their factor Xa inhibitory activity. This led to potent and
      selective achiral inhibitors against fXa such as compounds 9k and 9w.

PMID- 15203159
TI  - A new family of quinoline and quinoxaline analogues of combretastatins.
AB  - The 3-hydroxy-4-methoxyphenyl ring of combretastatin A-4 can be replaced by a 2
      naphthyl moiety without significant loss of cytotoxicity and inhibition of
      tubulin polymerization potency. In this paper we show that the 6- or 7-quinolyl
      systems can in turn replace both cyclic moieties, keeping in the first case most
      of the potency as cytotoxic agent and in the second case as inhibitor of tubulin
      polymerization, related to the activities displayed by model compounds.

PMID- 15203160
TI  - Structure-activity relationships of adenosine A3 receptor ligands: new potential
      therapy for the treatment of glaucoma.
AB  - Structure-activity relationships (SAR) of fused 1,2,4-triazolo[1,5-c ]pyrimidine
      were performed. Various substituents were introduced into the heterocyclic ring
      to improve the potency of adenosine A(3) receptor binding affinity and A(3)
      selectivity against other subtypes. Potent and selective A(3) receptor
      antagonists were identified and were evaluated in a monkey model of intraocular
      pressure by eye-drop administration. As a result, compound 1c (OT-7999) was found
      to significantly decrease intraocular pressure in the animal model.

PMID- 15203161
TI  - (+)-3-[2-(Benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane as potent
      agonists for the alpha7 nicotinic acetylcholine receptor.
AB  - A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the alpha7
      nicotinic acetylcholine (alpha7) receptor agonists. It was found that (+)-3-[2
      (benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent
      agonistic activity for the alpha7 receptor.

PMID- 15203162
TI  - Synthesis of a bromotyrosine-derived natural product inhibitor of mycothiol-S
      conjugate amidase.
AB  - Recently we described the structures of two new bromotyrosine-derived alkaloids
      that inhibit the detoxification enzyme mycothiol-S-conjugate amidase (MCA) from
      Mycobacterium tuberculosis. Here we describe a concise total synthesis of
      bromotyrosine oxime 1. The six-step synthesis of 1 utilized a
      trifluoromethyloxazole intermediate, whose hydrolysis product underwent
      alkylation and coupling to agmatine to give the inhibitor in approximately 40%
      overall yield. Oxime 1 inhibited MCA and its homolog AcGI deacetylase with IC(50)
      values of 30 and 150 microM, respectively.

PMID- 15203163
TI  - Specific inhibition effects of N-pentafluorobenzyl-1-deoxynojirimycin on human
      CD4+ T cells.
AB  - We first synthesized N-pentafluorobenzyl-1-deoxynojirimycin (5F-DNM), one new
      derivative of 1-deoxynojirimycin (DNM). Effects on human peripheral blood
      mononuclear cells (PMBC) and secretion of cytokines from human PBMC by 5F-DNM
      were investigated. It was first found that 5F-DNM remarkably inhibited the
      secretion of interleukin-4 (IL-4) and had a specific inhibition on the expression
      of CD4 molecules. 5F-DNM, much less toxic than cyclosporin A, might be used as a
      new candidate of immunosuppressant for specifically treating Th2-mediated immune
      diseases.

PMID- 15203164
TI  - Structure-affinity relationships of 5'-aromatic ethers and 5'-aromatic sulfides
      as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic
      agents.
AB  - Atrial fibrillation (AF) is the most commonly encountered sustained clinical
      arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine
      receptor agonists can slow the electrical impulse propagation through the
      atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in
      prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce
      ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor
      can cause high grade AV block. Therefore, it is envisioned that a compound that
      is a partial agonist of the A(1) adenosine receptor could avoid this deleterious
      effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers
      (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal
      effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding
      data suggesting partial activity of the A(1) adenosine receptor, and PK results
      for 5(') modified adenosine derivatives are shown.

PMID- 15203165
TI  - Synthesis and structure-activity relationship of novel benzoxazole derivatives as
      melatonin receptor agonists.
AB  - A series of benzoxazole derivatives was synthesized and evaluated as
      melatoninergic ligands. The binding affinity of these compounds for human MT(1)
      and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the
      radioligand. From this series of benzoxazole derivatives, compounds 14 and 17
      were identified as melatonin receptor agonists.

PMID- 15203166
TI  - DNA sequence recognition in the minor groove by hairpin pyrrole polyamide-Hoechst
      33258 analogue conjugate.
AB  - A hairpin pyrrole polyamide conjugated to a Hoechst 33258 (Ht) analogue, PyPyPy
      gamma-PyPyPy-gamma-Ht, was synthesized on solid-phase by adaptation of an Fmoc
      technique using a series of PyBOP/HOBt mediated coupling reactions. Sequence
      selectivity and complex stabilities were characterized by spectrofluorometric
      titrations and thermal melting studies. The polyamide of the conjugate was
      observed to bind in a hairpin motif forming 1:1 conjugate:dsDNA complexes. The
      conjugate is able to recognize nine contiguous A/T bps, discriminating from the
      sequences containing fewer than nine contiguous A/T bps.

PMID- 15203167
TI  - Synthesis and antibacterial activity of novel bifunctional macrolides.
AB  - We report the discovery of a novel class of macrolide antibiotics that have
      improved antibacterial activity against Ery-resistant organisms.

PMID- 15203168
TI  - Synthesis of a key Mycobacterium tuberculosis biosynthetic phosphoinositide
      intermediate.
AB  - Regioselective mannosylations of a myoinositol acceptor diol are readily achieved
      by Lewis acid mediated iodinolysis of n-pentenyl ortho-esters. The procedure
      affords a psuedotrisaccharide to which the phosphoglyceryl and other lipid
      residues are added leading to the key biosynthetic intermediate of Mycobacterium
      species.

PMID- 15203169
TI  - Amidine derived 1,3-diazabuta-1,3-dienes as potential antibacterial and
      antifungal agents.
AB  - Several 1-aryl-2-phenyl-4-piperidino-4-thioalkyl-1,3-diazabuta-1,3-dienes were
      prepared by the treatment of N-arylimino isothiocyanate with piperidine followed
      by S-alkylation with alkyl iodides in the presence of dry acetone and potassium
      hydroxide. The constitution of the products was supported by IR, PMR and mass
      spectral study. The compounds synthesized were tested in in vitro against E.
      coli, S. aureus, P. aeruginosa, B. cereus and B. subtilis and fungal stains,
      Candida albicans and Aspergillus niger. Standard drugs were also tested under
      identical conditions for comparing the results.

PMID- 15203170
TI  - Novel dual inhibitors of calpain and lipid peroxidation.
AB  - A series of molecules with dual inhibitory activities on calpain and lipid
      peroxidation were synthesized. These hybrid compounds were built on the calpain
      pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l
      leucine linker. Compound 7, the most potent in cellular calpain and lipid
      peroxidation inhibitions, provided effective protection against glial cell death
      induced by maitotoxin.

PMID- 15203171
TI  - Design, synthesis, and evaluation of estradiol-linked genotoxicants as anti
      cancer agents.
AB  - A series of bifunctional compounds was prepared consisting of 17beta estradiol
      linked to a DNA damaging N,N-bis-(2-chloroethyl)aniline. The objective of our
      studies was to determine the characteristics of the linker that permitted both
      reaction with DNA and binding of the resultant covalent adducts to the estrogen
      receptor. Linker characteristics were pivotal determinants underlying the ability
      of the compounds to kill selectively breast cancer cells that express the
      estrogen receptor.

PMID- 15203172
TI  - Quinoxaline N,N'-dioxide derivatives and related compounds as growth inhibitors
      of Trypanosoma cruzi. Structure-activity relationships.
AB  - Quinoxaline derivatives presented good inhibitor activity of growth of
      Trypanosoma cruzi in in vitro assays. The 50% inhibitory doses were of the same
      order of that of Nifurtimox. Derivative 13, a quinoxaline N,N'-dioxide
      derivative, and the reduced derivatives 19 and 20 were the most cytotoxic
      compounds against the protozoan. Structural requirements for optimal activity
      were studied by computational methods. From statistical analysis we could
      establish a multiple correlation between activity and lipophilic properties and
      LUMO energy.

PMID- 15203173
TI  - Yeast and mammalian alpha-glucosidase inhibitory constituents from Himalayan
      rhubarb Rheum emodi Wall.ex Meisson.
AB  - The methanolic extract of rhizome of Himalayan rhubarb Rheum emodi displayed mild
      yeast as well as mammalian intestinal alpha-glucosidase inhibitory activity.
      However, further fractionation of active extract led to the isolation of several
      potent molecules in excellent yields, displaying varying degrees of inhibition on
      two test models of alpha-glucosidase. Rhapontigenin, desoxyrhapontigenin,
      chrysophanol-8-O-beta-d-glucopyranoside, torachrysone-8-O-beta-d-glucopyranoside
      displayed potent yeast alpha-glucosidase inhibition. However chrysophanol-8-O
      beta-d-glucopyranoside, desoxyrhaponticin and torachrysone-8-O-beta-d
      glucopyranoside displayed potent to moderate mammalian alpha-glucosidase
      inhibitory activity. Other compounds displayed mild activity on both the tests.
      Except desoxyrhapontigenin and rhapontigenin that increased Vmax, other compounds
      including crude extract decreased the Vmax significantly (p<0.02) in yeast alpha
      glucosidase test. Further kinetic analysis on mammalian alpha-glucosidase
      inhibition showed that chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin
      and torachrysone-8-O-beta-d-glucopyranoside may be classified as mixed
      noncompetitive inhibitors. However, desoxyrhapontigenin and rhapontigenin may be
      classified as modulators of enzyme activity. Presence and position of glycoside
      moiety in compounds appear important for better inhibition of mammalian alpha
      glucosidase. This is the first report assigning particularly, mammalian
      intestinal alpha-glucosidase inhibitory activity to these compounds. Chrysophanol
      8-O-beta-d-glucopyranoside, desoxyrhaponticin, desoxyrhapontigenin and
      rhapontigenin have been isolated in substantial yields from R. emodi for the
      first time. Therefore, these compounds may have value in the treatment and
      prevention of hyperglycemia associated diabetes mellitus.

PMID- 15203174
TI  - Prenatal marijuana and alcohol exposure and academic achievement at age 10.
AB  - The effects of prenatal marijuana and alcohol exposure on school achievement at
      10 years of age were examined. Women were interviewed about their substance use
      at the end of each trimester of pregnancy, at 8 and 18 months, and at 3, 6, 10,
      14, and 16 years. The women were of lower socioeconomic status, high-school
      educated, and light-to-moderate users of marijuana and alcohol. The sample was
      equally divided between Caucasian and African-American women. At the 10-year
      follow-up, the effects of prenatal exposure to marijuana or alcohol on the
      academic performance of 606 children were assessed. Exposure to one or more
      marijuana joints per day during the first trimester predicted deficits in Wide
      Range Achievement Test-Revised (WRAT-R) reading and spelling scores and a lower
      rating on the teachers' evaluations of the children's performance. This relation
      was mediated by the effects of first-trimester marijuana exposure on the
      children's depression and anxiety symptoms. Second-trimester marijuana use was
      significantly associated with reading comprehension and underachievement.
      Exposure to alcohol during the first and second trimesters of pregnancy predicted
      poorer teachers' ratings of overall school performance. Second-trimester binge
      drinking predicted lower reading scores. There was no interaction between
      prenatal marijuana and alcohol exposure. Each was an independent predictor of
      academic performance.

PMID- 15203175
TI  - Effects of prenatal marijuana on response inhibition: an fMRI study of young
      adults.
AB  - The neurophysiological effects of prenatal marijuana exposure on response
      inhibition were assessed in 18- to 22-year-olds. Thirty-one participants from the
      Ottawa Prenatal Prospective Study (OPPS) performed a blocked design Go/No-Go task
      while neural activity was imaged with functional magnetic resonance imaging
      (fMRI). The OPPS is a longitudinal study that provides a unique body of
      information collected from each participant over 20 years, including prenatal
      drug history, detailed cognitive/behavioral performance from infancy to young
      adulthood, and current and past drug usage. The fMRI results showed that with
      increased prenatal marijuana exposure, there was a significant increase in neural
      activity in bilateral prefrontal cortex and right premotor cortex during response
      inhibition. There was also an attenuation of activity in left cerebellum with
      increased prenatal exposure to marijuana when challenging the response inhibition
      neural circuitry. Prenatally exposed offspring had significantly more commission
      errors than nonexposed participants, but all participants were able to perform
      the task with more than 85% accuracy. These findings were observed when
      controlling for present marijuana use and prenatal exposure to nicotine, alcohol
      and caffeine, and suggest that prenatal marijuana exposure is related to changes
      in neural activity during response inhibition that last into young adulthood.

PMID- 15203176
TI  - Spatial acquisition in the Morris water maze and hippocampal long-term
      potentiation in the adult guinea pig following brain growth spurt--prenatal
      ethanol exposure.
AB  - Previous work has demonstrated that in the guinea pig, chronic prenatal ethanol
      exposure throughout gestation can result in deficits in spatial learning in the
      Morris water maze and impaired hippocampal long-term potentiation (LTP). The
      behavioural effects are known to be dose dependent because water maze deficits
      occur at a dose of 4 g ethanol/kg maternal body weight/day, but not at a dose of
      3 g/kg/day, administered throughout gestation. It is possible that the gradual,
      progressive development of tolerance to ethanol throughout gestation limits
      ethanol toxicity, especially for lower doses of ethanol. The present study
      examined whether neurobehavioural deficits are produced by prenatal ethanol
      exposure at a dose of 3 g/kg/day, administered only during the brain growth spurt
      (BGS), a regimen designed to limit the development of ethanol tolerance. Pregnant
      guinea pigs [term, about gestational day (GD) 68] received oral administration of
      ethanol (1.5 g/kg maternal body weight/day on GD 43 and 44 and then 3 g/kg
      maternal body weight/day from GD 45 to 62), isocaloric-sucrose/pair-feeding, or
      water. Offsprings were studied between postnatal days (PD) 40 and 80. The
      maternal blood ethanol concentration (BEC) on GD 57 or 58, at 1 h after the daily
      dose, was 245+/-19 mg/dl (n=7). This BGS--prenatal ethanol exposure regimen did
      not affect spatial learning performance in the Morris water maze over a 7-day
      test period or in the LTP recorded in the CA1 region of the hippocampus. Thus,
      even when limiting the development of ethanol tolerance seen with chronic ethanol
      treatment throughout gestation, ethanol exposure during the BGS does not result
      in deficits in the behavioural and electrophysiological measures of hippocampal
      integrity assessed in the present study. These data indicate that in the guinea
      pig, the BGS may not constitute a critical period of vulnerability for ethanol
      induced deficits in spatial learning or hippocampal synaptic plasticity in young
      adult offspring.

PMID- 15203177
TI  - Prenatal exposure to methylmercury and child development: influence of social
      factors.
AB  - BACKGROUND: In the Seychelles Child Development Main Study (SCDS), at 19 months
      of age, enhanced MDI scores were associated with increasing methylmercury (MeHg)
      exposure in higher caregiver IQ groups at several levels of family income. We
      performed a similar analysis of the 66-month evaluations to determine if the
      modifying influences of social and environmental factors were consistent with
      those previously observed. METHODS: Prenatal MeHg exposure was determined by
      analysis of maternal hair growing during pregnancy. Children in the cohort
      (N=711) were evaluated for cognitive ability (McCarthy Scales of Children's
      Abilities), language development (Preschool Language Scale), drawing and copying
      (Bender Gestalt Test), scholastic achievement (the Woodcock-Johnson Test of
      Achievement), and behavior (the Child Behavior Checklist). Interactions between
      prenatal MeHg exposure and caregiver intelligence, socioeconomic status (SES),
      home environment, and gender were examined by multiple regression analysis.
      RESULTS: The median prenatal MeHg exposure was 5.9 ppm (range=0.5-26.7 ppm).
      Gender significantly influenced the association between prenatal exposure and
      drawing and copying; however, the effects were not consistent. Prenatal exposure
      interacted with one or more social or environmental covariates for general
      cognitive ability, overall language ability, and prearithmetic achievement.
      Again, the effects were not consistent across either endpoints or covariate
      categories. CONCLUSIONS: Evidence of a small influence by social and
      environmental variables at 66 months is neither internally consistent nor
      consistent with earlier results. Overall, a consistent pattern of effect
      modification (EM) has not been observed, suggesting that the results may be due
      to chance.

PMID- 15203178
TI  - Postnatal haloperidol eliminates the deficit in circling behavior produced by
      prenatal exposure to the same drug.
AB  - Up to 35% of pregnant women take psychotropic drugs at least once during
      gestation [Austin and Mitchell, 1998]. From concurrent animal and human evidence,
      it has been proposed that exposure to several psychoactive medications in utero
      or during lactation increases the risk for permanent brain disorders. Present
      preventive or therapy practices applied on humans for this type of long-lasting
      behavioral alterations are mainly based on empirical results. Here, we test an
      experimental approach designed to counteract a circling performance deficit that
      appears in Sprague-Dawley rats at puberty on exposure to the dopaminergic blocker
      haloperidol (HAL) during gestation [J.L. Bruses, J.M. Azcurra, The circling
      training: A behavioral paradigm for functional teratology testing, in: P.M. Conn
      (Ed.), Paradigms for the study of behavior, Acad. Press, New York, 1993, pp. 166
      179. Method Neurosci. 14]. Gestational exposure to HAL (GD 5-18, 2.5 mg/kg/day
      ip) induced the expected circling activity decrease in the offspring at the fifth
      week of life. When prenatal exposure to HAL was continued through lactation (PD5
      21, 1.5 mg/kg/day ip), rats otherwise showed a control-like circling performance.
      No difference was yet found between lactation-only, HAL-exposed pups and saline
      (SAL)-treated controls (n=8 each group). We further performed saturating (3H)
      spiroperidol (SPI) binding assays on striatal P2 membrane fractions 2 months
      later. The dopamine-type D2-specific binding results suggested that above
      circling behavior findings could be partially explained by enduring HAL-induced
      neurochemical changes. The role of critical periods of sensitivity as transient
      windows for opportunistic therapies for behavioral teratology is discussed.

PMID- 15203179
TI  - The relationship between hyperthermia and glycogenolysis in 3,4
      methylenedioxymethamphetamine-induced serotonin depletion in rats.
AB  - Although the exact mechanisms involved in the serotonergic neurotoxicity produced
      by substituted amphetamines are not completely known, evidence suggests that
      oxidative and/or bioenergetic stress may contribute in the mechanism of
      neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA). It has been postulated
      that MDMA-induced hyperthermia also contributes to the MDMA-induced
      neurotoxicity. MDMA produces brain glycogenolysis, and MDMA-induced hyperthermia
      appears to mediate this effect. The relationship of MDMA-induced hyperthermia and
      glycogenolysis in the serotonergic neurotoxicity of MDMA was investigated in the
      present study. The administration of MDMA (20 mg/kg sc) at an ambient temperature
      of 24 degrees C produced hyperthermia and brain glycogenolysis in Postnatal Day
      (PND)21 and PND70 rats; however, long-term reductions in serotonin (5-HT)
      concentrations in the striatum were detected only in the PND70 rats. Treatment of
      PND21 and PND70 rats with MDMA at 17 degrees C resulted in neither hyperthermia
      nor glycogenolysis; nevertheless, long-term reductions in 5-HT concentrations
      were still evident in the PND70 rats treated with MDMA. These results support the
      conclusion that hyperthermia, as well as glycogenolysis, are neither necessary
      nor sufficient in the serotonergic neurotoxicity of MDMA.

PMID- 15203180
TI  - Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced rat fetal brain
      lesions.
AB  - 1-beta-D-Arabinofuranosylcytosine (Ara-C), a cytidine analogue cytotoxic to
      proliferating cells, has a teratogenic effect in the brain of experimental
      animals and causes neural cell apoptosis in vitro and in vivo. In the present
      study, pregnant rats were injected with Ara-C on Day 13 of gestation and the
      fetal brain was collected from 1 to 48 h after treatment. Histopathological
      examinations revealed marked induction of apoptotic cell death and decrease of
      mitosis in neuroepithelial cells in the brain of Ara-C-treated fetus, and these
      changes were most prominent from 9 to 12 h. Expression of p53 protein, which
      mediates apoptosis and cell cycle arrest after DNA damage, was elevated
      remarkably and peaked at 3 h. p21, a cyclin-dependent kinase inhibitor
      responsible for p53-mediated cell cycle arrest, showed intense overexpression in
      protein and mRNA levels following the increase of p53 protein. The mRNA
      expressions of other p53 transcriptional target genes, bax, cyclinG1, and fas,
      also significantly increased and peaked at around 9 h. In conclusion, prenatal
      treatment of Ara-C is thought to induce apoptosis and inhibition of cell
      proliferation mediated by p53 and its target genes in the fetal brain.

PMID- 15203181
TI  - Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient
      mice.
AB  - gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the
      mammalian central nervous system. Gene targeting of GABA-synthetic glutamic acid
      decarboxylase (GAD) 67 and GABAA receptor beta(3) subunit induces cleft palate in
      the mouse. These findings appear to contradict previous pharmacological
      investigations using benzodiazepines and GABA itself, which indicate that GABA
      suppresses palatogenesis. Therefore, the effects of picrotoxin and 3
      mercaptopropionic acid (3-MP) on palate formation were investigated in the
      present study. Picrotoxin and 3-MP impair GABA functions by blocking the GABA
      receptor and synthesis, respectively. Pregnant mice in the critical period
      [Embryonic Day (E) 11-15] of palatogenesis were administered these substances by
      subcutaneous injection or continuous infusion at subconvulsive doses, and their
      fetuses at E17-18 were investigated. A complete cleft in the secondary palate was
      observed in 15% of 333 embryos in 28 litters. In the remaining fetuses, a
      complete cleft palate was not observed, but microscopic examination of serial
      sections revealed partial defects of the palate. Furthermore, rescue from cleft
      palate in GAD67-deficient mice was attempted by GABA infusion. Horizontal
      elevation of palatal shelves, which is not observed in nontreated mice, did occur
      after the infusion in all 14 GABA-infused GAD67-deficient fetuses, although cleft
      palate still persisted. These results indicate that GABA is required for
      palatogenesis and is consistent with findings in gene knockout mice.

PMID- 15203182
TI  - A population-based case-control study of oral chlordiazepoxide use during
      pregnancy and risk of congenital abnormalities.
AB  - The objective of the study was to check the human teratogenic potential of oral
      chlordiazepoxide treatment during pregnancy at the analysis of pairs of 22,865
      cases with congenital abnormalities (CAs) and 38,151 matched healthy controls in
      the population-based data set of the Hungarian Case-Control Surveillance of
      Congenital Abnormalities (HCCSCA) between 1980 and 1996. Two hundred and one
      (0.9%) case mothers and 268 (0.7%) control mothers had chlordiazepoxide treatment
      during pregnancy, respectively. Our analysis showed higher odds ratio (OR) with
      95% confidence interval (CI; 2.5, 1.0-6.0) for chlordiazepoxide use during the
      2nd-3rd month of gestation in the group of congenital cardiovascular
      malformations. However, this association was found when exposure data were based
      mainly on maternal self-reported chlordiazepoxide treatments (80% in cases and
      71% in controls). There was no increase in the rate of any specific congenital
      cardiovascular malformation type. In conclusion, therapeutic doses of
      chlordiazepoxide during pregnancy are unlikely to pose a substantial teratogenic
      risk to the human fetus, although a somewhat higher rate of congenital
      cardiovascular malformations cannot be excluded.

PMID- 15203183
TI  - Effects of 2,4-dichlorophenoxyacetic acid exposure on dopamine D2-like receptors
      in rat brain.
AB  - 2,4-Dichlorophenoxyacetic acid (2,4-D), a worldwide-used herbicide, has been
      associated with a range of adverse health effects on humans and different animal
      species. Although the mechanism of 2,4-D neurotoxicity remains unknown, we had
      previously reported changes in various neurotransmitter systems, such as
      serotonin (5-HT) and dopamine (DA), which were proposed to mediate some of the
      behavioral effects in rats. In the present work, we examined the impact of 2,4-D
      exposure on the ontogeny of dopaminergic D2-type receptors in prefrontal cortex
      (PFc), striatum (CPu), hippocampus (H) and cerebellum (Cer). Pregnant rats were
      orally exposed to 70 mg/kg/day of 2,4-D from gestation day (GD) 16 to postpartum
      day 23. After weaning, the pups were assigned to one of the two subgroups: T1
      [fed with untreated diet until postnatal day, (PD) 90] and T2 [maintained with
      2,4-D diet until PD 90]. Five to eight pups per age and sex were sacrificed at 6,
      15, 30, 45 or 90 days of age for membrane receptor binding assays employing
      [3H]nemonapride. Subchronic 2,4-D exposure (T2 group) increased DA D2-type
      receptor around 40% in CPu. In addition, DA D2-type receptor levels also
      increased in PFc (15 and 30 days) and Cer (30 and 90 days). Sex-dependent
      differences in D2 receptors were observed with T2 female rats being more affected
      than T2 male rats. When the herbicide treatment was interrupted after weaning (T1
      group), DA D2-type receptor density was apparently recovered and stabilized to
      control level. These findings suggest a reversible vulnerability of D2-type
      receptors to 2,4-D exposure. Regional increases of D2-type receptor density may
      explain certain behaviors reported early by us, such as catalepsy and right
      turning preference in rats exposed to 2,4-D.

PMID- 15203184
TI  - Prenatal exposure to dichlorvos: physical and behavioral effects on rat
      offspring.
AB  - The effects of prenatal exposure to dichlorvos (DDVP), an organophosphate (OP)
      pesticide, on pups' physical and neurobehavioral developments were investigated.
      Forty pregnant rats were treated by gavage with 8.0 mg/kg DDVP or its vehicle (1
      ml/kg) from the 6th to the 15th day of pregnancy. At birth, pups were weighed,
      the litters culled to eight animals (four male and four female), and then
      observed for physical (pinna detachment, incisor eruption, eye opening, testes
      descent, and vaginal opening) and neurobehavioral developments (palmar grasp,
      surface righting, negative geotaxis, and open-field behaviors). As adults, open
      field, apomorphine-induced stereotypy, and passive avoidance behaviors were also
      assessed. Results showed no differences between the body weight of DDVP and
      control-treated groups. No differences were observed on the measures of physical
      and neurobehavioral development. Locomotor activity of male pups at 21 days of
      age was decreased by DDVP exposure. Adult experimental offspring showed a
      decreased locomotor frequency and an increased immobility duration on open-field
      behavior in relation to control animals; the apomorphine-induced stereotyped
      behavior was decreased by the pesticide exposure as well as performance on the
      passive avoidance task. These data suggest that prenatal DDVP exposure was able
      to decrease offspring motor function (adolescence and adults) and conditioned
      response learning, probably by interference with the cholinergic-dopaminergic
      balance of activity involved with the control of motor function as well as the
      cholinergic system that modulates learning process.

PMID- 15203185
TI  - Isolation of long-lived mutants in Caenorhabditis elegans using selection for
      resistance to juglone.
AB  - The accumulation of molecular damage from attack by reactive oxygen species is
      one cause of aging. Therefore, some mutant organisms showing increased resistance
      to reactive oxygen species should live longer. We show that selection for
      Caenorhabditis elegans mutants that are resistant to juglone, a reactive oxygen
      species-generating compound, leads to the identification of long-lived mutants.
      Indeed, four of six resistant mutants isolated were also long-lived. This study
      illustrates once more the strong relationship between oxidative stress and the
      aging processes.

PMID- 15203186
TI  - Thiocyanate catalyzes myeloperoxidase-initiated lipid oxidation in LDL.
AB  - There is evidence that LDL oxidation may render the lipoprotein atherogenic. The
      myeloperoxidase-hydrogen peroxide (MPO/H2O2) system of activated phagocytes may
      be involved in this process. Chloride is supposed to be the major substrate for
      MPO, generating reactive hypochlorous acid (HOCl), modifying LDL. The pseudo
      halide thiocyanate (SCN-) has been shown to be a suitable substrate for MPO,
      forming reactive HOSCN/SCN*. As relatively abundant levels of SCN- are found in
      plasma of smokers--a well-known risk group for cardiovascular disease--the
      ability of SCN- to act as a catalyst of LDL atherogenic modification by MPO/H2O2
      was tested. Measurement of conjugated diene and lipid hydroperoxide formation in
      LDL preparations exposed to MPO/H2O2 revealed that SCN- catalyzed lipid oxidation
      in LDL. Chloride did not diminish the effect of SCN- on lipid oxidation.
      Surprisingly, SCN inhibited the HOCl-mediated apoprotein modification in LDL.
      Nitrite--recently found to be a substrate for MPO--showed some competing
      properties. MPO-mediated lipid oxidation was inhibited by heme poisons (azide,
      cyanide) and catalase. Ascorbic acid was the most effective compound in
      inhibiting the SCN- -catalyzed reaction. Bilirubin showed some action, whereas
      tocopherol was ineffective. When LDL oxidation was performed with activated human
      neutrophils, which employ the MPO pathway, SCN- catalyzed the cell-mediated LDL
      oxidation. The MPO/H2O2/SCN- system may have the potential to play a significant
      role in the oxidative modification of LDL--an observation further pointing to the
      link between the long-recognized risk factors of atherosclerosis: elevated levels
      of LDL and smoking.

PMID- 15203187
TI  - Apocynin prevents cyclooxygenase 2 expression in human monocytes through NADPH
      oxidase and glutathione redox-dependent mechanisms.
AB  - In the present study we report the preventive effect of apocynin, an active
      constituent of the Himalayan herb Picrorhiza kurrooa, on cyclooxygenase-2 (Cox-2)
      synthesis and activity in human adherent monocytes exposed to serum treated
      zymosan (STZ) and phorbol myristate acetate (PMA). Apocynin markedly decreases
      the intracellular reduced/oxidized glutathione ratio (GSH/GSSG) and prevents
      nuclear factor-kappaB (NF-kappaB) activation in stimulated monocytes. Moreover,
      it reduces intracellular reactive oxygen species (ROS) generation, NADPH oxidase
      activity in monocyte homogenates and translocation of p47phox subunit in monocyte
      membranes. p47phox levels are also reduced in lysates of apocynin-treated
      monocytes. The inhibition of Cox-2 by apocynin is completely abrogated by GSH
      provision. Results from this study indicate that apocynin inhibits Cox-2
      synthesis and activity induced in monocytes by an increased oxidative tone and
      provide an explanation for the protective effect exerted by this compound in
      numerous cell and animal models of inflammation. Attenuation of NADPH oxidase
      derived ROS coupled with GSH/GSSG reduction and suppression of NF-kappaB
      activation are highlighted as the molecular mechanisms responsible for Cox-2
      inhibition.

PMID- 15203188
TI  - Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor.
AB  - The aim of this study was to elucidate cellular mechanisms involved in ceramide
      induced apoptosis and its attenuation by hepatocyte growth factor (HGF). Human
      retinal pigmented epithelial cells (RPE) incubated with C2 ceramide accumulated
      reactive oxygen species (ROS) in mitochondria and underwent apoptosis in a dose
      dependent manner. Ceramide-treated cells showed increased caspase-3 activation
      and an increase in mitochondrial membrane permeability transition (MPT). Low
      doses of H2O2 (100 microM) alone induced negligible apoptosis; however, ceramide
      induced apoptosis was significantly enhanced by co-incubation with H2O2 (100
      microM). Furthermore, ceramide treatment significantly decreased catalase
      enzymatic activity and protein expression. HGF pretreatment (20 ng/ml)
      significantly inhibited ceramide-induced apoptosis and reduced the accumulation
      of ROS, the activation of caspase-3, and the increase in MPT and prevented the
      reduction in catalase activity and expression. Together, the data suggest that
      ceramide induces apoptosis in RPE cells by increasing ROS production, MPT, and
      caspase-3 activation. The ceramide effect is potentiated by H2O2 and associated
      with a reduction in catalase activity, suggesting that catalase plays a central
      role in regulating this apoptotic response. The ability of HGF to attenuate these
      effects demonstrates its effectiveness as an antioxidant growth factor.

PMID- 15203189
TI  - Effects of alpha-tocopherol on an animal model of tauopathies.
AB  - We have reported that transgenic (Tg) mice overexpressing human tau protein
      develop filamentous tau aggregates in the CNS. We overexpressed the smallest
      human tau isoform (T44) in the mouse CNS to model tauopathies. These tau Tg mice
      acquire age-dependent CNS pathologies, including insoluble, hyperphosphorylated
      tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive
      filaments. Therefore, these Tg mice are a model that can be exploited for drug
      discovery in studies that target amelioration of tau-induced neurodegeneration as
      well as for elucidating mechanisms of tau pathology in various neurodegenerative
      tauopathies. Oxidative stress has been implicated in the pathogenesis of various
      neurodegenerative diseases, including tauopathies, and many epidemiological,
      clinical, and basic studies have suggested the neuroprotective effects of vitamin
      E in neurodegenerative diseases. To elucidate the role of oxidative damage in the
      pathological mechanisms of these Tg mice, we fed them alpha-tocopherol, the major
      component of antioxidant vitamin E. Supplementation of alpha-tocopherol
      suppressed and/or delayed the development of tau pathology, which correlated with
      improvement in the health and attenuation of motor weakness in the Tg mice. These
      results suggest that oxidative damage is involved in the pathological mechanisms
      of the tau Tg mice and that treatment with antioxidative agents like alpha
      tocopherol may prevent neurodegenerative tauopathies.

PMID- 15203190
TI  - GPx-1 modulates Akt and P70S6K phosphorylation and Gadd45 levels in MCF-7 cells.
AB  - Selenium has been shown to prevent cancer in animal models, and recent data
      indicate it is likely to be effective in humans as well. One selenium-containing
      protein, the cytoplasmic form of glutathione peroxidase (GPx-1), has been
      implicated in cancer risk and development by genetic studies identifying at-risk
      alleles and loss of heterozygosity in tumors. In order to evaluate the biological
      consequences of GPx-1 overexpression, human MCF-7 cells were stably transfected
      with a GPx-1 expression construct and the effects of GPx-1 on protein kinases
      associated with stress responses were determined. GPx-1 overexpression affected
      phosphorylation of p70S6K, whereas Erk1/2 and p38 MAPK were not affected. Site
      specific phosphorylation of Akt declined and the levels of Gadd45, a DNA damage
      response protein, increased significantly as a consequence of elevated GPx-1
      expression. Effects on p70S6K and Gadd45 after selenium supplementation have been
      reported, and given previous data demonstrating a role for GPx-1 in cancer
      etiology, these results support the concept that the chemopreventive properties
      of selenium may be due, at least in part, to its role in regulating GPx-1.

PMID- 15203192
TI  - Reactive oxygen species mediate Endothelin-1-induced activation of ERK1/2, PKB,
      and Pyk2 signaling, as well as protein synthesis, in vascular smooth muscle
      cells.
AB  - Reactive oxygen species (ROS) have been shown to mediate the effects of several
      growth factors and vasoactive peptides, such as epidermal growth factor, platelet
      derived growth factor, and angiotensin II (AII). Endothelin-1 (ET-1) is a
      vasoactive peptide which also exhibits mitogenic activity in vascular smooth
      muscle cells (VSMCs), and is believed to contribute to the pathogenesis of
      vascular abnormalities such as atherosclerosis, hypertension, and restenosis
      after angioplasty. However, a possible role for ROS generation in mediating the
      ET-1 response on extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein
      kinase B (PKB), and protein tyrosine kinase 2 (Pyk2), key components of the
      growth-promoting and proliferative signaling pathways, has not been examined in
      detail. Our aim was to investigate the involvement of ROS in ET-1-mediated
      activation of ERK1/2, PKB, and Pyk2 in A-10 VSMCs. ET-1 stimulated ERK1/2, PKB,
      and Pyk2 phosphorylation in a dose- and time-dependent manner. Pretreatment of A
      10 VSMCs with diphenyleneiodonium (DPI), an inhibitor of reduced nicotinamide
      adenine dinucleotide phosphate oxidase, attenuated ET-1-enhanced ERK1/2, PKB, and
      Pyk2 phosphorylation. In addition, in parallel with an inhibitory effect on the
      above signaling components, DPI also blocked ET-1-induced protein synthesis. ET-1
      was also found to increase ROS production, which was suppressed by DPI treatment.
      N-Acetylcysteine, a ROS scavenger, exhibited a response similar to that of DPI
      and inhibited ET-1-stimulated ERK1/2, PKB, and Pyk2 phosphorylation. These
      results demonstrate that ROS are critical mediators of ET-1-induced signaling
      events linked to growth-promoting proliferative and hypertrophic pathways in
      VSMCs.

PMID- 15203191
TI  - Transforming growth factor Beta1 induction of tissue inhibitor of
      metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen
      species.
AB  - Transforming growth factor beta1 (TGF-beta1) stimulates cartilage extracellular
      matrix synthesis but, in excess, evokes synovial inflammation, hyperplasia, and
      osteophyte formation in arthritic joints. TGF-beta1 induces tissue inhibitor of
      metalloproteinases 3 (TIMP-3), an inhibitor of cartilage-damaging matrix
      metalloproteianases and aggrecanases. We investigated the role of reactive oxygen
      species (ROS) in TIMP-3 induction by TGF-beta1. In primary human and bovine
      chondrocytes, ROS scavenger and antioxidant N-acetylcysteine (NAC) inhibited TGF
      beta1-induced TIMP-3 mRNA and protein increases. Ebselen and ascorbate also
      reduced this induction. TGF-beta1 time-dependently induced ROS production that
      was suppressed by NAC. Hydrogen peroxide, a ROS, induced TIMP-3 RNA. The TIMP-3
      increase induced by TGF-beta1 was partly Smad2-dependent. TGF-beta1-stimulated
      Smad2 phosphorylation was inhibited by NAC. Reduced glutathione and L-cysteine
      also blocked Smad2 and TIMP-3 induction by TGF-beta1, whereas a nonthiol, N
      acetylalanine, did not. Smad2 was not activated by H2O2. Smad2 phosphorylation
      was independent, and TIMP-3 expression was dependent, on new protein synthesis.
      TGF-beta-stimulated ERK and JNK phosphorylation was also inhibited by NAC.
      However, inhibitory actions of NAC were not mediated by ERK activation. Thus, ROS
      mediate TGF-beta1-induced TIMP-3 gene expression. Blocking TGF-beta1-induced gene
      expression by modulating cellular redox status with thiols can be potentially
      beneficial for treating arthritic and other disorders caused by excessive TGF
      beta1.

PMID- 15203193
TI  - Nitric oxide metabolism in mammalian cells: substrate and inhibitor profiles of a
      NADPH-cytochrome P450 oxidoreductase-coupled microsomal nitric oxide dioxygenase.
AB  - Human intestinal Caco-2 cells metabolize and detoxify NO via a dioxygen- and
      NADPH-dependent, cyanide- and CO-sensitive pathway that yields nitrate. Enzymes
      catalyzing NO dioxygenation fractionate with membranes and are enriched in
      microsomes. Microsomal NO metabolism shows apparent KM values for NO, O2, and
      NADPH of 0.3, 9, and 2 microM, respectively, values similar to those determined
      for intact or digitonin-permeabilized cells. Similar to cellular NO metabolism,
      microsomal NO metabolism is superoxide-independent and sensitive to heme-enzyme
      inhibitors including CO, cyanide, imidazoles, quercetin, and allicin-enriched
      garlic extract. Selective inhibitors of several cytochrome P450s and heme
      oxygenase fail to inhibit the activity, indicating limited roles for a subset of
      microsomal heme enzymes in NO metabolism. Diphenyleneiodonium and cytochrome
      c(III) inhibit NO metabolism, suggesting a role for the NADPH-cytochrome P450
      oxidoreductase (CYPOR). Involvement of CYPOR is demonstrated by the specific
      inhibition of the NO metabolic activity by inhibitory anti-CYPOR IgG. In toto,
      the results suggest roles for a microsomal CYPOR-coupled and heme-dependent NO
      dioxygenase in NO metabolism, detoxification, and signal attenuation in mammalian
      cells.

PMID- 15203194
TI  - Impairment of conjunctival glutathione secretion and ion transport by oxidative
      stress in an adenovirus type 5 ocular infection model of pigmented rabbits.
AB  - Conjunctival epithelial cells of pigmented rabbits secrete reduced glutathione
      (GSH) into the apical (mucosal) fluid. The aim of the current study was to
      determine the effect of oxidative stress resulting from viral infection and that
      of GSH supplementation on redox status, GSH, and ion transport in freshly excised
      conjunctival tissues and epithelial cell layers in primary culture (RCEC) of
      adenovirus type 5 (Ad5)-infected rabbits. Lipid peroxidation (LPO) products,
      nitric oxide (NO), and expression of nitric oxide synthase (NOS2) were
      quantitated as a function of time after viral inoculation. Unidirectional fluxes
      of [3H]GSH and changes in short-circuit current (Isc) from mucosal
      supplementation of Ad5-inoculated conjunctival tissues with GSH and glutathione
      monoethyl ester (GSH-MEE) were also measured. Ad5 inoculation significantly
      decreased conjunctival GSH level by 19, 45, 48, and 50% at 8, 24, 48, and 72 h
      postinfection, respectively. LPO product and NO levels increased significantly (2
      and 100-fold, respectively) above that of uninfected controls on Day 3 post-Ad5
      inoculation, and co-treatment with GSH-MEE and tocopherol succinate abolished
      this effect. NO levels showed a progressive increase post-Ad5 inoculation,
      reaching 0.22 +/- 0.06, 8.12 +/- 0.91, and 2.05 +/- 0.65 microM on Days 1, 3, and
      5, respectively, and the highest level was observed on the day of maximal viral
      replication (Day 3). A very significant induction of the expression of NOS2 on
      Days 1, 3, and 5 post-Ad5 inoculation was observed. Uninfected control
      conjunctival tissues displayed a net serosal-to-mucosal GSH flux (Jsm), where the
      mucosal-to-serosal flux (Jms) was approximately 14 pmol h(-1) cm(-2) and the Jsm
      was approximately 22 pmol h(-1) cm(-2). In Ad5-inoculated rabbits similar GSH
      flux was observed in both the sm and ms directions, and the net GSH flux was
      negligible. Isc and potential difference (PD) across conjunctival tissues of Ad5
      inoculated rabbits decreased by > or = 50% compared with control, while the
      transepithelial electrical resistance (TEER) remained unchanged. Mucosal, but not
      serosal, superfusion of GSH or GSH-MEE in Ad5-inoculated conjunctival tissues
      increased the Isc by up to 40% in approximately 100 min. Our results show that
      net secretion of GSH across rabbit conjunctiva is totally blocked after Ad5
      inoculation and active ion transport rate decreased by approximately 50%.
      Decreased net GSH secretion into mucosal fluid after Ad5 infection may have
      resulted from a decreased intracellular GSH pool due to oxyradical-induced
      changes in redox status and lower active ion transport. Mucosal treatment of Ad5
      infected conjunctival tissues with pharmacological levels of GSH appears to
      transstimulate mucosal GSH secretion and restore active ion transport activity,
      suggesting a potentially useful therapeutic regimen for ocular infections.

PMID- 15203196
TI  - The increase in human plasma antioxidant capacity after apple consumption is due
      to the metabolic effect of fructose on urate, not apple-derived antioxidant
      flavonoids.
AB  - Regular fruit consumption lowers the risk of cardiovascular diseases and certain
      cancers, which has been attributed in part to fruit-derived antioxidant
      flavonoids. However, flavonoids are poorly absorbed by humans, and the increase
      in plasma antioxidant capacity observed after consumption of flavonoid-rich foods
      often greatly exceeds the increase in plasma flavonoids. In the present study,
      six healthy subjects consumed five Red Delicious apples (1037 +/- 38 g), plain
      bagels (263.1 +/- 0.9 g) and water matching the carbohydrate content and mass of
      the apples, and fructose (63.9 +/- 2.9 g) in water matching the fructose content
      and mass of the apples. The antioxidant capacity of plasma was measured before
      and up to 6 h after food consumption as ferric reducing antioxidant potential
      (FRAP), without or with ascorbate oxidase treatment (FRAPAO) to estimate the
      contribution of ascorbate. Baseline plasma FRAP and FRAPAO were 445 +/- 35 and
      363 +/- 35 microM trolox equivalents, respectively. Apple consumption caused an
      acute, transient increase in both plasma FRAP and FRAPAO, with increases after 1
      h of 54.6 +/- 8.7 and 61.3 = 17.2 microM trolox equivalents, respectively. This
      increase in plasma antioxidant capacity was paralleled by a large increase in
      plasma urate, a metabolic antioxidant, from 271 +/- 39 microM at baseline to 367
      +/- 43 microM after 1 h. In contrast, FRAP and FRAPAO time-dependently decreased
      after bagel consumption, together with urate. Consumption of fructose mimicked
      the effects of apples with respect to increased FRAP, FRAPAO, and urate, but not
      ascorbate. Taken together, our data show that the increase in plasma antioxidant
      capacity in humans after apple consumption is due mainly to the well-known
      metabolic effect of fructose on urate, not apple-derived antioxidant flavonoids.

PMID- 15203195
TI  - Superoxide dismutase mimetics elevate superoxide dismutase activity in vivo but
      do not retard aging in the nematode Caenorhabditis elegans.
AB  - According to the oxidative damage theory a primary cause of aging is the accrual
      of molecular damage from reactive oxygen species (ROS), particularly superoxide
      and its derivatives. This predicts that treatments that reduce ROS levels should
      retard aging. Using the nematode Caenorhabditis elegans, we tested the effects on
      stress resistance and life span of treatment with EUK-8 and EUK-134, synthetic
      mimetics of the antioxidant enzyme superoxide dismutase (SOD), which neutralises
      superoxide. Treatment with SOD mimetics elevated in vivo SOD activity levels,
      particularly in mitochondria, where up to 5-fold increases in SOD activity were
      recorded. Treatment with exogenous SOD mimetics did not affect endogenous protein
      SOD levels. Where life span was reduced by the superoxide generators paraquat and
      plumbagin, EUK-8 treatment increased life span in a dose-dependent fashion. Yet
      in the absence of a superoxide generator, treatment with EUK-8 or EUK-134 did not
      increase life span, even at doses that were optimal for protection against pro
      oxidants. Thus, an elevation of SOD activity levels sufficient to increase life
      span when it is limited by superoxide generators does not retard aging in the
      absence of superoxide generators. This suggests that C. elegans life span is not
      normally limited by levels of superoxide and its derivatives.

PMID- 15203197
TI  - Cell-induced copper ion-mediated low density lipoprotein oxidation increases
      during in vivo monocyte-to-macrophage differentiation.
AB  - Macrophage activation is associated with the production and release of reactive
      oxygen species (ROS), which are capable of mediating oxidative modification of
      low-density lipoprotein (LDL). In the present study we questioned whether
      cellular capacity to oxidize LDL increases during in vivo monocyte/macrophage
      maturation. We developed a novel model for macrophage maturation in vivo using
      mouse peritoneal macrophages (MPMs) harvested at increasing intervals after
      intraperitoneal thioglycollate injection. Macrophage maturation was evidenced by
      a progressive increase in cellular size, density, granulation, and expression of
      cell surface markers CD11b and CD36, and by a gradual decrement in
      myeloperoxidase activity. Cellular capacity to stimulate copper ion-mediated
      oxidation of LDL increased gradually by up to 2-fold during in vivo macrophage
      maturation in Balb/C mice, similar to the pattern observed during 1,25
      dihydroxyvitamin D3-induced in vitro differentiation of the PLB-985 cell line.
      These effects were attributed to a gradual increase in production of ROS by up to
      9-fold. The mechanism for the increase in cellular oxidative stress during
      macrophage maturation could be related, at least in part, to NADPH oxidase
      activation, as demonstrated by a gradual increase over time in p47phox expression
      (mRNA and protein) and in its translocation to the plasma membrane. In
      conclusion, in vivo monocyte-to-macrophage differentiation is associated with
      increased cell capacity to oxidize LDL, which may represent a protective
      mechanism for rapid removal of atherogenic LDL from extracellular spaces in the
      arterial wall.

PMID- 15203198
TI  - A manganese porphyrin complex is a novel radiation protector.
AB  - Exposure of cells to ionizing radiation leads to formation of reactive oxygen
      species, which are associated with radiation-induced cytotoxicity. Therefore,
      compounds that scavenge reactive oxygen species may confer radioprotective
      effects. Superoxide dismutase (SOD) mimetics have been shown to be protective
      against cell injury caused by reactive oxygen species. The objective of this
      study was to investigate the effects of manganese(III) tetrakis(N-methyl-2
      pyridyl)porphyrin (MnTMPyP), a cell-permeable SOD mimetic, on radiation-dependent
      toxicity. We investigated the protective role of MnTMPyP against ionizing
      radiation in U937 cells and mice. On exposure to ionizing radiation, there was a
      distinct difference between control cells and cells pretreated with MnTMPyP with
      respect to viability, cellular redox status, and oxidative damage to cells. Lipid
      peroxidation, oxidative DNA damage, and protein oxidation were significantly
      lower in the cells treated with MnTMPyP when the cells were exposed to ionizing
      radiation. The [GSSG]/[GSH + GSSG] ratio and the generation of intracellular
      reactive oxygen species were higher and the [NADPH]/[NADP+ + NADPH] ratio was
      lower in control cells compared with MnTMPyP-treated cells. Ionizing radiation
      induced mitochondrial damage, as reflected by the altered mitochondrial
      permeability transition, increase in accumulation of reactive oxygen species,
      reduction of ATP production, and morphological change, was significantly higher
      in control cells than in MnTMPyP-treated cells. MnTMPyP administration for 14
      days at a daily dosage of 5 mg/kg provided substantial protection against killing
      and oxidative damage in mice exposed to whole-body irradiation. These data
      indicate that MnTMPyP may have great application potential as a new class of in
      vivo, non-sulfur-containing radiation protectors.

PMID- 15203199
TI  - The MTG proteins: chromatin repression players with a passion for networking.
AB  - The human myeloid translocation genes (MTGs) encode a family of proteins with a
      modular structure that can be traced to the Drosophila protein nervy. The nuclear
      MTGs can mediate the formation of complex protein networks among nuclear
      corepressors (Sin3a, N-CoR, SMRT), chromatin-modifying enzymes (histone
      deacetylases), and DNA-binding transcription factors. Hierarchical modulation of
      repression at target genes by MTG protein complexes is likely required for fine
      spatial and temporal gene regulation during development and differentiation.
      Genomic changes can disrupt these sophisticated protein networks and underlie
      novel pathogenic causes of cancer and neurodegeneration.

PMID- 15203200
TI  - Probing the S100 protein family through genomic and functional analysis.
AB  - The EF-hand superfamily of calcium binding proteins includes the S100, calcium
      binding protein, and troponin subfamilies. This study represents a genome,
      structure, and expression analysis of the S100 protein family, in mouse, human,
      and rat. We confirm the high level of conservation between mammalian sequences
      but show that four members, including S100A12, are present only in the human
      genome. We describe three new members of the S100 family in the three species and
      their locations within the S100 genomic clusters and propose a revised
      nomenclature and phylogenetic relationship between members of the EF-hand
      superfamily. Two of the three new genes were induced in bone-marrow-derived
      macrophages activated with bacterial lipopolysaccharide, suggesting a role in
      inflammation. Normal human and murine tissue distribution profiles indicate that
      some members of the family are expressed in a specific manner, whereas others are
      more ubiquitous. Structure-function analysis of the chemotactic properties of
      murine S100A8 and human S100A12, particularly within the active hinge domain,
      suggests that the human protein is the functional homolog of the murine protein.
      Strong similarities between the promoter regions of human S100A12 and murine
      S100A8 support this possibility. This study provides insights into the possible
      processes of evolution of the EF-hand protein superfamily. Evolution of the S100
      proteins appears to have occurred in a modular fashion, also seen in other
      protein families such as the C2H2-type zinc-finger family.

PMID- 15203201
TI  - The human and mouse repertoire of the adhesion family of G-protein-coupled
      receptors.
AB  - The adhesion G-protein-coupled receptors (GPCRs) (also termed LN-7TM or EGF-7TM
      receptors) are membrane-bound proteins with long N-termini containing multiple
      domains. Here, 2 new human adhesion-GPCRs, termed GPR133 and GPR144, have been
      found by searches done in the human genome databases. Both GPR133 and GPR144 have
      a GPS domain in their N-termini, while GPR144 also has a pentraxin domain. The
      phylogenetic analyses of the 2 new human receptors show that they group together
      without close relationship to the other adhesion-GPCRs. In addition to the human
      genes, mouse orthologues to those 2 and 15 other mouse orthologues to human were
      identified (GPR110, GPR111, GPR112, GPR113, GPR114, GPR115, GPR116, GPR123,
      GPR124, GPR125, GPR126, GPR128, LEC1, LEC2, and LEC3). Currently the total number
      of human adhesion-GPCRs is 33. The mouse and human sequences show a clear one-to
      one relationship, with the exception of EMR2 and EMR3, which do not seem to have
      orthologues in mouse. EST expression charts for the entire repertoire of adhesion
      GPCRs in human and mouse were established. Over 1600 ESTs were found for these
      receptors, showing widespread distribution in both central and peripheral
      tissues. The expression patterns are highly variable between different receptors,
      indicating that they participate in a number of physiological processes.

PMID- 15203202
TI  - Degeneration of an ATP-binding cassette transporter gene, ABCC13, in different
      mammalian lineages.
AB  - The ABC transporter gene family has evolved by a gene "birth-and-death" process;
      however, the number of ABC pseudogenes in the human genome is surprisingly small.
      On chromosome 21q11.2, spanning 90 kb, is an ABC gene-like sequence (recently
      annotated as ABCC13) with the highest similarity to ABCC2. Here we show that
      while comparative analysis and in silico prediction methods indicate the presence
      of at least 28 exons, the major ABCC13 transcript in humans consists of only 6
      exons with a total length of 1.1 kb. The open reading frame of this transcript is
      capable of encoding a polypeptide of only 274 amino acids, compared to the more
      than 1500 amino acids of related ABC transporters. The truncated ABCC13
      transcript shows tissue-specific expression, highest in fetal liver, bone marrow,
      and colon. Since the last exon of the ABCC13 transcript contains an apparent
      frameshift, we sequenced the respective region from several primates and found
      that the frameshift is due to an 11-bp deletion that is shared between human,
      chimpanzee, and gorilla, but is not found in monkeys. In addition, the human
      ABCC13 gene contains two other frameshift indels in the exons that encode the
      second nucleotide-binding domain, indicating that ABCC13 is not capable of
      encoding a functional ABC protein. In an attempt to identify an intact ABCC13
      ortholog, we have sequenced the full-length cDNA from rhesus macaque, which
      contains an open reading frame of 1296 amino acids, producing an apparently
      functional ABC transporter. Although the mouse and rat genomes contain long-range
      similarity in the locus where Abcc13 is expected to reside, most of the Abcc13
      exons in rodents are degraded below the threshold of sequence homology searches
      or have been deleted completely.

PMID- 15203203
TI  - Lineage-specific imprinting and evolution of the zinc-finger gene ZIM2.
AB  - We have carried out an in-depth comparative analysis of a 100-kb genomic interval
      containing two imprinted genes, PEG3 and ZIM2, using sequences derived from
      human, mouse, and cow. In all three mammals, ZIM2 is located at a similar genomic
      distance and in the same orientation relative to PEG3, indicating the basic
      structural conservation of this imprinted locus. However, several lineage
      specific changes have occurred that affect the exon structure and imprinting
      status of ZIM2. Human ZIM2 and PEG3 share a set of 5' exons and a common
      promoter, and both genes are paternally expressed. In contrast, mouse and cow
      Zim2 genes do not share 5' exons with Peg3, and Zim2 employs a separate
      downstream promoter in both species. The imprinting status of Zim2 is also not
      conserved among mammals; mouse Zim2 is expressed biallelically in testis but
      predominantly from the maternal allele in brain, while cow Zim2 is expressed
      biallelically in testis. The separate transcription of Zim2 and Peg3 and the
      change in promoter usage and imprinting status appear to have resulted from
      independent insertional events that have placed unrelated genes, Zim1 and Ast1,
      respectively, between Zim2 and Peg3 in mouse and cow. Our results suggest that
      PEG3 and ZIM2 represent the two original genes at this locus and that
      rearrangements have occurred independently in different mammalian lineages in
      recent evolutionary times. Our data also suggest that exon-sharing of human PEG3
      and ZIM2 was not ancestral, but may represent a fusion event joining the two
      neighboring genes and bringing ZIM2 under paternal expression control. These
      observations are striking in light of the structural and functional conservation
      that typifies other imprinted domains and suggest that the PEG3/ZIM2 imprinted
      domain may have evolved in an unusual lineage-specific pattern.

PMID- 15203204
TI  - Role of H19 3' sequences in controlling H19 and Igf2 imprinting and expression.
AB  - The regulation of H19 and Igf2 imprinting and expression depends on common
      elements. Using comparative analysis between human and mouse, we identified
      conserved regions 3' of the H19 transcription unit, including the H19/Igf2
      endodermal enhancers and elements within a 4.2-kb domain between the H19
      transcription unit and the enhancers. Transgene experiments implicate these
      elements in imprinting regulation. To establish whether they are required at the
      endogenous locus, first we replaced the endodermal enhancers with the alpha
      fetoprotein endodermal enhancers (H19Afp). Second, we deleted the 4.2-kb region
      (H19delta4.2). Our analysis revealed that H19 and Igf2 imprinting and tissue
      specific expression were maintained for both mutations, except for a slight
      reduction in paternal Igf2 expression from the H19Afp allele in liver. These
      results demonstrate that the H19 insulator can interact with heterologous
      enhancers to imprint Igf2. Furthermore, for H19, chromatin context or additional
      sequences possibly compensate for loss of conserved 3' elements.

PMID- 15203205
TI  - Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a
      novel gene, FRA10AC1, encoding a nuclear protein.
AB  - Fragile sites appear visually as nonstaining gaps on chromosomes that are
      inducible by specific cell culture conditions. Expansion of CGG/CCG repeats has
      been shown to be the molecular basis of all five folate-sensitive fragile sites
      characterized molecularly so far, i.e., FRAXA, FRAXE, FRAXF, FRA11B, and FRA16A.
      In the present study we have refined the localization of the FRA10A folate
      sensitive fragile site by fluorescence in situ hybridization. Sequence analysis
      of a BAC clone spanning FRA10A identified a single, imperfect, but polymorphic
      CGG repeat that is part of a CpG island in the 5'UTR of a novel gene named
      FRA10AC1. The number of CGG repeats varied in the population from 8 to 13.
      Expansions exceeding 200 repeat units were methylated in all FRA10A fragile site
      carriers tested. The FRA10AC1 gene consists of 19 exons and is transcribed in the
      centromeric direction from the FRA10A repeat. The major transcript of
      approximately 1450 nt is ubiquitously expressed and codes for a highly conserved
      protein, FRA10AC1, of unknown function. Several splice variants leading to
      alternative 3' ends were identified (particularly in testis). These give rise to
      FRA10AC1 proteins with altered COOH-termini. Immunofluorescence analysis of full
      length, recombinant EGFP-tagged FRA10AC1 protein showed that it was present
      exclusively in the nucleoplasm. We show that the expression of FRA10A, in
      parallel to the other cloned folate-sensitive fragile sites, is caused by an
      expansion and subsequent methylation of an unstable CGG trinucleotide repeat.
      Taking advantage of three cSNPs within the FRA10AC1 gene we demonstrate that one
      allele of the gene is not transcribed in a FRA10A carrier. Our data also suggest
      that in the heterozygous state FRA10A is likely a benign folate-sensitive fragile
      site.

PMID- 15203206
TI  - Identification of two novel alternatively spliced Neuropilin-1 isoforms.
AB  - Neuropilin-1 (NRP1) is a coreceptor to a tyrosine kinase receptor for both the
      vascular endothelial growth factor (VEGF) family and semaphorin (Sema) family
      members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell
      survival, migration, and invasion. NRP1 contains three distinct extracellular
      domains, a1a2, b1b2, and c. We report here the identification of two novel
      soluble human NRP1 isoforms, which we named sIIINRP1 and sIVNRP1. These soluble
      NRP1 isoforms were generated by alternative splicing of the NRP1 gene, a common
      regulatory mechanism occurring in cell surface receptor families. Both sIIINRP1
      and sIVNRP1 contain a1a2 and b1b2 domains, but no c domain, and the rest of the
      NRP1 sequence. Additionally, sIIINRP1 is missing 48 amino acids within the C
      terminus of the b2 domain. Both sIIINRP1 and sIVNRP1 are expressed in human
      cancerous and normal tissues. These molecules are capable of binding to VEGF165
      and Sema3A. Furthermore, recombinant sIIINRP1 and sIVNRP1 proteins inhibit NRP1
      mediated MDA-MB-231 breast cancer cell migration. These results indicate the
      multiple levels of regulation in NRP1 function and suggest that these two novel
      NRP1 isoforms are useful antagonists for NRP1-mediated cellular activities.

PMID- 15203207
TI  - Characterization of the human DNAS1L2 gene and the molecular mechanism for its
      transcriptional activation induced by inflammatory cytokines.
AB  - DNAS1L2, a member of the DNase I-like endonuclease family, is the only divalent
      cation-dependent acid DNase so far identified in mammals. The presence of a
      proline-rich domain (PRD) is its unique feature among family members. We found
      that a novel transcript encoding a short product, DNAS1L2-S, is expressed in
      peripheral blood leukocytes. Although DNAS1L2-S lacks the PRD, its enzymatic
      properties are apparently the same as those of the previously identified long
      form, DNAS1L2-L. Sequence analysis reveals that DNAS1L2 consists of seven exons.
      The exon/intron boundaries agree with the GT/AG rule with one exception: GC
      replaces GT at the 5' splice site in the sixth intron. TNF-alpha and IL-1beta are
      found to be potent inducers of DNAS1L2 expression in keratinocytes. They induce
      DNAS1L2 activation via the NF-kappaB pathway, and an NF-kappaB binding site
      located within the 5' flanking region is identified as the cis-responsive
      element.

PMID- 15203208
TI  - Alternative splicing of mammalian Intersectin 1: domain associations and tissue
      specificities.
AB  - The Intersectin 1 (ITSN1) protein functions in clathrin-mediated endocytosis and
      in MAP kinase signaling. The complex domain structure comprises two EH and five
      SH3 domains in the short isoform, plus RhoGEF, pleckstrin, and putative calcium
      interaction domains in the long isoform. Alternative splicing of exon 20,
      affecting the SH3A domain, has been shown in rat and that of exons 25 + 26,
      affecting the SH3C domain, has been shown in human and rat. Here we report 7
      novel splice variants of the human and mouse ITSN1 genes and demonstrate
      conservation of alternative splicing affecting SH3A and SH3C in mouse. The novel
      variants encode transcripts with altered EH domain spacing and RhoGEF domain
      structure and possible targets of nonsense-mediated decay. Eight and 16 protein
      variants of the short and long ITSN1 isoforms, respectively, are predicted. These
      isoforms likely serve to modulate the many complex protein interactions and
      functions of ITSN1.

PMID- 15203209
TI  - PLET1 (C11orf34), a highly expressed and processed novel gene in pig and mouse
      placenta, is transcribed but poorly spliced in human.
AB  - Sequencing of porcine cDNAs identified a novel EST with high frequency in
      placenta tissue. Full-length PLET1 (placenta-expressed transcript 1, also called
      C11orf34) matched a mouse cDNA and many bovine and mouse ESTs but no human
      transcripts or ESTs. However, the porcine cDNA matched several putative exons
      within a human genomic DNA fragment on chromosome 11. This human locus is in a
      region of conserved synteny with pig chromosome 9, to which the porcine gene was
      subsequently mapped. RNA blot hybridization showed that this gene had high
      expression in porcine and mouse conceptus and throughout placenta development. In
      situ hybridization using mouse placenta showed PLET1 expression in trophoblast
      cells of the labyrinth, as well as in spongiotrophoblast and glycogen trophoblast
      cells. However, no expression of PLET1 was detected by RNA blot analysis of human
      placenta, although RT-PCR analysis detected very small amounts of partially
      spliced RNA that were significantly less abundant than the RNA levels in mouse
      placenta. Donor and acceptor splicing site sequences in the exons of the human
      gene are poorly conserved and may be the cause of inefficient splicing found
      specifically in human tissue. Our data correct GenomeScan annotation of this
      region of the human genome and describe functional gene discovery in mammals not
      recognized in human EST projects.

PMID- 15203210
TI  - Polycystin-1L2 is a novel G-protein-binding protein.
AB  - Mutations in genes encoding polycystin-1 (PC1) and polycystin-2 cause autosomal
      dominant polycystic kidney disease. The polycystin protein family is composed of
      Ca2+-permeable pore-forming subunits and receptor-like integral membrane
      proteins. Here we describe a novel member of the polycystin-1-like subfamily,
      polycystin-1L2 (PC1L2), encoded by PKD1L2, which has various alternative splicing
      forms with two translation initiation sites. PC1L2 short form starts in exon 12
      of the long form. The longest open reading frame of PKD1L2 short form, determined
      from human testis cDNA, encodes a 1775-amino-acid protein and 32 exons, whereas
      the long form is predicted to encode a 2460-residue protein. Both forms have a
      small receptor for egg jelly domain, a G-protein-coupled receptor proteolytic
      site, an LH2/PLAT, and 11 putative transmembrane domains, as well as a number of
      rhodopsin-like G-protein-coupled receptor signatures. RT-PCR analysis shows that
      the short form, but not the long form, of human PKD1L2 is expressed in the
      developing and adult heart and kidney. Furthermore, by GST pull-down assay we
      observed that PC1L2 and polycystin-1L1 are able to bind to specific G-protein
      subunits. We also show that PC1 C-terminal cytosolic domain binds to Galpha12,
      Galphas, and Galphai1, while it weakly interacts with Galphai2. Our results
      indicate that both PC1-like molecules may act as G-protein-coupled receptors.

PMID- 15203211
TI  - Characterization of the bombesin-like peptide receptor family in primates.
AB  - In mammals, bombesin-like peptides mediate a broad range of physiological
      functions through binding to three highly conserved G-protein-coupled receptors:
      the neuromedin B-preferring, the gastrin-releasing peptide-preferring, and the
      bombesin-receptor subtype 3. Selective modulation of these receptors presents
      opportunities for the development of novel therapeutics. To ascertain if rhesus
      monkey could serve as a surrogate animal model for the development of modulators
      of bombesin-like receptor function, we undertook a search for additional receptor
      family members and studied the expression profiles of the three known bombesin
      related receptors. We found no evidence for additional receptor family members in
      mammals, suggesting that the expression of the previously described bombesin
      receptor subtype 4 is limited to amphibians. We studied the distribution of the
      three receptors in a broad array of human and rhesus monkey tissues. Based on the
      similarity between the human and the rhesus expression profiles, we conclude that
      the rhesus monkey may be a suitable animal model to evaluate the clinical
      efficacy and potential side effects of bombesin-like peptide ligands.

PMID- 15203212
TI  - Taxon-specific evolution of glandular kallikrein genes and identification of a
      progenitor of prostate-specific antigen.
AB  - In a previous study we demonstrated that repeated duplications of the tissue
      kallikrein gene (Klk1) had resulted in 24 paralogs in mouse. Here we demonstrate
      a different evolution of rat glandular kallikrein genes. Repeated duplications of
      an approximately 30-kb region, encompassing Klk1, Klk15, and Klk2-ps, resulted in
      10 copies of each gene, but only the Klk1 paralogs are functional. The number of
      genes varies also between nonrodent mammals, e.g., there are probably no paralogs
      to KLK1 in cow and pig, whereas horse could have up to 5. In the dog, the gene
      encoding the prostatic arginine esterase was identified as an ortholog to the
      progenitor of the PSA and hK2 genes, and it carries the same conserved androgen
      responsive elements directing prostate transcription as these genes. This is
      highly interesting with respect to animal models of benign prostate hyperplasia
      and prostate adenocarcinoma--diseases that have been described only in humans and
      dogs.

PMID- 15203213
TI  - The LRIG gene family has three vertebrate paralogs widely expressed in human and
      mouse tissues and a homolog in Ascidiacea.
AB  - Human LRIG1 (formerly LIG1), human LRIG2, and mouse Lrig1 (also known as Lig-1)
      encode integral membrane proteins. The human genes are located at chromosomes
      3p14 and 1p13, which are regions frequently deleted in human cancers. We have
      searched for additional members of the LRIG family and by molecular cloning
      identified human LRIG3 and its mouse ortholog Lrig3. Human LRIG3 is located at
      chromosome 12q13. In silico analysis of public databases revealed a mouse Lrig2
      mRNA, three LRIG homologs in the puffer fish Fugu rubripes, and one LRIG homolog
      in the ascidian tunicate Ciona intestinalis. The human and mouse LRIG
      polypeptides have the same predicted domain organization: a signal peptide, 15
      tandem leucine-rich repeats with cysteine-rich N- and C-flanking domains, three
      immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The
      extracellular part--especially the IgC2.2 domain, the transmembrane domain, and
      the membrane-proximal part of the cytoplasmic tail--are the most conserved
      regions. Northern blot analysis and real-time RT-PCR revealed that the three LRIG
      paralogs are widely expressed in human and mouse tissues. In conclusion, the LRIG
      gene family was found to have three widely expressed mammalian paralogs,
      corresponding orthologs in fish, and a homolog in Ascidiacea.

PMID- 15203214
TI  - The amplified mouse squamous cell carcinoma antigen gene locus contains a serpin
      (Serpinb3b) that inhibits both papain-like cysteine and trypsin-like serine
      proteinases.
AB  - The clade B serpins occupy a unique niche among a larger superfamily by
      predominantly regulating intracellular proteolysis. In humans, there are 13
      family members that map to serpin gene clusters at either 6p25 or 18q21. While
      most of these serpins display a unique inhibitory profile and appear to be well
      conserved in mammals, the clade B loci of several species show evidence of
      relatively recent genomic amplification events. However, it is not clear whether
      these serpin gene amplification events yield paralogs with functional redundancy
      or, through selective pressure, inhibitors with more diverse biochemical
      activities. A recent comparative genomic analysis of the mouse clade B cluster at
      1D found nearly complete conservation of gene number, order, and orientation
      relative to those of 18q21 in humans. The only exception was the squamous cell
      carcinoma antigen (SCCA) locus. The human SCCA locus contains two genes, SERPINB3
      (SCCA1) and SERPINB4 (SCCA2), whereas the mouse locus contains four serpins and
      three pseudogenes. At least two of these genes encoded functional, dual cross
      class proteinase inhibitors. Mouse Serpinb3a was shown previously to inhibit both
      chymotrypsin-like serine and papain-like cysteine proteinases. We now report that
      mouse Serpinb3b extends the inhibitory repertoire of the mouse SCCA locus to
      include a second cross-class inhibitor with activity against both papain-like
      cysteine and trypsin-like serine proteinases. These findings confirmed that the
      genomic expansion of the clade B serpins in the mouse was associated with a
      functional diversification of inhibitory activity.

PMID- 15203216
TI  - Dynamic regulation of gene expression by the Flt-1 kinase and Matrigel in
      endothelial tubulogenesis.
AB  - A nontubulogenic endothelial cell line, NP31, can be transformed by the active
      form of the Flt-1 kinase (BCR-FLTm1) into Tb3 cells, which show a tubulogenic
      property only when cultured in Matrigel. By utilizing this strict dependence of
      NP31 on BCR-FLTm1 and Matrigel for experimental angiogenesis, we performed
      microarray analyses under several conditions and found 97 genes whose dynamically
      regulated profiles of gene expression are divided into nine groups, in two major
      clusters. In one major cluster, gene expression is interdependently regulated by
      BCR-FLTm1 or Matrigel. The second major cluster contains genes whose expression
      patterns under BCR-FLTm1 influence are reversed by Matrigel. Based on these gene
      expression patterns in NP31 driven by BCR-FLTm1 and/or Matrigel, we propose a
      model in which sequential and alternate stimulation by BCR-FLTm1 and Matrigel
      induces cooperative regulation of subsets of genes. Microarray analyses of Tb3
      under 11 different conditions revealed 5 candidate genes whose gene expression
      regulation is most closely associated with tubulogenesis.

PMID- 15203215
TI  - Comparative genomic analysis of the clade B serpin cluster at human chromosome
      18q21: amplification within the mouse squamous cell carcinoma antigen gene locus.
AB  - The human clade B serpins neutralize serine or cysteine proteinases and reside
      predominantly within the intracellular compartment. Genomic analysis shows that
      the 13 human clade B serpins map to either 6p25 (n = 3) or 18q21 (n = 10).
      Similarly, the mouse clade B serpins map to syntenic loci at 13A3.2 and 1D,
      respectively. The mouse clade B cluster at 13A3.2 shows a marked expansion in the
      number of serpin genes (n = 15). The purpose of this study was to determine
      whether a similar expansion occurred at 1D. Using STS-content mapping,
      comparative genomic DNA sequence analysis, and cDNA cloning, we found that the
      mouse clade B cluster at 1D showed nearly complete conservation of gene number,
      order, and orientation relative to those of 18q21. The only exception was the
      squamous cell carcinoma antigen (SCCA) locus. The human SCCA locus contains two
      genes, SERPINB3 (SCCA1) and SERPINB4 (SCCA2), whereas the mouse locus contains
      four serpins and three pseudogenes. Based on phylogenetic analysis and predicted
      amino acid sequences, amplification of the mouse SCCA locus occurred after
      rodents and primates diverged and was associated with some diversification of
      proteinase inhibitory activity relative to that of humans.

PMID- 15203217
TI  - Identification of 11 pseudogenes in the DNA methyltransferase gene family in
      rodents and humans and implications for the functional loci.
AB  - DNA (cytosine-5-)-methyltransferase genes are important for normal development in
      mice and humans. We describe here 11 pseudogenes spread among human, mouse, and
      rat belonging to this gene family, ranging from 1 pseudogene in humans to 7 in
      rat, all belonging to the Dnmt3 subfamily. All except 1 rat Dnmt3b pseudogene
      appear to be transcriptionally silent. Dnmt3a2, a transcript variant of Dnmt3a
      starting at an alternative promoter, had the highest number of processed
      pseudogenes, while none were found for the canonical Dnmt3a, suggesting the
      former transcript is more highly expressed in germ cells. Comparison of human,
      mouse, and rat Dnmt3a2 sequences also suggests that human exon 8 is a recent
      acquisition. Alignment of the 3'UTR of Dnmt3a2 among the functional genes and the
      processed pseudogenes suggested that a second polyadenylation site downstream of
      the RefSeq poly(A) was being used in mice, resulting in a longer 3'UTR, a finding
      confirmed by RT-PCR in mouse tissues. We also found conserved cytoplasmic
      polyadenylation elements, usually implicated in regulating translation in
      oocytes, in Dnmt3b and Dnmt1. Expression of DNMT3B in the mouse oocyte was
      confirmed by immunocytochemistry. These results clarify the structure of a number
      of loci in the three species examined and provide some useful insights into the
      structure and evolution of this gene family.

PMID- 15203218
TI  - Circular rapid amplification of cDNA ends for high-throughput extension cloning
      of partial genes.
AB  - The rapid amplification of cDNA ends (RACE) procedure is a widely used PCR-based
      method to clone the cDNA ends of mRNA transcripts. Current RACE methods often
      produce a high background of nonspecific PCR products, which can exclude the
      identification of the target cDNA of interest. We describe here an improved RACE
      procedure using circular cDNA templates and demonstrate the successful extension
      cloning of 4406 cDNAs.

PMID- 15203219
TI  - A computational approach to measuring coherence of gene expression in pathways.
AB  - This study uses a computational approach to analyze coherence of expression of
      genes in pathways. Microarray data were analyzed with respect to coherent gene
      expression in a group of genes defined as a pathway in the Kyoto Encyclopedia of
      Genes and Genomes (KEGG) database. Our hypothesis is that genes in the same
      pathway are more likely to be coordinately regulated than a randomly selected
      gene set. A correlation coefficient for each pair of genes in a pathway was
      estimated based on gene expression in normal or tumor samples, and statistically
      significant correlation coefficients were identified. The coherence indicator was
      defined as the ratio of the number of gene pairs in the pathway whose correlation
      coefficients are significant, divided by the total number of gene pairs in the
      pathway. We defined all genes that appeared in the KEGG pathways as a reference
      gene set. Our analysis indicated that the mean coherence indicator of pathways is
      significantly larger than the mean coherence indicator of random gene sets drawn
      from the reference gene set. Thus, the result supports our hypothesis. The
      significance of each individual pathway of n genes was evaluated by comparing its
      coherence indicator with coherence indicators of 1000 random permutation sets of
      n genes chosen from the reference gene set. We analyzed three data sets: two
      Affymetrix microarrays and one cDNA microarray. For each of the three data sets,
      statistically significant pathways were identified among all KEGG pathways. Seven
      of 96 pathways had a significant coherence indicator in normal tissue and 14 of
      96 pathways had a significant coherence indicator in tumor tissue in all three
      data sets. The increase in the number of pathways with significant coherence
      indicators may reflect the fact that tumor cells have a higher rate of metabolism
      than normal cells. Five pathways involved in oxidative phosphorylation, ATP
      synthesis, protein synthesis, or RNA synthesis were coherent in both normal and
      tumor tissue, demonstrating that these are essential genes, a high level of
      expression of which is required regardless of cell type.

PMID- 15203220
TI  - Rapid expansion of the Ly49 gene cluster in rat.
AB  - The cytotoxic activity of mouse natural killer cells is regulated in part through
      cell surface molecules belonging to the Ly49 multigene family. In mice, the
      genomic sequence of the Ly49 gene cluster has been examined in detail and this
      analysis provided a model of the expansion of this multigene family. In the
      present study, we have analyzed a 1.8-Mb region of the draft rat genome revealing
      surprising differences in size and gene content between the mouse and the rat
      Ly49 clusters. The rat cluster contains at least 36 Ly49 genes, including
      pseudogenes, while dot-plot analysis of the cluster reveals an equidistant
      spacing of genes, suggesting that duplication of genes in the cluster occurred
      through a mechanism similar to that in the mouse. Phylogenetic analysis of the
      predicted rat genes reveals a number of distinct gene clusters and indicates that
      the majority of gene duplication events occurred after the divergence of mice and
      rats. Thus, the rodent Ly49 locus is subject to extremely rapid gene
      amplification and diversification.

PMID- 15203221
TI  - Promoter analysis of the human p44 mitogen-activated protein kinase gene (MAPK3):
      transcriptional repression under nonproliferating conditions.
AB  - We have analyzed the promoter of the human p44mapk gene (approved symbol MAPK3)
      and found that the elements responsible for basal transcriptional activity are
      located within 200 bp upstream of the initiation codon in the 5' UTR. This
      sequence has a high G/C content (80.5%), with four Sp1 sites and an E box as the
      most relevant motifs. Site-directed mutagenesis, EMSA, and DNase I footprinting
      experiments demonstrate that all these elements are essential to achieve a
      significant level of transcription. We also report that the promoter activity is
      strongly repressed when the cells are brought under growth arrest conditions,
      such as confluence or serum withdrawal. This finding suggests that in the process
      of cell proliferation, together with the modulation of p44mapk kinase activity by
      the rapid mechanism of phosphorylation/dephosphorylation, a long-term more
      adaptive regulation, based on gene transcription, might also be important.

PMID- 15203222
TI  - Clinical examination of the ruminant nervous system.
AB  - Practical and rapid physical examination techniques that allow the clinician to
      neuroanatomically localize the site of disease to the cerebrum,cerebellum,
      brainstem/cranial nerves, or spinal cord/peripheral nerves are described. The
      physical examination methods discussed in this article can be performed easily
      and quickly and do not require any specialized or expensive equipment to perform.

PMID- 15203223
TI  - Diagnostic techniques and clinicopathologic findings in ruminant neurologic
      disease.
AB  - In ruminant species, cerebrospinal fluid (CSF) collection and analysis provide
      rapid (in some situations, instant) information to the veterinary clinician
      investigating a disease problem in the living animal. CSF analysis is
      particularly useful with respect to confirming the presence of an inflammatory
      lesion involving the leptomeninges,such as bacterial meningoencephalitis, and in
      investigating potential compressive lesions of the spinal cord. When correctly
      performed under local anesthesia, lumbar CSF collection in ruminants is a safe
      procedure and there are no harmful sequelae. Familiarity with the technique aids
      high extradural injection of lidocaine or xylazine, which has many applications
      in farm practice. There are few indications for cisternal CSF collection in food
      animals.

PMID- 15203224
TI  - Acquired spinal cord and peripheral nerve disease.
AB  - Acquired spinal cord diseases in ruminants result most commonly from infectious,
      traumatic, metabolic/nutritional, or toxic causes and rarely from neoplasia.
      Clinical signs of spinal cord disease depend on the neuroanatomic location of the
      lesion. Acquired spinal cord diseases including vertebral osteomyelitis/spinal
      abscess, cauda-equina disease, enzootic ataxia,
      lymphosarcoma,polyradiculoneuritis, and degenerative myeloencephalopathy are
      discussed. Acquired peripheral nerve disease in cattle most often is a result of
      injury, and most commonly only one limb is involved. Peripheral nerve injuries
      frequently occur secondary to myopathy in recumbent adult cattle. In small
      ruminants, peripheral nerve injury seems less common, most likely due to their
      smaller size,but may occur from predator wounds or iatrogenically following
      intramuscular drug administration. Injury to the brachial plexus and radial,
      suprascapular, sciatic, femoral, and obturator nerves is discussed.

PMID- 15203225
TI  - Brainstem and cranial nerve abnormalities: listeriosis, otitis media/interna, and
      pituitary abscess syndrome.
AB  - This article reviews three disorders associated with multiple asymmetric cranial
      nerve deficits in ruminants: encephalitic listeriosis,otitis media/interna, and
      pituitary abscess syndrome. Emphasis is placed on encephalitic listeriosis, an
      infectious disease of the brainstem and cranial nerves caused by Listeria
      monocytogenes. The epidemiology, pathophysiology, clinical manifestations,
      diagnosis,and treatment of encephalitic listeriosis are reviewed, and differences
      between cattle and small ruminants are noted. Physical and neurologic examination
      findings that distinguish otitis media/interna and pituitary abscess syndrome
      from encephalitic listeriosis are highlighted.

PMID- 15203226
TI  - Cerebellar disease and disease characterized by dysmetria or tremors.
AB  - Diseases of the cerebellum and diseases that cause signs of dysmetria or tremors
      occur infrequently in ruminants. A thorough neurologic examination should be
      performed to attempt to localize the lesion. A list of differential diagnoses can
      be organized in rank order based on the location of the lesion and the
      signalment, history,and results of physical examination. A definitive diagnosis
      is based on the results of diagnostic testing, response to treatment,or
      postmortem examination.

PMID- 15203227
TI  - Altered mentation caused by polioencephalomalacia, hypernatremia, and lead
      poisoning.
AB  - Polioencephalomalacia in general and the specific disorders associated with lead
      toxicosis and sodium imbalances all have commonalities in risk groups and
      clinical presentations but can be differentiated based on herd history, subtle
      clinical differences, and diagnostic tests. Treatment also has some overlap, but
      determining the specific etiology enables more specific treatment and more
      effective prophylactic measures.

PMID- 15203228
TI  - Transmissible spongiform encephalopathies in ruminants.
AB  - Transmissible spongiform encephalopathies (TSEs) have been observed in North
      American sheep, cervidae, and cattle. The causative agent of TSEs seems to be
      proteins that induce a conformational change in normal host proteins. Common
      clinical signs ofTSEs include chronic weight loss and deteriorating neurologic
      function. Mechanisms of TSE transmission vary among host species. The diagnostic
      approach for TSEs of ruminants is presented,and the history and justification of
      regulatory programs to control and eradicate TSEs are outlined.

PMID- 15203229
TI  - Viral diseases of the ruminant nervous system.
AB  - This article presents the etiology, epidemiology, clinical features,and diagnosis
      of the primary viral neurologic diseases observed in ruminants. In general, these
      viral neurologic diseases are uncommon but often fatal. Rabies virus is perhaps
      the most important cause of encephalitis in cattle because of the public health
      implications. Other viral encephalitis diseases in ruminants include bovine
      herpesvirus encephalomyelitis, pseudorabies, malignant catarrhal fever, ovine and
      caprine lentiviral encephalitis, West Nile virus encephalitis, Borna disease,
      paramyxoviral sporadic bovine encephalomyelitis,and ovine encephalomyelitis
      (louping-ill).

PMID- 15203230
TI  - Bacterial meningitis and encephalitis in ruminants.
AB  - The clinical aspects of bacterial meningitis in neonates are described in this
      article. Specific types of meningitis affecting adult cattle are also described.
      Other conditions occurring less frequently,such as frontal sinusitis and brain
      abscess, are discussed.

PMID- 15203231
TI  - Clostridial disease associated with neurologic signs: tetanus, botulism, and
      enterotoxemia.
AB  - Clostridial infections are found worldwide in almost all species of animals and
      may involve a variety of body systems and present with a diversity of clinical
      signs. Most damage done through clostridial infections is due to the action of
      toxins released from the bacteria.Thus, disease caused by Clostridium spp should
      more correctly be called intoxication. Two prominent clostridial infections are
      associated with neurologic signs: Clostridium botulinum and C tetani. In both
      infections, the mechanism that is responsible for causing the problem is similar,
      despite the remarkable difference in clinical presentation. In addition,
      neurologic signs are described with C perfringens types C and D but are not the
      dominant feature of these diseases.

PMID- 15203232
TI  - Parelaphostrongylus tenuis and other parasitic diseases of the ruminant nervous
      system.
AB  - There are many parasites that affect the ruminant central nervous system.
      Clinical signs can vary dramatically based on the location and mobility of the
      parasite. Clinical disease can occur due to the physical presence of the parasite
      and the resulting host immune response or the toxin produced by the parasite.
      Differentiating the cause of disease is particularly important because
      prognosis,treatment, and subsequent control measures vary dramatically depending
      on the disease process. This article focuses on the pathogenesis,treatment, and
      control of some of the more common parasitic diseases of the ruminant central
      nervous system.

PMID- 15203233
TI  - Congenital defects of the ruminant nervous system.
AB  - Abnormalities of the nervous system are common occurrences among congenital
      defects and have been reported in most ruminant species. From a clinical
      standpoint, the signs of such defects create difficulty in arriving at an
      antemortem etiology through historical and physical examination alone. By first
      localizing clinical signs to their point of origin in the nervous system,
      however, a narrower differential list can be generated so that the clinician can
      pursue a definitive diagnosis. This article categorizes defects of the ruminant
      nervous system by location of salient clinical signs into dysfunction of one of
      more of the following regions: cerebrum, cerebellum,and spinal cord. A brief
      review of some of the more recognized etiologies of these defects is also
      provided. It is important to make every attempt to determine the cause of nervous
      system defects because of the impact that an inherited condition would have on a
      breeding program and for prevention of defects caused by infectious or toxic
      teratogen exposure.

PMID- 15203235
TI  - Potential targets for anti-SARS drugs in the structural proteins from SARS
      related coronavirus.
AB  - This is a further study on the severe acute respiratory syndrome (SARS) using the
      probabilistic models. The purpose was to define the potential targets for anti
      SARS drugs in the structural proteins from human SARS related coronavirus (SARS
      CoV) while knowing little about the functional sites and possible mutations in
      these proteins. From a probabilistic viewpoint, we can theoretically select the
      amino acid pairs as potential candidates for anti-SARS drugs. These candidates
      have a greater chance of colliding with anti-SARS drugs, are more likely to link
      with the protein functions and are less vulnerable to mutations.

PMID- 15203236
TI  - Calcium and chlorpromazine binding to the EF-hand peptides of neuronal calcium
      sensor-1.
AB  - Neuronal calcium sensor-1, a protein of calcium sensor family, is known to have
      four structural EF-hands. We have synthesised peptides corresponding to all the
      four EF-hands and studied their conformation and calcium-binding. Our data
      confirm that the first putative site, a non-canonical one (EF1), does not bind
      calcium. We have investigated if this lack of binding is due to the presence of
      non-favoured residues (particularly at +x and -z co-ordinating positions) of the
      loop. We have mutated these residues and found that after modification the
      peptides bound calcium. However, these mutated peptides (EF1 and its functional
      mutants) do not show any Ca(2+) induced changes in far-UV CD. EF2, EF3, and EF4
      peptides bind Ca(2+), EF3 being the strongest binder, followed by EF4. Our data
      of Ca(2+)-binding to individual EF peptides show that there are three active
      Ca(2+)-binding sites in NCS-1. We have also studied the binding of a neuroleptic
      drug, chlorpromazine, with the protein as well as with its EF-hands. CPZ binds
      myristoylated as well as non-myristoylated NCS-1 in Ca(2+)-dependent manner, with
      dynamic interaction to myristoylated protein. CPZ does not bind to EF1, but binds
      to functional EF-hand peptides and induces changes in far-UV CD. Our results
      suggest that NCS-1 could be a target of such antipsychotic and neuroleptic drugs.

PMID- 15203237
TI  - Jelleines: a family of antimicrobial peptides from the Royal Jelly of honeybees
      (Apis mellifera).
AB  - Four antimicrobial peptides were purified from Royal Jelly of honeybees, by using
      reverse phase-HPLC and sequenced by using Q-Tof-MS/MS: PFKLSLHL-NH(2) (Jelleine
      I), TPFKLSLHL-NH(2) (Jelleine-II), EPFKLSLHL-NH(2) (Jelleine-III), and TPFKLSLH
      NH(2) (Jelleine-IV). The peptides were synthesized on-solid phase, purified and
      submitted to different biological assays: antimicrobial activity, mast cell
      degranulating activity and hemolysis. The Jelleines-I-III presented exclusively
      antimicrobial activities against yeast, Gram+ and Gram- bacteria; meanwhile,
      Jelleine-IV was not active in none of the assays performed. These peptides do not
      present any similarity with the other antimicrobial peptides from the honeybees;
      they are produced constitutively by the workers and secreted into Royal Jelly.

PMID- 15203238
TI  - Flammin and velin: new ribosome inactivating polypeptides from the mushroom
      Flammulina velutipes.
AB  - A protein designated flammin and exhibiting a molecular mass of 30kDa, and
      another protein designated velin and possessing a molecular mass of 19 kDa, were
      isolated from the fruiting bodies of the edible mushroom Flammulina velutipes.
      Flammin and velin inhibited translation in a rabbit reticulocyte lysate system
      with an IC(50) of 1.4 and 2.5 nM, respectively. Flammin demonstrated only a small
      degree of resemblance in N-terminal sequence to angiosperm type 1 ribosome
      inactivating proteins (RIPs) such as trichosanthin, alpha-momorcharin and beta
      momorcharin but no sequence similarity to other mushroom RIPs. Velin manifested
      limited sequence homology to the A chain of abrin, a type 2 angiosperm RIP.
      Neither flammin nor velin showed any ribonuclease or protease activity. Both
      flammin and velin were unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue
      gel and CM-Sepharose. They were separable in gel filtration on Superdex 75 by
      fast protein liquid chromatography.

PMID- 15203239
TI  - Isolation of a new ribonuclease from fruiting bodies of the silver plate mushroom
      Clitocybe maxima.
AB  - A ribonuclease, with an N-terminal sequence exhibiting some homology to
      ribonuclease from Pleurotus ostreatus (Family Pleurotaceae), has been purified
      from fruiting bodies of the silver plate mushroom Clitocybe maxima (Family
      Tricholomataceae). However, there is little resemblance between the N-terminal
      sequences of ribonucleases from various Pleurotus species, and a lesser extent of
      resemblance between ribonucleases from C. maxima and Pleurotus tuber-regium. No
      structural relationship exists between ribonuclease from C. maxima, and those
      from Volvariella volvacea, Lentinus edodes and Irpex lacteus. The purification
      protocol involved ion exchange chromatography on DEAE-cellulose, affinity
      chromatography on Affi-gel blue gel, ion exchange chromatography on CM-Sepharose,
      and fast protein liquid chromatography on Superdex 75. The ribonuclease was
      unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue gel and CM-Sepharose.
      It exhibited a molecular mass of 17.5 kDa in both gel filtration and sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis. It manifested roughly the
      same ribonucleolytic potency toward poly A and poly G followed by poly U. Its
      activity toward poly C was, by comparison, meager. The temperature and pH
      required for its optimal activity were, respectively, 70 degrees C and 6.5-7.0.

PMID- 15203240
TI  - Molecular identification of SGPP-5, a novel pacifastin-like peptide precursor in
      the desert locust.
AB  - Recently, a new serine protease inhibitor family has been described in
      arthropods. Eight members were purified from locusts and 13 peptides have been
      identified by cDNA cloning. The peptides share a conserved cysteine array (Cys
      Xaa(9-12)-Cys-Asn-Xaa-Cys-Xaa-Cys-Xaa(2-3)-Gly-Xaa(3-6)-Cys-Thr-Xaa(3)-Cys) with
      nine inhibitory domains (PLDs) of the light chain of the crayfish protease
      inhibitor, pacifastin. A molecular identification of a pacifastin-related
      precursor (SGPP-5) with three novel PLD-related peptides is presented in this
      study. This is a first report, identifying the presence of a SGPP-transcript in
      the brain, fore- and hindgut, including a 100-fold difference in fat body SGPP
      transcript level of male as compared with female locust.

PMID- 15203241
TI  - Purification, characterization and sequence determination of BmKK4, a novel
      potassium channel blocker from Chinese scorpion Buthus martensi Karsch.
AB  - The scorpion neurotoxin BmKK4 was purified from the venom of the Chinese scorpion
      Buthus martensi Karsch by a combination of gel-filtration, ion exchange and
      reversed phase chromatography. The primary sequence of BmKK4 was determined using
      the tandem MS/MS technique and the cDNA database searching as followings: ZTQCQ
      SVRDC QQYCL TPDRC SYGTC YCKTT (NH(2)). BmKK4 is the first isolated member of a
      new subfamily alpha-KTx17 of scorpion K(+) toxins.

PMID- 15203242
TI  - Ala-scan of ghrelin (1-14): interaction with the recombinant human ghrelin
      receptor.
AB  - Ghrelin, a 28 residues acylated peptide, is the natural ligand of the growth
      hormone secretagogue receptor (GHS-R), which also interacts with small synthetic
      peptides. We investigated the importance of each of the first 14 N-terminal
      residues by Ala replacement (Ala-scan) and also of the N-terminal positive
      charge, on the recombinant GHS-R expressed in HEK293 or CHO cells by binding, IP
      and Ca(2+) assays. Nearly all of the replacements had no significant effect on
      the ligand binding or IP(3)/Ca(2+) stimulation. Exceptions were the modification
      of the N-terminal residue to [A(1)]- or N(alpha)-acetyl-ghrelin (1-14),
      confirming the requirement for the positive charge at the amino-terminus.
      Mutation of [F(4)]- to [A(4)]- or [Y(4)]-ghrelin (1-14), were detrimental
      suggesting direct interaction with the GHS-R. [A(8)] and [Y(8)] were more potent
      than ghrelin (1-14), implying that the naturally occurring Glu(8) residue may not
      be the optimal.

PMID- 15203243
TI  - Galanin-like peptide gene expression in the hypothalamus and posterior pituitary
      of the obese fa/fa rat.
AB  - We examined the galanin-like peptide (GALP) gene expression in the arcuate
      nucleus (ARC) and posterior pituitary (PP) in 6- and 18-week-old male obese fa/fa
      rats. GALP mRNA in the ARC in fa/fa rats was significantly decreased in 6- and 18
      week-old and GALP mRNA in the PP in fa/fa rats was significantly increased in 18
      week-old compared to lean Fa/? rats. Insulin treatment in hyperglycemic fa/fa
      rats partially reversed those changes. These results suggest that the GALP gene
      expression in fa/fa rats might be regulated in part by leptin-independent
      mechanisms.

PMID- 15203244
TI  - Assessment of ethanol consumption and water drinking by NPY Y(2) receptor
      knockout mice.
AB  - In recent years, pharmacological and genetic evidence have emerged suggesting
      that neuropeptide Y (NPY) and the NPY Y(1) receptor are involved with
      neurobiological responses to ethanol. Pharmacological data implicate a role for
      the NPY Y(2) receptor in ethanol self-administration. The purpose of the present
      study was to determine if genetic mutation of the Y(2) receptor would modulate
      ethanol consumption and/or ethanol-induced sedation. Here, we report that mutant
      mice lacking the NPY Y(2) receptor (Y(2)(-/-)), when maintained on a mixed 50%
      129/ SvJ x 50 % Balb/cJ background, drink significantly less of solutions
      containing 3 or 6% (v/v) ethanol relative to wild-type (Y(2)(+/+)) mice. These
      mice drink normal amounts of solutions containing sucrose or quinine, have normal
      blood ethanol clearance, and show normal sensitivity to ethanol-induced sedation.
      However, Y(2)(-/-) mice that are backcrossed to a Balb/cJ background show normal
      consumption of ethanol, indicating that the contributions of the NPY Y(2)
      receptor to ethanol consumption are genetic background dependent. Consistent with
      previous data suggesting that NPY modulates water drinking, Y(2)(-/-) mice of
      both genetic backgrounds consume significantly more water than Y(2)(+/+) mice.
      The present results suggest roles for the NPY Y(2) receptor in the modulation of
      ethanol and water consumption.

PMID- 15203245
TI  - Enhancement of feeding suppression by PYY(3-36) in rats with area postrema
      ablations.
AB  - We investigated suppression of food intake by intraperitoneal (IP) injections of
      peptide YY(3-36) (PYY(3-36)) (24, 60, or 150 microg/kg) in rats with ablations of
      the area postrema (APX) and in controls with sham ablations. In controls, PYY(3
      36)-induced suppression was modest and short-lived, averaging 20% at most and
      persisting less than 6h. The highest dose tested (150 microg/kg) was even less
      effective than were the two lesser doses after 3h. APX did not diminish the
      potency of these effects of PYY(3-36). In fact, the magnitude of suppression
      produced by the greatest dose of PYY(3-36) in APX rats was significantly greater
      than in controls and PYY(3-36)-induced suppression was still present at 24h.

PMID- 15203246
TI  - Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in
      vivo.
AB  - Orexin-A (Hypocretin-1) has been localized in the posterior and lateral
      hypothalamic perifornical region. Orexin containing axon terminals have been
      found in hypothalamic nuclei and many other parts of the brain; for example, the
      hippocampus. Two types of orexin receptors have been discovered. Orexin 1 type of
      receptors have been described and been shown to be widely distributed in the rat
      brain including the hippocampus. Subsequently Orexin-A was found to impair both
      water maze performance and hippocampal long term potentiation (LTP). Leptin is
      expressed in adipose tissue and released into the blood where it affects food
      intake and can also produce widespread physiological changes mediated via
      autonomic preganglionic neurons, pituitary gland, and cerebral cortex.
      Immunoreactivity for leptin receptors has been found in various hypothalamic
      nuclei including the lateral hypothalamic area as well as the hippocampus
      especially in the dentate gyrus and CA1. Leptin receptor deficient rats and mice
      also show impaired LTP in CA1 and poor performance in the water maze. The present
      study was conducted to determine the effects of 0.0, 30, 60, 90, and 100 nM,
      orexin-A, and leptin, 0.0, 1.0, 100 nM, 1, and 10 microM, in 1.0 microl of ACSF,
      applied directly into the dentate gyrus, on LTP in medial perforant path dentate
      granule cell synapses in urethane anesthetized rats. Orexin-A specifically
      enhanced LTP at the 90 nM dose; and it was possible to block the enhancement by
      pretreating the animals with SB-334867, a specific orexin 1 receptor antagonist.
      Leptin enhanced normal LTP at 1.0 microM but inhibited LTP at lower and higher
      doses. These results and previous data indicate that the same peptide could
      possibly have different modulatory post synaptic effects in different hippocampal
      synapses dependent upon different types of post synaptic receptors.

PMID- 15203247
TI  - Seasonal changes of SP and NKA in frontal cortex, striatum and testes in the rat.
      Role of maternal pineal gland.
AB  - The concentrations of neurokinin A (NKA) and substance P (SP), members of
      tachykinins family, have been studied in all seasons of the year in frontal
      cortex, striatum and testes of male offspring 21-, 31-, or 60 days old of mother
      Wistar rats: control, pinealectomized (PIN-X) and pinealectomized + melatonin
      during pregnancy (PIN- X + MEL) kept under 12h:12h L:D. Control-offspring: in
      spite of having been kept under constant environmental conditions throughout the
      year, had marked differences in tachykinin concentrations. The highest tachykinin
      concentrations in the frontal cortex were found in summer and fall and the lowest
      in winter and spring. Maternal PIN-X resulted in alterations of this
      developmental pattern, mainly in PIN-X- and PIN- X + MEL-offspring in which the
      highest tachykinin concentrations at 21 and 31 days of age were only observed
      during summer. The alterations were observed up to 60 days of age for both
      tachykinins, when at this age control-offspring showed similar NKA
      concentrations. Seasonal variations were still observed in PIN-X- and PIN- X +
      MEL-offspring. In striatum and testes no mayor modifications throughout the four
      seasons of the year were found, with very few exceptions. PIN-X did not alter
      tachykinin concentrations, neither treatment with melatonin did it. In
      conclusion, our data clearly indicate for the first time that NKA and SP do
      indeed have seasonal rhythms in frontal cortex and that the maternal pineal gland
      plays a role in their entrainment already during fetal life.

PMID- 15203248
TI  - Leucopyrokinin (LPK) analog [d-Ala(5)]-[2-8]-LPK inhibits LPK-induced analgesia
      in rats.
AB  - It has been previously found in our laboratory that insect neuropeptide
      leucopyrokinin and [2-8]-leucopyrokinin, a truncated analog without the first
      aminoacid of leucopyrokinin peptide chain exert an antinociceptive effect in
      rats. The present study confirmed our previous results, and moreover it has been
      found that [d-Ala(5)]-[2-8]-leucopyrokinin, an analog of leucopyrokinin
      antagonized the antinociceptive effect of leucopyrokinin and of [2-8]
      leucopyrokinin. We conclude that this synthetic analog is a probable
      leucopyrokinin antagonist.

PMID- 15203249
TI  - Gastrointestinal effects of intracerebroventricularly injected
      nociceptin/orphaninFQ in rats.
AB  - Nociceptin/orphanin FQ/(N/OFQ), a novel heptadecapeptide recently isolated from
      porcine and rat brain, is the endogenous ligand of the N/OFQ peptide receptor
      (NOP, previously known as ORL-1). In this study we examined the effects of
      intracerebroventricularly (icv) injected N/OFQ on gastric emptying,
      gastrointestinal transit, colonic propulsion and gastric acid secretion in rats.
      N/OFQ (0.01-10 nmol/rat) significantly delayed gastric emptying of a phenol red
      meal, inhibited transit of a non-absorbable charcoal marker through the small
      intestine and increased the mean colonic bead expulsion time. These N/OFQ-motor
      effects were abolished by the NOP receptor selective antagonist [NPhe(1)]N/OFQ(1
      13)-NH(2) (50 nmol/rat), but were unaltered by the classical opioid receptor
      antagonist, naloxone (9.2 micromol/kg). Icv injected N/OFQ (10 nmol/rat)
      decreased gastric acid secretion in 2-h pylorus ligated rats in a naloxone
      sensitive manner. [NPhe(1)]N/OFQ(1-13)-NH(2) (100 nmol/rat) icv administered
      alone stimulated gastric acid secretion. These results indicate that N/OFQ
      activates via NOP receptor stimulation a central inhibitory pathway modulating
      gastrointestinal propulsive activity and gastric acid secretion in rats.

PMID- 15203250
TI  - Antigenicity and immunogenicity of the C-terminal peptide of human thyroglobulin.
AB  - Thyroglobulin (Tg) is cleaved into several peptides during thyroid hormone
      synthesis, an oxidative process. P40, an iodinated C-terminal peptide from human
      Tg, has a molecular weight of about 40 kDa and contains two hormonogenic sites.
      P40 is the smallest peptide that is still recognized by monoclonal antibodies
      from mice immunized with human Tg directed against its immunodominant region.
      Since P40 also contains several T-cell epitopes, it is a good candidate for
      studying the primary events involved in the process of hormone synthesis leading
      to thyroid autoimmunity. The present results show that P40 is recognized by Tg
      antibodies from patients with thyroid disorders and induces Tg antibodies in CBA
      mice. P40 may therefore be involved in the autoimmune process, thus providing a
      useful tool for diagnostic and therapeutic purposes.

PMID- 15203251
TI  - Differential response of human cardiac fibroblasts to angiotensin I and
      angiotensin II.
AB  - The vasoactive peptide angiotensin II (Ang II) has been implicated as a mediator
      of myocardial fibrosis. We carried out a comparative investigation of the effects
      of Ang II and its precursor Ang I on collagen metabolism and proliferation in
      cultured human cardiac fibroblasts. Cardiac fibroblasts responded to both Ang I
      and Ang II with concentration-dependent increases in collagen synthesis but no
      proliferation. The stimulatory effect of Ang II was abolished by the AT(1)
      receptor antagonist losartan but not the AT(2) receptor antagonist PD123319. The
      response to Ang I was not affected by either antagonist, nor by the angiotensin
      converting enzyme (ACE) inhibitor captopril. In conclusion, Both Ang I and Ang II
      stimulate collagen synthesis of human cardiac fibroblasts, the effect of Ang II
      occurring via the AT(1) receptor whilst Ang I appears to exert a direct effect
      through non-Ang II-dependent mechanisms. These results suggest distinct roles for
      angiotensin peptides in the development of cardiac fibrosis.

PMID- 15203252
TI  - Host-defence peptides of Australian anurans: structure, mechanism of action and
      evolutionary significance.
AB  - Host-defence peptides secreted from the skin glands of Australian frogs and
      toads, are, with a few notable exceptions, different from those produced by
      anurans elsewhere. This review summarizes the current knowledge of the following
      classes of peptide isolated and characterized from Australian anurans:
      neuropeptides (including smooth muscle active peptides, and peptides that inhibit
      the production of nitric oxide from neuronal nitric oxide synthase),
      antimicrobial and anticancer active peptides, antifungal peptides and
      antimalarial peptides. Other topics covered include sex pheromones of anurans,
      and the application of peptide profiling to (i). recognize particular populations
      of anurans of the same species and to differentiate between species, and (ii).
      investigate evolutionary aspects of peptide formation.

PMID- 15203253
TI  - Peptides and proteins from fungi.
AB  - The peptides and proteins secreted by fungi are reviewed in this article. They
      include ribosome inactivating peptides and proteins, antifungal peptides and
      proteins, lectins, ubiquitin-like peptides and proteins, peptides and proteins
      with nucleolytic activity, proteases, xylanases, cellulases, sugar
      oxidoreductases, laccases, invertases, trehalose phosphorylases, and various
      enzymes with applications in food industry, chemical production and the medical
      sector.

PMID- 15203254
TI  - Torsade de pointes: the clinical considerations.
AB  - Torsade de pointes is a form of polymorphic ventricular tachycardia occurring in
      a setting of prolonged QT interval on surface electrocardiogram. Congenital
      causes of prolonged QT interval occur in individuals with genetic mutations in
      genes that control expression of potassium and sodium channels and acquired
      causes are numerous, predominantly drugs causing prolonged QT interval by
      blockade of potassium channels. Among the drugs, antiarrhythmic agents most
      notably quinidine, sotalol, dofetilide and ibutilide have the potential to induce
      the fatal torsade de pointes. Many non-antiarrhythmic drugs can also cause
      torsade de pointes. Although it is important to distinguish between the
      congenital and the acquired forms of long QT syndrome as the later can often be
      reversed by correction of the underlying disorder or discontinuation of the
      offending drug, both forms are not mutually exclusive. Clinical considerations
      and management of torsade de pointes are described.

PMID- 15203255
TI  - Ischemic heart disease in women and the role of hormone therapy.
AB  - The prevalence of ischemic heart disease (IHD) has been increasing among the
      women in developed countries. The well recognized IHD excess in men has often
      obscured the fact that IHD is the leading cause of death in women. Women have
      atypical symptoms of IHD that lead to a delay in the diagnosis and an overall
      poor prognosis. Women have a delay in the onset of IHD due to the beneficial
      effects of their sex hormones. Postmenopausal women lose this beneficial effect
      of estrogen and undergo significant changes in their lipid profile, arterial
      pressure, glucose tolerance, and vascular reactivity that increase their risk for
      development of IHD. Recently there has been considerable interest in the sex
      hormones and their role in IHD in women. The general belief that hormone
      replacement therapy (HRT) has an overall beneficial effect on cardiovascular
      disease (CVD) in women and hence decreases CVD mortality and morbidity has not
      been shown in the recent multicenter prospective studies. With the availability
      of various types of estrogen and progestins, physicians prescribing these agents
      should take into consideration their varying effects on the cardiovascular
      system. Risk factor modifications should include diet, weight loss, regular
      exercise, smoking cessation and adequate control of hypertension (HTN), diabetes
      (DM) and hyperlipidemia. In the appropriate setting, treatment with proven
      beneficial agents like aspirin, beta-blockers, angiotensin converting enzyme
      (ACE) inhibitors and statins will help decrease the burden of IHD in women.

PMID- 15203256
TI  - Is measurement of plasma brain natriuretic peptide levels a useful test to detect
      for surgical timing of valve disease?
AB  - BACKGROUND: The optimal timing of valve surgery is very important. In patients
      who are severely symptomatic, the marked improvement in symptomatic status
      observed following successful valve surgery. However, in patients with no or only
      mild symptoms, the decision is more difficult. The aim of this retrospective
      study was to determine whether the measurement of plasma brain natriuretic
      peptides (BNP) levels is useful to decide surgical timing for valve disease.
      METHODS: Fifty-one patients with valve disease underwent single valve surgery
      (mitral stenosis, MS, 13; mitral regurgitation, MR, 16; aortic stenosis, AS, 14;
      aortic regurgitation, AR, 8 patients). Blood samples, echocardiographic and
      cardiac catheterization data were obtained before operation and echocardiographic
      examination were performed after 1-year of operations. RESULTS: In patients
      subjected to single heart valve surgery, plasma BNP mean levels were 214.6+/-48.5
      pg/ml. In plasma BNP levels, there was only significant difference between MS and
      AS group (MS 67.5+/-9.7 vs. AS 314.3+/-112.0 pg/ml, P=0.04). There were no
      relationships between plasma BNP levels and pre-operative cardiac functions.
      After 1-year of the valve surgery, NYHA functional class was reduced in 36
      patients (70.6%) and plasma BNP levels before the surgery significantly
      correlated with post-operative NYHA functional class. CONCLUSIONS: In this
      retrospective study, patients with high plasma BNP levels significantly impaired
      the improvement of clinical symptoms after surgery. We have suggested that plasma
      BNP levels is useful for detecting asymptomatic valvular disease, and is a
      clinical marker useful in determining the optimal surgical timing.

PMID- 15203257
TI  - Lack of association between water hardness and coronary heart disease mortality
      in Japan.
AB  - BACKGROUND: Elevated levels of water hardness are related to lower mortality from
      coronary heart disease (CHD) in different populations. This ecologic study
      assessed whether water hardness is related to lower mortality from CHD in Osaka
      Prefecture, with 44 municipalities, Japan. METHODS: The mortality rate from CHD
      per municipality was calculated based on the number of coronary deaths and
      midyear population in 1995. Values for water hardness in each of the
      municipalities were estimated based on the yearly amount of water supply per
      source and the yearly average of water hardness for each source in 1997. Multiple
      logistic regression analysis was used to control socioeconomic status and health
      care status in each municipality. RESULTS: In males, after adjustment for age, an
      inverse dose-response relationship between water hardness and mortality from CHD
      was significant (P for linear trend=0.004). However, this relationship virtually
      disappeared after further adjusting for socioeconomic status and health care
      status. In females, there was no material association between water hardness and
      coronary mortality. CONCLUSIONS: This study provides no evidence that water
      hardness is preventive against mortality from CHD in Japan.

PMID- 15203258
TI  - Coronary flow velocity reserve and indices describing aortic distensibility in
      patients after coronary angiography.
AB  - BACKGROUND: The purpose of this study was to assess the elastic properties of the
      descending aorta and the coronary flow velocity reserve (CFR) in patients after
      coronary angiography. METHODS AND PATIENTS: We recruited 112 subjects with stable
      angina pectoris without a previous myocardial infarction: 17 consecutive patients
      with anatomically normal coronary arteries, 24 patients with non-significant
      coronary artery disease (CAD), 31 patients with significant left anterior
      descending coronary artery (LAD) disease and 40 patients with multivessel disease
      (MVD). Transoesophageal echocardiography (TEE) is useful for evaluation of the
      elastic properties of the descending aorta. The physical behaviour of vessels in
      response to an intraluminal force is described by the elastic modulus (E(p)) and
      Young's circumferential static elastic modulus (E(s)). Coronary flow velocities
      can be measured in the LAD under baseline conditions and during dipyridamole
      stress. The CFR was calculated as the ratio of the average peak diastolic flow
      velocity during hyperaemia to that at rest. RESULTS: The indices of aortic
      distensibility, CFR and mean CFR, were different in patients with LAD disease and
      in those with normal coronary angiograms. There were no further changes in these
      parameters in cases with MVD. In patients with non-significant CAD, the CFR, mean
      CFR and stiffness moduli lie between those for negative cases and those for
      patients with LAD disease/MVD. CONCLUSIONS: When there was significant stenosis
      of the LAD, the CFR was significantly decreased, while indices of aortic
      distensibility were increased as compared with the negative controls.
      Interestingly, not only the CFR, but also E(p) and E(s) displayed no further
      changes in cases with MVD as compared with LAD disease.

PMID- 15203259
TI  - Elevated serum cardiac troponin I in rhabdomyolysis.
AB  - OBJECTIVE: To examine the etiology and clinical significance of elevated serum
      cardiac troponin I (cTnI) in patients with rhabdomyolysis. METHODS: Data on 91
      (63 men) consecutive patients with rhabdomyolysis were examined. RESULTS: The
      mean age was 57.8+/-19.6 years (range 24-97 years). Patients were divided into
      two groups: cTnI-positive with serum cTnI >0.6 ng/ml (n=19) and cTnI-negative
      with serum cTnI <0.6 ng/ml (n=72). Prevalence of cardiovascular risk factors was
      equal in both groups. Illicit substance use was more common in the cTnI-positive
      group (31% vs. 14%, P=0.04). Peak creatine kinase (CK) was higher in cTnI
      positive group (34,811+/-38,309 vs. 15,070+/-21,655 U/l, P=0.04) but there was no
      difference in the MB isoenzyme (CK-MB) (118+/-132 vs. 89+/-451 ng/ml, P=0.63). In
      cTnI-positive group, there was a strong correlation between peak CK and CK-MB
      (r(2)=0.606, P=0.00008) but not between peak cTnI and peak CK (r(2)=0.164 and
      P=0.08) or CK-MB (r(2)=0.134 and P=0.12) levels. Serum creatinine was higher in
      cTnI-positive group (3.58+/-2.73 vs. 1.83+/-2.01 mg/dl, P=0.02) but there was no
      correlation between serum creatinine and cTnI (r(2)=0.121, P=0.158). None of the
      cTnI-positive patient had segmental wall motion abnormalities. Seventeen (89%)
      patients in cTnI-positive and 19 (26%) in cTnI-negative group required admission
      to intensive care unit (P=0.0001). Hypotension (37% vs. 6%, P=0.0002) and sepsis
      (47% vs. 11%, P=0.0003) were more common in cTnI-positive group. Duration of
      hospitalization was longer in cTnI-positive group (17.7+/-11.7 vs. 8.9+/-13 days,
      P=0.007) but there was no significant difference in mortality. CONCLUSION: In
      rhabdomyolysis, serum cTnI may be elevated unrelated to the degree of muscle
      damage, renal failure and cardiovascular risk factors, and is likely related to
      the etiology of rhabdomyolysis, as is evidenced by significantly higher serum
      cTnI with illicit substance use, hypotension, and sepsis. Elevated serum cTnI is
      associated with a higher morbidity.

PMID- 15203260
TI  - Ischemic preconditioning prevents reperfusion heart injury in cardiac hypertrophy
      by activation of mitochondrial KATP channels.
AB  - BACKGROUND: Cardiac hypertrophy has been demonstrated to decreases the ATP
      sensitive potassium channels (K(ATP)), the major protective mechanism following
      the energy depletion, a common condition seen during the reperfusion after open
      heart surgery. In this study we have demonstrated the role of ischemic
      preconditioning (IP) in preventing the reperfusion injury of the hypertrophied
      heart by activation of the depleted K(ATP) channels. METHODS: Pressure overload
      left ventricular hypertrophy was induced in 6 weeks old male Wistar rats by supra
      renal transverse abdominal aortic constriction and the study was conducted 10-12
      weeks later. Hypertrophied rats were subjected to IP protocols by four episodes
      of 3 min ischemia each being separated by 10 min reperfusion, followed by 30 min
      of sustained ischemia and 120 min of reperfusion with or without treating the
      rats with K(ATP) channel antagonists 5-hydroxydecanoic acid (10 mg/kg per i.v.)
      or glibenclamide (1 mg/kg per i.v.), 10 min before the sustained ischemia.
      RESULTS: IP resulted in (a) less incidence of ventricular arrhythmias (b) less
      area of myocardial infarction (9.3% vs. 48.1%, IP to control) (c) less tissue
      water content (76.5% vs. 94.8%, IP to control) (d) well preserved myocardial ATP
      content (P<0.001 from control) content and (e) much fewer apoptotic cells (4.7%
      vs. 13.2%, IP to control). Pre treating the rats with the K(ATP) channel
      inhibitors before sustained ischemia resulted in inhibition of these protective
      effects of IP on cardiac hypertrophy. CONCLUSION: The above results, therefore,
      suggest to us that IP by activation of K(ATP) channels can afford protection
      against the ischemia-reperfusion injury in the hypertrophied heart.

PMID- 15203261
TI  - A pharmacoeconomic evaluation of aggressive cholesterol lowering in Sweden.
AB  - OBJECTIVE: To estimate the short-term healthcare costs and incremental cost per
      event avoided, associated with aggressive atorvastatin treatment in patients with
      acute coronary syndrome in Sweden. METHODS: The total expected 16-week healthcare
      costs per patient on atorvastatin 80 mg per day and placebo were compared using
      clinical outcomes data from The Myocardial Ischemia Reduction with Aggressive
      Cholesterol Lowering (MIRACL) study and Swedish cost data sources. The
      incremental cost per event avoided was also assessed for. The clinical outcomes
      measured in this pharmacoeconomic analysis included: death, cardiac arrest, non
      fatal myocardial infarction, fatal myocardial infarction, angina pectoris, non
      fatal stroke, congestive heart failure, and surgical or percutaneous coronary
      revascularizations. All direct medical costs were taken into account. RESULTS:
      The probability of the occurrence of an event was 40.4% per patient in the
      placebo cohort and 36.6% per patient in the atorvastatin cohort. The total
      expected cost per patient was SEK 17,887 (1950.21 euro) in the placebo group and
      SEK 18,465 (2013.06 euro) in the atorvastatin group, resulting in an incremental
      cost of SEK 578 (63.0137 euro) per patient. The cost per event avoided was SEK
      15,076 (1643.64 euro). Sixty six percent of the cost of atorvastatin treatment
      was offset by the cost savings obtained through the reduction in the number of
      events in the atorvastatin group compared to the placebo group. CONCLUSIONS: In
      Sweden, the clinical benefits of aggressive short-term atorvastatin treatment
      administered within a few days after acute coronary syndrome is associated with a
      substantial hospitalization cost offset secondary to the clinical benefits of
      atorvastatin.

PMID- 15203262
TI  - Use of transthoracic echocardiography combined with venous ultrasonography in
      patients with pulmonary embolism.
AB  - BACKGROUND: The diagnosis of pulmonary embolism (PE) remains difficult.
      Ultrasounds allow for the exploration of the venous system to great extent and
      for the detection of indirect signs of PE. The aim of this study was to determine
      the incidence of acute cor pulmonale (ACP) and deep venous thrombosis (DVT) found
      by ultrasonographic techniques in a population of patients with PE. METHODS: One
      hundred and seventy-three consecutive patients with acute PE (diagnosed either by
      spiral computed tomography or selective pulmonary angiography) had subsequently
      both transthoracic echocardiography (TTE) and venous ultrasonography. The
      diagnostic criterion used for defining ACP by echocardiography was the right to
      left ventricular end-diastolic area ratio over (or equal to) 0.6 with paradoxical
      septal wall motion. The diagnosis of DVT rested on vein incompressibility.
      RESULTS: ACP was found in 56% of our patients while 75% were found to have DVT
      and 89% of the patients had either ACP or DVT or both. All of the patients with
      proximal PE had ACP and/or DVT. The presence of ACP using echocardiography was
      significantly different according to the localization of PE (P<0.0001) and the
      clinical presentation (P=0.0001). The incidence of ACP and/or DVT was
      significantly different according to the localization of PE (P=0.001).
      Echocardiography combined with venous ultrasonography had improved the diagnosis
      value of venous ultrasonography in only 4% of patients with distal PE (P=0.65).
      CONCLUSION: A combined strategy using echocardiography with venous
      ultrasonography improves significantly the diagnostic value of venous
      ultrasonography in proximal and lobar PE and fails in distal PE.

PMID- 15203263
TI  - Clinical characteristics of young-onset hypertension-implications for different
      genders.
AB  - BACKGROUND: Hypertension may develop early, before the age of 40 years, in both
      genders, so-called young-onset hypertension. The clinical characteristics of
      young-onset hypertension have not been well defined. METHODS: The personal
      history and clinical characteristics were evaluated in a series of patients with
      young-onset hypertension. With the individual-matching, case-controlled design,
      patients were initially matched for age, gender and residence with the first
      control (C1) group in either 2:1 or 1:1 fashion. They were then additionally
      matched for body mass index (BMI) with the second control (C2) group in 1:1
      fashion. To elucidate the possible difference between genders, all the
      comparisons were conducted in males and females separately. RESULTS: A total of
      82 consecutive patients, 56 males and 26 females, with young-onset hypertension
      were included. Compared with the 148 subjects in C1 group, hypertensive patients
      were relatively highly educated and had less alcohol drinking in either gender.
      BMI (25.10+/-0.49 vs. 22.34+/-0.31 kg/m(2), P<0.001) and serum triglyceride level
      (153.35+/-10.71 vs. 98.76+/-5.12 mg/dl, P<0.001) were significantly increased in
      male patients, while serum uric acid (5.74+/-0.34 vs. 4.78+/-0.17 mg/dl, P=0.006)
      and triglyceride level (121.39+/-12.71 vs. 76.58+/-4.88 mg/dl, P=0.002) were
      increased in female ones. Compared to that in C2 group, serum triglyceride level
      was still increased in patients of either gender. Interestingly, serum
      cholesterol level in female patients was lower than that in either C1 or C2
      group. Further, serum triglyceride level was significantly correlated to BMI,
      serum cholesterol and glucose level in male patients but only to serum uric acid
      level in female ones. CONCLUSIONS: Clinical characteristics of young-onset
      hypertension were unique and different by gender. Though consistently increased
      in patients of either gender, serum triglyceride level was correlated to BMI,
      serum cholesterol and glucose level only in males, suggesting the gender-specific
      presence of metabolic syndrome in young-onset hypertension.

PMID- 15203264
TI  - Effects of beta-radiation with a 188rhenium-filled balloon catheter system on non
      stented adjacent coronary artery segments.
AB  - BACKGROUND: The effects of beta-radiation with a (188)rhenium ((188)Re)-filled
      balloon catheter system on angiographically normal reference segments have not
      been well defined. METHODS: In the Seoul National University Post-Angioplasty
      Rhenium irradiation (SPARE) trial, patients with de novo or restenotic lesions
      were first treated with a conventional catheter-based technique and then
      randomized to either a radiation group or a control group. Irradiation was
      performed using a (188)Re-filled conventional balloon catheter system. Among 97
      radiation group enrolled in this study from April 1998 through May 2001, 20
      patients with de novo lesions who received brachytherapy with a balloon at least
      10 mm longer than the length of an implanted stent, were selected and their post
      intervention and follow-up intravascular ultrasound (IVUS) images were analyzed.
      Each reference segment was divided into two segments; full dose-irradiation with
      injury segment (irradiated segment; from the stent edge to the radiopaque balloon
      markers), and low dose-irradiation without injury segment (edge segment; 5-mm
      long segment proximal or distal to the location of radiopaque markers). In
      control group, serial IVUS analysis was available only in 10 patients, and IVUS
      parameters of the non-stented adjacent segments in these patients were compared
      to those of irradiated segments in radiation group patients. RESULTS: Forty
      irradiated and 38 edge segments of the 20 radiation group patients were analyzed.
      In proximal irradiated segments, no significant changes were found in external
      elastic membrane (EEM), lumen or in the plaque plus media (P&M) areas. In distal
      irradiated segments, significant increases in the EEM (12.5+/-4.5 to 14.0+/-5.0
      mm(2), P<0.01) and P&M areas (5.5+/-2.0 to 6.6+/-2.3 mm(2), P<0.01) were found to
      occur without a change in lumen area. In proximal edge segments, P&M areas were
      significantly increased (9.0+/-1.7 to 10.5+/-2.6 mm(2), P=0.03). No significant
      changes in EEM, lumen or P&M areas were observed in the distal edge segments.
      Comparisons between the irradiated segments (n=40) in the radiation group and the
      non-stented adjacent segments (n=19) in the control group showed a significant
      difference in the percentage change of EEM areas (18.5+/-33.2% in radiation group
      vs. -3.1+/-32.1% in control group, P=0.02). CONCLUSIONS: beta-radiation with a
      (188)Re-filled conventional balloon catheter system appears to have no
      significant deleterious effect on angiographically normal reference segments over
      a 6 months follow up after brachytherapy.

PMID- 15203265
TI  - Prevalence of anemia in patients admitted to hospital with a primary diagnosis of
      congestive heart failure.
AB  - OBJECTIVES: To find the prevalence of anemia in patients hospitalized with the
      primary diagnosis of congestive heart failure (CHF). BACKGROUND: There is growing
      evidence that anemia is common in CHF and may contribute to the high morbidity
      and mortality associated with this condition. However, there is considerable
      disagreement about the prevalence of anemia in this condition. METHODS: In 338
      consecutive patients who were admitted to the medical wards with a primary
      diagnosis of CHF we extracted from the charts the hemoglobin (Hb), serum
      creatinine, age, sex, New York Heart Association (NYHA) functional class,
      presence of smoking, diabetes, hypertension, hyperlipidemia and the primary
      cardiac etiology of the CHF. Anemia was considered to be present when the Hb on
      admission was <12 g/dl. RESULTS: All the patients were NYHA functional class III
      IV. One hundred seventy seven (52.4%) of the 338 patients had a Hb on admission
      that was <12 g/dl. The mean Hb for the entire group was 12.0+/-1.8 g/dl. One
      hundred three (51.0%) of the 202 males were anemic compared to 74 (54.4%) of the
      136 women. The mean serum creatinine was 1.7+/-1.1 mg/dl. The prevalence of renal
      insufficiency (serum creatinine >1.5 mg%) was 47.6%. There was a negative
      correlation between the level of serum creatinine and Hb (r=-0.294) P<0.00001. Of
      the 177 patients who were anemic, most of 114 (64.4%) had a serum creatinine >1.5
      mg/dl. CONCLUSIONS: Anemia is a common finding in patients hospitalized with CHF
      and most anemic CHF patients have some degree of renal insufficiency. In view of
      the negative effect of anemia on cardiac function, it may be a common and
      important contributor to the mortality and morbidity of CHF in these patients.

PMID- 15203266
TI  - Thromboembolic prophylaxis in nonrheumatic atrial fibrillation: utilization
      patterns, efficacy, and complications in a long-term follow-up of community
      patients.
AB  - OBJECTIVES: To define the incidence, contemporary utilization patterns, efficacy,
      and complications of thromboembolic prophylactic treatment in patients with
      chronic (CAF) and paroxysmal atrial fibrillation (PAF). BACKGROUND: Although
      recent randomized trials with antithrombotic therapy in nonrheumatic atrial
      fibrillation (AF) patients emphasized the benefits of warfarin in preventing
      stroke, warfarin treatment is still far from optimal. METHODS: A retrospective
      analysis of the medical records of 506 patients with nonrheumatic PAF or CAF from
      23 clinics in the north of Israel, including an interview with the patients'
      family physician. RESULTS: (1) The most effective treatment for preventing
      thromboembolic events (a reduction of 75.9%) was warfarin at an international
      normalized ratio (INR) intensity of 2-3. (2) After diagnosis, 26.9% of the
      patients were treated with warfarin. (3) During the follow-up period (not
      following a thromboembolic event), an additional 26.9% of the patients began
      treatment with warfarin. (4) Elderly patients (p<0.001), patients with limited
      activity of daily living (ADL) (p<0.012) or instrumental activity of daily living
      (IADL) (p<0.001), and patients with PAF (p<0.0001) were less likely to be treated
      with warfarin. (5) Three new risk factors found for thromboembolic event were
      limited ADL (p<0.001), limited IADL (p<0.002), and extended duration of AF
      (p<0.006). CONCLUSIONS: Less than optimal utilization patterns of thromboembolic
      prophylactic treatment with anticoagulants were found, especially regarding
      elderly patients, patients with limited ADL and IADL, and patients with PAF,
      despite the fact that their thromboembolic risk is as high or higher than that of
      other patients with AF.

PMID- 15203267
TI  - Prehospital delay in acute coronary syndrome--an analysis of the components of
      delay.
AB  - BACKGROUND: Prompt hospital admission is essential when treating acute coronary
      syndrome. Delay prior to admission is unnecessarily long. Therefore, a thorough
      scrutiny of the influence of characteristics, circumstantial and subjective
      variables on elements of prehospital delay among patients admitted with acute
      coronary syndrome is warranted. METHODS: A structured interview was conducted on
      250 consecutive patients admitted alive with acute coronary syndrome. RESULTS:
      Median prehospital, decision, physician and transportation delays were 107, 74,
      25 and 22 min, respectively. Women (n=77) had more frequently atypical symptoms
      and increased prehospital delay caused by prolonged physician and transportation
      delay. Physician delay among women and men were 69 and 16 min, respectively.
      Patients with prior myocardial infarction had reduced prehospital delay, which
      was caused by shorter decision and physician delay; whereas patients with prior
      mechanical revascularisation or typical symptoms had prolonged prehospital delay
      due to long decision delay. When symptoms were interpreted as cardiac the
      decision and prehospital delay were reduced. CONCLUSION: The medical profession
      underestimates the risk of acute coronary syndrome among women, and thereby
      contributes to unnecessary long delay to treatment. The patient's prior
      experience and interpretation has a significant influence on behaviour.

PMID- 15203268
TI  - Unusual combination of coronary artery, abdominal aortic and iliac artery
      inflammatory aneurysmal disease.

PMID- 15203269
TI  - Three-vessel left-ventricular microfistulization syndrome: a rare case of angina.
AB  - A 55-year-old woman with angina was found to have multiple fistulae from all
      three major coronary arteries to the left ventricle. The aortography mimicked a
      severe aortic insufficiency. This rare vascular anomaly can cause a coronary
      steal phenomenon and subsequent myocardial ischemia in patients without
      angiographic evidence of major atherosclerotic coronary artery disease.

PMID- 15203270
TI  - Heart block in infant with atypical myocarditis: a case report and review of
      literature.

PMID- 15203271
TI  - References to sudden cardiac death by Hippocrates.

PMID- 15203272
TI  - Chronic cor pulmonale: a rare complication of undiagnosed pacemaker lead
      endocarditis.
AB  - Pacemaker lead infection is a rare life-threatening complication of permanent
      transvenous pacing. We describe the case of a young man who suffered recurrent
      undiagnosed septic pulmonary embolisms from pacemaker lead vegetations inducing
      chronic cor pulmonale with major pulmonary arterial hypertension. The potential
      complications of transvenous pacing and the systematic use of transesophageal
      echocardiography are emphasized.

PMID- 15203273
TI  - Left anterior descending coronary artery-left ventricular fistula presenting as
      unstable angina and syncope.

PMID- 15203274
TI  - Myelodysplasia, megakaryocytes, and methylation.

PMID- 15203275
TI  - Bone marrow mast cell immunophenotyping in adults with mast cell disease: a
      prospective study of 33 patients.
AB  - The aberrant co-expression of CD2 and CD25 antigens is the immunophenotypic
      hallmark of neoplastic mast cells, and has been consistently identified on bone
      marrow mast cells from patients with indolent mast cell disease (MCD). We
      prospectively analyzed the bone marrow mast cell immunophenotype by
      multiparametric flow cytometry (FC) for 33 MCD cases, to examine the role of CD2
      and CD25 expression in establishing diagnosis, detecting histologically occult
      bone marrow mast cell infiltration, and assessing treatment response. While CD25
      was almost uniformly expressed, only 6 of 13 patients with indolent MCD, 1 of 8
      with aggressive MCD, 2 of 7 with MCD and an associated hematological disorder,
      and none of the 2 patients with either mast cell leukemia or smoldering systemic
      mastocytosis, expressed CD2. One of three patients with cutaneous mastocytosis
      had an aberrant CD2+/CD25+ mast cell population suggesting histologically occult
      bone marrow involvement. CD25 expression was lost in one patient who achieved
      complete histologic remission with therapy, but not in two patients who achieved
      a partial remission. In conclusion, CD25, but not CD2, is a reliable marker for
      neoplastic mast cells, and CD25 expression indicates histologically occult bone
      marrow infiltration and residual disease after therapy.

PMID- 15203276
TI  - The effects of 5-aza-2'-deoxycytidine (Decitabine) on the platelet count in
      patients with intermediate and high-risk myelodysplastic syndromes.
AB  - 5-Aza-2'-deoxycytidine, a DNA-hypomethylating agent, can induce clinical
      remissions in patients with high-risk myelodysplastic syndromes (MDS). During
      treatment an increase in platelet count is frequently the first positive event to
      be seen. In this study, we analyzed the platelet response of patients with high
      risk MDS on low-dose 5-aza-2'-deoxycytidine therapy. We evaluated 162 from the
      170 patients entered in three consecutive Phase II studies. One hundred twenty
      six of them were thrombocytopenic at start of the therapy. All patients had an
      IPSS risk score of Intermediate I or higher. A rise in platelet count preceded a
      good trilineage response. In 58% of the thrombocytopenic patients a platelet
      response was already seen after one cycle of therapy. During therapy 69% of the
      patients with a low platelet count showed a response. Due to disease progression
      the final response rate was 63% in thrombocytopenic patients. No correlation was
      found between the platelet response and either the presence or absence of an
      adequate number of megakaryocytes or serum thrombopoietin levels. However,
      platelet response strongly predicted for overall survival (P < 0.0001). 5-Aza-2'
      deoxycytidine has a clinically significant, often long lasting, effect on the
      platelet count in a substantial number of high-risk MDS patients.

PMID- 15203277
TI  - Arsenic trioxide and thalidomide combination produces multi-lineage hematological
      responses in myelodysplastic syndromes patients, particularly in those with high
      pre-therapy EVI1 expression.
AB  - Twenty-eight myelodysplastic syndromes (MDS) patients were treated with arsenic
      trioxide (ATO) and thalidomide. Seven patients responded including one complete
      hematologic and cytogenetic response and one with regression in spleen size. Two
      trilineage responses were seen in patients with inv(3)(q21q26.2). Three of five
      patients who had high pre-therapy EVI1 levels showed unexpectedly good responses
      while two died early in the first cycle. In vitro studies using 32Dcl3 cells
      forced to express EVI1 confirmed increased sensitivity of these cells to ATO.
      Both low/high risk MDS may benefit significantly from therapy with
      ATO/thalidomide, and those with high pre-therapy EVI1 expression may be uniquely
      sensitive.

PMID- 15203278
TI  - Impaired clonogenic growth of myelodysplastic bone marrow progenitors in vitro is
      irrelevant to their apoptotic state.
AB  - Excessive intramedullary apoptosis has been considered to account for the paradox
      of hypercellular marrow and refractory cytopenias in myelodysplastic syndrome
      (MDS). However, a causative relationship of apoptosis to the progenitor's
      defective clonogenic growth has not been sufficiently demonstrated. We
      investigated the degree of apoptosis and its contribution to ineffective
      hematopoiesis in MDS, by assessing the differential clonogenic capacity of
      purified "apoptotic" and "non-apoptotic" bone marrow progenitors in a short-term
      semisolid culture system. Although increased apoptosis was indeed detected in MDS
      bone marrow progenitors, there was no correlation between the existence of
      apoptosis and culture performance. Non-apoptotic as well as apoptotic CD34+ cells
      gave similar patterns of growth, both defective compared to normal. The ability
      of "apoptotic" CD34+ cells to proceed in colony formation as well as the abnormal
      growth of "non-apoptotic" progenitors are probably pointing towards the need to
      reconsider the role of apoptosis in the defective clonogenicity of MDS.

PMID- 15203279
TI  - Modified VAD and PSC-833 in the treatment of resistant or relapsing chronic
      lymphocytic leukemia (E4996): a trial of the Eastern Cooperative Oncology Group.
AB  - BACKGROUND & METHOD: The role of multidrug resistance (MDR) was investigated in
      patients with relapsed chronic lymphocytic leukemia (CLL). PSC-833 was added to
      modified VAD (a 4-day infusion of vincristine, doxorubicin, with oral
      dexamethasone, every 3 weeks), in an attempt to improve the response rate (21%)
      in a prior study. Laboratory tests to determine MDR and apoptosis proteins were
      correlated with response. RESULTS: Two of the seven MDR-positive cases and one of
      the four MDR-negative patients achieved a partial response (no significant
      difference). No significant correlation with response was found in any of the
      laboratory tests for apoptosis. CONCLUSION: VAD plus PSC-833 had the same (21%)
      partial response rate as a prior ECOG study without PSC-833. No correlation of
      response with MDR or apoptosis testing was found. Other drug resistance factors
      must play a significant role in determining the response of relapsed patients
      with CLL.

PMID- 15203280
TI  - Inhibition of acute myeloid leukemia cell growth by mono-specific and bi-specific
      anti-CD33 x anti-CD64 antibodies.
AB  - Bi-specific anti-CD33 x anti-CD64 antibodies (BsAb) mediated more potent and
      longer-lasting inhibition of proliferation of human leukemia cell lines and
      primary acute myeloid leukemia (AML) samples compared to mono-specific anti-CD33
      mAb. There were no differences between these two antibodies in cellular
      internalization over time. The inhibitory effect of BsAb was mimicked by a mouse
      IgG2a subclass mono-specific anti-CD33 mAb. These findings indicate that enhanced
      inhibition of proliferation was caused by simultaneous ligation of both CD33 and
      CD64 molecules. We conclude that inhibition of leukemia cell growth initiated by
      BsAb during prolonged exposure may have therapeutic value for the treatment of
      AML.

PMID- 15203282
TI  - Treatment of human chronic lymphocytic leukemia cells with the proteasome
      inhibitor bortezomib promotes apoptosis.
AB  - New options are needed for the treatment of B-cell chronic lymphocytic leukemia
      (CLL). Proteasome inhibitors represent a potential therapeutic strategy. One such
      agent, bortezomib, was recently approved for the treatment of refractory multiple
      myeloma. In this study, lymphocytes were isolated from the blood of CLL patients,
      treated in vitro with bortezomib, and evaluated for apoptosis by flow cytometry.
      Bortezomib promoted apoptosis in CLL cells in a dose- and time-dependent manner.
      At 18 h incubation time, 10 nM bortezomib induced an average 4.27 fold (+/-2.57)
      increase in the percentage of apoptotic cells versus untreated controls. These
      data indicate that bortezomib has in vitro activity in CLL and support further
      investigations of this promising new drug.

PMID- 15203281
TI  - Bone marrow stroma in childhood myelodysplastic syndrome: composition, ability to
      sustain hematopoiesis in vitro, and altered gene expression.
AB  - We studied bone marrow stromal cell cultures from patients with childhood
      myelodysplastic syndromes (MDS, refractory anemia with excess of blasts, RAEB)
      and from matched normal donors. Stromal cell monolayers were characterized as
      myofibroblasts by the expression of smooth muscle alpha-actin, collagen IV,
      laminin and fibronectin. When normal cord blood cells were plated onto
      myelodysplastic stromas, a pathologic cell differentiation was observed,
      indicating altered myelosupportive properties. cDNA array analysis showed that
      patient stromas expressed increased levels of thrombospondin-1, collagen-I alpha2
      chain, osteoblast-specific factor-2 and osteonectin, indicating the presence of
      increased osteoblast content, as confirmed by enhanced alkaline phosphatase
      synthesis. Alterations in the myelodysplastic stroma environment might contribute
      to abnormal hematopoiesis in this pathology.

PMID- 15203283
TI  - Flavones and polyphenols inhibit the NO pathway during apoptosis of leukemia B
      cells.
AB  - We recently reported that resveratrol, a grape-derived polyphenol, in vitro
      induces the apoptosis of leukemic B-cells and simultaneously inhibits the
      production of endogenous nitric oxide (NO) through inducible NO synthase (iNOS)
      down-regulation. The same results were observed in the present study with not
      only acetate derivatives of polyphenols, particularly the pentaacetate of 
      viniferin (resveratrol dimer), but also with a synthetic flavone (a
      diaminomethoxyflavone) in both leukemia B-cell lines and B-cell chronic
      lymphocytic leukemia (B-CLL) patients' cells. Moreover, flavopiridol, another
      flavone already known for its pro-apoptotic properties in B-CLL cells, was also
      found to down-regulate both iNOS expression and NO production. Thus, inhibition
      of the NO pathway during apoptosis of leukemia B-cells appears a common mechanism
      for several compounds belonging to two distinct families of phytoalexins, the
      flavones and grape-derived polyphenols.

PMID- 15203284
TI  - Forced expression of AML1-AMP19, a fusion transcript generated from a radiation
      associated t(19;21) leukemia, blocks myeloid differentiation.
AB  - We isolated and characterized a novel AML1 (also termed Runx1) fusion transcript
      from a radiation-associated acute myeloid leukemia with a t(19;21). This fusion
      transcript, termed AML1-AMPl9, was joined out of frame, resulting in a truncated
      AML1 protein that inhibits activation of AML1 target promoters. It is now
      becoming clear that truncations of AMLl are more common in leukemia than
      previously thought. To analyze the effect of truncated AML1 species on myeloid
      differentiation and proliferation, AML1-AMPl9 was retrovirally transduced into
      the IL-3-dependent 32D cells. 32D cells over-expressing AML1-AMPl9 failed to
      differentiate normally when stimulated with G-CSF, but continued to proliferate
      and maintained a primitive phenotype. However, AML1-AMPl9 did not transform the
      cells to cytokine independence, implying that for full transformation of a
      myeloid progenitor by truncated AML1 another genetic lesion is required.

PMID- 15203285
TI  - Induction of CD28 on the new myeloma cell line MOLP-8 with t(11;14)(q13;q32)
      expressing delta/lambda type immunoglobulin.
AB  - The novel multiple myeloma (MM) cell line MOLP-8 carrying the t(11;14) (q13;q32)
      was established from the peripheral blood of a 52-year-old Japanese male patient
      with Bence-Jones delta/lambda type MM (stage IIIA with hyperammonemia). The
      growth of MOLP-8 cells is constitutively independent of exogenous growth factors
      or feeder cells. MOLP-8 cells grow mainly as free floating single cells and
      slightly adherent on the bottom of the plastic culture flask. Wright-Giemsa
      stained MOLP-8 cells show the typical plasma cell morphology with abundant
      cytoplasm, heterogeneous cell size and one to three nuclei. The immunoprofile of
      MOLP-8 corresponds to that seen typically in primary MM cells: positive for
      cytoplasmic immunoglobulin (Ig) delta/lambda chains, CD10, CD29, CD38, CD40,
      CD44, CD49b, CD49d, CD54, CD56, CD58, CD71, CD138 and PCA-1; the cells were
      negative for surface Igs and various other B-cell, T-cell and myelomonocyte
      associated immunomarkers. CD28 became positive after co-culture of MOLP-8 cells
      with bone marrow adherent stromal (BST) feeder cells for a week. About 30% of
      MOLP-8 cells adhered strongly to the BST cells, but the cellular adhesion was
      clearly inhibited by addition of either anti-CD29 or anti-CD106 monoclonal
      antibody, suggesting a specific cellular adhesion through alpha4beta1-integrin
      VCAM-1 interaction. The novel MOLP-8 cell line together with the present myeloma
      cell lines will present useful model systems in the investigation of the biology
      of MM.

PMID- 15203286
TI  - Delayed-late activation of a myeloid defensin minimal promoter by retinoids and
      inflammatory mediators.
AB  - Alpha-defensin-1 gene expression in promyelocytic HL-60 cells is ('delayed-late'
      > or =1-2 days) activated by retinoic acid (RA), lipopolysaccharide, tumor
      necrosis factor-alpha and elevated levels of cAMP. Using stably integrated
      reporter constructs, we show that this activation is directed through a proximal
      and distal element within a minimal (-83/+82) def1 promoter, and is mediated by
      phosphorylation of the associated factors, PU.1 and D1BP, in an inducer-dependent
      manner. Whereas binding of PU.1 to the proximal element confers cell specificity
      and relays the effects of most inducers, the selectively enhancing capacity of
      the distal element for RA- and cAMP-dependent activation is uniquely correlated
      with D1BP-binding. We propose that D1BP and PU.1 are the end-points of separate
      pathways.

PMID- 15203287
TI  - The association between panic disorder and the L/L genotype of catechol-O
      methyltransferase.
AB  - To clarify the role of catechol-O-methyltransferase (COMT) polymorphism in panic
      disorder (PD), we investigated a large group of Korean PD patients (N = 178) and
      controls (N = 182) using a case-control study. We also assessed the response to
      paroxetine treatment and other clinical variables in the PD patients. The
      increase in the COMT(L) allele was not statistically significant in PD (p =
      0.104). However, compared with the sum of the other genotypes, the frequency of
      the L/L genotype was significantly higher in PD (p = 0.042). The odd ratios (ORs)
      also indicated a significant effect of the homozygosity for the COMT(L) allele on
      an increased risk for PD (OR=2.38; 95% CI 1.03-5.51). In addition, patients with
      L/L genotype had higher trait-anxiety levels (p = 0.030) and poorer treatment
      response to paroxetine than those with other genotypes (p = 0.002). Our results
      suggest that the COMT L/L genotype is associated with PD and the genetic variant
      of the COMT enzyme may be related to the clinical severity and treatment response
      to paroxetine in PD.

PMID- 15203288
TI  - Family-based association studies between 5-HT5A receptor gene and schizophrenia.
AB  - BACKGROUND: Pharmacological and neurodevelopmental data support the idea that the
      gene, which codes for the 5-HT(5A) receptor is an important candidate gene for
      schizophrenia susceptibility. However, previous genetic studies focusing on this
      gene yielded conflicting results, potentially because of: (i) stratification
      biases of case-control association studies, (ii) genetic and phenotypic
      heterogeneity of schizophrenia, and (iii) variability in the loci analyzed (the 5
      HT(5A) gene having many polymorphic sites). METHODS: A transmission
      disequilibrium test was used in the present study aimed at investigating two
      polymorphisms in exon 1 of the 5-HT(5A) gene, the A12T silent substitution and
      the C43T transversion leading to a 15Pro --> Ser substitution, in 103 patients
      with DSM-IV diagnosis of schizophrenia, and their 206 parents. RESULTS: We found
      an excess of transmission of the 12T allele from the parents to their affected
      children (P = 0.02), with evidence for linkage disequilibrium between the 12T-43C
      haplotype and schizophrenia (P = 0.002). Furthermore, patients with the 12T
      allele had a significantly later age at onset (P = 0.003), and the Q-TDT approach
      confirmed that this allele was transmitted with an older age at onset (P = 0.01).
      CONCLUSIONS: These data provided convergent evidence for a significant role of
      the 5-HT(5A) gene in schizophrenia and more specifically in patients with later
      age at onset.

PMID- 15203289
TI  - Improvement of working but not declarative memory is correlated with HPA
      normalization during antidepressant treatment.
AB  - Previous research demonstrated that depression is associated with hyperactivity
      of the hypothalamus-pituitary-adrenocortical (HPA) system after stimulation.
      There is also strong evidence that the modulation of corticosteroids in the brain
      induces memory dysfunction which represents core features of depression.
      Antidepressant treatment with serotonin reuptake inhibitors (SSRIs) alleviates
      both dysfunctions. Thus, these previous observations propose a correlation
      between treatment induced changes of the endocrinological response of the HPA
      system to challenge with dexamethasone and CRH and changes of memory functions
      during antidepressant treatment. This study explores the relationship between
      depression, memory functions and the responsiveness of the HPA system as assessed
      by the combined DEX/CRH test during antidepressant treatment in n = 64 patients
      with major depression during a four weeks treatment with citalopram. We found
      that treatment induced changes of the cortisol response pattern in the DEX/CRH
      test were correlated with improvement of working memory but not so with episodic
      memory, sustained attention or global severity of depression. We suggest that
      improvement of working memory is more sensitive to the changes of hormones of the
      HPA system (e.g. cortisol) than other cognitive functions and the global severity
      of depression.

PMID- 15203290
TI  - Arginine vasopressin and adrenocorticotropin secretion in response to
      psychosocial stress is attenuated by ethanol in sons of alcohol-dependent
      fathers.
AB  - Familial risk and environmental stress promote the development of alcohol
      dependence. We investigated whether a positive family history of alcoholism
      affects the neuroendocrine response to a standardized laboratory stress test in
      healthy subjects without alcohol use disorders. Twenty-four high-risk subjects
      with a paternal history of alcoholism (PHA) and 16 family history negative (FHN)
      controls were evaluated. Psychosocial stress was induced by having subjects
      deliver a 5-min speech and mental arithmetics in front of an audience on separate
      days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized
      sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering
      up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was
      determined before the stressor, at the time of maximum ACTH secretion, and at 75
      min after stress onset. The stress test induced a phasic increase in ACTH
      secretion. At the time of maximum ACTH, AVP was significantly increased in
      relation to baseline. Compared to placebo, alcohol administration significantly
      attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased
      AVP measured in the same samples in PHA but not FHN subjects. We conclude that
      activation of the hypothalamic-pituitary-adrenal system by psychosocial stress is
      accompanied by an increase in peripheral plasma AVP levels. Secretion of both
      ACTH and AVP suggest that alcohol attenuates the stress response selectively in
      PHA but not FHN subjects. This might imply some short-term positive alcohol
      effect in sons of alcoholics, but also constitute a mechanism by which their risk
      to develop alcohol use disorders is increased.

PMID- 15203291
TI  - Increased risk of developing diabetes in depressive and bipolar disorders?
AB  - A few studies have suggested that the prevalence of diabetes is increased for
      patients with depression and for patients with bipolar disorder compared with the
      general population. However, no study has been published comparing the risk of
      getting a diagnosis of diabetes for patients with affective disorders with the
      risk for patients with other medical illnesses. It was the aim of the present
      study to investigate whether patients hospitalised for depressive or bipolar
      disorders are at increased risk of getting a diagnosis of diabetes at readmission
      compared to patients previously admitted for osteoarthritis. In a nationwide case
      register study, all patients who got a discharge diagnosis of depression,
      mania/bipolar disorder or osteoarthritis at first admission in a period from 1977
      to 1997 were identified. The probability of getting readmitted and discharged
      with a diagnosis of diabetes was estimated with competing risks models in
      survival analysis. In total, 29,035 patients with a diagnosis of depression at
      first discharge, 6683 patients with mania/mixed episode and 108,525 patients with
      a diagnosis of osteoarthritis were identified. The risk of getting readmitted
      with diabetes was not increased for patients who had previously been admitted
      with depression or mania/bipolar disorder compared to patients with
      osteoarthritis. There was no difference in the risks of developing Type 1 and
      Type 2 diabetes.

PMID- 15203292
TI  - Trans-cultural aspects of obsessive-compulsive disorder: a description of a
      Brazilian sample and a systematic review of international clinical studies.
AB  - Little is known about the extent and the mechanisms through which culture may
      affect the clinical manifestations of obsessive-compulsive disorder (OCD). In
      this study, our objective was to identify culture-related symptomatological
      patterns in OCD. We described the socio-demographic and phenomenological
      characteristics of 101 adult patients with OCD seen at an university clinic for
      anxiety and depressive disorders in Rio de Janeiro, Brazil, and compared them
      with those reported in 15 clinical samples from North and Latin America, Europe,
      Africa, and Asia identified through a systematic review in MEDLINE, PsychINFO,
      and LILACS. Patients with OCD were almost universally characterized by: (1) a
      predominance of females, (2) a relatively early age of onset, and (3) a
      preponderance of mixed obsessions and compulsions. In contrast, a predominance of
      aggressive and religious obsessions was found only in Brazilian and Middle
      Eastern samples, respectively. The core features of OCD are probably relatively
      independent of cultural variations. The sole exception to this rule seems to be
      the content of the obsessions, in which cultural factors may play a significant
      role.

PMID- 15203293
TI  - Homocysteine levels in newly admitted schizophrenic patients.
AB  - We previously found a marked elevation of plasma homocysteine in young male
      schizophrenic patients in hospital. It seemed important to determine if this
      finding is already present in newly admitted schizophrenic patients. Serum
      homocysteine levels were studied in 184 consecutively admitted schizophrenic
      patients and 305 control subjects from an employee screening program.
      Homocysteine levels were markedly increased in this population of newly admitted
      schizophrenic patients, especially in young males. Newly admitted male
      schizophrenic patients have elevated homocysteine levels that cannot be explained
      on the basis of poor hospital nutrition. Smoking may raise homocysteine by 1-2
      microM/L but this is not a large enough effect to explain our findings.

PMID- 15203295
TI  - Differential patterns of psychomotor functioning in unmedicated melancholic and
      nonmelancholic depressed patients.
AB  - Few studies examining psychomotor retardation (PR) in patients with major
      depressive disorder (MDD) included medication-free patients. The purpose of this
      study was (1) to examine whether unmedicated patients with MDD would exhibit PR,
      (2) to determine whether this retardation, if present, was more cognitive or
      motor in nature, and (3) to investigate whether any differences in PR could be
      established between melancholic and nonmelancholic depressed patients. Thirty
      eight unmedicated inpatients with severe MDD (20 melancholic and 18
      nonmelancholic patients) and 38 matched controls were compared on figure-copying
      tasks in which the cognitive task difficulty was manipulated. In addition, a
      simple motor task and the symbol digit substitution task (SDST) were
      administered. As a group, the patients were significantly slower performing all
      tasks and both initiation times (IT) and movement times (MT) were prolonged.
      However, when a distinction was made between the two subtypes, only the
      melancholic patients showed prolonged MTs compared to the controls. Furthermore,
      the melancholic patients differed significantly from the controls in IT in all
      tasks. The nonmelancholic patients had significantly longer ITs than the controls
      in two copying tasks. It can be concluded that there was clear cognitive and
      motor slowing in this group of unmedicated inpatients with MDD. The melancholic
      patients were more severely affected than the nonmelancholic patients and showed
      a slowing of cognitive as well as motor processes. Differences in psychomotor
      functioning between melancholic and nonmelancholic depressed patients could imply
      different underlying neurobiological disturbances in these subtypes of major
      depression.

PMID- 15203294
TI  - Comparison of characteristics between geriatric and younger subjects with
      schizophrenia in community.
AB  - Relatively little is known about the different characteristics of non
      institutionalized geriatric and younger subjects with schizophrenia. This study
      compared demographic and clinical characteristics of all the geriatric, middle
      age and young subjects with schizophrenia living in a Chinese rural community.
      Geriatric (age >/= 65 years) (N = 51), middle-age (age 41-64 years) (N = 263) and
      young subjects with schizophrenia (age 15-40 years) (N = 196) in a rural
      community were assessed with the Present State Examination and Social Disability
      Screening Schedule. Age at first onset was significantly older in geriatric male
      and female groups. While there were no significant differences of negative
      symptoms among the three groups, the rates of lifetime nuclear syndrome were
      significantly lower in geriatric subjects compared to the other two groups.
      Geriatric subjects were less likely to have been hospitalized (9.8%) than middle
      age (19.0%) and younger subjects (24.8%). Although the duration of illness was
      significantly longer in geriatric subjects than in the other two groups, the
      clinical outcome was significantly better in the geriatric group and social
      functioning scores were similar among the three groups. Geriatric subjects were
      more likely to be female, with longer duration of illness, fewer "core" symptoms,
      relatively stable social functioning and clinical outcome. The pathogenesis and
      psychopathology of geriatric subjects may be different compared to younger
      subjects with schizophrenia.

PMID- 15203296
TI  - Worsening of depressive symptoms prior to randomization in clinical trials: a
      possible screen for placebo responders?
AB  - A common practice in depression trials is to exclude patients whose depressive
      symptoms improve between Screen and Baseline evaluations under the assumption
      that they are more likely to respond to placebo. The present study investigated
      this contention by examining the relationship between pre-randomization changes
      in Hamilton depression rating scale (HAMD) scores to post-randomization placebo
      response and drug-placebo separation. Four randomized, double-blind, placebo
      controlled trials (active medication=fluoxetine or paroxetine) were conducted in
      outpatients with Major Depressive Disorder using a novel design in which a
      depressive severity inclusion criterion (HAMD >/= 22) was utilized only at
      Screen. Patients with no change or minimal (1 point) improvement on the HAMD
      between Screen and Baseline had the lowest placebo response and the best drug
      placebo separation. Patients with pre-randomization improvement of 2 points or
      greater had moderately higher placebo response and poorer drug-placebo
      separation. Patients who worsened between Screen and Baseline showed the highest
      placebo response and the poorest drug-placebo separation. There were no obvious
      differences in demographic variables between the groups which could account for
      the findings. In our original analyses 3/4 studies failed to show significant
      drug-placebo separation. When only patients with no change or pre-randomization
      improvement of 1 point were used in the analyses, 3/4 studies showed significant
      drug-placebo separation while the other study approached significance, p < 0.07.
      These results suggest that pre-randomization changes in HAMD scores may predict
      post-randomization placebo response and drug-placebo separation. Further, pre
      randomization increases in HAMD scores (i.e., worsening) may be the best
      predictor of heightened placebo responding and poor drug placebo separation.

PMID- 15203298
TI  - Knowing letter names and learning letter sounds: a causal connection.
AB  - Two experiments tested the common assumption that knowing the letter names helps
      children learn basic letter-sound (grapheme-phoneme) relation because most names
      contain the relevant sounds. In Experiment 1 (n=45), children in an experimental
      group learned English letter names for letter-like symbols. Some of these names
      contained the corresponding letter sounds, whereas others did not. Following
      training, children were taught the sounds of these same "letters." Control
      children learned the same six letters, but with meaningful real-word labels
      unrelated to the sounds learned in the criterion letter-sound phase. Differences
      between children in the experimental and control groups indicated that letter
      name knowledge had a significant impact on letter-sound learning. Furthermore,
      letters with names containing the relevant sound facilitated letter-sound
      learning, but not letters with unrelated names. The benefit of letter-name
      knowledge was found to depend, in part, on skill at isolating phonemes in spoken
      syllables. A second experiment (n=20) replicated the name-to-sound facilitation
      effect with a new sample of kindergarteners who participated in a fully within
      subject design in which all children learned meaningless pseudoword names for
      letters and with phoneme class equated across related and unrelated conditions.

PMID- 15203297
TI  - Effects of fluoxetine on ethanol withdrawal syndrome in rats.
AB  - The present study was designed to investigate the effects of fluoxetine, a
      selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats.
      Adult male Wistar rats (218-255 g) were subjects. Ethanol (7.2%, v/v) was given
      to rats by a liquid diet for 21 days. Control rats were pair fed an isocaloric
      liquid diet containing sucrose as a caloric substitute to ethanol. Fluoxetine
      (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just
      before ethanol withdrawal. After 2nd, 4th and 6th hour of ethanol withdrawal,
      rats were observed for 5 min, and withdrawal signs that included locomotor
      hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were
      recorded or rated. A second series of injections was given at 6 h after the first
      one, and subjects were then tested for audiogenic seizures. Fluoxetine produced
      some dose-dependent and significant inhibitory effects on all the signs of
      ethanol withdrawal during ethanol withdrawal period. Our results suggest that
      acute fluoxetine treatment has some beneficial effects on ethanol withdrawal in
      rats. Thus, this drug may be useful for treatment of ethanol withdrawal syndrome.

PMID- 15203299
TI  - Cruel intentions on television and in real life: can viewing indirect aggression
      increase viewers' subsequent indirect aggression?
AB  - Numerous studies have shown that viewing violence in the media can influence an
      individual's subsequent aggression, but none have examined the effect of viewing
      indirect aggression. This study examines the immediate effect of viewing indirect
      and direct aggression on subsequent indirect aggression among 199 children ages
      11 to 14 years. They were shown an indirect, direct, or no-aggression video and
      their subsequent indirect aggression was measured by negative evaluation of a
      confederate and responses to a vignette. Participants viewing indirect or direct
      aggression gave a more negative evaluation of and less money to a confederate
      than participants viewing no-aggression. Participants viewing indirect aggression
      gave less money to the confederate than those viewing direct aggression.
      Participants viewing indirect aggression gave more indirectly aggressive
      responses to an ambiguous situation and participants viewing direct aggression
      gave more directly aggressive responses. This study provides the first evidence
      that viewing indirect aggression in the media can have an immediate impact on
      subsequent aggression.

PMID- 15203300
TI  - Early predictors of letter knowledge.
AB  - This study examined the influence of phonological memory and rapid naming on the
      development of letter knowledge. Participants were 77 Dutch children, who were
      followed from the start of their first kindergarten year (mean age 4 years 6.8
      months) to the end of their second kindergarten year. Phonological memory was
      assessed by a nonword repetition test and a sentence repetition test. Rapid
      naming involved object naming. The study revealed found a substantial effect of
      phonological memory on the acquisition of letter knowledge that was particularly
      related to the ability to repeat nonwords. Vocabulary knowledge did not have an
      independent effect on letter learning after phonological memory was controlled.
      The study also showed a small effect of rapid naming on the acquisition of letter
      knowledge that was independent of the effect of phonological memory. Finally, the
      study also provided further evidence for a specific relation between phonological
      memory and vocabulary acquisition.

PMID- 15203301
TI  - Sensory processing, reading, IQ, and attention.
AB  - Detection thresholds for two visual- and two auditory-processing tasks were
      obtained for 73 children and young adults who varied broadly in reading ability.
      A reading-disabled subgroup had significantly higher thresholds than a normal
      reading subgroup for the auditory tasks only. When analyzed across the whole
      group, the auditory tasks and one of the visual tasks, coherent motion detection,
      were significantly related to word reading. These effects were largely
      independent of ADHD ratings; however, none of these measures accounted for
      significant variance in word reading after controlling for full-scale IQ. In
      contrast, phoneme awareness, rapid naming, and nonword repetition each explained
      substantial, significant word reading variance after controlling for IQ,
      suggesting more specific roles for these oral language skills in the development
      of word reading.

PMID- 15203302
TI  - Introduction: damage control at the start of 21st century.

PMID- 15203303
TI  - Damage control surgery and the abdomen.
AB  - There is a complex interplay between primary injury, particularly major abdominal
      injury in the multi-system trauma patient, and secondary injury, which relate to
      patient physiology, decision making and surgical technique. Analysis of outcomes
      is further confounded by the variety of surgical techniques used. The challenge
      is to match the correct operation, for a critically injured patient, with the
      patient's physiology. Excellence in general surgery does not equate with
      excellence in trauma surgery, and a clear understanding of damage control is
      essential.

PMID- 15203304
TI  - Damage control surgery for thoracic injuries.
AB  - Damage control of thoracic injuries begins frequently with an emergency
      department thoracotomy via an anterolateral incision. Bleeding and air leaks are
      quickly temporised. As opposed to abdominal damage control where most injuries
      can be temporised, most thoracic injuries require initial definitive repair.
      Thus, the goal of thoracic damage control is to perform the least definitive
      repair using the fastest and easiest techniques to shorten the operative time as
      much as possible. There are some injuries that can be temporised and require re
      operation once physiologic normality has been achieved.

PMID- 15203305
TI  - Damage control neurosurgery.
AB  - Damage control neurosurgery (DCNS) is abbreviated urgent neurosurgery performed
      on the injured patient which helps to prevent secondary brain injury, assists in
      stabilising the patient and improves survival and outcome. It may be urgent
      surgery done by the neurosurgeon in a trauma centre, but it has particular
      application in the remote, rural or military environment where the surgery can be
      performed by a generalist. This surgery should always be done in collaboration
      with the trauma team caring for the overall needs of the patient. The Definitive
      Surgery Trauma Course (DSTC) is an ideal educational vehicle to disseminate the
      principles of DCNS.

PMID- 15203306
TI  - Damage control surgery for spine trauma.
AB  - The concept of "damage control" surgery was originally developed for massive
      abdominal trauma and also successfully applied to the management of lone bone
      injuries. More recently this has been extended to severely injured patients with
      spine injuries. This paper provided an overview of how damage control principles
      can be applied to multitrauma patients with spine injuries, to patients with
      isolated spine injuries and to spine injuries with and without neurology. The
      role of neuroimaging in acute spine trauma and controversies in the
      pharmaceutical approach to spine injuries are discussed. Additional prospective
      controlled trials are required to delineate the role and timing of damage control
      surgery in acute spine injury. With improved neuroimaging early spinal damage
      control surgery will be formally established in the management of spine trauma.

PMID- 15203307
TI  - Damage control orthopaedics in unstable pelvic ring injuries.
AB  - Pelvic ring injuries are often associated with other system injuries and require
      a multidisciplinary approach for their treatment. Early mortality is usually
      secondary to uncontrolled haemorrhage whereas late mortality is due to associated
      injuries and sepsis-induced multiple organ failure. The management of the pelvic
      fracture should be conceived as part of the resuscitative effort as errors in
      early management may lead to significant increases in mortality. In severely
      multiple injured patients who are in an 'unstable' or 'in extremis' clinical
      condition damage control orthopedics is the current treatment of choice. By
      performing limited surgical interventions the subsequent reduction in blood loss
      and transfusion requirements can only be beneficial in these critically ill
      patients, reducing the risk of developing systemic complications and early
      mortality.

PMID- 15203308
TI  - Damage control: extremities.
AB  - The principles of fracture management in polytrauma patients continue to be of
      crucial importance. Over the last five decades, various strategies of fracture
      treatment in the multiply injured patient have evolved. The various new
      methodologies remain controversial. In the beginning, early surgical fracture
      treatment of long bone fractures after multiple trauma was not routinely
      advocated. It was believed that the polytraumatised patient did not have the
      physiological reserve to withstand prolonged operations. The introduction of
      standardised, definitive surgical protocols, led to the concept of early total
      care (ETC) in the 1980s. This concept was subsequently applied universally, in
      all patient groups, regardless of injury severity and distribution. Later, it
      became apparent that certain patients did not appear to benefit from ETC. Indeed,
      extended operative procedures, during the early phase of multiple trauma
      recovery, were associated with adverse outcome. This applied for patients with
      significant thoracic, abdominal and head injuries and those with high injury
      severity scores (ISS). In response, the concept of damage control orthopaedics
      (DCO) was developed in the 1990s. DCO methodology is characterised by primary,
      rapid, temporary fracture stabilization. Secondary definitive management follows,
      once the acute phase of systemic recovery has passed. We explore the processes
      underlying the systemic biological impact of fracture fixation, the evolution of
      operative treatment strategies for major fractures in polytrauma and the current
      trends toward staged management of these patients.

PMID- 15203309
TI  - Damage control surgery in ocular traumatology.
AB  - There seems to be no decrease in the incidence of serious eye injuries. Although
      recent developments in technology now allow salvage of eyes that would have been
      lost only a few years ago, certain rules must be followed to achieve optimal
      outcome. Damage control surgery in ocular traumatology means that the
      ophthalmologist understands that eye injuries must be treated only after life
      threatening conditions have been properly addressed by other specialists.
      Focusing on the injured eye, the ophthalmologist evaluates the types and severity
      of the trauma, and designs a management plan. Wounds should be cleaned and
      closed, infections treated and prevented, the retina reattached; however,
      conditions that do not require immediate intervention are usually better treated
      following a few days of delay, during which intense corticosteroid therapy is
      administered. The second, reconstructive surgery is typically performed 7-10 days
      postinjury, when the risk of intraoperative haemorrhage is dramatically reduced
      and the chance of visual rehabilitation is higher.

PMID- 15203310
TI  - Damage limitation in burn surgery.
AB  - Burn injury differs from other types of trauma in the apparent lack of urgency
      for treatment. We argue that in order to limit physiological damage and the
      development of multi-organ failure, management of the burn wound must be
      immediate and aggressive. Supportive fluid treatment should be judicious in order
      to prevent excessive oedema causing wound extension. Some potential strategies
      utilising oral fluid resuscitation are discussed, and potential pharmacological
      interventions. When associated with other trauma, major burn injury has a
      detrimental effect on morbidity and mortality, and surgical management of both
      aspects of a patient's injuries are altered.

PMID- 15203311
TI  - Damage control surgery in children.
AB  - Whilst the principles of damage control are the same in paediatric surgery as in
      adults the unique qualities of children must be appreciated. Children are more
      susceptible to hypothermia and multiple trauma. Technical aspects of the damage
      control laparotomy specific to children are outlined. Lessons learnt from damage
      control in neonatal surgery are transferable to paediatric trauma.

PMID- 15203312
TI  - Damage control surgery and intensive care.
AB  - The introduction and establishment of the 'damage control surgery' concept has
      led to increasing numbers of severely injured and unstable patients being
      presented to Intensive Care Units (ICU) for ongoing resuscitation. These patients
      present many challenges for the Intensive Care team and emphasise the need for a
      multidisciplinary approach to optimise trauma patient management. Multiple issues
      need to be addressed simultaneously while the overall aim is to rapidly achieve a
      physiological environment that will allow the best possible recovery. The 'lethal
      triad' of hypothermia, acidosis, and coagulopathy due to initial hypovolaemia
      require aggressive correction. From the outset ICU management must also attempt
      to minimise the complications of these injuries and the resuscitative process.
      This review will address some of the key issues relating to the care of these
      patients in the ICU.

PMID- 15203313
TI  - Hypoxia inhibits the expression of the CCR5 chemokine receptor in macrophages.
AB  - Hypoxia, a decrease in oxygen tension occurring in pathological tissues, has a
      profound effect on macrophage functions. Here, we provide the first evidence that
      hypoxia inhibits CCR5 chemokine receptor expression in mouse macrophages. CCR5
      was constitutively expressed in macrophages and upregulated by IFNgamma. Hypoxia
      downregulated both constitutive and IFNgamma-induced CCR5 mRNA and protein.
      Reoxygenation of hypoxic cells reverted CCR5 inhibition. CCR5 upregulation by IL
      10, LPS, and IL-4 was also antagonized by hypoxia. CCR5 inhibition may be a way
      to retain/concentrate recruited macrophages at hypoxic sites or a feedback
      mechanism to control the autocrine activation of macrophages which produce CCR5
      ligands.

PMID- 15203314
TI  - Normal differentiation and functions of mouse dendritic cells derived from RAG
      deficient bone marrow progenitors.
AB  - Dendritic cells (DC) mature upon infectious agent detection to elicit immune
      responses. It has been suggested that T cells influence peripheral DC function.
      However, it is not known if lymphocytes influence DC progenitors. Therefore, we
      determined the ability of bone marrow progenitors from T and B cell-deficient
      mice to generate functional DC. We report that bone marrow-derived DC from RAG-2(
      /-) mice differentiate and proliferate normally. Moreover, such generated DC
      efficiently internalize particles, mature in response to various Toll-like
      receptor engagement, and activate allogenic T cells. This work strongly supports
      that early signals delivered during DC ontogeny by mature lymphocytes do not
      influence the functional differentiation of DC progenitors.

PMID- 15203315
TI  - Splenic dendritic cell subsets prime and boost CD8 T cells and are involved in
      the generation of effector CD8 T cells.
AB  - The ability of the dendritic cell (DC) subsets, CD8alpha+ and CD8alpha- DCs, to
      initiate a CD8 T cell response or to activate memory CD8 T cells and generate
      effector CD8 T cells has been controversial. In this study, we analyse the
      capacity of splenic DC subsets to induce CD8 T cell responses to a CD8 T cell
      epitope (pb9) of a malaria antigen. The administration of peptide-pulsed CD8alpha
      or CD8alpha+ DCs primes and boosts a primed CD8 T cell response against the
      malaria epitope. In vitro, depletion of CD11c(+) DCs from mouse splenocytes,
      immunised with recombinant vaccinia virus Ankara (MVA) expressing pb9 epitope,
      significantly reduced the generation of pb9-specific IFNgamma producing effector
      CD8 T cells, indicating that splenic DCs are involved in the development of pb9
      specific IFNgamma producing effector cells. Taken together, this result shows
      that both DC subsets have the ability to prime and boost CD8 T cell responses and
      are involved in the activation of memory CD8 T cells.

PMID- 15203316
TI  - Allergen rush immunotherapy increases interleukin (IL)-12 production and IL-12
      receptor beta2 chain expression in patients with allergic asthma.
AB  - Interleukin (IL)-12 production and IL-12 receptor (IL-12R) beta2 chain expression
      were investigated in patients with allergic asthma successfully treated with rush
      immunotherapy (RIT) and control patients with mild allergic asthma. Peripheral
      blood mononuclear cells (PBMCs) were stimulated with Dermatophagoides farinae
      (Der f), and production of cytokines was measured. Furthermore, the effects of
      cytokines on IL-12R beta2 chain expression on CD4(+) T cells were investigated.
      Production by PBMCs of IL-12 and IFN-gamma was significantly higher and
      production of IL-4 was significantly lower after stimulation with Der f allergen
      in RIT-treated patients than in control patients. Significant increases in the
      expression of IL-12R beta2 chain before and after stimulation of CD4(+) T cells
      with IL-12 or IFN-gamma were observed in RIT-treated patients compared with that
      in control patients. Allergen RIT increases IL-12 production and IL-12R beta2
      chain expression and thus may convert cytokine production from Th2 to Th1 or Th0
      type in allergic asthma.

PMID- 15203317
TI  - Roxithromycin downmodulates Th2 chemokine production by keratinocytes and
      chemokine receptor expression on Th2 cells: its dual inhibitory effects on the
      ligands and the receptors.
AB  - Roxithromycin (RXM), an anti-bacterial macrolide, has various immunomodulatory
      activities. To investigate the ability of RXM to downregulate skin-infiltration
      of T-lymphocytes, we examined the effects of RXM on keratinocyte production of
      chemokines and T cell expression of chemokine receptors. Normal human and HaCaT
      keratinocytes were cultured with RXM and stimulants. RXM at 1 or 10 microM
      significantly suppressed the production/expression of Th2 chemokines MDC and TARC
      in these keratinocytes, but the production of IP-10 was not affected. The effect
      of RXM on T-cell expression of the corresponding chemokine receptors was also
      tested in Th2-rich peripheral blood lymphocytes. The IL-2-enhanced expression
      level of Th2 chemokine receptor CCR4 was decreased by RXM at 10 microM, whereas
      the expression of CXCR3 was unchanged. Thus, RXM downmodulates both the
      production and receptor expression of Th2 but not Th1 chemokines involved in
      cutaneous immunity, suggesting its beneficial therapeutic effects on Th2-mediated
      or allergic skin disorders.

PMID- 15203318
TI  - The differential interaction of p38 MAP kinase and tumor necrosis factor-alpha in
      human alveolar macrophages and monocytes induced by Mycobacterium tuberculois.
AB  - Cellular signaling by TNF-alpha is mediated through activation of mitogen
      activated protein (MAP) kinases. In particular, p38 MAP kinase is activated in
      mononuclear phagocytes and may be important in sustaining TNF-alpha activity.
      Here, we compared the activation and mutual regulation of p38 MAP kinase and TNF
      alpha by MTB in human alveolar macrophages (AM) and blood monocytes (MN). AM and
      autologous MN were prepared, and stimulated by MTB at 1:1 (bacteria/cell). MAP
      kinase activation was assessed by immunoprecipitation and kinase activity. TNF
      alpha mRNA was assessed by real-time RT-PCR, and TNF-alpha immunoreactivity was
      assessed by ELISA. MTB-induced p38MAP kinase rapidly in AM as compared to MN, and
      inhibition of p38 MAP kinase by SB203580 reduced both TNF-alpha mRNA and protein.
      Activation of ERK (1/2) by MTB followed similar kinetics in both AM and MN. TNF
      alpha produced by MTB sustained p38 MAP kinase activation in MN only. These data
      suggest that interaction of resident pulmonary macrophages and the more immature
      MN with MTB differ with regard to both p38 MAP kinase activation and TNF-alpha
      expression.

PMID- 15203319
TI  - The transcription factor, Bright, is not expressed in all human B lymphocyte
      subpopulations.
AB  - Bright is an ARID family transcription factor that increases immunoglobulin heavy
      chain transcription. In the mouse, Bright expression is tightly regulated and B
      cell-restricted and the Bright protein associates with Bruton's tyrosine kinase
      (Btk), the defective enzyme in X-linked immunodeficiency. Human X-linked
      agammaglobulinemia results from defects in Btk and leads to early blocks in B
      lymphocyte development. Because so little is known about human Bright, we sought
      to determine where human Bright is expressed in normal B cell differentiation and
      whether it also forms complexes with Btk. Although human and mouse Bright
      exhibited similar expression patterns in normal B cells, many human transformed B
      cell lines did not express Bright protein. However, the human protein bound
      prototypic Bright DNA-binding motifs and, like mouse Bright, was capable of
      associating with Btk. These data suggest potentially important similarities exist
      in Bright expression and activity in human and mouse B lymphocytes.

PMID- 15203320
TI  - Regulation of immune function by calorie restriction and cyclophosphamide
      treatment in lupus-prone NZB/NZW F1 mice.
AB  - We compared the effects of calorie restriction (CR) and cyclophosphamide (CTX) on
      the progression of lupus nephritis and immunological changes in NZB/NZW F1 mice.
      Ad libitum (AL)/CTX and CR delayed onset of proteinuria and significantly
      decreased serum levels of anti-dsDNA, anti-histone, and circulating immune
      complex antibodies. CTX and CR prevented the increase in and activation of B
      cells, the decline in CD8(+) T cells, and maintained a higher proportion of naive
      CD4(+) and CD8(+) cells. MHC class I antigen and LFA-1 expression on CD8(+) T
      cells and MHC class II antigen on B cells were also decreased. AL/CTX and CR
      prevented the increase in production of IL-10 and up-regulated IL-2 production in
      T cells ex vivo. We concluded that both CR and CTX can delay the onset of
      autoimmune disease, in part by maintaining higher numbers of naive T cells and
      the immune responsiveness of T cells and decreasing the proportion of B cells.

PMID- 15203321
TI  - IgE crosslinkage of Fcepsilon receptor I induces both production and activation
      of matrix metalloproteinase-9 in mast cells.
AB  - Since mast cells play pivotal roles in allergic inflammations, we investigated
      how IgE-mediated stimulation modulated mast cell matrix metalloproteinase (MMP)-9
      production, and its enzymatic activation. In this study, we clearly demonstrated
      that proMMP-9 released from murine bone marrow-derived cultured mast cells
      (BMCMC) was activated to its valid form after crosslinking of surface
      immunoglobulin (Ig)E. Serine protease inhibitors sensitive to chymases inhibited
      the phenomenon, indicating that certain chymases may be responsible for
      activation of proMMP-9. Although binding of IgE to its specific receptors did not
      alter MMP-9 production, the IgE crosslinkage increased both expression of mRNA,
      and production of MMP-9 in mast cells. Glucocorticoid declined extra cellular
      processing of proMMP-9 without affecting mRNA expression. These findings give
      rise to the possibility that production and activation of mast cell MMP-9 may be
      increased in the affected sites, thereby resulting in an exacerbation of tissue
      degradation in inflammatory conditions.

PMID- 15203322
TI  - Fluorescein isothiocyanate-hapten immunoassay for determination of peptide-cell
      interactions.
AB  - We have developed a fluorescein isothiocyanate (FITC)-hapten immunoassay, where a
      FITC-labeled peptide binding to a cell is assayed as the amount of immunoreactive
      fluorescein present in a cell lysate. An antifluorescein-horseradish peroxidase
      conjugate binds to either a fluoresceinated peptide in the lysate or a
      fluorescein attached to the wells of a microtiter plate in a competitive fashion.
      After washing, solid-phase peroxidase activity is measured and inversely related
      to the amount of FITC-labeled peptide present. To demonstrate the assay, the
      interaction of a FITC-labeled bombesin-like peptide with the gastrin-releasing
      peptide receptor on PC-3 and HT-29 cells was investigated. Using PC-3 cells, we
      obtained similar displacement curves and numbers of binding sites per cell by
      both the FITC-hapten immunoassay and a reference radioreceptor assay. The FITC
      hapten immunoassay is a sensitive and versatile method, since the same
      commercially available reagents can be used to assess interactions between any
      peptide and any receptor. In addition, the FITC-labeled peptide can be used to
      visualize receptors in fluorescent-activated cell sorting or fluorescent
      microscopy.

PMID- 15203324
TI  - Direct determination of phosphate in urine by sequential-injection analysis with
      single on-line dilution-calibration method and photometric detection.
AB  - In this work we report a sequential-injection (SI) analysis method for the direct
      determination of phosphate in urine with on-line dilution and photometric
      detection. The developed SI manifold incorporated an additional dilution coil
      (DC) connected to one of the ports of the selection valve. On-line dilution was
      performed by aspirating a zone of sample with volume V(S) from the sample line
      into the holding coil (HC), transferring volume V(T) of that zone into the DC,
      and, finally, aspirating a portion of V(T) with volume V(A) back into the HC.
      This dilution introduces an additional dispersion of the initial sample zone
      represented by the effective dispersion coefficient D(eff) which can be tailored
      to the desired value by appropriate selection of the volumes V(S), V(T), and
      V(A). Actual detection of phosphates was performed by the molybdenum blue method
      with detection at 690 nm. By employing an on-line dilution step with a D(eff)=
      100, the calibration curve for phosphate was linear in the range 0.05 x 10(-2) to
      3 x 10(-2) mol L(-1) which covers the actual phosphate concentration in urine
      samples. The regression coefficient was r2 = 0.996, the relative standard
      deviation was sr = 3.9% at the 1 x 10(-2) mol L(-1) level (n = 10), and the
      injection frequency was 30 injections h(-1). The method was applied to urine
      samples with recoveries > 97%.

PMID- 15203323
TI  - Determination of rat blood S-D-lactoylglutathione by a column-switching high
      performance liquid chromatography with precolumn fluorescence derivatization with
      4-fluoro-7-nitro-2,1,3-benzoxadiazole.
AB  - A method for the determination of S-d-lactoylglutathione (SLG), an intermediate
      metabolite of the glyoxalase system, in rat blood is described. After hemolysis
      and deproteinization of 30 microl of rat blood, SLG in the blood was determined
      by a column-switching HPLC system with precolumn fluorescence derivatization with
      a fluorogenic reagent, 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). Calibration
      curves for the determination of SLG showed a good linearity (r2 > 0.999) over the
      range of 20-100 pmol SLG spiked in rat blood samples. The accuracy was in the
      range of 97-104% (20-100 pmol SLG spiked in rat blood sample, N = 4). The
      detection limit was 8.12 fmol, and the quantitation limit was 27.07 fmol,
      respectively. The intra- and interday coefficients of variance were 4.63% (N = 5)
      and 9.98% (N = 5), respectively. The concentrations of SLG in whole blood from
      male Wistar-Kyoto rats (12 weeks old) were 3.48+/-0.78 microM (N = 4, mean+/-SE).
      In streptozotocin-induced diabetic rats, the concentration of SLG was
      significantly increased, approx 5-fold, compared with normal rats, suggesting
      that the metabolic flux of the glyoxalase system increases in red blood cells
      during hyperglycemia.

PMID- 15203325
TI  - A nuclear-magnetic-resonance-based assay for betaine-homocysteine
      methyltransferase activity.
AB  - Betaine-homocysteine methyltransferase (BHMT) activity can be measured directly
      and kinetically by (1)H-nuclear magnetic resonance spectroscopy. The
      disappearance of substrates and the formation of products are monitored
      simultaneously. Alternative substrates, separately and when mixed with glycine
      betaine, can also be monitored. Each assay can be completed in 1h. Using 2mM
      glycine betaine and homocysteine as substrates in 20 mM phosphate buffer (pH 7.5)
      and measuring the production of N,N-dimethylglycine, the CV is 6.3% (n=6) and the
      detection limit is 6 nkatal. An endpoint assay for BHMT activity was also
      developed, by measuring the N,N-dimethylglycine produced after incubation with 2
      mM glycine betaine and homocysteine (CV=5.3%, n = 6) with a detection limit of 2
      nkatal. These assays were used to show that the natural betaines trigonelline,
      proline betaine, arsenobetaine, and l-carnitine are neither substrates nor
      significant inhibitors of rat liver BHMT, that the thetins dimethylthetin and
      dimethylsulfoniopropionate are substrates and inhibit methyl transfer from
      glycine betaine, and that the K(m) for glycine betaine is 0.19+/-0.03 mM with a
      V(max) of 17+/-0.7 nMol min(-1) mg(-1).

PMID- 15203326
TI  - Multiplexed fluorescence detection in microfabricated devices with both time
      resolved and spectral-discrimination capabilities using near-infrared
      fluorescence.
AB  - We examined the feasibility of using a two-color time-resolved detection scheme
      with microdevices for DNA sequencing applications. A home-built dual-color
      optical-fiber-based time-resolved near-infrared (IR) fluorescence microscope
      successfully coupled lifetime discrimination with color discrimination,
      increasing fluorescence multiplexing capabilities. The instrument was constructed
      by using two pulsed-diode lasers (680/780-nm excitation) and two avalanche
      photodiodes as the basic building blocks. The data were processed using
      electronics configured in a time-correlated single-photon counting format. The
      use of near-IR fluorescence detection greatly simplified the hardware and allowed
      low detection limits (< 0.1nM). We examined the separation of a single-base tract
      on a microchip and compared the performance with that of conventional capillary
      gel electrophoresis. The microchip was fabricated in glass and contained an
      effective separation length of 7.0 cm. It was found that, without incorporating a
      solid-phase reversible immobilization cleanup procedure, the calculated lifetime
      of the dye label on the microchip was longer and the standard deviation was
      larger than those of the same sample analyzed using capillary electrophoresis.
      Using cleanup steps, the accuracy and precision of the measurements improved.
      Lifetimes of four near-IR dyes (AlexaFluor680, IRD700, IRD800, and IRD40) used in
      this study were determined to be 986 ps (RSD=2.1%), 1551 ps (RSD=1.8%), 520 ps
      (RSD=3.3%), and 788 ps (RSD=4.9%), respectively, in a microchannel filled with
      poly(dimethylacrylamide) (POP-6) gel. The lifetimes calculated using maximum
      likelihood estimators provided favorable precision on the microchip, where small
      numbers of photocounts were collected. An M13mp18 template was sequenced on the
      microchip using a two-color two-lifetime format with POP-6 as the sieving
      polymer. Read lengths of 294 bp with calling accuracies of 90.8 and 83.7% were
      achieved in each color channel. The relatively low calling accuracy and the short
      read length resulted primarily from the short separation channel, which yielded
      low electrophoretic resolution.

PMID- 15203327
TI  - A pH-sensitive assay for galactosyltransferase.
AB  - We report here a new pH-indicator-based assay for galactosyltransferase. The
      method is simple and fast, requires no specialized equipment, labeled substrate,
      or other expensive materials, and is thus expected to have broad applications
      including automated high-throughput screening. The method is based upon the
      detection of absorbance change of a pH indicator, phenol red, in response to
      proton release that accompanies the galactosyltransferase-catalyzed galactose
      transfer. The assay was used to compare three galactosyltransferases in our
      collection. As demonstrated here, subtle differences in substrate specificity
      were readily discerned with this sensitive method. All three enzymes accept both
      N-acetylglucosamine and glucose as acceptor but the relative activity varies with
      the origin of the enzyme. The method was demonstrated to be useful in the initial
      characterization of recombinant galactosyltransferase from crude cell extract.
      Optimal metal cofactor Mn(2+) concentration and temperature were determined with
      the method. Overall, the method offers a great improvement over current methods
      in reducing time and material consumption. It is the first pH-sensitive method
      for galactosyltransferase. The principles of using pH indicator in
      galactosyltransferase assay should be applicable to other glycosyltransferase
      enzymes.

PMID- 15203328
TI  - An integrative approach for the optical sequencing of single DNA molecules.
AB  - A new approach for optically sequencing ensembles of single DNA molecules using
      DNA polymerase to mediate the consecutive incorporation of fluorochrome-labeled
      nucleotides into an array of large single DNA molecules is presented. The
      approach utilizes cycles of labeled fluorochrome addition, detection to count
      incorporations, and bleaching to reset the counter. These additions are imaged
      and analyzed to estimate the number of labeled additions and to correlate them on
      a per-locus basis along DNA backbones. Initial studies used precisely labeled
      polymerase chain reaction products to aid the development and validation of
      simple models of fluorochrome point spread functions within the imaging system.
      In complementary studies, nucleotides labeled with the fluorochrome R110 were
      incorporated into surface-elongated lambda DNA, and fluorescent signals
      corresponding to the addition of R110-dUTP were counted and assigned precise loci
      along DNA backbones. The labeled DNAs were then subjected to photobleaching and
      to a second cycle of addition of R110-labeled nucleotides-a second round of
      additions was correlated with the first to establish strings of addition
      histories among the ensemble of largely double-stranded templates. These results
      confirm the basic operational validity of this approach and point the way to the
      development of a practical system for optical sequencing.

PMID- 15203329
TI  - Lanthanide-based time-resolved fluorescence of in cyto ligand-receptor
      interactions.
AB  - A lanthanide-based assay for ligand-receptor interactions provides an attractive
      alternative to the traditional radiolabeled determinations in terms of
      sensitivity, throughput, and biohazards. We designed and tested peptide ligands
      modified with an Eu-DTPA chelate. These labeled ligands were used in competitive
      binding assays with results comparable to those obtained using the traditional
      radiolabeled binding assays. The sensitivity of time-resolved fluorescence is
      sufficient to detect attomoles of europium, allowing assays in 96-well plates,
      compared with 30-mm dishes for (125)I binding assays to whole cells. We verified
      binding of Eu-DTPA-NDP-alpha-MSH to cells overexpressing the human melanocortin-4
      receptor. The Eu-labeled ligand bound to these cells with an affinity similar to
      that of unlabeled NDP-alpha-MSH and was used to optimize a competitive binding
      assay. The lanthanide-based assays provided superior results with higher
      throughput and eliminated the need for radioactive waste disposal. This assay is
      appropriate for high-throughput screening of ligand libraries.

PMID- 15203330
TI  - A fusion protein expression analysis using surface plasmon resonance imaging.
AB  - A surface plasmon resonance (SPR) imaging system was constructed and used to
      detect the affinity-tagged recombinant proteins expressed in Escherichia coli.
      With regards to model proteins, the hexahistidine-ubiquitin-tagged human growth
      hormone (His(6)-Ub-hGH), glutathione S-transferase-tagged human interleukin-6
      (GST-hIL6), and maltose-binding protein-tagged human interleukin-6 (MBP-hIL6)
      expressed in E. coli were analyzed. The cell lysates were spotted on gold thin
      films coated with 11-mercaptoundecanol (MUOH)/dextran derivatized with Ni(II)
      iminodiacetic acid (IDA-Ni(II)), glutathione, or cyclodextrin. After a brief
      washing of the gold chip, SPR imaging measurements were carried out in order to
      detect the bound affinity-tagged fusion proteins. Using this new approach, rapid
      high-throughput expression analysis of the affinity-tagged proteins were
      obtained. The SPR imaging protein chip system used to measure the expression of
      affinity-tagged proteins in a high-throughput manner is expected to be an
      attractive alternative to traditional laborious and time-consuming methods, such
      as SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blots.

PMID- 15203331
TI  - Glycoform composition profiling of O-glycopeptides derived from human serum IgA1
      by matrix-assisted laser desorption ionization-time of flight-mass spectrometry.
AB  - Pools of O-glycopeptides prepared from trypsin-digested reduced and alkylated
      human serum IgA1 have been analyzed using matrix-assisted laser desorption
      ionization-time of flight-mass spectrometry (MALDI-ToF-MS) in the positive-ion
      mode, using 2,4,6-trihydroxy acetophenone-ammonium citrate matrix. Dozens of such
      pools prepared from normal serum IgA1 and from serum of patients with a number of
      different medical conditions have been routinely analyzed in this manner. The
      glycopeptides present in these pools possess identical amino acid sequences but
      are substituted with a variety of neutral and sialylated glycans and the spectra
      obtained were such that individual compositional glycoforms were baseline
      resolved. In addition, the spectra were reproducible, exhibiting a relative peak
      intensity and area variation of around 11-16%, enabling the technique to be used
      for the relative quantitation of the different compositional glycoforms present.
      This could be achieved manually or by applying a Java program especially
      developed for this purpose. The MS analysis described here is a major improvement
      over present MALDI methods used for profiling the O-glycosylation of IgA1. The MS
      methodology together with the Java data analysis are expected to be generally
      applicable for profiling O-linked glycopeptides derived from other glycoproteins
      and probably for N-linked glycopeptide pools.

PMID- 15203332
TI  - Protein carboxyl amidation increases the potential extent of protein polyethylene
      glycol conjugation.
AB  - Chemical coupling of polyethylene glycol (PEG) to therapeutic proteins reduces
      their immunogenicity and prolongs their circulating half-life. The limitation of
      this approach is the number and distribution of sites on proteins available for
      PEGylation (the N terminus and the -amino group of lysines). To increase the
      extent of PEGylation, we have developed a method to increase the number of
      PEGylation sites in a model protein, recombinant methionine alpha,gamma-lyase
      (recombinant methioninase; rMETase), an enzyme cancer therapeutic cloned from
      Pseudomonas putida. rMETase was first PEGylated with methoxypolyethylene glycol
      succinimidyl glutarate-5000 with a molar ratio of PEG:rMETase of 15:1. The
      carboxyl groups of the initially PEGylated protein were then conjugated with
      diaminobutane, resulting in carboxyl amidation. This reaction was catalyzed by 1
      ethyl-3-(3-dimethylaminopropyl) carbodiimide, a water-soluble carbodiimide. The
      steric hindrance provided by the PEG chains already coupled to the protein
      prevented cross-linking between rMETase molecules during the carboxyl amidation
      reaction. The carboxyl-amidated PEGylated rMETase was hyper-PEGylated at a molar
      ratio of PEG to PEG-rMETase of 60:1. Biochemical analysis indicated that 13 PEG
      chains were coupled to each subunit of rMETase after hyper-PEGylation compared
      with 6-8 PEG chains attached to the non-carboxyl-amidated PEG-rMETase.
      Approximately 15-20% of the non-PEGylated rMETase activity was retained in the
      hyper-PEGylated molecule. Immunogenicity of the hyper-PEG-rMETase was
      significantly reduced relative to PEG-rMETase and rMETase. Initial results
      suggest that hyper-PEGylation may become a new strategy for PEGylation of protein
      biologics.

PMID- 15203333
TI  - Improvements in Pyrosequencing technology by employing Sequenase polymerase.
AB  - Pyrosequencing is a DNA sequencing technique based on the bioluminometric
      detection of inorganic pyrophosphate, which is released when nucleotides are
      incorporated into a target DNA. Since the technique is based on an enzymatic
      cascade, the choice of enzymes is a critical factor for efficient performance of
      the sequencing reaction. In this study we have analyzed the performance of an
      alternative DNA polymerase, Sequenase, on the sequencing performance of the
      Pyrosequencing technology. Compared to the Klenow fragment of DNA polymerase I,
      Sequenase could read through homopolymeric regions with more than five T bases.
      In addition, Sequenase reduces remarkably interference from primer-dimers and
      loop structures that give rise to false sequence signals. By using Sequenase,
      synchronized extensions and longer reads can be obtained on challenging
      templates, thereby opening new avenues for applications of Pyrosequencing
      technology.

PMID- 15203334
TI  - Performance of antibody microarrays fabricated by either DNA-directed
      immobilization, direct spotting, or streptavidin-biotin attachment: a comparative
      study.
AB  - Antibody microarrays have the potential to revolutionize protein diagnostics. The
      major problems in the fabrication of antibody arrays, however, concern the
      reproducibility and homogeneity of the attachment of the proteins on the solid
      substrate. We here compare the DNA-directed immobilization (DDI) method with two
      conventional strategies for immobilization of antibodies on glass substrates. DDI
      is based on the self-assembly of semisynthetic DNA-streptavidin conjugates which
      converts an array of DNA oligomers into an antibody microarray. DDI was compared
      with direct spotting of antibodies on chemically activated glass slides and with
      immobilization of biotinylated antibodies on streptavidin-coated slides. The
      immobilized antibodies were used as capture reagents in a two-sided (sandwich)
      immunoassay for the quantification of rabbit IgG as a model antigen. Detection
      limits down to 0.001nM (150 pg/mL) were attained with all three array formats;
      however, DDI and direct spotting of the antibodies led to the highest
      fluorescence intensities. DDI led to the best spot homogeneity and intra- and
      interexperimental reproducibility. Moreover, DDI allowed highly economical use of
      antibody materials; that is, at least 100-fold less antibody is needed for
      preparing an array by DDI instead of by direct spotting. Taking into account the
      greater versatility and convenience of handling of the self-assembly approach,
      this study demonstrates that DDI is an advantageous alternative for generating
      versatile and robust protein arrays.

PMID- 15203335
TI  - Refinement of single-nucleotide polymorphism genotyping methods on human genomic
      DNA: amplifluor allele-specific polymerase chain reaction versus ligation
      detection reaction-TaqMan.
AB  - Single-nucleotide polymorphisms (SNPs) have proven to be powerful genetic markers
      for a variety of genetic applications, e.g., association studies leading to
      dissection of both monogenetic and complex diseases. However, no single SNP
      genotyping method has been broadly accepted. In the present study, we compared
      and refined two promising methods with potential for research and for diagnostic
      SNP genotyping: Amplifluor allele-specific polymerase chain reaction (PCR) and
      ligation detection reaction (LDR)-TaqMan. The methods are based on allele
      specific primer extension and allele-specific ligation, respectively. Since LDR
      TaqMan had previously been tested on just Arabidopsis thaliana, we adjusted the
      method for the more complex human genome. Amplifluor allele-specific PCR has a
      single-step and closed-tube format, whereas the LDR-TaqMan assay comprises two
      simple steps. Contrary to the primer-extension-based method, the ligation-based
      method can be multiplexed. Refining the LDR-TaqMan technique, we successfully
      replaced a previously suggested three-step multiplexing procedure with a less
      laborious two-step approach. Comparing refined LDR-TaqMan with Amplifluor allele
      specific PCR in a family-based study, both techniques appeared similar with
      respect to high robustness and accuracy. As both approaches utilize primers with
      common tails, all SNPs can be assayed with the same couple of fluorescence
      reporting reagents, ensuring low establishing and running expenses.

PMID- 15203336
TI  - Optimization of ascorbic and uric acid separation in human plasma by free zone
      capillary electrophoresis ultraviolet detection.
AB  - In this paper we propose a new fast free zone capillary electrophoresis method
      for the simultaneous determination of ascorbic acid (AA) and uric acid (UA) in
      human plasma. We investigated the effect of analytical parameters, such as
      concentration and pH of borate running buffer, cartridge temperature, and sample
      treatment, on resolution, migration times, corrected peak areas, and efficiency.
      A good separation was achieved using a 60.2-cmx75-microm uncoated silica
      capillary and 100 mmol/L sodium borate buffer, pH 8, when metaphosphoric acid was
      employed as protein precipitant, in less than 4 min. These conditions gave a good
      reproducibility of migration times (CV 0.35 and 0.34%) and peak areas (CV 3.2 and
      3.1%) for ascorbate and urate, respectively. The limit of detection was 0.5mg/L
      for both analytes when the detection was performed at 254 nm for AA and at 292 nm
      for UA. We compared the present method with a validated capillary electrophoresis
      assay by measuring plasma urate and ascorbate in 32 normal subjects and the
      obtained data were analyzed by the Passing and Bablok regression.

PMID- 15203337
TI  - Electrochemical assay for determining nitrosyl derivatives of human hemoglobin:
      nitrosylhemoglobin and S-nitrosylhemoglobin.
AB  - Nitric oxide (NO) is an important biological regulator. It can bind to heme iron
      and form NO+, involved in the synthesis of S-nitrosothiols (-SNOs). NO reacts
      with human hemoglobin (Hb) to produce the derivatives: S-nitrosylhemoglobin (
      SNOHb) and nitrosylhemoglobin (HbNO). At neutral pH values, free NO does not
      react directly with the -SH groups of Hb. The reductive nitrosylation of Fe(III)
      heme upon reaction with NO has long been studied, but it is not yet completely
      known. To quantify the reaction of NO with Hb, we developed a new, sensitive
      (nanomolar concentration range) electrochemical assay to selectively measure HbNO
      and -SNOHb. The assay also allows the monitoring of free NO during the reaction
      with human Fe(III)Hb and Fe(II)HbO(2).

PMID- 15203338
TI  - Microarrays of peptides elevated on the protein layer for efficient protein
      kinase assay.
AB  - Peptide microarrays can be used for the high-throughput analysis of protein
      peptide interactions. However, current peptide microarrays are rather costly to
      make and require cumbersome steps of introducing novel polymeric surfaces and/or
      chemical derivatization of peptides. Here, we report a novel method for
      manufacturing peptide microarrays by elevating the peptide on the layer of
      protein by a fusion protein approach. Using two protein kinases and their peptide
      substrates as examples, we show that elevating peptides on the layer of protein
      allows sensitive, specific, and efficient detection of peptide-protein
      interactions without the need for complicated chemical modification of solid
      supports and peptides. It was found that kinase activity could be detected with
      as low as 0.09 fmol of kemptide, which is about 1000-fold more sensitive than the
      0.1 pmol obtained with other microarray systems. Furthermore, peptides can be
      produced as fusion proteins by fermentation of recombinant Escherichia coli and
      thus the expensive peptide synthesis process can be avoided. Therefore, this new
      strategy will not only be useful in high-throughput and cost-effective screening
      of kinase substrate peptides but also be generally applicable in studying various
      protein-peptide interactions.

PMID- 15203339
TI  - Toward fingerprinting cellular lipidomes directly from biological samples by two
      dimensional electrospray ionization mass spectrometry.
AB  - Cellular lipids are composed of linear combinations of aliphatic chains
      covalently attached to backbones and/or head groups that collectively represent
      the cellular lipidome. Herein we present a novel two-dimensional electrospray
      ionization mass spectrometric approach to fingerprint most of the major and many
      of the minor lipid classes in the hepatic cellular lipidome, which collectively
      represent >80% of the total lipid mass, directly from their chloroform extracts.
      Through lipid class-selective intrasource ionization and subsequent analysis of
      two-dimensional cross-peak intensities, the chemical identity and mass
      composition of individual molecular species of most mouse hepatic lipid classes
      were determined from its chloroform extract. This new integrated platform
      provides a robust foundation for the automated analysis of multidimensional mass
      spectra to advance the level of analytical scripting in lipidomics to a new
      plateau.

PMID- 15203340
TI  - A functional assay for measuring activated thrombin-activatable fibrinolysis
      inhibitor in plasma.
AB  - Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase found
      in plasma that is activated by thrombin, the thrombin-thrombomodulin complex, or
      plasmin. The active carboxypeptidase, TAFIa, attenuates fibrinolysis by removing
      newly exposed carboxy-terminal lysine residues on fibrin. The half-maximal effect
      of TAFIa on clot lysis occurs at 1 nM and the maximal effect occurs at 20 nM.
      Since the circulating concentration of the procarboxypeptidase is approximately
      75 nM, only a small portion needs to be activated to have a significant effect on
      clot lysis. Several assays to measure total plasma TAFI levels and plasma TAFIa
      levels after it is fully activated exist. However, no currently available assay
      is sufficiently sensitive and specific to measure endogenous TAFIa in plasma. We
      have devised a new sensitive and specific assay for TAFIa in plasma that is based
      on physiologic function. This assay is based on the fact that TAFIa decreases the
      cofactor activity of high-molecular-weight fibrin degradation products in the
      stimulation of plasminogen cleavage in a concentration-dependent fashion. With
      this assay, we can measure TAFIa concentrations as low as 10 pM in plasma and it
      is not affected by variability in other hemostatic factors. This assay is
      reliable and repeatable with intra- and interassay variabilities of 6.5 and 6.1%,
      respectively.

PMID- 15203341
TI  - Liposome-based microcapillary immunosensor for detection of Escherichia coli
      O157:H7.
AB  - Our group has previously reported a sandwich-based strip immunoassay for rapid
      detection of Escherichia coli O157:H7 [Anal. Chem. 75 (2003) 4330]. In the
      present study, a microcapillary flow injection liposome immunoanalysis (mFILIA)
      system was developed for the detection of heat-killed E. coli O157:H7. A fused
      silica microcapillary with anti-E. coli O157:H7 antibodies chemically immobilized
      on the internal surface via protein A served as an immunoreactor/immunoseparator
      for the mFILIA system. Liposomes tagged with anti-E. coli O157:H7 and
      encapsulating a fluorescent dye were used as the detectable label. In the
      presence of E. coli O157:H7, sandwich complexes were formed between the
      immobilized antibodies in the column, the sample of E. coli O157:H7 and the
      antibody-tagged sulforhodamine-dye-loaded liposomes. Signals generated by lysing
      the bound liposomes with 30 mM n-octyl-beta-D-glucopyranoside were measured by a
      fluorometer. The detected signal was directly proportional to the amount of E.
      coli O157:H7 in the test sample. The mFILIA system successfully detected as low
      as 360 cells/mL (equivalent to 53 heat-killed bacteria in the 150 microL of the
      sample solution injected). MeOH (30%) was used for the regeneration of antibody
      binding sites in the capillary after each measurement, which allowed the
      immunoreactor/immunoseparator to be used for at least 50 repeated assays. The
      calibration curve for heat-killed E. coli O157:H7 has a working range of 6 x
      10(3)-6 x 10(7)cells, and the total assay time was less than 45 min. A
      coefficient of variation for triplicate measurements was < or =8.9%, which
      indicates an acceptable level of reproducibility for this newly developed method.

PMID- 15203342
TI  - ViriChip enhances reverse transcriptase polymerase chain reaction in biological
      fluids and environmental samples.

PMID- 15203343
TI  - Phospholipase C activator 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)
      benzene-sulfonamide decays under ultraviolet light and shows strong self
      fluorescence.

PMID- 15203344
TI  - Molecular-weight-based hyaluronidase assay using fluorescent hyaluronic acid as a
      substrate.

PMID- 15203345
TI  - Separation of capsular polysaccharide-K4- and defructosylated-K4-derived
      disaccharides by high-performance liquid chromatography and postcolumn
      derivatization with 2-cyanoacetamide and fluorimetric detection.

PMID- 15203346
TI  - A colorimetric method for determination of amino amidase activity.

PMID- 15203347
TI  - Models relating traffic safety with road environment and traffic flows on
      arterial roads in Addis Ababa.
AB  - This paper presents the study carried out to develop accident predictive models
      based on the data collected on arterial roads in Addis Ababa. Poisson and
      negative binomial regression methods were used to relate the discrete accident
      data with the road and traffic flow explanatory variables. Significant accident
      predictive models were found with a number of significant explanatory variables.
      The results show that the existing inadequate road infrastructure and poor road
      traffic operations are the potential contributors of this ever-growing challenge
      of the road transport in Addis Ababa. The results also indicate that improvements
      in roadway width, pedestrian facilities, and access management are effective in
      reducing road traffic accidents.

PMID- 15203348
TI  - Sources of error in road safety scheme evaluation: a quantified comparison of
      current methods.
AB  - This paper considers the various factors that can have a confounding effect in
      the evaluation of road safety schemes and examines the extent to which current
      methods can effectively deal with these. A modification to current methods is
      proposed which allows the reduction in accidents attributable to risk and flow
      changes to be separately evaluated. Data are presented to demonstrate the
      relative magnitudes of the various sources of error. It is shown that a principal
      source of error is normally regression-to-mean (RTM) and a correction for this
      effect should always be applied. Changes in traffic flow can also result in
      substantial accident changes and it is important to establish whether flow
      changes have occurred and if they are attributable to the effect of the scheme.

PMID- 15203349
TI  - Sources of error in road safety scheme evaluation: a method to deal with outdated
      accident prediction models.
AB  - This paper considers the errors that arise in using outdated accident prediction
      models in road safety scheme evaluation. Methods to correct for regression-to
      mean (RTM) effects in scheme evaluation normally rely on the use of accident
      prediction models. However, because accident risk tends to decline over time,
      such models tend to become outdated and the estimated treatment effect is then
      exaggerated. A new correction procedure is described which can effectively
      eliminate such errors.

PMID- 15203350
TI  - Effects of an active accelerator pedal on driver behaviour and traffic safety
      after long-term use in urban areas.
AB  - The long-term effects of the active accelerator pedal (AAP) were evaluated in the
      city of Lund in 2000 and 2001. The system, installed in 284 vehicles, produced a
      counterforce in the accelerator pedal at the speed limit. It could, however be
      overridden by pressing the accelerator pedal harder. The results showed that test
      drivers' compliance with the speed limits improved considerably. Reduction in
      average speeds and less speed variation by the test vehicles indicate a great
      traffic-safety potential. Travel times were unaffected, while emission volumes
      decreased significantly.

PMID- 15203351
TI  - Prediction of accidents at full green and green arrow traffic lights in
      Switzerland with the aid of configuration-specific features.
AB  - In this study it was endeavored to predict full green and green arrow accidents
      at traffic lights, using configuration-specific features. This was done using the
      statistical method known as Poisson regression. A total of 45 sets of traffic
      lights (criteria: in an urban area, with four approach roads) with 178 approach
      roads were investigated (the data from two approach roads was unable to be used).
      Configuration-specific features were surveyed on all approach roads
      (characteristics of traffic lanes, road signs, traffic lights, etc.), traffic
      monitored and accidents (full green and green arrow) recorded over a period of 5
      consecutive years. It was demonstrated that only between 23 and 34% of variance
      could be explained with the models predicting both types of accidents. In green
      arrow accidents, the approach road topography was found to be the major
      contributory factor to an accident: if the approach road slopes downwards, the
      risk of a green arrow accident is approximately five and a half times greater
      (relative risk, RR = 5.56) than on a level or upward sloping approach road. With
      full green accidents, obstructed vision plays the major role: where vision can be
      obstructed by vehicles turning off, the accident risk is eight times greater (RR
      = 8.08) than where no comparable obstructed vision is possible. From the study it
      emerges that technical features of traffic lights are not able to control a
      driver's actions in such a way as to eradicate error. Other factors, in
      particular the personal characteristics of the driver (age, sex, etc.) and
      accident circumstances (lighting, road conditions, etc.), are likely to make an
      important contribution to explaining how an accident occurs.

PMID- 15203352
TI  - Warning signs as countermeasures to camel-vehicle collisions in Saudi Arabia.
AB  - The camel-vehicle collision (CVC) problem has been increasing in Saudi Arabia and
      countermeasures are urgently needed to alleviate the heavy losses from such
      accidents. A research project was funded by the Saudi Arabian government to
      investigate the problem and to develop techniques to deal with it. Among the
      different techniques investigated were camel-crossing warning signs. In this
      study, seven camel-crossing warning signs were tested to determine if they would
      reduce the number of CVCs on rural roads. The measure of effectiveness utilized
      was the mean speed reduction of motorists passing such signs. In this paper, the
      experiments of warning sign testing are detailed, and the evaluation of the
      signs, based on the results of the testing experiments, is presented. Although
      most of the signs brought about significant reductions in mean speed, indicating
      statistical effectiveness, the speed reductions were not relatively large; they
      ranged from around 3 to about 7 km/h. Furthermore, statistical analysis was used
      to rank the signs according to their effectiveness. A triangular warning sign
      with a black camel silhouette and diamond reflective material (220 cm x 220 cm x
      220 cm) is recommended in this study. This sign is similar to the standard
      warning sign used in Saudi Arabia except that it is twice the standard size and
      uses diamond reflective material.

PMID- 15203353
TI  - Vehicle mismatch: injury patterns and severity.
AB  - Light truck vehicles (LTV) are becoming more popular on US highways. This creates
      greater opportunity for collisions with passenger vehicles (PV). The mismatch in
      weight, stiffness, and height between LTV and PV has been surmised to result in
      increased fatalities among PV occupants when their vehicles collide with LTV. We
      reviewed cases of vehicle mismatch collisions in the Seattle Crash Injury
      Research and Engineering Network (CIREN) database to establish patterns and
      source of injury. Of the first 200 Seattle CIREN cases reviewed, 32 collisions
      with 41 occupant cases were found to involve LTV versus PV. The cases were
      reviewed by type of collision and vehicle of injured occupant: side impact of PV
      with LTV, front impact of PV with LTV, and front impact of LTV with PV. For each
      type of crash, injury patterns and mechanisms were identified. For side impact to
      PV, head and upper thorax injuries were frequently encountered due to LTV bumper
      frame contact above the PV side door reinforcement. For frontal impact to PV,
      severe multiple extremity fractures along with some head and chest injuries were
      caused by intrusion of the instrument panel and steering column due to bumper
      frame override of the LTV. Underriding of the PV when colliding with the LTV
      resulted in severe lower extremity fractures of the LTV occupant due to intrusion
      of the toe pan into the vehicle compartment of the LTV. The injuries and the
      sources identified in this case series support the need for re-designing both LTV
      and PV to improve vehicle compatibility. Revising Federal Motor Vehicle Safety
      Standard 214 to reinforce the entire door, consider adding side airbags, and re
      engineering LTV bumpers and/or frame heights and PV front ends are possible ways
      to reduce these injuries and deaths by making the vehicles more compatible.

PMID- 15203354
TI  - Influences during adolescence on perceptions and behaviour related to alcohol use
      and unsafe driving as young adults.
AB  - OBJECTIVE: To investigate whether aggression, parent and peer influences, and
      previous traffic-related experiences at ages 15 and 18 impacted on (a)
      differences between the perceived safe and estimated legal alcohol consumption
      limit, and (b) driving while impaired (DWI) behaviour at age 21. METHOD: The
      study population was a birth cohort involved in a longitudinal investigation of
      health and development. At the ages of 15 and 18, study members completed
      questionnaires assessing parent and peer attachment, experience travelling with
      an alcohol impaired adult or youth, aggression, and previous crash experience. At
      age 21, study members were questioned about how much alcohol they perceived they
      could drink and still drive safely, and whether they had driven after 'perhaps
      consuming too much alcohol'. For each participant their legal alcohol consumption
      limit was estimated using their height and weight. Path analysis was used to
      determine whether variables measured at ages 15 and 18 predicted differences
      between the perceived safe and estimated legal alcohol consumption limit and
      driving while impaired, both measured at age 21. RESULTS: Insufficient females
      drove while impaired at age 21, who also had complete data on all other
      variables, to conduct path analysis for this outcome. For males, aggression at
      ages 15 and 18, travelling with an impaired youth at age 18, and previous crash
      experience at age 18 predicted DWI behaviour at age 21. Only aggression at age 15
      predicted the difference between perceived safe and estimated legal alcohol
      consumption limit for the males. For females, aggression at ages 15 and 18, and
      travelling with an impaired adult at age 15 predicted the difference between
      perceived safe and estimated legal alcohol consumption limit. CONCLUSION: The
      results show that aggressive behaviours and adult and/or youth modelling of drink
      driving behaviours in mid- to late-adolescence are related to differences between
      perceived safe and estimated legal alcohol consumption limit for both genders and
      driving while impaired for males.

PMID- 15203355
TI  - Cost savings from a sustained compulsory breath testing and media campaign in New
      Zealand.
AB  - This paper evaluates three approaches to compulsory breath testing (CBT) where
      all drivers stopped are tested: (1) intensive, moderate-profile CBT (plus zero
      alcohol tolerance for drivers under age 20, which was implemented simultaneously,
      remains in effect, and unavoidably is commingled with CBT in the effectiveness
      estimates); (2) CBT plus an enhanced media campaign; and (3) shifting to
      aggressively visible booze buses, which also streamlined drunk-driver processing,
      plus enhanced community campaigns against drunk-driving. Approaches 1 and 2 were
      implemented throughout New Zealand (NZ) in 1993 and 1995. Booze buses and
      community programs were added for about one-third of the country in late 1996.
      ARIMA time series models estimated the impact on serious and fatal injury crashes
      between 10 p.m. and 3 a.m., a proxy for alcohol-related crashes. A benefit-cost
      analysis assessed return on investment. Cost savings were analyzed from four
      perspectives: societal, governmental, drunk-drivers', and people other than drunk
      drivers (external cost). CBT plus zero tolerance reduced expected night-time
      crashes by 22.1% and enhanced media by 13.9%. Booze buses yielded a further 27.4%
      reduction where implemented. The program and associated crash reduction persisted
      until at least 2001 (the most recent data available). Estimated societal benefit
      cost ratios were 14 for CBT, 19 for CBT plus enhanced media, and 26 for the
      comprehensive package. Government saved more than it spent on the program,
      especially with booze buses. Aggressive CBT plus zero alcohol tolerance for
      youth, media blitzes, and booze buses proved dramatically effective. Together,
      these four interventions halved late night serious and fatal injury crashes.
      Sustained effort seems to be critical. Better outcomes may be achieved with
      staged, increasingly visible and inescapable checkpoints than with an "ideal"
      initial program. It appears CBT is best implemented in conjunction with broader
      community-centered efforts to reduce drunk-driving.

PMID- 15203356
TI  - Collisions and traffic violations of alcohol, cannabis and cocaine abuse clients
      before and after treatment.
AB  - Prior research has shown that those with alcohol problems have significantly
      elevated rates of traffic events (i.e. traffic violations and collisions) than
      licensed drivers from the general population and that treatment is associated
      with reductions in alcohol-related collisions. However, very little research
      exists on traffic events and the impact of treatment for cannabis or cocaine
      clients. The objectives of this research are: (1) to determine whether clients in
      treatment for a primary problem of alcohol, cannabis or cocaine have
      significantly elevated rates of traffic events than a matched control group of
      licensed drivers; and (2) to assess whether a significant reduction in traffic
      events occurs after treatment for each client group compared to a control group.
      Driver records of patients admitted to substance abuse treatment in 1994 for a
      primary problem of alcohol (n = 117), cannabis (n = 80) or cocaine (n = 169) were
      accessed from the Ministry of Transportation for Ontario, Canada. A comparison
      group of 504 licensed drivers frequency matched by age, sex and place of
      residence, was also randomly selected. Data was collapsed into two 6-year time
      periods: 1988-1993 (i.e. before treatment) and 1995-2000 (i.e. after treatment).
      Six repeated measures analysis of variance tests were conducted where traffic
      violations and collisions of three treatment groups (i.e. alcohol, cannabis or
      cocaine) and a control group were compared before and after treatment. All three
      treatment groups had significantly more traffic violations than the control group
      and no significant interactions between time period and group membership were
      found. For collisions, there was a significant interaction between the alcohol
      and control groups and between the cocaine and control groups. The average number
      of collisions for the alcohol and cocaine groups decreased after completing
      treatment, whereas the number for the control group was stable over the same time
      periods. Neither the interaction term nor the between group effect was
      significant in the comparison of the cannabis and control groups. When rates of
      collisions were calculated based on the period that each driver had a valid
      license, the interaction term was still significant for the comparison of the
      alcohol and control groups but not for the cocaine and control groups. The
      results contribute to existing literature by demonstrating that cocaine and
      cannabis clients have a higher risk of traffic violations than matched controls
      and that reductions in collision risk was found after treatment for the alcohol
      and cocaine groups. More research is needed to better understand the reasons for
      the higher risk of traffic events and to determine reasons for declines.

PMID- 15203357
TI  - Costs of large truck-involved crashes in the United States.
AB  - This study provides the estimates of the costs of highway crashes involving large
      trucks by type of truck involved. These costs represent the present value of all
      costs over the victims' expected life span that result from a crash. They include
      medically related costs, emergency services costs, property damage costs, lost
      productivity, and the monetized value of the pain, suffering, and lost quality of
      life that a family experiences because of death or injury. Based on the latest
      data available, the estimated cost of police-reported crashes involving trucks
      with a gross weight rating of more than 10,000 pounds averaged US$ 59,153 (in
      2000 dollars). Multiple combination trucks had the highest cost per crash (US$
      88,483). The crash costs per 1000 truck miles however, were US$ 157 for single
      unit trucks, US$ 131 for single combination trucks, and US$ 63 for multiple
      combinations.

PMID- 15203358
TI  - The life cycle of the policy for preventing road accidents: an empirical example
      of the policy for reducing drunk driving crashes in Taipei.
AB  - The purpose of this paper is to examine the temporal variation of the effect of
      preventive policy on reducing traffic accidents. The life cycle theory was
      introduced to describe the safety effect of the intervening policy over time.
      Poisson regression models with dummy-based and time-based specifications were
      used to evaluate the effect of an intervening policy over an observation period
      following its implementation. The policy of "Criminal sanction for drunk driving
      (CSFDD)" in Taipei city was evaluated as an empirical example to determine
      whether the temporal variation of safety effect happened to the CSFDD policy. The
      study results showed that alcohol consumption, arresting the drunk driving
      offenders, and the implementation of the CSFDD were the significant factors
      affecting the rate of occurrence of fatal accidents involving drunk driving. The
      effect of the CSFDD policy appeared to be a rapid initial response followed by a
      lower rate of decay. The existence of the life cycle implies that employing
      different observation periods following the implementation of a specific policy
      to evaluate its performance may obtain different effects. The results of this
      study are crucial for policy evaluation. The effects of safety policy should be
      carefully interpreted in order to avoid misleading the relevant authorities in
      coming to the wrong conclusions and as such make the wrong decisions.

PMID- 15203359
TI  - The effect of changing from secondary to primary safety belt enforcement on
      police harassment.
AB  - The purpose of the study was to investigate whether changing Michigan's safety
      belt law from secondary to primary (standard) enforcement resulted in police
      harassment. The study investigated safety-belt-enforcement-related harassment by
      considering three measures: citizen complaints arising from enforcement of the
      safety belt law; citation over-representation, that is, a statistical
      determination of whether certain groups received more citations than would be
      expected based upon their presence in the driving population and their rate of
      violating the safety belt use law; and self-reported harassment among the
      population of people who receive safety belt citations. Safety-belt-related
      harassment complaints were very uncommon both before and after primary
      enforcement. Implementation of primary enforcement did not lead to an increase in
      citation over-representation, and, therefore, safety-belt-related harassment by
      sex, race, or age. The vast majority of people receiving safety belt citations
      reported officer behavior as professional and did not feel that they were singled
      out for their citation. However, a sizeable minority of Blacks and young people
      report perceptions of safety-belt-related harassment. Results suggest that states
      with secondary enforcement should continue their efforts to change to primary
      enforcement, but should also make a strong effort to educate both law enforcement
      and the public about the harassment issue.

PMID- 15203360
TI  - Vehicle speed affects both pre-skid braking kinematics and average tire/roadway
      friction.
AB  - Vehicles decelerate between brake application and skid onset. To better estimate
      a vehicle's speed and position at brake application, we investigated how vehicle
      deceleration varied with initial speed during both the pre-skid and skidding
      intervals on dry asphalt. Skid-to-stop tests were performed from four initial
      speeds (20, 40, 60, and 80 km/h) using three different grades of tire (economy,
      touring, and performance) on a single vehicle and a single road surface. Average
      skidding friction was found to vary with initial speed and tire type. The post
      brake/pre-skid speed loss, elapsed time, distance travelled, and effective
      friction were found to vary with initial speed. Based on these data, a method
      using skid mark length to predict vehicle speed and position at brake application
      rather than skid onset was shown to improve estimates of initial vehicle speed by
      up to 10 km/h and estimates of vehicle position at brake application by up to 8 m
      compared to conventional methods that ignore the post-brake/pre-skid interval.

PMID- 15203361
TI  - To what extent can theory account for the findings of road safety evaluation
      studies?
AB  - This paper proposes a conceptual framework that can be used to assess to what
      extent the findings of road safety evaluation research make sense from a
      theoretical point of view. The effects of road safety measures are modelled as
      passing through two causal chains. One of these, termed the engineering effect,
      refers to the intended effects of a road safety measure on a set of risk factors
      related to accident occurrence or injury severity. The engineering effect of road
      safety measures is modelled in terms of nine basic risk factors, one or more of
      which any road safety measure needs to influence in order to have the intended
      effect on accidents or injuries. The other causal chain producing the effects of
      road safety measures is termed the behavioural effect, and refers to road user
      behavioural adaptations to road safety measures. The behavioural effect is
      related to the engineering effect, in the sense that certain properties of the
      engineering effect of a road safety measure influence the likelihood that
      behavioural adaptation will occur. The behavioural effect of a road safety
      measure is modelled in terms of six factors that influence the likelihood that
      behavioural adaptation will occur. The nine basic risk factors representing the
      engineering effect of a road safety measure, and the six factors influencing the
      likelihood of behavioural adaptation can be used as checklists in assessing
      whether or not the findings of road safety evaluation studies make sense from a
      theoretical point of view. At the current state of knowledge, a more stringent
      evaluation of the extent to which theory can explain the findings of road safety
      evaluation studies is, in most cases, not possible.

PMID- 15203362
TI  - Work-related road fatalities in Australia.
AB  - This study aimed to provide a detailed description of all work-related road
      deaths in Australia during 1989-1992, compare the results to a prior
      investigation of work-related road fatalities, and consider the use of data from
      the Australian Transport Safety Bureau (ATSB) as a possible source of information
      on work-related road deaths. Results show that there were on average 136 workers,
      151 commuters, and 133 road bystanders who were fatally injured in vehicle
      incidents on a public roadway each year during the study timeframe, giving a rate
      of 1.7 per 100,000 workers per year for workers, a rate of 2.0 per 100,000
      commuters per year, and a rate of 0.78 per 100,000 persons per year for road
      bystanders. Workers employed in the transport and storage industry had the
      highest rate of work-related road deaths (15.5 per 100,000 workers per year) in
      1989-1992, although this was a decrease from 21.5 per 100,000 workers in 1982
      1984. The type of vehicle crash differed by vehicle type and location. High
      speed, possible fatigue, and wet weather, and/or alcohol and drugs appeared to be
      factors in many of the incidents, especially those involving prime movers and
      rigid trucks. Work-related road deaths can be identified in the ATSB data, as
      long as underenumeration of certain types of vehicle incidents (i.e. those
      involving cars and vans, wagons, utilities, and four-wheel drives) are taken into
      account.

PMID- 15203363
TI  - An Australian experience with tractor rollover protective structure rebate
      programs: process, impact and outcome evaluation.
AB  - The purpose of this study was to assess the effectiveness of the tractor rollover
      protective structure rebate program carried out by the Victorian Workcover
      Authority (Vic., Australia) in 1997-1998. The program was described using
      existing documents and records. Quantitative and qualitative information on
      tangible and intangible benefits were gathered through interviews with program
      applicants and other key informants. Information on the applicants and their
      tractors was obtained by analyzing the rebate application data. A cost-benefit
      analysis was conducted. The proportion of unprotected tractors was reduced from
      approximately 24%-7%. The program cost 7,886,067 Australian dollars ($AUD), which
      based on the projected prevention of 20 deaths over 10 years, equates to $AUD
      290,668 per life saved. The lifetime cost per rollover death was estimated at
      $AUD 694,879 and $AUD 1,407,991 for the human capital and willingness to pay
      models, respectively. The success of the program is attributable to a range of
      factors, including legislative changes, publicity and awareness raising, and the
      financial incentive of the rebate. Benefits appear to outweigh any costs.

PMID- 15203364
TI  - Bivariate ordered-response probit model of driver's and passenger's injury
      severities in collisions with fixed objects.
AB  - A bivariate ordered-response probit model of driver's and most severely injured
      passenger's severity (IS) in collisions with fixed objects is developed in this
      study. Exact passenger's IS is not necessarily observed, especially when only
      most severe injury of the accident and driver's injury are recorded in the police
      reports. To accommodate passenger IS as well, we explicitly develop a partial
      observability model of passenger IS in multi-occupant vehicle (HOV). The model
      has consistent coefficients for the driver IS between single-occupant vehicle
      (SOV) and multiple-occupant vehicle accidents, and provides more efficient
      coefficient estimates by taking into account the common unobserved factors
      between driver and passenger IS. The results of the empirical analysis using 4
      year statewide accident data in Washington State reveal the effects of driver's
      characteristics, vehicle attributes, types of objects, and environmental
      conditions on both driver and passenger IS, and that their IS have different
      elasticities to some of the risk factors.

PMID- 15203365
TI  - Perceptual and attentional effects on drivers' speed selection at curves.
AB  - This paper describes an experiment comparing the relative effectiveness of
      various types of warnings on drivers' speed selection at curves. The experiment
      compared three types of curve warnings across three different curve types in a
      driving simulator. All of the warnings worked reasonably well for severe curves
      (45 km/h), regardless of demands from a secondary (cell phone) task. For less
      demanding curves, only those warnings with a strong perceptual component (i.e.,
      implicit cues) were effective in reducing drivers' curve speeds in the presence
      of the cell phone task. The design implications of these data appear
      straightforward; curve warnings that contain perceptual components or emphasise
      the physical features of the curve work best, particularly in cognitively
      demanding situations. The cell phone task added to driver workload and drivers
      became less responsive to primary task demands (i.e., speeds were elevated and
      reaction times were longer).

PMID- 15203366
TI  - Investigation of the driving experience of a sample of Victorian learner drivers.
AB  - This paper presents the results of an investigation of the driving experience of
      a small sample of learner drivers in Victoria, Australia. Participants (n = 110)
      kept a continuous logbook of their driving experience over the 2 years of the
      learner-driver period, including information about the distance and time of each
      driving trip, their level of confidence, and monthly data concerning the number
      of crashes, near misses, and unpleasant emotional interactions with their
      supervising driver. The analysis of these data suggests that learner drivers
      accrue relatively little driving experience and that they tend to obtain this
      experience in daytime, fair-weather driving. The implications of these results
      are discussed.

PMID- 15203367
TI  - An evaluation of a supplementary road safety package.
AB  - A Supplementary Road Safety Package (SRSP) was developed in New Zealand in
      1995/1996 to supplement the compulsory breath test (CBT) and speed camera
      programmes introduced in 1993. A major feature of the package was the use of
      emotion and shock advertising campaigns not only to affect high risk driving
      attitudes and behaviours towards speeding and drink-driving but also to encourage
      the use of safety belts. Furthermore, the SRSP also emphasised targeting
      enforcement to these three areas. This package continued for 5 years. This paper
      estimates the effect of the package on road trauma. The analysis shows that the
      Package made substantial impact on road safety and saved over 285 lives over the
      5-year period.

PMID- 15203368
TI  - Environmental factors associated with crash-related mortality and injury among
      taxi drivers in New South Wales, Australia.
AB  - This exploratory study aims to investigate the associations between some
      environmental factors and the increased risk of motor vehicle crash-related
      injuries among taxi drivers. Information utilised in the study are obtained from
      police reports of all road traffic accidents that occurred on the roads between
      1996 and 2000 in New South Wales (NSW), Australia. Of the 7923 taxi drivers who
      involved in crashes, nearly 10% (n = 750) were killed or injured. Results
      indicate sex, and two environmental factors are significantly associated with an
      increased risk of crash-related mortality and injury among taxi drivers. The
      adjusted relative risk of crash-related mortality and injury is increased by 60%
      for those who work the night shift (OR = 1.59, 95%CI = 1.35-1.88), and by 20% for
      those who do not carry any passenger on board (OR = 1.20, 95%CI = 1.02-1.41)
      should these drivers involve in a crash. The increased relative risk of crash
      related mortality and injury is nearly 2.5 times for female taxi drivers (OR =
      2.30, 95%CI = 1.45-3.65) when compared with their male counterparts.

PMID- 15203369
TI  - Modeling of relative collision safety including driver characteristics.
AB  - We propose a new mathematical model for relative collision safety in cars. Our
      present research is restricted to head-on crashes between two cars and we try to
      determine how much of the injury risk in a crash depends on the car make.
      Previous work shows that a person's age and sex influence the injury risk in
      accidents that are otherwise similar. To explore the relative risks between
      different car makes we build a model where we let the car mass, change of speed,
      design of the car and the driver's age and sex explain the injury outcome in the
      crashes. The mathematical model we use is a birth process where the states
      correspond to the injury classes. A database containing police reported traffic
      accidents and hospital information is used to explore the relationships in our
      model. Different models are compared and the "best" model is chosen by a
      likelihood ratio test. The estimated relative risks compensated for the driver's
      age and sex are compared to the relative risks with the driver population
      included. The uncertainties of the different estimates are studied by a bootstrap
      analysis.

PMID- 15203370
TI  - Raising the bar: can increased statutory penalties deter drink-drivers?
AB  - The rate of road accidents per 100,000 vehicles registered was examined before
      and after the statutory penalties for drink-driving offences were doubled in New
      South Wales (NSW), Australia. Interrupted time-series analyses found significant
      increases in three non-fatal accident series after the implementation of the new
      penalties. The observed increase in the rate of single-vehicle night-time
      accidents, the accident category most likely to be alcohol-related, was not
      expected and runs contrary to the anticipated deterrent effect of the new laws.
      The failure of this policy to have an impact on aggregate-level road accident
      rates is discussed.

PMID- 15203371
TI  - A hypothesis: interaction between supplemental iron intake and fermentation
      affecting the risk of colon cancer. The Iowa Women's Health Study.
AB  - Fermentation in the large intestine can increase absorption of ferrous iron,
      which is the main form in supplements, because the solubility of ferrous iron is
      enhanced in the mildly acidic environments caused by fermentation. We therefore
      hypothesized that higher supplemental iron intake would increase the risk of
      colon cancer among those who consume large amounts of fermentable substrates,
      namely, dietary fiber and resistant starch. Among 34,708 postmenopausal women,
      supplemental iron was unrelated to proximal colon cancer in all women and to
      distal colon cancer among those consuming below the median of fermentable
      substrates. However, supplemental iron was positively associated with distal
      colon cancer among women who consumed above the median of fermentable substrates
      (P for interaction %lt; 0.01); the adjusted relative risks across categories of
      supplemental iron (0 g/day, 1-19 g/day, 20-49 g/day, and > or = 50 g/day) were
      1.0, 1.24, 1.78, and 3.78 (P for trend < 0.01). This hypothesis needs
      confirmation in other cohort studies because, despite the significant trend, only
      nine cases were included in the top category of > or = 50 mg supplemental iron,
      and this finding could have arisen by chance.

PMID- 15203372
TI  - Expression profiling and genetic alterations of the selenoproteins GI-GPx and
      SePP in colorectal carcinogenesis.
AB  - The trace element selenium is discussed as a chemopreventive agent in colorectal
      carcinogenesis. Selenocysteine-containing proteins, so-called selenoproteins,
      represent potential molecular targets for nutritive selenium supplementation. Due
      to their antioxidative potential, the selenoproteins gastrointestinal glutathione
      peroxidase (GI-GPx) and selenoprotein P (SePP) are considered to provide
      protection against reactive oxygen species (ROS), thereby reducing DNA damage and
      preventing development of colon cancer. GI-GPx and SePP are abundantly expressed
      in normal colon mucosa. Recently, we demonstrated both reduced SePP expression
      and increased GI-GPx expression in colorectal adenomas. In this study, we
      investigated the expression of SePP and GI-GPx in colorectal cancers compared
      with corresponding normal mucosa. Further, the occurrence of genetic alterations
      within the SePP and GI-GPx genes was analyzed. We observed a significant
      reduction or loss of SePP mRNA expression in colon cancers, whereas GI-GPx mRNA
      and protein expression varied between different tumor samples. In addition, we
      identified novel polymorphisms within the SePP and GI-GPx genes with so far
      unknown relevance for protein function. Our results argue against a general
      decrease of selenoprotein expression in colorectal carcinogenesis but imply
      specific differential regulation of expression of individual selenoproteins.

PMID- 15203374
TI  - Milk consumption is a risk factor for prostate cancer: meta-analysis of case
      control studies.
AB  - Prostate cancer has become the most common cancer among men in the United States.
      Although milk consumption is considered to be a risk factor in some
      epidemiological studies, the results are inconsistent. A meta-analysis method was
      conducted to estimate the combined odds ratio (OR) between milk consumption and
      prostate cancer from case-control studies published between 1984 and 2003 using
      commercial software (comprehensive meta-analysis). The combined OR was 1.68 (95%
      confidence interval = 1.34-2.12) in the 11 published case-control studies. The
      combined OR varied little by study stratification. Additionally, we evaluated the
      possible risk factors in milk for prostate cancer. In conclusion, we found a
      positive association between milk consumption and prostate cancer. The underlying
      mechanisms, including fat, calcium, hormones, and other factors, should be
      investigated further.

PMID- 15203373
TI  - Population-attributable risk of dietary aflatoxins and hepatitis B virus
      infection with respect to hepatocellular carcinoma.
AB  - BACKGROUND: Aflatoxins and hepatitis B virus (HBV) infections are important risk
      factors of hepatocellular carcinoma (HCC). This study assesses the population
      attributable risk of these two factors, both jointly and separately, with respect
      to HCC. METHODS: A case-control study was conducted in Sudan between 1996 and
      1998. Among 114 cases and 198 controls the consumption of peanut butter (a major
      source of aflatoxins) and HBV infection were investigated, as were drinking and
      smoking habits. RESULTS: A clear dose-response relation was observed between
      increasing peanut butter consumption and HCC in people without HBV infection. Age
      adjusted odds ratios for peanut butter consumption, HBV infection, and for the
      combination of both factors were, respectively, 5.1 (95% confidence interval =
      1.8-13.9), 32.2 (4.0-257), and 41.5 (11.2-155). In this study, about 80% of the
      HCC cases are attributable to either peanut butter consumption or HBV infection.
      Depending on assumptions in the data analysis, 27-60% of all cases can be
      attributed to aflatoxin exposure and 49-52% to HBV infection; of these figures, 7
      34% reflect a shared responsibility of the two factors. CONCLUSIONS: Both
      reduction of aflatoxin contamination of foods and HBV vaccination may be useful
      public health strategies in HCC prevention in Sudan.

PMID- 15203375
TI  - Vitamin A prevents high fat diet-induced ACF development and modifies the pattern
      of expression of peroxisome proliferator and retinoic acid receptor m-RNA.
AB  - Some dietary compounds, among them fats, are modulators of colon cancer risk.
      This study reports the modulating effects of n-6, with or without vitamin A, on
      promotion of colon preneoplasic lesions induced by 1,2-dimethylhydrazine (DMH)
      and on the expression of nuclear receptors (PPARgamma, RXRalpha, and RARbeta).
      One group of male Fisher rats was fed a basic diet (5% safflower oil) and two
      groups were fed a high-fat diet (HFD, 25% safflower oil). Of these, one was
      supplemented with 200 IU vitamin A for 5 mo. The safflower oil contained
      polyunsaturated fatty acids, mainly linoleic acid (73%). The data showed an
      increasing effect of safflower oil-enriched diet on aberrant crypt foci
      occurrence and multiplicity. This effect was impaired by vitamin A
      supplementation. In addition, an HFD-related up-regulation of PPARgamma and a
      concomitant down-regulation of RARbeta mRNA expression were observed with or
      without chemical initiation and were prevented by vitamin A. Moreover, when
      treated with DMH, HFD rats exhibited a dramatically decreased expression of
      RXRalpha mRNA (-49%). It was hypothesized that HFD, leading to hyperexpression of
      PPARgamma, would produce an alteration of retinoic acid signaling and, in this
      way, create a background modulating colon cancer risk.

PMID- 15203376
TI  - Inhibition of colonic aberrant crypt foci by curcumin in rats is affected by age.
AB  - Curcumin has antioxidative, anti-inflammatory, and chemopreventive activities. To
      determine whether aging affects the inhibition of colon carcinogenesis by
      curcumin, young (6 wk), mature (12 mo), and old (22 mo) F344 male rats were fed
      either AIN-93 containing 0.6% curcumin or AIN-93 control diet. Aberrant crypt
      foci (ACF) were induced with two weekly s.c. injections of azoxymethane. After an
      additional 3 mo on the diets, the number, multiplicity, and distribution of ACF
      were evaluated. Addition of curcumin to the diet reduced the number of ACF by 49%
      in young rats and by 55% in old rats (P < 0.05). However, interestingly, no
      reduction of ACF was found in mature rats fed curcumin. Inhibition of large ACF
      was also affected by age, with the greatest reduction of large ACF occurring in
      old rats. However, animal age did not significantly alter the effect of dietary
      curcumin on reduction of cyclooxygenase-2 mRNA expression in the liver or
      reduction of serum total cholesterol levels. These results indicate that age may
      play a significant role in the efficacy of chemoprevention of colon cancer by
      curcumin.

PMID- 15203377
TI  - Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in
      A/J mice by oral administration of green tea.
AB  - Oral administration of tea (Camellia sinensis) has been shown to inhibit the
      formation and growth of several tumor types in animal models. The present study
      investigated the effects of treatment with different concentrations of green tea
      on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung
      tumorigenesis in female A/J mice. Two days after a single dose of NNK (100 mg/kg
      body weight, i.p.), the mice were given 0.1, 0.2, 0.4, and 0.6% green tea
      solution (1, 2, 4, and 6 g of tea solids, respectively, dissolved in 1 l of
      water), 0.02% caffeine, or water as the sole source of drinking fluid until the
      termination of the experiment. Only the treatment with 0.6% tea preparation
      significantly reduced lung tumor multiplicity (mean +/- SE, 6.07 +/- 0.77 vs.
      8.60 +/- 0.50 tumors per mouse, P = 0.018). Treatment with 0.6% tea also
      inhibited angiogenesis, as indicated by the lower microvessel density (number of
      blood vessels/mm2) based on immunostaining for the von Willebrand factor antigen
      (81.9 +/- 9.5 vs. 129.4 +/- 8.2, P = 0.0018) and anti-CD31 antibody staining
      (465.3 +/- 61.4 vs. 657.1 +/- 43.6, P = 0.0012). Significantly lower vascular
      endothelial growth factor immunostaining scores were also observed in the 0.6%
      tea-treated group (0.98 +/- 0.17 vs. 1.43 +/- 0.07, P = 0.006). The apoptosis
      index was significantly higher in lung adenomas from 0.6% tea-treated mice based
      on morphological analysis of cell apoptosis (2.51 +/- 0.18% vs. 1.57 +/- 0.11%, P
      = 0.00005), and the result was further confirmed using the TUNEL method.
      Inhibition of angiogenesis and the induction of apoptosis by green tea may be
      closely related to the inhibition of pulmonary carcinogenesis.

PMID- 15203379
TI  - Natural alkylglycerols restrain growth and metastasis of grafted tumors in mice.
AB  - Alkylglycerols are natural etherlipids abundant in shark liver oil (SLO) in a
      diacylated form. SLO is known to have antitumor properties and was recently
      described as an inhibitor of tumor neovascularization. However, most studies did
      not discriminate between the respective activities of alkylglycerols and of fatty
      acids, which both have potent biological properties. In this work, a mouse model
      was used to investigate the antitumor effects of SLO and of alkylglycerols
      purified from the same source, both administered orally. We demonstrated that
      either pure alkylglycerols or SLO reduced the tumor growth in a similar manner,
      suggesting that alkylglycerols were involved in this effect. In alkylglycerol
      treated mice, metastasis dissemination was reduced by 64 +/- 8%, whereas SLO
      effect was 30 +/- 9% below control. Purified alkylglycerols also decreased
      significantly plasmalogen content in tumors, whereas SLO had no such effect.
      Finally, we demonstrated that a 5-day treatment with alkylglycerols curtailed the
      presence in tumors of von Willebrand factor, a marker of endothelial cells. This
      result suggested an anti-angiogenic effect of alkylglycerols. In summary,
      alkylglycerols were shown to decrease the growth, vascularization, and
      dissemination of Lewis lung carcinoma tumors in mice. These findings suggest that
      the antitumor activity of SLO is likely mediated by the presence of
      alkylglycerols.

PMID- 15203378
TI  - Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n
      pentylnitrosamine depentylation by rat esophageal microsomes, human and rat
      CYP2E1, and Rat CYP2A3.
AB  - Garlic and Cruciferae are associated with reduced risks of several human cancers,
      and some of their constituents are anticarcinogenic in animals. Here we studied
      inhibition of in vitro metabolism of the rat esophageal carcinogen methyl-n
      pentylnitrosamine (MPN) by garlic-derived allyl sulfides and by Cruciferae
      derived phenethyl isothiocyanate (PEITC) and sulforaphane. The test inhibitors
      were incubated with [3H]-MPN, NADPH-generating system and rat esophageal
      microsomes (REM) or a cytochrome P450 (CYP). [3H]-MPN activation by depentylation
      was assayed by HPLC with radiometric determination of [3H]-pentaldehyde 2,4
      dinitrophenylhydrazone. IC50 for depentylation of 40 microM MPN by rat CYP2E1 was
      5-12 microM for diallyl sulfide (DAS), diallyl disulfide (DADS), and PEITC and 10
      20 microM for diallyl sulfone, allyl mercaptan, and diallyl trisulfide. Maximum
      inhibition required preincubation of rat CYP2E1 with DAS for 15 min and with DADS
      for 30 min. Using these preincubation times, Ki for MPN depentylation by REM, rat
      and human CYP2E1, and rat CYP2A3 was 0.6-1.6 microM for inhibition by DAS and 1.7
      70 microM for inhibition by DADS. With PEITC, Ki for MPN depentylation by REM,
      rat CYP2E1, and rat CYP2A3 was 0.4-4.6 microM. These low Ki and IC50 values may
      help explain how garlic and Cruciferae inhibit carcinogenesis.

PMID- 15203380
TI  - Alteration in phase I and II enzyme activities and polycyclic aromatic
      hydrocarbons-DNA adduct formation by plant phenolics in mouse epidermis.
AB  - Several naturally occurring plant phenols were shown to inhibit the mutagenicity
      and/or tumorigenicity of chemical carcinogens, including polycyclic aromatic
      hydrocarbons (PAHs). In this study, the effect of the topical application of
      three structurally diverse phenolic acids and trihydroxystilbene, resveratrol, on
      epidermal aryl hydrocarbon hydroxylase (AHH), phase II enzymes, as well as the
      binding of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) to
      epidermal DNA were compared. The single, topical application of 8 and 16 mumol of
      protocatechuic or chlorogenic acid increased the activity of AHH by 10-30%,
      whereas resveratrol in a dose of 16 mumol almost completely (99%) inhibited the
      enzyme activity. Phenolic acids also increased the activities of phase II
      enzymes. Resveratrol did not affect the glutathione S-transferase activity but
      induced UDP glucuronosyltransferase (by approximately 100-150%) and to a lesser
      extent NAD(P)H:quinone oxidoreductase. In a dose of 16 micromol all phenolic
      acids afforded 40-50% inhibition of covalent benzo[a]pyrene-diol-epoxide
      (B[a]PDE) binding to DNA. Resveratrol had no effect on B[a]PDE adduct formation
      but reduced the levels of all the major DMBA adducts. Phenolic acids,
      particularly tannic acid, mostly affected the formation of syn- and anti-DMBADE
      dAdo adducts. These results indicate that both the modulation of carcinogen
      activating enzymes and the prevention of their ultimate metabolites binding to
      DNA by naturally occurring phenolics are involved in the antitumorigenic activity
      of these compounds. For phenolic acids, however, their interactions with reactive
      PAH metabolites and/or blocking of a specific binding site in a genome seem more
      important. Derivatives of stilbene, such as resveratrol, affect DNA adduct
      formation and thus the initiation of tumorigenesis through the interaction with
      the Ah receptor rather than the scavenging active metabolites.

PMID- 15203381
TI  - High dietary intake of sodium selenite induces oxidative DNA damage in rat liver.
AB  - One mechanism for the cancer-chemopreventive effects of high selenium (Se) intake
      is hypothesized to be antioxidant protection of DNA. In this work we examine DNA
      oxidation in whole animals as a function of dietary Se intake and carcinogen
      administration. Weanling male Sprague-Dawley rats were fed a basal, Torula yeast
      based, Se-deficient diet supplemented with 0, 0.15, or 2.0 ppm Se as sodium
      selenite for 10 wk. They were then injected with 0, 0.1, or 10 mg /kg body weight
      of the pro-oxidant carcinogen N-nitrosodiethylamine. High levels of carcinogen
      and high levels of selenite intake each increased concentration of 8-hydroxy-2'
      deoxyguanosine in liver DNA. Se-dependent glutathione peroxidase I gene
      expression and enzyme activity were dramatically reduced by dietary Se deficiency
      but were unaffected by carcinogen administration. There were no significant main
      or interactive effects of Se or carcinogen on activity or gene expression of the
      DNA repair enzyme 8-oxoguanine glycosylase I. These results do not support the
      hypothesis that high Se intake may be cancer-preventive by inhibiting oxidative
      DNA damage. Rather than inhibiting oxidative DNA damage, these findings suggest
      that high dietary intake of inorganic Se may promote in vivo DNA oxidation.

PMID- 15203382
TI  - Inactivation of akt and NF-kappaB play important roles during indole-3-carbinol
      induced apoptosis in breast cancer cells.
AB  - Despite significant advances in treatment, breast cancer is still the second
      leading cause of cancer-related deaths in women in the United States. Therefore,
      significant efforts are being given to develop novel strategies for the
      prevention of breast cancer in recent years. Our laboratory and others have been
      studying the effects of a potential chemopreventive agent, indole-3-carbinol
      (I3C), in breast cancer cells. We have previously shown that I3C induces
      apoptosis in breast cancer cells and found that the induction of apoptotic
      processes was partly mediated by dysregulation of anti- and pro-apoptotic
      molecules. However, the precise molecular mechanism(s) by which I3C induces
      apoptosis in breast cancer cells has not been fully elucidated. For the present
      study, we focused our investigation on important cell signaling molecules such as
      Akt and NF-kappaB during I3C-induced apoptosis in breast cancer cells. We found
      that I3C induces apoptotic processes in MCF10A-derived cell lines with
      premalignant (DCIS.com) and malignant (MCF10CA1a) phenotypes but not in
      nontumorigenic parental MCF10A cells. Immunoprecipitation, kinase assays, and
      Western blot analysis showed that I3C specifically inhibits Akt kinase activity
      and abrogates the EGF-induced activation of Akt in breast cancer cells. NF-kappaB
      DNA-binding analysis and transfection studies with Akt cDNA and NF-kappaB-Luc
      reporter constructs revealed that Akt gene transfection directly activates NF
      kappaB, and this activation was completely abrogated by I3C treatment. In
      addition, I3C also abrogated the EGF-induced activation of NF-kappaB, which was
      mediated via the Akt signaling pathway. From these results, we conclude that
      there is a direct cross-talk between Akt and NF-kappaB pathways and that the
      inactivation of Akt and NF-kappaB activity plays important roles in mediating I3C
      induced apoptosis in breast cancer cells. These results also suggest that I3C may
      be a potential chemopreventive agent by virtue of its selective apoptosis
      inducing ability in premalignant and malignant breast epithelial cells.

PMID- 15203383
TI  - Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a
      naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human
      breast cancer cells.
AB  - Vitamin E derivative, RRR-alpha-tocopheryl succinate (vitamin E succinate, VES),
      is a potent pro-apoptotic agent, inducing apoptosis by restoring both
      transforming growth factor-beta (TGF-beta) and Fas (CD95) apoptotic signaling
      pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)
      mediated apoptosis. Objectives of these studies were to characterize signaling
      events involved in the pro-apoptotic actions of a naturally occurring form of
      vitamin E, delta-tocotrienol, and a novel vitamin E analog, alpha-tocopherol
      ether acetic acid analog [alpha-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12
      trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, alpha-TEA and delta
      tocotrienol induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF
      7 human breast cancer cells to undergo high levels of apoptosis in a
      concentration- and time-dependent fashion. Like VES, the two compounds induced
      either no or lower levels of apoptosis in normal human mammary epithelial cells
      and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic
      mechanisms triggered by the structurally distinct alpha-TEA and delta-tocotrienol
      were identical to those previously reported for VES, that is, alpha-TEA- and
      delta-tocotrienol-induced apoptosis involved up-regulation of TGF-beta receptor
      II expression and TGF-beta-, Fas- and JNK-signaling pathways. These data provide
      a better understanding of the anticancer actions of a dietary form of vitamin E
      (delta-tocotrienol) and a novel nonhydrolyzable vitamin E analog (alpha-TEA).

PMID- 15203384
TI  - Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest
      in human colon carcinoma cell lines.
AB  - Apigenin has been previously shown to induce G2/M cell-cycle arrest in human
      colon cancer cell lines. The present study assessed the individual and
      interactive influence of seven apigenin analogs on cell cycle, cell number, and
      cell viability in human SW480 and Caco-2 colonic carcinoma cells. Cellular
      concentration of selected apigenin analogs was further assessed by high
      performance liquid chromatography to assess cellular availability. The apigenin
      analogs studied were acacetin, chrysin, kampherol, luteolin, myricetin,
      naringenin, and quercetin. DNA flow cytometric analysis indicated that treatment
      with either chrysin or acacetin at 0 to 80 microM for 48 h resulted in cell-cycle
      arrest at the G2/M phase in a dose-dependent manner in the SW480 cells but not in
      the Caco-2 cells. The percentage of SW480 cells at G2/M also increased when cells
      were treated with kampherol, luteolin, or quercetin between 5 and 30 microM, but
      the percentage of cells in G2/M decreased at doses greater than 40 microM. Cell
      number was significantly decreased in a time- and dose-dependent manner following
      the treatments with each analog except for naringenin and myricetin. The
      interactive effects of these analogs with apigenin were further assessed by
      combining each analog at doses from 0 to 80 microM with apigenin at 20 microM, a
      dose at which apigenin was found to double the proportion of SW480 cells in G2/M.
      When either acacetin, chrysin, luteolin, kampherol, or quercetin at doses between
      5 and 30 microM were combined with apigenin at 20 microM, there was an increase
      of 22% in the proportion of G2/M cells over that observed with 20 microM apigenin
      alone (P < 0.05). At doses higher than 40 microM, however, the interaction became
      antagonistic, and the proportion of cells in G2/M decreased below that observed
      with apigenin alone. Cell viability, as assessed by Trypan blue exclusion assay,
      significantly decreased by treatments with high doses of each agent or each agent
      combined with apigenin. Cellular concentration of apigenin, chrysin, or
      naringenin in SW480 cells significantly increased at doses of 40 microM or
      greater, but it was not correlated with their impact on G2/M cell-cycle arrest.
      The induction of cell-cycle arrest by five of seven tested apigenin analogs and
      the additive induction by the combination of flavonoids at low doses suggest that
      apigenin-related flavonoids may cooperatively protect against colorectal cancer
      through conjoint blocking of cell-cycle progression.

PMID- 15203399
TI  - Gender differences in depression: a study of older unlike-sex twins.
AB  - Gender differences in depressive symptoms, in the diagnosis of major/minor
      depression, and in the use of antidepressant medication were investigated. The
      sample included 249 pairs of unlike-sex twins, who were between 70 and 80 years
      of age at the initial, baseline assessment. A follow-up, in which both members of
      145 twin pairs participated, was carried out four years later. Participants
      completed the Centre for the Epidemiologic Studies Depression Scale (CES-D) for
      depressive symptoms. Current use of antidepressant medicine was assessed. Medical
      records of major/minor depression from the period 1985-1998, including a summary
      of those diagnoses in earlier years, were gathered from several sources. Women
      had a higher frequency of depressive symptoms and depression diagnoses than their
      twin brothers. Depressive symptoms and diagnosis of depression increased over
      time, slightly more among men. The gender difference and increase over time in
      the depressive symptoms were related to differences in socio-economic status and
      physical functioning in men and women. No gender difference was found in the use
      of antidepressant medication.

PMID- 15203400
TI  - Intergenerational exchange and mental health in later-life--the case of older
      Jewish Israelis.
AB  - The purpose of this study was to consider the contribution of intergenerational
      exchange to mental health. Using data from a national sample of Jewish Israelis
      age 60 and over with children (n = 1799), reciprocal and non-reciprocal exchange
      patterns were identified and examined in relation to respondents' scores on a 12
      item mood scale. Multiple regression analysis controlled for the effects of socio
      demographic background, need and intergenerational contact. Unbalanced exchange
      on the part of the respondents, whether giving more or receiving more, was
      unrelated to their current mental health. Equal reciprocal exchange was
      positively associated with mental health, albeit weakly. This positive effect was
      maintained despite the negative association of poor health with respondents'
      mental health and the positive association of income, education and contact with
      children. The analysis demonstrates that reciprocal intergenerational exchange
      may be a contributory factor to better mental health in later-life, and should be
      addressed as such.

PMID- 15203401
TI  - Effect of Meeting Centres Support Program on feelings of competence of family
      carers and delay of institutionalization of people with dementia.
AB  - The study tested the hypotheses that integrated support, in which patients and
      carers are both supported by one professional staff member, will be more
      effective in reducing the feelings of (over)burden of carers and in positively
      influencing some potential determinants of experienced burden than non-integrated
      support, such as psychogeriatric day-care. A quasi-experimental pre-test/post
      test control group design was applied with matched groups and measurements at
      baseline and after seven months. Fifty-five of the eighty dyads (31% dropped out)
      of persons with mild-to-moderate dementia and their carers who presented for four
      community meeting centres and three day-care centres in nursing homes over an 18
      month period, were included in the study. The carers in the Meeting Centres
      Support (MCS) Program participated in an integrated family support program
      together with the persons with dementia, while the carers in the control group
      only received respite through psychogeriatric day-care. Standardized
      questionnaires were applied to measure some indicators of burden experienced by
      the carers (feelings of stress, life dissatisfaction, psychological and
      psychosomatic complaints), as well as some potential determinants of experienced
      burden (feeling of competence, coping strategies, experienced support and
      loneliness). Furthermore, as an indicator of feelings of (over)burden of the
      carer, the time between start of participation in one of the programs and
      institutionalization in a nursing home was calculated. After seven months the
      carers in the MCS group (n = 36), compared to the carers in regular
      psychogeriatric day-care (n = 19), showed a moderate positive effect on the
      feeling of competence (effect size 0.45). No effect was found on feelings of
      stress, dissatisfaction or psychological and psychosomatic complaints. However,
      as compared to the control group in regular day-care, the persons with dementia
      in the MCS Program participated for a longer period of time before they were
      placed in a nursing home. The MCS Program proved more effective than
      psychogeriatric day-care in influencing the feeling of competence of the carers,
      and seems to lead to an increased delay of nursing home placement of the person
      with dementia, as compared to regular day-care. Because of the small sample and
      limited power of the study, and the possible influence of the selection of carers
      on the study outcome, further research into the value of meeting centres for
      carers of people with dementia is recommended.

PMID- 15203402
TI  - Sources of income and depression in elderly Hong Kong Chinese: mediating and
      moderating effects of social support and financial strain.
AB  - This study examines the relationship between major source of income (i.e., adult
      children, financial independence and government welfare) and depression among
      elderly Hong Kong people. We also assessed the mediating and moderating effects
      of family social support and financial strain in the linkage between source of
      income and depression. The data came from a cross-sectional survey of a
      representative community sample of 1106 elderly respondents in Hong Kong. Using
      multiple regression models, data revealed that there was a differential impact of
      major sources of income on depression. Welfare participation and financial
      independence contributed to a higher level of depressive symptoms whereas people
      whose source of income was their adult children were more likely to report a
      lower level of depression than the others who were not. We also found that family
      social support was either a complete mediator or partial mediator in the
      relationship between different major sources of income and depression but it was
      not a significant moderator in the linkage between different major sources of
      income and depression. In contrast, financial strain was a significant moderator
      in the link between different major sources of income and depression. Specific
      and effective interventions must be developed for those who are financially
      independent or on welfare.

PMID- 15203403
TI  - Emotion processing in Alzheimer's disease.
AB  - To date, there have been few studies of emotion processing in those suffering
      from Alzheimer's disease, yet this may have an important effect on the quality of
      life of both sufferers and their families. This paper describes an investigation
      of the relative changes in cognition and in recognition and identification of non
      verbal communicative signals of emotion in those suffering from Alzheimer's
      disease, and seeks to address the implications for clinical practice. Twelve
      adults with a diagnosis of "probable" Alzheimer's disease and 12 matched older
      adult healthy comparison participants undertook a series of tasks involving face
      and prosody discrimination. Facial stimuli were presented on cards, and prosodic
      stimuli on audiotape. Scores were compared with a measure of general cognitive
      ability. There was a significant difference between the Alzheimer's disease group
      and healthy older adult group on emotion and cognition tasks respectively.
      However, the ability to recognize and identify non-verbal affect cues in
      emotional facial expression and emotional prosody was preserved relative to
      general cognitive ability in those suffering from Alzheimer's disease. In
      addition, there were no differences found in the recognition of different
      emotions (happiness, sadness, anger, fear or neutral). This relative sparing of
      non-verbal emotional processing skills has implications for provision of
      assessment and interventions based on the creation of effective forms of
      communication that are less reliant on cognitive ability.

PMID- 15203404
TI  - Emotional and behavioural responses to music in people with dementia: an
      observational study.
AB  - Using continuous time sampling and direct observation methodology, this study
      examined the impact of social interaction in music listening on behavioural
      responses of people with moderate-to-severe dementia (n = 24). Using Kitwood's
      theory of personhood as a framework, it was hypothesized that levels of well
      being and engagement would be greatest during a live music condition compared
      with recorded and no music conditions and that levels of challenging behaviour
      would decrease most in the live music conditions compared with the other music
      conditions. The relationship between severity of cognitive impairment and well
      being, engagement and challenging behaviours across conditions was also examined.
      The findings suggest that live music was significantly more effective in
      increasing levels of engagement and well-being regardless of level of cognitive
      impairment. No significant differences across conditions were found for
      challenging behaviours, but the correlation between these and cognitive
      impairment revealed mixed results. Clinical implications regarding the use of
      live music in dementia care settings are highlighted and recommendations for
      future research of interventions aimed at reducing challenging behaviours are
      discussed.

PMID- 15203405
TI  - Attitudes to long-term use of benzodiazepine hypnotics by older people in general
      practice: findings from interviews with service users and providers.
AB  - The aim of this study was to explore beliefs and attitudes about continuing or
      stopping benzodiazepine hypnotics amongst older patients using such medicines,
      and amongst their general practitioners. One hundred and ninety two patients aged
      65 and over who were long-term users of benzodiazepine hypnotics were recruited
      from 25 general practices in inner city and suburban London, as were 83 practice
      staff. The practices had been recruited into a randomised controlled trial of
      benzodiazepine withdrawal in long-term users. Semi-structured interviews were
      conducted with patients recruited to the trial, and non-standardized
      (conversational) interviews with practice staff. Sixty percent of long-term
      benzodiazepine users had taken their hypnotic for more than 10 years, and one
      third for more than 20 years. Beliefs in the efficacy of hypnotics, and self
      report of insomnia despite their use, varied according to the willingness to
      attempt withdrawal. The majority of patients reported no warnings from
      professionals about adverse effects of using benzodiazepine hypnotics. Half had
      tried to stop at some time but most attempts had been short-lived. Patients and
      doctors had distinctly different views of the advantages, disadvantages and risks
      of stopping benzodiazepine hypnotic use. Both increased patient awareness of the
      problems of long-term benzodiazepine use and an evidence-based approach to
      withdrawal efforts in primary care are necessary to reduce the consumption of
      medication that has little real benefit.

PMID- 15203406
TI  - The use of assessment scales in Old Age Psychiatry Services in England and
      Northern Ireland.
AB  - Implementation of the Single Assessment Process in the UK is designed to ensure
      that more standardized assessment procedures are in place across all areas and
      agencies, that practice improves and older people's needs are comprehensively
      assessed. This study provides a unique picture of the range and prevalence of
      standardized scales used within Old Age Psychiatry Services in England and
      Northern Ireland, reported by 73% of old age psychiatrists. Most services (64%)
      used three or more standardized assessment scales (range 1-12). Sixty-two
      separate instruments were identified. The six most used measures were the Mini
      Mental State Examination (95%), the Geriatric Depression Scale (52%) and the
      Clock Drawing (50%), the Clifton Assessment Procedures for the elderly (26%), the
      Barthel Index (18%) and the Health of the Nation Outcome Scales (HoNOS) 65 +
      (18%). A number of factors were associated with greater use of certain
      standardized assessment scales. Shared documentation, along with other indicators
      of integration between health and social care were associated with greater use of
      standardized scales. The provision of a memory clinic was associated with greater
      use of neuropsychiatric scales and lower levels of use of cognitive scales. These
      results provide key material for shaping the provision of psychiatric services
      for older people

PMID- 15203407
TI  - Evaluating rural nursing home environments: dementia special care units versus
      integrated facilities.
AB  - Although one in four seniors currently lives in a rural area, little is known
      about the capacity of rural nursing homes to provide specialized dementia
      services. The physical and social environments are increasingly recognized as
      important factors in the quality of life and functional ability of persons with
      dementia. This study compared eight rural nursing homes (those located in centres
      with populations < or =15,000) that had created dementia Special Care Units
      (SCUs) to eight same-sized rural nursing homes that did not have SCUs. Outcomes
      were assessed in relation to residents, staff, family members, and the
      environment. In this paper we describe the overall study design and findings from
      the environmental assessment. Analysis of variance (ANOVA) was used to compare
      the SCU versus non-SCU environments on the nine dimensions of the Physical
      Environmental Assessment Protocol (PEAP), which was used to assess the physical
      environment. The SCUs were more supportive on six dimensions: maximizing
      awareness and orientation, maximizing safety and security, regulation of
      stimulation, quality of stimulation, opportunities for personal control, and
      continuity of the self. Analysis of variance was also used to compare the groups
      on the six subscales of the Nursing Unit Rating Scale (NURS), which assesses the
      social environment of dementia care settings. The SCUs were more supportive on
      the Separation and Stimulation subscales, indicating that SCUs had greater
      separation of residents with dementia from other residents for activities of
      daily living and programming, and better control of non-meaningful stimulation.

PMID- 15203408
TI  - The nexus of cardiovascular disease and depression revisited: the complete mental
      health perspective and the moderating role of age and gender.
AB  - This study employs a measure of mental health as a complete state that combines
      information about an individual's mental illness (i.e., major depressive episode
      in the past 12 months) and subjective well-being (i.e., mental health) status to
      investigate its linkage with cardiovascular diseases (CVD). Data are from a
      representative sample of USA adults between the ages of 25 and 74 collected in
      1995 (n = 3,032). About 12% of adults reported any CVD. Independent of mental
      health status, risk for any CVD increased with age and as education decreased,
      and the risk of any CVD was higher among males, married adults, and unemployed
      adults. The prevalence of any CVD was lowest in adults who were mentally healthy
      and higher among adults with major depressive episode, with minor depression,
      with languishing, and with moderate mental health. The relationship of CVD and
      mental health was moderated by age and sex; mental health status was associated
      with significant risk for any CVD primarily among females between the ages of 45
      and 74. Findings contribute to a growing literature on the protective effects of
      high, and risk effects of low, levels of subjective well-being, and the role of
      age and sex in specifying specific physical and mental health comorbidities.

PMID- 15203410
TI  - Factors influencing acceptability of voluntary counselling and HIV-testing among
      pregnant women in Northern Tanzania.
AB  - Guided by the conceptual framework of the Health Belief Model, this study aimed
      to identify factors associated with pregnant women's expressed willingness to
      accept voluntary counselling and HIV-testing (VCT). A cross-sectional interview
      survey of 500 pregnant women, complemented by focus group discussions, was
      conducted in the Kilimanjaro region of Tanzania. Constructs derived from the
      Health Belief Model explained 41.7% of women's willingness to accept VCT.
      Perceived high personal susceptibility to HIV/AIDS, barriers related to
      confidentiality and partner involvement, self-efficacy regarding alternative
      feeding methods and religion were all shown to be associated with willingness to
      accept VCT. The women's acceptance of VCT seems to depend upon their perceiving
      that VCT and alternative feeding strategies provide clear benefits, primarily for
      the child. Whether a positive attitude to VCT and alternative feeding strategies
      are transformed into actual behaviour depends on a set of complicated decisions
      in which several potential psychological consequences are assessed. Sharing the
      diagnosis with partners may not have the intended effect if there is a lack of
      sensitivity to the women's fear of blame and rejection. If pregnant women are to
      fully participate in and benefit from mother-to-child-transmission prevention
      efforts, their partners must be committed and involved in the process.

PMID- 15203411
TI  - HIV, STD and hepatitis prevention among women in methadone maintenance: a
      qualitative and quantitative needs assessment.
AB  - In the USA, as well as internationally, rates of HIV infection among women
      continue to grow. In addition, women who inject drugs are at further increased
      risk for hepatitis C co-infection. The purpose of this study was to conduct
      qualitative and quantitative needs assessments for HIV/STD/hepatitis prevention
      among women in methadone maintenance programmes. Qualitative interviews and a
      quantitative, self-administered questionnaire were used to develop an
      understanding of their needs, and perceptions of what they believed would
      constitute effective prevention intervention programmes. Results supported
      women's interest in these services and provided feedback on how to structure
      prevention programmes by placing them in the context of women's lives and
      addressing concrete barriers (e. g. transportation, child care, confidentiality
      concerns) to facilitate adherence to these programmes. Respondents indicated a
      desire for HIV prevention information, but also wanted information on hepatitis,
      relapse prevention, stress management and accessing services. The development of
      such programming would require partnering with the target population and their
      service providers to develop feasible and effective interventions.

PMID- 15203412
TI  - Qualitative needs assessment of HIV services among Dominican, Mexican and Central
      American immigrant populations living in the New York City area.
AB  - This paper reports on research designed to assess access to care by Latino
      immigrant populations in the New York area. A qualitative approach and methods
      were employed, involving focus groups with PLWAs (persons living with AIDS) and
      affected men and women from Mexico, the Dominican Republic and Central America to
      explore the perceptions, beliefs, experiences and knowledge of HIV care issues. A
      total of 57 men and women participated, ranging in age from 19-61. Results
      included detailed information on cultural meanings of HIV/AIDS; experience of
      stigma and rejection; gendered health-seeking behaviour; testing issues; and
      satisfaction with services. Data support the conclusion that to be effective in
      reaching and providing services to these immigrant groups, it is crucial to
      understand the environment from which they come and the impact of immigration.
      Poverty, repressive governments, lack of education/literacy, ethnicity, class,
      colour-based stigma and cultural norms are crucial factors in determining their
      attitudes, motivations, decisions and behaviour. AIDS agencies were seen to play
      a crucial role in connecting PLWAs to services and resources. The key elements
      for the provision of services to this population appear to be those that build on
      cultural norms and network human and institutional resources.

PMID- 15203413
TI  - Outpatient pharmacy care and HIV viral load response among patients on HAART.
AB  - Adherence to highly active antiretroviral therapy (HAART) is necessary to achieve
      long-term effectiveness. The impact of HIV/AIDS-specific pharmacy services on
      patient adherence and HIV viral suppression is currently not well described. This
      study aimed to compare the impact of differing levels of HIV-pharmacy care on
      adherence and time to HIV viral suppression among participants on HAART enrolled
      in a population-based HIV/AIDS drug treatment programme in British Columbia. We
      performed a retrospective observational study of 788 treatment-naive patients who
      started HAART between August 1997 and July 2000 and were followed until 31 March
      2002. The degree of outpatient pharmacy care was defined according to pharmacy
      dispensing site for the participants' first prescription of HAART: highest at the
      AIDS-tertiary care hospital outpatient pharmacies, intermediate at HIV/AIDS drug
      treatment programme funded off-site pharmacies and lowest at family physician's
      offices. Cox-proportional hazard models examined the independent effect of
      pharmacy dispensing site on time to two consecutive HIV viral suppressions
      controlling for other prognostic factors including physicians' experience, age,
      gender, injection drug use, use of therapy containing NNRTI versus PI, adherence
      >90%, AIDS diagnosis at baseline, baseline CD4 cell count and HIV viral load. The
      median time on antiretrovirals was 28 months (IQR=14-38). There were 489 (62.1%)
      participants who obtained their medications from the AIDS-tertiary care
      outpatient pharmacies; 98 (12.4%) from off-site pharmacies and 201 (25.5%) from
      their physicians' offices. The proportion of patients exhibiting >90% adherence
      to treatment was observed to be higher among patients receiving their HAART at
      the AIDS-tertiary care pharmacies compared to off-site pharmacies and to
      physicians' offices (70.4, 59.2 and 55.7%, respectively; p=0.0001). After
      adjusting for other prognostic factors, subjects who were first dispensed
      medications from the AIDS-tertiary care pharmacy were 1.42 times (CI: 1.10-1.84)
      more likely to achieve HIV viral suppression than those getting their medications
      from off-site pharmacies and physicians' offices. Providing regular outpatient
      pharmacy care is independently associated with improved HIV viral load response
      through enhanced adherence to HAART. Standardization of pharmacy practices for
      dispensing HAART may improve outcomes for patients who receive their HIV
      medications from other non-tertiary care pharmacy sites.

PMID- 15203414
TI  - Psychosocial factors associated with adherence to antiretroviral medications in a
      sample of HIV-positive African American drug users.
AB  - The purpose of the study was to investigate factors affecting antiretroviral
      adherence among African American drug users, specifically to identify
      associations between self-reported adherence levels and psychosocial measures
      selected with guidance from the Transactional Model of Stress and Coping (TMSC).
      The study was conducted using data collected from 137 HIV-positive African
      American drug users who were receiving antiretroviral medications at the time
      they were interviewed. Bivariate associations were investigated using
      correlational analyses and variables showing a significant correlation with
      adherence were entered into a multivariate regression model. The multivariate
      model showed only perceived efficacy of antiretrovirals and one measure of
      perceived barriers, simply forgetting to take medications, were independently
      related to adherence. These preliminary findings suggest that theoretical
      approaches to understanding antiretroviral adherence must address a range of
      variables, including but not limited to behavioural practices, cognitive
      appraisals, affective responses and social support. Further studies using the
      complete TMSC are recommended.

PMID- 15203415
TI  - Predictors of antiretroviral adherence.
AB  - This study was conducted in order to help determine the key factors that predict
      adherence to antiretroviral medications. A total of 115 HIV/AIDS patients who
      were having trouble adhering to their antiretroviral regimens completed face-to
      face interviews in which adherence levels, medication side effects, mental
      health, social support, patient-provider relationship characteristics, substance
      use and health anxiety were assessed. Three measures of adherence were used:
      adherence over the past three days, adherence over the past week, and adherence
      over the past month. Logistic regression analyses indicated strongest prediction
      of three-day adherence, with mental health, social support, patient-provider
      relationship characteristics and side effects contributing to prediction. Past
      week adherence was associated with age and social support measures, and showed a
      marginal association with side effects. Past month adherence was less strongly
      predicted, with social support and alcohol use contributing to prediction. Thus,
      a variety of factors were found to determine adherence, and implications of the
      findings for adherence models and interventions are discussed.

PMID- 15203416
TI  - Provider barriers to prescribing HAART to medically-eligible HIV-infected drug
      users.
AB  - We aimed to identify factors associated with a medical provider's resistance to
      prescribing HAART to medically-eligible HIV-infected illicit drug users. In four
      US cities, a mailed, self-administered survey queried 420 HIV care providers
      about patients' characteristics and barriers to care. Adjusted odds ratios (AOR)
      and 95% confidence intervals (CI) were estimated using logistic regression.
      Providers identified as resistant to prescribing HAART to medically-eligible HIV
      infected illicit drug users were more likely to be non-physicians (AOR=1.89, 95%
      CI: 1.04-3.46), to work in populations with a high prevalence of both mental
      illness (AOR=2.42; 95% CI: 1.11-5.26) and injection drug use (AOR=1.82 95% CI:
      1.02-3.25) and were deterred from prescribing HAART by patients' limited ability
      to keep appointments, (AOR=3.19; 95% CI: 1.39-7.37), alcoholism (AOR=1.92; 95%
      CI: 1.04-3.55) and homelessness (AOR=1.81; 95% CI: 1.07-3.06). Providers working
      in populations with a high injection drug use prevalence commonly reported higher
      prevalence of non-injection drug use, alcohol problems and mental illness, and
      higher antiretroviral therapy refusal rates within their patient populations. Our
      findings underscore the challenges to providers who treat HIV-infected drug users
      and suggest that their care and treatment would benefit from on-site drug
      treatment, mental health and social services.

PMID- 15203417
TI  - Correlates of HIV antiretroviral adherence in persons with serious mental
      illness.
AB  - Although several studies have examined the relationship between symptoms of
      depression or psychological distress and medication adherence, this is the first
      published study of HIV antiretroviral adherence and its correlates among persons
      diagnosed with serious mental illness. Forty-five of 47 (96%) participants
      completed a two-week study in which their adherence to antiretroviral medication
      was measured using electronic monitoring caps. Mean adherence (proportion of
      prescribed doses taken) was 66% (SD=34). There were several correlates (p<0.05)
      of adherence among background and medical characteristics, physical symptoms and
      side effects, cognitive and psychosocial functioning, and treatment-related
      attitudes and beliefs. However, in a forward stepwise regression, attendance at
      recent clinical appointments was the sole predictor that entered the model-
      accounting for 49% of the variance in adherence. Using attendance at recent
      clinic appointments as the criterion, adherence readiness (90+% adherence to
      antiretrovirals) was correctly determined for 72% of the sample. Although not
      sufficient to serve as the basis for treatment decision making, review of
      appointment-keeping records may provide clinicians with a simple, cost-effective
      method for predicting adherence to ongoing treatment, as well as for evaluating
      adherence readiness to inform the decision of whether to prescribe or defer
      treatment.

PMID- 15203418
TI  - Protection and participation: an interactive programme introducing the female
      condom to migrant sex workers in Cambodia.
AB  - The female condom has received much attention for its potential to empower users
      in negotiating safer sex. Studies demonstrate that the process used to introduce
      the method can influence subsequent use rates, resulting in calls for
      comprehensive documentation of introduction activities. This paper details an
      intervention study introducing the female condom to Vietnamese sex workers in
      Cambodia. Part of a wider community mobilization approach to reducing HIV/AIDS
      transmission, the intervention emphasized informed debate, group skills building
      and collective support. Research methods included both quantitative and
      qualitative data collection to evaluate the introduction's effect on sex workers'
      negotiation skills and social support networks. The findings show that
      approximately 16% of sex workers tried the female condom. Ever-use was
      significantly associated with participation in intervention workshops, and with
      indicators of both individual and community empowerment. Sex workers who
      incorporated the female condom into their work were also more likely to feel a
      sense of community identity. Introduced through an appropriate process, the
      female condom can serve as an 'entry point' to building community capacity. It
      can support sex workers in achieving protected sex and developing cooperative
      relationships, even in severely restrictive settings.

PMID- 15203419
TI  - Abused women report greater male partner risk and gender-based risk for HIV:
      findings from a community-based study with Hispanic women.
AB  - The purpose of this study was to assess the relationship between intimate partner
      violence (IPV) and sexual risk in terms of safer sex behaviour and intent,
      individual and gender-based HIV risk factors, and male partner HIV risk, among a
      lower-income community-based sample of Hispanic women reporting a current male
      sexual partner. Baseline survey data on HIV-related behaviours and risk factors
      gathered from participants (N=170) of an HIV intervention evaluation study for
      Hispanic women were used for current analyses. Participants were age 18-36 years,
      predominantly born outside of the continental US (88.8%) and not English fluent
      (68.2%). Adjusted logistic regression analyses and 95% confidence intervals were
      conducted to assess the relationships between male-perpetrated IPV in the past
      three months and sexual risk variables. One-fifth (21.2%) of the sample reported
      male-perpetrated IPV in the past three months. Abused women were significantly
      more likely than those not abused in the past three months to report high STD/HIV
      risk perceptions (OR=3.02, 95% CI=1.33-6.88), gender-based risk including sexual
      control by male partners (OR=3.09, 95% CI=1.41-6.76) and male partner risk
      including male infidelity (OR=4.58, 95% CI=1.57-13.32). Results support the need
      for emphasis on IPV prevention within HIV prevention programmes and demonstrate
      the need for HIV prevention efforts directed at men with a history of IPV
      perpetration.

PMID- 15203420
TI  - Identifying the psychosocial correlates of condom use by female sex workers in
      Hong Kong.
AB  - This study examined factors affecting condom use by Hong Kong female sex workers
      when they have sex with their clients and steady partners. Our respondents
      consisted of 109 active female sex workers, mainly streetwalkers or sex workers
      who worked in villas. During a 30-minute interview, respondents were interviewed
      individually and were asked questions regarding their condom use practice. These
      questions were designed to measure various factors affecting their condom use
      practice, including attitudes toward condom use, normative pressure, perceived
      behavioural control, perceived AIDS risks, past condom use behaviour, and future
      condom use intentions with respect to the two types of partners. Multiple
      regression analyses reveal that perceived behavioural control is the most
      important factor associated with these respondents' future condom use across the
      two types of partners. Perceived AIDS risk is the additional predictor for condom
      use with clients, while normative pressure is the additional predictor for condom
      use with steady partners. Past condom use behaviour also provided significant
      additional prediction for both types of partners, implying the habitual nature of
      condom use among our respondents. These results have significant implications for
      designing intervention programmes targeting at increasing condom use by female
      sex workers in Hong Kong.

PMID- 15203421
TI  - Sociodemographic characteristics of HIV-positive mother-child pairs in Ile-Ife,
      Nigeria.
AB  - This study was designed to identify sociodemographic characteristics of HIV
      positive mother-child pairs in the southwest of Nigeria. The aim was to identify
      factors that will be helpful in designing initiatives for preventing mother to
      child transmission (MTCT) of the virus. It was a hospital-based, case-control
      study carried out at the Obafemi Awolowo University Teaching Hospital, Ile-Ife,
      Nigeria from August 2000 to July 2002. Eligible mother-child pairs identified at
      the paediatric department, who consented to participate in the study, were
      interviewed using semi-structured questionnaires and screened for HIV
      seropositivity. Ninety-three (46.7%) of 199 mother-child pairs were HIV-positive.
      When compared with the 106 HIV-negative mothers, the HIV-positive mothers were
      younger, unemployed, had earlier sexual exposure, lower education and were
      married to polygynous spouses. It is recommended that initiatives designed to
      reduce MTCT of the HIV virus in the southwest of Nigeria should include education
      and improvement of the economic status of female adolescents; promotion of
      cultural practices such as virginity until marriage while discouraging polygyny
      and early marriage. Health education on prevention of HIV infection should target
      potential mothers and their partners.

PMID- 15203422
TI  - Coping styles among families of children with HIV infection.
AB  - The primary aim of this study was to examine coping strategies among families of
      HIV-infected children and how they relate to medical, central nervous system
      (CNS) and family environment factors. Caregivers of HIV-positive children (N=52)
      completed a family coping measure (F-COPES) and provided information regarding
      family environment. Data regarding medical and CNS status were obtained from
      patient records. Results indicated that families' passive coping and spiritual
      support were among the coping techniques used most often, and social support was
      used least often. Medical variables were unrelated to any coping styles. Families
      of children with CNS impairment endorsed more passive coping techniques than
      families of children with no apparent deficits. A trend was found for non
      biological caregivers to seek out more community resources and support than
      biological caregivers. Findings suggest the need to target families least likely
      to utilize resources, and to teach them to effectively seek out and benefit from
      social and community supports.

PMID- 15203423
TI  - The health and social environment of uninfected infants born to HIV-infected
      women.
AB  - Against a background of increasing numbers of uninfected children born to HIV
      infected women in Europe, we describe the social environment and occurrence of
      infectious disease in 1,667 infants enrolled in the European Collaborative Study
      (ECS) and followed prospectively. In the ECS, the proportion of children born to
      black women from Sub-Saharan Africa who acquired their HIV infection
      heterosexually has increased since the mid-1980s, while the proportion of those
      born to white women with a history of illicit drug use has decreased, in both
      northern and southern Europe. The percentage of children who had been in
      alternative (non-parental) care decreased from 17% (82/469) in 1985-1989 to 5%
      (23/436) in 1999-2002. A total of 135 infants (with 1,475 child-years of follow
      up) experienced at least one moderate/severe infective or febrile episode
      requiring medical attention in the first year of life; there was little
      correlation with recorded sociodemographic and child characteristics. The rate of
      hospitalization remained relatively stable over the study period at between 243
      299 admissions per 1,000 child-years. Description of disease burden and social
      circumstances of uninfected children is needed, not only because of their
      increasing numbers but also because they are often used as controls in studies
      addressing vertically-acquired HIV infection.

PMID- 15203424
TI  - Transition from paediatric to adult services: experiences of HIV-positive
      adolescents.
AB  - In this small, preliminary study, semi-structured interviews were conducted with
      seven adolescents to explore their experiences of transition between paediatric
      and adult HIV care services. In general, the transition process established
      between the two health care units was considered by most participants to be
      beneficial, particularly the introduction of adult service providers early on in
      the transition preparation period. Four of the participants found the transition
      'easy', whereas three had concerns that possibly delayed their transition,
      including coordination of haemophiliac and HIV care and fear of an adult
      environment. Individuals who had experienced little input into their care
      decisions during their paediatric appointments were more positive and ready for
      transition than those who had been more involved. Confidence and attachment with
      paediatric staff generally involved those who had been more involved in their
      care decision making. On transition, some of the participants were not prepared
      for the predominantly gay male population and were disappointed in not seeing
      other adolescents. The benefits of transition included the sense of independence,
      the shift in responsibility to the individual and general satisfaction in being
      treated as an adult. For those with strong paediatric staff rapport, a sense of
      loss in these relationships was expressed. Participants were forthcoming in
      suggesting recommendations for future transitions that are discussed.

PMID- 15203425
TI  - Delayed application of condoms, withdrawal and negotiation of safer sex among
      heterosexual young adults.
AB  - The aim of this study was to examine delayed application of condoms and
      withdrawal among heterosexual young adults. Seven focus group discussions were
      conducted with heterosexual men and women aged 18-25 in Melbourne, Australia. The
      data revealed that delayed application of condoms and withdrawal are widespread.
      Delayed application of condoms can be divided into two categories--condom use
      'after limited unprotected penetration' and condom use 'for ejaculation only'.
      The data reveal parallels between withdrawal and condom use 'for ejaculation
      only'. These two behaviours share the goal of avoiding unprotected ejaculation
      inside a partner, while allowing some unprotected intercourse. They are both more
      likely to occur in regular relationships than casual encounters, both are likely
      to be negotiated and both occur when there is no perceived risk of STI infection.
      In contrast, condom use 'after limited unprotected penetration' was likely to
      occur in casual encounters, and was likely to be unplanned and not negotiated.
      There is a need to ensure that heterosexual young adults use condoms and use them
      correctly. There is also a need to ensure that heterosexual young adults have the
      required skills to negotiate sexual activity and to negotiate condom use.

PMID- 15203426
TI  - Clinical assessment of medication adherence among HIV-infected children:
      examination of the Treatment Interview Protocol (TIP).
AB  - This paper presents findings of a multi-site study designed to document: (1)
      caregivers' regimen knowledge; (2) barriers to adherence; and (3) the
      relationships between adherence, regimen knowledge and barriers. Fifty-one
      predominantly female, African American parents and caregivers of HIV-infected
      children completed the Treatment Interview Protocol (TIP), a brief, structured
      interview designed to assess regimen knowledge and barriers to adherence. TIP
      data were compared to information obtained from medical records and pharmacy
      refill histories. Forty-nine per cent of children were considered adherent,
      defined as > or = 90% refill rate, which was significantly associated with
      virologic response. Significant regimen knowledge deficits were observed among
      caregivers, and inaccurate identification of prescribed medications was
      significantly associated with adherence. Caregivers identified 21 barriers to
      adherence, and poor adherence was significantly related to the number of barriers
      reported. Results indicate that the TIP is a successful tool for identifying
      regimen knowledge, potential adherence barriers and adherence problems. Results
      suggest that the TIP could be integrated into clinical practice as a quick,
      effective tool to identify poor adherers and guide interventions and treatment
      decision making.

PMID- 15203427
TI  - The sexual and reproductive health of young people in Adjumani district, Uganda:
      qualitative study of the role of formal, informal and traditional health
      providers.
AB  - This qualitative study of young people and health care workers in Adjumani,
      northern Uganda, found that young people are generally very knowledgeable about
      STD spread and prevention as well as methods for prevention of pregnancy. Health
      workers are the most important category of people providing information on sexual
      and reproductive health (SRH) for young people. However, many health workers are
      conservative with regard to adolescent sexuality. There is a lack of training in
      and guidelines for working with adolescents. This, along with inadequate access
      to SRH services for young people, accounts for the failure to adequately deal
      with young people's problems. Physical, social, psychological and economic
      factors create barriers to service accessibility. Socio-economic, religious and
      cultural factors affect sexual behaviour and outcomes in Adjumani district,
      making some young people vulnerable, particularly young women. In an effort to
      find alternative services that meet their needs better, young people visit
      informal and traditional health care providers despite having to pay for these
      services. The confidentiality and privacy that they offer could be a lesson for
      formal health care providers. Further training and integration of traditional
      health care providers is essential as they already play a major part in SRH
      service delivery to young people.

PMID- 15203428
TI  - Sexual activities and social relationships of people with HIV in Japan.
AB  - Sixty-one Japanese with sexually transmitted HIV were investigated to clarify the
      state of, and difficulties in, their sexual activities and social relationships.
      The study revealed the following difficulties in social relationships due to HIV
      infection. Thirty-one per cent had experienced discrimination or breach of
      confidentiality. Self-restriction due to anxiety over discrimination was observed
      in approximately 90%, and the self-restriction score tended to be higher in those
      who were not employed, those with economic problems, those who were in a
      relatively poor state of health, those who had developed AIDS and those who had
      previously experienced discrimination or breach of confidentiality. The
      experience of discrimination or breach of confidentiality, and the experience of
      receiving negative support tended to increase as the respondents had a wider
      emotional support network. About 60% were dissatisfied with their sex lives, and
      the degree of satisfaction was significantly lower in those who had fewer sexual
      contacts and those who had a suppressive attitude toward sexual contacts. A low
      degree of satisfaction with sex life was found to be an important factor that
      escalates the level of depression or anxiety.

PMID- 15203429
TI  - The mysteries and demands of HIV care: qualitative analyses of HIV specialists'
      views on their expertise.
AB  - To deepen our understanding of the mysteries and demands associated with HIV care
      and to inform the debate about HIV specialization, we conducted in-depth
      interviews with a purposive sample of 20 identified HIV specialists in the San
      Francisco Bay Area. Participants were from several medical specialties and
      reported a median of 50% of their time spent in HIV patient care. Through
      constant comparison, a template of open codes was constructed to identify themes
      that emerged from the data. Data were analyzed according to the conventions of
      qualitative research and revealed six interrelated themes: (1) coping with
      uncertainty and rapid change: being 'comfortable with mystery'; (2) the powerful
      role of experience; (3) the dual faces of knowledge: 'knowing the patient' and
      'knowing the facts'; (4) the dual faces of passion: challenge and calling; (5)
      stress and burnout; and (6) the relationship between academia and 'the trenches'.
      The themes underscore the dual dimensions of HIV care: providers must interweave
      the 'half-baked' science about drug therapies, side effects and drug interactions
      with the psychosocial and lifestyle factors of the patient. They also provide
      insight into quantitative findings linking greater HIV experience with better
      patient outcomes and suggest that providers need skills associated with
      generalist and specialist training, a phenomenon that argues for a 'special'
      specialty for HIV care.

PMID- 15203430
TI  - Psychosocial needs of HIV-positive individuals seeking workforce re-entry.
AB  - With the advent of more effective treatments and corresponding improvement in
      morbidity and mortality, people living with HIV and AIDS are increasingly
      considering a return to the workplace. This study examined subjective and
      objective indicators of need among a sample of 235 HIV-infected individuals
      entering a vocational rehabilitation programme for people with HIV. In addition
      to help with training and job placement, participants indicated a need for
      assistance with finances, money management, housing access and access to health
      care, as well as with alcohol or drug problems, legal problems and social
      relationships. Subsequent to learning of their diagnoses, the sample reported a
      median decrement in financial resources of 60%. Over half had experienced housing
      instability in the year prior to entering the study, including 15% who had been
      homeless, even though most were linked to case management services. A third had
      used illegal drugs in the prior month, 41% drank to intoxication and 20% lacked
      even monthly phone contact with friends. Results suggest that back to work
      programmes for people with HIV and AIDS will need to address a broad range of
      psychosocial issues beyond job training and placement.

PMID- 15203431
TI  - Physical activity and immunity in HIV-infected individuals.
AB  - The purpose of this study was to determine what relationship exists among
      physical activity levels and viral load and CD4+ cell count in HIV-infected
      individuals. Increased viral load is associated with disease progression and
      symptom severity. A convenience sample of 66 male and female subjects between the
      ages of 18 and 64 years of age (mean 39 +/- 8) was recruited from a hospital
      based HIV/AIDS clinic. Components of PA were assessed for three continuous days
      using a mini-motion logger wrist actigraph. These components included mean PA
      level, and PA index and acceleration index. Pearson's correlational analysis was
      used to test the strength of association between PA components and viral load or
      CD4+ cell count. A significant inverse relationship was found between mean PA
      level and viral load (p=0.047). An inverse relationship was also observed between
      PA index and viral load (p=0.0061). Neither mean PA nor PA index scores
      correlated with CD4+ cell counts. Acceleration index, a measure of PA intensity,
      showed no correlation to viral load or CD4+ cell counts. These findings suggest
      that increasing levels of physical activity might have beneficial effects on
      viral load in HIV-infected individuals.

PMID- 15203432
TI  - Predictors of attrition in HIV-positive subjects with peripheral neuropathic
      pain.
AB  - The objective of this paper was to identify predictors of attrition in a study
      designed to assess whether cognitive behavioural therapy (CBT) was more helpful
      than supportive therapy (SP) in reducing pain associated with peripheral
      neuropathy in HIV-positive patients. Sixty-one subjects were randomized into
      either CBT or SP for six weekly one-hour sessions. Twenty-eight subjects dropped
      out before week six. Demographic variables such as age, gender, ethnicity,
      socioeconomic status and level of education were not predictive of attrition.
      However, higher scores on the Hamilton Depression Inventory (HAM-D, 17-item) (t
      (59) = - 0.09, p<0.05) were predictive. These findings suggest that while
      dropouts were not more physically ill (e.g. CD4 counts, viral loads and
      opportunistic infections were not statistically higher), they reported greater
      psychological distress.

PMID- 15203433
TI  - Alcoholic macrocytosis--is there a role for acetaldehyde and adducts?
AB  - Although alcohol abuse is known to cause a wide array of adverse effects on blood
      cell formation, the molecular mechanisms by which alcohol exerts its toxic
      actions have remained poorly defined. Elevated mean corpuscular volume (MCV),
      macrocytosis, is the most typical morphological abnormality induced by excessive
      ethanol consumption. This paper reviews recent data indicating that acetaldehyde,
      the first metabolite of ethanol, may play a role in the haematological
      derangements in peripheral blood cells and in bone marrow of alcoholic patients.
      Studies in experimental animals and in human alcoholics have shown that
      acetaldehyde can bind to proteins and cellular constituents forming stable
      adducts. Elevated adduct levels have been found from the erythrocytes of alcohol
      abusers, which may also be associated with ethanol-induced effects in
      haematopoiesis and adverse consequences in cellular functions.

PMID- 15203434
TI  - Genetic study of alcoholism and novel gene expression in the alcoholic brain.
AB  - Alcohol dependence may result from neuroadaptation involving alteration of gene
      expression after long-term alcohol exposure. The systematic study of gene
      expression profiles of the human alcoholic brain was initiated using the method
      of polymerase chain reaction (PCR)-differential display and was followed by DNA
      microarray. To date, more than 100 alcohol-responsive genes have been identified
      from the frontal cortex, motor cortex and nucleus accumbens of the human brain.
      These genes have a wide range of functions in the brain and indicate diverse
      actions of alcohol on neuronal function. This review discusses the current
      information on the genetic basis of alcoholism and the induction and
      characterization of these alcohol-responsive genes.

PMID- 15203435
TI  - Functional changes in dopamine D3 receptors by prenatal and neonatal exposure to
      an endocrine disruptor bisphenol-A in mice.
AB  - Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has
      been evaluated extensively for toxicity and carcinogenicity. However, little is
      still known about its action on the central nervous system (CNS). In the previous
      study, we found that prenatal and neonatal exposure to BPA markedly enhanced the
      rewarding effect induced by morphine. Here we found that prenatal and neonatal
      exposure to BPA resulted in the attenuation of dopamine D3 receptor-mediated G
      protein activation by 7-OH-DPAT in the mouse limbic forebrain. This treatment
      also caused a significant decrease in the B(max) value of [(3)H]PD128907, a
      dopamine D3 receptor ligand, in this area. Under these conditions, no change in
      dopamine D3 receptor mRNA expression in the limbic forebrain and lower midbrain
      was observed by prenatal and neonatal exposure to BPA. The present data provide
      further evidence that prenatal and neonatal exposure to BPA leads to the
      reduction of functional dopamine D3 receptors without affecting the new synthesis
      of dopamine D3 receptors in the mouse limbic forebrain.

PMID- 15203436
TI  - Serum immunoglobulins and white blood cells status of drug addicts: influence of
      illicit drugs and sex habit.
AB  - The aim of this study was to investigate the serum immunoglobulins and white
      blood cells status of drug addicts and to assess the extent of influence of drug
      habit and sexual practice on the immune components. The study was conducted among
      253 male drug addicts and 100 non-addict controls of aged 18-45 years. An enzyme
      linked immunosorbent assay (ELISA) was employed to analyse the serum
      immunoglobulin concentrations. White blood cells profile was estimated by
      counting 200 cells. Results showed a significant increase (p<0.03) of serum IgG,
      IgA and IgM in the drug addicts (6.93+/-1.53 g/l, 2.90+/-1.13 g/l and 1.72+/-0.73
      g/l, respectively) compared to those in the cohort controls (6.52+/-1.05 g/l,
      2.61+/-0.83 g/l and 1.52+/-0.59 g/l, respectively). A significant (p=0.00)
      decrease of peripheral lymphocytes (51.8+/-15.2 vs. 71.9+/-11.5) was noted in the
      drug addicts. Monocytes (8.3+/-4.9), neutrophils (128.2+/-18.9) and eosinophils
      (11.4+/-5.8) were found to be increased in the drug addicts against those in the
      controls (5.2+/-2.5, 113.2+/-13.0 and 9.6+/-5.8, respectively). Multiple drug
      abuse for longer period had resulted in a significant (p<0.05) decrease of serum
      immunoglobulins and lymphocytes. The longer period of addiction had also made a
      significant (p<0.05) decrease of eosinophils (p=0.05) and an increase of
      monocytes and neutrophils. Sex with multiple sexual partners had shown a
      significant (p<0.01) decrease of serum immunoglobulins and eosinophils.

PMID- 15203437
TI  - Do smoking intensity-related differences in vigilance indicate altered
      glucocorticoid receptor sensitivity?
AB  - The relationship of critical flicker fusion frequency (CFF) and a
      pharmacologically induced cortisol suppression by means of dexamethasone (DEX)
      and metyrapone (MET) was investigated during nicotine deprivation in a between
      subjects design in 60 male smokers divided into light, medium and heavy smokers.
      DEX reduced vigilance in medium smokers and improved it in heavy smokers compared
      to placebo, whereas MET was more detrimental in heavy smokers. The hypothesis was
      put forward that the intensity of nicotine consumption is related to differences
      in glucocorticoid and mineralocorticoid receptor sensitivity.

PMID- 15203438
TI  - Treatment of alcohol withdrawal: chlormethiazole vs. carbamazepine and the effect
      on memory performance--a pilot study.
AB  - Although relatively little attention has been paid to the question how acute
      alcohol withdrawal might affect cognitive functions, this factor remains of
      particular interest because it influences psychotherapeutic treatment during
      detoxification. The clinical outcome and neuropsychological state of 37
      inpatients with alcohol withdrawal was investigated in a randomized single-blind
      approach. Two different medical strategies [chlormethiazole (CMZ) vs.
      carbamazepine (CBZ)] in the treatment of inpatients with alcohol withdrawal
      syndrome were compared. Among comparable groups (related to gender, age, initial
      alcohol level, severity of abuses, severity of initial withdrawal symptoms such
      as tremor, perspiration, psychomotor agitation, hallucinations, orientation,
      intelligence, patient demographics), CBZ is just as potent as CMZ in therapy of
      withdrawal symptoms (circulatory function, vegetative function, psychomotor
      activity). Patients in both groups showed initial impairments in some
      neuropsychological tests (d2, Zahlen-Verbundings test, Beck Depression Inventory,
      Anxiety Sensitivity Index) with significant improvement during detoxification.
      Additionally, CBZ-treated patients showed significantly better verbal memory
      performance during the first days of treatment. Without any addictive potential,
      CBZ therapy could be very supportive in alcohol detoxification. In addition a
      higher verbal memory performance state could be favourable for a
      psychotherapeutic approach.

PMID- 15203439
TI  - Effects of opium addiction on some serum factors in addicts with non-insulin
      dependent diabetes mellitus.
AB  - The aim of this study was to determine the effect of opium on biochemical
      parameters in addicts with non-insulin-dependent diabetes mellitus (NIDDM).
      Twenty-three males and 26 females between 35 and 65 years of age, with NIDDM,
      addicted to opium, were selected as the case group. Twenty-three males and 26
      females with NIDDM and no opium addiction served as controls. Fasting glucose,
      glycated haemoglobin (HbA1c), total cholesterol, high density lipoproteins
      cholesterol (HDL-c), triglycerides (TGs), sodium (Na(+)), potassium (K(+)),
      calcium (Ca(2+)), iron (Fe(2+)), total iron binding capacity (TIBC), serum total
      protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase
      (AST), uric acid and urea were measured in the serum of the two groups. Serum
      protein electrophoresis was also carried out. Compared to the control group, in
      addicted males with NIDDM, HbA1c, K(+) and Fe(2+) were higher, and serum total
      protein, ALT and HDL-c were lower. No significant difference was observed between
      other factors. Albumin was lower in addicts, but no significant difference was
      observed between the albumin/globulin ratios. In addicted females with NIDDM,
      serum total protein, TIBC, ALT and AST were lower compared to non-addicts.
      Cholesterol tends to be lower in diabetic addicted males, HbA1c in addicted
      females and uric acid in addicted males was higher compared to non-addicted
      diabetics. Their differences, however, were not significant. According to our
      results, smoking opium increases serum glucose and decreases HDL-c, and thus adds
      to metabolic disorders in NIDDM patients. It also increases potassium and Fe(2)
      in males and decreases TIBC in females, and could therefore potentially interfere
      with water and iron metabolism.

PMID- 15203440
TI  - Blood naltrexone and 6-beta-naltrexol levels following naltrexone implant:
      comparing two naltrexone implants.
AB  - The aim of this study was to profile and compare blood naltrexone and 6-beta
      naltrexol levels with time following treatment with two sustained-release
      naltrexone preparations produced by GoMedical Industries, Australia at a
      community heroin treatment clinic in Perth, Western Australia. A sample of 10
      patients who each received a 1.7 g naltrexone implant were compared to 24
      patients who each received a 3.4 g naltrexone implant as treatment for heroin
      dependence. Blood naltrexone levels following treatment with the 1.7 g naltrexone
      implant remained above 2 and 1 ng/ml for approximately 90 and 136 days,
      respectively. Use of the 3.4 g naltrexone implant extended the period of coverage
      to approximately 297 (1 ng/ml) or 188 (2 ng/ml) days. Blood 6-beta-naltrexol
      levels remained above 10 ng/ml for approximately 18 and 83 days, respectively,
      following use of the 1.7 g and 3.4 g naltrexone implants. The current study data
      indicate that blood naltrexone and 6-beta-naltrexol levels following treatment
      with either the 1.7 g or 3.4 g naltrexone implant are greater than those reported
      in other published data on other sustained-release naltrexone preparations.
      Furthermore, duration of blood naltrexone and 6-beta-naltrexol levels achieved
      following use of the 3.4 g implant were superior to those achieved with the 1.7 g
      naltrexone implant, with naltrexone blood levels maintained above 2 ng/ml for a
      period of approximately 6.3 months compared to 3 months, respectively. The
      implications of this in managing the heroin-dependent patient, especially those
      who find it difficult to shift away from dependent use patterns, are discussed.

PMID- 15203441
TI  - Achieving long-term continuous blood naltrexone and 6-beta-naltrexol coverage
      following sequential naltrexone implants.
AB  - The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol
      levels with time following treatment with sequential sustained-release naltrexone
      preparations. Data were collected from blood samples analysed independently for
      naltrexone and 6-beta-naltrexol and from clinical record review at a community
      heroin treatment clinic in Perth, Western Australia. Five patients received
      sequential 3.4 g (3.49+/-0.01 g and 3.36+/-0.05 g, respectively) naltrexone
      implants. The second implant was received on average within 131.2+/-15.67 days of
      the first implant. The mean length of follow-up was 307.2+/-18.28 days of the
      first implant. Blood naltrexone levels have the potential to remain above 2 and 1
      ng/ml for a total of 390 and 524 days, respectively, and blood 6-beta-naltrexol
      was maintained above 10 ng/ml for a total of 222 days following insertion of
      these implants. No patient relapsed to dependent heroin use during the implant
      coverage period while blood naltrexone concentrations were above 2 ng/ml. Results
      indicate that blood naltrexone and 6-beta-naltrexol levels can be maintained
      above therapeutic levels for prolonged periods following use of sequential 3.4 g
      naltrexone implants. These extended periods of coverage will offer significant
      benefits for managing the heroin-dependent patient.

PMID- 15203442
TI  - No association of CRH1 receptor polymorphism haplotypes, harm avoidance and other
      personality dimensions in alcohol dependence: results from the Munich gene bank
      project for alcoholism.
AB  - Because corticotrophin-releasing hormone (CRH) plays a central role in stress
      regulation, the possible role of CRH1 polymorphism for anxiety-related
      personality variables such as harm avoidance possibly associated with alcoholism
      was studied. The research instruments used to phenotype patients were adopted
      partly from the US collaborative study of the genetics of alcoholism and include
      a number of personality inventories such as the temperament and character
      inventory (TCI). Based on the examination of 170 alcoholic subjects no
      association was found between CRH1 receptor haplotypes of four single nuclotid
      polymorphisms (SNPs) and low and high temperament traits of harm avoidance,
      novelty seeking and reward dependence. The possible implications of these
      findings are discussed.

PMID- 15203443
TI  - Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a
      review of the literature.
AB  - Many clinicians appear to be concerned about the potential hepatotoxicity of the
      opiate antagonist naltrexone (NTX) and this may be one reason why it is not used
      more widely in treating both heroin and alcohol abusers. Some much-quoted early
      studies noted abnormalities in liver function tests (LFTs) in very obese patients
      taking high doses, although there was no evidence of clinically significant liver
      dysfunction. These concerns may be reinforced by advice in the UK product
      information sheet to perform LFTs before and during treatment, by high infection
      rates with hepatitis C virus (HCV) among injecting heroin addicts and by the
      frequency of abnormal LFTs in alcohol abusers. We describe a heroin abuser in
      whom clinical and laboratory manifestations of acute hepatitis B and C appeared a
      few days after the insertion of a subcutaneous naltrexone implant. A decision was
      made not to remove the implant but the hepatitis resolved completely and
      uneventfully well within the normal time-scale. A review of the literature
      indicates that even when given at much higher doses than are needed for treating
      heroin or alcohol abusers, there is no evidence that NTX causes clinically
      significant liver disease or exacerbates, even at high doses, serious pre
      existing liver disease. During the past decade, NTX has been shown to be safe and
      effective in the treatment of pruritus associated with severe jaundice caused by
      severe and sometimes life-threatening cirrhosis and other liver diseases. Its
      safety, even in these extreme conditions, is particularly reassuring. We suggest
      that it may be more appropriate and economical to advise patients to report
      promptly any suspected side effects than to perform regular LFTs, which may be
      misleading.

PMID- 15203448
TI  - Environmental influences on helminthiasis and nutritional status among Pacific
      schoolchildren.
AB  - This paper describes a study undertaken to: (1) determine the prevalence of
      Ascaris lumbricoides, Trichuris trichiura and hookworm infections and nutritional
      status among Pacific Island school children; (2) identify factors influencing
      helminthiasis; (3) identify interventions to improve school health. A total of
      3,683 children aged 5-12 years attending 27 primary schools in 13 Pacific Island
      countries were surveyed along with school environmental data. Stool samples were
      collected from 1996 children (54.2%) and analysed for ova and helminths. Total
      prevalence of helminthiasis was 32.8%. Anaemia prevalence was 12.4%. Children
      with helminthiasis and anaemia were found to be 8.7 times more likely to be
      stunted and 4.3 times more likely to be underweight than non-anaemic and non
      infected children. Four significant environmental influences on helminthiasis
      were identified: (1) an inadequate water supply; (2); availability of a school
      canteen; (3) regular water/sanitation maintenance regimes; and (4) overcrowded
      classrooms. Helminthiasis was found to be strongly associated with anaemia,
      stunting and underweight and environmental influences identified. Although mass
      anti-helminthic drug administrations (MDA) have been taking place, reinfection is
      common as drug therapy alone is not enough. Programme effectiveness depends upon
      upgrading school environments to include an adequate water supply, controlled
      food preparation/provision, well-maintained water/sanitation facilities and class
      sizes of 30 students or less.

PMID- 15203449
TI  - Assessment of waste amalgam management in dental clinics in Ramallah and al-Bireh
      cities in Palestine.
AB  - The behavior of dental health personnel was examined with regard to the handling
      and proper disposal of wastes generated at common dental clinics, and some of the
      amounts of waste they produce were estimated. In January 2002, a random sample of
      37 dental clinics was chosen in the cities of Ramallah and al-Bireh. The visited
      clinics were distributed between 31 private practices and six public/NGO dental
      clinics. The dentists were asked about the methods they follow in disposing and
      discarding of amalgam wastes. An average dentist is estimated to place two small,
      seven medium and nine large amalgam restorations releasing 22.6 grams of mercury
      each week. The majority of amalgam wastes ended up in trash or drain.

PMID- 15203450
TI  - Creating a GIS application for local health care planning in Saudi Arabia.
AB  - The purpose of this paper is to show how Geographical Information Systems can be
      used to support health planners on a micro-scale. The first part of this paper
      discusses the issue that affect local health care planning which include
      monitoring of catchment area and facilities management. The second part defines
      GIS and its possible uses in the health care field. The relevant GIS functions
      have also been explained. The third part of this paper discusses the created GIS
      application, which is made for a local health centre in Makkah City, Saudi
      Arabia. In this application, three sets of GIS models have been produced. These
      are catchment area, patient profile and patient distribution and patient flows
      models. The created GIS models are produced to help local health planners in
      their health care decision output.

PMID- 15203451
TI  - Food sampling practice in the United Kingdom.
AB  - As an integral part of the UK food surveillance scheme, routine food sampling is
      undertaken by officers at local councils. One of the main purposes of the food
      sampling programme is to detect food contaminants before they are sold to the
      public. This paper investigated the current UK food sampling activity undertaken
      by the local Environmental Health Departments and examined the effectiveness of
      the food programme. A national survey was undertaken by means of a questionnaire
      sent to 439 UK local authorities and a response rate of 39.2% (172 LAs) was
      achieved. Thirty-nine per cent of replies indicated that ensuring food safety and
      hygiene was the most important aim of sampling. Less than half of the returns
      suggested that their food programmes contributed to the prevention of foodborne
      illness. However, over three-quarters agreed that the current food sampling
      system could be improved upon. This study concluded that current UK food sampling
      is marginalized by financial constraints. In order to design an effective routine
      food programme, it should be based on an overall co-ordinated approach from local
      to European levels. Future work towards a statistically validated approach to the
      design will improve the effectiveness of food sampling programme.

PMID- 15203452
TI  - Ambient levels of benzene in Mumbai city.
AB  - An attempt has been made to determine the levels of benzene in air at different
      locations in Mumbai city. Levels of benzene in air have been determined by
      adsorbing air at a uniform flow rate on especially fabricated activated coconut
      charcoal cartridges followed by thermal desorption and detection on Varian GC-MS.
      The results show that maximum concentrations of benzene have been observed at
      traffic junctions and petrol pumps.

PMID- 15203453
TI  - Knowledge, attitudes and behaviours related to climate change in Alberta, Canada:
      implications for public health policy and practice.
AB  - Climate change has received recent extensive media attention (e.g., Kyoto
      Protocol) and is currently on the international public health agenda. The purpose
      of this study was to survey knowledge, attitudes and behaviours related to
      climate change in the province of Alberta, Canada. A random sample of 600 Alberta
      households, using proportional quotas based on the Canada Census of the Alberta
      population, was surveyed on knowledge, attitudes and behaviours related to
      climate change using a computer-assisted telephone interviewing protocol.
      Albertans are highly concerned, particularly about health problems related to the
      environment and air pollution; yet are only moderately informed about a variety
      of environmental issues. While the great majority of Albertans appear to be
      engaged in environmental behaviours at home, fewer consider energy efficiency
      when purchasing consumer goods. An even smaller percentage makes environmentally
      conscious transportation decisions. To encourage the population to make
      recommended environmental behaviours, mass media approaches may do well to target
      the specific beliefs that were deemed salient (e.g., promote the association
      between environment issues and health). The public health sector has a major role
      in working with inter-sectoral groups to address this significant public health
      issue.

PMID- 15203454
TI  - Contribution of air-proof doors and windows to asthma in Campania Plain (Italy).
AB  - The relation between the prevalence of doctor-diagnosed asthma in children and
      the presence of air-proof doors and windows (doors and windows with rubber
      gaskets) in their homes was investigated by a cross-sectional survey in the area
      of Campania Plain, South Italy. Information on the occurrence of asthma and
      home/family characteristics, including parental smoking habit and level of
      education, was obtained by a questionnaire given to school children, aged 8-14
      years, and their parents. After possible confounders were controlled, the risk of
      developing asthma was found to be significantly higher in children living in
      houses equipped with air-proof doors and windows (Odds ratio = 1.30, 95%
      Confidence interval = 1.1-1.5). By reducing the air exchange, these fixtures are
      likely to produce increased levels of indoor pollutants. No interaction was found
      between the two variables 'air-proof doors and windows' and 'parental smoking
      habit'.

PMID- 15203455
TI  - Association between nutritional status and arsenicosis due to chronic arsenic
      exposure in Bangladesh.
AB  - The role of nutritional factors in arsenic metabolism and toxicity is not clear.
      Provision of certain low protein diets resulted in decreased excretion of DMA and
      increased tissue retention of arsenic in experimental studies. This paper reports
      a prevalence comparison study conducted in Bangladesh to assess the nutritional
      status among the chronic arsenic exposed and unexposed population. 138 exposed
      individuals diagnosed as arsenicosis patients were selected from three known
      arsenic endemic villages of Bangladesh and age, sex matched 144 unexposed
      subjects were randomly selected from three arsenic free villages. The mean
      arsenic concentration in drinking water for the exposed and unexposed population
      was 641.15 and 13.5 microg L(-1) respectively. Body Mass Index was found to be
      lower than 18.5, the cut off point for malnutrition, in 57 (41.31%) out of 138
      exposed arsenicosis cases and 31 (21.53%) out of 144 unexposed individuals. The
      crude prevalence ratio (or risk) was 1.92 (95% CI = 1.33-2.78) for poor
      nutritional status among the arsenicosis cases compared to the unexposed
      population. The findings of this study add to the evidence that poor nutritional
      status may increase an individual's susceptibility to chronic arsenic toxicity,
      or alternatively that arsenicosis may contribute to poor nutritional status.

PMID- 15203456
TI  - An assessment of food hygiene and safety at farmers' markets.
AB  - Farmers' markets are becoming a more significant part of the food-retailing
      sector. A survey of farmers' markets was conducted to assess aspects of food
      hygiene and safety. The views of the public using the markets were also examined.
      The range of farm products was wide and the methods utilised varied. The markets
      were usually temporary outdoor events with few facilities. Traders had received
      elementary food hygiene training and rated their hygiene standards highly. Less
      than half had risk management procedures in place, most did not perceive their
      produce as high-risk. They believed consumers to be mainly interested in food
      quality and to regard food safety issues highly. Consumers shopped at the markets
      because of the quality of the products sold. Their overall satisfaction with the
      markets was high and they raised no concerns about food safety. Given the
      restricted facilities at farmers' markets and the early phase of implementation
      of hygiene management systems by market traders, it may be precautionary to
      restrict the sale of farm products at farmers markets to those that are regarded
      as low-risk.

PMID- 15203457
TI  - High levels of oxidative DNA damage in lymphocyte DNA of premenopausal breast
      cancer patients from Egypt.
AB  - Egypt shows a parallel increase in premenopausal breast cancer and environmental
      pollution. The purpose of this study is to explore a possible relationship
      between oxidative DNA damage, urinary estrogen metabolites and breast cancer in
      Egyptian premenopausal women. We conducted a pilot study of Egyptian breast
      cancer involving 29 cases and 32 controls and analysed lymphocyte DNA levels of
      7,8-dihydro-8-oxo-2'-deoxyguanine (8-oxo-dG), a measure of oxidative DNA damage
      using high performance liquid chromatography with electro-chemical detection
      (HPLC-ECD) method. We analysed levels of urinary estrogen metabolites, 2
      hydroxyestrone (2-OHE) and 16alpha-hydroxyestrone (16alpha-OHE) by an enzyme
      immuno assay. We also collected residential, occupational, and reproductive
      histories of all study subjects. We detected, in all subjects, exceptionally high
      levels of 8-oxo-dG and thus oxidative DNA damage, the levels (mean 8-oxo-dG/10(5)
      dG+/-SD) were significantly (P<0.01) higher in breast cancer cases (139.4+/-78.4)
      than in controls (60.9+/-51.5). Urinary 2-OHE and 16alpha-OHE or their ratio was
      not significantly different between cases and controls. However, 8-oxo-dG levels
      were positively correlated (P<0.05) with 2-OHE and 16alpha-OHE from cases while
      controls showed a negative correlation (P<0.05). Urban residence (Odds Ratio [OR]
      3.1; Confidence interval [CI], 1.1-9.3), infertility (OR [9.8]; CI [1.1-89.7]),
      age (OR [2.6]; CI [1.4-4.6]) and 8-oxo-dG (OR 5.8; CI 1.9-17.5) levels were found
      to be significant predictors of breast cancer. Our finding of exceptionally high
      levels of 8-oxo-dG, a common result of oxidative DNA damage, warrant future
      studies on a larger population of premenopausal women in Egypt with consideration
      of other susceptibility markers and dietary characteristics.

PMID- 15203458
TI  - Occupational exposure to urban pollutants and plasma insulin-like growth factor 1
      (IGF-1).
AB  - The aim of present study is to evaluate whether traffic policemen exposed to
      urban pollutants and possible psycho-social stressors could be at risk of
      alterations on plasma insulin-like growth factor (IGF-1) levels compared to a
      control group. Out of a population of 395 Municipal Police employees, the
      subjects with principal confounding factors (cigarette smoking habits, drinking
      habits, oral contraceptives being taken, use of paints, solvents and pesticides)
      were excluded from the study. The remaining traffic policemen were matched with
      those not exposed by sex, age and length of service; 49 traffic policemen (22 men
      and 27 women) with outdoor activity exposed to urban pollutants and 49 not
      exposed subjects (22 men and 27 women) with indoor activity were included in the
      study. The plasma levels of IGF-1 resulted significantly higher in the male and
      female traffic policemen compared with control subjects (respectively P<0.001;
      P<0.001). The authors hypothesise that occupational exposure to chemical
      stressors, that may interact with possible psycho-social stressors, could cause
      an alteration on IGF-1 levels in traffic policemen.

PMID- 15203459
TI  - Impact of blast induced transitory vibration and air-overpressure/noise on human
      brain--an experimental study.
AB  - Human response to blast induced ground vibration and air-overpressure/noise is a
      major concern of current mining activity. This is because the fact that mines are
      fast transgressing the habitats and people are getting educated. Consequently the
      response of humans is changing and expectedly will increase in days to come with
      no viable and economic alternative to blasting--an essential component of mining.
      The response of humans can be purely physiological or psychological in nature or
      combination of both depending upon the situation and conditions of mining. Where
      physiological response is documented in terms of effects on ears and lungs there
      is a meager amount or no literature available regarding effects of blasting on
      the brain. Moreover, the studies on transitory phenomenon like the effects of
      blasting on humans are rare in comparison to the whole body vibration studies.
      This study was designed to address the issues as a precursor to a major
      initiative. The preliminary investigations conducted with the monitoring of EEG
      responses of humans to vibration and air-overpressure/noise due to blasting
      revealed that there is no major response of the brain to transitory vibrations
      and noise.

PMID- 15203460
TI  - An investigation on physical, chemical, and bacteriological quality of
      municipally supplied and well waters of the towns and city centre in the province
      of Nigde, Turkey.
AB  - Physical, chemical, and bacteriological properties of municipally supplied water
      and well water in selected towns and the city centre (Nigde, population 76,000)
      of the province of Nigde, located in central Anatolia, in Turkey, were
      investigated in this study. A composition of 70 samples were collected, 31 from
      Nigde city centre; 17 from Bor; 8 from Ulukisla; 6 from Altunhisar; 6 from
      Ciftlik and 2 from Camardi. Analyses showed that all the samples collected were
      found to have been chemically safe to consume for domestic purposes. Twenty-three
      water samples were found potentially unsafe because of the existence of coliform
      bacteria in them, which was probably caused by the inexistence of sufficient
      chlorination. Physical tests indicated that 11 water samples were found to have
      deposit; therefore, the use of such water causes risks where human health is a
      concern, based upon Turkish national standards (TSE, 1984).

PMID- 15203462
TI  - Evaluation of the Ngati Porou Community Injury Prevention Project.
AB  - OBJECTIVE: To evaluate the Ngati Porou Community Injury Prevention Project based
      in a rural district in the North Island of New Zealand with an extensive
      indigenous population (Maori). METHOD: The evaluation design was quasi
      experimental and included process, impact and outcome measures. RESULTS: Process
      evaluation found that the Ngati Porou Community Injury Prevention Project was
      based on sound principles related to injury prevention, as well as addressing
      Maori aspirations. The main activities undertaken were: road safety campaigns;
      alcohol and drug programmes; family violence initiatives; and the development of
      a playground safety audit. A significant increase in awareness of injury
      prevention was found among Ngati Porou whanau (families) (pre 17% and post 25%, p
      < 0.05). Injury morbidity statistics for the period 1996-99 showed a significant
      decrease in injury rates for all age groups, compared with the comparison
      community (p < 0.05). CONCLUSION: The Ngati Porou Community Injury Prevention
      Project successfully applied the principles of role modelling, life span focus,
      accessibility, acceptability and active participation. This is a promising model
      that could be repeated in other indigenous communities.

PMID- 15203463
TI  - Investigating the mental abilities of rural Zulu primary school children in South
      Africa.
AB  - INTRODUCTION: Maximising the full potential of health and educational
      interventions in South African schools requires assessment of the current level
      of mental abilities of the school children as measured by cognitive and
      scholastic tests and the identification of any barriers to improved performance.
      OBJECTIVES: This study reports on the application and interpretation of a
      selected battery of mental ability tests among Zulu school children and the
      methodological and analytical issues that need to be addressed. DESIGN: The test
      scores of 806 primary school children from a rural community are presented, based
      on four tests: Raven's Coloured Progressive Matrices (CPM), an Auditory Verbal
      Learning Test (AVLT), the Symbol Digit Modalities Test (SDMT) and Young's Group
      Mathematics Test (GMT). RESULTS: Significant gender differences were found in the
      test scores, and the mean scores of Zulu children in this study were lower than
      those reported in other studies. The results of this selected test battery
      provide data for the further development of appropriate test instruments for
      South African conditions. CONCLUSION: These results can contribute towards the
      development of a test battery for South African children that can be used to
      assess and improve their school performance.

PMID- 15203464
TI  - Intended use of informal long-term care: the role of race and ethnicity.
AB  - OBJECTIVE: To examine the role of race/ethnicity in the use of informal long-term
      care among African American and white elders, using an expanded Andersen model of
      health services use (Bradley et al., Health Services Research, vol. 37, pp. 1221
      1242, 2002). DESIGN: Four hundred respondents (n = 200 African American; n=200
      white) aged 65 and older, who had been hospitalized within the last year. Data
      were collected using a cross-sectional survey analyzed with ordered logistic
      regression. Independent variables included individuals' predisposing factors,
      enabling factors, need, and psychosocial factors. Intended use of informal long
      term care was defined based on responses to a hypothetical scenario of future use
      of unpaid services by family members, relatives, friends, or neighbors for help
      with daily needs. RESULTS: African American respondents were more likely than
      white respondents to intend to use informal long-term care. This effect persisted
      (p < 0.05) after controlling for predisposing, enabling, and need factors.
      However, race/ethnicity-related differences in intended use were attenuated
      substantially (14-18%) after controlling for psychosocial differences. Further,
      in the fully adjusted models, race/ethnicity was no longer significantly
      associated with intended long-term care use. CONCLUSIONS: Psychosocial factors,
      particularly social norms concerning family caregiving, mediated the relationship
      between race/ethnicity and intended use of informal long-term care. A fuller
      appreciation of the multiple influences on healthcare decision making of older
      adults has the potential to inform policy efforts to appropriately meet the
      respective long-term care needs of an ethnically diverse frail older population.

PMID- 15203465
TI  - Ethiopian refugees in the UK: migration, adaptation and settlement experiences
      and their relevance to health.
AB  - OBJECTIVE: The study explores Ethiopian refugees' and asylum seekers' experiences
      of migration, adaptation and settlement in the UK and their health beliefs and
      practices. DESIGN: Data was collected using semi-structured depth interviews and
      a semi-structured questionnaire. The sample consisted of 106 Ethiopians resident
      in the UK. RESULTS: The majority of the participants fled Ethiopia due to
      political reasons. Whilst 65% of them had lived in the UK for over five years
      only 7% had full refugee status. Many of the participants faced difficulties with
      the immigration system, housing and social services and felt socially isolated.
      Many also had problems with gaining employment or employment appropriate to their
      qualifications, and 29% were unemployed. The majority of the participants believe
      that happiness is a prerequisite to healthiness and also an indication of
      healthiness. On the other hand the majority believed that sickness is caused by
      disease and mental illness is caused by both supernatural and psychosocial
      causes. Most of the participants sought the help of their GP in the first
      instance of illness although some had experienced difficulties accessing health
      services due to language problems and poor understanding of the primary
      healthcare system. The participants also believed that the stress of adaptation
      and settlement affected their mental health and led to depression. CONCLUSION:
      Migration, adaptation and settlement experiences impact on the health of refugees
      and are dependent on a number of barriers and enablers, both at a personal and
      societal level. These should be taken into account in the provision of health and
      social care services, in particular services should be provided in a culturally
      competent manner.

PMID- 15203466
TI  - How experiences and attitudes relating to female circumcision vary according to
      age on arrival in Britain: a study among young Somalis in London.
AB  - OBJECTIVE: To examine the association between age on arrival in Britain and
      experiences and attitudes relating to female circumcision among young, single
      Somalis living in London. DESIGN: The study population consisted of single male
      and female Somalis aged 16-22 years living in the Greater London area.
      Quantitative data were collected using a cross-sectional survey based on snowball
      sampling aiming to obtain data on 100 males and 100 females. Qualitative data
      were collected from 10 males and 10 infibulated females. RESULTS: Quantitative
      data were obtained for 94 females and 80 males. Living in Britain from a younger
      age was associated with increased assimilation in terms of language, dress and
      socialising. Seventy per cent of the females reported being circumcised with two
      thirds of operations being infibulation. Those who were living in Britain before
      the usual age range for circumcision (before age six) were less likely to be
      circumcised (42%) than those who arrived after the usual age range for
      circumcision (11 or older) (91%). During in-depth interviews, health and sexual
      problems due to female circumcision were described with great emotion and
      interviewees acknowledged the association between the importance of virginity for
      marriage and circumcision. Half of males who arrived aged 11 or older wanted a
      circumcised wife compared with less than a quarter of those who arrived at a
      younger age. Eighteen per cent of female respondents and 43% of males intended to
      circumcise any daughters. Females were less likely than males to agree with the
      assumptions about sexuality and religion that underpin the practice. Substantial
      proportions of respondents perceived that their parents' expectations in terms of
      marriage and circumcision were more traditional than their own. CONCLUSION:
      Living in Britain from a younger age appears to be associated with abandonment of
      female circumcision and with changes in the underlying beliefs on sexuality,
      marriage and religion that underpin it. Groups identified with more traditional
      views towards female circumcision include males, older generations, new arrivals
      and those who show few signs of social assimilation.

PMID- 15203468
TI  - Power and change.

PMID- 15203469
TI  - Assessment of the impact of community-based medical education of the University
      of Maiduguri on communities in three local government areas of Borno State,
      Nigeria: community leaders' perspectives.
AB  - BACKGROUND: The community-based training of the University of Maiduguri Medical
      College was expanded in 1990 to cover three rural local government areas (LGAs)
      located between 25 and 145 km from the University. This study was conducted
      between March and May 2000 to assess the impact and level of awareness of the
      training in the three LGAs in promoting the ideals of Primary Health Care (PHC)
      and community-based medical education, as perceived by community leaders. METHOD:
      Focus group discussions (FGDs) were held with community leaders of each of the
      communities. RESULTS: Consistency in the recollection of what time in the year
      and for how long the students were in the various communities indicates awareness
      in all the community leaders. They also indicated that the programme has had a
      positive impact on their community's health, they would like the students to
      focus on specific endemic diseases, such as guinea-worm, hypertension, etc, and
      intensify community outreach programmes, such as home visits and health
      education. Most participants indicated that their communities participated in the
      programme by providing accommodation, feeding and other logistics on an ad hoc
      basis. Community leaders mobilized the communities for health education and other
      related activities carried out by the students. CONCLUSION: The community-based
      medical training of the University of Maiduguri has increased community awareness
      of preventive aspects for various communicable and non-communicable diseases. In
      addition it has helped to encourage the communities to participate actively in
      supporting PHC activities.

PMID- 15203470
TI  - Use of Video-Projected Structured Clinical Examination (ViPSCE) instead of the
      traditional oral (Viva) examination in the assessment of final year medical
      students.
AB  - CONTEXT & BACKGROUND: Assessment of medical students using the traditional oral
      (viva) system has been marred by being highly subjective, non-structured, and
      biased. The use of the objective structured clinical examination (OSCE) would
      circumvent these disadvantages. The OSCE is, however, costly and time-consuming
      particularly if used for assessment of large numbers of students. The need for
      another form of examination that enjoys the advantages of the OSCE while avoiding
      its disadvantages in the face of limited resources has been the inspiration
      behind this innovative approach. OBJECTIVES: (1) To identify the characteristics
      of the new Video-Projected Structured Clinical Examination (ViPSCE). (2) To
      compare the acceptability of ViPSCE and OSCE by students and tutors. (3) To
      compare the time-effectiveness of ViPSCE and OSCE. METHODS: We used a slide video
      projection to assess the surgical knowledge, problem solving and management
      abilities of 112 final year medical students at Alazhari University, Khartoum,
      Sudan. Students completed evaluation forms at the end of the examination.
      RESULTS: The administration of the ViPSCE was smooth and straightforward.
      Feedback of the students showed that they preferred the ViPSCE to both
      traditional oral (viva) examination and OSCE. The examination time was 2 hours
      using video projection compared to the 6 hours that it used to take a class of
      112 students to complete a classical OSCE. CONCLUSION: The ViPSCE is a better
      replacement for the traditional oral exam. It is much less time- consuming than
      traditional OSCE.

PMID- 15203471
TI  - Teaching and learning about written communications in a United Kingdom medical
      school.
AB  - CONTEXT: Written communications have a long history in medicine. Today, doctors
      spend a significant part of their work time completing paper work. Although the
      importance of accurate written communications is acknowledged, medical curricula
      rarely include focused teaching on this topic. OBJECTIVES: The aim of this paper
      is to assess the feasibility of a teaching session for second-year medical
      students aimed at raising their awareness of written communications in the
      context of health care. METHODS: Immediately after the session, students and
      tutors completed written evaluations of their experiences. Four months after the
      session the entire cohort completed a knowledge test, and scores of attendees and
      non-attendees were compared. FINDINGS: Three of four learning objectives were
      completely met by at least half of the students and the exercises were rated as
      helpful. Students' and tutors' comments identified specific aspects of the
      session that require improvement, in particular, developing the exercise on
      patient-centred written communications. Students who attended the session scored
      significantly higher in a relevant knowledge test than non-attendees. DISCUSSION:
      The session provided students with the knowledge to identify patient-centred
      written communications and other features of effective writing in the context of
      medical care. CONCLUSIONS: Introducing the topic early in the medical curriculum
      may prove valuable in establishing effective practice. Providing students with
      opportunities to revisit this important topic throughout their medical education
      may also be beneficial. The long-term impact of the session needs to be
      evaluated.

PMID- 15203472
TI  - Teaching medical students what they think they already know.
AB  - OBJECTIVES: To discuss the problems encountered teaching interviewing skills to
      first year medical students and describe their responses to a structured workshop
      in interviewing skills. METHODS: Focus groups and a short evaluation
      questionnaire filled in by 56 first year medical students before and after a
      workshop in interviewing skills were used. RESULTS: All students evaluated their
      skills very highly prior to the workshop. After participating in the workshop,
      students evaluated their skills as lower than before. DISCUSSION: When
      communication skills are taught in an informal, unstructured manner, medical
      students might view this knowledge as unspecialized, repetitive, and even boring.
      It is suggested that employing a structured model for teaching doctor-patient
      communication skills awards psycho-social issues the status of formal knowledge.
      This can lead to students viewing communication skills as a relevant and
      consistent body of knowledge. Introducing a structured model can overcome two
      kinds of problems: over-confident students are formally introduced to unique
      aspects of medical interviewing, whilst those who lack confidence are offered a
      lifeline in the form of a structured model. Identifying possible sources of
      resistance to communications training has important implications for medical
      education as it allows for appropriate course planning and follow up.

PMID- 15203473
TI  - Sometimes we do get it right! Early clinical contact is a rewarding experience.
AB  - OBJECTIVE: Like many other medical education bodies, the Health Professions
      Council of South Africa has advocated changes in the education and training of
      medical practitioners. The suggested reform includes early clinical exposure in a
      range of settings. Early in the design of Curriculum 2001, a problem-based
      learning programme, health care visits in Year 1 were considered essential. Since
      the student population was diverse in many aspects, including age, it was
      necessary to evaluate whether students were prepared for the early exposure.
      METHODS: Data on the impact of the health care visits were collected directly
      through a survey administered towards the end of the academic year and indirectly
      from student comments regarding their most rewarding experiences during the year.
      RESULTS: Responses to survey items indicated that students were generally
      prepared for their health care visits and gave them insights into the activities
      of a medical practitioner. Sixty-nine per cent of students indicated that aspects
      of their health care visits, particularly the labour ward and an ambulance duty
      where many had hands-on experience, were their most rewarding experiences.
      DISCUSSION AND CONCLUSIONS: The decision of curriculum organisers to introduce
      students to patients in Year 1 of the new PBL curriculum was well received.
      Despite their young age, many students believed that they were psychologically
      prepared for this exposure. For many, it was the highlight of their academic
      year, often reinforcing their original desire to study medicine and allowing them
      to experience the real world of medicine.

PMID- 15203474
TI  - Capacity development through reflective practice and collaborative research among
      clinic supervisors in rural South Africa--a case study.
AB  - This article provides an example of one form of action research, collaborative
      enquiry, in the health sector. It argues that collaborative inquiry is a powerful
      tool to develop reflective capacity among health workers and can facilitate the
      ownership of learning and the production of usable knowledge. It reports the
      results of a research project investigating the roles and functions of clinic
      supervisors in three districts in the Eastern Cape Province, South Africa.
      BACKGROUND: Clinics are the cornerstone of the new district-based health system.
      They are staffed primarily by nurses and are often the only contact point for
      large parts of the rural population. In conditions of remoteness and isolation,
      clinic staff depend upon personal interaction with clinic supervisors to enable
      them to function productively. Yet experience has shown that supervisors do not
      always fulfil this role. This project aimed at gaining insight into the status of
      clinic supervision, understanding the factors that hinder effective supervision
      and making recommendations for improvements. METHODOLOGY: Using a participative
      approach of Collaborative Inquiry, a team of 10 clinic supervisors and the
      research co-ordinator collected data reflecting on their own practice over a
      period of 5 months. These data were then jointly analysed and written up.
      CONCLUSIONS: The participating clinic supervisors went through several periods of
      uncertainty, when many of them asked themselves why they agreed to this project.
      However, the engagement with stakeholders and colleagues and the joint analysis
      of research data soon proved to be a valuable source of insight. There was
      unanimity in the end that the research process had been very valuable and
      enabling.

PMID- 15203475
TI  - Teaching medical ethics: implementation and evaluation of a new course during
      residency training in bahrain.
AB  - AIM: This paper describes the development, implementation and evaluation of a new
      biomedical ethics course. The major educational goal was to enable the
      participants to critically analyse and resolve ethical dilemmas based on sound
      ethical and moral reasoning. BACKGROUND: The course was developed and implemented
      in the Family Practice Residency Program (FPRP) in the Kingdom of Bahrain.
      METHODOLOGY: Thirty-six family physician trainees participated in this course in
      May 2002 and January 2003. The curriculum was divided into five sessions, and
      each session had specific objectives, contents and teaching methods. The course
      was evaluated using pre- and post-tests, direct observation of participants and
      overall course assessment. RESULTS: Evaluations demonstrated that the
      participants scored higher in the post-test than in the pre-test. There was a
      significant statistical difference between the mean scores of both tests. After
      completing the course, participants produced more justifiable decisions than
      those generated at the beginning and felt more confident discussing and reasoning
      their decisions based on sound ethical and moral concepts. CONCLUSION: Our
      experience had demonstrated that the trainees benefited from a structured
      curriculum in biomedical ethics. We believe that the development and
      implementation of our course may serve as a case study for training and teaching
      postgraduates in the area of medical ethics.

PMID- 15203476
TI  - Teaching empathy to first year medical students: evaluation of an elective
      literature and medicine course.
AB  - BACKGROUND: Empathy is critical to the development of professionalism in medical
      students, and the humanities-particularly literature-have been touted as an
      effective tool for increasing student empathy. This quantitative/qualitative
      study was undertaken to assess whether reading and discussing poetry and prose
      related to patients and doctors could significantly increase medical student
      empathy and appreciation of the relevance of the humanities for their own
      professional development. METHOD: In 2000-2001, first year students (n=22)
      volunteered for an eight-session literature and medicine elective and were
      randomly assigned to either immediate participation in the class or a wait-list
      group, who participated in the same class 6 months later. Complete pre- and post
      intervention data for 16 students from both groups were obtained for two
      quantitative measures of empathy and an attitudes-toward-the-humanities scale.
      Students also participated in a qualitative group interview pre- and post
      intervention. RESULTS: Empathy and attitudes toward the humanities improved
      significantly (p<0.01) after participation in the class when both groups of
      students were combined. The scaled treatment effect size was in the moderate
      range (> or =0.60 standard deviation units) for both measures that had
      statistically significant pre-to-post changes. Furthermore, student understanding
      of the patient's perspective became more detailed and complex after the
      intervention. Students were also more likely post-intervention to note ways
      reading literature could help them cope with training-related stress. CONCLUSION:
      A brief literature-based course can contribute to greater student empathy and
      appreciation for the value of humanities in medical education.

PMID- 15203477
TI  - Strengthening PBL through a discursive practices approach to case-writing.
AB  - CONTEXT: In many ways the task of physicians is to listen to stories and place
      them within larger social contexts. Problem-based learning (PBL) can potentially
      reinforce such a view of the physician's work. The conventional PBL case,
      however, largely replicates the medical record, which in turn, is restricted in
      its purview to biomedical concerns. The conventional case thus encourages an
      approach to clinical reasoning that insufficiently recognizes (1) the cross
      cultural nature of all clinical encounters, (2) the central role of narrative,
      and (3) the political economic influences that contribute to disease and
      suffering in our world. METHODS: We suggest ways to modify the traditional
      medical curriculum to include the learning of cross-cultural health through
      appropriately written problem-based learning (PBL) cases. We discuss two cases to
      illustrate how PBL cases can incorporate dialogue between patients and
      physicians, demonstrate the narrative character of the medical encounter and
      examine the political economic contributors to disease production. CONCLUSION:
      Fluency in language games other than that of biomedicine is required if students
      are to become more aware of the wider factors that contribute to suffering, and
      to be able to respond with compassion and understanding to that suffering. Our
      approach is a discursive practices approach to culture that emphasizes the
      emergent, participant-constructed qualities of social phenomena while also
      acknowledging large-scale social forces.

PMID- 15203478
TI  - The importance of including bio-medical ethics in the curriculum of health
      education institutes.

PMID- 15203479
TI  - Introducing people to healthier food: an interview of Karin Dingena (social
      worker) and Remco Keijsers (supermarket manager). Interviewed by Gerard Moore.

PMID- 15203480
TI  - An interview of Janaina Garcia Goncalves. Interviewed by Jan van Dalen.

PMID- 15203482
TI  - The 2003 Network: TUFH conference in Newcastle, Australia--some observations and
      reflections.

PMID- 15203494
TI  - International trends in medical education: diversification contra convergence.

PMID- 15203495
TI  - Developing the teaching instinct, 13: How to teach in the clinical skills centre.

PMID- 15203496
TI  - The WAMI Program: 25 years later.
AB  - The Washington, Alaska, Montana and Idaho (WAMI) Program is a four-state
      decentralized medical education program initiated at the University of Washington
      School of Medicine (UWSM) in 1972 with the goals of: (1) admitting more students
      to medical school from all states, (2) training more primary care physicians, (3)
      bringing the UWSM's resources to needy communities, (4) redressing the
      maldistribution of physicians by placing more MDs in predominantly rural states
      and (5) avoiding new construction costs. The program consists of a University
      Phase and a Community Phase, the latter extending to residency/postgraduate
      medical training. Thirty-three years on, and now renamed WWAMI (with the
      inclusion of the State of Wyoming), nearly 1200 students have been admitted to
      the program, with 5947 clerkship experiences and 2282 resident rotations, and the
      original goals of this experiment in decentralized medical education have been
      largely met. Almost half of all residents supported by the program return home to
      practice, and of graduates who underwent a part of their training in Alaska,
      Montana and Idaho, 64.7% returned home to practice. This paper reports on some
      lessons learned and speculates whether the WAMI program can keep pace with the
      rapid changes in medical education.

PMID- 15203497
TI  - Medical education in China's leading medical schools.
AB  - This article gives a general overview of the evolution and present state of the
      undergraduate medical education system, programs, evaluation methods and
      conferred degrees in contemporary China. The publication is based on the
      information collected from on-site visits to the eight (8) leading medical
      universities, medical education conferences, visits to Ministries of Health and
      Education and their staff, and the contribution of Chinese medical education
      experts. As the Ministry of Education of the People's Republic of China (PRC)
      approves all tracks and strives for uniformity of educational programs as a
      cornerstone of quality, this overview reflects the general content of all five-
      and seven-year medical education programs that have provided the great majority
      of physicians since the founding of the People's Republic of China.

PMID- 15203498
TI  - The relationship between measures of patient satisfaction and enablement and
      professional assessments of consultation competence.
AB  - The authors examined the extent of the relationship between a Consultation
      satisfaction questionnaire and Patient enablement instrument scores and
      professionally assessed consultation competence scores of senior medical
      students. Three analyses were performed: (i) linear regression with mean overall
      competence score as response variable; (ii) sensitivity and specificity
      calculations using patient scores to classify competence; (iii) a repeated
      measures model with consultation-specific competence score as response variable.
      One hundred and nineteen students and 388 patients took part. Consultation
      satisfaction and enablement scores were weakly correlated with overall and
      consultation specific competence scores (correlation coefficient 0.16 to 0.44).
      'Satisfaction with professional care' had a sensitivity of 0.68, specificity of
      0.72 and positive and negative predictive values of 0.32 and 0.92 respectively.
      It is concluded that patient and professional assessments may complement, but do
      not replace, each other. Levels of patient satisfaction should not be used as
      proxy measures of the quality of consultation competence.

PMID- 15203499
TI  - Attitudes to concept maps as a teaching/learning activity in undergraduate health
      professional education: influence of preferred learning style.
AB  - Concept maps that integrate and relate concepts in a nonlinear fashion are widely
      accepted as an educational tool that can underpin meaningful learning in medical
      education. However, student take-up may be affected by a number of cognitive and
      non-cognitive influences. In the present study, student attitudes to pre-prepared
      concept maps introduced in Stage 2 conjoint MPharm and BSc Pharmacology lectures
      were examined in relation to preferred learning styles according to the Felder
      Silverman model. There was no statistically significant influence of dichotomous
      learning style dimension (sensing/intuitive; visual/verbal; active/reflector;
      sequential/global) on the self-reported utility of such concept maps to learning.
      However, when strength of preference was analysed within each dimension,
      moderate/strong verbal learners were found to be significantly less likely to
      self-report concept maps as useful relative to mild verbal learners. With this
      important exception, these data now suggest that student attitudes to concept
      maps are broadly not influenced by preferred learning styles and furthermore
      highlight the potential of concept maps to address a variety of different
      learning styles and thereby facilitate 'teaching to all types'. Concept maps
      could therefore potentially assist motivation, engagement and deep learning in
      medical and biomedical science education when used as a supplement to more
      traditional teaching/learning activities.

PMID- 15203500
TI  - Medical students' self-appraisal of first-year learning outcomes: use of the
      course valuing inventory.
AB  - The aims of this paper were: to appraise how medical students perceive the
      meaning and value of their first-year experiences in medical studies, as measured
      by the Course Valuing Inventory (CVI); and to identify the relationships between
      the CVI responses and the learners' attributes and expectations. The study
      involved 282 second-year students of a six-year medical programme over a four
      year timeframe. Factor analysis identified five dimensions of CVI responses:
      worthiness of learning experience, emotional awareness, personal development,
      cognitive enhancement and task drive. Higher CVI scores related positively and
      significantly to female gender, stronger self-confidence as a learner, greater
      motivation to learn, meaning orientation and reflection in learning. The CVI
      score was the strongest independent predictor of intention to continue the
      studies as a motivational consequence of first-year learning experience. In
      addition, a separate test showed significant relationships between the dimensions
      of CVI responses and the DREEM score (Dundee Ready Education Environment
      Measure). In conclusion, CVI responses that are more positive are likely to be
      associated with a quest for meaning, reflection in learning and autonomous
      motivation, given the relevance of the educational environment for the proximal
      interests of the students.

PMID- 15203501
TI  - Defining the learning outcomes of graduates from the medical school at the
      University of Barcelona (Catalonia, Spain).
AB  - It is generally accepted that medical schools must clearly define learning
      outcomes for their students. During the process of curriculum change initiated in
      1990, Spanish medical schools introduced a range of general objectives but no
      specific outcomes were defined. In 2001, in an effort to improve its curriculum,
      the Medical School at the University of Barcelona decided to define the specific
      learning outcomes for its graduates. The process was carried out by a teachers'
      group, comprising individuals from different branches of medicine, drawing
      largely on the Outcome-based Education in Medicine model introduced by the
      Scottish Deans' Medical Curriculum Group (2000). Other different stakeholders
      were asked to give any suggestions for modifications in order to prepare a
      definitive document to be approved by the medical school. The whole process took
      two years to complete. The authors discuss the advantages of such a process for
      students, teachers and the institution.

PMID- 15203502
TI  - Effect of curriculum reform on graduating student performance.
AB  - With the aim of evaluating the efficacy of a new curriculum implemented in the
      Faculty of Medicine of Ribeirao Preto (University of Sao Paulo, Brazil), a yearly
      objective assessment of both cognitive and practical skills of undergraduate
      (sixth year) students was performed. All graduating student underwent a multiple
      choice questions (MCQs) test and groups of 18-20 students were randomly assigned
      to OSCEs for either clinical (real and standardized patients) or procedure
      (manikins) skills. The average MCQs score for the students graduating in the new
      curriculum (63.1, SD = 8.9, n = 261) was significantly higher (p < 0.001) than
      for the previous curriculum (55.3, SD = 8.1, n = 222). Results for practical
      exams showed that the new curriculum was associated with significantly improved
      performance in five out of the six stations for procedure skills, but in only two
      of the 10 clinical skills stations. Final evaluation of graduating students
      revealed deficiencies in the local curriculum and may serve as a guide to take
      measures to correct them.

PMID- 15203503
TI  - Pre-registration house officers' comments on working in the NHS: a qualitative
      study of the views of UK medical graduates of 1999.
AB  - The authors aimed to report the views of pre-registration house officers (PRHOs)
      on their experience of working in the UK National Health Service (NHS). All
      doctors who qualified from UK medical schools in 1999 were surveyed towards the
      end of their pre-registration year. Structured questions concerning career
      choices and experiences were accompanied by a form inviting free-text comment.
      Comments were transcribed and coded by topic. Those related to working conditions
      were selected for analysis. Respondents commented that aspects of the PRHO year
      had been enjoyable but were critical of working conditions. For instance: heavy
      workloads caused working hours to regularly contravene contractual limits, out-of
      hours pay did not accurately reflect responsibilities, out-of-hours facilities
      were sometimes poor. A few respondents' experiences had deterred them from
      continuing their NHS hospital training. Most PRHOs had enjoyed the year despite
      poor working conditions; for a few, their educational experience was marred.

PMID- 15203504
TI  - Equal opportunity for all? Trends in flexible training 1995-2001.
AB  - This paper describes current patterns and trends in flexible training in the UK.
      It is a descriptive study based on (1) survey data on the number of flexible
      trainees from the annual survey of UK deaneries from 1995 to 2001; (2) Department
      of Health workforce figures on numbers of consultants and specialist registrars
      in England; (3) survey data from UK deaneries on the destination of those leaving
      flexible training schemes from 1999 to 2001. The absolute number and percentage
      of flexible SpRs in England increased from 389 (3.5%) in 1995 to 1067 (8.4%) in
      2001. There is substantial variation by region, with only 4% of SpRs in Mersey
      being flexible compared with 11% in South Western and Oxford in 2000, and by
      specialty, with 2% in general surgery compared with 22% in psychiatry and 19% in
      paediatrics. There was a continued increase in the number and percentage of
      flexible SpRs over the period 1995-2001. The rate slowed in 2001 and fell in
      three regions, suggesting a possible adverse effect of the New Pay Deal for
      junior doctors. Substantial geographical and specialty inequities in access to
      flexible training appear to exist. If skills and talents of female doctors
      required to achieve the medical workforce needed in the future are to be
      retained, these issues need to be urgently addressed.

PMID- 15203505
TI  - Development of an instrument to measure the surgical operating theatre learning
      environment as perceived by basic surgical trainees.
AB  - As a result of changes to surgical training in the United Kingdom, there has been
      a significant reduction in the number of hours worked by surgical trainees per
      week and in the total duration of surgical training. For trainees to achieve an
      acceptable level of surgical operative competence, the learning environment in
      the operating theatre needs to be optimized. In this context, an instrument to
      measure the learning environment in the operating theatre has been developed.
      Through a review of the literature and exploratory interviews with trainers and
      trainees, items that contribute to the learning environment in the operating
      theatre were identified. Based on these items a questionnaire was drawn up. For
      validation purposes, the questionnaire was circulated amongst basic surgical
      trainees on the Aberdeen rotation. This instrument was found to have high
      reliability and validity. Its potential usefulness for informing committees
      responsible for overseeing surgical training is discussed.

PMID- 15203506
TI  - The role of medical education in the recruitment and retention of rural
      physicians.
AB  - In many countries the sustainability of rural healthcare systems is being
      challenged by a shortage of rural physicians and difficulties in recruiting and
      retaining physicians in rural practice. There are numerous factors that influence
      efforts in rural physician recruitment and retention, many of which are beyond
      the scope of the academic medical centre and medical education. Nevertheless,
      there are strategies that medical schools can adopt to contribute to efforts to
      recruit and retain physicians in rural communities. Rural student recruitment,
      admissions policies, rural-oriented medical curriculum, rural practice learning
      experiences, faculty values and attitudes, and advanced procedural skills
      training are areas which the medical school has direct control of and which have
      been shown to influence the likelihood of medical students entering rural primary
      care practice. The purpose of this paper is to elaborate on some of the key
      strategies that have been identified in the literature.

PMID- 15203507
TI  - Parent education classes: teaching junior paediatric doctors and student nurses
      about normal baby care.
AB  - This paper describes the need for education on normal baby care and how a
      modified community parent education class was developed for junior doctors and
      student nurses. The aim was to increase their understanding of the subject and
      better able them to advise parents. The classes were developed by health visitors
      (HVs) and a National Child Birth Trust (NCT) counsellor. The evaluation results
      of a pilot are reported. Many benefits of interprofessional learning and teaching
      were identified.

PMID- 15203508
TI  - Impact of educational preparation on medical students in transition from final
      year to PRHO year: a qualitative evaluation of final-year training following the
      introduction of a new year 5 curriculum in a London medical school.
AB  - This study is a qualitative evaluation of PRHOs' perceptions of a new final year
      of the MB BS programme at Guy's, King's and St Thomas' (GKT) School of Medicine,
      undertaken in 2001 as a precursor to a prospective study. One-to-one interviews
      were carried out with 16 PRHOs two to four months after starting. These were
      independently thematically analysed, cross-referenced and joint agreement on the
      themes reached. PRHOs felt they were well prepared in clinical skills, history
      taking and examination. They reported lack of knowledge in pathology and
      therapeutics. The initial 1-4 weeks were stressful because of new responsibility
      for patients. Relationship with patients and staff changed through acquisition of
      a definite professional role. They adopted a number of coping strategies to
      control demands of the post. The PRHOs perceived the course as relevant and good
      preparation for their posts, with a better balance than the previous curriculum.
      Greater appreciation of aspects of professionalization in the final year may help
      the transition further.

PMID- 15203509
TI  - Problem-based learning: an educational strategy for interactive learning:
      experience from Universiti Sains Malaysia.

PMID- 15203510
TI  - Task-based learning (TBL) in Dokuz Eylul University Medical School, Turkey.

PMID- 15203515
TI  - Cultural competence is everyone's responsibility!

PMID- 15203516
TI  - Developing the teaching instinct, 12: appraisal.

PMID- 15203517
TI  - Multiple choice questions revisited.
AB  - MCQs of the multiple true/false (MTF) variety were widely used in summative
      assessment 25 years ago. They could test a number of skills in addition to recall
      of factual knowledge, and were reliable, discriminatory, reproducible and cost
      effective. However, there are now considerable doubts about their construct
      validity, mainly because of the varying responses of examinees to negative
      countermarking and the 'don't know' option, and the strategies they use when
      sitting examinations. Extended matching and one-from-five questions are now
      preferable, and negative countermarking is outmoded. MTF questions are still
      valuable in formative assessment and revision but are not recommended for
      summative examinations.

PMID- 15203518
TI  - Clinical placements for medical students: factors affecting patients' involvement
      in medical education.
AB  - Many medical students now have contact with patients from the very beginning of
      their course and the increasing numbers of medical students means that more and
      more patients will be exposed to students during their medical treatment. This
      paper presents the attitudes of 281 patients towards medical students encountered
      in a primary or secondary care setting. Particular attention is paid to consent,
      types of procedures undertaken and the title given to the medical student. The
      study showed that the likelihood of patients agreeing to be involved in medical
      education depended on the patient, the student and the procedure being
      undertaken. Recommendations have been made to the university on the basis of the
      results with the aim of maximizing patient involvement and satisfaction in order
      to further medical student education.

PMID- 15203520
TI  - Communication skills, cultural challenges and individual support: challenges of
      international medical graduates in a Canadian healthcare environment.
AB  - Physicians require good communication skills to develop effective patient
      physician relationships. Externally funded international medical graduates (IMGs)
      move directly from their home countries to complete residency training at the
      University of Ottawa, Canada. They must learn quickly how to work with patients,
      families and colleagues. A detailed needs assessment was designed to assess IMGs'
      communication skill needs through focus groups, interviews and surveys with IMGs,
      program directors, allied healthcare professionals and experts in communication
      skills. There was a high degree of consensus amongst all participants concerning
      specific educational needs for communication skills and training issues related
      to the healthcare system for externally funded IMGs. Specific recommendations
      include (1) English-language skills; (2) how to get things done in the
      hospital/healthcare system; (3) opportunities to practise specific skills, e.g.
      negotiating treatment, (4) adequate support system for IMGs; (5) faculty and
      staff education on the cultural challenges faced by IMGs.

PMID- 15203521
TI  - A new approach to developing cross-cultural communication skills.
AB  - The need for cross-cultural training (CCT) increases as physicians encounter more
      culturally diverse patients. However, most medical schools relegate this topic to
      non-clinical years, hindering skills development. Some residency programs have
      successfully addressed this deficit by teaching cross-cultural communication
      skills in a teaching objective structured clinical examination (tOSCE) context.
      The authors developed and evaluated a CCT workshop designed to teach cross
      cultural communication skills to third-year medical students using a tOSCE
      approach. A 1 and 1/2-day workshop incorporating didactic, group discussion and
      tOSCE components taught medical students cross-cultural awareness, interviewing
      skills, working with an interpreter, attention to complementary treatments, and
      consideration of culture in treatment and prevention. Six standardized patient
      cases introduced various clinical scenarios and the practical and ethical aspects
      of cross-cultural care. Student evaluation of the workshop was positive
      concerning educational value, skills advancement and pertinence to their clinical
      activities. Survey of students before and after the workshop demonstrated
      improvement in students' abilities to assess the culture and health beliefs of
      patients and negotiate issues regarding treatment. CCT in the context of medical
      student clinical training can be carried out effectively and efficiently using a
      dedicated multi-modal workshop including standardized patients.

PMID- 15203522
TI  - The choice of role models by students at a culturally diverse South African
      medical school.
AB  - Role models have long been considered important in training medical students in
      the professional and ethical values of medicine. This report discusses role
      models identified by South African medical students in Years 1-5 of their study
      in a traditional programme. Most students considering having a role model
      important. As students progressed, faculty role models were more likely to be
      selected. A parent (the mother, in particular) or parents were, however, most
      frequently identified as role models by all students. Attributes ascribed to
      parents as role models (caring, sympathetic, self-sacrificing) are similar to
      those considered desirable for professional role models in medicine. These
      findings are considered in the light of global medical training and the need for
      faculties to provide appropriate role models for students.

PMID- 15203523
TI  - Is culture important in the choice of role models? Experiences from a culturally
      diverse medical school.
AB  - In a multicultural student population at a South African medical school, for over
      one-third of students (Years 1-5) undertaking a traditional curriculum, culture
      was an important consideration in their choice of a role model. This was
      particularly so for senior students, perhaps reflecting their relatively recent
      exposure to patients and their forthcoming internship. Some student comments
      might, however, be interpreted as reflecting a rigid perception of culture that
      could translate into a possible lack of respect for other cultures. It is
      therefore imperative that each institution provide appropriate early and
      continuous mainstream diversity training, as well as identify role models to
      match the student profile. With the increasing diversity of students globally,
      this issue of culture should assume even greater importance in medical education
      than it is currently afforded.

PMID- 15203524
TI  - A case study in the globalization of medical education: assisting overseas-born
      students at the University of Melbourne.
AB  - Over the past decade there has been a remarkable increase in ethnic diversity
      among Australian medical students. This phenomenon has been driven by two forces:
      the disproportionate school-level academic success achieved by first-generation
      migrant and refugee-origin youth, and the rapid globalization of Australia's
      tertiary education system, in a context where reduced government funding has
      accelerated the development of 'academic capitalism' (Slaughter & Leslie, 1997 ).
      This paper briefly examines each trend, prior to exploring select pedagogical
      implications of these changes for the University of Melbourne, the destination of
      choice by 2001 for 30% of all international students electing to study medicine
      in Australia. Two key questions are addressed: (1) What are the potential
      problems in delivering Western-style medical education to culturally and
      linguistically disparate groups?; (2) What model of international student support
      has been developed by the Faculty of Medicine, Dentistry and Health Sciences at
      the University of Melbourne? The paper suggests the model may have potential
      relevance for other universities, in the context of the accelerating
      globalization of medical education.

PMID- 15203525
TI  - Development of a physician attributes database as a resource for medical
      education, professionalism and student evaluation.
AB  - In the light of the growing interest in professionalism and non-cognitive
      attributes in medical education, a focus group (FG) methodology was used to
      achieve a database of desired physician attributes. Ten FGs, consisting of
      medical faculty, service heads, residents, general practitioners, students and
      patients, took place, producing 169 desired attributes; further attributes were
      derived from a literature search, and the Mission and Vision Statement (MVS) of
      the authors' medical faculty. A total of 254 separate attributes finally emerged,
      after a process of combining and collapsing similar items. Attributes appearing
      with the highest frequency were: honest, empathic, patient, capacity to be an
      attentive listener, understanding, able to work in a team, intellectual
      curiosity, egalitarian. The high number of attributes generated in this study
      provides an indication of what the profession is wanting of itself. This database
      is multipotential and preliminary in nature and requires further processing
      before achieving full relevance.

PMID- 15203526
TI  - Design, delivery and evaluation of an email-based continuing professional
      development course on outdoor air pollution and health.
AB  - The authors designed an email-based discussion forum with the objective of
      promoting and supporting peer discussion on the health effects of outdoor air
      pollution, linked to a recently published review article. Clinical cases served
      as stimulus material and participants were provided with an online toolbox of
      resources. Message postings from 27 participants were most frequent (92) during
      the first of four weeks and lowest (17) during the second, suggesting that some
      participants were overwhelmed by the initial volume. Evaluation of short-term
      impact completed by 16 participants indicated that the course was successful in
      improving some participants' knowledge. Evaluation three months after course
      completion by 20 participants revealed an impact on clinical practice. As an
      alternative to email, requiring participants to visit a web page to view and
      submit postings may avoid problems related to volume of messages. Controlled
      delivery of small portions of information tied to specific self-directed tasks is
      also recommended.

PMID- 15203527
TI  - Curriculum and assessment in higher specialist training.
AB  - Higher Specialist Training (HST) has been radically reformed in the last decade,
      and specialties have been urged to conduct further reform. This paper reports on
      an explorative investigation into curriculum provision and assessment within four
      specialties in the West Midlands. Methods include analysis of curriculum
      documents; observation of the RITA process; and interviews with consultants (4),
      specialist registrars (5) and members of the regional higher specialist training
      management team (3). Three major themes identified within the interviews are
      discussed: the content and use of the curriculum; the impact of service-based
      learning; and issues around assessment.

PMID- 15203528
TI  - A computerized adaptive knowledge test as an assessment tool in general practice:
      a pilot study.
AB  - Advantageous to assessment in many fields, CAT (computerized adaptive testing)
      use in general practice has been scarce. In adapting CAT to general practice, the
      basic assumptions of item response theory and the case specificity must be taken
      into account. In this context, this study first evaluated the feasibility of
      converting written extended matching tests into CAT. Second, it questioned the
      content validity of CAT. A stratified sample of students was invited to
      participate in the pilot study. The items used in this test, together with their
      parameters, originated from the written test. The detailed test paths of the
      students were retained and analysed thoroughly. Using the predefined pass-fail
      standard, one student failed the test. There was a positive correlation between
      the number of items and the candidate's ability level. The majority of students
      were presented with questions in seven of the 10 existing domains. Although
      proved to be a feasible test format, CAT cannot substitute for the existing high
      stakes large-scale written test. It may provide a reliable instrument for
      identifying candidates who are at risk of failing in the written test.

PMID- 15203529
TI  - If formal CME is ineffective, why do physicians still participate?
AB  - Formal or traditional CME can be criticized because organizers often ignore adult
      learning principles when designing courses. Critics also suggest that formal CME
      courses have limited impact on attendees' behaviors and practices. The authors
      agree that attention must be paid to pedagogic principles to assure success of
      educational courses, but feel that the extant negative evidence related to the
      impact of formal CME is narrow in scope and of inadequate strength to seriously
      damn formal approaches. Survey responses were received from 853 practicing
      physicians who say they still regularly attend formal CME courses. They are
      motivated to attend to satisfy specific professional needs and for personal
      reasons. Formal CME is still popular despite what its critics say. The authors
      are convinced that attention to physicians' perceived needs, effective use of
      social marketing strategies, and adherence to adult learning principles can
      assure successful delivery of CME and that formal CME is a useful complement to
      physician-driven informal CME.

PMID- 15203530
TI  - A cardiological web as an adjunct to medical teaching: prospective analysis.
AB  - The aim of the study was to deliver and evaluate an educational web for medical
      students. A web of the complete cardiovascular course was prepared as an adjunct
      educational material for the classes. The use and utility of the web was assessed
      through a questionnaire (frequency of use, impact on in-class attendance and
      students' satisfaction). The number of visits, the time of the week and the hour
      when the web was used were registered. A total of 76 students returned the
      questionnaire. The web was available for 10 weeks and was visited 1062 times,
      especially at weekends. An increase in visits was noted prior to final
      examination. The web was accessed preferentially from the faculty or hospital
      computers. The quality of the web was assessed and rated a mean of 7.7 (score: 1
      10); 93.4% students attended the class, but the web freed them from transcribing
      the contents; 88.2% of students evaluated the web as a useful or very useful
      adjunct to medical teaching. The Internet can be used to deliver learning in
      medical students and could be considered as added value to the pedagogic process
      and did not deter students from attending ordinary classes.

PMID- 15203531
TI  - A virtual reality trauma simulator.
AB  - The authors have evaluated a trauma simulator based on virtual reality
      techniques. Ten surgeons and 15 medical students performed distal locking of a
      femoral nail (A). Furthermore, 10 medical students performed simulated
      osteosynthesis of a femoral neck fracture (B). Total surgery time (A) (mean
      value) was shorter for surgeons (108 s) compared with students (157 s) at the
      first (p = 0.033), second (102 respectively 138 s, p = 0.13) and third (96
      respectively 160 s, p = 0.15) operation. Total fluoroscopy time (A) (mean value)
      was shorter for surgeons compared with students at the first (45 respectively 89
      s, p = 0.001), second (48 respectively 83 s, p = 0.02) and third (50 respectively
      107 s, p = 0.10) operation. The positioning of the hip nails (B) improved between
      the first and last trial. Total surgery and fluoroscopy time were reduced. All
      participants thought that this and similar simulators should be part of the
      programme and that this simulator would be helpful if they were about to learn
      the procedures.

PMID- 15203549
TI  - Age-related differentiations of Th1/Th2 cytokines in newborn infants.
AB  - OBJECTIVE: To evaluate age-related differentiation of immune response in newborns
      by measuring serum concentrations of interleukin-2 (IL-2), interleukin-4 (IL-4)
      and interferon-gamma (IFN-gamma) during the perinatal period. SUBJECTS AND
      METHODS: Fifty-seven healthy term neonates, their mothers and 25 healthy adults
      (controls) age-matched to the mothers were included in the study. Cytokine
      concentrations were measured in the umbilical cord (UC), and in first-day (1N)
      and fifth-day (5N) neonatal samples, compared with those in maternal serum (MS)
      and control serum samples. RESULTS: Serum IL-2 concentrations in the UC were
      markedly elevated compared with those in MS and controls (p < 0.0001), decreasing
      significantly thereafter up to 5N (p < 0.001). IL-4 serum concentrations did not
      differ significantly between the UC, 1N and 5N samples; they were, however,
      markedly elevated compared with those in MS (p < 0.001, p < 0.0007 and p <
      0.0001, respectively) and controls (p < 0.05, p < 0.01 and p < 0.006,
      respectively). IFN-gamma serum concentrations were significantly lower in the UC
      compared with those in controls (p < 0.04), increasing significantly up to 5N (p
      < 0.03). Both IFN-gamma/IL-2 and IFN-gamma/IL-4 ratios increased significantly in
      5N, compared with those in the UC (p < 0.001 and p < 0.03). CONCLUSION: Our
      findings indicate a differential cytokine balance at birth with enhanced
      expression of IL-2 and IL-4 against IFN-gamma. However, a regularization of
      immune response seems to proceed quickly during the early neonatal life.

PMID- 15203548
TI  - The immunoregulatory and allergy-associated cytokines in the aetiology of the
      otitis media with effusion.
AB  - Inflammation in the middle ear mucosa, which can be provoked by different primary
      factors such as bacterial and viral infection, local allergic reactions and
      reflux, is the crucial event in the pathogenesis of otitis media with effusion
      (OME). Unresolved acute inflammatory responses or defective immunoregulation of
      middle inflammation can promote chronic inflammatory processes and stimulate the
      chronic condition of OME. Cytokines are the central molecular regulators of
      middle ear inflammation and can switch the acute phase of inflammation in the
      chronic stage and induce molecular-pathological processes leading to the
      histopathological changes accompanying OME. In this review we present cytokines
      identified in otitis media, immunoregulatory [interleukin (IL)-2, IL-10,
      transforming growth factor-beta]) and allergy associated (IL-4, IL-5, granulocyte
      macrophage colony-stimulating factor), as crucial molecular regulators,
      responsible for chronic inflammation in the middle ear and the chronic condition
      of OME.

PMID- 15203551
TI  - The presence of promatrix metalloproteinase-3 and its relation with different
      categories of coal workers' pneumoconiosis.
AB  - Extracellular matrix formation (ECM) and remodeling are critical events related
      to the pathogenesis of pulmonary fibrosis. Matrix metalloproteinases play an
      essential role in degrading and remodeling the ECM. In this study, we tried to
      show the presence and correlation of promatrix metalloproteinase-3 (proMMP-3)
      (the inactive form of metalloproteinase-3) levels in coal workers' pneumoconiosis
      (CWP) with different categories. The study population consisted of 44 coal miners
      with CWP (pos CWP). Coal miners without CWP (neg CWP, n = 24) and non-underground
      personnel (controls, n = 17) were taken as controls. All coal miners were stable
      and had no systemic infection or disease. Standard posterio-anterior chest
      radiographs and pulmonary function tests were performed to exclude any diseases
      other than CWP. Serum proMMP-3 was analysed using the sandwich enzyme-linked
      immunosorbent assay according to the manufacturer's instructions (The Binding
      Site, Birmingham, UK). Mean proMMP-3 values of the all three groups were compared
      and a significant statistical difference obtained (p < 0.001). In addition, a
      statistically significant difference was found between categories of the disease
      and proMMP-3 values (p < 0.05). The effects of age, exposure duration and
      cigarette smoking on proMMP-3 values in coal miners with CWP were investigated.
      There were no correlations between age, smoking and proMMP-3 values. However, a
      positive correlation was found between exposure duration and proMMP-3 values (r =
      0.447, p = 0.008). In conclusion, proMMP-3 (prostromelysin 1) may play an
      essential role in degrading and remodeling the ECM in workers with
      pneumoconiosis. ProMMP-3 may also reflect the stage of pneumoconiosis disease.

PMID- 15203550
TI  - Involvement of steroids in anti-inflammatory effects of PK11195 in a murine model
      of pleurisy.
AB  - BACKGROUND: Studies on peripheral benzodiazepine receptor function have yielded a
      diverse list of activities of which the anti-inflammatory effects need to be
      further examined. AIMS: To evaluate the role of steroids, nitric oxide and
      adenosine-deaminase in the anti-inflammatory effect of PK11195. METHODS: Pleurisy
      was induced by intrapleural injection of carrageenan in mice pre-treated or not
      with PK11195. Leukocytes, exudation, adenosine-deaminase (ADA) activity and
      nitric oxide (NO) level were measured. Steroid involvement was evaluated by pre
      treatment with D,L-aminogluthetimide before PK11195. RESULTS: Leukocytes,
      exudation and NO levels were reduced by PK11195 in the early (4 h) phase. In the
      late (48 h) phase, PK11195 decreased leukocytes and ADA activity. D,L
      aminogluthetimide reversed the effect of PK11195 on exudate (4 h), as well as
      total and differential leukocytes and NO levels (48 h). CONCLUSIONS: Steroids, NO
      and ADA are implicated in the anti-inflammatory action of PK11195.

PMID- 15203552
TI  - Anti-inflammatory and immunomodulating effects of clarithromycin in patients with
      cystic fibrosis lung disease.
AB  - BACKGROUND AND AIM: Macrolide antibiotics are widely used in the treatment of
      suppurative lung diseases including cystic fibrosis (CF), the most common
      inherited fatal disease in the Caucasian population. This condition is
      characterized by secondary Pseudomonas infection resulting in neutrophil
      infiltration within the airways. The aim of the study was to investigate the
      evolution of inflammatory process in CF patients receiving long-term
      clarithromycin therapy. METHODS: Twenty-seven CF patients (mean age, 12 years)
      were enrolled into the study. Beside the basic therapy the patients were treated
      with clarithromycin at a dose of 250 mg every other day orally. All patients were
      routinely examined every 3 months. Blood and sputum were collected before
      clarithromycin treatment and then again 3, 6 and 12 months after the drug
      prescription. Cytokine concentrations (tumor necrosis factor-alpha, interleukin
      8, interleukin-4, interferon-gamma) in the sputum and plasma were assayed.
      Peripheral blood lymphocyte response to phytohemagglutinin was also evaluated.
      RESULTS: Clarithromycin treatment resulted in a marked reduction of the cytokine
      levels both in the sputum and plasma specimens. At the same time, the interferon
      gamma/interleukin-4 ratio has been significantly elevated. In addition, a
      sustained increase of peripheral blood lymphocyte response to phytohemagglutinin
      was demonstrated. These changes were associated with a significant improvement of
      the lung function. CONCLUSIONS: The beneficial effect of the prolonged treatment
      of CF patients with a 14-membered ring macrolide antibiotic clarithromycin seems
      to be associated not only with down-regulation of the inflammatory response, but
      also with immunological changes including the switch from Th2 to Th1 type
      response.

PMID- 15203553
TI  - Effect of glucose concentration on peritoneal inflammatory cytokines in
      continuous ambulatory peritoneal dialysis patients.
AB  - OBJECTIVE: It is known that glucose concentrations of peritoneal dialysis
      solutions are detrimental to the peritoneal membrane. In order to determine the
      effect of glucose concentration on cytokine levels of peritoneal fluid of
      continuous ambulatory peritoneal dialysis (CAPD) patients, a cross-sectional
      study was performed. METHODS: Nine non-diabetic CAPD patients participated in two
      8-h dwell sessions of overnight exchanges in consecutive days, with 1.36% and
      3.86% glucose containing peritoneal dialysis solutions (Baxter-Eczacibas).
      Peritoneal dialysis fluid tumor necrosis factor (TNF)-alpha and interleukin (IL)
      6 levels were measured. RESULTS: TNF-alpha levels after 1.36% and 3.86% glucose
      used dwells were 23+/-14 pg/ml and 28+/-4 pg/ml, respectively (p=0.78). The IL-6
      levels were 106+/-57 pg/ml and 115+/-63 pg/ml (p=0.81), respectively. CONCLUSION:
      In our in vivo study we found that the glucose concentration of the conventional
      lactate-based CAPD solution has no effect on basal IL-6 and TNF-alpha levels of
      peritoneal fluid. Further in vivo studies with non-lactate-based CAPD solutions
      are needed in order to determine the effect of glucose concentration per se on
      cytokine release.

PMID- 15203554
TI  - Zymosan-induced luminol-dependent chemiluminescence response of circulating and
      extravasated leukocytes in experimental sepsis.
AB  - This study examines a concurrent profiling of circulating and extravasated
      polymorphonuclear leukocytes (PMNs) in a rat model of experimental sepsis. Fecal
      peritonitis was induced in Wistar male rats by intraperitoneal instillation of a
      fecal suspension in saline (1:1 w/v). Blood and peritoneal fluid were collected 8
      h following fecal inoculation for the evaluation of inflammatory response of PMNs
      using zymosan-induced luminol-dependent chemiluminescence. Fifty microliters of
      pre-diluted blood or peritoneal fluid samples were mixed with 150 microl of
      reaction mixture (4 x 10(-4) M luminol+50 microg opsonized zymosan+0.1% gelatin
      in Hank's balanced salt solution) and the chemiluminescence signal was measured
      in a luminometer at 37 degrees C. Fecal peritonitis caused a significant
      leukocytopenia (3540+/-297 mm(-3) versus control value of 7525+/-711 mm(-3), p <
      0.001) accompanied by massive infiltration of PMNs in the peritoneal cavity
      (34700+/-4006 versus 7325+/-425 mm(-3), p < 0.001). The phagocytic activity of
      circulating blood PMNs was down-regulated whereas a significant up-regulation was
      observed in the activity of PMNs from peritoneal fluid. In conclusion, this study
      clearly demonstrates sepsis-induced alterations in both blood and peritoneal
      fluid PMNs and their quantitative assessment may be helpful in disease evaluation
      and designing effective therapies.

PMID- 15203555
TI  - Use of caffeic acid phenethyl ester and cortisone may prevent proliferative
      vitreoretinopathy.
AB  - PURPOSE: To investigate whether caffeic acid phenethyl ester (CAPE) and cortisone
      prevent proliferative vitreoretinopathy (PVR). METHODS: Twenty pigmented rabbits
      were used in this study. All rabbits except controls received an intravitreal
      injection of 0.15 ml (75,000 U) of platelet-rich plasma into their left eye. The
      animals were divided into four groups: group I was treated with intraperitoneal
      injection of 0.5 ml (15 micromol/kg) of CAPE for 3 days, group II received 0.15
      ml (4 mg/kg) of intravitreal cortisone, group III received nothing (blank group),
      and group IV (control group) received only 1 ml of 1% ethanol intraperitoneally
      daily for 3 days. Proliferative changes were graded in a masked fashion by
      indirect ophthalmoscopy for a 15-day follow-up period. The malondialdehyde (MDA),
      reduced glutathione (GSH) and total nitrite (NO) levels were measured in the
      vitreous humor. RESULTS: The grades of PVR were B-C in group I, and C-D in group
      II. The PVR grade in the control group was C-D. The mean MDA level in group I
      (4.0+/-0.8 micromol/l) was significantly lower than in the blank group (6.0
      micromol/l) (p < 0.05). The mean GSH level in group I (71.0+/-11.2 micromol/l)
      was significantly different than in the blank group (p < 0.05). The MDA and GSH
      levels in group II were 4.7+/-0.6 micromol/l and 53.8+/-7.8 micromol/l,
      respectively. Both these levels were not significantly different from the blank
      group (p > 0.05). The NO levels in both treatment groups were significantly lower
      than in the blank group (p < 0.001). CONCLUSION: These findings suggest an
      inhibitory effect of CAPE on PVR. The inhibitory effect was supported by lower
      MDA and NO with higher GSH levels in treatment groups than in the blank group.
      There was no detected significant effect of cortisone for preventing PVR
      experimentally.

PMID- 15203557
TI  - Significance of NOx concentration in red blood cells.

PMID- 15203556
TI  - Salivary levels of tumor necrosis factor-alpha in oral lichen planus.
AB  - OBJECTIVE: Oral lichen planus (OLP) is chronic inflammatory disease of the oral
      mucosa, presenting in various clinical forms. The etiology of OLP is still
      unknown but mounting evidence points to the immunologic basis of this disorder.
      AIM: Our study was undertaken to quantify the salivary levels of pro-inflammatory
      tumor necrosis factor-alpha (TNF-alpha) in the reticular and the erosive/atrophic
      forms of OLP, compared with age-matched healthy control volunteers. SUBJECTS AND
      METHODS: Whole saliva from 40 patients with active lesions of OLP, as well as
      from 20 healthy persons, was investigated for the presence of TNF-alpha by enzyme
      immunoassay. RESULTS: Salivary TNF-alpha levels were significantly increased in
      patients with OLP in comparison with healthy subjects. The presence of TNF-alpha
      showed positive correlation to clinical forms of OLP, being significantly higher
      in the erosive/atrophic type than in the reticular type of disease. CONCLUSION:
      Saliva provides an ideal medium for the detection of pro-inflammatory markers of
      the oral cavity. In patients with OLP, TNF-alpha levels in saliva are elevated,
      correlating with the severity of illness. Salivary TNF-alpha analysis may be a
      useful diagnostic tool and a potential prognostic marker in OLP.

PMID- 15203558
TI  - Ozone as Janus: this controversial gas can be either toxic or medically useful.
AB  - Ozone is an intrinsically toxic gas and its hazardous employment has led to a
      poor consideration of ozone therapy. The aim of this review is to indicate that a
      wrong dogma and several misconceptions thwart progress: in reality, properly
      performed ozone therapy, carried out by expert physicians, can be very useful
      when orthodox medicine appears inadequate. The unbelievable versatility of ozone
      therapy is due to the cascade of ozone-derived compounds able to act on several
      targets leading to a multifactorial correction of a pathological state. During
      the past decade, contrary to all expectations, it has been demonstrated that the
      judicious application of ozone in chronic infectious diseases, vasculopathies,
      orthopedics and even dentistry has yielded such striking results that it is
      deplorable that the medical establishment continues to ignore ozone therapy.

PMID- 15203559
TI  - Protection by ozone preconditioning is mediated by the antioxidant system in
      cisplatin-induced nephrotoxicity in rats.
AB  - BACKGROUND: Acute renal failure is a dose-limiting factor of cisplatin
      chemotherapy. Here, we show the protective effect of ozone oxidative
      preconditioning against cisplatin-induced renal dysfunction in rats. Ozone
      oxidative preconditioning is a prophylactic approach, which favors the
      antioxidant-pro-oxidant balance for preservation of the cell redox state by
      increasing antioxidant endogenous systems in various in vivo and in vitro
      experimental models. AIMS: To analyze the protective role of ozone oxidative
      preconditioning against cisplatin-induced nephrotoxicity. METHODS: Male Sprague
      Dawley rats were pretreated with 15 intrarectal applications of ozone/oxygen
      mixture at 0.36, 0.72, 1.1, 1.8 and 2.5 mg/kg before cisplatin intraperitoneal
      injection (6 mg/kg). Serum and kidneys were extracted and analyzed 5 days after
      cisplatin treatment for determinations of the renal content of glutathione,
      thiobarbituric acid-reactive substances, renal concentration and enzymatic
      activities of catalase, superoxide dismutase and glutathione peroxidase. RESULTS:
      Ozone pretreatment prevented the increase in serum creatinine levels, the
      glutathione depletion and the inhibition of superoxide dismutase, catalase and
      glutathione peroxidase activities induced by cisplatin in the rat kidney. Also,
      the renal content of thiobarbituric acid-reactive substances was decreased by
      ozone therapy. These protective effects of ozone were dose dependent.
      CONCLUSIONS: Intrarectal ozone therapy prevented effectively the renal
      antioxidant unbalance induced by cisplatin treatment.

PMID- 15203560
TI  - Suppression of neutrophil recruitment in mice by geranium essential oil.
AB  - BACKGROUND: In aromatherapy, essential oils are used as anti-inflammatory
      remedies, but experimental studies on their action mechanisms are very limited.
      AIMS OF THE STUDY: To assess their anti-inflammatory activities, the effects of
      essential oils on neutrophil recruitment in mice were examined in vivo. METHOD:
      The effect of essential oils on leukocyte and neutrophil recruitment induced 6 h
      after intraperitoneal injection of casein in mice was examined. RESULTS:
      Leukocyte recruitment into the peritoneal cavity in mice was suppressed by
      intraperitoneal injections of geranium, lemongrass and spearmint oils at the dose
      of 5 microl/mouse, but was not by tea tree oil. This recruitment was inhibited
      dose-dependently by geranium oil. The suppression of leukocyte recruitment
      resulted from inhibition of neutrophil accumulation. CONCLUSION: Some essential
      oils used as anti-inflammatory remedies suppress neutrophil recruitment into the
      peritoneal cavity in mice.

PMID- 15203561
TI  - Serum levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 are
      not increased in dyspeptic patients with Helicobacter pylori-associated
      gastritis.
AB  - INTRODUCTION: Helicobacter pylori (H. pylori) is a non-invasive microorganism
      causing intense gastric mucosal inflammatory and immune reaction. H. pylori
      induced gastric mucosal cytokine overproduction has been clearly documented
      previously. The stomach has a large surface area and continuous spill-over of
      locally produced cytokines into the blood stream is a possibility. There are few
      and conflicting data on circulatory proinflammatory cytokine levels in patients
      with H. pylori infection. MATERIALS AND METHODS: Forty-two dyspeptic patients
      were enrolled into the study. The presence of H. pylori infection was diagnosed
      with antral histopathologic examination. After overnight fasting; serum samples
      were obtained from each patient to determine circulating interleukin (IL)-6, IL-8
      and tumor necrosis factor-alpha (TNF-alpha) levels. RESULTS: H. pylori was shown
      in 30 cases using Giemsa stain in antral histopathologic evaluation. Twelve cases
      were negative for H. pylori staining. Both the age and sex distribution had an
      insignificant difference in both H pylori-positive and H. pylori-negative groups.
      The mean circulatory levels of IL-6, IL-8 and TNF-a in both groups were not
      different. The situation was same in respect to the serum levels of these
      cytokines and the degree of inflammation, H. pylori density and activation scores
      according to Sydney classification. CONCLUSION: We could not show elevated
      circulatory levels of IL-6, IL-8 and TNF-alpha in H. pylori-infected cases. We
      believe that H. pylori-related cytokine activation become concentrated on gastric
      mucosa and this pathogen-induced local inflammatory cascade does not cause
      changes in circulatory levels of these cytokines. Moreover, there is no
      correlation between the levels of serum cytokines and Sydney parameters.

PMID- 15203562
TI  - Subpopulations of mononuclear leukocytes associated with inhibition of Ehrlich
      ascites tumor growth by treatment with Bothrops jararaca venom.
AB  - Snake venoms have been used as antineoplastic substances in several experimental
      models. We demonstrated in previous studies that Bothrops jararaca venom (BjV)
      induces inhibition of Ehrlich ascites tumor (EAT) growth accompanied by an
      increase of mononuclear (MN) leukocytes in all groups inoculated with EAT and/or
      venom. The objective of the present study was to characterize the subpopulations
      of MN leukocytes involved in the inhibition of EAT growth by treatment with BjV.
      Swiss mice were inoculated with 1.0x10(3) EAT cells by the intraperitoneal route
      and treated with 0.4 mg/kg of BjV by the same route (Group TV). Treatment was
      started 24 h after tumor cell inoculation and consisted of five intraperitoneal
      injections performed at 72 h intervals. After 2, 8 and 14 days, groups of animals
      were sacrificed and the number of B, TCD4 and TCD8 lymphocytes, macrophages and
      natural killer cells present in the peritoneal cavity was determined by flow
      cytometry. The control group consisted of animals inoculated with EAT and treated
      with 0.1 ml of saline under the same conditions as the experimental group (Group
      T). Two additional control groups consisted of animals not inoculated with EAT
      and treated with saline or venom. Data were analyzed statistically by the Kruskal
      Wallis non-parametric test for independent samples. On the 2nd and 8th day we
      observed a difference between groups T and TV (group T > group TV) for all cell
      types, except natural killer cells, that only differed on the 2nd day. However,
      on the 14th day there was no difference in MN cells among groups. These data
      suggest that the inhibition of EAT is related to the toxic action of BjV on tumor
      cells and/or to the proteolytic effect of the venom on the mediators produced by
      the cells for growth modulation.

PMID- 15203563
TI  - Analysis of leukocyte rolling and migration--using inhibitors in the undisturbed
      microcirculation of the rat mesentery--on inflammatory stimulation.
AB  - AIM: Our aim was to develop a method of migration analysis using the undisturbed
      microcirculation of rat mesentery, and using the new method, analyze leukocyte
      migration in casein-induced inflammation. METHOD: Sprague Dawley (SD) rats were
      injected with tumor necrosis factor (TNF) alpha, interleukin (IL)-1alpha, or
      casein intraperitoneally. Following this, the rats were sacrificed and the
      mesentery tissue removed was fixed and stained with Giemsa. The leukocytes were
      counted as a rolling index in the venules and as a migration index in the
      perivascular area. RESULTS: There was no relation between the diameter of venules
      and leukocyte migration. The time change curves of leukocyte activity in casein
      inflammation show about a 1 h difference between rolling and migration. From
      inhibitor experiments of casein-induced migration at 2 h, it has been suggested
      that selectin-related rolling is necessary. Platelet-activating factor (PAF) also
      appears partially involved. CONCLUSION: The improved undisturbed microcirculation
      method is helpful not only for rolling analysis but also in analysis of leukocyte
      migration. Casein inflammation analyzed using this method revealed that rolling
      is necessary and also suggested that partial involvement of PAF is necessary for
      pathogenesis of leukocyte extravasations.

PMID- 15203564
TI  - Monocyte chemoattractant protein-1 in patients with peripheral arterial disease.
AB  - BACKGROUND: Chemokine-driven migration of inflammatory cells has been implicated
      in the pathogenesis of atherosclerotic conditions including peripheral arterial
      disease (PAD). Monocyte chemoattractant protein-1 (MCP-1) is elevated in patients
      with coronary artery disease and in hypertensive patients. This study therefore
      investigated MCP-1 in patients with PAD. METHODS: Serum MCP-1 was determined by
      enzyme-linked immunosorbent assay in 36 healthy, control subjects and in 19
      patients with PAD. Statistical analysis utilised the Mann-Whitney test and
      Spearman correlation (p < 0.05). RESULTS: MCP-1 (pg/ml) was increased in patients
      compared with in controls (mean+/-standard error of the mean: PAD group, 748+/
      60; control group, 459+/-27; p=0.0001). MCP-1 levels tended to decrease with
      progressing disease. From atherosclerosis risk factors, diabetes inclined to
      increase MCP-1 levels; hypertension had no effect. Serum MCP-1 correlated with
      cholesterol, triglycerides, low-density lipoprotein but not high-density
      lipoprotein. CONCLUSION: Elevation of MCP-1 in the circulation of PAD patients
      shown in the present pilot study implicates this CC chemokine ligand 2 in
      inflammatory processes contributing to PAD clinical symptomatology. Further
      investigations are necessary to evaluate whether MCP-1 can be used as a potential
      marker of peripheral arterial disease follow-up and/or prognosis.

PMID- 15203565
TI  - Secretion of interleukin-8 by human-derived cell lines infected with
      Mycobacterium bovis.
AB  - BACKGROUND: The variable efficacy of bacillus Calmette-Guerin (Mycobacterium
      bovis BCG) in protecting humans against tuberculosis has prompted a search for
      the mechanisms through which BCG induces chemokines. In this study, our
      experiments were designed to determine the role of the transcription factor
      nuclear factor-kappaB (NF-kappaB) and intracellular calcium in the production of
      interleukin (IL)-8, a main chemotactic factor, by human-derived monocytic cell
      line U937 and by a human epithelial HEp-2 cell line infected with M. bovis BCG.
      METHODS: The concentrations of IL-8 in culture supernatants of U937 cells or HEp
      2 cells infected with M. bovis BCG were determined by enzyme-linked immunosorbent
      assay. We used sulfasalazine and curcumin, which are well-described inhibitors of
      NF-kappaB activity, and we used ethylenediamine tetraacetic acid to deplete
      extracellular Ca2+ or used the cell-permeable agent 1,2-bis (2-aminophenoxy)
      ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester to chelate
      releasable intracellular stores of Ca2+ in order to investigate the mechanisms
      through which M. bovis BCG induces IL-8 secretion in our system. RESULTS: The
      enzyme-linked immunosorbent assay showed that IL-8 protein secretion was elevated
      in M. bovis-infected cell lines. This effect was statistically significant (p <
      0.01). When calcium influx was suppressed in M. bovis-infected cell lines, IL-8
      secretion was inhibited. Notably, specific inhibitors of NF-kappaB (sulfasalazine
      and curcumin) inhibited M. bovis-induced IL-8 secretion from U937 cells or HEp-2
      cells. CONCLUSIONS: Collectively, these results indicate that activation of NF
      kappaB is an important signal transduction pathway in M. bovis-induced IL-8
      secretion in monocytic or epithelial cells. Furthermore, the results showed that
      calcium influx had a direct effect on IL-8 secretion in U937 cells or HEp-2 cells
      infected with M. bovis.

PMID- 15203566
TI  - Tissue-specific down-regulation of RIPK 2 in Mycobacterium leprae-infected nu/nu
      mice.
AB  - RIPK 2 is adapter molecule in the signal pathway involved in Toll-like receptors.
      However, there has been no reported association between receptor-interacting
      serine/threonine kinase 2 (RIPK 2) expression and the infectious diseases
      involving mycobacterial infection. This study found that its expression was down
      regulated in the footpads and skin but was up-regulated in the liver of
      Mycobacterium leprae-infected nu/nu mice compared with those of the M. leprae non
      infected nu/nu mice. It was observed that the interlukin-12p40 and interferon
      gamma genes involved in the susceptibility of M. leprae were down-regulated in
      the skin but were up-regulated in the liver. Overall, this suggests that
      regulation of RIPK 2 expression is tissue-specifically associated with M. leprae
      infection.

PMID- 15203567
TI  - Elevated plasma phospholipase A2 and platelet-activating factor acetylhydrolase
      activity in colorectal cancer.
AB  - This clinical study reports that blood levels of the pro-inflammatory mediator
      platelet-activating factor (PAF) did not change in colorectal cancer patients. In
      contrast, plasma levels of two enzymatic activities, one implicated in PAF
      production (i.e. phospholipase A2) and one in PAF degradation (i.e. PAF
      acetylhydrolase activity) were significantly elevated.

PMID- 15203568
TI  - Abstracts from a congress organized by the Groupe de Recherche et d'Etude des
      Mediateurs de I'Inflammation. March 26, 2004. Paris, France.

PMID- 15203569
TI  - Cremation of body parts and fetuses.
AB  - Crematoria are occasionally asked to cremate non-viable fetuses. Many doctors,
      especially those associated with crematoria, believe that there will be no
      cremated residue. However, if the cremation technique is modified, cremated
      remains are produced. These remains can form a focal point for the parent's
      grief. Crematoria are urged to ensure their technique yields a residue.

PMID- 15203570
TI  - The accuracy of risk scores in predicting preterm birth--a systematic review.
AB  - This review aims to determine the accuracy with which published risk scores
      predict spontaneous preterm birth in pregnant women. Studies were identified
      without language restrictions through nine different databases (up to June 2002),
      and manual searching of bibliographies of known primary and review articles. Two
      reviewers selected studies independently and extracted data on their
      characteristics, quality and accuracy. Accuracy data were used to form 2 x 2
      contingency tables of the results of risk scoring with spontaneous preterm birth
      as the reference standard. Heterogeneity was assessed and its reasons were
      explored. Summary estimates of accuracy were produced within clinically
      appropriate subgroups. There were 19 primary accuracy articles that met the
      selection criteria, including a total of 67390 women. There are 12 different risk
      scoring systems, the one developed by Creasy being the most commonly evaluated.
      Quality features of an ideal study, such as blinding and consecutive enrolment,
      were frequently missing from the included studies, no study fulfilled all
      criteria for high quality study, and there was heterogeneity between their
      accuracy estimates. The reference standard most often used was birth before 37
      weeks' gestation. The point estimates for the likelihood ratios (LRs) varied
      widely among the studies. LRs for an abnormal score (LR+) ranged from 1.0 (95%
      confidence interval (CI) 0.6-1.4) to 38.8 (95% CI 23.5-63.9) while that for a
      normal score (LR-) ranged from 0.1 (95% CI 0.02-0.6) to 1.2 (95% CI 0.9-1.6). In
      otherwise asymptomatic women, risk scoring in early pregnancy has a wide range of
      accuracy in predicting spontaneous preterm birth before 37 weeks' gestation. The
      evidence is of a relatively poor quality and lacks clinically important reference
      standards.

PMID- 15203571
TI  - A free-standing low-risk maternity unit in the United Kingdom: does it have a
      role?
AB  - This study aimed to evaluate the safety of this birth setting for low-risk
      deliveries based on our hospital protocol. The study was carried out at
      Heatherwood Hospital, Ascot (a low-risk unit) and Wexham Park Hospital, Slough,
      Berkshire (a consultant-led unit). This was a retrospective analysis of the
      computerised records and statistics of low-risk women delivered at Heatherwood
      Hospital, Ascot, UK following the unit protocol between July 1995 and December
      2001. Women were assessed to be at low risk in accord with the unit protocol.
      Those who had antenatal and intrapartum care at Heatherwood Hospital and those
      who were transferred to the consultant unit for delivery were included in this
      study. We analysed the appropriateness of the structure of the unit with its
      medical staff input, reviewed the inclusion and exclusion criteria, analysed the
      perinatal and maternal mortality rates and evaluated the safety of this birth
      setting. We have had a total of 5468 women delivered at this low-risk maternity
      unit since the unit was opened. Approximately 1950 women were transferred to
      consultant care during this period. The intrapartum transfer in the first 18
      months was 7.9%. However, since 1997 it has been static at 2.7% as confidence has
      grown in this model of care. The antenatal transfer rate has been static around
      23%. Our emergency caesarean section rate was around 6% and the normal delivery
      rate was around 85%. For the first time we noted a rise in the emergency
      caesarean rate in 2001 at 9.5%. There were no maternal deaths. We had no serious
      postpartum complications accounting for long-term maternal morbidity. The
      antepartum stillbirths accounted for the majority of the perinatal mortality for
      19/23 babies. Intrauterine growth retardation accounted for 4/23 babies in this
      group. The perinatal mortality rate in this low-risk population was 4.2 per 1000
      total births and the stillbirth rate was 3.6 per 1000 total births. We conclude
      that this birth setting is safe to deliver low-risk women with less intrapartum
      intervention and a low transfer rate and should be setting an example for any
      future similar birth centre in this country.

PMID- 15203572
TI  - Pregnancy-associated morbidity in Northern Nigeria.
AB  - We sought to determine the magnitude and spatio-temporal pattern of maternal
      morbidity in Kano State, Nigeria. Analysis was on deliveries within the period
      1990-1999. We counted 59772 maternal complications among 171621 deliveries,
      yielding an overall maternal morbidity ratio of 34.8%. We observed yearly
      variations and increment in the number of complications among mothers (p=0.04). A
      total of 4154 maternal deaths were registered within the period. The level of
      maternal deaths correlated significantly with burden of morbidity (r=0.44;
      p=0.0008). Case fatality rate was 6.9% with temporal fluctuations, and wide
      variations among the various health institutions. Our study revealed an extremely
      high morbidity ratio, which indicates that a high proportion of pregnant mothers
      are in need of essential obstetric care in this population.

PMID- 15203573
TI  - Emergency peripartum hysterectomy in a Nigerian hospital: a 20-year review.
AB  - Postpartum haemorrhage is a major cause of maternal morbidity and mortality and
      occasionally severe enough to warrant hysterectomy to prevent maternal death.
      Hysterectomy often is fraught with danger and regular audit is necessary to
      assist in the reduction of these dangers. A 20-year audit of all emergency
      peripartum hysterectomies, performed at Havana Specialist hospital Lagos,
      Nigeria, is reported. Of the 6599 deliveries and peripartum referrals seen during
      the period, 22 had an emergency hysterectomy as a result of severe postpartum
      haemorrhage (0.33%). The aetiological factors associated with the postpartum
      haemorrhage included uterine atony (45.5%), placenta praevia (27.3%),
      pathologically adherent placenta (18.2%) and ruptured uterus (9.1%). The majority
      of the procedures were subtotal hysterectomy (81.8%) and the mean operative time
      was significantly shorter than for total hysterectomy (P<0.05). The postoperative
      complications included postoperative anaemia (28.6%), febrile morbidity (36.9%),
      wound infection (19.0%) and urinary tract infection (9.5%), together with three
      maternal deaths. In conclusion, emergency peripartum hysterectomy, although life
      saving, is associated with severe morbidity and mortality and subtotal
      hysterectomy is usually the operation of choice.

PMID- 15203574
TI  - Maternal serum screening for trisomy 21 in women with a false positive result in
      last pregnancy.
AB  - Maternal serum screening for Down syndrome is a common practice in the United
      Kingdom. A number of factors have been shown to influence the chance of a false
      positive test result. Analysis of routinely collated information stored on an
      electronic database in a district general hospital has shown that women with a
      previous false positive maternal screen are at much greater chance of having a
      false positive result in their next pregnancy. Overall, there was a fivefold
      increased risk attributed to biological variation in their serum concentrations
      of alpha-feto protein (AFP) and human chorionic gonadotrophin (hCG). The
      potential effect of this was to increase the chance of such women having an
      unnecessary amniocentesis. Women should be advised of this effect in subsequent
      pregnancies. Ideally a correction factor should be applied which would reduce the
      false positive rate without affecting adversely the sensitivity of the test.

PMID- 15203575
TI  - The rise in caesarean birth rate in Sagamu, Nigeria: reflection of changes in
      obstetric practice.
AB  - A retrospective and comparative study of women delivered by caesarean section
      over two different 3-year periods was conducted at Olabisi Onabanjo University
      Teaching Hospital, Sagamu, Nigeria. The caesarean section rate (CSR) increased
      from 10.3% in 1989-1991 to 23.1% in 2000-2003. The most frequent indication in
      both periods was different: prolonged/obstructed labour (20.0%) in 1989-1991 and
      antepartum haemorrhage (14.9%) in 2000-2003. Malpresentation, antepartum
      haemorrhage and pre-eclampsia/eclampsia were responsible for 51.7% of the
      difference in the CSR recorded between both periods. The CSR rose from 13.3% to
      25.0% while the instrumental vaginal delivery (IVD) rate decreased significantly
      by 11.4% among the nulliparous women between the periods. Increase in CSR can be
      attributed mainly to reduction in IVD rate and alteration in the management of
      labour complications and induction policy. Strategies to reduce the CSR should
      cut across all indications and focus on encouraging instrumental vaginal
      deliveries, especially among nulliparous women.

PMID- 15203576
TI  - A randomised controlled trial of insulin lispro given before or after meals in
      pregnant women with type 1 diabetes--the effect on glycaemic excursion.
AB  - In order to study the glucose excursion associated with pre- and postprandial
      administration a randomised controlled trial with patients randomised to receive
      insulin lispro (IL) immediately before or after a standardised meal was
      performed. Pregnant women with diabetes who were treated with IL as part of a
      basal bolus regime were asked to bring their own usual lunch and administer their
      own IL. Maternal glycaemia was monitored preprandially and then at 15-minute
      intervals for 3 hours following the first bite of lunch. Glucose excursions were
      calculated by subtracting the preprandial glucose level from the subsequent
      values at each time point. Each woman was invited to attend on four occasions. On
      two random occasions she was asked to administer her IL after completing her meal
      and on two occasions IL was administered immediately before her meal. Nine women
      completed a total of 27 meals (14 preprandial IL and 13 postprandial IL). There
      was no significant difference between the mean (SD) fasting values between the
      two groups, before 5.8 (2.8) and after 5.7 (2.0) mmol/l. At each time-point there
      was no significant difference between the mean blood glucose excursion in the two
      groups. No patient suffered a hypoglycaemic attack and there was no evidence of
      fetal compromise. In the two groups there was a marked similarity in the glycemic
      excursion following a standard meal, whether or not IL was given before or after
      eating. Postprandial administration of IL may increase the flexibility of IL
      usage in pregnant women with diabetes.

PMID- 15203577
TI  - Audit of severe acute morbidity in hypertensive pregnancies in a developing
      country.
AB  - The aim of this study was to establish a population-based incidence of severe
      acute maternal morbidity (SAMM) in hypertensive pregnancies and to assess if
      substandard care was unique to cases of SAMM and mortality or whether it was
      apparent in uncomplicated pregnancies as well. The population-based incidence of
      hypertension was 12%. Using defined criteria for SAMM, the incidence of SAMM was
      3/1000 deliveries. The MMR was 42/100000 deliveries, i.e. SAMM is seven times
      greater than the mortality. Substandard care was similar in cases of SAMM and
      mortality and uncomplicated hypertensive patients. Audit of SAMM is informative,
      can be conducted more frequently, and in small sample population groups. It also
      allows interviews of patients, hence problems of inefficient documentation is
      obviated.

PMID- 15203578
TI  - Thromboprophylaxis for caesarean section--how can uptake and coverage be
      improved?
AB  - The objective of this study was to determine the proportion of patients requiring
      thromboprophylaxis and evaluate adherence to local protocols on
      thromboprophylaxis after caesarean section. This was a retrospective audit of 200
      consecutive patients undergoing caesarean section between January and March 2002.
      The study was carried out at two obstetric units in Hull. We evaluated the
      proportion of patients requiring prophylaxis, appropriate and inappropriate
      treatment given and those omitted from receiving prophylaxis. Adherence to a risk
      assessment protocol was also assessed. The majority of women (84.5%) had at least
      one risk factor for thromboembolism. Use of a checklist did not increase the
      appropriate use of thromboprophylaxis and did not reduce inappropriate use. The
      checklist was used appropriately in only 54% of cases. Thromboprophylaxis has not
      been associated with problems if given after operation, thus the inappropriate
      administration is probably not a serious mistake. Universal prophylaxis with low
      molecular weight heparin would prevent at-risk women being missed and should be
      considered.

PMID- 15203579
TI  - Poor obstetric performance of teenagers: is it age- or quality of care-related?
AB  - We studied prospectively the effect of antenatal care on the obstetric
      performance of teenagers seen at a university teaching hospital over a 14-month
      period. When the obstetric complications among the teenagers were compared to
      their older counterpart, there were significantly higher complication rates,
      especially anaemia, preterm delivery, low birth weight and neonatal admission.
      After controlling for utilisation of antenatal care, significant differences were
      observed only in the incidence of low birth weight babies. In conclusion, this
      study has shown that the poor obstetric outcome of teenage pregnancy is related
      to non-utilisation of prenatal care rather than their biological age.

PMID- 15203580
TI  - The first 18 months of a new perineal trauma clinic.
AB  - Anal incontinence after childbirth is both distressing and disabling. A perineal
      trauma clinic was set up at the Birmingham Women's Hospital with an obstetrician,
      a urogynaecologist and a colorectal surgeon to improve the follow-up of women
      with obstetric anal sphincter injury or childbirth-precipitated anal
      incontinence. Fifty-five women attended the clinic. Forty-one had sustained a
      recognised obstetric anal sphincter injury at delivery and of these women, 61%
      were symptomatic with 22% leaking solid or liquid faeces. Fourteen women attended
      with anal incontinence who had not been recognised as sustaining an anal
      sphincter injury at the time of delivery. Eleven women were offered a secondary
      surgical repair of their anal sphincter defect. Seven accepted surgical treatment
      and 85% (six) were continent following surgery. A perineal trauma clinic offers
      an opportunity for early assessment and reduction of morbidity from childbirth
      related anal incontinence.

PMID- 15203581
TI  - Carcinoma of the vulva: a retrospective review of 37 cases at a regional cancer
      centre in South India.
AB  - A retrospective review of 37 cases of carcinoma of the vulva presenting between
      1996 and 2000 has been carried out. Thirty-three cases were managed with curative
      intent and four cases with advanced loco-regional disease were managed with
      palliative intent. The surgical treatment consisted of wide excision in one case,
      radical vulvectomy (RV) in six cases, radical vulvectomy and bilateral groin node
      dissection (RV+BGND) in 25 cases and radical vulvectomy and unilateral groin node
      dissection in one case. Nine of these 33 women also received adjuvant
      chemotherapy preoperatively in the hope of achieving better tumour-free surgical
      margins. Eight cases had a partial response and one case achieved complete
      response; the surgical margins were free in all these patients. One case received
      neoadjuvant radiotherapy to the vulva and pelvis followed by RV+BGND, which
      revealed no residual tumour. Overall, 26/33 cases had groin/inguinal node
      dissection and 23 (88.4%) of them had groin wound dehiscence. Thirteen of these
      26 patients (50%) had inguinal node metastases (Stage III, four patients; Stage
      IV, nine patients). All the patients with negative nodes were free of disease
      while three of four patients with Stage III and two of nine patients with Stage
      IV with nodal metastases remained free of disease. The only patient with Stage
      III disease plus inguinal node metastases who recurred had multiple positive
      nodes with extracapsular spread. It appears that although bilateral involvement
      of the inguinal lymph nodes carries a worse prognosis, unilateral involvement
      with or without vaginal involvement carries an excellent prognosis provided
      multiple nodes are not involved. The role of neoadjuvant chemotherapy as compared
      to neoadjuvant radiotherapy, in locally advanced tumours, needs to be explored
      further.

PMID- 15203582
TI  - The pathophysiology of an enterocele and its management.
AB  - This paper describes 130 patients with enteroceles and their treatment. It
      includes analysis of all cases with enterocele over a 17-month period in a pelvic
      floor dysfunction database. Procedures performed included the Moschcowitz
      procedure with suspension of the vaginal vault to the sacrum in 13 patients
      (10%), colposacrosuspension (CSS) (mesh from the upper posterior half of the
      vagina to the sacrum with mobilisation and fixation of the rectum to the mesh) in
      39 patients (30%), perineocolposacrosuspension (PCSS) (similar to CSS, but the
      mesh is inserted further down to the perineum) in 48 patients (37%) and
      perineopubo-colposacrosuspension (PPCSS) (as PCSS, but with a second mesh between
      the bladder and vagina extending to the sacrum) in 30 patients (23%). An
      additional modified Burch colposuspension was performed in 87 patients (67%). A
      failure was defined as a recurrent vaginal prolapse of Grade II or more, or
      urinary incontinence requiring surgical correction. The patients' mean age was
      60.5 years, their mean parity 3.3 and 92.3% were white. Preoperatively, 33.8% of
      the patients complained of constipation, 33.1% of difficulty in defaecation and
      77% had bladder symptoms, suggesting urinary stress incontinence or detrusor
      instability. In 74.6% of the patients part of the vagina protruded through the
      vaginal introitus. The mean period of follow-up was 7.4 months (range 1-26) with
      only 13 patients (10%) not followed. Only two patients (1.5%) developed Grade II
      vaginal prolapse (both cystoceles and both from the PCSS group). Urinary stress
      incontinence in need of further treatment developed in 13 patients (10%). The
      failure rate, therefore, was 11.5%. In six patients (4.6%) the mesh had to be
      removed due to mesh reaction. In all cases the mesh was unabsorbable. Vaginal
      suspension procedures with mobilisation of the rectum provided satisfactory
      results for severe enterocele over the short term.

PMID- 15203583
TI  - Beneficial effects of raloxifene and atorvastatin on serum lipids and HDL
      phospholipids levels of postmenopausal women.
AB  - Selective oestrogen receptor modulators (raloxifene) and statins (atorvastatin)
      have been shown to reduce the risk of cardiovascular disease associated with the
      postmenopausal status. Their beneficial effects may be mediated partly by
      favourable changes in serum lipids and particular on HDL phospholipid
      composition. In the present study, individual administration of either raloxifene
      (Group A) or atorvastatin (Group B) or both (Group C) was compared for a period
      of 3 months and their effects on total lipids and HDL phospholipids were
      evaluated. The combined treatment of raloxifene and atorvastatin resulted in
      profound changes in the majority of serum lipids, including a significant
      reduction in total cholesterol and triglycerides (P<0.001), a rise in total
      phospholipids (P<0.01) and a reduction in LDL-C and Apo B levels (P<0.001).
      Furthermore, Apo A-I was elevated (P<0.001) whereas total HDL phospholipids were
      significantly increased (P<0.05). Specifically, HDL phosphatidylcholine levels
      were markedly increased (P<0.001) and HDL lysophosphatidylcholine, sphingomyelin
      and phosphatidylinositol levels were reduced (P<0.05). A further attempt to
      evaluate each treatment group was performed and the significance of these results
      is discussed.

PMID- 15203584
TI  - The effect of different types of hysterectomy on urinary and sexual functions: a
      prospective study.
AB  - A prospective observational study was designed to evaluate the effect of the
      different techniques of hysterectomy on urinary and sexual function. One hundred
      and eighty-seven women aged 29-73 years and admitted for hysterectomy for various
      indications were recruited to the study. Women presenting primarily with major
      uterine prolapse and those requiring radical hysterectomy were excluded. Patients
      underwent one of four different techniques of hysterectomy: total abdominal,
      vaginal, laparoscopic or subtotal. All patients completed a standardised
      questionnaire addressing urinary and sexual symptoms and underwent urodynamic
      testing using the Lectromed 6000 System (Lectromed, Letchworth, Herts, UK) before
      and 6 months after surgery. Out of 187 women, 184 (98.4%) had completed data.
      Seventy-three patients (39%) had a total abdominal hysterectomy, 62 (34%) had
      vaginal, 38 (21%) had laparoscopic and 11 (6%) had subtotal hysterectomy. At 6
      months after surgery, urinary symptoms occurred less frequently (P<0.01) and
      urodynamic studies remained unchanged. Moreover, patients reported significantly
      lower rates of stress incontinence (P=0.005), urgency (P=0.03) and deep
      dyspareunia (P<0.001) than before the operation, regardless of the hysterectomy
      technique used. The route of hysterectomy did not influence the outcome of
      surgery. We conclude that simple hysterectomy, whether performed abdominally,
      vaginally or laparoscopically, does not adversely affect urinary or sexual
      function at 6 months after surgery.

PMID- 15203585
TI  - Value of routine transvaginal ultrasound scan in women requesting early
      termination of pregnancy.
AB  - This was a retrospective study of 140 women attending a termination clinic from 1
      April 2002 to 31 March 2003. All women had a transvaginal ultrasound scan. Of 140
      women, 56 women benefited from the scan; 26.7% had non-viable pregnancy, 35.71%
      did not remember their LMP, 12.5% had discrepancy between the scan and LMP.
      Incidental findings were noted in 24.6% of which two had a twin gestation, nine
      had ovarian cysts, one had an ectopic pregnancy, one had a hydatidiform mole, one
      conceived with an IUCD and one had a bicornuate uterus with pregnancy in one
      horn. Two of the nine women with ovarian cysts needed a laparotomy. This study
      concludes that routine transvaginal scan (TVS) scan is an essential investigation
      for proper assessment of all women requesting termination of pregnancy. TVS is a
      safe and effective procedure which provides useful information regarding
      gestational age, viability of pregnancy and uncertain dates. In cases of the
      ectopic pregnancy and the hydatidiform mole transvaginal ultrasound helped us in
      appropriate management from the outset and minimised complications.

PMID- 15203586
TI  - Assessment of women's satisfaction with medical termination of pregnancy.
AB  - This was a prospective study involving 205 women seeking medical abortion with
      gestational age<or=63 days. Questionnaires regarding expectations, experience and
      satisfaction with medical abortion were self-completed at the end of the
      procedure. Women's satisfaction was assessed using the visual analogue scale from
      0 to 10. Satisfaction and acceptability parameters were correlated with socio
      demographic and obstetric data. The mean degree of overall satisfaction was 8.3
      (range 1-10). Around 90% of women would select the method again and would
      recommend it to a friend or relative. The degree of satisfaction showed a
      positive correlation with women's age (P<0.001) and number of children (P<0.05)
      and a significant negative correlation with gestational age (P<0.005). Marital
      status, type of financial support and acceptable pain and bleeding experience
      also showed a correlation with the satisfaction score. On the other hand,
      acceptability was correlated with husband/partner agreement and support during
      the procedure and adequate counselling regarding pain and bleeding.

PMID- 15203587
TI  - Are the anticipated benefits of myomectomy achieved in women of reproductive age?
      A 5-year review of the results at a UK tertiary hospital.
AB  - Fibroids are the most common benign tumours of the pelvis in women, with a
      prevalence estimated at 20-50%. They are more common towards the end of the
      reproductive years. There is a racial preponderance, being more common in black
      than white women. This may relate to the aetiology, which is still poorly
      understood. Generally, fibroids do not cause symptoms but some sufferers do
      complain about pressure symptoms, abnormal vaginal bleeding and infertility. For
      these reasons, myomectomy is often resorted to after failure of medical
      interventions on the premise that it brings about improvement/cure of symptoms
      and enhancement of fertility. However, the evidence for these indications for
      surgery is hazy. An analysis of the 109 medical records of symptomatic patients
      who had myomectomy over a 5-year period at a tertiary centre revealed the
      following. Single-symptom presentation in 41 (38%), menorrhagia in 20 (18%) being
      the most common. Only 52 (48%) patients had medical treatment of one form or
      another before myomectomy. Additional operative findings included pelvic
      adhesions, evidence of PID and endometriosis. Thirty-four (31%) had an estimated
      blood loss 500 ml and 23 of these patients needed blood transfusion. There were
      four cases of unscheduled hysterectomies due to uncontrollable bleeding. Pyrexia
      was the most common (38%) postoperative complication followed by superficial
      wound infection in 5%. We observed improvement of symptoms, assessed over a range
      of 2-24 months, in 34 cases (68%) in patients without fertility symptoms who
      accounted for 50 of these women. The symptomatic benefit was less (36%) in the
      'infertility group'. Following an observation period of over 12-36 months, 17
      patients in the 'infertility group' were lost to follow-up. Two (14%) of the 14
      patients who attempted in vitro fertilisation (IVF) were successful. In the non
      IVF group, 13 (46%) of the 28 achieved natural conception. These results suggest
      that symptomatic improvement and fertility enhancement may be possible in some
      patients with fibroids. In view of the risks and potential failure of treatment
      associated with myomectomy these results, yet again, support the fact that
      patients should be properly counselled before embarking on myomectomy and we
      strongly advocate local data to form the basis of the advice given during the
      consultation rather than what obtains in the literature.

PMID- 15203588
TI  - Emergency contraception: knowledge and practices of tertiary students in Durban,
      South Africa.
AB  - The aim of this study was to assess the knowledge, use and attitude to the use of
      emergency contraception among tertiary students in Durban, South Africa through
      the use of a self-administered confidential questionnaire. A scoring system was
      developed to analyse the response of each student. A total of 436 students
      (56.5%) had heard of emergency contraception. Few knew the specific methods of
      emergency contraception and only 11.8% knew the correct time limit in which it
      must be used. Only 60 students (7.8%) knew how effective emergency contraception
      was in preventing pregnancy. Ninety-one students (11.8%) had used emergency
      contraception and 50% responded that if they had to, they would use it or
      recommend it to a friend. A logistic regression model showed that the predictors
      for a high knowledge score were: University of Natal students, having heard of
      emergency contraception, having used it before and having received formal sex
      education. Overall, knowledge and use of emergency contraception by tertiary
      students is limited. There is a need for carefully designed education programmes
      and promotion of emergency contraception on campuses.

PMID- 15203589
TI  - Post-treatment hypomenorrhoea--a clinical indicator of long-term successful
      outcome of transcervical resection of the endometrium.
AB  - This study aims to evaluate the long-term effectiveness and define one of the
      indicators of successful outcome of endometrial resections. The study was carried
      out in a district general hospital setting. This was a retrospective analysis of
      54 consecutive women who underwent endometrial resection over a 5-year period.
      Three (5.5%) complications were noted. Two were primary haemorrhage and one was a
      postoperative vaginal discharge. Eighty per cent of the patients expressed
      satisfaction with the outcome of their treatment. Expression of satisfaction at a
      later date was related to reduced menstrual flow at 6 months (0.005<P<0.001,
      P=0.18 (95% CI=0.13-0.23). Dissatisfaction was noted in 10 patients. These
      included two patients whose expectations of outcome were amenorrhoea, although
      they admitted to reduced menstrual flow. Four patients had other complications,
      such as adenomyosis, pelvic inflammatory disease and pelvic endometriosis.
      Endometrial resection is still an effective option for the majority of patients
      for whom it is a preferred choice. Amenorrhoea at 6 months may be an objective
      indicator of long-term successful outcome of this procedure, and hence a useful
      tool for patient counselling.

PMID- 15203590
TI  - Intraperitoneal bupivacaine for the reduction of postoperative pain following
      operative laparoscopy: a pilot study and review of the literature.
AB  - This pilot case-control study was carried out to determine the value of
      intraperitoneal irrigation with a long-acting local anaesthetic agent in reducing
      postoperative analgesic requirements following gynaecological operative
      laparoscopy. Twenty women undergoing gynaecological laparoscopic surgery were
      recruited to receive dilute bupivacaine instilled into the peritoneal cavity at
      the completion of surgery. Analgesic requirements were assessed during the first
      10 hours, and pain scores at 4 and 24 hours. Analgesic requirements were then
      compared with historical controls. Our results revealed that the total parenteral
      opioid requirement after bupivacaine was significantly less than in the control
      group (0.50 mg vs. 7.17 mg, P=0.006). Oral analgesic requirements were not
      significantly different between the two groups. Pain scores in the bupivacaine
      group showed no difference at 4 and 24 hours postoperatively. Intraperitoneal
      irrigation with dilute bupivacaine at the end of gynaecological laparoscopic
      surgery appears to reduce early postoperative analgesic requirements in this
      pilot study.

PMID- 15203592
TI  - Cutaneous tuberculosis in pregnancy.

PMID- 15203591
TI  - The prevalence of positive anticardiolipin antibody in Jamaican women with
      spontaneous abortion and the correlation with past clinical history.
AB  - One hundred and thirty-eight (138) pregnant women who had spontaneous abortions
      were screened for immunoglobulin G (IgG) antibodies to cardiolipin (aCL) by
      enzyme immunoassay (EIA). A total of 85 (61.6%) tested negative, while 53 (38.4%)
      had positive aCL test results. A review of the patients' hospital notes was
      conducted and comparisons were made between patients with moderate/high positive
      (21/138, 15.2%), those with low positive (32/138, 23.1%) and those with negative
      aCL results (85/138, 61.6%). The variables examined were a history of previous
      abortions, the number of previous fetal deaths and a past history of medical
      problems such as thrombosis or high blood pressure. No significant differences
      were found between the patients with moderate/high positive aCL; low positive
      aCL; and those with negative aCL test results for any of the clinical variables
      examined. In conclusion, the prevalence of positive IgG aCL tests was high in
      this cohort of patients with spontaneous abortion. However, intervention is not
      necessary in many of these patients who have only a positive aCL test, but none
      of the clinical conditions of the antiphospholipid syndrome.

PMID- 15203593
TI  - Management of a massive caseous fibroid at caesarean section.

PMID- 15203594
TI  - Fetomaternal haemorrhage--a cause for unexplained neonatal death, presenting with
      reduced fetal movements and non-reactive fetal heart trace.

PMID- 15203595
TI  - Unilateral and bilateral multicystic dysplastic kidneys in fetuses.

PMID- 15203596
TI  - Delaying preterm delivery at the threshold of viability.

PMID- 15203597
TI  - Spontaneous rupture of splenic artery aneurysm in pregnancy.

PMID- 15203598
TI  - A pelvic mass due to infestation of the fallopian tube with Enterobius
      vermicularis.

PMID- 15203599
TI  - Ovarian Burkitt's lymphoma as a cause of 'omental cake' sign on computerised
      tomography.

PMID- 15203600
TI  - Sarcoidosis of the ovary.

PMID- 15203601
TI  - Severe ambustio in the vagina following thermal endometrial ablation.

PMID- 15203602
TI  - Thermal balloon ablation--a rare case of fibroid necrosis.

PMID- 15203603
TI  - Persistent post-coital bleeding due to cervical endometriosis.

PMID- 15203604
TI  - Surgical correction of congenital lymphoedema of external female genitalia: case
      report and review of the literature.

PMID- 15203605
TI  - Misleading CA-125 levels and computed tomography images in an endometrial cancer
      patient.

PMID- 15203606
TI  - Elevated CA-125 concentration associated with severe cardiac failure.

PMID- 15203607
TI  - A successful cycle of IVF-ET after treatment of endometrial ossification; case
      report and review.

PMID- 15203608
TI  - Intractable hiccoughs in pregnancy.

PMID- 15203610
TI  - Emerging issues over the choice of nifedipine, beta-agonists and atosiban for
      tocolysis in spontaneous preterm labour--a proposed systematic review by the
      International Preterm Labour Council.

PMID- 15203611
TI  - Interstitial cystitis.
AB  - Interstitial cystitis (IC) is a debilitating chronic inflammatory disorder of the
      bladder. It affects predominantly middle-aged Caucasian women. The diagnosis,
      made from the combination of symptoms, cystoscopic findings and bladder biopsies,
      is often delayed in the gynaecology setting because of a low index of suspicion.
      The pathophysiology is incompletely understood, although mast cell activation,
      altered bladder epithelial permeability and sensory afferent nerve up-regulation
      are thought to play key roles. Recent theories include the role of an
      antiproliferative factor. A wide assortment of therapies is available and many
      more are under trial. Until the causes and pathogenesis of IC are unraveled,
      mainstream medical treatment will remain palliative and cystectomy with urinary
      diversion, the only potential cure. In addition to our long experience on
      managing this disorder, we present a comprehensive review of the current thoughts
      on the aetiology and management of IC.

PMID- 15203612
TI  - Experience of the use of nimesulide, a cyclo-oxygenase-2 selective prostaglandin
      synthesis inhibitor, in the prevention of preterm labour in 44 high-risk cases.
AB  - We report pregnancy outcome and fetal side effects in women at high risk of
      second trimester loss and early preterm delivery treated with nimesulide. This
      was a prospective observational study of 44 women treated with nimesulide from 17
      to 32 weeks. All women underwent weekly ultrasound scans for AFI, Doppler studies
      of the ductus arteriosus and transvaginal assessment of cervical length. Outcome
      data were collected. Oligohydramnios occurred in 54% of cases; this returned to
      normal in all cases on discontinuation of treatment. There were no cases of
      constriction of the ductus arteriosus. Thirty-nine women took home a live baby.
      The mean gestation at delivery was 33 weeks and 1 day and the mean birth weight
      was 2105 g. Nimesulide appeared to have a significant benefit in women at high
      risk of preterm delivery with no long-term harmful effects on the fetus if
      monitored closely with an intensive ultrasound scanning regimen. Randomised
      placebo controlled trials are required to assess fully the benefit of COX-2
      selective and specific prostaglandin synthesis inhibitors.

PMID- 15203613
TI  - How long does it take to perform an operative vaginal delivery?
AB  - We set out to see how long it takes to achieve an operative vaginal delivery in
      normal practice. This was a prospective survey, conducted in a major and well
      staffed British maternity unit over 1 month. Sixty-two assisted vaginal
      deliveries occurred in the month of the study. Thirteen data collection sheets
      were spoiled or could not be confirmed and were discarded before analysis.
      Therefore the remaining data are based on 49 deliveries. The main outcome measure
      was the time interval between the decision to assist the vaginal delivery and the
      delivery. Fifty per cent of babies were delivered within 18 minutes once the
      decision to act had been made (range 6-85 minutes). If the primary indication for
      delivery was an abnormal CTG the median time was 16 minutes (mean 20 minutes).
      Any legal claim based on the assumption that a reasonably competent obstetrician
      should deliver a baby within 15 minutes cannot be supported by scientific data.

PMID- 15203614
TI  - Early mortality in twin pregnancies complicated by premature rupture of membranes
      in the United States.
AB  - There is little information on mortality among multiple gestations complicated by
      premature rupture of membranes (PROM). In this study, we estimated the occurrence
      of the components of early mortality (stillbirth, neonatal and infant mortality)
      among twin pregnancies using the generalised estimating equation framework to
      account for intra-cluster correlations. Using the population-attributable risk,
      we also computed the level of excess mortality that could be averted by
      preventing PROM. Our findings reveal that the likelihood of stillbirth (odds
      ratio (OR) = 1.88; 95% confidence interval (CI)=1.66-2.13), neonatal mortality
      (OR=3.45; 95% CI=3.18-3.74) and infant mortality (OR=3.26; 95% CI=3.03-3.50) was
      significantly higher among twin pregnancies exposed to PROM. Approximately 6% of
      all stillbirths, 15% of neonatal mortality and 14% of infant mortality among
      twins in the United States are attributable to PROM. We conclude that PROM is
      associated with an increased level of early mortality among twins.

PMID- 15203615
TI  - Vaginal misoprostol induction of labour: a Nigerian hospital experience.
AB  - We reviewed our experience with vaginal misoprostol induction of labour in 339
      consecutive women with a live fetus and intact fetal membrane using 100 mcg 12
      hourly until labour was established. The labours were monitored using the WHO
      partograph protocol. Two hundred and sixty-five women had a successful induction
      while 74 had an emergency caesarean section because of cephalopelvic
      disproportion (63.5%), fetal distress (14.9%), prolonged labour (12.2%),
      antepartum haemorrhage (6.8%) and other indications (2.8%). The induction
      delivery interval among the women who had successful induction ranged from 3
      hours 42 minutes to 26 hours 15 minutes with a mean of 9 hours 23 minutes (SD 2
      hours 41 minutes). Most (73.6%) of these patients delivered within 12 hours of
      starting induction, the majority (95.3%) requiring only 100 mcg to go into
      established labour. Complications recorded in this series include fetal distress
      in 32 (9.4%), postpartum haemorrhage in 23 (6.8%), hyperstimulation in six
      (1.8%), uterine rupture in one (0.3%), birth asphyxia in eight (2.5%), admission
      in neonatal intensive care ward in five (1.5%), neonatal death in one (0.3%) and
      maternal death in one (0.3%) patient. In conclusion, misoprostol was found not
      only to be efficacious but relatively safe in comparison to other methods of
      induction in use in our hospital.

PMID- 15203616
TI  - Vaginal prostaglandin E2 gel versus tablet in the induction of labour at term--a
      retrospective analysis.
AB  - Our aim in this retrospective analysis was to compare labour outcomes between 145
      consecutive women with unfavourable cervices, who received prostaglandin E2
      vaginal gel (1-2 mg) for labour induction over a 3-month period, and 149 women
      receiving a prostaglandin E2 vaginal tablet (3 mg) over the following 3 months.
      Our results showed that cervical dilatation in the gel group was significantly
      more than in the tablet group at transfer to labour ward [4 cm (SD 2.5 cm) versus
      3.3 cm (SD 2 cm), mean difference -0.7, 95% CI -1.2 to -0.2, P=0.01), with fewer
      women requiring oxytocin augmentation, but this was not statistically significant
      (41.4% versus 50%, RR 0.8, 95% CI 0.7-1.1). There were no significant differences
      in the mode of delivery in the number delivering vaginally within 24 hours of the
      induction (60.4% in the gel group versus 56.2% in the tablet group, RR1.1, 95% CI
      0.9-1.4), in the number of doses of PGE2 administered, or in the neonatal
      outcomes between the two groups. In conclusion, there were no significant
      differences in labour or neonatal outcomes between prostaglandin E2 gel or tablet
      use in the induction of labour in this retrospective analysis.

PMID- 15203617
TI  - Relationship between uterine contractions and serum magnesium levels in patients
      treated for threatened preterm labour with intravenous magnesium sulphate.
AB  - We aimed to correlate the assessment of preterm uterine activity with serum
      magnesium levels in women with threatened preterm labour. The observational study
      involved twelve women receiving intravenous magnesium sulphate for threatened
      preterm labour. Mean gestational age at initiation of therapy was 26.9+/-2.9
      weeks. Mean cervical dilatation at initiation of therapy was 1.5 cm. Serum
      magnesium levels and evaluation of uterine contractions by external tocograph
      were assessed twice daily. Presence or absence of contractions was analysed for
      correlation with plasma magnesium levels. Eighty-eight measurements were
      analysed. The mean serum magnesium levels were 1.9+/-0.5 mmol/l and 1.9+/-0.3
      mmol/l in the presence (n=22) or absence (n=66) of contractions, respectively.
      The difference did not reach statistical significance. No correlation was found
      between serum magnesium levels and presence of contractions (P=0.3, logistic
      regression odds ratio 1.1, 95% confidence interval of 0.6-2.0). The abolition of
      premature uterine contractions during intravenous magnesium sulphate therapy does
      not correlate with serum magnesium levels.

PMID- 15203618
TI  - A retrospective population-based study of primigravid women on the potential
      effect of threatened miscarriage on obstetric outcome.
AB  - The aim of this study was to ascertain any potential link between threatened
      miscarriage and obstetric outcome. Threatened miscarriage was associated
      independently with an increased incidence of abruption (OR 2.8, 2.0-3.7),
      unexplained antepartum haemorrhage (APH) (OR 2.3, 1.1-5.1) and preterm delivery
      (OR 2.0, 1.3-3.3). The incidence of low and very low birth weight deliveries,
      although significantly higher compared with the control population, was not
      affected independently by this early pregnancy complication on logistic
      regression (OR 1.3, 0.8-1.9). The early neonatal mortality rates were
      significantly higher in the threatened miscarriage group, which on logistic
      regression was due independently to preterm delivery, placental abruption and low
      birth weight deliveries. All forms of APH were significantly higher in term
      deliveries complicated by threatened miscarriage. Pregnancies presenting with
      threatened miscarriage should be highlighted as 'high risk' for a suboptimal
      obstetric outcome and a prospective observational trial followed by a randomised
      controlled trial may be needed to establish whether the need exists for increased
      feto-maternal surveillance in this cohort of women.

PMID- 15203619
TI  - Correlation of fetal outcome with mode of delivery for breech presentation.
AB  - The objective of this retrospective analysis of 344 singleton pregnancies of
      gestational ages greater than 24 weeks conducted at a tertiary hospital was to
      determine the fetal outcome in relation to the mode of delivery of the fetus with
      a breech presentation. Caesarean section was performed in 157 mothers, and 187
      babies were delivered vaginally. There was no statistical difference in the
      perinatal outcome for breech fetuses delivered either abdominally or vaginally.
      Cord prolapse and arrest of the after-coming head were responsible for five fetal
      losses, four of which were delivered vaginally. Neonatal morbidity comprising
      nerve injury, birth asphyxia and seizures occurred in 11 newborns, nine of whom
      were delivered vaginally. One mother sustained a massive intra-operative
      haemorrhage during a caesarean section which necessitated an emergency
      hysterectomy. We conclude that a policy of planned vaginal birth for selected
      breech fetuses with a low threshold to proceed to caesarean section may be in the
      best interests of both mother and child.

PMID- 15203620
TI  - Maternal mortality: a twenty-year survey at the King Faisal University Hospital,
      Al-Khobar, Eastern Saudi Arabia.
AB  - This was an institutional study of all maternal deaths that occurred among 56422
      total births at the King Faisal University Hospital, Al-Khobar, Saudi Arabia,
      between 1983 and 2002. The underlying cause of each maternal death and
      potentially avoidable factors were analysed. There were 16 maternal deaths in the
      hospital during the study period, giving a maternal mortality rate of
      28.4/100,000 births. The leading cause of death was haemorrhage in seven (43.75%)
      patients, followed by pulmonary embolism in four (25%) and general anaesthesia in
      two (12.5%) mothers. The risk factors noted were maternal age 35 years and parity
      5 coupled with iron deficiency anaemia. The main avoidable factors were failure
      of the patients to seek timely medical care and to follow medical advice. More
      than half the number of direct obstetrical causes of death was thought to be
      preventable. A rapidly changing attitude of women towards childbirth is occurring
      through progressively increasing female education and community health programmes
      in the region. Further reduction of maternal mortality rates in the community is
      envisaged through greater patient acceptance of medical advice, family spacing
      and proficient obstetric services.

PMID- 15203621
TI  - Risk of uterine rupture following induction of labour in women with a previous
      caesarean section in a large UK teaching hospital.
AB  - To determine the outcome of induction of labour for women who had had previous
      caesarean sections, we identified all women who had induction of labour at the
      Leicester Royal Infirmary between January 1994 and September 2001. During the
      study period, there were 43,175 deliveries and 8761 inductions of labour (20.3%).
      Of these, 5047 (57.6%) were induced with prostaglandins and 138 women in this
      group had a previous caesarean section but eight were excluded from the analysis
      because of induction for early intrauterine death (five) and late terminations
      for fetal anomalies (three). The remaining 130 women formed the study group.
      Induction of labour resulted in spontaneous vaginal delivery in 50% of cases,
      with 11% requiring instrumental delivery and 39% had caesarean sections. There
      were no cases of uterine rupture in this series. We conclude that prostaglandins
      are safe for inducing labour in women with previous caesarean sections, but
      should be administered with caution.

PMID- 15203622
TI  - Prevention of mother-to-child transmission of HIV at Maiduguri, Nigeria.
AB  - The human immunodeficiency virus (HIV) can be transmitted vertically through the
      placenta in utero, during labour and delivery and through breast milk. In
      Nigeria, about 5.8% of women attending antenatal clinics were HIV infected as of
      December 2002. It was projected that by the end of the year 2002, there were
      about 849,000 orphans resulting from AIDS and about 755,000 established
      paediatric AIDS in this country. Interventions to prevent mother-to-child
      transmission of HIV include voluntary counselling and testing (VCT),
      administration of antiretroviral drugs (ARV), modification of obstetric practices
      and infant feeding options in HIV infection. Over the period July 2002-June 2003,
      262 pregnant women received VCT at the antenatal clinic of the University of
      Maiduguri Teaching Hospital, and 207 (79%) agreed to be tested. Thirty-one
      (11.8%) were HIV positive. The majority of the HIV positive mothers received
      nevirapine in labour while 35% had combination ARV drugs in pregnancy. All the
      infants received nevirapine suspension within 72 hours of delivery. Expensive and
      slow testing facilities, insufficient and inconsistent counsellors, lack of ARV
      drugs for both mother and baby as well as unaffordable caesarean delivery were
      some of the constraints being faced at this centre. It is recommended that the
      governments at various levels should show more commitment to the programme of
      preventing mother-to-child transmission of HIV.

PMID- 15203623
TI  - Clinical associations of striae gravidarum.
AB  - Striae gravidarum are a common finding in the abdominal skin of pregnant women.
      This study of 128 pregnant women examined factors which are associated with their
      occurrence. It is clear that women with higher body mass indices have more striae
      and that striae are also more common in younger women. These findings may be
      explained by the greater degrees of stretch applied to the skin in obese women
      with larger babies, and by changes in skin collagen and connective tissue that
      are age-related and affect its tendency to tear.

PMID- 15203624
TI  - Mode of delivery in the next pregnancy in women who had a vaginal delivery in
      their first pregnancy.

PMID- 15203625
TI  - Are obstetric risk factors and bowel symptoms associated with defaecographic and
      manometric abnormalities in women awaiting hysterectomy?
AB  - Abdominal hysterectomy has been shown to affect anorectal function. These studies
      are either population-based or have been performed retrospectively. It is not
      clear from the literature whether those subjects awaiting hysterectomy already
      have an element of pelvic floor failure and which may be related to obstetric
      risk factors. A complete anorectal assessment was performed in a group of women
      awaiting hysterectomy who did not volunteer any bowel symptoms. The patients
      studied were part of an ongoing study of the functional effects of abdominal
      hysterectomy. All had their anorectal function assessed before their respective
      surgery by a questionnaire (functional bowel score), Cleveland continence score,
      endoanal ultrasound (U/S), anal manometry, defaecatory proctogram and colonic
      transit. A detailed obstetric history, which included risk factors such as
      parity, type of delivery, duration of labour and elevated birth weight, were also
      recorded. Patients with previous bowel disease, bowel surgery and anal sphincter
      repair were excluded. There were 39 subjects with a median age of 43 years (range
      31-65), respectively. Thirty-three rectocoeles and 22 intussusceptions were
      demonstrated. Two had poor puborectalis function, while five had cough
      incontinence. Two women had abnormal colonic transit. Thirteen had abnormal anal
      manometry. Endoanal ultrasound was normal in all patients. None of the obstetric
      risk factors were associated with rectocoele, intussusception or abnormal anal
      manometry. Low squeeze pressure was associated significantly with more bowel
      symptoms (P=0.03). However, rectocoele, intussusception, abnormal colonic
      transit, abnormal resting anal pressure and maximal tolerated volume were not
      statistically significantly associated with bowel symptoms. The majority of
      female subjects who were awaiting hysterectomy had physiological and
      proctographic abnormalities consistent with pelvic floor failure. Obstetric risk
      factors were not associated with rectocoele, intussusception, abnormal colonic
      transit and anal manometry in this cohort of patients. Similarly, the majority of
      proctographic abnormalities were not associated with bowel symptoms. However, a
      trend was noted associating bowel symptoms with manometric abnormalities.

PMID- 15203626
TI  - Adherence to published guidelines for the management of menorrhagia in women
      undergoing second generation endometrial ablation.
AB  - Second-generation endometrial ablation techniques provide an effective surgical
      treatment option for women with menorrhagia. Their ease of use might result in
      inappropriate surgical treatment without previous medical therapy. We sought to
      establish local compliance with national guidelines following the recent
      introduction of second generation ablation techniques into routine practice. We
      collected data at the time of ablation on the preceding medical management of
      women undergoing either microwave endometrial ablation or thermal balloon
      ablation. One hundred and thirty-two consecutive women underwent second
      generation endometrial ablation. At least one medical treatment (range 1-5) was
      used before ablation in 86% of women. The majority (86%) of women undergoing a
      second-generation endometrial ablation technique received at least one effective
      medical therapy before surgical intervention, indicating a high level of
      compliance with published guidelines.

PMID- 15203627
TI  - Female genital mutilation: an analysis of 522 cases in South-Western Nigeria.
AB  - This study was conducted at three teaching hospitals in South-Western Nigeria.
      Paturients were examined to find out if they had had female genital mutilation.
      Those who did were given a self-administered questionnaire. Results show that all
      the patients had either Type I (69%) or Type II (31%) mutilation (using WHO
      classification). The average age at which the procedure was performed was 6.9+/
      2.9 years, with 4% of women having the procedure performed in pregnancy. The
      majority of the procedures were performed by medically untrained personnel (89%).
      Up to 67% of the women reported complications following the procedure. Severe
      pain and bleeding were the most common (69%) of the complications reported. The
      most common reason given for the procedure is cultural/traditional (63%). About a
      fifth of the women want their female child to undergo female genital mutilation.
      This study highlights the need for further interventions aimed at discouraging
      the practice of female genital mutilation.

PMID- 15203628
TI  - Vocal pitch levels during connected speech associated with oral contraceptive
      use.
AB  - Although the use of oral contraceptives among young women is common, there are
      relatively few data concerning the effect of such medication upon vocal function.
      This paper investigated differences in objective voice measures in young women
      taking a triphasic oral contraceptive compared to women not taking any such
      medication. The results of paired t-tests revealed no significant difference in
      vocal pitch levels or variability of pitch during a paragraph reading task,
      indicating that oral contraceptives have a negligible effect upon women's voices,
      at least during connected speech.

PMID- 15203629
TI  - Evaluation of chest X-ray findings to determine metastatic gestational
      trophoblastic disease according to the proposed new staging system: a case
      series.
AB  - Recently, a new staging system has been proposed for gestational trophoblastic
      disease (GTD) to ensure uniformity in staging as well as to facilitate comparison
      of treatment outcomes. However, the use of a chest X-ray was considered adequate
      for the detection of lung metastases. We describe a case-series of patients with
      malignant GTD and pulmonary metastases undetected by conventional chest X-ray.
      The scoring and therefore treatment according to high-risk or low-risk depends on
      various risk factors, including the number of metastases. In all three patients
      described, a computerised axial scan (CT) of the chest confirmed the presence of
      lung metastases. With the increasing availability of CT scanning in most parts of
      the world, particularly in tertiary hospitals in which trophoblastic tumours are
      likely to be managed, we propose that CT scan of the chest be performed if the
      chest X-ray is negative, especially if the clinical findings point to a diagnosis
      of malignant GTD.

PMID- 15203630
TI  - Does surgical staging of clinical Stage I endometrial carcinoma significantly
      alter adjuvant management?
AB  - Full surgical staging for endometrial cancer has been advocated since 1988, when
      FIGO redefined stage of disease on the basis of surgico-pathological criteria.
      However, such extensive surgery, performed on often elderly women, must
      counterbalance any increased morbidity against the potential gains of altered
      subsequent management. We report a 2-year review of 22 patients undergoing full
      surgical staging for Stage I endometrial cancer. Nine women (41%) had altered
      adjuvant treatment as a result. In seven patients, decisions regarding
      postoperative radiotherapy treatment were influenced and two women had an
      unsuspected ovarian tumour. Postoperative complications were minor, apart from
      one wound dehiscence. There were no perioperative deaths and no blood
      transfusions. Surgical staging was found to be a safe intervention with a
      significant impact on adjuvant management.

PMID- 15203631
TI  - Daily low-dose oral etoposide for recurrent epithelial ovarian cancer after
      platinum-based therapy.
AB  - The activity and toxicity of oral etoposide in women with recurrent ovarian
      cancer are described from a case series of women who had measurable disease. All
      patients had had previous platinum-based chemotherapy. Etoposide was given as 50
      mg/day for 21 days every 4 weeks until there was progression of the disease or
      prohibitive toxicity. Twelve patients were enrolled into this study. Ten patients
      received a total of 48 cycles of etoposide; the median number of cycles was 4
      (range 1-11). There were two partial responses (20%; 95% CI, 0-45%). The
      responses lasted 3.5 and 6 months. Median progression-free interval (PFI) was 7.5
      months (range 5.5-11), and median survival time was 8.5 months (range 1.2-21.5).
      The main haematological toxicity was leukopenia and no treatment-related death
      occurred. Although etoposide appears to exhibit activity in recurrent ovarian
      cancer, response and survival durations are short, with a high rate of
      complications.

PMID- 15203632
TI  - Ovarian cancer in Ibadan: characteristics and management.
AB  - Ovarian cancer has the highest case fatality rate among gynaecological cancers
      worldwide because of lack of effective screening methods and non-specific early
      warning symptoms with late presentation. A reinvigorated study is necessary in
      the developing countries because of a projected increase in its incidence. The
      decreasing fertility rate and increasing use of ovulation induction drugs are
      some of the reasons. The Ovarian Cancer Service of the Department of Obstetrics
      and Gynaecology, University College Hospital, Ibadan, Oyo State, Nigeria
      commenced the first longitudinal study of this malignancy from 1 December 1998 in
      order to establish a regional management and research centre. It is a
      questionnaire survey detailing the demography, clinical and staging laparotomy
      findings and histology of all confirmed cases. Twenty-one staging laparotomy and
      histologically confirmed ovarian cancer cases were managed from 1 December 1998
      to 31 July 2002, about 1.5% of the 1387 gynaecological admissions. It is the
      third most common of the gynaecological cancers, representing 9.8% of the 214
      cases. More than 60% of the patients were 50 years or younger. Only 19% were
      nulliparous, with 47.6% having had five or more deliveries. Only two patients
      (9.5%) had used the oral contraceptive pill, for a maximum period of 1 month.
      Only one patient (4.8%) had a positive family history of cancer. Abdominal
      swelling was the most common presenting symptom. Eighty-one per cent of the
      patients presented in Stages III and IV. Epithelial ovarian cancer constituted
      about 76.2% of the cases. Only 23.8% had adjuvant therapy, consisting of
      combination chemotherapy using cisplatin-based regimes. The case fatality rate 6
      months after surgery was 76%. The ovarian cancer patients in this environment are
      younger and of higher parity than expected. The risk factors for this disease
      require further study.

PMID- 15203633
TI  - Impact of post-abortion counselling in a semi-urban town of Western Nigeria.
AB  - This study is designed to evaluate the impact of post-abortion counselling in
      bringing about changes in sexual behaviour among patients who had treatment for
      an induced abortion and/or its complication in the department of gynaecology and
      obstetrics of Wesley Guild Hospital Ilesa and Folasola Specialist Hospital
      between January 1999 and December 2001. A structured questionnaire designed to
      evaluate the impact of counselling was administered to 108 patients, who formed
      part of 238 patients who had undergone induced abortion and who benefitted from
      the behavioural contract counselling technique. The results showed that the
      percentage of women using contraception increased from 30 (27.8%) to 53 (49.1%)
      at the time of interview. The number of subjects with multiple sexual partners
      fell from about 62 (58%) to 12 (11%). About 24 (45%) found access to
      contraception difficult. Major factors influencing contraceptive usage and change
      in behaviour include suffering experienced at the time of termination 26 (49%)
      and knowledge of contraception 19 (36%). The study advocates post-abortion
      counselling as a tool to increasing contraceptive usage in women and influencing
      behavioural changes positively towards health promotives measures.

PMID- 15203634
TI  - A prospective study of pain following loop excision of the transformation zone
      under local anaesthesia.

PMID- 15203635
TI  - Serum and seminal plasma prolactin levels in male attenders of an infertility
      clinic in Ibadan.
AB  - Serum and seminal plasma prolactin and testosterone were studied in 51 healthy
      looking men who presented at the infertility clinic. They included 20 men with
      normospermia, 20 with oligospermia and 11 with azoospermia. The mean serum
      prolactin and gonadotrophin levels of the oligospermics and azoospermics were
      similar but significantly higher than those of the normospermics. The mean
      seminal plasma prolactin levels in the three groups were similar. The mean serum
      testosterone of the azoospermics was significantly higher than those of the
      oligospermics and normospermics who had similar levels. The seminal plasma
      testosterone of the oligospermics was similar to that of the azoospermics but
      significantly higher than that of the normospermics. A significant correlation
      occurred between serum prolactin and sperm motility. No correlation occurred
      between the serum and seminal plasma prolactin levels, and seminal plasma
      testosterone or between serum and seminal plasma testosterone. Seminal prolactin
      has no correlation with any biophysical parameters. It was concluded that poor
      spermatogenesis is associated with high serum prolactin in patients with
      infertility. Serum but not seminal plasma prolactin assay is useful in assessing
      male infertility.

PMID- 15203636
TI  - Ischaemic haemorrhagic necrosis of the intestine secondary to volvulus of the
      midgut: a silent cause of intrauterine death.

PMID- 15203637
TI  - Prenatal meconium peritonitis managed expectantly.

PMID- 15203638
TI  - Severe early-onset intrauterine growth restriction (IUGR) in a woman with
      Asherman's syndrome.

PMID- 15203639
TI  - Successful consecutive pregnancies in separate horns of a uterus didelphys.

PMID- 15203640
TI  - Successful pregnancy outcome after surgical removal of arteriovenous malformation
      of the uterus.

PMID- 15203641
TI  - Rupture of splenic arteriovenous malformation in pregnancy: a rare case with
      maternal and fetal survival.

PMID- 15203642
TI  - A case report of spontaneous splenic capsular rupture associated with atypical
      presentation of haemolysis, elevated liver enzymes, low platelet count (HELLP)
      syndrome.

PMID- 15203643
TI  - Parathyroidectomy in pregnancy for primary hyperparathyroidism with successful
      pregnancy outcome: a report of two pregnancies.

PMID- 15203644
TI  - Advanced sigmoid colon cancer in pregnancy presented as an abscess.

PMID- 15203645
TI  - Acute puerperal uterine inversion: careful usage of oxytocic agents for the
      success of immediate replacement.

PMID- 15203646
TI  - A case of cervical dysgenesis.

PMID- 15203647
TI  - Rupture of rudimentary uterine horn of a unicornuate uterus at 15 weeks'
      gestation.

PMID- 15203648
TI  - Hypovolaemic shock caused by hypermenorrhoea with primary hypothyroidism.

PMID- 15203649
TI  - Beware: failed medical termination of pregnancy.

PMID- 15203650
TI  - Female genital tract Mycobacterium chelonae infection.

PMID- 15203651
TI  - Vesical endometriosis.

PMID- 15203652
TI  - Spontaneous extrusion of a migrating Filshie clip through the anterior abdominal
      wall.

PMID- 15203653
TI  - Was it benign or malignant bleed?

PMID- 15203654
TI  - Not all endometriosis is benign.

PMID- 15203655
TI  - Ovarian granulosa cell tumour recurring 36 years after primary treatment.

PMID- 15203656
TI  - A case of urachal carcinoma.

PMID- 15203670
TI  - Partnerships: panacea or pretence?
AB  - This article seeks to explore the centrality and reality of partnerships or
      partnership working in current British social policy. The article will
      investigate the rhetoric and reality of partnerships using research based on the
      Early Years Development and Childcare Partnerships (EYDCPs) as an exemplar to
      critically question whether partnerships have become more pretence than panacea?
      In so doing the article will suggest that partnerships are deserving of greater
      critical analysis and research as their rhetorical force potentially represents
      another metaphor for social control.

PMID- 15203671
TI  - Interprofessional perspectives on transitional mental health services for young
      people aged 16-19 years.
AB  - This qualitative study investigated the need for transitional mental health
      services for young people aged 16-19 years in a health district, as perceived by
      professionals from mental health, social, education and non-statutory services.
      Semi-structured interviews with 39 managers and practitioners who planned or
      provided services for this age range, from a wide range of agencies, explored
      issues related to older adolescents' needs, service communication, transfer
      arrangements, current gaps, and recommendations. Interviews were transcribed
      verbatim and themes emerged according to grounded theory. The four identified
      themes, with 21 categories, were: (i) older adolescents have multi-faceted needs,
      (ii) statutory mental health services are not geared towards this age group,
      (iii) communication between services is variable, and (iv) there are no formal
      transfer arrangements from child to adult services. The findings support the need
      for specialist transitional services, and the adoption of an interprofessional
      service model incorporating education, social services and non-statutory
      agencies.

PMID- 15203672
TI  - Social services and the Single Assessment Process: early warning signs?
AB  - Following the publication of policy documents such as the NHS Plan and the
      National Service Framework for Older People, health and social care agencies in
      the UK have been charged with devising and implementing a Single Assessment
      Process by April 2004. Although service users and carers are often frustrated at
      having to give the same information to many different professionals, this paper
      cites research which raises significant doubts about the present capacity of
      social services departments to deliver on this government initiative. Based on
      telephone interviews with 25 local authorities, this paper describes the findings
      of research into the use of dependency measures in residential and nursing care.
      Although this research was conducted prior to the introduction of the Single
      Assessment Process, the study suggests that some local agencies may lack the
      expertise and skills to develop effective assessment tools/scales and that
      considerable Developmental work may be required to prepare organisations for
      April 2004.

PMID- 15203673
TI  - Dynamic role boundaries in intermediate care services.
AB  - This paper examines the impact of intermediate care service delivery on the role
      boundaries of service providers. Two intermediate care teams were selected as
      case studies to explore the roles of workers in the context of an admission
      avoidance and assisted discharge service. Data were collected through semi
      structured interviews with 26 intermediate care staff, including
      physiotherapists, occupational therapists, nurses, a social worker and support
      workers. The study found that therapists' roles were most closely aligned with
      each other, whilst nurses perceived their roles as being distinct from
      therapists, with a more medical emphasis. Therapists and nurses delegate a range
      of tasks to support workers, although the nature of task delegation differed
      across the two teams. A number of factors were associated with the role
      flexibility of staff including the setting, duration and nature of care, access
      to alternative care providers and the ability of staff to undertake joint visits.
      Contrary to previous research, the practitioners were not threatened by
      overlapping roles, and recognised that confidence in their own roles and an
      understanding of the roles of other workers was necessary to avoid feeling
      threatened. The study concludes that intermediate care can promote role overlap
      across a range of workers. Role overlap can enhance clinician confidence in their
      own area of expertise whilst optimising patient care. Role overlap has the
      potential to optimise limited staff resources in an interprofessional working
      environment. Interprofessional working can be enhanced in the workplace through
      joint visits and shared working practices.

PMID- 15203674
TI  - Towards interprofessional family-oriented teamwork in primary services: the
      evaluation of an education programme.
AB  - A 2-year interprofessional family-oriented training programme for professionals
      working in the field of primary services (e.g. health care, social welfare,
      schools, day care) started in Oulu Province, Finland, in 2000. It aimed to
      provide the trainees with skills to work with families in interprofessional
      teams, to support them to cope better and to encourage them to develop new models
      for helping clients. Seventy-six trainees from 13 professions participated. This
      paper describes the structure, methods and the content of the programme and
      evaluates its success. Material was content analysed from participants'
      evaluations at the end of the programme and discussion during a focus group in
      which three trainees and three trainers participated. During the programme
      trainees' working methods moved from being detached experts towards client and
      family-orientation. Job satisfaction also improved. They began to appreciate
      interprofessional teamwork and found that client and family-oriented working
      methods supported families in using their own resources in solving problems. The
      study indicated that the sufficiently long process of education where the
      interprofessional collaboration has been put in practice already during the
      education is needed to change the theoretical framework and practical working
      methods of the trainees.

PMID- 15203675
TI  - Preparing placement supervisors for primary care: an interprofessional
      perspective from the UK.
AB  - All the professions working in primary care provide placements for students. How
      common, or how profession-specific, are the competency requirements of the
      different professions for their members who supervise students on placements? If
      there is a significant degree of commonality in these competency requirements,
      how feasible would it be to develop an integrated interprofessional development
      and support programme for placement educators? These were the main questions
      addressed in this research project. The requirements for placement educators of
      four professions in the UK - nursing, medicine, occupational therapy and social
      work - were analysed and classified. Categories identified included the skills of
      enabling learning, knowledge of the theory and principles of learning, the
      ability to manage the learning environment and the ability to impart a sense of
      professional responsibility, as well as up-to-date knowledge on professional
      practice and on the relevant curricula. We concluded that only the last of these
      was profession-specific. The potential to use this classification for the
      development of an interprofessional placement educator training and support
      programme was explored, and the potential benefits of using this area to promote
      interprofessional learning were discussed. Issues that need to be considered
      include gaining cross professional involvement, whether service providers or
      universities should run programmes, whether there should be one or several
      programmes, and accreditation. In order to explore and take action on these
      issues a working group with representatives of the four professions was set up in
      the Primary Care Trust.

PMID- 15203676
TI  - Developing and measuring progress toward collaborative, integrated,
      interdisciplinary health care teams.
AB  - In this article we report the results of a longitudinal study of an intervention
      to enhance interdisciplinary team functioning in a primary care setting.
      Components of the team development intervention are outlined. Team members'
      assessments of progress towards expressing values consistent with an effective
      team--as measured through the System for the Multiple Level Observation of Groups
      (SYMLOG)--are presented and discussed. Institutional, organizational, and team
      related supports and barriers that affect the development of collaborative,
      integrated teams are identified and discussed; implications for ensuring teams'
      success are presented.

PMID- 15203677
TI  - Using community collaboration to develop the first successful needs assessment of
      the street homeless population in Canada.

PMID- 15203678
TI  - Learning about interprofessional education: student voices.

PMID- 15203679
TI  - Developing methods to improve the quality of end-of-life care.

PMID- 15203693
TI  - Medical illustrators: who needs them?

PMID- 15203694
TI  - Improving software environments through usability and interaction design.
AB  - This paper introduces the fields of usability and interaction design in order to
      highlight their benefits and provide further resources for those that wish to
      find out more. It is hoped that this review will encourage medical illustrators
      to adopt certain principles and practices in their own project work, in order to
      strive towards (and ultimately produce) products and environments that provide
      more positive interactions for their users. Usability and interaction design are
      fields of study concerned with aims relating to ensuring that any given
      interactive product or environment is efficient, effective and safe to use, as
      well as easy to learn and remember. Of primary importance is the experience of
      the user whose interactions should be positive, as opposed to frustrating or
      counter-intuitive.

PMID- 15203695
TI  - The principles of ethical practice in professional clinical photography.
AB  - Rules and regulations founded on ethical principles permeate healthcare practice.
      NHS Trusts formulate policy to govern their activities in which duties and
      responsibilities are defined to protect patients from harm and protect themselves
      from potential litigation. Clinical photographers are not immune from the demands
      of ethical practice and need to have clearly defined duties and responsibilities.
      This paper maps the dynamics of ethical practice and how this may be expressed in
      codes of practice related to the principles of professional clinical photography.

PMID- 15203696
TI  - Colour management: a workable solution.
AB  - Within clinical photography, colour reproduction has always been a contentious
      issue. With the development of new technologies, the variables affecting colour
      reproduction have changed and photographers have altered practices, moving away
      from the realm of film to digital photographic imaging systems. In order to
      standardize the output of digital clinical images, the author researched, and
      successfully implemented, the GretagMacbeth EYE-ONE Pro colour management system.
      This system, which is maintained on a monthly basis, has ensured a colour
      consistent, reliable and efficient workflow throughout the digital clinical set
      up.

PMID- 15203697
TI  - The state of the profession.

PMID- 15203699
TI  - The Institute of Medical Illustrators' 36th annual conference, Dunblane, 17-19
      September 2003.

PMID- 15203703
TI  - Microscopic photography of a pinworm.

PMID- 15203704
TI  - Patient privacy.
AB  - As part of the Institute of Medical Illustrators' (IMI) scheme for continuing
      professional development (CPD), worksheets will be published at regular intervals
      in this Journal. These are designed to provide the members of IMI with a
      structured CPD activity that offers one way to earn credits. It is recognized
      that this worksheet requires some time spent obtaining and reading a number of
      publications. As a way of ensuring that the allocated time has been spent on the
      activities a number of self-assessment exercises (SAEs) have been included. Upon
      completion of this worksheet, you will be credited with 15 CPD points. The
      answers to the SAEs, along with any notes you make and other publications you
      find, should be kept in your CPD portfolio.

PMID- 15203710
TI  - Does the use of statins compromise the effectiveness of platelet inhibition by
      clopidogrel?

PMID- 15203711
TI  - GPIb potentiates GPVI-induced responses in human platelets.
AB  - Platelet adhesion to vascular subendothelial proteins at the site of blood vessel
      injury is critical for initiating haemostasis. Collagen is a major matrix protein
      that binds plasma von Willebrand factor (vWF) when the endothelium becomes
      damaged and therefore in vivo platelets are likely to encounter both of these
      agonists simultaneously, through glycoprotein VI (GPVI) and alpha2beta1 receptors
      for collagen and GPIb-V-IX and alphaIIbbeta3 receptors for vWF. We hypothesised a
      potentiatory role for vWF that would synergise with collagen leading to
      functional activation and show this to be the case for platelet aggregation, 5-HT
      secretion and calcium responses. Synergy between these two agonists is likely to
      involve receptors GPVI and GPIb-V-IX, for collagen and vWF, respectively, since 5
      HT secretion in response to collagen is potentiated by vWF in the presence of
      either EGTA or EDTA, which prevent binding to integrins alphaIIbbeta3 (EGTA) or
      both alphaIIbbeta3 and alpha2beta1 (EDTA). In addition, vWF is also able to
      potentiate 5-HT secretion responses to collagen-related peptide, confirming that
      GPVI is able to support synergy with vWF. These findings are important in that
      they reveal a novel role for vWF in platelet activation as a potentiator of
      platelet activation by collagen.

PMID- 15203712
TI  - Dextran 40 reduces in vitro platelet aggregation in peripheral arterial disease.
AB  - Dextran 40 has been used to prevent post-operative thrombosis. However, its
      antithrombotic and antiplatelet effects in peripheral arterial disease (PAD) are
      poorly understood. We studied the in vitro effects of Dextran 40 on platelet
      function in control subjects and PAD patients using whole blood methods. Platelet
      function was assessed in 20 control subjects and 20 PAD patients. Spontaneous
      platelet aggregation (SPA) and agonist-induced platelet aggregation in response
      to increasing concentrations of Dextran 40 in vitro were measured by whole blood
      aggregometry. Flow cytometric measurements of platelet P-selectin, GpIIb/IIIa,
      GpIb and PAC-1 binding were also performed. There was no difference in SPA or ADP
      induced aggregation in control patients with Dextran 40 in vitro. However,
      Dextran 40 inhibited collagen-induced aggregation in control patients (P < 0.05,
      Friedman test). In PAD patients, SPA and ADP (1 microM)-induced aggregation were
      significantly reduced by Dextran 40 in vitro (P < 0.001, Friedman test). In PAD
      patients, collagen-induced platelet aggregation (1 and 5 microg/ml) was
      significantly reduced by Dextran 40 in vitro (P < 0.01, Friedman test).
      GpIIb/IIIa, PAC-1 and P-selectin expression were significantly reduced in whole
      blood samples from PAD patients following incubation with Dextran 40 (P < 0.05,
      Wilcoxon rank test) but not in samples from control patients. Dextran 40 reduces
      spontaneous and agonist-induced platelet aggregation as well as the surface
      expression of markers of platelet activation in PAD patients. This antiplatelet
      effect may be of benefit to patients undergoing vascular surgical procedures
      where thrombosis is a significant risk.

PMID- 15203713
TI  - Collagen-induced generation of platelet-derived microparticles in whole blood is
      dependent on ADP released from red blood cells and calcium ions.
AB  - We have evaluated the effects of different anti-coagulants or agonists on the
      generation of platelet-derived microparticles (PMPs) using flow cytometry. Twenty
      microg/ml of collagen induced significantly greater PMP formation in whole blood
      anti-coagulated with argatroban, a selective thrombin inhibitor, as compared with
      platelet-rich plasma, or whole blood anti-coagulated with citrate. Thus, whole
      blood kept at the physiological Ca2+ concentration provides an optimal condition
      for the formation of PMP. Convulxin, a GPVI-selective agonist, also induced PMP
      formation at the magnitude which far exceeds those of other agonists, such as
      thrombin receptor-activating peptide, ADP or epinephrine. These findings suggest
      that GPVI-mediated platelet activation plays a key role in the formation of PMP
      in the presence of physiological Ca2+ in whole blood. The addition of red blood
      cells to PRP potentiated PMP formation induced by collagen. Pretreatment of whole
      blood with the combination of creatine phosphate and creatine phosphokinase
      reduced PMP formation induced by collagen. Blockade of ADP receptors, P2Y12 with
      AR-C69931MX and P2Y1 with A3P5P, respectively, further suppressed collagen
      induced PMP formation. We conclude that ADP released from red blood cells
      enhances PMP formation induced by collagen, and that both P2Y12 and P2Y1
      contribute to ADP-potentiation of PMP generation induced by collagen.

PMID- 15203715
TI  - Emerging roles for P2X1 receptors in platelet activation.
AB  - The platelet surface membrane possesses three P2 receptors activated by
      extracellular adenosine nucleotides; one member of the ionotropic receptor family
      (P2X(1)) and two members of the G-protein-coupled receptor family (P2Y(1) and
      P2Y(12)). P2Y(1) and P2Y(12) receptors have firmly established roles in platelet
      activation during thrombosis and haemostasis, whereas the importance of the
      P2X(1) receptor has been more controversial. However, recent studies have
      demonstrated that P2X(1) receptors can generate significant functional platelet
      responses alone and in synergy with other receptor pathways. In addition, studies
      in transgenic animals indicate an important role for P2X(1) receptors in platelet
      activation, particularly under conditions of shear stress and thus during
      arterial thrombosis. This review discusses the background behind discovery of
      P2X(1) receptors in platelets and their precursor cell, the megakaryocyte, and
      how signalling via these ion channels may participate in platelet activation.

PMID- 15203716
TI  - The platelet function defect of paroxysmal nocturnal haemoglobinuria.
AB  - Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired stem cell
      disorder, characterised by an abnormal susceptibility of red blood cells to
      complement induced lysis, resulting in repeated episodes of intravascular
      haemolysis and haemoglobinuria, thromboembolic events at atypical locations and,
      to a much lesser extent, bleeding complications. Platelet function is assumed to
      be abnormal, however, a defect has not yet been characterised and underlying
      mechanisms remain elusive. To explore these issues, we investigated platelet
      function in PNH patients using assays for clot formation under low and high shear
      force (thrombelastography and PFA100 device), adhesion to glass beads in native
      whole blood (Hellem method), aggregometry using various agonists (Born method),
      and flow cytometric assays for baseline and agonist-induced surface expression
      density of alpha-granule (CD62P) and lysosomal granule proteins (CD63), ligand
      binding to surface receptors (thrombospondin), and expression density of
      activation-induced neoepitopes of the fibrinogen receptor complex (PAC-1).
      Platelet PNH clone size determined by CD55 and CD59 labelling was compared to the
      clone sizes of granulocytes, monocytes, erythrocytes, and reticulocytes. A
      profound reduction of platelet reactivity was observed in PNH patients for all
      "global function" assays (clot formation, adhesion, aggregation). Platelet
      hyporeactivity was confirmed using flow cytometric assays. Whereas baseline
      levels of flow cytometrically determined platelet activation markers did not
      differ significantly between controls and PNH patients, agonist-induced values of
      all markers were distinctly reduced in the PNH group. Moreover, significantly
      reduced white blood cell counts (3.1/nl vs. 5.9/nl), haemoglobin values (9.5 vs.
      14.3/g per dl), and platelet counts (136 vs. 219/nl) delineate profound
      tricytopenia in PNH patients. The fraction of particular cell types lacking the
      surface expression of GPI-anchored glycoproteins is referred to as the respective
      PNH clone; median PNH clone sizes of cells with short life spans (reticulocytes,
      platelets, granulocytes) was 50-80% of total cell populations compared to 20% of
      red blood cells. The results of our laboratory investigations show, that in PNH,
      reduced platelet counts coincide with reduced platelet reactivity. The foremost
      clinical complication in PNH, however, is venous thromboembolism, very probably
      induced by an activated and dysregulated plasmatic coagulation system. From these
      seemingly contradictory findings we infer, that part of the platelet
      hyporeactivity is probably due to reactive downregulation of platelet function in
      response to chronic hyperstimulation. The overall result is thought to be an
      unsteady balance, associated with thromboembolism in a larger proportion of
      patients, and with bleeding in a smaller proportion.

PMID- 15203717
TI  - Differential activation and inhibition of human platelet thrombin receptors by
      structurally distinct alpha-, beta- and gamma-thrombin.
AB  - The development of drugs to neutralize the action of thrombin has to date focused
      on the alpha form of the protease. It is generally agreed that inactive
      prothrombin is proteolytically converted to active alpha-thrombin which may be
      further hydrolyzed to beta- and gamma-thrombin. While all three forms of the
      enzyme retain catalytic activities, only alpha-thrombin is presumed to be
      physiologically important. The beta- and gamma-thrombin are presumed to be
      degradation products of no physiological significance. Our demonstration that
      beta- and gamma-thrombin selectively activate PAR-4 in this and a previous report
      (J. Biol. Chem. 276, 21173-21183, 2001) necessitates a reevaluation of how we
      view their physiological roles and how we approach the pharmacological regulation
      of their actions. Beta-thrombin, like gamma-thrombin, at nM levels selectively
      activates PAR-4. This was demonstrated by full retention of aggregatory activity
      with platelets whose PAR-1 and GP Ib receptors were inactivated. Furthermore, the
      beta-thrombin response was abrogated by desensitizing platelets with suboptimal
      levels of the thrombin receptor activating peptide for PAR-4 (TRAP-4). For beta
      thrombin and gamma-thrombin to have a physiological role, it is necessary to show
      they can be generated under physiological conditions. We demonstrate, for the
      first time, that alpha-thrombin is hydrolyzed in less than 1 min by activated
      factor X at physiological pH, in vitro. This implies that alpha-thrombin may be
      rapidly converted to beta-thrombin and/or gamma-thrombin in vivo in the proper
      microenvironment. The differential activation of the three platelet thrombin
      receptors by alpha-, beta- and gamma-thrombin implies selective structural
      variations between these thrombin species. Structural differences are likely to
      account for the marked differential responses observed with the antithrombotic,
      hirudin, which inhibits alpha-thrombin , is a slightly weaker inhibitor of beta
      thrombin and a very weak inhibitor of gamma-thrombin -induced platelet
      aggregations. The converse order of inhibition is observed with the physiological
      protease inhibitor, alpha(1)-antitrypsin. Finally, a non-traditional inhibitor,
      histone-1, selectively inhibits only beta- and gamma-thrombin , primarily at the
      receptor level of PAR-4 rather than on the thrombin molecule. Trypsin, like beta-
      and gamma-thrombin , activates PAR-4 and is also inactive with TRAP-4
      desensitized platelets. Therefore, it was reasoned that trypsin would be more
      structurally similar to gamma-thrombin than to alpha-thrombin. The analysis of
      the crystalline structures of alpha-, gamma-thrombin and trypsin from the
      databases confirm that this is the case. These findings should help to elucidate
      structure-function relationships of the different thrombins and may aid in the
      development of new anti-thrombotic drugs.

PMID- 15203719
TI  - The White platelet syndrome: a new autosomal dominant platelet disorder.
AB  - The present study has evaluated 46 members from four generations of a large
      family with mild to moderate bleeding symptoms, prolonged bleeding times and poor
      responses to all aggregating agents. Twenty-one members of the family had all of
      the abnormal structural features of the disorder brought to Minnesota in 1870 by
      Esther White and, therefore, referred to as the White platelet syndrome (WPS).
      Their platelet counts were decreased and mean platelet volumes increased. Four to
      13% of their platelets contained large, fully developed Golgi complexes actively
      budding smooth and coated vesicles and frequently associated with centrioles.
      Such structures are usually present in megakaryocytes only during the major phase
      of granulopoiesis. As many as seven Golgi complexes and five centrioles were
      present in single platelets. Alpha granule formation appeared incomplete in
      patient platelets. The organelles were often immature in appearance and markedly
      decreased in number in many of their cells. As a result 30% or more of WPS
      platelets were "gray platelets" similar to, yet very different from the cells in
      patients with the gray platelet syndrome. Other abnormal features included
      cytoplasmic sequestration by residual dense tubular system membranes,
      autodigestion, larger than normal mitochondria and half normal-sized dense
      bodies. Thirteen of the 46 family members had a "touch" of WPS. Three to 5% of
      their platelets contained Golgi complexes. However, gray platelets were not
      present among their circulating cells. The WPS is a unique autosomal dominant
      condition that can be classified among the platelet granule deficiency disorders.

PMID- 15203718
TI  - Platelet activation markers, microparticles and soluble adhesion molecules are
      elevated in patients with arteriosclerosis obliterans: therapeutic effects by
      cilostazol and potentiation by dipyridamole.
AB  - We evaluated the plasma concentrations of platelet activation markers,
      microparticles and soluble adhesion molecules in patients with arteriosclerosis
      obliterans (ASO) and compared the beneficial effects of cilostazol alone and
      combination therapy of cilostazol and dipyridamole in these patients. There was a
      significant elevation of CD62P, CD63, PAC-1, annexin V, platelet-derived
      microparticles (PDMPs), sP-selectin, sE-selectin, sICAM-1 and sVCAM-1 in the ASO
      patients compared with the controls. Platelet aggregation was decreased by 2
      weeks of cilostazol monotherapy in the ASO patients. Adding dipyridamole to the
      cilostazol therapy for 2 weeks further reduced platelet aggregation. While
      treatment with cilostazol alone reduced levels of CD62P, CD63, PAC-1, annexin V,
      PDMP, and sP-selectin, the combination therapy reduced these parameters further.
      While sE-selectin and cell adhesion molecules did not change significantly after
      2 weeks of combination therapy, they exhibited a remarkable decrease after 16
      weeks of combination treatment. These findings suggest that platelets are
      activated in ASO patients, and cilostazol is effective to reduce platelet
      activation. Furthermore, dipyridamole may potentiate the beneficial effect of
      cilostazol in ASO patients. Combination use of both drugs may help to prevent the
      onset of cardiovascular complications in patients with ASO by activated platelets
      and PDMP.

PMID- 15203720
TI  - Mean platelet volume in the patients with dengue hemorrhagic fever.

PMID- 15203725
TI  - Histological markers that predict clinical recurrence in ductal carcinoma in situ
      of the breast: an Australian population-based study.
AB  - AIMS: The incidence of ductal carcinoma in situ (DCIS) has increased
      substantially since the advent of widespread screening mammography.
      Identification of histological markers that predict recurrent disease is
      essential for optimal treatment management. To assist the clinico-pathological
      stratification of DCIS, we sought to determine histological markers of recurrence
      in DCIS in an Australian population-based series. METHODS: In a study of all DCIS
      reported in Victoria between 1988 and 1992, managed by breast conserving therapy
      (wide local excision or subtotal mastectomy) with or without adjuvant
      radiotherapy and/or hormonal therapy, the histological features of DCIS lesions
      with subsequent ipsilateral recurrence as in situ or invasive breast cancer were
      compared with a similarly managed control group of DCIS without recurrence.
      RESULTS: Large lesion size, presence of nuclear pleomorphism, absence of cellular
      polarisation and extensive necrosis were all significant predictors of recurrence
      (P<0.05). Primary and recurrent DCIS lesions had similar morphological features,
      and invasive recurrence was characterised by ductal type with high nuclear grade.
      CONCLUSION: This study identifies histological markers in DCIS associated with
      recurrence in an Australian population, and demonstrates similar histological
      appearances between primary and secondary lesions. These histological
      characteristics may be used to stratify DCIS subtypes and facilitate the future
      optimisation of disease management.

PMID- 15203726
TI  - Mesenchymal chondrosarcoma: an immunohistochemical study of 10 cases examining
      prognostic significance of proliferative activity and cellular differentiation.
AB  - AIMS: Mesenchymal chondrosarcoma is a rare malignant chondrogenic neoplasm that
      tends to affect young adults and teenagers. The prognosis is unpredictable, and
      the identification of prognostic markers that could aid in determining the
      behaviour of this tumour would be helpful. There are few studies in the
      literature that have attempted to address this issue. METHODS AND RESULTS: In
      this study, we explored the prognostic significance of three different
      parameters: (1) tissue morphology of small cell areas, (2) the expression of
      tumour differentiation marker genes, and (3) the proliferation rate. Our results
      did not show a correlation of prognosis with the histological features of the
      neoplastic small cell areas or the expression of tumour differentiation genes.
      However, the proliferative activity of the tumour cells appeared to have some
      prognostic significance as related to patient survival. CONCLUSION: Mesenchymal
      chondrosarcoma is a rare tumour with a wide clinical range of behaviour.
      Therefore, it is difficult to obtain reliable prognostic parameters.
      Nevertheless, our study suggests that proliferative activity may be a useful
      prognostic parameter for mesenchymal chondrosarcomas.

PMID- 15203727
TI  - Digital imaging in pathology: theoretical and practical considerations, and
      applications.
AB  - Digital imaging is rapidly replacing photographic prints and Kodachromes for
      pathology reporting and conference purposes. Advanced systems linked to computers
      allow greater versatility and speed of turn-around as well as lower costs,
      allowing the incorporation of macroscopic and microscopic pictures into routine
      pathology reports and publications. Digital images allow transmission to remote
      sites via the Internet for primary diagnosis, consultation, quality assurance and
      educational purposes and can be stored and disseminated in CD-ROMs. Total slide
      digitisation is now a reality and has the potential to replace glass slides to a
      large extent. There are extensive applications of digital images in education and
      research, allowing more objective and automated quantitation of a variety of
      morphological and immunohistological parameters. Three-dimensional images of
      gross specimens can be developed and posted on websites for interactive
      educational programs and preliminary reports indicate that medical vision systems
      are a reality and can provide for automated computer generated histopathological
      diagnosis and quality assurance.

PMID- 15203728
TI  - Ultrastructural changes in Langerhans cells in gingival overgrowth in cyclosporin
      A-treated renal transplant patients.
AB  - AIM: Our research was focused on the ultrastructural features of gingival
      epithelium in kidney transplant patients and, in particular, on Langerhans cells,
      with the aim of verifying whether ultrastructural modifications might explain
      gingival overgrowth. METHODS: Using electron microscopy and immunohistochemical
      S100 staining at optical microscopy, we examined gingival samples obtained from
      18 kidney transplant patients who presented with gingival overgrowth following
      cyclosporin A treatment. RESULTS: The hyperkeratosis shown by the epithelium, and
      especially the absence of Birbeck granules in the Langerhans cells observed in
      serial sections, lead us to correlate these data to an immunodeficiency which
      affects the epithelium in the complex mechanism determining overgrowth.
      CONCLUSIONS: In our previous studies we attributed the responsibility of
      overgrowth to the connective tissue alone. However, in the light of the present
      results, we cannot exclude a contribution of the epithelium to gingival
      overgrowth.

PMID- 15203729
TI  - The significance of cerebral mantle thickness in fetal ventriculomegaly at
      autopsy.
AB  - AIMS: To confirm the validity of the method of diagnosing fetal ventriculomegaly
      at autopsy by measuring cerebral mantle thickness at the frontal lobe and to
      further evaluate whether taking three measurements at three separate sites is
      even more reliable. METHODS: The thickness of the cerebral mantle was measured at
      three sites: the frontal lobe, posterior-frontal lobe and occipital lobe, in 10
      human fetuses which were clinically diagnosed by ultrasound to have
      ventriculomegaly, and in 120 control fetuses. Most fetuses were obtained during
      the second trimester. The mantle thicknesses were charted against foot length and
      crown-rump length in each case. RESULTS: Fetal cerebral mantle thickness was
      reduced in the three sites examined in eight of ten fetuses with a pre-autopsy
      diagnosis of ventriculomegaly. The mantle thickness was in the normal range in a
      growth-restricted fetus of 19 weeks gestational age with trisomy 21, mild
      ventriculomegaly, hydrops and cerebral oedema, when correlated with crown-rump
      and foot lengths. In a 32-week growth-retarded fetus with a prenatal ultrasound
      diagnosis of ventriculomegaly, cerebral mantle thickness was also within the
      normal range relative to crown-rump and foot lengths. CONCLUSION: Measurement at
      autopsy of cerebral mantle thickness is a reproducible and reliable method of
      confirming the diagnosis of ventriculomegaly in second trimester fetuses. Fetal
      cerebral mantle thickness measurement taken at the three sites must be correlated
      with crown-rump and foot length. In most cases where ventriculomegaly was
      established, the mantle thickness was reduced in fetuses in all three sites
      examined. The relative thickness of the cerebral mantle in different areas was
      often abnormal in the presence of ventriculomegaly. Our study of small numbers of
      cases also suggested that the method of measurement may not be reliable in some
      cases where there is only mild ventriculomegaly, cerebral oedema or growth
      retardation.

PMID- 15203730
TI  - Granulomatous mastitis: a clinicopathological review of 26 cases.
AB  - AIMS: Twenty-six cases of granulomatous mastitis were examined to determine the
      common histological and clinical features and the possible association with micro
      organisms. METHODS: A retrospective review of the clinical and histological
      features of these cases was undertaken, including granuloma, inflammatory cell
      infiltrate, multinucleated giant cells, necrosis and lymphocytic lobulitis, as
      well as special stains for micro-organisms including Mycobacterium, other
      bacteria and fungus. PCR for Mycobacterium tuberculosis DNA was also performed in
      19 cases. RESULTS: Granulomas were present in all cases (100%) while
      multinucleated giant cells were seen in 17 cases (65%), background inflammatory
      cell infiltrate in 23 cases (88%), predominantly lymphocytes in 18 cases (69%),
      significant lymphocytic lobulitis in 13 of 19 cases (68%) and necrosis in three
      cases (11%). Special stains and cultures for micro-organisms were all negative.
      Clinically, four cases (15%) were associated with duct ectasia, eight (31%) with
      abscess, and there was no such association in 14 cases (54%). Of the 19 cases
      with PCR for tuberculosis, one case showed Mycobacterium DNA in the sample,
      raising the possibility of occult tuberculosis infection. CONCLUSIONS:
      Granulomatous mastitis is a heterogeneous group of diseases with a diverse
      clinical picture and association. Most idiopathic cases are not associated with
      specific micro-organisms.

PMID- 15203731
TI  - The frequency and distribution of mast cells in pleomorphic adenomas of salivary
      glands.
AB  - AIM: To investigate whether the frequency and distribution of mast cells (MCs) in
      pleomorphic adenomas (PAs) of major and minor salivary glands justifies the
      suggestion that there exists an association between MCs and mucoid stromal
      changes in PAs. METHODS: The material consisted of 22 cases of pleomorphic
      adenoma (eight arising in major and 14 in minor salivary glands) and a control
      group represented by five cases of monomorphic adenoma (MA). Representative 3
      microm thick, paraffin-embedded sections were stained with H&E and Azur A.
      Computer-aided image analysis was performed in order to evaluate the relative
      surface area occupied by epithelial and connective tissue components, as well as
      the absolute number of MCs. RESULTS: According to our findings, PAs from minor
      salivary glands contain significantly greater numbers of mast cells compared with
      tumours from major glands. Additionally, the distribution of MCs within the
      stromal connective tissue appeared not to be random. CONCLUSION: It is possible
      that differences in the pattern of connective tissue might influence the actual
      concentration of MCs and that these differences are responsible for the observed
      variations between major and minor gland PAs.

PMID- 15203732
TI  - Identification of WASP mutations in 10 Australian families with Wiskott-Aldrich
      syndrome and X-linked thrombocytopenia.
AB  - Mutations of the gene encoding the Wiskott-Aldrich syndrome protein (WASP) have
      been previously shown to be responsible for classical Wiskott-Aldrich syndrome
      (WAS), isolated X-linked thrombocytopenia (XLT) and severe congenital X-linked
      neutropenia. AIMS: Identification of WASP mutations in 10 unrelated Australian
      families presenting with clinical features of WAS/XLT. METHODS: Mutation analysis
      was performed by PCR and sequence analysis. RESULTS AND CONCLUSIONS: Two novel
      mutations and seven mutations which have previously been reported were
      identified. The novel mutations consisted of a missense mutation in exon 2
      (C290A) associated with the phenotype of XLT and a mutation in intron 10
      (1372+1G>A) in the mother of two boys presenting with a classical WAS phenotype.

PMID- 15203734
TI  - Test and Teach. Recurrent breast lumps in a Chinese woman. Adenomyoepithelioma of
      the breast.

PMID- 15203733
TI  - A PCR method for the identification of methicillin-resistant Staphylococcus
      aureus (MRSA) from screening swabs.
AB  - AIM: The aim of this study was to assess the discriminatory power and potential
      turn around time (TAT) of a PCR-based method for the detection of methicillin
      resistant Staphylococcus aureus (MRSA) from screening swabs. METHODS: Screening
      swabs were examined using the current laboratory protocol of direct culture on
      mannitol salt agar supplemented with oxacillin (MSAO-direct). The PCR method
      involved pre-incubation in broth for 4 hours followed by a multiplex PCR with
      primers directed to mecA and nuc genes of MRSA. The reference standard was
      determined by pre-incubation in broth for 4 hours followed by culture on MSAO
      (MSAO-broth). RESULTS: A total of 256 swabs was analysed. The rates of detection
      of MRSA using MSAO-direct, MSAO-broth and PCR were 10.2, 13.3 and 10.2%,
      respectively. For PCR, the sensitivity, specificity, positive predictive value
      and negative predictive values were 66.7% (95%CI 51.9-83.3%), 98.6% (95%CI 97.1
      100%), 84.6% (95%CI 76.2-100%) and 95.2% (95%CI 92.4-98.0%), respectively, and
      these results were almost identical to those obtained from MSAO-direct. The
      agreement between MSAO-direct and PCR was 61.5% (95%CI 42.8-80.2%) for positive
      results, 95.6% (95%CI 93.0-98.2%) for negative results and overall was 92.2%
      (95%CI 88.9-95.5%). CONCLUSIONS: (1) The discriminatory power of PCR and MSAO
      direct is similar but the level of agreement, especially for true positive
      results, is low. (2) The potential TAT for the PCR method provides a marked
      advantage over conventional methods. (3) Further modifications to the PCR method
      such as increased broth incubation time, use of selective broth and adaptation to
      real-time PCR may lead to improvement in sensitivity and TAT.

PMID- 15203736
TI  - Fine needle aspiration cytology of lymph node with metastatic undifferentiated
      carcinoma and granulomatous (sarcoid-like) reaction.

PMID- 15203737
TI  - Calcium oxalate crystals in an aspirate sample from a benign breast cyst.

PMID- 15203738
TI  - Gordonia terrae-induced suppurative granulomatous mastitis following nipple
      piercing.

PMID- 15203739
TI  - Peri-adrenal malignant lymphoma masquerading as adrenal cortical neoplasm.

PMID- 15203740
TI  - The perils of untimed serum cortisol measurement.

PMID- 15203741
TI  - Mixed nephrogenic adenoma and Mullerian metaplasia of the urinary bladder mucosa.

PMID- 15203742
TI  - Re: Antibody and genetic testing in coeliac disease.

PMID- 15203744
TI  - Oncocytic mucinous cystadenoma of the pancreas.

PMID- 15203746
TI  - Immunohistochemistry in gynaecological pathology: a review.
AB  - This paper reviews some aspects of the application of immunohistochemistry in
      gynaecological pathology. The use of cytokeratins 7 and 20 are discussed with
      reference to applications in ovarian pathology, including metastatic disease to
      the ovaries. Developments in utilising MIB-1 and p16 in cervical squamous and
      glandular lesions are discussed. Recent assertions regarding the differential
      diagnosis between endocervical and endometrial carcinomas are also reviewed.
      Antibodies that may be of use in the diagnosis of uterine mesenchymal and ovarian
      tumours are highlighted, as are antibodies of use in trophoblastic lesions
      including the use of p57 in evaluating hydatidiform moles.

PMID- 15203747
TI  - The significance of the Wnt pathway in the pathology of human cancers.
AB  - The wingless-type (Wnt) signalling transduction pathway is essentially a network
      of a number of separate but interacting pathways. Specific Wnt ligands bind to
      their target 'frizzled' membrane receptor and interfere with the multi-protein
      destruction complex, resulting in downstream activation of gene transcription by
      beta-catenin. Simplistically, the multi-protein destruction complex involves Axin
      and APC serving as scaffolds binding both beta-catenin and GSK3, to facilitate
      phosphorylation of beta-catenin by GSK-3beta. Phosphorylated beta-catenin is
      degraded in proteasomes by the ubiquination machinery. Unphosphorylated beta
      catenin accumulates and associates with nuclear transcription factors leading to
      the eventual transcription and expression of target genes such as c-myc, c-jun,
      Fra and cyclin D1. There are several regulatory mechanisms for the down
      regulation of the Wnt/beta-catenin signal, perhaps reflecting the pivotal nature
      of the pathway and the detrimental consequences of inappropriate activation.
      There has been intense investigation into the role of Wnt genes in human cancer.
      Although no documentation is made of any mutation or amplification of genes
      encoding Wnt ligands or receptors linked to human cancer to date, several
      components of the Wnt pathway have been implicated in carcinogenesis, especially
      APC and beta-catenin.

PMID- 15203748
TI  - Laboratory tests for the antiphospholipid syndrome: current concepts.
AB  - There is increased scientific interest in the diagnosis of the antiphospholipid
      syndrome (APS), as therapeutic interventions can lead to substantial improvement
      in clinical outcome. As the clinical features of APS are far from specific, a
      sound laboratory method is needed to support or exclude the diagnosis. Two
      methods are currently used for the diagnosis of APS: (1). ELISA-based
      immunoassays for the detection of anticardiolipin (aCL) antibodies; and (2).
      clotting assays for determination of the lupus anticoagulant (LA). However, the
      first method is limited by a low specificity, and the second by low sensitivity.
      Furthermore, for both methods standardisation is unsatisfactory. Therefore, a
      number of new assays have been proposed as alternative or supplementary to aCL
      and LA tests. These include the anti-beta-2-glycoprotein I or antiprothrombin
      ELISAs, an ELISA utilising a phospholipid mixture, clotting assays with varying
      activators and assays utilising chromogenic substrates. This review presents a
      brief outline of APS, the autoantibodies associated with this syndrome, the basic
      principles of the standard assays used and a description of newer methods
      currently being validated.

PMID- 15203749
TI  - Subependymal giant cell astrocytoma: a clinicopathological study of 23 cases with
      special emphasis on proliferative markers and expression of p53 and
      retinoblastoma gene proteins.
AB  - AIMS: To gain a better insight into the biological behaviour of subependymal
      giant cell astrocytoma (SEGA), tumour suppressor gene protein expression and
      various proliferative indices were studied in these tumours and correlated with
      histological features and clinical outcome. METHODS: We studied 23 cases of SEGA,
      19 from our own Institute and four from the National Institute of Mental Health
      and Neurological Sciences (NIMHANS), Bangalore, India. Immunohistochemical
      staining for various glial and neuronal markers, proliferative markers (MIB-1,
      Topoisomerase II alpha PCNA) and tumour suppressor gene protein expression of p53
      and retinoblastoma (Rb) were performed. RESULTS: Nineteen cases of SEGA were
      collected over a period of 23 years (January 1978-December 2001), which accounted
      for 0.16% of all intracranial tumours and 0.51% of all gliomas reported at this
      centre. Ages ranged from 4 to 37 years (mean 13.2 years) with a male
      preponderance. Nine of the 23 cases were associated with tuberous sclerosis (TS),
      six at the time of diagnosis, while three developed TS during the follow-up
      period. Treatment consisted of surgical resection (total in nine cases and
      subtotal in 14 cases) followed by radiotherapy in seven cases. Except for two
      patients who died in the immediate post-operative period of surgical
      complications, the remaining patients were all alive in the follow-up period
      (mean 37.1 months). One patient experienced recurrence 22 years after the first
      surgery and a second patient after 2 years. Necrosis and/or mitoses were observed
      in five cases. Immunohistochemically, tumours were positive for both glial and
      neuronal markers. Interspersed inflammatory cells were a mixture of mast cells
      and lymphocytes of T immunophenotype. The MIB-1 labelling index (LI) ranged from
      0 to 8% (mean 3.0%), topoisomerase II alpha (topo II alpha) LI from 0 to 9.5%
      (mean 2.9%) and PCNA LI from 10 to 59% (mean 32.5%). The difference in the
      labelling indices of tumours with and without mitoses and/or necrosis was not
      statistically significant. None of the tumours revealed loss of Rb gene protein
      expression. p53 immunopositivity was seen in 14 cases (labelling indices ranged
      from 1 to 7.3% with a mean of 2.4%). The correlation between the MIB-1 LI and
      topo II alpha LI, and topo II alpha LI and PCNA LI was significant (P<0.05) but
      not so with other parameters like p53 protein expression, duration of survival
      and morphological features such as mitoses and necrosis. CONCLUSIONS: SEGAs are
      rare intraventricular tumours associated with TS and express both neuronal and
      glial markers. They have a low proliferative potential. Mitoses and necrosis are
      not associated with a worse prognosis. In view of the low proliferative indices
      and long survival of these patients without recurrence, the role of post
      operative radiotherapy is questionable. These patients should be followed up
      closely as many of them develop stigmata of tuberous sclerosis at a later stage.

PMID- 15203750
TI  - Genetic changes of the E-cadherin and APC tumour suppressor genes in clear cell
      renal cell carcinoma.
AB  - AIMS: The roles of tumour suppressor genes: adenomatous polyposis coli (APC) and
      E-cadherin (CDH1) were investigated in clear cell renal cell carcinoma. METHODS:
      Forty-five human clear cell renal cell carcinomas were tested for APC gene
      instability by polymerase chain reaction/loss of heterozygosity using the
      restriction fragment length polymorphism method. E-cadherin gene was analysed by
      PCR amplification of tetranucleotide marker (D16S752) and the alleles were
      visualised by PAGE/silver staining. RESULTS: The overall proportion of loss of
      heterozygosity of the APC gene was 37.5% (9/24). D16S752 marker linked to E
      cadherin gene (informativeness 91%) revealed three samples with loss of
      heterozygosity (7.5%). Interestingly, replication error phenotype was detected in
      9.1% of clear cell renal cell carcinoma samples. Multivariate statistical
      analysis of samples informative for both APC and E-cadherin genes showed that, in
      this data set, loss of heterozygosity of the APC gene is correlated with advanced
      age and more severe TNM stages. Genetic changes of the E-cadherin gene, on the
      other hand, appear to be correlated with younger age groups and less severe TNM
      stages. CONCLUSIONS: Our results suggest that alterations, both in APC and E
      cadherin genes, are involved in the evolution and progression of clear cell renal
      cell carcinoma. Microsatellite genetic instability of the E-cadherin gene
      indicates that another cellular mechanism, mismatch repair, may also be targeted
      in this malignancy.